Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[N:8]=[C:7]([N:9]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][CH2:24]OS(C)(=O)=O)=[CH:18][CH:17]=2)[CH2:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH:6]=[CH:5][N:4]=1)#[N:2].[C:30]([C:32]1[N:37]=[C:36]([N:38]([CH2:44][C:45]2[CH:50]=[CH:49][C:48]([CH:51]([CH3:58])[CH2:52][O:53][S:54]([CH3:57])(=[O:56])=[O:55])=[CH:47][CH:46]=2)[CH2:39][C:40]([CH3:43])([CH3:42])[CH3:41])[CH:35]=[CH:34][N:33]=1)#[N:31].O>CN(C=O)C>[CH3:12][C:11]([CH3:14])([CH3:13])[CH2:10][N:9]([CH2:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][CH2:24][N:38]2[CH2:44][CH2:45][CH2:50][CH2:49][CH2:48]2)=[CH:18][CH:17]=1)[C:7]1[CH:6]=[CH:5][N:4]=[C:3]([C:1]#[N:2])[N:8]=1.[C:30]([C:32]1[N:37]=[C:36]([N:38]([CH2:44][C:45]2[CH:46]=[CH:47][C:48]([CH:51]([CH3:58])[CH2:52][O:53][S:54]([CH3:57])(=[O:55])=[O:56])=[CH:49][CH:50]=2)[CH2:39][C:40]([CH3:43])([CH3:42])[CH3:41])[CH:35]=[CH:34][N:33]=1)#[N:31]
Reactant: CC(C)(C)CN(Cc1ccc(CCCOS(C)(=O)=O)cc1)c1ccnc(C#N)n1
Agent: CC(COS(C)(=O)=O)c1ccc(CN(CC(C)(C)C)c2ccnc(C#N)n2)cc1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)CN(Cc1ccc(CCCN2CCCCC2)cc1)c1ccnc(C#N)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of methanesulfonic acid 3-(4-{[(2-cyano-pyrimidin-4-yl)-(2,2-dimethyl-propyl)-amino]-methyl}-phenyl)-propyl ester and methanesulfonic acid 2-(4-{[(2-cyano-pyrimidin-4-yl)-(2,2-dimethyl-propyl)-amino]-methyl}-phenyl)-propyl ester (in ratio of 3:1) (130 mg, 0.31 mmoles) is dissolved in 3 ml of DMF and 1-piperizine (0.06 ml, 0.64 mmoles) is added at rt. The mixture is stirred at rt for overnight. Water is added and the organic layer is extracted with AcOEt, dried over magnesum sulfate and concentrated. The crude product is purified by silica gel column chromatography to give 56 mg of desired 4-{(2,2-dimethyl-propyl)-[4-(3-piperidin-1-yl-propyl)-benzyl]-amino}-pyrimidine-2-carbonitrile (A) in 56% yield and 24 mg of desired methanesulfonic acid 2-(4-{[(2-cyano-pyrimidin-4-yl)-(2,2-dimethyl-propyl)-amino]-methyl}-phenyl)-propyl ester (B) in 18% yield.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[C:11]([O:15][C:16]([NH:18][CH2:19][CH2:20][CH2:21][O:22][C:23]1[CH:58]=[CH:57][CH:56]=[CH:55][C:24]=1[C:25]([NH:27][C:28]1[CH:52]=[CH:51][C:31]([C:32]([N:34]([CH3:50])[C:35]2[CH:40]=[CH:39][C:38]([CH3:41])=[CH:37][C:36]=2[O:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][OH:49])=[O:33])=[CH:30][C:29]=1[O:53][CH3:54])=[O:26])=[O:17])([CH3:14])([CH3:13])[CH3:12].C(N(CC)CC)C>ClCCl.O>[C:11]([O:15][C:16]([NH:18][CH2:19][CH2:20][CH2:21][O:22][C:23]1[CH:58]=[CH:57][CH:56]=[CH:55][C:24]=1[C:25]([NH:27][C:28]1[CH:52]=[CH:51][C:31]([C:32]([N:34]([CH3:50])[C:35]2[CH:40]=[CH:39][C:38]([CH3:41])=[CH:37][C:36]=2[O:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH:48]=[O:49])=[O:33])=[CH:30][C:29]=1[O:53][CH3:54])=[O:26])=[O:17])([CH3:14])([CH3:12])[CH3:13]
Reactant: COc1cc(C(=O)N(C)c2ccc(C)cc2OCCCCCCO)ccc1NC(=O)c1ccccc1OCCCNC(=O)OC(C)(C)C
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: O
Product: COc1cc(C(=O)N(C)c2ccc(C)cc2OCCCCCC=O)ccc1NC(=O)c1ccccc1OCCCNC(=O)OC(C)(C)C
Temperature: -15 °C
Reaction time: 0.17 h
Yield: 121.7 %

Procedure:
To a solution of oxalyl chloride (95 mg) in dichloromethane (10 ml) was added dimethyl sulfoxide (117 mg) dropwise at -78° C. The mixture was warmed to -15° C. and a solution of 4-[2-(3-tert-butoxycarbonylaminoprop-1-yl)oxybenzoyl]amino-3-methoxy-N-methyl-N-[2-(6-hydroxyhex-1-yl)oxy-4-methylphenyl]benzamide (450 mg) in dichloromethane (10 ml) was added thereto. After being stirred at the same temperature for 10 minutes, to the reaction mixture was added triethylamine (343 mg) and stirred at the same temperature for 5 minutes. The resulting solution was warmed to ambient temperature and poured into water. The mixture was extracted with chloroform (15 ml×3) and the organic layer was washed with brine. The solution was dried over magnesium sulfate and the solvent was evaporated to give 4-[2-(3-tert-butoxycarbonylaminoprop-1-yl)oxybenzoyl]amino-3-methoxy-N-methyl-N-[2-(5-formylpent-1-yl)oxy-4-methylphenyl]benzamide (546 mg)
Reaction SMILES: C[C:2]([C:9]1[C:10]([C:22]([CH3:25])([CH3:24])[CH3:23])=[C:11]2[C:18]3[CH2:19][CH2:20][CH2:21][C:17]=3[S:16][C:12]2=[N:13][C:14]=1[CH3:15])([CH2:6][CH2:7][CH3:8])[C:3]([O-:5])=[O:4].[OH-].[Na+].Cl>C(O)C>[CH3:15][C:14]1[N:13]=[C:12]2[S:16][C:17]3[CH2:21][CH2:20][CH2:19][C:18]=3[C:11]2=[C:10]([C:22]([CH3:25])([CH3:24])[CH3:23])[C:9]=1[CH:2]([CH2:6][CH2:7][CH3:8])[C:3]([OH:5])=[O:4]
Reactant: CCCC(C)(C(=O)[O-])c1c(C)nc2sc3c(c2c1C(C)(C)C)CCC3
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCC(C(=O)O)c1c(C)nc2sc3c(c2c1C(C)(C)C)CCC3
Temperature: 100 °C
Yield: 44.8 %

Procedure:
To a solution of Methyl[2-methyl-4-(tert-butyl)-6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-b]pyridin-3-yl]pentanoate (0.035 g, 0.097 mmol) in ethanol (1.0 mL) was added a solution of sodium hydroxide 10 N (0.10 ml) and the mixture was heated in a sealed tube at 100° C. for 18 h. After cooling, the reaction mixture was acidified with 1N HCl (pH˜2) and partially concentrated under reduced pressure. The residue was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over magnesium sulphate, filtered and concentrated under reduced pressure. The residue was crystallized from ethyl acetate to afford 0.015 g (44%) of the title compound as a white solid
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[C:4]([CH3:10])[CH:3]=1.C(O)(=O)[CH2:12][C:13]([OH:15])=[O:14].N1CCCCC1.Cl>N1C=CC=CC=1>[F:1][C:2]1[CH:9]=[CH:8][C:5](/[CH:6]=[CH:12]/[C:13]([OH:15])=[O:14])=[C:4]([CH3:10])[CH:3]=1
Reactant: O=C(O)CC(=O)O
Reactant: Cc1cc(F)ccc1C=O
Agent: Cl
Solvent: c1ccncc1
Solvent: C1CCNCC1
Product: Cc1cc(F)ccc1/C=C/C(=O)O
Temperature: 70 °C
Yield: 68.9 %

Procedure:
A stirred solution of 4-fluoro-2-methyl-benzaldehyde (20 g, 144.9 mmol) and malonic acid (30.1 g, 289.8 mmol) in pyridine (100 mL) was heated to 50° C. Piperidine (10 mL) was added and the reaction mixture was heated at 70° C. for 18 h. The reaction mixture was cooled RT and poured into chilled aqueous 1N HCl solution (1500 mL), the resulting precipitate was filtered and washed with petroleum ether 60-80 and dried in vacuo to obtain (E)-3-(4-fluoro-2-methylphenyl)acrylic acid (18 g, 69%) as an off white solid.
Reaction SMILES: [F:1][C:2]([F:6])([F:5])[CH2:3]O.[CH3:7][C:8]1[CH:12]=[C:11]([C:13]([O:15]CC)=[O:14])[NH:10][N:9]=1.CCOCC.[OH-].[NH4+]>C(O)C>[F:1][C:2]([F:6])([F:5])[CH2:3][N:10]1[C:11]([C:13]([OH:15])=[O:14])=[CH:12][C:8]([CH3:7])=[N:9]1
Reactant: OCC(F)(F)F
Reactant: CCOC(=O)c1cc(C)n[nH]1
Agent: [NH4+]
Agent: [OH-]
Solvent: CCO
Solvent: CCOCC
Product: Cc1cc(C(=O)O)n(CC(F)(F)F)n1
Temperature: 70 °C
Yield: 72 %

Procedure:
A mixture of 100 g (0.35 mol) of the trichloromethanesulfonate ester of 2,2,2-trifluoroethanol [J. Med. Chem. 16 1354 (1973)] and 55 g (0.35 mol) of ethyl 3-methylpyrazole-5-carboxylate is heated at 150°-155° C. for two hours. The cooled (70° C.) melt is poured with stirring into 400 ml of ether, 80 ml of conc. ammonium hydroxide, and 150 g ice. The ether layer is separated and distilled to give 48 g bp 100°-110°/11 mm. The ester is stirred under reflux two hours in 175 ml of ethanol and 40 ml of water containing 14 g of potassium hydroxide and evaporated in vacuo. The residue is dissolved in 60 ml of water and acidified with conc. HCl to give 32 g (72%) of 1-(2,2,2-trifluoroethyl)-3-methylpyrazole-5carboxylic acid, mp 135°-139° C.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([C@H:11]([CH3:16])[C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=1)(=S)[NH2:2].NC1C=CC(C(C)C(OC)=[O:26])=CC=1.[O-]C#N.[Na+]>>[C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]([CH3:16])[C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=1)(=[O:26])[NH2:2]
Reactant: COC(=O)[C@@H](C)c1ccc(NC(N)=S)cc1
Reactant: COC(=O)C(C)c1ccc(N)cc1
Agent: N#C[O-]
Agent: [Na+]
Product: COC(=O)C(C)c1ccc(NC(N)=O)cc1

Procedure:
Following the same procedure described for (S)-methyl 2-[4-(carbamothioylamino)phenyl]propanoate and starting from methyl 2-(4-aminophenyl)propanoate (98 mmol) and sodium cyanate (128 mmol), after workup methyl 2-[4-(carbamoylamino)phenyl]propanoate was isolated as white solid (65%). 1H-NMR (CDCl3): δ 8.90 (bs, 1H, CONH), 7.55 (d, 2H, J=7 Hz), 7.20 (d, 2H, J=7 Hz), 6.50 (bs, 2H, CONH2), 3.75 (m, 1H), 3.60 (s, 3H), 1.50 (d, 3H, J=7 Hz).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:7](O)=[N:8][CH:9]=1)([O-:3])=[O:2].P(Br)(Br)([Br:19])=O.P(Br)(Br)Br>O>[Br:19][C:7]1[C:6]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][N:8]=1
Reactant: O=[N+]([O-])c1cnc(O)c(-c2ccccc2)c1
Reactant: O=P(Br)(Br)Br
Agent: BrP(Br)Br
Solvent: O
Product: O=[N+]([O-])c1cnc(Br)c(-c2ccccc2)c1
Temperature: 120 °C
Yield: 61.9 %

Procedure:
A mixture of 5-nitro-3-phenylpyridin-2-ol (4.63 mmol, 1 g), POBr3 (4.74 mmol, 0.45 ml) and PBr3 (4.71 mmol, 1.4 g) was heated at 120° C. for 3.5 hours. The crude mixture was poured into a mixture of ice and water and extracted with DCM. The organic phase was dried and evaporated affording 0.8 g (yield 62%) of the expected product.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([C:12]2[S:13][CH:14]=[CH:15][CH:16]=2)=[CH:6][C:3]=1[CH:4]=[O:5].C(=O)([O-])[O-].[K+].[K+].[C:23]([Si:27]([CH3:47])([CH3:46])[O:28][CH2:29][CH:30]([C:37]([CH3:45])([CH3:44])[O:38][SiH2:39][C:40]([CH3:43])([CH3:42])[CH3:41])[CH2:31]OS(C)(=O)=O)([CH3:26])([CH3:25])[CH3:24]>CN(C)C=O.O>[C:23]([Si:27]([CH3:46])([CH3:47])[O:28][CH2:29][CH:30]([C:37]([CH3:45])([CH3:44])[O:38][SiH2:39][C:40]([CH3:43])([CH3:42])[CH3:41])[CH2:31][O:1][C:2]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([C:12]2[S:13][CH:14]=[CH:15][CH:16]=2)=[CH:6][C:3]=1[CH:4]=[O:5])([CH3:25])([CH3:26])[CH3:24]
Reactant: COc1cc(O)c(C=O)cc1-c1cccs1
Reactant: CC(C)(C)[SiH2]OC(C)(C)C(CO[Si](C)(C)C(C)(C)C)COS(C)(=O)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(OCC(CO[Si](C)(C)C(C)(C)C)C(C)(C)O[SiH2]C(C)(C)C)c(C=O)cc1-c1cccs1
Temperature: 80 °C
Reaction time: 24 h
Yield: 80.8 %

Procedure:
Ex-64A: To a solution of 2-hydroxy-4-methoxy-5-thiophen-2-yl-benzaldehyde (10.0 g, 42.7 mmol) in N,N-dimethylformamide (100 mL) was added potassium carbonate (11.8 g, 85.4 mmol) and the resulting yellow slurry was heated to 80° C. Once at 80° C., methanesulfonic acid 3-(tert-butyl-dimethyl-silanyloxy)-2-(tert-butyl-dimethyl-silanyloxymethyl)-propyl ester (Ex-50A, 19.5 g, 46.9 mmol) was added dropwise and the reaction was stirred for an additional 24 h at 80° C. and cooled to room temperature. The mixture was diluted with water (500 mL) and extracted with ethyl acetate (3×150 mL). The combined organic layers was sequentially washed with a saturated sodium bicarbonate solution (1×150 mL), water (1×150 mL), and brine (1×150 mL), dried over sodium sulfate, and concentrated to a brown oil. Silica gel chromatography (100% ethyl acetate to 10% ethyl acetate/hexanes) gave 19.0 g (81%) of 2-[3-(tert-butyl-dimethyl-silanyloxy)-2-(tert-butyl-dimethyl-silanyloxymethyl)-propoxy]-4-methoxy-5-thiophen-2-yl-benzaldehyde as an off-white solid, mp 91–92° C. 1H-NMR (300 MHz, CDCl3) δ 10.37 (s, 1H), 8.12 (s, 1H), 7.44 (dd, 1H, J=3.6, 1.2 Hz), 7.29 (d, 1H, J=5.1 Hz), 7.07 (dd, 1H, J=5.1, 3.6 Hz), 6.54 (s, 1H), 4.19 (d, 2H, J=6.0 Hz), 3.99 (s, 3H), 3.72–3.82 (m, 4H), 2.28 (pentet, 1H, J=6.0 Hz), 0.88 (s, 18H), 0.048 (s, 12H). MS (EI) m/z=550 ([M]+, 100%). Anal. Calcd. for C28H46O5SSi2: C, 61.05; H, 8.42; S, 5.82. Found: C, 61.20; H, 8.74; S, 5.69.
Reaction SMILES: Cl.[C:2]([N:5]1[C:13]2[C:8](=[C:9]([CH3:19])[C:10]([CH2:15][C:16]([OH:18])=[O:17])=[C:11]([CH3:14])[CH:12]=2)[CH2:7][CH2:6]1)(=[O:4])[CH3:3].[CH2:20](O)[CH3:21]>>[C:2]([N:5]1[C:13]2[C:8](=[C:9]([CH3:19])[C:10]([CH2:15][C:16]([O:18][CH2:20][CH3:21])=[O:17])=[C:11]([CH3:14])[CH:12]=2)[CH2:7][CH2:6]1)(=[O:4])[CH3:3]
Reactant: CCO
Reactant: CC(=O)N1CCc2c1cc(C)c(CC(=O)O)c2C
Agent: Cl
Product: CCOC(=O)Cc1c(C)cc2c(c1C)CCN2C(C)=O
Reaction time: 0.5 h
Yield: 87 %

Procedure:
To a solution of hydrogen chloride (665 g) in ethanol (2000 ml) was added (1-acetyl-4,6-dimethylindolin-5-yl)acetic acid obtained in Example 15 (150 g), and the resulting mixture was stirred for 30 minutes at 45–50° C., and then an ethanol fraction containing hydrochloric acid (1000 ml) was evaporated off in vacuo. At about 20° C., water (2000 ml) was added, and crystals precipitated were separated by filtration and dried to afford 1-acetyl-5-ethoxycarbonylmethyl-4,6-dimethylindoline (146 g, yield: 87%), of which the physico-chemical properties were the same as those of the product obtained in Example 2.
Reaction SMILES: [C:1]([NH:4][CH2:5][CH2:6][CH2:7][C:8]([C:10]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:11]=1[CH2:12][CH2:13][C:14]([OH:16])=[O:15])=[O:9])(=[O:3])[CH3:2].S(Cl)(Cl)=O.O[CH2:27][C:28]1[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=1>C(Cl)Cl>[C:1]([NH:4][CH2:5][CH2:6][CH2:7][C:8]([C:10]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:11]=1[CH2:12][CH2:13][C:14]([O:16][CH2:27][C:28]1[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=1)=[O:15])=[O:9])(=[O:3])[CH3:2]
Reactant: OCc1cccnc1
Reactant: CC(=O)NCCCC(=O)c1ccc(Cl)cc1CCC(=O)O
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: CC(=O)NCCCC(=O)c1ccc(Cl)cc1CCC(=O)OCc1cccnc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2.00 g (0.006 mol) of 2-(4-acetamidobutyryl)-5-chlorohydrocinnamic acid and 0.5 ml (0.006 mol) of thionyl chloride in 20 ml of methylene chloride are stirred at room temperature for 5 minutes and then a solution of 2.2 ml (0.023 mol) of 3-hydroxymethylpyridine in 20 ml of methylene chloride is added thereto at 0°. After stirring at room temperature for 1 hour, the solution is concentrated, extracted with methylene chloride/water, dried with magnesium sulfate and the solvent is distilled in a vacuum. Chromatography on aluminum oxide with ethyl acetate gives 3-pyridylmethyl 2-(4-acetamidobutyryl)-5-chlorohydrocinnamate as a beige oil.
Reaction SMILES: CN(C)[CH:3]=[O:4].P(Cl)(Cl)(Cl)=O.[N:11]1([CH2:17][CH2:18][CH2:19][C:20]2[C:28]3[CH2:27][CH2:26][CH2:25][CH2:24][C:23]=3[NH:22][CH:21]=2)[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1.[OH-].[Na+]>ClCCl>[N:11]1([CH2:17][CH2:18][CH2:19][C:20]2[C:28]3[CH2:27][CH2:26][CH2:25][CH2:24][C:23]=3[NH:22][C:21]=2[CH:3]=[O:4])[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1
Reactant: CN(C)C=O
Reactant: c1[nH]c2c(c1CCCN1CCOCC1)CCCC2
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClCCl
Product: O=Cc1[nH]c2c(c1CCCN1CCOCC1)CCCC2
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 80.4 %

Procedure:
To an ice-cooled solution of 0.32 mL (4.1 mmol) of dimethylformamide in 3 mL of dichloromethane was added dropwise 0.4 mL (4.1 mmol) of phosphorus oxychloride. The reaction mixture was stirred at room temperature for 15 minutes and a solution of 680 mg (2.7 mmol) of 3-(3-morpholin-4-yl-propyl)-4,5,6,7-tetrahydro-1H-indole in 20 mL of dichloromethane was added dropwise at 0° C. The mixture was refluxed at 60° C. for 4 hours and cooled in an ice bath. Ice cubes were slowly added to the mixture followed by addition of 2 N sodium hydroxide to pH 12. The mixture was stirred at room temperature for 30 minutes and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated to give crude product which was purified on a silica gel column eluting with dichloromethane-methanol-ammonium hydroxide (98:2:1) to give 600 mg (83% yield) of 3-(3-morpholin-4-yl-propyl)-4,5,6,7-tetrahydro-1H-indole-2-carbaldehyde as a dark red oil. 1H-NMR (360 MHz, dimethylsulfoxide-d6) δ 11.33 (s, br, 1H, NH). MS m/z 277 [M+1].
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1.[F:18][C:19]1[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[CH:24][C:20]=1[C:21](Cl)=[O:22]>>[F:18][C:19]1[CH:27]=[C:26]([C:28]([F:29])([F:30])[F:31])[CH:25]=[CH:24][C:20]=1[C:21]([NH:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1)=[O:22]
Reactant: CN1CCC(c2c[nH]c3ccc(N)nc23)CC1
Reactant: O=C(Cl)c1ccc(C(F)(F)F)cc1F
Product: CN1CCC(c2c[nH]c3ccc(NC(=O)c4ccc(C(F)(F)F)cc4F)nc23)CC1

Procedure:
Beginning with 0.010 gm (0.044 mMol) 5-amino-3-(1-methylpiperidin-4-yl)pyrrolo[3,2-b]pyridine and 0.012 mL (0.053 mMol) 2-fluoro-4-trifluoromethylbenzoyl chloride, the title compound was prepared essentially by the procedure described in Example 7.
Reaction SMILES: [C:1]1([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:6]=[CH:5][C:4]([C:7](=[O:13])[CH2:8][CH2:9][CH2:10][CH:11]=[CH2:12])=[CH:3][CH:2]=1.B(F)(F)F.CC[O:26]CC.[OH-].[Na+].OO.C([O-])([O-])=O.[K+].[K+]>[BH4-].[Na+].COCCOCCOC.O>[C:1]1([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:2]=[CH:3][C:4]([CH:7]([OH:13])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][OH:26])=[CH:5][CH:6]=1
Reactant: C=CCCCC(=O)c1ccc(-c2ccccc2)cc1
Reactant: CCOCC
Agent: FB(F)F
Agent: O=C([O-])[O-]
Agent: OO
Solvent: O
Solvent: COCCOCCOC
Product: OCCCCCC(O)c1ccc(-c2ccccc2)cc1
Reaction time: 1 h
Yield: 65 %

Procedure:
1-Biphenyl-4-yl-hex-5-en-1-one (1 g) was dissolved in 0.5 M NaBH4 in diglyme (9 ml) and chilled in an ice bath. BF3.OEt2 (1 ml) in diglyme (4 ml) was added with vigorous stirring. Stirring was continued for 1 hour and water (1 ml) was added. 3M NaOH (2 ml) was added followed by 30% H2O2 (3 ml). Anhydrous K2CO3 (5 g) was added and the solvent decanted. The K2CO3 was washed with ethyl acetate and the combined organics dried (Na2SO4) and evaporated. Distillation under vacuum (oil bath temperature 175° C.) removed most of the remaining diglyme. The residue was purified by column chromatography (light petroleum:diethyl ether 2:1) to give a clear oil which solidified to give the title compound as a white powder (65%). δC (CDCl3, 62.9 MHz): 25.6, 25.7, 32.6, 39.0, 62.8, 74.2, 126.4, 127.1, 127.2, 127.3, 128.8, 140.4, 140.8 and 143.9. δH (CDCl3, 250 MHz): 1.39 (4H, m), 1.54 (2H, m), 1.81 (2H, m), 2.11 (1 or 2H, s), 3.37 (0 or 1H, s), 3.60 (2H, m), 4.69 (1H, t, J 6.4), 7.40 (5H, m) and 7.56 (4H, m). GCMS (EI+) (Found M, 270. C18H22O2 requires 270).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[CH:12]=[C:11]([O:13][C:14]3[CH:19]=[CH:18][C:17]([CH:20]([O:23][CH3:24])[O:21][CH3:22])=[CH:16][CH:15]=3)[N:10]([CH2:25][CH3:26])[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:27][C:28]([S:31]([N:33]=[C:34]1[CH2:37][O:36][CH2:35]1)=[O:32])([CH3:30])[CH3:29]>C1COCC1>[CH3:22][O:21][CH:20]([O:23][CH3:24])[C:17]1[CH:18]=[CH:19][C:14]([O:13][C:11]2[N:10]([CH2:25][CH3:26])[N:9]=[C:8]([C:4]3[CH:3]=[C:2]([C:34]4([NH:33][S:31]([C:28]([CH3:30])([CH3:29])[CH3:27])=[O:32])[CH2:37][O:36][CH2:35]4)[CH:7]=[CH:6][CH:5]=3)[CH:12]=2)=[CH:15][CH:16]=1
Reactant: CC(C)(C)S(=O)N=C1COC1
Reactant: CCn1nc(-c2cccc(Br)c2)cc1Oc1ccc(C(OC)OC)cc1
Solvent: C1CCOC1
Product: CCn1nc(-c2cccc(C3(NS(=O)C(C)(C)C)COC3)c2)cc1Oc1ccc(C(OC)OC)cc1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 88.1 %

Procedure:
A solution of n-Butylllithium in hexanes (2.5M, 3.83 mL, 9.59 mmol, 2.0 equiv) was added dropwise to a solution of 3-(3-bromophenyl)-5-[4-(dimethoxymethyl)phenoxy]-1-ethyl-1H pyrazole (2.0 g, 4.79 mmol, 1.0 equiv) in THF (32 mL) at −78° C. To this mixture was added dropwise a solution of 2-methyl-N-oxetane-3-ylidenepropane-2-sulfinamide (0.840 g, 4.79 mmol, 1.0 equiv, Example 95, Step 4) in 5 mL THF. The reaction mixture was stirred at −78° C. for 10 minutes and the cooling bath was removed. Saturated aqueous ammonium chloride solution was added, and the crude product was partitioned between ethyl acetate and water. The organic layer was washed with saturated aqueous sodium chloride solution and dried over magnesium sulfate. The dried solution was filtered and the filtrate was concentrated. The residue was purified by flash chromatography on silica gel (0-100% ethyl acetate:hexanes then flushing with 10% methanol/dichloromethane) to afford N-[3-{3-{5-[4-(dimethoxymethyl)phenoxy]-1-ethyl-1H-pyrazol-3-yl}phenyl)oxetan-3-yl]-2-methylpropane-2-sulfinamide (2.17 g, 4.22 mmol, 88% yield). Calc'd (M+1)+501.23. Found: 468.1. Found mass is aldehyde formed from deprotection of acetal on LCMS.
Reaction SMILES: [O:1]=[C:2]([CH3:20])[CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[C:15]2[C:14](=[O:16])[N:13]([CH3:17])[C:12](=[O:18])[N:11]([CH3:19])[C:10]=2[N:9]=[CH:8]1.[BH4-].[Na+]>C(O)C>[OH:1][CH:2]([CH3:20])[CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[C:15]2[C:14](=[O:16])[N:13]([CH3:17])[C:12](=[O:18])[N:11]([CH3:19])[C:10]=2[N:9]=[CH:8]1
Reactant: CC(=O)CCCCn1cnc2c1c(=O)n(C)c(=O)n2C
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CC(O)CCCCn1cnc2c1c(=O)n(C)c(=O)n2C

Procedure:
15 g of 7-(5-oxohexyl)-1,3-dimethylxanthine are dissolved in 100 ml of ethanol and mixed portionwise at room temperature with 3.8 g of sodium borohydride (110% of theory) in solid form or in alcoholic suspension. At the end of addition stirring takes place for 30 minutes. Subsequently heating takes place to boiling temperature. At this time the reaction is completed. The course of the reaction is followed by thin layer chromatography. The solvent is evaporated on a rotary evaporator. The residue is boiled e.g. with 50 ml of isopropanol or ethyl acetate. The insoluble substance is filtered off and discarded. The extract is crystallised by evaporation. 7-(5-hydroxyhexyl)-1,3-dimethylxanthine of m.p. 93° to 94° C. in a yield of 86% by weight is obtained. The substance after chromatography with silica gel F254 (Merck sheets) as the absorbent and with a mixture of benzene and acetone in a volume ratio of 60:40 as the eluting agent has a Rf -value of 0.15.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([O:11][CH2:12][CH2:13][CH3:14])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([O:22]C)[N:6]2[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.N>Cl>[NH2:1][C:2]1[N:10]=[C:9]([O:11][CH2:12][CH2:13][CH3:14])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([OH:22])[N:6]2[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CCCOc1nc(N)c2nc(OC)n(Cc3ccccc3)c2n1
Agent: Cl
Agent: N
Product: CCCOc1nc(N)c2nc(O)n(Cc3ccccc3)c2n1
Yield: 82.1 %

Procedure:
6-Amino-9-benzyl-8-methoxy-2-propoxypurine (75 mg, 0.24 mmol) in concentrated hydrochloric acid (15 ml) was stirred for 3 hours at room temperature. The reaction mixture was made basic with 28% aqueous ammonia, and the resulting crystals were filtered and washed with water to give the subject compound (59 mg, yield 83%).
Reaction SMILES: [CH2:1]([N:3]1[CH2:7][CH2:6][N:5]=[C:4]1SC)[CH3:2].[NH2:10][C:11]1[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][C:12]=1[C:13](O)=[O:14]>CC(N(C)C)=O>[CH2:1]([N:3]1[C:4]2=[N:10][C:11]3[C:12]([C:13](=[O:14])[N:5]2[CH2:6][CH2:7]1)=[CH:16][C:17]([C:20]([F:21])([F:22])[F:23])=[CH:18][CH:19]=3)[CH3:2]
Reactant: Nc1ccc(C(F)(F)F)cc1C(=O)O
Reactant: CCN1CCN=C1SC
Solvent: CC(=O)N(C)C
Product: CCN1CCn2c1nc1ccc(C(F)(F)F)cc1c2=O

Procedure:
A solution of 3.6 g. of 1-ethyl-2-methylthioimidazoline, 5.0 g. of 2-amino-5-trifluoromethylbenzoic acid and 50 ml. of dimethylacetamide is refluxed for 24 hours and then the reaction mixture concentrated in vacuo. The residue is dissolved in methylene chloride, washed first with 2 N sodium hydroxide solution and then with water, dried over magnesium sulfate, filtered and chromatographed on silica gel while eluding with methylene chloride to obtain 1-ethyl-7-trifluoromethyl-2,3-dihydro-imidazo[2.1-b]quinazolin-5(1H)-one.
Reaction SMILES: [Cl-].[NH:2]1[C:10]2[C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[CH2:7][CH2:6][C:5]=2[C:4]([C:15]2[CH:20]=[CH:19][N:18]=[C:17]([CH2:21][NH3+:22])[CH:16]=2)=[N:3]1.C(N(CC)CC)C.[CH:30](OCCC)=[O:31]>C(O)C.ClCCl>[NH:2]1[C:10]2[C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[CH2:7][CH2:6][C:5]=2[C:4]([C:15]2[CH:20]=[CH:19][N:18]=[C:17]([CH2:21][NH:22][CH:30]=[O:31])[CH:16]=2)=[N:3]1
Reactant: CCCOC=O
Reactant: [NH3+]Cc1cc(-c2n[nH]c3c2CCc2ccccc2-3)ccn1
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: CCO
Solvent: ClCCl
Product: O=CNCc1cc(-c2n[nH]c3c2CCc2ccccc2-3)ccn1

Procedure:
The product from Example 19 (100 mg) was suspended in propyl form ate (10 ml) and ethanol (1.5 ml). This mixture was boiled under reflux and after 2 minutes triethylamine (0.5 ml) was added. The mixture was boiled under reflux for 4 hours and then cooled and diluted with dichloromethane (50 ml). The mixture was washed with water, then dried, filtered and evaporated to give a residue which was triturated with ether and dichloromethane to give N-{[4-(4,5-dihydro-1H-benzo[g]-indazol-3-yl)-2-pyridyl]methyl}formamide.