Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([O:5][C:6]2[CH:7]=[C:8]3[C:13](=[CH:14][C:15]=2[O:16][CH2:17][CH2:18][O:19][CH3:20])[N:12]=[CH:11][N:10]=[C:9]3[NH:21][C:22]2[CH:27]=[CH:26][C:25]([F:28])=[C:24]([Cl:29])[C:23]=2[F:30])[CH2:2]1.N1CC([O:35][C:36]2C=C3C(=[CH:44][C:45]=2O)N=CN=C3NC2C=CC(F)=C(Cl)C=2F)C1>>[Cl:29][C:24]1[C:23]([F:30])=[C:22]([NH:21][C:9]2[C:8]3[C:13](=[CH:14][C:15]([O:16][CH2:17][CH2:18][O:19][CH3:20])=[C:6]([O:5][CH:3]4[CH2:2][N:1]([C:36](=[O:35])[CH:45]=[CH2:44])[CH2:4]4)[CH:7]=3)[N:12]=[CH:11][N:10]=2)[CH:27]=[CH:26][C:25]=1[F:28]
Reactant: Oc1cc2ncnc(Nc3ccc(F)c(Cl)c3F)c2cc1OC1CNC1
Reactant: COCCOc1cc2ncnc(Nc3ccc(F)c(Cl)c3F)c2cc1OC1CNC1
Product: C=CC(=O)N1CC(Oc2cc3c(Nc4ccc(F)c(Cl)c4F)ncnc3cc2OCCOC)C1
Yield: 50 %

Procedure:
The procedure of step 3) of Example 115 was repeated except for using the compound obtained in step 2) instead of 6-(azetidin-3-yloxy)-4-(3-chloro-2,4-difluorophenylamino)quinazolin-7-ol to obtain the title compound (21 mg, 50%).
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([C:13]([N:15]2[CH2:20][C:19](=O)[CH2:18][CH2:17][CH:16]2[CH2:22][NH:23][C:24]([C:26]2[CH:27]=[CH:28][CH:29]=[C:30]3[C:35]=2[N:34]=[CH:33][CH:32]=[CH:31]3)=[O:25])=[O:14])=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:6]=1.[NH2:36][CH2:37][CH2:38][OH:39]>>[OH:39][CH2:38][CH2:37][NH:36][CH:19]1[CH2:20][N:15]([C:13]([C:4]2[S:3][C:2]([CH3:1])=[N:6][C:5]=2[C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[O:14])[CH:16]([CH2:22][NH:23][C:24]([C:26]2[CH:27]=[CH:28][CH:29]=[C:30]3[C:35]=2[N:34]=[CH:33][CH:32]=[CH:31]3)=[O:25])[CH2:17][CH2:18]1
Reactant: Cc1nc(-c2ccccc2)c(C(=O)N2CC(=O)CCC2CNC(=O)c2cccc3cccnc23)s1
Reactant: NCCO
Product: Cc1nc(-c2ccccc2)c(C(=O)N2CC(NCCO)CCC2CNC(=O)c2cccc3cccnc23)s1

Procedure:
N-((5-(2-Hydroxyethylamino)-1-(2-methyl-4-phenylthiazole-5-carbonyl)piperidin-2-yl)methyl)quinoline-8-carboxamide was prepared according to general procedure N using N-((1-(2-methyl-4-phenylthiazole-5-carbonyl)-5-oxopiperidin-2-yl)methyl)quinoline-8-carboxamide and 2-aminoethanol. (ESI) 530 (M+H).
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH3:6][O:7][C:8](=[O:20])[C:9]([NH:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][N:14]=1)=O>C1(C)C=CC=CC=1>[CH3:6][O:7][C:8]([C:9]1[N:14]2[CH:15]=[C:16]([F:19])[CH:17]=[CH:18][C:13]2=[CH:12][N:11]=1)=[O:20]
Reactant: COC(=O)C(=O)NCc1ccc(F)cn1
Solvent: O=P(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: COC(=O)c1ncc2ccc(F)cn12
Temperature: 105 °C
Reaction time: 8 h
Yield: 31 %

Procedure:
In a round-bottomed flask, N-(5-fluoro-pyridin-2-ylmethyl)-oxalamic acid methyl ester (crude from Step 1) was dissolved in toluene (8 ml) and phosphorus oxychloride (1.5 ml, 16.1 mmol) was added. The reaction mixture was stirred at 105° C. in an oil bath overnight then cooled to 0° C. and carefully quenched with ice. Aqueous 25% ammonium hydroxide was added until pH=˜9. The mixture was diluted with water and extracted with dichloromethane (3×). The organic layers were combined, dried over sodium sulfate, filtered and concentrated. The residue was absorbed on silica gel and chromatographed with EtOAc/hexanes (gradient 0-50% EtOAc) to give 230 mg (31%, 2 steps) of 6-fluoro-imidazo[1,5-a]pyridine-3-carboxylic acid methyl ester as a light brown solid. 1H NMR (CDCl3, 300 MHz): δ (ppm) 9.33 (dd, J=5.1, 1.3 Hz, 1H), 7.75 (s, 1H), 7.69 (dd, J=9.8, 5.3 Hz, 1H), 7.09 (ddd, J=9.7, 7.5, 2.1 Hz, 1H), 4.06 (s, 3H).
Reaction SMILES: [CH3:1][O:2][CH:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:14]([C:16]3[CH:17]=[N:18][N:19]([CH2:22][CH3:23])[C:20]=3[OH:21])=[O:15])[C:11]=2[CH3:13])[S:6](=[O:25])(=[O:24])[CH2:5][CH2:4]1.[CH2:26](Br)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C(=O)([O-])[O-].[K+].[K+].O>CC(C)=O>[CH3:1][O:2][CH:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:14]([C:16]3[CH:17]=[N:18][N:19]([CH2:22][CH3:23])[C:20]=3[O:21][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[O:15])[C:11]=2[CH3:13])[S:6](=[O:24])(=[O:25])[CH2:5][CH2:4]1
Reactant: CCn1ncc(C(=O)c2ccc3c(c2C)C(OC)CCS3(=O)=O)c1O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: CCn1ncc(C(=O)c2ccc3c(c2C)C(OC)CCS3(=O)=O)c1OCc1ccccc1
Yield: 74 %

Procedure:
4-Methoxy-5-methyl-6-(1-ethyl-5-hydroxypyrazol-4-yl) carbonylthiochroman-1,1-dioxide was used as a starting material (XIH). And, 0.4 g (1.10 mmol) thereof was dissolved in 5 ml of acetone, and 0.21 g (1.21 mmol) of benzyl bromide as a reaction reagent (XII) and 0.15 g (1.10 mmol) of potassium carbonate as a base were added. The resultant mixture was refluxed under heat for 3 hours. Water was added to the reaction mixture, and the reaction mixture was extracted with ethyl acetate. Its organic layer was separated, and dried over anhydrous sodium sulfate. Then, the solvent was distilled off under reduced pressure, and the resultant oil was purified with flush column chromatography (Wako Gel C-300: hexane/ethyl acetate=2:3) to give 0.37 g (yield 74%) of 4-methoxy-5-methyl-6-(5-benzyloxy-1-ethylpyrazol-4-yl)carbonylthiochroman-1,1-dioxide (Compound No. 62) as an end compound which comes under the general formula (XI). Table 21 shows the structures of the starting material (XIH) and the reaction reagent (XII), and the structure and the yield of the end product (I).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][CH:9]1[CH2:14][CH2:13][N:12]([C:15](=[O:39])[CH2:16][NH:17][C:18]([C:20]2[CH:24]=[C:23]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[O:31]CC3C=CC=CC=3)[O:22][N:21]=2)=[O:19])[CH2:11][CH2:10]1>CO.C1COCC1.[Pd]>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][CH:9]1[CH2:14][CH2:13][N:12]([C:15](=[O:39])[CH2:16][NH:17][C:18]([C:20]2[CH:24]=[C:23]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[OH:31])[O:22][N:21]=2)=[O:19])[CH2:11][CH2:10]1
Reactant: O=C(NCC(=O)N1CCC(Nc2ccccc2Cl)CC1)c1cc(-c2ccccc2OCc2ccccc2)on1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(NCC(=O)N1CCC(Nc2ccccc2Cl)CC1)c1cc(-c2ccccc2O)on1
Reaction time: 1 h
Yield: 16.9 %

Procedure:
To a stirred solution of 5-(2-benzyloxy-phenyl)-isoxazole-3-carboxylic acid {2-[4-(2-chloro-phenylamino)-piperidin-1-yl]-2-oxo-ethyl}-amide (0.142 g, 0.00026 mole) in a mixture of methanol (60 mL) and THF (10 mL) was added 10% Pd/C (0.05 g) and the resulting mixture was stirred under an atmosphere of hydrogen for 1 hour. The mixture was then filtered through celite, the celite was washed with methanol and the organic layers were concentrated under reduced pressure. The resulting residue was recrystallized from ethyl acetate to afford 0.02 g (13%) of 5-(2-hydroxy-phenyl)-isoxazole-3-carboxylic acid {2-[4-(2-chloro-phenylamino)-piperidin-1-yl]-2-oxo-ethyl}-amide. LCMS: 455.14 (M+1)+. 94.82%, 1H NMR (DMSO-d6): δ 10.8 (s, 1H), 8.7 (t, 1H), 7.81 (d, 1H), 7.38 (t, 1H), 7.25 (d, 1H), 7.0 (m, 4H), 6.8 (d, 1H), 6.6 (t, 1H), 4.9 (d, 1H), 4.3 (d, 1H), 4.1 (d, 2H), 3.9 (d, 1H), 3.6 (s, 1H), 3.2 (m, 1H), 2.7 (m, 1H), 2.2 (m, 2H), 1.5 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][CH:6]=[C:5]2[S:13][C@H:14]1[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C@H:16]([CH2:27][O:28][Si:29]([C:42]([CH3:45])([CH3:44])[CH3:43])([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH2:15]1.CS(O[CH2:51][C:52]([CH3:63])([CH3:62])[CH2:53][O:54][Si:55]([C:58]([CH3:61])([CH3:60])[CH3:59])([CH3:57])[CH3:56])(=O)=O>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([CH2:51][C:52]([CH3:63])([CH3:62])[CH2:53][O:54][Si:55]([C:58]([CH3:61])([CH3:60])[CH3:59])([CH3:56])[CH3:57])[CH:6]=[C:5]2[S:13][C@H:14]1[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:24])([CH3:26])[CH3:25])=[O:21])[C@H:16]([CH2:27][O:28][Si:29]([C:42]([CH3:45])([CH3:44])[CH3:43])([C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH2:15]1
Reactant: CC(C)(CO[Si](C)(C)C(C)(C)C)COS(C)(=O)=O
Reactant: CC(C)(C)OC(=O)N1CC[C@H](Sc2c[nH]c(=O)c3ccc(Br)cc23)C[C@H]1CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Product: CC(C)(CO[Si](C)(C)C(C)(C)C)Cn1cc(S[C@H]2CCN(C(=O)OC(C)(C)C)[C@H](CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)C2)c2cc(Br)ccc2c1=O
Yield: 99.7 %

Procedure:
tert-Butyl (2S,4S)-4-[(6-bromo-1-oxo-1,2-dihydroisoquinolin-4-yl)sulfanyl]-2-({[tert-butyl(diphenyl)silyl]oxy}methyl)piperidine-1-carboxylate (Example 67e, 0.68 g) and 3-(tert-butyldimethylsilyloxy)-2,2-dimethylpropyl methanesulfonate (0.315 g) were reacted by the method of Example 58c to afford crude tert-butyl (2S,4S)-4-{[6-bromo-2-(3-{[tert-butyl(dimethyl)silyl]oxy}-2,2-dimethylpropyl)-1-oxo-1,2-dihydroisoquinolin-4-yl]sulfanyl}-2-({[tert-butyl(diphenyl)silyl]oxy}methyl)piperidine-1-carboxylate (0.87 g) as a colourless oil. This was reacted with N-cyclopropyl-3-fluoro-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (0.306 g) by the method of Example 58d to afford tert-butyl (2S,4S)-4-({2-(3-{[tert-butyl(dimethyl)silyl]oxy}-2,2-dimethylpropyl)-6-[5-(cyclo-ropylcarbamoyl)-3-fluoro-2-methylphenyl]-1-oxo-1,2-dihydroisoquinolin-4-yl}sulfanyl)-2-({[tert-butyl(diphenyl)silyl]oxy}methyl)piperidine-1-carboxylate as a colourless oil. This was diluted in ethanol (3 mL) and treated with 4M HCl in dioxane (1 mL) and stirred at room temperature for 20 h. The volatiles were removed in vacuo. The crude material was dissolved in methanol (2 mL) and loaded on to a 10 g SCX cartridge. The impurities were washed through with methanol (50 mL) and discarded. The product was eluted with 1N methanolic ammonia (75 mL) and the solvents evaporated in vacuo. Purification by preparative HPLC (Gemini-NX C18 column using a 95-5% gradient of aqueous 0.1% ammonia in methanol as eluent) afforded the title compound (32 mg) as a white solid.
Reaction SMILES: [C:1]([C:4]1[CH:33]=[CH:32][C:7]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][O:14][C:15]2[CH:28]=[CH:27][C:18]3[CH2:19][CH2:20][CH:21]([C:23]([O:25][CH3:26])=[O:24])[O:22][C:17]=3[C:16]=2[CH2:29][CH2:30][CH3:31])=[C:6]([CH2:34][CH2:35][CH3:36])[C:5]=1[OH:37])(=[O:3])[CH3:2].[CH3:38]C(C)=O.S(OC)(OC)(=O)=O>[OH-].[K+]>[C:1]([C:4]1[CH:33]=[CH:32][C:7]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][O:14][C:15]2[CH:28]=[CH:27][C:18]3[CH2:19][CH2:20][CH:21]([C:23]([O:25][CH3:26])=[O:24])[O:22][C:17]=3[C:16]=2[CH2:29][CH2:30][CH3:31])=[C:6]([CH2:34][CH2:35][CH3:36])[C:5]=1[O:37][CH3:38])(=[O:3])[CH3:2]
Reactant: CCCc1c(OCCCCCOc2ccc3c(c2CCC)OC(C(=O)OC)CC3)ccc(C(C)=O)c1O
Reactant: CC(C)=O
Agent: [K+]
Agent: [OH-]
Solvent: COS(=O)(=O)OC
Product: CCCc1c(OCCCCCOc2ccc(C(C)=O)c(OC)c2CCC)ccc2c1OC(C(=O)OC)CC2
Temperature: 40 °C

Procedure:
Methyl 7-[[5-(4-acetyl-3-hydroxy-2-propylphenoxy)pentyl]oxy]-3,4-dihydro-8-propyl-2H-1-benzopyran-2-carboxylate (1 mMol), prepared as described in U.S. Pat. No. 4,565,882, was dissolved in acetone containing 2.5 equivalents of potassium hydroxide and 3 equivalents of dimethyl sulfate. The mixture was heated at 40° C. for 10 hours and then cooled; the solvent was removed in vacuo and the residue partitioned between ethyl acetate and water. The organic layer was separated and dried over magnesium sulfate. Evaporation of the volatiles in vacuo afforded the methyl ether.
Reaction SMILES: C(N1CCCCC1)C.[CH3:9][C:10]([NH:12][C:13]1[NH:19][C:18]2[N:20](C(C)=O)[CH:21]=[N:22][C:17]=2[C:15](=O)[N:14]=1)=[O:11].P(Cl)(Cl)([Cl:28])=O.N>[Cl-].C([N+](CC)(CC)CC)C.C(#N)C.O>[C:10]([NH:12][C:13]1[N:19]=[C:18]2[C:17]([NH:22][CH:21]=[N:20]2)=[C:15]([Cl:28])[N:14]=1)(=[O:11])[CH3:9]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CC(=O)Nc1nc(=O)c2ncn(C(C)=O)c2[nH]1
Agent: CCN1CCCCC1
Agent: CC[N+](CC)(CC)CC
Agent: N
Solvent: CC#N
Solvent: O
Product: CC(=O)Nc1nc(Cl)c2[nH]cnc2n1
Temperature: 25 °C
Reaction time: 20 h
Yield: 89.5 %

Procedure:
45.0 g (0.27 mol) of tetraethylammonium chloride and 22.8 g (0.2 mol) of N-ethylpiperidine are added to a suspension of 42.6 g (0.18 mol) of 2,9-diacetylguanine in 450 ml of acetonitrile. 165.3 g (1.08 mol) of phosphorus oxychloride are then metered in at a temperature of 0° C. to 5° C. of the reaction mixture. The mixture is stirred at 25° C. for 20 hours, then introduced into 1.25 l of water such that 15° C. is not exceeded and the pH is at the same time kept between 4.8 and 5.5 using 12% strength ammonia solution. The mixture is stirred at 0° C. to 5° C. for 1 hour at a constant pH of 5, then the product is filtered off, washed with water and dried in vacuo at 50° C. 34.1 g of 2-acetamido-6-chloropurine are obtained. The final product is determined with the aid of HPLC on an RP-18 column in a reaction mixture of water, acetonitrile and acetic acid in the ratio 6:1:0.5.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:13]([CH3:14])[C:12]3[CH:15]=[CH:16][CH:17]=[CH:18][C:11]=3[N:10]=2)=[CH:4][CH:3]=1.[C:19]1([S:25](Cl)(=[O:27])=[O:26])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>N1C=CC=CC=1.CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]([C:9]2[N:13]([CH3:14])[C:12]3[CH:15]=[CH:16][CH:17]=[CH:18][C:11]=3[N:10]=2)[S:25]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)(=[O:27])=[O:26])=[CH:6][CH:7]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: Cn1c(Nc2ccc(Cl)cc2)nc2ccccc21
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: Cn1c(N(c2ccc(Cl)cc2)S(=O)(=O)c2ccccc2)nc2ccccc21
Temperature: 100 °C

Procedure:
To (4-chloro-phenyl)-(1-methyl-1H-benzimidazol-2-yl)-amine (258 mg, 1.0 mmol) in anhydrous pyridine (4 mL) at room temperature was added benzenesulfonyl chloride (706.5 mg, 4.0 mmol). The resulting mixture was heated to 100° C. in a microwave reactor for 1 h. The resulting mixture was then diluted with EtOAc, washed with 1 N HCl and the organic layer was dried over Na2SO4, filtered, and concentrated in vacuo. The resultant residue was purified by flash column chromatography (SiO2), eluting with a hexanes-EtOAc gradient to yield the title compound as a crude residue, which was dissolved in ether containing 2.0M hydrogen chloride, and then concentrated in vacuo to yield the title compound as its corresponding HCl salt. MS 398 (M+1)+
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[C:8]([O:14][CH3:15])=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].C(Cl)(=O)[C:17](Cl)=[O:18]>O1CCCC1.C(Cl)(Cl)Cl>[CH3:15][O:14][C:8]1[CH:7]=[C:3]2[C:2](=[CH:10][C:9]=1[N+:11]([O-:13])=[O:12])[NH:1][C:17](=[O:18])[NH:6][C:4]2=[O:5]
Reactant: COc1cc(C(N)=O)c(N)cc1[N+](=O)[O-]
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: COc1cc2c(=O)[nH]c(=O)[nH]c2cc1[N+](=O)[O-]
Temperature: 60 °C
Reaction time: 5 h
Yield: 100 %

Procedure:
108 mg (0.5 mmol) of 2-amino-5-methoxy-4-nitrobenzamide were dissolved in 5 ml of tetrahydrofuran and 5 ml of chloroform, and oxalyl chloride (solution in toluene) was added. The mixture was stirred at 60° C. for 5 hours and then concentrated in vacuo. Addition of toluene was followed by renewed concentration. 120 mg (100%) of the desired product were obtained.
Reaction SMILES: [CH:1]1([C:7]2[C:15]3[C:10](=[CH:11][C:12]([C:16]([O:18]C)=[O:17])=[CH:13][CH:14]=3)[N:9]([CH2:20][C:21]([N:23]([CH3:25])[CH3:24])=[O:22])[C:8]=2[C:26]2[CH:27]=[N:28][C:29]([O:32][CH3:33])=[CH:30][CH:31]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CO.Cl>C1COCC1>[CH:1]1([C:7]2[C:15]3[C:10](=[CH:11][C:12]([C:16]([OH:18])=[O:17])=[CH:13][CH:14]=3)[N:9]([CH2:20][C:21]([N:23]([CH3:25])[CH3:24])=[O:22])[C:8]=2[C:26]2[CH:27]=[N:28][C:29]([O:32][CH3:33])=[CH:30][CH:31]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c(-c3ccc(OC)nc3)n(CC(=O)N(C)C)c2c1
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc(-c2c(C3CCCCC3)c3ccc(C(=O)O)cc3n2CC(=O)N(C)C)cn1
Temperature: 60 °C
Yield: 90 %

Procedure:
Methyl 3-cyclohexyl-1-[2-(dimethylamino)-2-oxoethyl]-2-(6-methoxypyridin-3-yl)-1H-indole-6-carboxylate (from Step 1, 1 eq.) was dissolved in a mixture THF:MeOH (0.07 M, 1:1, v/v) then an aqueous solution of LiOH monohydrate (3 eq, 0.21 M) was added. The reaction mixture was heated at 60° C. for 4 h. It was allowed to cool to RT, and then hydrochloric acid was added. The precipitate that formed was collected by filtration and dried in vacuo to give the title compound (90%). 1H NMR (400 MHz; DMSO-d6, 300 K) δ 1.17-1.28 (m, 3H), 1.65-1.86 (m, 7H), 2.45-2.55 (m, 1H), 2.8 (s, 3H), 2.96 (s, 3H), 3.94 (s, 3H), 4.91 (s, 2H), 6.97 (d, J 8.4, 1H), 7.62 (d, J 8.8, 1H), 7.65 (d, J 8.8, 1H), 7.82 (d, J 8.4, 1H), 7.95 (s, 1H), 8.11 (s, 1H), 12.6 (bs, 1H); MS (ES+) m/z 436 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[O:10][CH2:9][CH:8]([N+:12]([O-])=O)[CH2:7]2>C(O)(=O)C.[Zn]>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[O:10][CH2:9][CH:8]([NH2:12])[CH2:7]2
Reactant: O=[N+]([O-])C1COc2c(Br)cccc2C1
Agent: [Zn]
Solvent: CC(=O)O
Product: NC1COc2c(Br)cccc2C1
Temperature: 100 °C
Yield: 60.5 %

Procedure:
8-Bromo-3-nitrochroman (400 mg; 1.55 mmol) was dissolved in glacial acetic acid (30 ml) and zinc dust (2 g) was added. The mixture was heated to 100° C. for 15 minutes. The zinc dust was filtered off and washed with dichloromethane. The solvent was evaporated and the remaining oil extracted with diluted hydrochloric acid/dichloromethane. The phases were separated and the pH of the water layer was adjusted to 11 with 2N NaOH. The water layer was extracted with dichloro-methane. The phases were separated and the organic layer dried (Na2SO4). The solvent was evaporated yielding 214 mg (61%) of 8-bromo-3-aminochroman.
Reaction SMILES: [NH2:1][C:2]1[C:3]([OH:14])=[N:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)=[N:6][CH:7]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(CC)CC.[C:46]1([CH:52]([C:56]2[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=2)[C:53](O)=[O:54])[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1>CC#N.O>[OH:14][C:3]1[C:2]([NH:1][C:53](=[O:54])[CH:52]([C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)[C:56]2[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=2)=[CH:7][N:6]=[C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[N:4]=1
Reactant: O=C(O)C(c1ccccc1)c1ccccc1
Reactant: Nc1cnc(-c2ccccn2)nc1O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CC#N
Solvent: CCN(CC)CC
Product: O=C(Nc1cnc(-c2ccccn2)nc1O)C(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 5-amino-2-(pyridin-2-yl)pyrimidin-4-ol (10-e) (120 mg, 0.64 mmol) in MeCN (5 ml) were added HATU (254 mg, 0.67 mmol), Et3N (130 mg, 1.28 mmol) and 2,2-diphenylacetic acid (135 mg, 0.64 mmol). The resulting mixture was stirred at room temperature for 1 hour. Then the mixture was diluted with water and followed by extraction with dichloromethane. The organic layer was washed with brine, dried over sodium sulfate and concentrated under vacuum. The residue was purified by prep-HPLC to provide compound 10-1. 1H NMR (DMSO-d6, 300 MHz): δ 12.50 (br, 1H), 9.85 (br, 1H), 8.73 (m, 2H), 8.10 (m, 1H), 8.00 (m, 1H), 7.60 (m, 1H), 7.35 (m, 10H), 5.75 (s, 1H). (M+H)+=383.2.
Reaction SMILES: [OH:1][C:2]1[CH:24]=[CH:23][C:5]([O:6][C:7]2[C:8]([CH3:22])=[CH:9][C:10]([NH:16][C:17](=[O:21])[C:18]([OH:20])=[O:19])=[C:11]3[C:15]=2[CH2:14][CH2:13][CH2:12]3)=[CH:4][C:3]=1[CH:25]([CH3:27])[CH3:26].[OH-].[Na+:29]>C(O)C>[OH:1][C:2]1[CH:24]=[CH:23][C:5]([O:6][C:7]2[C:8]([CH3:22])=[CH:9][C:10]([NH:16][C:17](=[O:21])[C:18]([O-:20])=[O:19])=[C:11]3[C:15]=2[CH2:14][CH2:13][CH2:12]3)=[CH:4][C:3]=1[CH:25]([CH3:27])[CH3:26].[Na+:29]
Reactant: Cc1cc(NC(=O)C(=O)O)c2c(c1Oc1ccc(O)c(C(C)C)c1)CCC2
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cc(NC(=O)C(=O)[O-])c2c(c1Oc1ccc(O)c(C(C)C)c1)CCC2
Reaction time: 0.08 h

Procedure:
N-[7-(4-hydroxy-3-isopropylphenoxy)-6-methylindan-4-yl]oxamic acid (2.25 g) was dissolved in ethanol (20 mL). Adding a 1 mol/L aqueous solution of sodium hydroxide (6.09 mL), the mixture was stirred for 5 min. The reaction mixture was evaporated under reduced pressure to dryness. Adding water (0.115 mL) and diisopropyl ether (20 mL), the residue was stirred for 3 hours. The precipitate was filtrated to give the title compound (2.4 g).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:6][CH:7]=1.C(O[C:17]1(O[Si](C)(C)C)[CH2:19][CH2:18]1)C.C(O)(=O)C.C([BH3-])#N.[Na+]>C1COCC1.O>[Cl:1][C:2]1[N:3]=[N:4][C:5]([N:8]2[CH2:9][CH2:10][N:11]([CH:17]3[CH2:19][CH2:18]3)[CH2:12][CH2:13]2)=[CH:6][CH:7]=1
Reactant: Clc1ccc(N2CCNCC2)nn1
Reactant: CCOC1(O[Si](C)(C)C)CC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: C1CCOC1
Product: Clc1ccc(N2CCN(C3CC3)CC2)nn1
Temperature: 62 °C

Procedure:
3-Chloro-6-piperazin-1-ylpyridazine (9.93 g, 50 mmol) was suspended in THF (80 mL), and water (18.9 mL), [(1-ethoxycyclopropyl)oxy]trimethylsilan (17.423 g, 100 mmol), acetic acid (8.5 mL, 150 mmol) and sodium cyanoborohydride (4.08 g, 65 mmol) were added. The mixture was heated at 62° C. for 16 h, solvents removed in vacuo and the remainder stirred with DCM (100 mL) and water (75 mL). The pH was adjusted to 10, the organic phase was separated, washed with water and dried over magnesium sulphate. Evaporation in vacuo yielded 3-chloro-6-(4-cyclopropylpiperazin-1-yl)pyridazine as a solid which was recrystallized from acetonitrile to yield the product, 8.18 g, 69%.
Reaction SMILES: [Br:1][C:2]1[C:3]([F:9])=[N:4][C:5]([CH3:8])=[CH:6][CH:7]=1.[F:10][C:11]([F:15])([F:14])[CH2:12][OH:13]>>[Br:1][C:2]1[C:3]([F:9])=[N:4][C:5]([CH2:8][O:13][CH2:12][C:11]([F:15])([F:14])[F:10])=[CH:6][CH:7]=1
Reactant: Cc1ccc(Br)c(F)n1
Reactant: OCC(F)(F)F
Product: Fc1nc(COCC(F)(F)F)ccc1Br

Procedure:
The title compound was prepared in an analogous manner to that described in Example 198 (Step 1) using 3-bromo-2-fluoro-6-methylpyridine (1.44 g, 7.58 mmol) (Waterstone Technology) and 2,2,2-trifluoroethanol. 1H NMR (400 MHz, d6-DMSO) δ 8.34 (1H, t, J=8.5 Hz); 7.34 (1H, d, J=7.9 Hz); 4.69 (2 H, s); 4.22 (2 H, q, J=9.5 Hz). m/z (ESI, +ve ion) 288/290 (M+H)+.
Reaction SMILES: [S-2:1].[Li+].[Li+].Cl[Si:5]([CH3:8])([CH3:7])[CH3:6]>O1CCCC1>[CH3:6][Si:5]([CH3:8])([CH3:7])[S:1][Si:5]([CH3:8])([CH3:7])[CH3:6]
Reactant: [S-2]
Reactant: C[Si](C)(C)Cl
Agent: [Li+]
Solvent: C1CCOC1
Product: C[Si](C)(C)S[Si](C)(C)C
Yield: 45 %

Procedure:
R. Detty et al. in J. Org. Chem. 1982, 47, 1354-1356 reiterated the above statement about the substantial nonreactivity of lithium sulfide and chlorotrimethylsilane and indicated that commercially available dilithium sulfide and chlorotrimethylsilane, when refluxed for seventy-two hours in tetrahydrofuran, gave only a 45% yield of hexamethyldisilthiane, also called "bis(trimethylsilyl)sulfide.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH2:11][C@@H:10]2[C:14]3[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[CH:18][C:15]=3[O:16][CH2:17][C@@H:9]12)C1C=CC=CC=1.[H][H]>C(O)C.[Pd]>[CH3:23][O:22][C:20]1[CH:19]=[CH:18][C:15]2[O:16][CH2:17][CH:9]3[NH:8][CH2:13][CH2:12][CH2:11][CH:10]3[C:14]=2[CH:21]=1
Reactant: [H][H]
Reactant: COc1ccc2c(c1)[C@H]1CCCN(Cc3ccccc3)[C@@H]1CO2
Agent: [Pd]
Solvent: CCO
Product: COc1ccc2c(c1)C1CCCNC1CO2

Procedure:
A solution of 1.5 g of trans-4-benzyl-9-methoxy-1,2,3,4a,5,10b-hexahydro-4H-[1]-benzopyrano[3,4-b]pyridine in 30 ml of ethanol is hydrogenated at 300 kPa pressure in the presence of 0.5 g of 10% palladium on charcoal until one mole of hydrogen is consumed. The reaction mixture is filtered, evaporated to dryness to give 9-methoxy-1,2,3,4a,5,10b-hexahydro-4H-[1]-benzopyrano[3,4-b]pyridine.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=O)=[CH:4][CH:3]=1.C(=O)=O.[C:15]1([C:21]23[CH2:26][CH:25]2[CH2:24][NH:23][CH2:22]3)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>O1CCCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([N:23]2[CH2:24][CH:25]3[C:21]([C:15]4[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=4)([CH2:26]3)[CH2:22]2)=[O:11])=[CH:6][CH:7]=1
Reactant: c1ccc(C23CNCC2C3)cc1
Reactant: O=C(O)Cc1ccc(F)cc1
Agent: O=C=O
Solvent: C1CCOC1
Product: O=C(Cc1ccc(F)cc1)N1CC2CC2(c2ccccc2)C1
Reaction time: 1 h

Procedure:
To a solution of 6.2 g. of p-fluorophenylacetic acid in 60 ml. of dry tetrahydrofuran is added 6.8 g. of N,N'-carbonyl diimidazole. The resultant mixture is allowed to stand 1 hour, at which time the evolution of carbon dioxide has ceased. To this solution is added 6.4 g. of 1-phenyl-3-azabicyclo[3.1.0]hexane and the reaction solution is allowed to stand 1/2 hour and then warmed on a steam bath for 1/2 hour. After removal of the solvent, the residue is poured into ice-water and the mixture is extracted with chloroform. The extracts are dried and evaporated to give the product as an amber oil; IR 6.04μ.