Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[C:7]([O:13][CH3:14])[CH:6]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:22][CH:23]([CH3:26])[CH2:24][Cl:25].O>CN(C)C=O>[CH3:1][N:2]([CH:24]([Cl:25])[CH:23]([CH3:26])[CH3:22])[CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[C:7]([O:13][CH3:14])[CH:6]=1
Reactant: CNCCc1ccc(OC)c(OC)c1
Reactant: CC(CCl)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(CCN(C)C(Cl)C(C)C)cc1OC
Yield: 40 %

Procedure:
8.0 g of N-methyl-(2-(3,4-dimethoxyphenyl)ethyl)amine was dissolved in 120 ml of N,N-dimethylformamide, followed by the addition of 6.8 g of anhydrous potassium carbonate and 14.4 ml of 1-bromo-3-chloro-2-methylpropane. The obtained mixture was reacted at a room temperature for 12 hours, followed by the addition of water. The obtained mixture was extracted with ethyl acetate. The ethyl acetate phase was washed with water and a saturated aqueous solution of common salt, dried over anhydrous potassium carbonate and distilled to remove the solvent. The obtained residue was purified by silica gel column chromatography [solvent: dichloromethane/methanol (50:1)] to obtain 4.67 g of the title compound as a pale yellow oil (yield: 40%).
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:8]([CH3:36])([CH3:35])[C@H:9]2[C@:22]([CH3:25])([CH2:23][CH:24]=1)[C@@H:21]1[C@:12]([CH3:34])([C@@:13]3([CH3:33])[C@H:18]([CH2:19][CH2:20]1)[C@H:17]1[C@H:26]([C:29]([CH3:31])=[CH2:30])[CH2:27][CH2:28][C@:16]1([NH2:32])[CH2:15][CH2:14]3)[CH2:11][CH2:10]2)(=O)=O.CC1(C)C(C)(C)OB([C:47]2[CH2:51][CH2:50][CH:49]([CH2:52][C:53]([O:55][CH3:56])=[O:54])[CH:48]=2)O1>>[NH2:32][C@:16]12[CH2:28][CH2:27][C@@H:26]([C:29]([CH3:31])=[CH2:30])[C@@H:17]1[C@@H:18]1[C@@:13]([CH3:33])([CH2:14][CH2:15]2)[C@@:12]2([CH3:34])[C@@H:21]([C@:22]3([CH3:25])[C@@H:9]([CH2:10][CH2:11]2)[C:8]([CH3:35])([CH3:36])[C:7]([C:47]2[CH2:51][CH2:50][CH:49]([CH2:52][C:53]([O:55][CH3:56])=[O:54])[CH:48]=2)=[CH:24][CH2:23]3)[CH2:20][CH2:19]1
Reactant: C=C(C)[C@@H]1CC[C@]2(N)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(OS(=O)(=O)C(F)(F)F)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Reactant: COC(=O)CC1C=C(B2OC(C)(C)C(C)(C)O2)CC1
Product: C=C(C)[C@@H]1CC[C@]2(N)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(C6=CC(CC(=O)OC)CC6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Yield: 55.7 %

Procedure:
The title compound was prepared as a mixture of diastereomers in 55.7% yield following the method for the preparation of Example 1, Step 1 described above, using (1R,3aS,5aR,5bR,7aR,11aR,11bR,13aR,13bR)-3a-amino-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl trifluoromethanesulfonate and methyl 2-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopent-2-en-1-yl)acetate as the reactant. MS: m/e 531.5 (M−16)+, 2.69 min (method 3). 1H NMR (400 MHz, CHLOROFORM-d) δ 5.54 (s, 1H), 5.50-5.44 (m, 1H), 4.73 (s, 1H), 4.60 (s, 1H), 3.67 (s, 3H), 3.14 (t, J=7.0 Hz, 1H), 2.81-2.61 (m, 1H), 2.59-2.27 (m, 5H), 2.16-1.96 (m, 4H), 1.79-1.18 (m, 20H), 1.09-1.02 (m, 11H), 0.96 (s, 3H), 0.85 (s, 3H).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:20]([O:24][C:25]1[C:30]([C:31]2[NH:32][C:33](=[O:46])[C:34]3[C:35](=[C:37]([CH2:44][CH3:45])[N:38]([CH2:40][CH2:41][O:42][CH3:43])[N:39]=3)[N:36]=2)=[CH:29][C:28]([C:47](=[O:50])[CH2:48]O)=[CH:27][N:26]=1)[CH2:21][CH2:22][CH3:23].C(Br)(Br)(Br)[Br:52]>ClCCl>[CH2:20]([O:24][C:25]1[C:30]([C:31]2[NH:32][C:33](=[O:46])[C:34]3[C:35](=[C:37]([CH2:44][CH3:45])[N:38]([CH2:40][CH2:41][O:42][CH3:43])[N:39]=3)[N:36]=2)=[CH:29][C:28]([C:47](=[O:50])[CH2:48][Br:52])=[CH:27][N:26]=1)[CH2:21][CH2:22][CH3:23]
Reactant: BrC(Br)(Br)Br
Reactant: CCCCOc1ncc(C(=O)CO)cc1-c1nc2c(CC)n(CCOC)nc2c(=O)[nH]1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCCCOc1ncc(C(=O)CBr)cc1-c1nc2c(CC)n(CCOC)nc2c(=O)[nH]1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Triphenylphosphine (110 mg, 0.42 mmol) in dichloromethane (1 mL) was added slowly to an ice cooled solution of 5-(2-butoxy-5-glycoloyl-3-pyridinyl)-3-ethyl-2-(2-methoxyethyl)-2,6-dihydro-7H-pyrazolo[4,3-d]-pyrimidin-7-one (Example 33) (150 mg, 0.35 mmol) and carbon tetrabromide (140 mg, 0.42 mmol) in dichloromethane (3 mL). The solution was allowed to warm to room temperature. After 2 h further carbon tetrabromide (25 mg, 0.075 mmol) and triphenylphosphine were added and stirring continued for 2 h. Concentration and purification of the product by flash column chromatography (gradient elution with ethyl acetate/pentane (10:90-70:30) gave 5-[2-butoxy-5-(2-bromoacetyl)-3-pyridinyl]-3-ethyl-2-(2-methoxyethyl)-2,6-dihydro-7H-pyrazolo[4,3-d]-pyrimidin-7-one which was used without any further purification (slight contamination with triphenylphosphine oxide). 5-[2-Butoxy-5-(2-bromoacetyl)-3-pyridinyl]-3-ethyl-2-(2-methoxyethyl)-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one (205 mg, 0.42 mmol) was dissolved in dichloromethane and the solution cooled to 0° C. Morpholine (54 mg, 0.62 mmol) and triethylamine (84 mg, 0.83 mmol) were added and the mixture was allowed to warm to room temperature and stirred for 2 h. The solvent was evaporated and the residue dissolved in ethyl acetate, washed with water (twice), saturated sodium bicarbonate (twice) and brine, dried (MgSO4) and concentrated. Purification by flash column chromatography (gradient elution 20% ethyl acetate/pentane:100% ethyl acetate:3% methanol/methyl acetate) gave 70 mg product.
Reaction SMILES: [I:1][C:2]1[N:11]=[CH:10][C:9]2[CH2:8][CH2:7][C:6]3[C:12]([C:16]([O:18]CC)=[O:17])=[N:13][N:14]([CH3:15])[C:5]=3[C:4]=2[N:3]=1.[OH-].[K+:22]>C(O)C>[I:1][C:2]1[N:11]=[CH:10][C:9]2[CH2:8][CH2:7][C:6]3[C:12]([C:16]([O-:18])=[O:17])=[N:13][N:14]([CH3:15])[C:5]=3[C:4]=2[N:3]=1.[K+:22]
Reactant: CCOC(=O)c1nn(C)c2c1CCc1cnc(I)nc1-2
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: Cn1nc(C(=O)[O-])c2c1-c1nc(I)ncc1CC2
Yield: 82 %

Procedure:
Ethyl 8-iodo-1-methyl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxylate (384 mg, 1 mmol) was suspended in anhydrous ethanol (10 mL) and treated with a 1.5 M solution of potassium hydroxide in ethanol (6.6 mL, 10 mmol) at room temperature, overnight. The resulting precipitate was collected by filtration to give the title compound (323 mg, 82% yield) as a white solid.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[Cl:14][C:15]1[C:19](Cl)=[N:18][S:17][N:16]=1.Cl>CN(C=O)C.O>[C:4]([O:3][C:1]([N:8]1[CH2:9][CH2:10][N:11]([C:19]2[C:15]([Cl:14])=[N:16][S:17][N:18]=2)[CH2:12][CH2:13]1)=[O:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: Clc1nsnc1Cl
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(c2nsnc2Cl)CC1
Temperature: 100 °C
Yield: 82.4 %

Procedure:
1-Boc-piperazine (30.2 g, 165 mmol) was dissolved in DMF (30.0 mL) and heated to 100° C. 3,4-Dichloro-1,2,5-thiadiazole (7.5 mL, 80 mmol) was added dropwise with stirring and the mixture heated at 100° C. for 5.5 h. The reaction mixture was diluted with H2O and the pH adjusted to 2.0 with 1N HCl. The resulting solids were filtered, washed with H2O and dried under vacuum to give 20.1 g (83%) of 4-(4-chloro-[1,2,5]thiadiazol-3-yl)-piperazine-1-carboxylic acid tert-butyl ester as a tan solid. 1H NMR (DMSO-d6) 3.48 (m, 4H), 3.36 (m, 4H), 1.42 (s, 9H) ppm. LC-MS (MH+)=205 (-Boc).
Reaction SMILES: [CH2:1]([N:8]1[C:12]2[CH:13]=[CH:14][C:15]3[N:16]([C:17]([CH3:20])=[N:18][N:19]=3)[C:11]=2[CH:10]=[C:9]1[C:21]1[NH:25][N:24]=[CH:23][CH:22]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.Cl[CH2:28][CH2:29][N:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[CH2:1]([N:8]1[C:12]2[CH:13]=[CH:14][C:15]3[N:16]([C:17]([CH3:20])=[N:18][N:19]=3)[C:11]=2[CH:10]=[C:9]1[C:21]1[CH:22]=[CH:23][N:24]([CH2:28][CH2:29][N:30]2[CH2:35][CH2:34][O:33][CH2:32][CH2:31]2)[N:25]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1nnc2ccc3c(cc(-c4ccn[nH]4)n3Cc3ccccc3)n12
Reactant: ClCCN1CCOCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Cc1nnc2ccc3c(cc(-c4ccn(CCN5CCOCC5)n4)n3Cc3ccccc3)n12
Temperature: 70 °C

Procedure:
A mixture of 6-benzyl-1-methyl-7-(1H-pyrazol-5-yl)-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyridine (4.2 mg, 0.013 mmol, from Example 62), 4-(2-chloroethyl)morpholine hydrochloride (7.1 mg, 0.038 mmol, Aldrich) and Cs2CO3 (21 mg, 0.064 mmol) in DMF (0.21 mL) was heated at 70° C. overnight. The product was purified via preparative HPLC-MS (C18 eluting with a gradient of MeCN and H2O containing 0.15% NH4OH) and the major isomer was isolated. Yield: (2.4 mg, 42%).
Reaction SMILES: [CH3:1][O:2][CH2:3][C@H:4]([CH3:31])[O:5][C:6]1[CH:7]=[C:8]([C:23]2[NH:27][C:26]([C:28](=O)[CH3:29])=[CH:25][CH:24]=2)[CH:9]=[C:10]([O:12][C:13]2[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:14]=2)[CH:11]=1.Cl.[NH2:33][OH:34].C([O-])(=O)C.[Na+]>CO.ClCCl>[CH3:1][O:2][CH2:3][C@H:4]([CH3:31])[O:5][C:6]1[CH:7]=[C:8]([C:23]2[NH:27][C:26](/[C:28](=[N:33]/[OH:34])/[CH3:29])=[CH:25][CH:24]=2)[CH:9]=[C:10]([O:12][C:13]2[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:14]=2)[CH:11]=1
Reactant: COC[C@H](C)Oc1cc(Oc2ccc(S(C)(=O)=O)cc2)cc(-c2ccc(C(C)=O)[nH]2)c1
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: COC[C@H](C)Oc1cc(Oc2ccc(S(C)(=O)=O)cc2)cc(-c2ccc(/C(C)=N/O)[nH]2)c1
Yield: 41.9 %

Procedure:
1-(5-{3-[(1S)-2-Methoxy-1-methylethoxy]-5-[4-(methylsulfonyl)phenoxy]phenyl}-1H-pyrrol-2-yl)ethanone (117 mg, 0.26 mmol) synthesized in Example (15c) was dissolved in methanol (6 mL), and hydroxylamine hydrochloride (37 mg, 0.53 mmol) and sodium acetate (26 mg, 0.32 mmol) were added, followed by heating to reflux for 6 hours under nitrogen atmosphere. The reaction solution was diluted with dichloromethane (60 mL), washed with water and saturated brine, and subsequently dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate/hexane=30%-50%) to afford the desired product (50 mg, yield 41%) as a white solid.
Reaction SMILES: [CH3:1][C@@H:2]1[N:7]([C:8]2[C:9](=[O:22])[NH:10][C:11]3[C:16]([N:17]=2)=[CH:15][C:14]([C:18]([O:20][CH3:21])=[O:19])=[CH:13][CH:12]=3)[CH2:6][CH2:5][O:4][CH2:3]1.N1C=CC=CC=1.[O:29](S(C(F)(F)F)(=O)=O)[S:30]([C:33]([F:36])([F:35])[F:34])(=O)=[O:31]>ClCCl>[CH3:1][C@@H:2]1[N:7]([C:8]2[C:9]([O:22][S:30]([C:33]([F:36])([F:35])[F:34])(=[O:31])=[O:29])=[N:10][C:11]3[C:16]([N:17]=2)=[CH:15][C:14]([C:18]([O:20][CH3:21])=[O:19])=[CH:13][CH:12]=3)[CH2:6][CH2:5][O:4][CH2:3]1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: COC(=O)c1ccc2[nH]c(=O)c(N3CCOC[C@@H]3C)nc2c1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)c1ccc2nc(OS(=O)(=O)C(F)(F)F)c(N3CCOC[C@@H]3C)nc2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (S)-methyl 3-(3-methylmorpholino)-2-oxo-1,2-dihydroquinoxaline-6-carboxylate (200 mg, crude) in dichloromethane (30 mL) was added pyridine (79 mg, 2.64 mmol). Then Tf2O (372 mg, 1.32 mmol) was added and stirred overnight at room temperature. The reaction was then quenched by the addition of ice-water (100 mL) and extracted with dichloromethane (3×15 mL), the organic layers combined and dried over anhydrous magnesium sulfate and concentrated in vacuo to afford (S)-methyl 3-(3-methylmorpholino)-2-(trifluoromethylsulfonyloxy)quinoxaline-6-carboxylate as red oil (250 mg, crude).
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[CH:5][NH:4][N:3]=1.CN(C)[CH:9]=[CH:10][C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=1)=O>C(O)(=O)C>[F:20][C:19]([F:21])([F:22])[C:15]1[CH:16]=[CH:17][CH:18]=[C:13]([C:11]2[N:3]3[N:4]=[CH:5][CH:6]=[C:2]3[N:1]=[CH:9][CH:10]=2)[CH:14]=1
Reactant: CN(C)C=CC(=O)c1cccc(C(F)(F)F)c1
Reactant: Nc1cc[nH]n1
Solvent: CC(=O)O
Product: FC(F)(F)c1cccc(-c2ccnc3ccnn23)c1

Procedure:
A mixture of 8.31 g. of 3-aminopyrazole, 24.32 g. of 3-dimethylamino-3'-(trifluoromethyl)acrylophenone and 100 ml. of glacial acetic acid is refluxed for 8 hours and evaporated in vacuo to an oil. This oil is treated as described in Example 1, giving the desired product, m.p. 103°-104.5° C.
Reaction SMILES: [CH:1]1([CH2:4][N:5]([CH2:19][CH:20]2[CH2:22][CH2:21]2)[C:6]2[C:15]([CH:16]=O)=[CH:14][C:13]3[C:8](=[C:9]([CH3:18])[CH:10]=[CH:11][CH:12]=3)[N:7]=2)[CH2:3][CH2:2]1.[F:23][C:24]([F:38])([F:37])[C:25]1[CH:26]=[C:27]([CH:30]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:32]=1)[CH2:28][NH2:29].C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[F:23][C:24]([F:37])([F:38])[C:25]1[CH:26]=[C:27]([CH:30]=[C:31]([C:33]([F:36])([F:34])[F:35])[CH:32]=1)[CH2:28][NH:29][CH2:16][C:15]1[C:6]([N:5]([CH2:19][CH:20]2[CH2:22][CH2:21]2)[CH2:4][CH:1]2[CH2:3][CH2:2]2)=[N:7][C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[CH:10][C:9]=2[CH3:18]
Reactant: Cc1cccc2cc(C=O)c(N(CC3CC3)CC3CC3)nc12
Reactant: NCc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: Cc1cccc2cc(CNCc3cc(C(F)(F)F)cc(C(F)(F)F)c3)c(N(CC3CC3)CC3CC3)nc12
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 69.8 %

Procedure:
2-(Bis(cyclopropylmethyl)amino)-8-methylquinoline-3-carbaldehyde (0.081 g, 0.39 mmol), 3,5-bis-trifluoromethylbenzylamine (0.096 g, 0.39 mmol) and acetic acid (0.047 g, 0.78 mmol) were put in a 25 mL RB flask. To this, 2 mL of methanol was added and stirred at RT for 15 min. Sodium cyanoborohydride (0.075 g, 0.77 mmol) was added portionwise and stirring was continued at RT for another 1 h. Methanol was removed from the reaction mixture under vacuum, water was added to this crude and was extracted with ethyl acetate (3×50 mL). The organic layer was washed with saturated NaHCO3 solution, brine and dried over sodium sulphate. The solvent was evaporated and the crude residue was purified by column chromatography over silica gel (100-200 mesh) eluting with 4% ethyl acetate in petroleum ether to give the title amine (0.142 g, yield: 99%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH2:8][S:9]([CH3:11])=[O:10])[CH:7]=1.[N-:12]=[N+]=[N-].[Na+].OS(O)(=O)=O>C(Cl)(Cl)Cl>[Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH2:8][S:9](=[NH:12])([CH3:11])=[O:10])[CH:7]=1
Reactant: CS(=O)Cc1cncc(Br)c1
Reactant: [N-]=[N+]=[N-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CS(=N)(=O)Cc1cncc(Br)c1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 49.4 %

Procedure:
3-Bromo-5-methanesulfinylmethyl-pyridine (3.0 g, 13 mmol) is dissolved in chloroform (100 mL) and the solution is cooled to 0° C. Sodium azide (1.3 g, 21 mmol) is added and the reaction mixture is stirred for 5 minutes. Then concentrated H2SO4 (10 mL) is slowly added at 0° C. and then the mixture is heated up to 50° C. for 16 hrs. After cooling down to room temperature, ice cold water is added and the mixture is extracted with CH2Cl2. The aqueous layer is separated, basified with saturated Na2CO3 solution and extracted with more CH2Cl2. Organic layers are combined, dried over anhydrous Na2SO4 and concentrated to give the crude product. Purification by flash column chromatography affords 1.6 g of 3-bromo-5-[imino(methyl)oxo-λ6-sulfanyl]methyl-pyridine.
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][C:8]=2[C:15]2[CH:20]=[CH:19][N:18]=[C:17]3[C:21]([C:25]([NH:27][C@H:28]4[C@H:32]([OH:33])[CH2:31][NH:30][CH2:29]4)=[O:26])=[C:22]([CH3:24])[NH:23][C:16]=23)[CH2:4][CH2:3]1.[C:34](Cl)(=[O:37])[CH2:35][CH3:36]>>[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][C:8]=2[C:15]2[CH:20]=[CH:19][N:18]=[C:17]3[C:21]([C:25]([NH:27][C@H:28]4[C@H:32]([OH:33])[CH2:31][N:30]([C:34](=[O:37])[CH2:35][CH3:36])[CH2:29]4)=[O:26])=[C:22]([CH3:24])[NH:23][C:16]=23)[CH2:4][CH2:3]1
Reactant: COc1ccc(OCC2CC2)c(-c2ccnc3c(C(=O)N[C@@H]4CNC[C@H]4O)c(C)[nH]c23)c1
Reactant: CCC(=O)Cl
Agent: Cl
Product: CCC(=O)N1C[C@@H](O)[C@H](NC(=O)c2c(C)[nH]c3c(-c4cc(OC)ccc4OCC4CC4)ccnc23)C1

Procedure:
Starting from 7-[2-(cyclopropylmethoxy)-5-methoxyphenyl]-N-[(3R*,4R*)-4-hydroxypyrrolidin-3-yl]-2-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide hydrochloride (example D.f17) and commercially available propionyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]=[O:10])=[CH:4][CH:3]=1.[N:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][NH2:18])[CH:12]=1>C1C=CC=CC=1>[N:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][NH:18][C:9]([NH:8][C:5]2[CH:6]=[CH:7][C:2]([SH:1])=[CH:3][CH:4]=2)=[O:10])[CH:12]=1
Reactant: NCc1cccnc1
Reactant: O=C=Nc1ccc(S)cc1
Solvent: c1ccccc1
Product: O=C(NCc1cccnc1)Nc1ccc(S)cc1
Temperature: 25 °C
Yield: 77.5 %

Procedure:
To 4-mercaptophenyl isocyanate (0.9 g., 0.006 mol) in 50 ml. of anhydrous benzene was added 3-pyridylmethylamine (0.65 g., 0.006 mol). An exothermic reaction caused the temperature to rise to 40° C. and a white precipitate formed. The reaction mixture was momentarily heated to reflux, then cooled to room temperature and filtered to give 1.2 g. melting at 155°-159° C. The product was a 77.5% yield of 1-(3-pyridylmethyl)-3-(4-mercaptophenyl)urea.
Reaction SMILES: [CH3:1][C:2]([NH2:27])([CH3:26])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:14]=[CH:13][N:12]([C:15]3[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=3)[N:11]=2)=[CH:6][CH:5]=1.[N+](C1C=CC([CH:37]2[S:41]/[C:40](=[N:42]\[C:43](=O)[O-:44])/[N:39]([C:46]3[CH:51]=[C:50]([CH3:52])[CH:49]=[CH:48][C:47]=3[CH:53]([CH3:55])[CH3:54])[C:38]2=[O:56])=CC=1)([O-])=O>>[CH:53]([C:47]1[CH:48]=[CH:49][C:50]([CH3:52])=[CH:51][C:46]=1[N:39]1[C:38](=[O:56])[CH2:37][S:41]/[C:40]/1=[N:42]\[C:43]([NH:27][C:2]([CH3:1])([CH3:26])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:14]=[CH:13][N:12]([C:15]3[CH:20]=[CH:19][C:18]([O:21][C:22]([F:24])([F:23])[F:25])=[CH:17][CH:16]=3)[N:11]=2)=[CH:6][CH:5]=1)=[O:44])([CH3:55])[CH3:54]
Reactant: CC(C)(N)Cc1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Reactant: Cc1ccc(C(C)C)c(N2C(=O)C(c3ccc([N+](=O)[O-])cc3)S/C2=N\C(=O)[O-])c1
Product: Cc1ccc(C(C)C)c(N2C(=O)CS/C2=N\C(=O)NC(C)(C)Cc2ccc(-c3ncn(-c4ccc(OC(F)(F)F)cc4)n3)cc2)c1

Procedure:
The title compound was prepared as described in Example 95 using 2-methyl-1-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)propan-2-amine (CB28) and (Z)-4-nitrophenyl(3-(2-isopropyl-5-methylphenyl)-4-oxothiazolidin-2-ylidene)carbamate (CA50), purified by flash column chromatography using 0-100% ethyl acetate/B, where B=1:1 dichloromethane/hexanes, as eluent and isolated as a brown oil (0.018 g, 9%).
Reaction SMILES: C(O[C:4]([C:6]1[C:7]([C:17]2[S:18][C:19]([I:23])=[C:20]([CH3:22])[CH:21]=2)=[CH:8][S:9][C:10]=1[NH:11][C:12](=[O:16])[CH2:13][C:14]#[N:15])=[O:5])C.[H-].[Na+]>C1COCC1.CN(C=O)C>[OH:5][C:4]1[C:6]2[C:7]([C:17]3[S:18][C:19]([I:23])=[C:20]([CH3:22])[CH:21]=3)=[CH:8][S:9][C:10]=2[NH:11][C:12](=[O:16])[C:13]=1[C:14]#[N:15]
Reactant: CCOC(=O)c1c(-c2cc(C)c(I)s2)csc1NC(=O)CC#N
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: Cc1cc(-c2csc3[nH]c(=O)c(C#N)c(O)c23)sc1I
Temperature: 25 °C
Reaction time: 8 h
Yield: 56.8 %

Procedure:
To 5′-(2-Cyano-acetylamino)-5-iodo-4-methyl-[2,3′]bithiophenyl-4′-carboxylic acid ethyl ester (1.7 g, 3.7 mmol, Example 222 d) in THF : DMF (1:1, 18.5 ml) under N2 at 0° C. was added NaH (95%, 442 mg, 18.5 mmol). The suspension was allowed to warm to rt with stirring overnight. The reaction was quenched with H2O. The mixture was placed in a separatory funnel, overwhelmed with H2O and extracted with EtOAc. Most of the color is removed with this washing step. The aqueous layer was acidified with 6 M HCl and a solid ppt out which was collected by filtration to give 4-hydroxy-3-(5-iodo-4-methylthien-2-yl)-6-oxo-6,7-dihydrothieno[2,3-b]pyridine-5-carbonitrile (880 mg, 2.1 mmol, 58%); MS (ESI) m/z 415.0 (M+H+); 1H NMR (300 MHz, DMSO-d6) δ ppm 7.32 (s, 1H), 7.04 (s, 1H), 6.86 (s, 1H), 2.13 (s, 3H).
Reaction SMILES: [C:1]1([CH:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[CH2:27]([O:34][C:35]1[CH:40]=[CH:39][C:38]([C:41](=[O:44])[CH2:42]Br)=[CH:37][CH:36]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>C(OCC)(=O)C>[CH2:27]([O:34][C:35]1[CH:36]=[CH:37][C:38]([C:41](=[O:44])[CH2:42][N:11]2[CH2:10][CH2:9][N:8]([CH:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:13][CH2:12]2)=[CH:39][CH:40]=1)[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: O=C(CBr)c1ccc(OCc2ccccc2)cc1
Reactant: c1ccc(C(c2ccccc2)N2CCNCC2)cc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: O=C(CN1CCN(C(c2ccccc2)c2ccccc2)CC1)c1ccc(OCc2ccccc2)cc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 87.4 %

Procedure:
To 90 ml of an ethyl acetate solution containing 7.56 g (30 mmol) of 1-diphenylmethylpiperazine and 3.33 g (33 mmol) of triethylamine was added 9.15 g (30 mmol) of p-benzyloxy-α-bromoacetophenone. The resultant mixture was stirred at room temperature for 45 minutes. After addition of 100 ml of ice water, the thus obtained mixture was stirred for about 10 minutes. Precipitated crystals were collected by filtration and then washed successively with water, ethanol and ethyl acetate and thereafter dried to give 12.5 g of 1-(4-benzyloxyphenyl)-2-(4-diphenylmethylpiperazinyl)ethanone (yield: 87.4%).
Reaction SMILES: [S-2:1].[Na+].[Na+].[S].Cl[C:6]1[CH:15]=[CH:14][C:9]([C:10]([O:12][CH3:13])=[O:11])=[CH:8][C:7]=1[N+:16]([O-:18])=[O:17]>CO.O.CO>[N+:16]([C:7]1[CH:8]=[C:9]([CH:14]=[CH:15][C:6]=1[S:1][S:1][C:6]1[CH:15]=[CH:14][C:9]([C:10]([O:12][CH3:13])=[O:11])=[CH:8][C:7]=1[N+:16]([O-:18])=[O:17])[C:10]([O:12][CH3:13])=[O:11])([O-:18])=[O:17]
Reactant: [S-2]
Reactant: COC(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Agent: [Na+]
Agent: [S]
Solvent: CO
Solvent: O
Product: COC(=O)c1ccc(SSc2ccc(C(=O)OC)cc2[N+](=O)[O-])c([N+](=O)[O-])c1
Reaction time: 0.25 h
Yield: 65 %

Procedure:
A solution of sodium sulfide.nanohydrate (1.15 g, 4.9 mmol) in methanol-water (ca. 10 mL, 1:1) is warmed on a hot plate. To this solution is added elemental sulfur (150 mg, 4.6 mmol). Heating is continued for 15 min before the solution is poured into a separate solution of 1.0 g (4.6 mmol) of methyl 4-chloro-3-nitrobenzoate (see: Kuene, J. Am. Chem. Soc. 1962, 48, 837.) in MeOH (5.0 mL). The mixture is stirred for 30 min, followed by cooling in a refrigerator overnight. The solid precipitate is filtered, washed with water and methanol, and dried in vacuo at 50° C. to afford 650 mg (65%) of dimethyl 4,4′-dithio-bis-(3-nitrobenzoate) as a yellow solid: 1H NMR (400 MHz, CDCl3) δ 9.0, 8.2, 7.9, 4.0.
Reaction SMILES: [CH3:1][N:2]1[C:11](=[O:12])[CH:10]=[C:9]2[C:4]([CH:5]=[CH:6][CH:7]=[CH:8]2)=[CH:3]1.C1C=CC(CC(Cl)=[O:21])=CC=1>>[CH:3]([N:2]([CH3:1])[C:11](=[O:12])[CH2:10][C:9]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1)=[O:21]
Reactant: O=C(Cl)Cc1ccccc1
Reactant: Cn1cc2ccccc2cc1=O
Product: CN(C=O)C(=O)Cc1ccccc1

Procedure:
In this case, the yield of N-methyl-2H-3-isoquinolone, with a melting point of 235°-236°C., calculated upon the amount of phenacetyl chloride used, reaches 40- 45%.
Reaction SMILES: [CH3:1][C:2]1([C:7]2[O:11][C:10]([CH2:12][N:13]3[CH:17]=[CH:16][C:15]([NH2:18])=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[CH3:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[O:31][C:30]([CH3:32])=[N:29][C:28]=2[C:33](O)=[O:34])=[CH:23][CH:22]=1>>[C:2]([C:7]1[O:11][C:10]([CH2:12][N:13]2[CH:17]=[CH:16][C:15]([NH:18][C:33]([C:28]3[N:29]=[C:30]([CH3:32])[O:31][C:27]=3[C:24]3[CH:25]=[CH:26][C:21]([O:20][CH3:19])=[CH:22][CH:23]=3)=[O:34])=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: CC1(c2ccc(Cn3ccc(N)n3)o2)OCCO1
Reactant: COc1ccc(-c2oc(C)nc2C(=O)O)cc1
Product: COc1ccc(-c2oc(C)nc2C(=O)Nc2ccn(Cc3ccc(C(C)=O)o3)n2)cc1

Procedure:
Following general procedure B followed by either C or D, starting from 1-[5-(2-methyl-[1,3]dioxolan-2-yl)-furan-2-ylmethyl]-1H-pyrazol-3-ylamine and 5-(4-methoxy-phenyl)-2-methyl-oxazole-4-carboxylic acid.