Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([F:11])[C:5]([CH2:9]Br)=[C:6]([F:8])[CH:7]=1.[C-:12]#[N:13].[K+]>CN(C=O)C.O>[Br:1][C:2]1[CH:3]=[C:4]([F:11])[C:5]([CH2:9][C:12]#[N:13])=[C:6]([F:8])[CH:7]=1
Reactant: [C-]#N
Reactant: Fc1cc(Br)cc(F)c1CBr
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: N#CCc1c(F)cc(Br)cc1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 45.9 %

Procedure:
To a solution of 5-bromo-2-(bromomethyl)-1,3-difluorobenzene (1.6 g, 5.60 mmol) in DMF (20 mL) was added KCN (0.401 g, 6.16 mmol). The resulting mixture was stirred at 25° C. for 16 h. The mixture was dissolved in H2O (50 mL) and extracted by EA (50 mL). The organic layer was dried over Na2SO4, filtered and concentrated. The crude material was purified by silica column chromatography (PE/EA=3/1) to yield a white solid of 2-(4-bromo-2,6-difluorophenyl)acetonitrile (1.1 g, 2.57 mmol, 45.9% yield): 1H NMR (400 MHz, CD3OD) δ 7.39-7.36 (m, 2H), 3.89 (s, 2H).
Reaction SMILES: CS(O)(=O)=O.C([N:13]1[CH2:18][CH2:17][C:16]([C:24]2(O)[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:15][CH2:14]1)(OC(C)(C)C)=O.[OH-].[Na+]>O>[O:27]1[CH2:28][CH2:29][C:24]([C:16]2([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:15][CH2:14][NH:13][CH2:18][CH2:17]2)=[CH:25][CH2:26]1
Reactant: CCOC(=O)C1(C2(O)CCOCC2)CCN(C(=O)OC(C)(C)C)CC1
Agent: CS(=O)(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCOC(=O)C1(C2=CCOCC2)CCNCC1
Temperature: 60 °C
Reaction time: 8 h
Yield: 65.7 %

Procedure:
Methanesulfonic acid (1.48 gm; 15.4 mmol) was add to the alcohol of Step A (1.07 gm; 2.99 mmol) in TMF at 0° C. The reaction mixture was then warmed to 60° C. and stirred overnight. Water was added and 1N NaOH was added until mixture turned to basic. The aqueous layer was extracted with ethyl acetate (3×100 mL). The organic layer was washed with brine and then dried over magnesium sulfate, filtered and then concentrated to give 0.47 gm of the title compound.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:22])[NH:10][C@H:11]([C:15](=[O:21])[NH:16][CH2:17][CH2:18][CH:19]=O)[C@@H:12]([OH:14])[CH3:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:23][C@@H:24]([C@@H:32]([C@@H:34]1[C@@H:38]([O:39][Si:40]([C:43]([CH3:46])([CH3:45])[CH3:44])([CH3:42])[CH3:41])[C@@H:37]([O:47][Si:48]([C:51]([CH3:54])([CH3:53])[CH3:52])([CH3:50])[CH3:49])[C@H:36]([N:55]2[CH:60]=[CH:59][C:58](=[O:61])[N:57]([CH2:62][C:63]3[CH:68]=[CH:67][C:66]([O:69][CH3:70])=[CH:65][CH:64]=3)[C:56]2=[O:71])[O:35]1)[OH:33])[C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(O)(=O)C.O1CCCC1>[Si:40]([O:39][C@H:38]1[C@@H:37]([O:47][Si:48]([C:51]([CH3:53])([CH3:54])[CH3:52])([CH3:49])[CH3:50])[C@H:36]([N:55]2[CH:60]=[CH:59][C:58](=[O:61])[N:57]([CH2:62][C:63]3[CH:68]=[CH:67][C:66]([O:69][CH3:70])=[CH:65][CH:64]=3)[C:56]2=[O:71])[O:35][CH:34]1[C@@H:32]([OH:33])[C@@H:24]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[NH:23][CH2:19][CH2:18][CH2:17][NH:16][C:15](=[O:21])[C@H:11]([C@@H:12]([OH:14])[CH3:13])[NH:10][C:9](=[O:22])[O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)([C:43]([CH3:44])([CH3:45])[CH3:46])([CH3:42])[CH3:41]
Reactant: COc1ccc(Cn2c(=O)ccn([C@@H]3O[C@H]([C@@H](O)[C@H](N)C(=O)OC(C)(C)C)[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]3O[Si](C)(C)C(C)(C)C)c2=O)cc1
Reactant: C[C@H](O)[C@H](NC(=O)OCc1ccccc1)C(=O)NCCC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: COc1ccc(Cn2c(=O)ccn([C@@H]3OC([C@@H](O)[C@H](NCCCNC(=O)[C@@H](NC(=O)OCc4ccccc4)[C@H](C)O)C(=O)OC(C)(C)C)[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]3O[Si](C)(C)C(C)(C)C)c2=O)cc1
Yield: 33.1 %

Procedure:
By using an analogous procedure to that described in Example 1, a solution of [(1S,2S)-2-hydroxy-1-(3-oxo-propylcarbamoyl)-propyl]-carbamic acid benzyl ester (99 mg, 0.32 mmol, obtained from Reference Example 18), tert-butyl (2S,3S)-2-amino-3-[(2R,3R,4R,5R)-3,4-bis{[tert-butyl-(dimethyl)silyl]oxy}-5-(3-(4-methoxybenzyl)-2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl)-tetrahydro-2-furanyl]-3-hydroxypropanoate (165 mg, 0.229 mmol, obtained from Reference example 5), acetic acid (4 drops) and sodium triacetoxyborohydride (97 mg, 0.457 mmol) in anhydrous tetrahydrofuran (4 ml) was stirred at room temperature under nitrogen for 4 hours. The residue was chromatographed (flash column, silica gel, 5% methanol in methylene chloride) to provide tert-butyl (5S,12S)-12-[(S)-[(3R,4R,5R)-3,4-bis{[tert-butyl(dimethyl)silyl]oxy}-5-(3-(4-methoxybenzyl)-2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl)tetrahydro-2-furanyl](hydroxy)methyl]-5-[(1S)-1-hydroxyethyl]-3,6-dioxo-1-phenyl-2-oxa-4,7,11-triazatridecan-13-oate (77 mg, 33%) as a white amorphous solid.
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH2:7]O)=[CH:5][C:4]([N+:9]([O-:11])=[O:10])=[N:3]1.P(Br)(Br)[Br:13]>C(Cl)(Cl)Cl>[Br:13][CH2:7][C:6]1[N:2]([CH3:1])[N:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=1
Reactant: Cn1nc([N+](=O)[O-])cc1CO
Reactant: BrP(Br)Br
Solvent: ClC(Cl)Cl
Product: Cn1nc([N+](=O)[O-])cc1CBr
Temperature: 0 °C
Yield: 99.7 %

Procedure:
A 25-mL round-bottomed flask equipped with a magnetic stirrer and reflux condenser was purged with nitrogen and charged with 156c (0.56 g, 3.6 mmol) and chloroform (10 mL). The reaction was cooled to 0° C. using an ice bath and phosphorous tribromide (0.98 g, 3.6 mmol) was added dropwise. The cooling bath was removed and the reaction stirred at reflux for 3 h. After this time, the reaction was cooled to 0° C. and diluted with methylene chloride (25 mL). Saturated aqueous sodium bicarbonate was added until a pH of 8.5 was reached. The layers were separated, and the aqueous layer was extracted with methylene chloride (3×25 mL). The combined organic layers were washed with brine (30 mL), dried over sodium sulfate and concentrated under reduced pressure to afford a quantitative yield (0.79 g) of 156d as an off-white solid: MS (ESI+) m/z 222.1 (M+H).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH2:11][C:12]([OH:14])=O)=[CH:3]1.Cl.[NH2:16][C:17]([NH:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][NH:28][C:29](=[O:42])[C@@H:30]([CH2:32][CH2:33][CH2:34][NH:35][C:36]([NH2:41])=[N:37][N+:38]([O-:40])=[O:39])[NH2:31])=[CH:23][CH:22]=1)=[O:18].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>>[NH2:16][C:17]([NH:19][CH2:20][C:21]1[CH:22]=[CH:23][C:24]([CH2:27][NH:28][C:29](=[O:42])[C@@H:30]([CH2:32][CH2:33][CH2:34][NH:35][C:36]([NH2:41])=[N:37][N+:38]([O-:40])=[O:39])[NH:31][C:12](=[O:14])[CH2:11][C:4]2[C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[N:2]([CH3:1])[CH:3]=2)=[CH:25][CH:26]=1)=[O:18]
Reactant: NC(=O)NCc1ccc(CNC(=O)[C@H](N)CCCNC(N)=N[N+](=O)[O-])cc1
Reactant: Cn1cc(CC(=O)O)c2ccccc21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Product: Cn1cc(CC(=O)N[C@H](CCCNC(N)=N[N+](=O)[O-])C(=O)NCc2ccc(CNC(N)=O)cc2)c2ccccc21
Yield: 34 %

Procedure:
Prepared analogously to Example 69a) from 1-methyl-1H-indole-3-acetic acid, (R)-N-[[4-(aminocarbonylaminomethyl)phenyl]methyl]-N5 -[amino(nitroimino)methyl]-ornithinamide-hydrochloride and TBTU in a yield of 34% of theory. Colourless, amorphous substance, which was used in the following step without purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:15]=[CH:14][C:6]2[NH:7][C:8](=[O:13])[NH:9][S:10](=[O:12])(=[O:11])[C:5]=2[CH:4]=1.[H-].[Na+].[Na].[Br:19][CH2:20][CH2:21][CH2:22]Br>CN(C=O)C>[Br:19][CH2:20][CH2:21][CH2:22][N:9]1[C:8](=[O:13])[NH:7][C:6]2[CH:14]=[CH:15][C:3]([O:2][CH3:1])=[CH:4][C:5]=2[S:10]1(=[O:12])=[O:11]
Reactant: BrCCCBr
Reactant: COc1ccc2c(c1)S(=O)(=O)NC(=O)N2
Agent: [H-]
Agent: [Na+]
Agent: [Na]
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)S(=O)(=O)N(CCCBr)C(=O)N2
Temperature: 80 °C
Reaction time: 0.25 h

Procedure:
0.03 mol of 7-methoxy-1,2,4-benzothiadiazin-3(4H)one 1,1-dioxide is dissolved in 50 ml of absolute DMF, and 0.03 mol of sodium hydride is added. After 15 minutes, formation of the sodium salt was complete. Then 0.06 mol of 1,3-dibromopropane is added dropwise and the mixture is heated at 80° C. for 2 hours. The solvent is then distilled out and the residue is purified by column chromatography on silica gel. The eluting agent used was a mixture of CH2Cl2CH3OH (98:2).
Reaction SMILES: [Cl:1][C:2]([Cl:12])=[CH:3][C@H:4]1[C@H:6]([C:7](Cl)=[O:8])[C:5]1([CH3:11])[CH3:10].[C:13]1([C:19]2[CH:27]=[CH:26][CH:25]=[C:24]3[C:20]=2[CH2:21][CH:22]([OH:28])[CH2:23]3)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.N1C=CC=CC=1>C1(C)C=CC=CC=1>[Cl:1][C:2]([Cl:12])=[CH:3][C@H:4]1[C@H:6]([C:7]([O:28][CH:22]2[CH2:21][C:20]3[C:24](=[CH:25][CH:26]=[CH:27][C:19]=3[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:23]2)=[O:8])[C:5]1([CH3:11])[CH3:10]
Reactant: CC1(C)[C@@H](C=C(Cl)Cl)[C@@H]1C(=O)Cl
Reactant: OC1Cc2cccc(-c3ccccc3)c2C1
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: CC1(C)[C@@H](C=C(Cl)Cl)[C@@H]1C(=O)OC1Cc2cccc(-c3ccccc3)c2C1

Procedure:
In a manner similar to Example 12A, the reaction of 0.41 g (0.0018 mole) of (±)-trans-3-(2,2-dichloroethenyl)-2,2-dimethylcyclopropanecarbonyl chloride with 0.37 g (0.0018 mole) of (+)-4-phenyl-2-indanol (EE 50%), 0.16 g (0.002 mole) of pyridine and toluene gave (+)-4-phenyl-2-indanyl (±)-trans-3-(2,2-dichloroethenyl)-2,2-dimethylcyclopropanecarboxylate, EE 50% (alcohol moiety). The nmr and ir spectra were consistent with the proposed structure.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([N:8]([CH3:28])[C:9](=[O:27])[C:10]([C:13]2[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=[C:15]([C:23]([F:26])([F:25])[F:24])[CH:14]=2)([CH3:12])[CH3:11])=[C:4]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[CH3:35])[CH:3]=1.C(N(C(C)C)C(C)C)C.[C:45](OC(=O)C)(=[O:47])[CH3:46]>ClCCl>[C:45]([NH:1][C:2]1[N:7]=[CH:6][C:5]([N:8]([CH3:28])[C:9](=[O:27])[C:10]([C:13]2[CH:14]=[C:15]([C:23]([F:26])([F:24])[F:25])[CH:16]=[C:17]([C:19]([F:20])([F:21])[F:22])[CH:18]=2)([CH3:12])[CH3:11])=[C:4]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[CH3:35])[CH:3]=1)(=[O:47])[CH3:46]
Reactant: Cc1ccccc1-c1cc(N)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)Nc1cc(-c2ccccc2C)c(N(C)C(=O)C(C)(C)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)cn1
Reaction time: 8 h
Yield: 93 %

Procedure:
To a solution of 100 mg (0.20 mmol) N-(6-amino-4-o-tolyl-pyridin-3-yl)-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramide in 3 ml dichloromethane were added 27 mg (0.21 mmol) N-ethyldiisopropylamine and 70 mg (0.69 mmol) acetic anhydride. After stirring overnight, the solvent was evaporated and the residue was purified by flash-chromatography to give 100 mg (92%) of the title compound as white solid. MS m/e (%): 537 (M+, 68), 282 (100).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:30])[CH:5]([C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[C:15]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:14]=1)C(OC(C)(C)C)=O)[CH3:2]>C(O)=O>[CH2:1]([O:3][C:4](=[O:30])[CH2:5][C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[C:15]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:14]=1)[CH3:2]
Reactant: CCOC(=O)C(C(=O)OC(C)(C)C)c1ccc([N+](=O)[O-])c(OCc2ccccc2)c1
Solvent: O=CO
Product: CCOC(=O)Cc1ccc([N+](=O)[O-])c(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
2-(3-Benzyloxy-4-nitrophenyl)-malonic acid tert-butyl ester ethyl ester (5.00 g, 12.0 mmol) is suspended in formic acid (60 mL) and stirred at RT for 18 h. The solvent is removed under reduced pressure and the residue taken up in EtOAc (100 mL). The organic solution is extracted with saturated NaHCO3 (2×50 mL) and brine (30 mL), before being dried over Na2SO4 and concentrated to an oil. Purification by flash column (10-15% EtOAc/hexanes) affords (3-benzyloxy-4-nitrophenyl)-acetic acid ethyl ester as a yellow oil: MS (M+H)+=316.
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([OH:24])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:27])[F:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:29][CH:30]([F:40])[O:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[CH2:38]O>>[CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH2:38][C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=3[O:31][CH:30]([F:29])[F:40])[CH:19]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:26])[F:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Oc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Reactant: OCc1ccccc1OC(F)F
Product: FC(F)Oc1ccccc1COc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1

Procedure:
This compound was prepared according to the procedure of example 69, substituting 3-(3-benzyl-8-trifluoromethyl-quinolin-4-yl)-phenol and (2-difluoromethoxy-phenyl)-methanol. MS (ESI) m/z 535.
Reaction SMILES: C1COCC1.[H-].[Na+].[C:8]([O:12][CH3:13])(=[O:11])[CH2:9][OH:10].[F:14][C:15]1[CH:20]=[C:19](F)[C:18]([N+:22]([O-:24])=[O:23])=[CH:17][C:16]=1[C:25]1[C:26](=[O:36])[N:27]([CH3:35])[C:28]([C:31]([F:34])([F:33])[F:32])=[CH:29][CH:30]=1>O>[F:14][C:15]1[CH:20]=[C:19]([O:10][CH2:9][C:8]([O:12][CH3:13])=[O:11])[C:18]([N+:22]([O-:24])=[O:23])=[CH:17][C:16]=1[C:25]1[C:26](=[O:36])[N:27]([CH3:35])[C:28]([C:31]([F:32])([F:33])[F:34])=[CH:29][CH:30]=1
Reactant: COC(=O)CO
Reactant: Cn1c(C(F)(F)F)ccc(-c2cc([N+](=O)[O-])c(F)cc2F)c1=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)COc1cc(F)c(-c2ccc(C(F)(F)F)n(C)c2=O)cc1[N+](=O)[O-]
Reaction time: 0.25 h
Yield: 64.7 %

Procedure:
To 20 ml of THF, 0.24 g (60 mmol) of 60% sodium hydride was suspended under cooling with ice, and 0.32 g (6.6 mmol) of methyl glycolate, was added thereto, followed by stirring for 15 minutes. To this mixture, 2 g (6.0 mmol) of 3-(2,4-difluoro-5-nitrophenyl)-1-methyl-6-trifluormethyl-2(1H)-pyridone was added, followed by stirring at room temperature for 3 hours. The product was poured into water and extracted with ethyl acetate. After washing with water, the organic layer was dried over anhydrous magnesium sulfate. After distilling off ethyl acetate under reduced pressure, the obtained residue was purified by silica gel column chromatography to obtain 1.57 g (yield: 65%) of the desired product. 1H-NMR (400 MHz, CDCl3) δ value: 3.70(3H,s), 3.84(3H,s), 4.81(2H,s), 6.76(1H,d), 6.78(1H,d), 7.53(1H,d), 8.26(1H,d)ppm.
Reaction SMILES: [CH2:1]([C:12]#[N:13])[C:2]1[CH:11]=[CH:10][C:7]([O:8][CH3:9])=[C:4]([O:5][CH3:6])[CH:3]=1.CN>[Ni]>[CH2:12]([NH2:13])[CH2:1][C:2]1[CH:11]=[CH:10][C:7]([O:8][CH3:9])=[C:4]([O:5][CH3:6])[CH:3]=1
Reactant: COc1ccc(CC#N)cc1OC
Agent: [Ni]
Agent: CN
Product: COc1ccc(CCN)cc1OC

Procedure:
DE-A-33 38 681 discloses the catalytic hydrogenation of veratryl cyanide with a ten-fold molar excess of methylamine on a nickel catalyst. Homoveratrylamine is obtained as byproduct with more than 3% selectivity and has to be removed by adding benzaldehyde.
Reaction SMILES: I([O-])(=O)(=O)=[O:2].[Na+].[CH3:7][O:8][C:9]([C:11]1[CH:12]=[C:13]2[CH:19]=[C:18]([C:20]([C:27]3[CH:28]=[N:29][C:30]([S:33][CH3:34])=[CH:31][CH:32]=3)=[CH:21][CH:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)[N:17]([S:35]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)(=[O:37])=[O:36])[C:14]2=[N:15][CH:16]=1)=[O:10]>O.CO>[CH3:7][O:8][C:9]([C:11]1[CH:12]=[C:13]2[CH:19]=[C:18]([C:20]([C:27]3[CH:28]=[N:29][C:30]([S:33]([CH3:34])=[O:2])=[CH:31][CH:32]=3)=[CH:21][CH:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)[N:17]([S:35]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)(=[O:37])=[O:36])[C:14]2=[N:15][CH:16]=1)=[O:10]
Reactant: COC(=O)c1cnc2c(c1)cc(C(=CC1CCCC1)c1ccc(SC)nc1)n2S(=O)(=O)c1ccccc1
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COC(=O)c1cnc2c(c1)cc(C(=CC1CCCC1)c1ccc(S(C)=O)nc1)n2S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 60 h
Yield: 97.8 %

Procedure:
To a mixture of sodium metaperiodate (360 mg, 1.69 mmol) in water (10 ml) was added a solution of 1-benzenesulfonyl-2-[2-cyclopentyl-1-(6-methylsulfanyl-pyridin-3-yl)-vinyl]-1H-pyrrolo[2,3-b]pyridin-5-carboxylic acid methyl ester (300 mg, 0.56 mmol) in methanol (40 ml). The reaction mixture was stirred at 25° C. for 60 h. The suspension was filtered. The filtrate was concentrated and extracted with ethyl acetate (2×30 mL). The combined organic extracts were washed with water (2×20 mL), dried over anhydrous sodium sulfate and then concentrated in vacuo to afford 1-benzenesulfonyl-2-[2-cyclopentyl-1-(6-methanesulfinyl-pyridin-3-yl)-vinyl]-1H-pyrrolo[2,3-b]pyridin-5-carboxylic acid methyl ester (301 mg, 97%) as a solid which was used in the next step without further purification: LC/MS m/e calcd for C28H27N3O5S2 [M+H]+ 550.67, observed 549.9.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH3:12])[CH:6]=1)[OH:4].O=[C:14]([CH3:28])[CH2:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][C:24]([O:26][CH3:27])=[O:25])=[CH:19][CH:18]=1.C1C=CC=CC=1.C([BH3-])#N.[Na+]>CO>[CH3:27][O:26][C:24]([CH2:23][C:20]1[CH:19]=[CH:18][C:17]([O:16][CH2:15][CH:14]([NH:1][CH2:2][CH:3]([C:5]2[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH3:12])[CH:6]=2)[OH:4])[CH3:28])=[CH:22][CH:21]=1)=[O:25]
Reactant: COC(=O)Cc1ccc(OCC(C)=O)cc1
Reactant: COc1cccc(C(O)CN)c1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: c1ccccc1
Product: COC(=O)Cc1ccc(OCC(C)NCC(O)c2cccc(OC)c2)cc1
Yield: 55.7 %

Procedure:
Following a procedure similar to that described in Example 3, but using 2.5 g of 2-amino-1-(3-methoxyphenyl)ethanol (prepared as described in Preparation 43), 4.0 g of methyl 4-(2-oxopropoxy)phenylacetate (prepared as described in Preparation 3), 80 ml of benzene, 60 ml of absolute methanol and 2.75 g of sodium cyanoborohydride, and then purifying the reaction product by column chromatography through silica gel, using ethyl acetate as the eluent, 3.11 g of the title compound were obtained having an Rf=0.21 (thin layer chromatography over silica gel, using ethyl acetate as the developing solvent).
Reaction SMILES: [OH:1][CH:2]1[CH2:6][N:5]([S:7]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)(=[O:9])=[O:8])[C@@H:4]([CH2:17][OH:18])[CH2:3]1.[C:19]1([CH3:29])[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1.Cl>N1C=CC=CC=1>[C:13]1([CH3:16])[CH:14]=[CH:15][C:10]([S:7]([N:5]2[CH2:6][C@@H:2]([O:1][S:25]([C:22]3[CH:23]=[CH:24][C:19]([CH3:29])=[CH:20][CH:21]=3)(=[O:27])=[O:26])[CH2:3][C@@H:4]2[CH2:17][O:18][S:7]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)(=[O:9])=[O:8])(=[O:9])=[O:8])=[CH:11][CH:12]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Cc1ccc(S(=O)(=O)N2CC(O)C[C@@H]2CO)cc1
Agent: Cl
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OC[C@H]2C[C@H](OS(=O)(=O)c3ccc(C)cc3)CN2S(=O)(=O)c2ccc(C)cc2)cc1
Temperature: 10 °C
Reaction time: 2 h
Yield: 86 %

Procedure:
To an ice-cold solution of 219.2 g (0.808 mole) of 2R, 4S-1-(4-toluenesulfonyl)-2-hydroxymethyl-4-hydroxy-pyrrolidine (6) in 1 L of pyridine were added 539.2 g (2.828 mole) of 4-toluenesulfonyl chloride in one portion. The temperature rose to 50° C. The mixture was cooled at 10° C. and kept for 2 hours at this temperature and then at room temperature overnight. The mixture was pured into 5 L of 2.4N hydrochloric acid. After cooling, a precipitate was collected, washed with cold water, dried under reduced pressure. This presicpitate was taken up with 1 L of ethanol, filtered and washed with cold ethanol, dried under reduce pressure to give 406 g (86%) of the titled compound. M.P. =134° C. [α]D =+57.13° (c=1.9, acetone).
Reaction SMILES: [CH3:1][C:2]1[NH:7][C:6](=O)[C:5]([CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:4]([C:16]([F:19])([F:18])[F:17])[N:3]=1.C(N(CC)C1C=CC=CC=1)C.O=P(Cl)(Cl)[Cl:33]>>[Cl:33][C:6]1[C:5]([CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:4]([C:16]([F:19])([F:18])[F:17])[N:3]=[C:2]([CH3:1])[N:7]=1
Reactant: CCOC(=O)CCc1c(C(F)(F)F)nc(C)[nH]c1=O
Reactant: O=P(Cl)(Cl)Cl
Solvent: CCN(CC)c1ccccc1
Product: CCOC(=O)CCc1c(Cl)nc(C)nc1C(F)(F)F

Procedure:
A mixture of ethyl 3-(2-methyl-6-trifluoromethyl-3H-pyrimidin-4-on-5-yl)propionate (0.61 g, 2.20 mmol), N,N-diethylaniline (0.33 g, 2.2 mmol), and POCl3 (8 mL) was heated under reflux for 2 h. The mixture was concentrated, poured onto ice, and extracted with ether. The combined extracts were dried (MgSO4) and concentrated to give 0.65 g of product as a brown oil.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:9]=[C:8]([CH2:10][CH2:11][OH:12])[S:7][C:6]=2[CH:13]=1.[CH3:14][S:15](Cl)(=[O:17])=[O:16].CCN(C(C)C)C(C)C>ClCCl>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:9]=[C:8]([CH2:10][CH2:11][O:12][S:15]([CH3:14])(=[O:17])=[O:16])[S:7][C:6]=2[CH:13]=1
Reactant: CS(=O)(=O)Cl
Reactant: Cc1ccc2cc(CCO)sc2c1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc2cc(CCOS(C)(=O)=O)sc2c1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a cooled (0° C.) solution of 2-(6-methyl-benzo[b]thiophen-2-yl)-ethanol (3.22 g, 16.8) mmol) in dichloromethane (100 mL), methanesulfonylchloride (1.56 mL, 20.1 mmol) and DIEA (5.96 mL, 33.5 mmol) were added. The mixture was stirred for 15 min at 0° C. and then allowed to reach room temperature and stirred for an additional 2.5 hrs. It was washed with sat. NaHCO3 (2×) and brine (1×), dried (Na2SO4), filtered and concentrated in vacuo. Methanesulfonic acid 2-(6-methyl-benzo[b]thiophen-2-yl)-ethyl ester was obtained as a solid and used without further purification.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]2[CH:14]=[N:15][N:16]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH:17]=2)[N:3]=1.[C:25]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[CH:33]([CH3:37])[C:34]([NH2:36])=[O:35])#[CH:26].F[B-](F)(F)F.CCN(C(C)C)C(C)C>O1CCOCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[NH2:36][C:34](=[O:35])[CH:33]([C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=1[C:25]#[C:26][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]2[CH:14]=[N:15][N:16]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH:17]=2)[N:3]=1)[CH3:37]
Reactant: CC(C)(C)OC(=O)n1cc(Nc2ncc(C(F)(F)F)c(Cl)n2)cn1
Reactant: C#Cc1ccccc1C(C)C(N)=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: F[B-](F)(F)F
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C(N)=O)c1ccccc1C#Cc1nc(Nc2cnn(C(=O)OC(C)(C)C)c2)ncc1C(F)(F)F

Procedure:
A degassed mixture of tert-butyl 4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)-1H-pyrazole-1-carboxylate A61 (0.373 g, 1.03 mmol), 2-(2-ethynylphenyl)propanamide K7 (0.452 g, 2.40 mmol), PdCl2(PPh3)2 (0.015 g, 0.02 mmol), t-Bu3PH.BF4 (0.011 g, 0.038 mmol) and CuI (0.007 g, 0.04 mmol) in 1,4-dioxane (6.0 mL) and DIPEA (0.90 mL, 5.2 mmol) was heated in the microwave at 100° C. for 30 minutes. The mixture was concentrated under reduced pressure and purified using silica gel column chromatography (0-100% EtOAc in petroleum benzine 40-60° C.) to give the title compound A62 (0.309 g, 58%). LCMS-D: rt 3.533 min; m/z 502.2 499.2 [M−H]−.
Reaction SMILES: Cl[C:2]1[C:11]([C:12]#[N:13])=[C:10]([Cl:14])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.C([O-])(=[O:17])C.[NH4+]>C(O)(=O)C>[Cl:14][C:10]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[NH:3][C:2](=[O:17])[C:11]=1[C:12]#[N:13]
Reactant: N#Cc1c(Cl)nc2ccccc2c1Cl
Reactant: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Product: N#Cc1c(Cl)c2ccccc2[nH]c1=O
Temperature: 25 °C
Yield: 76.6 %

Procedure:
2,4-dichloroquinoline-3-carbonitrile (Example 72a) (0.95 g, 4.26 mmol) and ammonium acetate (0.36 g, 4.67 mmol) were heated in acetic acid (20 mL) at 140° C. for 4 hours, then cooled to room temperature. The reaction was poured into ice water (400 mL), and the resultant precipitate was collected by filtration to give 4-chloro-2-oxo-1,2-dihydroquinoline-3-carbonitrile (0.668 g, 77%) as a light yellow solid. M.p.: >250° C. 1H NMR (400 MHz, DMSO-d6) δ 7.42 (m, 2H), 7.79 (m, 1H), 7.96 (d, J=8.4 Hz, 1H), 12.72 (s, 1H). MS 205 (MH+).