Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:8]2[CH:17]=[C:16]3[C:11]([CH2:12][CH2:13][C:14](=S)[N:15]3[CH:18]([CH3:24])[C:19](OCC)=[O:20])=[CH:10][CH:9]=2)[C:4]([CH3:7])=[CH:5][CH:6]=1.O.[NH2:27][NH2:28]>CCO>[CH3:7][C:4]1[N:3]([C:8]2[CH:17]=[C:16]3[C:11]([CH2:12][CH2:13][C:14]4[N:15]3[CH:18]([CH3:24])[C:19](=[O:20])[NH:27][N:28]=4)=[CH:10][CH:9]=2)[C:2]([CH3:1])=[CH:6][CH:5]=1
Reactant: CCOC(=O)C(C)N1C(=S)CCc2ccc(-n3c(C)ccc3C)cc21
Reactant: NN
Solvent: O
Solvent: CCO
Product: Cc1ccc(C)n1-c1ccc2c(c1)N1C(=NNC(=O)C1C)CC2
Temperature: 25 °C
Yield: 81 %

Procedure:
To a solution of ethyl 2-(7-(2,5-dimethyl-1H-pyrrol-1-yl)-2-thioxo-3,4-dihydroquinolin-1(2H)-yl)propanoate (0.2 g, 0.561 mmol) in EtOH (10 mL) was added hydrazine hydrate (6 mL) and the solution was heated to reflux overnight. The reaction mixture was cooled to ambient temperature and the solvent was removed in vacuo. Water (10 mL) was added to the residue and the mixture was extracted with EtOAc (2×30 mL). The combined organic layer was dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel (eluting with 30-50% EtOAc in petroleum ether) to give 9-(2,5-dimethyl-1H-pyrrol-1-yl)-1-methyl-5,6-dihydro-1H-[1,2,4]-triazino[4,3-a]quinolin-2(3H)-one (0.14 g, 81%). 1H NMR (CDCl3, 400 MHz): δ 8.04 (brs, 1H), 7.21 (d, J=8.0 Hz, 1H), 6.82 (d, J=8.0 Hz, 1H), 6.73 (s, 1H), 5.89 (s, 2H), 4.56 (q, J=6.8 Hz, 1H), 2.93 (m, 2H), 2.63 (m, 2H), 2.05 (s, 6H), 1.42 (d, J=6.8 Hz, 3H).
Reaction SMILES: [OH:1][C:2]([CH3:18])([CH3:17])[CH2:3][N:4]1[CH2:9][CH2:8][N:7](C(OCCCC)=O)[CH2:6][CH2:5]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:18][C:2]([OH:1])([CH3:17])[CH2:3][N:4]1[CH2:5][CH2:6][NH:7][CH2:8][CH2:9]1
Reactant: CCCCOC(=O)N1CCN(CC(C)(C)O)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(O)CN1CCNCC1
Reaction time: 0.17 h
Yield: 60.1 %

Procedure:
A solution of 563 (460 mg, 1.78 mmol) and TFA (5 ml) in DCM (20 ml) was stirred at rt for 5 h. The reaction mixture was concentrated (azeotropes with DCM), diluted with water, stirred for 10 min. The pH was adjusted to around 10 with 1N NaOH, and the alkaline solution was extracted with DCM. The organic extract was dried over anhydrous magnesium sulfate, filtered, concentrated under high vacuum to afford the desired product 564 (170 mg, 1.07 mmol, 60% yield) as a dark orange sticky solid. The crude product was used in the next step without any further purification. MS (m/z): 159.13 (M+H).
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[Cl:9][C:10]1[N:15]=[C:14]([S:16]([CH3:18])=[O:17])[N:13]=[C:12]([NH2:19])[CH:11]=1>CN(C=O)C>[Br:1][C:11]1[C:12]([NH2:19])=[N:13][C:14]([S:16]([CH3:18])=[O:17])=[N:15][C:10]=1[Cl:9]
Reactant: O=C1CCC(=O)N1Br
Reactant: CS(=O)c1nc(N)cc(Cl)n1
Solvent: CN(C)C=O
Product: CS(=O)c1nc(N)c(Br)c(Cl)n1
Temperature: 25 °C
Reaction time: 0.83 h
Yield: 81 %

Procedure:
11.2 g (62.6 mmol) de N-bromosuccinimide were slowly added to a cooled suspension of 10 g (52.2 mmol) 6-chloro-2-(methylsulfinyl)pyrimidine-4-amine in 130 ml of DMF. After 50 minutes stirring at room temperature the precipitate was filtered washed with cool DMF, several times with cool water and dried in vacuum. There was obtained 11.4 g (81%) of a white solid.
Reaction SMILES: [N+:1]([C:4]1[C:9](=O)[NH:8][CH:7]=[C:6]([C:11]2[C:16]([C:17]([F:20])([F:19])[F:18])=[CH:15][CH:14]=[CH:13][N:12]=2)[CH:5]=1)([O-:3])=[O:2].S(Cl)([Cl:23])=O>CN(C=O)C>[Cl:23][C:9]1[N:8]=[CH:7][C:6]([C:11]2[C:16]([C:17]([F:20])([F:19])[F:18])=[CH:15][CH:14]=[CH:13][N:12]=2)=[CH:5][C:4]=1[N+:1]([O-:3])=[O:2]
Reactant: O=S(Cl)Cl
Reactant: O=c1[nH]cc(-c2ncccc2C(F)(F)F)cc1[N+](=O)[O-]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cc(-c2ncccc2C(F)(F)F)cnc1Cl
Yield: 93 %

Procedure:
Heat a solution of 5′-nitro-3-trifluoromethyl-1′H-[2,3′]bipyridinyl-6′-one (25 g, 0.088 mol), thionyl chloride (300 mL) and DMF (3 mL) to reflux for 4 hours. Remove the volatiles by rotary evaporation and partition the residue between ethyl acetate (350 mL) and saturated sodium bicarbonate solution (250 mL). Extract the aqueous layer with further ethyl acetate (250 mL) and wash the combined organics with brine (250 mL). Dry (MgSO4) and concentrate under reduced pressure to give the title compound (25 g, 93%) as a yellow oil.
Reaction SMILES: [NH2:1][CH2:2][C:3]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([OH:7])[CH2:4][CH2:5][CH3:6].[F:14][C:15]1[C:16]([C:34](O)=[O:35])=[N:17][CH:18]=[CH:19][C:20]=1[S:21][C:22]1[S:26][C:25]([NH:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=2)=[N:24][CH:23]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.C(N(C(C)C)CC)(C)C>CN1C(=O)CCC1>[F:14][C:15]1[C:16]([C:34]([NH:1][CH2:2][C:3]([OH:7])([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:4][CH2:5][CH3:6])=[O:35])=[N:17][CH:18]=[CH:19][C:20]=1[S:21][C:22]1[S:26][C:25]([NH:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=2)=[N:24][CH:23]=1
Reactant: CCCC(O)(CN)c1ccccc1
Reactant: O=C(O)c1nccc(Sc2cnc(Nc3ccccn3)s2)c1F
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: CCCC(O)(CNC(=O)c1nccc(Sc2cnc(Nc3ccccn3)s2)c1F)c1ccccc1
Temperature: 23 °C
Reaction time: 2 h
Yield: 36.1 %

Procedure:
1-Amino-2-phenylpentan-2-ol (0.099 g, 0.45 mmol, 1.5 eq) was dissolved in NMP (3 mL) and to this solution was added 3-fluoro-4-(2-(pyridin-2-ylamino)thiazol-5-ylthio)picolinic acid (0.101 g, 0.30 mmol), EDAC (0.089 g, 0.45 mmol, 1.5 eq), HOBt (0.042 g, 0.30 mmol, 1 eq) and diisopropylethylamine (0.16 mL, 0903 mmol, 3 eq). The resulting mixture was stirred at 23° C. for 2 h. The mixture was then purified on preparative HPLC (ammonium acetate/water/acetonitrile) and freeze dried to give the title compound (0.0552 g, 36%). 1H NMR (400 MHz, DMSO-d6) δ ppm: 0.76 (3H, t, J=7.33 Hz), 0.84-0.96 (1H, m), 1.19-1.30 (1H, m), 1.68-1.79 (2H, m), 3.63 (2H, d, J=5.81 Hz), 5.29 (1H, s), 7.01 (1H, dd, J=6.82 and 5.56 Hz), 7.05 (1H, t, J=5.18 Hz), 7.12 (1H, d, J=8.34 Hz), 7.20 (1H, t, J=7.33 Hz), 7.31 (2H, t, J=7.71 Hz), 7.42-7.46 (2H, m), 7.78 (1H, td, J=7.77 and 1.89 Hz), 7.82 (1H, s), 8.22-8.26 (2H, m), 8.31 (1H, dd, J=5.05 and 1.01 Hz), 11.88 (1H, s). LC/MS (M+H)+: 510. HPLC ret. time (Condition J): 6.095 min. HRMS calcd: 510.1434; found: 510.1412.
Reaction SMILES: Cl[CH:2]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:3]([NH:5][C:6]1[C:11]([C:12]([F:15])([F:14])[F:13])=[CH:10][CH:9]=[CH:8][C:7]=1[C:16](=[O:26])[CH2:17][C:18]([NH:20][C:21]1[S:22][CH:23]=[CH:24][N:25]=1)=[O:19])=O>CN(C)C1C=CN=CC=1.O1CCCC1>[C:27]1([CH:2]2[C:3]3=[N:5][C:6]4[C:11]([C:12]([F:15])([F:14])[F:13])=[CH:10][CH:9]=[CH:8][C:7]=4[C:16]([OH:26])=[C:17]3[C:18](=[N:20][C:21]3[S:22][CH:23]=[CH:24][N:25]=3)[O:19]2)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: O=C(CC(=O)c1cccc(C(F)(F)F)c1NC(=O)C(Cl)c1ccccc1)Nc1nccs1
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Product: Oc1c2c(nc3c(C(F)(F)F)cccc13)C(c1ccccc1)OC2=Nc1nccs1
Temperature: 25 °C
Reaction time: 16 h
Yield: 100.3 %

Procedure:
1.82 g of 4-dimethylamino-pyridine were added to a solution of 6 g of the product of Step B in 150 ml of tetrahydrofuran and the mixture was stirred at room temperature for 16 hours and was evaporated to dryness under reduced pressure. The residue was extracted with 100 ml of water and 3 ml of hydrochloric acid were added to the aqueous extract which was stirred at room temperature for 15 minutes and was vacuum filtered. The product was washed with water and dried under reduced pressure at 90° C. to obtain 5.34 g of 1,3-dihydro-3-phenyl-1-[(2-thiazolyl)-imino]-5-trifluoromethyl-furo[3,4-b]quinoline-9-ol melting at 270° C. (decomposition).
Reaction SMILES: [NH:1]=[C:2]1[N:6]([OH:7])[C:5]([CH2:8][C:9]([NH:11][CH:12]2[C:27](=[O:28])[N:14]3[C:15]([C:24]([OH:26])=[O:25])=[C:16]([CH2:19]OC(=O)C)[CH2:17][S:18][C@H:13]23)=[O:10])=[CH:4][S:3]1.[OH:29][CH2:30][C:31]1[N:35]([CH3:36])[C:34]([SH:37])=[N:33][N:32]=1.C(=O)([O-])O.[Na+:42].O>P([O-])([O-])([O-])=O>[NH:1]=[C:2]1[N:6]([OH:7])[C:5]([CH2:8][C:9]([NH:11][CH:12]2[C:27](=[O:28])[N:14]3[C:15]([C:24]([O-:26])=[O:25])=[C:16]([CH2:19][S:37][C:34]4[N:35]([CH3:36])[C:31]([CH2:30][OH:29])=[N:32][N:33]=4)[CH2:17][S:18][C@H:13]23)=[O:10])=[CH:4][S:3]1.[Na+:42]
Reactant: Cn1c(S)nnc1CO
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)C(NC(=O)Cc3csc(=N)n3O)[C@H]2SC1
Agent: O=C([O-])O
Agent: O=P([O-])([O-])[O-]
Agent: [Na+]
Solvent: O
Product: Cn1c(CO)nnc1SCC1=C(C(=O)[O-])N2C(=O)C(NC(=O)Cc3csc(=N)n3O)[C@H]2SC1
Temperature: 70 °C
Reaction time: 2 h

Procedure:
In 20 ml of phosphate buffer (pH 6.4) is dissolved 1.0 g of 7-[2-(2-imino-3-hydroxy-4-thiazolin-4-yl)acetamido]-3-acetoxymethyl-3-cephem-4-carboxylic acid together with 0.3 g of 3-hydroxymethyl-4-methyl-1,2,4-triazole-5-thiol and 0.336 g of sodium hydrogen carbonate and the solution is stirred at 70° C. for 2 hours. This reaction mixture is subjected to column chromatography on polystyrene resin (Amberlite XAD-2) with water as the developer and the fractions containing the contemplated product are pooled. This solution contains 3-hydroxymethyl-4-methyl-1,2,4-triazole-5-thiol together with the desired compound. The solution is lyophilized and the resultant powder is redissolved in water. The solution is then subjected to column chromatography on dextran gel (Sephadex LH-20®, Pharmacia) with water as the developer. The fractions containing the contemplated compound are pooled and lyophilized. By the above procedure is obtained the captioned compound. Yield 0.28 g.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[C:12]([Cl:14])[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[NH2:19])([CH3:4])([CH3:3])[CH3:2].C([O:25][C:26](=O)[CH2:27][C:28](=[O:41])[C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([C:35]2[CH:36]=[N:37][CH:38]=[N:39][CH:40]=2)[CH:30]=1)(C)(C)C>>[C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[C:12]([Cl:14])[C:11]([C:15]([F:17])([F:18])[F:16])=[CH:10][C:9]=1[NH:19][C:26](=[O:25])[CH2:27][C:28](=[O:41])[C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([C:35]2[CH:40]=[N:39][CH:38]=[N:37][CH:36]=2)[CH:30]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1cc(Cl)c(C(F)(F)F)cc1N
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-c2cncnc2)c1
Product: CC(C)(C)OC(=O)Nc1cc(Cl)c(C(F)(F)F)cc1NC(=O)CC(=O)c1cccc(-c2cncnc2)c1

Procedure:
The title compound was prepared from (2-amino-5-chloro-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example J19) (311 mg, 1.0 mmol) and 3-oxo-3-(3-pyrimidin-5-yl-phenyl)-propionic acid tert-butyl ester (Example K13) (298 mg, 1.0 mmol) according to the general procedure M. Obtained as a yellow oil (420 mg, 79%).
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[C:11](=[C:12](OS(C(F)(F)F)(=O)=O)[N:13]([CH:18]([CH3:20])[CH3:19])[N:14]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[CH3:29][O:30][C:31]1[CH:36]=[CH:35][C:34](B(O)O)=[CH:33][CH:32]=1>>[CH:18]([N:13]1[C:12]([C:34]2[CH:35]=[CH:36][C:31]([O:30][CH3:29])=[CH:32][CH:33]=2)=[C:11]2[C:15]([CH2:16][CH2:17][NH:8][CH2:9][CH2:10]2)=[N:14]1)([CH3:19])[CH3:20]
Reactant: COc1ccc(B(O)O)cc1
Reactant: CC(C)n1nc2c(c1OS(=O)(=O)C(F)(F)F)CCN(C(=O)OC(C)(C)C)CC2
Product: COc1ccc(-c2c3c(nn2C(C)C)CCNCC3)cc1
Yield: 107.6 %

Procedure:
The title compound (148 mg) was prepared according to Example 189 using 206 mg of 2-isopropyl-3-trifluoromethanesulfonyloxy-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 189, Step A) and 219 mg of 4-methoxyphenylboronic acid. MS (ESI): exact mass calculated for C17H23N3O, 285.18. found, m/z 286.5 [M+H]+. 1H NMR (500 MHz, CD3OD): 7.30-7.28 (m, 2H), 7.13-7.11 (m, 2H), 4.68 (m, 1H), 4.47 (m, 1H), 3.87 (s, 3H), 3.47-3.44 (m, 1H), 3.25-3.23 (m, 1H), 2.89-2.81 (m, 2H), 1.43 (d, J=6.6 Hz, 6H).
Reaction SMILES: ClC1C=C(C=CC=1)C(OO)=[O:6].[CH2:12]([O:16][C:17]([N:19]([C:39]1[C:44]([O:45][CH3:46])=[N:43][C:42]([CH3:47])=[CH:41][N:40]=1)[S:20]([C:23]1[C:24]([C:29]2[CH:34]=[CH:33][C:32]([CH2:35][C:36]([CH3:38])=[CH2:37])=[CH:31][CH:30]=2)=[N:25][CH:26]=[CH:27][CH:28]=1)(=[O:22])=[O:21])=[O:18])[CH:13]([CH3:15])[CH3:14]>ClCCl>[O:6]1[CH2:37][C:36]1([CH3:38])[CH2:35][C:32]1[CH:33]=[CH:34][C:29]([C:24]2[C:23]([S:20]([N:19]([C:17]([O:16][CH2:12][CH:13]([CH3:14])[CH3:15])=[O:18])[C:39]3[C:44]([O:45][CH3:46])=[N:43][C:42]([CH3:47])=[CH:41][N:40]=3)(=[O:22])=[O:21])=[CH:28][CH:27]=[CH:26][N:25]=2)=[CH:30][CH:31]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C=C(C)Cc1ccc(-c2ncccc2S(=O)(=O)N(C(=O)OCC(C)C)c2ncc(C)nc2OC)cc1
Solvent: ClCCl
Product: COc1nc(C)cnc1N(C(=O)OCC(C)C)S(=O)(=O)c1cccnc1-c1ccc(CC2(C)CO2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 8.6 %

Procedure:
3-Chloroperoxybenzoic acid (50%, 2.4 g) was added over 5 minutes to a solution of N-(isobutoxycarbonyl)-N-(3-methoxy-5-methylpyrazin-2-yl)-2-[4-(2-methylprop-2-enyl)phenyl]pyridine-3-sulphonamide (1.8 g) in dichloromethane (75 ml) at 0° C. The reaction mixture was allowed to warm to ambient temperature and stirred a further 1 hour. The mixture was washed with saturated aqueous sodium hydrogen carbonate solution (20 ml), water and saturated sodium chloride solution then dried (MgSO4). Volatile material was removed by evaporation and the residue was purified by suction flash chromatography followed by gradient elution with 0-40% ethyl acetate/hexane through a silica gel Mega Bond Elut column to give 2-[4-(2,3-epoxy-2-methylpropyl)phenyl]-N-(isobutoxycarbonyl)-N-(3-methoxy-5-methylpyrazin-2-yl)pyridine-3-sulphonamide (0.16 g) as a solid, 1H NMR (CDCl3): 0.65 (d, 6H), 1.3 (s, 3H), 1.7 (m, 1H), 2.5 (s, 3H), 2.65 (dd, 2H), 2.9 (q, 2H), 3.85 (d, 2H), 4.0 (s, 3H), 7.3 (d, 2H), 7.5 (dd, 1H), 7.6 (d, 2H), 7.95 (s, 1H), 8.85 (dd, 1H), 8.95 (dd, 1H); mass spectrum (+ve ESP): 527 (M+H)+.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[CH:6][CH:7]=[C:8]2[OH:13].[F:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][C:22]=1F)[C:18]#[N:19].C([O-])([O-])=O.[K+].[K+]>C1CS(=O)(=O)CC1>[F:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][C:22]=1[O:13][C:8]1[C:9]2[C:4](=[C:3]([CH2:2][OH:1])[CH:12]=[CH:11][CH:10]=2)[CH:5]=[CH:6][CH:7]=1)[C:18]#[N:19]
Reactant: OCc1cccc2c(O)cccc12
Reactant: N#Cc1ccc(F)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=S1(=O)CCCC1
Product: N#Cc1ccc(Oc2cccc3c(CO)cccc23)c(F)c1
Temperature: 80 °C

Procedure:
To a solution of 5-hydroxymethylnaphthalen-1-ol (Preparation 32) (350 mg, 2.01 mmol) and 3,4-difluorobenzonitrile (279 mg, 2.01 mmol) in sulfalone (8 mL) was added K2CO3 (1.39 g, 10.05 mmol) and the mixture heated to 80° C. for 16 h before cooling to rt. The mixture was partitioned between water (50 mL) and EtOAc (3×50 mL), the organic phase was washed with water (3×50 mL), brine (50 mL) and dried (MgSO4). Solvent was removed in vacuo and the residue purified by column chromatography (SiO2, MeOH:DCM, 2:98) to give the title compound: RT=3.54 min; m/z (ES+)=276.1 [M H2O]+.
Reaction SMILES: [Si]([O:8][C@@H:9]1[CH2:13][C:12](=[O:14])[N:11]([C:15]2[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[C:17]([O:23][CH3:24])[CH:16]=2)[C@H:10]1[CH2:25][CH3:26])(C(C)(C)C)(C)C.C(O)C.Cl.C(=O)([O-])O.[Na+]>O1CCCC1>[CH2:25]([C@H:10]1[C@H:9]([OH:8])[CH2:13][C:12](=[O:14])[N:11]1[C:15]1[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[C:17]([O:23][CH3:24])[CH:16]=1)[CH3:26]
Reactant: CC[C@H]1[C@H](O[Si](C)(C)C(C)(C)C)CC(=O)N1c1ccc(C#N)c(OC)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Product: CC[C@H]1[C@H](O)CC(=O)N1c1ccc(C#N)c(OC)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 73.1 %

Procedure:
To a solution of 4-[(2S,3R)-3-(tert-butyldimethylsilyloxy)-2-ethyl-5-oxopyrrolidin-1-yl]-2-methoxybenzonitrile (1.04 g) in tetrahydrofuran (30 mL)-ethanol (15 mL) was added 6 mol/L hydrochloric acid (15 mL), and the mixture was stirred at room temperature for 18 hr. Saturated aqueous sodium hydrogen carbonate was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent:hexane/ethyl acetate=5/1→0/1) to give the title compound as a colorless solid (yield: 528.3 mg, 73%).
Reaction SMILES: [Cl-:1].[Li+].[O:3]=[C:4]1[C:12]2[C:7](=[CH:8][C:9]([O:15][CH2:16][C:17]([O:19][CH3:20])=[O:18])=[C:10]([Cl:14])[C:11]=2[Cl:13])[CH2:6][CH:5]1[CH2:21][CH3:22].CO>CN(C)C=O>[O:3]=[C:4]1[C:12]2[C:7](=[CH:8][C:9]([O:15][CH2:16][C:17]([O:19][CH3:20])=[O:18])=[C:10]([Cl:14])[C:11]=2[Cl:13])[CH2:6][C:5]1([CH2:21][CH3:22])[Cl:1]
Reactant: CCC1Cc2cc(OCC(=O)OC)c(Cl)c(Cl)c2C1=O
Reactant: [Cl-]
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: CO
Product: CCC1(Cl)Cc2cc(OCC(=O)OC)c(Cl)c(Cl)c2C1=O
Temperature: 90 °C
Yield: 53 %

Procedure:
A stirred solution of cupric chloride dihydrate (4.25 g. and lithium chloride (0.765 g.) in dimethylformamide (10 ml.) is heated to 90° C. and to the mixture is added a solution of methyl (1-oxo-2-ethyl-6,7-dichloro-5-indanyloxy)-acetate (4.7 g., 0.015 mole) in dimethylformamide. The reaction mixture is heated at 90° C. for two hours and poured onto ice. The product is extracted into ether (100 ml.), washed with water, dried over anhydrous sodium sulfate and the ether distilled at reduced pressure. There is thus obtained 2.5 g. of methyl (1-oxo-2-ethyl-2,6,7-trichloro-5-indanyloxy)acetate (53% yield) which melts at 111° C. after recrystallization from methanol.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]([NH2:11])[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][NH:6]2.[CH3:12][O:13][C:14]1[CH:15]=[C:16]([CH:20]=[C:21]([O:25][CH3:26])[C:22]=1[O:23][CH3:24])[C:17](Cl)=[O:18]>N1C=CC=CC=1>[NH2:11][C:9]1[N:8]=[C:7]2[C:3]([N:4]=[CH:5][N:6]2[C:17]([C:16]2[CH:20]=[C:21]([O:25][CH3:26])[C:22]([O:23][CH3:24])=[C:14]([O:13][CH3:12])[CH:15]=2)=[O:18])=[C:2]([Cl:1])[N:10]=1
Reactant: COc1cc(C(=O)Cl)cc(OC)c1OC
Reactant: Nc1nc(Cl)c2nc[nH]c2n1
Solvent: c1ccncc1
Product: COc1cc(C(=O)n2cnc3c(Cl)nc(N)nc32)cc(OC)c1OC

Procedure:
A solution of 6-chloro-9H-purin-2-ylamine in pyridine was treated with 3,4,5-trimethoxybenzoyl chloride at r.t. for 2 h. Work-up and purification by preparative TLC (EtOAc:hexane 1:1) gave the title compound. HPLC Rt: 5.305 min. 1H-NMR (CDCl3): δ 8.24 (s, 1H), 7.13 (s, 2H), 5.36 (s, 2H), 3.99 (s, 3H), 3.88 (s, 6H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@:8]([CH3:26])([CH2:21][CH2:22][CH:23]([CH3:25])[CH3:24])[C:9](N[C@H](C2C=CC=CC=2)CO)=[O:10])=[CH:4][CH:3]=1.FC1C=CC([C@@](C)(CCC(C)C)C(N[C@H](C2C=CC=CC=2)CO)=[O:36])=CC=1>CCO>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C@:8]([CH3:26])([CH2:21][CH2:22][CH:23]([CH3:25])[CH3:24])[C:9]([OH:10])=[O:36])=[CH:6][CH:7]=1
Reactant: CC(C)CC[C@](C)(C(=O)N[C@@H](CO)c1ccccc1)c1ccc(F)cc1
Reactant: CC(C)CC[C@@](C)(C(=O)N[C@@H](CO)c1ccccc1)c1ccc(F)cc1
Solvent: CCO
Product: CC(C)CC[C@](C)(C(=O)O)c1ccc(F)cc1

Procedure:
The title compound was prepared according to the procedure of Example 22E, substituting the product of Example 23A, for the product of Example 22D. 1H NMR (300 MHz, CDCl3): δ 0.88 (m, 7 H) 1.06 (m, 1 H) 1.48 (m, 1 H) 1.55 (s, 3 H) 1.96 (m, 2 H) 3.76 (m, 2 H) 5.03 (m, 1 H) 5.83 (d, J=6.99 Hz, 1 H) 7.06 (m, 4 H) 7.29 (m, 5 H). Specific rotation: [α]D+12.4° (c 2.16, EtOH).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[CH:12]=[CH:11][C:10]([S:13]([NH:16][C:17]3[S:18][CH:19]=[CH:20][N:21]=3)(=[O:15])=[O:14])=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.[Cl:22][C:23]1[CH:24]=[C:25]2[CH:31]=[CH:30][N:29]([CH2:32][C:33](O)=[O:34])[C:26]2=[N:27][CH:28]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C1COCC1>[Cl:22][C:23]1[CH:24]=[C:25]2[CH:31]=[CH:30][N:29]([CH2:32][C:33]([N:1]3[CH2:2][CH2:3][CH:4]([C:7]4[CH:8]=[CH:9][C:10]([S:13]([NH:16][C:17]5[S:18][CH:19]=[CH:20][N:21]=5)(=[O:14])=[O:15])=[CH:11][CH:12]=4)[CH2:5][CH2:6]3)=[O:34])[C:26]2=[N:27][CH:28]=1
Reactant: O=C(O)Cn1ccc2cc(Cl)cnc21
Reactant: O=S(=O)(Nc1nccs1)c1ccc(C2CCNCC2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Cn1ccc2cc(Cl)cnc21)N1CCC(c2ccc(S(=O)(=O)Nc3nccs3)cc2)CC1
Yield: 46.7 %

Procedure:
Synthesized according to general procedure 17, method C using THF as solvent. To a solution of 4-(piperidin-4-yl)-N-(thiazol-2-yl)benzenesulfonamide (0.35 g, 1.08 mmol) and 2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-1-yl)acetic acid (0.25 g, 1.19 mmol) in THF (6 mL) was added HATU (0.533 g, 1.40 mmol) followed by the addition of DIEA (0.279 g, 2.16 mmol) at 0° C. under inert atmosphere. The reaction was quenched with water after 15 minutes, the layers were separated and the aqueous layer was extracted with DCM. The combined organic layers were dried over Na2SO4, filtered and concentrated. Purification via silica gel chromatography using 0-3% methanol in DCM gave 4-(1-(2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-1-yl)acetyl)piperidin-4-yl)-N-(thiazol-2-yl)benzenesulfonamide (0.26 g, 46% yield). 1H NMR (400 MHz, DMSO-d6) δ 12.71 (s, 1H), 8.22 (d, J=2.3 Hz, 1H), 8.10 (d, J=2.3 Hz, 1H), 7.75 (d, J=8.4 Hz, 2H), 7.57 (d, J=3.5 Hz, 1H), 7.44 (d, J=8.4 Hz, 2H), 7.26 (d, J=4.6 Hz, 1H), 6.83 (d, J=4.6 Hz, 1H), 6.49 (d, J=3.5 Hz, 1H), 5.25 (d, J=2.6 Hz, 2H), 4.44 (d, J=12.9 Hz, 1H), 4.16 (d, J=12.8 Hz, 1H), 3.24 (t, J=11.7 Hz, 1H), 2.95-2.88 (m, 1H), 2.70 (t, J=11.7 Hz, 1H), 1.91-1.66 (m, 3H), 1.55-1.45 (m, 1H). LC/MS (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)), m/z: M+1 obs=516.5; tR=1.57 min.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([CH3:7])[NH:4][N:3]=1.[H-].[Na+].[CH2:10]([N:12]1[C:16]([OH:17])=[C:15]([C:18](=[O:31])[C:19]2[CH:24]=[CH:23][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[C:21](F)[C:20]=2[Cl:30])[CH:14]=[N:13]1)[CH3:11]>CN(C)C=O>[CH2:10]([N:12]1[C:16]([OH:17])=[C:15]([C:18](=[O:31])[C:19]2[CH:24]=[CH:23][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[C:21]([N:3]3[C:2]([CH3:1])=[CH:6][C:5]([CH3:7])=[N:4]3)[C:20]=2[Cl:30])[CH:14]=[N:13]1)[CH3:11]
Reactant: CCn1ncc(C(=O)c2ccc(S(C)(=O)=O)c(F)c2Cl)c1O
Reactant: Cc1cc(C)[nH]n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCn1ncc(C(=O)c2ccc(S(C)(=O)=O)c(-n3nc(C)cc3C)c2Cl)c1O
Temperature: 50 °C
Reaction time: 8 h

Procedure:
3,5-Dimethylpyrazole (215 mg, 2.23 mmol) was added to a suspension of 150 mg (3.75 mmol) of 60 percent oil dispersed sodium hydride in 6 mL of dry dimethylformamide. After gas evolution had subsided, 500 mg (1.45 mmol) of 1-ethyl-4-(2-chloro-3-fluoro-4-methylsulfonylbenzoyl)-5-hydroxypyrazole was added and the mixture was stirred at 50° C. overnight. The reaction mixture was concentrated by evaporation under reduced pressure and partitioned between dichloromethane and 1N aqueous hydrochloric acid. The aqueous phase was extracted with additional dichloromethane. The organic layers were combined and extracted with dilute aqueous sodium bicarbonate. The aqueous extract was acidified with 1N aqueous hydrochloric acid and the resulting mixture was extracted with ethyl acetate. The solvent was removed from the organic extract by evaporation under reduced pressure and the crystalline residue obtained was purified by rinsing with diethyl ether to obtain 360 mg (59 percent of theory) of the title compound as a white powder melting at 217-218° C.
Reaction SMILES: Cl[C:2]1([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[O:19][CH3:20])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([Cl:11])[CH:9]=2)[NH:4][C:3]1=[O:12].[NH2:21][C@@H:22]([CH2:28][C:29]1[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=1)[C:23]([N:25]([CH3:27])[CH3:26])=[O:24]>>[Cl:11][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[NH:4][C:3](=[O:12])[C:2]2([NH:21][C@@H:22]([CH2:28][C:29]1[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=1)[C:23]([N:25]([CH3:27])[CH3:26])=[O:24])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[O:19][CH3:20]
Reactant: COc1ccccc1C1(Cl)C(=O)Nc2ccc(Cl)cc21
Reactant: CN(C)C(=O)[C@@H](N)Cc1cccnc1
Product: COc1ccccc1C1(N[C@@H](Cc2cccnc2)C(=O)N(C)C)C(=O)Nc2ccc(Cl)cc21

Procedure:
With 1.82 g of 3,5-dichloro-3-(2-methoxyphenyl)-1,3-dihydro-2H-indol-2-one and 0.61 g of the compound obtained in Step 85-2 as starting materials, 246 mg (Isomer A, yellow amorphous) and 536 mg (Isomer B, pale yellow amorphous) of the respective diastereoisomers of the title compound were obtained by a similar method to Step 4-2.