Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[F:8][C:9]([F:36])([F:35])[C:10]1[CH:32]=[C:31]([C:33]#[N:34])[CH:30]=[CH:29][C:11]=1[NH:12][C:13](=[O:28])[C:14]1[C:15](=[C:17]([C:24]([CH3:27])([CH3:26])[CH3:25])[CH:18]=[C:19]([C:22]#[N:23])[C:20]=1[CH3:21])[OH:16].C(NC1C=CC=CC=1)(=O)C1C(=CC=CC=1)O.Cl>N1C=CC=CC=1.C(Cl)(Cl)Cl>[C:1]([O:16][C:15]1[C:14](=[C:20]([CH3:21])[C:19]([C:22]#[N:23])=[CH:18][C:17]=1[C:24]([CH3:27])([CH3:26])[CH3:25])[C:13]([NH:12][C:11]1[CH:29]=[CH:30][C:31]([C:33]#[N:34])=[CH:32][C:10]=1[C:9]([F:35])([F:36])[F:8])=[O:28])(=[O:3])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1c(C#N)cc(C(C)(C)C)c(O)c1C(=O)Nc1ccc(C#N)cc1C(F)(F)F
Agent: Cl
Agent: O=C(Nc1ccccc1)c1ccccc1O
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: CC(=O)Oc1c(C(C)(C)C)cc(C#N)c(C)c1C(=O)Nc1ccc(C#N)cc1C(F)(F)F
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of acetic anhydride (0.1 ml.) in dry pyridine (1 ml.) is added dropwise to a stirred solution of 2'-trifluoromethyl-4',5-dicyano-3-t-butyl-6-methylsalicylanilide (0.38 g.) in dry pyridine (4 ml.) at 0°-5° C. The mixture is stirred at 0°-5° C. for 1 hour and then at room temperature until no starting salicylanilide is left, as shown by the absence of the characteristic ferric chloride positive spot, on TLC analysis on silica using chloroform as eluant. The mixture is then poured onto a mixture of ice (30 g.) and 2N hydrochloric acid solution (20 ml.). The solid which is formed is collected and washed with water. After drying, the solid is recrystallised from a mixture containing equal parts of ether and cyclohexane to give 2-O-acetyl-2'-trifluoromethyl-4',5-dicyano-3-t-butyl-6-methylsalicylanilide, m.p. 171°-172° C., having spectroscopic properties consistent with those of an O-acetate.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH:5]=O.[CH3:12][NH:13][CH3:14].C([BH3-])#N.[Na+]>CO>[Br:1][C:2]1[CH:3]=[C:4]([CH2:5][N:13]([CH3:14])[CH3:12])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11]
Reactant: COc1ccc(C=O)cc1Br
Reactant: CNC
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: COc1ccc(CN(C)C)cc1Br
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 10.0 g of 3-bromo-4-methoxy benzaldehyde in MeOH (155 ml) was added an aqueous solution of 50% dimethylamine (2.52 ml) and the reaction mixture was stirred at room temperature for 30 minutes. Thereafter, to the solution was added 4.38 g of sodium cyanoborohydride, the reaction mixture was stirred for 15 hours under the same temperature condition, and the reaction solution was concentrated under reduced pressure. Water was added to the residue and extracted with CHCl3; the organic layer was washed with saturated brine and dried over MgSO4, then, the drying agent was separated by filtration and the solvent was evaporated under reduced pressure. The obtained residue was purified by column chromatography (silicagel 60; mobile phase: EtOAc/hexane=1/1, then, MeOH/CHCl3=1/9; v/v) to obtain 2.20 g of the title compound (colorless oil).
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C@H:11]([OH:15])[CH2:12][CH2:13][CH3:14])=[CH:7][CH:6]=1)[CH:2]([CH3:4])[CH3:3].O[C:17]1[CH:26]=[CH:25][C:20]([C:21]([O:23][CH3:24])=[O:22])=[CH:19][CH:18]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1(C)C=CC=CC=1.O1CCCC1.O>[CH2:1]([C:5]1[CH:6]=[CH:7][C:8]([C@@H:11]([O:15][C:17]2[CH:26]=[CH:25][C:20]([C:21]([O:23][CH3:24])=[O:22])=[CH:19][CH:18]=2)[CH2:12][CH2:13][CH3:14])=[CH:9][CH:10]=1)[CH:2]([CH3:4])[CH3:3]
Reactant: COC(=O)c1ccc(O)cc1
Reactant: CCC[C@@H](O)c1ccc(CC(C)C)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Solvent: Cc1ccccc1
Product: CCC[C@H](Oc1ccc(C(=O)OC)cc1)c1ccc(CC(C)C)cc1
Reaction time: 1.5 h
Yield: 79.4 %

Procedure:
To a solution of 1-(R)-(4-isobutylphenyl)butanol (1.13 g), methyl 4-hydroxybenzoate (917 mg) and triphenylphosphine (1.58 g) in toluene (40 ml) and tetrahydrofuran (10 ml) was added diethyl azodicarboxylate (0.95 ml) at -20° C. The mixture was stirred at -15°--20° C. for 1.5 hours and then added water (0.5 ml). The mixture was evaporated, dissolved in a mixture of n-hexane and ethyl acetate (4:1), filtered off and evaporated. The residue was chromatographed on silica gel eluting with a mixture of n-hexane and dichloromethane (1:1) to give methyl 4-[1-(S)-(4-isobutylphenyl)butoxy]benzoate as an oil (1.48 g).
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH3:7])=[CH:5][C:4]([NH:8][C:9]2[C:10](=[O:25])[N:11]([CH3:24])[CH:12]=[C:13](B3OC(C)(C)C(C)(C)O3)[CH:14]=2)=[N:3]1.[C:26]([O:29][CH2:30][C:31]1[C:36]([N:37]2[CH2:48][CH2:47][N:46]3[C:39](=[CH:40][C:41]4[CH2:42][C:43]([CH3:50])([CH3:49])[CH2:44][C:45]=43)[C:38]2=[O:51])=[CH:35][C:34]([F:52])=[CH:33][C:32]=1Br)(=[O:28])[CH3:27].COCCOC.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CO.C(OCC)C.O.CCOC(C)=O>[CH3:1][N:2]1[C:6]([CH3:7])=[CH:5][C:4]([NH:8][C:9]2[C:10](=[O:25])[N:11]([CH3:24])[CH:12]=[C:13]([C:32]3[C:31]([CH2:30][O:29][C:26](=[O:28])[CH3:27])=[C:36]([N:37]4[CH2:48][CH2:47][N:46]5[C:39](=[CH:40][C:41]6[CH2:42][C:43]([CH3:49])([CH3:50])[CH2:44][C:45]=65)[C:38]4=[O:51])[CH:35]=[C:34]([F:52])[CH:33]=3)[CH:14]=2)=[N:3]1
Reactant: CC(=O)OCc1c(Br)cc(F)cc1N1CCn2c(cc3c2CC(C)(C)C3)C1=O
Reactant: Cc1cc(Nc2cc(B3OC(C)(C)C(C)(C)O3)cn(C)c2=O)nn1C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CO
Solvent: O
Product: CC(=O)OCc1c(-c2cc(Nc3cc(C)n(C)n3)c(=O)n(C)c2)cc(F)cc1N1CCn2c(cc3c2CC(C)(C)C3)C1=O
Temperature: 130 °C
Yield: 88.6 %

Procedure:
A microwave tube equipped with a magnetic stirrer was charged with 196a (450 mg, 1.3 mmol), 189a (240 mg, 0.5 mmol), DME (4 mL) and 1M aqueous sodium carbonate (1.5 mL). After bubbling N2 for 15 min, Pd(PPh3)4 (31 mg, 0.03 mmol) was added. The mixture was heated in microwave to 130° C. for 10 min. After this time, EtOAc (5 mL) and water (5 mL) were added. The separated aqueous layer was extracted with EtOAc (2×5 mL). The combined organics were washed with brine (10 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by column chromatography eluting with a gradient of methylene chloride-60:35:5 methylene chloride:diethyl ether:methanol to afford a 83% yield (260 mg) of 196b.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]2[N:6]=[C:7]([NH:9][C:10]([NH:12][CH2:13][CH3:14])=[O:11])[S:8][C:4]=2[CH:3]=1.[N+:17]([O-])([OH:19])=[O:18]>S(=O)(=O)(O)O>[Cl:1][C:2]1[C:16]([N+:17]([O-:19])=[O:18])=[CH:15][C:5]2[N:6]=[C:7]([NH:9][C:10]([NH:12][CH2:13][CH3:14])=[O:11])[S:8][C:4]=2[CH:3]=1
Reactant: O=[N+]([O-])O
Reactant: CCNC(=O)Nc1nc2ccc(Cl)cc2s1
Agent: O=S(=O)(O)O
Product: CCNC(=O)Nc1nc2cc([N+](=O)[O-])c(Cl)cc2s1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Three grams of N-(6-chloro-1,3-benzothiazol-2-yl)-N′-ethylurea was dissolved in about 15 mL of concentrated sulfuric acid (about 92–94%). The solution was cooled to about 0–5° C. About 1.5 g of ice cooled nitric acid (70% concentration was used, though this is not necessary) was added dropwise. The reaction was held at 0–5° C. for about one hour then poured into water. The pH was then adjusted to about 7–8 with ammonia and the solids were isolated by filtration. The solids were washed with water then dried in vacuo. The product was further purified by chromatography then dried in vacuo. 1H NMR 1.08 (t, 3H, J=7.2 Hz), 3.19 (m, 2H), 6.92 (br s, 1H), 8.26 (s, 1H), 8.31 (s, 1H), LC/MS 3.72 min, 302 (M+1)
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:3]=1[C:4](=[O:7])[CH2:5]Cl.[N:13]1([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[Cl:1][C:2]1[CH:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:3]=1[C:4](=[O:7])[CH2:5][N:16]1[CH2:15][CH2:14][N:13]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:18][CH2:17]1
Reactant: O=C(CCl)c1ccc(Cl)cc1Cl
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(CC(=O)c2ccc(Cl)cc2Cl)CC1

Procedure:
1 mmol of 2,4-dichlorophenacyl chloride in DMF was added drop wise to 1.2 mmol of tert-butyl piperazinecarboxylate and 1.2 mmol Cs2CO3 in DMF at room temperature for fourteen hours. The reaction mixture was concentrated in vacuo and diluted with water and ethyl acetate. The solution was extracted three times with ethyl acetate, dried over sodium sulfate, and purified by column chromatography eluting with 50% ethyl acetate and 50% hexane to obtain tert-butyl 4-[2-(2,4-dichlorophenyl)-2-oxoethyl]piperazinecarboxylate.
Reaction SMILES: [Si](OC[C@@H]1C(C)=CC(=O)CN1C(OC(C)(C)C)=O)(C(C)(C)C)(C)C.[Si:25]([O:32][CH2:33][C@H:34]1[N:39]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:38][C:37]([O:47][Si](C)(C)C)=[CH:36][CH:35]1[CH:52]([CH3:54])[CH3:53])([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26]>>[Si:25]([O:32][CH2:33][C@@H:34]1[C:35]([CH:52]([CH3:54])[CH3:53])=[CH:36][C:37](=[O:47])[CH2:38][N:39]1[C:40]([O:42][C:43]([CH3:45])([CH3:44])[CH3:46])=[O:41])([C:28]([CH3:29])([CH3:30])[CH3:31])([CH3:27])[CH3:26]
Reactant: CC(C)C1C=C(O[Si](C)(C)C)CN(C(=O)OC(C)(C)C)[C@@H]1CO[Si](C)(C)C(C)(C)C
Agent: CC1=CC(=O)CN(C(=O)OC(C)(C)C)[C@@H]1CO[Si](C)(C)C(C)(C)C
Product: CC(C)C1=CC(=O)CN(C(=O)OC(C)(C)C)[C@@H]1CO[Si](C)(C)C(C)(C)C
Yield: 14.32 %

Procedure:
(S)-tert-butyl 2-((tert-butyldimethylsilyloxy)methyl)-3-isopropyl-5-oxo-5,6-dihydropyridine-1(2H)-carboxylate (804 mg, 14.32%) (over two steps) was prepared as described in Intermediate 78 as a yellow oil, using (6S)-tert-butyl 6-((tert-butyldimethylsilyloxy)methyl)-5-isopropyl-3-(trimethylsilyloxy)-5,6-dihydropyridine-1(2H)-carboxylate (Intermediate 88, theoretically 6.7 g, 14.64 mmol).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([S:8]([CH2:11][CH2:12]C)(=[O:10])=[O:9])[CH:5]=[CH:4][C:3]=1[F:14].F[C:16]1C=CC(S(C(C)C)(=O)=O)=CC=1>>[Br:1][C:2]1[CH:7]=[C:6]([S:8]([CH:11]([CH3:12])[CH3:16])(=[O:9])=[O:10])[CH:5]=[CH:4][C:3]=1[F:14]
Reactant: CCCS(=O)(=O)c1ccc(F)c(Br)c1
Reactant: CC(C)S(=O)(=O)c1ccc(F)cc1
Product: CC(C)S(=O)(=O)c1ccc(F)c(Br)c1
Yield: 89 %

Procedure:
Following the general method as outlined in Intermediate 106, starting from 1-fluoro-4-(isopropylsulfonyl)benzene, the title compound was obtained as an oil which solidifies upon standing in 89% yield.
Reaction SMILES: NC1(C2C=CC(C3C(=O)C4C(=CC=C(F)C=4)OC=3C3C=CC=CC=3)=CC=2)CCC1.C(OC(=O)[NH:36][C:37]1([C:41]2[CH:46]=[CH:45][C:44]([C:47]3[C:48](=[O:72])[C:49]4[C:54]([O:55][C:56]=3[C:57]3[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=3)=[C:53]3[N:63](S(=O)(=O)N(C)C)[N:64]=[CH:65][C:52]3=[CH:51][CH:50]=4)=[CH:43][CH:42]=2)[CH2:40][CH2:39][CH2:38]1)(C)(C)C>>[NH2:36][C:37]1([C:41]2[CH:42]=[CH:43][C:44]([C:47]3[C:48](=[O:72])[C:49]4[C:54]([O:55][C:56]=3[C:57]3[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=3)=[C:53]3[NH:63][N:64]=[CH:65][C:52]3=[CH:51][CH:50]=4)=[CH:45][CH:46]=2)[CH2:40][CH2:39][CH2:38]1
Reactant: CN(C)S(=O)(=O)n1ncc2ccc3c(=O)c(-c4ccc(C5(NC(=O)OC(C)(C)C)CCC5)cc4)c(-c4ccccc4)oc3c21
Agent: NC1(c2ccc(-c3c(-c4ccccc4)oc4ccc(F)cc4c3=O)cc2)CCC1
Product: NC1(c2ccc(-c3c(-c4ccccc4)oc4c(ccc5cn[nH]c54)c3=O)cc2)CCC1
Yield: 71 %

Procedure:
Following the procedure used to prepare 3-[4-(1-amino-cyclobutyl)-phenyl]-6-fluoro-2-phenyl-chromen-4-one, {1-[4-(1-dimethylsulfamoyl-6-oxo-8-phenyl-1,6-dihydro-9-oxa-1,2-diaza-cyclopenta[a]naphthalen-7-yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester was reacted to give the title compound as a white solid (31 mg, 71%). 1H NMR (400 MHz, DMSO-d6): δ 14.26 (bs, 1H), 8.32 (s, 1H), 7.77 (d, J=8.5 Hz, 1H), 7.68 (d, J=8.5 Hz, 1H), 7.53-7.49 (m, 2H), 7.41-7.30 (m, 5H), 7.14 (d, J=8.5 Hz, 2H), 3.28 (bs, 2H), 2.40-2.32 (m, 2H), 2.12-2.03 (m, 2H), 2.02-1.91 (m, 1H), 1.68-1.57 (m, 1H). LCMS (Method E): RT=3.05 min, [M+H]+=408.
Reaction SMILES: C(O[C:9]1[CH:14]=[CH:13][N:12]=[C:11]([NH:15][NH:16][C:17](=O)[CH2:18][CH:19]2[CH2:21][CH2:20]2)[C:10]=1[C:23]#[N:24])C1C=CC=CC=1.O(Cl)[Cl:26].[P+5]>ClCCCl.C(Cl)Cl>[Cl:26][C:9]1[CH:14]=[CH:13][N:12]2[C:17]([CH2:18][CH:19]3[CH2:21][CH2:20]3)=[N:16][N:15]=[C:11]2[C:10]=1[C:23]#[N:24]
Reactant: N#Cc1c(OCc2ccccc2)ccnc1NNC(=O)CC1CC1
Reactant: ClOCl
Agent: [P+5]
Solvent: ClCCCl
Solvent: ClCCl
Product: N#Cc1c(Cl)ccn2c(CC3CC3)nnc12
Temperature: 150 °C
Yield: 64.3 %

Procedure:
Intermediate compound D4 (1.4 g, 4.343 mmol) and phosphorous (V) oxychloride (0.810 ml, 8.686 mmol) in DCE (15 ml) were subjected to microwave heating at 150° C. for 5 min. After cooling, the mixture was diluted with DCM and washed with NaHCO3 (aqueous sat. solution). The organic layer was separated, dried (Na2SO4) and concentrated in vacuo. The crude product was purified by column chromatography (silica gel; DCM/7M solution of NH3 in MeOH up to 2% as eluent). The desired fractions were collected and concentrated in vacuo to yield intermediate compound D5 (0.650 g, 64%).
Reaction SMILES: [CH2:1]([N:3]1[CH:7]=[C:6](I)[CH:5]=[C:4]1[S:9]([CH3:12])(=[O:11])=[O:10])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C.[Br:39][C:40]1[CH:45]=[C:44]([C:46]#[CH:47])[CH:43]=[CH:42][C:41]=1[F:48]>CN(C=O)C.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.CCOC(C)=O>[Br:39][C:40]1[CH:45]=[C:44]([C:46]#[C:47][C:6]2[CH:5]=[C:4]([S:9]([CH3:12])(=[O:11])=[O:10])[N:3]([CH2:1][CH3:2])[CH:7]=2)[CH:43]=[CH:42][C:41]=1[F:48]
Reactant: C#Cc1ccc(F)c(Br)c1
Reactant: CCn1cc(I)cc1S(C)(=O)=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCn1cc(C#Cc2ccc(F)c(Br)c2)cc1S(C)(=O)=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 2 %

Procedure:
A solution of 1-ethyl-4-iodo-2-methanesulfonyl-1H-pyrrole (0.28 g, 0.94 mmol) in DMF was treated with dichlorobis(triphenylphosphine)-palladium(II) (0.033 g, 0.05 mmol), triphenylphosphine (0.0054 g, 0.028 mmol) and triethylamine (0.68 mL, 4.9 mmol), treated dropwise with a solution of 2-bromo-4-ethynyl-1-fluorobenzene (0.28 g, 1.4 mmol) in DMF, stirred at room temperature for 18 h, poured into EtOAc and washed sequentially with water and brine. The organic phase is separated, dried (Na2SO4) and concentrated in vacuo. Chromatography of the resultant residue (silica gel, 2%-20% EtOAC-hexanes as eluent) yielded an oil; 1H NMR (400 MHz, CDCl3) δ: 1.50 (t, 3H, J=7.3 Hz), 3.12 (s, 3H), 4.28 (q, 2H, J=7.3 Hz), 7.01 (d, 1H, J=1.8 Hz), 7.07 (t, 1H, J=8.5 Hz), 7.12 (d, 1H, J=1.8 Hz), 7.37 (m, 1H), 7.66 (dd, 1H, J=2.1, 6.6 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:12][CH2:11][CH2:10][NH:9]1.[C:13]1([CH3:23])[CH:18]=[CH:17][C:16]([S:19](Cl)(=[O:21])=[O:20])=[CH:15][CH:14]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:12][CH2:11][CH2:10][N:9]1[S:19]([C:16]1[CH:17]=[CH:18][C:13]([CH3:23])=[CH:14][CH:15]=1)(=[O:21])=[O:20]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Clc1ccccc1C1CCCN1
Product: Cc1ccc(S(=O)(=O)N2CCCC2c2ccccc2Cl)cc1

Procedure:
The title compound, white solid, m.p. 149° C. and MS: m/e=336.2 (M+H+) was prepared in accordance with the general method of example 1e from (RS)-2-(2-chloro-phenyl)-pyrrolidine and toluene-4-sulfonyl chloride.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([CH:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl[C:21]1[C:26]([Cl:27])=[CH:25][CH:24]=[CH:23][N:22]=1.CCN(C(C)C)C(C)C>O1CCOCC1>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([S:11]([CH:14]2[CH2:15][CH2:16][N:17]([C:21]3[C:26]([Cl:27])=[CH:25][CH:24]=[CH:23][N:22]=3)[CH2:18][CH2:19]2)(=[O:13])=[O:12])=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Clc1cccnc1Cl
Reactant: CC(C)(C)c1ccc(S(=O)(=O)C2CCNCC2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CC(C)(C)c1ccc(S(=O)(=O)C2CCN(c3ncccc3Cl)CC2)cc1
Yield: 28.3 %

Procedure:
Using the procedure from Example 7A, 4-[(4-tert-butylphenyl)sulfonyl]piperidine (100 mg, 0.36 mmol) was reacted with 2,3-dichloropyridine (108 mg, 0.72 mmol), DIEA (0.25 ml, 1.44) and 1,4-dioxane (0.3 ml) at 185° C. to afford the title compound (40 mg), a white solid, in 28% yield.
Reaction SMILES: [F:1][C:2]1[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].C(N(CC)CC)C.[NH2:19][C:20]1[CH:41]=[CH:40][C:23]([C:24]([N:26]2[C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=3[CH2:30][N:29]3[CH:37]=[CH:38][CH:39]=[C:28]3[CH2:27]2)=[O:25])=[CH:22][CH:21]=1>C(Cl)Cl>[CH:39]1[CH:38]=[CH:37][N:29]2[CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[N:26]([C:24]([C:23]3[CH:22]=[CH:21][C:20]([NH:19][C:4](=[O:5])[C:3]4[CH:7]=[CH:8][CH:9]=[C:10]([F:11])[C:2]=4[F:1])=[CH:41][CH:40]=3)=[O:25])[CH2:27][C:28]=12
Reactant: O=C(Cl)c1cccc(F)c1F
Reactant: Nc1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)cc1)c1cccc(F)c1F
Reaction time: 0.05 h
Yield: 0 %

Procedure:
To a stirred solution of 0,350 g of 2,3-difluorobenzoyl chloride in 5 ml of methylene chloride is added 0.346 ml of triethylamine. After stirring for 3 minutes, 0,500 g of 10,11-dihydro-10-(4-aminobenzoyl)-5H-pyrrolo[2,1-c][1,4]benzodiazepine is added and stirring continued for 72 hours. The reaction mixture is filtered and the solid washed with methylene chloride. The solid is saved. The combined filtrate is washed with water, 2N citric acid, 1M NaHCO3, and brine. The reaction mixture is dried with Na2SO4, filtered and evaporated in vacuo to give 100 mg of a solid. The two solids are combined and dried to afford 790 mg of the desired product as a solid, m.p. 252°-258° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:32])=[C:4]([C:23]2[CH:24]=[CH:25][C:26]([C:29]([OH:31])=O)=[N:27][CH:28]=2)[C:5]([O:20][CH2:21][CH3:22])=[C:6]([CH:8]([NH:10][C:11]2[N:19]=[CH:18][N:17]=[C:16]3[C:12]=2[N:13]=[CH:14][NH:15]3)[CH3:9])[CH:7]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)[N:51]([CH3:53])[CH3:52])C2C=CC=CC=2N=N1.CNC.C1COCC1.C(N(CC)CC)C>CN(C=O)C.CCOC(C)=O>[Cl:1][C:2]1[C:3]([F:32])=[C:4]([C:23]2[CH:24]=[CH:25][C:26]([C:29]([N:51]([CH3:53])[CH3:52])=[O:31])=[N:27][CH:28]=2)[C:5]([O:20][CH2:21][CH3:22])=[C:6]([CH:8]([NH:10][C:11]2[N:19]=[CH:18][N:17]=[C:16]3[C:12]=2[N:13]=[CH:14][NH:15]3)[CH3:9])[CH:7]=1
Reactant: CCOc1c(C(C)Nc2ncnc3[nH]cnc23)cc(Cl)c(F)c1-c1ccc(C(=O)O)nc1
Reactant: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: CNC
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CCOc1c(C(C)Nc2ncnc3[nH]cnc23)cc(Cl)c(F)c1-c1ccc(C(=O)N(C)C)nc1
Temperature: 20 °C
Reaction time: 3 h
Yield: 7.5 %

Procedure:
A solution of 5-{3-chloro-6-ethoxy-2-fluoro-5-[1-(9H-purin-6-ylamino)ethyl]phenyl}pyridine-2-carboxylic acid (61 mg, 0.13 mmol) and benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (0.11 g, 0.26 mmol) in DMF (1.4 mL) was treated with 2.0 M dimethylamine in THF (0.26 mL, 0.52 mmol) followed by triethylamine (0.072 mL, 0.52 mmol) and stirred at 20° C. for 3 hours. The reaction mixture was diluted with EtOAc and washed with water and brine. The organic layer was separated, dried with magnesium sulfate, filtered, and concentrated to give a crude oil. The crude material was purified by flash column chromatography using EtOAc in hexanes (0%-70%) to give the desired product (4.7 mg, 7%). LCMS for C23H24ClFN7O2 (M+H)+: m/z=484.2. Found: 484.1.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:20]2[CH:25]=[CH:24][C:23]([CH2:26][C:27]([NH2:29])=[O:28])=[C:22]([F:30])[CH:21]=2)[CH:7]=[N:8][C:9]=1[O:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1)[CH3:2].Br[C:32]1[CH:39]=[CH:38][C:35]([C:36]#[N:37])=[C:34]([C:40]([F:43])([F:42])[F:41])[CH:33]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:36]([C:35]1[CH:38]=[CH:39][C:32]([NH:29][C:27](=[O:28])[CH2:26][C:23]2[CH:24]=[CH:25][C:20]([C:6]3[CH:7]=[N:8][C:9]([O:10][CH2:11][C:12]4[CH:13]=[CH:14][C:15]([O:18][CH3:19])=[CH:16][CH:17]=4)=[C:4]([O:3][CH2:1][CH3:2])[CH:5]=3)=[CH:21][C:22]=2[F:30])=[CH:33][C:34]=1[C:40]([F:41])([F:42])[F:43])#[N:37]
Reactant: N#Cc1ccc(Br)cc1C(F)(F)F
Reactant: CCOc1cc(-c2ccc(CC(N)=O)c(F)c2)cnc1OCc1ccc(OC)cc1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CCOc1cc(-c2ccc(CC(=O)Nc3ccc(C#N)c(C(F)(F)F)c3)c(F)c2)cnc1OCc1ccc(OC)cc1
Yield: 54.2 %

Procedure:
A solution of 2-(4-(5-ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl) acetamide (10 mg, 0.024 mmol), 4-bromo-2-(trifluoromethyl)benzonitrile (6.09 mg, 0.024 mmol), Pd2(dba)3 (2.231 mg, 2.436 μmol), Xantphos (1.410 mg, 2.436 μmol) and Cs2CO3 (15.88 mg, 0.049 mmol) in 1,4-dioxane (1 mL) was stirred at 120° C. for 1 h. After LCMS analysis showed the starting material had disappeared, the solvent was removed in vacuo. The residue was dissolved in EA (20 mL) and washed with H2O (10 mL) and brine (10 mL). The organic layer was dried over Na2SO4, filtered and concentrated. The crude material was purified by preparative TLC (PE/EA=1/1) to yield a white solid of N-(4-cyano-3-(trifluoromethyl)phenyl)-2-(4-(5-ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)acetamide (15 mg, 0.013 mmol, 51.4% yield): 1H NMR (400 MHz, CD3OD) δ 8.23 (s, 1H), 7.98 (m, 1H), 7.94-7.90 (m, 2H), 7.44-7.37 (m, 6H), 6.90 (d, J=8.4 Hz, 2H), 5.32 (s, 2H), 4.16-4.11 (m, 2H), 2.85 (s, 2H), 3.77 (s, 3H), 1.41 (t, J=7.2 Hz, 3H); ES-LCMS m/z 460.1 (M-120).
Reaction SMILES: C(S([N:6]1C[CH2:10][CH:9]([C:12]2C3C(=C(C(N)=O)C=C(C4SC(CNCC(C)CC)=CC=4)C=3)NC=2)[CH2:8][CH2:7]1)(=O)=O)C.[CH:36]([C:38]1[S:42][C:41]([B:43]([OH:45])[OH:44])=[CH:40][CH:39]=1)=O.CC(C)CCN.[BH3-]C#N.[Na+]>>[CH3:10][CH:9]([CH3:12])[CH2:8][CH2:7][NH:6][CH2:36][C:38]1[S:42][C:41]([B:43]([OH:45])[OH:44])=[CH:40][CH:39]=1
Reactant: O=Cc1ccc(B(O)O)s1
Reactant: CCC(C)CNCc1ccc(-c2cc(C(N)=O)c3[nH]cc(C4CCN(S(=O)(=O)CC)CC4)c3c2)s1
Agent: CC(C)CCN
Agent: [BH3-]C#N
Agent: [Na+]
Product: CC(C)CCNCc1ccc(B(O)O)s1

Procedure:
Following the general procedure of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-{[(2-methylbutyl)amino]methyl}-2-thienyl)-1H-indole-7-carboxamide, (5-formyl-2-thienyl)boronic acid (50 mg, 0.32 mmol), (3-methylbutyl)amine (28 mg, 0.32 mmol), and NaCNBH3 (40 mg, 0.64 mmol) were reacted to give 46 mg of crude (5-{[(3-methylbutyl)amino]methyl}-2-thienyl)boronic acid. The crude (5-{[(3-methylbutyl)amino]methyl}-2-thienyl)boronic acid was then reacted with 5-bromo-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide (65 mg, 0.157 mmol), K2CO3 (130 mg, 0.942 mmol), and tetrakis(triphenylphosphine)palladium(0) (4 mg, 0.003 mmol) to give 38.3 mg of the title compound (37%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([O:10]CC)=[O:9])=[CH:6][N:5]=[C:4]2[NH:13][CH:14]=[CH:15][C:3]=12.[OH-].[Na+].Cl>C(O)C>[Cl:1][C:2]1[C:7]([C:8]([OH:10])=[O:9])=[CH:6][N:5]=[C:4]2[NH:13][CH:14]=[CH:15][C:3]=12
Reactant: CCOC(=O)c1cnc2[nH]ccc2c1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1cnc2[nH]ccc2c1Cl
Temperature: 50 °C
Reaction time: 2 h
Yield: 85.7 %

Procedure:
To a solution of ethyl 4-chloro-1H-pyrrolo[2,3-b]pyridine-5-carboxylate (100 mg) in ethanol (1 mL) was added 1M NaOH solution (0.89 mL) and the mixture was stirred at 50° C. for 2 hours. The mixture was cooled to 4° C. and acidified with 1M HCl and the precipitate was filtrated and washed with water to give 4-chloro-1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid (75 mg) as a white powder.