Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[NH:17][C:18]1[CH:32]=[CH:31][C:21]([CH2:22][NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[CH:20][CH:19]=1.[Cl:33][C:34]1[CH:39]=[C:38](B2OC(C)(C)C(C)(C)O2)[CH:37]=[C:36]([F:49])[C:35]=1[OH:50]>>[Cl:33][C:34]1[CH:39]=[C:38]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[CH:7][C:6]([C:12]([CH:14]2[CH2:16][CH2:15]2)=[O:13])=[C:5]3[NH:17][C:18]2[CH:32]=[CH:31][C:21]([CH2:22][NH:23][C:24](=[O:30])[O:25][C:26]([CH3:27])([CH3:29])[CH3:28])=[CH:20][CH:19]=2)[CH:37]=[C:36]([F:49])[C:35]=1[OH:50]
Reactant: CC1(C)OB(c2cc(F)c(O)c(Cl)c2)OC1(C)C
Reactant: CC(C)(C)OC(=O)NCc1ccc(Nc2c(C(=O)C3CC3)cnc3ccc(Br)cc23)cc1
Product: CC(C)(C)OC(=O)NCc1ccc(Nc2c(C(=O)C3CC3)cnc3ccc(-c4cc(F)c(O)c(Cl)c4)cc23)cc1
Yield: 98.1 %

Procedure:
Following general procedure F, tert-butyl 4-[6-bromo-3-(cyclopropanecarbonyl)quinolin-4-ylamino]benzylcarbamate (63 mg, 0.127 mmol) was reacted with 2-chloro-6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (52 mg, 0.191 mmol) to afford the crude product (70 mg) as a yellow solid: ESI MS m/z 562 [C31H29ClFN3O4+H]+.
Reaction SMILES: Br[C:2]1[N:10]=[C:9]([S:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[C:14]=2[F:20])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([NH:21]C(=O)OCC)[NH:6]2.[NH2:27][CH:28]([CH2:31][OH:32])[CH2:29][OH:30].C(N(C(C)C)CC)(C)C>CN1C(=O)CCC1>[NH2:21][C:5]1[NH:6][C:7]2[C:3]([N:4]=1)=[C:2]([NH:27][CH:28]([CH2:31][OH:32])[CH2:29][OH:30])[N:10]=[C:9]([S:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[C:14]=1[F:20])[N:8]=2
Reactant: NC(CO)CO
Reactant: CCOC(=O)Nc1nc2c(Br)nc(SCc3cccc(F)c3F)nc2[nH]1
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: Nc1nc2c(NC(CO)CO)nc(SCc3cccc(F)c3F)nc2[nH]1
Temperature: 150 °C
Yield: 27.6 %

Procedure:
The product of example 5, step (e) (40 mg) was dissolved in NMP and 2-amino-1,3-propanediol (49.2 mg) and diisopropylethylamine (31 μl) base was added and the solution was heated at 150° C. for 36 hr. The reaction mixture was then evaporated to a residue that was purified by preparative HPLC to yield the titled compound as a pale yellow solid (9.5 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8](B2OC(C)(C)C(C)(C)O2)=[CH:7][CH:6]=[CH:5][N:4]=1.[C:18]([O:22][C@@H:23]([C:29]1[C:44]([CH3:45])=[CH:43][C:32]2[N:33]=[C:34]([C:36]3[CH:41]=[CH:40][N:39]=[C:38](Cl)[CH:37]=3)[S:35][C:31]=2[C:30]=1[C:46]1[CH:51]=[CH:50][C:49]([Cl:52])=[CH:48][CH:47]=1)[C:24]([O:26][CH2:27][CH3:28])=[O:25])([CH3:21])([CH3:20])[CH3:19].C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.C(OCC)(=O)C.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>[C:18]([O:22][C@@H:23]([C:29]1[C:44]([CH3:45])=[CH:43][C:32]2[N:33]=[C:34]([C:36]3[CH:41]=[CH:40][N:39]=[C:38]([C:8]4[C:3]([O:2][CH3:1])=[N:4][CH:5]=[CH:6][CH:7]=4)[CH:37]=3)[S:35][C:31]=2[C:30]=1[C:46]1[CH:47]=[CH:48][C:49]([Cl:52])=[CH:50][CH:51]=1)[C:24]([O:26][CH2:27][CH3:28])=[O:25])([CH3:19])([CH3:20])[CH3:21]
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccnc(Cl)c3)sc2c1-c1ccc(Cl)cc1
Reactant: COc1ncccc1B1OC(C)(C)C(C)(C)O1
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: [K+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccnc(-c4cccnc4OC)c3)sc2c1-c1ccc(Cl)cc1
Temperature: 100 °C

Procedure:
A mixture of 2-methoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (13 mg, 0.0878 mmol), (S)-ethyl 2-tert-butoxy-2-(7-(4-chlorophenyl)-2-(2-chloropyridin-4-yl)-5-methylbenzo[d]thiazol-6-yl)acetate (31 mg, 0585 mmol) and 2M potassium carbonate solution (88 μL, 0.178 mmol) in dioxane (0.5 mL) was sparged with nitrogen for 10 minutes. Pd(PPh3)4 (6.9 mg, 0.0059 mmol) was added and reaction mixture was heated in microwave at 100° C. for 1 h . Reaction mixture was diluted with ethyl acetate, washed with brine. The aqueous layer was back extracted with ethyl acetate and the combined organic layer was dried (MgSO4), filtered, concentrated and purified by CombiFlash (0 to 40% EtOAc/Hex) to give product. LCMS-ESI+: calc'd for C33H33ClN3O4S: 602.1 (M+H+); Found: 602.3 (M+H+).
Reaction SMILES: O=[C:2]1[NH:7][C:6]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[N:5][C:4]2[S:13][C:14]3[CH2:19][N:18]([CH3:20])[CH2:17][CH2:16][C:15]=3[C:3]1=2.P(Cl)(Cl)([Cl:23])=O>>[Cl:23][C:2]1[C:3]2[C:15]3[CH2:16][CH2:17][N:18]([CH3:20])[CH2:19][C:14]=3[S:13][C:4]=2[N:5]=[C:6]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:7]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOC(=O)c1nc2sc3c(c2c(=O)[nH]1)CCN(C)C3
Product: CCOC(=O)c1nc(Cl)c2c3c(sc2n1)CN(C)CC3
Temperature: 90 °C
Reaction time: 3 h

Procedure:
10 g of ethyl 5,6,7,8-tetrahydro-4-oxo-7-methylpyrido[4′,3′:4,5]thieno[2,3-d]pyrimidine-2-carboxylate was added to 60 ml of phosphorus oxychloride, and stirred at 80 to 100° C. for 3 hours. After phosphorus oxychloride was distilled off under reduced pressure, 100 ml of cool water was added to the reaction residue. The reaction solution was made alkaline with an aqueous saturated solution of sodium hydrogen carbonate, and extracted with chloroform. The organic layer was washed with saturated salt water and dried over anhydrous magnesium sulfate. After magnesium sulfate was filtered off, the filtrate was concentrated under reduced pressure to give 9.5 g of ethyl 5,6,7,8-tetrahydro-4-chloro-7-methylpyrido[4′,3′:4,5]thieno[2,3-d]pyrimidine-2-carboxylate.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].Cl.[NH2:9][CH2:10][C:11]1[CH:12]=[CH:13][C:14]2[O:18][C:17]([N+:19]([O-:21])=[O:20])=[C:16]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:15]=2[CH:28]=1>C(O)(C)C>[C:1]([NH:9][CH2:10][C:11]1[CH:12]=[CH:13][C:14]2[O:18][C:17]([N+:19]([O-:21])=[O:20])=[C:16]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:15]=2[CH:28]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: NCc1ccc2oc([N+](=O)[O-])c(-c3ccccc3)c2c1
Agent: Cl
Solvent: CC(C)O
Product: CC(=O)NCc1ccc2oc([N+](=O)[O-])c(-c3ccccc3)c2c1

Procedure:
A mixture of 5 ml. of acetic anhydride and 0.3 g. of 5-aminomethyl-2-nitro-3-phenylbenzofuran hydrochloride (from Example 17) is heated on a steam bath for about 30 minutes. The mixture is then partially evaporated to provide a residue which is treated with aqueous isopropanol to form yellow crystals of 5-acetamidomethyl-2-nitro-3-phenylbenzofuran, m.p. 201°-203° C., having the structure
Reaction SMILES: [CH2:1]([C:11]1[S:12][C:13]([C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[C:18]([F:23])[CH:17]=2)=[N:14][N:15]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[C:24](O)(=[O:29])[CH2:25][CH2:26][CH2:27][CH3:28].C1(N=C=NC2CCCCC2)CCCCC1.N1(C2C=CN=CC=2)CCCC1>ClCCl>[CH2:1]([C:11]1[S:12][C:13]([C:16]2[CH:21]=[CH:20][C:19]([O:22][C:24](=[O:29])[CH2:25][CH2:26][CH2:27][CH3:28])=[C:18]([F:23])[CH:17]=2)=[N:14][N:15]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCCCCCc1nnc(-c2ccc(O)c(F)c2)s1
Reactant: CCCCC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: c1cc(N2CCCC2)ccn1
Solvent: ClCCl
Product: CCCCCCCCCCc1nnc(-c2ccc(OC(=O)CCCC)c(F)c2)s1
Temperature: 25 °C
Yield: 56 %

Procedure:
40 ml of dichloromethane was added to a mixture of 2.0 g (5.94 mM) of 2-decyl-5-(3-fluoro-4-hydroxyphenyl)-1,3,4-thiadiazole and 0.61 g (5.97 mM) of pentanoic acid. Under stirring at room temperature, 1.21 g (5.86 mM) of N,N'-dicyclohexylcarbodiimide (DCC) and 0.05 g of 4-pyrrolidinopyridine were successively added to the above mixture, followed by stirring for 19 hours at room temperature. After the reaction, precipitated N,N'-dicyclohexylurea was recovered by filtration, washed with dichloromethane and added to the filtrate. The resultant dichloromethane solution was subjected to distillation under reduced pressure to obtain a residue. The residue was purified by silica gel column chromatography (eluent: benzene) and recrystallized from ethanol to obtain 1.40 g of 2-decyl-5-(3-fluoro-4-pentanoyloxyphenyl)-1,3,4-thiadiazole (Yield: 56.9%). ##STR132##
Reaction SMILES: [Br-].[C:2]([CH2:4][CH2:5][CH2:6][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)#[N:3].CC([O-])(C)C.[K+].[CH2:32]([N:39]1[CH2:44][CH2:43][CH2:42][C:41](=O)[CH2:40]1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>C1(C)C=CC=CC=1>[CH2:32]([N:39]1[CH2:44][CH2:43][CH2:42][C:41](=[CH:6][CH2:5][CH2:4][C:2]#[N:3])[CH2:40]1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: O=C1CCCN(Cc2ccccc2)C1
Reactant: N#CCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [Br-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: N#CCCC=C1CCCN(Cc2ccccc2)C1
Reaction time: 8 h

Procedure:
77.3 g (188.3 mmol) 3-cyanopropyl-triphenylphosphonium bromide are suspended in 300 ml toluene and added to 22.0 g (191.9 mmol) potassium tert-butylate. The mixture is cooled to ca 0° C. under moisture exclusion and a solution of 34.6 g (182.8 mmol) 1-benzyl-3-piperidone in 50 ml toluene is added dropwise under cooling. The batch is left to stand overnight at ca. 0° C. and subsequently diluted with 200 ml toluene and washed twice, each with 100 ml water. The organic phase is extracted with 150 ml half concentrated hydrochloric acid. Subsequently, the aqueous phase is made basic with 200 ml 10% sodium hydroxide solution and extracted twice, each with 250 ml toluene.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[CH2:5]([CH:12]1[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][CH2:20]OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:14][CH2:13]1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>CN(C=O)C.O>[CH2:5]([CH:12]1[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][CH2:20][N:1]=[N+:2]=[N-:3])[CH2:14][CH2:13]1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)OCCCN2CCC(Cc3ccccc3)CC2)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: [N-]=[N+]=NCCCN1CCC(Cc2ccccc2)CC1
Temperature: 80 °C
Reaction time: 3 h

Procedure:
Sodium azide was added to a solution of 4-benzyl-1-(3-p-toluenesulfonyloxypropyl)piperidine (0.216 g, 0.56 mmol) in DMF (5 mL). The resulting solution was stirred at 80° C. for 3 h then cooled at 25° C., diluted with water (50 mL) and extracted with diethyl ether (2×50 mL). The collected organic phase was washed with water (2×50 mL), dried and concentrated in vacuum to afford crude title compound as an oil (0.15 g). 1H-NMR (CDCl3): 1.2-1.4 (m, 2H), 1.4-1.6 (m, 1H) 1.628 (dd, J=13.2 Hz, 2H), 1. 761 (t, J=7.2 Hz, 2H), 1.857 (t, J=11.4 Hz, 2H), 2.367 (t, J=7.2 Hz, 2H), 2.53 (d, J=7.2 Hz, 2H), 2.86 (bd, J=11.4, 2H), 3.314 (t, J=6.9 Hz, 2H), 7.14 (d, J=7.5 Hz, 2H), 7.19 (d, J=6.9, 1H), 7.275 (t, J=7.2 Hz, 2H).
Reaction SMILES: CO[C:3](=[O:23])[CH2:4][N:5]1[CH2:9][C:8]([OH:10])=[C:7]([C:11]2[CH2:15][N:14]([CH2:16][C:17]([O:19]C)=O)[C:13](=[O:21])[CH:12]=2)[C:6]1=[O:22].[NH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1>>[OH:10][C:8]1[CH2:9][N:5]([CH2:4][C:3]([N:24]2[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)=[O:23])[C:6](=[O:22])[C:7]=1[C:11]1[CH2:15][N:14]([CH2:16][C:17]([N:24]2[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)=[O:19])[C:13](=[O:21])[CH:12]=1
Reactant: C1CCNCC1
Reactant: COC(=O)CN1CC(C2=C(O)CN(CC(=O)OC)C2=O)=CC1=O
Product: O=C1C=C(C2=C(O)CN(CC(=O)N3CCCCC3)C2=O)CN1CC(=O)N1CCCCC1

Procedure:
Analogously to the procedure described in Example 2, from 4.8 g (0.015 mol) of 1,1',5,5'-tetrahydro-4-hydroxy-2,2'-dioxo-[3,4'-bi-2H-pyrrole]-1,1'-diacetic acid dimethyl ester and 25 ml of piperidine there is obtained 1,1',5,5'-tetrahydro-4-hydroxy-2,2'-dioxo-[3,4'-bi-2H-pyrrole]-1,1'-diacetic acid dipiperidide in the form of pale yellow microcrystals having a melting point of 150°-155° (decomposition).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:13][CH2:12][C@H:11]([C:14]3[C:15](=[O:26])[C:16]4[C:21]([C:22](=[O:25])[C:23]=3Cl)=[CH:20][CH:19]=[CH:18][CH:17]=4)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[OH-:27].[K+]>CO.O>[CH:18]1[CH:19]=[CH:20][C:21]2[C:22]([C:23]([OH:27])=[C:14]([C@@H:11]3[CH2:10][CH2:9][C@@H:8]([C:5]4[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=4)[CH2:13][CH2:12]3)[C:15](=[O:26])[C:16]=2[CH:17]=1)=[O:25]
Reactant: [OH-]
Reactant: O=C1C(Cl)=C([C@H]2CC[C@H](c3ccc(Cl)cc3)CC2)C(=O)c2ccccc21
Agent: [K+]
Solvent: O
Solvent: CO
Product: O=C1C(O)=C([C@H]2CC[C@H](c3ccc(Cl)cc3)CC2)C(=O)c2ccccc21
Temperature: 31 °C

Procedure:
The residue obtained (Formula IV) was suspended in 4.5 liter methanol. A solution of potassium hydroxide (225 gm) in water (1550 ml) was added drop-wise under heating over a period of one hour. The reaction mass was then refluxed for 2 hours and cooled to 30-32° C. and filtered. The filtrate was neutralized with 50% aqueous hydrochloric acid to precipitate atovaquone in a cis/trans-isomeric mixture (116 gm).
Reaction SMILES: [CH:1]1([CH:6]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][N:21]3[C:29](=[O:30])[C:28]4[C:23](=[C:24]([F:32])[CH:25]=[CH:26][C:27]=4[F:31])[C:22]3=[O:33])=[CH:16][CH:15]=2)[C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2]1.[BH4-].[Na+].ClCCl>C(O)C>[CH:1]1([CH:6]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][N:21]3[C:22](=[O:33])[C:23]4[C:28](=[C:27]([F:31])[CH:26]=[CH:25][C:24]=4[F:32])[CH:29]3[OH:30])=[CH:16][CH:15]=2)[C:7]([O:9][C:10]([CH3:12])([CH3:11])[CH3:13])=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)C(c1ccc(CN2C(=O)c3c(F)ccc(F)c3C2=O)cc1)C1CCCC1
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCO
Product: CC(C)(C)OC(=O)C(c1ccc(CN2C(=O)c3c(F)ccc(F)c3C2O)cc1)C1CCCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 200.0 mg (0.44 mmol) of tert-butyl(+/−)-cyclopentyl{4-[(4,7-difluoro-1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]phenyl}acetate in 1 ml of ethanol was cooled to 0° C., and 18.3 mg (0.48 mmol) of sodium borohydride were added. 0.2 ml of dichloromethane was added, and the reaction mixture was warmed to RT. After 1 h of stirring, the mixture was concentrated and the residue was purified by chromatography on silica gel (mobile phase cyclohexane/ethyl acetate 6:1 to 4:1). This gave 182 mg (90.6% of theory) of the target compound.
Reaction SMILES: [NH:1]1[CH2:9][CH2:8][CH2:7][CH2:6][C@@H:2]1[C:3]([OH:5])=[O:4].[OH-].[Na+].Cl[C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14]>O1CCCC1.O>[N:1]1([C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:14])[CH2:9][CH2:8][CH2:7][CH2:6][C@@H:2]1[C:3]([OH:5])=[O:4]
Reactant: O=C(O)[C@H]1CCCCN1
Reactant: O=C(Cl)OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)[C@H]1CCCCN1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.2 %

Procedure:
D-hPro-OH (5.0 g, 38.7 mmol) was dissolved in tetrahydrofuran (100 mL) and water (30 mL). The pH of the solution was adjusted to 9.5 with 2N NaOH and benzyl chloroformate (5.5 mL, 38.7 mmol) was added dropwise and the pH maintained at 9.5 with 2N NaOH. The reaction was stirred for an additional 1 hour at room temperature. The organic solvent was evaporated in vacuo, and diethyl ether (100 mL) and water (50 mL) were added to the residue. The aqueous layer was separated, the pH of the aqueous solution was adjusted to 2.8 with 3N HCl, and ethyl acetate (150 mL) was added. The organic layer was separated and dried (MgSO4) and the filtrate was concentrated in vacuo to give 9.6 g (95%) of a clear oil.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:14]=[CH:13][C:12]([CH:15]3[CH2:17][CH:16]3[C:18]([O:20]CC)=[O:19])=[CH:11][CH:10]=2)O1.Br[C:25]1[CH:26]=[C:27]([N:31]2[C:40]3[C:35](=[CH:36][CH:37]=[CH:38][N:39]=3)[C:34](=[O:41])[C:33]([C:42]([N:44]3[CH2:49][CH2:48][O:47][CH2:46][CH2:45]3)=[O:43])=[CH:32]2)[CH:28]=[CH:29][CH:30]=1.C([O-])([O-])=O.[Na+].[Na+]>C(O)CC.CN(C=O)C.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>[N:44]1([C:42]([C:33]2[C:34](=[O:41])[C:35]3[C:40](=[N:39][CH:38]=[CH:37][CH:36]=3)[N:31]([C:27]3[CH:26]=[C:25]([C:9]4[CH:10]=[CH:11][C:12]([C@@H:15]5[CH2:17][C@H:16]5[C:18]([OH:20])=[O:19])=[CH:13][CH:14]=4)[CH:30]=[CH:29][CH:28]=3)[CH:32]=2)=[O:43])[CH2:45][CH2:46][O:47][CH2:48][CH2:49]1
Reactant: CCOC(=O)C1CC1c1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Reactant: O=C(c1cn(-c2cccc(Br)c2)c2ncccc2c1=O)N1CCOCC1
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: CN(C)C=O
Solvent: CCCO
Product: O=C(O)[C@@H]1C[C@H]1c1ccc(-c2cccc(-n3cc(C(=O)N4CCOCC4)c(=O)c4cccnc43)c2)cc1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
A mixture of acid from step 2 (1 eq), amide from step 1 (1 eq), Na2CO3 (3.5eq.; 2M in H2O), Pd(PPh3)4 (0.15eq.) in n-propanol-DMF (1:1, 0.1M) was stirred at 80° C. for 2 h. The mixture was cooled to rt, quenched with brine and diluted with EtOAc. The organic extracts were washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by flash chromatography (CHCl3:THF; 50:50), triturated in ether/acetone and then isolated by filtration to afford the title compound as a solid.
Reaction SMILES: [C:1]([S:4][CH2:5][C@H:6]1[N:11]([CH2:12][CH:13]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[C:17]([C:22]#[N:23])[C:16]=2[CH3:24])O)[CH2:10][CH2:9][N:8]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:7]1)(=[O:3])[CH3:2].S(Cl)([Cl:34])=O.N1C=CC=CC=1>C1(C)C=CC=CC=1>[C:1]([S:4][CH2:5][C@H:6]1[N:11]([CH2:12][CH:13]([Cl:34])[C:15]2[CH:20]=[CH:19][C:18]([F:21])=[C:17]([C:22]#[N:23])[C:16]=2[CH3:24])[CH2:10][CH2:9][N:8]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:7]1)(=[O:3])[CH3:2]
Reactant: O=S(Cl)Cl
Reactant: CC(=O)SC[C@@H]1CN(C(=O)OC(C)(C)C)CCN1CC(O)c1ccc(F)c(C#N)c1C
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: CC(=O)SC[C@@H]1CN(C(=O)OC(C)(C)C)CCN1CC(Cl)c1ccc(F)c(C#N)c1C
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
To a solution of (3S)-tert-butyl 3-(acetylthiomethyl)-4-(2-(3-cyano-4-fluoro-2-methylphenyl)-2-hydroxyethyl)piperazine-1-carboxylate (30.8 mg, 0.0680 mmol) in toluene (0.62 mL) was added thionyl chloride (14.9 μL, 0.205 mmol). The mixture was cooled with an ice bath and then pyridine (22.1 μL, 0.273 mmol) was added dropwise. The reaction mixture was stirred at 0° C. for 20 min, and then allowed to warm to room temperature over an hour and finally heated at 70° C. for 30 min. The reaction mixture was concentrated and the residue was diluted with ethyl acetate, washed with a minimum amount of saturated sodium bicarbonate aqueous solution, and then brine. The organic layer was separated, filtered through a pad of anhydrous sodium sulfate and concentrated. Used directly in the next step.
Reaction SMILES: C([O-])(=O)C.[Na+].C(O)(=O)C.IC1C=CC(C2N=[C:19]([C@H:23]([N:25](C)[C:26](=[O:35])[O:27][CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)C)N(C)C=2)=CC=1.[C:37]([O-:40])([OH:39])=O.[Na+]>O1CCOCC1>[NH:25]([C:26]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:35])[C@@H:23]([C:37]([OH:40])=[O:39])[CH3:19]
Reactant: O=C([O-])O
Reactant: C[C@H](c1nc(-c2ccc(I)cc2)cn1C)N(C)C(=O)OCc1ccccc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CC(=O)O
Product: C[C@@H](NC(=O)OCc1ccccc1)C(=O)O
Temperature: 65 °C
Reaction time: 2 h
Yield: 79 %

Procedure:
A mixture of 2-amino-4′-bromoacetophene hydrochloride (10.0 g, 40 mmol), sodium acetate (16.4 g, 200 mmol), acetic acid (11.5 mL, 200 mmol) and compound 2 (19.2 g, 80 mmol) in dioxane (70 mL) was stirred at 65° C. until TLC show no compound 2 left (about 2 h). The reaction mixture was carefully neutralized with saturated NaHCO3 solution, and extracted with ethyl acetate. The organic solution was dried over Na2SO4 and concentrated. Purification with flash column chromatography (EtOAc:Hexs 1:1) gave product 3 (9.11 g, 79%) as white solid.
Reaction SMILES: C(C1NC=CN=1)(C1NC=CN=1)=O.[NH2:13][C:14]1[CH:28]=[CH:27][CH:26]=[CH:25][C:15]=1[CH2:16][N:17]1[CH:21]=[CH:20][CH:19]=[C:18]1[C:22]([OH:24])=O.[CH3:29][N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1>O1CCCC1>[NH2:13][C:14]1[CH:28]=[CH:27][CH:26]=[CH:25][C:15]=1[CH2:16][N:17]1[CH:21]=[CH:20][CH:19]=[C:18]1[C:22]([N:33]1[CH2:34][CH2:35][N:30]([CH3:29])[CH2:31][CH2:32]1)=[O:24]
Reactant: Nc1ccccc1Cn1cccc1C(=O)O
Reactant: CN1CCNCC1
Agent: O=C(c1ncc[nH]1)c1ncc[nH]1
Solvent: C1CCOC1
Product: CN1CCN(C(=O)c2cccn2Cc2ccccc2N)CC1
Reaction time: 0.5 h

Procedure:
A mixture of 3.40 g. of carbonyl diimidazole and 25 ml. of tetrahydrofuran is cooled and 4.32 g. of 1-o-aminobenzyl-2-pyrrolecarboxylic acid is added. The mixture is allowed to stand at 25°-30° C. for 30 minutes and 2.6 ml. of N-methylpiperazine is added. The mixture is allowed to stand 48 hours, then concentrated to about 1/2 volume and treated with ether. The mixture is filtered. The filtrate is evaporated to remove the solvent. The residue is treated with water and methylene chloride. The methylene chloride layer is separated and concentrated and further purified by partition chromatography giving 1-[1-(o-aminobenzyl)-2-pyrrolecarbonyl]-4-methylpiperazine as a viscous oil.
Reaction SMILES: [CH2:1]([N:8]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=1[F:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Li])CCC.Cl[C:30]([O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:31].O>C1COCC1>[CH2:33]([O:32][C:30](=[O:31])[C:11]1[C:12]([F:15])=[CH:13][CH:14]=[C:9]([N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:10]=1[F:16])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: Fc1ccc(N(Cc2ccccc2)Cc2ccccc2)c(F)c1
Reactant: O=C(Cl)OCc1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: O=C(OCc1ccccc1)c1c(F)ccc(N(Cc2ccccc2)Cc2ccccc2)c1F
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a solution of dibenzyl-(2,4-difluoro-phenyl)-amine (17.5 g, 0.056 mol) in THF (140 mL), under nitrogen atmosphere, cooled at −78° C., n-butyllithium (1.6 M in hexane, 38 mL, 0.06 mol) was slowly added. The reaction was stirred for 1 hour, and then quickly added via a cannula to a solution of benzyl chloroformate (11.78 mL, 0.084 mol) in THF (140 mL) previously cooled at −78° C. The reaction was then allowed to warm to room temperature, poured into water and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 5% ethyl acetate in hexane grading to 10% acetate (quant.).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[N:10]([CH3:14])[C:9]1[N:15]([CH3:27])[C:16](=[O:26])[C:17]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)=[CH:18][C:8]2=1)=O.[NH2:28][C:29]([NH2:31])=[S:30]>>[NH2:31][C:29]1[S:30][CH:2]=[C:3]([C:5]2[CH:6]=[C:7]3[C:11](=[CH:12][CH:13]=2)[N:10]([CH3:14])[C:9]2[N:15]([CH3:27])[C:16](=[O:26])[C:17]([C:19]4[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=4)=[CH:18][C:8]3=2)[N:28]=1
Reactant: Cn1c(=O)c(-c2ccc(F)cc2)cc2c3cc(C(=O)CBr)ccc3n(C)c21
Reactant: NC(N)=S
Product: Cn1c(=O)c(-c2ccc(F)cc2)cc2c3cc(-c4csc(N)n4)ccc3n(C)c21

Procedure:
The process is carried out as for Example 21 above, using compound A, 6-(2-bromoacetyl)-3-(4-fluorophenyl)-1,9-dimethyl-1,9-dihydropyrido[2,3-b]indol-2-one and thiourea.