Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[NH2:12][C:13]1[CH:18]=[CH:17][C:16]([SH:19])=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+]>C(O)C>[NH2:12][C:13]1[CH:18]=[CH:17][C:16]([S:19][C:2]2[CH:11]=[CH:10][C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[N:3]=2)=[CH:15][CH:14]=1
Reactant: Nc1ccc(S)cc1
Reactant: Clc1ccc2ccccc2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: Nc1ccc(Sc2ccc3ccccc3n2)cc1
Yield: 39.6 %

Procedure:
2-Chloroquinoline (0.04 moles, 6.54 g), 4-aminothiophenol (0.04 moles, 5.0 g) and potassium carbonate (0.04 moles, 5.52 g) were stirred at room temperature in 200 ml of ethanol for 18 hr. The reaction mixture was concentrated, ethyl acetate was added and the solution washed with water, dried over sodium sulfate and concentrated. The product was purified by HPLC over silica gel eluted with ethyl acetate/hexane to yield 2-(4-aminophenylthio)quinoline 4.0 g, 40%. Mass Spec (FD) 252. Calculated for C15H12N2S: C, 71.40; H, 4.79, N, 11.10. Found: C, 71.11; H, 4.98 N, 11.20.
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH2:14][C:13](=[O:15])[N:12]([CH3:16])[N:11]=2)=[CH:6][CH:5]=1.Cl[CH:18]([F:20])[F:19]>O.O1CCOCC1>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[CH:14]=[C:13]([O:15][CH:18]([F:20])[F:19])[N:12]([CH3:16])[N:11]=2)=[CH:8][CH:9]=1
Reactant: CN1N=C(c2ccc(Cl)cc2)CC1=O
Reactant: FC(F)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: Cn1nc(-c2ccc(Cl)cc2)cc1OC(F)F

Procedure:
A solution of 162 g (4.0 mol) of sodium hydroxide in l 1 of water was addedto a solution of 169.1 g (0,811 mol) of 3-(4-chlorophenyl)-1-methyl-2-pyrazolin-5-one in 2.5 1 of dioxane. Chlorodifluoromethane (about 175 g) was passed in over the course of 5 hours at 60°-65° C., after which the reaction solution was stirred into 1.5 1 of water. Extraction three times with methyl tertbutyl ether, followed by drying of the organic phase and removal of the solvent in vacuo, gave the crude product, which was purified further by chromatography on silica gel (hexane/ethyl acetate 7:3). Yield: 142.9 g; 1H-NMR (400 MHz, in CDCl3): δ [ppm]=7.60 (d,2H), 7.28 (d,2H), 6.54 (t,1H), 6.08 (s,1H), 3.69 (s,3H).
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][C:5]2[C:6](=O)[C:7](=[CH:17]N(C)C)[CH2:8][N:9]=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:4]=2[CH:3]=1.Cl.[C:25]([NH2:28])(=[NH:27])[CH3:26].C[O-].[Na+]>CO.C(Cl)Cl>[Cl:1][C:2]1[CH:23]=[CH:22][C:5]2[C:6]3[N:28]=[C:25]([CH3:26])[N:27]=[CH:17][C:7]=3[CH2:8][N:9]=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:4]=2[CH:3]=1
Reactant: CC(=N)N
Reactant: CN(C)C=C1CN=C(c2ccccc2)c2cc(Cl)ccc2C1=O
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: Cc1ncc2c(n1)-c1ccc(Cl)cc1C(c1ccccc1)=NC2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A suspension of 1.6 g (0.005 mol) of 8-chloro-3,4-dihydro-4-(dimethylaminomethylene)-1-phenyl-5H-2-benzazepin-5-one and 0.7 g (0.0075 mol) of acetamidine hydrochloride in 50 ml of methanol was stirred at room temperature, under argon, and treated with 0.8 g (0.015 mol) of sodium methylate in one portion. After stirring for 10 min, 30 ml of methylene chloride was added and stirring was continued. Another 0.8 g (0.015 mol) of sodium methylate and 0.7 g (0.0075 mol) of acetamidine hydrochloride were added after 2 hrs. The addition of 0.015 mol of sodium methylate and 0.0075 mol of acetamidine hydrochloride was repeated after another 2 hr and stirring at room temperature was continued overnight. After diluting with 50 ml of methylene chloride, the mixture was washed with water, dried over sodium sulfate and evaporated at reduced pressure. Crystallization occurred when the residue was dissolved in 20 ml of warm hexane and cooled. Evaporation of the solvent gave a second crop of product. Recrystallization from hexane (charcoal) gave off-white crystals: mp 120°-122° C.
Reaction SMILES: C[Mg]Br.[F:4][C:5]1[N:16]=[C:15]([F:17])[CH:14]=[CH:13][C:6]=1[C:7](N(OC)C)=[O:8].[Cl-].[NH4+].[C:20](OCC)(=O)C>C1COCC1>[F:4][C:5]1[C:6]([C:7](=[O:8])[CH3:20])=[CH:13][CH:14]=[C:15]([F:17])[N:16]=1
Reactant: CON(C)C(=O)c1ccc(F)nc1F
Reactant: CCOC(C)=O
Agent: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(=O)c1ccc(F)nc1F

Procedure:
A solution of methylmagnesium bromide in THF (0.96 M, 88.1 mL) was added to a solution of 2,6-difluoro-N-methoxy-N-methylnicotinamide (7.01 g) in tetrahydrofuran (180 mL) under ice-cooling, and the reaction solution was stirred under ice-cooling for two hours. A saturated ammonium chloride solution and ethyl acetate were added to the reaction solution under ice-cooling, and the organic layer was separated. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: hexane-ethyl acetate) to obtain 4.74 g of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH2:15])[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]1.[F:16][C:17]1[CH:18]=[C:19]([CH:28]=[C:29]([F:32])[C:30]=1[F:31])[CH2:20][C:21]1[CH:26]=[CH:25][N:24]=[C:23](Cl)[N:22]=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:15][C:23]2[N:22]=[C:21]([CH2:20][C:19]3[CH:18]=[C:17]([F:16])[C:30]([F:31])=[C:29]([F:32])[CH:28]=3)[CH:26]=[CH:25][N:24]=2)[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]1
Reactant: COc1cc(N)ccc1-n1cnc(C)c1
Reactant: Fc1cc(Cc2ccnc(Cl)n2)cc(F)c1F
Product: COc1cc(Nc2nccc(Cc3cc(F)c(F)c(F)c3)n2)ccc1-n1cnc(C)c1
Yield: 54 %

Procedure:
The title compound was prepared in analogous manner as described in example 1e) from 3-methoxy-4-(4-methyl-imidazol-1-yl)-phenylamine and 4-(3,4,5-trifluoro-benzyl)-2-chloro-pyrimidine. It was obtained as a pale-brown solid in 54% yield.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][CH:9]([NH:12][CH2:13][CH2:14]O)[C:10]#[N:11])=[CH:4][CH:3]=1.S(Cl)([Cl:18])=O>N1C=CC=CC=1.C(Cl)(Cl)Cl>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][CH:9]([NH:12][CH2:13][CH2:14][Cl:18])[C:10]#[N:11])=[CH:4][CH:3]=1
Reactant: N#CC(Cc1ccc(Cl)nc1)NCCO
Reactant: O=S(Cl)Cl
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: N#CC(Cc1ccc(Cl)nc1)NCCCl

Procedure:
This compound was prepared in a manner analogous to that set forth in Step C of Example 1, using 5.7 grams (0.0255 mole) of 2-{[(6-chloro(3-pyridyl)methyl](2-hydroxyethylamino}ethanenitrile 3.2 grams (0.0268 mole) of thionyl chloride and one drop (catalyst) of pyridine in 50 mL of chloroform. The yield of the subject compound was 6.0 grams. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[CH2:9]1[O:11][CH:10]1[CH2:12][OH:13]>N1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][CH:10]([OH:11])[CH2:12][OH:13])=[CH:4][CH:3]=1
Reactant: Oc1ccc(Cl)cc1
Reactant: OCC1CO1
Solvent: c1ccncc1
Product: OCC(O)COc1ccc(Cl)cc1
Yield: 67.1 %

Procedure:
A mixture of 25.7 g (0.2 mole) of 4-chlorophenol, 18.5 g (0.25 mole) of glycidol and 1 ml of pyridine was stirred and heated at 85°-90° C. overnight. The pot residue was partitioned between ethyl ether and water. The organic layer was washed with water and brine, dried over sodium sulfate, and concentrated to give a gum which crystallized when triturated with petroleum ether (boiling point range, 30°-60° C.). The solid was collected by filtration and recrystallized from isopropyl ether to yield 27.2 g (67%) of off-white solid, mp 73°-75° C. (lit1 mp 77° C.).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[CH:4][CH:3]=1.I[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][N:8]2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:4][CH:3]=1
Reactant: Clc1ccc2cc[nH]c2c1
Reactant: Ic1ccccc1
Product: Clc1ccc2ccn(-c3ccccc3)c2c1

Procedure:
Prepared by Procedure C and Scheme O using 6-chloro-1H-indole and iodobenzene: ESMS m/e: 228.0 (M+H)+.
Reaction SMILES: [CH:1]([OH:3])=O.C(OC(=O)C)(=O)C.[CH3:11][O:12][C:13]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][C:14]=1[NH2:15]>C1COCC1>[CH3:11][O:12][C:13]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][C:14]=1[NH:15][CH:1]=[O:3]
Reactant: COc1ccc([N+](=O)[O-])cc1N
Reactant: O=CO
Solvent: CC(=O)OC(C)=O
Solvent: C1CCOC1
Product: COc1ccc([N+](=O)[O-])cc1NC=O
Temperature: 55 °C
Reaction time: 2 h
Yield: 102 %

Procedure:
A mixture of formic acid (0.45 ml, 0.012 mole) and acetic anhydride (1.06 ml, 0.011 mole) was stirred at 55° C. under Ar for 2 h, and cooled to room temperature. Dry THF (10 ml) was added. To this solution was added 2-methoxy-5-nitroaniline (0.69 g, 0.004 mole). After stirring for 1 h, the suspension was evaporated in vacuo to leave the title compound as a brown solid (0.80 g, 99%).
Reaction SMILES: Br[C:2]1[NH:3][C:4]2[CH:5]=[CH:6][CH:7]=[C:8]3[C:14](=[O:15])[NH:13][CH2:12][CH2:11][C:10]=1[C:9]=23.[Sn].[C:17]([C:21]1[CH:26]=[C:25](C)[CH:24]=[C:23](C(C)(C)C)[C:22]=1O)(C)(C)[CH3:18]>CN(C=O)C.O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C:21]1([C:17]#[C:18][C:2]2[NH:3][C:4]3[CH:5]=[CH:6][CH:7]=[C:8]4[C:14](=[O:15])[NH:13][CH2:12][CH2:11][C:10]=2[C:9]=34)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Reactant: O=C1NCCc2c(Br)[nH]c3cccc1c23
Agent: [Pd]
Agent: [Sn]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CN(C)C=O
Product: O=C1NCCc2c(C#Cc3ccccc3)[nH]c3cccc1c23
Temperature: 60 °C
Yield: 55 %

Procedure:
Tricyclic bromide 11 (58.6 mg, 0.22 mmol) in DMF (1 mL) was degassed and treated with tributylephenylethynyl)tin (95.2 mg, 0.24 mmol) and tetrakis(triphenylphosphine) palladium(0) (13 mg, 2 mol %). One crystal of 2,6-di-t-butyl-4-methyl phenol was added, and the solution was heated at 60° C. for 10 h. Starting material was still present, so the solution was heated at 100° C. for an additional 2 h. The reaction mixture was cooled to ambient temperature and diluted with water (2 mL) and extracted with EtOAc (5 mL×3). The organic solution was washed with water and brine, dried (Na2SO4), filtered, and concentrated. The crude product was purified by radial chromatography (2 mm SiO2; 3% MeOH in CH2Cl2) to yield 17 as a white solid (34.8 mg, 55%). mp 255-256° C. (dec); 1H NMR (DMSO-d6) δ11.86 (s, 1H), 8.17 (m, 1H), 7.75 (d, 1H, J=7.6 Hz), 7.63 (m, 3H), 7.51 (m, 3H), 7.33 (t, 1H, J=7.6 Hz), 3.50 (m, 2H), 3.09 (m, 2H); HRMS (FAB, M+H) Calcd for C19H14N2O+H: 287.1184, Found: 287.1192; Anal. (C19H14N2O.0.6 H2O) C, H, N.
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[CH2:7]/[N:8]=[CH:9]/[CH2:10][C:11]([CH3:16])([CH3:15])[CH:12]([CH3:14])[CH3:13])([CH3:4])([CH3:3])[CH3:2].[Cl:18][C:19]1[C:20]([F:37])=[C:21](/[CH:25]=[C:26](/[C:29]2[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][C:30]=2[F:36])\[C:27]#[N:28])[CH:22]=[CH:23][CH:24]=1.C(N(CC)CC)C>ClCCl>[C:1]([O:5][C:6]([CH:7]1[CH:25]([C:21]2[CH:22]=[CH:23][CH:24]=[C:19]([Cl:18])[C:20]=2[F:37])[C:26]([C:29]2[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][C:30]=2[F:36])([C:27]#[N:28])[CH:9]([CH2:10][C:11]([CH3:15])([CH3:16])[CH:12]([CH3:13])[CH3:14])[NH:8]1)=[O:17])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)C(C)(C)C/C=N/CC(=O)OC(C)(C)C
Reactant: N#C/C(=C\c1cccc(Cl)c1F)c1ccc(Cl)cc1F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)C(C)(C)CC1NC(C(=O)OC(C)(C)C)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Yield: 57 %

Procedure:
In a manner similar to the method described in Example 1c, [3,3,4-trimethyl-pent-(E)-ylideneamino]-acetic acid tert-butyl ester prepared in Example 78a (1.5 g, 6.2 mmol) was reacted with (Z)-3-(3-chloro-2-fluoro-phenyl)-2-(4-chloro-2-fluoro-phenyl)-acrylonitrile (1.1 g, 3.5 mmol) prepared in Example 52a, AgF (1.2 g, 9.5 mmol), and triethylamine (2 g, 20 mmol) in dichloromethane (150 mL) at room temperature for 18 h to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2,3-trimethyl-butyl)-pyrrolidine-2-carboxylic acid tert-butyl ester as a white foam (1.1 g, 56%).
Reaction SMILES: [CH3:1][C@@:2]12[C@@:10]([OH:15])([C:11]([CH2:13][OH:14])=[O:12])[CH2:9][CH2:8][C@H:7]1[C@@H:6]1[CH2:16][CH2:17][C:18]3[C@@:24]([CH3:25])([C@H:5]1[C@@H:4]([OH:26])[CH2:3]2)[CH:23]=[CH:22][C:20](=[O:21])[CH:19]=3.[CH:27]1[C:32]([CH2:33][CH2:34][CH2:35][C:36](O)=[O:37])=[CH:31][CH:30]=[C:29]([N:39]([CH2:43][CH2:44][Cl:45])[CH2:40][CH2:41][Cl:42])[CH:28]=1.CC1C=CC(S(O)(=O)=O)=CC=1.C1CCC(N=C=NC2CCCCC2)CC1>CN(C1C=CN=CC=1)C.C(Cl)Cl.C(O)(=O)C>[CH3:1][C@@:2]12[C@@:10]([OH:15])([C:11]([CH2:13][O:14][C:36]([CH2:35][CH2:34][CH2:33][C:32]3[CH:27]=[CH:28][C:29]([N:39]([CH2:40][CH2:41][Cl:42])[CH2:43][CH2:44][Cl:45])=[CH:30][CH:31]=3)=[O:37])=[O:12])[CH2:9][CH2:8][C@H:7]1[C@@H:6]1[CH2:16][CH2:17][C:18]3[C@@:24]([CH3:25])([C@H:5]1[C@@H:4]([OH:26])[CH2:3]2)[CH:23]=[CH:22][C:20](=[O:21])[CH:19]=3
Reactant: C[C@]12C=CC(=O)C=C1CC[C@@H]1[C@@H]2[C@@H](O)C[C@@]2(C)[C@H]1CC[C@]2(O)C(=O)CO
Reactant: O=C(O)CCCc1ccc(N(CCCl)CCCl)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Solvent: CC(=O)O
Product: C[C@]12C=CC(=O)C=C1CC[C@@H]1[C@@H]2[C@@H](O)C[C@@]2(C)[C@H]1CC[C@]2(O)C(=O)COC(=O)CCCc1ccc(N(CCCl)CCCl)cc1
Temperature: 0 °C
Reaction time: 20 h
Yield: 91 %

Procedure:
To 250 ml CH2Cl2 is added with stirring 36 g prednisolone (0.10 mol), 31.3 g chlorambucil (0,103 mol), 1.2 g DMAP (0,01 mol) and 1.1 g pTSA (0,06 mol). The reaction mixture is cooled to 0° C. and with continued stirring at this temperature a solution of 22.7 g DCC (0,11 mol) in 50 ml CH2Cl2 is slowly added. The reaction mixture is then kept at 0° C. with stirring for 20 h. 3 ml acetic acid is added and precipitated urea filtered off. The filtrate is evaporated in vacuo and the residue recrystallized from ethanol to give 58.9 g of TLC pure prednimustine (91% yield) without any discolouration. M.P. 165°-166° C.
Reaction SMILES: C(Cl)Cl.Br[C:5]1[N:10]=[C:9]([NH:11][C:12]2[CH:16]=[C:15]([C@@H:17]3[CH2:19][C@H:18]3[CH3:20])[NH:14][N:13]=2)[C:8]([Cl:21])=[CH:7][N:6]=1.[C:22]([NH:26][S:27]([C:30]1[S:34][C:33](B(O)O)=[CH:32][CH:31]=1)(=[O:29])=[O:28])([CH3:25])([CH3:24])[CH3:23]>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[C:22]([NH:26][S:27]([C:30]1[S:34][C:33]([C:5]2[N:10]=[C:9]([NH:11][C:12]3[CH:16]=[C:15]([C@@H:17]4[CH2:19][C@H:18]4[CH3:20])[NH:14][N:13]=3)[C:8]([Cl:21])=[CH:7][N:6]=2)=[CH:32][CH:31]=1)(=[O:28])=[O:29])([CH3:25])([CH3:23])[CH3:24]
Reactant: C[C@@H]1C[C@H]1c1cc(Nc2nc(Br)ncc2Cl)n[nH]1
Reactant: CC(C)(C)NS(=O)(=O)c1ccc(B(O)O)s1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: ClCCl
Solvent: C1COCCO1
Product: C[C@@H]1C[C@H]1c1cc(Nc2nc(-c3ccc(S(=O)(=O)NC(C)(C)C)s3)ncc2Cl)n[nH]1
Temperature: 90 °C
Yield: 63.2 %

Procedure:
The mixture of Pd(dppf)Cl2.CH2Cl2 (74 mg, 0.09 mmol, 0.15 eq.), 2-bromo-5-chloro-N-(5-(trans-2-methylcyclopropyl)-1H-pyrazol-3-yl)pyrimidin-4-amine (200 mg, 0.61 mmol, 1.0 eq), 5-(N-tert-butylsulfamoyl)thiophen-2-ylboronic acid (192 mg, 0.73 mmol, 1.2 equiv.) and saturate Ka2CO3 (5 mL) in dioxane (10 mL) was heated to 90° C. for 1 h under nitrogen atmosphere. The reaction mixture was cooled to rt, and extracted with THF. The combined layers were purified by silica gel chromatography (EtOAc/Petroleum ether from 10:1 to 2:1) to afford compound N-tert-butyl-5-(5-chloro-4-(5-(trans-2-methylcyclopropyl)-1H-pyrazol-3-ylamino)pyrimidin-2-yl)thiophene-2-sulfonamide (180 mg, 63%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@@H:10]2[CH2:13][NH:14][CH2:15][C@H:9]12)=[O:7])([CH3:4])([CH3:3])[CH3:2].C=O.[C:18]([BH3-])#N.[Na+]>CO.[OH-].[Na+]>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@@H:10]2[CH2:13][N:14]([CH3:18])[CH2:15][C@H:9]12)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC[C@@H]2CNC[C@@H]21
Reactant: [BH3-]C#N
Agent: C=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CN1C[C@H]2CCN(C(=O)OC(C)(C)C)[C@H]2C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (3aR,6aR)-hexahydro-pyrrolo[3,4-b]pyrrole-1-carboxylic acid tert-butyl ester (18.31 g, 0.86 mol) in MeOH (450 ml) was added paraformaldehyde (52 g, 1.72 mole), and the mixture was stirred at room temperature for 1 hour. Sodium cyanoborohydride was then added, and the mixture was stirred at room temperature for 10 hours, diluted with 1N NaOH (450 ml), extracted with dichloromethane (5×200 ml). The combined organic layers were dried (Na2SO4), filtered and concentrated to provide the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 4.18 (m, 1 H) 3.47-3.59 (m, 1 H) 3.34-3.46 (m, 2 H) 2.75-2.90 (m, 1 H) 2.71 (m, 1 H) 2.44-2.60 (m, 2 H) 2.29 (s, 3 H) 1.89-2.06 (m, 1 H) 1.65-1.81 (m, 1 H) 1.42-1.49 (m, 9 H). MS: (M+H)+=226.
Reaction SMILES: ClCCl.Cl[C:5]([N:7]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[NH:11][C:10](=[O:18])[C:9]2=[CH:19][S:20][C:21]([CH3:22])=[C:8]12)=[O:6].[CH2:23]([N:25]([CH2:38][CH3:39])[CH2:26][CH2:27][N:28]([CH3:37])[CH2:29][CH2:30][CH:31]1[CH2:36][CH2:35][CH2:34][CH2:33][NH:32]1)[CH3:24]>C(#N)C>[CH2:38]([N:25]([CH2:23][CH3:24])[CH2:26][CH2:27][N:28]([CH3:37])[CH2:29][CH2:30][CH:31]1[CH2:36][CH2:35][CH2:34][CH2:33][N:32]1[C:5]([N:7]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[NH:11][C:10](=[O:18])[C:9]2=[CH:19][S:20][C:21]([CH3:22])=[C:8]12)=[O:6])[CH3:39]
Reactant: Cc1scc2c1N(C(=O)Cl)c1ccccc1NC2=O
Reactant: CCN(CC)CCN(C)CCC1CCCCN1
Solvent: CC#N
Solvent: ClCCl
Product: CCN(CC)CCN(C)CCC1CCCCN1C(=O)N1c2ccccc2NC(=O)c2csc(C)c21
Yield: 22 %

Procedure:
Prepared analogously to Example 4, but using dichloromethane instead of acetonitrile as solvent, from 4-(chlorocarbonyl)-4,9-dihydro-3-methyl-10H-thieno[3,4-b][1,5]benzodiazepin-10-one and 2-[2-[[2-(diethylamino)ethyl]methylamino]ethyl]piperidine (b.p.0.3 mmHg 92°-95° C.) in a yield of 22% of theory. Colourless crystals, m.p. 131°-133° C. (acetonitrile).
Reaction SMILES: [C:1]([NH:11][C@H:12]([C:20]([OH:22])=[O:21])[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].[CH:23](=O)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>ClC(Cl)(Cl)C>[CH2:4]([O:3][C:1]([N:11]1[C@@H:12]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:20](=[O:22])[O:21][C@H:23]1[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:2])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: O=C(N[C@@H](Cc1ccccc1)C(=O)O)OCc1ccccc1
Reactant: O=Cc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(Cl)(Cl)Cl
Product: O=C1O[C@@H](c2ccccc2)N(C(=O)OCc2ccccc2)[C@H]1Cc1ccccc1
Yield: 12.4 %

Procedure:
Following the procedure of Karady, Tett. Lett., 1984, 25:4337. N-Cbz-L-phenylalanine (25 g, 83.5 mmol), benzaldehyde (18 g, 170 mmol), and p-toluenesulfonic acid (11.2 g, 58 mmol) were suspended in 1,1,1-trichloroethane (300 ml). The solution was refluxed for 18 hr and the water was removed by azeotropic distillation using a Dean-Stark trap for liquids heavier than water. After cooling, the reaction was washed with saturated aqueous NaHCO3 (3×50 ml), water (1×50 ml), dried over sodium sulfate and concentrated in vacuo to produce an orange oil. After about 1 h a solid crystallized from the oil and it was collected by vacuum filtration. The orange solid was recrystallized from ethyl acetate/hexane to produce colorless crystals (4.0 g, 12%); mp 120°-122° C. MS (CI): 405 (M+NH4)+, 388 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([NH:13][CH:14]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[Cl:30])[CH2:15][O:16][CH2:17][CH:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)=[O:12])=[CH:8][CH:9]=2)[NH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:38][CH2:39][F:40].O>CS(C)=O>[Cl:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([NH:13][CH:14]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[Cl:30])[CH2:15][O:16][CH2:17][CH:18]3[CH2:23][CH2:22][N:21]([CH2:38][CH2:39][F:40])[CH2:20][CH2:19]3)=[O:12])=[CH:8][CH:9]=2)[NH:4][CH:3]=1
Reactant: O=C(NC(COCC1CCNCC1)c1ccccc1Cl)c1ccc2c(Cl)c[nH]c2c1
Reactant: FCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: O=C(NC(COCC1CCN(CCF)CC1)c1ccccc1Cl)c1ccc2c(Cl)c[nH]c2c1
Yield: 32.9 %

Procedure:
To a solution of 3-chloro-N-[1-(2-chlorophenyl)-2-(piperidin-4-ylmethoxy)ethyl]-1H-indole-6-carboxamide (600 mg, 1.3 mmol) in 6 mL of DMSO was added potassium carbonate (716 mg, 5.2 mmol) and 2-bromo-1-fluoroethane (0.10 mL, 1.1 mmol). The reaction was allowed to stir at room temperature overnight after which time water was added and the resulting precipitate was isolated by filtration. Purification of the filtrate (SiO2: EtOAc) provided 178 mg (28%) of the title compound.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[C:18](I)[C:17]([O:21][CH3:22])=[CH:16][C:15]=2[F:23])[CH2:10][CH2:9]1)=[O:7])(=[O:3])[CH3:2].[F:24][C:25]([F:64])([F:63])[C:26]1[CH:27]=[C:28]([C@H:36]2[O:40][C:39](=[O:41])[N:38]([CH2:42][C:43]3[CH:48]=[C:47]([C:49]([F:52])([F:51])[F:50])[CH:46]=[CH:45][C:44]=3B3OC(C)(C)C(C)(C)O3)[C@H:37]2[CH3:62])[CH:29]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:31]=1.C>[Pd](Cl)Cl.C(P(C(C)(C)C)[C-]1C=CC=C1)(C)(C)C.[C-]1(P(C(C)(C)C)C(C)(C)C)C=CC=C1.[Fe+2]>[C:1]([O:4][CH2:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[C:18]([C:44]3[CH:45]=[CH:46][C:47]([C:49]([F:52])([F:51])[F:50])=[CH:48][C:43]=3[CH2:42][N:38]3[C@@H:37]([CH3:62])[C@@H:36]([C:28]4[CH:29]=[C:30]([C:32]([F:35])([F:33])[F:34])[CH:31]=[C:26]([C:25]([F:24])([F:63])[F:64])[CH:27]=4)[O:40][C:39]3=[O:41])[C:17]([O:21][CH3:22])=[CH:16][C:15]=2[F:23])[CH2:10][CH2:9]1)=[O:7])(=[O:3])[CH3:2]
Reactant: C[C@H]1[C@@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)OC(=O)N1Cc1cc(C(F)(F)F)ccc1B1OC(C)(C)C(C)(C)O1
Reactant: COc1cc(F)c(C2CCN(C(=O)COC(C)=O)CC2)cc1I
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(C)(C)P([c-]1cccc1)C(C)(C)C
Product: COc1cc(F)c(C2CCN(C(=O)COC(C)=O)CC2)cc1-c1ccc(C(F)(F)F)cc1CN1C(=O)O[C@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1C

Procedure:
A mixture of 2-[4-(2-fluoro-5-iodo-4-methoxyphenyl)piperidin-1-yl]-2-oxoethyl acetate (Step A; 33 mg; 0.076 mmol) and (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-3-[2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)benzyl]-1,3-oxazolidin-2-one (Intermediate 9; 68 mg, 0.114 mmol) was treated with 1,1′-bis(di-t-butylphosphino)ferrocene palladium dichloride (˜5 mg) as described earlier. The product was purified by chiral HPLC (ChiralPak IA column, 15% IPA/heptane) to afford 2-{4-[2′-({(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)-4-fluoro-6-methoxy-4′-(trifluoromethyl)biphenyl-3-yl]piperidin-1-yl}-2-oxoethyl acetate as a colorless glass. LCMS=779.0 (M+1)+. 1H NMR (CDCl3, 500 MHz, mixture of atropisomers) δ 7.86 (s, 1 H), 7.69 (s, 2 H), 7.68-7.60 (m, 2 H), 7.32 (d, J=7.8 Hz, 1 H), 6.96-6.91 (m, 1 H), 6.72 (dd, J=11.9, 2.1 Hz, 1 H), 5.59-5.54 (m, 1 H), 4.90 (d, J=15.6 Hz, 1 H), 4.80-4.65 (m, 3 H), 4.13-4.04 (m, 1 H), 3.88-3.72 (m, 2 H), 3.78 (s, 3H), 3.21-3.04 (m, 2H), 2.72-2.67 (m, 1H), 2.17 (s, 3H), 1.96-1.83 (m, 2 H), 1.70-1.59 (m, 2 H), 0.42-0.39 (m, 3 H)
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:18](Cl)(=[O:20])[CH3:19]>ClCCl>[C:8]([C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:18](=[O:20])[CH3:19])=[CH:3][CH:4]=1)(=[O:10])[CH3:9]
Reactant: CC(=O)c1ccc(N)cc1
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)Nc1ccc(C(C)=O)cc1
Temperature: 0 °C
Yield: 73.8 %

Procedure:
Into a 100-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of 1-(4-aminophenyl)ethanone (3.1 g, 22.96 mmol, 1.00 equiv) in dichloromethane (30 mL), triethylamine (4.64 g, 45.94 mmol, 2.00 equiv). This was followed by the addition of acetyl chloride (1.79 g, 22.95 mmol, 1.00 equiv) dropwise with stirring at 0° C. The resulting solution was stirred for 30 min at 0° C. The reaction was then quenched by the addition of 2 mL of water. The resulting mixture was washed with 3×50 mL of saturated aqueous sodium chloride. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum to give 3.0 g (74%) of N-(4-acetylphenyl)acetamide as a white solid.