Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][C:3]=1[N:11]1[CH:15]=[N:14][CH:13]=[N:12]1.Br[C:17]1[N:21]2[CH:22]=[CH:23][C:24]([C:26]([F:29])([F:28])[F:27])=[N:25][C:20]2=[N:19][CH:18]=1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:17]2[N:21]3[CH:22]=[CH:23][C:24]([C:26]([F:27])([F:28])[F:29])=[N:25][C:20]3=[N:19][CH:18]=2)=[CH:4][C:3]=1[N:11]1[CH:15]=[N:14][CH:13]=[N:12]1
Reactant: FC(F)(F)c1ccn2c(Br)cnc2n1
Reactant: OB(O)c1ccc(F)c(-n2cncn2)c1
Product: Fc1ccc(-c2cnc3nc(C(F)(F)F)ccn23)cc1-n1cncn1

Procedure:
4-Fluoro-3-([1,2,4]triazol-1-yl)phenylboronic acid (100 mg, 0.48 mmol) was coupled to 3-bromo-7-trifluoromethylimidazo[1,2-α]pyrimidine (117 mg, 0.44 mmol) using the method in Example 1. Purification by chromatography on silica gel eluting with dichloromethane containing 2% methanol, then recrystallisation from dichloromethane/isohexane, gave 3-[4-fluoro-3-([1,2,4]triazol-1-yl)phenyl]-7-trifluoromethylimidazo[1,2-α]pyrimidine as a yellow solid: δH (360 MHz, CDCl3) 7.31 (1H, d, J 7), 7.51-7.60 (2H, m), 8.16 (2H, m), 8.21 (1H, dd, J 7 and 2), 8.80-8.83 (2H, m); m/z (ES+) 349 (M++H).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([Cl:15])=[CH:10][C:9]=1[NH:16][C:17](=[O:33])[CH2:18][C:19](=O)[C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([C:26]2[CH:31]=[CH:30][N:29]=[N:28][CH:27]=2)[CH:21]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:15][C:11]1[C:12]([CH3:14])=[CH:13][C:8]2[N:7]=[C:19]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]4[CH:31]=[CH:30][N:29]=[N:28][CH:27]=4)[CH:21]=3)[CH2:18][C:17](=[O:33])[NH:16][C:9]=2[CH:10]=1
Reactant: Cc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3ccnnc3)c2)cc1Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc2c(cc1Cl)NC(=O)CC(c1cccc(-c3ccnnc3)c1)=N2

Procedure:
The title compound was prepared from {4-chloro-5-methyl-2-[3-oxo-3-(3-pyridazin-4-yl-phenyl)-propionylamino]-phenyl}-carbamic acid tert-butyl ester (Example M44) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a white solid (59 mg).
Reaction SMILES: [N:1]1([C:7]2[C:8]3[C:15]([C:16]4[CH:17]=[C:18]([CH:21]=[CH:22][CH:23]=4)[C:19]#[N:20])=[CH:14][NH:13][C:9]=3[N:10]=[CH:11][N:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.ClC1C2C(I)=CN([CH2:35][O:36][CH2:37][CH2:38][Si:39]([CH3:42])([CH3:41])[CH3:40])C=2N=CN=1>>[N:1]1([C:7]2[C:8]3[C:15]([C:16]4[CH:17]=[C:18]([CH:21]=[CH:22][CH:23]=4)[C:19]#[N:20])=[CH:14][N:13]([CH2:35][O:36][CH2:37][CH2:38][Si:39]([CH3:42])([CH3:41])[CH3:40])[C:9]=3[N:10]=[CH:11][N:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: C[Si](C)(C)CCOCn1cc(I)c2c(Cl)ncnc21
Reactant: N#Cc1cccc(-c2c[nH]c3ncnc(N4CCOCC4)c23)c1
Product: C[Si](C)(C)CCOCn1cc(-c2cccc(C#N)c2)c2c(N3CCOCC3)ncnc21

Procedure:
3-[4-(Morpholin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]benzonitrile (4) was converted to the product using the method described for synthesis of 4-chloro-5-iodo-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidine (C1) in Preparation P1. The product was obtained as a yellow solid. Yield: 0.90 g, 2.1 mmol, 70%. 1H NMR (400 MHz, CDCl3) δ 8.55 (s, 1H), 7.86 (br s, 1H), 7.79 (br d, J=7.6 Hz, 1H), 7.63 (br d, J=7.6 Hz, 1H), 7.57 (dd, J=7.6, 7.6 Hz, 1H), 7.29 (s, 1H), 5.67 (s, 2H), 3.58-3.64 (m, 2H), 3.52-3.58 (m, 4H), 3.27-3.32 (m, 4H), 0.92-0.98 (m, 2H), −0.03 (s, 9H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[C:5]([C:10]3[N:11]=[C:12]([N:24]4[CH2:29][CH2:28][O:27][CH2:26][CH2:25]4)[C:13]4[S:18][C:17]([CH:19]([CH3:23])C(O)=O)=[CH:16][C:14]=4[N:15]=3)[CH:6]=[CH:7][CH:8]=2)[CH:3]=[N:2]1.[C:30](N1C=CN=C1)([N:32]1[CH:36]=CN=[CH:33]1)=[O:31].C(N(CC)CC)C.Cl.CNC>CN(C=O)C>[NH:1]1[C:9]2[C:4](=[C:5]([C:10]3[N:11]=[C:12]([N:24]4[CH2:25][CH2:26][O:27][CH2:28][CH2:29]4)[C:13]4[S:18][C:17]([CH2:19][CH2:23][C:30]([N:32]([CH3:36])[CH3:33])=[O:31])=[CH:16][C:14]=4[N:15]=3)[CH:6]=[CH:7][CH:8]=2)[CH:3]=[N:2]1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CC(C(=O)O)c1cc2nc(-c3cccc4[nH]ncc34)nc(N3CCOCC3)c2s1
Agent: CNC
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CN(C)C(=O)CCc1cc2nc(-c3cccc4[nH]ncc34)nc(N3CCOCC3)c2s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 62.1 %

Procedure:
To a solution of 3-[2-(1H-indazol-4-yl-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-yl]-propionic acid (145 mg) in DMF (5 mL) at room temperature was added carbonyldiimidazole (115 mg). The reaction mixture was then stirred at room temperature for 1 h. Then, triethylamine (0.15 mL) and dimethylamine hydrochloride (58 mg) were added and the solution was stirred at room temperature for 16 h. The reaction was then quenched with water (20 mL) and extracted into ethyl acetate (2×20 mL). The combined organics were washed with aqueous brine solution (3×20 mL), dried (MgSO4), concentrated and purified using column chromatography to give 148 as a white solid (96 mg). NMR: DMSO: 2.68-2.84 (2 H, m, CH2), 2.86 (3 H, s, Me), 3.02 (3 H, s, Me), 3.18 (2 H, t, J 7.22, CH2), 3.79-3.84 (4 H, m, CH2), 3.98-4.02 (4 H, m, CH2), 7.40 (1 H, s, Ar), 7.44 (1 H, t, J 8.0, Ar), 7.62 (1 H, d, J 8.15, Ar), 8.21 (1 H, d, J 7.35, Ar), 8.85 (1 H, s, Ar) and 13.15 (1 H, s, NH). MS: (ESI+): MH+ 437.22
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9](=[O:16])[N:10]2[CH2:13][CH:14]=O)=[N:5][CH:4]=1.[OH:17][C@H:18]1[CH2:22][NH:21][CH2:20][C@H:19]1[CH2:23][NH:24][C:25](=[O:34])[O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C(N(CC)CC)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>CO.C(Cl)(Cl)Cl>[OH:17][C@H:18]1[CH2:22][N:21]([CH2:14][CH2:13][N:10]2[C:11]3[C:6](=[N:5][CH:4]=[C:3]([O:2][CH3:1])[CH:12]=3)[CH:7]=[CH:8][C:9]2=[O:16])[CH2:20][C@H:19]1[CH2:23][NH:24][C:25](=[O:34])[O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: COc1cnc2ccc(=O)n(CC=O)c2c1
Reactant: O=C(NC[C@@H]1CNC[C@@H]1O)OCc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Solvent: CO
Product: COc1cnc2ccc(=O)n(CCN3C[C@@H](CNC(=O)OCc4ccccc4)[C@@H](O)C3)c2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 73 %

Procedure:
To a solution of [7-(methoxy)-2-oxo-1,5-naphthyridin-1(2H)-yl]acetaldehyde (as the methyl hemiacetal) (0.500 g, 2.29 mmol) in 1:1 (MeOH/CHCl3) (40 mL) were added phenylmethyl {[(3S,4R)-4-hydroxypyrrolidin-3-yl]methyl}carbamate (0.658 g, 2.29 mmol) and triethylamine (0.351 mL, 2.52 mmol). The resulting solution was stirred at ambient temperature for 1 h. Na(OAc)3BH (1.46 g, 6.87 mmol) was added and the solution stirred at rt for an additional 18 h. The reaction mixture was concentrated onto silica gel and chromatographed on a silica gel column [0-100% CHCl3/(90:10:1) CHCl3/MeOH/NH4OH)] to yield a colorless oil (0.760 g, 73%).
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][C:10]([O:13][CH:14]([CH3:16])[CH3:15])=[CH:9][C:8]=1[Cl:17].C[O:19][B:20](OC)[O:21]C.Cl>C1COCC1>[Cl:17][C:8]1[CH:9]=[C:10]([O:13][CH:14]([CH3:16])[CH3:15])[CH:11]=[CH:12][C:7]=1[B:20]([OH:21])[OH:19]
Reactant: COB(OC)OC
Reactant: CC(C)Oc1ccc(Br)c(Cl)c1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)Oc1ccc(B(O)O)c(Cl)c1
Temperature: 25 °C
Yield: 43.7 %

Procedure:
n-Butyllithium (1.6 M solution in hexanes, 23.5 mmol, 14.7 mL) was added to 1-bromo-2-chloro-4-isopropoxybenzene (19.4 mmol, 4.85 g) in THF (120 mL) at −78° C. under an atmosphere of nitrogen. After stirring for thirty minutes the trimethylborate (76.6 mmol, 8.7 mL) was added over twenty minutes. The reaction was allowed to warm to room temperature overnight while stirring. The solution was then acidified with HCl (3 M, 200 mL), and extracted into EtOAc. The EtOAc was then extracted with NaOH (1 N, 4×100 mL), which was subsequently acidified with concentrated HCl forming (2-Chloro-4-isopropoxyphenyl)boronic acid (1.82 g, 44%) as a white precipitate, which was filtered and dried. 1H NMR (CD3OD, 300 MHz): 7.19 (1H, d, J 8.4 Hz), 6.87 (1H, d, J 2.2 Hz), 6.82 (1H, dd, J 8.4 and 2.2 Hz), 4.58 (1H, m), 1.28 (6H, d, J 5.9 Hz.)
Reaction SMILES: CS[C:3](SC)=[N:4][S:5]([CH3:8])(=[O:7])=[O:6].[NH2:11][CH2:12][CH2:13][CH2:14][O:15][C:16]1[CH:17]=[C:18]([CH2:22][N:23]([CH3:25])[CH3:24])[CH:19]=[CH:20][CH:21]=1.[CH3:26][NH2:27]>C(O)C>[CH3:8][S:5]([NH:4][C:3]([NH:27][CH3:26])=[N:11][CH2:12][CH2:13][CH2:14][O:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][N:23]([CH3:24])[CH3:25])[CH:17]=1)(=[O:7])=[O:6]
Reactant: CSC(=NS(C)(=O)=O)SC
Reactant: CN
Reactant: CN(C)Cc1cccc(OCCCN)c1
Solvent: CCO
Product: CNC(=NCCCOc1cccc(CN(C)C)c1)NS(C)(=O)=O

Procedure:
N-Methanesulphonylcarbonimidodithioic acid dimethyl ester (3 g) and 3-[3-aminopropoxy]-N,N-dimethylbenzenemethanamine (2.5 g) were heated at reflux in ethanol for 4 hours. Methylamine was then added and the reflux continued for 11/2 hours. The solvent was removed and the residue was purified by column chromatography on silica with methanol to yield the title compound as a yellow gum (1.9 g). TLC methanol:0.88 ammonia (80:1) Rf 0.65. NMR (CDCl3) 2.85 m (1H); 2.9-3.3 m (3H); 3.0-4.3 brs (2H); 5.90 t (2H); 6.5 q (2H); 6.6 s (2H); 7.1 s (6H); 7.75 s (6H); 7.9 m (2H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[C:5]1[CH:13]=[C:12]([CH2:14][OH:15])[CH:11]=[C:7]([C:8]([OH:10])=O)[CH:6]=1)[CH3:2].[CH3:17][NH:18][CH2:19][CH2:20][CH3:21].Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1>ClCCl.CN(C=O)C>[CH2:1]([O:3][C:4](=[O:16])[C:5]1[CH:13]=[C:12]([CH2:14][OH:15])[CH:11]=[C:7]([C:8]([N:18]([CH3:17])[CH2:19][CH2:20][CH3:21])=[O:10])[CH:6]=1)[CH3:2]
Reactant: CCCNC
Reactant: CCOC(=O)c1cc(CO)cc(C(=O)O)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCCN(C)C(=O)c1cc(CO)cc(C(=O)OCC)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 60.9 %

Procedure:
Mix 5-hydroxymethyl-isophthalic acid monoethyl ester (3.3 g, 14.7 mmol), N-methyl propylamine (1.5 mL, 14.7 mmol), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (2.8 g, 14.7 mmol), and 1-hydroxybenzotriazole hydrate (2.0 g, 14.7 mmol) in dichloromethane (40 mL) and DMF (4 mL). Stir at room temperature for 3 h. Concentrate and redissolve in ethyl acetate (150 mL). Wash with aqueous sodium bicarbonate solution, aqueous ammonium chloride solution, water, saturated aqueous sodium chloride, dry (sodium sulfate), concentrate and purify (silica gel chromatography, eluting with ethyl acetate and hexanes) to give the title compound (2.5 g, 61%).
Reaction SMILES: CN1C(=O)CCC1.[OH-].[Na+].Cl[C:11]1[CH:12]=[C:13]([C:20]([O-:22])=[O:21])[C:14](=[CH:18][CH:19]=1)[C:15]([OH:17])=O.[Na+]>[Ti].O>[C:20]1(=[O:21])[O:22][C:15](=[O:17])[C:14]2=[CH:18][CH:19]=[CH:11][CH:12]=[C:13]12
Reactant: O=C([O-])c1cc(Cl)ccc1C(=O)O
Agent: [Ti]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CN1CCCC1=O
Product: O=C1OC(=O)c2ccccc21
Temperature: 250 °C

Procedure:
A titanium-lined autoclave was charged with 108 g of a poly(phenylene sulfide) (melt viscosity: 2800 poises) produced by Kureha Chemical Industry Co., Ltd., 500 g of NMP, 7 g of sodium hydroxide, 8.43 g (0.05 mole as S content) of hydrated sodium sulfide and 8.8 g of water. After the autoclave being purged with nitrogen gas, the contents were gradually heated up to 250° C. to react them for 30 minutes, thereby depolymerizing the poly(phenylene sulfide). Thereafter, the contents were cooled to room temperature. Then, 17.8 g (0.08 mole) of sodium hydrogen 4-chlorophthalate and 48.6 g of water were added to the autoclave, and the contents were heated up to 255° C. to react them for 2 hours.
Reaction SMILES: C([S:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([C:20]3[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[CH:22][C:21]=3[O:28][CH3:29])=[N:14][C:15]([CH3:19])=[N:16]2)=[CH:11][CH:10]=1)C1C=CC=CC=1.CC(O)=O.[OH2:34].[Cl:35]N1C(C)(C)C(=O)N(Cl)C1=O.[OH2:46]>C(Cl)Cl>[C:24]([C:23]1[CH:26]=[CH:27][C:20]([C:13]2[C:12]3[C:17](=[CH:18][C:9]([S:8]([Cl:35])(=[O:46])=[O:34])=[CH:10][CH:11]=3)[N:16]=[C:15]([CH3:19])[N:14]=2)=[C:21]([O:28][CH3:29])[CH:22]=1)#[N:25]
Reactant: COc1cc(C#N)ccc1-c1nc(C)nc2cc(SCc3ccccc3)ccc12
Reactant: O
Reactant: CC1(C)C(=O)N(Cl)C(=O)N1Cl
Solvent: CC(=O)O
Solvent: ClCCl
Product: COc1cc(C#N)ccc1-c1nc(C)nc2cc(S(=O)(=O)Cl)ccc12
Reaction time: 0.25 h
Yield: 61.3 %

Procedure:
A solution of 4-(7-(benzylthio)-2-methylquinazolin-4-yl)-3-methoxybenzonitrile (0.371 g, 0.933 mmol) in 8 mL DCM and 0.2 mL (3:2 HOAc/water) solution was cooled to 0° C. and was treated with 1,3-dichloro-5,5-dimethylimidazolidine-2,4-dione (0.368 g, 1.867 mmol). After stirring for 15 minutes, LC/MS showed mostly product, so the reaction mixture was diluted with water. The layers were separated, and the organics were dried over MgSO4 and concentrated. Purification of the crude residue by silica gel column chromatography (0-50% EtOAc/heptane) gave 4-(4-cyano-2-methoxyphenyl)-2-methylquinazoline-7-sulfonyl chloride (0.214 g, 0.572 mmol, 61.3% yield). (M+H)+=374.1.
Reaction SMILES: [NH2:1][CH:2]1[CH:7]2[CH2:8][CH2:9][N:4]([CH2:5][CH2:6]2)[CH2:3]1.[CH2:10]([O:13][C:14]1[CH:24]=[CH:23][CH:22]=[CH:21][C:15]=1[C:16]([N:18]=[C:19]=[O:20])=[O:17])[CH:11]=[CH2:12].C([O-])(=O)/C=C/C([O-])=O>>[CH2:10]([O:13][C:14]1[CH:24]=[CH:23][CH:22]=[CH:21][C:15]=1[C:16]([NH:18][C:19]([NH:1][CH:2]1[CH:7]2[CH2:8][CH2:9][N:4]([CH2:5][CH2:6]2)[CH2:3]1)=[O:20])=[O:17])[CH:11]=[CH2:12]
Reactant: NC1CN2CCC1CC2
Reactant: C=CCOc1ccccc1C(=O)N=C=O
Agent: O=C([O-])/C=C/C(=O)[O-]
Product: C=CCOc1ccccc1C(=O)NC(=O)NC1CN2CCC1CC2

Procedure:
The above compound was prepared, following the procedure of Example 1, from 3-aminoquinuclidine (0.28 g, 2.2 mmol) and 2-allyloxybenzoyl isocyanate (0.53 g, ca 2.2 mmol). The product (0.61 g) was converted to the 1:1 fumarate.
Reaction SMILES: C[CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][N:3]1[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([F:15])=[C:11]([F:16])[CH:10]=1.B.[CH2:18]1[CH2:22]O[CH2:20][CH2:19]1.CO>C1COCC1>[C:18]1([CH:22]([NH:3][CH2:2][CH2:7][CH:6]2[CH2:7][CH2:2][N:3]([CH2:8][C:9]3[CH:14]=[CH:13][C:12]([F:15])=[C:11]([F:16])[CH:10]=3)[CH2:4][CH2:5]2)[C:11]2[CH:10]=[CH:9][CH:14]=[CH:13][CH:12]=2)[CH:4]=[CH:5][CH:6]=[CH:20][CH:19]=1
Reactant: CC1CCCCN1Cc1ccc(F)c(F)c1
Reactant: C1CCOC1
Agent: B
Solvent: CO
Product: Fc1ccc(CN2CCC(CCNC(c3ccccc3)c3ccccc3)CC2)cc1F
Temperature: 25 °C
Yield: 90 %

Procedure:
To the solution of 4-[2-diphenylmethyl)aminocarbonyl]methyl-1-[(3,4-difluorophenyl)methyl]piperidine (0.12 g, 0.28 mmol) in dry THF 20 ml was added 1M BH3/THF (1.0 ml). The reaction solution was refluxed for 6 hours. After the solution was cooled to room temperature, MeOH (5 ml) was added slowly. The solvent was removed under reduced pressure. 10% HCl/MeOH (10 ml) was added into the residue and the solution was refluxed for 1 hour. Solid NaHCO3 was added after MeOH was evaporated. The mixture was extracted with EtOAc. The combined organic phase was dried over Na2SO4 and evaporated to give the crude product, which was purified by chromatography (Hexane/EtOAc/Et3N=1/2/1%) to a white solid, 0.11 g (90% yield) (“Procedure E”). 1H NMR (CD3Cl) δ 7.39-6.99 (13H, m, Ar—H), 4.79 (1H, s, Ph2CH), 3.39 (2H, s, F2PhCH2), 2.80-2.76 (2H, d, J=11.1 Hz, N(CH)2), 2.60-2.55 (2H, t, J=7.0 Hz, NCH2), 1.93-1.86 (2H, t, J=11.1 Hz, N(CH)2), 1.62-1.58 (2H, d, J=12 Hz), 1.49-1.42 (2H, q, J=6.3 Hz, NCH2CH2), 1.35-1.31 (1H, m, NCH2CH2CH(CH2)2), 1.26-1.19 (2H, t, J=12.0 Hz). The free base was converted into its HCl salt, m.p.=280-281° C. Anal: (C27H30N2F2.2HCl.0.25H2O) Calculated: C, 65.12; H, 6.85; N, 5.62; Found: C, 65.13; H, 6.80, N, 5.28.
Reaction SMILES: CS[C:3]([NH:8][CH2:9][C:10]#[CH:11])=[CH:4][N+:5]([O-:7])=[O:6].Cl.N[CH2:14][CH2:15][SH:16]>>[N+:5]([CH:4]=[C:3]([NH:8][CH2:9][C:10]#[CH:11])[CH2:14][CH2:15][SH:16])([O-:7])=[O:6]
Reactant: C#CCNC(=C[N+](=O)[O-])SC
Reactant: NCCS
Agent: Cl
Product: C#CCNC(=C[N+](=O)[O-])CCS

Procedure:
A solution of the product of Step A of Example 2 is reacted with about an equimolar amount of cysteamine hydrochloride and about one equivalent of base, to produce 1-nitro-2-(2-propynylamino)-2-(2-mercaptoethyl)ethylene.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([CH2:24][CH:25]=[O:26])=[CH:20][CH:19]=3)[C:11]3[CH2:16][CH2:15][CH2:14][C:12]=3[N:13]=2)[CH:5]=[CH:6][CH:7]=1.C[Si](C)(C)[C:29]([F:32])([F:31])[F:30].[F-].C([NH+](CCCC)CCCC)CCC>C1COCC1.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]([NH:17][C:18]3[CH:19]=[CH:20][C:21]([CH2:24][CH:25]([OH:26])[C:29]([F:32])([F:31])[F:30])=[CH:22][CH:23]=3)[C:11]3[CH2:16][CH2:15][CH2:14][C:12]=3[N:13]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=CCc1ccc(Nc2nc(-c3cccc(Cl)c3)nc3c2CCC3)cc1
Reactant: C[Si](C)(C)C(F)(F)F
Agent: CCCC[NH+](CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: OC(Cc1ccc(Nc2nc(-c3cccc(Cl)c3)nc3c2CCC3)cc1)C(F)(F)F
Temperature: 25 °C
Reaction time: 16 h
Yield: 7.4 %

Procedure:
To a solution of 2-(4-((2-(3-chlorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)amino)phenyl)acetaldehyde (0.114 g, 0.31 mmol) in THF (10 mL) was added trimethyl(trifluoromethyl)silane (0.053 g, 0.38 mmol). The mixture stirred at 0° C. for 1 h after which tributylammonium fluoride (1.0 M, 0.078 mL, 0.078 mmol) was added. The mixture stirred at rt for 16 h. After this time, the reaction was diluted with water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by preparative HPLC (water/acetonitrile with 0.05% TFA) to afford the title compound (0.010 g, 7%) as a light yellow solid. MW=433.85. 1H NMR (DMSO-d6, 500 MHz) δ 8.82 (s, 1H), 8.30-8.22 (m, 2H), 7.75 (d, J=8.5 Hz, 2H), 7.56-7.49 (m, 2H), 7.31 (d, J=8.5 Hz, 2H), 6.20 (d, J=11.5 Hz, 1H), 4.23-4.12 (m, 1H), 2.95-2.85 (m, 4H), 2.76-2.68 (m, 1H), 2.10 (quin, J=7.5 Hz, 2H); APCI MS m/z 434 [M+H]+.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:15]=[C:14]2[C:6]([C:7]3[C:8]([C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([N:25]5[CH2:33][C:32]6[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=6)[C:26]5=[O:34])[C:20]=4[CH3:35])=[CH:9][CH:10]=[C:11]([C:16]([NH2:18])=[O:17])[C:12]=3[NH:13]2)=[CH:5][CH:4]=1.[CH3:36][S:37](Cl)(=[O:39])=[O:38]>C1COCC1>[CH3:35][C:20]1[C:21]([N:25]2[CH2:33][C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[C:26]2=[O:34])=[CH:22][CH:23]=[CH:24][C:19]=1[C:8]1[C:7]2[C:6]3[C:14](=[CH:15][C:3]([CH2:2][NH:1][S:37]([CH3:36])(=[O:39])=[O:38])=[CH:4][CH:5]=3)[NH:13][C:12]=2[C:11]([C:16]([NH2:18])=[O:17])=[CH:10][CH:9]=1
Reactant: CS(=O)(=O)Cl
Reactant: Cc1c(-c2ccc(C(N)=O)c3[nH]c4cc(CN)ccc4c23)cccc1N1Cc2ccccc2C1=O
Solvent: C1CCOC1
Product: Cc1c(-c2ccc(C(N)=O)c3[nH]c4cc(CNS(C)(=O)=O)ccc4c23)cccc1N1Cc2ccccc2C1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 20 %

Procedure:
A solution of 7-(aminomethyl)-4-(2-methyl-3-(1-oxoisoindolin-2-yl)phenyl)-9H-carbazole-1-carboxamide (Example 33-1, 60 mg, 0.065 mmol) and TEA (23 μL, 0.163 mmol) in THF (1.3 mL) was treated with methanesulfonyl chloride (5.6 μL, 0.072 mmol) and the mixture was stirred at rt overnight. The mixture was concentrated and purified by preparative HPLC. The appropriate effluent fractions were concentrated and partitioned between EtOAc and NaHCO3 (aq). The organic phase was dried and concentrated, and the residue was purified further by column chromatography (eluting with a gradient from 40:60 hexane-EtOAc to EtOAc) to provide 4-(2-methyl-3-(1-oxoisoindolin-2-yl)phenyl)-7-(methylsulfonamidomethyl)-9H-carbazole-1-carboxamide as an off-white solid (7 mg, 18%). 1H NMR (400 MHz, DMSO-d6) δ 11.57 (1H, s), 8.19 (1H, br. s.), 8.02 (1H, d, J=7.7 Hz), 7.81 (1H, d, J=7.7 Hz), 7.73 (1H, s), 7.69 (2H, d, J=3.7 Hz), 7.61-7.65 (1H, m), 7.54-7.61 (2H, m), 7.51 (2H, t, J=7.7 Hz), 7.35 (1H, dd, J=7.5, 1.1 Hz), 7.00-7.08 (2H, m), 6.93-6.99 (1H, m), 4.88-5.05 (2H, m), 4.26 (2H, d, J=5.9 Hz), 2.87 (3H, s), 1.84 (3H, s). Mass spectrum m/z 539.2 (M+H)+.
Reaction SMILES: [C:1]([N:8]1[CH2:15][C@H:14]([F:16])[CH2:13][C@H:9]1[C:10]([OH:12])=O)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C([N:45]1[C:49]([C:50]2[CH:51]=[C:52]([Cl:59])[C:53]([F:58])=[C:54]([CH:57]=2)[CH2:55][NH2:56])=[N:48][N:47]=[N:46]1)(C)(C)C.ClC1C(F)=C(C=C(C2N=NNN=2)C=1)CN.CCN(C(C)C)C(C)C>CN(C=O)C>[C:4]([O:3][C:1]([N:8]1[CH2:15][C@H:14]([F:16])[CH2:13][C@H:9]1[C:10](=[O:12])[NH:56][CH2:55][C:54]1[CH:57]=[C:50]([C:49]2[N:48]=[N:47][NH:46][N:45]=2)[CH:51]=[C:52]([Cl:59])[C:53]=1[F:58])=[O:2])([CH3:5])([CH3:6])[CH3:7]
Reactant: CC(C)(C)n1nnnc1-c1cc(Cl)c(F)c(CN)c1
Reactant: CC(C)(C)OC(=O)N1C[C@H](F)C[C@H]1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: NCc1cc(-c2nn[nH]n2)cc(Cl)c1F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1C[C@H](F)C[C@H]1C(=O)NCc1cc(-c2nn[nH]n2)cc(Cl)c1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of N-boc-trans-4-fluoro-L-proline (107 mg, 0.46 mmol) and HATU (260 mg, 0.69 mmol) in DMF (2 mL) was added a 1:2 mixture of 5-(1-tert-butyl-1H-tetrazol-5-yl)-3-chloro-2-fluoro-benzylamine and 3-chloro-2-fluoro-5-(2H-tetrazol-5-yl)-benzylamine (preparation described in Part C, 220 mg, 0.46 mmol) and DIPEA (319 μl, 1.8 mmol) and the resulting solution was stirred overnight at ambient temperature. The reaction mixture was purified without aqueous workup by RP-preparative HPLC (Waters Sunfire, C18-ODB, 5 μm, 30×100 mm, 5-100% CH3CN/H2O/20 min, 100% CH3CN/2 min, CH3CN and H2O containing 0.1% TFA, flow: 40 ml/min) to give the title compounds (2S,4R)-2-[3-chloro-2-fluoro-5-(2H-tetrazol-5-yl)-benzylcarbamoyl]-4-fluoro-pyrrolidine-1-carboxylic acid tert-butyl ester: MS (LC-MS): 343.0 [M−100]+; tR (HPLC conditions c): 3.27 min and (2S,4R)-2-[5-(1-tert-butyl-1H-tetrazol-5-yl)-3-chloro-2-fluoro-benzylcarbamoyl]-4-fluoro-pyrrolidine-1-carboxylic acid tert-butyl ester: MS (LC-MS): 499.0 [M]+; tR (HPLC conditions c): 4.02 min.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:16]=[CH:15][C:12]([CH:13]=O)=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.[CH2:19]([N:21]([CH2:25][CH3:26])[CH2:22][CH2:23][NH2:24])[CH3:20].[BH4-].[Na+].[H][H]>ClCCl.C(O)C>[CH2:19]([N:21]([CH2:25][CH3:26])[CH2:22][CH2:23][NH:24][CH2:13][C:12]1[CH:15]=[CH:16][C:9]([C:6]2[CH:7]=[CH:8][C:3]([C:2]([F:18])([F:17])[F:1])=[CH:4][CH:5]=2)=[CH:10][CH:11]=1)[CH3:20]
Reactant: CCN(CC)CCN
Reactant: [H][H]
Reactant: O=Cc1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: ClCCl
Product: CCN(CC)CCNCc1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Reaction time: 16 h
Yield: 93.7 %

Procedure:
4-(4-Trifluoromethylphenyl)benzaldehyde (85.43 g, 0.3414 mol) (Int. D2) and 4A molecular sieve (400 g, predried at 120° C.) were suspended in dichloromethane (1.4 L), then N,N-diethylethylenediamine (47.97 ml, 0.3414 mol) was added. The mixture was left at room temperature for 16 h with occasional shaking, then the sieves were filtered off and washed with dichloromethane. The combined filtrates were evaporated to a yellow solid and dried under high vacuum. This material (114.3 g, 0.328 mol) in ethanol (1 L) was cooled in an ice bath, and sodium borohydride (12.41 g, 0.328 mol) was added under argon with stirring. Hydrogen evolution was observed. After 30 min the ice bath was removed, and the cloudy yellow solution was left to stand at room temperature for 16 h. The solvent was removed in vacuo, water and brine were added, and the mixture was extracted 3× with dichloromethane. The combined extracts were dried over potassium carbonate and evaporated to give the title compound as a yellow solid, (112.1 g, 98%). 1H-NMR (CDCl3) δ 7.66 (4H, s), 7.53-7.56 (2H, m), 7.40-7.44 (2H, m), 3.86 (2H, s), 2.47-2.75 (9H, m), 0.96-1.10 (6H, m); MS(APCI+) found (M+1)=351, C20H25F3N2 requires 350.