Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[S:2]1(=[O:18])[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[CH:17]=[CH:16][C:10]([C:11]([O:13]CC)=O)=[CH:9][N:8]=1.[CH3:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)=[C:22]([C:32]([F:35])([F:34])[F:33])[CH:21]=1>>[O:18]=[S:2]1(=[O:1])[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[N:8]=[CH:9][C:10]([C:11]([N:29]2[CH2:28][CH2:27][N:26]([C:23]3[CH:24]=[CH:25][C:20]([CH3:19])=[CH:21][C:22]=3[C:32]([F:34])([F:35])[F:33])[CH2:31][CH2:30]2)=[O:13])=[CH:16][CH:17]=1
Reactant: CCOC(=O)c1ccc(N2CCCS2(=O)=O)nc1
Reactant: Cc1ccc(N2CCNCC2)c(C(F)(F)F)c1
Product: Cc1ccc(N2CCN(C(=O)c3ccc(N4CCCS4(=O)=O)nc3)CC2)c(C(F)(F)F)c1
Yield: 27.4 %

Procedure:
Using ethyl 6-(1,1-dioxo-1λ6-isothiazolidin-2-yl)nicotinate (363 mg) described in Preparation Example 25 and 1-(4-methyl-2-trifluoromethylphenyl)piperazine (327 mg) described in Preparation Example 96 and by the reaction and treatment in the same manner as in Example 109, the title compound (172 mg) was obtained.
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([C:7]([OH:9])=[O:8])=[CH:4][CH:3]=1.[CH2:10](N=C=NCCCN(C)C)[CH3:11].O>C(O)C.CN(C)C1C=CN=CC=1>[Br:1][C:2]1[S:6][C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccc(Br)s1
Reactant: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1ccc(Br)s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.7 %

Procedure:
5-Bromothiophene-2-carboxylic acid (5.40 g) was dissolved in ethanol (50 ml), 4-dimethylaminopyridine (3.82 g) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (6.0 g) were successively added, and the mixture was stirred overnight at room temperature. Water was added to the reaction mixture, and the mixture was extracted 3 times with ethyl acetate. The organic layer was washed successively with water, 10% aqueous citric acid (twice), water, saturated aqueous sodium hydrogencarbonate and brine, and dried over sodium sulfate. The organic layer was concentrated under reduced pressure to give the title compound (5.99 g).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[CH:5]([N:17]=[C:18]=[O:19])[CH2:6][CH2:7][CH2:8][NH:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH3:2].[NH:21]1[CH:29]=[C:27]([CH3:28])[C:25](=[O:26])[NH:24][C:22]1=[O:23]>>[CH2:1]([O:3][C:4](=[O:20])[CH:5]([NH:17][C:18]([N:21]1[CH:29]=[C:27]([CH3:28])[C:25](=[O:26])[NH:24][C:22]1=[O:23])=[O:19])[CH2:6][CH2:7][CH2:8][NH:9][C:10]([O:12][C:13]([CH3:14])([CH3:15])[CH3:16])=[O:11])[CH3:2]
Reactant: CCOC(=O)C(CCCNC(=O)OC(C)(C)C)N=C=O
Reactant: Cc1c[nH]c(=O)[nH]c1=O
Product: CCOC(=O)C(CCCNC(=O)OC(C)(C)C)NC(=O)n1cc(C)c(=O)[nH]c1=O
Reaction time: 12 h

Procedure:
The reaction solution from Example 10 is placed in a flask and to this is added thymine (12.6 g, 0.1 mol) . The resulting solution is allowed to stir for 12 hours, then is evaporated to a solid, which is purified by column chromatography using dichlormethane:ethanol as the eluent.
Reaction SMILES: [C:1]([CH2:3][CH:4]1[CH2:13][CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:14][CH3:15])[CH:10]=2)[C:5]1=O)#[N:2].[H][H]>C(O)C.[Ni]>[CH3:15][O:14][C:9]1[CH:8]=[CH:7][C:6]2[C:5]3[CH:4]([CH2:3][CH2:1][N:2]=3)[CH2:13][CH2:12][C:11]=2[CH:10]=1
Reactant: COc1ccc2c(c1)CCC(CC#N)C2=O
Reactant: [H][H]
Agent: [Ni]
Solvent: CCO
Product: COc1ccc2c(c1)CCC1CCN=C21

Procedure:
The solution of 50 g of 2-cyanomethyl-6-methoxy-1-tetralone in 1000 ml of ethanol is hydrogenated in the presence of 15 g of Raney nickel at atmospheric pressure and room temperature until 2 mole equivalents of hydrogen are consumed. The mixture is filtered, the filtrate evaporated and the crude product dissolved in 500 ml of N hydrochloric acid. The solution is washed with diethyl ether, treated with charcoal, filtered and the filtrate is basified with 3 N aqueous sodium hydroxide. It is extracted with methylene chloride, the extract dried, evaporated, the residue crystallized from petroleum ether and recrystallized from hexane, to yield the 7-methoxy-3,3a,4,5-tetrahydro-2H-benz[g]indole melting at 102°-104°.
Reaction SMILES: C(OC([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([CH2:17][N:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)[CH:14]=2)[CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[N:18]1([CH2:17][C:13]2[CH:14]=[C:15]3[C:10](=[CH:11][CH:12]=2)[CH2:9][NH:8][CH2:16]3)[CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: CC(C)(C)OC(=O)N1Cc2ccc(CN3CCCC3)cc2C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: c1cc2c(cc1CN1CCCC1)CNC2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 1.90 g 5-pyrrolidin-1-ylmethyl-1,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester (raw material; 4.96 mmol) in 5 ml dichloromethane was added 3.82 ml trifluoroacetic acid (49.6 mmol) and the reaction mixture was stirred at room temperature overnight. The trifluoroacetic acid and dichloromethane were evaporated under reduced pressure, water was added to the residue, the acidic aqueous phase extracted two times with ethyl acetate, the aqueous phase was basified with diluted NaOH and then subsequently extracted three times with dichloromethane. The dichloromethane phase was washed once with brine, dried over Na2SO4, filtered, and the solvent was removed under vacuum. The title compound was used without further purification in the next step. LCMS: m/z 203.2 (M+H).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[S:11]([NH:14][CH:15]1[CH:20]2[CH:16]1[CH2:17][N:18](C(OC(C)(C)C)=O)[CH2:19]2)(=[O:13])=[O:12].[C:28]([OH:34])([C:30]([F:33])([F:32])[F:31])=[O:29]>C(Cl)Cl>[F:31][C:30]([F:33])([F:32])[C:28]([OH:34])=[O:29].[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[S:11]([NH:14][CH:15]1[CH:20]2[CH:16]1[CH2:17][NH:18][CH2:19]2)(=[O:13])=[O:12]
Reactant: CC(C)(C)OC(=O)N1CC2C(C1)C2NS(=O)(=O)c1ccc2ccccc2c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=S(=O)(NC1C2CNCC21)c1ccc2ccccc2c1

Procedure:
A solution of tert-butyl 6-[(2-napthylsulfonyl)amino]-3-azabicyclo[3.1.0]hexane-3-carboxylate (27.50 g, 68.43 mmol) in 20% TFA in DCM (300 ml) was stirred at r.t. for 2 h. The reaction mixture was concentrated in vacuo and then DCM (100 ml) was added and removed in vacuo three times to remove excess TFA giving the title compound as the trifluoroacetate salt (crude yield=34.0 g). This product was used in the next step without further purification. 1H NMR (400 MHz, d6-DMSO) δ: 1.86 (2H, s), 2.20 (1H, m), 3.22 (4H, m), 7.70-7.75 (2H, m), 7.83 (1H, dd), 8.08 (1H, d), 8.18-8.23 (3H, m), 8.33 (1H, br s), 8.48 (1H, s), 9.20 (1H, br s).
Reaction SMILES: [C:1]([C:4]1[C:5](=[O:34])[N:6]([CH3:33])[C:7]2[C:12]([C:13]=1[NH:14][C:15](=[O:17])[CH3:16])=[CH:11][C:10]([C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=1)=[C:9]([C:25]1[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][C:26]=1[Cl:32])[N:8]=2)(=[O:3])[CH3:2].C1COCC1.[BH4-].[Na+]>CO>[Cl:24][C:21]1[CH:22]=[CH:23][C:18]([C:10]2[CH:11]=[C:12]3[C:7](=[N:8][C:9]=2[C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][C:26]=2[Cl:32])[N:6]([CH3:33])[C:5](=[O:34])[C:4]([CH:1]([OH:3])[CH3:2])=[C:13]3[NH:14][C:15](=[O:17])[CH3:16])=[CH:19][CH:20]=1
Reactant: CC(=O)Nc1c(C(C)=O)c(=O)n(C)c2nc(-c3ccc(Cl)cc3Cl)c(-c3ccc(Cl)cc3)cc12
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CC(=O)Nc1c(C(C)O)c(=O)n(C)c2nc(-c3ccc(Cl)cc3Cl)c(-c3ccc(Cl)cc3)cc12

Procedure:
The product of Example 1 (65 mg), THF (3 mL), MeOH (0.33 mL) and NaBH4 (9.6 mg) were combined at room temperature. After 7 minutes the reaction was concentrated and then dissolved in EtOAc before washing with water and drying (Na2SO4). The concentrated residue was purified by preparative TLC (silica gel) eluted with EtOAc affording the title compound. HPLC/MS: 515.9 (M+1), 517.9 (M+3); Rt=3.68 min.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[CH:6]=[CH:5][NH:4][C:3]1=O.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.Cl.[OH:38][C@@H:39]1[CH2:43][CH2:42][CH2:41][C@H:40]1[NH2:44].C1CCN2C(=NCCC2)CC1>CN(C=O)C>[OH:38][C@@H:39]1[CH2:43][CH2:42][CH2:41][C@H:40]1[NH:44][C:3]1[N:2]([CH3:1])[C:7](=[O:8])[CH:6]=[CH:5][N:4]=1
Reactant: Cn1c(=O)cc[nH]c1=O
Reactant: N[C@@H]1CCC[C@H]1O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: Cn1c(N[C@@H]2CCC[C@H]2O)nccc1=O
Temperature: 25 °C
Reaction time: 0.03 h
Yield: 76.5 %

Procedure:
3-Methyluracil (12.6 mg, 0.1 mmol) was dissolved in 0.5 mL of DMF, and then BOP (71 mg, 0.16 mmol) was added. The mixture was stirred at room temperature for two minutes, then (1R,2R)-(−)-2-hydroxycyclopentylamine hydrochloride salt (22 mg, 0.16 mmol) was added, followed by DBU (51 uL, 3.4 mmol). The mixture was stirred at room temperature overnight. The reaction mixture was purified by a semi-preparative HPLC to give pure product (16 mg, yield 76%). MS (ESI) m/z 210.1 [M+H]+.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][CH:7]=1)=[O:3].Cl.[NH2:16][CH2:17][CH:18]1[CH2:23][CH2:22][CH:21]([C:24]([N:26]2[CH2:35][C:34]3[CH:33]=[N:32][N:31]([CH3:36])[C:30]=3[NH:29][C:28]3[CH:37]=[C:38]([CH3:41])[CH:39]=[CH:40][C:27]2=3)=[O:25])[CH2:20][CH2:19]1>ClCCl.C(N(CC)CC)C>[N+:12]([C:9]1[CH:10]=[CH:11][C:6]([CH2:5][O:4][C:2](=[O:3])[NH:16][CH2:17][CH:18]2[CH2:23][CH2:22][CH:21]([C:24]([N:26]3[CH2:35][C:34]4[CH:33]=[N:32][N:31]([CH3:36])[C:30]=4[NH:29][C:28]4[CH:37]=[C:38]([CH3:41])[CH:39]=[CH:40][C:27]3=4)=[O:25])[CH2:20][CH2:19]2)=[CH:7][CH:8]=1)([O-:14])=[O:13]
Reactant: O=C(Cl)OCc1ccc([N+](=O)[O-])cc1
Reactant: Cc1ccc2c(c1)Nc1c(cnn1C)CN2C(=O)C1CCC(CN)CC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc2c(c1)Nc1c(cnn1C)CN2C(=O)C1CCC(CNC(=O)OCc2ccc([N+](=O)[O-])cc2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 4-nitrobenzyl chloroformate (1.08 mg, 0.005 mmol) in dichloromethane (0.05 ml) was added to a solution of (4-Aminomethyl-cyclohexyl)-(3,6-dimethyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulen-9-yl)-methanone hydrochloride (Compound number 149) (1.95 mg, 0.005 mmol) in dichloromethane (0.05 ml) and triethyl-amine (0.0035 ml). The mixture was stirred at room temperature for 1 h then solvents were removed in vacuo to yield the title compound. (ESI)+: [M+H]+=533.3
Reaction SMILES: [O:1]=[C:2]1[C:7]2[CH:8]=[CH:9][C:10]([C:12]([OH:14])=O)=[CH:11][C:6]=2[S:5][C:4]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)=[N:3]1.[NH:21]1[CH2:25][CH2:24][CH2:23][CH2:22]1>O1CCCC1>[N:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[C:4]1[S:5][C:6]2[CH:11]=[C:10]([C:12]([N:21]3[CH2:25][CH2:24][CH2:23][CH2:22]3)=[O:14])[CH:9]=[CH:8][C:7]=2[C:2](=[O:1])[N:3]=1
Reactant: O=C(O)c1ccc2c(=O)nc(-c3ccccn3)sc2c1
Reactant: C1CCNC1
Solvent: C1CCOC1
Product: O=C(c1ccc2c(=O)nc(-c3ccccn3)sc2c1)N1CCCC1
Temperature: 60 °C
Reaction time: 2 h
Yield: 11.7 %

Procedure:
N,N′-carbonyldiimidazole (445 mg, 2.7 mmol) was added to a mixture of 4-oxo-2-(2-pyridyl)-4H-1,3-benzothiazine-7-carboxylic acid (600 mg, 2.1 mmol) and tetrahydrofuran (20 ml), and the mixture was stirred at 60° C. for 2 hrs. Successively, pyrrolidine (300 mg, 4.2 mmol) was added to the reaction mixture, and the mixture was stirred at 60° C. for 1 hr. The solvent was evaporated, and the residue was subjected to a silica gel column chromatography. The fractions eluted with ethyl acetate were collected, concentrated and recrystallized from hexane-tetrahydrofuran to give the titled compound (83 mg, 11%) as white crystals.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][N:3]=1.[O:9]1[CH:14]=[CH:13][CH2:12][CH2:11][CH2:10]1.C1(C)C=CC(S(O)(=O)=O)=CC=1>ClCCl.C(Cl)(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH:10]2[CH2:11][CH2:12][CH2:13][CH2:14][O:9]2)=[CH:4][N:3]=1
Reactant: C1=COCCC1
Reactant: Oc1ccc(Br)nc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: Brc1ccc(OC2CCCCO2)cn1
Yield: 54.6 %

Procedure:
A mixture of 2-bromo-5-hydroxypyridine (1.0 g, 5.75 mmols), 3,4-dihydro-2H-pyran (0.80 mL, 8.77 mmols) and p-toluenesulfonic acid (110 mg, 0.578 mmol) was stirred overnight in dichloromethane (20 mL) at room temperature. The reaction liquid was diluted with chloroform, washed with saturated brine and dried over anhydrous magnesium sulfate. Concentrating the solvent under reduced pressure, the resulting residue was purified on silica gel column chromatography (C-300; ethyl acetate:hexane=1:20-1:10) to provide the title compound (0.81 g, 55%).
Reaction SMILES: Cl.[NH2:2][OH:3].C([O-])(O)=O.[Na+].[C:9]1(/[CH:15]=[CH:16]/[S:17]([NH:20][C:21]2[CH:22]=[C:23]([CH:27]=[CH:28][C:29](Cl)=[O:30])[CH:24]=[CH:25][CH:26]=2)(=[O:19])=[O:18])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>O1CCCC1>[OH:3][NH:2][C:29](=[O:30])[CH:28]=[CH:27][C:23]1[CH:24]=[CH:25][CH:26]=[C:21]([NH:20][S:17](/[CH:16]=[CH:15]/[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)(=[O:19])=[O:18])[CH:22]=1
Reactant: NO
Reactant: O=C(Cl)C=Cc1cccc(NS(=O)(=O)/C=C/c2ccccc2)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(C=Cc1cccc(NS(=O)(=O)/C=C/c2ccccc2)c1)NO
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of hydroxylamine hydrochloride (0.27 g, 3.88 mmol) in tetrahydrofuran (5 ml) a saturated NaHCO3 solution (3 ml) was added and the resultant mixture was stirred at ambient temperature for 10 min. To the reaction mixture a solution of crude 3-{3-[(E)-2-phenylethenesulfonylamino]phenyl}acryloyl chloride (27a) (0.27 g, 0.77 mmol) in tetrahydrofuran (3.5 ml) was added and the mixture was stirred at ambient temperature for one hour. The reaction mixture was partitioned between ethyl acetate and 2N HCl. The organic layer was washed successively with water and saturated NaCl, then the solvent was removed. The residue was crystallised from ethyl acetate and washed with diethyl ether affording the title compound (0.115 g, 42%) as white crystals. M.p. 171° C. 1H NMR (DMSO-d6, HMDSO) δ: 6.38 (d, J=16.0 Hz, 1H); 7.07-7.80 (m, 12H); 9.03 (br s, 1H); 10.16 (s, 1H); 10.76 (br s, 1H). HPLC analysis on Symmetry C18 column: impurities 1% (column size 3.9×150 mm; mobile phase acetonitrile-0.1M phosphate buffer (pH 2.5), 35:65; sample concentration 0.4 mg/ml; flow rate 1.2 ml/min; detector UV 254 nm). Anal. Calcd for C17H16N2O4S, %: C, 59.29; H, 4.68; N, 8.13. Found %: C, 59.13; H, 4.70; N, 7.92.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:17]#[N:18])=[C:4]([CH:14]=[CH:15][CH:16]=1)[O:5][CH2:6][CH2:7][CH2:8][CH2:9][NH:10][C:11](=[O:13])[CH3:12].[S:19](Cl)(=[O:22])(=[O:21])[NH2:20]>>[C:17]([C:3]1[C:2]([NH:1][S:19](=[O:22])(=[O:21])[NH2:20])=[CH:16][CH:15]=[CH:14][C:4]=1[O:5][CH2:6][CH2:7][CH2:8][CH2:9][NH:10][C:11](=[O:13])[CH3:12])#[N:18]
Reactant: NS(=O)(=O)Cl
Reactant: CC(=O)NCCCCOc1cccc(N)c1C#N
Product: CC(=O)NCCCCOc1cccc(NS(N)(=O)=O)c1C#N
Yield: 100 %

Procedure:
Prepared as in Example 215a from N-(4-(3-amino-2-cyanophenoxy)butyl)acetamide (Example 234b) and sulfamoyl chloride in 100% yield. 1H NMR (400 MHz, DMSO-d6) δ 1.51-1.54 (m, 2H), 1.70-1.73 (m, 2H), 1.77 (s, 3H), 3.04-3.09 (m, 2H), 4.09 (t, J=6.4 Hz, 2H), 6.93 (d, J=8.4 Hz, 1H), 7.13 (d, J=8.0 Hz, 1H), 7.25 (s, 2H), 7.54 (t, J=8.0 Hz, 1H), 7.85 (brs, 1H), 9.42 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:10]([F:11])=[CH:9][CH:8]=[C:7]([F:12])[C:3]=1[C:4](Cl)=[O:5].[NH2:13][CH2:14][C:15]1([CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][N:27]2[CH3:32])[CH2:18][N:17]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:16]1.C(N(CC)CC)C>ClCCl>[Cl:1][C:2]1[C:10]([F:11])=[CH:9][CH:8]=[C:7]([F:12])[C:3]=1[C:4]([NH:13][CH2:14][C:15]1([CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][N:27]2[CH3:32])[CH2:16][N:17]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:18]1)=[O:5]
Reactant: O=C(Cl)c1c(F)ccc(F)c1Cl
Reactant: CN1CCCCC1C1(CN)CN(C(=O)OC(C)(C)C)C1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN1CCCCC1C1(CNC(=O)c2c(F)ccc(F)c2Cl)CN(C(=O)OC(C)(C)C)C1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
2-chloro-3,6-difluorobenzoyl chloride (0.38 ml, 2.7 mmol) was added to tert-butyl 3-(aminomethyl)-3-(1-methylpiperidin-2-yl)azetidine-1-carboxylate (0.55 g, 1.9 mmol) in dichloromethane (6 ml) and triethylamine (0.54 ml, 3.9 mmol) at 0° C. The reaction was stirred at 0° C. for 15 mins, before warming to room temperature. After 30 mins, lc-ms showed complete consumption of starting material. The reaction was quenched and the resulting mixture was partitioned between dichloromethane and water. The organic phase was washed with brine, dried over anhydrous magnesium sulfate and evaporated to dryness. Purification by flash column chromatography on silica gel eluting with dichloromethane (containing 1% ammonia) on a gradient of methanol (0-8%) led to tert-butyl 3-{[(2-chloro-3,6-difluorobenzoyl)amino]methyl}-3-(1-methylpiperidin-2-yl)azetidine-1-carboxylate as a white solid. m/z (M++H) 458.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)/[CH:5]=[CH:6]/[C:7](O)=[O:8].S1C=CC=C1[Cl:18]>C1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)/[CH:5]=[CH:6]/[C:7]([Cl:18])=[O:8]
Reactant: Clc1cccs1
Reactant: O=C(O)/C=C/c1cccc(Br)c1
Solvent: c1ccccc1
Product: O=C(Cl)/C=C/c1cccc(Br)c1
Yield: 99 %

Procedure:
A mixture of trans 3-bromocinnamic acid (m.p. 177°-179° C; 11.4 g), thienyl chloride (11.9 g) and dry benzene (150 ml) was heated at reflux for 2 hours. Solvent and excess thienyl chloride were removed by distillation under reduced pressure leaving trans 3-bromocinnamoyl chloride (12.2 g), b.p. 100°-100.5°C/0.2 mm Hg.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[C:18]([Cl:20])[N:17]=[CH:16][N:15]=2)=[CH:10][CH:9]=1)(C)(C)C.C(Cl)Cl.Cl>O>[Cl:20][C:18]1[N:17]=[CH:16][N:15]=[C:14]([C:11]2[CH:12]=[CH:13][C:8]([NH2:7])=[CH:9][CH:10]=2)[CH:19]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2cc(Cl)ncn2)cc1
Agent: Cl
Solvent: O
Solvent: ClCCl
Product: Nc1ccc(-c2cc(Cl)ncn2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of [4-(6-chloro-pyrimidin-4-yl)-phenyl]-carbamic acid tert-butyl ester (918 mg, 3.00 mmol), CH2Cl2 (30 mL) and HCl (4 N in dioxane; 3.80 mL) was stirred overnight at rt and the solid isolated by filtration. The resultant solid was taken up in water, treated with satd. aq. NaHCO3 and extracted with CH2Cl2. The extract was dried, filtered, and concentrated. The material was used directly in Step C.
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([NH:8][CH2:9][CH:10]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:11]([OH:13])=O)=[O:7])([CH3:4])[CH3:3].[Cl:20][C:21]1[C:25]([C:26]2[N:30]([CH3:31])[N:29]=[CH:28][CH:27]=2)=[C:24]([Cl:32])[S:23][C:22]=1[NH2:33].CCN(C(C)C)C(C)C.F[P-](F)(F)(F)(F)F.Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1>ClCCl>[Cl:20][C:21]1[C:25]([C:26]2[N:30]([CH3:31])[N:29]=[CH:28][CH:27]=2)=[C:24]([Cl:32])[S:23][C:22]=1[NH:33][C:11](=[O:13])[CH:10]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:9][NH:8][C:6](=[O:7])[O:5][C:2]([CH3:1])([CH3:3])[CH3:4]
Reactant: Cn1nccc1-c1c(Cl)sc(N)c1Cl
Reactant: CC(C)(C)OC(=O)NCC(C(=O)O)c1ccccc1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cn1nccc1-c1c(Cl)sc(NC(=O)C(CNC(=O)OC(C)(C)C)c2ccccc2)c1Cl
Reaction time: 12 h
Yield: 38.1 %

Procedure:
To a solution of 3-({[(1,1-dimethylethyl)oxy]carbonyl}amino)-2-phenylpropanoic acid (342 mg, 1.290 mmol), [3,5-dichloro-4-(1-methyl-1H-pyrazol-5-yl)-2-thienyl]amine (320 mg, 1.290 mmol) and DIPEA (1.126 ml, 6.45 mmol) in dichloromethane (12.100 ml) at 25° C. was added bromo-tris-pyrrolidino-phosphonium hexafluorophosphate (723 mg, 1.548 mmol) in one portion. After 12 h, additional DIPEA (1.126 ml, 6.45 mmol), 3-({[(1,1-dimethylethyl)oxy]carbonyl}amino)-2-phenylpropanoic acid (342 mg, 1.290 mmol) and Bromo-tris-pyrrolidino-phosphonium hexafluorophosphate (723 mg, 1.548 mmol) were added and the solution stirred 24 h. The reaction mixture was then dry loaded onto silica and purified by chromatography (0-70% EtOAc in hexanes) affording 1,1-dimethylethyl (3-{[3,5-dichloro-4-(1-methyl-1H-pyrazol-5-yl)-2-thienyl]amino}-3-oxo-2-phenylpropyl)carbamate (320 mg, 0.491 mmol, 38.1% yield) as an yellow oil: LCMS (ES) m/e 495, 497 (M, M+2)+.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[C:17]([C:18]2[N:23]=[CH:22][CH:21]=[CH:20][N:19]=2)=[CH:16][CH:15]=[CH:14][C:13]=1[CH3:24])=[O:11].Cl[C:26]1[N:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][N:27]=1>>[CH3:9][C@@H:8]1[CH2:7][CH2:6][CH2:5][N:4]([C:10]([C:12]2[C:17]([C:18]3[N:19]=[CH:20][CH:21]=[CH:22][N:23]=3)=[CH:16][CH:15]=[CH:14][C:13]=2[CH3:24])=[O:11])[C@@H:3]1[CH2:2][NH:1][C:26]1[N:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][N:27]=1
Reactant: FC(F)(F)c1cnc(Cl)nc1
Reactant: Cc1cccc(-c2ncccn2)c1C(=O)N1CCC[C@@H](C)[C@H]1CN
Product: Cc1cccc(-c2ncccn2)c1C(=O)N1CCC[C@@H](C)[C@H]1CNc1ncc(C(F)(F)F)cn1

Procedure:
The title compound was prepared following the same general protocol as described for Example A306 using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(2-methyl-6-(pyrimidin-2-yl)phenyl)methanone and 2-chloro-5-(trifluoromethyl)pyrimidine. ESI-MS (m/z): 471 [M+1]+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19](Br)[C:20]([C:24]#[N:25])=[CH:21][CH:22]=4)[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1.[Cl-].[CH3:29][O:30][C:31]1[CH:38]=[CH:37][C:34]([CH2:35][Zn+])=[CH:33][CH:32]=1>>[CH3:1][O:2][C:3](=[O:27])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19]([CH2:35][C:34]5[CH:37]=[CH:38][C:31]([O:30][CH3:29])=[CH:32][CH:33]=5)[C:20]([C:24]#[N:25])=[CH:21][CH:22]=4)[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c3ccc(C#N)c4Br)ccc21
Reactant: COc1ccc(C[Zn+])cc1
Agent: [Cl-]
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c3ccc(C#N)c4Cc3ccc(OC)cc3)ccc21

Procedure:
The title compound is prepared from {(S)-6-[(R)-4-bromo-5-cyano-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester and 4-methoxy-benzylzinc chloride following a procedure analogous to that described in Step 6 of Intermediate 1. LC (method 4): tR=1.22 min; Mass spectrum (ESI+): m/z=492 [M+Na]+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].Br[CH2:18][CH:19]1[CH2:21][CH2:20]1>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][CH2:18][CH:19]2[CH2:21][CH2:20]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: BrCC1CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(OCC2CC2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 53.4 %

Procedure:
A reaction flask was charged with 4-hydroxypiperidine-1-carboxylic acid t-butyl ester (10.05 g, 49.9 mmol) in dry DMF (50 mL) under Argon. NaH (60% in oil, 2.0 g, 50.0 mmol) was added in portions and the mixture was stirred at 50° for 1 h. The mixture was cooled to rt and bromomethylcyclopropane (6.752 g, 50.0 mmol) was added followed by stirring at rt for 20 h under Argon. The reaction mixture was quenched with water and the product extracted into EtOAc. The combined organic phases were dried over Na2SO4, filtered, and concentrated. The product was purified by flash column chromatography (SiO2; n-heptane/EtOAc 2:1) to give the title compound (6.809 g, 53%). 1H NMR (CDCl3) d 3.66-3.58 (m, 2H), 3.31-3.24 (m, 1H), 3.12 (d, 2H), 2.90-2.83 (m, 2H), 1.68-1.60 (m, 2), 1.38-1.30 (m, 2H), 1.28 (s, 9H), 0.91-0.82 (m, 1H), 0.38-0.33 (m, 2H), 0.04-0.00 (m, 2H); 13C NMR (CDCl3) d 154.8, 79.3, 74.4, 72.6, 41.4, 31.2, 28.4, 10.9, 3.0
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:9][C@H:10]([NH2:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[CH2:1]([NH:17][C@@H:10]([CH3:9])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[C@H](N)c1ccccc1
Reactant: O=Cc1ccccc1
Product: C[C@H](NCc1ccccc1)c1ccccc1
Yield: 96.1 %

Procedure:
Benzaldehyde (3.94 mL, 38.8 mmol) and (S)-α-methylbenzylamine (5.0 mL, 38.8 mmol, 96% ee.) were allowed to react according to the procedure of Example 86 to yield 7.88 g (96%) of N-benzyl-(S)-α-methylbenzylamine as an oil contaminated with ~5% of benzyl alcohol and (S)-α-methylbenzylamine: 1H NMR (DMSO-d6, 250 MHz) δ 7.15-7.45 (m, 10 H, Ar), 3.69 (q, 1 H, J=6.5 Hz), 3.48 (dd, 2 H, j1 =13.6 Hz, J2 =20.9 Hz), 2.45 (br s, 1 H, NH), 1.26 (d, 3 H, J=6.5 Hz, CH3); 13C NMR (DMSO-d6) δ 146.0, 141.0, 128.1, 128.0, 127.8, 126.4, 126.3, 56.7, 50.6, 24.5. This mixture was directly used in the next reaction.