Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[CH:10]=[C:9]([C:11]([OH:13])=O)[N:8]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[CH:16]=3)[C:5]2=[N:6][CH:7]=1.[CH:22]12[CH2:27][CH:26]1[CH2:25][N:24]([C:28]1[N:33]=[CH:32][C:31]([NH2:34])=[CH:30][CH:29]=1)[CH2:23]2>>[CH:26]12[CH2:27][CH:22]1[CH2:23][N:24]([C:28]1[N:33]=[CH:32][C:31]([NH:34][C:11]([C:9]3[N:8]([CH2:14][C:15]4[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[CH:16]=4)[C:5]4=[N:6][CH:7]=[C:2]([F:1])[CH:3]=[C:4]4[CH:10]=3)=[O:13])=[CH:30][CH:29]=1)[CH2:25]2
Reactant: O=C(O)c1cc2cc(F)cnc2n1Cc1cccc(F)c1
Reactant: Nc1ccc(N2CC3CC3C2)nc1
Product: O=C(Nc1ccc(N2CC3CC3C2)nc1)c1cc2cc(F)cnc2n1Cc1cccc(F)c1
Yield: 67.6 %

Procedure:
According to a method similar to that described in Stage 12.3, starting from 0.45 g (1.56 mmol) of 5-fluoro-1-[(3-fluorophenyl)methyl]-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid, described in the preceding stage, and 0.3 g (1.71 mmol) of 6-(3-azabicyclo[3.1.0]hex-3-yl)-3-aminopyridine, prepared in Stage 21.2, we obtain 0.47 g of the expected product.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:10]=[N:11][C:12]3[C:17]([CH:18]=2)=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:5]=[CH:4][N:3]=1.[CH3:19]I.[H-].[Na+].O>CN(C=O)C>[Cl:1][C:2]1[N:7]=[C:6]([N:8]([CH3:19])[C:9]2[CH:10]=[N:11][C:12]3[C:17]([CH:18]=2)=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:5]=[CH:4][N:3]=1
Reactant: Clc1nccc(Nc2cnc3ccccc3c2)n1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CN(c1cnc2ccccc2c1)c1ccnc(Cl)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (2-chloro-pyrimidin-4-yl)-quinolin-3-yl-amine (0.400 g, 1.64 mmol) in DMF (7 mL) at 0° C. was added MeI (0.133 mL, 2.13 mmol) and NaH (60% dispersion in mineral oil, 0.079 g, 1.97 mmol). The reaction mixture was warmed to RT, accompanied by the appearance of a yellow color and solid precipitate. After stirring for 1 h at RT, H2O (25 mL) was added and the mixture was extracted with EtOAc (3×10 mL). The combined organic layers were washed with brine, dried with MgSO4, filtered and concentrated under reduced pressure. Chromatography on silica gel (1:1 EtOAc:Hexanes) provided the title compound.
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[Br:9][C:10]1[CH:14]=[CH:13][NH:12][N:11]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Br:9][C:10]1[CH:14]=[CH:13][N:12]([C:2]2[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][N:3]=2)[N:11]=1
Reactant: Clc1cccnc1Cl
Reactant: Brc1cc[nH]n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Clc1cccnc1-n1ccc(Br)n1
Temperature: 125 °C
Reaction time: 1.5 h

Procedure:
To a mixture of 2,3-dichloropyridine (27.4 g, 185 mmol) and 3-bromopyrazole (i.e. the product of Step B) (25.4 g, 176 mmol) in dry N,N-dimethylformamide (88 mL) was added potassium carbonate (48.6 g, 352 mmol), and the reaction mixture was heated to 125° C. for 18 hours. The reaction mixture was cooled to room temperature and poured into ice water (800 mL). A precipitate formed. The precipitated solids were stirred for 1.5 hrs, filtered and washed with water (2×100 mL). The solid filter cake was taken up in methylene chloride and washed sequentially with water, 1N hydrochloric acid, saturated aqueous sodium bicarbonate solution, and brine. The organic extracts were then dried over magnesium sulfate and concentrated to afford 39.9 g of a pink solid. The crude solid was suspended in hexane and stirred vigorously for 1 hr. The solids were filtered, washed with hexane and dried to afford the title product as an off-white powder (30.4 g) determined to be >94% pure by NMR. This material was used without further purification in Step D.
Reaction SMILES: [N+](C1C=CC(O[C:11]([C:13]2[CH:14]=[CH:15][C:16]([O:27][CH:28]([F:30])[F:29])=[C:17]3[O:21][C:20]([CH:22]4[CH2:26][CH2:25][O:24][CH2:23]4)=[CH:19][C:18]=23)=[O:12])=CC=1)([O-])=O.[NH2:31][C:32]1[N:36]([CH3:37])[N:35]=[CH:34][C:33]=1[C:38]#[N:39]>O>[C:38]([C:33]1[CH:34]=[N:35][N:36]([CH3:37])[C:32]=1[NH:31][C:11]([C:13]1[CH:14]=[CH:15][C:16]([O:27][CH:28]([F:30])[F:29])=[C:17]2[O:21][C:20]([CH:22]3[CH2:26][CH2:25][O:24][CH2:23]3)=[CH:19][C:18]=12)=[O:12])#[N:39]
Reactant: Cn1ncc(C#N)c1N
Reactant: O=C(Oc1ccc([N+](=O)[O-])cc1)c1ccc(OC(F)F)c2oc(C3CCOC3)cc12
Solvent: O
Product: Cn1ncc(C#N)c1NC(=O)c1ccc(OC(F)F)c2oc(C3CCOC3)cc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 46.6 %

Procedure:
Prepared from 7-difluoromethoxy-2-(tetrahydrofuran-3-yl)-benzofuran-4-carboxylic acid 4-nitrophenyl ester (380 mg) and 5-amino-1-methyl-1-H-pyrazole-4-carbonitrile (220 mg). The reaction was stirred for 2 hours at room temperature. Water (1 ml) was added and the solvent removed in vacuo. The residue was dissolved in ethyl acetate (50 ml) and washed with water (2×40 ml), followed by 1N hydrochloric acid (40 ml). The organic extract was dried over magnesium sulphate, filtered and preadsorbed onto silica. Purification by column chromatography on silica eluting with 70% ethyl acetate in heptane, followed by trituration with diethyl ether afforded the title compound as a white solid (170 mg).
Reaction SMILES: [C:1]1([N:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:14][C:15]1[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[CH:17][CH:16]=1.CC(C)=O>C(O)C>[C:1]1([N:7]2[CH2:12][CH2:11][N:10]([CH2:14][C:15]3[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[CH:17][CH:16]=3)[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: N#Cc1ccc(CBr)cc1
Reactant: c1ccc(N2CCNCC2)cc1
Solvent: CC(C)=O
Solvent: CCO
Product: N#Cc1ccc(CN2CCN(c3ccccc3)CC2)cc1
Yield: 79.3 %

Procedure:
4-phenylpiperazine (41.4 g, 0.26 mol) was added to a solution of 4-(bromomethyl)benzonitrile (25 g, 0.13 mol) in 60 ml ethanol and the mixture was refluxed for one hour. After filtration of the precipitated N-phenylpiperazinium bromide, the filtrate was evaporated and the residue was recrystallized in a chloroform: acetone mixture to afford 28.6 g (79% yield) of 4-(4-phenylpiperazinylmethyl)benzonitrile.
Reaction SMILES: [CH3:1][N:2]1[CH2:15][CH2:14][C:5]2[NH:6][C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.Br[C:17]1[CH:22]=[CH:21][C:20]([Br:23])=[CH:19][N:18]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].N1CCC[C@H]1C(O)=O>CN(C=O)C.O.[Cu]I>[Br:23][C:20]1[CH:21]=[CH:22][C:17]([N:6]2[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]3[CH2:3][N:2]([CH3:1])[CH2:15][CH2:14][C:5]2=3)=[N:18][CH:19]=1
Reactant: Cc1ccc2[nH]c3c(c2c1)CN(C)CC3
Reactant: Brc1ccc(Br)nc1
Agent: [Cu]I
Agent: O=C(O)[C@@H]1CCCN1
Agent: O=P([O-])([O-])[O-]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc2c(c1)c1c(n2-c2ccc(Br)cn2)CCN(C)C1

Procedure:
A solution of 2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (1 g, 5 mmol), 2,5-dibromopyridine (1.78 g, 7.5 mmol), K3PO4 (3.18 g, 15 mmol), CuI (95 mg, 0.5 mmol) and L-proline (115 mg, 1 mmol) in dry DMF (10 mL) was stirred at 150° C. for 16 h. The reaction mixture was diluted with water (100 mL) and extracted with EtOAc (300 mL). The organic layer was washed with water (8×50 mL), dried over anhydrous sodium sulfate and evaporated to afford crude material, which was purified by column chromatography using neutral alumina and 5% EtOAc-hexane, to yield 5-(5-bromopyridin-2-yl)-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole.
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:24])=[C:4]2[C:9](=[C:10]([CH3:13])[C:11]=1[CH3:12])[O:8][C:7]([CH3:23])([C:14]([N:16]([CH2:20][CH2:21][OH:22])[CH2:17][CH2:18][OH:19])=[O:15])[CH2:6][CH2:5]2.[O:25]=[N+]([O-])[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[Ce+4].[NH4+].[NH4+]>>[OH:25][C:7]([CH3:23])([CH2:6][CH2:5][C:4]1[C:9](=[O:8])[C:10]([CH3:13])=[C:11]([CH3:12])[C:2](=[O:1])[C:3]=1[CH3:24])[C:14]([N:16]([CH2:20][CH2:21][OH:22])[CH2:17][CH2:18][OH:19])=[O:15]
Reactant: Cc1c(C)c2c(c(C)c1O)CCC(C)(C(=O)N(CCO)CCO)O2
Reactant: O=[N+]([O-])[O-]
Agent: [Ce+4]
Agent: [NH4+]
Product: CC1=C(C)C(=O)C(CCC(C)(O)C(=O)N(CCO)CCO)=C(C)C1=O
Yield: 25.6 %

Procedure:
Oxidation as described in protocol B, using 68.4 mg (0.203 mmol) of precursor 6-hydroxy-N,N-bis(2-hydroxyethyl)-2,5,7,8-tetramethylchroman-2-carboxamide and 244 mg CAN (0.446 mmol) yielding 18.4 mg of 2-hydroxy-N,N-bis(2-hydroxyethyl)-2-methyl-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide as a yellow oil (25.7%).
Reaction SMILES: [CH3:1][CH:2]([CH3:31])[CH2:3][C@H:4]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]2[C:19]3[C:14](=[CH:15][N:16]=[CH:17][CH:18]=3)[C:13](=[O:20])[N:12]([CH3:21])[C:11]=2[CH:22]=1.C1C(=O)N([Cl:39])C(=O)C1>>[Cl:39][C:8]1[C:7]([O:6][CH2:5][C@@H:4]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[CH2:3][CH:2]([CH3:31])[CH3:1])=[CH:22][C:11]2[N:12]([CH3:21])[C:13](=[O:20])[C:14]3[C:19]([C:10]=2[CH:9]=1)=[CH:18][CH:17]=[N:16][CH:15]=3
Reactant: O=C1CCC(=O)N1Cl
Reactant: CC(C)C[C@@H](COc1ccc2c3ccncc3c(=O)n(C)c2c1)NC(=O)OC(C)(C)C
Product: CC(C)C[C@@H](COc1cc2c(cc1Cl)c1ccncc1c(=O)n2C)NC(=O)OC(C)(C)C
Yield: 61 %

Procedure:
(S)-tert-butyl (4-methyl-1-((6-methyl-5-oxo-5,6-dihydrobenzo[c][2,7]naphthyridin-8-yl)oxy)pentan-2-yl)carbamate (0.4 g, 0.714 mmol), prepared as described in Example 19, Part B, was subjected to chlorination using NCS as described in Example 41, to afford (S)-tert-butyl (1-((9-chloro-6-methyl-5-oxo-5,6-dihydrobenzo[c][2,7]naphthyridin-8-yl)oxy)-4-methylpentan-2-yl)carbamate (0.3 g, 0.437 mmol, 61% yield) as a yellow solid. LC/MS (ESI) m/e 460.2 [(M+H)+, calcd for C24H31ClN3O4, 460.2]; LC/MS retention time (Method C) tR=2.17 min.
Reaction SMILES: S=[C:2]1[NH:6][C:5]2[CH:7]=[C:8]([C:11]([O:13][CH3:14])=[O:12])[CH:9]=[CH:10][C:4]=2[O:3]1.[N:15]1([CH:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1>C1(C)C(C)=CC=CC=1.ClCCl>[N:15]1([CH:21]2[CH2:26][CH2:25][N:24]([C:2]3[O:3][C:4]4[CH:10]=[CH:9][C:8]([C:11]([O:13][CH3:14])=[O:12])=[CH:7][C:5]=4[N:6]=3)[CH2:23][CH2:22]2)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: C1CCN(C2CCNCC2)CC1
Reactant: COC(=O)c1ccc2oc(=S)[nH]c2c1
Solvent: Cc1ccccc1C
Solvent: ClCCl
Product: COC(=O)c1ccc2oc(N3CCC(N4CCCCC4)CC3)nc2c1
Temperature: 130 °C

Procedure:
Methyl 2-thioxo-2,3-dihydrobenzo[d]oxazole-5-carboxylate (Example 94A, 300 mg, 1.43 mmol) and 1,4′-bipiperidine (483 mg, 2.87 mmol) were combined in xylene (2 mL). The mixture was heated in a microwave to 130° C. for 20 minutes. The reaction mixture was diluted with dichloromethane, washed with water, and the organic layer was absorbed on silica gel. The crude mixture was purified using silica gel chromatography (40 g column) eluting with a gradient of methanol/dichloromethane (3-18%) to afford the title compound. 1H NMR (300 MHz, CDCl3) δ ppm 1.38-1.50 (m, 2 H) 1.54-1.72 (m, 5 H) 1.95 (d, J=12.89 Hz, 2 H) 2.46-2.59 (m, 6 H) 3.03-3.16 (m, 2 H) 3.91 (s, 3 H) 4.32-4.36 (m, 1 H) 4.36-4.41 (m, 1 H) 7.25 (d, 1 H) 7.79 (dd, J=8.48, 1.70 Hz, 1 H) 8.00 (d, J=1.70 Hz, 1 H); MS (ESI+) m/z 344.3 (M+H)+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][C@H:8]2[C@H:17]([OH:18])[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([OH:19])[CH:15]=3)[O:10][CH2:9]2)[CH:2]=1.Br[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([CH3:28])[N:23]=1>>[CH3:21][C:22]1[N:23]=[C:24]([CH2:28][O:19][C:14]2[CH:15]=[C:16]3[C:11](=[CH:12][CH:13]=2)[O:10][CH2:9][C@@H:8]([CH2:7][C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)[C@@H:17]3[OH:18])[CH:25]=[CH:26][CH:27]=1
Reactant: Oc1ccc2c(c1)[C@@H](O)[C@H](Cc1cccnc1)CO2
Reactant: Cc1cccc(CBr)n1
Product: Cc1cccc(COc2ccc3c(c2)[C@@H](O)[C@H](Cc2cccnc2)CO3)n1

Procedure:
By the method of Example 5, 0.50 g (1.95 mmol) of trans-3-(3-pyridylmethyl)-4,6-chromandiol and 400 mg (2.15 mmol) of 2-(bromomethyl)-6-methyl pyridine were converted to present title product, purified by flash chromatography on silica gel using ethyl acetate as eluant to yield purified title product, 0.14 g (20%), m.p. 66-68° C.
Reaction SMILES: [CH2:1]([N:3]([CH2:32][CH3:33])[CH2:4][CH2:5][N:6]1[C:14]2[C:9](=[C:10]([C:16]([F:19])([F:18])[F:17])[CH:11]=[C:12](I)[CH:13]=2)[C:8]([OH:30])([C:20]2[CH:29]=[CH:28][C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH:21]=2)[C:7]1=[O:31])[CH3:2].[C:34]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])(=[O:37])[CH2:35][CH3:36]>>[CH2:1]([N:3]([CH2:32][CH3:33])[CH2:4][CH2:5][N:6]1[C:14]2[C:9](=[C:10]([C:16]([F:19])([F:18])[F:17])[CH:11]=[C:12]([C:36]#[C:35][C:34]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH:13]=2)[C:8]([OH:30])([C:20]2[CH:29]=[CH:28][C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH:21]=2)[C:7]1=[O:31])[CH3:2]
Reactant: CCN(CC)CCN1C(=O)C(O)(c2ccc3ccccc3c2)c2c1cc(I)cc2C(F)(F)F
Reactant: CCC(=O)OC(C)(C)C
Product: CCN(CC)CCN1C(=O)C(O)(c2ccc3ccccc3c2)c2c1cc(C#CC(=O)OC(C)(C)C)cc2C(F)(F)F

Procedure:
The title compound (75.7 mg, quant.) was prepared from 1-(2-diethylaminoethyl)-4-trifluoromethyl-6-iodo-3-hydroxy-3-(2-naphthyl)oxindole of Example 48 (75.1 mg, 0.132 mmol) and t-butyl propionate by the procedure similar to that described in Reference Example 21.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:12][CH2:11][NH:10]2)=[CH:5][CH:4]=1.CCN(C(C)C)C(C)C.Cl[C:31]([O:33][C:34]1[CH:39]=[CH:38][C:37]([N+:40]([O-:42])=[O:41])=[CH:36][CH:35]=1)=[O:32].O>C(Cl)Cl>[F:20][C:2]([F:1])([F:19])[C:3]1[CH:4]=[CH:5][C:6]([CH:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:12][CH2:11][N:10]2[C:31]([O:33][C:34]2[CH:35]=[CH:36][C:37]([N+:40]([O-:42])=[O:41])=[CH:38][CH:39]=2)=[O:32])=[CH:7][CH:8]=1
Reactant: FC(F)(F)c1ccc(C2NCCc3ccccc32)cc1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: O
Product: O=C(Oc1ccc([N+](=O)[O-])cc1)N1CCc2ccccc2C1c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline (200 mg, 0.721 mmol, example 9 (step 3) and DIEA (126 μL, 0.721 mmol) in DCM (4 mL) was added 4-nitrophenyl chloroformate (145 mg, 0.721 mmol). The resulting mixture was stirred at RT for 16 h. Then, H2O (10 mL) was added and the mixture was extracted with DCM (2×5 mL). The combined organic extracts were dried over MgSO4 and concentrated. The residue was purified by silica gel flash column chromatography (0%-50% EtOAc/hexane) to give the title compound as a white oil. MS (ESI, positive ion) m/z: 443 (M+H).
Reaction SMILES: C(C1C=CC=CC=1N[C@@H](CC1C=CC(C2C=CC=C(NC)C=2)=CC=1)C(OCC)=O)(=O)C1C=CC=CC=1.[NH2:37][C@@H:38]([CH2:44][C:45]1[CH:50]=[CH:49][C:48]([C:51]2[CH:56]=[CH:55][CH:54]=[C:53]([CH2:57][NH:58][CH2:59][C:60](=[O:67])[C:61]3[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=3)[CH:52]=2)=[CH:47][CH:46]=1)[C:39]([O:41][CH2:42][CH3:43])=[O:40].O=[C:69]1[CH2:74][CH2:73][CH2:72][CH2:71][CH:70]1[C:75]([O:77][CH2:78][CH3:79])=[O:76]>>[C:60]([CH2:59][NH:58][CH2:57][C:53]1[CH:52]=[C:51]([C:48]2[CH:47]=[CH:46][C:45]([CH2:44][C@H:38]([NH:37][C:71]3[CH:72]=[CH:73][CH:74]=[CH:69][C:70]=3[C:75]([O:77][CH2:78][CH3:79])=[O:76])[C:39]([O:41][CH2:42][CH3:43])=[O:40])=[CH:50][CH:49]=2)[CH:56]=[CH:55][CH:54]=1)(=[O:67])[C:61]1[CH:62]=[CH:63][CH:64]=[CH:65][CH:66]=1
Reactant: CCOC(=O)[C@@H](N)Cc1ccc(-c2cccc(CNCC(=O)c3ccccc3)c2)cc1
Reactant: CCOC(=O)C1CCCCC1=O
Agent: CCOC(=O)[C@H](Cc1ccc(-c2cccc(NC)c2)cc1)Nc1ccccc1C(=O)c1ccccc1
Product: CCOC(=O)c1ccccc1N[C@@H](Cc1ccc(-c2cccc(CNCC(=O)c3ccccc3)c2)cc1)C(=O)OCC
Yield: 9.9 %

Procedure:
In a manner similar to the preparation of the ethyl (S)-2-(2-benzoylphenylamino)-3-(3′-methylaminobiphenyl-4-yl)propionate (Example 1g), using 6.7 g (16.1 mmol) of ethyl (S)-2-amino-3-{3′-[(benzoylmethylamino)methyl]biphenyl-4-yl}propionate (Example 28f) and 3 ml (19.3 mmol) of ethyl 2-oxocyclohexanecarboxylate, 0.90 g of ethyl (S)-2-(2-{3′-[(benzoylmethylamino)methyl]biphenyl-4-yl}-1-ethoxycarbonylethylamino)-benzoate is isolated with a 10% yield.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N+:10]([O-:12])=[O:11])[CH:5]=[C:6]([F:9])[C:7]=1F.[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][C:7]2[C:6]([F:9])=[CH:5][C:4]([N+:10]([O-:12])=[O:11])=[CH:3][C:2]=2[F:1])=[CH:16][CH:15]=1
Reactant: Oc1ccc(Cl)cc1
Reactant: O=[N+]([O-])c1cc(F)c(F)c(F)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cc(F)c(Oc2ccc(Cl)cc2)c(F)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 106.9 %

Procedure:
A mixture of 3,4,5-trifluoronitrobenzene (6.6 g, 37 mmol), dry DMF (30 ml), 4-chlorophenol (5.26 g, 41 mmol), and Cs2CO3 (18.8 g, 58 mmol) was stirred under N2 at 60-70 C for 1-2 hrs. After cooling to room temperature, the reaction mixture was partitioned between H2O and EtOAc. The phases were separated and the aqueous phase was further extracted with EtOAc (2×). The EtOAc extractions were washed with sat'd NaCl (1×), dried over Na2SO4, and concentrated in vacuo to give 4-(4-chlorophenoxy)-3,5-difluoronitrobenzene (11.3 g, 106%) which was used in the next step without further purification. 1H NMR (CDCl3): δ 6.90 (d, 2H, J=7.6 Hz), 7.28 (d, 2H, J=7.6 Hz), 7.94 (d, 2H, J=6.4 Hz). Note: K2CO3/acetonitrile can be used in lieu of Cs2CO3/DMF.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][C@H:13]([NH:24]C(=O)OCC1C=CC=CC=1)[C:14](=[O:23])[NH:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.[Pd]>[NH2:24][C@H:13]([C:14](=[O:23])[NH:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=1)[CH2:12][CH2:11][CH2:10][CH2:9][NH:8][C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NCCCC[C@H](NC(=O)OCc1ccccc1)C(=O)NCc1ccccn1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)NCCCC[C@H](N)C(=O)NCc1ccccn1
Reaction time: 2 h

Procedure:
To a solution of (S)-benzyl 6-((tert-butoxycarbonyl)-amino)-1-oxo-1-(pyridin-2-ylmethylamino)hexan-2-ylcarbamate, 27, (3.8 g, 8.2 mmol) in methanol (80 mL) was added palladium (10 wt % on carbon, 0.5 g). The mixture was stirred under a hydrogen atmosphere for 2 h. The mixture was filtered through Celite and washed with methanol. The resulting filtrate was concentrated in vacuo. The crude residue was used without further purification: ESI+ MS: m/z (rel intensity) 337.2 (100, [M+H]+).
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[C:9]([O:11][C:12]([F:15])([F:14])[F:13])[CH:8]=[CH:7][C:5]=1[NH2:6])([O-])=O.N1C2C=CC(C#N)=CC=2N[CH:17]=1.NC1C=CC(C#N)=CC=1[N+]([O-])=O>>[F:13][C:12]([F:15])([F:14])[O:11][C:9]1[CH:8]=[CH:7][C:5]2[N:6]=[CH:17][NH:1][C:4]=2[CH:10]=1
Reactant: Nc1ccc(OC(F)(F)F)cc1[N+](=O)[O-]
Reactant: N#Cc1ccc2nc[nH]c2c1
Agent: N#Cc1ccc(N)c([N+](=O)[O-])c1
Product: FC(F)(F)Oc1ccc2nc[nH]c2c1

Procedure:
6-(trifluoromethoxy)-1H-benzo[d]imidazole (4) was prepared in two steps from 2-nitro-4-(trifluoromethoxy)aniline (5) using procedures identical to those used to make 3H-benzo[d]imidazole-5-carbonitrile (3) from 4-amino-3-nitrobenzonitrile (1, examples 1, 2).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]([CH3:31])[C:10]([NH:12][CH2:13][C:14]2[C:15]([C:24]3[CH:25]=[C:26]([CH3:30])[CH:27]=[CH:28][CH:29]=3)=[N:16][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:18][CH:19]=2)=[O:11])=[CH:5][CH:4]=1)#[N:2].[BH4-].[Na+]>C(O)C>[NH2:2][CH2:1][C:3]1[CH:4]=[CH:5][C:6]([CH:9]([CH3:31])[C:10]([NH:12][CH2:13][C:14]2[C:15]([C:24]3[CH:25]=[C:26]([CH3:30])[CH:27]=[CH:28][CH:29]=3)=[N:16][C:17]([C:20]([F:23])([F:21])[F:22])=[CH:18][CH:19]=2)=[O:11])=[CH:7][CH:8]=1
Reactant: Cc1cccc(-c2nc(C(F)(F)F)ccc2CNC(=O)C(C)c2ccc(C#N)cc2)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: Cc1cccc(-c2nc(C(F)(F)F)ccc2CNC(=O)C(C)c2ccc(CN)cc2)c1
Temperature: 25 °C
Yield: 54.3 %

Procedure:
To a stirred solution of 2-(4-cyanophenyl)-N-((2-m-tolyl-6-(trifluoromethyl)pyridin-3-yl)methyl)propanamide (305 mg, 0.72 mmol) in ethanol was cooled to 0° C. and added NiCl2.6H2O (17 mg, 0.072 mmol) and stirred more then 15 min. Sodium borohydride (191 mg, 5.04 mmol) was then added in small portions. The reaction was exothermic and effervescent. The resulting reaction mixture was allowed to warm to room temperature and left to stir for 2 hour. The mixture was filtered using celite pad. The filtrate was concentrated was evaporated. The residue was dissolved in ethylacetate and washed with water and brine, but when it does not separate easily, small amount of 1N HCl and saturated NaHCO3 was used. The organic layer was dried over magnesium sulfate and filtered. The filtrate removed in vacuo. The crude was purified by column chromatography. 2-(4-(Aminomethyl)phenyl)-N-((2-m-tolyl-6-(trifluoromethyl)pyridin-3-yl)methyl)propanamide (167 mg) was obtained as 64% yield.
Reaction SMILES: [CH3:1][NH:2][NH2:3].C(N(CC)CC)C.[CH3:11][C:12]1[CH:17]=[CH:16][C:15]([S:18](Cl)(=[O:20])=[O:19])=[CH:14][CH:13]=1>C1COCC1>[CH3:1][N:2]([S:18]([C:15]1[CH:16]=[CH:17][C:12]([CH3:11])=[CH:13][CH:14]=1)(=[O:20])=[O:19])[NH2:3]
Reactant: CNN
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)N(C)N)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.9 %

Procedure:
Into a 100 mL three necked round bottom flask equipped with a mechanical stirrer, thermometer, and dropping funnel under an atmosphere of nitrogen was added THF (25 mL), methylhydrazine (2.53 g, 2.92 mL, 55 mmol), and triethylamine (4.35 g, 5.99 mL, 55 mmol). The temperature of the mixture was lowered to approximately 5° C. and 4-methylbenzenesulfonyl chloride (9.5 g, 50 mmol) dissolved in 25 mL of THF was added dropwise at a rate such that the temperature did not rise over 10° C. The cooling bath was removed and the mixture was allowed to stir overnight at RT. Ether (100 mL) was added to the reaction mixture and the resulting slurry was washed with water (50 mL), brine (50 mL), dried (Na2SO4), and the solvent was removed in vacuo to give 9.5 g (95% yield) of the title product. 1H NMR (CDCl3) δ 7.7 (d, 2H), 7.4 (d, 2H), 3.6 (s, b, 2H), 2.8 (s, 3H), 2.4 (s, 3H)
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH:13]2[CH2:17][C:16]3[C:18](Br)=[CH:19][CH:20]=[CH:21][C:15]=3[O:14]2)(=O)=O)=CC=1.[N-:23]=[N+:24]=[N-:25].[Na+]>>[CH3:17][C:16]1[CH:18]=[CH:19][C:20]([C:18]2[C:16]3[CH2:17][CH:13]([CH2:12][N:23]=[N+:24]=[N-:25])[O:14][C:15]=3[CH:21]=[CH:20][CH:19]=2)=[CH:21][CH:15]=1
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1ccc(S(=O)(=O)OCC2Cc3c(Br)cccc3O2)cc1
Agent: [Na+]
Product: Cc1ccc(-c2cccc3c2CC(CN=[N+]=[N-])O3)cc1
Yield: 187.1 %

Procedure:
Treatment of (±)-(4-bromo-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (5.0 g, 13.0 mmol), o-tolylboronic acid (2.66 g, 19.57 mmol), dichlorobis(tri-o-tolylphosphine)-palladium(II) (0.512 g, 0.651 mmol), and potassium carbonate (4.51 g, 32.63 mmol) generally according to the procedure described for Intermediate 37 provided 4.0 g (77%) of (±)-1-[4-(4-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine as a yellow oil. Treatment of (±)-(4-bromo-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (3.8 g, 9.63 mmol) with sodium azide (2.5 g, 38.53 mmol) generally according to the procedure described for Intermediate 98 gave 2.39 g (94%) of [4-(4-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl azide. Treatment of the azide with palladium on carbon (0.239 g, 10 wt. %) generally according to the procedure described for Example 1 provided 2.3 g (93%) of (±)-1-[4-(4-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine as a white solid, hydrochloride salt. mp 239-241° C.; Anal. calcd. for C16H17NOHCl: C, 69.69; H, 6.58; N, 5.08. Found: C, 69:36; H, 6.64; N, 4.93.