Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS[C:3]1[S:4]/[C:5](=[CH:9]\[C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[CH:15][CH:14]=[CH:13]3)/[C:6](=[O:8])[N:7]=1.[CH2:20]([NH2:25])[CH2:21][CH2:22][CH2:23][CH3:24].CCN(C(C)C)C(C)C>>[CH2:20]([NH:25][C:3]1[S:4]/[C:5](=[CH:9]\[C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[CH:15][CH:14]=[CH:13]3)/[C:6](=[O:8])[N:7]=1)[CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: CCCCCN
Reactant: CSC1=NC(=O)/C(=C/c2ccc3ncccc3c2)S1
Solvent: CCN(C(C)C)C(C)C
Product: CCCCCNC1=NC(=O)/C(=C/c2ccc3ncccc3c2)S1

Procedure:
Similar procedure as described in example 1b was used, starting from 2-methylsulfanyl-5-[1-quinolin-6-yl-meth-(Z)-ylidene]-thiazol-4-one, pentylamine and DIEA to give 2-pentylamino-5-[1-quinolin-6-yl-meth-(Z)-ylidene]-thiazol-4-one. LC-MS m/e 326 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:25]CC2C=CC=CC=2)=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:14]2[N:19]=[C:18]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:17]=[CH:16][CH:15]=2)[CH:7]=1.Br>C(O)(=O)C.C(OCC)C.O.C(=O)([O-])[O-].[K+].[K+]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:25])=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:14]2[N:19]=[C:18]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:17]=[CH:16][CH:15]=2)[CH:7]=1
Reactant: CCOC(=O)c1cccc(-c2ccccc2-c2cc(Cl)ccc2OCc2ccccc2)n1
Agent: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOCC
Solvent: CC(=O)O
Product: CCOC(=O)c1cccc(-c2ccccc2-c2cc(Cl)ccc2O)n1
Reaction time: 16 h
Yield: 82.3 %

Procedure:
Ethyl 6-{5′-chloro-2′-[(phenylmethyl)oxy]-2-biphenylyl}-2-pyridinecarboxylate (1.22 g, 2.75 mmol) was dissolved in acetic acid (5 ml) and 48% hydrogen bromide in acetic acid (5 ml), left at room temperature for 0.5 hours then diluted with diethyl ether/water and basified with potassium carbonate. The organic phase was separated, dried (magnesium sulphate), evaporated and chromatographed on silica eluting with ethyl acetate/iso-hexane (1:3). The product was dissolved in ethanol (20 ml), 60% sodium hydride (2 mg) added and the solution left at room temperature for 16 hours. The resulting solution was acidified with acetic acid, diluted with water/ether and the organic phase washed with saturated sodium bicarbonate solution, dried (magnesium sulphate), evaporated and chromatographed on silica to give 801 mg of colourless gum. LC/MS t=3.33, [MH+] 354.3, 356.3
Reaction SMILES: C(O[C:6](=O)[N:7]([CH2:9][C:10]([N:12]1[CH2:17][CH2:16][N:15]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([CH2:24][S:25]([CH:28]=[C:29]3[CH2:32][N:31]([CH:33]([C:41]4[CH:46]=[CH:45][C:44]([Cl:47])=[CH:43][CH:42]=4)[C:34]4[CH:39]=[CH:38][C:37]([Cl:40])=[CH:36][CH:35]=4)[CH2:30]3)(=[O:27])=[O:26])[CH:19]=2)[CH2:14][CH2:13]1)=[O:11])C)(C)(C)C>C(O)=O>[Cl:40][C:37]1[CH:36]=[CH:35][C:34]([CH:33]([C:41]2[CH:42]=[CH:43][C:44]([Cl:47])=[CH:45][CH:46]=2)[N:31]2[CH2:30][C:29](=[CH:28][S:25]([CH2:24][C:20]3[CH:19]=[C:18]([N:15]4[CH2:14][CH2:13][N:12]([C:10](=[O:11])[CH2:9][NH:7][CH3:6])[CH2:17][CH2:16]4)[CH:23]=[CH:22][CH:21]=3)(=[O:27])=[O:26])[CH2:32]2)=[CH:39][CH:38]=1
Reactant: CN(CC(=O)N1CCN(c2cccc(CS(=O)(=O)C=C3CN(C(c4ccc(Cl)cc4)c4ccc(Cl)cc4)C3)c2)CC1)C(=O)OC(C)(C)C
Solvent: O=CO
Product: CNCC(=O)N1CCN(c2cccc(CS(=O)(=O)C=C3CN(C(c4ccc(Cl)cc4)c4ccc(Cl)cc4)C3)c2)CC1
Yield: 83.3 %

Procedure:
A solution of 81 mg of (2-{4-[3-({1-[bis-(4-chlorophenyl)methyl]azetidin-3-ylidene}methanesulfonylmethyl)phenyl]piperazin-1-yl}-2-oxoethyl)-N-methylcarbamic acid tert-butyl ester in 2.5 cm3 of formic acid is stirred for 1 hour at a temperature close to 45° C. The reaction mixture is concentrated to dryness under reduced pressure (5 kPa) at a temperature close to 30° C., taken up in 10 cm3 of ethyl acetate and alkalinized with 10 cm3 of a saturated aqueous sodium bicarbonate solution. After separating after settling out, the organic phase is washed with 10 cm3 of water, dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure (1 kPa) at a temperature close to 40° C. 58 mg of 1-{4-[3-({1-[bis-(4-chlorophenyl)methyl]azetidin-3-ylidene}methanesulfonylmethyl)phenyl]piperazin-1-yl}-2-methylaminoethanone are thus obtained in the form of a beige lacquer [1H NMR spectrum (300 MHz, CDCl3), δ in ppm): from 1.95 to 2.15 (broad unresolved complex, 1H), 2.51 (broad s, 3H), 2.77 (s, 3H), from 3.10 to 3.30 (mt, 4H), 3.49 (broad s, 2H), 3.58 (mt, 2H), from 3.75 to 3.90 (mt, 4H), 4.33 (mt, 2H), 4.49 (s, 1H), 6.83 (broad d, J=8 Hz, 1H), 6.90 (dd, J=8 and 2 Hz, 1H), 7.00 (mt, 1H), from 7.20 to 7.40 (mt, 9H)].
Reaction SMILES: NC1C(Cl)=C(C=C([Cl:12])C=1)C(OC)=O.CCN(C(C)C)C(C)C.CS(Cl)(=O)=O.[Cl:28][C:29]1[C:38]([NH:39][S:40]([CH3:43])(=[O:42])=[O:41])=[CH:37][C:36]([Cl:44])=[CH:35][C:30]=1[C:31]([O:33]C)=[O:32].[OH-].[Na+]>C(Cl)Cl.CO>[ClH:12].[Cl:28][C:29]1[C:38]([NH:39][S:40]([CH3:43])(=[O:41])=[O:42])=[CH:37][C:36]([Cl:44])=[CH:35][C:30]=1[C:31]([OH:33])=[O:32]
Reactant: COC(=O)c1cc(Cl)cc(N)c1Cl
Reactant: COC(=O)c1cc(Cl)cc(NS(C)(=O)=O)c1Cl
Agent: CS(=O)(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Solvent: ClCCl
Product: CS(=O)(=O)Nc1cc(Cl)cc(C(=O)O)c1Cl
Product: Cl
Temperature: 0 °C
Reaction time: 2 h

Procedure:
From common intermediate methyl 3-amino-2,5-dichlorobenzoate following the procedure outlined in scheme. Methyl 3-amino-2,5-dichlorobenzoate (2.10 g, 9.55 mmol), DIEA (3.0 ml) were stirred in DCM (40 ml) at 0° C. methanesulfonyl chloride (2.18 g, 19.08 mmol) was added dropwise whike stirring at 0° C. After 2 hrs at 0° C., reaction was allowed to warm to room temperature while stirring overnight. Quenched rxn with saturated NH4Cl and washed with brine. Organic layer with dried to yield crude methyl 2,5-dichloro-3-[(methylsulfonyl)amino]benzoate (3.10 g) which will be carried on. methyl 2,5-dichloro-3-[(methylsulfonyl)amino]benzoate (3.10 g) was treated with NaOH, methanol following procedure outlined in scheme to form 2,5-dichloro-3-[(methylsulfonyl)amino]benzoic acid hydrochloride (3.53 g).
Reaction SMILES: [ClH:1].N1CC(C2C=CC3C4C(CCOC=3C=2)=CN(C2N(C3C=CC(F)=CC=3F)N=CN=2)N=4)C1.C(OC([N:40]1[CH2:43][CH:42]([C:44]2[CH:65]=[CH:64][C:47]3[C:48]4[N:52]([CH2:53][CH2:54][O:55][C:46]=3[CH:45]=2)[CH:51]=[C:50]([C:56]2[N:57]([CH:61]([CH3:63])[CH3:62])[N:58]=[CH:59][N:60]=2)[N:49]=4)[CH2:41]1)=O)(C)(C)C>>[ClH:1].[NH:40]1[CH2:41][CH:42]([C:44]2[CH:65]=[CH:64][C:47]3[C:48]4[N:52]([CH2:53][CH2:54][O:55][C:46]=3[CH:45]=2)[CH:51]=[C:50]([C:56]2[N:57]([CH:61]([CH3:62])[CH3:63])[N:58]=[CH:59][N:60]=2)[N:49]=4)[CH2:43]1
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(C3CN(C(=O)OC(C)(C)C)C3)cc1OCC2
Agent: Cl
Agent: Fc1ccc(-n2ncnc2-n2cc3c(n2)-c2ccc(C4CNC4)cc2OCC3)c(F)c1
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(C3CNC3)cc1OCC2

Procedure:
8-Azetidin-3-yl-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene hydrochloride was prepared similarly to 8-azetidin-3-yl-2-[2-(2,4-difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-2H-6-oxa-1,2-diaza-benzo[e]azulene hydrochloride from 3-[2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-yl]-azetidine-1-carboxylic acid tert-butyl ester. LCMS: RT=2.44 min, M+H+=351
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[OH:6][CH2:7][CH2:8][C:9]1[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][CH:10]=1.O>C(Cl)Cl>[CH3:1][S:2]([O:6][CH2:7][CH2:8][C:9]1[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][CH:10]=1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: N#Cc1ccc(CCO)cc1
Solvent: O
Solvent: ClCCl
Product: CS(=O)(=O)OCCc1ccc(C#N)cc1
Temperature: 25 °C

Procedure:
MsCl (18.6 g; 164 mmol) was added to a stirred solution of 4-(2-hydroxyethyl)benzonitrile (20 g; 136 mmol) and TEA (20.6 g; 204 mmol) in DCM (200 mL) at 0° C. The reaction mixture was stirred at rt. until tlc indicated that the reaction was complete. Water (200 mL) was added and the organic layer was separated, dried and concentrated to give the sub-title compound in a quantitative yield.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:11][CH2:10][C:9]2[C:4](=[C:5]([N:12]3[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]3)[CH:6]=[CH:7][CH:8]=2)[CH2:3]1.C(N(CC)CC)C.[C:26](Cl)(=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C(Cl)Cl>[CH3:18][N:15]1[CH2:16][CH2:17][N:12]([C:5]2[CH:6]=[CH:7][CH:8]=[C:9]3[C:4]=2[CH2:3][C@H:2]([NH:1][C:26](=[O:33])[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:11][CH2:10]3)[CH2:13][CH2:14]1
Reactant: CN1CCN(c2cccc3c2C[C@H](N)CC3)CC1
Reactant: O=C(Cl)c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN1CCN(c2cccc3c2C[C@H](NC(=O)c2ccccc2)CC3)CC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To an ice-cooled solution of (R)-2-amino-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydronaphthalene (210 mg, 0.86 mmol) and triethylamine (180 μL, 1.28 mmol) in methylene chloride (30 mL) was added dropwise benzoyl chloride (130 mg, 0.90 mmol) in methylene chloride (5 mL). After the addition the reaction was allowed to stir at ambient temperature for 15 min and then washed with water. The phases were separated and the combined organic phases were dried (Na2SO4), filtered and evaporated in vacuo to give a crude product which was purified on a silica gel column using chloroform/ethanol saturated with NH3 (100:3) as the eluent. Yield: 250 mg (84%) of the title compound as white crystals: mp 195-196° C.; [α]21D −31° (c 1.0, CHCL3); EIMS (70 eV) m/z (relative intensity) 349 (53, M+).
Reaction SMILES: [CH2:1]([CH:3]1[CH2:12][C:11]2[C:6](=[CH:7][C:8]([N+:13]([O-:15])=[O:14])=[CH:9][CH:10]=2)[CH:5]=[N:4]1)[CH3:2].[BH4-].[Na+].O>CO>[CH2:1]([CH:3]1[CH2:12][C:11]2[C:6](=[CH:7][C:8]([N+:13]([O-:15])=[O:14])=[CH:9][CH:10]=2)[CH2:5][NH:4]1)[CH3:2]
Reactant: CCC1Cc2ccc([N+](=O)[O-])cc2C=N1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CCC1Cc2ccc([N+](=O)[O-])cc2CN1
Yield: 99 %

Procedure:
To a solution of 3-ethyl-7-nitro-3,4-dihydroisoquinoline (15.8 g, Example 2 (d)) in methanol (100 ml) at 0° C. was added sodium borohydride (4g). After foaming had stopped, the reaction was poured into water (750 ml) and then the aqueous phase was extracted with ethyl acetate (3×300 ml). Evaporation gave 3-ethyl-7-nitro-1,2,3,4-tetrahydroisoquinoline as a tan oil (15.8 g).
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[C:10]([NH:11][NH2:12])=[CH:9][C:8](=[O:13])[N:7]([CH3:14])[C:6]2=[O:15])[CH2:3][CH2:2]1.[Cl:16][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[NH:22][CH:21]=[C:20]2[CH:26]=O.[CH3:28][N:29]1[CH:33]=[C:32]([C:34](=[O:39])[C:35]([F:38])([F:37])[F:36])[CH:31]=[C:30]1[CH:40]=O>>[Cl:16][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[NH:22][CH:21]=[C:20]2[CH2:26][N:12]1[C:40]([C:30]2[N:29]([CH3:28])[CH:33]=[C:32]([C:34](=[O:39])[C:35]([F:37])([F:36])[F:38])[CH:31]=2)=[C:9]2[C:10]([N:5]([CH2:4][CH:1]3[CH2:2][CH2:3]3)[C:6](=[O:15])[N:7]([CH3:14])[C:8]2=[O:13])=[N:11]1
Reactant: O=Cc1c[nH]c2ccc(Cl)cc12
Reactant: Cn1c(=O)cc(NN)n(CC2CC2)c1=O
Reactant: Cn1cc(C(=O)C(F)(F)F)cc1C=O
Product: Cn1cc(C(=O)C(F)(F)F)cc1-c1c2c(=O)n(C)c(=O)n(CC3CC3)c2nn1Cc1c[nH]c2ccc(Cl)cc12

Procedure:
This compound was made following the procedure described above, starting with 1-(cyclopropylmethyl)-6-hydrazino-3-methylpyrimidine-2,4(1H,3H)-dione, and condensing first with 5-chloro-1H-indole-3-carbaldehyde, followed by 1-methyl-4-(trifluoroacetyl)-1H-pyrrole-2-carbaldehyde. Mass: 559.15 (M+H).
Reaction SMILES: C([O:8][C@H:9]1[C@H:15]([O:16]CC2C=CC=CC=2)[C@@H:14]([O:24]CC2C=CC=CC=2)[C@:13]2([C:33]3[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([CH2:40][C:41]4[CH:46]=[CH:45][C:44]([O:47][CH3:48])=[C:43]([F:49])[C:42]=4[F:50])[CH:34]=3)[O:32][C@@:10]1([C:51]([OH:54])([CH3:53])[CH3:52])[CH2:11][O:12]2)C1C=CC=CC=1.ClC1C=CC=CC=1Cl>[Pd].CO.O1CCCC1>[Cl:39][C:36]1[CH:37]=[CH:38][C:33]([C@@:13]23[O:32][C@@:10]([C:51]([OH:54])([CH3:53])[CH3:52])([CH2:11][O:12]2)[C@@H:9]([OH:8])[C@H:15]([OH:16])[C@H:14]3[OH:24])=[CH:34][C:35]=1[CH2:40][C:41]1[CH:46]=[CH:45][C:44]([O:47][CH3:48])=[C:43]([F:49])[C:42]=1[F:50]
Reactant: COc1ccc(Cc2cc([C@]34OC[C@](C(C)(C)O)(O3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]4OCc3ccccc3)ccc2Cl)c(F)c1F
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Solvent: Clc1ccccc1Cl
Product: COc1ccc(Cc2cc([C@]34OC[C@](C(C)(C)O)(O3)[C@@H](O)[C@H](O)[C@H]4O)ccc2Cl)c(F)c1F
Temperature: 25 °C
Reaction time: 4 h
Yield: 82 %

Procedure:
To a solution of 2-[(1S,2S,3S,4R,5S)-2,3,4-tribenzyloxy-5-[4-chloro-3-[(2,3-difluoro-4-methoxy-phenyl)methyl]phenyl]-6,8-dioxabicyclo[3.2.1]octan-1-yl]propan-2-ol 22c (86 mg, 0.11 mmol) in a methanol/tetrahydrofuran mixture (v/v=4/1, 10 mL) were added o-dichlorobenzene (0.064 mL, 0.57 mmol) and 10% Pd/C (13 mg, 0.01 mmol) at room temperature. The mixture was stirred at room temperature under H2 for 4 hours and filtered. The filtrate was concentrated in vacuo and the residue was purified by silica gel chromatography eluted with PE/EtOAc(v/v)=1/3 to give the title compound 22 as white oil (43.9 mg, 79.8%, HPLC: 92.7%). The compound was characterized by the following spectroscopic data: MS (ESI, pos. ion) m/z: 531.0 [M+HCOO]−; and 1H NMR (400 MHz, DMSO-d6) δ(ppm): 7.42 (m, 1H), 7.37 (m, 2H), 6.96 (m, 1H), 6.93-6.85 (m, 1H), 5.51 (d, 1H), 5.05 (d, 1H), 5.00 (d, 1H), 4.24 (s, 1H), 4.05 (m, 3H), 3.85 (s, 3H), 3.79 (d, 1H), 3.75-3.65 (m, 1H), 3.50-3.36 (m, 2H), 1.20 (s, 3H), 1.15 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2([CH2:28][CH2:29][N:30]3[C@H:35]4[CH2:36][CH2:37][C@@H:31]3[CH2:32][CH:33]([N:38]3[C:42]5[CH:43]=[CH:44][CH:45]=[CH:46][C:41]=5[N:40]=[C:39]3[CH3:47])[CH2:34]4)[CH2:13][CH2:12][N:11]([C:14]([C@@H:16]3[CH2:20][CH2:19][CH2:18][N:17]3C(OC(C)(C)C)=O)=[O:15])[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.Cl>>[F:1][C:2]1[CH:3]=[C:4]([C:8]2([CH2:28][CH2:29][N:30]3[C@H:35]4[CH2:36][CH2:37][C@@H:31]3[CH2:32][CH:33]([N:38]3[C:42]5[CH:43]=[CH:44][CH:45]=[CH:46][C:41]=5[N:40]=[C:39]3[CH3:47])[CH2:34]4)[CH2:13][CH2:12][N:11]([C:14](=[O:15])[C@@H:16]3[CH2:20][CH2:19][CH2:18][NH:17]3)[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1nc2ccccc2n1C1C[C@H]2CC[C@@H](C1)N2CCC1(c2cccc(F)c2)CCN(C(=O)[C@@H]2CCCN2C(=O)OC(C)(C)C)CC1
Agent: Cl
Product: Cc1nc2ccccc2n1C1C[C@H]2CC[C@@H](C1)N2CCC1(c2cccc(F)c2)CCN(C(=O)[C@@H]2CCCN2)CC1
Yield: 99.2 %

Procedure:
1-[(1R,5S)-8-(2-{4-(3-fluorophenyl)-1-[1-(trifluoroacetyl)-L-prolyl]-4-piperidinyl}ethyl)-8-azabicyclo[3.2.1]oct-3-yl]-2-methyl-1H-benzimidazole was obtained from treating 1,1-dimethylethyl (2S)-2-[(4-(3-fluorophenyl)-4-{2-[(1R,5S)-3-(2-methyl-1H-benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-1-piperidinyl)carbonyl]-1-pyrrolidinecarboxylate (0.645 g, 1.01 mmol) with HCl as outlined in the procedure for Example 890 to form 1-((1R,5S)-8-{2-[4-(3-fluorophenyl)-1-L-prolyl-4-piperidinyl]ethyl}-8-azabicyclo[3.2.1]oct-3-yl)-2-methyl-1H-benzimidazole (0.545 g, 99%). 1-((1R,5S)-8-{2-[4-(3-fluorophenyl)-1-L-prolyl-4-piperidinyl]ethyl}-8-azabicyclo[3.2.1]oct-3-yl)-2-methyl-1H-benzimidazole (0.050 g, 0.09 mmol), trifluoroaceticanhydirde (0.019 g, 0.09 mmol) and DIEA (0.034 g, 0.534 mmol) were reacted following the procedure outlined in Example 890 to give the title compound, 1-[(1R,5S)-8-(2-{4-(3-fluorophenyl)-1-[1-(trifluoroacetyl)-L-prolyl]-4-piperidinyl}ethyl)-8-azabicyclo[3.2.1]oct-3-yl]-2-methyl-1H-benzimidazole (0.021 g, 36%) as an oil. ES-LCMS m/z 640 (M+1).
Reaction SMILES: [Mg].BrC(Br)C.[CH2:6]([C:8]1[CH:13]=[C:12]([CH3:14])[CH:11]=[C:10]([CH2:15][CH3:16])[C:9]=1Br)[CH3:7].[C:18](OCC)(=[O:24])[C:19]([O:21][CH2:22][CH3:23])=[O:20].Cl>O1CCCC1>[CH2:6]([C:8]1[CH:13]=[C:12]([CH3:14])[CH:11]=[C:10]([CH2:15][CH3:16])[C:9]=1[C:18](=[O:24])[C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH3:7]
Reactant: CCc1cc(C)cc(CC)c1Br
Reactant: CCOC(=O)C(=O)OCC
Agent: CC(Br)Br
Agent: Cl
Agent: [Mg]
Solvent: C1CCOC1
Product: CCOC(=O)C(=O)c1c(CC)cc(C)cc1CC
Temperature: 30 °C
Reaction time: 0.5 h
Yield: 98.1 %

Procedure:
To a 3 L volume four-necked flask, magnesium (turnings, 35.31 g), tetrahydrofuran (anhydrous, 600 ml) were added under nitrogen atmosphere at room temperature. After the stirring was started, the mixture was heated to about 30° C. of the internal temperature, and then dibromoethane (25.4 g) was added dropwise over 20 minutes. The resulting mixture was stirred for 30 minutes, and heated to about 50° C. of the internal temperature. To the mixture was added a solution of 2,6-diethyl-4-methylbromobenzene (300.18 g) in tetrahydrofuran (150 ml) dropwise over 2 hours. The resulting mixture was stirred at 50° C. for 1 hour, and then diethyl oxalate (192.5 g) was added dropwise at about 0° C. over 15 minutes. The resulting mixture was stirred at room temperature for 2 hours. To the mixture was added 3.5 weight % of hydrochloric acid (1000 ml) and concentrated hydrochloric acid (60 ml) with cooling. Then, the organic layer was evaporated, and the aqueous layer was extracted with tert-butyl methyl ether. The organic layer was concentrated under reduced pressure to give 320.82 g of ethyl (2,6-diethyl-4-methylphenyl)glyoxylate.
Reaction SMILES: C([Li])CCC.[CH3:6][C:7]1[C:12]2[CH:13]=[CH:14][O:15][C:11]=2[C:10]([CH3:16])=[CH:9][CH:8]=1.CN(C)[CH:19]=[O:20].C(OCC)(=O)C>O1CCCC1>[CH3:6][C:7]1[C:12]2[CH:13]=[C:14]([CH:19]=[O:20])[O:15][C:11]=2[C:10]([CH3:16])=[CH:9][CH:8]=1
Reactant: Cc1ccc(C)c2occc12
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1ccc(C)c2oc(C=O)cc12
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Under nitrogen atmosphere at -35° C., 18.4 ml of n-butyllithium (1.56M hexane solution) was added to 50 ml of a solution of 3.5 g of 4,7-dimethylbenzofuran in anhydrous tetrahydrofuran, and the resulting mixture was stirred for 15 minutes, followed by the dropwise addition thereto of 5.6 ml of N,N-dimethylformamide. The temperature of the resulting mixture was raised to room temperature, followed by the addition of ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated. The resulting crude crystal was washed with n-hexane to give 2.3 g of the title compound as a pale-yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.[F:9][C:10]1[CH:11]=[C:12]([OH:17])[CH:13]=[CH:14][C:15]=1[NH2:16]>>[Cl:1][C:2]1[CH:7]=[C:6]([O:17][C:12]2[CH:13]=[CH:14][C:15]([NH2:16])=[C:10]([F:9])[CH:11]=2)[CH:5]=[CH:4][N:3]=1
Reactant: Clc1ccnc(Cl)c1
Reactant: Nc1ccc(O)cc1F
Product: Nc1ccc(Oc2ccnc(Cl)c2)cc1F
Yield: 85.4 %

Procedure:
Using a procedure analogous to Example A2, 2,4-dichloropyridine (8.0 g, 54 mmol) and 3-fluoro-4-aminophenol (8.0 g, 62.9 mmol) were combined to provide 4-(2-chloro-pyridin-4-yloxy)-2-fluorophenylamine (11 g, 86% yield). 1H NMR (300 MHz, DMSO-d6) δ 8.24 (d, J=5.7 Hz, 1H), 7.00 (dd, J=9.0, 2.7 Hz, 1H), 6.89-6.73 (m, 4H), 5.21 (br s, 2H); MS (ESI) m/z: 239.2 (M+H+).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([NH:10][C@H:11]([C:13]2[CH:25]=[CH:24][C:16]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[CH:15][CH:14]=2)[CH3:12])=[O:9])=[CH:6][C:5]([Cl:26])=[CH:4][N:3]=1.[Cl:27][C:28]1[CH:33]=[CH:32][C:31]([OH:34])=[CH:30][C:29]=1[CH3:35]>>[Cl:26][C:5]1[CH:6]=[C:7]([C:8]([NH:10][C@H:11]([C:13]2[CH:25]=[CH:24][C:16]([C:17]([O:19][C:20]([CH3:22])([CH3:23])[CH3:21])=[O:18])=[CH:15][CH:14]=2)[CH3:12])=[O:9])[C:2]([O:34][C:31]2[CH:32]=[CH:33][C:28]([Cl:27])=[C:29]([CH3:35])[CH:30]=2)=[N:3][CH:4]=1
Reactant: C[C@H](NC(=O)c1cc(Cl)cnc1Cl)c1ccc(C(=O)OC(C)(C)C)cc1
Reactant: Cc1cc(O)ccc1Cl
Product: Cc1cc(Oc2ncc(Cl)cc2C(=O)N[C@@H](C)c2ccc(C(=O)OC(C)(C)C)cc2)ccc1Cl

Procedure:
The title compound was prepared according to the procedure described in step 2 of Example 45 from tert-butyl 4-((1S)-1-{[(2,5-dichloropyridin-3-yl)carbonyl]amino}ethyl)benzoate (step 1 of Example 45) and 4-chloro-3-methylphenol: 1H-NMR (CDCl3) δ 8.54 (1H, d, J=2.6 Hz), 8.15 (1H, d, J=2.6 Hz), 8.09 (1H, d, J=7.3 Hz), 7.95 (2H, d, J=8.3 Hz), 7.47–7.37 (3H, m), 7.03 (1H, d, J=2.8 Hz), 6.96 (1H, dd, J=8.6, 2.8 Hz), 5.36 (1H, dq, J=7.3, 7.0 Hz), 2.41 (3H, s), 1.60 (3H, d, J=7.0 Hz), 1.58 (9H, s); MS (ESI) m/z 501 (M+H)+, 499 (M−H)−.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][NH:9][CH:10]=1)=[O:5])[CH3:2].[H-].[Na+].[CH2:13]([O:15][C:16]([C@@H:18]1[CH2:27][C@@H:26]2[C@@H:21]([CH2:22][CH2:23][C@H:24]([CH2:28]OS(C3C=CC=C([N+]([O-])=O)C=3)(=O)=O)[CH2:25]2)[CH2:20][N:19]1C(OC)=O)=[O:17])[CH3:14]>C1COCC1>[CH2:13]([O:15][C:16]([C@@H:18]1[CH2:27][C@@H:26]2[C@@H:21]([CH2:22][CH2:23][C@H:24]([CH2:28][N:9]3[CH:10]=[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[N:7]=[CH:8]3)[CH2:25]2)[CH2:20][NH:19]1)=[O:17])[CH3:14]
Reactant: CCOC(=O)c1c[nH]cn1
Reactant: CCOC(=O)[C@@H]1C[C@H]2C[C@@H](COS(=O)(=O)c3cccc([N+](=O)[O-])c3)CC[C@H]2CN1C(=O)OC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)c1cn(C[C@H]2CC[C@H]3CN[C@H](C(=O)OCC)C[C@H]3C2)cn1
Temperature: 25 °C
Reaction time: 0.92 h
Yield: 92.2 %

Procedure:
Ethyl-4-imidazolecarboxylate (486 mg, 3.46 mmol) was added in portions to a slurry of sodium hydride (146 mg of a 60% mineral oil dispersion, 3.64 mmol) in THF (3.0 mL). The resulting tea-colored solution was stirred at room temperature for 55 minutes. It was then treated with [3S,4aR,6S,8aR]-ethyl-6-((3-nitrophenylsulfonyloxy)methyl)-2-(methoxycarbonyl)-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylate (1.68 g, 3.46 mmol, prepared in example 1) dissolved in THF (3.5 mL), and the reaction mixture was stirred overnight at room temperature. The reaction was then partitioned between dichloromethane (6.5 mL) and water (6.5 mL), and the layers were separated. The aqueous layer was extracted with dichloromethane (5 mL). The organic extract and organic layer were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to provide the crude title compound. This material was purified flash chromatography (5% to 10% ethanol/toluene containing 0.5% dimethylamine, 34 g silica gel) to provide the purified intermediate title compound (1.16 g, 79%) as a colorless film.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:15][CH2:14][C@@H:13]([OH:16])[CH2:12][NH:11][C:10]1=[O:17])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Si:18](Cl)([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19].N1C=CN=C1.CN(C=O)C>O>[C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:15][CH2:14][C@@H:13]([O:16][Si:18]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19])[CH2:12][NH:11][C:10]1=[O:17])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](O)CNC1=O
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](O[Si](C)(C)C(C)(C)C)CNC1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.9 %

Procedure:
(3S,6R)-3-(tert-butoxycarbonyl)aminohexahydro-6-hydroxy-2H-azepin-2-one (25 g, 102 mmol), tert-butyldimethylsilyl chloride (23.16 g, 153 mmol), and imidazole (10.45 g, 153 mmol) are combined with 60 mL of DMF. The reaction is stirred at room temperature overnight. The mixture is diluted with 1 L of water. The resulting mixture is extracted with a 1:1 (2×200 mL) mixture of ethyl acetate and hexane. All organic layers are combined, washed with brine solution, dried with NaSO4, and concentrated. The residue is purified by recrystallization with ethyl acetate/hexane to give 28.5 g (78%) of (3S,6R)-3-(tert-butoxycarbonyl)aminohexahydro-6-tert-butyldimethylsilyloxy-2H-azepin-2-one as a white solid: 1H NMR (CDCl3) δ 5.86 (d, J=6 Hz, 1H), 5.58 (t, J=6 Hz, 1H), 4.18 (m, 1H), 3.91 (s, 1H), 3.35(dd, J=6 Hz and 16 Hz, 1H), 3.07 (m, 1H), 1.80 (m, 4H), 1.40 (s, 9H), 0.83 (s, 9H), 0.004 (s, 6H).