Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]([CH:13]=[CH:14][C:15]([OH:17])=O)=[O:12])=[CH:3]1.[NH:18]1[CH2:25][CH2:24][CH2:23][C@H:19]1[C:20]([OH:22])=[O:21]>>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]([CH:13]=[CH:14][C:15]([N:18]2[CH2:25][CH2:24][CH2:23][C@H:19]2[C:20]([OH:22])=[O:21])=[O:17])=[O:12])=[CH:3]1
Reactant: Cn1cc(C(=O)C=CC(=O)O)c2ccccc21
Reactant: O=C(O)[C@@H]1CCCN1
Product: Cn1cc(C(=O)C=CC(=O)N2CCC[C@H]2C(=O)O)c2ccccc21

Procedure:
As for Example 29, 3-(1-methyl-3-indolylcarbonyl)acrylic acid is coupled to L-proline to give 1-[3-(1-methyl-3-indolylcarbonyl)acryloyl]-L-proline.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH2:8][OH:9])=[C:6]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:5]([CH:16]=[CH:17][CH2:18][CH2:19][CH3:20])=[C:4]([CH3:21])[N:3]=1>C(OCC)(=O)C.CCCCCC>[CH3:1][C:2]1[C:7]([CH2:8][OH:9])=[C:6]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:5]([CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[C:4]([CH3:21])[N:3]=1
Reactant: CCCC=Cc1c(C)nc(C)c(CO)c1-c1ccccc1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CCCCCc1c(C)nc(C)c(CO)c1-c1ccccc1

Procedure:
The title compound was prepared from 2,6dimethyl-3-hydroxymethyl-4-phenyl-5-(1-pentenyl)pyridine (Example 3) according to the procedure described in Example 1, Step H. 1H NMR (300 MHz, CDCl3): δ7.42 (m, 3 H), 7.15 (m, 2 H), 4.33 (s, 2 H), 2.65 (s, 3 H), 2.56 (s, 3 H), 2.27 (m, 2 H), 1.29 (m, 2 H), 1.11 (m, 4 H), 0.76 (t, J =7 Hz, 3 H). EI-MS: calculated for (C19H25NO) 283, found 283 (M+). Anal. calculated for C19H25NO: C, 80.52; H, 8.89; N, 4.94. Found: C, 80.39; H, 8.85; N, 4.85. mp 99-100° C. Rf=0.3 (90% ethyl acetate/hexane).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([O:12][CH3:13])[CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:14][C:15]2[CH:19]=[C:18]([CH3:20])[NH:17][N:16]=2)[N:3]=1.[S:21]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22]1>>[CH3:20][C:18]1[NH:17][N:16]=[C:15]([NH:14][C:4]2[N:3]=[C:2]([C:23]3[CH:24]=[CH:25][S:21][CH:22]=3)[C:11]3[C:6]([CH:5]=2)=[C:7]([O:12][CH3:13])[CH:8]=[CH:9][CH:10]=3)[CH:19]=1
Reactant: OB(O)c1ccsc1
Reactant: COc1cccc2c(Cl)nc(Nc3cc(C)[nH]n3)cc12
Product: COc1cccc2c(-c3ccsc3)nc(Nc3cc(C)[nH]n3)cc12

Procedure:
Similar procedure as described in example 131 was used, starting from (1-chloro-5-methoxy-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine and thiophene-3-boronic acid to give (5-methyl-1H-pyrazol-3-yl)-(1-thiophen-3-yl-5-methoxy-isoquinolin-3-yl)-amine. LC-MS m/e 337(MH+).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5](B(O)O)[CH:6]=[CH:7][CH:8]=1)=[O:2].[NH:12]1[CH:16]=[CH:15][CH:14]=[N:13]1.N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[N:12]1([C:5]2[CH:4]=[C:3]([CH:8]=[CH:7][CH:6]=2)[CH:1]=[O:2])[CH:16]=[CH:15][CH:14]=[N:13]1
Reactant: O=Cc1cccc(B(O)O)c1
Reactant: c1cn[nH]c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=Cc1cccc(-n2cccn2)c1
Reaction time: 24 h

Procedure:
A mixture of 3-formylphenylboronic acid (2.00 g, 13.34 mmol), pyrazole (0.46 g, 6.67 mmol), copper(II) acetate (1.82 g, 10.01 mmol), pyridine (1.10 mL, 13.34 mmol), and powdered 4A molecular sieves (2.5 g) in dichloromethane (20 mL) was stirred under an air atmosphere for 24 h. The mixture was then filtered through Celite, the filtered solids were washed with MeOH, and the combined filtrate was concentrated. Purification by chromatography (SiO2, 3:1 hexane/ethyl acetate) yielded the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:9][CH:8]([CH2:10][O:11][CH3:12])[CH2:7][N:6]1[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[O:4].[Li+].[OH-].Cl.BrC[C:25]([C:27]1[CH:32]=[CH:31][C:30]([Br:33])=[CH:29][CH:28]=1)=[O:26].C(N(CC)CC)C>CO>[C:16]([O:15][C:13]([N:6]1[CH2:7][CH:8]([CH2:10][O:11][CH3:12])[CH2:9][CH:5]1[C:3]([O:2][CH2:1][C:25]([C:27]1[CH:32]=[CH:31][C:30]([Br:33])=[CH:29][CH:28]=1)=[O:26])=[O:4])=[O:14])([CH3:19])([CH3:18])[CH3:17]
Reactant: O=C(CBr)c1ccc(Br)cc1
Reactant: COCC1CC(C(=O)OC)N(C(=O)OC(C)(C)C)C1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: CCN(CC)CC
Product: COCC1CC(C(=O)OCC(=O)c2ccc(Br)cc2)N(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 5 h
Yield: 97.3 %

Procedure:
4-Methoxymethyl-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (461 mg, 1.68 mmol) was dissolved in MeOH (17 mL) and LiOH (1 M in H2O, 8.5 mL, 8.5 mmol) was added. After stirring at RT for 5 h, the MeOH was removed under reduced pressure. The aqueous solution was poured into a separatory funnel, diluted with 1 M HCl (9 mL, 9 mmol) and extracted with DCM (3×). The combined organics were dried over MgSO4, filtered and concentrated. The residue was dissolved in MeCN (17 mL) and treated with 2,4′-dibromoacetophenone (514 mg, 1.85 mmol), and triethylamine (0.258 mL, 1.85 mmol). After stirring for 2 h, the solvent was removed and the solid was suspended in EtOAc. The organic layer was washed with saturated aqueous NaHCO3 and brine then dried over MgSO4, filtered and concentrated. The crude residue was purified by silica column chromatography (15% to 35% EtOAc/Hex) to afford the title compound (746 mg, 97%).
Reaction SMILES: [CH3:1][N:2]([CH3:14])[CH2:3][CH2:4][N:5]([C:8]1[CH:13]=[N:12][CH:11]=[CH:10][N:9]=1)[C:6]#[N:7].[OH-:15].[Na+]>Cl>[CH3:1][N:2]([CH3:14])[CH2:3][CH2:4][N:5]([C:8]1[CH:13]=[N:12][CH:11]=[CH:10][N:9]=1)[C:6]([NH2:7])=[O:15]
Reactant: CN(C)CCN(C#N)c1cnccn1
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Product: CN(C)CCN(C(N)=O)c1cnccn1
Reaction time: 1 h

Procedure:
N-(2-Dimethylaminoethyl)-N-(2-pyrazinyl) cyanamide (2.83 g, 0.015 mole) is dissolved in 20 ml of 6 N hydrochloric acid. After one hour, the mixture is made alkaline with concentrated sodium hydroxide and concentrated. The residue is extracted with ether which is concentrated. The residue is crystallized from butyl chloride and N-(2-dimethylaminoethyl)-N-(2-pyrazinyl)urea melting at 105°-108° C. is obtained.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[C:7]([NH2:12])=[N:8][CH:9]=[CH:10][CH:11]=2)[CH:3]=[N:2]1.[H-].[Na+].Cl[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:19][CH:18]=1>CN(C)C=O>[O:23]([C:20]1[CH:19]=[CH:18][C:17]([CH2:16][N:1]2[CH:5]=[C:4]([C:6]3[C:7]([NH2:12])=[N:8][CH:9]=[CH:10][CH:11]=3)[CH:3]=[N:2]2)=[CH:22][CH:21]=1)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: ClCc1ccc(Oc2ccccc2)cc1
Reactant: Nc1ncccc1-c1cn[nH]c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Nc1ncccc1-c1cnn(Cc2ccc(Oc3ccccc3)cc2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 92.1 %

Procedure:
To a solution of 3-(1H-pyrazol-4-yl)-pyridin-2-ylamine (20 mg, 0.13 mmol) described in Manufacturing Example 32-1-4 in N,N-dimethylformamide (10 mL) was added sodium hydride (7.5 mg, 0.19 mmol, 60% in oil) under nitrogen atmosphere on an ice bath (0° C.), which was stirred for 30 minutes at room temperature. 1-Chloromethyl-4-phenoxy-benzene (32.8 mg, 0.15 mmol) described in Manufacturing Example 34-1-1 was then added to the mixture and stirred for 30 minutes at room temperature. The reaction mixture was partitioned into water and ethyl acetate at room temperature. The organic layer was washed with water and saturated aqueous sodium chloride, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under a reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate:heptane=2:1, then ethyl acetate only) to obtain the title compound (41 mg, 86%, purity: 90%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]([CH3:27])([CH3:26])[CH2:10][C:11]([NH:13][C@@H:14]1[CH2:20][CH2:19][C:18]2[CH:21]=[CH:22][CH:23]=[CH:24][C:17]=2[NH:16][C:15]1=[O:25])=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[CH2:29][C:30]1[CH:35]=[CH:34][C:33]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=2[C:42]2[N:43]=[CH:44][N:45]([C:47]([C:60]3[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=3)([C:54]3[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=3)[C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=3)[CH:46]=2)=[CH:32][CH:31]=1>>[C:1]([O:5][C:6]([NH:8][C:9]([CH3:27])([CH3:26])[CH2:10][C:11]([NH:13][C@@H:14]1[CH2:20][CH2:19][C:18]2[CH:21]=[CH:22][CH:23]=[CH:24][C:17]=2[N:16]([CH2:29][C:30]2[CH:31]=[CH:32][C:33]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=3[C:42]3[N:43]=[CH:44][N:45]([C:47]([C:60]4[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=4)([C:54]4[CH:55]=[CH:56][CH:57]=[CH:58][CH:59]=4)[C:48]4[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=4)[CH:46]=3)=[CH:34][CH:35]=2)[C:15]1=[O:25])=[O:12])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(CC(=O)N[C@@H]1CCc2ccccc2NC1=O)NC(=O)OC(C)(C)C
Reactant: BrCc1ccc(-c2ccccc2-c2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)cc1
Product: CC(C)(CC(=O)N[C@@H]1CCc2ccccc2N(Cc2ccc(-c3ccccc3-c3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)cn3)cc2)C1=O)NC(=O)OC(C)(C)C

Procedure:
Prepared from 3-t-butoxycarbonylamino-3-methyl-N-[2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-3(R)-yl]-butanamide (Example 1, Step I) and 4-bromomethyl-2'-[1-(triphenylmethyl)imidazol-4-yl]-1,1'-biphenyl by the procedure described in Example 2, Step E.
Reaction SMILES: [CH:1]([C:3]1[C:4]([O:14][CH2:15][C:16]2[CH:41]=[CH:40][C:19]([O:20][CH2:21][C:22]3[N:23]=[C:24]([C:28]4[CH:29]=[C:30]([CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])[CH:31]=[CH:32][CH:33]=4)[O:25][C:26]=3[CH3:27])=[C:18]([O:42][CH2:43]C)[CH:17]=2)=[N:5][N:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:7]=1)=O.[CH2:45]([P:54](=[O:61])([O:58][CH2:59][CH3:60])[O:55][CH2:56][CH3:57])P(=O)(OCC)OCC.CN(C)C=O.[H-].[Na+]>O>[CH2:59]([O:58][P:54](/[CH:45]=[CH:1]/[C:3]1[C:4]([O:14][CH2:15][C:16]2[CH:41]=[CH:40][C:19]([O:20][CH2:21][C:22]3[N:23]=[C:24]([C:28]4[CH:29]=[C:30]([CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])[CH:31]=[CH:32][CH:33]=4)[O:25][C:26]=3[CH3:27])=[C:18]([O:42][CH3:43])[CH:17]=2)=[N:5][N:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:7]=1)([O:55][CH2:56][CH3:57])=[O:61])[CH3:60]
Reactant: CCOC(=O)Cc1cccc(-c2nc(COc3ccc(COc4nn(-c5ccccc5)cc4C=O)cc3OCC)c(C)o2)c1
Reactant: CCOP(=O)(CP(=O)(OCC)OCC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)Cc1cccc(-c2nc(COc3ccc(COc4nn(-c5ccccc5)cc4/C=C/P(=O)(OCC)OCC)cc3OC)c(C)o2)c1
Reaction time: 3 h
Yield: 77 %

Procedure:
To a mixture of ethyl (3-{4-[(4-{[(4-formyl-1-phenyl-1H-pyrazol-3-yl)oxy]methyl}-2-ethoxyphenoxy)methyl]-5-methyl-1,3-oxazol-2-yl}phenyl)acetate (2.0 g), tetraethyl methylenediphosphonate (1.07 g) and N,N-dimethylformamide (50 mL) was added sodium hydride (60% in oil, 0.16 g) at room temperature, and the mixture was stirred at the same temperature for 3 hrs. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to give ethyl {3-[4-({4-[({4-[(E)-2-(diethoxyphosphoryl)ethenyl]-1-phenyl-1H-pyrazol-3-yl}oxy)methyl]-2-methoxyphenoxy}methyl)-5-methyl-1,3-oxazol-2-yl]phenyl}acetate as a colorless oil from a fraction eluted with ethyl acetate-hexane (9:1, v/v) (1.87 g, yield 77%).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[CH:5][N:6]=1.C(N(CC)CC)C.Cl[C:15]([O:17][CH3:18])=[O:16]>CN(C1C=CN=CC=1)C.O1CCCC1>[S:3]1[CH:4]=[CH:5][N:6]=[C:2]1[NH:1][C:15](=[O:16])[O:17][CH3:18]
Reactant: Nc1nccs1
Reactant: COC(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)Nc1nccs1
Temperature: 25 °C
Yield: 107.6 %

Procedure:
2-Aminothiazole (10.00 g, 99.86 mmole), triethylamine (20.2 g, 200 mmol) and a catalytic amount of 4-(N,N-dimethylamino)pyridine in anhydrous tetrahydrofuran (200 mL) were stirred at 0° C. Methyl chloroformate (18.9 g, 200 mmol) was added slowly to the mixture at 0° C. Then the reaction mixture was stirred at room temperature for several hours. The tetrahydrofuran was evaporated, the residue was dissolved in chloroform, and the resulting solution was washed with water, dried through magnesium sulfate, filtered, and then the solvent was evaporated. The residue was purified by flash chromatography using a gradient of ammoniated methanol in chloroform to give the sub-title compound as a pale yellow solid (17.0 g), m/z 159 (MH+).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([S:9]([NH2:12])(=[O:11])=[O:10])[CH:6]=[CH:7][CH:8]=1.[H-].[Na+].[CH3:15][Si:16]([CH3:23])([CH3:22])[CH2:17][CH2:18][O:19][CH2:20]Cl.P([O-])([O-])([O-])=O>CN(C=O)C>[OH:1][CH2:2][C:3]1[CH:4]=[C:5]([S:9]([N:12]([CH2:20][O:19][CH2:18][CH2:17][Si:16]([CH3:23])([CH3:22])[CH3:15])[CH2:20][O:19][CH2:18][CH2:17][Si:16]([CH3:23])([CH3:22])[CH3:15])(=[O:10])=[O:11])[CH:6]=[CH:7][CH:8]=1
Reactant: NS(=O)(=O)c1cccc(CO)c1
Reactant: C[Si](C)(C)CCOCCl
Agent: O=P([O-])([O-])[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCN(COCC[Si](C)(C)C)S(=O)(=O)c1cccc(CO)c1
Reaction time: 0.25 h

Procedure:
A solution of 3-(hydroxymethyl)benzenesulfonamide (670 mg) in DMF (20 ml) under nitrogen was treated with sodium hydride (315 mg, 60% in oil) and the mixture was stirred at 20° for 15 min. The mixture was then treated with 2-(trimethylsilyl)ethoxymethyl chloride (1.27 ml) and the mixture was stirred at 20° for 1 h. Phosphate buffer solution (50 ml, pH6.5) was added and the mixture was extracted with EtOAc. The extract was washed with water, dried (Na2SO4) and the solvent evaporated in vacuo to give a residue. The residue was purified by chromatography on flash silica gel (40 mm diameter column). Elution with EtOAc-cyclohexane (3:7) gave the title compound (985 mg). LCMS RT=3.84 min.
Reaction SMILES: C(OC([N:8]([CH2:15][CH2:16][CH2:17][N:18]1[C:22]([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)=[CH:21][S:20][C:19]1=[N:30][C:31]1[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][C:32]=1[O:38][CH3:39])[CH2:9][C:10]([NH:12][CH2:13][CH3:14])=[O:11])=O)(C)(C)C.Cl>>[Cl:37][C:34]1[CH:35]=[CH:36][C:31]([N:30]=[C:19]2[N:18]([CH2:17][CH2:16][CH2:15][NH:8][CH2:9][C:10]([NH:12][CH2:13][CH3:14])=[O:11])[C:22]([C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)=[CH:21][S:20]2)=[C:32]([O:38][CH3:39])[CH:33]=1
Reactant: CCNC(=O)CN(CCCn1c(-c2ccc(F)cc2)csc1=Nc1ccc(Cl)cc1OC)C(=O)OC(C)(C)C
Agent: Cl
Product: CCNC(=O)CNCCCn1c(-c2ccc(F)cc2)csc1=Nc1ccc(Cl)cc1OC

Procedure:
The compound (900 mg) obtained in the above (1) was treated in a similar manner to in Example 9 (2) to give the title compound (850 mg) as hydrochloride.
Reaction SMILES: [K].Cl[C:3]1[N:11]=[CH:10][CH:9]=[CH:8][C:4]=1[C:5]([O-:7])=[O:6].[N+:12]([C:15]1[CH:16]=[C:17]([CH:19]=[CH:20][CH:21]=1)[NH2:18])([O-:14])=[O:13].C(N1CCOCC1)C.Cl>CN(C)C=O>[N+:12]([C:15]1[CH:16]=[C:17]([CH:19]=[CH:20][CH:21]=1)[NH:18][C:3]1[C:4]([C:5]([OH:7])=[O:6])=[CH:8][CH:9]=[CH:10][N:11]=1)([O-:14])=[O:13]
Reactant: O=C([O-])c1cccnc1Cl
Reactant: Nc1cccc([N+](=O)[O-])c1
Agent: CCN1CCOCC1
Agent: Cl
Agent: [K]
Solvent: CN(C)C=O
Product: O=C(O)c1cccnc1Nc1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 56.3 %

Procedure:
Potassium-2-chloro-nicotinate (89 g, 455 mmole) was suspended in 630 ml of dimethylformamide. To this suspension was added 3-nitroaniline (75.3 gm, 546 mmole), cupric acetate (5.1 g, 25.5 mmole) and N-ethyl morpholine (52.3 g, 455 mmoles). The suspension was refluxed with stirring under N2 for 4 hours. The reaction mixture was cooled to room temperature and the pH was adjusted to 4-5 by the addition of 6M HCl. A yellow precipitate was isolated from the reaction mixture, washed with water and air dried yielding 66.3 g (256 mmole, 56% yield) of 2-(3-nitroanilino)-3-carboxypyridine (mp 262°-264° C.).
Reaction SMILES: [NH2:1][C:2]1[CH:22]=[CH:21][C:5]([C:6]([N:8]2[CH2:14][CH2:13][C:12]3[CH:15]=[N:16][NH:17][C:11]=3[C:10]3[S:18][CH:19]=[CH:20][C:9]2=3)=[O:7])=[CH:4][CH:3]=1.[H-].[Na+].[C:25]1([CH3:34])[C:26]([C:31](Cl)=[O:32])=[CH:27][CH:28]=[CH:29][CH:30]=1>O1CCOCC1>[N:17]1[NH:16][CH:15]=[C:12]2[CH2:13][CH2:14][N:8]([C:6]([C:5]3[CH:21]=[CH:22][C:2]([NH:1][C:31](=[O:32])[C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=4[CH3:34])=[CH:3][CH:4]=3)=[O:7])[C:9]3[CH:20]=[CH:19][S:18][C:10]=3[C:11]=12
Reactant: Cc1ccccc1C(=O)Cl
Reactant: Nc1ccc(C(=O)N2CCc3cn[nH]c3-c3sccc32)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2CCc3c[nH]nc3-c3sccc32)cc1
Reaction time: 0.25 h

Procedure:
To a solution of 400 mg of 6-(4-aminobenzoyl)-1,4,5,6-tetrahydropyrazolo[3,4-d]thieno[3,2-b]azepine in 12.0 ml of dioxane under argon is added 65 mg of sodium hydride (60% in mineral oil). After stirring for 15 minutes, 176 μl of o-toluoyl chloride is added. The reaction mixture is stirred at room temperature for 18 hours under argon. The reaction mixture is evaporated in vacuo to a residue which is dissolved in 40 ml of methylene chloride and washed with 20 ml each of water and brine. The organic layer is dried (Na2SO4) and filtered. The filtrate is concentrated in vacuo to give a residue which is purified by chromatography on silica gel plates by elution with 1:1 ethyl acetate:hexane 100 mg of N-[4-[[4,5-dihydro-2-(2-methylbenzoyl)pyrazolo[4,3-d]thieno[3,2-b]azepin-6(2H)-yl]carbonyl]phenyl-2-methylbenzamide as a white foam and 200 mg of the product as a white foam.
Reaction SMILES: [CH3:1][C:2]([CH3:18])([CH3:17])[CH2:3][C:4]1[C:8]2[CH:9]=[CH:10][C:11]([OH:16])=[C:12]([CH2:13][CH2:14][CH3:15])[C:7]=2[O:6][N:5]=1.[Br:19][CH2:20][CH2:21][CH2:22]Br.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[CH3:18][C:2]([CH3:17])([CH3:1])[CH2:3][C:4]1[C:8]2[CH:9]=[CH:10][C:11]([O:16][CH2:22][CH2:21][CH2:20][Br:19])=[C:12]([CH2:13][CH2:14][CH3:15])[C:7]=2[O:6][N:5]=1
Reactant: BrCCCBr
Reactant: CCCc1c(O)ccc2c(CC(C)(C)C)noc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCCc1c(OCCCBr)ccc2c(CC(C)(C)C)noc12
Reaction time: 8 h

Procedure:
A solution of 3-(2,2-dimethylpropyl)-6-hydroxy-7-propylbenz[4,5]isoxazole (2.000 grams; 8.090 mmol) in dry DMF (20 mL) was treated with 1,3-dibromopropane (4.29 mL; 42.263 mmol). Cesium carbonate (2.900 grams; 8.901 mmol) was added and the mixture stirred at 20° for 8 hours. The reaction mixture was partitioned between isopropyl acetate and pH 4 buffer. The organic was washed with water, then dried over magnesium sulfate. Filtration and evaporation afforded an oil which was chromatographed over silica gel, giving the title compound.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[CH:6](OCC)([O:10][CH2:11][CH3:12])[O:7][CH2:8][CH3:9]>C1(C)C=CC(S(O)(=O)=O)=CC=1.C(O)C>[CH2:8]([O:7][CH:6]([O:10][CH2:11][CH3:12])[N:1]1[CH:5]=[CH:4][N:3]=[CH:2]1)[CH3:9]
Reactant: CCOC(OCC)OCC
Reactant: c1c[nH]cn1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Product: CCOC(OCC)n1ccnc1
Yield: 68.6 %

Procedure:
A mixture of imidazole (25.6 g, 0.4 mol), triethyl orthoformate (236.8 g, 1.6 mol) and p-toluenesulfonic acid (2 g) was heated at 130° C. overnight with no condenser so ethanol can boil off. The excess orthoformate was removed by rotary evaporation and the residue was purified by vacuum distillation to give 1-(diethoxymethyl)-1H-imidazole (46.7 g). To a solution of the resulting protected imidazole (46.7 g) in anhydrous THF (350 mL) under N2 cooled at −40° C., was added n-butyllithium (2.5 M in hexane, 110 mL) at such a rate that the temperature did not rise above −35° C. After complete addition, a solution of tert-butyl 4-oxopiperidine-1-carboxylate (18.25 g, 91.5 mmol) in anhydrous THF (70 mL) under N2 was added dropwise over 10 minutes keeping the temperature below −40° C. The reaction was stirred at 40° C. for 2 hours then 350 mL of 0.1 N HCl added and stirred for 15 minutes, ethyl acetate (350 mL) added and stirred for 5 minutes. The organic layer was separated and aqueous extracted with ethyl acetate (350 mL). The combined organic layers were washed with saturated NaHCO3, brine, dried over MgSO4, filtered and evaporated. The residue was purified by column chromatography on silica eluting with 10% methanol in ethyl acetate with 0.5% ammonia hydroxide to give tert-butyl 4-hydroxy-4-(1H-imidazol-2-yl)piperidine-1-carboxylate (10.5 g).
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@@H:8]([C:9](OCC)=[O:10])[C@H:7]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)[C@@H:6]([O:21][C@@H:22]([C:24]2[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[C:26]([C:34]([F:37])([F:36])[F:35])[CH:25]=2)[CH3:23])[CH2:5][CH2:4]1.[C:38]1(=O)[CH2:42][CH2:41][C:40](=[O:43])[CH2:39]1.CC1C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[F:31][C:30]([F:32])([F:33])[C:28]1[CH:29]=[C:24]([C@H:22]([O:21][C@H:6]2[CH2:5][CH2:4][C@H:3]([CH2:2][NH:1][C:38]3[CH2:42][CH2:41][C:40](=[O:43])[CH:39]=3)[C@@H:8]([CH2:9][OH:10])[C@@H:7]2[C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)[CH3:23])[CH:25]=[C:26]([C:34]([F:36])([F:37])[F:35])[CH:27]=1
Reactant: CCOC(=O)[C@@H]1[C@@H](CN)CC[C@H](O[C@H](C)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@H]1c1ccc(F)cc1
Reactant: O=C1CCC(=O)C1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: C[C@@H](O[C@H]1CC[C@H](CNC2=CC(=O)CC2)[C@@H](CO)[C@@H]1c1ccc(F)cc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: -78 °C
Reaction time: 16 h
Yield: 10.7 %

Procedure:
To a solution of ethyl (1R,2R,3S,6S)-6-(aminomethyl)-3-{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy}-2-(4-fluorophenyl)cyclohexanecarboxylate (0.07 g, 0.13 mmol, intermediate from Step E) in 30 mL dry toluene was added cyclopentane-1,3-dione (0.064 g, 0.65 mmol) and a catalytic amount (˜0.5 mg) of PTSA. The resulting mixture was heated at reflux for 1 hr. The solvent was removed under vacuum. The residue was dissolved in 10 mL toluene and was cooled to −78° C. under nitrogen. Dibal-H (2 mL, 1.0 M) was added. The reaction mixture was stirred for 16 hr at −78° C., quenched with water and diluted with ethyl acetate (10 mL). The organic layer was separated and the aqueous was extracted with ethyl acetate (10 mL). The combined extracts were washed with brine, dried over MgSO4, filtered and the solvent was removed under vacuum. The residue was purified by preparative TLC (silica gel eluting with 9:1 ethyl acetate: methanol) to give 8 mg of the title compound. MS: (MH)+ 574.2. The rest of the material was still unreacted ester.
Reaction SMILES: [O:1]=[C:2]1[C:10]2([CH2:14][O:13][C:12]3[CH:15]=[C:16]4[C:20](=[CH:21][C:11]2=3)[CH2:19][CH2:18][O:17]4)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[CH2:22][C:23]1[O:27][C:26]([C:28]([O:30]C)=[O:29])=[CH:25][CH:24]=1.[OH-].[Na+].CO>O>[O:1]=[C:2]1[C:10]2([CH2:14][O:13][C:12]3[CH:15]=[C:16]4[C:20](=[CH:21][C:11]2=3)[CH2:19][CH2:18][O:17]4)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[CH2:22][C:23]1[O:27][C:26]([C:28]([OH:30])=[O:29])=[CH:25][CH:24]=1
Reactant: COC(=O)c1ccc(CN2C(=O)C3(COc4cc5c(cc43)CCO5)c3ccccc32)o1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1ccc(CN2C(=O)C3(COc4cc5c(cc43)CCO5)c3ccccc32)o1
Yield: 97.3 %

Procedure:
A solution of methyl 5-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]furan-2-carboxylate (5.5 g, 13.0 mmol) and sodium hydroxide (1.04 g, 26.0 mmol) in water 100 ml) and methanol (40 mL) was stirred at 65° C. for 16 h. The solvent methanol was evaporated under reduced pressure, and the residue was cooled in ice-bath and acidified with 10% hydrochloric acid to pH 1-2. The solid precipitate was filtered off, and recrystallized from ethanol (100 mL) to afford 5-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]furan-2-carboxylic acid (5.10 g, 92%) as a colorless solid: 1H NMR (300 MHz, CDCl3) δ7.36-6.92 (m, 5H), 6.51 (s, 1H), 6.44 (d, J=3.5 Hz, 1H), 6.40 (s, 1H), 5.02 (ABq, 2H), 4.81 (ABq, 2H), 4.51 (t, J=8.6 Hz, 2H), 3.04-2.91 (m, 2H); 13C NMR (75 MHz, CDCl3) δ177.2, 161.6, 160.9, 159.6, 153.7, 145.0, 142.1, 132.7, 129.1, 124.0, 123.7, 121.0, 120.4, 119.6, 119.1, 111.1, 109.7, 92.9, 80.0, 72.6, 57.4, 37.3, 28.8; MS (ES+) m/z 403.8 (M+1).