Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1([CH3:10])[CH2:7][CH2:6][C:5](Cl)([CH3:8])[CH2:4][CH2:3]1.[C:11]1([OH:17])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[Cl-].[Al+3].[Cl-].[Cl-]>>[CH3:10][C:2]12[CH2:7][CH2:6][C:5]([CH3:8])([CH2:4][CH2:3]1)[C:14]1[CH:15]=[CH:16][C:11]([OH:17])=[CH:12][C:13]2=1
Reactant: Oc1ccccc1
Reactant: CC1(Cl)CCC(C)(Cl)CC1
Agent: [Al+3]
Agent: [Cl-]
Product: CC12CCC(C)(CC1)c1cc(O)ccc12
Temperature: 120 °C

Procedure:
To a solution of 1,4-dichloro-1,4-dimethylcyclohexane (Compound 1, 3 g, 16.5 mmol) and phenol (1.55 g, 16.5 mmol) under argon at 25° C. was slowly added aluminum chloride (0.22g, 0.165 mmol). The resulting mixture was heated to 120° C. for 12 hours, and then it was quenched with ice. The products were extracted with CH2Cl2, the layers separated, and the organic layer was washed with water and brine. The organic layer was dried over Na2SO4, and filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using ethyl acetate:hexane (1:9) to yield the title compound as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([CH2:12][O:13][C:14]3[CH:34]=[CH:33][C:17]4[O:18][CH2:19][C:20]5[CH:27]=[C:26]([C:28]6[NH:32][N:31]=[N:30][N:29]=6)[CH:25]=[CH:24][C:21]=5[CH:22](O)[C:16]=4[CH:15]=3)=[N:9]2)=[CH:4][CH:3]=1.[SH:35][CH2:36][CH2:37][C:38]([OH:40])=[O:39]>>[C:38]([CH2:37][CH2:36][S:35][CH:22]1[C:21]2[CH:24]=[CH:25][C:26]([C:28]3[NH:29][N:30]=[N:31][N:32]=3)=[CH:27][C:20]=2[CH2:19][O:18][C:17]2[CH:33]=[CH:34][C:14]([O:13][CH2:12][C:8]3[CH:7]=[CH:6][C:5]4[C:10](=[CH:11][C:2]([Cl:1])=[CH:3][CH:4]=4)[N:9]=3)=[CH:15][C:16]1=2)([OH:40])=[O:39]
Reactant: O=C(O)CCS
Reactant: OC1c2ccc(-c3nnn[nH]3)cc2COc2ccc(OCc3ccc4ccc(Cl)cc4n3)cc21
Product: O=C(O)CCSC1c2ccc(-c3nnn[nH]3)cc2COc2ccc(OCc3ccc4ccc(Cl)cc4n3)cc21

Procedure:
2-(7-Chloroquinolin-2-yl)methoxy-11-hydroxy-8-(tetrazol-5-yl)-6,11-dihydrodibenz[b,e]oxepine and 3-mercaptopropionic acid were used and reacted in the same manner as in Example 1 to obtain the title compound.
Reaction SMILES: [Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.C(Cl)Cl.[NH:25]1[CH:29]=[CH:28][N:27]=[C:26]1[C:30]#[C:31][CH:32]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[OH:33]>C(OCC)C>[C:34]1([C:32](=[O:33])[C:31]#[C:30][C:26]2[NH:25][CH:29]=[CH:28][N:27]=2)[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: OC(C#Cc1ncc[nH]1)c1ccccc1
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: CCOCC
Product: O=C(C#Cc1ncc[nH]1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Place pyridinium dichromate (0.75 g, 2 mmol) and methylene chloride (15 mL) under argon atmosphere and cool to 0° C. Add α-[(2-imidazolyl)ethynyl]-benzenemethanol (297 mg, 1.5 mmol). Stir overnight while slowly warming to room temperature. Dilute with ethyl ether and filter the chromium salts. Purify by silica gel chromatography to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1Cl.[NH:12]1[CH:16]=[CH:15][N:14]=[CH:13]1.CCN(C(C)C)C(C)C>CC(N(C)C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1[N:12]1[CH:16]=[CH:15][N:14]=[CH:13]1
Reactant: O=[N+]([O-])c1ccc(Cl)c(Cl)c1
Reactant: c1c[nH]cn1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: O=[N+]([O-])c1ccc(-n2ccnc2)c(Cl)c1

Procedure:
1.0 g (5.21 mmol) of 3,4-dichloronitrobenzene (Fluka, Buchs, Switzerland), 532 mg (7.81 mmol) imidazole (Aldrich, Buchs, Switzerland) and 1.35 g (10.4 mmol) Hünig's base in 4 ml of DMA are heated in a microwave oven at 180° C. for 1 h 40 min. The reaction mixture is quenched with sat. aqueous NaHCO3 and extracted with EtOAc (2×). The organic layers is washed with sat. aqueous NaHCO3 (3×), with brine, dried over MgSO4, filtered and evaporated. The residue is purified by flash chromatography on silica gel (CH2Cl2-MeOH 1:0 to 93:7) to provide the title compound as an oil. ES-MS: 224 (M+H)+; analytical HPLC: tret=2.11 minutes (Grad 1).
Reaction SMILES: [CH:1]1([C:4]2[C:5]([NH:24][S:25]([CH3:28])(=[O:27])=[O:26])=[CH:6][C:7]3[O:11][C:10]([C:12]4[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=4)=[C:9]([C:19]([NH:21][CH3:22])=[O:20])[C:8]=3[CH:23]=2)[CH2:3][CH2:2]1.[Br:29][C:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1.C(N(CC)CC)C>ClCCl.O.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[Br:29][C:30]1[CH:35]=[CH:34][C:33]([N:24]([C:5]2[C:4]([CH:1]3[CH2:3][CH2:2]3)=[CH:23][C:8]3[C:9]([C:19]([NH:21][CH3:22])=[O:20])=[C:10]([C:12]4[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=4)[O:11][C:7]=3[CH:6]=2)[S:25]([CH3:28])(=[O:27])=[O:26])=[CH:32][CH:31]=1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(NS(C)(=O)=O)c(C3CC3)cc12
Reactant: OB(O)c1ccc(Br)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(c3ccc(Br)cc3)S(C)(=O)=O)c(C3CC3)cc12
Reaction time: 48 h
Yield: 26 %

Procedure:
A mixture of 5-cyclopropyl-2-(4-fluorophenyl)-N-methyl-6-[(methylsulfonyl)amino]-1-benzofuran-3-carboxamide (500 mg, 1.244 mmol), 4-bromophenylboronic acid (1.5 g, 7.464 mmol), copper(II) acetate monohydrate (372 mg, 1.866 mmol), triethylamine (252 mg, 2.488 mmol), and 4 Å molecular sieves (1 g) in dichloromethane (160 mL) was stirred for 2 days. The solution was filtered, concentrated to dryness, and purified by column chromatography to afford 6-(N-(4-bromophenyl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide (180 mg, 0.323 mmol, 26% yield) as a brown solid. LCMS (m/z, ES+)=557, 559 (M+H+).
Reaction SMILES: C[O:2][C:3](=[O:33])[C@H:4]([CH2:23][C:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[NH:26][CH:25]=1)[NH:5][C:6](=[O:22])[C@H:7]([C:18]([CH3:21])([CH3:20])[CH3:19])[NH:8][C:9](=[O:17])[CH:10]([CH3:16])[CH2:11][S:12]C(=O)C.[OH-].[Na+]>C(O)C>[SH:12][CH2:11][CH:10]([CH3:16])[C:9]([NH:8][C@H:7]([C:6]([NH:5][C@H:4]([C:3]([OH:33])=[O:2])[CH2:23][C:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[NH:26][CH:25]=1)=[O:22])[C:18]([CH3:21])([CH3:20])[CH3:19])=[O:17]
Reactant: COC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)[C@@H](NC(=O)C(C)CSC(C)=O)C(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(CS)C(=O)N[C@H](C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O)C(C)(C)C

Procedure:
The title compound is prepared using the previously described procedures and the following reagants: 0.90 g (1.89 mmoles) of N-(S-acetyl-β-mercaptoisobutyroyl)-3-methylvalyl-tryptophan methyl ester, 8 ml of 95 percent ethanol, 4.0 ml of 1 N NaOH. Chromatographed yield is 0.54 grams (63 percent). Analysis calculated for C21H29N3O4S: C, 60.12; H, 6.97; N, 10.02; S, 7.64. Found: C, 60.27; H, 7.14; N, 9.42; S, 7.25.
Reaction SMILES: [CH2:1]([C@@H:8]1[C@@H:16]([OH:17])[C@H:15]([CH3:18])[O:14][C:13](=[O:19])[C@@H:12]([NH:20][C:21]([C:23]2[C:28]([OH:29])=[C:27]([O:30][CH3:31])[CH:26]=[CH:25][N:24]=2)=[O:22])[CH2:11][O:10][C:9]1=[O:32])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:33][S:34][CH3:35].C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.C(=O)(O)[O-].[Na+]>C(#N)C.C(OCC)C.C(OCC)(=O)C.C(O)(=O)C>[CH2:1]([C@@H:8]1[C@@H:16]([O:17][CH2:33][S:34][CH3:35])[C@H:15]([CH3:18])[O:14][C:13](=[O:19])[C@@H:12]([NH:20][C:21]([C:23]2[C:28]([OH:29])=[C:27]([O:30][CH3:31])[CH:26]=[CH:25][N:24]=2)=[O:22])[CH2:11][O:10][C:9]1=[O:32])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccnc(C(=O)N[C@H]2COC(=O)[C@H](Cc3ccccc3)[C@@H](O)[C@H](C)OC2=O)c1O
Reactant: CSC
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: COc1ccnc(C(=O)N[C@H]2COC(=O)[C@H](Cc3ccccc3)[C@@H](OCSC)[C@H](C)OC2=O)c1O
Temperature: 2.5 °C
Reaction time: 0.17 h

Procedure:
Compound 1b (2.0 g, 4.5 mmol) was dissolved in acetonitrile. Dimethylsulfide (6.6 mL) and acetic acid (2 mL) were added and the resulting mixture cooled to 0-5° C. (ice bath) under nitrogen. Benzoyl peroxide (6.36 g, 26 mmol) was added in several portions over 5 hours, then stirred for an additional 10 minutes, and then the reaction mixture was poured into a mixture of ethyl acetate and saturated aq. sodium bicarbonate (100 mL each). The organic phase was separated, rinsed with water, brine (×2), and concentrated in vacuo to give a gum. This gum upon addition of 50 mL of diethyl ether afforded 1.56 g (70%) of an off a white crystalline solid. m.p.=159-160° C. Spectral data were consistent with the title compound.
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[CH:9]=2)=[CH:6][CH:5]=[C:4]([F:15])[C:3]=1[CH2:16][NH:17][C:18]1[C:19]([F:26])=[C:20]([OH:25])[CH:21]=[CH:22][C:23]=1[F:24].C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36].O>CN(C=O)C>[F:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[CH:9]=2)=[CH:6][CH:5]=[C:4]([F:15])[C:3]=1[CH2:16][NH:17][C:18]1[C:19]([F:26])=[C:20]([CH:21]=[CH:22][C:23]=1[F:24])[O:25][CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36]
Reactant: Oc1ccc(F)c(NCc2c(F)ccc(-c3cccc(F)c3)c2F)c1F
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)COc1ccc(F)c(NCc2c(F)ccc(-c3cccc(F)c3)c2F)c1F
Reaction time: 1 h
Yield: 64.8 %

Procedure:
To a solution of 3-[[2,6-difluoro-3-(3-fluorophenyl)phenyl]methylamino]-2,4-difluoro-phenol (300 mg, 0.82 mmol, 1.0 eq) in DMF (5 mL) was added Cs2CO3 (375 mg, 1.15 mmol, 1.4 eq) at room temperature. The reaction mixture was stirred for 1 h, then ethyl 2-bromoacetate (151 mg, 0.90 mmol, 1.1 eq) was added. The reaction mixture was stirred for a further 1 h and the resulting mixture was poured into water and extracted with EtOAc. The organic extract was washed with water and brine, dried (Na2SO4), filtered, evaporated in vacuo and purified by column chromatography (EtOAc:petroleum ether, 0:1 to 1:10) to give the title compound as an oil (240 mg, 65%).
Reaction SMILES: [CH3:1][C:2]1([C:20]#[N:21])[C:7]2[N:8]=[C:9]([C:11]3[CH:16]=[CH:15][N:14]=[C:13]4[NH:17][N:18]=[CH:19][C:12]=34)[S:10][C:6]=2[CH2:5][CH2:4][CH2:3]1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[CH3:1][C:2]1([CH2:20][NH2:21])[C:7]2[N:8]=[C:9]([C:11]3[CH:16]=[CH:15][N:14]=[C:13]4[NH:17][N:18]=[CH:19][C:12]=34)[S:10][C:6]=2[CH2:5][CH2:4][CH2:3]1
Reactant: CC1(C#N)CCCc2sc(-c3ccnc4[nH]ncc34)nc21
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC1(CN)CCCc2sc(-c3ccnc4[nH]ncc34)nc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 4 %

Procedure:
A solution of 4-methyl-2-(1H-pyrazolo[3,4-b]pyridin-4-yl)-6,7-dihydro-5H-1,3-benzothiazole-4-carbonitrile (67 mg, 0.2268 mmol) in THF (7 mL) was allowed to cool in an ice bath and treated with LiAlH4 in THF (453.6 μL of 2 M, 0.9072 mmol) dropwise. The mixture was allowed to warm to RT, stirred for 3 hours and then quenched with water whilst cooling. The aqueous layer was extracted with EtOAc (2×) and the combined organics dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by reverse phase preparative HPLC [Waters Sunfire C18, 10 mM, 100 Å column, gradient 10%-95% B (solvent A: 0.05% TFA in water; solvent B: CH3CN) over 16 minutes at 25 mL/min]. The fractions were collected, passed through a sodium bicarbonate cartridge and freeze-dried to give the title compound as a white solid (2.7 mg, 4% Yield). 1H NMR (DMSO, 400 MHz) δ 1.29 (3H, s), 1.50-1.55 (1H, m), 1.85-1.98 (3H, m), 2.77-2.93 (4H, m), 7.58 (1H, d), 8.58 (1H, s), 8.60 (1H, d); MS (ES+) 300.05
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([N+:10]([O-])=O)=[C:6]([CH:9]=1)[CH:7]=O.O.O.[Sn](Cl)Cl.[CH2:18]([O:20][C:21](=[O:30])[CH2:22][CH:23](OCC)OCC)[CH3:19]>C(O)C>[Br:1][C:2]1[CH:9]=[C:6]2[C:5](=[CH:4][CH:3]=1)[N:10]=[CH:23][C:22]([C:21]([O:20][CH2:18][CH3:19])=[O:30])=[CH:7]2
Reactant: O=Cc1cc(Br)ccc1[N+](=O)[O-]
Reactant: CCOC(=O)CC(OCC)OCC
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1cnc2ccc(Br)cc2c1
Temperature: 90 °C
Reaction time: 8 h
Yield: 55.9 %

Procedure:
To a solution of 5-bromo-2-nitrobenzaldehyde (2 g, 9 mmol) in ethanol (46 mL) was added tin(II) chloride dihydrate (7.95 g, 35.2 mmol) and 3,3-diethoxypropionic acid ethyl ester (4.2 mL, 22 mmol). The reaction was heated to 90° C. for 16 hours. The reaction was then allowed to cool to room temperature and stir overnight. The reaction mixture was concentrated and the residue was dissolved in ethyl acetate. The mixture was poured into saturated aqueous sodium bicarbonate. The resulting emulsion was filtered through Celite, rinsing with ethyl acetate. The layers were separated and the aqueous was extracted with ethyl acetate. The combined organics were washed with brine, dried over magnesium sulfate, filtered, and concentrated. Purification by flash column chromatography (0-50% ethyl acetate/heptanes) gave the title compound (1.41 g, 60%) as a solid.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[CH3:5][O:6][C:7]1[CH:16]=[C:15]2[C:10]([CH2:11][CH2:12][CH:13]([CH2:17]OS(C3C=CC(C)=CC=3)(=O)=O)[CH2:14]2)=[CH:9][CH:8]=1>O.C(O)C>[CH3:5][O:6][C:7]1[CH:16]=[C:15]2[C:10]([CH2:11][CH2:12][CH:13]([CH2:17][N:1]=[N+:2]=[N-:3])[CH2:14]2)=[CH:9][CH:8]=1
Reactant: COc1ccc2c(c1)CC(COS(=O)(=O)c1ccc(C)cc1)CC2
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: COc1ccc2c(c1)CC(CN=[N+]=[N-])CC2

Procedure:
A solution of 3.9 g of sodium azide in 10 ml of water is added to a solution of 13.86 g (40 mmol) of p-toluenesulphonic acid (7-methoxy-1,2,3,4-tetrahydro-naphth-2-ylmethyl) ester in 200 ml of ethanol and the whole is boiled under reflux for 18 hours. After cooling, the alcohol is evaporated off under reduced pressure, water is added to the residue and extraction is carried out with dichloromethane. The organic phase is washed with water, dried over sodium sulphate and concentrated by evaporation. (7-methoxy-1,2,3,4-tetrahydro-naphth-2-yl)methylazide is obtained in the form of a yellow oil.
Reaction SMILES: I([O-])(=O)(=O)=O.[Na+].[O:7]([CH2:14][CH:15]([OH:18])CO)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>ClCCl>[O:7]([CH2:14][CH:15]=[O:18])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: OCC(O)COc1ccccc1
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: ClCCl
Product: O=CCOc1ccccc1
Reaction time: 0.17 h
Yield: 99.9 %

Procedure:
Sodium periodate (0.65 M in water, 20 mL) was added to a vigorously stirred suspension of silica gel (20 g) in dichloromethane (160 mL), followed by a solution of 3-phenoxy-1,2-propanediol (1.68 g, 10.0 mmol) in dichloromethane (20 mL). After stirring for 10 min the mixture was filtered and the filtrate was concentrated to give the subtitle compound (1.36 g, 100%).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[NH2:7][C:8]1[CH:9]=[CH:10][C:11]2[O:27][CH2:26][CH2:25][C:14]3([CH2:19][CH2:18][N:17]([C:20](OCC)=O)[CH2:16][CH2:15]3)[C:12]=2[CH:13]=1.O.[OH-].[Na+]>C1COCC1>[NH2:7][C:8]1[CH:9]=[CH:10][C:11]2[O:27][CH2:26][CH2:25][C:14]3([CH2:19][CH2:18][N:17]([CH3:20])[CH2:16][CH2:15]3)[C:12]=2[CH:13]=1
Reactant: CCOC(=O)N1CCC2(CCOc3ccc(N)cc32)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CN1CCC2(CCOc3ccc(N)cc32)CC1
Reaction time: 1.5 h
Yield: 86.1 %

Procedure:
A stirred suspension of lithium aluminium hydride (76 mg, 0.0020 mole) in THF (15 ml) at 0° C. under argon was treated with a solution of 6-amino-2,3-dihydro-1'-ethoxycarbonylspiro[4H-benzopyran-4,4'-piperidine] (D104, 300 mg, 0.0010 mole) in THF (5 ml). The reaction mixture was allowed to warm to room temp. and stir for 1.5 h, then treated with more lithium aluminium hydride (38 mg, 0.0010 mole) suspended in THF (5 ml). The mixture was heated under reflux for 0.75 h, then cooled in an ice bath and treated with water (0.10 ml), 10% NaOH solution (0.10 ml) and water (0.30 ml). The resulting mixture was filtered through kieselguhr and the filtrate concentrated in vacuo to afford the title compound as a yellow oil (200 mg, 84%).
Reaction SMILES: [CH:1]1([CH2:7][C@H:8]([NH:21][C:22](=[O:35])[C:23]2[CH:34]=[CH:33][CH:32]=[C:25]([C:26](N(OC)C)=[O:27])[CH:24]=2)[CH2:9][N:10]([CH3:20])[C:11]([O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])=[O:12])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:36][O:37][CH2:38][CH2:39][CH2:40][CH2:41][Mg]Cl>C1COCC1>[CH:1]1([CH2:7][C@H:8]([NH:21][C:22](=[O:35])[C:23]2[CH:34]=[CH:33][CH:32]=[C:25]([C:26](=[O:27])[CH2:41][CH2:40][CH2:39][CH2:38][O:37][CH3:36])[CH:24]=2)[CH2:9][N:10]([CH3:20])[C:11]([O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:17])[CH3:18])=[O:12])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COCCCC[Mg]Cl
Reactant: CON(C)C(=O)c1cccc(C(=O)N[C@@H](CC2CCCCC2)CN(C)C(=O)OCC[Si](C)(C)C)c1
Solvent: C1CCOC1
Product: COCCCCC(=O)c1cccc(C(=O)N[C@@H](CC2CCCCC2)CN(C)C(=O)OCC[Si](C)(C)C)c1
Reaction time: 2 h

Procedure:
To a solution of (S)—N1-(1-cyclohexyl-3-(N-methyl-N-(2-(trimethylsilyl)ethoxycarbonyl)-amino)propan-2-yl)-N3-methoxy-N3-methylisophthalamide (0.7361 g, 1.46 mmol, 1.0 equiv) in THF (15 mL) was added 1.45 M 4-methoxybutylmagnesium chloride in THF (4 mL, 5.8 mmol, 4.0 equiv) at 0° C. under N2. After 2 h, the reaction mixture was quenched with 1 N aq HCl (15 mL) and extracted EtOAc (3×). The combined EtOAc extracts were dried over Na2SO4 and concentrated to afford crude (S)—N-(1-cyclohexyl-3-(N-methyl-N-(2-(trimethylsilyl)-ethoxycarbonyl)amino)propan-2-yl)-3-(5-methoxypentanoyl)benzamide (0.758 g), which was used in the next step without further purification. LC-MS (3 min) tR=2.34 min, m/z 555 (M+Na+), 534, 505.
Reaction SMILES: [F:1][C:2]([F:42])([F:41])[C:3]1[CH:4]=[C:5]([C@H:13]([N:15]([CH3:40])[C:16]([N:18]2[CH2:31][CH2:30][C@:21]3([NH:25][C@@H:24]([C:26]([O:28]C)=O)[CH2:23][CH2:22]3)[CH2:20][C@@H:19]2[C:32]2[CH:37]=[CH:36][C:35]([F:38])=[CH:34][C:33]=2[CH3:39])=[O:17])[CH3:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.CO.[NH3:45]>>[F:10][C:9]([F:12])([F:11])[C:7]1[CH:6]=[C:5]([C@H:13]([N:15]([CH3:40])[C:16]([N:18]2[CH2:31][CH2:30][C@:21]3([NH:25][C@@H:24]([C:26]([NH2:45])=[O:28])[CH2:23][CH2:22]3)[CH2:20][C@@H:19]2[C:32]2[CH:37]=[CH:36][C:35]([F:38])=[CH:34][C:33]=2[CH3:39])=[O:17])[CH3:14])[CH:4]=[C:3]([C:2]([F:1])([F:41])[F:42])[CH:8]=1
Reactant: N
Reactant: COC(=O)[C@H]1CC[C@@]2(CCN(C(=O)N(C)[C@H](C)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@@H](c3ccc(F)cc3C)C2)N1
Solvent: CO
Product: Cc1cc(F)ccc1[C@H]1C[C@]2(CC[C@H](C(N)=O)N2)CCN1C(=O)N(C)[C@H](C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1

Procedure:
In a sealed tube a solution of Methyl (2R, 5S,7R)-8-{[{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl}(methyl)amino]carbonyl}-7-(4-fluoro-2-methylphenyl)-1,8-diazaspiro[4.5]decane-2-carboxylate (Intermediate 12, 21.6 mg, 0.036 mmol) in 7N Ammonia in MeOH (5 mL, 35.0 mmol) was stirred at 25° C. for 1 day. The solvent was evaporated to dryness and the crude was purified by silica cartridge (2 g) (at first EtOAc and then 97.5:2.5 DCM/0.5 M NH3 in MeOH) to give 17.8 mg of the title compound as a white foam. 1H NMR (500 MHz, DMSO-d6) δ ppm 8.00 (s, 1H) 7.70 (s, 2H) 7.28 (d, 1H) 7.15 (dd, 1H) 7.03 (d, 1H) 6.92 (dd, 1H) 6.78 (t, 1H) 5.31 (q, 1H) 4.14 (dd, 1H) 3.47 (t, 1H) 3.27-3.38 (m, 1H) 2.75 (s, 3H) 2.76 (t, 1H) 2.32 (s, 3H) 2.05-2.15 (m, 1H) 1.68-1.85 (m, 3H) 1.52-1.68 (m, 3H) 1.47 (d, 3H) 1.39-1.54 (m, 1H). NMR analysis revealed the presence of a large amount of DCM (˜55% w/w). HPLC: Rt 4.90 mins. This batch was used directly in the next step.
Reaction SMILES: [CH2:1]([CH:4]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[C:5]([NH:7][C@@H:8]([C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[CH:11]=1)[CH3:9])=[O:6])[CH:2]=[CH2:3].[H-].[Na+].[C:26](Cl)(=[O:30])[O:27][CH2:28][CH3:29].Cl>CN(C=O)C.CCCCCC>[CH2:28]([O:27][C:26]([N:7]([C@@H:8]([C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[CH:11]=1)[CH3:9])[C:5](=[O:6])[CH:4]([CH2:1][CH:2]=[CH2:3])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[O:30])[CH3:29]
Reactant: C=CCC(CCCCCC)C(=O)N[C@H](C)c1cccc(OC)c1
Reactant: CCOC(=O)Cl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: C=CCC(CCCCCC)C(=O)N(C(=O)OCC)[C@H](C)c1cccc(OC)c1
Temperature: 50 °C
Reaction time: 1 h
Yield: 44.2 %

Procedure:
A solution of 0.40 g (1.3 mmol) of N-(2-allyloctanoyl)-(R)-1-(3-methoxyphenyl)ethylamine (diastereomer ratio (1R,2S):(1R,2R)=77:23) in 2 ml of DMF was added to a solution of 151 mg (3.8 mmol) of sodium hydride in 2 ml of DMF at room temperature, and the reaction was allowed to proceed at 50° C. for 1 hour. To the reaction mixture was added 0.48 ml (5.0 mmol) of ethyl chlorocarbonate, and the mixture was stirred at 50° C. for 12 hours. The reaction mixture was added dropwise to a mixed solution composed of 5 ml of a 1 N aqueous solution of hydrochloric acid and 5 ml of hexane with ice cooling, and the resulting mixture was extracted with two 20-ml portions of hexane. The organic layer was washed with 5 ml of a saturated aqueous solution of sodium chloride and concentrated under reduced pressure to give 0.49 g of a crude product. The crude product was purified on a silica gel column (ethyl acetate:hexane=20:1) to give 0.224 g of the title compound as a colorless oil (yield 46%, (1R,2S):(1R,2R)=77:23).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:20]=[CH:19][C:18]([C:21]4[CH:22]=[C:23]([CH:27]=[CH:28][C:29]=4[CH3:30])[C:24]([OH:26])=O)=[CH:17][C:11]=3[C:12]=2[C:13](=[O:16])[NH:14][CH3:15])=[CH:4][CH:3]=1.[CH3:31][C:32]1[S:36][C:35]([C:37]2([NH2:40])[CH2:39][CH2:38]2)=[N:34][CH:33]=1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>ClCCl.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:9][C:10]3[CH:20]=[CH:19][C:18]([C:21]4[CH:22]=[C:23]([C:24](=[O:26])[NH:40][C:37]5([C:35]6[S:36][C:32]([CH3:31])=[CH:33][N:34]=6)[CH2:39][CH2:38]5)[CH:27]=[CH:28][C:29]=4[CH3:30])=[CH:17][C:11]=3[C:12]=2[C:13]([NH:14][CH3:15])=[O:16])=[CH:6][CH:7]=1
Reactant: Cc1cnc(C2(N)CC2)s1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)O)ccc3C)cc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)NC4(c5ncc(C)s5)CC4)ccc3C)cc12
Temperature: 25 °C
Reaction time: 18 h

Procedure:
3-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-4-methylbenzoic acid (0.2 g, 0.5 mmol, 1 eq), 1-(5-methylthiazol-2-yl)cyclopropanamine (0.093 g, 0.6 mmol, 1.2 eq), EDCI.HCl (0.103 g, 0.54 mmol, 1.1 eq), HOBT (0.067 g, 0.5 mmol, 1.5 eq) and TEA (0.21 ml, 1.5 mmol, 3 eq) were dissolved in dichloromethane and the mixture was stirred at room temperature for 18 h. The mixture was then added with water, and the organic layer was separated and washed with water, and the product was purified by preparative TLC. Yield: 25 mg (15%). 1HNMR (400 MHz, DMSO-d6): δ1.34-1.37 (m, 2H), 1.50-1.53 (m, 2H), 2.31 (s, 3H), 2.35 (s, 3H), 2.83-2.84 (d, J=4.8 Hz, 3H), 7.27 (d, J=1.2 Hz, 1H), 7.39-7.47 (m, 4H), 7.60 (d, J=1.6 Hz, 1H), 7.76-7.78 (d, J=8.4 Hz 1H), 7.83-7.85 (m, 2H), 8.02 (m, 2H), 8.45 (m, 1H), 9.51 (s, 1H) LCMS: (ES+) m/z=540 (M+H)+
Reaction SMILES: O[CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][CH:7]([NH:10][C:11]([C:13]2[NH:14][C:15]3[C:20]([CH:21]=2)=[C:19]([O:22][CH2:23][CH:24]([CH3:26])[CH3:25])[CH:18]=[CH:17][CH:16]=3)=[O:12])[CH2:6][CH2:5]1.[NH:27]1[CH2:33][CH2:32][CH2:31][CH:30]([OH:34])[CH2:29][CH2:28]1>>[OH:34][CH:30]1[CH2:31][CH2:32][CH2:33][N:27]([CH2:2][CH2:3][N:4]2[CH2:5][CH2:6][CH:7]([NH:10][C:11]([C:13]3[NH:14][C:15]4[C:20]([CH:21]=3)=[C:19]([O:22][CH2:23][CH:24]([CH3:25])[CH3:26])[CH:18]=[CH:17][CH:16]=4)=[O:12])[CH2:8][CH2:9]2)[CH2:28][CH2:29]1
Reactant: CC(C)COc1cccc2[nH]c(C(=O)NC3CCN(CCO)CC3)cc12
Reactant: OC1CCCNCC1
Product: CC(C)COc1cccc2[nH]c(C(=O)NC3CCN(CCN4CCCC(O)CC4)CC3)cc12

Procedure:
This compound is synthesized analogously to example 150 from 4-isobutoxy-1H-indole-2-carboxylic acid [1-(2-hydroxy-ethyl)piperidin-4-yl]-amide, 190 and azepan-4-ol.