Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[CH2:10][C:9]2[NH:8][CH:7]=[C:6]([CH2:11][CH3:12])[C:5]=2[C:4](=[O:13])[CH2:3]1.[F:15][C:16]1[CH:17]=[C:18](B(O)O)[CH:19]=[CH:20][CH:21]=1.C(N(CC)CC)C>C(Cl)Cl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH3:14][C:2]1([CH3:1])[CH2:10][C:9]2[N:8]([C:20]3[CH:19]=[CH:18][CH:17]=[C:16]([F:15])[CH:21]=3)[CH:7]=[C:6]([CH2:11][CH3:12])[C:5]=2[C:4](=[O:13])[CH2:3]1
Reactant: CCc1c[nH]c2c1C(=O)CC(C)(C)C2
Reactant: OB(O)c1cccc(F)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCc1cn(-c2cccc(F)c2)c2c1C(=O)CC(C)(C)C2
Yield: 20.2 %

Procedure:
6,6-Dimethyl-3-ethyl-4,5,6,7-tetrahydro-1H-indol-4-one (50 mg, 0.26 mmol), copper acetate (71 mg, 0.39 mmol), 3-fluorophenyl boronic acid (73 mg, 0.52 mmol) and triethylamine (73 μL, 0.52 mmol) and triethylamine (73 μL, 0.52 mmol) in DCM (1 mL) was stirred at room temperature for 48 h. The crude reaction mixture was poured onto a bond elut tube (Anachem 1225-6034 10 g/60 mL) and eluted using isohexane : EtOAc (100:0→5:1) to afford a yellow solid. The solid was triturated in ether to afford the title compound (15 mg, 20%) as a colourless solid. 1H NMR (360 MHz, CDCl3) δ 1.08 (6H,s), 1.22 (3H,t, J=7.4Hz), 2.36 (2H,s), 2.62 (2H,s), 2.81 (2H,q, J=7.4 Hz), 6.57 (1H,s), 7.02-7.11 (3H,m), 7.41-7.45 (1H,m). MS (ES+) 286 (M+1).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[N:7]1[CH:11]=[CH:10][N:9]=[CH:8]1.[Li]CCCC.[CH3:17][C:18]1([CH3:21])[CH2:20][O:19]1.CO>C1COCC1>[CH3:17][C:18]([OH:19])([CH3:21])[CH2:20][C:8]1[N:7]([CH:2]2[CH2:3][CH2:4][CH2:5][CH2:6][O:1]2)[CH:11]=[CH:10][N:9]=1
Reactant: CC1(C)CO1
Reactant: c1cn(C2CCCCO2)cn1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(O)Cc1nccn1C1CCCCO1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 71.3 %

Procedure:
To the solution of 1-(tetrahydro-pyran-2-yl)-1H-imidazole (7.6 g, 50 mmol) in dry THF (500 ml) at −78° C. was added n-BuLi solution (2.5 M in hexanes, 25 mL, 60 mmol, 1.2 equiv). The reaction mixture was slowly warmed to 0° C. and stirred at 0° C. for 30 min. After it was cooled to −78° C., 2,2-dimethyloxirane (7.2 g, 100 mmol) was added and it was stirred for 1 h. The reaction mixture was warmed to r.t. slowly and stirred at r.t. overnight. MeOH was added and the reaction mixture was concentrated by a rotary evaporator. Water (30 ml) was added and it was extracted with CH2Cl2 (15 ml×3). The organic layer was dried over MgSO4, concentrated, and purified by neutral Al2O3 column chromatography (CH2Cl2:MeOH=100:1) to give 8 gm of 2-methyl-1-[1-(tetrahydro-pyran-2-yl)-1H-imidazol-2-yl]-propan-2-ol (75%). 1H NMR (CDCl3): δ 7.04 (s, 1H), 6.95 (s, 1H), 5.13 (dd, J=2.6, 9.5 Hz, 1H), 4.05-4.02 (m, 1H), 3.68-3.62 (m, 1H), 2.82 (d, J=12.0 Hz, 2H), 2.01-1.89 (m, 4H), 1.92 (m, 1H), 1.69-1.60 (m, 3H), 1.24 (m, 6H)
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:15][CH:16]2[CH2:33][CH2:32][C:19]3([CH2:24][CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21][CH2:20]3)[CH2:18][CH2:17]2)=[N:4][C:5]([NH:8][C:9]2[CH:10]=[N:11][N:12]([CH3:14])[CH:13]=2)=[N:6][CH:7]=1.Cl.CCOC(C)=O>ClCCl>[Cl:1][C:2]1[C:3]([NH:15][CH:16]2[CH2:33][CH2:32][C:19]3([CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)[CH2:18][CH2:17]2)=[N:4][C:5]([NH:8][C:9]2[CH:10]=[N:11][N:12]([CH3:14])[CH:13]=2)=[N:6][CH:7]=1
Reactant: Cn1cc(Nc2ncc(Cl)c(NC3CCC4(CC3)CCN(C(=O)OC(C)(C)C)CC4)n2)cn1
Agent: Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: Cn1cc(Nc2ncc(Cl)c(NC3CCC4(CCNCC4)CC3)n2)cn1
Temperature: 25 °C
Reaction time: 5 h
Yield: 79.8 %

Procedure:
To a solution of tert-butyl 9-((5-chloro-2-((1-methyl-1H-pyrazol-4-yl)amino) pyrimidin-4-yl)amino)-3-azaspiro[5.5]undecane-3-carboxylate (87.0 mg, 0.18 mmol) in dichloromethane (5 mL) was added a solution of HCl in EtOAc (2 mL, 8 mmol). The mixture was stirred at room temperature for 5 h and then concentrated in vacuo. The residue was dissolved in MeOH (2 mL) and adjusted to pH=10 with a saturated Na2CO3 aqueous solution, then extracted with DCM (20 mL×3). The combined organic phases were washed with brine (20 mL), dried over anhydrous Na2SO4, then filtered and concentrated in vacuo. The residue was purified by preparative TLC (MeOH/DCM (v/v)=1/5) to give the product as a light yellow solid (54.0 mg, 78.6%).
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[N:21]=[C:22]([S:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[N:23]([CH3:33])[C:24]=2[C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=2)=[CH:16][CH:15]=1>ClCCl>[CH3:12][O:13][C:14]1[CH:15]=[CH:16][C:17]([C:20]2[N:21]=[C:22]([S:34]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)=[O:9])[N:23]([CH3:33])[C:24]=2[C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=2)=[CH:18][CH:19]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COc1ccc(-c2nc(Sc3ccccc3)n(C)c2-c2ccc(OC)cc2)cc1
Solvent: ClCCl
Product: COc1ccc(-c2nc(S(=O)c3ccccc3)n(C)c2-c2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 72.8 %

Procedure:
A solution of 2.164 g of 3-chloroperbenzoic acid (80%) in 150 ml of dichloromethane is added dropwise to a solution of 4.03 g of 4,5-bis(4-methoxyphenyl)-2-phenylthio-1-methylimidazole in 100 ml of dichloromethane. The solution is agitated for 3 hours at room temperature, washed with sodium bicarbonate solution, dried over sodium sulfate, and concentrated to dryness under vacuum. The residue is chromatographed on 200 g of silica gel with ethyl acetate/cyclohexane 2:3, thus obtaining 3.05 g of 4,5-bis(4-methoxyphenyl)-2-phenylsulfinyl-1-methylimidazole, which has a melting point of 114°-115° after recrystallization from dichloromethane/ether.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][C:7]2[C:12]([C:13]=1[NH:14][CH2:15][C:16]1([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1)=[CH:11][CH:10]=[CH:9][CH:8]=2)([O-])=O>[Pt].C1(C)C=CC=CC=1.C(O)C>[NH2:1][C:4]1[CH:5]=[N:6][C:7]2[C:12]([C:13]=1[NH:14][CH2:15][C:16]1([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:27])([CH3:26])[CH3:28])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1)=[CH:11][CH:10]=[CH:9][CH:8]=2
Reactant: CC(C)(C)OC(=O)NC1(CNc2c([N+](=O)[O-])cnc3ccccc23)CCCCC1
Agent: [Pt]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)NC1(CNc2c(N)cnc3ccccc23)CCCCC1
Reaction time: 4 h
Yield: 100 %

Procedure:
A mixture of tert-butyl 1-{[(3-nitroquinolin-4-yl)amino]methyl}cyclohexylcarbamate (29.5 g, 73.7 mmol) and 5% platinum on carbon (0.30 g) in toluene (300 mL) was hydrogenated at 50 psi (3.5×105 Pa) for 4 hours (h) on a Parr apparatus. The reaction mixture was diluted with ethanol (200 mL) and was filtered through CELITE filter agent. The filtrate was concentrated to give tert-butyl 1-{[(3-aminoquinolin-4-yl)amino]methyl}cyclohexylcarbamate as a brown solid (27.3 g, 100%).
Reaction SMILES: [C:1]1([C:7]([NH:20][CH2:21][C:22]2[N:23]([CH2:27][CH:28]3[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]3)[CH:24]=[CH:25][N:26]=2)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:34][O:35][CH:36]([O:40][CH3:41])N(C)C>>[CH3:34][O:35][CH:36]([O:40][CH3:41])[N:31]1[CH2:32][CH2:33][CH:28]([CH2:27][N:23]2[CH:24]=[CH:25][N:26]=[C:22]2[CH2:21][NH:20][C:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:29][CH2:30]1
Reactant: c1ccc(C(NCc2nccn2CC2CCNCC2)(c2ccccc2)c2ccccc2)cc1
Reactant: COC(OC)N(C)C
Product: COC(OC)N1CCC(Cn2ccnc2CNC(c2ccccc2)(c2ccccc2)c2ccccc2)CC1
Temperature: 100 °C

Procedure:
A mixture of 4-[(2-triphenylmethylaminomethyl-1H-imidazol-1-yl)methyl]piperidine (1.45 g, 0.0033 M) and dimethylformamide dimethylacetal was heated at 100° C. for 8 hours. After this period, the reaction was stripped to dryness to give 4-[(2-triphenylmethylaminomethyl-1H-imidazol-1-yl)methyl]-piperidine carboxaldehyde dimethylacetal. The solution of the piperidinecarboxaldehydedimethylacetal in methylene chloride (5 ml) was added to the mixture of 6-aminopenicillanic acid (0.57 g, 0.0026 M) and diisopropylethylamine (0.45 ml) in methylene chloride (5 ml) at 0° C. and stirred at room temperature for 3 hrs. The solvent was removed and the residue was stirred for 2 hrs in water (20 ml) which was maintained at pH 3 with 1 NHCl. The mixture was filtered and the filtrate was purified on Sephadex LH 20 columns to give [2S-(2alpha,5alpha,6beta)]-6-[[[4-[[2-(aminomethyl)-1H-imidazol-1-yl]methyl] -1-piperidinyl]methylene]amino]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid hydrochloride (0.27 g, 24% yield).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([C:12]2[C:13](=[O:25])[N:14]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[N:15]([CH3:18])[C:16]=2[CH3:17])=[O:11])[CH:5]=[CH:6][C:7]=1[OH:8].Cl[C:27]1[CH:32]=[CH:31][N:30]=[C:29]([C:33]([NH2:35])=[O:34])[CH:28]=1.[H-].[Na+]>CS(C)=O.O>[CH3:18][N:15]1[C:16]([CH3:17])=[C:12]([C:10]([NH:9][C:4]2[CH:5]=[CH:6][C:7]([O:8][C:27]3[CH:32]=[CH:31][N:30]=[C:29]([C:33]([NH2:35])=[O:34])[CH:28]=3)=[C:2]([F:1])[CH:3]=2)=[O:11])[C:13](=[O:25])[N:14]1[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: NC(=O)c1cc(Cl)ccn1
Reactant: Cc1c(C(=O)Nc2ccc(O)c(F)c2)c(=O)n(-c2ccccc2)n1C
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: Cc1c(C(=O)Nc2ccc(Oc3ccnc(C(N)=O)c3)c(F)c2)c(=O)n(-c2ccccc2)n1C
Temperature: 160 °C
Reaction time: 20 h
Yield: 28.8 %

Procedure:
To a suspension of N-(3-fluoro-4-hydroxyphenyl)-1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide (2.2 g, 6.4 mmol) and 4-chloropicolinamide (1 g, 6.39 mmol) in DMSO (12 mL) was added NaH (615 mg, 12.3 mmol, 50% dispersed in mineral oil). The reaction was stirred at 160° C. for 20 hours, then cooled to rt, and diluted with H2O (70 mL). The mixture was extracted with EtOAc (100 mL×3). The combined organic phases were washed with brine (100 mL), dried over Na2SO4 and concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/EtOAc (v/v)=1/4) to give the title compound as a white solid (0.85 g, 29%).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:23][C:24](=[O:26])[NH2:25])[C:3]([NH:5][C@@H:6]([C@H:10]([NH:12][C@H:13]([C:20]([OH:22])=[O:21])[CH2:14][C:15]1[N:16]=[CH:17][NH:18][CH:19]=1)[CH3:11])[C:7]([OH:9])=[O:8])=[O:4].C(N(CC)CC)C.[C:34](OC(=O)C)(=[O:36])[CH3:35]>CO.O>[C:34]([NH:1][C@@H:2]([CH2:23][C:24](=[O:26])[NH2:25])[C:3]([NH:5][C@@H:6]([C@H:10]([NH:12][C@H:13]([C:20]([OH:22])=[O:21])[CH2:14][C:15]1[N:16]=[CH:17][NH:18][CH:19]=1)[CH3:11])[C:7]([OH:9])=[O:8])=[O:4])(=[O:36])[CH3:35]
Reactant: C[C@@H](N[C@@H](Cc1c[nH]cn1)C(=O)O)[C@H](NC(=O)[C@@H](N)CC(N)=O)C(=O)O
Reactant: CC(=O)OC(C)=O
Solvent: CO
Solvent: O
Solvent: CCN(CC)CC
Product: CC(=O)N[C@@H](CC(N)=O)C(=O)N[C@H](C(=O)O)[C@@H](C)N[C@@H](Cc1c[nH]cn1)C(=O)O
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a mixture of (2S, 3R)-2-[[(2S)-2-amino-3-carbamoylpropionyl] amino]-3-[[(1S)-1-carboxy-2-(4imidazolyl)ethyl]amino]butyric acid (500 mg) and triethylamine (0.38 ml) in a mixture of methanol(30 ml) and water (6 ml) was added acetic anhydride (0.13 ml) and the mixture was stirred for 20 hours at room temperature After removal of the solvent in vacuo, the residue was dissolved in water and adjusted to pH 3 with 1N hydrochloric acid. The solution was subjected to a column of Dowex 50W X 8 (H+ form, 10 ml) and the column was washed with water. The elution was carried out with 2% aqueous ammonia. The object fractions were collected and evaporated in vacuo and the residue was dissolved in a mixture of acetic acid (28.6 ml) and water (500 ml). The solution was lyophilized and the residue was solidified with methanol to give (2S, 3R)-2-[[(2S)-2-acetylamino-3-carbamoylpropionyl]amino]-3-[[(1S)-1 -carboxy-2-(4-imidazolyl)ethyl]amino]butyric acid (500 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[NH:11]1[CH2:16][CH2:15][C:14](=[O:17])[CH2:13][CH2:12]1.[OH-].[K+].O>C(O)C>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:14]3([OH:17])[CH2:15][CH2:16][NH:11][CH2:12][CH2:13]3)=[CH:7][NH:8]2)=[CH:4][CH:3]=1
Reactant: O=C1CCNCC1
Reactant: Clc1ccc2cc[nH]c2c1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: OC1(c2c[nH]c3cc(Cl)ccc23)CCNCC1
Temperature: 25 °C
Reaction time: 48 h
Yield: 7.7 %

Procedure:
A mixture of 2.0 gm (13.2 mMol) 6-chloroindole and 4.06 gm (26.3 mMol) 4-piperidinone in 30 mL ethanol which contained 2.21 gm (39.6 mMol) potassium hydroxide was stirred at room temperature for 48 hours. Water (50 mL) was added dropwise to the reaction mixture over 30 minutes. The reaction mixture was allowed stir an additional 2 hours and the solid which formed was collected by filtration to provide a sticky orange solid. A portion of the solid was triturated with acetonitrile and filtered, washed with diethyl ether and dried under reduced pressure to provide 0.254 gm (7.4%) of the title compound as a colorless powder.
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[CH:5]=[C:6]([CH:15]=[CH:16][CH:17]=1)[O:7][C:8]1[CH:9]=[CH:10][C:11]([NH2:14])=[N:12][CH:13]=1.[F:18][C:19]([F:30])([F:29])[C:20]1[CH:21]=[C:22]([CH:26]=[CH:27][CH:28]=1)[C:23](Cl)=[O:24]>CN(C)C(=O)C>[NH2:14][C:11]1[N:12]=[CH:13][C:8]([O:7][C:6]2[CH:5]=[C:4]([NH:3][C:23](=[O:24])[C:22]3[CH:26]=[CH:27][CH:28]=[C:20]([C:19]([F:18])([F:29])[F:30])[CH:21]=3)[CH:17]=[CH:16][CH:15]=2)=[CH:9][CH:10]=1
Reactant: O=C(Cl)c1cccc(C(F)(F)F)c1
Reactant: Nc1cccc(Oc2ccc(N)nc2)c1
Agent: Cl
Solvent: CC(=O)N(C)C
Product: Nc1ccc(Oc2cccc(NC(=O)c3cccc(C(F)(F)F)c3)c2)cn1
Temperature: 25 °C
Reaction time: 6 h
Yield: 83.3 %

Procedure:
To a solution of 5-(3-aminophenoxy)pyridine-2-amine dihydrochloride (3.5 g, 12.7 mmol) in N,N-dimethylacetamide (30 mL) was added 3-(trifluoromethyl)benzoyl chloride (2.8 g, 13.4 mmol), and the mixture was stirred at room temperature for 6 hr. The reaction mixture was concentrated under reduced pressure, 5% aqueous sodium hydrogen carbonate solution (100 mL) was added to the residue, and the mixture was extracted with ethyl acetate (200 mL). The organic layer was washed with water (100 mL) and saturated brine (100 mL), and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. Ethyl acetate (30 mL)/hexane (20 mL) was added to the obtained residue, and the obtained precipitate was collected by filtration and dried to give the title compound (3.95 g, 83%) as a colorless powder.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([OH:8])=O.[NH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[C:10]1([NH:9][C:6]([C:2]2[NH:1][CH:5]=[CH:4][CH:3]=2)=[O:8])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=C(O)c1ccc[nH]1
Reactant: Nc1ccccc1
Product: O=C(Nc1ccccc1)c1ccc[nH]1
Yield: 77.6 %

Procedure:
Prepared following the experimental method described in preparation 1a starting from 10.0 g (90.0 mmol) of 1H-pyrrole-2-carboxylic acid (purchased from Aldrich®, cat. no. P7,360-9) and 9.22 g (99.0 mmol) of aniline. 13.0 g (78% yield) of the title compound were obtained as a brownish solid.
Reaction SMILES: I[C@H:2]1[CH2:6][CH2:5][O:4][CH2:3]1.C([O-])([O-])=O.[K+].[K+].[Br:13][C:14]1[CH:19]=[CH:18][C:17]([SH:20])=[CH:16][CH:15]=1.O>CN(C=O)C>[Br:13][C:14]1[CH:19]=[CH:18][C:17]([S:20][C@@H:2]2[CH2:6][CH2:5][O:4][CH2:3]2)=[CH:16][CH:15]=1
Reactant: Sc1ccc(Br)cc1
Reactant: I[C@H]1CCOC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Brc1ccc(S[C@@H]2CCOC2)cc1
Reaction time: 8 h

Procedure:
To a suspension of (3S)-3-iodotetrahydrofuran [prepared according to the method outline in US2006004018] (1.2 g, 6.061 mmol) and K2CO3 (1.675 g, 12.12 mmol) in DMF (12.00 mL) at ambient temperature was added 4-bromobenzenethiol (1.146 g, 6.061 mmol). The resulting suspension was stirred at this temperature overnight. Water was added and then the aqueous layer extracted with DCM (×3). The combined organic extracts were dried (MgSO4), filtered and concentrated in vacuo to give the sub-title compound as a clear oil which was used directly in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH2:8]O)[CH:5]=[CH:4][N:3]=1.S(Cl)([Cl:12])=O.CN(C)C=O.O>ClCCl>[Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][Cl:12])[CH:5]=[CH:4][N:3]=1
Reactant: OCc1ccnc(Cl)c1
Reactant: O=S(Cl)Cl
Solvent: O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: ClCc1ccnc(Cl)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 11.3 g of 2-chloro-4-hydroxymethylpyridine obtained in stage a) below in 200 mL of dichloromethane are added dropwise 6.896 mL of thionyl chloride, followed by 2.1 mL of dimethylformamide, the reaction mixture is stirred for 3 hours at room temperature and 50 mL of water are then added dropwise. The phases are separated and the organic phase is washed with water, dried over magnesium sulphate, filtered and concentrated under reduced pressure to give 12.8 g of 2-chloro-4-chloromethylpyridine in the form of an amber-coloured liquid, which is used without further purification.
Reaction SMILES: [CH:1]1([CH2:6][C:7]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].[CH2:19](I)[CH3:20]>COCCOC>[CH:1]1([CH:6]([CH2:19][CH3:20])[C:7]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCI
Reactant: COc1ccc(C(=O)CC2CCCC2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: CCC(C(=O)c1ccc(OC)cc1)C1CCCC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 2888.9 %

Procedure:
α-Cyclopentyl-p-methoxyacetophenone (13.0 g, 0.06 mol) was added slowly in dry DME (DME=Dimethoxyethane) to the suspension of NaH (8 g, 55-60% dispersion, 0.018 mmol) in dry DME under N2 atmosphere at room temperature. The suspension was stirred over night. Ethyl iodide (27.7 g, 0.18 mmol) was added and stirring continued for another two hours. Ice water was added cautiously and the water layer extracted with toluene. The organic layer was washed with water, dried and evaporated to give 12.7 g (0.0052 mol, 86%) of the product.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].BrC1C=CC(Cl)=CC=1[CH2:20][O:21][CH2:22]OC>>[Br:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:3]=1[CH2:4][O:5][CH2:20][O:21][CH3:22]
Reactant: COCOCc1cc(Cl)ccc1Br
Reactant: O=C(O)c1ccc(F)cc1Br
Product: COCOCc1ccc(F)cc1Br

Procedure:
This compound was made from 2-bromo-4-fluorobenzoic acid in the same manner as compound 18d and was used for the next step without purification.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:12]=1)[C:7]([OH:9])=[O:8])([O-])=O.[H][H]>C(O)C.[Ni]>[NH2:1][C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([C:13]([F:14])([F:15])[F:16])[CH:12]=1)[C:7]([OH:9])=[O:8]
Reactant: [H][H]
Reactant: O=C(O)c1cc([N+](=O)[O-])cc(C(F)(F)F)c1
Agent: [Ni]
Solvent: CCO
Product: Nc1cc(C(=O)O)cc(C(F)(F)F)c1

Procedure:
A solution of 3-nitro-5-(trifluoromethyl)benzoic acid (Lancaster Synthesis GmbH; 11.75 g, 50 mmol) in ethanol (300 mL) is hydrogenated at atmospheric pressure over Raney nickel (1 g) at 40° C. The calculated amount of hydrogen is taken up after 8 hours. The mixture is then filtered and the solvent is evaporated off under reduced pressure to yield the crude product which is purified by recrystallisation from diethylether-hexane to give the title compound as a beige crystalline solid, m.p. 134-139° C.
Reaction SMILES: [NH2:1][C:2]([C:4]1[CH:5]=[C:6]([CH:37]=[C:38]([Cl:40])[CH:39]=1)[O:7][C@@H:8]([C:30]1[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=1)[C@@H:9]([C:16]1[CH:29]=[CH:28][C:19]([C:20]([NH:22][CH2:23][CH2:24][C:25]([OH:27])=[O:26])=[O:21])=[CH:18][CH:17]=1)[CH2:10][CH2:11][C:12]([F:15])([F:14])[F:13])=O>O.C(#N)C.[Pd](Cl)Cl>[Cl:40][C:38]1[CH:37]=[C:6]([CH:5]=[C:4]([C:2]#[N:1])[CH:39]=1)[O:7][C@@H:8]([C:30]1[CH:31]=[CH:32][C:33]([Cl:36])=[CH:34][CH:35]=1)[C@@H:9]([C:16]1[CH:29]=[CH:28][C:19]([C:20]([NH:22][CH2:23][CH2:24][C:25]([OH:27])=[O:26])=[O:21])=[CH:18][CH:17]=1)[CH2:10][CH2:11][C:12]([F:15])([F:13])[F:14]
Reactant: NC(=O)c1cc(Cl)cc(O[C@@H](c2ccc(Cl)cc2)[C@H](CCC(F)(F)F)c2ccc(C(=O)NCCC(=O)O)cc2)c1
Agent: Cl[Pd]Cl
Solvent: CC#N
Solvent: O
Product: N#Cc1cc(Cl)cc(O[C@@H](c2ccc(Cl)cc2)[C@H](CCC(F)(F)F)c2ccc(C(=O)NCCC(=O)O)cc2)c1
Temperature: 50 °C
Reaction time: 12 h

Procedure:
To a solution of the product from Step A (50 mg, 0.087 mmol) in water (0.5 mL) and acetonitrile (0.5 mL) at room temperature was added palladium (II) chloride (1.5 mg, 8.7 μmol). The resulting mixture was stirred at 50° C. for 12 hours. After cooling to room temperature, the mixture was extracted with EtOAc, then the organic layer was filtered through celite. The filtrate was concentrated, then the resulting residue was purified by PTLC eluting with 5% MeOH/DCM+0.1% HOAc to afford the title compound. NMR (500 MHz, CD3OD): δ 7.74 (d, J=8.0 Hz, 2H); 7.36 (d, J=8.0 Hz, 2H); 7.31 (d, J=8.0 Hz, 2H); 7.24 (d, J=9.0 Hz, 2H); 7.22 (s, 1H); 7.12 (s, 1H); 7.09 (s, 1H); 5.64 (d, J=6.5 Hz, 1H); 3.63 (t, J=9.2 Hz, 2H); 3.26-3.23 (m, 1H); 2.62 (t, J=9.5 Hz, 2H); 2.10-2.05 (m, 2H); 2.00-1.95 (m, 2H); LC3 3.59 min. (M+H)+ 579.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:10]=[C:11]([OH:13])[CH:12]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6].Br[CH2:15][CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1>>[Br:1][C:2]1[CH:3]=[C:4]([CH:10]=[C:11]([O:13][CH2:15][CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[CH:12]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: CCOC(=O)c1cc(O)cc(Br)c1
Reactant: BrCC1CCCCC1
Product: CCOC(=O)c1cc(Br)cc(OCC2CCCCC2)c1

Procedure:
Alkylation of ethyl 3-bromo-5-hydroxybenzoate using (bromomethyl)cyclohexane gave ethyl 3-bromo-5-(cyclohexylmethoxy)benzoate. Yield (1.36 g, 100%): 1H NMR (400 MHz, CDCl3) δ 7.72 (t, J=1.6 Hz, 1H), 7.46 (dd, J=2.4, 1.2 Hz, 1H), 7.20 (dd, J=2.4, 1.6 Hz, 1H), 4.35 (q, J=7.2 Hz, 2H), 3.76 (d, J=6.4 Hz, 2H), 1.67-1.88 (m, 6H), 1.38 (t, J=7.2 Hz, 3H), 1.16-1.32 (m, 3H), 1.01-1.11 (m, 2H).
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[CH:6][C:7]([C@H:11]3[C@@:13]4([C:21]5[C:16](=[CH:17][CH:18]=[C:19]([O:22][CH3:23])[CH:20]=5)[N:15]([CH3:24])[C:14]4=[O:25])[CH2:12]3)=[CH:8][CH:9]=2)[NH:4][N:3]=1.CC1(C)C(C)(C)OB([C:34]2[CH:39]=[CH:38][C:37]([N:40]3[CH2:45][CH2:44][N:43](C(OC(C)(C)C)=O)[CH2:42][CH2:41]3)=[CH:36][CH:35]=2)O1.[C:54]([OH:60])([C:56]([F:59])([F:58])[F:57])=[O:55]>C(Cl)Cl>[F:57][C:56]([F:59])([F:58])[C:54]([OH:60])=[O:55].[CH3:23][O:22][C:19]1[CH:20]=[C:21]2[C:16](=[CH:17][CH:18]=1)[N:15]([CH3:24])[C:14](=[O:25])[C@:13]12[CH2:12][C@H:11]1[C:7]1[CH:6]=[C:5]2[C:10]([C:2]([C:34]3[CH:35]=[CH:36][C:37]([N:40]4[CH2:41][CH2:42][NH:43][CH2:44][CH2:45]4)=[CH:38][CH:39]=3)=[N:3][NH:4]2)=[CH:9][CH:8]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Reactant: COc1ccc2c(c1)[C@]1(C[C@H]1c1ccc3c(I)n[nH]c3c1)C(=O)N2C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc2c(c1)[C@]1(C[C@H]1c1ccc3c(-c4ccc(N5CCNCC5)cc4)n[nH]c3c1)C(=O)N2C
Yield: 42 %

Procedure:
The Boc protected title compound was synthesized according to the method of Example 9B, except substituting (1R,2S)-2-(3-iodo-1H-indazol-6-yl)-5′-methoxy-1′-methylspiro[cyclopropane-1,3′-indolin]-2′-one (Example 6C, 600 mg, 1.35 mmol) and tert-butyl 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperazine-1-carboxylate (534 mg, 1.37 mmol). The Boc protected compound was purified by column chromatography (silica gel, hexanes/EtOAc, 100:0 to 5:95) which gave 400 mg. This material was dissolved in CH2Cl2(12 mL) and TFA (3 mL) and the reaction stirred for 3 h at which time the solvent was removed and the residue purified by prep-HPLC which yielded the title product as a pale-yellow solid (339 mg, 42%, TFA salt); 1H NMR (400 MHz, CD3OD) δ 7.90 (d, J=8.2 Hz, 1H), 7.86 (d, J=8.4 Hz, 2H), 7.48 (s, 1H), 7.17 (d, J=8.4 Hz, 2H), 7.00 (d J=8.6 Hz, 1H,), 6.92 (d, J=8.5 Hz, 1H), 6.69 (d, J=8.6 Hz, 1H), 5.64 (s, 1H), 3.53-3.48 (m, 4H), 3.43-3.37 (m, 5H), 3.31 (s, 3H), 3.29 (s, 3H), 2.29-2.26 (m, 1H), 2.22-2.18 (m, 1H); MS ESI [M+H]+ 480.3, calcd for [C29H29N5O2+H]+ 480.24. Optical Rotation: [α]22D=−113° (c 0.62, MeOH).