Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O)(=O)/C=C/C(O)=O.[NH2:9][C:10]1[CH:18]=[C:17]([C:19]([NH:21][CH2:22][CH:23]2[CH2:27][CH2:26][CH2:25][N:24]2[CH2:28][CH3:29])=[O:20])[C:13]2[O:14][CH2:15][CH2:16][C:12]=2[CH:11]=1.[CH3:30][S:31](Cl)(=[O:33])=[O:32]>C(Cl)Cl>[CH2:28]([N:24]1[CH2:25][CH2:26][CH2:27][CH:23]1[CH2:22][NH:21][C:19]([C:17]1[C:13]2[O:14][CH2:15][CH2:16][C:12]=2[CH:11]=[C:10]([NH:9][S:31]([CH3:30])(=[O:33])=[O:32])[CH:18]=1)=[O:20])[CH3:29]
Reactant: CCN1CCCC1CNC(=O)c1cc(N)cc2c1OCC2
Reactant: CS(=O)(=O)Cl
Agent: O=C(O)/C=C/C(=O)O
Solvent: ClCCl
Product: CCN1CCCC1CNC(=O)c1cc(NS(C)(=O)=O)cc2c1OCC2
Yield: 98.8 %

Procedure:
A solution of 5-amino-N-(1-ethyl-2-pyrrolidinylmethyl)-2,3-dihydrobenzo[b]furan-7-carboxamide (161) (1.80 g, 6.2 mmol) and methanesulfonyl chloride (12.78 g, 0.11 mol) in 30 ml of methylene chloride was heated to reflux overnight. The solution was diluted with CH2Cl2 (30 ml), and then extracted with water (2×30 ml). The combined aqueous layers were made basic with NaHCO3 powder, and extracted with CH2Cl2 (4×50 ml). The organic extracts were combined, dried over anhydrous Na2SO4, and evaporated to give crude 16n (2.25 g, 98.8%). This was recrystallized from EtOH/charcoal to afford 1.70 g of amide as a white solid, mp 180°-182° C.
Reaction SMILES: [C:1]([C:3]1[C:8]2[NH:9][C:10]3[CH:11]=[C:12]([C:16]([O:18][CH3:19])=[O:17])[CH:13]=[CH:14][C:15]=3[C:7]=2[C:6](=O)[NH:5][CH:4]=1)#[N:2].P(Cl)(Cl)([Cl:23])=O>O1CCOCC1>[CH3:19][O:18][C:16]([C:12]1[CH:13]=[CH:14][C:15]2[C:7]3[C:6]([Cl:23])=[N:5][CH:4]=[C:3]([C:1]#[N:2])[C:8]=3[NH:9][C:10]=2[CH:11]=1)=[O:17]
Reactant: COC(=O)c1ccc2c(c1)[nH]c1c(C#N)c[nH]c(=O)c12
Reactant: O=P(Cl)(Cl)Cl
Solvent: C1COCCO1
Product: COC(=O)c1ccc2c(c1)[nH]c1c(C#N)cnc(Cl)c12
Temperature: 93 °C
Reaction time: 5 h

Procedure:
A stirred slurry of methyl 4-cyano-1-oxo-2,5-dihydro-1H-pyrido[4,3-b]indole-7-carboxylate (1.000 g, 3.74 mmol) in Dioxane (Volume: 25 mL) was heated to 93° C. Phosphorus oxychloride (1.713 mL, 18.71 mmol) was added slowly dropwise over 30 minutes. After complete addition the reaction mixture was stirred at 93° C. for 5 hours then at room temperature overnight. LC-MS showed complete conversion to the desired product mass with minor by-products. The reaction mixture was diluted with 25 ml ethyl acetate and filtered. The filtrate was concentrated under vacuum to give 1.311 g crude solid tan product. The crude product was washed with diethyl ether, then triturated with acetonitrile and filtered to give Methyl-1-chloro-4-cyano-5H-pyrido[4,3-b]indole-7-carboxylate as a tan solid [0.855 g, 2.99 mmol, 80% yield]. The product had an HPLC Retention Time=3.658 min [4 min grad, 10% MeOH/water to 90% MeOH/water, 0.1% TFA, YMC COMBISCREEN® ODS-A, 4.6×50 mm, 220 nM]; LC/MS+1 286.1
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][N:11]=[CH:10][C:9]=1[NH:14][CH:15]([CH3:17])[CH3:16].[F:18][C:19]([F:34])([F:33])[C:20]1[CH:21]=[C:22]([CH:26]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:28]=1)[C:23](Cl)=[O:24]>CCCCCCC.CCOC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][N:11]=[CH:10][C:9]=1[N:14]([CH:15]([CH3:17])[CH3:16])[C:23](=[O:24])[C:22]1[CH:26]=[C:27]([C:29]([F:30])([F:31])[F:32])[CH:28]=[C:20]([C:19]([F:18])([F:33])[F:34])[CH:21]=1
Reactant: O=C(Cl)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: CC(C)Nc1cnccc1-c1ccccc1Cl
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: CC(C)N(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cnccc1-c1ccccc1Cl

Procedure:
The title compound was prepared in analogy to example 72, intermediate, from [4-(2-chloro-phenyl)-pyridin-3-yl]-isopropyl-amine and 3,5-bis(trifluoromethyl)benzoyl chloride (CAS RN 1271-19-8) and using a gradient of n-heptane:EtOAc (100:0 to 50:50) for the chromatographic purification. Yellow solid (19%). MS (ESI): m/z=487.10 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6](Cl)[N:5]=[CH:4][N:3]=1.OC(C(F)(F)F)=O.[F:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[C:25]1[C:34]([CH:35]([NH2:37])[CH3:36])=[CH:33][C:32]2[C:27](=[CH:28][CH:29]=[CH:30][N:31]=2)[N:26]=1.CCN(C(C)C)C(C)C.O>C(O)CCC>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([NH:37][CH:35]([C:34]2[C:25]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=3[F:18])=[N:26][C:27]3[C:32]([CH:33]=2)=[N:31][CH:30]=[CH:29][CH:28]=3)[CH3:36])[N:5]=[CH:4][N:3]=1
Reactant: CC(N)c1cc2ncccc2nc1-c1ccccc1F
Reactant: N#Cc1c(N)ncnc1Cl
Solvent: O=C(O)C(F)(F)F
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: CC(Nc1ncnc(N)c1C#N)c1cc2ncccc2nc1-c1ccccc1F
Temperature: 120 °C
Reaction time: 5 h

Procedure:
A mixture of 4-amino-6-chloro-5-pyrimidinecarbonitrile (0.045 g, 0.288 mmol), 1-(2-(2-fluorophenyl)-1,5-naphthyridin-3-yl)ethanamine TFA salt (0.110 g, 0.288 mmol), and n,n-diisopropylethylamine (0.251 mL, 1.44 mmol) in butan-1-ol (2.88 mL) was stirred at 120° C. After 5 h, the mixture was removed from the heat and cooled to room temperature. After cooling, the mixture was concentrated under reduced pressure to give brown syrup. To the residue was added water (30 mL) and the mixture was sonicated. The resulting precipitate was collected by filtration, washed with water (20 mL), and dried to give the desired product as a yellow solid. The solid was purified by column chromatography on a 40 g of Redi-Sep™ column using 0 to 100% gradient of CH2Cl2:MeOH:NH4OH (89:9:1) in CH2Cl2 over 14 min and then 100% isocratic of CH2Cl2:MeOH:NH4OH (89:9:1) for 14 min as eluent to give a yellow solid. The yellow solid was suspended in EtOAc-hexane (1:1) and filtered to give 4-amino-6-((1-(2-(2-fluorophenyl)-1,5-naphthyridin-3-yl)ethyl)amino)-5-pyrimidinecarbonitrile as a light yellow solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 9.03 (1H, dd, J=4.2, 1.7 Hz), 8.68 (1H, s), 8.41 (1H, ddd, J=8.6, 1.6, 0.8 Hz), 7.85 (1H, d, J=7.2 Hz), 7.73-7.81 (2H, m), 7.58 (1H, br. s.), 7.45-7.53 (1H, m), 7.26-7.37 (2H, m), 7.17 (2H, br. s.), 5.24-5.36 (1H, m), 1.52 (3H, d, J=7.0 Hz); LC-MS (ESI) m/z 386.0 [M+H]+.
Reaction SMILES: [CH2:1]([CH:3]1[CH:20]([OH:21])[CH:19]([CH3:22])[CH:18]=[C:17]([CH3:23])[CH:16]=[C:15]([O:24][CH3:25])[C:14](=[O:26])[O:13][CH:12]([CH:27]([CH:29]([OH:48])[CH:30]([CH3:47])/[C:31](=[N:41]\[O:42][CH2:43][C:44](O)=[O:45])/[CH:32]=[CH:33]/[CH:34]([CH3:40])[CH:35]([OH:39])/[CH:36]=[CH:37]/[CH3:38])[CH3:28])[CH:11]([O:49][CH3:50])[CH:10]=[CH:9][CH:8]=[C:7]([CH3:51])[CH2:6][CH:5]([CH3:52])[CH:4]1[OH:53])[CH3:2].C1C=CC2N(O)N=NC=2C=1.[F:64][C:65]1[CH:72]=[CH:71][C:68]([CH2:69][NH2:70])=[CH:67][CH:66]=1.O>ClCCl>[CH2:1]([CH:3]1[CH:20]([OH:21])[CH:19]([CH3:22])[CH:18]=[C:17]([CH3:23])[CH:16]=[C:15]([O:24][CH3:25])[C:14](=[O:26])[O:13][CH:12]([CH:27]([CH:29]([OH:48])[CH:30]([CH3:47])/[C:31](=[N:41]\[O:42][CH2:43][C:44]([NH:70][CH2:69][C:68]2[CH:71]=[CH:72][C:65]([F:64])=[CH:66][CH:67]=2)=[O:45])/[CH:32]=[CH:33]/[CH:34]([CH3:40])[CH:35]([OH:39])/[CH:36]=[CH:37]/[CH3:38])[CH3:28])[CH:11]([O:49][CH3:50])[CH:10]=[CH:9][CH:8]=[C:7]([CH3:51])[CH2:6][CH:5]([CH3:52])[CH:4]1[OH:53])[CH3:2]
Reactant: C/C=C/C(O)C(C)/C=C/C(=N/OCC(=O)O)C(C)C(O)C(C)C1OC(=O)C(OC)=CC(C)=CC(C)C(O)C(CC)C(O)C(C)CC(C)=CC=CC1OC
Reactant: NCc1ccc(F)cc1
Agent: C/C=C/C(O)C(C)/C=C/C(=N/OCC(=O)NCc1ccc(F)cc1)C(C)C(O)C(C)C1OC(=O)/C(OC)=C/C(C)=C/C(C)C(O)C(CC)C(O)C(C)C/C(C)=C/C=C/C1OC
Agent: C/C=C/C(O)C(C)/C=C/C(=N/OCC(=O)O)C(C)C(O)C(C)C1OC(=O)/C(OC)=C/C(C)=C/C(C)C(O)C(CC)C(O)C(C)C/C(C)=C/C=C/C1OC
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O
Product: C/C=C/C(O)C(C)/C=C/C(=N/OCC(=O)NCc1ccc(F)cc1)C(C)C(O)C(C)C1OC(=O)C(OC)=CC(C)=CC(C)C(O)C(CC)C(O)C(C)CC(C)=CC=CC1OC
Reaction time: 0.33 h

Procedure:
To a solution of compound of example 10 (10 mg) in dichloromethane (2 mL) dicyclohexylcarbodiimide (3 mg), and HOBt (2 mg) were added. After 20 min. 4-fluoro benzyl amine (1.5 mg) was added, The reaction mixture was stirred for 18 h under nitrogen atmosphere. Cold water was added to the reaction mixture, the organic layer was separated.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4]N.I.[C:7]1([CH:13]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[NH:14][C:15](=[NH:18])SC)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>ClC1C=CC=CC=1Cl>[C:7]1([CH:13]([NH:14][C:15]2[N:2]([CH3:1])[CH2:3][CH2:4][N:18]=2)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CSC(=N)NC(c1ccccc1)c1ccccc1
Reactant: CNCCN
Agent: I
Solvent: Clc1ccccc1Cl
Product: CN1CCN=C1NC(c1ccccc1)c1ccccc1

Procedure:
To 7.41 grams (0.10 mole) of N-methylethylenediamine was added 38.43 grams (0.10 mole) of 1-(diphenylmethyl)-2-methyl-2-thiopseudourea hydroiodide in 250 milliliters of o-dichlorobenzene and the resulting mixture allowed to reflux overnight to produce the desired 2-diphenylmethylamino-1-methyl-2-imidazoline product. After completion of the heating, the solvent was removed by decantation and the residue purified by first dissolving in methanol containing activated carbon, replacing the methanol with isopropanol and diluting the isopropanol with acetone-ether to precipitate 16.55 grams (65 percent yield) of 2-diphenylmethylamino-1-methyl-2-imidazoline hydroiodide, m.p. 226°-228° C. After purification by treating with activated charcoal in methanol and recrystallizations from methanol-isopropanol, the product melted at (225°) 227°-229° C.
Reaction SMILES: [F:1][C:2]1[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[C:3]=1[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12](=[O:22])[CH2:13][CH2:14][C:15]([O:17]C(C)(C)C)=[O:16])=[CH:8][CH:7]=1.FC(F)(F)C(O)=O>ClCCl>[F:1][C:2]1[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[C:3]=1[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12](=[O:22])[CH2:13][CH2:14][C:15]([OH:17])=[O:16])=[CH:8][CH:7]=1
Reactant: CC(C)(C)OC(=O)CCC(=O)c1ccc(OCc2c(F)cccc2F)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)CCC(=O)c1ccc(OCc2c(F)cccc2F)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of tert-Butyl 4-(4-(2,6-difluorobenzyloxy)phenyl)-4-oxobutyrate (Step B, 4.76 g, 12.6 mmol) in dichloromethane (40 ml) was treated with trifluoroacetic acid (20 ml). The mixture was stirred at ambient temperature for 3 hours and concentrated in vacuo. The purification was done by flash chromatography on silica gel column (chloroform: methanol, 95:5 spiked with acetic acid) to provide the title compound as a white powder.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[C:9]([O:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:10]=2)[C:5]([OH:26])=[C:4]([C:27]([NH:29][CH2:30][C:31]([OH:33])=[O:32])=[O:28])[N:3]=1.[CH3:34][N:35](C)C(=O)C>C(OCC)(=O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].[Zn].[C-]#N.[Zn+2].[C-]#N>[C:34]([C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[C:9]([O:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:10]=2)[C:5]([OH:26])=[C:4]([C:27]([NH:29][CH2:30][C:31]([OH:33])=[O:32])=[O:28])[N:3]=1)#[N:35]
Reactant: O=C(O)CNC(=O)c1nc(Cl)c2cc(Oc3ccccc3)c(Oc3ccccc3)cc2c1O
Reactant: CC(=O)N(C)C
Agent: [Fe+2]
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCOC(C)=O
Product: N#Cc1nc(C(=O)NCC(=O)O)c(O)c2cc(Oc3ccccc3)c(Oc3ccccc3)cc12
Temperature: 25 °C

Procedure:
[(1-Cyano-4-hydroxy-6,7-diphenoxy-isoquinoline-3-carbonyl)-amino]-acetic acid was prepared by adding 76 mg (0.164 mmol) of [(1-chloro-4-hydroxy-6,7-diphenoxy-isoquinoline-3-carbonyl)-amino]-acetic acid (prepared according to US 2006/0217416), 7.3 mg (0.008 mmol) tris(dibenzylideneacetone)dipalladium(0), 9.0 mg (0.016 mmol) 1,1′-bis(diphenylphosphino) ferrocene, 1.3 mg (0.020 mmol) zinc dust, and 12 mg (0.10 mmol) zinc cyanide to 0.35 mL of N,N-dimethylacetamide. The resultant mixture was heated at 115° C. for 3 hours under a nitrogen atmosphere, and then cooled to room temperature. The mixture was diluted with ethyl acetate and extracted three times with aqueous sodium bicarbonate and twice with 1 N NaOH solutions. The basic aqueous extracts were acidified with concentrated HCl, and extracted three times with ethyl acetate. The organic extracts were dried over sodium sulfate and concentrated to give 29 mg of the title compound as a white solid; MS (ESI−): m/z 454.0 (M−1)
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:7][C:8]1[C:16]2[C:11](=[N:12][CH:13]=[N:14][C:15]=2[NH2:17])[NH:10][N:9]=1.Cl[CH:19]([C:21]1[C:22]([O:41][CH2:42][CH3:43])=[C:23]([C:30]2[CH:31]=[CH:32][C:33]([C:36]([N:38]([CH3:40])[CH3:39])=[O:37])=[N:34][CH:35]=2)[C:24]([C:28]#[N:29])=[C:25]([CH3:27])[CH:26]=1)[CH3:20]>CN(C)C=O.CCOC(C)=O>[NH2:17][C:15]1[N:14]=[CH:13][N:12]=[C:11]2[N:10]([CH:19]([C:21]3[C:22]([O:41][CH2:42][CH3:43])=[C:23]([C:30]4[CH:31]=[CH:32][C:33]([C:36]([N:38]([CH3:39])[CH3:40])=[O:37])=[N:34][CH:35]=4)[C:24]([C:28]#[N:29])=[C:25]([CH3:27])[CH:26]=3)[CH3:20])[N:9]=[C:8]([CH3:7])[C:16]=12
Reactant: Cc1n[nH]c2ncnc(N)c12
Reactant: CCOc1c(C(C)Cl)cc(C)c(C#N)c1-c1ccc(C(=O)N(C)C)nc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOc1c(C(C)n2nc(C)c3c(N)ncnc32)cc(C)c(C#N)c1-c1ccc(C(=O)N(C)C)nc1
Temperature: 80 °C
Reaction time: 3 h
Yield: 77.4 %

Procedure:
Cesium carbonate (4000 mg, 10 mmol) was added to a mixture of 3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (1300 mg, 8.5 mmol) and 5-[3-(1-chloroethyl)-6-cyano-2-ethoxy-5-methylphenyl]-N,N-dimethylpyridine-2-carboxamide (2.1 g, 5.6 mmol) in N,N-dimethylformamide (100 mL). The reaction was stirred at 80° C. for 3 hrs and monitored by LC/MS. The reaction mixture was diluted with EtOAc, washed with water, brine, dried over Na2SO4, filtered and concentrated to give the crude product. The product was purified by FCC on silica gel eluting (hexane/10% EtOH in EtOAc, gradient 0-100%) gradient to give the title compound (2.1 g, 77%). LCMS calculated for C26H29N8O2(M+H)+: m/z=485.2; found: 485.2. 1H NMR (500 MHz, DMSO-d6) δ 8.70-8.63 (m, 1H), 8.10 (s, 1H), 8.06 (dd, J=8.0, 2.2 Hz, 1H), 7.69 (d, J=8.1 Hz, 1H), 7.51 (s, 1H), 6.34 (q, J=7.0 Hz, 1H), 3.59-3.47 (m, 1H), 3.33 (m, 1H), 3.03 (s, 3H), 2.96 (s, 3H), 2.57 (s, 3H), 2.45 (s, 3H), 1.79 (d, J=7.1 Hz, 3H), 0.90 (t, J=7.0 Hz, 3H). The enantiomers were separated by Chiral column HPLC using: AD column 20×25 cm, eluting hexane; 30% ethanol @ 13 mL/min 5 mg/injection to give: First peak retention time: 1.63 minutes, 5-{3-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-6-cyano-2-ethoxy-5-methylphenyl}-N,N-dimethylpyridine-2-carboxamide; Second peak retention time: 4.13 minutes, 5-{3-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-6-cyano-2-ethoxy-5-methylphenyl}-N N-dimethylpyridine-2-carboxamide.
Reaction SMILES: CON(C)[C:4]([C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:12]=[C:13]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[O:23][CH3:24])[CH:14]=[CH:15][CH:16]=2)[CH:10]=1)=[O:5].Br[C:27]1[C:32]([CH3:33])=[CH:31][CH:30]=[CH:29][N:28]=1>>[CH3:24][O:23][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[C:13]1[CH:14]=[CH:15][CH:16]=[C:11]([N:9]2[CH:10]=[C:6]([C:4]([C:27]3[C:32]([CH3:33])=[CH:31][CH:30]=[CH:29][N:28]=3)=[O:5])[N:7]=[CH:8]2)[CH:12]=1
Reactant: COc1ccccc1-c1cccc(-n2cnc(C(=O)N(C)OC)c2)c1
Reactant: Cc1cccnc1Br
Product: COc1ccccc1-c1cccc(-n2cnc(C(=O)c3ncccc3C)c2)c1

Procedure:
This compound is prepared by method C using compound 12c and 2-bromo-3-methylpyridine
Reaction SMILES: Cl[CH:2]1[C:8](=[O:9])[CH:7]2[CH2:10][CH2:11][CH:4]([CH:5]=[CH:6]2)[C:3]1=[O:12]>[Zn].C(O)(=O)C>[CH:7]12[CH2:10][CH2:11][CH:4]([CH:5]=[CH:6]1)[C:3](=[O:12])[CH2:2][C:8]2=[O:9]
Reactant: O=C1C2C=CC(CC2)C(=O)C1Cl
Agent: [Zn]
Solvent: CC(=O)O
Product: O=C1CC(=O)C2C=CC1CC2
Temperature: 95 °C
Yield: 93.2 %

Procedure:
0.19 g (1 mmol) of 3-chloro-bicyclo[3.2.2]non-6-ene-2,4-dione is treated in the presence of 4 ml of acetic acid with 0.27 g (4 mmol) of zinc and the mixture is heated for 3 hours at a temperature of 95° C. The cooled reaction mixture is then extracted with ethyl acetate against water and then washed again with saturated sodium chloride solution. 0.14 g of amorphous bicyclo[3.2.2]non-6-ene-2,4-dione is obtained as tautomeric form Da.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([CH2:11][OH:12])[CH:6]=[CH:7][C:8]=1[CH2:9][OH:10].[CH:13]([O-])([O-])[O:14][CH3:15].O.[O-2].[O-2].[O-2].O=[Si]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O.[Al+3].[Al+3]>COCCOC>[CH3:13][O:14][CH:15]1[O:1][CH2:2][C:3]2[CH:4]=[C:5]([CH2:11][OH:12])[CH:6]=[CH:7][C:8]=2[CH2:9][O:10]1
Reactant: COC([O-])[O-]
Reactant: OCc1ccc(CO)c(CO)c1
Agent: O=[Si]=O
Agent: [Al+3]
Agent: [O-2]
Solvent: COCCOC
Solvent: O
Product: COC1OCc2ccc(CO)cc2CO1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
4 g of (3,4-bis-hydroxymethylphenyl)methanol (23.8 mmol), 40 ml of 1,2-dimethoxyethane, 2.78 g of methyl orthoformate (26.2 mmol) and 0.24 g of Montmorillonite KSF (10 mg/mmol) are introduced into a flask. The reaction medium is stirred at room temperature for 4 hours 30 minutes and then the montmorillonite is filtered off and the 1,2-dimethoxyethane is evaporated under vacuum at 30° C. The residue is chromatographed on silica gel (dichloromethane/methanol=98/2) to give 3.2 g of (7-methoxy)-(5H,9H)-6,8-dioxabenzocyclohepten-2-yl)methanol in the form of an oil.
Reaction SMILES: [NH:1]([C:8]([NH:10][C:11]1[CH:31]=[CH:30][C:14]([CH2:15][C@H:16]2[CH2:20][O:19]C(C)(C)[N:17]2C(OC(C)(C)C)=O)=[CH:13][CH:12]=1)=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:32]>CO.C(OCC)(=O)C>[ClH:32].[NH2:17][C@H:16]([CH2:20][OH:19])[CH2:15][C:14]1[CH:13]=[CH:12][C:11]([NH:10][C:8]([NH:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:9])=[CH:31][CH:30]=1
Reactant: CC(C)(C)OC(=O)N1[C@@H](Cc2ccc(NC(=O)Nc3ccccc3)cc2)COC1(C)C
Agent: Cl
Solvent: CO
Solvent: CCOC(C)=O
Product: N[C@H](CO)Cc1ccc(NC(=O)Nc2ccccc2)cc1
Reaction time: 4 h

Procedure:
To a solution of tert-butyl (S)-4-[4-[(anilinocarbonyl)amino]benzyl]-2,2-dimethyl-1,3-oxazolidine-3-carboxylate (1.48 g) in methanol (20 ml) was added 4N hydrogen chloride in ethyl acetate (5 ml) at room temperature, and the solution was stirred at the same temperature for 4 hours. The mixture was evaporated in vacuo, and the residue was triturated with diisopropyl ether to give (S)-N-[4-(2-amino-3-hydroxypropyl)phenyl]-N′-phenylurea hydrochloride (660 mg) as a colorless solide.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:20]([O:21][CH2:22][C:23]#[N:24])=[CH:19][CH:18]=[C:17]3[C:12]=2[CH:13]=[CH:14][C:15]([CH2:25][NH:26][C:27]([C:29]2[C:33]4[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=4[O:31][C:30]=2[CH2:38][CH2:39][CH2:40][CH3:41])=[O:28])=[CH:16]3)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[N-:42]=[N+:43]=[N-:44].[Na+].[Cl-].[NH4+].[OH-].[Na+]>CN(C=O)C.O>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([C:11]2[C:20]([O:21][CH2:22][C:23]3[NH:44][N:43]=[N:42][N:24]=3)=[CH:19][CH:18]=[C:17]3[C:12]=2[CH:13]=[CH:14][C:15]([CH2:25][NH:26][C:27]([C:29]2[C:33]4[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=4[O:31][C:30]=2[CH2:38][CH2:39][CH2:40][CH3:41])=[O:28])=[CH:16]3)=[CH:9][CH:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCCc1oc2ccccc2c1C(=O)NCc1ccc2c(-c3ccc(C(C)(C)C)cc3)c(OCC#N)ccc2c1
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCc1oc2ccccc2c1C(=O)NCc1ccc2c(-c3ccc(C(C)(C)C)cc3)c(OCc3nnn[nH]3)ccc2c1
Temperature: 100 °C
Reaction time: 6 h
Yield: 83.3 %

Procedure:
A mixture of 2-butyl-benzofuran-3-carboxylic acid [5-(4-tert-butyl-phenyl)-6-cyanomethoxy-naphthalen-2-ylmethyl]-amide (207 mg, 0.38 mmol), prepared in the previous step, sodium azide (72.9 mg, 1.12 mmol) and ammonium chloride (58,7 mg, 1.10 mmol) in 10 mL of DMF was stirred under nitrogen at 100° C. for 6 h. If starting material remains additional quantities of sodium azide and ammonium chloride are added until the reaction is complete by TLC. The reaction was diluted with water, made basic by the addition of 1 N NaOH and extracted multiple times with ethyl acetate. The combined organic extracts were acidified by the addition of 1 N HCl and then concentrated under reduced pressure. The residue was diluted with water and the solid that formed was collected by filtration and dried under reduced pressure to give the title compound (186 mg, 84%) as a white solid, mp75-78° C.
Reaction SMILES: C(OC[O:5][C:6]1[C:44]([CH:45]([CH3:47])[CH3:46])=[CH:43][CH:42]=[CH:41][C:7]=1[CH2:8][Si:9]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([CH:33]([CH3:35])[CH3:34])[C:28]=1[O:36]COCC)([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH:18]([CH3:20])[CH3:19])[C:13]=1[O:21]COCC)[CH3:10])C.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>C(O)(C)C>[OH:36][C:28]1[C:29]([CH:33]([CH3:35])[CH3:34])=[CH:30][CH:31]=[CH:32][C:27]=1[CH2:26][Si:9]([CH2:8][C:7]1[CH:41]=[CH:42][CH:43]=[C:44]([CH:45]([CH3:46])[CH3:47])[C:6]=1[OH:5])([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH:18]([CH3:20])[CH3:19])[C:13]=1[OH:21])[CH3:10]
Reactant: CCOCOc1c(C[Si](C)(Cc2cccc(C(C)C)c2OCOCC)Cc2cccc(C(C)C)c2OCOCC)cccc1C(C)C
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CC(C)O
Product: CC(C)c1cccc(C[Si](C)(Cc2cccc(C(C)C)c2O)Cc2cccc(C(C)C)c2O)c1O
Yield: 63 %

Procedure:
A solution of tris(2-(ethoxymethoxy)-3-isopropylbenzyl)(methyl)silane (IIIc) (1.01 g, 1.52 mmol) and pyridinium p-toluenesulfonate (0.24 g, 0.955 mmol) in isopropanol (17 mL) was heated at 70° C. for 11 h. The solvent was removed and the residue was purified by flash column chromatography (hexanes/ethyl acetate=5:1, v/v) to afford the title compound (0.47 g, 63%) as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:42]=[CH:41][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([O:16][CH2:17][C:18]4[CH:27]=[CH:26][C:25]5[C:20](=[CH:21][CH:22]=[N:23][CH:24]=5)[N:19]=4)=[CH:13][CH:14]=3)[C:9]([S:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[C:8]2[CH2:33][C:34]([CH3:40])([CH3:39])[C:35]([O:37]C)=[O:36])=[CH:4][CH:3]=1.CO.[Li+].[OH-].CC(O)=O>C1COCC1.O>[Cl:1][C:2]1[CH:42]=[CH:41][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([O:16][CH2:17][C:18]4[CH:27]=[CH:26][C:25]5[C:20](=[CH:21][CH:22]=[N:23][CH:24]=5)[N:19]=4)=[CH:13][CH:14]=3)[C:9]([S:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[C:8]2[CH2:33][C:34]([CH3:40])([CH3:39])[C:35]([OH:37])=[O:36])=[CH:4][CH:3]=1
Reactant: COC(=O)C(C)(C)Cc1c(SC(C)(C)C)c2cc(OCc3ccc4cnccc4n3)ccc2n1Cc1ccc(Cl)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CC(C)(C)Sc1c(CC(C)(C)C(=O)O)n(Cc2ccc(Cl)cc2)c2ccc(OCc3ccc4cnccc4n3)cc12
Temperature: 25 °C

Procedure:
The compound from Step 2 (280 mg) was hydrolyzed by dissolving it in THF (3 mL), MeOH (1.5 mL), and 2N LiOH (0.27 mL) and heating at 70° C. for 6 hours. The solution was cooled to room temperature, diluted with H2O (50 mL), acidified with glacial AcOH to pH 5 and then diluted with 25% aqueous NH4OAc (50 mL). The mixture was extracted with ethyl acetate (3×50 mL), washed with brine (50 mL), and dried (MgSO4). The solution was evaporated to dryness and coevaporated with toluene (50 mL) to provide the title acid as a white solid; m.p. 204° C. (dec.).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:23][CH3:24])=[C:6]([C@@:8]2([F:22])[C:16]3[C:11](=[CH:12][C:13]([C:17]([F:20])([F:19])[F:18])=[CH:14][CH:15]=3)[NH:10][C:9]2=[O:21])[CH:7]=1.[C:25]([O-])([O-])=[O:26].[K+].[K+].C=O.O>C1COCC1.C(OCC)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:23][CH3:24])=[C:6]([C@@:8]2([F:22])[C:16]3[C:11](=[CH:12][C:13]([C:17]([F:20])([F:19])[F:18])=[CH:14][CH:15]=3)[N:10]([CH2:25][OH:26])[C:9]2=[O:21])[CH:7]=1
Reactant: COc1ccc(Cl)cc1[C@]1(F)C(=O)Nc2cc(C(F)(F)F)ccc21
Reactant: O=C([O-])[O-]
Agent: C=O
Agent: [K+]
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(Cl)cc1[C@]1(F)C(=O)N(CO)c2cc(C(F)(F)F)ccc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a mixture of (S)-3-(5-chloro-2-methoxy-phenyl)-3-fluoro-6-trifluoromethyl-1,3-dihydro-indol-2-one ((S)-II; prepared as described in U.S. Pat. No. 5,808,095) (60.0 g, 0.167 mol) and K2CO3 (27.7 g, 0.20 mol) in THF (600 mL) was added formaldehyde (37% solution in H2O, 240 mL, 3.2 mol) followed by H2O (300 mL). The lightly turbid mixture was stirred at room temperature for 3 hours, and diluted with diethyl ether (1000 mL). The organic layer was separated. The aqueous layer was washed with ether (200 mL×2). The combined organic layer was washed with brine, dried over Na2SO4. Evaporation of solvents provided the title compound as a white dry foam (64.5 g, 99% yield). LC/MS m/e: 390 (MH+), 96% purity. 1H NMR (CDCl3): δ 7.79 (dd, J=1.0, 3.0 Hz, 1H) 7.34 (m, 3H), 7.24 (m, 1H), 6.75 (dd, J=1.5, 6.5 Hz, 1H), 5.45 (m, 1H), 5.28 (m, 1H), 3.50 (s, 3H).