Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C:10]([CH:15]([O:23][C:24]2[C:32]3[C:27](=[CH:28][CH:29]=[C:30]([F:33])[CH:31]=3)[NH:26][N:25]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[F:22])(C)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].FC1C=C2C(=CC=1)N(C1C=CC=CC=1F)N=C2O.C(OC(N1CCC[C@@H](COS(C)(=O)=O)C1)=O)(C)(C)C.C(=O)([O-])N.Cl>CCOC(C)=O.O1CCOCC1.CO>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([CH:15]([O:23][C:24]2[C:32]3[C:27](=[CH:28][CH:29]=[C:30]([F:33])[CH:31]=3)[NH:26][N:25]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[F:22])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCCC(C)(C(Oc2n[nH]c3ccc(F)cc23)c2ccccc2F)C1
Agent: CC(C)(C)OC(=O)N1CCC[C@@H](COS(C)(=O)=O)C1
Agent: Cl
Agent: NC(=O)[O-]
Solvent: C1COCCO1
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCCC(C(Oc2n[nH]c3ccc(F)cc23)c2ccccc2F)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3-[5-fluoro-1-(2-fluoro-phenyl)-1H-indazol-3-yloxymethyl]-piperidine-1-carboxylic acid tert-butyl ester was prepared according to the procedure for Intermediate 57 from Intermediate 23 (0.500 g, 2.03 mmol) and (R)-3-methanesulfonyloxymethyl-piperidine-1-carboxylic acid tert-butyl ester (0.655 g, 2.23 mmol). A room temperature stirred solution of carbamate in EtOAc (5.43 ml) was treated with 5.30 ml of a 4.0 M HCl solution in dioxane. The reaction was allowed to stir overnight at room temperature and was concentrated under reduced pressure, triturated with EtOAc and again concentrated under reduced pressure. This process was repeated three times. Recrystallization of the foam was attempted from hexanes/EtOAc and acetone/hexanes without success. The free base was formed by adding Dowex 550A (OH) Anion Exchange Resin to a stirred solution of the salt in MeOH (10 ml). The mixture was stirred for 30 minutes, filtered and the beads washed three times with 20 of methanol. The organic phase was concentrated under reduced pressure to yield 0.3628 g of the free base as a yellow oil. To a stirred solution of the oil in EtOAc (10 ml) was added maleic acid (0.111 g, 1.0 equivalents). A solid precipitated out and the mixture was concentrated under reduced pressure. The solid was triturated with hexanes/Et2O, filtered and washed with Et2O. The white solid was dried in the oven under reduced pressure at 80° C. overnight to yield 0.390 g (69.6%) of the title maleate salt.
Reaction SMILES: [C:1]1([CH:7]2[CH2:15][C:14]3[NH:13][CH:12]=[CH:11][C:10]=3[C:9](=O)[CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:17]([NH:20][NH2:21])([NH2:19])=[NH:18].[ClH:22].Cl.O>C(O)C>[ClH:22].[NH:20]([N:21]=[C:9]1[CH2:8][CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:15][C:14]2[NH:13][CH:12]=[CH:11][C:10]1=2)[C:17]([NH2:19])=[NH:18]
Reactant: O=C1CC(c2ccccc2)Cc2[nH]ccc21
Reactant: N=C(N)NN
Agent: Cl
Solvent: O
Solvent: CCO
Product: N=C(N)NN=C1CC(c2ccccc2)Cc2[nH]ccc21
Yield: 44.3 %

Procedure:
A mixture of 6-phenyl-4,5,6,7-tetrahydroindol-4-one (0.11 g), aminoguanidine hydrochloride (0.06 g), concentrated hydrochloric acid (0.026 ml), water (0.026 ml) and ethanol (10 ml) was refluxed for 20 minutes. Under reduced pressure, the solvent was evaporated, and the residue was dissolved in water. The solution was washed with diethylether, and to the mixture was added 1N sodium hydroxide solution. The mixture was extracted with ethyl acetate, and the organic layer was dried with magnesium sulfate. Under reduced pressure, the solvent was evaporated, and the residue was dissolved in ethanol. To the solution was added 4N hydrochloric acid, and the solvent was evaporated. The residue was recrystallized from ethanol to give 4-guanidinoimino-6-phenyl-4,5,6,7-tetrahydroindole hydrochloride (Compound 1) (70 mg) as colorless crystals.
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[CH2:7][CH2:6][C:5]([CH3:9])([CH3:8])[CH2:4][C:3]1=[O:10].[CH3:12][Li]>CCOCC>[CH3:12][C:3]1([OH:10])[CH2:4][C:5]([CH3:9])([CH3:8])[CH2:6][CH2:7][C:2]1([CH3:11])[CH3:1]
Reactant: [Li]C
Reactant: CC1(C)CCC(C)(C)C(=O)C1
Solvent: CCOCC
Product: CC1(C)CCC(C)(C)C(C)(O)C1
Temperature: 0 °C
Reaction time: 2.5 h

Procedure:
A solution of 26.4 g of 2,2,5,5-tetramethylcyclohexanone in 250 ml of ether is added dropwise at -20° C. to 102.8 ml of methyl lithium (2 molar in ether). After stirring at 0° C. for 2.5 hours, the mixture is poured into ice/1N hydrochloric acid and extracted with ether. The organic phase is washed with water, dried and evaporated. The residue is distilled in a water-jet vacuum. There are obtained 22.6 g of 1,2,2,5,5-pentamethylcyclohexanol as a colorless liquid, b.p. 81°-87° C./17 mm.
Reaction SMILES: [Li]CCCC.C(NC(C)C)(C)C.[F:13][C:14]1[N:19]=[CH:18][C:17]([C:20]23[CH2:27][CH2:26][CH2:25][N:24]2[CH2:23][CH2:22][CH2:21]3)=[CH:16][CH:15]=1.[Cl:28]C(Cl)(Cl)C(Cl)(Cl)Cl>C1COCC1>[Cl:28][C:15]1[CH:16]=[C:17]([C:20]23[CH2:27][CH2:26][CH2:25][N:24]2[CH2:23][CH2:22][CH2:21]3)[CH:18]=[N:19][C:14]=1[F:13]
Reactant: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Reactant: Fc1ccc(C23CCCN2CCC3)cn1
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: Fc1ncc(C23CCCN2CCC3)cc1Cl
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 33.4 %

Procedure:
n-BuLi (2.5M in hexanes, 0.232 mL, 0.58 mmol) was added to di-isopropylamine (0.077 mL, 0.58 mmol) in THF and stirred at room temperature for 15 minutes, then cooled to -78° C. 7a-(6-Fluoro-3-pyridinyl)-hexahydro-1H-pyrrolizine (115 mg, 0.56 mmol, from Example 12d) and hexachloroethane (400 mg, 1.7 mmol) were added. The mixture was slowly warmed to room temperature and stirred overnight. The reaction was quenched with 2N HCl, and the mixture was washed with Et2O. The aqueous layer was basified with 15% NaOH and extracted with methylene chloride. The organic extracts were combined, dried, (MgSO4) and concentrated. The residue was chromatographed (silica gel; CHCl3 /MeOH, 99:1) to afford the title compound as an oil (45 mg, 34%): 1H NMR (CDCl3, 300 MHz) δ1.60-1.72 (m, 2H), 1.80-2.06 (m, 6H), 2.64-2.72 (m, 2H), 3.14-3.27 (m, 2H), 8.00 (dd, J=8.8, 2.0 Hz, 1H), 8.15 (dd, J=2.0, 1.0 Hz, 1H); MS (CI/NH3) m/z: 241 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([NH:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]3[O:20][CH2:21][O:22][C:16]=3[CH:15]=2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:23]#[N:24])[CH:8]=2)[N:3]=1.[OH:25][CH:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1.CN(C)C=O.O>C(OCC)(=O)C>[OH:25][CH:26]1[CH2:31][CH2:30][N:29]([C:2]2[N:11]=[C:10]([NH:12][CH2:13][C:14]3[CH:19]=[CH:18][C:17]4[O:20][CH2:21][O:22][C:16]=4[CH:15]=3)[C:9]3[C:4](=[CH:5][CH:6]=[C:7]([C:23]#[N:24])[CH:8]=3)[N:3]=2)[CH2:28][CH2:27]1
Reactant: N#Cc1ccc2nc(Cl)nc(NCc3ccc4c(c3)OCO4)c2c1
Reactant: OC1CCNCC1
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1ccc2nc(N3CCC(O)CC3)nc(NCc3ccc4c(c3)OCO4)c2c1
Yield: 35.9 %

Procedure:
A mixture comprising 339 mg of 2-chloro-4-(3,4-methylenedioxybenzyl)amino-6-cyanoquinazoline, 500 mg of 4-hydroxypiperidine and 20 ml of N,N-dimethylformamide was heated under reflux for 5 hours and poured into 50 ml of water, followed by the addition of 50 ml of ethyl acetate. The obtained mixture was filtered to remove insolubles. The organic layer of the filtrate was dried over magnesium sulfate and concentrated under a reduced pressure to give a crystalline residue. This residue was washed with chloroform to give 145 mg of the title compound.
Reaction SMILES: [CH3:1][N:2]([CH3:6])[CH2:3][C:4]#[CH:5].[Br:7][C:8]1[CH:13]=[CH:12][C:11](I)=[CH:10][CH:9]=1>C(NC(C)C)(C)C.[Cu]I>[Br:7][C:8]1[CH:13]=[CH:12][C:11]([C:5]#[C:4][CH2:3][N:2]([CH3:6])[CH3:1])=[CH:10][CH:9]=1
Reactant: Brc1ccc(I)cc1
Reactant: C#CCN(C)C
Agent: [Cu]I
Solvent: CC(C)NC(C)C
Product: CN(C)CC#Cc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 0.83 h
Yield: 105.1 %

Procedure:
Copper(I) iodide (17.4 mg, 0.0913 mmol), 0.113 ml (1.06 mmol) of N,N-dimethylprop-2-yn-1-amine, and 67.8 mg (0.0966 mmol) of bistriphenyl phosphine palladium dichloride were added in that order to a solution of 280.8 mg (0.993 mmol) of 1-bromo-4-iodobenzene in diisopropylamine (2 ml), and the mixture was stirred at room temperature for 50 min. The reaction solution was filtered through Celite. The solvent was removed by distillation, and the residue was then purified by column chromatography on silica gel (hexane:ethyl acetate=2:1 to 0:100) to give 248.4 mg (yield 99%) of the title compound.
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([N:18]3[CH2:25][CH2:24][CH2:23][C@H:19]3[C:20]([OH:22])=O)=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[Cl:26][C:27]1[CH:28]=[CH:29][C:30]([N:35]2[CH:39]=[N:38][CH:37]=[N:36]2)=[C:31]([CH:34]=1)[CH2:32][NH2:33].C(Cl)CCl.C1C=NC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CN(C=O)C.O>[Cl:26][C:27]1[CH:28]=[CH:29][C:30]([N:35]2[CH:39]=[N:38][CH:37]=[N:36]2)=[C:31]([CH:34]=1)[CH2:32][NH:33][C:20](=[O:22])[C@@H:19]1[CH2:23][CH2:24][CH2:25][N:18]1[C:16]([O:15][CH2:14][CH:12]1[C:13]2[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=2[C:6]2[C:11]1=[CH:10][CH:9]=[CH:8][CH:7]=2)=[O:17]
Reactant: NCc1cc(Cl)ccc1-n1cncn1
Reactant: O=C(O)[C@@H]1CCCN1C(=O)OCC1c2ccccc2-c2ccccc21
Agent: On1nnc2cccnc21
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: O=C(NCc1cc(Cl)ccc1-n1cncn1)[C@@H]1CCCN1C(=O)OCC1c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of [(9H-fluoren-9-ylmethoxy)carbonyl]-L-proline (3.23 g, 9.59 mmol), 1-[5-chloro-2-(1H-1,2,4-triazol-1-yl)phenyl]methanamine (Example 4, 2.00 g, 9.59 mmol, 1.0 equiv), EDC (2.76 g, 14.38 mmol, 1.5 equiv) and HOAt (652 mg, 4.79 mmol, 0.5 equiv) in DMF (5 mL) was brought to pH 6 by dropwise addition of Hünig's Base and stirred at room temperature for 18 h. The reaction was diluted with water and extracted into EtOAc three times. The combined organic layers were dried (anhydrous Na2SO4) and concentrated. The resulting oil was suspended and rigorously stirred in water to afford the title compound as white solid upon filtration. 1H NMR (400 MHz, CD3OD): δ 8.77 (m, 1 H), 8.24–8.22 (m, 1 H), 7.81–7.75 (m, 2 H), 7.66–7.62 (m, 2 H), 7.54–7.50 (m, 1 H), 7.45–7.31 (m, 5 H), 7.25–7.19 (m, 1 H), 4.43–4.36 (m, 2 H), 4.30–4.20 (m, 3 H), 4.05–4.02 (m, 1 H), 3.55–3.40 (m, 2 H), 2.28–2.18 (m, 1 H), 1.91–1.88 (m, 3 H). LCMS (M+H): 528.0.
Reaction SMILES: [O:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[S:11](Cl)([C:14]1[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=1)(=[O:13])=[O:12]>>[S:11]([C:14]1[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=1)([OH:1])(=[O:13])=[O:12].[O:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: c1ccc2c(c1)CCCO2
Product: Cc1ccc(S(=O)(=O)O)cc1

Procedure:
In step 8, a ring closure is effected by treatment of diol s with palladium diacetate in the presence of 2[P(t-Bu)2]-1,1-binaphthyl, to afford chroman compound t. Chroman t is treated with tosyl chloride to form chroman tosylate u in step 9. In step 10, tosylate u is reacted with amine v to afford chroman w, which is a compound of formula I in accordance with the invention.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:11]2[S:10](=[O:13])(=[O:12])[N:9]=[C:8]([C:14]3[C:15](=[O:30])[N:16]([NH:25][CH2:26][CH:27]4[CH2:29][CH2:28]4)[C:17]4[C:22]([C:23]=3[OH:24])=[CH:21][CH:20]=[CH:19][CH:18]=4)[NH:7][C:6]=2[S:5][CH:4]=1.C(N(CC)CC)C.[CH2:38]([S:41](Cl)(=[O:43])=[O:42])[CH2:39][CH3:40]>CN(C)C=O>[CH:27]1([CH2:26][NH:25][N:16]2[C:17]3[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:23]([OH:24])=[C:14]([C:8]3[NH:7][C:6]4[S:5][CH:4]=[C:3]([CH2:2][NH:1][S:41]([CH2:38][CH2:39][CH3:40])(=[O:43])=[O:42])[C:11]=4[S:10](=[O:12])(=[O:13])[N:9]=3)[C:15]2=[O:30])[CH2:28][CH2:29]1
Reactant: CCCS(=O)(=O)Cl
Reactant: NCc1csc2c1S(=O)(=O)N=C(c1c(O)c3ccccc3n(NCC3CC3)c1=O)N2
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCCS(=O)(=O)NCc1csc2c1S(=O)(=O)N=C(c1c(O)c3ccccc3n(NCC3CC3)c1=O)N2
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 48 %

Procedure:
To a solution of the product of Example 353E (16.7 mg, 0.037 mmol) in N,N-dimethylformamide (0.4 mL) was added triethylamine (0.011 mL, 0.079 mmol). The mixture was cooled to 0° C. and 1-propane sulfonyl chloride was added (0.005 mL, 0.041 mmol). The mixture was warmed to 23° C. and stirred for 1.5 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by reverse phase chromatography, eluting with a gradient of 10% acetonitrile/0.1% trifluoroacetic acid in water to 95% acetonitrile/0.1% trifluoracetic acid in water to give the title compound (9.9 mg, 48%). 1H NMR (300 MHz, DMSO-d6) δ 0.15 (d, J=4.04 Hz, 2 H) 0.42 (d, J=7.35 Hz, 2 H) 0.99 (m, 4 H) 1.69 (m, 2 H) 2.84 (d, J=7.35 Hz, 2 H) 3.06 (m, 2 H) 4.27 (d, J=6.25 Hz, 2 H) 6.35 (bs, 1 H) 7.37 (s, 1 H) 7.42 (t, J=7.54 Hz, 2 H) 7.75 (t, J=6.07 Hz, 1 H) 7.87 (t, J=7.17 Hz, 1 H) 8.07 (d, J=8.46 Hz, 1 H) 8.15 (dd, 1 H) 14.52 (bs, 1 H).
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]1[C:9](=[O:10])[N:8]2[CH2:11][CH2:12][CH2:13][CH:14]([OH:15])[C:7]2=[N:6][C:5]=1[CH3:16].C(N(C(C)C)CC)(C)C.[F:26][C:27]1[CH:41]=[CH:40][C:30]2[C:31]([CH:34]3[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]3)=[N:32][O:33][C:29]=2[CH:28]=1>CO>[CH3:16][C:5]1[N:6]=[C:7]2[N:8]([CH2:11][CH2:12][CH2:13][CH:14]2[OH:15])[C:9](=[O:10])[C:4]=1[CH2:3][CH2:2][N:37]1[CH2:36][CH2:35][CH:34]([C:31]2[C:30]3[CH:40]=[CH:41][C:27]([F:26])=[CH:28][C:29]=3[O:33][N:32]=2)[CH2:39][CH2:38]1
Reactant: Cc1nc2n(c(=O)c1CCCl)CCCC2O
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: Cc1nc2n(c(=O)c1CCN1CCC(c3noc4cc(F)ccc34)CC1)CCCC2O
Temperature: 62.5 °C
Reaction time: 16 h

Procedure:
3-(2-chloroethyl)-9-hydroxy-2-methyl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-4-one (formula-7) (5.2 grams) and diisopropyl ethyl amine (12.56 grams) was added to 6-fluoro-3-(piperidin-4-yl)benzo[d]isoxazole (formula-8) (5.0 grams) in methanol (75 ml) taken in autoclave and then heated to 60-65° C., 0.8 Kg pressure was applied and stirred for 16 hours. The reaction mixture cooled and then distilled under reduced pressure. Isopropyl alcohol was added to the obtained residue and stirred for 15 minutes and then distilled off under reduced pressure to get the title compound. Added methanol and heated the reaction mixture to reflux temperature and stirred for 2.0 hrs at same temperature. Cooled the reaction mixture to 20° C. and stirred for 90 minutes at the same temperature. Filtered the solid precipitated. Washed the solid with chilled methanol and dried the compound.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH3:8])=[C:6]([C:9]2[CH:10]=[N:11][N:12]([CH:14]([O:16][CH2:17][CH3:18])[CH3:15])[CH:13]=2)[C:5]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[CH:20]=2)=[C:4]([C:26](=O)[CH3:27])[CH:3]=1.C([O-])(=O)C.[NH4+].C([BH3-])#[N:35].[Na+].O1CCCC1>CO.C(#N)C>[Cl:1][C:2]1[C:7]([CH3:8])=[C:6]([C:9]2[CH:10]=[N:11][N:12]([CH:14]([O:16][CH2:17][CH3:18])[CH3:15])[CH:13]=2)[C:5]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[CH:20]=2)=[C:4]([CH:26]([NH2:35])[CH3:27])[CH:3]=1
Reactant: CCOC(C)n1cc(-c2c(C)c(Cl)cc(C(C)=O)c2-c2cccc(F)c2)cn1
Reactant: [BH3-]C#N
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Solvent: CC#N
Product: CCOC(C)n1cc(-c2c(C)c(Cl)cc(C(C)N)c2-c2cccc(F)c2)cn1
Temperature: 25 °C

Procedure:
A mixture of 1-{4-chloro-6-[1-(1-ethoxyethyl)-1H-pyrazol-4-yl]-3′-fluoro-5-methylbiphenyl-2-yl}ethanone (37 mg, 0.092 mmol), ammonium acetate (71 mg, 0.92 mmol) and 1.0 M sodium cyanoborohydride in tetrahydrofuran (0.23 mL, 0.23 mmol) in methanol (0.5 mL) and acetonitrile (0.5 mL) was heated at 65° C. overnight. The mixture was cooled to room temperature, quenched with saturated sodium bicarbonate solution, extracted with dichloromethane. The combined organic layers were dried over MgSO4, filtered and concentrated to give the desired product (35 mg). LCMS calculated for C22H26ClFN3O (M+H)+: m/z=402.2. found: 402.2.
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:16]2[C:11](=[C:12]([F:17])[CH:13]=[CH:14][CH:15]=2)[N:10]=[CH:9][CH:8]=1)(=O)=O.[Li+].[Cl-].[CH2:22]([O:24]C([Sn](CCCC)(CCCC)CCCC)=C)[CH3:23].C([O-])(O)=O.[Na+]>O1CCOCC1.ClCCl.C1COCC1>[F:17][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:11]=1[N:10]=[CH:9][CH:8]=[C:7]2[C:22](=[O:24])[CH3:23]
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Reactant: O=S(=O)(Oc1ccnc2c(F)cccc12)C(F)(F)F
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Li+]
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: C1CCOC1
Product: CC(=O)c1ccnc2c(F)cccc12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
1.3 g (4.4 mmol) 8-fluorochinoline-4-yl trifluoromethane sulfonate, 153 mg tetrakistriphenylphosphine palladium and 600 mg LiCl were suspended in a baked flask under protective gas in 30 ml dioxane, 1.6 g (4.43 mmol) (1-ethoxyvinyl)-tributylstannane was added, the mixture was heated for 2 hours at reflux. The mixture was diluted with dichloromethane, was washed with water, was dried (MgSO4) and was concentrated. The residue thus obtained was dissolved in 30 ml THF and, following addition 2 ml 5N HCL, was stirred for 3 hours at room temperature. For workup, the mixture was adjusted with saturated NaHCO3 solution to pH 11, was extracted with dichloromethane, the combined organic phases were washed with saturated NaCl solution and were dried with MgSO4. Purification by chromatography on silica gel (dichloromethane) yielded 700 mg; ESI-MS [M+H+]=190.05.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([C:14]=1[CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:12][C:11]([F:21])=[CH:10][CH:9]=2)=[O:5])[CH3:2].Br[CH2:23][C:24]1[C:33]2[C:28](=[CH:29][CH:30]=[C:31]([F:34])[CH:32]=2)[CH:27]=[CH:26][CH:25]=1>>[CH2:1]([O:3][C:4]([C:6]1[N:7]([CH2:23][C:24]2[C:33]3[C:28](=[CH:29][CH:30]=[C:31]([F:34])[CH:32]=3)[CH:27]=[CH:26][CH:25]=2)[C:8]2[C:13]([C:14]=1[CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:12][C:11]([F:21])=[CH:10][CH:9]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)Cc1c(C(=O)OCC)[nH]c2ccc(F)cc12
Reactant: Fc1ccc2cccc(CBr)c2c1
Product: CCOC(=O)Cc1c(C(=O)OCC)n(Cc2cccc3ccc(F)cc23)c2ccc(F)cc12

Procedure:
Using general procedure B, 3-ethoxycarbonylmethyl-5-fluoro-1H-indole-2-carboxylic acid ethyl ester (Lit. 10) was coupled with 1-bromomethyl-7-fluoro-naphthalene (from Example 49.3.) to give 3-ethoxycarbonylmethyl-5-fluoro-1-(7-fluoro-naphthalen-1-ylmethyl)-1H-indole-2-carboxylic acid ethyl ester which was hydrolyzed as described in the general procedure B (Exp. 2.2) to give 3-carboxymethyl-5-fluoro-1-(7-fluoro-naphthalen-1-ylmethyl)-1H-indole-2-carboxylic acid as a white solid. MS: 394.1 ([M−H]−).
Reaction SMILES: C([O-])(=O)C.[Na+].[N+:6]([C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[CH:11]=[N:12][NH:13]2)([O-:8])=[O:7].C(Cl)(Cl)Cl.[Br:22]Br>C(O)(=O)C>[Br:22][C:11]1[C:10]2[C:14](=[CH:15][CH:16]=[CH:17][C:9]=2[N+:6]([O-:8])=[O:7])[NH:13][N:12]=1
Reactant: O=[N+]([O-])c1cccc2[nH]ncc12
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: O=[N+]([O-])c1cccc2[nH]nc(Br)c12
Reaction time: 2 h
Yield: 86.9 %

Procedure:
Sodium acetate (52.8 g, 644 mmol) and 4-nitro-1H-indazole (100 g, 613 mmol) were mixed with acetic acid (1000 mL) and chloroform (1000 mL) in a 5 L 4-neck flask with mechanical stirring. A solution of bromine (103 g, 644 mmol) in acetic acid (120 mL) was added over approximately 3.5 hours, while keeping the temperature below 21° C. After the addition was completed, the reaction mixture was stirred for an additional 2 hours. The reaction mixture was concentrated under reduced pressure. Water (2000 mL) was added to the residue. The yellow solids were collected by filtration and washed with water (3×1000 mL). The solids were air-dried on the filter and then under vacuum at 40° C. to give the desired product (129 g) as a yellow solid.
Reaction SMILES: [NH2:1][CH:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH2:3][OH:4].[NH+]1C=CC=CC=1.[F:17][C:18]([F:23])([F:22])[C:19]([CH3:21])=O.O>C1(C)C=CC=CC=1>[CH3:21][C:19]1([C:18]([F:23])([F:22])[F:17])[NH:1][CH:2]([C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH2:3][O:4]1
Reactant: NC(CO)c1ccccc1
Reactant: CC(=O)C(F)(F)F
Agent: c1cc[nH+]cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CC1(C(F)(F)F)NC(c2ccccc2)CO1
Temperature: 0 °C
Reaction time: 16 h

Procedure:
45 g (328.0 mmol) of rac-2-amino-2-phenylethanol and 8.24 g (32.8 mmol) of pyridinium p-toluolsulphonate were added to 55.13 g (492.0 mmol) of 1,1,1-trifluoroacetone in toluene (1.35 l). The reaction mixture was boiled under reflux on a water separator for 16 h. The mixture was cooled to 0° C. and the solid formed was filtered off and dried under high vacuum. This gave 68.6 g (77% of theory, purity 85%) of the target compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:19][OH:20])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=1.Cl[C:22]1[CH:32]=[C:26]2[N:27]([CH3:31])[CH2:28][CH2:29][CH2:30][N:25]2[C:24](=[O:33])[N:23]=1>>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:17])([F:18])[F:16])[CH:10]=1)[CH2:19][O:20][C:22]1[CH:32]=[C:26]2[N:27]([CH3:31])[CH2:28][CH2:29][CH2:30][N:25]2[C:24](=[O:33])[N:23]=1
Reactant: CN1CCCn2c1cc(Cl)nc2=O
Reactant: OCc1ccc(Oc2cccc(C(F)(F)F)c2)c(F)c1
Product: CN1CCCn2c1cc(OCc1ccc(Oc3cccc(C(F)(F)F)c3)c(F)c1)nc2=O

Procedure:
The title compound or its salt was prepared by a procedure similar to that described for E2 starting from (3-fluoro-4-(3-(trifluoromethyl)phenoxy)phenyl)methanol and 8-chloro-1-methyl-3,4-dihydro-1H-pyrimido[1,6-a]pyrimidin-6(2H)-one.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][CH:3]=1.[F:12][CH:13]1[CH2:17][CH2:16][NH:15][CH2:14]1>>[F:12][CH:13]1[CH2:17][CH2:16][N:15]([C:2]2[N:7]=[C:6]([CH3:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][CH:3]=2)[CH2:14]1
Reactant: Cc1nc(Cl)ccc1[N+](=O)[O-]
Reactant: FC1CCNC1
Product: Cc1nc(N2CCC(F)C2)ccc1[N+](=O)[O-]

Procedure:
The title compound was prepared from 6-chloro-2-methyl-3-nitropyridine and 3-fluoropyrrolidine following the method used to prepare Intermediate 51. LCMS (ES+) 226 (M+H)+, RT 2.847 minutes (method 1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[CH2:24][N:23]([CH3:25])[CH2:22][CH2:21][C:7]=3[N:8]([CH2:11][C:12]([C:15]3[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=3)(O)[CH3:13])[C:9]=2[CH:10]=1.[OH-].[K+]>O=S(Cl)Cl.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[CH2:24][N:23]([CH3:25])[CH2:22][CH2:21][C:7]=3[N:8](/[CH:11]=[C:12](/[C:15]3[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=3)\[CH3:13])[C:9]=2[CH:10]=1
Reactant: CN1CCc2c(c3ccc(Cl)cc3n2CC(C)(O)c2ccncc2)C1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: O=S(Cl)Cl
Product: C/C(=C\n1c2c(c3ccc(Cl)cc31)CN(C)CC2)c1ccncc1
Temperature: 100 °C

Procedure:
1-(7-Chloro-2-methyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)-2-(pyridin-4-yl)propan-2-ol (1 g, 2.8 mmol) in SOCl2 (10 mL) was stirred RT for 2 h. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in N-methyl-2-pyrrolidone (6 mL), KOH (1.5 g, 28 mmol) was added and heated at 100° C. for 2 h. The reaction mixture was cooled to RT, diluted with water and extracted with EtOAc. The organic layer was washed with water and concentrated and purified by silica gel chromatography, 100-200 mesh (eluent in 5% MeOH-DCM). 1H NMR (CD3OD, HCl salt) δ (ppm): 8.90 (d, 2H), 8.40 (d, 2H), 7.80 (s, 1H), 7.55 (d, 1H), 7.38 (s, 1H), 7.22 (d, 1H), 4.80 (d, 1H), 4.40 (d, 1H), 3.90 (m, 1H), 3.60 (m, 2H), 3.25 (m, 1H), 3.18 (s, 3H), 2.20 (s, 3H).
Reaction SMILES: [CH:1]([NH:4][C:5]([NH:7][C@H:8]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:9][C:10](O)=[O:11])=[O:6])([CH3:3])[CH3:2].S(Cl)(Cl)=O>C1(C)C=CC=CC=1.O>[CH:1]([N:4]1[C:10](=[O:11])[CH2:9][C@@H:8]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[NH:7][C:5]1=[O:6])([CH3:3])[CH3:2]
Reactant: CC(C)NC(=O)N[C@@H](CC(=O)O)c1ccccc1
Solvent: Cc1ccccc1
Solvent: O
Solvent: O=S(Cl)Cl
Product: CC(C)N1C(=O)C[C@@H](c2ccccc2)NC1=O

Procedure:
A solution of (S)-3-{[(isopropylamino)carbonyl]amino}-3-phenylpropanoic acid from Step A (465 mg, 1.86 mmol) and thionyl chloride (0.270 mL, 3.72 mmol) in toluene (19 mL) was heated at reflux for 1 h. The reaction mixture was cooled, diluted with water (25 mL), and extracted with CH2Cl2 (3×25 mL). The combined CH2Cl2 extracts were dried over Na2SO4, filtered, and concentrated in vacuo to provide the title compound. MS: m/z=233 (M+1).