Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH3:8])[CH:5]=[CH:4][N:3]=1.[Cl:9][C:10]1[S:14][C:13]([C:15](OCC)=[O:16])=[CH:12][CH:11]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].O>C1COCC1.ClCCl>[Cl:1][C:2]1[N:7]=[C:6]([CH2:8][C:15]([C:13]2[S:14][C:10]([Cl:9])=[CH:11][CH:12]=2)=[O:16])[CH:5]=[CH:4][N:3]=1
Reactant: Cc1ccnc(Cl)n1
Reactant: CCOC(=O)c1ccc(Cl)s1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Solvent: ClCCl
Product: O=C(Cc1ccnc(Cl)n1)c1ccc(Cl)s1
Temperature: 5 °C
Reaction time: 2 h
Yield: 83.9 %

Procedure:
To a solution of 2-chloro-4-methylpyrimidine (1 eq, 46.7 mmol) and ethyl 5-chlorothiophene-2-carboxylate (1.1 eq, 51.3 mmol) in anhydrous THF (50 mL) at 0° C., under N2 was added dropwise a solution of lithium bis(trimethylsilyl)amide (1 molar solution in hexanes, 2 eq, 93.3 mmol). The mixture was stirred 2 h at 5° C. Water was then added followed by 300 mL of dichloromethane. The organic layer was separated and the yellow precipitate was then filtered and dried to afford 10.7 g (84% yield) of 2-(2-chloropyrimidin-4-yl)-1-(5-chloro-2-thienyl)ethanone.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:29]2[N:34]=[CH:33][CH:32]=[CH:31][N:30]=2)=[C:6]([CH:28]=1)[C:7]([N:9]1[CH2:14][CH2:13][CH2:12][C@@H:11]([CH3:15])[C@H:10]1[CH2:16][N:17]1C(=O)C2C(=CC=CC=2)C1=O)=[O:8].NN.O>CO>[NH2:17][CH2:16][C@@H:10]1[C@H:11]([CH3:15])[CH2:12][CH2:13][CH2:14][N:9]1[C:7]([C:6]1[CH:28]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=1[C:29]1[N:30]=[CH:31][CH:32]=[CH:33][N:34]=1)=[O:8]
Reactant: C[C@@H]1CCCN(C(=O)c2cc(F)ccc2-c2ncccn2)[C@@H]1CN1C(=O)c2ccccc2C1=O
Agent: NN
Solvent: CO
Solvent: O
Product: C[C@@H]1CCCN(C(=O)c2cc(F)ccc2-c2ncccn2)[C@@H]1CN
Temperature: 25 °C
Yield: 93.9 %

Procedure:
A stirred solution of the product of Step 228b (274 mg, 0.590 mmol) and NH2NH2.H2O (114 mg, 2.27 mmol) in MeOH (10 mL) was heated to reflux for 2.5 h. After this time, the reaction mixture was cooled to rt then concentrated under reduced pressure. The resulting residue was triturated with a mixture of CH2Cl2/hexanes (1:1) and the solid was filtered off. The filtrate was concentrated under reduced pressure and dried under high vacuum to afford the title compound as a white foam (182 mg, 93%). ESI MS (M+H) 329.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][S:5]([NH:8][C:9]1[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][C:10]=1[CH3:19])(=[O:7])=[O:6].[K].CC(C)([O-])C.O>CN(C=O)C>[O:6]=[S:5]1(=[O:7])[CH2:4][CH2:3][CH2:2][N:8]1[C:9]1[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][C:10]=1[CH3:19]
Reactant: COC(=O)c1ccc(NS(=O)(=O)CCCCl)c(C)c1
Agent: CC(C)(C)[O-]
Agent: [K]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(N2CCCS2(=O)=O)c(C)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
370 mg (0.85 mmol) 70% methyl 4-(3-chloropropane-sulphonylamino)-3-methyl-benzoate dissolved in 26 ml DMF are combined with 275 mg (2.45 mmol) potassium-tert.-butoxide and stirred for 16 hours at ambient temperature. The reaction mixture is combined with water and extracted with ethyl acetate. The combined organic phases are dried over sodium sulphate, evaporated down i. vac. and the residue is purified by chromatography on silica gel (eluant: dichloromethane/isopropanol 98:2).
Reaction SMILES: [Si:1]([O:8][CH:9]1[C:22]2[C:13](=[CH:14][N:15]=[C:16]3[C:21]=2[CH:20]=[CH:19][C:18]([OH:23])=[CH:17]3)[CH2:12][CH2:11][CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[H-].[Na+].[CH3:26][C:27]([CH3:37])([CH3:36])[C:28](N1CCSC1=S)=[O:29].C(OCC)C>C1COCC1.C1C=CC=CC=1>[Si:1]([O:8][CH:9]1[C:22]2[C:13](=[CH:14][N:15]=[C:16]3[C:21]=2[CH:20]=[CH:19][C:18]([O:23][C:28](=[O:29])[C:27]([CH3:37])([CH3:36])[CH3:26])=[CH:17]3)[CH2:12][CH2:11][CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)C(=O)N1CCSC1=S
Reactant: CC(C)(C)[Si](C)(C)OC1CCCc2cnc3cc(O)ccc3c21
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: c1ccccc1
Product: CC(C)(C)C(=O)Oc1ccc2c3c(cnc2c1)CCCC3O[Si](C)(C)C(C)(C)C
Reaction time: 0.17 h
Yield: 99.1 %

Procedure:
To a suspension of Compound 141a (1.28 g, 3.88 mmol) in dry THF (50 mL) cooled in an ice-water bath was added NaH (60 percent, 163 mg, 4.08 mmol) followed by stirring for 10 minutes. A yellow-colored solution of Compound 226 (0.789 g, 3.88 mmol) in dry THF (10 mL) was added, and the mixture was then stirred at 25° C. for five minutes. The reaction mixture was quenched with water, extracted with ethyl acetate (50 mL), washed with brine, dried over anhydrous Na2SO4, and evaporated in vacuo to give a residue. Flash column chromatography of the residue (silica gel, 20 percent ethyl ether in benzene) provided Compound 142a (1.59 g, 99 percent): white powder; mp 125°-126.5° C.; Rf =0.49 (silica, 20 percent ethyl ether in benzene); IR (CHCl3) νmax 2957, 2934, 1750, 1261, 1131, 1116, 1027 cm-1 ; 1 H NMR (300 MHz, CDCl3) δ 8.58 (s, 1 H, H6), 7.98 (d, J=9.1 Hz, 1 H, H1), 7.67 (d, J=2.1 Hz, 1 H, H4), 7.21 (dd, J=9.1, 2.1 Hz, 1 H, H2), 5.33 (t, J=2.9 Hz, 1 H, H10), 2.90 (br dd, J=17.2, 3.3 Hz, 1 H, H7), 2.72 (ddd, J=17.2, 11.2, 5.7 Hz, 1 H, H7), 2.17-1.96 (m, 2 H, H8 or H9), 1.83-1.67 (m, 2 H, H8 or H9), 1.31 (s, 9 H, COC(CH3)3), 0.74 (s, 9 H, SiC(CH3)3), 0.12 (s, 6 H, Si(CH3)2); MS (FAB+) m/e (rel intensity) 414 (M+H, 100), 357 (9), 330 (12), 283 (5), 198 (10); HRMS for C24H36NO3Si (M+H), calcd 414.2464, found 414.2484. Anal. Calcd for C24H35NO3Si: C, 69.69; H, 8.53; N, 3.39. Found: C, 69.68; H, 8.44; N, 3.23.
Reaction SMILES: C(OC([N:11]1[CH2:15][CH:14]2[CH2:16][CH:17]([CH2:19][O:20][C:21]3[CH:30]=[C:29]4[C:24]([C:25]([O:31][C:32]5[CH:37]=[CH:36][C:35]([N+:38]([O-:40])=[O:39])=[CH:34][C:33]=5[F:41])=[CH:26][CH:27]=[N:28]4)=[CH:23][C:22]=3[O:42][CH3:43])[CH2:18][CH:13]2[CH2:12]1)=O)C1C=CC=CC=1.Br>C(O)(=O)C.CCOC(C)=O>[F:41][C:33]1[CH:34]=[C:35]([N+:38]([O-:40])=[O:39])[CH:36]=[CH:37][C:32]=1[O:31][C:25]1[C:24]2[C:29](=[CH:30][C:21]([O:20][CH2:19][CH:17]3[CH2:18][CH:13]4[CH2:12][NH:11][CH2:15][CH:14]4[CH2:16]3)=[C:22]([O:42][CH3:43])[CH:23]=2)[N:28]=[CH:27][CH:26]=1
Reactant: COc1cc2c(Oc3ccc([N+](=O)[O-])cc3F)ccnc2cc1OCC1CC2CN(C(=O)OCc3ccccc3)CC2C1
Agent: Br
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: COc1cc2c(Oc3ccc([N+](=O)[O-])cc3F)ccnc2cc1OCC1CC2CNCC2C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 113 %

Procedure:
To a round bottom flask equipped with a magnetic stir bar was added 5-[4-(2-Fluoro-4-nitro-phenoxy)-6-methoxy-quinolin-7-yloxymethyl]-hexahydrocyclopenta[c]pyrrole-2-carboxylic acid benzyl ester (2.5 g, 4.1 mmol, 1.0 eq), 33% HBr in acetic acid (5 ml) and acetic acid (5 ml). The mixture was stirred at room temperature for 1 hour and diluted with EtOAc to give a pale orange solid. The solid was filtered, washed with EtOAc and dried, giving 4-(2-Fluoro-4-nitro-phenoxy)-6-methoxy-7-(octahydro-cyclopenta[c]pyrrol-5-ylmethoxy)-quinoline (2.1 g, 95% yield). 1H NMR (400 MHz, CDCl3): 8.83 (d, 1H), 8.32 (m, 2H), 8.02 (s, 1H), 7.76 (t, 1H), 7.65 (s, 1H), 6.89 (d, 1H), 5.3 (d, 2H), 4.11 (m, 3H), 3.26 (m, 4H), 2.95 (m, 2H), 2.68 (m, 3H), 2.36 (m, 2H), 1.68 (m, 2H); MS (EI) for C24H24FN3O5: 454 (M+H+).
Reaction SMILES: [SH:1][C:2]1[S:3][C:4]([SH:7])=[N:5][N:6]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:15][C:16]1[CH:24]=[CH:23][C:19]([C:20]([OH:22])=[O:21])=[CH:18][CH:17]=1.Cl>O.CN(C)C=O>[SH:7][C:4]1[S:3][C:2]([S:1][CH2:15][C:16]2[CH:24]=[CH:23][C:19]([C:20]([OH:22])=[O:21])=[CH:18][CH:17]=2)=[N:6][N:5]=1
Reactant: Sc1nnc(S)s1
Reactant: O=C(O)c1ccc(CBr)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(O)c1ccc(CSc2nnc(S)s2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 30.2 %

Procedure:
To a mixture of 1.5 g of 2,5-dimercapto-1,3,4-thiadiazole, 2.76 g of anhydrous potassium carbonate and 10 ml of N,N-dimethylformamide was added 1 g of p-(bromomethyl)benzoic acid followed by stirring at room temperature for 3 hours. The reaction mixture was diluted with 30 ml of water, made acidic with diluted hydrochloric acid and, extracted with ethyl acetate. The extract was washed with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was applied to silica gel column chromatography. Elution with a mixture of toluene-ethyl acetate (1:1) gave 400 mg of p-[(5-mercapto-1,3,4-thiadiazol-2-yl)thiomethyl]benzoic acid.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]([N:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)[C:9]2[C:4](=[CH:5][C:6]([OH:17])=[CH:7][CH:8]=2)[N:3]=1.CC(C)([O-])C.[K+].[CH3:24][N:25]([CH3:30])[S:26](Cl)(=[O:28])=[O:27]>CN(C=O)C>[CH3:1][C:2]1[CH:11]=[C:10]([N:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)[C:9]2[C:4](=[CH:5][C:6]([O:17][S:26](=[O:28])(=[O:27])[N:25]([CH3:30])[CH3:24])=[CH:7][CH:8]=2)[N:3]=1
Reactant: Cc1cc(N2CCCC2)c2ccc(O)cc2n1
Reactant: CN(C)S(=O)(=O)Cl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(N2CCCC2)c2ccc(OS(=O)(=O)N(C)C)cc2n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 29.8 %

Procedure:
229.4 mg (1 mmol) of 2-methyl-4-pyrrolidin-1-yl-quinolin-7-ol, product of example 2, were suspended under an argon atmosphere in 20 ml of DMF, 0.6 g (1.2 mmol) of molecular sieves (4 nm) were added followed by 138 mg (1.2 mmol) of potassium tert-butoxide, and the mixture was stirred for 1 h at RT. It was then cooled to 0° C., treated with 0.13 ml (1.2 mmol) N,N-dimethylsulfamoyl chloride and stirred for 3 h at 0° C. The reaction mixture was partitioned between EtOAc and water, the aqueous layer was extracted twice with EtOAc, the combined organic layers were washed with water then with saturated NaCl solution, dried over magnesium sulphate and concentrated in vacuo. The residue was triturated with diethyl ether; the viscous oil obtained was filtered off by suction and dried in a high vacuum. Upon further triturating with heptane solid material was obtained which was dried in a high vacuum to give 100 mg (29.3%) of dimethyl-sulfamic acid 2-methyl-4-pyrrolidin-1-yl-quinolin-7-yl ester as an off-white solid. ISP mass spectrum, m/e: 336.2 (M+1 calculated for C16H21N3O3S: 336).
Reaction SMILES: [C:1]([C:6]1[S:14][C:13]2[C:12](=[O:15])[N:11]([C:16]3[CH:21]=[CH:20][C:19]([N:22]4[CH2:28][CH2:27][CH2:26][N:25]([CH3:29])[CH2:24][CH2:23]4)=[CH:18][CH:17]=3)[CH:10]=[N:9][C:8]=2[CH:7]=1)(=[O:5])[CH:2]([CH3:4])[CH3:3].[BH4-].[Na+]>>[OH:5][CH:1]([C:6]1[S:14][C:13]2[C:12](=[O:15])[N:11]([C:16]3[CH:17]=[CH:18][C:19]([N:22]4[CH2:28][CH2:27][CH2:26][N:25]([CH3:29])[CH2:24][CH2:23]4)=[CH:20][CH:21]=3)[CH:10]=[N:9][C:8]=2[CH:7]=1)[CH:2]([CH3:3])[CH3:4]
Reactant: CC(C)C(=O)c1cc2ncn(-c3ccc(N4CCCN(C)CC4)cc3)c(=O)c2s1
Agent: [BH4-]
Agent: [Na+]
Product: CC(C)C(O)c1cc2ncn(-c3ccc(N4CCCN(C)CC4)cc3)c(=O)c2s1

Procedure:
6-Isobutyryl-3-[4-(4-methyl[1,4]diazepan-1-yl)phenyl]-3H-thieno[3,2-d]pyrimidin-4-one and sodium borohydride were reacted by method Y. The product with the molecular weight of 412.56 (C22H28N4O2S) was obtained in this way; MS (ESI): 411 (M+H+).
Reaction SMILES: [F:1][C:2]([N:5]=[C:6]=[O:7])([F:4])[F:3].[C:8]1([NH:14][OH:15])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.CCCCC>C(OCC)C>[F:1][C:2]([F:4])([F:3])[NH:5][C:6]([N:14]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[OH:15])=[O:7]
Reactant: ONc1ccccc1
Reactant: O=C=NC(F)(F)F
Solvent: CCOCC
Solvent: CCCCC
Product: O=C(NC(F)(F)F)N(O)c1ccccc1
Reaction time: 1 h

Procedure:
A solution of trifluoromethyl isocyanate (11.1 grams, 0.1 mol) in diethyl ether (35 ml) is added dropwise, with stirring to a solution of N-phenyl hydroxylamine (10.9 grams; 0.1 mol) in ether (60 ml) at room temperature. Stirring is continued for a period of about 1 hour resulting in a precipitate. Pentane is added to the mixture to form additional precipitate. The precipitate is then recovered by filtration, is washed and dried to yield 1-trifluoromethyl-3-phenyl-3-hydroxyurea.
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[NH:13][C:14]([NH:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[NH:15])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:29][CH:30](Cl)[C:31]1[CH:36]=[CH:35][C:34]([CH3:37])=[CH:33][CH:32]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1>[C:1]1([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[NH:13][C:14]([NH:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)=[N:15][CH2:37][C:34]2[CH:35]=[CH:36][C:31]([CH2:30][Cl:29])=[CH:32][CH:33]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Cc1ccc(C(Cl)Cl)cc1
Reactant: N=C(Nc1ccccc1-c1ccccc1)Nc1ccccc1-c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: ClCc1ccc(CN=C(Nc2ccccc2-c2ccccc2)Nc2ccccc2-c2ccccc2)cc1
Yield: 20.6 %

Procedure:
10.9 g (0.03 mole) of N,N'-bis-(2-phenylphenyl) guanidine, 5.7 g (0.033 mole) of α,α-dichloro-p-xylene and 2.1 g (0.015 mole) of anhydrous potassium carbonate were added to 50 ml of toluene. The thus-formed mixture was then refluxed under heating for 10 hours. After the mixture had been allowed to cool, the insoluble substance was removed by filtration. The thus-obtained filtrate was washed with water and then concentrated for the purpose of recovering the solvent and unreacted raw materials to obtain a slightly brown powder. The powder was then recrystallized from acetone to obtain 3.1 g of white powder.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]3[CH:15]=[C:16]([NH2:20])[CH:17]=[CH:18][CH:19]=3)[N:9]=2)[CH:5]=[C:4]([C:21]2[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=2)[CH:3]=1.C(N(CC)CC)C.[N:38]1([S:44](Cl)(=[O:46])=[O:45])[CH2:43][CH2:42][O:41][CH2:40][CH2:39]1>ClCCl>[CH3:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]3[CH:15]=[C:16]([NH:20][S:44]([N:38]4[CH2:43][CH2:42][O:41][CH2:40][CH2:39]4)(=[O:46])=[O:45])[CH:17]=[CH:18][CH:19]=3)[N:9]=2)[CH:5]=[C:4]([C:21]2[CH:26]=[CH:25][C:24]([C:27]([F:28])([F:30])[F:29])=[CH:23][CH:22]=2)[CH:3]=1
Reactant: O=S(=O)(Cl)N1CCOCC1
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2cccc(-c3cccc(N)c3)n2)n1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2cccc(-c3cccc(NS(=O)(=O)N4CCOCC4)c3)n2)n1
Temperature: 23 °C
Reaction time: 0.5 h
Yield: 12.6 %

Procedure:
To a stirred solution of 3-[6′-methyl-4′-(4-trifluoromethyl-phenyl)-[2,2′]bipyridinyl-6-yl]-phenylamine (example 327) (0.200 g, 0.5 mmol) and triethyl amine (0.21 mL, 1.5 mmol) in dichloromethane (5 mL) was added commercially available morpholine-4-sulfonyl chloride (0.101 mg, 0.55 mmol) and the mixture was stirred at 23° C. for 30 min. Diluted with DCM, washed with sat. NaHCO3-sol. and water, dried the organic layer over Na2SO4. Removal of the solvent in vacuum left a crude product which was purified by silica gel column chromatography with heptane/EtOAc, followed by trituration with heptane/diethyl ether to give the title compound as an off-white solid (0.035 g, 13%). MS (ISP) 555.2 [(M+H)+]; mp 191° C.
Reaction SMILES: [CH3:1][O-:2].[Na+].[Cl:4][C:5]1[CH:14]=[C:13](Cl)[C:12]2[C:7](=[CH:8][C:9]([C:16]3[C:21]([C:22]([F:25])([F:24])[F:23])=[CH:20][CH:19]=[CH:18][N:17]=3)=[CH:10][CH:11]=2)[N:6]=1.O>C1COCC1>[Cl:4][C:5]1[CH:14]=[C:13]([O:2][CH3:1])[C:12]2[C:7](=[CH:8][C:9]([C:16]3[C:21]([C:22]([F:25])([F:24])[F:23])=[CH:20][CH:19]=[CH:18][N:17]=3)=[CH:10][CH:11]=2)[N:6]=1
Reactant: FC(F)(F)c1cccnc1-c1ccc2c(Cl)cc(Cl)nc2c1
Reactant: C[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(Cl)nc2cc(-c3ncccc3C(F)(F)F)ccc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Add sodium methoxide (4M, 1.1 mmol) to a solution of 2,4-dichloro-7-(3-trifluoromethyl-pyridin-2-yl)-quinoline (1.0 mmol) in THF (10 mL). Stir at room temperature for 1 hour, add water (15 mL) and extract with ethyl acetate. Wash the combined organic extracts with brine, dry (MgSO4) and evaporate. Purify the mixture of 2-chloro-4-methoxy-7-[3-(trifluoromethyl)pyridin-2-yl]quinoline and 4-chloro-2-methoxy-7-[3-(trifluoromethyl)pyridin-2-yl]quinoline by flash chromatography (elute with 1:2 hexane:ether) to give the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH:9]([OH:12])[CH2:10][CH3:11].[C:13](OCC)(=[O:15])C>>[Cl:8][C:4]1[C:3]2[CH:9]([CH2:10][CH3:11])[O:12][C:13](=[O:15])[NH:1][C:2]=2[CH:7]=[CH:6][CH:5]=1
Reactant: CCOC(C)=O
Reactant: CCC(O)c1c(N)cccc1Cl
Product: CCC1OC(=O)Nc2cccc(Cl)c21
Yield: 73 %

Procedure:
This compound was prepared using General Method 2 (EXAMPLE 1) from (±)-1-(2-amino-6-chlorophenyl)propan-1-ol (0.18 g, 0.94 mmol) to afford 0.14 g (73%) of (±)-5-chloro-4-ethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one after flash chromatography (4:1 hexanes:ethyl acetate).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([CH:17]([CH2:25][CH:26]([CH3:28])[CH3:27])[C:18]([CH3:24])([CH3:23])[C:19]([O:21]C)=[O:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[OH-].[Na+].CO>CS(C)=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([CH:17]([CH2:25][CH:26]([CH3:28])[CH3:27])[C:18]([CH3:23])([CH3:24])[C:19]([OH:21])=[O:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: COC(=O)C(C)(C)C(CC(C)C)c1ccc2c(cnn2-c2ccc(F)cc2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: CO
Product: CC(C)CC(c1ccc2c(cnn2-c2ccc(F)cc2)c1)C(C)(C)C(=O)O

Procedure:
Methyl 3-(1-(4-fluorophenyl)-1H-indazol-5-yl)-2,2,5-trimethylhexanoate (0.4 mmol) was dissolved in 5 mL of DMSO, 10 mL of 1 NaOH and 5 mL of MeOH and heated at 100° C. overnight. The reaction was quenched with sat. KH2PO4 and extracted with 2× EtOAc. The EtOAc extracts were dried over MgSO4, filtered, and concentrated by rotary evaporator to give 3-(1-(4-fluorophenyl)-1H-indazol-5-yl)-2,2,5-trimethylhexanoic acid. MS found: (M+H)+=369.
Reaction SMILES: [I-:1].[Na+].Cl[CH2:4][C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[CH:7][CH:6]=1>CC(C)=O>[I:1][CH2:4][C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[CH:7][CH:6]=1
Reactant: N#Cc1ccc(CCl)cc1
Reactant: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: N#Cc1ccc(CI)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 81.1 %

Procedure:
Sodium iodide (99 mg, 0.660 mmol) and 4-(chloromethyl)benzonitrile (100 mg, 0.660 mmol) were dissolved in Acetone (Volume: 2.199 mL) and allowed to stir at room temperature for 4 hours. The resulting solid was filtered and the filtrate concentrated to obtain 4-(iodomethyl)benzonitrile (130 mg, 0.535 mmol, 81% yield) as an orange oil. It was taken directly to the next step without characterization and purification. N-benzyl-1-(1H-indole-2-carbonyl)-N-methylpiperidine-4-carboxamide (100 mg, 0.266 mmol) was dissolved in 1.0 mL of DMF and added to a suspension of sodium hydride (12.78 mg, 0.320 mmol) in 2.0 of DMF. The reaction was stirred at 80° C. for 10 minutes before adding 4-(iodomethyl)benzonitrile (129 mg, 0.533 mmol) dissolved in 2.0 mL of DMF. The reaction was allowed to stir overnight. After 18 hours, the reaction was cooled to room temperature before diluting with water and ethyl acetate. The organic phase was washed with water followed by saturated sodium chloride, dried over magnesium sulfate, filtered and concentrated. The crude material was purified via column chromatography using 50% ethyl acetate/hexanes to 100% ethyl acetate. The purification provided product as a white solid. (Yield: 50 mg, white solid) 1H-NMR (400 MHz, DMSO-d6) 7.78-7.67, 7.66-7.57, 7.49, 7.43-7.01, 6.80-6.68, 5.65-5.51, 4.62, 4.54-3.83, 3.16-2.83, 2.75, 2.35-2.26, 1.80-1.24
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][C:8]([CH3:21])=[CH:9][CH2:10][CH2:11][C:12]1[CH2:17][CH2:16][CH:15]([C:18](O)=[O:19])[CH2:14][CH:13]=1>C1COCC1>[CH3:7][C:8]([CH3:21])=[CH:9][CH2:10][CH2:11][C:12]1[CH2:17][CH2:16][CH:15]([CH2:18][OH:19])[CH2:14][CH:13]=1
Reactant: CC(C)=CCCC1=CCC(C(=O)O)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)=CCCC1=CCC(CO)CC1
Temperature: 0 °C
Yield: 95.3 %

Procedure:
4-(4-methyl-3-pentenyl)-3-cyclohexen-1-methanol was synthesized as follows. An oven-dried refluxing condenser and an oven-dried 125 ml pressure-equalized addition funnel was attached to an oven-dried 500 ml 3-neck round-bottom flask. A magnetic stir bar was added, along with lithium aluminum hydride (LAH; 3.64 g or 96 mmol). Tetrahydrofuran (100 ml) was then added, and the suspension was cooled to 0° C. in an ice bath. A solution of 4-(4-methyl-3-pentenyl)-3-cyclohexen-1-carboxylic acid (10 g or 48 mmol) and THF (30 ml) was placed in the addition funnel, and the acid solution was added dropwise to the LAH suspension over a period of about 10 minutes. The residual acid in the addition funnel was washed into the LAH suspension with two further 10 ml aliquots of THF, the ice bath was removed, and the reaction was allowed to stir for at least 3 hours. After stirring, the reaction was again cooled to 0° C. and 18 ml water (5 ml water for each g LAH) was placed in the addition funnel. A further 50 ml THF was added to the reaction mixture to make the LAH suspension less viscous, and the evolved hydrogen gas was allowed to escape. The water was added dropwise to the LAH suspension over a period of about 30 minutes. The ice bath was then removed and the gray suspension was allowed to stir (approximately 3 hours) until the reaction turned white with no residual gray color. The reaction mixture was then acidified with 2M HCl (150 ml), extracted with a 1:1 (v/v) ethyl acetate:hexane mixture (shaken with saturated NaCl), dried over a mixture of anhydrous Na2SO4 and K2CO3, filtered, and rotary evaporated. Thin layer chromatography using 1:4 (v/v) ethyl acetate:hexane showed the product at Rf 0.17, with small impurity at Rf 0.0 and Rf 0.26. Removal of solvent, at 92°-95° C., 1 torr, gave 8.89 g (95%) of 4-(4-methyl-3-pentenyl)-3-cyclohexen-1-methanol, as a slightly yellow oil.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6]1[CH:11]=[CH:10][C:9]([CH:12]([C:15]([F:18])([F:17])[F:16])[CH2:13][OH:14])=[CH:8][CH:7]=1)[CH3:4].[F:19][C:20]1[CH:34]=[CH:33][C:23]([O:24][C:25]2[CH:26]=[C:27]([CH:30]=[CH:31][CH:32]=2)[CH2:28]Br)=[CH:22][CH:21]=1>CN(C=O)C>[F:19][C:20]1[CH:34]=[CH:33][C:23]([O:24][C:25]2[CH:26]=[C:27]([CH:30]=[CH:31][CH:32]=2)[CH2:28][O:14][CH2:13][CH:12]([C:9]2[CH:8]=[CH:7][C:6]([O:5][CH2:3][CH3:4])=[CH:11][CH:10]=2)[C:15]([F:16])([F:17])[F:18])=[CH:22][CH:21]=1
Reactant: Fc1ccc(Oc2cccc(CBr)c2)cc1
Reactant: CCOc1ccc(C(CO)C(F)(F)F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOc1ccc(C(COCc2cccc(Oc3ccc(F)cc3)c2)C(F)(F)F)cc1
Temperature: 25 °C
Yield: 77.9 %

Procedure:
Under a nitrogen atmosphere, 171 mg of sodium hydride (60% oil dispersion) was added to 15 ml of dry DMF. A solution of 1.0 g of 2-(4-ethoxyphenyl)-3,3,3-trifluoropropanol and 1.08 g of 3-(4-fluorophenoxy)-benzyl bromide in 20 ml of dry DMF was then added with ice-cooling, and the reaction solution was stirred with ice-cooling for 1 hour and at room temperature for 12 hours. Thereafter, the reaction mixture was poured into dilute HCl-ice water and extracted twice with diethyl ether. The ether layers were combined, washed with saturated sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was removed under a reduced pressure, and the residue was subjected to column chromatography on silica gel [eluted with n-hexane/ethyl acetate (25:1) mixture] to obtain 1.30 g of the desired compound.
Reaction SMILES: [F:1][C:2]1[C:3]([NH2:20])=[C:4]2[C:9]3=[C:10]([CH2:13][CH:14]([CH3:15])[N:8]3[CH:7]=[C:6]([C:16]([OH:18])=[O:17])[C:5]2=[O:19])[C:11]=1F.[NH:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1>CN1CCCC1=O>[F:1][C:2]1[C:3]([NH2:20])=[C:4]2[C:9]3=[C:10]([CH2:13][CH:14]([CH3:15])[N:8]3[CH:7]=[C:6]([C:16]([OH:18])=[O:17])[C:5]2=[O:19])[C:11]=1[N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1
Reactant: CC1Cc2c(F)c(F)c(N)c3c(=O)c(C(=O)O)cn1c23
Reactant: C1CNCCN1
Solvent: CN1CCCC1=O
Product: CC1Cc2c(N3CCNCC3)c(F)c(N)c3c(=O)c(C(=O)O)cn1c23
Yield: 56.6 %

Procedure:
In the same manner as described in Example 3, 8,9-difluoro-7-amino-2-methyl-6-oxo-1,2-dihydro-pyrrolo[3,2,1-ij]quinoline-5-carboxylic acid (3 g), anhydrous piperazine (4.6 g) and N-methylpyrrolidone (30 ml) are treated to give 8-fluoro-2-methyl-9-(1-piperazinyl)-7-amino-6-oxo-1,2-dihydro-pyrrolo[3,2,1-ij]quinoline-5-carboxylic acid (2.1 g), as pale yellow cubic crystals. m.p. 256°-259° C. (decomp.)