Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]#[N:9])=[CH:6][C:5]2[C:10]3([CH2:29][O:30][C:4]=2[CH:3]=1)[C:18]1[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=1)[N:12](CC1C=CC(OC)=CC=1)[C:11]3=[O:28].COC1C(C#N)=CC2C3(COC=2C=1)C1C(=CC=CC=1)N(CC1C=CC(OC)=CC=1)C3=O>>[F:1][C:2]1[C:7]([C:8]#[N:9])=[CH:6][C:5]2[C:10]3([CH2:29][O:30][C:4]=2[CH:3]=1)[C:18]1[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=1)[NH:12][C:11]3=[O:28]
Reactant: COc1ccc(CN2C(=O)C3(COc4cc(F)c(C#N)cc43)c3ccccc32)cc1
Agent: COc1ccc(CN2C(=O)C3(COc4cc(OC)c(C#N)cc43)c3ccccc32)cc1
Product: N#Cc1cc2c(cc1F)OCC21C(=O)Nc2ccccc21

Procedure:
Following the procedure as described in EXAMPLE 3.29 and making non-critical variations using 6-fluoro-1′-(4-methoxybenzyl)-2′-oxo-1′,2′-dihydrospiro[1-benzofuran-3,3′-indole]-5-carbonitrile to replace of 6-methoxy-1′-(4-methoxybenzyl)-2′-oxo-1′,2′-dihydrospiro[1-benzofuran-3,3′-indole]-5-carbonitrile, 6-fluoro-2′-oxo-1′,2′-dihydrospiro[1-benzofuran-3,3′-indole]-5-carbonitrile was obtained (85%): mp 222-224° C.; 1H NMR (300 MHz, DMSO-d6) δ 10.70 (s, 1H), 7.40-7.38 (m, 1H), 7.28-7.23 (m, 2H), 7.17-7.15 (m, 1H), 6.99-6.90 (m, 2H), 4.91 (ABq, 2H); MS (ES+) m/z 280.9 (M+1).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:12]2[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:15][C:14]([CH2:23][NH:24][C:25](=O)OC(C)(C)C)=[CH:13]2)(=[O:11])=[O:10])=[CH:5][C:4]=1[F:32])#[N:2].C(OCC)(=O)C.[ClH:39]>>[ClH:39].[F:32][C:4]1[CH:5]=[C:6]([S:9]([N:12]2[CH:13]=[C:14]([CH2:23][NH:24][CH3:25])[CH:15]=[C:16]2[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)(=[O:11])=[O:10])[CH:7]=[CH:8][C:3]=1[C:1]#[N:2]
Reactant: CC(C)(C)OC(=O)NCc1cc(-c2ccccc2)n(S(=O)(=O)c2ccc(C#N)c(F)c2)c1
Agent: Cl
Solvent: CCOC(C)=O
Product: CNCc1cc(-c2ccccc2)n(S(=O)(=O)c2ccc(C#N)c(F)c2)c1
Yield: 14 %

Procedure:
Using tert-butyl ({1-[(4-cyano-3-fluorophenyl)sulfonyl]-5-phenyl-1H-pyrrol-3-yl}methyl)carbamate (54.7 mg) and 4 mol/L hydrogen chloride-ethyl acetate solution (4 mL), a procedure as in Example 30 was performed to give the title compound as a white solid (yield 6.9 mg, 14%).
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([O:14][CH3:15])=[O:13])[CH:10]=2)[NH:5][CH:4]=[CH:3]1.C(O)(=O)C.[I:20]N1C(=O)CCC1=O>O>[I:20][C:3]1[C:2](=[O:1])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([O:14][CH3:15])=[O:13])[CH:10]=2)[NH:5][CH:4]=1
Reactant: O=C1CCC(=O)N1I
Reactant: COC(=O)c1ccc2[nH]ccc(=O)c2c1
Solvent: O
Solvent: CC(=O)O
Product: COC(=O)c1ccc2[nH]cc(I)c(=O)c2c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 111.9 %

Procedure:
To a mixture of methyl 4-oxo-1,4-dihydroquinoline-6-carboxylate (1.1 g) and acetic acid (30 mL) was added N-iodosuccinimide (1.1 g), followed by stirring at room temperature for one day. The reaction mixture was diluted with water, and the precipitate was collected by filtration to obtain methyl 3-iodo-4-oxo-1,4-dihydroquinoline-6-carboxylate (1.8 g).
Reaction SMILES: Cl.[NH2:2][CH:3]1[CH2:26][C:7]2=[CH:8][N:9]([S:16]([C:19]3[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=3)(=[O:18])=[O:17])[C:10]3[CH:11]=[CH:12][C:13]([O:14][CH3:15])=[C:5]([C:6]=32)[C:4]1=[O:27].[F:28][C:29]([F:34])([F:33])[C:30](O)=[O:31].C(N(CC)CC)C>ClCCl>[CH3:15][O:14][C:13]1[CH:12]=[CH:11][C:10]2[N:9]([S:16]([C:19]3[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=3)(=[O:18])=[O:17])[CH:8]=[C:7]3[CH2:26][CH:3]([NH:2][C:30](=[O:31])[C:29]([F:34])([F:33])[F:28])[C:4](=[O:27])[C:5]=1[C:6]=23
Reactant: COc1ccc2c3c(cn2S(=O)(=O)c2ccc(C)cc2)CC(N)C(=O)c13
Reactant: O=C(O)C(F)(F)F
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc2c3c(cn2S(=O)(=O)c2ccc(C)cc2)CC(NC(=O)C(F)(F)F)C(=O)c13
Yield: 73.5 %

Procedure:
To a suspension of 4-amino-3,4-dihydro-6-methoxy-1-p-toluenesulfonylbenz[cd]indol-5(1H)-one hydrochloride (1.45 g, 3.50 mmol) in dichloromethane (30 ml) were added, while stirring under ice-cooling, anhydrous trifluoroacetic acid (0.61 ml, 4.27 mmol) and triethylamine (1.18 ml, 16.1 mmol). The mixture was stirred for 30 minutes as it was. After completion of the reaction, the reaction mixture was subjected to distillation under reduced pressure. The residue was shaken together with ethyl acetate (40 ml)-1N HCl (30 ml) to allow two layers to be formed. The organic layer was washed with an aqueous saline solution and dried (anhydrous Na2SO4). The solvent was distilled off under reduced pressure. The residue was recrystallized from ethyl acetate-n-hexane to afford the title compound (1.2 g, 73%, m.p.189°-190° C.)
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:9]([C:12]([F:15])([F:14])[F:13])=[CH:8][C:3]=1[CH2:4][NH:5][CH2:6][CH3:7].[CH3:16][N:17]=[C:18]=[O:19]>>[Br:1][C:2]1[CH:11]=[CH:10][C:9]([C:12]([F:13])([F:14])[F:15])=[CH:8][C:3]=1[CH2:4][N:5]([CH2:6][CH3:7])[C:18]([NH:17][CH3:16])=[O:19]
Reactant: CCNCc1cc(C(F)(F)F)ccc1Br
Reactant: CN=C=O
Product: CCN(Cc1cc(C(F)(F)F)ccc1Br)C(=O)NC

Procedure:
Prepared according to the procedure described in Example 95, Step 1, using the following starting materials: (2-bromo-5-trifluoromethyl-benzyl)-ethyl-amine and methyl isocyanate.
Reaction SMILES: Cl.C(OCC)(=O)C.[CH3:8][C:9]1[CH:14]=[C:13]([CH3:15])[CH:12]=[CH:11][C:10]=1[C:16]1[C:17]2[N:18]([C:23]([NH:28]C(=O)OC(C)(C)C)=[C:24]([CH2:26][CH3:27])[N:25]=2)[N:19]=[C:20]([CH3:22])[CH:21]=1.[OH-].[Na+]>C(OCC)(=O)C>[CH3:8][C:9]1[CH:14]=[C:13]([CH3:15])[CH:12]=[CH:11][C:10]=1[C:16]1[C:17]2[N:18]([C:23]([NH2:28])=[C:24]([CH2:26][CH3:27])[N:25]=2)[N:19]=[C:20]([CH3:22])[CH:21]=1
Reactant: CCc1nc2c(-c3ccc(C)cc3C)cc(C)nn2c1NC(=O)OC(C)(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: CCc1nc2c(-c3ccc(C)cc3C)cc(C)nn2c1N
Temperature: 25 °C
Reaction time: 14 h

Procedure:
4N hydrochloric acid/ethyl acetate (30 mL) was added to a solution of the resulting tert-butyl N-[8-(2,4-dimethylphenyl)-2-ethyl-6-methylimidazo[1,2-b]pyridazin-3-yl]carbamate in ethyl acetate (10 mL), and the mixture was stirred at room temperature for 14 hours. The mixture was neutralized by adding 5N aqueous sodium hydroxide solution under ice-cooling, which was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and evaporated, to give 8-(2,4-dimethylphenyl)-2-ethyl-6-methylimidazo[1,2-b]pyridazin-3-amine as a crude product.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=1)[CH2:12]O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CS([Cl:21])(=O)=O.C(N(CC)CC)C>ClCCl>[CH2:1]([O:8][C:9]1[CH:16]=[CH:15][CH:14]=[C:11]([CH2:12][Cl:21])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCc1cccc(OCc2ccccc2)c1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: ClCc1cccc(OCc2ccccc2)c1
Reaction time: 8 h
Yield: 67.5 %

Procedure:
To a solution of 3-benzyloxybenzyl alcohol (3.0 g, 14.0 mmol) in dichloromethane (30 mL) was added methanesulfonyl chloride (1.39 mL, 16.8 mmol) and triethylamine (2.34 mL, 16.8 mmol) on an ice bath, and the solution was stirred overnight. The reaction solution was diluted with dichloromethane, washed with aqueous solution of 5% sodium bicarbonate, and then, dried over anhydrous magnesium sulfate. The solvent was evaporated, then, the residue was purified by silica gel column chromatography (hexane:ethyl acetate=10:1), and 1-benzyloxy-3-chloromethyl-benzene (2.2 g, 67%) was obtained as a colorless oil.
Reaction SMILES: [C:1]([C:3]1[C:4]([CH3:23])=[CH:5][C:6]([O:20][CH2:21][CH3:22])=[C:7]([CH:19]=1)[C:8]([N:10]([CH3:18])[C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:9])#[N:2].N(C(C)(C)C#N)=NC(C)(C)C#N.[Br:36]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Br:36][CH2:23][C:4]1[C:3]([C:1]#[N:2])=[CH:19][C:7]([C:8]([N:10]([CH3:18])[C:11](=[O:17])[O:12][C:13]([CH3:15])([CH3:16])[CH3:14])=[O:9])=[C:6]([O:20][CH2:21][CH3:22])[CH:5]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOc1cc(C)c(C#N)cc1C(=O)N(C)C(=O)OC(C)(C)C
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: CCOc1cc(CBr)c(C#N)cc1C(=O)N(C)C(=O)OC(C)(C)C
Yield: 30 %

Procedure:
After dissolving tert-butyl N-(5-cyano-2-ethoxy-4-methylbenzoyl)-N-methylcarbamate (79.6 g) in carbon tetrachloride, azobisisobutyronitrile (4.1 g) was added and the mixture was heated to reflux. N-bromosuccinimide (50.3 g) was gradually added to the reaction mixture in small portions at a time. After heating to reflux for 2 hours, the mixture was filtered. The filtrate was concentrated and the residue was purified by silica gel column chromatography (solvent: n-hexane-ethyl acetate) to yield the title compound (29.81 g) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)[S:5][CH2:6][C:7](O)=[O:8].P(Cl)(Cl)Cl.[Cl-].[Al+3].[Cl-].[Cl-]>ClC1C=CC=CC=1>[Cl:1][C:2]1[CH:12]=[CH:11][C:10]2[C:7](=[O:8])[CH2:6][S:5][C:4]=2[CH:3]=1
Reactant: O=C(O)CSc1cccc(Cl)c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: Clc1ccccc1
Solvent: ClP(Cl)Cl
Product: O=C1CSc2cc(Cl)ccc21
Temperature: 100 °C
Reaction time: 2 h
Yield: 61.9 %

Procedure:
To a solution of m-chlorothiophenoxyacetic acid (5.00 g, 24.7 mmol) in chlorobenzene (25 ml) was added phosphorous trichloride (2.90 ml) at room temperature, and the reaction was allowed to proceed with vigorous stirring at 100° C. for 2 hours. After cooling to room temperature, anhydrous aluminum chloride (3.70 g, 27.7 mmol) was added thereto, and the reaction was allowed to proceed at room temperature for 30 minutes, followed by stirring at 100° C. for 1.5 hours. After cooling to room temperature, the reaction mixture was poured into ice-water and separated with a separatory funnel. The aqueous layer was extracted with toluene (150 ml×2). The combined organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was subjected to chromatography on silica gel to give 6-chloro-2,3-dihydro-benzothiofuran-3-one (2.83 g, 15.3 mmol; yield, 62%), m.p., 123.8° C.
Reaction SMILES: [C:1]12([C:11](Cl)=[O:12])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[F:14][C:15]([F:24])([F:23])[C:16]1[CH:17]=[C:18]([CH:20]=[CH:21][CH:22]=1)[NH2:19].C(N(CC)CC)C>C(Cl)Cl.CCCCCC>[F:14][C:15]([F:23])([F:24])[C:16]1[CH:17]=[C:18]([NH:19][C:11]([C:1]23[CH2:10][CH:5]4[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]4)[CH2:2]2)[CH2:8]3)=[O:12])[CH:20]=[CH:21][CH:22]=1
Reactant: O=C(Cl)C12CC3CC(CC(C3)C1)C2
Reactant: Nc1cccc(C(F)(F)F)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCCCCC
Product: O=C(Nc1cccc(C(F)(F)F)c1)C12CC3CC(CC(C3)C1)C2

Procedure:
Subject 2.0 g. of adamantane carboxylic acid chloride, 1.60 (10 mmoles) of m-trifluoromethylaniline and 5.0 ml. of triethylamine to the process of Example 11. Crystallize the residue obtained thereby from a methylene chloride-hexane mixture to obtain the title product, m.p. 171°-174°C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:32]=[CH:31][C:6]([CH2:7][N:8]([C:26]2[S:27][CH:28]=[CH:29][N:30]=2)[S:9]([C:12]2[CH:13]=[CH:14][C:15]3[NH:20][C:19](=O)[CH:18]([CH2:22][O:23][CH3:24])[O:17][C:16]=3[CH:25]=2)(=[O:11])=[O:10])=[CH:5][CH:4]=1.CSC>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]([C:26]2[S:27][CH:28]=[CH:29][N:30]=2)[S:9]([C:12]2[CH:13]=[CH:14][C:15]3[NH:20][CH2:19][CH:18]([CH2:22][O:23][CH3:24])[O:17][C:16]=3[CH:25]=2)(=[O:11])=[O:10])=[CH:31][CH:32]=1
Reactant: COCC1Oc2cc(S(=O)(=O)N(Cc3ccc(OC)cc3)c3nccs3)ccc2NC1=O
Solvent: CSC
Solvent: C1CCOC1
Product: COCC1CNc2ccc(S(=O)(=O)N(Cc3ccc(OC)cc3)c3nccs3)cc2O1
Temperature: 25 °C
Reaction time: 16 h
Yield: 72.2 %

Procedure:
To a solution of N-(4-methoxybenzyl)-2-(methoxymethyl)-3-oxo-N-(thiazol-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide (500 mg, 1.05 mmol) in THF (10 mL) was added BH3.DMS (0.15 mL, 1.57 mmol, Aldrich) at 0° C. The reaction mixture was stirred at ambient temperature for 16 h. After completion, the reaction mixture was quenched with methanol (7 mL) and was azeotroped with methanol (3×15 mL). The solvent was removed under reduced pressure and the crude material thus obtained was purified by column chromatography (silica: 100-200; elution: 30% ethyl acetate in hexane) to get pure N-(4-methoxybenzyl)-2-(methoxymethyl)-N-(thiazol-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide (350 mg, 71.6%) as a brown solid. m/z (ESI) 462.2 (M+H)+.
Reaction SMILES: [C:1]1([S:7](Cl)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:11][CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]([NH:23][CH2:24][CH2:25][CH2:26][N:27]2[CH:31]=[CH:30][N:29]=[CH:28]2)([CH3:22])[CH3:21])=[CH:16][CH:15]=1>ClCCl>[N:27]1([CH2:26][CH2:25][CH2:24][NH:23][C:20]([C:17]2[CH:18]=[CH:19][C:14]([CH2:13][CH2:12][NH:11][S:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)(=[O:9])=[O:8])=[CH:15][CH:16]=2)([CH3:22])[CH3:21])[CH:31]=[CH:30][N:29]=[CH:28]1
Reactant: CC(C)(NCCCn1ccnc1)c1ccc(CCN)cc1
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: ClCCl
Product: CC(C)(NCCCn1ccnc1)c1ccc(CCNS(=O)(=O)c2ccccc2)cc1
Temperature: 0 °C

Procedure:
A solution of benzenesulphonyl chloride (0.25 g) in dichloromethane (3 ml) was added dropwise to a solution of N-{1-[4-(2-aminoethyl)phenyl]-1-methylethyl}-3-(imidazol-1-yl)propylamine (0.4 g) in dichloromethane (7 ml) with stirring at 0° C. The mixture was treated in a similar manner to Example 55 to give N-[2-(4-{1-[3-(imidazol-1-yl)propylamino]-1-methylethyl}phenyl)ethyl]-benzenesulphonamide as an oil.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:11](=[C:12]([CH3:15])[C:13]=1[CH3:14])[O:10][CH2:9][C:6]1([CH2:8][CH2:7]1)[C:5]2=[O:16].[BH4-].[Na+]>CO>[CH3:14][C:13]1[C:12]([CH3:15])=[C:11]2[C:4]([CH:5]([OH:16])[C:6]3([CH2:9][O:10]2)[CH2:8][CH2:7]3)=[CH:3][C:2]=1[OH:1]
Reactant: Cc1c(O)cc2c(c1C)OCC1(CC1)C2=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Cc1c(O)cc2c(c1C)OCC1(CC1)C2O
Temperature: 25 °C
Reaction time: 2 h
Yield: 62.8 %

Procedure:
A mixture of 6-hydroxy-7,8-dimethyl-4H-spiro[chromene-3,1′-cyclopropan]-4-one (150 mg) and sodium borohydride (50 mg) in MeOH (15 mL) was stirred at room temperature for 2 h. After evaporation, the residue was applied to silica gel column eluting with 30-60% EtOAc in hexane to give 7,8-dimethyl-4H -spiro[chromene-3,1′-cyclopropane]-4,6-diol as an off-white solid (95 mg).
Reaction SMILES: F[C:2]1[C:7]([C:8]#[N:9])=[C:6]([F:10])[C:5]([C:11]#[N:12])=[C:4]([F:13])[C:3]=1[F:14].[CH:15]([OH:19])([CH2:17][CH3:18])[CH3:16]>C(#N)C>[F:10][C:6]1[C:5]([C:11]#[N:12])=[C:4]([F:13])[C:3]([F:14])=[C:2]([O:19][CH:15]([CH2:17][CH3:18])[CH3:16])[C:7]=1[C:8]#[N:9]
Reactant: CCC(C)O
Reactant: N#Cc1c(F)c(F)c(F)c(C#N)c1F
Solvent: CC#N
Product: CCC(C)Oc1c(F)c(F)c(C#N)c(F)c1C#N
Temperature: 25 °C
Reaction time: 24 h
Yield: 89 %

Procedure:
A 3.0 g amount of tetrafluoroisophthalonitrile and 1.26 g of 20 ml acetonitrile were dissolved in 20 ml of acetonitrile. A 1.66 g amount of sec-butanol was dropwise added to the mixture and the mixture was then stirred at room temperature for 24 hours. After the mixture was filtered, the filtrate was concentrated in vacuo and the concentrated liquid was poured into 50 ml of water. The mixture was extracted with carbon tetrachloride. After washing with water, the resultant mixture was dried with anhydrous magnesium sulfate and the solvent was then distilled off. Thus, 3.4 g (89% yield) of the desired compound No. 48 was obtained.
Reaction SMILES: FC(F)(F)S([O-])(=O)=O.[Br:9][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[NH:16][C:15](=[O:20])[C:14]([I+]C1C=CC=CC=1)=[C:13]2[OH:28].[NH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>C(Cl)Cl>[Br:9][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[NH:16][C:15](=[O:20])[C:14]([NH:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[C:13]2[OH:28]
Reactant: O=c1[nH]c2ccc(Br)cc2c(O)c1[I+]c1ccccc1
Reactant: Nc1ccccc1
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: ClCCl
Product: O=c1[nH]c2ccc(Br)cc2c(O)c1Nc1ccccc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of (6-bromo-4-hydroxy-2-oxo-1,2-dihydroquinolin-3-yl)(phenyl) iodoniumtrifluoromethane sulfonate (1.40 g, 2.36 mmol, Intermediate 11, step b) and aniline (1 mL) was stirred for 4 hours at room temperature. To this was added DCM and the resulting suspension was filtered. The solid was washed first with DCM followed by water and dried in the air and under vacuum at 50° C. to yield the title compound.
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[C:12]([F:15])([F:14])[F:13])[NH:5][CH:4]=[C:3]1[C:16]([OH:18])=O.[CH:19]12[N:25]([C:26]3[CH:32]=[CH:31][C:29]([NH2:30])=[C:28]([C:33]([F:36])([F:35])[F:34])[CH:27]=3)[CH:22]([CH2:23][CH2:24]1)[CH2:21][CH2:20]2.N1C=CC=CC=1>CC1CCCO1.C(OCC)(=O)C>[CH:22]12[N:25]([C:26]3[CH:32]=[CH:31][C:29]([NH:30][C:16]([C:3]4[C:2](=[O:1])[C:11]5[C:6](=[CH:7][CH:8]=[CH:9][C:10]=5[C:12]([F:13])([F:14])[F:15])[NH:5][CH:4]=4)=[O:18])=[C:28]([C:33]([F:36])([F:34])[F:35])[CH:27]=3)[CH:19]([CH2:20][CH2:21]1)[CH2:24][CH2:23]2
Reactant: Nc1ccc(N2C3CCC2CC3)cc1C(F)(F)F
Reactant: O=C(O)c1c[nH]c2cccc(C(F)(F)F)c2c1=O
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Solvent: CC1CCCO1
Product: O=C(Nc1ccc(N2C3CCC2CC3)cc1C(F)(F)F)c1c[nH]c2cccc(C(F)(F)F)c2c1=O
Temperature: 65 °C

Procedure:
To a solution of 4-oxo-5-(trifluoromethyl)-1H-quinoline-3-carboxylic acid (7) (9.1 g, 35.39 mmol) and 4-(7-azabicyclo[2.2.1]heptan-7-yl)-2-(trifluoromethyl)aniline (11A) (9.2 g, 35.74 mmol) in 2-methyltetrahydrofuran (91.00 mL) was added propyl phosphonic acid cyclic anhydride (T3P (50% solution in ethyl acetate), 52.68 mL, 88.48 mmol) and pyridine (5.6 g, 5.73 mL, 70.78 mmol) at room temperature. The reaction flask was heated at 65° C. for 10 h under a nitrogen atmosphere. After cooling to room temperature, the reaction mixture was then diluted with ethyl acetate and quenched with saturated Na2CO3 solution (50 mL). The layers were separated, and the aqueous layer was extracted twice more with ethyl acetate. The combined organic layers were washed with water, dried over Na2SO4, filtered and concentrated to a tan solid. The crude solid was slurried in a 2:1 mixture of ethyl acetate and diethyl ether, collected by vacuum filtration, and washed twice more with ethyl acetate/diethyl ether mixture to provide the crude product as a light yellow crystalline powder. The powder was dissolved in warm ethyl acetate and absorbed onto Celite. Purification by silica gel chromatography (0-50% ethyl acetate in dichloromethane) provided N-(4-(7-azabicyclo[2.2.1]heptan-7-yl)-2-(trifluoromethyl)phenyl)-4-oxo-5-(trifluoromethyl)-1,4-dihydroquinoline-3-carboxamide (Compound I) as a white crystalline solid in the solid form A. LC/MS m/z 496.0 [M+H]+, retention time 1.48 min (RP-C18, 10-99% CH3CN/0.05% TFA over 3 min). 1H NMR (400.0 MHz, DMSO-d6) δ 13.08 (s, 1H), 12.16 (s, 1H), 8.88 (s, 1H), 8.04 (dd, J=2.1, 7.4 Hz, 1H), 7.95-7.88 (m, 3H), 7.22 (dd, 2.5, 8.9 Hz, 1H), 7.16 (d, J=2.5 Hz, 1H), 4.33 (s, 2H), 1.67 (d, J=6.9 Hz, 4H), 1.44 (d, J=6.9 Hz, 4H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][N:6]=[C:5]2[Cl:13].[F:14][CH:15]([F:25])[O:16][C:17]1[CH:24]=[CH:23][CH:22]=[CH:21][C:18]=1[CH2:19][NH2:20].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.CC([O-])(C)C.[Na+]>CC(N(C)C)=O.CCOC(C)=O.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]>[Cl:13][C:5]1[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([NH:20][CH2:19][C:18]3[CH:21]=[CH:22][CH:23]=[CH:24][C:17]=3[O:16][CH:15]([F:14])[F:25])[CH:3]=2)[C:8](=[O:12])[NH:7][N:6]=1
Reactant: NCc1ccccc1OC(F)F
Reactant: O=c1[nH]nc(Cl)c2cc(Br)ccc12
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: O=c1[nH]nc(Cl)c2cc(NCc3ccccc3OC(F)F)ccc12
Yield: 6.9 %

Procedure:
A mixture 6-bromo-4-chloro-2H-phthalazin-1-one (150 mg, 0.578 mmol), 2-(difluoromethoxy)benzylamine (110 mg, 0.636 mmol), Pd2(dba)3 (47 mg, 0.051 mmol), rac-BINAP (108 mg, 0.173 mmol) and NaOtBu (139 mg, 1.445 mmol) in DMA (5 mL) was heated at 85° C. for 2 h. The mixture was allowed to cool, diluted with EtOAc and washed with water. The organic layer was washed with sat.aq. NaHCO3, brine and dried (Na2SO4). Chromatography on silica (EtOAc/hexanes) afforded 4-chloro-6-(2-difluoromethoxy-benzylamino)-2H-phthalazin-1-one (14 mg) as a yellow solid, 1H (400 MHz, d6-DMSO) δ: 4.43 (d, 2H), 6.81 (s, 1H), 7.14 (dd, 1H), 7.22 (m, 2H), 7.27 (t, 1H), 7.37 (m, 2H), 7.60 (t, 1H), 7.93 (d, 1H), 12.35 (s, 1H) ppm; m/z (M+1) 351.92.
Reaction SMILES: O[Li].O.O.[Cl:5][C:6]1[CH:7]=[C:8]2[C:13](=[C:14]([Cl:16])[CH:15]=1)[O:12][CH2:11][CH2:10][C:9]2([C:18]([O:20]C)=[O:19])[OH:17]>C1COCC1>[Cl:5][C:6]1[CH:7]=[C:8]2[C:13](=[C:14]([Cl:16])[CH:15]=1)[O:12][CH2:11][CH2:10][C:9]2([C:18]([OH:20])=[O:19])[OH:17]
Reactant: COC(=O)C1(O)CCOc2c(Cl)cc(Cl)cc21
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)C1(O)CCOc2c(Cl)cc(Cl)cc21

Procedure:
LiOH.H2O (0.15 g; 3.6 mmol) and water (2 mL) were added to a solution of 6,8-dichloro-4hydroxychroman-4yl-carboxylic acid, methyl ester (0.50 g; 1.8 mmol; from step (i) above) in THF (5 mL). The resultant mixture was stirred at room temperature for 30 min., THF was evaporated and the water phase was washed with methylene chloride. The reaction mixture was made acidic with HCl (2M) and extracted with methylene chloride. The organic layer was dried (Na2SO4) and evaporated, yielding the sub-title compound. Yield: 390 mg (83%).
Reaction SMILES: [CH2:1]([C:3]1[CH:19]=[CH:18][C:6]([O:7][C:8]2[CH:13]=[CH:12][C:11]([C:14](=O)[CH3:15])=[CH:10][C:9]=2[F:17])=[C:5]([OH:20])[CH:4]=1)[CH3:2].Cl.[CH3:22][O:23][NH2:24].C(N(CC)CC)C>C(O)C>[CH3:22][O:23]/[N:24]=[C:14](/[C:11]1[CH:12]=[CH:13][C:8]([O:7][C:6]2[CH:18]=[CH:19][C:3]([CH2:1][CH3:2])=[CH:4][C:5]=2[OH:20])=[C:9]([F:17])[CH:10]=1)\[CH3:15]
Reactant: CCc1ccc(Oc2ccc(C(C)=O)cc2F)c(O)c1
Reactant: CON
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCc1ccc(Oc2ccc(/C(C)=N/OC)cc2F)c(O)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 1-[4-(4-ethyl-2-hydroxyphenoxy)-3-fluorophenyl]ethanone (46 mg; 0.17 mmol), under argon, in ethanol (1 mL), was added O-methylhydroxylamine hydrochloride (14 mg; 0.17 mmol) and 0.05 mL of triethylamine. The reaction was stirred to room temperature overnight. The mixture was concentrated in vacuo to give the desired product as light brown oil after purification by preparative TLC (14.5 mg; 0.048 mmol; 28%).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]([NH2:11])[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH2:12][C:13]1[CH:14]=[N:15][C:16]([CH3:22])=[C:17]([OH:21])[C:18]=1[CH2:19][OH:20].[CH2:23](I)[CH3:24].C([O-])([O-])=O.[K+].[K+].CN(C=O)C>CCOC(C)=O>[Cl:1][C:2]1[N:10]=[C:9]([NH2:11])[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH2:12][C:13]1[CH:14]=[N:15][C:16]([CH3:22])=[C:17]([O:21][CH2:23][CH3:24])[C:18]=1[CH2:19][OH:20]
Reactant: Cc1ncc(Cn2cnc3c(Cl)nc(N)nc32)c(CO)c1O
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOc1c(C)ncc(Cn2cnc3c(Cl)nc(N)nc32)c1CO
Temperature: 50 °C

Procedure:
A mixture of 6-chloro-9-(5-hydroxy-4-hydroxymethyl-6-methyl-pyridin-3-ylmethyl)-9H-purin-2-ylamine (see previous example), EtI (excess), K2CO3 (excess) and DMF was heated to 50° C. for 15 min. Work-up (EtOAc), drying (MgSO4), evaporation, and purification by preparative TLC gave the title compound. HPLC Rt: 3.720 min. 1H-NMR (CDCl3) δ 8.27 (s, 1H), 7.90 (s, 1H), 5.40 (s, 2H), 5.11 (s, 2H), 4.85 (d, 2H), 4.50 (t, 1H), 3.95 (q, 2H), 2.51 (s, 3H), 1.45 (t, 3H).