Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[Cl:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:13]1[CH:18]=[C:17](O)[N:16]=[C:15]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([CH3:26])[N:21]=2)[N:14]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1>[Cl:3][C:17]1[CH:18]=[C:13]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[Cl:6])[N:14]=[C:15]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([CH3:26])[N:21]=2)[N:16]=1
Reactant: Cc1cccc(-c2nc(O)cc(-c3ccccc3Cl)n2)n1
Reactant: O=P(Cl)(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Cc1cccc(-c2nc(Cl)cc(-c3ccccc3Cl)n2)n1
Yield: 86.6 %

Procedure:
Phosphoryl chloride (5 g) was added to the solution of 4-o-chlorophenyl-6-hydroxy-2-(6-methyl-2-pyridinyl)pyrimidine (5 g) in toluene (100 ml). The mixture was heated under reflux for 1 hour and left to stand to room temperature. Aqueous sodium carbonate solution was added thereto until the reaction solution became about pH 8 to be separated into two layers. Toluene layer was washed with water and dried over anhydrous magnesium sulfate. The toluene layer was concentrated under reduced pressure to obtain 4-chloro-6-o-chlorophenyl-2-(6-methyl-2-pyridinyl)pyrimidine (4.6 g).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[N:11]=[CH:10][CH:9]=[C:8]2[O:13][C:14]1[CH:22]=[CH:21][C:17]([C:18]([NH2:20])=[O:19])=[CH:16][CH:15]=1.[CH3:23][CH:24]([CH3:28])[CH2:25][CH:26]=O.[BH4-].[Na+]>CO.O>[CH3:23][CH:24]([CH3:28])[CH2:25][CH2:26][NH:1][CH2:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[N:11]=[CH:10][CH:9]=[C:8]2[O:13][C:14]1[CH:22]=[CH:21][C:17]([C:18]([NH2:20])=[O:19])=[CH:16][CH:15]=1
Reactant: CC(C)CC=O
Reactant: NCc1cccc2c(Oc3ccc(C(N)=O)cc3)ccnc12
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC(C)CCNCc1cccc2c(Oc3ccc(C(N)=O)cc3)ccnc12
Temperature: 50 °C

Procedure:
To a solution of 4-(8-aminomethylquinolin-4-yloxy)benzamide (23 mg, 0.08 mmol, Preparation 90) in MeOH (5 mL) was added 3-methylbutyraldehyde (8.5 μL, 0.08 mmol) and 4 Å molecular sieves (500 mg). The resulting mixture was heated to 50° C. for 16 h then cooled to rt and NaBH4 (6 mg, 0.16 mmol) was added. After 3 h a few drops of water were added, the mixture filtered and washed with MeOH. Solvent was removed in vacuo and the residue purified by column chromatography (0.25% NH4OH(aq), 5% MeOH in DCM) to give the title compound: RT=2.65 min; m/z (ES+)=364.2 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:12]([Cl:13])=[C:11]([C:14]2[CH:19]([CH2:20][CH3:21])[CH2:18][CH2:17][C:16](=O)[CH:15]=2)[CH:10]=[CH:9][C:3]=1[O:4][CH2:5][C:6]([OH:8])=[O:7].Cl.[NH2:24][OH:25].Cl>N1C=CC=CC=1>[Cl:1][C:2]1[C:12]([Cl:13])=[C:11]([C:14]2[CH:19]([CH2:20][CH3:21])[CH2:18][CH2:17][C:16](=[N:24][OH:25])[CH:15]=2)[CH:10]=[CH:9][C:3]=1[O:4][CH2:5][C:6]([OH:8])=[O:7]
Reactant: NO
Reactant: CCC1CCC(=O)C=C1c1ccc(OCC(=O)O)c(Cl)c1Cl
Agent: Cl
Solvent: c1ccncc1
Product: CCC1CCC(=NO)C=C1c1ccc(OCC(=O)O)c(Cl)c1Cl
Temperature: 95 °C

Procedure:
A mixture of [2,3-dichloro-4-(6-ethyl-3-oxo-1-cyclohexen-1-yl)phenoxy]acetic acid (3.4 g, 0.01 mole), hydroxylamine hydrochloride (2.1 g, 0.03 mole) and pyridine (40 ml) were heated at 95° C. for 40 hours, poured into ice-water and hydrochloric acid, extracted with ether, washed with water, dried over magnesium sulfate and evaporated in vacuo. After recrystallization from toluene (120 ml) the [2,3-dichloro-4-(6-ethyl-3-(hydroxyimino)-1-cyclohexen-1-yl)-phenoxy]acetic acid hemitoluene solvate melted at 88°-90° C.
Reaction SMILES: [OH:1][C:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[S:5](=[O:13])(=[O:12])[N:4]([CH3:14])[C:3]=1[C:15]([NH:17][CH2:18][CH3:19])=[O:16].NC1C=[N:25][CH:24]=[C:23]([Cl:27])[N:22]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>>[Cl:27][C:23]1[N:22]=[C:18]([NH:17][C:15]([C:3]2[N:4]([CH3:14])[S:5](=[O:12])(=[O:13])[C:6]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[C:2]=2[OH:1])=[O:16])[CH:19]=[N:25][CH:24]=1
Reactant: CCNC(=O)C1=C(O)c2ccccc2S(=O)(=O)N1C
Reactant: Nc1cncc(Cl)n1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: CN1C(C(=O)Nc2cncc(Cl)n2)=C(O)c2ccccc2S1(=O)=O

Procedure:
This compound was prepared from 4-hydroxy-2-methyl-N-ethyl-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide, 2-amino-6-chloro-pyrazine and p-toluenesulfonic acid analogous to Example 14.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([NH2:19])[CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:20][C:21]([CH3:26])=[CH:22][C:23](Cl)=[O:24]>N1C=CC=CC=1.CCOCC>[Br:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([NH:19][C:23](=[O:24])[CH:22]=[C:21]([CH3:26])[CH3:20])[CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Nc1ccc2ncnc(Nc3cccc(Br)c3)c2c1
Reactant: CC(C)=CC(=O)Cl
Solvent: c1ccncc1
Solvent: CCOCC
Product: CC(C)=CC(=O)Nc1ccc2ncnc(Nc3cccc(Br)c3)c2c1

Procedure:
A solution of 1.58 g of N-(3-bromophenyl)-4,6-quinazolindiamine in 15 ml of pyridine was cooled in an ice bath and a solution of 0.67 ml of 3,3-dimethylacryloyl chloride in 7 ml of ether was added dropwise. After stirring and cooling for 2 hours, the solvents were removed at reduced pressure. The residue was treated with water and the resulting solid was recrystallized from methyl cellusolve to give 0.97 g of N-[4-[(3-bromophenyl)amino]-6-quinazolinyl]-3-methyl-2-butenamide: mp=300-301° C., mass spectrum (m/e): 396, 398.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][CH2:11][CH2:10][CH2:9]2)[N:5]=[C:4]([N:13]2[C:18]([CH3:20])([CH3:19])[CH2:17][CH2:16][CH2:15][C:14]2([CH3:22])[CH3:21])[N:3]=1.[NH:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1>>[CH3:20][C:18]1([CH3:19])[CH2:17][CH2:16][CH2:15][C:14]([CH3:21])([CH3:22])[N:13]1[C:4]1[N:3]=[C:2]([N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)[CH:7]=[C:6]([N:8]2[CH2:9][CH2:10][CH2:11][CH2:12]2)[N:5]=1
Reactant: CC1(C)CCCC(C)(C)N1c1nc(Cl)cc(N2CCCC2)n1
Reactant: C1CNCCN1
Product: CC1(C)CCCC(C)(C)N1c1nc(N2CCCC2)cc(N2CCNCC2)n1
Yield: 80.2 %

Procedure:
4-Chloro-2-(2,2,6,6-tetramethyl-1-piperidinyl)-6-pyrrolidinopyrimidine is reacted with piperazine as described in Example 42 to give the title compound in a yield of 80.2%, m.p.: 134°-137° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.[C:9]([O:13][C:14]([N:16]1[CH2:20][C@H:19](O)[CH2:18][C@H:17]1[C:22]([N:24]1[CH2:30][CH2:29][CH2:28][N:27]([CH:31]2[CH2:34][CH2:33][CH2:32]2)[CH2:26][CH2:25]1)=[O:23])=[O:15])([CH3:12])([CH3:11])[CH3:10].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[C:9]([O:13][C:14]([N:16]1[CH2:20][CH:19]([O:8][C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=2)[CH2:18][C@H:17]1[C:22]([N:24]1[CH2:30][CH2:29][CH2:28][N:27]([CH:31]2[CH2:32][CH2:33][CH2:34]2)[CH2:26][CH2:25]1)=[O:23])=[O:15])([CH3:12])([CH3:10])[CH3:11]
Reactant: Oc1cccc(F)c1
Reactant: CC(C)(C)OC(=O)N1C[C@H](O)C[C@H]1C(=O)N1CCCN(C2CCC2)CC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC(Oc2cccc(F)c2)C[C@H]1C(=O)N1CCCN(C2CCC2)CC1

Procedure:
Reaction of 3-fluorophenol and (2S,4R)-2-(4-cyclobutyl-[1,4]diazepane-1-carbonyl)-4-hydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester was performed as described in Example 11, using resin bound triphenylphosphine and CH2Cl2 to give the title compound as a mixture of diastereomers (89:11), as determined by chiral SFC. MS (ESI): mass calcd. for C25H36FN3O4, 461.27; m/z found, 462.3 [M+H]+. 1H NMR (CDCl3): 7.25-7.16 (m, 1H), 6.69-6.53 (m, 3H), 5.01-4.69 (m, 2H), 3.89-3.42 (m, 6H), 2.92-2.79 (m, 1H), 2.69-2.20 (m, 6H), 2.06-1.72 (m, 6H), 1.71-1.53 (m, 2H), 1.44-1.39 (m, 9H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:17]=[C:16]3[N:10]([CH2:11][CH2:12][C:13]4[CH:29]=[CH:28][CH:27]=[CH:26][C:14]=4[CH:15]3[O:18][CH:19]3[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]3)[CH:9]=2)=[CH:4][CH:3]=1.[Cl:30]N1C(=O)CCC1=O.CCOC(C)=O.[OH-].[Na+]>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:17]=[C:16]3[N:10]([CH2:11][CH2:12][C:13]4[CH:29]=[CH:28][CH:27]=[CH:26][C:14]=4[CH:15]3[O:18][CH:19]3[CH2:20][CH2:21][N:22]([CH3:25])[CH2:23][CH2:24]3)[C:9]=2[Cl:30])=[CH:6][CH:7]=1
Reactant: CN1CCC(OC2c3ccccc3CCn3cc(-c4ccc(Br)cc4)nc32)CC1
Reactant: O=C1CCC(=O)N1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CN1CCC(OC2c3ccccc3CCn3c2nc(-c2ccc(Br)cc2)c3Cl)CC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 2-(4-bromophenyl)-4-(1-methylpiperidin-4-yloxy)-9,10-dihydro-4H-3,10a-diaza-benzo[f]azulene (example 81A) (140 mg, 0.31 mmole) in CH2Cl2 (7 mL) cooled at 0° C. is added N-chlorosuccinimide (41 mg, 0.31 mmole). The reaction mixture is stirred at 0° C. for 1 h then is allowed to reach room temperature. Another portion of N-chlorosuccinimide (60 mg) is added. After 1 hour at room temperature, AcOEt is added and the reaction mixture is basified to pH 10 with 1N NaOH solution. The organic phase is washed with water, dried over magnesium sulphate, filtered and the solvent is removed under reduced pressure. The residue is purified by silica gel chromatography using (CH2Cl2:MeOH) with a gradient from (100:0) to (90:10) to give 2-(4-bromophenyl)-1-chloro-4-(1-methylpiperidin-4-yloxy)-9,10-dihydro-4H-3,10a-diaza-benzo[f]azulene melting at 169° C.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:10][CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]([NH:22][CH2:23][CH2:24][CH2:25][N:26]2[CH:30]=[CH:29][N:28]=[CH:27]2)([CH3:21])[CH3:20])=[CH:15][CH:14]=1>ClCCl>[N:26]1([CH2:25][CH2:24][CH2:23][NH:22][C:19]([C:16]2[CH:17]=[CH:18][C:13]([CH2:12][CH2:11][NH:10][C:1](=[O:8])[C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[CH:14][CH:15]=2)([CH3:21])[CH3:20])[CH:30]=[CH:29][N:28]=[CH:27]1
Reactant: CC(C)(NCCCn1ccnc1)c1ccc(CCN)cc1
Reactant: O=C(Cl)c1ccccc1
Solvent: ClCCl
Product: CC(C)(NCCCn1ccnc1)c1ccc(CCNC(=O)c2ccccc2)cc1
Temperature: 0 °C

Procedure:
A solution of benzoyl chloride (0.2 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]benzamide as an oil.
Reaction SMILES: [CH3:1][S:2]([CH3:5])(=[O:4])=[O:3].C([Li])CCC.[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2([C:22]#[N:23])[CH2:21][CH2:20][CH2:19]2)=[CH:14][CH:13]=1.O>O1CCCC1>[Cl:11][C:12]1[CH:13]=[CH:14][C:15]([C:18]2([C:22]([NH2:23])=[CH:1][S:2]([CH3:5])(=[O:4])=[O:3])[CH2:21][CH2:20][CH2:19]2)=[CH:16][CH:17]=1
Reactant: CS(C)(=O)=O
Reactant: N#CC1(c2ccc(Cl)cc2)CCC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: CS(=O)(=O)C=C(N)C1(c2ccc(Cl)cc2)CCC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of dimethylsulphone (8.3 g), in dry tetrahydrofuran (150 ml) was added dropwise to a stirred ice-cold solution of butyllithium (30 ml of 2.6M solution in hexane). The mixture was stirred at room temperature for 15 minutes and then a solution of 1-(4-chlorophenyl)cyclobutanecarbonitrile (15 g) in tetrahydrofuran (25 ml) was added over 15 minutes and the resulting solution was heated under reflux for 16 hours. The solution was cooled and treated with water and the organic layer separated. The aqueous layer was extracted with ether and the ether extracts combined with the previously separated organic layer, dried and the solvents were removed by evaporation. The resulting oil crystallised, and the solid was washed with petroleum ether (b.p. 40°-60° C.) to give 1-[1-(4-chlorophenyl)cyclobutyl]-2-methylsulphonylvinylamine (m.p. 125°-126° ).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][OH:4].[Li+].CC([N-]C(C)C)C.F[C:14]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=1[N+:21]([O-:23])=[O:22]>C1COCC1.O>[Cl:1][CH2:2][CH2:3][O:4][C:14]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=1[N+:21]([O-:23])=[O:22]
Reactant: OCCCl
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc(F)cc1OCCCl
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 91 %

Procedure:
In a round bottom flask under nitrogen, 2-chloro-ethanol (8.3 mL, 120 mmoles) in THF (40 mL) was cooled to 0° C. LDA (60 mL, 120 mmoles) was added dropwise, while maintaining the temperature constant at 0° C. The mixture was stirred at this temperature for 15 minutes, followed by the addition of 2,4-difluoronitrobenzene (11 mL, 100 mmoles). The mixture was stirred at room temperature overnight. Reaction mixture was diluted with water, extracted with EtOAc, washed with brine (1×), dried over Na2SO4, and concentrated under vacuum, to afford the title compound as an off-white solid (20.0 g, 91 mmoles).
Reaction SMILES: C(O)CC.Cl.[CH3:6][O:7][NH2:8].[CH3:9][C:10]1[CH:14]=[C:13]([C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[CH2:23][O:24][C:25]2[CH:30]=[C:29]([CH3:31])[CH:28]=[CH:27][C:26]=2[CH3:32])=O)[O:12][N:11]=1>O>[CH3:6][O:7][N:8]=[C:15]([C:13]1[O:12][N:11]=[C:10]([CH3:9])[CH:14]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH2:23][O:24][C:25]1[CH:30]=[C:29]([CH3:31])[CH:28]=[CH:27][C:26]=1[CH3:32]
Reactant: Cc1ccc(C)c(OCc2ccccc2C(=O)c2cc(C)no2)c1
Reactant: CON
Agent: Cl
Solvent: O
Solvent: CCCO
Product: CON=C(c1cc(C)no1)c1ccccc1COc1cc(C)ccc1C
Yield: 42.8 %

Procedure:
n-Propanol (2 ml) and methoxyamine hydrochloride (0.25 g, 3 mmol) were added to 2-(2,5-dimethylphenoxymethyl)phenyl 3-methylisoxazol-5-yl ketone (0.33 g, 1 mmol), and the mixture was stirred under reflux for 15 hours. After completion of the reaction, water (200 ml) was added, the mixture was extracted with dichloromethane. The dichloromethane layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure, and the residue was purified by silica gel chromatography (ethyl acetate/n-hexane) to give isomer A (0.18 g, 51.4%, as colorless crystals) and isomer B (0.15 g, 42.8%, as colorless crystals) of 2-(2,5-dimethylphenoxymethyl)phenyl 3-methylisoxazol-5-yl ketone O-methyloxime. One of the isomers A and B is the E-isomer and the other is Z-isomer.
Reaction SMILES: [N+:1]([C:4]1[CH:8]=[CH:7][NH:6][N:5]=1)([O-:3])=[O:2].[H-].[Na+].Br[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]>CN(C)C=O.C(OCC)(=O)C>[N+:1]([C:4]1[CH:8]=[CH:7][N:6]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[N:5]=1)([O-:3])=[O:2]
Reactant: CCCCCCCCBr
Reactant: O=[N+]([O-])c1cc[nH]n1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCCCCCCn1ccc([N+](=O)[O-])n1
Reaction time: 16 h
Yield: 66.8 %

Procedure:
3-Nitro-1H-pyrazole (prepared in example 3, 100 mg, 0.89 mmol) was dissolved in anhydrous N,N-dimethylformamide (4 mL) and a 60% dispersion of sodium hydride in mineral oil (42 mg, 1.06 mmol) was added while stirring under nitrogen. After the effervescence ceased and the reaction stirred for an additional 10 min before 1-bromo-octane (183 μL, 1.06 mmol) was added. The reaction continued to stir under nitrogen for 4 h. The reaction was stored at −25° C. for 16 h. The solution was diluted with ethyl acetate (30 mL), washed with water (2×10 mL), saturated aqueous brine solution (10 mL), dried over magnesium sulfate, filtered and concentrated in vacuo. Purification by ISCO flash column chromatography (Teledyne Isco RediSep Flash Column 40 g; 25% ethyl acetate/hexanes to 75% ethyl acetate/hexanes) afforded 3-nitro-1-octyl-1H-pyrazole (134 mg, 56%) as a clear oil.
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[C:3]1[N:7]2[C:8]3[CH:27]=[CH:26][CH:25]=[N:24][C:9]=3[O:10][C:11]3([CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13][CH2:12]3)[C:6]2=[CH:5][CH:4]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:28][C:2]([F:1])([F:29])[C:3]1[N:7]2[C:8]3[CH:27]=[CH:26][CH:25]=[N:24][C:9]=3[O:10][C:11]3([CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3)[C:6]2=[CH:5][CH:4]=1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)Oc1ncccc1-n1c(C(F)(F)F)ccc12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: FC(F)(F)c1ccc2n1-c1cccnc1OC21CCNCC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 95.4 %

Procedure:
To a solution of tert-butyl 9′-(trifluoromethyl)spiro[piperidine-4,6′-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazine]-1-carboxylate (83 mg, 0.20 mmol) in CH2Cl2 (3 mL) was added TFA (1.0 mL, 13 mmol) and the mixture was stirred at room temperature for 15 min before being evaporated to dryness. The residue was taken up in EtOAc and sat. aq. Na2CO3, the layers were separated, and aqueous layer was extracted with EtOAc (2×). The organics were combined, washed with sat. aq. Na2CO3, brine, dried (Na2SO4) and evaporated to dryness to give 9′-(trifluoromethyl)-spiro[piperidine-4,6′-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazine] as a pale yellow solid (59 mg). ESI-MS m/z calc. 309.1, found 310.3 (M+1)+; Retention time: 1.32 minutes (3 min run).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[CH:8][C:7]([O:10]C(=O)C)=[CH:6][C:5]=1[OH:14].OS(C(F)(F)F)(=O)=O.[C:24](Cl)(=[O:26])[CH3:25].CCOC(C)=O>O>[CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[C:8]([C:24](=[O:26])[CH3:25])[C:7]([OH:10])=[CH:6][C:5]=1[OH:14]
Reactant: CC(=O)Cl
Reactant: COC(=O)c1ccc(OC(C)=O)cc1O
Agent: O=S(=O)(O)C(F)(F)F
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(C(C)=O)c(O)cc1O
Temperature: 25 °C

Procedure:
The toluene solution from Step 1 was cooled in an ice bath under N2 and triflic acid (9.44 L) added slowly over 3 h. On stirring a fine white solid was formed which dissolved on warming to RT over 20 h and then stirring at RT for 37 h to give a yellow solution. To the solution was added acetyl chloride (726 mL) and the solution stirred at RT for a further 1 h. This solution was cannulated into a stirred cooled (0° C.) solution of EtOAc (217.8 L) and NaOAc.3H2O (14.52 Kg) dissolved in water (145 L). The organic phase was washed with saturated brine (twice, 72.6 L), and was evaporated to 5.5 Kg. Toluene:Isopropanol (2:3) was added and the crystalline solid removed by filtration and dried to give 12.6 Kg (61% over 2 steps), mp 124-126° C.
Reaction SMILES: NC1C=C(C=CC=1)O[C:6]1[CH:11]=[CH:10][N:9]=[C:8]([C:12](N)=O)[CH:7]=1.[NH2:18][C:19]1[CH:24]=[CH:23][C:22]([OH:25])=[C:21]([F:26])[CH:20]=1.ClC1C=CN=C(C#N)C=1>>[F:26][C:21]1[CH:20]=[C:19]([NH2:18])[CH:24]=[CH:23][C:22]=1[O:25][C:6]1[CH:11]=[CH:10][N:9]=[C:8]([CH3:12])[CH:7]=1
Reactant: Nc1ccc(O)c(F)c1
Reactant: NC(=O)c1cc(Oc2cccc(N)c2)ccn1
Agent: N#Cc1cc(Cl)ccn1
Product: Cc1cc(Oc2ccc(N)cc2F)ccn1

Procedure:
{3-Fluoro-4-[(2-methylpyridin-4-yl)oxy]phenyl}-amine (2J) was prepared by a method analogous to that described for 4-(3-aminophenoxy) pyridine-2-carboxamide (2C), starting from 4-amino-2-fluorophenol and 4-chloro-2-cyanopyridine, MS ES: 219 (M+H)+, calcd 219, RT=1.07 min.
Reaction SMILES: Cl.Cl.[NH2:3][C@H:4]([C:6]1[N:7]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:8]2[C:14]([CH2:15][OH:16])=[C:13]([F:17])[CH:12]=[CH:11][C:9]=2[N:10]=1)[CH3:5].[NH2:24][C:25]1[C:30]([C:31]#[N:32])=[C:29](Cl)[N:28]=[CH:27][N:26]=1.CCN(C(C)C)C(C)C>CC(O)C>[NH2:24][C:25]1[C:30]([C:31]#[N:32])=[C:29]([NH:3][C@H:4]([C:6]2[N:7]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:8]3[C:14]([CH2:15][OH:16])=[C:13]([F:17])[CH:12]=[CH:11][C:9]=3[N:10]=2)[CH3:5])[N:28]=[CH:27][N:26]=1
Reactant: C[C@H](N)c1nc2ccc(F)c(CO)c2n1-c1ccccc1
Reactant: N#Cc1c(N)ncnc1Cl
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: C[C@H](Nc1ncnc(N)c1C#N)c1nc2ccc(F)c(CO)c2n1-c1ccccc1
Temperature: 80 °C
Yield: 47.9 %

Procedure:
To a solution of [2-((S)-1-aminoethyl)-5-fluoro-3-phenyl-3H-benzoimidazol-4-yl]methanol dihydrochloride (159 mg, 0.45 mmol) in IPA (5 mL) was added 4-amino-6-chloropyrimidine-5-carbonitrile (69 mg, 0.45 mmol) and DIPEA (228 μL, 1.33 mmol) and the reaction mixture heated at 80° C. for 16 h. The reaction mixture was concentrated in vacuo and the resultant residue purified by prep HPLC (C18 phenomenex column, 10-90% MeCN in water 0.1% formic acid, 20 min gradient) to give 353 as a white solid (87 mg, 49%). 1H NMR 400 MHz δ (d6-DMSO): 7.78 (1H, s), 7.65-7.56 (2H, m), 7.55-7.38 (5H, m), 7.16 (2H, br s), 7.05 (1H, dd, J=10.6, 8.8 Hz), 5.15 (1H, quin, J=6.9 Hz), 4.51 (1H, t, J=5.0 Hz), 3.97 (2H, d, J=5.0 Hz), 1.43 (3H, d, J=6.9 Hz)
Reaction SMILES: O[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([N:12]2[CH2:16][CH2:15][CH2:14][CH:13]2[C:17]2[O:21][N:20]=[C:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=3)[CH:18]=2)[N:3]=1.[NH2:28][C:29]1[CH:33]=[C:32]([CH3:34])[NH:31][N:30]=1>>[CH3:34][C:32]1[NH:31][N:30]=[C:29]([NH:28][C:2]2[CH:7]=[C:6]([C:8]([F:9])([F:11])[F:10])[N:5]=[C:4]([N:12]3[CH2:16][CH2:15][CH2:14][CH:13]3[C:17]3[O:21][N:20]=[C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=4)[CH:18]=3)[N:3]=2)[CH:33]=1
Reactant: Cc1cc(N)n[nH]1
Reactant: Oc1cc(C(F)(F)F)nc(N2CCCC2c2cc(-c3ccccn3)no2)n1
Product: Cc1cc(Nc2cc(C(F)(F)F)nc(N3CCCC3c3cc(-c4ccccn4)no3)n2)n[nH]1

Procedure:
Starting materials: 4-hydroxy-6-trifluoromethyl-2-[2-{3-(pyrid-2-yl)isoxazol-5-yl}pyrrolidin-1-yl]pyrimidine (Method 37) and 3-amino-5-methyl-1H-pyrazole.
Reaction SMILES: [NH:1]([C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][N:10]=1)[C:6]#[N:7])[NH2:2].O=[C:12]([CH3:19])[CH2:13][C:14](OCC)=[O:15]>CCO.CC(O)=O>[OH:15][C:14]1[N:1]([C:3]2[CH:4]=[C:5]([C:6]#[N:7])[CH:8]=[CH:9][N:10]=2)[N:2]=[C:12]([CH3:19])[CH:13]=1
Reactant: CCOC(=O)CC(C)=O
Reactant: N#Cc1ccnc(NN)c1
Solvent: CC(=O)O
Solvent: CCO
Product: Cc1cc(O)n(-c2cc(C#N)ccn2)n1
Temperature: 90 °C
Reaction time: 8 h
Yield: 62.4 %

Procedure:
A mixture of 2-hydrazinylisonicotinonitrile (536 mg, 4 mmol, PREPARATION 2) and ethyl 3-oxobutanoate (780 mg, 6 mmol) in EtOH (10 mL) and AcOH (2 mL) was stirred at 90° C. overnight. The reaction mixture was cooled, concentrated, and purified by flash column chromatography (CH2Cl2) to afford the title compound (500 mg, 67%) as a yellow solid. [M+H] Calc'd for C10H8N4O, 201; Found, 201.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[N:10]=[N:11][NH:12][N:13]=1.[CH3:14][C:15](O)([CH3:17])[CH3:16].S(=O)(=O)(O)O.[OH-].[K+]>C(O)(C(F)(F)F)=O.C(OCC)(=O)C>[CH3:14][C:15]([N:13]1[C:9]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[O:2][CH3:1])=[N:10][NH:11][NH:12]1)([CH3:17])[CH3:16]
Reactant: CC(C)(C)O
Reactant: COc1ccccc1-c1nn[nH]n1
Agent: O=S(=O)(O)O
Agent: [K+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Product: COc1ccccc1C1=NNNN1C(C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 35.5 %

Procedure:
A mixture of 5-(2-methoxyphenyl)-2H-tetrazole (0.83 g, 4.71 mmol), 2-methyl-2-propanol (0.7 g, 9.4 mmol), and sulfuric acid (0.24 g, 2.4 mmol) in 4.6 mL of TFA was stirred under nitrogen at room temperature for 16 hours. The reaction mixture then was diluted with ethyl acetate, pouredinto 2M potassium hydroxide, and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried over magnesium sulfate and concentrated. Purification of the residue by column chromatography on silica gel (elution: 10% ethyl acetate/hexane) gave 1-(1,1-dimethylethyl)-5-(2-methoxyphenyl)-2H-tetrazole (0.5102 g, 1.67 mmol), as an oil.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][N:6]2[C:11](=[O:13])[CH3:12].FC1C=CC=C2C=1C=CN2.OS(O)(=O)=O.[N+:29]([O-])([OH:31])=[O:30]>C(O)(=O)C>[F:1][C:2]1[C:10]([N+:29]([O-:31])=[O:30])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][N:6]2[C:11](=[O:13])[CH3:12]
Reactant: CC(=O)N1CCc2c(F)cccc21
Reactant: O=[N+]([O-])O
Agent: Fc1cccc2[nH]ccc12
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: CC(=O)N1CCc2c1ccc([N+](=O)[O-])c2F

Procedure:
Treatment of 1-(4-fluoro-2,3-dihydro-indol-1-yl)-ethanone, prepared from 4-fluoroindole (See e.g., EP 0645385A1), with concentrated H2SO4 and fuming HNO3 in glacial acetic acid gave 1-(4-fluoro-5-nitro-2,3-dihydro-indol-1-yl)-ethanone. Deprotection of the acetyl group with Na2S in aqueous ethanol provided 4-fluoro-5-nitro-2,3-dihydro-1H-indole, which was treated with 2,3-dicyano-5,6-dichloro-parabenzoquinone (DDQ) to provide 4-fluoro-5-nitroindole. A subsequent hydrogenation over Pd/C gave 5-amino-4-fluoroindole.