Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[C:4]([C:6]1[C:11](=[O:12])[N:10]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[N:9]2[CH:24]=[CH:25][CH:26]=[C:8]2[C:7]=1[OH:27])=[O:5])C.[NH2:28][CH2:29][C:30]([O-:32])=[O:31].[Na+]>>[F:23][C:20]([F:22])([F:21])[C:17]1[CH:18]=[CH:19][C:14]([CH2:13][N:10]2[C:11](=[O:12])[C:6]([C:4]([NH:28][CH2:29][C:30]([OH:32])=[O:31])=[O:5])=[C:7]([OH:27])[C:8]3=[CH:26][CH:25]=[CH:24][N:9]23)=[CH:15][CH:16]=1
Reactant: CCOC(=O)c1c(O)c2cccn2n(Cc2ccc(C(F)(F)F)cc2)c1=O
Reactant: NCC(=O)[O-]
Agent: [Na+]
Product: O=C(O)CNC(=O)c1c(O)c2cccn2n(Cc2ccc(C(F)(F)F)cc2)c1=O

Procedure:
Prepared according to the glycinolysis condition used in Example 1 step d) from 1-(4-trifluoromethyl-benzyl)-4-hydroxy-2-oxo-1,2-dihydro-pyrrolo[1,2-b]pyridazine-3-carboxylic acid ethyl ester (1.0 eq.) and sodium glycinate (15 eq.). ESI (m/z): 410 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[C:3]1[CH:7]=[CH:6][NH:5][N:4]=1.Cl[C:11]1[C:16]([Cl:17])=[CH:15][CH:14]=[CH:13][N:12]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[Cl:17][C:16]1[C:11]([N:5]2[CH:6]=[CH:7][C:3]([C:2]([F:9])([F:8])[F:1])=[N:4]2)=[N:12][CH:13]=[CH:14][CH:15]=1
Reactant: Clc1cccnc1Cl
Reactant: FC(F)(F)c1cc[nH]n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: FC(F)(F)c1ccn(-c2ncccc2Cl)n1
Temperature: 130 °C
Reaction time: 14 h
Yield: 82.2 %

Procedure:
A mixture of 15.30 g of 3-trifluoromethyl-1H-pyrazole, 16.64 g of 2,3-dichloropyridine, 26.42 g of potassium carbonate and 100 ml of N,N-dimethylformamide was stirred at 130° C. for 14 hours. The reaction mixture was allowed to cool to room temperature and then water was poured thereto. The mixture was extracted with ethyl acetate two times. The organic layers were combined, washed successively with water and an aqueous saturated sodium chloride solution, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography to obtain 22.88 g of 3-chloro-2-(3-trifluoromethyl-1H-pyrazol-1-yl)pyridine of the formula:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:5]2[O:10]C[N:8]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH2:7][C:6]=2[CH:15]=1.[CH3:22][O:23][C:24]1[N:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1.C(=O)([O-])[O-].[K+].[K+]>COCCOCCOC.O>[C:11]([NH:8][CH2:7][C:6]1[CH:15]=[C:2]([C:27]2[CH:28]=[N:29][C:24]([O:23][CH3:22])=[CH:25][CH:26]=2)[CH:3]=[C:4]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:5]=1[OH:10])([CH3:14])([CH3:12])[CH3:13]
Reactant: CC(C)(C)N1COc2c(cc(Br)cc2-c2ccccc2)C1
Reactant: COc1ccc(B(O)O)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOCCOC
Product: COc1ccc(-c2cc(CNC(C)(C)C)c(O)c(-c3ccccc3)c2)cn1
Temperature: 64 °C
Yield: 80.2 %

Procedure:
A mixture of 6-bromo-3-(tert-butyl)-8-phenyl-3,4-dihydro-2H-benzo[e][1,3]oxazine (0.659 g, 1.91 mmol), (6-methoxypyridin-3-yl)boronic acid (0.438 g, 1.5 equiv), and potassium carbonate (1.056 g, 4 equiv) in 2-methoxyethyl ether (10 mL) and water (2 mL) was purged with nitrogen for 20 minutes. Tetrakis(triphenylphosphine)Pd (0) (110 mg, 5 mol %) was added and the resulting mixture was heated at 61-67° C. for 2.5 hours. The cooled reaction mixture was concentrated and the resulting residue was purified by column chromatograph to give 3-((tert-butylamino)methyl)-5-(6-methoxypyridine-3-yl)-[1,1′-biphenyl]-2-ol (0.555 g) as yellow oil. 0.28 g of the oil was dissolved in ethanol and a solution of tartaric acid (0.108 g) in ethanol was added. The resulting precipitate was filtered and rinsed with ethanol to give 3-((tert-butylamino)methyl)-5-(6-methoxypyridine-3-yl)-[1,1′-biphenyl]-2-ol tartarate (100 mg).
Reaction SMILES: Br[CH:2]=[C:3]1[C:16]2[CH:15]=[CH:14][C:13]([F:17])=[CH:12][C:11]=2[S:10][C:9]2[C:4]1=[CH:5][CH:6]=[C:7]([F:18])[CH:8]=2.CC1(C)C(C)(C)OB([C:27]2[CH:36]=[CH:35][C:30]3[NH:31][C:32](=[O:34])[NH:33][C:29]=3[CH:28]=2)O1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:18][C:7]1[CH:6]=[CH:5][C:4]2[C:3](=[CH:2][C:27]3[CH:36]=[CH:35][C:30]4[NH:31][C:32](=[O:34])[NH:33][C:29]=4[CH:28]=3)[C:16]3[C:11]([S:10][C:9]=2[CH:8]=1)=[CH:12][C:13]([F:17])=[CH:14][CH:15]=3
Reactant: Fc1ccc2c(c1)Sc1cc(F)ccc1C2=CBr
Reactant: CC1(C)OB(c2ccc3[nH]c(=O)[nH]c3c2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: O=c1[nH]c2ccc(C=C3c4ccc(F)cc4Sc4cc(F)ccc43)cc2[nH]1
Temperature: 95 °C
Yield: 17.3 %

Procedure:
Mix 9-bromomethylene-3,6-difluoro-9H-thioxanthene (104 mg, 0.32 mmol), 5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)- 1,3-dihydro-benzoimidazol-2-one (76 mg, 0.29 mmol), and Na2CO3 (2M/water, 363 μL, 0.73 mmol) in dioxane (2 mL) and sparge with nitrogen for 5 min. Add Pd(PPh3)4 (17 mg, 0.015 mmol), seal vial, and heat to 95° C. overnight. Concentrate and dilute with water (3 mL) and ethyl acetate (10 mL). Load mixture onto a Varian ChemElut CE1005 solid-phase extraction cartridge. Elute, collect, and concentrate 50 mL ethyl acetate. Purify on silica gel (50-60% THF/hexanes), then re-purify by semi-prep reverse-phase HPLC (10-95% CH3CN/H2O, 0.1% TFA added) to afford 19 mg (17%) of the title compound as a yellow foam. MS [ES] 379 (M+H), 377 (M−H); HPLC shows 100% purity;, 1H-NMR (DMSO-d6) δ 10.67 (s, 1H), 10.54 (s, 1H), 7.89 (dd, 1H, J=8.6, 5.5 Hz), 7.53 (dd, 1H, J=9.0, 2.9 Hz), 7.47 (dd, 1H, J=8.8, 2.6 Hz), 7.27 (m, 2H), 7.02 (m, 2H), 6.86 (dd, 2H, J=11.5, 8.4 Hz), 6.78 (s, 1H).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[CH3:11][N:12]([CH3:16])[CH2:13][CH2:14][NH2:15]>C(O)(C)C>[CH3:11][N:12]([CH3:16])[CH2:13][CH2:14][NH:15][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccccc1F
Reactant: CN(C)CCN
Solvent: CC(C)O
Product: CN(C)CCNc1ccccc1[N+](=O)[O-]
Temperature: 0 °C
Yield: 92 %

Procedure:
A mixture of 2-fluoro-nitrobenzene (2.8 g, 20 mmol) and N,N-dimethylethylenediamine (3.3 mL, 30 mmol) in isopropanol is heated at 90°-100° C. for 16 h, cooled to 0° C. and filtered. The filtercake is washed with cold isopropanol and air-dried to give the title compound as an orange solid, 3.83 g (92% yield), identified by HPLC and mass spectral analyses.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.Cl.[N:16]1([CH2:22][CH2:23][C:24]2[N:28]3[CH:29]=[CH:30][CH:31]=[CH:32][C:27]3=[C:26]([C:33](Cl)=[O:34])[N:25]=2)[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1>C(Cl)Cl>[N:4]1[CH:5]=[CH:6][CH:7]=[C:2]([NH:1][C:33]([C:26]2[N:25]=[C:24]([CH2:23][CH2:22][N:16]3[CH2:17][CH2:18][O:19][CH2:20][CH2:21]3)[N:28]3[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=23)=[O:34])[CH:3]=1
Reactant: O=C(Cl)c1nc(CCN2CCOCC2)n2ccccc12
Reactant: Nc1cccnc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Nc1cccnc1)c1nc(CCN2CCOCC2)n2ccccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 31.6 %

Procedure:
To a solution of 3-aminopyridine (0.051 g, 0.54 mmol) and triethylamine (0.16 mL, 1.14 mmol) in CH2Cl2 (10 mL) was added 3-(2-morpholin-4-yl-ethyl)-imidazo[1,5-a]pyridine-1-carbonyl chloride hydrochloride (150 mg, 0.45 mmol). The mixture was stirred at ambient temperature for 1 h then washed with sat. aq. NaHCO3 (20 mL). The organic layer was separated and the aqueous layer was extracted with dichloromethane (20 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was chromatographed on silica to yield the title compound (50 mg, 32%). 1H NMR (DMSO-d6) δ 10.05 (1H), 9.05 (1H), 8.45 (1H), 8.28 (2H), 8.15 (1H), 7.35 (1H), 7.20 (1H), 6.94 (1H), 3.58 (4H), 3.26 (2H), 2.80 (2H), 2.45 (4H); m/z (M+H)=352.17.
Reaction SMILES: Cl[C:2]1[C:11]([CH:12]=[O:13])=[CH:10][C:9]2[C:4](=[C:5]([CH3:14])[CH:6]=[CH:7][CH:8]=2)[N:3]=1.[F:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH3:23])[C:17]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>CC#N.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH3:23])[C:17]=1[C:2]1[C:11]([CH:12]=[O:13])=[CH:10][C:9]2[C:4](=[C:5]([CH3:14])[CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: Cc1cccc2cc(C=O)c(Cl)nc12
Reactant: COc1cccc(F)c1B(O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: COc1cccc(F)c1-c1nc2c(C)cccc2cc1C=O

Procedure:
Prepared according to Procedure A using 2-chloro-8-methylquinoline-3-carbaldehyde (1.07 g, 5.21 mmol), 2-fluoro-6-methoxyphenylboronic acid (0.9738 g, 5.73 mmol, 1.1 eq), tetrakis(triphenylphosphine)palladium (0.3011 g, 5% mmol), and sodium carbonate (2.76 g, 26.1 mol, 5 eq) in MeCN (37.5 mL) and water (12.5 mL). After purification, 2-(2-fluoro-6-methoxyphenyl)-8-methylquinoline-3-carbaldehyde was obtained as white solid. 1H NMR (DMSO-d6) δ ppm 9.88 (1H, s), 8.95 (1H, s), 8.10 (1H, d, J=8.1 Hz), 7.82 (1H, d, J=7.1 Hz), 7.62-7.69 (1H, m), 7.49-7.59 (1H, m), 6.96-7.10 (2H, m), 3.71 (3H, s), 2.70 (3H, s). Mass Spectrum (ESI) m/e=296.0 (M+1).
Reaction SMILES: C([O:5][C:6](=[O:34])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][N:18]([C:26]2[N:31]=[CH:30][C:29]([CH2:32][CH3:33])=[CH:28][N:27]=2)[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[N:15]=1)([CH3:9])[CH3:8])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH2:32]([C:29]1[CH:30]=[N:31][C:26]([N:18]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH2:17][CH2:16][C:14]2[N:15]=[C:11]([S:10][C:7]([CH3:8])([CH3:9])[C:6]([OH:34])=[O:5])[S:12][CH:13]=2)=[N:27][CH:28]=1)[CH3:33]
Reactant: CCCCCCCN(CCc1csc(SC(C)(C)C(=O)OC(C)(C)C)n1)c1ncc(CC)cn1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCCCCCN(CCc1csc(SC(C)(C)C(=O)O)n1)c1ncc(CC)cn1
Temperature: 25 °C
Reaction time: 20 h
Yield: 81.6 %

Procedure:
2-[(4-{2-[(5-Ethylpyrimidin-2-yl)(heptyl)amino]ethyl}-1,3-thiazol-2-yl)thio]-2-methylpropionic acid tert-butyl ester (6.20 g) obtained in Example 265-2 was dissolved in dichloromethane (60 mL), trifluoroacetic acid (12 mL) was added, and the mixture was stirred at room temperature for 20 hr. The reaction mixture was concentrated under reduced pressure, ethyl acetate was added, and the mixture was washed with saturated aqueous sodium hydrogen carbonate solution (the objective compound was extracted in the ethyl acetate layer). The ethyl acetate layer was washed with aqueous 10% citric acid solution and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent; hexane:ethyl acetate=1:1 to 0:1) to give the title compound (4.50 g) as a colorless oil.
Reaction SMILES: [C:1]([C:3]1[NH:4][N:5]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:6](=[O:25])[C:7]=1[N:8]=[N:9][C:10]1[CH:15]=[C:14]([S:16](O)(=[O:18])=[O:17])[C:13]([O:20][CH2:21][CH2:22][O:23][CH3:24])=[CH:12][CH:11]=1)#[N:2].CC(C)=O.P(Cl)(Cl)([Cl:38])=O>CN(C)C(=O)C>[C:1]([C:3]1[NH:4][N:5]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:6](=[O:25])[C:7]=1[N:8]=[N:9][C:10]1[CH:15]=[C:14]([S:16]([Cl:38])(=[O:18])=[O:17])[C:13]([O:20][CH2:21][CH2:22][O:23][CH3:24])=[CH:12][CH:11]=1)#[N:2]
Reactant: O=P(Cl)(Cl)Cl
Reactant: COCCOc1ccc(N=Nc2c(C#N)[nH]n(-c3ccccc3)c2=O)cc1S(=O)(=O)O
Solvent: CC(=O)N(C)C
Solvent: CC(C)=O
Product: COCCOc1ccc(N=Nc2c(C#N)[nH]n(-c3ccccc3)c2=O)cc1S(=O)(=O)Cl
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a mixture of 51.0 g of the 3-cyano-4-[4-(2-methoxyethoxy)-5-sulfophenylazo]-1-phenyl-5-pyrazolone, 250 ml of acetone and 50 ml of phosphorus oxychloride was dropwise added 50 ml of N,N-dimethylacetamide at 50° C. or below. After the addition, the reaction mixture was stirred for about 1 hour and gradually poured into 1.0 l of ice water. The crystals precipitated were collected by filtration, washed with 100 ml of acetonitrile and dried by air. Thus, 46.7 g of 3-cyano-4-[4-(2-methoxyethoxy)-5-chlorosulfonylphenylazo]-1-phenyl-5-pyrazolone was obtained.
Reaction SMILES: [CH:1]1([Mg]Br)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:9][C:10]1[CH:11]=[CH:12][C:13]([OH:20])=[C:14]([CH:19]=1)[C:15]([O:17]C)=O>CCOCC>[Cl:9][C:10]1[CH:11]=[CH:12][C:13]([OH:20])=[C:14]([C:15]([CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)([CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[OH:17])[CH:19]=1
Reactant: COC(=O)c1cc(Cl)ccc1O
Reactant: Br[Mg]C1CCCCC1
Solvent: CCOCC
Product: Oc1ccc(Cl)cc1C(O)(C1CCCCC1)C1CCCCC1

Procedure:
270 ml of a solution of cyclohexyl magnesium bromide titrating 1.3 M/liter in ether were added dropwise with stirring at room temperature to a mixture of 18.7 g of methyl 5-chloro-2-hydroxy-benzoate in 150 ml of ether and the ether was distilled while replacing it with 270 ml of benzene. The mixture was then refluxed for 20 hours and was cooled and poured into a mixture of 500 g of ice and 300 ml of an aqueous solution containing 105 g of ammonium chloride. The mixture was extracted once with 250 ml of ether, twice with 150 ml of ether and 3 times with 100 ml of methylene chloride. The organic phases were washed 3 times with 100 ml of water, were dried over magnesium sulfate in the presence of activated carbon and was evaporated to dryness. The residue was taken up in 50 ml of cyclohexane and the mixture was vacuum filtered. The product was dried to obtain 20,200 g of 5-chloro-α,α-dicyclohexyl-2-hydroxybenzene-methanol melting at 230° C.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.I[C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH3:17])[CH:12]=1>>[CH3:17][C:13]1[CH:12]=[C:11]([N:1]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[CH:3]=[CH:2]2)[CH:16]=[CH:15][CH:14]=1
Reactant: Cc1cccc(I)c1
Reactant: c1ccc2[nH]ccc2c1
Product: Cc1cccc(-n2ccc3ccccc32)c1

Procedure:
Prepared by Procedure C and Scheme O using 1H-indole and 1-iodo-3-methylbenzene: ESMS m/e: 208.0 (M+H)+.
Reaction SMILES: [C:1]1([C:7]2[C:11]3[CH:12]=[CH:13][C:14]([OH:19])=[C:15]([CH2:16][CH2:17][CH3:18])[C:10]=3[O:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:20][CH2:21][CH2:22][CH2:23]Br.C(=O)([O-])[O-].[K+].[K+]>C(C(C)=O)C>[C:1]1([C:7]2[C:11]3[CH:12]=[CH:13][C:14]([O:19][CH2:23][CH2:22][CH2:21][Br:20])=[C:15]([CH2:16][CH2:17][CH3:18])[C:10]=3[O:9][N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: BrCCCBr
Reactant: CCCc1c(O)ccc2c(-c3ccccc3)noc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCCc1c(OCCCBr)ccc2c(-c3ccccc3)noc12

Procedure:
To a mixture of 3-phenyl-7-propyl-6-hydroxy-benz-[4,5]-isoxazole (1.0 g; 3.95 mmol, Prepared in Example 16 Step C), 1,3-dibromopropane (3.98g, 19.5 mmol) and potassium carbonate (0.573g, 4.15 mmol) in 4.0 mL of methyl ethyl ketone was warmed to reflux for 16 hours. Filtered, concentrated and chromatographed (silica gel, 30% ethyl acetate in hexane) to yeild 1.025 g of the title compound as a white solid. NMR (CDCl3): δ 7.95 (d,2H); 7.69 (d,1H); 7.55 (m,3H); 7.03 (d,1H); 4.25 (t,2H); 3.68 (t,2H); 2.95 (t,2H); 2.41 (m,2H); 1.76 (m,2H); 1.01 (t,3H)
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][C:9]=2[O:15][CH3:16])[C:5]([F:17])=[CH:4][N:3]=1.[Cl:18][C:19]1[CH:20]=[C:21]([CH:23]=[C:24]([CH2:26][S:27][CH3:28])[CH:25]=1)[NH2:22]>>[Cl:18][C:19]1[CH:20]=[C:21]([NH:22][C:2]2[N:7]=[C:6]([C:8]3[CH:13]=[CH:12][C:11]([F:14])=[CH:10][C:9]=3[O:15][CH3:16])[C:5]([F:17])=[CH:4][N:3]=2)[CH:23]=[C:24]([CH2:26][S:27][CH3:28])[CH:25]=1
Reactant: CSCc1cc(N)cc(Cl)c1
Reactant: COc1cc(F)ccc1-c1nc(Cl)ncc1F
Product: COc1cc(F)ccc1-c1nc(Nc2cc(Cl)cc(CSC)c2)ncc1F

Procedure:
Intermediate 56.5 was prepared under similar conditions as described in the preparation of Intermediate 28.3 using 2-chloro-5-fluoro-4-(4-fluoro-2-methoxyphenyl)pyrimidine and 3-chloro-5-[(methylsulfanyl)-methyl]aniline. The batch was purified by chromatography (hexane to hexane/ethyl acetate 30%) to give the desired product.
Reaction SMILES: [C:1]1(C)[C:2]([S:7]([OH:10])(=[O:9])=[O:8])=[CH:3][CH:4]=[CH:5][CH:6]=1.[CH3:12]O>>[C:5]1([CH3:12])[CH:6]=[CH:1][C:2]([S:7]([OH:10])(=[O:9])=[O:8])=[CH:3][CH:4]=1
Reactant: Cc1ccccc1S(=O)(=O)O
Reactant: CO
Product: Cc1ccc(S(=O)(=O)O)cc1

Procedure:
Compound C (250 mg, prepared in analogous fashion to the process described in Example 12 above) was dissolved in methanol (10 mL). Toluenesulphonic acid (110 mg) was added to the solution. The methanol was removed under reduced pressure and the remaining gum was re-dissolved in the minimum amount of hot ethyl acetate possible. The solution was seeded with previously prepared salt (prepared by slow evaporation of solvent from a small portion of a solution of title compound, prepared in analogous fashion to this procedure) and left in the fridge for several days to crystallise. The resulting crystals were collected by filtration and washed with a small amount of cold ethyl acetate (recovered 280 mg, 78%).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][O:6][CH3:7].[Mg].[N:9]1[CH2:10][CH2:11][CH2:12][N:13]2[C:21]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[C:15](=[O:22])[C:14]=12.[Cl-].[NH4+]>ClCCCl.CCOCC>[OH:22][C:15]1([CH2:2][CH2:3][CH2:4][CH2:5][O:6][CH3:7])[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:21]=2[N:13]2[CH2:12][CH2:11][CH2:10][N:9]=[C:14]12
Reactant: O=C1C2=NCCCN2c2ccccc21
Reactant: COCCCCBr
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: CCOCC
Solvent: ClCCCl
Product: COCCCCC1(O)C2=NCCCN2c2ccccc21
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Ether (60 ml) and 4-bromo-1-methoxy-butane (10.2 g) were added to magnesium turnings (1.46 g). After formation of the Grignard reagent, the mixture was cooled to 0° and 3,4-dihydropyrimido[1,2-a]indol-10(2H)-one (3.72 g) in dry 1,2-dichloroethane (20 ml) added dropwise over 20 minutes. The solution was stirred under argon at 0° C. for 1 hour, poured onto a swirling mixture of ice (100 ml) and saturated aqueous ammonium chloride (60 ml) and the mixture was stirred for a further 20 minutes. The mixture was concentrated in vacuo and the aqueous residue extracted with chloroform (3×100 ml). The extracts were dried (Na2SO4) and concentrated in vacuo. Ether (20 ml) was added and the product was filtered and recrystallised from ethyl acetate to give the title compound or the free base (3.55 g), m.p. 128°-139° C. The free base was acidified with ethereal HCl to give the title compound as the hydrochloride, m.p. 178°-179° C.
Reaction SMILES: [CH3:1][N:2]([C:4]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:5])[NH2:3].[C:20](Cl)(Cl)=[S:21].C(N(CC)CC)C>O1CCCC1>[CH3:1][N:2]1[C:4](=[O:5])[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:20](=[S:21])[NH:3]1
Reactant: S=C(Cl)Cl
Reactant: CN(N)C(=O)Nc1ccccc1Oc1ccccc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cn1[nH]c(=S)n(-c2ccccc2Oc2ccccc2)c1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 1.54 g of 1-methyl-N-(2-phenoxyphenyl)hydrazinecarboxamide in 50 mL of tetrahydrofuran, cooled in an ice bath, was treated with 0.46 mL of thiophosgene, and then 1.68 mL of triethylamine. A precipitate formed and the mixture was stirred at ambient temperature overnight. The precipitate was removed by filtration and washed with tetrahydrofuran. The combined filtrate and washings were concentrated under reduced pressure to afford 1.8 g of an amber glassy oil. The crude material was used in the next step without further purification. 1H NMR (CDCl3): δ6.8-7.4 (m, 9H), 3.57 (s,3H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([Br:14])=[CH:10][C:9]=2N)=[C:4]([NH2:16])[CH:3]=1.C([O-])(O)=O.[Na+]>P(=O)(O)(O)O>[Br:14][C:11]1[CH:12]=[CH:13][C:8]2[C:5]3[C:4](=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=3)[NH:16][C:9]=2[CH:10]=1
Reactant: Nc1cc(Br)ccc1-c1ccc(Br)cc1N
Agent: O=C([O-])O
Agent: O=P(O)(O)O
Agent: [Na+]
Product: Brc1ccc2c(c1)[nH]c1cc(Br)ccc12
Temperature: 190 °C
Yield: 66.2 %

Procedure:
4,4′-dibromo-2,2′-diaminobiphenyl (3.5 g, 10.23 mmol) was dissolved in phosphoric acid and heated at 190° C. for 24 hours. The reaction mixture was cooled to room temperature and then NaHCO3 (aq) was gradually added thereto to form a solid. Then, the solid was filtered to obtain 2,7-dibromocarbazole (2.2 g, 66%), the compound represented by formula e. MS [M+] 323.
Reaction SMILES: [C:1]([C:9]1[CH:15]=[C:14]2[O:16][CH2:17][O:18][C:13]2=[CH:12][C:10]=1[NH2:11])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[O:20]([C:22]#[N:23])[Na]>CC(O)=O>[CH2:17]1[O:18][C:13]2[CH:12]=[C:10]3[C:9]([C:1]([C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)=[N:23][C:22](=[O:20])[NH:11]3)=[CH:15][C:14]=2[O:16]1
Reactant: N#CO[Na]
Reactant: Nc1cc2c(cc1C(=O)c1ccccc1)OCO2
Solvent: CC(=O)O
Solvent: O
Product: O=c1nc(-c2ccccc2)c2cc3c(cc2[nH]1)OCO3
Temperature: 10 °C
Reaction time: 1 h
Yield: 47.1 %

Procedure:
To a solution of 2-benzoyl-4,5-(methylenedioxy)aniline (200 mg) in AcOH (10 mL) was added water (1 mL) and NaOCN (64 mg) at 10° C. The mixture was stirred at 10° C. for 1 h, then at rt for 2 h. Water (70 mL) was added to the mixture. The resulting yellow solid was collected by filtration, washed with water and 3:2 hexane/EtOAc, recrystallized from DMSO/water to yield the title compound as a yellow solid (104 mg, 47%), mp: 351-354° C. 1H NMR (DMSO-d6): 11.86 (s, 1H), 7.63-7.58 (m, 5H), 6.94 (s, 1H), 6.85 (s, 1H), 6.16 (s, 2H).
Reaction SMILES: CC(C)([O-])C.[Na+].Br[C:8]1[CH:13]=[C:12]([CH3:14])[CH:11]=[C:10]([Br:15])[N:9]=1.[NH2:16][C:17]1[CH:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:20]=[CH:19][N:18]=1>>[Br:15][C:10]1[N:9]=[C:8]([NH:16][C:17]2[CH:22]=[C:21]([C:23]([F:25])([F:24])[F:26])[CH:20]=[CH:19][N:18]=2)[CH:13]=[C:12]([CH3:14])[CH:11]=1
Reactant: Cc1cc(Br)nc(Br)c1
Reactant: Nc1cc(C(F)(F)F)ccn1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Product: Cc1cc(Br)nc(Nc2cc(C(F)(F)F)ccn2)c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Sodium tert-butoxide (5.87 g, 61.1 mmol) and 1,1′-bis(di-tert-butylphsophino)ferrocene palladium dichloride (0.91 g, 1.4 mmol) were added to a solution of 2,6-dibromo-4-methyl pyridine (13.9 g, 55.5 mmol) and 2-amino-4-trifluoromethyl pyridine (9.0 g, 55.5 mmol) in nitrogen sparged dioxane (180 mL). The slurry was evacuated and refilled with nitrogen. The mixture was stirred at 25° C. for 15 minutes and then heated to 75° C. for 12 hours. The reaction mixture was cooled to 25° C., water (20 mL) was added, and the mixture was extracted with EtOAc (2×200 mL). The combined extracts were dried over sodium sulfate, filtered, concentrated under reduced pressure. The residue was purified by column chromatography on silica gel to afford 6-bromo-4-methyl-N-[4-(trifluoromethyl)pyridine-2-yl]pyridine-2-amine as a white solid. MS ESI calc'd. for C12H10BrF3N3 [M+H]+ 332 and 334. found 332 and 334. 1H NMR (600 MHz, DMSO-d6) δ 10.40 (s, 1H), 8.46 (d, J=6.0 Hz, 1H), 7.90 (s, 1H), 7.60 (s, 1H), 7.18 (d, J=6.0 Hz, 1H), 7.00 (s, 1H), 2.25 (s, 3H).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3]1.C(N(CC)CC)C.[Br:21][CH2:22][C:23](Br)=[O:24].Cl>ClCCl>[Br:21][CH2:22][C:23]([NH:1][C@H:2]1[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3]1)=[O:24]
Reactant: O=C(Br)CBr
Reactant: CC(C)(C)OC(=O)N1CC[C@H](N)C1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CC[C@H](NC(=O)CBr)C1
Temperature: 25 °C
Reaction time: 18.5 h
Yield: 76.1 %

Procedure:
A solution of (S)-3-amino-1-(tert-butoxycarbonyl)pyrrolidine (5.21 g) and triethylamine (4.68 ml) in dichloromethane (25 ml) was slowly added with bromoacetyl bromide (6.21 g, Wako Pure Chemical Industries) at 0° C., and the mixture was stirred at room temperature for 18.5 hours. The reaction mixture was added with 0.5 N hydrochloric acid, and the organic layer was separated. The aqueous layer was further extracted with dichloromethane, the combined organic layer was successively washed with saturated aqueous sodium hydrogencarbonate, and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to obtain the title compound (6.54 g).