Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12]C)[N:8]=[C:7]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=1)[C:6]([CH3:24])=[C:5]2[C:25]([OH:27])=[O:26].Br>C(O)(=O)C.O>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[OH:12])[N:8]=[C:7]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:21])[F:22])[CH:15]=1)[C:6]([CH3:24])=[C:5]2[C:25]([OH:27])=[O:26]
Reactant: COc1cc2nc(-c3cccc(C(F)(F)F)c3)c(C)c(C(=O)O)c2cc1F
Agent: Br
Solvent: O
Solvent: CC(=O)O
Product: Cc1c(-c2cccc(C(F)(F)F)c2)nc2cc(O)c(F)cc2c1C(=O)O
Temperature: 25 °C
Yield: 98.9 %

Procedure:
To a solution of 6-fluoro-3-methyl-7-(methyloxy)-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylic acid (19.5 g, 51.4 mmol) in acetic acid (50 mL) was added hydrobromic acid (140 mL, 2.57 mol) slowly. The resulting mixture was heated to reflux for 5 days. The mixture was cooled to room temperature, diluted with water and filtered. The filter cake was washed with water and air dried to afford 6-fluoro-7-hydroxy-3-methyl-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylic acid (18.57 g, 99% yield). 1H NMR (400 MHz, DMSO-d6) δ14.27 (br. s., 1H), 11.04 (s, 1H), 7.90-7.95 (m, 2H), 7.87 (d, J=7.78 Hz, 1H), 7.76 (t, J=7.65 Hz, 1H), 7.50 (d, J=2.76 Hz, 1H), 7.47 (s, 1H), 2.34 (s, 3H); MS (m/z) 366.0 (M+H+).
Reaction SMILES: Br[C:2]1[N:6]2[N:7]=[C:8]([C:11]3[CH:12]=[N:13][N:14]([CH3:16])[CH:15]=3)[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1.C([Mg]Br)C.[C:21]1([S:27]([N:30]2[C:34]3=[N:35][CH:36]=[CH:37][CH:38]=[C:33]3[C:32]([CH:39]=[O:40])=[CH:31]2)(=[O:29])=[O:28])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C1COCC1>[C:21]1([S:27]([N:30]2[C:34]3=[N:35][CH:36]=[CH:37][CH:38]=[C:33]3[C:32]([CH:39]([C:2]3[N:6]4[N:7]=[C:8]([C:11]5[CH:12]=[N:13][N:14]([CH3:16])[CH:15]=5)[CH:9]=[CH:10][C:5]4=[N:4][CH:3]=3)[OH:40])=[CH:31]2)(=[O:28])=[O:29])[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: Cn1cc(-c2ccc3ncc(Br)n3n2)cn1
Reactant: O=Cc1cn(S(=O)(=O)c2ccccc2)c2ncccc12
Agent: CC[Mg]Br
Solvent: C1CCOC1
Product: Cn1cc(-c2ccc3ncc(C(O)c4cn(S(=O)(=O)c5ccccc5)c5ncccc45)n3n2)cn1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
3-Bromo-6-(1-methyl-1H-pyrazol-4-yl)-imidazo[1,2-b]pyridazine (Example 8.1, 150 mg, 0.539 mmol) was dissolved in THF (15 mL) under Nitrogen. Ethylmagnesium bromide solution (3 M, 0.360 mL) was added and the mixture was stirred at rt for 30 min. Then 1-benzenesulfonyl-1H-pyrrolo[2,3-b]pyridine-3-carbaldehyde (Stage 199.2, 173 mg, 0.539 mmol) in THF (2 mL) was slowly added and the mixture was stirred at rt for 3.5 h. The mixture was quenched with 10% NH4Cl solution. It was extracted with EtOAc twice. The combined organic layers was washed with brine, dried over Na2SO4, filtered and evaporated. The title compound was obtained as a yellow solid (tR 1.4 min (conditions 1), MH+=486).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10](=[O:12])[CH3:11])[CH:5]=[CH:6][C:7]=1[Cl:8].[CH3:13][S:14](Cl)(=[O:16])=[O:15]>C(Cl)Cl.N1C=CC=CC=1>[Cl:8][C:7]1[CH:6]=[CH:5][C:4]([CH2:9][C:10](=[O:12])[CH3:11])=[CH:3][C:2]=1[NH:1][S:14]([CH3:13])(=[O:16])=[O:15]
Reactant: CS(=O)(=O)Cl
Reactant: CC(=O)Cc1ccc(Cl)c(N)c1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)Cc1ccc(Cl)c(NS(C)(=O)=O)c1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of 1-(3-Amino-4-chloro-phenyl)-propan-2-one (Intermediate D) (0.5 g, 2.73 mmol) in DCM (2 ml) and pyridine (1 ml) is added drop wise methanesulfonyl chloride (0.34 g, 0.23 ml, 3.0 mmol) at 0° C. (ice-bath). The reaction mixture is allowed to warm to room temperature and stirred for 3 days. The solvents are removed in vacuo and the residue is dissolved in EtOAc and washed with water, the organic portion is dried over MgSO4, filtered and concentrated in vacuo. Purification of the crude residue by flash chromatography on silica eluting with EtOAc affords the title compound.
Reaction SMILES: [F:1][C:2]1([F:24])[CH2:5][CH:4]([N:6]2[C:10]3[N:11]=[C:12]([S:22][CH3:23])[N:13]=[C:14]([C:15]4[CH:16]=[N:17][C:18]([NH2:21])=[N:19][CH:20]=4)[C:9]=3[CH2:8][CH2:7]2)[CH2:3]1.ClC1C=CC=C(C(OO)=[O:33])C=1>C(Cl)Cl>[F:24][C:2]1([F:1])[CH2:3][CH:4]([N:6]2[C:10]3[N:11]=[C:12]([S:22]([CH3:23])=[O:33])[N:13]=[C:14]([C:15]4[CH:20]=[N:19][C:18]([NH2:21])=[N:17][CH:16]=4)[C:9]=3[CH2:8][CH2:7]2)[CH2:5]1
Reactant: CSc1nc(-c2cnc(N)nc2)c2c(n1)N(C1CC(F)(F)C1)CC2
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CS(=O)c1nc(-c2cnc(N)nc2)c2c(n1)N(C1CC(F)(F)C1)CC2
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 26 %

Procedure:
To a suspension of crude 5-[7-(3,3-difluorocyclobutyl)-2-(methylsulfanyl)-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl]pyrimidin-2-amine (˜80% purity) (768 mg, 2.63 mmol) in DCM (87 mL) at 0° C. was added m-chloroperbenzoic acid (844 mg, 3.42 mmol, 70% purity) in three portions over 1 min. The reaction mixture was stirred at 0° C. for 15 min, whereupon it was diluted with DCM and washed with saturated aqueous NaHCO3 and water. The organic layer was concentrated and purified via HPLC reversed phase column (0-50% of gradient A to B over 25 min; A: water with 0.1% acetic acid, B: acetonitrile with 0.1% acetic acid) to afford the title compound (251 mg, 26%). 1H NMR (400 MHz, DMSO-d6) δ 8.80 (s, 2 H), 7.19 (s, 2 H), 4.61-4.48 (m, 1 H), 3.83 (t, J=8.4 Hz, 2 H), 3.38-3.31 (m, 2 H), 3.14-2.98 (m, 2 H), 2.97-2.85 (m, 2 H), 2.83 (s, 3 H). m/z (APCI+) for C15H16F2N6OS 367.1 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8](O)=[O:9])=[O:4].C(Cl)(=O)C([Cl:17])=O.CN(C)C=O>ClCCl>[Cl:17][C:8]([C:7]1[CH:6]=[C:5]([CH:13]=[CH:12][CH:11]=1)[C:3]([O:2][CH3:1])=[O:4])=[O:9]
Reactant: COC(=O)c1cccc(C(=O)O)c1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COC(=O)c1cccc(C(=O)Cl)c1
Temperature: 40 °C
Reaction time: 1 h

Procedure:
Into a 250-mL round bottom flask, was placed a solution of 3-(methoxycarbonyl)benzoic acid (6.2 g, 34.44 mmol, 1.00 equiv) in dichloromethane (50 mL), oxalyl dichloride (8.74 g, 69.37 mmol, 2.00 equiv), and N,N-dimethylformamide (cat.). The resulting solution was stirred for 1 h at 40° C. in an oil bath. The resulting mixture was concentrated under vacuum. This resulted in 6.6 g (87%) of methyl 3-(chlorocarbonyl)benzoate as brown oil.
Reaction SMILES: [C:1]1(=[N:8][OH:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:10][C:11]1[CH:12]=[C:13]([C:18]2[CH2:19][CH2:20][N:21]([CH2:24][CH2:25][CH2:26][C:27](OCC)=O)[CH2:22][CH:23]=2)[CH:14]=[CH:15][C:16]=1[F:17]>>[Cl:10][C:11]1[CH:12]=[C:13]([C:18]2[CH2:23][CH2:22][N:21]([CH2:24][CH2:25][CH2:26][C:27]3[O:9][N:8]=[C:1]4[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][C:2]=34)[CH2:20][CH:19]=2)[CH:14]=[CH:15][C:16]=1[F:17]
Reactant: CCOC(=O)CCCN1CC=C(c2ccc(F)c(Cl)c2)CC1
Reactant: ON=C1CCCCCC1
Product: Fc1ccc(C2=CCN(CCCc3onc4c3CCCCC4)CC2)cc1Cl

Procedure:
By the same reaction and treatment as in Example 48 using cycloheptanone oxime and ethyl 4-(4-(3-chloro-4-fluorophenyl)-1,2,3,6-tetrahydropyridin-1-yl)-n-butyrate, 3-(3-(4-(3-chloro-4-fluorophenyl)-1,2,3,6-tetrahydropyridin-1-yl)propyl)-5,6,7,8-tetrahydro-4H-cyclohepta[c]isoxazole is obtained.
Reaction SMILES: [C:1]([SH:9])(=[S:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:10][C:11]1[CH:19]=[CH:18][C:14]([C:15]([CH3:17])=[CH2:16])=[CH:13][CH:12]=1>CCCCCC>[C:1]([S:9][C:15]([C:14]1[CH:18]=[CH:19][C:11]([Cl:10])=[CH:12][CH:13]=1)([CH3:17])[CH3:16])(=[S:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=C(C)c1ccc(Cl)cc1
Reactant: S=C(S)c1ccccc1
Solvent: CCCCCC
Product: CC(C)(SC(=S)c1ccccc1)c1ccc(Cl)cc1
Temperature: 70 °C
Yield: 34.2 %

Procedure:
Dithiobenzoic acid (6.3 g) and 4-chloro-α-methylstyrene (6 g) were combined and the mixture heated at 70° C. overnight. The residue was subjected to column chromatography (Kieselgel-60, 70-230 mesh, n-hexane as eluent) which gave the title compound as a purple solid (34.2% yield) m.p. 77-78° C. 1H-nmr (CDCl3) d (ppm): 1.97 (s, 6H, 2×CH3), 7.20-7.52 (m, 7H, ArH) and 7.86 (d, 2H, ArH). 13C-nmr (CDCl3) d (ppm): 28.4, 55.7, 126.5, 128.1, 131.9, 132.4, 142.8, 146.0. The signal due to C═S (d>220.0 ppm) was beyond the frequency range of the spectrum.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5](Cl)=[O:6].Cl.[CH3:12][NH:13][O:14][CH3:15].C(NC(C)C)(C)C>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([N:13]([O:14][CH3:15])[CH3:12])=[O:6]
Reactant: CNOC
Reactant: O=C(Cl)c1cccc(Br)c1
Agent: Cl
Solvent: ClCCl
Solvent: CC(C)NC(C)C
Product: CON(C)C(=O)c1cccc(Br)c1
Reaction time: 0.5 h
Yield: 89.9 %

Procedure:
A solution of 3-bromobenzoyl chloride (20 g, 91.1 mmol) in CH2Cl2 was added dropwise to a cold (0° C.) solution of N,O-dimethylhydroxylamine hydrochloride (33.6 g, 319 mmol), diisopropylamine (98 mL, 551 mmol) in CH2Cl2 over 1 hour. The stirring continued at room temperature for 30 minutes then concentrated under vacuo. The resultant residue was dispersed in water and extracted with ethyl ether. The organic extracts were combined, dried over MgSO4 and concentrated in vacuo. This residue was purified on silica gel (ISCO) using hexanes/EtOAc (4/1) as the eluting solvent to give 3-bromo-N-methoxy-N-methylbenzamide as light yellow solid (20 g, 89% yield). m/e (M+H)+ 244. 1H NMR (400 MHz, DMSO-d6) δ ppm, 3.21 (s, 3H), 3.50 (s, 3H), 7.37-7.39, (m, 1H), 7.53-7.55 (m, 1H), 7.64-7.66 (m, 1H), 7.67-7.69 (m, 1H).
Reaction SMILES: [F:1][CH:2]([F:8])[C:3](=O)[CH2:4][C:5]#[N:6].O.[NH2:10][NH2:11]>CCO>[F:1][CH:2]([F:8])[C:3]1[NH:11][N:10]=[C:5]([NH2:6])[CH:4]=1
Reactant: NN
Reactant: N#CCC(=O)C(F)F
Solvent: O
Solvent: CCO
Product: Nc1cc(C(F)F)[nH]n1
Temperature: 25 °C
Yield: 27 %

Procedure:
To a solution of 4,4-difluoro-3-oxobutanenitrile in EtOH (200 mL) was added hydrazine hydrate (30 mL). The reaction was heated at reflux for 12 h before cooling to RT. After evaporation in vacuo, the residue was extracted into DCM. The organic layers were washed with water, brine, dried (MgSO4). After filtration, the solvent was evaporated in vacuo. The crude product was purified by SiO2 chromatography to afford 5-(difluoromethyl)-1H-pyrazol-3-amine (8.0 g, 27% for two steps) as an oil: MS (ESI) m/z: 134.0 [M+1]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15]([S:17][CH3:18])[CH:14]=[CH:13][N:12]=3)=[N:9][N:8]([C:19]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:5]2=[N:6][CH:7]=1.FC1C=C2C(B3OC(C)(C)C(C)(C)[O:49]3)=NN(C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)C2=NC=1.C1C=C(Cl)C=C(C(OO)=O)C=1>ClCCl>[F:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15]([S:17]([CH3:18])=[O:49])[CH:14]=[CH:13][N:12]=3)=[N:9][N:8]([C:19]([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)([C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:5]2=[N:6][CH:7]=1
Reactant: CC1(C)OB(c2nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c3ncc(F)cc23)OC1(C)C
Reactant: CSc1ccnc(-c2nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c3ncc(F)cc23)n1
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CS(=O)c1ccnc(-c2nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c3ncc(F)cc23)n1
Reaction time: 0.5 h

Procedure:
To a cold (0° C.) mixture of 5-fluoro-3-(4-(methylthio)pyrimidin-2-yl)-1-trityl-1H-pyrazolo[3,4-b]pyridine, 135a, (0.70 g, 1.38 mmol) in dichloromethane (10.4 mL) was added mCPBA (0.43 g, 1.93 mmol). After 30 minutes, the mixture was diluted with dichloromethane and washed with 2N NaOH and brine. The organic phase was brine dried over Na2SO4, filtered and stripped down twice with CH3CN to afford 660 mg of desired product that was used without further purification: LCMS Gradient 60-98%, 0.1% formic acid, 7 min, C4/ACN, Retention Time=2.68 minutes (M+H) 520.
Reaction SMILES: [N:1]1[CH:2]=[C:3]2[N:12]3[C:7](=[CH:8][CH:9]=[CH:10][C:11]=13)[S:6][C:5]([CH2:13][OH:14])=[CH:4]2.CN(C)C=O>C(OCC)(=O)C.[O-2].[O-2].[Mn+4]>[N:1]1[CH:2]=[C:3]2[N:12]3[C:7](=[CH:8][CH:9]=[CH:10][C:11]=13)[S:6][C:5]([CH:13]=[O:14])=[CH:4]2
Reactant: OCC1=Cc2cnc3cccc(n23)S1
Agent: [Mn+4]
Agent: [O-2]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=CC1=Cc2cnc3cccc(n23)S1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 7.777 g (38.076 mM) of 5-thia-1,8b-diazaacenaphthylene-4-methanol in ethyl acetate (50 ml)-N,N-dimethylformamide (50 ml) was added 23 g of active manganese dioxide and the mixture was stirred at room temperature for 4 hours. The reaction mixture was filtered and the precipitate was washed with N,N-dimethylformamide. The pooled filtrate was distilled under reduced pressure to remove the solvent. The crude 5-thia-1,8b-diazaacenaphthylene-4-carbaldehyde thus obtained was not purified but used as it was in the next reaction. To a solution of 9.39 g (41.9 mM) of ethyl diethylphosphonoacetate in 50 ml of toluene was added 1.68 g (41.9 mM) of a 60% suspension of sodium hydride in liquid paraffin at room temperature and the mixture was stirred for 0.5 hour. This mixture was added to a solution of the above crude 5-thia-1,8b-diazaacenaphthylene-4-carbaldehyde in N,N-dimethylformamide (50 ml)-toluene (200 ml) under ice cooling and the mixture was stirred at room temperature for one hour. This reaction mixture was poured in water and extracted with 3 portions of ethyl acetate. The organic layers were pooled and dried over MgSO4 and the solvent was distilled off under reduced pressure. The resulting crude ethyl 3-(5-thia-1,8b-diazaacenaphthylen-4-yl)acrylate was not purified but used as it was in the next reaction. To a solution of the above crude ethyl 3-(5-thia-1,8b-diazaacenaphthylen-4-yl)acrylate in 300 ml of ethanol was added 60 ml (120 mM) of 2N-aqueous solution of sodium hydroxide and the mixture was stirred at room temperature for 3 hours. To this reaction mixture was added concentrated hydrochloric acid (ca 10 ml) with stirring to bring the pH into the range of 4-5 and the resulting precipitate was recovered by filtration and rinsed serially with ethanol and diethyl ether to provide the title compound.
Reaction SMILES: [CH3:1][C:2]([O:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([N+:14]([O-])=O)[CH:9]=1)([CH3:6])[C:3]([NH2:5])=[O:4].C([SiH](CC)CC)C>CO.[Pd]>[NH2:14][C:10]1[CH:9]=[C:8]([CH:13]=[CH:12][CH:11]=1)[O:7][C:2]([CH3:6])([CH3:1])[C:3]([NH2:5])=[O:4]
Reactant: CC(C)(Oc1cccc([N+](=O)[O-])c1)C(N)=O
Agent: [Pd]
Agent: CC[SiH](CC)CC
Solvent: CO
Product: CC(C)(Oc1cccc(N)c1)C(N)=O
Reaction time: 0.5 h
Yield: 65.4 %

Procedure:
To a stirred solution of 2-methyl-2-(3-nitrophenoxy)propanamide (0.910 g, 4.06 mmol) in MeOH (15 ml) was added Pd—C (10%, 0.346 g) and triethylsilane (6.48 ml, 40.6 mmol) (slow addition) at room temperature. The reaction mixture was stirred at same temperature for 30 min. and filtered through celite, washed with methanol (50 ml). The Filtrate was concentrated under vacuum to get the crude compound. The crude compound was purified by flash chromatography to give the title product (0.516 g).
Reaction SMILES: [C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([OH:20])[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl[C:22]1[C:31]2[C:26](=[CH:27][C:28]([O:34][CH2:35][CH3:36])=[C:29]([O:32][CH3:33])[CH:30]=2)[N:25]=[CH:24][N:23]=1.CC(C)([O-])C.[K+]>C1COCC1>[C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:22]3[C:31]4[C:26](=[CH:27][C:28]([O:34][CH2:35][CH3:36])=[C:29]([O:32][CH3:33])[CH:30]=4)[N:25]=[CH:24][N:23]=3)[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOc1cc2ncnc(Cl)c2cc1OC
Reactant: CC(C)(C)c1cc(NC(=O)Nc2cccc(O)c2)no1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCOc1cc2ncnc(Oc3cccc(NC(=O)Nc4cc(C(C)(C)C)on4)c3)c2cc1OC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 1-(5-tert-butylisoxazol-3-yl)-3-(3-hydroxyphenyl)urea from Example 1A (0.2 g 0.73 mmol), 4-chloro-7-ethoxy-6-methoxyquinazoline from the previous step (0.18 g, 0.75 mmol), and potassium tert-butoxide (0.252 g, 2.25 mmol) in THF was stirred at room temperature overnight, and then was heated at 60° C. for 5 hours. The reaction was still found to be incomplete and additional 1-(5-tert-butylisoxazol-3-yl)-3-(3-hydroxyphenyl)urea (0.07 g, 0.025 mmol) was added. The mixture was heated further at 60° C. overnight. The reaction was quenched with water and extracted with EtOAc. Extracts were dried over MgSO4 and concentrated under reduced pressure. It was purified by silica gel chromatography with EtOAc/hexane as eluant to afford 1-(5-tert-butylisoxazol-3-yl)-3-[3-(7-ethoxy-6-methoxyquinazolin-4-yloxy)phenyl]urea as a solid (0.078 g). 1H NMR (300 MHz, CDCl3) δ 9.12 (br and s, 2H), 8.61 (s, 1H), 7.64 (s, 1H), 7.54 (s, 1H), 7.31 (m, 3H), 7.0 (d, 1H), 6.05 (s, 1H), 4.29 (q, 2H), 4.05 (s, 3H), 1.58 (t, 3H), 1.30 (s, 9H); LC-MS (ESI) m/z 478 (M+H)+.
Reaction SMILES: [F:1][C:2]1[C:9]([CH:10]=[O:11])=[C:8]([F:12])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[BH4-].[Na+].O>C(O)C>[F:1][C:2]1[C:9]([CH2:10][OH:11])=[C:8]([F:12])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: N#Cc1ccc(F)c(C=O)c1F
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: N#Cc1ccc(F)c(CO)c1F
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A stirred solution of 300 mg (3.48 mmol) of 2,4-difluoro-3-formylbenzonitrile (CAS 149489-14-5) in 10 ml of ethanol at 0° C. was admixed with 34 mg (0.89 mmol) of sodium borohydride in portions. After stirring at 0° C. for 1 h, the reaction mixture was mixed with water and extracted three times with methyl tert-butyl ether. The combined organic extracts were washed with water and saturated aqueous sodium chloride solution, and dried with a phase separation cartridge. The solvent was drawn off to dryness under reduced pressure, which gave 280 mg (82% of theory) of the target compound.
Reaction SMILES: [OH:1][N:2]([CH3:21])[C:3](=[O:20])[CH:4]([NH:6][C:7]1[C:12]([N+:13]([O-:15])=[O:14])=[CH:11][C:10]([CH3:16])=[CH:9][C:8]=1[N+:17]([O-:19])=[O:18])[CH3:5].[CH3:22][S:23](Cl)(=[O:25])=[O:24].CN1C=CN=C1.O>C(Cl)Cl>[CH3:22][S:23]([O:1][N:2]([CH3:21])[C:3](=[O:20])[CH:4]([NH:6][C:7]1[C:12]([N+:13]([O-:15])=[O:14])=[CH:11][C:10]([CH3:16])=[CH:9][C:8]=1[N+:17]([O-:19])=[O:18])[CH3:5])(=[O:25])=[O:24]
Reactant: Cc1cc([N+](=O)[O-])c(NC(C)C(=O)N(C)O)c([N+](=O)[O-])c1
Reactant: CS(=O)(=O)Cl
Agent: Cn1ccnc1
Solvent: ClCCl
Solvent: O
Product: Cc1cc([N+](=O)[O-])c(NC(C)C(=O)N(C)OS(C)(=O)=O)c([N+](=O)[O-])c1
Yield: 22.6 %

Procedure:
2.8 g of N-hydroxy-N-methyl-2-(4-methyl-2,6-dinitrophenylamino)propanamide in 50 ml methylene chloride was added at room temperature to a stirred suspension of the product prepared from 1.4 g methane sulfonyl chloride and 0.8 g N-methylimidazole. After 3 hours the resulting mixture was poured into water. The methylene chloride layer was evaporated to dryness and the residue was crystallized from ethanol to give a 0.8 g (22% yield) of product as a yellow solid; m.p. 145° C. with decomposition, (d,l) isomer form.
Reaction SMILES: [ClH:1].Cl.[CH3:3][C:4]1[N:5]=[C:6]([NH:9][C:10]2[N:15]=[CH:14][C:13]([S:16][CH2:17][C:18]3[C:23]([OH:24])=[CH:22][CH:21]=[CH:20][N:19]=3)=[CH:12][C:11]=2[O:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[S:7][CH:8]=1.[H-].[Na+].[CH3:34]I>CN(C=O)C>[ClH:1].[CH3:34][O:24][C:23]1[C:18]([CH2:17][S:16][C:13]2[CH:12]=[C:11]([O:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:10]([NH:9][C:6]3[S:7][CH:8]=[C:4]([CH3:3])[N:5]=3)=[N:15][CH:14]=2)=[N:19][CH:20]=[CH:21][CH:22]=1
Reactant: CI
Reactant: Cc1csc(Nc2ncc(SCc3ncccc3O)cc2Oc2ccccc2)n1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cccnc1CSc1cnc(Nc2nc(C)cs2)c(Oc2ccccc2)c1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 4.2 %

Procedure:
Placed 2-((6-(4-methylthiazol-2-ylamino)-5-phenoxypyridin-3-ylthio)methyl)pyridine-3-ol (prepared in Example 69) (0.180 g, 0.426 mmol) in DMF (5 mL) and cooled to 0° C. Sodium hydride (0.0307 g, 1.28 mmol) was added and stirred for 10 minutes then MeI (0.0605 g, 0.426 mmol) was added stirred at ambient temperature for 30 minutes. Added water and extracted with CH2Cl2. The organic layer was concentrated and purified by silica gel. The product was still impure. Mixture was purified by medium pressure reverse phase followed by two high pressure reverse phase purifications. Combined all clean fractions then dissolved in CH2Cl2 and added HCl in ether, then concentrated to give the title compound (0.0085 g, 4.22% yield). 1H NMR (d6-DMSO) δ 8.14 (m, 1H), 8.10 (d, 1H), 7.65 (m, 1H), 7.55 (m, 1H), 7.34-7.27 (m, 3H), 7.03 (m, 1H), 6.85 (d, 2H), 6.36 (s, 1H), 4.24 (s, 2H), 3.17 (s, 3H), 2.18 (s, 3H).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([N+:9]([O-:11])=[O:10])[CH:4]=1.[NH:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1.C([O-])([O-])=O.[K+].[K+]>C1COCC1>[N+:9]([C:5]1[CH:4]=[C:3]([CH:8]=[CH:7][CH:6]=1)[CH2:2][N:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1)([O-:11])=[O:10]
Reactant: C1CCNC1
Reactant: O=[N+]([O-])c1cccc(CBr)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: O=[N+]([O-])c1cccc(CN2CCCC2)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
1-(Bromomethyl)-3-nitrobenzene (5 g, 23.1 mmol) was taken up in 100 mL of anhydrous THF along with pyrrolidine (2.3 mL, 27.72 mmol) and K2CO3 (4.8 g, 34.6 mmol). The reaction mixture was stirred at room temperature for 18 h and then filtered. The filtrate was concentrated under reduced pressure to afford 1-(3-nitrobenzyl)pyrrolidine. This material was taken up in 100 mL of absolute EtOH and 10% Pd on C (300 mg) was added. The resulting reaction mixture was stirred at room temperature under 1 atm of hydrogen for 18 h. The mixture was then filtered through a pad of Celite and the filtrate was concentrated under reduced pressure to afford 2.81 g of 3-(pyrrolidin-1-ylmethyl)aniline (70%).
Reaction SMILES: [CH3:1][N:2]([CH3:7])[S:3](Cl)(=[O:5])=[O:4].[Br:8][C:9]1[C:17]2[N:16]([CH3:18])[C:15]3[CH2:19][CH2:20][N:21]([CH2:24][C:25]4[N:26]=[CH:27][NH:28][C:29]=4[CH3:30])[C:22](=[O:23])[C:14]=3[C:13]=2[CH:12]=[CH:11][CH:10]=1.C(N(CC)CC)C>ClCCl>[Br:8][C:9]1[C:17]2[N:16]([CH3:18])[C:15]3[CH2:19][CH2:20][N:21]([CH2:24][C:25]4[N:26]=[CH:27][N:28]([S:3]([N:2]([CH3:7])[CH3:1])(=[O:5])=[O:4])[C:29]=4[CH3:30])[C:22](=[O:23])[C:14]=3[C:13]=2[CH:12]=[CH:11][CH:10]=1
Reactant: CN(C)S(=O)(=O)Cl
Reactant: Cc1[nH]cnc1CN1CCc2c(c3cccc(Br)c3n2C)C1=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1c(CN2CCc3c(c4cccc(Br)c4n3C)C2=O)ncn1S(=O)(=O)N(C)C
Reaction time: 60 h

Procedure:
Dimethylsulphamoyl chloride (0.31 ml) was added dropwise to a stirred suspension of 6-bromo-2,3,4,5-tetrahydro-5-methyl-2-[(5-methyl-1H-imidazol-4-yl) methyl]-1H-pyrido[4,3-b]indol-1-one (1.1 g) and triethylamine (0.48 ml) in dry dichloromethane (100 ml). The mixture was heated at reflux for 18 h, then a further quantity of triethylamine (0.48 ml) and dimethylsulphamoyl chloride (0.31 ml) was added. The solution was heated at reflux for 8 h then left at 21° for ca. 60 h. The solution was concentrated in vacuo and purified by FCC eluting with System A (100:8:1) to give a solid, which was triturated with hexane (50 ml) to give the title compound (500 mg), m.p. 182°-185°.
Reaction SMILES: C([C@@H]1[O:9][C:8](=[O:10])[C@@:7]([CH3:14])([CH:11]([CH3:13])[CH3:12])[O:6]1)(C)(C)C.[OH-].[K+].Cl>CO.O>[CH3:14][C@:7]([OH:6])([CH:11]([CH3:13])[CH3:12])[C:8]([OH:10])=[O:9]
Reactant: CC(C)[C@@]1(C)O[C@H](C(C)(C)C)OC1=O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)[C@](C)(O)C(=O)O
Temperature: 25 °C
Yield: 95 %

Procedure:
To a magnetically stirred solution of (7) (94 g, 0.47 mol) in methanol (450 mL) and water (100 mL), in a 1-L, one-neck, round-bottom flask was added potassium hydroxide pellets (48 g, 0.85 mol, 1.8 equivalents). The reaction was then heated to reflux for 30 minutes. The mixture was cooled to room temperature and concentrated in vacuo to afford a milky suspension. This mixture was diluted with water (100 mL), cooled to 0° C., and acidified with concentrated hydrochloric acid (15 mL) to pH 6. Additional water (100 mL) was added, and the mixture extracted with ethyl acetate (3×400 mL). The combined organics were washed with water (1×600 mL), saturated aqueous chloride solution (1×600 mL), dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated in vacuo to afford a pale yellow oil which on drying in vacuo afforded 59 g (94% yield) of (8) as a crystalline solid. The 1H NMR of the product was consistent with the material previously prepared.