Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:27])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][C:16]=2[CH2:25]Br)[CH:7]=1)[CH3:2].Cl[C:29]1[CH:34]=[CH:33][C:32]([C@@H:35]2[O:39][C:38](=[O:40])[NH:37][C@@H:36]2[CH3:41])=[CH:31][CH:30]=1>>[CH2:1]([O:3][C:4](=[O:27])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][C:16]=2[CH2:25][N:37]2[C@H:36]([CH3:41])[C@H:35]([C:32]3[CH:33]=[CH:34][CH:29]=[CH:30][CH:31]=3)[O:39][C:38]2=[O:40])[CH:7]=1)[CH3:2]
Reactant: CCOC(=O)Cc1ccc(OC)c(Oc2ccc(C(F)(F)F)cc2CBr)c1
Reactant: C[C@H]1NC(=O)O[C@H]1c1ccc(Cl)cc1
Product: CCOC(=O)Cc1ccc(OC)c(Oc2ccc(C(F)(F)F)cc2CN2C(=O)O[C@@H](c3ccccc3)[C@H]2C)c1

Procedure:
Prepared according to the procedure described in Example 10, Step 7, using the following starting materials: [3-(2-Bromomethyl-4-trifluoromethyl-phenoxy)-4-methoxy-phenyl]-acetic acid ethyl ester and (4R,5S)-5-(4-chloro-phenyl)-4-methyl-oxazolidin-2-one.
Reaction SMILES: [CH:1]1[C:10]2[C:9]([NH2:11])=[N:8][C:7]3[CH:12]=[CH:13][CH:14]=[CH:15][C:6]=3[NH:5][C:4]=2[S:3][CH:2]=1.[CH3:16][O:17][CH2:18][CH2:19][C@H:20]1[CH2:25]N[CH2:23][CH2:22][NH:21]1.CS(C)=O.C1(C)C=CC=CC=1>C(OCC)(=O)C>[CH3:16][O:17][CH2:18][CH2:19][C@@H:20]1[NH:21][CH2:22][CH2:23][N:11]([C:9]2[C:10]3[CH:1]=[CH:2][S:3][C:4]=3[NH:5][C:6]3[CH:15]=[CH:14][CH:13]=[CH:12][C:7]=3[N:8]=2)[CH2:25]1
Reactant: COCC[C@H]1CNCCN1
Reactant: NC1=Nc2ccccc2Nc2sccc21
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: COCC[C@H]1CN(C2=Nc3ccccc3Nc3sccc32)CCN1
Temperature: 105 °C
Reaction time: 24 h
Yield: 19.8 %

Procedure:
Combine 4H-3-thia-4,9-diaza-benzo[f]azulen-10-ylamine (1.26 g, 5.85 mmol), (S)-2-(2-methoxy-ethyl)-piperazine (2.53 g, 17.56 mmol), DMSO (4.0 ml), and toluene (16.0 ml). Stir and heat the mixture at 105° C. After 24 hours, cool the mixture to ambient temperature. Dilute the mixture with ethyl acetate and wash the organic layer with 0.1N NaOH and brine. Dry (sodium sulfate) and concentrate the organic layer to residue. Purify the residue on silica gel using a gradient of dichloromethane to dichloromethane/methanol (85:15) to give 395.8 mg (20%) of an brown foam: mass spectrum (ion spray): m/z=343.1 (M+1).
Reaction SMILES: [C:1]1([C:7](Cl)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[C:28]1[NH:32][N:31]=[N:30][N:29]=1>C(Cl)Cl>[C:22]1([CH3:21])[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[C:28]1[N:32]([C:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[N:31]=[N:30][N:29]=1
Reactant: Cc1ccccc1-c1nnn[nH]1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Product: Cc1ccccc1-c1nnnn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 8 h
Yield: 31.6 %

Procedure:
A solution of triphenylmethyl chloride (348 mg, 1.25 mmol, 2 ml DCM) was added dropwise to a mixture of 5-(2-methylphenyl)-1H-tetrazole (200.5 mg, 1.25 mmol) and TEA (174 μl, 1.25 mmol) in 8 ml DCM. The reaction mixture was strirred overnight at RT, then washed with water (10 ml). The organic layer was dried over sodium sulfate and evaporated in vacuo. The residue was purified by preparative chromatography (Cyclohexane/EtOAc 95:5) to yield the above-titled compound (159 mg). 1H NMR (CDCl3): 8.1 (1H, d), 7.45-7.1 (18H, m), 2.5 (3H, s).
Reaction SMILES: [N:1]1([C:6]2[CH:7]=[C:8]([CH:12]=[CH:13][CH:14]=2)[C:9](O)=[O:10])[CH:5]=[CH:4][N:3]=[N:2]1.B.C1COCC1.CO.O>C1COCC1>[N:1]1([C:6]2[CH:7]=[C:8]([CH2:9][OH:10])[CH:12]=[CH:13][CH:14]=2)[CH:5]=[CH:4][N:3]=[N:2]1
Reactant: O=C(O)c1cccc(-n2ccnn2)c1
Agent: B
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: OCc1cccc(-n2ccnn2)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A cooled (0° C.) solution of the minor isomer 3-(1H-1,2,3-triazol-1-yl)benzoic acid (210 mg; 1.11 mmol) in anh. THF (3 ml) was treated dropwise with a BH3.THF (1.0 M in THF; 2.77 ml; 2.77 mmol), and this mixture was stirred at 0° C., under nitrogen, for 1 h, and then at rt for 17 h. The resulting reaction mixture was then cooled to 0° C., and treated successively with MeOH (10 ml) and water (10 ml). The organic solvents were removed under reduced pressure, and the resulting aq. layer was extracted with DCM (3×10 ml). The mixed organic layers were washed with brine, dried over anh. MgSO4, filtered, and concentrated to dryness under reduced pressure. Purification by FC (DCM/MeOH=20/1) afforded (3-(1H-1,2,3-triazol-1-yl)phenyl)methanol as a pale yellow solid. LC-MS (conditions A): tR=0.38 min.; [M+H]+: 176.18 g/mol.
Reaction SMILES: FC(F)(F)S([O-])(=O)=O.C[N+]1[CH:14]=[CH:13][N:12]([S:15](=[O:25])(=[O:24])[N:16]([CH3:23])[CH:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)C=1.[C@H:26]1([NH:35][C:36]2[CH:45]=[CH:44][C:43]3[C:38](=[CH:39][CH:40]=C(N)C=3)[N:37]=2)[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH2:28][CH2:27]1>>[C@H:26]1([NH:35][C:36]2[CH:45]=[CH:44][C:43]3[C:38](=[CH:39][CH:40]=[C:13]([NH:12][S:15]([N:16]([CH3:23])[CH:17]4[CH2:18][CH2:19][O:20][CH2:21][CH2:22]4)(=[O:24])=[O:25])[CH:14]=3)[N:37]=2)[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH2:28][CH2:27]1
Reactant: CN(C1CCOCC1)S(=O)(=O)n1cc[n+](C)c1
Reactant: Nc1ccc2nc(N[C@@H]3CCc4ccccc43)ccc2c1
Agent: O=S(=O)([O-])C(F)(F)F
Product: CN(C1CCOCC1)S(=O)(=O)Nc1ccc2nc(N[C@@H]3CCc4ccccc43)ccc2c1

Procedure:
The title compound was prepared in accordance with step C of the general method described in example 76 from 1-methyl-3-[methyl-(tetrahydro-pyran-4-yl)-sulfamoyl]-3H-imidazol-1-ium trifluoromethanesulfonate and (R)—N2-indan-1-yl-quinoline-2,6-diamine; MS: m/e=453.8 (M+H+).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH:5]([C:10]1[CH:15]=[C:14]([CH:16]([CH3:18])[CH3:17])[C:13]([O:19][CH3:20])=[CH:12][C:11]=1[CH3:21])[C:6]([NH:8][NH2:9])=O.[N:22]#[C:23][NH2:24].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(N(CC)CC)C>C(O)C>[CH:16]([C:14]1[C:13]([O:19][CH3:20])=[CH:12][C:11]([CH3:21])=[C:10]([CH:5]2[CH2:4][CH2:3][CH2:2][N:8]3[N:9]=[C:23]([NH2:24])[N:22]=[C:6]23)[CH:15]=1)([CH3:18])[CH3:17]
Reactant: COc1cc(C)c(C(CCCCl)C(=O)NN)cc1C(C)C
Reactant: N#CN
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: CCO
Product: COc1cc(C)c(C2CCCn3nc(N)nc32)cc1C(C)C
Temperature: 80 °C
Yield: 56.8 %

Procedure:
5-Chloro-2-(5-isopropyl-4-methoxy-2-methylphenyl)pentanoic acid hydrazide (4.4 g) and cyanamide (3.6 g) were dissolved in ethanol (150 mL). p-Toluenesulfonic acid monohydrate (4 g) was added and the mixture was heated under reflux at 80° C. for two hours. After cooling to room temperature, triethylamine (9.8 mL) was added and the mixture was further heated under reflux at 80° C. for three days. The reaction solution was concentrated under reduced pressure. A sodium bicarbonate solution and ethyl acetate were added and the organic layer was separated. The resulting organic layer was washed with brine and then dried over anhydrous sodium sulfate. The drying agent was separated by filtration, and then the organic layer was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound (2.4 g). The property values of the compound are as follows.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([O:13][CH3:14])=[CH:11][C:10]([C:15]([OH:17])=O)=[N:9]1.CN(C=O)C.C(Cl)(=O)C([Cl:26])=O>CC1CCCO1>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([O:13][CH3:14])=[CH:11][C:10]([C:15]([Cl:26])=[O:17])=[N:9]1
Reactant: COc1cc(C(=O)O)nn1-c1ccccc1F
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CC1CCCO1
Product: COc1cc(C(=O)Cl)nn1-c1ccccc1F
Temperature: 0 °C

Procedure:
A suspension of 1-(2-fluoro-phenyl)-5-methoxy-1H-pyrazole-3-carboxylic acid (39.1 g, 167 mmol) in 2-methyltetrahydrofuran (300 ml) was cooled to 0° C. and DMF (293 μl, 3.81 mmol) was added. Oxalyl chloride (23.1 g, 182 mmol) was added dropwise. After 16 h at room temperature ca. 100 ml of the solvent were removed by distillation. The resulting suspension of the title compound was used directly in the next step.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[O:3][C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH2:6]O.[Br-:14].[C:15]1([PH+:21]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C(#N)C>[Br-:14].[C:28]1([P+:21]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:6][C:5]2[CH:8]=[CH:9][CH:10]=[CH:11][C:4]=2[O:3][C:2]([F:13])([F:12])[F:1])[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: c1ccc([PH+](c2ccccc2)c2ccccc2)cc1
Reactant: OCc1ccccc1OC(F)(F)F
Agent: [Br-]
Solvent: CC#N
Product: FC(F)(F)Oc1ccccc1C[P+](c1ccccc1)(c1ccccc1)c1ccccc1

Procedure:
5 g (26 mmol) of 2-trifluoromethoxybenzyl alcohol and 8.5 g (24.7 mmol) of triphenylphosphonium bromide are heated under reflux in 100 ml of acetonitrile for 3 h. After cooling, the resulting precipitate is filtered off with suction and dried. 13.5 g (quant.) of the title compound are obtained.
Reaction SMILES: [CH2:1]([O:4][C:5]([C:7]1[C:8]([N+:19]([O-])=O)=[C:9]([CH:16]=[CH:17][CH:18]=1)[C:10]([O:12][CH2:13][CH:14]=[CH2:15])=[O:11])=[O:6])[CH:2]=[CH2:3]>C(O)C>[CH2:1]([O:4][C:5]([C:7]1[C:8]([NH2:19])=[C:9]([CH:16]=[CH:17][CH:18]=1)[C:10]([O:12][CH2:13][CH:14]=[CH2:15])=[O:11])=[O:6])[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)c1cccc(C(=O)OCC=C)c1[N+](=O)[O-]
Solvent: CCO
Product: C=CCOC(=O)c1cccc(C(=O)OCC=C)c1N

Procedure:
The above nitro compound was reduced by the method described in example 6, except that the solvent was ethanol, to give allyl 3-allyloxycarbonyl-2-aminobenzoate.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][CH2:8][CH2:9][OH:10])=[CH:3][CH:2]=1.C(N(CC)CC)C.[CH3:18][S:19](Cl)(=[O:21])=[O:20]>ClCCl>[N:1]1[CH:6]=[CH:5][C:4]([CH2:7][CH2:8][CH2:9][O:10][S:19]([CH3:18])(=[O:21])=[O:20])=[CH:3][CH:2]=1
Reactant: OCCCc1ccncc1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCCCc1ccncc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a stirring solution of 3-pyridin-4-yl-propan-1-ol (0.71 mL, 5.47 mmol) in dichloromethane (20 mL) in a 0° C. ice bath, is added triethylamine (0.95 mL, 6.83 mmol) and methanesulfonylchloride (0.44 mL, 5.74 mmol) and the ice bath removed. The mixture is stirred at room temperature for 15 min after which time the reaction is complete. The product is left in solution and used as is in the subsequent reaction.
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:3]=1[C:4]([C:6]1C=CC=CC=1)=[O:5].[CH:18]([C:21]1[N:22]=[C:23]([C:26](O)=[O:27])[S:24][CH:25]=1)(C)C.O=P(Cl)(Cl)Cl>N1C=CC=CC=1>[C:4]([C:3]1[CH:12]=[CH:13][C:14]([O:16][CH3:17])=[CH:15][C:2]=1[NH:1][C:26]([C:23]1[S:24][CH:25]=[C:21]([CH3:18])[N:22]=1)=[O:27])(=[O:5])[CH3:6]
Reactant: CC(C)c1csc(C(=O)O)n1
Reactant: COc1ccc(C(=O)c2ccccc2)c(N)c1
Solvent: c1ccncc1
Solvent: O=P(Cl)(Cl)Cl
Product: COc1ccc(C(C)=O)c(NC(=O)c2nc(C)cs2)c1
Temperature: -30 °C
Reaction time: 3 h
Yield: 56.4 %

Procedure:
Step E) To a suspension of 2.59 g (15.7 mmol) of 2-amino-4-methoxybenzophenone (product of step D) and 2.68 g (15.7 mmol) of 4-isopropylthiazole-2-carboxylic acid (product of step C) in 75 mL of pyridine cooled to −30° C., was added 1.93 mL (23.5 mmol) of POCl3 slowly dropwise over 5 min. The mixture was stirred 3 h, warmed to room temperature and was stirred overnite. The reaction mixture was poured into ice water, and extracted several times with EtOAc. The combined EtOAc extracts were dried (MgSO4), concentrated and chromatographed over SiO2 (eluted with 0% to 15% MeOH/EtOAc) to afford 2.57 g (51%) of 4-Methylthiazole-2-carboxylic acid (2-acetyl-5-methoxyphenyl)amide as a yellow solid: 1H NMR (500 MHz, CDCl3) δ 1.41 (d, J=6.7 Hz, 6H), 2.64 (s, 3H), 3.24 (m, 1H), 3.91 (s, 3H), 6.67 (dd, J=9, 2.5 Hz, 1H), 7.18 (s, 1H), 7.86 (d, J=9 Hz, 1H), 8.56 (d, J=2.5 Hz, 1H), 13.48 (s, 1H).
Reaction SMILES: [C:1]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14](CO)=[CH:13][C:12]=1[CH2:19][O:20][C:21](=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:29](Br)(Br)(Br)[Br:30].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>ClCCl>[C:21]([O:20][CH2:19][C:12]1[CH:13]=[C:14]([CH:15]=[CH:16][C:11]=1[CH2:10][O:9][C:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH2:29][Br:30])(=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: BrC(Br)(Br)Br
Reactant: O=C(OCc1ccc(CO)cc1COC(=O)c1ccccc1)c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: ClCCl
Product: O=C(OCc1ccc(CBr)cc1COC(=O)c1ccccc1)c1ccccc1
Temperature: 25 °C
Yield: 70 %

Procedure:
40 g (106 mmol) of 2-benzoyloxymethyl-4-hydroxymethylbenzyl benzoate are placed in 500 ml of dichloromethane and 77.6 g (234 mmol) of carbon tetrabromide in a round-bottomed flask and under a stream of nitrogen. At 0° C., a solution of 61.3 g (233 mmol) of triphenylphosphine in 200 ml of dichloromethane is added dropwise. The mixture is allowed to warm to room temperature over 2 hours. The reaction medium is poured into water and extracted with dichloromethane. The organic phase is dried over magnesium sulfate, filtered and then evaporated. The residue is purified by chromatography on a column of silica eluted with a mixture of heptane and ethyl acetate (70/30) to give 32.6 g (70%) of the expected product in the form of a white powder.
Reaction SMILES: [CH2:1]([NH:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[OH:34]O>C(O)C>[CH2:18]([N:17]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[OH:34])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]
Reactant: OO
Reactant: CCCCCCCCCCCCCCCCNCCCCCCCCCCCCCCCC
Solvent: CCO
Product: CCCCCCCCCCCCCCCCN(O)CCCCCCCCCCCCCCCC
Reaction time: 48 h

Procedure:
The general procedure of Example 11 is followed using 100 grams (0.19 mol) of dihexadecylamine (451 eq. wt., 88% secondary amine, 30.2 grams (0.44 mol) of 50% aqueous hydrogen peroxide solution and 400 ml of ethanol. After stirring for 48 hours, the reaction mixture is filtered to give the above-named product which is twice recrystallized from 500 ml of chloroform. The desired product is obtained in a yield of 29.4 grams (32%) as white needles melting at 97°-99° C.
Reaction SMILES: [CH3:1][N:2]([CH3:15])[C:3]1[S:7][C:6]2[CH:8]=[C:9]([O:13][CH3:14])[C:10]([F:12])=[CH:11][C:5]=2[CH:4]=1.[N+:16]([C:19]1[CH:27]=[CH:26][C:22]([C:23](Cl)=[O:24])=[CH:21][CH:20]=1)([O-:18])=[O:17]>ClC1C=CC=CC=1.CCOC(C)=O>[N+:16]([C:19]1[CH:20]=[CH:21][C:22]([C:23]([C:4]2[C:5]3[CH:11]=[C:10]([F:12])[C:9]([O:13][CH3:14])=[CH:8][C:6]=3[S:7][C:3]=2[N:2]([CH3:15])[CH3:1])=[O:24])=[CH:26][CH:27]=1)([O-:18])=[O:17]
Reactant: COc1cc2sc(N(C)C)cc2cc1F
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Solvent: CCOC(C)=O
Solvent: Clc1ccccc1
Product: COc1cc2sc(N(C)C)c(C(=O)c3ccc([N+](=O)[O-])cc3)c2cc1F
Temperature: 25 °C
Reaction time: 17 h
Yield: 116.4 %

Procedure:
A solution of 1.08 g (4.82 mmol) of 2-dimethylamino-5-fluoro-6-methoxybenzo[b]thiophene (Part B) in 15 mL of chlorobenzene was treated with 0.99 g (5.31 mmol) of 4-nitrobenzoyl chloride. The reaction was stirred at room temperature for 17 h and was diluted with 100 mL of EtOAc. The solution was washed sequentially with 2 N aqueous NaOH (2×50 mL), H2O (50 mL) and brine (50 mL), then dried over Na2SO4, and filtered. Evaporation of the solvent in vacuo afforded 2.1 g of a dark solid which was purified by flash chromatography (SiO2; gradient of 10% then 20% then 40% EtOAc in hexanes) to give 0.27 g of starting material and 1.25 g (3.34 mmol; 93% based on consumed starting material) of the title compound.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])=[N:10][C:9]=2[C:17]2[C:18]([F:35])=[C:19]([NH:23][S:24]([C:27]3[C:32]([F:33])=[CH:31][CH:30]=[CH:29][C:28]=3[F:34])(=[O:26])=[O:25])[CH:20]=[CH:21][CH:22]=2)[CH:5]=[CH:4][N:3]=1.[CH3:36][S:37]([N:40]1[CH2:45][CH2:44][CH:43]([NH2:46])[CH2:42][CH2:41]1)(=[O:39])=[O:38]>FC(F)(F)CO>[CH3:14][C:13]([C:11]1[S:12][C:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:46][CH:43]3[CH2:44][CH2:45][N:40]([S:37]([CH3:36])(=[O:39])=[O:38])[CH2:41][CH2:42]3)[N:7]=2)=[C:9]([C:17]2[C:18]([F:35])=[C:19]([NH:23][S:24]([C:27]3[C:32]([F:33])=[CH:31][CH:30]=[CH:29][C:28]=3[F:34])(=[O:26])=[O:25])[CH:20]=[CH:21][CH:22]=2)[N:10]=1)([CH3:16])[CH3:15]
Reactant: CS(=O)(=O)N1CCC(N)CC1
Reactant: CC(C)(C)c1nc(-c2cccc(NS(=O)(=O)c3c(F)cccc3F)c2F)c(-c2ccnc(Cl)n2)s1
Solvent: OCC(F)(F)F
Product: CC(C)(C)c1nc(-c2cccc(NS(=O)(=O)c3c(F)cccc3F)c2F)c(-c2ccnc(NC3CCN(S(C)(=O)=O)CC3)n2)s1
Yield: 20 %

Procedure:
Following a procedure analogous to the procedure described in Example 1 using N-{3-[5-(2-chloro-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide (0.10 g, 0.19 mmol) and 1-(methylsulfonyl)-4-piperidinamine (0.30 g, 1.7 mmol) in 2,2,2-trifluoroethanol (2 mL) the title compound was obtained (0.026 g, 0.038 mmol, 20% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.84 (s, 1H), 8.03 (br. s., 1H), 7.72-7.54 (m, 1H), 7.47-7.06 (m, 7H), 3.53-3.38 (m, 2H), 2.83 (s, 3H), 2.83-2.72 (m, 3H), 1.91-1.73 (m, 2H), 1.58-1.32 (m, 2H), 1.36 (s, 9H). MS (ESI): 681 [M+H]+.
Reaction SMILES: [C:1]1([C:7]2[O:11][C:10]([CH2:12][N:13]3[CH2:18][CH2:17][N:16]([C:19]4[CH:24]=[CH:23][C:22]([NH2:25])=[CH:21][CH:20]=4)[CH2:15][CH2:14]3)=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:26][S:27](Cl)(=[O:29])=[O:28].C(N(CC)CC)C>CCOCC>[C:1]1([C:7]2[O:11][C:10]([CH2:12][N:13]3[CH2:18][CH2:17][N:16]([C:19]4[CH:20]=[CH:21][C:22]([NH:25][S:27]([CH3:26])(=[O:29])=[O:28])=[CH:23][CH:24]=4)[CH2:15][CH2:14]3)=[CH:9][CH:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Nc1ccc(N2CCN(Cc3ccc(-c4ccccc4)o3)CC2)cc1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CS(=O)(=O)Nc1ccc(N2CCN(Cc3ccc(-c4ccccc4)o3)CC2)cc1
Reaction time: 8 h

Procedure:
The product from (b) (2.9g;0.009 mole) was stirred in anhydrous ether (50ml) at room temperature and reacted with methanesulphonyl chloride (0.68ml) in the presence of triethylamine (1.2ml). The mixture was stirred overnight, then the ether was evaporated to give a solid which was partitioned between water/chloroform. The chloroform extract was washed with saturated sodium chloride solution and evaporated to give the desired compound as a highly crystalline solid which was recrystallised from ethyl acetate, m.p. 178° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]#[N:9])[CH:5]=[CH:4][C:3]=1[C:10]1[N:15]=[C:14]2[O:16][C:17]([CH3:28])([CH3:27])[CH2:18][CH:19]([NH:20][C:21](=[O:26])[C:22]([CH3:25])([CH3:24])[CH3:23])[C:13]2=[CH:12][C:11]=1[C:29]1[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=1.Cl.[NH2:37][OH:38].C([O-])(O)=O.[Na+]>CCO>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([NH:37][OH:38])=[NH:9])[CH:5]=[CH:4][C:3]=1[C:10]1[N:15]=[C:14]2[O:16][C:17]([CH3:27])([CH3:28])[CH2:18][CH:19]([NH:20][C:21](=[O:26])[C:22]([CH3:25])([CH3:23])[CH3:24])[C:13]2=[CH:12][C:11]=1[C:29]1[CH:30]=[CH:31][C:32]([Cl:35])=[CH:33][CH:34]=1
Reactant: CC1(C)CC(NC(=O)C(C)(C)C)c2cc(-c3ccc(Cl)cc3)c(-c3ccc(C#N)cc3Cl)nc2O1
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CC1(C)CC(NC(=O)C(C)(C)C)c2cc(-c3ccc(Cl)cc3)c(-c3ccc(C(=N)NO)cc3Cl)nc2O1

Procedure:
A solution of Example 317 (120 mg, 0.24 mmol), hydroxylamine hydrochloride (65.6 mg, 0.94 mmol), and NaHCO3 (119 mg, 1.42 mmol) in 10 mL of EtOH was refluxed for 16 h. The reaction mixture was partitioned between brine (50 mL) and CH2Cl2 (50 mL). The aq layer was separated and extracted with CH2Cl2 (2×50 mL). The organic layers were combined, dried over MgSO4, and concentrated to give the product, which was taken into the next step without further purification.
Reaction SMILES: [C:1]([C:3]1[CH:19]=[CH:18][C:6]([O:7][C:8]2[CH:13]=[CH:12][C:11]([CH2:14][C:15]([OH:17])=[O:16])=[CH:10][CH:9]=2)=[CH:5][CH:4]=1)#[N:2].[CH3:20]O>S(Cl)(Cl)=O>[CH3:20][O:16][C:15](=[O:17])[CH2:14][C:11]1[CH:12]=[CH:13][C:8]([O:7][C:6]2[CH:18]=[CH:19][C:3]([C:1]#[N:2])=[CH:4][CH:5]=2)=[CH:9][CH:10]=1
Reactant: N#Cc1ccc(Oc2ccc(CC(=O)O)cc2)cc1
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)Cc1ccc(Oc2ccc(C#N)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 22.25 g of [p-(p-cyanophenoxy)phenyl]acetic acid in 55 ml of thionyl chloride is refluxed for one hour. The solvent is removed under vacuum, benzene is added (three times) and the solvent removed under vacuum. The residue is dissolved in 135 ml of methanol and stirred at room temperature for 1 hour. The solvent is removed under vacuum to give a gum. The gum is dissolved in 50 ml of warm methanol and the solution is chilled and filtered to give the product, mp 58°-60° C.
Reaction SMILES: [S:1]([C:5]1[O:13][C:12]2[CH:11]=[CH:10][N:9]=[C:8]([O:14]C)[C:7]=2[CH:6]=1)(=[O:4])(=[O:3])[NH2:2]>Cl>[S:1]([C:5]1[O:13][C:12]2[CH:11]=[CH:10][NH:9][C:8](=[O:14])[C:7]=2[CH:6]=1)(=[O:3])(=[O:4])[NH2:2]
Reactant: COc1nccc2oc(S(N)(=O)=O)cc12
Agent: Cl
Product: NS(=O)(=O)c1cc2c(=O)[nH]ccc2o1
Temperature: 100 °C

Procedure:
Alternate Procedure: A suspension of 2-sulfamoyl-4-methoxyfuro[3,2-c]pyridine (0.75 g, 3.3 mmol) in 10% aqueous hydrochloric acid (40 ml) was heated at 100° C. for 41/2 hours. Upon cooling, the product precipitated and was collected by filtration, washed with ethanol and diethyl ether to give 0.53 g (76% yield), m.p. 286°-289° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:20][C:21]([C:23]2[C:24](=[O:36])[N:25]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[N:26]([CH3:29])[C:27]=2[CH3:28])=[O:22])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([OH:19])=[CH:16][CH:17]=2)[N:12]=[CH:11][CH:10]=1.C([O-])([O-])=O.[Cs+].[Cs+].[CH3:43][C@@H:44]1[CH2:46][O:45]1>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([NH:20][C:21]([C:23]2[C:24](=[O:36])[N:25]([C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)[N:26]([CH3:29])[C:27]=2[CH3:28])=[O:22])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([O:19][CH2:43][C@H:44]([OH:45])[CH3:46])=[CH:16][CH:17]=2)[N:12]=[CH:11][CH:10]=1
Reactant: C[C@@H]1CO1
Reactant: Cc1c(C(=O)Nc2ccc(Oc3ccnc4cc(O)ccc34)c(F)c2)c(=O)n(-c2ccccc2)n1C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Cc1c(C(=O)Nc2ccc(Oc3ccnc4cc(OC[C@@H](C)O)ccc34)c(F)c2)c(=O)n(-c2ccccc2)n1C
Temperature: 40 °C
Reaction time: 48 h
Yield: 52.7 %

Procedure:
To a mixture of N-(3-fluoro-4-((7-hydroxyquinolin-4-yl)oxy)phenyl)-1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide (100 mg, 0.21 mmol) and Cs2CO3 (337 mg, 1.03 mmol) in 10 mL DMF was added (R)-2-methyloxirane (5 mL, 71.60 mmol). The reaction was warmed to 40° C. and stirred for two days. The mixture was concentrated in vacuo and the residue was purified by a silica gel column chromatography (1:15 (v/v) MeOH/DCM) to give the title compound as a white solid (60 mg, 54%).