Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[K+].[C:3]([NH:8][OH:9])([O:5][CH2:6][CH3:7])=[O:4].[K].[CH3:11][C:12]1[CH:19]=[C:18]([CH3:20])[CH:17]=[C:16]([CH3:21])[C:13]=1[CH2:14]Cl>>[C:3]([NH:8][O:9][CH2:14][C:13]1[C:16]([CH3:21])=[CH:17][C:18]([CH3:20])=[CH:19][C:12]=1[CH3:11])([O:5][CH2:6][CH3:7])=[O:4]
Reactant: CCOC(=O)NO
Reactant: Cc1cc(C)c(CCl)c(C)c1
Agent: [K+]
Agent: [K]
Agent: [OH-]
Product: CCOC(=O)NOCc1c(C)cc(C)cc1C
Temperature: 0 °C
Yield: 53.8 %

Procedure:
50 ml of a methanolic solution of 12.3 g (0.22 mole) of potassium hydroxide was added to 50 ml of an ice-cooled methanolic solution of 23.1 g (0.22 mole) of N-carboethoxyhydroxylamine to prepare a solution containing a potassium salt of N-carboethoxyhydroxylamine, and 50 ml of a methanolic solution of 33.7 g (0.2 mole) of 2,4,6-trimethylbenzyl chloride was added to the resulting solution at room temperature. The resulting mixture was heated under refluxing for 1 hour, and the solvent was distilled off. 150 ml of diethyl ether and 50 ml of water were then added to the residue and the organic layer was separated, dried over anhydrous sodium sulfate and concentrated under a reduced pressure. The residue thus obtained was distilled under a reduced pressure to obtain 25.5 g (53.8% yield) of substantially pure N-carboethoxy-O-(2,4,6-trimethylbenzyl)hydroxylamine having a boiling point of 148°-153° C/0.9 mmHg.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([Cl:9])[CH:6]=[C:5]([CH2:10][CH3:11])[C:3]=1[NH2:4].C(C1C([NH2:20])=CC=CC=1)C.ClN1C(=O)CCC1=O>C(#N)C>[Cl:9][C:7]1[CH:6]=[C:5]2[C:3](=[C:2]([Cl:1])[CH:8]=1)[NH:4][N:20]=[C:10]2[CH3:11]
Reactant: CCc1ccccc1N
Reactant: CCc1cc(Cl)cc(Cl)c1N
Agent: O=C1CCC(=O)N1Cl
Solvent: CC#N
Product: Cc1n[nH]c2c(Cl)cc(Cl)cc12

Procedure:
5,7-Dichloro-3-methyl-1H-indazole was prepared using a procedure similar to that described in Example 98, part a and b, except starting from 2,4-dichloro-6-ethylaniline (2.9 g) that was prepared by chlorination of 6-ethylaniline (10 g) with N-chlorosuccinimide (22 g) in acetonitrile (80 mL).
Reaction SMILES: C([O:3][CH:4](OCC)[C:5]1[C:10]([F:11])=[CH:9][C:8]([C:12]([OH:15])([CH3:14])[CH3:13])=[CH:7][C:6]=1[F:16])C>C1COCC1.O>[F:11][C:10]1[CH:9]=[C:8]([C:12]([OH:15])([CH3:14])[CH3:13])[CH:7]=[C:6]([F:16])[C:5]=1[CH:4]=[O:3]
Reactant: CCOC(OCC)c1c(F)cc(C(C)(C)O)cc1F
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(O)c1cc(F)c(C=O)c(F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Amberlist-15(wet) (0.64 g, 6.56 mmol) was added to a solution of 2-[4-(diethoxymethyl)-3,5-difluorophenyl]propan-2-ol (1.8 g, 6.56 mmol) in THF (33 mL) and water (5.3 mL). The mixture was vigorously stirred under argon at room temperature overnight. The reaction was then filtered through a fritted funnel. The filtrate was diluted with ethyl acetate and washed with saturated aqueous sodium bicarbonate, dried over magnesium sulfate, filtered, and concentrated in vacuo to afford the title compound. 1H NMR (400 MHz, CDCl3): δ 10.23 (s, 1H), 7.05 (d, 2H), 5.23 (s, 1H), 1.50 (s, 6H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:9]([S:12]([N:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)(=[O:14])=[O:13])=[CH:8][C:4]=1[C:5]([OH:7])=O.[CH3:21][O:22][C:23]1[CH:29]=[CH:28][C:26]([NH2:27])=[CH:25][CH:24]=1>>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:9]([S:12]([N:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)(=[O:14])=[O:13])=[CH:8][C:4]=1[C:5]([NH:27][C:26]1[CH:28]=[CH:29][C:23]([O:22][CH3:21])=[CH:24][CH:25]=1)=[O:7]
Reactant: COc1ccc(S(=O)(=O)N2CCCCC2)cc1C(=O)O
Reactant: COc1ccc(N)cc1
Product: COc1ccc(NC(=O)c2cc(S(=O)(=O)N3CCCCC3)ccc2OC)cc1

Procedure:
The entitled compound was produced according to the method of Example 92 but using 2-methoxy-5-(piperidin-1-ylsulfonyl)benzoic acid and 4-methoxyaniline as the starting materials.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[CH:5]=1)[CH3:2].[C:11]([O:15][CH:16]([CH3:18])[CH3:17])(=[O:14])[CH:12]=[CH2:13].C(O)(=O)C>CCOCC>[CH2:1]([N:3]([CH2:13][CH2:12][C:11]([O:15][CH:16]([CH3:18])[CH3:17])=[O:14])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[CH:5]=1)[CH3:2]
Reactant: C=CC(=O)OC(C)C
Reactant: CCNc1cccc(C)c1
Solvent: CC(=O)O
Solvent: CCOCC
Product: CCN(CCC(=O)OC(C)C)c1cccc(C)c1
Yield: 88.2 %

Procedure:
A mixture of 13.5 g (0.1 mole) N-ethyl-m-toluidine, 11.4 g (0.1 mole) isopropyl acrylate and 2 ml glacial acetic acid was heated over the steam bath for 16 hours. The mixture was cooled and diluted with ether. The ether solution was washed with 10 ml water, twice with 10 ml portions of 5% sodium carbonate solution, once with 10 ml of water and then dried over sodium sulfate. Removal of the ether with a rotary evaporator at 50° C. and reduced pressure gave 22.0 g (86%) of oil, which was pure by thin layer chromatography and was used as isolated.
Reaction SMILES: [Si:1]([O:8][CH2:9][C@@H:10]([NH:18][S:19]([C:22]1[CH:30]=[CH:29][C:25]2[N:26]=[CH:27][S:28][C:24]=2[CH:23]=1)(=[O:21])=[O:20])[C:11]1[S:12][C:13]([CH:16]=O)=[CH:14][CH:15]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH3:31][C:32]([S:35]([NH2:37])=[O:36])([CH3:34])[CH3:33]>C1COCC1.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[Si:1]([O:8][CH2:9][C@@H:10]([NH:18][S:19]([C:22]1[CH:30]=[CH:29][C:25]2[N:26]=[CH:27][S:28][C:24]=2[CH:23]=1)(=[O:21])=[O:20])[C:11]1[S:12][C:13](/[CH:16]=[N:37]\[S:35]([C:32]([CH3:34])([CH3:33])[CH3:31])=[O:36])=[CH:14][CH:15]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)S(N)=O
Reactant: CC(C)(C)[Si](C)(C)OC[C@@H](NS(=O)(=O)c1ccc2ncsc2c1)c1ccc(C=O)s1
Agent: [Ti+4]
Agent: CC(C)[O-]
Solvent: C1CCOC1
Product: CC(C)(C)S(=O)/N=C\c1ccc([C@@H](CO[Si](C)(C)C(C)(C)C)NS(=O)(=O)c2ccc3ncsc3c2)s1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of N-[(1R)-2-{[tert-butyl(dimethyl)silyl]oxy}-1-(5-formylthiophen-2-yl)ethyl]-1,3-benzothiazole-6-sulfonamide (5.0 g, 10.4 mmol) and 2-methylpropane-2-sulfinamide (1.51 g, 12.4 mmol) in THF (69 mL) was added titanium isopropoxide (6.52 mL, 31.1 mmol). The mixture was stirred at room temperature overnight.
Reaction SMILES: [C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=[CH:8][C:7]([CH2:17][CH2:18][CH:19]=O)=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[CH3:21][C:22]1[CH:23]=[C:24]([N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)[CH:25]=[CH:26][C:27]=1[CH3:28].CCN(C(C)C)C(C)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=[CH:8][C:7]([CH2:17][CH2:18][CH2:19][N:32]2[CH2:33][CH2:34][N:29]([C:24]3[CH:25]=[CH:26][C:27]([CH3:28])=[C:22]([CH3:21])[CH:23]=3)[CH2:30][CH2:31]2)=[N:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccc(N2CCNCC2)cc1C
Reactant: CC(C)(C)n1nc(CCC=O)cc1-c1ccc(F)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(N2CCN(CCCc3cc(-c4ccc(F)cc4)n(C(C)(C)C)n3)CC2)cc1C

Procedure:
126 mg (71%) of target compound was obtained by using a method same as in Example 1 by using 3-(1-tert-butyl-5-(4-fluorophenyl)-1H-pyrazol-3-yl)propanal (100 mg, 0.365 mmol), 1-(3,4-dimethylphenyl)piperazine (69 mg, 0.365 mmol), DIPEA (0.1 mL, 0.548 mmol) and NaBH(OAc)3 (232 mg, 1.095 mmol).
Reaction SMILES: ClC1C=CC([C:8]2[N:9]=C3C=CC=CN3C=2CC2N=C(C(NN)=O)ON=2)=CC=1.[F:27][C:28]1[CH:29]=[CH:30][C:31]2[N:32]([C:34]([CH2:44][C:45]3[N:49]=[C:48]([C:50]([O:52]CC)=O)[O:47][N:46]=3)=[C:35]([C:37]3[CH:42]=[CH:41][C:40]([F:43])=[CH:39][CH:38]=3)[N:36]=2)[CH:33]=1.CN>>[F:27][C:28]1[CH:29]=[CH:30][C:31]2[N:32]([C:34]([CH2:44][C:45]3[N:49]=[C:48]([C:50]([NH:9][CH3:8])=[O:52])[O:47][N:46]=3)=[C:35]([C:37]3[CH:38]=[CH:39][C:40]([F:43])=[CH:41][CH:42]=3)[N:36]=2)[CH:33]=1
Reactant: NNC(=O)c1nc(Cc2c(-c3ccc(Cl)cc3)nc3ccccn23)no1
Reactant: CCOC(=O)c1nc(Cc2c(-c3ccc(F)cc3)nc3ccc(F)cn23)no1
Agent: CN
Product: CNC(=O)c1nc(Cc2c(-c3ccc(F)cc3)nc3ccc(F)cn23)no1

Procedure:
The title compound was prepared in the same fashion as that for compound 215 from ethyl 3-((6-fluoro-2-(4-fluorophenyl)imidazo[1,2-a]pyridin-3-yl)methyl)-1,2,4-oxadiazole-5-carboxylate and methylamine. m/e+=370 (M+H−). 1H NMR (400 MHz, in DMSO-d6): δ 9.23 (H, D, brd, NH), δ 8.66-8.65 (1H, D, dd, J=5.2, 2.0 Hz, ArH), δ 7.81-7.78 (2H, D, m, ArH), δ 7.45-7.40 (1H, D, dd, J=9.6, 5.2 Hz, ArH), δ 7.32-7.28 (2H, D, m, ArH), δ 4.72 (2H, D, s, CH2), and 2.76 (3H, D, s, CH3).
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]([N+:11]([O-:13])=[O:12])=[C:6]([CH:10]=1)[C:7]([NH2:9])=[O:8].[C:14]1([S:20]([O:22][Na])=[O:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.O>CS(C)=O>[C:14]1([S:20]([C:2]2[CH:3]=[CH:4][C:5]([N+:11]([O-:13])=[O:12])=[C:6]([CH:10]=2)[C:7]([NH2:9])=[O:8])(=[O:22])=[O:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: NC(=O)c1cc(F)ccc1[N+](=O)[O-]
Reactant: O=S(O[Na])c1ccccc1
Solvent: CS(C)=O
Solvent: O
Product: NC(=O)c1cc(S(=O)(=O)c2ccccc2)ccc1[N+](=O)[O-]
Temperature: 50 °C
Yield: 85.3 %

Procedure:
5-Fluoro-2-nitro-benzamide (2.5 g, 13.59 mmol) in DMSO (40 mL) was treated with solid 97% PhSO2Na (2.48 g, 14.95 mmol) and heated at 50° C. (oil bath temperature) for 60 hours. The reaction was added dropwise into 40 mL of iced water. Filtration of the solid afforded 3.55 g (85% yield) of title compound.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4]([I:11])[N:3]=1.Br[CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:17]([O:16][C:14](=[O:15])[CH2:13][N:8]1[CH:7]=[N:6][C:5]2[C:9]1=[N:10][C:2]([NH2:1])=[N:3][C:4]=2[I:11])[CH3:18]
Reactant: Nc1nc(I)c2[nH]cnc2n1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)Cn1cnc2c(I)nc(N)nc21
Temperature: 25 °C
Reaction time: 12 h
Yield: 94.5 %

Procedure:
To a solution of 2-amino-6-iodo-purine (78.3 g, 0.3 mol) in DMF (1960 mL) was added ethyl bromoacetate (55.1 g, 0.33 mol) and potassium carbonate (82.9 g, 0.6 mol). The resulting reaction mixture was stirred for 12 h at room temperature. The reaction mixture was concentrated to small volume (about 150 mL) in vacuo and the residue was dissolved in water. The solid was filtered off, washed with water and ethyl ether, and dried in vacuo to give the titled compound (98.4 g, 95%). 1H-NMR (50 MHz; DMSO-d6) δ 8.06 (s, 1H), 6.90 (br.s, 2H), 4.94 (s, 2H), 4.17 (q, 2H), 1.22 (t, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]([CH3:12])[C:5]2[NH:6][C:7](=[O:9])[O:8][C:4]=2[CH:3]=1.[Cl:13][C:14]1[CH:19]=[C:18](Cl)[N:17]=[CH:16][N:15]=1>C(O)CCC>[Cl:13][C:14]1[N:15]=[CH:16][N:17]=[C:18]([NH:1][C:2]2[CH:11]=[C:10]([CH3:12])[C:5]3[NH:6][C:7](=[O:9])[O:8][C:4]=3[CH:3]=2)[CH:19]=1
Reactant: Cc1cc(N)cc2oc(=O)[nH]c12
Reactant: Clc1cc(Cl)ncn1
Solvent: CCCCO
Product: Cc1cc(Nc2cc(Cl)ncn2)cc2oc(=O)[nH]c12
Temperature: 25 °C

Procedure:
400 mg (2.40 mmol) 6-amino-4-methyl-3H-benzoxazol-2-one, 400 mg (2.70 mmol) 4,6-dichloropyrimidine and 1.10 mL (8.00 mmol) TEA in 5 mL 1-butanol were stirred for 1 h at 100° C. After cooling to RT the reaction mixture was evaporated down and the residue was washed with water and saturated sodium hydrogen carbonate solution. The organic phase was dried on sodium sulphate, filtered and evaporated down.
Reaction SMILES: [CH3:1][O-:2].[Na+].CO.Cl[CH2:7][N:8]([CH3:13])[S:9]([Cl:12])(=[O:11])=[O:10]>C1C=CC=CC=1>[CH3:1][O:2][CH2:7][N:8]([CH3:13])[S:9]([Cl:12])(=[O:11])=[O:10]
Reactant: CN(CCl)S(=O)(=O)Cl
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: c1ccccc1
Product: COCN(C)S(=O)(=O)Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 67 %

Procedure:
A solution of 13.5 parts of sodium methylate in 110 parts of methanol is added, in the course of 15 minutes at from 0° to 5° C., to a mixture of 44.5 parts of N-chloromethyl-N-methylsulfamic acid chloride in 260 parts of benzene. The reaction mixture is then stirred for 2 hours at 25° C., after which the sodium chloride which has precipitated is filtered off. After removing the solvent under reduced pressure, distillation gives 29.1 parts (67% of theory) of N-methoxymethyl-N-methylsulfamic acid chloride of boiling point 84°-87° C./12 mbar and nD25 =1.4536.
Reaction SMILES: [F:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][NH:7][C:8]([C:10]2[N:11]=[C:12]3[C:18]4([NH:21][CH3:22])[CH2:19][CH2:20][CH:15]([CH2:16][CH2:17]4)[CH2:14][N:13]3[C:23](=[O:26])[C:24]=2[OH:25])=[O:9])=[CH:4][CH:3]=1.[O:29]=[C:30]([N:34]1[CH2:38][CH2:37][CH2:36][CH2:35]1)[C:31]([OH:33])=O.C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C)C1C=CN=CC=1.CN(C=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8]([C:10]2[N:11]=[C:12]3[C:18]4([N:21]([CH3:22])[C:31](=[O:33])[C:30](=[O:29])[N:34]5[CH2:38][CH2:37][CH2:36][CH2:35]5)[CH2:19][CH2:20][CH:15]([CH2:16][CH2:17]4)[CH2:14][N:13]3[C:23](=[O:26])[C:24]=2[OH:25])=[O:9])=[CH:27][CH:28]=1
Reactant: CNC12CCC(CC1)Cn1c2nc(C(=O)NCc2ccc(F)cc2)c(O)c1=O
Reactant: O=C(O)C(=O)N1CCCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(C(=O)C(=O)N1CCCC1)C12CCC(CC1)Cn1c2nc(C(=O)NCc2ccc(F)cc2)c(O)c1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 39.1 %

Procedure:
To a stirred solution of N-(4-fluorobenzyl)-3-hydroxy-10-(methylamino)-4-oxo-4,6,7,8,9,10-hexahydro-7,10-ethanopyrimido[1,2-a]azepine-2-carboxamide (50 mg, 0.100 mmol) in (DMF (2 mL) was added 2-oxo-2-(pyrrolidin-1-yl)acetic acid (57.2 mg, 0.400 mmol), diisopropyl-ethylamine (0.105 mL, 0.599 mmol), O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU) (152 mg, 0.400 mmol) and 4-(dimethylamino)pyridine (DMAP) (1.221 mg, 9.99 μmol) and the resulting mixture was stirred at room temperature for 3 h. The crude was then purified by preparative HPLC and recrystallized from methanol to afford the title compound as a glassy white crystals (20 mg, 40% yield). 1H NMR (500 MHz, CDCl3) δ: 12.1 (1 H, s), 9.6 (1 H, brs), 7.4-7.4 (2 H, m), 7.0-7.0 (2 H, m), 4.8-4.9 (1 H, m), 4.6-4.7 (1 H, m), 4.4-4.5 (1 H, m), 3.6-3.7 (2 H, m), 3.5 (2 H, t, J=6.71 Hz), 3.3-3.4 (2 H, m), 3.0 (3 H, s), 2.5 (1 H, brs), 1.9-2.1 (9 H, m), 1.7-1.8 (2 H, m). LCMS (M+H)=512.24. HPLC purity: >95%.
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])[C:7]1[CH:12]=[CH:11][CH:10]=[C:9](Br)[CH:8]=1)([CH3:4])([CH3:3])[CH3:2].[C:15]1([CH3:24])[CH:20]=[CH:19][C:18](B(O)O)=[CH:17][CH:16]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.O>[C:1]([O:5][C:6](=[O:14])[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:18]2[CH:19]=[CH:20][C:15]([CH3:24])=[CH:16][CH:17]=2)[CH:8]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)c1cccc(Br)c1
Reactant: Cc1ccc(B(O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1ccc(-c2cccc(C(=O)OC(C)(C)C)c2)cc1
Temperature: 25 °C
Yield: 92.4 %

Procedure:
To a mixture of tert-butyl-3-bromobenzoate (65 g, 0.25 mol), 4-tolyl boronic acid (41.3 g, 0.30 mol) and sodium carbonate (150 g) in a mixture of toluene (500 mL) and water (50 mL), tetrakis-triphenylphosphine palladium(0) (14.5 g, 0.05 mol) was added and the reaction mixture was refluxed overnight. Cooled to RT, toluene layer was separated. The organic layer was washed with water, brine, dried. The solvent was removed under vacuum to give tert-butyl-3-(4-tolyl)benzoate (62 g, 90%).
Reaction SMILES: [Br:1][C:2]1[O:6][C:5]([C:7]([OH:9])=O)=[CH:4][CH:3]=1.[NH2:10][C:11]1[CH:12]=[C:13]([CH:17]=[CH:18][C:19]#[N:20])[CH:14]=[CH:15][CH:16]=1>>[C:19]([CH:18]=[CH:17][C:13]1[CH:12]=[C:11]([NH:10][C:7]([C:5]2[O:6][C:2]([Br:1])=[CH:3][CH:4]=2)=[O:9])[CH:16]=[CH:15][CH:14]=1)#[N:20]
Reactant: N#CC=Cc1cccc(N)c1
Reactant: O=C(O)c1ccc(Br)o1
Product: N#CC=Cc1cccc(NC(=O)c2ccc(Br)o2)c1

Procedure:
5-Bromo-furan-2-carboxylic acid (716 mg, 3.75 mmol) was coupled to aniline (88) (540 mg, 3.75 mmol) using Method C. The residue was purified by column chromatography eluting with 20% EtOAc in heptane, to give the title compound.
Reaction SMILES: [CH3:1][C:2]([NH2:11])([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([Cl:10])[CH:5]=1)[CH3:3].C=O.[C:14](=O)([O-])O.[Na+]>>[CH2:14]=[N:11][C:2]([CH3:1])([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([Cl:10])[CH:5]=1)[CH3:3]
Reactant: CC(C)(N)c1cccc(Cl)c1
Reactant: O=C([O-])O
Agent: C=O
Agent: [Na+]
Product: C=NC(C)(C)c1cccc(Cl)c1
Reaction time: 1 h

Procedure:
1-Methyl-1-(3-chlorophenyl)ethylamine (5.0 g) was added slowly to formalin (aqueous 37% HCHO solution) (3.5 g) at room temperature. This was allowed to react as it was for 1 hour. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, which was then extracted with ether. After it was washed with saturated saline, the organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain the captioned compound (5.6 g) as syrup.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([O:10][CH3:11])[N:3]=1.C(OC([N:19]1[CH2:26][CH:25]2[CH:21]([CH2:22][NH:23][CH2:24]2)[CH2:20]1)=O)(C)(C)C>>[CH3:11][O:10][C:4]1[CH:5]=[C:6]([O:8][CH3:9])[N:7]=[C:2]([N:19]2[CH2:26][CH:25]3[CH:21]([CH2:22][NH:23][CH2:24]3)[CH2:20]2)[N:3]=1
Reactant: CC(C)(C)OC(=O)N1CC2CNCC2C1
Reactant: COc1cc(OC)nc(Cl)n1
Product: COc1cc(OC)nc(N2CC3CNCC3C2)n1

Procedure:
The title compound was prepared in a manner analogous to Intermediate 23 utilizing 2-chloro-4,6-dimethoxypyrimidine and hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid tert-butyl ester as starting materials.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]([C:18]2[CH:23]=[CH:22][C:21]([N:24]3[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]3)=[CH:20][CH:19]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[CH2:31][CH2:32][S:33](Cl)(=[O:35])=[O:34].C(N(CC)CC)C>ClCCl>[C:1]([O:5][C:6]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]([C:18]2[CH:23]=[CH:22][C:21]([N:24]3[CH2:29][CH2:28][N:27]([S:33]([CH:32]=[CH2:31])(=[O:35])=[O:34])[CH2:26][CH2:25]3)=[CH:20][CH:19]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=S(=O)(Cl)CCCl
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(N3CCNCC3)cc2)c2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CS(=O)(=O)N1CCN(c2ccc(N3CCN(C(=O)OC(C)(C)C)c4ccccc43)cc2)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
2 g of 4-(4-(piperazin-1-yl)phenyl)-3,4-dihydro-2H-quinoxaline-1-carboxylic acid tert-butyl ester are placed in a 250 ml round-bottomed flask under an inert atmosphere. 72 ml of anhydrous dichloromethane are added and then, at 0° C., 1.22 ml of chloroethylsulphonyl chloride are added, followed by 3.67 ml of triethylamine. The reaction mixture is allowed to return gently to ambient temperature. The reaction mixture is stirred at ambient temperature for 3 h before being diluted with dichloromethane. The organic phase is washed with a saturated aqueous sodium hydrogencarbonate solution and the aqueous phase is extracted with dichloromethane. The organic phases are combined and washed with water, then dried over sodium sulphate, filtered through a sintered glass filter and concentrated under reduced pressure. 1.01 g of 4-[4-(4-(ethenesulphonyl)piperazin-1-yl)phenyl]-3,4-dihydro-2H-quinoxaline-1-carboxylic acid tert-butyl ester are obtained in the form of a white solid, after purification on a silica column, elution being carried out with a heptane/ethyl acetate gradient varying from 95/5 to 40/60.
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[C:6]([OH:9])[CH:5]=[CH:4][C:3]=1[C:10]([C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][CH:14]=1)=[N:11][OH:12].[H-].[Na+].Br[CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28].O>CN(C=O)C>[CH2:30]([O:29][C:27](=[O:28])[CH2:26][O:9][C:6]1[CH:5]=[CH:4][C:3]2[C:10]([C:13]3[C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[CH:16]=[CH:15][CH:14]=3)=[N:11][O:12][C:2]=2[C:7]=1[Cl:8])[CH3:31]
Reactant: ON=C(c1ccc(O)c(Cl)c1Cl)c1cccc2ccccc12
Reactant: CCOC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)COc1ccc2c(-c3cccc4ccccc34)noc2c1Cl
Temperature: 100 °C
Reaction time: 18 h

Procedure:
To a solution of 3 g of (2,3-dichloro-4-hydroxyphenyl)(1-naphthyl)methanone oxime in 25 ml of DMF, 0.54 g of NaH is added under N2. The mixture is heated to an internal temperature of 100° C. for one hour and 20 minutes. The reaction mixture is cooled to room temperature and 1.65 g of ethyl bromoacetate is added dropwise. The mixture is stirred for 18 hours, water is added and the product is extracted with ethyl acetate. The ethyl acetate extract is washed with water, dried over Na2SO4 and evaporated to give ethyl{[7-chloro-3-(1-napthyl)-1,2-benzisoxazol-6-yl]oxy}acetate, mp 75°-85° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH3:13])[CH:10]=[CH:11][N:12]=2)=[CH:4][C:3]=1[CH3:14].O.B([C:19]1[CH:27]=[CH:26][C:22]([C:23]([OH:25])=[O:24])=[CH:21][CH:20]=1)(O)O.C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC>[CH3:14][C:3]1[CH:4]=[C:5]([C:8]2[N:9]([CH3:13])[CH:10]=[CH:11][N:12]=2)[CH:6]=[CH:7][C:2]=1[C:19]1[CH:27]=[CH:26][C:22]([C:23]([OH:25])=[O:24])=[CH:21][CH:20]=1
Reactant: Cc1cc(-c2nccn2C)ccc1Br
Reactant: O=C(O)c1ccc(B(O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: Cc1cc(-c2nccn2C)ccc1-c1ccc(C(=O)O)cc1
Yield: 88.7 %

Procedure:
2-(4-Bromo-3-methylphenyl)-1-methylimidazole (D89, 600 mg, 2.39 mmol) was dissolved in dimethoxyethane (15 ml) and H2O (15 ml) and treated with 4-boronobenzoic acid (397 mg, 2.39 mmol), sodium carbonate (1.01 g, 9.56 mmol), tetrakis (triphenylphosphine)palladium (O) (60 mg) and heated at reflux for 36 hours. The dimethoxyethane was removed in vacuo, the aqueous residue treated with 10% Na2CO3 (approx. 10 ml) and washed with ethyl acetate. The aqueous phase was acidified with 5N HCl and the solid that formed collected by filtration and dried in vacuo to yield the title compound as an off-white solid (620 mg, 89%).
Reaction SMILES: [F:1][C@@H:2]1[C@H:8]([NH:9]C(=O)OC(C)(C)C)[CH2:7][CH2:6][C@@H:5]([C:17]2[N:21]([CH3:22])[N:20]=[CH:19][C:18]=2[N+:23]([O-])=O)[O:4][CH2:3]1.[F:26][C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[C:28]=1[C:34]1[S:35][CH:36]=[C:37]([C:39](O)=[O:40])[N:38]=1>>[NH2:9][C@H:8]1[C@@H:2]([F:1])[CH2:3][O:4][C@H:5]([C:17]2[N:21]([CH3:22])[N:20]=[CH:19][C:18]=2[NH:23][C:39]([C:37]2[N:38]=[C:34]([C:28]3[C:27]([F:26])=[CH:32][CH:31]=[CH:30][C:29]=3[F:33])[S:35][CH:36]=2)=[O:40])[CH2:6][CH2:7]1
Reactant: Cn1ncc([N+](=O)[O-])c1[C@@H]1CC[C@@H](NC(=O)OC(C)(C)C)[C@@H](F)CO1
Reactant: O=C(O)c1csc(-c2c(F)cccc2F)n1
Product: Cn1ncc(NC(=O)c2csc(-c3c(F)cccc3F)n2)c1[C@@H]1CC[C@@H](N)[C@@H](F)CO1

Procedure:
Following the procedure for Example 111 starting from tert-butyl ((3R,4R,7S)-3-fluoro-7-(1-methyl-4-nitro-1H-pyrazol-5-yl)oxepan-4-yl)carbamate (Intermediate 24), and replacing 5-((tert-butoxycarbonyl)amino)-2-(2,6-difluorophenyl)thiazole-4-carboxylic acid with 2-(2,6-difluorophenyl)thiazole-4-carboxylic acid (see US2012/225061) gave 319. 1H NMR (400 MHz, DMSO-d6) δ 10.02 (s, 1H), 8.63 (s, 1H), 7.86 (s, 1H), 7.74-7.59 (m, 1H), 7.38 (t, J=8.9 Hz, 2H), 5.03-4.81 (m, 2H), 4.19-3.88 (m, 2H), 3.75 (s, 2H), 2.24-2.10 (m, 1H), 1.93-1.81 (m, 1H), 1.82-1.70 (m, 1H), 1.65 (d, J=14.0 Hz, 1H). LCMS (ES+) m/z 452 (M+1).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1.[S:12](=O)(=[O:15])([OH:14])[OH:13]>>[Cl:1][C:2]1[C:11]2[CH:10]=[CH:9][CH:8]=[C:7]([S:12]([OH:15])(=[O:14])=[O:13])[C:6]=2[CH:5]=[CH:4][N:3]=1
Reactant: Clc1nccc2ccccc12
Reactant: O=S(=O)(O)O
Product: O=S(=O)(O)c1cccc2c(Cl)nccc12
Reaction time: 14 h

Procedure:
1-chloroisoquinoline is dropwise added to 2 to 20, preferably 3 to 10, equivalent of forming sulfuric acid while cooling with ice to carry out a reaction at 10° to 120° C., preferably at 20° to 100° C., for 4 to 24 hours. The reaction solution is poured on ice water to obtain a crystal of 1-chloro-5-isoquinolinesulfonic acid.