Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=1)[CH:6]=[C:5]2O.P(Cl)(Cl)([Cl:22])=O>O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=1)[CH:6]=[C:5]2[Cl:22]
Reactant: O=P(Cl)(Cl)Cl
Reactant: Oc1cc(-c2cccc(F)c2)nc2ccc(Br)cc12
Solvent: O
Product: Fc1cccc(-c2cc(Cl)c3cc(Br)ccc3n2)c1
Temperature: 110 °C
Yield: 83.8 %

Procedure:
6-Bromo-2-(3-fluorophenyl)-quinolin-4-ol (5.2 g, 16.3 mmoles) was placed in a 500 mL three-neck round-bottom flask equipped with a condenser, magnetic stirrer and nitrogen inlet. To this was added 15.2 mL (25.0 g, 163 mmoles, 10 equiv.) of phosphorus oxychloride with stirring. The mixture was heated to 110° C. for 4 hr. At the end of this time the reaction was cooled to room temperature and water was cautiously added dropwise until all of the POCl3 was consumed. Material crystallised from the water and solids were collected by filtration. The solids were washed with water, placed in a 250 mL Erlenmeyer and triturated with water. After collection by filtration, washing with water, and drying in a vacuum oven, 4.6 g (84%) of the product was obtained.
Reaction SMILES: [CH2:1]([CH:3]([N:6]1[CH2:11][CH2:10][N:9]([C:12]([C:14]2[CH:21]=[CH:20][C:17]([CH:18]=O)=[CH:16][CH:15]=2)=[O:13])[CH2:8][CH2:7]1)[CH2:4][CH3:5])[CH3:2].[CH2:22]([NH2:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>C(Cl)Cl.C(O)(=O)C>[CH2:22]([NH:29][CH2:18][C:17]1[CH:20]=[CH:21][C:14]([C:12]([N:9]2[CH2:10][CH2:11][N:6]([CH:3]([CH2:4][CH3:5])[CH2:1][CH3:2])[CH2:7][CH2:8]2)=[O:13])=[CH:15][CH:16]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: NCc1ccccc1
Reactant: CCC(CC)N1CCN(C(=O)c2ccc(C=O)cc2)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CCC(CC)N1CCN(C(=O)c2ccc(CNCc3ccccc3)cc2)CC1

Procedure:
To a solution of the product of Example 12 (150 mg) and benzylamine (0.062 mL) in DCM (5 mL) was added acetic acid (0.03 mL) and sodium triacetoxyborohydride (165 mg). After 16 h the reaction was treated with 1 N NaOH (20 mL) and extracted with DCM (3×20 mL). The organic layers were dried (Na2SO4), concentrated, and chromatographed (2-3% 2 M methanolic ammonia-DCM) to give the title compound as an oil (150 mg).
Reaction SMILES: C([O-])(O)=O.[Na+].[CH3:6][S:7][C:8]1[S:9][C:10]([CH:16]=O)=[CH:11][C:12]=1[N+:13]([O-:15])=[O:14].[NH2:18]O.Cl.C(O)=O>O>[CH3:6][S:7][C:8]1[S:9][C:10]([C:16]#[N:18])=[CH:11][C:12]=1[N+:13]([O-:15])=[O:14]
Reactant: CSc1sc(C=O)cc1[N+](=O)[O-]
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=CO
Solvent: O
Product: CSc1sc(C#N)cc1[N+](=O)[O-]

Procedure:
A sodium methyl mercaptide solution was prepared by adding 5 ml of methylmercaptan to 1.75 g of Na in 60 ml of absolute ethanol. While stirring and cooling this solution to below 10° C. it was added to a solution of 17.6 g of 2-bromo-3-nitro-5-formylthiophene in 200 ml of ethanol. After stirring at room temperature for another 2 hours, 200 ml of water were added, after which the formed precipitate was sucked off, washed with water-ethanol mixture (1:1 v/v), and recrystallized from isopropanol. 6.5 g of 2-methylthio-3-nitro-5-formylthiophene of melting point 129°-131° C. were obtained. Then 2.35 g of NaHCO3, 3.1 g of 2-methylthio-3-nitro-5-formylthiophene, and 1.2 g of NH2OH.HCl were added successively to 50 ml of formic acid. The reaction mixture was refluxed for 1 hour, after which, water was added and the formed precipitate was sucked off. After recrystallization from isopropanol the desired 2-methylthio-3-nitro-5-cyanthiophene was obtained in a yield of 2.3 g; melting point 150° C.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:3][CH2:2]1.C([N:23]1[CH2:27][CH2:26][CH:25]([NH2:28])[CH2:24]1)C.[C:29](#N)[CH3:30]>>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11]([N:23]4[CH2:27][CH2:26][CH:25]([NH:28][CH2:29][CH3:30])[CH2:24]4)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:2][CH2:3]1
Reactant: O=C(O)c1cn(C2CC2)c2c(F)c(F)c(F)cc2c1=O
Reactant: CC#N
Reactant: CCN1CCC(N)C1
Product: CCNC1CCN(c2c(F)cc3c(=O)c(C(=O)O)cn(C4CC4)c3c2F)C1
Reaction time: 8 h

Procedure:
To 0.80 g (2.8 mmol) of the 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid in 10 ml of acetonitrile and 0.43 g (2.8 mmol) of 1,8-diazobicyclo [5.4.0]undec-7-ene was added 0.35 g (3.1 mmol) of the N-ethyl-3-aminopyrrolidine. The mixture was refluxed for one hour and stirred overnight. The solids were filtered and washed with ether: acetonitrile (6:1), to give 0.81 g of the title compound, mp 236°-238° C.
Reaction SMILES: [C:1]([NH:4][C@H:5]([C:14]([NH:16][C@H:17]([C:21]([OH:23])=O)[CH:18]([CH3:20])[CH3:19])=[O:15])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)(=[O:3])[CH3:2].[NH:24]1[CH2:46][CH2:45][CH2:44][CH2:43][CH:25]1[C:26]([NH:28][CH:29]1[CH:33]([O:34]CC2C=CC=CC=2)[O:32][C:31](=[O:42])[CH2:30]1)=[O:27].ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>CN(C)C=O.C(OCC)(=O)C.ClCCl>[C:1]([NH:4][C@H:5]([C:14]([NH:16][C@H:17]([C:21]([N:24]1[CH2:46][CH2:45][CH2:44][CH2:43][CH:25]1[C:26]([NH:28][CH:29]([CH:33]=[O:34])[CH2:30][C:31]([OH:42])=[O:32])=[O:27])=[O:23])[CH:18]([CH3:19])[CH3:20])=[O:15])[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([OH:13])=[CH:11][CH:12]=1)(=[O:3])[CH3:2]
Reactant: O=C1CC(NC(=O)C2CCCCN2)C(OCc2ccccc2)O1
Reactant: CC(=O)N[C@@H](Cc1ccc(O)cc1)C(=O)N[C@H](C(=O)O)C(C)C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(=O)N[C@@H](Cc1ccc(O)cc1)C(=O)N[C@H](C(=O)N1CCCCC1C(=O)NC(C=O)CC(=O)O)C(C)C
Reaction time: 18 h
Yield: 53.4 %

Procedure:
N-Acetyl-tyrosinyl-valine (464 mg, 1.44 mmol) and N-Pipecolyl-4-amino-5-benzyloxy-2-oxotetrahydrofuran (412 mg, 1.3 mmol) were dissolved in 5 ml each of dimethylformamide and dichloromethane and cooled to 0° C. To the cooled solution was added 1-hydroxybenzotriazole (HOBT; 210 mg, 1.56 mmol) followed by the addition of 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide hydrochloride (EDC; 326 mg, 1.7 mmol). After stirring for 18 hours, the mixture was diluted with ethyl acetate and washed with water, 10% sodium hydrogen sulfate, 10% sodium bicarbonate, and water. The organic layer was concentrated to give a crude solid that was purified by flash chromatography (SiO2) eluting with 94:6:1 (dichloromethane:isopropanol: pyridine) to give 370 mg of the title compound.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[CH2:10][CH2:9][CH2:8][C@@H:7]([N:11]2[C:15]3[CH:16]=[C:17]([Cl:21])[C:18]([Cl:20])=[CH:19][C:14]=3[N:13]=[CH:12]2)[C@@H:6]1[O:22][C:23](=[O:25])[CH3:24])(=[O:3])[CH3:2].[Br:26]N1C(=O)CCC1=O>CN(C)C=O>[C:1]([O:4][C@@H:5]1[CH2:10][CH2:9][CH2:8][C@@H:7]([N:11]2[C:15]3[CH:16]=[C:17]([Cl:21])[C:18]([Cl:20])=[CH:19][C:14]=3[N:13]=[C:12]2[Br:26])[C@@H:6]1[O:22][C:23](=[O:25])[CH3:24])(=[O:3])[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(=O)O[C@H]1[C@H](n2cnc3cc(Cl)c(Cl)cc32)CCC[C@H]1OC(C)=O
Solvent: CN(C)C=O
Product: CC(=O)O[C@H]1[C@H](n2c(Br)nc3cc(Cl)c(Cl)cc32)CCC[C@H]1OC(C)=O

Procedure:
(±)-(1R*,2S*,3R*)-3-(5,6-Dichloro-1H-benzimidazol-1-yl)-1,2-cyclohexanediyl diacetate (part b of this example, 1.58 g, 4.10 mmol) was dissolved in dry N,N-dimethylformamide (6.4 ml) and maintained at 65° C. under nitrogen while N-bromosuccinimide (1.46 g, 8.2 mmol) was added in 2 portions over 1 h. Volatiles were evaporated in vacuo and the residue was chromatographed on silica gel. Title compound was eluted with ethyl acetate as an off-white powder (0.95 g, 49%), m.p. 71-79° C.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][N:6]2[CH3:12].[Cl:13][C:14]1[CH:15]=[CH:16][C:17]2[N:18]([C:20]([C:23](=[O:25])[CH3:24])=[CH:21][N:22]=2)[N:19]=1>C1COCC1>[Cl:13][C:14]1[CH:15]=[CH:16][C:17]2[N:18]([C:20]([C:23]([C:10]3[C:2]([F:1])=[C:3]4[C:7](=[CH:8][C:9]=3[F:11])[N:6]([CH3:12])[N:5]=[CH:4]4)([OH:25])[CH3:24])=[CH:21][N:22]=2)[N:19]=1
Reactant: CC(=O)c1cnc2ccc(Cl)nn12
Reactant: Cn1ncc2c(F)cc(F)cc21
Solvent: C1CCOC1
Product: Cn1ncc2c(F)c(C(C)(O)c3cnc4ccc(Cl)nn34)c(F)cc21
Reaction time: 1 h

Procedure:
N-BuLi, 6.88 mL, was added dropwise to a solution of 4,6-difluoro-1-methyl-1H-indazole ((xvi), 1.68 g, 10 mmol) in dry THF (50 mL) at −78° C. The solution was stirred at this temperature for 1 h, and then the solution of 1-(6-chloro-imidazo[1,2-b]pyridazin-3-yl)ethanone (CAS 90734-71-7, 1.95 g, 10 mmol) in 50 mL THF was added dropwise at −70/75° C. After stirring additional 3 h at −70/75° C. the RM was quenched with NH4C110%, and at 0° C. diluted with water, and extracted with EtOAc (3×). The organic layers were washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by flash chromatography to afford the title compound as a yellow foam (tR 4.40 min (conditions 5), MH+=364.2, 1H-NMR in DMSO-d6: 8.16 (d, 1H); 8.11 (s, 1H); 7.85 (s, 1H); 7.30 (d, 1H); 7.22 (d, 1H); 6.26 (s, 1H); 3.96 (s, 3H); 2.12 (d, 3H)).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:20][N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:34].C(N(CC)CC)C.[CH3:42][N:43]1[C:48]2[CH:49]=[CH:50][C:51]([S:53](Cl)(=[O:55])=[O:54])=[CH:52][C:47]=2[O:46][CH2:45][CH2:44]1>C(#N)C>[CH3:42][N:43]1[C:48]2[CH:49]=[CH:50][C:51]([S:53]([O:1][C:2]3[CH:10]=[CH:9][C:8]([C:11]4[N:12]([C:27]([O:29][C:30]([CH3:31])([CH3:33])[CH3:32])=[O:28])[C:13]5[C:18]([CH:19]=4)=[CH:17][C:16]([CH2:20][N:21]4[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]4)=[CH:15][CH:14]=5)=[C:7]4[C:3]=3[CH2:4][NH:5][C:6]4=[O:34])(=[O:55])=[O:54])=[CH:52][C:47]=2[O:46][CH2:45][CH2:44]1
Reactant: CN1CCOc2cc(S(=O)(=O)Cl)ccc21
Reactant: CC(C)(C)OC(=O)n1c(-c2ccc(O)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CN1CCOc2cc(S(=O)(=O)Oc3ccc(-c4cc5cc(CN6CCCCC6)ccc5n4C(=O)OC(C)(C)C)c4c3CNC4=O)ccc21
Yield: 58 %

Procedure:
In a similar manner to Step 1 of Example 233, 4-hydroxy-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (0.0324 g, 0.0702 mmol) was dissolved in acetonitrile (0.650 mL), and the solution was treated with triethylamine (0.0590 mL, 0.421 mmol) and 3,4-dihydro-4-methyl-1,4-benzoxazine-7-sulfonyl chloride (0.0520 g, 0.211 mmol) to obtain 4-(3,4-dihydro-4-methyl-1,4-benzoxazin-7-ylsulfonyloxy)-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (0.0274 g, yield 58%).
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[CH:11][C:12]([NH2:15])=[N:13][CH:14]=2)O1.I[C:18]1[CH:23]=[N:22][CH:21]=[CH:20][N:19]=1.C1(C)C=CC=CC=1.C([O-])([O-])=O.[Na+].[Na+]>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.C(O)C>[N:19]1[CH:20]=[CH:21][N:22]=[CH:23][C:18]=1[C:9]1[CH:10]=[CH:11][C:12]([NH2:15])=[N:13][CH:14]=1
Reactant: Ic1cnccn1
Reactant: CC1(C)OB(c2ccc(N)nc2)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: Cc1ccccc1
Solvent: CCO
Product: Nc1ccc(-c2cnccn2)cn1
Temperature: 90 °C
Reaction time: 10 h

Procedure:
To a sealed tube was added 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine 86-1 (2.2 g, 10 mmol), 2-iodopyrazine 86-2 (2.06 g, 10 mmol), Pd(PPh3)4 (577 mg, 0.5 mmol), toluene (70 mL), ethanol (15 mL) and 2M Na2CO3 (15 mL). The reaction mixture was bubbled with nitrogen for 2 minutes and stirred at 90° C. for 10 hours. After cooling to room temperature, the solvents were evaporated and the residue was redissolved in dichloromethane (200 ml) and treated with 1M HCl aqueous solution (50 mL). The two layers were separated and the aqueous layer was treated with 10% NaOH aqueous solution to adjust the pH to around 13. The resulting suspension was extracted with ethyl acetate (100 mL×3). The combined organic phases were washed with H2O (50 mL) and brine (50 mL), dried over Na2SO4, and concentrated to give 5-(pyrazin-2-yl)pyridin-2-amine 86-3 as white solid. MS m/z 173.1 (M+1); 1H NMR 400 MHz (DMSO-d6) δ 9.12(d, 1H, J=1.6 Hz), 8.73(m, 1H), 8.60(m, 1H), 8.46(d, 1H, J=2.8 Hz), 8.12(dd, 1H, J1=8.8 Hz, J2=2.4 Hz), 6.55(d, 1H, J=8.8 Hz), 6.46(s, 2H).
Reaction SMILES: [O:1]([C:8]1[N:9]=[C:10]2[C:16]([C:17](O)=[O:18])=[CH:15][N:14]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25])[C:11]2=[N:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C)CCCN=C=NCC.[CH:39]1([NH2:45])[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]1>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH:39]1([NH:45][C:17]([C:16]2[C:10]3[C:11](=[N:12][CH:13]=[C:8]([O:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)[N:9]=3)[N:14]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:26])([CH3:27])[CH3:25])[CH:15]=2)=[O:18])[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]1
Reactant: C[Si](C)(C)CCOCn1cc(C(=O)O)c2nc(Oc3ccccc3)cnc21
Reactant: NC1CCCCC1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: C[Si](C)(C)CCOCn1cc(C(=O)NC2CCCCC2)c2nc(Oc3ccccc3)cnc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-phenoxy-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (0.115 g, 0.30 mmol), 4-dimethylaminopyridine (0.048 g, 0.39 mmol) and (3-dimethylamino-propyl)-ethyl-carbodiimide (0.075 g, 0.39 mmol) in CH2Cl2 (2 mL) was added a solution of cyclohexylamine (0.039 g, 0.39 mmol) in CH2Cl2 (0.5 mL). The reaction mixture was stirred at room temperature overnight, then quenched with water and extracted with ethyl acetate (3×). The organic layer was washed with water and saturated aqueous NaCl solution and dried over MgSO4, filtered and concentrated to afford 2-phenoxy-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid cyclohexylamide which was used without further purification.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C@@H:16]([OH:27])[C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:18])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C(C)=CC=CC=1C.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.C(OC(NNC)=O)(C)(C)C>ClCCl.C(OCC)(=O)C>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C@H:16]([OH:27])[C:17]([O:19][CH2:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)=[O:18])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(OCc1ccccc1)[C@H](O)Cc1ccc(OCc2ccccc2)cc1
Agent: CNNC(=O)OC(C)(C)C
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: O=C(OCc1ccccc1)[C@@H](O)Cc1ccc(OCc2ccccc2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 53.5 %

Procedure:
To a solution of (R)-benzyl 3-(4-(benzyloxy)phenyl)-2-hydroxypropanoate (Compound XLIII-1) 1.81 g (5.00 mmol) and 2,6-lutidine 874 μl (7.50 mmol) in dichloromethane 15 ml, trifluoromethanesulfonic anhydride 1.26 ml (7.50 mmol) was added and the mixture was stirred at 0° C. for 0.5 hr. N-tert-butoxycarbonyl-N′-methylhydrazine (Compound XXXIV-1) 1.46 g (10.0 mol) was added to the solution mixture and the mixture was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate 100 ml and washed with water 100 ml. The organic phase was washed with brine 100 ml and dried over magnesium sulfate and filtered. The mother solution was concentrated in vacuo and the residue was purified on silica gel column chromatography (Merck 60N spherical, neutral elution by chloroform) to obtain the title compound 0.97 g (17.3%).
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][CH3:18])=[CH:14][CH:15]=3)[C:10]([CH2:19][NH:20][OH:21])=[C:9]2[CH3:22])=[O:7])=[CH:4][CH:3]=1.[CH2:25]([N:28]=[C:29]=[O:30])[CH:26]=[CH2:27].C([O-])(=O)C.[Na+]>O1CCOCC1.O>[Cl:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][CH3:18])=[CH:14][CH:15]=3)[C:10]([CH2:19][N:20]([OH:21])[C:29]([NH:28][CH2:25][CH:26]=[CH2:27])=[O:30])=[C:9]2[CH3:22])=[O:7])=[CH:4][CH:3]=1
Reactant: COc1ccc2c(c1)c(CNO)c(C)n2C(=O)c1ccc(Cl)cc1
Reactant: C=CCN=C=O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: C=CCNC(=O)N(O)Cc1c(C)n(C(=O)c2ccc(Cl)cc2)c2ccc(OC)cc12
Yield: 44 %

Procedure:
According to the procedure of Example 62, 1-(4-chlorobenzoyl)-N-hydroxy-5-methoxy-2-methyl-1H-indole-3-methanamine is reacted with 1.2 eq of allyl isocyanate in dioxane/water (1:1) in the presence of sodium acetate (2.5 eq). The crude product is purified by column chromatography (silica, 3:7 ethyl acetate:methylene chloride). Recrystallization from methylene chloride:hexane, and then from methanol:water gives pure 1-(4-chlorobenzoyl)-N-hydroxy-5-methoxy-2-methyl-N-[(2-propenylamino) carbonyl]-1H-indole-3-methanamine (44%); mp 148°-149° C.
Reaction SMILES: Br.Br[C:3]1[CH:8]=[CH:7][N:6]=[N:5][CH:4]=1.[CH3:9][C:10]1[CH:16]=[C:15](B2OC(C)(C)C(C)(C)O2)[CH:14]=[C:13]([CH3:26])[C:11]=1[NH2:12]>>[CH3:9][C:10]1[CH:16]=[C:15]([C:3]2[CH:8]=[CH:7][N:6]=[N:5][CH:4]=2)[CH:14]=[C:13]([CH3:26])[C:11]=1[NH2:12]
Reactant: Brc1ccnnc1
Reactant: Cc1cc(B2OC(C)(C)C(C)(C)O2)cc(C)c1N
Agent: Br
Product: Cc1cc(-c2ccnnc2)cc(C)c1N
Temperature: 70 °C
Reaction time: 12 h

Procedure:
The title compound is prepared from 4-bromopyridazine hydrobromide and 2,6-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline following a procedure analogous to that described in Step 2 of Intermediate 62. The mixture is stirred for 12 hours at 70° C. LC (method 9): tR=0.66 min; Mass spectrum (ESI+): m/z=200 [M+H]+.
Reaction SMILES: [C:1]([OH:10])(=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].[Cl:11][CH2:12][CH2:13]O.S(=O)(=O)(O)O>>[CH2:1]([O:10][CH2:13][CH2:12][Cl:11])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4]
Reactant: OCCCl
Reactant: O=C(O)c1ccccc1O
Agent: O=S(=O)(O)O
Product: Oc1ccccc1COCCCl

Procedure:
A solution of 13.8 g (0.1 mole) of salicylic acid in 48.3 g (0.6 mole) of 2-chloro-ethanol in the presence of 4 ml of sulfuric acid is heated to 110° for 2 hours. After removing the excess of 2-chloro-ethanol, the ether solution of the product is extracted with an aqueous solution of 5% CO3HNa. The ether is removed and the product is distilled. B.p.: 128°-129°/11 Torr.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([O:10][CH3:11])[CH:9]=1)[CH2:5][OH:6].CCN(CC)CC.[CH3:19][S:20](Cl)(=[O:22])=[O:21]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([O:10][CH3:11])[CH:9]=1)[CH2:5][O:6][S:20]([CH3:19])(=[O:22])=[O:21]
Reactant: CS(=O)(=O)Cl
Reactant: COc1cc(Cl)cc(CO)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc(Cl)cc(COS(C)(=O)=O)c1
Yield: 93.1 %

Procedure:
To a solution of 3-chloro-5-methoxybenzyl alcohol (14.7 mmol, 2.54 g) in DCM (20 ml) was added Et3N (22 mmol, 2.23 g, 3.1 ml) and the solution was cooled to −10° C. on an acetone-ice batch. Methanesulfonic chloride (17.7 mmol, 2.03 g, 1.4 ml) was added dropwise under stirring. After 45 min the mixture was separated between DCM and H3PO4 (5% v/v in water, cold). The organic phase was washed with H3PO4 (5% v/v in water, cold), NaHCO3 (10% in water, cold), brine and dried (MgSO4). Filtration and removal of solvents under reduced pressure yielded the title compound (3.43 g, 93%) as a white solid. The product was used in the next step without further purification. 1H NMR (CDCl3, 500 MHz) δ 2.97 (s, 3H), 3.82 (s, 3H), 5.16 (s, 2H), 6.82 (s, 1H), 6.90 (s, 1H) and 6.98 (s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]([F:14])([F:13])[F:12])[C:5]([OH:7])=[O:6].[CH2:15]([Li])CCC.IC.Cl>C1COCC1>[F:1][C:2]1[C:3]([CH3:15])=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]([F:12])([F:13])[F:14])[C:5]([OH:7])=[O:6]
Reactant: [Li]CCCC
Reactant: O=C(O)c1ccc(C(F)(F)F)c(F)c1
Agent: Cl
Solvent: CI
Solvent: C1CCOC1
Product: Cc1c(C(=O)O)ccc(C(F)(F)F)c1F
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
25.0 g (120.1 mmol) of 3-fluoro-4-trifluoromethylbenzoic acid were dissolved in 250 ml of dry THF, and 100.9 ml (2.5M in hexane, 252.3 mmol) of n-butyllithium were added dropwise at a temperature of −40° C. The mixture was stirred for 3.5 h, and a solution of 51.2 g (360.4 mmol) of iodomethane in 50 ml of dry THF was then added. The mixture was stirred for 16 h, and after half an hour the temperature slowly increased to RT. For work-up, 150 ml of 1M HCl were added carefully. The mixture was extracted with diethyl ether, and the organic phase was then extracted with 1M NaOH. The aqueous phase was acidified and then extracted with diethyl ether. The organic phase was washed with water, dried and concentrated. The residue was triturated with n-heptane, and the solid was collected by filtration. What was isolated were 13.5 g of the pure product.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([CH3:12])=[N:9]2)=[CH:4][CH:3]=1.C([Li:17])CCC.[C:18](=[O:20])=[O:19]>C1COCC1>[CH3:12][C:8]1[CH:7]=[CH:6][C:5]2[C:10](=[CH:11][C:2]([C:18]([O-:20])=[O:19])=[CH:3][CH:4]=2)[N:9]=1.[Li+:17]
Reactant: Cc1ccc2ccc(Br)cc2n1
Reactant: O=C=O
Reactant: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1ccc2ccc(C(=O)[O-])cc2n1
Product: [Li+]
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
To a solution of 7-bromo-2-methylquinoline (400 mg, supplier Bioblocks Inc.) in THF (8 mL) under argon at −78° C. was added n-butyllithium (0.865 mL) dropwise. The reaction was stirred for 15 minutes at −78° C. before it was poured onto solid carbon dioxide in a beaker. The mixture was swirled until warmed to room temperature to prevent bumping, then the solvent was removed in vacuo to give the crude title compound (404 mg), which was used directly in subsequent reactions.