Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([NH:4][C:5]([CH2:7][N:8]1[C:17](=[O:18])[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:19][CH2:20][C@@H:21]([CH3:28])[CH2:22]OS(C)(=O)=O)[CH:15]=2)[N:10]=[C:9]1[C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([O:35][CH3:36])[CH:30]=1)=[O:6])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH2:43]([NH:45][CH2:46][CH3:47])[CH3:44].CCCCCC>C(#N)C>[CH2:43]([N:45]([CH2:46][CH3:47])[CH2:22][C@H:21]([CH3:28])[CH2:20][O:19][C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][CH:13]=1)[N:10]=[C:9]([C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([O:35][CH3:36])[CH:30]=1)[N:8]([CH2:7][C:5]([NH:4][CH:1]([CH3:3])[CH3:2])=[O:6])[C:17]2=[O:18])[CH3:44]
Reactant: COc1cccc(-c2nc3ccc(OC[C@@H](C)COS(C)(=O)=O)cc3c(=O)n2CC(=O)NC(C)C)c1
Reactant: CCNCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCCCCC
Product: CCN(CC)C[C@H](C)COc1ccc2nc(-c3cccc(OC)c3)n(CC(=O)NC(C)C)c(=O)c2c1
Temperature: 80 °C
Yield: 64.2 %

Procedure:
To a solution of (R)-(−)-methanesulfonic acid 3-[3-(isopropylcarbamoylmethyl)-2-(3-methoxyphenyl)-4-oxo-3,4-dihydroquinazolin-6-yloxy]-2-methylpropyl ester (1.13 g, 2.18 mmol) in anhydrous acetonitrile (40 mL) was added potassium carbonate (1.51 g, 10.95 mmol) followed by diethyl amine (3.20 g, 4.53 mL, 43.80 mmol) and the reaction mixture was heated at 80° C. in a pressure tube. After 2 days (reaction complete by HPLC), the reaction mixture was concentrated in vacuo to dryness and the residue was partitioned between water (100 mL) and ethyl acetate (150 mL). The aqueous layer was extracted with ethyl acetate (5×150 mL) and with dichloromethane (5×100 mL). The combined organic phase was dried (Na2SO4), solvent evaporated in vacuo, and the resulting residue purified by chromatography on silica gel with a gradient of methanol:dichloromethane (1:19, v/v) to methanol:dichloromethane (1:4, v/v) as eluent. The resultant solid was recrystallised from diethyl ether:hexane to afford (S)-(+)-2-[6-(3-diethylamino-2-methylpropoxy)-2-(3-methoxyphenyl)-4-oxo-4H-quinazolin-3-yl]-N-isopropy-acetamide (EXAMPLE 4a) (0.69 g, 1.40 mmol, 65% from (S)-(+)-2-[6-(3-hydroxy-2-methylpropoxy)-2-(3-methoxyphenyl)-4-oxo-4H-quinazolin-3-yl]-N-isopropylacetamide) as a white solid.
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1([C:17]2[C:18]([O:23][CH2:24][CH3:25])=[N:19][CH:20]=[CH:21][CH:22]=2)[C:12]2[C:7](=[CH:8][C:9]([F:15])=[C:10]([C:13]#[N:14])[CH:11]=2)[NH:6][C:5]1=[O:16].[CH3:26][O:27][C:28]1[CH:33]=[C:32]([O:34][CH3:35])[CH:31]=[CH:30][C:29]=1[S:36](Cl)(=[O:38])=[O:37]>CN(C)C=O>[NH2:3][C:4]1([C:17]2[C:18]([O:23][CH2:24][CH3:25])=[N:19][CH:20]=[CH:21][CH:22]=2)[C:12]2[C:7](=[CH:8][C:9]([F:15])=[C:10]([C:13]#[N:14])[CH:11]=2)[N:6]([S:36]([C:29]2[CH:30]=[CH:31][C:32]([O:34][CH3:35])=[CH:33][C:28]=2[O:27][CH3:26])(=[O:38])=[O:37])[C:5]1=[O:16]
Reactant: CCOc1ncccc1C1(N)C(=O)Nc2cc(F)c(C#N)cc21
Reactant: COc1ccc(S(=O)(=O)Cl)c(OC)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOc1ncccc1C1(N)C(=O)N(S(=O)(=O)c2ccc(OC)cc2OC)c2cc(F)c(C#N)cc21
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 41.1 %

Procedure:
80 mg (1.68 mmol) of sodium hydride (60% dispersion in mineral oil) were added in portions to a solution of 350 mg (1.12 mmol) of 3-amino-3-(2-ethoxypyridin-3-yl)-6-fluoro-2-oxo-2,3-dihydro-1H-indole-5-carbonitrile in 15 ml of anhydrous dimethylformamide under a nitrogen atmosphere and while cooling in an ice bath. The mixture was stirred at 0° C. for 10 min and then 398 mg (1.68 mmol) of 2,4-dimethoxy-phenylsulfonyl chloride were added, and the mixture was stirred at room temperature for 15 min. The reaction mixture was poured into ice-water and then extracted with ethyl acetate. The organic phase was washed with saturated sodium chloride solution and dried over magnesium sulfate, and the solvent was evaporated. The residue was purified by chromatography on silica gel (Redisep cartridge, mobile phase gradient from 0 to 3% methanol in ethyl acetate). 236 mg of the title compound were obtained as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([C:9]2[NH:10][C:11]3[C:16]([C:17]=2[CH:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)=[CH:15][CH:14]=[CH:13][CH:12]=3)=[CH:7][CH:6]=[CH:5][N:4]=1.C(N(C(C)C)CC)(C)C.[C:33]1([S:39](Cl)(=[O:41])=[O:40])[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>ClCCl>[C:33]1([S:39]([N:21]2[CH2:22][CH2:23][CH:18]([C:17]3[C:16]4[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=4)[NH:10][C:9]=3[C:8]3[C:3]([O:2][CH3:1])=[N:4][CH:5]=[CH:6][CH:7]=3)[CH2:19][CH2:20]2)(=[O:41])=[O:40])[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: COc1ncccc1-c1[nH]c2ccccc2c1C1CCNCC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ncccc1-c1[nH]c2ccccc2c1C1CCN(S(=O)(=O)c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 24.1 %

Procedure:
To a solution of 2-(2-methoxy-pyridin-3-yl)-3-piperidin-4-yl-1H-indole (0.12 g, 0.39 mmol) in dichloromethane (10 ml) and diisopropylethylamine (0.20 ml, 1.17 mmol) was added phenylsulfonyl chloride (52 μl, 0.41 mmol). The reaction was stirred at room temperature for 4 h and quenched by adding water. The organic layer was separated, washed with aqueous sodium hydroxide, brine, dried over Na2SO4, filtered and concentrated. The crude product was purified by a flash chromatography (SiO2, 30% EtOAc in hexane) to give the desired product as a white solid (0.042 g, 24%); M.p.=231-234° C.; 400 MHz 1H NMR (DMSO-d6) δ: 11.00 (s, 1H), 8.20 (dd, J1=0.8 Hz, J2=4.8 Hz, 1H), 7.77 (m, 3H), 7.66 (m, 3H), 7.29 (m, 2H), 7.07 (m, 2H), 6.92 (m, 1H), 3.84 (m, 5H), 2.56 (m, 1H), 2.42 (m, 2H), 2.00 (m, 2H), 1.66 (m, 2H); LCMS: 448.69 [M+H].
Reaction SMILES: Cl[C:2]1[N:12]2[C:13]3[C:8]([CH2:9][CH2:10][CH2:11]2)=[CH:7][C:6]([CH3:14])=[CH:5][C:4]=3[N:3]=1.[CH3:15][N:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1>>[CH3:14][C:6]1[CH:7]=[C:8]2[C:13]3=[C:4]([N:3]=[C:2]([N:19]4[CH2:20][CH2:21][N:16]([CH3:15])[CH2:17][CH2:18]4)[N:12]3[CH2:11][CH2:10][CH2:9]2)[CH:5]=1
Reactant: Cc1cc2c3c(c1)nc(Cl)n3CCC2
Reactant: CN1CCNCC1
Product: Cc1cc2c3c(c1)nc(N1CCN(C)CC1)n3CCC2
Yield: 76 %

Procedure:
A solution of 2-chloro-5,6-dihydro-8-methyl-4H-imidazo[4,5,1-ij]quinoline (3.50 g) in N-methylpiperazine (20 ml) was stirred, under nitrogen, under reflux for 1.5 hrs. The reaction mixture was quenched with saturated sodium bicarbonate solution (200 ml) and extracted with chloroform. The combined organic extracts were dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated. The residue was purified by high performance liquid chromatography (silica; 9:1 dichloromethane-methanol). The appropriate fractions were collected and evaporated. The residue was recrystallized from ethyl acetate to give 3.48 g (76%) of product, mp 164°-165° C.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][O:5][C@@H:6]1[C@H:10]([OH:11])[C@@H:9]([CH2:12][OH:13])[O:8][C@H:7]1[N:14]1[CH:21]=[C:20]([CH3:22])[C:18](=[O:19])[NH:17][C:15]1=[S:16].C(N(CC)CC)C.[F:30][C:31]([F:38])([F:37])[C:32](OCC)=[O:33]>CO>[F:30][C:31]([F:38])([F:37])[C:32]([NH:1][CH2:2][CH2:3][CH2:4][O:5][C@@H:6]1[C@H:10]([OH:11])[C@@H:9]([CH2:12][OH:13])[O:8][C@H:7]1[N:14]1[CH:21]=[C:20]([CH3:22])[C:18](=[O:19])[NH:17][C:15]1=[S:16])=[O:33]
Reactant: CCOC(=O)C(F)(F)F
Reactant: Cc1cn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2OCCCN)c(=S)[nH]c1=O
Solvent: CCN(CC)CC
Solvent: CO
Product: Cc1cn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2OCCCNC(=O)C(F)(F)F)c(=S)[nH]c1=O

Procedure:
2′-O-Aminopropyl-5-methyl-2-thiouridine is dissolved in MeOH and 5 equivalents of triethylamine are added followed by 10 equivalents of ethyl trifluoroacetate. The title compound is isolated after purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([C:12](=[O:32])[C:13]3[CH:18]=[CH:17][C:16]([NH:19][C:20](=[O:31])[C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[O:27][CH2:28][CH2:29][OH:30])=[N:15][CH:14]=3)[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[CH:33]=1.N1C=CC=CC=1.[CH3:40][S:41](Cl)(=[O:43])=[O:42]>O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([C:12](=[O:32])[C:13]3[CH:18]=[CH:17][C:16]([NH:19][C:20](=[O:31])[C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[O:27][CH2:28][CH2:29][O:30][S:41]([CH3:40])(=[O:43])=[O:42])=[N:15][CH:14]=3)[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[CH:33]=1
Reactant: CS(=O)(=O)Cl
Reactant: O=C(Nc1ccc(C(=O)N2CCCCc3cc(Cl)ccc32)cn1)c1ccccc1OCCO
Solvent: c1ccncc1
Solvent: O
Product: CS(=O)(=O)OCCOc1ccccc1C(=O)Nc1ccc(C(=O)N2CCCCc3cc(Cl)ccc32)cn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 7-chloro-1-{6-[2-(2-hydroxyethoxy)benzoylamino]-nicotinoyl}-2,3,4,5-tetrahydro-1H-benzazepine (0.5 g )in pyridine (10 ml) is added with stirring methanesulfonyl chloride (0.1 ml) under ice-cooling, and the mixture is stirred at room temperature for 2 hours. To the reaction solution is added water, and the precipitated crystals are collected by filtration, and dissolved in dichloromethane. The mixture is washed successively with diluted hydrochloric acid and water, dried over magnesium sulfate and evaporated under reduced pressure. The residue is crystallized from diethyl ether to give 7-chloro-1-{6-[2-(2-methanesulfonyloxyethoxy)benzoylamino]nicotinoyl}-2,3,4,5-tetrahydro-1H-benzazepine (0.59 g) as white powder.
Reaction SMILES: [CH2:1]([N:3]=[C:4]=[S:5])[CH3:2].[CH2:6]([O:8][C:9](=[O:13])[CH2:10][C:11]#[N:12])[CH3:7].C(N(CC)CC)C>O>[CH2:6]([O:8][C:9](=[O:13])[CH:10]([C:11]#[N:12])[C:4](=[S:5])[NH:3][CH2:1][CH3:2])[CH3:7]
Reactant: CCOC(=O)CC#N
Reactant: CCN=C=S
Solvent: O
Solvent: CCN(CC)CC
Product: CCNC(=S)C(C#N)C(=O)OCC
Temperature: 50 °C

Procedure:
4.25 ml of ethyl isothiocyanate is added to a mixture that consists of 5 g of cyanoacetic acid ethyl ester and 5 ml of triethylamine at 25° C. Then, it is allowed to stir for 6 more hours at 50° C. Then, the reaction mixture is concentrated by evaporation in a vacuum. The residue is taken up in ethanol and poured into 150 ml of ice-cold IN hydrochloric acid. It is allowed to stir for 3 more hours at 25° C., and then the residue is filtered off. The solid that is obtained is rewashed with water. 7 g of product is obtained.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([CH2:14][CH3:15])=[N:8][CH:9]=[CH:10][C:11]=1[CH2:12][CH3:13])=[O:5])[CH3:2].C1C=C([Cl:22])C=C(C(OO)=O)C=1>C(Cl)(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1[C:7]([CH2:14][CH3:15])=[N:8][C:9]([Cl:22])=[CH:10][C:11]=1[CH2:12][CH3:13])=[O:5])[CH3:2]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCOC(=O)c1c(CC)ccnc1CC
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1c(CC)cc(Cl)nc1CC
Temperature: 25 °C
Reaction time: 6 h
Yield: 49.7 %

Procedure:
To a solution of 2.73 g (14.12 mmol) 2,4-diethyl-pyridine-3-carboxylic acid ethylester in chloroform (109 ml) was added 6.97 g, (70% pure, 28.29 mmol) mCPBA at 0° C. The reaction mixture was stirred at RT for 6 h and was then diluted with chloroform and washed with a sat. NaHCO3 sol and brine. The organic layer was dried over Na2SO4 and concentrated in vacuo. The residue was dissolved in POCl3 (70 ml) and the reaction mixture was heated at 110° C. for 6.5 h. Then excess POCl3 was evaporated and cold water was added to the residue. The mixture was basified with a sat. NaHCO3 sol to pH ˜10 and was extracted EtOAc. The organic layer was washed with water and brine, dried over Na2SO4 and concentrated in vacuo. Purification of this residue by CC (hexane/EtOAc 9:1) provided 1.6 g (7.02 mmol, 20%) 6-chloro-2,4-diethyl-pyridine-3-carboxylic acid ethylester.
Reaction SMILES: [C:1]1(C)[CH:6]=[CH:5][C:4](S(O)(=O)=O)=[CH:3][CH:2]=1.C1(=O)CCCCC1.[NH:19]1[CH2:23][CH2:22][CH2:21][CH2:20]1>C1C=CC=CC=1>[C:1]1([N:19]2[CH2:23][CH2:22][CH2:21][CH2:20]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH:6]=1
Reactant: C1CCNC1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O=C1CCCCC1
Solvent: c1ccccc1
Product: C1=C(N2CCCC2)CCCC1

Procedure:
1 g of para-toluenesulphonic acid is added to a mixture of 20 mmol of cyclohexanone and 22 mmol of pyrrolidine in 200 ml of dry benzene. The reaction mixture is stirred at reflux until, in the infra-red, the ketone has disappeared, with the enamine concomitantly appearing. The solvent is then evaporated off and the crude residue is purified by distillation in vacuo.
Reaction SMILES: [ClH:1].[C:2]([CH2:5][CH2:6][C:7]([NH:9][CH2:10][C:11]1[O:15][C:14]([C:16]([O:18][C:19]2[CH:28]=[CH:27][C:26]3[C:21](=[CH:22][CH:23]=[C:24]([C:29](=[NH:31])[NH2:30])[CH:25]=3)[CH:20]=2)=[O:17])=[CH:13][CH:12]=1)=[O:8])([OH:4])=[O:3].CC(C)[O-:34].[Al+3:36].CC(C)[O-:39].CC(C)[O-]>C(O)C.C1(C)C=CC=CC=1>[ClH:1].[OH-:3].[Al+3:36].[C:2]([CH2:5][CH2:6][C:7]([NH:9][CH2:10][C:11]1[O:15][C:14]([C:16]([O:18][C:19]2[CH:28]=[CH:27][C:26]3[C:21](=[CH:22][CH:23]=[C:24]([C:29](=[NH:30])[NH2:31])[CH:25]=3)[CH:20]=2)=[O:17])=[CH:13][CH:12]=1)=[O:8])([OH:4])=[O:3].[OH-:34].[OH-:39]
Reactant: CC(C)[O-]
Agent: Cl
Agent: N=C(N)c1ccc2cc(OC(=O)c3ccc(CNC(=O)CCC(=O)O)o3)ccc2c1
Agent: [Al+3]
Solvent: CCO
Solvent: Cc1ccccc1
Product: [OH-]
Reaction time: 3 h

Procedure:
In 1.84 l of 95% ethanol was dissolved 18.4 g of 6-amidino-2-naphthyl 5-(3-carboxypropionylaminomethyl)furan-2-carboxylate hydrochloride, and a solution of 8.42 g of aluminium isopropoxide in 670 ml of toluene was added dropwise thereto at room temperature. After completion of the addition, the reaction mixture was stirred for 3 hours and allowed to stand overnight. The crystals thus precipitated were collected by filtration to obtain 19.1 g of the intended product.
Reaction SMILES: Br[CH2:2][C:3]1[CH:13]=[CH:12][C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:5][C:4]=1[N+:14]([O-:16])=[O:15].[NH2:17][C:18]1[CH:19]=[C:20]([CH:23]=[CH:24][CH:25]=1)[C:21]#[N:22].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:21]([C:20]1[CH:19]=[C:18]([NH:17][CH2:2][C:3]2[CH:13]=[CH:12][C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:5][C:4]=2[N+:14]([O-:16])=[O:15])[CH:25]=[CH:24][CH:23]=1)#[N:22]
Reactant: N#Cc1cccc(N)c1
Reactant: CCOC(=O)c1ccc(CBr)c([N+](=O)[O-])c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)c1ccc(CNc2cccc(C#N)c2)c([N+](=O)[O-])c1
Temperature: 70 °C
Reaction time: 3 h
Yield: 54.9 %

Procedure:
Ethyl 4-bromomethyl-3-nitrobenzoate (26.00 g) was dissolved in 90 ml of acetonitrile, then 7.97 g of 3-aminobenzonitrile and 12.44 g of potassium carbonate were added and the mixture was stirred at 70° C. for 3 hours. The reaction solution was cooled to room temperature, and after filtration, the mother liquor was concentrated in vacuo. Ethyl acetate was added to the resulting residue. The mixture was washed with a 1N aqueous solution of hydrochloric acid and a saturated aqueous solution of sodium bicarbonate, dried over anhydrous magnesium sulfate and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography using hexane-ethyl acetate (80:20 to 75:25) as an eluting solvent to give 12.06 g of ethyl 4-[(3-cyanophenylamino)methyl]-3-nitrobenzoate.
Reaction SMILES: [NH2:1][CH:2]1[C:23](=[O:24])[N:4]2[C:5]([C:20]([OH:22])=[O:21])=[C:6]([CH2:9][S:10][C:11]3[O:12][C:13]([CH2:16][C:17]([OH:19])=[O:18])=[N:14][N:15]=3)[CH2:7][S:8][C@H:3]12.C(N(CC)CC)C.[F:32][C:33]([F:42])([F:41])[CH2:34][S:35]([CH2:37][C:38](O)=[O:39])=[O:36]>CN(C)C=O>[F:32][C:33]([F:42])([F:41])[CH2:34][S:35]([CH2:37][C:38]([NH:1][CH:2]1[C:23](=[O:24])[N:4]2[C:5]([C:20]([OH:22])=[O:21])=[C:6]([CH2:9][S:10][C:11]3[O:12][C:13]([CH2:16][C:17]([OH:19])=[O:18])=[N:14][N:15]=3)[CH2:7][S:8][C@H:3]12)=[O:39])=[O:36]
Reactant: O=C(O)CS(=O)CC(F)(F)F
Reactant: NC1C(=O)N2C(C(=O)O)=C(CSc3nnc(CC(=O)O)o3)CS[C@H]12
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(O)Cc1nnc(SCC2=C(C(=O)O)N3C(=O)C(NC(=O)CS(=O)CC(F)(F)F)[C@H]3SC2)o1
Reaction time: 0.25 h

Procedure:
A suspension of 3.4 g (0.01 mol) of 7-amino-3-(5-carboxymethyl-1,3,4-oxadiazol-2-ylthiomethyl)-3-cephem-4-carboxylic acid in 50 ml of dry dimethylformamide is treated with 2 of triethylamine and the mixture is stirred for 15 minutes at 25°. A slight excess of 0.01 mol of the activated ester of 2,2,2-trifluoroethylsulfinylacetic acid is added to the mixture and it is stirred an additional hour. The reaction mixture is evaporated to dryness in vacuo and water and ethyl acetate are added to the residue. The layers are separated, the ethyl acetate layer is discarded, fresh ethyl acetate is added to the aqueous phase and it is acidified to pH 2.5 by addition of 6N hydrochloric acid. The mixture is filtered, the layers are separated and the aqueous phase is extracted with ethyl acetate. The combined extracts are washed with water, dried (MgSO4) and evaporated to dryness to give the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH2:11][CH2:12][CH3:13])(=[O:10])=[O:9])=[C:4]([N+:14]([O-])=O)[CH:3]=1.[H][H]>CO.[Pd]>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH2:11][CH2:12][CH3:13])(=[O:10])=[O:9])=[C:4]([CH:3]=1)[NH2:14]
Reactant: CCCS(=O)(=O)c1ccc(C)cc1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CCCS(=O)(=O)c1ccc(C)cc1N
Yield: 93.8 %

Procedure:
A solution of 4-methyl-2-nitro-1-(propylsulfonyl)benzene (Intermediate 227; 11 g, 45 mmol) in methanol (150 ml) was treated with Pd/C (1.1 g) and the reaction mixture was stirred under 3 Kg/cm2 pressure of hydrogen at RT for 5 h. The catalyst was filtered through celite and the solvent was removed under reduced pressure to afford the title compound (9 g, 94%) as pale yellow liquid.
Reaction SMILES: C[C:2]1[S:3][C:4]([C:8]([NH:10][NH2:11])=O)=[C:5]([CH3:7])[N:6]=1.Cl.[CH3:13][NH:14][C:15](=NC)[CH2:16][CH2:17][CH2:18][CH:19]=[CH2:20]>>[CH3:13][N:14]1[C:15]([CH2:16][CH2:17][CH2:18][CH:19]=[CH2:20])=[N:11][N:10]=[C:8]1[C:4]1[S:3][CH:2]=[N:6][C:5]=1[CH3:7]
Reactant: C=CCCCC(=NC)NC
Reactant: Cc1nc(C)c(C(=O)NN)s1
Agent: Cl
Product: C=CCCCc1nnc(-c2scnc2C)n1C

Procedure:
The title compound was prepared in analogy to Preparation 11 in 0.31 g yield starting from 2,4-dimethyl-thiazole-5-carboxylic acid hydrazide (0.52 g) and N,N′-dimethyl-5-hexenimidamide hydrochloride (0.58 g). MS (m/z): 249 [MH]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.[CH3:15][O:16][C:17]1[CH:18]=[C:19]([C:23]2[C:24]([CH:29]=O)=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:20]=[CH:21][CH:22]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C1(C2C=CC=CC=2)C=CC=CC=1CN1CCN(C2C=CC=CC=2)CC1>>[CH3:15][O:16][C:17]1[CH:18]=[C:19]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[CH2:29][N:12]2[CH2:13][CH2:14][N:9]([C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[O:2][CH3:1])[CH2:10][CH2:11]2)[CH:20]=[CH:21][CH:22]=1
Reactant: COc1ccccc1N1CCNCC1
Reactant: COc1cccc(-c2ccccc2C=O)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: c1ccc(-c2ccccc2CN2CCN(c3ccccc3)CC2)cc1
Product: COc1cccc(-c2ccccc2CN2CCN(c3ccccc3OC)CC2)c1

Procedure:
176 mg of the target compound (0.45 mmol, 96.4%) was obtained using 1-(2-methoxyphenyl)piperazine (181 mg, 0.94 mmol), 3′-methoxybiphenyl-2-carbaldehyde (100 mg, 0.47 mmol) and NaBH(OAc)3 (303 mg, 1.41 mmol) according to the synthesis method of Compound 1.
Reaction SMILES: [I:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6](C=CC3C=CC=CC=3)=[N:7][N:8]2[CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])=[CH:4][CH:3]=1.CO.O=[O+][O-].[CH:32]([O:37][CH3:38])([O:35][CH3:36])OC>C(Cl)Cl>[CH3:38][O:37][CH:32]([C:6]1[C:5]2[C:9](=[CH:10][C:2]([I:1])=[CH:3][CH:4]=2)[N:8]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[N:7]=1)[O:35][CH3:36]
Reactant: C[Si](C)(C)CCOCn1nc(C=Cc2ccccc2)c2ccc(I)cc21
Reactant: COC(OC)OC
Agent: O=[O+][O-]
Solvent: ClCCl
Solvent: CO
Product: COC(OC)c1nn(COCC[Si](C)(C)C)c2cc(I)ccc12
Temperature: 25 °C
Reaction time: 4 h
Yield: 92 %

Procedure:
A solution of 6-iodo-3-styryl-1-[2-(trimethyl-silanyl)-ethoxymethyl]-1H-indazole [Example 14, step (i)] (1.28 g, 2.69 mmol) in CH2Cl2 (40mL)/MeOH (40 mL) was stirred at −78° C. The reaction was treated with ozone until a blue color persisted, and then was purged with argon. Methyl sulfide (4 mL) was added, and the reaction stirred 4 h while warming to r.t. Concentration in vacuo gave a crude mixture of acetal and aldehyde, which was converted completely to the acetal by stirring in trimethyl orthoformate (10 mL) with Amberlyst 15(wet) acidic ion-exchange resin (0.8 g) for 1 h. The resin was removed by filtration, and the solution was concentrated in vacuo. Purification by silica gel chromatography gave 1.11 g (92%) of 3-(1,1-dimethoxy-methyl)-6-iodo-1-(2-trimethylsilanyl-ethoxymethyl)-1H-indazole as a clear oil. 1H NMR (300 MHz, CDCl3) δ 7.98 (s, 1H), 7.68 (d, 1H, J=8.4 Hz), 7.48 (dd, 1H, J=8.4, 1.2 Hz), 5.77 (s, 1H), 5.69 (s, 2H), 3.53 (t, 2H, J=8.4 Hz), 3.43 (s, 6H), 0.88 (t, 2H, J=8.4 Hz), −0.06 (s, 9H).
Reaction SMILES: C[O:2][C:3](=[O:39])[CH2:4][CH2:5][NH:6][C:7](=[O:38])[C:8]1[CH:13]=[CH:12][C:11]([CH:14]([O:22][C:23]2[CH:28]=[CH:27][C:26](B3OC(C)(C)C(C)(C)O3)=[CH:25][CH:24]=2)[CH2:15][CH2:16][CH2:17][C:18]([F:21])([F:20])[F:19])=[CH:10][CH:9]=1.Br[C:41]1[CH:46]=[CH:45][C:44]([C:47]([F:50])([F:49])[F:48])=[C:43]([F:51])[CH:42]=1>>[F:20][C:18]([F:19])([F:21])[CH2:17][CH2:16][CH2:15][CH:14]([C:11]1[CH:10]=[CH:9][C:8]([C:7]([NH:6][CH2:5][CH2:4][C:3]([OH:2])=[O:39])=[O:38])=[CH:13][CH:12]=1)[O:22][C:23]1[CH:28]=[CH:27][C:26]([C:41]2[CH:46]=[CH:45][C:44]([C:47]([F:49])([F:50])[F:48])=[C:43]([F:51])[CH:42]=2)=[CH:25][CH:24]=1
Reactant: COC(=O)CCNC(=O)c1ccc(C(CCCC(F)(F)F)Oc2ccc(B3OC(C)(C)C(C)(C)O3)cc2)cc1
Reactant: Fc1cc(Br)ccc1C(F)(F)F
Product: O=C(O)CCNC(=O)c1ccc(C(CCCC(F)(F)F)Oc2ccc(-c3ccc(C(F)(F)F)c(F)c3)cc2)cc1

Procedure:
The title compound is prepared in a manner substantially similar to Example 359 starting from 3-(4-{5,5,5-trifluoro-1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenoxy]-pentyl}-benzoylamino)-propionic acid methyl ester and 4-bromo-2-fluoro-1-trifluoromethyl-benzene. MS: 570.2 [M−H]−.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:16]=[C:15]3[C:10]([C:11](=O)[NH:12][CH:13]=[N:14]3)=[CH:9][CH:8]=2)=[N:4][N:3]=1.P(Cl)(Cl)([Cl:20])=O>>[Cl:20][C:11]1[C:10]2[C:15](=[CH:16][C:7]([C:5]3[O:6][C:2]([CH3:1])=[N:3][N:4]=3)=[CH:8][CH:9]=2)[N:14]=[CH:13][N:12]=1
Reactant: Cc1nnc(-c2ccc3c(=O)[nH]cnc3c2)o1
Reactant: O=P(Cl)(Cl)Cl
Product: Cc1nnc(-c2ccc3c(Cl)ncnc3c2)o1

Procedure:
7-(5-Methyl-[1,3,4]oxadiazol-2-yl)quinazolin-4-one (0.09 g) was treated with phosphorous oxychloride (5 ml) at reflux under nitrogen for 2 hours. The mixture was cooled, evaporated and partitioned between saturated aqueous sodium carbonate and ethyl acetate. The organic phase was dried, concentrated in vacuo to give the title compound which was used crude in the subsequent synthetic step.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH2:8]O)=[C:6]([Cl:10])[CH:5]=[CH:4][C:3]=1[N:11]1[CH:15]=[CH:14][CH:13]=[C:12]1[CH2:16][NH:17][C:18](=[O:31])[CH:19]=[CH:20][C:21]1[CH:26]=[CH:25][C:24]([C:27](=[O:30])[NH:28][CH3:29])=[CH:23][CH:22]=1.C(N(CC)CC)C.CS([Cl:43])(=O)=O>CN(C)C=O>[Cl:1][C:2]1[C:7]([CH2:8][Cl:43])=[C:6]([Cl:10])[CH:5]=[CH:4][C:3]=1[N:11]1[CH:15]=[CH:14][CH:13]=[C:12]1[CH2:16][NH:17][C:18](=[O:31])[CH:19]=[CH:20][C:21]1[CH:22]=[CH:23][C:24]([C:27](=[O:30])[NH:28][CH3:29])=[CH:25][CH:26]=1
Reactant: CS(=O)(=O)Cl
Reactant: CNC(=O)c1ccc(C=CC(=O)NCc2cccn2-c2ccc(Cl)c(CO)c2Cl)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CNC(=O)c1ccc(C=CC(=O)NCc2cccn2-c2ccc(Cl)c(CCl)c2Cl)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a mixture of 1-(2,4-dichloro-3-hydroxymethylphenyl)-2-[4-(methylcarbamoyl)cinnamoylaminomethyl]pyrrole (148 mg), triethylamine (0.11 ml) and anhydrous dimethylformamide (1 ml) was added a 1M solution of methanesulfonyl chloride in dimethylformamide (0.77 ml) under ice-water cooling. The mixture was stirred at ambient temperature for 4 hours and partitioned between chloroform and saturated aqueous solution of sodium hydrogen carbonate. The organic layer was isolated, dried over magnesium sulfate and evaporated in vacuo to give a brown oil. The residue was purified by preparative thin layer chromatography (chloroform-methanol) to give 1-(2,4-dichloro-3-chloromethylphenyl)-2-[4-(methylcarbamoyl)cinnamoylaminomethyl]pyrrole (120 mg) as an amorphous powder.