Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[S:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[S:5][C:4]1=[N:12][CH2:13][CH2:14][C:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[NH:17][CH:16]=1.[CH:24]1[C:29]([CH2:30]Cl)=[CH:28][CH:27]=[C:26]([Cl:32])[CH:25]=1.O>COCCOC>[S:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[S:5][C:4]1=[N:12][CH2:13][CH2:14][C:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[N:17]([CH2:30][C:29]2[CH:28]=[CH:27][C:26]([Cl:32])=[CH:25][CH:24]=2)[CH:16]=1
Reactant: ClCc1ccc(Cl)cc1
Reactant: c1ccc2c(CCN=c3sc4ccccc4s3)c[nH]c2c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: Clc1ccc(Cn2cc(CCN=c3sc4ccccc4s3)c3ccccc32)cc1
Reaction time: 4 h

Procedure:
Sodium hydride (50% dispersion in mineral oil; 155 mg) is slurried in 5 ml of anhydrous 1,2-dimethoxyethane and treated dropwise with N-(1,3-benzodithiol-2-ylidene)-1H-indol-3-ethanamine (1g, prepared as described in Example 30) in 5 ml of anhydrous 1,2-dimethoxyethane. The mixture is heated at reflux for 3 hours. A solution of α,p-dichlorotoluene (520 mg) in 5 ml of anhydrous 1,2-dimethoxyethane is added dropwise to the refluxing reaction mixture. Refluxing is continued for four hours after addition is complete. The reaction mixture is then poured into water (50 ml) and extracted with two 50 ml portions of dichloromethane. The combined dichloromethane extracts are washed with water and brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The resultant solid is chromatographed on silica gel (200 ml) eluting with dichloromethanepentane (1:1). The fractions containing product with Rf =0.8 (silica gel, dichloromethane) are concentrated. The solid thus obtained is recrystallized from hexane to yield 600 mg of the title compound, melting point 120°-121° C.
Reaction SMILES: [C:1]1([C:7]2([CH2:12][OH:13])[CH2:11][CH2:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[S:21](Cl)([CH3:24])(=[O:23])=[O:22]>ClCCl>[C:1]1([C:7]2([CH2:12][O:13][S:21]([CH3:24])(=[O:23])=[O:22])[CH2:11][CH2:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CS(=O)(=O)Cl
Reactant: OCC1(c2ccccc2)CCCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCC1(c2ccccc2)CCCC1
Reaction time: 16 h
Yield: 83.16 %

Procedure:
To a stirred solution of (1-phenyl-cyclopentyl)-methanol] (278) (10 g, 56.73 mmol) in dichloromethane (110 mL) was added triethyl amine (16 mL, 113.47 mmol) followed by mesyl chloride (5.3 mL, 68.08 mmol) at 0° C. Stirring was continued at room temperature for 16 h. After completion of the reaction, the reaction mixture was diluted with dichloromethane (50 mL) and washed with water (100 mL) and saturated aqueous sodium bicarbonate solution (50 mL) and brine (50 mL). The separated organic fraction was dried and concentrated. The crude product was purified by Combi-Flash column (eluted at 10-20% ethyl acetate in hexane) to get methanesulfonic acid 1-phenyl-cyclopentylmethyl ester (279) (12 g, 83.16%) as a yellow semi-solid.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH2:5][C@H:4]([N:8]2[C:12]3=[C:13]4[S:19][CH:18]=[CH:17][C:14]4=[N:15][CH:16]=[C:11]3[N:10]=[C:9]2[C@H:20]([OH:22])[CH3:21])[CH2:3]1.C(N(CC)CC)C.Cl[C:31]([O:33][CH2:34][CH3:35])=[O:32]>C(Cl)Cl>[OH:22][C@@H:20]([C:9]1[N:8]([C@H:4]2[CH2:5][CH2:6][CH2:7][N:2]([C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH2:3]2)[C:12]2=[C:13]3[S:19][CH:18]=[CH:17][C:14]3=[N:15][CH:16]=[C:11]2[N:10]=1)[CH3:21]
Reactant: C[C@@H](O)c1nc2cnc3ccsc3c2n1[C@H]1CCCNC1
Reactant: CCOC(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)N1CCC[C@H](n2c([C@@H](C)O)nc3cnc4ccsc4c32)C1
Yield: 34 %

Procedure:
To a mixture of (1R)-1-{1-[(3S)-piperidin-3-yl]-1H-imidazo[4,5-d]thieno[3,2-b]pyridin-2-yl}ethanol hydrochloride (15 mg, 0.044 mmol) and triethylamine (18.5 μL, 0.133 mmol) in methylene chloride (0.3 mL) was added ethyl chloroformate (5.1 μL, 0.0531 mmol). The resulting mixture was stirred until completion then the solvent evaporated. The crude residue was purified using RP-HPLC (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 30 mL/min) to give 5.6 mg (34%) of the desired product. LCMS calculated for C18H23N4O3S (M+H)+: m/z=375.1. Found: 375.0. 1H NMR (300 MHz, CDCl3) δ 9.08 (d, J=1.3 Hz, 1H), 7.69 (dd, J=5.5 and 1.3 Hz, 1H), 7.62 (d, J=5.5 Hz, 1H), 5.21 (d, J=6.7 Hz, 1H), 4.83-4.68 (m, 1H), 4.43-4.23 (m, 2H), 4.15 (q, J=6.9 Hz, 2H), 3.93-3.66 (m, 1H), 3.18-3.01 (m, 1H), 2.76-2.60 (m, 1H), 2.20-2.10 (m, 1H), 2.00 (d, J=13.8 Hz, 1H), 1.79 (d, J=6.4 Hz, 3H), 1.70-1.61 (m, 2H), 1.30-1.16 (m, 3H) ppm.
Reaction SMILES: I[CH2:2][CH2:3][CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([CH2:14][S:15]([NH:18][CH3:19])(=[O:17])=[O:16])[CH:12]=2)[NH:7][CH:6]=1.[CH3:20][O:21][C:22]1[CH:23]=[N:24][CH:25]=[CH:26][C:27]=1[N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1.C([O-])([O-])=O.[K+].[K+]>CC#N>[CH3:20][O:21][C:22]1[C:27]([N:28]2[CH2:29][CH2:30][N:31]([CH2:2][CH2:3][CH2:4][C:5]3[C:13]4[C:8](=[CH:9][CH:10]=[C:11]([CH2:14][S:15]([NH:18][CH3:19])(=[O:17])=[O:16])[CH:12]=4)[NH:7][CH:6]=3)[CH2:32][CH2:33]2)=[CH:26][CH:25]=[N:24][CH:23]=1
Reactant: CNS(=O)(=O)Cc1ccc2[nH]cc(CCCI)c2c1
Reactant: COc1cnccc1N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CNS(=O)(=O)Cc1ccc2[nH]cc(CCCN3CCN(c4ccncc4OC)CC3)c2c1
Yield: 52 %

Procedure:
A solution of 3-(3-iodopropyl)-N-methyl-1H-indole-5-methanesulfonamide (0.556 g, 1.26 mmol), 1-(3-methoxy-4-pyridinyl)piperazine (0.4 g, 2.02 mmol), and K2CO3 (0.5 g, 3.6 mmol) in 30 mL of MeCN was heated to reflux for 12 h. The reaction mixture was cooled, concentrated in vacuo, and the residue dissolved EtOAc. The EtOAc solution was washed with water, dried (MgSO4), filtered and concentrated in vacuo. Silica gel chromatography (100:3:1 CH2Cl2 -MeOH-Et3N) of the residue gave 4-(5-methoxy-4-pyridinyl)-1-[3-[5-[[(methylamino)sulfonyl]methyl]-1-H-indol-3-yl]propyl]piperazine (300 mg, 52%). The hydrochloride salt was prepared by dissolving the free base in 3 equivalents of 1.5 M HCl in EtOH. The solution was concentrated in vacuo and the residue recrystallized from MeOH to yield the title compound (380 mg, 50%): mp 100°-103° C. Anal. Calcd for C23H31N5O3S.3.8 HCl: C, 46.34; H, 5.88; N, 11.78. Found: C, 46.32; H, 6.18; N, 11.67
Reaction SMILES: [NH2:1][CH:2]([C:11]1[C:16]([F:17])=[CH:15][CH:14]=[CH:13][C:12]=1[O:18][CH2:19][CH3:20])[CH2:3][CH:4]([CH3:10])[C:5]([O:7]CC)=O.[N:21]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:24]=[CH:23][C:22]=1[CH:31]=O>>[CH2:19]([O:18][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]([F:17])[C:11]=1[CH:2]1[N:1]([CH2:31][C:22]2[CH:23]=[CH:24][C:25]3[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=3)[N:21]=2)[C:5](=[O:7])[CH:4]([CH3:10])[CH2:3]1)[CH3:20]
Reactant: O=Cc1ccc2ccccc2n1
Reactant: CCOC(=O)C(C)CC(N)c1c(F)cccc1OCC
Product: CCOc1cccc(F)c1C1CC(C)C(=O)N1Cc1ccc2ccccc2n1

Procedure:
Prepared according to the described general procedure 2 (GP2) by reaction of ethyl 4-amino-4-(2-ethoxy-6-fluorophenyl)-2-methylbutanoate with commercially available quinoline-2-carbaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.71 min.; [M+H]+: 379.04 g/mol.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH3:11])[CH:8]=[CH:9][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[Br:12]N1C(=O)CCC1=O.C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>CCCCCC>[C:1]([C:5]1[CH:6]=[C:7]([CH:8]=[CH:9][CH:10]=1)[CH2:11][Br:12])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cccc(C(C)(C)C)c1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Solvent: CCCCCC
Product: CC(C)(C)c1cccc(CBr)c1
Temperature: 60 °C
Yield: 34.6 %

Procedure:
A dry 100 mL 3-necked flask equipped with a nitrogen inlet, a condenser, a thermometer, and a magnetic stirrer was charged with 2.0 g of 3-tert-butyltoluene (Wiley Organics, Coshocton, Ohio 43812), 2.40 g of N-bromosuccinimide (Aldrich), and 30 mL of CCl4. The mixture was treated with 0.16 g of benzoyl peroxide (Aldrich) and heated at 60° C. under N2. Careful temperature control is important to minimize by-product formation. After 1 h at 60° C. the reaction mixture was cooled to 0° C., filtered to remove succinimide, and the filtrate was concentrated in vacuo to afford a light yellow liquid. Analysis of this material by tlc (SiO2, hexane) indicated a major new component at Rf=0.50, a minor component at Rf=0.55, and a trace of 3-tert-butyltoluene at Rf=0.75. The crude product was purified by flash chromatography on 100 g of silica gel (hexane) to afford 1.06 g (35%) of 3-tert-butylbenzyl bromide as a clear liquid.
Reaction SMILES: [SH:1][CH2:2][CH2:3][OH:4].C([O-])(=O)C.[Na+].Cl[C:11]1[CH:16]=[CH:15][C:14]([S:17]([NH2:20])(=[O:19])=[O:18])=[CH:13][C:12]=1[N+:21]([O-:23])=[O:22].Cl>O>[OH:4][CH2:3][CH2:2][S:1][C:11]1[CH:16]=[CH:15][C:14]([S:17]([NH2:20])(=[O:19])=[O:18])=[CH:13][C:12]=1[N+:21]([O-:23])=[O:22]
Reactant: NS(=O)(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: OCCS
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: NS(=O)(=O)c1ccc(SCCO)c([N+](=O)[O-])c1
Yield: 75.8 %

Procedure:
A mixture of 2-mercaptoethanol (1.66 g, 0.02 mol), anhydrous sodium acetate (2 g) and 4-chloro-3-nitrobenzenesulfonamide (2.37 g, 0.01 mol) was heated on the steam bath for about 5 hours. The reaction mixture was diluted with water, acidified with 6N hydrochloric acid and cooled. Filtration and drying gave 2.11 g of a yellow solid that was recrystallized from ethyl acetate, m.p. 150°-152° C.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:10](=[O:28])[N:11]([CH2:21][CH:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)[CH:12]=[C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)[CH:14]=1)#[N:2].C(N(CC)CC)C.[C:36]1([S:42](Cl)(=[O:44])=[O:43])[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>C(Cl)(Cl)Cl>[C:36]1([S:42]([N:25]2[CH2:24][CH2:23][CH:22]([CH2:21][N:11]3[CH:12]=[C:13]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=4)[CH:14]=[C:9]([C:4]4[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=4[C:1]#[N:2])[C:10]3=[O:28])[CH2:27][CH2:26]2)(=[O:44])=[O:43])[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: N#Cc1ccccc1-c1cc(-c2ccccn2)cn(CC2CCNCC2)c1=O
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: N#Cc1ccccc1-c1cc(-c2ccccn2)cn(CC2CCN(S(=O)(=O)c3ccccc3)CC2)c1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 72.6 %

Procedure:
30 mg of 3-(2-cyanophenyl)-1-(piperidin-4-yl)methyl-5-(2-pyridyl)-1,2-dihydropyridin-2-one was dissolved in 2 ml of chloroform. Under ice-cooling, 0.04 ml of triethylamine and 23 mg of benzenesulfonyl chloride were added thereto, followed by stirring at room temperature for 2 hours. The reaction solution was diluted with chloroform, and washed with a saturated aqueous solution of sodium hydrogen carbonate and brine. The organic layer was dried over magnesium sulfate, and then evaporated and the residue was purified by silica gel chromatography (ethyl acetate/hexane), to give 30 mg of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:14]=[CH:15][CH:16]=1)[O:6][CH:7]1[CH2:10][N:9]([C:11](Cl)=[O:12])[CH2:8]1.[CH2:17]([NH2:20])[CH:18]=[CH2:19]>O1CCCC1.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:14]=[CH:15][CH:16]=1)[O:6][CH:7]1[CH2:10][N:9]([C:11]([NH:20][CH2:17][CH:18]=[CH2:19])=[O:12])[CH2:8]1
Reactant: C=CCN
Reactant: COc1cccc(OC2CN(C(=O)Cl)C2)c1
Solvent: O
Solvent: C1CCOC1
Product: C=CCNC(=O)N1CC(Oc2cccc(OC)c2)C1
Reaction time: 17 h
Yield: 76.8 %

Procedure:
A solution of 4.85 g (0.02 mole) of 3-(3-methoxyphenoxy)-1-azetidinecarbonyl chloride in 20 ml of tetrahydrofuran was treated with 4.5 g (0.06 mole) of 2-propenylamine and stirred for 17 hr, diluted with 200 ml of water and extracted with 3×50 ml of methylene chloride. The combined extracts were dried then concentrated in vacuo to yield 4.03 g of oil residue. The residue was chromatographed on a spinning TLC plate (chromatotron) in 3 portions (3 runs) using a ethyl acetate/methylene chloride gradient. The 4th fraction of each run was combined and concentrated in vacuo to yield a white solid (1.2 g), which was recrystallized from benzene-ligroin yielding 0.94 g (18%) of fine white crystals, m.p. 121°-123° C.
Reaction SMILES: [C:1]([CH2:4][CH2:5][CH2:6]/[CH:7]=[C:8]1\[CH2:9][C@@H:10]2[C@H:14]([CH2:15]\1)[C@@H:13]([CH2:16][CH2:17][CH:18]([OH:25])[CH:19]([F:24])[CH2:20][CH2:21][CH2:22][CH3:23])[C@H:12]([O:26][CH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][O:28]1)[CH2:11]2)([OH:3])=[O:2].CC(C)=O.OS(O)(=O)=O.O=[Cr](=O)=O>C(O)(C)C>[C:1]([CH2:4][CH2:5][CH2:6]/[CH:7]=[C:8]1\[CH2:9][C@@H:10]2[C@H:14]([CH2:15]\1)[C@@H:13]([CH2:16][CH2:17][C:18](=[O:25])[CH:19]([F:24])[CH2:20][CH2:21][CH2:22][CH3:23])[C@H:12]([O:26][CH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][O:28]1)[CH2:11]2)([OH:3])=[O:2]
Reactant: CCCCC(F)C(O)CC[C@@H]1[C@H]2C/C(=C/CCCC(=O)O)C[C@H]2C[C@H]1OC1CCCCO1
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: CC(C)=O
Solvent: CC(C)O
Product: CCCCC(F)C(=O)CC[C@@H]1[C@H]2C/C(=C/CCCC(=O)O)C[C@H]2C[C@H]1OC1CCCCO1
Reaction time: 0.67 h

Procedure:
(1S,2R,3R,5S)-7(E)-(4-Carboxybutylidene)-2-[4(RS)-fluoro-3(RS)-hydroxyoctyl]-3 -tetrahydropyranyloxybicyclo[3.3.0]octane (13) (0.184 g) was oxidized with Jones reagent between about -15° and -5° C. After stirring for 40 minutes, isopropyl alcohol (0.43 ml) was added, and the mixture was treated by a usual work-up. Obtained crude product was purified on column chromatography (hexane/ethyl acetate=15/1-10/1) using silica gel treated with an acid (CC-4: available from Mallineckrodt Co., Ltd.) to give (1S,2R,3R,5S)-7(E)-(4-carboxybutylidene)-2-[4(RS)-fluoro-3-oxooctyl]-3-tetrahydropyranyloxybicyclo[3.3.0]octane (14) as a colorless oily product. Yield: 0.072 g (40%)
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([F:17])=[CH:14][CH:15]=2)[C:10]([C:18](=[O:26])[C:19]([Cl:25])=[C:20]([Cl:24])[C:21]([OH:23])=O)=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:27][N:28]1[C:36]2[C:31](=[CH:32][CH:33]=[C:34]([N+:37]([O-:39])=[O:38])[CH:35]=2)[CH:30]=[CH:29]1>>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([F:17])=[CH:14][CH:15]=2)[C:10]([C:18]2([C:30]3[C:31]4[C:36](=[CH:35][C:34]([N+:37]([O-:39])=[O:38])=[CH:33][CH:32]=4)[N:28]([CH3:27])[CH:29]=3)[O:26][C:21](=[O:23])[C:20]([Cl:24])=[C:19]2[Cl:25])=[CH:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cn1ccc2ccc([N+](=O)[O-])cc21
Reactant: O=C(O)C(Cl)=C(Cl)C(=O)c1cn(Cc2ccccc2)c2ccc(F)cc12
Product: Cn1cc(C2(c3cn(Cc4ccccc4)c4ccc(F)cc34)OC(=O)C(Cl)=C2Cl)c2ccc([N+](=O)[O-])cc21

Procedure:
Following a procedure similar to that described above in part B of this example by using 4-(1-benzyl-5-fluoro-3-indolyl)-2,3-dichloro-4-oxo-2-butenoic acid instead of 4-(1,2-dimethyl-3-indolyl)-2,3-dichloro-4-oxo-2-butenoic acid and 1-methyl-6-nitroindole in place of 1,2-dimethylindole, there is obtained 5-(1-benzyl-5-fluoro-3-indolyl)-5-(1-methyl-6-nitro-3-indolyl)-3,4-dichloro-2(5H)-furanone (Formula V: R=C6H5CH2 ; R1 =R3 =H; R2 =CH3 ; Y=6-F; Y1 =6-NO2).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][C@H:9]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[CH3:10])[CH:5]=[C:4]([C:18]2[CH:19]=[N:20][N:21]([CH3:23])[CH:22]=2)[CH:3]=1.[H-].[Na+].[CH3:26]I.O>O1CCCC1>[Cl:1][C:2]1[N:7]=[C:6]([N:8]([C@H:9]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[CH3:10])[CH3:26])[CH:5]=[C:4]([C:18]2[CH:19]=[N:20][N:21]([CH3:23])[CH:22]=2)[CH:3]=1
Reactant: CI
Reactant: C[C@H](Nc1cc(-c2cnn(C)c2)cc(Cl)n1)c1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: C[C@@H](c1ccc(F)cc1)N(C)c1cc(-c2cnn(C)c2)cc(Cl)n1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
92 mg of (S)-6-chloro-N-[1-(4-fluorophenyl)ethyl]-4-(1-methyl-1H-pyrazol-4-yl)pyridine-2-amine was dissolved in 1.5 ml of tetrahydrofuran, and 17 mg of 60% sodium hydride was added thereto, and the mixture was stirred at room temperature for 10 minutes. 26 μl of methyl iodide was added thereto, and the reaction solution was subjected to microwave irradiation at 100° C. for 5 minutes. 8 mg of 60% sodium hydride and 26 μl of methyl iodide were added to the reaction solution, and the reaction solution was stirred at 130° C. for 10 minutes, and furthermore 17 mg of 60% sodium hydride and 26 μl of methyl iodide were added, and the mixture was stirred at 130° C. for 10 minutes. The reaction solution was added with water and subjected to extraction with ethyl acetate. The organic layer was washed in turn with water and brine, and then dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and then the obtained residue was purified by silica gel column chromatography to obtain 62 mg of the objective compound as pale yellow oil.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH2:14][C:13](O)([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N-:24]=[N+:25]=[N-:26].[Na+]>FC(F)(F)C(O)=O.O>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH2:14][C:13]([N:24]=[N+:25]=[N-:26])([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(OCc1ccccc1)N1CCCC(O)(c2ccccc2)C1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: [N-]=[N+]=NC1(c2ccccc2)CCCN(C(=O)OCc2ccccc2)C1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
g (3.212 mmol) 3-Hydroxy-3-phenyl-piperidine-1-carboxylic acid benzyl ester was dissolved in a cold mixture (10° C.) of trifluoroacetic acid (12.3 ml) and water (2.0 ml). The solution was cooled to 0° C. and 1.46 g (22.48 mmol) sodium azide were added portionwise. The temperature rose to 10° C. The ice bath was removed and the mixture was stirred at room temperature for 3 hours. The mixture was cooled in an ice bath and basified by dropwise addition of a 25% ammonium hydroxide solution (13.0 ml) maintaining the temperature below 20° C. The mixture was diluted with water (45 ml) and extracted 3 times with dichloromethane. The combined extracts were washed once with brine, dried over sodium sulfate, filtered and concentrated in vacuo to provide the title compound as a light yellow oil which was used in the next step without further purification.
Reaction SMILES: [OH-].[Na+].[C:3](=O)=O.[CH2:6]([O:11][C:12]1[CH:13]=[C:14]([CH:18]=[C:19]([N+:21]([O-:23])=[O:22])[CH:20]=1)[C:15]([OH:17])=[O:16])[CH2:7][CH:8]([CH3:10])[CH3:9].S(Cl)(Cl)=O>CO>[CH2:6]([O:11][C:12]1[CH:13]=[C:14]([CH:18]=[C:19]([N+:21]([O-:23])=[O:22])[CH:20]=1)[C:15]([O:17][CH3:3])=[O:16])[CH2:7][CH:8]([CH3:10])[CH3:9]
Reactant: O=C=O
Reactant: CC(C)CCOc1cc(C(=O)O)cc([N+](=O)[O-])c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cc(OCCC(C)C)cc([N+](=O)[O-])c1
Temperature: 0 °C

Procedure:
In a three-neck reaction flask with a reflux condensor attached to 2 gas wash bottles, the second one filled with NaOH(aq) for absorption of developing CO2 and SO2, 3.7 g (14.6 mmol) 3-iso-pentyloxy-5-nitrobenzoic acid (10) were dissolved in methanol and cooled to 0° C., then 1.6 mL (21.9 mmol) thionyl chloride were added dropwise under stirring. The mixture was refluxed for 4 h, then stirred overnight at r.t.. It was concentrated, then repeatedly taken up in methanol and concentrated again, and put under vacuum. Finally, 2.97 g (76%) of a red-brown liquid, which was found to be sufficiently pure by NMR, were obtained. 1H NMR (CDCl3) δ 8.44 (dd, J1=1.4 Hz, J2=2.2 Hz, 1H), 7.88 (t, J1=2.2 Hz, J2=2.2 Hz, 1H), 7.87 (dd, J1=1.4 Hz, J2=2.2 Hz, 1H), 4.41 (t, J=6.8 Hz, 2H, PhOCH2CH2CH(CH3)2), 3.94 (s, 3H, OCH3), 1.88-1.65 (m, 3H), 0.99 (d, J=6.6 Hz, 6H, CH(CH3)2).
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]1[CH:9]=[C:8]([C:10]2[O:11][CH:12]=[CH:13][N:14]=2)[CH:7]=[CH:6][C:5]=1[C:15]1[C:16]([S:21]([NH:24][C:25]2[O:29][N:28]=[C:27]([CH3:30])[C:26]=2[CH3:31])(=[O:23])=[O:22])=[CH:17][CH:18]=[CH:19][CH:20]=1.[Cl:32][C:33]1[CH:41]=[CH:40][CH:39]=[CH:38][C:34]=1[C:35](Cl)=[O:36].C(N(CC)CC)C>C(Cl)Cl>[Cl:32][C:33]1[CH:41]=[CH:40][CH:39]=[CH:38][C:34]=1[C:35]([N:2]([CH2:3][C:4]1[CH:9]=[C:8]([C:10]2[O:11][CH:12]=[CH:13][N:14]=2)[CH:7]=[CH:6][C:5]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[S:21]([NH:24][C:25]1[O:29][N:28]=[C:27]([CH3:30])[C:26]=1[CH3:31])(=[O:22])=[O:23])[CH3:1])=[O:36]
Reactant: O=C(Cl)c1ccccc1Cl
Reactant: CNCc1cc(-c2ncco2)ccc1-c1ccccc1S(=O)(=O)Nc1onc(C)c1C
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1noc(NS(=O)(=O)c2ccccc2-c2ccc(-c3ncco3)cc2CN(C)C(=O)c2ccccc2Cl)c1C
Temperature: 25 °C
Reaction time: 12 h
Yield: 25.7 %

Procedure:
To a solution of 0.12 g (0.29 mmol) of 2'-[(methylamino)methyl]-N-(3,4-dimethyl-5-isoxazolyl)-4'-(2-oxazolyl)[1,1'-biphenyl]-2-sulfonamide (prepared as described in Step (A) of Example 28) in 5 mL of CH2Cl2, 0.061 g (0.348 mmol) of 2-chlorobenzoyl chloride and 0.065 g (0.638 mmol) of triethylamine were added. The mixture was then stirred at room temperature for 12 hr and evaporated. The residue was purified by reverse phase preparative HPLC on a 30×500 mm ODS S10 column using 72% solvent B (90% MeOH, 10% H2O, 0.1% TFA) and 28% solvent A (10% MeOH, 90% H2O, 0.1% TFA). The appropriate fractions were collected and neutralized with aqueous sodium bicarbonate to pH 7 and concentrated to 10 mL. The solution was then acidified to pH 4 using aqueous sodium bisulfate and the white solid was filtered and dried to provide 0.043 g (26%) of the title compound of this Example as a white solid.
Reaction SMILES: N1C2C(=NC3C=CC=CC=3N=2)C(=O)NC=1[C:16]([OH:18])=[O:17].[CH2:19]([O:21][C:22]([C:24]1[NH:41][C:40](=[O:42])[C:27]2=[N:28][C:29]3[C:30](C)=[C:31](C)[C:32](C)=[C:33](C)[C:34]=3[N:35]=[C:26]2[N:25]=1)=[O:23])[CH3:20]>>[CH2:19]([O:21][C:22]([C:24]1[NH:41][C:40](=[O:42])[C:27]2=[N:28][C:29]3[CH:30]=[C:31]4[O:18][CH2:16][O:17][C:32]4=[CH:33][C:34]=3[N:35]=[C:26]2[N:25]=1)=[O:23])[CH3:20]
Reactant: O=C(O)c1nc2nc3ccccc3nc2c(=O)[nH]1
Reactant: CCOC(=O)c1nc2nc3c(C)c(C)c(C)c(C)c3nc2c(=O)[nH]1
Product: CCOC(=O)c1nc2nc3cc4c(cc3nc2c(=O)[nH]1)OCO4

Procedure:
pyrimido[5,6-b]quinoxaline-4(3H)-one-2-carboxylic acid, and ethyl-6,7,8,9-tetramethyl-pyrimido[5,6-b]quinoxaline-4(3H)-one-2-carboxylate.
Reaction SMILES: [CH2:1]([N:8]=[C:9]=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:11]1([C:17]2([CH2:27][CH:28]([CH3:30])[CH3:29])[C:21]3[CH2:22][NH:23][CH2:24][CH2:25][C:20]=3[C:19](=[O:26])[O:18]2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>ClCCl>[CH2:1]([NH:8][C:9]([N:23]1[CH2:24][CH2:25][C:20]2[C:19](=[O:26])[O:18][C:17]([CH2:27][CH:28]([CH3:29])[CH3:30])([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:21]=2[CH2:22]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C=NCc1ccccc1
Reactant: CC(C)CC1(c2ccccc2)OC(=O)C2=C1CNCC2
Solvent: ClCCl
Product: CC(C)CC1(c2ccccc2)OC(=O)C2=C1CN(C(=O)NCc1ccccc1)CC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 68 %

Procedure:
Benzyl isocyanate (0.02 9 g, 0.22 mmol) was added to a solution of 3-phenyl-3-isobutyl-4,5,6,7-tetrahydrofuro[3,4-c]pyridin-1(3H)-one (0.05 g, 0.184 mmol prepared in a manner analogous to compound 2) in dichloromethane (5 mL) and was stirred at room temperature for 1 h. The solvent was removed and the resulting residue was purified on silica to give the desired product (0.051 g, 68%). 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 0.85 (d, J=6.40 Hz, 3H), 0.89-0.98 (m, 3H), 1.65 (ddd, J=13.56, 6.78, 4.90 Hz, 1H), 1.73-1.87 (m, 1H), 2.24-2.40 (m, 3H), 3.27 (ddd, J=13.56, 7.35, 5.09 Hz, 1H), 3.54 (dt, J=13.66, 5.23 Hz, 1H), 3.92 (dt, J=18.84, 2.64 Hz, 1H), 4.40 (d, J=5.65 Hz, 2H), 4.49 (dt, J=19.12, 2.12 Hz, 1H), 5.00 (t, J=5.46 Hz, 1H), 7.21-7.42 (m, 10H).