Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH2:11][N:12]2[CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14][CH:13]2[CH3:25])[C:5]2[O:9][CH:8]=[CH:7][C:6]=2[CH:10]=1.[C:26]1([CH3:36])[C:27]([S:32]([Cl:35])(=[O:34])=[O:33])=[CH:28][CH:29]=[CH:30][CH:31]=1>>[ClH:35].[ClH:35].[CH3:36][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[S:32]([NH:1][C:2]1[CH:3]=[C:4]([CH2:11][N:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH:13]2[CH3:25])[C:5]2[O:9][CH:8]=[CH:7][C:6]=2[CH:10]=1)(=[O:34])=[O:33]
Reactant: CC1CN(C(=O)OC(C)(C)C)CCN1Cc1cc(N)cc2ccoc12
Reactant: Cc1ccccc1S(=O)(=O)Cl
Product: Cc1ccccc1S(=O)(=O)Nc1cc(CN2CCNCC2C)c2occc2c1
Product: Cl
Yield: 48 %

Procedure:
The title product was prepared according to the procedure of Example 112, Step 3, starting from tert-butyl 4-[(5-amino-1-benzofuran-7-yl)methyl]-3-methylpiperazine-1-carboxylate (45 mg crude material, 0.10 mmol; obtained in Example 112, Step 2) and o-toluenesulfonyl chloride (22 μL, 0.15 mmol). The title compound (17 mg, 35%) was obtained as an off-white solid. HPLC 99%, RT=1.42 min (System A; 10-97% MeCN over 3 min), 100%, RT=1.26 min (System B; 10-97% MeCN over 3 min). 1H NMR (400 MHz, methanol-d4) δ ppm 1.69-1.74 (m, 3H) 2.67 (s, 3H) 3.37-3.62 (m, 5H) 3.67-3.75 (m, 1H) 3.84-3.95 (m, 1H) 4.57-4.65 (m, 1H) 4.90-4.97 (m, J=13.55 Hz, 1H) 6.86 (d, J=2.26 Hz, 1H) 7.23-7.29 (m, J=7.65, 7.65 Hz, 1H) 7.31 (d, J=2.01 Hz, 1H) 7.32-7.36 (m, 1H) 7.40-7.46 (m, 1H) 7.50 (d, J=2.01 Hz, 1H) 7.85-7.90 (m, 2H). MS (ESI+) for C21H25N3O3S m/z 400 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4]2[CH:10]=[C:9]([O:11][CH2:12][CH3:13])[CH:8]=[CH:7][C:5]=2[N:6]=1.[Cl:14][CH2:15][S:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[Br:23]>>[Cl-:14].[NH2:1][C:2]1[N:6]([CH2:15][S:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[Br:23])[C:5]2[CH:7]=[CH:8][C:9]([O:11][CH2:12][CH3:13])=[CH:10][C:4]=2[N+:3]=1[CH2:15][S:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[Br:23]
Reactant: CCOc1ccc2nc(N)[nH]c2c1
Reactant: ClCSc1ccccc1Br
Product: CCOc1ccc2c(c1)[n+](CSc1ccccc1Br)c(N)n2CSc1ccccc1Br
Product: [Cl-]

Procedure:
Following the procedure of Example 2 and replacing 2-aminobenzimidazole with 2-amino-5-ethoxybenzimidazole and replacing 2-bromo-4-chlorophenyl chloromethyl ether with 2-bromophenyl chloromethyl sulfide, the title compound is obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O1CCOCC1.[O:14]1[CH:16]([CH2:17][CH3:18])[CH2:15]1.[F-].[K+]>O.C(Cl)Cl>[C:2]1([NH:1][CH2:15][CH:16]([OH:14])[CH2:17][CH3:18])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccccc1
Reactant: CCC1CO1
Agent: [F-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Solvent: ClCCl
Product: CCC(O)CNc1ccccc1

Procedure:
Aniline, (102.3 g, 1.1 mole) was added to 50 ml of dioxane, 108 g of 1,2-epoxy butane and 1 g of potassium fluoride in 25 ml of water. The mixture heated to reflux for 30 hours. The mixture was poured into water, taken up in 200 ml of methylene chloride, dried over anhydrous magnesium sulfate and stripped under vacuum. The residue was distilled under vacuum and the product, b.p. 98°-106° C. at 0.15 mm, weighed 94 g and was 97% pure by GLPC. It was characterized by IR and NMR.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([N+:13]([O-])=O)[CH:8]=1.O.O.[Sn](Cl)(Cl)(Cl)Cl.C(N(CC)CC)C>C(OCC)(=O)C>[CH3:1][O:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[C:9]([CH:10]=[CH:11][CH:12]=1)[NH2:13]
Reactant: COCCCOc1cccc([N+](=O)[O-])c1
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: O
Product: COCCCOc1cccc(N)c1
Temperature: 60 °C
Yield: 93.2 %

Procedure:
1-(3-methoxypropoxy)-3-nitrobenzene (10A) (2.0 g, 11.84 mmol) and tin chloride dihydrate (13.36 g, 59.18 mmol) in 25 mL of ethyl acetate was combined. The mixture was heated at 60° C. for about two hours. The reaction was then chilled at 0° C. Triethylamine (25-30 mL) was added slowly until a white precipitate formed. The white precipitate was filtered over a Celite plug, washed with brine, and then dried over MgSO4. The dried filtrate was then concentrated in vacuo and dried under vacuum to provide 10B (2.0 g, 93%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.90 (q, J=6.32 Hz, 2H) 3.24 (s, 3 H) 3.44 (t, J=6.32 Hz, 2H) 3.89 (t, J=6.44 Hz, 2H) 5.02 (br. s., 2H) 6.05 (dd, J=8.08, 1.26 Hz, 1H) 6.11-6.14 (m, 2H) 6.87 (t, J=8.21 Hz, 1H). ESI-MS: m/z 182.3 (M+H)+.
Reaction SMILES: [C:1]1([N:7]=[C:8]=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.FC(F)(F)C(O)=O.[CH2:17]([C:25]1([OH:42])[CH:33]=[C:32]2[CH2:34][NH:35][CH2:36][CH2:37][N:30]3[C:31]2=[C:27]([CH:28]=[CH:29]3)[CH:26]1[C:38]([F:41])([F:40])[F:39])[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(N(CC)CC)C>C1COCC1>[OH:42][C:25]1([CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:33]=[C:32]2[CH2:34][NH:35][CH:36]([C:8]([NH:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[O:9])[CH2:37][N:30]3[C:31]2=[C:27]([CH:28]=[CH:29]3)[CH:26]1[C:38]([F:41])([F:40])[F:39]
Reactant: O=C=Nc1ccccc1
Reactant: OC1(CCc2ccccc2)C=C2CNCCn3ccc(c32)C1C(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1ccccc1)C1Cn2ccc3c2C(=CC(O)(CCc2ccccc2)C3C(F)(F)F)CN1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Phenyl isocyanate (3.8 mg, 0.05 mmol) was added to a solution of 6-phenethyl-7-(trifluoromethyl)-1,2,3,4,6,7-hexahydro-[1,4]diazepino[6,7,1-hi]indol-6-ol trifluoroacetate (14 mg, 0.039 mmol) in THF (3 mL) containing triethylamine (11 mg, 0.11 mmol) at 0° C. The resulting mixture was stirred at 0° C. for 30 min, then stirred at room temperature overnight. The resulting mixture was concentrated under reduced pressure, the residue dissolved in ethyl acetate and the resulting solution was washed sequentially with water, NaHCO3 (sat'd. aq) and brine. The organic phase was dried (Na2SO4) and concentrated to yield 6-hydroxy-6-phenethyl-N-phenyl-7-(trifluoromethyl)-3,4,6,7-tetrahydro-[1,4]diazepino[6,7,1-hi]indole-2(1H)-carboxamide (MH+=482).
Reaction SMILES: [C:1]([O-:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[CH2:11][CH2:12][CH2:13][CH:14]([CH2:17][CH2:18][CH:19]([O:24]S([O-])(=O)=O)CC(C)C)CC.[Na+].[OH2:30]>C([O-])(=O)CCCCCCCCCCCCCCCCC.[Zn+2].C([O-])(=O)CCCCCCCCCCCCCCCCC>[C:1]([O:9][O:30][C:19](=[O:24])[C:18]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:17]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O
Reactant: CCCCC(CC)CCC(CC(C)C)OS(=O)(=O)[O-]
Reactant: O=C([O-])c1ccccc1
Agent: CCCCCCCCCCCCCCCCCC(=O)[O-]
Agent: [Na+]
Agent: [Zn+2]
Product: O=C(OOC(=O)c1ccccc1)c1ccccc1
Reaction time: 0.5 h

Procedure:
In this Example, the mixer was charged with BPO (BPO 75% in water), benzoate, water, and zinc stearate. A preproduct was formed after about 30 minutes of mixing. Nonionic surfactant (Tergitol XD) was then added to emulsify the oil into the water phase. After about 30 minutes, a smooth, short, uniform paste of the following composition was produced.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[NH2:8][CH:9]1[CH2:14][CH2:13][CH:12]([NH:15][C:16]([C:18]2[N:26]=[C:25]3[C:21]([N:22]=[CH:23][N:24]3[C@@H:27]3[CH2:31][C@H:30]([N:32]4[CH:36]=[C:35]([CH2:37][OH:38])[CH:34]=[N:33]4)[C@@H:29]([OH:39])[C@H:28]3[OH:40])=[C:20]([NH:41][CH2:42][CH:43]([C:50]3[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=3)[C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)[N:19]=2)=[O:17])[CH2:11][CH2:10]1.FC(F)(F)C(O)=O.C(NC(=O)NCCCNC(C1N=[C:81]2C(N=[CH:79][N:80]2[C@@H:83]2C[C@H](N3C=C(CO)C=N3)[C@@H](O)[C@H:84]2[OH:96])=C(NCC(C2C=CC=CC=2)C2C=CC=CC=2)N=1)=O)C.Cl.CC(C)(N)C(Cl)=O>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH3:79][N:80]([CH3:81])[CH2:83][C:84]([NH:8][CH:9]1[CH2:14][CH2:13][CH:12]([NH:15][C:16]([C:18]2[N:26]=[C:25]3[C:21]([N:22]=[CH:23][N:24]3[C@@H:27]3[CH2:31][C@H:30]([N:32]4[CH:36]=[C:35]([CH2:37][OH:38])[CH:34]=[N:33]4)[CH:29]([OH:39])[CH:28]3[OH:40])=[C:20]([NH:41][CH2:42][CH:43]([C:50]3[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=3)[C:44]3[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=3)[N:19]=2)=[O:17])[CH2:11][CH2:10]1)=[O:96]
Reactant: NC1CCC(NC(=O)c2nc(NCC(c3ccccc3)c3ccccc3)c3ncn([C@@H]4C[C@H](n5cc(CO)cn5)[C@@H](O)[C@H]4O)c3n2)CC1
Reactant: CCNC(=O)NCCCNC(=O)c1nc(NCC(c2ccccc2)c2ccccc2)c2ncn([C@@H]3C[C@H](n4cc(CO)cn4)[C@@H](O)[C@H]3O)c2n1
Agent: CC(C)(N)C(=O)Cl
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Product: CN(C)CC(=O)NC1CCC(NC(=O)c2nc(NCC(c3ccccc3)c3ccccc3)c3ncn([C@@H]4C[C@H](n5cc(CO)cn5)C(O)C4O)c3n2)CC1

Procedure:
This compound is prepared from 9-[(1R,2S,3R,4S)-2,3-dihydroxy-4-(4-hydroxymethyl-pyrazol-1-yl)-cyclopentyl]-6-(2,2-diphenyl-ethylamino)-9H-purine-2-carboxylic acid (4-amino-cyclohexyl)-amide trifluoroacetate (Example 83, first step a) using a procedure analogous to that of 9-[(1R,2S,3R,4S)-2,3-dihydroxy-4-(4-hydroxymethyl-pyrazol-1-yl)-cyclopentyl]-6-(2,2-diphenyl-ethylamino)-9H-purine-2-carboxylic acid [3-(3-ethyl-ureido)-propyl]-amide trifluoroacetate (Example 87) replacing ethyl isocyanate with dimethyl-amino-acetyl chloride hydrochloride.
Reaction SMILES: [C:1]1([CH3:25])[CH:6]=[CH:5][C:4]([S:7]([NH:10][C:11]2[CH:24]=[CH:23][CH:22]=[CH:21][C:12]=2[C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:14])(=[O:9])=[O:8])=[CH:3][CH:2]=1.[H-].[Na+].Br[CH2:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31].O>CN(C)C=O>[C:13]([C:12]1[CH:21]=[CH:22][CH:23]=[CH:24][C:11]=1[N:10]([CH2:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[S:7]([C:4]1[CH:3]=[CH:2][C:1]([CH3:25])=[CH:6][CH:5]=1)(=[O:9])=[O:8])(=[O:14])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: Cc1ccc(S(=O)(=O)Nc2ccccc2C(=O)c2ccccc2)cc1
Reactant: CC(C)(C)OC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(S(=O)(=O)N(CC(=O)OC(C)(C)C)c2ccccc2C(=O)c2ccccc2)cc1
Reaction time: 0.5 h
Yield: 95.4 %

Procedure:
To a stirred solution of 5.0 g of compound H in 10 cc of dimethylformamide was added 0.56 g of 63% sodium hydride in 5 cc of dimethylformamide under ice-cooling and the mixture was stirred for 30 minutes. Then, 2.3 cc of t-butyl bromoacetate was added dropwise at the same temperature and stirring was continued for 16 hours. Water was added to the reaction mixture and the desired compound was extracted with ethyl acetate. The extract was washed with water and dried over magnesium sulfate. The solvent was distilled off and the crude product thus obtained was washed with hexane to obtain 6.31 g of compound I. Yield: 95.4%.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6](=[O:17])[S:7][C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10](Br)[CH:9]=2)=[O:4].[Cl:18][C:19]1[CH:20]=[C:21](B(O)O)[CH:22]=[C:23]([Cl:25])[CH:24]=1>>[CH3:1][O:2][C:3]([C:5]1[C:6](=[O:17])[S:7][C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([C:21]1[CH:20]=[C:19]([Cl:18])[CH:24]=[C:23]([Cl:25])[CH:22]=1)[CH:9]=2)=[O:4]
Reactant: OB(O)c1cc(Cl)cc(Cl)c1
Reactant: COC(=O)c1c(O)c2ccc(Br)cc2sc1=O
Product: COC(=O)c1c(O)c2ccc(-c3cc(Cl)cc(Cl)c3)cc2sc1=O

Procedure:
7-(3,5-Dichloro-phenyl)-4-hydroxy-2-oxo-2H-thiochromene-3-carboxylic acid methyl ester was prepared from 7-bromo-4-hydroxy-2-oxo-2H-thiochromene-3-carboxylic acid methyl ester (Example 5 e) and 3,5-dichlorophenylboronic acid under conditions analogous to Example 7(a). The crude product was purified by silica gel chromatography (eluting with 5%-60% EtOAc in CH2Cl2) to provide 7-(3,5-dichloro-phenyl)-4-hydroxy-2-oxo-2H-thiochromene-3-carboxylic acid methyl ester. MS ESI(−) m/e: 378.98 (M−1).
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([N:11]2[C:16]3=[N:17][C:18]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)=[C:19]([N+:22]([O-:24])=[O:23])[C:20](=[O:21])[N:15]3[CH2:14][CH2:13][CH2:12]2)[CH:8]=[CH:7][N:6]=1)(=O)=O.[CH2:31]([NH2:39])[CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>ClCCl>[N+:22]([C:19]1[C:20](=[O:21])[N:15]2[CH2:14][CH2:13][CH2:12][N:11]([C:9]3[CH:8]=[CH:7][N:6]=[C:5]([NH:39][CH2:31][CH2:32][C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[N:10]=3)[C:16]2=[N:17][C:18]=1[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)([O-:24])=[O:23]
Reactant: NCCc1ccccc1
Reactant: CS(=O)(=O)c1nccc(N2CCCn3c2nc(-c2ccccc2)c([N+](=O)[O-])c3=O)n1
Solvent: ClCCl
Product: O=c1c([N+](=O)[O-])c(-c2ccccc2)nc2n1CCCN2c1ccnc(NCCc2ccccc2)n1

Procedure:
A solution of 9-(2-methanesulfonyl-pyrimidin-4-yl) -3-nitro-2-phenyl -6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one (220 mg, 0.51 mmol) and phenethylamine (0.13 mL, 1.0 mmol) in dichloromethane (2 mL) was heated to 80° C. for 1 h. Residue purified on silica, and final product isolated as a white solid. M+1=470.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][CH2:10][CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[OH:19].[H-].[Na+].Cl.[CH3:23][N:24]([CH3:29])[CH2:25][CH2:26][CH2:27]Cl>CC(N(C)C)=O>[CH3:23][N:24]([CH2:25][CH2:26][CH2:27][O:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[CH2:12][CH2:11][CH2:10][CH2:9][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[O:2][CH3:1])[CH3:29]
Reactant: CN(C)CCCCl
Reactant: COc1ccccc1CCCCc1ccccc1O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: COc1ccccc1CCCCc1ccccc1OCCCN(C)C
Yield: 85.2 %

Procedure:
Following a procedure similar to that described in Example 2(a), 200 mg of 2-[4-(2-methoxyphenyl)butyl]phenol (prepared as described in Preparation 4), 75 mg of sodium hydride (as a 55% w/w dispersion in mineral oil) and 0.14 g of 3-dimethylaminopropyl chloride hydrochloride were reacted in 20 ml of dimethylacetamide. The crude product, extracted as described in Example 2(a), was purified by column chromatography through silica gel, using a 10:1 by volume mixture of methylene chloride and methanol as the eluent, to give 227 mg (yield 85%) of the title compound as pale yellow solid.
Reaction SMILES: [N:1]1[N:2]([C:11]2[CH:19]=[CH:18][C:14]([C:15]([NH2:17])=[O:16])=[CH:13][CH:12]=2)[CH:3]=[C:4]2[CH2:10][CH2:9][NH:8][CH2:7][CH2:6][C:5]=12.[C:20]1(=O)[CH2:23][CH2:22][CH2:21]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].CO>ClCCl.C(O)(=O)C>[CH:20]1([N:8]2[CH2:9][CH2:10][C:4]3=[CH:3][N:2]([C:11]4[CH:19]=[CH:18][C:14]([C:15]([NH2:17])=[O:16])=[CH:13][CH:12]=4)[N:1]=[C:5]3[CH2:6][CH2:7]2)[CH2:23][CH2:22][CH2:21]1
Reactant: O=C1CCC1
Reactant: NC(=O)c1ccc(-n2cc3c(n2)CCNCC3)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Solvent: ClCCl
Product: NC(=O)c1ccc(-n2cc3c(n2)CCN(C2CCC2)CC3)cc1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of 4-(5,6,7,8-tetrahydropyrazolo[3,4-d]azepin-2(4H)-yl)benzamide (may be prepared as described in Description 37) (31 mg, 0.12 mmol) in dichloromethane (3 ml) was added cyclobutanone (17 mg, 0.24 mmol) and acetic acid (2 drops). The resulting mixture was stirred at room temperature, under argon, for 20 minutes. Sodium triacetoxyborohydride (51 mg, 0.24 mmol) was added and stirring continued for 2 hours. Methanol was added and the crude mixture was purified by SCX, eluting with methanol and then with 2M ammonia/methanol. The basic fractions were combined and solvent evaporated in vacuo to afford the title compound (E26). MS (ES+) m/e 311 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][NH:8]2)=[CH:4][CH:3]=1.[C:11]([O:17][CH2:18][CH3:19])(=[O:16])[CH2:12][C:13]([CH3:15])=O.S([O-])([O-])(=O)=O.[Ca+2].C(O)(=O)C>C(O)C>[NH:8]1[C:9]2[C:5](=[CH:4][CH:3]=[C:2]([NH:1][C:13]([CH3:15])=[CH:12][C:11]([O:17][CH2:18][CH3:19])=[O:16])[CH:10]=2)[CH:6]=[N:7]1
Reactant: Nc1ccc2cn[nH]c2c1
Reactant: CCOC(=O)CC(C)=O
Agent: O=S(=O)([O-])[O-]
Agent: [Ca+2]
Solvent: CC(=O)O
Solvent: CCO
Product: CCOC(=O)C=C(C)Nc1ccc2cn[nH]c2c1
Reaction time: 24 h
Yield: 84.5 %

Procedure:
To a suspension of 6-aminoindazole (40.0 g, 0.30 mol) in absolute ethanol (500 ml) was added ethyl acetoacetate (70.37 g, 54 mol), calcium sulfate (CaSO4) (20 g) and acetic acid (2 ml). The reaction mixture was heated to reflux and after 24 hours more calcium sulfate (10 g) and ethyl acetoacetate (19 ml) was added and the reflux continued for another 24 hour period. It was necessary to add more CaSO4 (5 g) and ethyl acetoacetate (10 ml) and to reflux the reaction mixture for an additional 24 hours to complete the conversion of 6-aminoindazole to product. The solid was removed by filtration and the filtrate subjected to rotary evaporation. Ethanol was added and the slurry cooled in a refrigerator. The solid was collected by filtration, washed with hexanes and dried in a vacuum oven to give the cyclization precursor ethyl 3-(indazol-6-ylamino)but-2-enoate as a light brown solid (62.19 g, 84%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:31])([F:30])[F:29])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=3)[C:21](O)=[O:22])=[CH:17][C:9]1=2.[CH:32]([NH2:45])([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>>[CH:32]([NH:45][C:21](=[O:22])[C:20]1[CH:24]=[CH:25][CH:26]=[C:18]([C:16]2[CH:15]=[N:14][C:10]3[NH:11][CH2:12][CH2:13][N:8]([CH2:7][C:6]4[CH:27]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=4[C:28]([F:31])([F:30])[F:29])[C:9]=3[CH:17]=2)[CH:19]=1)([C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: NC(c1ccccc1)c1ccccc1
Reactant: O=C(O)c1cccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)c1
Product: O=C(NC(c1ccccc1)c1ccccc1)c1cccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)c1

Procedure:
3-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoic acid was reacted with benzhydrylamine as in General Procedure 10 to give the title compound. LCMS: m/z=612.98 (M+H+); retention time=1.06 minutes.
Reaction SMILES: [C:1](O)(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8](O)=O.[NH2:13][NH:14][C:15]([NH2:17])=[S:16]>>[CH2:7]([C:8]1[S:16][C:15]([NH2:17])=[N:14][N:13]=1)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][C:1]1[S:16][C:15]([NH2:17])=[N:14][N:13]=1
Reactant: NNC(N)=S
Reactant: O=C(O)CCCCCCC(=O)O
Product: Nc1nnc(CCCCCCc2nnc(N)s2)s1

Procedure:
The title compound was synthesized from octanedioic acid I-59 and thiosemicarbazide by following the general procedure as described for compound I-2.
Reaction SMILES: [CH:1](NC(C)C)(C)[CH3:2].C([Li])CCC.[CH2:13]([C@@H:15]1[C@@H:20]([C:21](=[O:23])[CH3:22])[C@@H:19]([CH3:24])[CH:18]=[CH:17][CH2:16]1)[CH3:14].C(=O)C.Cl>O1CCCC1>[CH2:13]([C@@H:15]1[C@@H:20]([C:21](=[O:23])/[CH:22]=[CH:1]/[CH3:2])[C@@H:19]([CH3:24])[CH:18]=[CH:17][CH2:16]1)[CH3:14]
Reactant: CC[C@H]1CC=C[C@H](C)[C@@H]1C(C)=O
Reactant: CC(C)NC(C)C
Agent: CC=O
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C/C=C/C(=O)[C@@H]1[C@@H](CC)CC=C[C@@H]1C
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 55.9 %

Procedure:
At −78° C., a solution of diisopropylamine (6.6 g, 34 mmol) in tetrahydrofuran (23 ml) was treated with n-butyl lithium (21 ml, 1.6M in hexane, 34 mmol). The resulting solution was warmed to 0° C., cooled to −78° C., and treated with a solution of 1-(rel-(1R,2S,6S)-6-ethyl-2-methylcyclohex-3-enyl)ethan-1-one (4.5 g, 27 mmol) in tetrahydrofuran (23 ml). The resulting solution was stirred 20 min. at −20° C., cooled to −78° C. and treated with a solution of acetaldehyde (1.8 g, 41 mmol) in tetrahydrofuran (23 ml). After 1 h stirring, aqueous 1N HCl (50 ml) was added and the reaction mixture warmed to 20° C. The aq. phase was extracted with diethyl ether and the combined org. phases dried (MgSO4), and concentrated. A solution of the residue (4.9 g) in toluene (4.9 ml) was treated with para-toluene sulfonic acid monohydrate (20 mg) and refluxed overnight. The reaction mixture was cooled, treated with a saturated aqueous solution of NaHCO3 and the aqueous phase was extracted with diethyl ether. The combined organic phases were dried (MgSO4) and concentrated. FC (550 g SiO2, hexane/diethyl ether 9:1) of the crude product gave (2E)-1-(rel-(1R,2S,6S)-6-ethyl-2-methylcyclohex-3-enyl)but-2-en-1-one (2.9 g, 56%).
Reaction SMILES: [CH:1]([N:3]1[CH2:7][CH2:6]C[C:4]1=O)=C.CN(CCC[CH:15]=[C:16]([CH3:20])[C:17](N)=[O:18])C.CC(C(NCCC[N+](C)(C)C)=[O:25])=C.C=CN1C(=O)CCC1.[Cl-]>>[C:17]([O:25][CH2:6][CH2:7][N:3]([CH3:1])[CH3:4])(=[O:18])[C:16]([CH3:20])=[CH2:15]
Reactant: C=CN1CCCC1=O
Reactant: CC(=CCCCN(C)C)C(N)=O
Reactant: C=C(C)C(=O)NCCC[N+](C)(C)C
Agent: [Cl-]
Product: C=C(C)C(=O)OCCN(C)C

Procedure:
quaternized vinylpyrrolidone/dimethylaminopropylmethacrylamide copolymers such as the product sold under the name GAFQUAT HS 100 by the company ISP, and crosslinked polymers of methacryloyloxy(C1-C4)alkyltri(C1-C4)alkylammonium salts such as the polymers obtained by homopolymerization of dimethylaminoethyl methacrylate quaternized with methyl chloride, or by copolymerization of acrylamide with dimethylaminoethyl methacrylate quaternized with methyl chloride, the homo- or copolymerization being followed by crosslinking with a compound containing olefinic unsaturation, such as methylenebisacrylamide. In at least one embodiment, a crosslinked acrylamide/methacryloyloxyethyltrimethylammonium chloride copolymer (20/80 by weight) in the form of a dispersion containing 50% by weight of the copolymer in mineral oil can be used. This dispersion is sold under the name SALCARE® SC 92 by the company Ciba. In some embodiments, a crosslinked methacryloyloxyethyltrimethylammonium chloride homopolymer containing about 50% by weight of the homopolymer in mineral oil or in a liquid ester can be used. These dispersions are sold under the names SALCARE® SC 95 and SALCARE® SC 96 by the company Ciba.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].[Cl:11][CH2:12][CH2:13]O>S(=O)(=O)(O)O.C(OCC)(=O)C>[OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([O:7][CH2:13][CH2:12][Cl:11])=[O:6]
Reactant: OCCCl
Reactant: O=C(O)c1cccc(O)c1
Agent: O=S(=O)(O)O
Solvent: CCOC(C)=O
Product: O=C(OCCCl)c1cccc(O)c1
Yield: 95.2 %

Procedure:
##STR32## A solution of 3-hydroxybenzoic acid (15.0 g, 0.11 mol) in 2-chloroethanol (70 mL, 1.0 mol) and 1 mL of concentrated sulfuric acid was refluxed for overnight. TLC analysis (silica gel/20% ethyl acetate/hexane) showed clean conversion to a new material. The excess chloroethanol was removed by evaporation to obtain a brown solution which -was dissolved in ethyl acetate and washed with water. The organic layer was dried with MgSO4 and concentrated to obtain 21.0 g of the product as a white solid: mp 50° C.; 1H NMR (CDCl3) δ 3.81 (t, 2H, J=5.9 Hz), 4.57 (t, 2H, J=5.9 Hz), 4.77 (s, 1H), 7.06-7.66 (m, 4H), 13C NMR (CDCl3) δ 41.52, 64.75, 116.43, 120.77, 121.98, 129.80, 130.71, 156.04, 166.57; MS m/e (rel. intensity) 200 (26), 138 (59), 121 (100), 93 (31), 65 (21), 39 (12); MS exact mass; calcd. 200.0240, found 200.0242.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH:9]2[C:19]3[C:20]4[N:11]([C:12](=[O:22])[CH:13]=[N:14][C:15]=4[CH:16]=[CH:17][C:18]=3[F:21])[CH2:10]2)[CH2:4][CH2:3]1.[CH:23]([C:25]1[N:41]=[CH:40][C:28]2[O:29][CH2:30][CH2:31][N:32]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[C:27]=2[CH:26]=1)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)(Cl)Cl.CO>[F:21][C:18]1[CH:17]=[CH:16][C:15]2[N:14]=[CH:13][C:12](=[O:22])[N:11]3[CH2:10][CH:9]([CH2:8][N:5]4[CH2:4][CH2:3][CH:2]([NH:1][CH2:23][C:25]5[N:41]=[CH:40][C:28]6[O:29][CH2:30][CH2:31][N:32]([C:33]([O:35][C:36]([CH3:37])([CH3:39])[CH3:38])=[O:34])[C:27]=6[CH:26]=5)[CH2:7][CH2:6]4)[C:19]=1[C:20]=23
Reactant: NC1CCN(CC2Cn3c(=O)cnc4ccc(F)c2c43)CC1
Reactant: CC(C)(C)OC(=O)N1CCOc2cnc(C=O)cc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)N1CCOc2cnc(CNC3CCN(CC4Cn5c(=O)cnc6ccc(F)c4c65)CC3)cc21
Temperature: 25 °C
Reaction time: 5 h
Yield: 53.3 %

Procedure:
A solution of 6-[(4-amino-1-piperidinyl)methyl]-7-fluoro-5,6-dihydro-3H-pyrrolo[1,2,3-de]quinoxalin-3-one (95 mg, 0.31 mmol) and 1,1-dimethylethyl 7-formyl-2,3-dihydro-1H-pyrido[3,4-b][1,4]oxazine-1-carboxylate (83 mg, 0.31 mmol) in chloroform/methanol (1:1, 8 ml) was stirred with molecular sieves overnight, then heated under reflux for 3 h. After cooling, sodium triacetoxyborohydride (164 mg) was added and the mixture was stirred for 5 h at room temperature. The mixture was basified and the aqueous phase was extracted with 10% methanol/dichloromethane. Combined organic fractions were dried and evaporated. Chromatography on silica, eluting with 0-20% (2M ammonia in methanol)/dichloromethane, gave impure material. Further chromatography on silica, eluting with 0-10% methanol/dichloromethane, gave the pure product (91 mg).