Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(P(CCCC)CCCC)CCC.[CH3:14][O:15][C:16](=[O:30])[CH2:17][C:18]1[C:22]2[C:23]([Cl:29])=[CH:24][C:25]([OH:28])=[C:26]([Cl:27])[C:21]=2[S:20][CH:19]=1.[CH3:31][N:32]1[C:36]([CH2:37]O)=[CH:35][C:34]([C:39]([F:42])([F:41])[F:40])=[N:33]1.C1CCN(C(N=NC(N2CCCCC2)=O)=O)CC1>C1COCC1>[CH3:14][O:15][C:16](=[O:30])[CH2:17][C:18]1[C:22]2[C:23]([Cl:29])=[CH:24][C:25]([O:28][CH2:37][C:36]3[N:32]([CH3:31])[N:33]=[C:34]([C:39]([F:42])([F:40])[F:41])[CH:35]=3)=[C:26]([Cl:27])[C:21]=2[S:20][CH:19]=1
Reactant: Cn1nc(C(F)(F)F)cc1CO
Reactant: COC(=O)Cc1csc2c(Cl)c(O)cc(Cl)c12
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: COC(=O)Cc1csc2c(Cl)c(OCc3cc(C(F)(F)F)nn3C)cc(Cl)c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.2 %

Procedure:
To a mixture of tri-n-butylphosphine (0.193 mL), methyl(4,7-dichloro-6-hydroxy-1-benzothiophen-3-yl)acetate (150 mg), (1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)methanol (102 mg) and THF (5.0 mL) was added ADDP (195 mg) at room temperature. The mixture was stirred at room temperature under nitrogen atmosphere overnight. The mixture was concentrated in vacuo. To the residue was added IPE and the precipitate was filtered off. The filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (NH, EtOAc/hexane) to give the title compound (205.9 mg). The solid was crystallized from EtOAc-hexane to give the title compound.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([OH:11])[CH:9]=2)[N:4]([N:12]([CH2:19][CH2:20][CH3:21])[C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)[CH:3]=1.[C:22]([N:29]1[CH:33]=[CH:32]N=C1)(N1C=CN=C1)=[O:23].[CH2:34](N)[CH2:35][CH2:36][CH2:37][CH2:38]CC.C(=O)(O)[O-].[Na+]>C1COCC1.C(O)(=O)C>[CH2:33]([NH:29][C:22](=[O:23])[O:11][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[N:4]([N:12]([CH2:19][CH2:20][CH3:21])[C:13]1[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=1)[CH:3]=[C:2]2[CH3:1])[CH2:32][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CCCN(c1ccncc1)n1cc(C)c2cc(O)ccc21
Reactant: CCCCCCCN
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CCCCCCCNC(=O)Oc1ccc2c(c1)c(C)cn2N(CCC)c1ccncc1
Reaction time: 3 h

Procedure:
To a solution consisting of 3-methyl-1-(propyl-4-pyridinylamino)-1H-indol-5-ol (2.23 g) and tetrahydrofuran (53 ml) was added 1,1'-carbonyldiimidazole (2.57 g) at room temperature with stirring under nitrogen. Stirring was continued for 96 hours, at which time acetic acid (1.54 ml) was added. To the resulting reaction mixture was added a solution consisting of heptyl amine (1.76 ml), acetic acid (0.71 ml) and THF (5 ml). After stirring for 24 hours, an additional solution of heptyl amine (1.17 ml), acetic acid (0.48 ml) and THF (5 ml) was added and stirring continued for 3 hours. The reaction mixture was poured into a dilute aqueous sodium bicarbonate solution and the product extracted with ether (3x). The combined organic layer was washed with brine and dried (MgSO4). Filtration, concentration and purification via flash column chromatography (silica gel, 2% Et3N/ether) afforded 1.60 g of the desired carbamate after recrystallization from ether/pentane, m.p. 102°-104° C.
Reaction SMILES: Br[C:2]1[C:3]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=2.[CH3:22][CH:23]1[CH2:28][O:27][CH2:26][CH2:25][NH:24]1>CS(C)=O>[CH3:22][CH:23]1[N:24]([C:2]2[C:3]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[N:4][C:5]3[C:10]([N:11]=2)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=3)[CH2:25][CH2:26][O:27][CH2:28]1
Reactant: CC1COCCN1
Reactant: COC(=O)c1ccc2nc(-c3ccccc3)c(Br)nc2c1
Solvent: CS(C)=O
Product: COC(=O)c1ccc2nc(-c3ccccc3)c(N3CCOCC3C)nc2c1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
Into a 10-mL sealed tube, was placed methyl 3-bromo-2-phenylquinoxaline-6-carboxylate (150 mg, 0.44 mmol, 1.00 equiv), and 3-methylmorpholine (443 mg, 4.39 mmol, 10.00 equiv) in DMSO (1 mL). The resulting solution was stirred overnight at 100° C. in an oil bath. The resulting mixture was concentrated in vacuo. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:50). This resulted in 46 mg (29%) of methyl 3-(3-methylmorpholino)-2-phenylquinoxaline-6-carboxylate as a yellow solid.
Reaction SMILES: Cl[C:2]([O:4][CH:5]([CH3:7])[CH3:6])=[O:3].Cl.[CH3:9][N:10]1[CH2:15][CH2:14][N:13]([C:16]2[CH:21]=[C:20]([C:22]3[CH:31]=[C:30]4[C:25]([CH2:26][CH2:27][NH:28][CH2:29]4)=[CH:24][CH:23]=3)[N:19]=[C:18]([NH2:32])[N:17]=2)[CH2:12][CH2:11]1>>[NH2:32][C:18]1[N:19]=[C:20]([C:22]2[CH:31]=[C:30]3[C:25]([CH2:26][CH2:27][N:28]([C:2]([O:4][CH:5]([CH3:7])[CH3:6])=[O:3])[CH2:29]3)=[CH:24][CH:23]=2)[CH:21]=[C:16]([N:13]2[CH2:12][CH2:11][N:10]([CH3:9])[CH2:15][CH2:14]2)[N:17]=1
Reactant: CC(C)OC(=O)Cl
Reactant: CN1CCN(c2cc(-c3ccc4c(c3)CNCC4)nc(N)n2)CC1
Agent: Cl
Product: CC(C)OC(=O)N1CCc2ccc(-c3cc(N4CCN(C)CC4)nc(N)n3)cc2C1

Procedure:
This compound was prepared from isopropyl chloroformate and 4-(4-methylpiperazin-1-yl)-6-(1,2,3,4-tetrahydroisoquinolin-7-yl)pyrimidin-2-amine HCl salt using procedures analogous to those for Example 2. Analytic LCMS (M+H)+: m/z=411.4.
Reaction SMILES: [CH:1]([C:4]1[N:5]=[C:6]([CH2:9][CH2:10][C:11]2[CH:32]=[CH:31][N:14]3[C:15](=[O:30])[C:16](/[CH:25]=[CH:26]/[C:27](O)=[O:28])=[C:17]([N:19]4[CH2:24][CH2:23][O:22][CH2:21][CH2:20]4)[N:18]=[C:13]3[CH:12]=2)[S:7][CH:8]=1)([CH3:3])[CH3:2].[C:33]([O:37][C:38]([NH:40][CH2:41][CH2:42][CH2:43][S:44]([NH2:47])(=[O:46])=[O:45])=[O:39])([CH3:36])([CH3:35])[CH3:34].Cl.C(N=C=NCCCN(C)C)C.C(OCC)(=O)C>CN(C)C=O.CCCCCC>[CH:1]([C:4]1[N:5]=[C:6]([CH2:9][CH2:10][C:11]2[CH:32]=[CH:31][N:14]3[C:15](=[O:30])[C:16](/[CH:25]=[CH:26]/[C:27]([NH:47][S:44]([CH2:43][CH2:42][CH2:41][NH:40][C:38]([O:37][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:39])(=[O:45])=[O:46])=[O:28])=[C:17]([N:19]4[CH2:20][CH2:21][O:22][CH2:23][CH2:24]4)[N:18]=[C:13]3[CH:12]=2)[S:7][CH:8]=1)([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NCCCS(N)(=O)=O
Reactant: CC(C)c1csc(CCc2ccn3c(=O)c(/C=C/C(=O)O)c(N4CCOCC4)nc3c2)n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CC(C)c1csc(CCc2ccn3c(=O)c(/C=C/C(=O)NS(=O)(=O)CCCNC(=O)OC(C)(C)C)c(N4CCOCC4)nc3c2)n1
Temperature: 25 °C
Reaction time: 24 h
Yield: 40.7 %

Procedure:
(E)-3-{8-[2-(4-Isopropyl-1,3-thiazol-2-yl)ethyl]-2-morpholino-4-oxo-4H-pyrido -[1,2-a]pyrimidin-3-yl}-2-propenoic acid (53 mg) was dissolved in dimethylformamide (2 ml), added with 3-(N-tert-butoxycarbonylamino)propanesulfonamide (55 mg) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (67 mg), and the mixture was stirred at room temperature for 24 hours. The reaction solution was added with ethyl acetate and hexane, washed with 0.2 M hydrochloric acid, and dried over sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound (32 mg) as yellow powder.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[C:8]([CH:11]=O)[CH:9]=[CH:10][C:5]=2[N:4]=[N:3]1.[CH2:13]1[S:19][C:17](=[O:18])[NH:16][C:14]1=[O:15]>>[CH3:1][N:2]1[C:6]2[CH:7]=[C:8]([CH:11]=[C:13]3[S:19][C:17](=[O:18])[NH:16][C:14]3=[O:15])[CH:9]=[CH:10][C:5]=2[N:4]=[N:3]1
Reactant: O=C1CSC(=O)N1
Reactant: Cn1nnc2ccc(C=O)cc21
Product: Cn1nnc2ccc(C=C3SC(=O)NC3=O)cc21

Procedure:
Following the general method as outlined in Example 1, starting from 3-Methyl-3H-benzotriazole-5-carbaldehyde (intermediate 34) and thiazolidinedione, the title compound was obtained.
Reaction SMILES: [H-].[Na+].[C:3]1([CH:9]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[O:10][CH:11]2[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][CH2:19][OH:20])[CH2:13][CH2:12]2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl[C:28]1[C:29]([CH3:46])=[CH:30][C:31]2[N:32]([CH:34]=[C:35]([C:37]([CH3:45])([CH3:44])[C:38]([O:40][CH:41]([CH3:43])[CH3:42])=[O:39])[N:36]=2)[N:33]=1>CN(C)C=O>[C:21]1([CH:9]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)[O:10][CH:11]2[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][CH2:19][O:20][C:28]3[C:29]([CH3:46])=[CH:30][C:31]4[N:32]([CH:34]=[C:35]([C:37]([CH3:44])([CH3:45])[C:38]([O:40][CH:41]([CH3:42])[CH3:43])=[O:39])[N:36]=4)[N:33]=3)[CH2:13][CH2:12]2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: Cc1cc2nc(C(C)(C)C(=O)OC(C)C)cn2nc1Cl
Reactant: OCCCN1CCC(OC(c2ccccc2)c2ccccc2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc2nc(C(C)(C)C(=O)OC(C)C)cn2nc1OCCCN1CCC(OC(c2ccccc2)c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 24.9 %

Procedure:
To 10 ml of N,N-dimethylformamide, 0.16 g of a 60% dispersion of sodium hydride in mineral oil and 1.30 g of 4-(diphenylmethoxy)-1-piperidinepropanol were added, followed by stirring at room temperature under reduced pressure for 1 hour. While the reaction mixture was cooled with ice water, 1.31 g of isopropyl 2-(6-chloro-7-methylimidazo[1,2-b]pyridazin-2-yl)-2-methylpropionate was added, followed by stirring at room temperature for 1.5 hours. To the reaction mixture, ice water was added, followed by extraction with ethyl acetate; the extract was washed with saline, dried over magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography and eluted with hexane:ethyl acetate (1:5). The desired fraction was collected to yield 582 mg of isopropyl 2-[6-[3-[4-(diphenylmethoxy)piperidino]propoxy)-7-methylimidazo[1,2-b]pyridazin-2-yl]-2-methylpropionate as an oily substance. This oily substance was dissolved in 4 ml of ethanol; 2 ml of a 1 N aqueous solution of sodium hydroxide was added and reaction mixture was heated under reflux for 7 hours. After cooling, reaction mixture was concentrated under reduced pressure followed by extraction with ethyl acetate-tetrahydrofuran (1:1); the extract was washed with saturated saline, dried over magnesium sulfate and concentrated under reduced pressure. The residue was crystallized by the addition of a small amount of water and ethyl ether, collected by filtration, washed with ethyl ether and dried to yield 0.413 g of the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[CH:12][N:13]=[CH:14][CH:15]=3)[NH:10][C:9]=2[C:17]([NH2:19])=[O:18])=[CH:4][CH:3]=1.[F:20][C:21]([F:33])([F:32])[O:22][C:23]1[CH:28]=[CH:27][C:26]([N:29]=[C:30]=[O:31])=[CH:25][CH:24]=1>>[F:20][C:21]([F:32])([F:33])[O:22][C:23]1[CH:24]=[CH:25][C:26]([NH:29][C:30](=[O:31])[NH:1][C:2]2[CH:3]=[CH:4][C:5]([C:8]3[C:16]4[C:11](=[CH:12][N:13]=[CH:14][CH:15]=4)[NH:10][C:9]=3[C:17]([NH2:19])=[O:18])=[CH:6][CH:7]=2)=[CH:27][CH:28]=1
Reactant: O=C=Nc1ccc(OC(F)(F)F)cc1
Reactant: NC(=O)c1[nH]c2cnccc2c1-c1ccc(N)cc1
Product: NC(=O)c1[nH]c2cnccc2c1-c1ccc(NC(=O)Nc2ccc(OC(F)(F)F)cc2)cc1

Procedure:
94 mg of solid yellow 3-{4-[3-(4-trifluoromethoxyphenyl)ureido]phenyl}-1H-pyrrolo[2,3-c]pyridine-2-carboxamide are prepared as described in Example 1 starting with 3-(4-aminophenyl)-1H-pyrrolo[2,3-c]pyridine-2-carboxamide and 4-trifluoromethoxyphenyl isocyanate.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([OH:29])[CH2:9][NH:10][CH:11]([CH3:28])[CH2:12][C:13]2[CH:27]=[CH:26][C:16]3[O:17][C:18]([C:23]([OH:25])=[O:24])([C:20]([OH:22])=[O:21])[O:19][C:15]=3[CH:14]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:30][C:31]([N+:35]([O-:37])=[O:36])([CH3:34])[CH2:32]O.[K+].[Br-].Cl>>[CH3:30][C:31]([N+:35]([O-:37])=[O:36])([CH3:34])[CH2:32][O:24][C:23]([C:18]1([C:20]([O:22][CH2:30][C:31]([CH3:34])([N+:35]([O-:37])=[O:36])[CH3:32])=[O:21])[O:17][C:16]2[CH:26]=[CH:27][C:13]([CH2:12][C@H:11]([NH:10][CH2:9][C@@H:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)[OH:29])[CH3:28])=[CH:14][C:15]=2[O:19]1)=[O:25]
Reactant: CC(C)(CO)[N+](=O)[O-]
Reactant: CC(Cc1ccc2c(c1)OC(C(=O)O)(C(=O)O)O2)NCC(O)c1cccc(Cl)c1
Agent: Cl
Agent: [Br-]
Agent: [K+]
Product: C[C@H](Cc1ccc2c(c1)OC(C(=O)OCC(C)(C)[N+](=O)[O-])(C(=O)OCC(C)(C)[N+](=O)[O-])O2)NC[C@H](O)c1cccc(Cl)c1

Procedure:
The title compound was prepared from 5-{2-[2-(3-chloro-phenyl)-2-hydroxy-ethylamino]-propyl}-benzo[1,3]dioxole-2,2-dicarboxylic acid and 2-methyl-2-nitropropanol according to the procedure of Example 1 as an off-white solid; 1H NMR (DMSO-d6,400 MHz) δ 0.78 (s, 12H, 4×CH3), 0.8-1.0 (m, 4H, CH2), 1-1.2 (m, 11H, cyclohexyl, CH3), 1.5-1.65 (m, 10 H, cyclohexyl), 2.6 (m, 1H, CH), 3-3.3 (m, 3H, CH, CH2), 3.4 (brs, 1H, CH), 4.04 (s, 4H, OCH2, OCH2), 5.05 (m, 1H, CH), 6.35 (d, J=4.17 Hz, 1H, OH), 6.83 (dd, J=7.9, 1.32 Hz, 1H, Ar--H), 7.06 (s 1H, Ar--H), 7.09 (d, J=8.35 Hz), 7.38-7.42 (m, 3H, Ar--H), 7.5 (s, 1H, Ar--H), 8.8 (brs, 1H, NH), 9.4 (brs, 1H, NH); IR (KBr, cm-1) 3400 (OH), 2900 (NH), 1760 (CO); Analysis for: C28H34ClN3O11 ×HCl: Calc'd: C, 50.92; H, 5.34; N, 6.36; Found: C, 50.72; H, 5.42; N, 5.96.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6](Cl)=[O:7].[S:9]([C:13]1[CH:14]=[C:15]([NH:19][C:20]([N:22]([CH3:24])[CH3:23])=[O:21])[CH:16]=[CH:17][CH:18]=1)(=[O:12])(=[O:11])[NH2:10].C(N(CC)CC)C.CS(O)(=O)=O>CN(C)C1C=CN=CC=1.C(#N)C.O>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([NH:10][S:9]([C:13]1[CH:14]=[C:15]([NH:19][C:20]([N:22]([CH3:24])[CH3:23])=[O:21])[CH:16]=[CH:17][CH:18]=1)(=[O:11])=[O:12])=[O:7]
Reactant: O=C(Cl)c1ccco1
Reactant: CN(C)C(=O)Nc1cccc(S(N)(=O)=O)c1
Agent: CN(C)c1ccncc1
Agent: CS(=O)(=O)O
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: O
Product: CN(C)C(=O)Nc1cccc(S(=O)(=O)NC(=O)c2ccco2)c1
Temperature: 60 °C
Reaction time: 1 h
Yield: 80.7 %

Procedure:
6.1 g of 2-furancarboxylic acid chloride and 0.1 g of 4-dimethylaminopyridine are added to a suspension of 10.1 g of 1-(3-sulfamoylphenyl)-3,3-dimethylurea in 60 ml of acetonitrile. 9.5 g of triethylamine are added dropwise to that mixture at room temperature. The reaction mixture is stirred for 15 hours at room temperature and for one hour at 60° C. After the mixture has cooled, 4.5 g of methanesulfonic acid are added dropwise thereto and the mixture is taken up in 1 liter of water. The oil that separates out crystallises after a short time. The crystals are separated off, washed with methanol and dried, yielding 11.3 g of 1-[3-(N-2-furylcarbonylsulfamoyl)-phenyl]-3,3-dimethylurea, m.p. 216°-217° C. (with decomposition).
Reaction SMILES: C([O:3][C:4](=[O:24])[CH2:5][CH2:6][CH2:7][N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)C.[OH-].[Li+:26].C(#N)C>O1CCCC1>[Li+:26].[C:20]([C:17]1[CH:16]=[CH:15][C:14]([N:11]2[CH2:10][CH2:9][N:8]([CH2:7][CH2:6][CH2:5][C:4]([O-:24])=[O:3])[CH2:13][CH2:12]2)=[CH:19][CH:18]=1)([CH3:23])([CH3:21])[CH3:22]
Reactant: CCOC(=O)CCCN1CCN(c2ccc(C(C)(C)C)cc2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CC#N
Product: CC(C)(C)c1ccc(N2CCN(CCCC(=O)[O-])CC2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 189.9 %

Procedure:
To 4-[4-(4-tert-butyl-phenyl)-piperazin-1-yl]-butyric acid ethyl ester (1.41 g; 4.24 mmol, prepared in accordance with Example 166) is added a solution of lithium hydroxide (59 mg; 2.46 mmol in 3 mL of water) diluted with tetrahydrofuran (3 mL) and the resulting mixture is stirred at room temperature for one hour. Acetonitrile (50 mL) is added and the precipitate formed is then filtered and dried under high vacuum to afford the desired product (1.45 g) which is used in the next step without further purification.
Reaction SMILES: [OH:1][C:2]1[N:6]([CH3:7])[N:5]=[C:4]([C:8]([F:11])([F:10])[F:9])[CH:3]=1.[OH-].[Na+].[CH2:14]=O.[C:16]1([SH:22])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.Cl>O>[OH:1][C:2]1[N:6]([CH3:7])[N:5]=[C:4]([C:8]([F:11])([F:10])[F:9])[C:3]=1[CH2:14][S:22][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: C=O
Reactant: Sc1ccccc1
Reactant: Cn1nc(C(F)(F)F)cc1O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cn1nc(C(F)(F)F)c(CSc2ccccc2)c1O
Temperature: 25 °C
Yield: 76.4 %

Procedure:
5-Hydroxy-1-methyl-3-trifluoromethylpyrazole (1.7 g (10 mmol)) synthesized in Reference Example 1 and 0.6 g (15 mmol) of sodium hydroxide were dissolved in 10 mL of water. While stirring the resulting solution at room temperature, 1.7 g (20 mmol) of a 35% formalin solution was added dropwise thereto, followed by stirring at the same temperature for 1 hour. Furthermore, 11.0 g (10 mmol) of thiophenol was added dropwise thereto at room temperature, and the obtained mixture was stirred for 7 hours. After the reaction, 5.0 g (50 mmol) of 35% hydrochloric acid was added dropwise thereto, and the precipitated crystal was collected by filtration, washed twice with 5 mL of water and dried by a hot air drier to obtain 2.2 g (yield: 76.4%) of the title compound as a pale yellow crystal. This crystal was recrystallized from n-hexane-2-propanol and obtained as a white crystal.
Reaction SMILES: N.[H][H].COC(C)C#N.[C:10]([CH2:12][CH2:13][O:14][CH:15]([O:17][CH2:18][CH2:19][C:20]#[N:21])[CH3:16])#[N:11]>[Ni].CO>[NH2:21][CH2:20][CH2:19][CH2:18][O:17][CH:15]([O:14][CH2:13][CH2:12][CH2:10][NH2:11])[CH3:16].[CH3:15][O:14][CH2:13][CH2:12][CH2:10][NH2:11]
Reactant: [H][H]
Reactant: CC(OCCC#N)OCCC#N
Agent: [Ni]
Agent: COC(C)C#N
Agent: N
Solvent: CO
Product: CC(OCCCN)OCCCN
Product: COCCCN
Temperature: 90 °C
Reaction time: 0.5 h

Procedure:
Into a 2 liter stirred autoclave was placed 60 g of Raney nickel 2400 and 120 g of anhydrous ammonia. A heel of 200 g of methanol was then pumped into the reactor and the reactor externally heated to 90° C. The pressure was raised to 850 psig with hydrogen. The crude product mixture of methoxypropionitrile (MOPN) and bis(cyanoethoxy)ethane from Example 4 was then pumped into the autoclave at a rate of 5.0 g/min until 999 g of the mixture had been admitted. During the addition the temperature was maintained at 90° C. and the pressure at 850 psig with hydrogen. Following the addition, hydrogen uptake ceased within 30 min. and the reaction was terminated. The contents of the autoclave were cooled and then filtered through Celite™ filtration aid. The filtrate was analyzed by GC and found to be comprised of 16.8 wt % 3-methoxypropylamine (MOPA), 77.0 wt % of bis(3-aminopropoxy)ethane, 0.89 wt % of 3-aminopropoxyethanol, 1.96 wt % of N-methoxypropyl-bis(3-amino-propoxy)ethane, 0.35 wt % of bis(3-methoxypropyl)amine and 3.0 wt % of bis(aminopropoxyethoxypropyl)amine.
Reaction SMILES: Cl[C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][C:6]([Cl:15])=[CH:7][CH:8]=2)[N:3]=1.[N-:16]=[N+:17]=[N-:18].[Na+].CN(C=O)C>O.[Na+].[Cl-]>[Cl:15][C:6]1[CH:5]=[C:4]2[C:9]([CH:10]=[C:11]([C:12]([OH:14])=[O:13])[C:2]3[N:3]2[N:16]=[N:17][N:18]=3)=[CH:8][CH:7]=1
Reactant: [N-]=[N+]=[N-]
Reactant: O=C(O)c1cc2ccc(Cl)cc2nc1Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(O)c1cc2ccc(Cl)cc2n2nnnc12
Temperature: 70 °C
Reaction time: 24 h
Yield: 40.2 %

Procedure:
To a dry reaction vial with a screw cap was placed 2,7-dichloroquinoline-3-carboxylic acid (0.241 g, 1 mmol), sodium azide (0.078 g, 1.2 mmol) and dry DMF (3 mL) and shaken at 65-75° C. for a period of 24 h. The reaction mixture was diluted with water (100 mL), saturated with NaCl, the resulting solid was filtered and dried to give 0.100 g (41%) of the carboxytetrazole 5. TLC Rf: 0.06 (20% MeOH/EtOAc); 1H NMR (DMSO d6+CDCl3): δ 8.71 (bs, 1H), 8.60 (s, 1H), 8.30 (d, 1H, J=7.8 Hz), 7.79 (d, 1H, J=7.5 Hz); LCMS (ret. time): 21.28; MS (m/z): 249 (MH+).
Reaction SMILES: [C:1]1([P:7](Cl)([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[Si]([N:20]=[N+:21]=[N-:22])(C)C>>[C:1]1([P:7]([N:20]=[N+:21]=[N-:22])([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=P(Cl)(c1ccccc1)c1ccccc1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Product: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Temperature: 60 °C
Reaction time: 16 h

Procedure:
Following a previously [Paciorek et al, Inorg. Nucl. Chem. Letters, 2, 39 (1966)] developed procedure, diphenylphosphinyl chloride (14.87 g, 62.86 mmol) was introduced into a tube (in the inert atmosphere enclosure). Trimethylsilyl azide (10.45 g, 90.69 mmol) was then condensed onto this material on a vacuum line at liquid nitrogen temperature. The tube was sealed in vacuo and heated at 60° C. for 48 hr. Thereafter, it was cooled, opened to a vacuum system and the volatiles were collected in a liquid nitrogen trap (originally without pumping at room temperature, finally with pumping at 70° C.). The total time required to remove the volatiles (excess (CH3)3SiN3 and the by-product (CH3)3SiCl) was 16 hr. A quantitative yield of pure diphenylphosphinyl azide was realized.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2([OH:14])[CH2:13][CH2:12][NH:11][CH2:10]2)[CH:5]=[C:6]([F:8])[CH:7]=1.[CH2:15]=O>C(O)=O>[F:1][C:2]1[CH:3]=[C:4]([C:9]2([OH:14])[CH2:13][CH2:12][N:11]([CH3:15])[CH2:10]2)[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: C=O
Reactant: OC1(c2cc(F)cc(F)c2)CCNC1
Solvent: O=CO
Product: CN1CCC(O)(c2cc(F)cc(F)c2)C1
Reaction time: 5 h

Procedure:
Preparation according to Example 11: Enantiomer E2 of 3-(3,5-difluorophenyl)-pyrrolidin-3-ol (0.29 g, 1.45 mmol), formic acid (3.8 mL), aqueous formaldehyde (40%, 3.4 mL). 65° C. for 5 h. Purification by flash chromatography on silica gel (ethyl acetate/methanol, 10:1). Yield: 0.19 g. [α]D=−22.8° (methanol). The amine was converted to the oxalic acid salt and recrystallized from ethanol/diethyl ether/diisopropyl ether: M.p. 134-135° C.; MS m/z (relative intensity, 70 eV) 213 (M+, 15), 57.1 (bp), 58.1 (31), 113 (13), 127 (11), 141 (11).
Reaction SMILES: [N-:1]=[N+]=[N-].[Na+].Cl[CH2:6][C:7]([NH:9][C:10]([CH3:17])([CH3:16])[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])=[O:8]>O.CO.[Pd]>[NH2:1][CH2:6][C:7]([NH:9][C:10]([CH3:17])([CH3:16])[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])=[O:8]
Reactant: [N-]=[N+]=[N-]
Reactant: CCCCCC(C)(C)NC(=O)CCl
Agent: [Pd]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CCCCCC(C)(C)NC(=O)CN

Procedure:
A solution of sodium azide (6.7 g, 103 m mol) in water (56 ml) and methanol(104 ml) was treated with 2-chloro-N-(1,1-dimethylhexyl)acetamide (16.5 g, 80 m mol) and the mixture was refluxed for 5 hours. After cooling, the mixture was extracted with 40-60 petrol (3×200 ml), the extracts were dried over magnesium sulphate and evaporated under reduced pressure to give crude 2-azido-N-(1,1-dimethylhexyl)acetamide as a pale yellow oil.This oil was dissolved in methanol (200 ml) and hydrogenated over 10% palladium on charcoal (3.2 g) at atmospheric pressure and room temperaturefor 24 hours. The mixture was filtered and the filtrate evaporated to give a crude oil (13.6 g) which was distilled to give 2-amino-N-(1,1-dimethylhexyl)acetamide as a colourless oil, b.p. 88°-90° C. at 0.05 mm Hg.
Reaction SMILES: [C:1]1(=O)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][NH:2]1.[NH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[SH:22]>>[NH2:2][CH2:1][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][C:3]1[S:22][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[N:15]=1
Reactant: Nc1ccccc1S
Reactant: O=C1CCCCCCCCCCCN1
Product: NCCCCCCCCCCCc1nc2ccccc2s1

Procedure:
In the manner of Example 5, 2-azacylotridecanone was reacted with o-aminothiophenol to yield 2-(11-aminoundecyl)benzothiazole.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[N:13][N:12]([CH2:15][C:16]([C:18]2[CH:23]=[CH:22][C:21]([CH2:24]Br)=[CH:20][CH:19]=2)=[O:17])[C:11](=[O:26])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1>>[CH2:1]([O:8][C:9]1[CH:14]=[N:13][N:12]([CH2:15][C:16]([C:18]2[CH:23]=[CH:22][C:21]([CH2:24][N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)=[CH:20][CH:19]=2)=[O:17])[C:11](=[O:26])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C1COCCN1
Reactant: O=C(Cn1ncc(OCc2ccccc2)cc1=O)c1ccc(CBr)cc1
Product: O=C(Cn1ncc(OCc2ccccc2)cc1=O)c1ccc(CN2CCOCC2)cc1

Procedure:
5-Benzyloxy-2-[2-(4-morpholin-4-ylmethyl-phenyl)-2-oxo-ethyl]-2H-pyridazin-3-one is prepared as example 1.1b from 90 mg (0.22 mmol) 5-benzyloxy-2-[2-(4-bromomethyl-phenyl)-2-oxo-ethyl]-2H-pyridazin-3-one (preparation 17b) and 76 μL (0.87 mmol) morpholine.