Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:3]([C:12]2[O:13][CH:14]=[CH:15][CH:16]=2)=[N:4][C:5]([NH2:11])=[N:6][C:7]=1S(C)=O.[CH3:17][O:18][CH2:19][CH2:20][NH2:21]>O1CCOCC1>[Br:1][C:2]1[C:7]([NH:21][CH2:20][CH2:19][O:18][CH3:17])=[N:6][C:5]([NH2:11])=[N:4][C:3]=1[C:12]1[O:13][CH:14]=[CH:15][CH:16]=1
Reactant: COCCN
Reactant: CS(=O)c1nc(N)nc(-c2ccco2)c1Br
Solvent: C1COCCO1
Product: COCCNc1nc(N)nc(-c2ccco2)c1Br

Procedure:
From 5-bromo-4-furan-2-yl-6-methanesulfinyl-pyrimidin-2-yl-amine and 2-methoxyethylamine in dioxane. ES-MS m/e (%): 315 (M{81Br}+H+, 100), 313 (M{79Br}+H+, 80).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[N:9]1[C:13]([C:14]#[N:15])=[C:12]([C:16]([O:18]CC)=[O:17])[CH:11]=[N:10]1.[OH-:21].[K+]>C(O)C>[C:16]([C:12]1[CH:11]=[N:10][N:9]([C:3]2[CH:4]=[CH:5][CH:6]=[C:7]([Cl:8])[C:2]=2[Cl:1])[C:13]=1[C:14]([NH2:15])=[O:21])([OH:18])=[O:17]
Reactant: [OH-]
Reactant: CCOC(=O)c1cnn(-c2cccc(Cl)c2Cl)c1C#N
Agent: [K+]
Solvent: CCO
Product: NC(=O)c1c(C(=O)O)cnn1-c1cccc(Cl)c1Cl

Procedure:
A 15 g. portion of ethyl 1-(2,3-dichlorophenyl)-5-cyano-4-pyrazolecarboxylate was stirred under reflux overnight in 200 ml. of ethanol with 6 g. of potassium hydroxide. The reaction mixture was chromatographed over silica gel, and the product-containing fractions were combined and evaporated to dryness. The residues were recrystallized from ethanol-water to obtain 1.31 g. of the desired product, m.p. 228°-230°, which was identified by elemental analysis.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:20])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([OH:16])=O)=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18].[CH3:21][N:22]1[CH2:27][CH2:26][N:25]([CH2:28][CH2:29][NH2:30])[CH2:24][CH2:23]1>>[Cl:20][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([Cl:1])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([NH:30][CH2:29][CH2:28][N:25]2[CH2:26][CH2:27][N:22]([CH3:21])[CH2:23][CH2:24]2)=[O:16])=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18]
Reactant: CN1CCN(CCN)CC1
Reactant: O=C(O)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1
Product: CN1CCN(CCNC(=O)c2cc([N+](=O)[O-])c(Sc3c(Cl)cncc3Cl)s2)CC1

Procedure:
Prepared according to the procedure described for example 44 from 5-[(3,5-dichloro-4-pyridyl)sulfanyl]-4-nitro-thiophene-2-carboxylic acid (35 mg, 0.1 mmol) and 2-(4-methylpiperazin-1-yl)ethanamine (16 mg, 0.12 mmol). The title compound was obtained as a solid (13.6 mg, 29% yield). MS m/z: 476.04, 478.04 [M+H]+.
Reaction SMILES: C[O:2][C:3](=[O:26])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[C:13]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)=[N:14][O:15][C:16]=2[CH2:17][OH:18])=[N:6][CH:5]=1.[OH-].[Li+].Cl.C(OCC)(=O)C>C1COCC1.CO.O>[F:25][C:22]1[CH:23]=[CH:24][C:19]([C:13]2[C:12]([CH2:11][O:10][C:7]3[CH:8]=[CH:9][C:4]([C:3]([OH:26])=[O:2])=[CH:5][N:6]=3)=[C:16]([CH2:17][OH:18])[O:15][N:14]=2)=[CH:20][CH:21]=1
Reactant: COC(=O)c1ccc(OCc2c(-c3ccc(F)cc3)noc2CO)nc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1ccc(OCc2c(-c3ccc(F)cc3)noc2CO)nc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 104.1 %

Procedure:
To 6-[3-(4-fluoro-phenyl)-5-hydroxymethyl-isoxazol-4-ylmethoxy]-nicotinic acid methyl ester (1.00 g, 2.79 mmol) in THF (6.25 mL), methanol (1.75 mL) and water (6.25 mL) was added lithium hydroxide (136 mg, 5.58 mmol). The reaction mixture was stirred overnight at room temperature. Addition of aqueous hydrochloride solution (1 N, 100 mL) and extraction with ethyl acetate yielded the title compound (1.00 g, 100%) as a white solid. MS: m/e=345.2 [M+H]+.
Reaction SMILES: [C:1]1([NH:7][C:8](=[S:18])[NH:9]/[N:10]=[CH:11]/[C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>C(O)C.O.O.O.O.O.O.[Fe](Cl)(Cl)Cl>[C:1]1([NH:7][C:8]2[S:18][C:11]([C:12]3[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=3)=[N:10][N:9]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: S=C(N/N=C/c1cccnc1)Nc1ccccc1
Agent: Cl[Fe](Cl)Cl
Solvent: CCO
Solvent: O
Product: c1ccc(Nc2nnc(-c3cccnc3)s2)cc1
Temperature: 95 °C
Reaction time: 2 h
Yield: 25.1 %

Procedure:
Powdered iron(III) chloride hexahydrate (5.1 g, 19 mmol, 4.0 equiv) was added to a stirred suspension of (E)-4-phenyl-1-(pyridin-3-ylmethylene)thiosemicarbazide (1.2 g, 4.7 mmol, 1.0 equiv) in absolute ethanol (47 mL) at 23° C. The resulting dark brown suspension was heated to 95° C. and stirred for 2 h. The cooled reaction mixture was concentrated by rotary evaporation. The residue was diluted with a 1M solution of sodium hydroxide (200 mL) and extracted with dichloromethane (8×75 mL). The combined organic layers were dried (Na2SO4), gravity-filtered, and concentrated by rotary evaporation to afford the title compound as a tan solid (300 mg, 25%): mp 252-255° C.; IR (KBr thin film) 3460 (w), 3260 (w), 3198 (w), 2921 (w), 2851 (w), 2788 (w), 1620 (m), 1566 (m), 1501 (s) cm−1; 1H NMR (300 MHz, DMSO-d6) δ 10.65 (s, 1H), 9.05 (d, J=2 Hz, 1H), 8.67 (dd, J=5, 2 Hz, 1H), 7.66 (m, 2H), 7.56 (dd, J=8, 5 Hz, 1H), 7.38 (m, 2H), 7.05 (m, 1H); ESIMS m/z 255 ([M+H]+). Precursors N-methyl-5-[4-(trifluoromethyl)pyridin-3-yl]-1,3,4-thiadiazol-2-amine, N-methyl-5-[4-(trifluoromethyl)pyridin-3-yl]-1,3,4-thiadiazol-2-amine, N-methyl-5-pyrimidin-5-yl-1,3,4-thiadiazol-2-amine, 5-(6-chloropyridin-3-yl)-N-methyl-1,3,4-thiadiazol-2-amine, 5-(5-fluoropyridin-3-yl)-N-methyl-1,3,4-thiadiazol-2-amine, 5-(5-chloropyridin-3-yl)-N-methyl-1,3,4-thiadiazol-2-amine, N-methyl-5-(2-methylpyrimidin-5-yl)-1,3,4-thiadiazol-2-amine, N,N-dimethyl-5-[5-(methylamino)-1,3,4-thiadiazol-2-yl]pyrimidin-2-amine, N-methyl-5-[5-(trifluoromethyl)pyridin-3-yl]-1,3,4-thiadiazol-2-amine, N-methyl-5-pyridin-4-yl-1,3,4-thiadiazol-2-amine, and N-methyl-5-(5-methylpyridin-3-yl)-1,3,4-thiadiazol-2-amine were prepared as described in Example 3.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[N:12]=[C:11]3[N:13]([CH2:16][CH:17]4[CH2:22][CH2:21][CH2:20][N:19]([C:23]5[N:28]=[CH:27][C:26]([C:29]6[CH:33]=[CH:32][N:31]([CH2:34][CH2:35][O:36]C7CCCCO7)[N:30]=6)=[CH:25][N:24]=5)[CH2:18]4)[N:14]=[N:15][C:10]3=[N:9][CH:8]=2)[CH:4]=[N:3]1.O1CCOCC1.[ClH:49]>C(Cl)Cl>[ClH:49].[CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[N:12]=[C:11]3[N:13]([CH2:16][CH:17]4[CH2:22][CH2:21][CH2:20][N:19]([C:23]5[N:24]=[CH:25][C:26]([C:29]6[CH:33]=[CH:32][N:31]([CH2:34][CH2:35][OH:36])[N:30]=6)=[CH:27][N:28]=5)[CH2:18]4)[N:14]=[N:15][C:10]3=[N:9][CH:8]=2)[CH:4]=[N:3]1
Reactant: Cn1cc(-c2cnc3nnn(CC4CCCN(c5ncc(-c6ccn(CCOC7CCCCO7)n6)cn5)C4)c3n2)cn1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: Cn1cc(-c2cnc3nnn(CC4CCCN(c5ncc(-c6ccn(CCO)n6)cn5)C4)c3n2)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 83 %

Procedure:
6-(1-methyl-1H-pyrazol-4-yl)-1-((1-(5-(1-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-pyrazol-3-yl)pyrimidin-2-yl)piperidin-3-yl)methyl)-1H-[1,2,3]triazolo[4,5-b]pyrazine (28 mg, 0.049 mmol) was dissolved in CH2Cl2 (5 ml), and then 4 N HCl dioxane (1 ml) was added, followed by stirring at room temperature for 1 hour. After the reaction was completed, the reaction mixture was purified with ether to give 2-(3-(2-(3-((6-(1-methyl-1H-pyrazol-4-yl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-1-yl)methyl)piperidin-1-yl)pyrimidin-5-yl)-1H-pyrazol-1-yl)ethanolhydrochloride (21.5 mg, 83%).
Reaction SMILES: [O:1]1[CH2:3][CH:2]1[CH2:4][O:5][C:6]1[CH:23]=[CH:22][CH:21]=[CH:20][C:7]=1[C:8]([NH:10][C:11]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:12]=1[CH:13]=[CH:14][NH:15]2)=[O:9]>C(O)C.C(N)CC>[OH:1][CH:2]([CH2:3][NH:10][CH2:8][CH2:7][CH3:6])[CH2:4][O:5][C:6]1[CH:23]=[CH:22][CH:21]=[CH:20][C:7]=1[C:8]([NH:10][C:11]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:12]=1[CH:13]=[CH:14][NH:15]2)=[O:9]
Reactant: O=C(Nc1cccc2[nH]ccc12)c1ccccc1OCC1CO1
Solvent: CCO
Solvent: CCCN
Product: CCCNCC(O)COc1ccccc1C(=O)Nc1cccc2[nH]ccc12
Yield: 151.6 %

Procedure:
3.1 g of 2-[(2-oxiranyl) methoxy]-N-(1H-indol-4-yl) benzamide prepared as in example 4 is heated for 2 hours to reflux in 60 cm3 of ethanol and 8.5 cm3 of n-propylamine. The solvents are eliminated under reduced pressure at 50° C., the residue is chromatographed on silica (eluent: chloroform-methanol 7-3) to obtain 2.8 g of 2-[2-hydroxy-3-(propylamino)-propoxy]-N-(1H-indol-4-yl) benzamide.
Reaction SMILES: CO[CH2:3][N:4]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:5][Si](C)(C)C.[Cl:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20](/[CH:24]=[CH:25]/[N+:26]([O-:28])=[O:27])[CH:19]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:10]([N:4]1[CH2:5][CH:25]([N+:26]([O-:28])=[O:27])[CH:24]([C:20]2[CH:21]=[CH:22][CH:23]=[C:18]([Cl:17])[CH:19]=2)[CH2:3]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=[N+]([O-])/C=C/c1cccc(Cl)c1
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=[N+]([O-])C1CN(Cc2ccccc2)CC1c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 590.1 %

Procedure:
A solution of N-(methoxymethyl)-N-(phenylmethyl)-N-(trimethylsilyl)methylamine (9.69 g, 41 mmol) in CH2Cl2 (40 ml) was added drop wise, over a 30 minutes period, to a stirred solution of 1-chloro-3-((E)-2-nitro-vinyl)-benzene (0.68 g, 3.37 mmol) and trifluoroacetic acid (0.21 ml) in CH2Cl2 (40 ml) at 0° C. The ice bath was removed, and the solution was stirred at 25° C. for an additional 48 h. It was then concentrated and purification by flash chromatography (SiO2, EtOAc/H 1:4) afforded 6.30 g (73%) of the title compound as a colorless oil. ES-MS m/e: 317.1 (M+H+).
Reaction SMILES: [NH2:1][C:2]1([C:21](O)=[O:22])[CH2:6][CH:5]([C:7]2[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[CH:9][CH:8]=2)[O:4][CH2:3]1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[NH2:1][C:2]1([CH2:21][OH:22])[CH2:6][CH:5]([C:7]2[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[CH:9][CH:8]=2)[O:4][CH2:3]1
Reactant: CCCCCCCCc1ccc(C2CC(N)(C(=O)O)CO2)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCCCCCCCc1ccc(C2CC(N)(CO)CO2)cc1
Reaction time: 3 h
Yield: 42.5 %

Procedure:
3-Amino-5-(4-octylphenyl)tetrahydrofuran-3-carboxylic acid (0.246 g, 0.770 mmol) was dissolved in THF (15.40 ml). A solution of lithium aluminum hydride (0.770 ml, 1.540 mmol) (Aldrich) was added carefully and the reaction stirred for about 3 h. The reaction was quenched by addition of water (60 uL) and stirred for about 30 min. 10% NaOH (180 uL) was added and the reaction stirred for about 1 h. Finally, water (60 uL) was added and the reaction stirred overnight. The mixture was filtered through Celite® and the solvents removed under reduced pressure. The residue was purified by flash column chromatography (0.5″×7″ of silica) eluting with 10% MeOH in methylene chloride and the product fractions combined. The solvents were removed under reduced pressure to provide (3-amino-5-(4-octylphenyl)tetrahydrofuran-3-yl)methanol (0.1 g, 0.327 mmol, 42.5% yield) as a colorless oil: LC/MS (method A) Rt=3.12 min.; MS m/z: 306.42 (M+H)+.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:9]=[N:10][C:11]([S:38]([CH3:41])(=[O:40])=[O:39])=[CH:12][C:13]=1[C:14]#[C:15][CH2:16][C@@:17]([OH:37])([C:33]([F:36])([F:35])[F:34])[CH2:18][C:19]([C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=1[S:29]([CH3:32])(=[O:31])=[O:30])([CH3:21])[CH3:20])(C)(C)C.C1CCN2C(=NCCC2)CC1.[Cl-].[NH4+]>CO>[Cl:28][C:25]1[CH:26]=[CH:27][C:22]([C:19]([CH3:21])([CH3:20])[CH2:18][C@:17]([CH2:16][C:15]2[NH:7][C:8]3=[CH:9][N:10]=[C:11]([S:38]([CH3:41])(=[O:40])=[O:39])[CH:12]=[C:13]3[CH:14]=2)([OH:37])[C:33]([F:36])([F:35])[F:34])=[C:23]([S:29]([CH3:32])(=[O:30])=[O:31])[CH:24]=1
Reactant: CC(C)(C)OC(=O)Nc1cnc(S(C)(=O)=O)cc1C#CC[C@](O)(CC(C)(C)c1ccc(Cl)cc1S(C)(=O)=O)C(F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C)(C[C@@](O)(Cc1cc2cc(S(C)(=O)=O)ncc2[nH]1)C(F)(F)F)c1ccc(Cl)cc1S(C)(=O)=O
Temperature: 70 °C
Yield: 99.5 %

Procedure:
To a solution of the {4-[(S)-6-(4-chloro-2-methanesulfonylphenyl)-4-hydroxy-6-methyl-4-trifluoromethylhept-1-ynyl]-6-methanesulfonylpyridin-3-yl}carbamic acid tert-butyl ester (18.3 g, 28.0 mmol) in 200 mL of methanol was added DBU (12.5 mL, 84.0 mmol). The reaction was heated to 70° C. for 1.5 hours. The reaction was added to a solution of saturated aqueous ammonium chloride solution resulting in the precipitation of a white solid that was collected by vacuum filtration. The solid was washed with water and, after drying under vacuum for 30 minutes, was suspended in 50 mL of cold diethyl ether then vacuum filtered again and washed with 50 mL of cold diethyl ether. The colorless solid was dried on the filter paper under suction to provide (R)-4-(4-chloro-2-methanesulfonylphenyl)-1,1,1-trifluoro-2-(5-methanesulfonyl-1H-pyrrolo[2,3-c]pyridin-2-ylmethyl)-4-methylpentan-2-ol (15.4 g, 99%).
Reaction SMILES: [C@@H:1]1([N:10]2[CH:15]=[CH:14][C:13](=[O:16])[NH:12][C:11]2=[O:17])[O:7][C@H:6]([CH2:8][OH:9])[C@@H:4]([OH:5])[C@@H:2]1[OH:3].C(O[C:22](=[O:24])[CH3:23])(=O)C>N1C=CC=CC=1>[C:2]([O:3][C@H:2]1[C@H:4]([O:5][C:4](=[O:5])[CH3:6])[C@@H:6]([CH2:8][O:9][C:22](=[O:24])[CH3:23])[O:7][C@H:1]1[N:10]1[CH:15]=[CH:14][C:13](=[O:16])[NH:12][C:11]1=[O:17])(=[O:3])[CH3:1]
Reactant: O=c1ccn([C@@H]2O[C@H](CO)[C@@H](O)[C@@H]2O)c(=O)[nH]1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)OC[C@H]1O[C@@H](n2ccc(=O)[nH]c2=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O

Procedure:
500 mg (2.05 mmol) of the above product 3 is taken as the starting material, and dissolved in 35 mL of pyridine. Then 11 ml of acetic anhydride is added with continuously stirring. The solution is concentrated under reduced pressure by removing the residual part of the solution after the completion of the reaction, and then purified by rapid column chromatography (acetone/n-hexane=4:5). A white product (1-(2′,3′,5′-Tri-O-acetyl-β-D-arabinofuranosyl)-pyrimidin-2,4-(3H)-dione) 4 is obtained. Its weight and yield are 675 mg and 89% respectively.
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12](O)=[O:13])=[CH:9][CH:10]=2)[N:5]=[C:4]2[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][N:3]12.C1(C)C=CC=CC=1.[F:28][C:29]1[CH:39]=[CH:38][C:32](/[C:33](=[N:36]\[H])/[NH:34]O)=[CH:31][CH:30]=1>O=S(Cl)Cl.N1C=CC=CC=1>[F:28][C:29]1[CH:39]=[CH:38][C:32]([C:33]2[N:36]=[C:12]([C:8]3[CH:7]=[C:6]4[C:11]([C:2](=[O:1])[N:3]5[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][C:4]5=[N:5]4)=[CH:10][CH:9]=3)[O:13][N:34]=2)=[CH:31][CH:30]=1
Reactant: O=C(O)c1ccc2c(=O)n3c(nc2c1)CCCCCC3
Reactant: [H]/N=C(/NO)c1ccc(F)cc1
Solvent: O=S(Cl)Cl
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: O=c1c2ccc(-c3nc(-c4ccc(F)cc4)no3)cc2nc2n1CCCCCC2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 11.9 %

Procedure:
A solution of 13-oxo-7,8,9,10,11,13-hexahydro-6H-azocino[2,1-b]quinazoline-3-carboxylic acid (75 mg, 0.28 mmol) in SOCl2 (3 mL) was stirred at reflux for 0.5 h. The excess SOCl2 was removed and the residue was diluted with toluene (5 mL). The toluene solution was added dropwise to a solution of (E)-4-fluoro-N-hydroxybenzimidamide (51 mg, 0.33 mmol) in pyridine (2 mL). After stirring at room temperature for 0.5 h, the mixture was heated and kept at 60° C. overnight. The reaction mixture was concentrated and then diluted with water (25 mL). The aqueous mixture was extracted with ethyl acetate (2×25 mL). The combined organic layers were washed with brine and dried over Na2SO4. After concentration, the crude product was purified by column chromatography to give the desired product (13 mg). MS (ESI): 391 (MH+); 1H NMR (300 MHz, CDCl3) δ 8.52 (s, 1H), 8.45-8.42 (d, J=7.68 Hz, 1H), 8.25-8.18 (m, 3H), 7.23-7.20 (t, J=7.8 Hz, 2H), 4.38 (broad, 2H), 3.11-3.09 (m, 2H), 2.03 (broad, 2H), 1.94 (broad, 2H), 1.64 (broad, 2H), 1.48 (broad, 2H).
Reaction SMILES: C(OC([NH:8][CH2:9][C:10]1[CH:40]=[CH:39][C:38]([Cl:41])=[CH:37][C:11]=1[CH2:12][NH:13][C:14](=[O:36])[C@@H:15]1[CH2:19][CH2:18][CH2:17][N:16]1[C:20](=[O:35])[CH2:21][CH:22]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=O)(C)(C)C.Cl.CCOC(C)=O>CCOC(C)=O>[C:23]1([CH:22]([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH2:21][C:20]([N:16]2[CH2:17][CH2:18][CH2:19][C@H:15]2[C:14]([NH:13][CH2:12][C:11]2[CH:37]=[C:38]([Cl:41])[CH:39]=[CH:40][C:10]=2[CH2:9][NH2:8])=[O:36])=[O:35])[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: CC(C)(C)OC(=O)NCc1ccc(Cl)cc1CNC(=O)[C@@H]1CCCN1C(=O)CC(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: CCOC(C)=O
Product: NCc1ccc(Cl)cc1CNC(=O)[C@@H]1CCCN1C(=O)CC(c1ccccc1)c1ccccc1
Temperature: 0 °C

Procedure:
N-(2-{[(tert-butoxycarbonyl)amino]methyl}-5-chlorobenzyl)-1-(3,3-diphenylpropanoyl)-L-prolinamide from the previous step (0.050 g, 0.082 mmol, HPLC RT=2.9 min) was dissolved in EtOAc (2 mL) and cooled with stirring to 0° C. HCl/EtOAc (3.55M, 1.5 mL) was added. Remove bath and stir for 2 hours. HPLC analysis indicated completion and the solvent was removed under reduced pressure. The residue was triturated with Et2O and filtered to give the hydrochloride salt of the title compound as a solid. HPLC RT=1.84 min, Method B; LC-MS M+H=476, 478; 1H NMR, 400 MHz, DMSO-d6, 8.40, (t, J=6 Hz, 1H); 8.16, (br s, 2H); 7.40-7.44, (m, 4H); 7.10-7.32 (m, 9H); 4.48-4.52 (m, 1H); 4.30-4.31, (m, 2H); 4.15-4.17 (m, 1H); 4.07 (s, 2H); 3.58-3.60 (m, 1H); 3.48-3.51 (m, 1H); 2.94, (dd, J=5, 16 Hz, 1H); 1.72-1.99 (m, 5H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[C@:4]([CH3:16])([CH2:6][C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[NH:9][CH:8]=1)[NH2:5]>P([O-])([O-])([O-])=O.[Na+].[Na+].[Na+]>[CH3:1][O:2][C:3](=[O:17])[C@@:4]([CH3:16])([CH2:6][C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[NH:9][CH:8]=1)[NH2:5]
Reactant: COC(=O)[C@@](C)(N)Cc1c[nH]c2ccccc12
Agent: O=P([O-])([O-])[O-]
Agent: [Na+]
Product: COC(=O)[C@](C)(N)Cc1c[nH]c2ccccc12
Temperature: 25 °C
Reaction time: 4 h
Yield: 10402.5 %

Procedure:
To a suspension of (±)-α-methyltryptophan methyl ester (150.0 mg, 0.646 mmol) in 50 mL of 50 mM sodium phosphate buffer pH 7.5 was added carboxypeptidase Y from Bakers Yeast (6.4 mg). The resulting suspension was stirred at ambient temperature. After 4 h, 75% conversion was observed by HPLC (C18 column, 254 nm detection, acid tR =9.0 min and ester tR =11.9 min). The reaction was extracted with 2×25 mL chloroform. The combined extracts were treated with brine, dried with magnesium sulfate, then concentrated in vacuo to yield (R)-α-methyltryptophan methyl ester (15.6 mg, 67.2 mmol, 10.4%). A portion of this α-methyl amino ester was derivatized with 2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl isothiocyanate (TAGIT). HPLC analysis of the resulting thioureas showed the (R,S)-diastereomer to be in >99% diastereomeric excess (C18 column, 254 nm detection, S,S)-diastereomer tR =15.9 min and (R,S)-diastereomer tR =16.8 min).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[C:9](=[O:14])[CH2:10][CH2:11][CH2:12][CH:13]=1.[BH4-].[Na+]>CO>[NH2:1][C:2]1[N:3]=[N:4][CH:5]=[CH:6][C:7]=1[C@H:8]1[CH2:13][CH2:12][CH2:11][CH2:10][C@@H:9]1[OH:14]
Reactant: Nc1nnccc1C1=CCCCC1=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Nc1nnccc1[C@H]1CCCC[C@@H]1O
Yield: 100.9 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 72d by using the 2-(3-aminopyridazin-4-yl)cyclohex-2-en-1-one (40 mg, 0.20 mmol) prepared in Example 82d, sodium borohydride (20 mg, 0.59 mmol) and methanol (2.0 mL), to yield the title compound (39 mg, 99%) as a colorless oil.
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[Cl:21])[C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C(C1N=C(Cl)C2N=NN(CC3C=CC=CC=3Cl)C=2N=1)(C)(C)C.Cl.COC1CNC1>>[C:1]([C:5]1[N:6]=[C:7]([N:22]2[CH2:27][CH:26]([O:25][CH3:24])[CH2:23]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[Cl:21])[C:9]=2[N:10]=1)([CH3:2])([CH3:4])[CH3:3]
Reactant: CC(C)(C)c1nc(N2CCOCC2)c2nnn(Cc3ccccc3Cl)c2n1
Agent: CC(C)(C)c1nc(Cl)c2nnn(Cc3ccccc3Cl)c2n1
Agent: COC1CNC1
Agent: Cl
Product: COC1CN(c2nc(C(C)(C)C)nc3c2nnn3Cc2ccccc2Cl)C1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-3-(2-chloro-benzyl)-7-morpholin-4-yl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 1, step c), the title compound was prepared from 5-tert-butyl-7-chloro-3-(2-chlorobenzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 3-methoxyazetidine hydrochloride and isolated as white solid (11.0 mg, 60%). MS(m/e): 387.4 (MH+).
Reaction SMILES: Cl.C(O[C:5](=[NH:16])[CH2:6][S:7]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)(=[O:9])=[O:8])C.[OH-].[Na+].C(=O)(O)[O-].[Na+].[CH3:24][C:25]1[O:29][C:28]([C:30]([NH:32][NH2:33])=[O:31])=[CH:27][CH:26]=1>C(Cl)(Cl)Cl>[NH2:16][C:5](=[N:33][NH:32][C:30]([C:28]1[O:29][C:25]([CH3:24])=[CH:26][CH:27]=1)=[O:31])[CH2:6][S:7]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)(=[O:9])=[O:8]
Reactant: CCOC(=N)CS(=O)(=O)c1ccccc1
Reactant: Cc1ccc(C(=O)NN)o1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: Cc1ccc(C(=O)NN=C(N)CS(=O)(=O)c2ccccc2)o1
Yield: 82.8 %

Procedure:
A suspension of 85.0 g (0.32 mol) 2-(phenylsulfonyl)-ethanimidic acid ethyl ester hydrochloride in 700 ml chloroform was treated with 320 ml 1N aqueous sodium hydroxide. 100 ml of a saturated aqueous sodiumbicarbonate solution was added and the mixture was extracted with chloroform. The extracts were combined and dried with sodium sulfate and the solvents were distilled off under reduced pressure. 17.8 g (0.078 Mol) of the resulting colorless oil was stirred together with 9.15 g (0.065 mol) 5-methyl-furan-2-carboxylic acid hydrazide in 115 ml chloroform for 24 hours at 50° C. The resulting precipitate was filtered off and dried. 17.3 g of 5-methyl-furan-2-carboxylic acid (1-amino-2-benzenesulfonyl-ethylidene)-hydrazide was obtained as white crystals. Mp.: 219-220° C.
Reaction SMILES: [C:1]([NH:4][NH2:5])(=[O:3])[CH3:2].[F:6][C:7]1[CH:16]=[C:15]2[C:10]([CH:11]=[CH:12][CH:13]=[N:14]2)=[CH:9][C:8]=1[CH2:17][C:18]1[N:22]2[N:23]=[C:24]([C:27](=O)[CH3:28])[CH:25]=[CH:26][C:21]2=[N:20][CH:19]=1>>[F:6][C:7]1[CH:16]=[C:15]2[C:10]([CH:11]=[CH:12][CH:13]=[N:14]2)=[CH:9][C:8]=1[CH2:17][C:18]1[N:22]2[N:23]=[C:24](/[C:27](=[N:5]/[NH:4][C:1](=[O:3])[CH3:2])/[CH3:28])[CH:25]=[CH:26][C:21]2=[N:20][CH:19]=1
Reactant: CC(=O)c1ccc2ncc(Cc3cc4cccnc4cc3F)n2n1
Reactant: CC(=O)NN
Product: CC(=O)N/N=C(\C)c1ccc2ncc(Cc3cc4cccnc4cc3F)n2n1
Yield: 75 %

Procedure:
The title compound was prepared from acetic hydrazide and 1-[3-(7-fluoro-quinolin-6-ylmethyl)-imidazo[1,2-b]pyridazin-6-yl]-ethanone in analogy to the synthesis of example 1 in 75% yield as a white solid. 1H-NMR (400 MHz, DMSO-d6) δ ppm 8.86 (d, 1H), 8.83 (d, 1H), 8.07 (d, 1H), 7.95 (d, 1H), 7.79 (m, 2H), 7.70 (s, 1H), 7.47 (q, 1H), 4.58 (s, 2H), 2.28 (s, 3H). LCMS (method A): [MH]+=377, tR=4.83 min.
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:4][CH:3]=1.[CH3:13][N:14]([CH3:20])[CH2:15][CH2:16][CH2:17][NH:18][CH3:19].[N-]=C=O>O1CCCC1>[CH3:13][N:14]([CH3:20])[CH2:15][CH2:16][CH2:17][N:18]([CH3:19])[C:2]1[N:7]=[N:6][C:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:4][CH:3]=1
Reactant: CNCCCN(C)C
Reactant: CCOC(=O)c1ccc(Cl)nn1
Agent: [N-]=C=O
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc(N(C)CCCN(C)C)nn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of ethyl 6-chloropyridazine-3-carboxylate (37 mg) in tetrahydrofuran (1.5 mL) is added N,N,N′-trimethylpropane-1,3-diamine (46 mg) and the mixture is stirred at room temperature overnight. The reaction mixture is diluted with tetrahydrofuran (1.5 mL) and thereto is added MP-Isocyanate (polystyrene methylisocyanate, 1.43 mmol/g, 400 mg). The mixture is shaken at room temperature overnight. The reaction mixture is filtered to remove the resin and the filtrate is extracted with chloroform/methanol. The organic layer is concentrated to give crude ethyl 6-[N-(3-dimethylaminopropyl)-methylamino]-3-pyridazinecarboxylate. MS (ESI) m/z: 267 [M+H]+