Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][CH:6]=1.[CH3:14][N:15]([CH3:29])[C:16]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:21][CH2:20][C:19](=O)[CH2:18][CH2:17]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[Cl:48]CCCl>CC(=O)CC.CC(C)=O>[ClH:48].[ClH:48].[NH:7]1[C:8]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:5]([CH2:4][CH2:3][N:2]([CH3:1])[CH:19]2[CH2:20][CH2:21][C:16]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)([N:15]([CH3:29])[CH3:14])[CH2:17][CH2:18]2)=[CH:6]1
Reactant: CN(C)C1(c2ccccc2)CCC(=O)CC1
Reactant: ClCCCl
Reactant: CNCCc1c[nH]c2ccccc12
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(C)=O
Solvent: CCC(C)=O
Solvent: CC(=O)O
Product: CN(CCc1c[nH]c2ccccc12)C1CCC(c2ccccc2)(N(C)C)CC1
Product: Cl
Temperature: 25 °C
Reaction time: 48 h

Procedure:
N-ω-Methyltryptamine ([2-(1H-indol-3-yl)ethyl]methylamine, 348 mg) was dissolved in dry 1,2-dichloroethane (10 ml) under argon. After addition of 4-dimethylamino-4-phenylcyclohexanone (435 mg) and glacial acetic acid (114 μl), a bulky precipitate formed. The suspension was stirred for two hours at RT before sodium triacetoxyborohydride (660 mg) was added. The reaction mixture was stirred for two days at RT and was concentrated for working up, the residue was dissolved in water (15 ml) and diethyl ether (20 ml) and the organic phase was separated off. The aqueous phase was extracted with diethyl ether (2×10 ml) and adjusted to pH 10 with 1M NaOH. A white solid precipitated out here and was filtered off with suction, washed and dried (174 mg, m.p. 208-210° C., nonpolar diastereomer). The aqueous phase was brought to pH 11 with 1M NaOH and extracted with ethyl acetate (4×25 ml). The extracts were combined, dried with Na2SO4 and concentrated in vacuo. The residue (469 mg) was separated by flash chromatography with methanol/triethylamine (99:1). The nonpolar diastereomer so obtained (172 mg) was dissolved while warm in 2-butanone/acetone (15 ml/15 ml), and the hydrochloride of N′-[2-(1H-indol-3-yl)-ethyl]-N,N,N′-trimethyl-1-phenyl-cyclohexane-1,4-diamine was precipitated as a white solid at RT with chlorotrimethylsilane (174 μl) (173 mg; m.p. 195-198° C.).
Reaction SMILES: [C:1]([O:4]O)(=[O:3])[CH3:2].C([O-])(=O)C.[Na+].[CH:11]12[CH2:21][CH:17](C(=O)C1)[CH:16]1[CH:12]2[CH2:13][CH2:14][CH2:15]1>C(O)(=O)C.ClCCl>[CH:11]12[CH2:21][CH:17]([O:4][C:1](=[O:3])[CH2:2]1)[CH:16]1[CH:12]2[CH2:13][CH2:14][CH2:15]1
Reactant: O=C1CC2CC1C1CCCC21
Reactant: CC(=O)OO
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: O=C1CC2CC(O1)C1CCCC21
Reaction time: 48 h

Procedure:
18 g of a 50 % peracetic acid solution in acetic acid containing 1 g of sodium acetate were added to a stirred mixture of 15 g of tricyclo[5.2.1.02,6 ]decane-8-one (which can be purchased from Ruhrchemie, Bruchstrasse, D-42 Oberhausen Holten, West Germany) and 9 g of anhydrous sodium acetate in 60 g of dichloromethane. The temperature of the reaction mixture was kept at 20°-25° by external cooling by means of a ice-water bath during the whole addition, then it was kept at this value during 48 hours while stirring.
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([N:15]1[CH2:20][CH2:19][CH:18]([N:21]([CH2:28][CH2:29][CH:30]([CH3:32])[CH3:31])[CH2:22][C:23]2[S:24][CH:25]=[CH:26][N:27]=2)[CH2:17][CH2:16]1)=O)(C)(C)C>ClCCl>[CH3:31][CH:30]([CH3:32])[CH2:29][CH2:28][N:21]([CH2:22][C:23]1[S:24][CH:25]=[CH:26][N:27]=1)[CH:18]1[CH2:17][CH2:16][NH:15][CH2:20][CH2:19]1
Reactant: CC(C)CCN(Cc1nccs1)C1CCN(C(=O)OC(C)(C)C)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)CCN(Cc1nccs1)C1CCNCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.2 %

Procedure:
Trifluoroacetic acid (2.7 ml, 35 mmol) is added to a solution of 4-{(3-methyl-butyl)-[(thiazol-2-yl)-methyl]-amino}-piperidine-1-carboxylic acid tert-butyl ester (0.20 g, 0.55 mmol) in dichloromethane (2.7 ml). The reaction is stirred for 1 hour at room temperature. The reaction is concentrated, loaded onto a SCX-2 (5 g) column, and washed with water (50 ml) and methanol (50 ml). The product is then eluted off with 2M ammonia in methanol (100 ml) and concentrated on a rotary evaporator to yield (0.14 g) of N-(3-methylbutyl)-N-[(1,3-thiazol-2-yl)methyl]piperidin-4-amine: mass spectrum (ion spray): m/z=268 (M+1); 1H NMR (CDCl3): δ=7.67 (1H, d), 7.22 (1H, d), 3.95 (2H, s), 3.16-3.09 (2H, m), 2.67-2.49 (5H, m), 1.81 (2H, brd), 1.69-1.57 (2H, m), 1.50-1.32 (4H, m), 0.87 (6H, d).
Reaction SMILES: N[C:2](=[N:4][C:5]([NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]#[N:15])[CH:9]=1)=[S:6])[CH3:3].Br[CH2:17][C:18]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[C:26]([F:29])([F:28])[F:27])=[O:19].C(N(CC)CC)C>C(O)C.CO>[CH3:3][C:2]1[N:4]=[C:5]([NH:7][C:8]2[CH:9]=[C:10]([CH:11]=[CH:12][CH:13]=2)[C:14]#[N:15])[S:6][C:17]=1[C:18](=[O:19])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[C:26]([F:27])([F:28])[F:29]
Reactant: O=C(CBr)c1ccccc1C(F)(F)F
Reactant: CC(N)=NC(=S)Nc1cccc(C#N)c1
Solvent: CO
Solvent: CCO
Solvent: CCN(CC)CC
Product: Cc1nc(Nc2cccc(C#N)c2)sc1C(=O)c1ccccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 16 h
Yield: 11.7 %

Procedure:
To a mixture of 801 mg (5 mmol) 3-cyanophenylthioisocyanate in 5 ml 1N NaOH at 0° C. was added 473 mg acetamidine hydrochloride in 10 ml THF and allowed to stir at 0° C. for 16 h. The mixture was extracted with ethylacetate and the combined organic layers were dried with MgSO4 and evaporated to dryness. The residue was purified by flash column chromatography on silica eluting with ethylacetate/cyclohexane 1:2 to yield 510 mg (47%) of 1-(1-Amino-ethylidene)-3-(3-cyano-phenyl)-thiourea. (MS (m/e): 219.2 (M+H, 100%). A mixture of 50 mg (0.23 mmol) 1-(1-Amino-ethylidene)-3-(3-cyano-phenyl)-thiourea, 92 mg (0.345 mmol) 2-Bromo-1-(2-trifluoromethyl-phenyl)-ethanone and 48 ul triethylamine in 1 ml ethanol was stirred for 16 h at room temperature. The mixtures were diluted with methanol and directly subjected to preparative HPLC separation on reversed phase eluting with an acetonitrile/water gradient. Evaporation of the product fractions yielded 10.4 mg (12%) of the title compound. (MS (m/e): 386.2 (M−H, 100%)
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21]3[N:26]=[CH:25][C:24]4=[CH:27][CH:28]=[C:29]([C:30]5[CH:35]=[CH:34][C:33]([S:36]([CH3:39])(=[O:38])=[O:37])=[CH:32][CH:31]=5)[N:23]4[N:22]=3)=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[F:40][C:41]([F:46])([F:45])[C:42]([OH:44])=[O:43].C(Cl)Cl>>[F:40][C:41]([F:46])([F:45])[C:42]([OH:44])=[O:43].[CH3:39][S:36]([C:33]1[CH:34]=[CH:35][C:30]([C:29]2[N:23]3[C:24]([CH:25]=[N:26][C:21]([NH:20][C:17]4[CH:18]=[CH:19][C:14]([CH:11]5[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]5)=[CH:15][CH:16]=4)=[N:22]3)=[CH:27][CH:28]=2)=[CH:31][CH:32]=1)(=[O:37])=[O:38]
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(Nc3ncc4ccc(-c5ccc(S(C)(=O)=O)cc5)n4n3)cc2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CS(=O)(=O)c1ccc(-c2ccc3cnc(Nc4ccc(C5CCNCC5)cc4)nn23)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 10 %

Procedure:
To a round bottom flask 4-{4-[7-(4-Methanesulfonyl-phenyl)-pyrrolo[2,1-f][1,2,4]-triazin-2ylamino)-phenyl}-piperidine-1-carboxylic acid tert butyl ester (7-% pure, 0.762 g, 0.00135 mol) and 3.0 M Trifluoroacetic acid in DCM (10 mL, 0.030 mol) were added. The mixture was stirred at room temperature for 1 h then the solvent was removed by rotary evaporation. The crude product was purified via HPLC reverse phase chromatography with 0.1% TFA in Water and 0.1% TFA in ACN. The collected fractions were lyophilized to give [7-(4-Methanesulfonyl-phenyl)-pyrrolo[2,1-f][1,2,4]triazin-2-yl]-(4-piperidin-4-yl-phenyl)-amine; compound with trifluoro-acetic acid as a yellow fluffy solid (0.06 g, 10%). LCMS (E/I+) 448.1 (M+H). NMR 1H (CDCl3/DSMO-d6)-9.97 (s, 1H), 9.50 (s, 1H), 8.41 (d, 2H, J=8.52 Hz), 8.20 (s, 1H), 8.02 (d, 2H, J=8.51 Hz), 7.67 (d, 2H, J=8.67 Hz), 7.20 (d, 2H, J=7.6 Hz), 7.11 (d, 1H, J=4.90 Hz), 6.88 (d, 1H, J=4.88 Hz), 3.54 (d, 2H, J=12.06 Hz), 3.14 (s, 3H), 3.02 (m, 3H), 2.59 (m, 2H), 2.05 (m, 4H).
Reaction SMILES: [C:1](=[S:3])=S.[NH2:4][CH2:5][CH2:6][N:7]1[CH2:11][CH2:10][CH:9]([NH:12][C:13]2[N:21]([CH2:22][C:23]3[O:24][C:25]([CH3:28])=[CH:26][CH:27]=3)[C:16]3=[N:17][CH:18]=[CH:19][CH:20]=[C:15]3[N:14]=2)[CH2:8]1>O1CCCC1>[N:4]([CH2:5][CH2:6][N:7]1[CH2:11][CH2:10][CH:9]([NH:12][C:13]2[N:21]([CH2:22][C:23]3[O:24][C:25]([CH3:28])=[CH:26][CH:27]=3)[C:16]3=[N:17][CH:18]=[CH:19][CH:20]=[C:15]3[N:14]=2)[CH2:8]1)=[C:1]=[S:3]
Reactant: Cc1ccc(Cn2c(NC3CCN(CCN)C3)nc3cccnc32)o1
Reactant: S=C=S
Solvent: C1CCOC1
Product: Cc1ccc(Cn2c(NC3CCN(CCN=C=S)C3)nc3cccnc32)o1
Reaction time: 0.17 h
Yield: 100 %

Procedure:
To a stirred mixture of 4.2 parts of N,N-methyltetraylbis[cyclohexanamine] and 90 parts of tetrahydrofuran were added 10.6 parts of carbon disulfide. After stirring for 10 minutes, a solution of 6 parts of N-[1-(2-aminoethyl)-3-pyrrolidinyl]-3-[(5-methyl-2-furanyl)methyl]-3H-imidazo-[4,5-b]pyridin-2-amine in 36 parts of tetrahydrofuran was added dropwise to the thus obtained mixture (exothermic reaction, the temperature rose to 26° C.). Upon complete addition, stirring was continued for 30 minutes at room temperature. The reaction mixture was evaporated and the residue was taken up in 240 parts of acetonitrile. The precipitate was filtered off and the filtrate was evaporated, yielding 6.9 parts (100%) of N-[1-(2-isothiocyanatoethyl)-3-pyrrolidinyl]-3-[(5-methyl-2-furanyl)methyl]-3H-imidazo[4,5-b]pyridin-2-amine as a residue (compound 171).
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[C@H:7]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[NH:8][C:9](=[O:17])[C:10]1[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2].[C:26]([O:43][CH:44]([CH2:52][O:53][C:54](=[O:70])[CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH2:68][CH3:69])[CH2:45][S:46][CH2:47][CH2:48][C:49](O)=[O:50])(=[O:42])[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41].O>N1C=CC=CC=1>[C:1]([O:5][C:6](=[O:25])[C@H:7]([CH2:18][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)[NH:8][C:9](=[O:17])[C:10]1[CH:11]=[CH:12][C:13]([NH:16][C:49](=[O:50])[CH2:48][CH2:47][S:46][CH2:45][CH:44]([O:43][C:26](=[O:42])[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])[CH2:52][O:53][C:54](=[O:70])[CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH2:68][CH3:69])=[CH:14][CH:15]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)[C@H](Cc1ccccc1)NC(=O)c1ccc(N)cc1
Reactant: CCCCCCCCCCCCCCCC(=O)OCC(CSCCC(=O)O)OC(=O)CCCCCCCCCCCCCCC
Solvent: c1ccncc1
Solvent: O
Product: CCCCCCCCCCCCCCCC(=O)OCC(CSCCC(=O)Nc1ccc(C(=O)N[C@@H](Cc2ccccc2)C(=O)OC(C)(C)C)cc1)OC(=O)CCCCCCCCCCCCCCC
Temperature: 25 °C
Reaction time: 2 h
Yield: 85.1 %

Procedure:
To a solution of 4-arninobenzoylphenylalanine t-butyl ester (170 mg) in pyridine (5 ml), phospholic trichloride (0.022 ml) was added, followed by stirring at room temperature for 2 hours. After addition of 6,7-bis(palmitoyloxy)- 4-thiaheptanoic acid (164 mg) as obtained in Reference Example 4, the reaction mixture was stirred at room temperature for 24 hours. After addition of water, the reaction mixture was extracted with ethyl acetate. The extract was washed with a 5% aqueous solution of citric acid, a saturated aqueous solution of sodium hydrogen carbonate and saturated saline, dried over anhydrous sodium sulfate, and the solvent was distilled off. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=3:2) to yield the title compound (208 mg, yield 86%) as a colorless wax-like substance.
Reaction SMILES: CS([C:5]1[N:9]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=2)[S:7][N:6]=1)(=O)=O.[CH2:17]([OH:21])[C:18]#[C:19][CH3:20].[H-].[Na+].[Cl-].[Na+]>CN(C)C=O>[F:16][C:12]1[CH:11]=[C:10]([C:8]2[S:7][N:6]=[C:5]([O:21][CH2:17][C:18]#[C:19][CH3:20])[N:9]=2)[CH:15]=[CH:14][CH:13]=1
Reactant: CS(=O)(=O)c1nsc(-c2cccc(F)c2)n1
Reactant: CC#CCO
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC#CCOc1nsc(-c2cccc(F)c2)n1
Reaction time: 0.17 h
Yield: 85.9 %

Procedure:
In 3 ml of N,N-dimethylformamide, 350 mg of 3-methylsulfonyl-5-(3-fluorophenyl)-1,2,4-thiadiazole and 105 mg of 2-butyne-1-ol were dissolved, to the resulting solution was added 65 mg of sodium hydride (60% oily) with ice-cooling, and the mixture was stirred for 10 minutes, and further stirred at room temperature for 4 hours. Then, the reaction mixture was poured into an aqueous saturated sodium chloride solution, and the mixture was extracted with t-butyl methyl ether. The residue obtained by concentration of the organic layer was subjected to silica gel column chromatography to obtain 289 mg of 5-(3-fluorophenyl)-3-(2-butynyloxy)-1,2,4-thiadiazole (the compound (6) of the present invention).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][NH:11][CH:10]([CH2:14][C:15]([O:17][CH3:18])=[O:16])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[CH:21][C:20]=1[S:29](Cl)(=[O:31])=[O:30]>>[CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([S:29]([C:20]2[CH:21]=[CH:22][C:23]3[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH:19]=2)(=[O:31])=[O:30])[CH:10]([CH2:14][C:15]([O:17][CH3:18])=[O:16])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)CC1CN(Cc2ccccc2)CCN1
Reactant: O=S(=O)(Cl)c1ccc2ccccc2c1
Product: COC(=O)CC1CN(Cc2ccccc2)CCN1S(=O)(=O)c1ccc2ccccc2c1
Yield: 90 %

Procedure:
Using an analogous procedure to that described in Example 2, methyl 2-(1-benzylpiperazin-3-yl)acetate (J. Chem. Soc. Perkin I, 1992, 1035) was reacted with 2-naphthylsulphonyl chloride to give methyl 2-[4-benzyl-1-(2-naphthylsulphonyl)piperazin-2-yl]acetate in 90% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][O:11][C:12]1[CH:13]=[C:14]([CH:18]=[CH:19][C:20]=1[O:21][CH3:22])[C:15]([OH:17])=O.C(N1C=CN=C1)(N1C=CN=C1)=O.Cl.[NH2:36][CH2:37][CH:38]1[CH2:43][CH2:42][N:41]([C:44]([NH2:46])=[NH:45])[CH2:40][CH2:39]1.CS(C)=O>CN(C=O)C>[C:44]([N:41]1[CH2:42][CH2:43][CH:38]([CH2:37][NH:36][C:15](=[O:17])[C:14]2[CH:18]=[CH:19][C:20]([O:21][CH3:22])=[C:12]([O:11][CH2:10][CH2:9][C:3]3[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=3[Cl:1])[CH:13]=2)[CH2:39][CH2:40]1)(=[NH:45])[NH2:46]
Reactant: N=C(N)N1CCC(CN)CC1
Reactant: COc1ccc(C(=O)O)cc1OCCc1ccc(Cl)cc1Cl
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: CS(C)=O
Product: COc1ccc(C(=O)NCC2CCN(C(=N)N)CC2)cc1OCCc1ccc(Cl)cc1Cl
Reaction time: 8 h
Yield: 21.4 %

Procedure:
A solution of 100 mg 3-[2-(2,4-Dichlorophenyl)-ethoxy]-4-methoxy-benzoic acid in 2 ml DMF was activated by the addition of 53 mg carbonyldiimidazole. After stirring for 2 h at RT 90 mg of 4-Aminomethyl-piperidine-1-carboxamidine hydrochloride and 2 ml DMSO were added and the mixture was stirred overnight. Subsequent dilution with 3 ml water and filtration through a chem elut® cartridge, eluting with ethyl acetate yielded after concentration under reduced pressure a white solid. Purification by preparative HPLC (C18 reverse phase column, elution with a H2O/MeCN gradient with 0.5% TFA) and lyophilisation afforded 30 mg (20%) of the title compound as a white powder.
Reaction SMILES: [F:1][C:2]1[CH:32]=[CH:31][C:5]([CH2:6][NH:7][C:8]([C:10]2[N:11]=[C:12]3[N:17]([C:18](=[O:28])[C:19]=2[O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:16][CH2:15][O:14][C:13]3([CH3:30])[CH3:29])=[O:9])=[C:4]([N:33]2[C:37](=[O:38])[CH2:36][CH2:35][C@@H:34]2[CH2:39][OH:40])[CH:3]=1.C(N([CH2:46][CH3:47])CC)C.CS(Cl)(=O)=[O:50].O>C(Cl)Cl>[C:46]([O:40][CH2:39][C@H:34]1[CH2:35][CH2:36][C:37](=[O:38])[N:33]1[C:4]1[CH:3]=[C:2]([F:1])[CH:32]=[CH:31][C:5]=1[CH2:6][NH:7][C:8]([C:10]1[N:11]=[C:12]2[N:17]([C:18](=[O:28])[C:19]=1[O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH2:16][CH2:15][O:14][C:13]2([CH3:30])[CH3:29])=[O:9])(=[O:50])[CH3:47]
Reactant: CCN(CC)CC
Reactant: CC1(C)OCCn2c1nc(C(=O)NCc1ccc(F)cc1N1C(=O)CC[C@@H]1CO)c(OCc1ccccc1)c2=O
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: O
Product: CC(=O)OC[C@H]1CCC(=O)N1c1cc(F)ccc1CNC(=O)c1nc2n(c(=O)c1OCc1ccccc1)CCOC2(C)C
Temperature: 23 °C
Reaction time: 4 h
Yield: 103.2 %

Procedure:
(R)-(1-(2-((3-(Benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4oxazine-2-carboxamido)methyl)-5-fluorophenyl)-5-oxopyrrolidin-2-yl)methyl methanesulfonate. To a stirred solution of intermediate 192, (R)-N-(4-fluoro-2-(2-(hydroxymethyl)-5-oxopyrrolidin-1-yl)benzyl)-3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamide (0.160 g, 0.291 mmol) in CH2Cl2 (10 mL) at 0° C. was added triethylamine (81 μL, 0.582 mmol) and methanesulfonyl chloride (27 μL, 0.349 mmol). The reaction mixture was stirred at 23° C. for 4 h. Water (50 mL) was then added and the organic material was extracted with CH2Cl2 (2×50 mL). The combined organic extracts were dried (MgSO4), filtered and concentrated in vacuo to afford the title compound (0.178 g, 98% yield). The crude material was used without further purification for the next step: LCMS (M+H)+ m/z 629.
Reaction SMILES: [C:1]1([N:7]2[C:12](=[O:13])[C:11]3[S:14][CH:15]=[C:16]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[C:10]=3[N:9]=[CH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.NC1C(C2C=CC=CC=2[Cl:35])=CSC=1C(OC)=O.C([O:47][CH2:48]C)(OCC)OCC.COC1C=CC(N)=CC=1>C(O)(=O)C>[Cl:35][C:22]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:16]1[C:10]2[N:9]=[CH:8][N:7]([C:1]3[CH:6]=[CH:5][C:4]([O:47][CH3:48])=[CH:3][CH:2]=3)[C:12](=[O:13])[C:11]=2[S:14][CH:15]=1
Reactant: COC(=O)c1scc(-c2ccccc2Cl)c1N
Reactant: O=c1c2scc(-c3ccccc3)c2ncn1-c1ccccc1
Reactant: CCOC(OCC)OCC
Solvent: COc1ccc(N)cc1
Solvent: CC(=O)O
Product: COc1ccc(-n2cnc3c(-c4ccccc4Cl)csc3c2=O)cc1
Yield: 35 %

Procedure:
In the same manner as the synthesis of Compound 1, methyl 3-amino-4-(2-chlorophenyl)thiophene-2-carboxylate (100 mg, 0.373 mmol), triethyl orthoformate (2 ml), p-anisidine (85.56 mg, 0.70 mmol), and acetic acid (0.1 ml) were used to give 48.7 mg (0.13 mmol, 35% yield) of the title compound.
Reaction SMILES: [OH-].[Na+].Cl.[CH:4]1([N:10]2[CH2:14][CH2:13][NH:12][C:11]2=[NH:15])[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1.[C:16]([NH:21][CH2:22][CH2:23][C:24]1[S:28][C:27]([S:29](Cl)(=[O:31])=[O:30])=[CH:26][CH:25]=1)(=[O:20])[CH2:17][CH2:18][CH3:19]>O.CC(C)=O>[C:16]([NH:21][CH2:22][CH2:23][C:24]1[S:28][C:27]([S:29]([N:12]2[CH2:13][CH2:14][N:10]([CH:4]3[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9]3)[C:11]2=[NH:15])(=[O:31])=[O:30])=[CH:26][CH:25]=1)(=[O:20])[CH2:17][CH2:18][CH3:19]
Reactant: CCCC(=O)NCCc1ccc(S(=O)(=O)Cl)s1
Reactant: N=C1NCCN1C1CCCCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)=O
Product: CCCC(=O)NCCc1ccc(S(=O)(=O)N2CCN(C3CCCCC3)C2=N)s1
Reaction time: 18 h

Procedure:
20 ml (0.02 mol) of 1 N sodium hydroxide solution are added dropwise over the course of 10 minutes, whilst stirring, to a mixture of 2.04 g (0.01 mol) of 1-cyclohexyl-2-imino-imidazolidine hydrochloride and 2.96 g (0.01 mol) of 5-(2-butyramido-ethyl)-2-thiophenesulphonyl chloride in 45 ml of water-acetone (1:2), at 25°C. In the course thereof, the reaction temperature rises to 33°C. The reaction mixture is stirred for a further 18 hours at 24°-25°C and the acetone is then evaporated off with the aid of a rotary evaporator. The oil-water mixture which remains is extracted twice with 30 ml of ethyl acetate at a time. The extracts are washed with 20 ml of saturated sodium chloride solution, then combined, dried over sodium sulphate and evaporated in vacuo. The residue is chromatographed on a column of 120 g of silica gel which is eluted with a mixture of chloroform and methanol (95:5). The eluate is evaporated with the aid of a rotary evaporator and the residue is recrystallized from toluene. Colourless crystals of 1-[5-(2-butyramido-ethyl)-2-thienylsulphonyl]-2-imino-3-cyclohexyl-imidazolidine of melting point 121°-125°C are obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=3[Cl:20])[N:11]=[C:10]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH:9]=2)=[CH:4][CH:3]=1.[Br:26]Br>C(Cl)Cl.C(OCC)C>[Br:26][C:9]1[C:10]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[N:11][N:12]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=2[Cl:20])[C:8]=1[C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=1
Reactant: BrBr
Reactant: CCOC(=O)c1cc(-c2ccc(Cl)cc2)n(-c2ccc(Cl)cc2Cl)n1
Solvent: CCOCC
Solvent: ClCCl
Product: CCOC(=O)c1nn(-c2ccc(Cl)cc2Cl)c(-c2ccc(Cl)cc2)c1Br
Temperature: 25 °C
Reaction time: 1 h
Yield: 45.7 %

Procedure:
To a solution of ethyl 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-1H-pyrazole-3-carboxylate (1 g, 2.4 mmol) in methylene chloride (30 ml) at room temperature was added bromine (4.9 ml, prepared 1.0 M solution in methylenechlordie, 4.9 mmol) dropwisely. The reaction mixture was stirred at room temperature for 1 hour and the resulting solution was diluted with ethyl ether (50 ml). The reaction mixture was quenched with saturated sodium bicarbonate solution (30 ml) and extracted with ethyl ether (50 ml twice). The organic solution was evaporated under reduced pressure, and crude residue was purified with silica gel column (hexane/ethyl acetate=5/1) to recover starting material (401 mg, 40%) and produce the title compound (520 mg, 45% yield) as white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[Cl:22])[CH2:5][N:6]1[C:17](=[O:18])[N:9]2[CH:10]=[C:11]([C:14](O)=[O:15])[CH:12]=[CH:13][C:8]2=[N:7]1.[CH:23]1[CH:24]=[CH:25][C:26]2N(O)N=[N:29][C:27]=2[CH:28]=1.CCN=C=NCCCN(C)C.Cl.C(N(CC)CC)C.C(N)CCCCC>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[Cl:22])[CH2:5][N:6]1[C:17](=[O:18])[N:9]2[CH:10]=[C:11]([C:14]([NH:29][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH3:28])=[O:15])[CH:12]=[CH:13][C:8]2=[N:7]1
Reactant: O=C(O)c1ccc2nn(Cc3ccc(Cl)c(Cl)c3)c(=O)n2c1
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCCCCCN
Product: CCCCCCNC(=O)c1ccc2nn(Cc3ccc(Cl)c(Cl)c3)c(=O)n2c1
Reaction time: 8 h

Procedure:
In a 15-mL round-bottom flask 2-(3,4-dichlorobenzyl)-3-oxo-2,3-dihydro-[1,2,4]triazolo[4,3-a]pyridine-6-carboxylic acid (0.065 mmol) was dissolved in dichloromethane (2.4 mL). HOBT (0.01 mmol), EDC hydrochloride (0.13 mmol), triethylamine (0.13 mmol), and n-hexylamine (0.13 mmol) were added sequentially to the reaction flask and stirred overnight. Extracted with 1N aqueous HCl and dichloromethane. Organic layer concentrated and residue chromatographed on silica gel using 2% MeOH in dichloromethane as eluent. Product 2-(3,4-dichlorobenzyl)-3-oxo-N-hexyl-2,3-dihydro-[1,2,4]triazolo[4,3-a]pyridine-6-carboxamide was obtained as white solid.
Reaction SMILES: Cl[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])[C:5]([N+:18]([O-:20])=[O:19])=[CH:4][CH:3]=1.[CH:21]([O:24][C:25]1[NH:29][N:28]=[C:27]([NH2:30])[CH:26]=1)([CH3:23])[CH3:22].CCN(C(C)C)C(C)C>CCCCO>[F:17][C:14]1[CH:15]=[CH:16][C:11]([C@@H:9]([NH:8][C:6]2[C:5]([N+:18]([O-:20])=[O:19])=[CH:4][CH:3]=[C:2]([NH:30][C:27]3[CH:26]=[C:25]([O:24][CH:21]([CH3:23])[CH3:22])[NH:29][N:28]=3)[N:7]=2)[CH3:10])=[CH:12][CH:13]=1
Reactant: C[C@H](Nc1nc(Cl)ccc1[N+](=O)[O-])c1ccc(F)cc1
Reactant: CC(C)Oc1cc(N)n[nH]1
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)Oc1cc(Nc2ccc([N+](=O)[O-])c(N[C@@H](C)c3ccc(F)cc3)n2)n[nH]1
Temperature: 115 °C
Yield: 21.6 %

Procedure:
A mixture of (S)-6-chloro-N-(1-(4-fluorophenyl)ethyl)-3-nitropyridin-2-amine (Method 30, 1.08 g, 3.7 mmol), 5-isopropoxy-1H-pyrazol-3-amine (0.57 g, 4.0 mmol), and DIEA (0.80 ml, 4.6 mmol) in n-BuOH (10 ml) was heated in a sealed tube at 115° C. for 72 hours. The solvent was removed under reduced pressure and the residue was purified by chromatography (hexane-EtOAc=3:1) to give the title compound as a yellow solid (0.32 g, 22%). MS: Calcd.: 400. Found: [M+H]+ 401.