Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][NH:2][C:3]([CH3:15])([CH3:14])[CH2:4][NH:5][C:6](=[O:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH2:16](Br)[CH:17]=[CH2:18].C(=O)([O-])[O-].[Na+].[Na+].[I-].[Na+]>CCC(C)=O>[CH2:18]([CH2:1][NH:2][C:3]([CH3:15])([CH3:14])[CH2:4][NH:5][C:6](=[O:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH:17]=[CH2:16]
Reactant: CNC(C)(C)CNC(=O)c1ccccc1
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: CCC(C)=O
Product: C=CCCNC(C)(C)CNC(=O)c1ccccc1

Procedure:
A solution of N-[2-methylamino-2-methylpropyl]benzamide (1. g.,) in MEK (25 ml.) was added to a solution of allyl bromide (0.58 g.,) in MEK (25 ml.) containing sodium carbonate (0.55 g.,) and a few crystals of sodium iodide. The mixture was refluxed for 24 hrs. The inorganic solids were filtered off and the filtrant concentrated by evaporation under reduced pressure. The liquid residue was eluted down an alumina column with ethyl acetate to give N-[2-(allylmethylamino)-2-methylpropyl]benzamide 1.1 g.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]=[C:11]([O:14][Si](C)(C)C)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:19][B-](F)(F)F.F[B-](F)(F)F.ClC[N+]12CC[N+](F)(CC1)CC2>C(#N)C.[Cl-].[Na+].O>[F:19][CH:10]1[C:11](=[O:14])[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CC=C(O[Si](C)(C)C)CC1
Reactant: F[B-](F)(F)F
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Agent: [Cl-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(=O)C(F)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
4-Trimethylsilyloxy-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (13.2 g, 48.6 mmol) was dissolved in acetonitrile (250 mL). 1-Chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) (19.0 g, 53.5 mmol) was added and the reaction mixture was stirred at room temperature for 2 hours. Brine was added to the reaction mixture and the aqueous phase extracted ethyl acetate. The combined organic layers were dried over Na2SO4 and the solvent was evaporated. The residue was purified by flash chromatography (silica gel, 100 g, 0% to 100% EtOAc in heptane). The title compound was obtained as white solid (5.66 g, 53%).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1[C:13]([C:29](O)=[O:30])=[N:14][C:15]2[C:20]([CH:21]=1)=[CH:19][CH:18]=[C:17]([N:22]1[CH2:27][CH2:26][O:25][CH2:24][C:23]1=[O:28])[CH:16]=2)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:32][C:33]1[CH:34]=[N:35][CH:36]=[CH:37][C:38]=1[N:39]1[CH2:44][C@H:43]([CH3:45])[CH2:42][C@H:41]([NH:46]C(=O)OC(C)(C)C)[CH2:40]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.CCOC(C)=O.[OH-].[Na+]>[NH2:46][C@H:41]1[CH2:42][C@@H:43]([CH3:45])[CH2:44][N:39]([C:38]2[CH:37]=[CH:36][N:35]=[CH:34][C:33]=2[NH:32][C:29]([C:13]2[C:12]([NH:11][C:9](=[O:10])[O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[CH:21][C:20]3[C:15](=[CH:16][C:17]([N:22]4[CH2:27][CH2:26][O:25][CH2:24][C:23]4=[O:28])=[CH:18][CH:19]=3)[N:14]=2)=[O:30])[CH2:40]1
Reactant: O=C(Nc1cc2ccc(N3CCOCC3=O)cc2nc1C(=O)O)OCc1ccccc1
Reactant: C[C@@H]1C[C@H](NC(=O)OC(C)(C)C)CN(c2ccncc2N)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H]1C[C@H](N)CN(c2ccncc2NC(=O)c2nc3cc(N4CCOCC4=O)ccc3cc2NC(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 31.3 %

Procedure:
To a mixture of 3-{[(benzyloxy)carbonyl]amino}-7-(3-oxomorpholin-4-yl)quinoline-2-carboxylic acid (0.014 g, 0.033 mmol), tert-butyl [(3S,5R)-1-(3-aminopyridin-4-yl)-5-methylpiperidin-3-yl]carbamate (0.013 g, 0.043 mmol), HATU (0.034 g, 0.089 mmol) in DMF (0.30 mL), DIPEA (0.019 mL, 0.11 mmol) was added. The mixture was stirred at room temperature for 2 h. The mixture was diluted with 5 mL of EtOAc and 3 mL of 1 M NaOH. The layers were separated and the aqueous layer was extracted with EtOAc. The organic layers were combined and concentrated under reduced pressure. To the resulting residue, 1 mL of 4 M HCl in dioxane and 1 mL of MeOH were added. The mixture was stirred at room temperature for 1 h, then concentrated under reduced pressure. The resulting residue was purified by preparative HPLC (XBridge™ C18 column, eluting with a gradient of MeCN/water containing 0.1% NH4OH, at a flow rate of 60 mL/min.) to afford the sub-title compound (0.0063 g, 31%). LCMS calc. for C33H36N7O5 [M+H]+: m/z=610.3. found: 610.3.
Reaction SMILES: [Cl:1][C:2]1[CH:40]=[CH:39][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]([C:16]([C:18]3[N:19](COCC[Si](C)(C)C)[CH:20]=[C:21]([CH2:23][NH:24][C:25]4[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=4)[N:22]=3)=[O:17])=[CH:8]2)=[CH:4][CH:3]=1.[OH-].[Na+]>C(O)C.Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]([C:16]([C:18]3[NH:19][CH:20]=[C:21]([CH2:23][NH:24][C:25]4[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=4)[N:22]=3)=[O:17])=[CH:8]2)=[CH:39][CH:40]=1
Reactant: C[Si](C)(C)CCOCn1cc(CNc2cccnc2)nc1C(=O)c1cn(Cc2ccc(Cl)cc2)c2ccccc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(c1nc(CNc2cccnc2)c[nH]1)c1cn(Cc2ccc(Cl)cc2)c2ccccc12
Temperature: 25 °C
Yield: 54.2 %

Procedure:
A solution of [1-(4-chlorobenzyl)-1H-indol-3-yl]-[4-(pyridin-3-ylaminomethyl)-1-(2-trimethylsilanylethoxymethyl)-1H-imidazol-2-yl]methanone (43 mg, 7.52×10−5 mol) in ethanol (5 mL) and 2N HCl (5 mL) was heated to reflux for 2 h. The solution was allowed to cool to room temperature then neutralized with 2N NaOH. Solvent was removed under reduced pressure and ethyl acetate (50 mL) was added. The organic layer was washed with water, dried over MgSO4 and filtered. Solvent was removed under reduced pressure to produce a white powder (18 mg, 54%). 1H NMR; ESMS Calcd C25H20ClN5O 441.14, found: 442.2 (M+H)+.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:17]=[CH:16][CH:15]=[CH:14][C:4]=1[CH:5]([C:8]1[O:12][N:11]=[C:10]([CH3:13])[CH:9]=1)[O:6][CH3:7].O1CCCC1.Cl[C:24]1[C:29]([Cl:30])=[CH:28][C:27]([C:31]([F:34])([F:33])[F:32])=[CH:26][N:25]=1.[H-].[Na+]>CCOCC>[Cl:30][C:29]1[C:24]([O:1][CH2:2][C:3]2[CH:17]=[CH:16][CH:15]=[CH:14][C:4]=2[CH:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[CH:9]=2)[O:6][CH3:7])=[N:25][CH:26]=[C:27]([C:31]([F:33])([F:32])[F:34])[CH:28]=1
Reactant: COC(c1cc(C)no1)c1ccccc1CO
Reactant: FC(F)(F)c1cnc(Cl)c(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: COC(c1cc(C)no1)c1ccccc1COc1ncc(C(F)(F)F)cc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 86.1 %

Procedure:
To a mixture of 0.21 g (0.9 mmol) of 5-(2-hydroxymethyl-α-methoxybenzyl)-3-methylisoxazole, 3 ml of tetrahydrofuran and 0.29 g (1.35 mmol) of 2,3-dichloro-5-trifluoromethylpyridine was added 0.05 g (1.3 mmol) of 60% sodium hydride under ice-cooling and stirred at room temperature for 2 hours. After completion of the reaction, 100 ml of ether was added and washed with 80 ml of brine. The ether layer was dried over anhydrous magnesium and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (ethyl acetate/n-hexane) to give 5-[2-(3-chloro-5-trifluoromethyl-2-pyridyloxymethyl)-α-methoxybenzyl]-3-methylisoxazole (0.32 g, 86.1%) as colorless oil.
Reaction SMILES: Cl.[CH2:2]([N:9]1[C:17]2[C:12](=[CH:13][C:14]([NH:18][C:19]3[C:28]4[C:23](=[CH:24][C:25]([F:30])=[C:26](I)[CH:27]=4)[N:22]=[CH:21][N:20]=3)=[CH:15][CH:16]=2)[CH:11]=[N:10]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[O:31]1[CH2:35][CH2:34][O:33][CH:32]1[C:36]1[O:40][C:39]([Sn](CCCC)(CCCC)CCCC)=[CH:38][CH:37]=1>>[CH2:2]([N:9]1[C:17]2[C:12](=[CH:13][C:14]([NH:18][C:19]3[C:28]4[C:23](=[CH:24][C:25]([F:30])=[C:26]([C:39]5[O:40][C:36]([CH:32]6[O:33][CH2:34][CH2:35][O:31]6)=[CH:37][CH:38]=5)[CH:27]=4)[N:22]=[CH:21][N:20]=3)=[CH:15][CH:16]=2)[CH:11]=[N:10]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccc(C2OCCO2)o1
Reactant: Fc1cc2ncnc(Nc3ccc4c(cnn4Cc4ccccc4)c3)c2cc1I
Agent: Cl
Product: Fc1cc2ncnc(Nc3ccc4c(cnn4Cc4ccccc4)c3)c2cc1-c1ccc(C2OCCO2)o1

Procedure:
Prepared according to Procedure B from (1-benzyl-1H-indazol-5-yl)-(6-iodo-7-fluoro-quinazolin-4-yl)-amine hydrochloride and 5-(1,3-dioxolan-2-yl)-2-(tributylstannyl)furan. δ1H NMR (400 MHz, DMSO-d6) δ 10.27(s, 1H), 8.89(d, 1H), 8.46(s, 1H), 8.1(d, 2H), 7.69(d, 1H), 7.61(m, 2H), 7.26(m, 5H), 6.96(m, 1H), 6.74(d, 1H), 6.01 (s, 1H), 5.65(s, 2H), 4.09(m, 2H), 3.96(m, 2H). ESI-MS m/z 506(M−1).
Reaction SMILES: F[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH:11]1([OH:18])[CH2:16][CH2:15][CH:14]([OH:17])[CH2:13][CH2:12]1>>[N+:8]([C:7]1[C:2]([O:17][CH:14]2[CH2:15][CH2:16][CH:11]([OH:18])[CH2:12][CH2:13]2)=[N:3][CH:4]=[CH:5][CH:6]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1cccnc1F
Reactant: OC1CCC(O)CC1
Product: O=[N+]([O-])c1cccnc1OC1CCC(O)CC1

Procedure:
Prepared analogously to III.1 from 3.6 g 2-fluoro-3-nitropyridine and 2.9 g 1,4-cyclohexanediol
Reaction SMILES: S(Cl)([Cl:3])=O.O[CH2:6][C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][C:11]([O:21][CH3:22])=[C:12]([O:19][CH3:20])[C:13]=2[O:17][CH3:18])[N:8]=1>ClCCl>[Cl:3][CH2:6][C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][C:11]([O:21][CH3:22])=[C:12]([O:19][CH3:20])[C:13]=2[O:17][CH3:18])[N:8]=1
Reactant: O=S(Cl)Cl
Reactant: COc1cc2nc(CO)ccc2c(OC)c1OC
Solvent: ClCCl
Product: COc1cc2nc(CCl)ccc2c(OC)c1OC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Thionyl chloride (1.7 mL) was added to a solution of 2-hydroxymethyl-5,6,7-trimethoxyquinoline (1.45 g) in dichloromethane (15 mL) under ice cooling, and the mixture was stirred at room temperature for 30 minutes. After concentrating the reaction mixture under reduced pressure, an aqueous solution of potassium carbonate was added to the residue to alkalify it. The thus-treated residue was extracted with diethyl ether. The resultant organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (ethyl acetate:hexane=1:2) to obtain the title compound.
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[C:7]([CH3:12])[CH:8]=[CH:9][CH:10]=2)[C:5]([C:13]([OH:15])=[O:14])=[CH:4][N:3]=1.O=P(Cl)(Cl)[Cl:18]>>[Cl:18][C:2]1[C:11]2[C:6](=[C:7]([CH3:12])[CH:8]=[CH:9][CH:10]=2)[C:5]([C:13]([OH:15])=[O:14])=[CH:4][N:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1cccc2c(O)ncc(C(=O)O)c12
Product: Cc1cccc2c(Cl)ncc(C(=O)O)c12
Temperature: 0 °C
Yield: 86 %

Procedure:
A stirred solution of 1-hydroxy-5-methylisoquinolin-4-carboxylic acid (Intermediate-9) (600 mg, 3 mmol) in POCl3 (10 mL) was heated to 100° C. for 40-50 min. The reaction mixture was poured into ice-water, extracted with CH2Cl2 (2×100 mL), washed with water (2×100 mL), dried over Na2SO4, filtered and evaporated to give the desired compound (550 mg, 86%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]([CH:12]([CH3:14])[CH3:13])=[CH:10][C:9]([S:15](=[O:18])(=[O:17])[NH2:16])=[C:8]([CH3:19])[C:4]=1[C:5](O)=[O:6].S(Cl)([Cl:22])=O>CN(C)C=O.C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[C:11]([CH:12]([CH3:14])[CH3:13])=[CH:10][C:9]([S:15](=[O:18])(=[O:17])[NH2:16])=[C:8]([CH3:19])[C:4]=1[C:5]([Cl:22])=[O:6]
Reactant: O=S(Cl)Cl
Reactant: COc1c(C(C)C)cc(S(N)(=O)=O)c(C)c1C(=O)O
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: COc1c(C(C)C)cc(S(N)(=O)=O)c(C)c1C(=O)Cl
Reaction time: 1.5 h

Procedure:
72 g of 2-methoxy-3-isopropyl-5-sulphamoyl-6-methylbenzoic acid (0.25 mole), 250 ml of chloroform, 23 ml of thionyl chloride and 3 drops of dimethylformamide are placed in a 1 liter flask fitted with an agitator and a condenser. The mixture is heated to reflux for 1.5 hours, then 18 ml of thionyl chloride is added and the reflux is continued for 1.5 hours. The solids dissolve completely.
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]2[CH2:7][CH2:8][CH2:9][CH2:10][C:4]=2[C:3]=1[C:11]([O:13]CC)=O.C([O-])(=O)C.[NH4+].[CH:21]([NH2:23])=O>O>[N:1]1[C:2]2[S:6][C:5]3[CH2:7][CH2:8][CH2:9][CH2:10][C:4]=3[C:3]=2[C:11](=[O:13])[NH:23][CH:21]=1
Reactant: NC=O
Reactant: CCOC(=O)c1c(N)sc2c1CCCC2
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: O
Product: O=c1[nH]cnc2sc3c(c12)CCCC3
Temperature: 140 °C
Yield: 82.9 %

Procedure:
A mixture of ethyl 2-amino-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylate (0.7 g, 3.1 mmole), ammonium acetate (0.31 g, 4.04 mmole) and formamide (0.67 ml, 16.8 mmole), was stirred under reflux at 140° C. for 13 hours. It was then cooled, diluted with water (20 ml), extracted with ethyl acetate (3×35 ml), dried, concentrated and purified by column chromatography to obtain the pure 5,6,7,8-tetrahydrobenzothieno[2,3-d]pyrimidin-4(3H)-one of Formula (4-A09) (0.53 gm, 82%).
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([S:19]([NH:22][C:23]3[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=3)[C:26]([OH:28])=[O:27])(=[O:21])=[O:20])=[CH:16][CH:17]=2)[C:12]([NH:32][C:33]([NH2:35])=[NH:34])=[N:11][CH:10]=1.[H-].[Na+].ClC1[C:48]2[C:43](=[CH:44]C=C(S(NC3C=C(C=CC=3)C(OC(C)(C)C)=O)(=O)=O)C=2)[C:42](Cl)=CN=1.O>CS(C)=O>[Cl:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([S:19]([NH:22][C:23]3[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=3)[C:26]([O:28][C:43]([CH3:48])([CH3:44])[CH3:42])=[O:27])(=[O:20])=[O:21])=[CH:16][CH:17]=2)[C:12]([NH:32][C:33]([NH2:35])=[NH:34])=[N:11][CH:10]=1
Reactant: N=C(N)Nc1ncc(Cl)c2ccc(S(=O)(=O)Nc3cccc(C(=O)O)c3)cc12
Reactant: CC(C)(C)OC(=O)c1cccc(NS(=O)(=O)c2ccc3c(Cl)cnc(Cl)c3c2)c1
Agent: [H-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CS(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)c1cccc(NS(=O)(=O)c2ccc3c(Cl)cnc(NC(=N)N)c3c2)c1
Temperature: 60 °C
Yield: 22 %

Procedure:
3-{[(4-Chloro-1-guanidino-7-isoquinolinyl)sulphonyl]amino}benzoic acid trifluoroacetate ##STR11## Guanidine hydrochloride (140 mg, 1.47 mmol) was added in one portion to a suspension of NaH (44 mg, 80% dispersion by wt in mineral oil, 1.47 mmol) in DMSO (4.0 mL) and the mixture was heated at 60° C. under N2 for 30 min. A solution of tert-butyl 3-{[(1,4-dichloro-7-isoquinolinyl)-sulphonyl]amino}benzoate (280 mg, 0.59 mmol) in DMSO (2.0 mL) was added and the mixture heated at 90° C. for 18 h. The cooled mixture was poured into water (50 mL), extracted with EtOAc (×3) and the combined organic phase was then evaporated in vacuo. The residue was purified by column chromatography upon silica gel using CH2Cl2 -MeOH-0.880NH3 (97:3:0.3 to 95:5:0.5) as eluant to give tert-butyl 3-{[(4-chloro-1-guanidino-7-isoquinolinyl)sulphonyl]amino}benzoate (64 mg, 0.13 mmol) as a tan solid.
Reaction SMILES: Cl[C:2]1[C:3]([C:9]([OH:11])=[O:10])=[N:4][C:5](Cl)=[CH:6][CH:7]=1.[CH:12]1([SH:18])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1>>[CH:12]1([S:18][C:2]2[C:3]([C:9]([OH:11])=[O:10])=[N:4][C:5]([S:18][CH:12]3[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]3)=[CH:6][CH:7]=2)[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: SC1CCCCC1
Reactant: O=C(O)c1nc(Cl)ccc1Cl
Product: O=C(O)c1nc(SC2CCCCC2)ccc1SC1CCCCC1

Procedure:
The compound 3,6-bis(cyclohexylthio)-2-pyridinecarboxylic acid, m.p. 100°-101° C. was prepared by reacting 3,6-dichloro-2-pyridinecarboxylic acid and cyclohexyl mercaptan utilizing procedures substantially as described herein.
Reaction SMILES: C1(O[C:8](=[O:27])[NH:9][C:10]2[S:11][C:12]3[C:13]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)=[N:14][CH:15]=[C:16]([O:19][CH3:20])[C:17]=3[N:18]=2)C=CC=CC=1.[CH3:28][NH:29][C@H:30]1[CH2:35][CH2:34][C@H:33]([OH:36])[CH2:32][CH2:31]1>ClC(Cl)C.O1CCCC1>[OH:36][C@H:33]1[CH2:34][CH2:35][C@H:30]([N:29]([CH3:28])[C:8]([NH:9][C:10]2[S:11][C:12]3[C:13]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)=[N:14][CH:15]=[C:16]([O:19][CH3:20])[C:17]=3[N:18]=2)=[O:27])[CH2:31][CH2:32]1
Reactant: CN[C@H]1CC[C@H](O)CC1
Reactant: COc1cnc(N2CCOCC2)c2sc(NC(=O)Oc3ccccc3)nc12
Solvent: CC(Cl)Cl
Solvent: C1CCOC1
Product: COc1cnc(N2CCOCC2)c2sc(NC(=O)N(C)[C@H]3CC[C@H](O)CC3)nc12

Procedure:
From (7-methoxy-4-morpholin-4-yl-thiazolo[5,4-c]pyridin-2-yl)-carbamic acid phenyl ester with trans-4-Methylamino-cyclohexanol in dichloroethane and tetrahydrofuran. ES-MS m/e (%): 422 (M+H+, 100).
Reaction SMILES: C([O-])=O.Cl[C:5]1C=CC(C=O)=C[CH:6]=1.[CH2:13]([O:15][C:16]([N:18]1[CH2:23][CH2:22][CH:21]([NH:24][S:25]([C:28]2[C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[C:31]([CH2:38][NH:39][CH:40]3[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]3)=[CH:30][CH:29]=2)(=[O:27])=[O:26])[CH2:20][CH2:19]1)=[O:17])[CH3:14].C(OC(N1CCC(NS(C2C3C(=CC=CC=3)C(CN)=CC=2)(=O)=O)CC1)=O)C>>[CH2:13]([O:15][C:16]([N:18]1[CH2:19][CH2:20][CH:21]([NH:24][S:25]([C:28]2[C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[C:31]([CH2:38][N:39]([CH:40]3[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]3)[CH2:5][CH3:6])=[CH:30][CH:29]=2)(=[O:27])=[O:26])[CH2:22][CH2:23]1)=[O:17])[CH3:14]
Reactant: O=Cc1ccc(Cl)cc1
Reactant: CCOC(=O)N1CCC(NS(=O)(=O)c2ccc(CNC3CCCCC3)c3ccccc23)CC1
Agent: CCOC(=O)N1CCC(NS(=O)(=O)c2ccc(CN)c3ccccc23)CC1
Agent: O=C[O-]
Product: CCOC(=O)N1CCC(NS(=O)(=O)c2ccc(CN(CC)C3CCCCC3)c3ccccc23)CC1

Procedure:
The title compound was prepared as its formate salt following the general procedure in Scheme 13, substituting acetaldehyde for 4-chloro-benzaldehyde, and substituting 4-(4-cyclohexylaminomethyl-naphthalene-1-sulfonylamino)-piperidine-1-carboxylic acid ethyl ester (G-8) for 4-(4-aminomethyl-naphthalene-1-sulfonylamino)-piperidine-1-carboxylic acid ethyl ester. 1H NMR (300 MHz, MeOD) δ 8.79 (m, 1H), 8.36 (m, 2H), 8.27 (dd, 1H), 7.77 (m, 3H), 4.62 (s, 2H), 4.05 (q, 2H), 3.80 (d, 2H), 3.25 (m, 1H), 3.05 (m, 3H), 2.75 (m, 2H), 2.10 (d, 2H), 1.80 (d, 2H), 1.65 (m, 3H), 1.48 (m, 2H), 1.22 (m, 11H); LC/MS m/z 502 (M+H)+
Reaction SMILES: N#N.[CH3:3][C:4]1[O:5][C:6]([C:12]2[CH:13]=[C:14]([CH3:18])[CH:15]=[CH:16][CH:17]=2)=[C:7]([C:9]([OH:11])=O)[N:8]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.CCN(C(C)C)C(C)C.Cl.[NH2:51][C:52]1[N:53]=[C:54]([CH2:57][C:58]2[O:62][C:61]([C:63](=[O:65])[CH3:64])=[CH:60][CH:59]=2)[S:55][CH:56]=1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:63]([C:61]1[O:62][C:58]([CH2:57][C:54]2[S:55][CH:56]=[C:52]([NH:51][C:9]([C:7]3[N:8]=[C:4]([CH3:3])[O:5][C:6]=3[C:12]3[CH:13]=[C:14]([CH3:18])[CH:15]=[CH:16][CH:17]=3)=[O:11])[N:53]=2)=[CH:59][CH:60]=1)(=[O:65])[CH3:64]
Reactant: Cc1cccc(-c2oc(C)nc2C(=O)O)c1
Reactant: CC(=O)c1ccc(Cc2nc(N)cs2)o1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(=O)c1ccc(Cc2nc(NC(=O)c3nc(C)oc3-c3cccc(C)c3)cs2)o1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of 2-methyl-5-m-tolyl-oxazole-4-carboxylic acid (50 mg, 0.23 mmol) in CH2Cl2 (2.3 mL) was treated sequentially with DMAP (7 mg, 0.06 mmol), HOBt (37 mg, 0.28 mmol), EDC.HCl (110 mg, 0.58 mmol) and DIPEA (0.16 mL, 0.92 mmol) and the resulting mixture was stirred at rt for 1 h. This solution was then treated with 1-[5-(4-amino-thiazol-2-ylmethyl)-furan-2-yl]-ethanone hydrochloride (51 mg, 0.23 mmol) and the reaction mixture was stirred for 16 h at rt. CH2Cl2 (20 mL) was then added and the org. phase was washed with water (15 mL) and brine (15 mL). The org. phase was then dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the residue by FC (1:1 hept:EA) gave the title compound as an orange oil. TLC: rf (1:1 hept-EA)=0.28. LC-MS-conditions 02: tR=1.11 min, [M+H]+=421.93.
Reaction SMILES: [F:1][C:2]([F:28])([F:27])[C@@H:3]([C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH2:25][CH2:24][C:14]3([CH2:23][CH2:22][C:17]4(OCC[O:18]4)[CH2:16][CH2:15]3)[C:13]2=[O:26])=[CH:8][CH:7]=1)[O:4][CH3:5].Cl.C([O-])([O-])=O.[Na+].[Na+]>O1CCCC1>[F:28][C:2]([F:1])([F:27])[C@@H:3]([C:6]1[CH:7]=[CH:8][C:9]([N:12]2[CH2:25][CH2:24][C:14]3([CH2:23][CH2:22][C:17](=[O:18])[CH2:16][CH2:15]3)[C:13]2=[O:26])=[CH:10][CH:11]=1)[O:4][CH3:5]
Reactant: CO[C@H](c1ccc(N2CCC3(CCC4(CC3)OCCO4)C2=O)cc1)C(F)(F)F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CO[C@H](c1ccc(N2CCC3(CCC(=O)CC3)C2=O)cc1)C(F)(F)F
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 99.6 %

Procedure:
10-[4-((R)-2,2,2-Trifluoro-1-methoxy-ethyl)-phenyl]-1,4-dioxa-10-aza-dispiro[4.2.4.2]tetradecan-9-one (1.41 g) was dissolved in tetrahydrofuran (35.0 mL). Then hydrochloric acid (2M, 21.2 mL) was added dropwise over a period of 15 minutes to the reaction mixture. The mixture was stirred for 4.5 hours at RT and was then poured into ice/water and basified with saturated Na2CO3 solution. The aqueous phase was then extracted two times with ethyl acetate and the organic layers were washed brine, dried over Na2SO4, filtered and the solvent was evaporated. The crude material was purified by flash chromatography (gradient of ethyl acetate in heptane) to provide the title compound as a colorless solid (1.25 g). MS (ESI): 356.1 (MH+).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[CH:8][C:9]([N+:16]([O-])=O)=[C:10]([CH:15]=1)[C:11]([O:13][CH3:14])=[O:12]>[Pd].CO>[NH2:16][C:9]1[CH:8]=[CH:7][C:6]([O:5][CH2:4][CH2:3][O:2][CH3:1])=[CH:15][C:10]=1[C:11]([O:13][CH3:14])=[O:12]
Reactant: COCCOc1ccc([N+](=O)[O-])c(C(=O)OC)c1
Agent: [Pd]
Solvent: CO
Product: COCCOc1ccc(N)c(C(=O)OC)c1
Reaction time: 0.5 h
Yield: 100 %

Procedure:
To methyl 5-(2-methoxyethoxy)-2-nitrobenzoate (1.08 g, 4.2 mmol) under argon was added 10% Palladium on carbon and MeOH (20 mL). The flask was flushed with H2(g) and stirred under H2 (1 atm) for 30 minutes. The mixture was filtered through Celite and concentrated in vacuo to give methyl 2-amino-5-(2-methoxyethoxy)benzoate (964 mg, 4.2 mmol, 100%). LC-MS (ESI) m/z 226 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([NH:8][NH2:9])=[O:7])=[CH:4][CH:3]=1.S(O)(O)(=O)=O.C[NH:18][C:19](=[NH:21])S.[OH-].[Na+].O>CO>[C:19]([NH:9][NH:8][C:6](=[O:7])[C:5]1[CH:10]=[CH:11][C:2]([Cl:1])=[CH:3][CH:4]=1)(=[NH:18])[NH2:21]
Reactant: NNC(=O)c1ccc(Cl)cc1
Reactant: CNC(=N)S
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: N=C(N)NNC(=O)c1ccc(Cl)cc1
Temperature: 60 °C
Reaction time: 96 h
Yield: 104.7 %

Procedure:
The synthesis was carried out according to the method of Example 1-(1). 4-Chlorobenzoic acid hydrazide (34.8 g), methylisothiourea sulfate (115.4 g), sodium hydroxide (17.1 g), water (440 ml) and methanol (700 ml) were used as reagents. The mixture was stirred for 4 days at 60° C. to give 45.4 g of a pale-brown solid which was a mixture of a hydrazide compound and the objective compound.
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[OH:11][CH2:12][CH:13]1[CH2:16][CH:15]([CH2:17][O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:14]1.CCN(CC)CC>C(Cl)Cl>[CH2:19]([O:18][CH2:17][C@@H:15]1[CH2:16][C@H:13]([CH:12]=[O:11])[CH2:14]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: OCC1CC(COCc2ccccc2)C1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: O=C[C@H]1C[C@@H](COCc2ccccc2)C1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
In a 25 mL flask, a solution of dry DMSO (0.2 mL, 2.76 mmol) in 7 mL dry CH2Cl2 was cooled to −78° C., after which oxalyl chloride (0.12 mL, 1.37 mmol) was added drop by drop under argon. After stirring at −78° C. for 30 min, a CH2Cl2 solution of 1-hydroxymethyl-3-benzyloxymethyl-cyclobutane (cis/trans=2/1, 0.2 g, 0.97 mmol) was added drop by drop. After stirring for 1 hr, Et3N (0.7 mL, 4.9 mmol) was added dropwisely. After 15 min, the reaction was warmed to ambient temperature. After 4 hr, TLC showed no starting material. Then the reaction mixture was diluted with 30 mL CH2Cl2, washed with 30% aqueous NH4Cl (2×10 mL), H2O (1×10 mL) and brine (1×10 mL). The organic phase was dried over MgSO4 and the solvents were removed to give an oily product, which was purified by silica gel chromatography ((Hexane:EtOAc=9:1) to give the cis-diastereomer (74 mg, 37.4%, Rf=0.43 (Hexane:EtOAc=12:1)) as a colorless oil. 1H NMR (CDCl3, 400 MHz): δ 2.01-2.08 (m, 2H), 2.21-2.28 (m, 2H), 2.58-2.70 (m, 1H), 3.03-3.12 (m, 1H), 3.37-3.39 (d, J=8.0, 2H), 4.49 (s, 2H), 7.25-7.36 (m, 5H), 9.66-9.67 (d, J=4.0, 1H). MS (FAB): expected for C13H16O2 (M−H)+ 203.26. Found 203.10658. IR (neat) νmax 3054, 2935, 2858, 1704, 1454, 1266, 1092, 738, 704.