Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS(Cl)(=O)=O.[Cl:6][C:7]1[CH:11]=[C:10]([C:12]([OH:14])=O)[N:9]([C:15]2[C:20]([Cl:21])=[CH:19][CH:18]=[CH:17][N:16]=2)[N:8]=1.N1C=CC=CC=1.[NH2:28][C:29]1[C:37]([CH3:38])=[CH:36][C:35]([Cl:39])=[CH:34][C:30]=1[C:31](O)=[O:32]>C(#N)C.O>[Cl:39][C:35]1[CH:36]=[C:37]([CH3:38])[C:29]2[N:28]=[C:12]([C:10]3[N:9]([C:15]4[C:20]([Cl:21])=[CH:19][CH:18]=[CH:17][N:16]=4)[N:8]=[C:7]([Cl:6])[CH:11]=3)[O:14][C:31](=[O:32])[C:30]=2[CH:34]=1
Reactant: Cc1cc(Cl)cc(C(=O)O)c1N
Reactant: O=C(O)c1cc(Cl)nn1-c1ncccc1Cl
Agent: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: O
Solvent: CC#N
Product: Cc1cc(Cl)cc2c(=O)oc(-c3cc(Cl)nn3-c3ncccc3Cl)nc12
Temperature: -5 °C
Reaction time: 0.08 h

Procedure:
Methanesulfonyl chloride (1.0 mL, 1.5 g, 13 mmol) was dissolved in acetonitrile (10 mL), and the mixture was cooled to −5° C. A solution of 3-chloro-1-(3-chloro-2-pyridinyl)-1H-pyrazole-5-carboxylic acid (i.e. the carboxylic acid product of Example 3, Step D) (2.58 g, 10 mmol) and pyridine (1.4 mL, 1.4 g, 17 mmol) in acetonitrile (10 mL) was added dropwise over 5 minutes at −5 to 0° C. A slurry formed during the addition. The mixture was stirred 5 minutes at this temperature, and then 2-amino-3-methyl-5-chlorobenzoic acid (i.e. the product from Example 1, Step A) (1.86 g, 10 mmol) was added all at once. Then a solution of pyridine (2.8 mL, 2.7 g, 35 mmol) in acetonitrile (10 mL) was added dropwise in 5 min at −5 to 0° C. The mixture was stirred 15 minutes at −5 to 0° C., and then methanesulfonyl chloride (1.0 mL, 1.5 mL, 13 mmol) in acetonitrile (5 mL) was added dropwise in 5 min at −5 to 0° C. The reaction mixture was stirred 15 minutes at this temperature, then allowed to warm slowly to room temperature, and stirred 4 h. Water (15 mL) was added dropwise, and the mixture was stirred 15 minutes. Then the mixture was filtered, and the solids were washed with 2:1 acetonitrile-water (3×3 mL), then with acetonitrile (2×3 mL), and dried under nitrogen to afford the title product as a pale yellow powder, 3.83 g (94.0% crude yield), melting at 199-201° C. HPLC of the product using a Zorbax® RX-C8 chromatography column (4.6 mm×25 cm, eluent 25-95% acetonitrile/pH 3 water) showed a major peak corresponding to the title compound and having 97.8% of total chromatogram peak area.
Reaction SMILES: [C:1]([NH:4][CH:5]1[CH2:10][CH2:9][CH2:8][N:7]([C:11]2[C:20](F)=[C:19]3[C:14]([C:15](=[O:28])[C:16]([C:25]([OH:27])=[O:26])=[CH:17][N:18]3[CH:22]3[CH2:24][CH2:23]3)=[CH:13][C:12]=2[F:29])[CH2:6]1)(=[O:3])[CH3:2].[CH3:30][O-:31].[Na+]>CN(C)C=O>[C:1]([NH:4][CH:5]1[CH2:10][CH2:9][CH2:8][N:7]([C:11]2[C:20]([O:31][CH3:30])=[C:19]3[C:14]([C:15](=[O:28])[C:16]([C:25]([OH:27])=[O:26])=[CH:17][N:18]3[CH:22]3[CH2:23][CH2:24]3)=[CH:13][C:12]=2[F:29])[CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)NC1CCCN(c2c(F)cc3c(=O)c(C(=O)O)cn(C4CC4)c3c2F)C1
Reactant: C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1c(N2CCCC(NC(C)=O)C2)c(F)cc2c(=O)c(C(=O)O)cn(C3CC3)c12
Reaction time: 2 h

Procedure:
A mixture of 7-(3-acetamidopiperidin-1-yl)-1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (4.05 g), sodium methoxide (2.16 g) and N,N-dimethylformamide (120 ml) was stirred for 2 hours at 100°-140° C. The reaction mixture was concentrated in vacuumand water was added to the residue. The mixture was neutralized with 1N hydrochloric acid and the neutralized mixture was then concentrated in vacuum. Purification of the concentrated mixture by silica gel column chromatography (chloroform-methanol) gave 7-(3-acetamidopiperidin-1-yl)-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-4-oxoquinoline-3-carboxylic acid. m.p. 248°-250° C.
Reaction SMILES: [CH2:1]([O:8][CH:9](O)[CH3:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:12]=[O:13].[ClH:14]>>[CH2:1]([O:8][CH2:9][CH2:10][O:13][CH2:12][Cl:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cl
Reactant: CC(O)OCc1ccccc1
Reactant: C=O
Product: ClCOCCOCc1ccccc1

Procedure:
Following the procedure of Example 3, benzyloxyethanol is reacted with paraformaldehyde and hydrogen chloride gas furnishing (2-benzyloxyethoxy)methyl chloride.
Reaction SMILES: [C:1]1([S:7]([N:10]=[C:11]=[O:12])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:13]1([O:18][C:19]2[CH:20]=[C:21]([C@@H:27]([C:35]3[CH:41]=[CH:40][C:38]([NH2:39])=[CH:37][CH:36]=3)[CH2:28][C:29]3[CH:34]=[CH:33][N:32]=[CH:31][CH:30]=3)[CH:22]=[CH:23][C:24]=2[O:25][CH3:26])[CH2:17][CH2:16][CH2:15][CH2:14]1.CCOCC.[Cl:47]CCl>>[ClH:47].[CH:13]1([O:18][C:19]2[CH:20]=[C:21]([C@@H:27]([C:35]3[CH:36]=[CH:37][C:38]([NH:39][C:11]([NH:10][S:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)(=[O:8])=[O:9])=[O:12])=[CH:40][CH:41]=3)[CH2:28][C:29]3[CH:34]=[CH:33][N:32]=[CH:31][CH:30]=3)[CH:22]=[CH:23][C:24]=2[O:25][CH3:26])[CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: COc1ccc([C@H](Cc2ccncc2)c2ccc(N)cc2)cc1OC1CCCC1
Reactant: ClCCl
Reactant: O=C=NS(=O)(=O)c1ccccc1
Solvent: CCOCC
Product: COc1ccc([C@H](Cc2ccncc2)c2ccc(NC(=O)NS(=O)(=O)c3ccccc3)cc2)cc1OC1CCCC1
Product: Cl
Reaction time: 0.5 h

Procedure:
Benzenesulphonylisocyanate (205 μl) was added dropwise to a solution of 4-[1-(R)-(3-cyclopentyloxy-4-methoxyphenyl)-2-(4-pyridyl)ethyl]aniline (500 mg prepared as described in International Patent specification No. WO95/17386) in dichloromethane (10 ml) under nitrogen at room temperature. The mixture was stirred or 30 min at this temperature and the solvent then removed in vacuo to yield a yellow gum. Trituration with ether furnished a pale yellow solid (the free base of the title compound which was disolved in dichloromethane (5 ml) and treated with ethereal HCl to afford a yellow solid. Subsequent recrystallisation of the solid from methanol yielded the title compound (450 mg) as an off white solid δH (CD3OD) 1.40-1.90 (8H, br m), 3.64 (2H, d, J 9 Hz), 3.72 (3H, s), 4.34 (1H, t, J 9 Hz), 4.72 (1H, m), 6.75 (3H, d+d+s), 7.20 (4H, d+d), 7.50-7.75 (3H, m), 7.72 (2H, d, J 8 Hz), 8.00 (2H, d, J 8 Hz), and 8.55 (2H, d, J 8 Hz).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:21]=[CH:20][CH:19]=[CH:18][C:5]=1[C:6]([NH:8][N:9]1[CH:13]=[C:12]([CH3:14])[N:11]=[C:10]1[CH2:15][CH2:16][CH3:17])=[O:7])[CH3:2].C(=O)([O-])[O-].[Na+].[Na+].[I:28]I.C(OCC)(=O)C>O1CCOCC1.O>[CH2:1]([O:3][C:4]1[CH:21]=[CH:20][CH:19]=[CH:18][C:5]=1[C:6]([NH:8][N:9]1[C:13]([I:28])=[C:12]([CH3:14])[N:11]=[C:10]1[CH2:15][CH2:16][CH3:17])=[O:7])[CH3:2]
Reactant: CCCc1nc(C)cn1NC(=O)c1ccccc1OCC
Reactant: II
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Solvent: CCOC(C)=O
Product: CCCc1nc(C)c(I)n1NC(=O)c1ccccc1OCC
Temperature: 25 °C
Reaction time: 24 h

Procedure:
2-Ethoxy-N-(4-methyl-2-propylimidazol-1-yl)benzamide from Example D (3.5 g, 12.2 mmol) is dissolved in 480 ml of a dioxane/water mixture, and sodium carbonate (3.9 g, 36.6 mmol) and iodine (6.8 g, 26.8 mmol) are added. The mixture is stirred with exclusion of light at room temperature for 24 hours. 50 ml of ethyl acetate are added to the reaction mixture and washed twice with 50 ml of saturated sodium sulphite solution each time. The combined aqueous phases are re-extracted twice with 50 ml of ethyl acetate each time, and the combined organic phase is dried with sodium sulphate and concentrated in a rotary evaporator.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:16]1[C:21]([C:22]#[C:23][Si:24]([CH3:27])([CH3:26])[CH3:25])=[N:20][C:19](Br)=[CH:18][N:17]=1)[C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1>CN(C=O)C.CCOC(C)=O.O>[C:1]([O:5][C:6]([N:8]([C:16]1[C:21]([C:22]#[C:23][Si:24]([CH3:27])([CH3:26])[CH3:25])=[N:20][C:19]([N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)=[CH:18][N:17]=1)[C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1ncc(Br)nc1C#C[Si](C)(C)C
Reactant: C1CNCCN1
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1ncc(N2CCNCC2)nc1C#C[Si](C)(C)C
Temperature: 100 °C
Yield: 76.4 %

Procedure:
Tert-butyl N-tert-butoxycarbonyl-N-[5-bromo-3-((trimethylsilyl)ethynyl)pyrazin-2-yl]carbamate (640 mg, 1.360 mmol) was dissolved in DMF (5 mL) and treated with piperazine (351.4 mg, 4.080 mmol). The reaction was allowed to heat at 100° C. for 15 minutes and then allowed to cool to ambient temperature and diluted with EtOAc/water. The aqueous layer was extracted with EtOAc and the combined organics washed with water (2×) and brine (2×). This was dried (MgSO4), filtered and concentrated. The residue was purified by column chromatography (ISCO Companion™, 12 g column, 0-100% EtOAc/Petrol to 10% MeOH/DCM/1% NH4OH) to afford the title compound as a yellow oil (494 mg, 76% Yield). 1H NMR (400.0 MHz, DMSO) d 0.03 (s, 9H), 1.18 (s, 18H), 2.99 (m, 4H), 3.29 (m, 4H) and 7.88 (s, 1H) ppm; MS (ES+) 476.08
Reaction SMILES: [NH2:1][C:2]1[C:11]([Cl:12])=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[Br:13][CH2:14][C:15](=[O:21])[C:16]([O:18][CH2:19][CH3:20])=[O:17]>C(COC)OC>[Br-:13].[NH2:1][C:2]1[C:11]([Cl:12])=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N+:3]=1[CH2:14][C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[O:21]
Reactant: Nc1nc2ccccc2nc1Cl
Reactant: CCOC(=O)C(=O)CBr
Solvent: COCCOC
Product: CCOC(=O)C(=O)C[n+]1c(N)c(Cl)nc2ccccc21
Product: [Br-]

Procedure:
A solution of 9 g of 2-amino-3-chloro-quinoxaline [prepared by heating under pressure in ethanol, ammonia and 2,3-dichlorquinoxaline as taught by Saikachi et al (Chem. Pharm. Bull. Tokyo (1961), Vol. 9, P. 94)], 12 g of ethyl bromopyruvate and 180 ml of dimethoxyethane was stirred overnight and was then vacuum filtered to recover 5.33 g of a pale yellow crystalline solid. The filtrate stood in the refrigerator for several days to recover 1.20g and 3.62 g of the same compound for a total yield of 10.22 g of 2-amino-1-carbethoxycarbonylmethyl-3-chloro-quinoxalinium bromide.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([NH:12][C:13](=[O:30])[C:14]2[CH:19]=[CH:18][CH:17]=[N:16][C:15]=2[NH:20][C:21]2[CH:29]=[C:28]3[C:24]([CH:25]=[N:26][NH:27]3)=[CH:23][CH:22]=2)[CH:5]=[CH:6][C:7]=1[C:8]([CH3:11])([CH3:10])[CH3:9].[C:31]([N:38]1[CH2:43][CH2:42][C:41](=O)[CH2:40][CH2:39]1)([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32]>>[C:8]([C:7]1[CH:6]=[CH:5][C:4]([NH:12][C:13](=[O:30])[C:14]2[CH:19]=[CH:18][CH:17]=[N:16][C:15]=2[NH:20][C:21]2[CH:29]=[C:28]3[C:24]([CH:25]=[N:26][NH:27]3)=[CH:23][CH:22]=2)=[CH:3][C:2]=1[NH:1][CH:41]1[CH2:42][CH2:43][N:38]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:39][CH2:40]1)([CH3:11])([CH3:10])[CH3:9]
Reactant: CC(C)(C)c1ccc(NC(=O)c2cccnc2Nc2ccc3cn[nH]c3c2)cc1N
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Product: CC(C)(C)OC(=O)N1CCC(Nc2cc(NC(=O)c3cccnc3Nc3ccc4cn[nH]c4c3)ccc2C(C)(C)C)CC1

Procedure:
The title compound was prepared from N-(3-amino-4-tert-butyl-phenyl)-2-(1H-indazol-6-ylamino)-nicotinamide and Boc-piperidin-4-one by a method analogous to that described in Example 42. MS (ES+): 584 (M+H), Calc'd for C33H41N7O3—583.7.
Reaction SMILES: [CH2:1]([NH2:9])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl[C:11]1[C:12]2[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[S:23][C:13]=2[N:14]=[C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)[N:16]=1>>[N:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[C:15]1[N:16]=[C:11]([NH:9][CH2:1][CH2:2][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[C:12]2[CH:25]=[C:24]([C:26]([F:28])([F:29])[F:27])[S:23][C:13]=2[N:14]=1
Reactant: FC(F)(F)c1cc2c(Cl)nc(-c3ccccn3)nc2s1
Reactant: NCCc1ccccc1
Product: FC(F)(F)c1cc2c(NCCc3ccccc3)nc(-c3ccccn3)nc2s1

Procedure:
With the procedure of Example 1, the reaction of phenethylamine with 4-chloro-2-(pyridin-2-yl)-6-trifluoromethyl-thieno-[2,3-d]-pyrimidine yields 2-(pyridin-2-yl)-4-phenethylamino-6-trifluoromethyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[N:7][C:6]([CH3:9])=[C:5]2[O:10][C:11](=[O:14])[O:12][CH2:13][C:4]=12.CCOC(S)=[S:19]>>[SH:19][CH2:2][C:3]1[CH:8]=[N:7][C:6]([CH3:9])=[C:5]2[O:10][C:11](=[O:14])[O:12][CH2:13][C:4]=12
Reactant: Cc1ncc(CCl)c2c1OC(=O)OC2
Reactant: CCOC(=S)S
Product: Cc1ncc(CS)c2c1OC(=O)OC2

Procedure:
5-Chloromethyl-8-methyl-2-oxo-4H-m-dioxino[4,5-c]pyridine is converted to the corresponding ethyl xanthogenate and reduced in accordance with the procedure of Example 19, Step B, to give 5-mercaptomethyl-8-methyl-2-oxo-4H-m-dioxino[4,5-c]pyridine.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][NH:5][C:6]=1[Cl:7].[OH-:8].[K+].[Br:10][CH2:11][C:12]1[CH:25]=[CH:24][C:23]2[C:22](=[O:26])[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15](=[O:27])[C:14]=2[CH:13]=1>CN(C=O)C>[Br-:10].[CH3:11][C:12]1[CH:25]=[CH:24][C:23]2[C:22](=[O:26])[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15](=[O:27])[C:14]=2[C:13]=1[N+:3]1[C:2]([Cl:1])=[C:6]([Cl:7])[N:5]([C:13]2[C:14]3[C:15](=[O:8])[C:16]4[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=4)[C:22](=[O:26])[C:23]=3[CH:24]=[CH:25][C:12]=2[CH3:11])[CH:4]=1
Reactant: [OH-]
Reactant: O=C1c2ccccc2C(=O)c2cc(CBr)ccc21
Reactant: Clc1nc[nH]c1Cl
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ccc2c(c1-n1c[n+](-c3c(C)ccc4c3C(=O)c3ccccc3C4=O)c(Cl)c1Cl)C(=O)c1ccccc1C2=O
Product: [Br-]
Temperature: 80 °C

Procedure:
4,5-Dichloroimidazole (0.14 g, 1.0 mmol) and potassium hydroxide (0.06 g, 1.1 mmol) will be dissolved in the minimum volume of DMF in a high-pressure vessel. The solution will be heated at 80° C. for 30 min. The vessel will be removed from heat and 2-(bromomethyl)anthraquinone (1.20 g, 4.0 mmol) will be added. If not all solid dissolves, DMF will be added until all reactants are in solution. The vessel will be sealed and heated at 100° C. for 12 h. The volatile components will be removed under reduced pressure, and the remaining mixture washed with water to remove potassium bromide. The remaining solid will be collected and should be the product.
Reaction SMILES: [CH:1]([C:3]1[CH2:4][S:5][C@@H:6]2[CH:26]([NH:27][C:28](=[O:35])[CH2:29][C:30]3[S:31][CH:32]=[CH:33][CH:34]=3)[C:25](=[O:36])[N:7]2[C:8]=1[C:9]([O:11][CH:12]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10])=O.Cl.[C:38]([CH2:43][NH:44][NH2:45])([O:40][CH2:41][CH3:42])=[O:39]>O1CCCC1.O>[S:31]1[CH:32]=[CH:33][CH:34]=[C:30]1[CH2:29][C:28]([NH:27][CH:26]1[C:25](=[O:36])[N:7]2[C:8]([C:9]([O:11][CH:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)=[O:10])=[C:3]([CH:1]=[N:45][NH:44][CH2:43][C:38]([O:40][CH2:41][CH3:42])=[O:39])[CH2:4][S:5][C@H:6]12)=[O:35]
Reactant: O=CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)Cc3cccs3)[C@H]2SC1
Reactant: CCOC(=O)CNN
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)CNN=CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)Cc3cccs3)[C@H]2SC1
Reaction time: 48 h
Yield: 69.8 %

Procedure:
To a solution of diphenylmethyl 3-formyl-7-(2-thienylacetamido)-3-cephem-4-carboxylate (155 mg) in tetrahydrofuran (15 ml) is added a solution of carbethoxymethylhydrazine hydrochloride (69 mg) in water (2.5 ml), and the mixture is kept at room temperature for 2 days. The crystals obtained by concentration of the reaction mixture are collected by filtration, washed with ether and water, and dried to give diphenylmethyl 7-(2-thienylacetamido)-3-(2-carbethoxymethylhydrazono)methyl-3-cephem-4-carboxylate (129 mg). m.p. 70°-75° C. Yield: 69%. IR: νmaxNujol 3270, 1780, 1745, 1670; 1540cm-1. NMR: δd 6-DMSO (60MHz) 1.435 (6Hz) 3H, 3.52ABq (24; 17Hz) 2H, 3.48s2H, 3.60s2H, 4.17 quintet (6Hz) 2H, 4.95d(5Hz)1H, 5.70dd(8;4Hz)1H, 6.67-7.63m16H, 8.03s1H. [ α]D24.5 - 144° (c=0.340, CHCl3).
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:5][C@H:4]([CH2:6][OH:7])[CH2:3]1.[C:8](=O)([O:17]N1C(=O)CCC1=O)[O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(#N)C.CC(O)C>C(N(CC)CC)C>[OH:7][CH2:6][C@@H:4]1[CH2:5][C@H:2]([NH:1][C:8](=[O:17])[O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:3]1
Reactant: N[C@H]1C[C@@H](CO)C1
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Solvent: CC(C)O
Solvent: CC#N
Solvent: CCN(CC)CC
Product: O=C(N[C@H]1C[C@@H](CO)C1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 6.0 g of {cis-3-[(benzyloxy)methyl]cyclobutyl}amine, 2 g of 20% palladium hydroxide on carbon, 200 mL of methanol and 20 mL of acetic acid was stirred at room temperature under an atmosphere of hydrogen (balloon) for 24 h. The mixture was filtered to remove catalyst and concentrated under reduced pressure. Further drying under vacuum gave 6.5 g of the acetate salt of (cis-3-aminocyclobutyl)methanol as a thick resin. A mixture of 6.5 g of the acetate salt of (cis-3-aminocyclobutyl)methanol, 8 g of benzyl succinimidyl carbonate, 150 mL of anhydrous acetonitrile 15 mL of 2-propanol and 20 mL of triethylamine was stirred overnight at room temperature. The mixture was concentrated under reduced pressure and partitioned between 2×150 mL of ethyl acetate and 50 mL of water. The combined extracts were dried over magnesium sulfate and concentrated to dryness. Chromatography using a gradient of 25% to 75% ethyl acetate in hexane gave 10.8 g of product as a crystalline solid: MS (m+1)=236.3; 1H NMR (400 MHz, CDCl3) 7.37 (m, 5H), 5.18 (s, 2H), 4.92 (br s, 1H), 4.1 (m, 1H), 3.58 (s, 2H), 2.42 (dd, 2H), 2.1 (m, 1H), 1.7 (dd, 2H).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4](O)=[O:5].B.C(=O)([O-])[O-].[K+].[K+]>C1COCC1.O>[CH3:1][C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[CH2:4][OH:5]
Reactant: Cc1ccc([N+](=O)[O-])cc1C(=O)O
Agent: B
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc([N+](=O)[O-])cc1CO
Temperature: 25 °C
Reaction time: 18 h
Yield: 95.7 %

Procedure:
2-Methyl-5-nitrobenzoic acid (2.00 g, 11.0 mmol) was warmed under nitrogen, dissolved in anhydrous THF (25 mL), and treated with a 1N solution of borane in THF (16.5 mL). After stirring 18 hours at ambient temperature the reaction was quenched with a solution of potassium carbonate (1.8 g, 13 mmol) in water (50 mL), and the THF removed in vacuo. The remaining aqueous solution was extracted with DCM, and the organic layer washed with pH 7 buffer and brine, dried over sodium sulfate, and filtered. The evaporated filtrate gave the title compound as a pale yellow solid (1.76 g, 95%). 1H NMR (300 MHz, CDCl3) δ 8.29 (d, 1H, J=2.5 Hz), 8.04 (dd, 1H, J=8.3 Hz, 2.5 Hz), 7.31 (d, 1H, J=8.31 Hz), 4.77 (d, 2H, J=5.5 Hz), 2.41 (s, 3H), 2.09 (t, 1H, J=5.6 Hz).
Reaction SMILES: [O:1]1CCCO[CH:2]1[C:7]1[CH:8]=[CH:9][C:10]([C:13]2[S:21][C:20]3[C:15](=[N:16][CH:17]=[CH:18][C:19]=3[O:22][C:23]3[CH:28]=[CH:27][C:26]([NH:29][C:30]([NH:32][CH:33]4[CH2:35][CH2:34]4)=[O:31])=[CH:25][C:24]=3[F:36])[CH:14]=2)=[N:11][CH:12]=1>CC(C)=O.O.C(O)(C(F)(F)F)=O>[CH:33]1([NH:32][C:30]([NH:29][C:26]2[CH:27]=[CH:28][C:23]([O:22][C:19]3[CH:18]=[CH:17][N:16]=[C:15]4[CH:14]=[C:13]([C:10]5[CH:9]=[CH:8][C:7]([CH:2]=[O:1])=[CH:12][N:11]=5)[S:21][C:20]=34)=[C:24]([F:36])[CH:25]=2)=[O:31])[CH2:34][CH2:35]1
Reactant: O=C(Nc1ccc(Oc2ccnc3cc(-c4ccc(C5OCCCO5)cn4)sc23)c(F)c1)NC1CC1
Solvent: O=C(O)C(F)(F)F
Solvent: CC(C)=O
Solvent: O
Product: O=Cc1ccc(-c2cc3nccc(Oc4ccc(NC(=O)NC5CC5)cc4F)c3s2)nc1
Yield: 84.6 %

Procedure:
A suspension of 320 (0.65 g, 1.3 mmol) in 5:2:1 acetone/water/TFA (100 mL) was heated to reflux for 6 h. The mixture was then cooled and concentrated. The resulting solid residue was suspended in water, isolated by suction filtration, washed with ethyl acetate and dried in vacuo yielding 321 (0.49 g, 1.1 mmol, 85% yield) which was used without further purification in the next step. MS: 449.0 (M+H).
Reaction SMILES: [NH2:1][C@H:2]([C:6]([OH:8])=[O:7])[CH:3]([CH3:5])[CH3:4].[C:9](Cl)(=[O:27])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[S:16][S:17][C:18]1[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=1[C:20](Cl)=[O:21]>>[C:6]([CH:2]([NH:1][C:9]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[S:16][S:17][C:18]1[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=1[C:20]([NH:1][CH:2]([CH:3]([CH3:5])[CH3:4])[C:6]([OH:8])=[O:7])=[O:21])=[O:27])[CH:3]([CH3:5])[CH3:4])([OH:8])=[O:7]
Reactant: O=C(Cl)c1ccccc1SSc1ccccc1C(=O)Cl
Reactant: CC(C)[C@H](N)C(=O)O
Product: CC(C)C(NC(=O)c1ccccc1SSc1ccccc1C(=O)NC(C(=O)O)C(C)C)C(=O)O

Procedure:
Using the method employed in Preparation 30, 17.8 g (0.15 mol) of D,L valine was reacted with 17.2 g (0.05 mol) of 2,2'-dithiobisbenzoyl chloride to produce 11.4 g of the title compound after recrystallization from acetic acid, mp 226.5°-227.5° C.
Reaction SMILES: C=O.[C:3](O)(=O)C.[Cl:7][C:8]1[C:9]([N:34]2[CH2:39][CH2:38][CH:37]([C:40]([O:42][CH2:43][CH3:44])=[O:41])[CH2:36][CH2:35]2)=[N:10][CH:11]=[C:12]([C:14](=[O:33])[NH:15][C:16]2[S:17][C:18]([CH2:27][NH:28][CH:29]3[CH2:32][CH2:31][CH2:30]3)=[C:19]([C:21]3[S:22][CH:23]=[C:24]([Cl:26])[CH:25]=3)[N:20]=2)[CH:13]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)(Cl)Cl.ClCCCl>[Cl:7][C:8]1[C:9]([N:34]2[CH2:39][CH2:38][CH:37]([C:40]([O:42][CH2:43][CH3:44])=[O:41])[CH2:36][CH2:35]2)=[N:10][CH:11]=[C:12]([C:14](=[O:33])[NH:15][C:16]2[S:17][C:18]([CH2:27][N:28]([CH:29]3[CH2:32][CH2:31][CH2:30]3)[CH3:3])=[C:19]([C:21]3[S:22][CH:23]=[C:24]([Cl:26])[CH:25]=3)[N:20]=2)[CH:13]=1
Reactant: CCOC(=O)C1CCN(c2ncc(C(=O)Nc3nc(-c4cc(Cl)cs4)c(CNC4CCC4)s3)cc2Cl)CC1
Reactant: CC(=O)O
Agent: C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: ClC(Cl)Cl
Product: CCOC(=O)C1CCN(c2ncc(C(=O)Nc3nc(-c4cc(Cl)cs4)c(CN(C)C4CCC4)s3)cc2Cl)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
110 μl of a formaldehyde aqueous solution (35%) and 76 μl of acetic acid were added to 2 ml of 1.2-dichloroethane solution of 79 mg of ethyl 1-[3-chloro-5-({4-(4-chlorothiophen-2-yl)-5-[(cyclobutylamino)methyl]thiazol-2-yl}carbamoyl)-2-pyridyl]piperidine-4-carboxylate, and the mixture was stirred at room temperature for 1 hour. Subsequently, 45 mg of NaBH(OAc)3 was added, and the solution was stirred at room temperature for 1 hour. Chloroform was added to the reaction solution, and the organic layer was washed with a saturated sodium hydrogencarbonate aqueous solution, with water and with brine, and then dried over sodium sulfate. After the solvent was distilled off, the residue was purified by silica gel column chromatography (hexane:EtOAc=4:1 to 2:1) to obtain 58 mg of ethyl 1-{3-chloro-5-[(4-(4-chlorothiophen-2-yl)-5-{[cyclobutyl(methyl)amino]methyl}thiazol-2-yl)carbamoyl]-2-pyridyl}piperidine-4-carboxylate.