Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](Cl)[N:5]=[CH:4][N:3]=1.[F:9][C:10]([F:21])([F:20])[C:11]1[CH:16]=[CH:15][C:14](B(O)O)=[CH:13][CH:12]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(#N)C>[Cl:1][C:2]1[CH:7]=[C:6]([C:14]2[CH:15]=[CH:16][C:11]([C:10]([F:21])([F:20])[F:9])=[CH:12][CH:13]=2)[N:5]=[CH:4][N:3]=1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: Clc1cc(Cl)ncn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: FC(F)(F)c1ccc(-c2cc(Cl)ncn2)cc1
Temperature: 80 °C

Procedure:
To a 500-mL, round-bottomed flask was added 4,6-dichloropyrimidine (14 g, 95 mmol, Aldrich), 4-(trifluoromethyl)phenylboronic acid (6.0 g, 32 mmol, Aldrich), acetonitrile (95 mL) and 1 M aq sodium carbonate (95 mL). The mixture was deoxygenated by sparging with N2 for 15 min. The catalyst, Pd(PPh3)4 (1.9 g, 1.6 mmol, Strem), was added and the yellow mixture was heated at 80° C. for 15 h. After cooling to 25° C., the solution was concentrated to remove the acetonitrile. The solution was diluted with aq NaHCO3 and extracted with CH2Cl2. The combined extracts were dried over Na2SO4, filtered and concentrated in vacuo. Purification by silica gel chromatography with gradient from 1.5% to 10% solution of ethyl acetate in hexane afforded the title compound as a white solid. MS (ESI, pos. ion) m/z: 259 (M+1).
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[C:9](=[O:16])[NH:8][C:7]2[CH:17]=[CH:18][CH:19]=[CH:20][C:6]1=2)=[O:4].[N:21]1([CH2:26][CH:27]2[CH2:32][CH2:31][CH2:30][CH2:29][NH:28]2)[CH2:25][CH2:24][CH2:23][CH2:22]1>C(O)(C)C>[N:21]1([CH2:26][CH:27]2[CH2:32][CH2:31][CH2:30][CH2:29][N:28]2[CH2:2][C:3]([N:5]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[C:9](=[O:16])[NH:8][C:7]3[CH:17]=[CH:18][CH:19]=[CH:20][C:6]2=3)=[O:4])[CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: C1CCC(CN2CCCC2)NC1
Reactant: O=C1Nc2ccccc2N(C(=O)CCl)c2ccccc21
Solvent: CC(C)O
Product: O=C1Nc2ccccc2N(C(=O)CN2CCCCC2CN2CCCC2)c2ccccc21

Procedure:
The title compound is prepared analogously to Example 2 from 5-(chloroacetyl)-5,10-dihydro-11H-dibenzo[b,e][1,4]diazepin-11-one and 2-[(1-pyrrolidinyl)methyl]piperidine to give colorless crystals, mp. 199°-201° C. (isopropanol/activated charcoal).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([S:8][C:9]2[CH:14]=[N:13][CH:12]=[CH:11][N:10]=2)[CH:5]=[C:4]([CH3:15])[C:3]=1[C:16]1[N:17]=[C:18]([NH2:21])[S:19][CH:20]=1.C(N(CC)CC)C.Cl.[C:30](Cl)(=[O:37])[C:31]1[CH:36]=[CH:35][N:34]=[CH:33][CH:32]=1>C(Cl)Cl>[CH3:15][C:4]1[CH:5]=[C:6]([S:8][C:9]2[CH:14]=[N:13][CH:12]=[CH:11][N:10]=2)[CH:7]=[C:2]([CH3:1])[C:3]=1[C:16]1[N:17]=[C:18]([NH:21][C:30](=[O:37])[C:31]2[CH:36]=[CH:35][N:34]=[CH:33][CH:32]=2)[S:19][CH:20]=1
Reactant: Cc1cc(Sc2cnccn2)cc(C)c1-c1csc(N)n1
Reactant: O=C(Cl)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(Sc2cnccn2)cc(C)c1-c1csc(NC(=O)c2ccncc2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 58.5 %

Procedure:
To a solution of 4-(2,6-dimethyl-4-(pyrazin-2-ylthio)phenyl)thiazol-2-amine (11-5, 500 mg, 1.6 mmol) in CH2Cl2 (10.0 ml) was added triethylamine (0.7 ml, 4.0 mmol) followed by isonicotinoyl chloride hydrochloride (707.7 mg, 4.8 mmol). The reaction mixture was stirred at room temperature overnight. The solution was concentrated under reduced pressure and added with hot water. The resultant precipitate was filtered and dried under vacuum to give N-{4-(2,6-dimethyl-4-(pyrazin-2-ylthio)phenyl)thiazol-2-yl}isonicotinamide (11, 392.5 mg) as white solids in 59% yield: 1H NMR (500 MHz, DMSO-d) δ 13.1 (s, 1 H), 8.81 (d, J=5.7 Hz, 2 H), 8.50 (s, 1 H), 8.41 (s, 1 H), 8.36 (s, 1H), 8.00 (d, J=5.7 Hz, 2 H), 7.41 (s, 2 H), 7.30 (s, 1 H), 2.13 (s, 6 H). ESI-MS: m/z 420.2 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[C@@H:4]([NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1.[CH3:22][C:23]1[C:28]([CH3:29])=[C:27](B(O)O)[CH:26]=[CH:25][N:24]=1.O.CCOC(C)=O>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:21])[C@@H:4]([NH:13][C:14]([O:16][C:17]([CH3:18])([CH3:20])[CH3:19])=[O:15])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][C:27]2[CH:26]=[CH:25][N:24]=[C:23]([CH3:22])[C:28]=2[CH3:29])=[CH:8][CH:7]=1
Reactant: Cc1nccc(B(O)O)c1C
Reactant: COC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OC(C)(C)C
Solvent: O
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COC(=O)[C@H](Cc1ccc(Oc2ccnc(C)c2C)cc1)NC(=O)OC(C)(C)C
Yield: 4.4 %

Procedure:
A mixture of 304 mg of (S)-2-tert-butoxycarbonylamino-3-(4-hydroxy-phenyl)-propionic acid methyl ester, 314 mg 2,3-dimethylpyridine-4-boronic acid, 374 mg cupric acetate, and 2 grams of powdered 4 Å molecular sieves in 50 mL dry DCM and 0.75 mL TEA was stirred vigorously at rt under an O2 atmosphere for 40 h. The mixture was then poured into water-EtOAc. The organic layer was washed with water and saturated brine, dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography (DCM-EtOAc) to provide (S)-2-tert-Butoxycarbonylamino-3-[4-(2,3-dimethyl-pyridin-4-yloxy)-phenyl]-propionic acid methyl ester (18 mg). LCMS (m/z) 401.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][NH2:12])=[CH:6][CH:5]=1)([O-:3])=[O:2].Cl[CH2:14][O:15][CH:16]=[O:17]>C(Cl)Cl.CO>[CH3:14][O:15][C:16](=[O:17])[NH:12][CH2:11][CH2:10][C:7]1[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=1
Reactant: O=COCCl
Reactant: NCCc1ccc([N+](=O)[O-])cc1
Solvent: ClCCl
Solvent: CO
Product: COC(=O)NCCc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.1 %

Procedure:
To a stirred solution of [2-(4-nitrophenyl)ethyl]amine (6.06 g, 30 mmol) in CH2Cl2 (75 ml), MeOH (5 ml), and TEA (9.5 ml) at 0° C. was added chloromethylformate (3.39 g, 36 mmol) dropwise. The reaction mixture was stirred at room temperature for 1 hour concentrated in vacuo, and partitioned between ethyl acetate and water, and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with water (50 mL), brine (50 mL), dried (MgSO4), filtered and concentrated under reduced pressure to afford a yellow solid (6.6 g, 98%). Mp: 38° C., MS (ES−): 223 (M−H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:10]([Br:11])=[C:9]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[N:8]([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)[C:7]=1[CH2:26]Br)=[O:5])[CH3:2].[CH2:28]([O:30][C:31](=[O:41])[CH2:32][NH:33][C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH3:29]>>[CH2:1]([O:3][C:4]([C:6]1[C:10]([Br:11])=[C:9]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[N:8]([C:19]2[CH:20]=[CH:21][C:22]([F:25])=[CH:23][CH:24]=2)[C:7]=1[CH2:26][N:33]([C:34]([O:36][C:37]([CH3:38])([CH3:40])[CH3:39])=[O:35])[CH2:32][C:31]([O:30][CH2:28][CH3:29])=[O:41])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(Br)c(-c2ccc(F)cc2)n(-c2ccc(F)cc2)c1CBr
Reactant: CCOC(=O)CNC(=O)OC(C)(C)C
Product: CCOC(=O)CN(Cc1c(C(=O)OCC)c(Br)c(-c2ccc(F)cc2)n1-c1ccc(F)cc1)C(=O)OC(C)(C)C

Procedure:
Prepared in analogy to that of Example 1(c) from 4-bromo-2-bromomethyl-1,5-bis-(4-fluoro-phenyl)-1H-pyrrole-3-carboxylic acid ethyl ester and tert-butoxycarbonylamino-acetic acid ethyl ester. The title compound, ESI MS (m/z): 643 (M+Na+).
Reaction SMILES: [C:1]([O:5][C:6](=[O:47])[NH:7][CH:8]([CH2:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][C:28]2[CH:33]=[CH:32][C:31]([CH2:34][CH2:35][C:36](=[O:46])[NH:37][O:38]CC3C=CC=CC=3)=[CH:30][CH:29]=2)=[CH:23][CH:22]=1)[C:9]([N:11]1[CH2:16][CH2:15][N:14]([C:17](=[O:19])[CH3:18])[CH2:13][CH2:12]1)=[O:10])([CH3:4])([CH3:3])[CH3:2].[H][H]>CO.[Pd]>[C:1]([O:5][C:6](=[O:47])[NH:7][CH:8]([CH2:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][C:28]2[CH:29]=[CH:30][C:31]([CH2:34][CH2:35][C:36](=[O:46])[NH:37][OH:38])=[CH:32][CH:33]=2)=[CH:23][CH:22]=1)[C:9]([N:11]1[CH2:12][CH2:13][N:14]([C:17](=[O:19])[CH3:18])[CH2:15][CH2:16]1)=[O:10])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(=O)N1CCN(C(=O)C(Cc2ccc(Oc3ccc(CCC(=O)NOCc4ccccc4)cc3)cc2)NC(=O)OC(C)(C)C)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CC(=O)N1CCN(C(=O)C(Cc2ccc(Oc3ccc(CCC(=O)NO)cc3)cc2)NC(=O)OC(C)(C)C)CC1
Yield: 103.3 %

Procedure:
Palladium on BaSO4 (5%, 0.4 g) was added to a degassed solution of the benzyl hydroxamate 20 (0.9 g) in MeOH (75 mL) and the suspension was treated with hydrogen at atmospheric pressure for 6 h. The suspension was filtered over a Celite® bed and concentrated to yield the desired hydroxamate 21 (˜0.8 g, quantitative yield). 1H NMR (400 MHz, DMSO-d6): 10.38 (s, 1H), 8.72 (s, 1H), 7.24 (d, J=8.0 Hz, 2H), 7.16 (d, J=8.8 Hz, 2H), 6.88 (d, J=7.6 Hz, 2H), 6.83 (d, J=8.4 Hz, 2H), 4.58 (m, 1H) 3.10-3.45 (m, 8H), 2.76-2.85 (m, 4H), 2.24 (t, J=7.2 Hz, 2H), 2.00 (s, 3H), 1.32 (s, 9H).
Reaction SMILES: Cl[C:2]1[N:11]=[CH:10][C:9]2[N:8]3[CH:12]=[N:13][N:14]=[C:7]3[C@@H:6]([CH2:15][CH3:16])[N:5]([CH:17]3[CH2:21][CH2:20][CH2:19][CH2:18]3)[C:4]=2[N:3]=1.[CH:22]1([NH2:25])[CH2:24][CH2:23]1.CCN(C(C)C)C(C)C>C(O)CCC>[CH:17]1([N:5]2[C:4]3[N:3]=[C:2]([NH:25][CH:22]4[CH2:24][CH2:23]4)[N:11]=[CH:10][C:9]=3[N:8]3[CH:12]=[N:13][N:14]=[C:7]3[C@H:6]2[CH2:15][CH3:16])[CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: NC1CC1
Reactant: CC[C@@H]1c2nncn2-c2cnc(Cl)nc2N1C1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: CC[C@@H]1c2nncn2-c2cnc(NC3CC3)nc2N1C1CCCC1

Procedure:
(R)-7-chloro-5-cyclopentyl-4-ethyl-4,5-dihydro-[1,2,4]triazolo[4,3-f]pteridine (70 mg, 0.23 mmol), cyclopropylamine (0.5 ml, 7.18 mmol), DIPEA (0.16 ml, 0.918 mmol) in nBuOH (2 ml) were heated in a sealed tube in the microwave at 140° C. for 90 minutes. The reaction mixture was concentrated in vacuo, and purified by reverse phase preparative HPLC [Waters Sunfire C18, 10 M, 100 Å column, gradient 10%-95% B (solvent A: 0.05% TFA in water; solvent B: CH3CN) over 16 minutes at 25 mL/min] to afford the title compound as an off-white powder. The free base was generated using a bicarbonate resin, and was freeze-dried to give the title compound as a colourless solid (25.6 mg, 34% yield)
Reaction SMILES: [CH2:1]1[O:11][C:10]2[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][C:3]=2[O:2]1.[Cl:12][C:13]1[N:14]=[C:15](Cl)[C:16]2[CH:21]=[C:20]([CH2:22][CH3:23])[S:19][C:17]=2[N:18]=1>>[Cl:12][C:13]1[N:14]=[C:15]([NH:7][CH2:6][C:5]2[CH:8]=[CH:9][C:10]3[O:11][CH2:1][O:2][C:3]=3[CH:4]=2)[C:16]2[CH:21]=[C:20]([CH2:22][CH3:23])[S:19][C:17]=2[N:18]=1
Reactant: CCc1cc2c(Cl)nc(Cl)nc2s1
Reactant: NCc1ccc2c(c1)OCO2
Product: CCc1cc2c(NCc3ccc4c(c3)OCO4)nc(Cl)nc2s1

Procedure:
Following the procedure of Example 1, the reaction of 3,4-methylenedioxybenzylamine with 2,4-dichloro-6-ethyl-thieno-[2,3-d]-pyrimidine gives 2-chloro-6-ethyl-4-(3,4-methylenedioxybenzylamino)-thieno-[2,3-d]-pyrimidine Mp. 148° C.
Reaction SMILES: [Cl:1][C:2]1[NH:3][C:4]([Cl:25])=[C:5]([Cl:24])[C:6]=1[C:7](=[O:23])[C:8]1[CH:13]=[C:12]([C:14]([CH3:17])([CH3:16])[CH3:15])[C:11]([OH:18])=[C:10]([C:19]([CH3:22])([CH3:21])[CH3:20])[CH:9]=1.[H-].[Na+].[CH3:28]I.O>CN(C=O)C>[CH3:28][N:3]1[C:4]([Cl:25])=[C:5]([Cl:24])[C:6]([C:7](=[O:23])[C:8]2[CH:13]=[C:12]([C:14]([CH3:17])([CH3:16])[CH3:15])[C:11]([OH:18])=[C:10]([C:19]([CH3:22])([CH3:21])[CH3:20])[CH:9]=2)=[C:2]1[Cl:1]
Reactant: CC(C)(C)c1cc(C(=O)c2c(Cl)[nH]c(Cl)c2Cl)cc(C(C)(C)C)c1O
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cn1c(Cl)c(Cl)c(C(=O)c2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)c1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2,4,5-Trichloro-3-(3,5-di-t-butyl-4-hydroxybenzoyl)pyrrole (3.3 g) dissolved in DMF (35 ml) was treated with sodium hydride (50%, 0.432 g) in 4 portions, under nitrogen with stirring at room temperature. After 1 hour at room temperature, 0.56 ml of methyl iodide was added, dropwise, via microsyringe. After stirring 5 minutes more, the reaction mixture was poured into water (300 ml). The organic layer was separated, dried and evaporated to dryness. The residue was purified on silica gel, eluting with hexane:ethyl acetate (80:20). The pure product was recrystallized from ether-pentane to give 2.73 g of the title compound (mp 155°-156° C.).
Reaction SMILES: [CH3:1][C:2]([CH3:7])([CH3:6])[C:3](=[O:5])[CH3:4].C(O)C.[F:11][C:12]([F:16])([F:15])[S:13]Cl>ClCCl>[F:11][C:12]([F:16])([F:15])[S:13][CH2:4][C:3](=[O:5])[C:2]([CH3:7])([CH3:6])[CH3:1]
Reactant: FC(F)(F)SCl
Reactant: CC(=O)C(C)(C)C
Solvent: CCO
Solvent: ClCCl
Product: CC(C)(C)C(=O)CSC(F)(F)F
Temperature: 25 °C

Procedure:
A mixture of 3,3-dimethyl-2-butanone (1.13 mole), ethanol (1.5 g.) and dichloromethane (300 ml) was introduced into a sealed and pressure tested 2-liter vessel under reduced pressure. Trifluoromethanesulfenyl chloride (1.05 mole) was then added to the cooled, evacuated vessel. (Caution: It should be noted that trifluoromethanesulfenyl chloride is a highly hazardous material which must be handled with care to avoid inhalation and contact with the skin.) The vessel was warmed to about 25°C. and then rocked for 21/2 to 3 days. The vessel was vented through a cold gas trap (-78°C.) to trap any unreacted trifluoromethane sulfenyl chloride, and then through a scrubbing system to remove the vented hydrogen chloride gas. Residual liquid was transferred to a flask and distilled to give 1-trifluoromethylthio-3,3-dimethyl-2-butanone, b.p. 65°C./10mmHg.
Reaction SMILES: [Cl:1][C:2]1[CH:34]=[CH:33][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]([CH3:18])[CH3:17])=[CH:13][CH:14]=3)[C:9]([S:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[C:8]2[CH:26]([CH3:32])[C:27]([O:29]CC)=[O:28])=[CH:4][CH:3]=1.[Li+].[OH-].Cl>O1CCCC1.CO.CCOCC>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]([CH3:18])[CH3:17])=[CH:13][CH:14]=3)[C:9]([S:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[C:8]2[CH:26]([CH3:32])[C:27]([OH:29])=[O:28])=[CH:33][CH:34]=1
Reactant: CCOC(=O)C(C)c1c(Sc2ccccc2)c2cc(C(C)C)ccc2n1Cc1ccc(Cl)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: CO
Product: CC(C)c1ccc2c(c1)c(Sc1ccccc1)c(C(C)C(=O)O)n2Cc1ccc(Cl)cc1
Temperature: 25 °C

Procedure:
To 306 mg of the ethyl ester from Step 1 in 3 mL tetrahydrofuran and 1.5 mL methanol was added 1.5 mL of 2 N LiOH. After 1 h at reflux the mixture was cooled to room temperature, acidified with 1 N HCl and diluted with ether. The ether layer was washed with brine (2×) and dried over MgSO4. Filtration and concentration gave the title compound, mp 181°-181.5°.
Reaction SMILES: [CH3:1][C:2]1([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:6](=[O:7])[CH:5]=[C:4](/[CH:8]=[CH:9]/[C:10]2[CH:14]=[CH:13][S:12][CH:11]=2)[O:3]1.[CH2:21]([SH:26])[CH2:22][CH2:23][CH2:24][SH:25]>>[SH:25][CH2:24][CH2:23][CH2:22][CH2:21][S:26][CH:9]([C:10]1[CH:14]=[CH:13][S:12][CH:11]=1)[CH2:8][C:4]1[O:3][C:2]([CH3:1])([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:6](=[O:7])[CH:5]=1
Reactant: CC1(c2ccccc2)OC(/C=C/c2ccsc2)=CC1=O
Reactant: SCCCCS
Product: CC1(c2ccccc2)OC(CC(SCCCCS)c2ccsc2)=CC1=O

Procedure:
According to the procedure of Method A, Example 1, (E)-2-methyl-2-phenyl-5-[2-(3-thienyl)ethenyl]-3(2H)-furanone was reacted with 1,4-butanedithiol to provide 5-[2-[(4-mercaptobutyl)thio]-2-(3-thienyl)ethyl]-2-methyl-2-phenylfuran-3(2H)-one: 1H NMR (CDCl3) δ1.30 (m, 1H), 1.55-1.70 (broad s with fine structure, 4H) and 1.65 and 1.68 (singlets, 3H), 2.33-2.42 (m, 2H), 2.42-2.55 (m, 2H), 3.06-3.25 (m, 2H), 4.40 (m, 1H), 5.37 and 5.39 (singlets, 1H), 7.05-7.18 (m, 2H), 7.25-7.40 (m, 6H); MS (HR-FAB) m/z 405.1029 (M+H calcd. for C21H25O2S3 405.1017).
Reaction SMILES: [CH3:1][N:2]([C:6]1[CH:11]=[C:10]([CH3:12])[CH:9]=[CH:8][N:7]=1)[C:3](Cl)=[O:4].[CH:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][C:14]=1[OH:23].C(=O)([O-])[O-].[K+].[K+]>CC(CC)=O>[CH3:1][N:2]([C:6]1[CH:11]=[C:10]([CH3:12])[CH:9]=[CH:8][N:7]=1)[C:3](=[O:4])[O:23][C:14]1[CH:15]=[CH:16][C:17]2[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:13]=1
Reactant: Oc1ccc2ccccc2c1
Reactant: Cc1ccnc(N(C)C(=O)Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: Cc1ccnc(N(C)C(=O)Oc2ccc3ccccc3c2)c1
Temperature: 25 °C
Yield: 81.2 %

Procedure:
A mixture of 1.85 g of N-methyl-N-(4-methyl-2-pyridyl)carbamoyl chloride, 1.44 g of 2-naphthol and 1.38 g of anhydrous potassium carbonate in methylethylketone was refluxed under heating for 48 hours. After the reaction mixture was cooled to room temperature, inorganic salts were removed by filtration and then methylethylketone was removed by distillation under a reduced pressure. The residue was purified by the column chromatography (silica gel, developed with ethyl acetate/benzene=1/9 (V/V) ), to obtain 2.37 g of oily 2-naphthyl N-methyl-N-(4-methyl-2-pyridyl)carbamate (yield 81%, refraction index nD25 1.6191). The elementary analysis of this material was as follows:
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[CH2:8][NH:9][CH:10]1[CH2:19][CH2:18][C:17]2[C:12](=[CH:13][CH:14]=[C:15]([F:20])[CH:16]=2)[CH2:11]1.C1([O:27][C:28](=O)[NH:29][C:30]2[CH:35]=[C:34]([C:36]3[N:40]([CH3:41])[N:39]=[N:38][N:37]=3)[CH:33]=[C:32]([CH2:42][CH3:43])[CH:31]=2)C=CC=CC=1.C(N(CC)CC)C>C(#N)C>[CH2:42]([C:32]1[CH:31]=[C:30]([NH:29][C:28]([NH:1][C@@H:2]2[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]2[CH2:8][NH:9][CH:10]2[CH2:19][CH2:18][C:17]3[C:12](=[CH:13][CH:14]=[C:15]([F:20])[CH:16]=3)[CH2:11]2)=[O:27])[CH:35]=[C:34]([C:36]2[N:40]([CH3:41])[N:39]=[N:38][N:37]=2)[CH:33]=1)[CH3:43]
Reactant: CCc1cc(NC(=O)Oc2ccccc2)cc(-c2nnnn2C)c1
Reactant: N[C@@H]1CCCC[C@H]1CNC1CCc2cc(F)ccc2C1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCc1cc(NC(=O)N[C@@H]2CCCC[C@H]2CNC2CCc3cc(F)ccc3C2)cc(-c2nnnn2C)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 45.6 %

Procedure:
A mixture of N-{[(1S,2R)-2-aminocyclohexyl]methyl}-(2RS)-6-fluoro-1,2,3,4-tetrahydronaphthalen-2-amine (60 mg, 217 μmol) and phenyl[3-ethyl-5-(1-methyl-1H-tetrazol-5-yl)phenyl]carbamate (54 mg, 217 μmol) in acetonitrile (2 mL) was treated with triethylamine (75 μL, 540 μmol). After being stirred at room temperature for 18 hours, the mixture was concentrated under vacuum. The residue was purified by flash column chromatography, eluting with 5% methanol in dichloromethane containing 0.5% aqueous ammonia, to provide an amorphous solid (50 mg, 45%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:11]2[S:15][C:14]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[N:13][N:12]=2)[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].C(=O)([O-])[O-].[Cs+].[Cs+].[Si:30]([O:37][C@@H:38]([C:53]1[CH:58]=[CH:57][C:56]([C:59]([F:62])([F:61])[F:60])=[CH:55][CH:54]=1)[C@H:39]1[CH2:43]OS(=O)(=O)[N:40]1[C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47])([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31].S1C=CN=N1>C1COCC1>[C:49]([O:48][C:46]([NH:40][C@@H:39]([C@@H:38]([O:37][Si:30]([C:33]([CH3:34])([CH3:36])[CH3:35])([CH3:31])[CH3:32])[C:53]1[CH:54]=[CH:55][C:56]([C:59]([F:62])([F:61])[F:60])=[CH:57][CH:58]=1)[CH2:43][N:16]([C:14]1[S:15][C:11]([C:4]2[CH:5]=[CH:6][C:7]([N+:8]([O-:10])=[O:9])=[C:2]([F:1])[CH:3]=2)=[N:12][N:13]=1)[C:17](=[O:23])[O:18][C:19]([CH3:20])([CH3:22])[CH3:21])=[O:47])([CH3:52])([CH3:51])[CH3:50]
Reactant: CC(C)(C)OC(=O)N1[C@@H]([C@@H](O[Si](C)(C)C(C)(C)C)c2ccc(C(F)(F)F)cc2)COS1(=O)=O
Reactant: CC(C)(C)OC(=O)Nc1nnc(-c2ccc([N+](=O)[O-])c(F)c2)s1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: c1csnn1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@H](CN(C(=O)OC(C)(C)C)c1nnc(-c2ccc([N+](=O)[O-])c(F)c2)s1)[C@@H](O[Si](C)(C)C(C)(C)C)c1ccc(C(F)(F)F)cc1
Temperature: 55 °C
Reaction time: 1 h
Yield: 93.2 %

Procedure:
To a mixture of tert-butyl 5-(3-fluoro-4-nitrophenyl)-1,3,4-thiadiazol-2-ylcarbamate (0.64 g, 1.89 mmol) in THF (6 mL) was added cesium carbonate (1.07 g, 3.28 mmol). The mixture was heated to 55° C. for 10 minutes and then tert-butyl (4R)-4-((S)-((tert-butyl(dimethyl)silyl)oxy)(4-(trifluoromethyl)phenyl)methyl)-1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide (0.84 g, 1.64 mmol) in THF (4 mL) was added. The mixture was heated for 1 hour after the addition. HPLC-MS showed the product and thiadiazole starting material. The reaction was concentrated in vacuo and EtOAc (75 mL) was added. The mixture was cooled to 0° C. and 5% HCl (50 mL) was slowly added. The mixture was stirred for 1 hour. The organic phase was separated, and the aqueous phase was extracted twice with EtOAc. To the combined EtOAc solution was added saturated NaHCO3 and Na2CO3 until it was basic (pH=9). The organic layer was washed with brine, dried over Na2SO4, and then concentrated in vacuo. The residue was purified by chromatography on silica gel (50%-100% DCM-hexane) to provide the product as a yellow solid (1.18 g, 93%). LCMS (API-ES) m/z: 772 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:12])[C:9]([OH:11])=[O:10])=[CH:4][C:3]=1[Cl:13].Cl[CH2:15][CH:16]([OH:20])[CH2:17][CH2:18]Cl.C(=O)([O-])[O-].[K+].[K+]>C(O)C>[Cl:13][C:3]1[CH:4]=[C:5]([CH:8]([CH3:12])[C:9]([OH:11])=[O:10])[CH:6]=[CH:7][C:2]=1[N:1]1[CH2:18][CH2:17][CH:16]([OH:20])[CH2:15]1
Reactant: OC(CCl)CCCl
Reactant: CC(C(=O)O)c1ccc(N)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CC(C(=O)O)c1ccc(N2CCC(O)C2)c(Cl)c1

Procedure:
To the solution of 2.0 g of α-(4-amino-3-chlorophenyl)propionic acid in 20 ml of ethanol, 1.4 g of 1,4-dichloro-2-butanol are added, followed by 4 g of potassium carbonate while stirring. The mixture is stirred for 4 hours at the steam cone and evaporated under reduced pressure. The residue is taken up in water, the solution acidified with N hydrochloric acid to a pH of 5.5 and extracted with diethyl ether. The extract is dried, filtered and evaporated, to yield the α-[3-chloro-4-(3-hydroxypyrrolidino)-phenyl]-propionic acid of the formula ##SPC9##
Reaction SMILES: C(O[C:4](=[O:15])[C:5]1[C:10]([CH2:11]Br)=[CH:9][CH:8]=[CH:7][C:6]=1[O:13][CH3:14])C.[CH:16]([N:19](C(C)C)CC)(C)C.[C:25]([O:29][C:30]([C:32]1[C:40]2[CH:39](C)[CH:38](N)[N:37]([CH2:43][C:44]3[CH:49]=[CH:48][C:47]([O:50][CH3:51])=[CH:46][CH:45]=3)[CH2:36][C:35]=2[S:34][C:33]=1[NH2:52])=[O:31])([CH3:28])([CH3:27])[CH3:26]>C(#N)C>[C:25]([O:29][C:30]([C:32]1[C:40]2[CH2:39][CH:38]([CH2:16][N:19]3[CH2:11][C:10]4[C:5](=[C:6]([O:13][CH3:14])[CH:7]=[CH:8][CH:9]=4)[C:4]3=[O:15])[N:37]([CH2:43][C:44]3[CH:49]=[CH:48][C:47]([O:50][CH3:51])=[CH:46][CH:45]=3)[CH2:36][C:35]=2[S:34][C:33]=1[NH2:52])=[O:31])([CH3:27])([CH3:26])[CH3:28]
Reactant: CCOC(=O)c1c(CBr)cccc1OC
Reactant: COc1ccc(CN2Cc3sc(N)c(C(=O)OC(C)(C)C)c3C(C)C2N)cc1
Reactant: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: COc1ccc(CN2Cc3sc(N)c(C(=O)OC(C)(C)C)c3CC2CN2Cc3cccc(OC)c3C2=O)cc1
Reaction time: 2 h
Yield: 74.2 %

Procedure:
6-Bromomethyl-2-methoxy-benzoic acid ethyl ester (71.1 mg, 0.260 mmol) dissolved in acetonitrile (5 ml) and diisopropylethylamine (453 μl, 2.60 mmol) was stirred at room temperature. To this mixture 2-amino-5-amino-methyl-6-(4-methoxy-benzyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid tert-butyl ester (200 mg, 0.52 mmol) dissolved in acetonitrile (5 ml) was added syringe pump (0.2 ml/min.). Once addition was complete, the reaction mixture was allowed to stir for 2 hours. The reaction mixture was concentrated in vacuo, and the residue diluted with ethylacetate (50 ml). The organic layer was washed with saturated sodium bicarbonate (2×25 ml) and brine (2×25 ml). The organic layer was dried (MgSO4), filtered and concentrated in vacuo. The residue (308 mg) was subjected to column chromatography using a gradient of hexane/ethyl acetate (95:5) to (50:50) and then dichloromethane/ethyl acetate (95:5) as eluents, which afforded 106 mg (75%) of 2-amino-6-(4-methoxy-benzyl)-5-(7-methoxy-1-oxo-1,3-dihydro-isoindol-2-ylmethyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid tert-butyl ester as an oil.