Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]([N:11]2[CH2:16][CH2:15][C:14]([CH:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)([C:17]([OH:19])=O)[CH2:13][CH2:12]2)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(Cl)(=O)C(Cl)=O.[C:32]([NH2:36])([CH3:35])([CH3:34])[CH3:33]>C(Cl)Cl.CN(C=O)C>[C:1]1([CH2:7][O:8][C:9]([N:11]2[CH2:16][CH2:15][C:14]([CH:20]3[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]3)([C:17]([NH:36][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:19])[CH2:13][CH2:12]2)=[O:10])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(OCc1ccccc1)N1CCC(C(=O)O)(C2CCCCC2)CC1
Reactant: CC(C)(C)N
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)(C)NC(=O)C1(C2CCCCC2)CCN(C(=O)OCc2ccccc2)CC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 100.7 %

Procedure:
4-Cyclohexyl-1,4-piperidinedicarboxylic acid 1-(phenylmethyl) ester (8-4) (2.50 g, 7.24 mmol) was dissolved in 36 mL of methylene chloride and cooled at 0° C. in an ice-water bath. Oxalyl chloride (2.0 M solution in CH2Cl2, 3.98 mL, 7.96 mmol) was then added dropwise followed by the addition of 1-2 drops of DMF. This mixture was stirred at 0° C. for 2 h and then concentrated with toluene. The residue was dissolved in 36 mL of methylene chloride and cooled at 0° C. in an ice-water bath. tert-Butylamine (2.28 mL, 21.7 mmol) was then added dropwise, and the reaction mixture was stirred at 0° C. for 2 h, warmed to room temperature, and stirred at room temperature overnight. The resulting mixture was diluted with methylene chloride, washed with brine, dried over MgSO4, filtered, and concentrated to give 2.92 g of title compound 8-5 as a solid. LCMS (ESI): m/z 401 (M++1).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]([CH3:14])([CH3:13])[CH3:12])[C:6]=1[OH:15])([CH3:4])([CH3:3])[CH3:2].[OH-].[K+].[C:18](=[S:20])=[S:19]>CS(C)=O.O>[OH:15][C:6]1[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:10][C:9]([C:18]([SH:20])=[S:19])=[CH:8][C:7]=1[C:11]([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)c1cccc(C(C)(C)C)c1O
Reactant: S=C=S
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: CC(C)(C)c1cc(C(=S)S)cc(C(C)(C)C)c1O
Reaction time: 2 h

Procedure:
The compound 4-hydroxy-3,5-di-tert.-butyl dithiobenzoic acid was prepared by dissolving 2,6-di-tert.-butyl phenol (20.6 g) in dimethylsulfoxide (60 cm3). To this well stirred solution under a nitrogen blanket was added KOH (5.6 g) dissolved in a minimum amount of water. After the addition was completed carbon disulfide (7.6 g) was added while maintaining the temperature between 20°-25° C. The mixture was maintained at this temperature for 1 hour, then at 60° C. for 2 hours, cooled and poured into water (250 cm.3). After acidification (10% HCl), extraction into diethyl ether and drying over Na2SO4 the product was isolated by rotoevaporation.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]3[S:12][C:13]([C:17]([N:19]4[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]4)=[O:18])=[C:14]([CH3:16])[N:15]=3)[S:10][C:3]=12.[CH3:26][C:27]1[NH:28][C:29]2[C:34]([CH:35]=1)=[CH:33][C:32]([OH:36])=[CH:31][CH:30]=2>>[CH3:16][C:14]1[N:15]=[C:11]([C:9]2[S:10][C:3]3[C:4](=[N:5][CH:6]=[CH:7][C:2]=3[O:36][C:32]3[CH:33]=[C:34]4[C:29](=[CH:30][CH:31]=3)[NH:28][C:27]([CH3:26])=[CH:35]4)[CH:8]=2)[S:12][C:13]=1[C:17]([N:19]1[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]1)=[O:18]
Reactant: Cc1nc(-c2cc3nccc(Cl)c3s2)sc1C(=O)N1CCN(C)CC1
Reactant: Cc1cc2cc(O)ccc2[nH]1
Product: Cc1cc2cc(Oc3ccnc4cc(-c5nc(C)c(C(=O)N6CCN(C)CC6)s5)sc34)ccc2[nH]1
Yield: 51 %

Procedure:
The title compound (77 mg, 51%) was prepared from [2-(7-Chloro-thieno[3,2-b]pyridin-2-yl)-4-methyl-thiazol-5-yl]-(4-methyl-piperazin-1-yl)-methanone and 2-methyl-1H-indol-5-ol by a procedure analogous to Example 16 as a tan colored hydrochloride salt. C26H25N5O2S2: APCI m/z 504.3 (pos.); 1H NMR (CD3OD): δ 8.46 (d, 1H, J=5.4 Hz), 7.99 (s, 1H), 7.35 (d, 1H, J=8.3 Hz), 7.26 (s, 1H), 6.87 (d, 1H, J=8.3 Hz), 6.67 (d, 1H, J=5.4 Hz), 6.17 (s, 1H), 3.8–3.0 (bm, 8H), 2.95 (s, 3H), 2.49 (s, 3H), 2.43 (s, 3H) ppm.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:20][N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:34].C(N(CC)CC)C.[C:42]1([CH2:48][S:49](Cl)(=[O:51])=[O:50])[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1>ClCCl>[C:42]1([CH2:48][S:49]([O:1][C:2]2[CH:10]=[CH:9][C:8]([C:11]3[N:12]([C:27]([O:29][C:30]([CH3:31])([CH3:33])[CH3:32])=[O:28])[C:13]4[C:18]([CH:19]=3)=[CH:17][C:16]([CH2:20][N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)=[CH:15][CH:14]=4)=[C:7]3[C:3]=2[CH2:4][NH:5][C:6]3=[O:34])(=[O:51])=[O:50])[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1
Reactant: CC(C)(C)OC(=O)n1c(-c2ccc(O)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Reactant: O=S(=O)(Cl)Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)n1c(-c2ccc(OS(=O)(=O)Cc3ccccc3)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Yield: 37 %

Procedure:
In a similar manner to Step 1 of Example 227, 4-hydroxy-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (0.184 g, 0.399 mmol) was dissolved in dichloromethane (3.6 mL), and the solution was treated with triethylamine (0.250 mL, 1.79 mmol) and a-toluenesulfonyl chloride (0.152 g, 0.797 mmol), followed by purification by flash column chromatography (chloroform/methanol=85/15) to obtain 4-(a-toluenesulfonyloxy)-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (0.0908 g, yield 37%).
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([CH2:5][CH2:6]1)[CH2:3][C@@H:2]2[NH:8][C:9]1[S:10][CH:11]([CH3:15])[C:12](=[O:14])[N:13]=1.C([N-]C(C)C)(C)C.[Li+].[C:24]([O:28][C:29]([N:31]1[CH2:36][CH2:35][CH:34]([CH2:37]Br)[CH2:33][CH2:32]1)=[O:30])([CH3:27])([CH3:26])[CH3:25]>C1COCC1>[CH:1]12[CH2:7][CH:4]([CH2:5][CH2:6]1)[CH2:3][C@@H:2]2[NH:8][C:9]1[S:10][C:11]([CH2:37][CH:34]2[CH2:35][CH2:36][N:31]([C:29]([O:28][C:24]([CH3:25])([CH3:27])[CH3:26])=[O:30])[CH2:32][CH2:33]2)([CH3:15])[C:12](=[O:14])[N:13]=1
Reactant: CC1SC(N[C@H]2CC3CCC2C3)=NC1=O
Reactant: CC(C)(C)OC(=O)N1CCC(CBr)CC1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(CC2(C)SC(N[C@H]3CC4CCC3C4)=NC2=O)CC1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a solution of 2-((2S)-bicyclo[2.2.1]heptan-2-ylamino)-5-methylthiazol-4(5H)-one in anhydrous THF (30 mL) at −78° C. under N2 was added lithium diisopropylamide (Aldrich, 2.0 M in heptane/THF/ethylbenzene, 9.2 mL, 18.4 mmol). After stirring the reaction mixture at −78° C. for 1 h, a solution of 4-bromomethyl-piperidine-1-carboxylic acid tert-butyl ester (Pharma Core, 5.12 g, 18.4 mmol, 4.0 eq) in anhydrous THF (10 mL) was added under N2. The resulting reaction mixture was stirred at −78° C. for 4 h. The cooling bath was removed, and the reaction mixture was stirred at ambient temperature for ca. 18 h. Saturated NH4Cl was then added, and the THF was removed in vacuo. The residue was extracted with EtOAc (3×180 mL), and the combined organic layers were washed with saturated NaCl, dried over Na2SO4, filtered, and concentrated in vacuo. Flash column chromatography (silica gel, 0-60% EtOAc in hexane) afforded the title compound as an off-white solid (1.42 g). MS (ESI, neg. ion) m/z: 420 (M−H).
Reaction SMILES: [CH2:1]([O:5][C:6]([C:8]1[NH:9][C:10](=O)[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][C:14]([O:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH2:28][CH3:29])=[CH:22][CH:21]=1)=[CH:13][CH:12]=2)=[O:7])[CH2:2][CH2:3][CH3:4].P(Br)(Br)([Br:33])=O.C1(C)C=CC=CC=1>CCOC(C)=O>[CH2:1]([O:5][C:6]([C:8]1[N:9]=[C:10]([Br:33])[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][C:14]([O:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH2:28][CH3:29])=[CH:22][CH:21]=1)=[CH:13][CH:12]=2)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOC(=O)c1[nH]c(=O)c2ccc(Oc3ccc(OCCC)cc3)cc2c1O
Reactant: O=P(Br)(Br)Br
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CCCCOC(=O)c1nc(Br)c2ccc(Oc3ccc(OCCC)cc3)cc2c1O
Yield: 89.4 %

Procedure:
A mixture of 4-hydroxy-1-oxo-6-(4-propoxy-phenoxy)-1,2-dihydro-isoquinoline-3-carboxylic acid butyl ester (495 mg, 1.20 mmol), POBr3 (379 mg, 1.32 mmol), and toluene was microwaved at 110° C. for 25 min. Subsequently, the mixture was diluted with EtOAc, washed with aqueous NaHCO3 and saturated NaCl solution before it was dried over anhydrous sodium sulfate and concentrated in vacuo to give the crude title product (509 mg) that was used in the next step without further purification. 1H NMR (200 MHz, CDCl3): δ (ppm)=11.74 (s, 1H), 8.19 (d, 1H, J=9.2 Hz), 7.60-7.46 (m, 2H), 7.07-6.92 (m, 4H), 4.46 (t, 2H, =7.1 Hz), 3.94 (t, 2H, J=6.6 Hz), 1.83 (m, 4H), 1.45 (m, 2H), 1.10-0.94 (m, 6H).
Reaction SMILES: Cl[CH2:2][N:3]1[CH:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[N:4]1.[CH2:12]([CH:15]([C:18]#[N:19])[C:16]#[N:17])[CH:13]=[CH2:14].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH2:12]([C:15]([CH2:2][N:3]1[CH:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[N:4]1)([C:18]#[N:19])[C:16]#[N:17])[CH:13]=[CH2:14]
Reactant: C=CCC(C#N)C#N
Reactant: COC(=O)c1cnn(CCl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: C=CCC(C#N)(C#N)Cn1cc(C(=O)OC)cn1
Yield: 45.2 %

Procedure:
0.79 g of 1-(chloromethyl)-4-methoxycarbonyl-1H-pyrazole and 0.49 g of allyl malononitrile were dissolved in 15 ml of N,N-dimethylformamide. 1.26 g of potassium carbonate was added to the solution under ice cooling with stirring, followed by stirring at room temperature for overnight. Water was added to the reaction mixture, and then extracted with MTBE. The organic layer was washed with water, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, and then recrystallized from hexane-chloroform to obtain 0.50 g of allyl [{4-(methoxycarbonyl)-1H-pyrazole-1-yl}methyl]malononitrile (referred to as the compound of the present invention (24), hereinafter) shown by below formula.
Reaction SMILES: O=P(Cl)(Cl)Cl.[Cl:6][C:7]1[CH:15]=[C:14]2[C:10]([CH:11]=[CH:12][NH:13]2)=[CH:9][CH:8]=1.[OH-].[Na+].CN([CH:21]=[O:22])C>O>[Cl:6][C:7]1[CH:15]=[C:14]2[C:10]([C:11]([CH:21]=[O:22])=[CH:12][NH:13]2)=[CH:9][CH:8]=1
Reactant: CN(C)C=O
Reactant: Clc1ccc2cc[nH]c2c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: O=Cc1c[nH]c2cc(Cl)ccc12
Temperature: 37 °C
Reaction time: 0.75 h
Yield: 88 %

Procedure:
This Vilsmeyer reaction was performed according to H. G. O. Becker, Organikum, pp. 364-365, Johann Ambrosius Barth Verlag, Heidelberg-Leipzig (1996). To 5 mL DMF in a three-necked flask equipped with a thermometer, 1.8 mL POCl3 was added dropwise in a temperature range between 15° C. and 20° C. Then, a solution of 1 g (6.6 mMol) of 6-chloro-1H-indole in 2 mL DMF was added dropwise in a temperature range between 20° C. and 30° C. The reaction mixture was stirred for 45 minutes at 37° C. Afterwards, the reaction mixture was poured in a mixture of 15 g ice in 10 mL water under stirring. 3.4 g NaOH in 18 mL were added between in a temperature range between 20 and 30° C. The resulting mixture was then refluxed for 5 minutes. After cooling to room temperature, the precipitate was filtered off and washed with 10 mL cold water. Crystallization from ethanol yielded 6-chloro-1H-indole-3-carbaldehyde as a white solid (1.04 g, 88%).
Reaction SMILES: [BH4-].[Na+].[NH2:3][C:4]1[CH:26]=[CH:25][C:7]([C:8]([N:10]2[CH2:15][CH2:14][CH:13]([C:16](=[O:24])[C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)[CH2:12][CH2:11]2)=[O:9])=[CH:6][CH:5]=1>CO>[NH2:3][C:4]1[CH:5]=[CH:6][C:7]([C:8]([N:10]2[CH2:11][CH2:12][CH:13]([CH:16]([C:17]3[CH:18]=[CH:19][C:20]([F:23])=[CH:21][CH:22]=3)[OH:24])[CH2:14][CH2:15]2)=[O:9])=[CH:25][CH:26]=1
Reactant: Nc1ccc(C(=O)N2CCC(C(=O)c3ccc(F)cc3)CC2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Nc1ccc(C(=O)N2CCC(C(O)c3ccc(F)cc3)CC2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.4 %

Procedure:
Sodium borohydride (0.058 g) was added to a solution of 1-(4-aminobenzoyl)-4-(4-fluorobenzoyl)piperidine (1.0 g) in methanol (80 ml) and the mixture was stirred at room temperature for 2 hours. Additional sodium borohydride (0.050 g) was added. After being stirred at the same temperature for 1.5 hours, the resultant mixture was concentrated in vacuo. The residue was diluted with water and extracted twice with methylene chloride. The extracts were combined, washed with brine, dried over magnesium sulfate, and concentrated to dryness in vacuo. The powdery residue was washed with diisopropyl ether to give 1-(4-aminobenzoyl)-4-[(4-fluorophenyl)hydroxymethyl]piperidine (1.00 g) as pale yellow powder.
Reaction SMILES: C([O:5][C:6]([NH:8][C@H:9]1[CH2:14][C@H:13]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:12][CH2:11][C@H:10]1[NH:20][C:21]([C:23]1[S:24][C:25]2[CH2:26][N:27]([CH3:32])[CH2:28][CH2:29][C:30]=2[N:31]=1)=[O:22])=O)(C)(C)C.Cl.[Cl:34][C:35]1[CH:36]=[C:37]2[C:41](=[CH:42][CH:43]=1)[NH:40][C:39](C(O)=O)=[CH:38]2>C(O)C>[Cl:34][C:35]1[CH:36]=[C:37]2[C:41](=[CH:42][CH:43]=1)[NH:40][C:39]([C:6]([NH:8][C@H:9]1[CH2:14][C@H:13]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:12][CH2:11][C@H:10]1[NH:20][C:21]([C:23]1[S:24][C:25]3[CH2:26][N:27]([CH3:32])[CH2:28][CH2:29][C:30]=3[N:31]=1)=[O:22])=[O:5])=[CH:38]2
Reactant: O=C(O)c1cc2cc(Cl)ccc2[nH]1
Reactant: CCOC(=O)[C@@H]1CC[C@@H](NC(=O)c2nc3c(s2)CN(C)CC3)[C@@H](NC(=O)OC(C)(C)C)C1
Agent: Cl
Solvent: CCO
Product: CCOC(=O)[C@@H]1CC[C@@H](NC(=O)c2nc3c(s2)CN(C)CC3)[C@@H](NC(=O)c2cc3cc(Cl)ccc3[nH]2)C1

Procedure:
(1R*,2S*,4R*)-N2-tert-Butoxycarbonyl-4-ethoxycarbonyl-N1-[(5-methyl-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-2-yl)carbonyl]-1,2-cyclohexanediamine was treated with a saturated ethanol solution of hydrochloric acid and then condensed with 5-chloroindole-2-carboxylic acid in a similar manner to Example 118 to obtain the title compound.
Reaction SMILES: [OH:1][CH:2]([CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:11][CH:10]=1)[C:3]([O:5]CC)=[O:4].Cl>[OH-].[Na+]>[OH:1][CH:2]([CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:11][CH:10]=1)[C:3]([OH:5])=[O:4]
Reactant: CCOC(=O)C(O)Cc1ccc(OCc2ccccc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)C(O)Cc1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Yield: 80 %

Procedure:
A mixture of racemic ethyl 2-hydroxy-3-(4benzyloxyphenyl)propionate of the formula (10) (100 g) obtained according to the procedure described in step (iii) above and 10% aq. sodium hydroxide solution (500 ml) was stirred at room temperature for a period of 1–2 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was acidified with dil. hydrochloric acid at 15–20° C. and the solid thus obtained was filtered and washed with water to afford racemic 2-hydroxy-3-(4-benzyloxyphenyl)propionic acid (72–77 g, 80–85%).
Reaction SMILES: Cl.[N+:2]([C:5]1[CH:12]=[CH:11][C:8]([CH2:9][NH2:10])=[CH:7][CH:6]=1)([O-:4])=[O:3].Cl[C:14](=[O:22])[CH2:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18].C(=O)([O-])O.[Na+]>C(OCC)(=O)C>[N+:2]([C:5]1[CH:6]=[CH:7][C:8]([CH2:9][NH:10][C:14](=[O:22])[CH2:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:11][CH:12]=1)([O-:4])=[O:3]
Reactant: CCOC(=O)CCC(=O)Cl
Reactant: NCc1ccc([N+](=O)[O-])cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CCOC(=O)CCC(=O)NCc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 86.6 %

Procedure:
A mixture of 4-nitrobenzylamine hydrochloride (8.0 g), ethyl 4-chloro-4-oxobutanoate (10.47 g), saturated aqueous sodium hydrogen carbonate (100 ml) and ethyl acetate (100 ml) was stirred at room temperature for 2 hrs. The reaction mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and concentrated. Recrystallization of the residue from ethyl acetate-hexane gave ethyl 4-[(4-nitrobenzyl)amino]-4-oxobutanoate (10.3 g, 87%) as colorless prism crystals. melting point: 104-106° C.
Reaction SMILES: C(O)C.[NH2:4][C@@H:5]1[C:11](=[O:12])[N:10]([CH2:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C:9]2[CH:21]=[CH:22][CH:23]=[CH:24][C:8]=2[S:7][CH2:6]1.[CH3:25][C:26]1[CH:31]=[CH:30][C:29]([CH2:32][CH2:33][C:34](=O)[C:35]([O:37][CH2:38][CH3:39])=[O:36])=[CH:28][CH:27]=1>[C].[Pd].C(O)(=O)C>[CH2:38]([O:37][C:35]([CH:34]([NH:4][C@@H:5]1[C:11](=[O:12])[N:10]([CH2:13][C:14]([O:16][C:17]([CH3:19])([CH3:20])[CH3:18])=[O:15])[C:9]2[CH:21]=[CH:22][CH:23]=[CH:24][C:8]=2[S:7][CH2:6]1)[CH2:33][CH2:32][C:29]1[CH:28]=[CH:27][C:26]([CH3:25])=[CH:31][CH:30]=1)=[O:36])[CH3:39]
Reactant: CC(C)(C)OC(=O)CN1C(=O)[C@@H](N)CSc2ccccc21
Reactant: CCOC(=O)C(=O)CCc1ccc(C)cc1
Agent: [Pd]
Solvent: CCO
Solvent: CC(=O)O
Product: CCOC(=O)C(CCc1ccc(C)cc1)N[C@H]1CSc2ccccc2N(CC(=O)OC(C)(C)C)C1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 18 %

Procedure:
A mixture of 50 ml of ethanol, 1 g of tert-butyl 3(R)-amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetate, 0.4 g of acetic acid, 3.6 g of ethyl 4-(p-methylphenyl)-2-oxobutyrate and 5 g of molecular sieve 4A is stirred at room temperature for 1 hour, and the mixture is subjected to catalytic reduction over 0.5 g of 5% palladium carbon, at ordinary temperature and at atmospheric pressure. After 7 hours, the catalyst is filtered off and the mixture is concentrated. The residue is treated with oxalic acid in a manner similar to that described in Example 1. The resulting oil is purified by silica gel column chromatography to give 0.3 g of tert-butyl 3(R)-[1-ethoxycarbonyl-3-(p-tolyl)propyl]amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetate as colorless oil. This product is a mixture of two diastereomers (about 1:1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=[CH:5][C:4]=1[C:13]1[C:22]2[C:17](=[CH:18][C:19]([S:23](OC3C(F)=C(F)C(F)=C(F)C=3F)(=[O:25])=[O:24])=[CH:20][CH:21]=2)[CH:16]=[CH:15][N:14]=1.[S:38]1[CH:42]=[CH:41][N:40]=[C:39]1[NH2:43].C1COCC1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([C:9]([F:12])([F:10])[F:11])[CH:6]=[CH:5][C:4]=1[C:13]1[C:22]2[C:17](=[CH:18][C:19]([S:23]([NH:43][C:39]3[S:38][CH:42]=[CH:41][N:40]=3)(=[O:24])=[O:25])=[CH:20][CH:21]=2)[CH:16]=[CH:15][N:14]=1
Reactant: COc1cc(C(F)(F)F)ccc1-c1nccc2cc(S(=O)(=O)Oc3c(F)c(F)c(F)c(F)c3F)ccc12
Reactant: Nc1nccs1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: COc1cc(C(F)(F)F)ccc1-c1nccc2cc(S(=O)(=O)Nc3nccs3)ccc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 75.1 %

Procedure:
A solution of perfluorophenyl 1-(2-methoxy-4-(trifluoromethyl)phenyl)isoquinoline-6-sulfonate (INTERMEDIATE LLL) (425.75 mg, 0.775 mmol), thiazol-2-amine (78 mg, 0.775 mmol), and THF (3875 μl) was cooled in an ice-water bath for 15 min, then lithium bis(trimethylsilyl)amide (1M in THF) (1627 μl, 1.627 mmol) was added drop wise. After 30 min, the mixture was warmed to room temperature and loaded onto a 25-g silica gel loading column with DCM. The column was dried under vacuum for 5 min then eluted onto a pre-equilibrated 40-g silica gel column with 0 to 10% MeOH/DCM to give a yellow solid. The mixture was concentrated from DCM (2×). The residue was then taken up in DCM, sonicated, filtered, washed with DCM (3×), and dried under a stream of N2 (g) to give a white solid. The white solid was crushed with a spatula then dried under high vacuum to give 1-(2-methoxy-4-(trifluoromethyl)phenyl)-N-(thiazol-2-yl)isoquinoline-6-sulfonamide (271 mg, 0.582 mmol, 75% yield) as a white solid: 1H NMR (400 MHz, DMSO-d6) δ ppm=12.89 (br. s., 1H), 8.69 (d, J=5.7 Hz, 1H), 8.55 (d, J=1.8 Hz, 1H), 8.13 (d, J=5.7 Hz, 1H), 7.87 (dd, J=1.9, 8.9 Hz, 1H), 7.70 (d, J=8.9 Hz, 1H), 7.60-7.45 (m, 3H), 7.28 (d, J=4.6 Hz, 1H), 6.87 (d, J=4.6 Hz, 1H), 3.74 (s, 3H); m/z (ESI) 466.2 (M+H)+.
Reaction SMILES: [O:1]=[C:2]1[CH:6]([C:7]([O:9]C)=[O:8])[CH2:5][CH2:4][N:3]1[C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1.O[Li].O>C1COCC1.O>[O:1]=[C:2]1[CH:6]([C:7]([OH:9])=[O:8])[CH2:5][CH2:4][N:3]1[C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1
Reactant: COC(=O)C1CCN(c2cccnc2)C1=O
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)C1CCN(c2cccnc2)C1=O
Reaction time: 8 h
Yield: 102.6 %

Procedure:
To a stirred solution of 350 (514 mg, 2.33 mmol) in THF (20 ml) under nitrogen was added a solution of LiOH.H2O (147 mg, 3.50 mmol) in water (5 mL). The reaction mixture was stirred overnight, concentrated, diluted with a small amount of water, filtered, neutralized with 1N HCl (pH ˜5-6), and extracted twice with dichloromethane. The aqueous phase was concentrated, and the residue was triturated in methanol (with traces of acetone). After filtration, the mother liquid was concentrated and dried under high vacuum to afford title compound 351 (493 mg, quantitative yield, contaminated with salts) as a pale yellow sticky solid. MS (m/z): 207.1 (M+H)+−.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])/[C:5]/2=[CH:12]\[C:13]1[NH:17][C:16]([CH3:18])=[C:15]([C:19]([OH:21])=O)[C:14]=1[CH3:22].CN(C)C=O.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[NH2:55][CH2:56][CH2:57][N:58]1[CH2:62][CH2:61][CH2:60][CH2:59]1>C(N(CC)CC)C>[N:58]1([CH2:57][CH2:56][NH:55][C:19]([C:15]2[C:14]([CH3:22])=[C:13](/[CH:12]=[C:5]3\[C:6](=[O:11])[NH:7][C:8]4[C:4]\3=[CH:3][C:2]([F:1])=[CH:10][CH:9]=4)[NH:17][C:16]=2[CH3:18])=[O:21])[CH2:62][CH2:61][CH2:60][CH2:59]1
Reactant: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(F)cc32)c(C)c1C(=O)O
Reactant: NCCN1CCCC1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(F)cc32)c(C)c1C(=O)NCCN1CCCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 76.9 %

Procedure:
5-[5-Fluoro-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (100 g) and dimethylformamide (500 mL) were stirred and benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (221 g), 1-(2-aminoethyl)pyrrolidine (45.6 g) and triethylamine (93 mL) were added. The mixture was stirred for 2 hours at ambient temperature. The solid product was collected by vacuum filtration and washed with ethanol. The solids were slurry-washed by stirring in ethanol (500 mL) for one hour at 64° C. and cooled to room temperature. The solids were collected by vacuum filtration, washed with ethanol, and dried under vacuum to give 5-[5-fluoro-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-pyrrolidin-1-yl-ethyl)-amide (101.5 g, 77% yield). 1H-NMR (dimethylsulfoxide-d6) δ 1.60 (m, 4H, 2×CH2), 2.40, 2-44 (2×s, 6H, 2×CH3), 2.50 (m, 4H, 2×CH2), 2.57, 3.35 (2×m, 4H, 2XCH2), 7.53, 7.70, 7.73, 7.76 (4×m, 4H, aromatic and vinyl), 10.88 (s, 1H, CONH), 13.67 (s, 1H, pyrrole NH). MS m/z 396 [M+].
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][C:15]2[CH:16]=[N:17][C:18]([NH2:21])=[CH:19][CH:20]=2)[CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:23]([O:25][C:26]([N:28]=[C:29]=[S:30])=[O:27])[CH3:24].O>CS(C)=O>[CH2:23]([O:25][C:26](=[O:27])[NH:28][C:29]([NH:21][C:18]1[CH:19]=[CH:20][C:15]([O:14][C:10]2[CH:11]=[CH:12][CH:13]=[C:8]([NH:7][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:22])[CH:9]=2)=[CH:16][N:17]=1)=[S:30])[CH3:24]
Reactant: CCOC(=O)N=C=S
Reactant: CC(C)(C)OC(=O)Nc1cccc(Oc2ccc(N)nc2)c1
Solvent: O
Solvent: CS(C)=O
Product: CCOC(=O)NC(=S)Nc1ccc(Oc2cccc(NC(=O)OC(C)(C)C)c2)cn1
Temperature: 25 °C
Reaction time: 120 h
Yield: 69.4 %

Procedure:
To a solution of tert-butyl{3-[(6-aminopyridin-3-yl)oxy]phenyl}carbamate (4.60 g, 15.2 mmol) in dimethyl sulfoxide (90 mL) was added ethoxycarbonyl isothiocyanate (2.00 mL, 16.7 mmol), and the mixture was stirred at room temperature for 5 days. Water (200 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (400 mL). The organic layer was washed with 5% aqueous ammonium chloride solution (200 mL), 5% aqueous sodium hydrogen carbonate solution (200 mL) and saturated brine (200 mL), and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=90/10→50/50), and fractions containing the object product was concentrated under reduced pressure to give the title compound (4.56 g, 69%) as a colorless solid.