Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1](I)[CH3:2].C(=O)([O-])[O-].[Ca+2].C(#N)C.[Cl:12][C:13]1[CH:14]=[C:15]([CH:32]=[C:33]([Cl:36])[C:34]=1[OH:35])[C:16]([N:19]1[CH2:23][C:22]([CH3:24])=[C:21]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:20]1=[O:31])([CH3:18])[CH3:17]>O>[Cl:12][C:13]1[CH:14]=[C:15]([CH:32]=[C:33]([Cl:36])[C:34]=1[O:35][CH2:1][CH3:2])[C:16]([N:19]1[CH2:23][C:22]([CH3:24])=[C:21]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:20]1=[O:31])([CH3:18])[CH3:17]
Reactant: CCI
Reactant: CC1=C(c2ccccc2)C(=O)N(C(C)(C)c2cc(Cl)c(O)c(Cl)c2)C1
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: O
Solvent: CC#N
Product: CCOc1c(Cl)cc(C(C)(C)N2CC(C)=C(c3ccccc3)C2=O)cc1Cl
Yield: 90.7 %

Procedure:
0.6 g (0.004 mol) of ethyl iodide and 0.6 g (0.004 mol) of anhydrous calcium carbonate were added to an acetonitrile solution of 1.2 g (0.003 mol) of 1-(3,5-dichloro-4-hydroxy-α,α-dimethylbenzyl)-4-methyl-3-phenyl-3-pyrrolin-2-one prepared in Example 11, and the mixture was refluxed for about 30 minutes under stirring. After completion of the reaction, the reaction mixture was poured into a large amount of water and extracted with ethyl acetate. The ethyl acetate layer was dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The solid thereby obtained was washed with isopropyl ether to obtain 1.1 g (yield: 91.6%) of the desired compound as colorless crystals.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[C:11](I)=[CH:10][N:9]([CH2:13][C:14]3[C:19]([CH3:20])=[C:18]([O:21][CH3:22])[C:17]([CH3:23])=[CH:16][N:15]=3)[C:4]=2[N:5]=[C:6]([NH2:8])[N:7]=1.[CH2:24]([OH:28])[CH2:25][C:26]#[CH:27]>>[NH2:8][C:6]1[N:7]=[C:2]([Cl:1])[C:3]2[C:11]([C:27]#[C:26][CH2:25][CH2:24][OH:28])=[CH:10][N:9]([CH2:13][C:14]3[C:19]([CH3:20])=[C:18]([O:21][CH3:22])[C:17]([CH3:23])=[CH:16][N:15]=3)[C:4]=2[N:5]=1
Reactant: C#CCCO
Reactant: COc1c(C)cnc(Cn2cc(I)c3c(Cl)nc(N)nc32)c1C
Product: COc1c(C)cnc(Cn2cc(C#CCCO)c3c(Cl)nc(N)nc32)c1C

Procedure:
The title compound was prepared by Sonogashira coupling of 4-chloro-5-iodo-7-(4-methoxy-3,5-dimethyl-pyridin-2-ylmethyl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamine (see Example 1) with 3-butyn-1-ol according to the General Procedure A. tR: 4.54 min. 1H-NMR (DMSO-d6) δ 8.04 (s, 1H), 7.22 (s, 1H), 6.69 (br.s., 2H), 5.25 (s, 2H), 4.82 (d, 1H), 3.70 (s, 3H), 3.55 (q, 2H), 2.49 (t, 2H), 2.23 (s, 3H), 2.14 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2.[Cl-].[CH3:12][C:13]1[CH:22]=[CH:21][CH:20]=[CH:19][C:14]=1[CH:15]=[N+:16]([CH3:18])[CH3:17].CC1C=CC=CC=1C=O.CNC>>[CH3:17][N:16]([CH3:18])[CH:15]([C:10]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[NH:3][C:2]=1[CH3:1])[C:14]1[CH:19]=[CH:20][CH:21]=[CH:22][C:13]=1[CH3:12]
Reactant: Cc1ccccc1C=[N+](C)C
Reactant: Cc1cc2ccccc2[nH]1
Agent: CNC
Agent: Cc1ccccc1C=O
Agent: [Cl-]
Product: Cc1ccccc1C(c1c(C)[nH]c2ccccc12)N(C)C

Procedure:
The preparation was carried out in accordance with general synthesis instructions 4 from 2-methyl-1H-indole and (2-methyl-benzylidene)-dimethylammonium chloride, which had been prepared in accordance with example 44 from 2-methyl-benzaldehyde and dimethylamine.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].Cl[C:6]1[CH:11]=[CH:10][N:9]=[CH:8][C:7]=1[CH:12]=[O:13].C(OCC)(=O)C>CN(C=O)C>[N:1]([C:6]1[CH:11]=[CH:10][N:9]=[CH:8][C:7]=1[CH:12]=[O:13])=[N+:2]=[N-:3]
Reactant: O=Cc1cnccc1Cl
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: [N-]=[N+]=Nc1ccncc1C=O
Reaction time: 18 h
Yield: 86.9 %

Procedure:
Sodium azide (1.07 g, 16.5 mmol) was added to a mixture of 4-chloro-3-formylpyridine (2.22 g, 15.7 mmol) in DMF (15 mL) and the reaction mixture was stirred for 18 hours. Ethyl acetate was added and the organic layers were washed with water and brine. The combined organic phases were dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (0-60% ethyl acetate in cyclohexane) to afford the title compound as a white solid (2.02 g, 87% yield). 1H NMR (300 MHz, CDCl3): δ 10.35 (s, 1H), 8.99 (s, 1H), 8.72 (d, J=5.6 Hz, 1H), 7.20 (d, J=5.6 Hz, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:26]=[CH:25][C:5]([C:6]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]([CH2:17][CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:9]=2)=[O:7])=[CH:4][C:3]=1[OH:27].CO.[CH2:30]([C:32]1[CH:39]=[CH:38][C:35]([CH:36]=O)=[CH:34][CH:33]=1)[CH3:31].C([BH3-])#N.[Na+]>O.C(O)(=O)C>[CH2:30]([C:32]1[CH:39]=[CH:38][C:35]([CH2:36][NH:1][C:2]2[CH:26]=[CH:25][C:5]([C:6]([C:8]3[C:16]4[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=4)[N:10]([CH2:17][CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:9]=3)=[O:7])=[CH:4][C:3]=2[OH:27])=[CH:34][CH:33]=1)[CH3:31]
Reactant: CCOC(=O)CCCn1cc(C(=O)c2ccc(N)c(O)c2)c2ccccc21
Reactant: CCc1ccc(C=O)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Solvent: O
Product: CCOC(=O)CCCn1cc(C(=O)c2ccc(NCc3ccc(CC)cc3)c(O)c2)c2ccccc21
Yield: 81.5 %

Procedure:
Ethyl 4-[3-(4-amino-3-hydroxybenzoyl)indol-1-yl]butanoate (5.0 g) was suspended in a mixed solvent containing methanol (50 ml) and water (5 ml), and 4-ethylbenzaldehyde (3.66 g) and sodium cyanoborohydride (1.80 g) were added to the suspension. Acetic acid (2.5 ml) was further added dropwise to the mixture over five minutes, and the resultant mixture was stirred at room temperature for one hour. Water (50 ml) was added to the reaction mixture, and crystals so precipitated were collected by filtration. The produced crystals were recrystallized from ethanol, to thereby obtain 5.39 g of ethyl 4-{3-[4-(4-ethylphenyl)methylamino-3-hydroxybenzoyl)indol-1-yl}butanoate as yellow crystals.
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4]([CH:7]=[CH:8][N+:9]([O-:11])=[O:10])=[CH:5][CH:6]=1.[CH3:12][N:13]([CH3:17])[C:14](=[S:16])[S-:15].C[NH2+]C>C(=S)=S>[CH3:12][N:13]([CH3:17])[C:14](=[S:15])[S:16][CH:7]([CH2:8][N+:9]([O-:11])=[O:10])[C:4]1[S:3][C:2]([Cl:1])=[CH:6][CH:5]=1
Reactant: O=[N+]([O-])C=Cc1ccc(Cl)s1
Reactant: CN(C)C(=S)[S-]
Agent: C[NH2+]C
Solvent: S=C=S
Product: CN(C)C(=S)SC(C[N+](=O)[O-])c1ccc(Cl)s1

Procedure:
As in Example 17, reaction of 2-chloro-5-(2-nitrovinyl)thiophene with dimethylammonium dimethyldithiocarbamate in the presence of carbon disulfide gave 5-chloro-α-(nitromethyl)-2-thenyl dimethyldithiocarbamate melting at 76° C.-77° C., after recrystallization without heating from acetone-methanol solution.
Reaction SMILES: [OH:1][N:2]=[C:3]([C:5]1[S:9][C:8]([N:10]2[CH2:14][CH2:13][C@H:12]([O:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]([F:25])([F:24])[F:23])[CH2:11]2)=[N:7][CH:6]=1)[NH2:4].[CH3:26][CH2:27][O-].[Na+]>CCO.CCOC(C)=O.O>[CH3:26][C:27]1[O:1][N:2]=[C:3]([C:5]2[S:9][C:8]([N:10]3[CH2:14][CH2:13][C@H:12]([O:15][C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=4[C:22]([F:25])([F:24])[F:23])[CH2:11]3)=[N:7][CH:6]=2)[N:4]=1
Reactant: NC(=NO)c1cnc(N2CC[C@H](Oc3ccccc3C(F)(F)F)C2)s1
Reactant: CC[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1nc(-c2cnc(N3CC[C@H](Oc4ccccc4C(F)(F)F)C3)s2)no1
Temperature: 80 °C

Procedure:
To a suspension of N′-hydroxy-2-{(3S)-3-[2-(trifluoromethyl)phenoxy]-pyrrolidin-1-yl}-1,3-thiazole-5-carboximidamide (410 mg, 1.1 mmol) in EtOH (3 mL) and EtOAc (5 mL) was added NaOEt (1.7 mL, 4.4 mmol, 25 wt. %) at rt. The mixture was heated at 80° C. for 30 min. After cooling to rt, the mixture was diluted with water and extracted with EtOAc. The EtOAc extract was washed with water, dried (Na2SO4) and concentrated. Combi-Flash chromatography (10 g, 50-100% EtOAc in hexanes in 20 min, 35 mL/min, 15 mL/fraction) gave the title compound after trituration with Et2O-hexanes (1:1). 1H NMR (400 MHz, acetone-d6): δ 7.81 (s, 1 H), 7.71-7.65 (m, 2 H), 7.41 (d, 1 H), 7.17 (t, 1 H), 5.52 (s, 1 H), 3.98 (m, 1 H), 3.84-3.67 (m, 3 H), 2.61 (s, 3H), 2.60-2.43 (m, 2 H). MS (+ESI) m/z 397 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[CH:13]=[C:12]([C:14](OS(C3C=CC(C)=CC=3)(=O)=O)=[CH:15][CH:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)[N:11]([S:32]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)(=[O:34])=[O:33])[C:8]2=[N:9][CH:10]=1)=[O:4].[CH3:41][S:42]([C:45]1[CH:50]=[CH:49][C:48](B(O)O)=[CH:47][CH:46]=1)(=[O:44])=[O:43].C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.C(OCC)(=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[CH:13]=[C:12]([C:14]([C:48]3[CH:49]=[CH:50][C:45]([S:42]([CH3:41])(=[O:44])=[O:43])=[CH:46][CH:47]=3)=[CH:15][CH:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)[N:11]([S:32]([C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=3)(=[O:34])=[O:33])[C:8]2=[N:9][CH:10]=1)=[O:4]
Reactant: COC(=O)c1cnc2c(c1)cc(C(=CC1CCCC1)OS(=O)(=O)c1ccc(C)cc1)n2S(=O)(=O)c1ccccc1
Reactant: CS(=O)(=O)c1ccc(B(O)O)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: COC(=O)c1cnc2c(c1)cc(C(=CC1CCCC1)c1ccc(S(C)(=O)=O)cc1)n2S(=O)(=O)c1ccccc1
Yield: 93.1 %

Procedure:
To a mixture of 1-benzenesulfonyl-2-[2-cyclopentyl-1-(toluene-4-sulfonyloxy)-vinyl]-1H-pyrrolo[2,3-b]pyridin-5-carboxylic acid methyl ester (0.9 g, 1.55 mmol), 4-(methanesulfonyl)phenylboronic acid (930 mg, 4.6 mmol) and dichlorobis(triphenylphosphine)palladium (II) (110 mg, 0.15 mmol) in dioxane (8 mL) was added an aqueous sodium carbonate solution (2 M, 2.3 mL). The resulting mixture was subjected to microwave irradiation for 120 min at 100° C. The mixture was diluted with ethyl acetate (150 mL), washed with a saturated aqueous sodium bicarbonate solution (2×30 mL), brine, dried over anhydrous sodium sulfate and then concentrated in vacuo. Purification by flash column chromatography (QingDao silica gel, 200-300 mesh, 50% ethyl acetate/hexanes) afforded 1-benzenesulfonyl-2-[2-cyclopentyl-1-(4-methanesulfonyl-phenyl)-vinyl]-1H-pyrrolo[2,3-b]pyridin-5-carboxylic acid methyl ester (815 mg, 73%) as a white solid: LC/MS m/e calcd for C29H28N2O6S2 [M+H]+ 565.68, observed 565.1.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]([OH:6])=[O:5].C(=O)(O)[O-].[Na+].O1CCCC1.[C:17]([O:20][C@H:21]1[CH2:45][CH2:44][C@@:43]2([CH3:46])[C:23](=[CH:24][CH2:25][C@@H:26]3[C@@H:42]2[CH2:41][CH2:40][C@@:39]2([CH3:47])[C@H:27]3[CH2:28][CH2:29][C@@H:30]2[C@H:31]([CH3:38])[CH2:32][CH2:33][CH2:34][CH:35]([CH3:37])[CH3:36])[CH2:22]1)(Cl)=[O:18]>O.C(Cl)(Cl)Cl>[CH3:37][CH:35]([CH2:34][CH2:33][CH2:32][C@H:31]([C@@H:30]1[C@:39]2([CH3:47])[C@H:27]([C@H:26]3[C@H:42]([CH2:41][CH2:40]2)[C@:43]2([CH3:46])[C:23]([CH2:22][C@@H:21]([O:20][C:17]([NH:1][CH2:2][CH2:3][C:4]([OH:6])=[O:5])=[O:18])[CH2:45][CH2:44]2)=[CH:24][CH2:25]3)[CH2:28][CH2:29]1)[CH3:38])[CH3:36]
Reactant: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](OC(=O)Cl)CC[C@]4(C)[C@H]3CC[C@]12C
Reactant: NCCC(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](OC(=O)NCCC(=O)O)CC[C@]4(C)[C@H]3CC[C@]12C
Reaction time: 1 h
Yield: 59.3 %

Procedure:
To a solution of β-alanine (56 mg) and sodium bicarbonate (84 mg) in water (10 ml) were added tetrahydrofuran (20 ml) and cholesterol chlorocarbonate (449 mg) at 0° C. The mixture was stirred for 1 hour. The reaction mixture was concentrated in vacuo and to the residue were added 0.1N hydrochloric acid (10 ml) and chloroform (40 ml). Organic layer was separated, washed with water and dried over magnesium sulfate. Evaporation of the solvent gave a crude product, which was dissolved in chloroform and applied to a silica gel column (40 g). Elution with a mixture of chloroform and methanol gave N-(cholest-5-en-3β-oxycarbonyl)-β-alanine (187 mg) as a white powder.
Reaction SMILES: C[O:2][C:3](=O)/[C:4](/[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[N:5]/[OH:6].CO.[CH3:23][NH2:24].O>C1(C)C=CC=CC=1>[OH:6]/[N:5]=[C:4](\[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)/[C:3]([NH:24][CH3:23])=[O:2]
Reactant: COC(=O)/C(=N/O)c1ccccc1Oc1ccccc1
Reactant: CN
Solvent: CO
Solvent: O
Solvent: Cc1ccccc1
Product: CNC(=O)/C(=N/O)c1ccccc1Oc1ccccc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 61 %

Procedure:
To crude E-α-hydroxyimino-2-phenoxyphenylacetic acid methyl ester (39.6 g, 0.0747 mole, purity: 51.2%) were added methanol (100 ml) and 40% aqueous solution of methylamine (15.45 g, 0.199 mole) and the mixture was stirred at room temperature for 15 hours. Then, 40% aqueous solution of methylamine (7.73 g, 0.0995 mole) was added to the mixture which was stirred in an oil bath at 70° C. for 6 hours. After completion of the reaction, water (200 ml) and toluene (100 ml) were added to the reaction mixture, which was stirred with ice cooling for one hour. The precipitated crystals were filtered off and recrystallized (methanol/toluene) to obtain E-2-hydroxyimino-N-methyl-2-(2-phenoxyphenyl)acetamide (12.31 g, yield: 60.1%) as colorless crystals (melting point: 183°-184.5° C.).
Reaction SMILES: [CH2:1]([O:4][C:5]([NH:7][CH2:8][CH:9]([CH:12]([O:14][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16])[CH3:13])[CH2:10][OH:11])=[O:6])[CH:2]=[CH2:3].C(N(CC)CC)C.[CH3:29][S:30](Cl)(=[O:32])=[O:31].O>ClCCl>[CH2:1]([O:4][C:5]([NH:7][CH2:8][CH:9]([CH:12]([O:14][Si:15]([C:18]([CH3:20])([CH3:19])[CH3:21])([CH3:16])[CH3:17])[CH3:13])[CH2:10][O:11][S:30]([CH3:29])(=[O:32])=[O:31])=[O:6])[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)NCC(CO)C(C)O[Si](C)(C)C(C)(C)C
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: C=CCOC(=O)NCC(COS(C)(=O)=O)C(C)O[Si](C)(C)C(C)(C)C
Reaction time: 3 h

Procedure:
To a solution of 7.00 g of 2-(N-allyloxycarbonylaminomethyl)-3-t-butyldimethylsilyloxybutan-1-ol and 4.60 ml of triethylamine in 35 ml of dichloromethane was added dropwise 2.05 ml of methanesulfonyl chloride at -10° C. After stirring for 3 hours, water was added to the reaction mixture and then the solution was extracted with chloroform. The organic layer was washed in turn with 1N hydrochloric acid and brine, and dried over anhydrous magnesium sulfate. Evaporation of the solvent followed by a column chromatography on silica gel (hexane:ethyl acetate=3:1) gave 8.8 g of 2-(N-allyloxycarbonylaminomethyl)-3-t-butyldimethylsilyloxy-1-methanesulfonyloxybutane.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C@H:6]2[O:8][CH2:7]2)=[CH:4][CH:3]=1.[CH3:11][NH:12][CH2:13][CH2:14][OH:15]>>[ClH:1].[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C@@H:6]([OH:8])[CH2:7][N:12]([CH2:13][CH2:14][OH:15])[CH3:11])=[CH:4][CH:3]=1
Reactant: Clc1ccc([C@@H]2CO2)cc1
Reactant: CNCCO
Product: CN(CCO)C[C@H](O)c1ccc(Cl)cc1
Product: Cl
Temperature: 100 °C
Reaction time: 15 h

Procedure:
To (R)-4-chloro-styrene oxide (1.55 g, 10.0 mmol), N-methyl ethanolamine (788 mg, 1.05 equivalents) was added; and the mixture was stirred at 100° C. for 15 hours. The mixture was cooled to room temperature to obtain the reaction mixture of the title compound (chemical purity: 79.8 area %, N-methyl ethanolamine: 0.5 area %, 5.4 area % of regioisomer was contaminated). To the reaction mixture, 28 wt % hydrogen chloride solution in isopropanol (1.55 g, 1.2 equivalents) was added, and ethyl acetate (25 mL) was added dropwise thereto; as a result, crystals were precipitated. After the mixture was stirred at 25° C. for 17 hours, the crystals were separated by filtration under reduced pressure. The crystals were washed with ethyl acetate (10 mL), and dried under vacuum, to obtain 2.26 g of the title compound as white crystals (yield: 78%, chemical purity: 91.5 area %, N-methyl ethanolamine was not detected, 3.6 area % of regioisomer was contaminated). The retention time in the chemical purity analysis method was 1.8 min.
Reaction SMILES: C([O:3][C:4](=[O:31])[C:5]1[CH:10]=[CH:9][C:8](/[CH:11]=[CH:12]/[C:13]2([CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH2:21][C:20]3[C:19]([CH3:23])([CH3:22])[CH2:18][CH2:17][C:16]([CH3:25])([CH3:24])[C:15]=3[CH2:14]2)=[CH:7][CH:6]=1)C.[OH-].[K+].C1COCC1>C(O)C.O>[CH3:23][C:19]1([CH3:22])[CH2:18][CH2:17][C:16]([CH3:24])([CH3:25])[C:15]2[CH2:14][C:13]([CH:12]=[CH:11][C:8]3[CH:7]=[CH:6][C:5]([C:4]([OH:31])=[O:3])=[CH:10][CH:9]=3)([CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH2:21][C:20]1=2
Reactant: CCCCCC1(/C=C/c2ccc(C(=O)OCC)cc2)CC2=C(C1)C(C)(C)CCC2(C)C
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Solvent: O
Product: CCCCCC1(C=Cc2ccc(C(=O)O)cc2)CC2=C(C1)C(C)(C)CCC2(C)C
Yield: 61.2 %

Procedure:
The ester (0.7 g) was dissolved in 10 ml of ethanol and treated with a solution of 1.8 g of KOH in 5 ml of water. After having added 4 ml of THF, the reaction mixture was reacted for 3 hours at 40° C., poured on ice/water, acidified with 2N HCL and extracted with ethyl acetate. The organic phase was dried (Na2SO4), the solvent evaporated, and the crystalline residue recrystallized from pentane to give 0.4 g of 4-[2-(4,4,7,7-tetramethyl-2-pentyl-2,3,4,5,6,7-hexahydro-1H-indene-2-yl)-vinyl]-benzoic acid as colorless crystals, m.p. 121-123° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][N:3]=1.[CH2:12]([NH:19][CH2:20][CH2:21][NH2:22])[C:13]1C=CC=CC=1.[OH2:23]>>[ClH:1].[F:9][C:8]([F:11])([F:10])[C:5]1[CH:6]=[CH:7][C:2]([N:22]2[CH2:21][CH2:20][NH:19][CH2:12][C:13]2=[O:23])=[N:3][CH:4]=1
Reactant: FC(F)(F)c1ccc(Cl)nc1
Reactant: O
Reactant: NCCNCc1ccccc1
Product: Cl
Product: O=C1CNCCN1c1ccc(C(F)(F)F)cn1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
10 g of 2-chloro-5-(trifluoromethyl)pyridine and 40.5 ml of N-benzylethylenediamine are heated at 135° C. for 6 hours in a round-bottomed flask. The resulting mixture is poured into water and extracted with ethyl acetate. The extracts are dried and evaporated under vacuum; the crude product thus obtained is purified by flash chromatography. The isolated product (compound of formula (VIII)), 14 g, is dissolved in 200 ml of 2N HCl solution. 30 g of trimeric glyoxal dihydrate are added and the mixture is stirred at room temperature for 72 hours. The resulting mixture is extracted with ethyl acetate. The extracts are dried and evaporated under vacuum; the crude product thus obtained is purified by flash chromatography. The isolated product, 10 g, is dissolved in 450 ml of ethanol, followed by addition of 15 ml of a solution of isopropanol saturated with HCl and 3 g of 10% Pd/C. This mixture is reacted under a stream of hydrogen for 4 hours at a temperature of 40° C. The resulting mixture is filtered and evaporated under vacuum to give 3 g of the title compound, m.p.=205-207° C.
Reaction SMILES: [S:1]([C:5]1[CH:25]=[CH:24][CH:23]=[CH:22][C:6]=1[C:7]([O:9][C:10](=O)[C:11]1C=CC=CC=1S(O)(=O)=O)=[O:8])([OH:4])(=[O:3])=[O:2].[NH3:26].CO>C(O)C.CCOCC>[CH2:10]([O:9][C:7]([C:6]1[CH:22]=[CH:23][CH:24]=[CH:25][C:5]=1[S:1]([O-:4])(=[O:2])=[O:3])=[O:8])[CH3:11].[NH4+:26]
Reactant: N
Reactant: O=C(OC(=O)c1ccccc1S(=O)(=O)O)c1ccccc1S(=O)(=O)O
Solvent: CO
Solvent: CCOCC
Solvent: CCO
Product: CCOC(=O)c1ccccc1S(=O)(=O)[O-]
Product: [NH4+]
Reaction time: 2 h
Yield: 91 %

Procedure:
2-Sulfobenzoic anhydride (1; 50.2 g, 0.270 mol) in 160 ml of absolute ethanol was stirred overnight. After the addition of 60 ml of 7N methanolic ammonia, the mixture was stirred for a further 2 hours and the resulting thick white reaction mixture was clarified by addition of 160 ml of methanol. The solution was diluted with ether (1.1 L) until no more solids precipitated, and the product was collected by filtration and air-dried overnight to give 60.6 g (91% yield) of (2).
Reaction SMILES: FC(F)(F)C(O)=O.[S:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[NH:17][C:18](=[O:31])[C:19]1[CH:24]=[CH:23][C:22]([N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)=[CH:21][CH:20]=1.[C:32]1(=[O:42])[C:36]2([CH2:40][CH2:39][CH2:38][CH2:37]2)[CH2:35][C:34](=[O:41])[O:33]1.C(N(CC)CC)C>CN(C=O)C>[S:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[NH:17][C:18]([C:19]1[CH:24]=[CH:23][C:22]([N:25]2[CH2:26][CH2:27][N:28]([C:34](=[O:41])[CH2:35][C:36]3([C:32]([OH:42])=[O:33])[CH2:40][CH2:39][CH2:38][CH2:37]3)[CH2:29][CH2:30]2)=[CH:21][CH:20]=1)=[O:31]
Reactant: O=C(Nc1nc2ccccc2s1)c1ccc(N2CCNCC2)cc1
Reactant: O=C1CC2(CCCC2)C(=O)O1
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(Nc1nc2ccccc2s1)c1ccc(N2CCN(C(=O)CC3(C(=O)O)CCCC3)CC2)cc1
Reaction time: 5 h
Yield: 68.9 %

Procedure:
N-benzothiazol-2-yl-4-piperazin-1-yl-benzamide trifluoroacetate (40 mg) was mixed with 2-oxa-spiro[4,4]nonane-1,3-dione (30 mg) in DMF (5 mL) containing triethylamine (0.1 mL) and the mixture was stirred foe 5 hrs. Solvents were evaporated and the residue was treated with ethyl acetate and hydrochloric acid solution (0.1N). The precipitate from the organic layer was filtered to give 1-(2-{4-[4-(benzothiazol-2-ylcarbamoyl)-phenyl]-piperazin-1-yl}-2-oxo-ethyl)-cyclopentanecarboxylic acid as a white solid (30 mg). LCMS calc for C26H28N4O4S (m/e) 492, obsd 493.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([CH:16]=O)[CH:11]=1)[CH3:9])(C)(C)C.S([CH2:29][N+:30]#[C-])(C1C=CC(C)=CC=1)(=O)=O.[C:32](=[O:35])([O-])[O-].[K+].[K+]>C(O)C>[O:35]1[CH:32]=[C:16]([C:12]2[CH:11]=[C:10]([C@@H:8]([NH2:7])[CH3:9])[CH:15]=[CH:14][CH:13]=2)[N:30]=[CH:29]1
Reactant: C[C@H](NC(=O)OC(C)(C)C)c1cccc(C=O)c1
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: C[C@H](N)c1cccc(-c2cocn2)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 74.4 %

Procedure:
To a solution of (S)-[1-(3-formyl-phenyl)-ethyl]-carbamic acid tert-butyl ester (500 mg, 2 mmol) and tosylmethylisocyanide (391 g, 2 mmol) in ethanol (5 mL) was added potassium carbonate (277 mg, 2 mmol), and the reaction mixture was heated at reflux for 24 h. The reaction mixture was cooled down to room temperature and filtered. The filtrate was evaporated in vacuo, and the residue was purified by preparative HPLC (5 mM NH4OAc buffer; gradient 0% to 100% B in 10 min (A: 10 % CH3CN/H2O, B: 90% CH3CN/H2O); column: YMC 20×100 mm C-18 ) to provide the title compound (280 mg, 48% yield) as a brown oil.
Reaction SMILES: [CH2:1]([O:4][C:5](=[O:9])[C:6](Cl)=[O:7])[CH:2]=[CH2:3].[F-:10].[Cs+]>>[CH2:1]([O:4][C:5](=[O:9])[C:6]([F:10])=[O:7])[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)C(=O)Cl
Reactant: [F-]
Agent: [Cs+]
Product: C=CCOC(=O)C(=O)F

Procedure:
By the procedure of the preceding Preparation, allyl oxalochloride (252.5 g, 1.70 mol) and cesium fluoride (284 g, 1.87 mol) were converted to twice distilled title product, b.p. 48°-50° C./35 mm; 124°-126° C. (atmospheric pressure).
Reaction SMILES: [Mg].BrCCCO[Si]([C:10]([CH3:13])([CH3:12])[CH3:11])(C)C.[Br-].[C:15]([C:17]1[CH:22]=[CH:21][C:20]([C:23]([C:31]2[N:32]([CH3:36])[CH:33]=[N:34][CH:35]=2)=[N:24]S(CC(C)C)=O)=[CH:19][C:18]=1F)#[N:16].[CH2:38]1C[O:41][CH2:40][CH2:39]1>>[NH2:24][C:23]1([C:31]2[N:32]([CH3:36])[CH:33]=[N:34][CH:35]=2)[C:20]2=[CH:19][C:18](=[C:17]([C:15]#[N:16])[CH:22]=[CH:21]2)[O:41][C:40]2[CH:12]=[C:10]([CH:11]=[CH:38][CH:39]=2)[CH2:13][CH2:33][NH:32][CH2:31][CH2:23][CH2:20]1
Reactant: CC(C)(C)[Si](C)(C)OCCCBr
Reactant: C1CCOC1
Reactant: CC(C)CS(=O)N=C(c1ccc(C#N)c(F)c1)c1cncn1C
Agent: [Br-]
Agent: [Mg]
Product: Cn1cncc1C1(N)CCCNCCc2cccc(c2)Oc2cc1ccc2C#N

Procedure:
Magnesium (0.317 g, 12.03 mmol) was flame dried in a 50 mL RB flask equipped with addition funnel and magnetic stirrer under N2. When the flask had cooled, anhydrous THF (3 mL), a pinch of iodine, and a THF solution of Rieke magnesium (1 mL) were added, followed by a small portion of (3-bromopropoxy)-tert-butyldimethylsilane (3.048 g, 12.03 mmol) in THF (5 mL) with slight warming to initiate the reaction. The remainder of the bromide solution was added dropwise over 15 min. After 15 min. this Grignard solution was added to a solution of N-[(4-cyano-3-fluoro-phenyl)-(3-methyl-3H-imidazol-4-yl)-methylene]-2-methylpropanesulfinamide (Example 1, Step G) (1.00 g, 3.01 mmol) in THF (5 mL) with cooling in an ice-H2O bath. After 5 mL of Grignard solution was consumed, the reaction was complete by HPLC. The reaction mixture was quenched with H2O, diluted with saturated NaHCO3 solution and extracted with CH2Cl2 (2×20 mL). The organic layers were combined, washed with brine, dried (MgSO4), filtered and concentrated to give the crude product. Purification on an ISCO Combiflash eluting with 1-3% MeOH/CH2Cl2 w/NH4OH gave the title compound.