Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]([CH2:4][C:5]([NH:7][CH2:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[C:11](=[O:27])[N:12]([CH:19]1[CH2:24][CH2:23][C:22](=[O:25])[NH:21][C:20]1=[O:26])[C:13]2=[O:18])=[O:6])=[N+]=[N-].[H][H].[ClH:30]>CO.[Pd]>[ClH:30].[NH2:1][CH2:4][C:5]([NH:7][CH2:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[C:11](=[O:27])[N:12]([CH:19]1[CH2:24][CH2:23][C:22](=[O:25])[NH:21][C:20]1=[O:26])[C:13]2=[O:18])=[O:6]
Reactant: [H][H]
Reactant: [N-]=[N+]=NCC(=O)NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: NCC(=O)NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Yield: 84 %

Procedure:
A mixture of 2-azido-N-{[2-(2,6-dioxo(3-piperidyl))-1,3-dioxoisoindolin-4-yl]methyl}acetamide (1.2 g, 3.24 mmol), and 10% Pd/C (0.15 g) in 4N HCl (20 ml) and CH3OH (50 ml) was hydrogenated in Parr shake apparatus under 50 psi of hydrogen for 3 hours. The mixture was then filtered through celite and the filtrate was concentrated to a solid residue. The solid was slurried in ethanol (20 ml) and the suspension filtered to give 2-amino-N-{[2-(2,6-dioxo(3-piperidyl))1,3-dioxoisoindolin-4-yl]methyl}acetamide hydrochloride (0.86 g, 84%) as a white solid: mp 270–272° C.; 1H NMR (DMSO-d6) δ d 11.16 (s, 1H), 9.28 (t, J=5.7 Hz, 1H), 8.33 (s, 3H), 7.83 (s, 3H), 5.20–5.13 (dd, J=5.3 and 12.5 Hz, 1H), 4.81 (d, J=5.7 Hz, 2H), 3.69 (s, 2H), 2.92–2.87 (m, 1H), 2.65–2.51 (m, 2H), 2.09–2.05 (m, 1H); 13C NMR (DMSO-d6) δ d 172.76, 169.80, 167.44, 166.91, 166.52, 138.24, 134.74, 133.53, 131.51, 127.17, 122.08, 48.89, 37.89, 30.94, 21.99; Anal. Calcd. For C16H17N4O5Cl: C, 50.47; H, 4.50; N, 14.71; Cl, 9.31. Found: C, 50.39; H, 4.61; N, 14.42; Cl, 9.25.
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[C:12]([CH:15]=[O:16])[CH:11]=[CH:10][C:9]=2[O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:5])C>[OH-].[Na+].C(O)C>[CH2:18]([O:17][C:9]1[CH:10]=[CH:11][C:12]([CH:15]=[O:16])=[C:13]2[C:8]=1[NH:7][C:6]([C:4]([OH:5])=[O:3])=[CH:14]2)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CCOC(=O)c1cc2c(C=O)ccc(OCc3ccccc3)c2[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=Cc1ccc(OCc2ccccc2)c2[nH]c(C(=O)O)cc12
Yield: 107.6 %

Procedure:
2.26 g of 7-benzyloxy-4-formylindole-2-carboxylic acid ethyl ester is heated in a mixture of 15 ml of 1N sodium hydroxide solution and 15 ml of ethanol for one hour to 100° C. The ethanol is then distilled off under vacuum, the mixture is acidified with 10% hydrochloric acid and the precipitate is vacuum-filtered. The product is recrystallized from glacial acetic acid, thus obtaining 2.22 g of 7-benzyloxy-4-formylindole-2-carboxylic acid, mp 207° C.
Reaction SMILES: [C:1]1(=[O:11])[O:6][C:4](=[O:5])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[N+]([C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[NH:20][C:19]([CH3:24])=[CH:18]2)([O-])=O>C(Cl)CCl>[C:24]1([C:19]2[NH:20][C:21]3[C:17]([C:18]=2[C:4]([C:3]2[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=2[C:1]([OH:6])=[O:11])=[O:5])=[CH:16][CH:15]=[CH:23][CH:22]=3)[CH:4]=[CH:3][CH:2]=[CH:10][CH:9]=1
Reactant: O=C1OC(=O)c2ccccc21
Reactant: Cc1cc2cc([N+](=O)[O-])ccc2[nH]1
Solvent: ClCCCl
Product: O=C(O)c1ccccc1C(=O)c1c(-c2ccccc2)[nH]c2ccccc12

Procedure:
Proceeding in a manner similar to that described in part A of Example 10, 29.6 g (0.20 mole) of phthalic anhydride and 35.2 g (0.20 mole) of 5-nitro-2-methylindole were interacted in 100 ml of ethylene dichloride to obtain 2-[(2-methyl-5-nitro-3-indolyl)-carbonyl]benzoic acid (Formula VIII: R°=R1 =R2 =R3 =R6 =H; R5 =CH3 ; Y1 =5-NO2), a red brown solid melting at 144°-148° C. and showing a strong carbonyl absorption maximum at 1700 cm-1 in the infrared spectrum.
Reaction SMILES: C(O[C:6](=[O:31])[NH:7][C@H:8]([C:10](=[O:30])[NH:11][C@H:12]([B:17]1[O:25][C@H:24]2[C@:19]([CH3:29])([C@H:20]3[CH2:26][C@@H:22]([CH2:23]2)[C:21]3([CH3:28])[CH3:27])[O:18]1)[CH2:13][CH:14]([CH3:16])[CH3:15])[CH3:9])(C)(C)C.[C:32]1([C:54]2[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=2)[CH:37]=[CH:36][CH:35]=[C:34]([NH:38][C@@H:39]([CH2:43][C:44]2[CH:49]=[CH:48][C:47]([O:50][CH3:51])=[C:46]([O:52][CH3:53])[CH:45]=2)C(O)=O)[CH:33]=1>>[C:32]1([C:54]2[CH:55]=[CH:56][CH:57]=[CH:58][CH:59]=2)[CH:37]=[CH:36][CH:35]=[C:34]([NH:38][C@@H:39]([CH2:43][C:44]2[CH:49]=[CH:48][C:47]([O:50][CH3:51])=[C:46]([O:52][CH3:53])[CH:45]=2)[C:6]([NH:7][C@H:8]([C:10](=[O:30])[NH:11][C@H:12]([B:17]2[O:25][C@H:24]3[C@:19]([CH3:29])([C@H:20]4[CH2:26][C@@H:22]([CH2:23]3)[C:21]4([CH3:27])[CH3:28])[O:18]2)[CH2:13][CH:14]([CH3:16])[CH3:15])[CH3:9])=[O:31])[CH:33]=1
Reactant: COc1ccc(C[C@H](Nc2cccc(-c3ccccc3)c2)C(=O)O)cc1OC
Reactant: CC(C)C[C@H](NC(=O)[C@H](C)NC(=O)OC(C)(C)C)B1O[C@@H]2C[C@@H]3C[C@@H](C3(C)C)[C@]2(C)O1
Product: COc1ccc(C[C@H](Nc2cccc(-c3ccccc3)c2)C(=O)N[C@@H](C)C(=O)N[C@@H](CC(C)C)B2O[C@@H]3C[C@@H]4C[C@@H](C4(C)C)[C@]3(C)O2)cc1OC

Procedure:
The title compound is prepared as described in example 1 but using {(S)-1-[(R)-3-Methyl-1-((1S,2S,6R,8S)-2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.02,6]dec-4-yl)-butylcarbamoyl]-ethyl}-carbamic acid tert-butyl ester and (S)-2-(Biphenyl-3-ylamino)-3-(3,4-dimethoxyphenyl)-propionic acid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([O-:11])=[O:10])=[CH:5][CH:4]=1.[Na+].Br[C:14]1[CH:22]=[CH:21][C:20]2[N:19]([CH3:23])[C:18]3[CH2:24][CH:25]4[NH:29][CH:28]([C:17]=3[C:16]=2[C:15]=1[C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:27][CH2:26]4>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([S:9]([C:14]2[CH:22]=[CH:21][C:20]3[N:19]([CH3:23])[C:18]4[CH2:24][CH:25]5[NH:29][CH:28]([C:17]=4[C:16]=3[C:15]=2[C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:27][CH2:26]5)(=[O:11])=[O:10])=[CH:7][CH:8]=1
Reactant: Cn1c2c(c3c(C(=O)OC(C)(C)C)c(Br)ccc31)C1CCC(C2)N1
Reactant: COc1ccc(S(=O)[O-])cc1
Agent: [Na+]
Product: COc1ccc(S(=O)(=O)c2ccc3c(c2C(=O)OC(C)(C)C)c2c(n3C)CC3CCC2N3)cc1
Yield: 34 %

Procedure:
Intermediate 14 was coupled with the product of Example 27, step B following the procedure of Example 27, step C. The crude product was purified by flash column chromatography (8:2 hexanes/ethyl acetate) to give tert-butyl 2-(4-methoxyphenyl)sulfonyl-5-methyl-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole-carboxylate (106 mg, 34%) as a light-yellow solid: 1H NMR (CDCl3, 300 MHz) δ 8.17 (s, 1H), 7.88 (d, J=8.7 Hz, 2H), 7.60-7.71 (m, 1H), 7.27-7.32 (m, 1H), 6.92 (d, J=9.0 Hz, 2H), 5.26 (br s, 1H), 4.69 (br s, 1H), 3.82 (s, 3H), 3.59 (s, 3H), 3.40 (br s, 1H), 2.49 (d, J=16.2 Hz, 1H), 2.12-2.39 (m, 2H), 1.88-2.01 (m, 1H), 1.53-1.72 (m, 1H), 1.38 (br s, 9H).
Reaction SMILES: C(O[CH:4]=[C:5]1[C:9](=[O:10])[O:8][C:7]([C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH:14]=[CH:13][CH:12]=2)=[N:6]1)C.[CH:21](=[N:28][CH2:29][CH:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>O1CCCC1>[CH:21](=[N:28][CH2:29][CH:30]1[CH2:31][CH2:32][N:33]([CH:4]=[C:5]2[C:9](=[O:10])[O:8][C:7]([C:11]3[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[CH:14]=[CH:13][CH:12]=3)=[N:6]2)[CH2:34][CH2:35]1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CCOC=C1N=C(c2cccc3ccccc23)OC1=O
Reactant: C(=NCC1CCNCC1)c1ccccc1
Solvent: C1CCOC1
Product: O=C1OC(c2cccc3ccccc23)=NC1=CN1CCC(CN=Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 4-ethoxymethylene-2-naphthalen-1-yl-4H-oxazol-5-one (11.40 g, 43 mmol) in tetrahydrofuran, benzylidene-piperidin-4-ylmethyl-amine (8.60 g, 43 mmol) was added, and the mixture was stirred at room temperature for 24 h. The reaction mixture was concentrated under reduced pressure to yield 4-{4-[(benzylidene-amino)-methyl]-piperidin-1-ylmethylene}-2-naphthalen-1-yl-4H-oxazol-5-one.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:9]2[N:14]([CH2:15][C:16](O)=[O:17])[C:13](=[O:19])[C:12]3([CH2:25][O:24][CH2:23][CH2:22][O:21][CH2:20]3)[N:11]([CH3:26])[CH2:10]2)[CH:5]=[C:6]([F:8])[CH:7]=1.[NH2:27][C:28]1[CH:29]=[C:30]2[C:43](=[CH:44][CH:45]=1)[CH2:42][C@:32]1([C:40]3[C:35](=[N:36][CH:37]=[CH:38][CH:39]=3)[NH:34][C:33]1=[O:41])[CH2:31]2.Cl.C(N=C=NCCCN(C)C)C.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([C@H:9]2[N:14]([CH2:15][C:16]([NH:27][C:28]3[CH:29]=[C:30]4[C:43](=[CH:44][CH:45]=3)[CH2:42][C@:32]3([C:40]5[C:35](=[N:36][CH:37]=[CH:38][CH:39]=5)[NH:34][C:33]3=[O:41])[CH2:31]4)=[O:17])[C:13](=[O:19])[C:12]3([CH2:25][O:24][CH2:23][CH2:22][O:21][CH2:20]3)[N:11]([CH3:26])[CH2:10]2)[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: CN1C[C@@H](c2cc(F)cc(F)c2)N(CC(=O)O)C(=O)C12COCCOC2
Reactant: Nc1ccc2c(c1)C[C@@]1(C2)C(=O)Nc2ncccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CN1C[C@@H](c2cc(F)cc(F)c2)N(CC(=O)Nc2ccc3c(c2)C[C@@]2(C3)C(=O)Nc3ncccc32)C(=O)C12COCCOC2
Temperature: 50 °C
Reaction time: 1 h

Procedure:
75 mg (0.20 mmol) (R)-2-(3-(3,5-difluorophenyl)-1-methyl-5-oxo-8,11-dioxa-1,4-diazaspiro[5.6]dodecan-4-yl)-ethanoic acid, 55 mg (0.22 mmol) (R)-5-amino-1,3-dihydrospiro[inden-2,3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-one, 50 mg (0.26 mmol) 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide-hydrochloride, 35 mg (0.26 mmol) HOBT, 0.07 ml (0.50 mmol) TEA and 1.5 ml DMF were stirred overnight at RT. The reaction mixture was concentrated by rotary evaporation. The residue was stirred with 15 ml of a 1.25M methanolic hydrochloric acid for 1 h at 50° C. The mixture was concentrated by rotary evaporation and the residue was purified by HPLC. The fractions containing the product were combined and lyophilised.
Reaction SMILES: [C:1]1([N:7]2[C:15]([NH2:16])=[C:14]3[C:9]([CH:10]=[CH:11][CH:12]=[CH:13]3)=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:17](=O)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[C:1]1([N:7]2[C:15]([N:16]=[CH:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[C:14]3[C:9]([CH:10]=[CH:11][CH:12]=[CH:13]3)=[N:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Nc1c2ccccc2nn1-c1ccccc1
Reactant: O=Cc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: C(=Nc1c2ccccc2nn1-c1ccccc1)c1ccccc1
Yield: 107.1 %

Procedure:
To a solution of 2-phenyl-2H-indazol-3-amine (300 mg, 1.4 mmol; Shirtcliff, Laura D.; Rivers, Jazmin; Haley, Michael M, Journal of Organic Chemistry (2006), 71(17), 6619-6622) in CH2Cl2 (16 ml) was added benzaldehyde (730 μl, 7.2 mmol; [100-52-7]), acetic acid (220 ul, 4.3 mmol) and sodium triacetoxyborohydride (912 mg, 4.3 mmol) at ambient temperature under an argon atmosphere. The reaction mixture was heated under reflux conditions for 64 h, poured onto ice water/aqueous NaHCO3 solution 1/1 and extracted two times with CH2Cl2. The combined extracts were washed with ice water/brine 1/1 and dried over Na2SO4. After filtration the solvent was removed under reduced pressure, the resulting yellow oil was purified by column chromatography (silica gel, iPrOAc/heptane) to give the title compound (470 mg, 1.5 mmol; quant.) as yellow solid. MS: m/e=298.1 [M+H+].
Reaction SMILES: [Br:1]P(Br)Br.[Cl:5][C:6]1[CH:7]=[C:8]([CH2:13]O)[CH:9]=[N:10][C:11]=1[Cl:12].O>ClCCl>[Br:1][CH2:13][C:8]1[CH:7]=[C:6]([Cl:5])[C:11]([Cl:12])=[N:10][CH:9]=1
Reactant: OCc1cnc(Cl)c(Cl)c1
Reactant: BrP(Br)Br
Solvent: O
Solvent: ClCCl
Product: Clc1cc(CBr)cnc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 90 %

Procedure:
3.0 mL of tribromophosphine was added to 3.0 g of (5,6-dichloropyridin-3-yl)methanol (16.9 mmol) dissolved in 60 mL of dichloromethane, and stirred at room temperature for 2 hours. 30 mL of water was added dropwise thereto, and the organic layer was separated. The organic layer was washed with saturated sodium bicarbonate, and dried over magnesium sulfate. Then, the organic layer was concentrated under reduced pressure to obtain 3.66 g of 5-(bromomethyl)-2,3-dichloropyridine (yield 90%).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1CCC(N=C=NC2CCCCC2)CC1.CS(O[C:40]1[CH:45]=[CH:44][C:43]([C:46](=[NH:48])[NH2:47])=[CH:42][C:41]=1[C:49](=[O:56])[C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1)(=O)=O>N1C=CC=CC=1>[CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([O:19][C:40]1[CH:45]=[CH:44][C:43]([C:46](=[NH:47])[NH2:48])=[CH:42][C:41]=1[C:49](=[O:56])[C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1)=[O:18])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)CCCCCNC(=O)OCc1ccccc1
Reactant: CS(=O)(=O)Oc1ccc(C(=N)N)cc1C(=O)c1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: c1ccncc1
Product: N=C(N)c1ccc(OC(=O)CCCCCNC(=O)OCc2ccccc2)c(C(=O)c2ccccc2)c1
Reaction time: 0.5 h
Yield: 36.7 %

Procedure:
Into 50 ml of anhydrous pyridine, was dissolved 4.0 g of 6-benzyloxycarbonylaminocaproic acid. To the solution, while being cooled in ice, was added 3.7 g of DCC. After having been stirred for 30 minutes, the mixture was admixed with 5.0 g of 4-amidino-2-benzoylphenol methanesulfonate and stirred overnight at room temperature. The precipitate which was formed was separated by filtration and washed with pyridine. Ethyl ether was added to the filtrate to precipitate white crystals. The crystals were collected by filtration, washed with ethyl ether, dissolved in DMF, and admixed with ethyl ether to precipitate colorless crystals which were collected by filtration and dried to obtain 5.7 g of an anhydrous substance. This substance was recrystallized from ethanol to obtain 2.7 g of colorless needle crystals of 4-amidino 2-benzoylphenyl 6-benzyloxycarbonylaminocaproate methanesulfonate.
Reaction SMILES: [S:1]1[C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:4]=2[N:3]=[C:2]1[NH2:10].[Cl:11][C:12]1[CH:13]=[CH:14][C:15]([O:21][CH3:22])=[C:16]([CH:20]=1)[C:17](O)=[O:18]>>[Cl:11][C:12]1[CH:13]=[CH:14][C:15]([O:21][CH3:22])=[C:16]([CH:20]=1)[C:17]([NH:10][C:2]1[S:1][C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:4]=2[N:3]=1)=[O:18]
Reactant: COc1ccc(Cl)cc1C(=O)O
Reactant: Nc1nc2c(s1)CCCC2
Product: COc1ccc(Cl)cc1C(=O)Nc1nc2c(s1)CCCC2

Procedure:
Commercially available 4,5,6,7-tetrahydrobenzo[d]thiazol-2-amine (Aldrich) and 5-chloro-2-methoxybenzoic acid (Aldrich) were processed using the method described in Example 58 to afford the title compound MS (ESI+) m/z 323 (M+H)+.
Reaction SMILES: [N+](=[CH2:3])=[N-].[CH3:4][C:5]1[O:9][C:8]2[CH:10]=[CH:11][C:12]([C:14](=[O:18])[C:15]([OH:17])=[O:16])=[CH:13][C:7]=2[CH:6]=1>C(OCC)C.C(O)(=O)C>[CH3:4][C:5]1[O:9][C:8]2[CH:10]=[CH:11][C:12]([C:14](=[O:18])[C:15]([O:17][CH3:3])=[O:16])=[CH:13][C:7]=2[CH:6]=1
Reactant: Cc1cc2cc(C(=O)C(=O)O)ccc2o1
Reactant: C=[N+]=[N-]
Solvent: CCOCC
Solvent: CC(=O)O
Product: COC(=O)C(=O)c1ccc2oc(C)cc2c1
Reaction time: 0.08 h

Procedure:
An ethereal solution of diazomethane is added in portions to a solution of 2-methyl-5-benzo(b)furanylglyoxylic acid in dry ethyl ether until the yellow color of diazomethane persists. The resulting mixture is stirred five minutes and a few drops of ethereal acetic acid added to consume the excess reagent. The ether solution is washed with water, dilute sodium bicarbonate solution, water again and dried over anhydrous magnesium sulfate. The ether is evaporated to obtain methyl 2-methyl-5-benzo(b)furanylglyoxylate.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[C:6](=[O:14])[C:7]3[S:8][CH:9]=[CH:10][C:11]=3[C:12](=[O:13])[C:2]1=2.[OH-].[Na+].C1(C)C=CC(S(O[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])(=O)=O)=CC=1>[Zn].C(O)C>[CH2:5]([O:14][C:6]1[C:7]2[S:8][CH:9]=[CH:10][C:11]=2[C:12]([O:13][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH3:27])=[C:2]2[S:1][CH:5]=[CH:4][C:3]=12)[CH2:4][CH2:3][CH2:2][CH2:12][CH2:11][CH2:7][CH3:6]
Reactant: CCCCCCCCOS(=O)(=O)c1ccc(C)cc1
Reactant: O=C1c2ccsc2C(=O)c2ccsc21
Agent: [Na+]
Agent: [OH-]
Agent: [Zn]
Solvent: CCO
Product: CCCCCCCCOc1c2ccsc2c(OCCCCCCCC)c2ccsc12
Yield: 62 %

Procedure:
1.0 g (4.5 mmol) of benzo[1,2-b:4,5-b′]dithiophene-4,8-dione was mixed with 0.65 g (10 mmol) of zinc dust in a flask. Then, 4 ml of ethanol and 15 ml of 20% NaOH was added and the mixture was refluxed for 1 h. 4.3 mL octyl p-toluenesulfonate was added in portions with stirring until the color changed to red. The resulting precipitate was filtered, the filtrate was diluted with 100 mL water and extracted with 100 mL chloroform. The organic extraction was dried with anhydrous sodium sulfate and evaporated in vacuo. Column chromatography on silica gel using dichloromethane and hexanes mixed solvents yielded the pure title compound as a white solid (1.24 g, 62%). 1HNMR (CDCl3): δ0.88-0.91 (6H, t, J=7 Hz), 1.31-1.38 (16H, m), 1.54-1.58 (4H, m), 1.84-1.89 (4H, m), 4.26-4.29 (4H, J=7 Hz), 7.36-7.37 (2H, d, J=6 Hz), 7.47-7.48 (2H, d, J=6 Hz).
Reaction SMILES: [O:1]=[C:2]1[CH2:6][O:5][C:4]([NH:7][N:8]2[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)=[C:3]1[C:14]([O:16][CH2:17][CH3:18])=[O:15].[NH:19]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][N:26]=2)[C:21]([CH:28]=O)=[CH:20]1.N1CCC[C@H]1C(O)=O>C(O)C>[NH:19]1[C:27]2=[N:26][CH:25]=[CH:24][CH:23]=[C:22]2[C:21]([CH:28]=[C:6]2[O:5][C:4]([NH:7][N:8]3[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]3)=[C:3]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:2]2=[O:1])=[CH:20]1
Reactant: O=Cc1c[nH]c2ncccc12
Reactant: CCOC(=O)C1=C(NN2CCCCC2)OCC1=O
Agent: O=C(O)[C@@H]1CCCN1
Solvent: CCO
Product: CCOC(=O)C1=C(NN2CCCCC2)OC(=Cc2c[nH]c3ncccc23)C1=O
Temperature: 25 °C
Yield: 4 %

Procedure:
To a solution of ethyl 4-oxo-2-(N-piperidinoamino)-4,5-dihydrofuran-3-carboxylate (0.25 g, 0.98 mmol) which similarly prepared according to the procedure described in the Example 74, Fourth step and 7-azaindole-3-carboxaldehyde (0.14 g, 0.98 mmol) in ethanol (10 mL), L-proline (0.011 mg, 0.096 mmol) was added at ambient temperature. The mixture was refluxed for 2 days. Cooled to ambient temperature, the precipitate was collected by filtration, washed with ethanol and diethyl ether then dried to afford the titled compound as solid (0.015 g, y. 4%).
Reaction SMILES: [F:1][C:2]([C:14]([F:17])([F:16])[F:15])([CH2:6][CH:7]=[CH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])[C:3]([NH2:5])=[O:4].[H][H]>CO.[C].[Pd]>[F:1][C:2]([C:14]([F:15])([F:17])[F:16])([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])[C:3]([NH2:5])=[O:4]
Reactant: [H][H]
Reactant: CCCCCC=CCC(F)(C(N)=O)C(F)(F)F
Agent: [Pd]
Solvent: CO
Product: CCCCCCCCC(F)(C(N)=O)C(F)(F)F
Reaction time: 24 h
Yield: 120.8 %

Procedure:
Into a solution of 3.0 g (9.65 mmol) of 2-fluoro-2-trifluoromethyl-4-decenamide in 30 ml of methanol, palladium-carbon (75 mg) was added under nitrogen. After the atmosphere was replaced with hydrogen, the mixture was stirred for 24 hours. To remove the catalyst, the resulting mixture was filtered with celite and the filtrate was concentrated. The raw product was purified using silica gel column chromatography to obtain 3.0 g of the desired compound. The yield was 99.3%.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:27]=[CH:26][C:6]([C:7]([N:9]2[CH2:14][CH2:13][CH:12]([N:15]3[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[CH2:19][CH2:18][C:16]3=[O:17])[CH2:11][CH2:10]2)=[O:8])=[CH:5][CH:4]=1.[Cl:28][CH2:29][C:30](Cl)=[O:31].C(N(CC)CC)C>ClCCl>[Cl:28][CH2:29][C:30]([N:2]([C:3]1[CH:4]=[CH:5][C:6]([C:7]([N:9]2[CH2:14][CH2:13][CH:12]([N:15]3[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[CH2:19][CH2:18][C:16]3=[O:17])[CH2:11][CH2:10]2)=[O:8])=[CH:26][CH:27]=1)[CH3:1])=[O:31]
Reactant: O=C(Cl)CCl
Reactant: CNc1ccc(C(=O)N2CCC(N3C(=O)CCc4ccccc43)CC2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(C(=O)CCl)c1ccc(C(=O)N2CCC(N3C(=O)CCc4ccccc43)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1-{1-[4-(N-methylamino)benzoyl]-4-piperidinyl}-3,4-dihydrocarbostyril (200 mg) is dissolved in dichloromethane (5 ml) and thereto is added α-chloroacetyl chloride (55 μl) under ice cooling. Continually thereto is added triethylamine (0.23 ml) and the mixture is stirred at room temperature overnight. After the solvent is concentrated, the residue is purified by silica gel column chromatography (solvent: n-hexane:ethyl acetate=1:1) and recrystallized from n-hexane/ethanol to give 1-{1-[4-(N-α-chloroacetyl-N-methylamino)benzoyl)-4-piperidinyl]-3,4-dihydrocarbostyril (0.18 g) as white powder, m.p.: 220°-222° C. (decomposed).
Reaction SMILES: C([Si](C)(C)[O:6][CH2:7][CH2:8][N:9]1[C:17]2[C:12](=[CH:13][C:14]([C:18]([N:20]3[CH2:24][CH2:23][CH2:22][C@H:21]3[CH2:25][N:26]3[CH2:30][CH2:29][CH2:28][CH2:27]3)=[O:19])=[CH:15][CH:16]=2)[CH:11]=[C:10]1[C:31]([N:33]1[CH2:38][CH2:37][C:36]([F:40])([F:39])[CH2:35][CH2:34]1)=[O:32])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[F:40][C:36]1([F:39])[CH2:37][CH2:38][N:33]([C:31]([C:10]2[N:9]([CH2:8][CH2:7][OH:6])[C:17]3[C:12]([CH:11]=2)=[CH:13][C:14]([C:18]([N:20]2[CH2:24][CH2:23][CH2:22][C@H:21]2[CH2:25][N:26]2[CH2:27][CH2:28][CH2:29][CH2:30]2)=[O:19])=[CH:15][CH:16]=3)=[O:32])[CH2:34][CH2:35]1
Reactant: CC(C)(C)[Si](C)(C)OCCn1c(C(=O)N2CCC(F)(F)CC2)cc2cc(C(=O)N3CCC[C@H]3CN3CCCC3)ccc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(c1cc2cc(C(=O)N3CCC[C@H]3CN3CCCC3)ccc2n1CCO)N1CCC(F)(F)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 55.9 %

Procedure:
The solution of 90 mg (0.15 mmol) [1-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-5-((S)-2-pyrrolidin-1-ylmethyl-pyrrolidine-1-carbonyl)-1H-indol-2-yl]-(4,4-difluoro-piperidin-1-yl)-methanone in 3 mL dichloromethane was cooled to 0° C. and 1.0 mL (1.49 g, 13.1 mmol) trifluoroacetic acid were added. The cooling bath was removed and after stirring for 1 h at room temperature the pH of the solution was neutralized by adding 1M aqueous sodium hydroxide solution. The phases were separated and the aqueous phase was extracted three times with dichloromethane. The combined organic layers were dried over magnesium sulfate, filtered and evaporated. The crude product was purified by flash column chromatography on silica gel with dichloromethane:methanol as eluant (gradient 100:0 to 50:50) to give 41 mg (56%) of the desired compound as a white foam.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[SH:20][C:21]1[CH:22]=[C:23]2[C:28](=[CH:29][CH:30]=1)[N:27]([CH3:31])[C:26](=[O:32])[CH2:25][CH2:24]2.Br[C:34]1[S:38][C:37]([C@@:39]2([O:46][CH3:47])[CH2:44][CH2:43][O:42][C@@H:41]([CH3:45])[CH2:40]2)=[N:36][CH:35]=1>>[CH3:47][O:46][C@:39]1([C:37]2[S:38][C:34]([S:20][C:21]3[CH:22]=[C:23]4[C:28](=[CH:29][CH:30]=3)[N:27]([CH3:31])[C:26](=[O:32])[CH2:25][CH2:24]4)=[CH:35][N:36]=2)[CH2:44][CH2:43][O:42][C@@H:41]([CH3:45])[CH2:40]1
Reactant: CO[C@]1(c2ncc(Br)s2)CCO[C@@H](C)C1
Reactant: CN1C(=O)CCc2cc(S)ccc21
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CO[C@]1(c2ncc(Sc3ccc4c(c3)CCC(=O)N4C)s2)CCO[C@@H](C)C1
Yield: 72 %

Procedure:
Using an analogous procedure to that described in Example 1 except that triphenylphosphine (0.04 g) was added, 6-mercapto-1-methyl-1,2,3,4-tetrahydroquinolin-2-one (0.153 g) was reacted with (2S,4R)-4-(5-bromothiazol-2-yl)-4-methoxy-2-methyltetrahydropyran (0.23 g) to give (2S,4R)-4-methoxy-2-methyl-4-[5-(1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-ylthio)thiazol-2-yl]-tetrahydropyran in 72% yield as a foam;
Reaction SMILES: [C:1]1([C:7]2[CH:11]=[C:10]([CH2:12][CH2:13][C@@H:14]([OH:17])[CH2:15][OH:16])[NH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CO[C:20](OC)([CH3:22])[CH3:21].CC1C=CC(S(O)(=O)=O)=CC=1>CC(C)=O>[CH3:21][C:20]1([CH3:22])[O:17][C@H:14]([CH2:13][CH2:12][C:10]2[NH:9][N:8]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH:11]=2)[CH2:15][O:16]1
Reactant: OC[C@H](O)CCc1cc(-c2ccccc2)n[nH]1
Reactant: COC(C)(C)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)=O
Product: CC1(C)OC[C@@H](CCc2cc(-c3ccccc3)n[nH]2)O1
Reaction time: 3 h

Procedure:
To a solution of (R)-4-(3-phenyl-1H-pyrazol-5-yl)butane-1,2-diol (2.5 g, 10.76 mmol) in acetone (50 mL), were added 2,2-dimethoxypropane (11.21 g, 108 mmol) and PTSA (0.185 g, 1.076 mmol) at room temperature. After stirring for 3 h, the reaction was concentrated under reduced pressure. The resulting residue was poured into water and extracted with ethyl acetate. The extract was dried over MgSO4 and concentrated under reduced pressure to give the title compound without further purification. LCMS m/z=273.4 [M+H]+.