Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][NH:15][C:16]2[NH:20][C:19]3[CH:21]=[CH:22][CH:23]=[C:24]([C:25](=[O:31])[NH:26][CH2:27][CH2:28][O:29][CH3:30])[C:18]=3[N:17]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.O1CCOCC1.Cl>CO>[CH3:30][O:29][CH2:28][CH2:27][NH:26][C:25]([C:24]1[C:18]2[N:17]=[C:16]([NH:15][CH2:14][CH:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)[NH:20][C:19]=2[CH:21]=[CH:22][CH:23]=1)=[O:31]
Reactant: COCCNC(=O)c1cccc2[nH]c(NCC3CCN(C(=O)OC(C)(C)C)CC3)nc12
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: COCCNC(=O)c1cccc2[nH]c(NCC3CCNCC3)nc12
Temperature: 50 °C
Reaction time: 1 h

Procedure:
After dissolving 4-{[4-(2-methoxy-ethylcarbamoyl)-1H-benzimidazol-2-ylamino]-methyl}-piperidine-1-carboxylic acid tert-butyl ester (1.30 g, 3.01 mmol) in methanol (1 ml), a 4N hydrogen chloride-1,4-dioxane solution (7.0 ml, 28.0 mmol) was added and the mixture was stirred at 50° C. for 1 hour. The reaction mixture was concentrated under reduced pressure and vacuum dried to obtain 2-[(piperidin-4-ylmethyl)-amino]-1H-benzimidazole-4-carboxylic acid (2-methoxy-ethyl)-amide. The compound was identified by LC-MS.
Reaction SMILES: [CH3:1][C:2]([CH3:5])([O-])[CH3:3].[K+]>C(O)COCCOCCO>[C:1]([C:2]12[CH2:5][CH:3]3[CH2:1][CH:2]([CH2:5][CH:1]([CH2:2]3)[CH2:3]1)[CH2:3]2)#[CH:5]
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: OCCOCCOCCO
Product: C#CC12CC3CC(CC(C3)C1)C2

Procedure:
The Stetter and Goebel reference, also cited above, discloses the synthesis of 1-ethynyladamantane from 1-bromoadamantane in good yield. We repeated that procedure with minor modifications by reacting 1-bromoadamantane with vinyl bromide in the presence of aluminum bromide to give the 2,2-dibromoethyl derivative, then dehydrobrominating that derivative in situ with potassium t-butoxide in triethylene glycol to give 1-ethynyladamantane in 60% overall yield.
Reaction SMILES: N[C:2]1[CH:3]=[C:4]([C:8]2[C:9]([C:14]#[N:15])=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:5]=[CH:6][CH:7]=1.S(=O)(=O)(O)[OH:17].N([O-])=O.[Na+]>O1CCOCC1.O>[OH:17][C:2]1[CH:3]=[C:4]([C:8]2[C:9]([C:14]#[N:15])=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=S(=O)(O)O
Reactant: N#Cc1ccccc1-c1cccc(N)c1
Agent: O=N[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: N#Cc1ccccc1-c1cccc(O)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 65 %

Procedure:
A solution of 3′-aminobiphenyl-2-carbonitrile (10.9 g, 56 mmol) in 1,4-dioxane (30 ml) was treated with a solution of 25% aqueous sulphuric acid (150 ml). The resulting suspension was cooled to 0° C. before being treated dropwise over 10 minutes with a solution of sodium nitrite (4.6 g, 67 mmol) in water (10 ml). After stirring at 0° C. for 30 minutes the reaction was poured into hot (70° C.) water (500 ml). On cooling to ambient temperature the product was extracted into ethyl acetate (500 ml), the organics were washed with water (300 ml), brine (300 ml) and dried over anhydrous sodium sulfate. Filtration and concentration in vacuo afforded 3′-hydroxybiphenyl-2-carbonitrile as a dark oil (7.1 g, 65%). 1H NMR (400 MHz, CDCl3) δH 5.40 (1H, br), 6.92 (1H, ddd, J 8, 3 and 1), 7.04 (1H, dd, J 3 and 3), 7.11 (1H, ddd, J 8, 3 and 1), 7.35 (1H, dd, J 8 and 8), 7.44 (1H, ddd, J 8, 8 and 1), 7.51 (1H, dd, J 8 and 1), 7.64 (1H, ddd, J 8, 8 and 1), 7.75 (1H, dd, J 8 and 1).
Reaction SMILES: N1C2OCC(N)C=2C=CN=1.CO[N:13]=[C:14]1[C:22]2[C:17](=[C:18]([O:23][CH3:24])[N:19]=[CH:20][CH:21]=2)[O:16][CH2:15]1>>[CH3:24][O:23][C:18]1[N:19]=[CH:20][CH:21]=[C:22]2[CH:14]([NH2:13])[CH2:15][O:16][C:17]=12
Reactant: CON=C1COc2c1ccnc2OC
Agent: NC1COc2nnccc21
Product: COc1nccc2c1OCC2N

Procedure:
This compound was prepared using a method analogous to that of 5,6-dihydrofuro[2,3-c]pyridazin-5-amine (A.2.3.4), 7-methoxyfuro[2,3-c]pyridin-3(2H)-one O-methyl oxime replacing furo[2,3-c]pyridazin-5(6H)-one O-methyl oxime;
Reaction SMILES: [CH2:1]([OH:10])[CH:2]([OH:9])[CH:3]([OH:8])[CH:4]([OH:7])[CH:5]=[O:6].O=C[C@@H]([C@H]([C@@H](CO)O)O)O>C(O)C>[CH2:5]([OH:6])[C@@H:4]([C@H:3]([C@@H:2]([CH2:1][OH:10])[OH:9])[OH:8])[OH:7]
Reactant: O=CC(O)C(O)C(O)CO
Agent: O=C[C@H](O)[C@@H](O)[C@H](O)CO
Solvent: CCO
Product: OC[C@@H](O)[C@H](O)[C@@H](O)CO

Procedure:
Accordingly, in order to solve the problems as described above, the present invention provides a method for producing xylitol by fermentation of lignocellulosic hydrolysates without detoxification. A xylitol fermentation yeast strain is isolated and screened from the fermentation broth of a 100 liter pentose fermenter in the mini-pilot plant of the Institute of Nuclear Energy Research for cellulosic ethanol research and development, and then molecular analysis of the 18S rDNA sequence has identified the strain as a yeast strain of Candida sp. belonging to Candida genus. The strain is used to ferment the synthetic xylose solution to produce xylitol, and the maximum yield can be approximately to 0.8 g/g, which is higher than those of xylitol production strains also belonging to Candida genus, such as Candida boidinii, Candida guilliermondii, Candida utilis, and Candida maltosa (mostly with a xylitol yield of below 0.7 g/g). Meanwhile, the xylitol yield of this newly isolated strain also reaches a leading level, compared with other xylitol-producing stains belonging to different yeast genus.
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[CH:9]=[C:8]([O:10][C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[NH:16][CH:15]=[CH:14]3)[CH:7]=[CH:6][N:5]=1.[CH:20]1([NH:23][C:24](=O)[O:25]C2C=CC=CC=2)[CH2:22][CH2:21]1.O>CN(C)C=O>[CH:20]1([NH:23][C:24]([N:16]2[C:17]3[C:13](=[CH:12][C:11]([O:10][C:8]4[CH:7]=[CH:6][N:5]=[C:4]([NH2:3])[CH:9]=4)=[CH:19][CH:18]=3)[CH:14]=[CH:15]2)=[O:25])[CH2:22][CH2:21]1
Reactant: Nc1cc(Oc2ccc3[nH]ccc3c2)ccn1
Reactant: O=C(NC1CC1)Oc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Nc1cc(Oc2ccc3c(ccn3C(=O)NC3CC3)c2)ccn1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 1168.8 %

Procedure:
After adding 28 mg of sodium hydride (60% in oil) to a solution of 150 mg of 5-[(2-amino-4-pyridyl)oxy]-1H-indole in dimethylformamide at room temperature and stirring for 5 minutes, the mixture was cooled to 0° C., 124 mg of phenyl N-cyclopropylcarbamate was added and the mixture was further stirred for 30 minutes. Water was added, extraction was performed with ethyl acetate, the organic layer was washed 3 times with water and once with ammonium chloride water, and then silica gel was added and the solvent was distilled off under reduced pressure. The silica gel was charged into a dry column packed with silica gel and purification was performed by column chromatography (hexane:ethyl acetate=1:1, followed by ethyl acetate), to obtain 2.4 g of a colorless powder.
Reaction SMILES: [C:1]1([S:7]([C:10]2[C:11]([CH:18]=O)=[N:12][C:13]([S:16][CH3:17])=[N:14][CH:15]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:20][O:21][C:22](=[O:35])[CH2:23][N:24]1[C:32]2[C:27](=[CH:28][C:29]([F:33])=[CH:30][CH:31]=2)[CH:26]=[C:25]1[CH3:34]>>[CH3:20][O:21][C:22](=[O:35])[CH2:23][N:24]1[C:32]2[C:27](=[CH:28][C:29]([F:33])=[CH:30][CH:31]=2)[C:26]([CH2:18][C:11]2[C:10]([S:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)(=[O:8])=[O:9])=[CH:15][N:14]=[C:13]([S:16][CH3:17])[N:12]=2)=[C:25]1[CH3:34]
Reactant: COC(=O)Cn1c(C)cc2cc(F)ccc21
Reactant: CSc1ncc(S(=O)(=O)c2ccccc2)c(C=O)n1
Product: COC(=O)Cn1c(C)c(Cc2nc(SC)ncc2S(=O)(=O)c2ccccc2)c2cc(F)ccc21

Procedure:
The title compound was prepared by the method of Preparation 1c using 5-benzenesulfonyl-2-methylsulfanylpyrimidine-4-carbaldehyde and (5-fluoro-2-methylindol-1-yl)acetic acid methyl ester.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:10](=[O:15])[CH2:11][CH2:12][C:13]=1[CH3:14].N1C=CC=CC=1.[C:22]1([CH3:34])[CH:27]=[C:26]([CH3:28])[CH:25]=[C:24]([CH3:29])[C:23]=1[S:30](Cl)(=[O:32])=[O:31]>>[C:22]1([CH3:34])[CH:27]=[C:26]([CH3:28])[CH:25]=[C:24]([CH3:29])[C:23]=1[S:30]([NH:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:10](=[O:15])[CH2:11][CH2:12][C:13]=1[CH3:14])(=[O:31])=[O:32]
Reactant: Cc1cc(C)c(S(=O)(=O)Cl)c(C)c1
Reactant: CC1=C(c2ccc(F)cc2N)C(=O)CC1
Solvent: c1ccncc1
Product: CC1=C(c2ccc(F)cc2NS(=O)(=O)c2c(C)cc(C)cc2C)C(=O)CC1

Procedure:
0.800 g (3.90 mmol) of 2-(2-amino-4-fluorophenyl)-3-methyl-2-cyclopenten-1-one, 0.339 g (4.29 mmol) of pyridine, 0.938 g (4.29 mmol) of 2-mesitylenesulfonyl chloride, and 4 mL of M.C were loaded to a 20 mL vial, and then reacted for 12 hours. The work-up was the same as in Example 7 (1.29 g, 85%).
Reaction SMILES: [C:1]([CH:3]1[CH2:6][N:5]([C:7](=[O:31])[C@H:8]([NH:10][C:11]([C:13]2[C:21]3[C:16](=[N:17][CH:18]=[C:19](Br)[N:20]=3)[N:15](COCC[Si](C)(C)C)[CH:14]=2)=[O:12])[CH3:9])[CH2:4]1)#[N:2].C(C1CCN(C(=O)[C@H](NC(C2C3C(=NC=C(Br)N=3)N(COCC[Si](C)(C)C)C=2)=O)C2CC2)CC1)#N.[N:67]1([C:72]2[CH:77]=[CH:76][N:75]=[C:74]([Sn](CCCC)(CCCC)CCCC)[CH:73]=2)[CH:71]=[CH:70][CH:69]=[CH:68]1.C(C1C=CN=C([Sn](CCCC)(CCCC)CCCC)C=1)(C)(C)C>>[C:1]([CH:3]1[CH2:6][N:5]([C:7](=[O:31])[C@H:8]([NH:10][C:11]([C:13]2[C:21]3[C:16](=[N:17][CH:18]=[C:19]([C:76]4[CH:77]=[C:72]([N:67]5[CH:71]=[CH:70][CH:69]=[CH:68]5)[CH:73]=[CH:74][N:75]=4)[N:20]=3)[NH:15][CH:14]=2)=[O:12])[CH3:9])[CH2:4]1)#[N:2]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cc(-n2cccc2)ccn1
Reactant: C[C@@H](NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(Br)nc12)C(=O)N1CC(C#N)C1
Agent: CCCC[Sn](CCCC)(CCCC)c1cc(C(C)(C)C)ccn1
Agent: C[Si](C)(C)CCOCn1cc(C(=O)N[C@@H](C(=O)N2CCC(C#N)CC2)C2CC2)c2nc(Br)cnc21
Product: C[C@@H](NC(=O)c1c[nH]c2ncc(-c3cc(-n4cccc4)ccn3)nc12)C(=O)N1CC(C#N)C1

Procedure:
Prepared according to the procedure outlined in Example 111, steps 4-5 substituting 2-bromo-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(3-cyano-azetidin-1-yl)-1-methyl-2-oxo-ethyl]-amide for 2-bromo-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(4-cyano-piperidin-1-yl)-1-cyclopropyl-2-oxo-ethyl]-amide and 4-pyrrol-1-yl-2-tributylstannanyl-pyridine for 4-tert-butyl-2-(tributylstannyl)pyridine. MS: (M+H)+=441.
Reaction SMILES: Cl.[Cl:2][C:3]1[C:12]2[C:7](=[CH:8][C:9]([O:15][CH2:16][CH2:17][CH2:18][N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)=[C:10]([O:13][CH3:14])[CH:11]=2)[N:6]=[CH:5][CH:4]=1.[Cl:25][C:26]1[CH:32]=[CH:31][C:29]([NH2:30])=[C:28]([F:33])[CH:27]=1>>[ClH:2].[Cl:25][C:26]1[CH:32]=[CH:31][C:29]([NH:30][C:3]2[C:12]3[C:7](=[CH:8][C:9]([O:15][CH2:16][CH2:17][CH2:18][N:19]4[CH2:24][CH2:23][O:22][CH2:21][CH2:20]4)=[C:10]([O:13][CH3:14])[CH:11]=3)[N:6]=[CH:5][CH:4]=2)=[C:28]([F:33])[CH:27]=1
Reactant: Nc1ccc(Cl)cc1F
Reactant: COc1cc2c(Cl)ccnc2cc1OCCCN1CCOCC1
Agent: Cl
Product: COc1cc2c(Nc3ccc(Cl)cc3F)ccnc2cc1OCCCN1CCOCC1
Yield: 25 %

Procedure:
Using an analogous procedure to that described for Example 31, 4-chloro-6-methoxy-7-(3-morpholinopropoxy)quinoline hydrochloride (300 mg, 0.73 mmol), (prepared as described for the starting material in Example 7), was reacted with 4-chloro-2-fluoroaniline (160 μl, 1.4 mmol) to give 4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(3-morpholinopropoxy)quinoline hydrochloride (88 mg, 23%).
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=1[NH2:6])([O-])=O.C([N:14]1[C:22]2[C:17](=[CH:18][C:19]([C:23](Cl)=O)=[CH:20][CH:21]=2)[C:16]([C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)=[N:15]1)(=O)C.O>N1C=CC=CC=1>[N:6]1[C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[NH:1][C:23]=1[C:19]1[CH:18]=[C:17]2[C:22](=[CH:21][CH:20]=1)[NH:14][N:15]=[C:16]2[C:26]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=1
Reactant: Nc1ccccc1[N+](=O)[O-]
Reactant: CC(=O)n1nc(-c2ccc(F)cc2)c2cc(C(=O)Cl)ccc21
Solvent: O
Solvent: c1ccncc1
Product: Fc1ccc(-c2n[nH]c3ccc(-c4nc5ccccc5[nH]4)cc23)cc1
Reaction time: 8 h
Yield: 17 %

Procedure:
To a solution of 2-nitroaniline (92 mg, 0.67 mmol) in pyridine (4 mL) was added 1-acetyl-3-(4-fluorophenyl)-1H-indazole-5-carbonyl chloride (200 mg, 0.67 mmol). The reaction was stirred at room temperature overnight when water (30 mL) was added and the solid filtered and dried in a vacuum oven (45° C.). The solid was then taken up in ethyl acetate (20 mL)/ethanol (20 mL) and a scoup of palladium on carbon added. The resulting heterogenous solution was then subjected to an atmosphere of hydrogen. After stirring overnight, the solution was filtered and concentrated to an oil under vacuo and taken up in 4 N HCl (80 mL) which was refluxed for 12 hours. The reaction was quenched with saturated NaHCO3 and the product collected as a solid. The pure product was isolated after chromatography on silica gel eluting with 7% methanol in methylene chloride. (37 mg, 17% yield). 1H NMR (DMSO-d6) δ 13.6 (br s, 1H), 8.86 (s, 1H), 8.29 (d, 1H), 8.16–8.10 (m, 2H), 7.76 (d, 1H), 7.64 (dd, 2H), 7.45 (t, 2H), 7.24 (dd, 2H); ES-MS (m/z) 329 [M+1]+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(C)N=C=NC(C)C.[C:17]([O:21][C:22]([N:24]1[CH2:37][CH2:36][C:35]2[C:34]3[CH:33]=[C:32]([Cl:38])[C:31]([Cl:39])=[CH:30][C:29]=3[N:28]([CH2:40][C:41](O)=[O:42])[C:27]=2[CH2:26][CH2:25]1)=[O:23])([CH3:20])([CH3:19])[CH3:18]>CN(C1C=CN=CC=1)C.C1COCC1.CCOC(C)=O>[NH:1]([C:41](=[O:42])[CH2:40][N:28]1[C:29]2[CH:30]=[C:31]([Cl:39])[C:32]([Cl:38])=[CH:33][C:34]=2[C:35]2[CH2:36][CH2:37][N:24]([C:22]([O:21][C:17]([CH3:19])([CH3:18])[CH3:20])=[O:23])[CH2:25][CH2:26][C:27]1=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCc2c(n(CC(=O)O)c3cc(Cl)c(Cl)cc23)CC1
Reactant: Nc1ccccc1
Agent: CC(C)N=C=NC(C)C
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCc2c(n(CC(=O)Nc3ccccc3)c3cc(Cl)c(Cl)cc23)CC1
Reaction time: 18 h
Yield: 51.2 %

Procedure:
DMAP (60 mg, 0.49 mmol), aniline (0.050 mL, 0.55 mmol) and DIC (0.084 mL, 0.54 mmol) were added to the solution of crude [3-(tert-butoxycarbonyl)-8,9-dichloro-2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl]acetic acid (0.20 g, 0.48 mmol) in dry THF (2.5 mL). After 18 h, the reaction was diluted with EtOAc followed by washing with 10% aqueous citric acid, saturated aqueous NaHCO3, and brine. The organic layer was then dried over Na2SO4, decanted, and concentrated. The crude product was first purified by column chromatography (Biotage, 40S, SIM) with CH2Cl2/EtOAc (98:2) to give 0.12 g of impure product. Then, crystallization from EtOAc/heptane gave 91 mg (39%) of a white solid: mp 172.5° C.; IR (diffuse reflectance) 3288, 1699, 1661, 1602, 1550, 1498, 1472, 1442, 1421, 1367, 1309, 1298, 1268, 1252, 1162 cm−1; MS (CI) m/z 488 (M+H+), 390, 388, 354, 153, 152, 136, 95, 93, 52, 51; Anal. Calcd for C25H27Cl2N3O3: C, 61.48; H, 5.57; N, 8.60; found: C, 61.49; H, 5.67; N, 8.51.
Reaction SMILES: Cl[CH2:2]I.C([O-])([O-])=O.[K+].[K+].[Cl:10][C:11]1[N:16]=[C:15]([C:17]2[NH:25][C:20]3=[N:21][CH:22]=[CH:23][CH:24]=[C:19]3[CH:18]=2)[C:14]([OH:26])=[CH:13][CH:12]=1>CN(C=O)C>[Cl:10][C:11]1[CH:12]=[CH:13][C:14]2[O:26][CH2:2][N:25]3[C:20]4[N:21]=[CH:22][CH:23]=[CH:24][C:19]=4[CH:18]=[C:17]3[C:15]=2[N:16]=1
Reactant: Oc1ccc(Cl)nc1-c1cc2cccnc2[nH]1
Reactant: ClCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Clc1ccc2c(n1)-c1cc3cccnc3n1CO2
Temperature: 100 °C
Reaction time: 2 h
Yield: 9.6 %

Procedure:
To a mixture of chloroiodomethane (2.01 g, 11.40 mmol), K2CO3 (338 mg, 2.44 mmol) in DMF (15 mL), 6-chloro-2-(1H-pyrrolo[2,3-b]pyridin-2-yl)pyridin-3-ol (200 mg, 0.81 mmol) in DMF (5 mL) was added dropwise at 100° C. under N2 protection. After stirred at 100° C. for 2 hours, the reaction mixture was concentrated in vacuo, suspended in water and extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4 and concentrated in vacuo. The crude product was purified using prep-TLC (petroleum ether:EtOAc=8:1) to provide the product of 2-chloro-6H-pyrido[2,3-e]pyrido[3′,2′:4,5]pyrrolo[1,2-c][1,3]oxazine (20 mg, yield: 9%). 1H-NMR (CDCl3, 400 MHz) δ 8.35 (dd, J=4.8 Hz, 1.6 Hz, 1H), 7.99 (dd, J=8.0 Hz, 1.6 Hz, 1H), 7.36 (d, J=8.4 Hz, 1H), 7.21 (d, J=8.4 Hz, 1H), 7.16 (s, 1H), 7.13 (dd, J=8.0 Hz, 4.8 Hz, 1H), 6.14 (s, 2H). MS (M+H)+: 258/260.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[CH:10]=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[Cl:11][C:12]1[C:19]([F:20])=[CH:18][CH:17]=[C:16]([Cl:21])[C:13]=1[CH:14]=[O:15].[OH-].[K+].Cl>CO.O>[Br:1][C:2]1[CH:3]=[C:4]2[C:10]([CH:14]([C:13]3[C:16]([Cl:21])=[CH:17][CH:18]=[C:19]([F:20])[C:12]=3[Cl:11])[OH:15])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: Brc1cnc2[nH]ccc2c1
Reactant: O=Cc1c(Cl)ccc(F)c1Cl
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: OC(c1c(Cl)ccc(F)c1Cl)c1c[nH]c2ncc(Br)cc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred mixture of 5-bromo-1H-pyrrolo[2,3-b]pyridine (0.100 g, 0.508 mmol) and 2,6-dichloro-3-fluorobenzaldehyde (0.107 g, 0.558 mmol) in MeOH (5 mL) was added potassium hydroxide (0.199 g, 3.553 mmol) at 0° C. under nitrogen atmosphere. The resulting mixture was then stirred at r.t. overnight. The mixture was then poured into water (50 mL), acidified with 2N HCl and extracted with ethyl acetate (50 mL×3). The organics were combined, dried (Na2SO4) and concentrated under reduced pressure to give a crude residue which was then purified by chromatography (eluent: 20% ethyl acetate in hexane). MS (ES+): m/z=388.85, 390.84, 392.83 [MH+]. HPLC: tR=3.29 min (ZQ3, polar—5 min).
Reaction SMILES: C(O[C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)=O)(C)(C)C.BrC1[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][C:16]=1[F:25]>>[F:25][C:16]1[CH:17]=[C:18]([C:21]([F:24])([F:23])[F:22])[CH:19]=[CH:20][C:6]=1[N:8]1[CH2:9][CH2:10][NH:11][CH2:12][CH2:13]1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Fc1cc(C(F)(F)F)ccc1Br
Product: Fc1cc(C(F)(F)F)ccc1N1CCNCC1

Procedure:
The compound 1-(2-fluoro-4-trifluoromethyl-phenyl)-piperazine is synthesized according to the procedure outlined in Example 26 steps 1 and 2 using t-butyl-1-piperazine-carboxylate and 1-bromo-2-fluoro-4-trifluoromethyl-benzene.
Reaction SMILES: [C:1]([OH:7])([C:3]([F:6])([F:5])[F:4])=[O:2].[N:8]1([C:17](=[O:31])/[CH:18]=[CH:19]/[C@@H:20]([NH:23]C(=O)OC(C)(C)C)[CH2:21][CH3:22])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:10][CH2:9]1>C(Cl)Cl>[F:4][C:3]([F:6])([F:5])[C:1]([OH:7])=[O:2].[N:8]1([C:17](=[O:31])/[CH:18]=[CH:19]/[C@@H:20]([NH2:23])[CH2:21][CH3:22])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:10][CH2:9]1
Reactant: CC[C@@H](/C=C/C(=O)N1CCc2ccccc21)NC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC[C@H](N)/C=C/C(=O)N1CCc2ccccc21
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
TFA (25 mL, 324 mmol) was added to a solution of 1,1-dimethylethyl [(1S,2E)-4-(2,3-dihydro-1H-indol-1-yl)-1-ethyl-4-oxo-2-buten-1-yl]carbamate (7.21 g, 21.82 mmol) in CH2Cl2 (25 mL). The reaction was stirred at RT. After 3.5 h, CH2Cl2 (200 mL) was added, and the reaction was concentrated under reduced pressure and dried under high vacuum. LC-MS m/z 231 (M+H)+, 0.69 (ret time).
Reaction SMILES: C([O:3][C:4](=[O:31])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]2[CH2:15][CH2:14][CH2:13][C:12]=2[C:16]2[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=2[O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:6]=1)C>CO>[Cl:22][C:20]1[CH:19]=[CH:18][C:17]([O:23][CH2:24][C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)=[C:16]([C:12]2[CH2:13][CH2:14][CH2:15][C:11]=2[C:7]2[CH:6]=[C:5]([CH:10]=[CH:9][CH:8]=2)[C:4]([OH:31])=[O:3])[CH:21]=1
Reactant: CCOC(=O)c1cccc(C2=C(c3cc(Cl)ccc3OCc3ccccc3)CCC2)c1
Solvent: CO
Product: O=C(O)c1cccc(C2=C(c3cc(Cl)ccc3OCc3ccccc3)CCC2)c1

Procedure:
3-{2-[5-chloro-2-(benzyloxy)-phenyl)cyclopent-1-enyl]-benzoic acid ethyl ester (80 mg) was refluxed for 1 h in methanol/2N sodium hydroxide (10:10 mL). The reaction mixture was then evaporated down to 3 mL. 2N Hydrochloric acid (10 mL) was added and the product extracted with dichloromethane (2×10 mL), dried (magnesium sulphate) and evaporated to give an oil which solidified on standing (70 mg).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]([OH:6])=[O:5].[CH2:7]([O:9][C:10]([C@@H:12]([CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH2:13][C@H:14]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:15](O)=[O:16])=[O:11])[CH3:8].Cl.CN(C)CCCN=C=NCC.C(N(CC)CC)C>C(Cl)Cl.C(OCC)C>[CH2:7]([O:9][C:10]([C@@H:12]([CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH2:13][C@H:14]([CH2:18][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)[C:15]([NH:1][CH2:2][CH2:3][C:4]([OH:6])=[O:5])=[O:16])=[O:11])[CH3:8]
Reactant: CCOC(=O)[C@@H](Cc1ccccc1)C[C@H](Cc1ccccc1)C(=O)O
Reactant: NCCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCOCC
Solvent: ClCCl
Product: CCOC(=O)[C@@H](Cc1ccccc1)C[C@H](Cc1ccccc1)C(=O)NCCC(=O)O
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of 0.01 mole of 3-aminopropionic acid and 0.01 mole of (R*,R*)-4-ethoxycarbonyl-2,4-dibenzylbutyric acid in 40 ml of methylene chloride are added 0.01 mole of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 0.01 mole of triethylamine. The reaction mixture is stirred at room temperature for 3 days. Diethyl ether (250 ml) is added and the mixture is washed with 25 ml of water, 25 ml of 2N aqueous hydrochloric acid and 25 ml of saturated aqueous sodium bicarbonate solution. The organic layer is dried over magnesium sulfate and evaporated to give N-[4-ethoxycarbonyl-(R*,R*)-2,4-dibenzylbutyryl]-3-aminopropionic acid, the compound of example 5(a).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:37]=[CH:36][C:6]([CH2:7][N:8]2[C:12]3[N:13]=[CH:14][CH:15]=[C:16]([N:17]([C:26]4[CH:31]=[CH:30][C:29]([N+:32]([O-])=O)=[CH:28][C:27]=4[F:35])[CH2:18][CH2:19][N:20]4[CH2:25][CH2:24][O:23][CH2:22][CH2:21]4)[C:11]=3[CH:10]=[N:9]2)=[CH:5][CH:4]=1>CCO>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]2[C:12]3=[N:13][CH:14]=[CH:15][C:16]([N:17]([CH2:18][CH2:19][N:20]4[CH2:25][CH2:24][O:23][CH2:22][CH2:21]4)[C:26]4[CH:31]=[CH:30][C:29]([NH2:32])=[CH:28][C:27]=4[F:35])=[C:11]3[CH:10]=[N:9]2)=[CH:36][CH:37]=1
Reactant: COc1ccc(Cn2ncc3c(N(CCN4CCOCC4)c4ccc([N+](=O)[O-])cc4F)ccnc32)cc1
Solvent: CCO
Product: COc1ccc(Cn2ncc3c(N(CCN4CCOCC4)c4ccc(N)cc4F)ccnc32)cc1
Temperature: 25 °C
Yield: 93 %

Procedure:
1-(4-methoxybenzyl)-N-(2-fluoro-4-nitrophenyl)-N-(2-morpholinoethyl)-1H-pyrazolo[3,4-b]pyridin-4-amine (0.024 g, 0.0474 mmol) and SnCl2-dihydrate (0.0535 g, 0.237 mmol) were stirred in EtOH (2 mL) for 2 hours at reflux. The reaction was cooled to room temperature and then concentrated under reduced pressure and dried in vacuo. The residue was diluted with EtOAc and washed with saturated Na2CO3 (20 mL). The organics were dried over Na2SO4. The organics were filtered and concentrated to give 21 mg (92%) of product as a light yellow oil. 1H NMR (400 MHz, CDCl3) δ 8.21 (d, 1H), 7.27 (m, 2H), 7.11 (m, 1H), 6.558 (bs, 1H), 6.49 (m, 2H), 6.29 (d, 1H), 5.48 (s, 2H), 4.12 (m, 4H), 3.73 (s, 3H), 3.69 (m, 4H), 2.73 (t, 2H), 2.48 (m, 4H); F NMR (400 MHz, CDCl3) −120.43 (s, 1F); LRMS (apci pos): 477.3 (M+H)+.
Reaction SMILES: C(OC([N:11]1[CH2:17][C@H:16]2[C@:13]([NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])([CH2:14][C@@H:15]2[CH3:18])[CH2:12]1)=O)C1C=CC=CC=1.[H][H]>CO.O1CCCC1.[C].[Pd]>[C:23]([O:22][C:20]([NH:19][C@:13]12[CH2:14][C@H:15]([CH3:18])[C@H:16]1[CH2:17][NH:11][CH2:12]2)=[O:21])([CH3:26])([CH3:24])[CH3:25]
Reactant: [H][H]
Reactant: C[C@H]1C[C@]2(NC(=O)OC(C)(C)C)CN(C(=O)OCc3ccccc3)C[C@H]12
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: C[C@H]1C[C@]2(NC(=O)OC(C)(C)C)CNC[C@H]12

Procedure:
(1R,5S,6S)-1-tert-Butoxycarbonylamino-6-methyl-3-azabicyclo[3.2.0]heptane-3-carboxylic acid benzyl ester (1.4 g, 3.9 mmol) was dissolved in a mixed solvent of methanol (20 mL) and tetrahydrofuran (10 mL). A small amount of 10% palladium-carbon (50% wet) was added, and the mixture was stirred in a hydrogen atmosphere for three hours. After removing the catalyst by filtration, the filtrate was concentrated under reduced pressure to give 0.89 g (quantitative) of the title compound as a colorless oil.