Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][CH:3]1[O:7][N:6]([CH3:8])[C:5]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)([CH2:9][N:10]2[CH:14]=[CH:13][N:12]=[CH:11]2)[CH2:4]1.[H-].[Na+].[CH3:24]I.O>O1CCCC1>[CH3:24][O:1][CH2:2][CH:3]1[O:7][N:6]([CH3:8])[C:5]([C:15]2[CH:16]=[CH:17][C:18]([Cl:21])=[CH:19][CH:20]=2)([CH2:9][N:10]2[CH:14]=[CH:13][N:12]=[CH:11]2)[CH2:4]1
Reactant: CN1OC(CO)CC1(Cn1ccnc1)c1ccc(Cl)cc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COCC1CC(Cn2ccnc2)(c2ccc(Cl)cc2)N(C)O1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
5-(Hydroxymethyl)-3-(4-chlorophenyl)-3-(1H-imidazol-1-ylmethyl)-2-methylisoxazolidine (3: R1 =4-Cl, R2 =H) 2.50 g, 8 mmol) is added to a suspension of 1.32 g (24 mmol) of 50% by weight sodium hydride in 50 ml anhydrous tetrahydrofuran, at 0° C. under a nitrogen atmosphere. After stirring for 1 hour at 0° C., 1.28 g (9 mmol) of methyl iodide is added and the resulting suspension is heated to reflux and stirred for 20 hours. Upon cooling to room temperature, the reaction mixture is poured into 100 ml of water and then extracted with chloroform (3×75 ml). The combined organic extracts are dried over anhydrous magnesium sulfate and the solvent removed under reduced pressure. The crude residue is flash-chromatographed on neutral silica gel using chloroform-methanol (98:2 by volume) as eluent. Following crystallization from ethyl acetate, 1.67 g (64%) of compound 3 (R1 =4-Cl, R2 =CH3) are obtained, mp 123°-126° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][C@@H:9]([C@H:11]2[CH2:15][NH:14][C:13](=[O:16])[CH2:12]2)[CH3:10])[C:5]2[N:17]([CH:20]([F:22])[F:21])[CH:18]=[N:19][C:4]=2[CH:3]=1.[CH3:23][O:24][C:25]1[CH:30]=[C:29](B2OC(C)(C)C(C)(C)O2)[CH:28]=[CH:27][C:26]=1[N:40]1[CH2:45][CH2:44][N:43]([C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47])[CH2:42][CH2:41]1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O>[F:21][CH:20]([F:22])[N:17]1[C:5]2[C:6]([O:8][C@@H:9]([C@@H:11]3[CH2:12][C:13](=[O:16])[NH:14][CH2:15]3)[CH3:10])=[N:7][C:2]([C:29]3[CH:28]=[CH:27][C:26]([N:40]4[CH2:45][CH2:44][N:43]([C:46]([O:48][C:49]([CH3:50])([CH3:51])[CH3:52])=[O:47])[CH2:42][CH2:41]4)=[C:25]([O:24][CH3:23])[CH:30]=3)=[CH:3][C:4]=2[N:19]=[CH:18]1
Reactant: C[C@@H](Oc1nc(Cl)cc2ncn(C(F)F)c12)[C@H]1CNC(=O)C1
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)ccc1N1CCN(C(=O)OC(C)(C)C)CC1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: COc1cc(-c2cc3ncn(C(F)F)c3c(O[C@H](C)[C@H]3CNC(=O)C3)n2)ccc1N1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 100 °C

Procedure:
2.64 (102 mg, 0.308 mmol), tert-butyl 4-(2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperazine-1-carboxylate 7.08 (160 mg, 0.38 mmol), K3PO4 (191 mg, 0.9 mmol) and Bis[di-tert-butyl(4-dimethylaminophenyl)phosphine]dichloropalladium (II) (7.2 mg, 0.01 mmol) were taken up in 1,4-dioxane (4.4 mL) and water (0.44 mL). The stirred reaction mixture was heated to 100° C. for 1.5 h and was then cooled and partitioned between EtOAc, water and brine. The phases were separated and the aqueous phase was extracted with EtOAc. The combined organic phase was dried over Na2SO4, filtered, and concentrated. The crude residue was purified by silica gel chromatography (0-15% MeOH in DCM) to provide tert-butyl 4-(4-(3-(difluoromethyl)-4-((R)-1-((R)-5-oxopyrrolidin-3-yl)ethoxy)-3H-imidazo[4,5-c]pyridin-6-yl)-2-methoxyphenyl)piperazine-1-carboxylate. LCMS-ESI+ (m/z): [M+H]+ calcd for C29H37F2N6O5: 587.3; found: 587.2.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[C@H:20]3[C@H:15]([CH2:16][CH2:17][CH2:18][CH2:19]3)[C:14](=[O:21])[N:13]([CH2:22][CH2:23][CH2:24][CH2:25]Br)[N:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[ClH:27].COC1C=C(C2[C@H]3[C@H](CCCC3)C(=O)N(CC[N:51]3[CH:55]=[CH:54][N:53]=[CH:52]3)N=2)C=CC=1OC>>[ClH:27].[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[C@H:20]3[C@H:15]([CH2:16][CH2:17][CH2:18][CH2:19]3)[C:14](=[O:21])[N:13]([CH2:22][CH2:23][CH2:24][CH2:25][N:51]3[CH:55]=[CH:54][N:53]=[CH:52]3)[N:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(C2=NN(CCCCBr)C(=O)[C@H]3CCCC[C@@H]23)cc1OC
Reactant: COc1ccc(C2=NN(CCn3ccnc3)C(=O)[C@H]3CCCC[C@@H]23)cc1OC
Agent: Cl
Product: COc1ccc(C2=NN(CCCCn3ccnc3)C(=O)[C@H]3CCCC[C@@H]23)cc1OC

Procedure:
Prepared from compound 58 as described for compound 113. M.p. 210°-212° C.
Reaction SMILES: [C:1]([N:8]1[CH2:15][CH:14]([OH:16])[CH2:13][C@H:9]1[C:10]([OH:12])=[O:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].CC(C)([O-])C.[K+].Cl[C:24]1[C:33]2[C:28](=[CH:29][C:30]([O:34][CH3:35])=[CH:31][CH:32]=2)[CH:27]=[C:26]([CH3:36])[N:25]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CS(C)=O>[C:4]([O:3][C:1]([N:8]1[CH2:15][C@H:14]([O:16][C:24]2[C:33]3[C:28](=[CH:29][C:30]([O:34][CH3:35])=[CH:31][CH:32]=3)[CH:27]=[C:26]([CH3:36])[N:25]=2)[CH2:13][C@H:9]1[C:10]([OH:12])=[O:11])=[O:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: CC(C)(C)OC(=O)N1CC(O)C[C@H]1C(=O)O
Reactant: COc1ccc2c(Cl)nc(C)cc2c1
Agent: CC(C)(C)[O-]
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [K+]
Solvent: CS(C)=O
Product: COc1ccc2c(O[C@@H]3C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C3)nc(C)cc2c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
N-BOC-4-hydroxy-L-proline (A; 281 mg; 1.21 mmol) was dissolved in dimethylsulfoxide (3 mL) at room temperature then potassium t-butoxide (270 mg; 2.4 mmol) was added. The resulting solution was stirred at room temperature for 2 hours, then cooled to 0° C. A solution of 1-chloro-6-methoxy-3-methylisoquinoline in dimethylsulfoxide (3 mL) was then added dropwise to the cold solution, followed by t-BuOK, and the mixture was allowed to warn to room temperature. The solution was stirred for 16 hours. The reaction mixture was acidified to pH=4 with 5% aq. citric acid. The solution was extracted with ethyl acetate and the organic phase washed with water followed by brine. The organic phase was concentrated under reduced pressure to give (2S,4R)-1-(tert-butoxycarbonyl)-4-(6-methoxy-3-methylisoquinolin-1-yloxy)pyrrolidine-2-carboxylic acid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[C:5]1[CH:10]=[C:9]([Cl:11])[C:8]([NH2:12])=[C:7]([Cl:13])[CH:6]=1)[CH3:2].[C:15](OC(=O)C)(=[O:17])C>C(O)=O>[CH2:1]([O:3][C:4](=[O:14])[C:5]1[CH:10]=[C:9]([Cl:11])[C:8]([NH:12][CH:15]=[O:17])=[C:7]([Cl:13])[CH:6]=1)[CH3:2]
Reactant: CCOC(=O)c1cc(Cl)c(N)c(Cl)c1
Reactant: CC(=O)OC(C)=O
Solvent: O=CO
Product: CCOC(=O)c1cc(Cl)c(NC=O)c(Cl)c1
Yield: 78.9 %

Procedure:
Following the procedure in Rouot et al., in J. Med. Chem., 19, 1049 (1976), 4-amino-3,5-dichlorobenzoic acid ethyl ester (70.2 g., 030 m) is reacted with the product from acetic anhydride (61.3 g., 0.60 m) and formic acid (34.5 g., 0.75 m) to yield the desired 3,5-dichloro-4-formamidobenzoic acid ethyl ester (62.0 g., 0.237 m) in crude yield of 79% with a melting point of 168°-170° C. Reaction of this crude (16.35 g., 0.062 m) with a mixture of thionyl chloride (55.4 g., 0.47 m) and a sulfuryl chloride (3.4 g., 0.062 m) leads to the desired 3,5-dichloro-4-dichloromethaniminobenzoic acid ethyl ester (14.65 g., 46 mmol) which distills at 105° C. at 250 mm of Hg after standard workup. It should be noted that this material may solidify on standing. Finally, this distilled dichloromethamine (4.35 g., 0.0138 m) is reacted with ethylene diamine (1.66 g., 0.0276 m), and 10 mL of triethylamine in approximately 25 mL of ethyl acetate for 10 hours. An immediate white precipitate is noted, but stirring is continued overnight to ensure complete reaction. This reaction mixture then is vacuum filtered to yield 5.35 g. of white powder (which is greater than 100% yield, but is probably due to the fact that, in addition to the desired compound, triethylamine hydrochloride as well as the hydrochloride of the desired compound are present at this stage). Recrystallization of the white powder from absolute ethanol produced a white crystalline solid (2.3 g., 0.0076 m) in a yield of 55% with a melting point of 238°-240° C. This compound demonstrates the expected IR absorptions at 3380 (sharp), 3150 (broad), 1710 (sharp), 1660 (sharp and most intense), 1580 (sharp), 1275 (sharp), 1105 cm-1 (sharp).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[N:17]([CH2:24][CH2:25][CH:26]([CH3:28])[CH3:27])[C:16]2=[O:29])=[C:11]([OH:30])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:31]1(C(C2C=CC=CC=2)N2C3C(=CC=CC=3)C(C3C=C(C)C(OC)=CC=3O)C2=O)C=CC=CC=1>>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]2[C:15]3([CH2:31][O:30][C:11]=2[CH:10]=1)[C:23]1[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=1)[N:17]([CH2:24][CH2:25][CH:26]([CH3:27])[CH3:28])[C:16]3=[O:29])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)CCN1C(=O)C(c2ccc(OCc3ccccc3)cc2O)c2ccccc21
Reactant: COc1cc(O)c(C2C(=O)N(C(c3ccccc3)c3ccccc3)c3ccccc32)cc1C
Product: CC(C)CCN1C(=O)C2(COc3cc(OCc4ccccc4)ccc32)c2ccccc21

Procedure:
Following the procedure as described in EXAMPLE 2 and making non-critical variations using 3-[4-(benzyloxy)-2-hydroxyphenyl]-1-(3-methylbutyl)-1,3-dihydro-2H-indol-2-one to replace 1-(diphenylmethyl)-3-(2-hydroxy-4-methoxy-5-methylphenyl)-1,3-dihydro-2H-indol-2-one, 6-(benzyloxy)-1′-(3-methylbutyl)spiro[1-benzofuran-3,3′-indol]-2′(1′H)-one was obtained (67%): 1H NMR (300 MHz, CDCl3) 7.41-7.28 (m, 7H), 7.14-7.12 (m, 1H), 7.04-6.99 (m, 1H), 6.90-6.87 (m, 1H), 6.59-6.55 (m, 1H), 6.44-6.30 (m, 1H), 5.00 (s, 2H), 4.79 (ABq, 2H), 3.87-3.64 (m, 2H), 1.71-1.56 (m, 3H), 0.98 (d, J=6.0 Hz, 6H); MS (ES+) m/z 414.3 (M+1).
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([CH2:11][C@@H:12]([NH:16][C:17]([N:19]2[CH2:24][CH2:23][CH:22]([N:25]3[CH2:31][CH2:30][C:29]4[CH:32]=[CH:33][CH:34]=[CH:35][C:28]=4[NH:27][C:26]3=[O:36])[CH2:21][CH2:20]2)=[O:18])[C:13](O)=[O:14])[CH:6]=[CH:7][C:8]=1[CH2:9][CH3:10])[CH3:2].[N:37]1([CH:42]2[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]2)[CH2:41][CH2:40][CH2:39][CH2:38]1>>[CH2:1]([C:3]1[CH:4]=[C:5]([CH:6]=[CH:7][C:8]=1[CH2:9][CH3:10])[CH2:11][C@@H:12]([NH:16][C:17]([N:19]1[CH2:20][CH2:21][CH:22]([N:25]2[CH2:31][CH2:30][C:29]3[CH:32]=[CH:33][CH:34]=[CH:35][C:28]=3[NH:27][C:26]2=[O:36])[CH2:23][CH2:24]1)=[O:18])[C:13](=[O:14])[N:45]1[CH2:46][CH2:47][CH:42]([N:37]2[CH2:41][CH2:40][CH2:39][CH2:38]2)[CH2:43][CH2:44]1)[CH3:2]
Reactant: C1CCN(C2CCNCC2)C1
Reactant: CCc1ccc(C[C@@H](NC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)O)cc1CC
Product: CCc1ccc(C[C@@H](NC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)N2CCC(N3CCCC3)CC2)cc1CC

Procedure:
Prepared analogously to Example 9i) from 400 mg (0.81 mmol) (R)-3-(3,4-diethyl-phenyl)-2-{[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carbonyl]-amino}-propionic acid and 160 mg (0.99 mmol) 4-pyrrolidin-1-yl-piperidine.
Reaction SMILES: C([C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:5]=1[S:11][CH:12]([CH2:16][CH2:17][CH2:18][CH3:19])[C:13]([OH:15])=O)(O)=O.[C:20]([O-])(=[O:22])[CH3:21].[Na+].C(OC(=O)C)(=O)C>O>[C:20]([O:15][C:13]1[C:6]2[CH:7]=[C:8]([Cl:10])[CH:9]=[CH:4][C:5]=2[S:11][C:12]=1[CH2:16][CH2:17][CH2:18][CH3:19])(=[O:22])[CH3:21]
Reactant: CCCCC(Sc1ccc(Cl)cc1C(=O)O)C(=O)O
Reactant: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)OC(C)=O
Product: CCCCc1sc2ccc(Cl)cc2c1OC(C)=O
Temperature: 80 °C

Procedure:
A mixture of 2-(2'-carboxy-4'-chlorophenylthio)hexanoic acid (2.3 g, 7.6 mmol), anhydrous sodium acetate (1.0 g), and acetic anhydride (5 ml) was heated at 80° C. for 30 minutes. After gas evolution had ceased, the temperature was gradually raised to 120° C. which was maintained for 30 minutes. The cooled reaction mixture was then poured into water and extracted with diethyl ether. The combined ethereal extracts were washed with 1% aqueous sodium hydroxide solution, water, and saturated aqueous sodium chloride solution, dried (sodium sulfate) and evaporated. The residue was vacuum filtered through a pad of silica gel (Merck No. 7734) eluting with 25:1 hexane-ether to give 3-acetoxy-2-butyl-5-chlorobenzo[b]thiophene as a colorless oil; yield 1.1 g (40% overall from the 2-step sequence), m/z 282 (M+.).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[S:12][C:11]([CH:13]=[CH:14][C:15]([OH:17])=O)=[CH:10][CH:9]=1.[NH:18]1[CH2:23][CH2:22][NH:21][CH2:20][C:19]1=[O:24]>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[S:12][C:11]([CH:13]=[CH:14][C:15]([N:21]2[CH2:22][CH2:23][NH:18][C:19](=[O:24])[CH2:20]2)=[O:17])=[CH:10][CH:9]=1
Reactant: O=C(O)C=Cc1ccc(-c2ccccc2F)s1
Reactant: O=C1CNCCN1
Product: O=C1CN(C(=O)C=Cc2ccc(-c3ccccc3F)s2)CCN1

Procedure:
The compound was prepared analogously to Example 4(b) using 150 mg (0.6 mmol) of 3-[5-(2-fluoro-phenyl)-thiophen-2-yl]-acrylic acid and 54.2 mg (0.54 mmol) of piperazin-2-one. Yield: 109 mg.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH:15]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:16]([OH:18])=[O:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:33][C:34]1[C:39]([F:40])=[CH:38][CH:37]=[CH:36][C:35]=1[C:41]1[CH:46]=[CH:45][C:44]([O:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53]O)=[CH:43][CH:42]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[CH2:26]([O:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH:15]([CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:16]([O:18][CH2:53][CH2:52][CH2:51][CH2:50][CH2:49][CH2:48][O:47][C:44]1[CH:45]=[CH:46][C:41]([C:35]2[CH:36]=[CH:37][CH:38]=[C:39]([F:40])[C:34]=2[F:33])=[CH:42][CH:43]=1)=[O:17])[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: OCCCCCCOc1ccc(-c2cccc(F)c2F)cc1
Reactant: O=C(O)C(CCCCCCOCc1ccccc1)CCCCCCOCc1ccccc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C(OCCCCCCOc1ccc(-c2cccc(F)c2F)cc1)C(CCCCCCOCc1ccccc1)CCCCCCOCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.9 %

Procedure:
First, 2.47 g of 2,2-bis(6-benzyloxyhexyl)acetic acid, 1.85 g of 2,3-difluoro-4'-[6-hydroxyhexyl]oxybiphenyl, 1.6 g of triphenylphosphine, and 50 ml of tetrahyrofuran were placed in a 100 ml flask. Then, 1.1 g of diethyl azodicarboxylate was added dropwise to the reaction mixture at 5° C. Thereafter, the reaction mixture was allowed to warm to room temperature and stirred for 8 hours. The reaction mixture was concentrated, and the residue was purified by silica gel column chromatography (eluent: ethyl acetate/hexane=1/4) to obtain 4 g of 6-[2,3-difluorobiphenyl-4'-yl]oxyhexyl 2,2-bis(6-benzyloxyhexyl)acetate (Y: 97.8%). The compound thus obtained had a purity of 99% by HPLC.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([CH:27]2[CH2:32][CH2:31][CH2:30][CH:29]=[CH:28]2)=[CH:8][C:9]=1[N:10]([C:18]([C@H:20]1[CH2:25][CH2:24][C@H:23]([CH3:26])[CH2:22][CH2:21]1)=[O:19])[CH:11]1[CH2:16][CH2:15][C:14](=[O:17])[CH2:13][CH2:12]1)=[O:4].[BH4-].[Na+].Cl>CO>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([CH:27]2[CH2:32][CH2:31][CH2:30][CH:29]=[CH:28]2)=[CH:8][C:9]=1[N:10]([C@H:11]1[CH2:16][CH2:15][C@H:14]([OH:17])[CH2:13][CH2:12]1)[C:18]([C@H:20]1[CH2:21][CH2:22][C@H:23]([CH3:26])[CH2:24][CH2:25]1)=[O:19])=[O:4]
Reactant: COC(=O)c1sc(C2C=CCCC2)cc1N(C(=O)[C@H]1CC[C@H](C)CC1)C1CCC(=O)CC1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1sc(C2C=CCCC2)cc1N(C(=O)[C@H]1CC[C@H](C)CC1)[C@H]1CC[C@H](O)CC1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
To a mixture of 5-cyclohex-2-enyl-3-[(trans-4-methyl-cyclohexanecarbonyl)-(4-oxo-cyclohexyl)-amino]-thiophene-2-carboxylic acid methyl ester (40 mg) and MeOH (3 mL) cooled to 0° C. was added NaBH4 (15 mg) in one portion. Reaction was complete in 5 min. HCl (0.1 N, 0.5 mL) was added until it was acidic. It was evaporated and then extracted with DCM, washed with saturated NaHCO3 solution, brine, dried (MgSO4) and evaporated. The crude was purified by chromatography over silica gel (hexane:EtOAc—1:1 as eluent) yielding pure 5-Cyclohex-2-enyl-3-[(trans-4-hydroxy-cyclohexyl)-(trans-4-methyl-cyclohexanecarbonyl)-amino]-thiophene-2-carboxylic acid methyl ester (12 mg, 26%) in two steps.
Reaction SMILES: [CH:1]12[O:7][CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6]2.[CH2:8]([NH2:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>O>[CH2:8]([NH:15][C@@H:2]1[CH2:3][CH2:4][CH2:5][CH2:6][C@H:1]1[OH:7])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: NCc1ccccc1
Reactant: C1CCC2OC2C1
Solvent: O
Product: O[C@@H]1CCCC[C@H]1NCc1ccccc1

Procedure:
A mixture of cyclohexene oxide (1) (19 mL, 0.2 mol, Aldrich cat #C10, 280-4) and benzylamine (27) (21 mL, 0.2 mol, Aldrich cat #407712) in water (5 mL) was refluxed for 3 hours. The cooled reaction mixture was partitioned between 4M aq NaOH (100 mL) and methyl t-butyl ether (150 mL). The aqueous layer was further extracted with methyl t-butyl ether (2×100 mL), and the combined organic extracts were dried over anhydrous magnesium sulfate and concentrated in vacuo to give trans-2-benzylaminocyclohexan-1-ol (28) as a low melting point solid (39.4 g, 96% yield);
Reaction SMILES: C(N(CC)CC)C.[Cl:8][C:9]([C:29]([F:32])([F:31])[F:30])=[CH:10][C@@H:11]1[C@H:13]([C:14]([O:16][CH2:17][C:18]2[C:23]([CH3:24])=[CH:22][CH:21]=[C:20]([NH2:25])[C:19]=2[CH3:26])=[O:15])[C:12]1([CH3:28])[CH3:27].[C:33](Cl)(Cl)=[S:34]>C(Cl)(Cl)Cl>[Cl:8][C:9]([C:29]([F:30])([F:31])[F:32])=[CH:10][C@@H:11]1[C@H:13]([C:14]([O:16][CH2:17][C:18]2[C:23]([CH3:24])=[CH:22][CH:21]=[C:20]([N:25]=[C:33]=[S:34])[C:19]=2[CH3:26])=[O:15])[C:12]1([CH3:28])[CH3:27]
Reactant: Cc1ccc(N)c(C)c1COC(=O)[C@H]1[C@@H](C=C(Cl)C(F)(F)F)C1(C)C
Reactant: S=C(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: Cc1ccc(N=C=S)c(C)c1COC(=O)[C@H]1[C@@H](C=C(Cl)C(F)(F)F)C1(C)C
Yield: 81.8 %

Procedure:
Triethylamine (0.5 gram, 0.005 mole) was added to a solution of (3-amino-2,6-dimethylphenyl)methyl cis-3-(2-chloro-3,3,3-trifluoropropenyl)-2,2-dimethylcyclopropanecarboxylate (2.03 grams, 0.005 mole) in chloroform (20 ml) and cooled to 0°. Thiophosgene (0.58 gram, 0.005 mole) was added, and the reaction mixture was allowed to come to room temperature. The solvent was evaporated, and the residue was dissolved in diethyl ether. The solution was washed with water, dried over magnesium sulfate and filtered. The solvent was evaporated to give (3-isothiocyanato-2,6-dimethylphenyl)methyl cis-3-(2-chloro-3,3,3-trifluoropropenyl)-2,2-dimethylcyclopropanecarboxylate (1.71 grams, mp 60°).
Reaction SMILES: [C:1]([N:9]1[CH2:14][CH2:13][N:12]([CH2:15][C:16]([O:18]CC)=O)[CH2:11][CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:21][NH2:22]>CCO>[C:1]([N:9]1[CH2:10][CH2:11][N:12]([CH2:15][C:16]([NH:21][NH2:22])=[O:18])[CH2:13][CH2:14]1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)CN1CCN(C(=O)c2ccccc2)CC1
Reactant: NN
Solvent: CCO
Product: NNC(=O)CN1CCN(C(=O)c2ccccc2)CC1
Yield: 51.7 %

Procedure:
Synthesized according to General Procedure C: 51c (2.87 g, 10.4 mmol, 1.0 equiv.), anhydrous hydrazine (1.31 mL, 41.6 mmol, 4.0 equiv.), EtOH (20 mL, 0.5 M). 46c (1.41 g, 51.5%) was obtained as a white solid after extraction without further purification. 1H-NMR (500 MHz, CDCl3) δ 8.10 (s, 1H), 7.39-7.34 (m, 5H), 3.84 (br s, 2H), 3.77 (br s, 2H), 3.43 (br s, 2H), 3.08 (s, 2H), 2.56 (br s, 2H), 2.44 (br s, 2H). 13C-NMR (125 MHz, CDCl3) δ 170.5, 169.9, 135.5, 130.0, 128.7, 127.1, 60.6, 53.9 (br), 53.4 (br), 47.7 (br), 42.2 (br). HRMS (ESI): 263.1513 (M+1); calcd. for C13H19N4O2: 263.1508.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[F:7][C:8]1[CH:20]=[C:19]([OH:21])[C:18]([F:22])=[CH:17][C:9]=1[C:10]([NH:12][S:13]([CH3:16])(=[O:15])=[O:14])=[O:11].Br[C:24]1[CH:25]=[CH:26][C:27]([N+:30]([O-:32])=[O:31])=[N:28][CH:29]=1>CS(C)=O>[F:7][C:8]1[CH:20]=[C:19]([O:21][C:24]2[CH:29]=[N:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][CH:25]=2)[C:18]([F:22])=[CH:17][C:9]=1[C:10]([NH:12][S:13]([CH3:16])(=[O:14])=[O:15])=[O:11]
Reactant: O=[N+]([O-])c1ccc(Br)cn1
Reactant: CS(=O)(=O)NC(=O)c1cc(F)c(O)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CS(=O)(=O)NC(=O)c1cc(F)c(Oc2ccc([N+](=O)[O-])nc2)cc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 60.6 %

Procedure:
Potassium carbonate (0.220 g, 1.59 mmol) was added to a stirred solution of 2,5-difluoro-4-hydroxy-N-(methylsulfonyl)benzamide (Preparation 34, 0.200 g, 0.796 mmol) and 5-bromo-2-nitropyridine (0.170 g, 0.836 mmol) in DMSO (2.5 mL) at room temperature. The mixture was stirred at room temperature for 2 hours and then at 60° C. for 24 hours. The reaction mixture was partitioned between EtOAc and 2M aqueous HCl ensuring the water layer was acidic. The organic layer was separated and washed further with citric acid, water and brine, then dried over magnesium sulfate, filtered, evaporated in vacuo and triturated in diethyl ether to yield the title compound (0.180 g, 60%):
Reaction SMILES: [NH:1]1[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=[O:4].O.[C:10]1([CH3:20])[CH:15]=[CH:14][C:13]([S:16]([OH:19])(=[O:18])=[O:17])=[CH:12][CH:11]=1.[N+:21]([C:24]1[CH:31]=[CH:30][C:27]([CH2:28]O)=[CH:26][CH:25]=1)([O-:23])=[O:22]>C1C=CC=CC=1>[C:10]1([CH3:20])[CH:11]=[CH:12][C:13]([S:16]([OH:19])(=[O:17])=[O:18])=[CH:14][CH:15]=1.[N+:21]([C:24]1[CH:31]=[CH:30][C:27]([CH2:28][O:4][C:3](=[O:5])[C@@H:2]2[CH2:6][CH2:7][CH2:8][NH:1]2)=[CH:26][CH:25]=1)([O-:23])=[O:22]
Reactant: O=C(O)[C@@H]1CCCN1
Reactant: O=[N+]([O-])c1ccc(CO)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: O
Product: O=C(OCc1ccc([N+](=O)[O-])cc1)[C@@H]1CCCN1
Yield: 118.3 %

Procedure:
Preparation 6 ##STR64## (a) A mixture solution of 5.0 g of L-proline, 9.91 g of p-toluenesulfonic acid monohydrate and 6.65 g of p-nitrobenzyl alcohol in 100 ml of benzene was refluxed for 2 days by using Dean-Stark trap. After reaction, the solvent was removed under reduced pressure and the resulting residue was washed with diethyl ether to give 21.7 g of L-proline p-nitrobenzyl ester p-toluenesulfonic acid salt as oil. Then, a mixture solution of 12.17 g of Boc-glycine and 13.32 g of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide.hydrochloride in 150 ml of ethylene chloride was stirred for 25 minutes under ice-cooling at nitrogen atmosphere. To this reaction mixture was added a solution of 29.36 g of the compound obtained above in 100 ml ethylene chloride and the reaction mixture was stirred overnight at room temperature. After reaction, the reaction mixture was washed with 10% citric acid aqueous solution, 4% sodium bicarbonate aqueous solution and saline, and dried over magnesium sulfate. The solvent was removed under reduced pressure and the resulting residue was purified by silica gel column chromatography (chloroform-methanol) to give 8.00 g of [N-(t-butoxycarbonyl)glycyl]L-proline p-nitrobenzyl ester [Compound (22)].
Reaction SMILES: [C:1]([C:4]1[CH:5]([C:23]2[CH:31]=[CH:30][C:29]([C:32]#[N:33])=[CH:28][C:24]=2[C:25](O)=[O:26])[N:6]([CH3:22])[C:7](=[O:21])[N:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=2)[C:9]=1[CH3:10])(=[O:3])[CH3:2].C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.[N:48]1(OC(N(C)C)=[N+](C)C)[C:52]2N=CC=[CH:56][C:51]=2N=N1>CN(C)C=O>[C:1]([C:4]1[CH:5]([C:23]2[CH:31]=[CH:30][C:29]([C:32]#[N:33])=[CH:28][C:24]=2[C:25]([NH:48][CH2:52][C:51]#[CH:56])=[O:26])[N:6]([CH3:22])[C:7](=[O:21])[N:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:18])([F:19])[F:20])[CH:12]=2)[C:9]=1[CH3:10])(=[O:3])[CH3:2]
Reactant: CC(=O)C1=C(C)N(c2cccc(C(F)(F)F)c2)C(=O)N(C)C1c1ccc(C#N)cc1C(=O)O
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: C#CCNC(=O)c1cc(C#N)ccc1C1C(C(C)=O)=C(C)N(c2cccc(C(F)(F)F)c2)C(=O)N1C
Reaction time: 0.08 h

Procedure:
2-[5-Acetyl-3,6-dimethyl-2-oxo-1-(3-trifluoromethyl-phenyl)-1,2,3,4-tetrahydro-pyrimidin-4-yl]-5-cyano-benzoic acid (intermediate 6) (70 mg, 0.15 mmol) and triethylamine (35 μL, 0.25 mmol) are suspended in N,N-dimethylformamide (1.5 mL) and the mixture is shaken for 5 min. A solution of O-(7-azabenzotriazole-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (61.1 mg, 0.16 mmol) in N,N-dimethylformamide (0.5 mL) and triethylamine (35 μL, 0.25 mmol) is added and the reaction mixture is shaken for 1.5 h at room temperature. The product is purified by reversed phase HPLC. Yield 48 mg; ESI mass spectrum [M+H]+=495; Retention time HPLC: 0.99 min (HPLC method Z011_S03).