Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][S:5]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:22]3[C:17](=[C:18]([C:29]([NH2:31])=[O:30])[CH:19]=[C:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[CH:21]=3)[NH:16][N:15]=2)[CH2:10][CH2:9]1)(=[O:7])=[O:6].C([O-])([O-])=O.[K+].[K+].[NH:38]1[CH2:43][CH2:42][NH:41][CH2:40][CH:39]1[CH2:44][CH2:45][OH:46].[I-].[Na+]>C(#N)C>[OH:46][CH2:45][CH2:44][CH:39]1[NH:38][CH2:43][CH2:42][N:41]([CH2:2][CH2:3][CH2:4][S:5]([N:8]2[CH2:13][CH2:12][CH:11]([C:14]3[C:22]4[C:17](=[C:18]([C:29]([NH2:31])=[O:30])[CH:19]=[C:20]([C:23]5[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=5)[CH:21]=4)[NH:16][N:15]=3)[CH2:10][CH2:9]2)(=[O:7])=[O:6])[CH2:40]1
Reactant: OCCC1CNCCN1
Reactant: NC(=O)c1cc(-c2ccccc2)cc2c(C3CCN(S(=O)(=O)CCCCl)CC3)n[nH]c12
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: NC(=O)c1cc(-c2ccccc2)cc2c(C3CCN(S(=O)(=O)CCCN4CCNC(CCO)C4)CC3)n[nH]c12
Temperature: 60 °C
Reaction time: 0.02 h
Yield: 29 %

Procedure:
To a solution of 3-{1-[(3-chloropropyl)sulfonyl]-4-piperidinyl}-5-phenyl-1H-indazole-7-carboxamide (Intermediate 22) (20 mg, 0.0435 mmol) in acetonitrile (1 mL) was added K2CO3 (27 mg, 0.174 mmol), 2-(2-piperazinyl)ethanol (20 uL, 0.219 mmol) and sodium iodide (0.8 mg, 0.00435 mmol). The reaction mixture was heated to 60° C. for 14 hrs. The solution was filtered and concentrated. The residue was purified by using a Gilson semi-preparative HPLC system with a YMC ODS-A (C-18) column 50 mm by 20 mm ID, eluting with 10% B to 80% B in 10 min, hold for 1 min where A=H2O (0.1% trifluoroacetic acid) and B=CH3CN (0.1% trifluoroacetic acid) pumped at 25 mL/min to afford the title compound (7.0 mg, 30%).
Reaction SMILES: C(O[C:5](=[O:7])[CH3:6])(=O)C.[NH2:8][C:9]1[S:10][C:11]2[CH:17]=[C:16]([S:18][C:19]#[N:20])[CH:15]=[CH:14][C:12]=2[N:13]=1>N1C=CC=CC=1>[C:5]([NH:8][C:9]1[S:10][C:11]2[CH:17]=[C:16]([S:18][C:19]#[N:20])[CH:15]=[CH:14][C:12]=2[N:13]=1)(=[O:7])[CH3:6]
Reactant: CC(=O)OC(C)=O
Reactant: N#CSc1ccc2nc(N)sc2c1
Solvent: c1ccncc1
Product: CC(=O)Nc1nc2ccc(SC#N)cc2s1
Reaction time: 0.08 h

Procedure:
5 cm3 of acetic anhydride are added dropwise to 7 cm3 of pyridine at 20° C. After 5 min, 1 g of 2-amino-6-thiocyanatobenzothiazole (commercial) is added. The yellow suspension is stirred for 4 h and then concentrated to dryness under vacuum. The residue is made into a paste in ethyl ether. The insoluble material is isolated by filtration, to give 1.1 g of 2-(acetylamino)-1,3-benzothiazol-6-yl thiocyanate in the form of a yellow solid, the characteristics of which are as follows:
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:6]=1[CH:14]=[CH:15][CH2:16][CH:17]=O)([CH3:4])([CH3:3])[CH3:2].[NH:19]1[CH2:23][CH2:22][CH2:21][CH2:20]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C([O-])(O)=O.[Na+].[OH-].[Na+]>C1COCC1.CCOCC.CC(O)=O>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:6]=1[CH:14]=[CH:15][CH2:16][CH2:17][N:19]1[CH2:23][CH2:22][CH2:21][CH2:20]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: C1CCNC1
Reactant: CC(C)(C)c1ccc([N+](=O)[O-])cc1C=CCC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CC(C)(C)c1ccc([N+](=O)[O-])cc1C=CCCN1CCCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-(2-tert-Butyl-5-nitro-phenyl)-but-3-enal (895 mg) was dissolved in 40 ml THF, and to the solution was added pyrrolidine (0.317 ml). To the deep orange solution was added NaBH(OAc)3 (1.151 g) and glacial AcOH (0.207 ml). The reaction was stirred at RT overnight, then treated with saturated aqueous NaHCO3 and diluted with Et2O and some 1N NaOH. The layers were separated, and the organic layer was extracted with aqueous 2N HCl. The acidic aqueous layer was basified to pH>12 with 6 N NaOH, extracted with Et2O, brine-washed, dried over Na2SO4, filtered, and concentrated in vacuo to provide 1-[4-(2-tert-butyl-5-nitro-phenyl)-but-3-enyl]-pyrrolidine as a orange-brown oil.
Reaction SMILES: C([Li])CCC.[C:6]1(=[O:13])[NH:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.C[O:15][C:16]1[CH2:21][CH2:20][CH2:19][C:18](=O)[CH:17]=1.Cl>O1CCCC1>[O:15]=[C:16]1[CH2:21][CH2:20][CH2:19][C:18]([CH:7]2[CH2:8][CH2:9][CH2:10][CH2:11][NH:12][C:6]2=[O:13])=[CH:17]1
Reactant: COC1=CC(=O)CCC1
Reactant: O=C1CCCCCN1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=C1C=C(C2CCCCNC2=O)CCC1
Reaction time: 0.83 h

Procedure:
Butyllithium (143 ml of 1.4 molar solution in hexane) was added dropwise to a stirred solution of caprolactam (11.3 g) in dry tetrahydrofuran under nitrogen. After stirring for 50 minutes at 0°, 3-methoxy-2-cyclohexenone (12.6 g) in tetrahydrofuran was added. After a further 30 minutes the reaction was poured onto 5 M hydrochloric acid. The organic layer was separated and the aqueous layer was extracted with chloroform. The combined organic layers were dried over magnesium sulphate. Removal of the solvent under reduced pressure left 15 g of a yellow solid. The product was recrystallised from ethyl acetate affording 2.5 g of the title compound identical to that described in Example 17.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][C:5](Cl)=[O:6].[C:8]1([CH3:14])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>>[Cl:1][CH2:2][CH2:3][CH2:4][C:5]([C:11]1[CH:12]=[CH:13][C:8]([CH3:14])=[CH:9][CH:10]=1)=[O:6]
Reactant: O=C(Cl)CCCCl
Reactant: Cc1ccccc1
Product: Cc1ccc(C(=O)CCCCl)cc1
Temperature: 3 °C
Reaction time: 0.25 h
Yield: 95 %

Procedure:
Suspend anhydrous A1C13 (156 g, 1.15 mol) in toluene (1500 mL) and cool to 2-4° C. Add, by slow addition, a solution of 4-chlorobutyryl chloride (165.5 g, 1.15 mol) in toluene (300 mL). Stir for 15 minutes and pour into stirring ice-water (2.5 L). Stir for 30 hours, decant the toluene and extract the aqueous phase with toluene (700 mL). Combine the organic layers and wash three times with water (1 L, 1 L, 500 mL). Evaporate the solvent in vacuo to give the title compound as a pale yellow oil (292.3 g, 95%).
Reaction SMILES: N1C2C(=NC=CC=2)N([O:10][C:11]([C:13]2[C:17]([CH3:18])=[C:16](/[CH:19]=[C:20]3\[C:21](=[O:41])[NH:22][C:23]4[C:28]\3=[CH:27][C:26]([S:29]([CH2:32][C:33]3[C:38]([Cl:39])=[CH:37][CH:36]=[CH:35][C:34]=3[Cl:40])(=[O:31])=[O:30])=[CH:25][CH:24]=4)[NH:15][C:14]=2[CH3:42])=O)N=1.[CH:43]1([CH2:46][NH2:47])[CH2:45][CH2:44]1>CC(N(C)C)=O>[CH:43]1([CH2:46][NH:47][C:11]([C:13]2[C:17]([CH3:18])=[C:16](/[CH:19]=[C:20]3\[C:21](=[O:41])[NH:22][C:23]4[C:28]\3=[CH:27][C:26]([S:29]([CH2:32][C:33]3[C:34]([Cl:40])=[CH:35][CH:36]=[CH:37][C:38]=3[Cl:39])(=[O:30])=[O:31])=[CH:25][CH:24]=4)[NH:15][C:14]=2[CH3:42])=[O:10])[CH2:45][CH2:44]1
Reactant: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c(C)c1C(=O)On1nnc2cccnc21
Reactant: NCC1CC1
Solvent: CC(=O)N(C)C
Product: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c(C)c1C(=O)NCC1CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 5-[5-(2,6-dichloro-phenylmethanesulfonyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid [1,2,3]triazolo[4,5-b]pyridin-3-yl ester (100 mg, 0.162 mmol) in DMA (2 mL) was added C-cyclopropyl-methylamine (23 mg, 2 eq.). The mixture was stirred at rt for 18 hours. The reaction was concentrated, diluted with DCM, washed with sat.NaHCO3 and water, concentrated and triturated with methanol to give the titled compound as a yellow solid.
Reaction SMILES: [C:1]([O:4][C@H:5]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[C:7](=[CH:8][CH2:9][C@@H:10]3[C@@H:19]2[CH2:18][CH2:17][C@@:15]2([CH3:16])[C@H:11]3[CH2:12][CH2:13][C@@H:14]2[O:24][C:25](=[O:27])[CH3:26])[CH2:6]1)(=[O:3])[CH3:2].C([O:32]O)(C)(C)C>[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[Cr]>[C:1]([O:4][C@H:5]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[C:7](=[CH:8][C:9](=[O:32])[C@@H:10]3[C@@H:19]2[CH2:18][CH2:17][C@@:15]2([CH3:16])[C@H:11]3[CH2:12][CH2:13][C@@H:14]2[O:24][C:25](=[O:27])[CH3:26])[CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(C)(C)OO
Reactant: CC(=O)O[C@H]1CC[C@@]2(C)C(=CC[C@H]3[C@@H]4CC[C@H](OC(C)=O)[C@@]4(C)CC[C@@H]32)C1
Agent: [Cr]
Agent: [C-]#[O+]
Product: CC(=O)O[C@H]1CC[C@@]2(C)C(=CC(=O)[C@H]3[C@@H]4CC[C@H](OC(C)=O)[C@@]4(C)CC[C@@H]32)C1

Procedure:
A second method of preparing βAET has been developed which also used 3β,17β diacetoxyandrost-5-ene as a starting material as before. This compound was oxidized with t-butylhydroperoxide in the presence of chromium hexacarbonyl (Cr(CO)6) to form 3β,17β-diacetoxyandrost-5-en-7-one as described by Pearson [Pearson, et al., J. Chem Soc. Perkin Trans. I, 267 (1985)]. The enone formed then was reduced with triisobutylaluminum (TIBA) to give the acetylated 7β-hydroxy (I) product.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[C:9]([C:23](=[O:25])[CH3:24])[C:10]([O:16][CH2:17][CH2:18][O:19][CH2:20][CH2:21]Br)=[CH:11][CH:12]=2)[CH:7]=1.[OH:27][C:28]1[C:33]([CH2:34][CH2:35][CH3:36])=[C:32]([OH:37])[CH:31]=[CH:30][C:29]=1[C:38](=[O:40])[CH3:39].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.CN(C)C=O>[CH3:1][O:2][C:3](=[O:26])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[C:9]([C:23](=[O:25])[CH3:24])[C:10]([O:16][CH2:17][CH2:18][O:19][CH2:20][CH2:21][O:37][C:32]3[CH:31]=[CH:30][C:29]([C:38](=[O:40])[CH3:39])=[C:28]([OH:27])[C:33]=3[CH2:34][CH2:35][CH3:36])=[CH:11][CH:12]=2)[CH:7]=1
Reactant: COC(=O)COc1ccc2ccc(OCCOCCBr)c(C(C)=O)c2c1
Reactant: CCCc1c(O)ccc(C(C)=O)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC(C)=O
Product: CCCc1c(OCCOCCOc2ccc3ccc(OCC(=O)OC)cc3c2C(C)=O)ccc(C(C)=O)c1O
Yield: 75.7 %

Procedure:
A mixture of 2.4 g of [[8-acetyl-7-[2-[2-bromoethoxy)ethoxy]-2-naphthalenyl]oxy]acetic acid methyl ester, 1.32 g of 1-(2,4-dihydroxy-3-propylphenyl)-ethanone and 1.17 g of anhydrous potassium carbonate in 48 ml of anhydrous acetone and 16 ml of anhydrous dimethylformamide was stirred at reflux for 18 hours. The mixture was filtered and filtrate was concentrated to an oil. The oil was purified by flash column chromatography (10% ethyl acetate-toluene) to yield 2.3 g, mp. 89°-90° C. (76%) of [[8-acetyl-7-[2-[2-(4-acetyl-3-hydroxy-2-propylphenoxy)ethoxy]ethoxy]-2-naphthalenyl]oxy]acetic acid methyl ester.
Reaction SMILES: Cl[S:2]([C:5]1[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[CH3:15][N:16]1[C:20]2[CH:21]=[CH:22][C:23]([CH2:25][NH2:26])=[CH:24][C:19]=2[N:18]=[N:17]1>>[CH3:15][N:16]1[C:20]2[CH:21]=[CH:22][C:23]([CH2:25][NH:26][S:2]([C:5]3[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][CH:6]=3)(=[O:4])=[O:3])=[CH:24][C:19]=2[N:18]=[N:17]1
Reactant: COC(=O)c1ccc(S(=O)(=O)Cl)cc1
Reactant: Cn1nnc2cc(CN)ccc21
Product: COC(=O)c1ccc(S(=O)(=O)NCc2ccc3c(c2)nnn3C)cc1

Procedure:
The titled compound was prepared according to the procedure described in step-1 of Example 1 from methyl 4-(chlorosulfonyl)benzoate and (1-methyl-1H-benzo[d][1,2,3]triazol-5-yl)methanamine.
Reaction SMILES: Cl[C:2]1[C:11]([N:12]([CH3:16])[CH:13]([CH3:15])[CH3:14])=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:17]([O:19][CH3:20])=[O:18])[CH:8]=2)[N:3]=1.[S:21]1[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[N:23]=[CH:22]1.C(O[K])(C)=O>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[S:21]1[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[N:23]=[C:22]1[C:2]1[C:11]([N:12]([CH3:16])[CH:13]([CH3:15])[CH3:14])=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:17]([O:19][CH3:20])=[O:18])[CH:8]=2)[N:3]=1
Reactant: COC(=O)c1ccc2nc(Cl)c(N(C)C(C)C)nc2c1
Reactant: c1ccc2scnc2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(=O)O[K]
Product: COC(=O)c1ccc2nc(-c3nc4ccccc4s3)c(N(C)C(C)C)nc2c1
Temperature: 150 °C
Reaction time: 4 h
Yield: 9.4 %

Procedure:
Into a 10-mL sealed was placed methyl 2-chloro-3-[methyl(propan-2-yl)amino]quinoxaline-6-carboxylate (400 mg, 1.36 mmol), 1,3-benzothiazole (368 mg, 2.72 mmol), Pd(PPh3)4 (80 mg, 0.06 mmol) and AcOK (272 mg, 2.72 mmol) under nitrogen atmosphere. After stirring 4 h at 150° C., the reaction mixture was purified by silica gel column chromatography eluting with 10% ethyl acetate in petroleum ether to afford methyl 2-(1,3-benzothiazol-2-yl)-3-[methyl(propan-2-yl)amino]quinoxaline-6-carboxylate as a light yellow solid (50 mg, 9.4%).
Reaction SMILES: C(Cl)(Cl)Cl.[C:5]([O:8][C@@H:9]1[C@@H:14]([O:15][C:16](=[O:18])[CH3:17])[C@@H:13]([O:19][C:20](=[O:22])[CH3:21])[C@@H:12]([CH2:23][N:24]2[C:28](=[O:29])[C:27]3=[CH:30][CH:31]=[CH:32][CH:33]=[C:26]3[C:25]2=[O:34])[O:11][C@H:10]1[S:35]C(=N)N)(=[O:7])[CH3:6].S(S([O-])=O)([O-])(=O)=O.[K+].[K+]>O>[C:5]([O:8][C@@H:9]1[C@@H:14]([O:15][C:16](=[O:18])[CH3:17])[C@@H:13]([O:19][C:20](=[O:22])[CH3:21])[C@@H:12]([CH2:23][N:24]2[C:28](=[O:29])[C:27]3=[CH:30][CH:31]=[CH:32][CH:33]=[C:26]3[C:25]2=[O:34])[O:11][C@H:10]1[SH:35])(=[O:7])[CH3:6]
Reactant: CC(=O)O[C@H]1[C@@H](OC(C)=O)[C@@H](CN2C(=O)c3ccccc3C2=O)O[C@@H](SC(=N)N)[C@@H]1OC(C)=O
Agent: O=S([O-])S(=O)(=O)[O-]
Agent: [K+]
Solvent: O
Solvent: ClC(Cl)Cl
Product: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](S)O[C@H](CN2C(=O)c3ccccc3C2=O)[C@@H]1OC(C)=O
Yield: 80.4 %

Procedure:
Chloroform (9.0 ml.) is added to a solution of 2-S-(2,3,4-tri-O-acetyl-6-deoxy-6-phthalimido-β-D-galactopyranosyl)-2-thiopseudourea (3.4 g.) in water (10 ml.) containing potassium metabisulfite (1.38 g.). The mixture is heated with stirring under reflux for 15 minutes. The cooled solution is separated, and the organic layer is dried and evaporated in vacuo to give the title compound (2.5 g.). This material is used directly for the preparation of 6-(5-cholesten-3β-yloxy)hexyl 2,3,4-tri-O-acetyl-6-deoxy-6-phthalimido-1-thio-β-D-galactopyranoside.
Reaction SMILES: ClC(Cl)C.[CH3:5][N:6]1[CH2:20][CH:19]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:9]2=[CH:10][CH:11]=[C:12]3[C:16]([NH:15][C:14](=[O:17])[C:13]3=[O:18])=[C:8]2[CH2:7]1.[CH2:27](O)[CH2:28][OH:29].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>O>[O:17]=[C:14]1[CH:13]2[O:18][CH2:27][CH2:28][O:29][C:11]3=[C:12]2[C:16](=[C:8]2[CH2:7][N:6]([CH3:5])[CH2:20][CH:19]([C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=4)[C:9]2=[CH:10]3)[NH:15]1
Reactant: OCCO
Reactant: CN1Cc2c(ccc3c2NC(=O)C3=O)C(c2ccccc2)C1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(Cl)Cl
Solvent: O
Product: CN1Cc2c(cc3c4c2NC(=O)C4OCCO3)C(c2ccccc2)C1

Procedure:
100 ml of dichloroethane are added to 20.6 g (0.0624 mol) of 8-methyl-6-phenyl-6,7,8,9-tetrahydro-1H-pyrido[4,3-g]indole-2,3-dione, 21 ml (0.374 mol) of ethylene glycol and 0.336 g (0.00176 mol) of toluene-4-sulphonic acid monohydrate, with stirring, and the mixture is heated under reflux for 3.5 hours, using a water separator. Ice is added to the reaction mixture and the mixture is brought to pH 6.8 with aqueous KHCO3 solution. The mixture is extracted with CH2Cl2, the CH2Cl2 phase is washed with H2O and dried over Na2SO4 and the solvent is stripped off in a rotary evaporator. The residue is chromatographed on Al2O3 (aluminum oxide from E. Merck, Darmstadt) using an eluent mixture of ethyl acetate and MeOH (20:0.2). After trituration with ethyl acetate/petroleum ether, the substance becomes crystalline. It is dried over P2O5 at 80° C. in vacuo.
Reaction SMILES: C(O)(=O)/C=C/C(O)=O.[Cl:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH:16]1[CH2:21][CH2:20][CH2:19][NH:18][CH2:17]1.[CH:22]([C:24]1[CH:39]=[CH:38][C:27]([O:28][C:29]2[CH:37]=[CH:36][C:32]([C:33]([NH2:35])=[O:34])=[CH:31][N:30]=2)=[CH:26][CH:25]=1)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClCCCl.CO.C(Cl)Cl>[Cl:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH:16]1[CH2:21][CH2:20][CH2:19][N:18]([CH2:22][C:24]2[CH:39]=[CH:38][C:27]([O:28][C:29]3[CH:37]=[CH:36][C:32]([C:33]([NH2:35])=[O:34])=[CH:31][N:30]=3)=[CH:26][CH:25]=2)[CH2:17]1
Reactant: Clc1ccccc1C1CCCNC1
Reactant: NC(=O)c1ccc(Oc2ccc(C=O)cc2)nc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C(O)/C=C/C(=O)O
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Solvent: ClCCCl
Product: NC(=O)c1ccc(Oc2ccc(CN3CCCC(c4ccccc4Cl)C3)cc2)nc1
Yield: 62.9 %

Procedure:
Using a method similar to Example 345, 3-(2-chloro-phenyl)-piperidine fumaric acid salt (0.128 g, 0.410 minor), 6-(4-formyl-phenoxy)-nicotinamide (compound of example 332, step 1) (0.101 g, 0.417 mmol), sodium triacetoxyborohydride (0.129 g, 0.609 mmol), and acetic acid (0.034 mL, 0.594 mmol) in 1,2-dichloroethane (8.0 mL) provides, after silica gel chromatography (20:1→10:1 methylene chloride:methanol) and reverse-phase HPLC, 0.109 g (62%) of the title compound as a white foam: high resolution mass spectrum (electrospray): m/z calc for C24H25ClN3O2 422.1635, found 422.1664; 1H NMR (methanol-d4): 8.67 (d, 1H, J=2.2 Hz), 8.29 (dd, 1H, J=2.2, 8.3 Hz), 7.47 (d, 2H, J=8.8 Hz), 7.39 (d, 2H, J=7.9 Hz), 7.30 (t, 1H, J=7.0 Hz), 7.21 (dt, 1H, J=1.3, 7.5 Hz), 7.16 (d, 2H, J=8.8 Hz), 7.03 (d, 1H, J=8.3 Hz), 3.71 (d, 1H, J=13.2 Hz), 3.67 (d, 1H, J=13.6 Hz), 3.43 (tt, 1H, J=3.5, 11.9 Hz), 3.12-3.03 (m, 2H), 2.25-2.11 (m, 2H), 1.98-1.76 (m, 3H), 1.58 (dq, 1H, J=4.8, 11.9 Hz).
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[N:7]([CH3:15])[N:6]=1)([CH3:4])([CH3:3])[CH3:2].S(Cl)([Cl:19])(=O)=O.O>ClCCl>[C:1]([C:5]1[C:9]([Cl:19])=[C:8]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[N:7]([CH3:15])[N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=S(=O)(Cl)Cl
Reactant: CCOC(=O)c1cc(C(C)(C)C)nn1C
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)c1c(Cl)c(C(C)(C)C)nn1C
Temperature: 10 °C
Reaction time: 2 h

Procedure:
A 5-L, four neck round bottom flask equipped with overhead air stirrer, positive pressure nitrogen inlet, thermocouple, and addition funnel was charged with ethyl 3-tert-butyl-1-methyl-1H-pyrazole-5-carboxylate (250 g, 1.19 mol) in dichloromethane (2.5 L). The resulting solution was cooled to 10° C. with a wet-ice bath. Sulfuryl chloride (149 mL, 1.49 mol) was added via addition funnel at such which maintained the temperature between 21-31° C. The resulting mixture was then stirred for 2 h at room temperature. A separate 12-L, four neck flask equipped with overhead air stirrer and thermocouple was charged H2O (3.75 L) and cooled to 10° C. This mixture was then added via addition funnel, while maintaining the temperature below 32° C. and the resulting mixture was stirred for 30 min. The layers were separated, the aqueous layer was extracted with dichloromethane (2×1 L). The organic layer was carefully washed with NaHCO3 (saturated, 2×2 L), brine (1.25 L), dried over Na2SO4, filtered, and evaporated to yield ethyl 3-tert-butyl-4-chloro-1-methyl-1H-pyrazole-5-carboxylate as a white solid. 1H NMR (CHLOROFORM-d) δ: 4.39 (q, J=7.1 Hz, 2H), 4.07 (s, 3H), 1.29-1.49 (m, 12H)
Reaction SMILES: [Na].[C:2]1([CH:8]([C:12]([NH2:14])=[O:13])[C:9]([NH2:11])=[O:10])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:15](OCC)=O.O>C(O)C>[C:2]1([C:8]2[C:12]([OH:13])=[N:14][CH:15]=[N:11][C:9]=2[OH:10])[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC=O
Reactant: NC(=O)C(C(N)=O)c1ccccc1
Agent: [Na]
Solvent: CCO
Solvent: O
Product: Oc1ncnc(O)c1-c1ccccc1
Temperature: 50 °C
Reaction time: 1 h
Yield: 69.1 %

Procedure:
Sodium metal (0.92 g, 40 mmol) was dissolved by stirring in ethanol (30 mL) at room temperature under argon over 40 min. To the resulting solution at room temperature was added 2-phenylmalonamide (3.56 g, 20 mmol) and ethyl formate (1.9 mL, 24 mmol). The resulting suspension was heated at 50° C. under argon 16 h. After cooling the reaction mixture to room temperature, water (100 mL) was added and the mixture was stirred for 1 h. Solid was removed by filtration. The filtrate was acidified to pH˜4 with 1 M aqueous HCl. The resulting precipitate was collected by filtration and further washed with water (20 mL×2), then Et2O (10 mL×2). After drying under vacuum for 3 h, the title compound (2.6 g) was obtained as a light yellow solid. HPLC/MS: retention time=0.76 min, [M+H]+=189.
Reaction SMILES: [C:1]1([C:7]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:8]2[CH:12]=[CH:11][N:10]=[CH:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([Li])CCC.CN([CH:33]=[O:34])C.[NH4+].[Cl-]>C1COCC1.O.CCOCC>[C:7]([N:8]1[CH:12]=[CH:11][N:10]=[C:9]1[CH:33]=[O:34])([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)([C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: CN(C)C=O
Reactant: c1ccc(C(c2ccccc2)(c2ccccc2)n2ccnc2)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: O
Product: O=Cc1nccn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C

Procedure:
A cooled (−78° C.) yellow solution of 1-(triphenylmethyl)imidazole (25.000 g; 80.542 mmol) in anhydrous THF (750 ml) was treated dropwise (in 55 min.) with a 1.6M solution of butyllithium in hexanes (55.35 ml; 88.560 mmol). After addition, the resulting pink homogeneous solution was further stirred at −78° C., under nitrogen, for 30 min. before a solution of anhydrous DMF (6.8 ml; 88.186 mmol) in anhydrous THF (40 ml) was added dropwise (in 40 min.). The resulting mixture was additionally stirred at −78° C., under nitrogen, for 1 h before aq. sat. NH4Cl (50 ml) was added dropwise. Ether (300 ml) and water (400 ml) were successively added, and this mixture was allowed to warm-up to rt. The yellow organic layer was additionally washed with water (300 ml), dried over anh. MgSO4, filtered, and concentrated to dryness under reduced pressure. The crude was purified by FC (DCM/MeOH=30/1) to give the pure product 1-trityl-1H-imidazole-2-carbaldehyde as a pale yellow solid which was further dried under HV (20.660 g; 76%). LC-MS: tR=1.03 min.; [M+H]+: no ionisation.
Reaction SMILES: FC(F)(F)C(O)=O.C([O:12][C:13](=[O:42])[C:14]1[CH:19]=[C:18]([C:20]2[CH2:24][CH2:23][CH2:22][C:21]=2[C:25]2[CH:30]=[C:29]([Cl:31])[CH:28]=[CH:27][C:26]=2[O:32][CH2:33][C:34]2[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=2)[CH:17]=[CH:16][C:15]=1[CH3:41])(C)(C)C>ClCCl>[F:40][C:37]1[CH:36]=[CH:35][C:34]([CH2:33][O:32][C:26]2[CH:27]=[CH:28][C:29]([Cl:31])=[CH:30][C:25]=2[C:21]2[CH2:22][CH2:23][CH2:24][C:20]=2[C:18]2[CH:17]=[CH:16][C:15]([CH3:41])=[C:14]([CH:19]=2)[C:13]([OH:42])=[O:12])=[CH:39][CH:38]=1
Reactant: Cc1ccc(C2=C(c3cc(Cl)ccc3OCc3ccc(F)cc3)CCC2)cc1C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1ccc(C2=C(c3cc(Cl)ccc3OCc3ccc(F)cc3)CCC2)cc1C(=O)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 32.4 %

Procedure:
Trifluoroacetic acid (1 ml) was added to a solution of 5-[2-(2-(4-fluorobenzyloxy)-5-chlorophenyl)cyclopent-1-enyl]-2-methylbenzoic acid t-butyl ester (60 mg 0.12 mmol) in dichloromethane (5 ml). The reaction mixture was stirred at room temperature for three hours. The solvent was evaporated, and the residue chromatographed (RP silica C18, acetonitrile/water 30:70–100:0) to give the title compound as a colourless solid 17 mg 33%.
Reaction SMILES: [C:1]1([NH:7][C:8](=[S:10])[S-:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH4+].Br[C:13]([CH3:20])([CH3:19])[C:14](OCC)=[O:15]>C(O)C>[CH3:19][C:13]1([CH3:20])[S:10][C:8](=[S:9])[N:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:14]1=[O:15]
Reactant: S=C([S-])Nc1ccccc1
Reactant: CCOC(=O)C(C)(C)Br
Agent: [NH4+]
Solvent: CCO
Product: CC1(C)SC(=S)N(c2ccccc2)C1=O

Procedure:
Ammonium phenyldithiocarbamate (93 g, 0.5 mole) and ethyl 2-bromoisobutyrate (98 g, 0.5 mole) were dissolved in ethanol (100 mL) and heated at reflux overnight. The ethanol was distilled off and the residue poured into ice water. The solid was filtered and recrystallized in 95% ethanol. The product had a final weight of 31.4 g and an M.P. of 107-108 degrees.