Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:5]([CH3:13])=[C:6]2[C:11]=1[S:10][CH2:9][CH2:8][C:7]2=[O:12].[BH4-].[Na+].Cl>C(O)C.ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:5]([CH3:13])=[C:6]2[C:11]=1[S:10][CH2:9][CH2:8][CH:7]2[OH:12]
Reactant: CCOC(=O)c1cc(Cl)c2c(c1C)C(=O)CCS2
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCO
Product: CCOC(=O)c1cc(Cl)c2c(c1C)C(O)CCS2
Reaction time: 0.5 h
Yield: 97.3 %

Procedure:
88.4 g (311 mmol) of the 8-chloro-6-ethoxycarbonyl-5-methylthiochroman-4-one obtained in the above step (5) was dissolved in 200 ml of ethanol, and further dissolved in 200 ml of dichloromethane. This solution was cooled to 5~10° C., and 5.9 g (155 mmol) of sodium borohydride was added. The reaction mixture was stirred at the above temperature for 30 minutes, and further stirred at room temperature for 3 hours. Then, the reaction mixture was poured into 400 ml of a 5% hydrochloric acid aqueous solution and extracted with 900 ml of dichloromethane, and then the resultant organic layer was washed with a saturated sodium chloride aqueous solution and dried over anhydrous sodium sulfate. The solvent was distilled off to give 86.8 g (yield 97%) of 8-chloro-6-ethoxycarbonyl-5-methylthiochroman-4-ol.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:12][NH:11][CH2:10][CH:9]2[N:13]([CH3:28])[C:14](=[O:27])[C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([C:23]([F:26])([F:25])[F:24])[CH:16]=2)=[CH:4][CH:3]=1.[F:29][C:30]1[CH:38]=[CH:37][C:33]([C:34](O)=[O:35])=[C:32]([CH3:39])[CH:31]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH2:12][N:11]([C:34](=[O:35])[C:33]3[CH:37]=[CH:38][C:30]([F:29])=[CH:31][C:32]=3[CH3:39])[CH2:10][CH:9]2[N:13]([CH3:28])[C:14](=[O:27])[C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([C:23]([F:24])([F:25])[F:26])[CH:16]=2)=[CH:6][CH:7]=1
Reactant: Cc1cc(F)ccc1C(=O)O
Reactant: COc1ccc(C(=O)N(C)C2CNCC2c2ccc(Cl)cc2)cc1C(F)(F)F
Product: COc1ccc(C(=O)N(C)C2CN(C(=O)c3ccc(F)cc3C)CC2c2ccc(Cl)cc2)cc1C(F)(F)F

Procedure:
In analogy to the procedure described for the synthesis of example 87 (step c), the title compound N-[(3RS,4SR)-4-(4-chloro-phenyl)-1-(4-fluoro-2-methyl-benzoyl)-pyrrolidin-3-yl]-4-methoxy-N-methyl-3-trifluoromethyl-benzamide was prepared from N-[(3RS,4SR)-4-(4-chloro-phenyl)-pyrrolidin-3-yl]-4-methoxy-N-methyl-3-trifluoromethyl-benzamide using 4-fluoro-2-methylbenzoic acid instead of 1-(1-methyl-cyclopropanecarbonyl)-piperidine-4-carboxylic acid and was obtained as a light brown oil. MS m/e: 549.2 [M+H]+.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH2:10][CH2:11][O:12][CH3:13])[C:4]=1[O:14][CH2:15][CH2:16][O:17][CH3:18].[C-:19]#[N:20].[K+].C(OCC)(=O)C>CN(C=O)C>[CH3:18][O:17][CH2:16][CH2:15][O:14][C:4]1[C:5]([O:9][CH2:10][CH2:11][O:12][CH3:13])=[CH:6][CH:7]=[CH:8][C:3]=1[CH2:2][C:19]#[N:20]
Reactant: COCCOc1cccc(CCl)c1OCCOC
Reactant: [C-]#N
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COCCOc1cccc(CC#N)c1OCCOC
Temperature: 70 °C
Reaction time: 17 h
Yield: 84.6 %

Procedure:
A mixture of 1-(chloromethyl)-2,3-bis{[2-(methyloxy)ethyl]oxy}benzene (1.15 g, 4.19 mmol) and potassium cyanide (0.82 g, 12.56 mmol) in DMF (10 mL) was stirred at 70° C. for 17 h. After cooling to rt, ethyl acetate (100 mL) was added, and the mixture was washed with sat. sodium bicarbonate (30 mL), 5% aqueous LiCl (2×30 mL), and brine (30 mL), dried with sodium sulfate, and concentrated. Column chromatography on silica (2:1 hexanes/ethyl acetate) afforded (2,3-bis{[2-(methyloxy)ethyl]oxy}phenyl)acetonitrile (0.94 g, 85% yield) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ7.02 (m, 2H), 6.88 (dd, 1H), 4.28 (m, 2H), 4.13 (m, 2H), 3.84 (s, 2H), 3.75 (m, 2H), 3.63 (m, 2H), 3.43 (s, 3H), 3.41 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:6]([CH3:7])=[N:5][N:4]([CH3:8])[C:3]=1[C:9](Cl)=[O:10].OC=[C:14]1[C:22]2[C:17](=[CH:18][C:19]([C:23]([C:25]3[CH:26]=[C:27]([NH:31]C(=O)C)[CH:28]=[CH:29][CH:30]=3)=[O:24])=[CH:20][CH:21]=2)[NH:16][C:15]1=[O:35]>C1COCC1>[O:35]=[C:15]1[CH2:14][C:22]2[C:17](=[CH:18][C:19]([C:23]([C:25]3[CH:26]=[C:27]([NH:31][C:9]([C:3]4[N:4]([CH3:8])[N:5]=[C:6]([CH3:7])[C:2]=4[Cl:1])=[O:10])[CH:28]=[CH:29][CH:30]=3)=[O:24])=[CH:20][CH:21]=2)[NH:16]1
Reactant: CC(=O)Nc1cccc(C(=O)c2ccc3c(c2)NC(=O)C3=CO)c1
Reactant: Cc1nn(C)c(C(=O)Cl)c1Cl
Solvent: C1CCOC1
Product: Cc1nn(C)c(C(=O)Nc2cccc(C(=O)c3ccc4c(c3)NC(=O)C4)c2)c1Cl
Temperature: 25 °C
Yield: 57.7 %

Procedure:
A dry 25 mL flask was charged with 4-Chloro-2,5-dimethyl-2H-pyrazole-3-carbonyl chloride (0.152 g, 0.794 mmol) and THF (2 mL). 6-(4-Amino-benzoyl)-1,3-dihydro-indol-2-one (as prepared in Example 40, 0.200 g, 0.794 mmol) was added to the THF solution of the acid chloride, and the mixture was allowed to reflux for 4 h. The reaction mixture was then allowed to cool to room temperature. The room temperature reaction mixture was concentrated in vacuo. The tan solids were washed with THF (˜3 mL) and filtered to afford the pure 4-Chloro-2,5-dimethyl-2H-pyrazole-3-carboxylic acid [3-(2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide (0.187 g, 0.458 mmol, 58%).
Reaction SMILES: [CH3:1][C:2]1[N:6]=[C:5]([N:7]2[CH2:12][CH2:11][C:10](=O)[CH2:9][CH2:8]2)[S:4][N:3]=1.[CH3:14][C:15]1[CH:27]=[CH:26][C:18]([CH2:19][N:20]2[CH:24]=[N:23][C:22]([NH2:25])=[N:21]2)=[CH:17][CH:16]=1>>[CH3:14][C:15]1[CH:16]=[CH:17][C:18]([CH2:19][N:20]2[CH:24]=[N:23][C:22]([NH:25][CH:10]3[CH2:11][CH2:12][N:7]([C:5]4[S:4][N:3]=[C:2]([CH3:1])[N:6]=4)[CH2:8][CH2:9]3)=[N:21]2)=[CH:26][CH:27]=1
Reactant: Cc1ccc(Cn2cnc(N)n2)cc1
Reactant: Cc1nsc(N2CCC(=O)CC2)n1
Product: Cc1ccc(Cn2cnc(NC3CCN(c4nc(C)ns4)CC3)n2)cc1

Procedure:
Prepared in analogy to example 1 step h) starting from 1-(3-methyl-[1,2,4]thiadiazol-5-yl)-piperidin-4-one (example 1c) and 1-(4-methyl-benzyl)-1H-[1,2,4]triazol-3-ylamine. The title compound was obtained as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[NH:6][C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[C:9]([OH:14])[CH:8]=2)=[O:4].C([O-])([O-])=O.[Cs+].[Cs+].Cl[C:22]1[S:23][C:24]2[CH:30]=[CH:29][CH:28]=[CH:27][C:25]=2[N:26]=1>CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1[NH:6][C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[C:9]([O:14][C:22]1[S:23][C:24]3[CH:30]=[CH:29][CH:28]=[CH:27][C:25]=3[N:26]=1)[CH:8]=2)=[O:4]
Reactant: Clc1nc2ccccc2s1
Reactant: COC(=O)c1cc2ccc(O)cc2[nH]1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)c1cc2ccc(Oc3nc4ccccc4s3)cc2[nH]1
Temperature: 70 °C
Yield: 45.3 %

Procedure:
To a solution 6-hydroxy-1H-indole-2-carboxylic acid methyl ester (4.7 g, 24.5 mmol) in DMF (250 mL) was added Cs2CO3 (8.0 g, 24.5 mmol) followed by 2-chloro-benzothiazole (3.0 mL, 4.2 g, 24.5 mmol) and the reaction mixture was heated (70° C., 12 h). The reaction mixture was cooled (rt) and concentrated in vacuo. The resulting residue was partitioned between EtOAc (200 mL) and brine (100 mL). The organic layer was separated and the aqueous layer was extracted with EtOAc (2×300 mL). The organic layer was dried, filtered and concentrated in vacuo. The resulting residue was purified by silica gel flash chromatography using EtOAc:hexane (0-40%) to provide the title compound as a colorless foam (3.6 g, 45%). MS (ESI): mass calcd. for O17H12N2O3S, 324.1; m/z found, 325.0 [M+H]+. 1H NMR (400 MHz, CDCl3): 9.17 (s, 1H), 7.77-7.63 (m, 3H), 7.46-7.42 (m, 1H), 7.42-7.34 (m, 1H), 7.30-7.26 (m, 1H), 7.23-7.19 (m, 1H), 7.14 (dd, J=8.7, 2.1, 1H), 3.94 (s, 3H).
Reaction SMILES: Br[CH:2]1[C:8](=[O:9])[N:7]([CH3:10])[C:6]2[CH:11]=[CH:12][CH:13]=[CH:14][C:5]=2[N:4]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:3]1=[O:21].[CH2:22]([NH2:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>O>[CH3:10][N:7]1[C:6]2[CH:11]=[CH:12][CH:13]=[CH:14][C:5]=2[N:4]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:3](=[O:21])[CH:2]([NH:29][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:8]1=[O:9]
Reactant: CN1C(=O)C(Br)C(=O)N(c2ccccc2)c2ccccc21
Reactant: NCc1ccccc1
Solvent: O
Product: CN1C(=O)C(NCc2ccccc2)C(=O)N(c2ccccc2)c2ccccc21
Temperature: 100 °C

Procedure:
A mixture of 50 mg of the product of Step B and 2 ml of benzylamine was heated at 100° C. for 3 hours and the reaction medium was poured into water. The product obtained was separated, washed, and dried in the presence of phosphoric anhydride to obtain 50 mg of the sought product.
Reaction SMILES: [BH4-].[Li+].[F:3][C:4]1[CH:16]=[CH:15][C:7]2[N:8]=[C:9]([C:11](OC)=[O:12])[S:10][C:6]=2[CH:5]=1.O>CO>[F:3][C:4]1[CH:16]=[CH:15][C:7]2[N:8]=[C:9]([CH2:11][OH:12])[S:10][C:6]=2[CH:5]=1
Reactant: COC(=O)c1nc2ccc(F)cc2s1
Agent: [BH4-]
Agent: [Li+]
Solvent: O
Solvent: CO
Product: OCc1nc2ccc(F)cc2s1
Reaction time: 0.17 h
Yield: 101.2 %

Procedure:
16.5 mg of lithium borohydride were added to a solution of 106.1 mg of methyl (6-fluorobenzothiazol-2-yl)formate [prepared as described in step (a) above] in 2.1 ml of methanol cooled in an ice-water bath, and the resulting mixture was stirred at the same temperature for 10 minutes. At the end of this time a further 10 mg of lithium borohydride were added to the reaction mixture which was then stirred at the same temperature for a further 10 minutes. Water was then added to the reaction mixture and the resulting mixture was extracted with ethyl acetate. The resulting extract was washed consecutively with water and an aqueous sodium chloride solution and then dried over sodium sulfate. The solvent was then removed by evaporation under reduced pressure to give 93.1 mg of the title compound as a crude white crystalline solid.
Reaction SMILES: C(OC([N:8]([CH2:44][C:45]1[CH:50]=[CH:49][CH:48]=[C:47]([C:51]([F:54])([F:53])[F:52])[CH:46]=1)[C:9]1[CH:14]=[CH:13][N:12]=[C:11]([C:15]2[CH:20]=[C:19]([N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)[CH:18]=[CH:17][C:16]=2[NH:27][C:28]([C:30]2[CH:31]=[C:32]([CH:41]=[CH:42][CH:43]=2)[CH2:33][S:34][CH2:35][CH2:36][C:37]([O:39][CH3:40])=[O:38])=[O:29])[CH:10]=1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl.C([O-])(O)=O.[Na+]>[N:21]1([C:19]2[CH:18]=[CH:17][C:16]([NH:27][C:28]([C:30]3[CH:31]=[C:32]([CH:41]=[CH:42][CH:43]=3)[CH2:33][S:34][CH2:35][CH2:36][C:37]([O:39][CH3:40])=[O:38])=[O:29])=[C:15]([C:11]3[CH:10]=[C:9]([NH:8][CH2:44][C:45]4[CH:50]=[CH:49][CH:48]=[C:47]([C:51]([F:53])([F:54])[F:52])[CH:46]=4)[CH:14]=[CH:13][N:12]=3)[CH:20]=2)[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: COC(=O)CCSCc1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2-c2cc(N(Cc3cccc(C(F)(F)F)c3)C(=O)OC(C)(C)C)ccn2)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)CCSCc1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2-c2cc(NCc3cccc(C(F)(F)F)c3)ccn2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 28.7 %

Procedure:
Into a 50-mL round bottom flask, was placed a solution of methyl 3-(3-(2-(4-(tert-butoxycarbonyl(3-(trifluoromethyl)benzyl)amino)pyridin-2-yl)-4-(piperidin-1-yl)phenylcarbamoyl)-benzylthio)propanoate (800 mg, 1.05 mmol, 1.00 equiv) in dichloromethane (2 mL), and 2,2,2-trifluoroacetic acid (5 mL). The resulting solution was stirred for 3 h at room temperature. The reaction progress was monitored by LCMS. The resulting solution was diluted with 20 mL of NaHCO3 (aq), extracted with 3×50 mL of dichloromethane, and the organic layers combined. The resulting mixture was washed with 1×50 mL of brine. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column and eluted with petroleum ether:ethyl acetate (5:1). The product was obtained as 200 mg (29%) of a yellow solid.
Reaction SMILES: [CH:1]1[C:14]2[CH2:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[S:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[Na].[H-].[Na+].[CH:18]([O:20][CH2:21][CH2:22]Cl)=[CH2:19]>CS(C)=O.O>[CH:18]([O:20][CH2:21][CH2:22][C:13]1([CH2:22][CH2:21][O:20][CH:18]=[CH2:19])[C:12]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[S:6][C:5]2[C:14]1=[CH:1][CH:2]=[CH:3][CH:4]=2)=[CH2:19]
Reactant: C=COCCCl
Reactant: c1ccc2c(c1)Cc1ccccc1S2
Agent: [H-]
Agent: [Na+]
Agent: [Na]
Solvent: CS(C)=O
Solvent: O
Product: C=COCCC1(CCOC=C)c2ccccc2Sc2ccccc21
Temperature: 20 °C
Reaction time: 16 h

Procedure:
A solution of thioxanthene (29.7 g.) in dimethyl sulphoxide (1,200 ml.) is added gradually to a solution of sodium methylsulphinylmethide [prepared in the usual way from sodium hydride (24 g. of a 60% dispersion in mineral oil) and dimethyl sulphoxide (300 ml.)]. The dark red mixture is cooled in ice and chloroethyl vinyl ether (44 g.) is added dropwise. The mixture is stirred under nitrogen for a further 16 hours, allowed to warm to ambient temperature (18°to 20° C.), poured into water (3 1.) and extracted with ether. The ethereal solution is washed with water, dried, and then evaporated to give crude oily 9,9-bis(2'-vinyloxyethyl)thioxanthene.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:11][N:12]([CH2:23][C:24]2[C:29]([CH3:30])=[CH:28][C:27]([CH3:31])=[CH:26][N:25]=2)[CH:13]2[C:22]3[N:21]=[CH:20][CH:19]=[CH:18][C:17]=3[CH2:16][CH2:15][CH2:14]2)=[C:7]([CH2:9][OH:10])[CH:8]=1.[C:32]1([C@H:38]([CH2:42][CH3:43])[C:39](O)=[O:40])[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH3:30][C:29]1[C:24]([CH2:23][N:12]([CH2:11][C:6]2[CH:5]=[CH:4][C:3]([CH2:2][NH:1][C:39](=[O:40])[CH:38]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH2:42][CH3:43])=[CH:8][C:7]=2[CH2:9][OH:10])[CH:13]2[C:22]3[N:21]=[CH:20][CH:19]=[CH:18][C:17]=3[CH2:16][CH2:15][CH2:14]2)=[N:25][CH:26]=[C:27]([CH3:31])[CH:28]=1
Reactant: Cc1cnc(CN(Cc2ccc(CN)cc2CO)C2CCCc3cccnc32)c(C)c1
Reactant: CC[C@H](C(=O)O)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCC(C(=O)NCc1ccc(CN(Cc2ncc(C)cc2C)C2CCCc3cccnc32)c(CO)c1)c1ccccc1
Yield: 54.7 %

Procedure:
Using General Procedure G: To a solution of (5-aminomethyl-2-{[(3,5-dimethyl-pyridin-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amino]-methyl}-phenyl)-methanol (0.12 g, 0.26 mmol) dissolved in CH2Cl2 (10 mL) was added (S)-2-phenylbutyric acid (60 μl, 0.39 mmol), EDCI (0.08 g, 0.39 mmol), HOBT (0.05 g, 0.39 mmol), and DIPEA (67 μl, 0.39 mmol). Purification via column chromatography on silica gel (CH2Cl2:MeOH, 97:3, v/v) afforded the product as a colorless oil (0.08 g, 53%). 1H NMR (CDCl3) δ 0.88 (m, 3H), 1.51 (m, 1H), 1.86 (m, 1H), 2.05 (m, 1H), 2.11 (m, 3H), 2.14 (s, 3H), 2.24 (s, 3H), 2.79 (m, 2H), 3.20 (m, 1H), 3.70 (m, 4H), 4.09 (m, 2H), 4.33 (m, 3H), 5.69 (s, 1H), 6.95 (m, 2H), 7.13 (m, 2H), 7.22 (m, 7H), 8.15 (s, 1H), 8.35 (s, 1H); ES-MS m/z 564 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([O:13]C)=[O:12])=[CH:7][NH:8]2)=[CH:4][C:3]=1[C:15]1[CH:20]=[CH:19][C:18]([C@H:21]2[CH2:24][C@H:23]([OH:25])[CH2:22]2)=[CH:17][CH:16]=1.[OH-].[Na+].Cl>CO.O>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([OH:13])=[O:12])=[CH:7][NH:8]2)=[CH:4][C:3]=1[C:15]1[CH:16]=[CH:17][C:18]([C@H:21]2[CH2:24][C@H:23]([OH:25])[CH2:22]2)=[CH:19][CH:20]=1
Reactant: COC(=O)c1c[nH]c2cc(Cl)c(-c3ccc([C@H]4C[C@H](O)C4)cc3)cc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1c[nH]c2cc(Cl)c(-c3ccc([C@H]4C[C@H](O)C4)cc3)cc12
Temperature: 90 °C
Reaction time: 5 h
Yield: 53.5 %

Procedure:
To a solution of methyl 6-chloro-5-[4-(trans-3-hydroxycyclobutyl)phenyl]-1H-indole-3-carboxylate (290 mg, 0.82 mmol) in methanol/water (20 mL, v/v=1/1) was added sodium hydroxide (326 mg, 8.17 mmol). The mixture was stirred at 90° C. for 5 hours. The mixture was then acidified with 1M HCl to pH ˜5. The resulting suspension was extracted with dichloromethane. The combined organic layers were washed with brine, dried over sodium sulfate and concentrated. The residue was purified by reverse phase HPLC to give the title compound (150 mg, 54%) as a white solid. MS (AP+) 342.0 (M+H)+: 1H NMR (500 MHz, CD3OD) δ 8.03 (s, 1H), 8.02 (s, 1H), 7.59 (s, 1H), 7.41 (d, 2H), 7.34 (d, 2H), 4.53-4.50 (m, 1H), 3.67-3.65 (m, 1H), 2.55-2.43 (m, 4H).
Reaction SMILES: [C:1]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[Mg+2].[Cl-].[Cl-].[F:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]([CH3:27])([CH3:26])[C:23](O)=[O:24])=[CH:18][CH:17]=1>C(#N)C.S(Cl)(Cl)=O>[F:15][C:16]1[CH:17]=[CH:18][C:19]([C:22]([CH3:27])([CH3:26])[C:23]([CH:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[C:1]([O:9][CH2:10][CH3:11])=[O:8])=[O:24])=[CH:20][CH:21]=1
Reactant: CC(C)(C(=O)O)c1ccc(F)cc1
Reactant: CCOC(=O)CC(=O)OCC
Agent: [Cl-]
Agent: [Mg+2]
Solvent: CC#N
Solvent: O=S(Cl)Cl
Product: CCOC(=O)C(C(=O)OCC)C(=O)C(C)(C)c1ccc(F)cc1
Temperature: 0 °C
Yield: 96.3 %

Procedure:
A mixture of diethyl malonate (3 g, 16 mmol) in 50 mL ACN was stirred at 0° C., was treated with MgCl2 (2 g, 18 mmol) in one portion, and was treated dropwise with TEA (3 g, 33 mmol). The mixture was stirred at room temperature for 2.5 hours. A mixture of 2-(4-fluorophenyl)-2-methylpropanoic acid (3 g, 16 mmol) in thionyl chloride (20 mL) was refluxed for 2 hours and then concentrated in vacuo. The residue was diluted with 10 mL ACN, and was added dropwise to the above mixture. The mixture was stirred at 50° C. for 15 hours. The resulting mixture was then cooled to room temperature, diluted with 100 mL ether, washed with H2O (2×50 mL) and brine 20 mL, dried over anhydrous Na2SO4, and concentrated in vacuo. The crude product was purified by column chromatography eluting with 10-20% EtOAc/hexane to give 5 g of the product as pale yellow oil. MS m/e=325 (M+H)+.
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[C@@:28]2([CH3:29])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:27]2[CH2:26][CH2:25][C@@:24]2([CH3:30])[C@H:17]3[CH2:18][CH:19]=[C:20]2[C@@H:21]([OH:23])[CH3:22])[CH2:12][C@@H:11]([O:31][Si:32]([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:34])[CH3:33])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[H-].[Na+].Br[CH2:42]/[CH:43]=[CH:44]/[C:45]([CH3:55])([O:47][Si:48]([CH2:53][CH3:54])([CH2:51][CH3:52])[CH2:49][CH3:50])[CH3:46]>O1CCCC1>[Si:1]([O:8][C@@H:9]1[C@@:28]2([CH3:29])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:27]2[CH2:26][CH2:25][C@@:24]2([CH3:30])[C@H:17]3[CH2:18][CH:19]=[C:20]2[C@@H:21]([O:23][CH2:42]/[CH:43]=[CH:44]/[C:45]([CH3:55])([O:47][Si:48]([CH2:51][CH3:52])([CH2:53][CH3:54])[CH2:49][CH3:50])[CH3:46])[CH3:22])[CH2:12][C@@H:11]([O:31][Si:32]([C:35]([CH3:37])([CH3:36])[CH3:38])([CH3:33])[CH3:34])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC[Si](CC)(CC)OC(C)(C)/C=C/CBr
Reactant: C[C@H](O)C1=CC[C@H]2C3=CC=C4C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O[Si](C)(C)C(C)(C)C)[C@]4(C)[C@H]3CC[C@]12C
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC[Si](CC)(CC)OC(C)(C)/C=C/CO[C@@H](C)C1=CC[C@H]2C3=CC=C4C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O[Si](C)(C)C(C)(C)C)[C@]4(C)[C@H]3CC[C@]12C
Yield: 104.1 %

Procedure:
Under the same conditions as in Example 83, 1α,3β-bis(tert-butyldimethylsilyloxy)-20(S)-hydroxypregna-5,7,16-triene (60.0 mg, 0.107 mmol), sodium hydride (60%, 17.1 mg, 0.428 mmol), 15-crown-5(10 μl) and (E)-1-bromo-4-methyl-4-triethylsilyloxy-2-pentene (116 mg, 0.375 mmol) were reacted in tetrahydrofuran (1 ml) and worked up, and then the residue was purified by preparative thin layer chromatography (0.5 mm×2, hexane:ethyl acetate=40:1, developed once) to give the title compound as a colorless oil (85.9 mg, 99%).
Reaction SMILES: [C:1]1([N:7]2[C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[C:10]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[N:9]=[C:8]2Cl)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][C:33]([OH:35])=[O:34].[H-].[Na+]>CN(C)C=O>[C:1]1([N:7]2[C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[C:10]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[N:9]=[C:8]2[O:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][C:33]([OH:35])=[O:34])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Clc1nc(-c2ccccc2)c(-c2ccccc2)n1-c1ccccc1
Reactant: O=C(O)CCCCCCCO
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(O)CCCCCCCOc1nc(-c2ccccc2)c(-c2ccccc2)n1-c1ccccc1

Procedure:
1,4,5-Triphenyl-2-chloroimidazole was treated with 8-hydroxyoctanoic acid and sodium hydride in dimethylformamide to give the title compound, m.p. 158°-159° C., Found: C, 75.3; H, 6.6;N, 6.0%; C29H30N2O3.0.43H2O Requires: C, 75.3;H, 6.7; N, 6.0%
Reaction SMILES: [CH2:1]([N:6]([CH3:12])[C:7](=O)[N:8]([CH3:10])[CH3:9])[CH2:2][CH2:3][CH2:4][CH3:5].[NH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[N:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1.P(Cl)(Cl)(Cl)=O>C1C=CC=CC=1>[CH2:1]([N:6]([CH3:12])[C:7]([N:8]([CH3:10])[CH3:9])=[N:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[N:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCCN(C)C(=O)N(C)C
Reactant: Nc1ccccc1N1CCOCC1
Solvent: O=P(Cl)(Cl)Cl
Solvent: c1ccccc1
Product: CCCCCN(C)C(=Nc1ccccc1N1CCOCC1)N(C)C

Procedure:
Reaction of 3-pentyl-1,1,3-trimethylurea (7.5 g) in benzene (80 ml) with 4-(2-aminophenyl)morpholine (6.46 g) in benzene (30 ml) in the presence of phosphorus oxychloride (4.06 ml) for 45 hours at 70° C. gave 1-pentyl-2-(2-morpholinophenyl)-1,3,3-trimethyl guanidine (b.p. 98° C. at 1.5 mm Hg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[S:10][CH:11]=[C:12]([C:14]([O:16]CC)=[O:15])[N:13]=2)[CH:6]=[CH:7][CH:8]=1.[OH-].[Na+]>CCO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[S:10][CH:11]=[C:12]([C:14]([OH:16])=[O:15])[N:13]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: CCOC(=O)c1csc(-c2cccc(OC)c2)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1cccc(-c2nc(C(=O)O)cs2)c1
Temperature: 25 °C

Procedure:
To a stirred solution of the ethyl 2-(3-methoxy-phenyl)thiazole-4-carboxylate (0.23 g, 0.87 mmol) in EtOH (10 mL) was added 1N NaOH (aq) (5 mL). The resulting mixture was heated to reflux until the starting material was consumed (2 h). The mixture was cooled to RT, acidified with 1N HCl (aq) and concentrated by rotary evaporation. The residue was extracted with CH2Cl2 (3×15 mL). The extracts were combined, dried over MgSO4, filtered and concentrated by rotary evaporation to afford the title compound as an off-white solid. EI-MS m/z 236 (M+H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[C:6](I)[CH:5]=[CH:4][N:3]=1.[C:10]1([CH:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.CCN(C(C)C)C(C)C.C([O-])(O)=O.[Na+]>CC#N>[Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([N:19]2[CH2:20][CH2:21][CH:16]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH2:17][CH2:18]2)[CH:5]=[CH:4][N:3]=1
Reactant: Clc1nccc(I)c1Cl
Reactant: c1ccc(C2CCNCC2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: Clc1nccc(N2CCC(c3ccccc3)CC2)c1Cl
Temperature: 110 °C

Procedure:
A mixture of D10 (4 g, 14.605 mmol), 4-phenylpiperidine (3.532 g, 21.907 mmol) and DIPEA (5.088 ml, 29.209 mmol) in CH3CN (150 ml) was heated in a sealed tube at 110° C. for 16 h. The mixture was then treated with NaHCO3 (aqueous sat. solution). The resulting mixture was extracted with EtOAc. The organic layer was separated, dried (Na2SO4) and concentrated in vacuo. The crude product was purified by column chromatography (silica gel; DCM/7M solution of NH3 in MeOH/EtOAc gradient as eluent). The desired fractions were collected and concentrated in vacuo to yield intermediate compound D14 (2.32 g, 52%) as a white solid.