Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[I:7][C:8]1[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:9]=1[C:10]([OH:12])=O.C(N(CC)CC)C.[CH2:25]([NH:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH3:26]>ClCCl.CN(C1C=CN=CC=1)C.CN(C)C=O>[Cl:17][C:15]1[CH:14]=[CH:13][C:9]([C:10]([N:27]([CH2:25][CH3:26])[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[O:12])=[C:8]([I:7])[CH:16]=1
Reactant: O=C(O)c1ccc(Cl)cc1I
Reactant: CCNc1ccccc1
Agent: CN(C)c1ccncc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCN(C(=O)c1ccc(Cl)cc1I)c1ccccc1
Temperature: 23 °C

Procedure:
Oxalyl chloride (2.3 ml, 3.4 g, 26.6 mmol) was added dropwise to a solution of 2-iodo-4-Chlorobenzoic acid (5 g, 17.7 mmol) in dichloromethane (35 ml). N,N-Dimethylformamide (0.01 ml) was added to the reaction mixture via syringe and the reaction mixture was stirred at 23° C. for an hour. The reaction mixture was concentrated in vacuo. The residue was taken up in dichloromethane (50 ml) followed by the addition of DMAP (10 mg) and triethylamine (3.73 ml, 2.7 g, 26.6 mmol). The mixture was cooled to 0° C. and N-ethylaniline (2.6 ml, 2.6 g, 21.2 mmol) was added. The reaction mixture was warmed to 23° C. After an hour at this temperature, the reaction mixture was diluted with 1:1 ethyl acetate/hexanes (150 ml) and washed with 1N HCl (2 50-ml portions) and saturated aqueous sodium chloride (50 ml). The organics were dried over anhydrous sodium sulfate and concentrated. Purification of the residue by flash column chromatography (25% ethyl acetate in hexanes) afforded 4-chloro-N-ethyl-2-iodo-N-phenyl-benzamide I-14a (6.0 g, 88%).
Reaction SMILES: Cl.N[C@H](C)CSC1SC=C(C2C=CC=CC=2)N=1.SC1SC=C(C2C=CC=CC=2)N=1.C(O[C@@H]1[C@H](OC(=O)C)[C@@H](COC(=O)C)O[C@H]1N1C=NC2C1=NC(Cl)=NC=2Cl)(=O)C.C([O:62][C@@H:63]1[C@H:67]([O:68]C(=O)C)[C@@H:66]([CH2:72][O:73]C(=O)C)[O:65][C@H:64]1[N:77]1[C:101]2[N:100]=[C:99]([Cl:102])[N:98]=[C:81]([NH:82][C@H:83]([CH3:97])[CH2:84][S:85][C:86]3[S:87][CH:88]=[C:89]([C:91]4[CH:96]=[CH:95][CH:94]=[CH:93][CH:92]=4)[N:90]=3)[C:80]=2[N:79]=[CH:78]1)(=O)C.C[O-].[Na+]>CO>[Cl:102][C:99]1[N:98]=[C:81]([NH:82][C@H:83]([CH3:97])[CH2:84][S:85][C:86]2[S:87][CH:88]=[C:89]([C:91]3[CH:96]=[CH:95][CH:94]=[CH:93][CH:92]=3)[N:90]=2)[C:80]2[N:79]=[CH:78][N:77]([C:101]=2[N:100]=1)[C@@H:64]1[O:65][C@H:66]([CH2:72][OH:73])[C@@H:67]([OH:68])[C@H:63]1[OH:62]
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cnc3c(N[C@H](C)CSc4nc(-c5ccccc5)cs4)nc(Cl)nc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: CC(=O)OC[C@H]1O[C@@H](n2cnc3c(Cl)nc(Cl)nc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: C[C@@H](N)CSc1nc(-c2ccccc2)cs1
Agent: C[O-]
Solvent: CO
Product: C[C@H](CSc1nc(-c2ccccc2)cs1)Nc1nc(Cl)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Yield: 20 %

Procedure:
The title compound was prepared according to method A as described in Example 1 by reacting 2-[(R)-2-amino-1-propylthio]-4-phenylthiazole hydrochloride [prepared by a Mitsunobu reaction as described in Example 1 using 2-[(R)-N-tert-butyloxycarbonyl]amino-1-propanol (2.72 g, 15.5 mmol) and 2-mercapto-4-phenylthiazole (3.0 g, 15.5 mmol) followed by acidic hydrolysis] (1.15 g, 4.0 mmol) with 9-(2,3,5-tri-O-acetyl-β-D-ribofuranosyl)-2,6-dichloro-9H-purine (1.5 g, 3.35 mmol), followed by deacylation of the purified 2',3',5'-tri-O-acetyl-2-chloro-N-[(R)-1-(4-phenyl-2-thiazolyl)thio-2-propyl]adenosine using sodium methoxide in methanol to provide the title 2-chloro-N-[(R)-1-(4-phenyl-2-thiazolyl)thio-2-propyl]adenosine (0.36 g, 20%) as a foam after column chromatography. 1H NMR (DMSO-d6) δ1.37 (3H, d, --CHCH3), 3.4-3.73 (2H, m, 5'a and H-5'b and --CH2 --S--), 3.94 (1H, q, H-4), 4.13 (1H, q, H-3'), 4.52 (1H, q, H-2'), 4.71 (1H, m, --CHCH3), 5.06 (1H, t, 5'-OH), 5.22, 5.50 (2H, 2d, 2'- and 3'-OH), 5.83 (1H, d, H-1'), 7.33, 7.42 (3H, dt, Ar--H), 7.91 (2H, d, Ar--H), 8.41 (1H, s, H-2), 8.47 (1H, d, --NH). HPLC retention time 18.99 min [gradient elution, 20-80% acetonitrile/water (containing 0.1% TFA)].
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][C@H:12]2[CH2:17][CH2:16][C@H:15]([CH2:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:14][CH2:13]2)=[CH:6][CH:5]=1)[CH2:2][CH3:3].[Cl-].[Al+3].[Cl-].[Cl-].C(Cl)(=O)[C:31]([Cl:33])=[O:32].O>C(Cl)Cl>[CH2:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][C@H:12]2[CH2:17][CH2:16][C@H:15]([CH2:18][CH2:19][C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:25]=3[C:31]([Cl:33])=[O:32])[CH2:14][CH2:13]2)=[CH:6][CH:5]=1)[CH2:2][CH3:3]
Reactant: CCCc1ccc(CC[C@H]2CC[C@H](CCc3ccccc3)CC2)cc1
Reactant: O=C(Cl)C(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: O
Product: CCCc1ccc(CC[C@H]2CC[C@H](CCc3ccccc3C(=O)Cl)CC2)cc1
Temperature: 0 °C

Procedure:
Solution prepared by dissolving 47.2 g of (2-(trans-4-(2-(4-n-propylphenyl)ethyl)cyclohexyl)ethyl)benzene in 500 ml of methylene chloride was cooled down to 0° C., and 34.7 g of aluminum chloride was added thereto and stirred. Oxalyl chloride in an amount of 33 g was added dropwise little by little thereto, it was raised up to room temperature, and stirred for 2 hours. After finishing of the reaction, it was added to 500 ml of water and extracted with 500 ml of methylene chloride. Organic layer was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under a reduced pressure to obtain 33.2 g of (2-(trans-4-(2-(4-n-propylphenyl)ethyl)cyclohexyl)ethyl)benzoyl chloride.
Reaction SMILES: [Br-].[CH:2]1([Zn+])[CH2:5][CH2:4][CH2:3]1.Br[C:8]1[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:9]=1[C:10]([O:12][CH3:13])=[O:11]>>[CH:2]1([C:8]2[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:9]=2[C:10]([O:12][CH3:13])=[O:11])[CH2:5][CH2:4][CH2:3]1
Reactant: [Zn+]C1CCC1
Reactant: COC(=O)c1ccc(C)cc1Br
Agent: [Br-]
Product: COC(=O)c1ccc(C)cc1C1CCC1
Temperature: 65 °C
Yield: 80.8 %

Procedure:
Cyclobutylzinc(II) bromide (50 mL, 0.5 M in THF, 25.0 mmol) was added to a mixture of methyl 2-bromo-4-methylbenzoate (compound 89.1, 5.0 g, 21.8 mmol) and PdCl2(dppf)CH2Cl2 (1.78 g, 2.20 mmol). The mixture was degassed with argon, then heated at 65° C. under argon for 24 hours. The mixture was cooled to 0° C., then carefully quenched with water (10 mL). The mixture was diluted with EtOAc (200 mL) and washed with water then brine. The organic layer was dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexanes:EtOAc 30:1 to 20:1) to yield 3.6 g (81%) of the title compound. 1H NMR (400 MHz, Chloroform-d) δ 7.68 (d, 1H), 7.23-7.17 (s, 1H), 7.03 (d, 1H), 4.16 (m, 1H), 3.86 (s, 3H), 2.39 (s, 3H), 2.34 (m, 2H), 2.16-1.96 (m, 3H), 1.80 (m, 1H).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][OH:4].S(=O)(=O)(O)O.[F:10][C:11]1[CH:25]=[CH:24][C:14]([CH:15](O)[C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)=[CH:13][CH:12]=1>C1(C)C=CC=CC=1>[F:10][C:11]1[CH:12]=[CH:13][C:14]([CH:15]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)[O:4][CH2:3][CH2:2][Cl:1])=[CH:24][CH:25]=1
Reactant: OCCCl
Reactant: OC(c1ccc(F)cc1)c1ccc(F)cc1
Agent: O=S(=O)(O)O
Solvent: Cc1ccccc1
Product: Fc1ccc(C(OCCCl)c2ccc(F)cc2)cc1
Yield: 59.5 %

Procedure:
2-Chloroethanol (2) (4.1 g, 51 mmol) was added to a 500 ml three neck round bottom flask containing 250 ml of toluene and sulfuric acid(1 ml, 18 mmol). A solution of 4,4'-difluorobenzhydrol (1) (9.16 g, 41.6 mmol) in 50 ml of toluene was then added dropwise over 30 minutes. Once addition was complete the resulting mixture was heated to reflux for 3 hours. At the end of this time the mixture was washed with 10% sodium carbonate (150 ml), water (150 ml), and dried over anhydrous magnesium sulfate. The mixture was then filtered and the solvents were evaporated under reduced pressure to afford a clear yellow liquid. The material was distilled on a Kugelrohr distillation apparatus at 140° C., 0.5 mm Hg to afford the desired product (3) (7.0 g, 60%) as a clear and colorless liquid which crystallized slowly upon standing.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])/[C:5]/2=[CH:14]\[NH:15][C:16]1[CH:21]=[CH:20][C:19]([N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)=[CH:18][CH:17]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[CH3:42][N:43]([CH3:48])[CH2:44][C:45](=O)[CH3:46].C(O)(=O)C.C(=O)(O)[O-].[Na+]>CN1CCCC1=O.C(Cl)Cl>[CH3:42][N:43]([CH3:48])[CH2:44][CH:45]([N:25]1[CH2:24][CH2:23][N:22]([C:19]2[CH:18]=[CH:17][C:16]([NH:15]/[CH:14]=[C:5]3\[C:6](=[O:13])[NH:7][C:8](=[O:12])[C:9]4[C:4]\3=[CH:3][C:2]([I:1])=[CH:11][CH:10]=4)=[CH:21][CH:20]=2)[CH2:27][CH2:26]1)[CH3:46]
Reactant: CC(=O)CN(C)C
Reactant: O=C1NC(=O)c2ccc(I)cc2/C1=C/Nc1ccc(N2CCNCC2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: CN1CCCC1=O
Product: CC(CN(C)C)N1CCN(c2ccc(N/C=C3\C(=O)NC(=O)c4ccc(I)cc43)cc2)CC1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 57.2 %

Procedure:
(4Z)-6-Iodo-4-{[(4-piperazin-1-ylphenyl)amino]methylene}isoquinoline-1,3(2H,4H)-dione (47.4 mg, 0.1 mmol) is dissolved in N-methylpyrrolidinone (1 mL) and methylene chloride (0.3 mL), followed by addition of sodium triacetoxyborohydride (244 mg, 1.15 mmol), 1-dimethylamino-propan-2-one (0.296 mL, 2.58 mmol) and acetic acid (0.15 mL, 2.6 mmol). After stirring at room temperature for 40 min, methylene chloride and saturated sodium bicarbonate solution were added. The organic layer is separated and dried to give 32 mg (57%) of the title compound as a yellow solid. MS (ESI) m/z 560.4 (M+H)+1.
Reaction SMILES: C(N(CC)CC)C.CS([Cl:12])(=O)=O.O[CH2:14][C:15]1[C:24]2[C:19](=[CH:20][CH:21]=[C:22]([O:25][CH3:26])[CH:23]=2)[N:18]=[CH:17][CH:16]=1>ClCCl>[Cl:12][CH2:14][C:15]1[C:24]2[C:19](=[CH:20][CH:21]=[C:22]([O:25][CH3:26])[CH:23]=2)[N:18]=[CH:17][CH:16]=1
Reactant: CS(=O)(=O)Cl
Reactant: COc1ccc2nccc(CO)c2c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc2nccc(CCl)c2c1

Procedure:
1.16 ml of triethylamine and 0.64 ml of methanesulfonyl chloride are successively added to a solution of 1.2 g of 4-hydroxymethyl-6-methoxyquinoline in 45 ml of dichloromethane, under an inert atmosphere of argon at a temperature in the region of 20° C. Stirring is maintained at this temperature for 3 hours. The reaction medium is concentrated under reduced pressure to give a brown residue. The product is used without further purification in the following step.
Reaction SMILES: C(OC(=O)[NH:10][C:11]1([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)C1C=CC=CC=1>CO.[Pd]>[C:17]1([C:11]2([NH2:10])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C(NC1(c2ccccc2)CCCCC1)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: NC1(c2ccccc2)CCCCC1
Yield: 90.4 %

Procedure:
Dissolve (1-phenyl-cyclohexyl)-carbamic acid benzyl ester (Preparation 27) (2.87 g, 9.26 mmol) in MeOH (100 mL). Exchange air with nitrogen for three times and then add Pd—C (0.5 g, 10%). Exchange the nitrogen with H2 for three times. Stir the reaction mixture under H2 for over night then remove the Pd—C by filtration. Remove the solvent under reduced pressure to give 1.468 g (90%) of the crude title compound as a colorless oil.
Reaction SMILES: Cl[C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:15])[CH:8]=2)[N:3]=1.[C:16]([C:19]1[CH:20]=[C:21]([CH:28]=[CH:29][CH:30]=1)[CH2:22][CH:23]([C:25]([OH:27])=[O:26])[NH2:24])([OH:18])=[O:17]>>[C:25]([CH:23]([NH:24][C:25]([CH:23]([NH:24][C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:15])[CH:8]=2)[N:3]=1)[CH2:22][C:21]1[CH:28]=[CH:29][CH:30]=[C:19]([C:16]([OH:18])=[O:17])[CH:20]=1)=[O:26])[CH2:22][C:21]1[CH:28]=[CH:29][CH:30]=[C:19]([C:16]([OH:18])=[O:17])[CH:20]=1)([OH:27])=[O:26]
Reactant: NC(Cc1cccc(C(=O)O)c1)C(=O)O
Reactant: O=C(O)c1cc2cc(Cl)ccc2nc1Cl
Product: O=C(O)c1cccc(CC(NC(=O)C(Cc2cccc(C(=O)O)c2)Nc2nc3ccc(Cl)cc3cc2C(=O)O)C(=O)O)c1

Procedure:
In close analogy to the procedure described in Example 1, 2,6-dichloroquinoline-3-carboxylic acid is reacted with 3-carboxy-DL-phenylalanine to provide the title compound in good yield.
Reaction SMILES: Cl[C:2]1[S:3][C:4]2[CH:9]=[C:8]([C:10]3[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=3)[NH:7][C:5]=2[N:6]=1.[NH:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1>>[F:16][C:13]1[CH:14]=[CH:15][C:10]([C:8]2[NH:7][C:5]3[N:6]=[C:2]([N:17]4[CH2:22][CH2:21][O:20][CH2:19][CH2:18]4)[S:3][C:4]=3[CH:9]=2)=[CH:11][CH:12]=1
Reactant: C1COCCN1
Reactant: Fc1ccc(-c2cc3sc(Cl)nc3[nH]2)cc1
Product: Fc1ccc(-c2cc3sc(N4CCOCC4)nc3[nH]2)cc1
Yield: 91 %

Procedure:
126 mg (0.50 mmol) of 2-chloro-5-(4-fluorophenyl)-4H-pyrrolo[2,3-d]thiazole are suspended in 2 ml of morpholine in a microwave vessel and irradiated at 130° C. for 2 h and subsequently purified directly by chromatography on silica gel (eluent: cyclohexane/ethyl acetate 1/1), giving 139 mg (0.45 mmol, 91%) of 5-(4-fluorophenyl)-2-morpholin-4-yl-4H-pyrrolo[2,3-d]thiazole as beige crystals; m.p. 240-248;
Reaction SMILES: [BH4-].[Na+].[Br:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[CH2:13][C:12](=[O:14])[CH2:11]2)=[C:6]([O:15][CH3:16])[CH:5]=1>O1CCCC1>[Br:3][C:4]1[CH:9]=[CH:8][C:7]([C@@H:10]2[CH2:11][C@H:12]([OH:14])[CH2:13]2)=[C:6]([O:15][CH3:16])[CH:5]=1
Reactant: COc1cc(Br)ccc1C1CC(=O)C1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cc(Br)ccc1[C@H]1C[C@@H](O)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Sodium borohydride (0.25 g, 6.75 mmol) was added to a solution of 3-(4-bromo-2-methoxyphenyl)cyclobutanone (1.87 g, 7.3 mmol) in tetrahydrofuran (70 mL) at 0° C., the reaction was stirred room temperature 1 hr, extracted with 1:1 solution of ethyl acetate in heptane, the organic layers was washed with brine (50 mL), dried over sodium sulfate, and concentrated to give the title compound (1.34 g, 77.18%).
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4](/[CH:6]=[CH:7]/[CH2:8]P(OCC)(OCC)=O)=[O:5].C([Li])CCC.[C:22]([O:25][C@@H:26]1[CH2:48][CH2:47][C@@:46]2([CH3:49])[CH:28]([CH2:29][CH2:30][C@@H:31]3[C@@H:45]2[CH2:44][C@H:43]([O:50][C:51](=[O:53])[CH3:52])[C@@:42]2([CH3:54])[C@H:32]3[CH2:33][CH2:34][C@@H:35]2[C@H:36]([CH3:41])[CH2:37][CH2:38][CH:39]=O)[CH2:27]1)(=[O:24])[CH3:23].P([O-])([O-])([O-])=O.[Na+].[Na+].[Na+]>C(COC)OC.CCCCCC>[CH2:2]([O:3][C:4](=[O:5])/[CH:6]=[CH:7]/[CH:8]=[CH:39]/[CH2:38][CH2:37][CH:36]([C@@H:35]1[C@:42]2([CH3:54])[C@H:32]([C@H:31]3[C@H:45]([CH2:44][C@@H:43]2[O:50][C:51](=[O:53])[CH3:52])[C@:46]2([CH3:49])[C@@H:28]([CH2:27][C@H:26]([O:25][C:22](=[O:24])[CH3:23])[CH2:48][CH2:47]2)[CH2:29][CH2:30]3)[CH2:33][CH2:34]1)[CH3:41])[CH3:1]
Reactant: CCOC(=O)/C=C/CP(=O)(OCC)OCC
Reactant: CC(=O)O[C@@H]1CC[C@@]2(C)C(CC[C@H]3[C@@H]4CC[C@H]([C@H](C)CCC=O)[C@@]4(C)[C@@H](OC(C)=O)C[C@@H]32)C1
Agent: O=P([O-])([O-])[O-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CCCCCC
Solvent: COCCOC
Product: CCOC(=O)/C=C/C=C/CCC(C)[C@H]1CC[C@H]2[C@@H]3CC[C@@H]4C[C@H](OC(C)=O)CC[C@]4(C)[C@H]3C[C@H](OC(C)=O)[C@]12C
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 19.6 g of freshly distilled triethyl 4-phosphonocrotonate in 50 ml of dry glyme was added (at -70° ) 50 ml of a 1.6 M solution of butyl lithium in hexane. After 15 min the temperature was brought to -10° and 30 g of 3α,12α-diacetoxycholan-24-al was dissolved in 200 ml of dry glyme was added dropwise. After stirring for 20 min at this temperature the reaction mixture was allowed to warm to room temperature and stirred for 0.5 hr. The reaction mixture was then poured into 2 liters of a 5% monobasic sodium phosphate solution and the mixture extracted with ether. The ether solution was washed with a saturated aqueous sodium chloride solution and dried (MgSO4). The solvent was removed under reduced pressure and the residue after being dissolved in a minimum amount of benzene was washed through 300 g of silica gel. The column was eluted with 4 liters of benzene and then 4 liters of 0.5% ethyl acetate-benzene solution, and the solids obtained therefrom were combined to give 20.7 g of crude 7-(3α,12α-diacetoxy-5β-pregnane-20-yl)-trans,trans- 2,4-heptadienoic acid ethyl ester. Trituration with petroleum ether afforded 13.1 g of 7-(3α,12α-diacetoxy-5β-pregnane-20-yl)-trans,trans-2,4-heptadienoic acid ethyl ester, mp 129°-131°, plus a second crop of 2.4 g, mp 128°-130°. Crystallization from methanol afforded the analytical sample, mp 130°-132°.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[N:13]=[C:14]([CH3:24])[S:15][C:16]=1[C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=1)=[O:11].N1CCCC2CN(C(OC(C)(C)C)=O)CC12>>[F:23][C:20]1[CH:19]=[CH:18][C:17]([C:16]2[S:15][C:14]([CH3:24])=[N:13][C:12]=2[C:10]([N:4]2[CH2:5][CH2:6][CH2:7][CH:8]3[CH2:9][NH:1][CH2:2][CH:3]23)=[O:11])=[CH:22][CH:21]=1
Reactant: Cc1nc(C(=O)N2CCC[C@H](C)[C@H]2CN)c(-c2ccc(F)cc2)s1
Agent: CC(C)(C)OC(=O)N1CC2CCCNC2C1
Product: Cc1nc(C(=O)N2CCCC3CNCC32)c(-c2ccc(F)cc2)s1

Procedure:
The title compound was prepared following the same general protocol as described for rac-((2S,3S)-2-(aminomethyl)-3-methylpiperidin-1-yl)(5-(4-fluorophenyl)-2-methylthiazol-4-yl)methanone in Example A65 using tert-butyl hexahydro-1H-pyrrolo[3,4-b]pyridine-6(2H)-carboxylate. MS (ESI) 346 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:10]([O:11][CH3:12])=[CH:9][C:6]([C:7]#[N:8])=[C:5]([N+:13]([O-:15])=[O:14])[CH:4]=1.C([Sn](=O)CCCC)CCC.C[Si]([N:30]=[N+:31]=[N-:32])(C)C>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[C:10]([O:11][CH3:12])=[CH:9][C:6]([C:7]2[N:30]=[N:31][NH:32][N:8]=2)=[C:5]([N+:13]([O-:15])=[O:14])[CH:4]=1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: COc1cc(C#N)c([N+](=O)[O-])cc1OC
Agent: CCCC[Sn](=O)CCCC
Solvent: Cc1ccccc1
Product: COc1cc(-c2nn[nH]n2)c([N+](=O)[O-])cc1OC
Temperature: 100 °C
Reaction time: 16 h
Yield: 71.1 %

Procedure:
2.33 g of 4,5-dimethoxy-2-nitro-benzonitrile was added to 15 ml of toluene, 0.28 g of dibutyltinoxide and 2.58 g of trimethylsilyl azide was added thereto, and the mixture was stirred at 100° C. for 16 hours. The reaction mixture was distilled under a reduced pressure to remove the solvent, and the resulting solid was washed with 250 ml of dichloromethane to obtain 2.0 g of the title compound as a grey solid (yield 71%).
Reaction SMILES: [Li]C(CC)C.C1CCCCC1.[C:12]([C:16]1[CH:26]=[CH:25][C:19]([C:20]([NH:22][CH2:23][CH3:24])=[O:21])=[CH:18][CH:17]=1)([CH3:15])([CH3:14])[CH3:13].CN(CCN(C)C)C.[Cl:35]C(Cl)(Cl)C(Cl)(Cl)Cl.C([O-])(O)=O.[Na+]>C1COCC1>[Cl:35][C:18]1[CH:17]=[C:16]([C:12]([CH3:13])([CH3:15])[CH3:14])[CH:26]=[CH:25][C:19]=1[C:20]([NH:22][CH2:23][CH3:24])=[O:21]
Reactant: CCNC(=O)c1ccc(C(C)(C)C)cc1
Reactant: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Agent: CN(C)CCN(C)C
Agent: O=C([O-])O
Agent: [Li]C(C)CC
Solvent: C1CCCCC1
Solvent: C1CCOC1
Product: CCNC(=O)c1ccc(C(C)(C)C)cc1Cl
Temperature: -78 °C
Yield: 86.9 %

Procedure:
1.3 M s-BuLi in cyclohexane (41 mL, 0.053 mol) was added dropwise to a solution of the above amide (5 g, 0.024 mol) and TMEDA (4 ml, 0.027 mol) in THF, cooled to -78° C. under nitrogen. After 30 min a solution of hexachloroethane (6.4 g, 0.027 mol) in THF was added. After 0.5 h at -78° C. the reaction mixture was warmed to -30° C. and poured into dilute aq NaHCO3 and extracted with ether. The ether extract was washed with water and brine, dried (MgSO4) and concentrated. The resulting solid was recrystallized from cyclohexane to give 5 g of 2-chloro-4-t-butyl-N-ethylbenzamide, a white solid.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:25]=[CH:24][C:9]([CH2:10][O:11][C:12]2[C:13]([CH2:18][C:19]3[NH:20][CH:21]=[CH:22][N:23]=3)=[N:14][CH:15]=[CH:16][CH:17]=2)=[CH:8][CH:7]=1)=[O:5])C.[OH-].[Na+].Cl>O>[C:4]([C:6]1[CH:7]=[CH:8][C:9]([CH2:10][O:11][C:12]2[C:13]([CH2:18][C:19]3[NH:23][CH:22]=[CH:21][N:20]=3)=[N:14][CH:15]=[CH:16][CH:17]=2)=[CH:24][CH:25]=1)([OH:5])=[O:3]
Reactant: CCOC(=O)c1ccc(COc2cccnc2Cc2ncc[nH]2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)c1ccc(COc2cccnc2Cc2ncc[nH]2)cc1
Yield: 67.9 %

Procedure:
3-(4-Ethoxycarbonylbenzyloxy)-2-(1-imidazolylmethyl)pyridine (4.50 g) was heated in a solution of sodium hydroxide (0.70 g) in water (125 ml) for 100° C. for 2 hours. The solution was cooled and neutralized by the addition of 2 N hydrochloric acid. The solid product was collected by filtration and recrystallized from ethanol to give 3-(4-carboxybenzyloxy)-2-(1-imidazolylmethyl)pyridine (2.80 g), m.p. 210°-211° C. Found: C, 66.06; H, 4.74; N, 13.42. C17H15N3O3 requires: C, 66.01; H, 4.89; N, 13.59%.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:41])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH2:12][C:13]2[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([Cl:22])[CH:20]=3)[N:15]([CH:23]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:14]=2[CH2:36][CH2:37][C:38](O)=[O:39])=[CH:6][CH:5]=1.C(Cl)(=O)C(Cl)=O>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:41])[C:4]1[CH:5]=[CH:6][C:7]([O:10][CH2:11][CH2:12][C:13]2[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([Cl:22])[CH:20]=3)[N:15]([CH:23]([C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:14]=2[CH2:36][CH2:37][CH2:38][OH:39])=[CH:8][CH:9]=1
Reactant: COC(=O)c1ccc(OCCc2c(CCC(=O)O)n(C(c3ccccc3)c3ccccc3)c3ccc(Cl)cc23)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: COC(=O)c1ccc(OCCc2c(CCCO)n(C(c3ccccc3)c3ccccc3)c3ccc(Cl)cc23)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 83 %

Procedure:
100 mg of 4-{2-[1-Benzhydryl-2-(2-carboxy-ethyl)-5-chloro-1H-indol-3-yl]-ethoxy}-benzoic acid methyl ester (0.0002M, 1 eq.) was dissolved in 1.0 ml of anhydrous methylene chloride. To the solution 33.5 mg of oxalyl chloride (0.0003M, 1.5 eq.) was added and the reaction stirred for one hour at room temperature. The reaction was then evaporated to dryness and the residue dissolved in 1.0 mL of anhydrous ethyl ether to which 0.027 mL of TMEDA was added. To this solution 0.35 mL of zinc borohydride solution in ether prepared by the literature method (Tet. Lett. Vol. 22, pg. 4723, 1981) was added. The reaction was stirred for 15 min. at room temperature and quenched with 1.0 mL of water. The reaction was diluted with 10 mL of ethyl ether and the water layer separated, the organic layer was dried over magnesium sulfate, filtered and evaporated to a clear oil. The oil was chromatographed with ethyl acetate/hexanes (1:9) to result in isolation of 4-{2-[1-Benzhydryl-5-chloro-2-(3-hydroxy-propyl)-1H-indol-3-yl]-ethoxy}-benzoic acid methyl ester as a white foam (81 mg, 83% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[C:5]([N+:12]([O-])=O)[CH:4]=1.[NH4+].[OH-].C(O)(=O)C1C(=CC=CC=1)N>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH2:12])[C:6](=[CH:10][CH:11]=1)[C:7]([OH:9])=[O:8]
Reactant: COc1ccc(C(=O)O)c([N+](=O)[O-])c1
Agent: Nc1ccccc1C(=O)O
Agent: [NH4+]
Agent: [OH-]
Product: COc1ccc(C(=O)O)c(N)c1

Procedure:
A solution of 4-methoxy-2-nitrobenzoic acid (19.3 g., 97.9 mmole) in 200 ml. 1 N NH4OH was reduced overnight in presence of 5% Pd/BaCO3. The reaction mixture was filtered and acidified with acetic acid to yield 15.8 g. (96%) of the anthranilic acid, M.P. 186°-188° C.
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH2:7][CH2:8][OH:9])[N:5]=[C:4]([C:10]([CH3:13])([CH3:12])[CH3:11])[CH:3]=1.[C:14]([Si:18]([CH3:21])([CH3:20])Cl)([CH3:17])([CH3:16])[CH3:15].N1C=CN=C1>CN(C=O)C.[NH4+].[Cl-].C(Cl)Cl>[C:10]([C:4]1[CH:3]=[C:2]([NH2:1])[N:6]([CH2:7][CH2:8][O:9][Si:18]([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:21])[CH3:20])[N:5]=1)([CH3:13])([CH3:12])[CH3:11]
Reactant: CC(C)(C)c1cc(N)n(CCO)n1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: [Cl-]
Agent: [NH4+]
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)(C)c1cc(N)n(CCO[Si](C)(C)C(C)(C)C)n1
Reaction time: 6 h
Yield: 70.8 %

Procedure:
A solution of Intermediate 10a (1.00 g, 5.46 mmol), tert-butyl-dimethyl-chlorosilane (823 mg. 5.46 mmol), and imidazole (774 mg, 11.38 mmol) in DMF (9 mL) was stirred at RT under a nitrogen atmosphere for 18 h. Additional tert-butyl-dimethyl-chlorosilane (823 mg. 5.46 mmol) and imidazole (774 mg, 11.38 mmol) were added to the reaction mixture and stirred for 6 h. The reaction mixture was diluted with NH4Cl saturated aqueous solution (10 mL) and DCM (10 mL). The layers were separated and aqueous layer was extracted with DCM (3×10 mL). The combined organic layers were dried (MgSO4), filtered, concentrated in vacuo and purified by FCC, using 0-50% EtOAc in cyclohexane, to give the title compound (1.15 g, 70%). LCMS (Method 3): Rt 3.06, 3.23 min, m/z 298 [MH+].