Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)[NH:7][CH:8]([C:31](=[O:35])[N:32]([CH3:34])[CH3:33])[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]2[CH:22]=[CH:21][C:20]([CH2:23][CH:24]3[S:28][C:27](=[O:29])[NH:26][C:25]3=[O:30])=[CH:19][CH:18]=2)=[CH:12][CH:11]=1)(C)(C)C.C(Cl)[Cl:38]>>[ClH:38].[NH2:7][CH:8]([CH2:9][C:10]1[CH:11]=[CH:12][C:13]([O:16][C:17]2[CH:22]=[CH:21][C:20]([CH2:23][CH:24]3[S:28][C:27](=[O:29])[NH:26][C:25]3=[O:30])=[CH:19][CH:18]=2)=[CH:14][CH:15]=1)[C:31]([N:32]([CH3:34])[CH3:33])=[O:35]
Reactant: ClCCl
Reactant: CN(C)C(=O)C(Cc1ccc(Oc2ccc(CC3SC(=O)NC3=O)cc2)cc1)NC(=O)OC(C)(C)C
Product: CN(C)C(=O)C(N)Cc1ccc(Oc2ccc(CC3SC(=O)NC3=O)cc2)cc1
Product: Cl
Temperature: 2.5 °C
Yield: 73.1 %

Procedure:
(1-dimethylcarbamoyl-2-{4-[4-(2,4-dioxothiazolidin-5-ylmethyl)-phenoxy]-phenyl}-ethyl)-carbamic acid tert-butyl ester (0.25 g) was dissolved in CH2Cl2 and cooled to 0-5° C. Hydrogen chloride gas was bubbled through this solution for 30 min. The excess HCl was degassed and the CH2Cl2 was removed. The residual solid was triturated with EtOAc (2×25 mL), decanted, and dried to yield the desired compound 2-amino-3-{4-[4-(2,4-dioxothiazolidin-5-ylmethyl)-phenoxy]-phenyl}-N,N-dimethylpropionamide hydrochloric acid salt as a white amorphous solid (0.16 g, 73.1%). 1H NMR (DMSO-d6): 12.05 (br, 1H), 7.26 (d, J=8.4 Hz, 2H), 7.22 (d, J=8.4 Hz, 2H), 6.96 (d, J=8.4 Hz, 2H), 6.91 (d, J=8.4 Hz, 2H), 4.90 (dd, J=9.6 and 4.4 Hz, 1H), 4.53 (br, 1H), 2.91-3.14 (m, 4H), 2.81 (s, 3H), 3.05 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=O)[C:5]([OH:11])=[CH:4][CH:3]=1.[F:12][C:13]([F:26])([F:25])[C:14]1[CH:15]=[C:16]([CH:18]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:20]=1)N.C[CH2:28][N:29]=C=NCCCN(C)C>CN(C1C=CN=CC=1)C.ClCCl>[F:12][C:13]([F:26])([F:25])[C:14]1[CH:15]=[C:16]([CH:18]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:20]=1)[CH2:28][NH:29][C:7](=[O:9])[C:6]1[CH:10]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=1[OH:11]
Reactant: CCN=C=NCCCN(C)C
Reactant: Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: O=C(O)c1cc(Cl)ccc1O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: O=C(NCc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cc(Cl)ccc1O
Temperature: 25 °C
Reaction time: 12 h
Yield: 38.3 %

Procedure:
To 12 ml of dichloromethane were added 5-chlorosalicylic acid (690 mg, 4 mmol), 3,5-bis(trifluoromethyl)aniline (972 mg, 4 mmol), EDCI (1.2 g, 8 mmol), and DMAP (49 mg, 0.4 mmol) in the presence of argon gas, followed by stirring for 12 hours at room temperature. The mixture was concentrated under reduced pressure, and then dissolved in 60 ml of ethylacetate, which was washed with water (40 ml×2). The organic layer was concentrated under reduced pressure, followed by column chromatography (developing solvent: hexane/ethylacetate=1/10) to give 609 mg of the target compound (yield: 38%).
Reaction SMILES: [C:1]([NH:22][C@H:23]([C:30]([OH:32])=[O:31])[CH2:24][O:25][P:26]([OH:29])([OH:28])=[O:27])(=[O:21])[CH2:2][CH2:3][CH2:4]/[CH:5]=[CH:6]\[CH2:7][CH:8]=[CH:9][CH2:10][CH:11]=[CH:12][CH2:13][CH:14]=[CH:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].[C:33](O)(=O)[CH2:34]C/C=C\CC=CCC=CCC=CCC=CCC=CCC.Cl.[CH3:58]OC(=O)[C@H]([C@@H](C)O)N>>[C:1]([NH:22][C@H:23]([C:30]([OH:32])=[O:31])[C@@H:24]([CH3:58])[O:25][P:26]([OH:29])([OH:28])=[O:27])(=[O:21])[CH2:2][CH2:3]/[CH:4]=[CH:5]\[CH2:6][CH:7]=[CH:8][CH2:9][CH:10]=[CH:11][CH2:12][CH:13]=[CH:14][CH2:15][CH:16]=[CH:17][CH2:18][CH:19]=[CH:20][CH2:33][CH3:34]
Reactant: CCC=CCC=CCC=CCC=CCC=CC/C=C\CCC(=O)O
Reactant: COC(=O)[C@@H](N)[C@@H](C)O
Reactant: CCCCCC=CCC=CCC=CC/C=C\CCCC(=O)N[C@@H](COP(=O)(O)O)C(=O)O
Agent: Cl
Product: CCC=CCC=CCC=CCC=CCC=CC/C=C\CCC(=O)N[C@H](C(=O)O)[C@@H](C)OP(=O)(O)O

Procedure:
This compound was prepared as described above for (6) using 0.5 mmol (164 mg) of cis-4,7,10,13,16,19-docosahexaenoic acid and 1 mmol (170 mg) of L-threonine methyl ester hydrochloride; yield 109 mg, (43%); Rf 0.05-0.10 (system B); 1H-NMR (CD3SOCD3, 200 MHz) δ0.9-1.0 (t, 3H, ω-CH3); 1.2-1.4 (3H, d, CH3CHOP); 2.0-2.1 (t, 2H, CH2CO); 2.2-2.4 (m, 4H, 2CH2CH═CH); 2.7-2.9 (br s, 10H, 5HC═CHCH2CH═CH); 4.1-4.3 (m, 2H, 2CH); 5.2-5.4 (br s, 12H, 6HC═CH); 8.2-8.4 (m, 3H, NH and 2POH)
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=2)[NH:4][N:3]=1.C(O)(=O)C.[CH3:23][O:24][C:25](=[O:34])[C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([CH:32]=O)[CH:27]=1.[BH3-]C#N.[Na+]>CO.CN1C(=O)N(C)CC1>[Cl:18][C:14]1[CH:13]=[C:12]([NH:11][C:9]2[N:8]=[CH:7][N:6]=[C:5]3[NH:4][N:3]=[C:2]([NH:1][CH2:32][C:28]4[CH:29]=[CH:30][CH:31]=[C:26]([C:25]([O:24][CH3:23])=[O:34])[CH:27]=4)[C:10]=23)[CH:17]=[CH:16][CH:15]=1
Reactant: COC(=O)c1cccc(C=O)c1
Reactant: Nc1n[nH]c2ncnc(Nc3cccc(Cl)c3)c12
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CN1CCN(C)C1=O
Solvent: CO
Product: COC(=O)c1cccc(CNc2n[nH]c3ncnc(Nc4cccc(Cl)c4)c23)c1

Procedure:
Analogously to Example 21, 1.00 mmol of 3-amino-4-(3-chloro-phenylamino)-1H-pyrazolo[3,4-d]pyrimidine in 26 ml of methanol, 13 ml of DMEU and 3.0 mmol of acetic acid are first reacted with 3-formyl-benzoic acid methyl ester and then reduced with 7.00 mmol of NaCNBH3 (5-7 days). 4-(3-Chloro-phenylamino)-3-(3-methoxycarbonyl-benzylamino)-1H-pyrazolo[3,4-d]pyrimidine is obtained.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([C:8](=O)[CH3:9])[CH:5]=[CH:4][CH:3]=1.[NH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].CC(O)=O>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]([CH:8]([N:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)[CH3:9])[N:7]=1
Reactant: CC(=O)c1cccc(Br)n1
Reactant: C1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC(c1cccc(Br)n1)N1CCCCC1
Temperature: 40 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 1-(6-bromo-pyridin-2-yl)-ethanone (600 mg, 3.01 mmol) in dry CH2Cl2 (20 mL) was added piperidine (0.5 mL) followed by NaBH(OAc)3 (1.3 g, 12.06 mmol) and HOAc (0.7 mL, 6.03 mmol). The mixture was heated at 40° C. for 72 h. The reaction was quenched with 2M Na2CO3 and stirred 1 h. The organic layer was collected, dried over MgSO4 and concentrated in vacuo. This crude compound was purified by chromatography on silica gel. Elution with hexane:acetone mixture (90:10) gave a light yellow solid. MS m/z: 269.2 (M+H). Calc'd. for C12H17BrN2-268.06.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH:3]([CH2:7][NH:8][C:9]([C:11]2[S:15][C:14]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)=[N:13][C:12]=2[CH3:23])=[O:10])[CH2:2]1.I[C:25]1[CH:37]=[CH:36][CH:35]=[CH:34][C:26]=1[C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28]>>[Cl:22][C:19]1[CH:20]=[CH:21][C:16]([C:14]2[S:15][C:11]([C:9]([NH:8][CH2:7][CH:3]3[O:4][CH2:5][CH2:6][N:1]([C:34]4[CH:35]=[CH:36][CH:37]=[CH:25][C:26]=4[C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:2]3)=[O:10])=[C:12]([CH3:23])[N:13]=2)=[CH:17][CH:18]=1
Reactant: Cc1nc(-c2ccc(Cl)cc2)sc1C(=O)NCC1CNCCO1
Reactant: CC(C)(C)OC(=O)c1ccccc1I
Product: Cc1nc(-c2ccc(Cl)cc2)sc1C(=O)NCC1CN(c2ccccc2C(=O)OC(C)(C)C)CCO1
Yield: 62.8 %

Procedure:
Using N-(morpholin-2-yl methyl)-2-(4-chlorophenyl)-4-methylthiazole-5-carboxamide (120 mg, 0.341 mmol) and tert-butyl 2-iodobenzoate (104 mg, 0.341 mmol), the same procedure was followed as in Example 58 to give 113 mg (63%) of the desired compound as a pale yellow amorphous product.
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][C:5]([C:6]([N:8]([CH2:17][CH2:18][C:19](O)=[O:20])[C:9]2[CH:16]=[CH:15][C:12]([O:13][CH3:14])=[CH:11][CH:10]=2)=[O:7])=[CH:4][CH:3]=1.[NH2:24][CH2:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28]>>[Cl:1][C:2]1[CH:23]=[CH:22][C:5]([C:6]([N:8]([CH2:17][CH2:18][C:19]([NH:24][CH2:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])=[O:20])[C:9]2[CH:16]=[CH:15][C:12]([O:13][CH3:14])=[CH:11][CH:10]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: COc1ccc(N(CCC(=O)O)C(=O)c2ccc(Cl)cc2)cc1
Reactant: CCOC(=O)CCN
Product: CCOC(=O)CCNC(=O)CCN(C(=O)c1ccc(Cl)cc1)c1ccc(OC)cc1

Procedure:
Analogously to Example 1, by using equivalent quantities, reacting N-(p-chlorobenzoyl)-3-(p-anisidino)propionic acid and ethyl 3-aminopropionate and suitable processing produces ethyl N-[N-(p-chlorobenzoyl)-3-(p-anisidino)propionyl]-3-aminopropionate (oil), saponification of which and processing of the reaction product yields N-[N-(p-chlorobenzoyl)-3-(p-anisidino)propionyl]-3-aminopropionic acid (M.P. 171° to 172°).
Reaction SMILES: Br[C:2]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH3:14])[C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].CC1(C)C(C)(C)OB([C:23]2[NH:27][N:26]=[CH:25][CH:24]=2)O1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.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>[CH3:14][O:13][C:9]1[CH:10]=[CH:11][CH:12]=[C:2]([C:23]2[NH:27][N:26]=[CH:25][CH:24]=2)[C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CC1(C)OB(c2ccn[nH]2)OC1(C)C
Reactant: CCOC(=O)c1c(Br)cccc1OC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: CCOC(=O)c1c(OC)cccc1-c1ccn[nH]1
Temperature: 100 °C
Yield: 33 %

Procedure:
In a microwave vial was dissolved ethyl 2-bromo-6-methoxybenzoate (500 mg, 1.54 mmol) and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (330 mg, 1.70 mmol) in DME (10 mL) and water (2 mL). Na2CO3 (259 mg, 3.09 mmol) was then added followed by Pd(PPh3)4 (89 mg, 0.077 mmol) and the reaction mixture was degassed with N2 for 10 minutes. The reaction mixture was then heated at 100° C. for 1 h in the microwave. The mixture was cooled to room temperature, filtered through Celite and washed with EtOAc and DCM. The crude solution was concentrated in vacuo and directly purified via silica gel chromatography (10-80% EtOAc in hexanes) to afford the title compound (125 mg, 33%). MS (ESI) mass calcd. for C13H14N2O3, 246.3. m/z found 247.1 [M+H]+. 1H NMR (400 MHz, Chloroform-d) δ 7.63 (d, J=2.2 Hz, 1H), 7.44-7.37 (m, 1H), 7.24 (d, J=8.1 Hz, 1H), 6.94 (dd, J=8.3, 0.9 Hz, 1H), 6.53 (d, J=2.3 Hz, 1H), 4.29 (q, J=7.2 Hz, 2H), 3.88 (s, 3H), 1.25-1.16 (m, 3H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:31]=[CH:32][C:33]=1[CH2:34][N:35]1[CH2:39][CH2:38][CH2:37][CH2:36]1)[CH2:5][C:6]1[C:7]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][C:8]=2[S:9][C:10]=1[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][N:20]2[CH2:24][CH2:23][CH2:22][CH2:21]2)=[CH:13][CH:12]=1.[CH3:40][Sn](C)(C)C.C(N(CC)CC)C>C1(C)C=CC=CC=1.C(OCC)(=O)C.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>[CH3:30][O:29][C:26]1[CH:27]=[CH:28][C:7]2[C:6]([CH2:5][C:4]3[CH:31]=[CH:32][C:33]([CH2:34][N:35]4[CH2:36][CH2:37][CH2:38][CH2:39]4)=[C:2]([CH3:40])[CH:3]=3)=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][N:20]4[CH2:24][CH2:23][CH2:22][CH2:21]4)=[CH:13][CH:12]=3)[S:9][C:8]=2[CH:25]=1
Reactant: C[Sn](C)(C)C
Reactant: COc1ccc2c(Cc3ccc(CN4CCCC4)c(Br)c3)c(-c3ccc(OCCN4CCCC4)cc3)sc2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: COc1ccc2c(Cc3ccc(CN4CCCC4)c(C)c3)c(-c3ccc(OCCN4CCCC4)cc3)sc2c1
Temperature: 130 °C
Reaction time: 25 h
Yield: 73 %

Procedure:
3-[3-Bromo-4-[(1-pyrrolidinyl)methyl]benzyl]-6-methoxy-2-[4-[2-(1-pyrrolidinyl)ethoxy]phenyl]benzo[b]thiophene (Example 138, Part A) (93 mg, 0.15 mmol) in toluene (2 mL) in a pressure tube was treated with tetrakis(triphenylphosphine)palladium (0) (17 mg,) and tetramethyltin (0.2 mL) at ambient temperature. The mixture was flushed with argon and allowed to stir in the dark in the sealed tube at 130° C. for 25 h. The cooled reaction mixture was directly fractionated through flash chromatography with 5% triethylamine in ethyl acetate to afford the title compound as a colorless oil (61 mg, 73%) after the solvent removal.
Reaction SMILES: [CH2:1]([NH:19][CH:20]1[O:28][C@H:27]([CH2:29][OH:30])[C@@H:25]([OH:26])[C@H:23]([OH:24])[C@H:21]1[OH:22])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[CH2:31]([N:43]=[C:44]=[O:45])[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42]>O1CCCC1.C(O)C>[CH2:1]([N:19]([CH:20]1[O:28][C@H:27]([CH2:29][OH:30])[C@@H:25]([OH:26])[C@H:23]([OH:24])[C@H:21]1[OH:22])[C:44]([NH:43][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])=[O:45])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCCCCCCCCCCCCNC1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Reactant: CCCCCCCCCCCCN=C=O
Solvent: C1CCOC1
Solvent: CCO
Product: CCCCCCCCCCCCCCCCCCN(C(=O)NCCCCCCCCCCCC)C1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O

Procedure:
9 g of the compound from Example 1 are suspended in 160 ml of tetrahydrofuran and 40 ml of ethanol. 4.3 g of dodecyl isocyanate, dissolved in 20 ml of tetrahydrofuran, are added dropwise to this suspension in the course of 20 minutes. When the reaction has ended, the mixture is evaporated in vacuo and the resulting syrup is purified by column chromatography (mobile phase methylene chloride/methanol, 15:1)
Reaction SMILES: C(NCC)C.[Li]CCCC.[C:11]([Si:15]([CH3:28])([CH3:27])[N:16]1[CH:19]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:18][C:17]1=[O:26])([CH3:14])([CH3:13])[CH3:12].Br[CH2:30][CH2:31][CH:32]([Br:34])[CH3:33].[NH4+].[Cl-]>C1COCC1>[Br:34][CH:32]([CH3:33])[CH2:31][CH2:30][CH:18]1[CH:19]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[N:16]([Si:15]([C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:28])[CH3:27])[C:17]1=[O:26]
Reactant: CC(C)(C)[Si](C)(C)N1C(=O)CC1c1ccccc1
Reactant: CC(Br)CCBr
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCNCC
Product: CC(Br)CCC1C(=O)N([Si](C)(C)C(C)(C)C)C1c1ccccc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 68 %

Procedure:
To diethylamine (4.32 g, 59.0 mmol) in 22 mL of THF at 0° C. was added nBuLi (2.5 M in hexanes; 50.6 mmol, 20.2 mL). After 15 minutes the solution was added via cannula to a −50° C. solution of 1-(tert-Butyl-dimethyl-silanyl)-4-phenyl-azetidin-2-one (11.0 g, 42.2 mmol) in 110 mL of THF. After stirring for 20 minutes, 1,3-dibromobutane was added and the solution was stirred for 1 hour. Saturated aqueous NH4Cl was added and the mixture was warmed to room temperature and extracted once with ether. The extract was dried with MgSO4, concentrated and chromatographed (9:1 hexanes/EtOAc) to give 11.4 g (68%) of the title compound as a pale yellow oil. 1H NMR (400 MHz, CDCl3) δ comp, 10H), 4.21 (d, J=2.5 Hz, 1H), 4.16 (d, J=2.5 Hz, 1H), 4.08 (m, 1H), 3.02 (m, 1H), 1.80–2.10 (comp, 4H), 1.67 (d, J=6.6 Hz, 3H), 0.90 (s, 9H), 0.18 (s, 3H), −0.22 (s, 3H); Mass spectrum m/e calcd for M+H=396.2. Found 396.0 (base), 316.
Reaction SMILES: [Si:1]([O:8][CH:9]([C:27]1([C:30]([O:32]CC)=O)[CH2:29][CH2:28]1)[CH:10]([N:12](CC1C=CC=CC=1)CC1C=CC=CC=1)[CH3:11])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]>CO.[OH-].[Pd+2].[OH-].[C]>[Si:1]([O:8][CH:9]1[C:27]2([CH2:29][CH2:28]2)[C:30](=[O:32])[NH:12][CH:10]1[CH3:11])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CCOC(=O)C1(C(O[Si](C)(C)C(C)(C)C)C(C)N(Cc2ccccc2)Cc2ccccc2)CC1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CC1NC(=O)C2(CC2)C1O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 18 h
Yield: 22.7 %

Procedure:
To a solution of ethyl 1-[(1RS,2RS)-1-(tert-butyldimethylsilyloxy)-2-(dibenzylamino)propyl]cyclopropanecarboxylate (1.36 g) in methanol (16 mL) was added 10% palladium hydroxide-carbon (containing 50% water, 280 mg), and the mixture was stirred at room temperature for 18 hr under a hydrogen atmosphere. The reaction mixture was filtered. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=10/1→1/4) to give the title compound as a colorless solid (yield: 164 mg, yield: 22.8%).
Reaction SMILES: [C:1]1([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[NH2:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[C:22](Cl)(=O)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.CCOCC>ClCCl>[C:1]1([N:7]2[C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[N:14]=[C:22]2[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Nc1ccccc1Nc1ccccc1
Reactant: O=C(Cl)c1ccccc1
Solvent: CCOCC
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: c1ccc(-c2nc3ccccc3n2-c2ccccc2)cc1
Temperature: 0 °C
Reaction time: 6 h
Yield: 69.9 %

Procedure:
40 ml of N-phenyl-1,2-phenylenediamine (7.36 g, 40 mmol) was charged in a 250 ml round bottle, 10 ml of triethylamine was then added, and the mixture was cooled to 0° C. Benzoyl chloride (5.6 g, 40 mmol) was dissolved in 40 ml of dichloromethane and then slowly added to the 250 ml round bottle. The reaction was conducted under a nitrogen atmosphere for 6 hours. After the reaction was complete, ether was added to form precipitation. The solid product was collected by filtration, washed with ether several times, and heated under reduced pressure to form 1,2-diphenyl-1H-benzoimidazole (yield=7.56 g, 70%).
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1.[H-].[Na+].Br[CH2:13][CH2:14][CH2:15][Cl:16].C1(O)C=CC=CC=1>COCCOC>[Cl:16][CH2:15][CH2:14][CH2:13][O:9][C:6]1[CH:7]=[CH:8][C:3]([S:2][CH3:1])=[CH:4][CH:5]=1
Reactant: ClCCCBr
Reactant: CSc1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Solvent: Oc1ccccc1
Product: CSc1ccc(OCCCCl)cc1
Yield: 32 %

Procedure:
A solution of 4-(methylthio)phenol (10.0 g, 0.071 mole) in 150 ml. of 1,2-dimethoxyethane is added to a slurry of a 57% dispersion of sodium hydride (3.0 g., 0.071 mole) in mineral oil (previously washed with hexane to remove the mineral oil) in 100 ml. of 1,2-dimethoxyethane. After the initial reaction is complete, 1-bromo-3-chloropropane (12.63 g., 0.08 mole) is added in one portion. The resulting mixture is stirred and refluxed for a period of 68 hrs., cooled and then concentrated under reduced pressure. Residual material (oil) is dissolved in ether and washed with water. The ether solution (after drying over magnesium sulfate) is concentrated under reduced pressure to provide 14.6 g. of an oil containing approximately 25% starting phenol according to NMR spectra. Distillation of the oil under reduced pressure affords, after a forerun of 4-(methylmercapto)phenol, 5.0 g. (32% yield) of 1-chloro-3-[4-(methylthio)phenoxy]propane, b.p. 150°-152° C. at 27 mm Hg.
Reaction SMILES: [CH3:1][C@:2]12[CH2:19][CH2:18][C@H:17]3[C@@H:7]([CH2:8][CH2:9][C:10]4[C@:15]3([CH3:16])[CH2:14][CH2:13][C:12](=[O:20])[CH:11]=4)[C@@H:6]1[CH2:5][CH2:4][C:3]2=[O:21].C([O-])([O-])O[CH2:24][CH3:25]>>[CH2:24]([O:20][C:12]1[CH2:13][CH2:14][C@@:15]2([CH3:16])[C:10](=[CH:9][CH2:8][C@@H:7]3[C@@H:17]2[CH2:18][CH2:19][C@@:2]2([CH3:1])[C@H:6]3[CH2:5][CH2:4][C:3]2=[O:21])[CH:11]=1)[CH3:25]
Reactant: CCOC([O-])[O-]
Reactant: C[C@]12CCC(=O)C=C1CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Product: CCOC1=CC2=CC[C@@H]3[C@H](CC[C@]4(C)C(=O)CC[C@@H]34)[C@@]2(C)CC1

Procedure:
The process according to claim 1 wherein androst-4-en-3,17-dione is treated with ethyl orthoformate to yield 3-ethoxyandrosta-3,5(6)-dien-17-one.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([CH2:11]O)=[CH:8][CH:9]=2)[N:4]([S:13]([C:16]2(C)[CH:21]=[CH:20]C=[CH:18][CH2:17]2)(=[O:15])=[O:14])[CH:3]=1.P(Br)(Br)[Br:24].CCO[CH2:30][CH3:31]>>[Br:24][CH2:11][C:7]1[CH:6]=[C:5]2[C:10]([C:2]([Cl:1])=[CH:3][N:4]2[S:13]([C:16]2[CH:21]=[CH:20][C:30]([CH3:31])=[CH:18][CH:17]=2)(=[O:15])=[O:14])=[CH:9][CH:8]=1
Reactant: CC1(S(=O)(=O)n2cc(Cl)c3ccc(CO)cc32)C=CC=CC1
Reactant: CCOCC
Reactant: BrP(Br)Br
Product: Cc1ccc(S(=O)(=O)n2cc(Cl)c3ccc(CBr)cc32)cc1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a solution of [3-chloro-1-(toluene-1-sulfonyl)-1H-indol-6-yl]-methanol (0.45 g, 1.34 mmol) in 13 mL of Et2O at 0° C. is added phosphorous tribromide (0.04 mL, 0.40 mmol). The mixture is stirred at 0° C. for 15 min, then at room temperature for 2 hours. The mixture is quenched by the addition of water/ice and diluted with Et2O. The layers are separated and the organic phase is washed with saturated NaHCO3 solution, water and saturated NaCl solution. The organic layer is dried over anhydrous MgSO4, filtered and concentrated to provide the title compound (0.47 g, 1.18 mmol) as an oil. The crude product is used in the subsequent step without further purification. 1H NMR (CDCl3, 300 MHz) δ8.09 (s, 1H), 7.79 (d, 2H), 7.59 (s, 1H), 7.50 (d, 1H), 7.35 (d, 1H), 7.27 (m, 2H), 4.66 (s, 2H), 2.39 (s, 3H).
Reaction SMILES: C[O:2][C:3](=[O:29])[CH:4]([NH:8][C:9](=[O:28])[CH:10]([NH:20][C:21](OC(C)(C)C)=[O:22])[CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][CH:14]=1)[CH:5]([CH3:7])[CH3:6].COC(=O)C(N1C(=O)C(COC2C=CC(Br)=CC=2)NC1=O)C(C)C>Cl>[Br:19][C:16]1[CH:17]=[CH:18][C:13]([O:12][CH2:11][CH:10]2[C:9](=[O:28])[N:8]([CH:4]([CH:5]([CH3:7])[CH3:6])[C:3]([OH:2])=[O:29])[C:21](=[O:22])[NH:20]2)=[CH:14][CH:15]=1
Reactant: COC(=O)C(NC(=O)C(COc1ccc(Br)cc1)NC(=O)OC(C)(C)C)C(C)C
Agent: COC(=O)C(C(C)C)N1C(=O)NC(COc2ccc(Br)cc2)C1=O
Agent: Cl
Product: CC(C)C(C(=O)O)N1C(=O)NC(COc2ccc(Br)cc2)C1=O
Temperature: 80 °C
Reaction time: 2 h
Yield: 41 %

Procedure:
A mixture of the compound obtained in step g above (22g) (759 mg, 1.907 mmol) and 3 N HCl (20 mL) was stirred at 80° C. for 2 h. The reaction mixture was cooled down and then extracted with EtOAc. The combined organic layers were dried and concentrated; the crude product was purified by silica gel column chromatography which gave the title compound as colorless oil (300 mg, 41%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:19](=[CH:20][CH:21]=1)[C:9]1[O:10][C:11]3([CH2:17][S:18][C:8]=1[C:7](=[O:22])[C:6]2=[O:23])[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3.Br[CH2:25][C:26]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=1>>[F:32][C:29]1[CH:30]=[CH:31][C:26]([CH2:25][N:14]2[CH2:15][CH2:16][C:11]3([O:10][C:9]4[C:19]5[C:5]([C:6](=[O:23])[C:7](=[O:22])[C:8]=4[S:18][CH2:17]3)=[CH:4][C:3]([O:2][CH3:1])=[CH:21][CH:20]=5)[CH2:12][CH2:13]2)=[CH:27][CH:28]=1
Reactant: COc1ccc2c(c1)C(=O)C(=O)C1=C2OC2(CCNCC2)CS1
Reactant: Fc1ccc(CBr)cc1
Product: COc1ccc2c(c1)C(=O)C(=O)C1=C2OC2(CCN(Cc3ccc(F)cc3)CC2)CS1

Procedure:
Compound 154 was synthesized using 8-methoxyspiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione, 1-(bromomethyl)-4-fluorobenzene ad conditions outlined in procedure W. Mp.=219-221° C.; 400 MHz 1H NMR (DMSO-d6) δ: 7.64 (d, J=8.4 Hz, 1H), 7.37-7.27 (m, 4H), 7.15 (dd, J=8.8, 8.8 Hz, 2H), 3.88 (s, 3H), 3.54 (s, 2H), 3.05 (s, 2H), 2.69 (d, J=11.6 Hz, 2H), 2.36 (dd, J=10.4 Hz, 2H), 1.98 (d, J=13.2 Hz, 2H), 1.81 (dd, J=10.4, 10.4 Hz, 2H); LCMS: 440 [M+H].
Reaction SMILES: Br[C:2]1[C:3](=[O:11])[N:4]([CH3:10])[C:5](=[O:9])[N:6]([CH3:8])[N:7]=1.[F:12][C:13]([F:27])([F:26])[C:14]1[CH:15]=[C:16]([N:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)[CH:17]=[CH:18][CH:19]=1>>[CH2:3]([OH:11])[CH2:2][CH2:13][CH3:14].[CH3:8][N:6]1[C:5](=[O:9])[N:4]([CH3:10])[C:3](=[O:11])[C:2]([N:23]2[CH2:22][CH2:21][N:20]([C:16]3[CH:17]=[CH:18][CH:19]=[C:14]([C:13]([F:26])([F:27])[F:12])[CH:15]=3)[CH2:25][CH2:24]2)=[N:7]1
Reactant: Cn1nc(Br)c(=O)n(C)c1=O
Reactant: FC(F)(F)c1cccc(N2CCNCC2)c1
Product: CCCCO
Product: Cn1nc(N2CCN(c3cccc(C(F)(F)F)c3)CC2)c(=O)n(C)c1=O
Yield: 63 %

Procedure:
The compound 7 (solid) is prepared from the triazine 1b and from 1-(3-trifluoromethyl-phenyl)-piperazine according to the synthesis method 1 in n-butanol (yield: 63%).