Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]([NH:5][CH:6]([C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[CH:11]=1)[CH2:7][CH2:8][OH:9])=[O:4].[Li][CH2:21][CH2:22][CH2:23]C.CN1C(=O)N(C)CCC1.C(Br)C=C>C1COCC1>[CH2:23]([O:9][CH2:8][CH2:7][CH:6]([NH:5][C:3](=[O:4])[C:2]([F:18])([F:19])[F:1])[C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[CH:11]=1)[CH:22]=[CH2:21]
Reactant: [Li]CCCC
Reactant: COc1cccc(C(CCO)NC(=O)C(F)(F)F)c1
Solvent: CN1CCCN(C)C1=O
Solvent: C1CCOC1
Solvent: C=CCBr
Product: C=CCOCCC(NC(=O)C(F)(F)F)c1cccc(OC)c1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 26.8 %

Procedure:
Step R (2): 2,2,2-Trifluoro-N-(3-hydroxy-1-(3-methoxyphenyl)propyl)acetamide from step R (1) (1.99 g, 7.18 mmol) was dissolved in THF (20 mL) and chilled to −78° C. n-BuLi (5.76 mL, 14.4 mmol, 2.5 M in hexanes) and DMPU (1.73 mL, 14.4 mmol) were added and the resulting mixture was stirred for 45 min. Allyl bromide (3.04 mL, 36 mmol) was added. The mixture was warmed to rt and then heated to reflux for 3 days. The mixture was quenched with saturated NH4Cl. After 15 min, the mixture was diluted with 1 N NaOH and the aqueous mixture was extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. Purification by silica-gel column chromatography (0%-25% EtOAc/Hexanes) afforded 610 mg (27% yield) of N-(3-(allyloxy)-1-(3-methoxyphenyl)propyl)-2,2,2-trifluoroacetamide as a viscous yellow oil. LC-MS (M+H)+=318.37; 1H NMR (300 MHz, CDCl3) δ ppm 1.89-2.01 (m, 1H) 2.14-2.29 (m, 1H) 3.34-3.52 (m, 2H) 3.77 (s, 3H) 3.91 (d, J=5.86 Hz, 2H) 5.10-5.30 (m, 3H) 5.79-5.95 (m, 1H) 6.70-6.82 (m, 3H) 7.19-7.29 (m, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1[CH2:13][N:12]([C:14]([N:16]([CH3:18])[CH3:17])=[O:15])[C:11]([CH2:25]CC(O)=O)([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:10]=1.[Si]([O:37][NH2:38])(C(C)(C)C)(C)C.CCN=C=NCCCN(C)C.C1C=NC2N(O)N=NC=2C=1.C(N(CC)CC)C.F[C:68](F)(F)[C:69]([OH:71])=O>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1[CH2:13][N:12]([C:14]([N:16]([CH3:18])[CH3:17])=[O:15])[C:11]([CH2:25][CH2:68][C:69]([NH:38][OH:37])=[O:71])([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:10]=1
Reactant: CN(C)C(=O)N1CC(c2cc(F)ccc2F)=CC1(CCC(=O)O)c1ccccc1
Reactant: O=C(O)C(F)(F)F
Reactant: CC(C)(C)[Si](C)(C)ON
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2cccnc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CN(C)C(=O)N1CC(c2cc(F)ccc2F)=CC1(CCC(=O)NO)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 40 mg (0.10 mmol) of acid 24-1 in DMF was added 18 mg (0.12 mmol) of O-(t-butyldimethylsilyl)hydroxylamine, 29 mg (0.15 mmol) of EDCI, 17 mg (0.13 mmol) HOAT, and 28 μL (0.20 mmol) of triethylamine. After stirring overnight at room temperature, ˜300 μL of trifluoroacetic acid was added and stirring was continued for 1 h. The reaction was partitioned between EtOAc and saturated NaHCO3, the organic phase was washed with brine, dried over MgSO4, and concentrated. The residue was purified by column chromatography on silica gel with MeOH/CHCl3 to provide 26-1 as a white solid. Data for 26-1: HRMS (ES) calc'd M+Na for C22H23F2N3O3: 438.1599. Found: 438.1618.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]2[C:13]([C:14]([OH:16])=O)=[C:12]([CH3:17])[NH:11][C:10](=[O:18])[N:9]2[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:5]=[CH:6][CH:7]=1.[C:25]1([CH:31]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH2:32][CH2:33][NH2:34])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.CCN=C=NCCCN(C)C.Cl>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]2[N:9]([CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:10](=[O:18])[NH:11][C:12]([CH3:17])=[C:13]2[C:14](=[O:16])[NH:34][CH2:33][CH2:32][CH:31]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: NCCC(c1ccccc1)c1ccccc1
Reactant: CCOC(=O)CN1C(=O)NC(C)=C(C(=O)O)C1c1cccc(Cl)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: CCOC(=O)CN1C(=O)NC(C)=C(C(=O)NCCC(c2ccccc2)c2ccccc2)C1c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
109 mg (0.309 mmol) of 4-(3-chlorophenyl)-3-ethoxycarbonylmethyl-6-methyl-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid and 97.9 mg (0.463 mmol) of 3,3-diphenylpropylamine were dissolved in 20 ml of dichloromethane. 88.8 mg (0.463 mmol) of WSC hydrochloride was added to the obtained solution under cooling with ice, and they were stirred at room temperature overnight. After the concentration under reduced pressure, the reaction mixture was diluted with ethyl acetate and then washed with 1 N hydrochloric acid, saturated aqueous sodium hydrogencarbonate solution and saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was washed with hexane/ethyl acetate (1/1) and then dried under reduced pressure to obtain the title compound.
Reaction SMILES: [N:1]([C@@H:4]1[C@@H:8]([CH2:9][O:10][Si:11]([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12])[O:7][C@@H:6]([N:18]2[CH:25]=[CH:24][C:22](=[O:23])[NH:21][C:19]2=[O:20])[CH2:5]1)=[N+]=[N-].C(N(CC)CC)C.[C:33](Cl)([C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>C(Cl)Cl.N1C=CC=CC=1>[C:33]([NH:1][C@@H:4]1[C@@H:8]([CH2:9][O:10][Si:11]([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12])[O:7][C@@H:6]([N:18]2[CH:25]=[CH:24][C:22](=[O:23])[NH:21][C:19]2=[O:20])[CH2:5]1)([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)([C:46]1[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=1)[C:40]1[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)[Si](C)(C)OC[C@H]1O[C@@H](n2ccc(=O)[nH]c2=O)C[C@@H]1N=[N+]=[N-]
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](C)(C)OC[C@H]1O[C@@H](n2ccc(=O)[nH]c2=O)C[C@@H]1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 84.5 %

Procedure:
3'-(Trityl)amino-5'-O-(tert-butyldimethylsilyl)-2',3'-dideoxyuridine, 2du. Crude 1du (33.2 g, 90.3 mmol) was dissolved in 2:1 EtOH/CH2Cl2 (300 mL) and reduced via hydrogenation (60 psi H2) in the presence of 10% Pd/C (3.0 g) for 18 h. Subsequent removal of the catalyst via filtration and evaporation of solvent in vacuo, afforded quantitative yield (30.4 g, 89.8 mmol) of the corresponding 3'-amine which was taken on directly to the next reaction. The 5'-O-(tert-butyldimethylsilyl)-3'-amino-2',3'-dideoxyuridine (30.4 g, 89.8 mmol) was azeotroped from pyridine (2×300 mL), and dissolved in a mixture of CH2Cl2 (600 mL) and anhydrous pyridine (70 mL). To this solution was added triethylamine (25.0 mL, 179.6 mmol) and trityl chloride (35.0 g, 125.7 mmol), and the reaction mixture was stirred for 2 h at ambient temperature. Solvents were removed in vacuo, and the crude product was purified on silica (1-5% MeOH/CH2Cl2) to afford 85% yield (44.3 g, 75.9 mmol) of 3'-(Trityl)amino-5'-O-(tert-butyldimethylsilyl)-2',3'-dideoxyuridine, 2du.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([C:15]2([CH2:18][CH:19]=O)[CH2:17][CH2:16]2)[CH:8]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:21]([O:23][C:24]([CH:26]=[C:27]([CH3:33])[CH2:28]P(=O)([O-])[O-])=[O:25])[CH3:22]>>[CH2:21]([O:23][C:24](=[O:25])[CH:26]=[C:27]([CH3:33])[CH:28]=[CH:19][CH2:18][C:15]1([C:7]2[CH:8]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:10]=[C:5]([C:1]([CH3:2])([CH3:4])[CH3:3])[CH:6]=2)[CH2:16][CH2:17]1)[CH3:22]
Reactant: CC(C)(C)c1cc(C(C)(C)C)cc(C2(CC=O)CC2)c1
Reactant: CCOC(=O)C=C(C)CP(=O)([O-])[O-]
Product: CCOC(=O)C=C(C)C=CCC1(c2cc(C(C)(C)C)cc(C(C)(C)C)c2)CC1
Yield: 66.4 %

Procedure:
The above cyclopropyl aldehyde 10 (29 mg, 0.13 mmol) and 3-ethoxycarbonyl-2-methylprop-2-enylphosphonate (215 mg, 0.82 mmol) were condensed as described for Example 1 to give 33 mg of ethyl-6-[1-(3,5-di-t-butyl phenyl)-cyclopropyl]-3-methyl-2,4-hexadienoate (11) as a pale yellow oil in 97% yield.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C@H:11]([C@H:13]2[NH:18][C:17](=[O:19])[C@@H:16]([CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=3)[NH:15][C:14]2=[O:27])[CH3:12])=[CH:3]1.[CH3:28][I:29]>>[I-:29].[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C@H:11]([C@H:13]2[NH:18][C:17](=[O:19])[C@@H:16]([CH2:20][CH2+:21]3[CH:26]=[CH:25][CH:24]=[CH:23][N:22]3[CH3:28])[NH:15][C:14]2=[O:27])[CH3:12])=[CH:3]1
Reactant: CI
Reactant: C[C@H](c1cn(C)c2ccccc12)[C@H]1NC(=O)[C@@H](Cc2ccccn2)NC1=O
Product: C[C@H](c1cn(C)c2ccccc12)[C@H]1NC(=O)[C@@H](C[CH2+]2C=CC=CN2C)NC1=O
Product: [I-]

Procedure:
A mixture of (3R,6R)-3-[(R)-1-(1-methylindol-3-yl)ethyl]-6-(2-pyridylmethyl)piperazine-2,5-dione (0.10 g) and methyl iodide (5 ml) was stirred under reflux for 4 days. After evaporation of the excess methyl iodide, crude oily residue was washed with chloroform and ether, and dried in vacuo to give (3R,6R)-3-[(R)-1-(1-methylindol-3-yl)ethyl]-6-(1-methyl-2-pyridiniomethyl)piperazine-2,5-dione iodide as a solid (0.12 g).
Reaction SMILES: [H-].[K+].[Cl:3][C:4]1[C:9]2[CH2:10][CH2:11][N:12]([CH3:15])[CH2:13][CH2:14][C:8]=2[C:7]([OH:16])=[CH:6][CH:5]=1.Br[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20]>CN(C)C=O>[Cl:3][C:4]1[C:9]2[CH2:10][CH2:11][N:12]([CH3:15])[CH2:13][CH2:14][C:8]=2[C:7]([O:16][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:6][CH:5]=1
Reactant: CN1CCc2c(O)ccc(Cl)c2CC1
Reactant: CCOC(=O)CBr
Agent: [H-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)COc1ccc(Cl)c2c1CCN(C)CC2
Reaction time: 0.33 h
Yield: 76 %

Procedure:
A 35% dispersion of potassium hydride in mineral oil (2.6 g, 23 mmol) in dimethylformamide (40 ml) was stirred and treated with 9-chloro-2,3,4,5-tetrahydro-3-methyl-1H-3-benzazepin-6-ol (4.0 g, 19 mmol), stirred for 20 minutes, treated with ethyl bromoacetate (3.8 g, 23 mmol) and stirred for 72 hours. The mixture was concentrated, partitioned between water and methylene chloride and the organic phase was washed, dried with magnesium sulfate and concentrated. The residue was chromatographed on silica gel eluted with methanol-methylene chloride (8:92) to give 4.3 g of ethyl [(9-chloro-2,3,4,5-tetrahydro-3-methyl-1H-3-benzazepin-6-yl)oxy]acetate.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7](F)=[C:6]([N+:11]([O-:13])=[O:12])[CH:5]=1.Cl.[CH3:16][NH:17][CH3:18].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([N:17]([CH3:18])[CH3:16])=[C:6]([N+:11]([O-:13])=[O:12])[CH:5]=1
Reactant: COC(=O)c1ccc(F)c([N+](=O)[O-])c1
Reactant: CNC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: COC(=O)c1ccc(N(C)C)c([N+](=O)[O-])c1
Temperature: 60 °C
Reaction time: 8 h
Yield: 69 %

Procedure:
To a stirred solution of 4.48 g (22.5 mmol) 4-Fluoro-3-nitro-benzoic acid methyl ester (Bioorg. Med. Chem.; 6; 8; 1998; 1185-1208) and 60.0 ml dimethylsulphoxid were added 2.23 g (27.0 mmol) dimethylamine hydrochloride and 6.54 g (47.3 mmol) potassium carbonate. The reaction mixture was stirred for 8 h at 60° C. in an autoclave and was reduced with high vacuum rotation evaporator at 65° C. The residue was diluted with dichloromethane, washed twice with water. The combined water phases were extracted with dichloromethane. The combined dichloromethane phases were washed with diluted sodium hydrogen carbonate solution, dried with sodium sulphate and concentrated. The oily crude was purified by column chromatography and the desired product 11a was obtained in 69% yield (3.48 g, 15.5 mmol).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][NH2:9].[CH:10](=O)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[H][H]>C(O)C.[Pt]=O>[C:11]1([CH2:10][NH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][NH:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: [H][H]
Reactant: O=Cc1ccccc1
Reactant: NCCCCCCCN
Agent: O=[Pt]
Solvent: CCO
Product: c1ccc(CNCCCCCCCNCc2ccccc2)cc1
Yield: 64 %

Procedure:
Combine 1,7-diaminoheptane (65.0 g, 0.5 mol), benzaldehyde (106 gm, 1 mol) and platinum oxide (PTO2) [2.0 g] in ethanol (800 ml) and treat the mixture with hydrogen gas (45 lb/in2) until the uptake of gas ceases. Remove the catalyst by filtration and remove the solvent in vacuo. Purify the residue by bulb to bulb distillation to yield 99.4 g of the title compound (bp 191°-195° C. @ 1.0 mm/Hg).
Reaction SMILES: [NH2:1][CH:2]([CH2:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[CH:24][CH:23]=1)[C:3]([N:5]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:6][CH:7]([O:11][CH2:12][CH3:13])[O:8][CH2:9][CH3:10])=[O:4].[CH2:33]([NH:40][C:41](=[O:51])[NH:42][C@H:43]([CH2:48][CH:49]=[CH2:50])[CH2:44][C:45](O)=[O:46])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>C(Cl)Cl.CCOC(C)=O>[CH2:14]([N:5]([CH2:6][CH:7]([O:11][CH2:12][CH3:13])[O:8][CH2:9][CH3:10])[C:3]([CH:2]([NH:1][C:45](=[O:46])[CH2:44][CH:43]([NH:42][C:41]([NH:40][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:51])[CH2:48][CH:49]=[CH2:50])[CH2:21][C:22]1[CH:23]=[CH:24][C:25]([O:28][C:29]([CH3:30])([CH3:32])[CH3:31])=[CH:26][CH:27]=1)=[O:4])[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: C=CC[C@H](CC(=O)O)NC(=O)NCc1ccccc1
Reactant: CCOC(CN(Cc1ccccc1)C(=O)C(N)Cc1ccc(OC(C)(C)C)cc1)OCC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C=CCC(CC(=O)NC(Cc1ccc(OC(C)(C)C)cc1)C(=O)N(Cc1ccccc1)CC(OCC)OCC)NC(=O)NCc1ccccc1
Reaction time: 0.67 h

Procedure:
To a solution of 2-Amino-N-benzyl-3-(4-tert-butoxy-phenyl)-N-(2,2-diethoxy-ethyl)-propionamide in CH2Cl2(50 ml) was added a solution of (3R)-3-(3-Benzyl-ureido)-hex-5-enoic acid (1.6 g, 6.1 mmol), EDCl (1.17 g, 7.3 mmol, 1.2 eq), HOBt (0.93 g, 7.3 mmol, 1.2 eq), DIEA (2.13 mL, 12.2 mmol 2.4 eq) in CH2Cl2 (100 mL) stirred for 40 min. The reaction mixture was stirred at room temperature for 14 h, and then diluted with EtOAc, washed with water and brine. The organic layer was dried with Na2SO4 and concentrated in vacuo. The crude compound was used next step without further purification. MS ESI 687 (M+H), 709 (M+Na)
Reaction SMILES: BrC1C(Cl)=[N:4]C=C(C)C=1.OCC1CC1.ClC1C=CC(B(O)O)=CC=1.[NH2:25][CH2:26][C@H:27]1[CH2:32][CH2:31][CH2:30]C[C@H:28]1[OH:33]>>[C:28]([NH2:4])(=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[N:25][CH:26]=1
Reactant: Cc1cnc(Cl)c(Br)c1
Reactant: NC[C@H]1CCCC[C@H]1O
Agent: OB(O)c1ccc(Cl)cc1
Agent: OCC1CC1
Product: NC(=O)c1cccnc1

Procedure:
The title compound was synthesized in analogy to Example 2, using 3-bromo-2-chloro-5-methyl-pyridine, hydroxymethylcyclopropane, [4-chloro-phenyl]-boronic acid and cis-2-aminomethyl-1-cyclohexanol as starting materials to yield racemic cis-5-(4-chloro-phenyl)-6-cyclopropylmethoxy-N-2-hydroxy-cyclohexylmethyl)-nicotinamide. Separation with heptane/ethanol on ChiralpakAD® yielded the (−)-enantiomer, MS (ISP) 415.2 (M+H)+, αD20: −17.8° in MeOH.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:24])[C@H:10]([CH3:23])[NH:11][CH:12]([C:21]#N)[CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.O.C([O-])(O)=[O:28].[Na+].[CH2:32]([OH:34])[CH3:33]>ClCCl.C(#N)C>[CH2:1]([O:8][C:9](=[O:24])[C@H:10]([CH3:23])[NH:11][CH:12]([C:21]([O:34][CH2:32][CH3:33])=[O:28])[CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCO
Reactant: O=C([O-])O
Reactant: C[C@H](NC(C#N)CCc1ccccc1)C(=O)OCc1ccccc1
Agent: Cl
Agent: [Na+]
Solvent: CC#N
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)C(CCc1ccccc1)N[C@@H](C)C(=O)OCc1ccccc1
Reaction time: 48 h

Procedure:
N-(1-Cyano-3-Phenylpropyl)-L-Alanine Benzylester (4.24 g) is then dissolved in 65 ml dry dichloromethane and diluted with 2.39 g absolute ethanol. After cooling on ice, the solution is saturated with dry HCl, stored for 2 days at 0°-5° C., and evaporated to form a residue which is dissolved in 30 ml of a 2:1 acetonitrile:water mixture at room temperature for 15 minutes. An excess of aqueous NaHCO3 is then added to the mixture, which is extracted with chloroform several times, dried over MgSO4, and placed under vacuum to evaporate the solvent, yielding N-(1-Ethoxycarbonyl-3-Phenylpropyl)-L-Alanine Benzylester [TLC (Silica gel; CHCl3 /acetone=9:1); Rf=0.60].
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[C:10]([Cl:30])=[C:11]([N:17]2[CH2:22][CH2:21][N:20]([CH:23]3[CH2:26][O:25][CH2:24]3)[CH:19]([C:27]([O-:29])=O)[CH2:18]2)[CH:12]=[C:13]([C:15]#[N:16])[CH:14]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Li].CCN(C(C)C)C(C)C.[NH:41]1[CH2:46][CH2:45][O:44][CH2:43][CH2:42]1.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC>C1COCC1.C1(C)C=CC=CC=1>[Cl:30][C:10]1[C:11]([N:17]2[CH2:22][CH2:21][N:20]([CH:23]3[CH2:26][O:25][CH2:24]3)[CH:19]([C:27]([N:41]3[CH2:46][CH2:45][O:44][CH2:43][CH2:42]3)=[O:29])[CH2:18]2)=[CH:12][C:13]([C:15]#[N:16])=[CH:14][C:9]=1[NH:8][C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)Nc1cc(C#N)cc(N2CCN(C3COC3)C(C(=O)[O-])C2)c1Cl
Reactant: C1COCCN1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: [Li]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)Nc1cc(C#N)cc(N2CCN(C3COC3)C(C(=O)N3CCOCC3)C2)c1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4-(3-((tert-butoxycarbonyl)amino)-2-chloro-5-cyanophenyl)-1-(oxetan-3-yl)piperazine-2-carboxylate, lithium salt (200 mg, 0.452 mmol) was azeotroped 3× with toluene and 4 Å molecular sieves were added. THF (3 mL) was added, followed by DIPEA (0.118 mL, 0.677 mmol), morpholine (0.117 mL, 1.355 mmol), and T3P (0.538 mL, 0.903 mmol). The reaction was stirred at room temperature for 1 h. The reaction mixture was filtered through a small pad of celite, rinsing with EtOAc. The solvent was removed in vacuo and the material was purified by flash column chromatography (0-4% MeOH/DCM). Tert-butyl (2-chloro-5-cyano-3-(3-(morpholine-4-carbonyl)-4-(oxetan-3-yl)piperazin-1-yl)phenyl)carbamate (112 mg) was obtained as an off-white solid.
Reaction SMILES: N[C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[C:5]=2[N:6]=1.CC[N:14](CC)CC.[CH3:19][C:20]([O:23][C:24]([O:26]C(OC(C)(C)C)=O)=O)([CH3:22])[CH3:21]>C1COCC1.CN(C1C=CN=CC=1)C>[C:24]([C:2]1[S:3][C:4]2[CH:10]=[CH:9][C:8]([NH2:14])=[C:7]([CH3:11])[C:5]=2[N:6]=1)([O:23][C:20]([CH3:22])([CH3:21])[CH3:19])=[O:26]
Reactant: Cc1cccc2sc(N)nc12
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: CCN(CC)CC
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Product: Cc1c(N)ccc2sc(C(=O)OC(C)(C)C)nc12
Temperature: 30 °C
Reaction time: 12 h

Procedure:
A solution of 2-Amino-4-methyl benzothiazole (25.0 g, 152 mmol) in 456 mL of dry THF was treated with Et3N (42 mL, 300 mmol), (Boc)2O (40.0 g, 183 mmol) and DMAP (3.7 g, 30 mmol) at 20° C. and stirred at 30° C. for 12 h. The resulting solution was concentrated in vacuo, diluted with EtOAc (200 mL) and filtered through a glass filter (Celite) washing with EtOAc (200 mL). The filtrate was washed with NaHCO3 (saturated aqueous solution, 100 mL) and NaCl (saturated aqueous solution, 100 mL), dried over MgSO4 and concentrated in vacuo. The residue was filtered through a silica gel plug (flash column chromatography) eluting with toluene:Et2O=15:1 to 8:1 to afford 2-Boc-amino-4-methyl benzothiazole as a colorless oil (41.4 g, quant.) Rf=0.48 (toluene:Et2O=10:1); 1H NMR (400 MHz, CDCl3) δ 9.75 (1H, br s), 7.61 (1H, d, J=7.8 Hz), 7.19 (3H, m), 2.64 (3H, s), 1.47 (9H, s).
Reaction SMILES: [OH:1][C@@H:2]1[CH2:19][C@@:17]2([CH3:18])[C@@H:13]([CH:14]=[CH:15][C:16]2=[O:20])[C@H:12]2[C@H:3]1[C@:4]1([CH3:22])[CH:9]([CH2:10][CH2:11]2)[CH2:8][C:7](=[O:21])[CH2:6][CH2:5]1.O.[C:24]1(C)C(S(O)(=O)=O)=CC=C[CH:29]=1.C(OCC)(OCC)OCC>C(O)C>[CH2:24]([O:21][C:7]1[CH2:6][CH2:5][C@@:4]2([CH3:22])[C:9](=[CH:10][CH2:11][C@@H:12]3[C@@H:3]2[C@H:2]([OH:1])[CH2:19][C@@:17]2([CH3:18])[C@H:13]3[CH2:14][CH2:15][C:16]2=[O:20])[CH:8]=1)[CH3:29]
Reactant: Cc1ccccc1S(=O)(=O)O
Reactant: C[C@]12CCC(=O)CC1CC[C@@H]1[C@@H]2[C@H](O)C[C@]2(C)C(=O)C=C[C@@H]12
Solvent: O
Solvent: CCO
Solvent: CCOC(OCC)OCC
Product: CCOC1=CC2=CC[C@@H]3[C@H]([C@H](O)C[C@]4(C)C(=O)CC[C@@H]34)[C@@]2(C)CC1
Temperature: 5 °C

Procedure:
11α-Hydroxyandrostendione (429.5 g) and toluene sulfonic acid hydrate (7.1) were charged to a reaction flask under nitrogen. Ethanol (2.58 L) was added to the reactor, and the resulting solution cooled to 5° C. Triethyl orthoformate (334.5 g) was added to the solution over a 15 minute period at 0° to 15° C. After the triethyl orthoformate addition was complete the reaction mixture was warmed to 40° C. and reacted at that temperature for 2 hours, after which the temperature was increased to reflux and reaction continued under reflux for an additional 3 hours. The reaction mixture was cooled under vacuum and the solvent removed under vacuum to yield 3-ethoxy-11α-hydroxy-androsta-3,5-diene-17-one.
Reaction SMILES: I[C:2]1[C:3]2[S:11][CH:10]=[C:9]([C:12]3[CH:17]=[CH:16][C:15]([O:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[CH:14][CH:13]=3)[C:4]=2[C:5]([NH2:8])=[N:6][CH:7]=1.[C:25]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])(=[O:28])[CH:26]=[CH2:27].C(N(CC)CC)C>CN(C=O)C>[NH2:8][C:5]1[C:4]2[C:9]([C:12]3[CH:17]=[CH:16][C:15]([O:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[CH:14][CH:13]=3)=[CH:10][S:11][C:3]=2[C:2](/[CH:27]=[CH:26]/[C:25]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])=[CH:7][N:6]=1
Reactant: C=CC(=O)OC(C)(C)C
Reactant: Nc1ncc(I)c2scc(-c3ccc(Oc4ccccc4)cc3)c12
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)/C=C/c1cnc(N)c2c(-c3ccc(Oc4ccccc4)cc3)csc12
Temperature: 80 °C
Yield: 59.8 %

Procedure:
A mixture of Example 10B (0.417 g, 0.94 mmol), tert-butyl acrylate (0.26 mL, 1.74 mol) and triethylamine (0.7 mL, 5 mmol) in DMF (3 mL) was degassed with nitrogen for 45 minutes, treated with PdCl2(o-tol3P)2 (0.032 g, 0.046 mmol), and heated to 80° C. overnight. The resulting mixture was cooled to room temperature, then partitioned between water and ethyl acetate. The organic extract was washed with brine, dried (Na2SO4), filtered, and concentrated. The residue was purified by flash column chromatography on silica gel with 30% ethyl acetate/hexanes to provide 0.25 g (61% yield) of the desired product. MS (ESI(+)) m/e 445 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:25])[CH2:9][N:10]2[CH2:13][CH:12]([CH2:14][S:15]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)(=[O:17])=[O:16])[CH2:11]2)=[C:4]([O:26]C)[CH:3]=1.B(Br)(Br)Br.C(OCC)C>ClCCl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:25])[CH2:9][N:10]2[CH2:11][CH:12]([CH2:14][S:15]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)(=[O:16])=[O:17])[CH2:13]2)=[C:4]([OH:26])[CH:3]=1
Reactant: COc1cc(F)ccc1C(=O)CN1CC(CS(=O)(=O)c2ccc(F)cc2)C1
Agent: BrB(Br)Br
Solvent: CCOCC
Solvent: ClCCl
Product: O=C(CN1CC(CS(=O)(=O)c2ccc(F)cc2)C1)c1ccc(F)cc1O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 1-(4-fluoro-2-methoxyphenyl)-2-(3-{[(4-fluorophenyl)sulfonyl]methyl}azetidin-1-yl)ethanone (Step 2, 49.4 mg, 0.125 mmol) in dichloromethane (1 mL) at 0° C. was added boron tribromide (1M in dichloromethane, 0.5 mL, 0.5 mmol). The reaction was stirred at 0° C. for 30 minutes. Diethyl ether (5 mL) was added and the resulting slurry partitioned between saturated sodium carbonate solution and ethyl acetate. Water was added to dissolve some of the resulting precipitate and the biphasic mixture was decanted from the remaining solid. The aqueous layer was extracted with ethyl acetate and the combined organic layers were washed with water and brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by flash column chromatography on silica, eluting with ethyl acetate, to give the title compound which was treated with ethereal HCl to give the hydrochloride salt (10.5 mg, 20%). 1H NMR (500 MHz, d6-DMSO) δ 11.83 (1H, s), 10.34 (1H, s), 7.95 (2H, dd, J=5.3, 8.2 Hz), 7.83 (1H, dd, J=7.3, 8.5 Hz), 7.54 (2H, t, J=8.7 Hz), 6.91 (1H, dd, J=2.0, 10.7 Hz), 6.81–6.79 (1H, m), 4.83 (2H, s), 4.19 (2H, br s), 4.05–3.97 (2H, m), 3.87–3.78 (2H, m), 3.08–3.02 (1H, m); m/z (ES+) 382 (M+H)+.