Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS[C:3]1[N:8]=[C:7]([OH:9])[C:6]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:5][N:4]=1.[CH2:15]([NH2:23])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]>C(O)C>[CH2:15]([NH:23][C:3]1[N:8]=[C:7]([OH:9])[C:6]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:5][N:4]=1)[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: CCCCCCCCN
Reactant: CCOC(=O)c1cnc(SC)nc1O
Solvent: CCO
Product: CCCCCCCCNc1ncc(C(=O)OCC)c(O)n1

Procedure:
2-Methylthio-5-ethoxycarbonyl-4-hydroxypyrimidine (2.5 mmol, 535 mg) was refluxed overnight in ethanol with n-octylamine (4 mmol, 650 μl). The product was filtered off and washed with ethanol. Yield 402 mg (54.5%)
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([C:6]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[N:7][C:8]([Cl:12])=[N:9]2)=[CH:4][CH:3]=1.[CH3:19][C:20]1[O:24][C:23](B2OC(C)(C)C(C)(C)O2)=[CH:22][CH:21]=1.C(=O)([O-])[O-].[Na+].[Na+].CN(C=O)C>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[Cl:12][C:8]1[N:7]=[C:6]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[C:10](=[CH:11][C:2]([C:23]3[O:24][C:20]([CH3:19])=[CH:21][CH:22]=3)=[CH:3][CH:4]=2)[N:9]=1
Reactant: Cc1ccc(B2OC(C)(C)C(C)(C)O2)o1
Reactant: Clc1nc(N2CCOCC2)c2ccc(Br)cc2n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(-c2ccc3c(N4CCOCC4)nc(Cl)nc3c2)o1
Temperature: 95 °C
Reaction time: 2 h
Yield: 69.6 %

Procedure:
To a 50 mL round bottom flask, 7-bromo-2-chloro-4-morpholin-4-yl-quinazoline (2 g, 0.0061 mol), 5-methyl-2-furanboronic acid pinacol ester (1.1 g, 0.0091 mol), sodium carbonate (0.969 g, 0.0092 mol), DMF (80 mL) and water (20 mL) were added and degassed the reaction vessel with nitrogen for 5-10 min. To the same reaction mixture, Pd(PPh3)2Cl2 (0.213 g, 0.0003 mol) was added and again degassed with nitrogen for 5-10 min. The reaction mixture was stirred at 95° C. for 2 h. The reaction mixture was cooled and diluted with ethyl acetate. The organic layer was washed with water, brine and dried over sodium sulfate. The solvent was removed under reduced pressure to afford the crude product. The crude product was purified; using column chromatography (60-120 silica gel, 0-20% ethyl acetate in hexane) to yield the desired product [1.4 g, 70%]. 1H NMR: (400 MHz, CDCl3): δ 8.01 (d, J=1.6 Hz, 1H), 7.80 (d, J=8.8 Hz, 1H), 7.68 (dd, J′=8.8 Hz, J″=1.6 Hz, 1H), 6.78 (d, J=3.2, 1H), 6.14-6.45 (m, 1H), 3.88 (m, 8H), 2.42 (s, 3H); LC-MS (ESI): Calculated mass: 329.1; Observed mass: 330.0 [M+H]+ (RT: 1.71 min).
Reaction SMILES: C([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([NH:20][O:21][CH:22]1[CH2:28][CH:27]2[N:29]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH:24]([CH2:25][CH2:26]2)[CH2:23]1)=[O:19])C1C=CC=CC=1.[H][H]>CO.[Pd]>[OH:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([NH:20][O:21][CH:22]1[CH2:28][CH:27]2[N:29]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH:24]([CH2:25][CH2:26]2)[CH2:23]1)=[O:19]
Reactant: CC(C)(C)OC(=O)N1C2CCC1CC(ONC(=O)[C@@H]1CC[C@@H]3CN1C(=O)N3OCc1ccccc1)C2
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N1C2CCC1CC(ONC(=O)[C@@H]1CC[C@@H]3CN1C(=O)N3O)C2
Yield: 65.7 %

Procedure:
To a solution of tert-butyl 3-[({[(2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]-8-azabicyclo[3.2.1]octane-8-carboxylate 46 (0.26 g, 0.52 mml) in methanol (20 mL) was added 5% Pd/C (0.3 g). The mixture was hydrogenated under 35 psi hydrogen atmosphere at room temperature for 1 h. The catalyst was filtered out through Celite, and the filtrate was evaporated to give tert-butyl 3-[({[(2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]-8-azabicyclo[3.2.1]octane-8-carboxylate 47 (0.14 g, 66%) as a white solid.
Reaction SMILES: [CH3:1]C1CCCCC1=O.CC1CCCC1=O.[CH3:16][O:17][C:18](=[O:28])[CH2:19][CH2:20][C:21]1([CH3:27])[CH2:25][CH2:24][CH2:23][C:22]1=[O:26]>>[CH3:16][O:17][C:18](=[O:28])[CH2:19][CH2:20][C:21]1([CH3:27])[CH2:25][CH2:24][CH2:23][CH2:1][C:22]1=[O:26]
Reactant: CC1CCCCC1=O
Reactant: COC(=O)CCC1(C)CCCC1=O
Agent: CC1CCCC1=O
Product: COC(=O)CCC1(C)CCCCC1=O

Procedure:
In the same manner but replacing 2-methylcyclohexanone with an equivalent amount of 2-methylcyclopentanone, 1-methyl-2-oxocyclopentanepropionic acid methyl ester, bp 88°-100° C./1.1 mm, nmr (CDCl3) δ 1.0 (s, 3H), 1.8 (m, 6H), 2.3 (m, 4H), 3.7 (s, 3H), is obtained.
Reaction SMILES: [Cl:1][CH2:2][C:3]([N:5]([CH3:15])[C:6]1[CH:14]=[CH:13][C:9]([C:10]([OH:12])=O)=[CH:8][CH:7]=1)=[O:4].[C:16]([O:20][C:21](=[O:30])[NH:22][CH:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH:24]1[NH2:29])([CH3:19])([CH3:18])[CH3:17].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[C:16]([O:20][C:21](=[O:30])[NH:22][CH:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH:24]1[NH:29][C:10](=[O:12])[C:9]1[CH:8]=[CH:7][C:6]([N:5]([C:3](=[O:4])[CH2:2][Cl:1])[CH3:15])=[CH:14][CH:13]=1)([CH3:19])([CH3:17])[CH3:18]
Reactant: CN(C(=O)CCl)c1ccc(C(=O)O)cc1
Reactant: CC(C)(C)OC(=O)NC1CCCCC1N
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN(C(=O)CCl)c1ccc(C(=O)NC2CCCCC2NC(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 94.4 %

Procedure:
Part A. 4-[(2-Chloro-acetyl)-methyl-amino]-benzoic acid (0.23 g, 1.0 mmol.) was stirred in DMF (2 mL) at RT under N2. (2-Amino-cyclohexyl)-carbamic acid tert-butyl ester (0.21 g, 1.0 mmol), HATU (0.57 g, 1.5 eq) and DIEA (0.5 mL, 2.9 eq) were added. The mixture was stirred at RT for 30 min. It was partitioned between EtOAc and water. The organic layer was washed with brine, dried over MgSO4, filtered, and concentrated to dryness to give (2-{4-[(2-chloro-acetyl)-methyl-amino]-benzoylamino}-cyclohexyl)-carbamic acid tert-butyl ester (0.40 g, yield: 95%).
Reaction SMILES: C([Li])CCC.[CH2:6]([O:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][O:12]1)[CH2:7][C:8]#[CH:9].[C:17]([NH:21][C:22]1[C:31]([CH:32]=[O:33])=[CH:30][C:29]2[C:24](=[CH:25][CH:26]=[C:27]([C:34]3[C:39]([C:40]([N:42]4[CH2:46][CH2:45][CH2:44][CH2:43]4)=[O:41])=[CH:38][CH:37]=[CH:36][C:35]=3[CH3:47])[CH:28]=2)[N:23]=1)([CH3:20])([CH3:19])[CH3:18]>C1COCC1.[Cl-].[NH4+]>[C:17]([NH:21][C:22]1[C:31]([CH:32]([OH:33])[C:9]#[C:8][CH2:7][CH2:6][O:10][CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][O:12]2)=[CH:30][C:29]2[C:24](=[CH:25][CH:26]=[C:27]([C:34]3[C:35]([CH3:47])=[CH:36][CH:37]=[CH:38][C:39]=3[C:40]([N:42]3[CH2:43][CH2:44][CH2:45][CH2:46]3)=[O:41])[CH:28]=2)[N:23]=1)([CH3:20])([CH3:18])[CH3:19]
Reactant: Cc1cccc(C(=O)N2CCCC2)c1-c1ccc2nc(NC(C)(C)C)c(C=O)cc2c1
Reactant: C#CCCOC1CCCCO1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: Cc1cccc(C(=O)N2CCCC2)c1-c1ccc2nc(NC(C)(C)C)c(C(O)C#CCCOC3CCCCO3)cc2c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
n-Butyllithium (2.5 M) (0.624 mL, 1.559 mmol) was added to a solution of 2-(3-butynyloxy)tetrahydro-2H-pyran (0.244 mL, 1.559 mmol) in THF (10 mL) at −78° C. The solution was stirred 1 h at this temperature before warming to 0° C. for 30 min at which time it was slowly added by syringe to a solution of 2-(tert-butylamino)-6-(2-methyl-6-(pyrrolidine-1-carbonyl)phenyl)quinoline-3-carbaldehyde (0.324 g, 0.780 mmol) in THF (10 mL) cooled to −78° C. The resulting dark solution was stirred 10 min at this temperature before warming to 0° C. for 20 min. The reaction mixture was diluted with saturated ammonium chloride and extracted with EtOAc. The combined organic extracts were washed with water, saturated sodium chloride, and dried over sodium sulfate. The solution was filtered and concentrated in vacuo to give (2-(2-(tert-butylamino)-3-(1-hydroxy-5-(tetrahydro-2H-pyran-2-yloxy)pent-2-ynyl)quinolin-6-yl)-3-methylphenyl)(pyrrolidin-1-yl)methanone as an orange oil.
Reaction SMILES: [N:1]1([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Br:47][C:48]1[CH:49]=[CH:50][C:51]2[C:57]3[S:58][C:59]([C:61]([N:63]([C:65]4[CH:66]=[C:67]([CH:71]=[CH:72][C:73]=4[Cl:74])[C:68](O)=[O:69])[CH3:64])=[O:62])=[CH:60][C:56]=3[CH2:55][CH2:54][O:53][C:52]=2[CH:75]=1>C1COCC1.O>[Br:47][C:48]1[CH:49]=[CH:50][C:51]2[C:57]3[S:58][C:59]([C:61]([N:63]([C:65]4[CH:66]=[C:67]([CH:71]=[CH:72][C:73]=4[Cl:74])[C:68]([N:4]4[CH2:5][CH2:6][N:1]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:2][CH2:3]4)=[O:69])[CH3:64])=[O:62])=[CH:60][C:56]=3[CH2:55][CH2:54][O:53][C:52]=2[CH:75]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: CN(C(=O)c1cc2c(s1)-c1ccc(Br)cc1OCC2)c1cc(C(=O)O)ccc1Cl
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: O
Product: CN(C(=O)c1cc2c(s1)-c1ccc(Br)cc1OCC2)c1cc(C(=O)N2CCN(C(=O)OC(C)(C)C)CC2)ccc1Cl
Reaction time: 8 h
Yield: 96.9 %

Procedure:
To a mixture of tert-butyl piperazine-1-carboxylate (1.7 g, 9.13 mmol), DIPEA (3 mL), HATU (2.78 g, 7.31 mmol) in THF (60 mL) was added 3-(8-bromo-N-methyl-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carboxamido)-4-chlorobenzoic acid (3.0 g, 6.09 mmol) under nitrogen atmosphere at room temperature. The reaction mixture was stirred overnight, diluted with water, extracted with EtOAc. The organic layer was dried over Na2SO4, concentrated in vacuo to give tert-butyl 4-(3-(8-bromo-N-methyl-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carboxamido)-4-chlorobenzoyl)piperazine-1-carboxylate (3.9 g, yield: 97%). LC-MS: (ESI, m/z)=682 [M+Na]+
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([NH:16][C:17]2[S:18][CH:19]=[C:20]([CH2:22][CH2:23][C:24]([O:26][CH3:27])=[O:25])[N:21]=2)=[N:11][CH:12]=[C:13](Br)[N:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:28](B1C2CCCC1CCC2)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.O>CN(C=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].ClCCl>[CH2:28]([C:13]1[N:14]=[C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:10]([NH:16][C:17]2[S:18][CH:19]=[C:20]([CH2:22][CH2:23][C:24]([O:26][CH3:27])=[O:25])[N:21]=2)=[N:11][CH:12]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: COC(=O)CCc1csc(Nc2ncc(Br)nc2OCc2ccccc2)n1
Reactant: c1ccc(CB2C3CCCC2CCC3)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: ClCCl
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)CCc1csc(Nc2ncc(Cc3ccccc3)nc2OCc2ccccc2)n1
Yield: 78.7 %

Procedure:
Methyl 3-(2-(3-(benzyloxy)-5-bromopyrazin-2-ylamino)thiazol-4-yl)propanoate (0.826 g, 1.84 mmol), 9-benzyl-9-bora-bicyclo[3.3.1]nonane (11.0 mL, 5.51 mmol), PdCl2(dppf) dichloromethane adduct (0.151 g, 0.184 mmol), were placed in DMF (25 mL), and water (2.5 mL) and heated to 60° C. for 90 minutes. Cooled reaction mixture to room temperature and partitioned between water and DCM. Layers were separated, dried, filtered, and concentrated. Purified by silica gel to give methyl 3-(2-(5-benzyl-3-(benzyloxy)pyrazin-2-ylamino)thiazol-4-yl)propanoate (0.667 g, 78.8% yield). 28 mg of this was dissolved in DCM and 2M HCl was added and concentrated to give methyl 3-(2-(5-benzyl-3-(benzyloxy)pyrazin-2-ylamino)thiazol-4-yl)propanoate hydrochloride (0.027 g, 93%) 1H NMR (DMSO-d6) δ 7.79 (s, 1H), 7.52 (m, 2H), 7.32 (m, 4H), 7.27 (d, 4H), 7.20 (m, 1H), 5.44 (s, 2H), 3.93 (s, 2H), 3.60 (s, 3H), 2.86 (m, 2H), 2.68 (m, 2H). Mass spectrum (apci) m/z=461.1.0 (M+H-HCl).
Reaction SMILES: [C:1]([O:4][C@:5]1([C@:25]2([CH3:26])[C@H:11]([C@H:12]3[C@H:22]([CH2:23][CH2:24]2)[C@:20]2([CH3:21])[C:15](=[CH:16][C:17](=[O:28])[C@@H:18]4[CH2:27][C@@H:19]42)[CH:14]=[CH:13]3)[CH2:10][CH2:9]1)[C:6](=[O:8])[CH3:7])(=[O:3])[CH3:2]>[Pd].C([O-])([O-])=O.[Ca+2].CN(C)C=O>[C:1]([O:4][C@:5]1([C@:25]2([CH3:26])[C@H:11]([C@H:12]3[C@H:22]([CH2:23][CH2:24]2)[C@:20]2([CH3:21])[C:15](=[CH:16][C:17](=[O:28])[C@@H:18]4[CH2:27][C@@H:19]42)[CH2:14][CH2:13]3)[CH2:10][CH2:9]1)[C:6](=[O:8])[CH3:7])(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@]1(C(C)=O)CC[C@H]2[C@@H]3C=CC4=CC(=O)[C@@H]5C[C@@H]5[C@]4(C)[C@H]3CC[C@@]21C
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: CN(C)C=O
Product: CC(=O)O[C@]1(C(C)=O)CC[C@H]2[C@@H]3CCC4=CC(=O)[C@@H]5C[C@@H]5[C@]4(C)[C@H]3CC[C@@]21C

Procedure:
A solution of 60.0 g of 17α-acetoxy-1α,2α-methylene-4,6-pregnadiene-3,20-dione [R. Wiechert et al., Chem. Ber. 93: 1710 (1960)] in 1.25 1 of dimethylformamide is combined with 6.3 g of 10% Pd/CaCO3 and then hydrogenated. After a hydrogen absorption of 5.1 1, the catalyst is filtered off and the reaction solution stirred into ice water. The precipitate is suctioned off, worked up as usual, and the crude product is purified on 1.5 kg of silica gel with a pentane-acetone gradient (0-30% acetone). Yield: 34.3 g of 17α-acetoxy-1α,2α-methylene-4-pregnene-3,20-dione, mp 268°-270° C. [α]D =+215°.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:5]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:4][C:3]=1[C:18]([O-])=[O:19]>C1(C)C=CC=CC=1>[OH:19][CH2:18][C:3]1[CH:4]=[C:5]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:6]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[N:7][C:2]=1[CH3:1]
Reactant: CCOC(=O)c1cc(C(=O)[O-])c(C)nc1C(=O)OCC
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cc(CO)c(C)nc1C(=O)OCC
Yield: 9.9 %

Procedure:
A solution of 464 g 6-methyl-2,3,5-pyridinetricarboxylic acid, 2,3-diethyl ester in 2.5 L toluene is cooled, under nitrogen, 5° with mechanical stirring while 200 mL of borane-dimethylsulfide complex is added dropwise over a one hour and 30 minute period. After stirring at room temperature for three days, the reaction is cooled to 10° and quenched with 250 mL of concentrated hydrochloric acid. A further 500 mL of 3M hydrochloric acid and 250 mL of ethyl acetate is added, and the reaction is vigorously stirred for three hours and 30 minutes. The organic layer can be filter chromatographed through silica gel and concentrated in vacuo to recover 96 g unreacted starting material. The aqueous layer is neutralized with 50% sodium hydroxide, extracted with ethyl acetate, concentrated in vacuo, and chromatographed on silica gel using hexane-ethyl acetate mixtures to afford 44 g of the desired product as an oil.
Reaction SMILES: [CH3:1][O:2][C:3]([N:5]1[CH2:10][CH2:9][CH2:8][C@@H:7]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][C:18]([C:21]([O:23]CC3C=CC=CC=3)=[O:22])([CH3:20])[CH3:19])[CH:12]=2)[CH2:6]1)=[O:4]>[Pd].CO>[CH3:1][O:2][C:3]([N:5]1[CH2:10][CH2:9][CH2:8][C@@H:7]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][C:18]([C:21]([OH:23])=[O:22])([CH3:20])[CH3:19])[CH:12]=2)[CH2:6]1)=[O:4]
Reactant: COC(=O)N1CCC[C@@H](c2cccc(OC(C)(C)C(=O)OCc3ccccc3)c2)C1
Agent: [Pd]
Solvent: CO
Product: COC(=O)N1CCC[C@@H](c2cccc(OC(C)(C)C(=O)O)c2)C1
Reaction time: 3 h
Yield: 91.9 %

Procedure:
10% Palladium on carbon (18 mg, 10 wt %) was added to a solution of (S)-3-[3-(1-Benzyloxycarbonyl-1-methyl-ethoxy)-phenyl]-piperidine-1-carboxylic acid methyl ester (90 mg, 0.22 mmol) in methanol (3 mL) and the resulting mixture hydrogenated at atmospheric pressure for 3 h. The reaction mixture was filtered through a plug of celite and the celite plug washed thoroughly with ethyl acetate. The combined filtrates were concentrated under reduced pressure to provide 65 mg (92%) of (S)-3-[3-(1-carboxy-1-methyl-ethoxy)-phenyl]-piperidine-1-carboxylic acid methyl ester as a clear oil.
Reaction SMILES: [C:1]([O:4][C@H:5]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[C:7](=[CH:8][C:9](=[N:28][O:29][CH2:30][CH2:31][CH2:32]Cl)[C@@H:10]3[C@@H:19]2[CH2:18][CH2:17][C@@:15]2([CH3:16])[C@H:11]3[CH2:12][CH2:13][C@@H:14]2[O:24][C:25](=[O:27])[CH3:26])[CH2:6]1)(=[O:3])[CH3:2].[NH:34]1[CH:38]=[CH:37][N:36]=[CH:35]1>>[C:1]([O:4][C@H:5]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[C:7](=[CH:8][C:9](=[N:28][O:29][CH2:30][CH2:31][CH2:32][N:34]3[CH:38]=[CH:37][N:36]=[CH:35]3)[C@@H:10]3[C@@H:19]2[CH2:18][CH2:17][C@@:15]2([CH3:16])[C@H:11]3[CH2:12][CH2:13][C@@H:14]2[O:24][C:25](=[O:27])[CH3:26])[CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@H]1CC[C@@]2(C)C(=CC(=NOCCCCl)[C@H]3[C@@H]4CC[C@H](OC(C)=O)[C@@]4(C)CC[C@@H]32)C1
Reactant: c1c[nH]cn1
Product: CC(=O)O[C@H]1CC[C@@]2(C)C(=CC(=NOCCCn3ccnc3)[C@H]3[C@@H]4CC[C@H](OC(C)=O)[C@@]4(C)CC[C@@H]32)C1
Reaction time: 5 h

Procedure:
A mixture of 7-[O-(3-chloropropyl)oximino]-5-androstene-3β,17β-diol diacetate (23) (1 g, 2.08 mmol) and powdered imidazole (1.5 g) was fused at 110-120° C. for 5 h. The completion of reaction was monitored by TLC. The reaction was quenched with iced water to afford a the product 7-[O-{3-(imidazol-1-yl)propyl}oximino]-5-androstene-3β,17β-diol diacetate (24)
Reaction SMILES: O[N:2]=[C:3]([C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:19][CH3:20])[CH:15]=2)[CH:10]=1)[C:4]([O:6][CH2:7][CH3:8])=[O:5].C(O)=O>CO.[Zn]>[NH2:2][CH:3]([C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:19][CH3:20])[CH:15]=2)[CH:10]=1)[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCOC(=O)C(=NO)c1ccc2cc(OC)ccc2c1
Agent: [Zn]
Solvent: O=CO
Solvent: CO
Product: CCOC(=O)C(N)c1ccc2cc(OC)ccc2c1
Yield: 61.9 %

Procedure:
2-Bromo-6-methoxynaphthalene was converted to the 2-lithio derivative by reaction with n-butyllithium. Diethyl oxalate was then reacted with the 2-lithio-6-methoxynaphthalene to afford ethyl α-keto-6-methoxy-naphth-2-ylacetate. The latter compound was reacted with hydroxylamine hydrochloride and sodium acetate to provide ethyl α-hydroxyimino-6-methoxynaphth-2-ylacetate. A solution of 17.55 g of the oxime in 600 ml of methanol containing 5.3 g of zinc metal dust and 135 ml of 50% (v/v) aqueous formic acid was stirred at 0° C. for three hours. After filtering the reaction mixture, the solvent was removed by evaporation to give 10.3 g of ethyl α-amino-α-(6-methoxynaphth-2-yl)acetate.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[C@@H:4]([NH2:18])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:8][CH:7]=1.[I:20][C:21]1[CH:22]=[CH:23][C:24]([NH2:30])=[C:25]([CH:29]=1)[C:26](O)=[O:27]>>[CH3:1][O:2][C:3](=[O:19])[C@@H:4]([NH:18][C:26](=[O:27])[C:25]1[CH:29]=[C:21]([I:20])[CH:22]=[CH:23][C:24]=1[NH2:30])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:8][CH:7]=1
Reactant: Nc1ccc(I)cc1C(=O)O
Reactant: COC(=O)[C@@H](N)Cc1ccc(-c2ccccc2)cc1
Product: COC(=O)[C@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)c1cc(I)ccc1N
Yield: 74.6 %

Procedure:
(2S)-(2-Amino-5-iodo-benzoyl-amino)-3-biphenyl-4-yl-propionic acid methyl ester (1.53 g) was prepared from (2S)-amino-3-biphenyl-4-yl-propionic acid methyl ester (1.0 g, 4.1 mmol), 5-iodo-2-amino-benzoic acid (1.23 g, 4.9 mmol) as described in general procedure A.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:10]=[CH:11][C:12]3[O:18][CH2:17][CH2:16][N:15]([C:19]([N:21]4[CH:26]5[CH2:27][CH2:28][CH:22]4[CH2:23][C:24]([C:30]([F:33])([F:32])[F:31])([OH:29])[CH2:25]5)=[O:20])[CH2:14][C:13]=3[CH:34]=2)[CH:5]=[N:6][C:7]=1[NH2:8].[CH:35](OC)(OC)OC>C(OCC)C>[NH:1]1[C:2]2[C:7](=[N:6][CH:5]=[C:4]([C:9]3[CH:10]=[CH:11][C:12]4[O:18][CH2:17][CH2:16][N:15]([C:19]([N:21]5[CH:22]6[CH2:28][CH2:27][CH:26]5[CH2:25][C:24]([C:30]([F:33])([F:32])[F:31])([OH:29])[CH2:23]6)=[O:20])[CH2:14][C:13]=4[CH:34]=3)[CH:3]=2)[N:8]=[CH:35]1
Reactant: COC(OC)OC
Reactant: Nc1cc(-c2ccc3c(c2)CN(C(=O)N2C4CCC2CC(O)(C(F)(F)F)C4)CCO3)cnc1N
Solvent: CCOCC
Product: O=C(N1CCOc2ccc(-c3cnc4nc[nH]c4c3)cc2C1)N1C2CCC1CC(O)(C(F)(F)F)C2
Yield: 29 %

Procedure:
A slurry of 8-{[7-(5,6-diaminopyridin-3-yl)-2,3-dihydro-1,4-benzoxazepin-4(5H)-yl]carbonyl}-3-(trifluoromethyl)-8-azabicyclo[3.2.1]octan-3-ol (0.22 g, 0.46 mmol) and trimethyl orthoformate (3.5 mL) was heated (105° C.) for 30 minutes. The reaction mixture was diluted with ethyl ether and the resulting precipitate was collected by filtration. Purification by preparative reverse phase HPLC provided 8-{[7-(1H-imidazo[4,5-b]pyridin-6-yl)-2,3-dihydro-1,4-benzoxazepin-4(5H)-yl]carbonyl}-3-(trifluoromethyl)-8-azabicyclo[3.2.1]octan-3-ol (64 mg, 29% yield) as a white solid. 1H NMR (400 MHz, d6-DMSO) δ 9.39 (s, 1H), 8.87 (s, 1H), 8.44 (s, 1H), 7.66 (s, 1H), 7.62 (dd, 1H), 7.07 (d, 1H), 5.81 (bs, 1H), 4.57 (s, 2H), 4.26 (s, 2H), 4.05 (s, 2H), 3.70 (s, 2H), 2.03 (m, 4H), 1.74 (m, 4H); MS (ES) for C24H24F3N5O3: 488 (MH+).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3](B(CC)CC)[CH:2]=1.Br[C:13]1[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][OH:21])=[CH:15][CH:14]=1.[OH-].[K+].O>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C1COCC1.C(OCC)(=O)C>[OH:21][CH2:20][CH2:19][C:16]1[CH:17]=[CH:18][C:13]([C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)=[CH:14][CH:15]=1
Reactant: OCCc1ccc(Br)cc1
Reactant: CCB(CC)c1cccnc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: OCCc1ccc(-c2cccnc2)cc1

Procedure:
1 g (6.8 mmol) of (3-pyridyl)diethylborane, 0.87 ml (10.2 mmol) of 2-(4-bromophenyl)ethanol, 1.53 g (27 mmol) of KOH powder, 1.1 g (3.4 mmol) of tetrabutylammonium bromide and 0.39 g (0.34 mmol) of tetrakis(triphenylphosphine)Pd are mixed in 25 ml of anhydrous THF. The mixture is heated at reflux under a stream of argon for 4 hours. The mixture is poured into water, extraction is carried out with ethyl acetate, the organic phase is dried and the solvent is evaporated. The residue is purified by chromatography on a column of silica gel, elution being carried out with a cyclohexane/ethyl acetate=1/1 mixture, the title product thus being obtained.
Reaction SMILES: [N:1]([CH2:4][C@H:5]1[C@@H:9]([F:10])[CH2:8][N:7]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:6]1)=[N+]=[N-].[H-].[CH3:19][O:20]CCO[Al+]OCCOC.[Na+].[H-].C(OC=O)(=O)C>>[CH2:11]([N:7]1[CH2:8][C@H:9]([F:10])[C@H:5]([CH2:4][NH:1][CH:19]=[O:20])[CH2:6]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: [N-]=[N+]=NC[C@@H]1CN(Cc2ccccc2)C[C@@H]1F
Reactant: COCCO[Al+]OCCOC
Agent: CC(=O)OC=O
Agent: [H-]
Agent: [Na+]
Product: O=CNC[C@@H]1CN(Cc2ccccc2)C[C@@H]1F

Procedure:
cis-3-Azidomethyl-1-benzyl-4-fluoropyrrolidine was reduced with sodium bis-(2-methoxyethoxy)aluminium hydride and formylated with formic acid-acetic anhydride to yield cis-1-benzyl-4-fluoro-3-formylaminomethylpyrrolidine.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[CH2:5][CH:6]([C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=1)[C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)[CH3:2].Br[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[CH:35]=[C:34]([CH3:36])[CH:33]=[CH:32][C:31]=2[O:37][CH2:38][CH2:39][CH2:40][CH3:41])=[CH:26][CH:25]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl>CN(C=O)C.O>[CH2:1]([O:3][C:4](=[O:21])[CH2:5][CH:6]([C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:23][C:24]2[CH:25]=[CH:26][C:27]([C:30]3[CH:35]=[C:34]([CH3:36])[CH:33]=[CH:32][C:31]=3[O:37][CH2:38][CH2:39][CH2:40][CH3:41])=[CH:28][CH:29]=2)=[CH:9][CH:8]=1)[C:14]1[CH:15]=[CH:16][C:17]([F:20])=[CH:18][CH:19]=1)[CH3:2]
Reactant: CCOC(=O)CC(c1ccc(O)cc1)c1ccc(F)cc1
Reactant: CCCCOc1ccc(C)cc1-c1ccc(CBr)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCOc1ccc(C)cc1-c1ccc(COc2ccc(C(CC(=O)OCC)c3ccc(F)cc3)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.1 %

Procedure:
A mixture of 45.2 (48 mg, 0.166 mmol), 4′-Bromomethyl-2-butoxy-5-methyl-biphenyl (67 mg, 0.2 mmol) and cesium carbonate (81 mg, 0.25 mmol) in DMF (2 mL) was stirred at room temperature overnight. The reaction mixture was diluted with water, acidified with dilute HCl, extracted into ethyl acetate, washed with water and dried over magnesium sulfate. The residue obtained after concentration was flash chromatographed on silica gel to obtain 45.3 (71 mg).