Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[NH2:6][C:7]1[N:8]=[C:9](O)[C:10]2[CH:15]([C:16]([O:18][CH3:19])=[O:17])[CH2:14][CH2:13][C:11]=2[N:12]=1>>[NH2:6][C:7]1[N:8]=[C:9]([Cl:3])[C:10]2[CH:15]([C:16]([O:18][CH3:19])=[O:17])[CH2:14][CH2:13][C:11]=2[N:12]=1
Reactant: COC(=O)C1CCc2nc(N)nc(O)c21
Reactant: O=P(Cl)(Cl)Cl
Product: COC(=O)C1CCc2nc(N)nc(Cl)c21
Temperature: 100 °C
Reaction time: 0.25 h

Procedure:
Phosphorus oxychloride (16.0 mL, 172 mmol) was added to methyl 2-amino-4-hydroxy-6,7-dihydro-5H-cyclopenta[d]pyrimidine-5-carboxylate (5.84 g, 27.9 mmol). The resulting mixture was heated in a sealed tube at 100° C. in the microwave for 3 hours. The solvent was evaporated. The residue was dissolved in 6 mL acetonitrile and 6 mL ice/water was added. The resulting mixture was stirred at RT for 15 minutes and purified by reverse phase preparative HPLC on a SunFire column using a gradient from 0 to 100% acetonitrile over 10 minutes (11 injections) to afford the title compound. Additional product was obtained by re-purification of mixed fractions: LC/MS (M+H)=228, 230.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2([CH2:16][CH2:17][OH:18])[CH2:15][CH2:14][NH:13][CH2:12]2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].CN1CCOCC1.[CH2:26]([O:28][C:29]1[CH:30]=[C:31]([CH:35]=[C:36]([O:41][CH2:42][CH3:43])[C:37]=1[O:38][CH2:39][CH3:40])[C:32](Cl)=[O:33])[CH3:27].C(=O)=O.CC(C)=O>ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2([CH2:16][CH2:17][OH:18])[CH2:15][CH2:14][N:13]([C:32](=[O:33])[C:31]3[CH:30]=[C:29]([O:28][CH2:26][CH3:27])[C:37]([O:38][CH2:39][CH3:40])=[C:36]([O:41][CH2:42][CH3:43])[CH:35]=3)[CH2:12]2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(C2(CCO)CCNC2)cc1OC
Reactant: CCOc1cc(C(=O)Cl)cc(OCC)c1OCC
Agent: O=C=O
Solvent: ClCCl
Solvent: CN1CCOCC1
Solvent: CC(C)=O
Product: CCOc1cc(C(=O)N2CCC(CCO)(c3ccc(OC)c(OC)c3)C2)cc(OCC)c1OCC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2-[3-(3,4-Dimethoxy-phenyl)-pyrrolidin-3-yl]-ethanol (405 mg, 1.61 mmol) and dichloromethane (20 mL) were combined. 4-Methylmorpholine (350 L, 3.22 mmol, 2 eq.) was added. The mixture was cooled in a dry-ice/acetone bath and a solution of 3,4,5-triethoxy-benzoyl chloride (461 mg, 1.69 mmol) in dichloromethane (10 mL) was added dropwise. After the addition was complete, the dry-ice/acetone bath was changed to an ice bath and the mixture was stirred for 1 h. Allowed to warm to ambient temperature and maintained overnight. The solution was extracted with 1N HCl (2×50 mL), saturated NaHCO3 (50 mL), and H2O (50 mL). The organic phase was dried over Na2SO4, filtered, and concentrated in vacuo to obtain a residue. The residue was purified by chromatography on silica gel eluting with ethyl acetate/methanol (20:1) to obtain a residue. The residue was dissolved in dichloromethane (50 mL), extracted with water (2×50 mL), dried over Na2SO4, filtered, and concentrated in vacuo to obtain a residue. Heated at 70° C./0.5 Torr for 16 h to obtain the title compound: Rf =0.31 (silica gel, 20:1 ethyl acetate/methanol), mp=139°°141° C.
Reaction SMILES: S(=O)(=O)(O)O.[BH4-].[Na+].[CH2:8]([O:15][C:16]([C@@H:18]1[CH2:23][CH2:22][C:21](=[N:24][O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:20][NH:19]1)=[O:17])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O>O1CCCC1>[CH2:8]([O:15][C:16]([C@@H:18]1[CH2:23][CH2:22][C@@H:21]([NH:24][O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:20][NH:19]1)=[O:17])[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: O=C(OCc1ccccc1)[C@@H]1CCC(=NOCc2ccccc2)CN1
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Agent: O=S(=O)(O)O
Agent: [BH4-]
Solvent: C1CCOC1
Product: O=C(OCc1ccccc1)[C@@H]1CC[C@@H](NOCc2ccccc2)CN1
Reaction time: 22 h
Yield: 73.4 %

Procedure:
Under nitrogen atmosphere, tetrahydrofuran (3 ml) and sulfuric acid (0.151 g, 1.53 mmol) were added to sodium borohydride (0.101 g, 2.66 mmol). The obtained mixture was added dropwise at −10° C. to the mixture consisting of (2S)-5-benzyloxyimino-piperidine-2-carboxylic acid benzyl ester (0.168 g, 0.50 mmol), (+)-camphorsulfonic acid (0.695 g, 2.99 mmol) and tetrahydrofuran (2 ml) for 0.5 hour. After 22 hours of stirring, the obtained reaction mixture was analyzed with high performance liquid chromatography to find that the reaction mixture contained 0.125 g of the title compound, and the reduction reaction proceeded with yield of 74%. The diastereo selectivity was (2S,5R)/(2S,5S)=81.4/18.6 (62.8% de).
Reaction SMILES: [Li]CCCC.[N:6]1([C:11]2[CH:31]=[CH:30][C:14]([CH2:15][C:16]3[C:17]([O:28][CH3:29])=[N:18][C:19]4[C:24]([C:25]=3[Cl:26])=[CH:23][C:22](Br)=[CH:21][CH:20]=4)=[CH:13][CH:12]=2)[CH:10]=[CH:9][CH:8]=[N:7]1.[F:32][C:33]1[CH:38]=[CH:37][C:36]([C:39]([C:41]2[CH:42]=[N:43][CH:44]=[CH:45][CH:46]=2)=[O:40])=[CH:35][CH:34]=1>C1COCC1>[N:6]1([C:11]2[CH:31]=[CH:30][C:14]([CH2:15][C:16]3[C:17]([O:28][CH3:29])=[N:18][C:19]4[C:24]([C:25]=3[Cl:26])=[CH:23][C:22]([C:39]([C:36]3[CH:37]=[CH:38][C:33]([F:32])=[CH:34][CH:35]=3)([C:41]3[CH:42]=[N:43][CH:44]=[CH:45][CH:46]=3)[OH:40])=[CH:21][CH:20]=4)=[CH:13][CH:12]=2)[CH:10]=[CH:9][CH:8]=[N:7]1
Reactant: COc1nc2ccc(Br)cc2c(Cl)c1Cc1ccc(-n2cccn2)cc1
Reactant: O=C(c1ccc(F)cc1)c1cccnc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1nc2ccc(C(O)(c3ccc(F)cc3)c3cccnc3)cc2c(Cl)c1Cc1ccc(-n2cccn2)cc1
Temperature: 25 °C
Reaction time: 0.03 h

Procedure:
A solution of n-BuLi (2.5 M in hexanes, 0.095 mL, 0.238 mmol) was added dropwise by syringe to a solution of 3-(4-(1H-pyrazol-1-yl)benzyl)-6-bromo-4-chloro-2-methoxyquinoline (105.5 mg, 0.246 mmol, Intermediate 10) in dry THF (2.5 mL) in a dry ice-acetone bath. After 1.5 minutes, a solution of commercially available (4-fluorophenyl)(pyridin-3-yl)methanone (58.7 mg, 0.292 mmol) in dry THF (0.2 mL) was added dropwise. The reaction mixture was stirred for 5 minutes in a dry ice-acetone bath, then the reaction flask was placed into an ice-water bath. After 10 minutes, the mixture was warmed to room temperature and the reaction was quenched with methanol and water. The mixture was partitioned between water and ethyl acetate. The separated aqueous phase was further extracted with ethyl acetate. The organic phase was dried (Na2SO4), filtered, and concentrated. The crude product was purified by flash column chromatography (silica gel, 10-50% EtOAc-Hexanes followed by 0-10% MeOH-DCM) to provide the title compound as a white solid. 1H NMR (400 MHz, CDCl3) δ ppm 8.50-8.48 (m, 1H), 8.43 (dd, J=4.8, 1.6 Hz, 1H), 8.02 (d, J=2.1 Hz, 1H), 7.83 (d, J=2.4 Hz, 1H), 7.77 (d, J=8.8 Hz, 1H), 7.67-7.64 (m, 2H), 7.55-7.52 (m, 2H), 7.50 (dd, J=8.8, 2.2 Hz, 1H), 7.33 (d, J=8.6 Hz, 2H), 7.26-7.20 (m, 3H), 7.03-6.96 (m, 2H), 6.42-6.40 (m, 1H), 4.28 (s, 2H), 4.07 (s, 3H); MS m/e 551.2 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:8]2[CH:26]=[CH:25][C:11]([C:12]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:17][CH:16]=3)=[O:13])=[CH:10][CH:9]=2)=[N:4][CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.[CH3:34][S:35](Cl)(=[O:37])=[O:36]>C(Cl)Cl>[CH3:34][S:35]([N:1]([S:35]([CH3:34])(=[O:37])=[O:36])[C:2]1[C:3]([C:8]2[CH:9]=[CH:10][C:11]([C:12]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([C:21]([CH3:22])([CH3:23])[CH3:24])=[CH:17][CH:16]=3)=[O:13])=[CH:25][CH:26]=2)=[N:4][CH:5]=[CH:6][CH:7]=1)(=[O:37])=[O:36]
Reactant: CC(C)(C)c1ccc(NC(=O)c2ccc(-c3ncccc3N)cc2)cc1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)c1ccc(NC(=O)c2ccc(-c3ncccc3N(S(C)(=O)=O)S(C)(=O)=O)cc2)cc1
Reaction time: 8 h

Procedure:
The product from Example 3 (300 mg, 0.87 mmol) and triethylamine (0.6 mL, 4.3 mmol) in CH2Cl2 (10 mL) were treated with methanesulfonyl chloride (0.2 mL, 2.58 mmol) at room temperature and stirred overnight. The reaction mixture was diluted with CH2Cl2 (20 mL), washed with H2O (3×5 mL) and brine (5 mL), dried over Na2SO4, filtered, and the filtrate concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (99:1 CH2Cl2:CH3OH) to provide the title compound as a solid. 1H NMR (300 MHz, DMSO-d6) δ 10.30 (s, 1H), 8.81 (dd, J=4.6 Hz, 1.6 Hz, 1H), 8.25 (dd, J=8.1 Hz, 1.4 Hz, 1H), 8.11-8.14 (m, 2H), 7.61-7.77 (m, 5H), 7.37-7.41 (m, 2H), 3.19 (s, 6H), 1.29 (s, 9H); MS (ESI+) m/z 502 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[NH:11][C:12](=[O:20])[C:13]2[N:19]=[CH:18][CH:17]=[CH:16][C:14]=2[N:15]=1)[CH3:2].[N+:21]([O-])([OH:23])=[O:22]>S(=O)(=O)(O)O>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([N+:21]([O-:23])=[O:22])=[CH:6][C:5]=1[C:10]1[NH:11][C:12](=[O:20])[C:13]2[N:19]=[CH:18][CH:17]=[CH:16][C:14]=2[N:15]=1)[CH3:2]
Reactant: O=[N+]([O-])O
Reactant: CCOc1ccccc1-c1nc2cccnc2c(=O)[nH]1
Agent: O=S(=O)(O)O
Product: CCOc1ccc([N+](=O)[O-])cc1-c1nc2cccnc2c(=O)[nH]1
Temperature: 25 °C
Reaction time: 18 h
Yield: 86 %

Procedure:
A stirred solution of 2-(2-ethoxyphenyl)pyrido(3,2-d)pyrimidin-4(3H)-one (Preparation 10; 1.4 g, 0.0052 mol) in concentrated sulphuric acid (11 ml) at 0° C., was treated dropwise with concentrated nitric acid (0.4 ml). The reaction mixture was allowed to warm to ambient temperature, stirred for a further 18 hours, then added dropwise to ice/water (70 g). The resulting precipitate was collected by filtration, dried under vacuum and then crystallized from acetonitrile to give the title compound as a pale yellow solid (0.22 g, 86%), m.p. 251-254° C.
Reaction SMILES: CC1(C)[O:6][C@@H:5]([CH2:7][O:8][C:9]2[C:10]3[CH2:29][N:28]([C:30]4[CH:35]=[C:34]([CH:36]([CH3:38])[CH3:37])[CH:33]=[CH:32][C:31]=4[CH3:39])[CH2:27][CH2:26][C:11]=3[N:12]=[C:13]([C:15]3[C:23]([CH3:24])=[CH:22][CH:21]=[C:20]4[C:16]=3[C:17]([CH3:25])=[N:18][NH:19]4)[N:14]=2)[CH2:4][O:3]1>C(O)(C(F)(F)F)=O.O>[CH3:25][C:17]1[C:16]2[C:20](=[CH:21][CH:22]=[C:23]([CH3:24])[C:15]=2[C:13]2[N:14]=[C:9]([O:8][CH2:7][C@H:5]([OH:6])[CH2:4][OH:3])[C:10]3[CH2:29][N:28]([C:30]4[CH:35]=[C:34]([CH:36]([CH3:38])[CH3:37])[CH:33]=[CH:32][C:31]=4[CH3:39])[CH2:27][CH2:26][C:11]=3[N:12]=2)[NH:19][N:18]=1
Reactant: Cc1ccc(C(C)C)cc1N1CCc2nc(-c3c(C)ccc4[nH]nc(C)c34)nc(OC[C@H]3COC(C)(C)O3)c2C1
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: Cc1ccc(C(C)C)cc1N1CCc2nc(-c3c(C)ccc4[nH]nc(C)c34)nc(OC[C@H](O)CO)c2C1

Procedure:
A solution of (S)-4-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)-2-(3,5-dimethyl-1H-indazol-4-yl)-6-(5-isopropyl-2-methylphenyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine (20 mg, 0.037 mmol) in TFA (0.9 mL) and H2O (0.1 mL) was stirred at room temperature for 16 h. The reaction mixture was concentrated and the residue was partitioned between DCM and saturated aqueous NaHCO3. The layers were separated and the aqueous layer was extracted with DCM. The organics were combined and concentrated. The residue was purified by reverse phase HPLC (C18, 10-100% acetonitrile in H2O with 0.1% NH4OH) to give (R)-3-((2-(3,5-dimethyl-1H-indazol-4-yl)-6-(5-isopropyl-2-methylphenyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yl)oxy)propane-1,2-diol. 1H NMR (400 MHz, CD2Cl2) δ ppm 7.33 (d, J=8.46 Hz, 1H), 7.21 (d, J=8.59 Hz, 1H), 7.08 (d, J=7.96 Hz, 1H), 6.97 (d, J=1.52 Hz, 1H), 6.86 (dd, J=1.71, 7.77 Hz, 1H), 4.36-4.47 (m, 2H), 4.06 (s, 2H), 3.88-3.95 (m, 1H), 3.53-3.60 (m, 1H), 3.46-3.52 (m, 1H), 3.26 (t, J=5.68 Hz, 2H), 3.02-3.10 (m, 2H), 2.76-2.86 (m, 1H), 2.26 (s, 3H), 2.20 (s, 3H), 1.92 (s, 3H), 1.17 (d, J=6.95 Hz, 6H); MS (ESL) m/z 502.5 (M+H)+.
Reaction SMILES: [CH3:1][C@@H:2]([CH2:6][CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]([OH:5])=[O:4].[CH2:15](O)[CH3:16]>S(=O)(=O)(O)O>[CH3:1][C@@H:2]([CH2:6][CH2:7][CH2:8][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)[C:3]([O:5][CH2:15][CH3:16])=[O:4]
Reactant: CCO
Reactant: C[C@@H](CCCc1ccccc1)C(=O)O
Agent: O=S(=O)(O)O
Product: CCOC(=O)[C@@H](C)CCCc1ccccc1
Yield: 91 %

Procedure:
To a solution consisting of (S)-(+)-2-methyl-5-phenylpentanoic acid (20mb(i), 2.3 g, 12 mmol) in ethanol (200 mL) was added 4 drops of concentrated sulfuric acid. The stirring reaction mixture was brought to reflux overnight and was subsequently cooled and concentrated under vacuum. The residue was diluted with ethyl acetate and washed twice with brine. The organic layer was dried over sodium sulfate, filtered, and concentrated under vacuum to afford the title compound (2.4 g, 91%) as a clear oil; TLC Rf 0.66 (solvent system: 15:85:1 v/v/v ethyl acetate-heptane-acetic; MS (ESI+) m/z 221.2 (M+H)+; 1H-NMR (CDCl3) δ 7.29-7.25 (m, 2H), 7.21-7.13 (m, 3H), 4.12 (q, J=6.96 Hz, 2H), 2.64-2.57 (m, 2H), 2.48-2.39 (m, 1H), 1.75-1.54 (m, 3H), 1.52-1.41 (m, 1H), 1.24 (t, J=7.14 Hz, 3H) 1.16-1.11 (m, 3H); [α]Tλ=α/cl, [α]21.9D=+0.101/(0.01506 g/1.5 ml)(0.5)=+20.12° (c=1, CHCl3).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.[C:8]([C:10]1[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][C:11]=1[N+:17]([O-:19])=[O:18])#[CH:9]>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>[CH3:16][C:13]1[CH:14]=[CH:15][C:10]([C:8]#[C:9][C:2]2[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=2)=[C:11]([N+:17]([O-:19])=[O:18])[CH:12]=1
Reactant: C#Cc1ccc(C)cc1[N+](=O)[O-]
Reactant: Brc1cccnc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Product: Cc1ccc(C#Cc2cccnc2)c([N+](=O)[O-])c1
Temperature: 60 °C
Reaction time: 4 h

Procedure:
To a stirred solution of 3-bromopyridine (608 mg, 3.85 mmol), PdCl2(PPh3)2 (246 mg, 0.35 mmol), and Cu(1)I (733 mg, 3.85 mmol) was added TEA (10 mL) followed by 1-ethynyl-4-methyl-2-nitro-benzene (564 mg, 3.5 mmol). After stirring at 60° C. for 4 h, the reaction was filtered, and diluted with EtOAc (150 mL) and 10% Na2CO3 (150 mL). The organic layer was washed with brine, dried over MgSO4; filtered, and dried under reduced pressure. The material was purified using a Biotage 40M cartridge eluting with hexanes/EtOAc (7/3) to yield a light brown oil.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[C:7]([N:15]1[CH2:28][CH2:27][C:26]2[C:25]3[C:24]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)=[CH:23][CH:22]=[CH:21][C:20]=3[NH:19][C:18]=2[CH2:17][CH2:16]1)(=O)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>O1CCCC1>[CH2:7]([N:15]1[CH2:28][CH2:27][C:26]2[C:25]3[C:24]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)=[CH:23][CH:22]=[CH:21][C:20]=3[NH:19][C:18]=2[CH2:17][CH2:16]1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: O=C(c1ccccc1)N1CCc2[nH]c3cccc(-c4ccccc4)c3c2CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: c1ccc(CN2CCc3[nH]c4cccc(-c5ccccc5)c4c3CC2)cc1
Yield: 95 %

Procedure:
A solution of lithium aluminum hydride (0.73 g, 19.2 mmol) in tetrahydrofuran (10.0 mL) and a solution of 3-benzoyl-10-phenyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (0.73 g, 2.0 mmol) in tetrahydrofuran (20.0 mL) at 0° C. were reacted in a manner similar to Example 1 to give 0.67 g (96%) of the title compound as a white crystalline solid: mp 161-163° C.; 1H NMR (400 MHz, CDCl3) δ 7.83, 7.43-7.23, 7.14-7.10, 6.91, 3.70, 2.93-2.90, 2.86-2.83, 2.65-2.62, 2.42-2.40; 13C NMR (100 MHz, CDCl13) δ 142.0, 139.3, 137.2, 135.0, 134.7, 129.7, 128.9, 128.2, 127.6, 126.9, 126.6, 126.0, 121.6, 120.6, 113.6, 109.5, 61.8, 55.8, 53.4, 28.5, 25.9; IR (drift) 3407, 2810, 1454, 1377, 1347, 1334, 1319, 1175, 1120, 932, 785, 762, 754, 742, 700 cm−1; MS (EI) m/z 352 (M+); HRMS (FAB) calcd for C25H24N2+H: 353.2018, found: 353.2039; Anal. Calcd for C25H24N2: C, 85.19; H, 6.86; N, 7.95. Found: C, 84.83; H, 6.94; N, 7.83.
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:8]2[N:13]=[C:12]([CH2:14][C@@H:15]([C@@H:22]([OH:29])[C:23]([O:25][CH:26]([CH3:28])[CH3:27])=[O:24])[C:16]([O:18][CH:19]([CH3:21])[CH3:20])=[O:17])[CH:11]=[C:10]([CH3:30])[CH:9]=2)[C:4]([CH3:7])=[CH:5][CH:6]=1.[H-].[Na+].[CH2:33](Br)[CH:34]=[CH2:35]>C1COCC1>[CH2:35]([O:29][C@H:22]([C@H:15]([CH2:14][C:12]1[CH:11]=[C:10]([CH3:30])[CH:9]=[C:8]([N:3]2[C:4]([CH3:7])=[CH:5][CH:6]=[C:2]2[CH3:1])[N:13]=1)[C:16]([O:18][CH:19]([CH3:21])[CH3:20])=[O:17])[C:23]([O:25][CH:26]([CH3:28])[CH3:27])=[O:24])[CH:34]=[CH2:33]
Reactant: Cc1cc(C[C@H](C(=O)OC(C)C)[C@@H](O)C(=O)OC(C)C)nc(-n2c(C)ccc2C)c1
Reactant: C=CCBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C=CCO[C@@H](C(=O)OC(C)C)[C@H](Cc1cc(C)cc(-n2c(C)ccc2C)n1)C(=O)OC(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 95.8 %

Procedure:
To a solution of alcohol 4b (300 mg, 0.72 mmol) in THF (10 mL) at 0° C. was added NaH (60% in mineral oil, 35 mg, 0.87 mmol). The mixture was allowed to stir at 0° C. for an additional 30 min then allyl bromide (93 μL, 1.08 mmol) was added dropwise. The reaction was allowed to warm to room temperature and maintained for an additional 6 h. The reaction was quenched with saturated NH4Cl (1 mL) and partitioned between EtOAc (100 mL) and H2O (50 mL). The organic layer was washed with brine (50 mL) and dried over Na2SO4. The solvent was removed by rotary evaporation, the resulting brown oil was purified by flash column chromatography (EtOAc/hexanes, 1:9-1:1) to give 10 (316 mg, 0.69 mmol, 97%) as a pale yellow oil: 1H NMR (500 MHz, CDCl3) δ 1.07-1.09 (d, J=6.0 Hz, 3H), 1.16-1.19 (d, J=6.0 Hz, 3H), 1.25-1.35 (m, 6H), 2.13 (s, 6H), 2.39 (s, 3H), 3.01-3.05 (dd, J=5.5, 15.5 Hz, 1H), 3.20-3.25 (dd, J=9.5, 15.0 Hz, 1H), 3.67-3.68 (dd, J=3.0, 4.5 Hz, 1H), 3.89-3.94 (dd, J=7.0, 13.0 Hz, 1H), 4.02-4.03 (d, J=5.0 Hz, 1H), 4.24-4.28 (dd, J=4.5, 12.0 Hz, 1H), 4.93-4.96 (m, 1H), 4.97-5.17 (m, 1H), 5.17-5.19 (d, J=10.0 Hz, 1H), 5.25-5.29 (dd, J=1.5, 17.0 Hz, 1H), 5.80-5.95 (m, 3H), 6.86 (s, 1H), 7.02 (s, 1H); 13C NMR (125 MHz, CDCl3) δ 13.6, 21.2, 21.8, 21.9, 22.0, 22.1, 35.6, 47.7, 68.5, 68.9, 72.1, 78.1, 106.9, 118.0, 120.4, 123.7, 128.7, 134.2, 149.7, 151.8, 158.8, 170.4, 171.2; LCQ-MS (M+H+) calcd for C26H37N2O5 457. found 457; LC-TOF-MS (M+H+) calcd for C26H37N2O5 457.27025. found 457.26984.
Reaction SMILES: [CH3:1][C@@:2]12[C@@H:10]([OH:11])[CH2:9][CH2:8][C@H:7]1[C@@H:6]1[CH2:12][CH2:13][C@H:14]3[CH2:20][C:18](=[O:19])[CH:17]=[CH:16][C@:15]3([CH3:21])[C@H:5]1[CH2:4][CH2:3]2.N.[Cl-].[Na+]>[Au].O1CCCC1>[CH3:21][C@@:15]12[C@H:5]3[CH2:4][CH2:3][C@:2]4([CH3:1])[C@@H:10]([OH:11])[CH2:9][CH2:8][C@H:7]4[C@@H:6]3[CH2:12][CH2:13][C@H:14]1[CH2:20][C:18](=[O:19])[CH2:17][CH2:16]2
Reactant: C[C@]12C=CC(=O)C[C@@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](O)CC[C@@H]12
Agent: [Au]
Agent: N
Agent: [Cl-]
Solvent: C1CCOC1
Product: C[C@]12CCC(=O)C[C@@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](O)CC[C@@H]12

Procedure:
0.5 g. of 5α-androst-1-en-17β-ol-3-one in 20 ml. of tetrahydrofuran is reacted in 150 ml. of ammonia for 15 minutes at 0.2 A/cm2 in a divided cell with the use of sodium chloride as the conductive salt and a gold cathode and an anode of glass-like carbon. After the catholyte has been worked up and the crude product has been recrystallized, 0.38 g. of 5α-androstan-17β-ol-3-one is obtained, m.p. 173° - 175° C.
Reaction SMILES: [C]=O.[C:3](=O)=[O:4].[H][H].[Ni:8]>[Ni].O>[C-:3]#[O+:4].[C-:3]#[O+:4].[C-:3]#[O+:4].[C-:3]#[O+:4].[Ni:8]
Reactant: O=C=O
Reactant: [H][H]
Agent: [Ni]
Agent: [C]=O
Solvent: O
Product: [C-]#[O+]

Procedure:
U.S. Pat. No. 4,431,751 describes a method for producing superheated steam with the heat of catalytic methanation of a synthesis gas containing carbon monoxide, carbon dioxide and hydrogen. The process passes a gas stream first through a first internally water-cooled reactor, subsequently through an adiabatic reactor and a subsequent heat exchanger and finally through a second internally water-cooled reactor. The internally water-cooled reactors comprise a cooling system disposed within a catalyst bed through which water flows. As catalyst a nickel-containing catalyst is used. Water is passed in succession, first through the cooling system of the second internally water-cooled reactor for preheating thereof to a temperature approximating the saturated steam temperature, thereafter into the first internally water-cooled reactor for conversion into saturated steam and subsequently to the heat exchanger following the adiabatic reactor for superheating. In the exemplified process the second internally water-cooled reactor is set to operate at a gas entrance temperature between 250° C. and 350° C., specifically 300° C., at an average pressure of 37.5 bar and the product gas flowing out of the second internally water-cooled reactor is 300° C. In the example the water is brought up to a pressure of 110 bar and preheated up to 160° C. before entering the cooling system of the second internally water-cooled reactor (the boiling temperature of water at 110 bars is about 318° C.). A disadvantage of the process of U.S. Pat. No. 4,431,751 is that the very low entrance temperature of the water in the second internally water-cooled reactor, especially in combination with the cooling system used, can lead to cold spots in the catalyst bed which are expected to result deactivation of the nickel catalyst due to the formation of nickel carbonyl. In addition the process of U.S. Pat. No. 4,431,751 requires an adiabatic reactor to allow the steam to become superheated.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C@@H:3]([OH:21])[CH2:4][C@@H:5]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH3:29][O:30][C:31]([NH:33][C@@H:34]([C@@H:38]([CH3:41])[CH2:39][CH3:40])[C:35](O)=[O:36])=[O:32].CCOP(ON1N=NC2C=CC=CC=2C1=O)(OCC)=O.C(N(CC)C(C)C)(C)C>C1COCC1>[CH2:22]([C@H:2]([NH:1][C:35]([C@@H:34]([NH:33][C:31](=[O:32])[O:30][CH3:29])[C@@H:38]([CH3:41])[CH2:39][CH3:40])=[O:36])[C@@H:3]([OH:21])[CH2:4][C@@H:5]([NH:13][C:14]([O:15][C:16]([CH3:19])([CH3:17])[CH3:18])=[O:20])[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CC[C@H](C)[C@H](NC(=O)OC)C(=O)O
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C[C@H](O)[C@@H](N)Cc1ccccc1
Agent: CCOP(=O)(OCC)On1nnc2ccccc2c1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC[C@H](C)[C@H](NC(=O)OC)C(=O)N[C@@H](Cc1ccccc1)[C@@H](O)C[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of the product from Example 6A (0.50 g, 1.30 mmol) in THF (13 mL) was treated with the product from Example 5A (0.30 g, 1.59 mmol), DEPBT (0.45 g, 1.50 mmol), and N,N-diisopropylethylamine (1.1 mL, 6.31 mmol), stirred at 25° C. for 16 hours, and partitioned between ethyl acetate and 10% Na2CO3 solution. The organic phase was washed with additional 10% Na2CO3 solution and brine, dried over MgSO4, filtered and concentrated to give the title compound, used without further purification.
Reaction SMILES: [F:1][C:2]1[C:3]([C:22]([OH:24])=O)=[N:4][CH:5]=[CH:6][C:7]=1[S:8][C:9]1[S:13][C:12]([NH:14][C:15]2[CH:20]=[C:19]([CH3:21])[CH:18]=[CH:17][N:16]=2)=[N:11][CH:10]=1.[NH2:25][CH2:26][C:27]1([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][N:41]=2)[CH2:32][CH2:31][N:30]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:29][CH2:28]1>>[F:1][C:2]1[C:3]([C:22]([NH:25][CH2:26][C:27]2([C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][N:41]=3)[CH2:28][CH2:29][N:30]([C:33]([O:35][C:36]([CH3:38])([CH3:39])[CH3:37])=[O:34])[CH2:31][CH2:32]2)=[O:24])=[N:4][CH:5]=[CH:6][C:7]=1[S:8][C:9]1[S:13][C:12]([NH:14][C:15]2[CH:20]=[C:19]([CH3:21])[CH:18]=[CH:17][N:16]=2)=[N:11][CH:10]=1
Reactant: CC(C)(C)OC(=O)N1CCC(CN)(c2ccccn2)CC1
Reactant: Cc1ccnc(Nc2ncc(Sc3ccnc(C(=O)O)c3F)s2)c1
Product: Cc1ccnc(Nc2ncc(Sc3ccnc(C(=O)NCC4(c5ccccn5)CCN(C(=O)OC(C)(C)C)CC4)c3F)s2)c1

Procedure:
Following the amide bond forming procedure given in example 37, 3-fluoro-4-(2-(4-methylpyridin-2-ylamino)thiazol-5-ylthio)picolinic acid (intermediate B in example 1) and tert-butyl 4-(aminomethyl)-4-(pyridin-2-yl)piperidine-1-carboxylate (amine intermediate “N”) were reacted to give the title compound. LC/MS (M+H)+: 636. Ret. time: 1.69 min. (Condition I).