Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:6]([Sn](CCCC)(CCCC)CCCC)=[CH:5][CH:4]=[N:3]1.Br[C:21]1[CH:22]=[C:23]([CH:30]=[O:31])[C:24]2[O:28][CH:27]=[CH:26][C:25]=2[CH:29]=1>>[CH3:1][N:2]1[C:6]([C:21]2[CH:22]=[C:23]([CH:30]=[O:31])[C:24]3[O:28][CH:27]=[CH:26][C:25]=3[CH:29]=2)=[CH:5][CH:4]=[N:3]1
Reactant: O=Cc1cc(Br)cc2ccoc12
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccnn1C
Product: Cn1nccc1-c1cc(C=O)c2occc2c1

Procedure:
From 1-Methyl-5-tributylstannanyl-1H-pyrazole (826 mg) and 5-bromo-benzofuran-7-carboxaldehyde (500 mg).
Reaction SMILES: [CH3:1][C:2]([CH3:7])=[CH:3][C:4]([OH:6])=[O:5].[C:8]1([O:14][CH3:15])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[Cl-].[Al+3].[Cl-].[Cl-].Cl>ClCCl>[CH3:15][O:14][C:8]1[CH:13]=[CH:12][C:11]([C:2]([CH3:7])([CH3:1])[CH2:3][C:4]([OH:6])=[O:5])=[CH:10][CH:9]=1
Reactant: COc1ccccc1
Reactant: CC(C)=CC(=O)O
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COc1ccc(C(C)(C)CC(=O)O)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
In a dry flask was placed 3,3-dimethylacrylic acid (2.064 ml, 19.98 mmol). Dichloromethane (20 ml) and anisole (4.36 ml, 40.0 mmol) were added. Aluminum chloride (10.65 g, 80 mmol) was added in a single portion. After stirring at room temperature for 10 minutes, the reaction was heated to 65° C. After 2 hours, the reaction was cooled to room temperature and poured carefully onto 150 g of ice and 50 mL of concentrated HCl. The aqueous layer was extracted with CHCl3 (3×50 mL). The combined organics were extracted with water (150 mL) and saturated NaHCO3 (3×75 ml). These aqueous extracts were combined and acidified with 1N HCl. The acidified aqueous solution was extracted with 4×75 mL of Et2O. The Et2O extracts were dried over Mg2SO4, filtered, and concentrated. The residue was purified by flash chromatography on silica gel with 0 to 100% EtOAc/hexanes to afford 3-(4-methoxyphenyl)-3-methylbutanoic acid. 1H NMR (CDCl3, 500 MHz) δ 7.28 (d, J=8.8 Hz, 2H), 6.85 (d, J=8.8 Hz, 2H), 3.79 (s, 3H), 2.62 (s, 2H), 1.45 (s, 6H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([C:15]#[N:16])([F:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].B>C1COCC1>[NH2:16][CH2:15][C:11]1([F:14])[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[O:7])[CH2:13][CH2:12]1
Reactant: CC(C)(C)OC(=O)N1CCC(F)(C#N)CC1
Agent: B
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(F)(CN)CC1
Reaction time: 0.5 h

Procedure:
To a 0° C. solution of 4-3 (8.83 g, 38.7 mmol) in 75 mL dry THF was added a solution of 1 M borane in THF (155 mL, 155 mmol) over 30 min. After 30 min more, the cold reaction was slowly quenched with EtOH (200 mL) and all solvent was removed in vacuo. The residue was taken up in saturated aq. NH4Cl/EtOAc (150 mL) and extracted with EtOAc (3×150 mL). The organic layers were washed with 1 N aq. NaOH, brine, dried over MgSO4, filtered, and concentrated in vacuo, giving crude 4-4 as a pale yellow oil. The crude amine 4-4 was carried forward. 1H NMR (CDCl3, 300 MHz): 3.94 (br, 2H), 3.08 (m, 2H), 1.85 (m, 2H), 1.51 (m, 4H), 1.44 (s, 9H); MS (Electrospray): m/z 218.2 (M−Me+H), 177.2 (M−t−Bu+H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:3]=1.[Li]CCCC.C(OC([N:27]1[CH2:31][CH2:30][CH2:29][C:28]1=O)=O)(C)(C)C>C1COCC1>[O:8]([C:4]1[CH:3]=[C:2]([C:28]2[CH2:29][CH2:30][CH2:31][N:27]=2)[CH:7]=[CH:6][CH:5]=1)[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: CC(C)(C)OC(=O)N1CCCC1=O
Reactant: Brc1cccc(Oc2ccccc2)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: c1ccc(Oc2cccc(C3=NCCC3)c2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 63 %

Procedure:
To a cold solution (−78° C.) of 1-bromo-3-phenoxy-benzene (10.13 g, 40.6 mmol) in anhydrous THF (100 mL) and under nitrogen is added n-BuLi (1.6M, 44.7 mmol, 27 mL). The mixture is allowed to stir for 30 minutes before being added to a cold solution (−78° C.) of 1-(tert-Butoxycarbonyl)-2-pyrrolidinone in anhydrous THF (50 mL) under nitrogen via cannula. The resulting mixture is allowed to warm to room temperature overnight before being quenched with water (200 mL) and extracted with EtOAc (3×100 mL). The organics were collected, dried over Na2SO4, filtered and concentrated under reduced pressures. The residue is dissolved in CH2Cl2 (20 mL) and TFA (10 mL) is added with stirring. The mixture is stirred for 30 minutes and quenched over ice cold sat. NaHCO3, extracted with CH2Cl2 (3×100 mL) and the organics were combined, dried over Na2SO4, filtered and concentrated under reduced pressures. The residue is purified by silica gel column chromatography (20% EtOAc/Hexanes) to give 5-(3-phenoxy-phenyl)-3,4-dihydro-2H-pyrrole as light yellow oil (6.1 g, 63%). LCMS m/z 238 (M+1).
Reaction SMILES: [C:1](O)(=O)C.[OH:5][CH2:6][C@@:7]12[C@@H:24]3[C@H:15]([C@H:16]4[C@@:20]([CH2:22][CH2:23]3)([CH3:21])[C@@H:19]([O:25][C:26]3([O:32][CH3:33])[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]3)[CH2:18][CH2:17]4)[CH2:14][C@H:13]([CH3:34])[C:12]1=[CH:11][C:10](=[O:35])[CH2:9][CH2:8]2.C(O)(=O)C.OC[C@@]12[C@@H]3[C@H]([C@H]4[C@@](CC3)(C)[C@@H](OC3(OC)CCCCC3)CC4)CCC1=CC(=O)CC2>>[OH:5][CH2:6][C@@:7]12[C@@H:24]3[C@H:15]([C@H:16]4[C@@:20]([CH2:22][CH2:23]3)([CH3:21])[C@@H:19]([O:25][C:26]3([O:32][CH3:33])[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]3)[CH2:18][CH2:17]4)[CH2:14][CH2:13][C:12]1=[CH:11][C:10](=[O:35])[CH2:9][C@H:8]2[CH3:1].[OH:5][CH2:6][C@@:7]12[C@@H:24]3[C@H:15]([C@H:16]4[C@@:20]([CH2:22][CH2:23]3)([CH3:21])[C@@H:19]([O:25][C:26]3([O:32][CH3:33])[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]3)[CH2:18][CH2:17]4)[CH2:14][C@H:13]([CH3:34])[C:12]1=[CH:11][C:10](=[O:35])[CH2:9][CH2:8]2
Reactant: CC(=O)O
Agent: COC1(O[C@H]2CC[C@H]3[C@@H]4CCC5=CC(=O)CC[C@]5(CO)[C@H]4CC[C@]23C)CCCCC1
Agent: COC1(O[C@H]2CC[C@H]3[C@@H]4C[C@H](C)C5=CC(=O)CC[C@]5(CO)[C@H]4CC[C@]23C)CCCCC1
Product: COC1(O[C@H]2CC[C@H]3[C@@H]4CCC5=CC(=O)C[C@@H](C)[C@]5(CO)[C@H]4CC[C@]23C)CCCCC1

Procedure:
Following essentially the same procedure and substituting 19-hydroxy-17β-(1'-methoxycyclohexyloxy)-β-methylandrost-4-en-3-one acetate and 19-hydroxy-17β-(1'-methoxycyclohexyloxy)-6α-methylandrost-4-en-3-one acetate for the 19-hydroxy-17β-(1'-methoxycyclohexyloxy)androst-4-en-3-one acetate above, results in the preparation of 19-hydroxy-17β-(1'-methoxycyclohexyloxy)-1β-methylandrost-4-en-3-one and 19-hydroxy-17β-(1'-methoxycyclohexyloxy)-6α-methylandrost-4-en-3-one, respectively.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][O:11][C@H:10]([C:14]2[CH:19]=[CH:18][C:17]([NH2:20])=[C:16]([F:21])[CH:15]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN1CCOCC1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[F:51][C:52]1[CH:60]=[C:59]2[C:55]([C:56]([C:61](O)=[O:62])=[N:57][NH:58]2)=[CH:54][CH:53]=1>C1COCC1.CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][O:11][C@H:10]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:61]([C:56]3[C:55]4[C:59](=[CH:60][C:52]([F:51])=[CH:53][CH:54]=4)[NH:58][N:57]=3)=[O:62])=[C:16]([F:21])[CH:15]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(O)c1n[nH]c2cc(F)ccc12
Reactant: CC(C)(C)OC(=O)N1CCO[C@H](c2ccc(N)c(F)c2)C1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCO[C@H](c2ccc(NC(=O)c3n[nH]c4cc(F)ccc34)c(F)c2)C1
Temperature: 50 °C
Reaction time: 18 h
Yield: 24.2 %

Procedure:
To a stirred suspension of (+)-(R)-2-(4-amino-3-fluoro-phenyl)-morpholine-4-carboxylic acid tert-butyl ester (40 mg) in THF (6 ml) and DMF (2 ml) were added sequentially N-methylmorpholine (0.12 ml), TBTU (128 mg) and 6-fluoro-1H-indazole-3-carboxylic acid (47 mg, CAS 129295-30-3) and the mixture was heated at 50° C. for 24 h and then at 60° C. for 18 h. The mixture was then concentrated in vacuo and the residue was purified by column chromatography (SiO2; gradient: heptane/EtOAc) to give (R)-2-{3-fluoro-4-[(6-fluoro-1H-indazole-3-carbonyl)-amino]-phenyl}-morpholine-4-carboxylic acid tert-butyl ester (15 mg, 24%) as a white solid. MS (ISP): 476.1 ([M+NH4]+), 459.1 ([M+H]+), 403.1 ([M+H—C4H8]+).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:29])=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:27][CH3:28])=[C:16]([CH2:19][NH:20][C:21]([CH3:26])([C:23]([NH2:25])=[O:24])[CH3:22])[CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1.[CH2:30]=O>>[Cl:1][C:2]1[C:3]([F:29])=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:27][CH3:28])=[C:16]([CH2:19][N:20]([CH3:30])[C:21]([CH3:26])([C:23]([NH2:25])=[O:24])[CH3:22])[CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: C=O
Reactant: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1CNC(C)(C)C(N)=O
Product: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1CN(C)C(C)(C)C(N)=O
Yield: 76 %

Procedure:
N2-({4-[(3-chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}methyl)-2-methylalaninamide (Example 97) was coupled with aqueous formaldehyde using an analogous method to that described for the equivalent step in Example 96 to give the title product as a white solid, (0.078 g, 76%); 1H NMR Spectrum: (DMSO-d6) 1.24 (s, 3H), 2.14 (s, 3H), 3.55 (s, 2H), 3.95 (s, 3H), 7.11 (m, 1H), 7.21 (s, 1H), 7.30 (t, 1H), 7.37 (m, 1H), 7.52-7.58 (m, 2H), 8.44 (m, 2H), 9.76 (s, 1H); Mass Spectrum: (M+H)+ 432.
Reaction SMILES: Cl.[C:2]([CH2:4][NH:5][C:6]([C@@H:8]1[CH2:12][C@@H:11]([S:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[C:22]([F:25])([F:24])[F:23])(=[O:15])=[O:14])[CH2:10][NH:9]1)=[O:7])#[N:3].[CH3:26][N:27]1[CH2:32][CH2:31][CH:30]([C:33](O)=[O:34])[CH2:29][CH2:28]1>>[C:2]([CH2:4][NH:5][C:6]([C@@H:8]1[CH2:12][C@@H:11]([S:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[C:22]([F:25])([F:23])[F:24])(=[O:15])=[O:14])[CH2:10][N:9]1[C:33]([CH:30]1[CH2:31][CH2:32][N:27]([CH3:26])[CH2:28][CH2:29]1)=[O:34])=[O:7])#[N:3]
Reactant: CN1CCC(C(=O)O)CC1
Reactant: N#CCNC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2C(F)(F)F)CN1
Agent: Cl
Product: CN1CCC(C(=O)N2C[C@H](S(=O)(=O)c3ccccc3C(F)(F)F)C[C@H]2C(=O)NCC#N)CC1

Procedure:
(2S,4R)-4-(2-trifluoromethyl-benzenesulfonyl)-pyrrolidine-2-carboxylic acid cyanomethyl-amide hydrochloride from experiment K2 was coupled with 1-methylpiperidine-4-carboxylic acid in analogy to experiment A1 to give (2S,4R)-1-(1-methyl-piperidine-4-carbonyl)-4-(2-trifluoromethyl-benzenesulfonyl)-pyrrolidine-2-carboxylic acid cyanomethyl-amide; salt with formic acid as a colorless oil. MS: 487.3 [M+H]+.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH3:6][C:7]1([CH3:27])[O:11][C@H:10]([C@H:12]([OH:14])[CH3:13])[C@H:9]([CH2:15][O:16][Si:17]([CH:24]([CH3:26])[CH3:25])([CH:21]([CH3:23])[CH3:22])[CH:18]([CH3:20])[CH3:19])[O:8]1.C(N(CC)CC)C.O>C(OCC)(=O)C>[CH3:1][S:2]([O:14][C@@H:12]([C@H:10]1[C@H:9]([CH2:15][O:16][Si:17]([CH:24]([CH3:26])[CH3:25])([CH:18]([CH3:19])[CH3:20])[CH:21]([CH3:23])[CH3:22])[O:8][C:7]([CH3:6])([CH3:27])[O:11]1)[CH3:13])(=[O:4])=[O:3]
Reactant: CC(C)[Si](OC[C@@H]1OC(C)(C)O[C@@H]1[C@@H](C)O)(C(C)C)C(C)C
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)[Si](OC[C@@H]1OC(C)(C)O[C@H]1[C@@H](C)OS(C)(=O)=O)(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
0.75 mL of methanesulfonyl chloride was added dropwise to a solution of 1.6 g of (1R)-1-((4R,5S)-2,2-dimethyl-5-(((tris(propan-2-yl)silyl)oxy)methyl)-1,3-dioxolane-4-yl)ethan-1-ol and 2.7 mL of triethylamine in 16 mL of ethyl acetate at a temperature of 5° C. to 10° C., and the obtained mixture was then stirred at room temperature for 10 minutes. Thereafter, ethyl acetate and water were added to the reaction mixture. The organic layer was fractionated, and it was washed with a saturated sodium chloride aqueous solution and was then dried over anhydrous magnesium sulfate. The solvent was distilled away under reduced pressure, so as to obtain 1.98 g of (1R)-1-((4R,5S)-2,2-dimethyl-5-(((tris(propan-2-yl)silyl)oxy)methyl)-1,3-dioxolane-4-yl)ethyl methanesulfonate in the form of a colorless oily product.
Reaction SMILES: Br[C:2]1[C:3]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[OH:28][CH2:29][C:30]1[N:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1.C([O-])([O-])=O.[Na+].[Na+].COCCOC>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.CCO.O>[OH:28][CH2:29][C:30]1[N:35]=[CH:34][C:33]([C:2]2[C:3]([N:22]3[CH2:23][CH2:24][O:25][CH2:26][CH2:27]3)=[N:4][CH:5]=[C:6]([C:7]([NH:9][C:10]3[CH:15]=[CH:14][C:13]([O:16][C:17]([F:19])([F:20])[F:18])=[CH:12][CH:11]=3)=[O:8])[CH:21]=2)=[CH:32][CH:31]=1
Reactant: OCc1ccc(B(O)O)cn1
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CCOCC2)c(Br)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCO
Solvent: O
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CCOCC2)c(-c2ccc(CO)nc2)c1
Reaction time: 0.33 h

Procedure:
5-Bromo-6-morpholino-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 148.1, 60 mg, 0.134 mmol), (6-(hydroxymethyl)pyridin-3-yl)boronic acid (41.1 mg, 0.269 mmol), Pd(PPh3)2Cl2 (9.44 mg, 0.013 mmol) and Na2CO3 (42.8 mg, 0.403 mmol) were added to a MW vial and treated with a mixture of DME (570 μL), water (163 μL) and EtOH (81 μL). The vial was sealed, evacuated/purged with argon and subjected to MW irradiation at 125° C. for 20 min and then at 130° C. for 20 min, diluted with DME (2 mL) and treated with Si-Thiol (Silicycle, 1.44 mmol/g, 46.7 mg, 0.067 mmol). The RM was centrifuged, the supernatant was filtered and the solvent was evaporated off under reduced pressure to give a residue which was purified by preparative SFC (Column 2-EP, from 15% to 20% in 6 min) to yield the title product as a white solid. UPLC-MS (Condition 3) tR=0.95 min, m/z=475.4 [M+H]+, m/z=473.2 [M−H]−; 1H-NMR (400 MHz, DMSO-d6) δ ppm 3.07-3.22 (m, 4H) 3.48-3.62 (m, 4H) 4.63 (s, 2H) 5.54 (br. s, 1H) 7.38 (d, J=8.53 Hz, 2H) 7.60 (d, J=8.03 Hz, 1H) 7.82-7.92 (m, 2H) 8.11 (d, J=8.28 Hz, 1H) 8.13-8.16 (m, 1H) 8.75-8.79 (m, 1H) 8.79-8.86 (m, 1H) 10.38 (br. s, 1H).
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][N:5]([C:7](=[O:28])[CH2:8][C:9]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C@H:4]([C:29]([N:31]2[CH2:35][CH2:34][CH2:33][C@@H:32]2[C:36]([NH:38][CH2:39][C@@H:40]2[CH2:45][CH2:44][CH2:43][NH:42][CH2:41]2)=[O:37])=[O:30])[CH2:3]1.[CH3:46][C:47]([CH:49]1[CH2:54][CH2:53][CH2:52][CH2:51][CH2:50]1)=O>>[CH:49]1([CH:47]([N:42]2[CH2:43][CH2:44][CH2:45][C@@H:40]([CH2:39][NH:38][C:36]([C@H:32]3[CH2:33][CH2:34][CH2:35][N:31]3[C:29]([C@@H:4]3[CH2:3][C@@H:2]([OH:1])[CH2:6][N:5]3[C:7](=[O:28])[CH2:8][C:9]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)([C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[O:30])=[O:37])[CH2:41]2)[CH3:46])[CH2:54][CH2:53][CH2:52][CH2:51][CH2:50]1
Reactant: CC(=O)C1CCCCC1
Reactant: O=C(NC[C@@H]1CCCNC1)[C@H]1CCCN1C(=O)[C@@H]1C[C@@H](O)CN1C(=O)CC(c1ccccc1)(c1ccccc1)c1ccccc1
Product: CC(C1CCCCC1)N1CCC[C@@H](CNC(=O)[C@H]2CCCN2C(=O)[C@@H]2C[C@@H](O)CN2C(=O)CC(c2ccccc2)(c2ccccc2)c2ccccc2)C1

Procedure:
The title compound was prepared by a method similar to Step 3 of Example 17, using (2R)-1-{(2S,4R)-4-hydroxy-1-(3,3,3-triphenylpropanoyl)pyrrolidin-2-yl}carbonyl-N-((3R) -3-piperidyl-methyl)pyrrolidine-2-carboxamide and cyclohexyl methyl ketone. The compound was obtained as a white solid.
Reaction SMILES: O.O.[C:3]1([CH3:12])[CH:8]=[CH:7][C:6]([S:9]([O-:11])=[O:10])=[CH:5][CH:4]=1.[Na+].Cl[CH2:15][C:16](=[O:18])[CH3:17].O.C1C=CC=CC=1.CC(C)=O>C(OCC)(=O)C.CCCCCCC>[C:3]1([CH3:12])[CH:8]=[CH:7][C:6]([S:9]([CH2:15][C:16](=[O:18])[CH3:17])(=[O:11])=[O:10])=[CH:5][CH:4]=1
Reactant: CC(=O)CCl
Reactant: Cc1ccc(S(=O)[O-])cc1
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Solvent: CCCCCCC
Product: CC(=O)CS(=O)(=O)c1ccc(C)cc1
Yield: 94.2 %

Procedure:
was prepared according to Crandall et al. J. Org. Chem. 1985, (8) 50, 1327-1329 from sodium p-toluenesulfinate dihydrate (4.2 g, 18 mmol), chloroacetone (1.0 mL, 12 mmol), n-tetrabutylammonium bromide (0.30 g) and water-benzene-acetone 4:3:3 (10 mL). Work-up and chromatography on silica of the crude using ethyl acetate/n-heptane (1:3 through 1:2) as eluent gave 2.4 g (95%) of the title product as an oil which crystallised on standing in the fridge.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][C@H:6]1[CH2:11][CH2:10][C@H:9]([NH:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:8][CH2:7]1)C.CC(C[AlH]CC(C)C)C.O>C1(C)C=CC=CC=1>[C:16]([O:15][C:13](=[O:14])[NH:12][C@H:9]1[CH2:8][CH2:7][C@H:6]([CH2:5][CH:4]=[O:3])[CH2:11][CH2:10]1)([CH3:19])([CH3:17])[CH3:18]
Reactant: CCOC(=O)C[C@H]1CC[C@H](NC(=O)OC(C)(C)C)CC1
Agent: CC(C)C[AlH]CC(C)C
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@H](CC=O)CC1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of trans-(4-tert-Butoxycarbonylamino-cyclohexyl)-acetic acid ethyl ester (1.04 g, 4 mmol), in toluene (10 mL) at −78° C. a 1.2M solution of DIBAL-H (5.1 mL, 6 mmol) in toluene was added. The mixture was stirred at −78° C. until TLC after 0.5 h indicated completion of the reaction. Water was added and the solution was extracted three times with dichloromethane. The combined organic layers were washed with water and brine, dried over magnesium sulfate, filtered and evaporated. The crude product was used without purification on the next step. MS (m/e): 242.3 (M+H+).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([N+:8]([O-:10])=[O:9])=[N:6][CH:7]=1.[CH3:11][CH:12]1[O:17][CH:16]([CH3:18])[CH2:15][NH:14][CH2:13]1.C(=O)([O-])[O-].[K+].[K+]>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CS(C)=O.C(OCC)(=O)C>[CH3:18][CH:16]1[O:17][CH:12]([CH3:11])[CH2:13][N:14]([C:2]2[CH:7]=[N:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=2)[CH2:15]1
Reactant: O=[N+]([O-])c1ccc(Br)cn1
Reactant: CC1CNCC(C)O1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CC1CN(c2ccc([N+](=O)[O-])nc2)CC(C)O1
Temperature: 80 °C
Yield: 77.6 %

Procedure:
5-Bromo-2-nitropyridine (4.84 g, 23.84 mmol), tetra-n-butyl ammonium iodide (0.440 g, 1.19 mmol), 2,6-dimethyl-morpholine (3.02 g, 26.22 mmol) and potassium carbonate (3.62 g, 26.22 mmol) were mixed in DMSO (45 mL). The reaction mixture was warmed to 80° C. for 6 hours. The reaction mixture was diluted with ethyl acetate and filtered. The volume of the filtrate was reduced to remove ethyl acetate, and the remaining solution was diluted with water (50 mL). A precipitate immediately formed and was collected by filtration then washed on the funnel with water to provide 2,6-dimethyl-4-(6-nitro-pyridin-3-yl)-morpholine as an orange solid (4.39 g, 78.0%). 1H NMR δ (400 MHz, CDCl3) 8.16 (d, J=9.0 Hz, 1H), 8.11 (d, J=2.9 Hz, 1H), 7.19 (dd, J=2.9, 9.3 Hz, 1H), 3.77 (m, 2H), 3.65 (dd, J=2.2, 12.9 Hz, 2H), 2.66 (dd, J=10.7, 12.5 Hz, 2H), 1.29 (d, J=6.4 Hz, 6H).
Reaction SMILES: CON(C)[C:4]([C:6]1[CH:7]=[CH:8][C:9]([N:12]2[CH:16]=[CH:15][N:14]=[CH:13]2)=[N:10][CH:11]=1)=[O:5].[F:18][C:19]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:20]=1[CH2:21][Mg]Br.FC1C=C(F)C=CC=1CBr.[Mg].Cl>C1COCC1.CCOCC>[F:18][C:19]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:20]=1[CH2:21][C:4]([C:6]1[CH:7]=[CH:8][C:9]([N:12]2[CH:16]=[CH:15][N:14]=[CH:13]2)=[N:10][CH:11]=1)=[O:5]
Reactant: Fc1ccc(C[Mg]Br)c(F)c1
Reactant: CON(C)C(=O)c1ccc(-n2ccnc2)nc1
Agent: Cl
Agent: Fc1ccc(CBr)c(F)c1
Agent: [Mg]
Solvent: CCOCC
Solvent: C1CCOC1
Product: O=C(Cc1ccc(F)cc1F)c1ccc(-n2ccnc2)nc1
Temperature: -70 °C
Reaction time: 0.5 h

Procedure:
A solution of the product from part (i) (6.5 g, 28 mmol) in THF (100 ml) was stirred under a nitrogen atmosphere at -70° C. and was treated with a solution of 2,4-difluorobenzylmagnesium bromide [from 2,4-difluorobenzyl bromide (8.1 g, 39 mmol) and magnesium (1.0 g, 42 mmol) using the method of Preparation 20(i)] in ether (100 ml). The mixture was stirred at -70° C. for 0.5 hours and was allowed to warm to room temperature before the addition of dilute hydrochloric acid (2N, 100 ml). The layers were separated and the aqueous phase was extracted with dichloromethane (100 ml). The combined organic extracts were dried (MgSO4) and evaporated under reduced pressure to yield the title compound as a pale yellow solid which was characterised by
Reaction SMILES: [CH2:1]([N:4]1[CH2:8][CH2:7][CH2:6][CH:5]1[CH2:9][NH2:10])[CH:2]=[CH2:3].C(Cl)(Cl)Cl.[CH2:15]([S:17]([C:20]1[CH:21]=[C:22]([C:30](Cl)=[O:31])[C:23]2[O:28][CH2:27][CH2:26][O:25][C:24]=2[CH:29]=1)(=[O:19])=[O:18])[CH3:16]>O>[CH2:1]([N:4]1[CH2:8][CH2:7][CH2:6][CH:5]1[CH2:9][NH:10][C:30]([C:22]1[C:23]2[O:28][CH2:27][CH2:26][O:25][C:24]=2[CH:29]=[C:20]([S:17]([CH2:15][CH3:16])(=[O:19])=[O:18])[CH:21]=1)=[O:31])[CH:2]=[CH2:3]
Reactant: C=CCN1CCCC1CN
Reactant: CCS(=O)(=O)c1cc2c(c(C(=O)Cl)c1)OCCO2
Solvent: O
Solvent: ClC(Cl)Cl
Product: C=CCN1CCCC1CNC(=O)c1cc(S(=O)(=O)CC)cc2c1OCCO2
Yield: 93.3 %

Procedure:
58 g of 1-allyl-2-aminomethyl-pyrrolidine and 360 ml of chloroform were introduced into a balloon flask provided with an agitator and a thermometer and then, with the temperature being maintained at 5°-10° C., 120 g of 7-ethylsulfonyl-1,4-benzodioxane-5-carbonyl chloride was added. After agitation of the mixture and the addition of a liter of water, the chloroform was distilled. The resulting solution was filtered on carbon black and then the base was precipitated by the addition of 40 ml of 30% soda lye. The resulting crystals were dried off, washed with water and then dried. 152 g of N-(1-allyl-2-pyrrolidylmethyl)-7-ethylsulfonyl-1,4-benzodioxane-5-carboxamide was produced (M.P.: 78°-80° C.; yield: 93.4%). 146 g of the resulting base was dissolved hot in 290 ml of absolute alcohol, and then the solution was filtered on carbon black and acidified by the addition of a solution of 13.5 g of hydrochloric acid in 100 ml of absolute alcohol. After cooling the crystals formed were dried off, washed with absolute alcohol and dried and then purified by recrystallization from absolute alcohol. 119.5 g of N-(1-allyl-2-pyrrolidylmethyl)-7-ethylsulfonyl-1,4-benzodioxane-5-carboxamide hydrochloride was produced (M.P.: 138°-140° C.; yield: 75%).
Reaction SMILES: [CH2:1]([N:3]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[C:14]3[CH:15]=[C:16]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[S:17][C:13]=3[C:12](=[O:24])[N:11]([CH:25]3[CH2:30][CH2:29][N:28](C(OC(C)(C)C)=O)[CH2:27][CH2:26]3)[C:10]2=[O:38])=[N:4]1)[CH3:2].[F:39][C:40]([F:45])([F:44])[C:41]([OH:43])=[O:42]>C(Cl)Cl>[F:39][C:40]([F:45])([F:44])[C:41]([OH:43])=[O:42].[CH2:1]([N:3]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[C:14]3[CH:15]=[C:16]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[S:17][C:13]=3[C:12](=[O:24])[N:11]([CH:25]3[CH2:26][CH2:27][NH:28][CH2:29][CH2:30]3)[C:10]2=[O:38])=[N:4]1)[CH3:2]
Reactant: CCn1ccc(Cn2c(=O)n(C3CCN(C(=O)OC(C)(C)C)CC3)c(=O)c3sc(-c4ccccc4)cc32)n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCn1ccc(Cn2c(=O)n(C3CCNCC3)c(=O)c3sc(-c4ccccc4)cc32)n1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of tert-butyl 4-{1-[(1-ethyl-1H-pyrazol-3-yl)methyl]-2,4-dioxo-6-phenyl-1,4-dihydrothieno[3,2-d]pyrimidin-3(2H)-yl}piperidine-1-carboxylate (665 mg; compound B19) in DCM (5 ml) is added trifluoroacetic acid (5 ml). The reaction mixture is stirred for 3 h at RT. All volatile materials are removed in vacuo and the residue is taken up in diethyl ether. The resulting suspension is stirred at RT, then all solids are filtered off and dried in vacuo. The procedure is repeated a second time to afford the title compound as a solid.