Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:21]=[CH:20][C:5]([CH2:6][C:7]2[C:8]([CH2:18][CH3:19])=[N:9][N:10]3[C:15]([CH3:16])=[CH:14][C:13]([CH3:17])=[N:12][C:11]=23)=[CH:4][CH:3]=1.[N-:22]=[N+:23]=[N-:24].[Na+].CNCCNC.O=C1O[C@H]([C@H](CO)O)C([O-])=C1O.[Na+]>C(O)C.CCOC(C)=O.[Cu]I.O>[N:22]([C:2]1[CH:21]=[CH:20][C:5]([CH2:6][C:7]2[C:8]([CH2:18][CH3:19])=[N:9][N:10]3[C:15]([CH3:16])=[CH:14][C:13]([CH3:17])=[N:12][C:11]=23)=[CH:4][CH:3]=1)=[N+:23]=[N-:24]
Reactant: CCc1nn2c(C)cc(C)nc2c1Cc1ccc(Br)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Cu]I
Agent: CNCCNC
Agent: O=C1O[C@H]([C@@H](O)CO)C([O-])=C1O
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCc1nn2c(C)cc(C)nc2c1Cc1ccc(N=[N+]=[N-])cc1

Procedure:
A vial containing 3-(4-bromo-benzyl)-2-ethyl-5,7-dimethyl-pyrazolo[1,5-a]pyrimidine (3) (10 g, 29.0 mmol), sodium azide (3.78 g, 58.1 mmol), copper(I) iodide (0.553 g, 2.90 mmol), N,N′-dimethylethylenediamine (0.469 ml, 4.36 mmol) and sodium ascorbate (0.288 g, 1.452 mmol) in ethanol (45 ml)/water (15.00 ml) was submitted to microwave irradiations for 1 h at 100° C. The reaction was diluted with EtOAc and washed with sat aqu Na2 CO3, water and brine. The organic layer was dried over anhydrous Na2 SO4, filtered and concentrated under HV. The crude product was purified by flash chromatography (silica gel, EtOAc/heptane 5% to 40%) to give a pale yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([NH2:8])[N:5]=[C:4]([NH2:9])[CH:3]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[F:20][CH:21]([F:31])[CH2:22]OS(C(F)(F)F)(=O)=O>C1COCC1>[Br:1][C:2]1[CH:7]=[C:6]([NH2:8])[N:5]=[C:4]([NH:9][CH2:22][CH:21]([F:31])[F:20])[CH:3]=1
Reactant: O=S(=O)(OCC(F)F)C(F)(F)F
Reactant: Nc1cc(Br)cc(N)n1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Nc1cc(Br)cc(NCC(F)F)n1
Temperature: 0 °C
Reaction time: 1 h
Yield: 32 %

Procedure:
4-Bromo-pyridine-2,6-diamine (2.2 g) was dissolved under an argon atmosphere in THF (15 mL) and cooled to 0° C. At this temperature LiHMDS (12.9 mL 1 M solution in THF) was added slowly to the solution. The reaction mixture was stirred at 0° C. for 1 h. After that difluorethyltriflate (2.76 g) was added and the reaction mixture was stirred at 25° C. for 18 h. Complete conversion was observed by LC-MS analysis. The reaction mixture was evaporated to dryness, dissolved in ethyl acetate and extracted with water and brine. The organic layer was dried over Na2SO4, filtrated and evaporated to dryness. The crude product was purified by flash chromatography over silica gel (70 g SiO2, gradient ethyl acetate/n-heptane 1:4->1:0) to yield 4-bromo-N-(2,2-difluoroethyl)-pyridine-2,6-diamine (0.943 g; 32%) as a dark red oil.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:10]=[CH:11][C:12]([N:16]3[C:20](=[O:21])[NH:19][C:18]([C:22]4([CH3:25])[CH2:24][CH2:23]4)=[N:17]3)=[N:13][C:14]=2[CH3:15])[CH:5]=[CH:4][N:3]=1.[CH3:26][N:27]1[CH:31]=[C:30](B2OC(C)(C)C(C)(C)O2)[CH:29]=[N:28]1.C([O-])([O-])=O.[K+].[K+].[NH4+].[Cl-]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:15][C:14]1[N:13]=[C:12]([N:16]2[C:20](=[O:21])[NH:19][C:18]([C:22]3([CH3:25])[CH2:24][CH2:23]3)=[N:17]2)[CH:11]=[CH:10][C:9]=1[O:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([C:30]2[CH:29]=[N:28][N:27]([CH3:26])[CH:31]=2)[CH:7]=1
Reactant: Cc1nc(-n2nc(C3(C)CC3)[nH]c2=O)ccc1Oc1ccnc(Cl)c1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: C1COCCO1
Solvent: O
Product: Cc1nc(-n2nc(C3(C)CC3)[nH]c2=O)ccc1Oc1ccnc(-c2cnn(C)c2)c1
Temperature: 85 °C
Reaction time: 12 h
Yield: 46 %

Procedure:
1-(5-((2-Chloropyridin-4-yl)oxy)-6-methylpyridin-2-yl)-3-(1-methylcyclopropyl)-1H-1,2,4-triazol-5(4H)-one (0.10 g, 0.28 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.08 g, 0.36 mmol), and K2CO3 (0.10 g, 0.73 mmol) were suspended in dioxane (1.7 mL) and water (0.33 mL). The suspension was sonicated and sparged with Ar for 10 min. Pd(PPh3)4 (0.032 g, 0.028 mmol) was added and the reaction mixture was stirred at 85° C. for 12 h. Sat. NH4Cl (aq) (10 mL) was added and the resultant emulsion was extracted with EtOAc (4×10 mL). The combined organics were dried (Na2SO4) and concentrated in vacuo. The residue was purified by silica gel chromatography (MeOH/DCM) to afford 1-(6-methyl-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-3-(1-methylcyclopropyl)-1H-1,2,4-triazol-5(4H)-one (0.052 g, 46.1%) as an white solid. 1H NMR (400 MHz, DMSO-d6): δ 11.76 (s, 1H), 8.37 (d, J=5.7 Hz, 1H), 8.25 (s, 1H), 7.96 (s, 1H), 7.83 (d, J=8.8 Hz, 1H), 7.68 (d, J=8.8 Hz, 1H), 7.19 (d, J=2.4 Hz, 1H), 6.64 (dd, J=5.7, 2.4 Hz, 1H), 3.84 (s, 3H), 2.33 (s, 3H), 1.38 (s, 3H), 1.06 (d, J=2.3 Hz, 2H), 0.81 (t, J=2.3 Hz, 2H); MS (ESI) m/z: 404.2 (M+H+).
Reaction SMILES: [BH4-].[Na+].[N:3]1([CH2:8][CH2:9][CH2:10][O:11][C:12]2[CH:13]=[C:14]([CH:37]=[CH:38][CH:39]=2)[CH:15]=[C:16]2[CH2:21][C@H:20]3[C@H:22]4[C@H:32]([CH2:33][CH2:34][C@:18]3([CH3:19])[C:17]2=[O:36])[C@:30]2([CH3:31])[C:25]([CH2:26][C@@H:27]([OH:35])[CH2:28][CH2:29]2)=[CH:24][CH2:23]4)[CH:7]=[CH:6][N:5]=[CH:4]1>>[N:3]1([CH2:8][CH2:9][CH2:10][O:11][C:12]2[CH:13]=[C:14]([CH:37]=[CH:38][CH:39]=2)[CH:15]=[C:16]2[CH2:21][C@H:20]3[C@H:22]4[C@H:32]([CH2:33][CH2:34][C@:18]3([CH3:19])[C@H:17]2[OH:36])[C@:30]2([CH3:31])[C:25]([CH2:26][C@@H:27]([OH:35])[CH2:28][CH2:29]2)=[CH:24][CH2:23]4)[CH:7]=[CH:6][N:5]=[CH:4]1
Reactant: C[C@]12CC[C@H](O)CC1=CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)C(=Cc3cccc(OCCCn4ccnc4)c3)C[C@@H]12
Agent: [BH4-]
Agent: [Na+]
Product: C[C@]12CC[C@H]3[C@@H](CC=C4C[C@@H](O)CC[C@@]43C)[C@@H]1CC(=Cc1cccc(OCCCn3ccnc3)c1)[C@@H]2O

Procedure:
16-[3-{3-(IMIDAZOL-1-YL)PROPOXY}BENZYLIDENE]-5-ANDROSTENE-3β,17β-DIOL (20) (DPJ-RG-1310) was prepared by sodium borohydride reduction of 18 using a method as described for 14
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH:8]([F:10])[F:9])[C:5]([F:11])=[CH:4][N:3]=1.[Br:12][C:13]1[CH:14]=[C:15]([CH:17]=[C:18]([CH3:20])[CH:19]=1)[NH2:16]>O1CCOCC1>[Br:12][C:13]1[CH:14]=[C:15]([NH:16][C:2]2[N:7]=[C:6]([CH:8]([F:10])[F:9])[C:5]([F:11])=[CH:4][N:3]=2)[CH:17]=[C:18]([CH3:20])[CH:19]=1
Reactant: Cc1cc(N)cc(Br)c1
Reactant: Fc1cnc(Cl)nc1C(F)F
Solvent: C1COCCO1
Product: Cc1cc(Br)cc(Nc2ncc(F)c(C(F)F)n2)c1
Temperature: 105 °C
Reaction time: 72 h

Procedure:
2-Chloro-4-(difluoromethyl)-5-fluoropyrimidine (30 g, 162 mmol, 1.00 equiv) p-TsOH (37 g, 215 mmol, 1.33 equiv), 1,4-dioxane (600 mL), 3-bromo-5-methylaniline (46 g, 247 mmol, 1.53 equiv) were added into a 1000-mL pressure tank reactor purged and maintained with an inert atmosphere of nitrogen. The resulting solution was stirred for 72 h at 105° C. The reaction mixture was cooled to room temperature. The solid was filtered out and the filtrate was concentrated under reduced pressure. The residue was applied onto a silica gel and purified column chromatography on silica (1:20 ethyl acetate/petroleum ether) to afford N-(3-bromo-5-methylphenyl)-4-(difluoromethyl)-5-fluoropyrimidin-2-amine as a yellow solid. MS ESI calc'd. for C12H10BrF3N3 [M+H]+332/334. found 332/334. 1H NMR (400 MHz, CDCl3): δ 8.45 (1H, s), 7.73 (1H, s), 7.21 (1H, s), 7.18 (1H, s), 7.05 (1H, s), 6.63 (1H, t, J=53.37 Hz), 2.34 (3H, s).
Reaction SMILES: C(N=C=NC(C)C)(C)C.[F:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2([CH2:23][O:24][CH2:25][C:26]([OH:28])=O)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)=[CH:13][CH:12]=1.[C:29]([O:33][C:34]([CH:36]1[CH2:39][N:38]([CH2:40][C:41]2[CH:46]=[CH:45][C:44]([C:47](=[N:49]O)[NH2:48])=[CH:43][CH:42]=2)[CH2:37]1)=[O:35])([CH3:32])([CH3:31])[CH3:30].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>ClCCl>[F:10][C:11]1[CH:12]=[CH:13][C:14]([C:17]2([CH2:23][O:24][CH2:25][C:26]3[O:28][N:49]=[C:47]([C:44]4[CH:43]=[CH:42][C:41]([CH2:40][N:38]5[CH2:37][CH:36]([C:34]([O:33][C:29]([CH3:30])([CH3:32])[CH3:31])=[O:35])[CH2:39]5)=[CH:46][CH:45]=4)[N:48]=3)[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]2)=[CH:15][CH:16]=1
Reactant: O=C(O)COCC1(c2ccc(F)cc2)CCCCC1
Reactant: CC(C)(C)OC(=O)C1CN(Cc2ccc(C(N)=NO)cc2)C1
Agent: CC(C)N=C=NC(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)C1CN(Cc2ccc(-c3noc(COCC4(c5ccc(F)cc5)CCCCC4)n3)cc2)C1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 63.6 %

Procedure:
N,N′-Diisopropylcarbodiimide (17 mg, 135 μmol) was added to a stirred solution of crude 2-((1-(4-fluorophenyl)cyclohexyl)methoxy)acetic acid (30 mg, 113 μmol) and tert-butyl-1-(4-(N′-hydroxycarbamimidoyl)benzyl)azetidine-3-carboxylate (34 mg, 113 μmol) in dichloromethane (1.5 mL). The reaction mixture was stirred at room temperature for 40 min and concentrated. The residue was diluted with acetonitrile (1.5 mL) and treated with a 1 M solution of tetra-n-butylammonium fluoride (113 μL, 113 μmol). The mixture was stirred at room temperature for 16 h and concentrated. The crude residue was chromatographed on silica gel (Teledyne-Isco RediSep 12 g column), and eluted with 10%, 20% and 30% EtOAc in hexanes to obtain tert-butyl 1-(4-(5-(((1-(4-fluorophenyl)cyclohexyl)methoxy)methyl)-1,2,4-oxadiazol-3-yl)benzyl)azetidine-3-carboxylate (38.5 mg, 64% yield) as a viscous colorless oil.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][C:8]#[N:9])[CH:5]=[CH:4][CH:3]=[CH:2]1.[Cl-].[CH3:11][O:12][C:13]1[CH:22]=[CH:21][CH:20]=[CH:19][C:14]=1[CH:15]=[N+:16]([CH3:18])[CH3:17]>>[CH3:18][N:16]([CH:15]([C:14]1[CH:19]=[CH:20][CH:21]=[CH:22][C:13]=1[O:12][CH3:11])[C:2]1[N:1]([CH2:6][CH2:7][C:8]#[N:9])[CH:5]=[CH:4][CH:3]=1)[CH3:17]
Reactant: COc1ccccc1C=[N+](C)C
Reactant: N#CCCn1cccc1
Agent: [Cl-]
Product: COc1ccccc1C(c1cccn1CCC#N)N(C)C

Procedure:
The preparation was carried out in accordance with general synthesis instructions 4 from 3-pyrrol-1-yl-propionitrile and (2-methoxy-benzylidene)-dimethyl-ammonium chloride, which had been prepared in accordance with example 7.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:13][CH2:12][CH:11]([NH:14][C:15](=[O:17])[CH3:16])[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[H-].[Na+].I[CH3:21]>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:9][CH2:10][CH:11]([N:14]([CH3:21])[C:15](=[O:17])[CH3:16])[CH2:12][CH2:13]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)NC1CCN(c2cccc(Br)c2)CC1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(=O)N(C)C1CCN(c2cccc(Br)c2)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 103.3 %

Procedure:
A solution of N-[1-(3-bromophenyl)-4-piperidyl]acetamide (11.6 g, 39.2 mmol) in THF (392 mL) was added to sodium hydride (6.84 g, 55% in mineral oil, 157 mmol) portionwise at 0° C. and stirred at room temperature for 10 minutes under nitrogen. The reaction mixture was added to iodomethane (7.32 mL, 118 mmol) at 0° C. and stirred at room temperature for 6 hours. The mixture was slowly quenched with water at 0° C. and extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4 and filtered through a Celite pad. The combined filtrate and washings were concentrated. The residue was purified by silica gel column chromatography (hexane/AcOEt=80:20→0:100) to afford desired product (12.6 g, quant.) as brown oil.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]2[NH:15][C:16](=[O:19])[CH2:17][O:18][C:13]=2[C:12]([C:20](=[O:24])[CH:21](O)O)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:26][C:27]([CH3:48])([CH3:47])[CH2:28][CH2:29][N:30]1[C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=2[C:33]([CH2:43][CH2:44][CH3:45])([CH2:40][CH2:41][CH3:42])[O:32][C:31]1=[O:46]>CCOC(C)=O>[CH2:1]([O:8][C:9]1[C:14]2[NH:15][C:16](=[O:19])[CH2:17][O:18][C:13]=2[C:12]([CH:20]([OH:24])[CH2:21][NH:26][C:27]([CH3:47])([CH3:48])[CH2:28][CH2:29][N:30]2[C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=3[C:33]([CH2:43][CH2:44][CH3:45])([CH2:40][CH2:41][CH3:42])[O:32][C:31]2=[O:46])=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1COc2c(C(=O)C(O)O)ccc(OCc3ccccc3)c2N1
Reactant: CCCC1(CCC)OC(=O)N(CCC(C)(C)N)c2ccccc21
Agent: Cl
Solvent: CCOC(C)=O
Product: CCCC1(CCC)OC(=O)N(CCC(C)(C)NCC(O)c2ccc(OCc3ccccc3)c3c2OCC(=O)N3)c2ccccc21

Procedure:
The product is prepared analogously to Example 12a starting from 5-benzyloxy-8-(2,2-dihydroxyacetyl)-4H-benzo[1,4]oxazin-3-one and 1-(3-amino-3-methylbutyl)-4,4-dipropyl-1,4-dihydrobenzo[d][1,3]oxazin-2-one hydrochloride. The crude product is dissolved in EtOAc, washed with 5% aqueous NaOH solution, and purified by column chromatography (silica gel, dichloromethane/MeOH 98:2→90:10). Yield: 170 mg (49%); HPLC-MS: Rt=18.9 min. (method A).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:15][CH2:16][CH2:17][O:18][CH:19]3[CH2:24][CH2:23][CH2:22][CH2:21][O:20]3)[CH2:13][NH:12][C:11](=[O:14])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].[CH3:25][O:26][C:27]1[CH:28]=[C:29]([CH:32]=[C:33]([O:37][CH3:38])[C:34]=1[O:35][CH3:36])[CH2:30]Br>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:15][CH2:16][CH2:17][O:18][CH:19]3[CH2:24][CH2:23][CH2:22][CH2:21][O:20]3)[CH2:13][N:12]([CH2:30][C:29]3[CH:32]=[C:33]([O:37][CH3:38])[C:34]([O:35][CH3:36])=[C:27]([O:26][CH3:25])[CH:28]=3)[C:11](=[O:14])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C1CC(CCCOC2CCCCO2)(c2ccc(Cl)c(Cl)c2)CN1
Reactant: COc1cc(CBr)cc(OC)c1OC
Product: COc1cc(CN2CC(CCCOC3CCCCO3)(c3ccc(Cl)c(Cl)c3)CC2=O)cc(OC)c1OC

Procedure:
Prepare according to the procedure of example 11.4 using 4-(3,4-dichloro-phenyl)-4-[3-(tetrahydro-pyran-2-yloxy)-propyl]-pyrrolidin-2-one (2.79 mmol) and 3,4,5-trimethoxy-benzyl bromide (5.9 mmol). Chromatograph on silica gel to give the title compound.
Reaction SMILES: [NH:1]1[CH2:7][C:5](=[O:6])[NH:4][C:2]1=[S:3].[OH:8][C:9]1[CH:10]=[C:11]([CH:14]=[C:15]([N+:18]([O-:20])=[O:19])[C:16]=1[OH:17])[CH:12]=O.N1CCCCC1>C(O)(=O)C>[OH:8][C:9]1[CH:10]=[C:11]([CH:12]=[C:7]2[C:5](=[O:6])[NH:4][C:2](=[S:3])[NH:1]2)[CH:14]=[C:15]([N+:18]([O-:20])=[O:19])[C:16]=1[OH:17]
Reactant: O=C1CNC(=S)N1
Reactant: O=Cc1cc(O)c(O)c([N+](=O)[O-])c1
Solvent: C1CCNCC1
Solvent: CC(=O)O
Product: O=C1NC(=S)NC1=Cc1cc(O)c(O)c([N+](=O)[O-])c1
Temperature: 100 °C

Procedure:
A solution containing 2.9 g (0.025 mol) of 2-thiohydantoin, 4.6 g (0.025 mol) of 3,4-dihydroxy-5-nitrobenzaldehyde and 0.25 ml of piperidine in 50 ml of acetic acid was heated for 7-8 h at 100° C. The crystalls were filtered and washed with 2-propanol. Yield 5.0 g (71%), mp>350° C. (decom.).
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)[CH:8]=[CH:7][N:6]=1)(=O)=O.[O:17]1CCOCC1>>[N:13]1[CH:14]=[CH:15][CH:16]=[C:11]([C:9]2[CH:8]=[CH:7][NH:6][C:5](=[O:17])[N:10]=2)[CH:12]=1
Reactant: CS(=O)(=O)c1nccc(-c2cccnc2)n1
Reactant: C1COCCO1
Product: O=c1nc(-c2cccnc2)cc[nH]1
Temperature: 25 °C
Reaction time: 1 h
Yield: 80 %

Procedure:
2-Methanesulfonyl-4-pyridin-3-yl-pyrimidine (846 mg, 3.58 mmol) was dissolved in dioxane (36 ml) and then 2N NaOHaq (18 ml, 36 mmol) was added. After stirring at room temperature for 1 hour, the solution was acidified with 37% HClaq. The mixture was evaporated and the residue was re-dissolved in DCM-MeOH—NH4OH (90-10-1) and evaporated. The residue was purified by flash chromatography with DCM-MeOH (9-1) to give 500 mg of the title compound. (80% yield).
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[C:11]([F:13])[C:10]([O:14][CH3:15])=[CH:9][C:8]=2[C:16]2[C:17]3[NH:24][C:23]([CH3:25])=[C:22]([C:26]([NH:28][CH:29]4[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]4)=[O:27])[C:18]=3[N:19]=[CH:20][N:21]=2)[CH2:4][CH2:3]1.[CH3:35][O:36][CH2:37][C:38](Cl)=[O:39]>>[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[C:11]([F:13])[C:10]([O:14][CH3:15])=[CH:9][C:8]=2[C:16]2[C:17]3[NH:24][C:23]([CH3:25])=[C:22]([C:26]([NH:28][CH:29]4[CH2:30][CH2:31][N:32]([C:38](=[O:39])[CH2:37][O:36][CH3:35])[CH2:33][CH2:34]4)=[O:27])[C:18]=3[N:19]=[CH:20][N:21]=2)[CH2:4][CH2:3]1
Reactant: COCC(=O)Cl
Reactant: COc1cc(-c2ncnc3c(C(=O)NC4CCNCC4)c(C)[nH]c23)c(OCC2CC2)cc1F
Agent: Cl
Product: COCC(=O)N1CCC(NC(=O)c2c(C)[nH]c3c(-c4cc(OC)c(F)cc4OCC4CC4)ncnc23)CC1

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-4-fluoro-5-methoxyphenyl]-6-methyl-N-piperidin-4-yl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f35) and commercially available methoxy-acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7](C1CCCCO1)[N:6]=[C:5]2[C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=1.C(N(CC)CC)C.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.[C:53]1([C:59]#[CH:60])[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1>C(#N)C>[F:23][C:20]1[CH:19]=[CH:18][C:17]([C:5]2[C:4]3[C:8](=[CH:9][CH:10]=[C:2]([C:60]#[C:59][C:53]4[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=4)[CH:3]=3)[NH:7][N:6]=2)=[CH:22][CH:21]=1
Reactant: Fc1ccc(-c2nn(C3CCCCO3)c3ccc(Br)cc23)cc1
Reactant: C#Cc1ccccc1
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Fc1ccc(-c2n[nH]c3ccc(C#Cc4ccccc4)cc23)cc1
Yield: 40.7 %

Procedure:
A mixture of 5-bromo-3-(4-fluorophenyl)-1-(tetrahydropyran-2-yl)-1H-indazole (0.375 g, 1.0 mmol), triethylamine (1.5 mL), tri-o-tolylphosphine (0.122 g, 0.4 mmol), tri(dibenzylideneacetone)dipalladium(0) (0.092 g, 0.1 mmol) and phenylacetylene (0.204 g, 2.0 mmol) in dried acetonitrile (10 mL) under nitrogen was heated to reflux overnight. It was quenched with water and extracted with ethyl acetate. The extracts were dried over magnesium sulfate, filtered, and concentrated. The residue was then purified by chromatography (SiO2, 10–15% ethyl acetate/hexane) to provide the title compound (0.127 g, 32% yield). 1H NMR (CDCl3) δ 8.16 (t, 1H), 7.93–7.97 (m, 2H), 7.54–7.64 (m, 4H), 7.34–7.37 (m, 3H), 7.21 (t, 2H) 5.77 (dd, 1H), 4.08 (m, 1H), 3.79 (m, 1H), 2.62 (m, 1H), 2.11–2.21 (m, 2H), 1.57–1.83 (m, 3H); ES-MS (m/z) 397 [M+1]+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][C:17]=1[O:18][CH3:19])[C:12](Cl)=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:20]([NH:22][CH2:23][CH3:24])[CH3:21]>C(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][C:17]=1[O:18][CH3:19])[C:12]([N:22]([CH2:23][CH3:24])[CH2:20][CH3:21])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCNCC
Reactant: COc1ccc(C(=O)Cl)cc1OCc1ccccc1
Solvent: ClCCl
Product: CCN(CC)C(=O)c1ccc(OC)c(OCc2ccccc2)c1
Yield: 94.6 %

Procedure:
A solution of 3-benzyloxy-4-methoxy-benzoyl chloride (35.01 g, 0.127 mole), prepared as described in example 54, in CH2Cl2 (200 ml) was dropwise added at 5-10° C. with diethylamine (131 ml, 92.54 g, 1.27 mole) in CH2Cl2 (130 ml). The mixture was evaporated to dryness, dissolved in ethyl acetate, washed with water, 2% KHSO4, water again and NaHCO3, anhydrified over Na2SO4 and brought to dryness. The residue was taken up in petrolatum (250 ml) to give 37.65 g of the title compound (yield: 95%)
Reaction SMILES: [NH2:1][C:2]1[C:16]([O:17][CH3:18])=[CH:15][C:5]2[CH2:6][CH2:7][N:8]([CH2:11][C@@H:12]([OH:14])[CH3:13])[CH2:9][CH2:10][C:4]=2[CH:3]=1.C([Si](C)(C)[O:24][C@@H:25]1[CH2:29][CH2:28][N:27]([S:30]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=2[NH:39][C:40]2[C:45]([Cl:46])=[CH:44][N:43]=[C:42](Cl)[N:41]=2)(=[O:32])=[O:31])[CH2:26]1)(C)(C)C>>[Cl:46][C:45]1[C:40]([NH:39][C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=2[S:30]([N:27]2[CH2:28][CH2:29][C@@H:25]([OH:24])[CH2:26]2)(=[O:31])=[O:32])=[N:41][C:42]([NH:1][C:2]2[C:16]([O:17][CH3:18])=[CH:15][C:5]3[CH2:6][CH2:7][N:8]([CH2:11][C@@H:12]([OH:14])[CH3:13])[CH2:9][CH2:10][C:4]=3[CH:3]=2)=[N:43][CH:44]=1
Reactant: COc1cc2c(cc1N)CCN(C[C@H](C)O)CC2
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1CCN(S(=O)(=O)c2ccccc2Nc2nc(Cl)ncc2Cl)C1
Product: COc1cc2c(cc1Nc1ncc(Cl)c(Nc3ccccc3S(=O)(=O)N3CC[C@@H](O)C3)n1)CCN(C[C@H](C)O)CC2
Yield: 47 %

Procedure:
In an analogous manner to Example 1534, the product was prepared from (S)-1-(7-Amino-8-methoxy-1,2,4,5-tetrahydro-3-benzazepin-3-yl)-propan-2-ol and {2-[(R)-3-(tert-Butyl-dimethyl-silanyloxy)-pyrrolidine-1-sulfonyl]-phenyl}-(2,5-dichloro-pyrimidin-4-yl)-amine. The product was isolated as an off-white foam (55 mg, 47%). MS (ESI+): 603 (M+H), 1H-NMR (CDCl3, 400 MHz) δ 9.33 (s, 1H), 8.48 (d, J=8 Hz, 1H), 8.16 (s, 1H), 8.01 (s, 1H), 7.96 (d, J=8 Hz, 1H), 7.58-7.52 (m, 2H), 7.25 (t, J=8 Hz, 1H), 6.66 (s, 1H), 4.37 (br s, 1H), 3.88 (m, 4H), 3.42 (m, 3H), 3.31 (d, 1H), 2.91-2.52 (m, 10H), 2.27 (m, 1H), 1.17 (d, J=6 Hz, 3H).
Reaction SMILES: [O:1]1[C@H:3]2[CH2:4][C@H:5]3[C@:18]([CH3:20])([CH2:19][C@@H:2]12)[C@@H:17]1[C@H:8]([C@H:9]2[C@@:13]([CH2:15][CH2:16]1)([CH3:14])[C:12](=[O:21])[C@@H:11]([N:22]1[CH2:27][CH2:26][CH:25]([OH:28])[CH2:24][CH2:23]1)[CH2:10]2)[CH2:7][CH2:6]3.[BH4-].[Na+]>>[O:1]1[C@H:3]2[CH2:4][C@H:5]3[C@:18]([CH3:20])([CH2:19][C@@H:2]12)[C@@H:17]1[C@H:8]([C@H:9]2[C@@:13]([CH2:15][CH2:16]1)([CH3:14])[C@@H:12]([OH:21])[C@@H:11]([N:22]1[CH2:27][CH2:26][CH:25]([OH:28])[CH2:24][CH2:23]1)[CH2:10]2)[CH2:7][CH2:6]3
Reactant: C[C@]12C[C@H]3O[C@H]3C[C@@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)[C@@H](N3CCC(O)CC3)C[C@@H]12
Agent: [BH4-]
Agent: [Na+]
Product: C[C@]12C[C@H]3O[C@H]3C[C@@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](O)[C@@H](N3CCC(O)CC3)C[C@@H]12
Yield: 86.06 %

Procedure:
2α,3α-Epoxy-16β-(4-hydroxy-1-piperidinyl)-5α-androstane-17-one is reduced by using sodium borohydride as described in Example 2 to give the title product in a yield of 86.06%, m.p.: 204°-206° C.
Reaction SMILES: Cl[CH2:2][O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[S-:16][C:17]#[N:18].[K+]>CC(C)=O>[N:18]([CH2:2][O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[C:17]=[S:16]
Reactant: ClCOc1ccccc1-c1ccccc1
Reactant: N#C[S-]
Agent: [K+]
Solvent: CC(C)=O
Product: S=C=NCOc1ccccc1-c1ccccc1
Temperature: 0 °C
Yield: 65.2 %

Procedure:
Twenty grams (0.091 mole) of 2-(chloromethoxy)-1,1'-biphenyl was thereafter dissolved in 200 ml anhydrous acetone. To this solution was added 9.72 g (0.100 mole) potassium thiocyanate. The resulting mixture was stirred and refluxed for 6.5 hours, whereupon it was diluted with 500 ml ice water and extracted with ether. The extracts were dried with MgSO4 and concentrated to give an orange oil which was distilled in vacuo to give 14.32 g of 2-(isothiocyanatomethoxy)-1,1'-biphenyl as a pale yellow oil, boiling at 169°-171° C at 1.0 mm pressure.
Reaction SMILES: [CH3:1][C:2]1[C:7]([O:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:6]([CH2:14][O:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:5]([CH2:21]Cl)=[CH:4][N:3]=1.CCOC(S)=[S:27]>>[CH3:1][C:2]1[C:7]([O:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:6]([CH2:14][O:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:5]([CH2:21][SH:27])=[CH:4][N:3]=1
Reactant: CCOC(=O)OCc1c(CCl)cnc(C)c1OC(=O)OCC
Reactant: CCOC(=S)S
Product: CCOC(=O)OCc1c(CS)cnc(C)c1OC(=O)OCC

Procedure:
2-Methyl-3-ethoxycarbonyloxy-4-ethoxycarbonyloxymethyl-5-chloromethylpyridine is converted to the corresponding ethyl xanthogenate and reduced in accordance with the procedure of Example 19 Step B to give 2-methyl-3-ethoxycarbonyloxy-4-ethoxycarbonyloxymethyl-5-mercaptomethylpyridine.
Reaction SMILES: [C:1]([NH:4][C@H:5]1[C@H:11]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([Cl:19])[CH:13]=2)[O:10][CH2:9][CH2:8][N:7](C(OC(C)(C)C)=O)[CH2:6]1)(=[O:3])[CH3:2].C(OCC)(=O)C.Cl.[C:34]([OH:41])(=[O:40])/[CH:35]=[CH:36]/[C:37]([OH:39])=[O:38]>C(O)C>[C:34]([OH:41])(=[O:40])/[CH:35]=[CH:36]/[C:37]([OH:39])=[O:38].[Cl:19][C:14]1[CH:13]=[C:12]([C@@H:11]2[O:10][CH2:9][CH2:8][NH:7][CH2:6][C@H:5]2[NH:4][C:1](=[O:3])[CH3:2])[CH:17]=[CH:16][C:15]=1[Cl:18]
Reactant: CC(=O)N[C@@H]1CN(C(=O)OC(C)(C)C)CCO[C@H]1c1ccc(Cl)c(Cl)c1
Agent: Cl
Agent: O=C(O)/C=C/C(=O)O
Solvent: CCOC(C)=O
Solvent: CCO
Product: CC(=O)N[C@@H]1CNCCO[C@H]1c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 106.8 %

Procedure:
To tert-butyl (6R,7S)-6-(acetylamino)-7-(3,4-dichlorophenyl)-1,4-oxazepane-4-carboxylate (200 mg) was added 4.0 M hydrogen chloride-ethyl acetate solution (4 mL), and the mixture was stirred at room temperature for 1 hr. The residue obtained by concentration under reduced pressure was desalted by a solid phase extraction resin (column: PL StrastoSphere solid phase extraction resin (PL-HCO3 MP StratoSpheres™), 500 mg, StrastoSphere, mobile phase: methanol). To a solution of the residue obtained by concentration under reduced pressure in ethanol was added a solution of fumaric acid (33.7 mg) in ethanol. The mixture was concentrated under reduced pressure to give the title compound (130 mg).