Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([CH:12]([CH3:14])[CH3:13])=[CH:8][C:7]=2[C:15]2[C:16]3[N:23]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:22]([CH3:32])=[C:21]([C:33](O)=[O:34])[C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:3][CH2:2]1.[NH2:36][C@@H:37]1[CH2:42][CH2:41][C@H:40]([NH:43][C:44](=[O:50])[O:45][C:46]([CH3:49])([CH3:48])[CH3:47])[CH2:39][CH2:38]1>>[CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([CH:12]([CH3:13])[CH3:14])=[CH:8][C:7]=2[C:15]2[C:16]3[N:23]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:29])([CH3:30])[CH3:31])[C:22]([CH3:32])=[C:21]([C:33]([NH:36][C@@H:37]4[CH2:42][CH2:41][C@H:40]([NH:43][C:44](=[O:50])[O:45][C:46]([CH3:48])([CH3:47])[CH3:49])[CH2:39][CH2:38]4)=[O:34])[C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](N)CC1
Reactant: Cc1c(C(=O)O)c2ncnc(-c3cc(C(C)C)ccc3OCC3CC3)c2n1COCC[Si](C)(C)C
Product: Cc1c(C(=O)N[C@H]2CC[C@@H](NC(=O)OC(C)(C)C)CC2)c2ncnc(-c3cc(C(C)C)ccc3OCC3CC3)c2n1COCC[Si](C)(C)C

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-5-(propan-2-yl)phenyl]-6-methyl-5-{[2-(trimethylsilyl)ethoxy]methyl}-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (example D.c15) and commercially available tert-butyl cis-(4-amino-cyclohexyl)-carbamate the title compound is obtained as pale yellow viscous oil.
Reaction SMILES: [CH:1](=O)[CH3:2].[CH2:4]([O:6][C:7]([C:9]1[CH:10]=[N:11][N:12]([C:14]2[N:23]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:22](=[O:32])[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([NH2:33])[CH:20]=3)[N:15]=2)[CH:13]=1)=[O:8])[CH3:5].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(O)C.CCOC(C)=O>[CH2:4]([O:6][C:7]([C:9]1[CH:10]=[N:11][N:12]([C:14]2[N:23]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:22](=[O:32])[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([NH:33][CH2:1][CH3:2])[CH:20]=3)[N:15]=2)[CH:13]=1)=[O:8])[CH3:5]
Reactant: CC=O
Reactant: CCOC(=O)c1cnn(-c2nc3ccc(N)cc3c(=O)n2COCC[Si](C)(C)C)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCNc1ccc2nc(-n3cc(C(=O)OCC)cn3)n(COCC[Si](C)(C)C)c(=O)c2c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 33 %

Procedure:
Acetaldehyde (1 mL) was added to 1-[6-amino-4-oxo-3-(2-trimethylsilanyl-ethoxymethyl)-3,4-dihydro-quinazolin-2-yl]-1H-pyrazole-4-carboxylic acid ethyl ester (0.250 g, 0.582 mol) and 4 Å molecular sieves (0.35 g) in ethanol (1.9 g). The reaction mixture was stirred at room temperature for 18 h and was then filtered. Ethanol and acetaldehyde were removed under high vacuum. The residue was redissolved in DCE (1.5 mL) and sodium triacetoxyborohydride (0.308 g, 1.46 mmol) was added. The reaction mixture was stirred at room temperature for 6 d, then diluted with EtOAc (30 mL) and washed with saturated aqueous sodium bicarbonate (20 mL). The aqueous layer was extracted with EtOAc (30 mL) and the combined organic layers were washed with brine (20 mL), dried (MgSO4), and concentrated. The residue was purified via FCC (5-65% EtOAc/hexanes) to yield the titled compound (87.0 mg, 33% yield). MS (ESI/Cl): mass calcd. for C22H31N5O4Si, 457.2; m/z found, 458.2 [M+H]+.
Reaction SMILES: [CH2:1]([N:8]1[CH2:22][CH2:21][N:11]2[C:12]3[N:20]=[CH:19][CH:18]=[CH:17][C:13]=3[NH:14][CH2:15][CH2:16][CH:10]2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([CH2:30][C:31](Cl)=[O:32])=[CH:26][CH:25]=1.CO>C(Cl)Cl>[CH2:1]([N:8]1[CH2:22][CH2:21][N:11]2[C:12]3[N:20]=[CH:19][CH:18]=[CH:17][C:13]=3[N:14]([C:31](=[O:32])[CH2:30][C:27]3[CH:28]=[CH:29][C:24]([Cl:23])=[CH:25][CH:26]=3)[CH2:15][CH2:16][CH:10]2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1ccc(CN2CCN3c4ncccc4NCCC3C2)cc1
Reactant: O=C(Cl)Cc1ccc(Cl)cc1
Solvent: ClCCl
Solvent: CO
Product: O=C(Cc1ccc(Cl)cc1)N1CCC2CN(Cc3ccccc3)CCN2c2ncccc21
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
A solution of the product of Example 52 (135 mg, 0.367 mmol) in CH2Cl2 (3 mL) was added to 4-chlorophenylacetyl chloride (Aldrich, 0.058 mL, 0.38 mmol), and the resulting solution was stirred at room temperature for 45 minutes. Methanol (0.5 mL) was added and the mixture was stirred for 10 minutes and then concentrated under vacuum. The residue was crystallized from ethanol (4 mL) and water (0.2 mL) to provide the title compound as the HCl salt: 1H NMR (400 MHz, pyridine-d5) δ ppm 2.57-2.86 (m, 3H), 2.92-3.31 (m, 2H), 3.32-3.59 (m, 7H), 4.29-4.66 (m, 2H), 6.69-6.88 (m, 1H), 6.91-7.04 (m, 2H), 7.21 (d, J=8.2 Hz, 2H), 7.25 (d, J=7.3 Hz, 1H), 7.27-7.36 (m, J=7.3, 7.3 Hz, 3H), 7.37-7.44 (m, 2H), 8.23-8.33 (m, 1H), one proton obscured by solvent; MS (ESI) m/z 447/449 (M+H)+. Elemental analysis is calculated for C26H27N4OCl.HCl..0.4H2O: C, 63.65; H, 5.92; N, 11.42. Found: C, 63.72; H, 5.75; N, 11.26.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].C1C(=O)N([Br:17])C(=O)C1.O>CN(C=O)C>[NH2:1][C:2]1[CH:9]=[CH:8][C:7]([Br:17])=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: O=C1CCC(=O)N1Br
Reactant: N#Cc1ccccc1N
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1cc(Br)ccc1N
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-aminobenzonitrile (14.9 g, 100 mmol) was added a solution of NBS (17.8 g, 100 mmol) in DMF at rt. The mixture was stirred overnight at rt, then water (30 mL) was added and the mixture was extracted with Et2O (3×250 mL). The organic layer was washed with brine, dried over Na2SO4, concentrated and purified by CC to give compound P36a (19 g, 83%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1.[CH:12]([N:15](C(C)C)CC)(C)C.CN>C1COCC1.C(OCC)(=O)C>[Cl:1][C:2]1[N:7]=[C:6]([NH:15][CH3:12])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: O=[N+]([O-])c1cnc(Cl)nc1Cl
Agent: CN
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CNc1nc(Cl)ncc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 3 h
Yield: 89.7 %

Procedure:
To a solution of 2,4-dichloro-5-nitropyrimidine (5 g, 26 mmol) in THF (50 mL) was added diisopropylethylamine (3.36 g, 26 mmol) at −78° C., followed by the dropwise addition of methylamine (13 mL, 2 mol/L in methanol, 26 mmol). After the addition, the mixture was warmed to RT and stirred for 3 h. The reaction mixture was then diluted with ethyl acetate and washed with brine (50 mL*3). The organic layer was dried over sodium sulfate, filtered and concentrated to give the title compound (4.4 g, 100%) as a yellow solid. MS (ES+) C5H5ClN4O2 requires: 188, 190. found: 189, 191 [M+H]+.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH:18]=[CH:17][CH:16]=[CH:15]2)=[CH:10][C:9]=1[NH2:19])(C)(C)C.C(O[C:26](=[O:43])[CH2:27][C:28]([C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C:36]2[CH:41]=[CH:40][N:39]=[C:38]([CH3:42])[N:37]=2)[CH:31]=1)=O)(C)(C)C>>[CH3:42][C:38]1[N:37]=[C:36]([C:32]2[CH:31]=[C:30]([C:28]3[CH2:27][C:26](=[O:43])[NH:19][C:9]4[CH:10]=[C:11]([N:14]5[CH:18]=[CH:17][CH:16]=[CH:15]5)[CH:12]=[CH:13][C:8]=4[N:7]=3)[CH:35]=[CH:34][CH:33]=2)[CH:41]=[CH:40][N:39]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(-n2cccc2)cc1N
Reactant: Cc1nccc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)n1
Product: Cc1nccc(-c2cccc(C3=Nc4ccc(-n5cccc5)cc4NC(=O)C3)c2)n1

Procedure:
The title compound was prepared from (2-amino-4-pyrrol-1-yl-phenyl)-carbamic acid tert-butyl ester (Example J11) (137 mg, 0.5 mmol) and 3-[3-(2-methyl-pyrimidin-4-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K42) (187 mg, 0.6 mmol) according to the general procedure M and subsequent treatment of the crude product according to the general procedure N. Obtained as a light yellow solid (30 mg).
Reaction SMILES: [CH2:1]([N:4]([CH2:8][C:9]1[S:13][C:12]([S:14]([N:17]2[CH2:22][CH2:21][CH:20]([C:23](N(OC)C)=[O:24])[CH2:19][CH2:18]2)(=[O:16])=[O:15])=[CH:11][CH:10]=1)[CH2:5][CH:6]=[CH2:7])[CH:2]=[CH2:3].[CH2:29]([Li])[CH2:30][CH2:31][CH2:32][CH2:33][CH3:34].Cl.CCO>C1COCC1>[CH2:1]([N:4]([CH2:8][C:9]1[S:13][C:12]([S:14]([N:17]2[CH2:18][CH2:19][CH:20]([C:23](=[O:24])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[CH2:21][CH2:22]2)(=[O:16])=[O:15])=[CH:11][CH:10]=1)[CH2:5][CH:6]=[CH2:7])[CH:2]=[CH2:3]
Reactant: C=CCN(CC=C)Cc1ccc(S(=O)(=O)N2CCC(C(=O)N(C)OC)CC2)s1
Reactant: [Li]CCCCCC
Agent: Cl
Solvent: C1CCOC1
Solvent: CCO
Product: C=CCN(CC=C)Cc1ccc(S(=O)(=O)N2CCC(C(=O)CCCCCC)CC2)s1
Temperature: -20 °C
Reaction time: 3 h
Yield: 46.7 %

Procedure:
327b (376 mg, 0.88 mmol) was dissolved in anhydrous THF and cooled to −20° C. To this solution was added dropwise at −20° C. hexyllithium (2M in hexane) (2.46 mL, 6.2 mmol). The reaction was allowed to warm to rt. during 3 h and poured on 100 mL HCl/EtOH (5%). The aqueous phase was extracted with CH2Cl2 and the combined organic layers are washed with NaOH (2N) and brine, dried over MgSO4 and evaporated to dryness. The crude material was purified by flash chromatography on silica gel using cyclohexane/EtOAc 4:1 as eluent to obtain 186 mg (47%) of (327c) as a brownish oil: H1 NMR (CDCl3) δ 7.40 (d, J=3.6 Hz, 1H), 725 (d, J=3.6 1H), 5.95 (m, 2H), 5.50 (m, 4H), 4.32 (s, 2H), 3.70-3.50 (m, 6H), 2.50 (m, 2H), 2.32 (m, 3H), 1.85 (m, 2H), 1.68 (m, 2H), 1.46 (m, 2H), 0.130-1.12 (m, 6H), 0.80 (t, J=6.6 Hz, 3H), M/Z APCI: 453.2 (M+1)
Reaction SMILES: [F:1][C:2]1[C:3]([O:9][CH3:10])=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].Br.Br[CH:13]([C:15]1[CH:16]=[C:17]([C:32]([N:34]([CH3:36])[CH3:35])=[O:33])[CH:18]=[C:19]2[C:24]=1[O:23][C:22]([N:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1)=[CH:21][C:20]2=[O:31])[CH3:14]>>[F:1][C:2]1[C:3]([O:9][CH3:10])=[C:4]([NH:5][CH:13]([C:15]2[CH:16]=[C:17]([C:32]([N:34]([CH3:36])[CH3:35])=[O:33])[CH:18]=[C:19]3[C:24]=2[O:23][C:22]([N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)=[CH:21][C:20]3=[O:31])[CH3:14])[CH:6]=[CH:7][CH:8]=1
Reactant: COc1c(N)cccc1F
Reactant: CC(Br)c1cc(C(=O)N(C)C)cc2c(=O)cc(N3CCOCC3)oc12
Agent: Br
Product: COc1c(F)cccc1NC(C)c1cc(C(=O)N(C)C)cc2c(=O)cc(N3CCOCC3)oc12
Yield: 60.7 %

Procedure:
3-fluoro-2-methoxyaniline (115 mg, 0.82 mmol) was reacted with 8-(1-bromoethyl)-N,N-dimethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide hydrobromide (100 mg, 0.20 mmol) using an analogous procedure to the one described in Example 3.03 to give 8-(1-(3-fluoro-2-methoxyphenylamino)ethyl)-N,N-dimethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide (57 mg, 60%) as a white solid. Mass Spectrum: M+H+ 470. NMR Spectrum (DMSOd6): 1.59 (d, 3H), 2.70 (bs, 3H), 2.93 (bs, 3H), 3.50-3.63 (m, 4H), 3.71-3.79 (m, 4H), 3.83 (s, 3H), 5.02-5.11 (m, 1H), 5.60 (s, 1H), 5.95 (d, 1H), 6.11 (d, 1H), 6.39 (dd, 1H), 6.72 (ddd, 1H), 7.59 (d, 1H), 7.78 (d, 1H).
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]2[O:10][CH2:11][O:12][C:6]=2[CH:5]=1)=[O:3].C=CC1C=C[NH+]=CC=1.[Br-:21].[Br-].[Br-]>CO>[CH2:11]1[O:12][C:6]2[CH:5]=[C:4]([C:2]([CH2:1][Br:21])=[O:3])[CH:9]=[CH:8][C:7]=2[O:10]1
Reactant: CC(=O)c1ccc2c(c1)OCO2
Reactant: [Br-]
Agent: C=Cc1cc[nH+]cc1
Solvent: CO
Product: O=C(CBr)c1ccc2c(c1)OCO2
Yield: 37.8 %

Procedure:
To a solution of 2.5 g (15.23 mmol) of 3,4-methylenedioxy acetophenone in 200 mL of anhydrous methanol was added 61 mmol (20 g) of poly(4-vinylpyridinium tribromide), Aldrich Chemical Co., and allowed to reflux for 2.5 h. The solution was filtered and concentrated. 1-(2H-benzo[3,4-d]1,3-dioxolen-5-yl)-2-bromoethan-1-one (1.4 g, 38% yield) was obtained methylene chloride/hexanes as off-white crystals. 1H-NMR (DMSO-d6; 300 MHz) δ 8.2 (s, 1H), 8.07 (s, 1H), 7.61-7.64 (m,2H), 7.01-7.04 (dd, J=1.2 Hz and 7.1 Hz, 1H), 6.09 (s, 2H), 3.86 (s, 3H), 2.75 (s, 3H).
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]([C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)=[CH:9][CH:8]=1)([OH:6])[CH3:5].[C-:20]#[N:21].[Na+]>CS(C)=O>[C:20]([CH2:2][CH2:3][C:4]([C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)=[CH:9][CH:8]=1)([OH:6])[CH3:5])#[N:21]
Reactant: [C-]#N
Reactant: CC(O)(CCCl)c1ccc(-c2ccc(F)cc2)cc1
Agent: [Na+]
Solvent: CS(C)=O
Product: CC(O)(CCC#N)c1ccc(-c2ccc(F)cc2)cc1

Procedure:
A solution of 27.9 g. of 1-chloro-3-(4'-fluoro-4-biphenylyl)-butan-3-ol in 60 ml. of dimethylsulfoxide is added, at 80°, to a solution of 7.6 g. of NaCN in 100 ml. of dimethylsulfoxide. The mixture is warmed to 80°-90° for 6 hours, poured onto ice and worked up in the customary manner to give 1-cyano-3-(4'-fluoro-4-biphenylyl)-butan-3-ol, m.p. 118°-120°.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([O:15][C@H:16]1[CH2:20][CH2:19][N:18]([CH2:21][C:22]3C=CC=CC=3)[CH2:17]1)=[CH:10][CH:9]=2)=[O:5])[CH3:2].[C:28]([O-])([O-])=O.[K+].[K+].IC(C)C>[Pd].C(O)(=O)C>[CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([O:15][C@H:16]1[CH2:20][CH2:19][N:18]([CH:21]([CH3:22])[CH3:28])[CH2:17]1)=[CH:10][CH:9]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc2cc(O[C@H]3CCN(Cc4ccccc4)C3)ccc2[nH]1
Reactant: O=C([O-])[O-]
Agent: [Pd]
Agent: [K+]
Solvent: CC(=O)O
Solvent: CC(C)I
Product: CCOC(=O)c1cc2cc(O[C@H]3CCN(C(C)C)C3)ccc2[nH]1
Temperature: 50 °C
Reaction time: 16 h

Procedure:
A mixture of 18 g (49 mmol) 5-((S)-1-benzyl-pyrrolidin-3-yloxy)-1H-indole-2-carboxylic acid ethyl ester, 28.3 ml acetic acid and 2 g Pd/C 10% was hydrogenated with H2 at room temperature during 16 h. The mixture was filtered and the filtrate evaporated to dryness. The residue was taken up in 500 ml DMF and 34.1 g (247 mmol) K2CO3 and 42 g (247 mmol) 2-iodopropane was added and the mixture was stirred for 4 h at 50° C. After filtration and evaporation the residue was purified on silica eluting with a gradient formed from DCM/MeOH (2N NH3) 98/2 to 92/8 to yield after evaporation of the product fractions 60% of the title compound as light brown solid. MS (m/e): 317.3 (MH+, 100%).
Reaction SMILES: [C:1]([O:9]CC)(=[O:8])[CH2:2][C:3]([O:5]CC)=O.[Br:12][C:13]1[CH:19]=[CH:18][CH:17]=[CH:16][C:14]=1[NH2:15].C(=O)([O-])[O-].[Na+].[Na+].Cl>O.CO>[Br:12][C:13]1[CH:19]=[CH:18][CH:17]=[CH:16][C:14]=1[NH:15][C:3](=[O:5])[CH2:2][C:1]([OH:9])=[O:8]
Reactant: Nc1ccccc1Br
Reactant: CCOC(=O)CC(=O)OCC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: O=C(O)CC(=O)Nc1ccccc1Br
Temperature: 180 °C
Yield: 57.3 %

Procedure:
Diethyl malonate (101 mL, 0.989 mol) and 2-bromoaniline (50.g, 0.291 mol) were combined and heated at 180° C. for six hours. A Dean-Stark trap was used to collect the volatiles. The reaction was allowed to cool to ambient temperature overnight; a precipitate formed. The precipitate was isolated by filtration and combined with methanol (160 mL), water (800 mL), and solid sodium carbonate (105 g). The mixture was heated at reflux for two hours, allowed to cool to ambient temperature, and then cooled to 0° C. The mixture was adjusted to pH 2 with the addition of 3 N hydrochloric acid; a white precipitate formed. The precipitate was isolated by filtration, washed with water, and dried overnight on the filter funnel to provide 43 g of N-(2-bromophenyl)malonamic acid as a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH:10]=[CH:9][N:8]([C@@H:11]3[O:26][C@H:25]([CH2:27][O:28][CH2:29][C:30]4[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][C:31]=4[Cl:37])[C@@H:14]([O:15][CH2:16][C:17]4[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=4[Cl:24])[C@@:12]3([CH:38]=C)[OH:13])[C:4]=2[N:5]=[CH:6][N:7]=1.C[N+]1([O-])CC[O:44]CC1.[BH4-].[Na+]>O1CCOCC1.CCOC(C)=O.[Os](=O)(=O)(=O)=O>[Cl:1][C:2]1[C:3]2[CH:10]=[CH:9][N:8]([C@@H:11]3[O:26][C@H:25]([CH2:27][O:28][CH2:29][C:30]4[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][C:31]=4[Cl:37])[C@@H:14]([O:15][CH2:16][C:17]4[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=4[Cl:24])[C@@:12]3([CH2:38][OH:44])[OH:13])[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: C=C[C@@]1(O)[C@H](OCc2ccc(Cl)cc2Cl)[C@@H](COCc2ccc(Cl)cc2Cl)O[C@H]1n1ccc2c(Cl)ncnc21
Reactant: C[N+]1([O-])CCOCC1
Agent: O=[Os](=O)(=O)=O
Agent: [BH4-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: OC[C@@]1(O)[C@H](OCc2ccc(Cl)cc2Cl)[C@@H](COCc2ccc(Cl)cc2Cl)O[C@H]1n1ccc2c(Cl)ncnc21
Reaction time: 14 h
Yield: 52.1 %

Procedure:
To a solution of the compound from Example 137, Step B (300 mg, 0.48 mmol) in 1,4-dioxane (5 mL) were added N-methylmorpholine-N-oxide (300 mg, 2.56 mmol) and osmium tetroxide (4% solution in water, 0.3 mL). The mixture was stirred in the dark for 14 h. The precipitate was removed by filtration through a celite plug, diluted with water (3×), and extracted with EtOAc. The EtOAc layer was dried over Na2SO4 and concentrated in vacuo. The oily residue was taken up in dichloromethane (5 mL) and stirred over NaIO4 on silica gel (3 g, 10% NaIO4) for 12 h. The silica gel was removed by filtration and the residue was evaporated and taken up in absolute ethanol (5 mL). The solution was cooled in an ice bath and sodium borohydride (300 mg, 8 mmol) was added in small portions. The resulting mixture was stirred at room temperature for 4 h and then diluted with EtOAc. The organic layer was washed with water (2×20 mL), brine (20 mL) and dried over Na2SO4. The solvent was evaporated and the residue purified by flash chromatography (SiO2, 2:1 hexanes/EtOAc) to give the title compound (160 mg, 0.25 mmol) as white flakes.
Reaction SMILES: [Cl:1][CH:2]=[CH:3][NH:4][C:5](=[O:14])[C:6]1[C:11]([F:12])=[CH:10][CH:9]=[CH:8][C:7]=1[F:13].S(=O)(=O)(O)O.[CH3:20][N:21]([CH3:37])[C:22](=[O:36])[S:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[CH:26][CH:25]=1.O>ClCCl>[CH3:20][N:21]([CH3:37])[C:22](=[O:36])[S:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[CH:31]=[CH:32][C:33]([CH:3]([NH:4][C:5](=[O:14])[C:6]3[C:7]([F:13])=[CH:8][CH:9]=[CH:10][C:11]=3[F:12])[CH2:2][Cl:1])=[CH:34][CH:35]=2)=[CH:26][CH:25]=1
Reactant: O=C(NC=CCl)c1c(F)cccc1F
Reactant: CN(C)C(=O)Sc1ccc(-c2ccccc2)cc1
Agent: O=S(=O)(O)O
Solvent: O
Solvent: ClCCl
Product: CN(C)C(=O)Sc1ccc(-c2ccc(C(CCl)NC(=O)c3c(F)cccc3F)cc2)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 82.3 %

Procedure:
A solution of 1 g (4.59 mmol) N-(chloroethenyl)-2,6-difluorobenzamide in 2 mL of dichloromethane was added to 4 mL of concentrated sulfuric acid at 0° C. A portion of 1 g (3.89 mmol) of S-[1,1'-biphenyl]-4-yl dimethylcarbamothioate was added to the mixture and the mixture was stirred at 0° C. for 2 h. The mixture was stored in the refrigerator overnight. The mixture was poured into water (100 mL) and the mixture was filtered. The solid was washed with water (100 mL) and was dried overnight in vacuo at 70° C. to give the crude product 1.52 g (84% yield) as solid.
Reaction SMILES: O[C:2]1[CH:3]=[C:4]([NH:8][C:9]([N:11]([O:13][CH3:14])[CH3:12])=[O:10])[CH:5]=[CH:6][CH:7]=1.CN(C)C=O.[H-].[Na+].[CH3:22][CH:23]1[CH2:27][C:26]2[CH:28]=[C:29]([CH2:32][CH2:33][O:34]S(C3C=CC(C)=CC=3)(=O)=O)[CH:30]=[CH:31][C:25]=2[O:24]1>O>[CH3:22][CH:23]1[CH2:27][C:26]2[CH:28]=[C:29]([CH2:32][CH2:33][O:34][C:5]3[CH:6]=[CH:7][CH:2]=[CH:3][C:4]=3[NH:8][C:9]([N:11]([O:13][CH3:14])[CH3:12])=[O:10])[CH:30]=[CH:31][C:25]=2[O:24]1
Reactant: CON(C)C(=O)Nc1cccc(O)c1
Reactant: Cc1ccc(S(=O)(=O)OCCc2ccc3c(c2)CC(C)O3)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CON(C)C(=O)Nc1ccccc1OCCc1ccc2c(c1)CC(C)O2
Reaction time: 0.5 h
Yield: 93.3 %

Procedure:
2.0 g of 1-(3-hydroxyphenyl)-3-methoxy-3-methylurea was dissolved into 20 ml of dried N,N-dimethylformamide, and 0.4 g of 60% sodium hydride was added thereto. After the mixture was stirred for 30 minutes, 3.3 g of 2-(2,3-dihydro-2-methyl-5-benzofuranyl)ethyl-p-toluene sulfonate was added dropwise thereto under cooling with ice. After the mixture was stirred at room temperature for 5 hours, it was poured into water and extracted with ethyl acetate. After the organic layer was washed with water, it was dried over anhydrous magnesium sulfate and ethyl acetate was distilled off. The residue was subjected to silica gel column chromatography using ethyl acetate/n-hexane (1/2) as a developer to obtain 3.3 g of Compound No. 49 shown in Table 3.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([N:37]2[CH2:40][CH:39]([N:41]([CH3:43])[CH3:42])[CH2:38]2)[C:9]2[CH:10]=[C:11]([C:27]3[CH:32]=[CH:31][N:30]=[C:29]([NH:33][C:34](=[O:36])[CH3:35])[CH:28]=3)[S:12][C:13]=2[C:14]2[N:18]=[CH:17][N:16](COCC[Si](C)(C)C)[N:15]=2)=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([N:37]2[CH2:38][CH:39]([N:41]([CH3:42])[CH3:43])[CH2:40]2)[C:9]2[CH:10]=[C:11]([C:27]3[CH:32]=[CH:31][N:30]=[C:29]([NH:33][C:34](=[O:36])[CH3:35])[CH:28]=3)[S:12][C:13]=2[C:14]2[NH:18][CH:17]=[N:16][N:15]=2)=[CH:6][CH:7]=1
Reactant: CC(=O)Nc1cc(-c2cc(C(c3ccc(Cl)cc3)N3CC(N(C)C)C3)c(-c3ncn(COCC[Si](C)(C)C)n3)s2)ccn1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)Nc1cc(-c2cc(C(c3ccc(Cl)cc3)N3CC(N(C)C)C3)c(-c3nnc[nH]3)s2)ccn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.6 %

Procedure:
N-{4-[4-{(4-chlorophenyl)[3-(dimethylamino)azetidin-1-yl]methyl}-5-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-1,2,4-triazol-3-yl)-2-thienyl]pyridin-2-yl}acetamide (60 mg, 0.094 mmol) was dissolved in dichloromethane (1.19 mL) and trifluoroacetic acid (0.30 mL, 3.85 mmol) was added. The mixture was stirred at room temperature overnight. The mixture was concentrated in vacuo and distributed between EtOAc and saturated NaHCO3 solution. The aqueous layer was extracted with EtOAc twice. The combined organic layers were dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography (SiO2, elution with methanol in dichloromethane, 0-20% gradient) to afford the title compound as a white solid (34.2 mg, 71.6%). LCMS: (AA) ES+ 508, 510; 1H NMR (400 MHz, d4-methanol): 8.51 (s, 1H), 8.39 (s, 1H), 8.24 (br s, 1H), 7.78 (s, 1H), 7.59 (d, J=8.4 Hz, 2H), 7.32 (br s, 1H), 7.26 (d, J=8.4 Hz, 2H), 5.71 (s, 1H), 3.45-3.36 (m, 2H), 3.00-2.83 (m, 3H), 2.19 (s, 3H), 2.06 (s, 6H).
Reaction SMILES: [NH2:1][C:2]1[CH:31]=[CH:30][C:5]2[CH2:6][CH2:7][CH2:8][CH:9]([N:11]([CH2:19][C@H:20]([OH:29])[CH2:21][O:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:10][C:4]=2[CH:3]=1.Cl[C:33]([O:35][CH3:36])=[O:34].N1C=CC=CC=1.C(=O)([O-])O.[Na+]>CN(C)C1C=CN=CC=1.ClCCl>[CH3:36][O:35][C:33]([NH:1][C:2]1[CH:31]=[CH:30][C:5]2[CH2:6][CH2:7][CH2:8][CH:9]([N:11]([CH2:19][C@H:20]([OH:29])[CH2:21][O:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:10][C:4]=2[CH:3]=1)=[O:34]
Reactant: COC(=O)Cl
Reactant: Nc1ccc2c(c1)CC(N(Cc1ccccc1)C[C@H](O)COc1ccccc1)CCC2
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)Nc1ccc2c(c1)CC(N(Cc1ccccc1)C[C@H](O)COc1ccccc1)CCC2

Procedure:
Under nitrogen, a solution of (2S)-1-(N-(3-amino-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)-N-benzylamino]-3-phenoxy-2-propanol (150 mg), methyl chloroformate (29 μl), pyridine (25 μl) and catalytic amounts of 4-dimethylaminopyridine in dichloromethane (3 ml) was stirred at room temperature for 1.5 hours. The resulting mixture was poured into saturated aqueous sodium hydrogencarbonate and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and evaporated in vacuo. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate=3:1) to give (2S)-1-[N-(3-methoxycarbonylamino-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)-N-benzylamino]-3-phenoxy-2-propanol (158 mg).