Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[CH3:15][NH2:16]>O1CCCC1>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:13][CH2:12][C@H:11]([NH:16][CH3:15])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: CN
Reactant: O=C1CCC(c2ccc(O)cc2)CC1
Solvent: C1CCOC1
Product: CN[C@H]1CC[C@H](c2ccc(O)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 4-(4-hydroxyphenyl)cyclohexanone (3 g) in tetrahydrofuran (20 mL) and a solution of methylamine in tetrahydrofuran (7.9 mL, 2 M) is stirred overnight at room temperature, concentrated under reduced pressure, dissolved in a mixture of dichloromethane and methanol (30 mL, 1/1) and cooled at a temperature close to 0° C. Sodium borohydride (822 mg) is added portionwise and the mixture is stirred at room temperature for one hour. The precipitate is filtered and washed with diethyl oxide to give 1.1 g of trans-4-(4-hydroxyphenyl)-N-methylcyclohexanamine used without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][NH:5][CH:6]=1.I[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.N[C@@H]1CCCC[C@H]1N.C(=O)([O-])[O-].[K+].[K+].N#N>CCOC(C)=O.[Cu](I)I.O1CCOCC1>[Br:1][C:2]1[CH:3]=[N:4][N:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=1
Reactant: Ic1ccccc1
Reactant: Brc1cn[nH]c1
Agent: I[Cu]I
Agent: N#N
Agent: N[C@@H]1CCCC[C@H]1N
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: Brc1cnn(-c2ccccc2)c1
Temperature: 25 °C

Procedure:
A sealable tube was charged with 4-bromopyrazole (4.000 g, 27.2 mmol), 1-iodobenzene (3.64 ml, 32.7 mmol), (+/−)-trans-1,2-diaminocyclohexane (0.654 ml, 5.44 mmol), Copper iodide (I) (0.518 g, 2.72 mmol), potassium carbonate (8.28 g, 59.9 mmol) and 13 mL dioxane added. The mixture was blanketed with N2, the vessel sealed and heated to 100 C for 16 h. The mixture was allowed to cool to rt, diluted with EtOAc, washed with water, and an emulsion formed. The organic layer separated and the aqueous emulsion mixture was filter through a pad of celite and rinsed with EtOAc, and sat. NaHCO3. The combined organic layers were dried over Na2SO4, filtered and evaporate. The mixture was purified via flash chromatography using a 0% to 100% CH2Cl2 in hexanes gradient. The title compound was collected as a yellow solid (3.18 g)
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[CH:8]=[C:9]([C:13]3[N:18]=[CH:17][C:16]([C:19]4[CH:20]=[N:21][NH:22][CH:23]=4)=[CH:15][N:14]=3)[CH:10]=[CH:11][CH:12]=2)[CH:4]=[N:3]1.[H-].[Na+].Cl[CH2:27][CH2:28][CH2:29][O:30][CH3:31]>CN(C=O)C>[CH3:31][O:30][CH2:29][CH2:28][CH2:27][N:21]1[CH:20]=[C:19]([C:16]2[CH:17]=[N:18][C:13]([C:9]3[CH:10]=[CH:11][CH:12]=[C:7]([C:5]4[CH:4]=[N:3][N:2]([CH3:1])[CH:6]=4)[CH:8]=3)=[N:14][CH:15]=2)[CH:23]=[N:22]1
Reactant: COCCCCl
Reactant: Cn1cc(-c2cccc(-c3ncc(-c4cn[nH]c4)cn3)c2)cn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCCCn1cc(-c2cnc(-c3cccc(-c4cnn(C)c4)c3)nc2)cn1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of 2-[3-(1-methyl-1H-pyrazol-4-yl)phenyl]-5-(1H-pyrazol-4-yl)pyrimidine (example 3, 130 mg; 0.43 mmol; 1.0 eq.) in dry DMF (1 mL) was added over a suspension of NaH (60% in oil, 21 mg; 0.86 mmol; 2.0 eq.) in dry DMF (1 mL) maintained at 0° C. under nitrogen atmosphere. The resulting mixture was stirred for one hour at 0° C. then heated at 100° C. O/N after the addition of a solution of 1-chloro-3-methoxypropane (47 mg; 0.43 mmol; 1.0 eq.) in DMF (2 mL). Reaction mixture was then cooled down to RT, quenched with water and extracted with EtOAc (three times). Combined organic phases were washed with water, brine, dried over magnesium sulfate, filtered and concentrated. The resulting solid was dried O/N at 60° C. under reduced pressure to give the title compound a beige powder (165 mg; 75%). 1H NMR (300 MHz, DMSO-d6) δ 9.16 (s, 2H), 8.58-8.49 (m, 1H), 8.46 (s, 1H), 8.30-8.17 (m, 2H), 8.17-8.11 (m, 1H), 7.96-7.89 (m, 1H), 7.75-7.68 (m, 1H), 7.51 (t, J=7.8 Hz, 1H), 4.22 (t, J=7.0 Hz, 2H), 3.90 (s, 3H), 3.39-3.30 (m, 2H), 3.25 (s, 3H), 2.15-1.97 (m, 2H). HPLC (Condition A): Rt 3.34 min (purity 97.1%). MS (ESI+): 375.5.
Reaction SMILES: [N:1]1[C:10]2[CH:9]([NH2:11])[CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH:12]([C:14]1[CH:19]=[CH:18][C:17]([NH:20][S:21]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=2)(=[O:23])=[O:22])=[CH:16][CH:15]=1)=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[N:1]1[C:10]2[CH:9]([NH:11][CH2:12][C:14]3[CH:15]=[CH:16][C:17]([NH:20][S:21]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=4)(=[O:23])=[O:22])=[CH:18][CH:19]=3)[CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: NC1CCCc2cccnc21
Reactant: O=Cc1ccc(NS(=O)(=O)c2ccccn2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: O=S(=O)(Nc1ccc(CNC2CCCc3cccnc32)cc1)c1ccccn1
Yield: 66.7 %

Procedure:
Using General Procedure B: Reaction of 5,6,7,8-tetrahydro-quinolin-8-ylamine (68 mg, 0.46 mmol), pyridine-2-sulfonic acid (4-formyl-phenyl)-amide (120 mg, 0.46 mmol), and NaBH(OAc)3 (291 mg, 1.37 mmol) for 1 h at room temperature followed by purification of the crude product by column chromatography on silica gel (CH2Cl2/MeOH/NH4OH 98:1:1) gave the title compound (121 mg, 67%) as a white foam.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:16]3[C:15]([NH2:17])=[N:14][CH:13]=[N:12][C:11]=3[S:10][C:9]=2[CH3:18])[CH:5]=[CH:6][CH:7]=1.[N+:19]([O-])([OH:21])=[O:20].C([O-])([O-])=O.[Na+].[Na+]>OS(O)(=O)=O>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:16]3[C:15]([NH2:17])=[N:14][CH:13]=[N:12][C:11]=3[S:10][C:9]=2[CH3:18])[CH:5]=[CH:6][C:7]=1[N+:19]([O-:21])=[O:20]
Reactant: Cc1sc2ncnc(N)c2c1-c1cccc(Cl)c1
Reactant: O=[N+]([O-])O
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: Cc1sc2ncnc(N)c2c1-c1ccc([N+](=O)[O-])c(Cl)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 93 %

Procedure:
A 0° C. suspension of Example 143A (2.13 g, 7.74 mmol) in concentrated H2SO4 (15 mL) was treated dropwise over 3 minutes with a solution of fuming nitric acid (0.38 mL) in concentrated H2SO4 (5 mL). The mixture was stirred for 30 minutes while warming to room temperature, poured onto ice, adjusted to pH 7 with solid Na2CO3, and extracted with ethyl acetate. The extract was dried (MgSO4), filtered, and concentrated to provide 2.31 g (93% yield) of the desired product. MS(ESI(+)) m/e 321 (M+H)+.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:27]=[CH:28][C:29]=1[F:30])[CH2:5][N:6]1[CH2:15][CH2:14][C:13]2[C:8](=[C:9]([OH:25])[C:10](=[O:24])[N:11]([CH:21]([CH3:23])[CH3:22])[C:12]=2[C:16]([N:18]([CH3:20])[CH3:19])=[O:17])[C:7]1=[O:26].[H][H]>[Pd].CO>[F:30][C:29]1[CH:28]=[CH:27][C:4]([CH2:5][N:6]2[CH2:15][CH2:14][C:13]3[C:8](=[C:9]([OH:25])[C:10](=[O:24])[N:11]([CH:21]([CH3:22])[CH3:23])[C:12]=3[C:16]([N:18]([CH3:20])[CH3:19])=[O:17])[C:7]2=[O:26])=[CH:3][CH:2]=1
Reactant: CC(C)n1c(C(=O)N(C)C)c2c(c(O)c1=O)C(=O)N(Cc1ccc(F)c(Cl)c1)CC2
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CC(C)n1c(C(=O)N(C)C)c2c(c(O)c1=O)C(=O)N(Cc1ccc(F)cc1)CC2

Procedure:
A mixture of 6-(3-chloro-4-fluorobenzyl)-4-hydroxy-N,N-dimethyl-2-isopropyl-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxamide (95 mg, 0.22 mmol; Example 13) and 10% palladium on charcoal (0.11 g) in methanol (5 mL) was stirred under a balloon of hydrogen gas at room temperature overnight. The reaction mixture was filtered, and the filtrate concentrated under vacuum. The residue was subjected to preparative HPLC purification on C-18 reverse stationary phase column eluting with a gradient of water—acetonitrile in the presence of 0.1% trifluoroacetic acid. Collection and lyophilization of appropriate fractions provided the titled compound.
Reaction SMILES: [Si:1]([O:18][CH:19]1[CH2:22][N:21]([C:23]2[S:24][CH:25]=[C:26]([C:28](OCC)=[O:29])[N:27]=2)[CH2:20]1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:33][N:34]1[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1.C[Al](C)C.C(O)(=O)C.C(OCC)(=O)C>C1(C)C=CC=CC=1>[Si:1]([O:18][CH:19]1[CH2:22][N:21]([C:23]2[S:24][CH:25]=[C:26]([C:28]([N:37]3[CH2:38][CH2:39][N:34]([CH3:33])[CH2:35][CH2:36]3)=[O:29])[N:27]=2)[CH2:20]1)([C:14]([CH3:15])([CH3:17])[CH3:16])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1csc(N2CC(O[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)C2)n1
Reactant: CN1CCNCC1
Agent: C[Al](C)C
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: CN1CCN(C(=O)c2csc(N3CC(O[Si](c4ccccc4)(c4ccccc4)C(C)(C)C)C3)n2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 85 %

Procedure:
To a solution of 3-t-butyldiphenylsilyloxy-1-(4-ethoxycarbonyl-1,3-thiazol-2-yl)azetidine (1.00 g, 2.14 mmol) (obtained as described in Reference Example 2(1)) in toluene (50 ml) was added a solution of 0.67M 1-methylpiperazine-trimethylaluminium in toluene (7.40 ml) at room temperature under an atmosphere of nitrogen. The mixture was heated under reflux for 3 hours. After checking the completion of the reaction, 10% aqueous acetic acid solution (50 ml) and ethyl acetate (100 ml) were added to the reaction mixture in an ice bath, and the resulting mixture was stirred at room temperature for 2 hours. After adding ethyl acetate thereto, the reaction mixture was partitioned between ethyl acetate and water. The obtained organic layer was washed successively with saturated aqueous sodium hydrogencarbonate solution and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using ethyl acetate:methanol (10:1) as the eluant to afford 3-t-butyldiphenylsilyloxy-1-[4-(4-methylpiperazine-1-carbonyl)-1,3-thiazol-2-yl]azetidine (941 mg, yield 85%) as a pale brown solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:9]=[C:8]([C:10](=[N:12]OC)[CH3:11])[S:7][C:6]=2[CH:15]=1.[BH4-].[Na+].B(F)(F)F.Cl>C(COC)OC>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:9]=[C:8]([CH:10]([NH2:12])[CH3:11])[S:7][C:6]=2[CH:15]=1
Reactant: CON=C(C)c1cc2ccc(Cl)cc2s1
Agent: Cl
Agent: FB(F)F
Agent: [BH4-]
Solvent: COCCOC
Product: CC(N)c1cc2ccc(Cl)cc2s1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 14.7 %

Procedure:
Subsequently, 2.7 g of the crude 6-chloro-2-(1-methoxyiminoethyl)benzo[b]thiophene obtained was dissolved in 10 ml of dimethoxyethane, and the resultant solution was added dropwise at room temperature to a suspension of 0.85 g of sodium borohydride in 20 ml of dimethoxyethane. After agitating for 5 minutes at the same temperature, a solution containing 4.26 g of a boron trifluoride.diethyl ether complex in 5 ml of dimethoxyethane was then added dropwise at room temperature. After stirring for 30 minutes at the same temperature, the mixture was stirred for an additional 2 hours under reflux. The mixture was then allowed to cool to room temperature, after which 10% hydrochloric acid was added, adjusting the mixture to a pH of 3-4. The dimethoxyethane layer was concentrated and combined with the water layer, and the pH was raised to 7-8 using sodium carbonate. Extraction was then performed using dichloromethane, and the dichloromethane layer was then washed with water, dried over anhydrous magnesium sulfate, filtered through FLORISIL®, and concentrated to yield 0.35 g of the desired product, a transparent viscous fluid (refractive index nD20 =1.5973).
Reaction SMILES: [F:1][C:2]([F:30])([O:7][C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH:18]=[N:17][C:16]([C:19]3[CH:29]=[CH:28][C:22](C(N=[N+]=[N-])=O)=[CH:21][CH:20]=3)=[N:15]2)=[CH:10][CH:9]=1)[C:3]([F:6])([F:5])[F:4].C1(C)C=CC=CC=1.[N-:38]=[C:39]=[O:40]>ClCCl>[N:38]([C:22]1[CH:28]=[CH:29][C:19]([C:16]2[N:17]=[CH:18][N:14]([C:11]3[CH:12]=[CH:13][C:8]([O:7][C:2]([F:30])([F:1])[C:3]([F:4])([F:5])[F:6])=[CH:9][CH:10]=3)[N:15]=2)=[CH:20][CH:21]=1)=[C:39]=[O:40]
Reactant: [N-]=C=O
Reactant: [N-]=[N+]=NC(=O)c1ccc(-c2ncn(-c3ccc(OC(F)(F)C(F)(F)F)cc3)n2)cc1
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: O=C=Nc1ccc(-c2ncn(-c3ccc(OC(F)(F)C(F)(F)F)cc3)n2)cc1
Temperature: 100 °C
Reaction time: 1 h

Procedure:
A 250 mL, three-neck flask, fitted with magnetic stirring, air condenser, temperature probe and nitrogen inlet, was charged with 4-(1-(4-(perfluoroethoxy)-phenyl)-1H-1,2,4-triazol-3-yl)benzoyl azide (5.00 g, 11.2 mmol) and toluene (100 mL). The brown solution was heated to 100° C. slowly and allowed to stir for 1 hour. Analysis of crude reaction mixture by LCMS shows the desired isocyanate. The reaction was cooled to 25° C. and the solvent removed by rotary evaporation to give a solid. The solid was dissolved in dichloromethane and the solution filtered to remove a small amount of a black insoluble material. The light-brown filtrate was rotary evaporated to yield 4.6 g of a tan solid. The solid was taken up in 30 mL of methyl tert-butyl ether, heated to effect a slightly turbid solution and filtered hot. The filtrate was re-heated to effect solution again and heptane (about 10-15 mL) was slowly added. The solution was placed on a rotary evaporator and the solvent was slowly removed under reduced pressure. When the first sign of solid was noted, the vacuum was broken and the mixture was allowed to slowly rotate at 40° C. to effect precipitation of solid. The solid was collected by vacuum filtration to give 3.4 g (77% yield) of a light tan solid, mp=119-121° C. 1H NMR (600 MHz, DMSO-d6) δ 9.41 (s, 1H), 8.10-8.05 (m, 4H), 7.60 (d, J=8.7 Hz, 2H), 7.38 (dd, J=8.3, 1.6 Hz, 2H). 13C NMR (151 MHz, DMSO) δ 161.77, 146.66, 144.37, 136.23, 134.45, 128.26, 127.78, 125.91, 124.93, 123.57, 121.59.
Reaction SMILES: [CH:1]([NH:4][C:5]1[C:14]2[C:9](=[CH:10][C:11]([OH:17])=[C:12]([O:15][CH3:16])[CH:13]=2)[N:8]=[CH:7][N:6]=1)([CH3:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1CCN(C(/N=N/C(N2CCCCC2)=O)=O)CC1.[CH3:55][S:56][CH2:57][CH2:58][CH2:59][CH2:60]O>C(Cl)Cl.O>[CH:1]([NH:4][C:5]1[C:14]2[C:9](=[CH:10][C:11]([O:17][CH2:60][CH2:59][CH2:58][CH2:57][S:56][CH3:55])=[C:12]([O:15][CH3:16])[CH:13]=2)[N:8]=[CH:7][N:6]=1)([CH3:3])[CH3:2]
Reactant: COc1cc2c(NC(C)C)ncnc2cc1O
Reactant: CSCCCCO
Agent: O=C(/N=N/C(=O)N1CCCCC1)N1CCCCC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: ClCCl
Product: COc1cc2c(NC(C)C)ncnc2cc1OCCCCSC
Temperature: 25 °C
Reaction time: 20 h
Yield: 43 %

Procedure:
4-(Isopropylamino)-6-methoxyquinazolin-7-ol (380 mg, 1.63 mmol) is dissolved in methylene chloride (10 ml) under an argon atmosphere, treated with triphenylphosphine (641 mg, 2.44 mmol), azodicarboxylic acid dipiperidide (617 mg, 2.44 mmol) and 4-(methylthio)butan-1-ol (235 mg, 1.96 mmol) and stirred at room temperature for 20 hours. The batch is diluted with methylene chloride and water, and the organic phase is separated off and concentrated. The desired product is obtained after chromatography by means of preparative HPLC in 43% yield (258 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[OH:12])[O:8][CH:7]=[C:6]([C:13]1[CH:24]=[CH:23][C:16]([O:17][CH2:18][CH2:19][CH2:20][C:21]#[N:22])=[C:15]([O:25][CH2:26][CH2:27][CH2:28][C:29]#[N:30])[CH:14]=1)[C:5]2=O.O.[NH2:33][NH2:34]>>[Cl:1][C:2]1[C:11]([OH:12])=[CH:10][C:9]([OH:8])=[C:4]([C:5]2[C:6]([C:13]3[CH:24]=[CH:23][C:16]([O:17][CH2:18][CH2:19][CH2:20][C:21]#[N:22])=[C:15]([O:25][CH2:26][CH2:27][CH2:28][C:29]#[N:30])[CH:14]=3)=[CH:7][NH:34][N:33]=2)[CH:3]=1
Reactant: NN
Reactant: N#CCCCOc1ccc(-c2coc3cc(O)c(Cl)cc3c2=O)cc1OCCCC#N
Solvent: O
Product: N#CCCCOc1ccc(-c2c[nH]nc2-c2cc(Cl)c(O)cc2O)cc1OCCCC#N
Yield: 90.1 %

Procedure:
This compound was synthesised in the same manner as described above. 4-[4-(6-Chloro-7-hydroxy-4-oxo-4H-chromen-3-yl)-2-(3-cyano-propoxy)-phenoxy]-butyronitrile (0.12 g, 0.27 mmol), Hydrazine hydrate (5 ml). The precipitate formed on quenching was filtered to give 4-[4-[3-(5-Chloro-2,4-dihydroxy-phenyl)-1H-pyrazol-4-yl]-2-(3-cyano-propoxy)-phenoxy]-butyronitrile as a white solid (0.11 g, 90.1%); Rf 0.6 ethyl acetate/hexane (70/30)].
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:14](=[O:15])[CH2:13][C:12](=[O:16])[NH:11][C:10]3[C:17]4[C:22]([CH:23]=[CH:24][C:9]2=3)=[CH:21][CH:20]=[CH:19][CH:18]=4)=[CH:4][CH:3]=1.[CH3:25][C:26]1[C:34]([CH3:35])=[CH:33][CH:32]=[CH:31][C:27]=1[C:28](Cl)=[O:29].C(NC1C=CC(N2C(=O)CC(=O)NC3C4C(C=CC2=3)=CC=CC=4)=CC=1)(=O)C1C=CC=CC=1>>[CH3:25][C:26]1[C:34]([CH3:35])=[CH:33][CH:32]=[CH:31][C:27]=1[C:28]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:14](=[O:15])[CH2:13][C:12](=[O:16])[NH:11][C:10]3[C:17]4[C:22]([CH:23]=[CH:24][C:9]2=3)=[CH:21][CH:20]=[CH:19][CH:18]=4)=[CH:4][CH:3]=1)=[O:29]
Reactant: Nc1ccc(N2C(=O)CC(=O)Nc3c2ccc2ccccc32)cc1
Reactant: Cc1cccc(C(=O)Cl)c1C
Agent: O=C1CC(=O)N(c2ccc(NC(=O)c3ccccc3)cc2)c2ccc3ccccc3c2N1
Product: Cc1cccc(C(=O)Nc2ccc(N3C(=O)CC(=O)Nc4c3ccc3ccccc43)cc2)c1C
Yield: 10.5 %

Procedure:
By using 5-(4-aminophenyl)-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione (30 mg, 0.095 mmol) obtained in Example 1, (3), and 2,3-dimethylbenzoyl chloride (0.143 mmol), the title compound (4.5 mg, yield 11%) was obtained in the same manner as that of Example 1, (4).
Reaction SMILES: [CH3:1][O:2][CH2:3][C@H:4]1[CH2:8][CH2:7][CH2:6][N:5]1[S:9]([C:12]1[CH:20]=[CH:19][C:18]2[N:17]3[CH2:21][C:22]([CH3:26])([CH3:25])[CH2:23][N:24]=[C:16]3[C:15]3(OCCC[O:27]3)[C:14]=2[CH:13]=1)(=[O:11])=[O:10]>OS(O)(=O)=O>[CH3:1][O:2][CH2:3][C@H:4]1[CH2:8][CH2:7][CH2:6][N:5]1[S:9]([C:12]1[CH:20]=[CH:19][C:18]2[N:17]3[CH2:21][C:22]([CH3:25])([CH3:26])[CH2:23][N:24]=[C:16]3[C:15](=[O:27])[C:14]=2[CH:13]=1)(=[O:11])=[O:10]
Reactant: COC[C@H]1CCCN1S(=O)(=O)c1ccc2c(c1)C1(OCCCO1)C1=NCC(C)(C)CN12
Agent: O=S(=O)(O)O
Product: COC[C@H]1CCCN1S(=O)(=O)c1ccc2c(c1)C(=O)C1=NCC(C)(C)CN12
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.3 %

Procedure:
8′-{[(2R)-2-(Methoxymethyl)pyrrolidin-1-yl]sulfonyl}-3′,3′-dimethyl-3′,4′-dihydro-2′H-spiro[1,3-dioxane-2,10′pyrimido[1,2-a]indole] (0.765 g, 1.70 mmol) was added portion-wise to cold concentrated H2SO4 (10 mL) over a period of 0.5 hr. with cooling in an ice bath. The bath was removed and the reaction stirred at room temp for 1 hr. The reaction mixture was gradually added to ice over a period of 15 min. and was basified to pH 11.1 with concentrated NH4OH keeping the temperature cold by the addition of ice and an external ice bath. The reaction was filtered and the collected solid was dissolved in CH2Cl2, dried over Na2SO4 and concentrated to give the title compound as a bright yellow solid (0.601 g, 90% yield). NMR (400 MHz, DMSO-d6): consistent. IR: consistent. MS: (ES+) m/z 392 [M+H]. Opt. Rot: +74.84 (calculated) in CH2Cl2 (1% concentration) wavelength 589, 25° C.; m.p.: 161-164° C.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][C:7]2[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][N:8]=2)=[CH:4][CH:3]=1.CO.[BH4-].[Na+]>Cl>[Cl:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][CH:7]2[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][NH:8]2)=[CH:4][CH:3]=1
Reactant: Clc1ccc(CC2=NCCCCC2)cc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Clc1ccc(CC2CCCCCN2)cc1
Reaction time: 1 h

Procedure:
Dissolve the thus-obtained 2-(4-chlorobenzyl)-4,5,6,7-tetrahydro-3H-azepin in diluted hydrochloric acid (pH~5) and mix it with 200 ml of methyl alcohol. Add 7 g of sodium borohydride in small portions within 20 minutes, keeping the pH-value constant by occasional addition of hydrochloric acid. Stir for 1 hour, render alkaline with caustic soda solution and extract with dichlormethane. Dry the organic phase over sodium sulphate, concentrate and distil to obtain 58 g of the title compound with a BP of 93° at 0.1 mm Hg.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[H-].[Na+].Cl[CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][O:10]1.Cl.O1C=CCCC1>C1COCC1.CO>[O:10]1[CH2:11][CH2:12][CH2:13][CH2:14][CH:9]1[N:1]1[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: ClC1CCCCO1
Reactant: c1c[nH]cn1
Agent: C1=COCCC1
Agent: Cl
Agent: [H-]
Solvent: CO
Solvent: C1CCOC1
Product: c1cn(C2CCCCO2)cn1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 76 %

Procedure:
To a solution of imidazole (81.6 g, 1.2 mol) in dry THF (2.5 L) was slowly added NaH (86.4 g, 3.6 mol) in small portions at −78° C. After all NaH was added, the mixture was stirred at −78° C. for 30 min, and 2-chloro-tetrahydropyran solution, prepared by hydrogen chloride gas treatment of dihydropyran, was added to the reaction mixture dropwise. The mixture was slowly warmed to r.t. and it was stirred at r.t. for 2 h. Methanol was added to quench the excess NaH. The mixture was concentrated with a rotary evaporator. Water was added and it was extract with EtOAc (500 mL×3), dried over MgSO4, and purified by neutral Al2O3 column chromatography (petroleum ether 5 L, petroleum ether:CH2Cl2=10:1, petroleum ether:CH2Cl2=3:1, CH2Cl2 and EtOAc). The last four fractions were pooled and concentrated to give 1-(tetrahydro-pyran-2-yl)-1H-imidazole (140 g, 76%). 1H NMR (CDCl3): δ 7.65 (s, 1H), 7.08 (s, 1H), 7.05 (s, 1H), 5.20 (dd, J=2.6, 9.5 Hz, 1H), 4.05-4.02 (m, 1H), 3.68-3.62 (m, 1H), 2.01-1.89 (m, 3H), 1.69-1.60 (m, 3H)
Reaction SMILES: [F:1][CH:2]([F:29])[C:3]([N:5]1[C@H:9]([CH2:10][F:11])[C@@H:8]([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:19]=[N:20][C:21]([CH:24]([OH:26])[CH3:25])=[CH:22][CH:23]=3)=[CH:14][CH:13]=2)[O:7][C:6]1([CH3:28])[CH3:27])=[O:4].C(N(CC)CC)C.[CH3:37][S:38](Cl)(=[O:40])=[O:39].C(=O)(O)[O-]>C(Cl)Cl>[F:29][CH:2]([F:1])[C:3]([N:5]1[C@H:9]([CH2:10][F:11])[C@@H:8]([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:23]=[CH:22][C:21]([CH:24]([O:26][S:38]([CH3:37])(=[O:40])=[O:39])[CH3:25])=[N:20][CH:19]=3)=[CH:14][CH:13]=2)[O:7][C:6]1([CH3:28])[CH3:27])=[O:4]
Reactant: CS(=O)(=O)Cl
Reactant: CC(O)c1ccc(-c2ccc([C@H]3OC(C)(C)N(C(=O)C(F)F)[C@@H]3CF)cc2)cn1
Agent: O=C([O-])O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(OS(C)(=O)=O)c1ccc(-c2ccc([C@H]3OC(C)(C)N(C(=O)C(F)F)[C@@H]3CF)cc2)cn1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 68.6 %

Procedure:
To a stirred solution of 2,2-Difluoro-1-((4S,5R)-4-fluoromethyl-5-{4-[6-(1-hydroxy-ethyl)-pyridin-3-yl]-phenyl}-2,2-dimethyl-oxazolidin-3-yl)-ethanone (2.2 g, 5.39 mmol) in CH2Cl2 (25 mL) is added triethylamine (1.51 mL, 10.78 mmol) and methane sulfonyl chloride (0.527 mL, 6.47 mmol). Reaction mixture is stirred at 0° C. for 30 minutes then diluted using saturated bicarbonate solution and extracted with CH2Cl2 (30 mL) Organic layer is dried over sodium sulphate, solvent is evaporated in vacuo and purified by combiflash using 45% ethyl acetate in hexane as an eluent to afford the title compound (1.8 g). 1H NMR (400 MHz, DMSO-d6) δ: 1.53 (s, 3H), 1.60 (s, 3H), 1.68 (d, J=6.56 Hz, 3H), 3.21 (s, 3H), 4.54-4.58 (m, 0.5H), 4.66-4.71 (m, 1H), 4.81-4.84 (m, 0.5H), 4.90-4.95 (m, 1H), 5.27 (d, J=3.92 Hz, 1H), 5.79-5.84 (m, 1H), 6.64 (t, J=52.24, 1 H), 7.60-7.63 (m, 3H), 7.81 (d, J=8.2 Hz, 2H), 8.17-8.20 (dd, J1=8.08 Hz, J2=2.24 Hz, 1H), 8.92 (d, J=2.00 Hz, 1H). LC-Ms (m/z): 487.1 [M+H].
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:8]2[CH2:17][CH2:16][C:15]3[C:14]([NH:18][C:19]4[CH:27]=[C:26]5[C:22]([C:23]([CH3:32])([CH3:31])[CH2:24][N:25]5C(=O)C)=[CH:21][CH:20]=4)=[N:13][CH:12]=[N:11][C:10]=3[CH2:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.Cl>CCO>[Cl:1][C:2]1[C:3]([N:8]2[CH2:17][CH2:16][C:15]3[C:14]([NH:18][C:19]4[CH:27]=[C:26]5[C:22]([C:23]([CH3:32])([CH3:31])[CH2:24][NH:25]5)=[CH:21][CH:20]=4)=[N:13][CH:12]=[N:11][C:10]=3[CH2:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)N1CC(C)(C)c2ccc(Nc3ncnc4c3CCN(c3ncccc3Cl)C4)cc21
Agent: Cl
Solvent: CCO
Product: CC1(C)CNc2cc(Nc3ncnc4c3CCN(c3ncccc3Cl)C4)ccc21
Temperature: 55 °C
Reaction time: 8 h
Yield: 124.1 %

Procedure:
A mixture of compound of Example 68 (40 mg), EtOH (5 mL), and 5 N HCl (1.0 mL) was stirred at 55° C. overnight. After cooling, the solvent was removed in vacuo to give a yellow solid (45 mg).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[CH:4][C:3]=1[C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([OH:20])[CH:15]=1)=O.[Br:21][C:22]1[CH:23]=[C:24]([CH2:28][CH:29]=O)[CH:25]=[CH:26][CH:27]=1>>[Br:21][C:22]1[CH:23]=[C:24]([C:28]2[CH:29]=[N:1][C:2]3[C:3]([C:12]=2[C:14]2[CH:15]=[C:16]([OH:20])[CH:17]=[CH:18][CH:19]=2)=[CH:4][CH:5]=[CH:6][C:7]=3[C:8]([F:11])([F:10])[F:9])[CH:25]=[CH:26][CH:27]=1
Reactant: O=CCc1cccc(Br)c1
Reactant: Nc1c(C(=O)c2cccc(O)c2)cccc1C(F)(F)F
Product: Oc1cccc(-c2c(-c3cccc(Br)c3)cnc3c(C(F)(F)F)cccc23)c1

Procedure:
The title compound was prepared from [2-amino-3-(trifluoromethyl)phenyl]-(3-hydroxy-phenyl)methanone and (3-Bromo-phenyl)-acetaldehyde following the procedure of Example 457: MS (ES) m/z 441.8; HRMS: calcd for C22H13BrF3NO+H+, 444.02053; found (ESI, [M+H]+), 444.0206.