Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[CH2:16]([O:23][C:24]1[CH:31]=[CH:30][C:27]([CH:28]=[O:29])=[C:26]([OH:32])[CH:25]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.O>CN(C)C1C=CN=CC=1.ClC1C=CC=CC=1>[CH2:16]([O:23][C:24]1[CH:31]=[CH:30][C:27]([CH:28]=[O:29])=[C:26]([O:32][C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=3)[N:5]=[CH:4][CH:3]=2)[CH:25]=1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: O=Cc1ccc(OCc2ccccc2)cc1O
Reactant: COc1cc2nccc(Cl)c2cc1OC
Agent: CN(C)c1ccncc1
Solvent: Clc1ccccc1
Solvent: O
Product: COc1cc2nccc(Oc3cc(OCc4ccccc4)ccc3C=O)c2cc1OC
Temperature: 130 °C
Reaction time: 8 h

Procedure:
4-Chloro-6,7-dimethoxyquinoline (111 mg), 4-benzyloxy-2-hydroxybenzaldehyde (456 mg), and 4-dimethylaminopyridine (244 mg) were suspended in monochlorobenzene (2 ml), and the suspension was stirred at 130° C. overnight. The reaction solution was cooled to room temperature, water was then added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by chromatography on silica gel using ethyl acetate-hexane for development to give 4-(benzyloxy)-2-[(6,7-dimethoxy-4-quinolyl)oxy]benzaldehyde.
Reaction SMILES: CS(O[CH2:6][CH2:7][C@H:8]1[CH2:19][CH2:18][C:17]2[S:16][C:15]3[N:14]=[CH:13][N:12]=[C:11]([O:20][CH:21]4[CH2:26][CH2:25][CH:24]([N:27]5[CH2:32][CH2:31][O:30][CH2:29][CH2:28]5)[CH2:23][CH2:22]4)[C:10]=3[C:9]1=2)(=O)=O.[C-:33]#[N:34].[Na+]>CS(C)=O.CN(C)C1C=CN=CC=1>[N:27]1([CH:24]2[CH2:23][CH2:22][CH:21]([O:20][C:11]3[C:10]4[C:9]5[C@@H:8]([CH2:7][CH2:6][C:33]#[N:34])[CH2:19][CH2:18][C:17]=5[S:16][C:15]=4[N:14]=[CH:13][N:12]=3)[CH2:26][CH2:25]2)[CH2:28][CH2:29][O:30][CH2:31][CH2:32]1
Reactant: [C-]#N
Reactant: CS(=O)(=O)OCC[C@H]1CCc2sc3ncnc(OC4CCC(N5CCOCC5)CC4)c3c21
Agent: CN(C)c1ccncc1
Agent: [Na+]
Solvent: CS(C)=O
Product: N#CCC[C@H]1CCc2sc3ncnc(OC4CCC(N5CCOCC5)CC4)c3c21
Temperature: 80 °C
Reaction time: 2 h
Yield: 85.8 %

Procedure:
Into a 50-mL round-bottom flask, purged and maintained with an inert atmosphere of nitrogen, was placed a solution of 2-[(3R)-12-[[4-(morpholin-4-yl)cyclohexyl]oxy]-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-3-yl]ethyl methanesulfonate (230 mg, 0.48 mmol, 1.00 equiv) in DMSO (5 mL) at room temperature. Then NaCN (141 mg, 2.88 mmol, 6.00 equiv) and 4-dimethylaminopyridine (5.86 mg, 0.05 mmol, 0.10 equiv) were added and the resulting solution was stirred for 2 h at 80° C. After cooling down to room temperature, the reaction was quenched with brine, extracted with DCM. The organic phase was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by column chromatography on silica gel with EtOAc/petroleum ether (1:10 to 1:2) to afford the desired 3-[(3S)-12-[[4-(morpholin-4-yl)cyclohexyl]oxy]-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-3-yl]propanenitrile (170 mg, 86%) as a white solid. LCMS (ES): m/z 413 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[CH2:7][C:6](=O)[CH2:5][CH2:4][S:3]1.[Si](OS(C(F)(F)F)(=O)=O)(C)(C)C.[CH3:22][O:23][C:24]([C:26]1[CH:27]=[C:28]([Br:35])[CH:29]=[C:30]2[C:34]=1[NH:33][CH:32]=[CH:31]2)=[O:25].[SiH](CC)(CC)CC>C(Cl)Cl>[CH3:22][O:23][C:24]([C:26]1[CH:27]=[C:28]([Br:35])[CH:29]=[C:30]2[C:34]=1[NH:33][CH:32]=[C:31]2[CH:6]1[CH2:5][CH2:4][S:3][C:2]([CH3:9])([CH3:1])[CH2:7]1)=[O:25]
Reactant: CC1(C)CC(=O)CCS1
Reactant: COC(=O)c1cc(Br)cc2cc[nH]c12
Agent: CC[SiH](CC)CC
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)c1cc(Br)cc2c(C3CCSC(C)(C)C3)c[nH]c12
Reaction time: 2 h
Yield: 52.1 %

Procedure:
To a solution of 2,2-Dimethyl-tetrahydro-thiopyran-4-one (7.9 g, 55.1 mmol) in DCM (100 mL) was added TMSOTf (10 mL, 55.1 mmol) and 5-Bromo-1H-indole-7-carboxylic acid methyl ester (7.0 g, 27.6 mmol) at 0° C. After 2 hours, Et3SiH (15 mL, 110 mmol) was added at 0° C., then the mixture was stirred for 18 hours. The reaction mixture was quenched with sat. Sodium bicarbonate solution, extracted with DCM (3×100 mL). The combined organic layer was dried over MgSO4 and concentrated under vacuum. The residue was purified by column chromatography on silica gel (PE:EA=50:1 to 30:1) to give the title compound as a light yellow solid (5.5 g, 52%).
Reaction SMILES: [Cl:1][CH2:2][C:3]([NH:5][C:6]1[C:11]([Cl:12])=[CH:10][C:9]([C:13]#[N:14])=[CH:8][C:7]=1[Cl:15])=[O:4].CC(O)C.Cl.[H][H]>[Pd].CO>[NH2:14][CH2:13][C:9]1[CH:8]=[C:7]([Cl:15])[C:6]([NH:5][C:3](=[O:4])[CH2:2][Cl:1])=[C:11]([Cl:12])[CH:10]=1
Reactant: N#Cc1cc(Cl)c(NC(=O)CCl)c(Cl)c1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CC(C)O
Solvent: CO
Product: NCc1cc(Cl)c(NC(=O)CCl)c(Cl)c1
Yield: 100 %

Procedure:
A mixture of 10.5 parts of 2-chloro-N-(2,6dichloro-4-cyanophenyl) acetamide, 22 parts of 2-propanol, saturated with hydrogen chloride and 200 parts of methanol was hydrogenated at normal pressure and at room temperature with 2 parts of palladium-on-charcoal catalyst 10%. After the calculated amount of hydrogen was taken up, the catalyst was filtered off and the filtrate was evaporated. The residue was taken up in water and treated with a sodium hydroxide solution 50%. The product was extracted twice with dichloromethane. The combined extracts were dried, filtered and evaporated, yielding 10.7 parts (100%) of N-[4-(aminomethyl)-2,6-dichlorophenyl]-2-chloroacetamide as a residue (int. 100).
Reaction SMILES: [Br:1][C:2]1([C:7]([OH:9])=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3]1.[CH2:10](O)[CH3:11]>S(=O)(=O)(O)O>[Br:1][C:2]1([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: O=C(O)C1(Br)CCCC1
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)C1(Br)CCCC1

Procedure:
A solution of 1-bromocyclopentanecarboxylic acid (5.1 g) in ethanol (40 ml) containing concentrated sulphuric acid (10 drops) was refluxed for 4 hours. The solvent was removed by evaporation and the residual oil was partitioned between ether (50 ml) and 2N sodium carbonate (30 ml).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:7]([S:10]([N:13]2[CH2:18][CH2:17][N:16]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[C:26]([F:29])([F:28])[F:27])[CH2:15][C@H:14]2[CH3:30])(=[O:12])=[O:11])=[CH:6][C:3]=1[C:4]#[N:5].C(O)(C(F)(F)F)=[O:32].OS(O)(=O)=O.[OH-].[Na+]>>[F:1][C:2]1[CH:9]=[CH:8][C:7]([S:10]([N:13]2[CH2:18][CH2:17][N:16]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[C:26]([F:27])([F:29])[F:28])[CH2:15][C@H:14]2[CH3:30])(=[O:12])=[O:11])=[CH:6][C:3]=1[C:4]([NH2:5])=[O:32]
Reactant: C[C@@H]1CN(c2ccc(F)cc2C(F)(F)F)CCN1S(=O)(=O)c1ccc(F)c(C#N)c1
Reactant: O=C(O)C(F)(F)F
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: C[C@@H]1CN(c2ccc(F)cc2C(F)(F)F)CCN1S(=O)(=O)c1ccc(F)c(C(N)=O)c1
Temperature: 25 °C
Reaction time: 120 h
Yield: 58.4 %

Procedure:
To a flask containing 2-fluoro-5-({(2R)-4-[4-fluoro-2-(trifluoromethyl)phenyl]-2-methylpiperazin-1-yl}sulfonyl)benzonitrile (399 mg, 0.90 mmol) was added a mixture of TFA/H2SO4 (4 mL, 2/2 v/v). The reaction mixture was stirred at room temperature for 5 days. Reaction was complete as determined by TLC. Slowly poured the reaction mixture to the ice, then neutralized the reaction mixture with 3N NaOH until pH=7-8, extracted with EtOAc (2×150 mL). The combined organic layer washed with sat. brine and dried over Na2SO4, and concentrated under reduced pressure. Purification by prep HPLC under neutral condition to yield 2-fluoro-5-({(2R)-4-[4-fluoro-2-(trifluoromethyl)phenyl]-2-methylpiperazin-1-yl}sulfonyl)benzamide as a white solid (243.7 mg, 58.4%). HRMS: calcd for C19H18F5N3O3S+H+, 464.10618. found (ESI-FTMS, [M+H]1+), 464.10639.
Reaction SMILES: [BH4-].[Na+].[CH3:3][C:4]1[CH:5]=[C:6]([C:21](=[O:38])[CH:22]([N:24]2[CH2:29][CH2:28][C:27]([C:31]3[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=3)([OH:30])[CH2:26][CH2:25]2)[CH3:23])[CH:7]=[CH:8][C:9]=1[O:10][Si:11]([CH:18]([CH3:20])[CH3:19])([CH:15]([CH3:17])[CH3:16])[CH:12]([CH3:14])[CH3:13]>C(O)C>[CH3:3][C:4]1[CH:5]=[C:6]([C@@H:21]([OH:38])[C@H:22]([N:24]2[CH2:25][CH2:26][C:27]([C:31]3[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=3)([OH:30])[CH2:28][CH2:29]2)[CH3:23])[CH:7]=[CH:8][C:9]=1[O:10][Si:11]([CH:18]([CH3:19])[CH3:20])([CH:15]([CH3:16])[CH3:17])[CH:12]([CH3:13])[CH3:14]
Reactant: Cc1cc(C(=O)C(C)N2CCC(O)(c3ccc(F)cc3)CC2)ccc1O[Si](C(C)C)(C(C)C)C(C)C
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: Cc1cc([C@@H](O)[C@@H](C)N2CCC(O)(c3ccc(F)cc3)CC2)ccc1O[Si](C(C)C)(C(C)C)C(C)C
Reaction time: 0.17 h
Yield: 74.3 %

Procedure:
A mixture of sodium borohydride (0.564 g, 14.92 mmol) and ethanol (60 mL) was stirred 10 minutes and then 1-(3-methyl-4-triisopropylsilyloxyphenyl)-2-(4-(4-fluorophenyl)-4-hydroxypiperidin-1-yl)-propan-1-one (7.66 g, 14.92 mmol in 10 mL of ethanol) was added with two 30 mL ethanol rinses. The reaction mixture was stirred at ambient temperature overnight. The white solid that precipitated was collected by filtration and dried to yield 5.72 g (74%) of (1R*,2R*)-1-(3-methyl-4-triisopropylsilyloxyphenyl)-2-(4-(4-fluorophenyl)-4-hydroxypiperidin-1-yl)-propan-1-ol, which was suitable for use without further purification and had: m.p. 188-89° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[CH:5]([CH2:13][S:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[NH:6][C:7](=O)[CH2:8][CH:9]([CH3:11])[CH3:10])[CH3:2].[ClH:22]>O1CCCC1.C(O)C>[ClH:22].[CH2:1]([O:3][C:4](=[O:21])[CH:5]([CH2:13][S:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[NH:6][CH2:7][CH2:8][CH:9]([CH3:11])[CH3:10])[CH3:2]
Reactant: CCOC(=O)C(CSc1ccccc1)NC(=O)CC(C)C
Agent: Cl
Solvent: C1CCOC1
Solvent: CCO
Product: CCOC(=O)C(CSc1ccccc1)NCCC(C)C
Reaction time: 1 h
Yield: 15 %

Procedure:
A solution of N-isovaleryl-3-(phenylthio)-DL-alanine ethyl ester (1.0 g) in anhydrous tetrahydrofuran (3.2 ml) is added to a 1 M solution of a borane-tetrahydrofuran complex salt in tetrahydrofuran (4.85 ml) dropwise under a nitrogen atmosphere and ice cooling, and the mixture is refluxed with stirring for one hour. A 3 N solution of hydrogen chloride in ethanol (2 ml) is added to the reaction mixture under ice cooling, and the mixture is further refluxed for one hour. The reaction mixture is concentrated under reduced pressure, 5% sodium hydrogencarbonate is added to the concentrate, and the whole is extracted with ether. The organic layer is washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue is purified by silica gel column chromatography, and the resulting oily matter is dissolved in ether. A 4.6 N solution of hydrogen chloride in ethyl acetate is added thereto under ice cooling, and the resulting precipitate is filtered off to give 163 mg (15%) of the titled compound (Reference compound No. 5-1) as crystals.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:9][C:8](COCC)([CH3:10])[N:7]([C:15]([CH3:18])([CH3:17])[CH3:16])[C:6]=2[CH:19]=1>C(O)(C(F)(F)F)=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([CH3:10])[N:7]([C:15]([CH3:17])([CH3:16])[CH3:18])[C:6]=2[CH:19]=1
Reactant: CCOCC1(C)Nc2ccc(Br)cc2N1C(C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: Cc1nc2ccc(Br)cc2n1C(C)(C)C
Reaction time: 8 h
Yield: 60.4 %

Procedure:
A mixture of 6-bromo-1-tert-butyl-2-ethoxymethyl-2-methyl-2,3-dihydro-1H-benzoimidazole (Step 25.2) (2.04 g, 6.51 mmol) and TFA (10 ml) is stirred at it overnight, quenched by addition of a saturated solution of NaHCO3 (100 mL) and extracted with EtOAc (2×150 mL). The organic phase is washed with a saturated solution of NaHCO3 (2×50 mL), dried (Na2SO4), filtered and concentrated. The residue purified by silica gel column chromatography (DCM/MeOH, 1:0→98:2) to afford 1.05 g of the title compound as a white solid: ESI-MS: 267.0/269.0 [M+H]+; tR=2.99 min (System 1); TLC: Rf=0.58 (DCM/MeOH, 9:1).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([S:7]([OH:10])(=O)=[O:8])[CH:2]=1.P(Cl)(Cl)(Cl)(Cl)[Cl:12]>C1(C)C=CC=CC=1.C1C=CC=CC=1>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([S:7]([Cl:12])(=[O:10])=[O:8])[CH:2]=1
Reactant: O=S(=O)(O)c1cccnc1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Solvent: c1ccccc1
Product: O=S(=O)(Cl)c1cccnc1

Procedure:
3-pyridylsulfonic acid 5-5 (30 g, 0.188 mole) was added to PCl5 (46.8 g, 0.225 mole) suspended in 150 mL toluene and heated to reflux ovemight. The suspension was cooled and concentrated to yield a yellow oil, which was diluted with benzene, filtered through a pad of celite and concentrated to give 5-6 as a yellow oil that was used in the next step without purification. 1H NMR (300 MHz, CDCl3) a 9.27 (1H, s), 8.98 (1H, d, 8.35 (1H, d), 7.62 (1H, dd).
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:7]2[CH:12]=[CH:11][C:10]([S:13][C:14]3[CH:15]=[C:16]([C:20]4([CH2:26][OH:27])[CH2:25][CH2:24][O:23][CH2:22][CH2:21]4)[CH:17]=[CH:18][CH:19]=3)=[CH:9][CH:8]=2)[CH:4]=[CH:5][N:6]=1.CS(C)=O.C(Cl)(=O)C(Cl)=O.C(N(CC)CC)C>ClCCl>[CH3:1][C:2]1[N:3]([C:7]2[CH:12]=[CH:11][C:10]([S:13][C:14]3[CH:15]=[C:16]([C:20]4([CH:26]=[O:27])[CH2:25][CH2:24][O:23][CH2:22][CH2:21]4)[CH:17]=[CH:18][CH:19]=3)=[CH:9][CH:8]=2)[CH:4]=[CH:5][N:6]=1
Reactant: Cc1nccn1-c1ccc(Sc2cccc(C3(CO)CCOCC3)c2)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: ClCCl
Product: Cc1nccn1-c1ccc(Sc2cccc(C3(C=O)CCOCC3)c2)cc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 78.4 %

Procedure:
A solution of [4-[3-[4-(2-methylimidazol-1-yl)phenylthio]phenyl]-3,4,5,6-tetrahydro-2H-pyran-4-yl]methanol (230 mg, 0.6 mmol) in dichloromethane (5 ml) was added dropwise to the Swern reagent [1.2 mmol, 2 equiv., prepared by adding a solution of DMSO (143 mg) in dichloromethane (5 ml) to a solution of oxalyl chloride (155 mg, 1.2 mmol) in dichloromethane (10 ml) at -78° C.] under argon at -78° C. The reaction mixture was stirred for 0.5 h at -78° C. and then this was allowed to warm to -20° C. over 2 h. To the reaction mixture was added triethylamine (1 ml) and the resulted solution was stirred for 0.5 h at 0° C. The mixture was partitioned between saturated aqueous NH4Cl (50 ml) and ethyl acetate (50 ml), the organic phase was separated and the aqueous phase was extracted with ethyl acetate (20 ml×2). The combined organic extracts were washed with water (50 ml) and brine (50 ml), dried (MgSO4) and concentrated in vacuo. The residual oil was purified by column chromatography {SiO2, 100 g; eluted with dichloromethane/ethanol (20/1)} to afford 178 mg (77%) of the titled compound as white solids.
Reaction SMILES: Cl.[C:2](Cl)(=[O:9])[C:3]1[CH:8]=[CH:7][CH:6]=[N:5][CH:4]=1.[CH3:11][C@@:12]12[C:28](=[O:29])[CH2:27][CH2:26][C@H:25]1[C@H:24]1[C@@H:15]([C:16]3[CH:17]=[CH:18][C:19]([OH:30])=[CH:20][C:21]=3[CH2:22][CH2:23]1)[CH2:14][CH2:13]2>N1C=CC=CC=1>[C:2]([O:30][C:19]1[CH:18]=[CH:17][C:16]2[C@@H:15]3[C@H:24]([C@H:25]4[C@@:12]([CH2:13][CH2:14]3)([CH3:11])[C:28](=[O:29])[CH2:27][CH2:26]4)[CH2:23][CH2:22][C:21]=2[CH:20]=1)(=[O:9])[C:3]1[CH:8]=[CH:7][CH:6]=[N:5][CH:4]=1
Reactant: C[C@]12CC[C@@H]3c4ccc(O)cc4CC[C@H]3[C@@H]1CCC2=O
Reactant: O=C(Cl)c1cccnc1
Agent: Cl
Solvent: c1ccncc1
Product: C[C@]12CC[C@@H]3c4ccc(OC(=O)c5cccnc5)cc4CC[C@H]3[C@@H]1CCC2=O
Temperature: 0 °C

Procedure:
To nicotinoyl chloride hydrochloride (2.65 g, 0.015 mol) in pyridine (20 ml) at 0° C. was added estrone (2 g, 0.0074 mol). The mixture was refluxed for one hour and then poured over 100 ml of ice cold water, filtered, and dried over P2O5 under vacuum. Yield 72% (2.0076 g), m.p. 207°-210° C. NMR (CDCl3) δ 9.3-9.1 (br s, 1H, C2 pyridinium proton), 8.8-8.6 (br d, 1H, C6 pyridinium proton, 8.4-8.2 (br d, 1H, C4 pyridinium proton, 7.5-7.1 (m, 2-H, C5 pyridinium proton+C1 . estrone proton), 7.0-6.7 (m, 2H, C2,4 estrone protons), 3.2-1.3 (estrone skeletal protons, 15), 1.0-0.9 (s, 3H, C18 estrone protons). IR (KBr) 1750-1730 cm-1 (broad C=O stretching). Anal. calculated for C24H25NO3 ; C, 76.76; H, 6.72; N, 3.73. Found: C, 76.37; H, 6.96; N, 3.67. The product is further characterized by the structural formula; ##STR1561##
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]1[CH2:11][CH2:10][C:9]2[CH:12]=[C:13]([NH2:16])[CH:14]=[CH:15][C:8]=2[CH2:7][CH2:6]1.[C:17]([CH2:19][N:20]([C@@H:25]1[CH2:30][CH2:29][CH2:28][CH2:27][C@H:26]1[NH:31][C:32]1[C:37]([Cl:38])=[CH:36][N:35]=[C:34](Cl)[N:33]=1)[S:21]([CH3:24])(=[O:23])=[O:22])#[N:18]>>[Cl:38][C:37]1[C:32]([NH:31][C@@H:26]2[CH2:27][CH2:28][CH2:29][CH2:30][C@H:25]2[N:20]([CH2:19][C:17]#[N:18])[S:21]([CH3:24])(=[O:23])=[O:22])=[N:33][C:34]([NH:16][C:13]2[CH:14]=[CH:15][C:8]3[CH2:7][CH2:6][N:5]([CH2:4][CH2:3][O:2][CH3:1])[CH2:11][CH2:10][C:9]=3[CH:12]=2)=[N:35][CH:36]=1
Reactant: CS(=O)(=O)N(CC#N)[C@@H]1CCCC[C@H]1Nc1nc(Cl)ncc1Cl
Reactant: COCCN1CCc2ccc(N)cc2CC1
Product: COCCN1CCc2ccc(Nc3ncc(Cl)c(N[C@@H]4CCCC[C@H]4N(CC#N)S(C)(=O)=O)n3)cc2CC1

Procedure:
N-((1R,2R)-2-{5-Chloro-2-[3-(2-methoxy-ethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamino]-pyrimidin-4-ylamino}-cyclohexyl)-N-cyanomethyl-methanesulfonamide was prepared from 3-(2-methoxy-ethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamine and N-cyanomethyl-N-[(1R,2R)-2-(2,5-dichloro-pyrimidin-4-ylamino)-cyclohexyl]-methanesulfonamide in an analogous manner to Example 308c. Product isolated as a pale yellow foam (63 mg, 32%). LCMS (m/e) 562 (M+H); 1H-NMR (CDCl3, 400 MHz) δ 7.89 (s, 1H), 7.30-7.19 (m, 2H), 7.07 (d, 1H, J=7.9 Hz), 5.39 (d, 1H, J=8.7 Hz), 4.12-3.63 (m, 4H), 3.56 (t, 2H, J=5.6 Hz), 3.38 (s, 3H), 3.01-2.91 (m, 4H), 2.97 (s, 3H), 2.84-2.68 (m, 6H), 2.36-2.26 (m, 1H), 2.18-2.09 (m, 1H), 2.02-184 (m, 2H), 1.72-1.57 (m, 1H), 1.50-1.30 (m, 3H).
Reaction SMILES: [C:1]1([CH:7]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[CH2:8][NH:9][C:10]2[N:18]=[C:17]([CH2:19][NH:20][C:21]([NH:23][CH2:24][CH2:25][N:26]3[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]3)=[O:22])[N:16]=[C:15]3[C:11]=2[N:12]=[CH:13][N:14]3C2CCCCO2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl>CO>[C:38]1([CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:8][NH:9][C:10]2[N:18]=[C:17]([CH2:19][NH:20][C:21]([NH:23][CH2:24][CH2:25][N:26]3[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]3)=[O:22])[N:16]=[C:15]3[C:11]=2[N:12]=[CH:13][NH:14]3)[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1
Reactant: O=C(NCCN1CCCCC1)NCc1nc(NCC(c2ccccc2)c2ccccc2)c2ncn(C3CCCCO3)c2n1
Agent: Cl
Solvent: CO
Product: O=C(NCCN1CCCCC1)NCc1nc(NCC(c2ccccc2)c2ccccc2)c2nc[nH]c2n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 100.3 %

Procedure:
A solution of N-({6-[(2,2-diphenylethyl)amino]-9-tetrahydro-2H-pyran-2-yl-9H-purin-2-yl}methyl)-N′-[2-(1-piperidinyl)ethyl]urea (300 mg, 0.51 mmol) (Preparation 41) in methanol (150 ml) was treated with 2 molar aqueous hydrochloric acid (100 ml). The reaction mixture was stirred at room temperature for 2 hours. The solvent volume was then reduced to 100 ml by evaporation under reduced pressure. Saturated aqueous sodium hydrogen carbonate (50 ml) and ethyl acetate (200 ml) were added. The two phases were separated. The organic layer was washed with saturated aqueous sodium chloride solution (100 ml), dried (anhydrous MgSO4) and evaporated to give the title compound as a white solid (255 mg).
Reaction SMILES: [O:1]=[C:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][O:5][C:4]2[CH:13]=[CH:14][C:15]([CH:17]([OH:22])[CH2:18][NH:19][CH2:20][CH3:21])=[CH:16][C:3]1=2.[BH4-].[Na+]>CO>[OH:1][CH:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][O:5][C:4]2[CH:13]=[CH:14][C:15]([CH:17]([OH:22])[CH2:18][NH:19][CH2:20][CH3:21])=[CH:16][C:3]1=2
Reactant: CCNCC(O)c1ccc2c(c1)C(=O)c1ccccc1CO2
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CCNCC(O)c1ccc2c(c1)C(O)c1ccccc1CO2
Reaction time: 2 h
Yield: 65.4 %

Procedure:
A solution of 2-(6,11-dihydro-11-oxodibenz[b,e]oxepin-2-yl)-N-ethyl-N-hydroxyethylamine (4.1 g) in 100 ml methanol at 0° C. was treated with sodium borohydride (1.04 g) in two portions and stirred under a nitrogen blanket for 2 hours. The solution was evaporated and taken up in chloroform and washed with saturated bicarbonate. This solution was evaporated again and the residue purified by flash chromatography (silica gel, 19:1 Chloroform-methanol) to give an oil. This oil crystallized from ether to give 2.7 g of 2-(6,11-dihydro-11-hydroxydibenz[b,e]oxepin-2-yl)-N-ethyl-N-hydroxyethylamine, as crystals, m.p. 116°-118° C.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH:7]2[C:13]3=[CH:14][CH:15]=[CH:16][N:12]3[CH2:11][C:10]3[CH:17]=[CH:18][CH:19]=[CH:20][C:9]=3[O:8]2)[CH2:3][CH2:2]1.[CH3:21][C:22]1[CH:29]=[C:28]([CH3:30])[CH:27]=[C:26]([CH3:31])[C:23]=1[CH2:24]Cl.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH3:21][C:22]1[CH:29]=[C:28]([CH3:30])[CH:27]=[C:26]([CH3:31])[C:23]=1[CH2:24][N:1]1[CH2:2][CH2:3][CH:4]([CH:7]2[C:13]3=[CH:14][CH:15]=[CH:16][N:12]3[CH2:11][C:10]3[CH:17]=[CH:18][CH:19]=[CH:20][C:9]=3[O:8]2)[CH2:5][CH2:6]1
Reactant: Cc1cc(C)c(CCl)c(C)c1
Reactant: c1ccc2c(c1)Cn1cccc1C(C1CCNCC1)O2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(C)c(CN2CCC(C3Oc4ccccc4Cn4cccc43)CC2)c(C)c1

Procedure:
To 60 ml DMF, was added 11-(piperidin-4-yl)-5H,11H-pyrrolo[2,1-c][1,4]benzoxazepine (5.0 g, 0.0186 mole), 2,4,6-trimethylbenzyl chloride (4.2 g, 0.025 mole), milled K2CO3 (15 g, 0.1 mole) and KI (0.01 g).
Reaction SMILES: [H-].[Na+].[CH2:3]([O:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[C:18]([O:22][C:23]([N:25]1[CH2:29][CH2:28][CH2:27][C@H:26]1[CH2:30]OS(C1C=CC(C)=CC=1)(=O)=O)=[O:24])([CH3:21])([CH3:20])[CH3:19]>CN(C=O)C>[C:18]([O:22][C:23]([N:25]1[CH2:29][CH2:28][CH2:27][C@H:26]1[CH2:30][O:17][C:14]1[CH:13]=[CH:12][C:11]([O:10][CH2:3][C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=2)=[CH:16][CH:15]=1)=[O:24])([CH3:21])([CH3:19])[CH3:20]
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H]2CCCN2C(=O)OC(C)(C)C)cc1
Reactant: Oc1ccc(OCc2ccccc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC[C@H]1COc1ccc(OCc2ccccc2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 44.7 %

Procedure:
To a slurry of NaH (562 mg, 8.44 mmol, 60% dispersion in mineral oil) in anhydrous DMF (5 mL) at 0° C. was added p-benzyloxy phenol (1.41 g, 7.0 mmol) in anhydrous DMF (5 mL) dropwise over 30 min under N2 atmosphere. The resulting slurry was stirred at 0° C. for 30 minutes, warmed to ambient temperature and stirred for 1 h before a solution of (S)-2-(Toluene-4-sulfonyloxymethyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (2.5 g, 7.0 mmol) in DMF (10 mL) was added dropwise over 30 min at 0° C. The subsequent mixture was stirred at 85° C. 16 h. The reaction mixture was poured over ice-water, precipitated yellow solid was removed by filtration, washed with water and dried under reduced pressure. The crude product was crystallized from ether/hexane to obtain the title compound (1.2 g, 44%).