Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH:8]2[CH2:13][CH2:12][CH2:11][CH:10]([C:14]3[C:19]([CH3:20])=[CH:18][CH:17]=[CH:16][N:15]=3)[NH:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.[CH3:21][O:22][C:23](=[O:34])[C:24]1[CH:29]=[C:28]([C:30]#[N:31])[CH:27]=[CH:26][C:25]=1[CH2:32]Br>>[CH3:21][O:22][C:23](=[O:34])[C:24]1[CH:29]=[C:28]([C:30]#[N:31])[CH:27]=[CH:26][C:25]=1[CH2:32][N:9]1[CH:8]([C:3]2[C:2]([CH3:1])=[CH:7][CH:6]=[CH:5][N:4]=2)[CH2:13][CH2:12][CH2:11][CH:10]1[C:14]1[C:19]([CH3:20])=[CH:18][CH:17]=[CH:16][N:15]=1
Reactant: COC(=O)c1cc(C#N)ccc1CBr
Reactant: Cc1cccnc1C1CCCC(c2ncccc2C)N1
Product: COC(=O)c1cc(C#N)ccc1CN1C(c2ncccc2C)CCCC1c1ncccc1C
Yield: 77.6 %

Procedure:
Following General Procedure A: 3,3″-dimethyl-1′,2′,3′,4′,5′,6′-hexahydro-[2,2′;6′,2″]terpyridine (1.6 g, 6.0 mmol) was reacted with 2-bromomethyl-5-cyano-benzoic acid methyl ester (1.5 g, 6.0 mmol) to give 5-cyano-2-(3,3″-dimethyl-3′,4′,5′,6′-tetrahydro-2′H-[2,2′;6′,2″]terpyridin-1′-ylmethyl)-benzoic acid methyl ester (2.05 g, 78%), as a pale-yellow solid.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[N:8]([C:9]([C:11]2[N:12]=[C:13]([CH3:23])[S:14][C:15]=2[C:16]2[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=2)=[O:10])[CH2:7][C@H:6]2[C@@H:4]1[CH2:5]2.[O:24]1[C:33]2[CH:32]=[CH:31][CH:30]=[C:29]([C:34](O)=[O:35])[C:28]=2[CH2:27][CH2:26][CH2:25]1>>[CH3:23][C:13]1[S:14][C:15]([C:16]2[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=2)=[C:11]([C:9]([N:8]2[CH2:7][C@H:6]3[C@H:4]([CH2:5]3)[C@H:3]2[CH2:2][NH:1][C:34]([C:29]2[C:28]3[CH2:27][CH2:26][CH2:25][O:24][C:33]=3[CH:32]=[CH:31][CH:30]=2)=[O:35])=[O:10])[N:12]=1
Reactant: O=C(O)c1cccc2c1CCCO2
Reactant: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CN)c1
Product: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CNC(=O)c2cccc3c2CCCO3)c1

Procedure:
prepared by reaction of ((1S,2S,5R)-2-Aminomethyl-3-aza-bicyclo[3.1.0]hex-3-yl)-(2-methyl-5-m-tolyl-thiazol-4-yl)-methanone with Chroman-5-carboxylic acid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:19][CH3:20])[CH:15]=2)[C:10]=1Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:22]1([CH2:28][CH2:29][O:30][C:31]2[CH:36]=[CH:35][C:34]([OH:37])=[CH:33][CH:32]=2)[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1.C(=O)([O-])[O-].[Cs+].[Cs+].C(OCC)(=O)C>C1(C)C=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:19][CH3:20])[CH:15]=2)[C:10]=1[O:37][C:34]1[CH:33]=[CH:32][C:31]([O:30][CH2:29][CH2:28][N:22]2[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)=[CH:36][CH:35]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Oc1ccc(OCCN2CCCCC2)cc1
Reactant: COc1ccc2c(Br)c(OCc3ccccc3)ccc2c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: COc1ccc2c(Oc3ccc(OCCN4CCCCC4)cc3)c(OCc3ccccc3)ccc2c1
Temperature: 174 °C
Yield: 29.3 %

Procedure:
Combine toluene (200 mL), 2-benzyloxy-1-bromo-6-methoxy-naphthalene (30 g, 87.4 mmol), 4-(2-piperidin-1-yl-ethoxy)phenol (23.2 g, 105 mmol) and cesium carbonate (34.4 g, 105 mmol), heat the mixture to reflux. Remove a portion of the toluene (100 mL). Add ethyl acetate (390 mg, 4.37 mmol) and copper triflate benzene complex (2.20 g, 4.37 mmol) to the reaction mixture and stir for 5 minutes. Remove the solvent by distillation and heat the resulting residue to 174° C. for 1.5 hours. Dissolve the residue in a mixture of ethyl acetate (200 mL) and aqueous HCl (1 N, 90 mL). Separate and concentrate the organics to a residue. Column chromatograph the residue to give 12.4 g of 1-{2-[4-(2-benzyloxy-6-methoxy-naphthalen-1-yloxy)-phenoxy]-ethyl}-piperidine (30%).
Reaction SMILES: [CH3:1][C@:2]1([CH2:16][CH2:17]O)[CH2:11][CH2:10][C:9]2[C:4](=[C:5]([CH3:15])[C:6]([CH3:14])=[C:7]([OH:13])[C:8]=2[CH3:12])[O:3]1.C(Cl)(Cl)[Cl:20]>>[CH3:1][C@:2]1([CH2:16][CH2:17][Cl:20])[CH2:11][CH2:10][C:9]2[C:4](=[C:5]([CH3:15])[C:6]([CH3:14])=[C:7]([OH:13])[C:8]=2[CH3:12])[O:3]1
Reactant: Cc1c(C)c2c(c(C)c1O)CC[C@](C)(CCO)O2
Reactant: ClC(Cl)Cl
Product: Cc1c(C)c2c(c(C)c1O)CC[C@](C)(CCCl)O2

Procedure:
(R)-2,5,7,8-tetramethyl-6-hydroxy-2-(2-chloroethyl)-chroman was prepared from (R)-2,5,7,8-tetramethyl-6-hydroxy-2-(2-hydroxyethyl)-chroman by a procedure similar to that described in Example 10. [α]D20 =+9.0, (c=2, chloroform), mp.=111° C.
Reaction SMILES: F[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]([CH3:13])[CH3:12])=[C:4]([NH:14][CH2:15][C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)[N:3]=1.CCN(C(C)C)C(C)C.[NH2:31][C@@H:32]([CH2:38][CH3:39])[CH:33]([OH:37])[CH:34]([CH3:36])[CH3:35]>CCCCO.CS(C)=O>[CH:11]([N:8]1[CH:7]=[N:6][C:5]2[C:9]1=[N:10][C:2]([NH:31][C@@H:32]([CH2:38][CH3:39])[CH:33]([OH:37])[CH:34]([CH3:36])[CH3:35])=[N:3][C:4]=2[NH:14][CH2:15][C:16]1[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=1)([CH3:13])[CH3:12]
Reactant: CC[C@H](N)C(O)C(C)C
Reactant: CC(C)n1cnc2c(NCc3cccnc3)nc(F)nc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Solvent: CS(C)=O
Product: CC[C@H](Nc1nc(NCc2cccnc2)c2ncn(C(C)C)c2n1)C(O)C(C)C
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a stirred solution of (2-fluoro-9-isopropyl-9H-purin-6-yl)-pyridin-3-ylmethyl-amine (30 mg, 1 eq, 0.10 mmol) in n-BuOH/DMSO (2.5 mL, 4:1) at room temperature under an argon atmosphere was added DIEA (0.20 mL, 11 eq, 1.14 mmol) followed by (3RS,4S)-4-amino-2-methyl-hexan-3-ol (28 mg, 2.0 eq, 0.21 mmol). The reaction mixture was placed in a preheated oil bath at 160° C. and stirred at this temperature for 72 h. The reaction mixture was allowed to cool to room temperature and the solvent was evaporated in vacuo. The residue was partitioned between EtOAc (50 mL) and brine/water (1:1, 100 mL), the aqueous phase was extracted with more EtOAc (2×25 mL), and the combined organic phase was washed with brine (50 mL), dried (MgSO4) and evaporated in vacuo. The residue was purified by gradient column chromatography on silica gel eluted with CHCl3:MeOH (100:0→98:2), to afford the title compound as a white solid. Yield: 4.3 mg (10%). 50% de 4S,3R: 50% de 4S,3S). 1H-NMR (d-CDCl3, 250 MHz): δ 0.91-1.05 (m, 9H, —NHCH(CH2CH3)CH(CH(CH3)2)OH), 1.57 (d, 6H, J=6.95 Hz, —CH(CH3)2), 1.60-1.95 (m, 4H, —NHCH(CH2CH3)CH(CH(CH3)2)OH), 3.23-3.33 (m, 1H, —NHCH(CH2CH3)CH(CH(CH3)2)OH), 3.84-4.04 (m, 1H, —NHCH(CH2CH3)CH(CH(CH3)2)OH), 4.56-4.70 (m, 1H, —CH(CH3)2), 4.77-4.95 (m, 2H, —HNCH2-Pyr), 5.26-5.43+6.27-6.50 (m, 1H, —NHCH(CH2CH3)CH(CH2CH3)OH), 7.23-7.37 (m, 3H, 2×Pyr-H & —N═CH—N—), 7.51-7.63 (m, 1H, Pyr-H), 7.73 (d, 1H, J=7.74 Hz, Pyr-H), 8.48-8.76 (m, 1H, HNCH2-Pyr). FABMS m/z (relative intensity): 398 ([M+H]+, 100), 324 (60). Accurate Mass (M+H): Actual: 398.2668, Measured: 398.2654.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][C:16]=1[O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:12][NH2:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:25](Cl)(=[O:31])[CH2:26][CH2:27][C:28](Cl)=[O:29]>N1C=CC=CC=1.ClCCl>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][C:16]=1[O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:12][NH:13][C:25](=[O:31])[CH2:26][CH2:27][C:28]([NH:13][CH2:12][C:11]1[CH:14]=[CH:15][C:16]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH:10]=1)=[O:29])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Cl)CCC(=O)Cl
Reactant: NCc1ccc(OCc2ccccc2)c(OCc2ccccc2)c1
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(CCC(=O)NCc1ccc(OCc2ccccc2)c(OCc2ccccc2)c1)NCc1ccc(OCc2ccccc2)c(OCc2ccccc2)c1
Temperature: 0 °C

Procedure:
3,4-dibenzyloxybenzylamine (1.1 g, 3.45 mmol) was dissolved in anhydrous pyridine (8 ml) and cooled to 0° C. with stirring under nitrogen. To this solution, succinyl chloride (0.23 g, 1.42 mmol) was added dropwise over 30 minutes as a solution in dichloromethane (50 ml), while maintaining the reaction mixture at 0° C. The reaction was allowed to warm to room temperature and stirred for an additional 45 minutes. The reaction was poured onto crushed ice (70 g) and the dichloromethane layer was separated. The organic extract was washed with dilute aqueous hydrochloric acid (2×20 ml of 0.1M solution), water (20 ml), and dried (Na2SO4). Removal of the solvent at reduced pressure afforded a crude solid, which was triturated with methanol (5 ml) to afford after filtration the protected diamide, yield 300 mg.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1)([CH3:3])[CH3:2].[C:10]([C:12]1([NH:15][C:16]([C@H:18]2[CH2:22][C@H:21]([S:23]([C:26]3[CH:31]=[CH:30][C:29](Br)=[CH:28][C:27]=3[C:33]([F:36])([F:35])[F:34])(=[O:25])=[O:24])[CH2:20][C@@H:19]2[O:37][CH:38]2[CH2:42][CH2:41][CH2:40][CH2:39]2)=[O:17])[CH2:14][CH2:13]1)#[N:11].C(C1(NC([C@H]2C[C@H](S(C3C=CC(Br)=CC=3C(F)(F)F)(=O)=O)C[C@@H]2OC)=O)CC1)#N>>[C:10]([C:12]1([NH:15][C:16]([C@H:18]2[CH2:22][C@H:21]([S:23]([C:26]3[CH:31]=[CH:30][C:29]([N:7]4[CH2:8][CH2:9][N:4]([CH:1]([CH3:3])[CH3:2])[CH2:5][CH2:6]4)=[CH:28][C:27]=3[C:33]([F:36])([F:35])[F:34])(=[O:25])=[O:24])[CH2:20][C@@H:19]2[O:37][CH:38]2[CH2:42][CH2:41][CH2:40][CH2:39]2)=[O:17])[CH2:14][CH2:13]1)#[N:11]
Reactant: N#CC1(NC(=O)[C@H]2C[C@H](S(=O)(=O)c3ccc(Br)cc3C(F)(F)F)C[C@@H]2OC2CCCC2)CC1
Reactant: CC(C)N1CCNCC1
Agent: CO[C@H]1C[C@@H](S(=O)(=O)c2ccc(Br)cc2C(F)(F)F)C[C@@H]1C(=O)NC1(C#N)CC1
Product: CC(C)N1CCN(c2ccc(S(=O)(=O)[C@@H]3C[C@H](OC4CCCC4)[C@@H](C(=O)NC4(C#N)CC4)C3)c(C(F)(F)F)c2)CC1

Procedure:
The title compound was prepared in analogy to example 176 using 1-isopropyl-piperazine instead of morpholine and (1R,2R,4R) and (1S,2S,4S)-4-(4-bromo-2-trifluoromethyl-benzenesulfonyl)-2-cyclopentyloxy-cyclopentanecarboxylic acid (1-cyano-cyclopropyl)-amide (example 195) instead of (1R,2R,4R) and (1S,2S,4S)-4-(4-bromo-2-trifluoromethyl-benzenesulfonyl)-2-methoxy-cyclopentanecarboxylic acid (1-cyano-cyclopropyl)-amide. White solid. MS (EI): 595.4 (M−H)−.
Reaction SMILES: CN.C(=O)([O-])[O-].[Cs+].[Cs+].[Br:9][C:10]1[N:14]([CH3:15])[N:13]=[CH:12][C:11]=1[C:16]1[N:17]=[C:18]([CH3:30])[N:19]2[C:24]=1[C:23]([N:25]1[CH:29]=NC=N1)=[N:22][CH:21]=[N:20]2>O1CCCC1.CN(C)C=O>[Br:9][C:10]1[N:14]([CH3:15])[N:13]=[CH:12][C:11]=1[C:16]1[N:17]=[C:18]([CH3:30])[N:19]2[C:24]=1[C:23]([NH:25][CH3:29])=[N:22][CH:21]=[N:20]2
Reactant: Cc1nc(-c2cnn(C)c2Br)c2c(-n3cncn3)ncnn12
Agent: CN
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CNc1ncnn2c(C)nc(-c3cnn(C)c3Br)c12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Methylamine (4.31 mL of a 2 M solution in tetrahydrofuran, 8.62 mmol) was added to a mixture of cesium carbonate (9.78 g, 30.0 mmol) and 5-(5-bromo-1-methyl-1H-pyrazol-4-yl)-7-methyl-4-(1H-1,2,4-triazol-1-yl)imidazo[5,1-f][1,2,4]triazine (from the previous reaction, 2.1 g) in N,N-dimethylformamide (12 mL), and the reaction was stirred at room temperature for 1 hour. It was quenched with a 1:1 mixture of water and saturated aqueous sodium chloride solution, then extracted with ethyl acetate (2×20 mL) and with tetrahydrofuran (10 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo to provide C4. Yield: 1.65 g, 5.12 mmol, 78% over 2 steps. LCMS m/z 322.1 (M+1). 1H NMR (500 MHz, CDCl3) δ 2.70 (s, 3H), 3.10 (d, J=4.9 Hz, 3H), 4.00 (s, 3H), 5.46-5.52 (m, 1H), 7.69 (s, 1H), 7.97 (s, 1H).
Reaction SMILES: [H-].[Na+].[Cl-].[CH3:4][C:5]1[C:9]([CH2:10][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[C:8]([CH3:30])[O:7][N:6]=1.[CH2:31]1[CH:36]=[CH:35][O:34][CH:33]([CH:37]=O)[CH2:32]1.C1(C=CC(O)=CC=1)O>CCCCC.O>[CH3:4][C:5]1[C:9]([CH:10]=[CH:37][CH:33]2[CH2:32][CH2:31][CH:36]=[CH:35][O:34]2)=[C:8]([CH3:30])[O:7][N:6]=1
Reactant: O=CC1CCC=CO1
Reactant: Cc1noc(C)c1C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Oc1ccc(O)cc1
Agent: [Cl-]
Agent: [H-]
Solvent: CCCCC
Solvent: O
Product: Cc1noc(C)c1C=CC1CCC=CO1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
8.75 G. (0.20 mole) of 55 percent sodium hydride dispersion was washed undere nitrogen with dry pentane to remove the mineral oil. To the flask was added 600 ml. of dimethylsulfoxide (dried over Linde 3A molecular sieves). The resulting suspension was carefully degassed, placed unnder nitrogen, and heated at 70°-75° for 1 hour. The gray-green solution was cooled to approximately 15° and 91.6 g. (0.20 mole) of (3,5-dimethyl-4-isoxazolylmethyl)triphenylphosphonium chloride, prepared as described in Example 4 above, was added in one portion. After approximately 5 minutes, a bright orange precipitate formed in the initially dark red solution. This suspension was stirred at room temperature for 45 minutes. To the mixture was then added, drop-wise via syringe, 25.0 g. (0.223 mole) of acrolein dimer (freshly distilled from and into hydroquinone) at such a rate that the temperature remained less than 30°(10-15 minutes with water bath cooling). The light orange-brown solution was stirred at room temperature for 20 minutes, and then at 60°-65° for 3 hours. (In some experiments, the mixture became very black during the heating period). The reaction mixture was cooled, poured onto ice, and slurried until all of the dark oil solidified. The suspension was filtered and the filter cake was washed well with pentane. The filtrates were extracted with pentane and the pentane solutions were washed with water and brine and dried over anhydrous sodium sulfate. Solvent removal gave a slightly orange oil which was distilled from a small quantity of anhydrous potassium carbonate to give the desired product as a colorless liquid, b.p. 83°-85°/0.1 mm. A similarly prepared sample of b.p. 77°-85°/0.5 mm. was submitted for analysis.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13](=O)[N:14]=[CH:15][NH:16]2)=[CH:11][C:10]=1[F:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:23])=O>>[CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([Cl:23])=[N:14][CH:15]=[N:16]2)=[CH:11][C:10]=1[F:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1nc[nH]c2cc(OCc3ccccc3)c(F)cc12
Product: Fc1cc2c(Cl)ncnc2cc1OCc1ccccc1
Yield: 71 %

Procedure:
7-(Benzyloxy)-6-fluoroquinazolin-4(1H)-one (2.00 g, 7.41 mmol) was taken up in phosphorus oxychloride (20 ml) and the reaction heated at reflux for 90 minutes. The reaction was cooled, azeotroped with toluene (2×50 ml) and taken up in dichloromethane (5 ml) The organic phase was washed with saturated aqueous sodium hydrogen carbonate solution and then dried over magnesium sulphate. Solvent evaporation in vacuo followed by drying of the solid in vacuo yielded 7-(benzyloxy)-4-chloro-6-fluoroquinazoline (1.50 g, 71% yield) as a pale yellow solid:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:11](=[CH:12][C:13]=1[O:14][CH3:15])[C:7]1[NH:8][N:9]=[CH:10][C:6]=1[CH2:5]2.[Li]C1C=CC=CC=1.[Li]C(CC)C.CN([CH:31]=[O:32])C>C1COCC1>[CH3:15][O:14][C:13]1[CH:12]=[C:11]2[C:4]([CH2:5][C:6]3[CH:10]=[N:9][NH:8][C:7]=32)=[CH:3][C:2]=1[CH:31]=[O:32]
Reactant: CN(C)C=O
Reactant: COc1cc2c(cc1Br)Cc1cn[nH]c1-2
Agent: [Li]C(C)CC
Agent: [Li]c1ccccc1
Solvent: C1CCOC1
Product: COc1cc2c(cc1C=O)Cc1cn[nH]c1-2
Temperature: -78 °C
Reaction time: 1 h
Yield: 81.6 %

Procedure:
To a suspension of Example 104C (5.49 g, 0.0207 mol) in THF (300 mL) was added PhLi (1.9 M, 21.8 mL, 0.0414 mol) at −78° C. s-BuLi (1.4 M, 29.6 mL, 0.0414 mol) and DMF (12.8 mL, 0.166 mol) were added to the reaction mixture after 30 and 60 minutes, respectively. The mixture was stirred at −78° C. for 1 hour and the cold bath was removed. The reaction was quenched with saturated NH4Cl solution after 1 hour at room temperature. The mixture was extracted with EtOAc, washed with water, brine, dried over MgSO4, filtered, concentrated, and triturated with ether to give 3.62 g (81%) of the desired product. MS (DCI/NH3) m/z: 215.1 (M+H)+; 1H NMR (300 MHz, DMSO-D6) δ ppm 3.62 (s, 2H) 4.01 (s, 3H) 7.45 (s, 1H), 7.73 (s, 1H) 7.80 (s, 1H) 10.37 (s, 1H) 13.07 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:14][CH:13]3[N:15]([CH2:16][CH2:17][CH2:18][CH2:19][NH:20]C(=O)C(F)(F)F)[CH:10]([CH2:11][CH2:12]3)[CH2:9]2)=[CH:4][CH:3]=1>C(O)C.[OH-].[K+]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:14][CH:13]3[N:15]([CH2:16][CH2:17][CH2:18][CH2:19][NH2:20])[CH:10]([CH2:11][CH2:12]3)[CH2:9]2)=[CH:4][CH:3]=1
Reactant: O=C(NCCCCN1C2CCC1CN(c1ccc(Cl)cc1)C2)C(F)(F)F
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: NCCCCN1C2CCC1CN(c1ccc(Cl)cc1)C2
Reaction time: 3 h
Yield: 94.9 %

Procedure:
N-{4-[3-(4-Chloro-phenyl)-3,8-diaza-bicyclo[3.2.1]oct-8-yl]-butyl}-2,2,2-trifluoro-acetamide (0.88 g, 2.26 mmol) was dissolved in ethanol (18 mL) and 20% potassium hydroxide (3.26 mL). The clear solution was stirred for 3 hours, concentrated to dryness, diluted with methylene chloride (500 mL), added sodium sulfate and stirred for 3 hours. The mixture was filtered through Celite and concentrated to yield 4-[3-(4-Chloro-phenyl)-3,8-diaza-bicyclo[3.2.1]oct-8-yl]-butylamin (0.63 g, 94.9%) as a golden oil which had the following properties: 1H NMR CDCl3 δ: 7.14 (d, J=9.1 Hz, 2H), 6.68 (d, J=9.1 Hz, 2H), 3.35 (brd s, 2H), 3.26 (d, J=13.7 Hz, 2H), 2.96 (d, J=9.1 Hz, 2H), 2.75-2.68 (m, 2H), 2.47-2.18 (m, 4H), 1.98-1.88 (m, 2H), 1.76-1.67 (m, 2H), 1.69-1.45 (m, 4H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.[NH2:20][C:21]1[N:30]=[C:29]([NH:31][C@H:32]2[CH2:37][CH2:36][CH2:35][CH2:34][C@H:33]2[NH:38][C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[C:28]2[C:23](=[CH:24][CH:25]=[C:26]([O:46][CH3:47])[CH:27]=2)[N:22]=1.O>C(Cl)Cl>[C:42]([O:41][C:39]([NH:38][C@@H:33]1[CH2:34][CH2:35][CH2:36][CH2:37][C@@H:32]1[NH:31][C:29]1[C:28]2[C:23](=[CH:24][CH:25]=[C:26]([O:46][CH3:47])[CH:27]=2)[N:22]=[C:21]([NH:20][C:6](=[O:7])[C:5]2[CH:9]=[CH:10][C:2]([Cl:1])=[CH:3][CH:4]=2)[N:30]=1)=[O:40])([CH3:45])([CH3:44])[CH3:43]
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: COc1ccc2nc(N)nc(N[C@H]3CCCC[C@H]3NC(=O)OC(C)(C)C)c2c1
Solvent: ClCCl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc2nc(NC(=O)c3ccc(Cl)cc3)nc(N[C@H]3CCCC[C@H]3NC(=O)OC(C)(C)C)c2c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 58.9 %

Procedure:
A solution of 68 mg of 4-chlorobenzoyl chloride and 200 mg of diisopropylethylamine in 8 mL of methylene chloride was combined with 150 mg of cis-2-(2-amino-6-methoxyquinazolin-4-yl)amino-N-tert-butoxycarbonylcyclohexylamine, and stirred at room temperature for 15 hours. The reaction solution was combined with water, extracted with chloroform, and dried. After the solvent was distilled off, the residue was purified by column chromatography on silica gel (chloroform:methanol=30:1) to obtain 120 mg of the desirable compound.
Reaction SMILES: [NH2:1][CH2:2][C:3]1([CH2:6][O:7][C:8]2[C:13]([O:14][CH3:15])=[C:12]([O:16][CH3:17])[CH:11]=[CH:10][C:9]=2[C:18]2[CH:26]=[CH:25][CH:24]=[C:23]3[C:19]=2[CH2:20][CH2:21][C:22]3=[O:27])[CH2:5][CH2:4]1.C(N(CC)CC)C.[C:35](Cl)(=[O:41])[O:36][CH2:37][CH2:38][O:39][CH3:40]>ClCCl>[CH3:40][O:39][CH2:38][CH2:37][O:36][C:35](=[O:41])[NH:1][CH2:2][C:3]1([CH2:6][O:7][C:8]2[C:9]([C:18]3[CH:26]=[CH:25][CH:24]=[C:23]4[C:19]=3[CH2:20][CH2:21][C:22]4=[O:27])=[CH:10][CH:11]=[C:12]([O:16][CH3:17])[C:13]=2[O:14][CH3:15])[CH2:4][CH2:5]1
Reactant: COCCOC(=O)Cl
Reactant: COc1ccc(-c2cccc3c2CCC3=O)c(OCC2(CN)CC2)c1OC
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COCCOC(=O)NCC1(COc2c(-c3cccc4c3CCC4=O)ccc(OC)c2OC)CC1

Procedure:
To a stirring solution of 4-[2-(1-Aminomethyl-cyclopropylmethoxy)-3,4-dimethoxy-phenyl]-indan-1-one (Compound 182) (150 mg, 0.272 mmol) in dichloromethane (10 mL), were added triethylamine (0.082 g, 0.811 mmol) and 2-methoxyethyl carbonochloridate (68 mg, 0.544 mmol) and the resultant reaction mixture was subjected to the conditions used in the preparation of Compound 183 to afford the title compound as a solid
Reaction SMILES: C1(C[N:8]2[CH2:12][CH2:11][C@H:10]([NH:13][CH2:14][CH2:15][C:16]#[N:17])[CH2:9]2)C=CC=CC=1.C1CC=CCC=1>[OH-].[OH-].[Pd+2].C(O)C>[NH:8]1[CH2:12][CH2:11][C@H:10]([NH:13][CH2:14][CH2:15][C:16]#[N:17])[CH2:9]1
Reactant: N#CCCN[C@H]1CCN(Cc2ccccc2)C1
Agent: [Pd+2]
Agent: [OH-]
Solvent: C1=CCC=CC1
Solvent: CCO
Product: N#CCCN[C@H]1CCNC1
Temperature: 100 °C
Yield: 83.5 %

Procedure:
3-[[(3S)-1-(Phenylmethyl)-3-pyrrolidinyl]amino]-propanenitrile (as described in WO2000075137) (0.6 g), 20% palladium hydroxide on carbon (0.15 g), 1,4 cyclohexadiene (3 mL) and ethanol (2 mL) were loaded into a 10 mL microwave vial, capped and heated at 100° C. for 90 minutes within a single mode microwave. The reaction mixture was filtered and the volatiles removed under vacuum to afford the sub-title compound (0.304 g).
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:30][C@@H:31]2[CH2:36][CH2:35][C@H:34]([OH:37])[CH2:33][C@H:32]2[C:38]2[N:42]([CH3:43])[N:41]=[CH:40][CH:39]=2)=[CH:4][C:5]([F:29])=[C:6]([S:8]([N:11](CC2C=CC(OC)=CC=2OC)[C:12]2[CH:17]=[CH:16][N:15]=[CH:14][N:13]=2)(=[O:10])=[O:9])[CH:7]=1.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCl>[Cl:1][C:2]1[C:3]([O:30][C@@H:31]2[CH2:36][CH2:35][C@H:34]([OH:37])[CH2:33][C@H:32]2[C:38]2[N:42]([CH3:43])[N:41]=[CH:40][CH:39]=2)=[CH:4][C:5]([F:29])=[C:6]([S:8]([NH:11][C:12]2[CH:17]=[CH:16][N:15]=[CH:14][N:13]=2)(=[O:10])=[O:9])[CH:7]=1
Reactant: COc1ccc(CN(c2ccncn2)S(=O)(=O)c2cc(Cl)c(O[C@@H]3CC[C@H](O)C[C@H]3c3ccnn3C)cc2F)c(OC)c1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cn1nccc1[C@@H]1C[C@@H](O)CC[C@H]1Oc1cc(F)c(S(=O)(=O)Nc2ccncn2)cc1Cl
Yield: 59.7 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 1b by using the 5-chloro-N-(2,4-dimethoxybenzyl)-2-fluoro-4-{[(1R,2S,4S)-4-hydroxy-2-(1-methyl-1H-pyrazol-5-yl)cyclohexyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide (189 mg, 0.299 mmol) prepared in Example 164c, triethylsilane (0.050 mL), trifluoroacetic acid (0.50 mL) and dichloromethane (1.0 mL), to yield the title compound (86.0 mg, 60%) as a colorless solid.
Reaction SMILES: [CH:1]1([NH:6][C:7]2[CH:8]=[C:9]([Cl:23])[CH:10]=[C:11]3[C:15]=2[NH:14][C:13]([C:16]2[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=2)=[CH:12]3)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:24][S:25](Cl)(=[O:27])=[O:26]>>[Cl:23][C:9]1[CH:10]=[C:11]2[C:15](=[C:7]([NH:6][CH:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)[CH:8]=1)[NH:14][C:13]([C:16]1[CH:17]=[CH:18][C:19]([NH:22][S:25]([CH3:24])(=[O:27])=[O:26])=[CH:20][CH:21]=1)=[CH:12]2
Reactant: Nc1ccc(-c2cc3cc(Cl)cc(NC4CCCC4)c3[nH]2)cc1
Reactant: CS(=O)(=O)Cl
Product: CS(=O)(=O)Nc1ccc(-c2cc3cc(Cl)cc(NC4CCCC4)c3[nH]2)cc1

Procedure:
Cyclopentyl-[2-(4-aminophenyl)-5-chloro-1H-indol-7-yl]amine prepared in Example 82 and methanesulfonylchloride were reacted according to the same procedure as Example 22 to give the title compound.
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[CH:6][CH:5]=[N:4]1.[CH3:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([NH:15][C:16](=[O:31])[CH:17]=[CH:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27]Cl)=[C:21]([O:29][CH3:30])[CH:20]=2)[CH2:11][CH2:10]1.Cl>C1COCC1.C(Cl)Cl>[CH3:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([NH:15][C:16](=[O:31])[CH:17]=[CH:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][C:7]3[CH:6]=[CH:5][NH:4][N:3]=3)=[C:21]([O:29][CH3:30])[CH:20]=2)[CH2:11][CH2:10]1
Reactant: c1cn[nH]c1
Reactant: COc1cc(C=CC(=O)N[C@H]2CC[C@H](C)CC2)ccc1OCCCl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: COc1cc(C=CC(=O)N[C@H]2CC[C@H](C)CC2)ccc1OCCc1cc[nH]n1

Procedure:
0.5 g of sodium hydride was added to a solution of 0.68 g of pyrazole in 50 ml of THF. Next, 1.9 g of N-(trans-4-methylcyclohexyl)-4-(2-chloroethoxy)-3-methoxycinnamamide (Example 138) was added to the solution. The solution was reacted for 24 hours, while it was refluxed. After reaction, 2 N hydrochloric acid was added, acidifying the reaction solution. The solution was washed with 100 ml of methylene chloride. Ammonia water was added to the aqueous layer obtained, alkalizing the solution. Thereafter, the solution was extracted with 100 ml of methylene chloride. The organic layer obtained was dried over magnesium sulfate, and the solvent was removed in vacuo. The product obtained was refined by means of silica gel column chromatography using methylene chloride only. Thereafter, the solvent was removed in vacuo, yielding 0.44 g of N-(trans-4-methylcyclohexyl)-4-(2-pyrazolylethoxy)-3-methoxycinnamamide (a compound of the present invention) as white crystal, which had the following physiochemical properties: