Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@@H:2]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][C:16]2[N:17]=[C:18]([C:22]3[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=3)[O:19][C:20]=2[CH3:21])=[CH:9][CH:8]=1)[C:3]([OH:5])=[O:4].[C:32]1([C:38](=[O:44])[CH2:39][C:40](=O)[CH2:41][CH3:42])[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>>[CH2:41](/[C:40](/[NH:1][C@@H:2]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][C:16]2[N:17]=[C:18]([C:22]3[CH:23]=[CH:24][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:26][CH:27]=3)[O:19][C:20]=2[CH3:21])=[CH:9][CH:8]=1)[C:3]([OH:5])=[O:4])=[CH:39]/[C:38](=[O:44])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[CH3:42]
Reactant: Cc1oc(-c2ccc(C(F)(F)F)cc2)nc1CCOc1ccc(C[C@H](N)C(=O)O)cc1
Reactant: CCC(=O)CC(=O)c1ccccc1
Product: CC/C(=C/C(=O)c1ccccc1)N[C@@H](Cc1ccc(OCCc2nc(-c3ccc(C(F)(F)F)cc3)oc2C)cc1)C(=O)O

Procedure:
The title compound was prepared (as described above for the preparation of Example 2) from 40 mg (0.092 mmol) of Intermediate 50 and 17 mg (0.092 mmol) of Intermediate 16 to yield 21 mg of Example 5: TLC (DCM/MeOH, 4/1): Rf=0.50; 1H NMR (DMSO-d6, 400 MHz) δ11.59 (d, 1H, J=9.8), 8.09 (d, 2H, J=9.0), 7.85 (d, 2H, J=8.8), 7.78 (m, 2H), 7.39 (m, 3H), 7.12 (d, 2H, J=8.0), 6.80 (d, 2H, J=8.0), 5.54 (s, 1H), 4.15 (t, 2H, J=6.6), 4.17 (m, 1H), 3.11 (m, 1H), 2.90 (t, 2H, J=6.6), 2.72 (m, 1H), 2.33 (s, 3H), 1.98 (m, 2H), 0.9 (t, 3H, J=7.5); low resolution MS (ES+)m/e 593.1 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:18]([C:19](=[O:21])[CH3:20])=[C:11]3[CH:12]=[CH:13][C:14]([C:16]#[N:17])=[CH:15][N:10]3[N:9]=2)=[CH:4][CH:3]=1.CO[CH:24](OC)[N:25]([CH3:27])[CH3:26]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:18]([C:19](=[O:21])[CH:20]=[CH:24][N:25]([CH3:27])[CH3:26])=[C:11]3[CH:12]=[CH:13][C:14]([C:16]#[N:17])=[CH:15][N:10]3[N:9]=2)=[CH:6][CH:7]=1
Reactant: COC(OC)N(C)C
Reactant: CC(=O)c1c(-c2ccc(F)cc2)nn2cc(C#N)ccc12
Product: CN(C)C=CC(=O)c1c(-c2ccc(F)cc2)nn2cc(C#N)ccc12
Temperature: 130 °C

Procedure:
A mixture of 2-(4-fluorophenyl)-3-acetyl-6-cyanopyrazolo[1,5-a]pyridine (1.6 g, 5.6 mmol) and dimethylformamide-dimethylacetal (15 mL) was stirred and heated at 130° C., under N2, overnight. The solution was cooled and the resulting solid was collected by filtration and rinsed with acetone. The filtrate was evaporated and the resulting solid was purified using chromatography. The product solids were combined to afford the title compound as a brown solid, 1.3 g (68%). 1H NMR (d6-DMSO) showed a mixture of isomers. MS (ES+) m/z 335 (M++H), 264 (M+−70).
Reaction SMILES: [C:1]([N:6]1[CH2:11][CH2:10][C:9](=O)[CH:8]([CH3:13])[CH2:7]1)([O:3][CH2:4][CH3:5])=[O:2].[NH:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1>C1C=CC=CC=1>[CH2:4]([O:3][C:1]([N:6]1[CH2:11][CH:10]=[C:9]([N:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)[CH:8]([CH3:13])[CH2:7]1)=[O:2])[CH3:5]
Reactant: CCOC(=O)N1CCC(=O)C(C)C1
Reactant: C1CCNC1
Solvent: c1ccccc1
Product: CCOC(=O)N1CC=C(N2CCCC2)C(C)C1

Procedure:
A mixture of 92.2 g of 1-carbethoxy-3-methyl-4-piperidone and 53.5 g of pyrrolidine in 1.0 liter of benzene is heated to the boil at reflux for 2 hours and the resulting water is continuously removed azeotropically. The reaction mixture is concentrated and the crude 1,2,3,6-tetrahydro-3-methyl-4-pyrrolidinylpyridine-1-carboxylic acid ethyl ester, obtained as an oil, is used as such for the next reaction.
Reaction SMILES: C1C=C[NH+]=CC=1.C1C=C[NH+]=CC=1.[O-][Cr](O[Cr]([O-])(=O)=O)(=O)=O.[F:22][C:23]1[CH:28]=[CH:27][C:26]([CH:29]([C:31]2[C:40]([N+:41]([O-:43])=[O:42])=[C:39]3[C:34]([CH:35]=[CH:36][CH:37]=[N:38]3)=[CH:33][CH:32]=2)[OH:30])=[CH:25][CH:24]=1>C(Cl)Cl>[F:22][C:23]1[CH:24]=[CH:25][C:26]([C:29]([C:31]2[C:40]([N+:41]([O-:43])=[O:42])=[C:39]3[C:34]([CH:35]=[CH:36][CH:37]=[N:38]3)=[CH:33][CH:32]=2)=[O:30])=[CH:27][CH:28]=1
Reactant: O=[N+]([O-])c1c(C(O)c2ccc(F)cc2)ccc2cccnc12
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: O=C(c1ccc(F)cc1)c1ccc2cccnc2c1[N+](=O)[O-]
Temperature: 30 °C
Reaction time: 18 h
Yield: 75 %

Procedure:
PDC (404 mg, 1.08 mmol) was added to a solution of (4-fluoro-phenyl)-(8-nitro-quinolin-7-yl)-methanol (Intermediate 337) (214 mg, 0.72 mmol) in DCM (10 ml). The mixture was heated to 30° C. and stirring was continued for 18 h. After cooling, the mixture was concentrated in vacuo. The crude residue was dissolved in toluene, filtered and concentrated in vacuo to give the title compound (160 mg, 75%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH:16][CH:15]=1)[C:6]([CH:24]([OH:29])[CH2:25][CH2:26][CH2:27][CH3:28])=[C:5]2[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.CO.C(OC(C)C)(C)C>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([CH2:13][C:14]1[CH:15]=[CH:16][C:17]([S:20]([CH3:23])(=[O:21])=[O:22])=[CH:18][CH:19]=1)[C:6]([C:24](=[O:29])[CH2:25][CH2:26][CH2:27][CH3:28])=[C:5]2[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: CCCCC(O)c1c(-c2ccccc2)c2cc(Cl)ccc2c(=O)n1Cc1ccc(S(C)(=O)=O)cc1
Solvent: CC(C)OC(C)C
Solvent: CO
Product: CCCCC(=O)c1c(-c2ccccc2)c2cc(Cl)ccc2c(=O)n1Cc1ccc(S(C)(=O)=O)cc1

Procedure:
In the same manner as in Example 311, the title compound was synthesized using 6-chloro-3-(1-hydroxypentyl)-2-(4-methanesulfonylbenzyl)-4-phenyl-2H-isoquinolin-1-one. Crystals (methanol-diisopropyl ether).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:15]=[CH:16][C:17]=1[NH:18][C:19]1[N:24]=[C:23]([NH:25][C:26]2[CH:34]=[CH:33][CH:32]=[C:31]3[C:27]=2[C:28](=[O:36])[N:29]([CH3:35])[CH2:30]3)[C:22]([C:37]([F:40])([F:39])[F:38])=[CH:21][N:20]=1)[CH2:6][P:7](=[O:14])([O:11]CC)[O:8][CH2:9][CH3:10]>Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:15]=[CH:16][C:17]=1[NH:18][C:19]1[N:24]=[C:23]([NH:25][C:26]2[CH:34]=[CH:33][CH:32]=[C:31]3[C:27]=2[C:28](=[O:36])[N:29]([CH3:35])[CH2:30]3)[C:22]([C:37]([F:39])([F:40])[F:38])=[CH:21][N:20]=1)[CH2:6][P:7](=[O:11])([OH:14])[O:8][CH2:9][CH3:10]
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3cccc4c3C(=O)N(C)C4)n2)c(OC)c1)OCC
Agent: Cl
Product: CCOP(=O)(O)Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3cccc4c3C(=O)N(C)C4)n2)c(OC)c1

Procedure:
A solution of diethyl [3-methoxy-4-({4-[(2-methyl-3-oxo-2,3-dihydro-1H-isoindol-4-yl)amino]-5-(trifluoromethyl)pyrimidin-2-yl}amino)benzyl]phosphonate (14.7 mg, 0.0254 mmol) in 37% HCl (1 mL) was heated at 80° C. for 3.5 h. The reaction mixture was concentrated in vacuo. The residue was dissolved in DMSO and submitted for mass-directed purification (under basic conditions; ammonium bicarbonate buffer, pH 9). The fractions containing product were combined and concentrated in vacuo, yielding the title material as a white solid, 4.5 mg (32%). 1H NMR (400 MHz, MeOD) δ ppm: 8.50 (br s, 1H), 8.32 (s, 1H), 7.71 (d, J=8.1 Hz, 1H), 7.47 (t, J=8.0 Hz, 1H), 7.16 (d, J=7.3 Hz, 1H), 7.12 (t, J=1.6 Hz, 1H), 6.94 (dt, J=8.1, 1.9 Hz, 1H), 4.45 (s, 2H), 3.89 (s, 3H), 3.88 (quin, J=6.9 Hz, 2H), 3.16 (s, 3H), 3.02 (d, J=20.2 Hz, 2H), 1.20 (t, J=7.1 Hz, 3H). MS (ES+): m/z 552.15 [MH+]; HPLC: tR=2.81 min (ZQ3, polar—5 min).
Reaction SMILES: C[O:2][C:3](=[O:35])[C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11]2[CH:12]=[N:13][C:14]([O:17][CH2:18][C:19]3[C:20]([C:27]4[C:32]([Cl:33])=[CH:31][CH:30]=[CH:29][C:28]=4[Cl:34])=[N:21][O:22][C:23]=3[CH:24]([CH3:26])[CH3:25])=[CH:15][CH:16]=2)=[CH:6][CH:5]=1.[OH-].[Na+].O>CO>[Cl:33][C:32]1[CH:31]=[CH:30][CH:29]=[C:28]([Cl:34])[C:27]=1[C:20]1[C:19]([CH2:18][O:17][C:14]2[N:13]=[CH:12][C:11]([O:10][C:7]3[CH:6]=[CH:5][C:4]([C:3]([OH:35])=[O:2])=[CH:9][CH:8]=3)=[CH:16][CH:15]=2)=[C:23]([CH:24]([CH3:26])[CH3:25])[O:22][N:21]=1
Reactant: COC(=O)c1ccc(Oc2ccc(OCc3c(-c4c(Cl)cccc4Cl)noc3C(C)C)nc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)c1onc(-c2c(Cl)cccc2Cl)c1COc1ccc(Oc2ccc(C(=O)O)cc2)cn1
Temperature: 25 °C
Reaction time: 30 h

Procedure:
To a solution of 4-{6-[3-(2,6-dichloro-phenyl)-5-isopropyl-isoxazol-4-ylmethoxy]-pyridin-3-yloxy}-benzoic acid methyl ester (0.070 g, 0.14 mmol) in methanol (5 ml) was added NaOH (0.104 g, 2.6 mmol) and water (0.25 ml) and the reaction mixture was stirred at room temperature for 30 h. Then solvent was evaporated, water (1.5 ml) was added and the mixture was acidified to pH 6 with 1N hydrochloric acid and the resulting solution was extracted with ethyl acetate. The extract was dried over anhydrous Na2SO4 and the solvent was removed under reduced pressure to afford 4-{6-[3-(2,6-dichloro-phenyl)-5-isopropyl-isoxazol-4-ylmethoxy]-pyridin-3-yloxy}-benzoic acid as colorless oil. Yield: 0.037 g (53%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:44])[CH2:4][CH2:5][CH2:6][CH2:7][N:8]([CH2:33][C:34]1[CH:43]=[CH:42][C:37]([C:38]([O:40][CH3:41])=[O:39])=[CH:36][CH:35]=1)[CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[O:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22](/[CH:25]=[CH:26]/[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[CH:21][CH:20]=1.[H][H]>[Pd].C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:44])[CH2:4][CH2:5][CH2:6][CH2:7][N:8]([CH2:33][C:34]1[CH:43]=[CH:42][C:37]([C:38]([O:40][CH3:41])=[O:39])=[CH:36][CH:35]=1)[CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[O:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)=[CH:21][CH:20]=1
Reactant: COC(=O)CCCCN(CCc1ccccc1OCc1ccc(/C=C/c2ccccc2)cc1)Cc1ccc(C(=O)OC)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COC(=O)CCCCN(CCc1ccccc1OCc1ccc(CCc2ccccc2)cc1)Cc1ccc(C(=O)OC)cc1
Reaction time: 1 h

Procedure:
781.8 mg (1.34 mmol) of methyl 4-({(5-methoxy-5-oxopentyl)[2-({4-[(E)-2-phenyl-ethenyl]benzyl}oxy)phenethyl]amino)methyl)benzoate from Ex. 6 and 80.0 mg of 10% palladium on activated carbon in 10 ml of ethyl acetate are hydrogenated under atmospheric pressure. After 1 hour, the calculated amount of hydrogen has been taken up. The solution is filtered and the solvent distilled off under reduced pressure. The crude product is purified by chromatography over silica gel using the mobile phase cyclohexane/ethyl acetate=10:1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:39]=[CH:40][CH:41]=1)[CH2:5][NH:6][C:7]1[N:12]=[C:11]([C:13]2[C:21]3[C:16](=[N:17][C:18]([NH:22][CH2:23][CH2:24][N:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)=[N:19][CH:20]=3)[N:15](COCC[Si](C)(C)C)[N:14]=2)[CH:10]=[CH:9][CH:8]=1.C(O)(C(F)(F)F)=O.C([O-])(O)=O.[Na+]>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:39]=[CH:40][CH:41]=1)[CH2:5][NH:6][C:7]1[N:12]=[C:11]([C:13]2[C:21]3[C:16](=[N:17][C:18]([NH:22][CH2:23][CH2:24][N:25]4[CH2:26][CH2:27][O:28][CH2:29][CH2:30]4)=[N:19][CH:20]=3)[NH:15][N:14]=2)[CH:10]=[CH:9][CH:8]=1
Reactant: C[Si](C)(C)CCOCn1nc(-c2cccc(NCc3cccc(Cl)c3)n2)c2cnc(NCCN3CCOCC3)nc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Clc1cccc(CNc2cccc(-c3n[nH]c4nc(NCCN5CCOCC5)ncc34)n2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of [3-[6-(3-chloro-benzylamino)-pyridin-2-yl]-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl]-(2-morpholin-4-yl-ethyl)-amine (110 mg, 0.185 mmol) in dichloromethane (2.5 mL) was added TFA (2.5 mL). The reaction mixture was stirred for 2 hours at room temperature. The pH of the mixture was adjusted to about 8 with saturated NaHCO3 solution. The resulting mixture was extracted with ethyl acetate. The organic layer was dried and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, dichloromethane:MeOH, 20:1), then further purified by prep-HPLC to give {3-[6-(3-chloro-benzylamino)-pyridin-2-yl]-1H-pyrazolo[3,4-d]pyrimidin-6-yl}-(2-morpholin-4-yl-ethyl)-amine. (Yield 23 mg, 26%).
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[Br:7][C:8]1[CH:9]=[C:10]([C:14]#[C:15][Si](C)(C)C)[CH:11]=[CH:12][CH:13]=1>CO>[Br:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]#[CH:15])[CH:9]=1
Reactant: C[Si](C)(C)C#Cc1cccc(Br)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: C#Cc1cccc(Br)c1

Procedure:
To each of two 1 L flasks was charged K2CO3 (68 g, 493.7 mmol), a large magnetic stirbar, and MeOH (250 mL). Stirring was begun and once the reaction mixtures were stirring without any problems, ((3-bromophenyl)ethynyl)trimethylsilane (12.5 g, 49.4 mmol, 10.5 mL) was added to each reaction vessel and the reaction mixtures were refluxed overnight. The cooled reaction mixtures were filtered and the filter cake was washed with MeOH. The filtrate was diluted with water and washed with Hexanes (at least 500 mL) three times. The combined organic layers were concentrated to give a yellow oil that was absorbed onto 50 g Celite. Flash chromatography (SiO2, Hexanes) provided 9.1 g, 50%, of the title compound as a colorless to light yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([F:9])[C:5](Cl)=[N:6][CH:7]=1.[N:10]1([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.C(OCC)C>[Br:1][C:2]1[CH:3]=[C:4]([F:9])[C:5]([N:13]2[CH2:12][CH2:11][N:10]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:15][CH2:14]2)=[N:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Fc1cc(Br)cnc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1CCN(c2ncc(Br)cc2F)CC1
Yield: 27.8 %

Procedure:
In a pressure tube, 5-bromo-2-chloro-3-fluoropyridine (7.89 ml, 49.9 mmol), tert-butyl piperazine-1-carboxylate (9293.48 mg, 49.9 mmol), potassium carbonate (8275.33 mg, 59.88 mmol) in dimethylsulfoxide (40 ml) were combined and refluxed at 120 C for ovn. The reaction was cooled down, diluted with ethyl ether (100 mL). The solution was washed with water (40 mL×2), brine (50 mL), filtered, dried, and concentrated. The reaction was purified on silica by flash chromatography to provide of tert-butyl 4-(5-bromo-3-fluoropyridin-2-yl)piperazine-1-carboxylate (5000 mg, 28%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10](=[N:12][OH:13])[CH3:11].[C:14](OC(=O)C)(=[O:16])[CH3:15]>>[C:14]([O:13][N:12]=[C:10]([C:3]1[CH:4]=[C:5]([O:8][CH3:9])[CH:6]=[CH:7][C:2]=1[OH:1])[CH3:11])(=[O:16])[CH3:15]
Reactant: CC(=O)OC(C)=O
Reactant: COc1ccc(O)c(C(C)=NO)c1
Product: COc1ccc(O)c(C(C)=NOC(C)=O)c1
Temperature: 50 °C

Procedure:
A mixture of 1-(2-Hydroxy-5-methoxy-phenyl)-ethanone oxime (13.7 g, 0.076 mol.) and acetic anhydride (50 mL) was heated at 50° C. for 10 min. The mixture was cooled to 0° C., filtered, and the filtrant washed with water (50 mL) and dried to give 15.5 g solid. MS (m/e): 224 (M++1), 164 (100).
Reaction SMILES: [CH3:1][N:2]1[CH2:27][CH2:26][C:5]2[N:6]([CH2:14][C:15]([C:18]3[CH:19]=[CH:20][C:21]([C:24]#[N:25])=[N:22][CH:23]=3)([OH:17])[CH3:16])[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.[OH-:28].[K+]>C(O)(C)(C)C.[Cl-].[Na+].O>[CH3:1][N:2]1[CH2:27][CH2:26][C:5]2[N:6]([CH2:14][C:15]([C:18]3[CH:19]=[CH:20][C:21]([C:24]([NH2:25])=[O:28])=[N:22][CH:23]=3)([OH:17])[CH3:16])[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1
Reactant: Cc1ccc2c(c1)c1c(n2CC(C)(O)c2ccc(C#N)nc2)CCN(C)C1
Reactant: [OH-]
Agent: [Cl-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CC(C)(C)O
Product: Cc1ccc2c(c1)c1c(n2CC(C)(O)c2ccc(C(N)=O)nc2)CCN(C)C1
Temperature: 80 °C

Procedure:
A mixture of 5-(1-(2,8-dimethyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)-2-hydroxypropan-2-yl)picolinonitrile (300 mg, 0.833 mmol), crushed KOH (140 mg, 2.499 mmol) in 12 mL tert-butanol was heated at 80° C. for 2 h. The reaction was monitored by TLC. The reaction mixture was allowed to cool at RT, diluted with brine (30 mL) and extracted with ethyl acetate (2×100 mL). The combined organic layer was washed with water (3×100 mL), dried over anhydrous sodium sulfate and concentrated to obtain the crude product, which was purified by Preparative HPLC followed by chiral HPLC to obtain 5-(1-(1,2,3,4-tetrahydro-2,8-dimethylpyrido[4,3-b]indol-5-yl)-2-hydroxypropan-2-yl)pyridine-2-carboxamide. 1H NMR (CDCl3, freebase) δ (ppm): 8.49 (s, 1H), 8.04 (d, 1H), 7.86 (d, 1H), 7.66 (s, 1H), 7.01 (s, 1H), 6.85 (s, 1H), 6.78 bs (NH), 5.48 s (OH),4.16 (dd, 2H), 3.44 (q, 2H), 2.9 (m, 2H), 2.7 (m, 2H), 2.45 (s, 3H), 2.35 (s, 3H), 2.35 (s, 3H), 1.6 (s, 3H). Separation by chiral HPLC provided enantiomers II-136a-b.
Reaction SMILES: Br[C:2]1[C:3]([O:14][CH3:15])=[C:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.C([Li])CCC.[CH2:21]([O:28][C:29]1[C:34]([C:35]([CH3:38])([CH3:37])[CH3:36])=[CH:33][CH:32]=[CH:31][C:30]=1[C:39]([C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)=[O:40])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.[Cl-].[NH4+]>O1CCCC1>[CH2:21]([O:28][C:29]1[C:34]([C:35]([CH3:38])([CH3:37])[CH3:36])=[CH:33][CH:32]=[CH:31][C:30]=1[C:39]([C:2]1[C:3]([O:14][CH3:15])=[C:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1)([C:41]1[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=1)[OH:40])[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: COc1c(Br)cccc1-c1ccccc1
Reactant: CC(C)(C)c1cccc(C(=O)c2ccccc2)c1OCc1ccccc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1c(-c2ccccc2)cccc1C(O)(c1ccccc1)c1cccc(C(C)(C)C)c1OCc1ccccc1
Reaction time: 0.33 h
Yield: 42.9 %

Procedure:
A solution of 3-bromo-2-methoxybiphenyl (1.18 g, 4.5 mmol) in anhydrous tetrahydrofuran (20 mL) was stirred under nitrogen at −78° C. and 2.5 M n-butyllithium in hexanes (1.8 mL, 4.5 mmol) was added at such a rate that the temperature did not exceed −70° C. Stirring was continued on the cold bath for 20 min and a solution of 14 (1.55 g, 4.5 mmol) in dry tetrahydrofuran (8 mL) was added at such a rate that the temperature did not exceed −65° C. Stirring was continued on the cold bath for 30 min then the reaction mixture was allowed to reach room temperature and stirred for 2 hr. The reaction mixture was poured on saturated ammonium chloride (150 mL) and extracted with ethyl acetate (180 mL). The organic extract was washed with water (2×80 mL), dried over sodium sulfate and stripped. The crude product was purified by chromatography on silica (85 g) with 0.2% ethyl acetate in heptane (6 L). Pure 15 (1.02 g, 43%) was isolated.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH2:16][CH:17]([CH3:19])[CH3:18])[CH3:15])[C:11]([C:20]([F:23])([F:22])[F:21])=[CH:10][C:9]=1[NH:24][C:25](=[O:43])[CH2:26][C:27]([C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([C:35]2[CH:40]=[C:39]([CH3:41])[N:38]=[C:37]([CH3:42])[CH:36]=2)[CH:30]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:42][C:37]1[CH:36]=[C:35]([C:31]2[CH:30]=[C:29]([C:27]3[CH2:26][C:25](=[O:43])[NH:24][C:9]4[CH:10]=[C:11]([C:20]([F:22])([F:21])[F:23])[C:12]([N:14]([CH2:16][CH:17]([CH3:18])[CH3:19])[CH3:15])=[CH:13][C:8]=4[N:7]=3)[CH:34]=[CH:33][CH:32]=2)[CH:40]=[C:39]([CH3:41])[N:38]=1
Reactant: Cc1cc(-c2cccc(C(=O)CC(=O)Nc3cc(C(F)(F)F)c(N(C)CC(C)C)cc3NC(=O)OC(C)(C)C)c2)cc(C)n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(-c2cccc(C3=Nc4cc(N(C)CC(C)C)c(C(F)(F)F)cc4NC(=O)C3)c2)cc(C)n1

Procedure:
The title compound was prepared from [2-{3-[3-(2,6-dimethyl-pyridin-4-yl)-phenyl]-3-oxo-propionylamino}-5-(isobutyl-methyl-amino)-4-trifluoromethyl-phenyl]-carbamic acid tert-butyl ester (Example M303) (0.37 g, 0.60 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as an off-white solid (262 mg, 88%).
Reaction SMILES: [C:1]([C:3]1([C:6]2[CH:7]=[C:8]([CH:12]=[CH:13][CH:14]=2)[C:9](O)=[O:10])[CH2:5][CH2:4]1)#[N:2].C(Cl)(=O)C([Cl:18])=O.CN(C)C=O>O1CCCC1>[C:1]([C:3]1([C:6]2[CH:7]=[C:8]([CH:12]=[CH:13][CH:14]=2)[C:9]([Cl:18])=[O:10])[CH2:5][CH2:4]1)#[N:2]
Reactant: N#CC1(c2cccc(C(=O)O)c2)CC1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: N#CC1(c2cccc(C(=O)Cl)c2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 3-(1-cyanocyclopropyl)benzoic acid (2.6 g, 13.9 mmol) in tetrahydrofuran (60 mL) were added oxalyl chloride (1.63 mL, 19.1 mmol) and N,N-dimethylformamide (about 20 μL), and the mixture was stirred at room temperature for 1 hr. The reaction mixture was concentrated under reduced pressure to give 3-(1-cyanocyclopropyl)benzoyl chloride as a colorless oil.
Reaction SMILES: CN([CH:4]=[C:5]1[C:11](=O)[C:10]2[CH:13]=[CH:14][CH:15]=[CH:16][C:9]=2[NH:8][C:7](=[O:17])[CH2:6]1)C.Cl.[C:19]([NH2:27])(=[NH:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[C:20]1([C:19]2[N:26]=[CH:4][C:5]3[CH2:6][C:7](=[O:17])[NH:8][C:9]4[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=4[C:11]=3[N:27]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CN(C)C=C1CC(=O)Nc2ccccc2C1=O
Reactant: N=C(N)c1ccccc1
Agent: Cl
Product: O=C1Cc2cnc(-c3ccccc3)nc2-c2ccccc2N1
Yield: 83 %

Procedure:
Analogous to Scheme 1, them 4-[(dimethylamino)methylene]-3,4-dihydro-1H-benzazepine-2,5-dione and benzamidine hydrochloride. Yield: 83%.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([O:11][CH3:12])[O:9][CH3:10].O(CC)CC.C([Li])CCC.[N:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH:29]=[O:30])[CH:24]=1>CCCCCC>[CH3:10][O:9][CH:8]([O:11][CH3:12])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[CH:29]([C:25]1[CH:24]=[N:23][CH:28]=[CH:27][CH:26]=1)[OH:30]
Reactant: COC(OC)c1ccccc1Br
Reactant: O=Cc1cccnc1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOCC
Product: COC(OC)c1ccccc1C(O)c1cccnc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 99.9 %

Procedure:
To a stirred and cooled (-78° C.) mixture of 50 parts of 1-bromo-2-(dimethoxymethyl)benzene and 245 parts of 1,1'-oxybisethane were added dropwise 59 parts of a 1-butyllithium solution 2.5M in hexane. Upon complete addition, stirring was continued for 10 minutes at room temperature. A solution of 23.1 parts of 3-pyridinecarboxaldehyde in 42 parts of 1,1'-oxybisethane was added dropwise to the reaction mixture. Upon completion, the mixture was allowed to reach room temperature. The mixture was taken up in ice water and the product was extracted with 1,1'-oxybisethane. The extract was dried, filtered and evaporated, yielding 56 parts (99.9%) of α-[2-(dimethoxymethyl)phenyl]-3-pyridinemethanol as a residue (intermediate 1).
Reaction SMILES: [F:1][CH:2]([F:35])[O:3][C:4]1[CH:33]=[CH:32][C:7]([CH2:8][NH:9][C:10]([C@H:12]2[CH2:17][NH:16][CH2:15][CH2:14][N:13]2[S:18]([C:21]2[CH:26]=[CH:25][C:24]([O:27][C:28]([F:31])([F:30])[F:29])=[CH:23][CH:22]=2)(=[O:20])=[O:19])=[O:11])=[CH:6][C:5]=1[F:34].C(N(CC)C(C)C)(C)C.Cl[C:46]1[S:47][C:48]2[C:53]([Cl:54])=[N:52][C:51]([C:55]([F:58])([F:57])[F:56])=[N:50][C:49]=2[N:59]=1>C(Cl)(Cl)Cl>[F:35][CH:2]([F:1])[O:3][C:4]1[CH:33]=[CH:32][C:7]([CH2:8][NH:9][C:10]([C@H:12]2[CH2:17][N:16]([C:46]3[S:47][C:48]4[C:53]([Cl:54])=[N:52][C:51]([C:55]([F:58])([F:57])[F:56])=[N:50][C:49]=4[N:59]=3)[CH2:15][CH2:14][N:13]2[S:18]([C:21]2[CH:22]=[CH:23][C:24]([O:27][C:28]([F:29])([F:31])[F:30])=[CH:25][CH:26]=2)(=[O:20])=[O:19])=[O:11])=[CH:6][C:5]=1[F:34]
Reactant: O=C(NCc1ccc(OC(F)F)c(F)c1)[C@H]1CNCCN1S(=O)(=O)c1ccc(OC(F)(F)F)cc1
Reactant: FC(F)(F)c1nc(Cl)c2sc(Cl)nc2n1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Product: O=C(NCc1ccc(OC(F)F)c(F)c1)[C@H]1CN(c2nc3nc(C(F)(F)F)nc(Cl)c3s2)CCN1S(=O)(=O)c1ccc(OC(F)(F)F)cc1
Yield: 79 %

Procedure:
To a solution of the compound (796 mg) obtained in Step 5 in chloroform (8 ml) were successively added, with stirring under ice-cooling, N,N-diisopropylethylamine (234 mg) and 2,7-dichloro-5-trifluoromethyl-thiazolo[4,5-d]pyrimidine (414 mg). After stirring at room temperature for 1 hr, the mixture was partitioned by adding chloroform and water. The aqueous layer was extracted with chloroform, and the organic layer was dried over anhydrous magnesium sulfate, filtrated, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:n-hexane=6:1-1:2) to give the title compound (912 mg).