Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-].COC[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.FC1C=C(OC)C(F)=CC=1N1CCC(=O)CC1.[Br-].[CH2:42]([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH2:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1.[F:69][C:70]1[CH:75]=[C:74]([O:76][CH3:77])[C:73]([F:78])=[CH:72][C:71]=1[N:79]1[CH2:84][CH2:83][CH:82]([CH:85]=O)[CH2:81][CH2:80]1>>[F:69][C:70]1[CH:75]=[C:74]([O:76][CH3:77])[C:73]([F:78])=[CH:72][C:71]=1[N:79]1[CH2:84][CH2:83][CH:82](/[CH:85]=[CH:42]\[CH2:43][C:44]2[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=2)[CH2:81][CH2:80]1
Reactant: c1ccc(CC[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: COc1cc(F)c(N2CCC(C=O)CC2)cc1F
Agent: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: COc1cc(F)c(N2CCC(=O)CC2)cc1F
Agent: [Br-]
Product: COc1cc(F)c(N2CCC(/C=C\Cc3ccccc3)CC2)cc1F
Yield: 78.6 %

Procedure:
Production Example 74 was repeated except that methoxymethyltriphenylphosphonium chloride and 1-(2,5-difluoro-4-methoxyphenyl)piperidin-4-one were replaced with phenethyltri-phenylphosphonium bromide (133 mg) and 1-(2,5-difluoro-4-methoxyphenyl)-4-piperidinecarbaldehyde (35 mg), respectively, and the resulting crude product was purified on TLC (developer, hexane: ethyl acetate=10:1) to provide (Z)-1-(2,5-difluoro-4-methoxyphenyl)-4-(3-phenyl-1-propen-1-yl)piperidine (37 mg).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[C:5]([C:9]#[N:10])=[CH:4][N:3]=1.[CH2:11]([C:13]1[C:18]([CH2:19][NH2:20])=[CH:17][N:16]=[CH:15][N:14]=1)[CH3:12].CCN(C(C)C)C(C)C>C(O)(C)C>[Cl:8][C:6]1[C:5]([C:9]#[N:10])=[CH:4][N:3]=[C:2]([NH:20][CH2:19][C:18]2[C:13]([CH2:11][CH3:12])=[N:14][CH:15]=[N:16][CH:17]=2)[N:7]=1
Reactant: CCc1ncncc1CN
Reactant: N#Cc1cnc(Cl)nc1Cl
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: CCc1ncncc1CNc1ncc(C#N)c(Cl)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 11.4 %

Procedure:
To a mixture of 2,4-dichloropyrimidine-5-carbonitrile (1.0 equiv. 61.4) and (4-ethylpyrimidin-5-yl)methanamine (1.0 equiv.) in isopropanol (0.2 M) was added DIEA (2.0 equiv.). The mixture was stirred at room temperature under nitrogen overnight. The reaction mixture was extracted with ethyl acetate, the organic layer was washed with a solution of ammonium chloride and concentrated under vacuum to give crude product, which was purified by silica gel chromatography (30% ethyl acetate in petroleum ether) to afford the title compound (11.4% yield) as brown solid. 1H-NMR (400 MHz, CD3OD) δ (ppm) 9.95 (d, J=3.2 Hz, 1H), 8.64 (d, J=12.0 Hz, 1H), 8.58 (d, J=19.6 Hz, 1H), 4.70 (d, J=20.4 Hz, 2H), 2.97-2.87 (m, 2H), 1.33-1.27 (m, 3H); MS (ESI) m/z 275.1 [M+H]+.
Reaction SMILES: C([N:8]1[C@@H:12]2[CH2:13][CH2:14][C@@:15]3([CH2:19][C@@H:18]([C:20]4[CH:25]=[C:24]([O:26][C:27]([F:30])([F:29])[F:28])[CH:23]=[CH:22][C:21]=4[O:31]CC4C=CC=CC=4)[CH2:17][O:16]3)[C@:9]1([C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)[CH2:10][CH:11]2[C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])C1C=CC=CC=1>[Pd].C(O)C>[C:42]([O:41][C:39]([CH:11]1[CH2:10][C@:9]2([C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=3)[NH:8][C@@H:12]1[CH2:13][CH2:14][C@:15]12[CH2:19][C@@H:18]([C:20]2[CH:25]=[C:24]([O:26][C:27]([F:30])([F:29])[F:28])[CH:23]=[CH:22][C:21]=2[OH:31])[CH2:17][O:16]1)=[O:40])([CH3:45])([CH3:43])[CH3:44]
Reactant: CC(C)(C)OC(=O)C1C[C@]2(c3ccccc3)N(Cc3ccccc3)[C@@H]1CC[C@@]21C[C@@H](c2cc(OC(F)(F)F)ccc2OCc2ccccc2)CO1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)C1C[C@]2(c3ccccc3)N[C@@H]1CC[C@@]21C[C@@H](c2cc(OC(F)(F)F)ccc2O)CO1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 114 %

Procedure:
A mixture of (1R*,2R*,4′S*,5R*)-8-benzyl-4′-(2-benzyloxy-5-trifluoromethoxyphenyl)-6-(tert-butoxycarbonyl)-2′,3′,4′,5′-tetrahydro-1-phenylspiro[8-azabicyclo[3.2.1]octane-2,2′-furan] (Description 28; 1.065 g, 1.52 mmol), 10% palladium on charcoal (340 mg, 0.32 mmol) and ethanol (20 ml) was stirred under hydrogen atmosphere (1 atm) at +65° C. for 1.5 hour. The reaction mixture was cooled to room temperature, flushed with nitrogen gas and filtered through a pad of Celite™. The filtrate was concentrated to give the title compound (900 mg, 97%).
Reaction SMILES: [CH2:1]([S:3]([C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[NH:8][N:7]=1)(=[O:5])=[O:4])[CH3:2].[Cl:15][C:16]1[CH:33]=[CH:32][C:19]2[N:20]([CH2:25][CH2:26][CH2:27][S:28]([CH3:31])(=[O:30])=[O:29])[C:21]([CH2:23]Cl)=[N:22][C:18]=2[CH:17]=1>>[Cl:15][C:16]1[CH:33]=[CH:32][C:19]2[N:20]([CH2:25][CH2:26][CH2:27][S:28]([CH3:31])(=[O:29])=[O:30])[C:21]([CH2:23][N:8]3[C:9]4[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=4)[C:6]([S:3]([CH2:1][CH3:2])(=[O:5])=[O:4])=[N:7]3)=[N:22][C:18]=2[CH:17]=1
Reactant: CS(=O)(=O)CCCn1c(CCl)nc2cc(Cl)ccc21
Reactant: CCS(=O)(=O)c1n[nH]c2ccccc12
Product: CCS(=O)(=O)c1nn(Cc2nc3cc(Cl)ccc3n2CCCS(C)(=O)=O)c2ccccc12

Procedure:
The title compound was prepared in analogy to Example 1-2 by using 3-(ethylsulfonyl)-1H-indazole and 5-chloro-2-(chloromethyl)-1-(3-(methylsulfonyl)propyl)-1H-benzo[d]imidazole instead of 3-(methylsulfonyl)-1H-indole and 5-chloro-2-(chloromethyl)-1-(3-(methylsulfonyl)propyl)-1H-benzo[d]imidazole.
Reaction SMILES: [CH2:1]([S:3]([C:6]1[CH:7]=[C:8]([CH:10]=[CH:11][CH:12]=1)[NH2:9])(=[O:5])=[O:4])[CH3:2].[CH:13](S(C1C=CC=CC=1)(=O)=O)(C)C>>[CH:1]([S:3]([C:6]1[CH:7]=[C:8]([CH:10]=[CH:11][CH:12]=1)[NH2:9])(=[O:5])=[O:4])([CH3:13])[CH3:2]
Reactant: CC(C)S(=O)(=O)c1ccccc1
Reactant: CCS(=O)(=O)c1cccc(N)c1
Product: CC(C)S(=O)(=O)c1cccc(N)c1

Procedure:
3-Isopropylsulfonylaniline was synthesized in analogy to 3-ethylsulfonylaniline starting with 3-(isopropylsulfonyl)-benzene.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C@@H:11]([N:18]1[N:22]=[N:21][CH:20]=[N:19]1)[C@H:12]1[CH2:17][CH2:16][CH2:15][NH:14][CH2:13]1.[CH2:23](N(CC)CC)[CH3:24].ICC>C(#N)C.C(OCC)(=O)C>[CH2:23]([N:14]1[CH2:15][CH2:16][CH2:17][C@H:12]([C@@H:11]([C:2]2[CH:3]=[CH:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH:1]=2)[N:18]2[N:22]=[N:21][CH:20]=[N:19]2)[CH2:13]1)[CH3:24]
Reactant: c1ccc2cc([C@H]([C@H]3CCCNC3)n3ncnn3)ccc2c1
Reactant: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CCI
Solvent: CC#N
Product: CCN1CCC[C@H]([C@@H](c2ccc3ccccc3c2)n2ncnn2)C1
Temperature: 40 °C

Procedure:
(3S)-3-[(S)-naphthalen-2-yl(2H-tetrazol-2-yl)methyl]piperidine (2.0 mmol) from Example 2 was dissolved in acetonitrile and the solution was treated with triethylamine (3.0 mmol) at room temperature. To this solution was added iodoethane in acetonitrile slowly and the solution was warmed up to 40° C. After the completion of the reaction, the reaction mixture was diluted with ethyl acetate, washed with 5% aq NaOH, water, brine, and dried over MgSO4. After concentration, the crude product was purified by flash column chromatography with a 10% Methanol in dichloromethane to afford (3S)-1-ethyl-3-[(S)-naphthalen-2-yl(2H-tetrazol-2-yl)methyl]piperidine.
Reaction SMILES: [CH:1]1([N:4]2[C:12]3[C:7](=[C:8](OS(C(F)(F)F)(=O)=O)[CH:9]=[C:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:11]=3)[CH:6]=[CH:5]2)[CH2:3][CH2:2]1.[CH3:26][N:27](C=O)C>[C-]#N.[Zn+2].[C-]#N>[C:26]([C:8]1[CH:9]=[C:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:11]=[C:12]2[C:7]=1[CH:6]=[CH:5][N:4]2[CH:1]1[CH2:3][CH2:2]1)#[N:27]
Reactant: CN(C)C=O
Reactant: CCOC(=O)c1cc(OS(=O)(=O)C(F)(F)F)c2ccn(C3CC3)c2c1
Agent: [C-]#N
Agent: [Zn+2]
Product: CCOC(=O)c1cc(C#N)c2ccn(C3CC3)c2c1
Temperature: 90 °C
Reaction time: 1.5 h

Procedure:
In a 300-mL egg plant-type flask, tetrakistriphenylphosphine palladium (2.31 g, 2.0 mmol) was added to a DMF (50 mL) solution of ethyl 1-cyclopropyl-4-{[(trifluoromethyl)sulfonyl]oxy}-1H-indole-6-carboxylate (7.54 g, 20 mmol) and zinc cyanide (4.70 g, 40 mmol), then purged with nitrogen, and stirred at 90° C. for 1.5 hours. After left cooled, this was diluted with ethyl acetate (100 mL), and aqueous 25% ammonia (50 mL) and water (50 mL) were added thereto, stirred at room temperature for 30 minutes, extracted with ethyl acetate, and washed with water and saturated saline water in that order. The reaction solution was dried with sodium sulfate, filtered, concentrated, and purified through silica gel column chromatography (Biotage [SiO2, 40+M]) with a hexane/ethyl acetate developer system to obtain the title compound as a yellow solid.
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[C:7]([CH3:27])[NH:8][C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4].N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.C(P(CCCC)CCCC)CCC.[C:59]1([C:65]2[S:66][C:67]([CH2:70]O)=[CH:68][N:69]=2)[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=1>C(OCC)(=O)C.O1CCCC1>[CH2:1]([C:5]1[N:6]=[C:7]([CH3:27])[N:8]([CH2:70][C:67]2[S:66][C:65]([C:59]3[CH:60]=[CH:61][CH:62]=[CH:63][CH:64]=3)=[N:69][CH:68]=2)[C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(C)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: OCc1cnc(-c2ccccc2)s1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCCc1nc(C)n(Cc2cnc(-c3ccccc3)s2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 62.6 %

Procedure:
A mixture of 4′-[(4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile (1 g), 1,1′-(azodicarbonyl)dipiperidine (1.41 g), tributylphosphine (1.56 mL), (2-phenyl-1,3-thiazol-5-yl)methanol (0.8 g) and tetrahydrofuran (50 mL) was stirred at room temperature for 4 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.93 g, 63%).
Reaction SMILES: [C:1]1([CH3:10])[CH:6]=[CH:5][C:4]([C:7](Cl)=[O:8])=[CH:3][CH:2]=1.[C@@H:11]1([N:19]2[CH:27]=[C:25]([CH3:26])[C:23](=[O:24])[NH:22][C:20]2=[O:21])[O:18][C@H:15]([CH2:16][OH:17])[C@@H:13]([OH:14])[CH2:12]1>N1C=CC=CC=1>[C:1]1([CH3:10])[CH:6]=[CH:5][C:4]([C:7]([CH:16]([OH:17])[C@H:15]2[O:18][C@@H:11]([N:19]3[CH:27]=[C:25]([CH3:26])[C:23](=[O:24])[NH:22][C:20]3=[O:21])[CH2:12][C@@H:13]2[OH:14])=[O:8])=[CH:3][CH:2]=1
Reactant: Cc1cn([C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)[nH]c1=O
Reactant: Cc1ccc(C(=O)Cl)cc1
Solvent: c1ccncc1
Product: Cc1ccc(C(=O)C(O)[C@H]2O[C@@H](n3cc(C)c(=O)[nH]c3=O)C[C@@H]2O)cc1
Temperature: 25 °C
Reaction time: 16.5 h
Yield: 16.6 %

Procedure:
p-Toluoyl chloride (6.78 mL, 51.25 mmol) was added dropwise (to keep the temperature of the mixture below 5° C.) to a cooled (ice/water bath) stirred suspension of thymidine (12.112 g, 50 mmol) in anhydrous pyridine (50 mL) under an argon atmosphere. After complete addition, the bath was removed and the mixture was allowed to warm to room temperature. After 16.5 h, thin layer chromatography (using EtOAc as eluant) showed that no starting material was remaining. The mixture was poured into ice (50 g), and after the ice melted, a white precipitate was collected by filtration. The aqueous filtrate was extracted with CH2Cl2 (3×50 mL) and the combined organic extracts were washed with 1M HCl (3×50 mL), saturated aqueous NaHCO3 (3×50 mL) and water (3×50 mL). The CH2Cl2 solution was dried (MgSO4), filtered and the filtrate concentrated under reduced pressure to give a pale yellow foam (3.00 g). The solid material was combined, and recrystallized in ca. 2 g batches from CH2Cl2 (300 mL). After each filtration, the volume of the filtrate was reduced to 100 mL and cooled. A white solid crystallizing from solution was collected by filtration. This filtrate was used as the solvent for the next crystallization. This was done multiple times. The insoluble solids removed after each crystallization were combined and recrystallized as above.
Reaction SMILES: C[O:2][C:3](=[O:24])[C:4]1[CH:9]=[C:8]([C:10]2[S:11][CH:12]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=3)[N:14]=2)[CH:7]=[CH:6][C:5]=1Br.[Cl:25][C:26]1[C:31]([C:32]([F:35])([F:34])[F:33])=[CH:30][CH:29]=[CH:28][C:27]=1B(O)O>>[Cl:25][C:26]1[C:31]([C:32]([F:33])([F:34])[F:35])=[CH:30][CH:29]=[CH:28][C:27]=1[C:5]1[C:4]([C:3]([OH:2])=[O:24])=[CH:9][C:8]([C:10]2[S:11][CH:12]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=3)[N:14]=2)=[CH:7][CH:6]=1
Reactant: OB(O)c1cccc(C(F)(F)F)c1Cl
Reactant: COC(=O)c1cc(-c2nc(-c3ccc(Cl)c(Cl)c3)cs2)ccc1Br
Product: O=C(O)c1cc(-c2nc(-c3ccc(Cl)c(Cl)c3)cs2)ccc1-c1cccc(C(F)(F)F)c1Cl
Yield: 2.3 %

Procedure:
Using the conditions of General Procedure A for Suzuki Coupling and Hydrolysis in Parallel Mode, 2-bromo-5-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-benzoic acid methyl ester (which may be prepared as described for Intermediate 6; 111 mg, 0.25 mmol) was reacted with 2-chloro-3-(trifluoromethyl)phenylboronic acid (available from Combi-Blocks Inc.; 112 mg, 0.5 mmol). The resulting ester was hydrolyzed and the acid was purified to give 2′-chloro-4-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-3′-trifluoromethyl-biphenyl-2-carboxylic acid (3 mg, 2%). 1H NMR (300 MHz, DMSO-d6) δ 13.22 (br s, 1H), 8.58 (br. s., 1H), 8.50 (s, 1H), 8.27-8.36 (m, 2H), 8.10 (d, J=7.3 Hz, 1H), 7.87-7.93 (m, 1H), 7.78 (d, J=8.5 Hz, 1H), 7.61-7.70 (m, 2H), 7.47-7.53 (m, 1H).
Reaction SMILES: [CH3:1][C:2]1[C:8]([CH3:9])=[CH:7][C:5]([NH2:6])=[C:4]([N+:10]([O-:12])=[O:11])[CH:3]=1.[OH-].[Na+].S(OC)(O[CH3:19])(=O)=O>C1(C)C=CC=CC=1>[CH3:19][NH:6][C:5]1[CH:7]=[C:8]([CH3:9])[C:2]([CH3:1])=[CH:3][C:4]=1[N+:10]([O-:12])=[O:11]
Reactant: COS(=O)(=O)OC
Reactant: Cc1cc(N)c([N+](=O)[O-])cc1C
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: CNc1cc(C)c(C)cc1[N+](=O)[O-]
Temperature: 100 °C
Reaction time: 1 h
Yield: 69.4 %

Procedure:
A solution of 4,5-dimethyl-2-nitroaniline (2.00 g, 12 mmol) in toluene (25 mL) was added NaOH (1.93 g, 48 mmol). The reaction mass was stirred at 100° C. for 1 h, followed by addition of dimethyl sulphate (4.6 g, 36 mmol) and reaction mass was stirred at RT for 24 h. The reaction mass was quenched in water, extracted with DCM and concentrated to afford 1.5 g of desired product. 1H NMR (300 MHz, DMSO d6): δ 2.11 (s, 3H), 2.24 (d, J=7.8 Hz, 3H), 2.92 (s, 3H), 6.77 (m, 1H), 7.79 (m, 1H), 8.06 (s, 1H); MS (m/z): 180.92 (M+H)+.
Reaction SMILES: [OH:1][C@H:2]([C@H:10]1[O:15][CH2:14][CH2:13][N:12]([C:16]2[CH:21]=[CH:20][C:19](I)=[CH:18][CH:17]=2)[C:11]1=[O:23])[C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].[CH3:24][S:25]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1B(O)O)(=[O:27])=[O:26].S1C=CC=C1B(O)O>>[OH:1][C@H:2]([C@H:10]1[O:15][CH2:14][CH2:13][N:12]([C:16]2[CH:21]=[CH:20][C:19]([C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=3[S:25]([CH3:24])(=[O:27])=[O:26])=[CH:18][CH:17]=2)[C:11]1=[O:23])[C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4]
Reactant: CS(=O)(=O)c1ccccc1B(O)O
Reactant: CC(C)(C)OC(=O)[C@H](O)[C@H]1OCCN(c2ccc(I)cc2)C1=O
Agent: OB(O)c1cccs1
Product: CC(C)(C)OC(=O)[C@H](O)[C@H]1OCCN(c2ccc(-c3ccccc3S(C)(=O)=O)cc2)C1=O
Yield: 79.8 %

Procedure:
According to the Step 22-1 in synthetic method for EXAMPLE 22, compound 105-1 (0.12 g) and 2-methylsulfonylphenylboronic acid (0.11 g) were used instead of 14-4 and 2-thiopheneboronic acid to obtain compound 105-2 (102 mg) as yellow oil.
Reaction SMILES: [CH:1]1([NH:7][C:8]([NH:10][C:11]2[N:12]=[C:13]3[C:19]([C:20](=[O:25])[C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:18][N:17](COCC[Si](C)(C)C)[C:14]3=[N:15][CH:16]=2)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.O.O.O.C([O-])(=O)C.[Na+]>ClCCl.FC(F)(F)C(O)=O>[CH:1]1([NH:7][C:8]([NH:10][C:11]2[N:12]=[C:13]3[C:19]([C:20](=[O:25])[C:21]([CH3:23])([CH3:22])[CH3:24])=[CH:18][NH:17][C:14]3=[N:15][CH:16]=2)=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CC(C)(C)C(=O)c1cn(COCC[Si](C)(C)C)c2ncc(NC(=O)NC3CCCCC3)nc12
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)C(=O)c1c[nH]c2ncc(NC(=O)NC3CCCCC3)nc12
Reaction time: 16 h
Yield: 67.7 %

Procedure:
A solution of 1-cyclohexyl-3-[7-(2,2-dimethyl-propionyl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-urea (0.102 g, 0.215 mmol) in 2 mL of dichloromethane and 2 mL of trifluoroacetic acid was stirred for 1 h, then concentrated, chasing twice with toluene. The residue was dissolved in 2 mL of ethanol and treated with sodium acetate trihydrate (0.293 g, 2.15 mmol). The mixture was stirred for 16 h, then concentrated to a residue. Column chromatography (50→80% EtOAc/hexanes) afforded 0.050 g (68%) of 1-cyclohexyl-3-[7-(2,2-dimethyl-propionyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-urea as a white solid.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]([F:15])([F:14])[F:13])=[CH:6][C:5]=1[NH:16][CH:17]1[CH2:22][CH2:21][N:20]([CH:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[CH2:19][CH2:18]1)([O-])=O.O.NN>C(O)C.[Ni]>[O:26]1[CH2:27][CH2:28][CH:23]([N:20]2[CH2:19][CH2:18][CH:17]([NH:16][C:5]3[C:4]([NH2:1])=[CH:9][CH:8]=[C:7]([O:10][CH2:11][C:12]([F:13])([F:15])[F:14])[CH:6]=3)[CH2:22][CH2:21]2)[CH2:24][CH2:25]1
Reactant: O=[N+]([O-])c1ccc(OCC(F)(F)F)cc1NC1CCN(C2CCOCC2)CC1
Agent: [Ni]
Agent: NN
Solvent: O
Solvent: CCO
Product: Nc1ccc(OCC(F)(F)F)cc1NC1CCN(C2CCOCC2)CC1
Temperature: 25 °C
Yield: 97.8 %

Procedure:
A stirred solution of N-{2-nitro-5-[(2,2,2-trifluoroethyl)oxy]phenyl}-1-(tetrahydro-2H-pyran-4-yl)-4-piperidinamine (D56, 210 mg, 0.52 mmol) in ethanol (15 ml) at room temperature under argon was treated with Raney Nickel (20 mg) followed by dropwise addition of hydrazine hydrate (0.16 ml, 5.0 mmol). The mixture was maintained at room temperature for 1 hr, then filtered through Kieselguhr and the filtrate concentrated under vacuum to leave the title compound as a pale grey solid (190 mg, 98%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([N:11]2[CH2:16][CH2:15][CH:14]([CH2:17][OH:18])[CH2:13][CH2:12]2)=O)=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][N:11]2[CH2:16][CH2:15][CH:14]([CH2:17][OH:18])[CH2:13][CH2:12]2)=[CH:4][CH:3]=1
Reactant: O=C(Cc1ccc(Cl)cc1)N1CCC(CO)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: OCC1CCN(CCc2ccc(Cl)cc2)CC1

Procedure:
In a manner similar to Preparation 5, react 1-[2-(4-chlorophenyl)acetyl]-4-(hydroxymethyl)piperidine with lithium aluminum hydride to obtain the title compound.
Reaction SMILES: Cl.[C:2]1([C:8]2([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(CC)CC.[C:27](#[N:30])[CH:28]=[CH2:29]>CCO>[C:2]1([C:8]2([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:9][CH2:10][N:11]([CH2:29][CH2:28][C:27]#[N:30])[CH2:12][CH2:13]2)[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(C2(c3ccccc3)CCNCC2)cc1
Reactant: C=CC#N
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: N#CCCN1CCC(c2ccccc2)(c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 82.2 %

Procedure:
To a suspension of 4,4-diphenylpiperidine hydrochloride (0.195 g, 0.712 mmol) in EtOH (1.5 mL) was added Et3N (0.25 mL, 1.8 mmol, 2.6 eq) followed by acrylonitrile (0.13 mL, 2.01 mmol, 2.8 eq). The resulting solution was stirred at room temperature under argon for 15 min and then concentrated. Water was added, and the mixture was extracted with EtOAc (3×10 mL). The combined organic extracts were dried (MgSO4) and concentrated to give 170 mg (87%) of a tan solid, which was characterized spectroscopically and used in the next reaction without purification.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][C:16]3[N:17]([CH3:21])[CH:18]=[CH:19][N:20]=3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[N:4][CH:3]=1.[F:22][C:23]1[CH:29]=[C:28]([CH3:30])[C:27]([OH:31])=[CH:26][C:24]=1[NH2:25].Cl.C(O)(C)C>CC(O)CCC.CN(C=O)C>[ClH:1].[F:22][C:23]1[CH:29]=[C:28]([CH3:30])[C:27]([OH:31])=[CH:26][C:24]=1[NH:25][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][C:16]3[N:17]([CH3:21])[CH:18]=[CH:19][N:20]=3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[N:4][CH:3]=1
Reactant: COc1cc2c(Cl)cnnc2cc1OCc1nccn1C
Reactant: Cc1cc(F)c(N)cc1O
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCCC(C)O
Solvent: CC(C)O
Product: COc1cc2c(Nc3cc(O)c(C)cc3F)cnnc2cc1OCc1nccn1C
Temperature: 0 °C
Yield: 79.5 %

Procedure:
A suspension of 4-chloro-6-methoxy-7-[( 1-methylimidazol-2-yl)methoxy]cinnoline (109 mg, 0.35 mmol) and 2-fluoro-5-hydroxy-4-methylaniline (70 mg, 0.5 mmol), (prepared as described for the starting material in Example 11), in 2-pentanol (3 ml), DMF (0.5 ml) and a 5M solution of hydrogen chloride in isopropanol (74 μl, 0.35 mmol) was heated at reflux for 3 hours. The solution was then cooled to 0° C. and the resulting solid filtered off and washed with ether to give 4-(2-fluoro-5-hydroxy-4-methylanilino)-6-methoxy-7-[(1-methylimidazol-2-yl)methoxy]cinnoline hydrochloride as a yellow solid (124 mg, 73%).
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10](Br)=[CH:11][CH:12]=2)[C@H:7]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:6][C@@H:5]1[CH3:23])(=[O:3])[CH3:2].[CH3:24][O:25][C:26]([C:28]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=1)=[O:27].C(=O)([O-])[O-].[K+].[K+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].COCCOC.O>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:31]3[CH:32]=[CH:33][C:28]([C:26]([O:25][CH3:24])=[O:27])=[CH:29][CH:30]=3)=[CH:11][CH:12]=2)[C@H:7]([NH:15][C:16]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:22])[CH2:6][C@@H:5]1[CH3:23])(=[O:3])[CH3:2]
Reactant: CC(=O)N1c2ccc(Br)cc2[C@H](NC(=O)OC(C)(C)C)C[C@@H]1C
Reactant: COC(=O)c1ccc(B(O)O)cc1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: O
Solvent: COCCOC
Product: COC(=O)c1ccc(-c2ccc3c(c2)[C@H](NC(=O)OC(C)(C)C)C[C@H](C)N3C(C)=O)cc1
Temperature: 100 °C
Reaction time: 1 h
Yield: 94 %

Procedure:
To a flask charged with tert-butyl ((2S,4R)-1-acetyl-6-bromo-2-methyl-1,2,3,4-tetrahydroquinolin-4-yl)carbamate (for a preparation see Intermediate 29)(5 g, 13.05 mmol), (4-(methoxycarbonyl)phenyl)boronic acid (2.58 g, 14.35 mmol), tetrakis(triphenylphosphine)palladium (0) (1.507 g, 1.305 mmol) and potassium carbonate (5.41 g, 39.1 mmol) was added DME (50 mL) and water (10.0 mL) and the resulting mixture was stirred at 100° C. under nitrogen for 1 h. The reaction was cooled to room temperature and most of the DME was evaporated in vacuo. The residue was partitioned between EtOAc and water and the layers were separated. The aqueous phase was extracted with EtOAc and the combined organic phases were washed with brine, dried over MgSO4 and concentrated in vacuo. the residue was purified by chromatography, eluting with an EtOAc/hexanes gradient; which gave methyl 4-((2S,4R)-1-acetyl-4-((tert-butoxycarbonyl)amino)-2-methyl-1,2,3,4-tetrahydroquinolin-6-yl)benzoate (5.35 g, 12.20 mmol, 94% yield) as a white foam. LCMS (HpH, 2 min), Rt=1.18 min, MH+=439.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C:6]([O:8]CC)=O)=[CH:2]1.O.[NH2:12][NH2:13]>C(O)C>[O:1]1[CH:5]=[CH:4][C:3]([C:6]([NH:12][NH2:13])=[O:8])=[CH:2]1
Reactant: CCOC(=O)c1ccoc1
Reactant: NN
Solvent: CCO
Solvent: O
Product: NNC(=O)c1ccoc1
Reaction time: 6 h

Procedure:
Ethyl 3-furancarboxylate (7.0 g) and hydrazine monohydrate (4.8 ml) in ethanol (10 ml) were heated at reflux while stirring for 6 hours. The solvent was evaporated under reduced pressure, and the thus-precipitated crystals were recrystallized from ethanol, thereby giving 3.2 g of the desire compound.
Reaction SMILES: CO.[N+:3]([C:6]1[C:15]2[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=2[CH:9]=[CH:8][C:7]=1[NH:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=1)[C:20]#[N:21])([O-])=O>[Pt]=O.O1CCCC1>[NH2:3][C:6]1[C:15]2[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=2[CH:9]=[CH:8][C:7]=1[NH:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=1)[C:20]#[N:21]
Reactant: N#Cc1cccc(Nc2ccc3c(c2[N+](=O)[O-])CCCC3)c1
Agent: O=[Pt]
Solvent: CO
Solvent: C1CCOC1
Product: N#Cc1cccc(Nc2ccc3c(c2N)CCCC3)c1
Reaction time: 29 h
Yield: 55 %

Procedure:
To a methanol (10 mL) and anhydrous tetrahydrofuran (30 mL) solution of 3-(1-nitro-5,6,7,8-tetrahydronaphthalen-2-ylamino)benzonitrile (1.52 g, 5.17 mmol was added platinum oxide (50 mg), and the mixture was hydrogenated for 29 hours at room temperature under atmospheric pressure. After removal of the catalyst by filtration, the solvent was removed by evaporation under reduced pressure. The residue was purified by silica gel column chromatography (chloroform) to give the titled compound as yellow powder (747 mg, yield 55%).