Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][CH2:5][CH2:6]Cl.[NH2:8][C@@H:9]([CH2:14][NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C:10]([O:12][CH3:13])=[O:11].O>C(N(C(C)C)CC)(C)C>[C:19]([O:18][C:16]([NH:15][CH2:14][C@H:9]([N:8]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1)[C:10]([O:12][CH3:13])=[O:11])=[O:17])([CH3:22])([CH3:21])[CH3:20]
Reactant: COC(=O)[C@@H](N)CNC(=O)OC(C)(C)C
Reactant: ClCCOCCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: COC(=O)[C@H](CNC(=O)OC(C)(C)C)N1CCOCC1
Temperature: 127 °C
Reaction time: 18 h
Yield: 24.3 %

Procedure:
2.8 g (20 mmol) of 1-chloro-2-(2-chloroethoxy)ethane are added to a solution of 5 g (20 mmol) of commercial methyl(S)-2-amino-3-tert-butoxycarbonylaminopropanoate in 65 ml of diisopropylethylamine. The reaction mixture is stirred at 127° C. for 18 h. After the addition of water, the reaction medium is extracted with ethyl acetate. The organic phases are combined, dried over sodium sulfate, filtered and evaporated. The residue obtained is purified by chromatography on silica gel, elution being carried out with a 70/30 heptane/ethyl acetate mixture. 1.4 g (24%) of methyl(S)-3-tert-butoxycarbonylamino-2-morpholin-4-ylpropanoate are obtained in the form of an oil.
Reaction SMILES: COC1C=CC(N2CCN(C3C=CC([N:21]4[CH:25]=[N:24][NH:23][C:22]4=[O:26])=CC=3)CC2)=CC=1.[H-].[Na+].Br[CH2:30][CH2:31][CH3:32]>CS(C)=O>[CH2:30]([N:23]1[C:22](=[O:26])[N:21]=[CH:25][NH:24]1)[CH2:31][CH3:32]
Reactant: COc1ccc(N2CCN(c3ccc(-n4cn[nH]c4=O)cc3)CC2)cc1
Reactant: CCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CCCn1[nH]cnc1=O
Temperature: 50 °C

Procedure:
10 Parts of 2,4-dihydro-4-{4-[4-(4-methoxyphenyl)-1-piperazinyl]phenyl}-3H-1,2,4-triazol-3-one are dissolved in 300 parts of dimethyl sulfoxide at 100° C. Then there are added 1.6 parts of sodium hydride dispersion 50% and stirring is continued while the mixture is allowed to cool to about 50° C. 3.9 Parts of 1-bromopropane are added and the whole is stirred overnight at room temperature. The reaction mixture is poured onto water and the product is extracted with trichloromethane. The extract is washed with water, dried, filtered and evaporated. The residue is purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (98:2 by volume) as eluent. The pure fractions are collected and the eluent is evaporated. The residue is triturated in 2-propanol. The product is filtered off and dried; yielding 7.5 parts (65%) of 2,4-dihydro-4-55 4-[4-(4-methoxyphenyl)-1-piperazinyl]phenyl}-2-propyl-3H-1,2,4 -triazol-3-one.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([CH3:9])[C:6]([C:10]#[N:11])=[CH:5][CH:4]=1.CO[C:14](OC)([N:16]([CH3:18])[CH3:17])[CH3:15].CN(C)C=O>CO>[CH3:17][N:16]([CH3:18])[C:14]([CH3:15])=[CH:9][C:7]1[C:6]([C:10]#[N:11])=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[N:8]=1
Reactant: COC(C)(OC)N(C)C
Reactant: COc1ccc(C#N)c(C)n1
Solvent: CN(C)C=O
Solvent: CO
Product: COc1ccc(C#N)c(C=C(C)N(C)C)n1
Temperature: 130 °C
Reaction time: 0.75 h

Procedure:
A mixture containing 47.2 g of 6-methoxy-2-methyl-3-pyridinecarbonitrile, 100 ml of dimethylacetamide dimethyl acetal and 100 ml of dimethylformamide was heated with stirring in an oil bath at 130° C. for 1 hour and 45 minutes. The temperature of the oil bath was raised to 150° C. and the methanol formed by the reaction was distilled off using a 12" distillation column (Vigreux) while continuing the heating at 150° C. for 14 hours. The reaction mixture was concentrated, 50 ml of ether was added to the concentrated solution whereupon the product crystallized out. The mixture was chilled and the crystalline solid collected. The solid was washed with cold ether, dried and recrystallized from ethyl acetate using decolorizing charcoal to yield 33.5 g of 2-[2-(dimethylamino)-1-propenyl]-6-methoxy-3-pyridinecarbonitrile, m.p. 103°-104° C.
Reaction SMILES: [CH2:1]([O:11][C:12]1[CH:20]=[CH:19][C:15]([C:16]([OH:18])=O)=[CH:14][C:13]=1[O:21][CH3:22])/[CH:2]=[C:3](/[CH2:5][CH2:6][CH:7]=[C:8]([CH3:10])[CH3:9])\[CH3:4].[NH2:23][CH2:24][CH:25]1[CH2:29][CH2:28][CH2:27][N:26]1[CH2:30][CH3:31]>>[CH2:30]([N:26]1[CH2:27][CH2:28][CH2:29][CH:25]1[CH2:24][NH:23][C:16](=[O:18])[C:15]1[CH:19]=[CH:20][C:12]([O:11][CH2:1]/[CH:2]=[C:3](/[CH2:5][CH2:6][CH:7]=[C:8]([CH3:9])[CH3:10])\[CH3:4])=[C:13]([O:21][CH3:22])[CH:14]=1)[CH3:31]
Reactant: CCN1CCCC1CN
Reactant: COc1cc(C(=O)O)ccc1OC/C=C(\C)CCC=C(C)C
Product: CCN1CCCC1CNC(=O)c1ccc(OC/C=C(\C)CCC=C(C)C)c(OC)c1
Yield: 79 %

Procedure:
In a manner identical to Example 15, 4-geranyloxy-3-methoxybenzoic acid(1.52 g) was subjected to a condensation reaction with 2-aminomethyl-1-ethylpyrrolidine (0.7 ml), thereby yielding 1.63 g(79%) of the aimed compound.
Reaction SMILES: [C:1]([CH:3]([O:7][C:8]1[CH:9]=[C:10]2[C:15](=[C:16]([F:19])[C:17]=1[F:18])[O:14][CH:13]([CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH2:12][CH2:11]2)[CH2:4][CH2:5][CH3:6])#[CH:2]>C(N(CC)C1C=CC=CC=1)C.CC(OC)(C)C>[F:19][C:16]1[C:17]([F:18])=[C:8]2[C:9]([CH:2]=[CH:1][CH:3]([CH2:4][CH2:5][CH3:6])[O:7]2)=[C:10]2[CH2:11][CH2:12][CH:13]([CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[O:14][C:15]=12
Reactant: C#CC(CCC)Oc1cc2c(c(F)c1F)OC(CCCCC)CC2
Solvent: CCN(CC)c1ccccc1
Solvent: COC(C)(C)C
Product: CCCCCC1CCc2c3c(c(F)c(F)c2O1)OC(CCC)C=C3

Procedure:
9.0 g (26.8 mmol) of 6-(1-ethynylbutoxy)-7,8-difluoro-2-pentylchroman are heated at 205° C. for 3 h in 90 ml of N,N-diethylaniline. The batch is diluted with MTBE and washed a number of times with 3 N HCl. The organic phase is dried using sodium sulfate and evaporated to dryness. The residue is purified by column chromatography (SiO2, n-heptane:MTBE=4:1), giving 5,6-difluoro-3-pentyl-8-propyl-1,2,3,8-tetrahydropyrano[3,2-f]-chromene as a pale-brown oil.
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.C([Si]([O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([S:34][CH:35]2[CH2:39][CH2:38][CH2:37][CH2:36]2)[CH:29]=1)(C)C)(C)(C)C>C1COCC1>[CH:35]1([S:34][C:30]2[CH:29]=[C:28]([CH2:27][OH:26])[CH:33]=[CH:32][CH:31]=2)[CH2:39][CH2:38][CH2:37][CH2:36]1
Reactant: CC(C)(C)[Si](C)(C)OCc1cccc(SC2CCCC2)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: OCc1cccc(SC2CCCC2)c1
Reaction time: 18 h
Yield: 92.3 %

Procedure:
A solution of tetrabutylammonium fluoride in THF (1M, 6 ml) was added to a solution of tert-butyl{[3-(cyclopentylthio)benzyl]oxy}dimethylsilane (1.09 g) in dry THF (10 ml). The solution was stirred for 18 h under nitrogen and the solvent was evaporated in vacuo. The residue was partitioned between dichloromethane and water. The organic phase was separated and washed with water. The organic phase was separated and the solvent evaporated in vacuo. The residue was purified on a 10 g silica SPE cartridge, eluting with a stepped gradient of 10% to 100% dichloromethane-cyclohexane to give the title compound (0.65 g). LCMS RT=3.3 min
Reaction SMILES: [C:1](#[N:3])[CH3:2].[Li]CCCC.[C:9]([N:12]1[CH2:17][CH2:16][CH:15]([C:18]([O:20]CC)=O)[CH2:14][CH2:13]1)(=[O:11])[CH3:10]>C1COCC1>[C:9]([N:12]1[CH2:13][CH2:14][CH:15]([C:18](=[O:20])[CH2:2][C:1]#[N:3])[CH2:16][CH2:17]1)(=[O:11])[CH3:10]
Reactant: CCOC(=O)C1CCN(C(C)=O)CC1
Reactant: CC#N
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(=O)N1CCC(C(=O)CC#N)CC1
Yield: 76.9 %

Procedure:
To a solution of ethyl isonipecotate (8.0 g) in THF (100 mL) was added triethylamine (5.7 g), dimethylaminopyridine (0.6 g) and acetyl chloride (4.4 g) at 0° C. and the mixture was stirred for an hour. The mixture was extracted with ethyl acetate and the solvent was evaporated under reduced pressure to give ethyl 1-acetylpiperidine-4-carboxylate (10 g) as a colorless oil. To a solution of acetonitrile (2.5 g) in THF (300 mL) was added n-BuLi (57 mmol) at −78° C. Further, ethyl 1-acetylpiperidine-4-carboxylate (10 g) was added and the mixture was stirred for an hour. After acidification with hydrochloric acid, the mixture was extracted with ethyl acetate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (eluent:hexane-ethyl acetate (10:1)) to give 1-(1-acetylpiperidin-4-yl)-2-cyanoethan-1-one (7.5 g) as a colorless oil. A solution of 2,1,3-benzoxadiazole-4-aldehyde (0.3 g), 3-aminopyrazole (0.17 g) and 1-(1-acetylpiperidin-4-yl)-2-cyanoethan-1-one (0.4 g) in acetonitrile (10 mL) was heated under reflux overnight. The reaction mixture was cooled to room temperature, and the precipitated crystals were collected by filtration to give the title compound (0.49 g) as yellow crystals.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[C:5]([O:12][CH:13]([CH3:19])[CH2:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH:6]=[CH:7][CH:8]=2)[N:3]=1.C[CH2:21][N:22](CC)CC>CN1C(=O)CCC1>[CH3:21][NH:22][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[C:5]([O:12][CH:13]([CH3:19])[CH2:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: CCN(CC)CC
Reactant: CC(CC(C)(C)C)Oc1cccc2ccc(Cl)nc12
Solvent: CN1CCCC1=O
Product: CNc1ccc2cccc(OC(C)CC(C)(C)C)c2n1

Procedure:
A 7.5 mL conical microwave vessel (Personal Chemistry) equipped with a septum cap and a magnetic stirring bar was charged with 0.25 g (0.90 mmol) of 2-Chloro-8-(1,3,3-trimethylbutoxy)quinoline, NEt3 (1.26 mL) and NMP (1.26 mL). The resulting suspension was irradiated in Personal Chemistry Smith Synthesizer (220° C. for 25 min; 300 W). Upon cooling, the residue was dissolved in a 3:1 hexanes/CH2Cl2 mixture (10 mL) and washed with H2O. The organic layer was evaporated in vacuo and the residue was purified by silica gel column chromatography (5–15% MeOH/CH2Cl2) to afford the title compound. 1H NMR (500 MHz, DMSO-d6) δ ppm 6.67–7.79 (m, 5H), 4.87 (m, 1H), 3.11 (m, 3H), 2.03 (m, 1H), 1.56 (m, 1H), 1.30 (m, 3H), 0.89 (m, 9H); MS (DCI/NH3) m/z 273 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8]Br)=[CH:4][N:3]=1.[F:10][C:11]([F:22])([F:21])[C:12]([N:14]=[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][NH:16]1)=[O:13].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Br:1][C:2]1[N:3]=[CH:4][C:5]([CH2:8][N:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]2=[N:14][C:12](=[O:13])[C:11]([F:21])([F:22])[F:10])=[CH:6][CH:7]=1
Reactant: O=C(N=c1cccc[nH]1)C(F)(F)F
Reactant: BrCc1ccc(Br)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=C(N=c1ccccn1Cc1ccc(Br)nc1)C(F)(F)F

Procedure:
70 mg (0.28 mmol) of the 2-bromo-5-bromomethylpyridine obtained by the aforementioned method was dissolved in 10 ml of anhydrous acetonitrile, 54 mg (0.28 mmol) of 2,2,2-trifluoro-N-(pyridin-2(1H)-ylidene)acetoamide synthesized by the method described in (1) of Synthetic Example P1 and 46 mg (0.34 mmol) of potassium carbonate were added thereto in sequence, and the resulting mixture was heated and refluxed for 6 hours. After the reaction was completed, the reaction solution was returned to room temperature to filter insoluble materials, and the filtrate was concentrated under reduced pressure. Diethyl ether was added thereto to precipitate a solid, and thus the solid was collected, washed with diethyl ether, and then dried under reduced pressure in a desiccator to obtain the subject material. Amount obtained 81 mg (yield 82%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]#[C:9][C:10]2[CH:33]=[CH:32][C:13]([C:14]([NH:16][CH2:17][C@H:18]([NH:22][S:23]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)(=[O:25])=[O:24])[C:19]([OH:21])=[O:20])=[O:15])=[CH:12][CH:11]=2)[N:3]=1.[OH-].[Na+]>O.[Pd]>[NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][CH2:9][C:10]2[CH:33]=[CH:32][C:13]([C:14]([NH:16][CH2:17][C@H:18]([NH:22][S:23]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)(=[O:25])=[O:24])[C:19]([OH:21])=[O:20])=[O:15])=[CH:12][CH:11]=2)[N:3]=1
Reactant: Nc1cccc(C#Cc2ccc(C(=O)NC[C@H](NS(=O)(=O)c3ccccc3)C(=O)O)cc2)n1
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Nc1cccc(CCc2ccc(C(=O)NC[C@H](NS(=O)(=O)c3ccccc3)C(=O)O)cc2)n1

Procedure:
Alkyne 29-6 (60 mg, 0.13 mmol), was suspended in 1.3 mL H2O, 1N NaOH was added until the mixture was homogeneous, 10% Pd/C (12 mg) was added, and an H2 balloon was applied. After 16 h the reaction was filtered, concentrated, and purified by flash chromatography (silica, 12:10:1:1 EtOAc/EtOH/NH4OH/H2O) providing 29-7 as a white solid.
Reaction SMILES: [CH2:1]([O:46][C:47]1([C:80]2[CH:85]=[CH:84][CH:83]=[CH:82][C:81]=2[C:86]#[CH:87])[C@H:51]2[C@H:52](O[Si](C(C)(C)C)(C)C)[N:53](C(OCC(Cl)(Cl)Cl)=O)[C:54]3[CH:61]=[CH:60][C:59]([O:62][CH3:63])=[CH:58][C:55]=3[C:56](=[O:57])[N:50]2[CH:49]=[CH:48]1)[CH2:2][CH2:3][O:4][C:5]1([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=2[C:44]#[CH:45])[C@H:9]2[C@H:10](O[Si](C(C)(C)C)(C)C)[N:11](C(OCC(Cl)(Cl)Cl)=O)[C:12]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][C:13]=3[C:14](=[O:15])[N:8]2[CH:7]=[CH:6]1>C1COCC1>[CH2:3]([O:4][C:5]1([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=2[C:44]#[CH:45])[C@@H:9]2[CH:10]=[N:11][C:12]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][C:13]=3[C:14](=[O:15])[N:8]2[CH:7]=[CH:6]1)[CH2:2][CH2:1][O:46][C:47]1([C:80]2[CH:85]=[CH:84][CH:83]=[CH:82][C:81]=2[C:86]#[CH:87])[C@@H:51]2[CH:52]=[N:53][C:54]3[CH:61]=[CH:60][C:59]([O:62][CH3:63])=[CH:58][C:55]=3[C:56](=[O:57])[N:50]2[CH:49]=[CH:48]1
Reactant: C#Cc1ccccc1C1(OCCCOC2(c3ccccc3C#C)C=CN3C(=O)c4cc(OC)ccc4N(C(=O)OCC(Cl)(Cl)Cl)[C@@H](O[Si](C)(C)C(C)(C)C)[C@@H]32)C=CN2C(=O)c3cc(OC)ccc3N(C(=O)OCC(Cl)(Cl)Cl)[C@@H](O[Si](C)(C)C(C)(C)C)[C@@H]21
Solvent: C1CCOC1
Product: C#Cc1ccccc1C1(OCCCOC2(c3ccccc3C#C)C=CN3C(=O)c4cc(OC)ccc4N=C[C@H]32)C=CN2C(=O)c3cc(OC)ccc3N=C[C@H]21
Yield: 34.8 %

Procedure:
10% Cd/Pd couple (314 mg, 2.55 mmol, 20 eq) was added to a rapidly stirring mixture of 17 (162 mg, 0.13 mmol), THF (4 mL) and 1 N NH4OAc (4 mL). The reaction mixture was allowed to stir for 45 min when TLC showed the complete consumption of the starting material. The solids were filtered and rinsed with H2O and CHCl3. The aqueous layer was extracted with CHCl3 (3×25 mL) and the organic extracts were combined, washed with H2O (50 mL), brine (50 mL) and dried (MgSO4). Filtration and evaporation of solvent afforded the crude product which was purified by flash column chromatography (99.8:0.2 v/v CHCl3/MeOH then gradient to 97.5:2.5 v/v CHCl3/MeOH) to afford ZC-209 as a yellow glass (33 mg, 38%): 1H NMR (400 MHz, CDCl3) δ 7.79 (d, 2H, J=3.9 Hz, H11), 7.42 (s, 2H, H6), 7.39-7.37 (m, 4H, H15), 7.26-7.19 (m, 8H, H3, H16 and H17), 6.78 (s, 2H, H9), 4.30-4.19 (m, 6H, OCH2CH2CH2O and H11a), 3.86 (s, 6H, OCH3×2), 3.36 (dd, 2H, J=11.7, 16.4 Hz, H1), 3.18 (dd, 2H, J=5.4, 16.4 Hz, H1), 2.37-2.34 (m, 2H, OCH2CH2CH2O); 13C NMR (100.6 MHz, CDCl3) δ 162.0 (C11), 161.3 (Cquat), 151.4 (Cquat), 148.2 (Cquat), 140.3 (Cquat), 132.8 (C3), 131.4 (C15), 128.4 (C16 and C17), 122.9 (Cquat), 118.7 (Cquat), 112.0 (C6), 111.2 (C9), 105.1 (Cquat), 94.3 (Calkyne), 83.3 (Calkyne), 65.5 (OCH2CH2CH2O), 56.2 (OCH3), 53.8 (C11a), 37.9 (C1), 28.8 (OCH2CH2CH2O); MS (ES), m/z (relative intensity) 729 (M+., 100).
Reaction SMILES: O[CH:2]=[C:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([C:14]3[CH:19]=[CH:18][C:17]([NH:20][C:21]([C:23]4[N:24]([CH3:29])[N:25]=[C:26]([CH3:28])[CH:27]=4)=[O:22])=[CH:16][CH:15]=3)=[O:13])=[CH:9][CH:10]=2)[NH:5][C:4]1=[O:30].[NH2:31][C:32]1[CH:33]=[C:34]([OH:38])[CH:35]=[CH:36][CH:37]=1>C1COCC1>[OH:38][C:34]1[CH:33]=[C:32]([NH:31][CH:2]=[C:3]2[C:11]3[C:6](=[CH:7][C:8]([C:12]([C:14]4[CH:19]=[CH:18][C:17]([NH:20][C:21]([C:23]5[N:24]([CH3:29])[N:25]=[C:26]([CH3:28])[CH:27]=5)=[O:22])=[CH:16][CH:15]=4)=[O:13])=[CH:9][CH:10]=3)[NH:5][C:4]2=[O:30])[CH:37]=[CH:36][CH:35]=1
Reactant: Nc1cccc(O)c1
Reactant: Cc1cc(C(=O)Nc2ccc(C(=O)c3ccc4c(c3)NC(=O)C4=CO)cc2)n(C)n1
Solvent: C1CCOC1
Product: Cc1cc(C(=O)Nc2ccc(C(=O)c3ccc4c(c3)NC(=O)C4=CNc3cccc(O)c3)cc2)n(C)n1
Temperature: 65 °C
Reaction time: 24 h

Procedure:
A small screw cap test tube was charged with 2,5-Dimethyl-2H-pyrazole-3-carboxylic acid [4-(3-hydroxymethylene-2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide (as prepared in Example 25, 100 mg, 0.248 mmol) and THF (1.5 mL). To the resulting solution was added 3-aminophenol (29.8 mg, 0.273 mmol), and the mixture was stirred for 24 h at 65° C. Subsequently, the reaction mixture was cooled to room temperature. The solid precipitate that formed was filtered and washed with THF yielding 70% (86 mg, 0.174 mmol) of the title compound.
Reaction SMILES: CON(C)[C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([Br:24])[N:19]=2)[CH:7]=1)=[O:5].[CH3:26][O:27][C:28]1[CH:29]=[C:30]([Mg]Br)[CH:31]=[CH:32][CH:33]=1>C1COCC1>[Br:24][C:20]1[N:19]=[C:18]([CH2:17][N:8]2[C:9]3[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:15](=[O:16])[C:6]([C:4](=[O:5])[C:32]3[CH:31]=[CH:30][CH:29]=[C:28]([O:27][CH3:26])[CH:33]=3)=[CH:7]2)[CH:23]=[CH:22][CH:21]=1
Reactant: CON(C)C(=O)c1cn(Cc2cccc(Br)n2)c2ccccc2c1=O
Reactant: COc1cccc([Mg]Br)c1
Solvent: C1CCOC1
Product: COc1cccc(C(=O)c2cn(Cc3cccc(Br)n3)c3ccccc3c2=O)c1

Procedure:
Experimental conditions analogous to those described for Step 6 of Example 60 from 90 mg (0.22 mmol) of 1-(6-bromo-pyridin-2-ylmethyl)-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid methoxy-methyl-amide in 1.5 mL THF and 0.49 mL 1M 3-methoxyphenylmagnesium bromide. Yield: 53 mg of a white solid. LC-MSD, m/z for C23H17BrN2O3 [M+H]+=449.0, 451.0; HPLC retention time: 2.3 min.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10](Cl)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[NH2:13][CH2:14][C:15]1([NH2:19])[CH2:18][O:17][CH2:16]1.C(N(CC)CC)C>CO>[NH2:19][C:15]1([CH2:14][NH:13][C:10]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[N:3]=[C:2]([Cl:1])[N:11]=2)[CH2:18][O:17][CH2:16]1
Reactant: NCC1(N)COC1
Reactant: Clc1nc(Cl)c2ccccc2n1
Solvent: CO
Solvent: CCN(CC)CC
Product: NC1(CNc2nc(Cl)nc3ccccc23)COC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.2 %

Procedure:
To a solution of 2,4-dichloroquinazoline (1.0 g, 5.024 mmol) in methanol (15 mL) was added 3-(aminomethyl)oxetan-3-amine (855 mg, 60%, 5.024 mmol) and triethylamine (101 mg, 1.005 mmol). After being stirred at room temperature overnight, the mixture was concentrated in vacuo. The residue was purified by flash column chromatography to afford 1.2 g of the desired product as a white solid (yield was 92%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH:14]=[O:15])=[CH:4][CH:3]=1.[CH3:16][C:17]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)([CH3:21])[CH2:18][Mg]Cl>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH:14]([OH:15])[CH2:16][C:17]([CH3:21])([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH3:18])=[CH:6][CH:7]=1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1C=O
Reactant: CC(C)(C[Mg]Cl)c1ccccc1
Product: Cc1noc(-c2ccc(Br)cc2)c1C(O)CC(C)(C)c1ccccc1

Procedure:
Prepared according to the procedure described in Example 35, Step 3, using 5-(4-bromo-phenyl)-3-methyl-isoxazole-4-carbaldehyde and 2-methyl-2-phenylpropylmagnesium chloride.
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]([CH:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)=[N:10]2)=[CH:5][CH:4]=1.[CH3:26][N:27]=[C:28]=[O:29]>C1(C)C=CC=CC=1>[CH3:26][NH:27][C:28]([N:21]1[CH2:20][CH2:19][CH:18]([C:11]2[C:12]3[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=3)[N:9]([C:6]3[CH:7]=[CH:8][C:3]([C:2]([F:1])([F:24])[F:25])=[CH:4][CH:5]=3)[N:10]=2)[CH2:23][CH2:22]1)=[O:29]
Reactant: FC(F)(F)c1ccc(-n2nc(C3CCNCC3)c3ccccc32)cc1
Reactant: CN=C=O
Solvent: Cc1ccccc1
Product: CNC(=O)N1CCC(c2nn(-c3ccc(C(F)(F)F)cc3)c3ccccc23)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.3 %

Procedure:
A stirred mixture of 4-[1-(4-(trifluoromethyl)phenyl)-1H-indazol-3-yl]piperidine-1-carbonitrile of Example 101 (15 g, 0.041 moles) and 25% H2SO4 (100 ml) was refluxed for 20 hours. The mixture was cooled. poured into H2O and basified with a 25% NaOH solution. The product was extracted (dichloromethane), dried (MgSO4), and concentrated to yield 13 g (93%) of 1-[4-(trifluoromethyl)phenyl]-3-(4-piperidinyl)-1H-indazole as an oil. To a stirred suspension of the indazole (4.0 g, 0.012 moles) in toluene (60 ml) was added methyl isocyanate (0.75 ml., 0.013 moles). The temperature of the reaction mixture rose to 35° C. following the addition. The mixture was stirred for 2 hours at ambient temperature and then concentrated to yield 4.6 g of a solid. The product was purified by high pressure liquid chromatography (3.5% methanol-CHCl3 ; silica gel) and then recrystallized three times from toluene-hexane to yield 2.93 g (63%) of N-methyl-4-[1-(4-trifluoromethyl)phenyl]-1H-indazol-3-yl]piperidine-1-carboxamide, m.p.: 150°-152° C.
Reaction SMILES: C[O-].[Na+].C(OP([CH2:12][C:13]1[N:18]=[CH:17][C:16]([C:19]2[CH:20]=[C:21]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][N:35]=3)[C:22]3[S:26][C:25]([NH:27][C:28]([NH:30][CH2:31][CH3:32])=[O:29])=[N:24][C:23]=3[CH:33]=2)=[CH:15][N:14]=1)(OCC)=O)C.[CH:40](=O)[CH3:41]>C1COCC1.CCOC(C)=O>[CH2:31]([NH:30][C:28]([NH:27][C:25]1[S:26][C:22]2[C:21]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][N:35]=3)=[CH:20][C:19]([C:16]3[CH:15]=[N:14][C:13](/[CH:12]=[CH:40]/[CH3:41])=[N:18][CH:17]=3)=[CH:33][C:23]=2[N:24]=1)=[O:29])[CH3:32]
Reactant: CCNC(=O)Nc1nc2cc(-c3cnc(CP(=O)(OCC)OCC)nc3)cc(-c3ccccn3)c2s1
Reactant: CC=O
Agent: C[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C/C=C/c1ncc(-c2cc(-c3ccccn3)c3sc(NC(=O)NCC)nc3c2)cn1
Reaction time: 1.5 h

Procedure:
Sodium methoxide (0.5 M MeOH solution; 0.9 mL, 0.43 mmol) was added drop-wise to a suspension of iv (104 mg, 0.198 mmol) in THF (10 mL). Acetaldehyde (40 μL, 0.69 mmol) was introduced and the mixture stirred for 90 min. The reaction was diluted with EtOAc (60 mL), washed with sat. NaHCO3(aq) (60 mL). The organic fraction was dried (MgSO4), concentrated in vacuo, and purified over silica (gradient elution: 0-10%, DCM-MeOH) affording v (79 mg, 96%). MS: 417.1 [M+H]+.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.C[N:8](C)[CH:9]=[O:10].[Br:12][C:13]1[CH:14]=[C:15](C(O)=O)[CH:16]=[N:17][CH:18]=1>ClCCl>[Br:12][C:13]1[CH:14]=[C:15]([C:9]([NH2:8])=[O:10])[CH:16]=[N:17][CH:18]=1
Reactant: CN(C)C=O
Reactant: O=C(O)c1cncc(Br)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: NC(=O)c1cncc(Br)c1

Procedure:
Oxalyl chloride (1.33 ml) and N,N-dimethylformamide (catalytic amounts) were added dropwise under ice-cooling to a solution of 5-bromopyridine-3-carboxylic acid (2.02 g) in dichloromethane, and stirred for an hour. The solvent was evaporated in a evaporator, the residue was dissolved in tetrahydrofuran (10 ml), to which ammonia water (28%; 1 ml) was added dropwise under ice-cooling, and stirred at room temperature for 0.5 hours. After completion of the reaction, water was added to the reaction mixture and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and concentrated. The residue was purified with column chromatography to give 5-bromopyridine-3-carboxamide (734 mg).
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([C:21]3([C:26]([OH:28])=O)[CH2:25][CH2:24][CH2:23][CH2:22]3)=[CH:17][CH:16]=2)=[CH:11][CH:10]=1.Cl.[NH2:30][C@@H:31]([CH3:36])[C:32]([O:34][CH3:35])=[O:33].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl>CN(C=O)C>[CH3:1][C@@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][CH2:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:20]=[CH:19][C:18]([C:21]3([C:26]([NH:30][C@@H:31]([CH3:36])[C:32]([O:34][CH3:35])=[O:33])=[O:28])[CH2:25][CH2:24][CH2:23][CH2:22]3)=[CH:17][CH:16]=2)=[CH:13][CH:14]=1
Reactant: COC(=O)[C@H](C)N
Reactant: C[C@@H]1CCCN1CCc1ccc(-c2ccc(C3(C(=O)O)CCCC3)cc2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: COC(=O)[C@H](C)NC(=O)C1(c2ccc(-c3ccc(CCN4CCC[C@H]4C)cc3)cc2)CCCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of (R)-1-(4′-(2-(2-methylpyrrolidin-1-yl)ethyl)biphenyl-4-yl)cyclopentanecarboxylic acid (15 mg, 0.040 mmol), (S)-methyl 2-aminopropanoate hydrochloride (6.10 mg, 0.044 mmol), HATU (16.62 mg, 0.044 mmol), and TEA (0.017 mL, 0.119 mmol) in DMF (0.4 mL) was stirred at room temperature overnight. The mixture was acidified with 1M HCl and purified by HPLC to give the title compound. LCMS m/z=449.3 [M+H]+.