Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([Si:5]([CH3:46])([CH3:45])[O:6][C@H:7]([CH2:37][O:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[CH2:8][N:9]([CH2:17][C@H:18]1[CH2:27][CH2:26][C:25]2[C:20](=[CH:21][CH:22]=[C:23]([C:28]3[CH:33]=[CH:32][N:31]=[C:30]([C:34]([OH:36])=O)[CH:29]=3)[CH:24]=2)[O:19]1)[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([CH3:4])[CH3:3].[F:47][C:48]1[CH:55]=[CH:54][C:51]([CH2:52][NH2:53])=[CH:50][CH:49]=1.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>ClCCl>[CH3:1][C:2]([Si:5]([CH3:45])([CH3:46])[O:6][C@H:7]([CH2:37][O:38][C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1)[CH2:8][N:9]([CH2:17][C@H:18]1[CH2:27][CH2:26][C:25]2[C:20](=[CH:21][CH:22]=[C:23]([C:28]3[CH:33]=[CH:32][N:31]=[C:30]([C:34]([NH:53][CH2:52][C:51]4[CH:54]=[CH:55][C:48]([F:47])=[CH:49][CH:50]=4)=[O:36])[CH:29]=3)[CH:24]=2)[O:19]1)[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([CH3:4])[CH3:3]
Reactant: NCc1ccc(F)cc1
Reactant: CC(C)(C)[Si](C)(C)O[C@H](COc1ccccc1)CN(Cc1ccccc1)C[C@H]1CCc2cc(-c3ccnc(C(=O)O)c3)ccc2O1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)O[C@H](COc1ccccc1)CN(Cc1ccccc1)C[C@H]1CCc2cc(-c3ccnc(C(=O)NCc4ccc(F)cc4)c3)ccc2O1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Into a solution of 4-((2R)-2-{[[(2S)-2-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-3-(phenyloxy)propyl](phenylmethyl)amino]methyl}-3,4-dihydro-2H-chromen-6-yl)-2-pyridinecarboxylic acid (Example 90, 82 mg, 0.13 mmol) in dichloromethane (2 mL) was added 4-fluorobenzylamine (33 mg, 0.26 mmol, 2.0 eq.), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (50 mg, 0.26 mmol, 2.0 eq.), and 1-hydroxybenzotriazole (35 mg, 0.26 mmol, 2.0 eq.). The solution was stirred overnight at room temperature before being concentrated in vacuo to remove volatile components. The crude residue was purified by flash chromatography on silica gel eluted with 75:25 hexanes/ethyl acetate. The title compound was obtained as a yellow oil (34 mg, 35%): 1H NMR (300 MHz, CDCl3) δ8.47 (d, 1 H), 8.40 (s, 2 H), 7.55 (dd, 1 H), 7.44-7.39 (m, 2 H), 7.34-7.29 (m, 4 H), 7.25-7.20 (m, 4 H), 7.01 (t, 2 H), 6.93-6.80 (m, 4 H), 4.64 (d, 2 H), 4.22-4.16 (m, 1 H), 4.11-4.05 (m, 1 H), 3.83 (s, 2 H), 3.75 (dd, 1 H), 2.94-2.80 (m, 2 H), 2.73-2.67 (m, 4 H), 1.71-1.57 (m, 2 H), 0.86 (s, 9H), 0.09 (s, 3 H), 0.05 (s, 3 H); MS m/z 746.5 (M+).
Reaction SMILES: [CH3:1][C:2]1[C:6]2[C:7](=[O:20])[N:8]([CH2:12][CH2:13][N:14]3[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]3)[CH2:9][CH2:10][CH2:11][C:5]=2[NH:4][C:3]=1[CH:21]=O.[F:23][C:24]1[C:29]([F:30])=[CH:28][CH:27]=[CH:26][C:25]=1[C:31]1[CH:39]=[CH:38][CH:37]=[C:36]2[C:32]=1[CH2:33][C:34](=[O:40])[NH:35]2>>[F:23][C:24]1[C:29]([F:30])=[CH:28][CH:27]=[CH:26][C:25]=1[C:31]1[CH:39]=[CH:38][CH:37]=[C:36]2[C:32]=1/[C:33](=[CH:21]/[C:3]1[NH:4][C:5]3[CH2:11][CH2:10][CH2:9][N:8]([CH2:12][CH2:13][N:14]4[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]4)[C:7](=[O:20])[C:6]=3[C:2]=1[CH3:1])/[C:34](=[O:40])[NH:35]2
Reactant: O=C1Cc2c(cccc2-c2cccc(F)c2F)N1
Reactant: Cc1c(C=O)[nH]c2c1C(=O)N(CCN1CCCCC1)CCC2
Product: Cc1c(/C=C2\C(=O)Nc3cccc(-c4cccc(F)c4F)c32)[nH]c2c1C(=O)N(CCN1CCCCC1)CCC2
Yield: 80.9 %

Procedure:
The title compound was prepared under the same conditions as described in step 5 of Example 32 with 3-methyl-4-oxo-5-(2-piperidin-1-yl-ethyl)-1,4,5,6,7,8-hexahydro-pyrrolo[3,2-c]azepine-2-carbaldehyde 32d obtained from step 4 of Example 32 and 4-(2,3-difluoro-phenyl)-1,3-dihydro-indol-2-one 6d obtained from step 3 of Example 6 as starting materials to obtain (Z)-2-[4-(2,3-difluoro-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-3-methyl-5-(2-piperidin-1-yl-ethyl)-5,6,7,8-tetrahydro-1H-pyrrolo[3,2-c]azepin-4-one 33 (51 mg, yield 80.9%) as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([C@@H:16]3[CH2:19][CH2:18][C@H:17]3[C:20]([O:22]C)=[O:21])=[O:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.Cl[C:25]1[S:26][C:27]2[C:33]([F:34])=[CH:32][C:31]([F:35])=[CH:30][C:28]=2[N:29]=1.Cl.[OH-].[Na+].[CH2:39](O)CCC>>[F:35][C:31]1[CH:32]=[C:33]([F:34])[C:27]2[S:26][C:25]([NH:1][C:2]3[CH:3]=[CH:4][C:5]([C:8]4[CH:9]=[CH:10][C:11]([C:14]([C@@H:16]5[CH2:39][CH2:19][CH2:18][C@H:17]5[C:20]([OH:22])=[O:21])=[O:15])=[CH:12][CH:13]=4)=[CH:6][CH:7]=3)=[N:29][C:28]=2[CH:30]=1
Reactant: CCCCO
Reactant: COC(=O)[C@@H]1CC[C@H]1C(=O)c1ccc(-c2ccc(N)cc2)cc1
Reactant: Fc1cc(F)c2sc(Cl)nc2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)[C@@H]1CCC[C@H]1C(=O)c1ccc(-c2ccc(Nc3nc4cc(F)cc(F)c4s3)cc2)cc1
Temperature: 90 °C
Reaction time: 8 h
Yield: 58 %

Procedure:
To a solution of methyl trans-2-[(4′-amino-1,1′-biphenyl-4-yl)carbonyl]cyclobutanecarboxylate (80 mg, 0.25 mmol) in n-butanol (8 mL) was added 2-chloro-5,7-difluoro-1,3-benzothiazole (102 mg, 0.49 mmol) and HCl (4.0 M in dioxane, 0.2 mL). The resulting reaction mixture was heated at 90° C. overnight. The mixture was evaporated to dryness, and the residue was brought up in MeOH. Then 1 N aqueous NaOH (2.0 mL, 2.0 mmol) was added, and the reaction mixture was stirred at 50° C. overnight. The reaction mixture was concentrated and the residue was suspended in water. Conc. HCl was added to adjust the acidity to pH 1, and the suspension was extracted with EtOAc. The combined organic phases were washed with brine, dried over sodium sulfate, filtered, and concentrated. The residue was brought up in MeOH, and the precipitate was collected by filtration and dried under vacuum oven to afford trans-2-({4′-[(5,7-difluoro-1,3-benzothiazol-2-yl)amino]-1,1′-biphenyl-4-yl}carbonyl)cyclopentanecarboxylic acid (65 mg, 58%). LC-MS ret. time 3.75; m/z 479.2 (MH+). 1H NMR (400 MHz, DMSO-d6) δ 1.55-1.84 (m, 4H), 2.01 (m, 1H), 2.18 (m, 1H), 3.22 (q, 1H), 4.09 (q, 1H), 7.15 (m, 1H), 7.40 (m, 1H), 7.83 (m, 4H), 7.87 (d, 2H), 8.05 (d, 2H), 11.00 (s, 1H), 12.12 (s, 1H).
Reaction SMILES: [C:1]1([CH:9]=[CH:8][CH:7]=[C:5]([OH:6])[C:3]=1[OH:4])[OH:2].[Cl-].[Al+3].[Cl-].[Cl-].C(Cl)(Cl)Cl.[C:18](=[O:21])([O-])[O-].[Na+].[Na+]>CN(C)C=O.ClCCl>[OH:2][C:1]1[CH:9]=[CH:8][C:7]2[C:18](=[O:21])[C:1]3[C:9]([O:6][C:5]=2[C:3]=1[OH:4])=[CH:8][CH:7]=[CH:5][CH:3]=3
Reactant: O=C([O-])[O-]
Reactant: Oc1cccc(O)c1O
Agent: [Al+3]
Agent: [Cl-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=c1c2ccccc2oc2c(O)c(O)ccc12
Temperature: 25 °C
Reaction time: 17 h
Yield: 35.9 %

Procedure:
To a stirring solution of 2-fluorobenzoic acid (5.09 g, 36.3 mmol) and dichloromethane (110 mL) in an ice bath under argon was added dropwise a solution of oxalyl chloride (2.0 M in dichloromethane, 21 mL, 42 mmol), followed by dimethylformamide (6 drops). The ice bath was removed and the solution was stirred at room temperature for 1.5 h. The solution was then concentrated by rotary evaporation. The product was dissolved in hexane (3×50 mL) and the mixture was filtered. The filtrate was rotary evaporated to yield 5.42 g of colorless oil. The oil was added dropwise to a mixture of pyrogallol (6.48 g, 51.3 mmol), aluminum chloride (14.6 g, 110 mmol), chloroform (250 mL) and dichloromethane (700 mL), and the solution was stirred for 17 h at room temperature. The solution was then refluxed for 3 h and cooled to room temperature. The solution was washed with 1 N HCl (3×500 mL). The organic layer was filtered, dried over sodium sulfate, and evaporated to yield an oil. The oil was added to dimethylformamide (120 mL) with sodium carbonate (8.11 g, 76.5 mmol) and it was refluxed for 3.5 h. The solution was concentrated by rotary evaporation with heating, and the residue was purified by column chromatography (95:5 chloroform/methanol) to give a solid. The solid was washed with hexane (2×35 mL), filtered and dried to yield 2.10 g (25 %) of the title compound as an off-white solid. 1H NMR (DMSO-d6, 300 MHz): δ 8.16 (d, J=7.42 Hz, 1H), 7.84 (t, J=7.69 Hz, 1H), 7.64 (d, J=8.52 Hz, 1H), 7.57 (d, J=8.79 Hz, 1H), 7.44 (t, J=7.41 Hz, 1H), 6.94 (d, J=8.52 Hz, 1H).
Reaction SMILES: [OH:1][CH2:2][C:3]1([CH2:7][CH2:8][CH3:9])[CH2:6][O:5][CH2:4]1.N1C=[CH:14][CH:13]=[CH:12][CH:11]=1.CC[O:18][CH2:19][CH3:20]>>[C:19]([O:1][CH2:2][C:3]1([CH2:7][CH2:8][CH3:9])[CH2:6][O:5][CH2:4]1)(=[O:18])[CH2:20][CH2:14][CH2:13][C:12]#[CH:11]
Reactant: CCOCC
Reactant: c1ccncc1
Reactant: CCCC1(CO)COC1
Product: C#CCCCC(=O)OCC1(CCC)COC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of hex-5-ynoic acid (1 g) and thionyl chloride (1.95 ml) in benzene (25 ml) was heated under reflux for 3 hours. The resulting solution was cooled and then evaporated in vacuo. The acid halide thus obtained was taken up in ether (5 ml) and added, dropwise, to a stirred solution of 3-hydroxymethyl-3-n-propyloxetane (1.2 g) and pyridine (0.8 ml) in dry ether (20 ml.). The reaction mixture was stirred at room temperature for 16 hours. After this time the organic phase was washed with water, 5% hydrochloric acid, saturated sodium bicarbonate solution and brine before drying over anhydrous magnesium sulphate and then evaporation in vacuo. The residue was purified by chromatography on silica, pre-eluted with hexane containing 1% triethylamine. Elution with hexane/ether mixtures gave (3-propyloxetan-3-yl)methyl hex-5-ynoate (1.33 g) as a colourless oil.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10](=[O:12])[CH3:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].CO[CH:15](OC)[N:16]([CH3:18])[CH3:17]>>[CH3:15][N:16]([CH3:18])/[CH:17]=[CH:11]/[C:10]([C:7]1[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=1)=[O:12]
Reactant: COC(OC)N(C)C
Reactant: CC(=O)c1ccc([N+](=O)[O-])cc1
Product: CN(C)/C=C/C(=O)c1ccc([N+](=O)[O-])cc1

Procedure:
A solution of 1-(4-nitrophenyl)ethanone (2.2 g, 13 mmol) and N,N-dimethylformamide dimethyl acetal (25 ml) was heated to 120° C. in a sealed tube overnight. The volatiles were removed. The residue was dissolved in DCM and washed twice with H2O. The DCM layer was dried with MgSO4. The crude product was purified by flash chromatography (silica gel, 100% EtOAc) to isolate (E)-3-(dimethylamino)-1-(4-nitrophenyl)prop-2-en-1-one (2.2 g,) as a yellow solid. 1H NMR (400 MHz, CDCl3) δ 2.99 (s, 3H), 3.23 (s, 3H), 5.70 (d, J=12.4 Hz, 1H), 7.94 (d, J=12.4 Hz, 1H), 8.03 (m, 2H), 8.26 (m, 2H). MS (ESI): 221 (M+H+)
Reaction SMILES: [NH:1]([C:3]1[N:8]=[CH:7][CH:6]=[CH:5][N:4]=1)[NH2:2].[CH2:9]([N:11](CC)CC)[CH3:10].C[O:17][C:18](=O)[N:19]=[C:20](SC)[C:21]([C:35]1[CH:40]=[C:39]([O:41][CH3:42])[C:38]([O:43][CH3:44])=[CH:37][C:36]=1CC#N)=[N:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[N:33]=[C:32]([CH3:34])[O:31][N:30]=2)=[CH:25][CH:24]=1>CN(C=O)C>[CH3:44][O:43][C:38]1[C:39]([O:41][CH3:42])=[CH:40][C:35]([CH:21]([NH:22][C:23]2[CH:24]=[CH:25][C:26]([C:29]3[N:33]=[C:32]([CH3:34])[O:31][N:30]=3)=[CH:27][CH:28]=2)[C:20]2[NH:19][C:18](=[O:17])[N:1]([C:3]3[N:8]=[CH:7][CH:6]=[CH:5][N:4]=3)[N:2]=2)=[CH:36][C:37]=1[CH2:10][C:9]#[N:11]
Reactant: COC(=O)N=C(SC)C(=Nc1ccc(-c2noc(C)n2)cc1)c1cc(OC)c(OC)cc1CC#N
Reactant: NNc1ncccn1
Reactant: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1cc(C(Nc2ccc(-c3noc(C)n3)cc2)c2nn(-c3ncccn3)c(=O)[nH]2)cc(CC#N)c1OC
Temperature: 85 °C
Reaction time: 8 h

Procedure:
After adding 30 mg of 2-hydrazinopyrimidine and 50 μl of triethylamine to a solution of 152 mg of {2-(cyanomethyl-4,5-dimethoxyphenyl)-2-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylimino]-1-methylsulfanylethylidene}carbamic acid methyl ester in 2 ml of DMF, the mixture was stirred overnight at 85° C. under a nitrogen atmosphere. The reaction mixture was concentrated, and the residue was dissolved in 3 ml of methanol and 0.3 ml of acetic acid. After adding 100 mg of sodium cyanotrihydroborate to the solution, the mixture was stirred at room temperature for 1 hour. Water was added to the reaction mixture and extraction was performed with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate. The desiccating agent was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by NAM silica gel column chromatography (methanol-ethyl acetate) to give (2,3-dimethoxy-5-{[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylamino]-(5-oxo-1-pyrimidin-2-yl-4,5-dihydro-1H-[1,2,4]triazol-3-yl)methyl}phenyl)acetonitrile (72 mg) as a light brown solid.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21]([C:23]3[N:24]=[C:25]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[O:26][C:27]=3[C:28]([F:31])([F:30])[F:29])=[O:22])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[NH:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:15]=[CH:16][C:17]([NH:20][C:21]([C:23]3[N:24]=[C:25]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[O:26][C:27]=3[C:28]([F:29])([F:30])[F:31])=[O:22])=[CH:18][CH:19]=2)[CH2:10][CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(NC(=O)c3nc(-c4ccccc4)oc3C(F)(F)F)cc2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(Nc1ccc(C2CCNCC2)cc1)c1nc(-c2ccccc2)oc1C(F)(F)F
Temperature: 25 °C
Reaction time: 3 h
Yield: 98.7 %

Procedure:
To a suspension of 4-{4-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-phenyl}-piperidine-1-carboxylic acid tert-butyl ester (19.2 g, 37.3 mmol) in dichloromethane (250 mL) was added trifluoroacetic acid (30 mL). The solution was stirred at room temperature for 3 hrs. Solvents were evaporated and the residue was diluted with ethyl acetate (600 mL). The mixture was neutralized with 1N sodium hydroxide solution (final PH >10). The organic layer was separated and washed with water and brine. After the evaporation of solvents, a pale yellow solid was obtained as 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (4-piperidin-4-yl-phenyl)-amide (15.3 g, 99%). LC-MS calcd for C22H20F3N3O2 (m/e) 415, obsd 416 (M+H).
Reaction SMILES: [CH:1]12[NH:8][CH:5]([CH2:6][CH2:7]1)[CH2:4][CH:3]([C:9]1[N:13]=[C:12]([NH:14][C:15]3[N:20]=[CH:19][C:18]([S:21][CH2:22][C:23]([O:25][CH3:26])=[O:24])=[CH:17][C:16]=3[O:27][C:28]3[C:29]([CH3:34])=[N:30][CH:31]=[CH:32][CH:33]=3)[S:11][N:10]=1)[CH2:2]2.C(N(CC)CC)C.[C:42](OC(=O)C)(=[O:44])[CH3:43]>C(Cl)Cl>[C:42]([N:8]1[CH:5]2[CH2:6][CH2:7][CH:1]1[CH2:2][CH:3]([C:9]1[N:13]=[C:12]([NH:14][C:15]3[N:20]=[CH:19][C:18]([S:21][CH2:22][C:23]([O:25][CH3:26])=[O:24])=[CH:17][C:16]=3[O:27][C:28]3[C:29]([CH3:34])=[N:30][CH:31]=[CH:32][CH:33]=3)[S:11][N:10]=1)[CH2:4]2)(=[O:44])[CH3:43]
Reactant: COC(=O)CSc1cnc(Nc2nc(C3CC4CCC(C3)N4)ns2)c(Oc2cccnc2C)c1
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)CSc1cnc(Nc2nc(C3CC4CCC(C3)N4C(C)=O)ns2)c(Oc2cccnc2C)c1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 95.3 %

Procedure:
Methyl 2-(6-(3-(8-azabicyclo[3.2.1]octan-3-yl)-1,2,4-thiadiazol-5-ylamino)-5-(2-methylpyridin-3-yloxy)pyridin-3-ylthio)acetate (384 mg, 0.770 mmol) was dissolved in CH2Cl2 (7 mL), and triethylamine (16 μL, 1.16 mmol) and acetic anhydride (87.4 μL, 0.924 mmol) were added. The reaction was stirred at ambient temperature for 5 minutes. The reaction was partitioned between CH2Cl2 and saturated aqueous NaHCO3, dried over sodium sulfate, filtered and concentrated to afford methyl 2-(6-(3-(8-acetyl-8-azabicyclo[3.2.1]octan-3-yl)-1,2,4-thiadiazol-5-ylamino)-5-(2-methylpyridin-3-yloxy)pyridin-3-ylthio)acetate (397 mg, 0.734 mmol, 95.3% yield).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[N:13](C2CCCCO2)[N:12]=[C:11]3[C:23]2[N:28]=[C:27]([N:29]3[CH2:34][CH2:33][CH:32]([NH:35]C(=O)OC(C)(C)C)[CH2:31][CH2:30]3)[CH:26]=[N:25][CH:24]=2)[CH:5]=[CH:6][CH:7]=1.CC(O)C.O>Cl>[NH3:12].[F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[NH:13][N:12]=[C:11]3[C:23]2[N:28]=[C:27]([N:29]3[CH2:34][CH2:33][CH:32]([NH2:35])[CH2:31][CH2:30]3)[CH:26]=[N:25][CH:24]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)NC1CCN(c2cncc(-c3nn(C4CCCCO4)c4ccc(-c5cccc(F)c5)cc34)n2)CC1
Agent: Cl
Solvent: O
Solvent: CC(C)O
Product: N
Product: NC1CCN(c2cncc(-c3n[nH]c4ccc(-c5cccc(F)c5)cc34)n2)CC1
Temperature: 25 °C

Procedure:
A glass microwave reaction vessel was charged with tert-butyl 1-(6-(5-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)pyrazin-2-yl)piperidin-4-ylcarbamate (0.200 g, 0.359 mmol), 3-fluorophenylboronic acid (0.072 g, 0.515 mmol, Aldrich), Na2CO3 (0.210 g, 1.981 mmol, J. T. Baker) and trans-dichlorobis(triphenyl-phosphine)palladium (II) (0.022 g, 0.031 mmol, Strem). Dioxane (3 mL) and water (1 mL) were added and the reaction mixture was sealed under argon and heated in a Emrys Optmizer microwave reactor (Personal Chemistry, Biotage AB, Inc., Uppsala, Sweden) at 140° C. for 15 min. The mixture was partitioned between EtOAc/water. The aqueous layer was extracted with EtOAc (3×) and the combined organic layers were evaporated onto silica gel and purified by flash chromatography (Isco, (40 gram)) eluting with 2M NH3 in MeOH:DCM (0:1→1:49) to give 119 mg of tert-Butyl 1-(6-(5-(3-fluorophenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)pyrazin-2-yl)piperidin-4-ylcarbamate as a yellow amorphous solid. MS (ESI, pos. ion) m/z: 573.2 (M+1). A solution of tert-butyl 1-(6-(5-(3-fluorophenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)pyrazin-2-yl)piperidin-4-ylcarbamate (0.119 g, 0.208 mmol) in HCl, 5-6 N in IPA (5.00 mL, 25.00 mmol) and water (0.5 mL) was heated at 80° C. for 2.5 h. The reaction mixture was cooled to RT and the solid was filtered and washed with IPA. The material was dissolved in DMSO and purified by reverse-phase HPLC (Gilson; Gemini-NX 10μ C18 110 A AXIA, 100×50 mm column) eluting with 0.1% TFA-H2O:0.1% TFA ACN (9:1→1:9). The fractions containing the desired product were combined and concentrated in vacuo. The residue was dissolved in MeOH and loaded onto an SCX II cartridge eluting with MeOH then 2M NH3 in MeOH to give the title compound as a yellow crystalline solid. MS (ESI, pos. ion) m/z: 389.1 (M+1).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH:3]([OH:6])[CH2:2]1.[O:7]1[C:11]2[CH:12]=[CH:13][C:14]([CH:16]=O)=[CH:15][C:10]=2[O:9][CH2:8]1.C([Sn](CCCC)(Cl)Cl)CCC.C1([SiH3])C=CC=CC=1.Cl>COCCOC.C(Cl)Cl.O>[O:7]1[C:11]2[CH:12]=[CH:13][C:14]([CH2:16][N:1]3[CH2:5][CH2:4][C:3]([OH:6])=[CH:2]3)=[CH:15][C:10]=2[O:9][CH2:8]1
Reactant: O=Cc1ccc2c(c1)OCO2
Reactant: OC1CCNC1
Agent: CCCC[Sn](Cl)(Cl)CCCC
Agent: Cl
Agent: [SiH3]c1ccccc1
Solvent: COCCOC
Solvent: ClCCl
Solvent: O
Product: OC1=CN(Cc2ccc3c(c2)OCO3)CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 60.3 %

Procedure:
A solution of pyrrolidin-3-ol (0.539 g, 6.2 mmol) in ethyleneglycol dimethylether (DME) (5 mL) was treated with benzo[d][1,3]dioxole-5-carbaldehyde (272) (1.08 g, 7.2 mmol) and dibutyldichlorostannane (0.71 g, 2.3 mmol). After the suspension was stirred for 15 min at room temperature, phenylsilane (1.0 mL, 8.6 mmol) was added neat and the mixture was stirred for 18 h. The reaction mixture was diluted with DCM (50 mL), treated with 1N HCl (13 mL) and stirred for 30 min followed by dilution with H2O (50 mL) and DCM (50 mL). The aqueous layer was collected, basified with solid potassium carbonate (K2CO3), extracted with DCM, dried over MgSO4, filtered and concentrated to provide title compound 273 (0.82 g, 60% yield).
Reaction SMILES: Cl[CH:2](Cl)[C:3](=O)[CH3:4].[CH:7]1([CH:13]=O)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1.CC([O-])(C)C.[K+].[C:21]([CH2:23][C:24]([NH2:26])=[O:25])#[N:22]>C1COCC1>[CH:7]1([C:13]2[CH:2]=[C:3]([CH3:4])[NH:26][C:24](=[O:25])[C:23]=2[C:21]#[N:22])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]1
Reactant: CC(=O)C(Cl)Cl
Reactant: O=CC1CCCCC1
Reactant: N#CCC(N)=O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: Cc1cc(C2CCCCC2)c(C#N)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred suspension of CrCl2 (58 g, 472.8 mmol in THF (1500 mL) was added a THF solution (500 mL) of 1,1-dichloro-2-propanone (10 g, 78.8 mmol) and cyclohexanecarbaldehyde (8.84 g, 78.8 mmol). The reaction mixture was heated at reflux for 2 h, and then quenched by the addition of 1.0 M HCl. The reaction mixture was filtered through a pad of Celite and concentrated in vacuo. The crude residue (10 g) was added to a solution of DMSO (150 mL) containing t-BuOK (7.5 g, 65.7 mmol), and cyanoacetamide (6.1 g, 72.3 mmol) and stirred at room temperature for 30 min. Additional t-BuOK (22.5 g, 197.1 mmol) was added and the reaction mixture was stirred under an atmosphere of oxygen for an additional 1 h. The contents were purged with argon, diluted with 4 volumes of H2O, and then 5 volumes of 4 N HCl, which were added slowly. The reaction mixture was filtered, washed with water and dried to give 4-cyclohexyl-6-methyl-2-oxo-1,2-dihydro-3-pyridinecarbonitrile as 4.5 g (32%). 1H NMR (400 MHz, DMSO-d6) δ ppm 6.25 (s, 1H), 2.61-2.65 (m, 1H), 2.22 (s, 3H), 1.66-1.79 (m, 4H), 1.24-1.46 (m, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1Cl)[N:8]([CH2:13][CH3:14])[CH:7]=[C:6]([C:15]([OH:17])=[O:16])[C:5]2=[O:18].[NH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1>CN(C=O)C.COCCO.C(O)(C)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[N:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1)[N:8]([CH2:13][CH3:14])[CH:7]=[C:6]([C:15]([OH:17])=[O:16])[C:5]2=[O:18]
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(Cl)c(Cl)cc21
Reactant: C1CCNCC1
Solvent: CN(C)C=O
Solvent: CC(C)O
Solvent: COCCO
Product: CCn1cc(C(=O)O)c(=O)c2cc(Cl)c(N3CCCCC3)cc21
Temperature: 110 °C

Procedure:
A solution of 4.3 g of 6,7-dichloro-1-ethyl-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid and 5.5 cm3 of piperidine in a mixture of 20 cm3 of DMF and 20 cm3 of methyl cellosolve was heated for 5 hours at 110° C. After concentration of the solution in vacuo, the residue was taken up in 50 cm3 of isopropanol. The solid was filtered off and recrystallised from methyl cellosolve (50 cm3). 2.4 g of 6-chloro-1-ethyl-4-oxo-7-piperidino-1,4-dihydro-quinoline-3-carboxylic acid, m.p. 230° C., were obtained.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[Li].[Li].C1C2C(=CC=CC=2)C=CC=1.C=CC=C.C(=[O:33])CCCCC>O1CCCC1>[CH3:1][CH2:2][C:3]#[C:4][CH:5]([OH:33])[CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: c1ccc2ccccc2c1
Reactant: CCCCCC=O
Agent: C=CC=C
Agent: [Li]
Solvent: C1CCOC1
Product: CCC#CC(O)CCCCC
Temperature: 55 °C

Procedure:
Following the procedure of Example 1, but with a pressure equalizing dropping funnel in place of the gas addition tube, 100 g. of naphthalene (0.77 moles) were added to 7.3 g. of lithium metal powder (1.05 moles) in 100 ml. tetrahydrofuran forming a dark green-brown lithium-naphthalene adduct over a period of about 30 minutes. 168 g. of the gaseous hydrocarbon mixture of Example 1 dissolved in 800 ml. tetrahydrofuran were added to the flask over a two hour period while maintaining the slurry at a temperature of about 55°C. Near the end of the addition, the slurry turned to an olive green color and became light brown after stirring for an additional hour. An aliquot of the resultant product was reacted with 1-hexanal producing 3-decyn-5-ol which, by gas chromotograph analysis, establishes a yield of butynyllithium in excess of 90%, based on lithium.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([CH2:17][NH:18][C:19]2[CH:24]=[C:23]([CH3:25])[N:22]=[C:21]([NH:26]CC3C=CC(OC)=CC=3OC)[N:20]=2)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:1]([O:8][C:9]([N:11]1[CH2:12][CH2:13][CH:14]([CH2:17][NH:18][C:19]2[CH:24]=[C:23]([CH3:25])[N:22]=[C:21]([NH2:26])[N:20]=2)[CH2:15][CH2:16]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(CNc2nc(C)cc(NCC3CCN(C(=O)OCc4ccccc4)CC3)n2)c(OC)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(NCC2CCN(C(=O)OCc3ccccc3)CC2)nc(N)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of the 4-{[2-(2,4-dimethoxy-benzylamino)-6-methyl-pyrimidin-4-ylamino)-methyl}-piperidine-1-carboxylic acid benzyl ester from Step 1 above (0.4 g, 0.79 mmol) in CH2Cl2 (5 mL) was added trifluoroacetic acid (1 mL). The resulting reaction solution was stirred at rt for 1 h, then concentrated in vacuo. The residue was purified by silica gel chromatography (1–10 (10% NH4OH in MeOH)/99–90 CH2Cl2) to give 4-[(2-amino-6-methyl-pyrimidin-4-ylamino)-methyl]-piperidine-1-carboxylic acid benzyl ester. M.S. (M+1): 356.36