Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:16]=[C:15]3[C:11]([CH2:12][N:13]([C@@H:18]([CH:23]([CH3:25])[CH3:24])[C:19]([O:21][CH3:22])=[O:20])[C:14]3=[O:17])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[F:26][C:27]1[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:28]=1[N:34]=[C:35]=[O:36]>>[F:26][C:27]1[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:28]=1[NH:34][C:35](=[O:36])[NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:16]=[C:15]3[C:11]([CH2:12][N:13]([C@@H:18]([CH:23]([CH3:25])[CH3:24])[C:19]([O:21][CH3:22])=[O:20])[C:14]3=[O:17])=[CH:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: O=C=Nc1ccc(F)cc1F
Reactant: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(N)cc3)cc2C1=O
Product: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)Nc4ccc(F)cc4F)cc3)cc2C1=O

Procedure:
The compound of example 9 was prepared analogous to compound of example 7 by reaction of compound of example 6 with 2,4-difluorophenyl isocyanate. The compound of example 9 was used directly without isolation for the preparation of compound of example 10.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:8]=[CH:9][CH:10]=1)[NH2:7])([O-:3])=[O:2].[CH2:11]([N:29]=[C:30]=[O:31])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28].C(N(CC)CC)C>CN(C)C1C=CN=CC=1.C1COCC1>[N+:1]([C:4]1[CH:5]=[C:6]([NH:7][C:30]([NH:29][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[O:31])[CH:8]=[CH:9][CH:10]=1)([O-:3])=[O:2]
Reactant: CCCCCCCCCCCCCCCCCCN=C=O
Reactant: Nc1cccc([N+](=O)[O-])c1
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCCCCCCCNC(=O)Nc1cccc([N+](=O)[O-])c1
Yield: 83.3 %

Procedure:
A mixture of 0.5 g (3.6 mmol) of 3-nitroaniline, 1.2 mL (3.9 mmol) of octadecyl isocyanate 0.7 mL (5 mmol) of triethylamine and 0.1 mL of 4-dimethylaminopyridine in 30 mL of anhydrous THF was stirred at reflux for 18 hours. The reaction mixture was concentrated at reduced pressure and the residue was recrystallized from THF methanol-water to give 1.3 g of N-(3-nitrophenyl)-N'-octadecylurea.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:17][CH:18]2[CH2:35][CH2:34][C:21]3([CH2:26][CH2:25][N:24](C(OC(C)(C)C)=O)[CH2:23][CH2:22]3)[CH2:20][CH2:19]2)=[N:4][C:5]([NH:8][C:9]2[CH:13]=[C:12]([CH:14]3[CH2:16][CH2:15]3)[NH:11][N:10]=2)=[N:6][CH:7]=1.Cl.C(OCC)(=O)C>C(Cl)Cl>[ClH:1].[Cl:1][C:2]1[C:3]([NH:17][CH:18]2[CH2:35][CH2:34][C:21]3([CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)[CH2:20][CH2:19]2)=[N:4][C:5]([NH:8][C:9]2[CH:13]=[C:12]([CH:14]3[CH2:16][CH2:15]3)[NH:11][N:10]=2)=[N:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC2(CCC(Nc3nc(Nc4cc(C5CC5)[nH]n4)ncc3Cl)CC2)CC1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: Clc1cnc(Nc2cc(C3CC3)[nH]n2)nc1NC1CCC2(CCNCC2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 199.4 %

Procedure:
To a solution of tert-butyl 9-((5-chloro-2-((5-cyclopropyl-1H-pyrazol-3-yl)amino)pyrimidin-4-yl)amino)-3-azaspiro[5.5]undecane-3-carboxylate (364 mg, 0.7251 mmol) in DCM (10 mL) was added a solution of HCl in ethyl acetate (20 mL, 60 mmol). The reaction was stirred overnight at rt and then concentrated in vacuo to give the title compound as a yellow solid (317 mg, 99%).
Reaction SMILES: Br[C:2]1[C:3](=[O:27])[C:4]2[C:9]([C:10]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[CH:8][CH:7]=[C:6]([O:17][CH2:18][CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH:5]=2.[CH3:28][N:29](C)C=O>[Cu+]>[O:27]=[C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[C:6]([O:17][CH2:18][CH2:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH:5]=2)[C:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[C:2]1[C:28]#[N:29]
Reactant: O=C1C(Br)=C(c2ccccc2)c2ccc(OCCCc3ccccc3)cc21
Reactant: CN(C)C=O
Agent: [Cu+]
Product: N#CC1=C(c2ccccc2)c2ccc(OCCCc3ccccc3)cc2C1=O
Temperature: 150 °C
Reaction time: 3 h
Yield: 80 %

Procedure:
2-Bromo-3-phenyl-6-(3-phenyl-propoxy)-indene-1-one (1.0 g, 2.3 mmol) obtained in Step 2 was dissolved in N,N-dimethyl formamide (10 mL), copper(I) cyamide (617 mg, 6.9 mmol) was added thereto, and the mixture was stirred for 3 hrs at 150° C., followed by cooling. The resulting mixture was washed with saturated ammonium chloride and extracted with ethyl acetate. The organic layer was separated, dried over anhydrous MgSO4 and concentrated under a reduced pressure. The resulting residue was purified by flash chromatography (ethyl acetate:hexane=1:3) to obtain 700 mg of the titled compound (yield: 80%) as a red solid.
Reaction SMILES: C[O:2][C:3](=[O:30])[C:4]([NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([CH:14]2[C:23]([CH3:25])([CH3:24])[CH2:22][C:21]3[C:16](=[CH:17][CH:18]=[C:19]([C:26]([F:29])([F:28])[F:27])[CH:20]=3)[NH:15]2)[CH:9]=1)([CH3:6])[CH3:5].Cl>O1CCCC1.[OH-].[Li+].O>[CH3:24][C:23]1([CH3:25])[CH2:22][C:21]2[C:16](=[CH:17][CH:18]=[C:19]([C:26]([F:28])([F:27])[F:29])[CH:20]=2)[NH:15][CH:14]1[C:10]1[CH:9]=[C:8]([NH:7][C:4]([CH3:6])([CH3:5])[C:3]([OH:30])=[O:2])[CH:13]=[CH:12][CH:11]=1
Reactant: COC(=O)C(C)(C)Nc1cccc(C2Nc3ccc(C(F)(F)F)cc3CC2(C)C)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(Nc1cccc(C2Nc3ccc(C(F)(F)F)cc3CC2(C)C)c1)C(=O)O
Temperature: 25 °C
Reaction time: 12 h
Yield: 0.8 %

Procedure:
A mixture of 2-[3-(3,3-dimethyl-6-trifluoromethyl-1,2,3,4-tetrahydro-quinolin-2-yl)-phenylamino]-2-methyl-propionic acid methyl ester (400 mg, 0.95 mmol) in tetrahydrofuran (30 mL), 2M lithium hydroxide in water (15 mL) was stirred at 25° C. for 12 h. The mixture was neutralized with a 3 N aqueous hydrochloric acid solution and extracted with ethyl acetate (2×100 mL), washed with water, dried over anhydrous sodium sulfate and then concentrated in vacuo. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% formic acid in water) afforded 2-[3-(3,3-dimethyl-6-trifluoromethyl-1,2,3,4-tetrahydro-quinolin-2-yl)-phenylamino]-2-methyl-propionic acid (3 mg, 0.7%) as a light yellow oil: LC/MS m/e calcd for C22H25F3N2O2 (M+H)+: 407.45, observed: 407.2.
Reaction SMILES: [CH3:1][C:2]1[CH:23]=[CH:22][CH:21]=[C:20]([CH3:24])[C:3]=1[CH2:4][O:5][C:6]1[CH:7]=[C:8]([C:12](=[O:19])[CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:9]=[CH:10][CH:11]=1.CC(C)([O-])C.[K+].Br[CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35].Cl>C(O)(C)(C)C>[CH3:24][C:20]1[CH:21]=[CH:22][CH:23]=[C:2]([CH3:1])[C:3]=1[CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH:9]=[CH:10][CH:11]=1)[C:12]([CH:13]([CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[O:19]
Reactant: CCOC(=O)CC(=O)c1cccc(OCc2c(C)cccc2C)c1
Reactant: CCOC(=O)CCBr
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CC(C)(C)O
Product: CCOC(=O)CCC(C(=O)OCC)C(=O)c1cccc(OCc2c(C)cccc2C)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of Ethyl 3-(3-(2,6-dimethylbenzyloxy)phenyl)-3-oxopropanoate (Step A, 5 g, 16.02 mmol) in t-butyl alcohol (50 ml) was added a solution of potassium tert-butoxide (1M in t-butyl alcohol, 1.988 g, 17.7 mmol) and the reaction mixture was stirred for 30 minutes at room temperature. Ethyl 3-bromopropionate was added drop wise to the reaction mixture and stirring continued for another 2 hours and then poured into 1M HCl, extracted with ethyl acetate (2×), washed with brine, dried over Na2SO4, filtered, concentrated and purified by flash chromatography eluted with hexane:ethyl acetate (2:1) to give the title compound.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[C:8]([O:13][C:14]3[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][CH:15]=3)=[N:9][CH:10]=[CH:11][CH:12]=2)=[CH:3][CH:2]=1.Cl[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.CC(C)([O-])C.[Na+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[N:1]1[CH:2]=[CH:3][C:4]([C:7]2[C:8]([O:13][C:14]3[CH:19]=[CH:18][C:17]([NH:20][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=4)=[CH:16][CH:15]=3)=[N:9][CH:10]=[CH:11][CH:12]=2)=[CH:5][CH:6]=1
Reactant: Clc1ccccn1
Reactant: Nc1ccc(Oc2ncccc2-c2ccncc2)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Product: c1ccc(Nc2ccc(Oc3ncccc3-c3ccncc3)cc2)nc1
Temperature: 120 °C

Procedure:
A glass microwave reaction vessel was charged with 4-(3-(pyridin-4-yl)pyridin-2-yloxy)benzenamine (0.0965 g, 0.37 mmol), 2-chloropyridine (0.034 mL, 0.36 mmol), palladium(II) acetate (0.0098 g, 0.018 mmol), BINAP (0.0213 g, 0.037 mmol), and sodium tert-butoxide (0.0503 g, 0.55 mmol). The reaction mixture was stirred and heated in a Smith Synthesizer® microwave reactor (Personal Chemistry, Inc., Upssala, Sweden) at 120° C. for 45 min. Reaction was concentrated. The crude product was adsorbed onto a plug of silica gel and chromatographed through a Biotage™ pre-packed silica gel column (25M), eluting with a gradient of 1% to 5% methanol in DCM, to provide N-(4-(3-(pyridin-4-yl)pyridin-2-yloxy)phenyl)pyridin-2-amine. MS (ESI, pos. ion) m/z: 341.1 (M+1). IC50 (uM) 0.000659.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH2:9][CH2:8][CH:7]([N:15]([CH3:17])[CH3:16])[CH2:6][C:5]2=1.[S:18]1[CH:22]=[CH:21][C:20]([C:23](O)=[O:24])=[CH:19]1>>[S:18]1[CH:22]=[CH:21][C:20]([C:23]([NH:1][C:2]2[CH:3]=[C:4]3[C:12](=[CH:13][CH:14]=2)[NH:11][C:10]2[CH2:9][CH2:8][CH:7]([N:15]([CH3:17])[CH3:16])[CH2:6][C:5]3=2)=[O:24])=[CH:19]1
Reactant: O=C(O)c1ccsc1
Reactant: CN(C)C1CCc2[nH]c3ccc(N)cc3c2C1
Product: CN(C)C1CCc2[nH]c3ccc(NC(=O)c4ccsc4)cc3c2C1
Yield: 52.7 %

Procedure:
Beginning with 8.7 mg (0.038 mMol) 6-amino-3-(dimethyl)amino-1,2,3,4-tetrahydro-9H-carbazole and 11.0 mg (0.086 mMol) thiophene-3-carboxylic acid, 6.8 mg (53%) of the title compound were recovered as a beige solid.
Reaction SMILES: Cl[C:2]1[N:20]=[C:5]2[C:6]([C:10]3[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:12][CH:11]=3)=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1.[F:21][CH2:22][CH2:23][CH2:24][N:25]1[CH2:30][CH2:29][N:28]([C:31]2[CH:32]=[C:33]([NH2:37])[CH:34]=[CH:35][CH:36]=2)[CH2:27][CH2:26]1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)CCCCC1>>[F:21][CH2:22][CH2:23][CH2:24][N:25]1[CH2:30][CH2:29][N:28]([C:31]2[CH:32]=[C:33]([NH:37][C:2]3[N:20]=[C:5]4[C:6]([C:10]5[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:12][CH:11]=5)=[CH:7][CH:8]=[CH:9][N:4]4[N:3]=3)[CH:34]=[CH:35][CH:36]=2)[CH2:27][CH2:26]1
Reactant: CS(=O)(=O)c1ccc(-c2cccn3nc(Cl)nc23)cc1
Reactant: Nc1cccc(N2CCN(CCCF)CC2)c1
Agent: c1ccc(P(C2CCCCC2)C2CCCCC2)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c1
Product: CS(=O)(=O)c1ccc(-c2cccn3nc(Nc4cccc(N5CCN(CCCF)CC5)c4)nc23)cc1

Procedure:
187 a) To a suspension of 1-(3-nitro-phenyl)-piperazine; hydrochloride (1.0 g, 4.1 mmol) and potassium carbonate (0.62 g, 4.5 mmol) in acetonitrile (10 mL) was added 1-fluoro-3-iodo-propane (0.85 g, 4.5 mmol) and was stirred at room temperature for 3 days. The mixture was poured into water (50 mL) and extracted with dichloromethane (3×20 mL). The combined organic layers were washed with saturated aqueous sodium chloride (10 mL), dried over magnesium sulfate, filtered and evaporated. 1-(3-Fluoro-propyl)-4-(3-nitro-phenyl)-piperazine was isolated as a viscous orange oil (0.886 g, 80%). 1H NMR (400 MHz, CDCl3, δ, ppm): 7.71 (s, 1H), 7.65 (d, J=8.2 Hz, 1H), 7.37 (t, J=8.2 Hz, 1H), 7.18 (dd, J=8.3, 1.9 Hz, 1H), 4.54 (ddd, J=47.2, 5.9, 5.9 Hz, 2H), 3.32-3.27 (m, 4H), 2.65-2.60 (m, 4H), 2.55 (t, J=7.2 Hz, 2H), 2.00-1.85 (m, 2H). MS=268 (MH)+. 187 b) 3-[4-(3-Fluoro-propyl)-piperazin-1-yl]-phenylamine was prepared from 1-(3-fluoro-propyl)-4-(3-nitro-phenyl)-piperazine (0.20 g, 0.75 mmol) in a manner analogous to Example 111a. Product isolated as a tan waxy solid (0.18 g, 100%). 1H NMR (400 MHz, CDCl3, δ, ppm): 7.04 (t, J=8.1 Hz, 1H), 6.36 (d, J=8.3 Hz, 1H), 6.26 (s, 1H), 6.21 (d, J=7.9 Hz, 1H), 4.62-4.44 (m, 2H), 3.60 (br s, 2H), 3.20-3.15 (m, 4H), 2.62-2.57 (m, 4H), 2.53 (t, J=7.2 Hz, 2H), 2.00-1.85 (m, 2H). MS=238 (MH)+. 187 c) {3-[4-(3-Fluoro-propyl)-piperazin-1-yl]-phenyl}-[8-(4-methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-amine was prepared from 2-chloro-8-(4-methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridine (220.0 mg, 0.7148) and 3-[4-(3-fluoro-propyl)-piperazin-1-yl]-phenylamine (180.0 mg, 0.7585 mmol) with 2,2′-bis-dicyclohexylphosphanyl-biphenyl (60.0 mg, 0.110 mmol) as the ligand in a manner analogous to Example 2d. Product isolated as a tan solid (0.264 g, 73%). MP=157-169° C. 1H NMR (400 MHz, CDCl3, δ, ppm): 8.49 (d, J=6.7 Hz, 1H), 8.26 (d, J=8.0 Hz, 2H), 8.09 (d, J=8.0 Hz, 2H), 7.66 (d, J=7.4 Hz, 1H), 7.46 (br s, 1H), 7.22 (t, J=8.0 Hz, 1H), 7.02 (t, J=7.0 Hz, 1H), 6.93 (d, J=7.6 Hz, 1H), 6.89 (s, 1H), 6.59 (d, J=8.0 Hz, 1H), 4.64-4.48 (m, 2H), 3.30 (br s, 4H), 3.11 (s, 3H), 2.93-2.40 (m, 6H), 2.08-1.90 (m, 2H). MS=509 (MH)+.
Reaction SMILES: [CH:1]1([C:6](Cl)=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.FC(F)(F)C(O)=O.[CH2:16]([O:18][C:19]1[CH:40]=[CH:39][C:22]([O:23][C:24]2[N:29]=[CH:28][N:27]=[C:26]3[N:30]([CH:33]4[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]4)[N:31]=[CH:32][C:25]=23)=[C:21]([F:41])[CH:20]=1)[CH3:17].C(N(C(C)C)CC)(C)C.O>ClCCl>[CH:1]1([C:6]([N:36]2[CH2:37][CH2:38][CH:33]([N:30]3[C:26]4=[N:27][CH:28]=[N:29][C:24]([O:23][C:22]5[CH:39]=[CH:40][C:19]([O:18][CH2:16][CH3:17])=[CH:20][C:21]=5[F:41])=[C:25]4[CH:32]=[N:31]3)[CH2:34][CH2:35]2)=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(Cl)C1CCCC1
Reactant: CCOc1ccc(Oc2ncnc3c2cnn3C2CCNCC2)c(F)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CCOc1ccc(Oc2ncnc3c2cnn3C2CCN(C(=O)C3CCCC3)CC2)c(F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.6 %

Procedure:
Cyclopentanecarbonyl chloride (10 mg, 0.078 mmol) was added to a mixture of 4-(4-ethoxy-2-fluoro-phenoxy)-1-piperidin-4-yl-1H-pyrazolo[3,4-d]pyrimidine trifluoroacetate salt (Intermediate 29; 28 mg, 0.078 mmol), and diisopropylethylamine (30 mg, 0.235 mmol) in dichloromethane (2 mL). The reaction mixture was stirred at room temperature overnight. Water was added to quench the reaction and the aqueous layer was extracted three times with dichloromethane. The combined organic layers were dried (sodium sulfate), filtered, evaporated and purified by flash chromatography on silica gel, eluting with 4% methanol/dichloromethane to give cyclopentyl-{4-[4-(4-ethoxy-2-fluoro-phenoxy)-pyrazolo[3,4-d]pyrimidin-1-yl]-piperidin-1-yl}-methanone (31 mg, 87%) as a white solid. Mass spectrum MH+=454.
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:9](Cl)=[N:8][CH:7]=[N:6][C:5]=2[N:4]([CH2:12][CH2:13][CH:14]2[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]2)[CH:3]=1.[OH-].[NH4+:28]>>[NH2:28][C:9]1[C:10]2[C:2]([Br:1])=[CH:3][N:4]([CH2:12][CH2:13][CH:14]3[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]3)[C:5]=2[N:6]=[CH:7][N:8]=1
Reactant: CC(C)(C)OC(=O)N1CCC(CCn2cc(Br)c3c(Cl)ncnc32)CC1
Reactant: [NH4+]
Agent: [OH-]
Product: CC(C)(C)OC(=O)N1CCC(CCn2cc(Br)c3c(N)ncnc32)CC1
Temperature: 90 °C
Yield: 101 %

Procedure:
To 1,1-dimethylethyl 4-[2-(5-bromo-4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)ethyl]-1-piperidinecarboxylate (320 mg, 0.721 mmol) in a 5 ml sealable vial was added ammonium hydroxide (1.5 mL, 38.5 mmol). The vial was then capped and heated at 90° C. overnight. The reaction was then cooled and the solid was isolated filtration and washed with NH4OH. The solid was then air dried to give 1,1-dimethylethyl 4-[2-(4-amino-5-bromo-7H-pyrrolo[2,3-d]pyrimidin-7-yl)ethyl]-1-piperidinecarboxylate (309 mg) as an off white solid that contained a small amount of starting material. It was used without further purification. LC-MS (ES) m/z=424.4 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[C:4]([CH3:9])[N:3]=1.[CH2:10]([O:12][C:13]1[CH:14]=[CH:15][C:16]([F:22])=[C:17](B(O)O)[CH:18]=1)[CH3:11].C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.C1(C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)[Pd][P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:1][C:2]1[N:7]=[C:6]([C:15]2[CH:14]=[C:13]([O:12][CH2:10][CH3:11])[CH:18]=[CH:17][C:16]=2[F:22])[CH:5]=[C:4]([CH3:9])[N:3]=1
Reactant: Cc1cc(Cl)nc(Cl)n1
Reactant: CCOc1ccc(F)c(B(O)O)c1
Agent: c1ccc([P]([Pd][P](c2ccccc2)(c2ccccc2)c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: CCOc1ccc(F)c(-c2cc(C)nc(Cl)n2)c1
Temperature: 80 °C
Yield: 96.6 %

Procedure:
To a solution of 2,4-dichloro-6-methyl-pyrimidine (2.66 g, 16.31 mmol) and (5-ethoxy-2-fluoro-phenyl)boronic acid (2 g, 10.87 mmol) in 1,2-dimethoxyethane (25 mL) and water (15 mL) was added sodium carbonate (3.46 g, 32.62 mmol). This was degassed with nitrogen for 5 minutes. Bis(triphenylphosphine)palladium (II) dichloride (0.38 g, 0.54 mmol) was then added and the reaction was heated to 80° C. overnight. The solvent was evaporated and the residue was partitioned between water (300 mL) and EtOAc (300 mL). The organics were washed with brine (100 mL), dried over MgSO4 and concentrated in vacuo to afford a yellow oil. The material was purified using a Biotage SP4 eluting with 0 to 30% i-hexane/EtOAc and the product containing fractions were collected and the solvent evaporated to give a colourless solid (2.8 g) mainly 2-chloro-4-(5-ethoxy-2-fluoro-phenyl)-6-methyl-pyrimidine (D16)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[C:5]2Cl.Cl.[CH3:14][O:15][CH:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1.C(N(CC)CC)C.CN(C)C=O>O.C(OCC)(=O)C>[CH3:14][O:15][CH:16]1[CH2:21][CH2:20][N:19]([C:5]2[C:4]3[C:9](=[CH:10][CH:11]=[C:2]([Br:1])[CH:3]=3)[N:8]=[CH:7][CH:6]=2)[CH2:18][CH2:17]1
Reactant: COC1CCNCC1
Reactant: Clc1ccnc2ccc(Br)cc12
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: COC1CCN(c2ccnc3ccc(Br)cc23)CC1
Temperature: 130 °C
Reaction time: 8 h
Yield: 77.9 %

Procedure:
A mixture of 500 mg 6-bromo-4-chloroquinoline, 330 mg 4-methoxypiperidine monohydrochloride, 0.57 mL triethylamine and 10 mL N,N-dimethylformamide was stirred at 130° C. for 8 hours. Ethyl acetate and water were added to the reaction solution, and the organic layer was separated. The organic layer was washed with water and brine and dried over sodium sulfate, and the solvent was evaporated. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give 516 mg of the title compound as a pale yellow oil.
Reaction SMILES: CC1(C)CC1C(N[CH:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)=O.C1(C)C=CC(S(O[CH2:25][CH2:26][C:27]2[CH:32]=[CH:31][C:30](NC(OC(C)(C)C)=O)=[CH:29][CH:28]=2)(=O)=O)=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>[I-].[Na+].C(#N)C>[CH2:25]([N:11]1[CH2:10][CH2:9][CH2:8][CH2:13][CH2:12]1)[CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: CC1(C)CC1C(=O)NC1CCNCC1
Reactant: Cc1ccc(S(=O)(=O)OCCc2ccc(NC(=O)OC(C)(C)C)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Product: c1ccc(CCN2CCCCC2)cc1
Temperature: 100 °C
Yield: 65.5 %

Procedure:
An acetonitrile (5 ml) solution of the piperidine compound (23:R=2,2-dimethylcyclopropane) (50 mg, 0.25 mmol) obtained in the process 1 of example 15 was added with 2-(4-t-butoxycarbonylaminophenyl)ethanol paratoluensulfonate (57 mg, 0.31 mmol), sodium carbonate (32 mg, 0.31 mmol) and sodium iodide (2 mg), which was in turn heated and refluxed at 100° C. for 2 hours. The resultant was extracted with ethyl acetate, and further washed with water and saturated saline solution, dried and vacuum concentrated, and then separately purified with a silica gel TLC plate (chloroform, methanol), thus obtained a phenethylpiperidine compound (31 mg, 29%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:10])[CH2:4][C:5]([CH2:7][O:8][CH3:9])=[O:6].CO[CH:13](OC)[N:14]([CH3:16])[CH3:15]>CCCCCCC>[CH3:13][N:14]([CH:16]=[C:4]([C:5](=[O:6])[CH2:7][O:8][CH3:9])[C:3]([O:2][CH3:1])=[O:10])[CH3:15]
Reactant: COC(OC)N(C)C
Reactant: COCC(=O)CC(=O)OC
Solvent: CCCCCCC
Product: COCC(=O)C(=CN(C)C)C(=O)OC
Temperature: 90 °C
Reaction time: 2 h
Yield: 54.5 %

Procedure:
Methyl-4-methoxyacetoacetate (9 ml, 70 mmol) was added to dimethylformamide dimethylacetal (18.8 ml, 139 mmol) and the reaction stirred at 90° C. for 2 hours before cooling to room temperature and stirring for 18 hours. The reaction was concentrated in vacuo and purified by silica gel column chromatography, eluting with 70:30 to 100:0 ethyl acetate:heptane to afford the title compound as an oil (7.68 g, 50% yield).
Reaction SMILES: NN1CN=CS1.C(N(CC)CC)C.ClS([N:18]=[C:19]=O)(=O)=O.[F-].[CH2:22]([N+:26](CCCC)([CH2:31]CCC)[CH2:27]CCC)[CH2:23][CH2:24][CH3:25].O1CCCC1>ClCCl.CN(C1C=CN=CC=1)C>[CH3:27][N:26]([C:22]1[CH:23]=[CH:24][CH:25]=[CH:19][N:18]=1)[CH3:31]
Reactant: CCCC[N+](CCCC)(CCCC)CCCC
Reactant: O=C=NS(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Agent: NN1CN=CS1
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(C)c1ccccn1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
2-Amino-1,2,4 thiadiazole (0.006 g, 0.06 mmol) and triethylamine (0.0376 mL, 0.27 mmol) were added to 1 mL dichloromethane and cooled to 0° C. To this was slowly added chlorosulfonylisocyanate (0.007 mL, 0.08 mmol) at 0° C. Stirred thirty minutes until starting material consumed. Simultaneously, in a separate flask trimethylsilylethyl ether 44 was dissolved in 0.5 mL tetrahydrofuran. To this was added triethylamine (0.0376 mL, 0.27 mmol) and 1M tetrabutylammonium fluoride in tetrahydrofuran (0.135, 0.135 mmol) and stirred at room temperature. After 20 minutes, diluted with dichloromethane, washed with 1M HCl solution and brine, concentrated to give crude. At 0° C., dissolved in 0.5 mL dichloromethane and added to the solution prepared in situ above. Stirred at 0° C. for Sminutes, catalytic DMAP added, then stirred for one hour at room temperature. Diluted with dichloromethane, washed with 1M HCl solution, brine, concentrated to give crude. Chromatographed (5 to 30% methanol/dichloromethane) to give dimethylaminopyridine adduct 227 (0.033 g, 0.046 mmol, 68%.) 1H NMR (CDCl3) δ 8.97 (dd, 1H), 8.54 (d, 2H), 8.19 (d, 1H), 8.00 (s, 1H), 7.72 (d, 4H), 7.42 (dd, 1H), 7.26-7.14 (m, 7H), 7.02 (dd, 2H), 6.52 (d, 2H), 4.74 (s, 2H), 4.17 (s, 2H), 3.22 (s, 6H.) MS: 718 (M+1).
Reaction SMILES: [CH2:1]([C:5]1[NH:9][N:8]=[C:7]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)[C:6]=1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:2][CH:3]=C.[BH4-].[Na+].C[OH:26]>C(Cl)Cl>[C:17]1([C:6]2[C:7]([C:10]3[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=3)=[N:8][NH:9][C:5]=2[CH2:1][CH2:2][CH2:3][OH:26])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: C=CCCc1[nH]nc(-c2ccc(C)cc2)c1-c1ccccc1
Reactant: CO
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Product: Cc1ccc(-c2n[nH]c(CCCO)c2-c2ccccc2)cc1
Temperature: -78 °C

Procedure:
5-(But-3-enyl)-4-phenyl-3-p-tolyl-1H-pyrazole (360 mg, 1.248 mmol) was dissolved in MeOH (20 mL) and DCM (5 mL). The reaction was cooled to −78° C. and ozone was bubbled through the solution. After the starting material was consumed, the reaction was cooled in an ice bath. Sodium borohydride (70.8 mg, 1.872 mmol) was added to the reaction. The reaction was warmed to room temperature and stirred for an hour. The solvent was removed under reduced pressure and the reaction was extracted (50 mL each of H2O and EtOAc). The aqueous layer was extracted again with EtOAc (50 mL). The combined organic layer was dried, concentrated, and the residue was purified by silica gel column chromatography to give the title compound (130 mg) as a white solid. LCMS m/z=293.1 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ ppm 1.60-1.74 (m, 2H), 2.25 (s, 3H), 2.54-2.62 (m, 2H), 3.33-3.44 (m, 2H), 4.44 (br. s., 1H), 7.16 (t, J=6.44 Hz, 6H), 7.24-7.30 (m, 1H), 7.32-7.38 (m, 2H), 12.71 (s, 1H).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][C:9]2[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=2[NH:7][S:6]1(=[O:16])=[O:15].[C:17]1([CH3:26])[CH:22]=[CH:21][CH:20]=[C:19](B(O)O)[CH:18]=1>>[Cl:1][CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][C:9]2[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=2[N:7]([C:19]2[CH:20]=[CH:21][CH:22]=[C:17]([CH3:26])[CH:18]=2)[S:6]1(=[O:16])=[O:15]
Reactant: Cc1cccc(B(O)O)c1
Reactant: O=S1(=O)Nc2ccccc2CN1CCCCl
Product: Cc1cccc(N2c3ccccc3CN(CCCCl)S2(=O)=O)c1

Procedure:
In an analogous manner to Example 1 step 7, 3-(3-chloropropyl)-3,4-dihydro-1H-2,1,3-benzothiadiazine 2,2-dioxide (408 mg) was coupled to m-tolylboronic acid to provide 3-(3-chloropropyl)-1-(3-methylphenyl)-3,4-dihydro-1H-2,1,3-benzothiadiazine 2,2-dioxide (39 mg):