Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C@@H:9]([C:11]1[NH:12][CH:13]=[CH:14][N:15]=1)[CH3:10].C(N(CC)CC)C.Cl[C:24]([O:26][CH2:27][CH:28]([CH3:30])[CH3:29])=[O:25]>ClCCl>[CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C@@H:9]([C:11]1[N:15]([C:24]([O:26][CH2:27][CH:28]([CH3:30])[CH3:29])=[O:25])[CH:14]=[CH:13][N:12]=1)[CH3:10]
Reactant: CC(C)COC(=O)Cl
Reactant: Cc1cccc([C@H](C)c2ncc[nH]2)c1C
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cccc([C@H](C)c2nccn2C(=O)OCC(C)C)c1C
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of the compound of Example 58 (1.00 g, 5.0 mmol) and triethylamine (0.77 ml, 5.5 mmol) in anhydrous dichloromethane (10 ml) was added dropwise isobutyl chloroformate (2.60 ml, 20 mmol). The reaction mixture was stirred at room temperature for 18 h and then concentrated in vacuo. The residue was partitioned between water (10 ml) and ethyl acetate (10 ml) and the two layers were separated. The aqueous layer was extracted with ethyl acetate (10 ml) and the combined organic layers were dried (MgSO4) and concentrated in vacuo.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:26]=[CH:27][C:28]=1[Cl:29])[O:5][CH:6]1[CH2:11][CH2:10][N:9]([CH2:12][CH:13]2[CH2:18][CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14]2)[CH2:8][CH2:7]1.FC(F)(F)C(O)=O>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:26]=[CH:27][C:28]=1[Cl:29])[O:5][CH:6]1[CH2:7][CH2:8][N:9]([CH2:12][CH:13]2[CH2:18][CH2:17][CH2:16][NH:15][CH2:14]2)[CH2:10][CH2:11]1
Reactant: CC(C)(C)OC(=O)N1CCCC(CN2CCC(Oc3ccc(Cl)c(Cl)c3)CC2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Clc1ccc(OC2CCN(CC3CCCNC3)CC2)cc1Cl
Reaction time: 3 h
Yield: 84 %

Procedure:
1,1-Dimethylethyl 3-[[4-(3,4-dichlorophenoxy)-1-piperidinyl]methyl]-1-piperidinecarboxylate (1.63 g) was dissolved in dichloromethane (30 ml) and trifluoroacetic acid (10 ml) was added. The mixture was stirred for 3 h, then concentrated. The residue was neutralized with sodium hydroxide solution (2M) and extracted with ethyl acetate thrice. The extracts were dried, filtered and evaporated to give the title compound (1.06 g).
Reaction SMILES: Br[C:2]1[C:3]2[N:4]([N:8]=[C:9]([Cl:11])[N:10]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][C:15]=1B(O)O>>[Cl:11][C:9]1[N:10]=[C:3]2[CH:2]=[CH:7][CH:6]=[C:5]([C:15]3[CH:16]=[C:17]([C:20]([F:23])([F:22])[F:21])[CH:18]=[CH:19][C:14]=3[O:13][CH3:12])[N:4]2[N:8]=1
Reactant: Clc1nc2c(Br)cccn2n1
Reactant: COc1ccc(C(F)(F)F)cc1B(O)O
Product: COc1ccc(C(F)(F)F)cc1-c1cccc2nc(Cl)nn12

Procedure:
2-Chloro-5-(2-methoxy-5-trifluoromethyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridine was prepared from 8-bromo-2-chloro[1,2,4]triazolo[1,5-a]pyridine (0.5 g, 2.15 mmol) and 2-methoxy-5-trifluoromethylbenzeneboronic acid (0.71 g, 3.23 mmol) in a manner analogous to Example 2c. Product was isolated as a foam (0.7 g, 82%). 1H NMR (400 MHz, CDCl3, δ, ppm): 7.80 (d, J=8.8 Hz, 1H), 7.75-7.70 (m, 2H), 7.68-7.62 (m, 1H), 7.16 (d, J=8.8 Hz, 1H), 7.09 (d, J=6.8 Hz, 1H), 3.87 (s, 3H). MS=328 (MH)+. 234b) 7-[5-(2-Methoxy-5-trifluoromethyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl-amino]-1,2,4,5-tetrahydro-3-benzazepine-3-carboxylic acid tert-butyl ester was prepared from 2-chloro-5-(2-Methoxy-5-trifluoromethyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridine (0.46 g, 1.4 mmol) and 7-amino-1,2,4,5-tetrahydro-3-benzazepine-3-carboxylic acid tert-butyl ester (0.557 g, 2.12 mmol) in a manner analogous to Example 2d. Product was isolated as a foam (0.33 g, 42%). 1H NMR (400 MHz, CDCl3, δ, ppm): 7.94 (brs, 1H), 7.80-7.77 (m, 1H), 7.55-7.49 (m, 2H), 7.20-7.15 (m, 1H), 7.05-7.00 (m, 1H), 7.00-6.96 (m, 1H), 6.90 (brs, 1H), 3.88 (s, 3H), 3.60-3.48 (m, 4H), 2.89-2.78 (m, 4H), 1.52 (s, 9H). MS=554 (MH)+. 234c) 7-[5-(2-Methoxy-5-trifluoromethyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl-amino]-1,2,4,5-tetrahydro-3-benzazepine-3-carboxylic acid tert-butyl ester (0.33 g, 6.00 mmol), was dissolved in dichloromethane (10 mL, 156 mmol) and trifluoroacetic acid was added (2 mL, 20.0 mmol). Reaction was stirred at room temperature for 2 hours. Solvent was removed and residue was partitioned between dichloromethane and 1N sodium carbonate. Washed with water and brine, dried over sodium sulfate and concentrated. [5-(2-Methoxy-5-trifluoromethyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl-amino]-1,2,4,5-tetrahydro-3-benzazepin-7-yl)-amine was isolated as a foam (0.27 g, 96%). 1H NMR (400 MHz, CDCl3, δ, ppm): 7.94 (brs, 1H), 7.81-7.76 (m, 1H), 7.54-7.50 (m, 2H), 7.25 (brs, 1H), 7.17 (d, J=7.9 Hz, 1H), 7.02 (d, J=7.9 Hz, 1H), 6.99-6.95 (m, 1H), 6.83 (brs, 1H), 3.86 (s, 3H), 3.01-2.92 (m, 4H), 2.90-2.83 (m, 4H). MS=454 (MH)+.
Reaction SMILES: [OH:1][C@H:2]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:12]=[C:13]([NH:17][C:18](=[O:22])[CH:19]([CH3:21])[CH3:20])[CH:14]=[CH:15][CH:16]=2)[CH2:7][CH2:6]1.[N+:29]([C:32]1[CH:33]=[C:34](O)[CH:35]=[CH:36][CH:37]=1)([O-:31])=[O:30].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.N>C1COCC1.C(Cl)(Cl)Cl>[CH3:20][CH:19]([CH3:21])[C:18]([NH:17][C:13]1[CH:14]=[CH:15][CH:16]=[C:11]([CH:8]2[CH2:9][CH2:10][N:5]([CH2:4][CH2:3][C@@H:2]([O:1][C:36]3[CH:35]=[CH:34][CH:33]=[C:32]([N+:29]([O-:31])=[O:30])[CH:37]=3)[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH2:6][CH2:7]2)[CH:12]=1)=[O:22]
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CC[C@H](O)c3ccccc3)CC2)c1
Reactant: O=[N+]([O-])c1cccc(O)c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: N
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Product: CC(C)C(=O)Nc1cccc(C2CCN(CC[C@@H](Oc3cccc([N+](=O)[O-])c3)c3ccccc3)CC2)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 40.7 %

Procedure:
A mixture of N-(3-{1-[(3S)-3-hydroxy-3-phenylpropyl]-4-piperidinyl}phenyl)-2-methylpropanamide (5.20 mg, 0.0137 mmol), 3-nitrophenol (100 mg), triphenylphosphine (30.0 mg, 0.115 mmol) and diethyl azodicarboxylate (7.42 mg, 0.0426 mmol) in THF (0.50 mL) was stirred at room temperature for 3 days. Chromatography using silica preparative TLC plates [2.5% of NH3 (2.0 M in methanol) in CHCl3] gave the desired product (2.80 mg, 40.8% yield) as a thick oil: 1H NMR (400 MHz, CDCl3) δ 7.76 (dm, 1H), 7.71 (t, 1H, J=1.8 Hz), 7.50–7.40 (m, 2H), 7.40–7.25 (m, 7H), 7.17 (apparent dd, 1H, J=2.4, 8.2), 6.97 (apparent d, 1H, J=7.7 Hz), 5.45 (apparent dd, 1H, J=5.0, 8.1 Hz), 3.45 (m, 2H), 2.89 (m, 2H), 2.53 (apparent sept, partially hidden, 2H, J=8.3 Hz), 2.30–2.10 (m, 6H), 1.92 (m, 2H), 1.25 (d, 6H, J=6.8 Hz); ESMS m/e: 502.3 (M+H)+.
Reaction SMILES: [CH:1](I)([CH3:3])[CH3:2].[NH2:5][CH:6]1[CH2:11][CH2:10][CH:9]([CH2:12][NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH2:8][CH2:7]1.C(N(C(C)C)CC)(C)C>C1COCC1>[CH:1]([NH:5][CH:6]1[CH2:11][CH2:10][CH:9]([CH2:12][NH:13][C:14](=[O:20])[O:15][C:16]([CH3:18])([CH3:17])[CH3:19])[CH2:8][CH2:7]1)([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NCC1CCC(N)CC1
Reactant: CC(C)I
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(C)NC1CCC(CNC(=O)OC(C)(C)C)CC1
Temperature: 40 °C
Reaction time: 24 h
Yield: 22 %

Procedure:
Isopropyl iodide (2 equivalents) was added dropwise to a suspension of tert-butyl N-[4-aminocyclohexyl]methylcarbamate (1 equivalent) and diisopropylethyl amine (3 equivalents) in THF. The resulting mixture was stirred for 1 day. TLC analysis showed some starting amine. Additional isopropyl iodide (1 equivalent) and diisopropylethyl amine (3 equivalents) were added to the reaction mixture and heated at 40° C. for 1 day. The reaction mixture was concentrated and chromatrographed to give tert-butyl N-[4-(isopropylamino)cyclohexyl]methylcarbamate: 22% yield, 271 (ESMS, MH+); 1H NMR (CDCl3) δ 4.65 (broad, 1H), 2.91 (m, 3H), 2.42 (m, lH), 1.80 (ABm, 4H), 1.38 (s, 9H), 0.98 (d, 6H, J=6.3 Hz), 1.32-0.85 (m, 5H).
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[N:11][NH:12][CH:13]=2)[O:3]1.C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:22][CH2:23][OH:24].CN(C=O)C>C(OCC)(=O)C>[CH3:1][C:2]1([CH3:14])[C:6]([CH3:7])([CH3:8])[O:5][B:4]([C:9]2[CH:13]=[N:12][N:11]([CH2:22][CH2:23][OH:24])[CH:10]=2)[O:3]1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Reactant: OCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC1(C)OB(c2cnn(CCO)c2)OC1(C)C
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 31.5 %

Procedure:
To a flask charged with 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1.000 g, 5.154 mmol), Cs2CO3 (2.687 g, 8.246 mmol), and 2-bromoethanol (0.5479 mL, 7.730 mmol) was added 10 mL of DMF and the flask was sealed under nitrogen and heated to 100° C. for 48 hours. The reaction was diluted with ethyl acetate (100 mL) and stirred for 30 minutes before it was passed through a glass microfiber filter and the cake was washed with ethyl acetate. The organic was concentrated under reduced pressure. The crude was then purified by silica gel chromatography eluting with a gradient of 75-100% ethyl acetate in Hexanes to afford 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)ethanol (0.4290 g, 1.622 mmol, 31.47% yield). MS (apci) m/z=239.2 (M+H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([CH:13]([CH3:15])[CH3:14])=[N:10][C:9]=2[C:16]2[CH:17]=[C:18]([NH:22][S:23]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[CH:27]=3)(=[O:25])=[O:24])[CH:19]=[CH:20][CH:21]=2)[CH:5]=[CH:4][N:3]=1.[CH3:33][NH2:34].C([O-])([O-])=O.[K+].[K+]>C(O)CCC>[F:32][C:28]1[CH:27]=[C:26]([S:23]([NH:22][C:18]2[CH:19]=[CH:20][CH:21]=[C:16]([C:9]3[N:10]=[C:11]([CH:13]([CH3:15])[CH3:14])[S:12][C:8]=3[C:6]3[CH:5]=[CH:4][N:3]=[C:2]([NH:34][CH3:33])[N:7]=3)[CH:17]=2)(=[O:25])=[O:24])[CH:31]=[CH:30][CH:29]=1
Reactant: CN
Reactant: CC(C)c1nc(-c2cccc(NS(=O)(=O)c3cccc(F)c3)c2)c(-c2ccnc(Cl)n2)s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCO
Product: CNc1nccc(-c2sc(C(C)C)nc2-c2cccc(NS(=O)(=O)c3cccc(F)c3)c2)n1

Procedure:
Following a procedure analogous to the procedure described in Example 1 using N-{3-[5-(2-chloro-4-pyrimidinyl)-2-(1-methylethyl)-1,3-thiazol-4-yl]phenyl}-3-fluorobenzenesulfonamide (100 mg, 0.20 mmol), methylamine (2.0 M in THF, 2.0 mL, 4.0 mmol) and K2CO3 (283 mg, 2.0 mmol) in 1-butanol (5 mL) the title compound was obtained as a white powder (100 mg, 0.21 mmol, 100% yield). 1H NMR (400 MHz, DMSO-d6): δ 10.51 (s, 1H), 8.02 (d, J=5.1 Hz, 1H), 7.57-7.65 (m, 2H), 7.48-7.53 (m, 2H), 7.33 (t, J=7.8 Hz, 1H), 7.19-7.22 (m, 4H), 6.04 (s, 1H), 3.23-3.30 (m, 1H), 2.76 (s, 3H), 1.36 (d, J=6.7 Hz, 6H); m/z (ESI): 485.3 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[C:5]#[C:6][C:7]1[CH:8]=[CH:9][C:10]2[O:14][CH2:13][CH2:12][C:11]=2[CH:15]=1)[CH3:2].[C:17]([O:21][C:22]([N:24]1[C:33]2[C:28](=[CH:29][CH:30]=[C:31]([CH2:34][CH2:35][O:36][C:37]3[CH:38]=[C:39]4[C:43](=[CH:44][CH:45]=3)[NH:42][CH:41]=[CH:40]4)[N:32]=2)[CH2:27][CH2:26][CH2:25]1)=[O:23])([CH3:20])([CH3:19])[CH3:18]>>[C:17]([O:21][C:22]([N:24]1[C:33]2[C:28](=[CH:29][CH:30]=[C:31]([CH2:34][CH2:35][O:36][C:37]3[CH:38]=[C:39]4[C:43](=[CH:44][CH:45]=3)[N:42]([C:6]([C:7]3[CH:8]=[CH:9][C:10]5[O:14][CH2:13][CH2:12][C:11]=5[CH:15]=3)=[CH:5][C:4]([O:3][CH2:1][CH3:2])=[O:16])[CH:41]=[CH:40]4)[N:32]=2)[CH2:27][CH2:26][CH2:25]1)=[O:23])([CH3:20])([CH3:18])[CH3:19]
Reactant: CC(C)(C)OC(=O)N1CCCc2ccc(CCOc3ccc4[nH]ccc4c3)nc21
Reactant: CCOC(=O)C#Cc1ccc2c(c1)CCO2
Product: CCOC(=O)C=C(c1ccc2c(c1)CCO2)n1ccc2cc(OCCc3ccc4c(n3)N(C(=O)OC(C)(C)C)CCC4)ccc21
Yield: 52 %

Procedure:
The title compound was synthesized from (2,3-dihydro-benzofuran-5-yl)-propynoic acid ethyl ester and 7-[2-(1H-indol-5-yloxy)-ethyl]-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylic acid tert-butyl ester using the procedure described in Example 16, step (c1), in 52% yield as an E/Z mixture. 1H NMR (CDCl3) δ 7.31 (d, 1H, J=7.6 Hz), 7.18-7.01 (m, 4H), 6.94 (dd, 1H, J=3.5, 7.6 Hz), 6.82-6.71 (m, 3H), 6.56-6.48 (m, 1H), 6.10 (s, 0.6H), 6.00 (s, 0.4H), 4.62 (q, 2H, J=8.8 Hz), 4.39-4.35 (m, 2H), 4.13 (q, 0.8H, J=7.1 Hz), 3.98 (q, 1.2H, J=7.1 Hz), 3.76 (t, 2H, J=5.9 Hz), 3.23-3.14 (m, 4H), 2.73 (t, 2H, J=6.64 Hz), 1.95-1.89 (m, 2H), 1.52 (s, 9H), 1.21 (t, 1.2H, J=7.1 Hz), 1.00 (t, 1.8 Hz, J=7.1 Hz).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:12][N:11]=[CH:10][C:9]=2[C:13]2[S:14][CH:15]=[C:16]([CH2:18][C:19]([NH:21][CH2:22][CH:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)=[O:20])[N:17]=2)=[CH:4][CH:3]=1.Br[CH2:30][CH:31]1[CH2:34][CH2:33][CH2:32]1.C(=O)([O-])[O-].[K+].[K+].O>C(#N)C>[CH:31]1([CH2:30][N:12]2[C:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)=[C:9]([C:13]3[S:14][CH:15]=[C:16]([CH2:18][C:19]([NH:21][CH2:22][CH:23]4[CH2:28][CH2:27][O:26][CH2:25][CH2:24]4)=[O:20])[N:17]=3)[CH:10]=[N:11]2)[CH2:34][CH2:33][CH2:32]1.[CH:31]1([CH2:30][N:11]2[CH:10]=[C:9]([C:13]3[S:14][CH:15]=[C:16]([CH2:18][C:19]([NH:21][CH2:22][CH:23]4[CH2:28][CH2:27][O:26][CH2:25][CH2:24]4)=[O:20])[N:17]=3)[C:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)=[N:12]2)[CH2:34][CH2:33][CH2:32]1
Reactant: O=C(Cc1csc(-c2cn[nH]c2-c2ccc(F)cc2)n1)NCC1CCOCC1
Reactant: BrCC1CCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: O=C(Cc1csc(-c2cn(CC3CCC3)nc2-c2ccc(F)cc2)n1)NCC1CCOCC1
Product: O=C(Cc1csc(-c2cnn(CC3CCC3)c2-c2ccc(F)cc2)n1)NCC1CCOCC1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
A solution of 2-{2-[5-(4-fluorophenyl)-1H-pyrazol-4-yl]-1,3-thiazol-4-yl}-N-(tetrahydro-2H-pyran-4-ylmethyl)acetamide (58 mg, 0.14 mmol), (bromomethyl)cyclobutane (0.033 mL, 0.29 mmol) and potassium carbonate (40.0 mg, 0.29 mmol) in acetonitrile (3 mL) was stirred at 80° C. for 1 hr. To the reaction mixture were further added potassium carbonate (40.0 mg, 0.29 mmol) and (bromomethyl)cyclobutane (0.033 mL, 0.29 mmol), and the mixture was further stirred at 80° C. for 2 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried, and the solvent was evaporated under reduced pressure. The obtained residue was purified by NH-silica gel column chromatography (solvent gradient; 30→90% ethyl acetate/hexane) to give a mixture (1:3 (mol/mol), 55 mg, 0.118 mmol, 84%) of the title compound and 2-(2-(1-(cyclobutylmethyl)-3-(4-fluorophenyl)-1H-pyrazol-4-yl)thiazol-4-yl)-N-((tetrahydro-2H-pyran-4-yl)methyl)acetamide as a pale-yellow solid.
Reaction SMILES: [F:1][C:2]([F:39])([F:38])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[C:25](B4OC(C)(C)C(C)(C)O4)=[CH:24][N:23]=[C:22]([S:35][CH3:36])[N:21]=3)[C@H:14]2[CH3:37])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.Br[C:41]1[CH:42]=[C:43]([C:49]2[C:58]([CH3:59])=[CH:57][C:52]([C:53]([O:55][CH3:56])=[O:54])=[CH:51][C:50]=2[CH3:60])[CH:44]=[N:45][C:46]=1[O:47][CH3:48].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O1CCOCC1>[F:1][C:2]([F:39])([F:38])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[C:25]([C:41]4[CH:42]=[C:43]([C:49]5[C:58]([CH3:59])=[CH:57][C:52]([C:53]([O:55][CH3:56])=[O:54])=[CH:51][C:50]=5[CH3:60])[CH:44]=[N:45][C:46]=4[O:47][CH3:48])=[CH:24][N:23]=[C:22]([S:35][CH3:36])[N:21]=3)[C@H:14]2[CH3:37])[CH:6]=[C:7]([C:9]([F:10])([F:12])[F:11])[CH:8]=1
Reactant: CSc1ncc(B2OC(C)(C)C(C)(C)O2)c(CN2C(=O)O[C@H](c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@@H]2C)n1
Reactant: COC(=O)c1cc(C)c(-c2cnc(OC)c(Br)c2)c(C)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: COC(=O)c1cc(C)c(-c2cnc(OC)c(-c3cnc(SC)nc3CN3C(=O)O[C@H](c4cc(C(F)(F)F)cc(C(F)(F)F)c4)[C@@H]3C)c2)c(C)c1

Procedure:
(4S,5R)-5-[3,5-Bis(trifluoromethyl)phenyl]-4-methyl-3-{[2-(methylthio)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-4-yl]methyl}-1,3-oxazolidin-2-one (INTERMEDIATE 21, 1.12 g, 1.940 mmol), methyl 4-(5-bromo-6-methoxypyridin-3-yl)-3,5-dimethylbenzoate (INTERMEDIATE 33, 0.815 g, 2.328 mmol) and Pd(Ph3P)4 (0.224 g, 0.194 mmol) were evacuated and charged with nitrogen. Added 1,4-dioxane (9.70 mL) and 2N tribasic potassium phosphate (2.91 mL, 5.82 mmol), then stirred at 170° C. for 10 minutes in a microwave reactor. LCMS showed significant product formation. The crude was purified directly by silica gel chromatography, eluting with a gradient of 5-40% ethyl acetate/hexanes over 10 column volumes to give the title compound. 1H NMR (CDCl3, 500 MHz): δ 8.36 (s, 1H), 8.07 (d, 1H), 7.89 (s, 1H), 7.81 (s, 2H), 7.74 (s, 2H), 7.33 (d, 1H), 5.73 (d, 1H), 4.81 (d, 1H), 4.44 (br, 1H), 4.08 (m, 1H), δ4.01 (s, 3H), 3.93 (s, 3H), 2.62 (s, 3H), 2.16 (s, 3H), 2.14 (s, 3H), 0.75 (d, 3H).
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([C:20]3[CH:25]=[CH:24][N:23]=[C:22](S(C)=O)[N:21]=3)[C:10]([C:11]3[CH:16]=[CH:15][N:14]=[C:13](S(C)=O)[N:12]=3)=[C:6]2[CH:5]=[CH:4][CH:3]=1.[CH2:29]([NH2:33])[CH:30]([CH3:32])[CH3:31]>>[N:7]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1.[CH2:29]([NH:33][C:2]1[N:7]2[N:8]=[C:9]([C:20]3[CH:25]=[CH:24][N:23]=[C:22]([NH:7][CH2:6][CH:10]([CH3:11])[CH3:9])[N:21]=3)[C:10]([C:11]3[CH:16]=[CH:15][N:14]=[C:13]([NH:33][CH2:29][CH:30]([CH3:32])[CH3:31])[N:12]=3)=[C:6]2[CH:5]=[CH:4][CH:3]=1)[CH:30]([CH3:32])[CH3:31]
Reactant: CC(C)CN
Reactant: CS(=O)c1nccc(-c2nn3c(Cl)cccc3c2-c2ccnc(S(C)=O)n2)n1
Product: CC(C)CNc1nccc(-c2nn3c(NCC(C)C)cccc3c2-c2ccnc(NCC(C)C)n2)n1
Product: c1ccncc1

Procedure:
N-Isobutyl-2,3-bis[2-(isobutylamino)pyrimidin-4-yl]pyrazolo[1,5-a]pyridin-7-amine pyridine was prepared by treating 7-chloro-2,3-bis[2-(methylsulfinyl)pyrimidin-4-yl]pyrazolo[1,5-a]pyridine with isobutylamine as described in Example 7. 1H NMR, (400 MHz, CDCl3): δ 8.35 (d, 1H), 8.09 (d, 1H), 7.59 (d, 1H), 7.30 (d, 1H), 6.94 (bs, 1H), 6.57 (m, 1H), 6.16 (t, 1H), 6.00 (d, 1H), 5.26 (bs, 1H), 5.17 (bs, 1H), 3.25 (t, 3H), 3.18 (t, 3H), 2.00–2.15 (m, 1H), 1.85–1.95 (m, 2H), 0.90–1.10 (m, 18H); MS m/z 488 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]([N:8]2[CH2:14][C:13]3[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=3[CH2:11][C:10]3[CH:19]=[CH:20][CH:21]=[CH:22][C:9]2=3)=[O:7])=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:32](Cl)(=[O:37])[CH2:33][CH:34]([CH3:36])[CH3:35]>C(Cl)Cl>[CH3:35][CH:34]([CH3:36])[CH2:33][C:32]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([N:8]2[CH2:14][C:13]3[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=3[CH2:11][C:10]3[CH:19]=[CH:20][CH:21]=[CH:22][C:9]2=3)=[O:7])=[CH:23][CH:24]=1)=[O:37]
Reactant: CC(C)CC(=O)Cl
Reactant: Nc1ccc(C(=O)N2Cc3ccccc3Cc3ccccc32)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)CC(=O)Nc1ccc(C(=O)N2Cc3ccccc3Cc3ccccc32)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 103.5 %

Procedure:
To a stirred solution of 0.16 g of 6,11-di-hydro-5-(4-aminobenzoyl)-5H-dibenz [b,e]azepine in 2 ml of methylene chloride is added 0.10 g of triethylamine followed by 0.09 g of iso-valeryl chloride. After stirring at room temperature for 2 hours, the reaction mixture is evaporated in vacuo to a residue. The residue is extracted with ethyl acetate-methylene chloride, washed with brine, dried (Na2SO4), filtered through hydrous magnesium silicate and evaporated in vacuo to a residue which is stirred with ether-hexanes to give 0.21 g of light yellow solid.
Reaction SMILES: [CH2:1]1[N:3]([CH2:4][CH:5]([OH:15])[CH2:6][N:7]2[C:11]([N+:12]([O-:14])=[O:13])=[N:10][CH:9]=[CH:8]2)[CH2:2]1.[ClH:16].C>CC(C)=O>[ClH:16].[N+:12]([C:11]1[N:7]([CH2:6][CH:5]([OH:15])[CH2:4][NH:3][CH2:2][CH2:1][Cl:16])[CH:8]=[CH:9][N:10]=1)([O-:14])=[O:13]
Reactant: O=[N+]([O-])c1nccn1CC(O)CN1CC1
Agent: Cl
Solvent: CC(C)=O
Product: O=[N+]([O-])c1nccn1CC(O)CNCCCl
Temperature: 2.5 °C
Yield: 66.3 %

Procedure:
A solution of 1-(2-nitro-1-imidazolyl)-3-(1-aziridino)-2-propanol(2.12 g, 10.0 mmol) in acetone (20 cm3) red as described in Example 1(a) was stirred at 0-5° C. using external ice-water cooling. Concentrated aqueous hydrochloric acid (38% w/w HCl, 2.0 cm3) was added in one portion. The mixture was treated with decolourising charcoal (0.3 g), filtered and chilled to give 1-(2-nitro-1-imidazolyl)-3-(2-chloroethylamino)-2-propanol hydrochloride (1.89 g, 66.3%) as a pale yellow microcrystalline solid, m.p. 152.5°-153.5° C. (dec.) after drying in vacuo.
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[CH:7]=[N:8][CH:9]=[CH:10][C:11]=1[C:12]1[CH:13]=[C:14]([CH:27]=[CH:28][CH:29]=1)[C:15]([NH:17][C:18]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)([CH3:20])[CH3:19])=[O:16])(=[O:4])=[O:3].C(=O)([O-])[O-].[K+].[K+].Br[CH2:37][CH2:38][O:39][Si:40]([C:43]([CH3:46])([CH3:45])[CH3:44])([CH3:42])[CH3:41]>CN(C=O)C>[Si:40]([O:39][CH2:38][CH2:37][N:5]([C:6]1[CH:7]=[N:8][CH:9]=[CH:10][C:11]=1[C:12]1[CH:13]=[C:14]([CH:27]=[CH:28][CH:29]=1)[C:15]([NH:17][C:18]([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)([CH3:20])[CH3:19])=[O:16])[S:2]([CH3:1])(=[O:3])=[O:4])([C:43]([CH3:46])([CH3:45])[CH3:44])([CH3:42])[CH3:41]
Reactant: CC(C)(NC(=O)c1cccc(-c2ccncc2NS(C)(=O)=O)c1)c1ccccc1
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(NC(=O)c1cccc(-c2ccncc2N(CCO[Si](C)(C)C(C)(C)C)S(C)(=O)=O)c1)c1ccccc1
Temperature: 80 °C
Reaction time: 4 h

Procedure:
To a mixture containing 3-(3-(methylsulfonamido)pyridin-4-yl)-N-(2-phenylpropan-2-yl)benzamide (0.20 g, 0.50 mmol), potassium carbonate (0.30 g, 2.0 mmol) and DMF (1.6 mL) was added (2-bromoethoxy)(tert-butyl)dimethylsilane (0.10 mL, 0.50 mmol) in a steady stream via syringe. The mixture was stirred at 80° C. for 4 h, cooled to room temperature, filtered, concentrated and purified on silica gel (0-10% methanol/dichloromethane, 60 min gradient) to afford 3-(3-(N-(2-(tert-butyldimethylsilyloxy)ethyl)methylsulfonamido)pyridin-4-yl)-N-(2-phenylpropan-2-yl)benzamide as a brown oil. 1H NMR (500 MHz, DMSO-D6) δ ppm 8.75 (s, 1H), 8.64 (d, J=4.88 Hz, 1H), 8.35 (s, 1H), 7.96 (s, 1H), 7.91 (d, J=7.94 Hz, 1H), 7.77 (d, J=7.93 Hz, 1H), 7.52-7.60 (m, 2H), 7.40 (d, J=7.32 Hz, 2H), 7.28 (t, J=7.63 Hz, 2H), 7.17 (t, J=7.32 Hz, 1H), 3.42-3.50 (m, 1H), 3.25 (s, 3H), 3.03 (s, 1H), 1.64-1.71 (m, 6H), 0.71-0.78 (m, 9H), −0.12-−0.06 (m, 6H). LCMS: retention time: 2.497 min. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Waters-Sunfire, 5 u, C18, 4.6×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 4 mL/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 10% CH3CN/90% H2O/10 mM TFA and solvent B was 10% H2O/90% CH3CN/10 mM TFA. MS data was determined using a Micromass Platform for LC in electrospray mode. m/z 568 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH2:9][C@@H:10]([CH3:13])[CH2:11]Cl.[CH3:14][CH:15]([CH3:31])[C:16]([NH:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[CH:20]=1)=[O:17]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH2:9][C@@H:10]([CH3:13])[CH2:11][N:28]1[CH2:29][CH2:30][CH:25]([C:21]2[CH:20]=[C:19]([NH:18][C:16](=[O:17])[CH:15]([CH3:14])[CH3:31])[CH:24]=[CH:23][CH:22]=2)[CH2:26][CH2:27]1
Reactant: C[C@@H](CCl)COc1ccccc1Cl
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Product: CC(C)C(=O)Nc1cccc(C2CCN(C[C@H](C)COc3ccccc3Cl)CC2)c1

Procedure:
Prepared by Procedure G and Scheme B1 using 1-chloro-2-{[(2R)-3-chloro-2-methylpropyl]oxy}benzene and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 429.1 (M+H)+.