Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH2:7][CH:6]([C:10](=[O:18])[C:11]2[CH:16]=[CH:15][C:14](F)=[CH:13][CH:12]=2)[CH2:5]1)(=[O:3])[CH3:2].[CH3:19][NH:20][CH3:21].C(=O)([O-])O.[Na+]>>[C:1]([N:4]1[CH2:9][CH2:8][CH2:7][CH:6]([C:10](=[O:18])[C:11]2[CH:16]=[CH:15][C:14]([N:20]([CH3:21])[CH3:19])=[CH:13][CH:12]=2)[CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCCC(C(=O)c2ccc(F)cc2)C1
Reactant: CNC
Agent: O=C([O-])O
Agent: [Na+]
Product: CC(=O)N1CCCC(C(=O)c2ccc(N(C)C)cc2)C1
Temperature: 25 °C
Reaction time: 120 h

Procedure:
A mixture consisting of 2.49 g of 1-acetyl-3-(4-fluorobenzoyl)piperidine and 8 ml of 50% aqueous dimethylamine solution was stirred for 5 days at room temperature, followed by addition of a saturated aqueous solution of sodium hydrogen carbonate. The solution was extracted with ethyl acetate and the extract was dried. The solvent was then distilled off and the remaining oil was purified by silica gel column chromatography (eluent: ethyl acetate) to give 2.6 g of 1-acetyl-3-(4-dimethylaminobenzoyl)piperidine as a pale yellow oil.
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:14][N:13]=[C:12]([C:15]3[CH:23]=[CH:22][CH:21]=[C:20]4[C:16]=3[CH2:17][CH2:18][N:19]4[CH2:24][C:25]3([NH:33]C(=O)OC(C)(C)C)[CH2:30][O:29]C(C)(C)[O:27][CH2:26]3)[N:11]=2)=[CH:6][CH:5]=1)[CH2:2][CH3:3].C(OC1C=C(C2ON=C(C3C=CC=C4C=3CCN4CC3(NC(=O)OCCCC)COC(C)(C)OC3)N=2)C=CC=1OCC)C>>[NH2:33][C:25]([CH2:24][N:19]1[C:20]2[C:16](=[C:15]([C:12]3[N:11]=[C:10]([C:7]4[CH:6]=[CH:5][C:4]([CH2:1][CH2:2][CH3:3])=[CH:9][CH:8]=4)[O:14][N:13]=3)[CH:23]=[CH:22][CH:21]=2)[CH2:17][CH2:18]1)([CH2:30][OH:29])[CH2:26][OH:27]
Reactant: CCCc1ccc(-c2nc(-c3cccc4c3CCN4CC3(NC(=O)OC(C)(C)C)COC(C)(C)OC3)no2)cc1
Agent: CCCCOC(=O)NC1(CN2CCc3c(-c4noc(-c5ccc(OCC)c(OCC)c5)n4)cccc32)COC(C)(C)OC1
Product: CCCc1ccc(-c2nc(-c3cccc4c3CCN4CC(N)(CO)CO)no2)cc1
Yield: 80 %

Procedure:
When the product of Step C was substituted for tea-butyl 5-((4-(5-(3,4-diethoxyphenyl)-1,2,4-oxadiazol-3-yl)indolin-1-yl)methyl)-2,2-dimethyl-1,3-dioxan-5-ylcarbamate in Example 34, Step E, the identical process afforded the title compound in 80% yield, as a creamy solid. 1H-NMR (DMSO-d6) 0.85-0.95 (m, 3H); 1.33 (broad s, 2H); 2.6-2.66 (m, 2H); 2.98 (s, 2H); 3.2-3.34 (m, 8H+H2O); 3.54 (tr, 2H, J=8.3 Hz); 4.56 (broad s, 2H); 6.77 (d, 1H, J=7.77 Hz); 7.1-7.26 (m, 2H); 7.38-7.49 (m, 2H); 7.9-8.1 (m, 2H).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[C:6]([CH:16]=1)[C:7]([NH:9][C:10]1[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=1)=[O:8].[CH3:25][N:26]1[CH:30]=[C:29](B2OC(C)(C)C(C)(C)O2)[CH:28]=[N:27]1.C(=O)([O-])[O-].[Na+].[Na+]>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.COCCOC>[CH3:25][N:26]1[CH:30]=[C:29]([C:4]2[C:5]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[C:6]([CH:16]=[CH:2][CH:3]=2)[C:7]([NH:9][C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)=[O:8])[CH:28]=[N:27]1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: O=C(Nc1cccnc1)c1cc(Br)ccc1OCc1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: Cn1cc(-c2cccc(C(=O)Nc3cccnc3)c2OCc2ccccc2)cn1
Temperature: 120 °C

Procedure:
To a microwave vial was added 5-bromo-2-[(phenylmethyl)oxy]-N-3-pyridinylbenzamide (may be prepared as described in example 2; 100 mg, 0.26 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (59.7 mg, 0.29 mmol), 1,2-dimethoxyethane (2 ml), 1M sodium carbonate (0.52 ml, 0.52 mmol) and tetrakis(triphenylphosphine)palladium(0) (18.09 mg, 0.02 mmol). The vial was sealed and heated to 120° C. for 25 min under microwave conditions. The mixture was evaporated under reduced pressure. Water (5 ml) was added to the residue and the mixture was extracted with ethyl acetate (3×10 ml). The organics were combined and evaporated and the residue was purified using MDAP to yield the title compound. 31 mg.
Reaction SMILES: [OH:1][CH2:2][C:3]([CH3:32])([CH3:31])[C:4]([N:6]1[CH2:11][CH:10]=[C:9]([C:12]2[NH:30][C:15]3[N:16]=[CH:17][N:18]=[C:19]([NH:20][C:21]4[CH:29]=[CH:28][C:24]5[N:25]=[CH:26][S:27][C:23]=5[CH:22]=4)[C:14]=3[CH:13]=2)[CH2:8][CH2:7]1)=[O:5].C(Cl)CCl.CCOC(C)=O>CS(C)=O>[CH3:31][C:3]([CH3:32])([CH:2]=[O:1])[C:4]([N:6]1[CH2:7][CH:8]=[C:9]([C:12]2[NH:30][C:15]3[N:16]=[CH:17][N:18]=[C:19]([NH:20][C:21]4[CH:29]=[CH:28][C:24]5[N:25]=[CH:26][S:27][C:23]=5[CH:22]=4)[C:14]=3[CH:13]=2)[CH2:10][CH2:11]1)=[O:5]
Reactant: CC(C)(CO)C(=O)N1CC=C(c2cc3c(Nc4ccc5ncsc5c4)ncnc3[nH]2)CC1
Solvent: CCOC(C)=O
Solvent: ClCCCl
Solvent: CS(C)=O
Product: CC(C)(C=O)C(=O)N1CC=C(c2cc3c(Nc4ccc5ncsc5c4)ncnc3[nH]2)CC1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of 6-[1-(3-hydroxy-2,2-dimethylpropanoyl)-1,2,3,6-tetrahydropyridin-4-yl]-N-1,3-benzothiazol-6-yl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (Example 110) (150 mg, 0.33 mmol) in DMSO (4 mL) was added EDC (190 mg, 1 mmol). The reaction mixture stirred at rt for 5 h. The mixture was taken up in a large amount of EtOAc and extracted with water. The combined organic extracts were dried over sodium sulfate and concentrated in vacuo, which afforded the title compound as a yellow solid. MS (ES+): m/z: 446.93 (100) [MH+]. HPLC: tr=2.53 min (ZQ2000: polar—5 min). 1H NMR (400 MHz, DMSO-d6): δ=1.37 (s, 6H) 3.39-3.69 (m, 3H), 3.70-4.22 (m, 3H), 6.21 (bs, 1H), 6.82 (s, 1H), 6.84 (d, J=1.6 Hz, 1H), 7.87 (dd, J=1.6, 8.8 Hz, 1H), 8.03 (d, J=8.8 Hz, 1H), 8.34 (s, 1H), 8.91 (d, J=2.0 Hz, 1H), 9.23 (s, 1H), 9.62 (s, 1H), 12.03 (s, 1H).
Reaction SMILES: Cl[C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[C:5]=2[N:6]=1.FC(F)(F)C(O)=O.[NH:19]1[CH2:23][CH2:22][CH:21]([CH2:24][O:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[NH:32][S:33]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][N:37]=2)(=[O:35])=[O:34])[CH2:20]1>>[CH3:11][C:7]1[C:5]2[N:6]=[C:2]([N:19]3[CH2:23][CH2:22][CH:21]([CH2:24][O:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=4[NH:32][S:33]([C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][N:37]=4)(=[O:34])=[O:35])[CH2:20]3)[S:3][C:4]=2[CH:10]=[CH:9][CH:8]=1
Reactant: Cc1cccc2sc(Cl)nc12
Reactant: O=S(=O)(Nc1ccccc1OCC1CCNC1)c1ccccn1
Solvent: O=C(O)C(F)(F)F
Product: Cc1cccc2sc(N3CCC(COc4ccccc4NS(=O)(=O)c4ccccn4)C3)nc12

Procedure:
Compound 31 is prepared using synthesis method 3 using intermediates 2b and 6b (yield: 28%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[C:4]([CH3:9])[N:3]=1.[NH:10]1[CH2:15][CH2:14][S:13](=[O:17])(=[O:16])[CH2:12][CH2:11]1.C(N(CC)CC)C.O>C(O)(C)C>[Cl:1][C:2]1[N:7]=[C:6]([N:10]2[CH2:15][CH2:14][S:13](=[O:17])(=[O:16])[CH2:12][CH2:11]2)[CH:5]=[C:4]([CH3:9])[N:3]=1
Reactant: Cc1cc(Cl)nc(Cl)n1
Reactant: O=S1(=O)CCNCC1
Solvent: O
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: Cc1cc(N2CCS(=O)(=O)CC2)nc(Cl)n1
Yield: 39.2 %

Procedure:
A mixture of 2,4-dichloro-6-methylpyrimidine (579 mg, 3.55 mmol), thiomorpholine-1,1-dioxide (480 mg, 3.55 mmol) and triethylamine (0.99 mL, 7.10 mmol) in 7 mL isopropanol was refluxed overnight. Water was added and the mixture of the regioisomers were extracted with ethyl acetate. Chromatography on on Si—NH2 gel (Isolute) using cyclo-hexane/ethyl acetate(gradient 30 to 60% ethyl acetate) gave the title compound as a colourless solid (364 mg, 39%). MS ISP (m/e): 201.2 (33) [(M+H)+]. 1H NMR (CDCl3, 300 MHz): δ (ppm)=6.39 (s, 1H), 4.20 (t broad, 4H), 3.08 (t broad, 4H), 2.41 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[NH2:31][C:32]1[C:33]([C:39]([NH:41][C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)=[O:40])=[N:34][C:35](Br)=[CH:36][N:37]=1.C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C.Cl[Pd]Cl>[NH2:31][C:32]1[C:33]([C:39]([NH:41][C:42]2[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=2)=[O:40])=[N:34][C:35]([C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)=[CH:36][N:37]=1
Reactant: Nc1ncc(Br)nc1C(=O)Nc1ccccc1
Reactant: COc1ccc(B(O)O)cc1
Agent: Cl[Pd]Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(-c2cnc(N)c(C(=O)Nc3ccccc3)n2)cc1
Temperature: 88 °C
Yield: 42 %

Procedure:
A Greenhouse tube was charged with 4-Methoxyphenylboronic acid (31.4 mg, 0.207 mmol) and treated with a solution of dichloropalladium; triphenylphosphane (4.84 mg, 0.0069 mmol) and 3-amino-6-bromo-N-phenyl-pyrazine-2-carboxamide (40.45 mg, 0.138 mmol) in DMF (0.81 mL) followed by Na2CO3 (2M solution, 207 uL, 0.414 mmol). The mixture was flushed with nitrogen and heated to 88° C. for 18 hours. After this time the reaction was filtered to remove inorganics and the resultant residue was purified by reverse phase preparative HPLC [Waters Sunfire C18, 10 uM, 100 A column, gradient 10%-95% B (solvent A: 0.05% TFA in water, solvent B: CH3CN) over 16 minutes at 25 mL/min]. The fractions were freeze-dried to give the title compound as a solid (18.56 mg, 38% Yield). MS (ES+) 321
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[CH2:10][CH2:9][CH:8]([N:11]([CH3:32])[C:12](=[O:31])[CH2:13][O:14][C:15]3[N:20]=[C:19]([CH3:21])[C:18]([NH:22]C(=O)OC(C)(C)C)=[C:17]([CH3:30])[N:16]=3)[CH2:7][CH2:6]2)[CH2:3][CH2:2]1.Cl.[OH-].[Na+]>C(Cl)(Cl)Cl>[NH2:22][C:18]1[C:19]([CH3:21])=[N:20][C:15]([O:14][CH2:13][C:12]([N:11]([CH:8]2[CH2:9][CH2:10][N:5]([CH2:4][CH:1]3[CH2:3][CH2:2]3)[CH2:6][CH2:7]2)[CH3:32])=[O:31])=[N:16][C:17]=1[CH3:30]
Reactant: Cc1nc(OCC(=O)N(C)C2CCN(CC3CC3)CC2)nc(C)c1NC(=O)OC(C)(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: Cc1nc(OCC(=O)N(C)C2CCN(CC3CC3)CC2)nc(C)c1N
Temperature: 25 °C
Reaction time: 1 h
Yield: 61.9 %

Procedure:
To a chloroform (1 mL) solution of Compound 49 (78 mg), 6N HCl (1 mL) was added and the mixture was stirred at room temperature for 1 hour. While the reaction mixture was cooled with ice, a 4N aqueous sodium hydroxide solution was added to neutralize the mixture. The resulting product was extracted with chloroform and the organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by amino-coated silica gel (Fuji Sylysia Chemical Ltd.; NH-DM1020) column chromatography (ethyl acetate) to give 37.5 mg (62% yield) of 2-(5-amino-4,6-dimethylpyrimidine-2-yloxy)-N-(1-(cyclopropylmethyl)piperidine-4-yl)-N-methylacetamide. Then, to a methanol solution of 2-(5-amino-4,6-dimethylpyrimidine-2-yloxy)-N-(1-(cyclopropylmethyl)piperidine-4-yl)-N-methylacetamide, 2 equivalents of 4N HCl/1,4-dioxane solution was added and the mixture was concentrated under reduced pressure. The desired product was afforded by recrystallization from methanol/ethyl acetate as white crystals.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[F:14][C:15]([F:26])([F:25])[C:16]1[CH:24]=[CH:23][CH:22]=[CH:21][C:17]=1[C:18](Cl)=[O:19]>ClCCl.C(N(CC)CC)C>[C:4]([O:3][C:1]([N:8]1[CH2:9][CH2:10][N:11]([C:18](=[O:19])[C:17]2[CH:21]=[CH:22][CH:23]=[CH:24][C:16]=2[C:15]([F:14])([F:25])[F:26])[CH2:12][CH2:13]1)=[O:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=C(Cl)c1ccccc1C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCN(C(=O)c2ccccc2C(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred solution of 1-Boc-piperazine (1.96 g, 10.5 mmol) in dichloromethane (50 mL) was added 2-trifluoromethylbenzoyl chloride (2.08 g, 10.0 mmol) dissolved in dichloromethane in the presence of triethylamine (3 mL) at 0° C. The resulting mixture was stirred at room temperature for 18 hours and then quenched with water (25 mL). The organic phase was washed with water, brine, then dried over MgSO4 and concentrated in vacuo to afford 4-(2-trifluoromethylbenzoyl)piperazine-1-carboxylic acid tert-butyl ester as a pale yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[C:5](=[C:10](I)[CH:11]=[CH:12][CH:13]=1)[C:6]([O:8][CH3:9])=[O:7].[CH3:16][O:17][C:18]1[CH:23]=[C:22]([O:24][CH2:25][CH2:26][N:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)[CH:21]=[CH:20][C:19]=1[NH2:33].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.C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1.C(Cl)Cl.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:1][O:2][C:3](=[O:15])[C:4]1[C:5](=[C:10]([NH:33][C:19]2[CH:20]=[CH:21][C:22]([O:24][CH2:25][CH2:26][N:27]3[CH2:28][CH2:29][O:30][CH2:31][CH2:32]3)=[CH:23][C:18]=2[O:17][CH3:16])[CH:11]=[CH:12][CH:13]=1)[C:6]([O:8][CH3:9])=[O:7]
Reactant: COc1cc(OCCN2CCOCC2)ccc1N
Reactant: COC(=O)c1cccc(I)c1C(=O)OC
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: COC(=O)c1cccc(Nc2ccc(OCCN3CCOCC3)cc2OC)c1C(=O)OC
Yield: 72 %

Procedure:
A mixture of 3-iodophthalic acid dimethyl ester (1.0 g, 3.1 mmol), 2-methoxy-4-(2-morpholin-4-ylethoxy)phenylamine (0.78 g, 3.1 mmol), Pd2(dba)3 (0.13 g, 0.14 mmol), rac-BINAP (0.058 g, 0.093 mmol), and cesium carbonate (1.4 g, 4.3 mmol), in 6 mL toluene was heated to reflux under nitrogen for 24 hours. The reaction mixture was cooled, diluted with CH2Cl2 (10 mL), and filtered through Celite, and the filter was washed with additional CH2Cl2 (30 mL). The filtrate was evaporated, and the residue was chromatographed using a methylene chloride-methanol gradient, eluting 1.0 g of the product at 95:5 methylene chloride-methanol, in 72% yield: 1H NMR (CDCl3) δ 2.59 (t, J=4.6 Hz, 4H), 2.81 (t, J=5.7 Hz, 2H), 3.75 (t, J=4.6 Hz, 4H), 3.81 (s, 3H), 3.87 (s, 3H), 3.88 (s, 3H), 4.11 (t, J=5.7 Hz, 2H), 6.45 (dd, J=8.6 Hz, J=2.6 Hz, 1H), 6.56 (d, J=2.6 Hz, 1H), 6.98 (dd, J=7.3 Hz, J=1.0 Hz, 1H), 7.08-7.17 (m, 2H), 7.22 (t, J=7.5 Hz, 1H), 7.93 (br, 1H).
Reaction SMILES: [CH2:1]([N:4]1[C:12](=[O:13])[C:11]2[NH:10][C:9]([C:14]3[CH:19]=[CH:18][C:17]([S:20](O)(=[O:22])=[O:21])=[CH:16][CH:15]=3)=[N:8][C:7]=2[N:6]([CH2:24][CH2:25][CH3:26])[C:5]1=[O:27])[CH2:2][CH3:3].S(Cl)(Cl)=O.[CH3:32][N:33]([CH2:35][CH2:36][NH2:37])[CH3:34]>CN(C)C=O>[CH3:32][N:33]([CH3:34])[CH2:35][CH2:36][NH:37][S:20]([C:17]1[CH:18]=[CH:19][C:14]([C:9]2[NH:10][C:11]3[C:12](=[O:13])[N:4]([CH2:1][CH2:2][CH3:3])[C:5](=[O:27])[N:6]([CH2:24][CH2:25][CH3:26])[C:7]=3[N:8]=2)=[CH:15][CH:16]=1)(=[O:21])=[O:22]
Reactant: CN(C)CCN
Reactant: CCCn1c(=O)c2[nH]c(-c3ccc(S(=O)(=O)O)cc3)nc2n(CCC)c1=O
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: CCCn1c(=O)c2[nH]c(-c3ccc(S(=O)(=O)NCCN(C)C)cc3)nc2n(CCC)c1=O
Temperature: 0 °C
Yield: 13 %

Procedure:
A mixture of 4-(1,3-dipropyl-2,3,6,7-tetrahydro-2,6-dioxo-1H-purin-8-yl)benzenesulfonic acid (3.93 g, 0.01 moles) and N,N-dimethylformamide (100 ml) is prepared, cooled to 0° C., treated with thionyl chloride (2.4 g, 0.02 moles), and permitted to warm to ambient temperature with vigorous stirring. The resulting slurry is cooled to 0° C., treated with a solution of unsym dimethylethylenediamine (8.8 g, 0.10 mole) in N,N-dimethylformamide (11 ml) added in one portion, and allowed to warm to ambient temperature. The resulting solution is concentrated on a rotary evaporator. The residue is suspended in water, filtered, recrystallized from ethanol, and dried at 78° to yield 0.60 grams of N-[2-(dimethylamino)ethyl]-4-(2,3,6,7-tetrahydro-2,6-dioxo-1,3-dipropyl-1H-purin-8-yl)benzenesulfonamide, mp, 270°-272° C.(d).
Reaction SMILES: C(O[C:5]1[CH:10]=[C:9]([C:11](=[O:13])[CH3:12])[C:8]([OH:14])=[C:7](C)[C:6]=1C)(=O)C.[C:17]1(=O)CCC1.N1CCCC1>C1(C)C=CC=CC=1>[CH:5]1[CH:6]=[CH:7][C:8]2[O:14][CH2:17][CH2:12][C:11](=[O:13])[C:9]=2[CH:10]=1
Reactant: CC(=O)Oc1cc(C(C)=O)c(O)c(C)c1C
Reactant: O=C1CCC1
Solvent: Cc1ccccc1
Solvent: C1CCNC1
Product: O=C1CCOc2ccccc21

Procedure:
2,3-Dimethyl-1,4-phenylene diacetate (5.5 g) was heated up with boron trifluoride-acetic acid complex (25 mL) at 120° C. for 5 hours. The mixture was poured into ice, and extracted with ethyl acetate. The organic layer was washed with sodium bicarbonate water solution to pH about 7. Evaporation gave 5.5 g of 5-acetyl-4-hydroxy-2,3-dimethylphenyl acetate as yellow solid. Refluxing 5-acetyl-4-hydroxy-2,3-dimethylphenyl acetate (5.5 g) with cyclobutanone (1.9 g, 27 mmol) and pyrrolidine (2.1 mL, 24.8 mmol) in toluene failed to give chromanone but gave 3.4 g of 1-(2,5-dihydroxy-3,4-dimethylphenyl)-ethanone as a solid.
Reaction SMILES: Br[C:2]1[CH:24]=[CH:23][C:5]2[C:6]3[N:7]([CH:11]=[C:12]([C:14]4[N:18]([CH:19]([CH3:21])[CH3:20])[N:17]=[C:16]([NH2:22])[N:15]=4)[N:13]=3)[CH2:8][CH2:9][O:10][C:4]=2[CH:3]=1.[Cl:25][C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1.C([O-])([O-])=O.[Cs+].[Cs+].O1CCOCC1>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O>[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([C:2]2[CH:24]=[CH:23][C:5]3[C:6]4[N:7]([CH:11]=[C:12]([C:14]5[N:18]([CH:19]([CH3:21])[CH3:20])[N:17]=[C:16]([NH2:22])[N:15]=5)[N:13]=4)[CH2:8][CH2:9][O:10][C:4]=3[CH:3]=2)=[CH:28][CH:27]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: CC(C)n1nc(N)nc1-c1cn2c(n1)-c1ccc(Br)cc1OCC2
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)n1nc(N)nc1-c1cn2c(n1)-c1ccc(-c3ccc(Cl)cc3)cc1OCC2
Temperature: 130 °C
Yield: 17.3 %

Procedure:
After 5-(9-bromo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-2-yl)-1-isopropyl-1H-1,2,4-triazol-3-amine (400 mg, 1.03 mmol), 4-chlorophenylboronic acid (321 mg, 2.06 mmol), Pd(dppf)Cl2 (84 mg, 0.1 mmol) and Cs2CO3 (403 mg, 1.23 mmol) were combined in a tube, dioxane and water (3:1, 20 ml) was added. The mixture was bubbled with N2 for 10 min. The mixture was sealed to heat in the microwave reactor at 130° C. for 30 min. The reaction mixture was filtered. The filtrate was concentrated and purified by HPLC to give 569 (74.9 mg, 17%) 1H NMR (DMSO, 400 MHz) δ 8.44 (d, J=8.4 Hz, 1H), 7.74 (d, J=9.2 Hz, 3H), 7.51-7.46 (m, 3H), 7.34 (s, 1H), 7.75-7.72 (m, 1H), 5.19 (s, 2H), 4.51 (s, 4H), 1.39 (d, J=6.8 Hz, 6H). LCMS(ESI) m/z 421.0 (M+H+)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[NH2:12][C:13]1([CH2:19][OH:20])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1.C(N(CC)CC)C>O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:12][C:13]2([CH2:19][OH:20])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: NC1(CO)CCCCC1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=S(=O)(NC1(CO)CCCCC1)c1ccc(Cl)cc1
Reaction time: 8 h
Yield: 73.2 %

Procedure:
4-Chlorobenzenesulfonyl chloride (6.92 g, 32.8 mmol) was added to a solution of (1-aminocyclohexyl)methanol (prepared according to Helv. Chirp. Acta, 87:90-105 (2004)) (3.53 g, 27.3 mmol) and triethylamine (4.6 mL, 32.8 mmol) in 100 mL tetrahydrofuran at room temperature. The reaction was stirred overnight and concentrated. The residue was taken up in a mixture of 100 mL ethyl acetate and 100 mL brine. The organic layer was separated, dried over sodium sulfate, and purified by flash chromatography on 120 g silica gel with 20 to 100% ethyl acetate in hexane to yield 4-chloro-N-(1-(hydroxymethyl)cyclohexyl)benzenesulfonamide (6.07 g, 73%). 1H NMR (400 MHz, CDCl3) δ ppm 7.85-7.86 (1H, m), 7.81-7.84 (1H, m), 7.47-7.49 (1H, m), 7.44-7.46 (1H, m), 4.61 (1H, s), 3.60 (2H, d, J=5.54 Hz), 2.25 (1H, t, J=5.92 Hz), 1.57-1.69 (2H, m), 1.22-1.45 (8H, m). LC/MS R.T.=2.39 min; [M+H]+=304.03; [M+Na]+=326.05; [M−H]−=301.98.
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]1[CH:4]=[C:5]([CH:24]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:26]=1)[CH2:6][N:7]([CH3:23])[C:8](=O)[C:9]1[CH:14]=[CH:13][N:12]=[CH:11][C:10]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH3:21].Cl.[OH-].[Na+].C(OCC)(=O)C>O1CCCC1.CCOCC>[F:29][C:27]([F:28])([F:30])[C:25]1[CH:24]=[C:5]([CH:4]=[C:3]([C:2]([F:32])([F:31])[F:1])[CH:26]=1)[CH2:6][N:7]([CH3:23])[CH2:8][C:9]1[CH:14]=[CH:13][N:12]=[CH:11][C:10]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH3:21]
Reactant: Cc1ccccc1-c1cnccc1C(=O)N(C)Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: Cc1ccccc1-c1cnccc1CN(C)Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 60 °C
Reaction time: 16 h
Yield: 258.2 %

Procedure:
To a solution of 0.12 g (0.265 mmol) N-(3,5-bis-trifluoromethyl-benzyl)-N-methyl-3-o-tolyl-isonicotinamide in 3 ml tetrahydrofuran 1.6 ml of a 1M solution of BH3 in tetrahydrofuran was added and the reaction mixture stirred for 16 h at 60° C. After addition of 2 ml 3M HCl in ether the reaction mixture was stirred for 3 h at 60° C. The solution was cooled to room temperature and 5 ml 3N sodium hydroxide solution and 10 ml ethyl acetate were added. Stirring was continued for ½ h, the phases separated and the aqueous phase extracted twice with 15 ml ethyl acatate. The combined organic layers were washed with brine, dried (magnesium sulfate) and evaporated. Chromatography of the residue afforded 0.30 g (25%) of the title compound as a pale yellow oil.
Reaction SMILES: S(Cl)([Cl:3])=O.[CH3:5][C@@H:6]1[CH2:10][CH2:9][C@@H:8]([CH3:11])[N:7]1[CH2:12][C:13]1[CH:18]=[C:17]([CH2:19]O)[CH:16]=[CH:15][C:14]=1[C:21]1[CH:26]=[C:25]([O:27][CH3:28])[CH:24]=[CH:23][C:22]=1[F:29]>C(Cl)Cl>[Cl:3][CH2:19][C:17]1[CH:16]=[CH:15][C:14]([C:21]2[CH:26]=[C:25]([O:27][CH3:28])[CH:24]=[CH:23][C:22]=2[F:29])=[C:13]([CH2:12][N:7]2[C@H:8]([CH3:11])[CH2:9][CH2:10][C@H:6]2[CH3:5])[CH:18]=1
Reactant: O=S(Cl)Cl
Reactant: COc1ccc(F)c(-c2ccc(CO)cc2CN2[C@H](C)CC[C@H]2C)c1
Solvent: ClCCl
Product: COc1ccc(F)c(-c2ccc(CCl)cc2CN2[C@H](C)CC[C@H]2C)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.1 %

Procedure:
Thionyl chloride (0.25 g, 2.1 mmol) was added to a solution of 66.71B (0.029 g, 0.084 mmol) in DCM (0.7 mL) and the mixture was stirred at room temperature for 1 hour. After removing solvent, 66.71C (28 mg) was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]([C:19]([OH:21])=O)=[C:11]([CH2:13][CH:14]([O:17][CH3:18])[O:15][CH3:16])[N:12]=2)=[CH:4][CH:3]=1.[C:22]([O:26][C:27]([N:29]1[CH2:32][CH:31]([O:33][C:34]2[CH:39]=[CH:38][C:37]([NH2:40])=[CH:36][C:35]=2[O:41][CH3:42])[CH2:30]1)=[O:28])([CH3:25])([CH3:24])[CH3:23].O.ON1C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C.Cl.CN(C)CCCN=C=NCC>C1COCC1.O>[C:22]([O:26][C:27]([N:29]1[CH2:30][CH:31]([O:33][C:34]2[CH:39]=[CH:38][C:37]([NH:40][C:19]([C:10]3[S:9][C:8]([C:5]4[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=4)=[N:12][C:11]=3[CH2:13][CH:14]([O:15][CH3:16])[O:17][CH3:18])=[O:21])=[CH:36][C:35]=2[O:41][CH3:42])[CH2:32]1)=[O:28])([CH3:25])([CH3:24])[CH3:23]
Reactant: COC(Cc1nc(-c2ccc(Cl)cc2)sc1C(=O)O)OC
Reactant: COc1cc(N)ccc1OC1CN(C(=O)OC(C)(C)C)C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(NC(=O)c2sc(-c3ccc(Cl)cc3)nc2CC(OC)OC)ccc1OC1CN(C(=O)OC(C)(C)C)C1
Temperature: 10 °C
Yield: 90.2 %

Procedure:
Dissolve 2-(4-chloro-phenyl)-4-(2,2-dimethoxy-ethyl)-thiazole-5-carboxylic acid (147 g, 448 mmol), 3-(4-amino-2-methoxy-phenoxy)-azetidine-1-carboxylic acid tert-butyl ester (120 g, 402 mmol), and 1-hydroxybenzotriazole hydrate (75 g, 490 mmol) in THF (1.2 L) and cool to about 10° C. under a nitrogen atmosphere Treat the above solution with diisopropylethylamine (117 mL, 673 mmol) dropwise over 2 min while keeping the temperature between 10-15° C. Add 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (93 g, 489 mmol) to the solution and stir at room temperature for 19 h. Cool the solution to 0° C. and dilute with water (1.2 L). Collect the precipitate by filtration and triturate with water (5×700 mL). Dry the tan solid for 3 days at 50° C. under vacuum to obtain 219 g (90%) of the title compound. 1H NMR (300 MHz, CDCl3) δ: 10.03 (s, 1H), 7.90 (m, 2H), 7.66 (d, 1H, J=2.4), 7.42 (m, 2H), 6.88 (dd, 1H, J=2.4, 8.6), 6.57 (d, 1H, J=8.6), 4.86 (m, 1H), 4.84 (t, 1H, J=5.7), 4.26 (dd, 2H, J=6.7, 10.6), 4.08 (dd, 2H, J=4.3, 10.6), 3.90 (s, 3H), 3.53 (s, 6H), 3.37 (d, 2H, J=5.5), 1.43 (s, 9H).