Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:9]([OH:11])=O)=[N:4][C:5]([CH3:8])=[N:6][CH:7]=1.[C:12]1([C:18]2[N:19]=[C:20]3[N:25]=[C:24]([NH2:26])[CH:23]=[CH:22][N:21]3[CH:27]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(C(C)C)CC)(C)C.CCCP(=O)=O>O1CCCC1.C(OCC)(=O)C>[Cl:1][C:2]1[C:3]([C:9]([NH:26][C:24]2[CH:23]=[CH:22][N:21]3[CH:27]=[C:18]([C:12]4[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=4)[N:19]=[C:20]3[N:25]=2)=[O:11])=[N:4][C:5]([CH3:8])=[N:6][CH:7]=1
Reactant: Nc1ccn2cc(-c3ccccc3)nc2n1
Reactant: Cc1ncc(Cl)c(C(=O)O)n1
Agent: CCCP(=O)=O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ncc(Cl)c(C(=O)Nc2ccn3cc(-c4ccccc4)nc3n2)n1
Temperature: 25 °C
Reaction time: 24 h
Yield: 30.3 %

Procedure:
A mixture of 5-chloro-2-methylpyrimidine-4-carboxylic acid (100 mg, 0.579 mmol), 2-phenylimidazo[1,2-a]pyrimidin-7-amine (146 mg, 0.695 mmol, 1.2 eq), diisopropylethylamine (304 ul, 1.74 mmol, 3 eq) and propylphosphonic anhydride in ethyl acetate 50% (854 ul, 1.45 mmol, 2.5 eq) in tetrahydrofuran (6 ml) is stirred for 1 day at 25° C. The mixture is diluted with ethyl acetate and washed 2 times with water, the organic layer is dried over magnesium sulfate and evapoarted. The crude material was purified by flash chromatography over a 20 g silicagel column using ethyl acetate 100% as eluent to afford 5-chloro-2-methyl-N-(2-phenylimidazo[1,2-a]pyrimidin-7-yl)pyrimidine-4-carboxamide (64 mg, 30.3%) as a yellow solid. MS: m/e=365.1 (M+H+), mp: >250° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[CH:10][C:11]([NH2:14])=[N:12][CH:13]=2)=[C:4]([F:15])[CH:3]=1.[F:16][C:17]1[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=1B(O)O>>[F:16][C:17]1[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=1[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[CH:10][C:11]([NH2:14])=[N:12][CH:13]=2)=[C:4]([F:15])[CH:3]=1
Reactant: OB(O)c1ccc(F)cc1F
Reactant: Nc1cnc(-c2ccc(Br)cc2F)cn1
Product: Nc1cnc(-c2ccc(-c3ccc(F)cc3F)cc2F)cn1

Procedure:
The title compound was prepared using conditions analogous to those used to make Example 6 utilizing 5-(4-bromo-2-fluorophenyl)pyrazin-2-amine and (2,4-difluorophenyl)boronic acid. MS (ESI): mass calcd. for C16H10F3N3, 301.08; m/z found, 302.0 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.43-8.35 (m, 1H), 8.03 (d, J=1.4, 1H), 7.97 (m, 1H), 7.73-7.65 (m, 1H), 7.54-7.35 (m, 3H), 7.26-7.20 (m, 1H), 6.74 (s, 2H).
Reaction SMILES: [Cl:1][C:2]1[N:11]=[CH:10][C:9]2[N:8]([CH:12]3[CH2:17][CH2:16][S:15][CH2:14][CH2:13]3)[C:7](=[O:18])[CH:6]3[CH2:19][O:20][CH2:21][CH2:22][N:5]3[C:4]=2[N:3]=1.IC.[CH3:25]C([O-])(C)C.[Na+]>CS(C)=O>[Cl:1][C:2]1[N:11]=[CH:10][C:9]2[N:8]([CH:12]3[CH2:13][CH2:14][S:15][CH2:16][CH2:17]3)[C:7](=[O:18])[C:6]3([CH3:25])[CH2:19][O:20][CH2:21][CH2:22][N:5]3[C:4]=2[N:3]=1
Reactant: CC(C)(C)[O-]
Reactant: O=C1C2COCCN2c2nc(Cl)ncc2N1C1CCSCC1
Agent: [Na+]
Solvent: CI
Solvent: CS(C)=O
Product: CC12COCCN1c1nc(Cl)ncc1N(C1CCSCC1)C2=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 10.6 %

Procedure:
To a mixture of 2-chloro-5-(tetrahydro-2H-thiopyran-4-yl)-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-6(5H)-one (83.6 mg, 0.245 mmol) and iodomethane (0.077 ml, 1.226 mmol) in DMSO (3 ml) at 0° C. was added sodium 2-methylpropan-2-olate (47.1 mg, 0.491 mmol). The ice-bath was removed and the reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was poured into water and extracted with EtOAc. The organic layers were washed with water (containing Na2S2O3), dried and concentrated in vacuo to give a crude oil. The crude residue was purified by silica gel chromatography (hexane/ethyl acetate, 19:1 to 1:1) to afford 2-chloro-6a-methyl-5-(tetrahydro-2H-thiopyran-4-yl)-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-6(5H)-one (9.4 mg, 0.026 mmol, 11% yield) as a colorless oil. MS [M+H] found 355.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:11]1[C:26]([CH3:27])=[CH:25][C:14]2[N:15]=[C:16]([C:18]3[CH:23]=[CH:22][N:21]=[C:20](Cl)[N:19]=3)[S:17][C:13]=2[C:12]=1[C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=1)[C:7]([O:9][CH3:10])=[O:8])([CH3:4])([CH3:3])[CH3:2].[O:35]1[CH2:38][CH:37]([N:39]2[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]2)[CH2:36]1>O1CCOCC1>[C:1]([O:5][C@@H:6]([C:11]1[C:26]([CH3:27])=[CH:25][C:14]2[N:15]=[C:16]([C:18]3[CH:23]=[CH:22][N:21]=[C:20]([N:42]4[CH2:43][CH2:44][N:39]([CH:37]5[CH2:38][O:35][CH2:36]5)[CH2:40][CH2:41]4)[N:19]=3)[S:17][C:13]=2[C:12]=1[C:28]1[CH:29]=[CH:30][C:31]([Cl:34])=[CH:32][CH:33]=1)[C:7]([O:9][CH3:10])=[O:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: C1CN(C2COC2)CCN1
Reactant: COC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccnc(Cl)n3)sc2c1-c1ccc(Cl)cc1
Solvent: C1COCCO1
Product: COC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccnc(N4CCN(C5COC5)CC4)n3)sc2c1-c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To (S)-methyl 2-tert-butoxy-2-(7-(4-chlorophenyl)-2-(2-chloropyrimidin-4-yl)-5-methylbenzo[d]thiazol-6-yl)acetate (49.0 mg, 0.095 mmol) was added 1-(oxetan-3-yl)piperazine (27.0 mg, 0.190 mmol) in 1,4-dioxane (1 mL). The reaction mixture was stirred at room temperature for 6 h. Upon completion of the reaction, the reaction mixture was filtered through Celite (ethyl acetate eluent), concentrated, and used without further purification. LCMS-ESI+ calc'd for C32H37ClN5O4S (M+H+): 622.2; Found: 622.2 (M+H+).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][CH:15]=1)[O:5][CH2:6][CH:7]1[CH2:12][CH2:11][O:10][CH2:9][CH2:8]1.[CH2:16]([NH:19][C:20](=[O:25])[C:21]([F:24])([F:23])[F:22])[CH:17]=[CH2:18].CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.CCN(CC)CC>CC([O-])=O.CC([O-])=O.[Pd+2].CN(C=O)C>[F:22][C:21]([F:24])([F:23])[C:20]([NH:19][CH2:16]/[CH:17]=[CH:18]/[C:2]1[CH:15]=[CH:14][CH:13]=[C:4]([O:5][CH2:6][CH:7]2[CH2:12][CH2:11][O:10][CH2:9][CH2:8]2)[CH:3]=1)=[O:25]
Reactant: C=CCNC(=O)C(F)(F)F
Reactant: Brc1cccc(OCC2CCOCC2)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(NC/C=C/c1cccc(OCC2CCOCC2)c1)C(F)(F)F

Procedure:
A mixture of 4-((3-bromophenoxy)methyl)tetrahydro-2H-pyran (1.86 g, 6.86 mmol), N-allyl-2,2,2-trifluoroacetamide (1.14 g, 7.45 mmol), P(o-Tol)3 (0.31 g, 1.02 mmol), Pd(OAc)2 (0.12 g, 0.534 mmol), Et3N (2.0 mL, 14.35 mmol) and anhydrous DMF (10 mL) was degassed by bubbling Ar for at least 5 mins, then applying vacuum/Ar once. The reaction mixture was heated under Ar at +90° C. for 20 hrs then concentrated under reduced pressure. Aqueous NH4Cl was added to the residue and extracted twice with EtOAc. Combined organic layers were washed with brine, treated with activated charcoal and dried over anhydrous MgSO4 and concentrated under reduced pressure. Purification by flash chromatography (20%-50% EtOAc-hexanes gradient) gave (E)-2,2,2-trifluoro-N-(3-(3-((tetrahydro-2H-pyran-4-yl)methoxy)phenyl)allyl)acetamide as a light yellow oil. Yield (2.01 g, 85%); 1H NMR (400 MHz, DMSO-d6) δ 9.70 (m, 1H), 7.21 (t, J=7.63 Hz, 1H), 6.94-7.00 (m, 2H), 6.78-6.83 (m, 1H), 6.48 (d, J=15.85 Hz, 1H), 6.25 (dt, J=15.85, 5.87 Hz, 1H), 3.90-4.00 (m, 2H), 3.75-3.90 (m, 4H), 3.31 (t, J=11.74 Hz, 2H), 1.90-2.04 (m, 1H), 1.60-1.70 (m, 2H), 1.24-1.37 (m, 2H).
Reaction SMILES: Br[CH2:2][C:3]1[N:8]=[C:7]2[N:9]([CH3:12])[N:10]=[CH:11][C:6]2=[C:5]([C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=2)[CH:4]=1.[CH3:22][S:23]([O-:25])=[O:24].[Na+]>CCO.CN(C=O)C>[CH3:22][S:23]([CH2:2][C:3]1[N:8]=[C:7]2[N:9]([CH3:12])[N:10]=[CH:11][C:6]2=[C:5]([C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=2)[CH:4]=1)(=[O:25])=[O:24]
Reactant: CS(=O)[O-]
Reactant: Cn1ncc2c(-c3ccc([N+](=O)[O-])cc3)cc(CBr)nc21
Agent: [Na+]
Solvent: CCO
Solvent: CN(C)C=O
Product: Cn1ncc2c(-c3ccc([N+](=O)[O-])cc3)cc(CS(C)(=O)=O)nc21
Temperature: 25 °C
Yield: 100.1 %

Procedure:
1.04 g 6-bromomethyl-1-methyl-4-(4-nitro-phenyl)-1H-pyrazolo[3,4-b]pyridine (Intermediate 13.1; 3 mmol, 1 eq.) were dissolved in 55 mL 10:1 EtOH/DMF, treated with 459 mg sodium methanesulfinate (4.5 mmol, 1.5 eq.) and refluxed for 150 min. The mixture was cooled to rt and concentrated in vacuo. Addition of water was followed by precipitation to yield 1040 mg of the crude product (quantitative yield).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[NH:15][N:14]=[C:13]([CH:16]3[CH2:18][CH2:17]3)[CH:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.[C:19]([O:22][CH2:23][C:24]1[C:25]([N:39]2[CH2:51][CH2:50][N:42]3[C:43]4[CH2:44][CH2:45][CH2:46][CH2:47][C:48]=4[CH:49]=[C:41]3[C:40]2=[O:52])=[N:26][CH:27]=[CH:28][C:29]=1B1OC(C)(C)C(C)(C)O1)(=[O:21])[CH3:20].[O-]P([O-])([O-])=O.[K+].[K+].[K+].CC([O-])=O.[Na+]>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.CC#N>[C:19]([O:22][CH2:23][C:24]1[C:25]([N:39]2[CH2:51][CH2:50][N:42]3[C:43]4[CH2:44][CH2:45][CH2:46][CH2:47][C:48]=4[CH:49]=[C:41]3[C:40]2=[O:52])=[N:26][CH:27]=[CH:28][C:29]=1[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:12]=[C:13]([CH:16]3[CH2:18][CH2:17]3)[NH:14][N:15]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1)(=[O:21])[CH3:20]
Reactant: CC(=O)OCc1c(B2OC(C)(C)C(C)(C)O2)ccnc1N1CCn2c(cc3c2CCCC3)C1=O
Reactant: Cn1cc(Br)cc(Nc2cc(C3CC3)n[nH]2)c1=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: CC#N
Solvent: O
Product: CC(=O)OCc1c(-c2cc(Nc3cc(C4CC4)[nH]n3)c(=O)n(C)c2)ccnc1N1CCn2c(cc3c2CCCC3)C1=O
Temperature: 110 °C
Yield: 70.5 %

Procedure:
A sealed tube equipped with a magnetic stirrer was charged with 118b (310 mg, 1 mmol), 3-(acetoxymethyl)-2-(1-oxo-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-2(1H)-yl)pyridine-4-ylboronic acid 113i (385 mg, 1 mmol), Pd(dppf)Cl2 (80 mg, 0.1 mmol), K3PO4 (424 mg, 2 mmol), NaOAc (165 mg, 2 mmol), CH3CN (15 mL), and water (1 mL). After three cycles of vacuum/argon flush, the mixture was heated at 110° C. for 3 h. It was evaporated in vacuo. The residue was purified by silica gel column chromatography eluting with dichloromethane/methanol (50:1, V/V) to afford 118c (400 mg, 68%) as a yellow solid. LCMS: [M+H]+ 569
Reaction SMILES: [C:1]1([C:7]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[N:8]2[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[C:19]3[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=3)=[N:11][N:10]=[N:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1C(=O)N([Br:45])C(=O)C1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)Cl>[Br:45][CH2:25][C:22]1[CH:23]=[CH:24][C:19]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[C:12]2[N:8]([C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)[C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[N:9]=[N:10][N:11]=2)=[CH:20][CH:21]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClCCl
Product: BrCc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Temperature: 25 °C

Procedure:
To a nitrogen-saturated suspension of N-triphenylmethyl-5-[4′-methylbiphenyl-2-yl]tetrazole (10 g, 20.9 mmol) in DCM was added NBS (3.7 g, 20.9 mmol) and a catalytic amount of benzoyl peroxide (60 mg, 240 μmol). The mixture was stirred at reflux for 15 hours. After cooling to room temperature, the precipitate was filtered and the organic solution was concentrated in vacuo. Silica gel chromatography (EtOAc/hexane) gave the title compound as a white solid.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH2:12][C:13]([NH:15][C@:16]([C:31]1[CH:36]=[CH:35][C:34]([O:37][CH2:38][CH2:39][CH2:40][C:41]([F:44])([F:43])[F:42])=[CH:33][CH:32]=1)([CH2:21][C:22](=O)[C:23]1[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=1)[C:17]([F:20])([F:19])[F:18])=[O:14].[OH-].[Na+].Cl>CO>[O:14]=[C:13]1[C:12]([N:3]2[C:4](=[O:11])[C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[C:2]2=[O:1])=[C:22]([C:23]2[CH:24]=[CH:25][C:26]([CH3:29])=[CH:27][CH:28]=2)[CH2:21][C@:16]([C:31]2[CH:32]=[CH:33][C:34]([O:37][CH2:38][CH2:39][CH2:40][C:41]([F:43])([F:42])[F:44])=[CH:35][CH:36]=2)([C:17]([F:18])([F:19])[F:20])[NH:15]1
Reactant: Cc1ccc(C(=O)C[C@](NC(=O)CN2C(=O)c3ccccc3C2=O)(c2ccc(OCCCC(F)(F)F)cc2)C(F)(F)F)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1ccc(C2=C(N3C(=O)c4ccccc4C3=O)C(=O)N[C@@](c3ccc(OCCCC(F)(F)F)cc3)(C(F)(F)F)C2)cc1
Temperature: 69 °C
Reaction time: 0.75 h
Yield: 56.7 %

Procedure:
Intermediate 104A (145 mg, 0.234 mmol) was dissolved in MeOH (2.2 mL) and then 1 N NaOH (0.2 mL) was added. The mixture was stirred at 69° C. for 45 min and added another 0.2 mL of 1 N NaOH. The reaction was heated at 130° C. under microwave conditions for 10 min. The mixture was neutralized with 1 N HCl and then concentrated. The residue was purified by silica gel chromatography (12 g silica gel, eluted with EtOAc in hexanes) to yield the desired product (80 mg, 57%). LCMS Anal. Calc'd for C31H24F6N2O4 602.16, found [M+H] 603.3.
Reaction SMILES: [NH2:1][C:2]1[NH:7][C:6](=O)[CH:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:3]=1.P(Cl)(Cl)([Cl:17])=O>[OH-].[NH4+]>[Cl:17][C:6]1[CH:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:3]=[C:2]([NH2:1])[N:7]=1
Reactant: Nc1nc(-c2ccccc2)cc(=O)[nH]1
Reactant: O=P(Cl)(Cl)Cl
Agent: [NH4+]
Agent: [OH-]
Product: Nc1nc(Cl)cc(-c2ccccc2)n1
Temperature: 70 °C
Yield: 86.1 %

Procedure:
A stirred suspension of 3.69 g (19.7 mmol) 2-amino-6-phenyl-3H-pyrimidin-4-one in 4.5 ml (49.2 mmol) phosphorus oxychloride was heated at reflux for 2 h. The reaction mixture was then cooled to about 70° C. and poured cautiously onto 20 ml rapidly stirred ice-water. The mixture was briefly warmed to room temperature and then was recooled to 0° C. 100 ml 25% ammonium hydroxide solution was added and the resulting crystals were collected by filtration and washed with ice-cold water and then with a little ether to afford 3.49 g (86%) 4-chloro-6-phenyl-pyrimidin-2-ylamine as a pale yellow crystalline solid. EI-MS m/e (%): 207 (M{37Cl}+, 35), 206 ([M{37Cl}—H]+, 30)., 205 (M{35Cl}+, 100), 204 ([M{35Cl}—H]+, 56), 170 ([M—Cl]+, 35), 128 (([M—C6H5]+, 85).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[N:18][CH:17]=[C:16]([Cl:20])[N:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[F:21][C:22]([F:27])([F:26])[C:23]([OH:25])=[O:24]>ClCCl>[F:21][C:22]([F:27])([F:26])[C:23]([OH:25])=[O:24].[Cl:20][C:16]1[N:15]=[C:14]([N:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)[CH:19]=[N:18][CH:17]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2cncc(Cl)n2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Clc1cncc(N2CCNCC2)n1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
A solution of 2 mmol 6′-Chloro-2,3,5,6-tetrahydro-[1,2′]bipyrazinyl-4-carboxylic acid tert-butyl ester in 10 ml of dichloromethane was treated with 3 mmol of trifluoroacetic acid and stirred at room temperature for 17 hours. Concentration and crystallisation from diethylether yielded the title compound as a colorless solid. MS (m/e): 198.0 (M+, 100%)
Reaction SMILES: [Br:1][C:2]1[C:3]([OH:13])=[C:4]([C:9]([CH3:12])=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].S(OC)(O[CH3:18])(=O)=O.C(=O)([O-])[O-].[K+].[K+]>C1(S(CC2C(C(OC)=O)=C3C(C4C=COC=4CO3)=CC=2)(=O)=O)C=CC=CC=1>[Br:1][C:2]1[C:3]([O:13][CH3:18])=[C:4]([C:9]([CH3:12])=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1c(C)ccc(Br)c1O
Reactant: COS(=O)(=O)OC
Agent: COC(=O)c1c(CS(=O)(=O)c2ccccc2)ccc2c1OCc1occc1-2
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COC(=O)c1c(C)ccc(Br)c1OC

Procedure:
A mixture of methyl 3-bromo-2-hydroxy-6-methylbenzoate (Intermediate 44, 114.5 g), dimethyl sulfate (61 mL) and potassium carbonate (166 g) in acetone (11) was heated at reflux for 2.5 hours. After cooling, the mixture was filtered and the filtrate was evaporated to dryness. The residue was dissolved in DCM and washed with water, dried (MgSO4) and filtered. The filtrate was evaporated to dryness and the residue was purified by chromatography on silica, eluting with a mixture of tert-butyl methyl ether and pentane with a gradient of 0-40%. The product was purified again by chromatography on silica, eluting with a mixture of tert-butyl methyl ether and pentane with a gradient of 0-10%. The product was again purified by chromatography on silica, eluting with a mixture of tert-butyl methyl ether and pentane with a gradient of 0-10% to give methyl 3-bromo-2-methoxy-6-methylbenzoate (66 g).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([NH:7][C:8]([C:10]2[C:15]([NH2:16])=[N:14][CH:13]=[C:12](Br)[N:11]=2)=[O:9])=[CH:3][CH:2]=1.CC1(C)C(C)(C)OB([C:26]2[S:30][C:29]([CH2:31][N:32]3[CH2:36][CH2:35][CH2:34][CH2:33]3)=[CH:28][CH:27]=2)O1>>[N:1]1[CH:6]=[CH:5][C:4]([NH:7][C:8]([C:10]2[C:15]([NH2:16])=[N:14][CH:13]=[C:12]([C:26]3[S:30][C:29]([CH2:31][N:32]4[CH2:36][CH2:35][CH2:34][CH2:33]4)=[CH:28][CH:27]=3)[N:11]=2)=[O:9])=[CH:3][CH:2]=1
Reactant: Nc1ncc(Br)nc1C(=O)Nc1ccncc1
Reactant: CC1(C)OB(c2ccc(CN3CCCC3)s2)OC1(C)C
Product: Nc1ncc(-c2ccc(CN3CCCC3)s2)nc1C(=O)Nc1ccncc1

Procedure:
The reaction of 3-amino-6-bromo-pyrazine-2-carboxylic acid pyridin-4-ylamide (synthesis described for “A10”) with 1-[5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-thiophen-2-ylmethyl]-pyrrolidine gives the compound “A14”;
Reaction SMILES: Cl[C:2]1[N:25]=[C:5]2[C:6]([C:10]3[CH:15]=[C:14]([S:16]([CH3:19])(=[O:18])=[O:17])[CH:13]=[CH:12][C:11]=3[O:20][CH2:21][CH:22]([F:24])[F:23])=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1.[C:26]([O:30][C:31]([N:33]1[CH2:39][CH2:38][C:37]2[CH:40]=[CH:41][C:42]([NH2:44])=[CH:43][C:36]=2[CH2:35][CH2:34]1)=[O:32])([CH3:29])([CH3:28])[CH3:27]>>[C:26]([O:30][C:31]([N:33]1[CH2:39][CH2:38][C:37]2[CH:40]=[CH:41][C:42]([NH:44][C:2]3[N:25]=[C:5]4[C:6]([C:10]5[CH:15]=[C:14]([S:16]([CH3:19])(=[O:18])=[O:17])[CH:13]=[CH:12][C:11]=5[O:20][CH2:21][CH:22]([F:24])[F:23])=[CH:7][CH:8]=[CH:9][N:4]4[N:3]=3)=[CH:43][C:36]=2[CH2:35][CH2:34]1)=[O:32])([CH3:29])([CH3:27])[CH3:28]
Reactant: CS(=O)(=O)c1ccc(OCC(F)F)c(-c2cccn3nc(Cl)nc23)c1
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(N)cc2CC1
Product: CC(C)(C)OC(=O)N1CCc2ccc(Nc3nc4c(-c5cc(S(C)(=O)=O)ccc5OCC(F)F)cccn4n3)cc2CC1

Procedure:
7-{8-[2-(2,2-Difluoro-ethoxy)-5-methanesulfonyl-phenyl]-[1,2,4]triazolo[1,5-a]pyridin-2-ylamino}-1,2,4,5-tetrahydro-3-benzazepine-3-carboxylic acid tert-butyl ester was prepared from 2-chloro-8-[2-(2,2-difluoro-ethoxy)-5-methanesulfonyl-phenyl]-[1,2,4]-triazolo[1,5-a]pyridine (0.282 g, 727 mmol) and 7-amino-1,2,4,5-tetrahydro-3-benzazepine-3-carboxylic acid tert-butyl ester (0.286 g, 1.09 mmol) in a manner analogous to Example 311a and 311b to give product (0.340 g, 76%): 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 9.54 (s, 1H), 8.80 (d, 1H), 8.22 (s, 1H), 8.00 (d, 1H), 7.69 (d, 1H), 7.48 (m, 2H), 7.38 (s, 1H), 7.10 (t, 1H), 7.00 (d, 1H), 6.28 (br m, 1H), 4.54 (m, 2H), 3.44 (m, 4H), 3.23 (s, 3H), 2.76 (m, 4H), 1.41 (s, 9H). MS=614 (MH)+.
Reaction SMILES: [CH2:1]=[C:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.C(O)(=O)C1C(=CC=CC=1)C(O)=[O:19].C(=O)(O)[O-].[Na+]>CO>[O:19]1[C:2]2([CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]2)[CH2:1]1
Reactant: O=C(O)c1ccccc1C(=O)O
Reactant: C=C1CCN(C(=O)OC(C)(C)C)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC2(CC1)CO2
Temperature: 25 °C
Reaction time: 24 h
Yield: 83.6 %

Procedure:
13.5 g of tert-butyl 4-methylene-1-piperidinecarboxylate was dissolved in 300 ml methanol, and 28.3 g phthalic acid monoperacid magnesium salt and 8.62 g sodium bicarbonate were added thereto, and the mixture was stirred at room temperature for 1 day. The reaction solution was filtered through Celite, and the resulting filtrate was evaporated. Ethyl acetate was added to the resulting residue which was then washed with water and brine, dried over anhydrous magnesium sulfate, and then filtered. The filtrate was evaporated, and subjected to silica gel column chromatography to give 12.2 g of tert-butyl 1-oxa-6-azaspiro[2.5]octane-6-carboxylate.
Reaction SMILES: CCN(C(C)C)C(C)C.CCCCCC.C([Li])CCC.[Br:21][C:22]1[CH:23]=[C:24]([F:30])[C:25]([O:28][CH3:29])=[N:26][CH:27]=1.[CH:31]1([CH:36]=[O:37])[CH2:35][CH2:34][CH2:33][CH2:32]1.[Cl-].[NH4+]>C1COCC1>[Br:21][C:22]1[C:23]([CH:36]([CH:31]2[CH2:35][CH2:34][CH2:33][CH2:32]2)[OH:37])=[C:24]([F:30])[C:25]([O:28][CH3:29])=[N:26][CH:27]=1
Reactant: COc1ncc(Br)cc1F
Reactant: O=CC1CCCC1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COc1ncc(Br)c(C(O)C2CCCC2)c1F
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 29.1 %

Procedure:
To a solution of DIEA (0.827 mL) in THF (90 mL) was added 1.6 M n-butyllithium hexane solution (3.64 mL) at −78° C., and the mixture was stirred under argon atmosphere at −78° C. for 30 min. To the reaction mixture was added a solution of 5-bromo-3-fluoro-2-methoxypyridine (1.00 g) in THF (30 mL) at −78° C., and the mixture was stirred under argon atmosphere at −78° C. for 1 hr. To the reaction mixture was added cyclopentanecarbaldehyde (0.572 g) at −78° C., and the mixture was stirred under argon atmosphere at −78° C. for 1 hr. To the reaction mixture was added saturated aqueous ammonium chloride solution at −78° C., and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (430 mg).
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([NH:11][CH2:12][CH2:13][CH2:14][OH:15])[C:5]([CH3:16])=[C:4]([CH3:17])[N:3]=1.[N-:18]=[N+:19]=[N-:20].[Na+].O.O.O.O.O.O.O.[Cl-].[Ce+3].[Cl-].[Cl-].C(#N)C>CN(C=O)C.O>[CH3:17][C:4]1[N:3]2[N:18]=[N:19][N:20]=[C:2]2[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([NH:11][CH2:12][CH2:13][CH2:14][OH:15])[C:5]=1[CH3:16]
Reactant: Cc1nc(Cl)c([N+](=O)[O-])c(NCCCO)c1C
Reactant: [N-]=[N+]=[N-]
Agent: [Ce+3]
Agent: [Cl-]
Agent: [Na+]
Solvent: CC#N
Solvent: CN(C)C=O
Solvent: O
Product: Cc1c(NCCCO)c([N+](=O)[O-])c2nnnn2c1C
Temperature: 25 °C
Yield: 75.4 %

Procedure:
A mixture of 3-[(2-chloro-5,6-dimethyl-3-nitropyridin-4-yl)amino]propan-1-ol (12.4 g, 47.8 mmol), sodium azide (6.20 g, 95.5 mmol), and cerium (III) chloride heptahydrate (8.90 g, 23.9 mmol) in 9:1 acetonitrile:water (160 mL) was heated at reflux for 16 hours, then was allowed to cool to room temperature. DMF was added and the mixture was filtered. The filter cake was washed with DMF. The filtrate was concentrated under reduced pressure to give an orange solid that was triturated with ethyl acetate and isolated by filtration to yield 9.60 g of 3-[(5,6-dimethyl-8-nitrotetraazolo[1,5-α]pyridin-7-yl)amino]propan-1-ol as a yellow solid.
Reaction SMILES: [CH2:1]([C:5]1[N:14]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[C:28]3[N:32]([C:33]([C:46]4[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=4)([C:40]4[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=4)[C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)[N:31]=[N:30][N:29]=3)=[CH:18][CH:17]=2)[C:13](=[O:52])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([CH:53]=[O:54])[CH:11]=2)[N:6]=1)[CH2:2][CH2:3][CH3:4].[CH2:55]([Mg]Br)[CH3:56]>O1CCCC1>[CH2:1]([C:5]1[N:14]([CH2:15][C:16]2[CH:17]=[CH:18][C:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[C:28]3[N:32]([C:33]([C:40]4[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=4)([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)[C:46]4[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=4)[N:31]=[N:30][N:29]=3)=[CH:20][CH:21]=2)[C:13](=[O:52])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([CH:53]([OH:54])[CH2:55][CH3:56])[CH:11]=2)[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CC[Mg]Br
Reactant: CCCCc1nc2ccc(C=O)cc2c(=O)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCCCc1nc2ccc(C(O)CC)cc2c(=O)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a suspension of 1.00 g of 2-Butyl-3,4-dihydro-4-oxo-3-[[2'-[1-(triphenylmethyl)-1H-tetrazol-5yl][1,1'-biphenyl]-4-yl]methyl]-6-quinazolinecarboxaldehyde in 10 ml of tetrahydrofuran, cooled to -78° C. and 2.833 ml of a 1.0M solution of ethylmagnesium bromide rapidly added. The cooling bath is removed and the reaction mixture allowed to warm until a complete solution. The cooling bath is again applied and the reaction mixture cooled to -78° C. and stirred for 0.5 hours. The bath is removed and the reaction mixture allowed to reach room temperature. An aqueous solution of ammonium chloride is added and the reaction mixture extracted with ethyl acetate. The organic layer is dried and concentrated in vacuo to give 0.821 g of the desired product as a solid. FAB mass spec 737 (M+H).