Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:19](Cl)=[N:18][CH:17]=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:21]([O:24][C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1)([CH3:23])[CH3:22].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)CC.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:19]([C:28]3[CH:29]=[CH:30][C:25]([O:24][CH:21]([CH3:23])[CH3:22])=[CH:26][CH:27]=3)=[N:18][CH:17]=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCN(c2nccnc2Cl)CC1
Reactant: CC(C)Oc1ccc(B(O)O)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CCCO
Product: CC(C)Oc1ccc(-c2nccnc2N2CCN(C(=O)OC(C)(C)C)CC2)cc1
Temperature: 25 °C
Yield: 79.9 %

Procedure:
Couple 3′-chloro-2,3,5,6-tetrahydro-[1,2′]bipyrazinyl-4-carboxylic acid t-butyl ester (0.135 g, 0.452 mmol) and 4-isopropoxyphenylboronic acid (0.134 g, 0.743 mmol), in the presence of triphenylphosphine (0.0482 g, 0.184 mmol), palladium acetate (0.0118 g, 0.0526 mmol), aqueous 2 N sodium carbonate (0.3 mL) in a mixture of n-propanol (4 mL) and water (0.3 mL). Reflux for 17.5 hr.s, cool to room temperature and extract with DCM. Purify by silica gel chromatography, eluting with 0:100 to 1:1 ethyl acetate:hexanes, to give 3′-(4-isopropoxyphenyl)-2,3,5,6-tetrahydro-[1,2′]bipyrazinyl-4-carboxylic acid t-butyl ester (0.144 g, 80%).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:15]=[C:14]([CH3:16])[O:13][N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[N:7]=1.[C:17]([O:20][CH2:21][C:22]1[C:23]([N:37]2[N:46]=[CH:45][C:44]3[C:39](=[C:40]([F:51])[CH:41]=[C:42]([C:47]([CH3:50])([CH3:49])[CH3:48])[CH:43]=3)[C:38]2=[O:52])=[N:24][CH:25]=[CH:26][C:27]=1B1OC(C)(C)C(C)(C)O1)(=[O:19])[CH3:18].C([O-])(=O)C.[K+].[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O.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].C(#N)C>[C:17]([O:20][CH2:21][C:22]1[C:23]([N:37]2[N:46]=[CH:45][C:44]3[C:39](=[C:40]([F:51])[CH:41]=[C:42]([C:47]([CH3:49])([CH3:48])[CH3:50])[CH:43]=3)[C:38]2=[O:52])=[N:24][CH:25]=[CH:26][C:27]=1[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:15]=[C:14]([CH3:16])[O:13][N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[N:7]=1)(=[O:19])[CH3:18]
Reactant: Cc1cc(Nc2cc(Cl)nn(C)c2=O)no1
Reactant: CC(=O)OCc1c(B2OC(C)(C)C(C)(C)O2)ccnc1-n1ncc2cc(C(C)(C)C)cc(F)c2c1=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: O
Solvent: CC#N
Product: CC(=O)OCc1c(-c2cc(Nc3cc(C)on3)c(=O)n(C)n2)ccnc1-n1ncc2cc(C(C)(C)C)cc(F)c2c1=O
Temperature: 95 °C
Yield: 32 %

Procedure:
A 100-mL single-neck round-bottomed flask equipped with a magnetic stirrer and a reflux condenser was charged with 141a (288 mg, 1.2 mmol), 3-(acetoxymethyl)-2-(6-tert-butyl-8-fluoro-1-oxo-phthalazin-2(1H)-yl)pyridin-4-ylboronic acid 116c (1.49 g, 3.6 mmol), Pd(dppf)Cl2 (99 mg, 0.12 mmol), potassium acetate (235 mg, 2.4 mmol), K3PO4 (523 mg, 2.4 mmol), acetonitrile (20 mL), and water (10 drops). After three cycles of vacuum/argon flush, the mixture was heated at 95° C. for 2 h. It was then filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica-gel column chromatography eluting with 1:1 ethyl acetate/petroleum ether to afford 141b (220 mg, 32%) as a yellow solid. MS-ESI: [M+H]+ 574.2
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([C:10]([F:13])([F:12])[F:11])[C:3]=1[C:14]#[C:15][Si](C)(C)C.[NH2:20][C@@H:21]([C:24]1[CH:25]=[N:26][CH:27]=[C:28]([CH:31]=1)[C:29]#[N:30])[CH2:22][CH3:23].C([O-])([O-])=O.[K+].[K+].C([O-])(O)=O.[Na+]>CN1C(=O)CCC1>[C:29]([C:28]1[CH:31]=[C:24]([C@H:21]([N:20]2[C:2]3[C:3](=[C:4]([C:10]([F:13])([F:12])[F:11])[C:5]([C:6]#[N:7])=[CH:8][CH:9]=3)[CH:14]=[CH:15]2)[CH2:22][CH3:23])[CH:25]=[N:26][CH:27]=1)#[N:30]
Reactant: C[Si](C)(C)C#Cc1c(F)ccc(C#N)c1C(F)(F)F
Reactant: CC[C@@H](N)c1cncc(C#N)c1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: CC[C@H](c1cncc(C#N)c1)n1ccc2c(C(F)(F)F)c(C#N)ccc21
Temperature: 60 °C
Yield: 35.8 %

Procedure:
An oven-dried vial was charged with 4-fluoro-2-(trifluoromethyl)-3-((trimethylsilyl)ethynyl)benzonitrile (Example 21D), (0.171 g, 0.598 mmol), commercially available (R)-5-(1-aminopropyl)nicotinonitrile (0.106 g, 0.658 mmol) and K2CO3 (0.091 g, 0.658 mmol) and sealed with a rubber septum. Anhydrous NMP (3 mL) was added via syringe and the mixture was stirred in a heating block at 60° C. under N2. After 22 h the mixture was cooled, poured into satd NaHCO3 and extracted with EtOAc (×3). Combined organics were washed (water, brine), dried over Na2SO4 and concentrated in vacuo. The residue was purified by low pressure liquid chromatography (silica gel, EtOAc/hexanes, gradient elution) affording (R)-1-(1-(5-cyanopyridin-3-yl)propyl)-4-(trifluoromethyl)-1H-indole-5-carbonitrile (0.0758 g, 36% yield) as a tan gum: 1H NMR (400 MHz, CDCl3) δ 8.82 (s, 1H), 8.69 (br. s., 1H), 7.64 (br. s., 1H), 7.60-7.43 (m, 3H), 7.00 (br. s., 1H), 5.49 (t, J=7.5 Hz, 1H), 2.42 (sxt, J=7.1 Hz, 2H), 1.04 (t, J=7.1 Hz, 3H); MS (LCMS ES+) m/z 355 ([M+H]+, 62%), 396 ({[M+H]+MeCN}+, 100%).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:8]([S:11]([CH:14]([CH3:16])[CH3:15])(=[O:13])=[O:12])=[CH:7][C:3]=1[C:4](O)=[O:5].C[N:18](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>CN(C=O)C>[Br:1][C:2]1[CH:10]=[CH:9][C:8]([S:11]([CH:14]([CH3:16])[CH3:15])(=[O:13])=[O:12])=[CH:7][C:3]=1[C:4]([NH2:18])=[O:5]
Reactant: CC(C)S(=O)(=O)c1ccc(Br)c(C(=O)O)c1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)S(=O)(=O)c1ccc(Br)c(C(N)=O)c1
Reaction time: 1 h
Yield: 58.2 %

Procedure:
2-Bromo-5-(isopropylsulfonyl)benzoic acid (Preparation 23, 623 mg, 2.03 mmol) and HATU (925 mg, 2.44 mmol) were dissolved in DMF (10 mL) and diisopropylethylamine (1.74 mL, 10.0 mmol) was added dropwise to the mixture. The mixture was stirred for 1 hour and then partitioned between water (50 mL) and EtOAc (25 mL). The aqueous layer was extracted with EtOAc (2×10 mL) and the combined organic extracts were washed with saturated brine (20 mL) and dried (MgSO4). The solvent was removed under reduced pressure to leave a pale yellow solid. This material was purified by silica gel column chromatography eluting with MeOH/CH2Cl2 3:97 to give the title compound as a white solid 59% yield, 362 mg.
Reaction SMILES: [CH2:1]1[O:3][CH:2]1[CH2:4][OH:5].P([O-])([O-])(OCCCCCCCCCCCC)=O.[P:23]([O-:44])([O:38][CH2:39][CH:40]([CH2:42][OH:43])[OH:41])([O:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])=[O:24]>>[P:23]([O:44][CH2:1][CH:2]([CH2:4][OH:5])[OH:3])([O:38][CH2:39][CH:40]([CH2:42][OH:43])[OH:41])([O:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])=[O:24]
Reactant: OCC1CO1
Reactant: CCCCCCCCCCCCOP(=O)([O-])OCC(O)CO
Agent: CCCCCCCCCCCCOP(=O)([O-])[O-]
Product: CCCCCCCCCCCCOP(=O)(OCC(O)CO)OCC(O)CO

Procedure:
While keeping the reaction system at 60° C., 36.9 g of glycidol (oxirane value=683.7) was gradually dadded, followed by their reaction at 70° C. for 10 hours. The acid value of the reaction system was AV1=39.6, AV2=57.3, revealing that the reaction system contained about 27 mole % of unreacted monododecyl phosphate and about 33 mole % of the corresponding phosphoric diester, i.e., dodecyl glyceryl phosphate and about 40 mole % of the corresponding phosphoric triester, i.e., dodecyl diglyceryl phosphate were formed.
Reaction SMILES: [NH2:1][C:2]1[C:7]2[N:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[O:10][C:6]=2[CH:5]=[CH:4][CH:3]=1.[C:15]1(=O)[O:20][C:18](=[O:19])[CH:17]=[CH:16]1>C(O)(=O)C>[F:12][C:11]([F:14])([F:13])[C:9]1[O:10][C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([N:1]3[C:18](=[O:19])[CH:17]=[CH:16][C:15]3=[O:20])[C:7]=2[N:8]=1
Reactant: O=C1C=CC(=O)O1
Reactant: Nc1cccc2oc(C(F)(F)F)nc12
Solvent: CC(=O)O
Product: O=C1C=CC(=O)N1c1cccc2oc(C(F)(F)F)nc12
Yield: 57.2 %

Procedure:
Compound 476B (0.500 g, 2.48 mmol) was dissolved in acetic acid (10 mL) and maleic anhydride (0.267 g, 2.72 mmol) was added. The mixture was heated at reflux for 3 h, cooled and the solvent removed in vacuo to give a tan solid. The crude product was purified by flash chromatography on silica gel eluting with 2% MeOH/CH2Cl2 to give compound 476C (0.40 g, 57%) as an off-white solid. HPLC: 89.7% at 2.38 min (retention time) (YMC S5 ODS column, 4.6×50 mm, eluting with 10-90% aqueous methanol over 4 min containing 0.2% phosphoric acid, 4 mL/min, monitoring at 220 nm). MS (ES): m/z 283.21 [M+H]+.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][C:8]1([CH3:18])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[NH:10][C:9]1=O.S([O-])([O-])(=O)=O.[Na+].[Na+]>C1COCC1>[CH3:7][C:8]1([CH3:18])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[NH:10][CH2:9]1
Reactant: CC1(C)C(=O)Nc2ccccc21
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: CC1(C)CNc2ccccc21
Temperature: 60 °C

Procedure:
Under a nitrogen atmosphere a solution of 6.20 mL (6.20 mmol) of a 1M solution lithium aluminium hydride in THF and 10 mL THF was slowly added dropwise to 1.00 g (6.20 mmol) 3,3-dimethyl-1,3-dihydro-indol-2-one in 50 mL THF. Then the reaction mixture was heated to 60° C. for 1 h. After cooling to 0° C., 3 mL ice water were slowly added dropwise. 20 g sodium sulphate were added and the mixture was suction filtered. The solution was evaporated down i. vac.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([C:11]([OH:13])=O)[CH:2]=1.Cl.[CH3:15][NH:16][O:17][CH3:18].C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1>ClCCl>[CH3:18][O:17][N:16]([CH3:15])[C:11]([C:3]1[CH:2]=[N:1][C:10]2[C:5]([CH:4]=1)=[CH:6][CH:7]=[CH:8][CH:9]=2)=[O:13]
Reactant: O=C(O)c1cnc2ccccc2c1
Reactant: CNOC
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CON(C)C(=O)c1cnc2ccccc2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of the quinoline-3-carboxylic acid (480 mg, 2.77 mmol) and N,O-dimethyhydroxylamine hydrochloride (405 mg, 4.15 mmol), in dichloromethane (10 mL) was added triethyl amine (1.93 mL, 13.8 mmol) followed by bromo(trispyrrolidin-1yl)phosphonium hexafluorophosphate (1.55 g, 3.32 mmol). After stirring the reaction mixture at room temperature for 1 hour, it was quenched by the addition of water (10 mL). The resulting mixture was extracted with DCM. The organic layer dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography using 75% ethyl acetate-hexanes. 1H NMR (500 MHz, CDCl3): 8.25 (d, J=1.8 Hz, 1H), 8.67 (d, J=1.3 Hz, 1H), 8.18 (d, J=8.5 Hz, 1H), 7.96 (d, J=8.2 Hz, 1H), 7.84 (t, J=8.0 Hz, 1H), 7.65 (t, J=8.5 Hz, 1H), 3.61 (s, 3H), 3.48 (s, 3H). LC-MS: 1.24 min; (M+H)=217.1.
Reaction SMILES: [C:1](Cl)(=[O:5])[CH2:2][CH2:3][CH3:4].Cl.[NH2:8][C:9]1[CH:10]=[N:11][C:12]2[C:17]([C:18]=1[OH:19])=[CH:16][CH:15]=[C:14]([O:20][CH3:21])[CH:13]=2.C(N(CC)CC)C.ClCCl>CN(C)C=O>[OH:19][C:18]1[C:17]2[C:12](=[CH:13][C:14]([O:20][CH3:21])=[CH:15][CH:16]=2)[N:11]=[CH:10][C:9]=1[NH:8][C:1](=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: CCCC(=O)Cl
Reactant: COc1ccc2c(O)c(N)cnc2c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCCC(=O)Nc1cnc2cc(OC)ccc2c1O
Temperature: 25 °C
Yield: 62.8 %

Procedure:
Butyryl chloride (0.63 mL, 6.1 mmol) was added dropwise to a solution containing 3-amino-7-methoxyquinolin-4-ol hydrochloride (1.0 g, 5.26 mmol), triethylamine (2.35 mL, 16.8 mmol), dichloromethane (30 mL) and N,N-dimethylformamide (10 mL). The reaction mixture was maintained at ambient temperature overnight. The N,N-dimethylformamide was removed under vacuum and the resulting solid was partitioned between dichloromethane (100 mL) and water (100 mL). The organic fraction was washed with water, dried over magnesium sulfate, filtered and then concentrated under vacuum to provide 0.86 g of N-(4-hydroxy-7-methoxyquinolin-3-yl)butanamide as a tan solid.
Reaction SMILES: [C:1]([N:5]=[C:6]=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:8][C@@H:9]1[CH2:13][CH2:12][C@@H:11]([C:14]([N:16]2[CH2:23][CH2:22][C@:21]3([CH3:27])[C:24]([CH3:26])([CH3:25])[C@H:17]2[CH2:18][C:19]2[C:31]([OH:32])=[CH:30][CH:29]=[CH:28][C:20]=23)=[O:15])[CH2:10]1.C(N(C(C)C)C(C)C)C>CN(C)C=O>[C:1]([NH:5][C:6]([NH:8][C@@H:9]1[CH2:13][CH2:12][C@@H:11]([C:14]([N:16]2[CH2:23][CH2:22][C@:21]3([CH3:27])[C:24]([CH3:25])([CH3:26])[C@H:17]2[CH2:18][C:19]2[C:31]([OH:32])=[CH:30][CH:29]=[CH:28][C:20]=23)=[O:15])[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)N=C=O
Reactant: CC1(C)[C@H]2Cc3c(O)cccc3[C@]1(C)CCN2C(=O)[C@@H]1CC[C@@H](N)C1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)NC(=O)N[C@@H]1CC[C@@H](C(=O)N2CC[C@@]3(C)c4cccc(O)c4C[C@@H]2C3(C)C)C1
Temperature: 40 °C
Reaction time: 8 h

Procedure:
tert-Butylisocyanate (30 mg) is added to a solution of [(1R,3R)-3-amino-cyclopentyl]-[(2R,6S)-10-hydroxy-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocin-3-yl]-methanone (100 mg) and ethyldiisopropylamine (120 μL) in N,N-dimethylformamide (2 mL). The resulting solution is stirred at 40° C. overnight. Then, the solution is concentrated under reduced pressure and the residue is purified by HPLC on reversed phase (MeCN/H2O/F3CCO2H) to give the title compound.
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:14])=[C:4]2[C:8](=[CH:9][C:10]=1[CH3:11])[C:7](=O)[CH:6]([CH3:13])[CH2:5]2.[H-].[H-].[H-].[H-].[Li+].[Al+3].Cl>C1COCC1>[CH3:13][C:6]1[CH2:5][C:4]2[C:8]([CH:7]=1)=[CH:9][C:10]([CH3:11])=[C:2]([OH:1])[C:3]=2[CH3:14]
Reactant: Cc1cc2c(c(C)c1O)CC(C)C2=O
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: CC1=Cc2cc(C)c(O)c(C)c2C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Suspension of 5-hydroxy-2,4,6-trimethylindan-1-one (4.74 g, 24.9 mmol) in THF (30 ml) was added at 0° C. to suspension of LiAlH4 (0.94 g, 24.9 mmol) in THF (50 ml). The mixture was allowed to warm to room temperature, stirred for 2 h. 5% HCl (20 ml) was added, resulting mixture was extracted by CH2Cl2 (4×50 ml), combined organic fraction was washed by water, dried over MgSO4, passed through silica gel, and evaporated. Residue was washed by cold pentane and dried in vacuo. The yield 3.75 g (86%).
Reaction SMILES: P(Br)(Br)[Br:2].[CH3:5][O:6][C:7]1[CH:8]=[C:9]([CH:13]([CH3:17])[CH2:14][CH2:15]O)[CH:10]=[CH:11][CH:12]=1>CCOCC>[Br:2][CH2:15][CH2:14][CH:13]([C:9]1[CH:10]=[CH:11][CH:12]=[C:7]([O:6][CH3:5])[CH:8]=1)[CH3:17]
Reactant: COc1cccc(C(C)CCO)c1
Reactant: BrP(Br)Br
Solvent: CCOCC
Product: COc1cccc(C(C)CCBr)c1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
A solution of phosphorous tribromide (5.7 ml., 0.06 mole) in ether (30 ml.) is added to a solution of 3-(3-methoxyphenyl)-1-butanol (25.8 g., 0.143 mole) in ether (20 ml.) at -5° C. to -10° C. and the reaction mixture stirred at -5° C. to -10° C. for 2.5 hours. It is then warmed to room temperature and stirred for an additional 30 minutes. The mixture is poured over ice (200 g.) and the resulting mixture extracted with ether (3×50 ml.). The combined extracts are washed with 5% sodium hydroxide solution (3×50 ml.), saturated sodium chloride solution (1×50 ml.) and dried (Na2SO4). Removal of the ether and vacuum distillation of the residue affords the title product.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:12][CH:11]([C:13]([OH:15])=[O:14])[CH2:10]2)=[CH:5][CH:4]=1)=[O:2].[C:16](=O)([O-])[O-].[K+].[K+].CI>CN(C=O)C>[CH3:16][O:14][C:13]([CH:11]1[CH2:12][N:9]([C:6]2[CH:5]=[CH:4][C:3]([CH:1]=[O:2])=[CH:8][CH:7]=2)[CH2:10]1)=[O:15]
Reactant: O=C([O-])[O-]
Reactant: O=Cc1ccc(N2CC(C(=O)O)C2)cc1
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)C1CN(c2ccc(C=O)cc2)C1
Reaction time: 0.17 h
Yield: 60.8 %

Procedure:
To a solution of 1-(4-Formyl-phenyl)-azetidine-3-carboxylic acid (Preparation 8, 4 g, 19.51 mmol) in DMF (50 mL) was added potassium carbonate (4.04 g, 29.77 mmol) at 0° C. and allowed to stir for 10 minutes followed by addition of methyl iodide (2.77 g, 19.51 mmol) at 0° C. Resulting reaction mixture was stirred at room temperature for 2 hours under nitrogen atmosphere. After consumption of starting material, reaction mixture was quenched with ice cold water (150 mL) and extracted with EtOAc (3×150 mL). Combined organic layer was washed with water (2×300 mL), brine (250 mL), dried over sodium sulphate and evaporated under reduced pressure to afford brown colored semi solid (4.7 g, crude). Crude was purified by column chromatography on silica gel (100-200 mesh). Compound was eluted using 20% ethyl acetate in hexane to afford yellow semisolid (2.6 g, 61%). 1H NMR (400 MHz, CDCl3) δ: 3.58-3.62 (m, 1H), 3.76 (s, 3H), 4.15-4.22 (m, 4H), 6.42 (d, 2H, J=8.6 Hz), 7.72 (d, 2H, J=6.98 Hz), 9.74 (s, 1H); LC-MS (M+H): =220.20.
Reaction SMILES: [F:1][C:2]1[C:3]2[O:28][N:27]=[C:26]([C:29]3[CH:34]=[CH:33][N:32]=[C:31](S(C)(=O)=O)[N:30]=3)[C:4]=2[CH:5]=[C:6]2[C:19]=1[N:18]1[CH2:20][C@@H:21]([CH3:25])[O:22][C@@H:23]([CH3:24])[C@@H:17]1[C:8]1([C:13](=[O:14])[NH:12][C:11](=[O:15])[NH:10][C:9]1=[O:16])[CH2:7]2.[C-:39]#[N:40].[K+]>>[F:1][C:2]1[C:3]2[O:28][N:27]=[C:26]([C:29]3[CH:34]=[CH:33][N:32]=[C:31]([C:39]#[N:40])[N:30]=3)[C:4]=2[CH:5]=[C:6]2[C:19]=1[N:18]1[CH2:20][C@@H:21]([CH3:25])[O:22][C@@H:23]([CH3:24])[C@@H:17]1[C:8]1([C:13](=[O:14])[NH:12][C:11](=[O:15])[NH:10][C:9]1=[O:16])[CH2:7]2
Reactant: [C-]#N
Reactant: C[C@@H]1CN2c3c(cc4c(-c5ccnc(S(C)(=O)=O)n5)noc4c3F)CC3(C(=O)NC(=O)NC3=O)[C@H]2[C@H](C)O1
Agent: [K+]
Product: C[C@@H]1CN2c3c(cc4c(-c5ccnc(C#N)n5)noc4c3F)CC3(C(=O)NC(=O)NC3=O)[C@H]2[C@H](C)O1

Procedure:
Starting material: (2R,4 S,4 aS)-11-fluoro-2,4-dimethyl-8-(2-(methylsulfonyl)pyrimidin-4-yl)-2,4,4a,6-tetrahydro-1H,1′H-spiro[isoxazolo[4,5-g][1,4]oxazino[4,3-a]quinoline-5,5′-pyrimidine]-2′,4′,6′(3′H)-trione (Example 169) and potassium cyanide.
Reaction SMILES: [CH3:1][NH2:2].Br[CH2:4][C:5]1[CH:6]=[CH:7][C:8]2[C:14]3[S:15][C:16]([C:18]([N:20]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[Cl:28])[CH3:21])=[O:19])=[CH:17][C:13]=3[CH2:12][CH2:11][O:10][C:9]=2[CH:29]=1.O>CCO>[Cl:28][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[N:20]([CH3:21])[C:18]([C:16]1[S:15][C:14]2[C:8]3[CH:7]=[CH:6][C:5]([CH2:4][NH:2][CH3:1])=[CH:29][C:9]=3[O:10][CH2:11][CH2:12][C:13]=2[CH:17]=1)=[O:19]
Reactant: CN(C(=O)c1cc2c(s1)-c1ccc(CBr)cc1OCC2)c1ccccc1Cl
Reactant: CN
Solvent: O
Solvent: CCO
Product: CNCc1ccc2c(c1)OCCc1cc(C(=O)N(C)c3ccccc3Cl)sc1-2
Temperature: 60 °C
Reaction time: 2 h
Yield: 42.8 %

Procedure:
To a solution of CH3NH2 in EtOH (0.25 mL) was added TEA (0.5 mL) and 8-(bromomethyl)-N-(2-chlorophenyl)-N-methyl-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carboxamide (250 mg). The reaction mixture was stirred for 2 h at 60° C. before added water. The mixture was extracted with EtOAc (20 mL×3), dried over Na2SO4 and filtered. The filtrate was concentrated to give the crude product, which was purified by preparative TLC (CH2Cl2:MeOH=10:1) to afford 243 as a light yellow solid (95.6 mg, 42.8%). MS: (ESI+) 412.9
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH3:9])[N:3]=1.[Li]CCCC.B(OC)(OC)OC.Cl[C:23]1[C:29]2[CH:30]=[C:31]([Cl:34])[CH:32]=[CH:33][C:28]=2[N:27]([CH3:35])[C:26](=[O:36])[CH2:25][N:24]=1.[F-].[Cs+]>CCOCC.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.C(Cl)Cl.O.COCCOC>[Cl:34][C:31]1[CH:32]=[CH:33][C:28]2[N:27]([CH3:35])[C:26](=[O:36])[CH2:25][N:24]=[C:23]([C:2]3[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH3:9])[N:3]=3)[C:29]=2[CH:30]=1
Reactant: COc1cccc(Br)n1
Reactant: CN1C(=O)CN=C(Cl)c2cc(Cl)ccc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: COB(OC)OC
Agent: [Cs+]
Solvent: COCCOC
Solvent: O
Solvent: CCOCC
Product: COc1cccc(C2=NCC(=O)N(C)c3ccc(Cl)cc32)n1
Temperature: -40 °C
Reaction time: 0.33 h
Yield: 57 %

Procedure:
As illustrated in the scheme above, absolution of 2-bromo-6-methoxypyridine (0.022 mL, 0.18 mmol) in dry Et2O (0.3 mL) was added to a solution of n-BuLi (0.12 mL of 1.6 M in hexanes, 0.19 mmol) maintained at −40° C. The reaction was stirred at −40° C. for 20 min., and then B(OMe)3 (0.022 mL, 0.19 mmol) was added dropwise. The reaction was stirred at −40° C. for 30 min., and then at room temperature for 3.5 h. The reaction was concentrated in vacuo, anhydrous MeOH was added to the residue, and the reaction was concentrated in vacuo once again. Dry DME (0.8 mL), 5,7-dichloro-1,3-dihydro-1-methyl-2H-1,4-benzodiazepin-2-one (0.0392 g, 0.161 mmol), Pd(PPh3)4 (0.0093 g, 0.0080 mmol) and CsF (0.0612 g, 0.403 mmol) were added to the residue, and the mixture was heated to reflux for 15 h. Water (5 mL) and CH2Cl2 (5 mL) were added to the reaction mixture, and the layers were separated. The aqueous phase was extracted with additional CH2Cl2 (3×), and the combined organic phases were dried over Na2SO4, filtered, and concentrated in vacuo. Purification of the crude product by silica gel column chromatography (2:1 CH2Cl2:EtOAc) provided the title compound (0.029 g, 57%). 1H-NMR (CDCl3): δ 7.77 (d, J=7.6 Hz, 1H), 7.71-7.64 (m, 2H), 7.49 (dd, J=2.4 Hz, J=8.8 Hz, 1H), 7.27 (d, J=8.8 Hz, 1H), 6.83 (d, J=8.0 Hz, 1H), 4.85 (d, J=10.8 Hz, 1H), 3.86 (d, J=10.4 Hz, 1H), 3.81 (s, 3H), 3.39 (s, 3H). MS (ESI) (M+H)+=316.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:29]=[C:9]2[CH:10]=[C:11]([NH:14][C:15]([C:17]3[N:18]([CH3:28])[N:19]=[CH:20][C:21]=3[C:22]([N:24]3[CH2:27][CH2:26][CH2:25]3)=[O:23])=[O:16])[CH:12]=[CH:13][N:8]2[N:7]=1)=[O:5])C.O.[OH-].[Li+].Cl>CO.O.O1CCCC1>[N:24]1([C:22]([C:21]2[CH:20]=[N:19][N:18]([CH3:28])[C:17]=2[C:15]([NH:14][C:11]2[CH:12]=[CH:13][N:8]3[N:7]=[C:6]([C:4]([OH:5])=[O:3])[N:29]=[C:9]3[CH:10]=2)=[O:16])=[O:23])[CH2:27][CH2:26][CH2:25]1
Reactant: CCOC(=O)c1nc2cc(NC(=O)c3c(C(=O)N4CCC4)cnn3C)ccn2n1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: Cn1ncc(C(=O)N2CCC2)c1C(=O)Nc1ccn2nc(C(=O)O)nc2c1
Temperature: 60 °C
Reaction time: 6 h
Yield: 126.6 %

Procedure:
A mixture of ethyl 7-(4-(azetidine-1-carbonyl)-1-methyl-1H-pyrazole-5-carboxamido)-[1,2,4]triazolo[1,5-a]pyridine-2-carboxylate (example 33, step d) (658 mg, 1.66 mmol) and lithium hydroxide hydrate (139 mg, 3.31 mmol) in methanol (20 ml) and water (5 ml) and tetrahydrofuran (10 ml) was stirred for 6 hours at 60° C. (soluble when heated). The mixture was neutralized using hydrochloric acid 2N (1.655 ml, 3.31 mmol) and the mixture was evaporated affording 7-{[4-(azetidine-1-carbonyl)-2-methyl-2H-pyrazole-3-carbonyl]-amino}-[1,2,4]triazolo[1,5-a]pyridine-2-carboxylic acid (776 mg, 77.4%) as a light brown solid which was used in the following reactions. A mixture of 7-(4-(azetidine-1-carbonyl)-1-methyl-1H-pyrazole-5-carboxamido)-[1,2,4]triazolo[1,5-a]pyridine-2-carboxylic acid (120 mg, 244 μmol), dimethylamine hydrochloride (99.4 mg, 1.22 mmol), propylphosphonic anhydride (50% in ethyl acetate, 359 μl, 609 μmol) and diisopropylethylamine (298 μl, 1.71 mmol) in tetrahydrofuran (7 ml) was stirred for 20 hours at 25° C. The solvent was evaporated, the residue was triturated with sodium bicarbonate solution, the precipitated solid was filtered off, washed with water and dried. The material was applied on silicagel and purified by flash chromatography over a 5 g silicagel column using dichloromethane/methanol 5% as eluent affording 7-{[4-(azetidine-1-carbonyl)-2-methyl-2H-pyrazole-3-carbonyl]-amino}-[1,2,4]triazolo[1,5-a]pyridine-2-carboxylic acid dimethylamide (39 mg, 40.4%) as an off-white foam. MS: m/z=397.1 (M+H+)