Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:21])[C:13]2[CH:18]=[CH:17][C:16]([C:19]#[N:20])=[CH:15][CH:14]=2)=[CH:7][C:3]=1[C:4]([OH:6])=O.ClC1N=C(OC)N=C(OC)N=1.CN1CCOCC1.[C:40]([O:44][C:45]([N:47]1[CH2:52][CH2:51][CH:50]([S:53]([C:56]2[CH:61]=[CH:60][C:59]([NH:62][C:63]3[N:68]=[CH:67][C:66]([NH2:69])=[CH:65][N:64]=3)=[CH:58][CH:57]=2)(=[O:55])=[O:54])[CH2:49][CH2:48]1)=[O:46])([CH3:43])([CH3:42])[CH3:41]>C(Cl)Cl>[C:40]([O:44][C:45]([N:47]1[CH2:48][CH2:49][CH:50]([S:53]([C:56]2[CH:57]=[CH:58][C:59]([NH:62][C:63]3[N:68]=[CH:67][C:66]([NH:69][C:4](=[O:6])[C:3]4[CH:7]=[C:8]([NH:11][C:12](=[O:21])[C:13]5[CH:18]=[CH:17][C:16]([C:19]#[N:20])=[CH:15][CH:14]=5)[CH:9]=[CH:10][C:2]=4[Cl:1])=[CH:65][N:64]=3)=[CH:60][CH:61]=2)(=[O:54])=[O:55])[CH2:51][CH2:52]1)=[O:46])([CH3:43])([CH3:41])[CH3:42]
Reactant: N#Cc1ccc(C(=O)Nc2ccc(Cl)c(C(=O)O)c2)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(S(=O)(=O)c2ccc(Nc3ncc(N)cn3)cc2)CC1
Agent: COc1nc(Cl)nc(OC)n1
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CC(C)(C)OC(=O)N1CCC(S(=O)(=O)c2ccc(Nc3ncc(NC(=O)c4cc(NC(=O)c5ccc(C#N)cc5)ccc4Cl)cn3)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 38.2 %

Procedure:
Intermediate 16 (Example 24) (0.132 g, 0.439 mmol) was combined with 2-chloro-4,6-dimethoxy-1,3,5-triazine (CDMT) (0.093 g, 0.53 mmol) and diluted with DCM (4 mL). This was immediately treated with 4-methyl morpholine (0.10 mL, 0.88 mmol) and allowed to stir at ambient temperature for 1 h. Intermediate 13 (Example 20) (0.20 g, 0.462 mmol) was then added in one portion. Stirring was continued overnight. After 18 h, reaction solvents were removed and resulting crude solids purified via HPLC to afford the title compound as a white solid (0.12 g, 36%).
Reaction SMILES: [CH3:1][O:2][CH2:3][C@H:4]([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])[CH2:5][NH:6][C:7]1[N:12]=[C:11]([NH:13][C:14]2[CH:15]=[C:16]([CH3:20])[CH:17]=[CH:18][CH:19]=2)[C:10]2[C:21](=[O:24])[NH:22][CH2:23][C:9]=2[CH:8]=1.[B-](F)(F)(F)[F:34].[B-](F)(F)(F)F.C1[N+]2(CCl)CC[N+](F)(CC2)C1>C(Cl)Cl.CCOC(C)=O.C1COCC1.CCOC(C)=O>[F:34][C:8]1[C:9]2[CH2:23][NH:22][C:21](=[O:24])[C:10]=2[C:11]([NH:13][C:14]2[CH:15]=[C:16]([CH3:20])[CH:17]=[CH:18][CH:19]=2)=[N:12][C:7]=1[NH:6][CH2:5][C@@H:4]([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:29])([CH3:31])[CH3:30])[CH2:3][O:2][CH3:1]
Reactant: COC[C@@H](CNc1cc2c(c(Nc3cccc(C)c3)n1)C(=O)NC2)NC(=O)OC(C)(C)C
Reactant: F[B-](F)(F)F
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: ClCCl
Product: COC[C@@H](CNc1nc(Nc2cccc(C)c2)c2c(c1F)CNC2=O)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a screw-top vial was added (R)-tert-butyl 1-methoxy-3-(3-oxo-4-(m-tolylamino)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-6-ylamino)propan-2-ylcarbamate (27 mg, 0.061 mmol) in a mixture of DCM and MeOH (1/1, 1.2 mL). The resulting colorless solution was cooled to 0° C. SELECTFLUOR® (21.66 mg, 0.061 mmol) was added and the reaction mixture was stirred at 0° C. for 2 h. Next, the reaction mixture was diluted with EtOAc (10 mL) and washed with saturated aq sodium bicarbonate (5 mL), water (5 mL), and brine (5 mL). The organic layer was collected, dried over Na2SO4, and concentrated to give the title compound as a brown residue, which was used without further purification (32 mg, 114%). [M+H] calc'd for C23H30FN5O4, 460. found, 460.
Reaction SMILES: Cl.Cl.[CH2:3]([O:5][C:6](=[O:28])[CH2:7][C:8]1[CH:9]=[N:10][CH:11]=[C:12]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][C:15]=2[CH2:24][NH:25][CH2:26][CH3:27])[CH:13]=1)[CH3:4].[N:29]1[CH:34]=[CH:33][N:32]=[CH:31][C:30]=1[C:35]([OH:37])=O>>[CH2:3]([O:5][C:6](=[O:28])[CH2:7][C:8]1[CH:9]=[N:10][CH:11]=[C:12]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:22])([F:21])[F:23])=[CH:16][C:15]=2[CH2:24][N:25]([CH2:26][CH3:27])[C:35]([C:30]2[CH:31]=[N:32][CH:33]=[CH:34][N:29]=2)=[O:37])[CH:13]=1)[CH3:4]
Reactant: CCNCc1cc(C(F)(F)F)ccc1-c1cncc(CC(=O)OCC)c1
Reactant: O=C(O)c1cnccn1
Agent: Cl
Product: CCOC(=O)Cc1cncc(-c2ccc(C(F)(F)F)cc2CN(CC)C(=O)c2cnccn2)c1

Procedure:
[5-(2-Ethylaminomethyl-4-trifluoromethyl-phenyl)-pyridin-3-yl]-acetic acid ethyl ester, dihydrochloride and pyrazinecarboxylic acid were reacted as described in Example 8, Step 6 to provide [5-(2-{[N-ethyl-N-(pyrazine-2-carbonyl)-amino]-methyl}-4-trifluoromethyl-phenyl)-pyridin-3-yl]-acetic acid ethyl ester.
Reaction SMILES: N1C=CC=CC=1.F.[CH3:8][O:9][C:10]([CH:12]1[CH:16]([C@@H:17]([CH3:27])[CH2:18][O:19][Si](C(C)(C)C)(C)C)[CH2:15][N:14]([C:28]([O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[O:29])[CH2:13]1)=[O:11]>N1C=CC=CC=1>[CH3:8][O:9][C:10]([CH:12]1[CH:16]([C@@H:17]([CH3:27])[CH2:18][OH:19])[CH2:15][N:14]([C:28]([O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[O:29])[CH2:13]1)=[O:11]
Reactant: COC(=O)C1CN(C(=O)OCc2ccccc2)CC1[C@@H](C)CO[Si](C)(C)C(C)(C)C
Agent: F
Solvent: c1ccncc1
Product: COC(=O)C1CN(C(=O)OCc2ccccc2)CC1[C@@H](C)CO
Temperature: 25 °C
Reaction time: 13 h
Yield: 179.7 %

Procedure:
Hydrogen fluoride-pyridine (4 mL) was added to a solution of 4-[(R)-2-(tert-butyldimethylsilyloxy)-1-(methyl)ethyl]-pyrrolidine-1,3-dicarboxylic acid 1-benzyl ester 3-methyl ester (6.0 g, 7.1 mmol) in pyridine (20 mL) under ice-cooling, and the mixture was stirred at room temperature for 13 hours. The reaction mixture was poured into ice water, followed by extraction with ethyl acetate and washing with 1N hydrochloric acid and brine. After drying over magnesium sulfate and filtration, the solvent was evaporated under reduced pressure to give 4.1 g (93%) of the diastereomer mixture title compound as a colorless oil. The diastereomers were used for the next step without separation.
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=2)[C:8]([OH:10])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(Cl)(=O)C(Cl)=O.[NH2:26][C:27]1[S:28][CH:29]=[CH:30][N:31]=1.C(N(CC)C(C)C)(C)C>C(Cl)Cl.CN(C)C=O.O1CCCC1>[CH:1]1([CH2:6][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=2)[C:8]([NH:26][C:27]2[S:28][CH:29]=[CH:30][N:31]=2)=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=C(O)C(CC1CCCC1)c1ccc([N+](=O)[O-])cc1
Reactant: Nc1nccs1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1nccs1)C(CC1CCCC1)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 22 %

Procedure:
A solution of 3-cyclopentyl-2-(4-nitro-phenyl)-propionic acid (131 mg, 0.5 mmol) in methylene chloride (5.0 mL) was cooled to 0° C. and then treated with a 2.0M solution of oxalyl chloride in methylene chloride (1.0 mL, 2.0 mmol) and a few drops of N,N-dimethylformamide. The reaction mixture was stirred at 0° C. for 15 min and at 25° C. for 30 min. The reaction mixture was then treated with a solution of 2-aminothiazole (110 mg, 1.0 mmol) in tetrahydrofuran (5 mL) and N,N-diisopropylethylamine (0.28 mL, 0.55 mmol). The solution was stirred at 25° C. for 24 h. At this time, the reaction was concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 50/50 hexanes/ethyl acetate) afforded 3-cyclopentyl-2-(4-nitro-phenyl)-N-thiazol-2-yl-propionamide (38 mg, 22.4%) as a yellow solid: mp 186-187° C.; EI-HRMS m/e calcd for C17H19N3O3S (M+) 345.1147, found 345.1148.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[C:10]([F:13])([F:12])[F:11].[CH3:14][N:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1>CN(C)C(=O)C>[CH3:14][N:15]1[CH2:20][CH2:19][N:18]([C:2]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=2[C:10]([F:13])([F:12])[F:11])[CH2:17][CH2:16]1
Reactant: CN1CCNCC1
Reactant: N#Cc1ccc(Br)c(C(F)(F)F)c1
Solvent: CC(=O)N(C)C
Product: CN1CCN(c2ccc(C#N)cc2C(F)(F)F)CC1
Temperature: 95 °C
Reaction time: 14 h

Procedure:
A mixture of 4-bromo-3-(trifluoromethyl)-benzonitrile (Yonezawa et al., Synthetic Communications (1996) 26, 1575-8; 2.47 g, 12 mmol), 1-methylpiperazine (Fluka, Buchs, Switzerland, 5.33 mL, 48 mmol) and 15 mL N,N-dimethylacetamide is stirred in a tightly closed vessel for 14 hours at 95° C. After cooling, the reaction mixture is evaporated to dryness under reduced pressure and the residue is treated with a half-saturated aqueous solution of sodium carbonate and extracted with ethyl acetate. The combined extracts are dried (Na2SO4) and the solvent is evaporated off under reduced pressure. The crude product is purified by column chromatography on silica gel, eluent methylene chloride/methanol to give 4-(4-methyl-1-piperazinyl)-3-(trifluoromethyl)-benzonitrile as a pale yellow oil.
Reaction SMILES: [Cl:1][C:2]1[C:11]([OH:12])=[C:10]2[C:5]([CH:6]=[N:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.C([O-])(=O)C.[K+].[I:18]I>CO.O>[Cl:1][C:2]1[C:11]([OH:12])=[C:10]2[C:5]([CH:6]=[N:7][CH:8]=[N:9]2)=[C:4]([I:18])[CH:3]=1
Reactant: II
Reactant: Oc1c(Cl)ccc2cncnc12
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: Oc1c(Cl)cc(I)c2cncnc12

Procedure:
To a solution of 7-chloro-8-hydroxy-quinazoline (A69) (0.1 mol) and potassium acetate (0.15 mol) in MeOH and H2O (19:1, 250 mL) was added, over 30 min, a solution of iodine (0.095 mol) in MeOH and H2O (19:1, 350 mL). The mixture was then heated under reflux for 15 min, cooled and H2O (400 mL) was added. The precipitate was isolated by filtration, washed with saturated sodium thiosulfate and H2O, and dried. This provided 7-chloro-8-hydroxy-5-iodo-quinazoline (A70) as a solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([O:12][Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14])[CH:6]=[CH:5]2.[Li]CCCC.CN([CH:28]=[O:29])C>C1COCC1>[Si:13]([O:12][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[CH:3]=[C:2]([CH:28]=[O:29])[CH:11]=[CH:10]2)([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14]
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc2cc(Br)ccc2c1
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)Oc1ccc2cc(C=O)ccc2c1
Reaction time: 0.5 h
Yield: 76.8 %

Procedure:
To a solution of (6-bromonaphthalen-2-yloxy)(tert-butyl)dimethylsilane (4 g, 0.01 mol, 1.0 equiv) in dry THF (30 mL) at −78° C. under N2 atmosphere was added n-BuLi (2.5 M, 12 mL, 3.0 equiv) dropwise and stirred for 30 min. Then DMF (7.3 g, 0.1 mol, 10 equiv) was added and stirred for another 1 h, then quenched with water, extracted with ethyl acetate and washed with brine, dried over Na2SO4 and concentrated to obtain crude product. The crude product was purified by silica gel chromatography (PE:EA=20:1) to give compound the title compound (2.2 g, 64%) as a yellow liquid. ESI-MS (M+1)+: 287.0. 1H NMR (400 MHz, CDCl3) δ: 10.10 (s, 1H), 8.26 (s, 1H), 7.91-7.88 (m, 2H), 7.78-7.76 (m, 1H), 7.24-7.16 (m, 2H), 1.03 (s, 9H), 0.28 (s, 6H).
Reaction SMILES: [OH:1][C@H:2]([CH2:6][OH:7])[CH2:3][C:4]#[N:5].[S:8](Cl)([CH3:11])(=[O:10])=[O:9].Cl>N1C=CC=CC=1.C(Cl)Cl>[OH:1][C@H:2]([CH2:6][O:7][S:8]([CH3:11])(=[O:10])=[O:9])[CH2:3][C:4]#[N:5]
Reactant: CS(=O)(=O)Cl
Reactant: N#CC[C@H](O)CO
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CS(=O)(=O)OC[C@@H](O)CC#N
Temperature: 0 °C
Reaction time: 6 h

Procedure:
(3S)-3,4-Dihydroxybutyronitrile (16.2 g, 160 mmol) was dissolved in pyridine (26.0 ml). To the resulting solution, a solution of mesyl chloride (14.8 ml) in methylene chloride (160 ml) was added at 0° C. and stirred at 0° C. for 6 hours. Then, the pH of the mixture was adjusted at 2 with 6N hydrochloric acid, and the mixture was extracted with methylene chloride. After the organic layer was dried over anhydrous sodium sulfate, the solvent was evaporated off. The residue was purified with silica gel column chromatography (acetone:chloroform=5:95) to obtain (3S)-3-hydroxy-4-methanesulfonyloxybutyronitrile (15.2 g). Yield, 53 %.
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:27])=[CH:4][C:5]([F:26])=[C:6]([N:8]2[C:17]3[C:12](=[CH:13][C:14]([N+:19]([O-:21])=[O:20])=[C:15](F)[CH:16]=3)[C:11](=[O:22])[C:10]([C:23]([OH:25])=[O:24])=[CH:9]2)[CH:7]=1.C[O-].[Na+].C(O)(=O)C[C:33](CC(O)=O)(C(O)=O)[OH:34]>N1C=CC=CC=1>[NH2:1][C:2]1[C:3]([F:27])=[CH:4][C:5]([F:26])=[C:6]([N:8]2[C:17]3[C:12](=[CH:13][C:14]([N+:19]([O-:21])=[O:20])=[C:15]([O:34][CH3:33])[CH:16]=3)[C:11](=[O:22])[C:10]([C:23]([OH:25])=[O:24])=[CH:9]2)[CH:7]=1
Reactant: Nc1cc(-n2cc(C(=O)O)c(=O)c3cc([N+](=O)[O-])c(F)cc32)c(F)cc1F
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: C[O-]
Agent: [Na+]
Solvent: c1ccncc1
Product: COc1cc2c(cc1[N+](=O)[O-])c(=O)c(C(=O)O)cn2-c1cc(N)c(F)cc1F
Temperature: 40 °C
Reaction time: 2 h

Procedure:
1-(5-Amino-2,4-difluorophenyl)-7-fluoro-6-nitro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (60 mg) was added to a mixed liquid of a 28% sodium methoxide solution (135 mg) and pyridine (0.5 ml), and the mixture was stirred at 40° C. for 2 hours. The reaction mixture was acidified with a 3% aqueous solution of citric acid, and solids formed were collected by filtration. The solids were subjected to azeotropic distillation with ethanol and toluene. Hexane was added to the residue to conduct filtration, thereby obtaining the title compound (20 mg) as a yellow powder.
Reaction SMILES: [CH3:1][C:2]1[CH2:11][CH2:10][C:6](=[C:7]([CH3:9])[CH3:8])[C:4](=[O:5])[CH:3]=1.[H][H]>C(OCC)(=O)C>[CH3:1][C@H:2]1[CH2:3][C:4](=[O:5])[C:6](=[C:7]([CH3:8])[CH3:9])[CH2:10][CH2:11]1
Reactant: CC1=CC(=O)C(=C(C)C)CC1
Reactant: [H][H]
Solvent: CCOC(C)=O
Product: CC(C)=C1CC[C@@H](C)CC1=O
Reaction time: 20 h
Yield: 89.9 %

Procedure:
A 500 ml capacity autoclave was charged with 150 g (1 mol) of piperitenone, 18.6 mg (0.04 mmol) of [Rh(cod)2]PF6, 47.2 mg (0.04 mmol) of (S)-DIBM-SEGPHOS, 14.8 mg (0.02 mmol) of BrPPh3(CH2)4PPh3Br and 7.5 ml of ethyl acetate, and the reaction was carried out at 50° C. for 20 hours under a hydrogen pressure of 3 MPa. After completion of the reaction, hydrogen was purged, and the reaction solution was concentrated and distilled under a reduced pressure to obtain 136.8 g of d-pulegone (yield 90%).
Reaction SMILES: [C:1]([O:5][C:6]([CH2:8][N:9]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:13][CH:12]([NH2:20])[C:10]1=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:21][N:22]([CH3:32])[C:23]1[CH:31]=[CH:30][C:26]([C:27](O)=[O:28])=[CH:25][CH:24]=1.ON1C2C=CC=CC=2N=N1.C1(N=C=NC2CCCCC2)CCCCC1>>[C:1]([O:5][C:6]([CH2:8][N:9]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:13][CH:12]([NH:20][C:27](=[O:28])[C:26]2[CH:25]=[CH:24][C:23]([N:22]([CH3:21])[CH3:32])=[CH:31][CH:30]=2)[C:10]1=[O:11])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CN(C)c1ccc(C(=O)O)cc1
Reactant: CC(C)(C)OC(=O)CN1C(=O)C(N)Cc2ccccc21
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Product: CN(C)c1ccc(C(=O)NC2Cc3ccccc3N(CC(=O)OC(C)(C)C)C2=O)cc1
Yield: 43.5 %

Procedure:
The title compound (0.2 gm) was prepared from 0.3 gm of 1-t-butoxycarbonylmethyl-3-aminohomodihydrocarbostyril (Example 2, Compound B), 0.19 gm of 4-dimethylaminobenzoic acid, 0.15 gm of 1-hydroxybenzotriazole and 0.23 gm of dicyclohexylcarbodiimide by a procedure analogous to the one employed in Example 10.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:24]=[CH:23][C:6]([CH2:7][N:8]2[C:13]3[S:14][CH:15]=[C:16]([CH:17]=C)[C:12]=3[C:11]3=[N:19][CH:20]=[N:21][N:10]3[C:9]2=[O:22])=[CH:5][CH:4]=1.I([O-])(=O)(=O)=[O:26].[Na+]>O1CCCC1.O.[Os](=O)(=O)(=O)=O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]2[C:13]3[S:14][CH:15]=[C:16]([CH:17]=[O:26])[C:12]=3[C:11]3=[N:19][CH:20]=[N:21][N:10]3[C:9]2=[O:22])=[CH:23][CH:24]=1
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: C=Cc1csc2c1c1ncnn1c(=O)n2Cc1ccc(OC)cc1
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(Cn2c(=O)n3ncnc3c3c(C=O)csc32)cc1
Reaction time: 4 h
Yield: 67.9 %

Procedure:
6-(4-Methoxybenzyl)-9-vinylthieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one (850 mg, 2.51 mmol) was suspended in tetrahydrofuran (17 ml) and heated with a heat gun to effect dissolution. Similarly sodium periodate (1.24 g, 5.78 mmol) was heated in water (8.5 ml) to effect dissolution. The above solutions were combined with vigorous stifling. While the stirred mixture was at 40° C., osmium(VIII) oxide (737 μl, 2.50% w/w, 0.08 mmol) was added and the mixture was stirred vigorously for 4 hours. It was diluted with water (300 mL) and the resulting solids were collected via vacuum filtration to yield the aldehyde (0.58 g, 68%) as pale yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 3.74 (s, 3 H), 5.42 (s, 2H), 6.94 (d, J=8.66 Hz, 2H), 7.42 (d, J=8.53 Hz, 2H), 8.29 (s, 1H), 8.61 (s, 1H), 10.58 (s, 1H). LCMS (MH+, 341.1).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C@H:9]([C:11]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:15](=[O:23])[C:14]3=[C:24]([CH3:27])[CH:25]=[CH:26][N:13]3[N:12]=2)[CH3:10])[C:3]=1Br.[Cl:29][C:30]1[CH:31]=[C:32](B(O)O)[CH:33]=[C:34]([OH:36])[CH:35]=1.C(=O)([O-])[O-].[Na+].[Na+]>>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C@H:9]([C:11]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:15](=[O:23])[C:14]3=[C:24]([CH3:27])[CH:25]=[CH:26][N:13]3[N:12]=2)[CH3:10])[C:3]=1[C:32]1[CH:33]=[C:34]([OH:36])[CH:35]=[C:30]([Cl:29])[CH:31]=1
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc(N)c3Br)n(-c3ccccc3)c(=O)c12
Reactant: OB(O)c1cc(O)cc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: Cc1ccn2nc([C@H](C)Nc3ncnc(N)c3-c3cc(O)cc(Cl)c3)n(-c3ccccc3)c(=O)c12
Yield: 13.4 %

Procedure:
(S)-2-(1-((6-Amino-5-bromopyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (100 mg, 0.23 mmol) was treated with (3-chloro-5-hydroxyphenyl)boronic acid (59 mg, 0.34 mmol), sodium carbonate (2M, 510 μl, 1.02 mmol) and 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (9 mg, 0.01 mmol) according to the method described in Example 3 to give 15 mg (32% yield) of the title compound as a solid. Purity 100%.
Reaction SMILES: Br[CH2:2][C:3]1[NH:8][C:7]([C:9]2[S:10][CH:11]=[CH:12][N:13]=2)=[N:6][CH:5]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=2[Cl:21])[C:4]=1[C:22]([O:24][CH2:25][CH3:26])=[O:23].[NH:27]1[CH2:32][CH2:31][O:30][CH2:29][C@H:28]1[C:33]([OH:35])=[O:34]>>[Cl:21][C:15]1[CH:16]=[C:17]([F:20])[CH:18]=[CH:19][C:14]=1[CH:5]1[N:6]=[C:7]([C:9]2[S:10][CH:11]=[CH:12][N:13]=2)[NH:8][C:3]([CH2:2][N:27]2[CH2:32][CH2:31][O:30][CH2:29][C@H:28]2[C:33]([OH:35])=[O:34])=[C:4]1[C:22]([O:24][CH2:25][CH3:26])=[O:23]
Reactant: O=C(O)[C@@H]1COCCN1
Reactant: CCOC(=O)C1=C(CBr)NC(c2nccs2)=NC1c1ccc(F)cc1Cl
Product: CCOC(=O)C1=C(CN2CCOC[C@H]2C(=O)O)NC(c2nccs2)=NC1c1ccc(F)cc1Cl
Yield: 86.3 %

Procedure:
Ethyl 6-(bromomethyl)-4-(2-chloro-4-fluorophenyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate (1.55 g, 3.37 mmol) was reacted with (S)-morpholine-3-carboxylic acid (0.44 g, 3.37 mmol) according to the procedure as described in Example 28 to give the title compound as a yellow solid (1.48 g, 86%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[OH:12].[C:13](=O)([O-])[O-].[K+].[K+].S(OC)(OC)(=O)=O.O>CC(C)=O>[Br:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[O:12][CH3:13]
Reactant: COC(=O)c1ccc(Br)c(O)c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: COS(=O)(=O)OC
Solvent: O
Solvent: CC(C)=O
Product: COC(=O)c1ccc(Br)c(OC)c1
Yield: 98.2 %

Procedure:
A solution of methyl 4-bromo-3-hydroxybenzoate of Step A (27 mmol), potassium carbonate (33 mmol), and dimethyl sulfate (32 mmol) in acetone (40 mL) was stirred at reflux temperature under nitrogen atmosphere for three hours. The mixture was cooled and 5 mL of water was added. The acetone was evaporated and 30 mL of water was added. The product was extracted into dichloromethane. The organic solution was dried over anhydrous magnesium sulfate, filtered and evaporated to give the title compound (6.5 g, 99%) as a hard, white crystalline solid.
Reaction SMILES: Br[C:2]1[C:3]([O:16][CH3:17])=[N:4][C:5]([N:8]2[CH2:13][C@H:12]([CH3:14])[O:11][C@H:10]([CH3:15])[CH2:9]2)=[N:6][CH:7]=1.[CH3:18][C:19]1[CH:24]=[C:23](B2OC(C)(C)C(C)(C)O2)[CH:22]=[CH:21][N:20]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:15][C@H:10]1[O:11][C@@H:12]([CH3:14])[CH2:13][N:8]([C:5]2[N:4]=[C:3]([O:16][CH3:17])[C:2]([C:23]3[CH:22]=[CH:21][N:20]=[C:19]([CH3:18])[CH:24]=3)=[CH:7][N:6]=2)[CH2:9]1
Reactant: COc1nc(N2C[C@@H](C)O[C@@H](C)C2)ncc1Br
Reactant: Cc1cc(B2OC(C)(C)C(C)(C)O2)ccn1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: COc1nc(N2C[C@@H](C)O[C@@H](C)C2)ncc1-c1ccnc(C)c1
Temperature: 20 °C
Yield: 1.4 %

Procedure:
To a suspension of cis-4-(5-bromo-4-methoxypyrimidin-2-yl)-2,6-dimethylmorpholine (671 mg, 2.22 mmol), 2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (632 mg, 2.89 mmol) and potassium carbonate (798 mg, 5.77 mmol) in 1,4-dioxane (3 mL) and water (0.5 mL) stirred in air at 20° C. was added solid tetrakis(triphenylphosphine) palladium(0) (128 mg, 0.111 mmol). The reaction mixture was stirred under argon at 100° C. overnight. The reaction mixture was allowed to cool to room temperature, diluted with water and extracted with ethyl acetate (×3). The ethyl acetate layers were combined, dried over magnesium sulfate and evaporated under reduced pressure. The crude product was added to a silica gel column and was eluted with dichloromethane/methanol/triethylamine (20:1:0.5). Collected fractions were evaporated to give the title compound (120 mg, 0.031 mmol, 1.393% yield). LC/MS [M+H]+=318.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[C:13]([CH3:14])=[C:12]([C:15]([OH:17])=O)[N:11]=[N:10]2)=[CH:4][CH:3]=1.[CH3:18][O:19][C:20]1[CH:21]=[C:22]([CH:24]=[CH:25][C:26]=1[O:27][CH3:28])[NH2:23].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:18][O:19][C:20]1[CH:21]=[C:22]([NH:23][C:15]([C:12]2[N:11]=[N:10][N:9]([CH2:8][C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[C:13]=2[CH3:14])=[O:17])[CH:24]=[CH:25][C:26]=1[O:27][CH3:28]
Reactant: Cc1c(C(=O)O)nnn1Cc1ccc(F)cc1
Reactant: COc1ccc(N)cc1OC
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(NC(=O)c2nnn(Cc3ccc(F)cc3)c2C)cc1OC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 1-[(4-fluorophenyl)methyl]-5-methyl-1H-1,2,3-triazole-4-carboxylic acid (0.2 g, 0.85 mmol), 3,4-bis(methyloxy)aniline (0.156 g, 1.2 eq), HATU (0.485 g, 1.5 eq) and DIPEA (240 μL, 1.5 eq) in DMF was stirred at room temperature overnight. The solvent was evaporated and the residue was washed with water and extracted with DCM. The organic phase was dried over sodium sulphate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography eluting with DCM to give after precipitation from ether, the title compound as a white solid (180 mg, 57%). HRMS calculated for C19H19FN4O3 (M+H)+371.1519. found: 371.1500, Rt: 2.78 min. MP: 119.7° C.
Reaction SMILES: C(OC([N:8]1[CH:17]([CH3:18])[CH2:16][C:15]2[C:14]([O:19][C:20]3[CH:21]=[C:22]4[C:26](=[CH:27][CH:28]=3)[N:25]([C:29](=[O:40])[NH:30][C:31]3[NH:32][N:33]=[C:34]([C:36]([CH3:39])([CH3:38])[CH3:37])[CH:35]=3)[CH:24]=[CH:23]4)=[N:13][CH:12]=[N:11][C:10]=2[CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:36]([C:34]1[CH:35]=[C:31]([NH:30][C:29]([N:25]2[C:26]3[C:22](=[CH:21][C:20]([O:19][C:14]4[C:15]5[CH2:16][CH:17]([CH3:18])[NH:8][CH2:9][C:10]=5[N:11]=[CH:12][N:13]=4)=[CH:28][CH:27]=3)[CH:23]=[CH:24]2)=[O:40])[NH:32][N:33]=1)([CH3:39])([CH3:37])[CH3:38]
Reactant: CC1Cc2c(ncnc2Oc2ccc3c(ccn3C(=O)Nc3cc(C(C)(C)C)n[nH]3)c2)CN1C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC1Cc2c(ncnc2Oc2ccc3c(ccn3C(=O)Nc3cc(C(C)(C)C)n[nH]3)c2)CN1

Procedure:
A solution of 4-[1-(5-tert-butyl-2H-pyrazol-3-ylcarbamoyl)-1H-indol-5-yloxy]-6-methyl-5,8-dihydro-6H-pyrido[3,4-d]pyrimidine-7-carboxylic acid tert-butyl ester (300 mg, 0.55 mmol), DCM (5 mL), and TFA (5 mL) is stirred at it for 2 h. At that point the solution is concentrated and the residue separated via semi-prep HPLC (C18; 10-100% I/H2O with 0.1% NH4OH) to give the title compound.