Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]([C:8]1[N:13]=[C:12]([CH2:14][OH:15])[CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:16][Mg]Br>C1COCC1>[CH3:16][C:12]1([CH2:14][OH:15])[CH:11]=[CH:10][CH:9]=[C:8]([O:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[NH:13]1
Reactant: C[Mg]Br
Reactant: OCc1cccc(Oc2ccccc2)n1
Solvent: C1CCOC1
Product: CC1(CO)C=CC=C(Oc2ccccc2)N1

Procedure:
The alcohol, 2-methyl(6-phenoxy-2-pyridyl) methanol is prepared by oxidation of (6-phenoxy-2-pyridyl) methanol using chromuim trioxide-pyridine to the aldehyde, 6-phenoxypyridyl-2-carboxaldehyde, which by grignard reaction using methyl magnesium bromide in THF provides the desired alcohol.
Reaction SMILES: [CH2:1]([N:3]1[C:7]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH:15]=[O:16])=[CH:11][CH:10]=2)=[CH:6][C:5]([C:17]2[CH:18]=[C:19]([C:23]([NH:26][S:27]([CH2:30][C:31]([F:34])([F:33])[F:32])(=[O:29])=[O:28])([CH3:25])[CH3:24])[CH:20]=[CH:21][CH:22]=2)=[N:4]1)[CH3:2].C(=O)([O-])[O-].[K+].[K+].CC1C=CC(S([CH2:51][N+:52]#[C-:53])(=O)=O)=CC=1.[N+](CS(C1C=CC(C)=CC=1)(=O)=O)#[C-]>CO.O>[CH2:1]([N:3]1[C:7]([O:8][C:9]2[CH:10]=[CH:11][C:12]([C:15]3[O:16][CH:53]=[N:52][CH:51]=3)=[CH:13][CH:14]=2)=[CH:6][C:5]([C:17]2[CH:18]=[C:19]([C:23]([NH:26][S:27]([CH2:30][C:31]([F:34])([F:32])[F:33])(=[O:28])=[O:29])([CH3:25])[CH3:24])[CH:20]=[CH:21][CH:22]=2)=[N:4]1)[CH3:2]
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Reactant: CCn1nc(-c2cccc(C(C)(C)NS(=O)(=O)CC(F)(F)F)c2)cc1Oc1ccc(C=O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: CCn1nc(-c2cccc(C(C)(C)NS(=O)(=O)CC(F)(F)F)c2)cc1Oc1ccc(-c2cnco2)cc1
Temperature: 22 °C
Reaction time: 0.5 h
Yield: 3 %

Procedure:
N-(2-{3-[1-ethyl-5-(4-formylphenoxy)-1H-pyrazol-3-yl]phenyl}propan-2-yl)-2,2,2-trifluoroethanesulfonamide (340 mg, 0.69 mmol, 1 equiv) was added to a suspension of potassium carbonate (237 mg, 1.72 mmol, 2.5 equiv) stirring in MeOH (3.4 mL) at 22° C. 1-[(isocyanomethyl)sulfonyl]-4-methylbenzene isocyanomethyl 4-methylphenyl sulfone (161 mg, 0.82 mmol, 1.2 equiv) was added and the resulting mixture was stirred at 22° C. for 30 minutes. The reaction was diluted with water and extracted with ethyl acetate. The organic layer was washed with saturated aqueous ammonium chloride, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was purified by flash chromatography (0-40% EtOAc:Hex). Fractions were identified, combined and concentrated in vacuo but the isolated material was not pure. The residue was then purified by reversed phase HPLC (0-95% acetonitrile:water with 0.025% TFA). Pure fractions were identified, combined, basified with saturated aqueous sodium bicarbonate, and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and concentrated in vacuo to give the title compound (3% yield). Calc'd (M+1)+: 535.1. Found: 535.1.
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=2[Cl:17])=[CH:6][CH:5]=[CH:4][N:3]=1.Cl.[C:19]1([CH2:25][C:26](=[NH:30])OCC)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(O)C>[ClH:16].[Cl:17][C:11]1[CH:12]=[C:13]([Cl:16])[CH:14]=[CH:15][C:10]=1[CH2:9][O:8][C:7]1[C:2]([NH:1][C:26](=[NH:30])[CH2:25][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[N:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=N)Cc1ccccc1
Reactant: Nc1ncccc1OCc1ccc(Cl)cc1Cl
Agent: Cl
Solvent: CCO
Product: N=C(Cc1ccccc1)Nc1ncccc1OCc1ccc(Cl)cc1Cl
Yield: 14.8 %

Procedure:
A mixture of 2-amino-3-(2,4-dichlorobenzyloxy)pyridine (5.07 g, 18.8 mmol) and ethyl phenylacetimidate hydrochloride (3.52 g, 25.8 mmol) in ethanol (150 ml) was heated under reflux for 2 hours. Evaporation of the solvent gave an oil which was purified by flash chromatography (dichloromethane/methanol) and trituration with ether to obtain the product (0.59 g), m.p. 185°-187° C.
Reaction SMILES: C1(O[C:8]#[N:9])C=CC=CC=1.[Cl:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17]1[CH:26]=[N:25][CH:24]=[C:23]([NH:27][C:28]2[CH:33]=[CH:32][C:31]([I:34])=[CH:30][C:29]=2[F:35])[C:18]=1[C:19]([NH:21][NH2:22])=[O:20]>CS(C)=O>[NH2:9][C:8]1[O:20][C:19]([C:18]2[C:17]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[Cl:10])=[CH:26][N:25]=[CH:24][C:23]=2[NH:27][C:28]2[CH:33]=[CH:32][C:31]([I:34])=[CH:30][C:29]=2[F:35])=[N:21][N:22]=1
Reactant: NNC(=O)c1c(Nc2ccc(I)cc2F)cncc1-c1ccccc1Cl
Reactant: N#COc1ccccc1
Solvent: CS(C)=O
Product: Nc1nnc(-c2c(Nc3ccc(I)cc3F)cncc2-c2ccccc2Cl)o1
Temperature: 25 °C
Reaction time: 8 h
Yield: 24.6 %

Procedure:
Phenyl cyanate (5 mg, 0.04 mmol) was added to a solution of 3-(2-chloro-phenyl)-5-(2-fluoro-4-iodo-phenylamino)-isonicotinic acid hydrazide (7) (17 mg, 0.04 mmol) in DMSO (1 mL), and stirred overnight at room temperature. The reaction solution was quenched with H2O. The resulting precipitate was filtered, washed with H2O, and dried under vacuum to afford the desired product (5 mg, 28%). LC-MS (M+H=508, obsd.=508). 1H NMR: δ 8.92 (s, 1H), 8.47 (d, 1H), 8.03 (d, 1H), 7.74 (dd, 1H), 7.55 (m, 2H), 7.43 (m, 3H), 7.24 (t, 1H), 7.11 (s, 2H).
Reaction SMILES: [H-].[Na+].C(OP([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])(OCC)=O)C.[Br:17][C:18]1[CH:19]=[C:20]([C:25]([C:27]2[O:28][CH:29]=[CH:30][N:31]=2)=O)[CH:21]=[C:22]([F:24])[CH:23]=1.Cl>C1COCC1.O>[CH2:15]([O:14][C:12](=[O:13])/[CH:11]=[C:25](/[C:20]1[CH:21]=[C:22]([F:24])[CH:23]=[C:18]([Br:17])[CH:19]=1)\[C:27]1[O:28][CH:29]=[CH:30][N:31]=1)[CH3:16]
Reactant: O=C(c1cc(F)cc(Br)c1)c1ncco1
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)/C=C(/c1cc(F)cc(Br)c1)c1ncco1
Temperature: -78 °C
Reaction time: 1 h
Yield: 69.8 %

Procedure:
To a suspension of NaH (60%, 1.6 g, 40 mmol) in dry THF (30 mL) was added ethyl 2-(diethoxyphosphoryl)acetate (9.15 g, 40 mmol) at −78° C. After being stirred at −78° C. for 1 hour, a solution of (3-Bromo-5-fluoro-phenyl)-oxazol-2-yl-methanone (10.8 g, 40 mmol) in 20 ml THF was added drop wise over 30 min. The mixture was stirred at −78° C. for 30 min and then warmed to room temperature followed by stirring overnight. The mixture was cooled to 0° C. and treated with water (50 mL), pH value was adjusted to 6 with HCl (0.5N) and extracted with EtOAc (50 mL×3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with a petroleum ether/EtOAc mixture to afford 9.5 g of the desired product (Yield: 61%)
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][C:7]([N+:13]([O-:15])=[O:14])=[C:6]2O)[CH3:2].O=P(Cl)(Cl)[Cl:19]>>[Cl:19][C:6]1[C:5]2[C:10](=[CH:11][CH:12]=[C:3]([CH2:1][CH3:2])[CH:4]=2)[N:9]=[CH:8][C:7]=1[N+:13]([O-:15])=[O:14]
Reactant: CCc1ccc2ncc([N+](=O)[O-])c(O)c2c1
Reactant: O=P(Cl)(Cl)Cl
Product: CCc1ccc2ncc([N+](=O)[O-])c(Cl)c2c1

Procedure:
The title compound is prepared in analogy to Example 19c starting from 3.6 g (16.49 mmol) 6-ethyl-3-nitro-quinolin-4-ol (Example 49d) and 24 ml POCl3. mp: 290-295° C.; MS: 237 (M++1); HPLC: tret=13.72 min (Grad 1).
Reaction SMILES: Br[CH2:2][C:3]1[N:8]=[C:7]([N:9]2[CH2:13][CH2:12][CH2:11][C:10]2=[O:14])[CH:6]=[CH:5][CH:4]=1.C1(P(=O)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N-:35]=[N+:36]=[N-:37].[Na+]>CN(C=O)C>[N:35]([CH2:2][C:3]1[N:8]=[C:7]([N:9]2[CH2:13][CH2:12][CH2:11][C:10]2=[O:14])[CH:6]=[CH:5][CH:4]=1)=[N+:36]=[N-:37]
Reactant: O=C1CCCN1c1cccc(CBr)n1
Reactant: [N-]=[N+]=[N-]
Agent: O=P(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Na+]
Solvent: CN(C)C=O
Product: [N-]=[N+]=NCc1cccc(N2CCCC2=O)n1
Reaction time: 18 h

Procedure:
A solution of 1-(6-bromomethylpyridin-2-yl)pyrrolidin-2-one (10.19 g, 39.94 mol) containing triphenylphosphine oxide impurity in DMF (80 mL) was treated with sodium azide (2.60 g, 39.94 mmol), stirred for 18 h and partitioned between EtOAc and water. The organic phase was separated and the aqueous phase re-extracted with EtOAc (×2). The combined organic extracts were dried (MgSO4) and concentrated in vacuo to give the title compound as a yellow oil, contaminated with triphenylphosphine oxide; used in the next step without further purification; LC-MS retention time 2.19 min, (M+H)+ 218.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]([N:18]1[CH2:27][CH2:26][C:25]2[C:20](=[CH:21][C:22]([O:28][CH2:29][CH:30]3[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]3)=[CH:23][CH:24]=2)[CH2:19]1)=[N:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].N1C=CC=CC=1.[C:42]1([CH2:48][S:49](Cl)(=[O:51])=[O:50])[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1>O1CCCC1.CN(C)C1C=CN=CC=1>[C:14]([O:13][C:11]([NH:10][C:9]([N:18]1[CH2:27][CH2:26][C:25]2[C:20](=[CH:21][C:22]([O:28][CH2:29][CH:30]3[CH2:35][CH2:34][N:33]([S:49]([CH2:48][C:42]4[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=4)(=[O:51])=[O:50])[CH2:32][CH2:31]3)=[CH:23][CH:24]=2)[CH2:19]1)=[N:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])=[O:12])([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(C)(C)OC(=O)N=C(NC(=O)OC(C)(C)C)N1CCc2ccc(OCC3CCNCC3)cc2C1
Reactant: O=S(=O)(Cl)Cc1ccccc1
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N=C(NC(=O)OC(C)(C)C)N1CCc2ccc(OCC3CCN(S(=O)(=O)Cc4ccccc4)CC3)cc2C1
Temperature: 25 °C
Reaction time: 12 h
Yield: 36.5 %

Procedure:
To a solution of N,N′-di-tert-butoxycarbonyl-7-(piperidin-4-ylmethoxy)-1,2,3,4-tetrahydroisoquinoline-2-carboxamidine (100 mg) in tetrahydrofuran (1.5 ml) were added pyridine (0.02 ml), 4-dimethylaminopyridine (12 mg) and α-toluenesulfonyl chloride (43 mg), and the mixture was stirred at room temperature for 12 hours and then at 50° C. for 6 hours. After completion of the reaction, the mixture was extracted with ethyl acetate and washed successively with water and saturated brine. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated. The obtained residue was purified by silica gel column chromatography (hexane:acetone=3:1) and dried under reduced pressure to give the title compound (48 mg).
Reaction SMILES: [CH3:1][N:2]([CH2:7][C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]([CH3:17])[CH:9]=1)[C:3](=[O:6])[CH:4]=[CH2:5].CN(CC1SC2C=CC=CC=2C=1C)C(=O)C=C.Br[C:36]1[CH:37]=[C:38]([CH2:43][N:44]2[CH2:49][CH2:48][O:47][CH2:46][CH2:45]2)[C:39]([NH2:42])=[N:40][CH:41]=1.BrC1C=NC2NC(=O)C(C)(C)NCC=2C=1>>[NH2:42][C:39]1[N:40]=[CH:41][C:36](/[CH:5]=[CH:4]/[C:3]([N:2]([CH3:1])[CH2:7][C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]([CH3:17])[CH:9]=2)=[O:6])=[CH:37][C:38]=1[CH2:43][N:44]1[CH2:49][CH2:48][O:47][CH2:46][CH2:45]1
Reactant: C=CC(=O)N(C)Cc1cn(C)c2ccccc12
Reactant: Nc1ncc(Br)cc1CN1CCOCC1
Agent: C=CC(=O)N(C)Cc1sc2ccccc2c1C
Agent: CC1(C)NCc2cc(Br)cnc2NC1=O
Product: CN(Cc1cn(C)c2ccccc12)C(=O)/C=C/c1cnc(N)c(CN2CCOCC2)c1
Yield: 38 %

Procedure:
According to the procedure of Example 2(a), except substituting N-methyl-N-(1-methyl-1H-indol-3-ylmethyl)acrylamide for the N-methyl-N-(3-methyl-benzo[b]thiophen-2-ylmethyl)acrylamide, and substituting 5-bromo-3-morpholin-4-ylmethyl-pyridin-2-ylamine for the 7-bromo-3,3-dimethyl-1,3,4,5-tetrahydro-pyrido[2,3-e][1,4]diazepin-2-one, the title compound (510 mg, 38%) was prepared as an off-white powder: 1H NMR (300 MHz, DMSO-d6) δ 8.13 (s, 1H),7.78 (s, 1H), 7.63-6.91 (m, 7H), 6.51 (s, 2H), 4.89-4.72 (m, 2H), 3.76 (s, 3H), 3.57 (br s, 4H), 3.42-3.34 (m, 2H), 3.02-2.90 (m, 3H), 2.33 (br s, 4H); MS (ESI) m/e 420 (M+H)+.
Reaction SMILES: [OH:1][CH2:2][CH:3]([CH2:5][OH:6])[OH:4].[H-].[Na+].[CH2:9](Br)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.CO>C1COCC1>[CH2:2]([O:1][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH:3]([CH2:5][OH:6])[OH:4]
Reactant: BrCc1ccccc1
Reactant: OCC(O)CO
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: OCC(O)COCc1ccccc1
Temperature: 25 °C

Procedure:
As an alternative procedure to a stirred solution of the protected glycerol (6.7 g, 0.05 mole) in dry THF (100 mL) was added NaH (1.8 g, 0.075 mole) portionwise at 0° C. The reaction mixture was refluxed for 1.5 h, and benzyl bromide (10.3 g, 0.06 mole) was added. The mixture was stirred at room temperature. Once the reaction was completed, 2 mL of methanol was added at 0° C. to destroy the excess of NaH. The reaction mixture was extracted with 3×50 mL of ethyl ether, and the combined ether layers dried over sodium sulfate. After solvent removal, the residue of (11.9 g, Y=61%). was combined with 60 mL of 10% acetic acid, then heated (oil bath, 100° C.), until the original emulsion disappeared (about 0.5 h), After concentration, the residue was distilled in vacuo, giving 8.1 g (b.p.116-118° C./50μ) (Y=89%).
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@H:13]([C:15]2[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=2)[OH:14])(=O)=O)=CC=1.[N-:27]=[N+:28]=[N-:29].[Na+]>CN(C=O)C.[Cl-].[Na+].O>[N:27]([CH2:12][C@H:13]([C:15]1[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=1)[OH:14])=[N+:28]=[N-:29]
Reactant: COc1cc([C@H](O)COS(=O)(=O)c2ccc(C)cc2)cc(OC)c1OC
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc([C@H](O)CN=[N+]=[N-])cc(OC)c1OC

Procedure:
A solution/slurry of Example 23C (450 mg; 1.2 mmol) and sodium azide (153 mg; 2.4 mmol) in DMF (5 mL) was heated at 80-90° C. for 2 hours, treated with brine, and extracted with ethyl acetate. The extract was washed with brine (2×), dried (MgSO4), filtered, and concentrated. The concentrate was purified by flash chromatography on silica gel with 30% ethyl acetate/hexane) to provide 223 mg (75%).the desired product as a nearly colorless oil.
Reaction SMILES: [CH:1]1([N:4]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=2)[C:5]2[C:10]3=[N:11][CH:12]=[C:13]([C:14]#[N:15])[N:9]3[N:8]=[C:7](S(C)(=O)=O)[N:6]=2)[CH2:3][CH2:2]1.[NH2:29][C:30]1[C:31]([Cl:63])=[C:32]([N:38]2[CH2:43][CH2:42][C@@H:41]([NH:44][C:45](=[O:51])[O:46][C:47]([CH3:50])([CH3:49])[CH3:48])[C@H:40]([O:52][Si:53]([CH:60]([CH3:62])[CH3:61])([CH:57]([CH3:59])[CH3:58])[CH:54]([CH3:56])[CH3:55])[CH2:39]2)[CH:33]=[C:34]([C:36]#[N:37])[CH:35]=1>>[Cl:63][C:31]1[C:30]([NH:29][C:7]2[N:6]=[C:5]([N:4]([CH:1]3[CH2:3][CH2:2]3)[CH2:20][C:21]3[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=3)[C:10]3=[N:11][CH:12]=[C:13]([C:14]#[N:15])[N:9]3[N:8]=2)=[CH:35][C:34]([C:36]#[N:37])=[CH:33][C:32]=1[N:38]1[CH2:43][CH2:42][C@@H:41]([NH:44][C:45](=[O:51])[O:46][C:47]([CH3:50])([CH3:49])[CH3:48])[C@H:40]([O:52][Si:53]([CH:60]([CH3:62])[CH3:61])([CH:54]([CH3:56])[CH3:55])[CH:57]([CH3:58])[CH3:59])[CH2:39]1
Reactant: COc1ccc(CN(c2nc(S(C)(=O)=O)nn3c(C#N)cnc23)C2CC2)cc1
Reactant: CC(C)[Si](O[C@@H]1CN(c2cc(C#N)cc(N)c2Cl)CC[C@H]1NC(=O)OC(C)(C)C)(C(C)C)C(C)C
Product: COc1ccc(CN(c2nc(Nc3cc(C#N)cc(N4CC[C@@H](NC(=O)OC(C)(C)C)[C@H](O[Si](C(C)C)(C(C)C)C(C)C)C4)c3Cl)nn3c(C#N)cnc23)C2CC2)cc1

Procedure:
tert-butyl ((3R,4R)-1-(2-chloro-5-cyano-3-((7-cyano-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazin-2-yl)amino)phenyl)-3-((triisopropylsilyl)oxy)piperidin-4-yl)carbamate was prepared starting from 4-(cyclopropyl(4-methoxybenzyl)amino)-2-(methylsulfonyl)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (Intermediate 2) and tert-butyl ((3R,4R)-1-(3-amino-2-chloro-5-cyanophenyl)-3-((triisopropylsilyl)oxy)piperidin-4-yl)carbamate using a method analogous to that used to prepare Example 171.
Reaction SMILES: O[CH2:2][CH2:3][CH2:4][S:5][C:6]1[CH:11]=[CH:10][N:9]=[CH:8][CH:7]=1.C(N(CC)CC)C.CS(Cl)(=O)=O.[CH2:24]([NH2:36])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35]>C(Cl)Cl>[CH2:24]([NH:36][CH2:2][CH2:3][CH2:4][S:5][C:6]1[CH:11]=[CH:10][N:9]=[CH:8][CH:7]=1)[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35]
Reactant: OCCCSc1ccncc1
Reactant: CCCCCCCCCCCCN
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCNCCCSc1ccncc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 29.5 %

Procedure:
In 120 ml of methylene chloride was dissolved 5.60 g (33.1 mmol) of 4-(3-hydroxypropylthio)pyridine and 5.53 ml (39.7 mmol) of triethylamine. 3.07 ml (39.7 mmol) of methanesulfonyl chloride was added, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was washed with a saturated aqueous solution of sodium bicarbonate and water and dried, and then the solvent was distilled off. 5.34 g (28.8 mmol) of dodecylamine was added to 7.12.g of the residue, and the mixture was heated at 80° C. for 3 hours. After cooling, the mixture was purified by column chromatography (eluent: chloroform/methanol=25:1) to obtain 2.86 g of the desired compound (yield: 29.5%, yellow oil).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([S:29][CH3:30])[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:25]=[CH:26][C:27]=3[CH3:28])[C:22](O)=[O:23])[C:13]=2[CH2:12][NH:11][C:10]1=[O:31].C(Cl)CCl.C1[CH:37]=[CH:38][C:39]2N(O)N=[N:42][C:40]=2C=1.C1(CN)CC1>C(Cl)Cl>[CH:39]1([CH2:40][NH:42][C:22](=[O:23])[C:21]2[CH:25]=[CH:26][C:27]([CH3:28])=[C:19]([C:18]3[C:13]4[CH2:12][NH:11][C:10](=[O:31])[N:9]([C:3]5[C:2]([F:1])=[CH:7][CH:6]=[CH:5][C:4]=5[F:8])[C:14]=4[N:15]=[C:16]([S:29][CH3:30])[N:17]=3)[CH:20]=2)[CH2:37][CH2:38]1
Reactant: CSc1nc(-c2cc(C(=O)O)ccc2C)c2c(n1)N(c1c(F)cccc1F)C(=O)NC2
Reactant: On1nnc2ccccc21
Agent: NCC1CC1
Solvent: ClCCCl
Solvent: ClCCl
Product: CSc1nc(-c2cc(C(=O)NCC3CC3)ccc2C)c2c(n1)N(c1c(F)cccc1F)C(=O)NC2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 3-[8-(2,6-Difluorophenyl)-2-(methylthio)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methylbenzoic acid (500 mg) in methylenechloride (100 mL) were added EDC (260 mg), HOBt (160 mg) and cyclopropylmethylamine (260 uL). The reaction mixture was stirred at room temperature overnight and concentrated in vacuo. The residue was purified via column chromatography to provide the title compound as a white solid. LC-MS m/z 496 (M+H)+, 2.62 min (ret. time).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]=[CH:7]2.O.O.O.O.O.O.[F:18][C:19]([F:27])([F:26])[C:20]([C:22]([F:25])([F:24])[F:23])=[O:21]>C1(C)C=CC(S(O)(=O)=O)=CC=1>[NH2:1][C:2]1[C:11]([C:20]([OH:21])([C:22]([F:25])([F:24])[F:23])[C:19]([F:27])([F:26])[F:18])=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]=[CH:7]2
Reactant: Nc1cccc2cnccc12
Reactant: O=C(C(F)(F)F)C(F)(F)F
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Product: Nc1c(C(O)(C(F)(F)F)C(F)(F)F)ccc2cnccc12
Temperature: 150 °C
Yield: 21 %

Procedure:
5-Aminoisoquinoline (288 mg, 2.00 mmol) and p-toluenesulfonic acid (5 mg) were combined and treated with hexafluoroacetone hexahydrate (0.29 mL, 462 mg, 2.10 mmol). The mixture was stirred in a sealed pressure tube and heated to 150° C. for 18 hours. The reaction was allowed to cool to room temperature and partitioned between CH2Cl2 (20 mL) and water (10 mL). The organic layer was passed thru Na2SO4 and then filtered through activated charcoal. The charcoal was washed with methanol (3×10 mL) and the filtrate and washings were collected and concentrated under reduced pressure to provide the title compound (130 mg, 30%) as a yellow solid. MS (ESI+) m/z 311 (M+H)+; MS (ESI−) m/z 309 (M−H)−; 1H NMR (DMSO, 300 MHz) δ 6.64 (br s, 2H), 7.30 (d, J 8.7, 1H), 7.40 (d, J 8.7, 1H), 8.09 (d, J 6.1, 1H), 8.49 (d, J 6.1, 1H), 9.14 (s, 1H); 13C NMR (DMSO, 100 MHz) δ 107.02, 110.60, 113.95 (1), 115.46 (1), 122.03, 124.92, 124.92, 125.94, 126.98 (1), 128.17, 142.43 (1), 144.82, 151.85 (1).
Reaction SMILES: [F:1][C:2]([F:36])([F:35])[CH2:3][O:4][C:5]1[N:10]=[C:9]([NH:11][C:12]2[CH:20]=[CH:19][C:15]([C:16]([O-:18])=[O:17])=[CH:14][CH:13]=2)[N:8]=[C:7]([NH:21][C:22]2[CH:34]=[CH:33][C:25]([C:26]([O:28]C(C)(C)C)=[O:27])=[CH:24][CH:23]=2)[N:6]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:36][C:2]([F:1])([F:35])[CH2:3][O:4][C:5]1[N:6]=[C:7]([NH:21][C:22]2[CH:23]=[CH:24][C:25]([C:26]([OH:28])=[O:27])=[CH:33][CH:34]=2)[N:8]=[C:9]([NH:11][C:12]2[CH:20]=[CH:19][C:15]([C:16]([OH:18])=[O:17])=[CH:14][CH:13]=2)[N:10]=1
Reactant: CC(C)(C)OC(=O)c1ccc(Nc2nc(Nc3ccc(C(=O)[O-])cc3)nc(OCC(F)(F)F)n2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)c1ccc(Nc2nc(Nc3ccc(C(=O)O)cc3)nc(OCC(F)(F)F)n2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 22 %

Procedure:
To a solution of crude tert-butyl 4,4′-(6-(2,2,2-trifluoroethoxy)-1,3,5-triazine-2,4-diyl)bis(azanediyl)dibenzoate (562 mg) in CH2Cl2 (10 mL) was added TFA (3 mL). The mixture was stirred at room temperature for 16 hours. All solvents were removed under vacuum. The residue was purified by preparative HPLC to give 4,4′-(6-(2,2,2-trifluoroethoxy)-1,3,5-triazine-2,4-diyl)bis(azanediyl)dibenzoic acid (110 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[C:13]3[CH:14](O)[CH2:15][CH2:16][C:12]=3[N:11]=[C:10]2[CH:18]2[CH2:20][CH2:19]2)=[CH:4][CH:3]=1.[CH2:21]([O:23][C:24]([CH:26]([C:32]([O:34][CH2:35][CH3:36])=[O:33])[C:27]([O:29][CH2:30][CH3:31])=[O:28])=[O:25])[CH3:22].CP(C)C.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1(C)C=CC=CC=1.O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][N:9]2[C:13]3[CH:14]([C:26]([C:32]([O:34][CH2:35][CH3:36])=[O:33])([C:24]([O:23][CH2:21][CH3:22])=[O:25])[C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH2:15][CH2:16][C:12]=3[N:11]=[C:10]2[CH:18]2[CH2:20][CH2:19]2)=[CH:6][CH:7]=1
Reactant: OC1CCc2nc(C3CC3)n(Cc3ccc(Cl)cc3)c21
Reactant: CCOC(=O)C(C(=O)OCC)C(=O)OCC
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: CP(C)C
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CCOC(=O)C(C(=O)OCC)(C(=O)OCC)C1CCc2nc(C3CC3)n(Cc3ccc(Cl)cc3)c21
Temperature: -78 °C
Reaction time: 0.75 h

Procedure:
To a solution of Intermediate 30 (95 mg) and triethylmethanetricarboxylate (0.140 ml) in toluene (1.5 ml) and tetrahydrofuran (1.5 ml), stirred at RT under an inert atmosphere of nitrogen, was added trimethylphosphine, 1M in toluene (0.658 ml). The resulting solution was cooled to −78° C. and diisopropyl azodicarboxylate (0.130 ml) was added dropwise via syringe and the reaction was stirred at −78° C. for 45 mins. The reaction mixture was removed from the cold bath and allowed to warm to RT and stirred under N2 atmosphere overnight. Reaction mixture concentrated in vacuo. The residue was taken up in DCM (20 ml) and washed with water (20 mL). The 2 phases were separated, the organic extract was dried (hydrophobic frit) and concentrated under vacuum. The residue was purified on silica using a cyclohexane:ethyl acetate 0-100% gradient. The desired fractions were combined and concentrated under vacuum to give the title compound (146 mg). LC/MS MH+503, Rt 3.37 min (5 minute run).
Reaction SMILES: [F:1][CH:2]([F:18])[O:3][C:4]1[CH:9]=[C:8]([O:10]CC2C=CC=CC=2)[CH:7]=[CH:6][N:5]=1.C(O)C.[H][H]>[Pd].CCCCCC>[F:18][CH:2]([F:1])[O:3][C:4]1[CH:9]=[C:8]([OH:10])[CH:7]=[CH:6][N:5]=1
Reactant: [H][H]
Reactant: FC(F)Oc1cc(OCc2ccccc2)ccn1
Agent: [Pd]
Solvent: CCO
Solvent: CCCCCC
Product: Oc1ccnc(OC(F)F)c1
Yield: 87.3 %

Procedure:
2-Difluoromethoxy-4-benzyloxypyridine (219.75 g, 0.875 mol), ethanol (500 mL) and palladium on carbon (7.8 g, 5 mol %, 50% by weight water) were shaken on a Parr hydrogenator at 5393 kPa of hydrogen at RT for 2.5 h. The mixture was then filtered through celite and the solvent was evaporated in-vacuo. 2-Difluoromethoxy-4-hydroxypyridine (123 g, 87% yield) was obtained as a white solid after trituration with hexane, mp=88.6° C. -89.8° C. Anal. Calcd. for C6H5NO2F2 : C,44.73; H,3.13; N,8.69 Found: C,44.82; H,3.13; N,8.76.