Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]([O:9]C)=O.[F:11][C:12]([F:17])([F:16])[C:13](N)=[NH:14].FC(F)(F)C(O)=O>CCO>[F:11][C:12]([F:17])([F:16])[C:13]1[NH:14][C:7](=[O:9])[C:3]2[S:4][CH:5]=[CH:6][C:2]=2[N:1]=1
Reactant: N=C(N)C(F)(F)F
Reactant: COC(=O)c1sccc1N
Solvent: O=C(O)C(F)(F)F
Solvent: CCO
Product: O=c1[nH]c(C(F)(F)F)nc2ccsc12
Temperature: 150 °C
Yield: 27.7 %

Procedure:
To a stirring solution of methyl 3-aminothiophene-2-carboxylate (45a, 1.57, 10.0 mmol) in EtOH (10 mL) was added trifluoroacetamidine (2.24 g, 2 eq) and trifluoroacetic acid (1.54 ml, 2 eq). The resulting mixture was heated to 150° C. for 1 hour in microwave reactor. The reaction mixture was cool and filtered to provide 2-(trifluoromethyl)thieno[3,2-d]pyrimidine-4(3H)-one 45b as a solid (0.61 g). 1H NMR (400 MHz, MeOD) δ ppm: 7.49 (d, J=5.29 Hz, 2H), 8.18 (d, J=5.29 Hz, 1H).
Reaction SMILES: Br[CH:2]=[C:3]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[CH2:7][CH2:6][C:5]2[CH:14]=[CH:15][CH:16]=[CH:17][C:4]1=2.[F:18][C:19]([F:34])([F:33])[C:20]1[CH:21]=[C:22](B(O)O)[CH:23]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:25]=1>>[F:18][C:19]([F:33])([F:34])[C:20]1[CH:21]=[C:22]([CH:23]=[C:24]([C:26]([F:27])([F:28])[F:29])[CH:25]=1)[CH:2]=[C:3]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[CH2:7][CH2:6][C:5]2[CH:14]=[CH:15][CH:16]=[CH:17][C:4]1=2
Reactant: OB(O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: BrC=C1c2ccccc2CCc2ccccc21
Product: FC(F)(F)c1cc(C=C2c3ccccc3CCc3ccccc32)cc(C(F)(F)F)c1

Procedure:
Combine 5-bromomethylene-10,11-dihydro-5H-dibenzo[a,d]cycloheptene (0.5 g, 1.75 mmol) and 3,5-bis (trifluoromethyl)phenyl boronic acid (0.449 g, 1.75 mmol) using procedures essentially as described in Example 219, below. Pass through a plug of silica gel equilibrated with hexanes. Concentrate the filtrate to give the title product. Analysis for C24H16F6: Calcd: C, 68.90 H, 3.85. Found: C, 68.64 H, 3.80. HPLC (ISO80-10M)) t=5.64 min (98%).
Reaction SMILES: [C:1]([Si:5]([O:8][CH:9]([CH2:13][CH2:14][CH:15]1[CH:24]([S:25]([C:28]2[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=2)(=[O:27])=[O:26])[C:23]2[C:18](=[C:19]([F:36])[CH:20]=[CH:21][C:22]=2[F:35])[O:17][CH2:16]1)[CH2:10][CH:11]=C)([CH3:7])[CH3:6])([CH3:4])([CH3:3])[CH3:2].[O:37]=[O+][O-].[BH4-].[Na+]>CO.C(Cl)Cl>[C:1]([Si:5]([CH3:6])([CH3:7])[O:8][CH:9]([CH2:13][CH2:14][CH:15]1[CH:24]([S:25]([C:28]2[CH:29]=[CH:30][C:31]([Cl:34])=[CH:32][CH:33]=2)(=[O:27])=[O:26])[C:23]2[C:18](=[C:19]([F:36])[CH:20]=[CH:21][C:22]=2[F:35])[O:17][CH2:16]1)[CH2:10][CH2:11][OH:37])([CH3:3])([CH3:2])[CH3:4]
Reactant: O=[O+][O-]
Reactant: C=CCC(CCC1COc2c(F)ccc(F)c2C1S(=O)(=O)c1ccc(Cl)cc1)O[Si](C)(C)C(C)(C)C
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: CC(C)(C)[Si](C)(C)OC(CCO)CCC1COc2c(F)ccc(F)c2C1S(=O)(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Yield: 50 %

Procedure:
A solution of tert-butyl-(1-{2-[4-(4-chloro-benzenesulfonyl)-5,8-difluoro-chroman-3-yl]-ethyl}-but-3-enyloxy)-dimethyl-silane (1.45 g, 2.60 mmol) in 1:1 MeOH/CH2Cl2 (25 mL) at −78° C. was purged with ozone until the blue color persisted. The reaction mixture was then purged with N2 for 5 min, treated with NaBH4 (300 mg, 7.8 mmol) portionwise and slowly warmed to ambient temperature. Over the next 4.5 h, 2 additional portions of NaBH4 (500 mg each) were added, and the reaction mixture was quenched with saturated aqueous NH4Cl and concentrated in vacuo. The residue was extracted with CH2Cl2 (3×). The combined organic extracts were washed saturated aqueous NaHCO3, dried over MgSO4 and concentrated in vacuo. Flash chromatography (5→40% EtOAc/Hex) afforded the title compound (730 mg, 50%): 1H NMR (CDCl3 400 MHz) δ 7.72 (dd, J=8.8, 1.5 Hz, 2H), 7.52 (dd, J=8.8, 1.5 Hz, 2H), 7.02 (m, 1H), 6.38 (m, 1H), 4.90 (dd, J=11.7, 2.2 Hz, 1H), 4.33 (d, J=12.4 Hz, 1H), 4.28 (s, 1H), 3.85 (m, 1H), 3.73-3.64 (m, 2H), 2.76 (m, 1H), 1.91 (br s, 1H), 1.71-1.22 (m, 6H), 0.80 (s, 4.5H), 0.79 (s, 4.5H), 0.03 (s, 3H), −0.04 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10][CH2:9]2)=[CH:4][C:3]=1[NH:21][S:22]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)(=[O:24])=[O:23].[S:31](Cl)([C:34]1[C:46]2[CH:45]=[CH:44][CH:43]=[C:39]([N:40]([CH3:42])[CH3:41])[C:38]=2[CH:37]=[CH:36][CH:35]=1)(=[O:33])=[O:32]>>[CH3:41][N:40]([CH3:42])[C:39]1[CH:43]=[CH:44][CH:45]=[C:46]2[C:38]=1[CH:37]=[CH:36][CH:35]=[C:34]2[S:31]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:9][CH2:10][NH:11][CH2:12][CH2:13]2)=[CH:4][C:3]=1[NH:21][S:22]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)(=[O:23])=[O:24])(=[O:33])=[O:32]
Reactant: CN(C)c1cccc2c(S(=O)(=O)Cl)cccc12
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(N)c(NS(=O)(=O)c3ccccc3)c2)CC1
Product: CN(C)c1cccc2c(S(=O)(=O)Nc3ccc(N4CCNCC4)cc3NS(=O)(=O)c3ccccc3)cccc12

Procedure:
5-(Dimethylamino)-N-{4-(1-piperazinyl)-2-[(phenylsulfonyl)amino]phenyl}-1-naphthalenesulfonamide was synthesized from N-{2-amino-5-(4-t-butyloxycarbonyl-piperazinyl)-phenyl}benzenesulfonamide and dansylchloride (64 mg, 0.239 mmol) according to general method 3 to give 60 mg of a purple solid. MS (posES-FIA) m/z=Found: 566.3. Calcd: 566.18. 1H NMR δ 8.84 (d, 1H), 8.60 (d, 1H), 8.08 (d, 2H), 7.84-7.47 (m, 7H), 6.70 (d, 1H), 6.56-6.53 (m, 1H), 6.41-6.37 (m, 1H), 3.46 (s, 6H), 3.25-3.12 (m, 8H).
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][NH:5][C:6]([C:8]1[N:16]([CH:17]2[CH2:19][CH2:18]2)[C:15]2[CH:14]=[CH:13][N:12]=[CH:11][C:10]=2[C:9]=1[NH:20][C:21]1[CH:26]=[CH:25][C:24]([S:27][CH3:28])=[CH:23][C:22]=1[F:29])=[O:7].C[C:31]1(C)O[C@@H](CON)C[O:32]1>>[OH:1][C@H:2]([CH2:31][OH:32])[CH2:3][O:4][NH:5][C:6]([C:8]1[N:16]([CH:17]2[CH2:19][CH2:18]2)[C:15]2[CH:14]=[CH:13][N:12]=[CH:11][C:10]=2[C:9]=1[NH:20][C:21]1[CH:26]=[CH:25][C:24]([S:27][CH3:28])=[CH:23][C:22]=1[F:29])=[O:7]
Reactant: CSc1ccc(Nc2c(C(=O)NOCCO)n(C3CC3)c3ccncc23)c(F)c1
Reactant: CC1(C)OC[C@H](CON)O1
Product: CSc1ccc(Nc2c(C(=O)NOC[C@H](O)CO)n(C3CC3)c3ccncc23)c(F)c1

Procedure:
The title compound was prepared in an analogous fashion to 1-cyclopropyl-3-(2-fluoro-4-methylsulfanyl-phenylamino)-1H-pyrrolo[3,2-c]pyridine-2-carboxylic acid (2-hydroxy-ethoxy)-amide, replacing O-(2-vinyloxy-ethyl)-hydroxylamine with O—((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-hydroxylamine. 1H-NMR (500 MHz, DMSO-d6). δ ppm 11.58 (broad s, 1H), 8.51 (d, J=0.83 Hz, 1H), 8.31 (d, J=5.87 Hz, 1H), 7.56 (dd, J=5.88, 1.20 Hz, 1H), 7.36 (s, 1H), 7.18 (dd, J=12.13, 2.50 Hz, 1H), 6.87 (dd, J=8.46, 2.50 Hz, 1H), 6.45 (t, J=8.99 Hz, 1H), 4.94-4.78 (m, 1H), 4.62-4.53 (m, 1H), 3.94 (dd, J=9.91 Hz, 1H), 3.76 (dd, J=9.85, 7.0 Hz, 1H), 3.73-3.66 (m, 1H), 3.56-3.47 (m, 1H), 3.42-3.31 (m, 2H), 2.41 (s, 3H), 1.15-1.08 (m, 2H), 0.87-0.83 (m, 2H); LC-MS (method C): [M+H]+=447.2, RT=0.479 min.
Reaction SMILES: [CH3:1][N:2]([CH3:19])[CH2:3][CH2:4][O:5][C:6]1[C:11]([C:12]([F:15])([F:14])[F:13])=[CH:10][C:9]([N+:16]([O-])=O)=[CH:8][N:7]=1.C(Cl)Cl.CO>CO.[Pd]>[CH3:1][N:2]([CH3:19])[CH2:3][CH2:4][O:5][C:6]1[N:7]=[CH:8][C:9]([NH2:16])=[CH:10][C:11]=1[C:12]([F:15])([F:13])[F:14]
Reactant: CN(C)CCOc1ncc([N+](=O)[O-])cc1C(F)(F)F
Agent: [Pd]
Solvent: ClCCl
Solvent: CO
Product: CN(C)CCOc1ncc(N)cc1C(F)(F)F
Yield: 80.6 %

Procedure:
A solution of N,N-dimethyl-2-((5-nitro-3-(trifluoromethyl)pyridin-2-yl)oxy)ethanamine (500 mg, 1.791 mmol) and Pd/C (191 mg, 1.791 mmol) in MeOH (30 mL) was stirred at 20° C. under H2. After TLC analysis (DCM/MeOH=20/1) showed the starting material had disappeared, the mixture was filtered. The filtrate was concentrated to yield a oil of 6-(2-(dimethylamino)ethoxy)-5-(trifluoromethyl)pyridin-3-amine (360 mg, 1.444 mmol, 81.1% yield): 1H NMR (400 MHz, CD3OD) δ 7.77 (d, J=2.4 Hz, 1H), 7.37 (d, J=3.2 Hz, 1H), 4.43 (t, J=5.6 Hz, 2H), 2.78 (t, J=6.4 Hz, 2H), 2.35 (s, 6H); ES-LCMS m/z 250.1 (M+H).
Reaction SMILES: [NH2:1][C:2]1[C:11]([C:12]#[N:13])=[C:10]([NH:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([N:22]3[CH2:27][CH2:26][N:25]([C:28](=[O:30])[CH3:29])[CH2:24][CH2:23]3)[CH:8]=2)[N:3]=1.[CH3:31][O:32][C:33]1[CH:34]=[C:35]([CH:39]=[CH:40][CH:41]=1)[C:36](Cl)=[O:37]>N1C=CC=CC=1>[CH3:31][O:32][C:33]1[CH:34]=[C:35]([CH:39]=[CH:40][CH:41]=1)[C:36]([NH:1][C:2]1[C:11]([C:12]#[N:13])=[C:10]([NH:14][CH2:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([N:22]3[CH2:23][CH2:24][N:25]([C:28](=[O:30])[CH3:29])[CH2:26][CH2:27]3)[CH:8]=2)[N:3]=1)=[O:37]
Reactant: CC(=O)N1CCN(c2ccc3nc(N)c(C#N)c(NCc4ccccc4)c3c2)CC1
Reactant: COc1cccc(C(=O)Cl)c1
Solvent: c1ccncc1
Product: COc1cccc(C(=O)Nc2nc3ccc(N4CCN(C(C)=O)CC4)cc3c(NCc3ccccc3)c2C#N)c1
Temperature: 0 °C

Procedure:
To the solution of 1.2 g 2-amino-3-cyano-4-benzylamino-6-(4-acetylpiperazin-1-yl)quinoline in 20 ml pyridine, 1.5 g 3-methoxybenzoyl chloride is added and the mixture is heated at reflux temperature for 5 hours. The reaction mixture is poured onto 30 g ice-water and the precipitated solid material is filtered off. After drying 0.45 g of the title compound is obtained (MH+: 535).
Reaction SMILES: [CH3:1][N:2](S(C1C=CC(C)=CC=1)(=O)=O)[N:3]=[C:4](Cl)[C:5]1[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:6]=1[Cl:12].[Cl:24][C:25]1[CH:32]=[CH:31][C:28]([C:29]#[N:30])=[CH:27][C:26]=1[O:33][C:34]1[CH:39]=[CH:38][C:37]([C:40]([F:43])([F:42])[F:41])=[CH:36][N:35]=1.ClC1C=CC=CC=1Cl>C(Cl)(Cl)Cl.[Fe](Cl)(Cl)Cl>[Cl:12][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]([F:11])[C:5]=1[C:4]1[N:30]=[C:29]([C:28]2[CH:31]=[CH:32][C:25]([Cl:24])=[C:26]([O:33][C:34]3[CH:39]=[CH:38][C:37]([C:40]([F:43])([F:41])[F:42])=[CH:36][N:35]=3)[CH:27]=2)[N:2]([CH3:1])[N:3]=1
Reactant: Cc1ccc(S(=O)(=O)N(C)N=C(Cl)c2c(F)cccc2Cl)cc1
Reactant: N#Cc1ccc(Cl)c(Oc2ccc(C(F)(F)F)cn2)c1
Agent: Cl[Fe](Cl)Cl
Solvent: ClC(Cl)Cl
Solvent: Clc1ccccc1Cl
Product: Cn1nc(-c2c(F)cccc2Cl)nc1-c1ccc(Cl)c(Oc2ccc(C(F)(F)F)cn2)c1
Temperature: 140 °C
Reaction time: 0.5 h
Yield: 31.1 %

Procedure:
A mixture of N-methyl-N-(p-toluenesulfonyl)-2-chloro-6-fluorobenzohydrazonoyl chloride (1.00 g), 4-chloro-3-(5-trifluoromethylpyridine-2-yloxy)benzonitrile (0.90 g), anhydrous iron (III) chloride (0.50 g) and o-dichlorobenzene (5 ml) is stirred at an oil bath temperature of 140° C. for 30 minutes. After cooling, it is dissolved in chloroform (100 ml) and washed with dilute hydrochloric acid, dilute aqueous solution of sodium hydroxide and saline. Then, it is dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The concentrate is purified by silica gel column chromatography using mixed solvent of hexane-ethyl acetate as eluent to give 0.40 g of desired compound.
Reaction SMILES: [CH:1]1[C:14]2[C:5](=[CH:6][C:7]3[C:12]([C:13]=2[NH:15][C@H:16]([C:18]([OH:20])=[O:19])[CH3:17])=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH:4]=[CH:3][CH:2]=1.S(Cl)(Cl)=O.[CH3:25]O>>[CH3:25][O:19][C:18](=[O:20])[C@H:16]([CH3:17])[NH:15][C:13]1[C:12]2[C:7]([CH:6]=[C:5]3[C:14]=1[CH:1]=[CH:2][CH:3]=[CH:4]3)=[CH:8][CH:9]=[CH:10][CH:11]=2
Reactant: C[C@H](Nc1c2ccccc2cc2ccccc12)C(=O)O
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)[C@H](C)Nc1c2ccccc2cc2ccccc12
Temperature: 0 °C
Yield: 68 %

Procedure:
0.7 g of 9-anthryl alanine was mixed with 20 ml of anhydrous methanol, cooled to 0° C. 1.5 eq of thionyl chloride was added drop-wise, refluxing overnight. The solvent was removed on a rotary evaporator. The crude product was dissolved in ethyl acetate. The organic phase was washed by 5% of sodium bicarbonate, distilled water, and dried by anhydrous sodium carbonate. The solvent was removed on a rotary evaporator. The product was purified by column chromatography (hexane: ethyl acetate=1:2.5). 0.5 g of oil-like yellow solid was obtained. The yield was 68%. The product decomposes at 180° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH2:13][CH2:14][Cl:15])=[CH:6][C:5]=1[N+:16]([O-])=O.[Cl-].[NH4+].O>[Fe].CO>[CH3:1][O:2][C:3](=[O:19])[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH2:13][CH2:14][Cl:15])=[CH:6][C:5]=1[NH2:16]
Reactant: COC(=O)c1cc(OC)c(OCCCl)cc1[N+](=O)[O-]
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Solvent: O
Product: COC(=O)c1cc(OC)c(OCCCl)cc1N

Procedure:
A mixture of 68.2 g (235.4 mmol) of 4-(2-chloro-ethoxy)-5-methoxy-2-nitro-benzoic acid methyl ester and 52.6 g (941.8 mmol) of iron was mechanically stirred at reflux in a mixture containing 62.9 g ammonium chloride, 393 ml water, and 1021 ml methanol for 15 hr. The mixture was concentrated and mixed with ethyl acetate. The organic solution was washed with water and saturated sodium bicarbonate. The solution was dried over magnesium sulfate and filtered through a short column of silica gel. The solution was concentrated to 200 ml and diluted with 250 of hot hexane. After standing 47.7 g of the title compound was obtained as a solid: mass spectrum (electrospray, m/e) M+H 259.8.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([S:34]([CH3:37])(=[O:36])=[O:35])[CH:29]=2)[CH:5]=[CH:6][C:7]=1[N:8]1[CH:12]=[C:11]([C:13]([NH:15][C:16]([CH3:20])([CH3:19])[CH2:17]O)=O)[N:10]=[C:9]1[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[Cl:27].C1C=CC=CC=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:45]>CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([S:34]([CH3:37])(=[O:36])=[O:35])[CH:29]=2)[CH:5]=[CH:6][C:7]=1[N:8]1[CH:12]=[C:11]([C:13]2[S:45][CH2:17][C:16]([CH3:20])([CH3:19])[N:15]=2)[N:10]=[C:9]1[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[Cl:27]
Reactant: CC(C)(CO)NC(=O)c1cn(-c2ccc(-c3cccc(S(C)(=O)=O)c3)cc2Cl)c(-c2ccccc2Cl)n1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Solvent: CCOC(C)=O
Solvent: c1ccccc1
Product: CC1(C)CSC(c2cn(-c3ccc(-c4cccc(S(C)(=O)=O)c4)cc3Cl)c(-c3ccccc3Cl)n2)=N1
Yield: 18.9 %

Procedure:
To a N2 purged 50 mL round bottom flask attached with condenser was added 1-(3-chloro-3′-(methylsulfonyl)biphenyl-4-yl)-2-(2-chlorophenyl)-N-(1-hydroxy-2-methyl propan-2-yl)-1H-imidazole-4-carboxamide (361 mg, 646 μmol), anhydrous benzene (20 mL) and P2S5 (720 mg, 3.24 mmol). The reaction solution was stirred at reflux for 1.5 hr. The reaction solution was diluted with EtOAc (100 mL) and filtered through a Buchner funnel to remove excess P2S5. The filtrate was washed with aq. 0.1 N NaOH (60 mL) and H2O (100 mL). The partitioned organic phase was dried over Na2SO4, filtered, concentrated in vacuo, and chromatographed through a 12 g SiO2 column using a gradient of 100% hexane to 95% EtOAc to afford 68 mg (19% yield) of title compound. MS (ESI) 556.3, 558.3 [M+H]+; 1H NMR (400 MHz, CDCl3) δ 8.10 (t, J=2.0 Hz, 1H), 7.97 (d, J=8.0 Hz, 1H), 7.83 (d, J=8.0 Hz, 1H), 7.79 (br s, 1H), 7.66-7.70 (m, 2H), 7.55 (d, J=7.2 Hz, 1H), 7.43 (dd, J1 8.5=Hz, J2=2.0 Hz, 1H), 7.27-7.33 (m, 4H), 3.22 (s, 2H), 3.10 (s, 3H), 1.51 (s, 6H).
Reaction SMILES: [Si:1]([O:8][CH2:9][C@@H:10]([CH:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)[OH:11])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:25][S:26](Cl)(=[O:28])=[O:27].C([O-])(O)=O.[Na+]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:25][S:26]([O:11][C@H:10]([CH:12]1[CH2:13][CH2:14][O:15][CH2:16][CH2:17]1)[CH2:9][O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])(=[O:28])=[O:27]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)[Si](C)(C)OC[C@H](O)C1CCOCC1
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](C)(C)OC[C@H](OS(C)(=O)=O)C1CCOCC1
Temperature: 25 °C
Yield: 99.8 %

Procedure:
A solution of (1R)-2-{[tert-butyl(dimethyl)silyl]oxy}-1-tetrahydro-2H-pyran-4-ylethanol (3.29 g, 12.7 mmol) in 60 mL of CH2Cl2 was cooled to 0° C. under N2. Triethylamine (3.58 mL, 25.7 mmol) was then added followed by methanesulfonyl chloride (2.57 g, 17.0 mmol) and DMAP (61 mg, 0.50 mmol) and the reaction mixture was stirred and allowed to warm to ambient temperature overnight. The reaction mixture was treated with saturated aqueous NaHCO3 solution and the layers were separated. The organic portion was washed successively with aqueous 3.5% NaH2PO4 solution (2×), H2O and brine, dried over Na2SO4, filtered and concentrated under reduced pressure to give 4.29 g of (1R)-2-{[tert-butyl(dimethyl)silyl]oxy}-1-tetrahydro-2H-pyran-4-ylethyl methanesulfonate as a colorless oil.
Reaction SMILES: [C:1]([O:5][C:6](=[O:28])[NH:7][CH:8]([CH2:18][O:19][CH2:20][CH:21]1[CH2:25][O:24][C:23]([CH3:27])([CH3:26])[O:22]1)[CH2:9][O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH3:31]I>CN(C=O)C>[C:1]([O:5][C:6](=[O:28])[N:7]([CH:8]([CH2:18][O:19][CH2:20][CH:21]1[CH2:25][O:24][C:23]([CH3:27])([CH3:26])[O:22]1)[CH2:9][O:10][CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[CH3:31])([CH3:4])([CH3:2])[CH3:3]
Reactant: CI
Reactant: CC(C)(C)OC(=O)NC(COCc1ccccc1)COCC1COC(C)(C)O1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C(=O)OC(C)(C)C)C(COCc1ccccc1)COCC1COC(C)(C)O1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 96 %

Procedure:
To a solution of [2-Benzyloxy-1-(2,2-dimethyl-[1,3]dioxolan-4-ylmethoxymethyl)-ethyl]-carbamic acid tert-butyl ester (1.26 g, 3.18 mmol) in DMF (10 mL) was added sodium hydride (60%, 0.19 g, 4.78 mmol) at 0° C. in one portion. The reaction was stirred at 0° C. for 0.5 h then MeI (1.36 g, 9.56 mmol) was added. The reaction mixture was then stirred at 0° C. for 3 h at which time the LC-MS showed the reaction was complete. The reaction was quenched with saturated aq. NH4Cl solution and extracted with EtOAc (2×100 mL). The organic layer was then washed with water, brine and dried over Na2SO4. The organic layers were concentrated to give [2-benzyloxy-1-(2,2-dimethyl-[1,3]dioxolan-4-ylmethoxymethyl)-ethyl]-methyl-carbamic acid tert-butyl ester (1.25 g, 96%). LRMS (M−Boc+H+) m/z 310.1.
Reaction SMILES: [CH2:1]([N:8]1[CH2:18][CH2:17][C:11]2[N:12]=[CH:13][N:14]=[C:15](Cl)[C:10]=2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C(#N)C>[CH2:1]([N:8]1[CH2:18][CH2:17][C:11]2[N:12]=[CH:13][N:14]=[C:15]([NH:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:10]=2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Clc1ncnc2c1CN(Cc1ccccc1)CC2
Reactant: Nc1ccccc1
Solvent: CC#N
Product: c1ccc(CN2CCc3ncnc(Nc4ccccc4)c3C2)cc1
Temperature: 180 °C

Procedure:
6-Benzyl-4-chloro-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine (Intermediate 2, 1.0 g, 3.86 mmol) was dissolved in anhydrous acetonitrile (3 mL) and aniline was added (0.39 mL, 4.24 mmol). The mixture was heated at 180° C. for 600 s in a microwave (Emrys Optimizer model, Personal Chemistry). The solvents were removed under vacuum to give the desired product as a beige powder (1.5 g, quant.). The crude product was used as such for the subsequent step.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[C:9]([F:10])=[CH:8][C:7]([N+:11]([O-:13])=[O:12])=[CH:6][C:5]=1[OH:14].I[CH3:16]>CN(C=O)C.C1COCC1>[F:10][C:9]1[CH:8]=[C:7]([N+:11]([O-:13])=[O:12])[CH:6]=[C:5]([O:14][CH3:16])[C:4]=1[F:3]
Reactant: O=[N+]([O-])c1cc(O)c(F)c(F)c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COc1cc([N+](=O)[O-])cc(F)c1F
Temperature: 80 °C
Reaction time: 0.17 h
Yield: 49.1 %

Procedure:
Step M (4): Sodium hydride (120 mg, 5 mmol) was added to a solution of 2,3-difluoro-5-nitrophenol (250 mg, 1.4 mmol) in DMF/THF (4 mL/4 mL). After 10 min, iodomethane (0.2 mL, 5 mmol) was added. The mixture was heated at 80° C. for 2 h. The reaction mixture was quenched with 1 N HCl. The mixture was diluted with water and extracted with EtOAc. The organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo to afford 1,2-difluoro-3-methoxy-5-nitrobenzene (130 mg, 48% yield).
Reaction SMILES: [C:1]([CH2:4][N:5]1[C:10]([CH3:11])=[CH:9][N:8]=[C:7]([NH:12][NH2:13])[C:6]1=[O:14])([OH:3])=[O:2].C([O-])(O)=O.[Na+].[CH2:20]([O:27][C:28](Cl)=[O:29])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>O.O1CCOCC1>[CH2:20]([O:27][C:28]([NH:13][NH:12][C:7]1[C:6](=[O:14])[N:5]([CH2:4][C:1]([OH:3])=[O:2])[C:10]([CH3:11])=[CH:9][N:8]=1)=[O:29])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: Cc1cnc(NN)c(=O)n1CC(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: Cc1cnc(NNC(=O)OCc2ccccc2)c(=O)n1CC(=O)O
Temperature: 25 °C
Reaction time: 4 h
Yield: 88.5 %

Procedure:
To a solution of the compound of Example 5 (Step G) (5.0 g, 0.025 mol) and NaHCO3 (9.4 g, 0.112 mol) in water (180 mL), was added drop-wise a solution of benzylchloroformate (6.0 mL, 0.042 mol) in dioxane (300 mL). The resulting mixture was stirred at room temperature for 4 hours, diluted with water (200 mL), and washed with ether (200 mL). The aqueous phase was acidified with aqueous 2M KHSO4 and extracted with EtOAc (3×300 mL). The combined organic phases were washed with brine (400 mL), dried (Na2SO4), and concentrated in vacuo. The crude mixture was purified by flash chromatography on silica gel to afford the title compound (7.35 g, 90%) as a pale brown solid. 1H NMR (DMSO-d4) δ 2.15 (s, 3H), 4.3 (br s, 1H), 4.73 (s, 2H), 5.12 (s, 2H), 6.76 (s, 1H), 7.20-7.50 (m, 5H), 9.7 (br s, 1H), 10.0 (br s, 1H). HPLC Rt 8.10 minutes (water/ACN/TFA, 5 to 75%, 0.1% TFA, 20 minutes).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([F:11])[C:8]([N:12]2[C:17](=[O:18])[CH:16]=[C:15]([C:19]([F:25])([F:24])[C:20]([F:23])([F:22])[F:21])[N:14]([CH3:26])[C:13]2=[O:27])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[O:28]1[CH2:32][CH2:31][CH:30](O)[CH2:29]1>>[Cl:1][C:2]1[CH:10]=[C:9]([F:11])[C:8]([N:12]2[C:17](=[O:18])[CH:16]=[C:15]([C:19]([F:24])([F:25])[C:20]([F:23])([F:21])[F:22])[N:14]([CH3:26])[C:13]2=[O:27])=[CH:7][C:3]=1[C:4]([O:6][CH:30]1[CH2:31][CH2:32][O:28][CH2:29]1)=[O:5]
Reactant: OC1CCOC1
Reactant: Cn1c(C(F)(F)C(F)(F)F)cc(=O)n(-c2cc(C(=O)O)c(Cl)cc2F)c1=O
Product: Cn1c(C(F)(F)C(F)(F)F)cc(=O)n(-c2cc(C(=O)OC3CCOC3)c(Cl)cc2F)c1=O

Procedure:
In an analogous manner, starting from 2-chloro-5-[3,6-dihydro-2,6-dioxo-3-methyl-4-pentafluoroethyl-1(2H)-pyrimidinyl]-4-fluorobenzoic acid via its acid chloride and tetrahydrofuran-3-ol there is obtained 3-tetrahydrofuryl 2-chloro-5-[3,6-dihydro-2,6-dioxo-3-methyl-4-pentafluoroethyl-1(2H)-pyrimidinyl]-4-fluorobenzoate, 1H-NMR (D6 -DMSO, 400 MHz): 2.00-2.09 (m, 1H), 2.20-2.32 (m,1H), 3.43 (s,3H), 3.74-3.92 (m,4H), 5.48-5.56 (m,1H), 6.50 (s,1H), 7.89 (d,1H), 8.08 (d,1H);
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][N:10]=1)[C:5]([OH:7])=[O:6].CO.Cl.[CH2:14](N=C=NCCCN(C)C)C>ClCCl>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][N:10]=1)[C:5]([O:7][CH3:14])=[O:6]
Reactant: CCN=C=NCCCN(C)C
Reactant: O=C(O)c1ccnc(Br)c1
Agent: Cl
Solvent: ClCCl
Solvent: CO
Product: COC(=O)c1ccnc(Br)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.4 %

Procedure:
To an ice cooled solution of 2-bromoisonicotinic acid (73 g, 0.361 mol) in dichloromethane (500 mL) and methanol (35 g, 1.08 mol) was added 1-ethyl-3-[3-(dimethylamino)propyl]carbodiimide hydrochloride (67 g, 0.434 mol) by portions. The mixture was stirred at ambient temperature overnight. Then 120 g silica gel was added and the solvent evaporated. The residue was purified by flash chromatography, eluting with 5% ethyl acetate in petroleum ether to afford 58 g (75%) of methyl 2-bromoisonicotinate as a white solid.
Reaction SMILES: [C:1]1([C:7]#[C:8][C:9]2[CH:10]=[CH:11][C:12]([CH2:15]O)=[N:13][CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:17][C:18]1([CH3:24])[NH:22][C:21](=[O:23])[CH2:20][CH2:19]1>>[CH3:17][C:18]1([CH3:24])[N:22]([CH2:15][C:12]2[CH:11]=[CH:10][C:9]([C:8]#[C:7][C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[CH:14][N:13]=2)[C:21](=[O:23])[CH2:20][CH2:19]1
Reactant: OCc1ccc(C#Cc2ccccc2)cn1
Reactant: CC1(C)CCC(=O)N1
Product: CC1(C)CCC(=O)N1Cc1ccc(C#Cc2ccccc2)cn1

Procedure:
The title compound, light yellow oil, MS: m/e=305.2 (M+H+), can be prepared in accordance with the general method of example 31, step 2 from (5-phenylethynyl-pyridin-2-yl)-methanol (example 31, step 1) and 5,5-dimethyl-pyrrolidin-2-one.