Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O)(=O)C.[NH2:5][C:6]1[C:7](=[O:20])[N:8]([CH2:16][CH2:17][CH2:18][CH3:19])[C:9]2[CH2:10][CH2:11][CH2:12][CH2:13][C:14]=2[CH:15]=1.[CH2:21]([N:28]=[C:29]=[O:30])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.Cl>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH2:21]([NH:28][C:29]([NH:5][C:6]1[C:7](=[O:20])[N:8]([CH2:16][CH2:17][CH2:18][CH3:19])[C:9]2[CH2:10][CH2:11][CH2:12][CH2:13][C:14]=2[CH:15]=1)=[O:30])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=C=NCc1ccccc1
Reactant: CCCCn1c2c(cc(N)c1=O)CCCC2
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CC(=O)O
Solvent: ClCCl
Product: CCCCn1c2c(cc(NC(=O)NCc3ccccc3)c1=O)CCCC2
Temperature: 25 °C
Reaction time: 4 h
Yield: 78.6 %

Procedure:
3-Amino-1-butyl-5,6,7,8-tetrahydro-1H-quinolin-2-one acetic acid salt (6-001-01) (5 mg, 0.018 mmol) was dissolved in methylene chloride (1 mL), and to the reaction mixture were added benzylisocyanate (2.5 μL, 0.02 mmol) and 4-dimethylaminopyridine (2.4 mg, 0.02 mmol), and the reaction mixture was stirred at room temperature for 4 h. To the reaction mixture was added diluted hydrochloric acid (0.1 mol/L, 3 mL), and the reaction mixture was extracted with ethyl acetate (10 mL), washed with brine (3 mL), dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (toluene/ethyl acetate) to give 1-benzyl-3-(1-butyl-2-oxo-1,2,5,6,7,8-hexahydroquinolin-3-yl)urea (6-005) (5.0 mg, 79%) as a white crystal.
Reaction SMILES: C(N(CC)CC)C.[Cl:8][C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[CH:16]([OH:31])[C:17]([C:25]1[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=1)([OH:24])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23].[CH3:32][S:33](Cl)(=[O:35])=[O:34]>C(Cl)Cl>[Cl:8][C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[CH:16]([O:31][S:33]([CH3:32])(=[O:35])=[O:34])[C:17]([C:25]1[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=1)([OH:24])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: CCCCCCC(O)(c1cccnc1)C(O)c1ccc(Cl)cc1Cl
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCCC(O)(c1cccnc1)C(OS(C)(=O)=O)c1ccc(Cl)cc1Cl
Yield: 50.6 %

Procedure:
23.6 ml (177 mmol) of triethylamine were added dropwise to a mixture of 8.5 g (23 mmol) of 1-(2,4-dichlorophenyl)-2-(pyrid-3-yl)-octane-1,2-diol, 2.5 ml (32 mmol) of methanesulfonyl chloride and 100 ml of methylene chloride at about 20° C. Thereafter, the mixture was washed with 30 ml of saturated sodium bicarbonate solution and 30 ml of water and was worked up in a conventional manner to obtain the product. The crude product was purified by chromatography. Yield: 50.6%.
Reaction SMILES: [C:1]([CH2:3][C:4]([NH2:6])=[S:5])#[N:2].O=[C:8]([CH2:14][C:15](=O)[CH3:16])[C:9]([O:11][CH2:12][CH3:13])=[O:10].C(N(CC)CC)C>CCO>[CH2:12]([O:11][C:9](=[O:10])[C:8]1[CH:14]=[C:15]([CH3:16])[N:6]=[C:4]([SH:5])[C:3]=1[C:1]#[N:2])[CH3:13]
Reactant: N#CCC(N)=S
Reactant: CCOC(=O)C(=O)CC(C)=O
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cc(C)nc(S)c1C#N
Reaction time: 8 h
Yield: 63.8 %

Procedure:
To a stirred solution of 2-cyanothioacetamide (3.52 g, 35 mmol) and ethyl 2,4-dioxovalerate (5.0 g, 32 mmol) in anhydrous EtOH (75 mL) at room temperature was added triethylamine (0.5 mL) and the reaction was stirred overnight. Filtration and washing of the precipitates with EtOH gave 3-cyano-2-mercapto-6-methyl-isonicotinic acid ethyl ester as a yellow solid (4.54 g, 64.5%). A mixture of this ester (3.54 g, 16 mmol), bromoacetamide (2.15 g, 16 mmol) and sodium ethoxide (2.18 g, 32 mmol) in MeOH was heated at reflux overnight. It was then allowed to cool to room temperature. Filtration and washing of the precipitates with EtOH provided 3-amino-2-carbamoyl-6-methyl-thieno[2,3-b]pyridine-4-carboxylic acid ethyl ester as a solid (0.94 g, 21.1%).
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[Cl:13][C:14]1[CH:42]=[CH:41][C:17]([CH2:18][C:19]2[N:20]=[C:21]([O:37][CH2:38][CH2:39][CH3:40])[C:22]3[N:27]=[C:26]([C:28]4[CH:33]=[C:32]([CH3:34])[C:31]([OH:35])=[C:30]([CH3:36])[CH:29]=4)[O:25][C:23]=3[N:24]=2)=[CH:16][CH:15]=1.[CH3:43][C:44]1([CH3:51])[O:48][CH:47]([CH2:49]O)[CH2:46][O:45]1.C(N(CC)CC)C>O1CCCC1>[Cl:13][C:14]1[CH:42]=[CH:41][C:17]([CH2:18][C:19]2[N:20]=[C:21]([O:37][CH2:38][CH2:39][CH3:40])[C:22]3[N:27]=[C:26]([C:28]4[CH:29]=[C:30]([CH3:36])[C:31]([O:35][CH2:49][CH:47]5[CH2:46][O:45][C:44]([CH3:51])([CH3:43])[O:48]5)=[C:32]([CH3:34])[CH:33]=4)[O:25][C:23]=3[N:24]=2)=[CH:16][CH:15]=1
Reactant: CCCOc1nc(Cc2ccc(Cl)cc2)nc2oc(-c3cc(C)c(O)c(C)c3)nc12
Reactant: CC1(C)OCC(CO)O1
Agent: CCOC(=O)N=NC(=O)OCC
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCOc1nc(Cc2ccc(Cl)cc2)nc2oc(-c3cc(C)c(OCC4COC(C)(C)O4)c(C)c3)nc12
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A suspension of 0.736 mmol of polystyrene-bound triphenylphosphine (Argonaut) and 128 mg of diethyl azodicarboxylate in 10 ml of tetrahydrofuran was stirred for 15 min at 0° C. Then 260 mg of 4-[5-(4-chloro-benzyl)-7-propoxy-oxazolo[5,4-d]pyrimidin-2-yl]-2,6-dimethyl-phenol, 81 mg of (2,2-dimethyl-[1,3]dioxolan-4-yl)-methanol and 85 μl of triethylamine were added. The reaction mixture was stirred at room temperature for 3 h. Then another 81 mg of (2,2-dimethyl-[1,3]dioxolan-4-yl)-methanol, 0.736 mmol of polystyrene-bound triphenylphosphine and 128 mg of diethyl azodicarboxylate were added and the reaction mixture was stirred for 18 h. The polymer was filtered off and washed thoroughly with tetrahydrofuran. The solvent was removed in vacuo and the title compound isolated by silica gel chromatography (method SC1) and then by preparative HPLC (method HPLC2).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH:5]=[CH:4][N:3]=1.C([Li])(C)(C)C.CCCCC.CN([CH:29]=[O:30])C>C1COCC1>[Cl:1][C:2]1[C:7]([CH:29]=[O:30])=[C:6]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:12])([CH3:14])[CH3:13])[CH:5]=[CH:4][N:3]=1
Reactant: CN(C)C=O
Reactant: CC(C)(C)OC(=O)Nc1ccnc(Cl)c1
Agent: [Li]C(C)(C)C
Solvent: CCCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1ccnc(Cl)c1C=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of tert-butyl (2-chloropyridin-4-yl)carbamate (1.14 g, 5 mmol) in dry THF (20 mL) was cooled to −70° C. under an inert atmosphere and 1.7 M t-butyl lithium/pentane (8 mL, 13.5 mmol) was slowly added. The reaction was stirred for two hours and then dry DMF (1.2 mL, 15.5 mmol) was added. The reaction was allowed to slowly warm to room temperature over a three hour period. The reaction mixture was quenched with 3 N HCl (12 mL) and diluted with diethyl ether. The ether layer was washed with aqueous NaHCO3, dried (over Na2SO4), filtered and evaporated. The residue was triturated with cold diethyl ether to give pure t-butyl (2-chloro-3-formylpyridin-4-yl)carbamate. The mother liquors were chromatographed on silica gel eluting with 15-20% ethyl acetate/hexane to give additional product. 1H-NMR (500 MHz, CDCl3): δ 11.0 (1H, br s), 10.52 (1H, s), 8.38 (1H, d, J. 6 Hz), 8.31 (1H, d, J. 6 Hz), 1.54 (9H, s); m/e (m+1): 257.2.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]1[CH2:10][C:11]([OH:13])=[O:12].S(Cl)(Cl)=O.[CH3:18]O>>[CH2:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH2:1][CH:2]1[CH2:10][C:11]([O:13][CH3:18])=[O:12]
Reactant: CO
Reactant: O=C(O)CC1Cc2ccccc2C1
Solvent: O=S(Cl)Cl
Product: COC(=O)CC1Cc2ccccc2C1
Yield: 100 %

Procedure:
Under nitrogen atmosphere, 2-(2,3-dihydro-1H-inden-2-yl)acetic acid (Lanc, 19.6 g, 111 mmol) was dissolved in methanol (100 mL) and cooled in an ice bath. Thionyl chloride (9.7 mL, 133 mmol) was slowly added dropwise thereto under stirring. After completing the dropwise addition, the ice bath was removed and the reaction solution was additionally stirred for 30 minutes. Upon the completion of the reaction, the reaction solution was added in small portions to ice-cold sodium bicarbonate solution under stirring. The reaction mixture was extracted twice with ethyl acetate, and the obtained organic layer was washed once with water, dried over anhydrous magnesium sulfate, and the reaction solution was concentrated to obtain the target compound (21.2 g, Yield 100%).
Reaction SMILES: [NH2:1][C:2]1[C:3]([OH:14])=[C:4]([S:8]([N:11]([CH3:13])[CH3:12])(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.[CH2:15]([O:17][C:18]1[C:19](=O)[C:20](=[O:25])[C:21]=1[O:22]CC)C>CO>[OH:14][C:3]1[C:2]([NH:1][C:19]2[C:20](=[O:25])[C:21](=[O:22])[C:18]=2[O:17][CH3:15])=[CH:7][CH:6]=[CH:5][C:4]=1[S:8]([N:11]([CH3:12])[CH3:13])(=[O:10])=[O:9]
Reactant: CCOc1c(OCC)c(=O)c1=O
Reactant: CN(C)S(=O)(=O)c1cccc(N)c1O
Solvent: CO
Product: COc1c(Nc2cccc(S(=O)(=O)N(C)C)c2O)c(=O)c1=O
Temperature: 25 °C
Reaction time: 96 h
Yield: 64.3 %

Procedure:
A mixture of 0.94 g (4.10 mmol) of 3-amino-2-hydroxy-N,N-dimethylbenzenesulfonamide and 2.47 g (17.40 mmol) of 3,4-diethoxycyclobut-3-ene-1,2-dione in 20 ml of methanol was stirred at ambient temperature for 4 days. The reaction medium was concentrated. The residue (3.29 g) was chromatographed on silica gel (200 g prepacked column, 100 ml/min, eluent heptane/ethyl acetate, from 50% to 85% of ethyl acetate). 0.86 g of product was obtained in the form of a yellow solid. Yield=64%.
Reaction SMILES: FC1C=C(C=CC=1C1C(C2C=CN=CC=2)=CN(C)N=1)OCC1C=CC2C(=CC=CC=2)N=1.[F:32][C:33]1[CH:34]=[C:35]([OH:55])[CH:36]=[CH:37][C:38]=1[C:39]1[C:43]([C:44]2[CH:49]=[CH:48][N:47]=[CH:46][CH:45]=2)=[CH:42][N:41]([CH2:50][C:51]([F:54])([F:53])[F:52])[N:40]=1.Cl[CH2:57][C:58]1[CH:67]=[N:66][C:65]2[C:60](=[CH:61][CH:62]=[CH:63][CH:64]=2)[N:59]=1>CC(C)=O>[F:32][C:33]1[CH:34]=[C:35]([CH:36]=[CH:37][C:38]=1[C:39]1[C:43]([C:44]2[CH:49]=[CH:48][N:47]=[CH:46][CH:45]=2)=[CH:42][N:41]([CH2:50][C:51]([F:52])([F:53])[F:54])[N:40]=1)[O:55][CH2:57][C:58]1[CH:67]=[N:66][C:65]2[C:60](=[CH:61][CH:62]=[CH:63][CH:64]=2)[N:59]=1
Reactant: ClCc1cnc2ccccc2n1
Reactant: Oc1ccc(-c2nn(CC(F)(F)F)cc2-c2ccncc2)c(F)c1
Agent: Cn1cc(-c2ccncc2)c(-c2ccc(OCc3ccc4ccccc4n3)cc2F)n1
Solvent: CC(C)=O
Product: Fc1cc(OCc2cnc3ccccc3n2)ccc1-c1nn(CC(F)(F)F)cc1-c1ccncc1

Procedure:
Following the procedure for the preparation of 2-[3-Fluoro4-(1-methyl4-pyridin-4-yl-1H-pyrazol-3-yl)-phenoxymethyl]-quinoline but substituting 3-Fluoro4-[4-pyridin4-yl-1-(2,2,2-trifluoro-ethyl)-1H-pyrazol-3-yl]-phenol, 2-Chloromethyl-quinoxaline and acetone as the solvent provided the title compound. 1H NMR (400 MHz, CDCl3) δ 9.09 (s, 1 H), 8.46 (m, 2H), 8.15 (m, 1H), 8.09 (m, 1 H), 7.81 (m, 3H), 7.43 (t, J=8.7Hz, 1H), 7.12 (d, J=6.2 Hz, 2H), 6.93 (dd, J=7.9, 2.0 Hz, 1 H), 6.81 (dd, J=11.6, 2.5 Hz, 1 H), 5.43 (s, 2H), 4.80 (q, J=8.3 Hz, 2H); MS: (M+H m/z=480.1).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][CH:6]=[CH:7][CH:8]=1)#[N:2].C1C=C([O:15]O)C(C(O)=O)=C(C(O)=O)C=1>>[C:1]([C:3]1[CH:4]=[N+:5]([O-:15])[CH:6]=[CH:7][CH:8]=1)#[N:2]
Reactant: N#Cc1cccnc1
Reactant: O=C(O)c1cccc(OO)c1C(=O)O
Product: N#Cc1ccc[n+]([O-])c1

Procedure:
Other methods known to one skilled in the art are also useful in the preparation of certain compounds within the scope of the present invention. For example, in a method to prepare 2,4-diamino-5-chloro-6-substituted-5-deazapteridine derivatives, 3-cyanopyridine is oxidized with monoperoxyphthalic acid, magnesium salt, hexahydrate, affording 3-cyanopyridine N-oxide. The oxide is in turn nitrated with potassium nitrate and fuming sulfuric acid, yielding 4-nitro-3-cyanopyridine N-oxide. The nitro compound is then chlorinated with phosphorous oxychloride, giving the corresponding 2,4-dichloro-3-cyanopyridine. The dichloro compound is then cyclized with guanidine carbonate in N,N-dimethylformamide, yielding the corresponding 2,4-diamino-5-chloro-5-deazapteridine. The so-prepared 5-deazapteridine is in turn brominated using N-bromosuccinimide in N,N-dimethylformamide, affording 2,4-diamino-6-bromo-5-chloro-5-deazapteridine. This compound is then reacted with an appropriate boronic acid, for example, 3,5-di(trifluoromethyl)phenylboronic acid, yielding the targeted 2,4-diamino-5-chloro-6-substituted-5-deazapteridines, for example, 2,4-diamino-5-chloro-6-[3,5-di(trifluoromethyl)phenyl]-5-deazapteridine. Example 13 provides a detailed description of how this reaction is conducted.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[NH:10])[NH2:9].[Cl:11][C:12]([SH:15])(Cl)Cl.[OH-].[Na+]>ClCCl.O>[Cl:11][C:12]1[S:15][N:9]=[C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[F:1])[N:10]=1
Reactant: N=C(N)c1ccccc1F
Reactant: SC(Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: Fc1ccccc1-c1nsc(Cl)n1
Temperature: 25 °C
Yield: 87.6 %

Procedure:
To a solution of 2-fluorobenzenecarboximidamide (1.38 g, 10.0 mmol) and perchloromethyl mercaptan (1.07 ml, 10.0 mmol) in dichloromethane (10 ml) was added dropwise a solution of sodium hydroxide (1.60 g, 40.0 mmol) in water (4 ml) under ice-cooling. Then, the reaction mixture was stirred under ice-cooling for 1 hour and at room temperature for 1 hour. The organic layer was separated, washed with water, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=9:1) to give 1.88 g (87.4%) of the desired product as an oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[NH:5][C:6]1[C:7]2[CH:15]=[CH:14][C:13](F)=[N:12][C:8]=2[N:9]=[CH:10][N:11]=1.Cl.[CH3:21][NH:22][CH3:23].CCN(CC)CC>CCO>[Br:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[NH:5][C:6]1[C:7]2[CH:15]=[CH:14][C:13]([N:22]([CH3:23])[CH3:21])=[N:12][C:8]=2[N:9]=[CH:10][N:11]=1
Reactant: CNC
Reactant: Fc1ccc2c(Nc3cccc(Br)c3)ncnc2n1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: CN(C)c1ccc2c(Nc3cccc(Br)c3)ncnc2n1
Yield: 84 %

Procedure:
Reaction of 4-(3-bromoanilino)-7-fluoropyrido[2,3-d]pyrimidine (see a previous experimental) (0.12 g, 0.38 mmol) with dimethylamine. hydrochloride (92 mg, 1.13 mmol) and Et3N (0.18 mL, 1.32 mmol) in EtOH (15 mL) at 100° C. for 18 h in a pressure vessel, followed by evaporation of the solvent and workup, gives 4-(3-bromoanilino)-7-(dimethylamino)pyrido[2,3-d]pyrimidine (0.11 g, 84%). 1H NMR (DMSO) δ 9.58 (1H, brs), 8.56 (1H, d, J=9.3 Hz) 8.54 (1H, s), 8.18 (1H, t, J=1.9 Hz), 7.84 (dt, Jd=8.0, Hz, J=1.9 Hz), 7.33 (1H, dd, J=8.1, 8.0 Hz) 7.25 (1H, dt, Jd=9.3, Hz, Jt=1.9 Hz), 7.10 (1H, d, J=9.3 Hz), 3.18 (6H, s).
Reaction SMILES: O.[NH2:2][C:3]1[N:8]=[C:7]([CH:9]2[CH2:11][CH2:10]2)[N:6]=[C:5]([C:12]([OH:14])=[O:13])[C:4]=1[Cl:15].[C:16](=O)(OC)OC.S(=O)(=O)(O)O.[OH-].[Na+]>O.CO>[NH2:2][C:3]1[N:8]=[C:7]([CH:9]2[CH2:11][CH2:10]2)[N:6]=[C:5]([C:12]([O:14][CH3:16])=[O:13])[C:4]=1[Cl:15]
Reactant: COC(=O)OC
Reactant: Nc1nc(C2CC2)nc(C(=O)O)c1Cl
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COC(=O)c1nc(C2CC2)nc(N)c1Cl
Temperature: 70 °C
Yield: 92.3 %

Procedure:
A 500 mL multi-neck flask equipped with nitrogen bubbler, addition funnel, reflux condenser, and thermocouple was charged with 6-amino-5-chloro-2-cyclopropyl-4-pyrimidinecarboxylic acid monohydrate (47.8 g, 0.206 mol), methanol (32 g) and dimethyl carbonate (94.5 g, 1.05 mol). Concentrated sulfuric acid (50.0 g, 0.500 mol) was added over about 30 minutes with cooling to maintain the temperature below 60° C., and then the reaction mixture was heated at 70° C. for 10 h. The resulting mixture was cooled to 15° C. and diluted with 250 mL of water. The pH of the reaction mass was raised to 5-8 by adding about 42.7 g (0.534 mol) of 50 wt % aqueous NaOH over 30 minutes with cooling to maintain the temperature in the range of 10-15° C. The resulting slurry was cooled to 5° C. and filtered. The filtered wet cake was washed with water and dried to constant weight at 50° C. to give 43.3 g (93.5% yield) of the title compound with 98% purity as a solid melting at 147-148° C.
Reaction SMILES: [CH2:1]([C:4]1([OH:27])[C@@H:8]([NH:9][C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:11])[CH2:7][N:6]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:5]1)[CH:2]=[CH2:3].B1C2CCCC1CCC2.OO.CC([O-])=[O:41].[Na+].O>C1COCC1.O>[CH2:13]([O:12][C:10]([NH:9][C@H:8]1[CH2:7][N:6]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:5][C:4]1([OH:27])[CH2:1][CH2:2][CH2:3][OH:41])=[O:11])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: C=CCC1(O)CN(C(=O)OC(C)(C)C)C[C@@H]1NC(=O)OCc1ccccc1
Reactant: CC(=O)[O-]
Agent: B1C2CCCC1CCC2
Agent: OO
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1C[C@H](NC(=O)OCc2ccccc2)C(O)(CCCO)C1
Reaction time: 48 h

Procedure:
To a solution of 0.85 g of allyl alcohol of step C in 20 mL of anhydrous THF was added a solution of 15 mL of 0.5 N 9-BBN. The reaction was stirred for 2 days. Water (0.5 mL) was added followed with 1 mL of 30% H2O2 and 1 mL of NaOAc/water. After being stirred for 1 h, the organic phase was separated. The water solution was neutralized with HCl and extracted with EtOAc twice. The combined organic phase was dried over Na2SO4. Solvent was removed under vacuum. Column chromatography on silica gel using pure EtOAc as eluent provided 0.80 g of the title compound. MS (M+H)+ 395.
Reaction SMILES: Cl[C:2]1[N:6]([CH2:7][CH3:8])[N:5]=[C:4]([CH3:9])[C:3]=1[C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:11].[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=1.[H-].[Na+].O>CN(C)C=O>[CH2:7]([N:6]1[C:2]([O:26][C:23]2[CH:24]=[CH:25][C:20]([O:19][CH3:18])=[CH:21][CH:22]=2)=[C:3]([C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:11])[C:4]([CH3:9])=[N:5]1)[CH3:8]
Reactant: CCn1nc(C)c(C(=O)c2ccccc2)c1Cl
Reactant: COc1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCn1nc(C)c(C(=O)c2ccccc2)c1Oc1ccc(OC)cc1
Temperature: 110 °C
Reaction time: 5 h
Yield: 57.3 %

Procedure:
A mixture of 129 mg of (5-chloro-1-ethyl-3-methyl-1H-pyrazol-4-yl)-phenyl-methanone, 141 mg of 4-methoxyphenol and 33 mg of sodium hydride (60% in mineral oil) in 3 ml of anhydrous N,N-dimethylformamide was stirred under nitrogen at 110° C. for 5 h. Water (8 ml) was added and the mixture was extracted three times with 10 ml of dichloromethane. The combined extracts were dried over magnesium sulphate, filtered and evaporated. The residue was purified by flash chromatography on silica gel using ethyl acetate/petroleum ether (bp 40–60° C.) (1:3) for the elution to give 100 mg of [1-ethyl-5-(4-methoxyphenoxy)-3-methyl-1H-pyrazol-4-yl]-phenyl-methanone as a yellow oil. Mass spectrum (ES) m/z 337 [M]+, 378 [M+H+CH3CN]+.
Reaction SMILES: C1(C(C2C=CC=CC=2)(C2C=CC=CC=2)[O:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][O:14][CH2:15][CH2:16][N:17]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:19]([CH:26]=[O:27])=[CH:18]2)C=CC=CC=1.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCl>[OH:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][O:14][CH2:15][CH2:16][N:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:19]([CH:26]=[O:27])=[CH:18]1
Reactant: O=Cc1cn(CCOCCOCCOC(c2ccccc2)(c2ccccc2)c2ccccc2)c2ccccc12
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=Cc1cn(CCOCCOCCO)c2ccccc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 2.6 g of 1-(2-(2-(2-triphenylmethoxyethoxy)ethoxy)ethyl)-1H-indole-3-carbaldehyde (5.0 mmol) in 50 mL dichloromethane is added 4.0 mL of triethylsilane (2.9 g, 25 mmol) followed by 4.0 mL of trifluoroacetic acid (5.5 g, 50 mmol). The solution is stirred at room temperature for 2 hrs and then washed 3×100 mL saturated NH4CO3. The solution is dried over anhydrous Na2SO4 and the solvent is removed via vacuum. The resultant residue is purified via column chromatography over alumina, eluting with a gradient of methanol in dichloromethane.
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[C:11]([CH:13]3[CH2:18][NH:17][S:16](=[O:20])(=[O:19])[NH:15][CH2:14]3)[CH:10]=[CH:9][C:8]=2[NH2:21])[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.[C:22]([C:24]1[N:25]=[C:26]([C:37](O)=[O:38])[N:27]([CH2:29][O:30][CH2:31][CH2:32][Si:33]([CH3:36])([CH3:35])[CH3:34])[CH:28]=1)#[N:23].[K+].C(C1N=C(C([O-])=O)N(COCC[Si](C)(C)C)C=1)#N>>[C:1]1([C:7]2[CH:12]=[C:11]([CH:13]3[CH2:14][NH:15][S:16](=[O:20])(=[O:19])[NH:17][CH2:18]3)[CH:10]=[CH:9][C:8]=2[NH:21][C:37]([C:26]2[N:27]([CH2:29][O:30][CH2:31][CH2:32][Si:33]([CH3:36])([CH3:35])[CH3:34])[CH:28]=[C:24]([C:22]#[N:23])[N:25]=2)=[O:38])[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1
Reactant: C[Si](C)(C)CCOCn1cc(C#N)nc1C(=O)O
Reactant: Nc1ccc(C2CNS(=O)(=O)NC2)cc1C1=CCCCC1
Agent: C[Si](C)(C)CCOCn1cc(C#N)nc1C(=O)[O-]
Agent: [K+]
Product: C[Si](C)(C)CCOCn1cc(C#N)nc1C(=O)Nc1ccc(C2CNS(=O)(=O)NC2)cc1C1=CCCCC1
Yield: 25 %

Procedure:
2-Cyclohex-1-enyl-4-(1,1-dioxo-1λ6-[1,2,6]thiadiazinan-4-yl)-phenylamine (as prepared in the previous step, 30.7 mg, 0.100 mmol) was coupled to 4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylic acid, potassium salt (as prepared in Example 1, step (d), 33.6 mg, 0.260 mmol) as described in Example 1, step (1) to obtain the title compound (14 mg, 25%) after purification on silica (20-50% EtOAc-hexane): Mass spectrum (ESI, m/z): Calcd. for C26H36N6O4SSi, 557.2 (M+H). found 556.8.
Reaction SMILES: CS([C:5]1[N:6]=[N:7][C:8]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[C:9]([C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)[N:10]=1)(=O)=O.[OH-:23].[K+].Cl>O.C1COCC1>[C:17]1([C:8]2[C:9]([C:11]3[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=3)=[N:10][C:5](=[O:23])[NH:6][N:7]=2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CS(=O)(=O)c1nnc(-c2ccccc2)c(-c2cccnc2)n1
Reactant: [OH-]
Agent: Cl
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: O=c1nc(-c2cccnc2)c(-c2ccccc2)n[nH]1
Yield: 92.8 %

Procedure:
To a solution of 3-(methylsulfonyl)-6-phenyl-5-(pyridin-3-yl)-1,2,4-triazine (0.035 g, 0.112 mmol) in a 1:1 mixture of H2O/THF (1.5 mL) was added potassium hydroxide (0.037 g, 0.560 mmol). The reaction was heated at reflux for 2 h. Upon completion, the reaction mixture was cooled to room temperature and neutralized with 1 M HCl, then extracted with EtOAc. The combined organic layers were washed with H2O, brine, dried over MgSO4 and concentrated to give the title compound as a yellow solid (0.026 g) without further purification. LCMS m/z=251.1 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([C:9]([F:12])([F:11])[F:10])[CH:3]=1.N1C=CC=CC=1.[CH3:19][O:20][C:21](=[O:32])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[S:28](Cl)(=[O:30])=[O:29]>ClCCl>[CH3:19][O:20][C:21](=[O:32])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[S:28](=[O:29])(=[O:30])[NH:6][C:5]1[CH:7]=[CH:8][C:2]([F:1])=[CH:3][C:4]=1[C:9]([F:10])([F:11])[F:12]
Reactant: Nc1ccc(F)cc1C(F)(F)F
Reactant: COC(=O)c1ccccc1S(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)c1ccccc1S(=O)(=O)Nc1ccc(F)cc1C(F)(F)F
Temperature: 0 °C
Reaction time: 8 h

Procedure:
250 ml of dichloromethane is combined with 9.38 g (52.37 mmol) of 4-fluoro-2-trifluoromethylaniline and 6 ml (14.3 mmol) of pyridine. The mixture is cooled with ice water and under agitation and exclusion of moisture, 13.52 g (57.62 mmol) of 2-chlorosulfonylbenzoic acid methyl ester is added in small increments. The mixture is agitated overnight, washed with 2N hydrochloric acid and water, the dichloromethane solution is dried over sodium sulfate and concentrated to dryness under vacuum. The residue is crystallized from ethyl acetate/hexane. The title compound melts at 143°-145° C.
Reaction SMILES: [O:1]=[C:2]1[NH:7][CH2:6][CH2:5][N:4]([C:8]([N:10]2[CH2:15][CH:14]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)[CH2:13][CH:12]([C:26]([OH:28])=O)[CH2:11]2)=[O:9])[CH2:3]1.O[N:30]=[C:31]([NH2:36])[CH2:32][CH2:33][O:34][CH3:35]>>[CH3:35][O:34][CH2:33][CH2:32][C:31]1[N:36]=[C:26]([CH:12]2[CH2:13][CH:14]([C:16]3[CH:17]=[CH:18][C:19]([C:22]([F:24])([F:23])[F:25])=[CH:20][CH:21]=3)[CH2:15][N:10]([C:8]([N:4]3[CH2:5][CH2:6][NH:7][C:2](=[O:1])[CH2:3]3)=[O:9])[CH2:11]2)[O:28][N:30]=1
Reactant: O=C1CN(C(=O)N2CC(C(=O)O)CC(c3ccc(C(F)(F)F)cc3)C2)CCN1
Reactant: COCCC(N)=NO
Product: COCCc1noc(C2CC(c3ccc(C(F)(F)F)cc3)CN(C(=O)N3CCNC(=O)C3)C2)n1

Procedure:
250 mg (0.626 mmol) of 1-[(3-oxopiperazin-1-yl)carbonyl]-5-[4-(trifluoromethyl)phenyl]-piperidine-3-carboxylic acid (Example 206A) and 108 mg (0.689 mmol, 75% pure) of N′-hydroxy-3-methoxypropanimidamide were reacted according to the General Method 1. Yield: 72.0 mg (23% of theory).