Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH2:7][C:8](Cl)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl-].[Al+3].[Cl-].[Cl-].Cl.[F:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[F:16][C:17]1[CH:22]=[CH:21][C:20]([C:8]([CH2:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[O:9])=[CH:19][CH:18]=1
Reactant: O=C(Cl)Cc1ccccc1
Reactant: Fc1ccccc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Product: O=C(Cc1ccccc1)c1ccc(F)cc1
Temperature: 0 °C

Procedure:
28.4 g of phenylacetyl chloride was dissolved in 130 ml of fluorobenzene and cooled in ice. This solution was added to 27.0 g of freshly powdered aluminum chloride with continued cooling and stirring. After the vigorous reaction subsided, the mixture was stirred at room temperature overnight and then poured onto 150 g of ice containing 50 ml of concentrated hydrochloric acid. Extraction gave a pale brown solid. Recrystallization from petroleum ether gave 4-fluorodeoxybenzoin, 2A, as a white solid, mp: 80°-81° C.
Reaction SMILES: CO[CH:3](OC)[CH2:4][C:5]1[CH:30]=[CH:29][C:8]([NH:9][CH:10]2[CH2:15][CH2:14][N:13]([C:16]([N:18]3[CH2:23][CH2:22][CH2:21][CH:20]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:19]3)=[O:17])[CH2:12][CH2:11]2)=[CH:7][CH:6]=1.[I-].[Na+].Cl[Si](Cl)(Cl)C.C(O)(=O)C.[NH2:44][CH2:45][C@@H:46]([C:48]1[CH:49]=[CH:50][C:51]([OH:59])=[C:52]([NH:54][S:55]([CH3:58])(=[O:57])=[O:56])[CH:53]=1)[OH:47].C([BH3-])#N.[Na+]>C(#N)C.CO.ClCCl>[OH:47][C@H:46]([C:48]1[CH:49]=[CH:50][C:51]([OH:59])=[C:52]([NH:54][S:55]([CH3:58])(=[O:57])=[O:56])[CH:53]=1)[CH2:45][NH:44][CH2:3][CH2:4][C:5]1[CH:6]=[CH:7][C:8]([NH:9][CH:10]2[CH2:11][CH2:12][N:13]([C:16]([N:18]3[CH2:23][CH2:22][CH2:21][CH:20]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:19]3)=[O:17])[CH2:14][CH2:15]2)=[CH:29][CH:30]=1
Reactant: CCOC(=O)C1CCCN(C(=O)N2CCC(Nc3ccc(CC(OC)OC)cc3)CC2)C1
Reactant: CS(=O)(=O)Nc1cc([C@@H](O)CN)ccc1O
Agent: C[Si](Cl)(Cl)Cl
Agent: [BH3-]C#N
Agent: [I-]
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: CO
Product: CCOC(=O)C1CCCN(C(=O)N2CCC(Nc3ccc(CCNC[C@H](O)c4ccc(O)c(NS(C)(=O)=O)c4)cc3)CC2)C1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 4.9 %

Procedure:
Ethyl 1-([4-[4-(2,2-dimethoxyethyl)anilino]-1-piperidinyl}carbonyl)-3-piperidinecarboxylate (1.0 g, 2.23 mmol) was added to a pre-prepared mixture of sodium iodide (0.893 g, 5.96 mmol) and trichloro(methyl)silane (0.561 mL, 4.77 mmol) in anhydrous acetonitrile. The reaction was stirred at ambient temperature for 10 minutes. Dichloromethane was added and the reaction washed with 10% sodium thiosulfate solution, water and brine. The organic layer was dried over anhydrous magnesium sulfate, filtered and the solvent partially removed in vacuo. The aldehyde solution was used directly and treated with methanol, acetic acid (0.156 mL, 2.6 mmol), N-{5-[(1R)-2-amino-1-hydroxyethyl]-2-hydroxyphenyl}methanesulfonamide (0.587 g, 2.38 mmol) followed by sodium cyanoborohydride (0.164 g, 2.38 mmol). The reaction was stirred at ambient temperature for 24 hours. The reaction was taken to dryness in vacuo, adsorbed onto silica and purified by flash chromatography on silica gel Merck-60 (eluant: 5:1 chloroform-methanol containing 1% ammonium hydroxide) to yield the title compound (0.07 g, 0.11 mmol).
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[CH:9]=[C:8]([NH2:10])[CH:7]=[CH:6][C:5]=12.C(N(C(C)C)C(C)C)C.CN(C)C=O.[N:25]([C:28]1[CH:33]=[CH:32][C:31]([N+:34]([O-:36])=[O:35])=[CH:30][CH:29]=1)=[C:26]=[O:27]>O1CCCC1.O>[N:1]1[CH:2]=[CH:3][N:4]2[CH:9]=[C:8]([NH:10][C:26]([NH:25][C:28]3[CH:29]=[CH:30][C:31]([N+:34]([O-:36])=[O:35])=[CH:32][CH:33]=3)=[O:27])[CH:7]=[CH:6][C:5]=12
Reactant: Nc1ccc2nccn2c1
Reactant: O=C=Nc1ccc([N+](=O)[O-])cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: O=C(Nc1ccc([N+](=O)[O-])cc1)Nc1ccc2nccn2c1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A 0° C. solution of imidazo[1,2-a]pyridin-6-amine (1 g, 7.21 mmol), N-ethyl-N-isopropylpropan-2-amine (2.51 ml, 14.42 mmol) and dimethylformamide (21.85 ml) was treated with a solution of 1-isocyanato-4-nitrobenzene (1.313 g, 8.00 mmol) in tetrahydrofuran (10.92 ml) which was added dropwise via syringe over 5 minutes. The reaction mixture was allowed to stir at room temperature for 6 hours, and water was added. The suspension was filtered with water washes to give the title compound after vacuum drying.
Reaction SMILES: [C:1]([O-:4])([O-])=O.[Ca+2].[O:6]=[CH:7][C@@H:8]([C@H:10]([C@@H:12]([C@@H:14]([CH2:16][OH:17])[OH:15])O)O)O>>[CH:10]1[CH:12]=[C:14]([OH:15])[C:16]([OH:17])=[C:1]([OH:4])[C:7](=[O:6])[CH:8]=1
Reactant: O=C([O-])[O-]
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Agent: [Ca+2]
Product: O=c1cccc(O)c(O)c1O
Reaction time: 96 h

Procedure:
A loopful of Streptomyces tropolofaciens No. K611-97, taken from a mature slant culture was inoculated into 500-ml Erlenmeyer flask containing 100 ml of a seed medium consisted of 3% soybean meal, 2% corn starch, 0.33% MgSO4.7H2O and 1% CaCO3, the pH being adjusted to 7.0 before sterilization. The flask was then incubated at 28° C. for 4 days on a rotary shaker (200 rpm) and 5 ml of the growth was transferred into 500-ml Erlenmeyer flask containing 100 ml of a fermentation medium having the same composition as the seed medium. The fermentation was carried out at 28° C. for 6 days on a rotary shaker. The antibiotic production was monitored by the paper-disc agar diffusion method against Cryptococcus neoformans IAM 4514 as a test organism. For a large scale production, the fermentation studies were carried out in stainless-steel fermentors. The culture was prepared in twenty 500-ml Erlenmeyer flasks incubated at 32° C. for 4 days on the rotary shaker. The resultant culture was transferred into a 200-liter tank fermentor containing 120 liters of a production medium. The seed and production media consisted of 3% soybean meal, 3% glucose, 0.5% Pharmamedia, 0.1% yeast extract and 0.3% CaCO3. Tank fermentation was carried out at 28° C. with stirring at 250 rpm and aeration at 120 liter/min. The production reached a maximum after 115 hours fermentation.
Reaction SMILES: C([N:4]1[CH:8]=[C:7]([C:9]2[CH:10]=[C:11]([CH:57]=[CH:58][CH:59]=2)[CH2:12][CH2:13][O:14][CH2:15][CH2:16][C:17]([N:19]([CH2:26][CH2:27][N:28]([CH2:36][CH2:37][C:38]2[C:43]3[O:44][CH2:45][C:46](=[O:48])[NH:47][C:42]=3[C:41]([O:49]C(OC(C)(C)C)=O)=[CH:40][CH:39]=2)C(=O)OC(C)(C)C)[CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)=[O:18])[N:6]=[N:5]1)C=C.CN1C(=O)CC(=O)N(C)C1=O.[C:71]([OH:77])([C:73]([F:76])([F:75])[F:74])=[O:72]>C(Cl)Cl.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:74][C:73]([F:76])([F:75])[C:71]([OH:77])=[O:72].[NH:4]1[CH:8]=[C:7]([C:9]2[CH:10]=[C:11]([CH:57]=[CH:58][CH:59]=2)[CH2:12][CH2:13][O:14][CH2:15][CH2:16][C:17]([N:19]([CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)[CH2:26][CH2:27][NH:28][CH2:36][CH2:37][C:38]2[C:43]3[O:44][CH2:45][C:46](=[O:48])[NH:47][C:42]=3[C:41]([OH:49])=[CH:40][CH:39]=2)=[O:18])[N:6]=[N:5]1
Reactant: C=CCn1cc(-c2cccc(CCOCCC(=O)N(CCN(CCc3ccc(OC(=O)OC(C)(C)C)c4c3OCC(=O)N4)C(=O)OC(C)(C)C)C3CCCCC3)c2)nn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CN1C(=O)CC(=O)N(C)C1=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1COc2c(CCNCCN(C(=O)CCOCCc3cccc(-c4c[nH]nn4)c3)C3CCCCC3)ccc(O)c2N1
Temperature: 100 °C
Reaction time: 0.5 h

Procedure:
tert-Butyl 2-(3-(3-(1-allyl-1H-1,2,3-triazol-4-yl)phenethoxy)-N-cyclohexylpropanamido)ethyl(2-(5-(tert-butoxycarbonyloxy)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-8-yl)ethyl)carbamate [Example 14, Step iv)] (220 mg), 1,3-dimethylpyrimidine-2,4,6(1H,3H,5H)-trione (126 mg) and tetrakis(triphenylphosphine)palladium(0) (31 mg) were dissolved in DCM (2 mL) and sealed into a microwave tube. The reaction was heated to 100° C., over a period of 90 min in the microwave reactor. After cooling to room temperature, TFA (1 mL) was added and the mixture was stirred for 30 min, then concentrated. The crude product was purified by preparative HPLC on a Phenomenex Gemini column using a gradient of aqueous 0.1% trifluoroacetic acid in acetonitrile as eluent to afford the titled compound (63.5 mg) as a solid. MS [M+H]+=577.3 (calc=577.3138) (MultiMode+) 1H NMR (400 MHz, CD3OD) δ 8.12 (s, 1H), 7.71 (s, 1H), 7.63 (d, J=7.8 Hz, 1H), 7.33 (t, J=7.5 Hz, 1H), 7.21 (d, J=8.0 Hz, 1H), 6.69 (d, J=8.2 Hz, 1H), 6.47 (d, J=8.5 Hz, 1H), 4.61 (s, 2H), 3.72 (t, J=6.7 Hz, 2H), 3.72 (t, J=5.9 Hz, 2H), 3.71-3.63 (m, 1H), 3.47 (t, J=6.9 Hz, 2H), 3.11 (t, J=7.2 Hz, 2H), 3.02 (t, J=5.7 Hz, 2H), 2.89 (t, J=6.7 Hz, 2H), 2.87 (t, J=7.1 Hz, 2H), 2.62 (t, J=6.0 Hz, 2H), 1.80-1.72 (m, 2H), 1.69-1.58 (m, 3H), 1.46-1.24 (m, 4H), 1.16-1.05 (m, 1H).
Reaction SMILES: [Br:1][C:2]1[C:3]([F:22])=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[C:12]([C:18](O)=[O:19])=[C:13]([C:15](=[O:17])[NH2:16])[N:14]=[C:7]3[C:6]=2[CH:21]=1.[NH2:23][CH:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1>>[Br:1][C:2]1[C:3]([F:22])=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[C:12]([C:18]([NH:23][CH:24]4[CH2:29][CH2:28][O:27][CH2:26][CH2:25]4)=[O:19])=[C:13]([C:15]([NH2:16])=[O:17])[N:14]=[C:7]3[C:6]=2[CH:21]=1
Reactant: NC(=O)c1nc2n(c1C(=O)O)CCOc1cc(F)c(Br)cc1-2
Reactant: NC1CCOCC1
Product: NC(=O)c1nc2n(c1C(=O)NC1CCOCC1)CCOc1cc(F)c(Br)cc1-2

Procedure:
10-Bromo-2-carbamoyl-9-fluoro-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine-3-carboxylic acid (55 mg) was reacted with 4-aminotetrahydropyran similar to as described in Example 2 to produce crude 10-bromo-9-fluoro-N3-tetrahydropyran-4-yl-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine-2,3-dicarboxamide which was then reacted with 2-Methyl-3-butyne-ol similar to as described in Procedure E to afford 12.5 mg of 9-fluoro-10-(3-hydroxy-3-methyl-but-1-ynyl)-N3-tetrahydropyran-4-yl-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine-2,3-dicarboxamide following reverse phase hplc purification. MS (Q1) 457 (M)+. 1H NMR (400 MHz, DMSO) δ 11.42 (d, J=11.5 Hz, 1H), 8.60 (d, J=8.4 Hz, 1H), 8.38 (s, 1H), 7.88 (s, 1H), 7.01 (d, J=10.6 Hz, 1H), 5.47 (s, 1H), 5.08-4.94 (m, 2H), 4.60-4.49 (m, 2H), 4.10-3.92 (m, 1H), 3.91-3.79 (m, 2H), 3.54-3.43 (m, 2H), 1.93-1.80 (m, 2H), 1.49 (s, 6H), 1.48-1.42 (m, 1H).
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH:23]=[CH:22][C:21]([CH2:24][O:25][P:26]([O:32][CH2:33][CH:34]=[CH2:35])([O:28][CH2:29][CH:30]=[CH2:31])=[O:27])=[CH:20][C:7]=1[C:8]([O:10]CC1C=CC(OC)=CC=1)=[O:9])(=[O:3])[CH3:2].C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O>C1(C)C=CC=CC=1>[C:1]([O:4][CH2:5][C:6]1[CH:23]=[CH:22][C:21]([CH2:24][O:25][P:26]([O:32][CH2:33][CH:34]=[CH2:35])([O:28][CH2:29][CH:30]=[CH2:31])=[O:27])=[CH:20][C:7]=1[C:8]([OH:10])=[O:9])(=[O:3])[CH3:2]
Reactant: C=CCOP(=O)(OCC=C)OCc1ccc(COC(C)=O)c(C(=O)OCc2ccc(OC)cc2)c1
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: C=CCOP(=O)(OCC=C)OCc1ccc(COC(C)=O)c(C(=O)O)c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 106.2 %

Procedure:
A mixture of 4-methoxybenzyl 2-(acetoxymethyl)-5-[[bis(allyloxy)phosphoryl]oxymethyl]benzoate (590.3 mg, 1.17 mmol) obtained from Example 1-(10) and anisole (600 mg, 5.55 mmol) was cooled to 0° C., and then trifluoroacetic acid (2 ml) was added thereto with stirring. The mixture was warmed to room temperature and allowed to stand for 20 minutes. The mixture was diluted with toluene and was concentrated under reduced pressure to eliminate the volatile components (repeated three times), and an aqueous solution of sodium hydrogen carbonate was added thereto, then the aqueous layer was washed with ethyl acetate. To the aqueous layer was added carefully a 2N aqueous solution of hydrochloric acid (10 ml), and the liberated carboxylic acid was extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride, and the solvent was distilled off under reduced pressure to afford the title compound (477.5 mg, quantitative yield) as a colorless oil.
Reaction SMILES: [N:1]1([C:7]2[C:8](=[O:25])[N:9]([CH2:13][CH2:14][O:15][C:16]3[CH:21]=[C:20]([F:22])[C:19]([F:23])=[CH:18][C:17]=3[F:24])[CH:10]=[CH:11][N:12]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[ClH:26].N1(C2C(=O)N(CCOC3C=C(F)C(F)=CC=3F)C=CN=2)CCNCC1.[CH2:52](Br)[C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1>>[ClH:26].[CH2:52]([N:4]1[CH2:5][CH2:6][N:1]([C:7]2[C:8](=[O:25])[N:9]([CH2:13][CH2:14][O:15][C:16]3[CH:21]=[C:20]([F:22])[C:19]([F:23])=[CH:18][C:17]=3[F:24])[CH:10]=[CH:11][N:12]=2)[CH2:2][CH2:3]1)[C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1
Reactant: O=c1c(N2CCNCC2)nccn1CCOc1cc(F)c(F)cc1F
Reactant: BrCc1ccccc1
Agent: Cl
Product: O=c1c(N2CCN(Cc3ccccc3)CC2)nccn1CCOc1cc(F)c(F)cc1F

Procedure:
The title compound was prepared according to the procedure of Example 60 starting from 3-(1-piperazinyl)-1-[2-(2,4,5-trifluorophenoxy)ethyl]-2(1H)-pyrazinone (0.35 g, 1.0 mmol; from the free base of Example 3) and benzyl bromide (0.19 g, 1.1 mmol) Yield: 0.17 g (35%); HPLC purity: 99%; mp 214-214.5° C. HRMS calc for C23H23F3N4O2 (M)+ 444.1773, found 444.1789.
Reaction SMILES: [Cl:1][C:2]1[CH:37]=[CH:36][C:5]([CH2:6][C:7]2[C:15]3[C:10](=[CH:11][C:12]([O:16][CH2:17][C:18]4[CH:27]=[CH:26][C:25]5[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=5)[N:19]=4)=[CH:13][CH:14]=3)[NH:9][C:8]=2[CH2:28][C:29]([CH3:35])([CH3:34])[C:30]([O:32][CH3:33])=[O:31])=[CH:4][CH:3]=1.C[Si](C)(C)N[Si](C)(C)C.[K].[C:48]1([S:54](Cl)(=[O:56])=[O:55])[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1>C1COCC1.CN(P(N(C)C)(N(C)C)=O)C.C1(C)C=CC=CC=1>[C:48]1([S:54]([N:9]2[C:10]3[C:15](=[CH:14][CH:13]=[C:12]([O:16][CH2:17][C:18]4[CH:27]=[CH:26][C:25]5[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=5)[N:19]=4)[CH:11]=3)[C:7]([CH2:6][C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:37][CH:36]=3)=[C:8]2[CH2:28][C:29]([CH3:34])([CH3:35])[C:30]([O:32][CH3:33])=[O:31])(=[O:56])=[O:55])[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1
Reactant: COC(=O)C(C)(C)Cc1[nH]c2cc(OCc3ccc4ccccc4n3)ccc2c1Cc1ccc(Cl)cc1
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: [K]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: COC(=O)C(C)(C)Cc1c(Cc2ccc(Cl)cc2)c2ccc(OCc3ccc4ccccc4n3)cc2n1S(=O)(=O)c1ccccc1
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
To a solution of methyl 3-[3-(4-chlorobenzyl)-6-(quinolin-2-ylmethoxy)indol-2-yl]-2,2-d imethylpropanoate (Step D, Example 37) (208 mg) in dry THF (5 mL) and HMPA (0.5 mL) at -78° C. was added 0.58M potassium hexamethyldisilazane in toluene (0.77 mL) and the solution then stirred at -78° C. for 15 minutes. Then freshly distilled benzenesulfonyl chloride (0.062 mL) was added and stirred at -78° C. for 2.5 hours. The reaction mixture was quenched with 25% aq. NH4OAc, extracted with EtOAc, dried over Na2SO4 and evaporated to give crude product. Chromatography of the residue in a column of flash silica gel (eluting with EtOAc-hexane 25:75) afforded the title product as an oil.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:9]([OH:11])=O)=[CH:4][C:5]([Cl:8])=[N:6][CH:7]=1.O.[CH:13]([NH2:15])=O>>[Cl:8][C:5]1[N:6]=[CH:7][C:2]2[N:1]=[CH:13][NH:15][C:9](=[O:11])[C:3]=2[CH:4]=1
Reactant: Nc1cnc(Cl)cc1C(=O)O
Reactant: NC=O
Solvent: O
Product: O=c1[nH]cnc2cnc(Cl)cc12
Yield: 86 %

Procedure:
A solution of 5-amino-2-chloropyridine-4-carboxylic acid (8.1 g, 4.7 mmol) in formamide (100 mL) is stirred at 140° C. for 12 h. Dilution of the cooled mixture with water gives a precipitate of 6-chloro-3H-pyrido[3,4-d]pyrimidin-4-one (7.3 g, 86% yield). 1H NMR (DMSO) δ 12.73 (1H, m), 8.90 (1H, d, J=0.7 Hz), 8.23 (1H, s), 7.97 (1H, d, J=0.7 Hz).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][C@H:3]([NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10])[CH2:2]1.[CH2:14]=O.[BH4-].[Na+].O>CO>[CH3:14][N:1]1[CH2:5][CH2:4][C@H:3]([NH:6][C:7](=[O:13])[O:8][C:9]([CH3:10])([CH3:12])[CH3:11])[CH2:2]1
Reactant: C=O
Reactant: CC(C)(C)OC(=O)N[C@H]1CCNC1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CN1CC[C@H](NC(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 65 %

Procedure:
In a dried reaction flask, (S)-tert-butyl pyrrolidin-3-ylcarbamate (5.774 g, 31.0 mmol) and formaldehyde solution (6.82 mL, 37%) were dissolved in methanol (124 mL) under a nitrogen atmosphere. The solution was stirred at room temperature for 1 hr. Sodium borohydride (3.518 g, 93.1 mmol) was added in portion under an ice bath. The solution was stirred at room temperature for 3 hr. Water was added to the reaction solution. After rotary-evaporation, ethyl acetate and saturated aqueous sodium bicarbonate solution were added. The reaction solution was extracted with ethyl acetate. The combined organic phase was washed with salt water, dried over anhydrous sodium sulfate, filtered, and purified by silica gel column chromatography (ethyl acetate:petroleum ether=1:1) to produce a pale yellow solid (4.037 g) in 65% yield.
Reaction SMILES: [CH3:1][N:2]([N:9]=[O:10])[C:3]([NH:5][N+:6]([O-:8])=[O:7])=[NH:4].[OH2:11]>>[CH3:1][N:2]([N+:9]([O-:11])=[O:10])[C:3]([NH:5][N+:6]([O-:8])=[O:7])=[NH:4]
Reactant: CN(N=O)C(=N)N[N+](=O)[O-]
Reactant: O
Product: CN(C(=N)N[N+](=O)[O-])[N+](=O)[O-]

Procedure:
About 25 mg of N-methyl-N'-nitro-N-nitrosoguanidine (Aldrich Chemie BDR) were added to a 10 ml tared graduated cylinder supplied with a glass stopper. Water was supplied so as to obtain a total volume of 10 ml, and the N-methyl-N'-nitro-N-nitrosoguanidine was dissolved therein by shaking. 10×1 ml of stock solution were obtained from this solution.
Reaction SMILES: [CH3:1][N:2]([C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:17]=[N:18][C:19]3[C:24]([CH:25]=2)=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:12][CH:11]=1)C(=O)OC(C)(C)C.C(O)(C(F)(F)F)=O>>[CH3:1][NH:2][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:17]=[N:18][C:19]3[C:24]([CH:25]=2)=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:12][CH:11]=1
Reactant: CN(C(=O)OC(C)(C)C)c1ccc(-c2cnc3ccccc3c2)cc1
Solvent: O=C(O)C(F)(F)F
Product: CNc1ccc(-c2cnc3ccccc3c2)cc1

Procedure:
tert-Butyl methyl(4-(quinolin-3-yl)phenyl)carbamate (44 mg, 0.13 mmol) was then treated with TFA by using the general procedure P. The crude product was purified by HPLC to afford T477 as an orange-colored wax (13 mg, 29%). 1H NMR (400 MHz, CDCl3): δ 9.46 (d, J=2.0 Hz, 1H), 8.79 (d, J=1.6 Hz, 1H), 8.47 (d, J=8.4 Hz, 1H), 8.08 (d, J=8.4 Hz, 1H), 7.95 (m, 1H), 7.83 (m, 1H), 7.62 (m, 2H), 6.82 (m, 2H), 2.94 (s, 3H); MS (ESI): 235 (M+H+).
Reaction SMILES: [C:1]1([CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8]([OH:10])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:17][C@H:18]([C:20]([N:22]1[C:28](=[O:29])[CH:27]([CH3:30])[C:26]2[CH:31]=[CH:32][CH:33]=[CH:34][C:25]=2[C:24]2[C:35]([NH2:39])=[CH:36][CH:37]=[CH:38][C:23]1=2)=[O:21])[CH3:19]>>[C:11]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:8]([NH:17][C@H:18]([C:20]([N:22]2[C:28](=[O:29])[CH:27]([CH3:30])[C:26]3[CH:31]=[CH:32][CH:33]=[CH:34][C:25]=3[C:24]3[C:35]([NH2:39])=[CH:36][CH:37]=[CH:38][C:23]2=3)=[O:21])[CH3:19])=[O:10])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=C(O)C(c1ccccc1)c1ccccc1
Reactant: CC1C(=O)N(C(=O)[C@H](C)N)c2cccc(N)c2-c2ccccc21
Product: CC1C(=O)N(C(=O)[C@H](C)NC(=O)C(c2ccccc2)c2ccccc2)c2cccc(N)c2-c2ccccc21

Procedure:
Following General Procedure C-P above using diphenylacetic acid and 5-(L-alaninyl)-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one, as described in Example 7-B, the title compound was prepared. The molecular weight as determined by mass spectrometry (FD) was: 504 (M+H).
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19]#[N:20])[C:3]=1[C:21]#[CH:22].C1(C)C=CC(S(O)(=O)=[O:30])=CC=1.O.CCOCC>C(#N)C>[C:21]([C:3]1[C:4]([C:19]#[N:20])=[N:5][N:6]([C:7]2[C:8]([Cl:18])=[CH:9][C:10]([C:14]([F:16])([F:15])[F:17])=[CH:11][C:12]=2[Cl:13])[C:2]=1[NH2:1])(=[O:30])[CH3:22]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: C#Cc1c(C#N)nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c1N
Solvent: O
Solvent: CCOCC
Solvent: CC#N
Product: CC(=O)c1c(C#N)nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c1N
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 5-amino-3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-4-ethynylpyrazole (0.345 g) in acetonitrile (5 ml) was added p-toluenesulphonic acid (0.5 g) and the mixture was stirred at room temperature for 2 hours and then poured into water (100 ml) and ether (100 ml). The organic layer was separated, washed with saturated aqueous sodium hydrogen carbonate solution (50 ml), brine (50 ml), dried (Na2SO4) and evaporated. The residue was purified by column chromatography on silica gel (40 g) eluted with dichloromethane:hexane (10:1). Combination and evaporation of suitable fractions gave the title compound as a white crystalline solid, m.p. 200-1° C.
Reaction SMILES: [CH2:1]([N:3]1[C:7]([CH3:8])=[C:6](I)[C:5]([CH2:10][CH3:11])=[N:4]1)[CH3:2].[N:12]1[CH:17]=[CH:16][C:15](B(O)O)=[CH:14][CH:13]=1.CC(C)([O-])C.[K+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:1]([N:3]1[C:7]([CH3:8])=[C:6]([C:15]2[CH:16]=[CH:17][N:12]=[CH:13][CH:14]=2)[C:5]([CH2:10][CH3:11])=[N:4]1)[CH3:2]
Reactant: OB(O)c1ccncc1
Reactant: CCc1nn(CC)c(C)c1I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CCc1nn(CC)c(C)c1-c1ccncc1
Temperature: 100 °C

Procedure:
A mixture of 17.05 g (64.6 mmol) of 1,3-diethyl-4-iodo-5-methylpyrazole (from Step D) and 11.9 g (105.4 mmol) of pyridine 4-boronic acid in 300 mL of dioxane was treated with a solution of 44 g (392 mmol) of potassium t-butoxide in 100 mL of water. The resulting mixture was treated with 3.75 g (3.2 mmol) of tetrakis(triphenylphosphine)palladium(0), put under an argon atmosphere and heated at 100° C. for 18 h. The mixture was cooled and partitioned between 1 L of ether and 500 mL of water. The organic layer was separated, dried over MgSO4 and concentrated. Flash chromatography on a Biotage 75S afforded the title compound. 1H-NMR (500 MHz) δ 1.19 (t, J=7.5, 3H), 1.48 (t, J=7.5, 3H), 2.27 (s, 3H), 2.67 (q, J=7.5, 2H), 4.09 (q, J=7.5, 2H), 7.18 (dd, J=2.0, 4.5, 2H), 8.60 (dd, J=2.0, 4.5, 2H).
Reaction SMILES: [C:1]([O:9]CC)(=O)[CH2:2][C:3]([O:5]CC)=O.[CH2:12]([C:16]([NH2:18])=[O:17])[C:13]([NH2:15])=[NH:14].Cl.[O-]CC.[Na+]>CCO>[OH:9][C:1]1[CH:2]=[C:3]([OH:5])[N:15]=[C:13]([CH2:12][C:16]([NH2:18])=[O:17])[N:14]=1
Reactant: CCOC(=O)CC(=O)OCC
Reactant: N=C(N)CC(N)=O
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: NC(=O)Cc1nc(O)cc(O)n1

Procedure:
Diethyl malonate and malonamamidine hydrochloride were combined in EtOH (50 mL) with stirring. Sodium ethoxide was added dropwise via addition funnel over 10 minutes. The reaction was stirred overnight at room temperature to give 2-(4,6-dihydroxy-pyrimidin-2-yl)-acetamide.
Reaction SMILES: [CH2:1]([C:3]1[N:8]=[C:7](S(C)(=O)=O)[N:6]=[C:5]([N:13]2[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[N:14]2)[CH:4]=1)[CH3:2].[OH:22][C:23]1[CH:28]=[CH:27][N:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:24]=1.C([O-])([O-])=O.[K+].[K+].O>C(#N)C>[CH2:1]([C:3]1[N:8]=[C:7]([O:22][C:23]2[CH:28]=[CH:27][N:26]=[C:25]([C:29]([F:32])([F:30])[F:31])[CH:24]=2)[N:6]=[C:5]([N:13]2[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[N:14]2)[CH:4]=1)[CH3:2]
Reactant: Oc1ccnc(C(F)(F)F)c1
Reactant: CCc1cc(-n2cc(C(F)(F)F)cn2)nc(S(C)(=O)=O)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CCc1cc(-n2cc(C(F)(F)F)cn2)nc(Oc2ccnc(C(F)(F)F)c2)n1
Reaction time: 8 h
Yield: 65.5 %

Procedure:
A mixture of 0.4 g (1.25 mmol) of 6-ethyl-4-(4-trifluoromethyl-1H-1-pyrazolyl)-2-methylsulfonylpyrimidine, 0.2 g (1.25 mmol) of 4-hydroxy-2-trifluoromethylpyridine and 0.345 g (2.5 mmol) of K2CO3 in 20 ml of acetonitrile is stirred under reflux for 8 h and then allowed to stand at RT overnight. The mixture is put into 40 ml of water and extracted four times with in each case 20 ml of CH2Cl2. The combined organic phases are dried over Na2SO4 and concentrated. Chromatographic purification on silica gel using heptane/ethyl acetate (1:1) gives 0.33 g (65%) of 6-ethyl-4-(4-trifluoromethyl-1H-1-pyrazolyl)-2-(2-trifluoromethylpyridin-4-yloxy)pyrimidine.