Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:8][CH3:9])(=[O:7])/[CH:2]=[CH:3]/[C:4]([O-:6])=O.O.ON1C2C=CC=CC=2N=N1.C1(N=C=NC2CCCCC2)CCCCC1.[C:36]1([C@H:42]([CH2:44][OH:45])[NH2:43])[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>C(OCC)(=O)C>[OH:45][CH2:44][C@H:42]([NH:43][C:4](=[O:6])[CH:3]=[CH:2][C:1]([O:8][CH3:9])=[O:7])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: N[C@@H](CO)c1ccccc1
Reactant: COC(=O)/C=C/C(=O)[O-]
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)C=CC(=O)N[C@@H](CO)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of monomethyl fumarate (3.0 g, 23 mmol) in ethyl acetate (40 mL) was added 1-hydroxybenzotriazole hydrate (3.0 g, 22 mmol), followed by N,N'-dicyclohexylcarbodiimide (4.5 g, 22 mmol) and the reaction stirred at ambient temperature for 1 hour. The solid was filtered off and discarded. To the filtrate was added (R)-α-phenylglycinol (3.0 g, 22 mmol ) and stirring continued for 20 minutes. The volatiles were removed in vacuo (40° C.) and the residue purified by flash chromatography on normal phase silica gel using hexane: ethyl acetate (1:1) as eluant. Recovered 2.5 g (46%) of (18) as a white solid, m.p. 75°-77° C.; IR (neat) 3250 (OH), 1729 (C=O ester), 1666 (C=O amide), 1640 (C=C)cm-1 ;NMR (CDCl3) δ 7.3-7.4 (5H, m, Ph), 7.0 (1H, d, J 15 Hz, trans alkene), 6.8 (1H, d, J 15 Hz, trans alkene), 6.6 (1H, br d, NH), 5.2 (1H, m, CH), 3.9 (2H, t, J 3 Hz, CH2), 3.8 (3H, s, CH3), 2.3 (1H, t, J 5 Hz, OH); [α]D -53° (CHCl3, 24° C., c=1); anal C13H15NO4 ; requires C 62.64% H 6.07% N 5.62%; found C 62.72% H 5.92% N 5.48%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:15]([OH:17])=O)=[N:6][C:7]=1[C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[CH:9]=1.[CH3:18][C:19]([CH3:26])([C:21]1[O:22][CH:23]=[CH:24][N:25]=1)[NH2:20]>>[CH3:18][C:19]([NH:20][C:15]([C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[CH:9]=2)[N:6]=1)=[O:17])([C:21]1[O:22][CH:23]=[CH:24][N:25]=1)[CH3:26]
Reactant: O=C(O)c1ccc(Cl)c(-c2cccc(Cl)c2)n1
Reactant: CC(C)(N)c1ncco1
Product: CC(C)(NC(=O)c1ccc(Cl)c(-c2cccc(Cl)c2)n1)c1ncco1

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-chloro-6-(3-chloro-phenyl)-pyridine-2-carboxylic acid (Example 58 c) and α,α-dimethyl-2-oxazolemethanamine (CAN 1211519-76-4) as starting materials, MS (EI): m/e=376.0 [M+H]+.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CN([CH:10]=[O:11])C.C(Cl)Cl.[F:15][C:16]1[C:24]([F:25])=[CH:23][C:22]([N+:26]([O-:28])=[O:27])=[CH:21][C:17]=1[C:18](O)=[O:19]>CO>[F:15][C:16]1[C:24]([F:25])=[CH:23][C:22]([N+:26]([O-:28])=[O:27])=[CH:21][C:17]=1[C:18]([O:11][CH3:10])=[O:19]
Reactant: O=C(O)c1cc([N+](=O)[O-])cc(F)c1F
Reactant: CN(C)C=O
Agent: O=C(Cl)C(=O)Cl
Solvent: CO
Solvent: ClCCl
Product: COC(=O)c1cc([N+](=O)[O-])cc(F)c1F
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Oxalyl chloride (1 ml) and DMF (5 μl) were added to a CH2Cl2 (1.6 ml) solution containing 2,3-difluoro-5-nitrobenzoic acid (1.61 g) obtained in the 1st step, followed by stirring at room temperature for 15 minutes. The reaction solution was poured into a liquid mixture of MeOH/Py (100 ml/1.28 ml) and the solvent was distilled away under reduced pressure. The obtained residue was purified by silica gel chromatography (n-hexane:ethyl acetate=1:0 to 4:1). A light yellow solid of methyl 2,3-difluoro-5-nitrobenzoate (1.71 g) was thus obtained.
Reaction SMILES: [C:1]([C:5]1[CH:24]=[CH:23][C:8]([CH2:9][NH:10][C:11]([NH:13][C@H](C2C=CC(N)=CC=2)C)=[S:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C(C1C=CC(CNC(N[C@@H:38]([C:40]2[CH:45]=[CH:44][C:43]([NH2:46])=[CH:42][CH:41]=2)[CH3:39])=S)=CC=1)(C)(C)C>>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([CH2:9][N:10]([C@H:38]([C:40]2[CH:45]=[CH:44][C:43]([NH2:46])=[CH:42][CH:41]=2)[CH3:39])[C:11]([NH2:13])=[S:12])=[CH:23][CH:24]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: C[C@H](NC(=S)NCc1ccc(C(C)(C)C)cc1)c1ccc(N)cc1
Reactant: C[C@@H](NC(=S)NCc1ccc(C(C)(C)C)cc1)c1ccc(N)cc1
Product: C[C@@H](c1ccc(N)cc1)N(Cc1ccc(C(C)(C)C)cc1)C(N)=S

Procedure:
The spectral data of compound 16-4 were identical to those of compound 16-3.
Reaction SMILES: [C:1]([O-:4])(=[O:3])[CH3:2].[NH4+].[CH3:6][C:7]#N>>[CH2:2]1[CH2:1][O:4][CH2:7][CH2:6]1.[O:3]1[CH2:7][CH2:6][CH2:2][CH2:1]1
Reactant: CC#N
Reactant: CC(=O)[O-]
Agent: [NH4+]
Product: C1CCOC1
Reaction time: 0.04 h

Procedure:
Analytical HPLC/MS Analytical HPLC/MS was performed on a system consisting of a Waters Acquity UPLC, Waters Micromass LCT Premier XE mass spectrometer, Waters Acquity PDA. Column: Acquity UPLC HSS T3 1.8 μm; 2.1×50 mm; solventsystem: A=10 mM Ammonium acetate+0.1% HCOOH and B═CH3CN+0.1% HCOOH; flow rate=0.7 mL/min; method (4.8 min): Linear gradient method going from 1% B to 95% B in 2.6 minutes and staying at 95% B for 1.2 minute. General Procedure of Preparation:
Reaction SMILES: [O:1]1[C:5]2[C:6]([C:10]([CH3:16])([CH3:15])[CH2:11][C:12]([OH:14])=O)=[CH:7][CH:8]=[CH:9][C:4]=2[CH2:3][CH2:2]1.O=S(Cl)Cl.Cl.[CH3:22][NH:23][O:24][CH3:25].Cl>C(Cl)Cl.N1C=CC=CC=1>[CH3:22][N:23]([O:24][CH3:25])[C:12](=[O:14])[CH2:11][C:10]([C:6]1[C:5]2[O:1][CH2:2][CH2:3][C:4]=2[CH:9]=[CH:8][CH:7]=1)([CH3:16])[CH3:15]
Reactant: CC(C)(CC(=O)O)c1cccc2c1OCC2
Reactant: CNOC
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: CON(C)C(=O)CC(C)(C)c1cccc2c1OCC2
Reaction time: 0.5 h
Yield: 99.3 %

Procedure:
3-(2,3-Dihydrobenzofur-7-yl)-3-methylbutanoic acid (800 mg) in CH2Cl2 (10 mL) was treated with SOCl2 (0.315 mL) at 0° C. After 30 minutes, N,O-dimethylhydroxylamine hydrochloride (421 mg) in pyridine (1.5 mL) was added to the green mixture at 0° C. After another 30 minutes, 15 mL of 2 M HCl was added. The organic phase was separated and the aqueous layer was extracted with three 20 mL portions of CH2Cl2. The combined organic phases were dried over magnesium sulfate. The solvent was removed to yield 950 mg (99%) of 3-(2,3-dihydrobenzofur-7-yl)-3-methylbutanoic acid N,O-dimethylhydroxylamide as a yellowish oil.
Reaction SMILES: C([NH:11][C@:12]([CH3:24])([C:21]([OH:23])=[O:22])[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1)(OCC1C=CC=CC=1)=O.[H][H]>[Pd].CO>[CH3:24][C@@:12]([C:21]([OH:23])=[O:22])([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1)[NH2:11]
Reactant: C[C@@](Cc1ccc(O)cc1)(NC(=O)OCc1ccccc1)C(=O)O
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: C[C@](N)(Cc1ccc(O)cc1)C(=O)O

Procedure:
200 milligrams of (S)-N-carbobenzyloxy-α-methyltyrosine is mixed together with 20 milligrams of 10 percent palladium on carbon catalyst and 10 milliliters of methanol and the mixture subjected to hydrogen at a pressure of 40 psi for several hours. Thereafter, the catalyst is removed and the filtrate concentrated to obtain a (S)-α-methyltyrosine product.
Reaction SMILES: [OH:1][C:2]1[CH:38]=[CH:37][C:5]([C:6]([N:8]([CH:34]([CH3:36])[CH3:35])[C:9]2[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][C:10]=2[CH:17]2[CH2:26][CH2:25][C:24]3[CH:23]=[C:22]([O:27]C(=O)C(C)(C)C)[CH:21]=[CH:20][C:19]=3[CH2:18]2)=O)=[CH:4][CH:3]=1.[N:39]1([C:43](=O)[CH2:44]Cl)[CH2:42][CH2:41][CH2:40]1>>[N:39]1([CH2:43][CH2:44][O:1][C:2]2[CH:3]=[CH:4][C:5]([CH2:6][N:8]([CH:34]([CH3:36])[CH3:35])[C:9]3[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][C:10]=3[CH:17]3[CH2:26][CH2:25][C:24]4[CH:23]=[C:22]([OH:27])[CH:21]=[CH:20][C:19]=4[CH2:18]3)=[CH:37][CH:38]=2)[CH2:42][CH2:41][CH2:40]1
Reactant: COc1ccc(C2CCc3cc(OC(=O)C(C)(C)C)ccc3C2)c(N(C(=O)c2ccc(O)cc2)C(C)C)c1
Reactant: O=C(CCl)N1CCC1
Product: COc1ccc(C2CCc3cc(O)ccc3C2)c(N(Cc2ccc(OCCN3CCC3)cc2)C(C)C)c1
Yield: 20.2 %

Procedure:
Synthesized from pivalic acid 6-{2-[(4-hydroxybenzoyl)isopropylamino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (27 mg) and 1-azetidin-1-yl-2-chloroethanone (15 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (5.3 mg) was obtained.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH2:3][CH:2]1[C:6]1[C:20]([O:21][C:22]2[CH:23]=[N:24][C:25]([S:28]([CH2:31][CH3:32])(=[O:30])=[O:29])=[CH:26][CH:27]=2)=[CH:19][C:9]2[NH:10][C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)=[N:12][C:8]=2[CH:7]=1.[CH3:33]CCCCC.C(O)C>>[CH2:31]([S:28]([C:25]1[N:24]=[CH:23][C:22]([O:21][C:20]2[C:6]([CH:2]([OH:1])[CH2:3][CH2:4][CH:5]=[CH2:33])=[CH:7][C:8]3[N:12]=[C:11]([C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=4)[NH:10][C:9]=3[CH:19]=2)=[CH:27][CH:26]=1)(=[O:29])=[O:30])[CH3:32]
Reactant: CCS(=O)(=O)c1ccc(Oc2cc3[nH]c(-c4ccccn4)nc3cc2C2CCCO2)cn1
Reactant: CCCCCC
Solvent: CCO
Product: C=CCCC(O)c1cc2nc(-c3ccccn3)[nH]c2cc1Oc1ccc(S(=O)(=O)CC)nc1

Procedure:
1-(6-((6-(Ethylsulfonyl)pyridin-3-yl)oxy)-2-pyridin-2-yl-1H-benzimidazol-5-yl)pent-4-ene-1-ol (520 mg) obtained in Example 11 was optically resolved through an optical resolution column (CHIRALPAK OD 2 cmφ×25 cmL, by Daicel Chemical Industry, mobile phase: hexane/ethanol=1/1, flow rate: 10 ml/min) to obtain its enantiomer A (retention time, 11.7 min) and enantiomer B (retention time, 15.0 min) both as a yellow solid.
Reaction SMILES: [CH3:1][C:2]1[CH2:7][C:6]([CH3:9])([CH3:8])[C:5]([CH:10]=[O:11])=[CH:4][CH:3]=1>[Pd].C(O)C>[CH3:1][CH:2]1[CH2:7][C:6]([CH3:8])([CH3:9])[C:5]([CH:10]=[O:11])=[CH:4][CH2:3]1
Reactant: CC1=CC=C(C=O)C(C)(C)C1
Agent: [Pd]
Solvent: CCO
Product: CC1CC=C(C=O)C(C)(C)C1
Reaction time: 3.5 h
Yield: 87.6 %

Procedure:
A mixture of 4,6,6-trimethyl-1,3-cyclohexadiene-1-carbaldehyde (141 g, 0.94 mole), ethanol (1 l) and palladium on charcoal (10%, 0.5 g) was hydrogenated by shaking under a H2-atmosphere for 3.5 h. The H2-consumption was 23.5 l. After filtration and concentration of the thus-obtained solution, the residue was distilled at 50°/0.7 hPa, to obtain 125.3 g (87.6%) of the desired product.
Reaction SMILES: C(O[C:6]([NH:8][CH2:9][CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][CH:19]([OH:25])[C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:14][CH:13]=1)=[O:7])(C)(C)C.Cl.[N:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[C:33]1[CH:41]=[CH:40][C:36](C(Cl)=O)=[CH:35][CH:34]=1>C(N(CC)CC)C>[OH:25][CH:19]([CH2:18][C:15]1[CH:14]=[CH:13][C:12]([O:11][CH2:10][CH2:9][NH:8][C:6](=[O:7])[C:36]2[CH:35]=[CH:34][C:33]([C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][N:27]=3)=[CH:41][CH:40]=2)=[CH:17][CH:16]=1)[C:20]([O:22][CH2:23][CH3:24])=[O:21]
Reactant: CCOC(=O)C(O)Cc1ccc(OCCNC(=O)OC(C)(C)C)cc1
Reactant: O=C(Cl)c1ccc(-c2ccccn2)cc1
Agent: Cl
Solvent: CCN(CC)CC
Product: CCOC(=O)C(O)Cc1ccc(OCCNC(=O)c2ccc(-c3ccccn3)cc2)cc1
Yield: 91 %

Procedure:
In a similar manner to that described in Example 126, a reaction was carried out using ethyl 3-[4-(2-t-butoxycarbonylaminoethoxy)phenyl]-2-hydroxypropionate (168 mg), 4-pyridine-2-ylbenzoylchloride hydrochloride (126 mg) and triethylamine (0.28 ml) and the reaction mixture was treated to afford the title compound (188 mg) as colorless crystals.
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:16]=[C:17]([C:22]3[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=3)[C:18]([NH2:21])=[N:19][CH:20]=2)=[CH:11][CH:10]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Si:31]([O:38][C:39]1[CH:44]=[CH:43][C:42]([CH2:45][C:46](Cl)=[O:47])=[CH:41][CH:40]=1)([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:33])[CH3:32].O>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[Si:31]([O:38][C:39]1[CH:40]=[CH:41][C:42]([CH2:45][C:46]([NH:21][C:18]2[C:17]([C:22]3[CH:23]=[CH:24][C:25]([N+:28]([O-:30])=[O:29])=[CH:26][CH:27]=3)=[N:16][C:15]([C:12]3[CH:11]=[CH:10][C:9]([O:8][Si:1]([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2])=[CH:14][CH:13]=3)=[CH:20][N:19]=2)=[O:47])=[CH:43][CH:44]=1)([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:33])[CH3:32]
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(CC(=O)Cl)cc1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(-c2cnc(N)c(-c3ccc([N+](=O)[O-])cc3)n2)cc1
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: c1ccncc1
Product: CC(C)(C)[Si](C)(C)Oc1ccc(CC(=O)Nc2ncc(-c3ccc(O[Si](C)(C)C(C)(C)C)cc3)nc2-c2ccc([N+](=O)[O-])cc2)cc1
Temperature: 50 °C
Reaction time: 20 h
Yield: 48.1 %

Procedure:
Under an argon atmosphere, to a mixture of 5-[4-(tert-butyldimethylsilyloxy)phenyl]-3-(4-nitrophenyl)pyrazin-2-amine (7o) (317 mg, 751 μmol) and 4-(dimethylamino)pyridine (15.3 mg, 125 μmol) dissolved in anhydrous pyridine (15 mL) was added 2-[4-(tert-butyldimethylsilyl oxy)phenyl]acetyl chloride (10) prepared above at 0° C. and the mixture was heated with stirring at 50° C. for 20 hours. After cooling to room temperature, to this was added water and the product was extracted with ethyl acetate (100 mL×3). The combined organic extract was washed successively with water (200 mL) and brine (200 mL), followed by drying over anhydrous sodium sulfate. After filtration and concentration under reduced pressure, the residue was purified by column chromatography (silica gel 50 g, n-hexane/ethyl acetate=2/1) to give Compound 11o (242 mg, 361 μmol, 48.1%) as a yellow solid. Rf=0.30 (n-hexane/ethyl acetate=2/1); 1H NMR (400 MHz, DMSO-d6) δ 0.15 (s, 6H), 0.20 (s, 6H), 0.92 (s, 9H), 0.93 (s, 9H), 3.44 (s, 2H), 6.67-6.74 (AA′BB′, 2H), 6.94-7.07 (2AA′BB′, 4H), 7.80-7.86 (AA′BB′, 2H), 8.01-8.12 (2AA′BB′, 4H), 9.05 (s, 1H), 10.85 (s, 1H); 13C NMR (67.8 MHz, DMSO-d6) δ −4.5 (2C), −4.6 (2C), 17.9, 18.0, 25.50 (3C), 25.51 (3C), 41.6, 119.4 (2C), 120.4 (2C), 123.2 (2C), 127.4, 128.2, 128.52 (2C), 128.54 (2C), 130.4 (2C), 138.7, 143.0, 144.5, 145.0, 146.9, 147.9, 153.9, 156.9, 168.9; IR (KBr, cm−1) 700, 741, 781, 839, 914, 1169, 1265, 1348, 1443, 1508, 1603, 1670, 2857, 2930, 2955.
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]2[C:10]([CH2:15][CH2:16][CH2:17][OH:18])=[N:11][CH:12]=[CH:13][CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]Br.[OH-].[Na+]>O>[Br:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][O:18][CH2:17][CH2:16][CH2:15][C:10]1[C:9]([O:8][CH2:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[CH:14][CH:13]=[CH:12][N:11]=1
Reactant: BrCCCCCCBr
Reactant: OCCCc1ncccc1OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: BrCCCCCCOCCCc1ncccc1OCc1ccccc1
Reaction time: 144 h

Procedure:
A mixture of 3-(phenylmethoxy)-2-pyridinepropanol (1.4 g), 1,6-dibromohexane (4 ml), 40% aqueous sodium hydroxide (4 ml) and TAB (100 mg) was stirred vigorously for 6 days. Water (10 ml) was added and the mixture was extracted with ether (3×10 ml). The ether extracts were washed with water and brine, dried and concentrated to an oil which was purified by FCC eluting with cyclohexane followed by cyclohexane/ethyl acetate (4:1) to give the title compound as an orange oil (1.0 g) t.l.c. (cyclohexane/ethyl acetate 4:1) Rf 0.25.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[N:5]=[C:4](Cl)[N:3]=1.[NH2:10][CH2:11][CH2:12][O:13][CH2:14][CH2:15][OH:16].[OH-].[Na+]>O>[NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[N:5]=[C:4]([NH:10][CH2:11][CH2:12][O:13][CH2:14][CH2:15][OH:16])[N:3]=1
Reactant: NCCOCCO
Reactant: Nc1nc(N)nc(Cl)n1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Nc1nc(N)nc(NCCOCCO)n1
Temperature: 100 °C
Reaction time: 3 h
Yield: 63 %

Procedure:
14.5 g (0.1 mol) of 2,4-diamino-6-chloro-1,3,5-triazine and 11.6 g (0.11 mol) of 2-(2'-aminoethoxy)ethanol were added to 60 mL of water and heated to 100° C. while stirring the mixture as a suspension. After continuing the reaction for 2 hours, an aqueous solution of 4.0 g (0.1 mol) of sodium hydroxide in 20 mL of water was dropwise added over 1 hour while maintaining the reaction temperature, and the reaction was continued for further 3 hours at the same temperature. The homogeneous reaction mixture thus obtained was gradually cooled and allowed to stand at room temperature for one night. The crystals precipitated were collected by filtration, washed with a small amount of water, and recrystallized from water to obtain 13.5 g of the intended compound, 2,4-diamino-6-(5-hydroxy-3-oxapentylamino)-1,3,5-triazine as crystals. Yield 62%.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:13]=1[N:12]=[C:11]([NH:14][C:15]([CH3:26])([CH3:25])[CH2:16][NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[C:10]([CH3:27])=[N:9]2)(=[O:3])[CH3:2].FC(F)(F)S(O[Si:34]([C:37]([CH3:40])([CH3:39])[CH3:38])([CH3:36])[CH3:35])(=O)=O>C(Cl)Cl>[Si:34]([O:3][C:1]([C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:13]=1[N:12]=[C:11]([NH:14][C:15]([CH3:26])([CH3:25])[CH2:16][NH:17][C:18](=[O:24])[O:19][C:20]([CH3:21])([CH3:23])[CH3:22])[C:10]([CH3:27])=[N:9]2)=[CH2:2])([C:37]([CH3:40])([CH3:39])[CH3:38])([CH3:36])[CH3:35]
Reactant: CC(=O)c1cccc2nc(C)c(NC(C)(C)CNC(=O)OC(C)(C)C)nc12
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: ClCCl
Product: C=C(O[Si](C)(C)C(C)(C)C)c1cccc2nc(C)c(NC(C)(C)CNC(=O)OC(C)(C)C)nc12

Procedure:
A solution of tert-butyl (2-((8-acetyl-3-methylquinoxalin-2-yl)amino)-2-methylpropyl)carbamate (339a, 0.78 g, 2.094 mmol), tert-butyldimethylsilyl trifluoromethanesulfonate (0.72 mL, 3.14 mmol), and TEA (0.88 mL, 6.28 mmol) in DCM (21 mL) was stirred at 0° C. for 20 min when the silyl enol ether was observed via lcms. The reaction mixture was diluted with DCM (100 mL), added to a separatory funnel, and washed with saturated aq. NaHCO3 (100 mL) before the organic layer was separated, dried over Na2SO4, and concentrated to give tert-butyl (2-((8-(1-((tert-butyldimethylsilyl)oxy)vinyl)-3-methylquinoxalin-2-yl)amino)-2-methylpropyl)carbamate (339b) as a yellow oil. MS (ESI, pos. ion) m/z: 487.3 (M+1).
Reaction SMILES: [Mg].BrCCBr.Br[C:7]1[CH:8]=[CH:9][C:10]([F:18])=[C:11]([CH:13]2[O:17][CH2:16][CH2:15][O:14]2)[CH:12]=1.[N+:19]([C:22]1[C:23]([CH:32]=[O:33])=[CH:24][CH:25]=[C:26]2[C:31]=1[N:30]=[CH:29][CH:28]=[CH:27]2)([O-:21])=[O:20]>C1COCC1>[O:14]1[CH2:15][CH2:16][O:17][CH:13]1[C:11]1[CH:12]=[C:7]([CH:32]([C:23]2[C:22]([N+:19]([O-:21])=[O:20])=[C:31]3[C:26]([CH:27]=[CH:28][CH:29]=[N:30]3)=[CH:25][CH:24]=2)[OH:33])[CH:8]=[CH:9][C:10]=1[F:18]
Reactant: O=Cc1ccc2cccnc2c1[N+](=O)[O-]
Reactant: Fc1ccc(Br)cc1C1OCCO1
Agent: [Mg]
Solvent: C1CCOC1
Solvent: BrCCBr
Product: O=[N+]([O-])c1c(C(O)c2ccc(F)c(C3OCCO3)c2)ccc2cccnc12
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 73.8 %

Procedure:
Magnesium (983 mg, 40.5 mmol) was suspended in anhydrous THF (30 ml). 1,2-dibromoethane (0.17 ml, 2.02 mmol) was added and the solution was stirred at room temperature for 20 min. 2-(5-bromo-2-fluoro-phenyl)-[1,3]dioxolane 417 (3.2 g, 12.95 mmol) was added dropwise and the mixture was heated at 40° C. for 2 h. The mixture was allowed to cool to room temperature. The Grignard reagent (0.43M; 28.6 ml) was added to a suspension of 8-nitroquinoline-7-carbaldehyde 204 (2.5 g, 12.4 mmol) in dry THF (30 ml) at 0° C. under a nitrogen atmosphere. The mixture was stirred at room temperature for 30 min. The mixture was quenched with sat. NH4Cl (10 ml) and the aqueous phase was extracted with EtOAc (20 ml). The organic phase was washed with brine (10 ml), dried (Na2SO4) and concentrated in vacuo. The crude residue was purified by column chromatography with heptane/EtOAc (50:50) as the eluent to give the title compound (3.39 g, 74%).
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[C:11]([C:16](=[O:18])[CH3:17])=[N:12][CH:13]=[CH:14][CH:15]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].CO[CH:21](OC)[N:22]([CH3:24])[CH3:23]>>[Si:1]([O:8][CH2:9][C:10]1[C:11]([C:16](=[O:18])/[CH:17]=[CH:21]/[N:22]([CH3:24])[CH3:23])=[N:12][CH:13]=[CH:14][CH:15]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: COC(OC)N(C)C
Reactant: CC(=O)c1ncccc1CO[Si](C)(C)C(C)(C)C
Product: CN(C)/C=C/C(=O)c1ncccc1CO[Si](C)(C)C(C)(C)C

Procedure:
1-(3-((tert-butyldimethylsilyloxy)methyl)pyridin-2-yl)ethanone (10.8 g, 40.75 mmol) in dimethoxy-N,N-dimethylmethanamine (15.0 mL) was heated to reflux for 3 days. The mixture was concentrated and used for next step without further purification. MS (ESI) m/z 321.1 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:22])[C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[N:16]1[CH:20]=[N:19][N:18]=[C:17]1[CH3:21].[CH2:23]=[O:24]>C1(C)C(C)=CC=CC=1>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:22])[C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[N:16]1[C:17]([CH3:21])=[N:18][N:19]=[C:20]1[CH2:23][OH:24]
Reactant: Cc1nncn1-c1ccc(Cl)cc1C(=O)c1ccccc1F
Reactant: C=O
Solvent: Cc1ccccc1C
Product: Cc1nnc(CO)n1-c1ccc(Cl)cc1C(=O)c1ccccc1F
Temperature: 122 °C

Procedure:
In the manner given in Example 4, 2'-fluoro-5 -chloro-2-(3-methyl-4H-1,2,4-triazol-4-yl)benzophenone, paraformaldehyde and xylene are warmed under nitrogen to about 122° C. to give 2'-fluoro-5-chloro-2-[3-(hydroxymethyl)-5-methyl-4H-1,2,4-triazol-4-yl]benzophenone.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1)#[N:2].[CH2:10](Br)[CH:11]=[CH2:12].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:12]([O:9][C:6]1[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=1)[CH:11]=[CH2:10]
Reactant: C=CCBr
Reactant: N#Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=CCOc1ccc(C#N)cc1
Reaction time: 4 h
Yield: 96 %

Procedure:
A mixture comprising 29.75 g of 4-cyanophenol, 33.27 g of allyl bromide, 41.46 g of potassium carbonate and 350 ml of acetone, was refluxed under stirring for 4 hours. Acetone was distilled, and water was added to the residue. The mixture was extracted with benzene. The benzene layer was washed sequentially with a 5% sodium hydroxide aqueous solution and water, and dried over sodium sulfate. Then, the solvent was distilled off to obtain a pale yellow oily substance. The residual substance was crystallized from n-hexane-ethyl ether to obtain 38.16 g of 4-allyloxy benzonitrile as colorless crystals having a melting point of from 40.5° to 41° C.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[F:9].[CH3:10][S:11](Cl)(=[O:13])=[O:12]>N1C=CC=CC=1.CCOC(C)=O>[Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][S:11]([CH3:10])(=[O:13])=[O:12])=[CH:4][C:3]=1[F:9]
Reactant: Nc1ccc(Br)c(F)c1
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CS(=O)(=O)Nc1ccc(Br)c(F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.5 %

Procedure:
step 1—To a solution of 4-bromo-3-fluoro-aniline (1.00 g, 5.263 mmol) in pyridine (5 mL) at 0° C. was added methanesulfonyl chloride (0.500 mL, 6.424 mmol). The reaction was gradually warmed to RT and stirred overnight then diluted with EtOAc. The organic layer was washed successively with saturated aqueous CuSO4 solution, brine, dried (Na2SO4), filtered and concentrated. The crude residue was purified by SiO2 chromatography eluting with an EtOAc/hexane gradient (5 to 20% EtOAc) to afford 1.235 g (88%) of N-(4-bromo-3-fluoro-phenyl)-methanesulfonamide (72) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]3[C:10]([O:24][CH:25]([F:27])[F:26])=[CH:11][CH:12]=[C:13]([C:14]4[O:15][CH:16]=[C:17]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[N:18]=4)[C:7]=3[C:6]=2[CH:28]=1.N1C=CC=CC=1.[CH3:35][S:36](Cl)(=[O:38])=[O:37].O>O1CCCC1>[F:27][CH:25]([F:26])[O:24][C:10]1[C:8]2[O:9][C:5]3[CH:4]=[CH:3][C:2]([NH:1][S:36]([CH3:35])(=[O:38])=[O:37])=[CH:28][C:6]=3[C:7]=2[C:13]([C:14]2[O:15][CH:16]=[C:17]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[N:18]=2)=[CH:12][CH:11]=1
Reactant: CS(=O)(=O)Cl
Reactant: CCOC(=O)c1coc(-c2ccc(OC(F)F)c3oc4ccc(N)cc4c23)n1
Solvent: O
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CCOC(=O)c1coc(-c2ccc(OC(F)F)c3oc4ccc(NS(C)(=O)=O)cc4c23)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 44.8 %

Procedure:
To a solution of ethyl 2-(8-amino-4-(difluoromethoxy)dibenzo[b,d]furan-1-yl)oxazole-4-carboxylate (0.65 g, 1.667 mmol) in tetrahydrofuran (10 mL) was added pyridine (0.4 mL, 5.031 mmol). To this solution was added methane sulfonyl chloride (2.6 mL, 0.033 mol) at 0-5° C. After 30 minutes, the reaction slurry was stirred at room temperature for 18 hours. The reaction mass was poured into the cold water and extracted with dichloromethane (3×50 mL). The organics were dried over sodium sulphate and filtered. The organics were evaporated under reduced pressure to give the crude product. The product was purified by column chromatography by using gradient of ethyl acetate in hexane (0-20) %. Yield—44.8%. 1H-NMR (DMSO-d6) δ: 1.35-1.39 (m, 3H), 3.06 (s, 3H), 4.36-4.41 (m, 2H), 7.41 (s, 1H), 7.51 (d, 1H), 7.62 (d, 1H), 7.87 (d, 1H), 8.06 (d, 1H), 8.96 (s, 1H), 9.07 (s, 1H), 9.77 (s, 1H); HPLC (purity): 97.2%; Mass calculated for C20H16F2N2O7S-466.4, observed—467.0; Rf—0.47 (Ethyl acetate:Hexane (1:1)