Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N1C=CC=CC=1.[C:7]1([S:13](Cl)(=[O:15])=[O:14])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.Cl.[CH3:18][O:19][C:20](=[O:23])[CH2:21][NH2:22]>ClCCl.O>[CH3:18][O:19][C:20]([CH2:21][NH:22][S:13]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)(=[O:15])=[O:14])=[O:23]
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: COC(=O)CN
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)CNS(=O)(=O)c1ccccc1
Temperature: 25 °C
Yield: 53.1 %

Procedure:
A 47.5 g (0.6 mol) sample of pyridine was added dropwise to a stirred and cooled (ice bath) slurry of 53.0 g (0.3 mol) benzenesulfonyl chloride and 37.7 g (0.3 mol) glycine methyl ester hydrochloride in 500 ml dichloromethane. The reaction mixture was then allowed to warm to 25° C. and was stirred for about 16 hours. The reaction mixture was diluted with 250 ml water, the organic layer was separated, washed with water, washed with 10% aqueous hydrochloric acid solution, washed with water, dried over magnesium sulfate and evaporated to give 36.5 g N-(methoxycarbonylmethyl)benzenesulfonamide, which crystallized as a colorless solid melting at 62°-63° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:9](=[O:11])[CH3:10])=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1.C([O:15][CH2:16][C:17]([F:20])([F:19])[F:18])(=O)C.CCOCC.C([O-])C.[Na+]>C(O)C>[Cl:1][C:2]1[C:3]([C:9](=[O:11])[CH2:10][C:16]([C:17]([F:20])([F:19])[F:18])=[O:15])=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: CC(=O)c1ncc(Cl)cc1Cl
Reactant: CC(=O)OCC(F)(F)F
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CCOCC
Product: O=C(CC(=O)C(F)(F)F)c1ncc(Cl)cc1Cl
Reaction time: 8 h

Procedure:
15.8 g of 3,5-dichloro-2-acetylpyridine are introduced together with 12.0 ml of trifluoroethyl acetate into 125 ml of absolute ether. With stirring, the mixture is cooled using an ice-bath and 46.6 ml of, a 21% sodium ethanolate solution in ethanol are added dropwise. The ice-bath is then removed and the mixture is subsequently stirred overnight at 25° C. After cooling the reaction mixture in an ice-bath and adding dropwise 7.5 ml of glacial acetic acid, the mixture is concentrated in vacuo. 39.0 g of 1-(3,5-dichloro-2-pyridyl)-3-trifluoromethylpropane-1,3-dione are obtained, which can be used directly for the following cyclisation step.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5](F)=[CH:6][CH:7]=1.[NH:9]1[CH2:15][CH2:14][CH2:13][NH:12][CH2:11][C:10]1=[O:16].C(N(CC)CC)C>CN(C)C(=O)C.C(OCC)(=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:12]2[CH2:13][CH2:14][CH2:15][NH:9][C:10](=[O:16])[CH2:11]2)=[N:4][CH:3]=1
Reactant: Fc1ccc(Br)cn1
Reactant: O=C1CNCCCN1
Solvent: CCN(CC)CC
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: O=C1CN(c2ccc(Br)cn2)CCCN1

Procedure:
A solution of 3-bromo-6-fluoropyridine (315 mg, 1.79 mmol), 1,4-diazepan-2-one (200 mg, 1.75 mmol), and triethylamine (0.269 ml, 1.93 mmol) in N,N-dimethylacetamide (3 mL) was irradiated in a microwave reactor for twenty minutes at 220° C. The reaction mixture was diluted with ethyl acetate (35 mL) and then washed with saturated aqueous sodium bicarbonate (15 mL), water (3×10 mL), and brine (15 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (0.5-8.5% methanol/dichloromethane) to afford 4-(5-bromopyridin-2-yl)-1,4-diazepan-2-one. MS ESI calc'd. for C10H13BrN3O [M+H]+ 270 and 272. found 270 and 272. 1H NMR (500 MHz, DMSO-d6): δ 8.14 (d, J=2.4 Hz, 1H), 7.68 (dd, J=9.1, 2.7 Hz, 1H), 7.48 (m, 1H), 6.70 (d, J=9.1 Hz, 1H), 4.11 (s, 2H), 3.85 (s, 2H), 3.18 (m, 2H), 1.62 (m, 2H).
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][C:7]2[NH:8][CH2:9][CH2:10][O:11][C:6]=2[CH:5]=1)([O-:3])=[O:2].[H-].[Na+].Br[CH2:17][C:18]1[CH:27]=[CH:26][C:21]([C:22]([O:24][CH3:25])=[O:23])=[CH:20][CH:19]=1>CN(C=O)C>[N+:1]([C:4]1[CH:13]=[CH:12][C:7]2[N:8]([CH2:17][C:18]3[CH:27]=[CH:26][C:21]([C:22]([O:24][CH3:25])=[O:23])=[CH:20][CH:19]=3)[CH2:9][CH2:10][O:11][C:6]=2[CH:5]=1)([O-:3])=[O:2]
Reactant: COC(=O)c1ccc(CBr)cc1
Reactant: O=[N+]([O-])c1ccc2c(c1)OCCN2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(CN2CCOc3cc([N+](=O)[O-])ccc32)cc1
Yield: 90.5 %

Procedure:
The same operation as in Example (90a) was performed using 7-nitro-2,3-dihydro-4H-1,4-benzoxazine (described in Higuchi, Robert I.; Arienti, Kristen L.; Lopez, Francisco J.; Mani, Neelakhanda S.; Mais, Dale E.; Caferro, Thomas R.; Long, Yun Oliver; Jones, Todd K.; Edwards, James P.; Zhi, Lin; Schrader, William T.; et al.; J. Med. Chem.; 50; 10; 2007; 2486-2496, 0.6 g, 3.3 mmol), sodium hydride (55% content, 145 mg, 3.3 mmol), methyl 4-bromomethylbenzoate (0.76 g, 3.3 mmol) and DMF (20 mL). The resulting solid was washed with ethyl acetate/hexane=1/1 to obtain 0.98 g of the title compound as a yellow solid (90%).
Reaction SMILES: C(OC([NH:8][C@@H:9]([C:11]1[CH:20]=[CH:19][C:18]2[C:13](=[CH:14][C:15](/[CH:21]=[CH:22]/[C:23]3([C:29]([O:31][C@@H:32]([CH:49]([CH3:51])[CH3:50])[C:33]([NH:35][C@@H:36]([CH3:48])[C:37]([N:39]4[CH2:44][CH2:43][CH2:42][C@@H:41]([C:45]([OH:47])=[O:46])[NH:40]4)=[O:38])=[O:34])=[O:30])[CH2:28][CH2:27][CH2:26][CH2:25][O:24]3)=[CH:16][CH:17]=2)[N:12]=1)[CH3:10])=O)(C)(C)C.[ClH:52]>>[ClH:52].[NH2:8][C@@H:9]([C:11]1[CH:20]=[CH:19][C:18]2[C:13](=[CH:14][C:15](/[CH:21]=[CH:22]/[C:23]3([C:29]([O:31][C@@H:32]([CH:49]([CH3:51])[CH3:50])[C:33]([NH:35][C@@H:36]([CH3:48])[C:37]([N:39]4[CH2:44][CH2:43][CH2:42][C@@H:41]([C:45]([OH:47])=[O:46])[NH:40]4)=[O:38])=[O:34])=[O:30])[CH2:28][CH2:27][CH2:26][CH2:25][O:24]3)=[CH:16][CH:17]=2)[N:12]=1)[CH3:10]
Reactant: CC(C)[C@H](OC(=O)C1(/C=C/c2ccc3ccc([C@@H](C)NC(=O)OC(C)(C)C)nc3c2)CCCCO1)C(=O)N[C@@H](C)C(=O)N1CCC[C@@H](C(=O)O)N1
Agent: Cl
Product: CC(C)[C@H](OC(=O)C1(/C=C/c2ccc3ccc([C@@H](C)N)nc3c2)CCCCO1)C(=O)N[C@@H](C)C(=O)N1CCC[C@@H](C(=O)O)N1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of crude (S)-1-{(S)-2-[(S)-2-(2-{(E)-2-[2-((R)-1-tert-butoxycarbonylamino-ethyl)-quinolin-7-yl]-vinyl}-tetrahydro-pyran-2-carbonyloxy)-3-methyl-butyrylamino]-propionyl}-hexahydro-pyridazine-3-carboxylic acid (0.05 mmol) in hydrochloric acid (4 M in 1,4-dioxane, 2 mL) was stirred at room temperature for 1 h. The solvent was evaporated and the residue was co-evaporated with diethyl ether (2×) and the resulting solid was dried to afford (S)-1-{(S)-2-[(S)-2-(2-{(E)-2-[2-((R)-1-amino-ethyl)-quinolin-7-yl]-vinyl}-tetrahydro-pyran-2-carbonyloxy)-3-methyl-butyrylamino]-propionyl}-hexahydro-pyridazine-3-carboxylic acid hydrochloride (0.05 mmol) as an off-white solid and as a 1:1 mixture of diastereoisomers which was used crude in the next reaction. LCMS (m/z) 610.1 [M+H], Tr=1.60 min.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[CH:10]=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.ClC1C=CC=C(C(OO)=[O:19])C=1.ClCCl.CO>C(COC)OC>[F:1][C:2]1[CH:3]=[C:4]2[CH:10]=[CH:9][NH:8][C:5]2=[N+:6]([O-:19])[CH:7]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Fc1cnc2[nH]ccc2c1
Solvent: ClCCl
Solvent: CO
Solvent: COCCOC
Product: [O-][n+]1cc(F)cc2cc[nH]c21
Yield: 56.3 %

Procedure:
5-Fluoro-1H-pyrrolo[2,3-b]pyridine 7-oxide can be obtained as in example 4 stage 4(a) but starting from 2.7 g of 5-fluoro-1H-pyrrolo[2,3-b]pyridine, and 6.22 g of 3-chloro-perbenzoic acid in 70 cm3 of dimethoxyethane. In this way, after flash chromatography on a silica column [eluent: dichloromethane/methanol (95/5 by volume)], 1.70 g of 5-fluoro-1H-pyrrolo[2,3-b]pyridine 7-oxide is obtained as a powder with the following characteristics:
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8]Br)=[CH:6][CH:5]=1)([O-:3])=[O:2].N[N:13]1[CH:17]=[N:16][N:15]=[CH:14]1.O>C(O)(C)C>[N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8][N:15]2[CH:14]=[N:13][CH:17]=[N:16]2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Reactant: Nn1cnnc1
Solvent: CC(C)O
Solvent: O
Product: O=[N+]([O-])c1ccc(Cn2cncn2)cc1
Temperature: -2 °C
Reaction time: 0.67 h
Yield: 37.4 %

Procedure:
4-Nitrobenzyl bromide (64.22 g), 4-amino-1,2,4-triazole (26 g) and isopropyl alcohol (586 ml) were stirred together at reflux for 7% hours. The isopropanol solvent was replaced with water by using an azeotropic distillation procedure, in vacuo, on a Buchi rotary evaporator. The volume of the final aqueous slurry was 750 ml. 675 ml of this slurry was cooled to -2° C. and hydrochloric acid (50.8 ml, 12M) added over a few minutes. A solution of sodium nitrite (21.7 g) in water (86 ml) was then added dropwise, and subsurface over a 40 minute period. The temperature of the batch was kept between -2 and -1° C. during the addition and then allowed to warm to 18° C. over 30 minutes. The temperature was then increased to 28° C. and held for 1 hour and the solution treated with charcoal (4.5 g, Fisons) for 15 minutes. The charcoal was removed and the filtrate (750 ml) divided equally in two. One half of the solution was made basic with ammonia solution (22 ml) and the precipitated base collected, washed with water (2x30 ml) and dried (16 hours at 35° C. in vacuo). This gave an 83.3% yield (22.73 g) of 1-(4-nitrobenzyl)-1,2,4-triazole.
Reaction SMILES: [C:1](N)(=[O:5])C(C)=C.[C:7]([O:12][CH3:13])(=[O:11])[C:8]([CH3:10])=[CH2:9].C(N)=O>>[CH3:1][O:5][C:8]([CH3:10])([CH3:9])[C:7]([O:12][CH3:13])=[O:11]
Reactant: C=C(C)C(=O)OC
Reactant: C=C(C)C(N)=O
Solvent: NC=O
Product: COC(=O)C(C)(C)OC
Yield: 8 %

Procedure:
The reaction product was cooled, and analyzed by gas chromatography. This analysis showed that the conversion of methacrylic acid amide was 94%, the selectivity of methyl methacrylate based on methacrylic acid amide was 91%, and the selectivity of formamide was 98%. In addition, 8% of methyl α-methoxyisobutyrate was obtained in a yield of 8%.
Reaction SMILES: P([O:5][CH2:6][C@@H:7]([OH:16])[C@@H:8]([OH:15])[C@H:9]([OH:14])[C:10](=[O:13])[CH2:11][OH:12])(O)(O)=O.C1N=C(N)C2N=CN([C@@H]3O[C@H](COP(OP(OC[C@H]4O[C@@H](N5C=C(C(N)=O)CC=C5)[C@H](O)[C@@H]4O)(O)=O)(O)=O)[C@@H](O)[C@H]3O)C=2N=1.P(OC[C@@H](O)[C@@H](O)C=O)(O)(O)=O>C(O)C(N)(CO)CO.Cl>[OH:12][CH2:11][C:10]([C@H:9]([C@@H:8]([C@@H:7]([CH2:6][OH:5])[OH:16])[OH:15])[OH:14])=[O:13]
Reactant: O=C(CO)[C@@H](O)[C@H](O)[C@H](O)COP(=O)(O)O
Agent: Cl
Agent: NC(=O)C1=CN([C@@H]2O[C@H](COP(=O)(O)OP(=O)(O)OC[C@H]3O[C@@H](n4cnc5c(N)ncnc54)[C@H](O)[C@@H]3O)[C@@H](O)[C@H]2O)C=CC1
Agent: NC(CO)(CO)CO
Product: O=C(CO)[C@@H](O)[C@H](O)[C@H](O)CO

Procedure:
Cell disruption was performed in Tris/HCl buffer (100 mM, pH 7.8). The reaction for determination of transaldolase was performed in 50 mM Tris/HCl buffer (pH 7.8) additionally containing 1 mM fructose 6-phosphate, 0.5 mM NADH, 4 mM erythrose 4-phosphate, 6 U TPI/GDH and 50 μl of crude cell extract. TPI/GDH served as coupling enzymes to allow online monitoring at 340 nm.
Reaction SMILES: CO[C:3](=[O:28])[CH2:4][CH:5]([C:22]1[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=1)[CH2:6][N:7]1[C:15]2[CH:14]=[CH:13][C:12]([CH3:16])=[CH:11][C:10]=2[C:9]2[CH2:17][N:18]([CH3:21])[CH2:19][CH2:20][C:8]1=2.[C:29]([Li])([CH3:32])([CH3:31])[CH3:30]>C1COCC1>[CH3:21][N:18]1[CH2:19][CH2:20][C:8]2[N:7]([CH2:6][CH:5]([C:22]3[CH:23]=[CH:24][N:25]=[CH:26][CH:27]=3)[CH2:4][C:3](=[O:28])[C:29]([CH3:32])([CH3:31])[CH3:30])[C:15]3[CH:14]=[CH:13][C:12]([CH3:16])=[CH:11][C:10]=3[C:9]=2[CH2:17]1
Reactant: COC(=O)CC(Cn1c2c(c3cc(C)ccc31)CN(C)CC2)c1ccncc1
Reactant: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: Cc1ccc2c(c1)c1c(n2CC(CC(=O)C(C)(C)C)c2ccncc2)CCN(C)C1
Temperature: -78 °C
Reaction time: 1.5 h
Yield: 108 %

Procedure:
4-(2,8-Dimethyl-1,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-yl)-3-pyridin-4-yl-butyricacidmethylester (1.5 g, 3.9 mmol) was dissolved in THF (50 mL) and cooled to −78° C., tert-butyl lithium (16% in pentane) (6 mL, 15.13 mmol) was added dropwise under nitrogen. The reaction mixture was stirred at −78° C. for 90 min. After complete consumption of starting material, the reaction mixture was quenched with ammonium chloride solution and the reaction mixture was allowed to come to RT and extracted with EtOAc (3×100 mL), The combined organic layer was dried over anhydrous sodium sulfate and concentrated to obtain 1.7 g of crude 6-(2,8-dimethyl-1,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-yl)-2,2-dimethyl-5-pyridin-4-yl-hexan-3-one. 1H NMR (CDCl3, freebase) δ (ppm): 8.41 (d, 2H), 7.31 (d, 1H), 7.19 (s, 1H), 7.1 (d, 1H), 6.93 (d, 2H), 4.25 (dd, 1H), 3.9 (t, 2H), 3.8 (m, 1H), 3.67 (dd, 1H), 2.87 (m, 3H), 2.71 (m, 2H), 2.51 (s, 3H), 2.42 (s, 3H), 2.1 (m, 1H), 1.21 s (9H). Separation by chiral HPLC provides enantiomers II-222a-b.
Reaction SMILES: O.O.[NH2:3][CH:4]([C:8]1[N:9]=[C:10]([NH:13][C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:15])[S:11][CH:12]=1)[C:5]([OH:7])=[O:6].Cl[C:25]([N:27]1[CH2:31][CH2:30][N:29]([S:32]([CH3:35])(=[O:34])=[O:33])[C:28]1=[O:36])=[O:26]>C1COCC1.O>[O:36]=[C:28]1[N:29]([S:32]([CH3:35])(=[O:34])=[O:33])[CH2:30][CH2:31][N:27]1[C:25]([NH:3][CH:4]([C:8]1[N:9]=[C:10]([NH:13][C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:15])[S:11][CH:12]=1)[C:5]([OH:7])=[O:6])=[O:26]
Reactant: CS(=O)(=O)N1CCN(C(=O)Cl)C1=O
Reactant: NC(C(=O)O)c1csc(NC(=O)OCc2ccccc2)n1
Solvent: O
Solvent: C1CCOC1
Product: CS(=O)(=O)N1CCN(C(=O)NC(C(=O)O)c2csc(NC(=O)OCc3ccccc3)n2)C1=O

Procedure:
The compound is prepared analogously to Example 6 (a) from 15 g of α-amino-α-(2-benzyloxycarbonylamino-thiazol-4-yl)-acetic acid dihydrate in THF/water (1:1) and 10.9 g 1-chlorocarbonyl-2-oxo-3-methylsulfonyl-imidazolidine in a pH-range from 7.5 to 8.0. 14.1 g (65% of theory) are obtained.
Reaction SMILES: C1(P(C2CCCCC2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2N(C)C)CCCCC1.[CH3:37][CH:38]1[CH2:42][CH2:41][C:40](=[CH:43][N:44]([CH3:51])[C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[C:39]1=[O:52].Br[C:54]1[CH:61]=[CH:60][C:57]([C:58]#[N:59])=[CH:56][CH:55]=1.CC(C)([O-])C.[Na+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(C)C=CC=CC=1>[C:58]([C:57]1[CH:60]=[CH:61][C:54]([C:38]2([CH3:37])[CH2:42][CH2:41][C:40](=[CH:43][N:44]([CH3:51])[C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)[C:39]2=[O:52])=[CH:55][CH:56]=1)#[N:59]
Reactant: N#Cc1ccc(Br)cc1
Reactant: CC1CCC(=CN(C)c2ccccc2)C1=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: Cc1ccccc1
Product: CN(C=C1CCC(C)(c2ccc(C#N)cc2)C1=O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.02 h
Yield: 50.6 %

Procedure:
An oven dried Schlenk tube equipped with a rubber septum was cooled under an argon purge. The septum was removed and the tube was charged with palladium acetate (5.6 mg, 0.025 mmol, 5 mol % Pd), (−)-2-(dicyclohexylphosphino)-2′-(dimethylamino)-1,1′-binaphthyl (10.5 mg, 0.038 mmol, 7.5 mol %) and 2-methyl-5-(N-methyl-anilinomethylene)cyclopentanone (108 mg, 0.5 mmol). Toluene (2 mL) was added and the mixture was stirred for 1 min at room temperature. 4-Bromobenzonitrile (182 mg, 1.0 mmol) and sodium t-butoxide (96 mg, 1.0 mmol) were added to the tube. The tube was capped with the septum, purged with argon, and additional toluene (4 mL) was added through the septum. The mixture was heated to 100° C. with stirring until the starting ketone had been completely consumed as judged by GC analysis. The mixture was cooled to room temperature, quenched with saturated aqueous ammonium chloride (10 mL) and diluted with ether (20 mL). The mixture was poured into a separatory funnel and the layers were separated. The aqueous layer was extracted with ether (20 mL), and the combined organic layers were washed with brine (20 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The crude material was purified by flash chromatography on silica gel to afford 80 mg (51%) of the title compound. The ee was determined to be 80% by chiral HPLC analysis.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[N:5]=[C:4]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=2)[N:3]=1.O.[NH2:27][NH2:28]>O1CCOCC1.O>[NH:27]([C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[N:5]=[C:4]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=2)[N:3]=1)[NH2:28]
Reactant: NN
Reactant: FC(F)(F)Oc1ccc(Nc2nc(Cl)nc(N3CCOCC3)n2)cc1
Solvent: O
Solvent: C1COCCO1
Product: NNc1nc(Nc2ccc(OC(F)(F)F)cc2)nc(N2CCOCC2)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 95 %

Procedure:
To a solution of (4-chloro-6-morpholin-4-yl-1,3,5-triazin-2-yl)-(4-trifluoromethoxyphenyl)amine (XIV) (3.0 g, 8.51 mmol) in dioxane (16 mL) was added hydrazine hydrate (2 mL) and the mixture stirred at ambient temperature for 30 min. The mixture was diluted with water and the resulting slurry stirred for 10 min and filtered under vacuum. The white precipitate was washed with copious amount of water and dried under vacuum to give (4-hydrazino-6-morpholin-4-yl-1,3,5-triazin-2-yl)-(4-trifluoromethoxyphenyl)amine (XV) (3.01 g, 95% yield): 1H NMR (CDCl3) δ 7.55 (d, J=8.4 Hz, 2H), 7.13 (d, J=8.4 Hz, 2H), 3.74-3.87 (m, 8H); ESI/MS 372 (M+H), 370 (M−H).
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[NH:6][C:7]([C:10]([C:12]2[C:13](Cl)=[N:14][CH:15]=[CH:16][CH:17]=2)=O)=[CH:8][CH:9]=1)=[O:4].O.[NH2:20][NH2:21]>C(O)C>[CH3:1][NH:2][C:3]([C:5]1[NH:6][C:7]([C:10]2[C:12]3[C:13](=[N:14][CH:15]=[CH:16][CH:17]=3)[NH:21][N:20]=2)=[CH:8][CH:9]=1)=[O:4]
Reactant: CNC(=O)c1ccc(C(=O)c2cccnc2Cl)[nH]1
Reactant: NN
Solvent: O
Solvent: CCO
Product: CNC(=O)c1ccc(-c2n[nH]c3ncccc23)[nH]1
Temperature: 80 °C
Yield: 27 %

Procedure:
A mixture of 5-(2-chloro-pyridine-3-carbonyl)-1H-pyrrole-2-carboxylic acid methylamide (320 mg, 1.2 mmol) and hydrazine hydrate (2 mL) in ethanol (20 mL). The mixture was heated to at 80° C. for 48 hours. The precipitate was collected by vacuum filtration, washed with ethanol and water, dried to give 80 mg (27%) of the titled compound.
Reaction SMILES: [CH2:1]([O:4][CH2:5][CH:6]([CH2:8][OH:9])[OH:7])[CH:2]=[CH2:3].[OH-].[Na+].[C:12](=O)(OC)[O:13]C>>[CH2:1]([O:4][CH2:5][CH:6]1[CH2:8][O:9][C:12](=[O:13])[O:7]1)[CH:2]=[CH2:3]
Reactant: C=CCOCC(O)CO
Reactant: COC(=O)OC
Agent: [Na+]
Agent: [OH-]
Product: C=CCOCC1COC(=O)O1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 95 %

Procedure:
Into a 500 ml reaction vessel equipped with a Dean-Stark trap, a Dimroth condenser and a magnetic stirrer bar, 133 g (1 mol) of 1-allylglycerin, 300 ml of dimethyl carbonate, and 3 g (0.075 mol) of sodium hydroxide pellet were charged. The mixture was heated to 60° C., stirred for 30 minutes, and the temperature was then raised to 90° C. to remove a mixture of dimethyl carbonate and the methanol out of the reaction system until any distillate has been no longer distilled. The reaction mixture was cooled, and tetrahydrofuran was added thereto. After filtering off the precipitate, the filtrate was concentrated under reduced pressure to give 150.3 g (95% yield) of 4-allyloxymethyl-1,3-dioxolan-2-one.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[C@H:5]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([O:16][CH3:17])[CH:9]=1)[NH2:6])[CH3:2].[Br:19][C:20]1[CH:21]=[C:22]([CH:26]=[CH:27][N:28]=1)[C:23](O)=[O:24].O.ON1C2C=CC=CC=2N=N1.C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:18])[C@H:5]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([O:16][CH3:17])[CH:9]=1)[NH:6][C:23](=[O:24])[C:22]1[CH:26]=[CH:27][N:28]=[C:20]([Br:19])[CH:21]=1)[CH3:2]
Reactant: O=C(O)c1ccnc(Br)c1
Reactant: CCOC(=O)[C@@H](N)Cc1ccc(OC)c(OC)c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)[C@H](Cc1ccc(OC)c(OC)c1)NC(=O)c1ccnc(Br)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 64.9 %

Procedure:
To methylene chloride (120 ml) are added 3-(3,4-dimethoxyphenyl)alanine ethyl ester (12.4 g), 2-bromoisonicotinic acid (10.9 g), 1-hydroxybenzotriazole monohydrate (8.23 g) and 1,3-dicyclohexylcarbodiimide (11.1 g), and the mixture is stirred at room temperature overnight. The insoluble materials are removed by filtration, and the filtrate is concentrated. The residue is purified by silica gel chromatography (solvent; chloroform:acetone=10:1) to give N-(2-bromoisonicotinoyl)-3-(3,4-dimethoxyphenyl)alanine ethyl ester (13.9 g) as an oily product.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([F:11])[C:9]=1F)[CH:5]=[O:6].[CH3:12][S-:13].[Na+]>CS(C)=O.CCOC(C)=O>[F:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([F:11])[C:9]=1[S:13][CH3:12])[CH:5]=[O:6]
Reactant: O=Cc1cc(F)c(F)c(F)c1
Reactant: C[S-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CSc1c(F)cc(C=O)cc1F
Temperature: 125 °C

Procedure:
A solution of 3,4,5-trifluorobenzaldehyde (1.0 g, 6.3 mmol) in DMSO (7.8 mL) was treated with a slurry of sodium methanethiolate (0.438 g, 6.25 mmol) in DMSO (0.3 mL). The solution was warmed at 125° C. for 17 min in a microwave. Upon completion, the reaction was diluted with EtOAc and washed with H2O (1×) and saturated aqueous NaCl (1×). The combined aqueous was back-extracted with EtOAc (3×), and the combined organic layer was dried over Na2SO4, filtered and evaporated in vacuo to yield a crude oil that was purified by silica gel column chromatography (0-30%, EtOAc-hexanes) to yield the title compound. 1H NMR (500 MHz, CDCl3) δ 9.88 (s, 1H), 7.39 (d, J 7.0 Hz, 2H), 2.58 (s, 3H).
Reaction SMILES: I[CH:2]([CH3:4])[CH3:3].[NH:5]1[C:9]([C:10]2[CH:11]=[C:12]([C:16]3[CH:17]=[CH:18][C:19]4[O:23][C:22]([C:24]5[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=5)=[C:21]([C:31]([NH:33][CH3:34])=[O:32])[C:20]=4[CH:35]=3)[CH:13]=[CH:14][CH:15]=2)=[N:8][N:7]=[N:6]1.C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C>[F:30][C:27]1[CH:28]=[CH:29][C:24]([C:22]2[O:23][C:19]3[CH:18]=[CH:17][C:16]([C:12]4[CH:13]=[CH:14][CH:15]=[C:10]([C:9]5[N:8]=[N:7][N:6]([CH:2]([CH3:4])[CH3:3])[N:5]=5)[CH:11]=4)=[CH:35][C:20]=3[C:21]=2[C:31]([NH:33][CH3:34])=[O:32])=[CH:25][CH:26]=1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cccc(-c4nnn[nH]4)c3)cc12
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cccc(-c4nnn(C(C)C)n4)c3)cc12
Reaction time: 8 h
Yield: 31 %

Procedure:
2-iodopropane (29 mg, 0.169 mmol) was added to a stirring solution of 5-(3-(1H-tetrazol-5-yl)phenyl)-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide (35 mg, 0.085 mmol) and Na2CO3 (18 mg, 0.169 mmol) in DMF (1 mL) at 100° C. It was allowed to stir overnight. The mixture was concentrated and purified by preparative reverse phase HPLC on a C18 column using a suitably buffered H2O/CH3CN gradient, and concentrated to give the titled compound (12 mg, 30%). 1H NMR (500 MHz, DMSO-d6) δ ppm 8.49-8.57 (1H, m), 8.34 (1H, s), 8.08 (1H, d, J=7.32 Hz), 7.99-8.05 (2H, m), 7.87-7.94 (2 H, m), 7.79-7.83 (1H, m), 7.72-7.78 (1H, m), 7.70 (1H, t, J=7.78 Hz), 7.41 (2H, t, J=8.70 Hz), 5.17-5.27 (1H, m), 2.87 (3H, d, J=4.58 Hz), 1.66 (6H, d, J=6.71 Hz). LC-MS retention time: 2.02 min; m/z (MH+): 456. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Phenomenex-Luna 10u C18 3.0×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 5 ml/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where solvent A was 10% MeOH/90% H2O/0.1% trifluoroacetic acid and solvent B was 10% H2O/90% MeOH/0.1% trifluoroacetic acid. MS data was determined using a Micromass Platform for LC in electrospray mode. Additional HPLC method: Solvent A=5% CH3CN/95% H2O/0.1% TFA, Solvent B=95% CH3CN/5% H2O/0.1% TFA, Start % B=10, Final % B=100, Gradient time=15 min, Stop time=18 min, Flow Rate=1 ml/min. Column: Waters Sunfire C-18, 4.6×150 mm, 3.5 μm, Rt=15.35 min, purity=96%; Column: Waters Xbridge Phenyl column 4.6×150 mm, 3.5 μm, Rt=13.39 min, purity=97%.