Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[CH:12]=[C:11]([O:15][CH:16]3[CH2:21][CH2:20][N:19](C(OC(C)(C)C)=O)[CH2:18][CH2:17]3)[C:10]([C:29]#[N:30])=[N:9]2)=[CH:4][C:3]=1[F:31].[ClH:32].O1CCOCC1.CCOCC>C(Cl)Cl>[ClH:32].[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[CH:12]=[C:11]([O:15][CH:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)[C:10]([C:29]#[N:30])=[N:9]2)=[CH:4][C:3]=1[F:31]
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2cc(=O)n(-c3ccc(Br)c(F)c3)nc2C#N)CC1
Agent: Cl
Solvent: ClCCl
Solvent: CCOCC
Solvent: C1COCCO1
Product: N#Cc1nn(-c2ccc(Br)c(F)c2)c(=O)cc1OC1CCNCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
To a stirring solution of tert-butyl 4-(1-(4-bromo-3-fluorophenyl)-3-cyano-6-oxo-1,6-dihydropyridazin-4-yloxy)piperidine-1-carboxylate (493 mg, 1.0 mmol) in DCM (5 mL) at room temperature under argon was added 4 M HCl in dioxane (1.25 mL, 5.0 mmol). The reaction mixture was stirred at room temperature overnight. Et2O (10 mL) was added to the reaction mixture. The solid product was collected by filtration and further washed with ether (2 mL×2). After drying under vacuum for 2 hours, 411 mg (100%) of 1-(4-bromo-3-fluorophenyl)-6-oxo-4-(piperidin-4-yloxy)-1,6-dihydropyridazine-3-carbonitrile HCl salt was obtained as an off-white solid. MS (ESI) 393 (M+H).
Reaction SMILES: C1C2C(COC([NH:18][C:19]([CH3:68])([C:21]([NH:23][C@H:24]([C:28]([N:30]([C@@H:32]([C@@H:64]([CH3:67])[CH2:65][CH3:66])[C@H:33]([O:62][CH3:63])[CH2:34][C:35]([N:37]3[CH2:41][CH2:40][CH2:39][C@H:38]3[C@H:42]([O:60][CH3:61])[C@@H:43]([CH3:59])[C:44]([NH:46][C@@H:47]([CH2:52][C:53]3[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=3)[C:48]([O:50][CH3:51])=[O:49])=[S:45])=[O:36])[CH3:31])=[O:29])[CH:25]([CH3:27])[CH3:26])=[O:22])[CH3:20])=O)C3C(=CC=CC=3)C=2C=CC=1.C(NCC)C.[Cl:74]CCl>>[ClH:74].[CH3:20][C:19]([C:21]([NH:23][C@H:24]([C:28]([N:30]([C@@H:32]([C@@H:64]([CH3:67])[CH2:65][CH3:66])[C@H:33]([O:62][CH3:63])[CH2:34][C:35]([N:37]1[CH2:41][CH2:40][CH2:39][C@H:38]1[C@H:42]([O:60][CH3:61])[C@@H:43]([CH3:59])[C:44]([NH:46][C@@H:47]([CH2:52][C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1)[C:48]([O:50][CH3:51])=[O:49])=[S:45])=[O:36])[CH3:31])=[O:29])[CH:25]([CH3:27])[CH3:26])=[O:22])([CH3:68])[NH2:18]
Reactant: ClCCl
Reactant: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=S)N[C@@H](Cc1ccccc1)C(=O)OC)OC)N(C)C(=O)[C@@H](NC(=O)C(C)(C)NC(=O)OCC1c2ccccc2-c2ccccc21)C(C)C
Solvent: CCNCC
Product: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=S)N[C@@H](Cc1ccccc1)C(=O)OC)OC)N(C)C(=O)[C@@H](NC(=O)C(C)(C)N)C(C)C
Product: Cl
Yield: 70 %

Procedure:
According to general procedure A, from #43 (176 mg, 0.184 mmol, 1 eq.), dichloromethane (4 mL, 0.05 M) and diethylamine (4 mL) was synthesized the crude desired material, which was purified by reverse phase chromatography (Method C). The resulting trifluoroacetic acid salt was dissolved in methanol, treated with a 4 M solution of hydrochloric acid in dioxane, and concentrated in vacuo to give #45 (100 mg, 70%) as a white solid. LC-MS: m/z 734.6 [M+H+], retention time=0.72 minutes; 1H NMR (400 MHz, CD3OD), presumed to be a mixture of rotamers, characteristic signals: δ 7.18-7.31 (m, 5H), 5.41-5.47 and 5.55-5.62 (2 m, total 1H), 3.73 and 3.76 (2 s, total 3H), 3.35 and 3.36 (2 s, total 3H), 3.10 and 3.15 (2 br s, total 3H), 1.62 and 1.64 (2 s, total 3H), 1.53 and 1.55 (2 s, total 3H), [1.25 (d, J=6.6 Hz) and 1.29 (d, J=6.5 Hz), total 3H], 0.84-0.91 (m, 3H).
Reaction SMILES: O1CCOC1.[O:6]([C:13]1[CH:18]=[CH:17][C:16]([C:19]2([CH2:26][N:27]3[CH:31]=[N:30][CH:29]=[N:28]3)[O:23][CH:22]([CH2:24][OH:25])[CH2:21][O:20]2)=[CH:15][CH:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[H-].[Na+].[Cl:34][C:35]1[CH:42]=[CH:41][C:38]([CH2:39]Br)=[CH:37][CH:36]=1>O1CCOCC1>[O:6]([C:13]1[CH:18]=[CH:17][C:16]([C:19]2([CH2:26][N:27]3[CH:31]=[N:30][CH:29]=[N:28]3)[O:23][CH:22]([CH2:24][O:25][CH2:39][C:38]3[CH:41]=[CH:42][C:35]([Cl:34])=[CH:36][CH:37]=3)[CH2:21][O:20]2)=[CH:15][CH:14]=1)[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: Clc1ccc(CBr)cc1
Reactant: OCC1COC(Cn2cncn2)(c2ccc(Oc3ccccc3)cc2)O1
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: C1COCO1
Product: Clc1ccc(COCC2COC(Cn3cncn3)(c3ccc(Oc4ccccc4)cc3)O2)cc1
Temperature: 25 °C

Procedure:
14,1 parts of 2-[p-(Phenoxy)-phenyl]-2-(1H-1,2,4-triazolyl-methyl)-4-hydroxymethyl-1,3-dioxolane dioxolane dissolved in 100 ml absolute dioxane and then 1,8 parts of 55 % sodium hydrid dispersion in 100 ml absolute dioxane are stirred in at room temperature while introducing nitrogen. The mixture is heated 3 hours to 80° C., then cooled to room temperaLure, treated dropwise within 30 minutes with 8,6 parts of p-chlorobenzylbromide dissolved in 50 parts of absolute dioxane. The reaction mixture is beated 3 hours to 50° C., then cooled to room temperature, diluted with 1200 ml ice-water and extracted with three 200 ml portions of ethyl acetate. The combined extracts are washed with two 70 ml portions of water, dried over sodium sulfate, filtered and the solvent removed by evaporation. The remaining diastereoisomers are separated by column chromatography (silica gel/ethyl acetate). The eluant is then removed by evaporation to give the diastereoisomer B in the form of crystals with a melting point of 83°-85° C. The diastereoisomer A is obtained after the evaporation of the solvent in form of a viscous slightly brownish oil; nD26 : 1.5865.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([C:15]3[C:16]([F:32])=[CH:17][C:18]([F:31])=[C:19]([NH:21][C:22]([NH:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)=[O:23])[CH:20]=3)[C:8](=[O:14])[N:9]2[CH2:12][CH3:13])=[CH:4][N:3]=1.[C:33](Cl)(=[O:35])[CH3:34].C1C[O:40][CH2:39][CH2:38]1>>[C:33]([N:1]([C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([C:15]3[CH:20]=[C:19]([NH:21][C:22]([NH:24][C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=4)=[O:23])[C:18]([F:31])=[CH:17][C:16]=3[F:32])[C:8](=[O:14])[N:9]2[CH2:12][CH3:13])=[CH:4][N:3]=1)[C:39](=[O:40])[CH3:38])(=[O:35])[CH3:34]
Reactant: CC(=O)Cl
Reactant: C1CCOC1
Reactant: CCn1c(=O)c(-c2cc(NC(=O)Nc3ccccc3)c(F)cc2F)cc2cnc(N)cc21
Product: CCn1c(=O)c(-c2cc(NC(=O)Nc3ccccc3)c(F)cc2F)cc2cnc(N(C(C)=O)C(C)=O)cc21
Reaction time: 2 h
Yield: 84 %

Procedure:
A solution of 1-(5-(7-amino-1-ethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2,4-difluorophenyl)-3-phenylurea (150 mg, 0.344 mmol) and TEA (174.2 mg, 1.72 mmol) in THF (3 mL) was treated drop-wise with acetyl chloride (81 mg, 1.03 mmol) at RT. The resulting mixture was stirred for 2 h and the solvent was removed to give the crude product. It was diluted, washed with brine, dried over Na2SO4, concentrated under reduced pressure and purified by silica gel chromatography to give N-acetyl-N-{3-[2,4-difluoro-5-(3-phenyl-ureido)-phenyl]-1-ethyl-2-oxo-1,2-dihydro-[1,6]naphthyridin-7-yl}-acetamide (150 mg, 84% yield). 1H NMR (400 MHz, DMSO-d6): δ 10.86 (s, 1H), 9.41 (s, 1H), 8.79 (s, 1H), 8.74 (s, 1H), 8.27 (s, 1H), 8.20-8.16 (m, 1H), 8.08 (s, 1H), 8.00 (s, 1H), 7.46-7.39 (m, 3H), 7.29-7.25 (m, 2H), 6.98-6.95 (m, 1H), 4.25-4.22 (t, J=7.2 Hz, 3H), 2.16 (s, 3H), 1.27 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH:26][S:27]([C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([C:36]([F:39])([F:38])[F:37])[CH:31]=2)(=[O:29])=[O:28])[CH2:9][C:10]([NH:12][CH:13]2[CH2:22][CH2:21][CH2:20][C:19]3[N:18]=[C:17]([CH2:23][CH2:24][OH:25])[N:16]=[CH:15][C:14]2=3)=[O:11])=[CH:4][CH:3]=1.[CH3:40][S:41](Cl)(=[O:43])=[O:42].CCN(CC)CC>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH:26][S:27]([C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([C:36]([F:37])([F:38])[F:39])[CH:31]=2)(=[O:29])=[O:28])[CH2:9][C:10]([NH:12][CH:13]2[CH2:22][CH2:21][CH2:20][C:19]3[N:18]=[C:17]([CH2:23][CH2:24][O:25][S:41]([CH3:40])(=[O:43])=[O:42])[N:16]=[CH:15][C:14]2=3)=[O:11])=[CH:4][CH:3]=1
Reactant: O=C(CC(NS(=O)(=O)c1cccc(C(F)(F)F)c1)c1ccc(F)cc1)NC1CCCc2nc(CCO)ncc21
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCCc1ncc2c(n1)CCCC2NC(=O)CC(NS(=O)(=O)c1cccc(C(F)(F)F)c1)c1ccc(F)cc1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
To a solution of 3-(4-fluorophenyl)-N-[2-(2-hydroxy-ethyl)-5,6,7,8-tetrahydro-quinazolin-5-yl]-3-(3-trifluoromethyl-benzenesulfonylamino)-propionamide (56.6 mg, 0.1 mmol) in dry CH2Cl2 at 0 C was added MsCl (34 mg, 0.3 mmol), followed by Et3N (50 mg, 0.5 mmol). After stirring at 0° C. for 20 min, the reaction was quenched with Sat. NaHCO3 solution, extracted with EtOAc, dried over Na2SO4, and evaporated in vacuo. Flash chromatography (SiO2, EtOAc/MeOH=100:3 to 100:5 to 100:7) gave the title compound as a white solid. MS: 645.0 (M+1).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][N:7]([CH2:14][C:15]1[CH:22]=[CH:21][C:18]([CH:19]=O)=[CH:17][CH:16]=1)[CH2:8][C:9]1[NH:10][CH:11]=[CH:12][N:13]=1.[CH2:23]1[C:27]2([CH2:32][CH2:31][N:30]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:29][CH2:28]2)[CH2:26][CH:25]([C:40]([O:42][CH2:43][CH3:44])=[O:41])[NH:24]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(O)(=O)C.CN(C)C=O>[NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][N:7]([CH2:14][C:15]1[CH:16]=[CH:17][C:18]([CH2:19][N:24]2[CH:25]([C:40]([O:42][CH2:43][CH3:44])=[O:41])[CH2:26][C:27]3([CH2:28][CH2:29][N:30]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:31][CH2:32]3)[CH2:23]2)=[CH:21][CH:22]=1)[CH2:8][C:9]1[NH:10][CH:11]=[CH:12][N:13]=1
Reactant: O=Cc1ccc(CN(Cc2ncc[nH]2)Cc2ncc[nH]2)cc1
Reactant: CCOC(=O)C1CC2(CCN(C(=O)OC(C)(C)C)CC2)CN1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: CCOC(=O)C1CC2(CCN(C(=O)OC(C)(C)C)CC2)CN1Cc1ccc(CN(Cc2ncc[nH]2)Cc2ncc[nH]2)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 60.8 %

Procedure:
Under an argon atmosphere, 4-{[bis(1H-imidazol-2-ylmethyl)amino]methyl}benzaldehyde (International Publication WO 2007/058322 pamphlet, Example 28; 21.0 g) and 8-tert-butyl 3-ethyl 2,8-diazaspiro[4.5]decane-3,8-dicarboxylate (JP 2004-002470, Example 21f; 21.2 g) were dissolved in acetic acid (4.5 mL) and anhydrous N,N-dimethylformamide (225 mL), followed by stirring at room temperature for 10 minutes. To this solution, sodium triacetoxyborohydride (17.3 g) was added. The reaction solution was stirred at room temperature for 3 hours. To the reaction solution, an aqueous sodium hydrogen carbonate solution was added, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine and then dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was dissolved in ethanol (300 mL) and the solution was heated at reflux for 2 hours. The reaction solution was concentrated under reduced pressure and the residue was purified by silica gel chromatography (CHROMATOREX NH (trade name), manufactured by Fuji Silysia Chemical Ltd.) (n-hexane:ethyl acetate=1:1→1:2→0:1→ethyl acetate:ethanol=19:1→9:1) to obtain the title compound (24.4 g) having the following physical properties.
Reaction SMILES: [CH:1]([C:3]1[O:10][C:9]2[CH:8]=[C:7]([C:11]([OH:13])=[O:12])[NH:6][C:5]=2[CH:4]=1)=O.Cl.[NH2:15]O>>[C:1]([C:3]1[O:10][C:9]2[CH:8]=[C:7]([C:11]([OH:13])=[O:12])[NH:6][C:5]=2[CH:4]=1)#[N:15]
Reactant: NO
Reactant: O=Cc1cc2[nH]c(C(=O)O)cc2o1
Agent: Cl
Product: N#Cc1cc2[nH]c(C(=O)O)cc2o1

Procedure:
2-Formyl4H-furo[3,2-b]pyrrole-5-carboxylic acid (see, for example, Krutosikova, A.; Dandarova, M.; Alfoldi, J., Chem. Pap., 48: 268-73 (1994)) was treated with hydroxylamine hydrochloride according to Procedure G.
Reaction SMILES: [OH:1][C:2]1[CH:18]=[CH:17][C:5]([C:6]([C:8]2[O:9][C:10]3[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=3[CH:12]=2)=[O:7])=[CH:4][CH:3]=1.[OH-:19].[Na+].[CH2:21]([CH:23]1O[CH2:24]1)Cl>>[O:19]1[C:3]2[C:4]1=[C:5]([CH:17]=[CH:18][C:2]=2[O:1][CH2:21][CH2:23][CH3:24])[C:6]([C:8]1[O:9][C:10]2[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=2[CH:12]=1)=[O:7]
Reactant: ClCC1CO1
Reactant: O=C(c1ccc(O)cc1)c1cc2ccccc2o1
Reactant: [OH-]
Agent: [Na+]
Product: CCCOc1ccc(C(=O)c2cc3ccccc3o2)c2c1O2

Procedure:
2-[4'-(2,3-epoxy)propoxybenzoyl]benzofuran was prepared from 12.0 g. (0.050 mol.) of 2-(4'-hydroxybenzoyl)benzofuran, 3.0 g. of sodium hydroxide and 30 ml. of epichlorohydrin as described in the procedure of Example 7.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[CH:6]=[CH:7][CH:8]=[CH:9][C:2]1=2.C([Li])CCC.[Br:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]Br>O1CCCC1.CCCCCC>[S:1]1[C:5]([CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][Br:15])=[CH:4][C:3]2[CH:6]=[CH:7][CH:8]=[CH:9][C:2]1=2
Reactant: c1ccc2sccc2c1
Reactant: BrCCCCCCBr
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: BrCCCCCCc1cc2ccccc2s1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of benzo[b]thiophene (1.92 g., 14.3 mmol) in 90 ml anhydrous tetrahydrofuran at -10° to 0° under argon was added n-butyllithium (7.8 ml of a 1.86M solution in hexane). After two hours, this solution was transferred dropwise into a stirred, 0° solution of 1,6-dibromohexane (6.5 ml, 0.043 mol) in 250 ml tetrahydrofuran. The solution was warmed to room temperature, stirred for 15 hours, quenched with water and concentrated. The residue was acidified and partitioned between ethyl ether and water. The aqueous portion was extracted twice with ether, and the combined organic portions were washed with water, saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated to give a brown oil. Excess benzo[b]thiophene and 1,6-dibromohexane were removed by bulb to bulb distillation (85° to 90°/0.1 mm) to leave a dark brown syrup. This material was purified by flash chromatography (silica, hexane to 5% ethyl ether/hexane) to give the desired alkyl halide.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:15]#[N:16])[CH:11]=2)[CH:6]=1)=O.[Li+].[OH-].S(Cl)([Cl:21])=O>C1COCC1>[C:15]([C:10]1[CH:11]=[C:12]2[C:7](=[CH:8][CH:9]=1)[CH:6]=[C:5]([C:3]([Cl:21])=[O:2])[CH:14]=[CH:13]2)#[N:16]
Reactant: COC(=O)c1ccc2cc(C#N)ccc2c1
Reactant: O=S(Cl)Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: N#Cc1ccc2cc(C(=O)Cl)ccc2c1

Procedure:
Compounds of formula II, where T is a bond, B is H, each of-e and g is C—H, f is a bond, V is a substituted carbonyl group, and Z′ is NH can be prepared as follows. Hydrolysis of naphthalene-2,6 dicarboxylic acid dimethyl ester with one equivalent of a base such as KOH, followed by acidification of the product with an acid such as HCl, affords the naphthalene mono carboxylic acid. After conversion of the carboxylic acid to an acid chloride with a reagent such as thionyl chloride and subsequent reaction with ammonia in methylene chloride, the resulting 6-carbamoyl-naphthalene-2-carboxylic acid methyl ester is reacted with triphosgene in trimethylphosphate to provide 6-cyano-naphthalene-2-carboxylic acid methyl ester. Hydrolysis of the ester with LiOH in aqueous THF solution, followed by reaction with thionyl chloride, affords 6-cyano-naphthalene-2-carbonyl chloride, which can then be coupled with alcohols or amines to provide compounds of the formula XX. The amidine, hydroxyamidine, or aminoamidine groups can be obtained from the nitrile as described previously to afford compounds the formula XXI, where R19 is H, and R22 is H, alkyl, OH, or NH2, and V is an alkylaminocarbonyl, dialkylaminocarbonyl, cycloalkylaminocarbonyl, aralkylaminocarbonyl, arylaminocarbonyl, heterocyclylaminocarbonyl, alkoxycarbonyl, cycloalkoxycarbonyl, aralkoxycarbonyl, aryloxycarbonyl, heterocyclyloxycarbonyl, or heteroaralkyloxycarbonyl.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:17][CH:18]([C:20]1[CH:25]=[CH:24][C:23]([CH2:26][CH3:27])=[CH:22][N:21]=1)[OH:19].O>C(O)(C)(C)C>[CH2:26]([C:23]1[CH:24]=[CH:25][C:20]([CH:18]([OH:19])[CH2:17][O:1][C:2]2[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=2)=[N:21][CH:22]=1)[CH3:27]
Reactant: CCc1ccc(C(O)CBr)nc1
Reactant: O=Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Solvent: O
Product: CCc1ccc(C(O)COc2ccc(C=O)cc2)nc1

Procedure:
Into a solution of 22.6 g (0.181 mol) of 4-hydroxy benzaldehyde dissolved in 75 mL tertiary butanol, was added 38.5 g (0.278 mol) of potassium carbonate in 10 min. Reaction mixture was refluxed for 1 hr. and 15 g (0.06 mol) of 2-bromo-1-(5-ethyl-pyridin-2-yl)-ethanol dissolved in 75 mL tertiary butanol was added slowly in one hr. Reaction mixture was refluxed further for 10 hr, and at 25° C. poured into excess of water. Product was extracted with toluene. Subsequent concentration under reduced pressure and purification gave the desired product. Yield of the product was 12.37 g (70%). m.p. 80° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:14]2[CH2:18][CH:17]([CH2:19]OS(C3C=CC(C)=CC=3)(=O)=O)[O:16][C:15]2=[O:31])[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][S:11][CH2:10][CH2:9]1.[N-]=[N+]=[N-].[Na+].[CH3:36][C:37]#[N:38].C(Cl)(Cl)Cl.CN(C=[O:47])C>CCOC(C)=O>[F:1][C:2]1[CH:3]=[C:4]([N:14]2[CH2:18][C@H:17]([CH2:19][NH:38][C:37](=[O:47])[CH3:36])[O:16][C:15]2=[O:31])[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][S:11][CH2:10][CH2:9]1
Reactant: Cc1ccc(S(=O)(=O)OCC2CN(c3ccc(N4CCSCC4)c(F)c3)C(=O)O2)cc1
Reactant: CN(C)C=O
Reactant: CC#N
Agent: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CCOC(C)=O
Product: CC(=O)NC[C@H]1CN(c2ccc(N3CCSCC3)c(F)c2)C(=O)O1
Temperature: 65 °C
Reaction time: 158 h
Yield: 100 %

Procedure:
The [[3-[3-fluoro-4-(4-thiomorpholinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]-p-toluenesulfonate (2.0 g, 4.287 mmol) was dissolved in dry DMF (15 mL) and then treated with solid NaN3 (1.67 g, 25.722 mmol). The reaction was heated to 65° C. (external temperature) for 6 hours, after which the reaction was allowed to cool to ambient temperature, stirring over a long weekend (158 hours). At this point, the reaction was found to be complete by TLC (6% CH3CN/CHCl3, UV short wave). The reaction was diluted with EtOAc (300 mL) and then washed with water (3×250 mL). The aqueous portions were back-extracted with more EtOAc (2×150 mL). The EtOAc portions were combined, dried over Na2SO4, filtered and concentrated under reduced pressure to give 1.447 g (100%) of the title compound as an off-white solid with a melting point of 91.5°-93° C. and a HRMS (M+) calculated for C14 H16N5O5FS 337.1009, found 337.1009.
Reaction SMILES: [CH3:1][Mg]Br.[CH3:4][O:5][C:6]1[CH:7]=[C:8]([C:18]2[N:22]3[CH2:23][CH2:24][CH2:25][C:26]([O:32][C:33]4[CH:38]=[CH:37][C:36]([C:39]([F:42])([F:41])[F:40])=[CH:35][CH:34]=4)(C(OCC)=O)[C:21]3=[N:20][N:19]=2)[CH:9]=[CH:10][C:11]=1[C:12]1[O:16][C:15]([CH3:17])=[N:14][CH:13]=1.[Cl-].[NH4+].[CH2:45]1[CH2:49][O:48]CC1>>[CH3:4][O:5][C:6]1[CH:7]=[C:8]([C:18]2[N:22]3[CH2:23][CH2:24][CH2:25][C:26]([C:49]([OH:48])([CH3:45])[CH3:1])([O:32][C:33]4[CH:38]=[CH:37][C:36]([C:39]([F:41])([F:42])[F:40])=[CH:35][CH:34]=4)[C:21]3=[N:20][N:19]=2)[CH:9]=[CH:10][C:11]=1[C:12]1[O:16][C:15]([CH3:17])=[N:14][CH:13]=1
Reactant: C1CCOC1
Reactant: CCOC(=O)C1(Oc2ccc(C(F)(F)F)cc2)CCCn2c(-c3ccc(-c4cnc(C)o4)c(OC)c3)nnc21
Reactant: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Product: COc1cc(-c2nnc3n2CCCC3(Oc2ccc(C(F)(F)F)cc2)C(C)(C)O)ccc1-c1cnc(C)o1
Reaction time: 1 h

Procedure:
Methylmagnesium bromide (1M THF solution, 4.75 ml) was added to a mixture of ethyl 3-[3-methoxy-4-(2-methyl-1,3-oxazol-5-yl)phenyl]-8-[4-(trifluoromethyl)phenoxy]-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyridine-8-carboxylate (515 mg) in THF (7 mL) under ice-cooling, and the mixture was stirred for 1 hr. Saturated aqueous ammonium chloride solution was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by basic silica gel column chromatography (NH, ethyl acetate/hexane) to give the title compound (250 mg).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][C@H:2]1[C:6]1[O:10][N:9]=[C:8]([C:11]2[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=2)[C:14]#[N:15])[N:7]=1.[S:19]1[CH:23]=[CH:22][N:21]=[C:20]1[CH:24]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C>[S:19]1[CH:23]=[CH:22][N:21]=[C:20]1[CH2:24][N:1]1[CH2:5][CH2:4][CH2:3][C@H:2]1[C:6]1[O:10][N:9]=[C:8]([C:11]2[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=2)[C:14]#[N:15])[N:7]=1
Reactant: N#Cc1cccc(-c2noc([C@@H]3CCCN3)n2)c1
Reactant: O=Cc1nccs1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Product: N#Cc1cccc(-c2noc([C@@H]3CCCN3Cc3nccs3)n2)c1

Procedure:
3-[5-(1-Thiazol-2-ylmethyl-pyrrolidin-2-yl)-[1,2,4]oxadiazol-3-yl]-benzonitrile (63.5 mg, 91%) was obtained as described in Example 43 from (S)-3-(5-pyrrolidin-2-yl-[1,2,4]oxadiazol-3-yl)-benzonitrile (49.8 mg, 0.18 mmol) reacted with thiazole-2-carbaldehyde (35.2 mg, 0.31 mmol) and sodium triacetoxyborohydride (72 mg, 0.34 mmol) is in dichloroethane (3 mL) at room temperature. 1H NMR (CDCl3), δ(ppm): 8.39 (s, 1H), 8.32 (d, 1H), 7.78 (d, 1H), 7.68 (d, 1H), 7.60 (t, 1H), 7.27 (d, 1H), 4.32 (dd, 1H), 4.27 (dab, 1H), 4.17 (dab, 1H), 3.31 (m, 1H), 2.81 (q, 1H), 2.39 (m, 1H), 2.25 (m, 1H), 2.14 (m, 1H), 2.04 (m, 1H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([OH:8])[CH:7]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:19][C:20]([O:22][CH3:23])=[O:21].O>C(C(C)=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH:7]=1)[O:8][CH2:19][C:20]([O:22][CH3:23])=[O:21]
Reactant: O=[N+]([O-])c1ccc(F)cc1O
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCC(C)=O
Product: COC(=O)COc1cc(F)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.1 %

Procedure:
To 10 g (63.7 mmol) of 5-fluoro-2-nitrophenol in 100 ml of methyl ethyl ketone was added 10.5 g (76.4 mmol) of finely ground potassium carbonate followed by 10.7 g (70.1 mmol) of methyl bromoacetate. The resulting suspension was refluxed for 6 hours and then stirred at room temperature overnight. During this time it went from a deep red color to pale yellow. The reaction was poured into one liter of water, the layers were separated and the aqueous layer was extracted twice more with EtOAc (2×100 ml). The organics were combined, dried (Na2SO4), filtered and evaporated to dryness in vacuo to give 13.3 g (91% yield) of methyl 5-fluoro-2-nitrophenoxyacetate as a light yellow solid (m.p. 85°-87° C.).
Reaction SMILES: [CH:1]1[C:6]([CH:7]=O)=[CH:5][CH:4]=[C:3]([CH:9]=O)[CH:2]=1.[C:11]([CH2:13][CH2:14][NH:15][NH2:16])#[N:12]>CO>[C:11]([CH2:13][CH2:14][NH:15][N:16]=[CH:9][C:3]1[CH:4]=[CH:5][C:6]([CH:7]=[N:16][NH:15][CH2:14][CH2:13][C:11]#[N:12])=[CH:1][CH:2]=1)#[N:12]
Reactant: N#CCCNN
Reactant: O=Cc1ccc(C=O)cc1
Solvent: CO
Product: N#CCCNN=Cc1ccc(C=NNCCC#N)cc1
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
To a suspension of 102 g terephthaldehyde in 700 ml methanol 129.4 g of 2-cyanoethylhydrazine are added drop-wise within 20 minutes. The temperature increases to about 50° C., and an orange-red solution generally arises. After about 10 minutes further crystallization occurs. Stirring continues for 30 minutes and a precipitate that appears is filtered with suction. After washing with a little cold methanol the precipitate is dried under vacuum. 187 g of beige colored product are produced.