Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:10]2[O:11][C:12]3[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=3[N:14]=2)[CH:5]=[CH:6][C:7]=1[CH2:8]Br.[C-:19]#[N:20].[Na+].O>CN(C=O)C.O>[O:11]1[C:12]2[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=2[N:14]=[C:10]1[C:4]1[CH:5]=[CH:6][C:7]([CH2:8][C:19]#[N:20])=[C:2]([Br:1])[CH:3]=1
Reactant: BrCc1ccc(-c2nc3ccccc3o2)cc1Br
Reactant: [C-]#N
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: N#CCc1ccc(-c2nc3ccccc3o2)cc1Br
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 2-[3-bromo-4-(bromomethyl)phenyl]-1,3-benzoxazole (156 mg, 0.42 mmol), and sodium cyanide (41 mg, 0.84 mmol) in DMF:H2O (3:1, 16 mL) was stirred at rt for 18 h. Water (50 mL) was added to the reaction mixture and it was extracted with EtOAc (3×). The organics were combined, washed with brine (2×), dried over Na2SO4, and evaporated to dryness to give an orange oil. The crude oil was purified by flash chromatography eluting with a gradient of EtOAc:hexane (0 to 30 min: 0 to 20% EtOAc) to afford the desired [4-(1,3-benzoxazol-2-yl)-2-bromophenyl]acetonitrile as a yellow solid (M.p. 190–191° C.). 1H NMR (CDCl3, 300 MHz) δ 8.50 (s, 1H), 8.22 (dd, 1H), 7.78 (m, 1H), 7.70 (d, 1H), 7.60 (m, 1H), 7.39 (m, 2H), 3.91 (s, 2H). MS (ESI) 313 (M)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:39]=[C:40]([F:42])[CH:41]=1)[CH2:5][C@H:6]1[C@@H:10]([C@H:11]2[CH2:20][C:19]3[C:14](=[C:15]([O:21][CH2:22][CH:23]=[CH2:24])[CH:16]=[CH:17][CH:18]=3)[CH2:13][N:12]2[CH:25]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[O:9]C(=O)[NH:7]1.[Li+].[OH-].C(OCC)C>CCO.O>[CH2:22]([O:21][C:15]1[CH:16]=[CH:17][CH:18]=[C:19]2[C:14]=1[CH2:13][N:12]([CH:25]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)[C@@H:11]([C@@H:10]([OH:9])[C@@H:6]([NH2:7])[CH2:5][C:4]1[CH:39]=[C:40]([F:42])[CH:41]=[C:2]([F:1])[CH:3]=1)[CH2:20]2)[CH:23]=[CH2:24]
Reactant: C=CCOc1cccc2c1CN(C(c1ccccc1)c1ccccc1)[C@@H]([C@H]1OC(=O)N[C@H]1Cc1cc(F)cc(F)c1)C2
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Solvent: CCOCC
Product: C=CCOc1cccc2c1CN(C(c1ccccc1)c1ccccc1)[C@@H]([C@@H](O)[C@@H](N)Cc1cc(F)cc(F)c1)C2
Temperature: 110 °C
Reaction time: 5 h
Yield: 105.7 %

Procedure:
To a solution of (4S,5S)-4-(3,5-difluorobenzyl)-5-((R)-8-(allyloxy)-2-benzhydryl-1,2,3,4-tetrahydroisoquinolin-3-yl)oxazolidin-2-one (Step F (15), 40 mg, 0.07 mmol) in EtOH (3 mL) was added a solution of LiOH (17 mg, 0.7 mmol) in H2O (0.6 mL). This reaction mixture was stirred at 110° C. for 5 h and stirred at 80° C. overnight. Ethyl ether (50 mL) was added to the mixture and washed with 1N HCl (40 mL) twice. The aqueous phase was basified to pH 12 with 50% aqueous NaOH solution. This mixture was extracted with ethyl acetate (120 mL). The organic layer was dried (Na2SO4), and concentrated in vacuo to give 40 mg of the title compound of Preparation F. 1H NMR (CDCl3, 500 MHz) δ 1.87 (3H, brd s), 2.38 (1H, dd, J=10, 15 Hz), 2.79 (1H, d, J=20 Hz), 2.96-2.99 (2H, m), 3.05 (1H, dd, J=5, 15 Hz), 3.62 (1H, m), 3.66 (1H, dd, J=5, 10 Hz), 3.71 (1H, d, J=20 Hz), 4.04 (1H, d, J=15 Hz), 4.33-4.40 (2H, m), 4.77 (1H, s), 5.08-5.15 (2H, m), 5.81 (1H, m), 6.63 (1H, d, J=10 Hz), 6.71-6.75 (1H, m), 6.79 (1H, d, J=10 Hz), 6.88 (2H, m), 7.10-7.21 (5H, m), 7.28-7.31 (2H, m), 7.40 (2H, d, J=10 Hz), 7.44 (2H, d, J=5 Hz). MS (ESI) (M+H)+ 541.22.
Reaction SMILES: I([O-])(=O)(=O)=[O:2].[Na+].[C:7]1([CH:13]=[C:14]2[C:19](=[O:20])[C:18](=[CH:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:17][S:16][CH2:15]2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>O.CO>[C:22]1([CH:21]=[C:18]2[C:19](=[O:20])[C:14](=[CH:13][C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=3)[CH2:15][S:16](=[O:2])[CH2:17]2)[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: O=C1C(=Cc2ccccc2)CSCC1=Cc1ccccc1
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: O=C1C(=Cc2ccccc2)CS(=O)CC1=Cc1ccccc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 86.7 %

Procedure:
A solution of 10.4g of sodium periodate in 50ml of water is added to a suspension of 7.0g of tetrahydro-3,5-bis-(phenylmethylene)-4H-thiopyran-4-one in 300ml of methanol. The mixture is stirred at room temperature for 3 days (a water bath is used for the first hour to moderate a slightly exothermic reaction). Solvent is removed in vacuo and the residue is stirred with chloroform and filtered. The filtrate is concentrated in vacuo and the residue is crystallized from 150ml of methanol, giving 6.4g of the title compound, melting point 155°-160°C. A second crop of 0.5g of the title compound, melting point 154°-157°C is also obtained.
Reaction SMILES: [N:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=1[F:13])[C:7]([OH:9])=[O:8])=[N+:2]=[N-:3].[C:14]([C:16]1[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=1)#[CH:15].ClC1N=CC(C2N=NN(C3C=C(C=CC=3C)C(O)=O)C=2)=CC=1>>[F:13][C:12]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][C:4]=1[N:1]1[CH:15]=[C:14]([C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)[N:3]=[N:2]1
Reactant: [N-]=[N+]=Nc1cc(C(=O)O)ccc1F
Reactant: C#Cc1cccnc1
Agent: Cc1ccc(C(=O)O)cc1-n1cc(-c2ccc(Cl)nc2)nn1
Product: O=C(O)c1ccc(F)c(-n2cc(-c3cccnc3)nn2)c1

Procedure:
4-Fluoro-3-(4-pyridin-3-yl-[1,2,3]triazol-1-yl)-benzoic acid was prepared from 3-azido-4-fluoro benzoic acid (U.S. Ser. No. 04/102,492) and 3-ethynyl pyridine (Aldrich) in the same manner as 3-[4-(6-chloro-pyridin-3-yl)-1,2,3-triazol-1-yl]-4-methyl-benzoic acid (Example 1).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([C:11]([OH:14])([CH3:13])[CH3:12])[NH:8]2)=[C:4]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[N:3]=1.I[CH2:22][CH2:23][CH3:24]>>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([C:11]([OH:14])([CH3:13])[CH3:12])[N:8]2[CH2:22][CH2:23][CH3:24])=[C:4]([N:15]2[CH2:16][CH2:17][O:18][CH2:19][CH2:20]2)[N:3]=1
Reactant: CC(C)(O)c1nc2c(N3CCOCC3)nc(Cl)nc2[nH]1
Reactant: CCCI
Product: CCCn1c(C(C)(C)O)nc2c(N3CCOCC3)nc(Cl)nc21

Procedure:
2-(2-Chloro-6-morpholino-9H-purin-8-yl)propan-2-ol (100 mg) was treated with iodopropane via General Procedure C to give crude intermediate 2-(2-chloro-6-morpholino-9-propyl-9H-purin-8-yl)propan-2-ol which was treated with 2-aminopyrimidine-5-boronic acid, pinacol ester via General Procedure A and was purified via reverse phase HPLC to give 34 mg of 104 as a white solid. MS (Q1) 399.3 (M)+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:12][C:11]([C:17]3[CH:22]=[C:21]([Cl:23])[CH:20]=[C:19]([Cl:24])[CH:18]=3)([C:13]([F:16])([F:15])[F:14])[O:10][N:9]=2)=[CH:4][C:3]=1[CH3:25].C(O)C[CH2:28][CH2:29][OH:30].C(OC=C)=C.C1(NC2CCCCC2)CCCCC1.C(O)CCC>[Pd].C1(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(O)(=O)C.C(OCC)(=O)C>[Cl:24][C:19]1[CH:18]=[C:17]([C:11]2([C:13]([F:16])([F:15])[F:14])[O:10][N:9]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([C:29](=[O:30])[CH3:28])=[C:3]([CH3:25])[CH:4]=3)[CH2:12]2)[CH:22]=[C:21]([Cl:23])[CH:20]=1
Reactant: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1Br
Reactant: OCCCCO
Agent: [Pd]
Agent: C1CCC(NC2CCCCC2)CC1
Agent: C=COC=C
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: CCCCO
Product: CC(=O)c1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1C
Reaction time: 1 h
Yield: 58.8 %

Procedure:
A mixture of 3-(4-bromo-3-methyl-phenyl)-5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazole (500 mg), 1,4-butandiol-monovinyl-ether (385 mg), palladium on charcoal (10%, 23 mg), 1,3-bis(diphenylphosphino)propane (9 mg), dicyclohexylamine (259 mg) and n-butanol (3 mL) were refluxed over night. Ethyl acetate (30 mL) and aqueous acetic acid (1 M, 20 mL) were added, and left at room temperature for 1 h. After separation of the layers, the organic layer was washed with HCl (1 M, 10 mL), dried (Na2SO4) and concentrated in vacuum. The residue was purified by flash chromatography on silica gel to yield the title compound (270 mg, 60%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:11]=[C:12]([CH2:21]OS(C)(=O)=O)[C:13](=[O:20])[N:14]([CH2:16][CH:17]([CH3:19])[CH3:18])[N:15]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[CH3:27][N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:11]=[C:12]([CH2:21][N:31]3[CH2:32][CH2:33][N:28]([CH3:27])[CH2:29][CH2:30]3)[C:13](=[O:20])[N:14]([CH2:16][CH:17]([CH3:18])[CH3:19])[N:15]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: CN1CCNCC1
Reactant: COc1ccc(-c2cc(COS(C)(=O)=O)c(=O)n(CC(C)C)n2)cc1Cl
Product: COc1ccc(-c2cc(CN3CCN(C)CC3)c(=O)n(CC(C)C)n2)cc1Cl
Yield: 76.1 %

Procedure:
Following the procedure of Example 1(10), 6-(3-chloro-4-methoxyphenyl)-2-isobutyl-4-methanesulfonyloxymethyl-2H-pyridazin-3-one and 1-methylpiperazine were reacted to yield the title compound as a yellow oil (yield: 76.1%).
Reaction SMILES: [C:1]([N:8]1[CH2:14][CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[N+:16]([C:19]1[CH:20]=[C:21]([CH:23]=[CH:24][CH:25]=1)[NH2:22])([O-:18])=[O:17].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(Cl)Cl.C(OCC)(=O)C.C(O)(=O)C>[N+:16]([C:19]1[CH:20]=[C:21]([NH:22][CH:11]2[CH2:12][CH2:13][CH2:14][N:8]([C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[CH2:9][CH2:10]2)[CH:23]=[CH:24][CH:25]=1)([O-:18])=[O:17]
Reactant: CC(C)(C)OC(=O)N1CCCC(=O)CC1
Reactant: Nc1cccc([N+](=O)[O-])c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCCC(Nc2cccc([N+](=O)[O-])c2)CC1
Reaction time: 10 h
Yield: 71.1 %

Procedure:
To a solution of N-Boc-hexahydro-1H-azepin-4-one (141 mg) and 3-nitroaniline (91 mg) in methylene chloride (3 mL), sodium triacetoxyborohydride (210 mg) and acetic acid (38 μL) were added at room temperature, and the mixture was stirred at the same temperature for 10 hours. To the reaction mixture, ethyl acetate and saturated aqueous sodium hydrogencarbonate were added. The organic layer was separated, washed with saturated aqueous sodium chloride, and then dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent, 100 to 30% hexane in ethyl acetate) to obtain tert-butyl 4-((3-nitrophenyl)amino)azepane-1-carboxylate (C25, 157 mg).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH:10]([OH:35])[C@@H:11]1[CH2:15][CH2:14][CH2:13][N:12]1[C:16](=[O:34])[C@H:17]([CH:31]([CH3:33])[CH3:32])[NH:18][C:19](=[O:30])[C@H:20]([CH3:29])[NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23].C(Cl)(=O)C(Cl)=O.CS(C)=O>>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]([C@@H:11]1[CH2:15][CH2:14][CH2:13][N:12]1[C:16](=[O:34])[C@H:17]([CH:31]([CH3:33])[CH3:32])[NH:18][C:19](=[O:30])[C@H:20]([CH3:29])[NH:21][C:22]([O:24][C:25]([CH3:27])([CH3:28])[CH3:26])=[O:23])=[O:35]
Reactant: CC(C)[C@H](NC(=O)[C@H](C)NC(=O)OC(C)(C)C)C(=O)N1CCC[C@H]1C(O)c1nc2ccccc2s1
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Product: CC(C)[C@H](NC(=O)[C@H](C)NC(=O)OC(C)(C)C)C(=O)N1CCC[C@H]1C(=O)c1nc2ccccc2s1

Procedure:
39 (0.72 g, 0.14 mmol), oxalylchloride (0.221 ml, 2.57 mmol), DMSO (2.53 ml, 3.57 mmol), TEA (0.80 ml, 5.71 mmol)
Reaction SMILES: [CH:1]([C:4]1[Se:5][C:6]([C:9]2[CH:14]=[CH:13][C:12]([CH:15]3[CH2:20][CH2:19][CH:18]([CH2:21][CH2:22][CH3:23])[CH2:17][CH2:16]3)=[CH:11][CH:10]=2)=[CH:7][CH:8]=1)=[CH:2][CH3:3]>C(OCC)(=O)C.[Pd]>[CH2:1]([C:4]1[Se:5][C:6]([C:9]2[CH:10]=[CH:11][C:12]([CH:15]3[CH2:16][CH2:17][CH:18]([CH2:21][CH2:22][CH3:23])[CH2:19][CH2:20]3)=[CH:13][CH:14]=2)=[CH:7][CH:8]=1)[CH2:2][CH3:3]
Reactant: CC=Cc1ccc(-c2ccc(C3CCC(CCC)CC3)cc2)[se]1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCCc1ccc(-c2ccc(C3CCC(CCC)CC3)cc2)[se]1

Procedure:
1.0 g (2.69 mmol) of 2-(propenyl)-5-[4-(4-propylcyclohexyl)phenyl]selenophene is hydrogenated in 10 ml of ethyl acetate, in the presence of Pd/C (5% of Pd) at atmospheric pressure and RT. The reaction soln. is filtered and concentrated to dryness, and the crude product is purified by column chromatography (SiO2, n-heptane→n-heptane:EtOAc=20:1). The further purification is carried out by recrystallisation from n-heptane. 2-Propyl-5-[4-(4-propylcyclohexyl)phenyl]selenophene is obtained as a colourless solid.
Reaction SMILES: [Cl:1][C:2]1[CH:41]=[CH:40][C:5]([CH2:6][C:7]2[N:11]3[N:12]=[C:13]([NH:23][C:24]4[CH:28]=[C:27]([CH3:29])[N:26](CC5C=CC(OC)=CC=5)[N:25]=4)[CH:14]=[C:15]([CH2:16][N:17]4[CH2:22][CH2:21][O:20][CH2:19][CH2:18]4)[C:10]3=[N:9][C:8]=2[CH3:39])=[C:4]([F:42])[CH:3]=1>FC(F)(F)C(O)=O>[Cl:1][C:2]1[CH:41]=[CH:40][C:5]([CH2:6][C:7]2[N:11]3[N:12]=[C:13]([NH:23][C:24]4[CH:28]=[C:27]([CH3:29])[NH:26][N:25]=4)[CH:14]=[C:15]([CH2:16][N:17]4[CH2:18][CH2:19][O:20][CH2:21][CH2:22]4)[C:10]3=[N:9][C:8]=2[CH3:39])=[C:4]([F:42])[CH:3]=1
Reactant: COc1ccc(Cn2nc(Nc3cc(CN4CCOCC4)c4nc(C)c(Cc5ccc(Cl)cc5F)n4n3)cc2C)cc1
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(Nc2cc(CN3CCOCC3)c3nc(C)c(Cc4ccc(Cl)cc4F)n3n2)n[nH]1
Temperature: 120 °C
Yield: 68.4 %

Procedure:
Combine 3-(4-chloro-2-fluorobenzyl)-N-(1-(4-methoxybenzyl)-5-methyl-1H-pyrazol-3-yl)-2-methyl-8-(morpholinomethyl)imidazo[1,2-b]pyridazin-6-amine (0.447 g, 0.76 mmol) and trifluoroacetic acid (10 mL) in a 20 mL microwave reactor tube. Seal with a crimp cap then heat in a microwave reactor at 120° C. for 20 min. Partition between EA and water that is made basic with excess NaOH aqueous. Wash the organic phase three times with NaOH aqueous followed by aqueous saturated sodium chloride. Dry over anhydrous magnesium sulfate. Filter and concentrate in vacuo. Purify on silica gel (EA→10% methanol:EA) to give the title compound (0.246 g, 0.52 mmol) as a pale yellow solid. LCMS (8 min)=470.0, M+1.
Reaction SMILES: [CH2:1]([NH2:3])[CH3:2].C(N(CC)CC)C.[Cl:11][C:12]1[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[CH:25][C:13]=1[O:14][C:15]1[CH:16]=[C:17]([CH2:21][C:22](Cl)=[O:23])[CH:18]=[CH:19][CH:20]=1>O>[CH2:1]([NH:3][C:22](=[O:23])[CH2:21][C:17]1[CH:18]=[CH:19][CH:20]=[C:15]([O:14][C:13]2[CH:25]=[CH:26][C:27]([C:29]([F:30])([F:31])[F:32])=[CH:28][C:12]=2[Cl:11])[CH:16]=1)[CH3:2]
Reactant: CCN
Reactant: O=C(Cl)Cc1cccc(Oc2ccc(C(F)(F)F)cc2Cl)c1
Solvent: O
Solvent: CCN(CC)CC
Product: CCNC(=O)Cc1cccc(Oc2ccc(C(F)(F)F)cc2Cl)c1
Reaction time: 1 h
Yield: 97.6 %

Procedure:
0.7 g of ethylamine and 1.5 g of triethylamine were dissolved in 20 ml of N,N'-dimethylacetamide at 0° C., followed by addition of 3.5 g of 3-(2'-chloro-4'-trifluoromethylphenoxy)phenylacetyl chloride. The reaction was allowed to proceed at 0° C. for 1 hour and then at room temperature for further 3 hours to complete the reaction. After completion of the reaction, 50 ml of water was added to the liquid reaction mixture, followed by extraction twice with 30 ml portions of ether. The ether layer was washed with dilute hydrochloric acid and water and dried over anhydrous sodium sulfate, and the ether was distilled off under reduced pressure. As a result, there was obtained 3.5 g of N-ethyl-3-(2'-chloro-4'-trifluoromethylphenoxy)phenylacetamide.
Reaction SMILES: [OH:1][C@H:2]([C@H:4]([N:15]1[CH:19]=[N:18][C:17]([C:20]([O:22]CC)=O)=[N:16]1)[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([Cl:13])[C:8]=1[Cl:14])[CH3:3].[OH-].[NH4+:26]>O1CCCC1.ClCCl>[OH:1][C@H:2]([C@H:4]([N:15]1[CH:19]=[N:18][C:17]([C:20]([NH2:26])=[O:22])=[N:16]1)[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([Cl:13])[C:8]=1[Cl:14])[CH3:3]
Reactant: [NH4+]
Reactant: CCOC(=O)c1ncn([C@H](CCc2cccc(Cl)c2Cl)[C@H](C)O)n1
Agent: [OH-]
Solvent: C1CCOC1
Solvent: ClCCl
Product: C[C@H](O)[C@@H](CCc1cccc(Cl)c1Cl)n1cnc(C(N)=O)n1
Temperature: 120 °C

Procedure:
A mixture of ethyl 1-[(2S,3R)-2-hydroxy-5-(2,3-dichlorophenyl)-3-pentyl]-1,2,4-triazole-3-carboxylate (11.6 mg) and ammonium hydroxide (28% in water; 0.5 ml) in tetrahydrofuran (3 ml) was heated in a steel sealed tube at 120° C. overnight. The mixture was taken up in dichloromethane, washed with water, dried, and evaporated. The residue was purified by column chromatography on silica gel, eluting with a mixture of dichloromethane and methanol (20:1) to give a white powder of 1-[(2S,3R)-2-hydroxy-5-(2,3-dichlorophenyl)-3-pentyl]-1,2,4-triazole-3-carboxamide (4.2 mg).
Reaction SMILES: O=[CH:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[CH3:8][C:9]([S:12]([NH2:14])=[O:13])([CH3:11])[CH3:10]>C(Cl)Cl>[C:9]([S:12]([N:14]=[CH:2][C:3]([O:5][CH2:6][CH3:7])=[O:4])=[O:13])([CH3:11])([CH3:10])[CH3:8]
Reactant: CCOC(=O)C=O
Reactant: CC(C)(C)S(N)=O
Solvent: ClCCl
Product: CCOC(=O)C=NS(=O)C(C)(C)C
Temperature: 25 °C
Reaction time: 65 h

Procedure:
A mixture of ethyl 2-oxoacetate (50% solution in toluene; 4.066 g; 20.00 mmol), 2-methylpropane-2-sulfinamide (2.424 g; 20.00 mmol), and 4 angstrom molecular sieves (60 g) in anh. DCM (250 ml) was stirred at rt, under nitrogen, for 65 h. The reaction mixture was then filtered over celite, and the separated solids were washed with AcOEt (3×200 ml). The filtrate was then dried over anh. MgSO4, filtered, and concentrated to dryness under reduced pressure affording ethyl 2-((tert-butylsulfinyl)imino)acetate as a yellow oil.
Reaction SMILES: [CH3:1][C:2]([C:12]1[C:20]2[O:19][CH2:18][CH2:17][C:16]=2[CH:15]=[C:14]([S:21]([CH3:24])(=[O:23])=[O:22])[CH:13]=1)([CH3:11])[CH2:3][C:4]1([C:7]([F:10])([F:9])[F:8])[CH2:6][O:5]1.[CH3:25][C:26]1[CH:27]=[N:28][CH:29]=[C:30]([CH3:33])[C:31]=1[OH:32].[O-]CC.[Na+]>C(O)C.C(OCC)(=O)C>[OH:5][C:4]([C:7]([F:10])([F:8])[F:9])([CH2:3][C:2]([C:12]1[C:20]2[O:19][CH2:18][CH2:17][C:16]=2[CH:15]=[C:14]([S:21]([CH3:24])(=[O:23])=[O:22])[CH:13]=1)([CH3:1])[CH3:11])[CH2:6][N:28]1[CH:29]=[C:30]([CH3:33])[C:31](=[O:32])[C:26]([CH3:25])=[CH:27]1
Reactant: Cc1cncc(C)c1O
Reactant: CC(C)(CC1(C(F)(F)F)CO1)c1cc(S(C)(=O)=O)cc2c1OCC2
Agent: CC[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Product: Cc1cn(CC(O)(CC(C)(C)c2cc(S(C)(=O)=O)cc3c2OCC3)C(F)(F)F)cc(C)c1=O
Temperature: 85 °C

Procedure:
To a suspension of 7-[1,1-dimethyl-2-(2-trifluoromethyloxiranyl)ethyl]-5-methanesulfonyl-2,3-dihydrobenzofuran (51.0 mg) and 3,5-dimethylpyridin-4-ol (B. Boduszek et al., Synthesis, 1979, pp. 452-453) (34 mg) in anhydrous ethanol (0.40 mL) was added sodium ethoxide (21 wt. % solution in ethanol, 52.0 μL). After heating at 85° C. for 16 hours, the reaction mixture was diluted with ethyl acetate, dried over sodium sulfate, filtered, and concentrated in vacuo.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[C:4]([Cl:11])[CH:3]=1.ClC(OC(=O)C(C)C)=O.CN1CCOCC1.[BH4-].[Na+]>O1CCCC1.O>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][OH:7])=[C:4]([Cl:11])[CH:3]=1
Reactant: O=C(O)c1ccc(Br)cc1Cl
Agent: CC(C)C(=O)OC(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CN1CCOCC1
Product: OCc1ccc(Br)cc1Cl
Temperature: -15 °C
Reaction time: 0.17 h
Yield: 100 %

Procedure:
4-Bromo-2-chlorobenzoic acid (14, 92.0 g, 0.39 mol) was dissolved in dry tetrahydrofuran (920 mL) and cooled to −15° C. Isobutyryl choroformate (51.0 mL, 0.39 mol) was added followed by N-methylmorpholine (43.5 mL, 0.39 mol). The resulting mixture was stirred for 10 minutes at −15° C., cooled to −25° C. and the precipitated N-methylmorpholine hydrochloride salt was filtered off. The filtrate was warmed to −5° C. and a solution of sodium borohydride (22.19 g, 0.586 mol) in water (190 mL) was added dropwise to the mixture keeping the temperature below 0° C. After stirring for 1 h at 0° C., the volatiles were evaporated, and the residue was diluted with water (500 mL) and dichloromethane (450 mL). The layers were separated and the aqueous layer was extracted with dichloromethane (150 mL). The combined organic layers were washed with water (150 mL), dried over sodium sulfate and evaporated. The product (86.1 g, 0.39 mol, 99%) was obtained as a white crystalline solid.
Reaction SMILES: [NH2:1][C:2]1[N:12]=[CH:11][C:10]([Cl:13])=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].[O:14]([C:21]1[CH:22]=[C:23]([CH2:27][C:28](Cl)=[O:29])[CH:24]=[CH:25][CH:26]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>N1C=CC=CC=1.C(Cl)Cl>[Cl:13][C:10]1[CH:11]=[N:12][C:2]([NH:1][C:28](=[O:29])[CH2:27][C:23]2[CH:24]=[CH:25][CH:26]=[C:21]([O:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:22]=2)=[C:3]([CH:9]=1)[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: O=C(Cl)Cc1cccc(Oc2ccccc2)c1
Reactant: CCOC(=O)c1cc(Cl)cnc1N
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)c1cc(Cl)cnc1NC(=O)Cc1cccc(Oc2ccccc2)c1
Temperature: 130 °C

Procedure:
To a mixture of ethyl 2-amino-5-chloronicotinate (143, Example 18) (344.9 mg, 1.719 mmol) in pyridine (2.0 mL, distilled) in a 10 mL round-bottom flask with stirring was added a solution of 3-phenoxyphenylacetyl chloride (812.5 mg, 3.293 mmol) in dry CH2Cl2 (2.0 mL). The mixture was gradually heated to reflux (130° C., oil bath), over which time the CH2Cl2 was allowed to evaporate. The resulting solution was refluxed for 3.5 h, then cooled to room temperature. The reaction mixture was quenched with water (10 mL) and extracted with chloroform (3×15 mL). The combined organic extracts were washed with water (3×10 mL), dried (MgSO4), and rota-evaporated to dryness, leaving a dark green liquid. This liquid was chromatographed on silica gel (24 g, Mallinckrodt, grade 62, mesh 60-200) and eluted with hexanes-EtOAc (1:4, 250 mL). The desired fractions were collected (Rf =0.83) and rota-evaporated to dryness, leaving a green oil. This oil eventually precipitated out as a wet green mass. Crystallization from ethanol afforded the title compound as a light brown flakes, 114 mg (16.1%), mp 103°-4° C.; 1H NMR (CDCl3): δ1.39 (t, J=7.2, 3, CH3CH2), 3.88 (s, 2, benzylic), 4.35 (q, J=7.2, 2, CH3CH2O), 7.10 (m, 9, phenyl), 8.24 (d, J=2.4, 1, py), 8.52 (d, J=2.4, 1, py), 10.70 (d, J=2.4, 1, NH); IR (KBr): 3434, 3155, 2925, 1722, 1659, 1401, 1252, 1205, 1102, 775, 700; HPLC: 99%; LRMS: 410 (M+, 40), 211 (35), 210 (100), 200 (35), 183 (30), 181 (40), 128 (15), 89 (50), 77 (20), 51 (15); HRMS Calcd: 410. 1033. Found: 410.1026.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][C:26]4[N:27]=[C:28]([CH3:31])[S:29][CH:30]=4)[CH2:23][CH2:22][C:21]([C:32]([O:34]C)=[O:33])=[CH:20][C:19]=3[CH:36]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].O.Cl>O1CCCC1.CO>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][C:26]4[N:27]=[C:28]([CH3:31])[S:29][CH:30]=4)[CH2:23][CH2:22][C:21]([C:32]([OH:34])=[O:33])=[CH:20][C:19]=3[CH:36]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OC)CCN3Cc2csc(C)n2)cc1
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCN3Cc2csc(C)n2)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 79.8 %

Procedure:
To a solution of methyl 7-(4-butoxyethoxyphenyl)-1-[(2-methylthiazol-4-yl)methyl]-2,3-dihydro-1-benzazepine-4-carboxylate (550 mg) in a mixture of tetrahydrofuran (33 ml) and methanol (33 ml) was added solution (11 ml), and the mixture was stirred at room temperature for 2 days. Then, to the mixture was added water at 0° C., and 1N hydrochloric acid was further added to neutral, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried with magnesium sulfate. The solvent was evaporated under reduced pressure, which was recrystallized from hexane-ethyl acetate to give 7-(4-butoxyethoxyphenyl)-1-[(2-methylthiazol-4-yl)methyl]-2,3-dihydro-1-benzazepine-4-carboxylic acid (427 mg) as yellow crystals.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.[N+:12]([O-])([OH:14])=[O:13]>OS(O)(=O)=O>[Cl:1][C:2]1[C:11]2[C:6](=[C:7]([N+:12]([O-:14])=[O:13])[CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])O
Reactant: Clc1ccnc2ccccc12
Agent: O=S(=O)(O)O
Product: O=[N+]([O-])c1cccc2c(Cl)ccnc12
Temperature: 7.5 °C
Reaction time: 3 h

Procedure:
To a solution of 4-chloroquinoline (1.0 g, 6.13 mmol) in conc. H2SO4 (4.5 mL) was drop wise added conc. HNO3 (1.8 mL) at 0° C. and the reaction mixture was stirred at 0-15° C. for 3 h. Then the reaction mixture was quenched by addition of aq. NH4OH at 0° C. and the pH of the reaction mixture was adjusted to 8. The solid precipitate was filtered and the filter cake was further purified by column chromatography to afford 900 mg of the title product. 1H NMR (300 MHz, DMSO d6): δ 8.98 (d, J=5.1 Hz, 1H), 8.50-8.47 (d, J=9.0 Hz, 1H), 8.41 (d, J=7.8 Hz, 1H), 8.02-7.99 (d, J=4.8 Hz, 1H), 7.96-7.90 (t, J=7.8 Hz, 1H).