Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:16]=[CH:15][C:7]([O:8][CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].Br[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]([OH:34])([C:30]([F:33])([F:32])[F:31])[C:26]([F:29])([F:28])[F:27])=[CH:21][CH:20]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[F:27][C:26]([F:28])([F:29])[C:25]([C:22]1[CH:23]=[CH:24][C:19]([CH2:18][N:12]2[CH2:11][CH2:10][CH:9]([O:8][C:7]3[CH:15]=[CH:16][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=3)[CH2:14][CH2:13]2)=[CH:20][CH:21]=1)([OH:34])[C:30]([F:31])([F:33])[F:32]
Reactant: O=[N+]([O-])c1ccc(OC2CCNCC2)cc1
Reactant: OC(c1ccc(CBr)cc1)(C(F)(F)F)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=[N+]([O-])c1ccc(OC2CCN(Cc3ccc(C(O)(C(F)(F)F)C(F)(F)F)cc3)CC2)cc1

Procedure:
4-(4-Nitrophenoxy)piperidine (2.70 mmol, 600 mg), 2-(4-(bromomethyl)phenyl)-1,1,1,3,3,3-hexafluoropropan-2-ol (2.70 mmol, 910 mg) and potassium carbonate (5.40 mmol, 746 mg) were combined and stirred at 70° C. in acetonitrile (20 mL) overnight. The reaction mixture was filtered and the filtrate concentrated under vacuum to afford the title compound. MS (ESI) m/z 490.0 [M+H]+
Reaction SMILES: [F:1][CH:2]([F:25])[O:3][C:4]1[CH:24]=[CH:23][C:7]2[NH:8][C:9]([S:11][CH2:12][C:13]3[C:18]([O:19][CH3:20])=[C:17]([O:21][CH3:22])[CH:16]=[CH:15][N:14]=3)=[N:10][C:6]=2[CH:5]=1.[OH-].[Na+].ClN1C(=[O:34])C2=CC=CC=C2C1=O.S(S([O-])=O)([O-])(=O)=O.[Na+].[Na+]>CN(C)C=O.C(O)(=O)C.C(#N)C>[CH3:22][O:21][C:17]1[CH:16]=[CH:15][N:14]=[C:13]([CH2:12][S+:11]([O-:34])[C:9]2[NH:8][C:7]3[CH:23]=[CH:24][C:4]([O:3][CH:2]([F:1])[F:25])=[CH:5][C:6]=3[N:10]=2)[C:18]=1[O:19][CH3:20]
Reactant: COc1ccnc(CSc2nc3cc(OC(F)F)ccc3[nH]2)c1OC
Reactant: O=C1c2ccccc2C(=O)N1Cl
Agent: O=S([O-])S(=O)(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Solvent: CC#N
Product: COc1ccnc(C[S+]([O-])c2nc3cc(OC(F)F)ccc3[nH]2)c1OC
Temperature: -10 °C
Reaction time: 1 h
Yield: 98.3 %

Procedure:
A flask equipped with a stirrer is charged with acetonitrile (40 ml). Under mixing, compound VI (5 g) is added followed by 2N NaOH (17.5 ml, 4.9 eq.). The flask is cooled to −10° C. A solution of N-chlorophthalimide (2.6 g, 1.1 eq.) in dimethylformamide (DMF) (10 ml) is added dropwise over 45 min. The two-phase mixture is stirred at room temperature over 1 h. Saturated aqueous Na2S2O5 (20 ml) is then added, and the pH is adjusted to 8.5 with acetic acid. The phases are separated. The organic phase is washed with brine, and the aqueous phase is extracted twice with ethyl acetate. The organic phases are combined, dried, and evaporated to dryness. The residue is taken up in a mixture of ethyl acetate (10 ml), toluene (10 ml), and hexane (30 ml). On standing, a precipitate forms in the solution which is separated by filtration to give pantoprazole (5.13 g, 98%) containing 0.3% compound VI and free of sulfone within the limit of UV detection.
Reaction SMILES: [CH3:1][C:2]1([CH3:31])[C:25]2[CH2:24][CH2:23][N:22](C(=O)CCO)[CH2:21][C:20]=2[C:5]2[C:6]([OH:19])=[CH:7][C:8]([CH:10]([CH3:18])[CH:11]([CH3:17])[CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])=[CH:9][C:4]=2[O:3]1.Br[CH2:33][C:34](Br)=[O:35].C(N(CC)CC)C.[NH:44]1[CH2:49][CH2:48][O:47][CH2:46][CH2:45]1>C(Cl)Cl.O>[CH3:31][C:2]1([CH3:1])[CH:25]2[C:20](=[C:21]([C:34](=[O:35])[CH2:33][N:44]3[CH2:49][CH2:48][O:47][CH2:46][CH2:45]3)[NH:22][CH2:23][CH2:24]2)[C:5]2[C:6]([OH:19])=[CH:7][C:8]([CH:10]([CH3:18])[CH:11]([CH3:17])[CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])=[CH:9][C:4]=2[O:3]1
Reactant: CCCCCC(C)C(C)c1cc(O)c2c(c1)OC(C)(C)C1=C2CN(C(=O)CCO)CC1
Reactant: O=C(Br)CBr
Reactant: C1COCCN1
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCC(C)C(C)c1cc(O)c2c(c1)OC(C)(C)C1CCNC(C(=O)CN3CCOCC3)=C21
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 28.5 %

Procedure:
To an ice cold, stirred solution of 7.16 g (0.02 mole) of compound 1 (Scheme 3) in 40 ml of methylene chloride were added dropwise 9.70 g (0.048 mole) of bromoacetyl bromide dissolved in 10 ml of methylene chloride followed by a solution of 4.84 g (0.048 mole) of triethylamine in 10 ml of methylene chloride. The temperature was maintained below 8° C. during both additions. The reaction mixture was stirred in an ice bath for 1.5 hours and then at room temperature for 4 hours. Most of the solvent was removed under a rapid stream of nitrogen in a water bath held at 35°-40° C. The residue was taken up in 40 ml of dry dimethylformamide cooled in ice and treated dropwise with 8.71 g (0.10 mole) of morpholine, keeping the reaction temperature below 15° C. After being stirred at room temperature overnight, the reaction mixture was poured into water, insoluble material was taken up in methylene chloride, washed with water and concentrated to dryness. The residue (11.3 g) was taken up in 100 ml of methanol, cooled in ice, treated with 10 ml of 45 percent potassium hydroxide solution and stirred at room temperature under a nitrogen atmosphere for 2 hours. The solution was cooled in ice and neutralized to pH 9 (approximate) using 6 N hydrochloric acid and dry ice. The precipitate (about 11 g) was collected at the filter and shaken with a mixture of water and methylene chloride until solution was complete. The organic layer was separated, washed with water and concentrated to dryness. The crystalline residue (5.0 g), m.p. 205°-215° C., was recrystallized from dimethoxyethane to give 2.76 g of the above-titled compound, m.p. 217°-219° C.
Reaction SMILES: [C:1]1([CH3:7])[CH:6]=[CH:5]C=CC=1.[C:8]([OH:13])(=[O:12])[C:9]([CH3:11])=[O:10].C(O)CCC>O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>[C:8]([O:13][CH2:5][CH2:6][CH2:1][CH3:7])(=[O:12])[C:9]([CH3:11])=[O:10]
Reactant: CC(=O)C(=O)O
Reactant: Cc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CCCCO
Product: CCCCOC(=O)C(C)=O
Temperature: 25 °C
Yield: 70 %

Procedure:
A toluene solution (1 L) containing pyruvic acid (440 g, 5.0 mol), n-butanol (371 g, 5.0 mol) and p-toluenesulfonic acid monohydrate (2.5 g) was heated and refluxed for 16 hours under nitrogen flow. The reaction led to generation of water in the system. However, the water was removed using Dean-Stark trap. The resultant reaction solution was cooled down to room temperature, followed by removal of toluene using an evaporator under a reduced pressure. The residual was then purified using reduced pressure distillation (40 mmHg, 93 to 100° C.) to give butyl pyruvate (505 g, yield: 70%).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]([C:10]1[S:11][CH:12]=[CH:13][CH:14]=1)[C:7]([OH:9])=O.[C:15]([N:22]1[CH:26]=[CH:25][N:24]=[CH:23]1)(N1C=CN=C1)=O.[N-]1C=CN=C1.[CH2:32]1[CH2:36]OC[CH2:33]1>CCOCC>[N:22]12[CH2:15][CH2:36][CH:32]([CH2:33][CH2:23]1)[C@@H:25]([NH:24][C:7](=[O:9])[CH:6]([C:2]1[S:1][CH:5]=[CH:4][CH:3]=1)[C:10]1[S:11][CH:12]=[CH:13][CH:14]=1)[CH2:26]2
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: O=C(O)C(c1cccs1)c1cccs1
Reactant: C1CCOC1
Agent: c1c[n-]cn1
Solvent: CCOCC
Product: O=C(N[C@H]1CN2CCC1CC2)C(c1cccs1)c1cccs1

Procedure:
2,2-dithien-2-ylacetic acid was produced by hydrolysis of 2,2-dithien-2-ylacetic acid methyl ester, previously prepared as described in F. Leonard and 1. Ehranthal, J. Am. Chem. Soc, (1951), Vol 73, pag 2216. 1.2 g (0.0054 mol) of 2,2-dithien-2-ylacetic acid were dissolved in 25 ml of THF. To this solution were added 0.96 g (0.00594 mol) of 1,1′-carbonyldiimidazole and the mixture was refluxed for an hour. The reaction was monitored by TLC following the formation of the imidazolide. When the reaction was completed 0.75 g (0.00594 mol) of (3R)-aminoquinuclidine were added. The reaction mixture was refluxed for 16 h, cooled, diluted with ether and washed with water. The organic layer was extracted with HCl 2N, the acid solution basified with K2CO3 and extracted with CHCl3. The organic phase was dried over Na2SO4 and the solvent was evaporated to obtain 0.60 g of an oil which was purified by column chromatography (silica gel, CHCl3:MeOH:NH4OH 90:10:1 as eluent). Appropriate fractions were combined and evaporated to give 0.31 g of the title product (17.3%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:40])[C@@H:4]([NH:17][C:18]([C:20]1[CH:39]=[CH:38][C:23]2[N:24]([CH:32]3[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]3)[C:25]([C:27]3[CH:31]=[CH:30][O:29][CH:28]=3)=[N:26][C:22]=2[CH:21]=1)=[O:19])[CH2:5][C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([OH:15])[CH:13]=2)[N:8]([CH3:16])[CH:7]=1.[C:41](=[O:44])([O-])[O-:42].[Cs+].[Cs+].[CH3:47][C:48]([CH3:50])=O>O>[CH3:1][O:2][C:3](=[O:40])[C@@H:4]([NH:17][C:18]([C:20]1[CH:39]=[CH:38][C:23]2[N:24]([CH:32]3[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37]3)[C:25]([C:27]3[CH:31]=[CH:30][O:29][CH:28]=3)=[N:26][C:22]=2[CH:21]=1)=[O:19])[CH2:5][C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][C:48]([C:41]([OH:42])=[O:44])([CH3:50])[CH3:47])[CH:13]=2)[N:8]([CH3:16])[CH:7]=1
Reactant: CC(C)=O
Reactant: O=C([O-])[O-]
Reactant: COC(=O)[C@H](Cc1cn(C)c2ccc(O)cc12)NC(=O)c1ccc2c(c1)nc(-c1ccoc1)n2C1CCCCC1
Agent: [Cs+]
Solvent: O
Product: COC(=O)[C@H](Cc1cn(C)c2ccc(OC(C)(C)C(=O)O)cc12)NC(=O)c1ccc2c(c1)nc(-c1ccoc1)n2C1CCCCC1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
The title compound of example 114 (0.097 g, 0.18 mmol) was dissolved in acetone (1.5 mL). Cesium carbonate (0.175 g, 0.54 mmol) and teft-butylbromoisobutyrate (0.080 g, 0.36 mmol) were added and the mixture stirred at 60° C. overnight in a sealed tube. The reaction mixture was then diluted with water (10 mL) and the product extracted with EtOAc (50 mL). The organic phase was dried (MgSO4), concentrated and the residue purified by flash chromatography using 60-80% EtOAc in hexane as eluent. The purified diester was dissolved in DCM (0.5 mL) and TFA (0.5 mL) was added. After stirring at room temperature for 1.5 h, volatiles were removed under a stream of nitrogen and the residue purified by preparative C18 reversed-phase HPLC to give the title compound of example 115.
Reaction SMILES: [C:1]1([CH:7]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[O:8][CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][NH2:20])[CH2:11][CH2:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:28]1[CH:29]=[CH:30][C:31]2[N:32]([N:34]=[CH:35][N:36]=2)[N:33]=1.C(=O)(O)[O-].[Na+]>>[C:1]1([CH:7]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[O:8][CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][NH:20][C:28]3[CH:29]=[CH:30][C:31]4[N:32]([N:34]=[CH:35][N:36]=4)[N:33]=3)[CH2:11][CH2:10]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: NCCCCCN1CCC(OC(c2ccccc2)c2ccccc2)CC1
Reactant: Clc1ccc2ncnn2n1
Agent: O=C([O-])O
Agent: [Na+]
Product: c1ccc(C(OC2CCN(CCCCCNc3ccc4ncnn4n3)CC2)c2ccccc2)cc1
Yield: 66.9 %

Procedure:
0.705 g of 4-(diphenylmethoxy)-1-piperidinepentanamine and 0.309 g of 6-chloro[1,2,4]triazolo[1,5-b]pyridazine were stirred at 135-140° C. for 1.5 hours. After cooling, aqueous sodium bicarbonate was added, followed by extraction with ethyl acetate; the extract was washed with saline, dried over sodium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography and eluted with ethyl acetate:methanol:triethylamine (95:5:1). The desired fraction was collected, recrystallized from ethyl ether and dried to yield 0.629 g of the title compound.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]3[CH2:23][CH2:22][CH2:21][N:20]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30]([O:32]CC)=[O:31])[C:10]3=[N:11][C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Li+].[OH-]>C1COCC1.O>[C:1]1([C:7]2[N:8]=[C:9]3[CH2:23][CH2:22][CH2:21][N:20]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30]([OH:32])=[O:31])[C:10]3=[N:11][C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)CCCCCCN1CCCc2nc(-c3ccccc3)c(-c3ccc(C)cc3)nc21
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(-c2nc3c(nc2-c2ccccc2)CCCN3CCCCCCC(=O)O)cc1
Temperature: 70 °C
Reaction time: 18 h

Procedure:
A solution of ethyl 7-(2-phenyl-3-p-tolyl-7,8-dihydropyrido[2,3-b]pyrazin-5(6H)-yl)heptanoate (1.07 g, 2.338 mmol) in THF (12 ml) and water (6 ml) was treated with LiOH (0.560 g, 23.38 mmol) and stirred at 70° C. for 18 hours. After cooling to RT, the reaction mixture was concentrated in vacuo. The residue was diluted with water (20 ml) and the pH was adjusted to pH˜4 using 2M HCl. The aqueous portion was extracted with EtOAc (2×20 ml). The organic extracts were washed with brine, dried (MgSO4) and evaporated under vacuum. The residue was dissolved in hot (˜80° C.) ethanol (20 ml) and water (˜15 ml) was added until the solution became turbid. Upon cooling a solid precipitated. The mixture was kept cold for 72 hours. The solid was collected by filtration, washed with water and dried at 40° C. for 5 hours to afford the title compound;
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[C:15]3[CH:16]=[CH:17][C:18]([O:20]C)=[CH:19][C:14]=3[S:13][N:12]=2)=[O:10])=[CH:4][C:3]=1[C:22]([F:25])([F:24])[F:23].B(Br)(Br)Br.O.CCOC(C)=O>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[C:15]3[CH:16]=[CH:17][C:18]([OH:20])=[CH:19][C:14]=3[S:13][N:12]=2)=[O:10])=[CH:4][C:3]=1[C:22]([F:24])([F:23])[F:25]
Reactant: COc1ccc2c(C(=O)Nc3ccc(F)c(C(F)(F)F)c3)nsc2c1
Agent: BrB(Br)Br
Solvent: O
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: O=C(Nc1ccc(F)c(C(F)(F)F)c1)c1nsc2cc(O)ccc12
Temperature: 45 °C
Reaction time: 72 h

Procedure:
A suspension of 252 mg (0.68 mMol) 6-methoxy-benzo[d]isothiazole-3-carboxylic acid (4-fluoro-3-trifluoromethyl-phenyl)-amide in 15 ml CH2Cl2 is cooled in an ice-bath, then 20 ml of a 1 M solution of BBr3 in CH2Cl2 are added. The suspension is stirred for 3 days at 45° C., the resulting solution is cooled, poured into water and EtOAc, the aq. layer is separated off and extracted twice with EtOAc. The organic layers are washed twice with water and sat. NaHCO3, dried (Na2SO4) and concentrated. Chromatography (Combi Flash; acetone/hexane 1:95→2:3) gives the title compound: MS: [M−1]=355; TLC(hexane/acetone 2:1): Rf=0.46.
Reaction SMILES: [H-].[Na+].[NH:3]1[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][C:4]1=[O:10].[CH2:11](Br)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C1COCC1>[CH2:11]([N:3]1[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][C:4]1=[O:10])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: BrCc1ccccc1
Reactant: O=C1CCCCCN1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C1CCCCCN1Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirring 0° C. suspension of NaH (18.3 g, 763 mmol) in THF (195 mL) was added by addition funnel azepan-2-one (75.0 g, 667 mmol) in THF. An additional 2L of solvent was added as the reaction progressed in order to maintain agitation of the very viscous reaction suspension. Following addition, the reaction was allowed to warm to room temperature, and when the evolution of H2 gas ceased after stirring overnight, benzyl bromide was added dropwise by addition funnel and the reaction was stirred overnight. The crude product was filtered through Celite and concentrated in vacuo. Recrystallization from hexanes and ethyl acetate provided pure 1-benzyl-azepan-2-one as a white fluffy solid. 1H NMR (CDCl3, 300 MHz) 7.38–7.24 (5H, m), 4.61 (2H, s), 3.33–3.29 (2H, m), 2.65–2.61 (2H, m), 1.77–1.66 (4H, m), 1.56–1.46 (2H, m) ppm. 13C NMR (CDCl3, 75 MHz) 176.13, 138.06, 128.67, 128.31, 127.43, 51.20, 49.04, 37.33, 30.12, 28.26, 23.58 ppm.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.[NH2:9][C:10]1[CH:11]=[N:12][C:13]2[C:18]([CH:19]=1)=[CH:17][CH:16]=[CH:15][CH:14]=2.CCN(C(C)C)C(C)C.CCOC(C)=O>CC(O)C>[Cl:1][C:2]1[N:7]=[C:6]([NH:9][C:10]2[CH:11]=[N:12][C:13]3[C:18]([CH:19]=2)=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:5]=[CH:4][N:3]=1
Reactant: Clc1ccnc(Cl)n1
Reactant: Nc1cnc2ccccc2c1
Solvent: CCOC(C)=O
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: Clc1nccc(Nc2cnc3ccccc3c2)n1

Procedure:
A mixture of 2,4-dichloropyrimidine (1.0 g, 6.7 mmol), 3-aminoquinoline (1.1 g, 7.79 mmol) and DIEA (2.0 mL, 11.5 mmol) in IPA (8 mL) was heated to reflux for 48 h. The mixture was poured into EtOAc (200 mL) and washed with H2O (100 mL). The organics were dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude was purified via medium pressure liquid chromatography using 50:50 EtOAc/hexanes followed by 100% EtOAc followed by 5:95 MeOH/CH2Cl2 followed by 1.0:10:90 conc. NH4OH/MeOH/CH2Cl2 as the solvent system. (2-Chloropyrimidin-4-yl)-quinolin-3-yl-amine was obtained as a tan solid.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]([CH2:13][NH:14][CH:15]([C:31](=[O:37])[NH:32][C:33]([CH3:36])([CH3:35])[CH3:34])[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:19][CH:18]=1)[CH2:9][CH:10]([CH3:12])[CH3:11])(C)(C)C.FC(F)(F)C(O)=O.[ClH:46]>C(Cl)Cl.C(OCC)C>[ClH:46].[ClH:46].[NH2:7][CH:8]([CH2:9][CH:10]([CH3:12])[CH3:11])[CH2:13][NH:14][CH:15]([CH2:16][C:17]1[CH:18]=[CH:19][C:20]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:21][CH:22]=1)[C:31]([NH:32][C:33]([CH3:34])([CH3:35])[CH3:36])=[O:37]
Reactant: CC(C)CC(CNC(Cc1ccc(OCc2ccccc2)cc1)C(=O)NC(C)(C)C)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Solvent: CCOCC
Solvent: ClCCl
Product: CC(C)CC(N)CNC(Cc1ccc(OCc2ccccc2)cc1)C(=O)NC(C)(C)C
Reaction time: 0.42 h
Yield: 59 %

Procedure:
To a solution of (1-{[2-(4-benzyloxy-phenyl)-1-tert-butylcarbamoyl-ethylamino]-methyl}-3-methyl-butyl)-carbamic acid tert-butyl ester (0.4 g, 0.76 mmol, Example 8, Step A) in CH2Cl2 (7.5 mL) was added trifluoroacetic acid (2.5 mL) at ambient temperature under nitrogen atmosphere. The resulting reaction mixture was stirred for 25 minutes, then concentrated in vacuo. The viscous oil obtained was dissolved in 40 mL of CH2Cl2 and successively washed with saturated aqueous NaHCO3 solution (2×40 mL), brine (2×40 mL), and was dried over Na2SO4. The CH2Cl2 solution of free amine was concentrated in vacuo to afford the crude product as a viscous oil which was then dissolved in 10 mL of ethyl ether. To this solution was added saturated HCl solution in ethyl ether until no more white precipitate formed. Filtration and drying overnight under vacuum afforded 0.15 g (59%) of titled compound as a yellow solid; mp 228-230° C.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=O)[C:5]([SH:11])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].Br[CH:19]1[CH2:24][CH2:23][O:22][C:20]1=[O:21].Cl>O.C(OC(=O)C)(=O)C.C(N(CC)CC)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:11][C:19]3([C:7](=[O:9])[C:6]=2[CH:10]=1)[CH2:24][CH2:23][O:22][C:20]3=[O:21]
Reactant: O=C(O)c1cc(Cl)ccc1S
Reactant: O=C1OCCC1Br
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: O=C1OCCC12Sc1ccc(Cl)cc1C2=O
Temperature: 25 °C
Reaction time: 21 h
Yield: 28.1 %

Procedure:
In 250 ml of water were dissolved 18.9 g of 5-chlorothiosalicyclic acid and 26.5 g of sodium carbonate, and 25 g of α-bromo-γ-butyrolactone was added dropwise to the solution under ice-cooling, followed by stirring at room temperature for 21 hours. 100 ml of 3 N-HCl was added to the reaction solution at room temperature to acidify the solution, and the solution was subjected to extraction with ethyl acetate. The extract was washed with aqueous saturated solution of sodium chloride and dried, and then, the solvent was distilled off. The residue was dissolved in 300 ml of toluene and heated under reflux for 2 hours while distilling off the produced water. After cooling the solution, insolubles were filtered off, and the filtrate was evaporated to dryness under reduced pressure, resulting in crude α-[(2-carboxy-4-chlorophenyl)thio]-γ-butyrolactone. The crude product was dissolved in 200 ml of acetic anhydride and 40 ml of triethylamine, and heated under a stream of nitrogen at 130° C. for 10 minutes. The reaction solution was evaporated to dryness under reduced pressure and chromatographed on a column by use of 50 g of activated carbon, 50 g of silica gel and chloroform. Recrystallization from ethanol of the resulting crude crystals yielded 7.17 g of 5-chloro-4',5'-dihydrospiro[benzo[b]thiophene-2(3H),3'(2'H)-furan]-3,2'-dione as pale yellow needles. Melting point: 143°-143.5° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:10])=[C:6]([CH2:8][OH:9])[CH:7]=1.[C:11](=[O:14])([O-])[O-:12].[Na+].[Na+]>O1CCOCC1.O>[Cl:10][C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:11](=[O:14])[O:12][C:6]([CH3:8])([CH3:7])[CH3:5])=[CH:7][C:6]=1[CH2:8][OH:9]
Reactant: Nc1ccc(Cl)c(CO)c1
Reactant: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)Nc1ccc(Cl)c(CO)c1
Reaction time: 3 h
Yield: 136.9 %

Procedure:
To a solution of (5-amino-2-chlorophenyl)methanol (Aldrich, 500 mg, 3.17 mmol) in a mixture of dioxane (7.5 mL), water (7.5 mL) was added sodium carbonate (336 mg, 3.17 mmol) previously dissolved in 4 mL of water. Solution was stirred and cooled in an ice bath. Boc-anhydride (Aldrich, 692 mg, 3.17 mmol) was added in one portion, and stirring was continued at room temperature for 3 h. Dioxane was removed in vacuo conditions and the aqueous layer chilled, covered with a layer of ethyl acetate, and acidified to pH 4 with dilute KHSO4 (10%, aq) (ALDRICH). This was followed by extraction (EtOAc) and purification by chromatographic column 25 g cartridge (ISOLUTE silice) using Hex/EtOAc 100/0 to 50/50, giving 1,1-dimethylethyl [4-chloro-3-(hydroxymethyl)phenyl]carbamate (560 mg, 2.17 mmol, 68%). 1H NMR (300 MHz, DMSO-d6) δ ppm: 9.46 (br s, 1H), 7.72 (s, 1H), 7.21-7.32 (m, 2H), 5.35 (t, 1H), 4.48 (d, 2H), 1.47 (s, 9H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]3[N:11]([CH3:15])[CH:12]=[CH:13][CH:14]=3)=[N:7][C:6]=2[CH:16]=1.[C:17](Cl)(Cl)=[S:18].C(=O)([O-])[O-].[Ca+2].O>C(Cl)(Cl)Cl>[CH3:15][N:11]1[CH:12]=[CH:13][CH:14]=[C:10]1[C:8]1[O:9][C:5]2[CH:4]=[CH:3][C:2]([N:1]=[C:17]=[S:18])=[CH:16][C:6]=2[N:7]=1
Reactant: S=C(Cl)Cl
Reactant: Cn1cccc1-c1nc2cc(N)ccc2o1
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: ClC(Cl)Cl
Solvent: O
Product: Cn1cccc1-c1nc2cc(N=C=S)ccc2o1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1.0 g of 5-amino-2-(1-methyl-2-pyrrolyl)benzoxazole (0.0047 mole) is dissolved in 50 ml of chloroform and slowly added to the following cold mixture: 0.54 g of thiophosgene (0.0047 mole), 0.47 g of calcium carbonate (0.0047 mole), 100 ml of chloroform and 25 ml of water. After the addition is complete the reaction is stirred at room temperature for 2 hr. The chloroform layer is separated, dried over anhyd. MgSO4 and evaporated under vacuum yielding a light brown solid. This material is crystallized from petroleum ether yielding 0.650 g of tan crystals, mp 105°-106° (54%).
Reaction SMILES: [CH2:1]([C:5]1[C:6](=[O:22])[N:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[CH:10][N:9]=2)[CH2:2][CH2:3][CH3:4].[CH3:23][S:24]C1C=C(NC2C(C(OC)=O)=CC=CN=2)C=CC=1.C1(NC2C(C(OC)=O)=CC=CN=2)C=CC=CC=1>>[CH2:1]([C:5]1[C:6](=[O:22])[N:7]([C:16]2[CH:17]=[CH:18][CH:19]=[C:20]([S:24][CH3:23])[CH:21]=2)[C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[CH:10][N:9]=2)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1c(O)c2cccnc2n(-c2ccccc2)c1=O
Reactant: COC(=O)c1cccnc1Nc1cccc(SC)c1
Agent: COC(=O)c1cccnc1Nc1ccccc1
Product: CCCCc1c(O)c2cccnc2n(-c2cccc(SC)c2)c1=O

Procedure:
Prepare the 3-(n-butyl)-4-hydroxy-1-phenyl-1,8-naphthyridin-2(1H)one by the process of Example 1 by replacing the methyl 2-(3-methylthiophenylamino)-3-pyridine carboxylate with an equivalent amount of methyl 2-phenylamino-3-pyridine carboxylate.
Reaction SMILES: [CH3:1][CH:2]([C:4]1[CH:11]=[C:10]([OH:12])[C:8](=[O:9])[CH:7]=[CH:6][CH:5]=1)[CH3:3].O.O.O.O.O.O.[Cl-].[Al+3:20].[Cl-].[Cl-]>C(O)C>[CH3:3][CH:2]([C:4]1[CH:11]=[C:10]([OH:12])[C:8](=[O:9])[CH:7]=[CH:6][CH:5]=1)[CH3:1].[Al:20]
Reactant: [Al+3]
Agent: CC(C)c1cccc(=O)c(O)c1
Agent: [Cl-]
Solvent: O
Solvent: CCO
Product: [Al]

Procedure:
Subsequently, hinokitiol and aluminum chloride hexa-hydrate salt were mixed in aqueous ethanol solution at a molar ratio and the compounding amount shown in the following Table 27, and the complex compound of hinokitiol with an aluminum compound was respectively formed in the solution.