Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(=O)(=O)(O)[OH:2].[CH2:6]([CH:10]([OH:13])[C:11]#[N:12])[CH2:7][CH2:8][CH3:9].C#N>O>[OH:13][CH:10]([CH2:6][CH2:7][CH2:8][CH3:9])[C:11]([NH2:12])=[O:2]
Reactant: O=S(=O)(O)O
Reactant: CCCCC(O)C#N
Agent: C#N
Solvent: O
Product: CCCCC(O)C(N)=O
Reaction time: 0.5 h

Procedure:
A stirrer, a thermometer and a dropping funnel were set to a 1,000-mL four-necked flask and to a reaction apparatus, 95% sulfuric acid (450 g, 4.4 mol) was added and cooled so that the liquid temperature was lower than 30° C. To the cooled sulfuric acid with stirring, was added α-n-butyl-α-hydroxyacetonitrile prepared from n-butyl aldehyde and hydrocyanic acid (1.5 mol, content 87 to 94%, further containing unreacted hydrocyanic acid, starting material n-butyl aldehyde and water) with the use of dropping funnel. The addition was conducted in such a way that the reaction solution was kept at a temperature of lower than 40° C. After the dropwise addition, the reaction solution was aged at 40° C. for 0.5 hr. The pH of the reaction solution was less than 1. A part of the reaction solution was sampled and analyzed by HPLC. In result, the ratio of conversion of the starting materials was 100% and the corresponding 2-hydroxyhexanoic acid amide and 2-hydroxysulfonyl oxy hexanoic acid amide were produced.
Reaction SMILES: C[N:2]([CH3:12])[CH:3]=[C:4]([N+:10]#[C-:11])[C:5]([O:7][CH2:8][CH3:9])=[O:6].N[CH:14]1[CH:21]2[CH2:22][CH:17]3C[CH:19]([CH2:23][CH:15]1[CH2:16]3)[CH2:20]2.C(O)CCC>O>[CH:19]12[CH2:23][CH:15]3[CH2:14][CH:21]([CH2:22][CH:17]([CH2:16]3)[CH:12]1[N:2]1[CH:3]=[C:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[N:10]=[CH:11]1)[CH2:20]2
Reactant: [C-]#[N+]C(=CN(C)C)C(=O)OCC
Reactant: NC1C2CC3CC(C2)CC1C3
Solvent: CCCCO
Solvent: O
Product: CCOC(=O)c1cn(C2C3CC4CC(C3)CC2C4)cn1
Temperature: 150 °C
Reaction time: 13 h
Yield: 29.4 %

Procedure:
Ethyl 3-(dimethylamino)-2-isocyanoacrylate (0.50 g), 2-aminoadamantane (0.54 g), and n-butanol (2.5 mL) were added and stirred at 150° C. for 13 hours. To the reaction solution, water was added, and organic matter was extracted with ethyl acetate. The organic layer was concentrated and then purified by silica gel column chromatography (eluting solvent: methylene chloride-methylene chloride/methanol=95/5 and ethyl acetate) to obtain the title compound (0.24 g).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[C:5]1[CH:15]=[C:14]([CH2:16][OH:17])[CH:13]=[C:7]([C:8]([O:10]CC)=[O:9])[CH:6]=1)[CH3:2].[OH-].[Na+]>C(O)C>[CH2:1]([O:3][C:4](=[O:18])[C:5]1[CH:15]=[C:14]([CH2:16][OH:17])[CH:13]=[C:7]([C:8]([OH:10])=[O:9])[CH:6]=1)[CH3:2]
Reactant: CCOC(=O)c1cc(CO)cc(C(=O)OCC)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCOC(=O)c1cc(CO)cc(C(=O)O)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 74.3 %

Procedure:
Add commercially available 5-hydroxymethyl-isophthalic acid diethyl ester (5 g, 19.8 mmol) and NaOH (0.79 g, 19.8 mmol) to ethanol (100 mL). Stir for 4 h at room temperature. Concentrate and pour the residue into water (100 mL) and diethyl ether (100 mL). Separate the aqueous layer and wash it with diethyl ether (40 mL). Acidify the aqueous layer with 5 N HCl to about pH=1. Extract the acidic solution with ethyl acetate (3×40 mL). Wash the combined organic layers with Water, saturated aqueous sodium chloride, dry (sodium sulfate) and concentrate to give the title compound as a solid (3.3 g, 74%).
Reaction SMILES: [NH:1]1[C:5]2=[CH:6][N:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[C:2]1[C:10]([OH:12])=O.[C:13]1([NH:19][CH2:20][CH2:21][NH2:22])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[C:13]1([NH:19][CH2:20][CH2:21][NH:22][C:10]([C:2]2[NH:1][C:5]3=[CH:6][N:7]=[CH:8][CH:9]=[C:4]3[CH:3]=2)=[O:12])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C(O)c1cc2ccncc2[nH]1
Reactant: NCCNc1ccccc1
Product: O=C(NCCNc1ccccc1)c1cc2ccncc2[nH]1

Procedure:
The title compound was prepared as outlined in EXAMPLE 1 from 1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid (Preparation 15) and 2-phenylaminoethylamine to give the title compound as a pale yellow solid. δH (CD3OD): 3.37 (2H, t), 3.63 (2H, t), 6.61 (1H, t), 6.69 (2H, d), 7.08-7.13 (2H, m), 7.64 (1H, d), 8.10 (1H, d), 8.78 (1H, s); m/z (ES+)=281 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)N.C(ON=O)CC(C)C.[S:17]1[CH:21]=[CH:20][CH:19]=[CH:18]1>CCOCC>[Br:1][C:2]1[CH:3]=[C:4]([C:18]2[S:17][CH:21]=[CH:20][CH:19]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: c1ccsc1
Reactant: Nc1cccc(Br)c1
Agent: CC(C)CCON=O
Solvent: CCOCC
Product: Brc1cccc(-c2cccs2)c1
Temperature: 25 °C
Yield: 34 %

Procedure:
To a stirred solution of m-bromoaniline (34.4 g; 0.2M) in thiophene (200 mL) was added isoamylnitrite (46.86 g; 0.4M) dropwise over a period of 30 mins. at 0° C. The resulting mixture was cautiously warmed to R.T. and heated to reflux for 16 hours. The reaction mixture was cooled, diluted with 400 mL of ether, washed with 3×100 mL of satd sodium chloride solution, and dried over anhydrous magnesium sulfate. Solvent and excess thiophene were removed. A solution of the residue in 200 mL of ether was filtered through 50 G silica gel bed. Solvent was removed, and the residue was distilled to give 34% of 2-(3'-bromophenyl) thiophene as a yellow liquid boiling at 130°-2°/~0.2 m. This liquid solidified on standing in the refrigerator.
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][CH:5]=[CH:4][C:3]=1[CH3:11]>CCO.CCOC(C)=O.[Pt]>[Cl:1][C:2]1[C:3]([CH3:11])=[CH:4][CH:5]=[CH:6][C:7]=1[NH2:8]
Reactant: Cc1cccc([N+](=O)[O-])c1Cl
Agent: [Pt]
Solvent: CCOC(C)=O
Solvent: CCO
Product: Cc1cccc(N)c1Cl

Procedure:
A mixture of 2-chloro-3-nitrotoluene (1.0 g, 5.8 mmol) and 5% platinum-on-carbon (0.1 g) in 25 ml of EtOH was reacted overnight at room temperature and 60 psi. The reaction mixture was filtered and the filtrate concentrated in vacuo to provide an oil. This oil was dissolved in EtOAc, washed with H2O, dried over Na2SO4, filtered and then concentrated in vacuo.
Reaction SMILES: Cl[C:2]1[C:7]([CH3:8])=[CH:6][C:5]([F:9])=[CH:4][N:3]=1.[OH2:10]>Cl>[F:9][C:5]1[CH:6]=[C:7]([CH3:8])[C:2]([OH:10])=[N:3][CH:4]=1
Reactant: Cc1cc(F)cnc1Cl
Reactant: O
Agent: Cl
Product: Cc1cc(F)cnc1O
Temperature: 150 °C

Procedure:
2-chloro-5-fluoro-3-methylpyridine (1 g, 6.870 mmol) is dissolved in hydrochloric acid (37%, 20 mL) and the reaction is heated under microwave irradiation at 150° C. for 15 h. The mixture is diluted with water and washed with DCM. The aqueous layer is basified with NaOH and re-extracted with DCM several times. The organic layer is separated, dried and evaporated to furnish 5-fluoro-3-methyl-pyridin-2-ol (140 mg, content 74%, 12%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[C:10]([C:15]#[N:16])[CH:9]=2)=[O:5])[CH3:2].[H-].[Na+].I[CH3:20]>C1COCC1>[CH2:1]([O:3][C:4]([C:6]1[N:7]([CH3:20])[C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[C:10]([C:15]#[N:16])[CH:9]=2)=[O:5])[CH3:2]
Reactant: CI
Reactant: CCOC(=O)c1cc2ccc(C#N)cc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)c1cc2ccc(C#N)cc2n1C
Reaction time: 0.17 h
Yield: 59 %

Procedure:
Treat a solution of 6-cyano-1H-indole-2-carboxylic acid ethyl ester (86 mg, 0.40 mmol) in THF (3 mL) with sodium hydride (60% disp. in mineral oil, 18 mg, 0.44 mmol) under N2. After stirring for 10 min, add iodomethane (68 mg, 0.48 mmol) and stir at rt for 3 h. Quench the reaction with sat. NH4Cl solution and extract several times with EtOAc. Dry the combined organic layers (Na2SO4) and concentrate to give a solid. Purify the crude product by silica gel chromatography (MeOH/DCM: 0% to 10%) to give the desired 6-cyano-1-methyl-1H-indole-2-carboxylic acid ethyl ester in 59% yield (54 mg, 0.24 mmol).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([OH:6])=[CH:4][C:3]=1[OH:9].[CH2:10]([CH:17](C(C)=O)[C:18](OCC)=[O:19])C1C=CC=CC=1>OS(O)(=O)=O>[Cl:1][C:2]1[CH:8]=[C:7]2[C:5](=[CH:4][C:3]=1[OH:9])[O:6][C:18](=[O:19])[CH:17]=[CH:10]2
Reactant: Oc1ccc(Cl)c(O)c1
Reactant: CCOC(=O)C(Cc1ccccc1)C(C)=O
Agent: O=S(=O)(O)O
Product: O=c1ccc2cc(Cl)c(O)cc2o1
Temperature: 25 °C
Reaction time: 72 h
Yield: 104.9 %

Procedure:
4-Chlororesorcinol (26.25 g, 0.182 mol) and ethyl 2-benzylacetoacetate (40 g, 0.182 mol) are mixed in 70% H2SO4 (350 mL) at 0° C. The reaction mixture is stirred at room temperature for 72 hours and poured into ice water. The solid is filtered and washed with water. The crude product is recrystallized from ethanol/chloroform to afford 6-chloro-7-hydroxy coumarin intermediate (37.52 g, 68.7%).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2(O)[C:14]3[C:15]([CH3:37])=[C:16]([N:21]4[CH2:26][CH2:25][CH:24]([C:27]5[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[C:29]([O:35][CH3:36])[CH:28]=5)[CH2:23][CH2:22]4)[C:17]([CH3:20])=[C:18]([CH3:19])[C:13]=3[O:12][C:11]2([CH3:39])[CH3:38])=[CH:6][CH:5]=1)([CH3:3])[CH3:2]>CCCCCC.CO>[CH:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[C:14]3[C:15]([CH3:37])=[C:16]([N:21]4[CH2:22][CH2:23][CH:24]([C:27]5[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[C:29]([O:35][CH3:36])[CH:28]=5)[CH2:25][CH2:26]4)[C:17]([CH3:20])=[C:18]([CH3:19])[C:13]=3[O:12][C:11]2([CH3:39])[CH3:38])=[CH:6][CH:5]=1)([CH3:3])[CH3:2]
Reactant: COc1ccc(C2CCN(c3c(C)c(C)c4c(c3C)C(O)(c3ccc(C(C)C)cc3)C(C)(C)O4)CC2)cc1OC
Solvent: CO
Solvent: CCCCCC
Product: COc1ccc(C2CCN(c3c(C)c(C)c4c(c3C)C(c3ccc(C(C)C)cc3)C(C)(C)O4)CC2)cc1OC
Yield: 90 %

Procedure:
Using 3-(4-isopropylphenyl)-5-(4-(3,4-dimethoxyphenyl)piperidino)-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-3-ol obtained in Example 83, the title compound was synthesized in the same manner as in Example 46. Yield 90%. mp. 129–132° C. (hexane-methanol).
Reaction SMILES: [Cl:1][CH2:2][S:3]([NH:6][C:7]1[CH:12]=[C:11]([N:13]=[C:14]=[O:15])[C:10]([F:16])=[CH:9][C:8]=1[Cl:17])(=[O:5])=[O:4].[F:18][C@@H:19]1[CH2:23][NH:22][C@@H:21]([C:24]([OH:26])=[O:25])[CH2:20]1>O1CCCC1>[Cl:17][C:8]1[C:7]([NH:6][S:3]([CH2:2][Cl:1])(=[O:4])=[O:5])=[CH:12][C:11]([NH:13][C:14]([N:22]2[CH2:23][C@@H:19]([F:18])[CH2:20][C@@H:21]2[C:24]([OH:26])=[O:25])=[O:15])=[C:10]([F:16])[CH:9]=1
Reactant: O=C=Nc1cc(NS(=O)(=O)CCl)c(Cl)cc1F
Reactant: O=C(O)[C@H]1C[C@H](F)CN1
Solvent: C1CCOC1
Product: O=C(O)[C@H]1C[C@H](F)CN1C(=O)Nc1cc(NS(=O)(=O)CCl)c(Cl)cc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.1 %

Procedure:
1-chloro-N-(2-chloro-4-fluoro-5-isocyanatophenyl)methanesulfonamide (120 g, 401 mmol) was dissolved in 400 mL of dry tetrahydrofuran. 55.8 g (420 mmol) of (2R-trans)-4-fluoro-2-pyrrolidinecarboxylic acid was added in a single portion and the mixture was stirred overnight at room temperature. The mixture was then filtered and the tetrahydrofuran was evaporated under reduced pressure. The residue was dissolved in 800 mL of ethyl acetate, a solution of 86.0 g of sodium bicarbonate in 870 mL of water was added and then solid sodium chloride was added to saturate the aqueous layer. The aqueous layer was separated, washed with 250 mL of ethyl acetate, and then with diethyl ether (twice with 250 mL). The aqueous layer was then added slowly to a stirred mixture of 120 mL of concentrated hydrochloric acid, 240 mL of water, and 800 mL of tetrahydrofuran. Solid sodium chloride was then added to saturate the aqueous layer, the layers were separated, and the aqueous layer was extracted with 100 mL of tetrahydrofuran. The tetrahydrofuran layers were combined, dried over magnesium sulfate, and evaporated under reduced pressure to afford 173.43 g of the title compound as a glassy solid, suitable for use in the next step. 1H NMR (DMSO-d6): δ 2.0-2.3 (m, 1H), 2.5-2.6 (m, 1H), 3.66 (m, 1H), 3.86 (m, 1H), 4.97 (s, 2H), 5.40 (d, J=54 Hz, 1H), 7.52 (d, 1H), 7.66 (d, 1H), 8.48 (s, 1H), 10.10 (br s, 1H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]([Br:15])=[CH:13][C:12]([CH:16]([C:18]2[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][O:26][CH2:27][O:28][CH3:29])=[CH:20][CH:19]=2)O)=[C:11]([Cl:30])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[SiH](CC)(CC)CC.B(F)(F)F.CCOCC.C(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([Cl:30])[C:12]([CH2:16][C:18]2[CH:19]=[CH:20][C:21]([CH2:24][CH2:25][O:26][CH2:27][O:28][CH3:29])=[CH:22][CH:23]=2)=[CH:13][C:14]=1[Br:15])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COCOCCc1ccc(C(O)c2cc(Br)c(OCc3ccccc3)cc2Cl)cc1
Agent: CC[SiH](CC)CC
Agent: FB(F)F
Agent: O=C([O-])O
Solvent: ClC(Cl)Cl
Solvent: CCOCC
Product: COCOCCc1ccc(Cc2cc(Br)c(OCc3ccccc3)cc2Cl)cc1
Temperature: 25 °C
Yield: 39.8 %

Procedure:
To a chloroform solution (8 mL) of [4-(benzyloxy)-5-bromo-2-chlorophenyl][4-[2-(methoxymethoxy)ethyl]phenyl]methanol (750 mg, 1.53 mmol) cooled in ice were added Et3SiH (367 μL, 2.30 mmol) and BF3.Et2O (232 μL, 1.83 mmol), and the mixture was stirred for an hour at the same temperature. To this solution cooled in ice was added a saturated sodium bicarbonate aqueous solution, and warmed to room temperature. The resulting mixture was extracted with ethyl acetate, washed with brine, and dried with anhydrous magnesium sulfate. The drying agent was filtered off, and the solvent was evaporated under reduced pressure. Thus obtained residue was purified with silica gel column chromatography (hexane:ethyl acetate=4:1) to obtain the title compound (290 mg, 40%) as a colorless oily compound.
Reaction SMILES: [C:1]1(C(=O)C)[C:10]2[CH2:9][CH2:8][CH:7]=C[C:5]=2[CH:4]=[CH:3][CH:2]=1.FC(F)(F)C1C=C(CCC[NH2:25])C=CC=1.[BH4-].[Na+].Cl>CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-].C(OCC)C.CO>[C:10]1([CH:9]([NH2:25])[CH2:8][CH3:7])[CH:5]=[CH:4][CH:3]=[CH:2][CH:1]=1
Reactant: CC(=O)c1cccc2c1CCC=C2
Reactant: NCCCc1cccc(C(F)(F)F)c1
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: Cl
Solvent: CO
Solvent: CCOCC
Product: CCC(N)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 240.4 %

Procedure:
The mixture of 1-(7,8-dihydro-naphthalen-1-yl)-ethanone (10) (172 mg, 1.0 mmol) and 3-(3-trifluoromethyl-phenyl)-propylamine (13) (204 mg, 1.0 mmol) in titanium (IV) isopropoxide (1 mL) was stirred at room temperature overnight. Methanol(5 mL) was added followed by addition of sodium borohydride (55 mg, 2.0 mmol). The reaction mixture was stirred at room temperature for 1 hour and evaporated to dryness. The crude product was purified by chromatography on silica gel, loaded with dichloromethane and eluted with 2% methanol in dichloromethane containing 0.5% ammonium hydroxide. The pure fractions were combined and evaporated to give a colorless oil. The product was converted to a hydrochloride salt by addition of 1 N HCl in ethyl ether. Evaporation gave compound (1) as an off-white solid (325 mg, 82.2%).
Reaction SMILES: C([O:5][C:6]([NH:8][CH2:9][C:10]([CH3:32])([CH3:31])[CH2:11][N:12]1[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH:19]=2)[CH:14]=[C:13]1C(OCC)=O)=O)(C)(C)C.N1C2C(=CC=C(C(OCC)=O)C=2)C=C1C(OCC)=O.C(O)(C(F)(F)F)=O.C(N(CC)CC)C.C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl.C(O)C>[CH3:31][C:10]1([CH3:32])[CH2:11][N:12]2[C:20]3[CH:19]=[C:18]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH:17]=[CH:16][C:15]=3[CH:14]=[C:13]2[C:6](=[O:5])[NH:8][CH2:9]1
Reactant: CCOC(=O)c1ccc2cc(C(=O)OCC)n(CC(C)(C)CNC(=O)OC(C)(C)C)c2c1
Agent: CCOC(=O)c1ccc2cc(C(=O)OCC)[nH]c2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1ccc2cc3n(c2c1)CC(C)(C)CNC3=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 66 %

Procedure:
To a mixture of diethyl 1-{3-[(tert-butoxycarbonyl)amino-]-2,2-dimethylpropyl}-1H-indole-2,6-dicarboxylate and diethyl 1H-indole-2,6-dicarboxylate (Intermediate A, 21.9 g, 49 mmol) in CH2Cl2 (400 mL) is added TFA (100 mL). The mixture is stirred at room temperature for 2 h and then all the solvent is evaporated. The residue is dissolved in EtOAc (300 mL) and is washed with saturated NaHCO3 solution until the pH is about 7. The aqueous layer is extracted with EtOAc (100 mL) and the organic layers are combined, dried (Na2SO4) and concentrated. To a solution of the residue in ethanol (1000 mL) are added triethylamine (20.5 mL, 147 mmol) and K2CO3 (20.3 g, 147 mmol). The mixture is heated at 80° C. for 2 h and then cooled to room temperature and stirred for 16 h. The solid formed the reaction mixture is filtered off and set aside. The filtrate is concentrated and the residue is purified by flash column chromatography using methanol in CH2Cl2 to afford the title compound (7.6 g, 66% for 3 steps).
Reaction SMILES: [C:1]1([N:7]2[C:16]3[N:15]=[CH:14][CH:13]=[CH:12][C:11]=3[C:10]3[O:17][CH2:18][CH2:19][C:9]=3[C:8]2=[S:20])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[I-].[Na+]>CC(N(C)C)=O>[C:1]1([N:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][N:15]=3)[C:10](=[O:17])[C:9]3[CH2:19][CH2:18][S:20][C:8]2=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: S=c1c2c(c3cccnc3n1-c1ccccc1)OCC2
Agent: [I-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: O=c1c2c(n(-c3ccccc3)c3ncccc13)SCC2
Temperature: 0 °C

Procedure:
A solution of 3,5-dihydro-5-phenyl-furo-[3,2-c]-[1,8]naphthyridin-4(2H)-thione (500 mg.) and sodium iodide (500 mg.) in dry dimethylacetamide (5 ml.) was stirred in an atmosphere of nitrogen and heated at 125° for 2 hr. After cooling, the solution was poured into ice-water, filtered, washed with water and dried to yield the desired product, m.p. 260°-261° C.
Reaction SMILES: O[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]1[CH:11]=[C:10]([CH3:12])[O:9][N:8]=1.BrBr.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC1ON=C(CCC[Br:43])C=1>>[Br:43][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]1[CH:11]=[C:10]([CH3:12])[O:9][N:8]=1
Reactant: Cc1cc(CCCBr)no1
Reactant: Cc1cc(CCCCCO)no1
Agent: BrBr
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: Cc1cc(CCCCCBr)no1
Yield: 77 %

Procedure:
3-(5-Bromopentyl)-5-methylisoxazole [XXVII; R9 =CH3, Hal=Br] was prepared by reacting 3-(5-hydroxypentyl)-5-methylisoxazole with bromine and triphenylphosphine according to the procedure of part (f) above, and was obtained in 77% yield as an oil, b.p. 140°-150° C.(0.05 mm).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[S:10][C:11]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:12]=3[N:13]=2)=[CH:4][CH:3]=1.[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]=[C:27]=[S:28])=[CH:22][C:21]=1[C:29]([F:32])([F:31])[F:30]>>[Cl:18][C:15]1[CH:16]=[CH:17][C:11]2[S:10][C:9]([S:8][C:5]3[CH:4]=[CH:3][C:2]([NH:1][C:27]([NH:26][C:23]4[CH:24]=[CH:25][C:20]([Cl:19])=[C:21]([C:29]([F:32])([F:30])[F:31])[CH:22]=4)=[S:28])=[CH:7][CH:6]=3)=[N:13][C:12]=2[CH:14]=1
Reactant: Nc1ccc(Sc2nc3cc(Cl)ccc3s2)cc1
Reactant: FC(F)(F)c1cc(N=C=S)ccc1Cl
Product: FC(F)(F)c1cc(NC(=S)Nc2ccc(Sc3nc4cc(Cl)ccc4s3)cc2)ccc1Cl
Yield: 0 %

Procedure:
2-(4-aminophenylthio)-5-chlorobenzothiazole (5.5 moles, 1.6 g) and 4-chloro-3-trifluoromethylphenylisothiocyanate (5.5 moles, 1.3 g) were reacted according to procedure C to yield the title compound 0.7 g, 24%. Mass Spec (FD 529. Calculated for C21H12C12F3N3S3 : C, 47.55; H, 2.28; N, 7.92. Found: C, 47.55; H, 3.32; N, 7.87.
Reaction SMILES: FC1C=CC(NN[C:10](=[O:18])[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[F:17])=CC=1.P(Cl)(Cl)(Cl)(Cl)[Cl:20].C1(O)C=CC=CC=1.O>C(OCC)C.CO>[Cl:20][C:10](=[O:18])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[F:17]
Reactant: O=C(NNc1ccc(F)cc1)c1ccccc1F
Reactant: ClP(Cl)(Cl)(Cl)Cl
Solvent: O
Solvent: Oc1ccccc1
Solvent: CO
Product: O=C(Cl)c1ccccc1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 121.1 %

Procedure:
To a stirred mixture of 79.5 g of 2-fluorobenzoic acid, 2-(4-fluorophenyl)hydrazide in 350 ml of diethyl ether was added, portionwise, 80.0 g of phosphorous pentachloride. Upon completion of the addition, the reaction mixture was refluxed for 1 hr and then stirred at ambient temperature for 16 hrs. In the following order, a solution of 81.3 g of phenol in 80 ml of diethyl ether, 385 ml of methanol, and sufficient water to reach the solution cloud point, were added, dropwise, to the reaction mixture. Upon standing the reaction mixture separated into two layers. The bottom layer was collected, washed with water, and extracted with diethyl ether. The extract was washed with water, dried over anhydrous magnesium sulfate and concentrated to an oil. The oil was purified by flash chromatography on silica gel using 5% ethyl acetate-hexane as the eluent. Evaporation of the appropriate fractions gave 61.5 g of α-chloro-2-fluorobenzaldehyde, (4-fluorophenyl)hydrazone as an oil. Distillation gave the analytical sample bp 144°-155°.
Reaction SMILES: [OH:1][C:2]([C:30]1[CH:31]=[C:32]2[C:37](=[CH:38][CH:39]=1)[CH:36]=[C:35]([C:40](OC)=[O:41])[CH:34]=[CH:33]2)([C:6]1[N:7]=[CH:8][N:9](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:10]=1)[CH:3]([CH3:5])[CH3:4].OC(C1C=C2C(=CC=1)C=C(C(O)=O)C=C2)(C1N=CN(C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)C=1)C(C)C.[CH:86]1([NH2:92])[CH2:91][CH2:90][CH2:89][CH2:88][CH2:87]1>>[CH:86]1([NH:92][C:40]([C:35]2[CH:34]=[CH:33][C:32]3[C:37](=[CH:38][CH:39]=[C:30]([C:2]([OH:1])([C:6]4[N:7]=[CH:8][NH:9][CH:10]=4)[CH:3]([CH3:4])[CH3:5])[CH:31]=3)[CH:36]=2)=[O:41])[CH2:91][CH2:90][CH2:89][CH2:88][CH2:87]1
Reactant: NC1CCCCC1
Reactant: COC(=O)c1ccc2cc(C(O)(c3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)cn3)C(C)C)ccc2c1
Agent: CC(C)C(O)(c1ccc2cc(C(=O)O)ccc2c1)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Product: CC(C)C(O)(c1ccc2cc(C(=O)NC3CCCCC3)ccc2c1)c1c[nH]cn1

Procedure:
In a manner to that described in Example 9-(i), methyl 6-(1-hydroxy-2-methyl-1-(1-trityl-1H-imidazol-4-yl)propyl)-2-naphthoate (2.83 g) was converted to 6-(1-hydroxy-2-methyl-1-(1-trityl-1H-imidazol-4-yl)propyl)-2-naphthoic acid, which was reacted with cyclohexylamine (0.18 mL) in a similar manner as described in Example 24-(i) to give the titled compound (598 mg) as a colorless powder.
Reaction SMILES: C[O:2][C:3](=[O:21])[CH2:4][NH:5][C:6]([C:8]1[N:9]=[C:10]([Cl:20])[C:11]2[C:16]([C:17]=1[O:18][CH3:19])=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:7].[OH-].[K+]>CCO>[Cl:20][C:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:17]([O:18][CH3:19])=[C:8]([C:6]([NH:5][CH2:4][C:3]([OH:21])=[O:2])=[O:7])[N:9]=1
Reactant: COC(=O)CNC(=O)c1nc(Cl)c2ccccc2c1OC
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: COc1c(C(=O)NCC(=O)O)nc(Cl)c2ccccc12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of [(1-chloro-4-methoxy-isoquinoline-3-carbonyl)-amino]-acetic acid methyl ester (21 mg, 0.07 mmol), KOH (23 mg, 0.35 mmol) and EtOH (1 ml) was stirred at ambient temperature for 3 h. Then the solvent was evaporated in vacuo. The residue was dissolved in water (2 ml) and the pH of the solution was adjusted to 2-3 by the addition of aqueous 1N HCl. The mixture was extracted with EtOAc (4×10 ml). The combined org. phases were dried over MgSO4 and evaporated in vacuo to give the title compound as a slightly yellowish solid (18 mg); MS-(+)-ion: M+1=295.0.
Reaction SMILES: CC(OC(/N=N/C(OC(C)C)=O)=O)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:34]1(=[O:44])[C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[C:36](=[O:43])[NH:35]1.[F:45][C:46]([F:61])([F:60])[C:47]1[CH:52]=[CH:51][N:50]=[C:49]([CH2:53][CH:54]2[CH2:58][CH2:57][CH2:56][CH:55]2O)[CH:48]=1>C1COCC1>[F:61][C:46]([F:45])([F:60])[C:47]1[CH:52]=[CH:51][N:50]=[C:49]([CH2:53][CH:54]2[CH2:58][CH2:57][CH2:56][CH:55]2[N:35]2[C:36](=[O:43])[C:37]3[C:42](=[CH:41][CH:40]=[CH:39][CH:38]=3)[C:34]2=[O:44])[CH:48]=1
Reactant: OC1CCCC1Cc1cc(C(F)(F)F)ccn1
Reactant: O=C1NC(=O)c2ccccc21
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C1c2ccccc2C(=O)N1C1CCCC1Cc1cc(C(F)(F)F)ccn1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
DIAD (0.26 ml, 1.36 mmol) was added to a solution of triphenylphosphine (0.350 g, 1.34 mmol), 2,3-dihydro-1H-isoindole-1,3-dione (CAS number 136918-14-4; 0.197 g, 1.34 mmol) and 2-{[4-(trifluoromethyl)pyridin-2-yl]methyl}cyclopentan-1-ol (Diastereomer 2) (0.252 g, 1.03 mmol) in THF (5 ml). The reaction was stirred at room temperature for 24 hours and then further triphenylphosphine (0.175 g, 0.69 mmol) and DIAD (0.130 ml, 0.69 mmol) was added. The reaction was stirred for 72 hours at room temperature and then concentrated in vacuo. The crude product was purified by column chromatography (silica, 0-100% ethyl acetate/petrol) and then by column chromatography (basic silica, 0-100% ethyl acetate/petrol) to afford the title compound.