Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1C=C[CH:5]=[CH:4][CH:3]=1.[Al+3].[Cl-:9].[Cl-:10].[Cl-:11].ClCl.O.[Cl:15][CH2:16][CH2:17][Cl:18]>>[Cl:15][C:16]1[C:2]([F:1])=[C:3]([Cl:9])[C:4]([Cl:10])=[C:5]([Cl:11])[C:17]=1[Cl:18]
Reactant: ClCCCl
Reactant: [Cl-]
Reactant: Fc1ccccc1
Agent: ClCl
Agent: [Al+3]
Solvent: O
Product: Fc1c(Cl)c(Cl)c(Cl)c(Cl)c1Cl
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A solution of 144 g (1.5 mol) of fluorobenzene in 1080 ml of 1,2-dichloroethane was admixed with 10 g (0.075 mol) of powdered AlCl3, and 586 g of chlorine gas were then passed into the mixture at 5-15° C. The solution was then stirred at 25° C. for about 5 hours, then heated to 65° C. and 100 ml of water were subsequently added while stirring vigorously. At this temperature, the phases were separated and the organic phase was extracted with water. The solvent was distilled off and the residue was taken up in 1300 g of NMP. After gas-chromatographic analysis (GC), the yield was calculated as: 93.9% of pentachlorofluorobenzene, 4.9% of hexachlorobenzene and 1.1% of tetrachlorofluorobenzenes. The solution can directly be reacted further as described in example 6.
Reaction SMILES: [Cl:1][C:2]1[C:10]([OH:11])=[C:9]([OH:12])[C:8]([Cl:13])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].C([O-])([O-])=O.[K+].[K+].[CH2:20](Br)[CH:21]=[CH2:22]>CN(C=O)C>[Cl:1][C:2]1[C:10]([O:11][CH2:10][CH:2]=[CH2:3])=[C:9]([O:12][CH2:9][CH:8]=[CH2:7])[C:8]([Cl:13])=[CH:7][C:3]=1[C:4]([O:6][CH2:20][CH:21]=[CH2:22])=[O:5]
Reactant: O=C(O)c1cc(Cl)c(O)c(O)c1Cl
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=CCOC(=O)c1cc(Cl)c(OCC=C)c(OCC=C)c1Cl
Reaction time: 8 h

Procedure:
2,5-Dichloro-3,4-dihydroxybenzoic acid (10.7 g, see J. Antibiotics, 1987, 40, 22) and K2CO3 (33.1 g) were suspended in DMF (150 ml), and treated with allyl bromide (14.7 ml). After stirring overnight, the mixture was filtered, diluted with ethyl acetate, washed with sodium bicarbonate, dried (MgSO4), filtered and evaporated to give allyl 2,5-dichloro-3,4-diallyloxybenzoate (14.7 g): NMR (CDCl3) 4.55-4.65 (m, 4H); 4.82 (m, 2H); 5.24-5.50 (m, 6H); 5.94-6.22 (m, 3H); 7.70 (s, 1H).
Reaction SMILES: ClC1C(F)=CC(F)=C(C=1)C(NS(C)(=O)=O)=O.[Cl:17][C:18]1[C:19](F)=[CH:20][C:21]([F:33])=[C:22]([CH:32]=1)[C:23]([NH:25][S:26]([CH:29]1[CH2:31][CH2:30]1)(=[O:28])=[O:27])=[O:24].C12(CO)CC3CC(CC(C3)C1)C2.[CH2:47]1[C:49]2([CH2:54][CH2:53][CH:52]([CH2:55][OH:56])[CH2:51][CH2:50]2)[CH2:48]1>>[Cl:17][C:18]1[C:19]([O:56][CH2:55][CH:52]2[CH2:53][CH2:54][C:49]3([CH2:47][CH2:48]3)[CH2:50][CH2:51]2)=[CH:20][C:21]([F:33])=[C:22]([CH:32]=1)[C:23]([NH:25][S:26]([CH:29]1[CH2:31][CH2:30]1)(=[O:28])=[O:27])=[O:24]
Reactant: OCC1CCC2(CC1)CC2
Reactant: O=C(NS(=O)(=O)C1CC1)c1cc(Cl)c(F)cc1F
Agent: CS(=O)(=O)NC(=O)c1cc(Cl)c(F)cc1F
Agent: OCC12CC3CC(CC(C3)C1)C2
Product: O=C(NS(=O)(=O)C1CC1)c1cc(Cl)c(OCC2CCC3(CC2)CC3)cc1F

Procedure:
Following the procedure as described in Example 8 and making variations as required to replace 5-chloro-2,4-difluoro-N-(methylsulfonyl)benzamide with 5-chloro-N-(cyclopropylsulfonyl)-2,4-difluorobenzamide and to replace adamantan-1-ylmethanol with spiro[2.5]octan-6-ylmethanol, the title compound was obtained as a colorless solid (0.165 g, 28%): 1H NMR (300 MHz, CDCl3) δ8.72-8.59 (m, 1H), 8.16-8.07 (m, 1H), 6.76-6.65 (m, 1H), 3.97-3.86 (m, 2H), 3.17-3.05 (m, 1H), 2.03-1.72 (m, 5H), 1.51-1.42 (m, 2H), 1.36-1.11 (m, 4H), 1.00-0.90 (m, 2H), 0.38-0.14 (m, 4H); MS (ES+) m/z 416.2, 418.2 (M+1).
Reaction SMILES: [CH:1]1([N:4]2[C:8]3[CH:9]=[C:10]([F:13])[CH:11]=[CH:12][C:7]=3[N:6]=[C:5]2[C@@H:14]([NH2:16])[CH3:15])[CH2:3][CH2:2]1.Cl[C:18]1[N:26]=[CH:25][N:24]=[C:23]2[C:19]=1[N:20]=[CH:21][N:22]2C1CCCCO1.CCN(C(C)C)C(C)C>C(O)CCC>[CH:1]1([N:4]2[C:8]3[CH:9]=[C:10]([F:13])[CH:11]=[CH:12][C:7]=3[N:6]=[C:5]2[C@@H:14]([NH:16][C:18]2[N:26]=[CH:25][N:24]=[C:23]3[C:19]=2[N:20]=[CH:21][NH:22]3)[CH3:15])[CH2:3][CH2:2]1
Reactant: C[C@H](N)c1nc2ccc(F)cc2n1C1CC1
Reactant: Clc1ncnc2c1ncn2C1CCCCO1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: C[C@H](Nc1ncnc2[nH]cnc12)c1nc2ccc(F)cc2n1C1CC1
Temperature: 100 °C
Yield: 48.8 %

Procedure:
A mixture of (S)-1-(1-cyclopropyl-6-fluoro-1H-benzoimidazol-2-yl)ethylamine (166 mg, 0.76 mmol), 6-chloro-9-(tetrahydropyran-2-yl)-9H-purine (180 mg, 0.76 mmol) and DIPEA (0.7 mL, 3.8 mmol) in n-butanol (3 mL) was heated at 100° C. for 18 h. After cooling to RT, the volatiles were removed under reduced pressure and the resulting residue loaded onto an Isolute® SCX-2 cartridge. The cartridge was washed with MeOH followed by 2M NH3/MeOH. The basic fractions were combined, concentrated in vacuo and the resulting residue purified by column chromatography (Si—PCC, gradient 0-10% 2M NH3/MeOH in DCM) to afford 374 as a white solid (125 mg, 49%). LCMS (Method K): RT 2.72 min [M+H]+ 338.1. 1H NMR (DMSO-d6, 400 MHz): δ 8.23-8.09 (2H, m), 7.90 (1H, br s), 7.56 (1H, dd, J=8.77, 4.94 Hz), 7.37 (1H, dd, J=9.27, 2.53 Hz), 7.05-6.97 (1H, m), 5.94 (1H, br s), 3.43-3.36 (1H, m), 1.69 (3H, d, J=6.80 Hz), 1.33-1.00 (4H, m)
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][C:11](=O)[CH:10]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:9]1)C1C=CC=CC=1.[NH:21]1[CH2:26][CH2:25][S:24][CH2:23][CH2:22]1.[F:27][C:28]([F:43])([F:42])[C:29]1[CH:30]=[C:31]([CH:35]=[C:36]([C:38]([F:41])([F:40])[F:39])[CH:37]=1)[C:32](Cl)=[O:33]>>[F:27][C:28]([F:43])([F:42])[C:29]1[CH:30]=[C:31]([C:32]([N:8]2[CH2:13][CH2:12][C@H:11]([N:21]3[CH2:26][CH2:25][S:24][CH2:23][CH2:22]3)[C@H:10]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH2:9]2)=[O:33])[CH:35]=[C:36]([C:38]([F:41])([F:40])[F:39])[CH:37]=1
Reactant: O=C1CCN(Cc2ccccc2)CC1c1ccccc1
Reactant: C1CSCCN1
Reactant: O=C(Cl)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Product: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CC[C@H](N2CCSCC2)[C@H](c2ccccc2)C1

Procedure:
The title compound, MS: m/e=503.2 (M+H+), was prepared in accordance with the general method of example 26 from 1-benzyl-3-phenyl-piperidin-4-one, thiomorpholine and 3,5-bistrifluoromethyl-benzoyl chloride.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([N:17]3[CH:21]=[CH:20][N:19]=[C:18]3[CH3:22])[O:11][C:12]=2[CH2:13][CH2:14][CH2:15][OH:16])=[CH:4][CH:3]=1.O[CH:24]1[CH2:33][CH2:32][C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH2:25]1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[C:10]([N:17]3[CH:21]=[CH:20][N:19]=[C:18]3[CH3:22])[O:11][C:12]=2[CH2:13][CH2:14][CH2:15][O:16][C:24]2[CH:33]=[CH:32][C:31]3[CH2:30][CH2:29][CH2:28][CH2:27][C:26]=3[CH:25]=2)=[CH:6][CH:7]=1
Reactant: OC1CCc2ccccc2C1
Reactant: Cc1nccn1-c1nc(-c2ccc(Cl)cc2)c(CCCO)o1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: Cc1nccn1-c1nc(-c2ccc(Cl)cc2)c(CCCOc2ccc3c(c2)CCCC3)o1
Reaction time: 1 h

Procedure:
To a mixture of 4-(4-chlorophenyl)-2-(2-methyl-1-imidazolyl)-5-oxazolepropanol (318 mg), 2-hydroxytetralin (296 mg), tributylphosphine (405 mg) and tetrahydrofuran (10 ml) was added 1,1′-(azodicarbonyl)dipiperidine (400 mg) at room temperature, and the resulting mixture was stirred for 1 hour. After the reaction mixture was concentrated, the residue was subjected to silica gel column chromatography, and 4-(4-chlorophenyl)-2-(2-methyl-1-imidazolyl)-5-[3-(5,6,7,8-tetrahydro-2-naphthoxy)propyl]oxazole was obtained as an oil from an ethyl acetate-hexane (1:1, v/v)-eluted fraction. (358 mg, 80%).
Reaction SMILES: [CH3:1][NH:2][CH:3]([OH:5])[CH3:4].Cl[C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][C:8]=1[N+:16]([O-:18])=[O:17].C(=O)([O-])O.[Na+].O>C(O)C>[N+:16]([C:8]1[CH:9]=[C:10]([N+:13]([O-:15])=[O:14])[CH:11]=[CH:12][C:7]=1[N:2]([CH:3]([OH:5])[CH3:4])[CH3:1])([O-:18])=[O:17]
Reactant: CNC(C)O
Reactant: O=[N+]([O-])c1ccc(Cl)c([N+](=O)[O-])c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CC(O)N(C)c1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Temperature: 60 °C

Procedure:
20.3 g of N-methylaminoethanol was dissolved in 100 ml of ethanol and, while stirring, solid 1-chloro-2,4-dinitrobenzene was added to the solution by portions at room temperature. After completion of the addition, 8.4 g of sodium hydrogencarbonate was gradually added to the reaction mixture, followed by stirring for 10-15 minutes at room temperature. Then, the reaction mixture was heated at 60° C. After completion of the reaction, the reaction solution was cooled to room temperature, and poured into 300 ml of water. Continued stirring of the solution yielded a yellowish oily product. Stirring was then discontinued and, after completion of oil formation, the supernatant was removed. After adding water thereto, the solution obtained was stirred and the oil layer formed was collected by separation, and dried to obtain a yellowish oily product. Chemical structure of the product was confirmed by 1H-NMR. Absorptivity coefficient of the product at 365 nm was measured to be 1.79×104 by UV measurement in ethanol. 1H-NMR(CDCl3), TMS standard (400 MHz): 2.22(s,1H), 3.03(s,3H), 3.62(m,2H), 3.92(m,2H), 7.24(d,1H), 8.18(d,1H), 8.63(s,1H).
Reaction SMILES: [C:1]1([CH3:10])[CH:6]=[CH:5][C:4](S([O-])=O)=[CH:3][CH:2]=1.[Na+].[CH2:12]([N:14]([CH2:24]C)[C:15]1[CH:20]=[CH:19][CH:18]=[C:17](OCC)[CH:16]=1)C.[CH3:26][S:27]([OH:30])(=O)=[O:28]>>[CH4:1].[CH3:24][N:14]([CH3:12])[C:15]1[CH:16]=[CH:17][C:18]([C:2]2[C:3]([C:18]3[CH:19]=[CH:20][C:15]([N:14]([CH3:24])[CH3:12])=[CH:16][CH:17]=3)=[C:4]([S:27]([CH3:26])(=[O:30])=[O:28])[CH:5]=[CH:6][C:1]=2[CH3:10])=[CH:19][CH:20]=1
Reactant: CCOc1cccc(N(CC)CC)c1
Reactant: CS(=O)(=O)O
Reactant: Cc1ccc(S(=O)[O-])cc1
Agent: [Na+]
Product: C
Product: Cc1ccc(S(C)(=O)=O)c(-c2ccc(N(C)C)cc2)c1-c1ccc(N(C)C)cc1

Procedure:
Ten and three tenths grams of 86.4 percent sodium p-toluenesulfinate, 10.7 g of 90.7 percent N,N-diethyl-3-ethoxyaniline and 12 g of 4-(N-ethyl-N-benzyl)-aminobenzaldehyde were interacted in the presence of 18.2 g of 95 percent methanesulfonic acid to obtain a methane of Formula XV wherein R=4--CH3 ; R5 =C2H5O; R6 =N(C2H5)2 ; Q=4--[(C2H5)(C6H5CH2)NC6H4 ], an oil. A significant infrared maximum appeared at 1145 (SO2 ; s) cm-1. The product developed a violet colored image.
Reaction SMILES: [OH2:1].[C:2]1([CH3:12])[CH:7]=[CH:6][C:5](S(O)(=O)=O)=[CH:4][CH:3]=1.[CH3:13][C:14](C)=[O:15]>>[O:1]=[C:2]([CH3:12])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:13][CH2:14][OH:15]
Reactant: O
Reactant: CC(C)=O
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Product: CC(=O)CCCCCCCO
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution containing 56.6 g of 8-oxononan-1-ol ethylene ketol (prepared in Example 22 B-5) in 210 ml acetone and 50 mg p-toluenesulfonic acid monohydrate was stirred at room temperature for about 15 to 17 hr. The acetone was removed in vacuo to yield the title compound having the following physical characteristics:
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]2[O:8][C:9]3[C:14]([C@@:15]4([CH2:19][O:18][C:17]([NH2:20])=[N:16]4)[C:4]=2[CH:3]=1)=[CH:13][C:12]([C:21]1[CH:22]=[N:23][CH:24]=[C:25]([F:27])[CH:26]=1)=[CH:11][CH:10]=3.[CH3:28][C:29]1([CH3:44])[O:34][CH2:33][CH2:32][C:31](B2OC(C)(C)C(C)(C)O2)=[CH:30]1.O1CCOCC1>CCOC(C)=O.O>[CH3:28][C:29]1([CH3:44])[O:34][CH2:33][CH2:32][C:31]([C:2]2[N:7]=[CH:6][C:5]3[O:8][C:9]4[C:14]([C@@:15]5([CH2:19][O:18][C:17]([NH2:20])=[N:16]5)[C:4]=3[CH:3]=2)=[CH:13][C:12]([C:21]2[CH:22]=[N:23][CH:24]=[C:25]([F:27])[CH:26]=2)=[CH:11][CH:10]=4)=[CH:30]1
Reactant: CC1(C)C=C(B2OC(C)(C)C(C)(C)O2)CCO1
Reactant: NC1=N[C@@]2(CO1)c1cc(-c3cncc(F)c3)ccc1Oc1cnc(Cl)cc12
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: O
Product: CC1(C)C=C(c2cc3c(cn2)Oc2ccc(-c4cncc(F)c4)cc2[C@@]32COC(N)=N2)CCO1
Reaction time: 0.5 h

Procedure:
A glass microwave reaction vessel was charged with (S)-3-chloro-7-(5-fluoropyridin-3-yl)-5′H-spiro[chromeno[2,3-c]pyridine-5,4′-oxazol]-2′-amine (0.250 g, 0.653 mmol; prepared as described in Method BB41), 2-(6,6-dimethyl-3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.311 g, 1.306 mmol), bis(di-tert-butylphenylphosphine)dichloropalladium (II) (0.041 g, 0.065 mmol), dioxane (3 mL) and water (0.8 mL). The reaction mixture was exposed to MW radiation at 105° C. for 30 min in a microwave reactor. The mixture was diluted with EtOAc and water. The organic layer was washed with saturated sodium carbonate and dried over sodium sulfate. The crude material was initially purified by silica gel chromatography using 2-10% MeOH (2M NH3)-CH2Cl2) followed by further purification by SFC chromatography to give (S)-3-(6,6-dimethyl-3,6-dihydro-2H-pyran-4-yl)-7-(5-fluoropyridin-3-yl)-5′H-spiro[chromeno[2,3-c]pyridine-5,4′-oxazol]-2′-amine
Reaction SMILES: F[C:2](F)(F)C(O)=O.C(O[C:13]([N:15]1[CH2:22][C@@H:21]([OH:23])[CH2:20][C@H:16]1[C:17]([OH:19])=[O:18])=[O:14])(C)(C)C.[C:24]([O:28][C:29]([N:31]([CH2:33]C(O)=O)[CH3:32])=[O:30])([CH3:27])([CH3:26])[CH3:25].ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>ClCCl.C(N(CC)CC)C>[CH3:2][O:19][C:17](=[O:18])[C@@H:16]1[CH2:20][C@H:21]([OH:23])[CH2:22][N:15]1[C:13](=[O:14])[CH2:32][N:31]([C:29]([O:28][C:24]([CH3:25])([CH3:27])[CH3:26])=[O:30])[CH3:33]
Reactant: O=C(O)C(F)(F)F
Reactant: CN(CC(=O)O)C(=O)OC(C)(C)C
Reactant: CC(C)(C)OC(=O)N1C[C@@H](O)C[C@H]1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)[C@@H]1C[C@H](O)CN1C(=O)CN(C)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 17 h

Procedure:
Trifluoroacetic acid (10 mL) was added to a solution of N-tert-butoxycarbonyl-cis-4-hydroxy-L-proline methyl ester (Compound D101 (J), 1.10 g) in dichloromethane (10 mL) at 0° C. After stirring at 0° C. for 10 min and at room temperature for 3 hr, the mixture was evaporated in vacuo to give a crude N-tert-butoxycarbonyl-cis-4-hydroxy-L-proline trifluoroacetate. The crude N-tert-butoxycarbonyl-cis-4-hydroxy-L-proline trifluoroacetate was dissolved in dichloromethane (20 mL), and N-tert-butoxycarbonyl-sarcosine (844 mg), triethylamine (1.25 mL), 1-hydroxybenzotriazole (663 mg), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (856 mg) were added at 0° C. After stirring at 0° C. for 30 min and at room temperature for 17 hr, the solvent was removed in vacuo. The residue was diluted with 1 N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with saturated sodium hydrogen carbonate, water, and brine, dried over anhydrous sodium sulfate, and evaporated in vacuo. The residue as purified by silica gel column chromatography (chloroform then chloroform-methanol=50:1 to 30:1, v/v) to afford the title compound (452 mg) as a colorless oil. The compound appears as a mixture of rotamers: 1H NMR (400 MHz, CDCl3) δ 1.42 and 1.46 (each s, total 9H), 2.04-2.14 (m, 1H), 2.26-2.39 (m, 1H), 2.94 (s, 3H), 3.52-4.17 (m, 4H), 3.75 and 3.77 (each s, total 3H), 4.17-4.28 (m, 1H), and 4.38-4.62 (m, 2H).
Reaction SMILES: [CH3:1][O:2][CH:3]([O:6][CH3:7])[CH2:4][NH2:5].[Br:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][O:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C1(C)C=CC=CC=1>[BrH:8].[CH3:1][O:2][CH:3]([O:6][CH3:7])[CH2:4][NH:5][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][O:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: COC(CN)OC
Reactant: BrCCCCCCOCCCCc1ccccc1
Solvent: Cc1ccccc1
Product: Br
Product: COC(CNCCCCCCOCCCCc1ccccc1)OC
Reaction time: 0.25 h
Yield: 32.3 %

Procedure:
To a solution of 8.7 ml (79.85 mmol) aminoacetaldehyde dimethylacetal in 60 ml toluene at reflux is added dropwise a solution of 10 g (31.94 mmol) 4-(6-bromohexyloxy)butylbenzene in 40 ml toluene. After maintaining the reaction mixture under reflux for 4 hr, toluene is evaporated off under reduced pressure, and 50 ml CH2Cl2 is added thereto. The resulting solution is stirred for 15 min together with a solution of 20 ml 47% HBr diluted with 20 ml H2O. The reaction mixture is allowed to decant and the crude product obtained as a result of evaporating the CH2Cl2 phase to dryness is triturated with Et2O and filtered, thereby affording 4.31 g (32.3%) N-dimethoxyethyl-6-(4-phenylbutoxy)hexylamine hydrobromide.
Reaction SMILES: C1OC2C=CC(C3C4C(=CC=CC=4)C=C3C([O-])=O)=CC=2O1.[CH2:22]1[O:30][C:29]2[CH:28]=[CH:27][C:26]([C:31]3(O)[C:39]4[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=4)[C:33]([C:40]4[CH:45]=[CH:44][C:43]5[O:46][CH2:47][O:48][C:42]=5[CH:41]=4)=[C:32]3[C:49]([O:51]CC)=[O:50])=[CH:25][C:24]=2[O:23]1.C([SiH](CC)CC)C.B(F)(F)F.CCOCC>C(Cl)Cl>[CH2:22]1[O:30][C:29]2[CH:28]=[CH:27][C:26]([CH:31]3[C:39]4[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=4)[CH:33]([C:40]4[CH:45]=[CH:44][C:43]5[O:46][CH2:47][O:48][C:42]=5[CH:41]=4)[CH:32]3[C:49]([OH:51])=[O:50])=[CH:25][C:24]=2[O:23]1
Reactant: CCOC(=O)C1=C(c2ccc3c(c2)OCO3)c2ccccc2C1(O)c1ccc2c(c1)OCO2
Agent: CC[SiH](CC)CC
Agent: FB(F)F
Agent: O=C([O-])C1=Cc2ccccc2C1c1ccc2c(c1)OCO2
Solvent: ClCCl
Solvent: CCOCC
Product: O=C(O)C1C(c2ccc3c(c2)OCO3)c2ccccc2C1c1ccc2c(c1)OCO2
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 98.3 %

Procedure:
Ethyl (RS)-1,3-Di-(3,4-methylenedioxyphenylindene-2-carboxylate. To a solution of ethyl (1RS)-1,3-di-(3,4-methylenedioxyphenyl)-1-hydroxyindene-2-carboxylate (0.29 g, 0.65 mmol) in CH2Cl2 (3 ml) at 0° C. under an argon atmosphere was added triethylsilane (91 mg, 0.78 mmol), followed by boron trifluoride etherate (0.3 ml, 2.4 mmnol). The reaction mixture was stirred for 10 min, at which time was added ice-cold 1 M HCl, and the mixture was extracted with EtOAc. The organic extract was washed with saturated aqueous NaCl and dried (MgSO4). The solvent was removed in vacuo, and the residue was placed on a small pad of silica gel, eluting with CH2Cl2 to provide the title compound (257 mg, 92%).
Reaction SMILES: II.[CH2:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[SH:11])[CH3:4].COC1C=CC(S([C:23]2[C:31]3[C:26](=[CH:27][CH:28]=[C:29]([CH3:32])[CH:30]=3)[N:25]([CH2:33][C:34]([OH:36])=[O:35])[C:24]=2[CH3:37])(=O)=O)=CC=1>CN(C=O)C>[NH4+:25].[CH2:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[S:11][C:23]1[C:31]2[C:26](=[CH:27][CH:28]=[C:29]([CH3:32])[CH:30]=2)[N:25]([CH2:33][C:34]([O-:36])=[O:35])[C:24]=1[CH3:37])[CH3:4]
Reactant: COc1ccc(S(=O)(=O)c2c(C)n(CC(=O)O)c3ccc(C)cc23)cc1
Reactant: CCc1ccccc1S
Agent: II
Solvent: CN(C)C=O
Product: CCc1ccccc1Sc1c(C)n(CC(=O)[O-])c2ccc(C)cc12
Product: [NH4+]

Procedure:
Iodine (0.44 g) was added to a solution of 2-ethylbenzenethiol (0.32 g) and the product from example 13 step a) (0.2 g) in DMF (5 ml). After 1 h the solution was purified by reverse phase HPLC. The solvent was evaporated in vacuo and the oily residue treated with ether to give a solid. Filtered off and dried to yield the title compound as a white solid (0.18 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([OH:22])([CH2:16][N:17]1[CH:21]=[N:20][CH:19]=[N:18]1)[C:10]([F:15])([F:14])[C:11]([NH2:13])=O.ClC(Cl)(Cl)C(Cl)=O.C(OCC)(=O)C.Cl>N1C=CC=CC=1.O>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([OH:22])([CH2:16][N:17]1[CH:21]=[N:20][CH:19]=[N:18]1)[C:10]([F:14])([F:15])[C:11]#[N:13]
Reactant: NC(=O)C(F)(F)C(O)(Cn1cncn1)c1ccc(F)cc1F
Agent: Cl
Agent: O=C(Cl)C(Cl)(Cl)Cl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Solvent: O
Product: N#CC(F)(F)C(O)(Cn1cncn1)c1ccc(F)cc1F
Yield: 70.7 %

Procedure:
In 5 ml of pyridine was dissolved 150 mg of 3-(2,4-difluorophenyl)-2,2-difluoro-3-hydroxy4(1H-1,2,4triazol-1-yl)butanamide. To the solution was added 100 mg of trichloroacetyl chloride at 0°-5C. The resulting mixture was subjected to reaction at the same temperature for 2 hours. Then, the reaction mixture was introduced into a mixed solvent consisting of 10 ml of ethyl acetate and 5 ml of water. The resulting solution was adjusted to pH 2.0 with 6N hydrochloric acid. The organic layer was separated, washed with a saturated aqueous sodium chloride solution, and then dried over anhydrous magnesium sulfate. Thereafter, the solvent was removed by distillation under reduced pressure. The residue thus obtained was purified by a column chromatography (eluant: chloroform/methanol=50/1) to obtain 100 mg of 3-(2,4-difluorophenyl)-2,2-difluoro-3-hydroxy-4-(1H-1,2,4-triazol-1-yl)butanenitrile.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]1[C:11]([OH:13])=O.C(Cl)(=O)C([Cl:17])=O>ClCCl.CN(C)C=O>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]1[C:11]([Cl:17])=[O:13]
Reactant: Cn1c(C(=O)O)cc2ccccc21
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cn1c(C(=O)Cl)cc2ccccc21
Reaction time: 18 h

Procedure:
A suspension of 1-methylindole-2-carboxylic acid (0.805 g, 4.6 mmol) in dichloromethane (3 mL) was treated with oxalyl chloride (0.700 g, 5.52 mmol) and one drop of dimethylformamide. The reaction mixture was shaken for 18 h. The solvent was removed under reduced pressure and dried under high vacuum to afford a quantitative amount of 1-methyl-1H-2-indolecarbonyl chloride. The oil was directly used in the following reaction.
Reaction SMILES: [NH2:1][C:2]1[C:11]([Cl:12])=[CH:10][C:5]([C:6]([O:8]C)=[O:7])=[CH:4][C:3]=1[O:13]S(C)(=O)=O.[OH-].[Na+].CO.O>C(OCC)(=O)C>[NH2:1][C:2]1[C:11]([Cl:12])=[CH:10][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[OH:13]
Reactant: COC(=O)c1cc(Cl)c(N)c(OS(C)(=O)=O)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: CCOC(C)=O
Product: Nc1c(O)cc(C(=O)O)cc1Cl
Temperature: 25 °C
Yield: 73.7 %

Procedure:
In a 2-liter round-bottomed flask were placed methyl 4-amino-5-chloro-3-methylsulfonyloxybenzoate (8.7 g, 31.1 mmole), 50% aqueous sodium hydroxide (10.1 g, 126 mmole), methanol (250 ml) and water (550 ml). The resulting mixture was refluxed for 3 hours. The reaction mixture was cooled down to room temperature and poured into a mixture of water and ethyl acetate. The aqueous layer was separated, neutralized to pH 6 with concentrated aqueous hydrochloric acid, and extracted with ethyl acetate (3×400 ml). The combined organic layers were washed with water (2×200 ml), dried over anhydrous magnesium sulfate and the solvent eliminated in the rotary evaporator yielding 4.3 g of the expected 4-amino-5-chloro-3-hydroxybenzoic acid (intermediate XII). (1H-NMR, DMSO-d6 12.5(1,bs); 10(1,bs); 7.22(1,s); 5.4(2,s))
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:10][C@H:9]1[C:21](O)=[O:22])=[O:7])([CH3:4])([CH3:3])[CH3:2]>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([O:13][CH2:14][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:10][C@H:9]1[CH2:21][OH:22])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1C[C@H](OCc2ccccc2)C[C@H]1C(=O)O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1C[C@H](OCc2ccccc2)C[C@H]1CO
Temperature: 0 °C
Reaction time: 1 h

Procedure:
(2S,4R)-4-Benzyloxy-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester (960 mg, 3 mmol) in THF (5 mL) was cooled to 0° C. using ice-water bath. Then 1M solution of BH3 (6mL, 6 mmol) in THF was added under nitrogen over period of 30 min. Reaction was stirred at 0° C. for 2 h and at rt for another 1 h. Reaction mixture was poured over ice water and product was extracted with EtOAc. Organic layers were combined, washed with water, brine, saturated sodium bicarbonate, dried over anhydrous MgSO4 and concentrated to give the crude product. It was used in next step without purification (900 mg, 97%); MS; m/z 286.1 (M+H); 1H NMR (400 MHz, DMSO-4-d6); δ 1.90 (m, 1H), 2.01 (m, 1H), 3.09 (m, 1H), 3.34 (m, 1H), 4.12 (m, 2H); 4.27 (m, 1H), 4.46 (m, 1H), 5.46 (br s, 2H), 6.92 (d, J=6.8 Hz, 2H), 7.02 (s, 4H), 7.08 (t, J=5.6 Hz, 1H), 7.35 (m, 2H), 9.09 (br s, 1H), 9.62 (br s, 3H);