Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][C:6](=O)[CH2:7]2.[CH:14]([C:17]1[S:21][C:20]([NH:22][C:23](=[O:29])[C@@H:24]([NH2:28])[CH2:25][CH2:26][CH3:27])=[N:19][CH:18]=1)([CH3:16])[CH3:15].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClCCl.CCOC(C)=O>[CH:14]([C:17]1[S:21][C:20]([NH:22][C:23](=[O:29])[C@@H:24]([NH:28][CH:6]2[CH2:5][CH2:4][C:3]3[C:8](=[CH:9][C:10]([F:12])=[CH:11][C:2]=3[F:1])[CH2:7]2)[CH2:25][CH2:26][CH3:27])=[N:19][CH:18]=1)([CH3:15])[CH3:16]
Reactant: CCC[C@H](N)C(=O)Nc1ncc(C(C)C)s1
Reactant: O=C1CCc2c(F)cc(F)cc2C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCC[C@H](NC1CCc2c(F)cc(F)cc2C1)C(=O)Nc1ncc(C(C)C)s1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
The 5,7-difluoro-2-tetralone (0.3 mmol) was dissolved in 2.0 mL of anhydrous dichloromethane under N2 at rt. 2-(S)-Amino-pentanoic acid (5-isopropyl-thiazol-2-yl)-amide (0.3 mmol) was then added to the reaction solution, followed by sodium triacetoxy borohydride (0.3 mmol) and acetic acid (0.3 mmol). The reaction was stirred at rt for 16 h. The crude solution was then diluted with 20 mL of EtOAc and washed with 20 mL of aqueous 1N NaOH solution and brine. The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. The crude products were purified through flash chromatography to give 2-(S)-(5,7-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentanoic acid (5-isopropyl-thiazol-2-yl)-amide. LC-MS (retention time, M+1): 2.2 min, 408 [M+1].
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[C:9]([C:17]#[C:18][Si](C)(C)C)[C:10]([F:16])=[C:11]([F:15])[C:12]=3[F:14])[C:7](=[O:23])[C:6]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:5]2)[CH2:3][CH2:2]1.[F-].[K+].C(Cl)(Cl)Cl.O>CN(C)C=O>[CH:1]1([N:4]2[C:13]3[C:8](=[C:9]([C:17]#[CH:18])[C:10]([F:16])=[C:11]([F:15])[C:12]=3[F:14])[C:7](=[O:23])[C:6]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:5]2)[CH2:3][CH2:2]1
Reactant: CCOC(=O)c1cn(C2CC2)c2c(F)c(F)c(F)c(C#C[Si](C)(C)C)c2c1=O
Agent: [F-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: C#Cc1c(F)c(F)c(F)c2c1c(=O)c(C(=O)OCC)cn2C1CC1
Temperature: 0 °C
Yield: 76.6 %

Procedure:
1 g of the product of Example E and 0.45 g of potassium fluoride are stirred for 1 hour at room temperature in a mixture of 20 ml of dimethylformamide, 10 ml of chloroform and 1 ml of water. After chloroform has been added, the organic phase is separated off, extracted by shaking with water, dried over sodium sulphate and concentrated. The residue is boiled briefly in 20 ml of methanol. When the mixture has cooled to 0° C., the solid obtained is filtered off with suction and dried. 0.63 g of the title compound is obtained (77% of theory).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([NH2:6])=[O:5].[OH-].[Na+].O=[C:10]([CH3:18])[CH2:11][CH2:12][C:13](OCC)=[O:14]>O>[O:5]=[C:4]1[CH2:3][N:2]2[C:13](=[O:14])[CH2:12][CH2:11][C:10]2([CH3:18])[NH:6]1
Reactant: NCC(N)=O
Reactant: CCOC(=O)CCC(C)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC12CCC(=O)N1CC(=O)N2
Yield: 21 %

Procedure:
To a solution of glycinamide hydrochloride (18.4 g, 0.166 mol) in water (200 ml), adjusted to pH 9.5 with 10% sodium hydroxide (about 60 ml), ethyl 4-oxopentanoate (20 g, 0.139 mol) was added. The solution was refluxed for 24 hours. After cooling the solvent was evaporated under vacuum and the residue was chromatographed over silica gel (dichloromethane-methanol 9:1) to afford 4.5 g (21%) of the title compound, m.p. 187°-189° C. NMR (CDCl3): deltaH =4.17 and 3.53 (ABq, J=16 Hz, 2H, NCH2CO), 1.5 (s, 3H, CH3). MS (E.I., 70 eV, 1.5 mA) m/z=154 (M+), 139 (M--CH3)+, 111 (M--CONH+.
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([OH:9])=[C:4]([F:10])[CH:3]=1.CC(C)([O-])C.[K+].Cl[C:18]1[C:23]([I:24])=[CH:22][N:21]=[CH:20][N:19]=1>CN(C=O)C>[F:8][C:7]1[CH:6]=[C:5]([O:9][C:18]2[C:23]([I:24])=[CH:22][N:21]=[CH:20][N:19]=2)[C:4]([F:10])=[CH:3][C:2]=1[NH2:1]
Reactant: Nc1cc(F)c(O)cc1F
Reactant: Clc1ncncc1I
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Nc1cc(F)c(Oc2ncncc2I)cc1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 36.7 %

Procedure:
To a solution of 4-amino-2,5-difluorophenol (0.190 g, 1.310 mmol) in DMF (10 mL) was added potassium tert-butoxide (0.168 g, 1.497 mmol). The mixture was stirred at RT for 30 min. 4-Chloro-5-iodopyrimidine (0.30 g, 1.248 mmol) was added and the reaction mixture was heated at 80° C. overnight. The reaction mixture was quenched with water and the solution was extracted with EtOAc (3×). The organic solution was washed with 5% aqueous lithium chloride solution and brine. The organics were dried over MgSO4, filtered, and concentrated. The crude was purified by silica gel column chromatography (10% to 50% EtOAc/hexane) to obtain 2,5-difluoro-4-(5-iodopyrimidin-4-yloxy)benzenamine (160 mg, 36.7% yield) which was used for the next reaction. MS (ESI) m/z: 349.9 (M+H+).
Reaction SMILES: [N+:1]([C:4]1[CH:23]=[CH:22][C:7]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:11][CH:10]=2)=[CH:6][CH:5]=1)([O-])=O>C(O)C.[C].[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:11][CH:10]=2)=[CH:22][CH:23]=1
Reactant: CCOC(=O)CCc1ccc(Oc2ccc([N+](=O)[O-])cc2)cc1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)CCc1ccc(Oc2ccc(N)cc2)cc1

Procedure:
To a suspension of 5% palladium-carbon (0.50 g) in ethanol (50 mL) was added ethyl 3-[4-(4-nitrophenoxy)phenyl]propionate (5.00 g, 15.9 mmol), and the resulting solution was subjected to catalytic reduction at atmospheric pressure and at room temperature. Once the absorption of hydrogen had stopped, the catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure, to thereby yield 4.52 g of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:18]=[CH:17][C:6]([C:7]([NH:9][C:10]2[C:11]([NH2:16])=[CH:12][CH:13]=[CH:14][CH:15]=2)=[O:8])=[CH:5][CH:4]=1.[C:19]([C:21]1[CH:29]=[CH:28][C:24]([C:25](Cl)=[O:26])=[CH:23][CH:22]=1)#[N:20]>>[C:19]([C:21]1[CH:29]=[CH:28][C:24]([C:25]([NH:16][C:11]2[C:10]([NH:9][C:7](=[O:8])[C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:18][CH:17]=3)=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:26])=[CH:23][CH:22]=1)#[N:20]
Reactant: N#Cc1ccc(C(=O)Cl)cc1
Reactant: COc1ccc(C(=O)Nc2ccccc2N)cc1
Product: COc1ccc(C(=O)Nc2ccccc2NC(=O)c2ccc(C#N)cc2)cc1

Procedure:
Using a procedure similar to Example 1B except starting with N1-(4-methoxybenzoyl)-1,2-benzenediamine and 4-cyanobenzoyl chloride, the title compound was obtained as a solid (59%); MS(FD): 371.0.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[C:4]([CH3:9])[C:3]=1[F:10].C([Mg]Cl)(C)C.C(O[B:20]1[O:24][C:23]([CH3:26])([CH3:25])[C:22]([CH3:28])([CH3:27])[O:21]1)(C)C>O1CCCC1>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([B:20]2[O:24][C:23]([CH3:26])([CH3:25])[C:22]([CH3:28])([CH3:27])[O:21]2)=[C:3]([F:10])[C:4]=1[CH3:9]
Reactant: CC(C)OB1OC(C)(C)C(C)(C)O1
Reactant: Cc1c(Cl)ccc(Br)c1F
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: Cc1c(Cl)ccc(B2OC(C)(C)C(C)(C)O2)c1F
Temperature: -10 °C
Reaction time: 1 h
Yield: 85 %

Procedure:
To a stirred solution of 1-bromo-4-chloro-2-fluoro-3-methylbenzene (1.70 g, 7.61 mmol) in tetrahydrofuran (45 mL) cooled to −10° C. was added isopropylmagnesium chloride (2.9 M in THF) (3.0 mL, 8.75 mmol) dropwise. The reaction mixture was stirred at −10° C. for 1 h then allowed to warm to 0° C. and stirred for 1 h. The reaction mixture was cooled to −10° C. followed by the addition of 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.785 mL, 8.75 mmol) dropwise. The reaction was allowed to warm to room temperature and stirred for 14 h. The reaction mixture was quenched with 1 N aqueous sodium hydroxide solution and stirred for 10 min. The pH of the reaction was adjusted to 3 with concentrated HCl and the solution was extracted with ethyl acetate (2×30 mL). The combined organic layers were washed with water (50 mL), brine (50 mL), dried over sodium sulphate, and concentrated under reduced pressure to afford 2-(4-chloro-2-fluoro-3-methylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.75 g, 6.47 mmol, 85% yield) which was taken to the next step without purification. 1H NMR (400 MHz, CDCl3) δ 7.47 (m, 1 H), 7.14 (d, J=8 Hz, 1 H), 2.29 (d, J=2 Hz, 3 H), 1.36 (s, 12 H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[C:4]([C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=1)=[CH:5][C:6]1[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[C:8]([O:14][CH3:15])[CH:7]=1.[H-].[Na+].F[C:27]1[CH:34]=[CH:33][C:30]([CH:31]=[O:32])=[CH:29][CH:28]=1>CN(C=O)C.C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:23])[C:4]([C:16]1[CH:17]=[CH:18][C:19]([O:22][C:27]2[CH:34]=[CH:33][C:30]([CH:31]=[O:32])=[CH:29][CH:28]=2)=[CH:20][CH:21]=1)=[CH:5][C:6]1[CH:7]=[C:8]([O:14][CH3:15])[CH:9]=[C:10]([O:12][CH3:13])[CH:11]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: COC(=O)C(=Cc1cc(OC)cc(OC)c1)c1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)C(=Cc1cc(OC)cc(OC)c1)c1ccc(Oc2ccc(C=O)cc2)cc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 77.6 %

Procedure:
Under argon, 8 (433.0 g, 1.37 mol) was dissolved in dry DMF (1.6 L) and to this sodium hydride (60.4 g, 1.51 mol) was added. To the resulting orange solution 4-fluorobenzaldehyde (185.0 mL, 1.71 mol) was added and heated at 80° C. for 18 h. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (3.0 L) and extracted with water (3×1.0 L), then brine (1×1.0 L). The organic layer was dried over anhydrous sodium sulfate, filtered and solvent was evaporated. The residue was suspended in methanol (3.0 L) and stirred overnight. Solid was filtered and dried under vacuum at 40° C. to yield 9 as pale yellow solid (445 g, 77%): mp 108-110° C. 1HNMR(360 MHz, CDCl3) δ 9.94 (s, 1H), 7.86 (d, J=8.6 Hz, 2H), 7.80 (s, 1H), 7.28 (d, J=8.6 Hz, 2H), 7.11 (overlapped d, J=9.0 Hz, 2H), 7.08 (overlapped d, J=9.0 Hz, 2H), 6.36 (t, J=2.2 Hz, 1H), 6.25 (d, J=2.2 Hz, 2H), 3.83 (s, 3H), 3.63 (s, 6H); Anal. (C25H22O6) C, H.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][CH:11]([C:14]3[CH:19]=[CH:18][C:17]([OH:20])=[C:16]([CH3:21])[CH:15]=3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1>CO>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:9][CH2:10][C@H:11]([C:14]3[CH:19]=[CH:18][C:17]([OH:20])=[C:16]([CH3:21])[CH:15]=3)[CH2:12][CH2:13]2)=[CH:4][CH:3]=1
Reactant: Cc1cc(C2CCC(c3ccc(O)cc3)CC2)ccc1O
Solvent: CO
Product: Cc1cc([C@H]2CC[C@H](c3ccc(O)cc3)CC2)ccc1O

Procedure:
1 g of 4-(4′-(4″-hydroxyphenyl)cyclohexyl)-2-methyl-1-hydroxybenzene obtained in Example 1 was dissolved in 10 g of methanol at room temperature. The solution was injected into a preparative high performance liquid chromatography to carry out separation of cis- and trans-isomers (solvent: 60% aqueous solution of methanol; time: 40 minutes). As a result, about 50 mg of 4-(trans-4′-(4″-hydroxyphenyl)cyclohexyl)-2-methyl-1-hydroxybenzene was obtained as white crystals with a retention time of 17.6 minutes. It was found to have a purity of 99% and a melting point of 214° C. (DTA method). Furthermore, about 100 mg of 4-(cis-4′-(4″-hydroxyphenyl)cyclohexyl)-2-methyl-1-hydroxybenzene was obtained as pale yellow oily substance with a retention time of 28.2 minutes. It was found to have a purity of 99%.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].C([O:8][C:9]1[CH:18]=[C:17]([O:19][CH:20]([CH2:22][CH2:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH3:21])[CH:16]=[C:15]2[C:10]=1[CH:11]([CH2:35][CH2:36][C:37]#[N:38])[CH2:12][CH:13]1[CH2:34][CH2:33][CH2:32][CH2:31][N:14]12)(=O)C.Cl.CN1CCCCC1>CN1CCCCC1.C(O)C>[OH:8][C:9]1[CH:18]=[C:17]([O:19][CH:20]([CH2:22][CH2:23][CH2:24][C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH3:21])[CH:16]=[C:15]2[C:10]=1[CH:11]([CH2:35][CH2:36][C:37]1[NH:38][N:3]=[N:2][N:1]=1)[CH2:12][CH:13]1[CH2:34][CH2:33][CH2:32][CH2:31][N:14]12
Reactant: [N-]=[N+]=[N-]
Reactant: CC(=O)Oc1cc(OC(C)CCCc2ccccc2)cc2c1C(CCC#N)CC1CCCCN21
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: CN1CCCCC1
Product: CC(CCCc1ccccc1)Oc1cc(O)c2c(c1)N1CCCCC1CC2CCc1nnn[nH]1
Reaction time: 8 h

Procedure:
Finely ground sodium azide (325 mg., 5 mmole) is added to a solution of 7 -acetoxy-6-(2-cyanoethyl)-9-(5-phenyl-2-pentyloxy)-2,3,4,4a,5,6-hexahydro-1H-pyrido[1,2-a]quinoline (506 mg., 1 mmole) in 5 ml. of ethanol-free chloroform containing 271 mg. (2 mmole) N-methylpiperidine hydrochloride and 5 drops of N-methylpiperidine. The mixture is heated at reflux for one hour, another 2 mmole of N-methylpiperidine hydrochloride is added, refluxing continued for another hour and allowed to stand overnight at room temperature. The mixture is partitioned between chloroform and aqueous sodium carbonate solution. The aqueous layer is adjusted to pH 5, extracted again with chloroform and the combined organic layers washed with water and the chloroform is dried (MgSO4). Evaporation of solvent under reduced pressure affords the title compound.
Reaction SMILES: [C@H:1]1([C:11](OC)=[O:12])[CH2:6][CH2:5][C@H:4]([C:7](OC)=[O:8])[CH2:3][CH2:2]1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[C@H:1]1([CH2:11][OH:12])[CH2:6][CH2:5][C@H:4]([CH2:7][OH:8])[CH2:3][CH2:2]1
Reactant: COC(=O)[C@H]1CC[C@H](C(=O)OC)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OC[C@H]1CC[C@H](CO)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of trans-dimethyl cyclohexane-1,4-dicarboxylate (1000 g, 5 mol) in THF (3000 mL) cooled to −20° C. was added LiAlH4 (570 g, 15 mol). The mixture was stirred at room temperature for 3 h, quenched with water (10 L), and filtered. The filtrate was concentrated in vacuo to give trans-cyclohexane-1,4-diyldimethanol as white solid. 1H NMR (CDCl3, 400 MHz): δ 3.48-3.46 (m, 4H), 1.86-1.84 (m, 4H), 1.47-1.42 (m, 4H), 1.01-0.96 (m, 4H).
Reaction SMILES: [CH2:1](N(CC([O-])=O)CC([O-])=O)[CH2:2][N:3]([CH2:8][C:9]([O-:11])=O)[CH2:4][C:5]([O-])=[O:6].[Na+].[Na+].[Na+].[Na+].C(N(CC(O)=O)CC(O)=O)CN(CC(O)=O)CC(O)=[O:30]>>[N:3]([CH2:2][CH2:1][OH:30])([CH2:8][CH2:9][OH:11])[CH2:4][CH2:5][OH:6]
Reactant: O=C(O)CN(CCN(CC(=O)O)CC(=O)O)CC(=O)O
Reactant: O=C([O-])CN(CCN(CC(=O)[O-])CC(=O)[O-])CC(=O)[O-]
Agent: [Na+]
Product: OCCN(CCO)CCO

Procedure:
SEQUESTRENE® Na2 (disodium EDTA): 0.05 pbw
Reaction SMILES: Br[CH2:2][CH:3](OCC)OCC.Br.C(=O)(O)[O-].[Na+].[Br:16][C:17]1[C:18]([NH2:25])=[N:19][C:20]([CH3:24])=[C:21]([Br:23])[N:22]=1>>[Br:23][C:21]1[N:22]=[C:17]([Br:16])[C:18]2[N:19]([CH:2]=[CH:3][N:25]=2)[C:20]=1[CH3:24]
Reactant: CCOC(CBr)OCC
Reactant: Cc1nc(N)c(Br)nc1Br
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1c(Br)nc(Br)c2nccn12
Temperature: 25 °C

Procedure:
A mixture of 2-bromo-1,1-diethoxyethane (3.21 mL, 20.7 mmol) and 48% aqueous hydrobromic acid (1.0 mL) was stirred at reflux for 2 h. The reaction was then cooled to room temperature and treated with sodium bicarbonate until gas evolution ceased. The mixture was filtered and the filtrate diluted with ethanol (15 mL). To this mixture, 3,5-dibromo-6-methylpyrazin-2-amine VII (3.00 g, 11.2 mmol) was added and the reaction stirred at reflux for 16 h. After this time, the reaction was cooled to room temperature and concentrated under reduced pressure to a volume of approximately 10 mL. The suspension was filtered and the filter cake washed with cold ethanol (5 mL). The filter cake was then taken into water (50 mL) and the pH was adjusted to ˜8 with potassium carbonate. The resulting suspension was filtered and the filter cake dried to a constant weight under vacuum to provide 6,8-dibromo-5-methylimidazo[1,2-a]pyrazine VIII: 1H NMR (400 MHz, CDCl3) δ: 7.90 (s, 1H), 7.72 (s, 1H), 2.74 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:7]([CH3:10])=[CH:6][C:3]=1[C:4]#[N:5].[Br:11]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.O>C(Cl)(Cl)(Cl)Cl>[Br:11][CH2:10][C:7]1[CH:8]=[CH:9][C:2]([F:1])=[C:3]([CH:6]=1)[C:4]#[N:5]
Reactant: Cc1ccc(F)c(C#N)c1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Solvent: O
Product: N#Cc1cc(CBr)ccc1F
Temperature: 25 °C
Yield: 33.6 %

Procedure:
A solution of 2-fluoro-5-methylbenzonitrile (3.00 g, 22 mmol), N-bromosuccinimide (4.12 g, 23 mmol) and benzoyl peroxide (1.07 g, 4.4 mmol) in CCl4 (100 mL) was heated at reflux 6 h. The reaction mixture was cooled to room temperature and then combined with water. The separated organic phase was dried over MgSO4, filtered through a Celite™ pad, and evaporated under reduced pressure. Purification by flash chromatography (Hex/EtOAc, 20:1) gave 5-(bromomethyl)-2-fluorobenzonitrile (1.58 g, 33% yield) as an oil. 1H NMR (CDCl3, 400 MHz): δ 4.45 (s, 2H), 7.21 (m, 1H), 7.65 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[C:6]([NH2:8])[CH:7]=1.Cl[C:17]1[CH:26]=[CH:25][N:24]=[C:23]2[C:18]=1[CH:19]=[CH:20][C:21]([CH2:27][CH3:28])=[N:22]2>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[C:6]([NH:8][C:17]2[C:18]3[C:23](=[N:22][C:21]([CH2:27][CH3:28])=[CH:20][CH:19]=3)[N:24]=[CH:25][CH:26]=2)[CH:7]=1
Reactant: Nc1cc(Cl)ccc1Oc1ccccc1
Reactant: CCc1ccc2c(Cl)ccnc2n1
Product: CCc1ccc2c(Nc3cc(Cl)ccc3Oc3ccccc3)ccnc2n1

Procedure:
The product from Example 42b (100 mg, 0.46 mmol) was reacted with the product from Example 3f (88 mg, 0.46 mmol) following the procedure from Example 1g giving the title compound which was triturated with 2:1 ether/THF giving the product as a hydrochloride salt (134 mg, 70%). 1H NMR (300 MHz, DMSO-d6) δ ppm: 1.34 (t, J=7.35 Hz, 3H) 3.02 (q, J=7.35 Hz, 2H) 6.69 (d, J=6.99 Hz, 1H) 6.97 (d, J=8.82 Hz, 2H) 7.10 (dd, J=7.35 Hz, 1H) 7.15 (d, J=8.82 Hz, 2H) 7.30 (dd, J=8.09 Hz, J=7.72 Hz, 2H) 7.56 (dd, J=2.94 Hz, J=9.19 Hz, 1H) 7.71 (d, J=2.57 Hz, 1H) 7.88 (d, J=8.82 Hz, 1H) 8.52 (d, J=6.99 Hz, 1H) 9.02 (d, J=8.45 Hz, 1H) 11.16 (br s, 1H) 14.56 (br s, 1H); MS (ESI+) m/z 376 (M−Cl)+; (ESI−) m/z 374 (M−HCl)−.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([O:8][C:9]2[CH:10]=[C:11]([CH3:25])[C:12]3[CH:16]([CH2:17][C:18]([O:20]CC)=[O:19])[O:15][B:14]([OH:23])[C:13]=3[CH:24]=2)[CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>CO.C1COCC1>[Cl:1][C:2]1[N:7]=[C:6]([O:8][C:9]2[CH:10]=[C:11]([CH3:25])[C:12]3[CH:16]([CH2:17][C:18]([OH:20])=[O:19])[O:15][B:14]([OH:23])[C:13]=3[CH:24]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)CC1OB(O)c2cc(Oc3cccc(Cl)n3)cc(C)c21
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cc(Oc2cccc(Cl)n2)cc2c1C(CC(=O)O)OB2O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of ethyl 2-(6-(6-chloropyridin-2-yloxy)-1-hydroxy-4-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-3-yl)acetate in MeOH/THF (6 mL, 1:1) was added aqueous NaOH solution (100 mg in 1.5 mL of water). After stirring at room temperature for two hours, the reaction mixture was evaporated and then acidified to pH 3 using 1 M HCl. This was then extracted with EtOAc, the organic layers were combined, washed by brine and concentrated. HPLC purification gave desired product as a white powder. 1H NMR (400 MHz, DMSO-d6) δ 9.2 (b, 1H), 7.90 (t, J=7.6 Hz, 1H), 7.24 (m, 2H), 7.09 (s, 1H), 7.00 (d, J=8.4 Hz, 1H), 5.54 (dd, J=9.6, 2 Hz, 1H), 3.10 (dd, J=15.6, 2.4 Hz, 1H), 2.32 (s, 3H), 2.17 (dd, J=15.6, 9.6 Hz, 1H). 1 proton assumed to be exchanged with solvents. MS (ESI) m/z=332 [M−H]+.
Reaction SMILES: C1COCC1.[Cl:6][C:7]1[NH:8][C:9]2[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=2[N:11]=1.[O:16]1[CH:21]=[CH:20][CH2:19][CH2:18][CH2:17]1.C[O-].[Na+]>C1(C)C=CC(S(O)(=O)=O)=CC=1.CCCCCCC>[Cl:6][C:7]1[N:11]([CH:17]2[CH2:18][CH2:19][CH2:20][CH2:21][O:16]2)[C:10]2[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=2[N:8]=1
Reactant: C1=COCCC1
Reactant: Clc1nc2ccccc2[nH]1
Agent: C[O-]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCCCCCC
Product: Clc1nc2ccccc2n1C1CCCCO1
Reaction time: 2.5 h
Yield: 104.8 %

Procedure:
A 10 l reactor is charged, under argon and with stirring, with 2.5 l of THF, 180 g of 2-chlorobenzimidazole (1.18 mol) and 325 ml of 3,4-dihydro-2H-pyran (6.56 mol, 3 eq.). The reactor is heated until dissolution occurs (temperature of the mixture: 40° C.). Then 6.3 g of para-toluenesulphonic acid (0.033 mol, 0.028 eq.) are introduced. The temperature is held at between 49 and 52° C. for 2.5 h. Cooling takes place at 12° C. and 7.65 g of sodium methoxide (0.142 mol, 0.12 eq.) are added, with stirring maintained for a total time of 15 min. The temperature is then taken to 18° C., 5 l of n-heptane are added, and the whole mixture is filtered on 300 g of Clarcel FLO-M, the retentate being washed with 5 l of n-heptane. The filtrate is concentrated to dryness under reduced pressure to give 292.6 g of 2-chloro-1-(tetrahydro-pyran-2-yl)-1H-benzimidazole in the form of a slightly yellow oil (quantitative yield). 1H NMR (400 MHz, DMSO-d6): 1.42 to 2.01 (m, 5H); 2.21 to 2.34 (m, 1H); 3.69 to 3.78 (m, 1H); 4.12 (d, J=11.4 Hz, 1H); 5.72 (dd, J=2.4 and 11.2 Hz, 1H); 7.22 to 7.34 (m, 2H); 7.82 (d. J=72 Hz, 1H); 7.78 (d, J=7.2 Hz, 1H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][OH:6].C(N(CC)CC)C.C(N1[C:23](=[O:24])[C:22]2=[CH:25][CH:26]=[CH:27][CH:28]=[C:21]2[C:20]1=[O:29])(OCC)=O.CCCCCC>O1CCCC1.C(OCC)(=O)C>[OH:6][CH2:5][CH2:4][CH2:3][CH2:2][N:1]1[C:23](=[O:24])[C:22]2=[CH:25][CH:26]=[CH:27][CH:28]=[C:21]2[C:20]1=[O:29]
Reactant: NCCCCO
Reactant: CCOC(=O)N1C(=O)c2ccccc2C1=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: O=C1c2ccccc2C(=O)N1CCCCO
Yield: 65.9 %

Procedure:
A solution of 4-amino-1-butanol (5.616 g; 63 mmol) and triethylamine (12.3 ml; 88.2 mmol) in 130 ml tetrahydrofuran was treated with N-carbethoxyphthalimide (13.82 g; 63 mmol). The mixture was refluxed for 18 hours. TLC showed the formation of product (1:1 Ethyl acetate:Hexane Rf=0.3). The mixture was diluted with ethyl acetate and washed with water. The aqueous layer was extracted with more ethyl acetate and the organic layers combined, dried (MgSO4), filtered, concentrated and the residue purified by flash chromatography; 200 g silica gel column using 2:3 ethyl acetate:Hexane followed by 1:1 to provide N-(4-hydroxybutyl)phthalimide as a white solid (9.108 g; 65.9% yield). 1H NMR (300 MHz, CDCl3): 1.426 (t, 2H, J=4.93 Hz); 1.597-1.663 (m, 2H); 1.738-1.813 (m, 2H); 3.668-3.768 (m, 4H); 7.715 (m, 2H); 7.838 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([C:12](=[O:30])[C:13]3[CH:18]=[CH:17][C:16]([NH:19][C:20](=[O:28])[C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[CH3:27])=[CH:15][C:14]=3[CH3:29])[CH2:10][CH2:9][CH2:8][C:7](=[O:31])[C:6]=2[CH:32]=1>O>[CH3:27][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[C:20]([NH:19][C:16]1[CH:17]=[CH:18][C:13]([C:12]([N:11]2[C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:32][C:6]=3[CH:7]([OH:31])[CH2:8][CH2:9][CH2:10]2)=[O:30])=[C:14]([CH3:29])[CH:15]=1)=[O:28]
Reactant: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2CCCC(=O)c3cc(Cl)ccc32)c(C)c1
Solvent: O
Product: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2CCCC(O)c3cc(Cl)ccc32)c(C)c1

Procedure:
In a preferred embodiment of the present invention, starting material 7-chloro-1-[2-methyl-4-(2-methylbenzoylamino) benzoyl]-5-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine of Formula 2 is reduced using hydrogenating agent in a solvent mixture containing alcohol and water to obtain Tolvaptan of Formula 1.