Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=O)[NH:9][C:7](=O)[C:6]2=[CH:12][CH:13]=1.B.CO.Cl>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:6](=[CH:12][CH:13]=1)[CH2:7][NH:9][CH2:10]2
Reactant: COc1ccc2c(c1)C(=O)NC2=O
Agent: B
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc2c(c1)CNC2
Temperature: 0 °C
Yield: 46.6 %

Procedure:
A stirred solution of 4-methoxyphthalimide (21.3 g, 0.12 mol) in anhydrous tetrahydrofuran (425 ml) at 0° C. was treated dropwise with a solution of borane in tetrahydrofuran (1M, 340 ml, 0.34 mol) and the resulting mixture was stirred and held at reflux for 16 hours. The mixture was cooled to 0° C., methanol (150 ml) was added dropwise followed by 5M hydrochloric acid (150 ml) and the mixture was stirred and held at reflux for 3 hours. Upon cooling to room temperature the organic solvent was removed in vacuo, the mixture was diluted with water (750 ml) and was extracted with dichloromethane (3×750 ml). The aqueous layer was basified to pH 12 or above by the addition of 5M sodium hydroxide, extracted with dichloromethane (3×750 ml) and the combined extracts were evaporated to dryness in vacuo to afford 5-methoxyisoindoline (8.34 g, 47%) as a brown oil. 1H NMR (DMSO-d6) 7.13 (1H, d), 6.84 (1H, d), 6.74 (1H, dd), 4.05 (2H, s), 4.01 (2H, s), 3.73 (3H, s). MS: [M+H]+ 150.
Reaction SMILES: [Br:1][C:2]([F:10])([F:9])[C:3]([F:8])([F:7])[CH2:4][CH2:5]Br.[F:11][C:12]([F:24])([F:23])[CH2:13][CH2:14][S:15]([CH2:18][C:19]([O:21][CH3:22])=[O:20])(=[O:17])=[O:16].[H-].[Na+].Cl>CS(C)=O>[Br:1][C:2]([F:10])([F:9])[C:3]([F:8])([F:7])[CH2:4][CH2:5][CH:18]([S:15]([CH2:14][CH2:13][C:12]([F:23])([F:24])[F:11])(=[O:17])=[O:16])[C:19]([O:21][CH3:22])=[O:20]
Reactant: COC(=O)CS(=O)(=O)CCC(F)(F)F
Reactant: FC(F)(Br)C(F)(F)CCBr
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: COC(=O)C(CCC(F)(F)C(F)(F)Br)S(=O)(=O)CCC(F)(F)F
Reaction time: 72 h
Yield: 27.2 %

Procedure:
To a solution of 1.2 g of 1,4-dibromo-1,1,2,2-tetrafluorobutane and 1.0 g of methyl (3,3,3-trifluoropropylsulfonyl)acetate in 30 ml of dimethyl sulfoxide was added 0.2 g of sodium hydride (60% in oil) at room temperature. The mixture was stirred at the same temperature for 3 days. To the reaction mixture was added 10% hydrochloric acid, and then extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The obtained residue was subjected to silica gel chromatography to obtain 0.50 g of methyl 6-bromo-5,5,6,6-tetrafluoro-2-(3,3,3-trifluoropropylsulfonyl)hexanoate (hereinafter referred to as the present compound (4)).
Reaction SMILES: [NH:1]([C:5]1[S:6][CH:7]=[C:8]([CH:10]2[CH2:15][CH2:14][CH2:13][CH:12]([NH2:16])[CH2:11]2)[N:9]=1)[C:2]([NH2:4])=[NH:3].C(Cl)(Cl)Cl.CO>CO>[NH:1]([C:5]1[S:6][CH:7]=[C:8]([CH:10]2[CH2:15][CH2:14][CH2:13][CH:12]([NH:16][C:5](=[N:1][C:2]#[N:3])[S:6][CH3:7])[CH2:11]2)[N:9]=1)[C:2]([NH2:4])=[NH:3]
Reactant: N=C(N)Nc1nc(C2CCCC(N)C2)cs1
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CSC(=NC#N)NC1CCCC(c2csc(NC(=N)N)n2)C1
Reaction time: 8 h

Procedure:
To a stirred solution of 2-guanidino-4-(3-aminocyclohexyl)thiazole (0.25 g.) in methanol (10 ml.) was added dimethyl (cyanoimido)dithiocarbonate (0.15 g.) and the mixture allowed to stand overnight. The residue, obtained on evaporation of methanol, was subjected to preparative thin layer chromatography on silica gel GF (Uniplate, Analtech Inc., Delaware, USA) using chloroform/methanol (90:10 v/v) for development. Isolation of the appropriate region of the chromatogram and elution with warm ethanol/chloroform (50:50 v/v) and crystallisation of the material extracted from methanol ether gave 2-guanidino-4-[3-(3-cyano-2-methylisothioureido)-cyclohexyl]thiazole, m.p. 216°-218° (decomp.).
Reaction SMILES: [CH2:1]([C:4]1[CH2:5][C@@H:6]2[C@H:9]([CH:10]=1)[C:8](=[CH:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:7]2)[CH2:2][CH3:3].N12CCCN=C1CCCCC2.P([O-])(O)(O)=O.[K+].[N+:36]([CH3:39])([O-:38])=[O:37]>>[CH2:1]([C:4]1[CH2:5][C@@H:6]2[C@H:9]([CH:10]=1)[C@@:8]([CH2:11][C:12]([O:14][C:15]([CH3:17])([CH3:16])[CH3:18])=[O:13])([CH2:39][N+:36]([O-:38])=[O:37])[CH2:7]2)[CH2:2][CH3:3]
Reactant: C[N+](=O)[O-]
Reactant: CCCC1=C[C@@H]2C(=CC(=O)OC(C)(C)C)C[C@@H]2C1
Agent: O=P([O-])(O)O
Agent: [K+]
Solvent: C1CCC2=NCCCN2CC1
Product: CCCC1=C[C@H]2[C@@H](C1)C[C@]2(CC(=O)OC(C)(C)C)C[N+](=O)[O-]
Temperature: 55 °C
Reaction time: 8 h

Procedure:
Tert-butyl(±)-(1S,5R)-3-propyl-bicyclo[3.2.0]hept-3-en-6-ylideneacetate (1.81 g, 7.29 mmol) was dissolved in nitromethane (7 mL). To the solution, 1,8-diazabicyclo[5.4.0]undec-7-ene (1.5 mL, 10.2 mmol) was added, and the mixture was heated with stirring at 50 to 60° C. for 8 hours. The mixture was allowed to cool, and a saturated aqueous solution of potassium dihydrogen phosphate was then added thereto, followed by extraction with ethyl acetate. Then, the organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography to obtain the compound of interest as a colorless oil substance (2.22 g, 95%).
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][CH:2]=1.[H-].[Na+].ClC1C=CC([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[S:25]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2C2C=CC(Cl)=CC=2)(=[O:27])=[O:26])=CC=1>CN(C=O)C>[C:20]1([S:25]([C:28]2[CH:33]=[CH:32][C:31]([N:1]3[C:5]4[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=4[N:3]=[CH:2]3)=[CH:30][CH:29]=2)(=[O:27])=[O:26])[CH:19]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: c1ccc2[nH]cnc2c1
Reactant: O=S(=O)(c1ccccc1-c1ccc(Cl)cc1)c1ccccc1-c1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=S(=O)(c1ccccc1)c1ccc(-n2cnc3ccccc32)cc1
Temperature: 100 °C
Reaction time: 16 h
Yield: 91 %

Procedure:
To a solution of benzimidazole (11.8 g, 0.10 mol) in DMF (500 ml) is added, at room temperature under nitrogen, sodium hydride (60% in mineral oil, 4.4 g, 0.11 mol), and the mixture is stirred for 10 min. The mixture is admixed with 4-chlorophenyl phenylsulfone (26.1 g, 0.10 mol) and stirred at 100° C. for 16 h. After again adding sodium hydride (60% in mineral oil, 2.0 g, 0.05 mol) at room temperature, the mixture is stirred at 130° C. for 16 h. After cooling to room temperature, the mixture is added to ice-water. Precipitated product is filtered off and washed with water. Yield: 91%.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[S:6](=[O:14])(=[O:13])[N:5]([CH3:15])[C:4]=1[C:16]([OH:18])=O.S(Cl)([Cl:21])=O.CN(C)C=O>C1C=CC=CC=1>[CH3:1][O:2][C:3]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[S:6](=[O:14])(=[O:13])[N:5]([CH3:15])[C:4]=1[C:16]([Cl:21])=[O:18]
Reactant: COC1=C(C(=O)O)N(C)S(=O)(=O)c2ccccc21
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: c1ccccc1
Product: COC1=C(C(=O)Cl)N(C)S(=O)(=O)c2ccccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 21801.5 %

Procedure:
6.2 gm (23 millimols) of 4-methoxy-2-methyl-2H-1,2-benzothiazine-3-carboxylic acid-1,1-dioxide were suspended in 60 ml of benzene and 8.2 ml (0.11 millimols) of thionyl chloride and 0.5 ml of anhydrous dimethylformamide were added to the suspension. The reaction mixture was refluxed for 6 hours, stirred overnight at room temperature and evaporated in vacuo. The residue was dissolved in a little toluene, and the solution was evaporated, yielding 6.9 gm (100% of theory) of 4-methoxy-2-methyl-2H-1,2-benzothiazine-3-carboxylic acid chloride-1,1-dioxide.
Reaction SMILES: Br[C:2]1[C:8]([F:9])=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[F:10].[CH2:11]([S:13][C:14]1[CH:15]=[C:16](B(O)O)[CH:17]=[CH:18][CH:19]=1)[CH3:12]>>[CH2:11]([S:13][C:14]1[CH:19]=[C:18]([C:2]2[C:8]([F:9])=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=2[F:10])[CH:17]=[CH:16][CH:15]=1)[CH3:12]
Reactant: Nc1cc(F)c(Br)c(F)c1
Reactant: CCSc1cccc(B(O)O)c1
Product: CCSc1cccc(-c2c(F)cc(N)cc2F)c1
Yield: 108.3 %

Procedure:
The title compound (500 mg) was prepared from 4-bromo-3,5-difluoroaniline (300 mg, 1.74 mmol) and 3-(ethylthio)phenylboronic acid (340 mg, 1.86 mmol) as a yellow liquid.
Reaction SMILES: C(Cl)Cl.Cl.[CH3:5][O:6][C:7]1[CH:41]=[CH:40][C:10]([CH2:11][S:12][C@@H:13]2[CH2:17][N:16]([C:18]([O:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=3)=[O:19])[C@H:15]([C:31]([N:33]3[CH2:39][CH2:38][CH2:37][NH:36][CH2:35][CH2:34]3)=[O:32])[CH2:14]2)=[CH:9][CH:8]=1.[N+:42]([C:45]1[CH:58]=[CH:57][C:48]([CH2:49][O:50][C:51]([NH:53][C:54](=N)[CH3:55])=[O:52])=[CH:47][CH:46]=1)([O-:44])=[O:43]>CO>[CH3:5][O:6][C:7]1[CH:8]=[CH:9][C:10]([CH2:11][S:12][C@@H:13]2[CH2:17][N:16]([C:18]([O:20][CH2:21][C:22]3[CH:23]=[CH:24][C:25]([N+:28]([O-:30])=[O:29])=[CH:26][CH:27]=3)=[O:19])[C@H:15]([C:31]([N:33]3[CH2:39][CH2:38][CH2:37][N:36]([C:54](=[N:53][C:51]([O:50][CH2:49][C:48]4[CH:57]=[CH:58][C:45]([N+:42]([O-:44])=[O:43])=[CH:46][CH:47]=4)=[O:52])[CH3:55])[CH2:35][CH2:34]3)=[O:32])[CH2:14]2)=[CH:40][CH:41]=1
Reactant: COc1ccc(CS[C@H]2C[C@@H](C(=O)N3CCCNCC3)N(C(=O)OCc3ccc([N+](=O)[O-])cc3)C2)cc1
Reactant: CC(=N)NC(=O)OCc1ccc([N+](=O)[O-])cc1
Agent: Cl
Solvent: CO
Solvent: ClCCl
Product: COc1ccc(CS[C@H]2C[C@@H](C(=O)N3CCCN(C(C)=NC(=O)OCc4ccc([N+](=O)[O-])cc4)CC3)N(C(=O)OCc3ccc([N+](=O)[O-])cc3)C2)cc1
Yield: 14.5 %

Procedure:
25 ml of methylene chloride were added to a solution of 2.5 g of (2S,4S)-4-(4-methoxybenzylthio)-2-(1-homopiperazinylcarbonyl)-1-(4-nitrobenzyloxycarbonyl)pyrrolidine hydrochloride [prepared as described in step (i) above] in 25 ml of methanol, which was being heated under reflux, and then 904 mg of N-(4-nitrobenzyloxycarbonyl)acetamidine were added to the resulting mixture. The reaction mixture was heated under reflux for a further 5 hours, after which it was worked up and purified by the same procedure as described in Preparation 1(iii), to give 415 mg of the title compound, as a powder.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][C:9]([Br:13])=[CH:10][CH:11]=2)[C:6]([CH3:14])=[N:5]1)(=O)C.[ClH:15]>CO>[ClH:15].[Br:13][C:9]1[CH:8]=[C:7]2[C:12](=[CH:11][CH:10]=1)[NH:4][N:5]=[C:6]2[CH3:14]
Reactant: CC(=O)n1nc(C)c2cc(Br)ccc21
Agent: Cl
Solvent: CO
Product: Cc1n[nH]c2ccc(Br)cc12
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
1-Acetyl-5-bromo-3-methyl-1H-indazole (1.23 g) was added to the solution of hydrochloride in methanol (30 ml), and stirred for 30 min at 60° C. The mixture was concentrated under reduced pressure, and the residue was crystallized from mixed solvent of hexane and EtOAc to give the title compound as a yellow solid.
Reaction SMILES: IC.[CH3:3][C:4]([N+:14]([O-:16])=[O:15])([CH3:13])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1.[C:17](=O)([O-])[O-].[K+].[K+]>O1CCCC1.CN(C)C=O>[CH3:17][O:12][C:9]1[CH:10]=[CH:11][C:6]([CH2:5][C:4]([CH3:3])([N+:14]([O-:16])=[O:15])[CH3:13])=[CH:7][CH:8]=1
Reactant: O=C([O-])[O-]
Reactant: CC(C)(Cc1ccc(O)cc1)[N+](=O)[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COc1ccc(CC(C)(C)[N+](=O)[O-])cc1
Yield: 63.7 %

Procedure:
Iodomethane (0.12 mL, 1.3 mmol) was added to a mixture of 4-(2-methyl -2-nitropropyl)phenol (300 mg, 1.5 mmol) and potassium carbonate (425 mg, 3.1 mmol) in tetrahydrofuran (20 mL) and N,N-dimethylformamide (1 mL). After refluxing overnight, the mixture was cooled and concentrated under vacuum. The residue was dissolved in ethyl acetate, washed with water, dried over anhydrous sodium sulfate and concentrated to provide crude 1-methoxy-4-(2-methyl-2-nitropropyl)benzene (200 mg, 62% yield) as yellow oil which was used directly in the next step.
Reaction SMILES: C(OC([N:8](C)[C@H:9]([C:13]([NH:15][C@H:16](C(N([C@@H]([C@@H](C)CC)[C@H](OC)CC(O)=O)C)=O)C(C)C)=[O:14])[CH:10]([CH3:12])[CH3:11])=O)(C)(C)C.FC(F)(F)C(O)=O.C(OC(=O)[C@H](C)[C@@H](OC)[C@@H]1CCCN1)C1C=CC=CC=1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C=O)C>[CH3:16][NH:15][C:13](=[O:14])[C@H:9]([CH:10]([CH3:12])[CH3:11])[NH2:8]
Reactant: CC[C@H](C)[C@@H]([C@@H](CC(=O)O)OC)N(C)C(=O)[C@@H](NC(=O)[C@H](C(C)C)N(C)C(=O)OC(C)(C)C)C(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CO[C@@H]([C@@H]1CCCN1)[C@@H](C)C(=O)OCc1ccccc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: CNC(=O)[C@@H](N)C(C)C
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
1200 mg (2.33 mmol) N-(tert-butoxycarbonyl)-N-methyl-L-valyl-N-[(2R,3S,4S)-1-carboxy-2-methoxy-4-methyl-hexan-3-yl]-N-methyl-L-valinamide (intermediate 5) was combined with 910.8 mg (2.33 mmol) benzyl-(2R,3R)-3-methoxy-2-methyl-3-[(2S)-pyrrolidin-2-yl]propanoate trifluoroacetic acid salt (intermediate 6), 1327 mg (3.49 mmol) O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate and 2027 μL N,N-diisopropylethylamine in 50 mL DMF and stirred for 5 min at RT. Next the solvent was removed in vacuo. The remaining residue was dissolved in ethyl acetate and then extracted with 5% aqueous citric acid solution and saturated sodium bicarbonate solution in succession. The organic phase was separated and concentrated. The residue was purified by preparative HPLC. The product fractions were combined, concentrated and the residue was dried in a high vacuum, yielding 1000 mg (55% of the theoretical) of the benzyl ester intermediate N-(tert-butoxycarbonyl)-N-methyl-L-valyl-N-[(3R,4S,5S)-1-{(2S)-2-[(1R,2R)-3-benzyloxy)-1-methoxy-2-methyl-3-oxopropyl]pyrrolidin-1-yl}-3-methoxy-5-methyl-1-oxoheptan-4-yl]-N-methyl-L-valinamide as a resin.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)(=[O:12])=[O:11])[CH:7]=[CH:6][C:5]=1[Cl:19])([O-])=O.ClCCl>C(O)C>[Cl:19][C:5]1[C:4]([NH2:1])=[CH:9][C:8]([S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)(=[O:11])=[O:12])=[CH:7][CH:6]=1
Reactant: O=[N+]([O-])c1cc(S(=O)(=O)c2ccccc2)ccc1Cl
Solvent: ClCCl
Solvent: CCO
Product: Nc1cc(S(=O)(=O)c2ccccc2)ccc1Cl
Temperature: 75 °C
Yield: 82.8 %

Procedure:
2-Nitro-4-(phenylsulfonyl)chlorobenzene (9.8 g) and stannous chloride dihydrate (33.5 g) were suspended in absolute ethanol (200 mL) and heated to 75° C. for 40 minutes. The solution was evaporated and the resulting material was cooled to 0° C. Water (100 mL) was added, and the pH was adjusted to 8.0 with aqueous sodium hydroxide. The resulting solids were removed by filtration and the aqueous filtrate was extracted with ethyl acetate. The combined ethyl acetate solutions were evaporated to give a brown solid. Chromatography, with dichloromethane as the eluent yielded the aniline as an orange solid (7.3 g); mp: 105°-107° C.; 250 MHz NMR: 5.96 (s,2), 7.02 (dd,1 J=8, 2), 7.34 (d,1, J=2), 7.41 (d,1, J=8), 7.61 (m,3), 7.88 (d,2, J=7); MS: m/z=268(M+1).
Reaction SMILES: [I:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=O)[C:10]([CH3:13])([CH3:12])[CH3:11])=[N:6][CH:7]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:24])=CC=1>C1(C)C=CC=CC=1>[I:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[S:24])[C:10]([CH3:13])([CH3:12])[CH3:11])=[N:6][CH:7]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CC(C)(C)C(=O)Nc1ccc(I)cn1
Solvent: Cc1ccccc1
Product: CC(C)(C)C(=S)Nc1ccc(I)cn1
Temperature: 110 °C
Reaction time: 48 h

Procedure:
N-(5-Iodo-pyridin-2-yl)-2,2-dimethyl-propionamide (example 39, step 1) (5.8 g, 19.1 mmol) was dissolved in 30 ml of toluene and Lawesson's reagent (7.7 g, 19.1 mmol, 1 equiv.) was added at room temperature. The reaction mixture was stirred for 48 hours at 110° C. The crude product was purified by flash chromatography by directly loading the cooled toluene reaction mixture onto a 300 g silica gel column and eluting with heptane:ethyl acetate 100:0->80:20. The desired N-(5-iodo-pyridin-2-yl)-2,2-dimethyl-thiopropionamide was obtained as a yellow oil (5.1 g, 75% yield), MS: m/e=321.0 (M+H+).
Reaction SMILES: [BH4-].[Na+].[OH:3][C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:13]>C(O)C.C1COCC1>[OH:13][CH:12]([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[C:5]1[CH:6]=[CH:7][C:8]([O:10][CH3:11])=[CH:9][C:4]=1[OH:3]
Reactant: COc1ccc(C(=O)c2ccccc2)c(O)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Product: COc1ccc(C(O)c2ccccc2)c(O)c1

Procedure:
Sodium borohydride is dissolved in 75 ml of ethanol, and the starting material (2-hydroxy-4-methoxyphenyl)phenylmethanone, dissolved in 5 ml of THF, is added dropwise over the course of about 10 min. The reaction mixture is stirred at room temperature for 1 h until all the sodium borohydride has been consumed. The solvent is removed in vacuo. The residue is partitioned in methyl t-butyl ether (MTBE)/water, and the aqueous phase is extracted a further 3 times with 50 ml of MTBE. The combined organic phases are dried over sodium sulfate, and the solvent is removed in vacuo.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([N+:9]([O-])=O)[CH:6]=[CH:5][C:4]=1[C:12]1[O:16][N:15]=[C:14]([CH3:17])[CH:13]=1.[Sn](Cl)Cl.Cl.CO>C1COCC1>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH:6]=[CH:5][C:4]=1[C:12]1[O:16][N:15]=[C:14]([CH3:17])[CH:13]=1)[NH2:9]
Reactant: COc1cc([N+](=O)[O-])ccc1-c1cc(C)no1
Agent: Cl
Agent: Cl[Sn]Cl
Solvent: CO
Solvent: C1CCOC1
Product: COc1cc(N)ccc1-c1cc(C)no1
Temperature: 25 °C
Reaction time: 3 h
Yield: 84.2 %

Procedure:
Step H (2): 5-(2-Methoxy-4-nitrophenyl)-3-methylisoxazole (750 mg, 3.2 mmol) was added portionwise (exotherm observed) to a stirred mixture of tin(II) chloride (3.0 g), concentrated hydrochloric acid (3.0 mL), methanol (3.8 mL), and THF (15 mL). The resulting mixture was stirred at rt for 3 h. The solvent was removed in vacuo. The residue diluted with water and extracted with MTBE. The aqueous layer was basified with 10% NaOH solution to pH 13. The basic solution was extracted with chloroform. The organic layer was dried over sodium sulfate, filtered, and concentrated to afford 3-methoxy-4-(3-methylisoxazol-5-yl)aniline (550 mg, 84% yield).
Reaction SMILES: [CH3:1][C@@H:2]([NH:13]CCCC1C=CC=C(C(F)(F)F)C=1)[C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=12.Cl.C1([C@H](N)C)C2C(=CC=CC=2)C=CC=1.FC(F)(F)C1C=C(C=CC=O)C=CC=1>>[C:3]1([CH:2]([NH2:13])[CH3:1])[C:8]2[C:7](=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=1
Reactant: C[C@@H](NCCCc1cccc(C(F)(F)F)c1)c1cccc2ccccc12
Agent: C[C@@H](N)c1cccc2ccccc12
Agent: Cl
Agent: O=CC=Cc1cccc(C(F)(F)F)c1
Product: CC(N)c1cccc2ccccc12

Procedure:
The invention therefore relates to a process for the preparation of cinacalcet hydrochloride (I) which includes the steps of: a) reacting (R)-(+)-1-(1-naphthyl)ethylamine (II) with 3-[3-(trifluoromethyl)phenyl]propenaldehyde (III) to afford the non isolated intermediate (R)—N-[3-[3-(trifluoromethyl)phenyl]-2-propenylimino-N-[1-(1-naphthyl)ethylamine (IV); b) reducing the non isolated intermediate (R)—N-[3-[3-(trifluoromethyl)phenyl]-2-propenylimino-N-[1-(1-naphthyl)ethylamine (IV) with a sequential addition of:—a solution of sodium borohydride, methanol and a base,—oxalic acid and—a base to obtain (R)—N-[3-[3-(trifluoromethyl)phenyl]-2-propenyl]-1-(1-naphthyl)ethylamine (V) by passing through the precipitation of the oxalate salt of compound (V) after the addition of oxalic acid; c) hydrogenating (R)—N-[3-[3-(trifluoromethyl)phenyl]-2-propenyl]-1-(1-naphthyl)ethylamine (V) thus obtaining (R)—N-(3-(3-(trifluoromethyl)phenyl]propyl]-1-(1-naphthyl)ethylamine cinacalcet base (VI), which is retaken in ethyl acetate; and d) treating the solution of cinacalcet base (VI) in ethyl acetate with hydrochloric acid to afford cinacalcet hydrochloride (I). Preferably, the step a) of reacting (R)-(+)-1-(1-naphthyl)ethylamine (II) with 3-[3-(trifluoromethyl)phenyl]propenaldehyde (III) to afford the non isolated intermediate (R)—N-[3-[3-(trifluoromethyl)phenyl]-2-propenylimino-N-[1-(1-naphthyl)ethylamine (IV) occurs in the presence of methanol.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1C1NC(C2C=CC(C3C=CN=C(OCC4C=CC=CC=4)C=3)=CC=2)=CN=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].CCl.[Cl-].[NH4+]>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCCC1c1ncc(-c2ccc(-c3ccnc(OCc4ccccc4)c3)cc2)[nH]1
Agent: CCl
Agent: [Cl-]
Agent: [H-]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCCC1
Reaction time: 0.08 h
Yield: 270.9 %

Procedure:
To a solution of 2-{5-[4-(2-Benzyloxy-pyridin-4-yl)-phenyl]-1H-imidazol-2-yl}-pyrrolidine-1-carboxylic acid tert-butyl ester (0.530 g) in DMF (5.0 mL) at 0° C. was added 60% sodium hydride (0.047 g). After stirring for 5 minutes, 2-(trimethylsilyl)ethoxy]methyl chloride was added and reaction mixture stirred for 2 hours. Saturated ammonium chloride was added and mixture was extracted with ethyl acetate (2×). Organic layer was washed with 5% lithium chloride solution (2×), brine and dried (MgSO4). Concentrated and purified by flash column chromatography (silica gel, 20 to 80% ethyl acetate/hexanes) to give 245-[4-(2-Benzyloxy-pyridin-4-yl)-phenyl]-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazol-2-yl]-pyrrolidine-1-carboxylic acid tert-butyl ester (0.495 g). LCMS-ESI+: calc'd for C36H47N4O4Si: 627.87 (M+H+). Found: 627.1 (M−1-H+). A mixture of 245-[4-(2-Benzyloxy-pyridin-4-yl)-phenyl]-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazol-2-yl]-pyrrolidine-1-carboxylic acid tert-butyl ester (0.495 g) and 10% Pd/C (0.023 g) in ethanol (5.5 mL) was stirred under hydrogen atmosphere for 1 hour. Reaction mixture was filtered through a pad of Celite, which was washed with methanol. The filtrate was concentrated and purified by flash column chromatography (silica gel, 0 to 10% methanol/ethyl acetate) to give 2-[5-[4-(2-Oxo-1,2-dihydro-pyridin-4-yl)-phenyl]-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazol-2-yl]-pyrrolidine-1-carboxylic acid tert-butyl ester (0.3027 g): LCMS-ESI+: calc'd for C29H41N4O4Si: 537.47 (M+H+). Found: 537.0 (M+H+).
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:9]=[CH:8][CH:7]=[CH:6][C:4]=1[NH2:5].N1C=CC=CC=1.[N+:18]([C:21]1[CH:26]=[CH:25][C:24]([S:27](Cl)(=[O:29])=[O:28])=[CH:23][CH:22]=1)([O-:20])=[O:19]>C(Cl)Cl>[N+:18]([C:21]1[CH:22]=[CH:23][C:24]([S:27]([NH:5][C:4]2[CH:6]=[CH:7][CH:8]=[CH:9][C:3]=2[C:2]([F:10])([F:11])[F:1])(=[O:29])=[O:28])=[CH:25][CH:26]=1)([O-:20])=[O:19]
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Reactant: Nc1ccccc1C(F)(F)F
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=[N+]([O-])c1ccc(S(=O)(=O)Nc2ccccc2C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 82.4 %

Procedure:
A solution of 2-(trifluoromethyl)aniline (1.51 g, 9.37 mmol) and pyridine (1.08 mL, 13.38 mmol) in DCM (30 mL) was treated with 4-nitrobenzenesulfonyl chloride (1.48 g, 6.69 mmol) and stirred at room temperature for 18 hours. The mixture was diluted with DCM, washed with 1 M aqueous HCl, saturated aqueous NaHCO3, water and brine, dried over Na2SO4 and concentrated under vacuum. Trituration with pentane gave 4-nitro-N-(2-trifluoromethyl-phenyl)-benzenesulfonamide (1.91 g, 82%). 1H NMR (300 MHz, CDCl3) δ 8.31-8.23 (m, 2H), 7.95-7.85 (m, 3H), 7.64-7.50 (m, 2H), 7.31 (t, J=7.7 Hz, 1H), 6.89 (br s, 1H). LCMS (m/z, Method A) ES+ 347.1 [M+1]+.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:4]=[C:5]([NH:9][C:10](=[O:37])[NH:11][CH2:12][C:13]([N:15]2[CH:19]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH:18]([C:26]([O:28]C)=[O:27])[CH2:17][CH:16]2[C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])=[O:14])[CH:6]=[CH:7][CH:8]=1.O.CO>[OH-].[K+]>[CH3:1][S:2][C:3]1[CH:4]=[C:5]([NH:9][C:10](=[O:37])[NH:11][CH2:12][C:13]([N:15]2[CH:19]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH:18]([C:26]([OH:28])=[O:27])[CH2:17][CH:16]2[C:30]([O:32][C:33]([CH3:35])([CH3:34])[CH3:36])=[O:31])=[O:14])[CH:6]=[CH:7][CH:8]=1
Reactant: COC(=O)C1CC(C(=O)OC(C)(C)C)N(C(=O)CNC(=O)Nc2cccc(SC)c2)C1c1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CSc1cccc(NC(=O)NCC(=O)N2C(C(=O)OC(C)(C)C)CC(C(=O)O)C2c2ccccc2)c1
Yield: 71.9 %

Procedure:
A The reaction is carried out in a way analogous to that described in Example 3, but from 1.5 g of 2-tert-butyl 4-methyl (2RS,4RS,5SR)-1-{2-[3-(3-(methylthio)phenyl)ureido]acetyl}-5-phenylpyrrolidine-2,4-dicarboxylate in a mixture of 2.8 cm3 of a normal aqueous potassium hydroxide solution, 15 cm3 of distilled water and 60 cm3 of methanol. After treatment, there are obtained 1.05 g of 2-tert-butyl hydrogen (2RS,4SR,5SR)-1-{2-[3-(3-(methylthio)phenyl)ureido]-acetyl}-5-phenylpyrrolidine-2,4-dicarboxylate, melting at 130° C.