Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:5][C:6](=[O:39])[C@@H:7]([NH:28][C:29]([O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:30])[CH2:8][NH:9][C:10]([C:12]1[S:13][C:14]([CH2:17][CH2:18][C:19](=[O:27])[NH:20][C:21]2[NH:22][CH2:23][CH2:24][CH2:25][N:26]=2)=[CH:15][CH:16]=1)=[O:11])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH2:32]([O:31][C:29]([NH:28][C@@H:7]([CH2:8][NH:9][C:10]([C:12]1[S:13][C:14]([CH2:17][CH2:18][C:19](=[O:27])[NH:20][C:21]2[NH:22][CH2:23][CH2:24][CH2:25][N:26]=2)=[CH:15][CH:16]=1)=[O:11])[C:6]([OH:39])=[O:5])=[O:30])[C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1
Reactant: CC(C)(C)OC(=O)[C@H](CNC(=O)c1ccc(CCC(=O)NC2=NCCCN2)s1)NC(=O)OCc1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(CCc1ccc(C(=O)NC[C@H](NC(=O)OCc2ccccc2)C(=O)O)s1)NC1=NCCCN1

Procedure:
50 mg of the product obtained in step h) were dissolved in 5 ml of dichloromethane, and with stirring 0.5 ml of trifluoroacetic acid were added dropwise at room temperature. After 4 hours the ester was no more detectable. The mixture was evaporated under reduced pressure, and the remaining residue was dissolved in acetic acid and again evaporated under reduced pressure. This procedure was repeated twice. Then the residue was triturated vigorously with diethyl ether. The crystals formed were isolated by suction followed by washing with diethyl ether. After drying in vacuo 30 mg of the title compound were obtained as a pale yellow powder.
Reaction SMILES: C([Mg]Cl)(C)C.[C:6]([Si:10]([CH3:23])([CH3:22])[O:11][CH:12]1[CH2:15][CH:14]([N:16]2[CH:20]=[C:19](I)[CH:18]=[N:17]2)[CH2:13]1)([CH3:9])([CH3:8])[CH3:7].CO[B:26]1[O:30][C:29]([CH3:32])([CH3:31])[C:28]([CH3:34])([CH3:33])[O:27]1>C1COCC1>[Si:10]([O:11][CH:12]1[CH2:15][CH:14]([N:16]2[CH:20]=[C:19]([B:26]3[O:30][C:29]([CH3:32])([CH3:31])[C:28]([CH3:34])([CH3:33])[O:27]3)[CH:18]=[N:17]2)[CH2:13]1)([C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:23])[CH3:22]
Reactant: CC(C)(C)[Si](C)(C)OC1CC(n2cc(I)cn2)C1
Reactant: COB1OC(C)(C)C(C)(C)O1
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: CC1(C)OB(c2cnn(C3CC(O[Si](C)(C)C(C)(C)C)C3)c2)OC1(C)C
Temperature: 0 °C

Procedure:
Over the course of 5 minutes, a 2.00 M solution of isopropylmagnesium chloride in THF (0.13084 mL, 0.26168 mmol) was added dropwise to an ice cooled solution of 1-[3-(tert-butyl-dimethyl-silanyloxy)-cyclobutyl]-4-iodo-1H-pyrazole (Compound 100B, 30.00 mg, 0.07930 mmol) in THF (0.33 mL). The reaction mixture was stirred at 0° C. for another hour. 2-Methoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.057933 mL, 0.33939 mmol) was added at 0° C. and then the mixture was stirred at rt for another hour. The reaction mixture was cooled back down to 0° C., quenched with saturated aqueous NH4Cl, and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to dryness, giving the title compound as a colorless oil. Compound was taken on for the next step without further purification. MS (ES+): m/z 379.04 (100) [MH+]; HPLC: tR=3.85 min (ZQ3, polar—5 min).
Reaction SMILES: [C:1]1([C:7]2[NH:8][C:9](=[O:12])[NH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[F:15][C:16]([F:33])([F:32])[C:17]([N:19]1[C:27]2[C:22](=[CH:23][C:24]([S:28](Cl)(=[O:30])=[O:29])=[CH:25][CH:26]=2)[CH2:21][CH2:20]1)=[O:18].O>CN(C)C=O>[C:1]1([C:7]2[NH:8][C:9](=[O:12])[N:10]([S:28]([C:24]3[CH:23]=[C:22]4[C:27](=[CH:26][CH:25]=3)[N:19]([C:17](=[O:18])[C:16]([F:33])([F:15])[F:32])[CH2:20][CH2:21]4)(=[O:29])=[O:30])[CH:11]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(N1CCc2cc(S(=O)(=O)Cl)ccc21)C(F)(F)F
Reactant: O=c1[nH]cc(-c2ccccc2)[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(N1CCc2cc(S(=O)(=O)n3cc(-c4ccccc4)[nH]c3=O)ccc21)C(F)(F)F
Temperature: 0 °C
Yield: 70 %

Procedure:
4-Phenyl-2,3-dihydro-1H-2-imidazolone (4 g, 24.84 mmol) prepared in Preparation 1 was suspended in 30 ml of dimethylformamide and cooled down to 0 ° C. After sodium hydride (60% oily, 1.09 g, 27.3 mmol) was added thereto, the resulting mixture was stirred for a few minutes at 0° C. until it became a clear solution. To the reaction mixture was added portionwise at 0° C. the N-trifluoroacetyl-indoline-5-sulfonylchloride (8.56 g, 27.32 mmol) prepared in Preparation 2. The reaction mixture was stirred at room temperature for 4 hours, cooled down again to 0° C., and then water was slowly added to the mixture until precipitate was formed. The resulting precipitate was collected, washed with water, and dried to afford 7.6 g of 4-phenyl-1-(N-trifluoroacetylindoline-5-sulfonyl)-2-imidazolone.
Reaction SMILES: C(O[C:5]1([CH3:16])[CH:9]=[CH:8][C:7](=[O:10])[CH:6]1[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])(=O)C.S(=O)(=O)(O)[OH:18]>O1CCCC1>[OH:18][CH:9]1[CH2:8][C:7](=[O:10])[C:6]([CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])=[C:5]1[CH3:16]
Reactant: CCCCCC1C(=O)C=CC1(C)OC(C)=O
Reactant: O=S(=O)(O)O
Solvent: C1CCOC1
Product: CCCCCC1=C(C)C(O)CC1=O

Procedure:
In the same flask as in Example 1, there were charged 3-acetoxy-2-n-pentyl-3-methyl-4-cyclopentenone (2.24 g), tetrahydrofuran (10 ml) and 20% sulfuric acid (10 ml), and the resultant mixture was stirred at 30° to 50° C. for 6 hours. After completion of the reaction, the reaction mixture was subjected to post-treatment and purification as in example 1 to give 1.55 g of 4-hydroxy-2-n-pentyl-3-methyl-2-cyclopentenone. Yield, 85%.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][NH2:5].[CH2:6]([O:8][C:9](=[O:29])[N:10]([C:18]1[CH:23]=[C:22](Br)[N:21]=[C:20]([NH2:25])[C:19]=1[N+:26]([O-:28])=[O:27])[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH3:7]>>[CH2:6]([O:8][C:9](=[O:29])[N:10]([C:18]1[CH:23]=[C:22]([NH:5][CH2:4][CH2:3][O:2][CH3:1])[N:21]=[C:20]([NH2:25])[C:19]=1[N+:26]([O-:28])=[O:27])[CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[CH3:7]
Reactant: CCOC(=O)N(Cc1ccccc1)c1cc(Br)nc(N)c1[N+](=O)[O-]
Reactant: COCCN
Product: CCOC(=O)N(Cc1ccccc1)c1cc(NCCOC)nc(N)c1[N+](=O)[O-]

Procedure:
The title compound was prepared following the example in preparation 102 using 2-methoxyethylamine (1.0 ml) and (2-amino-6-bromo-3-nitro-pyridin-4-yl)-benzyl-carbamic acid ethyl ester (150 mg), giving the product (121 mg) as a yellow gum.
Reaction SMILES: [CH2:1]([CH:3]([CH2:18][CH2:19][CH2:20][CH3:21])[CH2:4][O:5][C:6]([C:8]1[CH:9]=[C:10]([S:14](Cl)(=[O:16])=[O:15])[CH:11]=[CH:12][CH:13]=1)=[O:7])[CH3:2].C(#[N:24])C.N>O>[CH2:1]([CH:3]([CH2:18][CH2:19][CH2:20][CH3:21])[CH2:4][O:5][C:6]([C:8]1[CH:9]=[C:10]([S:14]([NH2:24])(=[O:16])=[O:15])[CH:11]=[CH:12][CH:13]=1)=[O:7])[CH3:2]
Reactant: CCCCC(CC)COC(=O)c1cccc(S(=O)(=O)Cl)c1
Reactant: CC#N
Agent: N
Solvent: O
Product: CCCCC(CC)COC(=O)c1cccc(S(N)(=O)=O)c1
Temperature: 0 °C
Yield: 77 %

Procedure:
An ice-cooled solution of 460 g of 3-(2-ethylhexyloxycarbonyl)phenylsulfonyl chloride and 0.7 L of acetonitrile was added dropwise to 0.7 L of a 28% ammonia solution. The resultant mixture was stirred for 2 hours at room temperature. Thereafter, 0.7 L of water and 35 g of common salt were added thereto, followed by extraction with 1.0 L of ethyl acetate. The extract was washed with 0.5 L of diluted hydrochloric acid and 0.5 L of saturated brine and was then decolored with 20 g of active carbon. The active carbon was removed with Celite, and then the solvent was distilled off. 0.6 L of hexane was added and crystallized by cooling, and thus 338 g (1.08 mol, yield 77%) of 3-(2-ethylhexyloxycarbonyl)phenylsulfonamide was obtained m.p. 40° C. to 42° C.
Reaction SMILES: C(N(C(C)C)CC)(C)C.[C:10]([O:14][C:15]([N:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1)=[O:16])([CH3:13])([CH3:12])[CH3:11].[N+:23]([C:26]1[CH:31]=[CH:30][C:29]([S:32](Cl)(=[O:34])=[O:33])=[CH:28][CH:27]=1)([O-:25])=[O:24]>C(Cl)Cl>[C:10]([O:14][C:15]([N:17]1[CH2:22][CH2:21][N:20]([S:32]([C:29]2[CH:28]=[CH:27][C:26]([N+:23]([O-:25])=[O:24])=[CH:31][CH:30]=2)(=[O:33])=[O:34])[CH2:19][CH2:18]1)=[O:16])([CH3:13])([CH3:11])[CH3:12]
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCN(S(=O)(=O)c2ccc([N+](=O)[O-])cc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.8 %

Procedure:
Diisopropylethylamine (7.8 ml, 45 mmol) was added in one portion to a stirred solution of piperazine-1-carboxylic acid tert-butyl ester (7.6 g, 41 mmol) in DCM (100 ml) at room temperature. To this mixture was added 4-nitrophenyl sulfonyl chloride (10.0 g, 45 mmol) in one portion and the mixture was stirred at room temperature under a nitrogen atmosphere for 1 hour. After this time the mixture was diluted with DCM (50 ml) and washed with water (100 ml), saturated NaHCO3 (100 ml) and HCl (100 ml, 2M). The organic layer was separated, dried (MgSO4), filtered and concentrated under vacuum to give the title compound (14.9 g, 89% yield) as a white solid. δH (500 MHz, DMSO) 8.45 (2H, d), 7.97 (2H, d), 3.34 (4H, obscured), 2.96-2.92 (4H, m), 1.33 (9H, s). Tr=1.91 min m/z (ES+) ([(M−100)+H]+) 272.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[CH2:4][C@H:5]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:18])[C:9]2[CH:19]=[C:20]([Cl:23])[CH:21]=[CH:22][C:8]=2[NH:7][C:6]1=[O:24].[CH2:26](Br)[CH:27]([CH3:29])[CH3:28]>>[CH3:1][O:2][C:3](=[O:25])[CH2:4][C@H:5]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:18])[C:9]2[CH:19]=[C:20]([Cl:23])[CH:21]=[CH:22][C:8]=2[N:7]([CH2:26][CH:27]([CH3:29])[CH3:28])[C:6]1=[O:24]
Reactant: COC(=O)C[C@H]1N=C(c2ccccc2Cl)c2cc(Cl)ccc2NC1=O
Reactant: CC(C)CBr
Product: COC(=O)C[C@H]1N=C(c2ccccc2Cl)c2cc(Cl)ccc2N(CC(C)C)C1=O
Yield: 52.2 %

Procedure:
(3R)-7-Chloro-5-(2-chlorophenyl)-2,3-dihydro-2-oxo-1H,1,4-benzodiazepine-3-acetic acid methyl ester (0.5 g) obtained in Example 11 and isobutyl bromide (0.23 g) were allowed to proceed in substantially the same manner as in Example 4 to give 0.3 g of a colorless oily compound.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][N+:8]([O-])=[C:7]([CH3:12])[C:6]=1[CH3:13])([CH3:4])([CH3:3])[CH3:2].[Cl:14]C(Cl)(Cl)C(Cl)=O.C(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl>[Cl:14][CH2:12][C:7]1[C:6]([CH3:13])=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH:10]=[CH:9][N:8]=1
Reactant: Cc1c(C(C)(C)C)cc[n+]([O-])c1C
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: Cc1c(C(C)(C)C)ccnc1CCl

Procedure:
A solution of 9.8 g of 4-tert-butyl-2,3-dimethylpyridine N-oxide in 120 ml of abs. chloroform is boiled at reflux under argon and treated through the condenser with 25.5 ml of trichloroacetyl chloride. After 22 hours the reaction mixture is poured on to ice, whereupon 10% sodium bicarbonate solution is added, the mixture is extracted with methylene chloride and the methylene chloride solution is dried and concentrated. The thus-obtained crude product is chromatographed on silica gel (solvent: methylene chloride/ether [10:1]). The 2-chloromethyl-4-tert-butyl-3-methylpyridine obtained is processed directly.
Reaction SMILES: C([O:3][C:4](=[O:30])/[C:5](=[N:25]/[O:26][CH2:27][CH:28]=[CH2:29])/[C:6]1[S:7][C:8]([O:11][CH2:12][CH2:13][O:14][C:15]2[CH:24]=[CH:23][C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH:16]=2)=[CH:9][CH:10]=1)C.[OH-].[Na+]>CO.O1CCCC1>[CH:16]1[C:17]2[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:23]=[CH:24][C:15]=1[O:14][CH2:13][CH2:12][O:11][C:8]1[S:7][C:6](/[C:5](=[N:25]\[O:26][CH2:27][CH:28]=[CH2:29])/[C:4]([OH:30])=[O:3])=[CH:10][CH:9]=1
Reactant: C=CCO/N=C(/C(=O)OCC)c1ccc(OCCOc2ccc3ccccc3c2)s1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: C=CCO/N=C(/C(=O)O)c1ccc(OCCOc2ccc3ccccc3c2)s1
Temperature: 50 °C
Yield: 59.8 %

Procedure:
As in Example 306, a solution of (Z)-5-[2-(2-naphthalenyloxy)ethoxy]-alpha-[(2propenyloxy)imino]-2-thiopheneacetic acid ethyl ester (0.102 g) in methanol (2 mL) and tetrahydrofuran (1 mL) was treated with 4N sodium hydroxide (0.5 mL) and the stirred mixture was heated at 50° C. for 30 minutes. After the normal work up, the product was crystallized from ethyl acetate-hexane to furnish 0.057 g of (Z)-5-[2-(2-naphthalenyloxy)ethoxy]-alpha-[(2-propenyloxy)imino]-2-thiopheneacetic acid, mp 114°-115° C.
Reaction SMILES: [NH2:1][C@@H:2]([CH3:18])[CH2:3][N:4]1[CH:8]=[CH:7][C:6]([C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[C:11]([Cl:17])[CH:10]=2)=[N:5]1.[CH3:19][C:20]1[O:24][N:23]=[C:22]([C:25](O)=[O:26])[N:21]=1>>[Cl:17][C:11]1[CH:10]=[C:9]([C:6]2[CH:7]=[CH:8][N:4]([CH2:3][C@@H:2]([NH:1][C:25]([C:22]3[N:21]=[C:20]([CH3:19])[O:24][N:23]=3)=[O:26])[CH3:18])[N:5]=2)[CH:16]=[CH:15][C:12]=1[C:13]#[N:14]
Reactant: Cc1nc(C(=O)O)no1
Reactant: C[C@H](N)Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1
Product: Cc1nc(C(=O)N[C@@H](C)Cn2ccc(-c3ccc(C#N)c(Cl)c3)n2)no1
Yield: 15.3 %

Procedure:
(S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (573 mg, 2.20 mmol) was coupled with 5-methyl-1,2,4-oxadiazole-3-carboxylic acid (338 mg, 2.64 mmol) using the method of Example 34(d). Crude product was purified by CombiFlash (column: silica, eluent: 0-100% EtOAc in heptane) to yield 125 mg (15%) of the title compound. 1H-NMR (400 MHz; d6-DMSO): δ 1.61 (d, 3H), 2.66 (s, 3H), 4.28-4.39 (m, 2H), 4.41-4.53 (m, 1H), 6.95 (d, 1H), 6.83 (d, 1H), 7.94 (dd, 1H), 7.99 (dd, 1H), 8.09 (m, 1H), 9.02 (d, 1H).
Reaction SMILES: [CH2:1]([NH2:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[Li]CCCC.C([O:21][C:22](=O)[C:23]1[CH:28]=[C:27]([C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([C:35]([F:38])([F:37])[F:36])[CH:30]=2)[C:26]([O:39][CH2:40][CH2:41][OH:42])=[C:25]([C:43]2[CH:48]=[CH:47][CH:46]=[C:45]([C:49]([F:52])([F:51])[F:50])[CH:44]=2)[CH:24]=1)C.Cl>C1COCC1>[CH2:1]([NH:13][C:22](=[O:21])[C:23]1[CH:24]=[C:25]([C:43]2[CH:48]=[CH:47][CH:46]=[C:45]([C:49]([F:51])([F:52])[F:50])[CH:44]=2)[C:26]([O:39][CH2:40][CH2:41][OH:42])=[C:27]([C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([C:35]([F:38])([F:37])[F:36])[CH:30]=2)[CH:28]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCCCN
Reactant: CCOC(=O)c1cc(-c2cccc(C(F)(F)F)c2)c(OCCO)c(-c2cccc(C(F)(F)F)c2)c1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCCCCCCCCCCNC(=O)c1cc(-c2cccc(C(F)(F)F)c2)c(OCCO)c(-c2cccc(C(F)(F)F)c2)c1
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 92.6 %

Procedure:
To a flame-dried flask containing dodecyl amine (0.278 g, 1.5 mmol) in THF (5 mL) cooled to −78° C. was added n-BuLi (titrated to 2.37 M in hexanes) (0.670 mL, 1.59 mmol) dropwise. The solution was stirred at −78° C. for 20 min. and then warmed to room temperature over 20 min. The reaction was then recooled to −40° C. and 3,5-bis-(m-trifluoromethylphenyl)4-(2-hydroxyethoxy)benzoic acid ethyl ester (0.215 g, 0.43 mmol) in THF (5 mL) was added. This mixture was allowed to warm to room, temperature over 20 min. The reaction mixture was then poured into 0.1 N HCl solution and extracted with EtOAc. The combined organic layers were washed with 2 N HCl solution (3×), dried over MgSO4 and concentrated in vacuo. The residue was purified by flash chromatography (30% EtOAc:hexane) to afford N-dodecyl-3,5-bis(m-trifluoromethylphenyl)-4-(2-hydroxyethoxy)benzamide (0.254 g, 93%) as a white solid. 1H NMR (CDCl3) δ7.90 (m, 2H); 7.82-7.76 (m, 4H); 7.65-7.56 (m, 4H); 6.22 (bt, 1H); 3.45 (dd, 2H); 3.30 (m, 4H); 1.60 (m, 2H); 1.25 (m, 18H); 0.84 (m, 3H).
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].C(OC([N:18]1[C:22]([NH2:23])=[CH:21][C:20]([CH2:24][CH2:25][C:26]2[CH:31]=[C:30]([O:32][CH3:33])[CH:29]=[C:28]([O:34][CH3:35])[CH:27]=2)=[N:19]1)=O)(C)(C)C.[F:36][CH:37]1[CH2:42][CH2:41][CH2:40][N:39]([CH2:43][C:44]2[CH:53]=[CH:52][C:47]([C:48](OC)=[O:49])=[CH:46][CH:45]=2)[CH2:38]1.C(=O)([O-])[O-]>C1COCC1.CC#N>[CH3:33][O:32][C:30]1[CH:31]=[C:26]([CH2:25][CH2:24][C:20]2[NH:19][N:18]=[C:22]([NH:23][C:48](=[O:49])[C:47]3[CH:46]=[CH:45][C:44]([CH2:43][N:39]4[CH2:40][CH2:41][CH2:42][CH:37]([F:36])[CH2:38]4)=[CH:53][CH:52]=3)[CH:21]=2)[CH:27]=[C:28]([O:34][CH3:35])[CH:29]=1
Reactant: COC(=O)c1ccc(CN2CCCC(F)C2)cc1
Reactant: COc1cc(CCc2cc(N)n(C(=O)OC(C)(C)C)n2)cc(OC)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC#N
Product: COc1cc(CCc2cc(NC(=O)c3ccc(CN4CCCC(F)C4)cc3)n[nH]2)cc(OC)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 15.9 %

Procedure:
A solution of NaHMDS in THF (1 M, 0.86 ml, 0.86 mmol, 1.5 eq) was added dropwise at ambient temperature to a mixture of tert-butyl-5-amino-3-[2-(3,5-dimethoxyphenyl)ethyl]pyrazole-1-carboxylate (200 mg, 0.58 mmol, 1 eq) and methyl 4-[(3-fluoro-1-piperidyl)methyl]benzoate (174 mg, 0.69 mmol, 1.2 eq) in THF (1 ml). The reaction mixture was stirred at ambient temperature for 2 h. The reaction mixture was then concentrated and the crude product was purified by reverse-phase prep. HPLC (acidic) using a gradient of acetonitrile in water containing 0.1% TFA. The clean fractions were taken and evaporated. The residue was dissolved in 3:1 DCM:MeCN mixture (4 ml) and MP-carbonate (2.74 mmol/g, 1 g, 2.74 mmol) was added. The mixture was stirred for 4 h, filtered and the filtrate evaporated to afford the title compound as a pale yellow gum (43 mg, 16% yield); 1H NMR (399.902 MHz, DMSO) δ□ 1.46-1.34 (2H, m), 1.82-1.61 (2H, m), 2.36-2.28 (2H, m), 2.66-2.56 (2H, m), 2.81 (4H, s), 3.50 (2H, s), 3.65 (6H, s), 4.66-4.47 (1H, m), 6.26-6.24 (1H, m), 6.35 (2H, d), 6.40 (1H, s), 7.32 (2H, d), 7.88 (2H, d), 10.51 (1H, br.s), 12.07 (1H, br.s). MS: m/z 467 (MH+)
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=1[CH2:16][NH2:17].I[CH2:19][C:20]([NH2:22])=[O:21].C(=O)(O)[O-].[Na+]>C(O)C>[Cl:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=1[CH2:16][NH:17][CH2:19][C:20]([NH2:22])=[O:21]
Reactant: NC(=O)CI
Reactant: NCc1ccc(F)cc1-c1ccccc1Cl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: NC(=O)CNCc1ccc(F)cc1-c1ccccc1Cl

Procedure:
A reaction vessel was charged with 5 g (18.4 mmole) of [(2-chlorophenyl)-4-fluorophenyl]methylamine hydrochloride, 3.4 g (18.4 mmole) of iodoacetamide, 3.2 g (3.8 mmole) of sodium bicarbonate and 150 ml of absolute ethanol. The resulting suspension was brought to reflux and held at reflux for 42 hours. Solvent was evaporated under reduced pressure and the residue was dissolved in water. The aqueous phase was extracted with dichloromethane, and then the organic phase was dried over potassium bicarbonate and evaporated under reduced pressure. The brown oil was solidified in a mixture of ethyl acetate and pentane, and then crystallized twice in a mixture of ethyl acetate and pentane.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)=[C:6]([N+:19]([O-:21])=[O:20])[C:5]=1[NH2:22])([O-])=O.[Cl-].[NH4+].CCN(C(C)C)C(C)C.Cl[C:35]([O:37][CH2:38][CH3:39])=[O:36]>CO.[Zn]>[NH2:22][C:5]1[C:6]([N+:19]([O-:21])=[O:20])=[C:7]([NH:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[CH:8]=[CH:9][C:4]=1[NH:1][C:35](=[O:36])[O:37][CH2:38][CH3:39]
Reactant: Nc1c([N+](=O)[O-])ccc(NCc2ccc(F)cc2)c1[N+](=O)[O-]
Reactant: CCOC(=O)Cl
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)Nc1ccc(NCc2ccc(F)cc2)c([N+](=O)[O-])c1N
Reaction time: 5 h

Procedure:
To a stirred solution of compound 9 (1.5 g, 5 mmol, 1.00 equiv) in methanol (7 mL) is added zinc powder (1.64 g, 25 mmol, 5.00 equiv) followed by ammonium chloride solution (1.33 g, 25 mmol, 5.00 equiv) dropwise. After 5 h, DIPEA (0.806 g, 6.25 mmol, 1.25 equiv) and ethyl chloroformate (0.54 g, 5 mmol, 1.00 equiv) are added to reaction mixture at 10° C. and the stirring continued till consumption of starting material (by TLC). The reaction mixture is diluted with water (30 mL) and extracted in ethyl acetate (75 mL), dried using brine and over MgSO4. After concentration the crude material obtained is purified to afford the title compound.
Reaction SMILES: [C:1]([N:4]1[CH2:10][CH2:9][C:8]2[CH:11]=[C:12]([O:19][CH3:20])[C:13]([S:15](Cl)(=[O:17])=[O:16])=[CH:14][C:7]=2[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[OH-].[NH4+:22]>>[C:1]([N:4]1[CH2:10][CH2:9][C:8]2[CH:11]=[C:12]([O:19][CH3:20])[C:13]([S:15](=[O:17])(=[O:16])[NH2:22])=[CH:14][C:7]=2[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: [NH4+]
Reactant: COc1cc2c(cc1S(=O)(=O)Cl)CCN(C(C)=O)CC2
Agent: [OH-]
Product: COc1cc2c(cc1S(N)(=O)=O)CCN(C(C)=O)CC2
Reaction time: 2 h

Procedure:
3-Acetyl-7-chlorosulfonyl-8-methoxy-2,3,4,5-tetrahydro-1H-3-benzazepine (3 g, 0.007 m) was treated with concentrated ammonium hydroxide (10 ml), stirred for 2 hours and filtered to give 3-acetyl-8-methoxy-7-sulfamoyl-2,3,4,5-tetrahydro-1H-3-benzazepine, m.p. 260°-263°.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:10]([CH2:16][C:17]([F:20])([F:19])[F:18])[C@H:11]([C:13]([OH:15])=O)[CH3:12])[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].[CH2:21]([NH2:23])[CH3:22]>>[Cl:1][C:2]1[CH:3]=[C:4]([N:10]([CH2:16][C:17]([F:20])([F:19])[F:18])[C@H:11]([C:13]([NH:23][CH2:21][CH3:22])=[O:15])[CH3:12])[CH:5]=[CH:6][C:7]=1[C:8]#[N:9]
Reactant: CCN
Reactant: C[C@@H](C(=O)O)N(CC(F)(F)F)c1ccc(C#N)c(Cl)c1
Product: CCNC(=O)[C@H](C)N(CC(F)(F)F)c1ccc(C#N)c(Cl)c1

Procedure:
Synthesized in a manner similar to example 3 using N-(3-chloro-4-cyanophenyl)-N-(2,2,2-trifluoroethyl)alanine and ethylamine: MS (ES) m/z 334 (M+1).
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@H:10]([CH:13]([CH3:15])[CH3:14])[CH2:11]O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C(=O)N([Br:42])C(=O)C1>C(Cl)Cl>[Br:42][CH2:11][C@@H:10]([CH:13]([CH3:15])[CH3:14])[CH2:9][O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)[C@H](CO)COCc1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)[C@H](CBr)COCc1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 61 %

Procedure:
To a solution of (R)-2-(benzyloxymethyl)-3-methylbutan-1-ol (54 g, 0.26 mol) in dry CH2Cl2 (2 L) at 0° C., Ph3P (88 g, 0.31 mol) and NBS (55.5 g, 0.31 mol) were added in portions. After stirring for 18 h at rt, the mixture was evaporated and the residue was purified by flash chromatography on silica gel to give (S)-((2-(bromomethyl)-3-methylbutoxy)methyl)benzene (43 g, 61%). 1H NMR (400 MHz, CDCl3): 0.94 (m, 6H), 1.71 (m, 1H), 1.85 (m, 1H), 3.48 (m, 1H), 3.57 (m, 1H), 3.62 (m, 1H), 3.68 (m, 1H), 4.52 (s, 2H), 7.31 (m, 5H)
Reaction SMILES: N1C=CC=CC=1.[Si:7]([O:24][CH2:25][C:26]1[C:27]([N:40]2[CH2:45][C@H:44]([CH3:46])[O:43][C@H:42]([CH3:47])[CH2:41]2)=[C:28]([F:39])[C:29]([F:38])=[C:30]([C:32](=O)[C:33]([F:36])([F:35])[F:34])[CH:31]=1)([C:20]([CH3:23])([CH3:22])[CH3:21])([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.Cl.[NH2:49][OH:50]>C(O)C>[Si:7]([O:24][CH2:25][C:26]1[C:27]([N:40]2[CH2:41][C@H:42]([CH3:47])[O:43][C@H:44]([CH3:46])[CH2:45]2)=[C:28]([F:39])[C:29]([F:38])=[C:30]([C:32](=[N:49][OH:50])[C:33]([F:36])([F:35])[F:34])[CH:31]=1)([C:20]([CH3:21])([CH3:23])[CH3:22])([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: NO
Reactant: C[C@@H]1CN(c2c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)cc(C(=O)C(F)(F)F)c(F)c2F)C[C@H](C)O1
Agent: Cl
Solvent: CCO
Solvent: c1ccncc1
Product: C[C@@H]1CN(c2c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)cc(C(=NO)C(F)(F)F)c(F)c2F)C[C@H](C)O1
Temperature: 80 °C
Yield: 100.1 %

Procedure:
Pyridine (2597 μl, 32.11 mmol) was added to a mixture of 1-(5-((tert-butyldiphenylsilyloxy)methyl)-4-((2R,6S)-2,6-dimethylmorpholino)-2,3-difluorophenyl)-2,2,2-trifluoroethanone (Intermediate 130, 1900 mg, 3.21 mmol) and hydroxylamine hydrochloride (223 mg, 3.21 mmol) in 50 ml of ethanol and the solution was heated at 80° C. for 40 hours. The reaction mixture was concentrated, diluted with water, and extracted with ethyl acetate. The organic phases were combined, dried (Na2SO4), and concentrated to give the crude title compound (1.95 g, 98%), which was used in the next step without further purification.