Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[CH3:11])=[CH:8][C:7]([C:12]([O:14]CC)=[O:13])=[CH:6][CH:5]=2.[OH-].[Na+]>C(O)C>[CH3:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[CH3:11])=[CH:8][C:7]([C:12]([OH:14])=[O:13])=[CH:6][CH:5]=2
Reactant: CCOC(=O)c1ccc2[nH]c(C)c(C)c2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1[nH]c2ccc(C(=O)O)cc2c1C
Temperature: 50 °C
Yield: 114.9 %

Procedure:
To a solution of ethyl 2,3-dimethyl-1H-indole-5-carboxylate (500 mg, 2.3 mmol) in ethanol (10 mL) was added a 5N NaOH solution (9.2 mL). The resulting solution was heated at 50° C. for 4 h, and then quenched carefully by addition of a 6N HCl solution (10 mL). The mixture was diluted with ethyl acetate, washed with a 0.5 N HCl solution and brine, dried on MgSO4, and concentrated to afford a yellow powder (500 mg, 100%). ESI-MS (m/z): 190 [MH]+
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]1[CH2:16][CH2:15][N:14]([C@H:17]2[CH2:22][CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19][C@H:18]2[C:30]([O:32][CH3:33])=[O:31])[C:13]1=[O:34])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl.C(OCC)(=O)C>[CH2:1]([O:8][C:9]([NH:11][C@H:12]1[CH2:16][CH2:15][N:14]([C@H:17]2[CH2:22][CH2:21][NH:20][CH2:19][C@H:18]2[C:30]([O:32][CH3:33])=[O:31])[C:13]1=[O:34])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@@H]1N1CC[C@H](NC(=O)OCc2ccccc2)C1=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COC(=O)[C@@H]1CNCC[C@@H]1N1CC[C@H](NC(=O)OCc2ccccc2)C1=O
Reaction time: 3 h
Yield: 73.1 %

Procedure:
(3R,4S)-1-tert-Butyl 3-methyl 4-((3S)-3-(benzyloxycarbonylamino)-2-oxopyrrolidin-1-yl)piperidine-1,3-dicarboxylate (7.45 g) was dissolved in methylene chloride (20 mL) at room temperature under nitrogen, then TFA (10 mL) was added. After 3 hours, stripped the reaction 3 times from methylene chloride (25 mL). Obtained an oil which was dissolved in ethyl acetate (25 mL) and rinsed 4 times with 1.000 N NaOH (25 mL). The ethyl acetate layer was dried over sodium sulfate and stripped to give (3R,4S)-methyl 4-((3S)-3-(benzyloxycarbonylamino)-2-oxopyrrolidin-1-yl)piperidine-3-carboxylate (4.30 g) as a white glass. Yield=73%. LCMS detects (M+H)+=376.1.
Reaction SMILES: Cl.[CH3:2][N:3]([CH2:5][CH2:6]Cl)[CH3:4].[S:8]([O-])([O-])(=O)=[S:9].[Na+].[Na+].Cl.[OH-].[Na+]>O>[CH3:2][N:3]([CH3:4])[CH2:5][CH2:6][S:9][S:8][CH2:6][CH2:5][N:3]([CH3:4])[CH3:2]
Reactant: CN(C)CCCl
Reactant: O=S([O-])([O-])=S
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CN(C)CCSSCCN(C)C
Yield: 113.8 %

Procedure:
In a 100 ml round-bottom flask, 8.5 g of N,N-dimethyl-2-chloroethylamine hydrochloride, 8.7 g of sodium thiosulfate and 50 ml of distilled water were charged and heated under reflux for 2 hours. 36% hydrochloric acid (5.1 g) was added, and the mixture was further heated under reflux for 1 hour. With cooling the mixture on an ice bath, 5.5 g of sodium hydroxide was slowly added to make the mixture alkaline, which was then subjected to extraction twice with 50 ml of ethyl acetate. After desiccating with anhydrous potassium carbonate, the solvent was removed by distillation and distilled under reduced pressure to give 7.0 g of bis(N,N-dimethyl-2-aminoethyl)disulfide, the precursor.
Reaction SMILES: [Na].[N+:2]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][S:12][C:13]2[N:17]=[C:16]([SH:18])[S:15][N:14]=2)=[CH:7][CH:6]=1)([O-:4])=[O:3].Br[CH2:20][CH2:21][C:22]([F:26])=[C:23]([F:25])[F:24]>C(O)C.C(Cl)Cl>[N+:2]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][S:12][C:13]2[N:17]=[C:16]([S:18][CH2:20][CH2:21][C:22]([F:26])=[C:23]([F:25])[F:24])[S:15][N:14]=2)=[CH:7][CH:6]=1)([O-:4])=[O:3]
Reactant: O=[N+]([O-])c1ccc(CSc2nsc(S)n2)cc1
Reactant: FC(F)=C(F)CCBr
Agent: [Na]
Solvent: ClCCl
Solvent: CCO
Product: O=[N+]([O-])c1ccc(CSc2nsc(SCCC(F)=C(F)F)n2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 62.8 %

Procedure:
A solution of 0.25 gram (0.011 mole) of sodium in 35 ml of ethanol was stirred and 2.7 grams (0.0095 mole) of 3-(4-nitrophenylmethylthio)-5-mercapto-1,2,4-thiadiazole was added. Upon completion of addition the reaction mixture was stirred at ambient temperature for one hour. The ethanol solvent was removed under reduced pressure. The residue was dissolved in 35 ml of methyl ethyl ketone and 1.6 grams (0.0085 mole) of 4-bromo-1,1,2-trifluoro-1-butene was added. Upon completion of addition the reaction mixture was stirred for 16 hours, then was concentrated under reduced pressure to a residue. The residue was dissolved in 50 ml of toluene and washed with 25 ml of water, two 25 ml portions of aqueous 5% sodium hydroxide solution, and 25 ml of water. The organic layer was dried with sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to yield a residual oil. The oil was dissolved in methylene chloride and passed through a column of silica gel. The eluate was concentrated under reduced pressure to yield 2.1 grams of 3-(4-nitrophenylmethylthio)-5-(3,4,4-trifluoro-3-butenylthio)-1,2,4-thiadiazole. The nmr spectrum was consistent with the proposed structure.
Reaction SMILES: CC1C=C(C)N([C:8]([CH:10]2[C:23]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[O:17][C:16]3[C:11]2=[CH:12][CH:13]=[CH:14][CH:15]=3)=[O:9])N=1.[CH:24]1([CH2:27][C:28]2[O:32][C:31]([NH2:33])=[N:30][N:29]=2)[CH2:26][CH2:25]1>>[CH:24]1([CH2:27][C:28]2[O:32][C:31]([NH:33][C:8]([CH:10]3[C:11]4[CH:12]=[CH:13][CH:14]=[CH:15][C:16]=4[O:17][C:18]4[C:19]3=[CH:20][CH:21]=[CH:22][CH:23]=4)=[O:9])=[N:30][N:29]=2)[CH2:26][CH2:25]1
Reactant: Cc1cc(C)n(C(=O)C2c3ccccc3Oc3ccccc32)n1
Reactant: Nc1nnc(CC2CC2)o1
Product: O=C(Nc1nnc(CC2CC2)o1)C1c2ccccc2Oc2ccccc21

Procedure:
The title compound, white solid, m.p. 234-236° C. and MS: m/e=347.1(M+H+) was prepared in accordance with the general method of example 48a from (3,5-dimethylpyrazol-1-yl)-(9H-xanthen-9-yl)-methanone and 5-cyclopropylmethyl-[1,3,4]oxadiazol-2-ylamine.
Reaction SMILES: NC1N=CN=C2N(CC(OCC)=O)N=C(C3C=CC(NS(C4C=CC=C(Cl)C=4Cl)(=O)=O)=C(F)C=3)C=12.[O:36]1[C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][C:39]=2[N:38]=[C:37]1[NH:45][C:46]1[CH:51]=[CH:50][C:49](B2OC(C)(C)C(C)(C)O2)=[CH:48][CH:47]=1.[NH2:61][C:62]1[N:67]=[CH:66][N:65]=[C:64]2[N:68]([C:72]3[C:77]([C:78]#[N:79])=[CH:76][CH:75]=[CH:74][N:73]=3)[N:69]=[C:70](I)[C:63]=12>>[NH2:61][C:62]1[N:67]=[CH:66][N:65]=[C:64]2[N:68]([C:72]3[C:77]([C:78]#[N:79])=[CH:76][CH:75]=[CH:74][N:73]=3)[N:69]=[C:70]([C:49]3[CH:48]=[CH:47][C:46]([NH:45][C:37]4[O:36][C:40]5[CH:41]=[CH:42][CH:43]=[CH:44][C:39]=5[N:38]=4)=[CH:51][CH:50]=3)[C:63]=12
Reactant: N#Cc1cccnc1-n1nc(I)c2c(N)ncnc21
Reactant: CC1(C)OB(c2ccc(Nc3nc4ccccc4o3)cc2)OC1(C)C
Agent: CCOC(=O)Cn1nc(-c2ccc(NS(=O)(=O)c3cccc(Cl)c3Cl)c(F)c2)c2c(N)ncnc21
Product: N#Cc1cccnc1-n1nc(-c2ccc(Nc3nc4ccccc4o3)cc2)c2c(N)ncnc21
Yield: 7.3 %

Procedure:
The procedure for Suzuki coupling, used in the preparation of ethyl 2-[4-amino-3-(4-{[(2,3-dichlorophenyl)sulfonyl]amino}-3-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]acetate, was used to couple N-(1,3-benzoxazol-2-yl)-N-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]amine (0.052 g, 0.155 mmol) with 2-(4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-3-pyridyl cyanide (0.045 g, 0.124 mmol). Purification by preparative HPLC (25 to 100% acetonitrile in 0.1 M aqueous ammonium acetate over 20 min at 21 mL/min using an 8μ Hypersil HS C18, 250×21 mm column, Rt 10.1-11.2 min) afforded 2-{4-amino-3-[4-(1,3-benzoxazol-2-ylamino)phenyl]-1H-pyrazolo[3,4-d]pyrimidin-1-yl}-3-pyridyl cyanide as a yellow powder (0.004 g, 0.009 mmol): RP-HPLC (25 to 100% acetonitrile in 0.1 M aqueous ammonium acetate over 10 min at 1 mL/min using a 5μ Hypersil HS C18, 250×4.6 mm column) Rt 8.55 min; MS (MH)+ 446.
Reaction SMILES: [CH2:1]([C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[C:5]([O:23][CH2:24][O:25][CH3:26])=[C:6]([O:21][CH3:22])[CH:7]=[C:8]2/[CH:13]=[C:14](\[CH3:20])/[C:15]([O:17]CC)=[O:16])[CH3:2].[OH-].[K+].Cl>C(O)C>[CH2:1]([C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[C:5]([O:23][CH2:24][O:25][CH3:26])=[C:6]([O:21][CH3:22])[CH:7]=[C:8]2/[CH:13]=[C:14](\[CH3:20])/[C:15]([OH:17])=[O:16])[CH3:2]
Reactant: CCOC(=O)/C(C)=C/c1cc(OC)c(OCOC)c2c(CC)cccc12
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CCc1cccc2c(/C=C(\C)C(=O)O)cc(OC)c(OCOC)c12
Yield: 89.1 %

Procedure:
28 g of ethyl (E)-3-(5-ethyl-3-methoxy-4-methoxymethoxy-1-naphthyl)-2-methylpropenoate was dissolved in 240 ml of ethanol and a potassium hydroxide aqueous solution (potassium hydroxide 28 g/water 55 ml) was added, followed by refluxing for 1 hour. 280 ml of 2N hydrochloric acid was added to the reaction mixture at ice bath temperature to make it acidic, followed by extraction with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and evaporated. Diisopropyl ether was added to the resultant residue and the resultant crystals were filtered to obtain 23 g of the titled compound as pale yellow crystals.
Reaction SMILES: C[O-].[Na+].C([O:7][C@H:8]1[C@@H:17]([O:18]C(=O)C)[C@H:16]([O:22]C(=O)C)[C@@H:15]([CH2:26][O:27]C(=O)C)[O:14][C@@H:9]1[O:10][CH2:11][CH2:12][Br:13])(=O)C>CO>[O:10]([CH2:11][CH2:12][Br:13])[C@H:9]1[O:14][C@H:15]([CH2:26][OH:27])[C@@H:16]([OH:22])[C@H:17]([OH:18])[C@@H:8]1[OH:7]
Reactant: CC(=O)OC[C@H]1O[C@H](OCCBr)[C@@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: OC[C@H]1O[C@H](OCCBr)[C@@H](O)[C@@H](O)[C@@H]1O
Reaction time: 3 h

Procedure:
A solution of NaOMe (0.143 M, 0.7 mL) was added to a suspension of 4i (See FIG. 7) (1 g, 2.2 mmol) in MeOH (10 mL) under N2. After 3 hours, the resulting solution was passed through a Dowex 50W(H+) plug (2×1 cm, eluant MeOH) and the solvent removed. The residue was purified by flash chromatography (MeOH:EtOAc, 2:25) to give 2-bromoethyl α-D-mannopyranoside 4d (See FIG. 7) (The use of 4d as a reactant has been described previously, although no details of preparation or characterization were given. (U.S. Pat. No. 4,918,009 to Nilsson, which is hereby incorporated by reference)) (606 mg, 96%) as a white foam; [α]26D=+50.7 (c 0.91, H2O); IR (KBr) 3417 cm−1 (OH); 1H NMR (500 MHz. D2O. COSY) δ 3.38-3.44 (m, 3H, H-4, —CH2Br), 3.50-3.55 (m, 2H, H-5, H-6), 3.60 (dd, J2,3 3.5 Hz, J3,4 9.7 Hz, 1H, H-3), 3.66 (dd, J5,6′ 4.6 Hz, J6,6′ 11.2 Hz, 1H, H-6′), 3.68 (ddd, J 4.6 Hz, J 5.4 Hz, J 11.7 Hz, 1H, —OCHH′—), 3.76 (dd, J1,2 1.8 Hz, J2,3 3.5 Hz, 1H, H-2), 3.81 (ddd, J 5.1 Hz, J 6.5 Hz, J 11.7, 1H, —OCHH′—), 4.71 (d, J1,2 1.8 Hz, 1H, H-1); —C NMR (100 MHz, D2O) δ 32.1 (—CH2Br), 61.7 (—OCH2—), 67.5, 68.4, 70.7, 71.3, 73.8 (C-2, C-3, C-4, C-5, C-6), 100.5 (C-1); HRMS m/z (FAB+): Found 308.9985 (M+Na+); C8H15O679BrNa requires 308.9950. NaSSO2CH3 (150 mg, 1.12 mmol) was added to a solution of 4d (See FIG. 7) (245 mg, 0.85 mmol) in DMF (10 mL) under N2 and warmed to 50° C. After 16 hours, the solution was cooled and the solvent removed. The residue was purified by flash chromatography (MeOH:EtOAc, 1:9) to give 1d (See FIG. 7) (217 mg, 80%) as a hygroscopic foam; [α]29D=+58.0 (c 1.34, H2O); IR (KBr) 3441 cm−1 (OH), 1314, 1132 cm−1 (S—SO2); 1H NMR (500 MHz, D2O) δ 3.31 (t, J 5.8 Hz, 2H, —CH2S—), 3.35 (s, 3H, CH3SO2—), 3.45 (t, J 9.6 Hz, 1H, H-4), 3.49 (ddd, J4,5 9.8 Hz, J5,6 5.8 Hz, J5,6′ 1.9 Hz, 1H, H-5), 3.55 (dd, J5,6 5.8 Hz, J6,6′ 12.1 Hz, 1H, H-6), 3.60 (dd, J2,3 3.4 Hz, J3,4 9.0 Hz, 1H, H-3), 3.66 (dt, Jd 10.7 Hz, Jt 5.7 Hz, 1H, —OCHH′—), 3.69 (dd, J5,6 1.9 Hz, J6,6′ 12.1 Hz, 1H, H-6′), 3.77 (dd, J1,2 1.6 Hz, J2,3 3.4 Hz, 1H, H-2), 3.83 (dt, Jd 11.0 Hz, Jt 5.9 Hz, 1H, —OCHH′—), 4.72 (d, J1,2 1.6 Hz, 1H, H-1); 13C NMR (125 MHz, D2O) δ 36.7 (—CH2S—), 50.7 (CH3SO2—), 61.9 (—OCH2—), 66.7, 67.7, 70.9, 71.5, 74.0 (C-2, C-3, C-4, C-5, C-6), 100.8 (C-1); HRMS m/z (FAB+): Found 319.0528 (M+H−); C9H19O8S2 requires 319.0521.
Reaction SMILES: ClS(O)(=O)=O.[NH2:6][C:7]1[N:11]=[CH:10][NH:9][N:8]=1.[C:12]([CH:16]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[C:17]#[N:18])(=O)[CH2:13][CH3:14]>O.CC1C=CC=CC=1C>[CH2:13]([C:12]1[C:16]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])=[C:17]([NH2:18])[N:8]2[N:9]=[CH:10][N:11]=[C:7]2[N:6]=1)[CH3:14]
Reactant: Nc1nc[nH]n1
Reactant: CCCCCCCCC(C#N)C(=O)CC
Agent: O=S(=O)(O)Cl
Solvent: Cc1ccccc1C
Solvent: O
Product: CCCCCCCCc1c(CC)nc2ncnn2c1N
Temperature: 140 °C
Yield: 83 %

Procedure:
In a 2.5 l jacketed vessel fitted with condenser and water separator, 737 g of o-xylene was initially charged, and 39.5 g of chlorosulfonic acid was added. 191.2 g of 3-amino-1,2,4-triazole and 1254 g of a solution of 2-propionyldecanonitrile (37.7% by weight in o-xylene) were added, and the mixture was heated to reflux. The mixture was stirred under reflux for 12 hours, and the water of reaction formed was removed via a phase separator. Once no more water was separated off, the mixture was cooled to 140° C. and 59.4 g of triethylamine were added. On further cooling, the product precipitated in the form of colorless crystals. At a temperature 105° C., 152.8 g of methanol were added. The mixture was cooled further to 20° C., and the solid formed was separated off. The filtercake was washed with a mixture of 850 g of methanol and 119 g of water and then dried under reduced pressure. This gave 525.5 g of colorless crystals having a content of 98.3% a/a (HPLC). The title compound was obtained as a mixture of two modifications having melting points of 199° C. and 201° C., respectively. Yield: 83.0%.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:7]([I:10])=[CH:6][C:3]=1[C:4]#[N:5].[CH3:11][C:12]1[N:13]=[CH:14][NH:15][CH:16]=1.C(=O)([O-])[O-].[K+].[K+].IC1C=CC(N2C(C)=CN=C2)=C(C=1)C#N>>[I:10][C:7]1[CH:8]=[CH:9][C:2]([N:15]2[CH:16]=[C:12]([CH3:11])[N:13]=[CH:14]2)=[C:3]([CH:6]=1)[C:4]#[N:5]
Reactant: N#Cc1cc(I)ccc1F
Reactant: Cc1c[nH]cn1
Agent: Cc1cncn1-c1ccc(I)cc1C#N
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1cn(-c2ccc(I)cc2C#N)cn1

Procedure:
As described for example 84a, 2-fluoro-5-iodo-benzonitrile was reacted with 4-methylimidazole and potassium carbonate for 20 h at 90° C. Aqueous workup afforded a 1.9:1 mixture of the title compound and its regioisomer [5-iodo-2-(5-methyl-imidazol-1-yl)-benzonitrile] as a white solid (yield: 92%). MS: m/e=310.1 [M+H]+.
Reaction SMILES: OC(C(F)(F)F)=O.[NH2:8][C:9]1[NH:13][C:12](=[C:14]2[C:27]3[C:26]4[C:21](=[C:22]([N+:28]([O-])=O)[CH:23]=[CH:24][CH:25]=4)[NH:20][C:19]=3[C:18](=[O:31])[NH:17][CH2:16][CH2:15]2)[C:11](=[O:32])[N:10]=1>CO.[Pd]>[NH2:28][C:22]1[CH:23]=[CH:24][CH:25]=[C:26]2[C:21]=1[NH:20][C:19]1[C:18](=[O:31])[NH:17][CH2:16][CH2:15][C:14](=[C:12]3[C:11](=[O:32])[N:10]=[C:9]([NH2:8])[NH:13]3)[C:27]2=1
Reactant: NC1=NC(=O)C(=C2CCNC(=O)c3[nH]c4c([N+](=O)[O-])cccc4c32)N1
Agent: [Pd]
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: NC1=NC(=O)C(=C2CCNC(=O)c3[nH]c4c(N)cccc4c32)N1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 5-(2-amino-5-oxo-3,5-dihydro-imidazol-4-ylidene)-9-nitro-3,4,5,10-tetrahydro-2H-azepino[3,4-b]indol-1-one TFA salt (4 mg, 8.8 μmol) in MeOH (3 mL) is added 10% Pd/C (10 mg). The mixture is stirred at room temperature under hydrogen atmosphere overnight and then the catalyst is removed by filtration. The solution is concentrated and the residue purified by HPLC (C18 column, eluted with CH3CN/H2O with 0.05% TFA) to give 9-amino-5-(2-amino-5-oxo-3,5-dihydro-imidazol-4-ylidene)-3,4,5,10-tetrahydro-2H-azepino[3,4-b]indol-1-one; 1H NMR (MeOD-d4) δ 3.48-3.53 (m, 4H), 7.358 (d, 1H, J=6.0 Hz), 7.362 (d, 1H, J=3.2 Hz), 7.63 (dd, 1H, J1=3.2 Hz, J2=6.0 Hz); m/z [M++1] 311.1.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH2:10][CH2:11][C:12]([C:14]2[S:21][C:20]([CH3:22])=[C:19]3[C:15]=2[CH2:16][C@H:17]2[C:23]([CH3:25])([CH3:24])[C@H:18]23)=[O:13])[CH:5]=[C:6]([CH3:9])[C:7]=1[OH:8].[CH2:26]([CH:28]1[O:30][CH2:29]1)Cl>C(O)(C)C.[OH-].[Na+].C(OCC)C>[CH3:9][C:6]1[CH:5]=[C:4]([CH2:10][CH2:11][C:12]([C:14]2[S:21][C:20]([CH3:22])=[C:19]3[C:15]=2[CH2:16][C@H:17]2[C:23]([CH3:25])([CH3:24])[C@H:18]23)=[O:13])[CH:3]=[C:2]([CH3:1])[C:7]=1[O:8][CH2:26][CH:28]1[CH2:29][O:30]1
Reactant: Cc1cc(CCC(=O)c2sc(C)c3c2C[C@@H]2[C@H]3C2(C)C)cc(C)c1O
Reactant: ClCC1CO1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: CC(C)O
Product: Cc1cc(CCC(=O)c2sc(C)c3c2C[C@@H]2[C@H]3C2(C)C)cc(C)c1OCC1CO1
Temperature: 25 °C
Reaction time: 18 h
Yield: 74.3 %

Procedure:
A solution of 3-(3,5-dimethyl-4-hydroxy-phenyl)-1-((1aS,5aR)-1,1,2-trimethyl-1,1a,5,5a-tetrahydro-3-thia-cyclopropa[a]pentalen-4-yl)-propan-1-one (2.00 g, 5.64 mmol, Intermediate 10) in isopropanol (20 mL) and 3 N aq. NaOH (12 mL) is treated with epichlorohydrine (2.12 g, 16.92 mmol). The dark red reaction mixture is stirred at rt for 18 h. The mixture is diluted with diethyl ether (250 mL) and washed with sat. aq. NaHCO3 followed by water. The organic layer is dried over MgSO4 and evaporated. The crude product is purified by CC on silica gel eluting with heptane:EA 4:1 to give 3-(3,5-dimethyl-4-oxiranylmethoxy-phenyl)-1-((1aS,5aR)-1,1,2-trimethyl-1,1a,5,5a-tetrahydro-3-thia-cyclopropa[a]pentalen-4-yl)-propan-1-one (1.72 g, mixture of diastereoisomers) as a pale yellow oil; LC-MS: tR=1.16 min, [M+1]+=411.17; 1H NMR (CDCl3): δ 6.85 (s, 2H), 4.04-3.97 (m, 1H), 3.77-3.69 (s, 1H), 3.52-3.44 and 3.38-3.32 (2m, 1H), 3.05-2.84 (m, 6H), 2.79 (d, J=18.8 Hz, 1H), 2.72-2.68 (m, 1H), 2.38 (s, 3H), 2.26 (s, 6H), 1.92-1.86 (m, 2H), 1.11 (s, 3H), 0.71 (s, 3H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:12])[C@@H:7]1[CH2:11][CH2:10][CH2:9][NH:8]1)([CH3:4])([CH3:3])[CH3:2].[CH3:13][N:14]([CH2:57][CH:58]=O)[C:15](=[O:56])[C:16]1[CH:55]=[CH:54][CH:53]=[C:18]([C:19]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([N:28]3[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]3)=[CH:24][C:23]=2[C:34]2[CH:39]=[C:38]([C:40](=[O:52])[NH:41][C@@H:42]3[C:51]4[C:46](=[CH:47][CH:48]=[CH:49][CH:50]=4)[CH2:45][CH2:44][CH2:43]3)[CH:37]=[CH:36][N:35]=2)=[O:20])[CH:17]=1.CC(O)=O.C([BH3-])#N.[Na+]>C(O)C>[CH3:13][N:14]([CH2:57][CH2:58][N:8]1[CH2:9][CH2:10][CH2:11][C@H:7]1[C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:12])[C:15](=[O:56])[C:16]1[CH:55]=[CH:54][CH:53]=[C:18]([C:19](=[O:20])[NH:21][C:22]2[CH:27]=[CH:26][C:25]([N:28]3[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]3)=[CH:24][C:23]=2[C:34]2[CH:39]=[C:38]([C:40](=[O:52])[NH:41][C@@H:42]3[C:51]4[C:46](=[CH:47][CH:48]=[CH:49][CH:50]=4)[CH2:45][CH2:44][CH2:43]3)[CH:37]=[CH:36][N:35]=2)[CH:17]=1
Reactant: CN(CC=O)C(=O)c1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2-c2cc(C(=O)N[C@H]3CCCc4ccccc43)ccn2)c1
Reactant: CC(C)(C)OC(=O)[C@@H]1CCCN1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Product: CN(CCN1CCC[C@H]1C(=O)OC(C)(C)C)C(=O)c1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2-c2cc(C(=O)N[C@H]3CCCc4ccccc43)ccn2)c1
Temperature: 25 °C
Reaction time: 0.42 h
Yield: 47.8 %

Procedure:
To a solution of L-proline-t-butyl ester (0.096 mmol, 16 mg) in ethanol (0.2 mL) were added (S)—N1-methyl-N1-(2-oxoethyl)-N3-(4-(piperidin-1-yl)-2-(4-((1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl)pyridin-2-yl)phenyl)isophthalamide (0.032 mmol, 20 mg) and HOAc (0.064 mmol, 4 mg). The mixture was stirred at room temperature for 25 minutes, and then sodium cyanoborohydride (0.16 mmol, 10 mg) was added. The mixture was stirred for an additional 20 minutes and quenched with water. The yellow solid was collected via filtration and was purified by prep HPLC to give a yellow solid (12 mg, 37%). MS (ES, m/z): 786.1 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[CH:4]([C:9]1[CH:10]=[C:11]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=2)[CH:12]=[C:13]([OH:15])[CH:14]=1)[CH2:5][CH:6]([CH3:8])[CH3:7].[F:27][C:28]([F:39])([F:38])[C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1>>[CH3:1][O:2][C:3](=[O:26])[CH:4]([C:9]1[CH:10]=[C:11]([C:16]2[CH:17]=[CH:18][C:19]([C:22]([F:23])([F:25])[F:24])=[CH:20][CH:21]=2)[CH:12]=[C:13]([O:15][C:32]2[CH:33]=[CH:34][C:29]([C:28]([F:39])([F:38])[F:27])=[CH:30][CH:31]=2)[CH:14]=1)[CH2:5][CH:6]([CH3:8])[CH3:7]
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: COC(=O)C(CC(C)C)c1cc(O)cc(-c2ccc(C(F)(F)F)cc2)c1
Product: COC(=O)C(CC(C)C)c1cc(Oc2ccc(C(F)(F)F)cc2)cc(-c2ccc(C(F)(F)F)cc2)c1
Yield: 43 %

Procedure:
The title compound was prepared in 43% yield from 2-(5-hydroxy-4′-trifluoromethyl-biphenyl-3-yl)-4-methyl-pentanoic acid methyl ester and 4-trifluoromethylphenylboronic acid under the conditions described in Example 15, step (g).
Reaction SMILES: O[CH2:2][CH2:3][CH2:4][NH:5][C:6]1[CH:11]=[CH:10][C:9]([C:12](=[O:25])[C:13]([N:22]([CH3:24])[CH3:23])([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH3:14])=[CH:8][CH:7]=1.N1C=CN=C1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[I:50]I>C(Cl)Cl>[I:50][CH2:2][CH2:3][CH2:4][NH:5][C:6]1[CH:11]=[CH:10][C:9]([C:12](=[O:25])[C:13]([N:22]([CH3:24])[CH3:23])([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH3:14])=[CH:8][CH:7]=1
Reactant: CN(C)C(C)(Cc1ccccc1)C(=O)c1ccc(NCCCO)cc1
Reactant: II
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CN(C)C(C)(Cc1ccccc1)C(=O)c1ccc(NCCCI)cc1
Temperature: 20 °C
Reaction time: 1 h

Procedure:
6.7 g (0.02 mol) of 1-[4-(3-Hydroxypropylamino)phenyl]-2-dimethylamino-2-benzyl-propan-1-one, 3.35 g (0.05 mol) of imidazole and 12.9 g (0.05 mol) of triphenyl phosphine are dissolved in 50 ml of methylene chloride. To the solution are added 10 g (0.039 mol) of iodine and stirred at room temperature (about 20° C.) for 1 hour. 100 ml of methylene chloride is added to the reaction mixture and washed with aqueous solution of sodium sulfite and water, and dried over MgSO4. After distilling off the methylene chloride, the residue is purified by means of column chromatography on silica gel with ethyl acetate-hexane (1:3) as an eluent, and an oily product is obtained. The structure is confirmed by the 1H-NMR spectrum (CDCl3): δ [ppm]: 1.14 (s, 3H), 2.14 (m, 2H), 2.33 (s, 6H), 2.96 (d, 1H), 3.29 (t, 2H), 3.35-3.40 (m, 2H), 3.42 (d, 1H), 4.21 (br, 1H), 6.56 (d, 2H), 6.89-6.91 (m, 2H), 7.10-7.12 (m, 3H), 8.46 (d, 2H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[NH:10][S:9]1(=[O:18])=[O:17].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[CH2:39][CH2:40][N:41]1[CH2:46][CH2:45][N:44]([C:47]([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[O:48])[CH2:43][CH2:42]1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>O1CCCC1>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]([CH2:39][CH2:40][N:41]2[CH2:46][CH2:45][N:44]([C:47]([O:49][C:50]([CH3:51])([CH3:53])[CH3:52])=[O:48])[CH2:43][CH2:42]2)[S:9]1(=[O:18])=[O:17]
Reactant: Cc1ccccc1N1c2ccccc2NS1(=O)=O
Reactant: CC(C)(C)OC(=O)N1CCN(CCO)CC1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1ccccc1N1c2ccccc2N(CCN2CCN(C(=O)OC(C)(C)C)CC2)S1(=O)=O
Yield: 68.7 %

Procedure:
In an analogous manner as general procedure II, step 1, a solution of 1-(2-methylphenyl)-1,3-dihydro-2,1,3-benzothiadiazole2,2-dioxide (0.2 g, 0.77 mmol) in tetrahydrofuran (10 mL) was cooled to 0° C., treated with triphenylphosphine (0.3 g, 1.2 mmol), tert-Butyl 4-(2-hydroxyethyl)piperazine-1-carboxylate (0.36 g, 1.54 mmol) were added followed by diisopropylazodicarboxylate (0.23 mL, 1.2 mmol to provide tert-butyl 4-{2-[3-(2-methylphenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]ethyl}piperazine-1-carboxylate (0.25 g, 69%) as a white foam. HPLC purity 100.0% at 210-370 nm, 10.7 min.; Xterra RP18, 3.5 u, 150×4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for 10 min, hold 4 min. HRMS: calcd for C24H32N4O4S+H+, 473.22170; found (ESI, [M+H]+Obs'd), 473.2229;