Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N12CCCN=C1CCCCC2.Cl[C:13]1[C:14]2[CH:26]=[CH:25][C:24]([O:27][CH2:28][C:29]3[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=3)=[CH:23][C:15]=2[S:16][C:17]=1[C:18]([O:20][CH2:21][CH3:22])=[O:19].[C:35]1([SH:41])[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>CN(C)C=O>[C:35]1([S:41][C:13]2[C:14]3[CH:26]=[CH:25][C:24]([O:27][CH2:28][C:29]4[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=4)=[CH:23][C:15]=3[S:16][C:17]=2[C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: Sc1ccccc1
Reactant: CCOC(=O)c1sc2cc(OCc3cccnc3)ccc2c1Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: CCOC(=O)c1sc2cc(OCc3cccnc3)ccc2c1Sc1ccccc1
Temperature: 60 °C
Yield: 78.6 %

Procedure:
1,8-Diazabicyclo[5.4.0]undec-7-ene (DBU--1.46 ml, 9.5 mmol) was added to a mixture of ethyl 3-chloro-6-(3-pyridylmethoxy)benzo[b]thiophene-2-carboxylate (Preparation 4, 3.0 g, 8.6 mmol) and thiophenol (1.76 ml, 17.2 mmol) in dimethylformamide (15 ml) under a nitrogen atmosphere. The solution was heated to 60° C. for 5 hours and then partitioned between diethyl ether and water. The organics were separated and washed with water, dried (magnesium sulfate) and evaporated under reduced pressure. The residue was flash chromatographed on silica gel using diethyl ether, and then ethyl acetate, as eluant. The isolated product was crystallised from diethyl ether and hexane to give the title compound as a colourless solid (2.85 g).
Reaction SMILES: C[O:2][C:3]1[CH2:8][CH:7]=[C:6]([C:9]([OH:12])([CH3:11])[CH3:10])[CH2:5][CH:4]=1.[CH3:13][C:14]([C:22]1[CH:23]=[C:24](O)[CH:25]=[C:26]([CH:28]=1)[OH:27])=[C:15]([CH3:21])[CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]>ClCCl>[OH:27][C:26]1[C:25]2[C@H:5]3[CH2:4][C:3](=[O:2])[CH2:8][CH2:7][C@H:6]3[C:9]([CH3:11])([CH3:10])[O:12][C:24]=2[CH:23]=[C:22]([C:14]([CH3:13])=[C:15]([CH3:21])[CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH:28]=1
Reactant: CCCCCC(C)=C(C)c1cc(O)cc(O)c1
Reactant: COC1=CCC(C(C)(C)O)=CC1
Solvent: ClCCl
Product: CCCCCC(C)=C(C)c1cc(O)c2c(c1)OC(C)(C)[C@@H]1CCC(=O)C[C@H]21
Temperature: 24 °C
Reaction time: 4 h

Procedure:
A solution of 1-methoxy-4-(1-hydroxy-1-methylethyl)-1,4-cyclohexadiene in dichloromethane containing 5-(1,2-dimethyl-1-heptenyl)resorcinol was stirred at 0° C. while stannic chloride was added in one portion. The reaction mixture was then stirred for four hours at 24° C., and then washed with hydrochloric acid and water. The solution was dried and the solvent was removed by evaporation under reduced pressure to provide dl-cis-1-hydroxy-3-(1,2-dimethyl-1-heptenyl)-6,6-dimethyl-6,6a,7,8,10,10a-hexahydro-9H-dibenzo[b,d]pyran-9-one.
Reaction SMILES: [C:1]([OH:10])(=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][C:6]([OH:8])=[O:7].[CH2:11]1[O:13][CH2:12]1.[CH2:14]([C:18](C)=[O:19])C(C)C>>[OH:19][CH2:18][CH2:14][O:7][C:6](=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2][C:1]([O:10][CH2:12][CH2:11][OH:13])=[O:9]
Reactant: O=C(O)CCCCC(=O)O
Reactant: CC(=O)CC(C)C
Reactant: C1CO1
Product: O=C(CCCCC(=O)OCCO)OCCO
Reaction time: 1 h
Yield: 60 %

Procedure:
Adipic acid (36.5g, 0.25 mole) and the catalyst of Example II (0.4g) in methyl isobutyl ketone (250 ml) were heated at 160° C and subsequently ethylene oxide (24.23g, 0.55 mole) was added; the temperature was kept at 160° C. After 60 minutes, the pressure dropped from 103 psi to 57 psi. After solvent evaporation, the crude product (60.4g) was distilled under vacuum; a light yellow material (35.0g) was obtained boiling at 202°-203° C at 1 mm pressure in 60.0% yield, having a refractive index of 1.4619 at 25° C. The infrared spectrum was consistent with that expected for the ester (3450 cm-1 (OH), 2970 cm-1 (CH2), 1730 cm-1 (C=O), and 1180 cm-1 (C-O)). Anal. Calcd. for C10H18O6 : C, 51.28; H, 7.69; O, 41.03, Found: C, 50.80; H, 7.76; Molecular weight by hydroxy number: Theory: 234. Found: 234.
Reaction SMILES: [CH:1]1([C:4]2[N:9]3[N:10]=[CH:11][C:12]([C:13]([OH:15])=O)=[C:8]3[N:7]=[C:6]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)[CH:5]=2)[CH2:3][CH2:2]1.O[NH:27][C:28](=[NH:39])[C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([S:35](=[O:38])(=[O:37])[NH2:36])[CH:30]=1>>[CH:1]1([C:4]2[N:9]3[N:10]=[CH:11][C:12]([C:13]4[O:15][N:39]=[C:28]([C:29]5[CH:30]=[C:31]([S:35]([NH2:36])(=[O:37])=[O:38])[CH:32]=[CH:33][CH:34]=5)[N:27]=4)=[C:8]3[N:7]=[C:6]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)[CH:5]=2)[CH2:2][CH2:3]1
Reactant: O=C(O)c1cnn2c(C3CC3)cc(-c3ccc(C(F)(F)F)cc3)nc12
Reactant: N=C(NO)c1cccc(S(N)(=O)=O)c1
Product: NS(=O)(=O)c1cccc(-c2noc(-c3cnn4c(C5CC5)cc(-c5ccc(C(F)(F)F)cc5)nc34)n2)c1

Procedure:
The title compound was prepared from 7-cyclopropyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.29) (174 mg, 0.5 mmol) and N-hydroxy-3-sulfamoyl-benzamidine [CAS-No. 9000-88-7] (161 mg, 0.75 mmol) according to general procedure II. Obtained after purification by column chromatography (dichloromethane/MeOH/NH4OH) and crystallization (ethyl acetate/MeOH/hexane) as an off-white solid (142 mg, 54%). MS (EI) 526.1 [(M)+]; mp 277° C.
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]#[C:11][Si:12]([CH3:15])([CH3:14])[CH3:13])=[CH:6][CH:5]=1.C(N(CC)CC)C.Cl[C:24]([O:26][CH3:27])=[O:25].O>C(Cl)Cl>[CH3:27][O:26][C:24](=[O:25])[N:2]([CH3:1])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]#[C:11][Si:12]([CH3:13])([CH3:15])[CH3:14])=[CH:6][CH:5]=1
Reactant: CNCc1ccc(C#C[Si](C)(C)C)cc1
Reactant: COC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: COC(=O)N(C)Cc1ccc(C#C[Si](C)(C)C)cc1
Temperature: 5 °C
Reaction time: 12 h

Procedure:
Amine 3 (90.0 g, ˜0.41 mol) was dissolved in methylene chloride (810 ml). Triethylamine (66.6 g, 0.66 mol) was added and the solution was cooled to 5° C. Methyl chloroformate (47.0 g, 0.50 mol) in methylene chloride (100 ml) was then added slowly and the reaction temperature was maintained between 10° C. and 14° C. After addition was complete, the reaction solution was stirred at room temperature for 12 hours. Water (540 ml) was added. Aqueous phase was separated. Organic phase was concentrated to dryness to afford crude compound 4. The crude product was used in the next step without further purification. 1H NMR (300 MHz, CDCl3) δ 0.279 (s, 9H), 2.86 (d, br, 3H), 3.774 (s, 3H), 4.484 (s, br, 2H), 7.190 (s, br, 2H), 7.46 (d, 2H, J=8.10 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]([N:11]2[C:20]3[C:15](=[CH:16][C:17]([OH:21])=[CH:18][CH:19]=3)[CH2:14][CH2:13][CH2:12]2)=[O:10])=[CH:4][CH:3]=1.CN(C=O)C.[Br:27][CH:28]=[CH:29][CH2:30][CH2:31]Br.Cl>CCOC(C)=O.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]([N:11]2[C:20]3[C:15](=[CH:16][C:17]([O:21][CH2:31][CH:30]=[CH:29][CH2:28][Br:27])=[CH:18][CH:19]=3)[CH2:14][CH2:13][CH2:12]2)=[O:10])=[CH:4][CH:3]=1
Reactant: O=C(Oc1ccc(Cl)cc1)N1CCCc2cc(O)ccc21
Reactant: BrC=CCCBr
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(Oc1ccc(Cl)cc1)N1CCCc2cc(OCC=CCBr)ccc21
Temperature: 50 °C
Reaction time: 1 h
Yield: 57.2 %

Procedure:
To 304 mg (1 mmol) 6-Hydroxy-3,4-dihydro-2H-quinoline-1-carboxylic acid 4-chloro-phenyl ester in 4 ml DMF 420 mg (3 mmol) K2CO3 (powdered) and 416 mg (2 mmol) 1,4-dibromobutene were added. The mixture was stirred at 50° C. for 1 h, diluted with EtOAc and water. 2M HCl was added and the inorganic phase was extracted with EtOAc. The combined organic phases were washed with water and dried over Na2SO4. The crude product was purified by column chromatography on silica gel with hexane/EtOAc 9:1 to 4:1 to yield 250 mg (46%) 6-(4-Bromo-but-2-enyloxy)-3,4-dihydro-2H-quinoline-1-carboxylic acid 4-chloro-phenyl ester as colorless gum, MS: 436 (MH+, 1Br, 1Cl).
Reaction SMILES: [F:1][C:2]([F:48])([F:47])[C:3]1[CH:4]=[C:5]([CH:40]=[C:41]([C:43]([F:46])([F:45])[F:44])[CH:42]=1)[CH2:6][N:7]([C:28]1[N:33]=[CH:32][C:31]([N:34]2[CH2:39][CH2:38][O:37][CH2:36][CH2:35]2)=[CH:30][N:29]=1)[CH2:8][C:9]1[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[CH:11][C:10]=1B1OC(C)(C)C(C)(C)O1.Cl[C:50]1[C:55]([C:56]([O:58][CH2:59][CH3:60])=[O:57])=[CH:54][N:53]=[C:52]([C:61]([F:64])([F:63])[F:62])[N:51]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>O1CCOCC1.C(OCC)(=O)C>[F:46][C:43]([F:45])([F:44])[C:41]1[CH:40]=[C:5]([CH:4]=[C:3]([C:2]([F:48])([F:1])[F:47])[CH:42]=1)[CH2:6][N:7]([CH2:8][C:9]1[CH:14]=[C:13]([C:15]([F:17])([F:18])[F:16])[CH:12]=[CH:11][C:10]=1[C:54]1[C:55]([C:56]([O:58][CH2:59][CH3:60])=[O:57])=[CH:50][N:51]=[C:52]([C:61]([F:63])([F:64])[F:62])[N:53]=1)[C:28]1[N:29]=[CH:30][C:31]([N:34]2[CH2:39][CH2:38][O:37][CH2:36][CH2:35]2)=[CH:32][N:33]=1
Reactant: CCOC(=O)c1cnc(C(F)(F)F)nc1Cl
Reactant: CC1(C)OB(c2ccc(C(F)(F)F)cc2CN(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2ncc(N3CCOCC3)cn2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: O
Product: CCOC(=O)c1cnc(C(F)(F)F)nc1-c1ccc(C(F)(F)F)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ncc(N2CCOCC2)cn1
Temperature: 80 °C
Reaction time: 8 h
Yield: 70.2 %

Procedure:
(3,5-Bis-trifluoromethyl-benzyl)-(5-morpholin-4-yl-pyrimidin-2-yl)-[2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-5-trifluoromethyl-benzyl]-amine (250 mg) is dissolved in 1,4-dioxane (5 ml) and thereto are added ethyl 4-chloro-2-trifluoromethyl-pyrimidine-5-carboxylate (140 mg), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (30 mg) and cesium carbonate (177 mg), and the mixture is stirred under nitrogen atmosphere at 80° C. overnight. The reaction solution is cooled to room temperature, and thereto are added water and ethyl acetate and the insoluble materials are removed by filtration through Celite™. The filtrate is separated, and the organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane:ethyl acetate=9:1→4:1) to give ethyl 4-(2-{[(3,5-bis-trifluoromethyl-benzyl)-(5-morpholin-4-yl-pyrimidin-2-yl)-amino]-methyl}-4-trifluoromethyl-phenyl)-2-trifluoromethyl-pyrimidine-5-carboxylate (199 mg). MS (m/z): 783 [M+H]+
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:12][OH:13])=[C:6]([C:8]([OH:11])([CH3:10])[CH3:9])[CH:7]=1.N1C=CN=C1.[C:19]([Si:23]([CH3:26])([CH3:25])Cl)([CH3:22])([CH3:21])[CH3:20].O>CN(C)C=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:12][O:13][Si:23]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:26])[CH3:25])=[C:6]([C:8]([OH:11])([CH3:10])[CH3:9])[CH:7]=1
Reactant: CC(C)(O)c1cc(Br)ccc1CO
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(O)c1cc(Br)ccc1CO[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.5 %

Procedure:
2-[5-Bromo-2-(hydroxymethyl)phenyl]propan-2-ol (1.1 g, 4.4 mmol) and imidazole (0.78 g, 12 mmol) were dissolved in N,N-dimethylformamide (5 mL), and tert-butyldimethylchlorosilane (0.86 g, 5.7 mmol) was added, followed by stirring at room temperature overnight. Water was added to the reaction solution, followed by extraction with hexane, and subsequently the extract was washed sequentially with water and a saturated aqueous sodium chloride solution, and dried over anhydrous sodium sulfate. After the organic layer was concentrated under reduced pressure, the resulting residue was purified by chromatography on a silica gel column (Biotage Ltd., elution solvent: hexane/ethyl acetate) to afford the title compound (1.1 g, 3.1 mmol) as a colorless oil (yield 70%).
Reaction SMILES: [O:1]=[C:2]1[N:10]([CH2:11][CH2:12][CH3:13])[C:9]2[N:8]=[C:7]([C:14]34[CH2:21][CH2:20][C:17]([C:22](=[S:24])[NH2:23])([CH2:18][CH2:19]3)[CH2:16][CH2:15]4)[NH:6][C:5]=2[C:4](=[O:25])[N:3]1[CH2:26][CH2:27][CH3:28].Br[CH2:30][C:31](=O)[C:32]([O:34][CH2:35][CH3:36])=[O:33].N1C=CC=CC=1.O>C1COCC1>[CH2:35]([O:34][C:32]([C:31]1[N:23]=[C:22]([C:17]23[CH2:20][CH2:21][C:14]([C:7]4[NH:6][C:5]5[C:4](=[O:25])[N:3]([CH2:26][CH2:27][CH3:28])[C:2](=[O:1])[N:10]([CH2:11][CH2:12][CH3:13])[C:9]=5[N:8]=4)([CH2:19][CH2:18]2)[CH2:15][CH2:16]3)[S:24][CH:30]=1)=[O:33])[CH3:36]
Reactant: CCOC(=O)C(=O)CBr
Reactant: CCCn1c(=O)c2[nH]c(C34CCC(C(N)=S)(CC3)CC4)nc2n(CCC)c1=O
Solvent: C1CCOC1
Solvent: c1ccncc1
Solvent: O
Product: CCCn1c(=O)c2[nH]c(C34CCC(c5nc(C(=O)OCC)cs5)(CC3)CC4)nc2n(CCC)c1=O
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 88.1 %

Procedure:
A suspension of 4-(2,6-dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-bicyclo[2.2.2]octane-1-carbothioic acid amide (20 mg, 50 μmol) and KLCO3 (8.0 eq, 400 μmol) in THF (5 ml) was stirred vigorously for 5 min and ethyl bromopyruvate (29 mg, 150 μmol) was added neat via syringe. The resulting, pale yellow solution was stirred at rt for 1 h, cooled to 0° C. with the aid of an ice bath and treated sequentially with pyridine (8.0 eq, 400 μmol) and (F3CCO)2O (4.0 eq, 42 mg, 200 μmol). The resulting deep red solution was allowed to reach ambient temperature overnight. Following the addition of water (4 ml), the mixture was concentrated in vacuo and extracted with CH2Cl2 (2×10 ml). The combined organic phases were washed with 2 N HCl, dried (Na2SO4), filtered and concentrated in vacuo. The solution was purified by radial chromatography (1 mm plate) using 2-5% MeOH in CH2Cl2 as eluent to afford a white solid (22 mg, 88%). MS: 500 (MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[Cl:11].[CH2:12]([N:14]1[CH2:19][CH2:18][CH:17]([NH2:20])[CH2:16][CH2:15]1)[CH3:13].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:20][CH:17]2[CH2:18][CH2:19][N:14]([CH2:12][CH3:13])[CH2:15][CH2:16]2)=[O:8])=[CH:4][C:3]=1[Cl:11]
Reactant: Nc1ccc(C(=O)O)cc1Cl
Reactant: CCN1CCC(N)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCN1CCC(NC(=O)c2ccc(N)c(Cl)c2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 83.8 %

Procedure:
To a mixture of 4-amino-3-chloro-benzoic acid (Fluorochem; 2.575 g, 15 mmol) and 1-ethylpiperidin-4-amine (Fluorochem; 2.12 g, 16.5 mmol) in DMF (50 mL), was added DIPEA (5.2 mL, 30 mmol). The mixture was cooled with an ice-bath. HATU (6.27 g), added and the reaction mixture stirred at ambient temperature for 18 hours. The solvent was evaporated and the residue partitioned between saturated aqueous sodium bicarbonate solution (100 mL), and Ethyl Acetate (4×50 mL). The organic extracts were washed with brine (2×75 ml), dried over anhydrous Magnesium sulphate, filtered, and the solvent evaporated to give the crude product as a gum, which was triturated with ether to yield the title compound as a tan solid (3.54 g, 84%).
Reaction SMILES: Cl[C:2]1[CH:29]=[CH:28][C:5]([C:6]([NH:8][CH2:9][C:10]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][C:15]([Cl:21])=[CH:16][CH:17]=3)[N:12]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:11]=2)=[O:7])=[CH:4][N:3]=1.[NH:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1>>[Cl:21][C:15]1[CH:14]=[C:13]2[C:18]([C:19](=[O:20])[C:10]([CH2:9][NH:8][C:6](=[O:7])[C:5]3[CH:28]=[CH:29][C:2]([N:30]4[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]4)=[N:3][CH:4]=3)=[CH:11][N:12]2[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)=[CH:17][CH:16]=1
Reactant: C1CNCCN1
Reactant: O=C(NCc1cn(-c2ccccc2)c2cc(Cl)ccc2c1=O)c1ccc(Cl)nc1
Product: O=C(NCc1cn(-c2ccccc2)c2cc(Cl)ccc2c1=O)c1ccc(N2CCNCC2)nc1

Procedure:
N-(7-Chloro-4-oxo-1-phenyl-1,4-dihydro-quinolin-3-ylmethyl)-6-piperazin-1-yl-nicotin-amide was prepared starting from intermediate E and piperazine. MS calcd. for C26H24ClN5O2 [(M+H)+] 474.2, obsd. 474.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:33])[CH2:5][N:6]1[C:14]2[CH2:13][CH2:12][CH2:11][C@@H:10]([N:15]([S:17]([C:20]3[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[C:22]([C:30]([CH3:32])=[CH2:31])[CH:21]=3)(=[O:19])=[O:18])[CH3:16])[C:9]=2[CH:8]=[N:7]1)[CH3:2].[N+](=[CH2:36])=[N-]>O1CCCC1.C(OCC)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:1]([O:3][C:4](=[O:33])[CH2:5][N:6]1[C:14]2[CH2:13][CH2:12][CH2:11][C@@H:10]([N:15]([CH3:16])[S:17]([C:20]3[CH:25]=[C:24]([C:26]([F:27])([F:28])[F:29])[CH:23]=[C:22]([C:30]4([CH3:36])[CH2:32][CH2:31]4)[CH:21]=3)(=[O:18])=[O:19])[C:9]=2[CH:8]=[N:7]1)[CH3:2]
Reactant: C=[N+]=[N-]
Reactant: C=C(C)c1cc(C(F)(F)F)cc(S(=O)(=O)N(C)[C@@H]2CCCc3c2cnn3CC(=O)OCC)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCOC(=O)Cn1ncc2c1CCC[C@H]2N(C)S(=O)(=O)c1cc(C(F)(F)F)cc(C2(C)CC2)c1
Reaction time: 0.17 h
Yield: 99 %

Procedure:
To a solution of {(R)-4-[(3-isopropenyl-5-trifluoromethyl-benzenesulfonyl)-methyl-amino]-4,5,6,7-tetrahydro-indazol-1-yl}-acetic acid ethyl ester (70.7 mg, 0.15 mmol) in tetrahydrofuran (2 mL) was added a solution of diazomethane in diethyl ether (1M, 8 mL) slowly at 0° C. under an argon atmosphere, and then a portion of palladium acetate (5 mg) was added. After the mixture was stirred for 10 minutes, a second portion of palladium acetate (5 mg) was added and the mixture was stirred for another 20 minutes, followed by addition of a second portion of a solution of diazomethane in diethyl ether (1M, 5 mL). After being stirred at 0° C. for 2 hours under an argon atmosphere, the reaction mixture was then quenched by the addition of a few drops of acetic acid, and then filtered through a glass funnel and concentrated in vacuo. The residue was purified by flash column (gradient elution, 0-10% methanol in dichloromethane) to afford ((R)-4-{methyl-[3-(1-methyl-cyclopropyl)-5-trifluoromethyl-benzenesulfonyl]-amino}-4,5,6,7-tetrahydro-indazol-1-yl)-acetic acid ethyl ester (74.5 mg, 99%) as a colorless semisolid. MS cald. for C23H28F3N3O4S 499, obsd. (ESI+) [(M+H)+] 500.
Reaction SMILES: [C:1]([NH:4][C:5]1[NH:9][N:8]=[C:7](CC2C=CC=CC=2)[C:6]=1[C:17]([O:19][CH3:20])=S)(=[O:3])[CH3:2].[OH2:21].[S:22]([Cl:26])(Cl)(=[O:24])=[O:23]>C(Cl)Cl>[C:1]([NH:4][C:5]1[NH:9][N:8]=[C:7]([S:22]([Cl:26])(=[O:24])=[O:23])[C:6]=1[C:17]([O:19][CH3:20])=[O:21])(=[O:3])[CH3:2]
Reactant: COC(=S)c1c(Cc2ccccc2)n[nH]c1NC(C)=O
Reactant: O=S(=O)(Cl)Cl
Reactant: O
Solvent: ClCCl
Product: COC(=O)c1c(S(=O)(=O)Cl)n[nH]c1NC(C)=O
Temperature: 0 °C
Reaction time: 3 h

Procedure:
73.0 g (239 mmol) Methyl 5-acetamido-3-benzylthiopyrazole-4-carboxylate was dissolved in 470 ml methylene chloride and treated with 124.15 g silica gel and 25.6 g water and cooled to 0° C. 160.6 g (1.19 mol) Sulphuryl chloride in 730 ml methylene chloride was added dropwise. The mixture was stirred for 3 hours at 0° C., filtered, washed several times with methylene chloride, dried over magnesium sulphate and concentrated. The residue was triturated with ether/hexane, the crystals suction filtered, washed with hexane and dried.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([CH2:12][N:13]3[CH2:18][CH2:17][NH:16][CH:15]([CH2:19][CH2:20][CH3:21])[C:14]3=[O:22])=[CH:9][CH:10]=2)[N:5]=[CH:4][N:3]=1.[Cl:23][C:24]1[S:28][C:27]([O:29][CH2:30][C:31](O)=[O:32])=[CH:26][CH:25]=1>>[NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([CH2:12][N:13]3[CH2:18][CH2:17][N:16]([C:31](=[O:32])[CH2:30][O:29][C:27]4[S:28][C:24]([Cl:23])=[CH:25][CH:26]=4)[C@@H:15]([CH2:19][CH2:20][CH3:21])[C:14]3=[O:22])=[CH:9][CH:10]=2)[N:5]=[CH:4][N:3]=1
Reactant: CCCC1NCCN(Cc2ccc3c(N)ncnc3c2)C1=O
Reactant: O=C(O)COc1ccc(Cl)s1
Product: CCC[C@H]1C(=O)N(Cc2ccc3c(N)ncnc3c2)CCN1C(=O)COc1ccc(Cl)s1

Procedure:
The title compound is prepared as described in EXAMPLE 123, using 1-(4-aminoquinazoline-7-ylmethyl)-3-propyl-piperazine-2-one, EXAMPLE 78 and 5-chloro-2-thienyloxyacetic acid, EXAMPLE 24. 1H NMR (d6-DMSO, 300 MHz) δ9.78 (bs, 2H), 8.81 (s, 1H), 8.35 (d, 1H), 7.60 (m, 2H), 7.51 (s, 1H), 6.69 (m, 1H), 6.21 (d, 1H), 4.91 (AB, 2H), 4.72 (m, 2H), 3.84 (m, 1H), 3.52 (m, 2H), 3.23 (m, 1H), 1.80 (m, 2H), 1.24 (m, 2H), 0.82 (m, 3H). MS (ion spray), m/z, 474, 476, (M+H) (Cl pattern). Elemental analysis, cal C22H22ClN5O2S.C2HF3O2.1.15H2O % C=47.31, % H=4.52, % N=11.50; found % C=47.39, % H=4.140, % N=11.19.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:8]=[C:9]([CH:38]=[CH:39][CH:40]=1)[CH2:10][O:11][CH:12]1[CH2:17][CH2:16][N:15]([C:18]([CH3:37])([CH3:36])[CH2:19][CH2:20][C:21]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:22]#[N:23])[CH2:14][CH2:13]1.C(=O)=O>O1CCCC1>[NH3:15].[CH2:10]([O:11][CH:12]1[CH2:13][CH2:14][N:15]([C:18]([CH3:37])([CH3:36])[CH2:19][CH2:20][C:21]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:22]#[N:23])[CH2:16][CH2:17]1)[C:9]1[CH:8]=[CH:7][CH:40]=[CH:39][CH:38]=1
Reactant: CC(C)(CCC(C#N)(c1ccccc1)c1ccccc1)N1CCC(OCc2cccc(Br)c2)CC1
Agent: O=C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(CCC(C#N)(c1ccccc1)c1ccccc1)N1CCC(OCc2ccccc2)CC1
Product: N
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
n-Butyl lithium (2.5M in hexanes, 0.23 mL, 0.56 mmol) was added dropwise to a solution of the product of example 87 (200 mg, 0.38 mmol) in tetrahydrofuran (8 mL), cooled to −78° C., and the mixture was stirred for 30 minutes. Carbon dioxide was then passed through the solution, with stirring at −78° C., for 3.5 hours before the mixture was allowed to warm to room temperature. The reaction mixture was concentrated in vacuo and the residue was partitioned between ethyl acetate (30 mL) and water (20 mL). The organic layer was separated, washed with water, dried over magnesium sulfate and concentrated in vacuo. Purification of the residue by column chromatography on silica gel, eluting with dichloromethane:methanol:0.88 ammonia, 100:0:0 to 98:2:0.2, afforded the title compound as a by-product, as an off white solid in 68% yield, 116 mg.
Reaction SMILES: [CH2:1]([Si:3]1([CH2:19][CH3:20])[Si:6]([CH2:9][CH3:10])([CH2:7][CH3:8])[Si:5]([CH2:13][CH3:14])([CH2:11][CH3:12])[Si:4]1([CH2:17][CH3:18])[CH2:15][CH3:16])[CH3:2].[C:21]1([Si:27]([Li])([CH3:29])[CH3:28])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[C:31]1([Si:37]([CH3:40])([CH3:39])Cl)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.C(=O)(O)[O-].[Na+]>CCCCCC.O1CCCC1>[CH2:9]([Si:6]([CH2:7][CH3:8])([Si:3]([CH2:1][CH3:2])([CH2:19][CH3:20])[Si:4]([CH2:15][CH3:16])([CH2:17][CH3:18])[Si:5]([CH2:13][CH3:14])([CH2:11][CH3:12])[Si:37]([CH3:40])([CH3:39])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[Si:27]([CH3:29])([CH3:28])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH3:10]
Reactant: CC[Si]1(CC)[Si](CC)(CC)[Si](CC)(CC)[Si]1(CC)CC
Reactant: [Li][Si](C)(C)c1ccccc1
Reactant: C[Si](C)(Cl)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC[Si](CC)([Si](C)(C)c1ccccc1)[Si](CC)(CC)[Si](CC)(CC)[Si](CC)(CC)[Si](C)(C)c1ccccc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 46 %

Procedure:
In an argon atmosphere; to a tetrahydrofuran solution (1 ml) of 52 mg (0.15 mmol) of octaethylcyclotetrasilane was added 0.56 ml (0.15 mmol) of a tetrahydrofuran solution (0.27M) of phenyldimethylsilyllithium, and stirred at 0° C. for 15 minutes. Phenyldimethylchlorosilane in an amount of 26 mg (0.15 mmol) was added, and reacted at room temperature for 3 hours. Hexane (2 ml) and saturated aqueous sodium bicarbonate solution (2 ml) were added, stirred, the hexane layer was separated, and dried with magnesium sulfate, The resulting crude product was purified by a silica gel column chromatography (hexane) to give 42 mg (46% yield) of 2,2,3,3,4,4,5,5-octaethyl-1,1,6,6-tetramethyl-1,6-diphenylhexasilane (1).