Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]1[C:40](=[O:41])[N:11]2[C:12]([C:24]([O:26][CH:27]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[O:25])=[C:13](OS(C(F)(F)F)(=O)=O)[CH2:14][S:15][C@H:10]12)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:42][CH:43]([O:45][C:46]1[C:49](=[O:50])[C:48](=[O:51])[C:47]=1[Sn](CCCC)(CCCC)CCCC)[CH3:44].O1C=CC=C1P(C1OC=CC=1)C1OC=CC=1>CN1CCCC1=O.C(OCC)(=O)C.[Cl-].[Zn+2].[Cl-].[Pd].C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1>[C:1]([O:5][C:6]([NH:8][CH:9]1[C:40](=[O:41])[N:11]2[C:12]([C:24]([O:26][CH:27]([C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=3)[C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[O:25])=[C:13]([C:47]3[C:48](=[O:51])[C:49](=[O:50])[C:46]=3[O:45][CH:43]([CH3:44])[CH3:42])[CH2:14][S:15][C@H:10]12)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(OS(=O)(=O)C(F)(F)F)CS[C@H]12
Reactant: CCCC[Sn](CCCC)(CCCC)c1c(OC(C)C)c(=O)c1=O
Agent: [Pd]
Agent: O=C(C=Cc1ccccc1)C=Cc1ccccc1
Agent: [Cl-]
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: CC(C)Oc1c(C2=C(C(=O)OC(c3ccccc3)c3ccccc3)N3C(=O)C(NC(=O)OC(C)(C)C)[C@H]3SC2)c(=O)c1=O
Reaction time: 0.5 h
Yield: 75.4 %

Procedure:
A solution of diphenylmethyl 7-(t-butyloxycarbonylamino)-3-trifluoromethylsulfonyloxy-3-cephem-4-carboxylate (307 mg, 0.50 mmol) and 4-(2-propoxy)-3-(tri-n-butylstannyl)cyclobut-3-ene-1,2-dione (236 mg, 0.55 mmol) in N-methyl-2-pyrrolidinone (NMP, 4.5 mL) was degassed with a gentle stream of argon. Tris(2-furyl)phosphine (11.5 mg, 0.050 mmol), zinc chloride (136 mg, 1.0 mmol), and bis(dibenzylideneacetone) palladium (0) (14.4 mg, 0.025 mmol) were successively added. The mixture was stirred at an oil bath temperature of 60°-65° C. for 0.5 hr and was diluted with ethyl acetate. The resulting solution was sequentially washed with saturated aqueous NH4Cl (3X), H2O, and saturated NaCl and then was dried over Na2SO4. The filtrate was concentrated, and a solution of the residue in acetonitrile was washed with n-pentane (3X). Removal of the acetonitrile left a dark oil which was chromatographed on SiO2 (19 g) with methylene chloride-acetone (97:3) to afford the title compound (228 mg, 75% yield) as a bright yellow solid. Recrystallization from diisopropyl ether gave the analytical sample.
Reaction SMILES: N1C=CC=CC=1.[ClH:7].[NH:8]1[CH2:12][CH2:11][N:10]=[C:9]1[NH:13][C:14]1[CH:22]=[CH:21][C:17]([C:18]([OH:20])=[O:19])=[CH:16][CH:15]=1.Cl.[C:24]([C:27]1[CH:28]=[C:29]2[C:34](=[CH:35][CH:36]=1)[C:33]([CH2:37][C:38](=[O:40])[NH2:39])=[C:32](O)[CH:31]=[CH:30]2)(=[NH:26])[NH2:25].C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C1C=CN=CC=1.O>[ClH:7].[ClH:7].[NH:10]1[CH2:11][CH2:12][N:8]=[C:9]1[NH:13][C:14]1[CH:15]=[CH:16][C:17]([C:18]([O:20][C:32]2[CH:31]=[CH:30][C:29]3[C:34](=[CH:35][CH:36]=[C:27]([C:24](=[NH:25])[NH2:26])[CH:28]=3)[C:33]=2[CH2:37][C:38](=[O:40])[NH2:39])=[O:19])=[CH:21][CH:22]=1
Reactant: N=C(N)c1ccc2c(CC(N)=O)c(O)ccc2c1
Reactant: O=C(O)c1ccc(NC2=NCCN2)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: N=C(N)c1ccc2c(CC(N)=O)c(OC(=O)c3ccc(NC4=NCCN4)cc3)ccc2c1
Reaction time: 2 h

Procedure:
45 Milliliters of 20% hydrous pyridine was added to 2.85 g of 4-[(4,5-dihydro-1H-imidazol-2-yl)amino]benzoic acid.hydrochloride, 3 g of 6-amidino-1-carbamoylmethyl-2-naphthol.hydrochloride, 2.65 g of N,N'-dicyclohexylcarbodiimide (hereinafter referred to as "DCC") and 131 mg of 4-dimethylaminopyridine (hereinafter referred to as "DMAP"), followed by stirring for 2 hours under cooling with ice and 3 days under cooling with water. The precipitate was filtered and the filtrate was concentrated under reduced pressure. To the residue was added 15 ml of N,N-dimethylformamide (hereinafter referred to as "DMF"), and a small amount of the insoluble matter was filtered off. The filtrate was added dropwise to 500 ml of a mixed liquid of ether and acetone (10:1) and this was stirred for 24 hours under cooling with ice. Then, the precipitate was collected by filtration to obtain a crude product.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:64])[NH:10][C@H:11]([C:37](=[O:63])[N:38]([CH2:53][CH2:54][NH:55]C(OC(C)(C)C)=O)[CH2:39][C:40](=[O:52])[NH:41][CH2:42][C:43]([CH3:51])([C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)[CH3:44])[CH2:12][C:13]1[N:14]=[CH:15][N:16](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:17]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>>[CH2:1]([O:8][C:9](=[O:64])[NH:10][CH:11]([C:37](=[O:63])[N:38]([CH2:53][CH2:54][NH2:55])[CH2:39][C:40](=[O:52])[NH:41][CH2:42][C:43]([CH3:44])([C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)[CH3:51])[CH2:12][C:13]1[NH:14][CH:15]=[N:16][CH:17]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)NCCN(CC(=O)NCC(C)(C)c1ccccc1)C(=O)[C@H](Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1)NC(=O)OCc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(CNC(=O)CN(CCN)C(=O)C(Cc1cnc[nH]1)NC(=O)OCc1ccccc1)c1ccccc1
Yield: 45 %

Procedure:
The compound from Step 4 (1.09 g, 1.26 mmol) was treated with 95% aqueous trifluoroacetic acid (50 mL) for 1 hour at room temperature. The solvent was reduced to a few milliliters, and pipetted into 200 mL of ether/hexanes. The product was allowed to precipitate overnight at −40° C. The solid was collected, rinsed and dried. Purification was carried out via reversed-phase HPLC (0.1% trifluoroacetic acid in acetonitrile and 0.1% aqueous trifluoroacetic acid as eluent; C-18 column) to give a white powder; 0.30 g (45% yield). MS-APCI: M+1=521.2.
Reaction SMILES: CS(C)=O.[Cl-].[OH:6][CH2:7][C:8]1[C:17]([CH2:18][O:19][CH3:20])=[CH:16][C:15]2[C:14]([CH3:22])([CH3:21])[CH2:13][CH2:12][C:11]([CH3:24])([CH3:23])[C:10]=2[CH:9]=1.C(N(CC)CC)C>ClCCl.O>[CH3:20][O:19][CH2:18][C:17]1[C:8]([CH:7]=[O:6])=[CH:9][C:10]2[C:11]([CH3:24])([CH3:23])[CH2:12][CH2:13][C:14]([CH3:22])([CH3:21])[C:15]=2[CH:16]=1
Reactant: COCc1cc2c(cc1CO)C(C)(C)CCC2(C)C
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: COCc1cc2c(cc1C=O)C(C)(C)CCC2(C)C
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 66 %

Procedure:
0.321 ml dimethyl sulfoxide was added to 5 ml solution of 0.198 ml oxazalyl chloride in dichloromethane at −78° C., and the mixture was stirred at the same temperature for 5 minutes. 2 ml solution of 290 mg 2-hydroxymethyl-3-methoxymethyl-5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphthalene in dichloromethane was added to the mixture at −78° C., and the mixture was further stirred at the same temperature for 40 minutes. After 0.946 ml triethylamine was added to the reaction mixture at −78° C., the temperature was raised to room temperature over 45 minutes. After water was added thereto, the reaction solution was extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. Then, the residue obtained under reduced pressure was subjected to silica gel column chromatography to give 190 mg of the title compound as a yellow oil.
Reaction SMILES: C(OCOC([C:9]1[CH:14]=[CH:13][C:12]([C:15](=[O:17])[CH3:16])=[CH:11][C:10]=1[B:18]1[O:22]C(C)(C)[C:20]([CH3:26])([CH3:25])[O:19]1)(C)C)C.Cl.O>C1COCC1>[OH:22][B:18]1[C:10]2[CH:11]=[C:12]([C:15](=[O:17])[CH3:16])[CH:13]=[CH:14][C:9]=2[C:20]([CH3:25])([CH3:26])[O:19]1
Reactant: CCOCOC(C)(C)c1ccc(C(C)=O)cc1B1OC(C)(C)C(C)(C)O1
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)c1ccc2c(c1)B(O)OC2(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 84 %

Procedure:
To a solution of 1-(4-(2-(ethoxymethoxy)propan-2-yl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaboro-lan-2-yl)phenyl)ethanone (684 mg, 1.89 mmol) in THF (15 mL) was added 6N HCl (10 mL). The reaction mixture was stirred at rt overnight. Water was added and the mixture was extracted with EA. The organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography over silica gel eluted with PE-EA (5:1) to give 1-(1-hydroxy-3,3-dimethyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)ethanone (324 mg; yield 50% over 2 steps) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 9.26 (b, 1H), 8.29 (s, 1H), 8.07 (d, J=8.0 Hz, 1H), 7.59 (d, J=8.0 Hz, 1H), 2.61 (s, 3H), 1.44 (s, 6H) ppm; MS: m/z=205.1 (M+1, ESI+).
Reaction SMILES: [CH2:1]([N:3]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][N:5]=[C:4]1[C:11](=[NH:15])OCC)[CH3:2].[NH2:16][NH:17][C:18]([NH2:20])=[S:19]>>[CH2:1]([N:3]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][N:5]=[C:4]1[C:11]([NH:16][NH:17][C:18]([NH2:20])=[S:19])=[NH:15])[CH3:2]
Reactant: NNC(N)=S
Reactant: CCOC(=N)c1ncc([N+](=O)[O-])n1CC
Product: CCn1c([N+](=O)[O-])cnc1C(=N)NNC(N)=S

Procedure:
According to the above procedure, ethyl 1-ethyl-5-nitro-2-imidazolecarboximidate and thiosemicarbazide are allowed to react to give 1-(1-ethyl-5-nitro-2-imidazolecarboximidoyl)-3-thiosemicarbazide (IIIN).
Reaction SMILES: CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[F:23][C:24]1[CH:32]=[CH:31][C:30]([CH:33]2[C:46]3[CH:45]=[CH:44][C:43]4[C:38](=[N:39][CH:40]=[CH:41][CH:42]=4)[C:37]=3[NH:36][S:35](=[O:48])(=[O:47])[N:34]2[CH3:49])=[CH:29][C:25]=1[C:26]([OH:28])=O.[NH:50]1[CH2:55][CH2:54][O:53][CH2:52][CH2:51]1.CCN(C(C)C)C(C)C>C(Cl)Cl.O>[F:23][C:24]1[CH:32]=[CH:31][C:30]([CH:33]2[C:46]3[CH:45]=[CH:44][C:43]4[C:38](=[N:39][CH:40]=[CH:41][CH:42]=4)[C:37]=3[NH:36][S:35](=[O:47])(=[O:48])[N:34]2[CH3:49])=[CH:29][C:25]=1[C:26]([N:50]1[CH2:55][CH2:54][O:53][CH2:52][CH2:51]1)=[O:28]
Reactant: C1COCCN1
Reactant: CN1C(c2ccc(F)c(C(=O)O)c2)c2ccc3cccnc3c2NS1(=O)=O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CN1C(c2ccc(F)c(C(=O)N3CCOCC3)c2)c2ccc3cccnc3c2NS1(=O)=O
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 46.7 %

Procedure:
TBTU (49.73 mg, 0.15 mmol) was added to a suspension of 2-fluoro-5-(2-methyl-3,3-dioxo-1,2,3,4-tetrahydro-3λ*6*-thia-2,4,5-triaza-phenanthren-1-yl)-benzoic acid 424 (60 mg, 0.15 mmol) in DCM (1 ml) and the mixture was stirred at room temperature for 20 min. Morpholine (13.6 μl, 0.15 mmol) and DIPEA (25.6 μl, 0.15 mmol) were added and the mixture was stirred at room temperature for 3 h. The mixture was diluted with water (1 ml) and the mixture was extracted with DCM (3 ml). The organic phase was concentrated in vacuo. The crude residue was purified by preparative HPLC (acidic conditions 1) to give the title compound (32 mg, 45%).
Reaction SMILES: [F:1][C:2]1([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:7]2[CH:3]1[CH:4]([OH:9])[CH2:5][C:6]2=[O:8].[C:15]([Si:19]([CH3:22])([CH3:21])Cl)([CH3:18])([CH3:17])[CH3:16].CN(C)C=O.N1C=CN=C1>O>[F:1][C:2]1([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:3]2[CH:7]1[CH:6]([O:8][Si:19]([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:22])[CH3:21])[CH2:5][C:4]2=[O:9]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CCOC(=O)C1(F)C2C(=O)CC(O)C21
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C1(F)C2C(=O)CC(O[Si](C)(C)C(C)(C)C)C21
Temperature: 25 °C
Reaction time: 24 h
Yield: 86.7 %

Procedure:
2.8 g of (1RS,4SR,5SR,6RS)ethyl 6-fluoro-4-hydroxy-2-oxobicyclo[3.1.0]hexane-6-carboxylate and 2.5 g of t-butyldimethylchlorosilane were dissolved into 14 ml of N,N-dimethylformamide. 1.0 g of imidazole was further added thereto with ice-cooling, and this was stirred at room temperature for one day. The reaction solution was poured into water, and extracted with n-hexane-ethyl acetate (1:9). The obtained organic layer was washed with, in sequence, water and a saturated aqueous solution of sodium chloride, and then dried over anhydrous sodium sulfate. After filtering off the desiccant, concentration of the filtrate was carried out under reduced pressure. The residue was purified by column chromatography (silica gel: Wako gel (made by Wako Pure Chemical Industries Ltd.), eluent: hexane-ethyl acetate=15:1), yielding 3.8 g of (1RS,4SR,5SR,6RS)ethyl 6-fluoro-4-t-butyldimethylsilyloxy-2-oxobicyclo[3.1.0]hexane-6-carboxylate. The proton NMR and mass spectrograph data are shown below.
Reaction SMILES: C(N(CC)CC)C.[NH:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[C:9]1[C:17](Cl)=[O:18].[NH2:20][CH2:21][C:22]([N:24]([CH2:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:23].C(=O)([O-])O.[Na+]>ClCCCl.ClCCl>[C:35]([O:34][C:32]([CH2:31][N:24]([C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[C:22]([CH2:21][NH:20][C:17]([C:9]1[NH:8][C:16]2[C:11]([CH:10]=1)=[CH:12][CH:13]=[CH:14][CH:15]=2)=[O:18])=[O:23])=[O:33])([CH3:38])([CH3:36])[CH3:37]
Reactant: O=C(Cl)c1cc2ccccc2[nH]1
Reactant: CC(C)(C)OC(=O)CN(C(=O)CN)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)CN(C(=O)CNC(=O)c1cc2ccccc2[nH]1)c1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 54.1 %

Procedure:
Triethylamine (0.7 g), and then 2-indolecarbonyl chloride (1.2 g) dissolved in 1,2-dichloroethane (35 cc), are added to a solution, stirred at a temperature in the region of 25° C., of tert-butyl 2-(2-amino-N-phenylacetamido)acetate (1.2 g) in 1,2-dichloroethane (35 cc). The reaction mixture is stirred for 18 hours at a temperature in the region of 25° C. Dichloromethane (250 cc) is then added, followed by saturated aqueous sodium hydrogen carbonate solution (125 cc). The organic phase is washed with distilled water (2×125 cc), dried over magnesium sulphate and concentrated to dryness under reduced pressure (2.7 kPa) at 40° C. After recrystallization in acetonitrile, N-[N-(tert-butoxycarbonylmethyl) phenylcarbamoylmethyl]-2-indolecarboxamide (1 g), m.p. 203° C., is obtained.
Reaction SMILES: [CH:1]1([CH2:4][C@H:5]([C@H:16]([CH2:24][CH:25]2[CH2:27][CH2:26]2)[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C:6]([O:8]CC2C=CC=CC=2)=[O:7])[CH2:3][CH2:2]1>CO.[Pd]>[C:20]([O:19][C:17](=[O:18])[C@@H:16]([CH2:24][CH:25]1[CH2:26][CH2:27]1)[C@@H:5]([CH2:4][CH:1]1[CH2:2][CH2:3]1)[C:6]([OH:8])=[O:7])([CH3:23])([CH3:21])[CH3:22]
Reactant: CC(C)(C)OC(=O)[C@@H](CC1CC1)[C@@H](CC1CC1)C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)[C@@H](CC1CC1)[C@@H](CC1CC1)C(=O)O
Reaction time: 1.5 h
Yield: 100 %

Procedure:
To a solution of (2R,3S)-1-benzyl 4-tert-butyl 2,3-bis(cyclopropylmethyl)succinate, Intermediate S8G (0.530 g, 1.423 mmol) in MeOH (10 mL) was added 10% Pd/C (Degussa) (0.300 g, 1.423 mmol). The reaction mixture was evacuated with vacuum and filled with H2 (Repeated this for 3×). Next, the reaction mixture was stirred under H2 balloon for 1.5 h, evacuated, and filled with N2. The mixture was then filtered through CELITE®. The filtrate was concentrated to afford (2R,3S)-4-(tert-butoxy)-2,3-bis(cyclopropylmethyl)-4-oxobutanoic acid, Intermediate S8 (0.400 g, 1.417 mmol, 100% yield) as a colorless liquid. 1H NMR (400 MHz, chloroform-d) δ 2.69 (td, J=9.9, 3.7 Hz, 2H), 1.71-1.54 (m, 2H), 1.47 (s, 9H), 1.38-1.22 (m, 2H), 0.80-0.62 (m, 2H), 0.51-0.36 (m, 4H), 0.16-0.05 (m, 2H), 0.05-−0.02 (m, 2H).
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[CH:10]=[CH:9][N:8]=[CH:7][C:6]=2[N:5]=[C:4]1[C:12]1[C:13]([NH2:17])=[N:14][O:15][N:16]=1)[CH3:2].[Br:18]Br>C(O)(=O)C>[Br:18][C:10]1[C:11]2[N:3]([CH2:1][CH3:2])[C:4]([C:12]3[C:13]([NH2:17])=[N:14][O:15][N:16]=3)=[N:5][C:6]=2[CH:7]=[N:8][CH:9]=1
Reactant: BrBr
Reactant: CCn1c(-c2nonc2N)nc2cnccc21
Solvent: CC(=O)O
Product: CCn1c(-c2nonc2N)nc2cncc(Br)c21
Temperature: 100 °C
Yield: 34.3 %

Procedure:
To a solution of the product of Example 1 Step 1 (3.0 g, 17.9 mmol) in acetic acid (40 ml) was added bromine (3.12 g, 1 ml, 19.7 mmol) and the mixture was heated at 100° C. for 20 hours. After cooling the solvent was removed in vacuo and the residue was partitioned between dichloromethane and saturated sodium bicarbonate solution. The organic phase was washed with water (×3), dried and evaporated in vacuo. Purification of the residue by silica gel chromatography eluting with 50% dichloromethane in ethyl acetate afforded the title compound (1.9 g, 43%). 1H NMR (DMSO-d6) 8.73 (1H, s), 8.52 (1H, s), 7.0 (1H, br), 3.25 (2H, m), 1.16 (3H, t, J=7.2 Hz).
Reaction SMILES: [C:1]([CH2:3][CH2:4][CH2:5][CH:6]([CH2:14][CH:15]=[CH2:16])[CH2:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])#[N:2].C(#N)C.Br[C:21]1[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=1>C(N(CC)CC)C>[C:1]([CH2:3][CH2:4][CH2:5][CH:6]([CH2:14][CH:15]=[CH:16][C:21]1[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=1)[CH2:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])#[N:2]
Reactant: Brc1cccnc1
Reactant: C=CCC(CCCC#N)CCC(=O)OCC
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCOC(=O)CCC(CC=Cc1cccnc1)CCCC#N

Procedure:
A mixture of 1300 g of ethyl 4-(3-cyanopropyl)-6-heptenoate, 6397 ml of acetonitrile, 3190 ml of triethylamine and 920.9 g of 3-bromopyridine is degassed and then heated to reflux. Palladium(II)acetate catalyst (13 g) and 36.42 g of tri-o-tolylphosphine are added and the mixture is heated under reflux overnight. Additional catalyst (13 g) is added and the mixture is again heated under reflux for 7 h. Further catalyst (6.5 g) is again added and the reaction mixture is again heated under reflux overnight. The reaction mixture is cooled, diluted with 6 l of methylene chloride, and evaporated to dryness. The residue is partitioned between ether and water. The ether layer is separated and the aqueous layer is extracted two more times with ether. The combined ether extracts are extracted with 2×8 l of 1N hydrochloric acid. The acid extract is cooled and made basic with 1200 ml of conc. aqueous ammonia to pH 10, and extracted with ether (3×8 l). The ether extract is dried over sodium sulfate and evaporated to dryness to yield ethyl 4-(3-cyanopropyl)-7-(3-pyridyl)-6-heptenoate.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]([CH3:15])[C:5](=[O:14])[O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[CH3:15][N:4]([CH2:3][CH:2]=[O:1])[C:5](=[O:14])[O:6][CH2:7][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CN(CCO)C(=O)OCc1ccccc1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: CN(CC=O)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of phenylmethyl (2-hydroxyethyl)methylcarbamate (2.02 g, 9.64 mmol) and Dess Martin's Reagent (6.36 g, 15.6 mmol) in CH2Cl2 (100 mL) were combined under nitrogen and stirred for 4 h at ambient temperature. Added CH2Cl2 (100 mL) and washed the organics with 2M Na2CO3 (aq.), saturated NaHCO3, water, and brine, dried over Na2SO4, filtered and evaporated in vacuo. Purified the residue by flash chromatography using silica gel and a gradient between 0 and 10% MeOH in CH2Cl2 over 20 minutes to provide the desired material, after combining and concentrating pure fractions in vacuo, as a yellow viscous oil: 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 3.03 (d, J=6.59 Hz, 3 H), 4.06 (s, 1 H), 4.13 (s, 1 H), 5.12-5.21 (m, 2 H), 7.29-7.40 (m, 5 H), 9.63 (d, J=16.28 Hz, 1 H); ES+ MS: 230 (M+Na+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:21][C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)=[C:6]([NH:8][S:9]([C:12]2[CH:20]=[CH:19][C:15]([C:16](O)=[O:17])=[CH:14][CH:13]=2)(=[O:11])=[O:10])[CH:7]=1.Cl.[CH2:30]([O:32][C:33](=[O:36])[CH2:34][NH2:35])[CH3:31]>>[CH2:30]([O:32][C:33](=[O:36])[CH2:34][NH:35][C:16](=[O:17])[C:15]1[CH:19]=[CH:20][C:12]([S:9](=[O:10])(=[O:11])[NH:8][C:6]2[CH:7]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=2[O:21][C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)=[CH:13][CH:14]=1)[CH3:31]
Reactant: O=C(O)c1ccc(S(=O)(=O)Nc2cc(F)ccc2Oc2ccc(F)cc2)cc1
Reactant: CCOC(=O)CN
Agent: Cl
Product: CCOC(=O)CNC(=O)c1ccc(S(=O)(=O)Nc2cc(F)ccc2Oc2ccc(F)cc2)cc1

Procedure:
The title compound was prepared from 4-[5-fluoro-2-(4-fluoro-phenoxy)-phenylsulfamoyl]-benzoic acid and glycine ethyl ester hydrochloride (Aldrich) according to the method described in Example 1.1/d.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:11]1[C:40]([CH3:41])=[C:39]([CH:42]=[CH2:43])[C:38]2=[N:44][C:35]3=[CH:36][N:37]2[C:12]=1[N:13]1[CH2:49][CH2:48][C:16]([CH3:50])([O:17][CH2:18][CH2:19][CH2:20][CH2:21][C@H:22]([CH3:47])[O:23][C:24]2[CH:25]=[CH:26][C:27]([F:46])=[CH:28][C:29]=2[C:30]2[CH:45]=[C:34]3[CH:33]=[CH:32][CH:31]=2)[CH2:15][CH2:14]1)[C:7]([O:9][CH3:10])=[O:8])([CH3:4])([CH3:3])[CH3:2]>CO.[Pd]>[C:1]([O:5][C@@H:6]([C:11]1[C:40]([CH3:41])=[C:39]([CH2:42][CH3:43])[C:38]2=[N:44][C:35]3=[CH:36][N:37]2[C:12]=1[N:13]1[CH2:49][CH2:48][C:16]([CH3:50])([O:17][CH2:18][CH2:19][CH2:20][CH2:21][C@H:22]([CH3:47])[O:23][C:24]2[CH:25]=[CH:26][C:27]([F:46])=[CH:28][C:29]=2[C:30]2[CH:45]=[C:34]3[CH:33]=[CH:32][CH:31]=2)[CH2:15][CH2:14]1)[C:7]([O:9][CH3:10])=[O:8])([CH3:2])([CH3:3])[CH3:4]
Reactant: C=Cc1c(C)c([C@H](OC(C)(C)C)C(=O)OC)c2n3cc(nc13)-c1cccc(c1)-c1cc(F)ccc1O[C@@H](C)CCCCOC1(C)CCN2CC1
Agent: [Pd]
Solvent: CO
Product: CCc1c(C)c([C@H](OC(C)(C)C)C(=O)OC)c2n3cc(nc13)-c1cccc(c1)-c1cc(F)ccc1O[C@@H](C)CCCCOC1(C)CCN2CC1
Reaction time: 2 h

Procedure:
Methyl(2S)-2-(tert-butoxy)-2-[(22S)-5-ethenyl-17-fluoro-4,22,28-trimethyl-21,27-dioxa-1,7,34-triazahexacyclo[26.2.2.16,9.110,14.02,7.015,20]tetratriaconta-2,4,6(34),8,10(33),11,13,15(20),16,18-decaen-3-yl]acetate (30 mg, 0.044 mmol, 1.0 equiv) was dissolved in MeOH (439 μl). To this solution was added Pd/C (4.67 mg, 4.39 μmol, 0.1 equiv) and stirred under H2 balloon for 2 hours. The solid was filtered off through the celite. The filter was concentrated and the residue was used as is. LCMS (ESI, M+1): 686.4.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:9]2[C:14](=[O:15])[C:13]([O:16][CH2:17][CH:18]([CH3:20])[CH3:19])=[C:12]([C:21]3[CH:26]=[CH:25][C:24]([S:27]([NH2:30])(=[O:29])=[O:28])=[CH:23][CH:22]=3)[CH:11]=[N:10]2)[CH:5]=[CH:6][C:7]=1[F:8].[C:31](OC(=O)C)(=[O:33])[CH3:32].C(N(CC)CC)C>CN(C)C1C=CN=CC=1>[F:1][C:2]1[CH:3]=[C:4]([N:9]2[C:14](=[O:15])[C:13]([O:16][CH2:17][CH:18]([CH3:20])[CH3:19])=[C:12]([C:21]3[CH:22]=[CH:23][C:24]([S:27]([NH:30][C:31](=[O:33])[CH3:32])(=[O:29])=[O:28])=[CH:25][CH:26]=3)[CH:11]=[N:10]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)COc1c(-c2ccc(S(N)(=O)=O)cc2)cnn(-c2ccc(F)c(F)c2)c1=O
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Product: CC(=O)NS(=O)(=O)c1ccc(-c2cnn(-c3ccc(F)c(F)c3)c(=O)c2OCC(C)C)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 2-(3,4-difluorophenyl)-4-(2-methyl-1-propoxy)-5-[4-(aminosulfonyl)phenyl]-3(2H)-pyridazinone (Example 403, 1 equivalent), acetic anhydride (3 equivalents), 4-(dimethylamino)pyridine (0.3 equivalents), and triethylamine (1.2 equivalents) is stirred at room temperature for 16 hours. The reaction mixture is partitioned between ethyl acetate and water. The organic layer is washed with brine then dried over MgSO4 and filtered. The filtrate is concentrated in vacuo to give the title compound.
Reaction SMILES: [Si:1]([N:8]([CH2:12][CH2:13][CH2:14][CH3:15])[CH2:9][CH:10]=[CH2:11])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH3:16][O:17][SiH:18]([O:21][CH3:22])[O:19][CH3:20]>[Pt].C([Si](C)(C)O[Si](C=C)(C)C)=C.C1(C)C=CC=CC=1>[Si:1]([N:8]([CH2:12][CH2:13][CH2:14][CH3:15])[CH2:9][CH2:10][CH2:11][Si:18]([O:21][CH3:22])([O:19][CH3:20])[O:17][CH3:16])([C:4]([CH3:6])([CH3:7])[CH3:5])([CH3:2])[CH3:3]
Reactant: C=CCN(CCCC)[Si](C)(C)C(C)(C)C
Reactant: CO[SiH](OC)OC
Agent: [Pt]
Agent: C=C[Si](C)(C)O[Si](C)(C)C=C
Solvent: Cc1ccccc1
Product: CCCCN(CCC[Si](OC)(OC)OC)[Si](C)(C)C(C)(C)C
Temperature: 50 °C
Reaction time: 1 h

Procedure:
A flask equipped with a stirrer, reflux condenser, dropping funnel and thermometer was charged with 22.8 g (0.1 mol) of N-t-butyldimethylsilyl-N-butyl-N-allylamine and 0.07 g of a toluene solution of platinum/1,3-divinyl-1,1,3,3-tetramethyldisiloxane complex (Pt concentration 3 wt %) and heated at 50° C. Once the internal temperature became steady, 12.2 g (0.1 mol) of trimethoxysilane was added dropwise over 1 hour. Stirring was continued at the temperature for a further 1 hour. The reaction solution was distilled, collecting 27.3 g of a fraction having a boiling point of 128-129° C./0.4 kPa.