Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[C:3]1[CH:4]=[C:5]([CH:23]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:25]=1)[CH2:6][O:7][CH2:8][C:9]1([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:15][CH2:14][CH2:13][CH:12]([OH:16])[CH2:11][CH2:10]1.[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>ClCCl>[F:1][C:2]([F:30])([F:31])[C:3]1[CH:4]=[C:5]([CH:23]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:25]=1)[CH2:6][O:7][CH2:8][C:9]1([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:15][CH2:14][CH2:13][C:12](=[O:16])[CH2:11][CH2:10]1
Reactant: OC1CCCC(COCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)(c2ccccc2)CC1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: O=C1CCCC(COCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)(c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of 4-((3,5-bis(trifluoromethyl)benzyloxy)methyl)-4-phenylcycloheptanol (26 mg, step F) in dichloromethane (0.5 mL) at room temperature were added pyridinium chlorochromate (25 mg) and powdered 4A° molecular sieves (26 mg), and the resulting mixture was stirred at room temperature for 1.5 h and then filtered through a small pad of silica gel. The filtrate was evaporated in vacuo and the residue was purified by preparative TLC eluting with 30% ethyl acetate/70% hexanes to give the title compound as an oily material (21 mg). 1H NMR (400 MHz, CDCl3) δ 1.74 (3H, m), 1.98 (1H, dd, J=11.6, 1.2 Hz), 2.48 (6H, m), 3.37 (1H, d, J=8.8 Hz), 3.39 (1H, d, J=8.8 Hz), 4.42 (2H, s), 7.28 (1H, m), 7.35 (4H, m), 7.56 (2H, m), and 7.74 (1H, s). HRMS m/z calcd. for C23H21F6O2 (M−H)− 443.1446, found 443.1457.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[CH:4]([C:11]1[CH:23]=[CH:22][C:14]([C:15]([O:17]C(C)(C)C)=[O:16])=[CH:13][CH:12]=1)[CH2:5][NH:6][C:7]([NH:9][CH3:10])=[O:8].FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:24])[CH:4]([C:11]1[CH:12]=[CH:13][C:14]([C:15]([OH:17])=[O:16])=[CH:22][CH:23]=1)[CH2:5][NH:6][C:7]([NH:9][CH3:10])=[O:8]
Reactant: CNC(=O)NCC(C(=O)OC)c1ccc(C(=O)OC(C)(C)C)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CNC(=O)NCC(C(=O)OC)c1ccc(C(=O)O)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of tert-butyl 4-[2-methoxy-1-({[(methylamino)carbonyl]amino}methyl)-2-oxoethyl]benzoate (760 mg, 2.26 mmol) in CH2Cl2 (20 mL) was added trifluoroacetic acid (5 mL), and the reaction was stirred at room temperature for 2 h. The solution was evaporated to dryness to yield 4-[2-methoxy-1-({[(methylamino)carbonyl]amino}methyl)-2-oxoethyl]benzoic acid as an off-white powder that was carried on without further purification. MS (ESI) calcd [M+H]+281.1, found 281.1.
Reaction SMILES: ClC1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17]OCC2)[C:5]2SC(C=O)=C[C:6]=2N=1.C(N1CCN[C@@H](C)C1)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.Cl.[OH-].[Na+].C[C@H]1CNCCN1CC1N=C(N2CCOCC2)C2SC=CC=2N=1.C(O)(=O)C(C)O.Cl[C:78]1[N:79]=[C:80]([N:100]2[CH2:105][CH2:104][O:103][CH2:102][CH2:101]2)[C:81]2[S:86][C:85]([CH2:87][N:88]3[CH2:93][CH2:92][N:91]([C:94](=[O:98])[C@@H:95]([OH:97])[CH3:96])[CH2:90][C@@H:89]3[CH3:99])=[CH:84][C:82]=2[N:83]=1.CC1(C)C(C)(C)OB(C2C=CC(N)=NC=2)O1>CO>[NH2:3][C:4]1[N:13]=[CH:18][C:17]([C:78]2[N:79]=[C:80]([N:100]3[CH2:105][CH2:104][O:103][CH2:102][CH2:101]3)[C:81]3[S:86][C:85]([CH2:87][N:88]4[CH2:93][CH2:92][N:91]([C:94](=[O:98])[C@@H:95]([OH:97])[CH3:96])[CH2:90][C@@H:89]4[CH3:99])=[CH:84][C:82]=3[N:83]=2)=[CH:6][CH:5]=1
Reactant: C[C@H](O)C(=O)N1CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)[C@@H](C)C1
Reactant: O=Cc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Agent: CC(O)C(=O)O
Agent: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Agent: C[C@H]1CN(C(c2ccccc2)(c2ccccc2)c2ccccc2)CCN1
Solvent: CO
Product: C[C@H](O)C(=O)N1CCN(Cc2cc3nc(-c4ccc(N)nc4)nc(N4CCOCC4)c3s2)[C@@H](C)C1
Yield: 14.4 %

Procedure:
2-Chloro-4-morpholinothieno[3,2-d]pyrimidine-6-carbaldehyde 10 from Example 3 (200 mg) was used according to General Procedure B-3 with (S)-4-N-trityl-2-methyl-piperazine. The crude product was then dissolved in 10 mL of methanol and reacted with 0.5 mL of concentrated HCl for several hours before basifying with NaOH and extracting into EtOAc. After evaporation the crude reaction mixture containing 200 mg of 2-chloro-6-(((S)-2-methylpiperazin-1-yl)methyl-4-morpholinothieno[3,2-d]pyrimidine was reacted with lactic acid via General Procedure B-2. 120 mg of (S)-1-((S)-4-((2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)-3-methylpiperazin-1-yl)-2-hydroxypropan-1-one was reacted with 88 mg of 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine via General Procedure A to give 19.6 mg of 193. MS (Q1) 498.3 (M)+.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[C:2]=1[CH:9]=O.[C:12](#[N:16])[CH2:13][C:14]#[N:15].N1CCCCC1>C(O)CCC>[C:1]1([CH3:11])[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[C:2]=1[CH:9]=[C:13]([C:12]#[N:16])[C:14]#[N:15]
Reactant: Cc1cc(C)c(C=O)c(C)c1
Reactant: N#CCC#N
Solvent: C1CCNCC1
Solvent: CCCCO
Product: Cc1cc(C)c(C=C(C#N)C#N)c(C)c1
Temperature: -20 °C
Reaction time: 5 h

Procedure:
In analogy to the methods described by M. Boehringer et al., WO 03/068748, a solution of 25 g (169 mmol) of mesitaldehyde (2,4,6-trimethylbenzaldehyde) and 13.5 g (204 mmol) of malononitrile in 70 mL of n-butanol was stirred at room temperature for 1 h and then treated dropwise with 0.4 mL of piperidine, resulting in a color change and precipitation. After 5 h, the mixture was cooled in a freezer (−20° C.) for 10 min and then filtered. The solid was washed three times with cold n-butanol and then dried to give the title compound as a white solid. LC-MS 197 (M+1). This material has been reported as being made by a similar procedure [A. M. Shestapalov et al., Chem. Heterocycl. Compd. (Engl. Transl. of Khim. Geterotsikl. Soedin.), 38, 1345 (2002)].
Reaction SMILES: [CH:1]([O:14][C:15]([C:17]1[N:22]2[C:23](=[O:66])[CH:24]([NH:25][C:26](=[O:65])[C:27](=[N:53][O:54][C:55]([CH3:64])([C:57]([O:59][C:60]([CH3:63])([CH3:62])[CH3:61])=[O:58])[CH3:56])[C:28]3[N:29]=[C:30]([NH:33][C:34]([C:47]4[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=4)([C:41]4[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=4)[C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)[S:31][CH:32]=3)[C@H:21]2[S:20][CH2:19][C:18]=1[CH2:67]Cl)=[O:16])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[I-].[Na+].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:90]([C:92]1[CH:99]=[CH:98][C:95]([CH:96]=O)=[CH:94][CH:93]=1)#[N:91].C(=O)([O-])O.[Na+].NC1SC=C(C(=NOC(C(O)=O)(C)C)C(NC2C(=O)N3C(C(O)=O)=C(C=CC4C=CC([N+]([O-])=O)=CC=4[N+]([O-])=O)CS[C@H]23)=O)N=1>>[CH:1]([O:14][C:15]([C:17]1[N:22]2[C:23](=[O:66])[CH:24]([NH:25][C:26](=[O:65])[C:27](=[N:53][O:54][C:55]([CH3:64])([C:57]([O:59][C:60]([CH3:63])([CH3:62])[CH3:61])=[O:58])[CH3:56])[C:28]3[N:29]=[C:30]([NH:33][C:34]([C:47]4[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=4)([C:41]4[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=4)[C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)[S:31][CH:32]=3)[C@H:21]2[S:20][CH2:19][C:18]=1[CH:67]=[CH:96][C:95]1[CH:98]=[CH:99][C:92]([C:90]#[N:91])=[CH:93][CH:94]=1)=[O:16])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)C(C)(C)ON=C(C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CCl)CS[C@H]12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reactant: N#Cc1ccc(C=O)cc1
Agent: CC(C)(ON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(C=Cc3ccc([N+](=O)[O-])cc3[N+](=O)[O-])CS[C@H]12)c1csc(N)n1)C(=O)O
Agent: O=C([O-])O
Agent: [I-]
Product: CC(C)(C)OC(=O)C(C)(C)ON=C(C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(C=Cc3ccc(C#N)cc3)CS[C@H]12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Yield: 55.4 %

Procedure:
7-[2-(1-methyl-1-tert-butoxycarbonylethoxyimino)-2-(2-tritylaminothiazol-4-yl)acetamido]-3-chloromethyl-3-cephem-4-carboxylic acid benzhydryl ester (775 mg, 0.8 mmol), sodium iodide (120 mg, 0.8 mmol), triphenylphosphine (210 mg, 0.8 mmol), 4-cyanobenzaldehyde (428 mg, 3.2 mmol) and sodium hydrogen carbonate (200 mg, 2.4 mmol) were used to conduct the procedure similar to that shown in (1) of Example 1 to obtain 464 mg (yield: 55%) of 7-[2-(1-methyl-1-tert-butoxycarbonylethoxyimino)-2-(2-tritylaminothiazol-4-yl)acetamido]-3-(4-cyanostyryl)-3-cephem-4-carboxylic acid benzhydryl ester as cream color powder.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12](=[O:15])[N:13]=[N:14][C:10]3=[CH:9][C:8](=[O:16])[N:7]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:6]=2[CH:23]=1.[C:24]([O-])(=O)[CH3:25].[K+]>BrC1C=CC=CC=1.C(Cl)Cl.[Cu]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12](=[O:15])[N:13]([C:25]4[CH:24]=[CH:6][CH:23]=[CH:2][CH:3]=4)[NH:14][C:10]3=[CH:9][C:8](=[O:16])[N:7]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:6]=2[CH:23]=1
Reactant: CC(=O)[O-]
Reactant: O=c1cc2nnc(=O)n-2c2ccc(Cl)cc2n1-c1ccccc1
Agent: [Cu]
Agent: [K+]
Solvent: ClCCl
Solvent: Brc1ccccc1
Product: O=C1N(c2ccccc2)NC2=CC(=O)N(c3ccccc3)c3cc(Cl)ccc3N12

Procedure:
A mixture of 8.2 g of 8-chloro-6-phenyl-1H-s-triazolo[4,3-a][1,5]benzodiazepine-1,5-dione, 5 g of copper powder and 2.5 g of potassium acetate in 100 ml of bromobenzene are refluxed for six hours with stirring. The reaction is diluted with methylene chloride, filtered through a short Florisil column and the filtrate washed with dilute aqueous ammonium hydroxide. The organic phase is washed with water, dried and the solvent evaporated to give the title compound.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)[C:10]([C:11](=[O:13])[CH3:12])=[C:6]2[CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH:28]1([NH2:33])[CH2:32][CH2:31][CH2:30][CH2:29]1.C(OCC)C>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>[CH:28]1([NH:33][C:2]2[N:7]3[N:8]=[C:9]([C:14]4[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=4)[C:10]([C:11](=[O:13])[CH3:12])=[C:6]3[CH:5]=[CH:4][CH:3]=2)[CH2:32][CH2:31][CH2:30][CH2:29]1
Reactant: COc1ccc(-c2nn3c(Cl)cccc3c2C(C)=O)cc1
Reactant: NC1CCCC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCOCC
Product: COc1ccc(-c2nn3c(NC4CCCC4)cccc3c2C(C)=O)cc1
Temperature: 95 °C
Reaction time: 4 h
Yield: 97.6 %

Procedure:
To a solution of 1-[7-(chloro)-2-(4-methoxyphenyl)pyrazolo[1,5-α]pyridin-3-yl]ethanone (5.0 g, 16.6 mmol) in toluene (100 mL) was added successively racemic-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (620 mg, 1.0 mmol), cesium carbonate (8.12 g, 24.9 mmol), cyclopentylamine (8.2 mL, 83.1 mmol), and palladium (II) acetate (150 mg, 0.66 mmol). The resulting mixture was stirred at 95° C. for 4 hours, at which time the reaction was judged complete by thin layer chromatography. The solution was cooled to room temperature and diethyl ether and water were added to the reaction mixture. The phases were separated, and the aqueous phase again extracted with diethyl ether. The combined organic phases were dried (magnesium sulfate), filtered and concentrated. The resulting residue was purified by flash chromatography (4:1 hexanes:ethyl acetate) to give 1-[7-(cyclopentylamino)-2-(4-methoxyphenyl)pyrazolo[1,5-α]pyridin-3-yl]ethanone (5.66 g, 97%) as a yellow foam. 1H NMR (CDCl3): δ 7.65 (d, 1H), 7.48 (d, 2H), 7.39 (t, 1H), 6.99 (d, 2H), 6.09 (d, 1H), 6.01 (d, 1H), 3.95 (m, 1H), 3.84 (s, 3H), 2.09 (s, 3H), 2.09–2.00 (m, 2H) 1.76–1.22 (m, 6H); MS m/z 350 (M+1).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]([C:11]2([C:14]3[CH:24]=[CH:23][C:17]4[O:18][C:19]([F:22])([F:21])[O:20][C:16]=4[CH:15]=3)[CH2:13][CH2:12]2)=[O:10])[CH:5]=[C:4]([CH3:25])[CH:3]=1.[CH3:26][O:27][C:28]1[N:33]=[CH:32][C:31](B(O)O)=[C:30]([CH3:37])[CH:29]=1>COCCOC.C([O-])([O-])=O.[Na+].[Na+].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:21][C:19]1([F:22])[O:18][C:17]2[CH:23]=[CH:24][C:14]([C:11]3([C:9]([NH:8][C:6]4[N:7]=[C:2]([C:31]5[CH:32]=[N:33][C:28]([O:27][CH3:26])=[CH:29][C:30]=5[CH3:37])[CH:3]=[C:4]([CH3:25])[CH:5]=4)=[O:10])[CH2:13][CH2:12]3)=[CH:15][C:16]=2[O:20]1
Reactant: COc1cc(C)c(B(O)O)cn1
Reactant: Cc1cc(Cl)nc(NC(=O)C2(c3ccc4c(c3)OC(F)(F)O4)CC2)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: COc1cc(C)c(-c2cc(C)cc(NC(=O)C3(c4ccc5c(c4)OC(F)(F)O5)CC3)n2)cn1
Temperature: 80 °C
Yield: 52.4 %

Procedure:
To N-(6-chloro-4-methylpyridin-2-yl)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide (59 mg, 0.16 mmol), 6-methoxy-4-methylpyridin-3-ylboronic acid (40 mg, 0.24 mmol) and tetrakis(triphenylphosphine)palladium (0) (9 mg, 0.008 mmol) in 1,2-dimethoxyethane (1.63 mL), aqueous saturated Na2CO3 (163 uL) was added. The reaction mixture was stirred and heated at 80° C. for 18 hours under N2 atmosphere. The reaction mixture was diluted with 1,2-dimethoxyethane, dried over Na2SO4, filtered and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel (0-30% ethyl acetate in hexane) to yield 1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(6′-methoxy-4,4′-dimethyl-2,3′-bipyridin-6-yl)cyclopropanecarboxamide (38 mg, 52%). ESI-MS m/z calc. 453.44. found 454.5 (M+1)+. Retention time 2.01 minutes.
Reaction SMILES: [CH:1]1[C:11]2[CH2:10][CH2:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[C:6](=[CH:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3B(O)O)[C:5]=2[CH:4]=[CH:3][CH:2]=1.Cl[C:27]1[CH:32]=[N:31][CH:30]=[CH:29][N:28]=1.[F-].[Cs+]>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH:1]1[C:11]2[CH2:10][CH2:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[C:6](=[CH:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:27]3[CH:32]=[N:31][CH:30]=[CH:29][N:28]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: Clc1cnccn1
Reactant: OB(O)c1ccccc1C=C1c2ccccc2CCc2ccccc21
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: C(=C1c2ccccc2CCc2ccccc21)c1ccccc1-c1cnccn1
Temperature: 85 °C
Yield: 2.1 %

Procedure:
In a 1-dram vial, mix 2-(10,11-dihydro-dibenzo[a,d]cyclohepten-5-ylidenemethyl)-phenylboronic acid (100 mg, 0.307 mmol), chloropyrazine (69 mg, 0.460 mmol), cesium fluoride (94 mg, 0.614 mmol), and [1,1′-bis(diphenylphosphino)-ferrocene]dichloropalladium(II) (1:1 complex with CH2C2, 25 mg, 0.031 mmol) in dioxane (2 mL). Heat to 85° C. for 72 h, then remove solvent under nitrogen. Take up the resulting residue in H2O (1 mL) and CH2Cl2 (1 mL) and load onto a Varian ChemElut CE1005 solid-phase extraction cartridge. Elute, collect, and concentrate 15 mL CH2Cl2 to obtain crude product. Purify by mass-guided reverse-phase HPLC to obtain 2.3 mg (2%) of the title compound. MS (ES) 361 (M+H); HPLC shows 93% purity.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][C:12](/[C:15](/[CH3:22])=[CH:16]/[C:17](OCC)=[O:18])=[CH:11][CH:10]=1.CC(C[AlH]CC(C)C)C>>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][C:12](/[C:15](/[CH3:22])=[CH:16]/[CH2:17][OH:18])=[CH:11][CH:10]=1
Reactant: CCOC(=O)/C=C(\C)c1ccc(-c2cccc(Cl)c2Cl)cc1
Agent: CC(C)C[AlH]CC(C)C
Product: C/C(=C\CO)c1ccc(-c2cccc(Cl)c2Cl)cc1

Procedure:
(E)-Ethyl 3-(2′,3′-dichloro-biphenyl-4-yl)-but-2-enoate (1.07 g, 3.19 mmol) was reduced with DIBAL-H by a procedure analogous to that described in example 52b to give (E)-3-(2′,3′-dichloro-biphenyl-4-yl)-but-2-en-1-ol as a colourless solid; 0.74 g (79%).
Reaction SMILES: C(C1C=C2C(=CC=1)NC(=O)/C/2=C\C1NC=CC=1)#C.[CH3:19][O:20][C:21]1[CH:25]=[CH:24][NH:23][C:22]=1/[CH:26]=[C:27]1\[C:28](=[O:42])[NH:29][C:30]2[C:35]\1=[CH:34][C:33]([C:36]#[C:37][Si](C)(C)C)=[CH:32][CH:31]=2.[C-]#N.[K+]>C(O)C.O1CCCC1.O.[N+]([O-])([O-])=O.[Ag+]>[C:36]([C:33]1[CH:34]=[C:35]2[C:30](=[CH:31][CH:32]=1)[NH:29][C:28](=[O:42])/[C:27]/2=[CH:26]\[C:22]1[NH:23][CH:24]=[CH:25][C:21]=1[O:20][CH3:19])#[CH:37]
Reactant: COc1cc[nH]c1/C=C1\C(=O)Nc2ccc(C#C[Si](C)(C)C)cc21
Agent: [Ag+]
Agent: C#Cc1ccc2c(c1)/C(=C/c1ccc[nH]1)C(=O)N2
Agent: O=[N+]([O-])[O-]
Solvent: C1CCOC1
Solvent: CCO
Solvent: O
Product: C#Cc1ccc2c(c1)/C(=C/c1[nH]ccc1OC)C(=O)N2
Yield: 88.3 %

Procedure:
This compound was also prepared in a manner analogous to the preparation of (Z)-1,3-dihydro-5-ethynyl-3-[(1H-pyrrol-2-yl)methylene]-2H-indol-2-one in Example 82 above. In this example, (Z)-1,3-dihydro-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-5-(trimethylsilyl)ethynyl-2H-indol-2-one (100 mg, 0.3 mmol) (Example 92) in 5 mL ethanol and 1.5 mL tetrahydrofuran was treated with silver nitrate (0.112 g, 0.6 mmol) in 1.5 mL ethanol and 0.5 mL water, followed by potassium cyanide (218 mg, 3.35 mmol) in 1 mL water to give 70 mg (89%) of (Z)-1,3-dihydro-5-ethynyl-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one (61 mg after recrystallization).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][N:23]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30][NH:29][CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)[CH:7]=[C:8]([C:10]([OH:12])=[O:11])[CH:9]=1)([OH:3])=[O:2].Cl[CH2:36][C:37]([O-:39])=[O:38].[Na+].Cl>>[C:37]([CH2:36][N:26]1[CH2:25][CH2:24][N:23]([CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][C:6]2[CH:7]=[C:8]([C:10]([OH:12])=[O:11])[CH:9]=[C:4]([C:1]([OH:3])=[O:2])[CH:5]=2)[CH2:34][CH2:33][N:32]([CH2:4][C:1]([OH:3])=[O:2])[CH2:31][CH2:30][N:29]([CH2:8][C:10]([OH:12])=[O:11])[CH2:28][CH2:27]1)([OH:39])=[O:38]
Reactant: O=C([O-])CCl
Reactant: O=C(O)c1cc(CCCCCCCCCCN2CCNCCNCCNCC2)cc(C(=O)O)c1
Agent: Cl
Agent: [Na+]
Product: O=C(O)CN1CCN(CCCCCCCCCCc2cc(C(=O)O)cc(C(=O)O)c2)CCN(CC(=O)O)CCN(CC(=O)O)CC1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
To an aqueous solution of 1-[10-(3,5-dicarboxyphenyl)decyl]-1,4,7,10-tetraazacyclododecane (0.16 mols in 500 mL water) is added an aqueous solution of sodium chloroacetate (0.71 mols sodium chloroacetate in 68 mL of water). This solution is stirred at 80° C. overnight while maintaining the pH at 9-10. After cooling to ambient temperature the pH of the solution is adjusted to 2.5 with aqueous HCl. The resulting precipitate is collected by filtration, washed with acetone, and dried in vacuo to afford 18.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:16])[CH3:15])[C:11]([Cl:17])=[CH:10][C:9]=1[NH:18][C:19](=[O:34])[CH2:20][C:21](=O)[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([N:28]2[CH:32]=[N:31][CH:30]=[N:29]2)[CH:23]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:17][C:11]1[C:12]([N:14]([CH3:16])[CH3:15])=[CH:13][C:8]2[N:7]=[C:21]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([N:28]4[CH:32]=[N:31][CH:30]=[N:29]4)[CH:23]=3)[CH2:20][C:19](=[O:34])[NH:18][C:9]=2[CH:10]=1
Reactant: CN(C)c1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-n3cncn3)c2)cc1Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN(C)c1cc2c(cc1Cl)NC(=O)CC(c1cccc(-n3cncn3)c1)=N2

Procedure:
The title compound was prepared from {4-Chloro-5-dimethylamino-2-[3-oxo-3-(3-[1,2,4]triazol-1-yl-phenyl)-propionylamino]-phenyl}-carbamic acid tert.-butyl ester (Example M64) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a yellow solid (316 mg).
Reaction SMILES: COP([CH2:7][C:8](=[O:20])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])(=O)OC.[H-].[Na+].[CH3:23][Si:24]([CH3:33])([CH3:32])[C:25]1[O:29][CH:28]=[C:27]([CH:30]=O)[CH:26]=1>O1CCCC1>[O:20]=[C:8]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH:7]=[CH:30][C:27]1[CH:26]=[C:25]([Si:24]([CH3:33])([CH3:32])[CH3:23])[O:29][CH:28]=1
Reactant: C[Si](C)(C)c1cc(C=O)co1
Reactant: CCCCCCCCCCCC(=O)CP(=O)(OC)OC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCCCCCCCCC(=O)C=Cc1coc([Si](C)(C)C)c1
Reaction time: 1.5 h

Procedure:
A solution of dimethyl-2-oxotridecylphosphonate (984 mg, 3.21 mmol) in tetrahydrofuran (25 ml) was added dropwise to a suspension of sodium hydride (128 mg; a 60% suspension in mineral oil) in tetrahydrofuran (5 ml) at 0° under argon. After 1.5 hours at room temperature, the mixture was cooled to 0° and a solution of 5-trimethylsilyl-3-furaldehyde (450 mg, 2.68 mmol) in tetrahydrofuran (15 ml) was added. Stirring was continued for 14 hours, while the cooling bath attained room temperature. The mixture was quenched with 5% ammonium chloride and washed with 5% sodium bicarbonate and water. Evaporation of the dried (magnesium sulfate) organic phase gave a residue, which was purified by a silica column using 5% ethyl acetate/hexane to give the titled ketone.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O.[CH3:32][C:33]1([CH3:44])[O:38][CH2:37][C:36]([CH2:42][OH:43])([N+:39]([O-:41])=[O:40])[CH2:35][O:34]1.[CH3:45][C:46]1[CH:51]=[C:50]([C:52]2[N:56]=[C:55]([C:57]3[S:64][C:63]([CH3:65])=[C:62]4[C:58]=3[CH2:59][C@H:60]3[C:66]([CH3:68])([CH3:67])[C@H:61]34)[O:54][N:53]=2)[CH:49]=[C:48]([CH3:69])[C:47]=1O>C1COCC1>[CH3:32][C:33]1([CH3:44])[O:34][CH2:35][C:36]([CH2:42][O:43][C:47]2[C:48]([CH3:69])=[CH:49][C:50]([C:52]3[N:56]=[C:55]([C:57]4[S:64][C:63]([CH3:65])=[C:62]5[C:58]=4[CH2:59][C@H:60]4[C:66]([CH3:67])([CH3:68])[C@H:61]45)[O:54][N:53]=3)=[CH:51][C:46]=2[CH3:45])([N+:39]([O-:41])=[O:40])[CH2:37][O:38]1
Reactant: CC1(C)OCC(CO)([N+](=O)[O-])CO1
Reactant: Cc1cc(-c2noc(-c3sc(C)c4c3C[C@@H]3[C@H]4C3(C)C)n2)cc(C)c1O
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1cc(-c2noc(-c3sc(C)c4c3C[C@@H]3[C@H]4C3(C)C)n2)cc(C)c1OCC1([N+](=O)[O-])COC(C)(C)OC1
Reaction time: 168 h
Yield: 40.7 %

Procedure:
To a solution of triphenylphosphine (161 mg, 0.615 mmol) in dry THF (2.5 mL) is added DEAD (0.097 mL, 0.615 mmol). The solution is stirred at rt for 1 h before (2,2-dimethyl-5-nitro-[1,3]dioxan-5-yl)-methanol (118 mg, 0.615 mmol) and 2,6-dimethyl-4-[5-((1aS,5aR)-1,1,2-trimethyl-1,1a,5,5a-tetrahydro-3-thia-cyclopropa[a]pentalen-4-yl)-[1,2,4]oxadiazol-3-yl]-phenol (150 mg, 0.410 mmol) is added. Stirring is continued for 7 days. The formed precipitate is collected, washed with isopropanol and dried under high vacuum to give 3-[4-(2,2-dimethyl-5-nitro-[1,3]dioxan-5-ylmethoxy)-3,5-dimethyl-phenyl]-5-((1aS,5aR)-1,1,2-trimethyl-1,1a,5,5a-tetrahydro-3-thia-cyclopropa[a]pentalen-4-yl)-[1,2,4]oxadiazole (90 mg) as an almost colourless solid; LC-MS: tR=1.30 min, [M+1]+=540.28; 1H NMR (CDCl3): δ 7.77 (s, 2H), 4.50 (d, J=12.9 Hz, 2H), 4.29-4.21 (m, 4H), 3.10 (dd, J=6.4, 18.8 Hz, 1H), 2.93 (d, J=18.8 Hz, 1H), 2.43 (s, 3H), 2.28 (s, 6H), 2.00-1.91 (m, 2H), 1.48 (s, 3H), 1.45 (s, 3H), 1.15 (s, 3H), 0.76 (s, 3H).
Reaction SMILES: [CH2:1]([S:8][CH2:9][C@@H:10]([C:12]([OH:14])=[O:13])[NH2:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:15]([S:22][CH2:23][C:24]([CH3:29])([CH3:28])[C:25](Cl)=[O:26])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.Cl>[OH-].[Na+].CCOCC>[CH2:1]([S:8][CH2:9][C@@H:10]([C:12]([OH:14])=[O:13])[NH:11][C:25](=[O:26])[C:24]([CH3:28])([CH3:29])[CH2:23][S:22][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N[C@@H](CSCc1ccccc1)C(=O)O
Reactant: CC(C)(CSCc1ccccc1)C(=O)Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Product: CC(C)(CSCc1ccccc1)C(=O)N[C@@H](CSCc1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 85.4 %

Procedure:
To a stirred solution of S-benzyl-L-cysteine(11.5 g) in 2N sodium hydroxide solution(68 ml), 3-benzylthio-2,2-dimethylpropionyl chloride (14.6 g) dissolved in ether(10 ml) was added dropwise under ice-cooling. After the addition, the reaction mixture was stirred for 20 minutes under ice-cooling and 2 hours at room temperature. The reaction mixture was acidified with 6N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate and concentrated in vacuo. The oily residue was purified by a silica gel column chromatography to give 19.4 g(85.1%) of the titled compound.