Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][CH2:7][CH2:6][C:5]2=[O:12].[CH:13](=O)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CCO>[CH:13](=[C:6]1/[CH2:7][O:8][C:9]2[C:4]([C:5]/1=[O:12])=[CH:3][C:2]([F:1])=[CH:11][CH:10]=2)/[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C1CCOc2ccc(F)cc21
Reactant: O=Cc1ccccc1
Solvent: CCO
Product: O=C1/C(=C/c2ccccc2)COc2ccc(F)cc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
6-Fluoro-4-chromanone (5.0 g, 30.1 mmol) and 3.35 g (31.6 mmol) benzaldehyde were dissolved in 100 mL of EtOH, and HCl gas was bubbled through the solution until it was nearly boiling. The flask was then capped, allowed to cool to room temperature and stirred overnight. The solids were filtered off and rinsed with a minimum amount of Et2O to provide 1-1 as a light-pinkish solid. Data for 1-1: 1HNMR (500 MHz, CDCl3) δ 7.9 (s, 1H), 7.65 (m, 1H), 7.5-7.4 (m, 3H), 7.3 (m, 2H), 7.2 (m, 1H), 6.95 (m, 1H), 5.35 (s, 2H) ppm. LC-MS: rt=2.8 min, m/z=255 (M+1).
Reaction SMILES: C(OC([N:7]1[CH2:11][C@@H:10]([S:12][C:13]2[C@H:19]([CH3:20])[C@H:18]3[N:15]([C:16](=[O:24])[C@@H:17]3[C@H:21]([OH:23])[CH3:22])[C:14]=2[C:25]([O:27]CC=C)=[O:26])[CH2:9][C@H:8]1[CH2:31][O:32][CH2:33][CH2:34][NH:35][C:36]([NH2:38])=[O:37])=O)C=C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC1(C)CC(=O)CC(=O)C1.C(OCC)(=O)C>O1CCCC1.O.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>[OH:23][C@@H:21]([C@H:17]1[C:16](=[O:24])[N:15]2[C@@H:18]1[C@@H:19]([CH3:20])[C:13]([S:12][C@@H:10]1[CH2:11][NH:7][C@H:8]([CH2:31][O:32][CH2:33][CH2:34][NH:35][C:36]([NH2:38])=[O:37])[CH2:9]1)=[C:14]2[C:25]([OH:27])=[O:26])[CH3:22]
Reactant: C=CCOC(=O)C1=C(S[C@H]2C[C@@H](COCCNC(N)=O)N(C(=O)OCC=C)C2)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC1(C)CC(=O)CC(=O)C1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)O)=C(S[C@@H]3CN[C@H](COCCNC(N)=O)C3)[C@H](C)[C@H]12
Temperature: 25 °C
Yield: 54.4 %

Procedure:
To a solution of allyl (4R,5S,6S)-3-[(2S,4S)-1-allyloxycarbonyl-2-{(2-ureidoethyl)oxymethyl}pyrrolidin-4-yl]thio-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1azabicyclo[3.2.0]hept-2-ene-2-carboxylate (1.73 g) in a mixture of tetrahydrofuran (34 ml) and water (11 ml) were added triphenylphosphine (0.41 g), dimedone (1.32 g) and tetrakis(triphenylphosphine)palladium(0) (0.18 g) successively with stirring at ambient temperature. The mixture was stirred at the same temperature for 3 hours. To the solution were added ethyl acetate (50 ml) and water (30 ml). The aqueous layer was separated and washed 3 times with ethyl acetate (30 ml). This aqueous layer was concentrated in vacuo to remove the organic solvent. The residue was chromatographed on activated charcoal (made by Wako Pure Chemical Industries) (30 ml) eluting in turn with water (90 ml) and 15% aqueous isopropyl alcohol (200 ml). The fractions containing the desired compound were collected and lyophilized to give (4R,5S, 6S)-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-3-[(2S,4S)-2-{(2-ureidoethyl)oxymethyl}pyrrolidin-4-yl]thio-1azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid (0.73 g).
Reaction SMILES: C1(C)C=CC(S([O-])(=O)=O)=CC=1.[CH2:12]([N+:30]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[C:33]([CH3:34])=[CH:32][CH:31]=1)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29].Cl[C:42]1[CH:47]=[CH:46][C:45]([N+:48]([O-:50])=[O:49])=[CH:44][C:43]=1[C:51]([F:54])([F:53])[F:52].C(N(C(C)C)CC)(C)C>C(#N)C>[N+:48]([C:45]1[CH:46]=[CH:47][C:42]([CH:34]=[C:33]2[C:35]3[C:40](=[CH:39][CH:38]=[CH:37][CH:36]=3)[N:30]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH:31]=[CH:32]2)=[C:43]([C:51]([F:52])([F:53])[F:54])[CH:44]=1)([O-:50])=[O:49]
Reactant: O=[N+]([O-])c1ccc(Cl)c(C(F)(F)F)c1
Reactant: CCCCCCCCCCCCCCCCCC[n+]1ccc(C)c2ccccc21
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CCCCCCCCCCCCCCCCCCN1C=CC(=Cc2ccc([N+](=O)[O-])cc2C(F)(F)F)c2ccccc21

Procedure:
A mixture of 1-octadecyllepidinium p-toluenesulfonate (24.6 g.), 2-chloro-5-nitrobenzotrifluoride (10 g.) and acetonitrile (700 ml.) was treated with diisopropylethylamine (20.7 g.) and refluxed for 6 hours with stirring. After filtering and evaporating, 1,4-dihydro-4-(4-nitro-2-trifluoromethylbenzylidene)-1-octadecylquinoline was formed. This colored dye was changed to the colorless compound having the formula: ##STR5## by reacting with a molar equivalent of p-toluenesulfonic acid in methanol.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:10]2[O:11][CH:12]=[C:13]([CH2:15][NH:16][C:17](=[O:25])[C:18]3[C:23]([CH3:24])=[CH:22][CH:21]=[CH:20][N:19]=3)[N:14]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].C(=O)([O-])[O-].[K+].[K+].[F:32][C:33]([F:37])([F:36])[CH2:34]I.O>CN(C)C=O>[CH3:9][O:8][C:7]1[CH:6]=[CH:5][C:4]([C:10]2[O:11][CH:12]=[C:13]([CH2:15][NH:16][C:17](=[O:25])[C:18]3[C:23]([CH3:24])=[CH:22][CH:21]=[CH:20][N:19]=3)[N:14]=2)=[CH:3][C:2]=1[O:1][CH2:34][C:33]([F:37])([F:36])[F:32]
Reactant: FC(F)(F)CI
Reactant: COc1ccc(-c2nc(CNC(=O)c3ncccc3C)co2)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(-c2nc(CNC(=O)c3ncccc3C)co2)cc1OCC(F)(F)F
Temperature: 80 °C

Procedure:
A 0.15 g quantity of the N-[2-(3-hydroxy-4-methoxy phenyl)oxazol-4-ylmethyl]-3-methylpicolinamide obtained in Example 17 and 0.18 g of potassium carbonate were dissolved in 4 ml of dimethylformamide, and 0.19 g of 1,1,1-trifluoro-2-iodoethane was added thereto. The mixture was stirred with heating at 80° C. overnight. The reaction mixture was allowed to cool, water was then added thereto, and extraction was performed with ethyl acetate. The extract was washed with water twice, and the organic layer was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=3:1) to give 0.11 g of white powdery N-{2-[4-methoxy-3-(2,2,2-trifluoroethoxy)phenyl]oxazol-4-ylmethyl}-3-methylpicolinamide.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH2:4][S:5][C@@H:6]2[CH:13]([NH:14][C:15](=[O:26])/[C:16](/[C:20]3[N:21]=[C:22]([NH2:25])[S:23][CH:24]=3)=[N:17]\[O:18][CH3:19])[C:12](=[O:27])[N:7]2[C:8]=1[C:9]([OH:11])=[O:10].C(N(CC)CC)C.[C:35](Cl)(Cl)=[S:36].C(O)(C(F)(F)F)=O>C(#N)C.O>[NH2:25][C:22]1[S:23][CH:24]=[C:20](/[C:16](=[N:17]/[O:18][CH3:19])/[C:15]([NH:14][CH:13]2[C:12](=[O:27])[N:7]3[C:8]([C:9]([OH:11])=[O:10])=[C:3]([CH2:2][N:1]=[C:35]=[S:36])[CH2:4][S:5][C@H:6]23)=[O:26])[N:21]=1
Reactant: S=C(Cl)Cl
Reactant: CO/N=C(\C(=O)NC1C(=O)N2C(C(=O)O)=C(CN)CS[C@H]12)c1csc(N)n1
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CO/N=C(\C(=O)NC1C(=O)N2C(C(=O)O)=C(CN=C=S)CS[C@H]12)c1csc(N)n1
Reaction time: 0.5 h

Procedure:
To a solution of 3-aminomethyl-7-[2-(2-aminothiazol-4-yl)-2-((Z)-methoxyimino)acetamido]ceph-3-em-4-carboxylic acid (1.34 g.) in acetonitrile (100 ml.), water (30 ml.) and triethylamine (1.01 g.) at -15° was dropwise added thiophosgene (250 ul.). The mixture was stirred for 30 minutes at -15° and then the pH of the mixture was adjusted to 3-4 by addition of TFA. The solvent was evaporated and the residue purifed by HPLC using an aqueous ammonium carbonate buffer, pH 6-7/MeOH 70:30 v/v as eluant to give 7-[2-(2-aminothiazol-4-yl)-2-((Z)-methoxyimino)acetamido]3-isothiocyanatomethylceph-3-em-4-carboxylic acid having the following nmr in solvent B:--3.56 (d, 1 H); 3.84 (d, 1 H); 4.08 (s, 3 H); 4.6 (d, 1 H); 4.84 (d, 1 H); 5.3 (d, 1 H); 5.96 (d, 1 H); 7.14 (s, 1 H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:12]=[C:11]([O:23][C:24]2[CH:29]=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][CH:25]=2)[C:10]=1[C:33](=[O:35])[CH3:34])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li].C[Si]([N-][Si](C)(C)C)(C)C.C1COCC1.[C:51](OCC)(=[O:57])[C:52]([O:54][CH2:55][CH3:56])=[O:53].Cl>C1COCC1.[Cl-].[Na+].O>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:12]=[C:11]([O:23][C:24]2[CH:25]=[CH:26][C:27]([N+:30]([O-:32])=[O:31])=[CH:28][CH:29]=2)[C:10]=1[C:33](=[O:35])[CH2:34][C:51](=[O:57])[C:52]([O:54][CH2:55][CH3:56])=[O:53])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(=O)OCC
Reactant: CC(=O)c1c(OCc2ccccc2)cc(OCc2ccccc2)cc1Oc1ccc([N+](=O)[O-])cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)C(=O)CC(=O)c1c(OCc2ccccc2)cc(OCc2ccccc2)cc1Oc1ccc([N+](=O)[O-])cc1
Reaction time: 0.5 h
Yield: 75 %

Procedure:
To a stirred solution of 1-[2,4-bis(benzyloxy)-6-(4-nitrophenoxy)phenyl]ethanone (5.1 g, 11 mmol) in THF (50 mL) was added drop wise 1M lithium (bis trimethylsilylamide/THF solution (12 mL, 12 mmol) at −50° C. After 30 minutes, a solution of diethyl oxalate (1.7 mL) in THF (15 mL) was slowly added and the stirring was continued for 1 hours. The solution was taken up in brine (200 mL) and treated with 1 M HCl solution (13 mL), then extracted with ethyl acetate. The organic phase was dried and the solvent removed. The crude was filtered on a small pad of silica gel eluting with hexane/ethyl acetate 2/1 to afford the title compound (5.7 g, 75% yield).
Reaction SMILES: Cl.[CH3:2][C:3]1([CH3:26])[CH2:12][CH2:11][C:10]([CH3:14])([CH3:13])[C:9]2[CH:8]=[C:7]([C:15]3[O:16][CH:17]=[C:18]([CH:20]4[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]4)[N:19]=3)[CH:6]=[CH:5][C:4]1=2.[OH:27][CH2:28][CH2:29][CH2:30][CH2:31][CH:32]=O>>[CH3:2][C:3]1([CH3:26])[CH2:12][CH2:11][C:10]([CH3:13])([CH3:14])[C:9]2[CH:8]=[C:7]([C:15]3[O:16][CH:17]=[C:18]([CH:20]4[CH2:25][CH2:24][N:23]([CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][OH:27])[CH2:22][CH2:21]4)[N:19]=3)[CH:6]=[CH:5][C:4]1=2
Reactant: O=CCCCCO
Reactant: CC1(C)CCC(C)(C)c2cc(-c3nc(C4CCNCC4)co3)ccc21
Agent: Cl
Product: CC1(C)CCC(C)(C)c2cc(-c3nc(C4CCN(CCCCCO)CC4)co3)ccc21

Procedure:
The preparation was carried out as already described via a reductive amination starting from 200 mg (0.32 mmol) of 4-[2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)oxazol-4-yl]piperidine hydrochloride and 65 mg (0.64 mmol) of 5-hydroxypentanal. The product was purified by means of preparative HPLC and converted into the hydrochloride by treatment with methanolic HCl.
Reaction SMILES: [CH:1]1[C:11]2[CH:10]=[CH:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[CH:6]([O:16][CH2:17][CH2:18][OH:19])[C:5]=2[CH:4]=[CH:3][CH:2]=1.C(P(CCCC)CCCC)CCC.[CH2:33]([O:35][C:36](=[O:49])[CH:37]([O:46][CH2:47][CH3:48])[CH2:38][C:39]1[CH:44]=[CH:43][C:42](O)=[CH:41][CH:40]=1)[CH3:34].O>C1C=CC=CC=1>[CH2:33]([O:35][C:36](=[O:49])[CH:37]([O:46][CH2:47][CH3:48])[CH2:38][C:39]1[CH:44]=[CH:43][C:42]([O:19][CH2:18][CH2:17][O:16][CH:6]2[C:7]3[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=3[CH:9]=[CH:10][C:11]3[CH:1]=[CH:2][CH:3]=[CH:4][C:5]2=3)=[CH:41][CH:40]=1)[CH3:34]
Reactant: OCCOC1c2ccccc2C=Cc2ccccc21
Reactant: CCOC(=O)C(Cc1ccc(O)cc1)OCC
Agent: CCCCP(CCCC)CCCC
Solvent: O
Solvent: c1ccccc1
Product: CCOC(=O)C(Cc1ccc(OCCOC2c3ccccc3C=Cc3ccccc32)cc1)OCC
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 46.3 %

Procedure:
Under a nitrogen atmosphere, 2-(5H-dibenzo[a,d]cyclohepten-5-yloxy)-ethanol (400 mg, 1.6 mmol), tributylphosphine (480 mg, 2.4 mmol) and 2-ethoxy-3-(4-hydroxy-phenyl)-propionic acid ethyl ester (380 mg, 1.6 mmol) were successively dissolved in dry benzene (10 mL). Solid azodicarboxylic dipiperidine (ADDP) (480 mg, 2.4 mmol) was added under stirring at 0° C. to the solution. After 10 min, the reaction mixture was brought to room temperature and the stirring was continued for 2 h. The mixture was added water and the product extracted with ethyl acetate. The combined organic phases was dried (MgSO4), and concentrated in vacuo. The residue was purified chromatography eluting with ethyl acetate/hexane (1:9) to give 350 mg (47%) of the title compound: MS 472 (M+).
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([Cl:12])[C:3]=1[C:13]1[N:18]=[CH:17][C:16]2[C:19](I)=[N:20][NH:21][C:15]=2[CH:14]=1.[CH3:23][N:24]([CH3:45])[C:25](=[O:44])[CH2:26][O:27][C:28]1[CH:33]=[CH:32][C:31](B2OC(C)(C)C(C)(C)O2)=[CH:30][C:29]=1[CH3:43]>>[Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([Cl:12])[C:3]=1[C:13]1[N:18]=[CH:17][C:16]2[C:19]([C:31]3[CH:32]=[CH:33][C:28]([O:27][CH2:26][C:25]([N:24]([CH3:23])[CH3:45])=[O:44])=[C:29]([CH3:43])[CH:30]=3)=[N:20][NH:21][C:15]=2[CH:14]=1
Reactant: Cc1cc(B2OC(C)(C)C(C)(C)O2)ccc1OCC(=O)N(C)C
Reactant: COc1cc(OC)c(Cl)c(-c2cc3[nH]nc(I)c3cn2)c1Cl
Product: COc1cc(OC)c(Cl)c(-c2cc3[nH]nc(-c4ccc(OCC(=O)N(C)C)c(C)c4)c3cn2)c1Cl

Procedure:
This compound was prepared using procedures analogous to those described for the synthesis of Example 4, Step 2 starting from 6-(2,6-dichloro-3,5-dimethoxyphenyl)-3-iodo-1H-pyrazolo[4,3-c]pyridine and N,N-dimethyl-2-[2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]acetamide. LCMS (M+H)+=515.1/517.1.
Reaction SMILES: [C:1]1([CH:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:8][NH2:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:16]#[C:17]Br>CCOCC>[C:10]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:8][NH:9][C:17]#[N:16])[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: N#CBr
Reactant: NCC(c1ccccc1)c1ccccc1
Solvent: CCOCC
Product: N#CNCC(c1ccccc1)c1ccccc1

Procedure:
A cold (0° C.) solution of 2,2-diphenylethylamine (3.36 g, 17.0 mmol) in 50 ml of Et2O, was treated with a solution of cyanogen bromide (1.15 g, 10.9 mmol) in 10 ml of Et2O, under N2, resulting in the formation of a white precipitate. This precipitate was removed by filtration and the filtrate was concentrated in vacuo.
Reaction SMILES: [N:1]1([S:7]([C:10]2[CH:15]=[CH:14][C:13]([N:16]3[CH2:25][CH2:24][C:19]4(OCC[O:20]4)[CH2:18][CH2:17]3)=[CH:12][CH:11]=2)(=[O:9])=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1>C(O)=O>[N:1]1([S:7]([C:10]2[CH:11]=[CH:12][C:13]([N:16]3[CH2:17][CH2:18][C:19](=[O:20])[CH2:24][CH2:25]3)=[CH:14][CH:15]=2)(=[O:9])=[O:8])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=S(=O)(c1ccc(N2CCC3(CC2)OCCO3)cc1)N1CCCCC1
Solvent: O=CO
Product: O=C1CCN(c2ccc(S(=O)(=O)N3CCCCC3)cc2)CC1
Temperature: 60 °C
Yield: 79.5 %

Procedure:
8-[4-(1-Piperidinylsulfonyl)phenyl]-1,4-dioxa-8-azaspiro[4.5]decane (1.0 g, 2.73 mmol) was dissolved in formic acid and heated at 60° C. for 1 hour. The solvent was removed in vacuo and the residue crystallized from ethanol to give the title compound (0.70 g, 2.17 mmol).
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:16][CH:15]=1.[C:25](=[O:27])=[O:26]>O1CCCC1>[Cl:13][C:14]1[CH:15]=[CH:16][C:17]([O:20][C:21]([F:22])([F:23])[F:24])=[C:18]([CH:19]=1)[C:25]([OH:27])=[O:26]
Reactant: FC(F)(F)Oc1ccc(Cl)cc1
Reactant: O=C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: O=C(O)c1cc(Cl)ccc1OC(F)(F)F
Temperature: -100 °C
Reaction time: 2 h

Procedure:
A 1.6 M solution of butyllithium in hexanes (26.5 mmol, 16.5 mL) was added to a 0° C. solution of diisopropylamine (2.65 g, 26.5 mmol) in tetrahydrofuran (50 mL). The solution was cooled to −100° C., and 1-chloro-4-(trifluoromethoxy)benzene (Matrix) (5.0 g, 26.5 mmol) was added. After 2 h at −100° C., the mixture was poured onto an excess of freshly crushed dry ice. After evaporation of the volatiles, the residue was dissolved in a 1 M aqueous solution (50 mL) of sodium hydroxide, washed with diethyl ether (2×15 mL), and acidified to pH 1 by the addition of concentrated hydrochloric acid (7 mL). The aqueous layers were extracted with diethyl ether (3×30 mL). The combined organic extracts were dried (MgSO4), filtered and concentrated to afford the title product. 1H NMR (300 MHz, DMSO-d6) δ ppm 7.54 (dd, J=8.8, 1.0 Hz, 1H) 7.78 (dd, J=8.8, 2.7 Hz, 1H) 7.92 (d, J=2.7 Hz, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([CH3:18])=[C:8]2[C:13](=O)[C:12]([C:15]#[N:16])=[CH:11][NH:10][N:9]2[CH:17]=1)=[O:5])[CH3:2].O=P(Cl)(Cl)[Cl:21]>>[CH2:1]([O:3][C:4]([C:6]1[C:7]([CH3:18])=[C:8]2[C:13]([Cl:21])=[C:12]([C:15]#[N:16])[CH:11]=[N:10][N:9]2[CH:17]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cn2[nH]cc(C#N)c(=O)c2c1C
Reactant: O=P(Cl)(Cl)Cl
Product: CCOC(=O)c1cn2ncc(C#N)c(Cl)c2c1C
Temperature: 75 °C

Procedure:
A 15 mL round bottom flask containing the compound 1C (370 mg, 1.51 mmol) was charged with POCl3 (1 mL) and heated to 75° C. for 2 h. The reaction mixture was concentrated in vacuo and the resulting yellow residue was dissolved in dichloromethane (10 mL) and added, via pipette, to a saturated aqueous solution of NaCHO3 with stirring at 0° C. The heterogeneous mixture was stirred for 10 min at 0° C. then warmed to room temperature and stirred for an additional 1h. The mixture was poured into a separatory funnel and the layers were separated. The aqueous phase was extracted with dichloromethane (2×20 mL) and the combined organic extracts were washed with NaHCO3 (sat. aq., 1×20 mL), dried over Na2SO4, filtered and concentrated in vacuo. The resulting residue was dissolved in EtOAc (20 mL) and filtered through a pad of silica using EtOAc (100 mL) to wash the silica pad. The filtrate was concentrated in vacuo to afford compound 1D as a yellow solid which was used without further purification. HPLC: 100% at 4.160 min (retention time) (YMC S5 ODS column, 4.6×50 mm, eluting with 10-90% aqueous methanol over 4 min containing 0.2% phosphoric acid, 4 mL/min, monitoring at 220 nm).
Reaction SMILES: [C:1]([C:3]([C:20]#[N:21])=[CH:4][NH:5][NH:6][C:7]1[C:12]([Cl:13])=[CH:11][C:10]([S:14][C:15]([F:18])([F:17])[F:16])=[CH:9][C:8]=1[Cl:19])#[N:2].C>C(OCCO)C>[NH2:2][C:1]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([S:14][C:15]([F:16])([F:17])[F:18])=[CH:9][C:8]=2[Cl:19])[N:5]=[CH:4][C:3]=1[C:20]#[N:21]
Reactant: N#CC(C#N)=CNNc1c(Cl)cc(SC(F)(F)F)cc1Cl
Solvent: CCOCCO
Product: N#Cc1cnn(-c2c(Cl)cc(SC(F)(F)F)cc2Cl)c1N
Yield: 69.4 %

Procedure:
14.1 g (0.04 mole) of 1-(2,2-dicyanethen-1-yl)-2-(2,6-dichloro-4-trifluoromethylthio-phenyl)-hydrazine in 30 ml of ethylene glycol monoethyl ether are heated under reflux for 2 hours. Active charcoal is added to the hot solution, the mixture is filtered and the filtrate is diluted with 60 ml of water. The precipitate which has separated out is filtered off with suction and dried. 9.8 g (70% of theory) of 5-amino-4-cyano-1-(2,6-dichloro-4-trifluoromethylthio-phenyl)-pyrazole of melting point 185° C. to 187° C. are obtained. ##STR119##
Reaction SMILES: P(Cl)(Cl)(Cl)(Cl)[Cl:2].[C:7]([CH:13]([C:16]#[N:17])[C:14]#[N:15])(=O)[C:8]([CH3:11])([CH3:10])[CH3:9].S(=O)=O>C(Cl)Cl>[Cl:2][C:7]([C:8]([CH3:11])([CH3:10])[CH3:9])=[C:13]([C:16]#[N:17])[C:14]#[N:15]
Reactant: CC(C)(C)C(=O)C(C#N)C#N
Reactant: ClP(Cl)(Cl)(Cl)Cl
Agent: O=S=O
Solvent: ClCCl
Product: CC(C)(C)C(Cl)=C(C#N)C#N
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Phosphorous pentachloride (86 g) was added slowly to a stirred suspension of the above pivaloylmalononitrile intermediate (a) (57 g) in methylene chloride (500 ml) and was allowed to stir at room temperature for 16 hours. Sulfur dioxide was passed through the solution for 20 minutes and the solvent was removed on a rotary evaporator. The residue was poured onto ice and filtered. The product was used without further purification.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([OH:13])=O)[CH:10]=1)[NH:7][CH:6]=[CH:5]2.[C:14]([C:18]1[CH:33]=[CH:32][C:21]([CH2:22][NH:23][CH2:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[CH:20][CH:19]=1)([CH3:17])([CH3:16])[CH3:15].CCN=C=NCCCN(C)C.Cl>C(Cl)Cl>[C:14]([C:18]1[CH:33]=[CH:32][C:21]([CH2:22][N:23]([CH2:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:11]([C:9]2[CH:10]=[C:2]([F:1])[CH:3]=[C:4]3[C:8]=2[NH:7][CH:6]=[CH:5]3)=[O:13])=[CH:20][CH:19]=1)([CH3:17])([CH3:15])[CH3:16]
Reactant: CC(C)(C)c1ccc(CNCCc2ccccc2)cc1
Reactant: O=C(O)c1cc(F)cc2cc[nH]c12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: CC(C)(C)c1ccc(CN(CCc2ccccc2)C(=O)c2cc(F)cc3cc[nH]c23)cc1
Temperature: 25 °C
Yield: 66.1 %

Procedure:
66 mg (0.33 mol) of 5-fluoro-1H-indol-7-carboxylic acid, 80 mg (0.30 mmol) of (4-tert-butyl-benzyl)-2-phenyl-ethyl-amine and 63 mg (0.33 mmol) of EDC.HCl were dissolved in 3 ml DCM. The reaction mixture was stirred at rt over night. The solvent was evaporated and the residue was purified by column chromatography (20 g silica gel; heptane/EtOAc 7:3) to yield 85 mg (66%) product as a light yellow viscous oil. MS (ISP) 429.4 (M+H)+.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5]/[CH:6]=[CH:7]/[C:8]1[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][CH:9]=1>CO.[C].[Pd]>[OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]1[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][CH:9]=1
Reactant: COC(=O)c1ccc(/C=C/CCCCO)cc1
Agent: [Pd]
Solvent: CO
Product: COC(=O)c1ccc(CCCCCCO)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 88 %

Procedure:
In a solution of the compound 29 (2.50 g) in methanol (30 mL), 10% palladium carbon (250 mg) was added under an argon atmosphere. The reaction mixture was stirred under a hydrogen atmosphere at room temperature for 3 hours. The reaction mixture was filtered with Celite (trade name) and the filtrate was concentrated. The residue was purified by silica gel chromatography (n-hexane:ethyl acetate=7:3→3:7) to obtain methyl 4-(6-hydroxyhexyl)benzoate (2.22 g). The same procedure as a series of reactions of Example 25 was carried out, except that methyl 4-(6-hydroxyhexyl)benzoate was used in place of the compound 24, to obtain the title compound having the following physical properties.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10]([NH:13][CH2:14][C:15]#[CH:16])(=[O:12])=[O:11])([O-:3])=[O:2].C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:24][CH2:25][CH2:26][Cl:27]>CC(C)=O>[Cl:27][CH2:26][CH2:25][CH2:24][N:13]([CH2:14][C:15]#[CH:16])[S:10]([C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[N+:1]([O-:3])=[O:2])(=[O:11])=[O:12]
Reactant: ClCCCBr
Reactant: C#CCNS(=O)(=O)c1ccccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Product: C#CCN(CCCCl)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 48 h
Yield: 68.8 %

Procedure:
To a mixture of 2-nitro-N-(prop-2-yn-1-yl)benzenesulfonamide (1.08 g, 4.48 mmol) and cesium carbonate (7.30 g, 22.42 mmol) in acetone (40 mL) was added neat 1-bromo-3-chloropropane (6.5 mL, 66 mmol) dropwise. Upon complete addition, the reaction mixture was stirred at room temperature for 2 days. The reaction mixture was concentrated and the residue partitioned between EtOAc (25 mL) and water (15 mL). The aqueous layer was extracted with additional EtOAc (20 mL), the combined organic layers dried over anhydrous MgSO4 and concentrated. Purification via silica chromatography (25-40% EtOAc/hexane) afforded Intermediate 18 as an oil (0.9764 g, 69%). 1H NMR (400 MHz, CDCl3) δ 8.10-8.05 (m, 1H), 7.76-7.62 (m, 3H), 4.22 (d, J=2.5 Hz, 2H), 3.57 (td, J=6.6, 2.9 Hz, 4H), 2.21 (t, J=2.5 Hz, 1H), 2.14-2.06 (m, 2H).