Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[C:7]3[CH:14]=[CH:13][N:12]([CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[C:8]=3[N:9]=[CH:10][N:11]=2)[CH:3]=[N:2]1.[C:23]([CH:25]=[C:26]1[CH2:29][CH:28]([C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH2:27]1)#[N:24].N12CCCN=C1CCCCC2>C(#N)C>[C:23]([CH2:25][C:26]1([N:1]2[CH:5]=[C:4]([C:6]3[C:7]4[CH:14]=[CH:13][N:12]([CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[C:8]=4[N:9]=[CH:10][N:11]=3)[CH:3]=[N:2]2)[CH2:29][CH:28]([C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH2:27]1)#[N:24]
Reactant: CCOC(=O)C1CC(=CC#N)C1
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cn[nH]c3)ncnc21
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: CCOC(=O)C1CC(CC#N)(n2cc(-c3ncnc4c3ccn4COCC[Si](C)(C)C)cn2)C1
Temperature: 25 °C
Reaction time: 136 h

Procedure:
To a solution of 4-(1H-pyrazol-4-yl)-7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidine (5.23 g, 16.6 mmol) and ethyl 3-(cyanomethylene)cyclobutanecarboxylate (prepared in Step 4) in acetonitrile (40 mL) was added 1,8-diazabicyclo[5.4.0]undec-7-ene (2.48 mL, 16.6 mmol). The mixture was stirred for 136 hours at room temperature. The solvent was removed in vacuo. Flash column chromatography, eluting with a gradient of 50-90% ethyl acetate in hexanes afforded product as a mixture of cis- and trans-isomers (4.53 g, 52% over the two steps).
Reaction SMILES: [CH2:1]([C@@H:8]([CH2:12][CH2:13][C@H:14]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:15]([NH:17][C@H:18]1[CH2:24][CH2:23][CH2:22][CH2:21][N:20]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[O:31][CH3:32])[C:19]1=[O:33])=[O:16])[C:9](O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:41][C@H:42]1[CH2:48][CH2:47][S:46][C@H:45]2[CH2:49][CH2:50][CH2:51][C@@H:52]([C:53]([F:56])([F:55])[F:54])[N:44]2[C:43]1=[O:57]>>[CH2:34]([C@@H:14]([CH2:13][CH2:12][C@H:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:9]([NH:41][C@H:42]1[CH2:48][CH2:47][S:46][C@H:45]2[CH2:49][CH2:50][CH2:51][C@@H:52]([C:53]([F:54])([F:56])[F:55])[N:44]2[C:43]1=[O:57])=[O:10])[C:15]([NH:17][C@H:18]1[CH2:24][CH2:23][CH2:22][CH2:21][N:20]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[O:31][CH3:32])[C:19]1=[O:33])=[O:16])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: N[C@H]1CCS[C@H]2CCC[C@@H](C(F)(F)F)N2C1=O
Reactant: COc1ccccc1N1CCCC[C@H](NC(=O)[C@H](CC[C@H](Cc2ccccc2)C(=O)O)Cc2ccccc2)C1=O
Product: COc1ccccc1N1CCCC[C@H](NC(=O)[C@H](CC[C@H](Cc2ccccc2)C(=O)N[C@H]2CCS[C@H]3CCC[C@@H](C(F)(F)F)N3C2=O)Cc2ccccc2)C1=O

Procedure:
(2R,5R)-2,5-Dibenzyl-N1-((S)-1-(2-methoxyphenyl)-2-oxoazepan-3-yl)-N6-((4S,7S,10aS)-5-oxo-7-(trifluoromethyl)octahydro-2H-pyrido[2,1-b][1,3]thiazepin-4-yl)hexanediamide was synthesized as described in General Procedure H using Intermediate 70 (19 mg, 0.035 mmol) and Intermediate 77 (9.0 mg, 0.034 mmol) to give a white solid (25 mg, 90% yield). Anal. Calcd. for C43H51F3N4O5S m/z 792.7. found: 793.3 (M+H)+; 1H NMR (400 MHz, CDCl3) δ ppm 7.40-6.82 (m, 16H), 5.21 (t, J=6.7 Hz, 2H), 4.97-4.84 (m, 2H), 4.76 (t, 1H), 3.98-3.82 (m, 1H), 3.79 (s, 3H), 3.46-3.30 (m, 1H), 3.25-3.08 (m, 1H), 2.93-2.75 (m, 2H), 2.75-2.53 (m, 3H), 2.44-2.29 (m, 3H), 2.21-1.28 (m, 16H).
Reaction SMILES: C[O:2][C:3](=[O:32])[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([F:14])=[CH:11][CH:12]=2)[C:7]([CH2:15][C:16]2[C:17]([S:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)(=[O:24])=[O:23])=[N:18][CH:19]=[CH:20][CH:21]=2)=[C:6]1[CH3:31].[OH-].[Li+]>O1CCCC1>[C:25]1([S:22]([C:17]2[C:16]([CH2:15][C:7]3[C:8]4[C:13](=[CH:12][CH:11]=[C:10]([F:14])[CH:9]=4)[N:5]([CH2:4][C:3]([OH:32])=[O:2])[C:6]=3[CH3:31])=[CH:21][CH:20]=[CH:19][N:18]=2)(=[O:24])=[O:23])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: COC(=O)Cn1c(C)c(Cc2cccnc2S(=O)(=O)c2ccccc2)c2cc(F)ccc21
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1c(Cc2cccnc2S(=O)(=O)c2ccccc2)c2cc(F)ccc2n1CC(=O)O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 70.9 %

Procedure:
A mixture of [3-(2-benzenesulfonylpyridin-3-ylmethyl)-5-fluoro-2-methylindol-1-yl]acetic acid methyl ester (0.16 g) and tetrahydrofuran (5.0 mL) was treated with 1.0 M aqueous lithium hydroxide solution (0.5 mL), and the resulting mixture was stirred at room temperature for 30 minutes. The mixture was concentrated under reduced pressure, pH adjusted to 4 by the addition of 0.1 M aqueous hydrochloric acid solution and extracted with ethyl acetate. The combined organic extract was washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by preparative reverse-phase HPLC, eluting with a mixture of acetonitrile and water (5:95 to 98:2 by volume) to afford the title compound as a white solid (0.11 g).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][N:5]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:6]=1[C:7]([NH2:9])=[O:8].[CH3:17][O:18][C:19]1[CH:27]=[CH:26][CH:25]=[CH:24][C:20]=1[C:21](Cl)=[O:22].C(Cl)(=O)C1C=CC=CC=1>>[CH3:17][O:18][C:19]1[CH:27]=[CH:26][CH:25]=[CH:24][C:20]=1[C:21]([NH:1][C:2]1[N:3]=[CH:4][N:5]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:6]=1[C:7]([NH2:9])=[O:8])=[O:22]
Reactant: COc1ccccc1C(=O)Cl
Reactant: NC(=O)c1c(N)ncn1Cc1ccccc1
Solvent: O=C(Cl)c1ccccc1
Product: COc1ccccc1C(=O)Nc1ncn(Cc2ccccc2)c1C(N)=O
Yield: 53 %

Procedure:
An amidation reaction and post-treatment were carried out according to the conditions of Example 1, using 2.2 g (10 mmol) of 4-amino-1-benzyl-5-imidazolecarboxamide prepared in Reference Example 2 and 2-methoxybenzoyl chloride separately prepared according to a conventional method, instead of benzoyl chloride, to obtain a crude amide product. The crude amide product was purified by suspension in hot methanol to obtain 1.87 g of 4-(2-methoxybenzoylamino)-1-benzyl-5-imidazolecarboxamide (yield 53%).
Reaction SMILES: [CH:1]1[CH:6]=[C:5]([Cl:7])[CH:4]=[C:3]([C:8]([O:10]O)=[O:9])[CH:2]=1>C(Cl)Cl>[Cl:7][C:5]1[CH:4]=[C:3]([C:8]([OH:10])=[O:9])[CH:2]=[CH:1][CH:6]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: O=C(O)c1cccc(Cl)c1

Procedure:
m-CPBA (14 g, 62.47 mmol based on 77% purity) was dried in vacuum until vacuum reached 10 mTorr. Anhydrous methylene chloride (100 mL) was added to dissolve m-CPBA. Me(EtO)2SiCH═CH2 (10 g, 62.5 mmol) was added to the clear solution of m-CPBA in CH2Cl2. No visual changes immediately occurred. The white precipitate of m-ClC6H4COOH formed within 2 hours. The reaction mixture was reduced in volume under vacuum (about 75 mL of CH2Cl2 were removed). Pentane (50 mL) was added and then the mixture was filtered. Low boiling point volatiles were removed in vacuum. The mixture of unreacted Me(EtO)2SiCH═CH2 (10%) and the product (90%) was isolated under vacuum distillation. Second distillation yielded high purity oxirane. Yield: 50%. Boiling point: 30° C. at 0.2 Torr. Mass spectrum: (EI, %): m/z 176 (M+, 1), 161 (M+-Me, 10), 133 (M+-CHCH2O, 100). 1H NMR (C6D6): δ 3.76–3.64 (m, 4H, SiOCH2CH3), 2.59–2.5 (m, 2H, SiCHCH2), 2.08–2.05 (m, 1H, SiCHCH2), 1.17–1.07 (m, 6H, SiOCH2CH3), 0.07 (s, 3H, SiCH3). 13C NMR: (C6D6) δ 59.15 (SiOCH2CH3), 44.07 (SiCHCH2), 18.91 (SiOCH2CH3), −6.25 (SiCH3).
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][O:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19]2[CH:24]([O:25][CH2:26][C:27]3[CH:36]=[CH:35][C:34]4[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=4)[CH:28]=3)[CH2:23][N:22]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:21][CH:20]2[CH2:44][OH:45])=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:46][O:47][CH2:48][CH2:49]Br>>[CH2:1]([O:8][CH2:9][CH2:10][O:11][CH2:12][C:13]1[CH:14]=[CH:15][C:16]([CH:19]2[CH:24]([O:25][CH2:26][C:27]3[CH:36]=[CH:35][C:34]4[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=4)[CH:28]=3)[CH2:23][N:22]([C:37]([O:39][C:40]([CH3:41])([CH3:42])[CH3:43])=[O:38])[CH2:21][CH:20]2[CH2:44][O:45][CH2:49][CH2:48][O:47][CH3:46])=[CH:17][CH:18]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CC(CO)C(c2ccc(COCCOCc3ccccc3)cc2)C(OCc2ccc3ccccc3c2)C1
Reactant: COCCBr
Product: COCCOCC1CN(C(=O)OC(C)(C)C)CC(OCc2ccc3ccccc3c2)C1c1ccc(COCCOCc2ccccc2)cc1

Procedure:
In an analogous manner to that described in Example 1 (g), by alkylating tert-butyl (3SR,4RS,5RS)-4-[4-(2-benzyloxy-ethoxymethyl)-phenyl]-3-hydroxymethyl-5-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylate with 2-methoxy-ethyl bromide there was obtained tert-butyl (3SR,4RS,5RS)-4-[4-(2-benzyloxy-ethoxymethyl)-phenyl]-3-(2-methoxy-ethoxymethyl)-5-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylate as a colourless oil; MS: 687 (M+NH4)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([NH2:20])[CH:11]=[N:12][C:13]=2[O:14][CH2:15][C:16]([F:19])([F:18])[F:17])=[CH:4][CH:3]=1.[CH3:21][C:22]1[C:26]([C:27](O)=[O:28])=[CH:25][O:24][N:23]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[C:10]([NH:20][C:27]([C:26]3[C:22]([CH3:21])=[N:23][O:24][CH:25]=3)=[O:28])[CH:11]=[N:12][C:13]=2[O:14][CH2:15][C:16]([F:17])([F:18])[F:19])=[CH:6][CH:7]=1
Reactant: Nc1cnc(OCC(F)(F)F)c(-c2ccc(Cl)cc2)c1
Reactant: Cc1nocc1C(=O)O
Product: Cc1nocc1C(=O)Nc1cnc(OCC(F)(F)F)c(-c2ccc(Cl)cc2)c1

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-(4-chloro-phenyl)-6-(2,2, 2-trifluoro-ethoxy)-pyridin-3-ylamine and 3-methyl-4-isoxazolecarboxylic acid as starting materials, MS (LC/MS): 412.2 (M+H).
Reaction SMILES: ClC1C=C(Cl)C=CC=1C1N=C(CC)C(N[C@@H]2C3C(=CC=CC=3)C[C@@H]2OCC)=NC=1CC.[CH2:32]([C:34]1[C:35]([NH:42][C@H:43]2[C@@H:47]([OH:48])[CH2:46][N:45]([C:49]([O:51][CH2:52][C:53]3[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=3)=[O:50])[CH2:44]2)=[N:36][C:37]([CH2:40][CH3:41])=[CH:38][N:39]=1)[CH3:33].[F:59][CH2:60][CH2:61]Br>>[CH2:32]([C:34]1[C:35]([NH:42][C@H:43]2[C@@H:47]([O:48][CH2:61][CH2:60][F:59])[CH2:46][N:45]([C:49]([O:51][CH2:52][C:53]3[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=3)=[O:50])[CH2:44]2)=[N:36][C:37]([CH2:40][CH3:41])=[CH:38][N:39]=1)[CH3:33]
Reactant: FCCBr
Reactant: CCc1cnc(CC)c(N[C@@H]2CN(C(=O)OCc3ccccc3)C[C@@H]2O)n1
Agent: CCO[C@H]1Cc2ccccc2[C@H]1Nc1nc(CC)c(-c2ccc(Cl)cc2Cl)nc1CC
Product: CCc1cnc(CC)c(N[C@@H]2CN(C(=O)OCc3ccccc3)C[C@@H]2OCCF)n1

Procedure:
Following the procedure for the preparation of 5-(2,4-dichlorophenyl)-N-[(1R,2S)-2-ethoxy-2,3-dihydro-1H-inden-1-yl]-3,6-diethylpyrazin-2-amine but substituting benzyl (3R,4S)-3-[(3,6-diethylpyrazin-2-yl)amino]-4-hydroxypyrrolidine-1-carboxylate and 2-fluoro-1-bromo ethane, and making non-critical variations provided the title compound as a oil: 1H NMR (400 MHz, DMSO-d6) δ) 7.61, 7.38-7.36, 5.85, 5.08, 4.52, 4.50, 4.38, 4.22, 3.75-3.40, 2.60, 2.53, 1.19-1.13; IR (liq.) 2970 (s), 2937 (s), 2340 (w), 2068 (w), 1996 (w), 1954 (w), 1705 (s), 1546 (s), 1499 (s), 1448 (s), 1422 (s), 1395 (s), 1351 (s), 1136 (s), 1107 (s), cm−1; HRMS (FAB) calcd for C22H29FN4O3+H 417.2302, found 417.2299.
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[C:3]=1[C:11]([NH2:13])=[O:12].ClS([N:18]=[C:19]=[O:20])(=O)=O.O>C(Cl)Cl>[NH:1]([C:2]1[S:6][C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[C:3]=1[C:11]([NH2:13])=[O:12])[C:19]([NH2:18])=[O:20]
Reactant: NC(=O)c1c(N)sc2ccccc12
Reactant: O=C=NS(=O)(=O)Cl
Solvent: O
Solvent: ClCCl
Product: NC(=O)Nc1sc2ccccc2c1C(N)=O
Yield: 40.9 %

Procedure:
To the mixture of 2a (20 mg, 0.104 mmol) in CH2Cl2 (10 mL) was added chlorosulfonyl isocyanate (15 μL, 0.15 mmol). The resultant mixture was stirred at room temperature for 1 h and mixed with water (0.5 mL). Separation via a reverse phase HPLC provided the title compound (10 mg, 40%) as a white solid: MS (ES) m/z 236 (M+H)+; 1H NMR (400 MHz, DMSO-d6) δ10.77 (s, 1H), 7.84 (m, 2H), 7.56 (brs, 3H), 7.20 (m, 1H), 7.08 (m, 1H), 6.98 (brs, 1H).
Reaction SMILES: C([O:8][C:9](=[O:22])[CH2:10][NH:11][C:12](=[O:21])[CH2:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])C1C=CC=CC=1.[H][H]>CO.[Pd]>[C:17]([O:16][C:14]([CH2:13][C:12]([NH:11][CH2:10][C:9]([OH:22])=[O:8])=[O:21])=[O:15])([CH3:20])([CH3:18])[CH3:19]
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)CC(=O)NCC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)CC(=O)NCC(=O)O
Yield: 94.6 %

Procedure:
Benzyl-2-[2-(tert-butoxycarbonyl)-acetamido]-acetate (14; 0.57 g, 1.85 mmol) was dissolved in methanol (15 mL), and then 10% Pd/C (0.06 g) was added therein with stirring for 1 h under pressure of 40 psi of hydrogen. After the reaction is completed, Pd/C was removed by filter paper and methanol was removed by concentration under reduced pressure to obtain colorless oil-like 15a (0.38 g; 100%). 1H-NMR (200 MHz) (DMSO) δ: 12.60 (br, s, 1H, CO2H), 8.07 (t, 1H, CONHCH2), 7.00 (t, 1H, NHBOC), 3.77 (d, 2H, CH2CO2H), 3.57 (d, 2H, CH2NHBOC), 1.40 [s, 9H, CO2C(CH3)3].
Reaction SMILES: [NH2:1][C:2]1[CH:21]=[CH:20][C:5]([O:6][CH2:7][CH2:8][O:9][S:10]([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)(=[O:12])=[O:11])=[CH:4][C:3]=1[CH2:22][S:23]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)(=[O:25])=[O:24].Cl.[N:33]([O-])=O.[Na+].C(=O)([O-])[O-].[Na+].[Na+]>C(O)C.O>[C:26]1([S:23]([C:22]2[C:3]3[C:2](=[CH:21][CH:20]=[C:5]([O:6][CH2:7][CH2:8][O:9][S:10]([C:13]4[CH:14]=[CH:15][C:16]([CH3:19])=[CH:17][CH:18]=4)(=[O:11])=[O:12])[CH:4]=3)[NH:1][N:33]=2)(=[O:24])=[O:25])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: Cc1ccc(S(=O)(=O)OCCOc2ccc(N)c(CS(=O)(=O)c3ccccc3)c2)cc1
Reactant: O=N[O-]
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Cc1ccc(S(=O)(=O)OCCOc2ccc3[nH]nc(S(=O)(=O)c4ccccc4)c3c2)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 79.8 %

Procedure:
To a mixture of toluene-4-sulfonic acid 2-(4-amino-3-benzenesulfonylmethyl-phenoxy)-ethyl ester (11.7 g, 25.3 mmol) of in ethanol (350 mL) and 1.0 N hydrochloric acid (425 mL) was dropwise added sodium nitrite (2.67 g, 38.7 mmol) in water (50 mL). After stirring at ambient temperature for 1.5 hours, solid sodium carbonate was added to basic pH. The reaction mixture was stirred for an additional 2 hours. It was then solvent evaporated and extracted with warm ethyl acetate. The organic phase was washed with water and brine, dried with anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by flash chromatography with 2% methanol in chloroform to yield toluene-4-sulfonic acid 2-(3-benzenesulfonyl-1H-indazol-5-yloxy)-ethyl ester as an orange solid (9.54 g, 79.5%): MP: 174-7° C.; Mass Spectrum (−EI, [M−H]−) m/z 471. 1HNMR (500 MHz, DMSO-d6): δ14.11 (s, 1H), 7.96-7.98 (m, 2H), 7.74-7.77 (m, 2H), 7.62-7.66 (m, 1H), 7.53-7.59 (m, 3H), 7.39 (d, 2H, J=8.05 Hz), 7.24 (d, 1H, J=2.32 Hz), 6.97-7.00 (m, 1H), 4.35-4.37 (m, 2H), 4.21-4.23 (m, 2H), 2.33 ppm (s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[OH:9].Br[CH2:11][CH:12]([F:14])[F:13].C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[Br:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[O:9][CH2:11][CH:12]([F:14])[F:13]
Reactant: Oc1ccc(Cl)cc1Br
Reactant: FC(F)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: FC(F)COc1ccc(Cl)cc1Br
Yield: 84 %

Procedure:
A stirred suspension of 2-bromo-4-chlorophenol (2.07 g, 10 mmol), 2-bromo-1,1-difluoroethane (1.74 g, 12 mmol) and potassium carbonate (1.65 g, 12 mmol) in 2-butanone (10 mL) was heated at reflux temperature for 16 hours. The suspension was allowed to cool and then filtered. The filtrate was concentrated and distilled in vacuo to afford the title compound as a colorless oil (2.28 g, 84%): bp 78-80° C. @ 0.1 torr
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[C:8]([NH:9][C:10](=[O:20])[CH2:11][CH2:12][S:13][CH2:14][CH2:15][C:16]([F:19])([F:18])[F:17])=[CH:7][N:6]([C:21]2[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=2)[N:5]=1.[CH2:27](Br)[CH3:28].[I-].[K+]>S1(CCCC1)(=O)=O>[Cl:3][C:4]1[C:8]([N:9]([CH2:27][CH3:28])[C:10](=[O:20])[CH2:11][CH2:12][S:13][CH2:14][CH2:15][C:16]([F:18])([F:17])[F:19])=[CH:7][N:6]([C:21]2[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=2)[N:5]=1
Reactant: CCBr
Reactant: O=C(CCSCCC(F)(F)F)Nc1cn(-c2cccnc2)nc1Cl
Agent: [H-]
Agent: [I-]
Agent: [K+]
Solvent: O=S1(=O)CCCC1
Product: CCN(C(=O)CCSCCC(F)(F)F)c1cn(-c2cccnc2)nc1Cl
Reaction time: 0.08 h

Procedure:
To 3-neck round bottomed flask (50 mL) was added sodium hydride (60% in oil, 0.130 g, 3.28 mmol) and sulfolane (16 mL). The gray suspension was stirred for 5 minutes then N-(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)-3-((3,3,3-trifluoropropyl)thio)propanamide (1.20 g, 3.16 mmol) dissolved in sulfolane (25 mL) was slowly added dropwise over 5 minutes. The mixture became a light gray suspension after 3 minutes and was allowed to stir for 5 minutes after which time ethyl bromide (0.800 mL, 10.7 mmol) and potassium iodide (0.120 g, 0.720 mmol) were added sequentially. The cloudy suspension was then allowed to stir at room temperature. The reaction was quenched after 6 hours by being poured drop-wise into cooled ammonium formate/acetonitrile solution (30 mL). The resulting orange colored solution was stirred and tetrahydrofuran (40 mL) was added. The mixture was assayed, using octanophenone as a standard, and found to contain 1.09 g (85%) of the desired product with a selectivity versus the retro-Michael-like decomposition product of 97:3.
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([C:42]1[N:43]=[C:44]([NH:47][CH:48]=[O:49])[S:45][CH:46]=1)[C:5]([NH:7][CH:8]1[C:40](=[O:41])[N:10]2[C:11]([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:12]([CH:16]=[CH:17][C:18]3[N:19]=[N:20][CH:21]=[CH:22][CH:23]=3)[CH2:13][S:14](=O)[C@H:9]12)=[O:6].P(Cl)(Cl)Cl.C(=O)(O)[O-].[Na+]>CN(C)C=O>[CH3:1][O:2][N:3]=[C:4]([C:42]1[N:43]=[C:44]([NH:47][CH:48]=[O:49])[S:45][CH:46]=1)[C:5]([NH:7][CH:8]1[C:40](=[O:41])[N:10]2[C:11]([C:24]([O:26][CH:27]([C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)[C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)=[O:25])=[C:12]([CH:16]=[CH:17][C:18]3[N:19]=[N:20][CH:21]=[CH:22][CH:23]=3)[CH2:13][S:14][C@H:9]12)=[O:6]
Reactant: CON=C(C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(C=Cc3cccnn3)CS(=O)[C@H]12)c1csc(NC=O)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClP(Cl)Cl
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(C=Cc3cccnn3)CS[C@H]12)c1csc(NC=O)n1
Temperature: 0 °C
Yield: 51.2 %

Procedure:
To a solution of benzhydryl 7-[2-methoxyimino-2-(2-formamidothiazol-4-yl)acetamido]-3-[2-(3-pyridazinyl)vinyl]-3-cephem-4-carboxylate-1-oxide (syn isomer) (trans isomer) (1.8 g) in N,N-dimethylformamide (18 ml) was added phosphorus trichloride (0.45 ml) at -30° C. with stirring. The reaction mixture was stirred at -15° to -10° C. for 30 minutes and added dropwise to ice-water (100 ml). The suspension was adjusted to pH 7.5 with saturated aqueous sodium bicarbonate. The precipitate was collected by filtration, washed with water, dried under reduced pressure, and subjected to column chromatography on silica gel to give benzhydryl 7-[2-methoxyimino-2-(2-formamidothiazol-4-yl)-acetamido]-3-[2-(3-pyridazinyl)vinyl]-3-cephem-4-carboxylate (syn isomer) (trans isomer) (0.9 g).
Reaction SMILES: [Br:1][C:2]1[O:6][C:5]([C:7](Cl)=[O:8])=[CH:4][CH:3]=1.[C:10]([NH:13][CH2:14][CH2:15][NH2:16])(=[O:12])[CH3:11]>C(Cl)Cl.C(N(CC)CC)C>[NH:13]([CH2:14][CH2:15][NH:16][C:7]([C:5]1[O:6][C:2]([Br:1])=[CH:3][CH:4]=1)=[O:8])[C:10]([CH3:11])=[O:12]
Reactant: CC(=O)NCCN
Reactant: O=C(Cl)c1ccc(Br)o1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)NCCNC(=O)c1ccc(Br)o1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 22.6 g of 5-bromo-2-furancarboxylic acid chloride in 100 ml of methylene chloride was added dropwise within 20 minutes at 0°-8° to a solution, pre-cooled to 0°, of 11.0 g of monoacetyl-ethylenediamine in 250 ml of methylene chloride and 18 ml of triethylamine. The reaction mixture was stirred at room temperature overnight, suction filtered and washed with methylene chloride. There was obtained N-(2-acetamino ethyl)-5-bromo-2-furancarboxamide as pale beige crystals, m.p. 175°-176°.
Reaction SMILES: [H-].[Na+].I[CH3:4].[OH:5][CH:6]1[C:12]2[CH:13]=[C:14]([CH2:17][N:18]([CH2:34][CH:35]([CH3:37])[CH3:36])[C:19]([CH:21]3[O:26][CH2:25][CH2:24][N:23]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:22]3)=[O:20])[CH:15]=[CH:16][C:11]=2[CH2:10][CH2:9][CH2:8][CH2:7]1>O1CCCC1.C(=O)(O)[O-].[Na+]>[CH2:34]([N:18]([CH2:17][C:14]1[CH:15]=[CH:16][C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][CH:6]([O:5][CH3:4])[C:12]=2[CH:13]=1)[C:19]([CH:21]1[O:26][CH2:25][CH2:24][N:23]([C:27]([O:29][C:30]([CH3:31])([CH3:32])[CH3:33])=[O:28])[CH2:22]1)=[O:20])[CH:35]([CH3:37])[CH3:36]
Reactant: CI
Reactant: CC(C)CN(Cc1ccc2c(c1)C(O)CCCC2)C(=O)C1CN(C(=O)OC(C)(C)C)CCO1
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC1CCCCc2ccc(CN(CC(C)C)C(=O)C3CN(C(=O)OC(C)(C)C)CCO3)cc21
Temperature: 25 °C
Reaction time: 72 h
Yield: 110.8 %

Procedure:
To a stirred mixture of 25 mg (0.62 mmol, 1.2 equiv) of 60% sodium hydride/mineral oil dispersion and 0.047 mL (0.75 mmol, 1.5 equiv) of iodomethane in 1 mL of anhydrous tetrahydrofuran under nitrogen was added a solution of 230 mg (0.50 mmol) of (±)-tert-butyl 2-{[[(9-hydroxy-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl)methyl](isobutyl)amino]-carbonyl}morpholine-4-carboxylate in 1 mL of anhydrous tetrahydrofuran over five minutes. The mixture was stirred at ambient temperature in a sealed flask for three days. The mixture was diluted with 2 mL of saturated sodium bicarbonate solution and extracted with 2×10 mL of ethyl acetate. The extract was washed with 3 mL each of water and brine, dried over sodium sulfate, filtered, and concentrated to give 263 mg of a gum. Purification by flash chromatography (10-50% ethyl acetate in hexanes) gave 171 mg (72%) of product as a solid white foam. MS (m+1)=475.4; H NMR (400 MHz, CDCl3) 7.06 (m, 2H), 6.96 (m, 1H), 4.7 (m, 1H), 4.50 (d, 1H, J 16 Hz), 4.28 (m, 1H), 4.18-4.02 (m, 2H), 3.97-3.80 (m, 2H), 3.50 (m, 1H), 3.31 (d, 3H, J 10 Hz), 3.22 (m, 2H), 2.99 (m, 3H), 2.65 (m, 1H), 2.01 (m, 2H), 1.86 (m, 2H), 1.75 (m, 1H), 1.60 (m, 2H), 1.45 (d, 9H, J 14 Hz), 0.89 (m, 6H).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[CH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][CH:6]=1.[O:11]=[CH:12][C:13]([Cl:16])([Cl:15])[Cl:14].Cl>>[CH:5]1([CH:12]([OH:11])[C:13]([Cl:16])([Cl:15])[Cl:14])[CH2:10][CH2:9][CH2:8][CH:7]=[CH:6]1
Reactant: O=CC(Cl)(Cl)Cl
Reactant: C1=CCCCC1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Product: OC(C1C=CCCC1)C(Cl)(Cl)Cl
Temperature: 0 °C
Reaction time: 1 h
Yield: 65.4 %

Procedure:
Anhydrous aluminum chloride (8.4 g; 0.063 mole) was added portionwise over a period of 2 hours to a stirred mixture of cyclohexene (108 g; 1.32 moles) and chloral (97 g; 0.653 mole), the temperature of which was maintained at 0° C. The reaction was allowed to proceed for a further 1 hour at 0° C. and then poured into a mixture of ice and concentrated hydrochloric acid. The reaction mixture was extracted three times with ether and the combined extracts washed with water (2×200 ml). The dried (MgSO4) extract was evaporated and the residue distilled to give crude product (116 g; 85% purity as judged by G.L.C.), b.p. 90°-94° C./0.1 mm. The crude product was redistilled through a Widmer column to give 1-(2-cyclohexen-1-yl)-2,2,2-trichloroethanol (98 g; 65% yield based on chloral; 93% purity as judged by G.L.C.) b.p. 67°-68° C./0.03 mm. A sample was redistilled for analysis.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[C:14]([OH:15])=[CH:13][CH:12]=[C:11]([Cl:16])[C:5]=1[C:6]([O:8][CH2:9][CH3:10])=[O:7].[CH3:17][O:18][CH2:19]Cl.O>CN(C)C=O>[Cl:3][C:4]1[C:14]([O:15][CH2:17][O:18][CH3:19])=[CH:13][CH:12]=[C:11]([Cl:16])[C:5]=1[C:6]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: CCOC(=O)c1c(Cl)ccc(O)c1Cl
Reactant: COCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1c(Cl)ccc(OCOC)c1Cl
Reaction time: 1 h

Procedure:
To a suspension of sodium hydride (60% in oil, 474 mg) in N,N-dimethylformamide (2 ml) was added a solution of ethyl 2,6-dichloro-3-hydroxybenzoate (2.42 g) in N,N-dimethylformamide (10 ml) under nitrogen at ambient temperature and the mixture was stirred for 1 hour at the same temperature. Chloromethyl methyl ether (1.15 ml) was added thereto and the mixture was stirred for 1 hour at the same temperature. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over magnesium sulfate and evaporated in vacuo. The residue was chromatographed on silica gel eluting with a mixture of ethyl acetate and hexane (1:8, V/V) to give ethyl 2,6-dichloro-3-(methoxymethoxy)benzoate (2.58 g) as an oil.