Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[Cl:15][C:16]1[CH:17]=[N:18][C:19]2[NH:20][C:21]3[CH:22]=[CH:23][CH:24]=[C:25]([CH:43]=3)[CH2:26][CH2:27][C:28]3[CH:36]=[C:32]([NH:33][C:34]=1[N:35]=2)[CH:31]=[CH:30][C:29]=3[N:37]1[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1.[N:44]([C:47]1[CH:48]=[C:49]([CH:52]=[CH:53][CH:54]=1)[C:50]#[N:51])=[C:45]=[O:46]>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[Cl:15][C:16]1[CH:17]=[N:18][C:19]2[NH:20][C:21]3[CH:22]=[CH:23][CH:24]=[C:25]([CH:43]=3)[CH2:26][CH2:27][C:28]3[CH:36]=[C:32]([NH:33][C:34]=1[N:35]=2)[CH:31]=[CH:30][C:29]=3[N:37]1[CH2:42][CH2:41][N:40]([C:45]([NH:44][C:47]2[CH:54]=[CH:53][CH:52]=[C:49]([C:50]#[N:51])[CH:48]=2)=[O:46])[CH2:39][CH2:38]1
Reactant: N#Cc1cccc(N=C=O)c1
Reactant: Clc1cnc2nc1Nc1ccc(N3CCNCC3)c(c1)CCc1cccc(c1)N2
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1cccc(NC(=O)N2CCN(c3ccc4cc3CCc3cccc(c3)Nc3ncc(Cl)c(n3)N4)CC2)c1
Yield: 35 %

Procedure:
The desired compound was prepared according to the procedure of Example D41 using 6-chloro-12-piperazin-1-yl-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaene bis(trifluoroacetate) and 3-isocyanatobenzonitrile as the starting materials in 35% yield. LCMS for C30H28ClN8O (M+H)+: m/z=551.0. 1H NMR (300 MHz, DMSO-d6): δ 9.49 (s, 1H), 9.34 (s, 1H), 8.95 (s, 1H), 8.14 (s, 1H), 7.97-7.96 (m, 2H), 7.79-7.75 (m, 2H), 7.48-7.37 (m, 2H), 7.13-7.03 (m, 3H), 6.89-6.82 (m, 2H), 3.63 (br s, 4H), 2.99 (s, 4H), 2.84 (brs, 4H).
Reaction SMILES: C([O:3][C:4](=[O:16])[C:5]1[CH:10]=[CH:9][CH:8]=[N:7][C:6]=1[C:11]1[CH:15]=[CH:14][NH:13][N:12]=1)C.[OH-].[Na+:18]>CO.O>[Na+:18].[NH:13]1[CH:14]=[CH:15][C:11]([C:6]2[N:7]=[CH:8][CH:9]=[CH:10][C:5]=2[C:4]([O-:16])=[O:3])=[N:12]1
Reactant: CCOC(=O)c1cccnc1-c1cc[nH]n1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C([O-])c1cccnc1-c1cc[nH]n1
Reaction time: 1 h

Procedure:
2.61 g of 2-(pyrazol-3-yl)-nicotinic acid ethyl ester are dissolved in 20 ml of methanol and 0.5 g of NaOH in 5 ml of water added. After standing for 1 hr the methanol is removed under vacuum and an additional 0.07 g of NaOH added and dissolved by warming. After standing for 1 hr the mixture is diluted with H2O to 20 ml and divided into 4 aliquots of 5 ml. Each aliquot is chromatographed on Waters C18 sep. pak cartridge with 5 ml MeOH and 5 ml H2O each. The aqueous phases are combined, adjusted to pH 7.7 with HCl and freeze dried to give the title compound, m.p. 260°.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH:14]([OH:23])[CH2:15][S:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:4][CH:3]=1.[CH2:24]([O:26][C:27]([C:29]1([C:32]2[CH:37]=[CH:36][C:35](B3OC(C)(C)C(C)(C)O3)=[CH:34][CH:33]=2)[CH2:31][CH2:30]1)=[O:28])[CH3:25]>>[CH2:24]([O:26][C:27]([C:29]1([C:32]2[CH:37]=[CH:36][C:35]([C:2]3[CH:7]=[CH:6][C:5]([C:8]4[O:12][N:11]=[C:10]([CH3:13])[C:9]=4[CH:14]([OH:23])[CH2:15][S:16][C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)=[CH:4][CH:3]=3)=[CH:34][CH:33]=2)[CH2:30][CH2:31]1)=[O:28])[CH3:25]
Reactant: CCOC(=O)C1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1C(O)CSc1ccccc1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4C(O)CSc4ccccc4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 1, Step 7, using 1-[5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-2-phenylsulfanyl-ethanol and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester.
Reaction SMILES: [H-].[Na+].P(=O)([O-])O[C:5](CC)(CC)[C:6]#[N:7].[C:14]1(=O)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1>O1CCCC1>[C:14]1(=[CH:5][C:6]#[N:7])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: CCC(C#N)(CC)O[PH](=O)[O-]
Reactant: O=C1CCCCC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: N#CC=C1CCCCC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 65.1 %

Procedure:
Sodium hydride (60% in oil, 0.80 g, 20 mmol) was suspended in 50 mL tetrahydrofuran and chilled in ice under nitrogen. Diethylcyanomethyl phosphonate (3.85 g, 22 mmol) was added dropwise in 10 mL tetrahydrofuran and stirring continued for 15 minutes to give a clear solution. Cyclohexanone (1.90 g, 19 mmol) was added in 5 mL tetrahydrofuran and the reaction mixture allowed to warm up to room temperature. The liquor was decanted and the residue washed three times with ether. The liquor and washings were combined, washed with dilute hydrochloric acid and water, dried over magnesium sulphate, filtered, and evaporated to dryness. The residue was purified by chromatography on silica eluting with heptane/ethyl acetate 4:1 to give the required product as a colorless oil (1.5 g, 67%).
Reaction SMILES: [O:1]=[C:2]1[CH2:7][NH:6][CH2:5][CH2:4][N:3]1[C@H:8]1[CH2:17][CH2:16][C:15]2[CH:14]=[C:13]([C:18]#[N:19])[CH:12]=[CH:11][C:10]=2[CH2:9]1.O=[C:21]1[CH2:30][CH2:29][C:28]2[CH:27]=[C:26]([C:31]#[N:32])[CH:25]=[CH:24][C:23]=2[CH2:22]1>>[O:1]=[C:2]1[CH2:7][N:6]([CH:21]2[CH2:30][CH2:29][C:28]3[CH:27]=[C:26]([C:31]#[N:32])[CH:25]=[CH:24][C:23]=3[CH2:22]2)[CH2:5][CH2:4][N:3]1[C@H:8]1[CH2:17][CH2:16][C:15]2[CH:14]=[C:13]([C:18]#[N:19])[CH:12]=[CH:11][C:10]=2[CH2:9]1
Reactant: N#Cc1ccc2c(c1)CC[C@H](N1CCNCC1=O)C2
Reactant: N#Cc1ccc2c(c1)CCC(=O)C2
Product: N#Cc1ccc2c(c1)CCC(N1CCN([C@H]3CCc4cc(C#N)ccc4C3)C(=O)C1)C2

Procedure:
The title compound was prepared from (6S)-6-(2-Oxopiperazin-1-yl)-5,6,7,8-tetrahydronaphthalene-2-carbonitrile and 6-Oxo-5,6,7,8-tetrahydronaphthalene-2-carbonitrile following essentially the same procedure as Example 6. The product was purified by mass-directed reverse phase HPLC (AcCN-Water with 0.1% TFA). LC-MS (IE, m/z): 411 [M+1]+.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]([NH:10][CH:11]([C:13]2[CH:14]=[N:15][C:16]([O:20][CH2:21][C:22]([F:25])([F:24])[F:23])=[C:17]([Cl:19])[CH:18]=2)[CH3:12])=[O:9])[CH:5]=[CH:4][N:3]=1.[C:26](Cl)(=[O:28])[CH3:27]>>[C:26]([NH:1][C:2]1[N:7]=[C:6]([C:8]([NH:10][CH:11]([C:13]2[CH:14]=[N:15][C:16]([O:20][CH2:21][C:22]([F:24])([F:23])[F:25])=[C:17]([Cl:19])[CH:18]=2)[CH3:12])=[O:9])[CH:5]=[CH:4][N:3]=1)(=[O:28])[CH3:27]
Reactant: CC(NC(=O)c1ccnc(N)n1)c1cnc(OCC(F)(F)F)c(Cl)c1
Reactant: CC(=O)Cl
Product: CC(=O)Nc1nccc(C(=O)NC(C)c2cnc(OCC(F)(F)F)c(Cl)c2)n1

Procedure:
The title compound is prepared from 2-amino-N-(1-(5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)pyrimidine-4-carb oxamide (20 mg, 0.05 mmol, Step-1 of Example 210, single enantiomer) and acetyl chloride (21 mg, 0.27 mmol) according to the procedure similar to that described in Step-2 of Example 8.
Reaction SMILES: [CH3:1][C:2]1[C:8]([N+:9]([O-:11])=[O:10])=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].[CH:12](=O)[CH2:13][CH3:14].CC(O)=O.[BH3-]C#N.[Na+]>CO>[CH3:1][C:2]1[C:8]([N+:9]([O-:11])=[O:10])=[CH:7][CH:6]=[CH:5][C:3]=1[NH:4][CH2:12][CH2:13][CH3:14]
Reactant: CCC=O
Reactant: Cc1c(N)cccc1[N+](=O)[O-]
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CCCNc1cccc([N+](=O)[O-])c1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 109.2 %

Procedure:
To a solution of 2-methyl-3-nitroaniline (0.5 g, 3.3 mmol) and MeOH (20 mL) was added propionaldehyde (2.3 mL, 33 mmol), AcOH (1.9 mL, 33 mmol), and NaBH3CN (2 g, 33 mmol). Reaction was stirred at rt for 2 hours then quenched with H2O and concentrated in vacuo. Diluted with EtOAc (20 mL) and adjusted to pH=7 with saturated NaHCO3. Washed organic layer with H2O (3×10 mL) and brine (3×10 mL), dried (Na2SO4) and concentrated in vacuo. The crude product was purified by flash chromatography (5% EtOAc/hex) to afford 0.7 g of the 2-methyl-3-nitro-N-propylaminobenzene. A solution of the product and EtOAc (25 mL) was hydrogenated over 10% Pd/C (70 mg) at rt and 1 atm. After 15 hours filtered reaction mixture through a pad of Celite and concentrated the filtrate to afford the desired Compound 568 (0.10 g) as yellow oil.
Reaction SMILES: [Cl:1][C:2]1([Cl:11])[C:6]([Cl:7])=[C:5]([Cl:8])[C:4]([Cl:9])=[C:3]1[Cl:10].[C:12]1(=[O:19])[CH:17]=[CH:16][C:15](=[O:18])[CH:14]=[CH:13]1.C1(C)C=CC=CC=1>C(O)C>[Cl:7][C:6]12[C:2]([Cl:11])([Cl:1])[C:3]([Cl:10])([C:17]3[C:12]([OH:19])=[CH:13][CH:14]=[C:15]([OH:18])[C:16]=31)[C:4]([Cl:9])=[C:5]2[Cl:8]
Reactant: O=C1C=CC(=O)C=C1
Reactant: ClC1=C(Cl)C(Cl)(Cl)C(Cl)=C1Cl
Solvent: CCO
Solvent: Cc1ccccc1
Product: Oc1ccc(O)c2c1C1(Cl)C(Cl)=C(Cl)C2(Cl)C1(Cl)Cl

Procedure:
A mixture of 54.6 g. (0.2 mole) of hexachlorocyclopentadiene, 21.6 g. (0.2 mole) of p-benzoquinone, and 10 ml. of toluene were placed in a 125 ml. round bottom flask and heated for 3 hours so that the toluene refluxed gently. At the end of this period the reaction mixture suddenly solidified completely, indicating completion of the reaction. The crude product was bright yellow. The damp material was transferred to a Buchner funnel, raised with absolute ethanol, dried on the funnel, and crystallized from ethanol. 49 g. of bright yellow dense crystals were obtained, m.p. 189° -193° C. (reported 188° C.). The yield was 64%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7](N)[CH:6]=[CH:5][C:4]=1[C:10]1[N:11]=[C:12]2[C:17](=[O:18])[NH:16][NH:15][CH:14]=[C:13]2[N:19]=1.N([O-])=O.[Na+].[ClH:24]>O>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([Cl:24])[CH:6]=[CH:5][C:4]=1[C:10]1[N:11]=[C:12]2[C:17](=[O:18])[NH:16][NH:15][CH:14]=[C:13]2[N:19]=1
Reactant: Cl
Reactant: COc1cc(N)ccc1-c1nc2c[nH][nH]c(=O)c-2n1
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: COc1cc(Cl)ccc1-c1nc2c[nH][nH]c(=O)c-2n1
Reaction time: 0.67 h

Procedure:
An amount of 1.05 gm of 2-(2-methoxy-4-amino-phenyl)-5H-imidazo[4,5-d]pyridazin-4-one is suspended in 20 ml of 6N hydrochloric acid. The suspension is cooled to 0° to -3° C., and 0.28 gm of sodium nitrite, dissolved in 2 ml of water, are added dropwise thereto. The mixture is stirred for a further 40 minutes and then heated to 80°-85° C. for one hour. The product precipitated on cooling is purified by chromatography on silica gel [eluant: first methylene chloride/ethanol (100:0 to 100:20, then 1.5 to 2.5% of glacial acetic aicd is added)].
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[CH:4][C:3]=1[C:17]1[N:18]=[CH:19][C:20]([NH2:23])=[N:21][CH:22]=1.Br[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[S:31]([CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])(=[O:33])=[O:32]>>[F:1][C:2]1[CH:7]=[C:6]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[S:31]([CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])(=[O:32])=[O:33])[CH:5]=[CH:4][C:3]=1[C:17]1[N:18]=[CH:19][C:20]([NH2:23])=[N:21][CH:22]=1
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)cn3)c(F)c2)OC1(C)C
Reactant: CCCCCCS(=O)(=O)c1ccccc1Br
Product: CCCCCCS(=O)(=O)c1ccccc1-c1ccc(-c2cnc(N)cn2)c(F)c1

Procedure:
The title compound was prepared using analogous conditions to those described in Example 1 utilizing 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrazin-2-amine and 1-bromo-2-(hexylsulfonyl)benzene MS (ESI): mass calcd. for C22H24FN3O2S, 413.16; m/z found, 414.2 [M+H]+. 1H NMR (400 MHz, CD3OD) δ 8.66 (s, 1H), 8.31 (s, 1H), 8.21-8.13 (m, 2H), 7.81 (m, 1H), 7.72 (m, 1H), 7.49 (dd, J=7.6, 1.2, 1H), 7.43 (dd, J=3.6, 1.4, 1H), 7.40 (s, 1H), 2.89-2.80 (m, 2H), 1.50 (m, 2H), 1.31-1.11 (m, 6H), 0.85 (t, J=7.1, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([CH:8]([O:10][N:11]=[C:12]([C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[C:18]([Cl:23])[CH:17]=1)[C:13]([OH:15])=O)[CH3:9])=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:24][CH:25]1[C:43](=[O:44])[N:27]2[C:28]([C:40]([OH:42])=[O:41])=[C:29]([CH2:32][S:33][C:34]3[N:38]([CH3:39])[N:37]=[N:36][N:35]=3)[CH2:30][S:31][C@H:26]12>>[C:1]([O:5][C:6]([CH:8]([O:10][N:11]=[C:12]([C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[C:18]([Cl:23])[CH:17]=1)[C:13]([NH:24][CH:25]1[C:43](=[O:44])[N:27]2[C:28]([C:40]([OH:42])=[O:41])=[C:29]([CH2:32][S:33][C:34]3[N:38]([CH3:39])[N:37]=[N:36][N:35]=3)[CH2:30][S:31][C@H:26]12)=[O:15])[CH3:9])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: Cn1nnnc1SCC1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Reactant: CC(ON=C(C(=O)O)c1ccc(O)c(Cl)c1)C(=O)OC(C)(C)C
Product: CC(ON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(CSc3nnnn3C)CS[C@H]12)c1ccc(O)c(Cl)c1)C(=O)OC(C)(C)C
Yield: 94.6 %

Procedure:
2-(1-t-Butoxycarbonylethoxyimino)-2-(3-chloro-4-hydroxyphenyl)acetic acid (syn isomer) (2 g.) and 7-amino-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (2 g.) were reacted according to similar manners to those of Examples 1 and 2 to give powder of 7-[2-(1-t-butoxycarbonylethoxyimino)-2-(3-chloro-4-hydroxyphenyl)acetamido]-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer) (3.6 g.).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9](Cl)(=[O:11])=[O:10])=[CH:5][CH:4]=1.[OH-].[NH4+:14]>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([NH2:14])(=[O:11])=[O:10])=[CH:5][CH:4]=1
Reactant: [NH4+]
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Agent: [OH-]
Product: COc1ccc(S(N)(=O)=O)cc1

Procedure:
Following the procedure described in Example 1, part B above, 94.94 g (0.45 m) of 4-methoxybenzenesulfonyl chloride from part A above was interacted with ammonium hydroxide to obtain 70.41 g of 4-methoxybenzenesulfonamide, shiny white crystals which melted at 111°-112° C.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[CH:12]=[CH:11][CH:10]=[C:9]3[N:5]2[C:6]=1[C:7](=[O:19])[N:8]3[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][NH2:18].C(N(CC)CC)C.C([O:29][C:30](=O)[C:31]([F:34])([F:33])[F:32])C>C(#N)C>[CH3:1][C:2]1[N:3]=[C:4]2[CH:12]=[CH:11][CH:10]=[C:9]3[N:5]2[C:6]=1[C:7](=[O:19])[N:8]3[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][NH:18][C:30](=[O:29])[C:31]([F:34])([F:33])[F:32]
Reactant: Cc1nc2cccc3n(CCCCCN)c(=O)c1n23
Reactant: CCOC(=O)C(F)(F)F
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cc1nc2cccc3n(CCCCCNC(=O)C(F)(F)F)c(=O)c1n23

Procedure:
To a solution of 2.58 g (10.0 mmol) of 3-methyl-1-[5-(amino)pentyl]-1,4,7b-triazacyclopent[cd]inden-2-one and 1.81 ml (13.0 mmol) of triethylamine in 100 ml of acetonitrile was added, while stirring under ice-cooling, 1.43 ml (12.0 mmol) of trifluoroacetic acid ethyl ester. The mixture was stirred for one hour at the same temperature. The solvent was distilled off. To the residue was added ethyl acetate—tetrahydrofuran. The mixture was washed with an aqueous saline solution, and dried over anhydrous magnesium sulfate. The solvent was distilled off. The residue was purified by column chromatography (eluent: ethyl acetate), which was recrystallized from ethyl acetate—n-hexane to afford 2.57 g (72.6%, a pale yellow crystals) of the desired compound.
Reaction SMILES: IC.[C:3]([O-])([O-])=O.[K+].[K+].[O:9]=[C:10]1[C@@H:16]([NH:17][C:18](=[O:23])[C:19]([F:22])([F:21])[F:20])[CH2:15][CH2:14][S:13][C@H:12]2[CH2:24][CH2:25][CH2:26][C@@H:27]([C:28]([O:30][CH3:31])=[O:29])[N:11]12>CN(C=O)C>[O:9]=[C:10]1[C@@H:16]([N:17]([CH3:3])[C:18](=[O:23])[C:19]([F:20])([F:21])[F:22])[CH2:15][CH2:14][S:13][C@H:12]2[CH2:24][CH2:25][CH2:26][C@@H:27]([C:28]([O:30][CH3:31])=[O:29])[N:11]12
Reactant: COC(=O)[C@@H]1CCC[C@@H]2SCC[C@H](NC(=O)C(F)(F)F)C(=O)N21
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)[C@@H]1CCC[C@@H]2SCC[C@H](N(C)C(=O)C(F)(F)F)C(=O)N21
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.7 %

Procedure:
Iodomethane (77 mg, 0.54 mmol) and K2CO3 (150 mg, 1.08 mmol) were added to a solution of (4S,7S,10aS)-methyl 5-oxo-4-(2,2,2-trifluoroacetamido)octahydro-2H-pyrido[2,1-b][1,3]thiazepine-7-carboxylate (64 mg, 0.18 mmol) in DMF (1 mL). The reaction mixture was stirred at rt overnight. The reaction mixture was partitioned between EtOAc and water. The organic phase was isolated, washed with saturated NaHCO3 and saturated aqueous NaCl, dried over MgSO4, filtered and concentrated to give (4S,7S,10aS)-methyl 5-oxo-4-(2,2,2-trifluoro-N-methylacetamido)octahydro-2H-pyrido[2,1-b][1,3]thiazepine-7-carboxylate (47.6 mg, 0.129 mmol, 72% yield) of a yellow oil. Anal. Calcd. for C14H19F3N2O4S m/z 368.3. found: 391.1 (M+Na)+.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:22]=[CH:21][C:10]2[C:11]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)=[N:12][S:13][C:9]=2[CH:8]=1.[CH3:23][NH:24][CH2:25][CH:26]1[CH2:28][CH2:27]1>>[Cl:20][C:17]1[CH:18]=[CH:19][C:14]([C:11]2[C:10]3[CH:21]=[CH:22][C:7]([O:6][CH2:5][CH2:4][CH2:3][CH2:2][N:24]([CH2:25][CH:26]4[CH2:28][CH2:27]4)[CH3:23])=[CH:8][C:9]=3[S:13][N:12]=2)=[CH:15][CH:16]=1
Reactant: CNCC1CC1
Reactant: Clc1ccc(-c2nsc3cc(OCCCCBr)ccc23)cc1
Product: CN(CCCCOc1ccc2c(-c3ccc(Cl)cc3)nsc2c1)CC1CC1

Procedure:
According to the method in example 7, 6-(4-Bromo-butoxy)-3-(4-chloro-phenyl)-benzo[d]isothiazole and N-Methylcyclopropanemethylamine were converted to yield {4-[3-(4-Chloro-phenyl)-benzo[d]isothiazol-6-yloxy]-butyl}-cyclopropylmethyl-methyl-amine, MS: 401 (MH+, 1Cl).
Reaction SMILES: S(=O)(=O)(O)O.[F:6][C:7]1[C:12]([N+:13]([O-:15])=[O:14])=[CH:11][CH:10]=[CH:9]C=1C.[C:17]([OH:20])(=[O:19])[CH3:18]>O.[O-2].[O-2].[O-2].[Cr+6]>[F:6][C:7]1[C:12]([N+:13]([O-:15])=[O:14])=[CH:11][CH:10]=[CH:9][C:18]=1[C:17]([OH:20])=[O:19]
Reactant: CC(=O)O
Reactant: Cc1cccc([N+](=O)[O-])c1F
Agent: [Cr+6]
Agent: O=S(=O)(O)O
Agent: [O-2]
Solvent: O
Product: O=C(O)c1cccc([N+](=O)[O-])c1F
Temperature: 95 °C
Reaction time: 2 h

Procedure:
Concentrated sulfuric acid (195 ml) was added carefully with stirring to a solution of 2-fluoro-3-nitrotoluene (100 g, 645 mmol) in acetic acid (1000 ml). The mixture was warmed up to 95° C. and the solution of chromium trioxide (226 g, 2.25 mol) in water (200 ml) was added dropwise with stirring over 2 h. After addition the mixture was heated with stirring for another 3 h, allowed to cool down to room temperature and poured into water (3 L). The mixture was extracted with ethyl acetate (3×1 L), the combined organic layers were dried over Na2SO4 and concentrated under reduced pressure to afford a light green solid, which was washed with dichloromethane (3×300 ml) and dried under vacuum to afford the title compound was obtained as a light yellow solid (75 g, 62.8%). 1H NMR (300 MHz, DMSO) δ ppm 8.27 (m, 1H), 8.15 (m, 1H), 7.48 (m, 1H).
Reaction SMILES: CC[O:3][C:4]([C:6]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH3:16])[C:10]=1[C:17]([NH2:19])=[O:18])=[O:7])=O.[NH3:20]>C(O)C>[C:17]([C:10]1[C:11]([O:15][CH3:16])=[CH:12][CH:13]=[CH:14][C:9]=1[NH:8][C:6]([C:4]([NH2:20])=[O:3])=[O:7])(=[O:18])[NH2:19]
Reactant: N
Reactant: CCOC(=O)C(=O)Nc1cccc(OC)c1C(N)=O
Solvent: CCO
Product: COc1cccc(NC(=O)C(N)=O)c1C(N)=O
Reaction time: 2 h

Procedure:
2'-Carbamoyl-3'-methoxyoxanilic acid ethyl ester (5.0 g, 0.0188 mole) is added to 50 ml of ethanol saturated with ammonia at 0°-5°C., and the mixture is stirred in an ice-bath for 2 hours, then filtered. The cake is washed with ethanol, giving 1.41 g of the title compound, m.p. 252°-255°C., after crystallization from water.
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[Cl:11][CH2:12][CH2:13][CH2:14][C:15](Cl)=[O:16]>>[Cl:11][CH2:12][CH2:13][CH2:14][C:15]([N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1)=[O:16]
Reactant: O=C(Cl)CCCCl
Reactant: c1ccc2c(c1)CCCN2
Product: O=C(CCCCl)N1CCCc2ccccc21

Procedure:
from 3,4-dihydro-2H-quinoline and 4-chlorobutanoyl chloride
Reaction SMILES: Cl[C:2]([C:4]1[CH:5]=[CH:6][C:7]2[C:13](=[O:14])[CH2:12][C:11]3[CH:15]=[CH:16][CH:17]=[CH:18][C:10]=3[S:9][C:8]=2[CH:19]=1)=[O:3].[CH3:20][N:21]([CH3:25])[CH2:22][CH2:23][OH:24]>O1CCCC1>[CH3:20][N:21]([CH3:25])[CH2:22][CH2:23][O:24][C:2]([C:4]1[CH:5]=[CH:6][C:7]2[C:13](=[O:14])[CH2:12][C:11]3[CH:15]=[CH:16][CH:17]=[CH:18][C:10]=3[S:9][C:8]=2[CH:19]=1)=[O:3]
Reactant: O=C(Cl)c1ccc2c(c1)Sc1ccccc1CC2=O
Reactant: CN(C)CCO
Solvent: C1CCOC1
Product: CN(C)CCOC(=O)c1ccc2c(c1)Sc1ccccc1CC2=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Dissolve 1.0 gm. of 3-chlorocarbonyl-10,11- dihydro-11-oxodibenzo[b,f]thiepin as prepared in Example 31, Step 1, in 10 cc. of anhydrous tetrahydrofuran with stirring and add 2 ml. of N,N-dimethylethanolamine. Stir at room temperature for 18 hours and strip the mixture to dryness. Partition the residue between ether and dilute hydrochloric acid and separate the aqueous layer. Basify the aqueous layer with aqueous ammonia and extract with ethyl acetate. Evaporate the organic phase and chromatograph the residue over silica-gel eluting with 90% chloroform in methanol to obtain the title product.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:20]([O:27][C:28]1[CH:33]=[CH:32][C:31]([NH:34][C:35](=O)[C:36]([F:39])([F:38])[F:37])=[CH:30][CH:29]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(Cl)(Cl)(Cl)[Cl:42]>>[CH2:20]([O:27][C:28]1[CH:33]=[CH:32][C:31]([N:34]=[C:35]([Cl:42])[C:36]([F:39])([F:38])[F:37])=[CH:30][CH:29]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: ClC(Cl)(Cl)Cl
Reactant: O=C(Nc1ccc(OCc2ccccc2)cc1)C(F)(F)F
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: FC(F)(F)C(Cl)=Nc1ccc(OCc2ccccc2)cc1

Procedure:
A mixture of resin-supported triphenylphosphine (3 mmol triphenylphosphine/g resin; 58.6 g) and N-(4-benzyloxy-phenyl)-2,2,2-trifluoro-acetamide in carbon tetrachloride (800 ml) was heated to reflux under nitrogen for 18 h. The mixture was allowed to cool then filtered, washing the resin with dichloromethane (1l) and ether (1l). The organics were concentrated in vacuo to give the title compound as a yellow solid (20.7 g). T.l.c. (Cyclohexanelethyl acetate (9:1)) Rf 0.81
Reaction SMILES: [NH:1]1[CH:5]=[N:4][N:3]=[N:2]1.C(N(C(C)C)CC)(C)C.[CH2:15]([CH:17]1[O:19][CH2:18]1)[Cl:16]>C(#N)C>[N:1]1[N:2]([CH2:18][CH:17]([OH:19])[CH2:15][Cl:16])[N:3]=[N:4][CH:5]=1
Reactant: ClCC1CO1
Reactant: c1nnn[nH]1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: OC(CCl)Cn1ncnn1

Procedure:
6.905 g of tetrazole (100 mmol) and 1.75 ml of diisopropylethylamine (10 mmol) and 11.73 ml of epichlorohydrine (150 mmol) in anhydrous acetonitrile (30 ml) was stirred at 60° C. for 4 hours. The obtained solution was evaporated, dried on highvac and purified on a column of silica in chloroform-methanol 100:8. The first fraction provided pure 3-(2-H-tetrazol-2-yl)-2-hydroxy-1-chloropropane, 6.215 g (colorless oil, 38% Y), the second fraction yielded 9.208 g of pure 3-(1-H-tetrazol-1-yl)]-2-hydroxyl-1-chloropropane (sticky gum; 57% Y).
Reaction SMILES: [CH2:1]([O:8][N:9]([C@H:22]1[CH2:27][N:26]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[C@H:25]([C:35]([OH:37])=O)[CH:24]=[C:23]1[CH2:38][CH2:39][N+:40]([O-:42])=[O:41])[S:10]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[N+:19]([O-:21])=[O:20])(=[O:12])=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O[N:47]([C@H]1CN(C(OC(C)(C)C)=O)[C@H](C(=O)N)C=C1C)S(C1C=CC=CC=1[N+]([O-])=O)(=O)=O)C=C>>[CH2:1]([O:8][N:9]([C@H:22]1[CH2:27][N:26]([C:28]([O:30][C:31]([CH3:32])([CH3:34])[CH3:33])=[O:29])[C@H:25]([C:35](=[O:37])[NH2:47])[CH:24]=[C:23]1[CH2:38][CH2:39][N+:40]([O-:42])=[O:41])[S:10]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[N+:19]([O-:21])=[O:20])(=[O:12])=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1C[C@H](N(OCc2ccccc2)S(=O)(=O)c2ccccc2[N+](=O)[O-])C(CC[N+](=O)[O-])=C[C@H]1C(=O)O
Reactant: C=CCON([C@H]1CN(C(=O)OC(C)(C)C)[C@H](C(N)=O)C=C1C)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Product: CC(C)(C)OC(=O)N1C[C@H](N(OCc2ccccc2)S(=O)(=O)c2ccccc2[N+](=O)[O-])C(CC[N+](=O)[O-])=C[C@H]1C(N)=O

Procedure:
The title compound was prepared from (2S,5R)-5-(N-(benzyloxy)-2-nitrophenylsulfonamido)-1-(tert-butoxycarbonyl)-4-(2-nitroethyl)-1,2,5,6-tetrahydropyridine-2-carboxylic acid (Intermediate 222, 4.0 g, 6.59 mmol) according to the procedure described for Intermediate 20. The desired product was obtained as an off-white foam (2 g, 50%).