Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].[N:2]1([CH2:8][CH2:9][N:10]2[CH2:15][C:14]3[CH:16]=[C:17](/[CH:20]=[CH:21]/[C:22]([OH:24])=O)[CH:18]=[N:19][C:13]=3[NH:12][C:11]2=[O:25])[CH2:7][CH2:6][O:5][CH2:4][CH2:3]1.Cl.[CH3:27][N:28]1[CH2:34][C:33]2[CH:35]=[C:36](/[CH:39]=[CH:40]/[C:41](O)=O)C=N[C:32]=2[NH:31][C:30](=O)[CH2:29]1.CNCC1N(C)C2C(C=1)=CC=CC=2.CNCC1C=CC2C(=CC=CC=2)C=1CCC>>[ClH:1].[CH3:32][N:31]([CH2:30][C:29]1[N:28]([CH3:27])[C:34]2[C:40]([CH:41]=1)=[CH:39][CH:36]=[CH:35][CH:33]=2)[C:22](=[O:24])/[CH:21]=[CH:20]/[C:17]1[CH:18]=[N:19][C:13]2[NH:12][C:11](=[O:25])[N:10]([CH2:9][CH2:8][N:2]3[CH2:7][CH2:6][O:5][CH2:4][CH2:3]3)[CH2:15][C:14]=2[CH:16]=1
Reactant: CN1CC(=O)Nc2ncc(/C=C/C(=O)O)cc2C1
Reactant: O=C(O)/C=C/c1cnc2c(c1)CN(CCN1CCOCC1)C(=O)N2
Agent: CCCc1c(CNC)ccc2ccccc12
Agent: CNCc1cc2ccccc2n1C
Agent: Cl
Product: CN(Cc1cc2ccccc2n1C)C(=O)/C=C/c1cnc2c(c1)CN(CCN1CCOCC1)C(=O)N2
Yield: 61 %

Procedure:
According to the procedure of Example 1, except substituting (E)-3-[3-(2-morpholin-4-yl-ethyl)-2-oxo-1,2,3,4-tetrahydro-pyrido[2,3-d]pyrimidin-6-yl]acrylic acid hydrochloride for the (E)-3-(4-methyl-2-oxo-2,3,4,5-tetrahydro-1H-pyrido[2,3-e][1,4]diazepin-7-yl)acrylic acid hydrochloride, and substituting methyl-(1-methyl-1H-indol-2-ylmethyl)amine for the methyl-(1-propyl-naphthalen-2-ylmethyl)amine, the tide compound (355 mg, 61%) was prepared as a pale yellow solid: 1H NMR (300 MHz, DMSO-d6) δ 10.16-9.98 (m, 2H), 8.42-8.37 (m, 1H), 8.00-7.92 (m, 1H), 7.58-7.39 (m, 3H), 7.24-6.99 (m, 3H), 6.42-6.15 (m, 1H), 5.06-4.85 (m, 2H), 4.57-4.51 (m, 2H), 4.00-3.97 (m, 2H), 3.73-3.37 (m, 11H), 3.15-2.98 (m, 5H); MS (ESI) m/e 489 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:25]=[CH:24][C:23]([C:26]2[CH:31]=[CH:30][N:29]=[C:28]([CH3:32])[CH:27]=2)=[CH:22][C:4]=1[CH2:5][NH:6][CH:7]1[CH2:12][CH2:11][CH:10]([N:13]([CH3:21])[C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH2:9][CH2:8]1.[Cl:33][C:34]1[C:35]2[C:45]([F:46])=[CH:44][CH:43]=[C:42]([F:47])[C:36]=2[S:37][C:38]=1[C:39](Cl)=[O:40]>>[Cl:33][C:34]1[C:35]2[C:45]([F:46])=[CH:44][CH:43]=[C:42]([F:47])[C:36]=2[S:37][C:38]=1[C:39]([N:6]([CH2:5][C:4]1[CH:22]=[C:23]([C:26]2[CH:31]=[CH:30][N:29]=[C:28]([CH3:32])[CH:27]=2)[CH:24]=[CH:25][C:3]=1[O:2][CH3:1])[CH:7]1[CH2:8][CH2:9][CH:10]([N:13]([CH3:21])[C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH2:11][CH2:12]1)=[O:40]
Reactant: O=C(Cl)c1sc2c(F)ccc(F)c2c1Cl
Reactant: COc1ccc(-c2ccnc(C)c2)cc1CNC1CCC(N(C)C(=O)OC(C)(C)C)CC1
Product: COc1ccc(-c2ccnc(C)c2)cc1CN(C(=O)c1sc2c(F)ccc(F)c2c1Cl)C1CCC(N(C)C(=O)OC(C)(C)C)CC1

Procedure:
Crude biaryl amine 88 (1.96 g, 4.45 mmol) is treated with acid chloride 8 (1.43 g, 5.35 mmol) using Method D to give the title compound.
Reaction SMILES: C(OC(=O)[CH2:5][O:6][C@H:7]1[CH2:12][CH2:11][C@H:10]([N:13]2[C:18](=[O:19])[C:17]([CH2:20][C:21]3[S:22][C:23]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=4[C:32]#[N:33])=[CH:24][CH:25]=3)=[C:16]([CH2:34][CH2:35][CH3:36])[N:15]3[N:37]=[CH:38][N:39]=[C:14]23)[CH2:9][CH2:8]1)C.C[Mg]Br.[Cl-].[NH4+]>O1CCCC1>[OH:6][C:7]([CH3:12])([CH3:8])[CH2:5][O:6][C@H:7]1[CH2:12][CH2:11][C@H:10]([N:13]2[C:18](=[O:19])[C:17]([CH2:20][C:21]3[S:22][C:23]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=4[C:32]#[N:33])=[CH:24][CH:25]=3)=[C:16]([CH2:34][CH2:35][CH3:36])[N:15]3[N:37]=[CH:38][N:39]=[C:14]23)[CH2:9][CH2:8]1
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)s2)c(=O)n([C@H]2CC[C@H](OCC(=O)OCC)CC2)c2ncnn12
Agent: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)s2)c(=O)n([C@H]2CC[C@H](OCC(C)(C)O)CC2)c2ncnn12
Temperature: 70 °C
Reaction time: 6 h

Procedure:
Ethyl({trans-4-[6-{[5-(2-cyanophenyl)thiophen-2-yl]methyl}-5-oxo-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-4(5H)-yl]cyclohexyl}oxy)acetate (0.25 g) was dissolved in tetrahydrofuran (10 mL), and methylmagnesium bromide (1.0 M tetrahydrofuran solution, 0.44 mL) was added at room temperature. The reaction mixture was stirred at 70° C. for 6 hr, saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The obtained ethyl acetate layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.12 g, 49%).
Reaction SMILES: C([N:4]1[CH2:13][C@@H:12]([C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[C:16]([OH:21])[CH:15]=2)[C:11]2[C:6](=[C:7]([OH:23])[C:8]([OH:22])=[CH:9][CH:10]=2)[CH2:5]1)(=[O:3])C.[ClH:24]>C(O)C>[OH2:3].[ClH:24].[OH:22][C:8]1[C:7]([OH:23])=[C:6]2[C:11]([C@@H:12]([C:14]3[CH:19]=[CH:18][C:17]([OH:20])=[C:16]([OH:21])[CH:15]=3)[CH2:13][NH:4][CH2:5]2)=[CH:10][CH:9]=1
Reactant: CC(=O)N1Cc2c(ccc(O)c2O)[C@H](c2ccc(O)c(O)c2)C1
Agent: Cl
Solvent: CCO
Product: O
Product: Oc1ccc([C@H]2CNCc3c2ccc(O)c3O)cc1O

Procedure:
(i) to 1.15 g of (R)-(-)-N-acetyl-7,8-dihydroxy-4-(3,4-dihydroxyphenyl)-1,2,3,4-tetrahydroisoquinoline 1/4 hydrate were added 9 ml of 3N hydrochloric acid and 9 ml of ethanol, and the mixture was heated under an argon gas stream for 24 hours. After the reaction solution was cooled, the crystals which separated out were collected by filtration, affording 1.09 g of (R)-(+)-7,8-dihydroxy-4-(3,4-dihydroxyphenyl)-1,2,3,4-tetrahydroisoquinoline hydrochloride monohydrate. [α]D20 =+15° (C=1, CH3OH)
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].N1C2C(=CC=CC=2)C=C(N[C:16](=[O:40])[C@@H:17]2[CH2:21][C@H:20](OS(C3C=CC(C)=CC=3)(=O)=O)[CH2:19][N:18]2[C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])C=1.[OH2:41]>CN(C)C=O>[N:1]([C@H:20]1[CH2:19][N:18]([C:33]([O:35][C:36]([CH3:37])([CH3:38])[CH3:39])=[O:34])[C@H:17]([C:16]([OH:40])=[O:41])[CH2:21]1)=[N+:2]=[N-:3]
Reactant: Cc1ccc(S(=O)(=O)O[C@H]2C[C@@H](C(=O)Nc3cnc4ccccc4c3)N(C(=O)OC(C)(C)C)C2)cc1
Reactant: [N-]=[N+]=[N-]
Reactant: O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1C[C@H](N=[N+]=[N-])C[C@H]1C(=O)O
Reaction time: 4 h

Procedure:
Sodium azide (206 mg) was added to a stirred solution of N-tert-butoxycarbonyl-cis-4-p-toluenesulfonyloxy-L-proline 3-quinolylamide (C, 805 mg) in N,N-dimethylformamide (8 mL)-water (1.5 mL). After sting at 70° C. for 4 hr, the solvents were removed in vacuo. The residue was diluted with ethyl acetate, and washed with water and brine. The organic layer was dried over anhydrous sodium sulfate and evaporated in vacuo. The residue was purified by silica gel column chromatography (chloroform:ethyl acetate=1:1 to 1:2, v/v) to afford the title compound (532 mg) as a pale yellow sticky oil: 1H NMR (400 MHz, CD3OD) δ 1.3-1.5 (m, 9H), 2.32 (m, 1H), 2.47 (m, 1H), 3.63 (m, 1H), 3.72 (m, 1H), 4.38 (m, 1H), 4.48 (m, 1H), 7.60 (m, 1H), 7.69 (m, 1H), 7.90 (m, 1H), 7.98 (m, 1H), 8.72-8.75 (m, 1H), and 8.92-8.93 (m, 1H).
Reaction SMILES: S(Cl)([Cl:3])=O.[CH:5]1[C:13]2[C:12]3[CH:14]=[CH:15][CH:16]=[CH:17][C:11]=3[O:10][C:9]=2[C:8]([CH2:18]O)=[CH:7][CH:6]=1>>[Cl:3][CH2:18][C:8]1[C:9]2[O:10][C:11]3[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=3[C:13]=2[CH:5]=[CH:6][CH:7]=1
Reactant: OCc1cccc2c1oc1ccccc12
Reactant: O=S(Cl)Cl
Product: ClCc1cccc2c1oc1ccccc12

Procedure:
Thionyl chloride (6 ml) is added to a solution of Dibenzofuran-4-ylmethanol (0.9 g). The solution is refluxed for 1 hour. Excess of reagent is evaporated to yield 4-(chloromethyl) Dibenzofuran (0.97 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:13](=O)[CH3:14])[CH:5]=[CH:6][C:7]=1[CH:8]1[CH2:12][CH2:11][CH2:10][CH2:9]1.C([O:18]/[C:19](/[CH3:26])=[CH:20]/C(OCC)=O)C>>[Cl:1][C:2]1[CH:3]=[C:4](/[C:13](/[CH3:14])=[CH:20]/[C:19](=[O:18])[CH3:26])[CH:5]=[CH:6][C:7]=1[CH:8]1[CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: CC(=O)c1ccc(C2CCCC2)c(Cl)c1
Reactant: CCOC(=O)/C=C(\C)OCC
Product: CC(=O)/C=C(\C)c1ccc(C2CCCC2)c(Cl)c1
Yield: 82 %

Procedure:
(E)-4-(3-chloro-4-cyclopentyl-phenyl)-3-pentene-2-one was prepared analogous to Example 52 from 3'-chloro-4'-cyclopentyl-acetophenone (b.p. 130°-135°C at 0.1 mm Hg) and ethyl (E)-3-ethoxy-crotonate with a yield of 82% of theory. B.p. 130°-135°C at 0.1 mm Hg.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[F:9][C:10]1[CH:11]=[C:12]([N:16]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:18]=[C:17]2[CH:25]([NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[CH3:26])[CH:13]=[CH:14][CH:15]=1>CN(C=O)C.O>[Br:1][C:18]1[C:19]2[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:16]([C:12]2[CH:13]=[CH:14][CH:15]=[C:10]([F:9])[CH:11]=2)[C:17]=1[CH:25]([NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[CH3:26]
Reactant: CC(NC(=O)OC(C)(C)C)c1cc2ccccc2n1-c1cccc(F)c1
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Solvent: O
Product: CC(NC(=O)OC(C)(C)C)c1c(Br)c2ccccc2n1-c1cccc(F)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 65.4 %

Procedure:
A solution of N-bromosuccinimide (0.24 g, 1.3 mmol) in DMF (1 mL) was added dropwise to an ice-cooled solution of tert-butyl {1-[1-(3-fluorophenyl)-1H-indol-2-yl]ethyl}carbamate (0.41 g, 1.2 mmol) in N,N-dimethylformamide (5 mL) The resulting mixture was allowed to warm to room temperature and stirred for an additional 4 hours. The mixture was diluted with water and extracted with EtOAc. The extracts were combined, dried over MgSO4, concentrated, and purified on silica gel (eluting with 0-10% EtOAc/hexane) to give the desired product (0.34 g, 68%). LCMS calculated for C21H22BrFN2O2Na(M+Na)+: m/z=455.1. Found: 455.0.
Reaction SMILES: [C:1]([O:4][CH2:5][C@H:6]([CH3:19])[CH2:7][CH:8]([NH:15][C:16](=[O:18])[CH3:17])[C:9]1[S:10][C:11](Br)=[CH:12][CH:13]=1)(=[O:3])[CH3:2].[C:20]1([CH2:26][CH2:27][CH2:28][C:29]#[CH:30])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(N(CC)CC)C.O>CN(C)C=O.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:1]([O:4][CH2:5][C@H:6]([CH3:19])[CH2:7][CH:8]([NH:15][C:16](=[O:18])[CH3:17])[C:9]1[S:10][C:11]([C:30]#[C:29][CH2:28][CH2:27][CH2:26][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:12][CH:13]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)NC(C[C@@H](C)COC(C)=O)c1ccc(Br)s1
Reactant: C#CCCCc1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)NC(C[C@@H](C)COC(C)=O)c1ccc(C#CCCCc2ccccc2)s1
Temperature: 80 °C
Reaction time: 2 h
Yield: 74.6 %

Procedure:
(2R)-Acetylamino-2-methyl-4-(5-bromothiophen-2-yl)butyl acetate (1.60 g, 4.59 mmol) obtained in Example 47 (c) was dissolved in dimethylformamide (16 ml), and 5-phenylpent-1-yne (1.99 g, 13.8 mmol), triethylamine (6.40 ml, 45.9 mmol), copper(I) iodide (175 mg, 0.92 mmol), and dichlorobis(triphenylphosphine)palladium (322 mg, 0.46 mmol) were added thereto followed by stirring for 2 hours at 80° C. under a nitrogen atmosphere. The reaction solution was poured into water, extracted with ethyl acetate, and after the ethyl acetate layer was dried over anhydrous magnesium sulfate, the solvent was evaporated in vacuo. The residue was purified by chromatography on a silica gel column (elution solvent; hexane:ethyl acetate=2:1-2:3) to give the title compound (1.41 g, 75% yield).
Reaction SMILES: [OH:1][C:2]1[CH2:7][C:6]([CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=2)([CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)[O:5][C:4](=[O:26])[CH:3]=1.[C:27]([C:31]1[C:32]([S:43]S(C2C=CC(C)=CC=2)(=O)=O)=[CH:33][C:34]([CH3:42])=[C:35]([CH:41]=1)[O:36][CH2:37][C:38]([OH:40])=[O:39])([CH3:30])([CH3:29])[CH3:28].C([O-])([O-])=O.[K+].[K+].CN(C=O)C.[CH3:65][CH2:66]O>>[CH2:65]([O:40][C:38](=[O:39])[CH2:37][O:36][C:35]1[CH:41]=[C:31]([C:27]([CH3:28])([CH3:29])[CH3:30])[C:32]([S:43][C:3]2[C:4](=[O:26])[O:5][C:6]([CH2:17][CH2:18][C:19]3[CH:20]=[CH:21][C:22]([OH:25])=[CH:23][CH:24]=3)([CH2:8][CH2:9][C:10]3[CH:11]=[CH:12][C:13]([OH:16])=[CH:14][CH:15]=3)[CH2:7][C:2]=2[OH:1])=[CH:33][C:34]=1[CH3:42])[CH3:66]
Reactant: Cc1ccc(S(=O)(=O)Sc2cc(C)c(OCC(=O)O)cc2C(C)(C)C)cc1
Reactant: O=C1C=C(O)CC(CCc2ccc(O)cc2)(CCc2ccc(O)cc2)O1
Reactant: CCO
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)COc1cc(C(C)(C)C)c(SC2=C(O)CC(CCc3ccc(O)cc3)(CCc3ccc(O)cc3)OC2=O)cc1C

Procedure:
The title compound was synthesized via General Method 9 using 209 mg (0.6 mmol) of 4-hydroxy-6,6-bis-[2-(4-hydroxy-phenyl)-ethyl]-5,6-dihydro-pyran-2-one (prepared in Example PP), 250 mg (0.6 mmol) of [5-tert-butyl-2-methyl-4-(toluene-4-sulfonylsulfanyl)-phenoxy]-acetic acid (prepared in Example NNNN), 327 mg (2.4 mmol) of K2CO3, and DMF (2 mL). The reaction was conducted in EtOH to effect ester exchange. The reaction was worked up as described. The residue was chromatographed on silica gel eluting with (1:1 CH2Cl2 :EtOAc+2% MeOH) to yield the product, m.p. 162°-163° C. 1H NMR (DMSO-d6) δ 1.21 (t, 3 H), 1.47 (s, 9 H), 1.8 (s, 3 H), 2.0 (m, 4 H), 2.6 (m, 6 H), 2.95 (s, 2 H), 4.25 (q, 2 H), 4.75 (s, 2 H), 6.65 (m, 5 H), 6.75 (s, 1 H), 7.0 (d 4 H), 9.18 (s, 2 H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16](S(C)=O)[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:28]=[CH:29][C:30]=3[CH3:31])[C:22]([NH:24][CH:25]([CH3:27])[CH3:26])=[O:23])[C:13]=2[CH2:12][NH:11][C:10]1=[O:35].[NH:36]1[CH2:40][CH2:39][CH2:38][CH2:37]1>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([N:36]3[CH2:40][CH2:39][CH2:38][CH2:37]3)[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:28]=[CH:29][C:30]=3[CH3:31])[C:22]([NH:24][CH:25]([CH3:27])[CH3:26])=[O:23])[C:13]=2[CH2:12][NH:11][C:10]1=[O:35]
Reactant: Cc1ccc(C(=O)NC(C)C)cc1-c1nc(S(C)=O)nc2c1CNC(=O)N2c1c(F)cccc1F
Reactant: C1CCNC1
Solvent: ClCCl
Product: Cc1ccc(C(=O)NC(C)C)cc1-c1nc(N2CCCC2)nc2c1CNC(=O)N2c1c(F)cccc1F
Yield: 67.1 %

Procedure:
To a solution of compound 3-[8-(2,6-difluorophenyl)-2-(methylsulfinyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methyl-N-(1-methylethyl)benzamide (50 mg, 0.10 mmol) in DCM (5 mL) was added pyrrolidine (0.025 mL, 0.30 mmol). The resultant solution was stirred at room temperature over night. The result mixture was concentrated. CombiFlash chromatography (mobile phase DCM/DCM[90]+MeOH[7]+NH4OH[3]) provided the title compound as a white solid (34 mg, 67%). LC-MS m/z 507 (M+H)+; 1H-NMR (MeOD) δ 1.27 (d, 6H), 1.87 (m, 4H), 2.31 (s, 3H), 3.33 (m, 4H), 4.11 (m, 2H), 4.23 (m, 1H), 7.13 (t, 2H), 7.44 (d, 1H), 7.48 (m, 1H), 7.70 (s, 1H), 7.85 (d, 1H).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[CH:9]=[CH:8][CH:7]=[C:6]3[CH2:11][CH2:12][CH2:13][CH:4]([C:5]=23)[C:3]1=[O:14].[H-].[Na+].[Br:17][CH2:18][CH2:19][CH2:20][CH2:21]Br.C(OC(C)C)(C)C>CN(C)C=O.O>[Br:17][CH2:18][CH2:19][CH2:20][CH2:21][C:4]12[CH2:13][CH2:12][CH2:11][C:6]3[C:5]1=[C:10]([CH:9]=[CH:8][CH:7]=3)[N:2]([CH3:1])[C:3]2=[O:14]
Reactant: BrCCCCBr
Reactant: CN1C(=O)C2CCCc3cccc1c32
Agent: [H-]
Agent: [Na+]
Solvent: CC(C)OC(C)C
Solvent: O
Solvent: CN(C)C=O
Product: CN1C(=O)C2(CCCCBr)CCCc3cccc1c32
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 75 %

Procedure:
1-Methyl-2a,3,4,5-tetrahydrobenz[cd]indole-2(1H) -one (3.7 g, 20 mmol) was dissolved in anhydrous N,N-dimethylformamide (50 ml). Thereto was added sodium hydride (60% content, 800 mg, 20 mmol), and the resulting solution was stirred at a room temperature for 30 minutes. The reaction solution was cooled in an ice bath of −10° C., mixed with 1,4-dibromobutane (7.0 ml) and then 1 hour of the reaction was carried out while temperature of the reaction solution was increased to a room temperature. The reaction solution was mixed with diisopropyl ether (150 ml) and water (100 ml), and the reaction product was extracted. Then the resulting organic layer was washed three times with water and dried with anhydrous sodium sulfate. Diisopropyl ether was evaporated under a reduced pressure, and the thus obtained oily residue was separated and purified by a silica gel column chromatography (developing system: diisopropyl ether) to obtain 4.8 g of the title compound (15 mmol, 75% in yield).
Reaction SMILES: C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.C(N(C(C)C)CC)(C)C.[OH:25][C@@H:26]([C@H:28]1[C:49](=[O:50])[N:30]2[CH:31]([C:36]([O:38][CH2:39][C:40]3[CH:45]=[CH:44][C:43]([N+:46]([O-:48])=[O:47])=[CH:42][CH:41]=3)=[O:37])[C:32](=O)[C@H:33]([CH3:34])[C@H:29]12)[CH3:27].[OH:51][CH2:52][CH2:53][N:54]1[CH2:59][CH2:58][N:57]([C:60]([C@@H:62]2[CH2:66][C@H:65]([SH:67])[CH2:64][N:63]2[C:68]([O:70][CH2:71][C:72]2[CH:77]=[CH:76][C:75]([N+:78]([O-:80])=[O:79])=[CH:74][CH:73]=2)=[O:69])=[O:61])[CH2:56][CH2:55]1>C(#N)C>[OH:51][CH2:52][CH2:53][N:54]1[CH2:55][CH2:56][N:57]([C:60]([C@@H:62]2[CH2:66][C@H:65]([S:67][C:32]3[C@H:33]([CH3:34])[C@@H:29]4[C@@H:28]([C@H:26]([OH:25])[CH3:27])[C:49](=[O:50])[N:30]4[C:31]=3[C:36]([O:38][CH2:39][C:40]3[CH:41]=[CH:42][C:43]([N+:46]([O-:48])=[O:47])=[CH:44][CH:45]=3)=[O:37])[CH2:64][N:63]2[C:68]([O:70][CH2:71][C:72]2[CH:73]=[CH:74][C:75]([N+:78]([O-:80])=[O:79])=[CH:76][CH:77]=2)=[O:69])=[O:61])[CH2:58][CH2:59]1
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)C(=O)[C@H](C)[C@H]12
Reactant: O=C([C@@H]1C[C@H](S)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1)N1CCN(CCO)CC1
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(S[C@H]3C[C@@H](C(=O)N4CCN(CCO)CC4)N(C(=O)OCc4ccc([N+](=O)[O-])cc4)C3)[C@H](C)[C@H]12
Reaction time: 1 h
Yield: 52.5 %

Procedure:
1.82 ml of diphenylphosphoryl chloride and 1.54 ml of diisopropylethylamine were added dropwise, whilst ice-cooling, to a solution of 3.0 g of 4-nitrobenzyl (1R,5R,6S)-6-[(1R)-1-hydroxyethyl]-1-methyl-2-oxo-1-carbapenam-3-carboxylate in 38 ml of dry acetonitrile, and the resulting mixture was stirred at the same temperature for 1 hour. 1.54 ml of diisopropylethylamine and a solution of 3.63 g of (2S,4S)-2-[4-(2-hydroxyethyl)-1-piperazinylcarbonyl]-4-mercapto-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (prepared as described in Preparation 54) in 30 ml of dry acetonitrile were then simultaneously added dropwise to the mixture, whilst ice-cooling, and the resulting mixture was stirred at the same temperature for 3 hours, after which it was allowed to stand overnight in a refrigerator. At the end of this time, the reaction mixture was worked up in a similar manner to that described in Example 49(b). The crude product was then purified by column chromatography through silica gel, using a 2:1 by volume mixture of ethyl acetate and methanol as the eluent, to give 3.4 g of the title compound, as a powder. The infrared absorption spectrum and nuclear magnetic resonance spectrum of the product were identical with those of the compound prepared as described in step 54(i), above.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]([O:20][CH2:21][CH2:22]Cl)([C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:13])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[NH:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1>CCOCC>[O:27]1[CH2:28][CH2:29][N:24]([CH2:2][CH2:3][O:4][C:5]([O:20][CH2:21][CH2:22][N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:13])[CH2:25][CH2:26]1
Reactant: C1COCCN1
Reactant: O=C(c1ccccc1)C(OCCCl)(OCCCl)c1ccccc1
Solvent: CCOCC
Product: O=C(c1ccccc1)C(OCCN1CCOCC1)(OCCN1CCOCC1)c1ccccc1

Procedure:
With stirring, 35 g (0.1 mole) of benzil-di-(2-chloroethyl)ketal and 52 g (0.6 mole) of morpholine are kept for 6 hours at 110° C. After cooling, the product is taken up in ether. The ether layer is washed with water, dried over Na2SO4 and concentrated. The residual oil is dried in a high vacuum at 50°-60° C.
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8][CH2:9][C:10]2[C:15]([Cl:16])=[CH:14][CH:13]=[CH:12][C:11]=2[Cl:17])=[CH:6][CH:5]=[CH:4][N:3]=1.Cl.[C:19]1([CH2:25][C:26](=[NH:30])OCC)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(O)C>[ClH:16].[Cl:17][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]([Cl:16])[C:10]=1[CH2:9][O:8][C:7]1[C:2]([NH:1][C:26](=[NH:30])[CH2:25][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[N:3][CH:4]=[CH:5][CH:6]=1
Reactant: Nc1ncccc1OCc1c(Cl)cccc1Cl
Reactant: CCOC(=N)Cc1ccccc1
Agent: Cl
Solvent: CCO
Product: N=C(Cc1ccccc1)Nc1ncccc1OCc1c(Cl)cccc1Cl
Yield: 36 %

Procedure:
A mixture of 2-amino-3-(2,6-dichlorobenzyloxy)pyridine (5.38 g, 20 mmol) and ethyl phenylacetimidate hydrochloride (4.39 g, 22 mmol) in ethanol (80 ml) was heated under reflux for 2 hours. Evaporation of the solvent gave an oil which was purified by flash chromatography (chloroform/methanol) to obtain the product as a hygroscopic foam (1.52 g), m.p. 69°-74° C.
Reaction SMILES: [H-].[Na+].[OH:3][CH2:4][CH2:5][N:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1.Br[C:12]1[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][N:13]=1>CN(C=O)C.CCOC(C)=O>[Br:18][C:15]1[CH:16]=[CH:17][C:12]([O:3][CH2:4][CH2:5][N:6]2[CH2:10][CH2:9][CH2:8][CH2:7]2)=[N:13][CH:14]=1
Reactant: OCCN1CCCC1
Reactant: Brc1ccc(Br)nc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Brc1ccc(OCCN2CCCC2)nc1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
280 mg (7.00 mmol, 60%) NaH are added to a solution of 0.76 mL (6.14 mmol) N-(2-hydroxyethyl)pyrrolidine in 20 mL DMF at RT. The reaction solution is stirred for 45 min at RT and then 1.35 g (5.53 mmol) 2,5-dibromopyridine are added. The solution is stirred for 16 h at 70° C. and the solvent is eliminated i.vac. The residue is taken up in 100 mL EtOAc and 50 mL water and the organic phase is extracted with 40 mL saturated NaCl solution. The organic phase is dried over Na2SO4 and the solvent is eliminated i.vac. Further purification is carried out by column chromatography on silica gel (gradient: cyc/EtOAc 1:1 to EtOAc).
Reaction SMILES: [F:1][C:2]1[CH:14]=[CH:13][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)=[CH:4][CH:3]=1.[CH3:15][S:16][C:17](SC)=[N:18][C:19]#[N:20]>C(O)C>[C:19]([N:18]=[C:17]([N:10]1[CH2:11][CH2:12][N:7]([CH2:6][C:5]2[CH:13]=[CH:14][C:2]([F:1])=[CH:3][CH:4]=2)[CH2:8][CH2:9]1)[S:16][CH3:15])#[N:20]
Reactant: Fc1ccc(CN2CCNCC2)cc1
Reactant: CSC(=NC#N)SC
Solvent: CCO
Product: CSC(=NC#N)N1CCN(Cc2ccc(F)cc2)CC1

Procedure:
A 28.7 g. (0.1 mole) portion of N-(p-fluorobenzyl)piperazine was dissolved in 25 ml. of ethanol and then added dropwise over 30 minutes to a stirred solution of 14.6 g. (0.1 mole) of dimethyl cyanodithioiminocarbonate in 200 ml. of ethanol. The mixture was refluxed for 6 hours, the evolved gas being led through a sodium hypochlorite trap. The mixture was then evaporated to a syrup.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:26]2[N:30]=[CH:29][NH:28][N:27]=2)=[C:4]([NH:7][C:8](=[O:25])[CH2:9][N:10]2[C:19]3[C:14](=[CH:15][C:16]([C:20]([F:23])([F:22])[F:21])=[CH:17][CH:18]=3)[CH:13]=[CH:12][C:11]2=[O:24])[S:5][CH:6]=1.[O:31]1[CH2:36][CH2:35][N:34]([CH2:37][CH2:38][CH2:39]O)[CH2:33][CH2:32]1>>[Cl:1][C:2]1[C:3]([C:26]2[N:30]=[CH:29][N:28]([CH2:39][CH2:38][CH2:37][N:34]3[CH2:35][CH2:36][O:31][CH2:32][CH2:33]3)[N:27]=2)=[C:4]([NH:7][C:8](=[O:25])[CH2:9][N:10]2[C:19]3[C:14](=[CH:15][C:16]([C:20]([F:23])([F:22])[F:21])=[CH:17][CH:18]=3)[CH:13]=[CH:12][C:11]2=[O:24])[S:5][CH:6]=1
Reactant: O=C(Cn1c(=O)ccc2cc(C(F)(F)F)ccc21)Nc1scc(Cl)c1-c1nc[nH]n1
Reactant: OCCCN1CCOCC1
Product: O=C(Cn1c(=O)ccc2cc(C(F)(F)F)ccc21)Nc1scc(Cl)c1-c1ncn(CCCN2CCOCC2)n1

Procedure:
The title compound was prepared from N-(4-chloro-3-(1H-1,2,4-triazol-3-yl)thiophen-2-yl)-2-(2-oxo-6-(trifluoromethyl)quinolin-1(2H)-yl)acetamide (110 mg, 242 umol) and 3-morpholinopropan-1-ol (350 mg, 2.41 mmol) using the procedure described in Example 1.76. HPLC purification gave N-(4-chloro-3-(1-(3-morpholinopropyl)-1H-1,2,4-triazol-3-yl)thiophen-2-yl)-2-(2-oxo-6-(trifluoromethyl)quinolin-1(2H)-yl)acetamide. Method [7] Retention time 4.58 min by HPLC (M+=581 and 583) and (M+Na=603 and 605). 1H NMR (300 MHz, DMSO-d6) δ 12.10 (s, 1H), 8.47 (s, 1H), 8.26 (s, 1H), 8.20 (d, J=9.3 Hz, 1H), 7.91 (d, J=7.2 Hz, 1H), 7.70 (d, J=9.3 Hz, 1H), 7.16 (s, 1H), 6.86 (d, J=9.3 Hz, 1H), 5.30 (s, 2H), 4.30 (t, J=7.2 Hz, 2H), 3.20 (broad m, 10H), 1.20 (m, 2H).