Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1([CH:12]([C:14]2[N:19]=[CH:18][CH:17]=[CH:16][N:15]=2)[CH3:13])[CH2:11][O:10]1.[NH:20]1[CH:24]=[N:23][CH:22]=[N:21]1.[Na].C(OCC)(=O)C>CN(C)C=O>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([OH:10])([CH:12]([C:14]1[N:19]=[CH:18][CH:17]=[CH:16][N:15]=1)[CH3:13])[CH2:11][N:20]1[CH:24]=[N:23][CH:22]=[N:21]1
Reactant: CC(c1ncccn1)C1(c2ccc(F)cc2F)CO1
Reactant: c1nc[nH]n1
Agent: [Na]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(c1ncccn1)C(O)(Cn1cncn1)c1ccc(F)cc1F

Procedure:
Treatment of the product of part (iii) (0.80 g) with 1H-1,2,4-triazole, sodium salt (0.82 g) in N,N-dimethylformamide according to the method of Example 12(iv), followed by chromatography of the crude product on silica gel using ethyl acetate as eluant, first gave, after combination and evaporation of appropriate fractions, the title compound, diastereoisomeric pair A, (0.26 g), m.p. 193°-195° (from dichloromethane/ether).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][N:16]=3)[C:11](=[O:18])[C:10]([C:19](O)=[O:20])=[CH:9]2)[CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.ClC(OCC(C)C)=O.[CH:37]([NH2:40])([CH3:39])[CH3:38]>O1CCCC1>[CH:37]([NH:40][C:19]([C:10]1[C:11](=[O:18])[C:12]2[C:17](=[N:16][CH:15]=[CH:14][CH:13]=2)[N:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=2)[CH:9]=1)=[O:20])([CH3:39])[CH3:38]
Reactant: CC(C)N
Reactant: O=C(O)c1cn(-c2cccc(Br)c2)c2ncccc2c1=O
Agent: CC(C)COC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)NC(=O)c1cn(-c2cccc(Br)c2)c2ncccc2c1=O
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a suspension of 1-(3-bromophenyl)-1,4-dihydro[1,8]naphthyridin-4-one-3-carboxylic acid from Step 3 (26.3 g, 76 mmol) and triethylamine (23.2 g, 230 mmol) in tetrahydrofuran (1000 mL) at 0° C. was added isobutyl chloroformate (18.85 g, 138 mmol). After stirring at 0° C. for 2 hours, isopropylamine (23 g, 390 mmol) was added and the mixture was allowed to warm up to room temperature and stirred overnight. The mixture was then partitioned between ethyl acetate and water, the organic phase was dried and evaporated to a solid which was stirred in ether at room temperature for 3 hours and filtered to afford the N-Isopropyl-1-(3-bromophenyl)-1,4-dihydro[1,8]naphthyridin-4-one-3-carboxamide as a white solid.
Reaction SMILES: COC[O:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:14]([CH3:16])([CH3:15])[C:13](=[O:17])[N:12]2[CH:18]2[CH:25]3[CH2:26][CH:21]4[CH2:22][CH:23]([CH2:27][CH:19]2[CH2:20]4)[CH2:24]3)=[CH:7][CH:6]=1.Cl.[Cl-].[NH4+]>CO>[CH3:15][C:14]1([CH3:16])[N:11]([C:8]2[CH:9]=[CH:10][C:5]([OH:4])=[CH:6][CH:7]=2)[N:12]([CH:18]2[CH:19]3[CH2:27][CH:23]4[CH2:22][CH:21]([CH2:26][CH:25]2[CH2:24]4)[CH2:20]3)[C:13]1=[O:17]
Reactant: COCOc1ccc(N2N(C3C4CC5CC(C4)CC3C5)C(=O)C2(C)C)cc1
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Product: CC1(C)C(=O)N(C2C3CC4CC(C3)CC2C4)N1c1ccc(O)cc1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 68.9 %

Procedure:
A solution of 1-[4-(methoxymethoxy)phenyl]-4,4-dimethyl-2-(adamantan-2-yl)-1,2-diazetidin-3-one (62.5 mg, 0.169 mmol) prepared in Example 214 in methanol was added with concentrated hydrochloric acid (0.3 mL) under ice-cold conditions, and the resultant was stirred at 50° C. for 30 minutes. The reaction solution was added under ice-cold conditions with a saturated aqueous solution of ammonium chloride, extracted with chloroform, and concentrated in vacuo. The obtained residue was purified using Preparatory Thin-Layer chromatography (chloroform:methanol=10:1), and the title compound (38.0 mg, 68.8%) was obtained as a white crystalline solid.
Reaction SMILES: [C:1]([Cl:6])([C:3](Cl)=O)=[O:2].CN(C=O)C.[CH2:12]([N:14]1[C:20]2[N:21]=[CH:22][C:23]([CH2:25][CH2:26][O:27][C:28]3[CH:36]=[CH:35]C(C(O)=O)=[CH:30][C:29]=3[CH3:37])=[CH:24][C:19]=2[C:18](=[O:38])[N:17]([CH3:39])[C:16]2[CH:40]=[CH:41][CH:42]=[N:43][C:15]1=2)[CH3:13]>C(Cl)Cl>[CH2:12]([N:14]1[C:20]2[N:21]=[CH:22][C:23]([CH2:25][CH2:26][O:27][C:28]3[CH:36]=[CH:35][C:3]([C:1]([Cl:6])=[O:2])=[CH:30][C:29]=3[CH3:37])=[CH:24][C:19]=2[C:18](=[O:38])[N:17]([CH3:39])[C:16]2[CH:40]=[CH:41][CH:42]=[N:43][C:15]1=2)[CH3:13]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CCN1c2ncc(CCOc3ccc(C(=O)O)cc3C)cc2C(=O)N(C)c2cccnc21
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCN1c2ncc(CCOc3ccc(C(=O)Cl)cc3C)cc2C(=O)N(C)c2cccnc21
Yield: 101.6 %

Procedure:
(COCl)2 (25 μL, 0.87 mmol) and DMF (10 μL) were added to a solution of 4-[2-(11-ethyl-6,11-dihydro-5-methyl-6-oxo-5H-dipyrido[3,2-b:2′,3′-e][1,4]diazepin-8-yl)ethoxy]-3-methylbenzoic acid (52.8 mg, 0.12 mmol) in CH2Cl2 (5 mL). The reaction mixture was heated to reflux for 1 h. The cooled mixture was concentrated under reduced pressure to give the title compound (55 mg, 100% yield), which was used without further purification.
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[C:6]([C:14]([F:17])([F:16])[F:15])[C:3]=1[CH:4]=O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:29]([NH2:33])[CH2:30][CH2:31][CH3:32]>C1(C)C=CC=CC=1>[CH2:29]([N:33]=[CH:4][C:3]1[C:6]([C:14]([F:17])([F:16])[F:15])=[CH:7][C:8]([C:10]([F:13])([F:12])[F:11])=[CH:9][C:2]=1[F:1])[CH2:30][CH2:31][CH3:32]
Reactant: CCCCN
Reactant: O=Cc1c(F)cc(C(F)(F)F)cc1C(F)(F)F
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CCCCN=Cc1c(F)cc(C(F)(F)F)cc1C(F)(F)F

Procedure:
2-Fluoro-4,6-bis(trifluoromethyl)benzaldehyde (10 g, 38 mmol) was dissolved in 30 mL toluene. p-Toluenesulfonic acid (140 mg, 0.74 mmol) and N-butylamine (2.94 g, 40 mmol) were added. The reaction mixture was refluxed overnight. The mixture was extracted with 2N sodium carbonate solution and ethyl acetate. The combined organic phases were dried on sodium sulfate, filtered and evaporated. The crude material, orange oil (12 g, >100%) was used without further purification.
Reaction SMILES: C(N(CC)C(C)C)(C)C.[Cl:10][C:11]1[CH:12]=[C:13]([N:18]2[C:22]([C:23]3[CH:24]=[N:25][CH:26]=[C:27]([F:29])[CH:28]=3)=[CH:21][C:20]([C:30]([OH:32])=O)=[N:19]2)[CH:14]=[CH:15][C:16]=1[F:17].Cl.[NH:34]1[CH:38]=[CH:37][NH:36][C:35]1=O.C1CN([P+]([O:56]N2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>C1COCC1>[Cl:10][C:11]1[CH:12]=[C:13]([N:18]2[C:22]([C:23]3[CH:24]=[N:25][CH:26]=[C:27]([F:29])[CH:28]=3)=[CH:21][C:20]([C:30]([N:34]3[CH2:38][C:37](=[O:56])[NH:36][CH2:35]3)=[O:32])=[N:19]2)[CH:14]=[CH:15][C:16]=1[F:17]
Reactant: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Reactant: O=c1[nH]cc[nH]1
Reactant: O=C(O)c1cc(-c2cncc(F)c2)n(-c2ccc(F)c(Cl)c2)n1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: O=C1CN(C(=O)c2cc(-c3cncc(F)c3)n(-c3ccc(F)c(Cl)c3)n2)CN1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
0.16 ml (0.89 mmol) of N,N-diisopropylethylamine is added to a solution of 100 mg (0.30 mmol) of the compound of Example 60A, 40 mg (0.33 mmol) of 4-imidazolinone-hydrochloride, and 217 mg (0.42 mmol) of PYBOP in 2 ml of THF, and the mixture that is obtained is stirred for 16 hours at room temperature. The reaction mixture is concentrated by evaporation in a vacuum. The residue is diluted with acetonitrile, filtered over a Millipore spray filter, and separated by means of preparative HPLC (mobile solvent: acetonitrile/water gradient). Solvent is removed from the product-containing fractions in a rotary evaporator, and the residue is recrystallized from acetonitrile. 96 mg (80% of theory) of the title compound is obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C(O)(=O)C.CS[C:20]1[N:21]=[C:22]([OH:29])[C:23]2[S:28][CH2:27][CH2:26][C:24]=2[N:25]=1>O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:20]3[N:21]=[C:22]([OH:29])[C:23]4[S:28][CH2:27][CH2:26][C:24]=4[N:25]=3)[CH2:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: Clc1ccc(N2CCNCC2)cc1
Reactant: CSc1nc(O)c2c(n1)CCS2
Solvent: O
Solvent: CC(=O)O
Product: Oc1nc(N2CCN(c3ccc(Cl)cc3)CC2)nc2c1SCC2
Temperature: 180 °C
Yield: 92.8 %

Procedure:
20.45 g 1-(4-chloro-phenyl)-piperazine are placed in 5.95 ml (104 mmol) glacial acetic acid and heated to 180° C. 8.01 g 2-methylsulphanyl-6,7-dihydro-thieno[3,2-d]pyrimidin-4-ol are added, the non-stirrable reaction mixture is heated for 2.5 hours to 180° C. After cooling, water is added, the precipitate is suction filtered and dried in the air. The substance is treated with ethanol under ultrasound, suction filtered and dried. 12.95 g of the product are obtained as a powder.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][C@H:8]([C@H:16]1[CH2:18][O:17]1)[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2].[CH:20]1([NH2:26])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1>CCO>[C:1]([O:5][C:6](=[O:19])[NH:7][C@@H:8]([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C@H:16]([OH:17])[CH2:18][NH:26][CH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@H]1CO1
Reactant: NC1CCCCC1
Solvent: CCO
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@H](O)CNC1CCCCC1
Yield: 65.3 %

Procedure:
((S)-(S)-1-Oxiranyl-2-phenyl-ethyl)-carbamic acid tert-butyl ester (D101) (10 g, 38 mmol, 1 equiv) [Chirex 1819W94 Lot#9924382] was dissolved in EtOH (100 ml) and cyclohexylamine (13 ml, 114 mmol, 3 equiv) was added. The resulting mixture was heated, under an atmosphere of nitrogen, for 12 h at reflux temperature. The mixture was cooled and the solvent was removed by evaporation in vacuo. The resulting white solid was washed with H2O and then with Et2O before drying in vacuo to give ((1S,2R)-1-benzyl-3-cyclohexylamino-2-hydroxy-propyl)-carbamic acid tert-butyl ester (H1) (9.0 g, 66%). [M+H]+=363.2
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:21]=[CH:20][C:8]2[CH:9]=[C:10]([C:17]([OH:19])=[O:18])[CH:11]([C:13]([F:16])([F:15])[F:14])[O:12][C:7]=2[CH:6]=1)([CH3:4])[CH3:3].[Br:22]Br>[Fe].C(Cl)(Cl)Cl>[Br:22][C:21]1[C:5]([C:2]([CH3:1])([CH3:3])[CH3:4])=[CH:6][C:7]2[O:12][CH:11]([C:13]([F:14])([F:15])[F:16])[C:10]([C:17]([OH:19])=[O:18])=[CH:9][C:8]=2[CH:20]=1
Reactant: CC(C)(C)c1ccc2c(c1)OC(C(F)(F)F)C(C(=O)O)=C2
Reactant: BrBr
Agent: [Fe]
Solvent: ClC(Cl)Cl
Product: CC(C)(C)c1cc2c(cc1Br)C=C(C(=O)O)C(C(F)(F)F)O2

Procedure:
7-(1,1-Dimethylethyl-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylic acid (Example 12) (0.6 g, 2 mmol), chloroform (50 mL), iron filings (0.01 g, 0.2 mmol), and bromine (0.48 g, 3.00 mmol) were stirred at reflux for 16 h. The mixture was allowed to cool and was washed with brine (2×50 mL). After drying over MgSO4, the mixture was filtered, concentrated in vacuo, and the residue crystallized from ether-hexanes yielding the title compound as a white solid (0.5 g, 66%): mp 198.6-199.9° C. 1H NMR (acetone-d6/300 MHz) 7.85 (s, 1H), 7.72 (s, 1H), 7.13 (s, 1H), 5.83 (q, 1H, J=7.2 Hz), 1.5 (s, 9H). Anal. Calc'd for C15H14O3F3Br: C, 47.52; H, 3.72; N, 21.07. Found: C, 47.42; H, 3.68; N, 21.15.
Reaction SMILES: Br.Br[CH2:3][CH2:4][C:5]1[C:14](=[O:15])[N:13]2[C:8]([S:9][CH2:10][CH2:11][CH2:12]2)=[N:7][C:6]=1[CH3:16].[CH3:17][C:18]1[C:26]2[O:25][N:24]=[C:23]([N:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)[C:22]=2[CH:21]=[CH:20][CH:19]=1.C(=O)([O-])[O-].[Na+].[Na+].CN(C)C=O>O>[CH3:16][C:6]1[N:7]=[C:8]2[N:13]([C:14](=[O:15])[C:5]=1[CH2:4][CH2:3][N:30]1[CH2:31][CH2:32][N:27]([C:23]3[C:22]4[CH:21]=[CH:20][CH:19]=[C:18]([CH3:17])[C:26]=4[O:25][N:24]=3)[CH2:28][CH2:29]1)[CH2:12][CH2:11][CH2:10][S:9]2
Reactant: Cc1cccc2c(N3CCNCC3)noc12
Reactant: Cc1nc2n(c(=O)c1CCBr)CCCS2
Agent: Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1nc2n(c(=O)c1CCN1CCN(c3noc4c(C)cccc34)CC1)CCCS2
Temperature: 90 °C
Reaction time: 8 h
Yield: 44.6 %

Procedure:
A mixture of 7.4 parts of 7-(2-bromoethyl)-3,4-dihydro-8-methyl-2H,6H-pyrimido[2,1-b][1,3]thiazin-6-one monohydrobromide, 4.4 parts of 7-methyl-3-(1-piperazinyl)-1,2-benzisoxazole, 10 parts of sodium carbonate and 94 parts of N,N-dimethylformamide was stirred overnight at 90° C. After cooling, the reaction mixture was poured into water and the product was extracted with 4-methyl-2-pentanone. The extract was dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (95:5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from 4-methyl-2-pentanone. The product was filtered off and dried, yielding 3.8 parts (44.6%) of 3,4-dihydro-8-methyl-7-[2-[4-(7-methyl-1,2-benzisoxazol-3-yl)-1-piperazinyl]ethyl]-2H,6H-pyrimido[2,1-b][1,3]-thiazin-6-one; mp. 170.0° C. (compound 2).
Reaction SMILES: Cl[C:2]1[C:3]([NH2:8])=[CH:4][N:5]=[N:6][CH:7]=1.[CH3:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1B(O)O>>[C:10]1([CH3:9])[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:2]1[C:3]([NH2:8])=[CH:4][N:5]=[N:6][CH:7]=1
Reactant: Nc1cnncc1Cl
Reactant: Cc1ccccc1B(O)O
Product: Cc1ccccc1-c1cnncc1N

Procedure:
The title compound was prepared in analogy to example 1, intermediate b, from 5-chloro-pyridazin-4-ylamine (CAS RN 53180-92-0) and 2-methylphenylboronic acid (CAS RN). Light yellow solid (37%). MS (ESI+): m/z=186.103 ([M+H]+).
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:7](I)[CH2:8][CH3:9].[Br:11][C:12]1[N:13]=[C:14]([C:21]([C:23]2[CH:24]=[C:25]3[C:30](=[CH:31][CH:32]=2)[NH:29][C:28](=[O:33])[N:27]([CH2:34][CH2:35][O:36][C:37]2[CH:42]=[CH:41][C:40]([F:43])=[CH:39][CH:38]=2)[C:26]3=[O:44])=[O:22])[N:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=12>CN(C=O)C>[Br:11][C:12]1[N:13]=[C:14]([C:21]([C:23]2[CH:24]=[C:25]3[C:30](=[CH:31][CH:32]=2)[N:29]([CH2:7][CH2:8][CH3:9])[C:28](=[O:33])[N:27]([CH2:34][CH2:35][O:36][C:37]2[CH:38]=[CH:39][C:40]([F:43])=[CH:41][CH:42]=2)[C:26]3=[O:44])=[O:22])[N:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=12
Reactant: CCCI
Reactant: O=C(c1ccc2[nH]c(=O)n(CCOc3ccc(F)cc3)c(=O)c2c1)c1nc(Br)c2ccccn12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCCn1c(=O)n(CCOc2ccc(F)cc2)c(=O)c2cc(C(=O)c3nc(Br)c4ccccn34)ccc21
Temperature: 25 °C
Reaction time: 12 h
Yield: 91.6 %

Procedure:
7.22 g (22.16 mmol) of caesium carbonate and 5.65 g (33.24 mmol) of propyl iodide are added, under an inert atmosphere, to 5.6 g (11.08 mmol) of 6-[(1-bromoimidazo[1,5-a]pyridin-3-yl)carbonyl]-3-[2-(4-fluorophenoxy)ethyl]quinazoline-2,4(1H,3H)-dione in 300 ml of DMF. The reaction medium is stirred for 12 hours at ambient temperature under a nitrogen atmosphere and then concentrated under reduced pressure. The residue obtained is washed with 700 ml of water and then dried under reduced pressure at 40° C. overnight. 5.74 g of a yellow solid are obtained.
Reaction SMILES: [I-].[K+].Br[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][S:13]([CH3:16])(=[O:15])=[O:14])=[CH:8][CH:7]=1.[CH2:17]([NH:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH3:18]>CN(C=O)C>[CH2:17]([N:19]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][S:13]([CH3:16])(=[O:15])=[O:14])=[CH:8][CH:7]=1)[CH3:18]
Reactant: CCCCCCCNCC
Reactant: CS(=O)(=O)Nc1ccc(CCBr)cc1
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCCCCN(CC)CCc1ccc(NS(C)(=O)=O)cc1
Temperature: 25 °C

Procedure:
A mixture of potassium iodide (4.15 g, 0.025 mol), N-[4-(2-bromoethyl)phenyl]methanesulfonamide as prepared in Preparation 5 above (7.0 g, 0.025 mol), ethylheptylamine (7.16 g, 0.05 mol) and 120 ml of DMF, under N2, is allowed to stir at ambient temperature. After 18 hours the reaction mixture is concentrated under reduced pressure and the residue is combined with cold dilute NaOH. The alkaline mixture is extracted with Et2O, neutralized to pH 7 with dilute HCl and extracted with CH2Cl2. The CH2Cl2 extracts are concentrated and the residue chromatographed over silica gel with 5% MeOH-0.5% NH4OH--CH2Cl2 to give N-[4-[2-(ethylheptylamino)ethyl]phenyl]methanesulfonamide, a gum. MS calc'd for C18H32N2O2S (M+): 340.2184. Found: 340.2170.
Reaction SMILES: [C:1]([CH:4]1[O:10][CH:9]2[C:6]([C:26](=[O:34])[CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)([C:7](=[O:25])[N:8]2[C:11](=[C:22]([CH3:24])[CH3:23])[C:12]([O:14]CC2C=CC=CC=2)=[O:13])[NH:5]1)(=[O:3])[CH3:2]>O1CCCC1.[C].[Pd]>[C:1]([CH:4]1[O:10][CH:9]2[C:6]([C:26](=[O:34])[CH2:27][C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)([C:7](=[O:25])[N:8]2[C:11](=[C:22]([CH3:24])[CH3:23])[C:12]([OH:14])=[O:13])[NH:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)C1NC2(C(=O)Cc3ccccc3)C(=O)N(C(C(=O)OCc3ccccc3)=C(C)C)C2O1
Agent: [Pd]
Solvent: C1CCOC1
Product: CC(=O)C1NC2(C(=O)Cc3ccccc3)C(=O)N(C(C(=O)O)=C(C)C)C2O1
Reaction time: 2 h
Yield: 95.1 %

Procedure:
To a solution of 550 mg of benzyl α-(3ξ-acetyl-2-phenylacetyl-7-oxo-4-oxa-2,6-diazabicyclo[3.2.0]heptan-6-yl)-α-isopropylideneacetate in 8 ml of tetrahydrofuran is added 5% palladium carbon, and the mixture catalytically hydrogenated under atmospheric pressure for 2 hours. The insoluble material is removed by filtration, and the filtrate concentrated under reduced pressure. The residue (471 mg) is crystallized from a mixture of ether and petroleum ether to yield 421 mg of α-(3ξ-acetyl-2-phenylacetyl-7-oxo-4-oxa-2,6-diazabicyclo[3.2.0]heptan-6-yl)-α-isopropylideneacetic acid in 95% yield.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH2:22])[C:5]2[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=3)=[C:9]([CH:19]([CH3:21])[CH3:20])[S:8][C:6]=2[N:7]=1.[CH3:23][N:24]1[CH:28]=[C:27]([S:29](Cl)(=[O:31])=[O:30])[N:26]=[C:25]1[CH3:33].[C:34]([OH:40])([C:36]([F:39])([F:38])[F:37])=[O:35]>>[F:37][C:36]([F:39])([F:38])[C:34]([OH:40])=[O:35].[CH3:23][N:24]1[CH:28]=[C:27]([S:29]([NH:22][C:4]2[CH:3]=[C:2]([CH3:1])[N:7]=[C:6]3[S:8][C:9]([CH:19]([CH3:20])[CH3:21])=[C:10]([C:11]4[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=4)[C:5]=23)(=[O:31])=[O:30])[N:26]=[C:25]1[CH3:33]
Reactant: COc1cccc(-c2c(C(C)C)sc3nc(C)cc(N)c23)c1
Reactant: Cc1nc(S(=O)(=O)Cl)cn1C
Solvent: O=C(O)C(F)(F)F
Product: COc1cccc(-c2c(C(C)C)sc3nc(C)cc(NS(=O)(=O)c4cn(C)c(C)n4)c23)c1

Procedure:
Following general method outlined in Example 52, starting from 6-methyl-2-(1-methylethyl)-3-[3-(methyloxy)phenyl]thieno[2,3-b]pyridin-4-amine (35 mg, 0.112 mmol) (Description 21) and 1,2-dimethylimidazole-4-sulfonyl chloride (21.8 mg, 0.112 mmol), the title compound (9.0 mg) was isolated as a TFA salt. LCMS (B) m/z: 471 [M+1]+, Rt 2.14 min.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][CH:12]=1)[C:8]#[N:9])=O.[F:13][C:14]([F:25])([F:24])[C:15]1[CH:20]=[CH:19][N:18]=[CH:17][C:16]=1[C:21](=[S:23])[NH2:22]>>[F:24][C:14]([F:13])([F:25])[C:15]1[CH:20]=[CH:19][N:18]=[CH:17][C:16]=1[C:21]1[S:23][CH:2]=[C:3]([C:5]2[CH:6]=[C:7]([CH:10]=[CH:11][CH:12]=2)[C:8]#[N:9])[N:22]=1
Reactant: NC(=S)c1cnccc1C(F)(F)F
Reactant: N#Cc1cccc(C(=O)CBr)c1
Product: N#Cc1cccc(-c2csc(-c3cnccc3C(F)(F)F)n2)c1
Yield: 76.3 %

Procedure:
By the reaction in the same manner as in Example 25-iii) using 3-(bromoacetyl)benzonitrile (913 mg) and 4-trifluoromethylpyridine-3-thiocarboxamide (840 mg), the title compound (1.03 g) was obtained as colorless powder crystals.
Reaction SMILES: C([O:8][CH2:9][C:10]1[N:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:13]=[N:12][C:11]=1[C:21]([N:23]([CH2:41][CH:42]([CH3:44])[CH3:43])[C@@H:24]1[CH2:29][N:28]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:27][C@H:26]([C:37]([O:39][CH3:40])=[O:38])[CH2:25]1)=[O:22])C1C=CC=CC=1>CO.[OH-].[Pd+2].[OH-].[C]>[OH:8][CH2:9][C:10]1[N:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:13]=[N:12][C:11]=1[C:21]([N:23]([CH2:41][CH:42]([CH3:44])[CH3:43])[C@@H:24]1[CH2:29][N:28]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:27][C@H:26]([C:37]([O:39][CH3:40])=[O:38])[CH2:25]1)=[O:22]
Reactant: COC(=O)[C@@H]1C[C@H](N(CC(C)C)C(=O)c2nnn(-c3ccccc3)c2COCc2ccccc2)CN(C(=O)OC(C)(C)C)C1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: COC(=O)[C@@H]1C[C@H](N(CC(C)C)C(=O)c2nnn(-c3ccccc3)c2CO)CN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 10 h
Yield: 96.2 %

Procedure:
1-tert-Butyl 3-methyl (3R,5S)-5-[({5-[(benzyloxy)methyl]-1-phenyl-1H-1,2,3-triazol-4-yl}carbonyl)(2-methylpropyl)amino]piperidine-1,3-dicarboxylate (2.92 g) and palladium(II) hydroxide-carbon (500 mg) were suspended in methanol, and the mixture was stirred under a hydrogen atmosphere (5 atom) at room temperature for 10 hr. The palladium catalyst was filtered off, and the filtrate was concentrated under reduced pressure to give the object product (2.39 g) as a solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:26])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:14]=[CH:13][C:12]([C@@H:15]([CH3:25])[CH2:16][NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:11][CH:10]=2)[O:3]1.[CH3:27][Si]([N-][Si](C)(C)C)(C)C.[Na+].CI>C1COCC1>[CH3:27][N:17]([CH2:16][C@@H:15]([C:12]1[CH:13]=[CH:14][C:9]([B:4]2[O:3][C:2]([CH3:26])([CH3:1])[C:6]([CH3:7])([CH3:8])[O:5]2)=[CH:10][CH:11]=1)[CH3:25])[C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21]
Reactant: C[C@@H](CNC(=O)OC(C)(C)C)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CI
Solvent: C1CCOC1
Product: C[C@@H](CN(C)C(=O)OC(C)(C)C)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Reaction time: 1 h
Yield: 66.3 %

Procedure:
A solution of (R)-tert-butyl 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propylcarbamate (9.0 g, 24.93 mmol) in anhydrous THF (120 mL) was cooled to 0° C. and NaHMDS (30 mL, 29.9 mmol) was added. The mixture was stirred for 1 h, methyl iodide (1.9 mL, 29.9) in THF (40 mL) added and stirred for 14 h. The reaction mixture was quenched with water (20 mL) and diluted with ethyl acetate (250 mL). The layers were separated and the organic layer was dried over anhydrous sodium sulfate, filtered, concentrated and the residue purified by column chromatography (silica, 0-30% ethyl acetate/heptane) to afford the desired product (6.2 g, 66%) as light yellow oil: ESI MS m/z 376 [C21H13NO4+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].[CH2:14]([NH2:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[CH2:14]([NH:21][C:6](=[O:7])[C:5]1[CH:9]=[CH:10][C:2]([Cl:1])=[C:3]([N+:11]([O-:13])=[O:12])[CH:4]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: NCc1ccccc1
Reactant: O=C(Cl)c1ccc(Cl)c([N+](=O)[O-])c1
Product: O=C(NCc1ccccc1)c1ccc(Cl)c([N+](=O)[O-])c1

Procedure:
A mixture of 4-chloro-3-nitrobenzoyl chloride was reacted with Benzylamine to produce N-Benzyl-4-chloro-3-nitro-benzamide according to the procedure of Example 10A, which was treated sequentially using the procedures from Examples 22A and 22B to provide the title product.
Reaction SMILES: [C:1]1([N:11]2[C:15]([SH:16])=[N:14][N:13]=[N:12]2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.Br[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[C:1]1([N:11]2[C:15]([S:16][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])=[N:14][N:13]=[N:12]2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: Sc1nnnn1-c1cccc2ccccc12
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CSc1nnnn1-c1cccc2ccccc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 94.5 %

Procedure:
A mixture of 1-(Naphthalen-1-yl)-1H-tetrazole-5-thiol (235 mg, 1.03 mmol), ethyl bromoacetate (189 mg, 1.13 mmol) and potassium carbonate (171 mg, 1.24 mmol) in DMF (3 mL) was stirred at room temperature for 16 hours. Water was then added to the reaction mixture and the precipitate that formed collected to give ethyl 2-(1-(naphthalen-1-yl)-1H-tetrazol-5-ylthio)acetate as a solid (306 mg, 94%).