Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7](=[N:15][OH:16])[CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:17][CH2:18][CH2:19]Br.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CC(C)=O.O>[Br:17][CH2:18][CH2:19][O:16][N:15]=[C:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[CH2:8][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: ON=C(Cc1ccccc1)c1ccccc1
Reactant: BrCCBr
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: BrCCON=C(Cc1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A suspension of the above oxime (5.0 g, 24 mmol), 1,2-dibromoethane (25 ml) and potassium carbonate (10.0 g, 72 mmol) in acetone (25 ml) was heated at reflux for 1 h, then stirred at ambient temperature for 72 h and finally heated at reflux for 4.5 h. Potassium iodide (0.5 g) was added and refluxing continued for an additional 16 h. Water (100 ml) was added and the resulting mixture extracted with dichloromethane (2×100 ml). The combined organic phases were washed with water (100 ml) and brine (10 ml) and dried (MgSO4). The solvent was evaporated in vacuo and the residue was purified by column chromatography on silica gel (60 g, n-heptane/ethyl acetate 10/1) to give 3.6 g of 1,2-diphenylethanone O-(2-bromoethyl)oxime.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([C:26]3[C:31]([F:32])=[CH:30][N:29]=[C:28](Cl)[N:27]=3)[CH:21]=2)[S:15]([CH3:18])(=[O:17])=[O:16])[CH2:10][CH2:9]1)=O)(C)(C)C.[NH2:34][CH2:35][CH2:36][C:37]1[CH:42]=[CH:41][C:40]([OH:43])=[C:39]([O:44][CH3:45])[CH:38]=1>>[F:32][C:31]1[C:26]([C:22]2[CH:21]=[C:20]([CH:25]=[CH:24][CH:23]=2)[CH2:19][N:14]([CH:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)[S:15]([CH3:18])(=[O:17])=[O:16])=[N:27][C:28]([NH:34][CH2:35][CH2:36][C:37]2[CH:42]=[CH:41][C:40]([OH:43])=[C:39]([O:44][CH3:45])[CH:38]=2)=[N:29][CH:30]=1
Reactant: CC(C)(C)OC(=O)N1CCC(N(Cc2cccc(-c3nc(Cl)ncc3F)c2)S(C)(=O)=O)CC1
Reactant: COc1cc(CCN)ccc1O
Product: COc1cc(CCNc2ncc(F)c(-c3cccc(CN(C4CCNCC4)S(C)(=O)=O)c3)n2)ccc1O

Procedure:
Intermediate 77 was coupled with 4-(2-amino-ethyl)-2-methoxy-phenol following procedure Q. The resulting product was deprotected following procedure R. LC-MS showed the product had the expected M+H+ of 530. 1H NMR (Varian 300 MHz, CD3OD, shifts relative to the solvent peak at 3.3 ppm) δ 8.25 (d, 1H), 8.14 (s, 1H), 7.97 (d, 1H), 7.48 (m, 2H), 6.82 (s, 1H), 6.69 (s, 2H), 4.54 (s, 2H), 3.91 (m, 1H), 3.80 (s, 3H) 3.60 (t, 2H), 3.32 (m, 2H), 3.03 (s, 3H), 2.94 (m, 2H), 2.81 (t, 2H), 1.87 (m, 4H).
Reaction SMILES: [C:1]1(=[O:11])[NH:5][C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[K].[Br:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH:21](Br)[CH2:22][CH2:23][CH2:24][CH3:25]>CN(C)C=O>[Br:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:10]1[CH:9]=[CH:8][CH:7]=[C:3]2[C:4]([NH:5][C:1](=[O:11])[C:2]=12)=[O:6]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CCCCC(Br)CCCCCCCBr
Agent: [K]
Solvent: CN(C)C=O
Product: O=C1NC(=O)c2c(CCCCCCCCCCCCBr)cccc21

Procedure:
Potassium phthalimide (1 g; 5.4 mmoles) was added to a solution of 1,8-dibromododecane (5.31 g; 16.2 mmoles) in dimethylformamide (8 ml) and heated to 80° C. approx. under stirring. Reaction times and process as per Example 4.
Reaction SMILES: [CH3:1][S:2]([C:5]1[N:9]([C:10]2[CH:11]=[CH:12][C:13]([O:19][CH3:20])=[C:14]([CH:18]=2)[C:15]([OH:17])=O)[CH:8]=[N:7][N:6]=1)(=[O:4])=[O:3].Cl.Cl.[CH2:23]([O:25][CH2:26][CH2:27][N:28]1[C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=2[N:30]=[C:29]1[N:37]1[CH2:43][CH2:42][CH2:41][N:40]([CH2:44][CH2:45][C@:46]2([C:51]3[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=3)[CH2:50][CH2:49][NH:48][CH2:47]2)[CH2:39][CH2:38]1)[CH3:24].O.ON1C2C=CC=CC=2N=N1.CN(C)CCCN=C=NCC.C(N(C(C)C)CC)(C)C>ClCCl.CO>[CH2:23]([O:25][CH2:26][CH2:27][N:28]1[C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=2[N:30]=[C:29]1[N:37]1[CH2:43][CH2:42][CH2:41][N:40]([CH2:44][CH2:45][C@:46]2([C:51]3[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=3)[CH2:50][CH2:49][N:48]([C:15]([C:14]3[CH:18]=[C:10]([N:9]4[CH:8]=[N:7][N:6]=[C:5]4[S:2]([CH3:1])(=[O:3])=[O:4])[CH:11]=[CH:12][C:13]=3[O:19][CH3:20])=[O:17])[CH2:47]2)[CH2:39][CH2:38]1)[CH3:24]
Reactant: CCOCCn1c(N2CCCN(CC[C@]3(c4ccccc4)CCNC3)CC2)nc2ccccc21
Reactant: COc1ccc(-n2cnnc2S(C)(=O)=O)cc1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: ClCCl
Product: CCOCCn1c(N2CCCN(CC[C@]3(c4ccccc4)CCN(C(=O)c4cc(-n5cnnc5S(C)(=O)=O)ccc4OC)C3)CC2)nc2ccccc21
Yield: 20.9 %

Procedure:
Condense 5-(3-methanesulfonyl-[1,2,4]triazol-4-yl)-2-methoxy-benzoic acid (0.125 g, 0.42 mmol) and 1-(2-ethoxy-ethyl)-2-{4-[2-((S)-3-phenyl-pyrrolidin-3-yl)-ethyl]-[1,4]diazepan-1-yl}-1H-benzoimidazole dihydrochloride (0.23 g, 0.42 mmol) in the presence of 1-hydroxybenzotriazole hydrate (0.062 g, 0.51 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (0.97 g, 0.51 mmol), diisopropylethylamine (0.22 mL, 1.26 mmol), and dichloromethane (15 mL) as described for the preparation of Example 124 to afford 0.065 g of the title compound, Rf=0.28 (silica gel, 10% methanol in dichloromethane). The compound may be converted to the dihydrochloride salt by methods well known in the art.
Reaction SMILES: C(OC(=O)[N:7]([CH2:28][C:29]1[CH:38]=[CH:37][C:32]2[O:33][CH2:34][CH2:35][O:36][C:31]=2[CH:30]=1)[CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][N:16]2[C:25]3[C:20](=[CH:21][C:22]([NH2:26])=[CH:23][CH:24]=3)[CH:19]=[CH:18][C:17]2=[O:27])[CH2:10][CH2:9]1)(C)(C)C.[ClH:40].O1CCOCC1>O1CCOCC1>[ClH:40].[O:33]1[C:32]2[CH:37]=[CH:38][C:29]([CH2:28][NH:7][CH:8]3[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][N:16]4[C:25]5[C:20](=[CH:21][C:22]([NH2:26])=[CH:23][CH:24]=5)[CH:19]=[CH:18][C:17]4=[O:27])[CH2:10][CH2:9]3)=[CH:30][C:31]=2[O:36][CH2:35][CH2:34]1
Reactant: CC(C)(C)OC(=O)N(Cc1ccc2c(c1)OCCO2)C1CCN(CCn2c(=O)ccc3cc(N)ccc32)CC1
Agent: Cl
Solvent: C1COCCO1
Product: Nc1ccc2c(ccc(=O)n2CCN2CCC(NCc3ccc4c(c3)OCCO4)CC2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 60 mg of tert-butyl(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(1-(2-(6-amino-2-oxoquinolin-1(2H)-yl)ethyl)piperidin-4-yl)carbamate, 3 mL of 1,4-dioxane and 1 mL of 4 mol/L hydrogen chloride/1,4-dioxane were added, and stirred at room temperature overnight. The solvent was removed under reduced pressure, and the resulting solid was recrystallized in methanol-ethyl acetate to give 40 mg of 1-(2-(4-((2,3-dihydro-1,4-benzodioxin-6-ylmethyl)amino)piperidin-1-yl)ethyl)-6-aminoquinolin-2(1H)-one hydrochloride as a brown solid.
Reaction SMILES: Cl.[S:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[CH2:7][O:8][CH:9]1[CH2:12][NH:11][CH2:10]1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.C(N(C(C)C)CC)(C)C.Cl.[CH2:44]([O:46][C:47](=[O:65])[CH2:48][N:49]1[CH2:54][C:53]2[CH:55]=[C:56](/[CH:59]=[CH:60]/[C:61](O)=[O:62])[CH:57]=[N:58][C:52]=2[NH:51][C:50]1=[O:64])[CH3:45]>CN(C)C=O>[O:64]=[C:50]1[NH:51][C:52]2[N:58]=[CH:57][C:56](/[CH:59]=[CH:60]/[C:61](=[O:62])[N:11]3[CH2:12][CH:9]([O:8][CH2:7][C:3]4[S:2][CH:6]=[CH:5][CH:4]=4)[CH2:10]3)=[CH:55][C:53]=2[CH2:54][N:49]1[CH2:48][C:47]([O:46][CH2:44][CH3:45])=[O:65]
Reactant: c1csc(COC2CNC2)c1
Reactant: CCOC(=O)CN1Cc2cc(/C=C/C(=O)O)cnc2NC1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)CN1Cc2cc(/C=C/C(=O)N3CC(OCc4cccs4)C3)cnc2NC1=O
Reaction time: 48 h

Procedure:
3-(Thiophen-2-ylmethoxy)-azetidine hydrochloride (243 mg, 1.18 mmol), EDCI (227 mg, 1.18 mmol), HOBt (160 mg, 0.6 mmol) and diisopropylethylamine (340 μL, 1.97 mmol) were successively added to a solution of (E)-3-(3-(2-ethoxy-2-oxoethyl)-2-oxo-1,2,3,4-tetrahydropyrido[2,3-d]pyrimidin-6-yl)acrylic acid hydrochloride (270 mg, 0.79 mmol) in dimethylformamide (15 mL) at room temperature. The reaction mixture was stirred for 2 days then partitioned between ethyl acetate (30 mL) and water (40 mL). The aqueous layer was separated and successively extracted with ethyl acetate (2×30 mL) and dichloromethane (2×30 mL). The combined organic phases were washed with a saturated solution of sodium chloride (3×40 mL), dried over sodium sulfate, filtered and concentrated to dryness. The residue was purified by chromatography on silica gel using dichloromethane/methanol (10:0 to 98:2) as eluent. The title product was obtained as an off-white solid (215 mg, 60%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13](=[O:14])[C:12]([CH3:15])=[C:11]([CH3:16])[CH:10]2O)[CH:5]=[CH:6][C:7]=1[Cl:8].[F-:18].[K+].C1OCCOCCOCCOCCOCCOC1>C(#N)C>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13](=[O:14])[C:12]([CH3:15])=[C:11]([CH3:16])[CH:10]2[F:18])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CC1=C(C)C(O)N(c2ccc(Cl)c(Cl)c2)C1=O
Reactant: [F-]
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Solvent: CC#N
Product: CC1=C(C)C(F)N(c2ccc(Cl)c(Cl)c2)C1=O

Procedure:
23.2 g N-(3,4-dichlorophenyl)-3,4-dimethyl-2-hydroxy-5-oxo-2,5-dihydropyrrole (see Example 3) is refluxed together with 11.6 g of potassium fluoride and 0.3 g of 18-crown-6 (cyclic polyethylene ether) in 50 ml of acetonitrile for 14 hours. After cooling, undissolved constituents are filtered off, and the filtrate is concentrated by evaporation. The residue is recrystallised from methanol to yield 8 g (35% of theory) of the above product in the form of colourless crystals, m.p. 102°-103°.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH2:9][NH:10][CH2:11][CH2:12][CH2:13][NH:14][CH2:15][CH2:16][CH2:17][CH2:18][NH:19][CH2:20][CH2:21][CH2:22][NH:23][CH2:24][C:25]2[CH:30]=[CH:29][C:28]([OH:31])=[C:27]([O:32][CH3:33])[CH:26]=2)[CH:6]=[CH:5][C:4]=1[OH:34].[CH2:35]([O:42][CH:43]1[N:47]2[C:48]3[C:53]([C:54]([CH2:57][C:58]#[N:59])(O)[CH2:55][CH:46]2[CH2:45][CH2:44]1)=[CH:52][CH:51]=[C:50]([CH:60]([CH3:68])[CH:61](C)CCCCC)[CH:49]=3)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.CS(O)(=O)=O.[OH-].[Na+]>O1CCCC1>[CH3:33][O:32][C:27]1[CH:26]=[C:25]([CH2:24][NH:23][CH2:22][CH2:21][CH2:20][NH:19][CH2:18][CH2:17][CH2:16][CH2:15][NH:14][CH2:13][CH2:12][CH2:11][NH:10][CH2:9][C:7]2[CH:6]=[CH:5][C:4]([OH:34])=[C:3]([O:2][CH3:1])[CH:8]=2)[CH:30]=[CH:29][C:28]=1[OH:31].[CH2:35]([O:42][CH:43]1[N:47]2[C:48]3[C:53]([C:54](=[CH:57][C:58]#[N:59])[CH2:55][CH:46]2[CH2:45][CH2:44]1)=[CH:52][CH:51]=[C:50]([C:60]([CH3:61])([CH3:68])[CH2:7][CH2:8][CH2:3][CH2:4][CH2:5][CH3:6])[CH:49]=3)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: CCCCCC(C)C(C)c1ccc2c(c1)N1C(CCC1OCc1ccccc1)CC2(O)CC#N
Agent: COc1cc(CNCCCNCCCCNCCCNCc2ccc(O)c(OC)c2)ccc1O
Agent: CS(=O)(=O)O
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCCCC(C)(C)c1ccc2c(c1)N1C(CCC1OCc1ccccc1)CC2=CC#N
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 10.9 g. (23.7 mmole) dl-6-benzyloxy-5-cyanomethyl-5-hydroxy-8-(1,2-dimethylheptyl)-2,3,3a,4-tetrahydro-1H-pyrrolo[1,2-a]quinoline in 250 ml. dry tetrahydrofuran is added a few grams of molecular sieves and 2.30 g. (23.9 mmole) methanesulfonic acid. The mixture is stirred for 16 hours at room temperature, made alkaline with sodium hydroxide solution, washed with water, the organic layer dried (MgSO4) and the solvent evaporated in vacuo to afford the crude product which was used in the next step.
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.OS(O)(=O)=O.[CH3:17][CH2:18]O>>[CH2:17]([O:10][C:9](=[O:11])[CH2:8][C:5]1[CH:4]=[CH:3][C:2]([SH:1])=[CH:7][CH:6]=1)[CH3:18]
Reactant: CCO
Reactant: O=C(O)Cc1ccc(S)cc1
Agent: O=S(=O)(O)O
Product: CCOC(=O)Cc1ccc(S)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a stirred solution of (4-mercapto-phenyl)-acetic acid (5.0 g, 29.8 mmol) in absolute EtOH (100 mL) at room temperature was added concentrated H2SO4 (10 mL) and the mixture was warmed to reflux. After 4 hrs, the reaction was cooled to room temperature, evaporated under reduced pressure, diluted with DCM (500 mL) and stirred over solid K2CO3. After 1 hr, the resulting mixture was filtered and concentrated to dryness to afford the title compound.
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[C:10]2[C:5](=[CH:6][CH:7]=[C:8](OS(C(F)(F)F)(=O)=O)[CH:9]=2)[C:4](=[O:19])[CH2:3]1.[Cl:21][C:22]1[CH:23]=[C:24](B(O)O)[CH:25]=[CH:26][CH:27]=1>>[Cl:21][C:22]1[CH:27]=[C:26]([C:8]2[CH:9]=[C:10]3[C:5](=[CH:6][CH:7]=2)[C:4](=[O:19])[CH2:3][C:2]3([CH3:20])[CH3:1])[CH:25]=[CH:24][CH:23]=1
Reactant: CC1(C)CC(=O)c2ccc(OS(=O)(=O)C(F)(F)F)cc21
Reactant: OB(O)c1cccc(Cl)c1
Product: CC1(C)CC(=O)c2ccc(-c3cccc(Cl)c3)cc21

Procedure:
The title compound was prepared from trifluoro-methanesulfonic acid 3,3-dimethyl-1-oxo-indan-5-yl ester and 3-chlorophenyl boronic acid according to the procedure described in example 21. MS (ES) m/z 271.1; HRMS: calcd for C17H15ClO+H+, 271.08842; found (ESI, [M+H]+), 271.0881.
Reaction SMILES: [C:1]([C:4]1([NH:10][C:11]([C:13]2[CH:14]=[N:15][N:16]3[C:21]([C:22]4[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=4)=[C:20]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=4[Cl:35])[CH:19]=[N:18][C:17]=23)=[O:12])[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1)(O)=[O:2].Cl.CN.O.O[N:41]1[C:45]2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.C(=O)([O-])O.[Na+]>C(Cl)Cl.C(N(CC)CC)C>[Cl:35][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=1[C:20]1[CH:19]=[N:18][C:17]2[N:16]([N:15]=[CH:14][C:13]=2[C:11](=[O:12])[NH:10][C:4]2([C:1](=[O:2])[NH:41][CH3:45])[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]2)[C:21]=1[C:22]1[CH:23]=[CH:24][C:25]([Cl:28])=[CH:26][CH:27]=1
Reactant: O=C(NC1(C(=O)O)CCCCC1)c1cnn2c(-c3ccc(Cl)cc3)c(-c3ccccc3Cl)cnc12
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: CN
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CNC(=O)C1(NC(=O)c2cnn3c(-c4ccc(Cl)cc4)c(-c4ccccc4Cl)cnc23)CCCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 48.8 %

Procedure:
To a solution of the compound obtained in Example A4 (50 mg) and methylamine hydrochloride (8 mg) in methylene chloride (1 mL) were added 1-hydroxybenzotriazole monohydrate (23 mg), 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride (29 mg) and triethylamine (21 μL), and the mixture was stirred at room temperature overnight. To the reaction mixture were added methylene chloride and an aqueous saturated sodium hydrogencarbonate solution. After stirring vigorously for 10 minutes, the organic layer was separated and concentrated in vacuo. The resultant crude product was purified by column chromatography on silica gel (solvent; chloroform/methanol=100/0 to 95/5) and triturated to give 6-(2-chlorophenyl)-7-(4-chlorophenyl)-3-[N-[1-(N-methylcarbamoyl)cyclohexyl]-carbamoyl]pyrazolo[1,5-a]pyrimidine (25 mg; yield: 61%)
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([N:13]([CH2:15][C:16]([O:18][CH3:19])=[O:17])[CH3:14])[S:11][CH:12]=2)=[CH:4][CH:3]=1.C(O[CH:25](N(C)C)[N:26]([CH3:28])[CH3:27])(C)(C)C>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[C:10]([N:13]([C:15](=[CH:25][N:26]([CH3:28])[CH3:27])[C:16]([O:18][CH3:19])=[O:17])[CH3:14])[S:11][CH:12]=2)=[CH:6][CH:7]=1
Reactant: COC(=O)CN(C)c1nc(-c2ccc(Br)cc2)cs1
Reactant: CN(C)C(OC(C)(C)C)N(C)C
Product: COC(=O)C(=CN(C)C)N(C)c1nc(-c2ccc(Br)cc2)cs1
Temperature: 25 °C
Yield: 88.6 %

Procedure:
17 g (0.04982 mol) of methyl N-[4-(4-bromophenyl)-2-thiazolyl]-N-methylamino-acetate and 17.4 g (0.1078 mol) of t-butoxy-bis-(dimethylamino)-methane are stirred for 6 hours at 100° C., the mixture is cooled, treated with ice-water and stirred for a few hours at room temperature, and precipitated crystals are filtered off with suction and dried. 17.5 g (89% of theory) of methyl 2-{N-[4-(4-bromophenyl)-2-thiazolyl]-N-methylamino}-3-dimethylaminoacrylate of melting point 184°-185° C. are obtained.
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[F:6][C:7]1[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[CH:10]=[CH:9][C:8]=1[NH:16][CH3:17]>C1(C)C=CC=CC=1>[Cl:1][CH2:2][C:3]([N:16]([C:8]1[CH:9]=[CH:10][C:11]([N+:13]([O-:15])=[O:14])=[CH:12][C:7]=1[F:6])[CH3:17])=[O:4]
Reactant: CNc1ccc([N+](=O)[O-])cc1F
Reactant: O=C(Cl)CCl
Solvent: Cc1ccccc1
Product: CN(C(=O)CCl)c1ccc([N+](=O)[O-])cc1F

Procedure:
Chloroacetyl chloride (1.87 ml, 0.0235 mol) is added to (2-fluoro-4-nitro-phenyl)-methyl-amine (14, 2.00 g, 0.0118 mol) in toluene (20 ml) and the mixture refluxed for 3 hours. The mixture is evaporated under vacuum and the residue triturated with ethanol to give the title compound as a white solid. HPLC r.t. 4.57 min; MS for C9H8ClFN2O3 m/z 247 (M+H)+.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[CH2:11]([OH:21])[C:12]1[CH:20]=[CH:19][C:18]2[O:17][CH2:16][O:15][C:14]=2[CH:13]=1>>[O:17]1[C:18]2[CH:19]=[CH:20][C:12]([CH2:11][O:21][C:2]3[CH:7]=[CH:6][N:5]=[CH:4][C:3]=3[N+:8]([O-:10])=[O:9])=[CH:13][C:14]=2[O:15][CH2:16]1
Reactant: OCc1ccc2c(c1)OCO2
Reactant: O=[N+]([O-])c1cnccc1Cl
Product: O=[N+]([O-])c1cnccc1OCc1ccc2c(c1)OCO2

Procedure:
In accordance with the same procedures as in Preparation 2, except for using 4-chloro-3-nitropyridine (3.0 g, 18.92 mmol) prepared in Step 1 of Preparation 1 and piperonyl alcohol (3.45 ml, 18.92 mmol), the titled compound was obtained as a yellow solid. (3.08 g, 88.6%)
Reaction SMILES: [C:1]([Cl:4])(Cl)=[O:2].[Cl:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-:14])=[O:13])[C:7]=1[CH2:15][CH2:16][OH:17]>C1COCC1>[Cl:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-:14])=[O:13])[C:7]=1[CH2:15][CH2:16][O:17][C:1]([Cl:4])=[O:2]
Reactant: O=C(Cl)Cl
Reactant: O=[N+]([O-])c1cccc(Cl)c1CCO
Solvent: C1CCOC1
Product: O=C(Cl)OCCc1c(Cl)cccc1[N+](=O)[O-]
Yield: 97 %

Procedure:
Phosgene was introduced in a solution of 2-(2-chloro-6-nitrophenyl)ethanol (31 g, 154 mmol) in THF (190 ml, dist. over CaH2) at room temperature under stirring. After 2.5 h the excess phosgene and the solvent were removed by distillation in a high vacuum. 2-(2-chloro-6-nitrophenyl)ethoxycarbonyl chloride (39.4 g, 97%) was obtained as a yellow oil.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([CH:12]([CH3:14])[CH3:13])=[CH:8][C:7]=2[C:15]2[C:16]3[N:23]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:22]([CH3:32])=[C:21]([C:33](O)=[O:34])[C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:3][CH2:2]1.[NH2:36][CH:37]1[CH2:42][CH2:41][N:40]([C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[CH2:39][CH2:38]1>>[CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([CH:12]([CH3:14])[CH3:13])=[CH:8][C:7]=2[C:15]2[C:16]3[N:23]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:22]([CH3:32])=[C:21]([C:33]([NH:36][CH:37]4[CH2:38][CH2:39][N:40]([C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[CH2:41][CH2:42]4)=[O:34])[C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:3][CH2:2]1
Reactant: Cc1c(C(=O)O)c2ncnc(-c3cc(C(C)C)ccc3OCC3CC3)c2n1COCC[Si](C)(C)C
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Product: Cc1c(C(=O)NC2CCN(C(=O)OC(C)(C)C)CC2)c2ncnc(-c3cc(C(C)C)ccc3OCC3CC3)c2n1COCC[Si](C)(C)C

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-5-(propan-2-yl)phenyl]-6-methyl-5-{[2-(trimethylsilyl)ethoxy]methyl}-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (example D.c15) and commercially available tert-butyl 4-amino-piperidine-1-carboxylate the title compound is obtained as pale yellow viscous oil.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[C:5](=O)[C:6]1[S:7][CH:8]=[CH:9][CH:10]=1)[CH3:2].[CH3:13][CH:14]([CH3:19])[CH2:15][CH2:16][NH:17][NH2:18]>C(O)C>[CH2:1]([O:3][C:4](=[O:12])[C:5](=[N:18][NH:17][CH2:16][CH2:15][CH:14]([CH3:19])[CH3:13])[C:6]1[S:7][CH:8]=[CH:9][CH:10]=1)[CH3:2]
Reactant: CCOC(=O)C(=O)c1cccs1
Reactant: CC(C)CCNN
Solvent: CCO
Product: CCOC(=O)C(=NNCCC(C)C)c1cccs1
Temperature: 80 °C
Reaction time: 13.5 h
Yield: 47.1 %

Procedure:
To a solution of oxo-thiophen-2-yl-acetic acid ethyl ester (1d) (3.97 g, 21.6 mmol) in absolute ethanol (100 mL), (3-Methyl-butyl)-hydrazine (2b) (2.0 g, 19.6 mmol) was added. The mixture was stirred at 80° C. under N2 atmosphere for 2-25 hours. The reaction mixture was concentrated under reduced pressure and the residue was purified by flash chromatography on silica gel to give the desired product (3d) (2.48 g) that was directly used in the next step. LC-MS (ESI+): m/e 269.2 [M+1]+, 537.4 [2M+1]+, 559.0 [2M+Na]+ (exact ms: 268.12).
Reaction SMILES: [NH2:1][C@H:2]1[C@@H:5]([CH2:6][OH:7])[NH:4][C:3]1=[O:8].C(=O)([O-])O.[Na+].Cl.[Cl:15][CH2:16][C:17]([NH:19][C:20]1[S:21][CH:22]=[C:23](/[C:25](=[N:29]/[O:30][CH3:31])/[C:26](Cl)=[O:27])[N:24]=1)=[O:18]>O1CCCC1.O>[Cl:15][CH2:16][C:17]([NH:19][C:20]1[S:21][CH:22]=[C:23]([C:25](=[N:29][O:30][CH3:31])[C:26]([NH:1][C@H:2]2[C@@H:5]([CH2:6][OH:7])[NH:4][C:3]2=[O:8])=[O:27])[N:24]=1)=[O:18]
Reactant: N[C@@H]1C(=O)N[C@@H]1CO
Reactant: CO/N=C(\C(=O)Cl)c1csc(NC(=O)CCl)n1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CON=C(C(=O)N[C@@H]1C(=O)N[C@@H]1CO)c1csc(NC(=O)CCl)n1

Procedure:
In a mixture of 2 ml of tetrahydrofuran and 2 ml of water is dissolved 75 mg of cis-3-amino-4-hydroxymethyl-2-oxoazetidine as obtained in Reference Example 53C and, under ice-cooling and stirring 168 mg of sodium hydrogen carbonate and then 332 mg of 2-(2-chloroacetamido-4-thiazolyl)-(Z)-2-methoxyiminoacetyl chloride hydrochloride are added. The mixture is stirred under ice-cooling for one hour and the reaction mixture is made neutral with aqueous sodium hydrogen carbonate and extracted with ethyl acetate-tetrahydrofuran (2:1). The extract is washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate. The solvent is then distilled off under reduced pressure and after addition of ethyl acetate-ether (1:2), the crystalline residue is recovered by filtration to give cis-3-[2-(2-chloroacetamido-4-thiazolyl)-2-methoxyiminoacetamido]-4-hydroxymethyl-2-oxoazetidine (syn-isomer) as colorless crystals, m.p. 238°-241° C. (decomp.).
Reaction SMILES: CON(C)[C:4]([C@@:6]1([CH3:13])[CH2:10][O:9][C:8]([CH3:12])([CH3:11])[O:7]1)=[O:5].[H-].[H-].[H-].[H-].[Li+].[Al+3].[NH4+].[Cl-]>C1COCC1>[CH3:11][C:8]1([CH3:12])[O:7][C@@:6]([CH3:13])([CH:4]=[O:5])[CH2:10][O:9]1
Reactant: CON(C)C(=O)[C@@]1(C)COC(C)(C)O1
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Solvent: C1CCOC1
Product: CC1(C)OC[C@](C)(C=O)O1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 61.4 %

Procedure:
(R)-N-methoxy-N,2,2,4-tetramethyl-1,3-dioxolane-4-carboxamide (22.9 g, 113 mmol) was dissolved in THF (500 mL) and cooled to −78° C. 1M LAH (124 ml, 124 mmol) was added slowly through an addition funnel over about 30 minutes. The reaction was stirred for another 30 minutes, a saturated aqueous NH4Cl was added (125 mL) and the reaction was allowed to warm to ambient temperature. After filtration, the slurry mixture was washed several times with EtOAc, and concentrated to afford crude (R)-2,2,4-trimethyl-1,3-dioxolane-4-carbaldehyde (10 g, 69.4 mmol, 61.6% yield) which was taken on to next reaction without further purification.
Reaction SMILES: [C:1]1([S:7](Cl)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:11]1[CH:15]2[CH2:16][NH:17][CH2:18][CH:14]2[CH2:13][O:12]1>N1C=CC=CC=1>[C:1]1([S:7]([N:17]2[CH2:18][CH:14]3[CH2:13][O:12][CH2:11][CH:15]3[CH2:16]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C1NCC2COCC12
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: c1ccncc1
Product: O=S(=O)(c1ccccc1)N1CC2COCC2C1
Temperature: 5 °C
Reaction time: 2 h

Procedure:
Benzenesulfonyl chloride (0.05 mole, 8.83 grams) dissolved in 15 ml pyridine was slowly added to a mixture of hexahydro-1H-furo(3,4-c)pyrrole, represented by formula (X), (0.05 mole, 5.66 grams) in 10 ml of pyridine at 5°C. The reaction mixture was stirred for 2 hours at 5°C. and then for 16 hours while warming to room temperature.