Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH2:7][C:8]([NH:10][CH:11]2[C:37](=[O:38])[N:13]3[C:14]([C:21]([O:23][CH:24]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)=[O:22])=[C:15]([CH2:19]Cl)[CH2:16][S:17](=[O:18])[C@H:12]23)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH:39]1[C:43]([SH:44])=[N:42][N:41]=[N:40]1.CN(C)C=O.Cl>C(N(CC)CC)C>[C:1]1([CH2:7][C:8]([NH:10][CH:11]2[C:37](=[O:38])[N:13]3[C:14]([C:21]([O:23][CH:24]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)=[O:22])=[C:15]([CH2:19][S:44][C:43]4[NH:42][N:41]=[N:40][N:39]=4)[CH2:16][S:17](=[O:18])[C@H:12]23)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Cc1ccccc1)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CCl)CS(=O)[C@H]12
Reactant: Sc1nnn[nH]1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(Cc1ccccc1)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CSc3nnn[nH]3)CS(=O)[C@H]12
Temperature: 0 °C
Yield: 100.5 %

Procedure:
A mixture of benzhydryl 7-(2-phenylacetamido)-3-chloromethyl-3-cephem-4-carboxylate-1-oxide (70.0 g), 1H-tetrazole-5-thiol (15.6 g) and N,N-dimethylformamide (700 ml) was stirred to give a homogeneous solution and thereto was added triethylamine (32.1 g), keeping the temperature at 20° to 30° C. The resulting solution was stirred for 40 minutes at room temperature. After the reaction mixture was added to ice water (2.8 l), the mixture was adjusted to pH 2.0 with 10% hydrochloric acid and then filtered. The filter cake was washed with water and dried over phosphorus pentoxide under reduced pressure to give benzhydryl 7-(2-phenylacetamido)-3-(1H-tetrazole-5-yl)thiomethyl-3-cephem-4-carboxylate-1-oxide (78.8 g).
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:3]=1[NH2:4].[CH2:10](Br)[C:11]#[CH:12]>>[CH3:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:3]=1[NH:4][CH2:12][C:11]#[CH:10]
Reactant: C#CCBr
Reactant: Cc1cccc(C)c1N
Product: C#CCNc1c(C)cccc1C

Procedure:
2,6-Dimethyl-N-propargyl-aniline was prepared by reacting 2,6-dimethyl-aniline with propargyl bromide according to the statements in the literature (see U.S. Pat. No. 4,001,325). ##STR100##
Reaction SMILES: [CH:1]([C:3]([CH3:5])=[O:4])=[CH2:2].N12CCCN=C1CCCCC2.[CH2:17]([CH:21]1[CH2:29][C:28]2[C:23](=[CH:24][CH:25]=[C:26]([O:31][CH3:32])[C:27]=2[CH3:30])[C:22]1=[O:33])[CH2:18][CH2:19][CH3:20]>O1CCCC1.CCOCC>[CH2:17]([C:21]1([CH2:2][CH2:1][C:3](=[O:4])[CH3:5])[CH2:29][C:28]2[C:23](=[CH:24][CH:25]=[C:26]([O:31][CH3:32])[C:27]=2[CH3:30])[C:22]1=[O:33])[CH2:18][CH2:19][CH3:20]
Reactant: C=CC(C)=O
Reactant: CCCCC1Cc2c(ccc(OC)c2C)C1=O
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: C1CCC2=NCCCN2CC1
Product: CCCCC1(CCC(C)=O)Cc2c(ccc(OC)c2C)C1=O
Temperature: 25 °C
Reaction time: 30 h
Yield: 81.4 %

Procedure:
Methyl vinyl ketone (MVK, 0.49 mL, 5.9 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU, 0.12 mL, 0.8 mmol) were added to a solution of impure 2-butyl-5-methoxy-4-methyl-1-indanone (0.90 g, 3.9 mmol) in anhydrous tetrahydrofuran (THF, 3.9 mL). The resulting solution was stirred at room temperature for 30 hours, then diluted with Et2O (50 mL), washed with water (20 mL), 1N HCl (20 mL), and brine (20 mL), dried over MgSO4, filtered, and evaporated under vacuum to an amber oil (1.23 g). The crude product was purified by chromatography on EM silica gel 60 (230-400 mesh, 125 mL dry, packed under 4:1 hexanes-EtOAc). The column was eluted with 4:1 hexanes-EtOAc, collecting 25 mL fractions. Fractions 14-27 gave a 93:2:5 mixture (0.96 g) of 2-butyl-5-methoxy-4-methyl-2-(3-oxo-butyl)-1-indanone, the 6-methyl isomer, and the desmethyl product. This material was used in the next step.
Reaction SMILES: Br[C:2]1[S:6][C:5]([C:7]2[CH:8]=[CH:9][C:10]3[CH2:17][CH:16]4[C:18]5([CH2:22][N:21]([CH2:23][C:24]([F:27])([F:26])[F:25])[S:20](=[O:29])(=[O:28])[NH:19]5)[CH:13]([CH2:14][CH2:15]4)[CH2:12][C:11]=3[CH:30]=2)=[N:4][CH:3]=1.[F:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1B(O)O>>[F:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[C:2]1[S:6][C:5]([C:7]2[CH:8]=[CH:9][C:10]3[CH2:17][CH:16]4[C:18]5([CH2:22][N:21]([CH2:23][C:24]([F:27])([F:26])[F:25])[S:20](=[O:29])(=[O:28])[NH:19]5)[CH:13]([CH2:14][CH2:15]4)[CH2:12][C:11]=3[CH:30]=2)=[N:4][CH:3]=1
Reactant: OB(O)c1ccccc1F
Reactant: O=S1(=O)NC2(CN1CC(F)(F)F)C1CCC2Cc2cc(-c3ncc(Br)s3)ccc2C1
Product: O=S1(=O)NC2(CN1CC(F)(F)F)C1CCC2Cc2cc(-c3ncc(-c4ccccc4F)s3)ccc2C1

Procedure:
Prepared using the bromide from Example 36 Step 2 and 2-fluorobenzeneboronic acid by the method described for Example 36 Step 3. MS (ES+) 538 ([MH]+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][C:10]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)(O)[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:6]=[CH:7][CH:8]=1>C(O)(=O)C.[Pd]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][CH:10]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:6]=[CH:7][CH:8]=1
Reactant: CCOC(=O)CC(O)(Cc1cccc(OC)c1)c1ccccc1
Agent: [Pd]
Solvent: CC(=O)O
Product: CCOC(=O)CC(Cc1cccc(OC)c1)c1ccccc1
Reaction time: 24 h
Yield: 45.3 %

Procedure:
A mixture of ethyl 4-(m-methoxyphenyl)-3-phenyl-3-hydroxybutyrate (4.39 g, 13.98 mmol), palladium/carbon (10%, 2.5 g) hydrochloric acid (1.2 mL) in acetic acid (150 mL) was subjected to hydrogenation (50 psi) for 24 hours. The catalyst was filtered, and the filtrate was concentrated to afford the desired product (1.89 g; 45% yield). 1H NMR was consistent with the desired product.
Reaction SMILES: [H-].[Na+].[O:3]=[C:4]1[N:9]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=2)[C:8]2[CH2:20][CH2:21][C:22](=[O:23])[C:7]=2[C@@H:6]([C:24]2[CH:31]=[CH:30][C:27]([C:28]#[N:29])=[CH:26][C:25]=2[S:32]([CH3:35])(=[O:34])=[O:33])[NH:5]1.[CH3:36][S:37](Cl)(=[O:39])=[O:38].O>O1CCCC1>[CH3:35][S:32]([C:25]1[CH:26]=[C:27]([CH:30]=[CH:31][C:24]=1[CH:6]1[N:5]([S:37]([CH3:36])(=[O:39])=[O:38])[C:4](=[O:3])[N:9]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:17])[F:18])[CH:11]=2)[C:8]2[CH2:20][CH2:21][C:22](=[O:23])[C:7]1=2)[C:28]#[N:29])(=[O:33])=[O:34]
Reactant: CS(=O)(=O)c1cc(C#N)ccc1[C@H]1NC(=O)N(c2cccc(C(F)(F)F)c2)C2=C1C(=O)CC2
Reactant: CS(=O)(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CS(=O)(=O)c1cc(C#N)ccc1C1C2=C(CCC2=O)N(c2cccc(C(F)(F)F)c2)C(=O)N1S(C)(=O)=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Sodium hydride (60% in mineral oil, 20 mg, 0.50 mmol) is added to a solution of (S)-4-(2,5-dioxo-1-(3-(trifluoromethyl)phenyl)-2,3,4,5,6,7-hexahydro-1H-cyclopenta[d]-pyrimidin-4-yl)-3-(methylsulfonyl)benzonitrile (example 10A, 100 mg, 0.18 mmol based on 85% purity) in tetrahydrofuran (4.0 mL), and the mixture is stirred at room temperature for 20 min Methanesulfonyl chloride (29 μL, 0.38 mmol) is added and the mixture is stirred at room temperature for 2 h. Water is added and the mixture is extracted with dichloromethane. The phases are separated and the organic layer is concentrated under a) reduced pressure. The residue is purified by reversed phase HPLC (Waters Xbridge™-C18, gradient of acetonitrile in water, 0.1% TFA). Yield: 76 mg; ESI mass spectrum [M+H]+=554; Retention time HPLC: 0.57 min (X012_S01).
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH2:9][CH2:10][C:4]=2[C:3]=1[OH:19].C([O-])([O-])=O.[K+].[K+].[CH3:26][N:27]([CH3:31])[C:28](Cl)=[S:29]>CC(C)=O.O.CN(C)C(Cl)=S>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:15])([F:13])[F:14])[CH2:9][CH2:10][C:4]=2[C:3]=1[O:19][C:28](=[S:29])[N:27]([CH3:31])[CH3:26]
Reactant: O=C(N1CCc2ccc(Cl)c(O)c2CC1)C(F)(F)F
Reactant: CN(C)C(=S)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: CN(C)C(=S)Oc1c(Cl)ccc2c1CCN(C(=O)C(F)(F)F)CC2
Temperature: 25 °C
Reaction time: 1.25 h
Yield: 91.1 %

Procedure:
Place 7-chloro-6-hydroxy-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (64.3 g, 219 mmol) in acetone (450 mL) and water (200 mL) with K2CO3 (91.8 g, 664 mmol) and dimethylthiocarbamoyl chloride (31.5 g, 255 mmol). Stir at ambient temperature for 1.25 h. Add additional dimethylthiocarbamoyl chloride (3 g, 24 mmol) and stir for an additional 1.75 h at ambient temperature. Add more dimethylthiocarbamoyl chloride (0.7 g, 5.7 mmol) and water (150 mL) to the mixture and stir for 0.5 h at ambient temperature. Slowly add water (500 mL) to the reaction over 2 h to promote crystallization and stir the resulting slurry at ambient temperature for 1.5 h. Collect the solid by filtration to give the desired intermediate (76 g, 91%).
Reaction SMILES: [CH3:1][N:2]([CH3:22])[CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[N:9][C:10]([C:13]2[CH:14]=[C:15]([C:19](=[O:21])[CH3:20])[CH:16]=[CH:17][CH:18]=2)=[N:11][CH:12]=1.C(O)C.[BH4-].[Na+].O>ClCCl>[CH3:22][N:2]([CH3:1])[CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[N:11][C:10]([C:13]2[CH:14]=[C:15]([CH:19]([OH:21])[CH3:20])[CH:16]=[CH:17][CH:18]=2)=[N:9][CH:8]=1
Reactant: CC(=O)c1cccc(-c2ncc(OCCCN(C)C)cn2)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCO
Solvent: O
Product: CC(O)c1cccc(-c2ncc(OCCCN(C)C)cn2)c1
Temperature: 0 °C

Procedure:
3.114 g of 1-{3-[5-(3-dimethylaminopropoxy)pyrimidin-2-yl]phenyl}ethanone (10.4 mmol) are dissolved in 30 ml of abs. ethanol in a 100 ml one-necked flask, and 0.394 g of sodium borohydride (10.4 mmol) is subsequently added in portions with ice/water cooling and stirring, and the reaction batch is stirred at RT for a further 20 h. For work-up, the reaction mixture is diluted with 50 ml of dichloromethane and shaken 2× against water, and the dichloromethane phase is evaporated to dryness and purified by chromatography (silica gel/DCM/MeOH 9:1);
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]3[O:17][CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH:13]([CH3:25])[C:11]3=2)[NH:6][CH:5]=1.[C:26]1([S:32](Cl)(=[O:34])=[O:33])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.[C:36]([OH:42])([C:38]([F:41])([F:40])[F:39])=[O:37]>CN(C=O)C>[F:39][C:38]([F:41])([F:40])[C:36]([OH:42])=[O:37].[Cl:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]3[O:17][CH2:16][CH2:15][NH:14][CH:13]([CH3:25])[C:11]3=2)[N:6]([S:32]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)(=[O:34])=[O:33])[CH:5]=1
Reactant: CC1c2c(ccc3[nH]cc(Cl)c23)OCCN1C(=O)OC(C)(C)C
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: CC1NCCOc2ccc3c(c(Cl)cn3S(=O)(=O)c3ccccc3)c21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Sodium hydride (60% in mineral oil, 0.010 g, 0.42 mmol) was added to tert-butyl 10-chloro-1-methyl-1,3,4,8-tetrahydro-2H-[1,4]oxazepino[6,7-e]indole-2-carboxylate (Intermediate 43, 18 mg, 0.050 mmol) and benzenesulfonyl chloride (0.030 mL, 0.23 mmol) in DMF (2 mL). The mixture was was stirred at room temperature for 30 minutes. TFA (0.50 mL) was added to the reaction mixture and the solvent was evaporated. The residue was dissolved in DCM (1 mL) and TFA (1 mL) was added. The reaction mixture was stirred for 10 minutes and evaporated. The crude material was purified by preparative HPLC (ACE C8, 0.1% TFA-CH3CN) to give the title compound as a white solid (16.8 mg) in the form of the trifluoroacetate salt. MS m/z 377 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[CH:5]=[C:6]1[CH2:12][CH:11]2[N:13]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:8]([CH2:9][CH2:10]2)[CH2:7]1)[CH3:2].[H][H]>[Pd].CCO>[CH2:1]([O:3][C:4](=[O:21])[CH2:5][CH:6]1[CH2:12][CH:11]2[N:13]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:8]([CH2:9][CH2:10]2)[CH2:7]1)[CH3:2]
Reactant: [H][H]
Reactant: CCOC(=O)C=C1CC2CCC(C1)N2C(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)CC1CC2CCC(C1)N2C(=O)OC(C)(C)C
Yield: 99.3 %

Procedure:
10% palladium on carbon (about 50% wet) (170 mg) was added to a mixture of tert-butyl 3-(2-ethoxy-2-oxoethylidene)-8-azabicyclo[3.2.1]octane-8-carboxylate (1.7 g) and EtOH (34 mL), and the mixture was stirred at room temperature for 4 hours in a hydrogen atmosphere at 3 atm. The reaction mixture was separated by filtration using Celite, and the filtrate was concentrated under reduced pressure, whereby tert-butyl 3-(2-ethoxy-2-oxoethyl)-8-azabicyclo[3.2.1]octane-8-carboxylate (1.7 g) was obtained as a colorless oil.
Reaction SMILES: Br[CH2:2][CH:3]1[CH2:17][C:6]2=[C:7]3[C:12](=[N:13][CH:14]=[C:5]2[O:4]1)[CH:11]=[CH:10][C:9]([O:15][CH3:16])=[N:8]3.C(OC([N:25]1[CH2:30][CH2:29][CH:28]([NH2:31])[CH2:27][CH2:26]1)=O)(C)(C)C.[O:32]=[C:33]1[NH:38][C:37]2[CH:39]=[C:40]([C:43](O)=[O:44])[CH:41]=[CH:42][C:36]=2[S:35][CH2:34]1>>[CH3:16][O:15][C:9]1[CH:10]=[CH:11][C:12]2[C:7]([N:8]=1)=[C:6]1[CH2:17][CH:3]([CH2:2][N:25]3[CH2:26][CH2:27][CH:28]([NH:31][C:43]([C:40]4[CH:41]=[CH:42][C:36]5[S:35][CH2:34][C:33](=[O:32])[NH:38][C:37]=5[CH:39]=4)=[O:44])[CH2:29][CH2:30]3)[O:4][C:5]1=[CH:14][N:13]=2
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: O=C1CSc2ccc(C(=O)O)cc2N1
Reactant: COc1ccc2ncc3c(c2n1)CC(CBr)O3
Product: COc1ccc2ncc3c(c2n1)CC(CN1CCC(NC(=O)c2ccc4c(c2)NC(=O)CS4)CC1)O3

Procedure:
The titled compound is prepared as a white lyophilized powder following Scheme 1 and in analogy to Example 1 using 2-bromomethyl-8-methoxy-1,2-dihydro-3-oxa-5,9-diaza-cyclopenta[a]naphthalene, 4-amino-piperidine-1-carboxylic acid tert-butyl ester and 3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylic acid as starting material.
Reaction SMILES: [CH3:1]N(C=O)C.[Br:6][C:7]1[CH:8]=[C:9]([NH:13][C:14](=[O:16])[CH3:15])[CH:10]=[CH:11][CH:12]=1.[H-].[Na+].CI>O>[Br:6][C:7]1[CH:8]=[C:9]([N:13]([CH3:1])[C:14](=[O:16])[CH3:15])[CH:10]=[CH:11][CH:12]=1
Reactant: CC(=O)Nc1cccc(Br)c1
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: O
Product: CC(=O)N(C)c1cccc(Br)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 94 %

Procedure:
To a DMF solution (15 ml) of N-(3-bromo-phenyl)-acetamide (1.19 g) obtained in Step A, 60% oily sodium hydride (279 mg) was added, followed by stirring at room temperature for 10 minutes. To this, methyl iodide (434 μl) was added, followed by stirring at room temperature for 21 hours. To this, water (30 ml) was added, followed by extraction with ethyl acetate (30 ml×2), and the organic layer was dried over sodium sulfate. The sodium sulfate was filtered off, followed by purification by silica gel column chromatography (dichloromethane/methanol=200/1), to obtain the desired compound (1.20 g, 94%).
Reaction SMILES: Br[CH2:2][C:3](=[CH2:9])[C:4]([O:6][CH2:7][CH3:8])=[O:5].[CH3:10][NH2:11].CO.[CH2:14]1[O:24][C:17]2([CH2:22][CH2:21][C:20](=O)[CH2:19][CH2:18]2)[O:16][CH2:15]1>C1(C)C=CC=CC=1>[CH3:10][N:11]1[C:20]2[CH2:21][CH2:22][C:17]3([O:24][CH2:14][CH2:15][O:16]3)[CH2:18][C:19]=2[CH2:9][CH:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH2:2]1
Reactant: C=C(CBr)C(=O)OCC
Reactant: CN
Reactant: O=C1CCC2(CC1)OCCO2
Solvent: Cc1ccccc1
Solvent: CO
Product: CCOC(=O)C1CC2=C(CCC3(C2)OCCO3)N(C)C1
Temperature: 25 °C

Procedure:
To a mixture of ethyl 2-(bromomethyl)acrylate (20.42 g) and toluene (320 mL) was added dropwise a mixture of a 40% methylamine-methanol solution (240.1 mL) and toluene (80 mL) under ice cooling while stirring. The mixture was stirred for 3 minutes. To the mixture was added a mixture of 1,4-cyclohexandione monoethylene ketal (14.00 g) and toluene (100 mL) under the same conditions. The mixture was refluxed with the Dean-Stark apparatus for 4.5 hours. After cooling to room temperature, the mixture was passed through a layer of Celite (registered mark). The filtrate was concentrated under reduced pressure. The residue was purified by aminopropyl silica gel column chromatography (eluent: 0%-40% ethyl acetate/hexane, gradient elution) to give the title compound (22.92 g).
Reaction SMILES: [CH3:1]N(CN(C)C)C.[C:8]([C:10]1[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][N:18]2[CH2:23][CH2:22][C:21]3([CH2:28][C:27](=[O:29])[C:26]4[CH:30]=[C:31]([NH:34][S:35]([CH3:38])(=[O:37])=[O:36])[CH:32]=[CH:33][C:25]=4[O:24]3)[CH2:20][CH2:19]2)=[CH:12][CH:11]=1)#[N:9].C(O)(=O)C.C(=O)([O-])O.[Na+]>C1COCC1.O>[C:8]([C:10]1[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][N:18]2[CH2:23][CH2:22][C:21]3([C:28](=[CH2:1])[C:27](=[O:29])[C:26]4[CH:30]=[C:31]([NH:34][S:35]([CH3:38])(=[O:36])=[O:37])[CH:32]=[CH:33][C:25]=4[O:24]3)[CH2:20][CH2:19]2)=[CH:12][CH:11]=1)#[N:9]
Reactant: CS(=O)(=O)Nc1ccc2c(c1)C(=O)CC1(CCN(CCc3ccc(C#N)cc3)CC1)O2
Reactant: CN(C)CN(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: C=C1C(=O)c2cc(NS(C)(=O)=O)ccc2OC12CCN(CCc1ccc(C#N)cc1)CC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.7 %

Procedure:
N,N,N',N'-Tetramethyldiaminomethane (1.36 ml, 1.02 g, 10 mmol) was added to a solution of 1'-[2-(4-cyanophenyl)ethyl]-3,4-dihydro-6-methanesulfonamidospiro(2H-1-benzopyran-2,4'-piperidine)-4-one (2.20 g, 5 mmol) and acetic acid (1.14 ml, 1.20 g, 20 mmol) in THF (40 ml) and the mixture was heated under reflux for 24 h. Further N,N,N',N'-tetramethyldiaminomethane (1.36 ml, 1.02 g, 10 mmol) and acetic acid (1.14 ml, 1.20 g, 20 mmol) were added and the mixture was heated under reflux for 6 h, cooled and poured into saturated aqueous sodium hydrogen carbonate (150 ml), diluted with water (50 ml) and extracted with methylene chloride (3×150 ml). The combined organic fractions were dried (Na2SO4) and evaporated under reduced pressure. Toluene (600 ml) was added and the volume was reduced by distillation to 300 ml. Further toluene (300 ml) was added and the volume was reduced by distillation to 300 ml. The mixture was allowed to cool with stirring to room temperature then refrigerated overnight. The solid was collected and dried in vacuo to give the ketone as a yellow solid (1.98 g, 88%).
Reaction SMILES: Br[CH:2]([CH3:12])[CH2:3][CH2:4][CH2:5][CH2:6][C:7]([O:9]CC)=[O:8].[CH3:13][C:14]([C:16]1[CH:17]=[CH:18][C:19]([OH:23])=[CH:20][C:21]=1[OH:22])=[O:15]>>[C:14]([C:16]1[CH:17]=[CH:18][C:19]([O:23][CH:2]([CH3:12])[CH2:3][CH2:4][CH2:5][CH2:6][C:7]([OH:9])=[O:8])=[CH:20][C:21]=1[OH:22])(=[O:15])[CH3:13]
Reactant: CCOC(=O)CCCCC(C)Br
Reactant: CC(=O)c1ccc(O)cc1O
Product: CC(=O)c1ccc(OC(C)CCCCC(=O)O)cc1O

Procedure:
Following the procedure of Example 40, 4.74 g. of ethyl 6-bromoheptanoate and 3.04 g. of 2,4-dihydroxyacetophenone were reacted in the usual manner and the resulting product hydrolyzed to give the title product, m.p. about 116°-118° C.
Reaction SMILES: [O:1]=[S:2]1(=[O:25])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][N:5]([C:13]2[CH:22]=[C:21]([NH2:23])[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([CH3:24])[CH:19]=3)[N:14]=2)[CH2:4][CH2:3]1.Br[CH:27]([CH2:31][CH3:32])[C:28](Cl)=[O:29].[N-:33]=[N+]=[N-].[Na+]>>[NH2:33][CH:27]([CH2:31][CH3:32])[C:28]([NH:23][C:21]1[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([CH3:24])[CH:19]=2)[N:14]=[C:13]([N:5]2[CH2:6][C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[S:2](=[O:1])(=[O:25])[CH2:3][CH2:4]2)[CH:22]=1)=[O:29]
Reactant: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(N)c2c1
Reactant: CCC(Br)C(=O)Cl
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Product: CCC(N)C(=O)Nc1cc(N2CCS(=O)(=O)c3ccccc3C2)nc2ccc(C)cc12

Procedure:
The title compound was prepared in analogy to Example 40-2 in Scheme 18 by using 2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-amine, 2-bromobutyryl chloride and sodium azide. MS obsd. (ESI+) [(M+H)+] 439, 1H NMR (400 MHz, CD3OD) δ ppm 8.07 (m, 3 H), 7.53 (m, 2 H), 7.45 (m, 2 H), 5.33 (m, 2 H), 4.32 (m, 1 H), 3.59 (m, 2 H), 3.37 (s, 3 H), 2.44 (m, 2 H), 1.70 (d, J=8.02 Hz, 1 H), 1.38 (d, J=2.56 Hz, 2 H), 1.22 (m, 3 H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([N:9]2[C:13]3=[N:14][C:15]([CH3:26])=[CH:16][C:17](OS(C(F)(F)F)(=O)=O)=[C:12]3[C:11]([CH3:27])=[CH:10]2)=[C:4]([CH3:28])[CH:3]=1.[NH:29]1[CH2:39][CH2:38][CH:32]([C:33]([O:35][CH2:36][CH3:37])=[O:34])[CH2:31][CH2:30]1.C(N(CC)C(C)C)(C)C>O>[CH2:36]([O:35][C:33]([CH:32]1[CH2:38][CH2:39][N:29]([C:17]2[CH:16]=[C:15]([CH3:26])[N:14]=[C:13]3[N:9]([C:5]4[C:4]([CH3:28])=[CH:3][C:2]([Cl:1])=[CH:7][C:6]=4[CH3:8])[CH:10]=[C:11]([CH3:27])[C:12]=23)[CH2:30][CH2:31]1)=[O:34])[CH3:37]
Reactant: CCOC(=O)C1CCNCC1
Reactant: Cc1cc(OS(=O)(=O)C(F)(F)F)c2c(C)cn(-c3c(C)cc(Cl)cc3C)c2n1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CCOC(=O)C1CCN(c2cc(C)nc3c2c(C)cn3-c2c(C)cc(Cl)cc2C)CC1
Temperature: 160 °C
Yield: 79.7 %

Procedure:
A mixture of the crude trifluoromethanesulfonic acid 1-(4-chloro-2,6-dimethylphenyl)-3,6-dimethyl-1H-pyrrolo[2,3-b]pyridin-4-yl ester (20.5 g), ethyl isonipecotate (74.4 g) and N,N-diisopropylethylamine (12.2 g) was heated at 150-170° C. for 1 hour. To the reaction mixture, water was added and extracted with ethyl acetate. The organic layer was washed with water, and brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by a silica gel column chromatography (silica gel: Wako Gel (C200), eluent: hexane/ethyl acetate=5:1) to give 1-[1-(4-chloro-2,6-dimethylphenyl)-3,6-dimethyl-1H-pyrrolo[2,3-b]pyridin-4-yl]piperidine-4-carboxylic acid ethyl ester (16.6 g) as a pale yellow solid.
Reaction SMILES: [CH:1]1([N:7]([CH3:32])[S:8]([CH2:11][CH2:12][NH:13][CH2:14][C:15]2[CH:20]=[C:19]([C:21](=[O:28])[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:18]=[CH:17][C:16]=2[N+:29]([O-])=O)(=[O:10])=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.S1C=CC=C1>CO.[Pd]>[CH:1]1([N:7]([CH3:32])[S:8]([CH2:11][CH2:12][NH:13][CH2:14][C:15]2[CH:20]=[C:19]([C:21](=[O:28])[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:18]=[CH:17][C:16]=2[NH2:29])(=[O:10])=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CN(C1CCCCC1)S(=O)(=O)CCNCc1cc(C(=O)c2ccccc2)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Solvent: c1ccsc1
Product: CN(C1CCCCC1)S(=O)(=O)CCNCc1cc(C(=O)c2ccccc2)ccc1N

Procedure:
A mixture of 2-(5-benzoyl-2-nitro-benzylamino)-ethanesulfonic acid cyclohexyl-methyl-amide (0.009 mol) in methanol (150 mL) was hydrogenated with 10% Pd/C (1 g) as a catalyst in the presence of thiophene solution (1 mL). After uptake of H2 (3 equiv.), the catalyst was filtered off, and the filtrate was evaporated. The residue was purified by column chromatography over Biotage (eluent: 98:2 CH2Cl2:CH3OH). The purest product fractions were collected and the solvent was evaporated to yield the title compound as a residue.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[NH:5][C:6]1[C:7]2[N:15]=[C:14](F)[CH:13]=[CH:12][C:8]=2[N:9]=[CH:10][N:11]=1.Cl.CN.[CH2:23]([N:25](CC)CC)C>C(O)C>[CH3:23][NH:25][C:14]1[CH:13]=[CH:12][C:8]2[N:9]=[CH:10][N:11]=[C:6]([NH:5][C:4]3[CH:17]=[CH:18][CH:19]=[C:2]([Br:1])[CH:3]=3)[C:7]=2[N:15]=1
Reactant: Fc1ccc2ncnc(Nc3cccc(Br)c3)c2n1
Reactant: CCN(CC)CC
Agent: CN
Agent: Cl
Solvent: CCO
Product: CNc1ccc2ncnc(Nc3cccc(Br)c3)c2n1
Yield: 81.4 %

Procedure:
Reaction of 4-(3-bromoanilino)-6-fluoropyrido[3,2-d]pyrimidine (50 mg, 0.16 mmol)(described in a previous experimental) with methylamine hydrochloride (32 mg, 0.47 mmol) and triethylamine (70 μL, 0.55 mmol) in ethanol (10 mL) in a pressure vessel at 100° C. for 18 h gives 6-methylamino-4-(3-bromoanilino)pyrido[3,2-d]pyrimidine (43 mg, 81%). 1H NMR (CDCl3) δ 8.81 (1H, brs), 8.61 (1H, s), 8.19 (1H, t, J=1.8 Hz), 7.86 (1H, d, J=9.1 Hz,), 7.83 (1H, dt, Jd=7.7 Hz, Jt=1.8 Hz), 7.28-7.21 (2H, m), 6.92 (1H, d, J=9.1 Hz), 4.97 (1H, q, J=5.0 Hz), 3.13 (3H, d, J=5.0 Hz).
Reaction SMILES: [Br:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([S:9](Cl)(=[O:11])=[O:10])=[CH:4][C:3]=1[F:13].[CH2:14]([NH:18][C:19]1[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][C:20]=1[CH3:26])[CH:15]([CH3:17])[CH3:16]>N1C=CC=CC=1>[Br:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([S:9]([N:18]([C:19]2[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][C:20]=2[CH3:26])[CH2:14][CH:15]([CH3:17])[CH3:16])(=[O:11])=[O:10])=[CH:4][C:3]=1[F:13]
Reactant: O=S(=O)(Cl)c1cc(F)c(Br)c(F)c1
Reactant: Cc1ccc(NCC(C)C)c(C)c1
Solvent: c1ccncc1
Product: Cc1ccc(N(CC(C)C)S(=O)(=O)c2cc(F)c(Br)c(F)c2)c(C)c1
Temperature: 20 °C
Reaction time: 2 h

Procedure:
To a solution of 4-bromo-3,5-difluorobenzene-1-sulfonyl chloride (1462 mg, 5.02 mmol) in pyridine (10 mL) at 20° C. was added N-isobutyl-2,4-dimethylaniline (889 mg, 5.01 mmol) and the reaction mixture was stirred at 20° C. for 2 hours. The reaction mixture was then evaporated in vacuo and redissolved in ethyl acetate. The organic phase was washed with saturated sodium carbonate (25 mL), dried using a hydrophobic frit and evaporated in vacuo to give the required product as a yellow oil, 2.06 g. LCMS [LCMS2] Rt 1.57 min, m/z (ES+) 432/434 (M+H).