Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:16][CH:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1)=[CH:13][CH:12]=[CH:11][C:10]=2[O:22][CH3:23])=[O:5])C.[N:24]([C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([O:33][CH3:34])[CH:28]=1)=[C:25]=[O:26]>>[CH:17]1([N:16]2[C:15]3[C:14]4[CH:13]=[CH:12][CH:11]=[C:10]([O:22][CH3:23])[C:9]=4[N:8]=[CH:7][C:6]=3[C:4](=[O:5])[N:24]([C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([O:33][CH3:34])[CH:28]=3)[C:25]2=[O:26])[CH2:18][CH2:19][CH2:20][CH2:21]1
Reactant: COc1cccc(N=C=O)c1
Reactant: CCOC(=O)c1cnc2c(OC)cccc2c1NC1CCCC1
Product: COc1cccc(-n2c(=O)c3cnc4c(OC)cccc4c3n(C3CCCC3)c2=O)c1
Yield: 76.7 %

Procedure:
1-Cyclopentyl-7-methoxy-3-(3-methoxy-phenyl)-1H-pyrimido[5,4-c]quinoline-2,4-dione (32 mg) was prepared from 4-cyclopentylamino-8-methoxy-quinoline-3-carboxylic acid ethyl ester (0.1 mmol) and 1-isocyanato-3-methoxy-benzene (0.5 mmol) following general procedure C. LCMS: m/z 418 [M+1]+. 1H NMR (400 MHz, CDCl3): δ 9.50 (s, 1H), 7.86 (d, 1H), 7.64 (t, 1H), 7.44 (t, 1H), 7.30 (d, 1H), 6.82 (dd, 1H), 6.60 (d, 1H), 6.28 (s, 1H), 5.04 (p, 1H), 4.17 (s, 3H), 3.80 (s, 3H), 2.40 (m, 2H), 2.04-2.20 (m, 4H), 1.24 (m, 2H) ppm.
Reaction SMILES: [C:1]([C:3]1[N:4]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([CH3:12])=[CH:7][CH:6]=2)#[N:2].[Br:20]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.CC(N=NC(C#N)(C)C)(C#N)C>[C:1]([C:3]1[N:4]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([CH2:12][Br:20])=[CH:7][CH:6]=2)#[N:2]
Reactant: Cc1ccc2c(c1)cc(C#N)n2C(=O)OC(C)(C)C
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(C)OC(=O)n1c(C#N)cc2cc(CBr)ccc21
Yield: 78 %

Procedure:
To a stirred solution of 334 mg of tert-butyl 2-cyano-5-methyl-1H-indole-1-carboxylate (1.3 mmol) in carbon tetrachloride (5 mL) was added 232 mg of N-bromosuccinimide (1.3 mmol) and 11 mg of AIBN (0.065 mmol). The mixture was refluxed for 1 h, then cooled and concentrated, and the residues were purified by chromatography on silica gel using hexane-ethyl acetate 20:1 to give 340 mg of tert-butyl 2-cyano-5-bromomethyl-1H-indole-1-carboxylate. 1H NMR (600 MHz, CDCl3): δ 8.22 (d, 1H, J=8.8 Hz), 7.64 (s, 1H), 7.53 (d, 1H, J=8.8 Hz), 7.31 (s, 1H), 4.60 (s, 2H), 1.73, (s, 9H). 13C NMR (150 MHz, CDCl3): δC 147.64, 136.27, 133.92, 129.34, 127.45, 122.33, 121.15, 116.46, 113.02, 109.75, 87.14, 33.23, 28.01.
Reaction SMILES: Cl[C:2]1[C:3]2[CH:25]=[C:24]([Cl:26])[CH:23]=[CH:22][C:4]=2[N:5]([CH3:21])[C:6](=[O:20])[CH:7]([CH2:9][C:10]2[CH:19]=[CH:18][C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]=2)[N:8]=1.[NH:27]1[CH2:32][CH2:31][CH:30]([NH:33][C:34](=[O:40])[O:35][C:36]([CH3:39])([CH3:38])[CH3:37])[CH2:29][CH2:28]1>>[Cl:26][C:24]1[CH:25]=[CH:3][C:4]2[N:5]([CH3:21])[C:6](=[O:20])[CH:7]([CH2:9][C:10]3[CH:11]=[CH:12][C:13]4[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=4)[CH:19]=3)[N:8]=[C:2]([N:27]3[CH2:28][CH2:29][CH:30]([NH:33][C:34](=[O:40])[O:35][C:36]([CH3:38])([CH3:37])[CH3:39])[CH2:31][CH2:32]3)[C:22]=2[CH:23]=1
Reactant: CN1C(=O)C(Cc2ccc3ccccc3c2)N=C(Cl)c2cc(Cl)ccc21
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Product: CN1C(=O)C(Cc2ccc3ccccc3c2)N=C(N2CCC(NC(=O)OC(C)(C)C)CC2)c2cc(Cl)ccc21

Procedure:
5,7-Dichloro-1-methyl-3-(naphthalen-2-ylmethyl)-1H-benzo[e][1,4]diazepin-2(3H)-one (170 mg, 0.44 mmol) and tert-butyl piperidin-4-ylcarbamate (89 mg, 0.44 mmol) were coupled according to the corresponding procedure described in Example 14 to yield intermediate tert-butyl 1-(7-chloro-1-methyl-3-(naphthalen-2-ylmethyl)-2-oxo-2,3-dihydro-1H-benzo[e][1,4]diazepin-5-yl)piperidin-4-ylcarbamate. (85 mg, 35%). Tert-butyl 1-(7-chloro-1-methyl-3-(naphthalen-2-ylmethyl)-2-oxo-2,3-dihydro-1H-benzo[e][1,4]diazepin-5-yl)piperidin-4-ylcarbamate (85 mg, 0.16 mmol) was dissolved in dichloromethane (1 mL) and trifluoroacetic acid (1 mL) and stirred at ambient temperature for 2 hours. The solution was concentrated, redissolved in ethyl acetate and extracted into 1 M aqueous hydrochloric acid (3×10 mL). The extracts were neutralized with saturated sodium bicarbonate, extracted with dichloromethane (3×25 mL), then dried with sodium sulfate, filtered, and concentrated to yield 5-(4-aminopiperidin-1-yl)-7-chloro-1-methyl-3-(naphthalen-2-ylmethyl)-1H-benzo[e][1,4]diazepin-2(3H)-one (20 mg, 29% yield). MS (M+H)+447.2.
Reaction SMILES: [CH3:1][NH:2][CH3:3].C[Al](C)C.C[Al](C)C.C1N2CCN(CC2)C1.C[O:21][C:22]([C:24]1[CH:29]=[CH:28][C:27]([C:30]2[O:34][N:33]=[C:32]([C:35]3[N:40]=[C:39]([NH2:41])[N:38]=[C:37]([N:42]([CH3:49])[C:43]4[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=4)[N:36]=3)[N:31]=2)=[CH:26][N:25]=1)=O>C1(C)C=CC=CC=1.CCOC(C)=O>[CH3:1][N:2]([CH3:3])[C:22]([C:24]1[CH:29]=[CH:28][C:27]([C:30]2[O:34][N:33]=[C:32]([C:35]3[N:40]=[C:39]([NH2:41])[N:38]=[C:37]([N:42]([CH3:49])[C:43]4[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=4)[N:36]=3)[N:31]=2)=[CH:26][N:25]=1)=[O:21]
Reactant: COC(=O)c1ccc(-c2nc(-c3nc(N)nc(N(C)c4ccccc4)n3)no2)cn1
Reactant: CNC
Agent: C1CN2CCN1CC2
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CN(C)C(=O)c1ccc(-c2nc(-c3nc(N)nc(N(C)c4ccccc4)n3)no2)cn1
Temperature: 25 °C
Reaction time: 18 h
Yield: 12 %

Procedure:
Dimethylamine (248 μL, 0.495 mmol) and bis(trimethylaluminum)-1,4-diazabicyclo[2.2.2]-octane (128 mg, 0.495 mmol) were stirred together in anhydrous toluene (2 mL) at 40 C under nitrogen for 1 h. 5-{3-[4-Amino-6-(methyl-phenyl-amino)-[1,3,5]triazin-2-yl]-[1,2,4]oxadiazol-5-yl}-pyridine-2-carboxylic acid methyl ester (prepared in an analogous manner to Example 279, 80 mg, 0.198 mmol) was added and the reaction stirred at 80 C for approximately 18 h. The mixture was then allowed to cool to room temperature and diluted with EtOAc (20 mL). The solution was then washed with 2M HCl (2×6 mL), saturated aq. sodium bicarbonate (2×6 mL), dried over sodium sulfate and evaporated under vacuum. The crude residue was purified by flash chromatography (0-3% MeOH in DCM) and the material obtained was then further purified by flash chromatography (0-80% EtOAc in heptane) to afford the title compound (10 mg, 12%).
Reaction SMILES: [N:1]1([CH2:7][C:8]#[CH:9])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[F:10][C:11]1[C:12](I)=[C:13]2[C:17](=[CH:18][CH:19]=1)[NH:16][C:15](=[O:20])/[C:14]/2=[CH:21]\[C:22]1[NH:26][CH:25]=[N:24][C:23]=1[CH3:27]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CN(C=O)C.CCN(CC)CC>[F:10][C:11]1[C:12]([C:9]#[C:8][CH2:7][N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)=[C:13]2[C:17](=[CH:18][CH:19]=1)[NH:16][C:15](=[O:20])/[C:14]/2=[CH:21]\[C:22]1[NH:26][CH:25]=[N:24][C:23]=1[CH3:27]
Reactant: C#CCN1CCOCC1
Reactant: Cc1nc[nH]c1/C=C1\C(=O)Nc2ccc(F)c(I)c21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1nc[nH]c1/C=C1\C(=O)Nc2ccc(F)c(C#CCN3CCOCC3)c21

Procedure:
Using Method C above, 3-(4-morpholinyl)-1-propyne (63.6 mg, 0.51 mmol) (prepared according to H. Kano et al., J. Med. Chem. 10:411-418 (1967)) was coupled with (Z)-1,3-dihydro-5-fluoro-4-iodo-3-[(4-methyl-1H-imidazol-5-yl) methylene]-2H-indol-2-one (75 mg, 0.203 mmol) (Starting Material 3 supra) using (Ph3P)4Pd (23.5 mg) and Cul (4 mg) as catalyst in DMF (3 mL) and Et3N (3 mL) as solvent at 80° C. for 18 h to give (Z)-1,3-dihydro-5-fluoro-3-[(4-methyl-1H-imidazol-5-yl)methylene]-4-[3-(4-morpholinyl)-1-propynyl]-2H-indol-2-one. (Yield 40 mg, 54%).
Reaction SMILES: [NH:1]([C:3]1[CH:8]=[C:7]([C:9]#[N:10])[CH:6]=[CH:5][N:4]=1)[NH2:2].[Cl:11][C:12]1[CH:13]=[C:14]([CH2:19][C:20](=O)[CH2:21][C:22](OC)=[O:23])[CH:15]=[C:16]([Cl:18])[CH:17]=1>>[Cl:11][C:12]1[CH:13]=[C:14]([CH2:19][C:20]2[CH:21]=[C:22]([OH:23])[N:1]([C:3]3[CH:8]=[C:7]([C:9]#[N:10])[CH:6]=[CH:5][N:4]=3)[N:2]=2)[CH:15]=[C:16]([Cl:18])[CH:17]=1
Reactant: N#Cc1ccnc(NN)c1
Reactant: COC(=O)CC(=O)Cc1cc(Cl)cc(Cl)c1
Product: N#Cc1ccnc(-n2nc(Cc3cc(Cl)cc(Cl)c3)cc2O)c1

Procedure:
The title compound was prepared from 2-hydrazinylpyridine-4-carbonitrile (PREPARATION 2) and methyl 4-(3,5-dichlorophenyl)-3-oxobutanoate according to the procedure for the preparation of Example 158, part A.
Reaction SMILES: C(OC(=O)[NH:10][CH:11]([C:13]1[NH:14][CH:15]=[C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:17]=1)[CH3:12])C1C=CC=CC=1>CO.[Pd]>[C:18]1([C:16]2[N:17]=[C:13]([CH:11]([NH2:10])[CH3:12])[NH:14][CH:15]=2)[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: CC(NC(=O)OCc1ccccc1)c1nc(-c2ccccc2)c[nH]1
Agent: [Pd]
Solvent: CO
Product: CC(N)c1nc(-c2ccccc2)c[nH]1
Reaction time: 8 h
Yield: 100.6 %

Procedure:
To a solution of [1-(4-phenyl-1H-imidazol-2-yl)-ethyl]-carbamic acid benzyl ester (1.5 g, 4.67 mmol) in methanol (25 mL) was added 10% palladium on carbon (0.16 g). The mixture was shaken in a hydrogenation apparatus at it under a hydrogen atmosphere (10 psi) for 8 h. Filtration followed by evaporation to dryness under reduced pressure gave the crude product 1-(4-Phenyl-1H-imidazol-2-yl)-ethylamine (0.88 g, 100%). 1H NMR (300 MHz, CDCl3): δ 1.53 (3H, d), 4.33 (1H, q), 7.23 (3H, m), 7.37 (2H, m), 7.67 (2H, m). MS (ES+): 188.1 (38%).
Reaction SMILES: C([O:8][C:9]([C:11]1([CH:19]=[CH2:20])[CH2:16][O:15][C:14]([CH3:18])([CH3:17])[CH2:13][O:12]1)=[O:10])C1C=CC=CC=1.O.[OH-].[Li+]>O1CCCC1.O>[CH3:17][C:14]1([CH3:18])[CH2:13][O:12][C:11]([CH:19]=[CH2:20])([C:9]([OH:10])=[O:8])[CH2:16][O:15]1
Reactant: C=CC1(C(=O)OCc2ccccc2)COC(C)(C)CO1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: C=CC1(C(=O)O)COC(C)(C)CO1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 54.2 %

Procedure:
To a stirred solution of 5,5-dimethyl-2-vinyl-[1,4]dioxane-2-carboxylic acid benzyl ester (189 mg, 0.684 mmol) in tetrahydrofuran (7 mL) at 0° C. was added a solution of lithium hydroxide hydrate (34 mg, 0.821 mmol) in water (1.6 mL). The reaction mixture was stirred at 0° C. for 30 min and allowed to warm to ambient temperature and stirred for 19 h. The mixture was diluted with water and washed with ethyl acetate (2×). The aqueous layer was acidified to pH 5 with hydrochloric acid (2 M) and extracted with ethyl acetate (2×). The organic extracts were dried over anhydrous magnesium sulfate, filtered and evaporated to give the title compound (69 mg, 54%) as a colorless oil. 1H NMR (300 MHz, CDCl3): δ 1.19 (s, 3H), 1.32 (s, 3H), 3.58 (d, J=11.8 Hz, 1H), 3.72 (d, J=11.8 Hz, 1H), 3.75 (d, J=12.3 Hz, 1H), 4.21 (d, J=12.3 Hz, 1H), 5.39 (dd, J=10.7, 0.9 Hz, 1H), 5.60 (dd, J=17.4, 0.9 Hz, 1H), 5.84 (dd, J=17.4, 10.7 Hz, 1H). LCMS (m/z) 185.2 [M−H], Tr=1.32 min.
Reaction SMILES: Cl[C:2]1[NH:3][C:4]2[C:9]([C:10]=1[C:11]([O:13][CH3:14])=[O:12])=[CH:8][CH:7]=[CH:6][CH:5]=2.[H-].[Na+].[CH3:17][NH:18][CH:19](NC)[CH2:20][CH2:21]Cl>C1COCC1.C1(C)C=CC=CC=1>[CH3:17][N:18]1[C:2]2=[C:10]([C:11]([O:13][CH3:14])=[O:12])[C:9]3[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=3[N:3]2[CH2:21][CH2:20][CH2:19]1
Reactant: COC(=O)c1c(Cl)[nH]c2ccccc12
Reactant: CNC(CCCl)NC
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: COC(=O)c1c2n(c3ccccc13)CCCN2C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of methyl 2-chloroindole-3-carboxylate (3.4 g, 0.016 mole) in dry THF (70 ml) at 5° C. under nitrogen was treated portionwise with sodium hydride (480mg of 80% oil dispersion, 0.016 mole) and then stirred at room temperature for 30 mins. The resulting solution was treated with a solution of 3,3-dimethylaminopropyl chloride (0.020 mole) in toluene (30 ml) and heated under reflux for 48 h, then concentrated in vacuo and the residue treated with 10% Na2CO3 solution (50 ml) and extracted with ethyl acetate (2×70 ml). The combined extracts were dried (Na2SO4) and concentrated in vacuo to leave a yellow oil, which was chromatographed on silica gel eluting with ether/60-80 petrol (1:1). The title compound (D11) was obtained as a beige solid (1.95 g, 50%).
Reaction SMILES: [CH3:1][N:2]([CH2:13][CH:14]1[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15]1)[C:3]1[O:4][C:5]2[CH:11]=[CH:10][C:9]([NH2:12])=[CH:8][C:6]=2[N:7]=1.[F:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[CH:32]=[CH:31][C:30]([C:33](O)=[O:34])=[CH:29][CH:28]=2)=[CH:23][CH:22]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[CH3:1][N:2]([CH2:13][CH:14]1[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15]1)[C:3]1[O:4][C:5]2[CH:11]=[CH:10][C:9]([NH:12][C:33]([C:30]3[CH:29]=[CH:28][C:27]([C:24]4[CH:25]=[CH:26][C:21]([F:20])=[CH:22][CH:23]=4)=[CH:32][CH:31]=3)=[O:34])=[CH:8][C:6]=2[N:7]=1
Reactant: CN1CCC(CN(C)c2nc3cc(N)ccc3o2)C1
Reactant: O=C(O)c1ccc(-c2ccc(F)cc2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Product: CN1CCC(CN(C)c2nc3cc(NC(=O)c4ccc(-c5ccc(F)cc5)cc4)ccc3o2)C1
Temperature: 25 °C
Reaction time: 72 h
Yield: 30.4 %

Procedure:
Combine rac-N2-methyl-N2-(1-methyl-pyrrolidin-3-ylmethyl)-benzooxazole-2,5-diamine (0.700 g, 2.69 mmol), 4′-fluoro-biphenyl-4-carboxylic acid (0.872 g, 4.03 mmol), HATU (1.43 g, 3.76 mmol), polystyrene-bound diisopropylamine (7.53 g, loading: 2.0 to 3.5 mmol/g), and CH2Cl2 (15 mL). Shake the mixture overnight at room temperature. Filter the mixture and wash the polystyrene resin with 1:1 CH2Cl2/MeOH. Subject the mixture to flash column chromatography on an ISCO Companion (120 g column, eluting with 20% 2M NH3 in MeOH/CH2Cl2) to yield a mixture of products. Subject the mixture to flash column chromatography (3×40 g, eluting with 20% 2M NH3 in MeOH/CH2Cl2) to yield a mixture of products. Concentrate the fractions and suspend the residue in anhydrous diethyl ether. Stir at room temperature for 3 d. Filter the mixture to yield the product as a white solid (0.375 g, 30%). Submit the racemic mixture to chiral chromatography to yield the product (0.187 g) as the second eluting enantiomer; mass spectrum (m/e): 459.2 (M+1), 457.3 (M−1). 1H NMR (400 MHz, DMSO-d6): δ 10.22 (s, 1H), 8.07-8.03 (m, 2H), 7.85-7.79 (m, 4H), 7.73 (d, J=2.0 Hz, 1H), 7.40-7.31 (m, 4H), 3.50 (d, J=7.6 Hz, 2H), 3.13 (s, 3H), 2.65-2.56 (m, 1H), 2.54-2.47 (m, 2H), 2.43-2.36 (m, 1H), 2.29-2.24 (m, 1H), 2.23 (s, 3H), 1.93-1.84 (m, 1H), 1.49-1.40 (m, 1H).
Reaction SMILES: S(C)C.[CH2:4]([O:11][CH2:12][CH:13]1[CH2:18][CH2:17][CH:16]=[CH:15][O:14]1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.C1C[O:22]CC1>>[CH2:4]([O:11][CH2:12][CH:13]1[O:14][CH2:15][CH:16]([OH:22])[CH2:17][CH2:18]1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: C1=COC(COCc2ccccc2)CC1
Reactant: C1CCOC1
Solvent: CSC
Product: OC1CCC(COCc2ccccc2)OC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
BH3.SMe2 (17 mL, 1 M in THF) was added slowly to a stirred solution of 2-(benzyloxymethyl)-3,4-dihydro-2H-pyran (2.87 g, 14.06 mmol) (13) in THF (100 mL) at −78° C. The resulting mixture was allowed to warm to room temperature overnight. The mixture was quenched by the slow addition of 1M NaOH (50 mL) at 0° C. followed by H2O2 (13 mL, 30% in water). The resulting mixture was stirred for 2 hours at room temperature. After aqueous work up the residue was purified on silica gel using EtOAc and hexane to give 6-(benzyloxymethyl)tetrahydro-2H-pyran-3-ol (14).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]([NH:13][C:14](=[O:37])[CH2:15][CH:16]([NH:23][S:24]([C:27]1[CH:36]=[CH:35][C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[CH:28]=1)(=[O:26])=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:8][CH2:7][CH2:6]2)=O.[CH3:38][NH:39][CH3:40]>>[CH3:38][N:39]([CH2:1][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]([NH:13][C:14](=[O:37])[CH2:15][CH:16]([NH:23][S:24]([C:27]1[CH:36]=[CH:35][C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[CH:28]=1)(=[O:26])=[O:25])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[CH2:8][CH2:7][CH2:6]2)[CH3:40]
Reactant: CNC
Reactant: O=Cc1ccc2c(c1)CCCC2NC(=O)CC(NS(=O)(=O)c1ccc2ccccc2c1)c1ccccc1
Product: CN(C)Cc1ccc2c(c1)CCCC2NC(=O)CC(NS(=O)(=O)c1ccc2ccccc2c1)c1ccccc1

Procedure:
The title compound was prepared from N-(6-formyl-1,2,3,4-tetrahydro-naphthalen-1-yl)-3-(naphthalen-2-yl-sulfonylamino)-3-phenyl-propionamide (Example 8, Step G) using essentially the same procedure used in Example 8, Step H except using dimethylamine. MS (+ESI m/z): 542 (M+H)+.
Reaction SMILES: CS(O[CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH:7]1[N:12]1[C:20]2[CH:19]=[CH:18][C:17]([CH3:21])=[CH:16][C:15]=2[C:14]2[CH2:22][N:23]([CH3:26])[CH2:24][CH2:25][C:13]1=2)(=O)=O.[OH-].[K+]>CN1C(=O)CCC1.O>[C:7]1([N:12]2[C:20]3[CH:19]=[CH:18][C:17]([CH3:21])=[CH:16][C:15]=3[C:14]3[CH2:22][N:23]([CH3:26])[CH2:24][CH2:25][C:13]2=3)[CH2:8][CH2:9][CH2:10][CH2:11][CH:6]=1
Reactant: Cc1ccc2c(c1)c1c(n2C2CCCCC2OS(C)(=O)=O)CCN(C)C1
Agent: [K+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Solvent: O
Product: Cc1ccc2c(c1)c1c(n2C2=CCCCC2)CCN(C)C1
Temperature: 120 °C
Yield: 82 %

Procedure:
To a solution of 2-(2,8-dimethyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)yl)cyclohexyl methanesulfonate (0.33 g, 0.87 mmol) in NMP (3 mL), KOH (0.49 g, 8.7 mmol) was added at RT. The reaction mixture was heated overnight at 120° C. The reaction was monitored by LCMS. Upon completion, the reaction mixture was diluted with water and extracted with EtOAc. The combined organic layer was separated, dried over sodium sulfate and concentrated under reduced pressure and purified by column chromatography (silica gel 3% MeOH in DCM) to afford 200 mg of the desired product. 1H NMR (CDCl3, HCl salt) δ (ppm): 7.50 (d, 2H), 7.40 (d, 2H), 7.23 (d, 1H), 7.1-7.0 (m, 2H), 6.9 (s, 1H), 3.8 (s, 2H), 3.0-2.8 (m, 4H), 2.6 (s, 3H), 2.45 (s, 3H), 2.0 (s, 3H).
Reaction SMILES: [OH:1][N:2]=[C:3](Cl)[C:4]1[CH:5]=[N:6][CH:7]=[N:8][CH:9]=1.[C:11]([C:13]1[CH:18]=[C:17]([F:19])[CH:16]=[C:15]([F:20])[CH:14]=1)#[CH:12].N>>[F:19][C:17]1[CH:18]=[C:13]([C:11]2[O:1][N:2]=[C:3]([C:4]3[CH:5]=[N:6][CH:7]=[N:8][CH:9]=3)[CH:12]=2)[CH:14]=[C:15]([F:20])[CH:16]=1
Reactant: C#Cc1cc(F)cc(F)c1
Reactant: ON=C(Cl)c1cncnc1
Agent: N
Product: Fc1cc(F)cc(-c2cc(-c3cncnc3)no2)c1

Procedure:
The titled compound was prepared as the hydrochloride salt according to Method CB using the product of Example 44B (79 mg, 0.5 mmol) and 1-ethynyl-3,5-difluorobenzene (Apollo, 69 mg, 0.5 mmol). 1H NMR (300 MHz, DMSO-d6) δ 7.52 (tt, J=9.5, 2.4 Hz, 1H), 7.62-7.78 (m, 2H), 7.93 (s, 1H), 9.30 (s, 2H), 9.36 (s, 1H) ppm; MS (DCI/NH3) m/z 260 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH:11]2[CH2:14][C:13]([F:16])([F:15])[CH2:12]2)=[C:6](N)[CH:5]=1.N([O-])=O.[Na+].[BrH:23]>O>[CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH:11]2[CH2:14][C:13]([F:16])([F:15])[CH2:12]2)=[C:6]([Br:23])[CH:5]=1
Reactant: COC(=O)c1ccc(OC2CC(F)(F)C2)c(N)c1
Reactant: Br
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: COC(=O)c1ccc(OC2CC(F)(F)C2)c(Br)c1
Reaction time: 0.25 h

Procedure:
1.0 g of 3-Amino-4-(3,3-difluoro-cyclobutoxy)-benzoic acid methyl ester was dissolved in 100 ml of half-concentrated aqueous HBr-solution. Then, a solution of 295 mg NaNO2 in 5 ml of water was added dropwise at 0° C. Stirring was continued at 0° C. for 15 minutes. Then, a solution of 558 mg CuBr in 10 ml of half-concentrated aqueous HBr-solution was added dropwise and the reaction mixture was stirred for 2 h at room temperature. Then, the reaction mixture was extracted three times using 100 ml of EA each. The organic layer was then washed three times using 100 ml of a saturated aqueous NaHCO3-solution, dried using MgSO4 and volatiles were evaporated to yield 150 mg of the title compound that was used without further purification.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:11]2[S:10](=[O:13])(=[O:12])[N:9]=[C:8]([C:14]3[C:15](=[O:34])[N:16]([CH2:26][C:27]4[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=4)[C@@H:17]4[C@H:22]([C:23]=3[OH:24])[C@@H:21]3[CH2:25][C@H:18]4[CH2:19][CH2:20]3)[NH:7][C:6]=2[S:5][CH:4]=1.C(N(CC)CC)C.[CH:42]1([S:45](Cl)(=[O:47])=[O:46])[CH2:44][CH2:43]1>ClCCl>[F:33][C:30]1[CH:29]=[CH:28][C:27]([CH2:26][N:16]2[C:15](=[O:34])[C:14]([C:8]3[NH:7][C:6]4[S:5][CH:4]=[C:3]([CH2:2][NH:1][S:45]([CH:42]5[CH2:44][CH2:43]5)(=[O:47])=[O:46])[C:11]=4[S:10](=[O:12])(=[O:13])[N:9]=3)=[C:23]([OH:24])[C@H:22]3[C@@H:17]2[C@H:18]2[CH2:25][C@@H:21]3[CH2:20][CH2:19]2)=[CH:32][CH:31]=1
Reactant: NCc1csc2c1S(=O)(=O)N=C(C1=C(O)[C@@H]3[C@H]4CC[C@H](C4)[C@@H]3N(Cc3ccc(F)cc3)C1=O)N2
Reactant: O=S(=O)(Cl)C1CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C1C(C2=NS(=O)(=O)c3c(CNS(=O)(=O)C4CC4)csc3N2)=C(O)[C@@H]2[C@H]3CC[C@H](C3)[C@@H]2N1Cc1ccc(F)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 85 %

Procedure:
To a solution of (1R,2S,7R,8S)-5-(7-aminomethyl-1,1-dioxo-1,4-dihydro-1λ6-thieno[2,3-e][1,2,4]thiadiazin-3-yl)-3-(4-fluoro-benzyl)-6-hydroxy-3-aza-tricyclo[6.2.1.02,7]undec-5-en-4-one (0.10 g, 0.20 mmol) in dichloromethane (3 mL) at 0° C. was added triethylamine (56 μL, 0.40 mmol) and cyclopropanesulfonyl chloride (23 μL, 0.22 mmol). The reaction was stirred at 0° C. for 30 min, then at 25° C. for 2 h. The reaction was quenched with water (10 mL). The resulting mixture was extracted with ethyl acetate (3×10 mL). The organic layers were combined, dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified via flash column chromatography (Teledyne Isco RediSep column; 0-1% methanol in dichloromethane) to afford the desired product, cyclopropanesulfonic acid {3-[(1R,2S,7R,8S)-3-(4-fluoro-benzyl)-6-hydroxy-4-oxo-3-aza-tricyclo[6.2.1.02,7]undec-5-en-5-yl]-1,1-dioxo-1,4-dihydro-1λ6-thieno[2,3-e][1,2,4]thiadiazin-7-ylmethyl}-amide (0.10 g, 0.17 mmol, 84%), as a white solid.
Reaction SMILES: [N+:1]([C:4]1[CH:14]=[CH:13][CH:12]=[C:6]2[C:7]([NH:9][C:10](=[O:11])[C:5]=12)=[O:8])([O-:3])=[O:2].[K].Cl[CH2:17][CH2:18][N:19]1[C:23]([N+:24]([O-:26])=[O:25])=[CH:22][N:21]=[C:20]1[CH3:27].C1(C)C=CC=CC=1>C(Cl)(Cl)Cl>[CH3:27][C:20]1[N:19]([CH2:18][CH2:17][N:9]2[C:10](=[O:11])[C:5]3=[C:4]([N+:1]([O-:3])=[O:2])[CH:14]=[CH:13][CH:12]=[C:6]3[C:7]2=[O:8])[C:23]([N+:24]([O-:26])=[O:25])=[CH:22][N:21]=1
Reactant: Cc1ncc([N+](=O)[O-])n1CCCl
Reactant: O=C1NC(=O)c2c1cccc2[N+](=O)[O-]
Agent: [K]
Solvent: ClC(Cl)Cl
Solvent: Cc1ccccc1
Product: Cc1ncc([N+](=O)[O-])n1CCN1C(=O)c2cccc([N+](=O)[O-])c2C1=O

Procedure:
3-Nitrophthalimide is converted to the potassium salt by the procedure described in Example 13 and then reacted with 1-(2-chloroethyl)-2-methyl-5-nitroimidazole according to the procedure described in Example 1. The crude reaction mixture is digested with toluene and then filtered to remove some insoluble material. Evaporation of the solvent leaves a syrup which is diluted with chloroform and then filtered to remove some insoluble material. The filtrate is further diluted with toluene and again filtered to remove some precipitate. The solvent is then evaporated from the filtrate and the resulting residue is recrystallized first from ethanol and then from acetone to give N-[2-(2-methyl-5-nitro-1-imidazolyl)ethyl]-3-nitrophthalimide melting at about 175°-176° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:12][CH2:11][CH:10]([CH2:13][NH:14][C:15]3[C:20]([NH2:21])=[CH:19][CH:18]=[CH:17][N:16]=3)[CH2:9][CH2:8]2)=[CH:3][CH:2]=1.[CH3:22][O:23][C:24]1[CH:32]=[CH:31][C:27]([C:28](Cl)=[O:29])=[CH:26][CH:25]=1>>[CH3:22][O:23][C:24]1[CH:32]=[CH:31][C:27]([C:28]([NH:21][C:20]2[C:15]([NH:14][CH2:13][CH:10]3[CH2:11][CH2:12][N:7]([C:4]4[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=4)[CH2:8][CH2:9]3)=[N:16][CH:17]=[CH:18][CH:19]=2)=[O:29])=[CH:26][CH:25]=1
Reactant: Nc1cccnc1NCC1CCN(c2ccncc2)CC1
Reactant: COc1ccc(C(=O)Cl)cc1
Product: COc1ccc(C(=O)Nc2cccnc2NCC2CCN(c3ccncc3)CC2)cc1
Yield: 15.1 %

Procedure:
Using a similar procedure to that described in Example 2, Part D, N2-[1-(4-pyridyl)piperidin-4-ylmethyl]-2,3-pyridinediamine (300 mg, 1.06 mmol) and 4-methoxybenzoyl chloride (200 mg, 1.17 mmol) yielded 67 mg (15%) of the title compound.