Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:5]([C:16]#[N:17])=[C:4]([NH:18][CH2:19][CH2:20][OH:21])[N:3]=1.CC(C)([O-])C.[K+].[CH2:28]([OH:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[CH2:28]([O:35][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:5]([C:16]#[N:17])=[C:4]([NH:18][CH2:19][CH2:20][OH:21])[N:3]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: OCc1ccccc1
Reactant: N#Cc1c(Cl)nc(NCCO)c(C#N)c1-c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Product: N#Cc1c(NCCO)nc(OCc2ccccc2)c(C#N)c1-c1ccccc1
Temperature: 40 °C
Reaction time: 16 h

Procedure:
58 mg (0.2 mmol) of 2-chloro-4-phenyl-6-(2-hydroxyethylamino)-3,5-pyridinedicarbonitrile (example 17, step 1) are, together with 27 mg (0.24 mmol) of potassium tert-butoxide, dissolved in 0.96 g (=1 ml, 8.9 mmol) of benzyl alcohol, and the mixture is stirred at 40° C. for about 16 h. The reaction mixture is purified by preparative HPLC on reversed-phase silica gel (gradient: water+0.1% formic acid/acetonitrile 90:105:95 in 35 minutes).
Reaction SMILES: [NH3:1].C(=O)=O.CC(C)=O.[N:9]1([CH2:15][CH2:16][CH2:17][S:18](Cl)(=[O:20])=[O:19])[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1>ClCCl>[N:9]1([CH2:15][CH2:16][CH2:17][S:18]([NH2:1])(=[O:20])=[O:19])[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1
Reactant: O=S(=O)(Cl)CCCN1CCOCC1
Reactant: N
Agent: O=C=O
Solvent: CC(C)=O
Solvent: ClCCl
Product: NS(=O)(=O)CCCN1CCOCC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Dichloromethane (40 ml) was saturated with ammonia gas with cooling (dry ice/acetone), and then 3-morpholin-4-yl-propane-1-sulphonyl chloride (279 mg, 1.23 mmoles) was added. The mixture was stirred at room temperature for 24 hours. The mixture was filtered, the filtrate evaporated and the residue was dried at 40° C. in vacuo to afford compound 58 (210 mg) as a gum. LC/MS System A; Rt=0.28 mins, m/z (ES+)=209 (M+H for C7H16N2O3S).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:13])=[CH:9][C:10]=2[F:12])[N:5]=[C:4]([N:14]2[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C@H:16]([CH3:27])[CH2:15]2)[C:3]=1[CH3:28].[O:29]1[CH2:34][CH2:33][N:32]([C:35]2[CH:36]=[C:37]([NH2:41])[CH:38]=[N:39][CH:40]=2)[CH2:31][CH2:30]1>C1(C)C=CC=CC=1>[F:12][C:10]1[CH:9]=[C:8]([F:13])[CH:7]=[C:6]2[C:11]=1[C:2]([NH:41][C:37]1[CH:38]=[N:39][CH:40]=[C:35]([N:32]3[CH2:33][CH2:34][O:29][CH2:30][CH2:31]3)[CH:36]=1)=[C:3]([CH3:28])[C:4]([N:14]1[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:24])([CH3:26])[CH3:25])=[O:21])[C@H:16]([CH3:27])[CH2:15]1)=[N:5]2
Reactant: Nc1cncc(N2CCOCC2)c1
Reactant: Cc1c(N2CCN(C(=O)OC(C)(C)C)[C@H](C)C2)nc2cc(F)cc(F)c2c1Cl
Solvent: Cc1ccccc1
Product: Cc1c(N2CCN(C(=O)OC(C)(C)C)[C@H](C)C2)nc2cc(F)cc(F)c2c1Nc1cncc(N2CCOCC2)c1

Procedure:
Prepared according to Procedure H using (R)-tert-butyl 4-(4-chloro-5,7-difluoro-3-methylquinolin-2-yl)-2-methylpiperazine-1-carboxylate (230 mg, 0.56 mmol) and 5-morpholinopyridin-3-amine in toluene to give (R)-tert-butyl 4-(5,7-difluoro-3-methyl-4-(5-morpholinopyridin-3-ylamino)quinolin-2-yl)-2-methylpiperazine-1-carboxylate. 1H NMR (CDCl3) δ ppm 7.94 (1H, d, J=2.3 Hz), 7.69 (1H, d, J=2.2 Hz), 7.30 (1H, ddd, J=10.0, 2.5, 1.2 Hz), 6.88 (1H, d, J=12.9 Hz), 6.80 (1H, ddd, J=13.9, 8.6, 2.5 Hz), 6.58 (1H, t, J=2.3 Hz), 4.38 (1H, br. s.), 3.98 (1H, d, J=13.1 Hz), 3.85 (4H, dd, J=5.7, 3.9 Hz), 3.70 (1H, d, J=10.2 Hz), 3.56 (1H, dt, J=12.9, 1.8 Hz), 3.32 (1H, td, J=12.7, 3.1 Hz), 3.14-3.21 (4H, m), 3.11 (1H, dd, J=12.8, 3.8 Hz), 2.92 (1H, td, J=12.5, 3.3 Hz), 2.10 (3H, s), 1.50 (9H, s), 1.29 (3H, d, J=6.8 Hz). Mass Spectrum (ESI) m/e=555.7 (M+1).
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:20][C:21]2[CH:30]=[CH:29][CH:28]=[CH:27][C:22]=2[C:23]([NH:25][CH3:26])=[O:24])=[N:4][C:5]([NH:8][C:9]2[CH:19]=[CH:18][C:12]3[CH2:13][CH2:14][NH:15][CH2:16][CH2:17][C:11]=3[CH:10]=2)=[N:6][CH:7]=1.C=O.[C:33]([BH3-])#N.[Na+]>C(#N)C>[Cl:1][C:2]1[C:3]([NH:20][C:21]2[CH:30]=[CH:29][CH:28]=[CH:27][C:22]=2[C:23]([NH:25][CH3:26])=[O:24])=[N:4][C:5]([NH:8][C:9]2[CH:19]=[CH:18][C:12]3[CH2:13][CH2:14][N:15]([CH3:33])[CH2:16][CH2:17][C:11]=3[CH:10]=2)=[N:6][CH:7]=1
Reactant: CNC(=O)c1ccccc1Nc1nc(Nc2ccc3c(c2)CCNCC3)ncc1Cl
Reactant: [BH3-]C#N
Agent: C=O
Agent: [Na+]
Solvent: CC#N
Product: CNC(=O)c1ccccc1Nc1nc(Nc2ccc3c(c2)CCN(C)CC3)ncc1Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2-[5-Chloro-2-(2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamino)-pyrimidin-4-ylamino]-N-methyl-benzamide was suspended in acetonitrile (5 mL). Aqueous formaldehyde (37%, 325 μL/4 mmol) and sodium cyanoborohydride (210 mg/3.3 mmol) were added sequentially and the reaction stirred at room temperature for two hours. The material was concentrated onto celite and the desired product was isolated by sequential column chromatography on silica gel (eluting with 0→50% methanol/methylene chloride) followed by basic alumina (eluting with 0→40% methanol/methylene chloride). Yield 50 mg/35%. 1H NMR (400 MHz, DMSO-d6) δ 11.58 (s, 1H), 9.41 (s, 1H), 8.82-8.69 (m, 2H), 8.22 (s, 1H), 7.79 (d, J=7.8 Hz, 1H), 7.56-7.41 (m, 3H), 7.19 (dd, J=7.3, 7.3 Hz, 1H), 7.09 (d, J=8.1 Hz, 1H), 3.19-2.78 (m, 14H). LC/MS found 436 (M+H). mp 125-130° C. (dec.).
Reaction SMILES: Br[CH2:2][C:3]([NH:5][C:6]1[CH:14]=[CH:13][CH:12]=[CH:11][C:7]=1[C:8]([OH:10])=[O:9])=[O:4].[F:15][C:16]1[CH:17]=[C:18]([CH:20]=[CH:21][CH:22]=1)[NH2:19].CN(C=O)C.[OH-].[K+]>O>[F:15][C:16]1[CH:17]=[C:18]([NH:19][CH2:2][C:3]([NH:5][C:6]2[CH:14]=[CH:13][CH:12]=[CH:11][C:7]=2[C:8]([OH:10])=[O:9])=[O:4])[CH:20]=[CH:21][CH:22]=1
Reactant: Nc1cccc(F)c1
Reactant: O=C(CBr)Nc1ccccc1C(=O)O
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(CNc1cccc(F)c1)Nc1ccccc1C(=O)O
Yield: 78.3 %

Procedure:
A solution of 2-(N-bromoacetylamino) benzoic acid from Example 79 (8.00 g, 31.0 mmol), meta-fluoroaniline (7.45 mL, 77.5 mmol) and DMF (80 mL) was heated to 80° C. for 8 h. The mixture was cooled, poured over H2O (1 L) and 5% KOH (300 mL) and washed with CH2Cl2 (3×300 mL). The aqueous layer was acidified to pH 2 with 2N HCl, cooled below room temperature, and filtered. The filter cake was rinsed with cold water (100 mL) and dried under high vacuum at 45° C. to yield 7.00 g (78%) of the title compound as a grey solid; 1H NMR (DMSO-d6) δ 13.5 (broad s, 1H), 11.94 (s, 1H), 8.70 (d, J=8.4, 1H), 7.94 (dd, J=7.8, J=1.4, 1H), 7.60 (td, J=8.0, J=1.4, 1H), 7.15-7.07 (m, 2H), 6.83 (broad s, 1H), 6.43-6.35 (m, 3H), 3.88 (s, 2H); 13C NMR (DMSO-d6) δ 170.29, 169.12, 163.25 (J=240.3), 150.17 (J=10.6), 140.52, 134.18, 131.13, 130.43 (J=10.6), 122.73, 119.40, 115.98, 108.42, 103.09 (J=21.2), 98.97 (J=25), 48.48; MS (EI, m/z) 388 (M+).
Reaction SMILES: [CH:1]1([C:7]2[CH:20]=[CH:19][C:10]([O:11][CH2:12][C@H:13]3[O:17][C:16]([NH2:18])=[N:15][CH2:14]3)=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C[O:22][C:23](=O)[CH:24]([CH:29]=O)[CH2:25][CH2:26][O:27][CH3:28]>C(Cl)(Cl)Cl>[CH:1]1([C:7]2[CH:20]=[CH:19][C:10]([O:11][CH2:12][CH:13]3[O:17][C:16]4=[N:18][C:23](=[O:22])[C:24]([CH2:25][CH2:26][O:27][CH3:28])=[CH:29][N:15]4[CH2:14]3)=[CH:9][CH:8]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: NC1=NC[C@@H](COc2ccc(C3CCCCC3)cc2)O1
Reactant: COCCC(C=O)C(=O)OC
Solvent: ClC(Cl)Cl
Product: COCCc1cn2c(nc1=O)OC(COc1ccc(C3CCCCC3)cc1)C2

Procedure:
The title compound was prepared from (S) -5-(4-cyclohexyl-phenoxy methyl)-4,5-dihydro-oxazol-2-ylamine and 2-formyl-4-methoxy-butyric acid methyl ester employing the procedure described in Step2 of Example 87. [α]D25 −19.00 (c 0.5, CHCl3).
Reaction SMILES: [O:1]=[CH:2]/[CH:3]=[CH:4]/[CH:5]=[CH:6]/[C:7]1[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][CH:8]=1.[F:15][C:16]1[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=1[C@:23]([OH:38])([C@H:30]([S:32][CH:33]([CH2:36]O)[CH2:34][OH:35])[CH3:31])[CH2:24][N:25]1[CH:29]=[N:28][CH:27]=[N:26]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)([O-])O.[Na+]>ClCCl>[C:11]([C:10]1[CH:13]=[CH:14][C:7](/[CH:6]=[CH:5]/[CH:4]=[CH:3]/[C@H:2]2[O:35][CH2:34][C@H:33]([S:32][C@H:30]([CH3:31])[C@:23]([C:17]3[CH:18]=[CH:19][C:20]([F:22])=[CH:21][C:16]=3[F:15])([OH:38])[CH2:24][N:25]3[CH:29]=[N:28][CH:27]=[N:26]3)[CH2:36][O:1]2)=[CH:8][CH:9]=1)#[N:12]
Reactant: N#Cc1ccc(/C=C/C=C/C=O)cc1
Reactant: C[C@@H](SC(CO)CO)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: C[C@@H](S[C@H]1CO[C@H](/C=C/C=C/c2ccc(C#N)cc2)OC1)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Temperature: 25 °C
Yield: 81.3 %

Procedure:
A mixture of 240 mg (1.31 mmol) of 4-[(1E,3E)-5-oxo-1,3-pentadienyl]benzonitrile [prepared as described in Step 1(i) above], 392 mg (1.09 mmol) of (2R,3R)-2-(2,4-difluorophenyl)-3-[[1-(hydroxymethyl)-2-hydroxyethyl]thio]-1-(1H-1,2,4-triazol-1-yl)-2-butanol [prepared as described in Japanese Patent Application (Kokai) Hei 8-333350)], 249 mg (1.31 mmol) of p-toluenesulfonic acid monohydrate, 16 ml of dichloromethane and 3.9 g of molecular sieves 4A was stirred at ambient temperature over night. Aqueous sodium hydrogen carbonate was then added to the reaction mixture and insoluble material was removed by filtration. The resulting filtrate was extracted with ethyl acetate and the organic layer was dried and then concentrated. The resulting residue was purified by chromatography on silica gel (15 g) column using a 1:1 mixture of ethyl acetate and hexane as the eluant to give 465 mg (yield 81%) of the title compound as a solid. This solid was recrystallized from a mixture of ethyl acetate and hexane to afford crystals.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]([C:10]2[C:14]3[CH:15]=[N:16][CH:17]=[CH:18][C:13]=3[N:12]([C:19]([CH3:30])([CH3:29])[CH2:20][O:21][Si](C(C)(C)C)(C)C)[CH:11]=2)=[O:9])[CH:3]=1.[F:31][C:32]([F:44])([F:43])[C:33]1[CH:38]=[CH:37][C:36]([CH2:39][C:40](O)=[O:41])=[CH:35][CH:34]=1>>[OH:21][CH2:20][C:19]([N:12]1[C:13]2[CH:18]=[CH:17][N:16]=[CH:15][C:14]=2[C:10]([C:8]([C:4]2[CH:3]=[C:2]([NH:1][C:40](=[O:41])[CH2:39][C:36]3[CH:35]=[CH:34][C:33]([C:32]([F:43])([F:31])[F:44])=[CH:38][CH:37]=3)[CH:7]=[CH:6][N:5]=2)=[O:9])=[CH:11]1)([CH3:30])[CH3:29]
Reactant: CC(C)(CO[Si](C)(C)C(C)(C)C)n1cc(C(=O)c2cc(N)ccn2)c2cnccc21
Reactant: O=C(O)Cc1ccc(C(F)(F)F)cc1
Product: CC(C)(CO)n1cc(C(=O)c2cc(NC(=O)Cc3ccc(C(F)(F)F)cc3)ccn2)c2cnccc21

Procedure:
Prepared according to Method M (Example 206) using (4-aminopyridin-2-yl)[1-(2-{[tert-butyl(dimethyl)silyl]oxy}-1,1-dimethylethyl)-1H-pyrrolo[3,2-c]pyridin-3-yl]methanone (Preparation 27) and 4-trifluoromethylphenylacetic acid at 70° C. The residue was purified over neutral alumina eluting with 50% EtOAc in hexane followed by acid deprotection using 10% HCl in dioxane at room temperature for 18 hours. The reaction was concentrated in vacuo and purified using preparative HPLC to afford the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[CH:14][C:5]([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.[C:16](Cl)(=[O:25])[C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=1.C(N(CC)CC)C>C1COCC1>[C:6]([C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:16](=[O:25])[C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)=[CH:15][CH:14]=1)(=[O:7])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: Nc1ccc(C(=O)c2ccccc2)cc1
Reactant: COc1ccc(C(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1ccc(C(=O)Nc2ccc(C(=O)c3ccccc3)cc2)cc1
Yield: 98 %

Procedure:
Reaction of 4-aminobenzophenone (98 mg, 0.51 mmol) in THF (6 mL) with p-anisoyl chloride (90 μL, 0.65 mmol) in presence of triethylamine (90 μL, 0.65 mmol) according to method A gave N-(4-benzoyl-phenyl)-4-methoxy-benzamide (165 mg, 0.50 mmol, 98% yield) as a white powder after purification by washing the crude product with ethyl acetate and hexane.
Reaction SMILES: C([O:4][CH2:5][C:6]([CH2:21][O:22]C(=O)C)([C:8]([NH:10][C:11]1[CH:16]=[CH:15][C:14]([S:17]([NH2:20])(=[O:19])=[O:18])=[CH:13][CH:12]=1)=[O:9])[CH3:7])(=O)C.[OH-].[Na+].C(O)C>O>[OH:4][CH2:5][C:6]([CH2:21][OH:22])([C:8]([NH:10][C:11]1[CH:12]=[CH:13][C:14]([S:17]([NH2:20])(=[O:18])=[O:19])=[CH:15][CH:16]=1)=[O:9])[CH3:7]
Reactant: CC(=O)OCC(C)(COC(C)=O)C(=O)Nc1ccc(S(N)(=O)=O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(CO)(CO)C(=O)Nc1ccc(S(N)(=O)=O)cc1

Procedure:
Then, 22 g (0.06 mole) of p-(1,1-bis(acetoxymethyl)ethylcarbonylamino)benzenesulfonamide, 4.8 g (0.12 mole) of sodium hydroxide, 50 ml of ethanol and 50 ml of water were introduced into a 300 ml three-necked flask equipped with a stirring machine and a condenser and refluxed while heating for 2 hours. The reaction mixture was poured into 1 l of water while stirring, then stirred for 30 minutes and filtered to give white solid of p-(1,1-bis(hydroxymethyl)ethylcarbonylamino)benzenesulfonamide. The white solid was purified by recrystallization from ethanol (yield 11 g).
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:4]=1[CH2:5][N:6]1[CH2:11][CH2:10][CH:9]([CH:12]=O)[CH2:8][CH2:7]1.[O:24]=[C:25]1[N:29]=[C:28]([NH:30][C@H:31]2[C@H:36]([OH:37])[CH2:35][CH2:34][O:33][CH2:32]2)[CH2:27][S:26]1.C([O-])(=O)C.[NH2+]1CCCCC1>CC(O)C>[F:23][C:2]([F:1])([F:22])[C:3]1[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:4]=1[CH2:5][N:6]1[CH2:11][CH2:10][CH:9](/[CH:12]=[C:27]2/[C:28]([NH:30][C@H:31]3[C@H:36]([OH:37])[CH2:35][CH2:34][O:33][CH2:32]3)=[N:29][C:25](=[O:24])[S:26]/2)[CH2:8][CH2:7]1
Reactant: O=C1N=C(N[C@@H]2COCC[C@H]2O)CS1
Reactant: O=CC1CCN(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)CC1
Agent: C1CC[NH2+]CC1
Agent: CC(=O)[O-]
Solvent: CC(C)O
Product: O=C1N=C(N[C@@H]2COCC[C@H]2O)/C(=C/C2CCN(Cc3ccc(C(F)(F)F)cc3C(F)(F)F)CC2)S1
Temperature: 75 °C
Reaction time: 8 h
Yield: 54.1 %

Procedure:
To a solution of 1-[2,4-bis(trifluoromethyl)benzyl]piperidine-4-carbaldehyde (941 mg) in 2-propanol (20 mL) were added 1,5-anhydro-2,4-dideoxy-2-[(2-oxo-2,5-dihydro-1,3-thiazol-4-yl)amino]-threo-pentitol (900 mg) and piperidinium acetate (411 mg). The reaction mixture was stirred at 75° C. overnight, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) and silica gel column chromatography (NH, methanol/ethyl acetate) to give the title compound (806 mg). Absolute configuration undetermined.
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH:8]2[CH2:13][CH2:12][CH2:11][CH:10]([C:14]3[C:19]([CH3:20])=[CH:18][CH:17]=[CH:16][N:15]=3)[NH:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.Br[CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([C:29]#[N:30])[CH:24]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:1][C:2]1[CH2:7][CH2:6][CH:5]=[N:4][C:3]=1[CH:8]1[CH2:13][CH2:12][CH2:11][CH:10]([C:14]2[C:19]([CH3:20])=[CH:18][CH:17]=[CH:16][N:15]=2)[N:9]1[CH2:22][C:23]1[CH:24]=[C:25]([CH:26]=[CH:27][CH:28]=1)[C:29]#[N:30]
Reactant: N#Cc1cccc(CBr)c1
Reactant: Cc1cccnc1C1CCCC(c2ncccc2C)N1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC1=C(C2CCCC(c3ncccc3C)N2Cc2cccc(C#N)c2)N=CCC1
Yield: 75 %

Procedure:
Using General Procedure A: A solution of 3,3″-dimethyl-1′,2′,3′,4′,5′,6′-hexahydro-[2,2′;6′,2″]terpyridine (0.414 g, 1.55 mmol), α-bromo-m-tolunitrile (0.466 g, 2.38 mmol), KI (53 mg, 0.32 mmol), and DIPEA (0.55 mL, 3.16 mmol) in DMF (8 mL) was heated at 60° C. for 18 hours. Purification of the crude material by column chromatography on silica gel (40:1:1 CH2Cl2—CH3OH—NH4OH) provided 0.447 g (75%) of 3-(3,3″-dimethyl-3′,4′,5 ,6′-tetrahydro-2′H-[2,2′;6′,2″]terpyridin-1′-ylmethyl)-benzonitrile as a beige solid. 1H NMR (CDCl3) δ 1.56-1.72 (m, 3H), 2.05-2.10 (m, 1H), 2.18-2.34 (m, 2H), 2.41 (s, 6H), 3.53 (s, 2H), 4.10 (d, 2H, J=11.1 Hz), 6.71 (s, 1H), 6.83 (d, 1H, J=7.8 Hz), 6.93-7.00 (m, 3H), 7.13 (d, 1H, J=7.5 Hz), 7.25-7.27 (m, 2H), 8.39 (dd, 2H, J=4.8, 1.2 Hz); ES-MS m/z 383 (M+H).
Reaction SMILES: ClC(Cl)(O[C:5](=[O:11])[O:6][C:7](Cl)(Cl)Cl)Cl.[CH2:13]([O:15][C:16]([C:18]1[C:24]2[NH:25][C:26]3[CH:27]=C(O)[CH:29]=[CH:30][C:31]=3[C:23]=2[C:22]([CH3:34])([CH3:33])[CH2:21][N:20]([C:35](=[O:43])[C:36]2[CH:41]=[CH:40][C:39]([F:42])=[CH:38][CH:37]=2)[CH:19]=1)=[O:17])[CH3:14].C(N(C(C)C)CC)(C)C.[CH3:53][N:54]([CH3:58])[CH2:55][CH2:56][NH2:57]>C(Cl)Cl>[CH2:13]([O:15][C:16]([C:18]1[C:24]2[NH:25][C:26]3[CH:27]=[C:7]([O:6][C:5](=[O:11])[NH:57][CH2:56][CH2:55][N:54]([CH3:58])[CH3:53])[CH:29]=[CH:30][C:31]=3[C:23]=2[C:22]([CH3:34])([CH3:33])[CH2:21][N:20]([C:35](=[O:43])[C:36]2[CH:37]=[CH:38][C:39]([F:42])=[CH:40][CH:41]=2)[CH:19]=1)=[O:17])[CH3:14]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CN(C)CCN
Reactant: CCOC(=O)C1=CN(C(=O)c2ccc(F)cc2)CC(C)(C)c2c1[nH]c1cc(O)ccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(=O)C1=CN(C(=O)c2ccc(F)cc2)CC(C)(C)c2c1[nH]c1cc(OC(=O)NCCN(C)C)ccc21
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 28.9 %

Procedure:
Triphosgene (58 mg, 0.195 mmol) was added to a stirred solution of 3-(4-fluorobenzoyl)-8-hydroxy-1,1-dimethyl-1,2,3,6-tetrahydroazepino[4,5-b]indole-5-carboxylic acid ethyl ester (49 mg, 0.116 mmol) and diisopropylethylamine (0.8 mL, 4.01 mmol) in dry DCM (10 mL) at 0° C. under N2. The resulting mixture was stirred at ambient temperature for 1.5 hours, and N,N-dimethylethylenediamine (0.1 mL, 0.91 mmol) was added. The mixture was stirred at ambient temperature overnight. The solvents were removed in vacuo, and the residue was purified by preparative reverse-phase HPLC to give the title compound (18 mg); 1H-NMR (CDCl3): 10.63 (1H, s), 7.76 (2H, m), 7.63-7.60 (2H, m), 7.16-7.11 (3H, m), 6.88-6.86 (1H, dd), 5.61 (1H, t), 4.24 (2H, q), 4.10 (2H, br s), 3.37 (2H, m), 2.48 (2H, m), 2.27 (6H, s), 1.59 (6H, s), 1.24 (3H, t); MS (ES): 537 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[CH3:10][C:11]1([CH3:19])[O:18][C:16](=[O:17])[CH2:15][C:13](=[O:14])[O:12]1.N1CCCC1C(O)=O.[F:28][C:29]1[CH:30]=[C:31]2[C:35](=[C:36]([CH2:38][S:39][CH3:40])[CH:37]=1)[NH:34][CH:33]=[CH:32]2>C(#N)C>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]([C:32]2[C:31]3[C:35](=[C:36]([CH2:38][S:39][CH3:40])[CH:37]=[C:29]([F:28])[CH:30]=3)[NH:34][CH:33]=2)[CH:15]2[C:16](=[O:17])[O:18][C:11]([CH3:19])([CH3:10])[O:12][C:13]2=[O:14])=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(Cl)cc1
Reactant: CC1(C)OC(=O)CC(=O)O1
Reactant: CSCc1cc(F)cc2cc[nH]c12
Agent: O=C(O)C1CCCN1
Solvent: CC#N
Product: CSCc1cc(F)cc2c(C(c3ccc(Cl)cc3)C3C(=O)OC(C)(C)OC3=O)c[nH]c12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
0.62 g (4.41 mmol) of 4-chlorobenzaldehyde, 0.64 g (4.41 mmol) of Meldrum's acid and 24 mg (0.21 mmol) of D,L-proline were added to a solution of 1.00 g (4.20 mmol) of the compound from Example 11A in 34 ml of acetonitrile. The reaction mixture was stirred at RT overnight. It was concentrated to result in 2.21 g (73% of theory) of the title compound with a purity of 64% which were reacted without further purification.
Reaction SMILES: Br[C:2]1[CH:16]=[CH:15][C:5]([CH2:6][NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[CH:4][CH:3]=1.B1(B2OC(C)(C)C(C)(C)O2)OC(C)(C)C(C)(C)O1.Br[C:36]1[C:37]2[C:38]3[CH:51]=[CH:50][S:49][C:39]=3[C:40](=[O:48])[NH:41][C:42]=2[CH:43]=[CH:44][C:45]=1[O:46][CH3:47]>>[CH3:47][O:46][C:45]1[CH:44]=[CH:43][C:42]2[NH:41][C:40](=[O:48])[C:39]3[S:49][CH:50]=[CH:51][C:38]=3[C:37]=2[C:36]=1[C:2]1[CH:16]=[CH:15][C:5]([CH2:6][NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[CH:4][CH:3]=1
Reactant: COc1ccc2[nH]c(=O)c3sccc3c2c1Br
Reactant: CC(C)(C)OC(=O)NCc1ccc(Br)cc1
Agent: CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C
Product: COc1ccc2[nH]c(=O)c3sccc3c2c1-c1ccc(CNC(=O)OC(C)(C)C)cc1
Yield: 68.7 %

Procedure:
Following General Procedure E, tert-butyl 4-bromobenzylcarbamate (2.9 g, 10 mmol) was reacted with bis(pinacolato)diborane (2.8 g, 11 mmol) to afford the crude boronic ester which was reacted with 9-bromo-8-methoxythieno[2,3-c]quinolin-4(5H)-one (2.8 g, 9.0 mmol) to afford the desired product (2.7 g, 68%) as a brown solid: ESI MS m/z 437 [C24H24N2O4S+H]+.
Reaction SMILES: [CH3:1][C:2]1[S:6][CH:5]=[C:4]([S:7]([NH2:10])(=[O:9])=[O:8])[CH:3]=1.[C:11]1([O:17]C(Cl)=O)C=CC=CC=1.C(N(CC)CC)C.[NH2:28][C:29]1[N:34]=[C:33]([NH:35][C:36]([NH:38][CH3:39])=[O:37])[CH:32]=[C:31]([Br:40])[CH:30]=1>C(#N)C>[Br:40][C:31]1[CH:32]=[C:33]([NH:35][C:36](=[O:37])[NH:38][CH3:39])[N:34]=[C:29]([NH:28][C:11]([NH:10][S:7]([C:4]2[CH:3]=[C:2]([CH3:1])[S:6][CH:5]=2)(=[O:9])=[O:8])=[O:17])[CH:30]=1
Reactant: CNC(=O)Nc1cc(Br)cc(N)n1
Reactant: Cc1cc(S(N)(=O)=O)cs1
Reactant: O=C(Cl)Oc1ccccc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CNC(=O)Nc1cc(Br)cc(NC(=O)NS(=O)(=O)c2csc(C)c2)n1
Temperature: 0 °C
Reaction time: 1 h
Yield: 35.5 %

Procedure:
To a solution of 0.089 g 5-methyl-thiophene-3-sulfonic acid amide (example 2a) in 4 ml acetonitrile was added at 0° C. 0.094 g phenylchloroformate and 0.127 g triethylamine. The mixture was stirred at 0° C. for 1 h. To the resulting suspension was added 0.127 g 1-(6-amino-4-bromo-pyridin-2-yl)-3-methyl-urea and the mixture was heated to 60° C. for 18 h. The reaction mixture was partitioned between water and ethyl acetate. The phases were separated and the pH of the aqueous phase was adjusted to 2 by addition of 1N hydrochloric acid. The product was extracted with ethyl acetate. The organic phase was washed with water and brine, dried over sodium sulfate and evaporated to yield 0.080 g of the title compound as an orange yellow powder. MS (ISN) M−H+=445.8 and 447.7
Reaction SMILES: [Li][CH2:2]CCC.[S:6]([N:16]1[CH2:21][C:20](=O)[C:19]2[S:23][CH:24]=[CH:25][C:18]=2[CH2:17]1)([C:9]1[CH:15]=[CH:14][C:12]([CH3:13])=[CH:11][CH:10]=1)(=[O:8])=[O:7]>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[CH2:2]=[C:20]1[CH2:21][N:16]([S:6]([C:9]2[CH:15]=[CH:14][C:12]([CH3:13])=[CH:11][CH:10]=2)(=[O:8])=[O:7])[CH2:17][C:18]2[CH:25]=[CH:24][S:23][C:19]1=2
Reactant: Cc1ccc(S(=O)(=O)N2CC(=O)c3sccc3C2)cc1
Reactant: [Li]CCCC
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Product: C=C1CN(S(=O)(=O)c2ccc(C)cc2)Cc2ccsc21
Reaction time: 0.5 h

Procedure:
To a solution of methyltriphenylphosphonium bromide (2.05 g, 5.73 mmol, 2.0 equiv) in THF (10.0 mL) at −78° C. was added n-BuLi (3.58 mL, 1.6 M solution, 2.0 equiv) and stirred for 30 min followed by addition of 5,6-dihydro-5-tosylthieno[3,2-c]pyridin-7(4H)-one (880 mg, 2.86 mmol, 1.0 equiv) in THF (5.00 mL). The reaction mixture was stirred at rt for 1 h, then quenched by the addition of a saturated aqueous solution of ammonium chloride. Purification by column chromatography using 5% ethyl acetate in hexanes elution gave 175 mg of the yellow solid, 20%.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-:10])=[O:9])[CH:3]=1.[C:11](Cl)(Cl)=[S:12].C([N:17](CC)CC)C>O1CCCC1>[N+:8]([C:4]1[CH:3]=[C:2]([NH:1][C:11]([NH2:17])=[S:12])[CH:7]=[CH:6][CH:5]=1)([O-:10])=[O:9]
Reactant: Nc1cccc([N+](=O)[O-])c1
Reactant: CCN(CC)CC
Reactant: S=C(Cl)Cl
Solvent: C1CCOC1
Product: NC(=S)Nc1cccc([N+](=O)[O-])c1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
To a cooled (0° C. ) and stirred solution of 1-amino-3-nitrobenzene (10 g) in anhydrous tetrahydrofuran (500 ml), under nitrogen, was added thiophosgene (5.6 ml) dropwise. After 5 min triethylamine (29 ml) was added dropwise and the mixture stirred for a further 5 min at 0° C. then at room temperature for 10 min. The mixture was then re-cooled to 0° C. and ammonia gas bubbled through the mixture for 15 min. The resultant solid was removed by filtration and the filtrate evaporated in vacuo to afford a gum which was triturated with ethyl acetate to give the thiourea (7.3 g) as a solid. 1H NMR (250 MHz, D6 -DMSO)δ7.59 (1H, dd, J=8.2 and 8.2 Hz), 7.83 (1H, m), 7.92 (1H, m), 8.64 (1H, m), 10.09 (1H, brs). MS (CI, NH3) 197 (M+).