Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:40])([F:39])[C:3]1[CH:4]=[C:5]([CH:13]([NH2:38])[CH2:14][NH:15][CH2:16][C:17]2[CH:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:20]=[CH:19][C:18]=2[C:27]2[CH:32]=[C:31]([CH:33]([CH3:35])[CH3:34])[CH:30]=[CH:29][C:28]=2[O:36][CH3:37])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[S:41](N)(N)(=[O:43])=[O:42]>N1C=CC=CC=1.CCOC(C)=O>[F:1][C:2]([F:39])([F:40])[C:3]1[CH:4]=[C:5]([CH:13]2[NH:38][S:41](=[O:43])(=[O:42])[N:15]([CH2:16][C:17]3[CH:22]=[C:21]([C:23]([F:24])([F:25])[F:26])[CH:20]=[CH:19][C:18]=3[C:27]3[CH:32]=[C:31]([CH:33]([CH3:35])[CH3:34])[CH:30]=[CH:29][C:28]=3[O:36][CH3:37])[CH2:14]2)[CH:6]=[C:7]([C:9]([F:11])([F:10])[F:12])[CH:8]=1
Reactant: NS(N)(=O)=O
Reactant: COc1ccc(C(C)C)cc1-c1ccc(C(F)(F)F)cc1CNCC(N)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: COc1ccc(C(C)C)cc1-c1ccc(C(F)(F)F)cc1CN1CC(c2cc(C(F)(F)F)cc(C(F)(F)F)c2)NS1(=O)=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 1-[3,5-bis(trifluoromethyl)phenyl]-N2-{[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}ethane-1,2-diamine (8.0 mg, 0.014 mmol) and sulfamide (2.0 mg, 0.021 mmol) in pyridine (300 μL) was heated to 120° C. in a sealed tube. After 3 hours, the reaction was cooled to room temperature and diluted with 25 mL of EtOAc. The organic solution was washed with 1 N HCl (2×5 mL) and brine (1×5 mL), dried over Na2SO4, filtered, and concentrated. Purification of the residue by PTLC with 25% EtOAc/hexanes afforded 4-[3,5-bis(trifluoromethyl)phenyl]-2-{[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}-1,2,5-thiadiazolidine 1,1-dioxide. Rf=0.29 (25% EtOAc/hexanes). LCMS=641.1 (M+1)+. 1H NMR (CDCl3, 500 MHz; atropisomers present) δ 7.58-7.85 (m, 5H), 7.35-6.86 (m, 4H), 4.82-4.94 (m, 2H), 3.54-4.42 (m, 6H), 2.71-2.91 (m, 2H), 1.11-1.26 (m, 6H).
Reaction SMILES: [NH2:1][C:2]1[C:44]([NH2:45])=[CH:43][CH:42]=[CH:41][C:3]=1[C:4]([NH:6][C:7]1[CH:38]=[CH:37][C:10]([C:11]([N:13]([CH3:36])[C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][C:15]=2[O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]([N:29]2[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]2)=[O:28])=[O:12])=[CH:9][C:8]=1[O:39][CH3:40])=[O:5].[C:46](N1C=CN=C1)(N1C=CN=C1)=[S:47]>O1CCCC1>[SH:47][C:46]1[NH:45][C:44]2[CH:43]=[CH:42][CH:41]=[C:3]([C:4]([NH:6][C:7]3[CH:38]=[CH:37][C:10]([C:11]([N:13]([CH3:36])[C:14]4[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][C:15]=4[O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]([N:29]4[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]4)=[O:28])=[O:12])=[CH:9][C:8]=3[O:39][CH3:40])=[O:5])[C:2]=2[N:1]=1
Reactant: S=C(n1ccnc1)n1ccnc1
Reactant: COc1cc(C(=O)N(C)c2ccc(C)cc2OCCCCCC(=O)N2CCN(C)CC2)ccc1NC(=O)c1cccc(N)c1N
Solvent: C1CCOC1
Product: COc1cc(C(=O)N(C)c2ccc(C)cc2OCCCCCC(=O)N2CCN(C)CC2)ccc1NC(=O)c1cccc2[nH]c(S)nc12
Reaction time: 24 h
Yield: 81.7 %

Procedure:
To a solution of 4-(2,3-diaminobenzoyl)amino-3-methoxy-N-methyl-N-[4-methyl-2-[5-(4-methylpiperazin-1-yl)carbonylpent-1-yloxy]phenyl]benzamide (110 mg) in anhydrous tetrahydrofuran (2 ml) was added 1,1′-thiocarbonyldiimidazole (48 mg) under nitrogen at ambient temperature and stirred at same temperature for 1 day. After being concentrated in vacuo, the residue was diluted with a mixture of chloroform and saturated sodium bicarbonate aqueous solution and the organic layer was separated. The organic layer was washed with water and brine and the solution was dried over magnesium sulfate. The solvent was evaporated in vacuo and the residue was purified by preparative thin-layer chromatography (ethyl acetate-methanol=1:1) to give 4-(2-mercapto-1H-benzimidazol-4-yl)carbonylamino-3-methoxy-N-methyl-N-[4-methyl-2-[5-(4-methylpiperazin-1-yl)carbonylpent-1-yloxy]phenyl]benzamide (96 mg) as a powder.
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:5]([N+:17]([O-])=O)=[CH:4][CH:3]=1.[NH4+].[Cl-]>CO.O.[Fe]>[NH2:17][C:5]1[C:6]([NH:10][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)=[C:7]([C:2]([F:1])=[CH:3][CH:4]=1)[C:8]#[N:9]
Reactant: N#Cc1c(F)ccc([N+](=O)[O-])c1Nc1ccccc1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CO
Product: N#Cc1c(F)ccc(N)c1Nc1ccccc1
Temperature: 90 °C
Yield: 39 %

Procedure:
To a mixture of 6-fluoro-3-nitro-2-phenylaminobenzonitrile (2.7 g, 10.5 mmol) in a mixture of MeOH (50 mL) and water (20 mL) were added NH4Cl (3.23 g, 62.9 mmol) and iron powder (2.3 g, 41.9 mmol) and the reaction mixture was heated at 90° C. for 1 h. After cooling to RT, the solid was filtered through a pad of Celite® and the filtrate concentrated in vacuo. The resulting residue was partitioned between EtOAc and water and the aqueous phase was extracted with EtOAc (×3). The combined organic fractions were washed with brine, dried (MgSO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, gradient 0-100% EtOAc in cyclohexane) to afford the title compound (930 mg, 39%). LCMS (Method B): RT 3.27 min [M+H]+ 227.8.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[CH:7][C:6]=2[CH:5]=[C:4]([C:16]#[N:17])[CH:3]=1.[C:18]([C:22]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][CH:23]=1)([CH3:21])([CH3:20])[CH3:19]>>[C:18]([C:22]1[CH:27]=[CH:26][C:25]([C:2]2[C:10]3[N:9]4[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]4=[CH:7][C:6]=3[CH:5]=[C:4]([C:16]#[N:17])[CH:3]=2)=[CH:24][CH:23]=1)([CH3:21])([CH3:20])[CH3:19]
Reactant: N#Cc1cc(Br)c2c(c1)cc1n2CCNC1=O
Reactant: CC(C)(C)c1ccc(B(O)O)cc1
Product: CC(C)(C)c1ccc(-c2cc(C#N)cc3cc4n(c23)CCNC4=O)cc1

Procedure:
The title compound, off-white solid (76 mg, 89%), MS (ISN) m/z=344.5 [(M+H)+], mp 300° C., was prepared in accordance with the general method of example 1 from 6-bromo-1-oxo-1,2,3,4-tetrahydro-pyrazino[1,2-a]indole-8-carbonitrile (intermediate 15) (72.5 mg, 0.25 mmol) and commercially available 4-tert-butyl-phenylboronic acid (57.9 mg, 0.325 mmol).
Reaction SMILES: C(OC([N:6]1[CH:11]2[CH2:12][CH2:13][CH:7]1[CH2:8][C:9](=[C:14]1[C:27]3[CH:26]=[CH:25][C:24]([C:28](=[O:34])[N:29]([CH2:32][CH3:33])[CH2:30][CH3:31])=[CH:23][C:22]=3[O:21][C:20]3[C:15]1=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH2:10]2)=O)C.Br>C(O)(=O)C>[CH2:32]([N:29]([CH2:30][CH3:31])[C:28]([C:24]1[CH:25]=[CH:26][C:27]2[C:14](=[C:9]3[CH2:10][CH:11]4[NH:6][CH:7]([CH2:13][CH2:12]4)[CH2:8]3)[C:15]3[C:20]([O:21][C:22]=2[CH:23]=1)=[CH:19][CH:18]=[CH:17][CH:16]=3)=[O:34])[CH3:33]
Reactant: CCOC(=O)N1C2CCC1CC(=C1c3ccccc3Oc3cc(C(=O)N(CC)CC)ccc31)C2
Agent: Br
Solvent: CC(=O)O
Product: CCN(CC)C(=O)c1ccc2c(c1)Oc1ccccc1C2=C1CC2CCC(C1)N2
Yield: 56.6 %

Procedure:
A sample of compound 8a (16.0 g, 34.8 mmol) was dissolved in 35 mL acetic acid and 100 mL of 30% HBr in acetic acid was added to the reaction under Argon before heating on a steam bath for 1 h. The reaction was cooled, added to ice cold NaOH and extracted with CH2Cl2. The combined organics were washed with brine and dried over potassium carbonate. Evaporation of the solvent provided 12 g of crude Compound 10a, which was purified by column chromatography with 7% 2 N NH3 in methanol/93% CH2Cl2. to give 7.66 g (19.7 mmol) of Compound 10a. MS m/z=389.3 (M+1); 1H NMR 300 MHz (CDCl3) δ 1.1-1.4 (m, 6H), 1.7 (m, 2H), 2.7-3.0 (m, 4H), 3.4 (br s, 4H), 3.5-3.7 (m, 4H), 7.0-7.3 (m, 7H).
Reaction SMILES: B.O1CCCC1.[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14]2[CH2:19][N:18]([CH2:20][CH2:21][CH3:22])[C:17](=O)[CH2:16][O:15]2)=[CH:10][C:9]=1[O:24][CH3:25]>C1COCC1>[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14]2[CH2:19][N:18]([CH2:20][CH2:21][CH3:22])[CH2:17][CH2:16][O:15]2)=[CH:10][C:9]=1[O:24][CH3:25]
Reactant: CCCN1CC(c2ccc(Cl)c(OC)c2)OCC1=O
Agent: B
Solvent: C1CCOC1
Product: CCCN1CCOC(c2ccc(Cl)c(OC)c2)C1
Yield: 99.1 %

Procedure:
Borane-tetrahydrofuran complex (1M in THF) (3.5 mL, 3.5 mmol) was added dropwise to a solution of the product from example 52 (0.33 g 1.16 mmol) in dry THF (3 mL) under an atmosphere of nitrogen. The reaction mixture was refluxed for 2.5 hours then cooled and quenched by addition of methanol (1 mL). The reaction mixture was concentrated in vacuo and the residue suspended in 4N HCl (aq., 8 mL) and refluxed for 2 hours. The reaction mixture was cooled and extracted with dichloromethane (2×10 mL). The organic layers were discarded. The aqueous layer was rendered basic (pH 9-10) by addition of solid potassium carbonate before re-extracting with dichloromethane (2×15 mL). The dichloromethane extracts were washed with water (10 mL), dried over anhydrous magnesium sulphate, filtered and concentrated in vacuo to give the title compound as an oil (0.31 g: 1.15 mmol, 99%). 1H NMR (CDCl3, 400 MHz) δ: 0.95 (t, 3H), 1.45-1.60 (m, 2H), 2.00 (t, 1H), 2.20 (t, 1H), 2.35 (t, 2H), 2.80 (d, 1H), 2.90 (d, 1H), 3.80 (t, 1H), 3.90 (s, 3H), 4.03 (dd 1H), 4.55 (d 1H), 6.85 (dd 1H), 7.00 (s, 1H), 7.30 (dd, 1H). LRMS (APCI): m/z 270 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:15]=[CH:14][C:5]([C:6]([CH:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[O:7])=[CH:4][CH:3]=1.Br[CH2:17][CH2:18][NH:19][C:20](=[O:31])[C:21]1[CH:26]=[C:25]([C:27]#[N:28])[CH:24]=[CH:23][C:22]=1[O:29][CH3:30].C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1>[C:27]([C:25]1[CH:24]=[CH:23][C:22]([O:29][CH3:30])=[C:21]([CH:26]=1)[C:20]([NH:19][CH2:18][CH2:17][N:11]1[CH2:12][CH2:13][CH:8]([C:6](=[O:7])[C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:15][CH:14]=2)[CH2:9][CH2:10]1)=[O:31])#[N:28]
Reactant: COc1ccc(C#N)cc1C(=O)NCCBr
Reactant: O=C(c1ccc(F)cc1)C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: COc1ccc(C#N)cc1C(=O)NCCN1CCC(C(=O)c2ccc(F)cc2)CC1
Temperature: 25 °C
Reaction time: 60 h

Procedure:
41.4 g (0.2 mol) of 4-(p-fluorobenzoyl)-piperidine are dissolved in 120 ml of dioxan, and 28.3 g (0.1 mol) of N-(2-bromoethyl)-5-cyano-2-methoxybenzamide are added and the whole is then stirred at room temperature for 60 hours. A solution of potassium carbonate is then added to the reaction mixture and the whole is then extracted with methylene chloride. The methylene chloride solution is washed neutral with water and concentrated in a water-jet vacuum. A light yellow crystalline product remains behind which is suspended in 200 ml of ethanol and stirred for 2 hours. The solid product is then filtered with suction and subsequently washed with 20 ml of ice-cold ethanol. 5-Cyano-N-[2-[4-(p-fluorobenzoyl)-piperidinyl]-ethyl]-2-methoxybenzamide is obtained in the filtration residue in the form of white powder of melting point 167°-169°.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:4]=[CH:5][C:6]([N+:10]([O-])=O)=[C:7]([CH:9]=1)[NH2:8]>C(O)(=O)C.[Zn]>[CH3:1][S:2][C:3]1[CH:4]=[CH:5][C:6]([NH2:10])=[C:7]([NH2:8])[CH:9]=1
Reactant: CSc1ccc([N+](=O)[O-])c(N)c1
Agent: [Zn]
Solvent: CC(=O)O
Product: CSc1ccc(N)c(N)c1
Temperature: 85 °C
Yield: 100.9 %

Procedure:
A solution of 5-methylthio-2-nitroaniline (50 mg; 0.27 mmol) in acetic acid (2 ml) was heated to 85° C. Zinc powder (71 mg; 1.09 mmol) was then added portionwise over 15 minutes and the resulting solution was maintained at 85° C. for 2 hours. The hot reaction mixture was then filtered through celite and the filter cake washed with hot acetic acid (10 ml). The filtrate was evaporated to dryness to give crude 4-methylthio-1,2-phenylenediamine (42 mg, 100%). This was used directly in the next step without purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([N:17]3[CH:21]=[CH:20][N:19]=[C:18]3[CH3:22])[O:11][C:12]=2[CH2:13][CH2:14][CH2:15][OH:16])=[CH:4][CH:3]=1.[CH3:23][C:24]1([CH3:37])[CH2:33][CH2:32][C:31]([CH3:35])([CH3:34])[C:30]2[CH:29]=[C:28](O)[CH:27]=[CH:26][C:25]1=2.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[C:10]([N:17]3[CH:21]=[CH:20][N:19]=[C:18]3[CH3:22])[O:11][C:12]=2[CH2:13][CH2:14][CH2:15][O:16][C:28]2[CH:27]=[CH:26][C:25]3[C:24]([CH3:37])([CH3:23])[CH2:33][CH2:32][C:31]([CH3:35])([CH3:34])[C:30]=3[CH:29]=2)=[CH:6][CH:7]=1
Reactant: Cc1nccn1-c1nc(-c2ccc(Cl)cc2)c(CCCO)o1
Reactant: CC1(C)CCC(C)(C)c2cc(O)ccc21
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: Cc1nccn1-c1nc(-c2ccc(Cl)cc2)c(CCCOc2ccc3c(c2)C(C)(C)CCC3(C)C)o1
Reaction time: 1 h

Procedure:
To a mixture of 4-(4-chlorophenyl)-2-(2-methyl-1-imidazolyl)-5-oxazolepropanol (318 mg), 5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthalenol (409 mg), tributylphosphine (405 mg) and tetrahydrofuran (10 ml) was added 1,1′-(azodicarbonyl)dipiperidine (500 mg) at room temperature, and the resulting mixture was stirred for 1 hour. After the reaction mixture was concentrated, the residue was subjected to silica gel column chromatography, and 4-(4-chlorophenyl)-2-(2-methyl-1-imidazolyl)-5-[3-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthalenyloxy)propyl]oxazole was obtained as a yellow oil (400 mg, 79%) from an ethyl acetate-hexane (1:1, v/v)-eluted fraction.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.F[C:9]1[CH:30]=[CH:29][C:12]([C:13]([C:15]2[CH:20]=[CH:19][C:18]([C:21]#[C:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:17][CH:16]=2)=[O:14])=[CH:11][CH:10]=1.C1(C)C=CC=CC=1>CC(N(C)C)=O>[O:7]([C:9]1[CH:30]=[CH:29][C:12]([C:13]([C:15]2[CH:20]=[CH:19][C:18]([C:21]#[C:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:17][CH:16]=2)=[O:14])=[CH:11][CH:10]=1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Oc1ccccc1
Reactant: O=C(c1ccc(F)cc1)c1ccc(C#Cc2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: CC(=O)N(C)C
Product: O=C(c1ccc(C#Cc2ccccc2)cc1)c1ccc(Oc2ccccc2)cc1
Temperature: 23 °C
Yield: 96.3 %

Procedure:
A 100 mL flask equipped with nitrogen inlet, overhead stirring assembly, Dean-Stark trap, and reflux condenser was charged with phenol (0.35 g, 0.0038 mol), 4-fluoro-4'-phenylethynylbenzophenone (0.10 g, 0.0038 mol) potassium carbonate (0.39 g, 0.003 mol), 25 mL of toluene, and 50 mL of DMAc. The mixture was heated to reflux and water was removed by azeotropic distillation, followed by the removal of toluene over a 20 hour period. The reaction was cooled to 23° C., and the mixture was poured into 1 L of acidic (HCl) water. The precipitate was collected by filtration to afford 1.37 g (96%) of 4-phenoxy-4'-phenylethynylbenzophenone as a white powder: mp 165.5° C. IR (KBr): 2216 cm-1 (ethynyl), 1650 cm-1 (carbonyl): 1H-NMR (CDCl3): 7.8-6.8 pp, (m H aromatic). Anal Calcd. for C27H18O2 : %C=86.61, %H=4.85. Found: %C=86.46, %H=4.68. The structure of this compound is given below: ##STR10## The DSC thermogram of this compound is presented in FIG. 3.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[NH:15][CH:14]=[C:13]3[CH:19]2[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20]2)=[C:5]([N+:25]([O-])=O)[CH:4]=1)#[N:2].[CH:28](OCC)(OCC)OCC.C(O)=O.C(Cl)Cl.CO.[OH-].[NH4+]>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]2[N:9]([C:10]3[CH:11]=[C:12]4[C:16](=[CH:17][CH:18]=3)[NH:15][CH:14]=[C:13]4[CH:19]3[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20]3)[CH:28]=[N:25][C:5]=2[CH:4]=1)#[N:2]
Reactant: CN1CCC(c2c[nH]c3ccc(Nc4ccc(C#N)cc4[N+](=O)[O-])cc23)C1
Reactant: CCOC(OCC)OCC
Agent: [NH4+]
Agent: [OH-]
Solvent: CO
Solvent: ClCCl
Solvent: O=CO
Product: CN1CCC(c2c[nH]c3ccc(-n4cnc5cc(C#N)ccc54)cc23)C1
Yield: 22 %

Procedure:
5-(4-Cyano-2-nitrophenyl)amino-3-(N-methylpyrrolidin-3-yl)-1H-indole was used. Reduction was by catalytic hydrogenation, the cyclization reaction used triethyl orthoformate/formic acid, and the cyclization reaction was heated for 2 hours. Chromatography using 9:1:0.5 [methylene chloride/methanol/ammonium hydroxide] afforded the title compound (22%) as a light yellow solid: Rf =0.35 in 9:1:0.1 [methylene chloride/methanol/ammonium hydroxide]; 13C NMR (CDCl3) δ 145.7, 143.3, 137.5, 136.5, 127.5, 126.8, 126.7, 125.4, 123.0, 120.3, 119.9, 118.5, 115.8, 112.7, 111.9, 105.7, 62.8, 56.3, 42.3, 35.0, 32.3; FAB LRMS (m/z, relative intensity) 342 (MH+).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[C:5]2[S:10][C:9]([CH2:11]N3CCC(NCC4CC4)CC3)=[CH:8][C:6]=2[N:7]=1.[C:29]([O:33][C:34]([N:36]1[C:40]2([CH2:45][CH2:44][NH:43][CH2:42][CH2:41]2)[CH2:39][CH2:38][CH2:37]1)=[O:35])([CH3:32])([CH3:31])[CH3:30]>>[C:29]([O:33][C:34]([N:36]1[C:40]2([CH2:45][CH2:44][N:43]([CH2:11][C:9]3[S:10][C:5]4[C:4]([N:23]5[CH2:28][CH2:27][O:26][CH2:25][CH2:24]5)=[N:3][C:2]([Cl:1])=[N:7][C:6]=4[CH:8]=3)[CH2:42][CH2:41]2)[CH2:39][CH2:38][CH2:37]1)=[O:35])([CH3:32])([CH3:30])[CH3:31]
Reactant: CC(C)(C)OC(=O)N1CCCC12CCNCC2
Reactant: Clc1nc(N2CCOCC2)c2sc(CN3CCC(NCC4CC4)CC3)cc2n1
Product: CC(C)(C)OC(=O)N1CCCC12CCN(Cc1cc3nc(Cl)nc(N4CCOCC4)c3s1)CC2

Procedure:
Prepared according to the method used in the preparation of [1-(2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-piperidin-4-yl]-cyclopropylmethyl-amine using 1,8-diaza-spiro[4.5]decane-1-carboxylic acid tert-butyl ester in place of cyclopropanemethylamine. The title compound was obtained as a white solid (184 mg, 45%).
Reaction SMILES: [CH3:1][C:2](=[O:9])[C:3](=[N:7]O)[C:4](=O)[CH3:5].[N:10]1[CH:15]=[CH:14][C:13]([CH2:16][NH2:17])=[CH:12][CH:11]=1>CN(C)C=O>[CH3:5][C:4]1[NH:17][C:16]([C:13]2[CH:14]=[CH:15][N:10]=[CH:11][CH:12]=2)=[N:7][C:3]=1[C:2](=[O:9])[CH3:1]
Reactant: CC(=O)C(=NO)C(C)=O
Reactant: NCc1ccncc1
Solvent: CN(C)C=O
Product: CC(=O)c1nc(-c2ccncc2)[nH]c1C
Temperature: -10 °C
Reaction time: 4 h
Yield: 39.8 %

Procedure:
A mixture of 6.5 g (0.05 mole) of 2,3,4-pentanetrione 3-oxime and 6.0 g (0.055mole) of 4-pyridylmethylamine in 75 ml of N,N-dimethylformamide was stirred at the reflux temperature for 4 hours. The solvent was removed in vacuo and 100 ml of acetonitrile was added to the residual oil. The mixture was boiled then was cooled at -10° C. to yield precipitate. The precipitate was collected, washed with 50 ml of cold acetonitrile and air dried. The material was recrystallized from 150 ml of boiling acetonitrile after treatment with activated charcoal and filtration by cooling at -10° C. The product of the Example was collected by filtration, washed with 50 ml of cold acetonitrile and dried to give 4.0 g of a tan solid, mp 181°-183° C.
Reaction SMILES: [CH2:1]([C:3]1[C:4]([O:15]C)=[N:5][C:6]([CH3:14])=[C:7]([N:9]2[CH:13]=[CH:12][CH:11]=[N:10]2)[CH:8]=1)[CH3:2].[I-].[Na+].C(#N)C.Cl[Si](C)(C)C>O>[CH2:1]([C:3]1[C:4](=[O:15])[NH:5][C:6]([CH3:14])=[C:7]([N:9]2[CH:13]=[CH:12][CH:11]=[N:10]2)[CH:8]=1)[CH3:2]
Reactant: CCc1cc(-n2cccn2)c(C)nc1OC
Agent: C[Si](C)(C)Cl
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: CCc1cc(-n2cccn2)c(C)[nH]c1=O
Temperature: 65 °C
Reaction time: 13 h
Yield: 81.6 %

Procedure:
To a mixture of 3-ethyl-2-methoxy-6-methyl-5-pyrazol-1-yl-pyridine (98 mg, 0.452 mmol) and sodium iodide (203 mg, 1.35 mmol) under a N2 atmosphere is added anhydrous acetonitrile (3 mL) followed by dropwise addition of chlorotrimethylsilane (170 μL, 1.35 mmol). The reaction mixture is stirred at 65° C. under nitrogen for 13 h. The reaction mixture is allowed to cool, diluted with water and the resulting mixture is extracted with 3 portions of dichloromethane. The combined extracts are dried over magnesium sulfate and evaporated to leave an orange residue. The crude product is triturated with ether/heptane to give 3-ethyl-6-methyl-5-pyrazol-1-yl-1H-pyridin-2-one as a light orange solid (75 mg, 82% yield). This material (30 mg) is dissolved in dichloromethane (2 mL) and treated with ethereal hydrochloric acid (2.0 M, 0.444 mL). The mixture is stirred for 1.5 h, evaporated and triturated with ether to give 3-ethyl-6-methyl-5-pyrazol-1-yl-1H-pyridin-2-one hydrochloride (29 mg) as a white powder. LC/MS: RT: 2.15 min, MS: m/e=204 (M+H); 1H NMR (CDCl3, δ ppm): 7.73 (1H, d), 7.55 (1H, d), 7.47 (1H, s), 6.47 (1H, t), 2.62 (2H, q), 2.33 (3H, s), 1.22 (3H, t).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:10]=[C:11]([CH2:15][S:16]([NH2:19])(=[O:18])=[O:17])[CH:12]=[CH:13][CH:14]=2)[N:3]=1.[NH:20]1[CH2:24][CH2:23][CH2:22][CH2:21]1>>[N:20]1([C:2]2[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]3[CH:10]=[C:11]([CH2:15][S:16]([NH2:19])(=[O:18])=[O:17])[CH:12]=[CH:13][CH:14]=3)[N:3]=2)[CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: NS(=O)(=O)Cc1cccc(Nc2ncnc(Cl)n2)c1
Reactant: C1CCNC1
Product: NS(=O)(=O)Cc1cccc(Nc2ncnc(N3CCCC3)n2)c1

Procedure:
B14 was prepared following the general procedure reported for B10 using A1 and pyrrolidine. Yield: 96.6 mg (29%), colorless amorphous solid. 1H NMR (400 MHz, d6-DMSO, 300K) δ 1.84-1.96 (m, 4H), 3.43-3.55 (m, 4H), 4.18 (s, 2H), 6.81 (s, 2H), 6.96 (d, J=7.6 Hz, 1H), 7.25 (t, J=7.9 Hz, 1H), 7.69 (d, J=9.5 Hz, 1H), 7.86 (s, 1H), 8.18 (s, 1H), 9.59 (s, 1H). MS (ES) C14H18N6O2S requires: 334. found: 335 (M+H)+.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH2:11][CH2:12][CH2:13][NH:14][CH2:15][C:16]1[CH:17]=[C:18]([CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][N:23]2[CH:28]=O)[CH:19]=[CH:20][CH:21]=1)([CH3:3])[CH3:2].C([O:33]C1C=CC=CC=1NCCN)(C)C>>[CH:1]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH2:11][CH2:12][CH2:13][NH:14][CH2:15][C:16]1[CH:17]=[C:18]([C:22]([N:23]2[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]2)=[O:33])[CH:19]=[CH:20][CH:21]=1)([CH3:2])[CH3:3]
Reactant: CC(C)Oc1ccccc1NCCN
Reactant: CC(C)Oc1ccccc1CCCNCc1cccc(C2CCCCN2C=O)c1
Product: CC(C)Oc1ccccc1CCCNCc1cccc(C(=O)N2CCCCC2)c1

Procedure:
(3-{[3-(2-Isopropoxy-phenyl)-propylamino]-methyl}-phenyl)-piperidin methanone. The title compound was prepared as in Example 1, steps D and E, substituting 3-(2-isopropoxy-phenyl)-propylamine for N1-(2-isopropoxy-phenyl) -ethane-1,2-diamine in step E. MS (ESI): mass calculated for C25H34N2O2, 394.26; m/z found, 395.3 [M+H]+, 417.3 [M+Na]+. 1H NMR (400 MHz, CDCl3): 7.38-7.32 (m, 3H), 7.27-7.24 (m, 1H), 7.15-7.10 (m, 2H), 6.86-6.82 (m, 2H), 4.53 (hept, J=6.1 Hz, 1H), 3.81 (s, 2H), 3.70 (br s, 2H), 3.32 (br s, 2H), 2.68-2.62 (m, 4H), 1.85-1.77 (m, 2H), 1.67 (br s, 4H), 1.50 (br s, 2H), 1.32 (d, J=6.1 Hz, 6H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][C:18]=1[Cl:19])[C:5]([NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[O:14][CH3:15])=[O:6].[H-].[Na+].I[CH3:23]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][C:18]=1[Cl:19])[C:5]([N:7]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[O:14][CH3:15])[CH3:23])=[O:6]
Reactant: CI
Reactant: COc1ccccc1NC(=O)c1ccc(Cl)c(Br)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccccc1N(C)C(=O)c1ccc(Cl)c(Br)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 78.8 %

Procedure:
To 3-bromo-4-chloro-N-(2-methoxy-phenyl)-benzamide (13.5 g, 39 mmol) in DMF (100 mL) at 0-5° C., was added NaH (1.9 g, 46.8 mmol, 60% in mineral oil) in several portions, followed by addition of iodomethane (3.15 mL, 50.7 mmol). The mixture was stirred at room temperature for 4 hrs and was partitioned between ethyl acetate and water. The organic layer was then washed with 1N HCl, saturated NaHCO3, brine and dried over MgSO4. Filtration over a silica gel pad followed by concentration and crystallization from ether/hexane yielded 3-bromo-4-chloro-N-(2-methoxy-phenyl)-N-methyl-benzamide (10.9 g) as a white solid. MS (M+H)+: 353.9, tR=2.812 min (method 1); NMR (CDCl3), δ, 7.62 (1H, d, J=1.5 Hz), 7.23-7.09 (3H, m), 7.06-7.00 (1H, m), 6.88-6.78 (2H, m), 3.75 (3H, s), 3.34 (3H, s)
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](OS(C2C(C)=CC(C)=CC=2C)(=O)=O)[C:5]([CH2:21][C:22]2[CH:37]=[CH:36][C:25]([CH2:26][N:27]([CH2:34][CH3:35])[CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:24][C:23]=2[O:38][CH3:39])=[C:4]([CH3:40])[N:3]=1.[CH2:41]([NH2:45])[CH2:42][CH2:43][CH3:44]>>[NH2:1][C:2]1[N:7]=[C:6]([NH:45][CH2:41][CH2:42][CH2:43][CH3:44])[C:5]([CH2:21][C:22]2[CH:37]=[CH:36][C:25]([CH2:26][N:27]([CH2:34][CH3:35])[CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:24][C:23]=2[O:38][CH3:39])=[C:4]([CH3:40])[N:3]=1
Reactant: CCCCN
Reactant: CCOC(=O)CN(CC)Cc1ccc(Cc2c(C)nc(N)nc2OS(=O)(=O)c2c(C)cc(C)cc2C)c(OC)c1
Product: CCCCNc1nc(N)nc(C)c1Cc1ccc(CN(CC)CC(=O)OCC)cc1OC
Yield: 66 %

Procedure:
The sub-title compound was synthesized by the method of example 1 step (viii) from the product of example 1 step (vii) (150 mg) and 1-butylamine (56 mg). The sub-title compound (77 mg) was obtained as a yellow oil; 1H NMR (CDCl3); 6.94 (1H, s), 6.86 (1H, d), 6.77 (1H, d), 4.84 (1H, t), 4.55 (2H, br s), 4.13 (2H, q), 3.88 (3H, s), 3.70 (2H, s), 3.64 (2H, s), 3.30-3.23 (4H, m), 2.66 (2H, q), 2.30 (3H, s), 1.43-1.34 (2H, m), 1.24 (3H, t), 1.19-1.12 (2H, m), 1.06 (3H, t), 0.83 (3H, t).