Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:15]([BH3-])#[N:16].[Na+]>CO.Cl>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([NH:8][CH2:1][CH2:2][NH:16][C:15]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CCN(Cc2ccccc2)CC1
Reactant: [BH3-]C#N
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: c1ccc(CN2CCC(NCCNc3ccccc3)CC2)cc1
Temperature: 25 °C

Procedure:
To the solution of 12.6 g of N-phenylethyleneidamine in 200 ml of methanol, 50 ml of 4.1 N ethanolic hydrogen chloride are added dropwise followed by 18.9 g of 1-benzyl-4-piperidone in 100 ml of methanol. Then, 9.45 g sodium cyanoborohydride are added in portions while stirring at room temperature. After 72 hours the mixture is filtered, the residue dissolved in water and the solution made basic with 12.5% aqueous sodium hydroxide. It is extracted with methylene chloride, dried and evaporated to yield the 1-benzyl-4-(2-phenylaminoethylamino)-piperidine.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[C:16](=[O:32])[NH:17][C:18]1[S:19][CH:20]=[C:21]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2C(O)=O)[N:22]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN([C:36]([O:40]N1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[C:66]([O:70][C:71]([N:73]1[CH2:76][CH:75]([NH2:77])[CH2:74]1)=[O:72])([CH3:69])([CH3:68])[CH3:67]>CN(C=O)C>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[C:16](=[O:32])[NH:17][C:18]1[S:19][CH:20]=[C:21]([C:23]2[CH:24]=[CH:25][C:26]([C:36](=[O:40])[NH:77][CH:75]3[CH2:76][N:73]([C:71]([O:70][C:66]([CH3:69])([CH3:67])[CH3:68])=[O:72])[CH2:74]3)=[CH:27][CH:28]=2)[N:22]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccccc1-c1csc(NC(=O)C2CCCN2C(=O)OCc2ccccc2)n1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: CC(C)(C)OC(=O)N1CC(N)C1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CC(NC(=O)c2ccc(-c3csc(NC(=O)C4CCCN4C(=O)OCc4ccccc4)n3)cc2)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2-[4-(2-Carboxy-phenyl)-thiazol-2-ylcarbamoyl]-pyrrolidine-1-carboxylic acid benzyl ester (IS2277-52, 125 mg, 0.28 mmol) was dissolved in 4 mL of DMF. To this solution was added HATU (160.9 mg, 0.42 mmol) and DIEA (0.05 mL, 0.36 mmol). This solution was stirred at room temperature for 1 hour. To this solution was added 48.2 mg (0.28 mmol) of 3-amino-azetidine-1-carboxylic acid tert-butyl ester. Reaction mixture was stirred at room temperature overnight to yield crude 2-{4-[4-(1-tert-butoxycarbonyl-azetidin-3-ylcarbamoyl)-phenyl]-thiazol-2-ylcarbamoyl}-pyrrolodine-1-carboxylic acid benzyl ester, which was then purified using reverse phase HPLC. The purified material was dissolved in 4 mL of 1:1 solution of CH2Cl2/TFA and stirred for 1.5 hours at room temperature. Reaction mixture was evaporated under reduced pressure to give pure desired product. MS: 506.1 (M+H+); H1 NMR (DMSO-d6): δ(ppm) 12.50 (br s, 1H), 8.47 (br s, 1H), 7.91 (m, 5H), 7.10 (m, 4H), 5.31 (br s, 1H), 5.02 (m, 2H), 4.51 (m, 1H), 4.08 (m, 3H), 2.47 (m, 3H), 2.23 (m, 1H), 1.90 (m, 4H), 1.94 (m, 2H).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][CH2:9][N:10]2[C:19]3[C:14](=[CH:15][C:16]([N+:20]([O-:22])=[O:21])=[CH:17][CH:18]=3)[CH2:13][CH2:12][C:11]2=O)[CH2:3][CH2:2]1.C1COCC1>>[N+:20]([C:16]1[CH:15]=[C:14]2[C:19](=[CH:18][CH:17]=1)[N:10]([CH2:9][CH2:8][CH2:7][N:4]1[CH2:3][CH2:2][O:1][CH2:6][CH2:5]1)[CH2:11][CH2:12][CH2:13]2)([O-:22])=[O:21]
Reactant: O=C1CCc2cc([N+](=O)[O-])ccc2N1CCCN1CCOCC1
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc2c(c1)CCCN2CCCN1CCOCC1
Temperature: 0 °C
Yield: 49.4 %

Procedure:
1-(3-Morpholinopropyl)-6-nitro-3,4-dihydroquinolin-2(1H)-one (550 mg, 1.722 mmol) was stirred in borane tetrahydrofuran complex, 1M in THF (17.200 mL, 17.20 mmol) overnight at reflux temperature. The reaction mixture was then cooled to 0° C. and quenched via addition of methanol (10 mL). The solution was then concentrated, and the residue was redissolved in a small amount of methanol and stirred at reflux with 2N HCl for 2 h. The mixture was then neutralized and basified with 3N NaOH and extracted with dichloromethane (3×). The combined organics were dried, filtered and concentrated, then chromatographed in ethyl acetate, followed by 5-10% (2M NH3 in methanol) in dichloromethane, giving the desired 4-(3-(6-nitro-3,4-dihydroquinolin-1(2H)-yl)propyl)morpholine (260 mg, 0.851 mmol, 49.4% yield). 1H NMR (DMSO-d6) δ 7.87 (dd, J=9.3, 2.7 Hz, 1H), 7.77 (d, J=2.7 Hz, 1H), 6.72 (d, J=9.3 Hz, 1H), 3.60-3.56 (m, 4H), 3.45-3.39 (m, 4H), 2.74 (t, J=6 Hz, 2H), 2.35-2.26 (m, 6H), 1.88-1.80 (m, 2H), 1.76-1.66 (m, 2H).
Reaction SMILES: BrC1C=CC(OC)=C(C)C=1.Br[C:12]1[C:17]([F:18])=[CH:16][C:15]([O:19][CH3:20])=[C:14]([F:21])[CH:13]=1.C(N1CCNCC1)CC1C=CC=CC=1.[CH2:36]([CH:43]1[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]1)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>>[CH2:36]([CH:43]1[CH2:48][CH2:47][N:46]([C:12]2[CH:13]=[C:14]([F:21])[C:15]([O:19][CH3:20])=[CH:16][C:17]=2[F:18])[CH2:45][CH2:44]1)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: COc1cc(F)c(Br)cc1F
Reactant: c1ccc(CC2CCNCC2)cc1
Agent: COc1ccc(Br)cc1C
Agent: c1ccc(CCN2CCNCC2)cc1
Product: COc1cc(F)c(N2CCC(Cc3ccccc3)CC2)cc1F

Procedure:
Production Example 9 was repeated except that 5-bromo-2-methoxytoluene was replaced with 4-bromo-2,5-difluoroanisole (446 mg), and 1-phenethylpiperazine was replaced with 4-benzylpiperidine (2.30 mL). The resulting crude product was purified on silica gel column chromatography (eluent, hexane: ethyl acetate=4:1) to provide 4-benzyl-1-(2,5-difluoro-4-methoxyphenyl)piperidine (304 mg).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:11]=[CH:12][C:13]=1[O:14][CH3:15])[CH2:5][N:6]1[CH:10]=[CH:9][N:8]=[CH:7]1.[N:16]1[O:20][N:19]=[C:18]2[CH:21]=[C:22](B(O)O)[CH:23]=[CH:24][C:17]=12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[N:6]1([CH2:5][C:4]2[CH:11]=[CH:12][C:13]([O:14][CH3:15])=[C:2]([C:22]3[CH:23]=[CH:24][C:17]4[C:18]([CH:21]=3)=[N:19][O:20][N:16]=4)[CH:3]=2)[CH:10]=[CH:9][N:8]=[CH:7]1
Reactant: OB(O)c1ccc2nonc2c1
Reactant: COc1ccc(Cn2ccnc2)cc1Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: COc1ccc(Cn2ccnc2)cc1-c1ccc2nonc2c1
Temperature: 85 °C
Reaction time: 8 h
Yield: 3.4 %

Procedure:
A suspension of 1-(3-bromo-4-methoxy-benzyl)-1H-imidazole (I-167, 267 mg, 1.00 mmol), benzo[1,2,5]oxadiazole-5-boronic acid (I-105, 164 mg, 1.00 mmol), palladium(0)bis(dibenzylideneacetone) (28.7 mg, 0.050 mmol), and triphenylphosphine (26.2 mg, 0.10 mmol) in dimethylformamide (20 mL) and 1 M aqueous cesium carbonate (3.0 mL, 3.0 mmol) was heated to 85° C. with stirring overnight. The solvent was removed under vacuum and the residue suspended in ethyl acetate (25 mL). The organic suspension was washed with water (3×20 mL) and brine, dried over sodium sulfate, decolorized over activated carbon, filtered, and concentrated under. The residue was purified by silica gel preparatory thin layer chromatography (ethyl acetate:dichloromethane 3:1) to give 10.4 mg of P-006 in 9.1% yield. 1H NMR (400 MHz, CDCl3) 3.86 (s, 3H) 5.13 (s, 2H) 6.93 (s, 1H) 7.01 (d, J=8.32 Hz, 1H) 7.10 (s, 1H) 7.17-7.25 (m, 2H) 7.52-7.62 (m, 2H) 7.78-7.85 (m, 2H) ppm. LCMS=100% purity. APCI (+)=307.1 (M+1).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH:3]([CH2:6][C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:16]#[N:17])[CH:14]=3)[NH:9][CH:8]=2)[CH2:2]1.[Cl:18][CH2:19][CH2:20][N:21]1[C:30](=[O:31])[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[NH:23][C:22]1=[O:32].C(=O)([O-])O.[Na+].Cl>CN(C)C=O.C(O)C>[ClH:18].[O:32]=[C:22]1[N:21]([CH2:20][CH2:19][N:1]2[CH2:5][CH2:4][CH:3]([CH2:6][C:7]3[C:15]4[C:10](=[CH:11][CH:12]=[C:13]([C:16]#[N:17])[CH:14]=4)[NH:9][CH:8]=3)[CH2:2]2)[C:30](=[O:31])[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[NH:23]1
Reactant: N#Cc1ccc2[nH]cc(CC3CCNC3)c2c1
Reactant: O=c1[nH]c2ccccc2c(=O)n1CCCl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: CN(C)C=O
Product: N#Cc1ccc2[nH]cc(CC3CCN(CCn4c(=O)[nH]c5ccccc5c4=O)C3)c2c1
Reaction time: 6 h

Procedure:
Under an inert atmosphere and at ambient temperature, 47.3 mmol (10 g) of 3-[3-pyrrolidinylmethyl]-1H-indole-5-carbonitrile, 47.3 mmol (9.97 g) of 3-(2-chloroethyl)-2,4-(1H,3H)-quinazolinedione and 47.3 mmol (3.73 g) of sodium hydrogen carbonate are dissolved in 100 ml of dimethylformamide, and stirring is carried out at 100° C. for 6 hours. The reaction mixture is concentrated and the residue is taken up in dichloromethane. The organic phase is washed with water and then with saturated sodium chloride solution, and is dried over magnesium sulphate. Purification is carried out by chromatography on silica using a mixture of dichloromethane/methanol/ammonia 95/5/0.5 as eluant. The compound obtained is converted into the salt by one equivalent of hydrochloric acid in ethanol.
Reaction SMILES: [C:1]1([N:7]=[C:8]=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[F:11][C:12]1[CH:17]=[CH:16][C:15]([C:18](=[O:22])[CH2:19][NH:20][CH3:21])=[CH:14][CH:13]=1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[F:11][C:12]1[CH:13]=[CH:14][C:15]([C:18](=[O:22])[CH2:19][N:20]([CH3:21])[C:8]([NH:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[O:9])=[CH:16][CH:17]=1
Reactant: O=C=Nc1ccccc1
Reactant: CNCC(=O)c1ccc(F)cc1
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CN(CC(=O)c1ccc(F)cc1)C(=O)Nc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1.26 g (12.5 mmol) of phenyl isocyanate are used to a suspension of 3 g (12.5 mmol) of the compound from Example 2 in 30 ml of toluene and 1.5 g (12.5 mmol) of triethylamine are slowly added dropwise at 0° C. The mixture is stirred overnight at 25° C. The toluene phase is washed with water, the product precipitating out. After drying 3.54 g are obtained.
Reaction SMILES: [S:1]1[C:10]2[C:9]3[CH:11]=[C:12]([C:15]#[N:16])[CH:13]=[CH:14][C:8]=3[O:7][CH2:6][CH2:5][C:4]=2[CH:3]=[CH:2]1.[Br:17]N1C(=O)CCC1=O.O>ClCCl.C(O)(=O)C>[Br:17][C:2]1[S:1][C:10]2[C:9]3[CH:11]=[C:12]([C:15]#[N:16])[CH:13]=[CH:14][C:8]=3[O:7][CH2:6][CH2:5][C:4]=2[CH:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: N#Cc1ccc2c(c1)-c1sccc1CCO2
Solvent: O
Solvent: ClCCl
Solvent: CC(=O)O
Product: N#Cc1ccc2c(c1)-c1sc(Br)cc1CCO2
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 4,5-dihydro-6-oxa-1-thia-benzo[e]azulene-9-carbonitrile (4.58 g) in dichloromethane (30 mL) and acetic acid (30 mL) was added N-bromosuccinimide (3.95 g) and the reaction stirred at room temperature for 16 h. Water (100 mL) was then added and the solid collected by filtration and air-dried to give 2-bromo-4,5-dihydro-6-oxa-1-thia-benzo[e]azulene-9-carbonitrile.
Reaction SMILES: [Br-].[C:2]([C:6]1[CH:31]=[CH:30][C:29]([C:32]([O:34]C)=[O:33])=[CH:28][C:7]=1[CH2:8][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:4]C)=[O:3].[CH3:36][O:37][C:38]1[CH:39]=[C:40]([CH:43]=[CH:44][CH:45]=1)[CH:41]=O.C(#N)C.C1(C2CCCCCCCC=2)CCCCCCNN=1>O>[CH3:36][O:37][C:38]1[CH:39]=[C:40]([CH:43]=[CH:44][CH:45]=1)/[CH:41]=[CH:8]/[C:7]1[C:6]([C:2]([OH:4])=[O:3])=[CH:31][CH:30]=[C:29]([C:32]([OH:34])=[O:33])[CH:28]=1
Reactant: COC(=O)c1ccc(C(=O)OC)c(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)c1
Reactant: COc1cccc(C=O)c1
Agent: C1=C(C2=NNCCCCCC2)CCCCCCC1
Agent: [Br-]
Solvent: CC#N
Solvent: O
Product: COc1cccc(/C=C/c2cc(C(=O)O)ccc2C(=O)O)c1

Procedure:
20 G. of 2,5-bis(carbomethoxy)benzyltriphenylphosphonium bromide and 7.65 g. of m-methoxybenzaldehyde were added to 100 ml of acetonitrile and 22 ml of diazabicyclononene was added. After 16 hours the mixture was added to water and extracted with ethyl acetate. The extract was washed, dried and evaporated. The residue was refluxed for 1 hour in 250 ml of methanol and 250 ml of water containing 10 g. of potassium hydroxide. The solution was cooled and extracted with chloroform. The aqueous layer was acidified with dilute hydrochloric acid and extracted with ethyl acetate. The extract was washed, dried and evaporated to afford cis and trans 3'-methoxystilbene-2,5-dicarboxylic acid. 7.8 G. of this compound was hydrogenated for 11/2 hours in 800 ml of ethanol containing 1.5 g. of 5% palladium on carbon catalyst. The solution was filtered and evaporated to give 2-(m-methoxyphenethyl)-benzene-1,4-dicarboxylic acid which was cyclized according to the procedure set forth in Example I, A to afford 2-carboxy-8-methoxy-10,11-dihydro-5-oxo-5H-dibenzo[a,d]cycloheptene having a m.p. of 220°-222° C. Similarly, other 8-substituted compounds of this invention may be obtained by reacting 2,5-bis(carbomethoxy) benzyltriphenylphosphonium bromide with a m-substituted benzaldehyde having a halogen such as fluoro, chloro or bromo, a lower alkyl of 1-4 carbons, or a lower alkoxy such as ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, n-pentyloxy, n-hexyloxy and the like. By reacting an o-substituted benzaldehyde or a p-substituted benzaldehyde with 2,5-bis(carbomethoxy) benzyltriphenylphosphonium bromide a 2-carboxy-9-substituted-10,11-dihydro-5-oxo-5H-dibenzo[a,d]cycloheptene or a 2-carboxy-7-substituted 10,11-dihydro-5-oxo-5 H-dibenzo[a,d]cycloheptene is obtained, respectively. For example 2-carboxy-7-methyl-10,11-dihydro-5-oxo-5H-dibenzo[a,d]cycloheptene having a m.p of 235° C. was obtained from p-methylbenzaldehyde; 2-carboxy-8-methyl-10,11-dihydro-5-oxo-5H-dibenzo[a,d]cycloheptene having a m.p. of 196°-197° C. was obtained from m-methylbenzaldehyde; and 2-carboxy-9-methyl-10,11-dihydro-5-oxo-5H-dibenzo[a,d]cycloheptene having a m.p. of 232°-234° C. was obtained from o-methylbenzaldehyde.
Reaction SMILES: [Li].BrC1C=CC=CC=1.[NH2:9][C:10]1[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=1[C:12]#[N:13].[CH3:18][N:19]([CH3:22])[C:20]#[N:21]>O.C(OCC)C>[NH2:13][C:12]1[C:11]2[C:10](=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:9]=[C:20]([N:19]([CH3:22])[CH3:18])[N:21]=1
Reactant: CN(C)C#N
Reactant: N#Cc1ccccc1N
Agent: [Li]
Solvent: Brc1ccccc1
Solvent: O
Solvent: CCOCC
Product: CN(C)c1nc(N)c2ccccc2n1
Reaction time: 0.17 h

Procedure:
Under a nitrogen atmosphere 0.7 g. (0.10 g. at.) of lithium and 7.85 g. (0.05 mol) of bromobenzene are dissolved in 60 ml. of anhydrous diethyl ether. Over the course of about 20 minutes this solution is added to a solution of 5.9 g. of o-aminobenzonitrile in 60 ml. of anhydrous diethyl ether. After 10 minutes, 3.5 g. of dimethylcyanamide, dissolved in 20 ml. of anhydrous diethyl ether, are added and the reaction mixture is refluxed under the nitrogen atmosphere for 6 hours. The next day the mixture is decomposed by addition of water and the precipitate is filtered off. The product is crystallized from a mixture of ethanol and petroleum ether (boiling range 28°-40°C.). 6 g. of 4-amino-2-dimethylaminoquinazoline, m.p. 141°-142°C., are obtained.
Reaction SMILES: [OH-].[Li+].[Cl:3][C:4]1[C:9](=[O:10])[N:8]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[CH:7]=[C:6]([C:20]([O:22]C)=[O:21])[C:5]=1[C:24]([O:26][CH3:27])=[O:25].O.Cl>CO>[CH3:19][O:18][C:15]1[CH:14]=[CH:13][C:12]([CH2:11][N:8]2[CH:7]=[C:6]([C:20]([OH:22])=[O:21])[C:5]([C:24]([O:26][CH3:27])=[O:25])=[C:4]([Cl:3])[C:9]2=[O:10])=[CH:17][CH:16]=1
Reactant: COC(=O)c1cn(Cc2ccc(OC)cc2)c(=O)c(Cl)c1C(=O)OC
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COC(=O)c1c(C(=O)O)cn(Cc2ccc(OC)cc2)c(=O)c1Cl
Reaction time: 12 h
Yield: 95.9 %

Procedure:
Lithium hydroxide (1.884 g, 44.8 mmol) was added to a solution of compound (9) (8.2 g, 22.42 mmol) in MeOH (150 ml)/water (100 ml). The reaction was stirred for about 12 h at r. t. and the reaction solution was adjusted to pH=2 with diluted aqueous HCl. The solid was filtered and washed with cold ether to give the title compound (8.4 g, 21.49 mmol, 96% yield). LC-MS (ESI+): m/e 352(M+H)+, Rt: 1.73 min; 1H-NMR (DMSO-d6, 400 MHz): δ=3.75 (s, 3H), 3.83 (s, 3H), 5.20 (s, 2H), 6.93 (d, 2H, J=8.8 Hz), 7.33 (d, 2H, J=8.8 Hz), 8.68 (s, 1H), 13.39 (br, 1H).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].CO[CH2:14][CH2:15][O:16][CH3:17]>C([O-])([O-])=O.[Na+].[Na+].CCOCC>[CH3:8][C:3]1[CH:4]=[CH:14][C:15]2[O:16][C:17]([C:2]3[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=3[C:4]([O:6][CH3:7])=[O:5])=[CH:10][C:11]=2[CH:2]=1
Reactant: COC(=O)c1ccccc1Br
Reactant: COCCOC
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOCC
Product: COC(=O)c1ccccc1-c1cc2cc(C)ccc2o1
Temperature: 25 °C

Procedure:
A solution of methyl 2-bromobenzoate (11.70 g), Intermediate 1 (12.75 g) and tetrakistriphenylphosphine palladium (0) (0.5 g) in DME (300 ml) and 2N Na2CO3 (60 ml) was heated to reflux with vigorous stirring under nitrogen. After 1.5 h a further 500 mg of catalyst was added and stirring at reflux under nitrogen continued. After about 5 h the reaction was cooled to room temperature and diluted with ether (300 ml). The organic layer was separated and washed with water (3×100 ml) and dried. Filtration and evaporation gave a yellow oily suspension (19.27 g) which was purified by chromatography eluting with System A (1:9) to give a yellow oil (11.06 g). This was further purified by Kugelrohr distillation to give the title compound (4.31 g).
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[CH:5][C:6]([Cl:24])=[C:7]([CH:23]=1)[C:8]([NH:10][CH2:11][CH2:12][C:13]12[CH2:22][CH:17]3[CH2:18][CH:19]([CH2:21][CH:15]([CH2:16]3)[CH2:14]1)[CH2:20]2)=[O:9].[C:25]([O:29][C:30]([N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1)=[O:31])([CH3:28])([CH3:27])[CH3:26].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.[I-].[K+]>[Cl:24][C:6]1[CH:5]=[CH:4][C:3]([CH2:2][N:35]2[CH2:34][CH2:33][N:32]([C:30]([O:29][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:31])[CH2:37][CH2:36]2)=[CH:23][C:7]=1[C:8]([NH:10][CH2:11][CH2:12][C:13]12[CH2:20][CH:19]3[CH2:18][CH:17]([CH2:16][CH:15]([CH2:21]3)[CH2:14]1)[CH2:22]2)=[O:9]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=C(NCCC12CC3CC(CC(C3)C1)C2)c1cc(CBr)ccc1Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)N1CCN(Cc2ccc(Cl)c(C(=O)NCCC34CC5CC(CC(C5)C3)C4)c2)CC1
Yield: 87.1 %

Procedure:
A mixture 5-(bromomethyl)-2-chloro-N-(2-tricyclo[3.3.1.13,7]dec-1-ylethyl)-benzamide (Example 18a, 0.35 g), 1-tertbutyloxycarbonylpiperazine (0.213 g), potassium carbonate (0.20 g) and potassium iodide (10 mg) in acetone (5 ml) was heated at 60° C. for 2 h. The acetone was removed under vacuum, the residue taken into dichlorometane and the solid removed by filtration. The crude material was purified on a silica gel eluting with dichloromethane/ethanol (0-10% gradient) to afford the subtitle compound as a white foam (0.383 g).
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[CH:8]=[C:9]([NH2:23])[CH:10]=[CH:11][C:12]=2[O:13][CH2:14][CH2:15][CH2:16][N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)=[CH:5][CH:4]=[N:3]1.[Cl:24][C:25]1[CH:34]=[CH:33][C:28]([CH2:29][N:30]=[C:31]=[O:32])=[CH:27][CH:26]=1>C(Cl)Cl>[Cl:24][C:25]1[CH:26]=[CH:27][C:28]([CH2:29][NH:30][C:31]([NH:23][C:9]2[CH:10]=[CH:11][C:12]([O:13][CH2:14][CH2:15][CH2:16][N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[C:7]([C:6]3[N:2]([CH3:1])[N:3]=[CH:4][CH:5]=3)[CH:8]=2)=[O:32])=[CH:33][CH:34]=1
Reactant: Cn1nccc1-c1cc(N)ccc1OCCCN1CCOCC1
Reactant: O=C=NCc1ccc(Cl)cc1
Solvent: ClCCl
Product: Cn1nccc1-c1cc(NC(=O)NCc2ccc(Cl)cc2)ccc1OCCCN1CCOCC1
Reaction time: 1 h
Yield: 96.8 %

Procedure:
A solution of 3-(1-methyl-1H-pyrazol-5-yl)-4-(3-morpholinopropoxy)benzenamine (0.025 g, 0.079 mmol) in CH2Cl2 (0.6 mL) was treated with 4-chlorobenzyl isocyanate (0.012 mL, 0.083 mmol). The reaction was stirred for 1 h, and concentrated and purified by RP-HPLC. Lyophilization afforded a TFA salt as a white solid (0.037 g, 78%). LCMS m/z (%)=484 (M+H35Cl, 100), 486 (M+H37Cl, 38). 1H NMR (400 MHz, DMSO-d6) δ: 9.60 (s, 1H), 8.63 (s, 1H), 7.46 (d, J=1.8 Hz, 1H), 7.43 (dd, J=2.6, 8.9 Hz, 1H), 7.40-7.29 (m, 4H), 7.07 (d, J=9.0 Hz, 1H), 6.75-6.70 (m, 1H), 6.25 (d, J=1.8 Hz, 1H), 4.26 (d, J=5.8 Hz, 2H), 4.02-3.90 (m, 4H), 3.65 (s, 3H), 3.58 (t, J=12.0 Hz, 2H), 3.34 (d, J=12.4 Hz, 2H), 3.09-2.92 (m, 4H), 2.06-1.97 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[C:22]([N+:24]([O-])=O)[CH:21]=[CH:20][C:3]=1[C:4]([N:6]1[CH2:12][CH2:11][C:10]2[CH:13]=[N:14][NH:15][C:9]=2[C:8]2[N:16]=[CH:17][CH:18]=[CH:19][C:7]1=2)=[O:5].[Cl-]>C(O)C>[Cl:1][C:2]1[CH:23]=[C:22]([NH2:24])[CH:21]=[CH:20][C:3]=1[C:4]([N:6]1[CH2:12][CH2:11][C:10]2[CH:13]=[N:14][NH:15][C:9]=2[C:8]2[N:16]=[CH:17][CH:18]=[CH:19][C:7]1=2)=[O:5]
Reactant: O=C(c1ccc([N+](=O)[O-])cc1Cl)N1CCc2cn[nH]c2-c2ncccc21
Agent: [Cl-]
Solvent: CCO
Product: Nc1ccc(C(=O)N2CCc3cn[nH]c3-c3ncccc32)c(Cl)c1

Procedure:
As described for Reference Example 204, 6-(2-chloro-4-nitrobenzoyl)-1,4,5,6-tetrahydropyrazolo-[3,4-d]pyrido[3,2-b]azepine is reduced with stannus chloride (SnCl2) in ethanol to give the product as a solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([CH3:13])[C:10]=2[CH:11]=O)[CH:7]=1.Cl.[NH2:15][CH2:16][CH:17]([CH2:24][CH2:25][CH3:26])[CH2:18][C:19](OCC)=[O:20].C(N(CC)CC)C.[BH4-].[Na+]>CO.O>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([CH3:13])[C:10]=2[CH2:11][N:15]2[CH2:16][CH:17]([CH2:24][CH2:25][CH3:26])[CH2:18][C:19]2=[O:20])[CH:7]=1
Reactant: Cc1nn2cc(Br)cnc2c1C=O
Reactant: CCCC(CN)CC(=O)OCC
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CO
Solvent: O
Product: CCCC1CC(=O)N(Cc2c(C)nn3cc(Br)cnc23)C1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 45 %

Procedure:
To a solution of 6-bromo-2-methylpyrazolo[1,5-a]pyrimidine-3-carbaldehyde x21 (0.83 mmol, 1 eq, 200 mg) in MeOH (10 ml), is added ethyl 3-(aminomethyl)hexanoate hydrochloride x31 (0.916 mmol, 1.1 eq, 192 mg) and the resulting solution is stirred at room temperature for 5 minutes. Triethylamine (0.916 mmol, 1.1 eq, 128 □l) is then added and the mixture is heated at 65° C. for 1 hour. After this time 1 hour, sodium borohydride is added (0.916 mmol, 1.1 eq, 34 mg). The reaction mixture is then heated at 65° C. for 2 hours. Water (100 ml) is added and the resulting mixture is extracted with CH2Cl2 (3×100 ml). The combined organic layers are combined, washed with brine (100 ml) and dried over MgSO4. Volatiles are removed under reduce pressure and purified by chromatography on silicagel (CH2Cl2/MeOH/NH4OH: 97/3/0.3) to give 130 mg of 1-[(6-bromo-2-methylpyrazolo[1,5-a]pyrimidin-3-yl)methyl]-4-propylpyrrolidin-2-one 184 as a solid.
Reaction SMILES: [NH2:1][C:2]1[C:7](/[CH:8]=[CH:9]/[C:10](OCC)=[O:11])=[C:6]([O:15][C:16]2[CH:21]=[CH:20][C:19]([N+:22]([O-])=O)=[CH:18][CH:17]=2)[CH:5]=[CH:4][N:3]=1.CO.[H][H]>[C].[Pd].O1CCCC1>[O:11]=[C:10]1[NH:1][C:2]2[N:3]=[CH:4][CH:5]=[C:6]([O:15][C:16]3[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=3)[C:7]=2[CH2:8][CH2:9]1
Reactant: [H][H]
Reactant: CCOC(=O)/C=C/c1c(Oc2ccc([N+](=O)[O-])cc2)ccnc1N
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: Nc1ccc(Oc2ccnc3c2CCC(=O)N3)cc1
Yield: 16.8 %

Procedure:
Ethyl (E)-3-[2-amino-4-(4-nitrophenoxy)-3-pyridyl]-2-propenoate (330 mg), palladium-carbon (10%, aqueous, 100 mg), methanol (5 ml) and tetrahydrofuran (5 ml) were stirred overnight at under a hydrogen atmosphere at 1 atmosphere. The palladium-carbon was filtered off, the filtrate was distilled off under reduced pressure, and then the residue was purified by silica gel column chromatography (ethyl acetate, followed by ethyl acetate:methanol=5:1) to obtain 43 mg of a white solid.