Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][CH:14]([NH:17][C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[C:25]([C:28]4[CH:29]=[N:30][C:31]5[C:36]([CH:37]=4)=[CH:35][CH:34]=[CH:33][CH:32]=5)[N:26]=3)[N:21]=[CH:20][C:19]=2C(O)=O)[CH2:13][CH2:12]1)=O)C1C=CC=CC=1.[CH2:41]([N:43]([CH2:46]C)CC)C.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=[O:55])C=CC=CC=1>CN(C)C=O>[CH3:41][N:43]1[C:19]2[CH:20]=[N:21][C:22]3[CH:23]=[CH:24][C:25]([C:28]4[CH:29]=[N:30][C:31]5[C:36]([CH:37]=4)=[CH:35][CH:34]=[CH:33][CH:32]=5)=[N:26][C:27]=3[C:18]=2[N:17]([CH:14]2[CH2:13][CH2:12][NH:11][CH2:16][CH2:15]2)[C:46]1=[O:55]
Reactant: CCN(CC)CC
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: O=C(O)c1cnc2ccc(-c3cnc4ccccc4c3)nc2c1NC1CCN(C(=O)OCc2ccccc2)CC1
Solvent: CN(C)C=O
Product: Cn1c(=O)n(C2CCNCC2)c2c3nc(-c4cnc5ccccc5c4)ccc3ncc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 68.2 %

Procedure:
A suspension of compound 47 (7.8 g, 15 mmol) and triethylamine (4.1 mL, 29 mmol) in N,N-dimethylformamide (200 mL) was stirred at room temperature for 2 hr. Diphenyl phosphoryl azide (6.5 mL, 29 mmol) was added dropwise to the suspension via a syringe pump. After stirring 2 hours at room temperature the mixture was heated to 60° C., resulting in a solution. After 1.5 hr the reaction was cooled to room temperature overnight. The precipitate was collected by filtration to afford the title compound (4.2 g, 54%). The filtrate was concentrated and the residue was triturated with methanol to afford benzyl 4-(2-oxo-8-quinolin-3-yl-2,3-dihydro-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)piperidine-1-carboxylate (compound 48) (2.7 g, 35%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([F:13])[C:10]=1[CH:11]=[O:12])[C:5](O)=[O:6].C(Cl)(=O)C(Cl)=O.[CH3:20][NH2:21].Cl>ClCCl.CN(C)C=O>[F:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([F:13])[C:10]=1[CH:11]=[O:12])[C:5]([NH:21][CH3:20])=[O:6]
Reactant: CN
Reactant: O=Cc1c(F)cc(C(=O)O)cc1F
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CNC(=O)c1cc(F)c(C=O)c(F)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 80.2 %

Procedure:
To an ice-cold solution of 3,5-difluoro-4-formylbenzoic acid (120 g, 645 mmol) in dichloromethane (1.5 L) and N,N-dimethylformamide (2.0 g, 27 mmol) was added oxalyl chloride (90 g, 709 mmol) drop-wise at a rate that allowed the mixture to not exceed an internal temperature of 10° C. The resulting mixture was stirred at the same temperature for 0.5 hr, warmed to room temperature, and stirred for an additional 1.5 hr. The solution was then cooled to 0° C., and aqueous methylamine (40%, 168 mL, 1.94 mol) was added drop-wise at a rate that allowed the mixture to not exceed an internal temperature of 7° C. Afterward, the mixture was quenched with aqueous HCl (2M, 335 mL, 670 mmol) and warmed to room temperature. The organic layer was separated, washed with brine (500 mL), dried over MgSO4, filtered, and concentrated under vacuum. The resulting residual solid was taken in MTBE (500 mL), and the resulting mixture was heated to reflux for 0.5 hr, cooled to room temperature, and stirred for 18 hr. Afterward, the mixture was cooled to 0° C., filtered, rinsed with pentane, and dried under vacuum to form the title compound (103 g, 80%) as a solid. 1H NMR (300 MHz, CDCl3) δ ppm 3.03 (d, J=4.86 Hz, 3H), 6.37 (br s, 1H), 7.36-7.42 (m, 2H), 10.36 (s, 1H); MS m/z 200.06 [M+H]+ (ESI).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[C:6]([OH:12])[C:5]([Br:13])=[CH:4][CH:3]=1.Br[CH2:15][C:16]([NH2:18])=[O:17].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[NH2:1][C:2]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[C:6]([O:12][CH2:15][C:16](=[O:17])[NH2:18])[C:5]([Br:13])=[CH:4][CH:3]=1
Reactant: NC(=O)CBr
Reactant: COC(=O)c1c(N)ccc(Br)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1c(N)ccc(Br)c1OCC(N)=O
Temperature: 60 °C
Yield: 62.5 %

Procedure:
A mixture of methyl 6-amino-3-bromo-2-hydroxybenzoate (prepared according to Wang et al, Bioorg Med Chem Lett, 2007, 17, 2817, 7.55 g), bromoacetamide (4.55 g) and potassium carbonate (10.0 g) in DMF (70 mL) was heated to 60° C. for 17 hours. After cooling, the mixture was concentrated in vacuo and the residue was dissolved in ethyl acetate and water and the layers were separated. The aqueous layer was extracted with ethyl acetate and the combined organic layers were dried (Na2SO4) and filtered. The filtrate was concentrated in vacuo to give an orange solid which was triturated with ether to give methyl 6-amino-3-bromo-2-carbamoylmethoxybenzoate (5.81 g) as a sandy coloured solid.
Reaction SMILES: C[O:2][C:3](=[O:26])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])=[C:6]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH:5]=1.[OH-].[K+].O.Cl>C(O)C>[CH2:19]([O:18][C:6]1[CH:5]=[C:4]([CH:9]=[CH:8][C:7]=1[O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[C:3]([OH:26])=[O:2])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: CCCCCCCOc1ccc(C(=O)OC)cc1OCCCCCCC
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCCCCCCOc1ccc(C(=O)O)cc1OCCCCCCC
Temperature: 25 °C
Yield: 93.9 %

Procedure:
A mixture of 25 g of product from Example 109, 11.54 g of potassium hydroxide, 30 ml of water and 500 ml ethyl alcohol is heated at reflux temperature for 24 hours. The reaction mixture is cooled and maintained at room temperature for 48 hours. The mixture is acidified to pH 2 with concentrated hydrochloric acid, concentrated in vacuo, diluted with water and extracted with chloroform. The combined chloroform extracts are washed with saturated sodium chloride, dried and concentrated in vacuo to give 22.58 g of the desired product as colorless crystals.
Reaction SMILES: C(N(C(C)C)CC)(C)C.[CH3:10][O:11][C:12]1[CH:13]=[C:14](/[CH:24]=[CH:25]/[C:26]([OH:28])=O)[CH:15]=[CH:16][C:17]=1[N:18]1[CH:22]=[C:21]([CH3:23])[N:20]=[CH:19]1.C1N(P(Cl)(N2C(=O)OCC2)=O)C(=O)OC1.Cl.[Cl:45][CH2:46][CH2:47][CH2:48][CH2:49][CH:50]([C:55]1[CH:60]=[C:59]([F:61])[C:58]([F:62])=[C:57]([F:63])[CH:56]=1)[C:51]([NH:53][NH2:54])=O>C(Cl)Cl.O>[Cl:45][CH2:46][CH2:47][CH2:48][CH2:49][CH:50]([C:51]1[O:28][C:26](/[CH:25]=[CH:24]/[C:14]2[CH:15]=[CH:16][C:17]([N:18]3[CH:22]=[C:21]([CH3:23])[N:20]=[CH:19]3)=[C:12]([O:11][CH3:10])[CH:13]=2)=[N:54][N:53]=1)[C:55]1[CH:56]=[C:57]([F:63])[C:58]([F:62])=[C:59]([F:61])[CH:60]=1
Reactant: COc1cc(/C=C/C(=O)O)ccc1-n1cnc(C)c1
Reactant: NNC(=O)C(CCCCCl)c1cc(F)c(F)c(F)c1
Agent: Cl
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: ClCCl
Product: COc1cc(/C=C/c2nnc(C(CCCCCl)c3cc(F)c(F)c(F)c3)o2)ccc1-n1cnc(C)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 47.7 %

Procedure:
A solution of 4 N hydrogen chloride in ethyl acetate (30 mL) was added to tert-butyl N′-[6-chloro-2-(3,4,5-trifluorophenyl)hexanoyl]hydrazinecarboxylate synthesized according to the method described in Examples 112 and 113 (ESI-MS; m/z 417 [M++Na], 2.08 g). The reaction solution was stirred at room temperature for one hour and then concentrated under reduced pressure to obtain 6-chloro-2-(3,4,5-trifluorophenyl)hexanoic acid hydrazide hydrochloride (1.81 g). IPEA (1.5 mL), (E)-3-[3-methoxy-4-(4-methylimidazol-1-yl)phenyl]acrylic acid (450 mg) and BOPCl (0.53 g) were added to a solution of 6-chloro-2-(3,4,5-trifluorophenyl)hexanoic acid hydrazide hydrochloride (612 mg) in methylene chloride (15 mL) at room temperature, and the reaction solution was stirred at room temperature for three hours. Water was added to the reaction solution, followed by extraction with chloroform. The resulting extract was washed with a saturated sodium chloride solution, dried over magnesium sulfate and then concentrated under reduced pressure. A solution of the resulting residue in phosphorus oxychloride (8 mL) was heated under reflux for three hours. The reaction solution was left to cool to room temperature and concentrated under reduced pressure. A saturated sodium bicarbonate solution was added to the resulting residue, followed by extraction with ethyl acetate. The resulting extract was dried over magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: heptane-ethyl acetate system) to obtain 430 mg of the title compound. The property value of the compound is as follows.
Reaction SMILES: C([BH3-])#N.[Na+].[C:5]([O:9][C:10](=[O:59])[C@H:11]([CH2:47][C:48]1[CH:53]=[CH:52][C:51]([O:54][C:55]([CH3:58])([CH3:57])[CH3:56])=[CH:50][CH:49]=1)[NH:12][C:13]([C:15]1([CH2:20][C@H:21]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:22][NH:23][C:24](=[O:39])[C@H:25]([CH2:27][CH2:28][CH2:29][CH2:30][NH:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[NH2:26])[CH2:19][CH2:18][CH2:17][CH2:16]1)=[O:14])([CH3:8])([CH3:7])[CH3:6].[CH:60](=O)[CH3:61].Cl>C(O)C>[C:5]([O:9][C:10](=[O:59])[C@H:11]([CH2:47][C:48]1[CH:49]=[CH:50][C:51]([O:54][C:55]([CH3:58])([CH3:57])[CH3:56])=[CH:52][CH:53]=1)[NH:12][C:13]([C:15]1([CH2:20][C@H:21]([C:40]([O:42][C:43]([CH3:44])([CH3:45])[CH3:46])=[O:41])[CH2:22][NH:23][C:24](=[O:39])[C@H:25]([CH2:27][CH2:28][CH2:29][CH2:30][NH:31][C:32]([O:34][C:35]([CH3:36])([CH3:37])[CH3:38])=[O:33])[NH:26][CH2:60][CH3:61])[CH2:16][CH2:17][CH2:18][CH2:19]1)=[O:14])([CH3:6])([CH3:7])[CH3:8]
Reactant: CC(C)(C)OC(=O)NCCCC[C@H](N)C(=O)NC[C@H](CC1(C(=O)N[C@@H](Cc2ccc(OC(C)(C)C)cc2)C(=O)OC(C)(C)C)CCCC1)C(=O)OC(C)(C)C
Reactant: CC=O
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCO
Product: CCN[C@@H](CCCCNC(=O)OC(C)(C)C)C(=O)NC[C@H](CC1(C(=O)N[C@@H](Cc2ccc(OC(C)(C)C)cc2)C(=O)OC(C)(C)C)CCCC1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 70.4 %

Procedure:
Sodium cyanoborohydride (45 mg) was added in one portion to a stirred, ice cold solution of N-{1-[2-(S)-t-butyloxycarbonyl-3(N6 -t-butyloxycarbonyl-(S)-lysylamino)propyl]-1-cyclopentanecarbonyl}O-t-butyl-(S)-tyrosine-t-butyl ester (507 mg) and acetaldehyde (31 mg) in aqueous ethanol (80%, 10 ml) and the pH adjusted to 5 with 1N hydrochloric acid. The resulting solution was allowed to warm to room temperature and stirred for 1.5 hours. The reaction mixture was evaporated to dryness and the residue partitioned between water and ethyl acetate. The phases were separated and the organic phase washed with a little aqueous sodium bicarbonate, dried (MgSO4), filtered and evaporated. The residue was chromatographed over silica gel, eluting with mixtures of hexane and ethyl acetate containing 1% diethylamine to yield the title compound as an oil (370 mg, 64%) Rf 0.55 (silica; CH2Cl2, CH3OH, NH4OH; 90:10:1).
Reaction SMILES: [Cl:1][C:2]1[C:6]([CH3:7])=[C:5]([Cl:8])[NH:4][C:3]=1[C:9]([O:11]CC)=[O:10].C(O)C.O.Cl>O>[Cl:1][C:2]1[C:6]([CH3:7])=[C:5]([Cl:8])[NH:4][C:3]=1[C:9]([OH:11])=[O:10]
Reactant: CCOC(=O)c1[nH]c(Cl)c(C)c1Cl
Agent: Cl
Solvent: O
Solvent: CCO
Product: Cc1c(Cl)[nH]c(C(=O)O)c1Cl
Yield: 104.1 %

Procedure:
A solution of 1.1 gm (4.95 mmol) of ethyl 3,5-dichloro-4-methyl-1H-pyrrole-2-carboxylate (Intermediate 194) and 1.7 g (9.9 mmol) of Ba(OH)2 in 50 ml 1:1 EtOH—H2O was heated at 85° C. for 9 h. The mixture was diluted with water, acidified with 20 ml 1N HCl and extracted 3 times with ether. The ether was washed with water, dried (MgSO4) and concentrated to give 1.0 g of product as a solid. MS (ES) (M−H−): 194 for C6H5Cl2NO2; NMR (d6-DMSO): 1.9 (s, 3H), 12.7 (s, 1H), 12.8 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[N:3]([CH3:30])[C:4](=[O:29])[C:5]([C:20]2[CH:21]=[C:22]([CH:27]=O)[N:23]([CH2:25][CH3:26])[CH:24]=2)([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]3[C:14]([F:19])=[N:15][CH:16]=[CH:17][CH:18]=3)[CH:8]=2)[N:6]=1.[ClH:31].[O:32]([NH2:34])[CH3:33]>C1COCC1>[ClH:31].[CH3:33][O:32][N:34]=[CH:27][C:22]1[N:23]([CH2:25][CH3:26])[CH:24]=[C:20]([C:5]2([C:7]3[CH:12]=[CH:11][CH:10]=[C:9]([C:13]4[C:14]([F:19])=[N:15][CH:16]=[CH:17][CH:18]=4)[CH:8]=3)[C:4](=[O:29])[N:3]([CH3:30])[C:2]([NH2:1])=[N:6]2)[CH:21]=1
Reactant: CON
Reactant: CCn1cc(C2(c3cccc(-c4cccnc4F)c3)N=C(N)N(C)C2=O)cc1C=O
Agent: Cl
Solvent: C1CCOC1
Product: CCn1cc(C2(c3cccc(-c4cccnc4F)c3)N=C(N)N(C)C2=O)cc1C=NOC
Yield: 64 %

Procedure:
A stirred suspension of 4-{2-amino-4-[3-(2-fluoropyridin-3-yl)phenyl]-1-methyl-5-oxo-4,5-dihydro-1H-imidazol-4-yl}-1-ethyl-1H-pyrrole-2-carbaldehyde (0.10 g; 0.25 mmol), in THF (5 mL), was added methoxylamine hydrochloride (0.021 g; 0.25 eq). The mixture was stirred at reflux temperature for 2 hours. The mixture was cooled and the solvent was evaporated. The residue was dissolved in dichloromethane and washed with water. The dichloromethane solution was dried over MgSO4, filtered and evaporated. The resultant residue was crystallized from ethyl acetate and hexane to yield the title compound, 0.069 g (64% yield), mp 190-193° C., MS (ES) m/z 433.1; [M−H]
Reaction SMILES: Cl[CH2:2][C:3]([C:5]1[C:6]([CH:14]([CH3:16])[CH3:15])=[N:7][N:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=12)=O.[NH2:17][C:18]([NH2:20])=[S:19].[H-].[Na+].O>O1CCOCC1>[CH:14]([C:6]1[C:5]([C:3]2[CH2:2][S:19][C:18](=[NH:17])[N:20]=2)=[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][N:8]2[N:7]=1)([CH3:16])[CH3:15]
Reactant: CC(C)c1nn2ccccc2c1C(=O)CCl
Reactant: NC(N)=S
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)c1nn2ccccc2c1C1=NC(=N)SC1
Yield: 61.4 %

Procedure:
A mixture of 200 mg (0.63 mmol) of 2-chloro-1-(2-isopropylpyrazolo[1,5-a]pyridin-3-yl)ethanone, 100 mg of thiourea and 160 mg of sodium hydride were stirred in 2 ml of dioxane containing 120 μl of H2O at 60-70° C. for 30 minutes. 100 mg of 4-(2-isopropylpyrazolo[1,5-a]pyridin-3-yl)thiazol-2(5H)-imine was obtained after workup. Compound 1087.
Reaction SMILES: [CH2:1]([C:8](=[CH2:12])[C:9]([OH:11])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:13]([O:20][C:21](=[O:24])[CH2:22][NH2:23])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C1C=CC2N(O)N=NC=2C=1.C1CCC(N=C=NC2CCCCC2)CC1>C1COCC1.C(Cl)(Cl)Cl.C(N(CC)CC)C>[CH2:13]([O:20][C:21](=[O:24])[CH2:22][NH:23][C:9](=[O:11])[C:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[CH2:12])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: NCC(=O)OCc1ccccc1
Reactant: C=C(Cc1ccccc1)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Product: C=C(Cc1ccccc1)C(=O)NCC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
2.42 g (15 mmoles) of 2-benzyl acrylic acid are dissolved in 30 ml of THF and 10 ml of CHCl3. There is added a solution in 50 ml of THF of 1.87 g of glycine benzyl ester hydrochlorate, 2.2 g of triethylamine, then 2.20 g of HOBT and 3.4 g of DCC. The mixture is stirred for 20 hours at room temperature. The precipitate of DCU formed is collected. After evaporating to dryness and taking up with ethyl acetate the organic phase is washed in succession with 2×20 ml of citric acid, then 3×20 ml of NaHCO3. The material is concentrated under a vacuum and the rest of the DCU formed is suction filtered. A yellow oil which crystallizes slowly is obtained.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[S:11][CH:12]=[CH:13][CH:14]=2)=[CH:6][C:5]=1[NH:15][C:16]([NH:18][CH2:19][CH:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1)=[O:17])([O-])=O>CO.[Pd]>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[S:11][CH:12]=[CH:13][CH:14]=2)=[CH:6][C:5]=1[NH:15][C:16]([NH:18][CH2:19][CH:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1)=[O:17]
Reactant: O=C(NCC1CCNCC1)Nc1cc(-c2cccs2)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Product: Nc1ccc(-c2cccs2)cc1NC(=O)NCC1CCNCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 64.8 %

Procedure:
To a solution of 1-(2-nitro-5-(thiophen-2-yl)phenyl)-3-(piperidin-4-ylmethyl)urea (0.10 g, 0.28 mmol, 1.0 equiv.) in methanol was added Pd/C (0.03 g, 0.03 mmol, 0.10 equiv.). The reaction mixture was stirred at room temperature under H2 balloon pressure for 1h. The reaction was filtered through celite and concentrated under reduced pressure. The crude solid was washed with ether to obtain of pure 1-(2-amino-5-(thiophen-2-yl)phenyl)-3-(piperidin-4-ylmethyl)urea (0.06 g, 65% yield). ESI+ MS: m/z 331 ([M]+); 1H NMR (500 MHz, d6-DMSO): δ 7.64 (d, J=12.0 Hz, 2H), 7.33 (d, J=5.5 Hz, 1H), 7.17 (d, J=3.0 Hz, 1H), 7.10-7.09 (m, 1H), 7.03 (t, J=5.0 Hz, 1H), 6.71 (d, J=8.0 Hz, 1H), 6.34 (m, 1H), 4.90-4.89 (bs, 2H), 3.16 (d, J=12.5 Hz, 2H), 2.99 (t, J=6.0 Hz, 3H), 2.65 (t, J=12.5 Hz, 2H), 1.71 (d, J=13.0 Hz, 1H), 1.62-1.60 (m, 2H), 1.20-1.13 (m, 2H).
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH2:15][CH2:14][CH:13]([CH:16]3[CH2:21][CH2:20][C:19](=[O:22])[CH2:18][CH2:17]3)[CH2:12][CH:11]=2)=[CH:6][CH:5]=1)[CH2:2][CH3:3].[BH4-].[Na+]>C1COCC1.C(O)C.Cl>[OH:22][CH:19]1[CH2:18][CH2:17][CH:16]([CH:13]2[CH2:12][CH2:11][CH:10]([C:7]3[CH:8]=[CH:9][C:4]([CH2:1][CH2:2][CH3:3])=[CH:5][CH:6]=3)[CH2:15][CH2:14]2)[CH2:21][CH2:20]1
Reactant: CCCc1ccc(C2=CCC(C3CCC(=O)CC3)CC2)cc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Product: CCCc1ccc(C2CCC(C3CCC(O)CC3)CC2)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
The 1-(4-propylphenyl)-4-(4-oxocyclohexyl)-1-cyclohexene described above in an amount of 9.5 g (32 mmol) was dissolved in mixed solvent of 200 ml of THF and 50 ml of ethanol, and cooled down to 0° C. Sodium borohydride in an amount of 1.2 g (32 mmol) was gradually added thereto and the mixture was stirred at the same temperature for 1 hour. The reaction solution was added in 150 ml of 1N hydrochloric acid and extracted with diethyl ether. After the extract was washed with saturated aqueous sodium bicarbonate solution and water in this turn, the solvent was distilled off under a reduced pressure. The residue was dissolved in 80 ml of mixed solvent of ethanol/ethyl acetate (1/1), the solution was subjected to a hydrogenation by using Raney Nickel catalyst, and then the catalyst was filtered off. The solvent was distilled off and then the residue was recrystallized by using toluene to give 2.5 g (8.3 mmol) of 4-(4-(4-hydroxycyclohexyl)cyclohexyl)-1-propylbenzene. Yield of this compound was 26%.
Reaction SMILES: [CH:1]12[NH:8][CH:5]([CH2:6][CH2:7]1)[CH2:4][N:3]([C:9]1[C:10]3[CH:17]=[CH:16][NH:15][C:11]=3[N:12]=[CH:13][N:14]=1)[CH2:2]2.C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[F:49][C:50]([F:61])([F:60])[C:51]1[CH:59]=[CH:58][C:54]([C:55](O)=[O:56])=[CH:53][CH:52]=1>CN(C=O)C>[N:12]1[C:11]2[NH:15][CH:16]=[CH:17][C:10]=2[C:9]([N:3]2[CH2:2][CH:1]3[N:8]([C:55]([C:54]4[CH:53]=[CH:52][C:51]([C:50]([F:49])([F:60])[F:61])=[CH:59][CH:58]=4)=[O:56])[CH:5]([CH2:6][CH2:7]3)[CH2:4]2)=[N:14][CH:13]=1
Reactant: O=C(O)c1ccc(C(F)(F)F)cc1
Reactant: c1nc(N2CC3CCC(C2)N3)c2cc[nH]c2n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(c1ccc(C(F)(F)F)cc1)N1C2CCC1CN(c1ncnc3[nH]ccc13)C2
Reaction time: 16 h

Procedure:
4-(3,8-Diaza-bicyclo[3.2.1]oct-3-yl)-7H-pyrrolo[2,3-d]pyrimidine (intermediate 4) (0.05 mmol) was dissolved in dry DMF (0.3 mL). Triethylamine (0.18 mmol) and HATU (0.09 mmol) was added followed by 4-trifluoromethylbenzoic acid (0.07 mmol). The reaction mixture was left at it for 16 hours. The pure compounds were obtained by standard preparative HPLC purification of the reaction mixture.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH2:8][NH:7][CH:6]([C:12](O)=O)[CH2:5]2.[C:15]1(=[O:26])[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:18](=[O:25])[CH:17]=[CH:16]1.[C:27](OC(=O)C)(=O)C>>[OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH2:8][N:7]1[C:16]([CH3:27])=[C:17]3[C:12]([C:15](=[O:26])[C:24]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[C:18]3=[O:25])=[C:6]1[CH2:5]2
Reactant: O=C1C=CC(=O)c2ccccc21
Reactant: O=C(O)C1Cc2cc(O)ccc2CN1
Reactant: CC(=O)OC(C)=O
Product: Cc1c2c(c3n1Cc1ccc(O)cc1C3)C(=O)c1ccccc1C2=O
Temperature: 100 °C
Reaction time: 0.25 h

Procedure:
A mixture of 6-hydroxy-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (2 g) and 1,4-naphthalenedione (3.4 g) in acetic anhydride (150 ml) was stirred in an oil bath at 100° C. for 15 minutes. It was then allowed to cool to room temperature and the green solid (2.74 g) was collected by filtration, washed with acetic anhydride and ether and dried at 100° C. for 2 h in vacuo, to give the title compound m.p. 275°-320° C. (decomp), λmax (in ethanol) 244.5 nm (ε26,220) 318 nm (ε4,510) and 383 nm (ε6,390).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:8]2[C:16]3[CH:15]=[CH:14][C:13]([CH3:17])=[CH:12][C:11]=3[C:10]3[CH2:18][N:19]([CH3:22])[CH2:20][CH2:21][C:9]2=3)[CH:5]=[CH:6][CH:7]=1.[CH3:23][C:24]1[C:28](B2OC(C)(C)C(C)(C)O2)=[C:27]([CH3:38])[O:26][N:25]=1.C([O-])([O-])=O.[K+].[K+]>COCCOC.O.CCOC(C)=O.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>[CH3:22][N:19]1[CH2:18][CH2:10][C:9]2[N:8]([C:4]3[CH:3]=[C:2]([C:28]4[C:24]([CH3:23])=[N:25][O:26][C:27]=4[CH3:38])[CH:7]=[CH:6][CH:5]=3)[C:16]3[CH:11]=[CH:12][C:13]([CH3:17])=[CH:14][C:15]=3[C:21]=2[CH2:20]1
Reactant: Cc1ccc2c(c1)c1c(n2-c2cccc(Br)c2)CCN(C)C1
Reactant: Cc1noc(C)c1B1OC(C)(C)C(C)(C)O1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: Cc1ccc2c(c1)c1c(n2-c2cccc(-c3c(C)noc3C)c2)CCN(C)C1
Temperature: 90 °C
Reaction time: 0.75 h

Procedure:
To a de-aerated solution of 5-(3-bromophenyl)-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (100 mg, 0.281 mmol), 3,5-dimethylisoxazole-4-boronic acid pinacol ester (125 mg, 0.56 mmol) and K2CO3 (116 mg, 0.84 mmol) in DME-water (2:1) was added Pd(PPh3)4 (16 mg, 0.014 mmol). The reaction mixture was stirred at 90° C. for 45 min. The reaction mixture was concentrated under reduced pressure. The residue obtained was dissolved in EtOAc (50 mL) and washed with water (20 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain crude, which was purified by reverse phase HPLC to yield 4-(3-(2,8-dimethyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)phenyl)-3,5-dimethylisoxazole. 1H NMR (TFA salt, CD3OD) d (ppm): 7.7 (t, 1H), 7.41-7.5 (m, 2H), 7.4 (s, 1H), 7.37 (s, 1H), 7.18 (d, 1H), 7.03 (d, 1H), 4.7 (m, 1H), 4.4 (m, 1H), 3.8 (m, 1H), 3.6 (m, 1H), 3.2 (m, 4H), 3.01 (m, 1H), 3.43 (m, 6H), 2.31 (s, 3H).
Reaction SMILES: [C:1](Cl)(=O)[O:2]C(C)C.[NH2:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[C:10]=1[C:11]([OH:13])=[O:12].C(Cl)(=O)C>O1CCOCC1>[Cl:18][C:14]1[C:10]2[C:11](=[O:13])[O:12][C:1](=[O:2])[NH:8][C:9]=2[CH:17]=[CH:16][CH:15]=1
Reactant: Nc1cccc(Cl)c1C(=O)O
Reactant: CC(C)OC(=O)Cl
Solvent: CC(=O)Cl
Solvent: C1COCCO1
Product: O=c1[nH]c2cccc(Cl)c2c(=O)o1
Temperature: 90 °C
Yield: 76 %

Procedure:
Under an atmosphere of nitrogen, isopropyl carbonochloridate (50 ml, 4.50 equiv) was added dropwise to a suspension of 2-amino-6-chlorobenzoic acid (20 g, 116.56 mmol, 1.00 equiv) in 1,4-dioxane (150 ml). The resulting solution was maintained at about 90° C. for 30 minutes, and then cooled to about 50° C. Acetyl chloride (50 ml, 6.00 equiv) was added in one portion, and the solution was maintained at about 50° C. for about 30 minutes. The resulting solids were collected by filtration and purified by silica gel chromatography (ethyl acetate/petroleum ether 10:1) to afford the title product as a gray white solid (17.6 g, yield: 76%).
Reaction SMILES: Br[CH:2]([CH3:6])[C:3](=O)[CH3:4].[NH2:7][C:8]1[CH:13]=[CH:12][C:11]([I:14])=[CH:10][N:9]=1.CCO>O>[I:14][C:11]1[CH:12]=[CH:13][C:8]2[N:9]([C:2]([CH3:6])=[C:3]([CH3:4])[N:7]=2)[CH:10]=1
Reactant: Nc1ccc(I)cn1
Reactant: CC(=O)C(C)Br
Solvent: O
Solvent: CCO
Product: Cc1nc2ccc(I)cn2c1C
Temperature: 70 °C
Yield: 25.3 %

Procedure:
To a mixture of 3-bromobutan-2-one (1.0 g) and 2-amino-5-iodopyridine (800 mg) was added EtOH (25 ml), and the mixture was heated at 70° C. for 30 h. The reaction mixture was cooled, diluted with water, and extracted with DCM. The DCM layer was washed with brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography (hexane/EtOAc) to give the title compound (250 mg) as a yellow solid.