Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:13]2[C:4]([C:5](=O)[N:6]=[C:7]3[C:12]=2[CH:11]=[CH:10][CH:9]=[CH:8]3)=[N:3][N:2]=1.C1(P([N:29]=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1>>[C:1]1([NH2:29])[NH:2][N:3]=[C:4]2[C:13]=1[C:12]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[N:6]=[CH:5]2
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: O=C1N=c2ccccc2=C2C=NN=C12
Product: Nc1[nH]nc2cnc3ccccc3c12

Procedure:
In step (2) of Reaction Scheme III, a pyrazolo[3,4-c]quinolin-4-one of Formula XXIII is treated with diphenyl phosphoryl azide to provide a pyrazolo[3,4-c]quinolin-1-amine of Formula XXIII.
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[O:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH:11]([NH:15][C:16](=[O:30])[C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH2:25][C:26]([F:29])([F:28])[F:27])=[CH:19][CH:18]=2)[C:12](O)=[O:13])=[CH:6][CH:5]=1.Cl.[F:34][CH2:35][CH2:36][NH2:37]>>[F:34][CH2:35][CH2:36][NH:37][C:12](=[O:13])[CH:11]([NH:15][C:16](=[O:30])[C:17]1[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH2:25][C:26]([F:29])([F:28])[F:27])=[CH:19][CH:18]=1)[CH2:10][C:7]1[CH:6]=[CH:5][C:4]([O:3][C:2]([F:32])([F:31])[F:1])=[CH:9][CH:8]=1
Reactant: NCCF
Reactant: O=C(NC(Cc1ccc(OC(F)(F)F)cc1)C(=O)O)c1ccc(OCCC(F)(F)F)cc1
Agent: Cl
Product: O=C(NC(Cc1ccc(OC(F)(F)F)cc1)C(=O)NCCF)c1ccc(OCCC(F)(F)F)cc1
Yield: 116.5 %

Procedure:
A reaction similar to that described in Example 32 (32c) was conducted using 3-[4-(trifluoromethoxy)phenyl]-2-{[4-(3,3,3-trifluoropropoxy)benzoyl]amino}propanoic acid (6.00 g) prepared in Example 70 (70a) and 2-fluoroethylamine hydrochloride (1.71 g) to give 7.67 g of the title compound (white powder).
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([C@H:23]([OH:44])[CH2:24][N:25]([CH2:33][CH2:34][CH2:35][C:36]2[CH:41]=[CH:40][C:39]([O:42][CH3:43])=[CH:38][CH:37]=2)CC2C=CC=CC=2)[CH:12]=[CH:13][C:14]=1[O:15]CC1C=CC=CC=1)C1C=CC=CC=1.[C:45](O)(=[O:49])[C:46]([OH:48])=[O:47]>C(O)C>[C:46]([OH:48])(=[O:47])[C:45]([O:44][C@@H:23]([C:11]1[CH:12]=[CH:13][C:14]([OH:15])=[C:9]([OH:8])[CH:10]=1)[CH2:24][NH:25][CH2:33][CH2:34][CH2:35][C:36]1[CH:37]=[CH:38][C:39]([O:42][CH3:43])=[CH:40][CH:41]=1)=[O:49]
Reactant: COc1ccc(CCCN(Cc2ccccc2)C[C@@H](O)c2ccc(OCc3ccccc3)c(OCc3ccccc3)c2)cc1
Reactant: O=C(O)C(=O)O
Solvent: CCO
Product: COc1ccc(CCCNC[C@@H](OC(=O)C(=O)O)c2ccc(O)c(O)c2)cc1
Reaction time: 8 h

Procedure:
To a solution of 1.50 g (2.6 mmole) of the above benzyl-protected amino alcohol (the product of step (c)) in 150 ml ethanol containing 10% dioxane, 400 mg of 10% Pd on carbon atom were added. The reaction mixture was hydrogenated overnight at 25 psi. To the resulting mixture, a solution of 0.23g (2.60 m mole) of oxalic acid in 2 ml ethanol was added. After mixing, the solution was filtered and evaporated under reduced pressure The residue was slurred in ether. The precipitate was collected by filtration, rinsed with ether and then acetone, and dried under vacuum to give 0.570 g of the above-identified product, melting point 158°-162° C. 1H NMR (CD3OD) δ7.0-6.5 (m, 7H, ArH), 4.8 (m, 1H, CHOH), 3.3 (S, 3H, CH3O), 3.00-2.90 (m,4H, CH2N), 2.5-2.4 (m, 2H, ArCH2), 1.6-1.5 (m, 2H, CH2).
Reaction SMILES: C(O)(=O)C(O)=O.[CH2:7]([NH:9][NH2:10])[CH3:8].[C:11]([C:13]1[CH:14]=[C:15]([C:19]#[C:20][C:21](OCC)=[O:22])[CH:16]=[CH:17][CH:18]=1)#[N:12].C(N(CC)CC)C>C(O)C>[CH2:7]([N:9]1[C:19]([C:15]2[CH:14]=[C:13]([CH:18]=[CH:17][CH:16]=2)[C:11]#[N:12])=[CH:20][C:21](=[O:22])[NH:10]1)[CH3:8]
Reactant: CCNN
Reactant: CCOC(=O)C#Cc1cccc(C#N)c1
Agent: O=C(O)C(=O)O
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCn1[nH]c(=O)cc1-c1cccc(C#N)c1
Temperature: 80 °C
Yield: 92.2 %

Procedure:
Ethyl hydrazine oxalate (4.01 g, 26.7 mmol, 1.50 equiv) was added to a solution of ethyl 3-(3-cyanophenyl)prop-2-ynoate (3.55 g, 17.8 mmol, 1 equiv) and triethylamine (3.73 mL, 26.7 mmol, 1.50 equiv) in ethanol (180 mL). The reaction mixture was heated to 80° C. for 3.5 hours, then cooled to 22° C. The cooled reaction mixture was concentrated by rotary evaporation, and the residue was partitioned between ethyl acetate and water. The organic layer was washed with saturated aqueous sodium chloride solution, and the washed solution was dried over sodium sulfate. The dried solution was filtered, and the filtrate was concentrated to afford 3-(2-ethyl-5-oxo-2,5-dihydro-1H-pyrazol-3-yl)benzonitrile (3.5 g, 3:1 mixture of regioisomers in favor of desired product). The mixture of regioisomers was used without separating in the next step. Calcd (M+1)+: 214.1. Found: 214.1.
Reaction SMILES: O[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[OH:9].[CH2:10]([SH:12])[CH3:11]>ClC1C=CC=CC=1Cl>[CH2:10]([S:12][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[OH:9])[CH3:11]
Reactant: CCS
Reactant: OCc1ccccc1O
Solvent: Clc1ccccc1Cl
Product: CCSCc1ccccc1O
Yield: 87 %

Procedure:
A mixture of 49.6 g (0.4 mol) of 2-hydroxymethyl-phenol, 24.8 g (0.4 mol) of ethylmercaptan and 200 ml of o-dichlorobenzene was heated in a flask equipped with a stirrer and a reflux condenser, under normal pressure, and starting from room temperature, in such a way that there was always a moderate reflux and that the final temperature in the flask did not exceed about 125° C. In total, the mixture was heated under reflux for about 20 hours. Thereafter, working up by distillation gave 2-ethylthiomethyl-phenol in a yield of 87% of theory. The o-dichlorobenzene distilled off could be re-used in a subsequent batch.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([CH2:18][C:19]3[N:24]=[C:23]([C:25](=[N:27][OH:28])[NH2:26])[CH:22]=[CH:21][CH:20]=3)=[C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[NH:9]2)=[CH:5][CH:4]=1.[C:29](N1C=CN=C1)(N1C=CN=C1)=[O:30].C1CCN2C(=NCCC2)CC1.Cl>O1CCCC1>[CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([CH2:18][C:19]3[N:24]=[C:23]([C:25]4[NH:26][C:29](=[O:30])[O:28][N:27]=4)[CH:22]=[CH:21][CH:20]=3)=[C:8]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)[NH:9]2)=[CH:5][CH:4]=1
Reactant: COc1ccc2c(Cc3cccc(C(N)=NO)n3)c(-c3ccccc3)[nH]c2c1
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: Cl
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: COc1ccc2c(Cc3cccc(-c4noc(=O)[nH]4)n3)c(-c3ccccc3)[nH]c2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 86.1 %

Procedure:
Under an argon atmosphere, to a solution of 6-(6-methoxy-2-phenyl-1H-indol-3-ylmethyl)pyridine-2-carboxamidoxime (46.9 mg) in tetrahydrofuran (0.63 mL) were added 1,1′-carbonyldiimidazole (24.5 mg) and 1,8-diazabicyclo[5,4,0]-7-undecene (0.019 mL), and this mixture was stirred at room temperature for 3 hours. 1,1′-Carbonyldiimidazole (16.3 mg) was added thereto, followed by stirring for 80 minutes. Then, 1,8-diazabicyclo[5,4,0]-7-undecene (0.019 mL) was added thereto, followed by stirring for additional 1 hour. To the reaction mixture was added 1 mol/L hydrochloric acid, followed by extraction with ethyl acetate. The organic layer was washed with 1 mol/L hydrochloric acid, a saturated aqueous sodium hydrogen carbonate solution, and saturated brine successively, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting solvent: methanol-dichloromethane) to obtain the title compound (43.2 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:12])[CH2:7][CH2:8][S:9]2)=[CH:4][CH:3]=1.[Br:13]Br>C(Cl)(Cl)Cl>[Br:13][CH:7]1[C:6](=[O:12])[C:5]2[C:10](=[CH:11][C:2]([Cl:1])=[CH:3][CH:4]=2)[S:9][CH2:8]1
Reactant: BrBr
Reactant: O=C1CCSc2cc(Cl)ccc21
Solvent: ClC(Cl)Cl
Product: O=C1c2ccc(Cl)cc2SCC1Br
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Dissolve 7-chlorothiochroman-4-one (10 gms., 50.3 mmols) in chloroform (100 ml.) and cool the solution to 0°-5° C. Add bromine (2.60 ml., 50.3 mmols) dropwise over a 10-minute period. Stir the reaction mixture at room temperature for one hour, then add chloroform (100 ml.) and extract with 10% aqueous sodium sulfite (100 ml.) followed by water (200 ml.). Dry the chloroform solution over anhydrous magnesium sulfate, filter and evaporate in vacuo to a residue. Recrystallize the residue from cyclohexane to give 3-bromo-7-chlorothiochroman-4-one, m.p. 109°-110° C.
Reaction SMILES: [C:1]([CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1)#[N:2].[OH-].[K+].C[N:16](C)C=O>>[C:1]([CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]([NH2:16])[CH:5]=1)#[N:2]
Reactant: CN(C)C=O
Reactant: N#CCc1c[nH]c2ccccc12
Agent: [K+]
Agent: [OH-]
Product: N#CCc1cn(N)c2ccccc12

Procedure:
To a cold solution of 3-cyanomethyl-1H-indole (25 g) in 200 ml dimethylformamide (DMF), was added milled KOH (48 g) portionwise maintaining the temperature at 0° to 5° C.
Reaction SMILES: C([O:8][C:9]([CH2:11][N:12]1[CH2:25][CH2:24][CH2:23][NH:22][CH2:21][CH2:20][N:19]([CH2:26][C:27]([O:29]CC2C=CC=CC=2)=[O:28])[CH2:18][CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1)=[O:10])C1C=CC=CC=1.C(OCC)C>C(O)C.[Pd]>[C:9]([CH2:11][N:12]1[CH2:25][CH2:24][CH2:23][NH:22][CH2:21][CH2:20][N:19]([CH2:26][C:27]([OH:29])=[O:28])[CH2:18][CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1)([OH:10])=[O:8]
Reactant: O=C(CN1CCCNCCN(CC(=O)OCc2ccccc2)CCCNCC1)OCc1ccccc1
Agent: [Pd]
Solvent: CCOCC
Solvent: CCO
Product: O=C(O)CN1CCCNCCN(CC(=O)O)CCCNCC1
Yield: 95.5 %

Procedure:
To a solution of compound (4) (0.48 g, 0.96 mmol) in absolute ethanol (40 ml) was added 10% Pd/C (0.12 g). The resultant mixture was stirred at an ambient temperature under H2 atmosphere for 10 hours. The reaction mixture was filtered through a celite pad, and washed with ethanol (2×10 ml). The combined filtrate was evaporated in vacuo to give an oily residue, which was then treated with diethyl ether (Et2O) to obtain an off-white solid (0.29 g, 98% yield). 1H NMR (500 MHz, D2O): δ 3.48 (brs, 2H), 3.01-3.19 (m, 10H), 2.80 (brs, 6H), 2.67 (brs, 2H), 1.84 (brs, 4H); 13C NMR (125 MHz, D2O): δ 179.0, 56.3, 55.7, 48.9, 45.4, 22.8; HRMS (FAB) calculated for C14H28N4O4: 317.2189 [(M+H)+], measured value: 317.2185 [(M+H)+].
Reaction SMILES: [N:1]1C=CC=CC=1.[I:7][C:8]1[CH:16]=[CH:15][C:11]([C:12](Cl)=[O:13])=[CH:10][CH:9]=1>C(Cl)Cl>[I:7][C:8]1[CH:16]=[CH:15][C:11]([C:12]([NH2:1])=[O:13])=[CH:10][CH:9]=1
Reactant: c1ccncc1
Reactant: O=C(Cl)c1ccc(I)cc1
Solvent: ClCCl
Product: NC(=O)c1ccc(I)cc1
Reaction time: 8 h

Procedure:
The optically pure resin-bound secondary amine resin (from C) was swelled in DCM (200 mL). To the suspension was added pyridine (3.19 g) and then 4-iodobenzoyl chloride (5.3 g, 20.0 millimole). The suspension was shaken overnight. The resin was filtered and washed with 3 portions of DCM, 3 portions of methanol, 3 portions of DCM, and 3 portions of methanol. The resin was dried in vacuo overnight.
Reaction SMILES: [Br:1][C:2]1[NH:13][C:5]2[C:6](=[O:12])[NH:7][CH2:8][CH2:9][C:10](=[O:11])[C:4]=2[C:3]=1[Br:14].[BH4-].[Na+]>CN(C=O)C.CO>[Br:1][C:2]1[NH:13][C:5]2[C:6](=[O:12])[NH:7][CH2:8][CH2:9][CH:10]([OH:11])[C:4]=2[C:3]=1[Br:14]
Reactant: O=C1NCCC(=O)c2c1[nH]c(Br)c2Br
Agent: [BH4-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Product: O=C1NCCC(O)c2c1[nH]c(Br)c2Br
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2,3-dibromo-6,7-dihydro-1H,5H-pyrrolo[2,3-c]azepine-4,8-dione (2.5 g, 7.74 mmol) in a mixture of DMF-MeOH (6 mL) is added NaBH4 (1.47 g, 38.7 mmol). The mixture is stirred at room temperature overnight. It is concentrated and water is added. The mixture is extracted with EtOAc, washed with brine and dried. After the solvent is removed, the residue is subjected to silica gel column chromatography and eluted with CH2Cl2-MeOH to give 2,3-dibromo-4-hydroxy-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]azepin-8-one; 1H NMR (DMSO-d6) δ 1.74-1.84 (m, 1H), 2.01-2.10 (m, 1H), 3.00-3.10 (m, 1H), 3.42-3.50 (m, 1H), 4.63-4.68 (m, 1H), 5.06 (d, 1H, J=6.4 Hz), 7.92 (d, 1H, J=4.4 Hz); m/z [M++1] 324.9.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[N:5]([CH:27]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:6]2[C:11]([C:12]=1[CH2:13][CH2:14][O:15][C:16]1[CH:25]=[CH:24][C:19]([C:20]([O:22]C)=[O:21])=[CH:18][CH:17]=1)=[CH:10][C:9]([Cl:26])=[CH:8][CH:7]=2.C([O-])(O)=O.[Na+].[C:45]1([CH2:51][S:52](Cl)(=[O:54])=[O:53])[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1>C(Cl)Cl>[CH:27]([N:5]1[C:6]2[C:11](=[CH:10][C:9]([Cl:26])=[CH:8][CH:7]=2)[C:12]([CH2:13][CH2:14][O:15][C:16]2[CH:17]=[CH:18][C:19]([C:20]([OH:22])=[O:21])=[CH:24][CH:25]=2)=[C:4]1[CH2:3][CH2:2][NH:1][S:52]([CH2:51][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)(=[O:54])=[O:53])([C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: COC(=O)c1ccc(OCCc2c(CCN)n(C(c3ccccc3)c3ccccc3)c3ccc(Cl)cc23)cc1
Reactant: O=S(=O)(Cl)Cc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: O=C(O)c1ccc(OCCc2c(CCNS(=O)(=O)Cc3ccccc3)n(C(c3ccccc3)c3ccccc3)c3ccc(Cl)cc23)cc1
Yield: 86 %

Procedure:
To methyl 4-{2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoate (1.0 equiv) and sat. NaHCO3 (0.14 M) in CH2Cl2 (0.07 M) was added α-toluenesulfonyl chloride (1.0 equiv). After 1 h the mixture was poured into saturated sodium bicarbonate and extracted with CH2Cl2. The combined organic phase was washed with brine, dried over sodium sulfate and purified by column chromatography (gradient elution using 20% EtOAc-hexanes→50% EtOAc-hexanes) to afford 86% of the desired product.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][C:9]2[C:14]([F:15])=[CH:13][C:12]([NH:16][C:17]([C:19]3[C:20](=[O:32])[N:21]([C:25]4[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=4)[CH:22]=[CH:23][CH:24]=3)=[O:18])=[C:11]([F:33])[CH:10]=2)[CH:5]=[CH:4][N:3]=1.[Si:34]([O:41][CH2:42][CH2:43][N:44]1[CH:48]=[C:47](B2OC(C)(C)C(C)(C)O2)[CH:46]=[N:45]1)([C:37]([CH3:40])([CH3:39])[CH3:38])([CH3:36])[CH3:35].C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.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>[Si:34]([O:41][CH2:42][CH2:43][N:44]1[CH:48]=[C:47]([C:2]2[CH:7]=[C:6]([O:8][C:9]3[C:14]([F:15])=[CH:13][C:12]([NH:16][C:17]([C:19]4[C:20](=[O:32])[N:21]([C:25]5[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=5)[CH:22]=[CH:23][CH:24]=4)=[O:18])=[C:11]([F:33])[CH:10]=3)[CH:5]=[CH:4][N:3]=2)[CH:46]=[N:45]1)([C:37]([CH3:40])([CH3:38])[CH3:39])([CH3:36])[CH3:35]
Reactant: CC1(C)OB(c2cnn(CCO[Si](C)(C)C(C)(C)C)c2)OC1(C)C
Reactant: O=C(Nc1cc(F)c(Oc2ccnc(Cl)c2)cc1F)c1cccn(-c2ccc(F)cc2)c1=O
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: C1COCCO1
Solvent: O
Product: CC(C)(C)[Si](C)(C)OCCn1cc(-c2cc(Oc3cc(F)c(NC(=O)c4cccn(-c5ccc(F)cc5)c4=O)cc3F)ccn2)cn1
Temperature: 70 °C
Yield: 87.6 %

Procedure:
A mixture of N-(4-((2-chloropyridin-4-yl)oxy)-2,5-difluorophenyl)-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide (0.101 g, 0.214 mmol), 1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.098 g, 0.278 mmol) and K2CO3 (0.089 g, 0.642 mmol) in dioxane (2 mL) and H2O (0.333 mL) was sparged with Ar, treated with Pd(PPh3)4 (0.012 g, 10.70 μmol), sparged with Ar again, and heated to 70° C. overnight. The mixture was cooled to RT, treated with satd. NaHCO3, extracted with EtOAc (2×) and the combined organics were washed with brine, dried over MgSO4, concentrated to dryness and purified via silica gel chromatography (EtOAc/Hex) to afford N-(4-((2-(1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-1H-pyrazol-4-yl)pyridin-4-yl)oxy)-2,5-difluorophenyl)-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide (124 mg, 88%) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 12.44 (s, 1H); 8.58-8.59 (m, 2H); 8.39 (d, J=5.7 Hz, 1H); 8.23 (s, 1H); 8.16 (dd, J=6.6, 2.2 Hz, 1H); 8.01 (s, 1H); 7.60-7.62 (m, 3H); 7.43 (m, 2H); 7.19 (d, J=2.5 Hz, 1H); 6.43-6.75 (m, 2H); 4.18 (t, J=5.1 Hz, 2H); 3.89 (t, J=5.2 Hz, 2H); 0.75 (s, 9H); −0.12 (s, 6H); MS (ESI) m/z: 662.3 (M+H+).
Reaction SMILES: [CH3:1][C:2]1[NH:11][C:10](=[O:12])[C:9]2[C:4](=[CH:5][C:6]3[CH2:15][CH2:14][C@@H:13]([N:16]([C:20]4[CH:28]=[CH:27][C:23]([C:24]([OH:26])=[O:25])=[CH:22][CH:21]=4)[CH2:17][C:18]#[CH:19])[C:7]=3[CH:8]=2)[N:3]=1.[F:29][C:30]1[C:35](O)=[C:34]([F:37])[C:33]([F:38])=[C:32]([F:39])[C:31]=1[F:40]>>[CH3:1][C:2]1[NH:11][C:10](=[O:12])[C:9]2[C:4](=[CH:5][C:6]3[CH2:15][CH2:14][C@@H:13]([N:16]([C:20]4[CH:21]=[CH:22][C:23]([C:24]([O:26][C:35]5[C:34]([F:37])=[C:33]([F:38])[C:32]([F:39])=[C:31]([F:40])[C:30]=5[F:29])=[O:25])=[CH:27][CH:28]=4)[CH2:17][C:18]#[CH:19])[C:7]=3[CH:8]=2)[N:3]=1
Reactant: C#CCN(c1ccc(C(=O)O)cc1)[C@@H]1CCc2cc3nc(C)[nH]c(=O)c3cc21
Reactant: Oc1c(F)c(F)c(F)c(F)c1F
Product: C#CCN(c1ccc(C(=O)Oc2c(F)c(F)c(F)c(F)c2F)cc1)[C@@H]1CCc2cc3nc(C)[nH]c(=O)c3cc21
Yield: 68 %

Procedure:
Using an analogous procedure to that described in the first paragraph of Example 3, p-[N-((6R)-2-methyl-4-oxo-3,4,7,8-tetrahydro-6H-cyclopenta[g]quinazolin-6-yl)-N-(prop-2-ynyl)amino]benzoic acid was reacted with pentafluorophenol to give pentafluorophenyl p-[N-((6R)-2-methyl-4-oxo-3,4,7,8-tetrahydro-6H-cyclopenta[g]quinazolin-6-yl)-N-(prop-2-ynyl)amino]benzoate in 68% yield.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10](=[O:12])[CH3:11])=[C:6]([OH:13])[CH:5]=1)([CH3:3])[CH3:2].[C:14]([O-])([O-])=O.[K+].[K+].CI>CC(C)=O>[CH:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10](=[O:12])[CH3:11])=[C:6]([O:13][CH3:14])[CH:5]=1)([CH3:3])[CH3:2]
Reactant: O=C([O-])[O-]
Reactant: CC(=O)c1ccc(C(C)C)cc1O
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: COc1cc(C(C)C)ccc1C(C)=O

Procedure:
4′-isopropyl-2′-hydroxyacetophenone (33.4 g, 187.4 mmol) is dissolved in acetone (233 ml). Following addition of K2CO3 (51.8 g, 374.8 mmol) and methyl iodide (23.33 ml, 374.8 mmol) the batch is heated at reflux for three days. The reaction mixture is cooled and filtered through a glass fibre filter and the residue is washed with cold acetone. The solvent is removed and the residue is chromatographed (silica gel, eluent: ethyl acetate/hexane). This isolates 31.85 g (88.4%) of the desired compound.
Reaction SMILES: [F:1][CH:2]1[CH2:15][C:14]2[CH:13]=[C:12]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH:11]=[CH:10][C:9]=2[C:8]2[C:3]1=[CH:4][C:5]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])=[CH:6][CH:7]=2.C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N>C1(C)C=CC=CC=1>[F:1][C:2]1[C:3]2[C:8]([C:9]3[CH:10]=[CH:11][C:12]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:13][C:14]=3[CH:15]=1)=[CH:7][CH:6]=[C:5]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[CH:4]=2
Reactant: CCCCCCCCc1ccc2c(c1)CC(F)c1cc(CCCCCCCC)ccc1-2
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: Cc1ccccc1
Product: CCCCCCCCc1ccc2c(c1)cc(F)c1cc(CCCCCCCC)ccc12

Procedure:
From 9-fluoro-2,7-dioctyl-9,10-dihydrophenanthrene by dehydrogenation with DDQ in toluene.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:8][O:9][C:10](=[O:13])[CH:11]=[CH2:12].C(N(CC)CC)C>C(#N)C>[C:10]([O:9][CH3:8])(=[O:13])/[CH:11]=[CH:12]/[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Ic1ccccc1
Reactant: C=CC(=O)OC
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COC(=O)/C=C/c1ccccc1
Temperature: 100 °C
Reaction time: 12 h
Yield: 35 %

Procedure:
To a solution of iodobenzene (102 mg), methylacrylate (1.25 eq.) and triethylamine (1.25 eq.) in acetonitrile (3.00 ml) was added the catalyst substrate (5×5) obtained in Example 2. The mixture was stirred at 100° C. for 12 h under an argon atmosphere. The organic layers were then washed with brine and dried over sodium sulfate. The solvents were removed under reduced pressure and the resulting residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=5:1). The intended product, trans-methyl cinnamate was obtained with yield of 35%. The recycled substrate was subjected to the above reaction conditions in a 2nd run and the intended product methyl cinnamate was obtained with yield of 13%. Further conducted the 3rd run and the intended methyl cinnamate was obtained with yield of 9%.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](=[O:12])[NH:4][N:3]=1.[NH:13]1[CH2:18][CH2:17][S:16][CH2:15][CH2:14]1>>[S:16]1[CH2:17][CH2:18][N:13]([C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5](=[O:12])[NH:4][N:3]=2)[CH2:14][CH2:15]1
Reactant: C1CSCCN1
Reactant: O=c1[nH]nc(Cl)c2ccccc12
Product: O=c1[nH]nc(N2CCSCC2)c2ccccc12

Procedure:
4-chlorophthalazin-1(2H)-one and thiomorpholine were processed using a method similar to that described in Example 1A to afford the title compound. MS (APCI+) M/Z 248 (M+H)+.
Reaction SMILES: [N:1]1([C:7]2[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][C:8]=2[C:9](O)=[O:10])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.S(Cl)([Cl:21])=O>C1(C)C=CC=CC=1.CN(C=O)C>[N:1]1([C:7]2[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][C:8]=2[C:9]([Cl:21])=[O:10])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1cc([N+](=O)[O-])ccc1N1CCOCC1
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: O=C(Cl)c1cc([N+](=O)[O-])ccc1N1CCOCC1
Temperature: 80 °C
Yield: 92.4 %

Procedure:
To a suspension of 2-Morpholin-4-yl-5-nitro-benzoic acid (4.0 g, 16 mmol) in toluene were added 2 drops of DMF and thionylchloride (5.7 ml, 79.3 mmol). The mixture was heated to 80° C. for 50 minutes. The solvent was removed in vacuo, and the resulting solid was stirred in ether, filtered and dried to provide the title compound (4.0 g, 93%) as a yellow solid.
Reaction SMILES: [OH:1][C:2]1[C:6]([CH2:7][C:8]([O:10][CH3:11])=[O:9])=[CH:5][N:4]([CH3:12])[N:3]=1.Cl[CH2:14][C:15]1[O:19][N:18]=[C:17]([O:20][CH2:21][C:22]2[CH:31]=[CH:30][C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[N:23]=2)[CH:16]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH3:12][N:4]1[CH:5]=[C:6]([CH2:7][C:8]([O:10][CH3:11])=[O:9])[C:2]([O:1][CH2:14][C:15]2[O:19][N:18]=[C:17]([O:20][CH2:21][C:22]3[CH:31]=[CH:30][C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[N:23]=3)[CH:16]=2)=[N:3]1
Reactant: ClCc1cc(OCc2ccc3ccccc3n2)no1
Reactant: COC(=O)Cc1cn(C)nc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)Cc1cn(C)nc1OCc1cc(OCc2ccc3ccccc3n2)no1
Temperature: 60 °C
Reaction time: 4 h
Yield: 94.5 %

Procedure:
A mixture of methyl (3-hydroxy-1-methyl-1H-pyrazol-4-yl)acetate (298 mg), 2-(5-chloromethyl-3-isoxazolyloxymethyl)quinoline (481 mg), potassium carbonate (484 mg) and N,N-dimethylformamide (10 ml) was stirred at 60° C. for 4 hrs. The reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and methyl [1-methyl-3-[3-(2-quinolylmethoxy)-5-isoxazolylmethoxy]-1H-pyrazol-4-yl]acetate (676 mg, yield 95%) was obtained as a colorless oil from a fraction eluted with ethyl acetate-hexane (2:1, volume ratio).
Reaction SMILES: Cl[C:2]1[C:6]([C:7]([N:9]([O:11][CH3:12])[CH3:10])=[O:8])=[CH:5][N:4]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[N:3]=1.[NH:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1.CCOC(C)=O>CN1C(=O)CCC1>[CH3:12][O:11][N:9]([CH3:10])[C:7]([C:6]1[C:2]([N:22]2[CH2:26][CH2:25][CH2:24][CH2:23]2)=[N:3][N:4]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[CH:5]=1)=[O:8]
Reactant: COc1ccc(Cn2cc(C(=O)N(C)OC)c(Cl)n2)cc1
Reactant: C1CCNC1
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: COc1ccc(Cn2cc(C(=O)N(C)OC)c(N3CCCC3)n2)cc1
Yield: 89.7 %

Procedure:
According to Scheme 14 Step 1: A solution of 3-chloro-N-methoxy-1-(4-methoxybenzyl)-N-methyl-1H-pyrazole-4-carboxamide (0.97 mmol, 300 mg) and pyrrolidine (14.5 mmol, 1.03 g) in NMP (10 mL) was stirred at 220° C. for 40 minutes under microwave heating. AcOEt was then added and the organic phase was washed with water. The organic layer was dried over MgSO4, was filtered and was concentrated. The crude compound was purified by flash chromatography with silica gel using cyclohexane/AcOEt (100:0 to 50:50) to yield N-methoxy-1-(4-methoxybenzyl)-N-methyl-3-(pyrrolidin-1-yl)-1H-pyrazole-4-carboxamide (0.87 mmol, 300 mg, 90%) as an oil.