Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:7]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[C:6]([O:13][CH3:14])[N:5]=[CH:4][N:3]=1.[CH:15]1[C:20]([OH:21])=[CH:19][CH:18]=[CH:17][C:16]=1[CH3:22].C(=O)([O-])[O-].[K+].[K+].C1OCCOCCOCCOCCOCCOC1>CN(C)C=O.CCOCC>[CH3:22][C:16]1[CH:15]=[C:20]([CH:19]=[CH:18][CH:17]=1)[O:21][C:2]1[C:7]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[C:6]([O:13][CH3:14])[N:5]=[CH:4][N:3]=1
Reactant: COC(=O)Cc1c(Cl)ncnc1OC
Reactant: Cc1cccc(O)c1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: COC(=O)Cc1c(OC)ncnc1Oc1cccc(C)c1

Procedure:
A mixture of methyl 4-chloro-6-methoxy-pyrimidin-5-yl-acetate (21.7 g, 100 mmol), m-cresol (10.8 g, 100mmol), potassium carbonate (20.7 g, 150 mmol) and a catalytic amount of 18-crown-6 in dimethylformamide (50 ml) is heated to +120° C. for 1 hour. Addition of crushed ice, extraction with ether and drying gives the methyl 4-(3-methylphenoxy)-6-methoxy-pyrimidin-5-yl-acetate as an oil.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]([N:14]1[CH2:19][CH2:18][CH:17]([C:20]([O:22][CH3:23])=[O:21])[CH2:16][CH2:15]1)=[O:13])[CH:6]=[CH:5]2.[C:24]([C@@H:28]1[CH2:33][CH2:32][C@H:31](O)[CH2:30][CH2:29]1)([CH3:27])([CH3:26])[CH3:25].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1.C(OCC)(=O)C>[C:24]([C@H:28]1[CH2:33][CH2:32][C@H:31]([O:1][C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[CH:8]=[C:7]([C:12]([N:14]2[CH2:19][CH2:18][CH:17]([C:20]([O:22][CH3:23])=[O:21])[CH2:16][CH2:15]2)=[O:13])[CH:6]=[CH:5]3)[CH2:30][CH2:29]1)([CH3:27])([CH3:26])[CH3:25]
Reactant: CC(C)(C)[C@H]1CC[C@@H](O)CC1
Reactant: COC(=O)C1CCN(C(=O)c2ccc3cc(O)ccc3c2)CC1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)C1CCN(C(=O)c2ccc3cc(O[C@H]4CC[C@H](C(C)(C)C)CC4)ccc3c2)CC1
Temperature: 80 °C
Reaction time: 12 h

Procedure:
To a stirring mixture of methyl 1-(6-hydroxy-2-naphthoyl)piperidine-4-carboxylate (500 mg, 1.59 mmol), cis-4-(t-butyl)cyclohexanol (487 mg, 3.18 mmol, 2 equiv) and PPh3 (833 mg, 3.18 mmol, 2 eq) in THF (5 mL) was added DIAD (642 g, 3.18 mmol, 2 eq) at room temperate under N2 atmosphere, then the mixture was stirred at 80° C. for 12 h. The reaction mixture was diluted with ethyl acetate (20 mL) and washed with water (5 mL*3). The organic solvent was removed in vacuum and the residue was purified by silica gel chromatography (petroleum ether:ethyl acetate=1:1) to give methyl 1-(6-(trans-4-tert-butylcyclohexyloxy)-2-naphthoyl)piperidine-4-carboxylate (230 mg, yield: 32%) as a yellow solid. ESI-MS (M+1)+: 453.2. 1HNMR (400 MHz, CDCl3) δ: 7.76-7.70 (m, 3H), 7.43 (d, 1H), 7.18 (d, 1H), 7.16 (s, 1H), 4.32-4.26 (m, 1H), 3.71 (s, 3H), 3.08-3.06 (m, 2H), 2.60-2.58 (m, 1H), 2.28-2.26 (m, 2H), 1.91-1.88 (m, 4H), 1.67-1.65 (m, 4H), 1.29-1.26 (m, 2H), 1.12-1.11 (m, 3H), 0.88 (s, 9H).
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:6]([C:31]1[CH:36]=[CH:35][N:34]=[CH:33][N:32]=1)[S:7]([C:10]1[CH:15]=[CH:14][C:13]([O:16][C@H:17]2[CH2:21][CH2:20][CH2:19][C@@H:18]2[C:22]2[N:26]([CH2:27][CH3:28])[N:25]=[CH:24][CH:23]=2)=[C:12]([F:29])[C:11]=1[F:30])(=[O:9])=[O:8].C([SiH](CC)CC)C>ClCCl.FC(F)(F)C(O)=O>[CH2:27]([N:26]1[C:22]([C@H:18]2[CH2:19][CH2:20][CH2:21][C@@H:17]2[O:16][C:13]2[CH:14]=[CH:15][C:10]([S:7]([NH:6][C:31]3[CH:36]=[CH:35][N:34]=[CH:33][N:32]=3)(=[O:8])=[O:9])=[C:11]([F:30])[C:12]=2[F:29])=[CH:23][CH:24]=[N:25]1)[CH3:28]
Reactant: CCn1nccc1[C@H]1CCC[C@@H]1Oc1ccc(S(=O)(=O)N(Cc2ccc(OC)cc2OC)c2ccncn2)c(F)c1F
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCn1nccc1[C@H]1CCC[C@@H]1Oc1ccc(S(=O)(=O)Nc2ccncn2)c(F)c1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To the N-(2,4-dimethoxybenzyl)-4-{[(1S,2R)-2-(1-ethyl-1H-pyrazol-5-yl)cyclopentyl]oxy}-2,3-difluoro-N-(pyrimidin-4-yl)benzenesulfonamide (100.3 g, 167 mmol) prepared in Example 119b and triethylsilane (30 mL) in dichloromethane (300 mL), trifluoroacetic acid (300 mL) was added with cooling on ice, and the reaction solution was stirred at room temperature for 1 hour. The reaction solution was concentrated, and the residue was purified with silica gel chromatography (ethyl acetate/methanol=9:1) to yield the title compound as a colorless solid. A suspension of this title compound in ethyl acetate (200 mL) was further irradiated with ultrasonic wave for 20 minutes. The suspension was filtered, and crystals collected by filtration were washed with ethyl acetate and dried at 40° C. for 24 hours to yield the title compound (32.9 g, 44%) as colorless crystals.
Reaction SMILES: [OH:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[NH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>O.CC(C)=O>[C:10]1([NH:9][C:5]2[C:4]([NH:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)=[N:3][C:2](=[O:1])[C:7](=[O:8])[CH:6]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: Oc1cccnc1O
Reactant: Nc1ccccc1
Solvent: CC(C)=O
Solvent: O
Product: O=C1C=C(Nc2ccccc2)C(Nc2ccccc2)=NC1=O
Reaction time: 2 h
Yield: 25 %

Procedure:
2,3-dihydroxypyridine (0.0027 mol), aniline (0.0054 mol), and NaIO3 (0.0009 mol) were dissolved in 160 ml water/acetone (80:1, v/v) solvent. The reaction mixture was stirred for 2 hours, and maintained still overnight. Product was then filtered and recrystallized with petroleum ether. 5,6-diphenylamino-2,3-pyridindione can then be obtained in a brown yellow powder. The yield was 25%-45%.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:20])=[C:6]([CH:8]=[CH:9][C:10]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)=O)[CH:7]=1.[BH4-].[Na+].C(O)(=O)C>C(O)C>[Br:1][C:2]1[CH:7]=[C:6]2[C:5](=[CH:4][CH:3]=1)[O:20][CH:10]([C:12]1[CH:13]=[CH:14][C:15]([O:18][CH3:19])=[CH:16][CH:17]=1)[CH2:9][CH2:8]2
Reactant: COc1ccc(C(=O)C=Cc2cc(Br)ccc2O)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Product: COc1ccc(C2CCc3cc(Br)ccc3O2)cc1
Reaction time: 0.5 h

Procedure:
5-Bromo-2-hydroxy-4'-methoxychalcone (16.7 g) was suspended in ethanol (200 ml) and sodium borohydride (3.78 g) added in portions. The resulting solution was stirred for 30 min, then allowed to stand overnight. The solvent was evaporated off, and the residue dissolved in chloroform and washed with water. Evaporation of the solvent gave the crude carbinol intermediate which was boiled under reflux with acetic acid for 2 hr. On cooling, 6-bromo-4'-methoxyflavan crystallised out and was filtered off and dried, 10.2 g, m.p. 121°-123°.
Reaction SMILES: [OH:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.[C:17](Cl)(=[O:22])[C:18]([CH3:21])([CH3:20])[CH3:19]>N1C=CC=CC=1>[C:17]([O:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1)(=[O:22])[C:18]([CH3:21])([CH3:20])[CH3:19]
Reactant: CC(C)(C)C(=O)Cl
Reactant: O=C(c1ccc(O)cc1)c1ccc(Cl)cc1
Solvent: c1ccncc1
Product: CC(C)(C)C(=O)Oc1ccc(C(=O)c2ccc(Cl)cc2)cc1

Procedure:
2.16 g (0.01 mole) of 4-hydroxy-4'-chlorobenzophenone and 1.2 g (0.015 mole) of pivaloyl chloride in solution were warmed to 50° C. for 3 hrs in 60 mls of dry pyridine with a drying tube attached. The solvent was removed via rotary evaporator and H2O added. The product was filtered and recrystallized from ethanol; 2.3 g (73%) yield; M.P.~113°-114° C.
Reaction SMILES: [CH3:1][C:2]1([CH2:7][CH2:8][CH2:9][CH2:10][N:11]2[CH:15]=[C:14]([NH2:16])[CH:13]=[N:12]2)[O:6]CCO1.[CH3:17][C:18]1[S:19][C:20]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[C:21]([C:23](O)=[O:24])[N:22]=1>>[O:6]=[C:2]([CH3:1])[CH2:7][CH2:8][CH2:9][CH2:10][N:11]1[CH:15]=[C:14]([NH:16][C:23]([C:21]2[N:22]=[C:18]([CH3:17])[S:19][C:20]=2[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)=[O:24])[CH:13]=[N:12]1
Reactant: Cc1nc(C(=O)O)c(-c2ccccc2)s1
Reactant: CC1(CCCCn2cc(N)cn2)OCCO1
Product: CC(=O)CCCCn1cc(NC(=O)c2nc(C)sc2-c2ccccc2)cn1

Procedure:
Following general procedure B followed by either C or D, starting from 1-[4-(2-methyl-[1,3]dioxolan-2-yl)-butyl]-1H-pyrazol-4-ylamine and 2-methyl-5-phenyl-thiazole-4-carboxylic acid. LC-MS-conditions 01: tR=0.94 min; [M+H]+=383.10.
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[CH2:13][C:12]2[S:11][C:10]3[C:9](=[O:14])[NH:8][N:7]=[CH:6][C:5]=3[C:4]=2[CH2:3]1.Br[C:17]1[N:24]=[CH:23][CH:22]=[C:21]([Cl:25])[C:18]=1[CH:19]=[O:20]>>[Cl:25][C:21]1[CH:22]=[CH:23][N:24]=[C:17]([N:8]2[N:7]=[CH:6][C:5]3[C:4]4[CH2:3][C:2]([CH3:15])([CH3:1])[CH2:13][C:12]=4[S:11][C:10]=3[C:9]2=[O:14])[C:18]=1[CH:19]=[O:20]
Reactant: CC1(C)Cc2sc3c(=O)[nH]ncc3c2C1
Reactant: O=Cc1c(Cl)ccnc1Br
Product: CC1(C)Cc2sc3c(=O)n(-c4nccc(Cl)c4C=O)ncc3c2C1

Procedure:
Following the procedures as described in Example 108a, and starting with 282h (330 mg, 1.5 mmol) and 2-bromo-4-chloronicotinaldehyde (950 mg, 4.5 mmol), 282i was obtained as a yellow solid (260 mg, 48%). MS-ESI: [M+H]+ 359.9
Reaction SMILES: [OH:1][CH2:2][N:3]1[C:8](=[O:9])[CH2:7][N:6]([CH2:10][CH2:11][N:12]2[CH2:17][C:16](=[O:18])[N:15]([CH2:19][OH:20])[C:14](=[O:21])[CH2:13]2)[CH2:5][C:4]1=[O:22].[C:23]1([C:28](Cl)=[O:29])[S:27][CH:26]=[CH:25][CH:24]=1>N1C=CC=CC=1>[C:23]1([C:28]([O:20][CH2:19][N:15]2[C:14](=[O:21])[CH2:13][N:12]([CH2:11][CH2:10][N:6]3[CH2:7][C:8](=[O:9])[N:3]([CH2:2][O:1][C:28](=[O:29])[C:23]4[S:27][CH:26]=[CH:25][CH:24]=4)[C:4](=[O:22])[CH2:5]3)[CH2:17][C:16]2=[O:18])=[O:29])[S:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=C(Cl)c1cccs1
Reactant: O=C1CN(CCN2CC(=O)N(CO)C(=O)C2)CC(=O)N1CO
Solvent: c1ccncc1
Product: O=C(OCN1C(=O)CN(CCN2CC(=O)N(COC(=O)c3cccs3)C(=O)C2)CC1=O)c1cccs1
Temperature: 25 °C
Reaction time: 4 h
Yield: 76.5 %

Procedure:
To a mixture of 1,2-bis(4-hydroxymethyl-3,5-dioxopiperazin-1-yl)ethane (6.30 g, 22 m mol) and pyridine (60 ml), thenoyl chloride (6.45 g, 44 m mol) was added gradually at 0° C., and then the mixture was stirred for 4 hours at room temperature. The solvent was removed from the reaction mixture under reduced pressure, and the residue was extracted with chloroform. The extract solution was washed with 10% sulfuric acid solution and successively with water, and was dried over magnesium sulfate. The residue obtained by removing the solvent from the extract solution under reduced pressure was purified by silica gel column chromatography (ethyl acetate, Rf value=0.6) to give the titled compound (8.20 g; yield 70%).
Reaction SMILES: [NH2:1][C:2]1[CH:36]=[CH:35][CH:34]=[CH:33][C:3]=1[C:4]([NH:6][CH2:7][CH2:8][CH2:9][CH2:10][N:11]1[CH2:16][CH2:15][CH:14]([CH2:17][C:18]2[N:22]([CH2:23][C:24]3[O:25][CH:26]=[CH:27][CH:28]=3)[C:21]3[CH:29]=[CH:30][CH:31]=[CH:32][C:20]=3[N:19]=2)[CH2:13][CH2:12]1)=[O:5].C(N(CC)CC)C.[C:44](Cl)(=O)[O:45]C(Cl)(Cl)Cl>O1CCCC1>[O:25]1[CH:26]=[CH:27][CH:28]=[C:24]1[CH2:23][N:22]1[C:21]2[CH:29]=[CH:30][CH:31]=[CH:32][C:20]=2[N:19]=[C:18]1[CH2:17][CH:14]1[CH2:13][CH2:12][N:11]([CH2:10][CH2:9][CH2:8][CH2:7][N:6]2[C:4](=[O:5])[C:3]3[C:2](=[CH:36][CH:35]=[CH:34][CH:33]=3)[NH:1][C:44]2=[O:45])[CH2:16][CH2:15]1
Reactant: Nc1ccccc1C(=O)NCCCCN1CCC(Cc2nc3ccccc3n2Cc2ccco2)CC1
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=c1[nH]c2ccccc2c(=O)n1CCCCN1CCC(Cc2nc3ccccc3n2Cc2ccco2)CC1
Reaction time: 8 h
Yield: 73 %

Procedure:
To a stirred mixture of 3.88 parts of 2-amino-N-[4-[4-[[1-(2-furanylmethyl)-1H-benzimidazol-2-yl]methyl]-1-piperidinyl]butyl]benzamide, 2 parts of N,N-diethylethanamine and 90 parts of tetrahydrofuran were added dropwise 1.64 parts of trichloromethyl carbonochloridate. Upon completion, stirring was continued overnight. Another portion of 1.6 parts of B was added and the whole was stirred overnight. The precipitate was filtered off and the filtrate was evaporated. Water was added to the residue. The solution was treated with ammonium hydroxide; The product was extracted with dichloromethane. The extract was dried, filtered and evaporated. The residue was crystallized from acetonitrile. The product was filtered off and dried, yielding 3 parts (73%) of 3-[4-[4-[[1-(2-furanylmethyl)-1H-benzimidazol-2-yl]methyl]-1-piperidinyl]butyl]-2,4(1H,3H)-quinazolinedione; mp. 185.5° C. (490).
Reaction SMILES: C[Si](C)(C)CC[O:5][C:6](=[O:33])[C:7]1[C:12]([Cl:13])=[CH:11][CH:10]=[CH:9][C:8]=1[NH:14][C:15]([O:17][CH2:18][CH2:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[CH:23][CH:22]=1)=[O:16].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C1COCC1.Cl>CN(C=O)C>[C:24]1([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:23]=[CH:22][C:21]([O:20][CH2:19][CH2:18][O:17][C:15]([NH:14][C:8]2[CH:9]=[CH:10][CH:11]=[C:12]([Cl:13])[C:7]=2[C:6]([OH:33])=[O:5])=[O:16])=[CH:26][CH:25]=1
Reactant: C[Si](C)(C)CCOC(=O)c1c(Cl)cccc1NC(=O)OCCOc1ccc(-c2ccccc2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [F-]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: O=C(Nc1cccc(Cl)c1C(=O)O)OCCOc1ccc(-c2ccccc2)cc1
Yield: 44.2 %

Procedure:
To a solution of 2-[2-(biphenyl-4-yloxy)-ethoxycarbonylamino]-6-chloro-benzoic acid 2-trimethylsilanyl-ethyl ester (340 mg, 0.664 mmol) and 1.0M tetrabutyl ammonium fluoride in THF (0.66 mL, 0.6636 mmol) in DMF (6 mL) and the mixture was stirred for 2 h. 2N HCl was added to adjust the pH to 1-2 and the mixture was partitioned between water and ethyl acetate. The combined organics were washed with water, then brine dried over magnesium sulfate and concentrated to dryness. Purification by crystallization gave 0.121 g of 2-[2-(biphenyl-4-yloxy)-ethoxycarbonylamino]-6-chloro-benzoic acid as a white solid, 801, mp:157.5-158.9.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([C:9]([OH:11])=O)[NH:5][C:6]=1[CH2:7][CH3:8].S(Cl)(Cl)=O.[NH2:16][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[CH2:22][N:21]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:20]2>N1C=CC=CC=1>[Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:16][C:17]2[CH:18]=[C:19]3[C:23](=[CH:24][CH:25]=2)[CH2:22][N:21]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:20]3)=[O:11])[NH:5][C:6]=1[CH2:7][CH3:8]
Reactant: CCc1[nH]c(C(=O)O)nc1Cl
Reactant: CC(C)(C)OC(=O)N1Cc2ccc(N)cc2C1
Solvent: O=S(Cl)Cl
Solvent: c1ccncc1
Product: CCc1[nH]c(C(=O)Nc2ccc3c(c2)CN(C(=O)OC(C)(C)C)C3)nc1Cl
Yield: 64 %

Procedure:
The same operation as in Example (91c) was performed using 4-chloro-5-ethyl-1H-imidazole-2-carboxylic acid (410 mg, 2.36 mmol), thionyl chloride (5 mL), tert-butyl 5-amino-1,3-dihydro-2H-isoindole-2-carboxylate (described in Andronati, S. A.; Krys'ko, A. A.; Chugunov, B. M.; Kabanova, T. A.; Artemenko, A. G.; Russ. J. Org. Chem., 42, 8, 2006, 1174-1182, 0.94 g, 4 mmol) and pyridine (5 mL), to obtain 619 mg of the title compound as a white solid (64%).
Reaction SMILES: [CH2:1]([N:8]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([C:17]3[CH:18]=[C:19]([CH2:27][CH2:28][CH2:29]Br)[N:20]4[C:25]=3[C:24]([NH2:26])=[N:23][CH:22]=[N:21]4)[CH:13]=[CH:14]2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:31]1[CH2:35][CH2:34][CH2:33][CH2:32]1.C(N(CC)CC)C.[I-].[Na+]>CN(C=O)C>[CH2:1]([N:8]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([C:17]3[CH:18]=[C:19]([CH2:27][CH2:28][CH2:29][N:31]4[CH2:35][CH2:34][CH2:33][CH2:32]4)[N:20]4[C:25]=3[C:24]([NH2:26])=[N:23][CH:22]=[N:21]4)[CH:13]=[CH:14]2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ncnn2c(CCCBr)cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c12
Reactant: C1CCNC1
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Nc1ncnn2c(CCCN3CCCC3)cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c12
Yield: 84.2 %

Procedure:
A solution of 5-(2-benzyl-2H-indazol-6-yl)-7-(3-bromopropyl)pyrrolo[2,1-f][1,2,4]-triazin-4-ylamine (2.62 g, 5.68 mmol), pyrrolidine (808 mg, 11.36 mmol, 2.0 eq), triethylamine (575 mg, 5.68 mmol, 1.0 eq); and sodium iodide (85 mg, 0.56 mmol, 0.1 eq) in anhydrous DMF (28 mL) was stirred at 55° C. for 17 h. The reaction mixture was partitioned between EtOAc and water, and the organic layer was washed with 50% aq. brine (3×), dried over Na2SO4, filtered, and concentrated at reduced pressure. The crude was triturated from MeOH, filtered, and washed with cold MeOH and ether to provide 2.16 g (84.2%) of the desired product as a white solid. 1H-NMR (DMSO-d6) 8.54 (s, 1H), 7.89 (s, 1H), 7.80 (d, 1H), 7.58 (s, 1H), 7.36 to 7.30 (m, 5H), 7.14 (d, 1H), 6.59 (s, 1H), 5.65 (s, 2H), 2.90 (t, 2H), 2.48 to 2.39 (m, 6H), 1.87 to 1.83 (m, 2H), 1.67 to 1.64 (m, 4H); LC-MS [M+H]+=452, RT=2.14 min.
Reaction SMILES: C(N(CC)CC)C.Cl.[NH2:9][CH2:10][C:11]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:12]=1[C:13](=[O:29])[N:14]([CH:21]1[CH2:26][CH2:25][C:24](=[O:27])[NH:23][C:22]1=[O:28])[C:15]2=[O:20].[C:30]1([CH3:39])[CH:35]=[CH:34][CH:33]=[C:32]([C:36](Cl)=[O:37])[CH:31]=1>C1COCC1>[O:28]=[C:22]1[CH:21]([N:14]2[C:13](=[O:29])[C:12]3[C:16](=[CH:17][CH:18]=[CH:19][C:11]=3[CH2:10][NH:9][C:36](=[O:37])[C:32]3[CH:33]=[CH:34][CH:35]=[C:30]([CH3:39])[CH:31]=3)[C:15]2=[O:20])[CH2:26][CH2:25][C:24](=[O:27])[NH:23]1
Reactant: NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Reactant: Cc1cccc(C(=O)Cl)c1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1cccc(C(=O)NCc2cccc3c2C(=O)N(C2CCC(=O)NC2=O)C3=O)c1
Temperature: 5 °C
Reaction time: 0.17 h

Procedure:
Triethylamine (0.5 g, 5.0 mmol) was added to a stirred suspension of 4-aminomethyl-2-(2,6-dioxo-piperidin-3-yl)-isoindole-1,3-dione hydrochloride (0.7 g, 2.0 mmol) and m-toluoyl chloride (0.4 g, 2.8 mmol) in THF (30 mL) at 5-10° C. After stirring at 5° C. for 10 minutes, the mixture was stirred at room temperature overnight. The mixture was concentrated, and the residue was stirred with 1N HCl (20 mL). The residue was dissolved in CH2Cl2 (80 mL), washed with H2O (30 mL) and brine (30 mL), and dried (MgSO4). Solvent was removed and the residue was purified by chromatography (silica gel) to N-[2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3 dihydro-1H-isoindol-4-ylmethyl]-3-methyl-benzamide (0.5 g, 66%) as a white solid: mp 218-220° C.; 1H NMR (DMSO-d6) δ 2.06-2.10 (m, 1H), 2.37 (s, 3H, CH3), 2.50-2.65 (m, 2H), 2.84-2.97 (m, 1H), 4.94 (d, J=5.7 Hz, 2H, CH2), 5.14-5.21 (dd, J=5.4 and 12.7 Hz, 1H, CH), 7.37-7.41 (m, 2H, Ar), 7.72-7.86 (m, 5H, Ar), 9.10 (t, J=5.6 Hz, 1H, NH), 11.14 (s, 1H, NH); 13C NMR (DMSO-d6) δ 20.91, 21.98, 30.93, 38.30, 48.87, 121.82, 124.42, 127.10, 127.83, 128.24, 131.52, 131.98, 132.99, 133.92, 134.77, 137.64, 139.39, 166.71, 166.96, 167.53, 169.81, 172.73; Anal. calcd. for C22H19N3O5+0.04H2O: C, 65.06; H, 4.74; N, 10.35. Found: C, 64.75; H, 4.68; N, 10.02.
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:19].[C:20]12([CH2:30][C:31](O)=[O:32])[CH2:29][CH:24]3[CH2:25][CH:26]([CH2:28][CH:22]([CH2:23]3)[CH2:21]1)[CH2:27]2>>[C:20]12([CH2:30][C:31]([NH:1][N:2]3[N:11]=[C:10]([C:12]4[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=4)[C:9]4[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=4)[C:3]3=[O:19])=[O:32])[CH2:27][CH:26]3[CH2:25][CH:24]([CH2:23][CH:22]([CH2:28]3)[CH2:21]1)[CH2:29]2
Reactant: O=C(O)CC12CC3CC(CC(C3)C1)C2
Reactant: Nn1nc(-c2cccc(Cl)c2)c2ccccc2c1=O
Product: O=C(CC12CC3CC(CC(C3)C1)C2)Nn1nc(-c2cccc(Cl)c2)c2ccccc2c1=O

Procedure:
The product of Example 125A and 2-(adamantan-1-yl)acetic acid were processed using a method similar to that described in Example 17C to afford the title compound. 1H NMR (400 MHz, DMSO) δ 11.29 (s, 1H), 8.46-8.39 (m, 1H), 8.02-7.92 (m, 2H), 7.76-7.69 (m, 1H), 7.68-7.54 (m, 4H), 2.06 (s, 2H), 1.95 (s, 3H), 1.74-1.51 (m, 12H); MS (APCI) m/z 448 (M+H)+.
Reaction SMILES: [C:1]([C:4]1[CH:8]=[CH:7][S:6][C:5]=1[NH:9][C:10](=[O:18])[C:11]([O:14][C:15](=[O:17])[CH3:16])([CH3:13])[CH3:12])(=[O:3])[NH2:2].C1C(=O)N([Cl:26])C(=O)C1>CC(O)=O.O>[C:1]([C:4]1[CH:8]=[C:7]([Cl:26])[S:6][C:5]=1[NH:9][C:10](=[O:18])[C:11]([O:14][C:15](=[O:17])[CH3:16])([CH3:12])[CH3:13])(=[O:3])[NH2:2]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CC(=O)OC(C)(C)C(=O)Nc1sccc1C(N)=O
Solvent: CC(=O)O
Solvent: O
Product: CC(=O)OC(C)(C)C(=O)Nc1sc(Cl)cc1C(N)=O
Temperature: 25 °C

Procedure:
Intermediate 10 (78.5 g, 291 mmol) is dissolved in AcOH (850 mL). To the resulting suspension, NCS (42.9 g, 320 mmol) is added. The mixture is stirred at room temperature, after which it is evaporated to give a slurry. This slurry is taken up in water to give a suspension that is filtered. Resulting precipitate is dried in the vacuum oven and used as such.
Reaction SMILES: [C:1]1([CH2:7][C:8]2[CH:15]=[CH:14][CH:13]=[C:10]([CH:11]=[O:12])[C:9]=2[OH:16])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-:17].[K+]>C(O)C.O.[N+]([O-])([O-])=O.[Ag+]>[C:1]1([CH2:7][C:8]2[CH:15]=[CH:14][CH:13]=[C:10]([C:11]([OH:17])=[O:12])[C:9]=2[OH:16])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: [OH-]
Reactant: O=Cc1cccc(Cc2ccccc2)c1O
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: O=C(O)c1cccc(Cc2ccccc2)c1O
Temperature: 25 °C
Reaction time: 6 h
Yield: 34.3 %

Procedure:
According to the general method of Sharma et al., 2000, Synth. Commun., 30:397-405, a stirred solution of the 3-(phenylmethyl)salicylaldehyde (1.27 g, 6 mmol) in ethanol (16 ml) was treated dropwise with a solution of silver nitrate (2.0 g, 12 mmol) in water (16 ml). A solution of potassium hydroxide (2.69 g, 48 mmol) was then added dropwise over 40 minutes. The solution was allowed to stir at RT for 6 h. The mixture was filtered through a pad of celite, and the filter pad washed with water (2×10 ml). The filtrate was washed with diethyl ether (2×15 ml) and then acidified with 1N HCl. The milky suspension was extracted with diethyl ether (2×30 ml), and the combined extracts were dried (Na2SO4) and the solvent removed to yield 3-(phenylmethyl)salicylic acid as a tan solid (0.47 g, 34%). 1H-NMR (CDCl3, 400 MHz): δ 4.02 (s, 2H), 6.84 (t, 1H, J=8 Hz), 7.19-7.32 (m, 6H), 7.79 (d, 1H, J=8 Hz), 10.74 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[CH:9][S:10][C:3]=12.[Li]CCCC.[O:16]1[CH:20]=[CH:19][CH:18]=[C:17]1[C:21](Cl)=[O:22]>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:21]([C:17]3[O:16][CH:20]=[CH:19][CH:18]=3)=[O:22])[S:10][C:3]=12
Reactant: Clc1ccnc2ccsc12
Reactant: O=C(Cl)c1ccco1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=C(c1ccco1)c1cc2nccc(Cl)c2s1
Reaction time: 0.25 h
Yield: 22.5 %

Procedure:
To a solution of 2 (100 mg, 0.589 mmol) in THF (6 mL) at −78° C., was added n-BuLi (2.5 M in hexane, 0.259 mL, 8.84 mmol) and the reaction mixture was stirred 15 minutes. 2-Furoyl chloride (0.087 mL, 0.884 mmol) was added drop wise; the mixture was stirred for additional 2 hours and partitioned between DCM and water. The organic layer was separated, dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford title compound 239 (35 mg, 23% yield, crude) as a yellow solid, that was used in the next step without additional purification. MS (m/z): 264.0 (100%), 266.0 (40%) (M+1).
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[C:7]([S:10][C:11]1[CH:20]=[CH:19][C:18]2[CH2:17][CH:16]([NH:21][CH2:22][CH3:23])[CH2:15][CH2:14][C:13]=2[CH:12]=1)([CH3:9])[CH3:8])([CH3:4])([CH3:3])[CH3:2].[F:25][C:26]([F:38])([F:37])[O:27][C:28]1[CH:33]=[CH:32][C:31]([N:34]=[C:35]=[O:36])=[CH:30][CH:29]=1>C(Cl)Cl>[C:1]([O:5][C:6](=[O:24])[C:7]([S:10][C:11]1[CH:20]=[CH:19][C:18]2[CH2:17][CH:16]([N:21]([CH2:22][CH3:23])[C:35]([NH:34][C:31]3[CH:32]=[CH:33][C:28]([O:27][C:26]([F:25])([F:37])[F:38])=[CH:29][CH:30]=3)=[O:36])[CH2:15][CH2:14][C:13]=2[CH:12]=1)([CH3:9])[CH3:8])([CH3:2])([CH3:3])[CH3:4]
Reactant: O=C=Nc1ccc(OC(F)(F)F)cc1
Reactant: CCNC1CCc2cc(SC(C)(C)C(=O)OC(C)(C)C)ccc2C1
Solvent: ClCCl
Product: CCN(C(=O)Nc1ccc(OC(F)(F)F)cc1)C1CCc2cc(SC(C)(C)C(=O)OC(C)(C)C)ccc2C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 58 %

Procedure:
To a mixture of 2-(6-ethylamino-5,6,7,8-tetrahydronaphthalen-2-ylsulfanyl)-2-methylpropionic acid tert-butyl ester and borane complex (1.9 g; 5.2 mmol) dissolved in CH2Cl2 (15 mL) is added 4-trifluoromethoxyphenyl isocyanate (1.6 g; 7.8 mmol) and the reaction was stirred at RT for 18 h. The solvent was removed under reduced pressure and the crude residue was purified by flash chromatography (SiO2) eluting with a hexanes-EtOAc gradient to provide 1.66 g (58%) of 2-{6-[1-ethyl-3-(4-trifluoromethoxyphenyl)ureido]-5,6,7,8-tetrahydronaphthalen-2-ylsulfanyl}-2-methylpropionic acid tert butyl ester as a white foam.