Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]([CH3:14])([C:6]#[C:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:3]([O-:5])=[O:4].C(=O)([O-])[O-].[K+].[K+].CO.Cl>O>[OH:1][C:2]([CH3:14])([C:6]#[C:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:3]([OH:5])=[O:4]
Reactant: CC(O)(C#Cc1ccccc1)C(=O)[O-]
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: CC(O)(C#Cc1ccccc1)C(=O)O
Yield: 89 %

Procedure:
A magnetically stirred mixture of 2.20 g (0.01 mole) of twice distilled 2-hydroxy-2-methyl-4-phenylbutynoate, ethyl ester 1.40 g (0.01 mole) of potassium carbonate and 3 ml of methanol in 20 ml of water was heated under a dry nitrogen atmosphere at 75°-80° C. for 1.5 hours, during which time the substrate dissolved to afford a faint yellow solution. After cooling, 20 ml of water was added and the solution was exhaustively extracted with ether. The aqueous phase was then treated with 1.5 g of Darco® activated carbon, filtered with suction through a Celite® pad and acidified in an ice bath with 2.0 ml (0.02 mole) of concentrated hydrochloric acid. The resulting oil was extracted with three 25 ml portions of ether and the combined extracts were washed with three 35 ml portions of water and dried over MgSO4. Filtration and concentration at the stripper provided an almost colorless oil which solidified on cooling. Recrystallization from hexane containing a trace of ether afforded 1.60 g (89% yield) of 2-hydroxy-2-methyl-4-phenylbutynoic acid as colorless plates, m.pt. 104.5°-106.0° C.
Reaction SMILES: [OH:1][C:2]([C:4]([F:7])([F:6])[F:5])=[O:3].C([N:15]1[CH2:24][CH2:23][C:22]2[C:17](=[N:18][C:19]([N:30]3[CH2:35][CH2:34][CH:33]([O:36][C:37]4[CH:42]=[CH:41][C:40]([F:43])=[CH:39][C:38]=4[F:44])[CH2:32][CH2:31]3)=[C:20]([NH:25][C:26]([CH3:29])([CH3:28])[CH3:27])[N:21]=2)[CH2:16]1)C1C=CC=CC=1>C1COCC1.[OH-].[OH-].[Pd+2]>[C:26]([NH:25][C:20]1[N:21]=[C:22]2[CH2:23][CH2:24][NH:15][CH2:16][C:17]2=[N:18][C:19]=1[N:30]1[CH2:31][CH2:32][CH:33]([O:36][C:37]2[CH:42]=[CH:41][C:40]([F:43])=[CH:39][C:38]=2[F:44])[CH2:34][CH2:35]1)([CH3:29])([CH3:27])[CH3:28].[C:2]([OH:3])([C:4]([F:7])([F:6])[F:5])=[O:1]
Reactant: CC(C)(C)Nc1nc2c(nc1N1CCC(Oc3ccc(F)cc3F)CC1)CN(Cc1ccccc1)CC2
Agent: [Pd+2]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)Nc1nc2c(nc1N1CCC(Oc3ccc(F)cc3F)CC1)CNCC2
Reaction time: 2 h

Procedure:
A solution of 6-benzyl-N-(tert-butyl)-3-(4-(2,4-difluorophenoxyl)piperidin-1-yl)-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-2-amine TFA salt (155 mg, 0.249 mmol) and Pd(OH)2 on carbon (35.0 mg, 0.050 mmol) in THF (2.49 mL) was purged and placed under hydrogen (balloon) atmosphere for 2 h. Filtration through Celite™ and concentration gave the title compound as a TFA salt (125 mg).
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[N:14]=[C:13]([NH:15][C:16]([NH:18][C:19]3[N:20]=[C:21]([C:24]4[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=4)[S:22][CH:23]=3)=[O:17])[CH:12]=[CH:11][CH:10]=2)[CH2:4][CH2:3]1.[CH2:30]([CH2:32][NH2:33])[OH:31]>CO>[OH:31][CH2:30][CH2:32][NH:33][CH:2]1[CH2:3][CH2:4][N:5]([CH2:8][C:9]2[N:14]=[C:13]([NH:15][C:16]([NH:18][C:19]3[N:20]=[C:21]([C:24]4[CH:25]=[CH:26][N:27]=[CH:28][CH:29]=4)[S:22][CH:23]=3)=[O:17])[CH:12]=[CH:11][CH:10]=2)[CH2:6][CH2:7]1
Reactant: O=C1CCN(Cc2cccc(NC(=O)Nc3csc(-c4ccncc4)n3)n2)CC1
Reactant: NCCO
Solvent: CO
Product: O=C(Nc1cccc(CN2CCC(NCCO)CC2)n1)Nc1csc(-c2ccncc2)n1

Procedure:
N-[2-(4-Pyridinyl)-4-thiazolyl]-N′-2-[6-(piperidon-4-yl)methyl]urea (60 mg, 0.147 mmol, Example 175) and ethanolamine (0.09 mL, 1.47 mmol) were heated in MeOH (10 mL) yielded the title compound as pale yellow solid. MS m/z: 454.6 (M+H). Calc'd. for C22H27N7O2S-453.57.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[Br:7][CH2:8][CH2:9][CH2:10]Br.[C:12]1([SH:18])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>CC(CC)=O>[Br:7][CH2:8][CH2:9][CH2:10][S:18][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Sc1ccccc1
Reactant: BrCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: BrCCCSc1ccccc1
Reaction time: 18 h

Procedure:
Powdered anhydrous potassium carbonate (4.3 kg, 31 moles) was added to a mixture of 1,3-dibromopropane (6.55 kg, 32 moles), thiophenol (1.2 kg, 10.9 moles) and methylethylketone (9 L). The alkylation was carried out under a hood in a 22 liter flask equipped with a mechanical stirrer, heating mantle, and 2 reflux condensers. Nitrogen gas was passed over the top of the condensers. Within 30 minutes the mixture had generated enough heat to attain reflux. Reflux was then maintained for another 30 to 60 minutes. The mixture was permitted to come to room temperature over an 18 hour period. The solvent layer was siphoned off and filtered through celite. The salts were filtered and washed with acetone. The filtrates were concentrated. The residue was vacuum distilled. Three fractions were collected:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH3:25])[CH:19]=2)(O)[CH2:10][CH:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[CH:6]=[CH:7][CH:8]=1>FC(F)(F)C(O)=O>[CH3:25][O:24][C:20]1[CH:19]=[C:18]([C:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=2)=[CH:10][CH:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[CH:23]=[CH:22][CH:21]=1
Reactant: COc1cccc(C(O)(CC2CCNCC2)c2cccc(OC)c2)c1
Solvent: O=C(O)C(F)(F)F
Product: COc1cccc(C(=CC2CCNCC2)c2cccc(OC)c2)c1
Yield: 90.1 %

Procedure:
A solution of alpha,alpha-bis(3-methoxyphenyl)-4-piperidine-ethanol (15 g) in trifluoroacetic acid (30 ml) was stirred at ambient temperature for one hour, then the solvent was removed in vacuo. The residue was partitioned between toluene (50 ml) and 1N sodium hydroxide (100 ml), and the separated aqueous layer was reextracted with toluene (20 ml). The combined toluene extracts were washed with 1N sodium hydroxide solution, then were dried over potassium carbonate and evaporated to give 12.8 g of 4-[2,2-bis(3-methoxyphenyl)ethenyl]piperidine as an oil.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[C:7](O)=[N:8][C:9]([CH2:12][S:13]([CH3:16])(=[O:15])=[O:14])=[N:10][CH:11]=2)[CH2:3][CH2:2]1.O=P(Cl)(Cl)[Cl:20].CO>CC#N.[N+](C)(C)(C)C.[Cl-]>[Cl:20][C:7]1[C:6]([O:5][CH2:4][CH:1]2[CH2:3][CH2:2]2)=[CH:11][N:10]=[C:9]([CH2:12][S:13]([CH3:16])(=[O:15])=[O:14])[N:8]=1
Reactant: CS(=O)(=O)Cc1ncc(OCC2CC2)c(O)n1
Reactant: O=P(Cl)(Cl)Cl
Agent: C[N+](C)(C)C
Agent: [Cl-]
Solvent: CO
Solvent: CC#N
Product: CS(=O)(=O)Cc1ncc(OCC2CC2)c(Cl)n1
Temperature: 80 °C
Yield: 49.1 %

Procedure:
To the title compound of step 1 (1.9 g, 7.36 mmol) in MeCN (30 mL) was added Me4NCl (1.6 g, 14.72 mmol) and POCl3 (6.8 g, 44.16 mmol). The mixture was heated at 80° C. for 6 h. After concentration under vacuum, the residue was subjected to EA extractive work up. Trituration with methanol (20 mL) gave the title compound (1 g, yield: 49.3%) as a white solid. 1H NMR (CDCl3, 400 MHz) δ 7.60 (s, 1H), 5.50 (s, 2H), 3.85 (d, J=6.8 Hz, 2H), 3.09 (s, 3H), 1.31-1.28 (m, 1H), 0.70-0.65 (m, 2H), 0.39-0.36 (m, 2H). LCMS: 277.1 (M+H)+
Reaction SMILES: C[C:2]([CH:5]([N:9]1[CH:13]=[C:12](B2OC(C)(C)C(C)(C)O2)[C:11]([C:23]2[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=2)=[N:10]1)[C:6]([O-])=O)(C)C.Cl.[C:33](NN)(C)(C)C>>[CH3:33][C:5]([N:9]1[CH:13]=[CH:12][C:11]([C:23]2[CH:24]=[CH:25][C:26]([N+:29]([O-:31])=[O:30])=[CH:27][CH:28]=2)=[N:10]1)([CH3:2])[CH3:6]
Reactant: CC(C)(C)NN
Reactant: CC(C)(C)C(C(=O)[O-])n1cc(B2OC(C)(C)C(C)(C)O2)c(-c2ccc([N+](=O)[O-])cc2)n1
Agent: Cl
Product: CC(C)(C)n1ccc(-c2ccc([N+](=O)[O-])cc2)n1

Procedure:
Following the procedure described for Intermediate 1 with t-butylhydrazine hydrochloride, provided the title compound as the minor isomer. ESMS (M-C(CH3)3+2H): 190.0; HNMR (400 MHz, d6-DMSO) 8.20 (d, 2H), 7.86 (d, 2H), 7.7 (d, 1H), 6.55 (d, 1H), 1.25 (s, 9H)
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[N:13]=[C:12]([CH3:14])[CH:11]=[C:10]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[C:17]([CH3:25])[CH:16]=3)[N:9]=2)[CH:5]=[CH:4][N:3]=1.[NH2:26][C:27]1[CH:32]=[CH:31][C:30](B2OC(C)(C)C(C)(C)O2)=[CH:29][N:28]=1>>[CH3:14][C:12]1[CH:11]=[C:10]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[C:17]([CH3:25])[CH:16]=2)[N:9]=[C:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([C:30]3[CH:29]=[N:28][C:27]([NH2:26])=[CH:32][CH:31]=3)[CH:7]=2)[N:13]=1
Reactant: Cc1cc(-c2ccc(C(F)(F)F)c(C)c2)nc(-c2ccnc(Cl)c2)n1
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Product: Cc1cc(-c2ccc(C(F)(F)F)c(C)c2)nc(-c2ccnc(-c3ccc(N)nc3)c2)n1

Procedure:
The title compound was prepared from 2-(2-chloro-pyridin-4-yl)-4-methyl-6-(3-methyl-4-trifluoromethyl-phenyl)-pyrimidine (example E.52) (0.11 g, 0.27 mmol) and commercially available 2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.079 g, 0.36 mmol) according to the general procedure VI. Obtained as a light brown solid (0.021 g, 18%). MS (ISP) 422.1 [(M+H)+]; mp 188° C.
Reaction SMILES: COP([CH2:7][C:8](=[O:25])[CH2:9][N:10]1[C@H:14]([CH3:15])[CH2:13][C@H:12]([NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C:11]1=[O:24])(=O)OC.C(=O)([O-])[O-].[K+].[K+].[CH3:32][C:33]1[N:38]=[CH:37][C:36]([CH:39]=O)=[CH:35][N:34]=1>C1COCC1.C(OCC)(=O)C>[C:20]([O:19][C:17](=[O:18])[NH:16][C@H:12]1[CH2:13][C@@H:14]([CH3:15])[N:10]([CH2:9][C:8](=[O:25])[CH:7]=[CH:39][C:36]2[CH:35]=[N:34][C:33]([CH3:32])=[N:38][CH:37]=2)[C:11]1=[O:24])([CH3:21])([CH3:22])[CH3:23]
Reactant: Cc1ncc(C=O)cn1
Reactant: COP(=O)(CC(=O)CN1C(=O)[C@@H](NC(=O)OC(C)(C)C)C[C@H]1C)OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1ncc(C=CC(=O)CN2C(=O)[C@@H](NC(=O)OC(C)(C)C)C[C@H]2C)cn1
Temperature: 25 °C

Procedure:
A stirred suspension of 4-3 (2.5 g, 6.61 mmol), potassium carbonate (1.83 g, 13.2 mmol), and 2-methyl-pyrimidine-5-carboxaldehyde (for preparation, see U.S. Pat. No. 6,048,861) (0.81 g, 6.61 mmol) in THF (50 mL) was heated at 60-65° C. for 3 hours and then cooled to ambient temperature. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate, saturated aqueous sodium chloride, dried over magnesium sulfate, and filtered. Following evaporative removal of the solvent, the residue was purified by flash column chromatography (silica gel, 95:5% ethyl acetate/methanol) to give 5-1 as a white foam.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:14]([OH:16])=O)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[NH2:17][CH2:18][CH2:19][CH2:20][N:21]1[CH2:26][CH2:25][CH:24]([C:27]2[CH:28]=[C:29]([NH:33][C:34](=[O:38])[CH:35]([CH3:37])[CH3:36])[CH:30]=[CH:31][CH:32]=2)[CH2:23][CH2:22]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([C:14]([NH:17][CH2:18][CH2:19][CH2:20][N:21]3[CH2:26][CH2:25][CH:24]([C:27]4[CH:32]=[CH:31][CH:30]=[C:29]([NH:33][C:34](=[O:38])[CH:35]([CH3:36])[CH3:37])[CH:28]=4)[CH2:23][CH2:22]3)=[O:16])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]2)=[CH:6][CH:7]=1
Reactant: O=C(O)C1(c2ccc(Cl)cc2)CCCCC1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCN)CC2)c1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCNC(=O)C3(c4ccc(Cl)cc4)CCCCC3)CC2)c1

Procedure:
Example 45 was prepared from 1-(4-chlorophenyl)cyclohexanecarboxylic acid and N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}-2-methylpropanamide according to the procedures described in Scheme 9: 1H NMR (400 MHz, CDCl3) δ 7.57 (s, 1H), 7.52 (s, 1H), 7.38–7.35 (m, 2H), 7.30–7.21 (m, 4H), 6.93 (d, 1H, J=7.2 Hz), 6.88–6.83 (m, 1H), 3.28 (q, 2H, J=5.6 Hz), 2.95–2.88 (m, 2H), 2.56–2.41 (m, 2H), 2.35–2.26 (m, 3H), 2.07 (s, 1H), 1.96–1.84 (m, 4H), 1.83–1.76 (m, 2H), 1.70–1.53 (m, 10H), 1.24 (d, 6H, J=7.1 Hz); ESMS m/e: 524.3 (M+H)+.
Reaction SMILES: [C:1]([C:4]1[C:5]([C:10]([C:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]([CH3:21])[C:13]=2[CH3:22])=[O:11])=[N:6][CH:7]=[CH:8][CH:9]=1)([OH:3])=O.[CH:23]1([O:29][C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([N:36]([CH2:39][CH3:40])[CH2:37][CH3:38])[CH:31]=2)[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1>C(OC(=O)C)(=O)C>[CH2:39]([N:36]([CH2:37][CH3:38])[C:32]1[CH:33]=[CH:34][C:35]([C:10]2([C:12]3[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[N:14]([CH3:21])[C:13]=3[CH3:22])[C:5]3[C:4](=[CH:9][CH:8]=[CH:7][N:6]=3)[C:1](=[O:3])[O:11]2)=[C:30]([O:29][CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)[CH:31]=1)[CH3:40]
Reactant: CCN(CC)c1cccc(OC2CCCCC2)c1
Reactant: Cc1c(C(=O)c2ncccc2C(=O)O)c2ccccc2n1C
Solvent: CC(=O)OC(C)=O
Product: CCN(CC)c1ccc(C2(c3c(C)n(C)c4ccccc34)OC(=O)c3cccnc32)c(OC2CCCCC2)c1
Temperature: 25 °C
Yield: 75.3 %

Procedure:
Into 150 ml of acetic anhydride, 14.7 g of (1,2-dimethylindol-3-yl) (3-carboxypyridin-2-yl) ketone and 13.3 g of 1-cyclohexyloxy-3-diethylaminobenzene were added and the resultant mixture was stirred for 3 hours at 60° to 65° C. After cooling the reaction mixture to room temperature, the cooled mixture was treated by the same procedures as in Synthetic Example 7 and 19.7 g of the object compound was obtained as pale blue crystals (melting point: 161° to 165° C.).
Reaction SMILES: [CH3:1][C:2]([C@H:5]([NH2:8])[CH2:6][OH:7])([CH3:4])[CH3:3].C(N(CC)CC)C.[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1>C(Cl)Cl>[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([S:23]([NH:8][C@H:5]([CH2:6][OH:7])[C:2]([CH3:4])([CH3:3])[CH3:1])(=[O:25])=[O:24])=[CH:19][CH:18]=1
Reactant: CC(C)(C)[C@H](N)CO
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)[C@@H](CO)NS(=O)(=O)c1ccc(Cl)cc1
Reaction time: 16 h

Procedure:
To a solution of S-tert-leucinol (0.20 g, 1.70 mmol), triethylamine (0.19 g, 1.87 mmol) and methylene chloride (10 mL) at 0° C., was added a solution of 4-chloro benzenesulfonyl chloride (0.36 g, 1.70 mmol) in CH2Cl2 (5 mL). After 15 minutes the ice bath was removed and the reaction allowed to reach 25° C. After 16 hours, the reaction was quenched by pouring into saturated sodium bicarbonate solution (20 mL) and additional-methylene chloride (15 mL). The organic phase was separated and washed sequentially with 1N HCl solution (20 mL), distilled water and brine, dried over MgSO4 and evaporated to give the desired product as a white solid, mp 128-130° C. (0.46 g, 94%). MS (+APCI) 292.06 ([M+H]+). Anal. Calc'd for C12H18ClNO3S: C, 49.39; H, 6.22; N, 4.80; Found: C, 49.40; H, 6.17; N, 4.79.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][N:2]1[C:10]([O:12][CH:13]1[CH2:31][CH:30]2[N:15]([C:16](=[O:36])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH:23]=[CH:24][CH:25]3[C:27]([C:33](O)=[O:34])([NH:28][C:29]2=[O:32])[CH2:26]3)[CH2:14]1)=[O:11].C1N=CN(C(N2C=NC=C2)=O)C=1.[CH:49]1([S:52]([NH2:55])(=[O:54])=[O:53])[CH2:51][CH2:50]1.C1CCN2C(=NCCC2)CC1>C1COCC1>[CH2:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH2:1][N:2]1[C:10]([O:12][CH:13]1[CH2:31][CH:30]2[N:15]([C:16](=[O:36])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH:23]=[CH:24][CH:25]3[C:27]([C:33]([NH:55][S:52]([CH:49]4[CH2:51][CH2:50]4)(=[O:54])=[O:53])=[O:34])([NH:28][C:29]2=[O:32])[CH2:26]3)[CH2:14]1)=[O:11]
Reactant: O=C1NC2(C(=O)O)CC2C=CCCCCCCC(=O)N2CC(OC(=O)N3Cc4ccccc4C3)CC12
Reactant: NS(=O)(=O)C1CC1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: O=C1NC2(C(=O)NS(=O)(=O)C3CC3)CC2C=CCCCCCCC(=O)N2CC(OC(=O)N3Cc4ccccc4C3)CC12
Temperature: 25 °C

Procedure:
The mixture of carboxylic acid 18 (30 mg, 0.06 mmole) and CDI (20 mg, 2 eq) in dry THF (3 mL) was stirred at reflux for 2 h30 under nitrogen. Optionally, the azalactone derivative, if desired, can be isolated. Then, the reaction mixture was cooled at room temperature and cyclopropylsulfonamide (15 mg, 2 eq) and DBU (18 mg, 2 eq) were added. The reaction mixture was stirred at 50° C. until completion as indicated by LC-MS. The RM was then concentrated, redissolved in DCM and extracted with HCl 1M then brine, dried and concentrated. Purification by flash chromatography on silica gel afforded the desired product 19. m/z=599 (M+H+).
Reaction SMILES: [C:1]([O:5][C:6](=[O:34])[NH:7][CH2:8][CH2:9][CH2:10][N:11]([C:25](=[O:33])[C:26]1[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=1)[CH:12]([C:15]1[NH:20][C:19](=[O:21])[C:18]2=[CH:22][CH:23]=[CH:24][N:17]2[N:16]=1)[CH2:13][CH3:14])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].[F:41][C:42]1[CH:49]=[CH:48][C:45]([CH2:46]Br)=[CH:44][CH:43]=1>O1CCOCC1.C(OCC)(=O)C>[C:1]([O:5][C:6](=[O:34])[NH:7][CH2:8][CH2:9][CH2:10][N:11]([CH:12]([C:15]1[N:20]([CH2:46][C:45]2[CH:48]=[CH:49][C:42]([F:41])=[CH:43][CH:44]=2)[C:19](=[O:21])[C:18]2=[CH:22][CH:23]=[CH:24][N:17]2[N:16]=1)[CH2:13][CH3:14])[C:25](=[O:33])[C:26]1[CH:27]=[CH:28][C:29]([CH3:32])=[CH:30][CH:31]=1)([CH3:2])([CH3:4])[CH3:3]
Reactant: Fc1ccc(CBr)cc1
Reactant: CCC(c1nn2cccc2c(=O)[nH]1)N(CCCNC(=O)OC(C)(C)C)C(=O)c1ccc(C)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CCC(c1nn2cccc2c(=O)n1Cc1ccc(F)cc1)N(CCCNC(=O)OC(C)(C)C)C(=O)c1ccc(C)cc1
Temperature: 40 °C
Reaction time: 0.75 h
Yield: 15.2 %

Procedure:
A mixture of (±)-(3-{(4-methylbenzoyl)-[1-(4-oxo-3,4-dihydropyrrolo[2,1-f][1,2,4] triazin-2-yl)-propyl]-amino}-propyl)-carbamic acid tert-butyl ester (Example 3 A, 38 mg, 0.08 mmol) and cesium carbonate (40 mg, 0.12 mmol) in dioxane (1 mL) was stirred at 40° C., under Ar, for 45 min. To the mixture was added 4-fluorobenzyl bromide (22 mg, 0.12 mmol) and the reaction mixture was stirred at 40° C. for 24 h before being diluted with ethyl acetate. The ethyl acetate layer was washed twice with water and once with brine, before being dried over anhydrous magnesium sulfate and concentrated in vacuo. The crude product was purified by preparative HPLC (YMC S10 ODS, 30×500 mm, 30 minute gradient from 74–90% aqueous methanol with 0.1% TFA). The appropriate fractions were combined, neutralized with saturated aqueous sodium bicarbonate, and then concentrated in vacuo to remove methanol. The mixture was extracted with ethyl acetate (3×10 mL). The combined organic layers were washed once each with water and brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo to yield the title compound (7 mg, 15%): 1H NMR (CDCl3) δ 7.44–6.99 (m, 10H), 6.61 (m, 1H), 5.91 (m, 1H), 5.88 (m, 1H), 4.83 (m, 1H), 3.86 (m, 1H), 3.33 (m, 2H), 2.71 (m, 2H), 2.39 (s, 3H), 2.05 (m, 1H), 1.85 (m, 1H), 1.62 (m, 2H), 1.39 (s, 9H), 0.71 (m, 3H); MS (ESI+), 576.17 (M++H).
Reaction SMILES: [BH4-].[Na+].[C:3]([C:7]1[C:12]([N+:13]([O-])=O)=[CH:11][CH:10]=[C:9]([C:16]([CH3:19])([CH3:18])[CH3:17])[C:8]=1[OH:20])([CH3:6])([CH3:5])[CH3:4].O>CO.Cl[Ni]Cl>[NH2:13][C:12]1[C:7]([C:3]([CH3:6])([CH3:5])[CH3:4])=[C:8]([OH:20])[C:9]([C:16]([CH3:17])([CH3:18])[CH3:19])=[CH:10][CH:11]=1
Reactant: CC(C)(C)c1ccc([N+](=O)[O-])c(C(C)(C)C)c1O
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC(C)(C)c1ccc(N)c(C(C)(C)C)c1O
Reaction time: 0.01 h
Yield: 77.7 %

Procedure:
NaBH4 (433 mg, 11.45 mmol) was added to a solution of 2,6-di-tert-butyl-3-nitrophenol (950 mg, 3.780 mmol) and NiCl2 (1.24 g, 9.568 mmol) in methanol (15 mL) at −15° C. After the addition was complete, the reaction mixture was stirred for 20 seconds and water was added immediately and the reaction mixture was extracted with ethyl acetate. The combined organic layers were dried over anhydrous Na2SO4 and evaporated in vacuo to afford 3-amino-2,6-di-tert-butyl-phenol (650 mg, 78%). 1H NMR (300 MHz, CDCl3) δ 6.92 (d, J=8.4 Hz, 1H), 6.24 (d, J=8.4 Hz, 1H), 5.39 (s, 1H), 1.62 (s, 9H), 1.39 (s, 9H); MS (ESI) m/z: 222.2 [M+H+].
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.[H-].[Na+].BrCCCC[C:13]1[CH:23]=[CH:22][CH:21]=[C:15]2[C:16]([NH:18][C:19](=[O:20])[C:14]=12)=[O:17]>CN(C)C=O>[N:1]1([CH2:23][CH2:13][CH2:14][CH2:15][N:18]2[C:19](=[O:20])[C:14]3[C:15](=[CH:21][CH:22]=[CH:23][CH:13]=3)[C:16]2=[O:17])[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: O=C1NC(=O)c2c(CCCCBr)cccc21
Reactant: c1nc[nH]n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1CCCCn1cncn1
Reaction time: 1.5 h
Yield: 172.7 %

Procedure:
A mixture of about 9.0 g of 1H-1,2,4-triazole, about 6.24 g of approximately 50% sodium hydride in oil and about 130 ml of dimethylformamide was stirred for about 1.5 hours, then about 33 g of bromobutylphthalimide was added and this mixture was heated on a steam bath for about 6 hours, then concentrated to a solid residue. Water and methylene chloride were added, the organic layer was separated, washed with water, dried and concentrated to a residue. This residue was recrystallized from ethanol, giving about 27.3 g of 2-[4-(1H-1,2,4-triazol-1-yl)butyl]-1H-isoindol-1,3(2H)-dione.
Reaction SMILES: [CH:1]1([NH:4][C:5]([C:7]2[CH:8]=[C:9]([F:28])[C:10]([CH3:27])=[C:11]([C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][CH:21]=3)[N:18]([CH2:22][C:23]([O:25]C)=O)[N:17]=[CH:16]4)[CH:12]=2)=[O:6])[CH2:3][CH2:2]1.[CH2:29]([NH2:32])[CH2:30][CH3:31]>>[CH:1]1([NH:4][C:5](=[O:6])[C:7]2[CH:12]=[C:11]([C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][CH:21]=3)[N:18]([CH2:22][C:23](=[O:25])[NH:32][CH2:29][CH2:30][CH3:31])[N:17]=[CH:16]4)[C:10]([CH3:27])=[C:9]([F:28])[CH:8]=2)[CH2:3][CH2:2]1
Reactant: COC(=O)Cn1ncc2cc(-c3cc(C(=O)NC4CC4)cc(F)c3C)ccc21
Reactant: CCCN
Product: CCCNC(=O)Cn1ncc2cc(-c3cc(C(=O)NC4CC4)cc(F)c3C)ccc21

Procedure:
Example 136 was prepared by General Method D using methyl (5-{5-[(cyclopropylamino)carbonyl]-3-fluoro-2-methylphenyl}-1H-indazol-1-yl)acetate (Example 123) and 1-propylamine to give the title compound (0.005 g).
Reaction SMILES: [C:1]1([O:11][CH2:12][CH2:13][NH:14][C:15]2[CH:25]=[CH:24][C:18]([C:19]([O:21]CC)=[O:20])=[CH:17][CH:16]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[OH-].[K+].C(O)C.Cl>O>[C:1]1([O:11][CH2:12][CH2:13][NH:14][C:15]2[CH:16]=[CH:17][C:18]([C:19]([OH:21])=[O:20])=[CH:24][CH:25]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)c1ccc(NCCOc2cccc3ccccc23)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)c1ccc(NCCOc2cccc3ccccc23)cc1

Procedure:
A solution of 12 g. of ethyl p-[2-(1-naphthyloxy)ethylamino]benzoate and 15.8 g. of potassium hydroxide in 100 ml. of 95% ethanol is refluxed for 3 hours. The solution is diluted with 75 ml. of water and acidified with concentrated hydrochloric acid. The solid is filtered, washed with 50% ethanol and with water. Recrystallization from ethanol gives the product as crystals, m.p. 193°-194° C.
Reaction SMILES: [CH2:1]([N:8]([CH2:19][C:20]1[CH:33]=[CH:32][C:23]([O:24][C:25]2[CH:26]=[C:27]([OH:31])[CH:28]=[CH:29][CH:30]=2)=[CH:22][CH:21]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[C:10]=1[CH3:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:53][O:54][CH2:55][CH2:56]O>C1COCC1.C(OCC)(=O)C>[CH2:1]([N:8]([CH2:19][C:20]1[CH:33]=[CH:32][C:23]([O:24][C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([O:31][CH2:56][CH2:55][O:54][CH3:53])[CH:26]=2)=[CH:22][CH:21]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[C:10]=1[CH3:18])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COCCO
Reactant: Cc1c(N(Cc2ccccc2)Cc2ccc(Oc3cccc(O)c3)cc2)cccc1[N+](=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COCCOc1cccc(Oc2ccc(CN(Cc3ccccc3)c3cccc([N+](=O)[O-])c3C)cc2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The product from Example 61F (0.100 g, 0.227 mmoles), polystyrene supported triphenylphosphine (0.151 g, 0.454 mmoles, 3 mmoles P/g resin), and di-t-butylazodicarboxylate (0.079 g, 0.341 mmoles) in THF (2 mL) were treated with 2-methoxyethanol (0.022 g, 0.284 mmoles). The reaction mixture was shaken overnight at room temperature. The mixture was diluted with ethyl acetate, washed with H2O, brine, dried (Na2SO4), filtered, and the filtrate concentrated under reduced pressure to provide the title compound without further purification.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](=[C:13](Cl)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:5]1=[O:21])(=O)C.[CH3:22][O:23][C:24]1[CH:25]=[C:26]([CH:28]=[CH:29][CH:30]=1)[NH2:27].[OH-].[Na+]>C1COCC1>[CH3:22][O:23][C:24]1[CH:25]=[C:26]([NH:27]/[C:13](=[C:6]2\[C:5](=[O:21])[NH:4][C:12]3[C:7]\2=[CH:8][CH:9]=[CH:10][CH:11]=3)/[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:28]=[CH:29][CH:30]=1
Reactant: CC(=O)N1C(=O)C(=C(Cl)c2ccccc2)c2ccccc21
Reactant: COc1cccc(N)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1cccc(N/C(=C2\C(=O)Nc3ccccc32)c2ccccc2)c1

Procedure:
Prepared analogously to Example 2 from 1-acetyl-3-(1-chloro-1-phenyl-methylidene)-2-indolinone and 3-methoxyaniline in THF and subsequent treatment with sodium hydroxide solution.