Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]([C:6]([N:8]2[CH2:14][CH2:13][C:12](=O)[C:11](=O)[CH2:10][CH2:9]2)=[O:7])=[CH:4][CH:3]=1.ClC1C=CC(C(N2CCCC(=O)CC2)=O)=CC=1.[Se](=O)=O.Br.Br.[NH2:41][CH2:42][C:43]([NH2:45])=[NH:44].[OH-].[Na+]>O1CCOCC1.O.CO.C(OCC)(=O)C>[NH2:45][C:43]1[CH:42]=[N:41][C:12]2[CH2:13][CH2:14][N:8]([C:6](=[O:7])[C:5]3[CH:17]=[CH:18][C:2]([Cl:1])=[CH:3][CH:4]=3)[CH2:9][CH2:10][C:11]=2[N:44]=1
Reactant: N=C(N)CN
Reactant: O=C1CCN(C(=O)c2ccc(Cl)cc2)CCC1=O
Agent: Br
Agent: O=C1CCCN(C(=O)c2ccc(Cl)cc2)CC1
Agent: O=[Se]=O
Solvent: O
Solvent: CCOC(C)=O
Solvent: CO
Product: Nc1cnc2c(n1)CCN(C(=O)c1ccc(Cl)cc1)CC2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
53 mg (0.2 mol) of a mixture of 1-(4-chloro-benzoyl)-hexahydroazepine-4,5-dione and 1-(4-chloro-benzoyl)-hexhydroazepine-3,4-dione [prepared from 1-(4-chloro-benzoyl)-hexahydroazepine-4-one by selenium dioxide oxidation in dioxane/water] and 47 gm (0.2 mol) of 2-amino-acetamidine dihydrobromide were dissolved in 700 ml of methanol, and 200 ml of 2N sodium hydroxide were added dropwise to the solution at 5° C. The mixture was stirred at room temperature for one hour, then concentrated by evaporation and then, after addition of more sodium hydroxide, extracted with chloroform. The dried extract solution was concentrated by evaporation and chromatographed on silicagel with ethyl acetate/methanol (10:1) as the mobile phase. The crystals obtained thereby were digested with ethyl acetate and suction-filtered.
Reaction SMILES: [F:1][C@@H:2]1[CH2:6][CH2:5][N:4]([CH2:7][C@H:8]([NH:10][C:11]([C:13]2[C:21]3[C:16](=[N:17][CH:18]=[C:19]([C:22]4[C:30]5[C:25](=[CH:26][C:27]([Cl:31])=[CH:28][CH:29]=5)[N:24]([CH3:32])[N:23]=4)[N:20]=3)[N:15](COCC[Si](C)(C)C)[CH:14]=2)=[O:12])[CH3:9])[CH2:3]1.FC(F)(F)C(O)=O.C(N)CN.O>ClCCl.C(OCC)(=O)C>[F:1][C@@H:2]1[CH2:6][CH2:5][N:4]([CH2:7][C@H:8]([NH:10][C:11]([C:13]2[C:21]3[C:16](=[N:17][CH:18]=[C:19]([C:22]4[C:30]5[C:25](=[CH:26][C:27]([Cl:31])=[CH:28][CH:29]=5)[N:24]([CH3:32])[N:23]=4)[N:20]=3)[NH:15][CH:14]=2)=[O:12])[CH3:9])[CH2:3]1
Reactant: C[C@H](CN1CC[C@@H](F)C1)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C)c4cc(Cl)ccc34)nc12
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Product: C[C@H](CN1CC[C@@H](F)C1)NC(=O)c1c[nH]c2ncc(-c3nn(C)c4cc(Cl)ccc34)nc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 65.8 %

Procedure:
2-(6-Chloro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-((R)-3-fluoro-pyrrolidin-1-yl)-1-methyl-ethyl]-amide (65 mg, 0.11 mmol) was dissolved in dichloromethane (0.7 ml) and cooled in ice bath. Trifluoroacetic acid (0.4 ml) was slowly added and the reaction was stirred at room temperature for 3 h. The reaction was evaporated and the residue was suspended in dichloromethane (1.1 ml). Ethylenediamine (0.45 ml, 6.65 mmol) was added and the mixture was stirred for 18 h. Water and then ethyl acetate were added to the mixture. The layers were separated and the aqueous layer was extracted twice more with ethyl acetate. The combined organic layers were washed with sodium chloride solution and dried over sodium sulfate. After evaporation, the residue was purified by silica gel chromatography (methanol/dichloromethane) to afford 33 mg (65%) of 2-(6-chloro-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-((R)-3-fluoro-pyrrolidin-1-yl)-1-methyl-ethyl]-amide. MS (M+H)+=456; mp=233-234° C. 1H NMR (300 MHz, DMSO-d6) δ: 12.81-12.93 (m, 1H), 9.10 (s, 1H), 8.44 (s, 1H), 8.38-8.46 (m, 1H), 8.07 (d, J=8.3 Hz, 1H), 7.99-8.03 (m, 1H), 7.28-7.36 (m, 1H), 4.97-5.24 (m, 1H), 4.20-4.33 (m, 1H), 4.17 (s, 3H), 2.54-2.90 (m, 1H), 2.54-2.90 (m, 4H), 2.32-2.44 (m, 1H), 1.66-2.13 (m, 2H), 1.32 (d, J=6.4 Hz, 3H).
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([C:8]([O:10][CH3:11])=[O:9])=[CH:4][CH:3]=1.[F:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]([CH3:23])([CH3:22])[CH2:20][NH2:21])=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+]>C(O)(C)C>[F:12][C:13]1[CH:14]=[CH:15][C:16]([C:19]([CH3:23])([CH3:22])[CH2:20][NH:21][C:2]2[N:7]=[N:6][C:5]([C:8]([O:10][CH3:11])=[O:9])=[CH:4][CH:3]=2)=[CH:17][CH:18]=1
Reactant: COC(=O)c1ccc(Cl)nn1
Reactant: CC(C)(CN)c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)O
Product: COC(=O)c1ccc(NCC(C)(C)c2ccc(F)cc2)nn1
Temperature: 120 °C
Yield: 40.9 %

Procedure:
To a 25 mL round bottom flask was added methyl 6-chloropyridazine-3-carboxylate (0.50 g, 2.90 mmol, 1.0 equiv), 2-(4-fluorophenyl)-2-methylpropan-1-amine (0.60 g, 3.6 mmol, 1.2 equiv), potassium carbonate (300 mg, 2.2 mmol, 0.75 equiv), and isopropanol (3 mL). The reaction mixture was stirred and heated at 120° C. for 12 h. The reaction was then filtered through celite, concentrated, and purified by silica gel chromatography (0-40% EtOAC/hexanes) to afford 360 mg (43%) of methyl 6-(2-(4-fluorophenyl)-2-methylpropylamino)pyridazine-3-carboxylate as an off-white foam.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[CH2:11]([C:15]1[CH:23]=[CH:22][C:18]([C:19](Cl)=[O:20])=[CH:17][CH:16]=1)[CH2:12][CH2:13][CH3:14].[OH-].[Na+]>C(Cl)Cl.N1C=CC=CC=1>[CH2:11]([C:15]1[CH:16]=[CH:17][C:18]([C:19]([NH:1][C:2]2[S:3][C:4]3[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=3[N:6]=2)=[O:20])=[CH:22][CH:23]=1)[CH2:12][CH2:13][CH3:14]
Reactant: CCCCc1ccc(C(=O)Cl)cc1
Reactant: Nc1nc2ccccc2s1
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCCc1ccc(C(=O)Nc2nc3ccccc3s2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 2-amino-1,3-benzthiazole (40 mg, 0.27 mmol) in methylene chloride (1 ml) and pyridine (100 μl) was treated with 4-n-butylbenzoyl chloride and stirred at 25° C. for 30 minutes. After this time, the reaction was treated with NaOH (0.5 ml, 5.0 M) and the resulting mixture stirred overnight. The resulting precipitate was collected by filtration and recrystallized from water to give 2-(4-n-butylbenzamido)-1,3-benzthiazole as pale yellow needles. (47 mg, 53%)
Reaction SMILES: O[CH:2]=[C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5][C:4]1=[O:12].[NH2:13][C:14]1[CH:22]=[C:21]2[C:17]([CH:18]=[N:19][NH:20]2)=[CH:16][CH:15]=1>>[NH:20]1[C:21]2[C:17](=[CH:16][CH:15]=[C:14]([N:13]=[C:2]=[C:3]3[C:11]4[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=4)[NH:5][C:4]3=[O:12])[CH:22]=2)[CH:18]=[N:19]1
Reactant: Nc1ccc2cn[nH]c2c1
Reactant: O=C1Nc2ccccc2C1=CO
Product: O=C1Nc2ccccc2C1=C=Nc1ccc2cn[nH]c2c1
Yield: 79 %

Procedure:
The title compound was prepared in 79% yield from 3-hydroxymethylene-1,3-dihydro-indol-2-one and 6-aminoindazole according to Procedure J: 1H NMR (DMSO-d6): δ 13.02 (s, 1H), 10.86 (d, 1H), 10.51 (s, 1H), 8.7 (d, 1H) ) 8.0 (s, 1H), 7.74 (d, 1H), 7.63 (d, 1H) 7.51 (s, 1H), 7.15 (dd, 1H), 7.02 (m, 1H), 6.94 (m, 1H), 6.85 (d, 1H); ESI−MS m/z 275 (M−H)−.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:10])[C:5](=[CH:8][CH:9]=1)[CH:6]=[O:7].C(=O)([O-])[O-].[K+].[K+].[CH2:17](Br)[CH:18]=[CH2:19]>CN(C)C=O.O>[CH2:19]([O:10][C:4]1[CH:3]=[C:2]([Br:1])[CH:9]=[CH:8][C:5]=1[CH:6]=[O:7])[CH:18]=[CH2:17]
Reactant: O=Cc1ccc(Br)cc1O
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: C=CCOc1cc(Br)ccc1C=O
Temperature: 25 °C
Reaction time: 17 h
Yield: 100.2 %

Procedure:
4-Bromosalicylaldehyde (4.02 g, 20.0 mmol) [prepared from 3-bromophenyl analogous to the procedure of Casiraghi, et. al. Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1978), 318-21] was dissolved in anhydrous N,N-dimethylformamide (13 mL). Potassium carbonate (3.9 g, 28.0 mmol) was added as a solid to give a yellow suspension. Allyl bromide (2.6 mL, 3.63 g, 30.0 mmol) was added via syringe. The reaction stirred for 17 h at room temperature and was then diluted with water and extracted three times with 1:1 ethyl acetate-hexane. The combined organic layers were washed with water (5×), brine, dried over sodium sulfate, filtered and concentrated to afford 2-(allyloxy)-4-bromobenzaldehyde (4.83 g, 100% yield) as a yellow solid which was used without further purification in the next step; Rf 0.38 (1:9 ethyl acetate-hexane); MS [M+H]+241.0.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17](=[O:18])[C:16]3[C:11](=[CH:12][C:13]([O:19]C(=O)C(C)C)=[CH:14][CH:15]=3)[O:10][C:9]=2[CH:25]([CH3:27])[CH3:26])=[CH:4][CH:3]=1.[OH-].[K+]>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:17](=[O:18])[C:16]3[C:11](=[CH:12][C:13]([OH:19])=[CH:14][CH:15]=3)[O:10][C:9]=2[CH:25]([CH3:27])[CH3:26])=[CH:6][CH:7]=1
Reactant: CC(C)C(=O)Oc1ccc2c(=O)c(-c3ccc(Cl)cc3)c(C(C)C)oc2c1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CC(C)c1oc2cc(O)ccc2c(=O)c1-c1ccc(Cl)cc1
Reaction time: 1.5 h

Procedure:
A mixture of 2-(4-chlorophenyl)-1-(2,4-dihydroxyphenyl)-ethanone (100 g, 0.382 mol), iso-butyric acid anhydride (380 ml, 2.29 mol) and dry pyridine (380 ml, 4.69 mol) is stirred at 140° C. for 12 h and then allowed to cool to room temperature. The volatile components are removed in vacuo, and the resulting dark brown oil is dried under high vacuum to give crude isobutyric acid 3-(4-chlorophenyl)-2-isopropyl-4-oxo-4H-chromen-7-yl ester. To a mixture of this crude ester and methanol (400 ml) is added aqueous KOH (250 ml, 5 M) [CAUTION: EXOTHERM]. The dark solution is stirred for 1.5 h, and the methanol is then evaporated in vacuo. The resulting solution is acidified with 2 M HCl to pH 3 to give a brown precipitate, which is removed by filtration. The brown solid is washed with water (3×) and isopropyl ether and then air-dried. The remaining aqueous solution is extracted with ethyl acetate (4×), and the combined organic phases are washed with water (3×), dried (Na2SO4) and evaporated to give a red oil, which solidifies to give a brown solid. The brown solid is washed with isopropyl ether and air-dried. The combined aqueous phases are extracted again (ethyl acetate) to provide a third crop of product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[CH:11]1[NH:16][C:15](=[O:17])[CH2:14][CH2:13][CH2:12]1.Br[CH:19]([C:22]1[CH:27]=[CH:26][C:25]([O:28][C:29]([F:32])([F:31])[F:30])=[CH:24][CH:23]=1)[CH2:20][CH3:21]>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[CH:11]1[N:16]([CH:19]([C:22]2[CH:23]=[CH:24][C:25]([O:28][C:29]([F:30])([F:31])[F:32])=[CH:26][CH:27]=2)[CH2:20][CH3:21])[C:15](=[O:17])[CH2:14][CH2:13][CH2:12]1
Reactant: COc1cccc(OC)c1C1CCCC(=O)N1
Reactant: CCC(Br)c1ccc(OC(F)(F)F)cc1
Product: CCC(c1ccc(OC(F)(F)F)cc1)N1C(=O)CCCC1c1c(OC)cccc1OC

Procedure:
Prepared according to the described general procedure 4 (GP4) by reaction of 6-(2,6-dimethoxyphenyl)piperidin-2-one with 1-(1-bromopropyl)-4-(trifluoromethoxy)benzene. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.99 min.; [M+H]+: 438.22 g/mol.
Reaction SMILES: C[O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][NH2:8])=[CH:5][CH:4]=1.[BrH:11]>>[BrH:11].[OH:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][NH2:8])=[CH:5][CH:4]=1
Reactant: COc1ccc(CN)cc1
Agent: Br
Product: NCc1ccc(O)cc1

Procedure:
4-Methoxybenzylamine (1.00 ml) in 48% HBr aq (10 ml) and heated at reflux for 10 hours. The cooled reaction mixture was filtered to give the sub-title compound (2.25 g).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[O:9][CH2:10][CH2:11][C@:12]([C:15]2[CH:20]=[C:19]([NH2:21])[CH:18]=[CH:17][C:16]=2[F:22])([CH3:14])[N:13]=1)(C)(C)C.[F:24][C:25]1[CH:26]=[CH:27][C:28]([C:31](O)=[O:32])=[N:29][CH:30]=1>>[NH2:7][C:8]1[O:9][CH2:10][CH2:11][C@:12]([C:15]2[CH:20]=[C:19]([NH:21][C:31]([C:28]3[CH:27]=[CH:26][C:25]([F:24])=[CH:30][N:29]=3)=[O:32])[CH:18]=[CH:17][C:16]=2[F:22])([CH3:14])[N:13]=1
Reactant: O=C(O)c1ccc(F)cn1
Reactant: CC(C)(C)OC(=O)NC1=N[C@](C)(c2cc(N)ccc2F)CCO1
Product: C[C@@]1(c2cc(NC(=O)c3ccc(F)cn3)ccc2F)CCOC(N)=N1

Procedure:
The coupling of [(S)-4-(5-amino-2-fluoro-phenyl)-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-yl]-carbamic acid tert-butyl ester from experiment F1 (R3=Me) and 5-fluoro-pyridine-2-carboxylic acid followed by deprotection using procedure H yielded the title compound. MS (ESI): m/z=347.0 [M+H]+.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[N:10]([C:11]2[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=2[C:13]([NH2:15])=O)[N:9]=[C:8]([C:20]([F:23])([F:22])[F:21])[CH:7]=1.C(N(CC)CC)C.ClC(Cl)(Cl)C(Cl)=O>C(Cl)Cl>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[N:10]([C:11]2[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=2[C:13]#[N:15])[N:9]=[C:8]([C:20]([F:22])([F:21])[F:23])[CH:7]=1
Reactant: NC(=O)c1ccccc1-n1nc(C(F)(F)F)cc1-c1ccco1
Agent: O=C(Cl)C(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: N#Cc1ccccc1-n1nc(C(F)(F)F)cc1-c1ccco1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 102.2 %

Procedure:
2-[5-(2-Furyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzamide (6.73 g, 21 mmol) and triethylamine (5.8 mL, 42 mmol) were combined in dry CH2Cl2 (55 mL) under argon and cooled to 0° C. Trichloroacetyl chloride (2.7 mL, 24 mmol) in CH2Cl2 (15 mL) was added dropwise over 30 min. The resulting solution was stirred at 0° C. for 20 min, then at room temperature for 65 min. The reaction was quenched with a small amount of water, then partitioned between 1M HCl and CH2Cl2. The organic layer was removed and extracted with sat. NaHCO3, then dried over Na2SO4, filtered, and evaporated to yield crude product (6.66 g). The crude product was chromatographed on silica gel (30-40% EtOAc/hexanes) to yield a yellow solid (6.51 g, >100%). 1H NMR (CDCl3) δ7.79 (m, 2H), 7.64 (m, 2H), 7.39 (d, 1H, J=1.8), 6.96 (s, 1H), 6.37 (m, 1H), 6.04 (d, 1H, J=3.7).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]2[C:14]([C:23]([F:26])([F:25])[F:24])=[N:15][C:16]([C:17](=[O:22])N(OC)C)=[C:10]2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:27]1([Mg]Br)[CH2:31][CH2:30][CH2:29][CH2:28]1.[Cl-].[NH4+]>O1CCCC1.[Cl-].[Na+].O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]2[C:14]([C:23]([F:25])([F:24])[F:26])=[N:15][C:16]([C:17]([CH:27]3[CH2:31][CH2:30][CH2:29][CH2:28]3)=[O:22])=[C:10]2[CH2:9]1)=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: Br[Mg]C1CCCC1
Reactant: CON(C)C(=O)c1nc(C(F)(F)F)n2c1CN(C(=O)OC(C)(C)C)CC2
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCn2c(C(F)(F)F)nc(C(=O)C3CCCC3)c2C1
Yield: 32.7 %

Procedure:
1-(Methoxy-methyl-carbamoyl)-3-trifluoromethyl-5,6-dihydro-8H-imidazo[1,5-a]pyrazine-7-carboxylic acid tert-butyl ester 27e (0.3 g, 0.79 mmol) was dissolved in 20 mL of tetrahydrofuran under stirring, and then cyclopentylmagnesium bromide (0.79 mL, 1.58 mmol) was added dropwise to the solution at 0° C. The reaction mixture was stirred at 0° C. for 3 hours and monitored by thin layer chromatography until the disappearance of the starting materials. 50 mL of saturated ammonium chloride and 10 mL of saturated brine were added. The crude mixture was extracted with ethyl acetate (100 mL×3), and then the combined organic phase was dried with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound 1-cyclopentanecarbonyl-3-trifluoromethyl-5,6-dihydro-8H-imidazo[1,5-a]pyrazine-7-carboxylic acid tert-butyl ester 28a (0.1 g, yield 30%) as a yellow oil.
Reaction SMILES: CO.[CH2:3]([N:6]([CH2:34][CH2:35][CH3:36])[CH2:7][CH2:8][CH2:9][C:10]1[N:15]=[C:14]([C:16]2[CH:33]=[CH:32][C:19]([CH2:20][N:21]3C(=O)C4C(=CC=CC=4)C3=O)=[CH:18][CH:17]=2)[CH:13]=[CH:12][CH:11]=1)[CH2:4][CH3:5].O.NN>C(Cl)(Cl)Cl>[NH2:21][CH2:20][C:19]1[CH:32]=[CH:33][C:16]([C:14]2[N:15]=[C:10]([CH2:9][CH2:8][CH2:7][N:6]([CH2:34][CH2:35][CH3:36])[CH2:3][CH2:4][CH3:5])[CH:11]=[CH:12][CH:13]=2)=[CH:17][CH:18]=1
Reactant: CCCN(CCC)CCCc1cccc(-c2ccc(CN3C(=O)c4ccccc4C3=O)cc2)n1
Agent: NN
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CCCN(CCC)CCCc1cccc(-c2ccc(CN)cc2)n1
Temperature: 60 °C
Reaction time: 1.5 h
Yield: 105.3 %

Procedure:
A methanol solution (2.0 ml) containing the compound (40.0 mg) obtained in Example 36-4 was added with hydrazine monohydrate (44 mg) and the whole was stirred at 60° C. for 1.5 hours, followed by distillating off the solvent. The residue was dissolved in chloroform and filtrated through Celite, the solvent was distilled off, thereby obtaining the subject compound (30.1 mg) as an amber liquid.
Reaction SMILES: [ClH:1].CN([CH2:5][CH:6]1[CH2:18][CH2:17][C:9]2[O:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[C:8]=2[C:7]1=[O:19])C.[CH3:20][C:21]1[NH:22][CH:23]=[CH:24][N:25]=1.Cl>O>[ClH:1].[CH3:20][C:21]1[N:22]([CH2:5][CH:6]2[CH2:18][CH2:17][C:9]3[O:10][C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=4[C:8]=3[C:7]2=[O:19])[CH:23]=[CH:24][N:25]=1
Reactant: CN(C)CC1CCc2oc3ccccc3c2C1=O
Reactant: Cc1ncc[nH]1
Agent: Cl
Solvent: O
Product: Cc1nccn1CC1CCc2oc3ccccc3c2C1=O
Yield: 15.5 %

Procedure:
A stirred mixture of 2-[(dimethylamino)methyl]-3,4-dihydro-1(2H)-dibenzofuranone hydrochloride (1.00 g), 2-methylimidazole (1.47 g) and water (25 ml) was heated under reflux for 20 h. The cooled mixture was acidified to pH 1 with aqueous 2M hydrochloric acid and extracted with ethyl acetate (2×50 ml; discarded). The aqueous layer was basified to pH 8 with aqueous saturated sodium bicarbonate, extracted with ethyl acetate (5×40 ml), and the combined organic extracts were washed with water (50 ml). The organic layer was dried and evaporated, and the residue was crystallised from ethyl acetate to give the free base of the title compound (176 mg). Evaporation of the mother liquors afforded a further quantity of the free base of the title compound (370 mg). A portion of this solid (166 mg) was treated with ethyl acetate (40 ml), filtered, and concentrated to ca. 10 ml. The solution was acidified to pH 1 by the addition of ethanolic hydrogen chloride, and the precipitate was collected to give the title compound (171 mg), m.p. 217°-222°.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[CH2:5]([O:8][C:9]1[CH:18]=[C:17]([NH2:19])[C:16]([Cl:20])=[CH:15][C:10]=1[C:11]([O:13][CH3:14])=[O:12])[CH:6]=[CH2:7].O>N1C=CC=CC=1>[CH2:5]([O:8][C:9]1[CH:18]=[C:17]([NH:19][C:1](=[O:3])[CH3:2])[C:16]([Cl:20])=[CH:15][C:10]=1[C:11]([O:13][CH3:14])=[O:12])[CH:6]=[CH2:7]
Reactant: C=CCOc1cc(N)c(Cl)cc1C(=O)OC
Reactant: CC(=O)Cl
Solvent: O
Solvent: c1ccncc1
Product: C=CCOc1cc(NC(C)=O)c(Cl)cc1C(=O)OC
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
Acetyl chloride (6.5 g) is added dropwise to a stirring solution of the amine of step 4 above (5 g) in pyridine (80 ml) cooled in an ice bath. The reaction mixture is allowed to warm to RT with stirring for 45 minutes. Water is added, the mixture again cooled in ice, and partitioned between H2O and CH2Cl2. The organic layer is separated and washed successively with H2O, 10% HCl, aqueous saturated NaHCO3, dried, filtered and evaporated affording a solid residue which is recrystallized from Hexane-Ethyl acetate, M.P. 110°-112° C. NMR (90 MHz, DMSO-d6) shows the correct compound.
Reaction SMILES: [O:1]=[C:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:11]#[N:12])[CH:8]=2)[NH:3]1.[N:13]1[CH:18]=[CH:17][C:16](/[CH:19]=[CH:20]/[C:21]2[C:29]3[C:24](=[CH:25][C:26]([CH:30]=O)=[CH:27][CH:28]=3)[N:23](COCC[Si](C)(C)C)[N:22]=2)=[CH:15][CH:14]=1>>[O:1]=[C:2]1[C:10](=[CH:30][C:26]2[CH:25]=[C:24]3[C:29]([C:21](/[CH:20]=[CH:19]/[C:16]4[CH:15]=[CH:14][N:13]=[CH:18][CH:17]=4)=[N:22][NH:23]3)=[CH:28][CH:27]=2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:11]#[N:12])[CH:8]=2)[NH:3]1
Reactant: C[Si](C)(C)CCOCn1nc(/C=C/c2ccncc2)c2ccc(C=O)cc21
Reactant: N#Cc1ccc2c(c1)CC(=O)N2
Product: N#Cc1ccc2c(c1)C(=Cc1ccc3c(/C=C/c4ccncc4)n[nH]c3c1)C(=O)N2

Procedure:
The title compound was synthesized according to the method described in Example A57 from 2-oxoindoline-5-carbonitrile (10 mg, 0.063 mmol) and (E)-3-(2-(pyridin-4-yl)vinyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole-6-carbaldehyde (25 mg, 0.063 mmol) with a modified purification procedure. The product was precipitated with EtOAc and filtered washing with EtOAc to give 4.5 mg, 30% of a yellow powder which was a 65:35 mixture of (E)/(Z) isomers. 1H NMR (400 MHz, d6-DMSO) δ 14.04, 13.94 (s, 1H), 11.24, 11.22 (s, 1H), 9.01, 8.42 (s, 1H), 8.83 (d, J=5.5 Hz, 2H), 8.50-8.17 (m, 3H), 8.03 (s, 1H), 7.99 (s, 1H), 7.86 (s, 1H), 7.81-7.65 (m, 3H), 7.07, 7.01 (d, J=8.4 Hz, 1H); MS ESI 390.1 [M+H]+, calcd for [C24H15N5O+H]+ 390.14.
Reaction SMILES: [CH2:1]([CH:3]([NH:6][C:7]1[CH:12]=[C:11]([CH3:13])[N:10]=[C:9]([O:14][C:15]2[C:20]([CH3:21])=[CH:19][C:18]([CH3:22])=[CH:17][C:16]=2[CH3:23])[C:8]=1[OH:24])[CH2:4][CH3:5])[CH3:2].Cl[C:26](Cl)([O:28]C(=O)OC(Cl)(Cl)Cl)Cl>>[CH2:1]([CH:3]([N:6]1[C:7]2[CH:12]=[C:11]([CH3:13])[N:10]=[C:9]([O:14][C:15]3[C:20]([CH3:21])=[CH:19][C:18]([CH3:22])=[CH:17][C:16]=3[CH3:23])[C:8]=2[O:24][C:26]1=[O:28])[CH2:4][CH3:5])[CH3:2]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CCC(CC)Nc1cc(C)nc(Oc2c(C)cc(C)cc2C)c1O
Product: CCC(CC)n1c(=O)oc2c(Oc3c(C)cc(C)cc3C)nc(C)cc21

Procedure:
The title compound was prepared as a grey solid by the method analogous to that described in the Example 21 starting from 4-(1-Ethyl-propylamino)-6-methyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-3-ol and triphosgene. 1H NMR (CDCl3) δ 6.87(s,2H), 6.55(s,1H), 3.98(m,1H), 2.29(s,3H), 2.28(s,3H), 2.09(s,6H), 1.9–2.05(m,2H), 1.8–1.9(m,2H), 0.90(t,6H) ppm.
Reaction SMILES: [C:1]([N:9]=[C:10]=[S:11])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:12][C:13]1([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:17]([CH2:18][OH:19])[CH2:16][N:15]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:14]1.C(=O)(O)[O-].[Na+].ClCCl>O1CCCC1>[C:1]([NH:9][C:10]([NH:12][C:13]1([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:17]([CH2:18][OH:19])[CH2:16][N:15]([C:20]([O:22][C:23]([CH3:26])([CH3:24])[CH3:25])=[O:21])[CH2:14]1)=[S:11])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(N=C=S)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CC(CO)C(N)(c2ccccc2)C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC(CO)C(NC(=S)NC(=O)c2ccccc2)(c2ccccc2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 0.1 %

Procedure:
Benzoyl isothiocyanate (81.37 μL, 603.33 mmol) is added to a 0° C. solution of tert-butyl 3-amino-4-(hydroxymethyl)-3-phenyl-pyrrolidine-1-carboxylate (0.168 g, 574.60 mmol) in tetrahydrofuran (2.3 mL). The mixture is warmed to room temperature and stirred overnight. Benzoyl isothiocyanate (15.50 μL, 114.92 mmol) is added and the mixture is stirred for 2 hr. Sodium bicarbonate solution and dichloromethane are added and the aqueous layer is separated, the aqueous mixture is extracted with dichloromethane (3×25 mL), dried over sodium sulfate, filtered, and concentrated to dryness. The crude product is purified via silica gel chromatography eluting with 0-100% ethyl acetate/hexanes to give the title compound (0.178 g, 68%). ES/MS (m/e): 454.3 (M−1).