Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:44])=[C:6]([N:8]2[C:12](=[O:13])[N:11]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[S:27](=[O:39])(=[O:38])[NH:28][C:29](=[O:37])[C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=4[Cl:36])=[CH:17][CH:16]=3)[C:10]([CH2:40][CH2:41][CH2:42][CH3:43])=[N:9]2)[CH:7]=1.Cl[C:46]([O:48][CH2:49][CH2:50][CH3:51])=[O:47]>CN(C1C=CN=CC=1)C.N1C=CC=CC=1>[CH2:40]([C:10]1[N:11]([CH2:14][C:15]2[CH:16]=[CH:17][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[S:27](=[O:38])(=[O:39])[NH:28][C:29](=[O:37])[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[Cl:36])=[CH:19][CH:20]=2)[C:12](=[O:13])[N:8]([C:6]2[CH:7]=[C:2]([NH:1][C:46]([O:48][CH2:49][CH2:50][CH3:51])=[O:47])[CH:3]=[CH:4][C:5]=2[Cl:44])[N:9]=1)[CH2:41][CH2:42][CH3:43]
Reactant: CCCOC(=O)Cl
Reactant: CCCCc1nn(-c2cc(N)ccc2Cl)c(=O)n1Cc1ccc(-c2ccccc2S(=O)(=O)NC(=O)c2ccccc2Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: CCCCc1nn(-c2cc(NC(=O)OCCC)ccc2Cl)c(=O)n1Cc1ccc(-c2ccccc2S(=O)(=O)NC(=O)c2ccccc2Cl)cc1
Yield: 65.7 %

Procedure:
At room temperature, under N2, a solution of 20 mg (0.031 mmole) of 2-(5-amino-2-chlorophenyl)-5-n-butyl-4-[[2'-[N-(2-chlorobenzoyl)sulfamoyl]biphenyl-4-yl]methyl]-2,4-dihydro-3H-1,2,4-triazol-3-one (from Example 60), 3.8 mg (0.031 mmole) of DMAP, 18.9 mg (0.154 mmole) of propyl chloroformate, and 1 mL pyridine was stirred overnight. After quenching with methanol and water, the organic material was extracted with EtOAc, washed with water and brine, and dried over sodium sulfate. The crude product obtained after filtration and removal of volatiles was flash chromatographed over silica gel (gradient elution with 0.5-5% MeOH/CH2Cl2) to give 15 mg (65%) of the desired compound as a white solid, mp >119° C. (gradual), homogeneous by TLC (9:1 MeOH/CH2Cl2), mass spectrum (FAB) m/e 736 (M+1)+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:25]=[C:24]3[C:10]([C:11](=[O:27])[C:12](=[O:26])[C:13]4[S:23][CH2:22][C:16]5([CH2:21][CH2:20][NH:19][CH2:18][CH2:17]5)[O:15][C:14]=43)=[CH:9][CH:8]=2)=[CH:3][CH:2]=1.[Cl:28][C:29]1[CH:30]=[C:31]([CH:35]=[CH:36][CH:37]=1)[C:32](Cl)=[O:33]>>[Cl:28][C:29]1[CH:30]=[C:31]([CH:35]=[CH:36][CH:37]=1)[C:32]([N:19]1[CH2:20][CH2:21][C:16]2([O:15][C:14]3[C:24]4[C:10]([C:11](=[O:27])[C:12](=[O:26])[C:13]=3[S:23][CH2:22]2)=[CH:9][CH:8]=[C:7]([C:4]2[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=2)[CH:25]=4)[CH2:17][CH2:18]1)=[O:33]
Reactant: O=C(Cl)c1cccc(Cl)c1
Reactant: O=C1C(=O)c2ccc(-c3ccncc3)cc2C2=C1SCC1(CCNCC1)O2
Product: O=C1C(=O)c2ccc(-c3ccncc3)cc2C2=C1SCC1(CCN(C(=O)c3cccc(Cl)c3)CC1)O2
Yield: 99 %

Procedure:
Compound 66 was synthesized using 9-pyridin-4-ylspiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione, 3-chlorobenzoyl chloride and conditions outlined in procedure N. Yield: 99%. Mp.: 265-267° C.; 400 MHz 1H NMR (DMSO-d6) δ 8.75 (m, 2H), 8.08 (d, J=1.6 Hz, 1H), 8.03 (d, J=8.4 Hz, 1H), 7.98 (dd, J=1.6, 8.0 Hz, 1H), 7.83 (m, 2H), 7.56-7.47 (m, 3H), 7.41 (dt, J=1.2, 7.6 Hz, 1H), 4.32 (br, 1H), 3.50 (br, 2H), 3.38-3.30 (m, 1H), 3.14 (s, 2H), 2.15 (m, 1H), 2.02 (m, 1H), 1.91 (m, 2H); LCMS: 517 [M+H].
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:19])[CH:5]=[N:6][C:7]=1[O:8][C:9]1[CH:10]=[N:11][C:12]2[C:17]([CH:18]=1)=[CH:16][CH:15]=[CH:14][CH:13]=2.[CH3:20][C:21]1[CH:26]=[CH:25][C:24]([S:27](Cl)(=[O:29])=[O:28])=[CH:23][CH:22]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:19][S:27]([C:24]2[CH:25]=[CH:26][C:21]([CH3:20])=[CH:22][CH:23]=2)(=[O:29])=[O:28])[CH:5]=[N:6][C:7]=1[O:8][C:9]1[CH:10]=[N:11][C:12]2[C:17]([CH:18]=1)=[CH:16][CH:15]=[CH:14][CH:13]=2
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Nc1cnc(Oc2cnc3ccccc3c2)c(Cl)c1
Product: Cc1ccc(S(=O)(=O)Nc2cnc(Oc3cnc4ccccc4c3)c(Cl)c2)cc1

Procedure:
The title compound was prepared by reacting 5-chloro-6-(quinolin-3-yloxy)pyridin-3-amine (obtained as per procedure described in preparation 1) and 4-methylbenzene-1-sulfonyl chloride.
Reaction SMILES: [O:1]=[C:2]1[CH:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:5][C:4](=[O:12])[NH:3]1.[N:13]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])=[N:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16].C(=O)([O-])[O-].[K+].[K+]>C(OCC)(=O)C>[C:25]([O:24][C:22]([N:13]([C:6]1([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:5][C:4](=[O:12])[NH:3][C:2]1=[O:1])[NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[O:23])([CH3:28])([CH3:27])[CH3:26]
Reactant: CCOC(=O)C1CC(=O)NC1=O
Reactant: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Product: CCOC(=O)C1(N(NC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)CC(=O)NC1=O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 83.1 %

Procedure:
To a solution of ethyl 2,5-dioxopyrrolidine-3-carboxylate (2.96 g) in ethyl acetate (25 ml) were added di-tert-butyl azodicarboxylate (4.19 g) and then potassium carbonate (4.78 g) at room temperature. After this reaction mixture was stirred at room temperature for 15 minutes, the resulting mixture was filtered through a Celite pad and the filtrate was concentrated. The residue was purified by a flash column chromatography (hexane:ethyl acetate=3:1) to give ethyl 3-[N,N′-bis(tert-butyloxycarbonyl)hydrazino]-2,5-dioxopyrrolidine-3-carboxy late (5.77 g, 83%) as amorphous.
Reaction SMILES: C(O)C.[CH3:4][O:5][C:6]1[CH:7]=[C:8]([CH:14]=[CH:15][C:16]=1[O:17][CH3:18])[C:9]([O:11]CC)=O.CC[O-].[Na+].[N:23]1([C:29]([C:31]2[CH:32]=[C:33]3[C:38](=[CH:39][CH:40]=2)[NH:37][C:36](=[O:41])[CH2:35][CH2:34]3)=[O:30])[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1>C(Cl)(Cl)Cl>[CH3:4][O:5][C:6]1[CH:7]=[C:8]([CH:14]=[CH:15][C:16]=1[O:17][CH3:18])[C:9]([N:26]1[CH2:27][CH2:28][N:23]([C:29]([C:31]2[CH:32]=[C:33]3[C:38](=[CH:39][CH:40]=2)[NH:37][C:36](=[O:41])[CH2:35][CH2:34]3)=[O:30])[CH2:24][CH2:25]1)=[O:11]
Reactant: O=C1CCc2cc(C(=O)N3CCNCC3)ccc2N1
Reactant: CCOC(=O)c1ccc(OC)c(OC)c1
Agent: CC[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CCO
Product: COc1ccc(C(=O)N2CCN(C(=O)c3ccc4c(c3)CCC(=O)N4)CC2)cc1OC
Yield: 6.5 %

Procedure:
To 100 ml of ethanol was added 1.9 g of ethyl 3,4-dimethoxybenzoate, 0.5 g sodium ethylate and 2.4 g of 6-(1-piperazinylcarbonyl)-3,4-dihydrocarbostyril, the mixture was reacted in an autoclave under 110 atmospheric pressure at 140°-150° C. for 6 hours. After the reaction was completed, the reaction mixture was cooled and concentrated under a reduced pressure. The residue thus obtained was dissolved in 200 ml of chloroform and the chloroform solution was washed with 1%-potassium carbonate aqueous solution, a dilute hydrochloric acid and water in this order, then dried with anhydrous sodium sulfate. The solvent was removed by distillation and the residue was treated by means of a silica gel column chromatography (Silica gel: Wako C-200, eluent: chloroform:methanol (volume/volume)=20:1) and the crude crystals were recrystallized from ethanol-chloroform to obtain 250 mg of 6-[4-(3,4-dimethoxybenzoyl)-1-piperazinylcarbonyl]-3,4-dihydrocarbostyril. Colorless granular crystals. Melting point: 238°-239.5° C.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH2:11]([NH:13][CH2:14][C:15]([CH2:21][NH:22][C:23]1[CH:31]=[CH:30][CH:29]=[C:28]2[C:24]=1[CH:25]=[N:26][N:27]2[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)([OH:20])[C:16]([F:19])([F:18])[F:17])[CH3:12]>>[CH2:11]([N:13]([CH2:14][C:15]([OH:20])([CH2:21][NH:22][C:23]1[CH:31]=[CH:30][CH:29]=[C:28]2[C:24]=1[CH:25]=[N:26][N:27]2[C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)[C:16]([F:19])([F:18])[F:17])[C:4](=[O:6])[C:3]1[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=1[F:1])[CH3:12]
Reactant: O=C(O)c1ccccc1F
Reactant: CCNCC(O)(CNc1cccc2c1cnn2-c1ccccc1)C(F)(F)F
Product: CCN(CC(O)(CNc1cccc2c1cnn2-c1ccccc1)C(F)(F)F)C(=O)c1ccccc1F

Procedure:
Prepared similarly to Example 1 from 2-fluorobenzoic acid and 3-(ethylamino)-1,1,1-trifluoro-2-{[(1-phenyl-1H-indazol-4-yl)amino]methyl}-2-propanol.
Reaction SMILES: [CH2:1]([N:4]([CH2:15][CH2:16][CH3:17])[CH:5]1[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([OH:14])[CH:11]=2)[CH2:6]1)[CH2:2][CH3:3].C(N(CC)CC)C.[C:25]1([CH3:35])[CH:30]=[CH:29][C:28]([S:31](Cl)(=[O:33])=[O:32])=[CH:27][CH:26]=1.C([O-])([O-])=O.[Na+].[Na+]>ClCCl>[CH2:15]([N:4]([CH2:1][CH2:2][CH3:3])[CH:5]1[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:14][S:31]([C:28]3[CH:29]=[CH:30][C:25]([CH3:35])=[CH:26][CH:27]=3)(=[O:33])=[O:32])[CH:11]=2)[CH2:6]1)[CH2:16][CH3:17]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCCN(CCC)C1Cc2ccc(O)cc2C1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCN(CCC)C1Cc2ccc(OS(=O)(=O)c3ccc(C)cc3)cc2C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 74.1 %

Procedure:
2-Dipropylamino-indan-5-ol (Preparation 9, 140 mg, 0.47 mmol) was dissolved in dichloromethane (25 mL) and cooled to 0 C. Thereafter was added triethylamine (99 mg, 0.98 mmol) and toluene-4-sulfonyl chloride (101 mg, 0.54 mmol). The reaction mixture was allowed to reach room temperature and was then stirred at ambient temperature for 2 h. Aqueous Na2CO3 solution (25 mL, 10%) was added and the mixture was stirred for an additional 5 min. The layers were separated and the organic layer was washed, dried (Na2SO4) and the solvent evaporated. The crude product was chromatograped using dichloromethane-methanol (19:1) as eluant. The pure fractions were pooled, and the solvent removed in vacuo yielding 135 mg (78%) of toluene-4-sulfonic acid 2-dipropylamino-indan-5-yl ester as an oil. The amine was converted to its hydrochloride salt (hydroscopic).; 1H NMR (300 MHz, CDCl3) δ 0.85 (t, 6H), 1.45 (m, 4H), 2.4-2.5 (m, 7H), 2.75-2.85 (m, 2H), 2.90-3.00 (m, 2H), 3.60-3.70 (m, 1H), 6.65 (dd, J=2.5, 8.3 Hz, 1H), 6.85 (d, J=2.5 Hz, 1H), 7.05 (d, J=8.0 Hz, 1H), 7.30 (d, J=8.5 Hz, 2H), 7.70 (d, J=8.7 Hz, 2H); 13C NMR (75.4 MHz, CDCl3) δ 11.99, 20.24, 21.73, 36.11, 36.70, 53.37, 63.44, 118.57, 120.14, 125.03, 128.51, 129.67, 132.60, 140.96, 143.74, 145.16, 148.27; MS m/e 387 (3, M+), 358 (100), 232 (49), 91 (15), 155 (13).
Reaction SMILES: [CH2:1]([N:3]([CH2:27][CH3:28])[C:4](=[O:26])[NH:5][C@H:6]1[CH2:20][C@H:19]2[C@@H:9]([CH2:10][C:11]3[C:21]4[C:14](=[CH:15][CH:16]=[C:17]([C:22]([NH2:24])=O)[C:18]2=4)[NH:13][CH:12]=3)[N:8]([CH3:25])[CH2:7]1)[CH3:2].P(Cl)(Cl)(Cl)=O.[OH-].[K+]>C(Cl)(Cl)Cl>[C:22]([C:17]1[C:18]2=[C:21]3[C:14]([NH:13][CH:12]=[C:11]3[CH2:10][C@@H:9]3[C@@H:19]2[CH2:20][C@H:6]([NH:5][C:4](=[O:26])[N:3]([CH2:27][CH3:28])[CH2:1][CH3:2])[CH2:7][N:8]3[CH3:25])=[CH:15][CH:16]=1)#[N:24]
Reactant: CCN(CC)C(=O)N[C@H]1C[C@@H]2c3c(C(N)=O)ccc4[nH]cc(c34)C[C@H]2N(C)C1
Agent: [K+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Product: CCN(CC)C(=O)N[C@H]1C[C@@H]2c3c(C#N)ccc4[nH]cc(c34)C[C@H]2N(C)C1
Temperature: 55 °C
Reaction time: 16 h
Yield: 43 %

Procedure:
383 mg of [8α-(3,3-diethylureido)-6-methylergolin-12-yl]carboxylic acid amide (1 mmol) is dissolved in 25 ml of chloroform, 3 ml of phosphorus oxychloride is added thereto, and the mixture is agitated for 16 hours at 55° C. The mixture is poured on ice, allowed to stand for 30 minutes, then made alkaline with 1N potassium hydroxide solution, and extracted with methylene chloride. The organic phase is dried with sodium sulfate and evaporated. The residue is crystallized from ethyl acetate in a 43% yield. [α]D =+16° (0.5% in chloroform).
Reaction SMILES: [N+:1]([O-:4])([O-])=[O:2].[K+].FC(F)(F)C(O)=O.[F:13][C:14]1[CH:15]=[C:16]([NH:31]C(=O)OC(C)(C)C)[CH:17]=[CH:18][C:19]=1[O:20][C:21]1[CH:22]=[N:23][C:24]([S:27]([CH3:30])(=[O:29])=[O:28])=[CH:25][CH:26]=1>>[F:13][C:14]1[C:19]([O:20][C:21]2[CH:22]=[N:23][C:24]([S:27]([CH3:30])(=[O:29])=[O:28])=[CH:25][CH:26]=2)=[CH:18][C:17]([N+:1]([O-:4])=[O:2])=[C:16]([NH2:31])[CH:15]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(Oc2ccc(S(C)(=O)=O)nc2)c(F)c1
Reactant: O=[N+]([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Product: CS(=O)(=O)c1ccc(Oc2cc([N+](=O)[O-])c(N)cc2F)cn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
0.98 g of potassium nitrate was added to a trifluoroacetic acid (35 ml) solution of 3.38 g of tert-butyl (3-fluoro-4-(6-methanesulfonyl-pyridin-3-yloxy)-phenyl)-carbamate obtained in (step 2), the reaction liquid was stirred at room temperature for 1 hour, and then the solvent was evaporated away under reduced pressure. The residue was diluted with ethyl acetate, washed with aqueous saturated sodium bicarbonate and saturated saline in order, and dried with anhydrous sodium sulfate. The solvent was evaporated away under reduced pressure, and the resulting residue was purified through silica gel column chromatography (developing solvent: hexane/ethyl acetate=1/2) to obtain the entitled compound.
Reaction SMILES: CS[C:3]1[S:4][CH2:5][C:6](=[O:8])[N:7]=1.[NH:9]1[CH2:15][CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1>>[N:9]1([C:3]2[S:4][CH2:5][C:6](=[O:8])[N:7]=2)[CH2:15][CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1
Reactant: CSC1=NC(=O)CS1
Reactant: C1CNCCNC1
Product: O=C1CSC(N2CCCNCC2)=N1

Procedure:
2-[1,4]-Diazepan-1-yl-thiazol-4-one was prepared from 2-Methylsulfanyl-thiazol-4-one and [1,4]diazepane following General Procedure E
Reaction SMILES: [F:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][NH:7][C:8]([C:10]2[N:11]=[C:12]3[C:21]([CH3:23])([CH3:22])[NH:20][CH2:19][CH2:18][N:13]3[C:14](=[O:17])[C:15]=2[OH:16])=[O:9])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[CH2:32](Cl)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>CN(C=O)C>[CH2:32]([O:16][C:15]1[C:14](=[O:17])[N:13]2[CH2:18][CH2:19][NH:20][C:21]([CH3:22])([CH3:23])[C:12]2=[N:11][C:10]=1[C:8]([NH:7][CH2:6][C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:25][CH:24]=1)=[O:9])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: ClCc1ccccc1
Reactant: CC1(C)NCCn2c1nc(C(=O)NCc1ccc(F)cc1)c(O)c2=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC1(C)NCCn2c1nc(C(=O)NCc1ccc(F)cc1)c(OCc1ccccc1)c2=O
Temperature: 65 °C
Reaction time: 8 h

Procedure:
To a stirred solution of N-(4-fluorobenzyl)-3-hydroxy-9,9-dimethyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrazino[1,2-a]pyrimidine-2-carboxamide (see Example 1) in DMF was added K2CO3 (2 eq.) followed by BnCl (1.1 eq.). The mixture was stirred at 65° C. overnight, after which time additional BnCl (0.3 eq.) was added and the mixture was left for a further 6 hours. The solvent was removed under reduced pressure and the brown oil was taken into EtOAc, washed with 1N HCl and brine, dried (Na2SO4) and evaporated under reduced pressure. The residue was purified by flash column chromatography, eluting with 2% MeOH/DCM to afford the title product. 1H NMR (300 MHz, d6-DMSO) δ 8.88 (t, J=6.2 Hz, 1H), 7.30-7.44 (m, 7H), 7.06 (t, J=8.8 Hz, 2H), 5.05 (s, 2H), 4.41 (d, J=6.2 Hz, 2H), 3.80 (t, J=5.4 Hz, 2H), 3.09 (br. s, 2H), 1.44 (s, 6H); MS (ES) C24H25FN4O3 requires 436. Found: 437 (M+H+).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]2[C:8]([C:11]([NH:13][C:14]3[CH:22]=[CH:21][CH:20]=[C:19]4[C:15]=3[C:16]([CH3:31])=[N:17][N:18]4[CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([CH3:30])[N:25]=3)=[O:12])=[CH:9][N:10]=[C:4]2[CH:3]=1.CC1C(P(C2C(C)=CC=CC=2)C2C(C)=CC=CC=2)=CC=CC=1.C([Sn](CCCC)(CCCC)/[CH:59]=[CH:60]\[O:61][CH2:62][CH3:63])CCC.C(N(CC)CC)C>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CN(C=O)C>[CH2:62]([O:61]/[CH:60]=[CH:59]\[C:2]1[CH:7]=[CH:6][N:5]2[C:8]([C:11]([NH:13][C:14]3[CH:22]=[CH:21][CH:20]=[C:19]4[C:15]=3[C:16]([CH3:31])=[N:17][N:18]4[CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([CH3:30])[N:25]=3)=[O:12])=[CH:9][N:10]=[C:4]2[CH:3]=1)[CH3:63]
Reactant: CCCC[Sn](/C=C\OCC)(CCCC)CCCC
Reactant: Cc1cccc(Cn2nc(C)c3c(NC(=O)c4cnc5cc(Br)ccn45)cccc32)n1
Agent: [Pd]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCO/C=C\c1ccn2c(C(=O)Nc3cccc4c3c(C)nn4Cc3cccc(C)n3)cnc2c1
Temperature: 100 °C
Reaction time: 10 h
Yield: 84.5 %

Procedure:
A flask was charged with 7-bromo-N-(3-methyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide (Example 50, Steps A-B; 100 mg, 0.21 mmol), tri-O-tolylphosphine (12.8 mg, 0.042 mmol) and tris(dibenzylideneacetone)dipalladium (19.3 mg, 0.021 mmol). To the flask was added DMF (3 mL), followed by (Z)-tributyl(2-ethoxyvinyl)stannane (114 mg, 0.316 mmol) and triethylamine (0.04 mL, 0.30 mmol). The reaction mixture was degassed under nitrogen, and stirred at 100° C. for 10 hours. The reaction mixture was cooled, diluted with water, and extracted with DCM and EtOAc. The combined organic extracts were dried over anhydrous sodium sulfate and concentrated. The crude product was subjected to preparative thin-layer chromatography on silica with 5% MeOH/DCM as eluent to afford 82.8 mg of product as a yellow solid.
Reaction SMILES: [CH3:1][N:2]([CH2:14][C:15]([OH:17])=O)[NH:3][C:4](=[O:13])[NH:5][CH2:6][C:7]1[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=1.[NH2:18][C@@H:19]([CH2:42][C:43]1[CH:48]=[CH:47][C:46]([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[CH:45][CH:44]=1)[C:20]([N:22]([CH2:32][C:33]1[C:34]2[CH:41]=[CH:40][CH:39]=[CH:38][C:35]=2[S:36][CH:37]=1)[C@@H:23]([CH3:31])[CH:24]([O:28][CH2:29][CH3:30])[O:25][CH2:26][CH3:27])=[O:21]>>[S:36]1[CH:37]=[C:33]([CH2:32][N:22]([C@@H:23]([CH3:31])[CH:24]([O:25][CH2:26][CH3:27])[O:28][CH2:29][CH3:30])[C:20](=[O:21])[C@@H:19]([NH:18][C:15](=[O:17])[CH2:14][N:2]([CH3:1])[NH:3][C:4]([NH:5][CH2:6][C:7]2[CH:8]=[CH:9][N:10]=[CH:11][CH:12]=2)=[O:13])[CH2:42][C:43]2[CH:44]=[CH:45][C:46]([O:49][C:50]([CH3:51])([CH3:53])[CH3:52])=[CH:47][CH:48]=2)[C:34]2[CH:41]=[CH:40][CH:39]=[CH:38][C:35]1=2
Reactant: CN(CC(=O)O)NC(=O)NCc1ccncc1
Reactant: CCOC(OCC)[C@H](C)N(Cc1csc2ccccc12)C(=O)[C@@H](N)Cc1ccc(OC(C)(C)C)cc1
Product: CCOC(OCC)[C@H](C)N(Cc1csc2ccccc12)C(=O)[C@H](Cc1ccc(OC(C)(C)C)cc1)NC(=O)CN(C)NC(=O)NCc1ccncc1

Procedure:
According to the procedure described in the synthesis method of Compound II-15, 2-(1-methyl-2-(pyridin-4-ylmethylcarbamoyl)hydrazinyl)acetic acid (Compound VI-6) 70 mg (0.29 mmol) was coupled with (S)-2-amino-N-(benzo[b]thiophen-3-ylmethyl)-3-(4-tert-butoxyphenyl)-N—((S)-1,1-diethoxypropan-2-yl)propanamide (Compound IV-6) 100 mg (0.20 mmol) to obtain the title compound.
Reaction SMILES: C1COCC1.[NH2:6][C:7]1[C:12]2=[C:13]([C:23]3[CH:28]=[CH:27][C:26]([NH:29][C:30]([NH:32][C:33]4[CH:38]=[C:37]([C:39]([F:42])([F:41])[F:40])[CH:36]=[CH:35][C:34]=4[F:43])=[O:31])=[CH:25][CH:24]=3)[C:14]([CH2:16][CH2:17][C:18](OCC)=[O:19])=[CH:15][N:11]2[N:10]=[CH:9][N:8]=1.CC(C[AlH]CC(C)C)C>CCOC(C)=O>[NH2:6][C:7]1[C:12]2=[C:13]([C:23]3[CH:28]=[CH:27][C:26]([NH:29][C:30]([NH:32][C:33]4[CH:38]=[C:37]([C:39]([F:40])([F:41])[F:42])[CH:36]=[CH:35][C:34]=4[F:43])=[O:31])=[CH:25][CH:24]=3)[C:14]([CH2:16][CH2:17][CH2:18][OH:19])=[CH:15][N:11]2[N:10]=[CH:9][N:8]=1
Reactant: CCOC(=O)CCc1cn2ncnc(N)c2c1-c1ccc(NC(=O)Nc2cc(C(F)(F)F)ccc2F)cc1
Agent: CC(C)C[AlH]CC(C)C
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Nc1ncnn2cc(CCCO)c(-c3ccc(NC(=O)Nc4cc(C(F)(F)F)ccc4F)cc3)c12
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.5 %

Procedure:
To a solution of THF (6 mL) was added ethyl 3-(4-amino-5-{4-[({[2-fluoro-5-(trifluoromethyl)phenyl]amino}carbonyl)amino]phenyl}pyrrolo[2,1-f][1,2,4]triazin-6-yl)propanoate (62 mg, 0.12 mmol) followed by DIBAL (0.6 mL, 0.6 mmol, 1.0M solution in toluene). The reaction was stirred at rt for 1 h. Additional DIBAL (1.2 mL, 1.2 mmol, 1.0M solution in toluene) was added and stirred at rt for an additional 1 h. The reaction was diluted with EtOAc and quenched with saturated aqueous Rochelle's salt. Reaction was extracted with EtOAc (4×). The combined organic layers were dried (Na2SO4), filtered, and evaporated to dryness to afford a crude yellow solid (56 mg, 98%) that was used directly in the next step without further purification. 1H-NMR (CD3OD) δ 8.62 (d, J=7.6 Hz, 1H), 7.74 (s, 1H), 7.61 (d, J=7.6 Hz, 2H), 7.52 (s, 1H), 7.38 to 7.31 (m, 4H), 3.50 (t, J=7.1 Hz, 2H), 2.61 (t, J=7.8 Hz, 2H), 1.77 to 1.65 (m, 2H); MS [M+H]+=489; LCMS RT=2.50 min.
Reaction SMILES: [CH3:1][C:2]1[CH2:7][C:6]([CH3:9])([CH3:8])[NH:5][C:4]([CH3:11])([CH3:10])N=1.CC(C)=[O:14].CS(O)(=O)=O>CO>[CH3:10][C:4]1([CH3:11])[NH:5][C:6]([CH3:9])([CH3:8])[CH2:7][C:2](=[O:14])[CH2:1]1
Reactant: CC1=NC(C)(C)NC(C)(C)C1
Reactant: CC(C)=O
Agent: CS(=O)(=O)O
Solvent: CO
Product: CC1(C)CC(=O)CC(C)(C)N1
Temperature: 25 °C
Yield: 95.3 %

Procedure:
A solution of 6.3 g. of acetonine in a mixed solvent comprising 30 g. of acetone and 30 g. of methanol was added with 1.6 g. of methanesulfonic acid. The mixture was maintained at room temperature for 24 hours in a sealed equipment to effect the reaction. After completion of the reaction, the reaction mixture was purified in the same manner as in Example 1 to obtain triacetonamine in a yield of 95.3%.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:3][CH2:2]1.Br.C([N:29]1[CH2:37][CH2:36][C:35]2[CH2:34][NH:33][CH2:32][C:31]=2[CH2:30]1)C1C=CC=CC=1.N12CCCN=C1CCCCC2>C(#N)C>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11]([N:33]4[CH2:32][C:31]5[CH2:30][NH:29][CH2:37][CH2:36][C:35]=5[CH2:34]4)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:2][CH2:3]1
Reactant: c1ccc(CN2CCC3=C(CNC3)C2)cc1
Reactant: O=C(O)c1cn(C2CC2)c2c(F)c(F)c(F)cc2c1=O
Agent: Br
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: O=C(O)c1cn(C2CC2)c2c(F)c(N3CC4=C(CNCC4)C3)c(F)cc2c1=O
Reaction time: 8 h
Yield: 60.9 %

Procedure:
0.3 g of 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid and 0.6 g of 3-benzyl-3,8-diazabicyclo[4.3.0]non-1(6)-ene hydrobromide were suspended in 30 ml of acetonitrile. 0.6 ml of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) was added to the suspension. The reaction mixture was refluxed for 5 hours and then kept overnight at room temperature. The produced precipitate was filtered and dissolved in 30 ml of 5% acetic acid in ethanol. After adding 0.5 g of 10% Palladium charcoal, the reaction mixture was stirred under hydrogen stream for 6 hours and then filtered. The filtrate was concentrated under reduced pressure. 0.25 g of the title compound (yield 61%).
Reaction SMILES: [C:1]([C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:13]([NH:15][C:16]3[C:21]([CH3:22])=[CH:20][C:19]([C:23]([F:35])([C:28]([F:34])([F:33])[C:29]([F:32])([F:31])[F:30])[C:24]([F:27])([F:26])[F:25])=[CH:18][C:17]=3[CH2:36][CH3:37])=[O:14])[CH:9]=2)[N+:4]=1[O-])#[N:2].P(Br)(Br)([Br:41])=O.C(=O)([O-])O.[Na+]>C(#N)C>[Br:41][C:11]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:13]([NH:15][C:16]3[C:21]([CH3:22])=[CH:20][C:19]([C:23]([F:35])([C:28]([F:34])([F:33])[C:29]([F:32])([F:31])[F:30])[C:24]([F:27])([F:26])[F:25])=[CH:18][C:17]=3[CH2:36][CH3:37])=[O:14])[CH:9]=2)[N:4]=[C:3]([C:1]#[N:2])[CH:12]=1
Reactant: CCc1cc(C(F)(C(F)(F)F)C(F)(F)C(F)(F)F)cc(C)c1NC(=O)c1ccc2c(ccc(C#N)[n+]2[O-])c1
Reactant: O=P(Br)(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: CCc1cc(C(F)(C(F)(F)F)C(F)(F)C(F)(F)F)cc(C)c1NC(=O)c1ccc2nc(C#N)cc(Br)c2c1
Temperature: 100 °C
Reaction time: 5 h
Yield: 43 %

Procedure:
2-Cyano-N-[2-ethyl-6-methyl-4-(1,1,1,2,3,3,4,4,4-nonafluorobutan-2-yl)phenyl]-quinoline-6-carboxamide-1-oxide (96 mg) was dissolved in acetonitrile, added with phosphoryl bromide (250 mg), and stirred at 100° C. for 5 hours. After cooling to room temperature, the reaction solution was poured into ice water and neutralized with sodium hydrogen carbonate. After extracting the mixture twice with ethyl acetate, the organic phases were combined and washed with water, and dried over anhydrous magnesium sulfate. The drying agent was filtered off and the solvent was removed by distillation under the reduced pressure. The resulting residues were purified by column chromatography to obtain 4-bromo-2-cyano-N-[2-ethyl-6-methyl-4-(1,1,1,2,3,3,4,4,4-nonafluorobutan-2-yl)phenyl]quinoline-6-carboxamide (46 mg, 43%).