Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([F:30])=[C:6]([NH:8][C:9]2[CH:14]=[C:13]([NH:15][CH:16]3[CH2:18][CH2:17]3)[N:12]3[N:19]=[CH:20][C:21](/[CH:22]=[C:23]4/[C:24](=[O:29])[NH:25][C:26](=[O:28])[NH:27]/4)=[C:11]3[N:10]=2)[CH:7]=1.[CH2:31]=[O:32]>C(#N)C.N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([F:30])=[C:6]([NH:8][C:9]2[CH:14]=[C:13]([NH:15][CH:16]3[CH2:18][CH2:17]3)[N:12]3[N:19]=[CH:20][C:21](/[CH:22]=[C:23]4/[C:24](=[O:29])[N:25]([CH2:31][OH:32])[C:26](=[O:28])[NH:27]/4)=[C:11]3[N:10]=2)[CH:7]=1
Reactant: C=O
Reactant: O=C1NC(=O)/C(=C/c2cnn3c(NC4CC4)cc(Nc4cc(Cl)ccc4F)nc23)N1
Solvent: c1ccncc1
Solvent: CC#N
Product: O=C1N/C(=C\c2cnn3c(NC4CC4)cc(Nc4cc(Cl)ccc4F)nc23)C(=O)N1CO
Temperature: 65 °C
Reaction time: 0.08 h
Yield: 84 %

Procedure:
To (Z)-5-((5-(5-chloro-2-fluorophenylamino)-7-(cyclopropylamino)pyrazolo[1,5-a]pyrimidin-3-yl)methylene)imidazolidine-2,4-dione (500 mg, 1.17 mmol) in acetonitrile (15 mL) and pyridine (1.5 mL) was added formaldehyde (37% aq) (5.0 mL). The reaction mixture was stirred at 65° C. for 5 minutes. Cooled to room temperature and filtered off the resulting solid. Washed with water and dried under vacuum to provide 450 mg (84%) of (Z)-5-((5-(5-chloro-2-fluorophenylamino)-7-(cyclopropylamino)pyrazolo[1,5-a]pyrimidin-3-yl)methylene)-3-(hydroxymethyl)imidazolidine-2,4-dione as a yellow solid. LCMS (ES): >95% pure, m/z 458 [M+1]+.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]2[CH:10]=[C:11]([NH:28][CH2:29][CH3:30])[C:12]3[N:13]([C:15]([C:18]([NH:20][C:21]4[CH:26]=[CH:25][N:24]=[CH:23][C:22]=4[F:27])=[O:19])=[CH:16][N:17]=3)[N:14]=2)[CH2:4][CH2:3]1.[F:31][C:32]1[CH:37]=[CH:36][C:35]([N:38]=[C:39]=[O:40])=[CH:34][CH:33]=1>C1COCC1>[CH2:29]([NH:28][C:11]1[C:12]2[N:13]([C:15]([C:18]([NH:20][C:21]3[CH:26]=[CH:25][N:24]=[CH:23][C:22]=3[F:27])=[O:19])=[CH:16][N:17]=2)[N:14]=[C:9]([NH:8][C@H:5]2[CH2:4][CH2:3][C@H:2]([NH:1][C:39](=[O:40])[NH:38][C:35]3[CH:36]=[CH:37][C:32]([F:31])=[CH:33][CH:34]=3)[CH2:7][CH2:6]2)[CH:10]=1)[CH3:30]
Reactant: O=C=Nc1ccc(F)cc1
Reactant: CCNc1cc(N[C@H]2CC[C@H](N)CC2)nn2c(C(=O)Nc3ccncc3F)cnc12
Solvent: C1CCOC1
Product: CCNc1cc(N[C@H]2CC[C@H](NC(=O)Nc3ccc(F)cc3)CC2)nn2c(C(=O)Nc3ccncc3F)cnc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To suspension of 82B (20 mg, 0.048 mmol) in THF was added 4-fluorophenylisocyanate (6.54 μL, 0.058 mmol). The mixture was stirred at room temperature overnight. The solvent was removed under reduced and MeOH (1 mL) was added. The mixture was sonicated and the solid was collected by filtration, rinsed with a small amount of MeOH and dried under vacuum to give 8-(ethylamino)-6-((trans-4-(((4-fluorophenyl)carbamoyl)amino)cyclohexyl)amino)-N-(3-fluoro-4-pyridinyl)imidazo[1,2-b]pyridazine-3-carboxamide (20.8 mg) as an off white solid. HPLC Rt=3.176 minutes (Chromolith SpeedROD 4.6×50 mm, 10-90% aqueous methanol containing 0.1% TFA, 4 min gradient, monitored at 220 nm). [M+H]=550.
Reaction SMILES: [CH:1]1([N:7]=[C:8]=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[F:11][C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][C:21]=1[C:22]1[CH:27]=[C:26]([N:28]3[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]3)[N:25]=[C:24]([NH2:35])[N:23]=1)[CH2:18][NH:17][CH2:16][CH2:15]2>>[NH2:35][C:24]1[N:23]=[C:22]([C:21]2[CH:20]=[C:19]3[C:14]([CH2:15][CH2:16][N:17]([C:8]([NH:7][CH:1]4[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]4)=[O:9])[CH2:18]3)=[CH:13][C:12]=2[F:11])[CH:27]=[C:26]([N:28]2[CH2:29][CH2:30][N:31]([CH3:34])[CH2:32][CH2:33]2)[N:25]=1
Reactant: CN1CCN(c2cc(-c3cc4c(cc3F)CCNC4)nc(N)n2)CC1
Reactant: O=C=NC1CCCCC1
Agent: Cl
Product: CN1CCN(c2cc(-c3cc4c(cc3F)CCN(C(=O)NC3CCCCC3)C4)nc(N)n2)CC1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 75, Step 6 starting from cyclohexylisocyanate (Aldrich, Cat. #C105198) and 4-(6-fluoro-1,2,3,4-tetrahydroisoquinolin-7-yl)-6-(4-methylpiperazin-1-yl)pyrimidin-2-amine HCl salt. Analytic LCMS (M+H)+: m/z=468.2.
Reaction SMILES: [NH2:1][C:2]1[O:6][N:5]=[C:4]([CH3:7])[C:3]=1[Br:8].[Cl:9][C:10]1[CH:23]=[CH:22][C:13]2[S:14][C:15]([S:18](Cl)(=[O:20])=[O:19])=[C:16]([CH3:17])[C:12]=2[CH:11]=1>>[Br:8][C:3]1[C:4]([CH3:7])=[N:5][O:6][C:2]=1[NH:1][S:18]([C:15]1[S:14][C:13]2[CH:22]=[CH:23][C:10]([Cl:9])=[CH:11][C:12]=2[C:16]=1[CH3:17])(=[O:20])=[O:19]
Reactant: Cc1noc(N)c1Br
Reactant: Cc1c(S(=O)(=O)Cl)sc2ccc(Cl)cc12
Product: Cc1noc(NS(=O)(=O)c2sc3ccc(Cl)cc3c2C)c1Br
Yield: 18 %

Procedure:
N-(4-bromo-3-methyl-5-isoxazolyl)-5-chloro-3-methylbenzo[b]thiophene-2-sulfonamide was prepared in the same manner as described in Example 2 from 5-amino-4-bromo-3-methylisoxazole and 5-chloro-3-methylbenzo[b]thiophene-2-sulphonyl chloride in 18% yield. Purification was achieved by recrystallization from ethyl acetate/hexanes to give a crystalline solid, m.p. 153°-155° C.
Reaction SMILES: CON(C)[C:4]([C:6]1[C:11]([N:12]([S:16]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([C:26]([F:29])([F:28])[F:27])[CH:20]=2)(=[O:18])=[O:17])COC)=[CH:10][C:9]([CH3:30])=[CH:8][N:7]=1)=[O:5].I[C:33]1[C:34]2[CH:41]=[CH:40][N:39](COCC[Si](C)(C)C)[C:35]=2[N:36]=[CH:37][N:38]=1.CO.Cl>C1COCC1.C([Mg]Cl)(C)C>[Cl:25][C:22]1[CH:23]=[CH:24][C:19]([S:16]([NH:12][C:11]2[C:6]([C:4]([C:33]3[C:34]4[CH:41]=[CH:40][NH:39][C:35]=4[N:36]=[CH:37][N:38]=3)=[O:5])=[N:7][CH:8]=[C:9]([CH3:30])[CH:10]=2)(=[O:18])=[O:17])=[CH:20][C:21]=1[C:26]([F:29])([F:27])[F:28]
Reactant: COCN(c1cc(C)cnc1C(=O)N(C)OC)S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Reactant: C[Si](C)(C)CCOCn1ccc2c(I)ncnc21
Agent: CC(C)[Mg]Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cnc(C(=O)c2ncnc3[nH]ccc23)c(NS(=O)(=O)c2ccc(Cl)c(C(F)(F)F)c2)c1

Procedure:
Prepared from 200 mg (0.42 mmol) of 3-[(4-chloro-3-trifluoromethyl-benzenesulfonyl)-methoxymethyl-amino]-5-methyl-pyridine-2-carboxylic acid methoxy-methyl-amide, 202 mg (0.50 mmol) of 90% 4-iodo-7-(2-trimethylsilanyl-ethoxymethyl)-7H-pyrrolo[2,3-d]pyrimidine dissolved in 2 mL THF with 0.25 mL of 2 M isopropylmagnesium chloride solution in THF added. All of the resulting intermediate ketone was used in the second step with 2 mL methanol and 2 mL 6N hydrochloric acid mixture to give after purification 29 mg of the final product as a yellow solid.
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]=1[CH:4]=[O:5].[CH2:13]([CH2:20][NH2:21])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:13]([CH2:20][NH:21][C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]=1[CH:4]=[O:5])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: NCCc1ccccc1
Reactant: O=Cc1cc([N+](=O)[O-])ccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=Cc1cc([N+](=O)[O-])ccc1NCCc1ccccc1
Temperature: 80 °C
Yield: 66.2 %

Procedure:
A mixture of 300 mg (1.62 mmol) of 2-chloro-5-nitrobenzaldehyde, 196 mg (1.62 mmol) of N-benzylmethylamine and 268 mg (1.94 mmol) of potassium carbonate in dimethylformamide was heated at 80° C. for 5 hour. The solvent was removed and the residue was partitioned between water and ethyl acetate (×2). The combined organic phases were evaporated and the residue was purified by column chromatography eluting with 25% ethyl acetate/petroleum ether (40-60° C.) to give 290 mg of 2-(benzylmethylamino)-5-nitrobenzaldehyde as a yellow oil which solidified on standing; MS: m/e 270.9 [M+H]+.
Reaction SMILES: [C:1]([O:4][C@H:5]([C@H:8]([C@@H:13]([C@@H:18]([CH2:23][O:24][C:25](=[O:27])[CH3:26])[O:19][C:20](=[O:22])[CH3:21])[O:14][C:15](=[O:17])[CH3:16])[O:9][C:10](=[O:12])[CH3:11])[CH:6]=[O:7])(=[O:3])[CH3:2].C(Cl)Cl.[BrH:31]>CC(O)=O>[C:1]([O:4][C@H:5]([C@H:8]([C@@H:13]([C@@H:18]([CH2:23][O:24][C:25](=[O:27])[CH3:26])[O:19][C:20](=[O:22])[CH3:21])[O:14][C:15](=[O:17])[CH3:16])[O:9][C:10](=[O:12])[CH3:11])[CH:6]=[O:7])(=[O:3])[CH3:2].[Br-:31]
Reactant: Br
Agent: CC(=O)OC[C@@H](OC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H](C=O)OC(C)=O
Solvent: ClCCl
Solvent: CC(=O)O
Product: [Br-]
Reaction time: 0.5 h

Procedure:
To a 500 ml flask was added 50 g of glucose pentaacetate (C6H22O11) and 80 ml of methylene chloride. The mixture was stirred at ice-water bath for 20 min HBr in HOAc (33%, 50 ml) was added to the reaction mixture. After stirring for 2.5 hr another 5 ml of HBr was added to the mixture. After another 30 min, the mixture was added 600 ml of methylene chloride. The organic mixture was washed with cold water (200 ml×2), Saturated NaHCO3(200 ml×2), water (200 ml) and brine (200 ml×2). The organic layer was dried over Na2SO4 and the mixture was evaporated at RT to give white solid as final product, bromide derivative, IntD1 (˜95% yield). C14H19BrO9, TLC Rf=0.49, SiO2, 40% ethyl acetate/60% hexanes; Exact Mass 410.02.
Reaction SMILES: CCN=C=NCCCN(C)C.Cl.[F:13][C:14]1[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:15]=1[C:16]([OH:18])=O.[NH2:24][C:25]([CH3:29])([CH3:28])[CH2:26][OH:27].C1C=CC2N(O)N=NC=2C=1>C(Cl)Cl>[OH:27][CH2:26][C:25]([NH:24][C:16](=[O:18])[C:15]1[CH:19]=[CH:20][C:21]([F:23])=[CH:22][C:14]=1[F:13])([CH3:29])[CH3:28]
Reactant: O=C(O)c1ccc(F)cc1F
Reactant: CC(C)(N)CO
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CC(C)(CO)NC(=O)c1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 67.6 %

Procedure:
WSC HCl (7.68 g, 40 mmol) was added to a mixture of 2,4-difluorobenzoic acid (6.32 g, 40 mmol), 2-amino-2-methyl-1-propanol (3.56 g, 40 mmol) and HOBt (5.40 g, 40 mmol) in methylene chloride (150 ml), and stirred at room temperature for 3 hours. The reaction mixture was concentrated, dilutedwith ethyl acetate andwashed with saturated aqueous NaHCO3, 1N hydrochloric acid, saturated aqueous NaHCO3 and brine, successively, dried over MgSO4 and concentrated under a reduced pressure. The residue was purified by silica gel chromatography (hexane/ethyl acetate=3/1) to give the title compound (6.20 g; 68%).
Reaction SMILES: Cl.[C:2]1([CH:8]2[CH2:17][CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([O:18][C@@H:19]4[CH2:24][CH2:23][C@H:22]([CH2:25][NH2:26])[CH2:21][CH2:20]4)[CH:14]=3)[O:9]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:27][S:28](Cl)(=[O:30])=[O:29]>N1C=CC=CC=1.O>[C:2]1([CH:8]2[CH2:17][CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([O:18][C@@H:19]4[CH2:24][CH2:23][C@H:22]([CH2:25][NH:26][S:28]([CH3:27])(=[O:30])=[O:29])[CH2:21][CH2:20]4)[CH:14]=3)[O:9]2)[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)Cl
Reactant: NC[C@H]1CC[C@@H](Oc2ccc3c(c2)CCC(c2ccccc2)O3)CC1
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: CS(=O)(=O)NC[C@H]1CC[C@@H](Oc2ccc3c(c2)CCC(c2ccccc2)O3)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 58.4 %

Procedure:
To a solution of 150 mg [cis-4-(2-phenyl-chroman-6-yloxy)-cyclohexylmethyl]amine hydrochloride (0.40 mmol) at room temperature in 4 ml of pyridine 47 μl of methanesulfonyl chloride (0.60 mmol) were added and stirring at room temperature was continued for 16 h. The reaction mixture was diluted with water and extracted with dichloromethane The combined organic layers were washed with diluted aqueous hydrochloric acid, dried with sodium sulfate and filtered, and the solvent removed under reduced pressure. The crude product was purified by reversed phase HPLC. 97 mg of the title compound were isolated as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[CH3:10][O:11][C:12]1[CH:18]=[CH:17][C:15]([NH2:16])=[CH:14][C:13]=1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[NH2:16][C:15]1[CH:14]=[C:13]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:12]([O:11][CH3:10])=[CH:18][C:17]=1[C:4]([C:3]1[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=1[Cl:1])=[O:5]
Reactant: O=Cc1ccccc1Cl
Reactant: COc1ccc(N)cc1-c1ccccc1
Product: COc1cc(C(=O)c2ccccc2Cl)c(N)cc1-c1ccccc1

Procedure:
(2-amino-5-methoxy-4-phenylphenyl)-(2-chlorophenyl)-methanone (Xff) was prepared by reacting 2-chlorobenzaldehyde with 0.0226 moles of 4-methoxy-3-phenyl aniline in a manner analogous to the Example 1. MH+/Z=338.
Reaction SMILES: Cl.C[O:3][C:4](=[O:16])[C@H:5]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[C:10]([Br:15])[CH:9]=1)[NH2:6].[N:17]1[S:21][N:20]=[C:19]2[C:22]([S:26]([NH:29][C:30]3[CH:38]=[C:37]([Br:39])[CH:36]=[CH:35][C:31]=3[C:32](O)=[O:33])(=[O:28])=[O:27])=[CH:23][CH:24]=[CH:25][C:18]=12>>[N:17]1[S:21][N:20]=[C:19]2[C:22]([S:26]([NH:29][C:30]3[CH:38]=[C:37]([Br:39])[CH:36]=[CH:35][C:31]=3[C:32]([NH:6][C@@H:5]([CH2:7][C:8]3[CH:13]=[CH:12][C:11]([Cl:14])=[C:10]([Br:15])[CH:9]=3)[C:4]([OH:3])=[O:16])=[O:33])(=[O:28])=[O:27])=[CH:23][CH:24]=[CH:25][C:18]=12
Reactant: COC(=O)[C@@H](N)Cc1ccc(Cl)c(Br)c1
Reactant: O=C(O)c1ccc(Br)cc1NS(=O)(=O)c1cccc2nsnc12
Agent: Cl
Product: O=C(N[C@@H](Cc1ccc(Cl)c(Br)c1)C(=O)O)c1ccc(Br)cc1NS(=O)(=O)c1cccc2nsnc12

Procedure:
The title compound was prepared from 3-bromo-4-chloro-L-phenylalanine methyl ester hydrochloride and 2-(benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-bromobenzoic acid as in Example 1, Part C, followed by hydrolysis of the resulting methyl ester as in EXAMPLE 2, Part E. HPLC: RT=10.05 min. MS (ESI−): mass calcd. for C22H15Br2ClN4O5S2, 674.77; m/z found, 673/675 [M−H]−. 1H NMR (400 MHz, acetone-d6): 11.77 (s,1H), 8.46-8.42 (m,1H), 8.34-8.29 (m,1H), 8.19-8.13 (m,1H), 7.93-7.87 (m, 1H), 7.87-7.82 (m, 1H), 7.73-7.69 (m, 1H), 7.54-7.46 (m, 2H), 7.40-7.35 (m, 1H), 7.17-7.12 (m, 1H), 4.97-4.88 (m, 1H), 3.40-3.32 (m, 1H), 3.22-3.14 (m, 1H).
Reaction SMILES: Cl[CH:2]([CH3:5])[CH:3]=[CH2:4].[CH3:6][O:7][CH:8]([O:16][CH3:17])[CH2:9][NH:10][C:11](=[O:15])[O:12][CH2:13][CH3:14].[OH-].[K+].O>CN(C)C=O>[CH2:4]=[CH:3][CH:2]([N:10]([CH2:9][CH:8]([O:7][CH3:6])[O:16][CH3:17])[C:11](=[O:15])[O:12][CH2:13][CH3:14])[CH3:5]
Reactant: C=CC(C)Cl
Reactant: CCOC(=O)NCC(OC)OC
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: C=CC(C)N(CC(OC)OC)C(=O)OCC

Procedure:
22 g (0.24 mol) of 3-chloro-1-butene are added to 35.5 g (0.2 mol) of ethyl N-(2,2-dimethoxyethyl)-carbamate and 26 g of powdered potassium hydroxide in 400 ml of dimethylformamide and the mixture is warmed overnight to 40° C. The salts are dissolved with water and the mixture is extracted several times with methylene chloride. The organic extracts are dried over potassium carbonate and concentrated, and the residue is distilled.
Reaction SMILES: Br[C:2]1[C:7]2[CH:8]=[C:9]([C:12]([F:15])([F:14])[F:13])[CH:10]=[CH:11][C:6]=2[O:5][C:4]([CH2:18][F:19])([CH2:16][F:17])[CH:3]=1.C([Li])CCC.[C:25](=[S:32])(OCC)[O:26][CH2:27][CH3:28].[Cl-].[NH4+]>COC(C)(C)C>[F:17][CH2:16][C:4]1([CH2:18][F:19])[CH:3]=[C:2]([C:25](=[S:32])[O:26][CH2:27][CH3:28])[C:7]2[CH:8]=[C:9]([C:12]([F:15])([F:14])[F:13])[CH:10]=[CH:11][C:6]=2[O:5]1
Reactant: FCC1(CF)C=C(Br)c2cc(C(F)(F)F)ccc2O1
Reactant: CCOC(=S)OCC
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: COC(C)(C)C
Product: CCOC(=S)C1=CC(CF)(CF)Oc2ccc(C(F)(F)F)cc21
Reaction time: 0.25 h
Yield: 52 %

Procedure:
An amount (58 mg) of 4-bromo-2,2-bis(fluoromethyl)-6-trifluoromethyl-2H-1-benzopyran was dissolved in t-butyl methyl ether (2 ml); to the solution, 1.69 M n-butyllithium (0.108 ml) was added at −70° C. under a nitrogen atmosphere and the mixture was stirred for 15 minutes. Then, diethyl thiocarbonate (67 mg) was added dropwise to the reaction mixture, which was stirred for 30 minutes at −70° C. To the reaction mixture, a saturated aqueous solution of ammonium chloride was added, followed by extraction with hexane/ethyl acetate (3/1). The resulting organic layers were washed with a saturated aqueous solution of sodium chloride, dried with anhydrous sodium sulfate and concentrated under reduced pressure; the resulting residue was subjected to silica gel column chromatography (eluent; hexane/ethyl acetate=2/1) to give the titled compound (31 mg) as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:20]=[C:21]([Cl:23])[CH:22]=1)[CH2:5][NH:6][C:7]1[CH:12]=[C:11](F)[CH:10]=[CH:9][C:8]=1[C:14](=[O:19])[C:15]([F:18])([F:17])[F:16].[N:24]1([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1.C(N(CC)C(C)C)(C)C>C(#N)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:20]=[C:21]([Cl:23])[CH:22]=1)[CH2:5][NH:6][C:7]1[CH:12]=[C:11]([N:27]2[CH2:26][CH2:25][N:24]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:29][CH2:28]2)[CH:10]=[CH:9][C:8]=1[C:14](=[O:19])[C:15]([F:18])([F:17])[F:16]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=C(c1ccc(F)cc1NCc1cc(Cl)cc(Cl)c1)C(F)(F)F
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(C(=O)C(F)(F)F)c(NCc3cc(Cl)cc(Cl)c3)c2)CC1
Temperature: 25 °C
Yield: 27.7 %

Procedure:
A mixture of 1-(2-(3,5-dichlorobenzylamino)-4-fluorophenyl)-2,2,2-trifluoroethanone (0.78 g, 2.1 mmol), t-butyl piperazine-1-carboxylate (0.41 g, 2.2 mmol), N,N-diisopropylethylamine (0.8 mL, 4.4 mmol) and acetonitrile (10 mL) was heated at reflux for 18 h, cooled to room temperature and concentrated in vacuo. The residue was dissolved in ethyl acetate; this solution was washed with water, dried over Na2SO4 and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel using 10% ethyl acetate in hexanes as eluent to yield the title compounds as a yellow solid (0.31 g, 28%). 1H NMR (400 MHz, CDCl3): δ 9.38 (br, 1 H), 7.67 (d, 1 H), 7.31 (s, 1 H), 7.21 (s, 2 H), 6.13 (dd, 1 H), 5.70 (d, 1 H), 4.42 (d, 2 H), 3.54 (m, 4 H), 3.38 (m, 4 H), 1.49 (s, 9 H). MS (ESI) m/z: Calculated: 531; Observed: 532 (M+H+).
Reaction SMILES: Br[C:2]1[S:3][C:4]2[CH2:5][C:6]3[C:12]([C:13]4[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=4)=[N:11][N:10]([CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])[C:7]=3[C:8]=2[CH:9]=1.[CH3:29][O:30][C:31]1[CH:36]=[CH:35][C:34](B2OC(C)(C)C(C)(C)O2)=[CH:33][CH:32]=1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:29][O:30][C:31]1[CH:36]=[CH:35][C:34]([C:2]2[S:3][C:4]3[CH2:5][C:6]4[C:12]([C:13]5[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=5)=[N:11][N:10]([CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:26])([CH3:28])[CH3:27])[C:7]=4[C:8]=3[CH:9]=2)=[CH:33][CH:32]=1
Reactant: COc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Reactant: COc1ccc(-c2nn(COCC[Si](C)(C)C)c3c2Cc2sc(Br)cc2-3)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1ccc(-c2cc3c(s2)Cc2c(-c4ccc(OC)cc4)nn(COCC[Si](C)(C)C)c2-3)cc1
Temperature: 100 °C
Yield: 76 %

Procedure:
A mixture of the corresponding 2-Bromo-6-(4-methoxy-phenyl)-4-(2-trimethylsilanyl-ethoxymethyl)-4,7-dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalene (0.76 g, 1.5 mmol), 2-(4-Methoxy-phenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (0.36 g, 2.3 mmol), Na2CO3 (2 M, 3.7 mL), and Pd(PPh3)2Cl2 (150 mg, 0.012 mmol) in toluene/ethanol (1:1, 10 mL) was heated at 100° C. for 8 hr. The solution was cooled to room temperature and extracted with ethyl acetate. The target product was purified by gravity column chromatography (20% EtOAc in hexane) to give 2,6-Bis-(4-methoxy-phenyl)-4-(2-trimethylsilanyl-ethoxymethyl)-4,7-dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalene as orange solid in 76% yield.
Reaction SMILES: [CH3:1][C:2]1([C:7]2[O:11][C:10]([CH2:12][N:13]3[CH:17]=[CH:16][C:15]([NH2:18])=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[CH3:19][C:20]1[CH:21]=[C:22]([C:26]2[O:30][CH:29]=[N:28][C:27]=2[C:31](O)=[O:32])[CH:23]=[CH:24][CH:25]=1>>[C:2]([C:7]1[O:11][C:10]([CH2:12][N:13]2[CH:17]=[CH:16][C:15]([NH:18][C:31]([C:27]3[N:28]=[CH:29][O:30][C:26]=3[C:22]3[CH:21]=[C:20]([CH3:19])[CH:25]=[CH:24][CH:23]=3)=[O:32])=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: CC1(c2ccc(Cn3ccc(N)n3)o2)OCCO1
Reactant: Cc1cccc(-c2ocnc2C(=O)O)c1
Product: CC(=O)c1ccc(Cn2ccc(NC(=O)c3ncoc3-c3cccc(C)c3)n2)o1

Procedure:
Following general procedure B followed by T, starting from 1-[5-(2-methyl-[1,3]dioxolan-2-yl)-furan-2-ylmethyl]-1H-pyrazol-3-ylamine and 5-(3-methyl-phenyl)-oxazole-4-carboxylic acid. LC-MS-conditions 02: tR=1.01 min; [M+H]+=391.5.
Reaction SMILES: [C:1]([NH2:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.I[C:11]1[CH:22]=[CH:21][C:14]([C:15]([O:17][CH2:18][CH:19]=[CH2:20])=[O:16])=[CH:13][CH:12]=1>>[CH2:18]([O:17][C:15]([C:14]1[CH:21]=[CH:22][C:11]([NH:9][C:1](=[O:8])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:12][CH:13]=1)=[O:16])[CH:19]=[CH2:20]
Reactant: NC(=O)c1ccccc1
Reactant: C=CCOC(=O)c1ccc(I)cc1
Product: C=CCOC(=O)c1ccc(NC(=O)c2ccccc2)cc1
Yield: 90.9 %

Procedure:
Using general procedure A, benzamide (150 mg, 1.24 mmol) was coupled with allyl 4-iodobenzoate (300 mg, 1.04 mmol). The crude product was purified by flash chromatography on silica gel (2×15 cm; hexane-ethyl acetate 3:1; 10 mL fractions). Fractions 8-15 provided 266 mg (91% yield) of the product as white crystals. 1H NMR (400 MHz, CDCl3): δ 8.14-8.09 (m, 2H), 8.00 (br s, 1H), 7.93-7.88 (m, 2H), 7.80-7.75 (m, 2H), 7.63-7.58 (m, 1H), 7.56-7.51 (m, 2H), 6.07 (ddt, J=17.2, 11.7, 5.6 Hz, 1H), 5.45 (dq, J=17.2, 1.4 Hz, 1H), 5.32 (dq, J=11.7, 1.4 Hz, 1H), 4.85 (dt, J=5.6, 1.4 Hz, 2H).
Reaction SMILES: CC1N=C(N2C(=O)NN=C2)SC=1C(OCC)=O.[C:18]([C:21]1[S:25][C:24]([N:26]2[CH2:30][CH2:29][NH:28][C:27]2=[O:31])=[N:23][C:22]=1[CH3:32])(=[O:20])[CH3:19].[F:33][C:34]([F:44])([F:43])[C:35]1[CH:36]=[C:37]([CH:40]=[CH:41][CH:42]=1)[CH2:38]Br>>[C:18]([C:21]1[S:25][C:24]([N:26]2[CH2:30][CH2:29][N:28]([CH2:38][C:37]3[CH:40]=[CH:41][CH:42]=[C:35]([C:34]([F:33])([F:43])[F:44])[CH:36]=3)[C:27]2=[O:31])=[N:23][C:22]=1[CH3:32])(=[O:20])[CH3:19]
Reactant: CC(=O)c1sc(N2CCNC2=O)nc1C
Reactant: FC(F)(F)c1cccc(CBr)c1
Agent: CCOC(=O)c1sc(-n2cn[nH]c2=O)nc1C
Product: CC(=O)c1sc(N2CCN(Cc3cccc(C(F)(F)F)c3)C2=O)nc1C
Yield: 50 %

Procedure:
Following the procedure as describe in Preparation 16, making variations as required to replace ethyl 4-methyl-2-(5-oxo-1H-1,2,4-triazol-4(5H)-yl)thiazole-5-carboxylate with 1-(5-acetyl-4-methylthiazol-2-yl)imidazolidin-2-one to react with 3-(trifluoromethyl)benzyl bromide, the title compound was obtained as a yellow solid in 50% yield: mp 149-151° C.; 1H NMR (300 MHz, DMSO-d6) δ 7.70-7.58 (m, 4H), 4.55 (s, 2H), 4.04 (t, J=6.0 Hz, 2H), 3.51 (t, J=6.0 Hz, 2H), 2.51 (s, 3H), 2.45 (s, 3H); 13C NMR (75 MHz, DMSO-d6) δ 190.9, 160.4, 155.6, 155.1, 138.5, 132.5, 130.4, 129.9 (q, 3JC-F=38 Hz), 126.6, 125.9, 125.1-124.8 (m), 122.9, 47.1, 42.6, 42.4, 30.5, 18.8; MS (ES+) m/z 384.2 (M+1).