Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1(=O)[CH2:4][CH2:3][CH2:2]1.[C:6]([O:10][C:11]([N:13]1[CH2:17][CH2:16][CH:15]([C:18](=[O:28])[CH2:19]P(OCC)(OCC)=O)[CH2:14]1)=[O:12])([CH3:9])([CH3:8])[CH3:7].[OH-].[K+]>C(O)C>[C:6]([O:10][C:11]([N:13]1[CH2:17][CH2:16][CH:15]([C:18](=[O:28])[CH:19]=[C:1]2[CH2:4][CH2:3][CH2:2]2)[CH2:14]1)=[O:12])([CH3:9])([CH3:7])[CH3:8]
Reactant: O=C1CCC1
Reactant: CCOP(=O)(CC(=O)C1CCN(C(=O)OC(C)(C)C)C1)OCC
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(C(=O)C=C2CCC2)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 35.6 %

Procedure:
Add cyclobutanone (0.738 mL; 9.89 mmol) to a stirred mixture of 3-(2-(diethoxyphosphoryl)-acetyl)pyrrolidine-1-carboxylic acid tert butyl ester (3.14 g, 8.99 mmol) and potassium hydroxide (656 mg, 11.7 mmol) in ethanol (45 mL) kept under nitrogen at 5° C. Warm to room temperature and stir for 3 hours. Concentrate under reduced pressure and subject the residue to silica gel chromatography, eluting with 20% ethyl acetate in hexanes to afford 0.85 g (36%) of the crude desired compound, which is used in the next step without further purification.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.C(=O)([O-])[O-].[K+].[K+].[Cl:12][C:13]1[CH:30]=[CH:29][C:16]([O:17][CH:18](Br)[C:19](=[O:27])[C:20]([CH3:26])([CH3:25])[CH:21]([Br:24])[CH2:22]Br)=[CH:15][CH:14]=1.O>C1(C)C=CC=CC=1>[Cl:12][C:13]1[CH:30]=[CH:29][C:16]([O:17][C:18]([N:1]2[CH:5]=[CH:4][N:3]=[CH:2]2)=[C:19]2[C:20]([CH3:26])([CH3:25])[CH:21]([Br:24])[CH2:22][O:27]2)=[CH:15][CH:14]=1
Reactant: c1c[nH]cn1
Reactant: CC(C)(C(=O)C(Br)Oc1ccc(Cl)cc1)C(Br)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: CC1(C)C(=C(Oc2ccc(Cl)cc2)n2ccnc2)OCC1Br
Temperature: 90 °C
Reaction time: 10 h
Yield: 10.3 %

Procedure:
35 g (0.5 mole) of imidazole and 103.5 g (0.75 mole) of potassium carbonate are dissolved in 700 ml of toluene at 60° C. 132 g (0.269 mole) of 1-(4-chlorophenoxy)-3,3-dimethyl-1,4,5-tribromo-2-pentanone in 100 ml of toluene are added dropwise to this solution in the course of 20 minutes. The reaction mixture is subsequently stirred at 90° C. for 10 hours and cooled and water is added. The organic phase is separated off, washed with water dried over sodium sulphate and concentrated. The residue is purified by column chromatography (silica gel; ethyl acetate/cyclohexane=3:1). 10.6 g (10% of theory) of (4-chlorophenoxy)-(imidazol-1-yl)-(4-bromo-3,3-dimethyltetrahydrofuran-2-ylidene)-methane of refractive index nD20 1.5837 are obtained.
Reaction SMILES: Cl.O1CCOCC1.[Cl:8][C:9]1[N:14]=[C:13]([C:15]2[S:19][C:18]([N:20]3[CH2:25][CH2:24][N:23](C(OC(C)(C)C)=O)[CH2:22][CH2:21]3)=[N:17][C:16]=2[C:33]2[CH:38]=[CH:37][CH:36]=[C:35]([NH:39][S:40]([C:43]3[CH:48]=[C:47]([F:49])[CH:46]=[CH:45][C:44]=3[F:50])(=[O:42])=[O:41])[C:34]=2[F:51])[CH:12]=[CH:11][N:10]=1>C(Cl)Cl.CO>[Cl:8][C:9]1[N:14]=[C:13]([C:15]2[S:19][C:18]([N:20]3[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]3)=[N:17][C:16]=2[C:33]2[C:34]([F:51])=[C:35]([NH:39][S:40]([C:43]3[CH:48]=[C:47]([F:49])[CH:46]=[CH:45][C:44]=3[F:50])(=[O:42])=[O:41])[CH:36]=[CH:37][CH:38]=2)[CH:12]=[CH:11][N:10]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2nc(-c3cccc(NS(=O)(=O)c4cc(F)ccc4F)c3F)c(-c3ccnc(Cl)n3)s2)CC1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: CO
Product: O=S(=O)(Nc1cccc(-c2nc(N3CCNCC3)sc2-c2ccnc(Cl)n2)c1F)c1cc(F)ccc1F
Reaction time: 8 h
Yield: 130.6 %

Procedure:
A 4 N solution of HCl in 1,4-dioxane (1.1 ml, 4.3 mmol) was added to a stirring solution of 1,1-dimethylethyl 4-[5-(2-chloro-4-pyrimidinyl)-4-(3-{[(2,5-difluorophenyl)sulfonyl]amino}-2-fluorophenyl)-1,3-thiazol-2-yl]-1-piperazinecarboxylate (0.36 g, 0.54 mmol) in DCM (8 mL) and MeOH (1 mL) at rt. The reaction was allowed to stir overnight. LCMS analysis indicated complete consumption of the starting material. The volatiles were removed in vacuo to afford the HCl salt of the desired product of Step C (0.40 g, 100% yield) which was carried forward without further purification. MS (ES+): 568 [M+H]+.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][N:7]([CH2:10][CH2:11][CH2:12][O:13][C:14]2[CH:23]=[C:22]3[C:17]([C:18](Cl)=[N:19][CH:20]=[N:21]3)=[CH:16][C:15]=2[O:25][CH3:26])[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[OH:27][C:28]1[CH:29]=[C:30]2[C:34](=[CH:35][CH:36]=1)[NH:33][C:32]([CH3:37])=[CH:31]2.C(=O)([O-])[O-].[K+].[K+]>CC(N(C)C)=O>[C:1]([N:4]1[CH2:9][CH2:8][N:7]([CH2:10][CH2:11][CH2:12][O:13][C:14]2[CH:23]=[C:22]3[C:17]([C:18]([O:27][C:28]4[CH:29]=[C:30]5[C:34](=[CH:35][CH:36]=4)[NH:33][C:32]([CH3:37])=[CH:31]5)=[N:19][CH:20]=[N:21]3)=[CH:16][C:15]=2[O:25][CH3:26])[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: Cc1cc2cc(O)ccc2[nH]1
Reactant: COc1cc2c(Cl)ncnc2cc1OCCCN1CCN(C(C)=O)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3)ncnc2cc1OCCCN1CCN(C(C)=O)CC1
Temperature: 85 °C
Reaction time: 3 h
Yield: 53.1 %

Procedure:
A mixture of 7-[3-(4-acetylpiperazin-1-yl)propoxy]-4-chloro-6-methoxyquinazoline (190 mg, 0.50 mmol), (prepared as described for the starting material in Example 4), 5-hydroxy-2-methylindole (81 mg, 0.55 mmol), (WO 00/47212, Example 48), and potassium carbonate (76 mg, 0.55 mmol) in DMA (6 ml) was stirred at 85° C. for 3 hours, allowed to cool to ambient temperature and the solvent evaporated under vacuum. The residue was purified by column chromatography eluting with methylene chloride/methanol (saturated with ammonia) (92/8) to give a white solid. This was triturated with a mixture of ether and acetone, filtered and dried to give 7-[3-(4-acetylpiperazin-1-yl)propoxy]-6-methoxy-4-[(2-methyl-1H-indol-5-yl)oxy]quinazoline (130 mg, 53%).
Reaction SMILES: ClCC([O:5][CH:6]([CH2:41][O:42]C(=O)CCl)[CH2:7][NH:8][C:9](=[O:40])[C:10]1[C:31]([I:32])=[C:30]([NH:33][C:34](=[O:37])[CH2:35][Cl:36])[C:29]([I:38])=[C:12]([C:13]([NH:15][CH2:16][CH:17]([O:24]C(=O)CCl)[CH2:18][O:19]C(=O)CCl)=[O:14])[C:11]=1[I:39])=O.[OH-].[Na+].O.Cl>CN(C)C(=O)C.C(#N)C>[OH:5][CH:6]([CH2:41][OH:42])[CH2:7][NH:8][C:9](=[O:40])[C:10]1[C:31]([I:32])=[C:30]([NH:33][C:34](=[O:37])[CH2:35][Cl:36])[C:29]([I:38])=[C:12]([C:13]([NH:15][CH2:16][CH:17]([OH:24])[CH2:18][OH:19])=[O:14])[C:11]=1[I:39]
Reactant: O=C(CCl)Nc1c(I)c(C(=O)NCC(COC(=O)CCl)OC(=O)CCl)c(I)c(C(=O)NCC(COC(=O)CCl)OC(=O)CCl)c1I
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)N(C)C
Solvent: CC#N
Solvent: O
Product: O=C(CCl)Nc1c(I)c(C(=O)NCC(O)CO)c(I)c(C(=O)NCC(O)CO)c1I
Yield: 92.2 %

Procedure:
N,N'-bis[2,3-di(2-chloroacetoxy)propyl]-5-(2-chloroacetamido)-2,4,6-triiodoisophthalamide in N,N-dimethylacetamide and acetonitrile, from Example 3, was hydrolyzed by adding 130 mL of 10N sodium hydroxide solution (1.3 moles). Water (36 mL) was then added to the mixture to give a homogeneous solution. 1N Hydrochloric acid (100 mL, 0.1 moles) was added to precipitate the N,N'-bis(2,3-dihydroxypropyl)-5-(2-chloroacetamido)-2,4,6-triiodoisophthalamide. The precipitate was collected and washed with water. The wet product was dried at 60° C. in a vacuum oven to give 71.6 g of product, 92.2% yield. The material was 100% pure by HPLC analysis.
Reaction SMILES: [N+:1]([C:4]1[O:8][C:7]([C:9](Cl)=[O:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].[NH:12]([C:14]1[S:15][C:16]2[CH:22]=[C:21]([N+:23]([O-:25])=[O:24])[CH:20]=[CH:19][C:17]=2[N:18]=1)[NH2:13]>>[N+:23]([C:21]1[CH:20]=[CH:19][C:17]2[N:18]=[C:14]([NH:12][NH:13][C:9]([C:7]3[O:8][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=3)=[O:10])[S:15][C:16]=2[CH:22]=1)([O-:25])=[O:24]
Reactant: NNc1nc2ccc([N+](=O)[O-])cc2s1
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])o1
Product: O=C(NNc1nc2ccc([N+](=O)[O-])cc2s1)c1ccc([N+](=O)[O-])o1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
The compound 4h was prepared according to above described method by using 5-nitro-2-furancarboxylic acid chloride (430 mg, 1.5 mmol) and 2-hydrazino-6-nitrobenzothiazole (290 mg, 1 mmol) which stirred for 1 h at 0° C. and stirring continued at 25° C. for 11 h (yield 283 mg, 87%).
Reaction SMILES: Cl(O)(=O)(=O)=O.[NH:6]1[C:10](=[O:11])[CH2:9][CH2:8][C@H:7]1[C:12]([OH:14])=[O:13].C(OC[CH2:20][CH2:21][CH3:22])(=O)C.[C:23](=O)([O-])[O-].[Na+].[Na+]>C(Cl)(Cl)(Cl)Cl.CCOCC>[NH:6]1[C:10](=[O:11])[CH2:9][CH2:8][C@H:7]1[C:12]([O:14][C:21]([CH3:20])([CH3:22])[CH3:23])=[O:13]
Reactant: O=C([O-])[O-]
Reactant: O=C1CC[C@@H](C(=O)O)N1
Reactant: CCCCOC(C)=O
Agent: [Na+]
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: CCOCC
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(C)OC(=O)[C@@H]1CCC(=O)N1
Reaction time: 24 h
Yield: 57.5 %

Procedure:
Perchloric acid (70% aqueous, 0.521 cm3, 6.05 mmol) was added dropwise to a stirred suspension of (S)-pyroglutamic acid 9 (1 g, 7.75 mmol) in tent-butyl acetate (12 cm3, 85.5 mmol). The mixture was stirred for 24 h then sodium carbonate (0.80 g, 7.60 mmol) was added cautiously, ether was added and the organic phase washed with saturated sodium hydrogen carbonate solution and brine. The aqueous phase was extracted with ethyl acetate, dried (MgSO4), filtered and the solvent removed to yield an oil to which was added carbon tetrachloride and the solvent evaporated in vacuo to remove traces of acetic acid to give ester 10 (0.81 g, 56%) as a white solid: δH (300 MHz; CDCl3; Me4Si) 1.48 [9H, s, C(CH3)], 2.33-2.45 (4H, m, 3-H2, 4-H2), 4.12-4.16 (1H, m, 5-H) and 6.16 (1H, br s, N—H); δC (75 MHz; CDCl3) 24.7 (CH2, 4-C), 27.8 [CH3, C(CH3)], 29.2 (CH2, 3-C), 55.9 (CH, 5-C), 82.3 [quat., C(CH3)], 170.9 (quat., 5-CO) and 177.7 (quat., 2-C).
Reaction SMILES: OO.[NH2:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]([O:12][CH3:13])=[O:11])=[N:8][CH:9]=1.[BrH:14].N>>[NH2:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]([O:12][CH3:13])=[O:11])=[N:8][C:9]=1[Br:14]
Reactant: COC(=O)c1ccc(N)cn1
Reactant: Br
Agent: N
Agent: OO
Product: COC(=O)c1ccc(N)c(Br)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2.0 ml of hydrogen peroxide solution (32% strength) were added to methyl 5-aminopyridine-2-carboxylate (2.0 g, 13.15 mmol) and 30 ml of 48% strength hydrobromic acid, and the reaction was stirred at room temperature for two hours. Another 0.32 ml of hydrogen peroxide solution were then added, and the mixture was stirred for a further hour. The mixture was adjusted to pH 8 by addition of concentrated ammonia solution with ice cooling and extracted three times with in each case 60 ml of ethyl acetate. The organic phase was dried over sodium sulphate, concentrated on a rotary evaporator and chromatographed on silica gel (mobile phase: cyclohexane/ethyl acetate). This gave 1.32 g of the desired product (42.3% of theory).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH3:11])[CH:5]=1)([CH3:3])[CH3:2].[Br:12]N1C(=O)CCC1=O.O>C(Cl)(Cl)(Cl)Cl>[Br:12][C:9]1[CH:8]=[CH:7][C:6]([O:10][CH3:11])=[CH:5][C:4]=1[CH:1]([CH3:3])[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1cccc(C(C)C)c1
Solvent: O
Solvent: ClC(Cl)(Cl)Cl
Product: COc1ccc(Br)c(C(C)C)c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 81.3 %

Procedure:
A mixture of 1-isopropyl-3-methoxy-benzene (Intermediate 142, 3.50 g, 23.3 mmols), molecular sieves, and silica gel in 150 mL CCl4 was treated with N-bromosuccinimide (4.98 g, 28.0 mmols) at 35° C. for 18 hours. An additional portion of N-bromosuccinimide (830.0 mg, 4.46 mmols) was added and stirring continued for 6 hours. The mixture was cooled to room temperature, H2O was added, and the mixture was filtered to remove the solids. The mixture was extracted with E2O and the combined organic layers were washed with 10% aqueous HCl, H2O, saturated aqueous NaHCO3, and saturated NaCl before being dried (MgSO4) and concentrated under reduced pressure. Column chromatography (2.5% EtOAc-hexanes) afforded 4.34 g (81%) of the title compound as a pale-yellow oil.
Reaction SMILES: [CH3:1][C@H:2]1[NH:7][C@@H:6]([CH3:8])[CH2:5][N:4]([C:9]2[N:14]=[C:13](N)[C:12]([O:16][CH3:17])=[CH:11][CH:10]=2)[CH2:3]1.N1C=CC=CC=1.[Br:24][C:25]1[CH:30]=[CH:29][C:28]([S:31](Cl)(=[O:33])=[O:32])=[C:27]([F:35])[CH:26]=1>C(Cl)Cl>[Br:24][C:25]1[CH:30]=[CH:29][C:28]([S:31]([C:13]2[N:14]=[C:9]([N:4]3[CH2:3][C@H:2]([CH3:1])[NH:7][C@H:6]([CH3:8])[CH2:5]3)[CH:10]=[CH:11][C:12]=2[O:16][CH3:17])(=[O:32])=[O:33])=[C:27]([F:35])[CH:26]=1
Reactant: COc1ccc(N2C[C@@H](C)N[C@@H](C)C2)nc1N
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1F
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1ccc(N2C[C@@H](C)N[C@@H](C)C2)nc1S(=O)(=O)c1ccc(Br)cc1F
Temperature: 25 °C
Yield: 38.8 %

Procedure:
6-[(3R,5S)-3,5-Dimethyl-1-piperazinyl]-3-(methyloxy)-2-pyridinamine (D7, Method D) (2.25 mmol) was dissolved in DCM (5 mL) and pyridine (5 mL) and then cooled to 0° C. 4-Bromo-2-fluoro benzenesulfonyl chloride (0.738 g, 2.706 mmol), dissolved in DCM (5 mL) was then added dropwise and the reaction then allowed to warm to rt overnight. The reaction was then evaporated to a minimum and redissolved in DCM (100 mL) and washed with water (2×75 mL), saturated sodium hydrogen carbonate (3×75 mL) and brine (75 mL). The organic layer was dried (MgSO4) and evaporated to give a brown oil which was triturated with methanol and dried at 50° C. under high vac to give the title compound as a pale brown powder (D18) (0.400 g). MS (ES+) m/e 473/475 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[O:3][C:4]1[CH:11]=[CH:10][C:7]([CH2:8]Br)=[CH:6][CH:5]=1.C([O-])([O-])=O.[K+].[K+].[F:20][C:21]1[CH:22]=[C:23]2[C:27](=[CH:28][CH:29]=1)[NH:26][C:25]([CH3:30])=[C:24]2[C:31]1[C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=2[S:34](=[O:42])(=[O:41])[NH:33][N:32]=1.Br[CH2:44][C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46]>CC#N.O.C(Cl)Cl>[C:48]([O:47][C:45](=[O:46])[CH2:44][N:26]1[C:27]2[C:23](=[CH:22][C:21]([F:20])=[CH:29][CH:28]=2)[C:24]([C:31]2[C:36]3[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=3[S:34](=[O:41])(=[O:42])[N:33]([CH2:8][C:7]3[CH:10]=[CH:11][C:4]([O:3][C:2]([F:13])([F:12])[F:1])=[CH:5][CH:6]=3)[N:32]=2)=[C:25]1[CH3:30])([CH3:51])([CH3:50])[CH3:49]
Reactant: Cc1[nH]c2ccc(F)cc2c1C1=NNS(=O)(=O)c2ccccc21
Reactant: FC(F)(F)Oc1ccc(CBr)cc1
Reactant: CC(C)(C)OC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CC#N
Solvent: O
Product: Cc1c(C2=NN(Cc3ccc(OC(F)(F)F)cc3)S(=O)(=O)c3ccccc32)c2cc(F)ccc2n1CC(=O)OC(C)(C)C
Temperature: 80 °C
Reaction time: 8 h

Procedure:
4-Trifluoromethoxybenzyl bromide (11 μL, 67 μmol) and K2CO3 (10 mg, 72 μmol) were added to a solution of 4-(5-fluoro-2-methyl-1H-indol-3-yl)-2H-benzo[e][1,2,3]thiadiazine 1,1-dioxide (20 mg, 61 μmol) in CH3CN (1 mL), and stirred overnight at 80° C. An additional amount of K2CO3 (10 mg, 72 μmol) and tert-butyl bromoacetate (14 μL, 92 μmol) was added, and the reaction mixture stirred an additional 2 h at 80° C. The reaction mixture was diluted with H2O and CH2Cl2, and filtered through an Extrelut column. The Extrelut column was washed with CH2Cl2, and the filtrate was concentrated to afford the sub-title compound, which was carried onto the next step without further purification or characterization.
Reaction SMILES: [CH:1]([C:3]1[S:7][C:6]([C:8]([OH:10])=[O:9])=[CH:5][C:4]=1[CH3:11])=[O:2].[CH2:12](O)[CH2:13][OH:14]>C1(C)C=CC=CC=1.CC(=O)OCC.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[O:2]1[CH2:12][CH2:13][O:14][CH:1]1[C:3]1[S:7][C:6]([C:8]([OH:10])=[O:9])=[CH:5][C:4]=1[CH3:11]
Reactant: Cc1cc(C(=O)O)sc1C=O
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1cc(C(=O)O)sc1C1OCCO1
Yield: 97.9 %

Procedure:
A suspension of 5-formyl-4-methyl-thiophene-2-carboxylic acid (3.00 g, 17.6 mmol), ethylene glycol (3.28 g, 52.9 mmol) and p-toluene sulfonic acid hydrate (61 mg, 0.353 mmol) in toluene (80 mL) is refluxed for 3 h in a Dean-Stark apparatus. The clear solution is diluted with EA and washed twice with water. The washings are extracted back with EA. The combined organic extracts are dried over Na2SO4, filtered, concentrated and dried to give 5-[1,3]dioxolan-2-yl-4-methyl-thiophene-2-carboxylic acid (3.69 g) as a pale yellow resin, LC-MS: tR=0.46 min, [M+1]+=215.15. b) To a mixture of 5-[1,3]dioxolan-2-yl-4-methyl-thiophene-2-carboxylic acid (3.00 g, 14.0 mmol), HOBt (2.52 g, 16.8 mmol) and EDC (2.95 g, 15.4 mmol) in isopropanol (240 mL), hydrazine hydrate (1.50 g, 29.4 mmol) is added at 0° C. The suspension is stirred at 0° C., diluted with DMF and warmed to rt. Stirring is continued at rt for 2 h before the solvent is evaporated. The residue is dissolved in acetonitrile and separated by prep. HPLC (XBridge C18, 50×50 +100×50 mm, 10 μm, gradient of acetonitrile in water containing 0.5% of aq. ammonia) to give the title compound (2.43 g) as a colourless solid; LC-MS: tR=0.57 min, [M+1]+=228.96; 1H NMR (D6-DMSO): δ2.20 (s, 3H), 3.90-3.99 (m, 2H), 3.99-4.08 (m, 2H), 4.43 (s, 2H), 6.06 (s, 1H), 7.43 (s, 1H), 9.69 (s, 1H).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[N:12]=[C:11]([C:13]3[CH:14]=[N:15][NH:16][CH:17]=3)[N:10]3[CH:18]=[CH:19][N:20]=[C:9]3[CH:8]=2)[CH:4]=[N:3]1.C[C:22](C)(C)[CH2:23][CH:24]=[CH:25][C:26]#[N:27].[N:30]1CCCN2CCCCCC=12>CN(C)C=O>[CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[N:12]=[C:11]([C:13]3[CH:14]=[N:15][N:16]([CH:24]([CH2:23][C:22]#[N:30])[CH2:25][C:26]#[N:27])[CH:17]=3)[N:10]3[CH:18]=[CH:19][N:20]=[C:9]3[CH:8]=2)[CH:4]=[N:3]1
Reactant: CC(C)(C)CC=CC#N
Reactant: Cn1cc(-c2cc3nccn3c(-c3cn[nH]c3)n2)cn1
Reactant: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: Cn1cc(-c2cc3nccn3c(-c3cnn(C(CC#N)CC#N)c3)n2)cn1
Temperature: 50 °C
Yield: 230.1 %

Procedure:
7-(1-Methyl-1H-pyrazol-4-yl)-5-(1H-pyrazol-4-yl)imidazo[1,2-c]pyrimidine (Preparation K; 0.040 mg, 0.15 mmol) was dissolved in dimethylformamide (0.6 mL) and 5,5-dimethylhex-2-enenitrile (Table 1, compound k; 56 mg, 0.045 mmol) and 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine (34 mg, 0.23 mmol) were added and the reaction was heated at 50° C. for 7 hours. The reaction was then cooled and the solvent was removed. The crude reaction was purified by silica gel chromatography using a gradient (1 to 4% MeOH/DCM) to provide 3-(4-(7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-c]pyrimidin-5-yl)-1H-pyrazol-1-yl)pentanedinitrile (37 mg, 63% yield) as a solid. MS (apci) m/z=389.2 (M+H).
Reaction SMILES: [CH2:1]([O:5][C:6]([C:8]1[N:9]=[C:10]([C:26]#[N:27])[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][CH:14]=[C:13](SC1CCCCC1)[CH:12]=2)=[O:7])[CH2:2][CH2:3][CH3:4].[CH:28]1[CH:33]=[C:32](Cl)[CH:31]=[C:30](C(OO)=O)[CH:29]=1.[O-:39][S:40]([O-:43])(=S)=O.[Na+].[Na+]>C(Cl)Cl>[CH2:1]([O:5][C:6]([C:8]1[N:9]=[C:10]([C:26]#[N:27])[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][CH:14]=[C:13]([S:40]([CH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1)(=[O:43])=[O:39])[CH:12]=2)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOC(=O)c1nc(C#N)c2cc(SC3CCCCC3)ccc2c1O
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CCCCOC(=O)c1nc(C#N)c2cc(S(=O)(=O)C3CCCCC3)ccc2c1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 84 %

Procedure:
A mixture of 1-cyano-7-cyclohexylsulfanyl-4-hydroxy-isoquinoline-3-carboxylic acid butyl ester (325 mg, 0.85 mmol) and mCPBA (526 mg, 3.05 mmol) in CH2Cl2 was stirred at room temperature overnight. The reaction was quenched by adding Na2S2O3 (3.6 equivalents). It was then filtered and rinsed with CH2Cl2. Filtrate was concentrated and purified by silica gel chromatography, eluting with 10-100% EtOAc/hexanes to provide the title compound 297 mg (0.71 mmol) in 84% yield. LC-MS ESI−: 414.99 (M−1)−.
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH2:7][NH:8][C:9]2[CH:10]=[C:11]([CH:26]=[CH:27][CH:28]=2)[C:12]([C:14]2[CH:22]=[C:21]3[C:17]([C:18](=[CH:24]O)[C:19](=[O:23])[NH:20]3)=[CH:16][CH:15]=2)=[O:13])=[CH:5][C:4]([CH3:29])=[N:3]1.[CH3:30][N:31]1[CH2:36][CH2:35][N:34]([C:37]2[CH:42]=[CH:41][C:40]([NH2:43])=[CH:39][CH:38]=2)[CH2:33][CH2:32]1>C1COCC1>[CH3:1][N:2]1[C:6]([CH2:7][NH:8][C:9]2[CH:10]=[C:11]([CH:26]=[CH:27][CH:28]=2)[C:12]([C:14]2[CH:22]=[C:21]3[C:17](/[C:18](=[CH:24]/[NH:43][C:40]4[CH:39]=[CH:38][C:37]([N:34]5[CH2:33][CH2:32][N:31]([CH3:30])[CH2:36][CH2:35]5)=[CH:42][CH:41]=4)/[C:19](=[O:23])[NH:20]3)=[CH:16][CH:15]=2)=[O:13])=[CH:5][C:4]([CH3:29])=[N:3]1
Reactant: CN1CCN(c2ccc(N)cc2)CC1
Reactant: Cc1cc(CNc2cccc(C(=O)c3ccc4c(c3)NC(=O)C4=CO)c2)n(C)n1
Solvent: C1CCOC1
Product: Cc1cc(CNc2cccc(C(=O)c3ccc4c(c3)NC(=O)/C4=C\Nc3ccc(N4CCN(C)CC4)cc3)c2)n(C)n1
Temperature: 65 °C
Reaction time: 24 h
Yield: 39 %

Procedure:
A small screw cap test tube was charged with 6-{3-[(2,5-Dimethyl-2H-pyrazol-3-ylmethyl)-amino]-benzoyl}-3-hydroxymethylene-1,3-dihydro-indol-2-one (prepared below, 0.045 g, 0.117 mmol) and THF (2 mL). To the resulting solution was added 4-(4-Methyl-piperazin-1-yl)-phenylamine (23 mg, 0.117 mmol), and the mixture was stirred for 24 h at 65° C. The reaction mixture was cooled to room temperature and the precipitate that formed was collected by filtration. The yellow solid was dissolved in 5 mL of a solvent mixture containing 98% EtOAc/2% i-prOH and washed with water (2×5 mL). The organic layers were combined, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The crude residue was columned over silica (95/5, chloroform/Hexanes w/0.5% NEt3 to afford the title compound in 39% yield (26 mg, 0.045 mmol).
Reaction SMILES: C[C:2]1[CH:7]=[CH:6]C=C[C:3]=1[S:8]([N:11]1[C:19]2[C:14](=[C:15]([CH:20]=[CH2:21])[CH:16]=[CH:17][CH:18]=2)[CH:13]=[CH:12]1)(=[O:10])=[O:9].BrC1C=CC=C2C=1C=CN2[S:32](C1SC=CC=1)(=O)=O.C([Sn](CCCC)(CCCC)C=C)CCC>>[S:32]1[CH:6]=[CH:7][CH:2]=[C:3]1[S:8]([N:11]1[C:19]2[C:14](=[C:15]([CH:20]=[CH2:21])[CH:16]=[CH:17][CH:18]=2)[CH:13]=[CH:12]1)(=[O:10])=[O:9]
Reactant: C=Cc1cccc2c1ccn2S(=O)(=O)c1ccccc1C
Reactant: O=S(=O)(c1cccs1)n1ccc2c(Br)cccc21
Agent: C=C[Sn](CCCC)(CCCC)CCCC
Product: C=Cc1cccc2c1ccn2S(=O)(=O)c1cccs1
Yield: 79 %

Procedure:
The experimental for Intermediate 15 was followed using 4-bromo-1-(2-thienylsulfonyl)-1H-indole (500 mg, 1.46 mmol; Intermediate 20), tributyl(vinyl)stannane (tot 0.864 mL, 2.92 mmol) and Pd(PPh3)2OAc2 (tot 55 mg, 0.073 mmol). The title compound (333 mg, 79%) was obtained as a colorless solid. MS (ESI+) for C14H11NO2S2 m/z 290 (M+H)+.
Reaction SMILES: C([Li])CCC.[CH2:6]([N:13]1[CH2:19][CH2:18][CH2:17][C:16](=[O:20])[CH2:15][CH2:14]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[NH4+].[Cl-].[CH3:23][CH2:24][O:25][C:26]([CH3:28])=[O:27]>C1COCC1.CCCCCC.O>[CH2:6]([N:13]1[CH2:19][CH2:18][CH2:17][C:16]([CH2:28][C:26]([O:25][CH2:24][CH3:23])=[O:27])([OH:20])[CH2:15][CH2:14]1)[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: CCOC(C)=O
Reactant: O=C1CCCN(Cc2ccccc2)CC1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)CC1(O)CCCN(Cc2ccccc2)CC1
Temperature: 0 °C
Reaction time: 0.67 h

Procedure:
To a solution of DIPA (3.1 mL) in THF (30 mL) was added dropwise a 2.6 M solution (8.6 mL) of n-butyl lithium in hexane at −70° C. After stirring at 0° C. for 40 minutes, EtOAc (2.3 mL) was added dropwise thereto at −70° C., followed by stirring for 5 minutes. A solution of 1-benzylazepan-4-one (3.6 g) in THF (10 mL) was added dropwise thereto, followed by stirring for 40 minutes. To the reaction mixture was added a saturated aqueous NH4Cl solution, followed by addition of water and extraction with EtOAc. The organic layer was washed with brine, dried over MgSO4, and then concentrated under reduced pressure. The residue was purified by medium-pressure preparative liquid chromatography (silica gel, YAMAZEN YFLC WPrep2XY, CHCl3:MeOH: aqueous ammonia) to obtain ethyl (1-benzyl-4-hydroxyazepan-4-yl)acetate (5.0 g) as a yellow oily substance.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[C:6]([OH:11])[CH:5]=1.C[O-].[Na+].Br[CH2:17][CH2:18]Br>CO>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]2[O:10][CH2:17][CH2:18][O:11][C:6]=2[CH:5]=1
Reactant: COC(=O)c1ccc(O)c(O)c1
Reactant: BrCCBr
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1ccc2c(c1)OCCO2

Procedure:
A solution of 4.20 g. of 3,4-dihydroxybenzoic acid methyl ester in 10.0 ml. of methanol is combined with 7.0 g. of sodium methoxide and then 15.0 g. of 1,2-dibromoethane is added. The resulting mixture is refluxed under nitrogen for 24 hours, then cooled, filtered, evaporated in vacuo and the resulting oil dissolved in 50 ml. of chloroform. The resulting solution after again filtering is chromatographed over 100 ml. of silica gel eluting with chloroform to obtain 3,4-ethylenedioxybenzoic acid methyl ester, m.p. 43°-45°C.