Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC1C=C(F)C=C2C=1C=NN2C.ClC1C=CC2N(C(C=O)=CN=2)N=1.[Cl:25][C:26]1[CH:27]=[CH:28][C:29]2[N:30]([C:32]([C:35]([C:38]3[C:39]([F:49])=[C:40]4[C:44](=[CH:45][C:46]=3[F:47])[N:43]([CH3:48])[N:42]=[CH:41]4)([OH:37])C)=[CH:33][N:34]=2)[N:31]=1>>[Cl:25][C:26]1[CH:27]=[CH:28][C:29]2[N:30]([C:32]([CH:35]([C:38]3[C:39]([F:49])=[C:40]4[C:44](=[CH:45][C:46]=3[F:47])[N:43]([CH3:48])[N:42]=[CH:41]4)[OH:37])=[CH:33][N:34]=2)[N:31]=1
Reactant: Cn1ncc2c(F)c(C(C)(O)c3cnc4ccc(Cl)nn34)c(F)cc21
Agent: Cn1ncc2c(F)cc(F)cc21
Agent: O=Cc1cnc2ccc(Cl)nn12
Product: Cn1ncc2c(F)c(C(O)c3cnc4ccc(Cl)nn34)c(F)cc21
Yield: 41 %

Procedure:
The title compound as a yellow solid (60 mg, 41%) was synthesized from (intermediate P) (70 mg, 0.416 mmol) and 6-chloroimidazo[1,2-b]pyridazine-3-carbaldehyde (intermediate N) (76 mg, 0.416 mmol) using the same procedure as described in the synthesis of compound 51.1. 1H-NMR (400 MHz, MeOH-d4) δ ppm 8.08 (s, 1H), 8.03 (d, 1H), 7.85 (s, 1H), 7.26 (q, 2H), 6.76 (s, 1H), 4.03 (s, 3H). LCMS (method B): [MH]+=349.9, tR=2.12 min.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:8]([O:18][CH:19]2[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]2)[C:9]2[NH:13][C:12]3[CH:14]=[CH:15][CH:16]=[CH:17][C:11]=3[N:10]=2)[CH:5]=[CH:6][CH:7]=1.[H-].[Na+].I[CH3:29]>C(#N)C.CC(C)=O>[I:1][C:2]1[CH:3]=[C:4]([CH:8]([O:18][CH:19]2[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]2)[C:9]2[N:13]([CH3:29])[C:12]3[CH:14]=[CH:15][CH:16]=[CH:17][C:11]=3[N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CN1CCC(OC(c2cccc(I)c2)c2nc3ccccc3[nH]2)CC1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: CC#N
Product: CN1CCC(OC(c2cccc(I)c2)c2nc3ccccc3n2C)CC1
Temperature: 0 °C
Reaction time: 15 h

Procedure:
A solution of 2-[(3-iodophenyl)(1-methylpiperidin-4-yloxy)methyl]-1H-benzimidazole (example 51, 260 mg) in anhydrous acetonitrile (10 mL) is treated with 60% sodium hydride (47 mg) for 1 h at room temperature. The mixture is then cooled to 0° C. and iodomethane (36 μL) is introduced. After stirring for 15 h, dilution with water and extraction with ethyl acetate, the organic phase is dried over magnesium sulfate and concentrated under reduced pressure. The residue is purified by chromatography over silica gel (gradient dichloromethane/methanol/ammonia from 95/5/0.5 to 90/10/0.5) to afford the pure base that is then converted into its dioxalate salt in acetone to give 2-[(3-iodophenyl)(1-methylpiperidin-4-yloxy)methyl]-1-methyl-1H-benzimidazole, dioxalate, melting at 76° C.
Reaction SMILES: C[O-].[Na+].[N:4]1[CH:9]=[CH:8][C:7]([CH2:10][SH:11])=[CH:6][CH:5]=1.[CH2:12]([O:14][CH:15]([O:18][CH2:19][CH3:20])[CH2:16]Br)[CH3:13]>C(O)C>[CH2:12]([O:14][CH:15]([O:18][CH2:19][CH3:20])[CH2:16][S:11][CH2:10][C:7]1[CH:8]=[CH:9][N:4]=[CH:5][CH:6]=1)[CH3:13]
Reactant: CCOC(CBr)OCC
Reactant: SCc1ccncc1
Agent: C[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(CSCc1ccncc1)OCC
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Under a nitrogen atmosphere, sodium methoxide (0.60 g., 11 moles) is dissolved in approximately 15 ml. of stirring ethanol and cooled in an ice bath. 4-Picolyl mercaptan (1.4 g., 11 mmoles) in approximately 3 ml. of absolute ethanol is added over 5 minutes and the mixture stirred for 15 minutes. Bromoacetaldehyde diethylacetal (2.4 g., 11 mmoles) in approximately 15 ml. of absolute ethanol is then added over 5 minutes. The reaction mixture is warmed to room temperature and stirred for 16 hours. The reaction mixture is filtered and the filtrate evaporated to yield title product, which if desired, can be further purified by chromatography on silica gel.
Reaction SMILES: [CH2:1]([S:8][C:9]1[N:17]=[C:16]2[C:12]([NH:13][CH:14]=[N:15]2)=[C:11](Cl)[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH2:20]([NH2:25])[CH2:21][C:22]([CH3:24])=[CH2:23].C(N(CC)CC)C>C(O)CCC>[CH2:1]([S:8][C:9]1[N:17]=[C:16]2[C:12]([NH:13][CH:14]=[N:15]2)=[C:11]([NH:25][CH2:20][CH:21]=[C:22]([CH3:24])[CH3:23])[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Clc1nc(SCc2ccccc2)nc2nc[nH]c12
Reactant: C=C(C)CCN
Agent: Cl
Solvent: CCCCO
Solvent: CCN(CC)CC
Product: CC(C)=CCNc1nc(SCc2ccccc2)nc2nc[nH]c12
Temperature: 110 °C

Procedure:
A mixture of 2-benzylthio-6-chloropurine (1.2 g) and isopentenylamine hydrochloride (1.04 g) in 1-butanol (25 ml) containing triethylamine (2.2 ml) is heated in a sealed tube at 110° C. for 2 hours. The butanol is removed under vacuum and the mixture shaken with ice-water (100 ml). The product is filtered recrystallized from ethanol with charcoal decolorization and dried under vacuum with phosphorous pentoxide. Yield 0.64 g. Yield 1.3 g of 2-benzyl-thio-N6 -(2-iso-pentyenyl)adenine as a colorless solid. The crude product is used directly in the next step.
Reaction SMILES: [F:1][C:2]1[C:3]([O:9][CH3:10])=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].[Br:11]Br>C(O)(=O)C>[Br:11][C:8]1[CH:7]=[CH:6][C:4]([NH2:5])=[C:3]([O:9][CH3:10])[C:2]=1[F:1]
Reactant: COc1c(N)cccc1F
Reactant: BrBr
Solvent: CC(=O)O
Product: COc1c(N)ccc(Br)c1F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To 3-fluoro-2-methoxyaniline (2.8 g, 20 mmol) in 10 mL of acetic acid was added bromine (0.82 mL, 16 mmol) in acetic acid (10 mL) dropwise. The reaction mixture was stirred at rt. for 30 min. Solid was filtered and washed with acetic acid to give the HBr salt. It was then dissolved in water, basified by addition of KOH, extracted with ethyl acetate. The organic layer was dried and concentrated to give a white solid (2.8 g, 80%). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 3.93 (s, 3H) 6.42 (dd, J=8.6, 1.8 Hz, 1H) 7.01 (dd, J=8.6, 7.1 Hz, 1H). [M+H] calc'd for C7H7BrFNO, 222. found 222.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]([C:17](O)=[O:18])[C:10]3[C:15]([CH:16]=2)=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(Cl)(Cl)=O.[CH3:24][NH:25][CH:26]([CH2:28][CH3:29])[CH3:27]>N1C=CC=CC=1>[CH3:24][N:25]([CH:26]([CH3:27])[CH2:28][CH3:29])[C:17]([C:9]1[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:16]=[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:8]=1)=[O:18]
Reactant: O=C(O)c1cc(-c2ccccc2)cc2ccccc12
Reactant: CCC(C)NC
Solvent: O=S(Cl)Cl
Solvent: c1ccncc1
Product: CCC(C)N(C)C(=O)c1cc(-c2ccccc2)cc2ccccc12

Procedure:
The procedure of Example 20 is followed using 3-phenylnaphthalene-1-carboxylic acid (4.3 g), thionyl chloride (20 ml) and N-methylbut-2-ylamine (1.5 g) in pyridine (20 ml) as the starting materials. After recrystallisation from petroleum ether, N-methyl-N-(1-methylpropyl)-3-phenylnaphthalene-1-carboxamide (2.8 g), melting at 125° C., is obtained.
Reaction SMILES: [Br:1]Br.[Cl:3][C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:5]=1[C:11]1[N:12]=[C:13]([CH3:19])[N:14]([CH:16]([F:18])[F:17])[CH:15]=1.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[Br:1][C:15]1[N:14]([CH:16]([F:17])[F:18])[C:13]([CH3:19])=[N:12][C:11]=1[C:5]1[CH:6]=[CH:7][C:8]([Cl:10])=[CH:9][C:4]=1[Cl:3]
Reactant: Cc1nc(-c2ccc(Cl)cc2Cl)cn1C(F)F
Reactant: BrBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1nc(-c2ccc(Cl)cc2Cl)c(Br)n1C(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 63.4 %

Procedure:
Bromine (0.54 g, 3.1 mmol), in 7 ml of methylene chloride, was added dropwise to a solution of 0.9 g (3.2 mmol) of 4-(2,4-dichlorophenyl)-1-difluoromethyl-2-methylimidazole stirring in 35 ml of methylene chloride. The reaction mixture was stirred at room temperature overnight. Another 0.3 g of bromine, in 5 ml of methylene chloride, were added and the reaction stirred overnight. Methylene chloride (250 ml) and saturated sodium bicarbonate (200 ml) were added and the organic layer separated and washed with saturated sodium bicarbonate and brine followed by drying over magnesium sulfate. Evaporating in vacuo gave a red oil residue. Flash chromatography on silica gel (20:1-10:1-5:1-3:1 hexane/ethyl acetate) afforded 0.7 g of 5-bromo-4-(2,4-dichlorophenyl)-1-difluoromethyl-2-methylimidazole as a white solid (m.p. 81-83° C.). NMR (CDCl3, 200 MHz) δ: 2.65 (s, 3H), 7.20 (t, 1H), 7.27-7.40 (m, 2H), 7.52 (s, 1H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[CH3:15][Si](C=[N+]=[N-])(C)C>CO.C1(C)C=CC=CC=1>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH3:15])=[O:10])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13]
Reactant: O=C(O)Cc1ccc(O)c([N+](=O)[O-])c1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: Cc1ccccc1
Solvent: CO
Product: COC(=O)Cc1ccc(O)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 0.83 h

Procedure:
In methanol/toluene (1:10, 55 ml) was dissolved 4-hydroxy-3-nitrophenylacetic acid (2.0 g, 10.1 mmol). Trimethylsilyldiazomethane (2.0M hexane solution, 5.0 ml) was added dropwise to the resulting solution. After stirring at room temperature for 50 minutes, the reaction mixture was distilled under reduced pressure to remove the solvent. The residue was diluted with ethyl acetate. The ethyl acetate extract was then washed with a saturated aqueous solution of sodium bicarbonate and saturated brine, dried over anhydrous sodium sulfate and distilled under reduced pressure to remove the solvent, whereby the title compound (2.15 g, 100%) was obtained as a yellow solid (this compound was provided for the subsequent reaction without further purification).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([N+:10]([O-:12])=[O:11])[C:3]=1[O:13][CH3:14].[CH3:15][O:16][CH2:17]Cl.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH3:14][O:13][C:3]1[C:4]([N+:10]([O-:12])=[O:11])=[C:5]([CH:8]=[CH:9][C:2]=1[O:1][CH2:15][O:16][CH3:17])[C:6]#[N:7]
Reactant: COc1c(O)ccc(C#N)c1[N+](=O)[O-]
Reactant: COCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COCOc1ccc(C#N)c([N+](=O)[O-])c1OC
Temperature: 50 °C
Reaction time: 2 h
Yield: 84 %

Procedure:
A mixture of 4-hydroxy-3-methoxy-2-nitrobenzonitrile 1.00 g, chloromethyl methyl ether 0.47 mL (6.18 mmol) and potassium carbonate 3.56 g (25.8 mmol) in N,N-dimethylformamide 10 mL was stirred at 50° C. for 2 hours. The reaction mixture was poured into water and extracted into diethyl ether. The organic layer was washed with brine, dried over MgSO4, filtrated and the solvent was evaporated. Silica gel chromatography (n-hexane/AcOEt=4/1) afforded the title compound 1.03 g as colorless solid. Yield 83.5%.
Reaction SMILES: Cl[C:2]1[C:3]([N:17]([CH2:20][CH3:21])[CH2:18][CH3:19])=[CH:4][C:5]2[N:6]([C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[N:9][N:10]=2)[N:7]=1.[CH3:22][N:23]1[CH:27]=[N:26][C:25]([CH2:28][OH:29])=[N:24]1.[H-].[Na+]>CN(C=O)C.O>[CH2:18]([N:17]([CH2:20][CH3:21])[C:3]1[C:2]([O:29][CH2:28][C:25]2[N:26]=[CH:27][N:23]([CH3:22])[N:24]=2)=[N:7][N:6]2[C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[N:9][N:10]=[C:5]2[CH:4]=1)[CH3:19]
Reactant: CCN(CC)c1cc2nnc(-c3ccccc3)n2nc1Cl
Reactant: Cn1cnc(CO)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCN(CC)c1cc2nnc(-c3ccccc3)n2nc1OCc1ncn(C)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 64.9 %

Procedure:
To a solution of N-(6-chloro-3-phenyl-1,2,4-triazolo[4,3-b]pyridazin-7-yl)-N,N-diethylamine (180 mg, 0.33 mmol) and (1-methyl-1 H-1,2,4-triazol-3-yl)methanol (68 mg) in dry DMF (5 ml) was added sodium hydride (60% dispersion in oil, 34 mg, 0.36 mmol). The mixture was stirred at room temperature for 3 hours. The reaction mixture was diluted with water (50 ml) and extracted with dichloromethane (3×25 ml). The combined extracts were washed with brine, dried over magnesium sulphate, filtered and evaporated. The solid was recrystallised from ethyl acetate, and collected by filtration to afford the title pyridazine (81 mg, 36%). 1H NMR (500 MHz, DMSO-d6) δ1.08 (6 H, t, J=8.5 Hz), 3.31 (4 H, q, J=8.5 Hz), 3.87 (3 H, s), 5.50 (2 H, s), 7.22 (1 H, s), 7.47-7.59 (3 H, m), 8.37 (2 H, d, J=8.5 Hz), 8.51 (1 H, s). MS (ES+) 379 [MH]+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][OH:9].N1C=CN=C1.[Cl-].[C:16]([SiH:20]([CH3:22])[CH3:21])([CH3:19])([CH3:18])[CH3:17]>O1CCCC1>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][O:9][Si:20]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:22])[CH3:21]
Reactant: OCc1ccccc1Br
Reactant: C[SiH](C)C(C)(C)C
Agent: [Cl-]
Agent: c1c[nH]cn1
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OCc1ccccc1Br
Temperature: 25 °C
Reaction time: 48 h
Yield: 82.6 %

Procedure:
2.0 g of (2-bromophenyl)methanol are placed in a round-bottomed flask and dissolved in 100 ml of tetrahydrofuran. 1.1 g of 1H-imidazole are added thereto, followed by 2.1 g of tert-butyldimethylsilane chloride, and the mixture is left to stir at ambient temperature for 48 hours. The reaction mixture is then hydrolysed with water, and the organic phase, which has been extracted with ethyl acetate, is separated, dried over magnesium sulphate and concentrated under reduced pressure. The residue obtained is purified by silica gel chromatography, elution being carried out with a heptane/ethyl acetate mixture. 2.66 g of compound are obtained.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]([OH:9])=O)=[CH:3][CH:2]=1.CN1CCOCC1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[CH3:44][O:45][C:46]1[CH:47]=[C:48]([N:54]2[CH2:59][CH2:58][NH:57][CH2:56][CH2:55]2)[CH:49]=[C:50]([O:52][CH3:53])[CH:51]=1>CN(C=O)C>[CH3:44][O:45][C:46]1[CH:47]=[C:48]([N:54]2[CH2:55][CH2:56][N:57]([C:7]([C:4]3[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=3)=[O:9])[CH2:58][CH2:59]2)[CH:49]=[C:50]([O:52][CH3:53])[CH:51]=1
Reactant: COc1cc(OC)cc(N2CCNCC2)c1
Reactant: O=C(O)c1ccncc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: COc1cc(OC)cc(N2CCN(C(=O)c3ccncc3)CC2)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
5 g (45.8 mmol) of pyridine-4-carboxylic acid were suspended with stirring in 150 ml of DMF. With further stirring, 6.93 g (68.5 mmol) of N-methylmorpholine and then a solution of 35.6 g (68.5 mmol) of Py-BOP (1-benzotriazolyltripyrrolidinophosphonium hexafluorophosphate) and 10.18 g (45.8 mmol) of 1-(3,5-dimethoxyphenyl)piperazine in 60 ml of DMF were added to this mixture. The mixture was stirred at room temperature for 24 hours, the DMF was distilled off under reduced pressure and the residue was purified on a silica gel column (Kieselgel 60, from Merck AG, Darmstadt) using the mobile phase dichloromethane/methanol/25 percent ammonia (90:10:1 v/v/v).
Reaction SMILES: C[C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[CH:4][CH:3]=1.C1(CBr)CC1.C(OC(=O)C(SC1SC(N)=NC=1)C)C>>[NH:8]1[C:9]2[C:5](=[CH:4][CH:3]=[CH:2][CH:10]=2)[CH:6]=[CH:7]1
Reactant: Cc1ccc2cc[nH]c2c1
Agent: BrCC1CC1
Agent: CCOC(=O)C(C)Sc1cnc(N)s1
Product: c1ccc2[nH]ccc2c1

Procedure:
6-methylindole, R5X=cyclopropyl-methylbromide; NH2A=(2-aminothiazole-5-ylsulfanyl)-propionic acid ethyl ester
Reaction SMILES: [C:1]1(=[O:11])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[N-:12]=[N+]=[N-].[Na+].S(=O)(=O)(O)O>C(Cl)(Cl)Cl>[NH:12]1[C:10]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[CH2:4][CH2:3][CH2:2][C:1]1=[O:11]
Reactant: [N-]=[N+]=[N-]
Reactant: O=C1CCCc2ccccc21
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: O=C1CCCc2ccccc2N1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To an ice bath cooled solution of 3,4-dihydronaphthalen-1(2H)-one (20 mL, 150 mmol) in chloroform (300 mL) was added sodium azide (14.62 g, 225 mmol) and then concentrated sulfuric acid (80 mL, 1499 mmol) was added dropwise over 30 minutes, and the mixture was stirred at room temperature for 24 hours. The biphasic solution was poured into ice, and the product was extracted twice with ethyl acetate. The organic layer was washed with water, dried over Na2SO4 and concentrated to give the crude product which was purified by silica gel chromatography (Analogix IntelliFlash™ 280, SF 25-120) loading with dichloromethane and eluting with 30% ethyl acetate/hexanes to obtain the title compound. 1H NMR (500 MHz, DMSO-d6) δ ppm 9.50 (s, 1H), 7.28-7.14 (m, 2H), 7.07 (td, J=7.4, 1.2, 1H), 7.00-6.85 (m, 1H), 2.67 (t, J=6.9, 2H), 2.20-2.03 (m, 4H); MS (ESI−) m/z 160.1 (M−H)−.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([CH3:13])[CH3:12])(=[O:10])=[O:9])=[CH:4][C:3]=1[OH:14].[C:15]1(=O)[O:20][C:18](=[O:19])[C:17]2=[CH:21][CH:22]=[CH:23][CH:24]=[C:16]12>CC(O)=O.O>[O:19]=[C:18]1[C:17]2[C:16](=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:15](=[O:20])[N:1]1[C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([CH3:12])[CH3:13])(=[O:10])=[O:9])=[CH:4][C:3]=1[OH:14]
Reactant: CN(C)S(=O)(=O)c1ccc(N)c(O)c1
Reactant: O=C1OC(=O)c2ccccc21
Solvent: CC(=O)O
Solvent: O
Product: CN(C)S(=O)(=O)c1ccc(N2C(=O)c3ccccc3C2=O)c(O)c1
Temperature: 120 °C
Reaction time: 1 h
Yield: 73.9 %

Procedure:
A suspension of 4-amino-3-hydroxy-N,N-dimethylbenzenesulfonamide (120 mg, 0.555 mmol) and phthalic anhydride (82 mg, 0.555 mmol) in AcOH (3 mL) was stirred at 120° C. under microwave irradiation for 60 minutes. The reaction was cooled and diluted with water to afford a suspension. The precipitate was filtered, washed with water and dried under high vacuum to afford the title compound as a pink solid (142 mg, 74%).
Reaction SMILES: Br[C:2]1[CH:23]=[CH:22][C:5]([CH2:6]NC2C3C(=CC=CC=3)N=C(C)C=2C(=O)C)=[CH:4][CH:3]=1.[Br:24][C:25]1[CH:26]=[C:27]2[C:32](=[CH:33][CH:34]=1)[N:31]=[C:30]([CH3:35])[C:29]([C:36]([O:38][CH3:39])=[O:37])=[C:28]2[NH2:40].BrC1C=CC(CBr)=CC=1>>[Br:24][C:25]1[CH:26]=[C:27]2[C:32](=[CH:33][CH:34]=1)[N:31]=[C:30]([CH3:35])[C:29]([C:36]([O:38][CH3:39])=[O:37])=[C:28]2[NH:40][CH2:6][C:5]1[CH:22]=[CH:23][CH:2]=[CH:3][CH:4]=1
Reactant: CC(=O)c1c(C)nc2ccccc2c1NCc1ccc(Br)cc1
Reactant: COC(=O)c1c(C)nc2ccc(Br)cc2c1N
Agent: BrCc1ccc(Br)cc1
Product: COC(=O)c1c(C)nc2ccc(Br)cc2c1NCc1ccccc1

Procedure:
Methyl 6-bromo-4-benzylamino-2-methylquinoline-3-carboxylate was synthesized by the same process as described for 1-(4-(4-bromobenzylamino)-2-methylquinolin-3-yl)ethanone (Example 1, Intermediate 2c) starting from methyl 6-bromo4-amino-2-methylquinoline-3-carboxylate and 4-bromobenzyl bromide. Melting point: 89° C.; MS(ES+): 385/387.
Reaction SMILES: C(N(CC)CC)C.Cl[C:9]1[N:14]=[CH:13][N:12]=[C:11]([C:15]2([CH3:46])[C:23]3[C:18](=[CH:19][C:20]([C:24]4[CH:25]=[N:26][N:27]([CH:29]5[CH2:34][CH2:33][CH2:32][CH2:31][O:30]5)[CH:28]=4)=[CH:21][CH:22]=3)[C:17](=[O:35])[N:16]2[C@@H:36]([C:38]2[CH:43]=[CH:42][C:41]([O:44][CH3:45])=[CH:40][CH:39]=2)[CH3:37])[C:10]=1[F:47].[H][H]>C(OCC)(=O)C.[OH-].[OH-].[Pd+2].ClC1N=CN=C(C2(C)C3C(=CC(C4C=NN(C5CCCCO5)C=4)=CC=3)C(=O)N2[C@@H](C2C=CC(OC)=CC=2)C)C=1F>[F:47][C:10]1[C:11]([C:15]2([CH3:46])[C:23]3[C:18](=[CH:19][C:20]([C:24]4[CH:25]=[N:26][N:27]([CH:29]5[CH2:34][CH2:33][CH2:32][CH2:31][O:30]5)[CH:28]=4)=[CH:21][CH:22]=3)[C:17](=[O:35])[N:16]2[C@@H:36]([C:38]2[CH:39]=[CH:40][C:41]([O:44][CH3:45])=[CH:42][CH:43]=2)[CH3:37])=[N:12][CH:13]=[N:14][CH:9]=1
Reactant: COc1ccc([C@@H](C)N2C(=O)c3cc(-c4cnn(C5CCCCO5)c4)ccc3C2(C)c2ncnc(Cl)c2F)cc1
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: COc1ccc([C@@H](C)N2C(=O)c3cc(-c4cnn(C5CCCCO5)c4)ccc3C2(C)c2ncncc2F)cc1
Yield: 102.8 %

Procedure:
Add triethylamine (40 mL, 287 mmol) and 20% palladium hydroxide on carbon (14 g) to a solution of 3-(6-chloro-5-fluoro-pyrimidin-4-yl)-2-[(1R)-1-(4-methoxyphenyl)ethyl]-3-methyl-6-(1-tetrahydropyran-2-ylpyrazol-4-yl)isoindolin-1-one (80 g, 142 mmol) in ethyl acetate (2.1 L) and hydrogenate with hydrogen gas (30 psi) at 20-25° C. for 16 hours. Repeat reaction conditions with 5 grams 3-(6-chloro-5-fluoro-pyrimidin-4-yl)-2-[(1R)-1-(4-methoxyphenyl)ethyl]-3-methyl-6-(1-tetrahydropyran-2-ylpyrazol-4-yl)isoindolin-1-one. Combine both reactions and filter through diatomaceous earth and evaporate to give the title compound as a yellow foam (77 g, 102%). ES/MS m/z: 528 (M+H).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:13]([CH2:14][OH:15])=[C:12]([C:16]([F:19])([F:18])[F:17])[S:11][N:10]=2)=[CH:5][CH:4]=1)[CH3:2].C(N(CC)CC)C.[CH3:27][S:28](Cl)(=[O:30])=[O:29]>ClCCl>[CH3:27][S:28]([O:15][CH2:14][C:13]1[C:9]([C:6]2[CH:5]=[CH:4][C:3]([CH2:1][CH3:2])=[CH:8][CH:7]=2)=[N:10][S:11][C:12]=1[C:16]([F:19])([F:18])[F:17])(=[O:30])=[O:29]
Reactant: CS(=O)(=O)Cl
Reactant: CCc1ccc(-c2nsc(C(F)(F)F)c2CO)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCc1ccc(-c2nsc(C(F)(F)F)c2COS(C)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Into a 50-mL round-bottom flask, was placed [3-(4-ethylphenyl)-5-(trifluoromethyl)-1,2-thiazol-4-yl]methanol (50 mg, 0.17 mmol, 1.00 equiv), triethylamine (53 mg, 0.52 mmol, 3.01 equiv), dichloromethane (2.0 mL), MsCl (40 mg, 0.35 mmol, 2.02 equiv). The resulting solution was stirred for 0.5 h at 25° C. The reaction progress was monitored by LCMS. The reaction was then quenched by the addition of 10 mL of water. The resulting solution was extracted with 3×10 mL of dichloromethane and the organic layers combined. The resulting mixture was washed with 2×20 mL of sodium chloride. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. This resulted in 75 mg of [3-(4-ethylphenyl)-5-(trifluoromethyl)-1,2-thiazol-4-yl]methyl methanesulfonate as a light yellow solid. The crude could be used for the next step directly. Mass spectrum (ESI, m/z): Calcd. for C14H14F3NO3S2, 366.0 (M+H). found 366.0.
Reaction SMILES: [Br:1][C:2]1[NH:6][CH:5]=[N:4][C:3]=1[CH2:7][CH2:8][CH2:9][CH2:10][NH2:11].[N+](C=C(SC)SC)([O-])=O.[N+:21]([CH:24]=[C:25](SC)[NH:26][CH2:27]CCCC1N=CNC=1Br)([O-:23])=[O:22].CN>>[N+:21]([CH:24]=[C:25]([NH:26][CH3:27])[NH:11][CH2:10][CH2:9][CH2:8][CH2:7][C:3]1[N:4]=[CH:5][NH:6][C:2]=1[Br:1])([O-:23])=[O:22]
Reactant: NCCCCc1nc[nH]c1Br
Reactant: CSC(=C[N+](=O)[O-])NCCCCc1nc[nH]c1Br
Agent: CN
Agent: CSC(=C[N+](=O)[O-])SC
Product: CNC(=C[N+](=O)[O-])NCCCCc1nc[nH]c1Br

Procedure:
When 5-bromo-4-(4-aminobutyl)imidazole is reacted with 1-nitro-2,2-bis-methylthioethylene according to the procedure of Example 8(i) and the resultant 1-nitro-2-methylthio-2-[4-(5-bromo-4-imidazolyl)butylamino]ethylene, m.p. 157°-158° treated with methylamine by the procedure of Example 8(ii) , the title compound, m.p. 145°-148° is produced.
Reaction SMILES: [CH3:1][C:2]1([CH2:19][CH2:20][CH2:21][C:22]([OH:24])=O)[C:14]2[N:13]3[CH:15]=[CH:16][N:17]=[C:12]3[C:11](=[O:18])[NH:10][C:9]=2[C:8]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]1=2.C(Cl)(=O)C(Cl)=O.C[N:32](C)C=O.N>C(Cl)(Cl)Cl.CO>[CH3:1][C:2]1([CH2:19][CH2:20][CH2:21][C:22]([NH2:32])=[O:24])[C:14]2[N:13]3[CH:15]=[CH:16][N:17]=[C:12]3[C:11](=[O:18])[NH:10][C:9]=2[C:8]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]1=2
Reactant: CN(C)C=O
Reactant: CC1(CCCC(=O)O)c2ccccc2-c2[nH]c(=O)c3nccn3c21
Agent: N
Agent: O=C(Cl)C(=O)Cl
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CC1(CCCC(N)=O)c2ccccc2-c2[nH]c(=O)c3nccn3c21
Reaction time: 3 h

Procedure:
To a very fine suspension of 0.4 g of 4-(10-methyl-4,5-dihydro-4-oxo-10H-imidazo[1,2-a]indeno-[1,2-e]pyrazin-10-yl)butyric acid in 20 ml of chloroform is added, at a temperature in the region of 20° C., 0.13 g of oxalyl chloride followed by a solution of 0.5 ml of dimethylformamide in 5 ml of chloroform, and the stirring is continued for 3 hours. 2 ml of a 5.6N solution of ammonia in methanol are then added and the stirring is continued for 18 hours. The reaction mixture is concentrated on a rotary evaporator and the evaporation residue is stirred for 2 hours with 30 ml of distilled water. The solid is filtered off and purified by chromatography on a column of silica (25 g), eluting under a pressure of 0.5 bar with a mixture of dichloromethane and methanol (9/1 by volume). 0.045 g of 4-(10-methyl-4,5-dihydro-4-oxo-10H-imidazo[1,2-a]indeno[1,2-e]pyrazin-10-yl)butyramide is obtained in the form of a light-beige-coloured solid melting above 260° C. (1H NMR spectrum: (300 MHz; (CD3)2SO-d6 ; δ in ppm): 0.65 (mt, 2H: CH2); 1.53 (s, 3H: CH3); 1.80 (t, J=7.5 Hz, 2H: CH2CON); 2.10 and 2.28 (2 mts, 1H each: hetero-CH2); 6.58 and 7.10 (2 broad s, 1H each: CONH2); 7.27 and 7.33 (2 t, J=7.5 Hz, 1H each: H 7 and H 8); 7.42 and 7.92 (2 broad s, 1H each: H of the imidazole); 7.50 and 7.68 (2 broad d, J=7.5 Hz, 1H each: H 6 and H 8)).