Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]=1[CH2:4]Cl.[F:13][C:14]([F:21])([C:17]([F:20])([F:19])[F:18])[CH2:15][OH:16].[OH-].[K+].ClCCl>CN(C)C=O>[F:13][C:14]([F:21])([C:17]([F:20])([F:19])[F:18])[CH2:15][O:16][CH2:4][C:3]1[CH:6]=[C:7]([N+:10]([O-:12])=[O:11])[CH:8]=[CH:9][C:2]=1[CH3:1]
Reactant: OCC(F)(F)C(F)(F)F
Reactant: Cc1ccc([N+](=O)[O-])cc1CCl
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1ccc([N+](=O)[O-])cc1COCC(F)(F)C(F)(F)F
Reaction time: 8 h
Yield: 95.4 %

Procedure:
To a solution of 5.00 g (0.027 mol) of 2-methyl-5-nitrobenzyl chloride and 21.3 g (0.135 mol) of 2,2,3,3,3-pentafluoropropanol in 16.5 ml of dimethylformamide, was added 2.29 g (0.041 mol) of KOH pellets and the solution was stirred overnight. Then dichloromethane was added and the salts were filtered out. The filtrate was made acid and then the solvents were distilled off. The residue was dissolved in a 9/1 (v/v) mixed solvent of hexane/ethyl acetate, washed with dilute hydrochloric acid, water and a saturated sodium chloride aqueous solution, and then dried over magnesium sulfate. The solvents were distilled off and the resulting oil was subjected to silica gel chromatography using hexane/ethyl acetate (19/1, v/v) as developing solvent to obtain 7.71 g of 3-(2,2,3,3,3-pentafluoropropoxy)methyl-4-methyl-1-nitrobenzene having a melting point of 53.5°-54.5° C. in a 95.5% yield.
Reaction SMILES: Cl.Cl.[N:3]1([NH:9][C:10]([C:12]2[CH:13]=[N:14][C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[N:16][CH:17]=2)=[O:11])[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1.Br[CH:25]1[CH2:29][CH2:28][O:27][C:26]1=[O:30].[H-].[Na+]>CN(C=O)C>[O:30]=[C:26]1[CH:25]([N:6]2[CH2:5][CH2:4][N:3]([NH:9][C:10]([C:12]3[CH:17]=[N:16][C:15]([C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)=[N:14][CH:13]=3)=[O:11])[CH2:8][CH2:7]2)[CH2:29][CH2:28][O:27]1
Reactant: O=C1OCCC1Br
Reactant: O=C(NN1CCNCC1)c1cnc(-c2ccccc2)nc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(NN1CCN(C2CCOC2=O)CC1)c1cnc(-c2ccccc2)nc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.6 %

Procedure:
A solution of 2-phenyl-pyrimidine-5-carboxylic acid piperazin-1-ylamide dihydrochloride (0.45 mmol) and bromo-dihydro-furan-2-one (1.8 mmol) in DMF (10 mL) is stirred under N2 at 0° C. for 15 min, then NaH (60%, 1.8 mmol) is added and the mixture is warmed to rt and stirred overnight. The mixture is quenched with water, and extracted with EtOAC. The organic layer is dried (Na2SO4), filtered and concentrated in vacuo. The residue is purified by silica gel chromatography eluting with 0-2% methanol in DCM to afford give 2-phenyl-pyrimidine-5-carboxylic acid [4-(2-oxo-tetrahydro-furan-3-yl)-piperazin-1-yl]-amide (120 mg, 73%) as a solid. MS: 368 (M+H); 1H NMR (300 MHz, CDCl3): δ 2.34 (s, 2H), 2.50-3.30 (m, 8H), 3.42-3.70 (m, H), 4.17-4.50 (m, 2H), 7.34-7.68 (m, 3H), 8.50 (d, 2H), 9.06-9.38 (d, 2H). IC50=26 nM.
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][CH2:7][N:8]1[C:20]2[C:19]3[CH:18]=[CH:17][C:16]([Br:21])=[CH:15][C:14]=3[N:13]=[CH:12][C:11]=2[NH:10][C:9]1=[S:22])(=[O:3])[CH3:2].O.[OH-].[NH4+].I[CH3:27]>C(O)C>[C:1]([O:4][CH2:5][CH2:6][CH2:7][N:8]1[C:20]2[C:19]3[CH:18]=[CH:17][C:16]([Br:21])=[CH:15][C:14]=3[N:13]=[CH:12][C:11]=2[N:10]=[C:9]1[S:22][CH3:27])(=[O:3])[CH3:2]
Reactant: CI
Reactant: CC(=O)OCCCn1c(=S)[nH]c2cnc3cc(Br)ccc3c21
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CSc1nc2cnc3cc(Br)ccc3c2n1CCCOC(C)=O
Temperature: 25 °C
Yield: 74.1 %

Procedure:
To a round-bottomed flask containing 3-(7-bromo-2-thioxo-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl)propyl acetate (28.9 g, 76.0 mmol) was added water (180 mL), ethanol (180 mL), and ammonium hydroxide (38 mL). The resulting suspension was stirred at ambient temperature. To this suspension was added iodomethane (9.5 mL, 152 mmol), and the reaction was stirred for 2 h. The suspension was filtered through a sintered glass funnel and the residue was washed with diethyl ether and dried under reduced pressure to afford 3-[7-bromo-2-(methylthio)-1H-imidazo[4,5-c]quinolin-1-yl]propyl acetate (22.2 g) as tan solid.
Reaction SMILES: [CH2:1]([S:3](Cl)(=[O:5])=[O:4])[CH3:2].[F:7][C:8]1[CH:19]=[CH:18][C:11]2[CH2:12][CH2:13][CH2:14][CH2:15][CH:16]([NH2:17])[C:10]=2[CH:9]=1.C(N(CC)CC)C>C1COCC1>[F:7][C:8]1[CH:19]=[CH:18][C:11]2[CH2:12][CH2:13][CH2:14][CH2:15][CH:16]([NH:17][S:3]([CH2:1][CH3:2])(=[O:5])=[O:4])[C:10]=2[CH:9]=1
Reactant: NC1CCCCc2ccc(F)cc21
Reactant: CCS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCS(=O)(=O)NC1CCCCc2ccc(F)cc21
Reaction time: 8 h
Yield: 71.2 %

Procedure:
2.3 g (18 mmol) of ethanesulfonyl chloride were added dropwise with ice-cooling to a solution of 2.68 g (15 mmol) of 3-fluoro-5-amino-6,7,8,9-tetrahydro-5H-benzocycloheptene and 1.5 g (60 mmol triethylamine in 40 ml of THF. The mixture was allowed to come to room temperature and was stirred overnight, and the solvent was distilled off in vacuo. After stirring the residue with water, the precipitated product was filtered off with suction. 2.9 g of 3-fluoro-5-(N-ethylsulfonylamino)-6,7,8,9-tetrahydro-5H-benzocycloheptene were obtained, m.p. 118-121° C.
Reaction SMILES: [N+:1]([C:4]1[CH:14]=[CH:13][C:7]2[S:8](=[O:12])(=[O:11])[CH:9]=[CH:10][C:6]=2[CH:5]=1)([O-])=O>[Pd].CCO.C1COCC1>[O:11]=[S:8]1(=[O:12])[CH2:9][CH2:10][C:6]2[CH:5]=[C:4]([NH2:1])[CH:14]=[CH:13][C:7]1=2
Reactant: O=[N+]([O-])c1ccc2c(c1)C=CS2(=O)=O
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: Nc1ccc2c(c1)CCS2(=O)=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 92.5 %

Procedure:
Palladium on carbon (25 mg) was placed under an inert atmosphere and suspended in 1:1 v/v EtOH/THF (10 mL). A solution of 5-nitrobenzo[b]thiophene 1,1-dioxide (250 mg, 1.18 mmol) in EtOH/THF (1:1) was then added, and the reaction mixture placed under H2 atmosphere (1 Atm pressure) and stirred at RT for 3 h. Reaction is filtered through a Celite pad and washed well with MeOH to obtain the title compound (200 mg, 92%) as a brown solid: TLC (10% MeOH/DCM w/5% NH4OH), Rf=0.40; LC MS m/z 184.1 (MH+).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.O[CH:33]1[CH2:36][N:35]([C:37]2[S:38][CH2:39][CH2:40][N:41]=2)[CH2:34]1.[C:42]([OH:45])(=[S:44])[CH3:43]>O1CCCC1>[C:42]([S:44][CH:33]1[CH2:36][N:35]([C:37]2[S:38][CH2:39][CH2:40][N:41]=2)[CH2:34]1)(=[O:45])[CH3:43]
Reactant: CC(O)=S
Reactant: OC1CN(C2=NCCS2)C1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(=O)SC1CN(C2=NCCS2)C1
Reaction time: 1 h
Yield: 65 %

Procedure:
To a mixture solution of triphenylphosphine and diethyl azodicarboxylate in 10 ml of tetrahydrofuran was added a mixture of 119 mg of Compound (3) and thioacetic acid under ice-cooling, and the reaction mixture was stirred for 1 hour at the same condition, then for 1 hour at room temperature. After the reaction solvent was removed under reduced pressure, the resulting residue was purified by silica gel column chromatography (chloroform : ethanol =1:1) to give 107 mg (65%) of 3-acetylthio-1-(thiazolin-2-yl)azetidine [Compound (4)].
Reaction SMILES: C([O-])(=O)C.[Na+].Cl.[NH2:7][OH:8].[OH:9][CH:10]1[CH2:14][CH2:13][C:12](=O)[C:11]1([CH3:17])[CH3:16].Cl>C(O)C.O>[OH:9][CH:10]1[CH2:14][CH2:13][C:12](=[N:7][OH:8])[C:11]1([CH3:17])[CH3:16]
Reactant: CC1(C)C(=O)CCC1O
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CC1(C)C(=NO)CCC1O
Temperature: 25 °C
Yield: 92.1 %

Procedure:
Sodium acetate (3.58 g, 43.7 mmol) and hydroxylamine hydrochloride (2.85 g, 41.0 mmol) were added to a solution of 3-hydroxy-2,2-dimethylcyclopentanone (3.50 g, 27.3 mmol, from Step 1) in ethanol (50 mL) and water (10 mL). The resultant mixture was heated to 80° C. for 15 h, cooled to room temperature and acidified to pH 2-3 with 1 N hydrochloric acid. After removal of ethanol in vacuo, the aqueous residue was extracted with ethyl acetate (3×200 mL). The combined organic extracts were washed with brine (30 mL), dried (MgSO4), filtered and concentrated, to give 3-hydroxy-2,2-dimethylcyclopentanone oxime (3.60 g, 92% yield). 1H NMR (400 MHz, methanol-d4) δ ppm 3.76 (1 H, t, J=6.16 Hz), 2.51-2.80 (1 H, m), 2.32-2.53 (1 H, m), 1.91-2.16 (1 H, m), 1.58-1.81 (1 H, m), 0.92-1.13 (6 H, m).
Reaction SMILES: [H-].[Na+].[CH2:3]([N:10]1[C:14](=[O:15])[CH2:13][C:12]2([C:23]3[C:18](=[CH:19][CH:20]=[C:21]([Cl:24])[CH:22]=3)[NH:17][C:16]2=[O:25])[C:11]1=[O:26])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Br[CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30].O>O1CCCC1>[CH2:32]([O:31][C:29](=[O:30])[CH2:28][N:17]1[C:18]2[C:23](=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)[C:12]2([CH2:13][C:14](=[O:15])[N:10]([CH2:3][C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=3)[C:11]2=[O:26])[C:16]1=[O:25])[CH3:33]
Reactant: CCOC(=O)CBr
Reactant: O=C1CC2(C(=O)Nc3ccc(Cl)cc32)C(=O)N1Cc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)CN1C(=O)C2(CC(=O)N(Cc3ccccc3)C2=O)c2cc(Cl)ccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 70 %

Procedure:
A stirred suspension of sodium hydride (60% dispersion in oil [39 mg, 0.969 mmol]) in anhydrous tetrahydrofuran (10 ml) was treated with 1′-benzyl-5-chloro-1H-spiro[indole-3,3′-pyrrolidine]-2,2′,5′-trione, intermediate 14 (300 mg, 0.88 mmol). After stirring at ambient temperature for 30 min, the clear solution was treated with ethyl bromoacetate (0.13 ml, 1.16 mmol). The resultant suspension was stirred for 3 hours and then left to stand overnight. Water (50 ml) was added and the mixture extracted with ethyl acetate (3×50 ml). The combined extracts were washed with brine (50 ml), dried (MgSO4) and the solvent removed in vacuo to give the crude (1′-benzyl-5-chloro-2,2′,5′-trioxo-spiro[indole-3,3′-pyrrolidin]-1-yl)-acetic acid ethyl ester. Purification by flash chromatography (silica) eluting with petroleum ether (40-60) containing an increasing amount (0 to 50%) of ethyl acetate, followed by trituration with di-isopropyl ether gave a white solid (264 mg, 70%), m.pt. 143-144° C.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[CH:6][C:7]([O:13][CH3:14])=[C:8](B(O)O)[CH:9]=1)([CH3:3])[CH3:2].Br[C:16]1[CH:17]=[C:18]([CH:22]([C:27]2[O:28][C:29]([CH3:32])=[N:30][N:31]=2)[CH2:23][C:24]([OH:26])=[O:25])[CH:19]=[CH:20][CH:21]=1>CN(C=O)C.O.[NH4+].[Cl-].C1(C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)[Pd][P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH:1]([C:4]1[CH:5]=[CH:6][C:7]([O:13][CH3:14])=[C:8]([C:20]2[CH:21]=[CH:16][CH:17]=[C:18]([CH:22]([C:27]3[O:28][C:29]([CH3:32])=[N:30][N:31]=3)[CH2:23][C:24]([OH:26])=[O:25])[CH:19]=2)[CH:9]=1)([CH3:3])[CH3:2]
Reactant: Cc1nnc(C(CC(=O)O)c2cccc(Br)c2)o1
Reactant: COc1ccc(C(C)C)cc1B(O)O
Agent: c1ccc([P]([Pd][P](c2ccccc2)(c2ccccc2)c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(C(C)C)cc1-c1cccc(C(CC(=O)O)c2nnc(C)o2)c1
Yield: 57 %

Procedure:
12.83 g (66.11 mmol) of 5-isopropyl-2-methoxybenzeneboronic acid, 48.97 g (150.3 mmol) and 18.7 g (60.1 mmol) of 3-(3-Bromo-phenyl)-3-(5-methyl-[1,3,4]oxadiazol-2-yl)-propionic acid are heated together with 3 mmol of bis(triphenylphosphine)palladium (II) dichloride in 200 ml of DMF and 30 ml of water for 10 hours at 100° C. The reaction mixture is diluted with conc. NH4Cl solution (200 ml) and extracted with methyl-tetrahydrofurane. The organic phase is filtrated over Celite and 100 g of SiO2 and the solvent is removed in vacuo. The obtained crude 3-(5′-Isopropyl-2′-methoxy-biphenyl-3-yl)-3-(5-methyl-[1,3,4]oxadiazol-2-yl)-propionic acid is used directly in the next step. (Yield=57%, 28 g)
Reaction SMILES: [CH3:1][N:2]([CH:4]=[N:5][S:6]([CH2:9][CH2:10][C:11]([CH3:15])([CH3:14])[CH2:12]I)(=[O:8])=[O:7])[CH3:3].[C-:16]#[N:17].[K+].CS(C)=O>O.C1OCCOCCOCCOCCOCCOC1>[C:16]([CH2:12][C:11]([CH3:15])([CH3:14])[CH2:10][CH2:9][S:6]([N:5]=[CH:4][N:2]([CH3:3])[CH3:1])(=[O:8])=[O:7])#[N:17]
Reactant: CN(C)C=NS(=O)(=O)CCC(C)(C)CI
Reactant: [C-]#N
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CN(C)C=NS(=O)(=O)CCC(C)(C)CC#N
Temperature: 100 °C
Reaction time: 14 h
Yield: 84.7 %

Procedure:
A mixture of 1.85 g of 4-(N,N-dimethylaminomethylene)aminosulfonyl-1-iodo-2,2-dimethylbutane, 0.49 g of potassium cyanide, 0.06 g of 18-crown-6 and 30 ml of dimethyl sulfoxide was stirred at 100° C. for 14 hours. After cooling, the reaction mixture was diluted with 100 ml of water and extracted with ethyl acetate. The extract was washed with water and dried (MgSO4) and the solvent was distilled off. The residue was subjected to silica gel (70 g) column chromatography and elution was carried out with ethyl acetate-hexane (9:1). The fractions containing the objective compound were pooled and concentrated and the residue was recrystallized from ethyl ether to provide 1.11 g of the title compound. m.p. 53°-54° C.
Reaction SMILES: [NH2:1][C:2]1[CH:24]=[CH:23][C:5]([O:6][CH:7]2[CH2:12][CH2:11][N:10]([C:13]([C:15]3[C:20]([Cl:21])=[CH:19][CH:18]=[CH:17][C:16]=3[Cl:22])=[O:14])[CH2:9][CH2:8]2)=[CH:4][CH:3]=1.ClC(Cl)(Cl)C[O:28][C:29](=O)[NH:30][C:31]1[N:32]([CH3:40])[N:33]=[C:34]([C:36]([CH3:39])([CH3:38])[CH3:37])[CH:35]=1.C(N(CC)C(C)C)(C)C>CS(C)=O>[C:36]([C:34]1[CH:35]=[C:31]([NH:30][C:29]([NH:1][C:2]2[CH:24]=[CH:23][C:5]([O:6][CH:7]3[CH2:8][CH2:9][N:10]([C:13](=[O:14])[C:15]4[C:20]([Cl:21])=[CH:19][CH:18]=[CH:17][C:16]=4[Cl:22])[CH2:11][CH2:12]3)=[CH:4][CH:3]=2)=[O:28])[N:32]([CH3:40])[N:33]=1)([CH3:39])([CH3:37])[CH3:38]
Reactant: Cn1nc(C(C)(C)C)cc1NC(=O)OCC(Cl)(Cl)Cl
Reactant: Nc1ccc(OC2CCN(C(=O)c3c(Cl)cccc3Cl)CC2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: Cn1nc(C(C)(C)C)cc1NC(=O)Nc1ccc(OC2CCN(C(=O)c3c(Cl)cccc3Cl)CC2)cc1
Temperature: 60 °C
Reaction time: 6 h

Procedure:
Nitrogen gas is bubbled through a solution of [4-(4-amino-phenoxy)-piperidin-1-yl]-(2,6-dichlorophenyl)-methanone (47 mg, 0.12 mmol) and (5-tert-butyl-2-methyl-2H-pyrazol-3-yl)-carbamic acid 2,2,2-trichloro-ethyl ester (42 mg, 0.12 mmol) in DMSO (1.5 mL) for 5 min. Next, N,N-diisopropylethylamine (40 μL, 0.24 mmol) is added. The reaction mixture is stirred at 60° C. for 6 hours. Then, DMSO is removed by passing the reaction mixture through an SCX column. The crude product is obtained by eluting the SCX column with 2M ammonia in methanol and purifying the residue on silica gel with ethyl acetate-hexanes (25%) to give a white solid (ES+(m/z) 544.2 [M+H]).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:17][C:16]2[C:11](=[N:12][C:13](S(C)(=O)=O)=[N:14][CH:15]=2)[N:10]([CH3:22])[C:9]1=[O:23].[OH:24][CH2:25][CH:26]1[O:31][C:30]2[CH:32]=[CH:33][C:34]([NH2:36])=[CH:35][C:29]=2[O:28][CH2:27]1.C(O)(C(F)(F)F)=O.Cl>CN1C(=O)CCC1>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:17][C:16]2[C:11](=[N:12][C:13]([NH:36][C:34]3[CH:33]=[CH:32][C:30]4[O:31][CH:26]([CH2:25][OH:24])[CH2:27][O:28][C:29]=4[CH:35]=3)=[N:14][CH:15]=2)[N:10]([CH3:22])[C:9]1=[O:23]
Reactant: CN1C(=O)N(c2ccccc2Br)Cc2cnc(S(C)(=O)=O)nc21
Reactant: Nc1ccc2c(c1)OCC(CO)O2
Agent: Cl
Solvent: CN1CCCC1=O
Solvent: O=C(O)C(F)(F)F
Product: CN1C(=O)N(c2ccccc2Br)Cc2cnc(Nc3ccc4c(c3)OCC(CO)O4)nc21
Temperature: 140 °C

Procedure:
1.2 g 3-(2-bromo-phenyl)-3,4-dihydro-7-methanesulphonyl-1-methyl-pyrimido[4,5-d]pyrimidin-2(1H)-one and 1.54 g 2 hydroxymethyl-6-amino-1,4-benzodioxane (starting material b)) were mixed in 20 ml NMP. 0.348 g TFA were added and the mixture was heated to 140° C. for 7 hrs. The mixture was poured into 10% aqueous HCl and extracted with ethyl acetate. The aqueous phase was adjusted to pH>9 and extracted with CH2Cl2. The organic phases were combined and evaporated. The residue was suspended in CH2Cl2 at room temperature and solid impurities were filtered off. The filtrate was washed again with water to remove remainders of NMP, then evaporated. The residue was triturated with water, filtered and dried to give 0.6 g of the title product (mp: 156–158° C.). NMR (CDCl3, δ in ppm): 2.03 (broad s, 1 H); 3.48 (s, 3H); 3.89 (dd, 1H); 3.95 (dd, 1H); 4.15 (dd, 1H); 4.28 (m, 1H); 4.33 (dd, 1H); 4.55 (d, 1H); 4.71 (d, 1H); 6.89 (m, 1H); 6.98 (m, 2H); 7.25 (m, 1H); 7.40 (m, 3H); 7.71 (d, 1H); 7.98 (s, 1H). MS (APCI+): 498 (M+1), 420 (M-Br)
Reaction SMILES: C([Li])CCC.[CH:6]([N:9]1[CH2:14][CH2:13][N:12]([C:15]2[S:19][CH:18]=[N:17][CH:16]=2)[CH2:11][CH2:10]1)([CH3:8])[CH3:7].C(Br)(Br)(Br)[Br:21]>C1COCC1>[Br:21][C:18]1[S:19][C:15]([N:12]2[CH2:11][CH2:10][N:9]([CH:6]([CH3:8])[CH3:7])[CH2:14][CH2:13]2)=[CH:16][N:17]=1
Reactant: BrC(Br)(Br)Br
Reactant: CC(C)N1CCN(c2cncs2)CC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)N1CCN(c2cnc(Br)s2)CC1
Temperature: -78 °C
Reaction time: 2 h

Procedure:
At −78° C., n-butyl lithium (2.5 N in hexane, 0.27 mL, 2 eq.) was added to 5-(4-isopropylpiperazin-1-yl)thiazole (28 mg, 0.132 mmol) in 1 mL THF. CBr4 (22 mg, 0.5 eq.) was added after 30 minutes. The reaction was stirred at −78° C. for 2 hours. The reaction was quenched by adding water. The reaction crude was extracted using EtOAc. The organic layers were concentrated and purified via Combiflash (0-20% MeOH in EtOAc) to give desired product. LCMS-ESI+: calc'd for C10H17BrN3S: 290.0 (M+H+); Found: 290.1 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:32])[C:4]([NH:7][C:8]([C:10]1[C:15]([O:16]CC2C=CC=CC=2)=[CH:14][C:13]([O:24]CC2C=CC=CC=2)=[CH:12][N:11]=1)=[O:9])([CH3:6])[CH3:5]>CO.[Pd]>[CH3:1][O:2][C:3](=[O:32])[C:4]([NH:7][C:8]([C:10]1[C:15]([OH:16])=[CH:14][C:13]([OH:24])=[CH:12][N:11]=1)=[O:9])([CH3:6])[CH3:5]
Reactant: COC(=O)C(C)(C)NC(=O)c1ncc(OCc2ccccc2)cc1OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: COC(=O)C(C)(C)NC(=O)c1ncc(O)cc1O
Reaction time: 22 h
Yield: 94 %

Procedure:
A solution of 2-[(3,5-bis-benzyloxy-pyridine-2-carbonyl)-amino]-2-methylpropionic acid methyl ester, 17, (0.58 g, 1.34 mmol) in MeOH (100 mL) containing 10% Pd/C (0.116 g) is stirred under an atmosphere of H2 for 22 hours. The reaction solution is filtered through Celite™ and the collected solids are washed with hot MeOH. The combined filtrate and washings are concentrated under reduced pressure to afford 0.321 g (94% yield) of the desired compound as a grey solid. 1H NMR (250 MHz, MeOD) δ ppm 7.67 (1H, d, J=2.4 Hz), 6.58 (1H, d, J=2.4 Hz), 3.69 (3H, s), 1.56 (6H, s). HPLC-MS: m/z 255 [M+H]+.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][C:11](=[O:16])[CH2:10][CH2:9]2)=[O:5].C(N(CC)CC)C.[CH3:24][O:25][C:26]1[CH:27]=[C:28]([CH:32]=[CH:33][C:34]=1[O:35][CH3:36])[C:29](Cl)=[O:30]>O1CCCC1>[CH3:24][O:25][C:26]1[CH:27]=[C:28]([CH:32]=[CH:33][C:34]=1[O:35][CH3:36])[C:29]([NH:2][CH2:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][C:11](=[O:16])[CH2:10][CH2:9]2)=[O:5])=[O:30]
Reactant: COc1ccc(C(=O)Cl)cc1OC
Reactant: NCC(=O)c1ccc2c(c1)CCC(=O)N2
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1ccc(C(=O)NCC(=O)c2ccc3c(c2)CCC(=O)N3)cc1OC
Temperature: 25 °C
Reaction time: 3 h
Yield: 50569.4 %

Procedure:
3 g of 6-α-aminoacetyl-3,4-dihydrocarbostyril monohydrochloride was suspended in 60 ml of tetrahydrofuran. Thereto were added 7 ml of triethylamine and 2.8 mg of 3,4-dimethoxybenzoyl chloride. The mixture was stirred at room temperature. After 3 hours, the resulting crystals were collected by filtration, methanol-washed and dried to obtain 2.6 g of 6-[2-(3,4-dimethoxybenzoylamino)acetyl]-3,4-dihydrocarbostyril as white acicular crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[N:7]([C:9]([CH2:12][C:13]3[CH:23]=[CH:22][C:16]4[N:17]=[C:18]([S:20][CH3:21])[S:19][C:15]=4[CH:14]=3)=[CH:10][N:11]=2)[N:8]=1.C1C=C(Cl)C=C(C(OO)=[O:32])C=1.[O-]S([O-])=O.[Na+].[Na+]>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[N:7]([C:9]([CH2:12][C:13]3[CH:23]=[CH:22][C:16]4[N:17]=[C:18]([S:20]([CH3:21])=[O:32])[S:19][C:15]=4[CH:14]=3)=[CH:10][N:11]=2)[N:8]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COc1ccc2ncc(Cc3ccc4nc(SC)sc4c3)n2n1
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: COc1ccc2ncc(Cc3ccc4nc(S(C)=O)sc4c3)n2n1
Temperature: 0 °C
Reaction time: 2 h
Yield: 95.5 %

Procedure:
To a solution of 6-((6-methoxyimidazo[1,2-b]pyridazin-3-yl)methyl)-2-(methylthio)benzo[d]thiazole (500 mg, 1.46 mmol) in DCM (30 mL) was added m-CPBA (314 mg, 1.82 mmol) at 0° C. The reaction mixture was stirred for 2 h at 0° C., then aq Na2SO3 (15 mL) was added and the mixture was stirred for 0.5 h. The organic layer was separated, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 50:1 to 20:1 DCM/MeOH to afford 6-((6-methoxyimidazo[1,2-b]pyridazin-3-yl)methyl)-2-(methylsulfinyl)benzo[d]thiazole as a yellow solid (500 mg, 95%). 1H NMR (300 MHz, CDCl3) δ 7.99-7.93 (m, 2H), 7.76 (d, J=9.6 Hz, 1H), 7.53 (dd, J=1.5, 8.4 Hz, 1H), 7.46 (s, 1H), 6.65 (d, J=9.3 Hz, 1H), 4.42 (s, 2H), 3.94 (s, 3H), 3.06 (s, 3H). LCMS (ESI) m/z 359 (M+H)+.
Reaction SMILES: [CH:1]([C:4]1[CH:13]=[C:12]2[C:7]([CH:8]=[CH:9][CH:10]=[N:11]2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[N+:14]([O-])([O-:16])=[O:15].[K+].OS(O)(=O)=O>>[CH:1]([C:4]1[C:13]([N+:14]([O-:16])=[O:15])=[C:12]2[C:7]([CH:8]=[CH:9][CH:10]=[N:11]2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2]
Reactant: CC(C)c1ccc2cccnc2c1
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: CC(C)c1ccc2cccnc2c1[N+](=O)[O-]
Yield: 39 %

Procedure:
In a similar fashion using route 7 general procedure 15, 7-isopropylquinoline (Intermediate 56) (1.36 g, 7.94 mmol), potassium nitrate (1.04 g, 10.3 mmol) and H2SO4 (4.2 ml) gave the title compound (670 mg, 39%) after purification by column chromatography with n-hexane/EtOAc (9:1-22:3) as the eluent.
Reaction SMILES: Br[CH:2](Br)[C:3]1[CH:4]=[C:5]([C:10]2[C:14]([Cl:15])=[C:13]([O:16][CH:17]([F:19])[F:18])[N:12]([CH3:20])[N:11]=2)[CH:6]=[CH:7][C:8]=1[Cl:9].S(=O)(=O)(O)[OH:23]>>[Cl:15][C:14]1[C:10]([C:5]2[CH:6]=[CH:7][C:8]([Cl:9])=[C:3]([CH:2]=[O:23])[CH:4]=2)=[N:11][N:12]([CH3:20])[C:13]=1[O:16][CH:17]([F:19])[F:18]
Reactant: Cn1nc(-c2ccc(Cl)c(C(Br)Br)c2)c(Cl)c1OC(F)F
Reactant: O=S(=O)(O)O
Product: Cn1nc(-c2ccc(Cl)c(C=O)c2)c(Cl)c1OC(F)F
Temperature: 100 °C
Reaction time: 0.08 h

Procedure:
At 85° C., 4.65 g (10 mmol) of 3-(3-dibromomethyl-4-chloro-phenyl)-4-chloro-5-difluoromethoxy-1-methyl-1H-pyrazole were introduced a little at a time into 7 ml of concentrated sulfuric acid. The reaction solution was then stirred at 100° C. for 5 minutes, then stirred into 40 ml of ice-water. The solid product formed was filtered off and dried. Yield: 3.0 g;
Reaction SMILES: Cl.[C:2]1([N:8]([CH2:32][CH2:33][C:34]([O:36][CH3:37])=[O:35])[C:9]([C:11]2[CH:31]=[CH:30][C:14]3[N:15]([CH3:29])[C:16]([CH2:18][NH:19][C:20]4[CH:25]=[CH:24][C:23]([C:26](=[NH:28])[NH2:27])=[CH:22][CH:21]=4)=[N:17][C:13]=3[CH:12]=2)=[O:10])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:39]([O:41][CH:42]1[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]1)=[O:40]>ClCCl.C(O)C>[C:2]1([N:8]([CH2:32][CH2:33][C:34]([O:36][CH3:37])=[O:35])[C:9]([C:11]2[CH:31]=[CH:30][C:14]3[N:15]([CH3:29])[C:16]([CH2:18][NH:19][C:20]4[CH:25]=[CH:24][C:23]([C:26](=[NH:27])[NH:28][C:39]([O:41][CH:42]5[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]5)=[O:40])=[CH:22][CH:21]=4)=[N:17][C:13]=3[CH:12]=2)=[O:10])[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)CCN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C(=N)N)cc1)n2C)c1ccccc1
Reactant: O=C(Cl)OC1CCCCC1
Agent: Cl
Solvent: ClCCl
Solvent: CCO
Product: COC(=O)CCN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C(=N)NC(=O)OC3CCCCC3)cc1)n2C)c1ccccc1
Yield: 25 %

Procedure:
Prepared analogously to Example 90 from 1-methyl-2-[N-(4-amidinophenyl)aminomethyl]benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-methoxycarbonylethyl)amide hydrochloride and cyclohexyl chloroformate. Yield: 25% of theory, C34H38N6O5 (610.7); Rf value: 0.44 (silica gel; dichloromethane/ethanol=19:1); EKA mass spectrum: (M+H)+=611; (M+2H)++=306.