Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([CH:8]([OH:10])[CH3:9])[CH:5]=[CH:4][CH:3]=1.[NH2:11][C:12]1[S:13][C:14]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[F:26])=[CH:15][C:16]=1[C:17]([NH2:19])=[O:18]>>[F:26][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[C:14]1[S:13][C:12]([NH:11][C:2]2[CH:3]=[CH:4][CH:5]=[C:6]([CH:8]([OH:10])[CH3:9])[N:7]=2)=[C:16]([C:17]([NH2:19])=[O:18])[CH:15]=1
Reactant: CC(O)c1cccc(Br)n1
Reactant: NC(=O)c1cc(-c2ccccc2F)sc1N
Product: CC(O)c1cccc(Nc2sc(-c3ccccc3F)cc2C(N)=O)n1

Procedure:
The title compound was prepared according to the general procedure in Example 1 using 1-(6-bromopyridin-2-yl)ethanol (65.0 mg, 0.322 mmol) and 2-amino-5-(2-fluorophenyl)thiophene-3-carboxamide (78.0 mg, 0.330 mmol) as the starting materials.
Reaction SMILES: C1([CH:7]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH2:8][CH2:9][O:10][C:11]([C:13]2[C:14]([CH3:30])=[N:15][C:16]([CH3:29])=[C:17](C(O)=O)[C:18]=2[C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=2)=[O:12])C=CC=CC=1.S(Cl)(Cl)=O.[CH3:41][N:42]([CH:44]=[O:45])[CH3:43]>>[C:19]1([CH:7]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH2:8][CH2:9][O:10][C:11](=[O:12])[C:13]2[C:18]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=3)=[C:17]([C:44]([N:42]3[CH2:43][CH2:11][O:10][CH2:9][CH2:41]3)=[O:45])[C:16]([CH3:29])=[N:15][C:14]=2[CH3:30])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: Cc1nc(C)c(C(=O)OCCC(c2ccccc2)c2ccccc2)c(-c2cccc(Cl)c2)c1C(=O)O
Reactant: CN(C)C=O
Solvent: O=S(Cl)Cl
Product: Cc1nc(C)c(C(=O)N2CCOCC2)c(-c2cccc(Cl)c2)c1C(=O)OCCC(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
50.0 mg (0.100 mmol) of 4-(3-chlorophenyl)-2,6-dimethylpyridine-3,5-dicarboxylic acid mono (3,3-diphenylpropyl) ester and 5 ml of thionyl chloride were stirred in DMF at room temperature for 1 hour. After concentration under reduced pressure, the residue was dissolved in 3 ml of dichloromethane. 1 ml of morpholine was added and stirred at room temperature for 6 hours. After concentration under reduced pressure, ethyl acetate was added and the residue was washed with water. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by the basic silica gel chromatography (hexane/ethyl acetate=20/1 to 1/4) to obtain the title compound.
Reaction SMILES: C[O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7](=[O:24])[C:8]([C:14]3[CH:23]=[CH:22][C:17]([C:18]([O:20]C)=[O:19])=[CH:16][CH:15]=3)=[C:9]([CH3:13])[S:10]2)=[CH:5][CH:4]=1.B(Br)(Br)Br.Cl>C(Cl)Cl>[OH:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7](=[O:24])[C:8]([C:14]3[CH:23]=[CH:22][C:17]([C:18]([OH:20])=[O:19])=[CH:16][CH:15]=3)=[C:9]([CH3:13])[S:10]2)=[CH:5][CH:4]=1
Reactant: COC(=O)c1ccc(-c2c(C)sc3cc(OC)ccc3c2=O)cc1
Agent: BrB(Br)Br
Agent: Cl
Solvent: ClCCl
Product: Cc1sc2cc(O)ccc2c(=O)c1-c1ccc(C(=O)O)cc1
Reaction time: 20 h

Procedure:
To a solution of methyl 4-(7-methoxy-2-methyl-4-oxo-4H-thiochromen-3-yl)benzoate (200 mg, 0.588 mmol) in DCM (10 ml) was added BBr3 (0.83 ml, 8.813 mmol) at room temperature and stirred for 20 hours. The mixture was poured into icy 1 N HCl (50 ml) with stirring and the precipitate was collected by filtration to obtain crude product, which was purified by prep-HPLC to afford the desired product in Example 8 as a yellow solid (57.3 mg, 31%).
Reaction SMILES: [C:1]([C:4]1[C:5]([O:9][CH3:10])=[N:6][S:7][CH:8]=1)(=[O:3])N.S(=O)(=O)(O)[OH:12].N([O-])=O.[Na+]>O>[C:1]([C:4]1[C:5]([O:9][CH3:10])=[N:6][S:7][CH:8]=1)([OH:12])=[O:3]
Reactant: COc1nscc1C(N)=O
Reactant: O=S(=O)(O)O
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: COc1nscc1C(=O)O
Temperature: 60 °C

Procedure:
To a solution of 7.9 g. (0.05 mole) of 4-carbamoyl-3-methoxyisothiazole prepared as in Example 19 in 90 ml. of 80% sulfuric acid at 10°-15° C. was added slowly beneath the surface of the liquid a solution of 9.5 g. (0.137 mole) of sodium nitrite in 13 ml. of H2O. When addition was complete the solution was allowed to come to 25° C., and then was heated to 60° C. for several minutes. After cooling to 25° C. the reaction solution was poured onto ice to precipitate 3.64 g. (46%) of 4-carboxy-3-methoxyisothiazole as a white solid, m.p. 182°-185° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:7]1[S:8][CH:9]=[CH:10][N:11]=1)([O:5][CH3:6])[CH3:4].[Li]CCCC.C(Br)(Br)(Br)[Br:18]>C1COCC1>[Br:18][C:9]1[S:8][C:7]([C:3]([O:5][CH3:6])([O:2][CH3:1])[CH3:4])=[N:11][CH:10]=1
Reactant: BrC(Br)(Br)Br
Reactant: COC(C)(OC)c1nccs1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COC(C)(OC)c1ncc(Br)s1
Temperature: -78 °C
Reaction time: 1 h
Yield: 43.1 %

Procedure:
To a solution of 2-(1,1-dimethoxyethyl)-1,3-thiazole (40 g, 0.23 mol) in THF (600 ml) was added n-BuLi (100 ml, 0.25 mol) dropwise at −78° C. After stirring for 1 h at −78° C., a solution of CBr4 (300 g, 0.9 mol) in THF (300 ml) was added drop-wise. The reaction mixture was stirred for another 1 h at −78° C., and then was quenched by the addition of sat. aq. NH4Cl and was extracted with ethyl acetate (150 ml×3). The organic layers were washed with brine, dried over Na2SO4 and concentrated. The residue was purified by column (eluted by petroleum ether/EtOAc=10:1) to afforded 25 g of 5-bromo-2-(1,1-dimethoxyethyl)-1,3-thiazole as solid (43%). 1H-NMR (CDCl3 400 MHz) δ 7.81 (s, 1H, Ar—H), 3.23 (s, 6H, —OCH3), 1.72 (s, 3H, —CH3).
Reaction SMILES: [NH:1]=[C:2]1[N:6]([CH3:7])[CH2:5][CH2:4][S:3]1.[C:8]1([N:14]=[C:15]=[S:16])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.CCOCC>C1C=CC=CC=1>[CH3:7][N:6]1[CH2:5][CH2:4][S:3][C:2]1=[N:1][C:15]([NH:14][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[S:16]
Reactant: S=C=Nc1ccccc1
Reactant: CN1CCSC1=N
Solvent: c1ccccc1
Solvent: CCOCC
Product: CN1CCSC1=NC(=S)Nc1ccccc1
Yield: 75 %

Procedure:
A solution of 0.043 mole of 2-imino-3-methylthiazolidine and an equimolar amount of phenylisothiocyanate in 70 ml of dry benzene is refluxed under nitrogen for 2.5 hours. Some ether is added to the cooled reaction mixture and solids are filtered off, 9.8 g (90%). Recrystallization from acetonitrile-ether (1:1) gives 8.0 g (75%) of pure N-(3-methyl-2-thiazolidinylidene)-N'-phenylthiourea; m.p. 168.5°-170.5° C.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[CH:11][C:12](=[O:15])[NH:13][CH:14]=2)=[CH:5][CH:4]=1.Cl.O1[CH:22]=[CH:21][C:20](=[O:23])[CH:19]=[CH:18]1>O>[O:23]=[C:20]1[CH:21]=[CH:22][N:2]([C:3]2[CH:4]=[CH:5][C:6]([C:9]3[N:10]=[CH:11][C:12](=[O:15])[NH:13][CH:14]=3)=[CH:7][CH:8]=2)[CH:18]=[CH:19]1
Reactant: O=c1ccocc1
Reactant: Nc1ccc(-c2c[nH]c(=O)cn2)cc1
Agent: Cl
Solvent: O
Product: O=c1ccn(-c2ccc(-c3c[nH]c(=O)cn3)cc2)cc1

Procedure:
A stirred mixture of 5-(4-aminophenyl)-2(1H)pyrazinone hydrochloride (1.5 g, from hydrolysis of the corresponding acetamido derivative with hydrochloric acid), 4H-pyran-4-one (0.71 g) and water (15 ml) was heated under reflux for 21/2 hours under a nitrogen atmosphere. The resultant solution was neutralised to give a solid, 1.79 g, m.p. 345° C. (dec). Recrystallisation from aqueous ethanol gave the title compound, 0.93 g, m.p. 354°-357° C. (dec).
Reaction SMILES: [CH:1]1([N:6]2[C:10]3[N:11]=[C:12]([NH:15][C:16]4[CH:21]=[CH:20][C:19]([N:22]5[C:29](=[O:30])[CH2:28][C@@H:27]6[NH:31][C@@H:24]([CH2:25][CH2:26]6)[CH2:23]5)=[CH:18][N:17]=4)[N:13]=[CH:14][C:9]=3[CH:8]=[C:7]2[C:32]([N:34]([CH3:36])[CH3:35])=[O:33])[CH2:5][CH2:4][CH2:3][CH2:2]1.FC(F)(F)S(O[CH2:43][C:44]([F:47])([F:46])[F:45])(=O)=O.O>CN(C)C=O>[CH:1]1([N:6]2[C:10]3[N:11]=[C:12]([NH:15][C:16]4[CH:21]=[CH:20][C:19]([N:22]5[C:29](=[O:30])[CH2:28][C@H:27]6[N:31]([CH2:43][C:44]([F:47])([F:46])[F:45])[C@H:24]([CH2:25][CH2:26]6)[CH2:23]5)=[CH:18][N:17]=4)[N:13]=[CH:14][C:9]=3[CH:8]=[C:7]2[C:32]([N:34]([CH3:36])[CH3:35])=[O:33])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Reactant: CN(C)C(=O)c1cc2cnc(Nc3ccc(N4C[C@@H]5CC[C@H](CC4=O)N5)cn3)nc2n1C1CCCC1
Solvent: O
Solvent: CN(C)C=O
Product: CN(C)C(=O)c1cc2cnc(Nc3ccc(N4C[C@H]5CC[C@@H](CC4=O)N5CC(F)(F)F)cn3)nc2n1C1CCCC1
Temperature: 80 °C
Yield: 64.1 %

Procedure:
A sample of 7-Cyclopentyl-N,N-dimethyl-2-(5-((1S,6R)-4-oxo-3,9-diazabicyclo[4.2.1]nonan-3-yl)pyridin-2-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide (60 mg, 0.123 mmol) was combined with 2,2,2-trifluoroethyl trifluoromethanesulfonate (0.035 ml, 0.246 mmol) in dimethylformamide (1 mL) and heated to (80° C.) overnight. The reaction was then poured into water and extracted with ethyl acetate. The aqueous was washed with ethyl acetate. The organics were combined, dried over sodium sulfate, filtered and concentrated which gave a crude material that was purified by silica gel column chromatography which gave 7-cyclopentyl-N,N-dimethyl-2-(5-((1R,6S)-4-oxo-9-(2,2,2-trifluoroethyl)-3,9-diazabicyclo[4.2.1]nonan-3-yl)pyridin-2-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide (45 mg) in 64% yield. 1H NMR (400 MHz, CDCl3) δ ppm 8.74 (s, 1H), 8.51 (d, J=9.09 Hz, 1H), 8.22 (s, 1H), 8.15 (d, J=2.53 Hz, 1H), 7.52 (dd, J=8.84, 2.78 Hz, 1H), 6.46 (s, 1H), 4.80 (t, J=8.59 Hz, 1H), 4.23 (d, J=13.64 Hz, 1H), 3.47 (m, 3H), 3.16 (s, 6H), 3.06 (m, 3H), 2.83 (dd, J=15.66, 7.07 Hz, 1H), 2.57 (dd, J=12.13, 8.59 Hz, 2H), 2.04 (m, 6H), 1.70 (m, 4H). MS m/z 571.6 (M+H)
Reaction SMILES: [CH2:1]([O:6][C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=O)=[CH:9][CH:8]=1)[CH:2]=[C:3]([CH3:5])[CH3:4].[NH2:16][CH2:17][CH:18]1[CH2:22][CH2:21][CH2:20][N:19]1[CH2:23][CH3:24]>>[CH2:23]([N:19]1[CH2:20][CH2:21][CH2:22][CH:18]1[CH2:17][NH:16][C:11](=[O:13])[C:10]1[CH:9]=[CH:8][C:7]([O:6][CH2:1][CH:2]=[C:3]([CH3:4])[CH3:5])=[CH:15][CH:14]=1)[CH3:24]
Reactant: CC(C)=CCOc1ccc(C(=O)O)cc1
Reactant: CCN1CCCC1CN
Product: CCN1CCCC1CNC(=O)c1ccc(OCC=C(C)C)cc1
Yield: 46 %

Procedure:
In a manner identical to Example 15, 4-prenyloxybenzoic acid (1.44 g) was subjected to a condensation reaction with 2-aminomethyl-1-ethylpyrrolidine (1.0 ml), thereby yielding 1.02 g (46%) of the aimed compound.
Reaction SMILES: [OH:1][C:2]1[C:3]([N+:14]([O-:16])=[O:15])=[C:4]([CH:10]=[CH:11][C:12]=1[OH:13])[C:5]([O:7][CH2:8][CH3:9])=[O:6].Br[CH2:18][CH2:19]Br.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[N+:14]([C:3]1[C:2]2[O:1][CH2:19][CH2:18][O:13][C:12]=2[CH:11]=[CH:10][C:4]=1[C:5]([O:7][CH2:8][CH3:9])=[O:6])([O-:16])=[O:15]
Reactant: BrCCBr
Reactant: CCOC(=O)c1ccc(O)c(O)c1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc2c(c1[N+](=O)[O-])OCCO2
Temperature: 80 °C
Reaction time: 8 h
Yield: 77.5 %

Procedure:
A mixture of ethyl 3,4-dihydroxy-2-nitrobenzoate (4.97 g, 21.9 mmol), 1,2-dibromoethane (6.70 g, 43.8 mmol), and potassium carbonate (6.04 g, 43.8 mmol) in DMF (100 mL) was stirred at 80° C. overnight. To the reaction mixture was added ice/water (100 mL), and the resulting mixture was extracted with EtOAc (200 mL×2). The extracts were combined and dried, and the solvent removed. The product was purified by silica gel column (10% v/v EtOAc in PE) to give ethyl 5-nitro-2,3-dihydrobenzo[b][1,4]dioxine-6-carboxylate (4.30 g, 78% yield). ESI MS: m/z 254 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[C:3]1[CH:4]=[N:5][N:6]([C:8]2[N:13]=[CH:12][C:11]([NH:14][CH:15]([C:19]3[CH:33]=[CH:32][C:22]([C:23]([NH:25][CH2:26][CH2:27][C:28]([O:30]C)=[O:29])=[O:24])=[CH:21][CH:20]=3)[CH2:16][CH2:17][CH3:18])=[CH:10][N:9]=2)[CH:7]=1.C(=O)=O>>[F:35][C:2]([F:1])([F:34])[C:3]1[CH:4]=[N:5][N:6]([C:8]2[N:13]=[CH:12][C:11]([NH:14][CH:15]([C:19]3[CH:33]=[CH:32][C:22]([C:23]([NH:25][CH2:26][CH2:27][C:28]([OH:30])=[O:29])=[O:24])=[CH:21][CH:20]=3)[CH2:16][CH2:17][CH3:18])=[CH:10][N:9]=2)[CH:7]=1
Reactant: CCCC(Nc1cnc(-n2cc(C(F)(F)F)cn2)nc1)c1ccc(C(=O)NCCC(=O)OC)cc1
Agent: O=C=O
Product: CCCC(Nc1cnc(-n2cc(C(F)(F)F)cn2)nc1)c1ccc(C(=O)NCCC(=O)O)cc1

Procedure:
The title compound was prepared by a method analogous to that described in Step C of Example 109, using Isomer 2 of methyl 3-(4-(1-(2-(4-(trifluoromethyl)-1H-pyrazol-1-yl)pyrimidin-5-ylamino)butyl)benzamido)propanoate. 1H NMR (400 MHz, CD3OD, δ): 8.73 (s, 1H), 7.97 (s, 2H), 7.89 (s, 1H), 7.68 (d, J=8.4 Hz, 2H), 7.38 (d, J=8.4 Hz, 2H), 4.40 (t, J=6.8 Hz, 1H), 3.50 (t, J=6.8 Hz, 2H), 2.52 (t, J=6.4 Hz, 2H), 1.67-1.82 (m, 2H), 1.20-1.50 (m, 2H), 0.87 (t, J=7.2 Hz, 3 H). MS (M+1) 477.2. Chiral SFC: Chiralpak AD-3, 4.6×150 mm, 3 μm. Modifier: 0.05% DEA. Gradient: 95% CO2/5% methanol linear to 60% CO2/40% methanol over 16.0 minutes. Flow rate: 2.5 mL/min. Retention time: 7.69 minutes, 99.8% ee (Isomer 1).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][C:5]1[CH:6]=[CH:7][C:8]2[C:9]3[N:18]([CH2:19][CH:20]([CH3:22])[CH3:21])[C:17]([CH3:23])=[N:16][C:10]=3[C:11]([NH2:15])=[N:12][C:13]=2[CH:14]=1.[N:24]1([C:30](Cl)=[O:31])[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1>C(Cl)(Cl)Cl>[NH2:15][C:11]1[C:10]2[N:16]=[C:17]([CH3:23])[N:18]([CH2:19][CH:20]([CH3:21])[CH3:22])[C:9]=2[C:8]2[CH:7]=[CH:6][C:5]([O:4][CH2:3][CH2:2][NH:1][C:30]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)=[O:31])=[CH:14][C:13]=2[N:12]=1
Reactant: Cc1nc2c(N)nc3cc(OCCN)ccc3c2n1CC(C)C
Reactant: O=C(Cl)N1CCOCC1
Solvent: ClC(Cl)Cl
Product: Cc1nc2c(N)nc3cc(OCCNC(=O)N4CCOCC4)ccc3c2n1CC(C)C
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 37.3 %

Procedure:
A suspension of 7-(2-aminoethoxy)-2-methyl-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinolin-4-amine (0.300 g, 0.958 mmol) in chloroform (10 mL) was cooled to 0° C. 4-Morpholinecarbonyl chloride (0.110 mL, 0.942 mmol) was added dropwise, and the reaction was stirred for five minutes at 0° C. The reaction was then allowed to warm to ambient temperature over a period of 15 minutes, and the solvent was removed under reduced pressure. The resulting off-white solid was dissolved in dichloromethane. The solution was washed sequentially with 10% aqueous sodium hydroxide, water, and brine; dried over magnesium sulfate; filtered; and concentrated under reduced pressure. The residue was recrystallized from acetonitrile to provide 0.150 g of N-(2-{[4-amino-2-methyl-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinolin-7-yl]oxy}ethyl)morpholine-4-carboxamide as a white powder, mp 215-219° C. (decomposition).
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.Cl[C:12]1[CH:17]=[CH:16][N:15]=[C:14]([CH3:18])[CH:13]=1>CN(C=O)C.O>[Br:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][C:12]2[CH:17]=[CH:16][N:15]=[C:14]([CH3:18])[CH:13]=2)=[CH:6][CH:5]=1
Reactant: Cc1cc(Cl)ccn1
Reactant: Oc1ccc(Br)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(Oc2ccc(Br)cc2)ccn1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 82 %

Procedure:
To a solution of NaH (60% in mineral oil) (0.13 g, 3.25 mmol) in DMF (5 ml) was added commercially available 4-bromophenol (0.50 g, 2.89 mmol) and the reaction was stirred at room temperature for 10 minutes. Then, 4-chloro-2-picoline (0.30 g, 2.40 mmol) was added and the resulting reaction mixture was then microwaved at 150° C. for 10 minutes. After cooling, the mixture was diluted with water and extracted with Et2O. The combined organic layers were dried over Na2SO4 and concentrated in vacuo. The residue thus obtained was purified by flash chromatography (DCM) to yield intermediate 25 (0.52 g, 81%).
Reaction SMILES: [Br:1][C:2](=O)[CH:3]([Br:5])C.C(O[CH:10]([O:14][CH2:15][CH3:16])[O:11][CH2:12][CH3:13])C>C(O)C>[CH2:15]([O:14][CH:10]([O:11][CH2:12][CH3:13])[CH:3]([Br:5])[CH2:2][Br:1])[CH3:16]
Reactant: CC(Br)C(=O)Br
Reactant: CCOC(OCC)OCC
Solvent: CCO
Product: CCOC(OCC)C(Br)CBr

Procedure:
7 g of 1,2-dibromo-propionaldehyde are added to a mixture of 5 g of ortho-formic acid triethyl-ester and 10 ml of ethanol. The solution is refluxed for 2 hours, remains standing for a night, then it is vacuum-distilled.
Reaction SMILES: [C:1]([Cl:6])(=O)[C:2](Cl)=O.[Cl:7][C:8]1[NH:12][C:11]2[CH:13]=[C:14]([NH:20][C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[C:29]([F:32])([F:31])[F:30])=[O:22])[CH:15]=[C:16]([C:17]([OH:19])=O)[C:10]=2[N:9]=1>C1COCC1.CN(C=O)C>[Cl:7][C:8]1[NH:12][C:11]2[CH:13]=[C:14]([NH:20][C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[C:29]([F:32])([F:31])[F:30])=[O:22])[CH:15]=[C:16]([C:17]([NH:9][C:10]3[CH:11]=[CH:13][CH:2]=[C:1]([Cl:6])[C:16]=3[CH3:15])=[O:19])[C:10]=2[N:9]=1
Reactant: O=C(Nc1cc(C(=O)O)c2nc(Cl)[nH]c2c1)c1ccccc1C(F)(F)F
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: Cc1c(Cl)cccc1NC(=O)c1cc(NC(=O)c2ccccc2C(F)(F)F)cc2[nH]c(Cl)nc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Oxalyl chloride (1.42 mL) was added dropwise to a stirring solution of 2-chloro-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxylic acid (1.27 g) in THF (13 mL) under ice-cooling. To the mixture was added DMF (five drops), and it was stirred at room temperature for 2 hours. From the reaction mixture was removed the solvent and excessive oxalyl chloride under reduced pressure. To the residue was added toluene, and it was concentrated under reduced pressure, dried, and then dissolved in THF (10 mL). The solution was dropped slowly to a solution of 3-chloro-2-methylaniline (0.42 mL) and N,N-diisopropylethylamine (2.3 mL) in THF (10 mL) under ice-cooling for 1 hour. The reaction mixture was diluted with ethyl acetate, washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified on column chromatography to obtain the titled compound (0.58 g) as white powder.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[C:7]([O:9][CH3:10])[C:6]([Cl:11])=[CH:5][C:3]=1[NH2:4].[O-:12][C:13]#[N:14].[K+].[OH-].[Na+]>C(O)(=O)C.O>[Br:1][C:2]1[CH:8]=[C:7]([O:9][CH3:10])[C:6]([Cl:11])=[CH:5][C:3]=1[NH:4][C:13]([NH2:14])=[O:12]
Reactant: COc1cc(Br)c(N)cc1Cl
Reactant: N#C[O-]
Agent: [K+]
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: COc1cc(Br)c(NC(N)=O)cc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 29 %

Procedure:
To a solution of 2.0 g (8.5 mmol) 2-bromo-5-chloro-4-methoxy aniline in 20 ml acetic acid and 20 ml water was added in small portions 1.37 g (17 mmol) potassium cyanate. The mixture was stirred at r.t. for 2 hours, neutralized with 2N NaOH and the product was extracted into ethyl acetate. Removal of the solvent and crystallization with ether gave 0.69 g (29%) of the desired urea.
Reaction SMILES: [CH:1]1([N:6]2[C:14]3[CH:13]=[CH:12][N:11]=[C:10]([O:15]C)[C:9]=3[C:8]([C:17]3[CH:18]=[C:19]([C:22]([NH:24][CH2:25][CH2:26][OH:27])=[O:23])[S:20][CH:21]=3)=[N:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[I-].[Na+].Cl[Si](C)(C)C.O>C(#N)C>[CH:1]1([N:6]2[C:14]3[CH:13]=[CH:12][NH:11][C:10](=[O:15])[C:9]=3[C:8]([C:17]3[CH:18]=[C:19]([C:22]([NH:24][CH2:25][CH2:26][OH:27])=[O:23])[S:20][CH:21]=3)=[N:7]2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COc1nccc2c1c(-c1csc(C(=O)NCCO)c1)nn2C1CCCC1
Agent: C[Si](C)(C)Cl
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: O=C(NCCO)c1cc(-c2nn(C3CCCC3)c3cc[nH]c(=O)c23)cs1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 81.2 %

Procedure:
To a solution of 4-(1-cyclopentyl-4-methoxy-1H-pyrazolo[4,3-c]pyridin-3-yl)-N-(2-hydroxyethyl)thiophene-2-carboxamide (62.6 mg) in acetonitrile (10 mL) were added sodium iodide (48.6 mg) and chloro(trimethyl)silane (0.164 mL), and the mixture was stirred at 60° C. for 30 min. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane/methanol), and the obtained solid was washed with ethyl acetate/diisopropyl ether to give the title compound (49.0 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([CH:14]([CH2:19][CH2:20][CH3:21])[C:15]([O:17]C)=[O:16])=[C:12]([CH3:22])[N:11]=[C:10]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[N:9]=2)=[C:4]([F:29])[CH:3]=1.[OH-].[Na+]>CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([CH:14]([CH2:19][CH2:20][CH3:21])[C:15]([OH:17])=[O:16])=[C:12]([CH3:22])[N:11]=[C:10]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[N:9]=2)=[C:4]([F:29])[CH:3]=1
Reactant: CCCC(C(=O)OC)c1c(C)nc(-c2ccccc2)nc1-c1ccc(Cl)cc1F
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCC(C(=O)O)c1c(C)nc(-c2ccccc2)nc1-c1ccc(Cl)cc1F
Yield: 51.8 %

Procedure:
This compound was prepared according to general method D from methyl 2-(4-(4-chloro-2-fluorophenyl)-6-methyl-2-phenylpyrimidin-5-yl)pentanoate (0.164 g; 0.397 mmol), sodium hydroxide 10N (0.397 mL; 3.97 mmol) in methanol (4 mL) to afford 0.082 g (49%) of the title compound as a white solid.
Reaction SMILES: [CH3:1][S:2]([CH2:5][C:6]1[CH:11]=[C:10]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[N:9]=[C:8]([C:18]2[CH:24]=[CH:23][C:21]([NH2:22])=[CH:20][CH:19]=2)[N:7]=1)(=[O:4])=[O:3].[CH:25]([N:28]=[C:29]=[O:30])([CH3:27])[CH3:26]>O1CCOCC1>[CH3:1][S:2]([CH2:5][C:6]1[CH:11]=[C:10]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[N:9]=[C:8]([C:18]2[CH:24]=[CH:23][C:21]([NH:22][C:29](=[O:30])[NH:28][CH:25]([CH3:27])[CH3:26])=[CH:20][CH:19]=2)[N:7]=1)(=[O:4])=[O:3]
Reactant: CC(C)N=C=O
Reactant: CS(=O)(=O)Cc1cc(N2CCOCC2)nc(-c2ccc(N)cc2)n1
Solvent: C1COCCO1
Product: CC(C)NC(=O)Nc1ccc(-c2nc(CS(C)(=O)=O)cc(N3CCOCC3)n2)cc1
Yield: 43.8 %

Procedure:
4-[4-(Methylsulfonylmethyl)-6-morpholin-4-yl-pyrimidin-2-yl]aniline (70 mg, 0.2 mmol) and isoproylisocyanate (0.1 mL, 1 mmol) were heated in dioxane (2 mL) at 70° C. for 4 hours. The reaction mixture was evaporated and the residue triturated with ethyl acetate. The suspension was filtered and the white solid washed with ethyl acetate and diethyl ether then dried under vacuum at 60° C. overnight to yield the title compound (38 mg).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([NH:6][CH:7]([C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:5].[C:21]([C:24]1[CH:32]=[CH:31][C:27]([C:28](O)=[O:29])=[CH:26][CH:25]=1)(=[O:23])[CH3:22]>>[C:21]([C:24]1[CH:32]=[CH:31][C:27]([C:28]([NH:2][CH2:3][C:4](=[O:5])[NH:6][CH:7]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:29])=[CH:26][CH:25]=1)(=[O:23])[CH3:22]
Reactant: NCC(=O)NC(c1ccccc1)c1ccc(Cl)cc1
Reactant: CC(=O)c1ccc(C(=O)O)cc1
Agent: Cl
Product: CC(=O)c1ccc(C(=O)NCC(=O)NC(c2ccccc2)c2ccc(Cl)cc2)cc1

Procedure:
Prepared in analogy to example 1.12 from rac-2-amino-N-[(4-chloro-phenyl)-phenyl-methyl]-acetamide hydrochloride (Example 3.1) and 4-acetylbenzoic acid.
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][CH2:10][C@@H:11]1[NH:16][CH2:15][CH2:14][N:13]([C:17]2[C:26]3[CH:25]=[C:24]([CH3:27])[S:23][C:22]=3[NH:21][C:20]3[CH:28]=[CH:29][CH:30]=[CH:31][C:19]=3[N:18]=2)[CH2:12]1.C=O.[C:36](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[F:33][C:2]([F:1])([F:32])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][CH2:10][C@@H:11]1[N:16]([CH3:36])[CH2:15][CH2:14][N:13]([C:17]2[C:26]3[CH:25]=[C:24]([CH3:27])[S:23][C:22]=3[NH:21][C:20]3[CH:28]=[CH:29][CH:30]=[CH:31][C:19]=3[N:18]=2)[CH2:12]1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: Cc1cc2c(s1)Nc1ccccc1N=C2N1CCN[C@@H](CCc2ccccc2C(F)(F)F)C1
Agent: C=O
Agent: [Na+]
Solvent: ClCCCl
Product: Cc1cc2c(s1)Nc1ccccc1N=C2N1CCN(C)[C@@H](CCc2ccccc2C(F)(F)F)C1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 80.5 %

Procedure:
Combine 10-((S)-3-[2-(2-trifluromethyl-phenyl)-ethyl]-piperazin-1-yl)-2-methyl-4H-3-thia-4,9-diaza-benzo[f]azulene (365.7 mg, 0.78 mmol), formaldehyde (69.4 μL, 0.85 mmol, 37% in water), and 1,2-dichloroethane (30.0 ml). Stir the mixture at ambient temperature for 5 minutes and then add sodium triacetoxyborohydride (247.0 mg, 1.17 mmol). After stirring for 30 minutes at ambient temperature, quench the reaction with saturated sodium bicarbonate. Remove the organic portion, extract the aqueous with dichloromethane and combine, wash (brine), dry (sodium sulfate), and reduce the extracts to residue. Purify the residue on silica gel using dichloromethane/methanol (95:5) to give 304.3 mg (81%) of the title compound as a tan foam: mp 68°, dec; mass spectrum (ion spray): m/z=485.2 (M+1).