Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[CH:6]=O.[CH2:13]([O:15][C:16](=[O:19])[CH2:17][NH2:18])[CH3:14].[BH4-].[Na+].CCO>C1COCC1.C(O[Ti](OC(C)C)(OC(C)C)OC(C)C)(C)C.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[CH2:6][NH:18][CH2:17][C:16]([O:15][CH2:13][CH3:14])=[O:19]
Reactant: CCOC(=O)CN
Reactant: COc1ccc(C=O)cc1OC
Agent: CC(C)O[Ti](OC(C)C)(OC(C)C)OC(C)C
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCO
Product: CCOC(=O)CNCc1ccc(OC)c(OC)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 6.1 %

Procedure:
3,4-Dimethoxybenzaldehyde (2.358 g, 14.19 mmol) was dissolved in dry THF (14.19 ml) under nitrogen atmosphere, and a solution of glycine ethyl ester (1.33 g, 12.90 mmol) in dry THF (6.47 ml) was added followed by a solution of tetraisopropoxytitanium (5.73 ml, 19.35 mmol) in dry THF (5.83 ml). The resulting mixture was stirred at RT overnight. NaBH4 (1.366 g, 36.1 mmol) was suspended in abs. EtOH (46.3 ml) and added drop wise to the reaction mixture, stirring for 3 hours. The reaction mixture was treated with water (30 ml) and then filtered through a sintered glass funnel. The filtrate was partitioned between EtOAc and brine and the aqueous phase was extracted with EtOAc (2×). The combined organic layers were dried over Na2SO4 and the solvent was removed under vacuum affording 2.52 g of crude product. 1.4 g of this product were purified by chromatography on silica gel column (DCM:EtOAc=70:30 to 50:50) affording ethyl 2-(3,4-dimethoxybenzylamino)acetate (0.200 g, 0.790 mmol, MS/ESI+ 254.2 [MH]+)
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][N:9]1[C:17]2[C:12](=[N:13][C:14]([C@@H:24]([NH2:26])[CH3:25])=[C:15]([C:18]3[N:22]([CH3:23])[N:21]=[CH:20][CH:19]=3)[CH:16]=2)[CH:11]=[CH:10]1.[Cl:27][C:28]1[N:33]=[C:32](Cl)[C:31]([C:35]#[N:36])=[CH:30][N:29]=1.C(N(C(C)C)C(C)C)C>C(#N)C>[Cl:27][C:28]1[N:33]=[C:32]([NH:26][C@H:24]([C:14]2[N:13]=[C:12]3[CH:11]=[CH:10][N:9]([CH3:8])[C:17]3=[CH:16][C:15]=2[C:18]2[N:22]([CH3:23])[N:21]=[CH:20][CH:19]=2)[CH3:25])[C:31]([C:35]#[N:36])=[CH:30][N:29]=1
Reactant: C[C@H](N)c1nc2ccn(C)c2cc1-c1ccnn1C
Reactant: N#Cc1cnc(Cl)nc1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: C[C@H](Nc1nc(Cl)ncc1C#N)c1nc2ccn(C)c2cc1-c1ccnn1C
Temperature: 120 °C
Yield: 28.2 %

Procedure:
(S)-1-(1-Methyl-6-(1-methyl-1H-pyrazol-5-yl)-1H-pyrrolo[3,2-b]pyridin-5-yl)ethanamine 2,2,2-trifluoroacetate (100 mg, 0.271 mmol), 2,4-dichloropyrimidine-5-carbonitrile (70.7 mg, 0.406 mmol) and N-ethyl-N-isopropylpropan-2-amine (146 μL, 0.812 mmol) were combined in acetonitrile (1725 μL), and the resulting mixture was heated to 120° C. in a microwave reactor for 1 hour. The mixture was concentrated and purified on a silica gel column, eluting with EtOAc. The fractions were collected and concentrated in vacuo to give the title compound as a yellow solid (30 mg, 28%). ESI-MS m/z [M+H]+ calc'd for C19H17ClN8, 393.13; found 393.3.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[CH2:7][C:6]([CH3:9])([CH3:8])[CH2:5][C:4](=[C:10]([CH3:13])[C:11]#[N:12])[CH2:3]1.[ClH:15].CC1(C)CC(C)(C)CC(=CCN)C1>>[ClH:15].[CH3:1][C:2]1([CH3:14])[CH2:7][C:6]([CH3:8])([CH3:9])[CH2:5][C:4](=[C:10]([CH3:13])[CH2:11][NH2:12])[CH2:3]1
Reactant: CC(C#N)=C1CC(C)(C)CC(C)(C)C1
Agent: CC1(C)CC(=CCN)CC(C)(C)C1
Agent: Cl
Product: CC(CN)=C1CC(C)(C)CC(C)(C)C1

Procedure:
Prepared from nitrile 21 according to the procedure for compound 22 (Example 10, b). Amine hydrochloride 23 obtained as a colorless solid. 1H-NMR: (CDCl3, TMS): 0.92 and 0.93 (total 12H, both s, c-Hex-3,5-CH3); 1.27 (2H, s, c-Hex-4-CH2); 1.89 (3H, s, propanamine-3-CH3); 1.99 and 2.01 (total 4H, both s, c-Hex-2,6-CH2); 3.64 (2H, br s, propanamine-1-CH2) and 8.40 ppm (3H, br s, NH3+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[C@@H:14]([O:15][CH2:16][C:17]3[CH:18]=[CH:19][C:20]4[O:25][CH2:24][CH2:23][N:22]([CH2:26][CH2:27][CH2:28][O:29][CH3:30])[C:21]=4[CH:31]=3)[CH2:13][N:12]([S:32]([C:35]3[CH:40]=[CH:39][C:38]([CH3:41])=[CH:37][CH:36]=3)(=[O:34])=[O:33])[C@H:11]([CH2:42][C:43]#[N:44])[CH2:10]2)=[CH:5][CH:4]=1.O1CCCC1.B>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C@@H:9]2[C@@H:14]([O:15][CH2:16][C:17]3[CH:18]=[CH:19][C:20]4[O:25][CH2:24][CH2:23][N:22]([CH2:26][CH2:27][CH2:28][O:29][CH3:30])[C:21]=4[CH:31]=3)[CH2:13][N:12]([S:32]([C:35]3[CH:40]=[CH:39][C:38]([CH3:41])=[CH:37][CH:36]=3)(=[O:33])=[O:34])[C@H:11]([CH2:42][CH2:43][NH2:44])[CH2:10]2)=[CH:7][CH:8]=1
Reactant: COCCCN1CCOc2ccc(CO[C@H]3CN(S(=O)(=O)c4ccc(C)cc4)[C@H](CC#N)C[C@@H]3c3ccc(OC)cc3)cc21
Agent: B
Solvent: C1CCOC1
Product: COCCCN1CCOc2ccc(CO[C@H]3CN(S(=O)(=O)c4ccc(C)cc4)[C@H](CCN)C[C@@H]3c3ccc(OC)cc3)cc21
Reaction time: 8 h

Procedure:
To a solution of 1.9 g of [(2S,4R,5R)-4-(4-methoxy-phenyl)-5-[4-(3-methoxy-propyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-1-(toluene-4-sulfonyl)-piperidin-2-yl]-acetonitrile (from example 25 g) in 30 ml of tetrahydrofuran are added 11.0 ml of a 1M solution of borane tetrahydrofuran. The reaction mixture is stirred overnight, quenched with methanol and concentrated under reduced pressure. The residue is purified by flash chromatography (SiO2 60 F) to afford the title compound as a yellow oil. Rf=0.09 (dichlormethane-methanol-25% ammonia conc. 200:10:1); Rt=4.32.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].S(=O)(=O)(O)O.[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([N:17]2[C:22](=[O:23])[CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[NH:19][C:18]2=[O:28])=[C:13]([F:29])[CH:12]=1>>[Cl:10][C:11]1[C:16]([N+:1]([O-:4])=[O:2])=[CH:15][C:14]([N:17]2[C:22](=[O:23])[CH:21]=[C:20]([C:24]([F:27])([F:25])[F:26])[NH:19][C:18]2=[O:28])=[C:13]([F:29])[CH:12]=1
Reactant: O=c1cc(C(F)(F)F)[nH]c(=O)n1-c1ccc(Cl)cc1F
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: O=c1cc(C(F)(F)F)[nH]c(=O)n1-c1cc([N+](=O)[O-])c(Cl)cc1F
Temperature: -15 °C

Procedure:
A nitrating solution consisting of 2.2 ml of nitric acid and 24 ml of sulphuric acid is pre-cooled to -15° C. 9.26 g of 3-(4-chloro-2-fluorophenyl)-6 -trifluoromethyl-2,4(1H,3H)-pyrimidinedione are added portion wise to the solution while stirring. The mixture is stirred at 15° C. for 30 minutes and subsequently at room temperature for 1 hour. Thereafter, the mixture is poured onto 150 ml of ice-water and the resulting crystalline precipitate is filtered off. In this manner there is obtained 3-(4-chloro-2-fluoro-5-nitrophenyl)-6 -trifluoromethyl-2,4(1H,3H)-pyrimidinedione. m.p. 204° C.
Reaction SMILES: C[O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][N:9]([CH2:13][CH2:14][CH2:15][CH2:16][NH:17][C:18](=[O:31])[C:19]3[CH:24]=[CH:23][C:22]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)=[CH:21][CH:20]=3)[CH2:10]2)=[CH:5][CH:4]=1.N>ClCCl>[OH:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][N:9]([CH2:13][CH2:14][CH2:15][CH2:16][NH:17][C:18](=[O:31])[C:19]3[CH:20]=[CH:21][C:22]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)=[CH:23][CH:24]=3)[CH2:10]2)=[CH:5][CH:4]=1
Reactant: COc1ccc2c(c1)CN(CCCCNC(=O)c1ccc(-c3ccccc3)cc1)CC2
Agent: N
Solvent: ClCCl
Product: O=C(NCCCCN1CCc2ccc(O)cc2C1)c1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 74.3 %

Procedure:
A solution of borontribromide i n dichloromethane (72 ml, 1M solution, 72 mmol) was added dropwise with stirring to an ice-cooled solution of 7-methoxy-N-(4-(4-phenylbenzoylamino)butyl)-1,2,3,4-tetrahydroisoquinoline (5.00 g, 12.1 mmol) in dichloromethane (150 ml). After stirring at room temperature for 16 h the reaction mixture was poured onto a mixture of crushed-ice (200 g) and 0.880 aqueous ammonia (400 ml). The resulting mixture was extracted with dichloromethane (3×200 ml). The combined organics were washed with brine (200 ml) then dried (Na2SO4) and the solvent evaporated in vacuo to give the title compound as a pale yellow solid (3.60 g, 75%).
Reaction SMILES: [C:1]([S:5]([CH2:8][O:9][C:10]1[N:17]=[C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[Cl:24])[C:15]([C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=2)=[CH:14][C:11]=1[C:12]#[N:13])(=[O:7])=[O:6])([CH3:4])([CH3:3])[CH3:2].C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>CN(C=O)C.C1COCC1>[C:1]([S:5]([C:8]1[O:9][C:10]2=[N:17][C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[Cl:24])=[C:15]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)[CH:14]=[C:11]2[C:12]=1[NH2:13])(=[O:6])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)S(=O)(=O)COc1nc(-c2ccccc2Cl)c(-c2ccc(Cl)cc2)cc1C#N
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CC(C)(C)S(=O)(=O)c1oc2nc(-c3ccccc3Cl)c(-c3ccc(Cl)cc3)cc2c1N

Procedure:
To a stirred solution of 1.87 g (3.9 mmol) of the product of Step B in 24 mL of DMF at 0° C. was added 7.9 mL of a 1.0 M solution of lithium bis(trimethylsilyl)amide in THF. The reaction mixture was stirred an addition 5 min then it was quenched with 0.45 mL of acetic acid and then partitioned between ethyl acetate and saturated NaCl solution. The organic layer was separated, dried (MgSO4), filtered and evaporated. The residue was then purified via silica gel flash chromatography eluting with a gradient of 0 to 40% ethyl acetate/hexane to afford the title compound. HPLC/MS: 475.1 (M+1), 477.0 (M+3); Rt=3.99 min.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH2:8][NH:9][CH:10]([CH3:15])[C:11]([F:14])([F:13])[F:12])[CH:5]=[CH:4][N:3]=1.[F:16][C:17]1[CH:22]=[CH:21][C:20](B(O)O)=[CH:19][CH:18]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C1(C)C=CC=CC=1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O.C(O)C>[F:12][C:11]([F:14])([F:13])[CH:10]([NH:9][CH2:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([C:20]2[CH:21]=[CH:22][C:17]([F:16])=[CH:18][CH:19]=2)[CH:7]=1)[CH3:15]
Reactant: OB(O)c1ccc(F)cc1
Reactant: CC(NCc1ccnc(Br)c1)C(F)(F)F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCO
Product: CC(NCc1ccnc(-c2ccc(F)cc2)c1)C(F)(F)F
Temperature: 100 °C
Yield: 90.5 %

Procedure:
A mixture of N-[(2-bromopyridin-4-yl)methyl]-1,1,1-trifluoropropan-2-amine (150 mg), 4-fluorophenylboronic acid (111 mg), cesium carbonate (345 mg), tetrakis(triphenylphosphine)palladium (61 mg), toluene (0.6 mL), ethanol (0.6 mL) and water (4.0 mL) was stirred while heating at 100° C. for 3 hr. The supernatant of the reaction mixture was purified by column chromatography (silica gel cartridge, hexane:ethyl acetate=95:5-60:40) to afford the title compound (143 mg).
Reaction SMILES: CN(C)CCCCCCO.C1(C)C=CC(S(OS(C2C=CC(C)=CC=2)(=O)=O)(=O)=O)=CC=1.C([O-])(=S)C.[K+].C([S:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][N:47]([CH3:49])[CH3:48])(C)=O.C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)Cl.CN(C=O)C.CO.C(N(CC)CC)C>[CH3:48][N:47]([CH3:49])[CH2:46][CH2:45][CH2:44][CH2:43][CH2:42][CH2:41][SH:40]
Reactant: CC(=O)SCCCCCCN(C)C
Agent: CC([O-])=S
Agent: CN(C)CCCCCCO
Agent: Cc1ccc(S(=O)(=O)OS(=O)(=O)c2ccc(C)cc2)cc1
Solvent: CO
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CN(C)CCCCCCS

Procedure:
6-dimethylaminohexanol was suspended in CH2Cl2 and treated with p-toluenesulphonic anhydride in the presence of triethylamine for 1 hour at 0° C. The reaction mixture was then treated with potassium thioacetate in DMF at 50° C. for a further hour. The resulting compound, AcS(CH2)6NMe2, was treated with sodium carbonate in methanol at room temperature for 20 hours to give 6-(dimethylamino)hexanethiol. This was suspended in dry DMSO at room temperature and sodium hydride was added. The reaction mixture was left stirring for 30 mixtures. 5-bromo-2-thiophenecarboxaldehyde in DMSO was then added and the reaction mixture was warmed to 80° C. for 30 minutes to give the title compound. This is the starting aldehyde used in the preparation of compound 5442.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-:14])=[O:13])[C:3]=1[C:4]([O:6][CH3:7])=[O:5].[Br:15]N1C(C)(C)C(=O)N(Br)C1=O.N(C(C)(C)C#N)=NC(C)(C)C#N.CC1C=CC=C([N+]([O-])=O)C=1C([O-])=O>C(OC)(=O)C>[Br:15][CH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-:14])=[O:13])[C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1c(C)cccc1[N+](=O)[O-]
Reactant: CC1(C)C(=O)N(Br)C(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: Cc1cccc([N+](=O)[O-])c1C(=O)[O-]
Solvent: COC(C)=O
Product: COC(=O)c1c(CBr)cccc1[N+](=O)[O-]
Temperature: 16.5 °C
Reaction time: 0.92 h

Procedure:
A mixture of methyl 2-methyl-6-nitrobenzoate (200.0 g, 1.02 moles, previously prepared), 1,3-dibromo-5,5-dimethylhydantoin (DBH, 162.0 g, 0.57 mole, from Aldrich Chemicals) and methyl acetate (1.20 L, from Aldrich Chemicals) was charged into a 3-L three-necked flask at about 20-25° C. under nitrogen. After the reaction mixture was refluxed for 0.5-1 hour, a solution of 2,2′-azobisisobutyronitrile (AIBN, 8.6 g, 52 mmol, from Aldrich Chemicals) in 100 mL of methyl acetate was charged over 15-30 minutes. The reaction mixture was refluxed for 6.5-8 hours until the amount of unreacted 2-methyl-6-nitrobenzoate was less than 5-10%. The reaction mixture was cooled to 15-18° C. and kept at 15-18° C. for 50-60 minutes. The solid was filtered, washed with cold (i.e., 5-10° C.) methyl acetate (2×100 mL) until there was less than 3% of methyl 2-bromomethyl-6-nitrobenzoate remained in the solid. Next, after heptane (1.00 L) was charged into the filtrate, the upper layer organic phase was washed with 2% of brine (2×500 mL) and deionizer water (1-2×500 mL) until there was less than 0.5% (area percentage at 210 nm) of unreacted 5,5-dimethylhydantoin according to measurement by HPLC. After the solution was concentrated under a reduced pressure to remove about 1.80-1.90 L of methyl acetate, methyl tert-butyl ether (MTBE, 300 mL) was charged. After the reaction mixture was refluxed at 65-70° C. for 10-15 minutes, the solution was cooled to 50-55° C. over 0.5-1 hour and seeded with 500 mg of methyl 2-bromomethyl-6-nitrobenzoate at 45-50° C. The suspension was cooled to 20-25° C. and kept at 20-25° C. for 2-3 hours. The solids were collected by filtration, washed with 5-10° C. a cold mixture of heptane and MTBE in a volume ratio of 1:2 (2×100 mL), and dried to a constant weight at 20-25° C. under a vacuum at 100-120 torr. The yield of methyl 2-bromomethyl-6-nitrobenzoate was 185.2 g (66%), based on 200.0 g input of methyl 2-methyl-6-nitrobenzoate. The product was found to have a purity of >98% measured by HPLC based on area percentage, and a water content of <0.1% measured by Karl Fisher titration.
Reaction SMILES: [CH:1]([NH:4][N:5]1[C:17]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[CH:9][C:8]=2[N:7]=[C:6]1[CH2:18][CH2:19][CH3:20])([CH3:3])[CH3:2].C1C=C(Cl)C=C(C(OO)=O)C=1.[OH-].[NH4+:33].C1(C)C=CC(S(Cl)(=O)=O)=CC=1>C(Cl)(Cl)Cl.O>[CH:1]([NH:4][N:5]1[C:17]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[C:9]([NH2:33])[C:8]=2[N:7]=[C:6]1[CH2:18][CH2:19][CH3:20])([CH3:3])[CH3:2]
Reactant: CCCc1nc2cnc3ccccc3c2n1NC(C)C
Reactant: [NH4+]
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: O
Product: CCCc1nc2c(N)nc3ccccc3c2n1NC(C)C
Reaction time: 1.5 h

Procedure:
A solution of N-isopropyl-(2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)amine (2.48 g, 9.24 mmol) in 75 mL of chloroform was cooled in a cold water bath. The solution was treated with MCPBA (3.32 g, 11.6 mmol) over 6 min. The reaction was allowed to come to ambient temperature. After 1.5 h, TLC showed complete conversion to the 5-N-oxide intermediate. The reaction mixture was again cooled in a cold water bath and then treated with concentrated ammonium hydroxide solution (30 mL, 30%) and stirred rapidly. The reaction mixture was treated with p-toluenesulfonyl chloride (1.85 g, 9.70 mmol) over 5 min. The reaction was allowed to come to ambient temperature. After 30 min, the reaction mixture was diluted with 50 mL of chloroform and 30 mL of water and the phases were separated. The organic portion was washed with 5% Na2CO3 solution (30 mL), water (30 mL) and brine (30 mL). The organic portion was dried over Na2SO4, filtered and concentrated under reduced pressure to yield a light brown foam. The material was purified by chromatography (SiO2, 97:3 CHCl3:MeOH) and recrystallized from EtOAc to yield 1.39 g of N1-isopropyl-2-propyl-1H-imidazo[4,5-c]quinoline-1,4-diamine as amber crystals.
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:24])=[C:4]([C:8]2[N:9]=[C:10]([C:20]([CH3:23])([CH3:22])[CH3:21])[S:11][C:12]=2[C:13]2[CH:18]=[CH:17][N:16]=[C:15]([NH2:19])[N:14]=2)[CH:5]=[CH:6][CH:7]=1.[N:25]1[CH:30]=[CH:29][CH:28]=[C:27]([S:31](Cl)(=[O:33])=[O:32])[CH:26]=1>>[NH2:19][C:15]1[N:14]=[C:13]([C:12]2[S:11][C:10]([C:20]([CH3:21])([CH3:23])[CH3:22])=[N:9][C:8]=2[C:4]2[C:3]([F:24])=[C:2]([NH:1][S:31]([C:27]3[CH:26]=[N:25][CH:30]=[CH:29][CH:28]=3)(=[O:33])=[O:32])[CH:7]=[CH:6][CH:5]=2)[CH:18]=[CH:17][N:16]=1
Reactant: CC(C)(C)c1nc(-c2cccc(N)c2F)c(-c2ccnc(N)n2)s1
Reactant: O=S(=O)(Cl)c1cccnc1
Product: CC(C)(C)c1nc(-c2cccc(NS(=O)(=O)c3cccnc3)c2F)c(-c2ccnc(N)n2)s1

Procedure:
Following a procedure analogous to the procedure described in Intermediate 14 using 4-[4-(3-amino-2-fluorophenyl)-2-(1,1-dimethylethyl)-1,3-thiazol-5-yl]-2-pyrimidinamine (100 mg, 0.291 mmol) and 3-pyridinesulfonyl chloride (94 mL, 0.430 mmol), the title compound was obtained as a tan solid (34 mg, 24% yield). MS (ESI): 485.0 [M+H]+.
Reaction SMILES: [Si]([O:18][CH:19]1[CH2:22][N:21]([C:23]2[S:24][CH:25]=[C:26]([CH2:28][NH:29][C:30]([C:32]3[O:33][CH:34]=[CH:35][CH:36]=3)=[O:31])[N:27]=2)[CH2:20]1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[O:33]1[CH:34]=[CH:35][CH:36]=[C:32]1[C:30]([NH:29][CH2:28][C:26]1[N:27]=[C:23]([N:21]2[CH2:20][CH:19]([OH:18])[CH2:22]2)[S:24][CH:25]=1)=[O:31]
Reactant: CC(C)(C)[Si](OC1CN(c2nc(CNC(=O)c3ccco3)cs2)C1)(c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: O=C(NCc1csc(N2CC(O)C2)n1)c1ccco1
Reaction time: 1 h
Yield: 41.4 %

Procedure:
To a solution of 3-t-butyldiphenylsilyloxy-1-[4-(furan-2-carbonyl-amino)methyl-1,3-thiazol-2-yl]azetidine (1.90 g, 3.68 mmol) (obtained as described in Reference Example 67(1)) in anhydrous tetrahydrofuran (95 ml) was added a solution of 1.0 M tetra-n-butylammonium fluoride in tetrahydrofuran (4.41 ml, 4.41 mmol) in an ice bath and the mixture was stirred in an ice bath for 1 hour. After checking the completion of the reaction, the mixture was partitioned between ethyl acetate and saturated aqueous sodium hydrogencarbonate solution. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using ethyl acetate:methanol (10:1) as the eluant to afford 1-[4-(furan-2-carbonylamino)methyl-1,3-thiazol-2-yl]-3-hydroxyazetidine (426 mg, yield 47%) as a white solid.
Reaction SMILES: COCC1C=C[C:7]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18]C)=[CH:14][CH:13]=2)=C([N+]([O-])=O)C=1.F[C:24](F)(F)C(O)=O>C(Cl)Cl>[CH3:24][C:14]1[CH:13]=[C:12]([CH2:11][O:10][CH3:7])[CH:17]=[CH:16][C:15]=1[OH:18]
Reactant: COCc1ccc(OCc2ccc(OC)cc2)c([N+](=O)[O-])c1
Reactant: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COCc1ccc(O)c(C)c1

Procedure:
To a solution of 4-[(methyloxy)methyl]-1-({[4-(methyloxy)phenyl]methyl}oxy)-2-nitrobenzene D54 (1.57 g, 5.18 mmol) in DCM (80 mL) was added trifluoroacetic acid (3.99 mL, 51.80 mmol). After 1 hr the mixture was washed with water (3×25 mL) and then extracted with 10% aq potassium carbonate solution (3×20 mL). The combined extracts were back washed with diethyl ether (20 mL) and then the pH was adjusted to 1 with 2N HCl, the mixture was extracted with DCM (3×25 mL), the combined extracts were washed with water (25 mL) and brine (25 mL), dried(MgSO4), filtered and concentrated in vacuo. The residue was purified by silica gel chromatography eluting with 5-40% EtOAc in isohexane to afford the title compound as a bright yellow oil. 0.72 g, 76% 1H NMR δ (CDCl3): 3.41 (3H, s), 4.42 (2H, d), 7.15 (1H, d, J=8.4 Hz), 7.56 (1H, m), 8.08 (1H, d).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=O.[CH2:10]([O:12][C:13](=[O:24])[NH:14][C:15]1[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][C:16]=1[O:22][CH3:23])[CH3:11]>CO>[CH2:10]([O:12][C:13](=[O:24])[NH:14][C:15]1[CH:20]=[CH:19][C:18]([NH:21][CH2:5][C:4]2[CH:7]=[CH:8][CH:9]=[C:2]([F:1])[CH:3]=2)=[CH:17][C:16]=1[O:22][CH3:23])[CH3:11]
Reactant: CCOC(=O)Nc1ccc(N)cc1OC
Reactant: O=Cc1cccc(F)c1
Solvent: CO
Product: CCOC(=O)Nc1ccc(NCc2cccc(F)c2)cc1OC
Temperature: 40 °C
Yield: 45 %

Procedure:
A solution of 3-fluorobenzaldehyde in dry methanol (84 μL, 476 mM) was added to a solution of (4-Amino-2-methyloxyphenyl)-carbamic acid ethyl ester (84 μL, 0.476 M in dry methanol). The resulting mixture was heated to 40° C. for 30 minutes. The solvent was evaporated in vacuo, and the remaining material was dissolved in 1,2-dichloroethane (1 mL). Sodium triacetoxyborohydrate (20 mg) was added, and the resulting mixture was kept at room temperature for 2 hours, under 2 periods of sonication for 10 minutes, respectively. The reaction mixture was filtered through silica gel (500 mg), and the column was washed with 1,2-dichloroethane (3 mL). The solvent was evaporated in vacuo yielding the title compound (5.7 mg, 45%).
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][C:5]2[S:6][C:7]3[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:8]=3[CH:9]([N:11]3[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3)[CH2:10][C:4]=2[CH:3]=1.C1(C)C=CC=CC=1.Cl[CH2:32][CH2:33][CH:34]1[O:39][CH2:38][CH2:37][CH2:36][O:35]1>C(N(CC)CC)C>[Cl:1][C:2]1[CH:23]=[CH:22][C:5]2[S:6][C:7]3[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:8]=3[CH:9]([N:11]3[CH2:16][CH2:15][N:14]([CH2:32][CH2:33][CH:34]4[O:39][CH2:38][CH2:37][CH2:36][O:35]4)[CH2:13][CH2:12]3)[CH2:10][C:4]=2[CH:3]=1
Reactant: Fc1ccc2c(c1)Sc1ccc(Cl)cc1CC2N1CCNCC1
Reactant: ClCCC1OCCCO1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: Fc1ccc2c(c1)Sc1ccc(Cl)cc1CC2N1CCN(CCC2OCCCO2)CC1
Reaction time: 23 h
Yield: 64 %

Procedure:
A mixture of 2-chloro-7-fluoro-10-piperazino-10,11-dihydro-dibenzo(b,f)thiepin (10.0 g), toluene (60 ml), triethylamine (10 g) and 2-(2-chloroethyl)-1,3-dioxane (15.3 g) is refluxed under stirring for 23 hours. On cooling, the precipitate is filtered off and washed with benzene. The combined filtrates are then washed with water, dried over anhydrous potassium carbonate, filtered with a small amount of active carbon, and evaporated under reduced pressure to dryness. The residue (19.0 g) crystallizes rapidly while standing. Another crystallization from a mixture of benzene (50 ml) and petroleum ether (50 ml) yields 8.5 g (65%) of the desired base, melting at 150.5°-152° C. Repeating the crystallization from the same solvent system does not increase the m.p. any more; the product is analytically pure, and its elemental analysis corresponds to the composition C24H28ClFN2O2S. Neutralization of the base, with maleic acid in a mixture of equal amounts of benzene, acetone and ethanol, provides the neutral maleate C28H32ClFN2O6S, which crystallizes from ethanol and melts in the pure state at 184°-185° C. This salt is only very slightly soluble in water. Neutralization of base with methanesulfonic acid in ethanol gives the monomethanesulfonate C25H32ClFN2O5S2, which crystallizes from ethanol and melts at 201°-203° C. This salt is excellently water-soluble.
Reaction SMILES: C([N:4]1[CH2:10][CH2:9][C:8]2[CH:11]=[CH:12][C:13]([N+:15]([O-:17])=[O:16])=[CH:14][C:7]=2[CH2:6][CH2:5]1)(=O)C.[OH-].[Na+]>Cl>[N+:15]([C:13]1[CH:12]=[CH:11][C:8]2[CH2:9][CH2:10][NH:4][CH2:5][CH2:6][C:7]=2[CH:14]=1)([O-:17])=[O:16]
Reactant: CC(=O)N1CCc2ccc([N+](=O)[O-])cc2CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: O=[N+]([O-])c1ccc2c(c1)CCNCC2
Yield: 97.9 %

Procedure:
A solution of 3-acetyl-7-nitro-2,3,4,5-tetrahydro-1H-3-benzazepine (2.9 g) in HCl (conc) (200 ml) as refluxed for 48 h. Mixture was cooled at 0° C. and neutralised with NaOH (conc.) then was extracted with DCM. The organic layer was collected and the aqueous phase extracted twice with DCM. The combined DCM layers were concentrated to provide the target compound (2.33 g).