Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[CH3:9])[NH2:5].[CH3:10][S:11](Cl)(=[O:13])=[O:12].CCOC(C)=O>N1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([NH:5][S:11]([CH3:10])(=[O:13])=[O:12])[CH:6]=[CH:7][C:8]=1[CH3:9]
Reactant: CS(=O)(=O)Cl
Reactant: Cc1ccc(N)cc1Br
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: Cc1ccc(NS(C)(=O)=O)cc1Br
Temperature: 25 °C
Reaction time: 1 h
Yield: 100.1 %

Procedure:
A cooled (0° C.) solution of 3-bromo-4-methylaniline (ABCR; 1.00 g; 5.37 mmol) in pyridine (20 ml) was treated with methanesulfonyl chloride (500 μl; 6.45 mmol). The reaction mixture was allowed to warm to RT and stirred for 1 hour, then EtOAc was added and the organic layer was washed with a 1N aqueous solution of HCl. The organic layer was dried over MgSO4, filtered and concentrated to dryness to give the title compound as a brown solid (1.42 g, quantitative).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH3:12])[C:3]=1[C:4](O)=[O:5].[CH3:13][NH:14][CH3:15]>>[NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH3:12])[C:3]=1[C:4]([N:14]([CH3:15])[CH3:13])=[O:5]
Reactant: COc1cccc(N)c1C(=O)O
Reactant: CNC
Product: COc1cccc(N)c1C(=O)N(C)C

Procedure:
The product was obtained starting from 2-amino-6-methoxybenzoic acid (100 mg, 0.6 mmol) and dimethylamine (2M in THF, 420 μl, 0.84 mmol) according to the method described in example 64, step 6 after extraction with ethyl acetate and purification by silica gel chromatography using an amine phase and a heptane/ethyl acetate gradient as colorless oil (26 mg, 22%).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH:12]([C:14]3[N:18]([CH3:19])[C:17]([CH3:20])=[N:16][CH:15]=3)[OH:13])[CH:10]=2)[N:5]=[C:4]([O:21][CH3:22])[C:3]=1[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=1.O1CCOCC1>[O-2].[O-2].[Mn+4].C1COCC1>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([C:14]3[N:18]([CH3:19])[C:17]([CH3:20])=[N:16][CH:15]=3)=[O:13])[CH:10]=2)[N:5]=[C:4]([O:21][CH3:22])[C:3]=1[CH2:23][C:24]1[CH:25]=[CH:26][C:27]([C:30]([F:32])([F:31])[F:33])=[CH:28][CH:29]=1
Reactant: COc1nc2ccc(C(O)c3cnc(C)n3C)cc2c(Cl)c1Cc1ccc(C(F)(F)F)cc1
Agent: [Mn+4]
Agent: [O-2]
Solvent: C1CCOC1
Solvent: C1COCCO1
Product: COc1nc2ccc(C(=O)c3cnc(C)n3C)cc2c(Cl)c1Cc1ccc(C(F)(F)F)cc1
Temperature: 45 °C
Reaction time: 1 h

Procedure:
To a flask containing (4-chloro-2-methoxy-3-(4-(trifluoromethyl)benzyl)quinolin-6-yl)(1,2-dimethyl-1H-imidazol-5-yl)methanol (1.68 g, 3.53 mmol, Intermediate 8: step a) was added 1,4-dioxane (75 mL) and THF (10 mL) which produced a suspension at room temperature. Warming to 45° C. formed a homogeneous solution. Then, manganese dioxide (1.5 g, 17.25 mmol) was introduced and the mixture was heated to 80° C. After 60 minutes, the contents were filtered through a Celite® pad, rinsing with THF, and then the solution was concentrated. Trituration with Et2O provided the title compound as a white powder.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH2:3][CH:2]1[C:6]([OH:8])=O.[NH2:9][C@H:10]([C:12]([N:14]1[C:20](=[O:21])[CH:19]([CH3:22])[C:18]2[CH:23]=[CH:24][CH:25]=[CH:26][C:17]=2[C:16]2[C:27]([NH2:31])=[CH:28][CH:29]=[CH:30][C:15]1=2)=[O:13])[CH3:11]>>[O:1]1[CH2:5][CH2:4][CH2:3][CH:2]1[C:6]([NH:9][C@H:10]([C:12]([N:14]1[C:20](=[O:21])[CH:19]([CH3:22])[C:18]2[CH:23]=[CH:24][CH:25]=[CH:26][C:17]=2[C:16]2[C:27]([NH2:31])=[CH:28][CH:29]=[CH:30][C:15]1=2)=[O:13])[CH3:11])=[O:8]
Reactant: CC1C(=O)N(C(=O)[C@H](C)N)c2cccc(N)c2-c2ccccc21
Reactant: O=C(O)C1CCCO1
Product: CC1C(=O)N(C(=O)[C@H](C)NC(=O)C2CCCO2)c2cccc(N)c2-c2ccccc21

Procedure:
Following General Procedure C-P above using tetrahydro-2-furoic acid and 5-(L-alaninyl)-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one, as described in Example 7-B, the title compound was prepared. The molecular weight as determined by mass spectrometry (FD) was:408 (M+H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([C:9]([O:11][CH3:12])=[O:10])[C:3]=1[O:13][CH3:14].S(Cl)([Cl:18])(=O)=O.C(=O)(O)[O-].[Na+].[Na+].[Cl-]>CC#N.CCOC(C)=O>[NH2:1][C:2]1[C:7]([Cl:18])=[C:6]([Cl:8])[N:5]=[C:4]([C:9]([O:11][CH3:12])=[O:10])[C:3]=1[O:13][CH3:14]
Reactant: COC(=O)c1nc(Cl)cc(N)c1OC
Reactant: O=S(=O)(Cl)Cl
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: COC(=O)c1nc(Cl)c(Cl)c(N)c1OC
Reaction time: 0.5 h
Yield: 79.7 %

Procedure:
Methyl 4-amino-6-chloro-3-methoxypicolinate (260 mg, 1.2 mmol) was dissolved in dry CH3CN (7 mL), treated with sulfuryl chloride (120 μL, 1.5 mmol) and stirred for 30 min The solution was stirred with satd aq sodium bicarbonate (NaHCO3; 10 mL) for 20 min and then mixed with EtOAc (20 mL) and satd aq NaCl (10 mL). The aqueous phase was extracted with EtOAc (15 mL), and the combined organic phases were washed with satd aq NaCl (10 mL), dried (Na2SO4) and evaporated to give the title compound as a white solid (240 mg, 80%): mp 119-121° C.; 1H NMR (400 MHz, CDCl3) δ 5.04 (s, 2H), 3.97 (s, 3H), 3.93 (s, 3H); EIMS m/z 250.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:20][CH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1)[C@@H:3]([O:12][Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14])[CH2:4][C:5]([NH:7][CH2:8][CH2:9][CH2:10][CH3:11])=[O:6].C([O-])(O)=O.[Na+].Cl[C:33]([O:35][C:36]1[CH:41]=[CH:40][C:39]([N+:42]([O-:44])=[O:43])=[CH:38][CH:37]=1)=[O:34]>CC#N>[CH2:8]([NH:7][C:5](=[O:6])[CH2:4][C@H:3]([O:12][Si:13]([C:16]([CH3:18])([CH3:17])[CH3:19])([CH3:14])[CH3:15])[C@@H:2]([NH:1][C:33](=[O:34])[O:35][C:36]1[CH:37]=[CH:38][C:39]([N+:42]([O-:44])=[O:43])=[CH:40][CH:41]=1)[CH2:20][CH:21]1[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]1)[CH2:9][CH2:10][CH3:11]
Reactant: CCCCNC(=O)C[C@H](O[Si](C)(C)C(C)(C)C)[C@@H](N)CC1CCCCC1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: CCCCNC(=O)C[C@H](O[Si](C)(C)C(C)(C)C)[C@H](CC1CCCCC1)NC(=O)Oc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 8.8 %

Procedure:
To a stirred solution of crude (3S,4S)-4-amino-N-butyl-3-(tertbutyldimethylsilyloxy)-5-cyclohexylpentanamide (311 mg, 0.81 mmol) in MeCN were added powdered NaHCO3 (203 mg, 2.43 mmol) and p-nitrophenyl chloroformate (244 mg, 1.21 mmol) and the mixture was stirred overnight at rt. The mixture was concentrated under reduced pressure. The residue was taken up in 1:1 EtOAc/Et2O (90 mL), washed with water (20 mL) and brine (20 mL), dried over MgSO4 and concentrated to leave an orange oil. This material was chromatographed on a 40-g silica cartridge eluted with a 0 to 100% ethyl acetate in hexanes gradient to afford 4-nitrophenyl (2S,3S)-5-(butylamino)-3-(tert-butyldimethylsilyloxy)-1-cyclohexyl-5-oxopentan-2-ylcarbamate (39 mg, 8%).
Reaction SMILES: [I-].[CH2:2]([N+:6]1[C:10]([CH3:11])=[C:9]([CH3:12])[S:8][C:7]=1[CH3:13])[CH2:3][CH2:4][CH3:5].[CH:14]1([N:20]=[C:21]=[O:22])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1.C1CCN2C(=NCCC2)CC1>C(Cl)Cl>[CH2:2]([N:6]1[C:10]([CH3:11])=[C:9]([CH3:12])[S:8]/[C:7]/1=[CH:13]\[C:21]([NH:20][CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)=[O:22])[CH2:3][CH2:4][CH3:5]
Reactant: CCCC[n+]1c(C)sc(C)c1C
Reactant: O=C=NC1CCCCC1
Agent: [I-]
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Product: CCCCN1C(C)=C(C)S/C1=C\C(=O)NC1CCCCC1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
To a solution of Example 1A (123 mg, 0.4 mmol) and cyclohexyl isocyanate (63 mg, 0.5 mmol) in CH2Cl2 (20 mL) at 0° C. was added dropwise a solution of DBU (0.076 mL, 0.5 mmol) in CH2Cl2 (5 mL). The mixture was allowed to warm to room temperature and stirred for 14 hours. The mixture was washed sequentially with water, brine and dried over anhydrous MgSO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography over silica gel (CH2Cl2-MeOH 9:1) to provide the title compound. 1H NMR (300 MHz, DMSO-d6) δ 0.96 (t, J=7 Hz, 3H), 1.10 (m, 3H), 1.29 (m, 4H), 1.51 (m, 3H), 1.70 (m, 4H), 1.95 (s, 3H), 2.02 (s, 3H), 3.33 (m, 3H), 5.02 (s, 1H), 6.74 (br d, J=7 Hz, 1H); MS (ESI) m/z 309 (M+H)+. Anal calcd for C17H28N2OS.0.25H2O: C, 65.24; H, 9.18; N, 8.95. Found: C, 65.49; H, 9.30; N, 8.93.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[C:18]([O:20][CH2:21][CH:22]=[C:23]([Cl:25])[Cl:24])[CH:17]=[C:16]([Cl:26])[C:3]=1[O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][O:10][CH2:11][C:12](=[N:14][OH:15])[CH3:13].S(=O)(=O)(O)O.[CH2:32]=[C:33]([CH3:35])[CH3:34].C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1>[C:33]([O:15][N:14]=[C:12]([CH2:11][O:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][O:4][C:3]1[C:2]([Cl:1])=[CH:19][C:18]([O:20][CH2:21][CH:22]=[C:23]([Cl:25])[Cl:24])=[CH:17][C:16]=1[Cl:26])[CH3:13])([CH3:35])([CH3:34])[CH3:32]
Reactant: C=C(C)C
Reactant: CC(COCCCCCOc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl)=NO
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CC(COCCCCCOc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl)=NOC(C)(C)C

Procedure:
First, 0.45 g of 5-(2,6-dichloro-4-(3,3-dichloro-2-propenyloxy)phenoxy)pentyloxyacetone oxime, 0.3 ml of concentrated sulfuric acid, and 10 ml of toluene are placed in a reaction vessel, into which isobutene gas is blown with stirring under ice cooling, and the mixture is further stirred at room temperature. After completion of the reaction, the reaction mixture is slowly poured into a saturated aqueous sodium hydrogencarbonate solution, and extracted twice with diethyl ether. The diethyl ether layers are combined, washed with water, dried over anhydrous magnesium sulfate, and concentrated to give a crude product. This crude product is subjected to silica gel chromatography, which affords 5-(2,6-dichloro-4-(3,3-dichloro-2-propenyloxy)phenoxy)pentyloxyacetone O-tert-butyloxime.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][O:9][C:10]2[CH:19]=[CH:18][C:13]([C:14]([O:16]C)=[O:15])=[CH:12][CH:11]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[N+:20]([O-])([OH:22])=[O:21]>S(=O)(=O)(O)O>[N:1]1([CH2:7][CH2:8][O:9][C:10]2[CH:19]=[CH:18][C:13]([C:14]([OH:16])=[O:15])=[CH:12][C:11]=2[N+:20]([O-:22])=[O:21])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: O=[N+]([O-])O
Reactant: COC(=O)c1ccc(OCCN2CCOCC2)cc1
Agent: O=S(=O)(O)O
Product: O=C(O)c1ccc(OCCN2CCOCC2)c([N+](=O)[O-])c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 76.7 %

Procedure:
Methyl 4-(2-morpholin-4-ylethoxy)benzoate (Example 206c) (30 g, 110 mmol) was dissolved in conc. sulfuric acid (70 ml) and cooled to 0° C. Nitric acid (d=1.52, 4.7 ml, 110 mmol) was added and the mixture was allowed to assume room temperature within 1 h. The reaction mixture was poured onto an ice water mixture (600 g) whereupon crystals formed. The crystals were collected by filtration and washed with water to give the pure product as a white powder (25 g, 80%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.Br[CH2:9][CH2:10][CH2:11][CH2:12][N:13]1[C:17](=[O:18])[C:16]2=[CH:19][CH:20]=[CH:21][CH:22]=[C:15]2[C:14]1=[O:23].C1CCN2C(=NCCC2)CC1>CN(C=O)C>[C:14]1(=[O:23])[N:13]([CH2:12][CH2:11][CH2:10][CH2:9][O:1][C:2]2[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=2)[C:17](=[O:18])[C:16]2=[CH:19][CH:20]=[CH:21][CH:22]=[C:15]12
Reactant: O=C1c2ccccc2C(=O)N1CCCCBr
Reactant: Oc1ccncc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1CCCCOc1ccncc1
Temperature: 25 °C
Reaction time: 7 h
Yield: 17.8 %

Procedure:
To a solution of 4.76 g (50 mmol) of 4-hydroxypyridine and 15.52 g (55 mmol) of N-(4bromobutyl)phthalimide in 80 ml of DMF was added 8.23 ml (5 mmol) of 1,8-diazabicyclo[5.4.0]-7-undecene. The mixture was stirred at room temperature for 7 hours. After the solvent was distilled off, the mixture was poured into water and extracted with ethyl acetate. The mixture was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off. The residue was purified by column chromatography (eluent: ethyl acetate) to obtain 2.63 g of the desired compound (yield: 17.2%, colorless crystals).
Reaction SMILES: [OH:1][CH:2]1[CH2:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[S:5][C:4]2[CH:13]=[C:14]([C:17]([OH:19])=[O:18])[CH:15]=[CH:16][C:3]1=2.[N+](=[CH2:22])=[N-]>CCOCC>[CH3:22][O:18][C:17]([C:14]1[CH:15]=[CH:16][C:3]2[CH:2]([OH:1])[CH2:8][C:7]3[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=3[S:5][C:4]=2[CH:13]=1)=[O:19]
Reactant: O=C(O)c1ccc2c(c1)Sc1ccccc1CC2O
Reactant: C=[N+]=[N-]
Solvent: CCOCC
Product: COC(=O)c1ccc2c(c1)Sc1ccccc1CC2O

Procedure:
13.5 G. 10,11-dihydro-11-hydroxydibenzo[b,f]thiepin-3-carboxylic acid is suspended in ether and excess diazomethane is added in portions. A clear solution results which is filtered from small particles in suspension and the filtrate evaporated to dryness to a yellow oil weighing 14.2 g.
Reaction SMILES: [C:1]([C:3]1[N:7]2[CH:8]=[C:9]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=3)[CH:10]=[C:11]([C:12]#[N:13])[C:6]2=[N:5][CH:4]=1)#[CH:2].[NH2:24][C:25]1[N:30]=[CH:29][C:28](I)=[CH:27][N:26]=1>>[NH2:24][C:25]1[N:30]=[CH:29][C:28]([C:2]#[C:1][C:3]2[N:7]3[CH:8]=[C:9]([C:14]4[CH:19]=[CH:18][C:17]([C:20]([F:22])([F:23])[F:21])=[CH:16][CH:15]=4)[CH:10]=[C:11]([C:12]#[N:13])[C:6]3=[N:5][CH:4]=2)=[CH:27][N:26]=1
Reactant: Nc1ncc(I)cn1
Reactant: C#Cc1cnc2c(C#N)cc(-c3ccc(C(F)(F)F)cc3)cn12
Product: N#Cc1cc(-c2ccc(C(F)(F)F)cc2)cn2c(C#Cc3cnc(N)nc3)cnc12

Procedure:
The title compound was prepared from 3-ethynyl-6-(4-trifluoromethyl-phenyl)-imidazo[1,2-a]pyridine-8-carbonitrile (example C.23) (150 mg, 0.5 mmol) and commercially available 2-amino-5-iodopyrimidine (107 mg, 0.5 mmol) according to general procedure II. Obtained as a dark brown solid (5 mg, 2%). MS (ISP) 405.3 [(M+H)+]; mp 290° C.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]([CH2:6][NH:7][CH2:8][C:9]2[CH:14]=[CH:13][C:12]([CH:15]([CH3:17])[CH3:16])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.[CH2:20]([O:22][C@H:23]([C:36]([O:38][CH2:39][CH3:40])=[O:37])[CH2:24][C:25]1[CH:35]=[CH:34][C:28]([O:29][CH2:30][C:31](O)=[O:32])=[CH:27][CH:26]=1)[CH3:21].C(N(CC)C(C)C)(C)C.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([CH:15]([CH3:17])[CH3:16])=[CH:11][CH:10]=2)[C:31](=[O:32])[CH2:30][O:29][C:28]2[CH:27]=[CH:26][C:25]([CH2:24][C@H:23]([O:22][CH2:20][CH3:21])[C:36]([O:38][CH2:39][CH3:40])=[O:37])=[CH:35][CH:34]=2)=[CH:18][CH:19]=1
Reactant: CCOC(=O)[C@H](Cc1ccc(OCC(=O)O)cc1)OCC
Reactant: CC(C)c1ccc(CNCc2ccc(Cl)cc2)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)[C@H](Cc1ccc(OCC(=O)N(Cc2ccc(Cl)cc2)Cc2ccc(C(C)C)cc2)cc1)OCC
Reaction time: 8 h
Yield: 46.4 %

Procedure:
To a solution of N-(4-chlorobenzyl)-N-(4-isopropylbenzyl)amine (1.64 g, 6.0 mmol) in methylene chloride (50 mL) at 0° C. were added {4-[(2S)-2,3-diethoxy-3-oxopropyl]phenoxy}acetic acid (1.48 g, 5.0 mmol) and N,N-diisopropylethylamine (2.0 mL, 11.5 mmol) followed by O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (1.93 g, 6.0 mmol) and the reaction mixture was stirred overnight. The mixture was diluted with methylene chloride (100 mL) and the organic phase was washed with 2 M HCl (3×75 mL), saturated aqueous NaHCO3 (2×75 mL, some emulsions), and brine (75 mL), dried over Na2SO4, and concentrated in vacuo. Twice repeated purification on silica gel with methanol (0-5% gradient) in methylene chloride as the eluent and collection of pure fractions afforded 1.28 g (46%) of a colourless oil.
Reaction SMILES: [CH:1]1([C:6]2[CH:10]=[C:9]([NH:11][C:12]([NH:14][C:15]3[CH:20]=[C:19]([C:21]4[C:32](=[O:33])[N:31]([CH3:34])[C:24]5[N:25]=[C:26](SC)[N:27]=[CH:28][C:23]=5[CH:22]=4)[CH:18]=[CH:17][C:16]=3[F:35])=[O:13])[N:8]([CH3:36])[N:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:37][NH2:38]>>[CH:1]1([C:6]2[CH:10]=[C:9]([NH:11][C:12]([NH:14][C:15]3[CH:20]=[C:19]([C:21]4[C:32](=[O:33])[N:31]([CH3:34])[C:24]5[N:25]=[C:26]([NH:38][CH3:37])[N:27]=[CH:28][C:23]=5[CH:22]=4)[CH:18]=[CH:17][C:16]=3[F:35])=[O:13])[N:8]([CH3:36])[N:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CN
Reactant: CSc1ncc2cc(-c3ccc(F)c(NC(=O)Nc4cc(C5CCCC5)nn4C)c3)c(=O)n(C)c2n1
Product: CNc1ncc2cc(-c3ccc(F)c(NC(=O)Nc4cc(C5CCCC5)nn4C)c3)c(=O)n(C)c2n1
Yield: 20 %

Procedure:
Using a procedure analogous to Example A1, 1-(3-cyclopentyl-1-methyl-1H-pyrazol-5-yl)-3-(2-fluoro-5-(8-methyl-2-(methylthio)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl)urea (0.068 g, 0.134 mmol) and MeNH2 (2.0 M in THF, 1.4 mL) were combined to afford 1-(3-cyclopentyl-1-methyl-1H-pyrazol-5-yl)-3-(2-fluoro-5-(8-methyl-2-(methylamino)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl)urea (0.013 g, 20%) as white solid. 1H NMR (400 MHz, DMSO-d6): δ 9.02 (s, 1H), 8.89 (d, J=2.0 Hz, 1H), 8.73 (s, 1H), 8.49 (d, J=7.6 Hz, 1H), 7.95 (m, 1H), 7.92 (m, 1H), 7.38-7.34 (m, 2H), 6.11 (s, 1H), 3.70-3.68 (m, 6H), 2.99-2.94 (m, 4H), 1.99-1.94 (m, 2H), 1.73-1.68 (m, 2H), 1.67-1.60 (m, 4H); MS (ESI) m/z: 491.2 (M+H+).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[O:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)[N:3]=1.[NH2:21][C@H:22]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH2:24][CH2:23]1>>[F:20][C:17]1[CH:18]=[CH:19][C:14]([CH2:13][O:12][C:8]2[CH:7]=[CH:6][CH:5]=[C:4]3[C:9]=2[CH:10]=[CH:11][C:2]([NH:21][C@H:22]2[C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[CH2:24][CH2:23]2)=[N:3]3)=[CH:15][CH:16]=1
Reactant: N[C@@H]1CCc2ccccc21
Reactant: Fc1ccc(COc2cccc3nc(Cl)ccc23)cc1
Product: Fc1ccc(COc2cccc3nc(N[C@@H]4CCc5ccccc54)ccc23)cc1

Procedure:
2-Chloro-5-(4-fluoro-benzyloxy)-quinoline (100 mg, 0.347 mmol) and (R)-1-aminoindane (138 mg, 1.04 mmol) were stirred in a sealed tube at 150° C. overnight. The reaction mixture was purified by flash chromatography on silica gel (heptane/ethyl acetate 75:25). The title compound was obtained as a light brown oil (68 mg, 51%), MS: m/e=385 (M+H+).
Reaction SMILES: [CH:1]1([Mg]Br)[CH2:3][CH2:2]1.[CH3:6][S:7]([C:10]([C:13]1[CH:14]=[C:15]2[C:20](=[C:21]([C:23]3[CH:24]=[C:25]([CH2:29][CH:30]([C:37]4[CH:42]=[CH:41][C:40]([S:43]([CH3:46])(=[O:45])=[O:44])=[CH:39][CH:38]=4)[C:31](N(OC)C)=[O:32])[CH:26]=[CH:27][CH:28]=3)[CH:22]=1)[N:19]=[CH:18][CH:17]=[CH:16]2)([CH3:12])[CH3:11])(=[O:9])=[O:8]>C1COCC1.C(OCC)(=O)C.[Cl-].[NH4+]>[CH:1]1([C:31](=[O:32])[CH:30]([C:37]2[CH:38]=[CH:39][C:40]([S:43]([CH3:46])(=[O:45])=[O:44])=[CH:41][CH:42]=2)[CH2:29][C:25]2[CH:26]=[CH:27][CH:28]=[C:23]([C:21]3[CH:22]=[C:13]([C:10]([S:7]([CH3:6])(=[O:9])=[O:8])([CH3:12])[CH3:11])[CH:14]=[C:15]4[C:20]=3[N:19]=[CH:18][CH:17]=[CH:16]4)[CH:24]=2)[CH2:3][CH2:2]1
Reactant: Br[Mg]C1CC1
Reactant: CON(C)C(=O)C(Cc1cccc(-c2cc(C(C)(C)S(C)(=O)=O)cc3cccnc23)c1)c1ccc(S(C)(=O)=O)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(c1cc(-c2cccc(CC(C(=O)C3CC3)c3ccc(S(C)(=O)=O)cc3)c2)c2ncccc2c1)S(C)(=O)=O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Anhydrous CeCl3 (266 mg, 1.26 mmol) was heated 2 h at 130° C. under high vacuum, refluxed in THF (10 mL) for 1 h then cooled to 0° C. To the resulting white suspension at 0° C. was added freshly prepared cyclopropylmagnesium bromide (0.6M, THF, 2.11 mL, 1.25 mmol) and the resulting mixture stirred at 0° C. for 1 h then cooled to −78° C. The 3-{3-[6-(1-methanesulfonyl-1-methyl-ethyl)-quinolin-8-yl]-phenyl}-2-(4-methanesulfonyl-phenyl)-N-methoxy-N-methyl-propionamide from Step 1 (in THF, 150 mg, 0.25 mmol) was added and the mixture warmed to 0° C. for 1 h, diluted with ethyl acetate and saturated ammonium chloride solution. The organic extracts were washed (H2O), (brine), dried (MgSO4), filtered and concentrated. Purification by flash chromatography (eluting with hexane/ethyl acetate, 1:4) provided the 1-cyclopropyl-3-{3-[6-(1-methanesulfonyl-1-methyl-ethyl)-quinolin-8-yl]-phenyl}-2-(4-methanesulfonyl-phenyl)-propan-1-one compound as a white foam.
Reaction SMILES: [Br:1][C:2]1[C:7]2[N:8]([CH2:12][CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:9](=O)[NH:10][C:6]=2[CH:5]=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:22])=O>>[Br:1][C:2]1[C:7]2[N:8]([CH2:12][CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:9]([Cl:22])=[N:10][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)CCCn1c(=O)[nH]c2cccc(Br)c21
Reactant: O=P(Cl)(Cl)Cl
Product: CCOC(=O)CCCn1c(Cl)nc2cccc(Br)c21
Temperature: 100 °C
Reaction time: 4 h
Yield: 36 %

Procedure:
A mixture of ethyl 4-(7-bromo-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)butanoate (4.11 g, 12.6 mmol) and phosphoryl chloride (49 g, 320 mmol) was stirred at 100° C. for 4 hr. After cooling, phosphoryl chloride was evaporated in vacuo. The residue was neutralized with saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was is purified by flash column chromatography on silica gel eluting with a 5-30% ethyl acetate/n-hexane gradient mixture. The filtrate was concentrated in vacuo to give the title compound as a colorless powder (1.57 g, 4.54 mmol, 36%).
Reaction SMILES: O[CH2:2][CH2:3][CH2:4][C:5]1[N:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:8]2[CH:16]=[CH:17][CH:18]=[CH:19][C:7]=2[N:6]=1.S(Cl)([Cl:22])=O>C(Cl)(Cl)Cl.C(=O)(O)[O-].[Na+]>[Cl:22][CH2:2][CH2:3][CH2:4][C:5]1[N:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:8]2[CH:16]=[CH:17][CH:18]=[CH:19][C:7]=2[N:6]=1
Reactant: OCCCc1nc2ccccc2n1-c1ccccc1
Reactant: O=S(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: ClCCCc1nc2ccccc2n1-c1ccccc1
Yield: 81 %

Procedure:
A solution of 2-(3-hydroxypropyl)-1-phenyl-1H-benzimidazole (1.15 g) and thionyl chloride (0.6 g) in chloroform (23 ml) was refluxed for 1.5 hours. After being cooled, the mixture was diluted with a saturated aqueous solution of sodium bicarbonate. The chloroform layer was washed with water and a saturated aqueous solution of sodium chloride in turn, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure to afford 2-(3-chloropropyl)-1-phenyl-1H-benzimidazole (1.0 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](/[CH:15]=[CH:16]/[C:17]([OH:19])=[O:18])[CH:6]=[CH:7][C:8]=1[O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].Cl[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][OH:27]>C(#N)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5](/[CH:15]=[CH:16]/[C:17]([O:19][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][OH:27])=[O:18])[CH:6]=[CH:7][C:8]=1[O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CCCCCOc1ccc(/C=C/C(=O)O)cc1OC
Reactant: OCCCCCCCl
Solvent: CC#N
Product: CCCCCOc1ccc(/C=C/C(=O)OCCCCCCO)cc1OC

Procedure:
7.30 g (27.6 mmol) (2E)-3-[3-methoxy-4-(pentyloxy)phenyl]prop-2-enoic acid were suspended in 3 ml acetonitrile. A mixture of 4.20 g (27.6 mmol) 1,8-diazabicyclo[5.4.0]undec-7-ene(1,5-5) (DBU) and 3 ml acetonitrile was added dropwise over a period of 5 minutes. 3.43 g (25.1 mmol) 6-chlorohexanol were added and the resulting mixture was then refluxed for 6 hours. The reaction mixture was cooled and then extracted using ethyl acetate and water. The ethyl acetate phase was washed with water, dried over sodium sulphate, filtered and concentrated by rotary evaporation. Chromatography of the residue using a silica gel column yield 6-hydroxyhexyl (2E)-3-[3-methoxy-4-(pentyloxy)phenyl]prop-2-enoate.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][C:7]2[C:12]([C:13]=1[NH2:14])=[CH:11][CH:10]=[CH:9][CH:8]=2)([O-])=O>C(O)C.[Pd]>[NH2:1][C:4]1[CH:5]=[N:6][C:7]2[C:12]([C:13]=1[NH2:14])=[CH:11][CH:10]=[CH:9][CH:8]=2
Reactant: Nc1c([N+](=O)[O-])cnc2ccccc12
Agent: [Pd]
Solvent: CCO
Product: Nc1cnc2ccccc2c1N

Procedure:
Compound 8 was prepared as described elsewhere [Van Galen, P. J. M. et. al. (1991) ibid.]. In brief, to a mixture of 3-nitro-4-aminoquinoline 7 (3.2 g, 20 mmol) in absolute ethanol (60 ml) was added 10% palladium on charcoal (0.17 g). The mixture was hydrogenated under 2.5-3.5 atm pressure till the product was formed and subsequently filtered over Hyflo. The filtrate was evaporated and the residue was gradually solidified and dried in vacuum. Yield: 2.66 g (98%). Mp.: 183-185° C. MS (ESI) m/z 161.0 (M+1)+. 1H NMR (DMSO-d6): δ 4.73 (broad s, 2H, NH2); 5.88 (s, 2H, NH2); 7.16-7.37 (m, 2H, Ar); 7.64-7.70 (m, 1H, Ar); 7.98-8.03 (m, 1H, Ar); 8.22 (s, 1H, Ar).