Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]([C:4]1[CH:5]=[CH:6][C:7]([O:10][CH3:11])=[N:8][CH:9]=1)=[C:2]=[S:3].Cl.[CH3:13][C:14]1[CH:26]=[CH:25][CH:24]=[CH:23][C:15]=1[O:16][CH:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1.C(N(CC)C(C)C)(C)C>ClCCl>[CH3:11][O:10][C:7]1[N:8]=[CH:9][C:4]([NH:1][C:2]([N:20]2[CH2:21][CH2:22][CH:17]([O:16][C:15]3[CH:23]=[CH:24][CH:25]=[CH:26][C:14]=3[CH3:13])[CH2:18][CH2:19]2)=[S:3])=[CH:5][CH:6]=1
Reactant: COc1ccc(N=C=S)cn1
Reactant: Cc1ccccc1OC1CCNCC1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(NC(=S)N2CCC(Oc3ccccc3C)CC2)cn1
Temperature: 25 °C
Reaction time: 3 h
Yield: 85 %

Procedure:
5-Isothiocyanato-2-methoxypyridine [(829 mg, 4.99 mmol), J. Org. Chem. (1980), 45, 4219] was added to a solution of 4-(2-methylphenoxy)-piperidine hydrochloride [(990 mg, 4.3 mmol), J. Med. Chem. (1978), 21, 309] and N,N-diisopropylethylamine (0.79 mL, 4.7 mmol) in dichloromethane (10 mL) and the mixture was stirred for 3 hours at room temperature. The organic solution was then diluted with dichloromethane and washed with sodium hydrogen carbonate solution and brine. The organic solution was dried over magnesium sulfate and concentrated in vacuo. Trituration of the residue with diethyl ether afforded the title compound as a solid in 85% yield, 1.3 g. LRMS APCI m/z 358 [M+H]+
Reaction SMILES: C(OC([N:7]1[C:13]2[CH:14]=[C:15]([O:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:16]([O:18][CH3:19])=[CH:17][C:12]=2[C:11](=[O:28])[N:10]2[CH:29]=[C:30]([CH2:32][C:33]([O:35][CH3:36])=[O:34])[CH2:31][C@H:9]2[C@@H:8]1O)=O)C=C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1CCCC1>C(Cl)Cl.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>[CH3:19][O:18][C:16]1[CH:17]=[C:12]2[C:11]([N:10]3[C@H:9]([CH:8]=[N:7][C:13]2=[CH:14][C:15]=1[O:20][CH2:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[CH2:31][C:30]([CH2:32][C:33]([O:35][CH3:36])=[O:34])=[CH:29]3)=[O:28]
Reactant: C=CCOC(=O)N1c2cc(OCc3ccccc3)c(OC)cc2C(=O)N2C=C(CC(=O)OC)C[C@H]2[C@@H]1O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCNC1
Solvent: ClCCl
Product: COC(=O)CC1=CN2C(=O)c3cc(OC)c(OCc4ccccc4)cc3N=C[C@@H]2C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A catalytic amount of tetrakis(triphenylphosphine)palladium (5.0 mg, 4.33 μmol) was added to a stirred solution of the Alloc-protected carbinolamine 23 (88 mg, 0.17 mmol), triphenylphosphine (2.27 mg, 8.65 μmol) and pyrrolidine (13 mg, 0.18 mmol) in CH2Cl2 (15 mL). After 2 hours stirring at room temperature under a nitrogen atmosphere, TLC (80% EtOAc/Petroleum Ether) revealed the complete consumption of starting material. The solvent was evaporated in vacuo and the crude residue was purified by flash chromatography (60% EtOAc/Petroleum Ether) to afford the novel PBD (SJG-245) as a colourless glass (54 mg, 77%) which was repeatedly evaporated in vacuo with CHCl3 in order to provide the N10-C11 imine form 24: 1H NMR (270 MHz, CDCl3) (imine) δ7.80 (d, 1H, J=4.03 Hz, HC═N), 7.50 (s, 1Harom), 7.45-7.26 (m, 5Harom), 6.91 (br s, 1H, NCH═CCH2OC2CH3), 6.83 (s, 1Harom), 5.21-5.12 (m, 2H, PhCH2O), 3.94 (s, 3H, OCH3), 3.73 (s, 3H, CO2CH3), 3.23 (s, 2H, NCH═CCH2CO2CH3), 3.15 (m, 2H, NCH═CCH2CO2CH3CH2); 13C NMR (67.8 MHz, CDCl3) (imine) δ170.7 (CO2CH3), 162.7 (HC═N), 161.4 (NC═O), 150.9 (Carom), 148.1 (Carom), 140.1 (Carom), 136.0 (Carom), 128.7, 128.2 and 127.3 (BnC—Harom), 127.3 (NCH═CCH2CO2CH3), 119.2 (Carom), 117.5 (NCH═CCH2CO2CH3), 111.8 (C—Harom), 111.5 (C—Harom), 70.8 (PhCH2O), 56.2 (OCH3), 53.8 (NCHHC═N), 52.0 (CO2CH3), 37.4 (NCH═CCH2CO2CH3), 33.6 (NCH═CCH2CO2CH3CH2)
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:11]=[CH:10][C:9]([C:12]([N:14]3[C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=4[CH2:18][N:17]4[CH:25]=[CH:26][CH:27]=[C:16]4[CH2:15]3)=[O:13])=[CH:8][CH:7]=2)=[N:2]1.[C:28](OC(=O)C)(=[O:30])[CH3:29].O>N1C=CC=CC=1>[CH:27]1[CH:26]=[CH:25][N:17]2[CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[N:14]([C:12]([C:9]3[CH:10]=[CH:11][C:6]([C:3]4[CH:4]=[CH:5][N:1]([C:28](=[O:30])[CH3:29])[N:2]=4)=[CH:7][CH:8]=3)=[O:13])[CH2:15][C:16]=12
Reactant: O=C(c1ccc(-c2cc[nH]n2)cc1)N1Cc2cccn2Cc2ccccc21
Reactant: CC(=O)OC(C)=O
Solvent: O
Solvent: c1ccncc1
Product: CC(=O)n1ccc(-c2ccc(C(=O)N3Cc4cccn4Cc4ccccc43)cc2)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 82.2 %

Procedure:
To a solution of [4-(1H-pyrazol-3-yl)-phenyl]-(5H,11H-pyrrolo[2,1-c][1,4]benzodiazepin-10-yl)-methanone (0.50 g) in dry pyridine (10 ml) was added acetic anhydride (0.20 g). After stirring at room temperature for 18 hours the reaction mixture was poured into water and the precipitate was collected by filtration. The crude product was dissolved in dichloromethane and dried over anhydrous sodium sulfate. This solution was filtered through a short column of hydrous sodium magnesium silicate, eluting with several additional volumes of dichloromethane. The eluant was concentrated on a hot plate with the gradual addition of hexane until crystallization occurred. After cooling, the crystals were collected by filtration to yield the title compound (0.46 g), m.p. 192-194° C.
Reaction SMILES: [Cl:1][C:2]1[CH:34]=[CH:33][C:5]([CH2:6][C@H:7]([C:9]([N:11]2[CH:16]3[CH2:17][CH2:18][CH:12]2[CH2:13][CH:14]([N:19]([CH:27]2[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]2)[C:20]([N:22]([CH2:25][CH3:26])[CH2:23][CH3:24])=[O:21])[CH2:15]3)=[O:10])[NH2:8])=[CH:4][CH:3]=1.O=[CH:36][CH2:37][NH:38][C:39](=[O:45])[O:40][C:41]([CH3:44])([CH3:43])[CH3:42].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][C@@H:7]([NH:8][CH2:36][CH2:37][NH:38][C:39](=[O:45])[O:40][C:41]([CH3:44])([CH3:43])[CH3:42])[C:9]([N:11]2[CH:16]3[CH2:17][CH2:18][CH:12]2[CH2:13][CH:14]([N:19]([CH:27]2[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32]2)[C:20]([N:22]([CH2:23][CH3:24])[CH2:25][CH3:26])=[O:21])[CH2:15]3)=[O:10])=[CH:33][CH:34]=1
Reactant: CC(C)(C)OC(=O)NCC=O
Reactant: CCN(CC)C(=O)N(C1CCCCC1)C1CC2CCC(C1)N2C(=O)[C@H](N)Cc1ccc(Cl)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CCN(CC)C(=O)N(C1CCCCC1)C1CC2CCC(C1)N2C(=O)[C@@H](Cc1ccc(Cl)cc1)NCCNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 45.1 %

Procedure:
0.24 g of the N-[8-(4-chloro-D-phenylalanyl)-8-azabicyclo[3.2.1]oct-3-yl]-N-cyclohexyl-N′,N′-diethylurea endo compound, obtained in step 1.5, is dissolved in 5 ml of dichloromethane under N2 in the presence of 0.10 g of tert-butyl N-(2-oxoethyl)carbamate and of 0.22 g of sodium triacetoxyborohydride. The reaction medium is stirred at ambient temperature for 16 h. After evaporation to dryness, 0.05 g of tert-butyl N-(2-oxoethyl)carbamate and 0.1 g of sodium triacetoxyborohydride are added, and stirring is maintained for 3 days. After the addition of 1 ml of methanol and 4 g of Dowex® 50X2 resin, the mixture is stirred for 1 h 30 min. After filtration and washing of the resin with tetrahydrofuran and methanol, the expected compound is released by adding a 1N solution of aqueous ammonia in methanol. The methanol is evaporated off, to give 0.14 g of tert-butyl (2-{[(1R)-1-(4-chlorobenzyl)-2-(3-{cyclohexyl[(diethylamino)carbonyl]amino}-8-azabicyclo[3.2.1]oct-8-yl)-2-oxoethyl]amino}ethyl)carbamate.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]([CH3:11])[N:7]([CH3:12])[C:6]=2[CH:5]=[CH:4][C:3]=1[C:13](OC)=[O:14].[BH4-].[Li+].Cl.C(Cl)(Cl)Cl>O1CCCC1>[Cl:1][C:2]1[C:10]2[N:9]=[C:8]([CH3:11])[N:7]([CH3:12])[C:6]=2[CH:5]=[CH:4][C:3]=1[CH2:13][OH:14]
Reactant: COC(=O)c1ccc2c(nc(C)n2C)c1Cl
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: Cc1nc2c(Cl)c(CO)ccc2n1C
Temperature: 60 °C
Reaction time: 2 h
Yield: 51.6 %

Procedure:
To a solution of methyl 4-chloro-1,2-dimethyl-1H-benzimidazole-5-carboxylate (1.07 g) in anhydrous tetrahydrofuran (11 ml) was added portionwise lithium borohydride (198 mg) at room temperature and the mixture was stirred for 2 hr and heated to 60° C. Thereafter, lithium borohydride (99 mg) was added 3 times at 1 hr intervals. The reaction mixture was ice-cooled and adjusted to pH 2 with 1N hydrochloric acid. The mixture was stirred at room temperature for 30 min, and chloroform was added to the mixture. The precipitated crystals were collected by filtration to give 4-chloro-5-hydroxymethyl-1,2-dimethyl-1H-benzimidazole as colorless crystals (487 mg). The filtrate was extracted 6 times with chloroform:methanol=5:1. The organic layer was dried over anhydrous magnesium sulfate, filtrated and concentrated. The residue was crystallized from isopropyl ether to give the objective product as colorless crystals (417 mg).
Reaction SMILES: [NH2:1][N:2]1[CH2:7][CH2:6][N:5]([CH3:8])[CH2:4][CH2:3]1.[F:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17]2[N:22]=[C:21]([C:23]3[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=3)[CH:20]=[CH:19][N:18]=2)=[CH:12][C:11]=1[NH:29][C:30](=[O:39])[C:31]1[CH:36]=[CH:35][C:34]([CH2:37]Cl)=[CH:33][CH:32]=1>>[CH3:8][N:5]1[CH2:6][CH2:7][N:2]([NH:1][CH2:37][C:34]2[CH:33]=[CH:32][C:31]([C:30]([NH:29][C:11]3[CH:12]=[C:13]([NH:16][C:17]4[N:22]=[C:21]([C:23]5[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=5)[CH:20]=[CH:19][N:18]=4)[CH:14]=[CH:15][C:10]=3[F:9])=[O:39])=[CH:36][CH:35]=2)[CH2:3][CH2:4]1
Reactant: O=C(Nc1cc(Nc2nccc(-c3cccnc3)n2)ccc1F)c1ccc(CCl)cc1
Reactant: CN1CCN(N)CC1
Product: CN1CCN(NCc2ccc(C(=O)Nc3cc(Nc4nccc(-c5cccnc5)n4)ccc3F)cc2)CC1
Yield: 53.2 %

Procedure:
1-Amino-4-methylpiperazine (0.66 g, 5.77 mol) and N-[4-fluoro-3-(4-chloromethyl benzoylamino)-phenyl]-4-(3-pyridyl)-2-pyrimidine-amine (1 g, 2.31 mmol) were reacted according to the same procedure as Example 3 to give 4-(4-methylpiperazin-1-ylaminomethyl)-N-[2-fluoro-5-(4-(pyridin-3-yl)pyrimidin-2-yl)aminophenyl]benzamide (0.63 g).
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][CH2:5][CH:4]([NH:8][C:9](=[O:11])[CH3:10])[CH2:3]1.Cl.[CH3:13][O:14][C:15]1[CH:16]=[C:17]([NH:21]N)[CH:18]=[CH:19][CH:20]=1.O>CC(O)=O>[CH3:13][O:14][C:15]1[CH:16]=[C:17]2[C:18]([C:7]3[CH2:6][CH2:5][CH:4]([NH:8][C:9](=[O:11])[CH3:10])[CH2:3][C:2]=3[NH:21]2)=[CH:19][CH:20]=1
Reactant: CC(=O)NC1CCCC(=O)C1
Reactant: COc1cccc(NN)c1
Agent: Cl
Solvent: CC(=O)O
Solvent: O
Product: COc1ccc2c3c([nH]c2c1)CC(NC(C)=O)CC3
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 0.05 mol of N-(3-oxocyclohexyl)acetamide and 0.05 mol of 3-methoxyphenylhydrazine hydrochloride in 50 ml of glacial HOAc was stirred for 2 hr at room temperature and then refluxed for 2 hr. The cooled reaction mixture was poured into H2O and the product triturated until solid. Filtration, drying, and recrystallization from ethanol gave the title compound, mp 192°-193°.
Reaction SMILES: C([O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[O:15][CH3:16])[N:11]=[CH:10][N:9]=[C:8]2[NH:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([Br:24])[CH:19]=1)C=C.[CH3:25][C:26]1C=CC=C[C:31]=1C>>[CH2:31]([C:6]1[C:5]([OH:4])=[C:14]([O:15][CH3:16])[CH:13]=[C:12]2[C:7]=1[C:8]([NH:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([Br:24])[CH:19]=1)=[N:9][CH:10]=[N:11]2)[CH:26]=[CH2:25]
Reactant: C=CCOc1cc2c(Nc3cccc(Br)c3)ncnc2cc1OC
Reactant: Cc1ccccc1C
Product: C=CCc1c(O)c(OC)cc2ncnc(Nc3cccc(Br)c3)c12

Procedure:
A solution of (6-allyloxy-7-methoxy-quinazolin-4-yl)-(3-bromo-phenyl)-amine (0.54 g, 1.39 mmol) (from Example 17, Step C, supra) in o-xylene (75 mL) was heated at 150° C. for 4.5 hours, during which time TLC analysis indicated almost complete consumption of the starting material and the formation of desired product as the major spot. The solution was concentrated and filtered. The solid was collected and dried in vacuo to give the desired 5-allyl-4-(3-bromo-phenylamino)-7-methoxy-quinazolin-6-ol as an off white solid. (Yield 0.33 g, 61%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH2:9][CH2:8][CH:7]([N:15]([CH3:17])[CH3:16])[CH2:6][C:5]2=1.[F:18][C:19]1[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1>>[F:18][C:19]1[CH:24]=[CH:23][C:22]([S:25]([NH:1][C:2]2[CH:3]=[C:4]3[C:12](=[CH:13][CH:14]=2)[NH:11][C:10]2[CH2:9][CH2:8][CH:7]([N:15]([CH3:17])[CH3:16])[CH2:6][C:5]3=2)(=[O:27])=[O:26])=[CH:21][CH:20]=1
Reactant: CN(C)C1CCc2[nH]c3ccc(N)cc3c2C1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Product: CN(C)C1CCc2[nH]c3ccc(NS(=O)(=O)c4ccc(F)cc4)cc3c2C1

Procedure:
Beginning with 10.4 mg (0.046 mMol) 6-amino-3-(dimethyl)amino-1,2,3,4-tetrahydro-9H-carbazole and 13.1 mg (0.067 mMol) 4-fluorobenzenesulfonyl chloride, the title compound was recovered as a light beige solid.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[N:9][CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].S(Cl)([Cl:13])=O>CN(C=O)C>[Cl:1][C:2]1[CH:10]=[N:9][CH:8]=[CH:7][C:3]=1[C:4]([Cl:13])=[O:5]
Reactant: O=C(O)c1ccncc1Cl
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: O=C(Cl)c1ccncc1Cl
Temperature: 25 °C

Procedure:
A mixture of 0.69 g of 3-chloroisonicotinic acid, 5 ml of thionyl chloride and 30 mg of DMF was heated to reflux for 3.5 hours. The reaction mixture was cooled to room temperature, and then the reaction mixture was concentrated under reduced pressure to give 3-chloroisonicotinic acid chloride. A mixture of the resultant 3-chloroisonicotinic acid chloride and 4 ml of DMF was added dropwise to a mixture of 0.85 g of 2-amino-5-fluoro-4-trifluoromethylphenol, 0.88 g of triethylamine and 4 ml of DMF while ice-cooling. Thereafter, the reaction mixture was stirred at room temperature for one hour and at 50° C. for one hour. The reaction mixture was cooled to room temperature, and then water was added, followed by extraction with ethyl acetate twice. The combined organic layers wee washed with water and a saturated sodium chloride solution, then dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The resultant solid was washed with diethyl ether to give 0.77 g of 3-chloro-N-[4-fluoro-2-hydroxy-5-(trifluoromethyl)phenyl]-isonicotinamide.
Reaction SMILES: CS(O[CH:6]([C:8]1[S:12][C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[N:10][N:9]=1)[CH3:7])(=O)=O.[Br-:19].[Li+]>CC(C)=O>[Br:19][CH:6]([C:8]1[S:12][C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[N:10][N:9]=1)[CH3:7]
Reactant: [Br-]
Reactant: CC(OS(C)(=O)=O)c1nnc(-c2ccccn2)s1
Agent: [Li+]
Solvent: CC(C)=O
Product: CC(Br)c1nnc(-c2ccccn2)s1

Procedure:
A mixture of (RS)-2-[5-(1-methanesulfonyloxy-ethyl)-1,3,4-thiadiazol-2-yl]-pyridine (1.0 gm), lithium bromide (0.5 gm) in acetone (20 ml) was stirred at reflux over a period of 1 h. The reaction mixture was evaporated under vacuum to provide a crude mass. Crude mass was stirred with ice cold water and extracted with dichloromethane (50 ml×2). The combined organic layer was evaporated under vacuum to afford the title compound in 0.8 gm quantity (85%) as oil.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[C:7]([O:11][CH3:12])(=[O:10])[CH:8]=[CH2:9]>ClCCl>[N:1]1([CH2:9][CH2:8][C:7]([O:11][CH3:12])=[O:10])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: C=CC(=O)OC
Reactant: C1COCCN1
Solvent: ClCCl
Product: COC(=O)CCN1CCOCC1
Reaction time: 72 h
Yield: 98.4 %

Procedure:
A solution of 4.9 ml (56 mmol) of morpholine in 50 ml of dichloromethane was treated dropwise with 5.0 ml (56 mmol) of methyl acrylate. The resulting solution was allowed to stand at ambient temperature for 3 days, after which it was concentrated in vacuo to an oil. Chromatography on silica gel using 0.5% methanol/2% isopropylamine in chloroform provided 9.54 g (99%) of the desired compound as a colorless liquid.
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15]2[CH:20]=[C:19]([NH:21][CH:22]3[CH2:27][CH2:26][CH2:25][NH:24][CH2:23]3)[N:18]=[CH:17][N:16]=2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:28](Cl)(=[O:31])[CH:29]=[CH2:30]>CN1C(=O)CCC1>[O:1]([C:8]1[CH:9]=[CH:10][C:11]([NH:14][C:15]2[N:16]=[CH:17][N:18]=[C:19]([NH:21][CH:22]3[CH2:27][CH2:26][CH2:25][N:24]([C:28](=[O:31])[CH:29]=[CH2:30])[CH2:23]3)[CH:20]=2)=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1ccc(Oc2ccc(Nc3cc(NC4CCCNC4)ncn3)cc2)cc1
Reactant: C=CC(=O)Cl
Solvent: CN1CCCC1=O
Product: C=CC(=O)N1CCCC(Nc2cc(Nc3ccc(Oc4ccccc4)cc3)ncn2)C1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
To a stirred solution of N4-(4-phenoxyphenyl)-N6-(piperidin-3-yl)pyrimidine-4,6-diamine (0.025 g, 0.069 mmol) in NMP (0.5 mL) at 0° C. was added acryloyl chloride (0.007 g, 0.083 mmol), and the reaction mixture was stirred at 0° C. for 5 min. The reaction mixture was quenched by adding 10% NaHCO3 solution and it was extracted with EtOAc (2×5 mL). The combined EtOAc extract was washed with water (3 mL) and brine (3 mL), was dried over Na2SO4 and was concentrated under reduced pressure. The residue obtained was purified by column chromatography (SiO2, 230-400, chloroform/methanol: 98/2) to give 1-(3-(6-(4-phenoxyphenylamino)pyrimidin-4-ylamino)piperidin-1-yl)prop-2-en-1one (I-86) as an off white solid. 1H NMR (MeOD) δ ppm: 1.5-1.75 (m, 2H), 1.80-2.00 (m, 1H), 2.0-2.20 (m, 1H), 2.70-2.90 (m, 1H), 2.90-3.05 (m, 1H), 3.80-4.00 (m, 2H), 4.30-4.45 (m, 1H), 5.65 & 5.75 (d, J=10.8 Hz & d, J=10.8 Hz respectively, together 1H), 5.81 (d, J=10.8 Hz, 1H), 6.14 & 6.18 (d, J=17.2 Hz & d, J=19.2 Hz respectively, together 1H), 6.60-6.70 & 6.70-6.85 (m, together 1H), 6.97-7.00 (m, 4H), 7.04 (t, J=7.6 Hz, 1H), 7.32-7.38 (m, 4H), 8.04 & 8.07 (s, together 1H); LCMS: m/e 416.1 (M+1).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]([C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH:21]=[C:20]([C@H:22]4[CH2:26][CH2:25][CH2:24][NH:23]4)[N:19]=[C:18]3[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[C:33]([F:36])([F:35])[F:34])=[CH:13][CH:12]=2)[CH:8]=[CH:9][CH:10]=1)(=[O:4])=[O:3].N1C=CC=CC=1.[C:43](Cl)(=[O:45])[CH3:44]>C1COCC1>[CH3:1][S:2]([C:5]1[CH:6]=[C:7]([C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH:21]=[C:20]([C@H:22]4[CH2:26][CH2:25][CH2:24][N:23]4[C:43](=[O:45])[CH3:44])[N:19]=[C:18]3[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[C:33]([F:36])([F:34])[F:35])=[CH:13][CH:12]=2)[CH:8]=[CH:9][CH:10]=1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)c1cccc(-c2ccc(-n3cc([C@H]4CCCN4)nc3-c3ccccc3C(F)(F)F)cc2)c1
Reactant: CC(=O)Cl
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CC(=O)N1CCC[C@@H]1c1cn(-c2ccc(-c3cccc(S(C)(=O)=O)c3)cc2)c(-c2ccccc2C(F)(F)F)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Into an 8 mL vial was weighed 26.8 mg (52 μmol) of 1-(3′-(methylsulfonyl)biphenyl-4-yl)-4-((R)-pyrrolidin-2-yl)-2-(2-(trifluoromethyl)phenyl)-1H-imidazole. The vial was charged with 0.5 mL of THF, followed by 15 μL (185 μmol) of pyridine, and 7 μL (98 μmol) of acetyl chloride. After stirring for 30 minutes at ambient temperature, LC/MS analysis of the reaction showed complete conversion to product. The reaction was quenched by addition of a small amount of water. The reaction solution was directly injected into the reverse phase preparative HPLC and eluted with acetonitrile/water. (Phenomenex Axia Gemini C18 30×100 mm 5 μm, A=H2O with 0.1% trifluoroacetic acid, B=acetonitrile with 0.1% trifluoroacetic acid, 17 minute gradient from 10% B to 100% B at 35 mL/minute). Product fractions were combined, made basic by the addition of sat. NaHCO3, and concentrated in vacuo to remove the acetonitrile. The resulting basic aqueous was extracted with CH2Cl2 (3×), and the organics were dried over Na2SO4, filtered and concentrated in vacuo. The resulting 1-((2R)-2-(1-(3′-(methylsulfonyl)biphenyl-4-yl)-2-(2-(trifluoromethyl)phenyl)-1H-imidazol-4-yl)pyrrolidin-1-yl)ethanone was isolated as a white powder, yield 20.2 mg (70%); 1H NMR (400 MHz, CDCl3): δ 8.10-8.07 (m, 1H), 7.95-7.90 (m, 1H), 7.83-7.79 (m, 1H), 7.77-7.72 (m, 1H), 7.67-7.61 (m, 1H), 7.56-7.42 (m, 4H), 7.38-7.34 (m, 0.6H), 7.30-7.26 (m, 0.4H), 7.20-7.16 (m, 2.4H), 7.05-7.04 (m, 0.6H), 5.34-5.31 (m, 0.4H), 5.08-5.05 (m, 0.6H), 3.78-3.67 (m, 1H), 3.63-3.49 (m, 1H), 3.09 (s, 1.8H), 3.08 (s, 1.2H), 2.52-2.46 (m, 0.4H), 2.36-2.26 (m, 1.6H), 2.14 (s, 1.8H), 2.12 (s, 1.2H), 2.08-1.95 (m, 2H); MS (ES): 554.3 [M+H]+.
Reaction SMILES: CN(C)[CH:3]=[O:4].P(Cl)(Cl)(Cl)=O.[CH3:11][C:12]1[C:16]([CH3:17])=[CH:15][NH:14][CH:13]=1>ClCCCl>[CH3:11][C:12]1[C:16]([CH3:17])=[CH:15][NH:14][C:13]=1[CH:3]=[O:4]
Reactant: CN(C)C=O
Reactant: Cc1c[nH]cc1C
Solvent: ClCCCl
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1c[nH]c(C=O)c1C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 49.5 %

Procedure:
To a solution of 0.92 mL (12 mmoles) of N,N-dimethylformamide in 10 mL of 1,2-dichloroethane was added dropwise 1.0 mL (12 mmoles) of phosphorus oxychloride at 0° C. The ice-bath was removed and the reaction mixture was further stirred for 30 min. 3,4-Dimethylpyrrole (960.0 mg, 10 mmoles) was added to the above solution portionwise and the reaction mixture was stirred at 50° C. for 5 h. The reaction mixture was poured into ice-cold 1N sodium hydroxide solution (pH=9 after mixing) and the resulting mixture was stirred at room temperature for 1 h. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with brine until pH=7, dried over anhydrous sodium sulfate and evaporated. The residue was chromatographed on a silica gel column eluting with a solvent mixture of ethyl acetate and hexane to afford 610 mg (50%) of the title compound.
Reaction SMILES: [C:1]1([C:7]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([CH2:17][N:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)[CH2:8][NH:9]C(=O)OC(C)(C)C)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.FC(F)(F)C(O)=O>ClCCl>[C:1]1([C:7]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([CH2:17][N:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)[CH2:8][NH2:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(C)OC(=O)NCC(CN1CCCCC1)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NCC(CN1CCCCC1)(c1ccccc1)c1ccccc1

Procedure:
The title material was obtained by treating a solution of tert-butyl 2,2-diphenyl-3-(piperidin-1-yl)propylcarbamate (0.109 g) in dichloromethane (5 mL) with trifluoroacetic acid (1 mL) at 23° C. for 45 minutes. The reaction was then concentrated to dryness and the residue was used as such in the next reaction.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13](I)[CH:12]=[CH:11][C:10]=1[N:16]1[S:20](=[O:22])(=[O:21])[N:19]([CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])[C:18](=[O:29])[CH2:17]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:30][C:31]1([CH3:39])[C:35](=[O:36])[O:34][C:33]([CH:37]=[CH2:38])=[N:32]1>>[CH2:1]([O:8][C:9]1[CH:14]=[C:13](/[CH:38]=[CH:37]/[C:33]2[O:34][C:35](=[O:36])[C:31]([CH3:39])([CH3:30])[N:32]=2)[CH:12]=[CH:11][C:10]=1[N:16]1[S:20](=[O:22])(=[O:21])[N:19]([CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])[C:18](=[O:29])[CH2:17]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=CC1=NC(C)(C)C(=O)O1
Reactant: C[Si](C)(C)CCN1C(=O)CN(c2ccc(I)cc2OCc2ccccc2)S1(=O)=O
Product: CC1(C)N=C(/C=C/c2ccc(N3CC(=O)N(CC[Si](C)(C)C)S3(=O)=O)c(OCc3ccccc3)c2)OC1=O

Procedure:
The title compound is prepared using 5-(2-benzyloxy-4-iodophenyl)-1,1-dioxo-2-(2-trimethylsilanylethyl)-1,2,5-thiadiazolidin-3-one and 4,4-dimethyl-2-vinyl-4H-oxazol-5-one analogous to Example 108, step A.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][N:5]2[CH:11]=1.[I:12]N1C(=O)CCC1=O.C(Cl)(Cl)Cl>CC#N>[Cl:1][C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][N:5]2[C:11]=1[I:12]
Reactant: O=C1CCC(=O)N1I
Reactant: Clc1ccc2nc(Cl)cn2c1
Solvent: ClC(Cl)Cl
Solvent: CC#N
Product: Clc1ccc2nc(Cl)c(I)n2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 80 %

Procedure:
To a suspension of 2,6-dichloro-imidazo[1,2-a]pyridine, compound 12 (4.0 g, 0.02 mol) in dry CH3CN (50 mL) was added N-iodosuccinimide (NIS, 5.3 g, 0.024 mol) and the mixture stirred at room temperature for 1 h. The reaction mixture was heated at reflux for 10 min and then cooled to room temperature. Chloroform (200 mL) was added to the reaction mixture and the organic phase washed successively with 10% NaOH (100 mL), sodium thiosulfate (100 mL) and water (2×100 mL) then dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure. The resulting solid was suspended in MeOH and filtered to give 5.0 g (80%) of compound 19 as white crystalline solid.