Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][C:5]([O:6][C:7]2[CH:8]=[C:9]([NH:13][CH2:14][CH:15]([OH:20])[C:16]([F:19])([F:18])[F:17])[CH:10]=[CH:11][CH:12]=2)=[CH:4][C:3]=1[CH2:23][CH3:24].[CH:25]1([CH:31]=O)[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>O1CCCC1>[Cl:1][C:2]1[CH:22]=[CH:21][C:5]([O:6][C:7]2[CH:8]=[C:9]([N:13]([CH2:31][CH:25]3[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]3)[CH2:14][CH:15]([OH:20])[C:16]([F:18])([F:19])[F:17])[CH:10]=[CH:11][CH:12]=2)=[CH:4][C:3]=1[CH2:23][CH3:24]
Reactant: O=CC1CCCCC1
Reactant: CCc1cc(Oc2cccc(NCC(O)C(F)(F)F)c2)ccc1Cl
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CCc1cc(Oc2cccc(N(CC3CCCCC3)CC(O)C(F)(F)F)c2)ccc1Cl
Temperature: 25 °C
Reaction time: 18 h
Yield: 61 %

Procedure:
The 3-[[3-(4-chloro-3-ethylphenoxy)phenyl]amino]-1,1,1-trifluoro-2-propanol product from EX-18C was dissolved in 12 mL of tetrahydrofuran. To this stirred solution was added cyclohexanecarboxaldehyde (0.032 g, 0.285 mmol), followed by sodium tri-acetoxyborohydride (0.079 g, 0.370 mmol and concentrated acetic acid (0.020 g, 0.325 mmol). The resulting mixture was stirred at room temperature for 18 h. Additional cyclohexanecarboxaldehyde (0.032 g, 0.285 mmol) was added and the mixture was allowed to stir at room temperature for another 18 h. The reaction was quenched with saturated sodium bicarbonate and extracted with methylene chloride. The organic layers were combined, dried over MgSO4 and concentrated to an orange/brown oil. The crude product was purified by flash column chromatography on silica gel eluting with 1:4 ethyl acetate in hexane to give 0.080 g (61%) of the desired 3-[[3-(4-chloro-3-ethylphenoxy)phenyl][3-cyclohexylmethyl]amino]-1,1,1-trifluoro-2-propanol product as a yellow-orange oil (>95% pure by HPLC). HRMS calcd.: 456.1917 [M+H]+, found: 456.1942. 1H NMR (CDCl3) δ 0.82-1.01 (m, 2H), 1.22-1.27 (m, 3H), 1.73-1.76 (m, 5H), 2.74 (dd, 2H), 3.15 (dd, 2H), 3.23 (dd, 1H), 3.52 (m, 1H), 3.80 (dd, 1H), 4.28 (m, 1H), 6.34 (d, 2H), 6.42 (d, 1H), 6.83 (dd, 1H), 6.98 (d, 1H), 7.19 (t, 1H), 7.29 (d, 1H). 19F NMR (CDCl3) δ−79.06 (d, 3F).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([Sn](C)(C)C)[CH:5]=[C:4]([CH3:12])[N:3]=1.Br[C:14]1[CH:23]=[C:22]2[C:17]([C:18](=[O:32])[C:19]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:20][N:21]2[CH:24]2[CH2:26][CH2:25]2)=[CH:16][C:15]=1[F:33]>O1CCOCC1.O>[CH:24]1([N:21]2[C:22]3[C:17](=[CH:16][C:15]([F:33])=[C:14]([C:6]4[CH:7]=[C:2]([CH3:1])[N:3]=[C:4]([CH3:12])[CH:5]=4)[CH:23]=3)[C:18](=[O:32])[C:19]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:20]2)[CH2:25][CH2:26]1
Reactant: CCOC(=O)c1cn(C2CC2)c2cc(Br)c(F)cc2c1=O
Reactant: Cc1cc([Sn](C)(C)C)cc(C)n1
Solvent: O
Solvent: C1COCCO1
Product: CCOC(=O)c1cn(C2CC2)c2cc(-c3cc(C)nc(C)c3)c(F)cc2c1=O
Yield: 72.1 %

Procedure:
2,6-dimethyl-4-(trimethylstannyl)pyridine (2.6 g) in dioxane (6 ml) is slowly dropped into a stirred mixture of ethyl 7-bromo-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylate (3.1 g), dioxane (55 ml) and hexamethylenphosphoramide (2.6 ml) kept under argon. To the stirred mixture, dichlorobis (triphenylphosphine) palladium (0.4 g) is added. The reaction mixture is heated under reflux for 24 hours. After cooling it is poured in water (200 ml) and repeatedly extracted with dichloromethane. The organic extracts are dried and evaporated to dryness. The residue, after trituration with ethyl ether, gives ethyl 1-cyclopropyl-7-(2,6-dimethyl-4-pyridinyl)-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylate (2.4 g) m.p. 196°-199° C.
Reaction SMILES: [ClH:1].Cl.OC1([C:10]2(O)[CH:15]=[CH:14][CH:13]=[CH:12][C:11]2([CH2:21][CH2:22][N:23]2[CH2:28][CH2:27][N:26]([CH3:29])[CH2:25][CH2:24]2)[O:16]C(F)(F)F)CCCCC1.Cl.Cl.OC1(C([C:48]2[CH:53]=[CH:52][C:51]([OH:54])=[C:50]([O:55][C:56]([F:59])([F:58])[F:57])[CH:49]=2)CN2CCNCC2)CCCCC1>>[ClH:1].[ClH:1].[OH:16][C:11]1([CH:21]([C:48]2[CH:53]=[CH:52][C:51]([OH:54])=[C:50]([O:55][C:56]([F:57])([F:59])[F:58])[CH:49]=2)[CH2:22][N:23]2[CH2:24][CH2:25][N:26]([CH3:29])[CH2:27][CH2:28]2)[CH2:10][CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: Oc1ccc(C(CN2CCNCC2)C2(O)CCCCC2)cc1OC(F)(F)F
Reactant: CN1CCN(CCC2(OC(F)(F)F)C=CC=CC2(O)C2(O)CCCCC2)CC1
Agent: Cl
Product: CN1CCN(CC(c2ccc(O)c(OC(F)(F)F)c2)C2(O)CCCCC2)CC1

Procedure:
In an analogous manner to Example 24, 4-[1-(1-hydroxycyclohexyl)-2-(4-methylpiperazin-1-ylethyl]-2-(trifluoromethoxy)phenol dihydrochloride was prepared from 4-[1-(1-hydroxycyclohexyl)-2-piperazin-1-ylethyl]-2-(trifluoromethoxy)phenol dihydrochloride (see Example 400). MS (ESI) m/z 403; HRMS: calcd for C20H29F3N2O3+H+, 403.22030; found (ESI, [M+H]+), 403.2201.
Reaction SMILES: Cl([O-])(=O)(=O)=O.[CH2:6]([CH:8]1[C:17]2[C:16]3[NH:18][C:19]4[C:24]([C:15]=3[CH2:14][CH2:13][N+:12]=2[CH2:11][CH2:10][CH2:9]1)=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH3:7].ClCCl.[OH-].[Na+]>O>[CH2:6]([C:8]1([CH:10]([CH3:9])[C:11]#[N:12])[CH:17]2[N:12]([CH2:13][CH2:14][C:15]3[C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[NH:18][C:16]=32)[CH2:11][CH2:10][CH2:9]1)[CH3:7]
Reactant: CCC1CCC[N+]2=C1c1[nH]c3ccccc3c1CC2
Agent: [Na+]
Agent: [O-][Cl+3]([O-])([O-])[O-]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: CCC1(C(C)C#N)CCCN2CCc3c([nH]c4ccccc34)C21
Reaction time: 0.17 h
Yield: 79.4 %

Procedure:
10.0 g (28.5 mmoles) of 1-ethyl-2,3,4,6,7,12-hexahydro-indolo(2,3-a)quinolizinium perchlorate are dissolved in 100 ml. of dichloromethane, and 75 ml. of distilled water and 20 ml. of a 2 n aqueous sodium hydroxide solution are added to the stirred soltion under argon atmosphere. The reaction mixture is stirred for 10 minutes, thereafter the separated organic phase is isolated and dried over anhydrous potassium carbonate. The drying agent is filtered off, 10 ml. of freshly distilled acrylonitrile are added to the filtrate, the mixture is flushed with argon, and it is allowed to stand at room temperature. The colour of the mixture turns deeper. After 2 days of standing the mixture is evaporated in vacuo at a bath temperature of maximum 40° to 50° C under argon atmosphere, and the dark red, oily residue is triturated with 5 ml. of methanol. The obtained orange red crystals, weighing 8.10 g., are filtered off, and recrystallized from 15-fold volume of methanol. 7.30 g. (79.4%) of (1-ethyl-1,2,3,4,6,7-hexahydro-12H-indolo[2,3-a]quinolizin-1-yl)-propionitrile are obtained: m.p.: 122°-123° C.
Reaction SMILES: [OH:1][C:2]1[C:3]([O:17][CH3:18])=[CH:4][C:5]2[O:10][C:9](=[O:11])[C:8]([CH2:12][CH2:13][OH:14])=[C:7]([CH3:15])[C:6]=2[CH:16]=1.CI.[C:21](=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[OH:14][CH2:13][CH2:12][C:8]1[C:9](=[O:11])[O:10][C:5]2[CH:4]=[C:3]([O:17][CH3:18])[C:2]([O:1][CH3:21])=[CH:16][C:6]=2[C:7]=1[CH3:15]
Reactant: COc1cc2oc(=O)c(CCO)c(C)c2cc1O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: COc1cc2oc(=O)c(CCO)c(C)c2cc1OC

Procedure:
40.0 g (160 mmol) of 6-hydroxy-3-(2-hydroxyethyl)-7-methoxy-4-methyl-2H-1-benzopyran-2-one (Example 41), 45.4 g (320 mmol) of methyl iodide and 66.3 g (480 mmol) of potassium carbonate in 500 ml of DMF are stirred for 22 hours at 60° to 80° C. The reaction solution is evaporated, extracted with chloroform, and the organic phase is washed with dilute sodium hydroxide and with water, dried with Na2SO4, and re-evaporated. Yield 31.6 g (75%); m.p. 184°-187° C. (from isopropanol).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4](C)[CH:5]=[CH:6][C:7]=1[N+]([O-])=O.[NH2:12][C:13]1[CH:21]=[CH:20][CH:19]=[CH:18][C:14]=1[C:15]([OH:17])=[O:16]>>[C:2]1([NH:12][C:13]2[C:14](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:15]([OH:17])=[O:16])[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccc([N+](=O)[O-])c(Br)c1
Reactant: Nc1ccccc1C(=O)O
Product: O=C(O)c1ccccc1Nc1ccccc1

Procedure:
As shown in Scheme 7, coupling of 3-bromo-4-nitrotoluene with 2-amino-benzoic acid via an Ullmann reaction yields an N-phenyl-anthranilic acid. After protection of the acid with 2-amino-2-methyl-1-propanol, oxidation affords the corresponding aldehyde. Addition of vinyl magnesium bromide and deprotection provides the N-phenyl-anthranilic acid containing a latent Michael acceptor. ##STR15## Figure legends
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:19].Cl.[N:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[CH2:27][C:28](O)=[O:29]>>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([C:10]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3](=[O:19])[N:2]([NH:1][C:28](=[O:29])[CH2:27][C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][N:21]=3)[N:11]=2)=[CH:13][CH:14]=1
Reactant: Nn1nc(-c2ccc(Cl)cc2)c2ccccc2c1=O
Reactant: O=C(O)Cc1ccccn1
Agent: Cl
Product: O=C(Cc1ccccn1)Nn1nc(-c2ccc(Cl)cc2)c2ccccc2c1=O

Procedure:
The product of Example 86A and 2-(pyridin-2-yl)acetic acid hydrochloride were treated using a method similar to that described in Example 57 to give the title compound. 1H NMR (500 MHz, DMSO-d6/Deuterium Oxide) δ ppm 8.71-8.73 (m, 1H), 8.41-8.43 (m, 1H), 8.22 (td, J=7.8, 1.7 Hz, 1H), 7.94-8.06 (m, 2H), 7.82 (d, J=7.9 Hz, 1H), 7.73-7.75 (m, 1H), 7.69 (d, J=6.8 Hz, 1H), 7.59-7.67 (m, 4H); MS (APCI+) M/Z 391 (M+H)+.
Reaction SMILES: [C:1]([C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[C:9]([N+:14]([O-:16])=[O:15])[CH:10]=2)[N:5]=1)([OH:3])=[O:2].[C:17]1(P(C2C=CC=CC=2)C2C=CC=CC=2)[CH:22]=CC=C[CH:18]=1.C(O)C=C.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[CH2:22]([O:2][C:1]([C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[C:9]([N+:14]([O-:16])=[O:15])[CH:10]=2)[N:5]=1)=[O:3])[CH:17]=[CH2:18]
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: O=C(O)c1ccc2cc([N+](=O)[O-])ccc2n1
Agent: CCOC(=O)/N=N/C(=O)OCC
Solvent: C1CCOC1
Solvent: C=CCO
Product: C=CCOC(=O)c1ccc2cc([N+](=O)[O-])ccc2n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 67.6 %

Procedure:
To a solution of 2-carboxy-6-nitroquinoline (1.5 g; 6.8 mM) in THF (30 ml) was added triphenylphosphine (2.7 g; 10.2 mM), allyl alcohol (0.7 ml; 10.2 mM) and DEAD (1.63 ml; 10.2 mM). After stirring at ambient temperature for 30 minutes, the mixture was extracted with ethyl acetate and purified by subjecting to flash chromatography, eluting with ethyl acetate/petroleum ether (40/60) to give 2-allyloxycarbonyl-6-nitroquinoline (1.2 g; 71%).
Reaction SMILES: [OH:1][CH:2]1[CH2:11][CH2:10][C:9]2[CH:5]([CH2:6][CH2:7][C:8]=2[CH3:12])[C:4](=[CH2:13])[CH2:3]1.[H][H]>C(O)C.[Pt]=O>[OH:1][CH:2]1[CH2:11][CH2:10][C:9]2[CH:5]([CH2:6][CH2:7][C:8]=2[CH3:12])[CH:4]([CH3:13])[CH2:3]1
Reactant: C=C1CC(O)CCC2=C(C)CCC12
Reactant: [H][H]
Agent: O=[Pt]
Solvent: CCO
Product: CC1=C2CCC(O)CC(C)C2CC1
Yield: 60.1 %

Procedure:
500 mg of platinum oxide were pre-hydrogenated in 300 ml of ethanol. After addition of 2.14 g of 6-hydroxy-1-methyl-4-methylen-2,3,3a,4,5,6,7,8-octahydroazulene, the mixture was hydrogenated until hydrogen was no longer taken up. The reaction mixture was filtered, the filtrate evaporated and the crude product distilled under reduced pressure in a bulb-tube. There were obtained 1.3 g of pure 6-hydroxy-1,4-dimethyl-2,3,3a,4,5,6,7,8-octahydroazulene; b.p.0.001 ca 85°; IR(film):νmax 3380, 1460, 1440, 1095, 1078, 1035/30, 985/75, 940 cm-1. The substance has a woody, flowery, fresh green odour.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[N:10]=[CH:9][N:8]([CH2:11][C:12]3[CH:28]=[CH:27][C:15]4[N:16]=[C:17]([NH:19][C@@H:20]5[CH2:25][CH2:24][CH2:23][CH2:22][C@@H:21]5O)[S:18][C:14]=4[CH:13]=3)[C:5]2=[N:6][CH:7]=1.CCN(C(C)C)C(C)C.S(Cl)([Cl:41])(=O)=O>C(Cl)Cl>[Cl:41][C@@H:21]1[CH2:22][CH2:23][CH2:24][CH2:25][C@H:20]1[NH:19][C:17]1[S:18][C:14]2[CH:13]=[C:12]([CH2:11][N:8]3[C:5]4=[N:6][CH:7]=[C:2]([F:1])[CH:3]=[C:4]4[N:10]=[CH:9]3)[CH:28]=[CH:27][C:15]=2[N:16]=1
Reactant: O=S(=O)(Cl)Cl
Reactant: O[C@H]1CCCC[C@H]1Nc1nc2ccc(Cn3cnc4cc(F)cnc43)cc2s1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Fc1cnc2c(c1)ncn2Cc1ccc2nc(N[C@@H]3CCCC[C@H]3Cl)sc2c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 10 %

Procedure:
To a stirred mixture of (1S,2R)-2-((6-((6-fluoro-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol (282 mg, 0.7 mmol) from Example 162, DIEA (247 μL, 1.4 mmol), and CH2Cl2 (15 mL) at 0° C. under argon was added sulfuryl chloride (142 mg, 2.0 mmol). The mixture was warmed to rt and stirred for 15 h, and then stirred at 60° C. for 15 h. The mixture was cooled to rt and purified directly by reverse-phase preparative HPLC using a mixture of water (5% CH3CN, 0.05% HCOOH) and CH3CN (0.05% HCOOH) as the mobile phase and Varian Pursuit XRs C18 column as the stationary phase. The product was further purified by triturating in CH2Cl2 (5 mL) to afford N-((1R,2R)-2-chlorocyclohexyl)-6-((6-fluoro-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-amine (29 mg, 10%) as a white solid. 1H NMR (500 MHz, CDCl3) δ 8.68 (s, 1H), 8.41 (s, 1H), 8.24 (d, J=8.4 Hz, 1H), 8.07 (dd, J=2.6, 9.5 Hz, 1H), 7.68 (s, 1H), 7.33 (d, J=8.4 Hz, 1H), 7.24 (dd, J=1.4, 8.2 Hz, 1H), 5.48 (s, 2H), 4.02 (m, 1H), 3.87 (m, 1H), 2.20 (m, 1H), 2.07 (m, 1H), 1.63-1.75 (m, 3H), 1.29-1.41 (m, 3H); LCMS (ESI) m/z 416 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][CH:21]=1)[C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]([F:18])([F:17])[F:16])=[CH:10][CH:9]=1)=[O:6].CC1(C)C(C)(C)OB([C:30]2[S:34][C:33]([CH2:35][N:36]3[CH2:40][CH2:39][CH2:38][CH2:37]3)=[CH:32][CH:31]=2)O1.O>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.COCCOC>[N:36]1([CH2:35][C:33]2[S:34][C:30]([C:2]3[CH:3]=[C:4]([CH:19]=[CH:20][CH:21]=3)[C:5]([NH:7][C:8]3[CH:13]=[CH:12][C:11]([O:14][C:15]([F:18])([F:17])[F:16])=[CH:10][CH:9]=3)=[O:6])=[CH:31][CH:32]=2)[CH2:37][CH2:38][CH2:39][CH2:40]1
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cccc(Br)c1
Reactant: CC1(C)OB(c2ccc(CN3CCCC3)s2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: COCCOC
Solvent: O
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cccc(-c2ccc(CN3CCCC3)s2)c1

Procedure:
3-Bromo-N-(4-(trifluoromethoxy)phenyl)benzamide (Stage 3.1, 50 mg, 0.139 mmol), 1-((5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiophen-2-yl)methyl)pyrrolidine (0.180 mmol), (Ph3P)4Pd (8 mg, 6.94 μmol) 2 M Na2CO3 (0.104 mL, 0.208 mmol), water (0.8 mL) and DME (2.4 mL) were added to a vial, which was sealed and subjected to MW irradiation at 150° C. for 600 sec (very high absorbance). The RM was filtered through a PL-Thiol MP SPE cartridge (StratoSpheres™, 6 mL), the cartridge was washed with MeOH (10 mL) and the combined filtrates were evaporated under reduced pressure to give the crude product was purified by preparative HPLC to afford the title compound. UPLC-MS (Condition 6) tR=1.92 min, m/z=447.4 [M+H]+.
Reaction SMILES: Cl[C:2]1[C:3]2[CH:11]=[C:10]([CH:12]3[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]3)[S:9][C:4]=2[N:5]=[C:6]([CH3:8])[N:7]=1.C1N2CC[N:20](CC2)[CH2:19]1.CS(C)=O.[C-]#N.[K+]>O>[CH:12]1([C:10]2[S:9][C:4]3[N:5]=[C:6]([CH3:8])[N:7]=[C:2]([C:19]#[N:20])[C:3]=3[CH:11]=2)[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: Cc1nc(Cl)c2cc(C3CCCCC3)sc2n1
Reactant: C1CN2CCN1CC2
Agent: [C-]#N
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: Cc1nc(C#N)c2cc(C3CCCCC3)sc2n1
Temperature: 25 °C
Reaction time: 15 h
Yield: 860.8 %

Procedure:
To a mixture of 4-chloro-6-cyclohexyl-2-methylthieno[2,3-d]pyrimidine (27.3 g), DABCO (1.2 g) and DMSO (150 mL) was slowly added an aqueous solution (14 mL) of KCN (8 g), followed by stirring at room temperature for 15 hours. To the reaction mixture was added water (150 mL) under ice-cooling, followed by stirring. The precipitate was collected by filtration and dissolved in chloroform. To the organic layer were added MgSO4, activated carbon (2 g), and basic silica gel (100 mL), followed by stirring. The mixture was filtered through Celite and then concentrated under reduced pressure to obtain 6-cyclohexyl-2-methylthieno[2,3-d]pyrimidine-4-carbonitrile (23.7 g).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)[CH:8]=1)[NH2:5].Cl[C:16]1[N:21]=[C:20]([O:22][CH:23]2[CH2:28][CH2:27][N:26]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:25][CH2:24]2)[CH:19]=[CH:18][N:17]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>O1CCOCC1.O.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:1][C:2]1[CH:3]=[C:4]([NH:5][C:16]2[N:21]=[C:20]([O:22][CH:23]3[CH2:24][CH2:25][N:26]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:27][CH2:28]3)[CH:19]=[CH:18][N:17]=2)[CH:6]=[C:7]([C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)[CH:8]=1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccnc(Cl)n2)CC1
Reactant: Cc1cc(N)cc(-c2cccnc2)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: C1COCCO1
Solvent: O
Product: Cc1cc(Nc2nccc(OC3CCN(C(=O)OC(C)(C)C)CC3)n2)cc(-c2cccnc2)c1
Temperature: 75 °C

Procedure:
3-Methyl-5-(pyridin-3-yl)aniline (50.7 mg, 0.275 mmol) was added a solution of tert-Butyl 4-[(2-chloropyrimidin-4-yl)oxy]piperidine-1-carboxylate (72.0 mg, 0.229 mmol) in dioxane (486 μL). The reaction mixture was flushed and purged with Ar(g) followed by the addition of Pd(OAc)2 (5.15 mg, 0.023 mmol) and Xantphos (19.9 mg, 0.034 mmol). The reaction was heated to 75° C. overnight and then cooled to room temperature. The reaction mixture was diluted with water and extracted with dichloromethane. The organic was dried over sodium sulfate and was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (10% MeOH in DCM:hexanes, 10:90 to 50:50) to yield tert-butyl 4-[(2-{[3-methyl-5-(pyridin-3-yl)phenyl]amino}pyrimidin-4-yl)oxy]piperidine-1-carboxylate.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[O:10][CH3:11].[Br:12][CH2:13][CH2:14][CH2:15]Br>C(#N)C>[Br:12][CH2:13][CH2:14][CH2:15][O:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[O:10][CH3:11]
Reactant: COc1cc(C#N)ccc1O
Reactant: BrCCCBr
Solvent: CC#N
Product: COc1cc(C#N)ccc1OCCCBr
Reaction time: 8 h

Procedure:
A mixture of 4-hydroxy-3-methoxybenzonitrile (7.5 g, 50 mmol), K2 CO3 (12.5 g), and 1,3-dibromopropane (15 g, 75 mmol) in acetonitrile (100 ml) was heated at reflux for 3 hours and left standing at room temperature overnight. The solvent of the reaction was removed on a rotary evaporator, and the crude solid was extracted into methylene chloride (500 ml). The insolubles were filtered off. The dichloromethane solution was concentrated and the material was purified on a flash chromatography column (SiO2, 105 g; eluted with 2:3 dichloromethane:hexane, and then with dichloromethane). The desired product thus purified weighed 7.74 g (52%). Recrystallization twice from ethanol gave analytically pure 4-(3-bromopropoxy)-3-methoxybenzonitrile, m.p.=99°-101° C.
Reaction SMILES: C1(C(C2C=CC=CC=2)(C2C=CC=CC=2)[N:8]2[C:12]3[CH:13]=[CH:14][C:15]([OH:17])=[CH:16][C:11]=3[N:10]=[CH:9]2)C=CC=CC=1.C1(C(C2C=CC=CC=2)(C2C=CC=CC=2)N2C3C=C(O)C=CC=3N=C2)C=CC=CC=1.F[C:60]1[CH:67]=[CH:66][C:63]([CH:64]=[O:65])=[CH:62][C:61]=1[O:68][CH3:69].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O.O>[NH:8]1[C:12]2[CH:13]=[CH:14][C:15]([O:17][C:60]3[CH:67]=[CH:66][C:63]([CH:64]=[O:65])=[CH:62][C:61]=3[O:68][CH3:69])=[CH:16][C:11]=2[N:10]=[CH:9]1
Reactant: COc1cc(C=O)ccc1F
Reactant: Oc1ccc2c(c1)ncn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: Oc1ccc2ncn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c2c1
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(C=O)ccc1Oc1ccc2[nH]cnc2c1
Reaction time: 96 h

Procedure:
A mixture of 1-(triphenylmethyl)-1H-benzimidazol-5-ol and 1-(triphenylmethyl)-1H-benzimidazol-6-ol (750 mg, 2.0 mmol), 4-fluoro-3-(methyloxy)benzaldehyde (461 mg, 3.0 mmol) and cesium carbonate (972 mg, 3.0 mmol) were heated in dimethylformamide at 80 degrees centigrade for 2 hours. The reaction was diluted with water and extracted twice with ethyl acetate. The organic layers were washed with brine, dried over MgSO4, concentrated and dried under vacuum for approximately 18 hours. The residue was dissolved in 15 mL of tetrahydrofuran and stirred with 5 mL or 4N HCl in dioxane for 4 days. The reaction was concentrated and purified by preparative HPLC. Pure fractions were diluted with 1N NaOH to make basic and then extracted twice with ethyl acetate. The organic layers were dried over MgSO4 and concentrated to give 4-(1H-benzimidazol-5-yloxy)-3-(methyloxy)benzaldehyde. (M+1) 269.0, 1.34 min (LC/MS method B)
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]#[N:13])=[C:5]2[NH:14][C:15]1[CH:20]=[CH:19][C:18]([S:21][C:22]2[N:23]([CH3:27])[CH:24]=[CH:25][N:26]=2)=[C:17]([Cl:28])[CH:16]=1.[CH2:29]1C[O:32][CH2:31][CH2:30]1.C(N(CC)CC)C.C(Cl)(=O)C=C>CN(C=O)C>[Cl:28][C:17]1[CH:16]=[C:15]([NH:14][C:5]2[C:4]3[C:9](=[CH:10][CH:11]=[C:2]([NH:1][C:31](=[O:32])[CH:30]=[CH2:29])[CH:3]=3)[N:8]=[CH:7][C:6]=2[C:12]#[N:13])[CH:20]=[CH:19][C:18]=1[S:21][C:22]1[N:23]([CH3:27])[CH:24]=[CH:25][N:26]=1
Reactant: C1CCOC1
Reactant: Cn1ccnc1Sc1ccc(Nc2c(C#N)cnc3ccc(N)cc23)cc1Cl
Agent: C=CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C=CC(=O)Nc1ccc2ncc(C#N)c(Nc3ccc(Sc4nccn4C)c(Cl)c3)c2c1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
Dissolved most of 1.00 g (2.46 mmol) 6-amino-4-[3-chloro-4-(1-methyl-1H-imidazol-2-ylsulfanyl)-phenylamino]-quinoline-3-carbonitrile in 3.5 ml hot DMF, added 12 ml THF and chilled to 0° C. Added 377 μl triethyl amine and 225 μl (2.70 mmol) acryloyl chloride. Removed ice bath at 15 minutes and stripped solvent at 2 hours. Slurried residue in water, collected solids and air dried overnight. Boiled in ethyl acetate, collected solids and dried in vacuo, giving 670 mg of yellow-brown solid: mass spectrum (electrospray m/e): M+H=461.1, 462.2.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[CH:5][C:6]2[N:7]([C:9]([CH2:19]Cl)=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=3)[N:11]=2)[CH:8]=1.[Cl:21][C:22]1[CH:27]=[C:26]([CH3:28])[N:25]=[C:24]([NH2:29])[N:23]=1>>[Cl:21][C:22]1[CH:27]=[C:26]([CH3:28])[N:25]=[C:24]([NH:29][CH2:19][C:9]2[N:7]3[CH:8]=[C:3]([Cl:2])[CH:4]=[CH:5][C:6]3=[N:11][C:10]=2[C:12]2[CH:13]=[CH:14][C:15]([F:18])=[CH:16][CH:17]=2)[N:23]=1
Reactant: Fc1ccc(-c2nc3ccc(Cl)cn3c2CCl)cc1
Reactant: Cc1cc(Cl)nc(N)n1
Agent: Cl
Product: Cc1cc(Cl)nc(NCc2c(-c3ccc(F)cc3)nc3ccc(Cl)cn23)n1

Procedure:
The title compound was prepared according to Method A and the experimentals described for compound 139 from 6-chloro-3-(chloromethyl)-2-(4-fluorophenyl)imidazo[1,2-a]pyridine hydrochloride and 4-chloro-6-methylpyrimidin-2-amine. m/e+ 402.0, 404.0 for C19H14C12FN5.