Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[NH:4][CH:5]=[N:6]2.[Cl:11][C:12]1[CH:21]=[CH:20][CH:19]=[C:18]2[C:13]=1[N:14]=[C:15]([C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[CH:27]=1)[C:16]([C:22]([NH2:25])([CH3:24])[CH3:23])=[N:17]2.C(N(CC)C(C)C)(C)C.C(O)CCC>>[Cl:11][C:12]1[CH:21]=[CH:20][CH:19]=[C:18]2[C:13]=1[N:14]=[C:15]([C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[CH:27]=1)[C:16]([C:22]([NH:25][C:2]1[N:10]=[CH:9][N:8]=[C:7]3[C:3]=1[N:4]=[CH:5][NH:6]3)([CH3:23])[CH3:24])=[N:17]2
Reactant: CC(C)(N)c1nc2cccc(Cl)c2nc1-c1cccc(F)c1
Reactant: Brc1ncnc2nc[nH]c12
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(Nc1ncnc2[nH]cnc12)c1nc2cccc(Cl)c2nc1-c1cccc(F)c1
Temperature: 100 °C
Reaction time: 62 h

Procedure:
A mixture of 6-bromopurine (0.2423 g, 1.218 mmol), 2-(5-chloro-3-(3-fluoro-phenyl)quinoxalin-2-yl)propan-2-amine (0.3845 g, 1.218 mmol), and N,N-diisopropylethylamine (0.6363 mL, 3.653 mmol) in 1-butanol (7.000 mL, 1.218 mmol) was stirred at 100° C. After 62 h, the mixture was removed from the heat and concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column using 30% of CH2Cl2:MeOH:NH4OH (89:9:1) in CH2Cl2 as eluent to give N-(2-(5-chloro-3-(3-fluorophenyl)quinoxalin-2-yl)propan-2-yl)-9H-purin-6-amine as a white solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 12.84 (1H, s), 8.12 (1H, dd, J=8.4, 1.0 Hz), 8.00 (2H, dd, J=7.5, 1.1 Hz), 7.80-7.91 (1H, m), 7.78 (1H, s), 6.88-7.19 (3H, m), 6.75 (1H, s), 6.41 (1H, s), 1.94 (6H, s); LC-MS (ESI) m/z 434.2 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)[NH:9][S@@:10]([C:12](C)([CH3:14])[CH3:13])=[O:11])=[CH:4][CH:3]=1.[CH3:23][PH:24]([O-])([O-:28])[O:25][CH2:26][CH3:27].CCN(CC)CC>C1COCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[F:22][C:19]1[CH:20]=[CH:21][C:16]([C@@H:8]([NH:9][S@@:10]([CH:12]([CH3:13])[CH3:14])=[O:11])[C:5]2[CH:6]=[CH:7][C:2]([P:24]([CH3:23])(=[O:28])[O:25][CH2:26][CH3:27])=[CH:3][CH:4]=2)=[CH:17][CH:18]=1
Reactant: CCO[PH](C)([O-])[O-]
Reactant: CC(C)(C)[S@@](=O)N[C@H](c1ccc(F)cc1)c1ccc(Br)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOP(C)(=O)c1ccc([C@H](N[S@](=O)C(C)C)c2ccc(F)cc2)cc1
Reaction time: 8 h

Procedure:
To (R)—N—((R)-(4-bromophenyl)(4-fluorophenyl)methyl)-2-methylpropane-2-sulfinamide, 18-c, (10 g, 0.026 mol), ethyl methylphosphite (5.6 g, 0.052 mol) and Et3N (7.88 g, 0.078 mol) in THF (100 ml) was added PdCl2(dppf) (2.2 g). The mixture was allowed to stir overnight at reflux. The mixture was filtered and the filtrate was concentrated under vacuum. The residue was taken into dichloromethane and washed with brine. The organic layer was concentrated under vacuum and the residue was purified over silica gel (petroleum ether:ethyl acetate=1/1) to provide the product, 18-d, (6.9 g, 68%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]#[N:9])[CH:5]=[C:4]([Cl:10])[N:3]=1.C[O-].[Na+].Cl.[CH:15]1([NH2:18])[CH2:17][CH2:16]1>CCO.CO>[Cl:1][C:2]1[CH:7]=[C:6]([CH:5]=[C:4]([Cl:10])[N:3]=1)[C:8]([NH:18][CH:15]1[CH2:17][CH2:16]1)=[NH:9]
Reactant: N#Cc1cc(Cl)nc(Cl)c1
Reactant: NC1CC1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: CCO
Product: N=C(NC1CC1)c1cc(Cl)nc(Cl)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 57.4 %

Procedure:
2,6-dichloropyridine-4-carbonitrile (5 g, 28.9 mmol), methanol (50 ml) and sodium methoxide (0.66 ml, 2.89 mmol) were mixed and stirred at r.t. for 3 h. HCl in EtOH (24% w/w, 10 ml) and cyclopropylamine (3 mL, 43.4 mmol) were added at 0° C., followed by stirring at r.t. o.n. The reaction mixture was concentrated in-vacuo. The isolated residue was treated with cold aq. NaOH (1N, 75 ml) and extracted with EA. The combined organic phase was washed sequentially with aq. NaOH and brine, dried (Na2SO4), filtered and concentrated in-vacuo. The isolated residue was triturated with Et2O to isolate the title compound (3.82 g). 1H-NMR: 7.59 (br. s, 2H), 4.96 (br. s, 2H), 2.60 (m, 1H), 0.90 (m, 2H), 0.69 (m, 2H).
Reaction SMILES: Br.Br.C([NH:10][C@H:11]1[C@H:16]2[CH2:17][CH2:18][C@H:13]([CH2:14][NH:15]2)[CH2:12]1)C1C=CC=CC=1.[CH:19]1([N:22]2[C:31]3[C:26](=[CH:27][C:28]([F:33])=[C:29](F)[CH:30]=3)[C:25](=[O:34])[C:24]([C:35]([OH:37])=[O:36])=[CH:23]2)[CH2:21][CH2:20]1.C1CCN2C(=NCCC2)CC1>>[NH2:10][C@H:11]1[C@H:16]2[CH2:17][CH2:18][C@H:13]([CH2:14][N:15]2[C:29]2[CH:30]=[C:31]3[C:26]([C:25](=[O:34])[C:24]([C:35]([OH:37])=[O:36])=[CH:23][N:22]3[CH:19]3[CH2:21][CH2:20]3)=[CH:27][C:28]=2[F:33])[CH2:12]1
Reactant: c1ccc(CN[C@@H]2C[C@@H]3CC[C@H]2NC3)cc1
Reactant: O=C(O)c1cn(C2CC2)c2cc(F)c(F)cc2c1=O
Agent: Br
Solvent: C1CCC2=NCCCN2CC1
Product: N[C@@H]1C[C@@H]2CC[C@H]1N(c1cc3c(cc1F)c(=O)c(C(=O)O)cn3C1CC1)C2

Procedure:
In a manner similar to that of Example 14, the title compound of Example 13 (0.80 g) was coupled to 1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinoline carboxylic acid in the presence of DBU and the product was subjected to catalytic hydrogenation to remove the benzyl group, yielding 0.16 g of the title compound as a solid, mp 268°-271° , [α]D20 -69.3°(DMSO). NMR data was the same as for the
Reaction SMILES: [CH3:1][N:2]1[C:6](=[O:7])[CH2:5][NH:4][C:3]1=[O:8].BrBr.[C:11]1([OH:17])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C(O)(=O)C>[OH:17][C:11]1[CH:16]=[CH:15][C:14]([CH:5]2[NH:4][C:3](=[O:8])[N:2]([CH3:1])[C:6]2=[O:7])=[CH:13][CH:12]=1
Reactant: CN1C(=O)CNC1=O
Reactant: Oc1ccccc1
Agent: BrBr
Solvent: CC(=O)O
Product: CN1C(=O)NC(c2ccc(O)cc2)C1=O
Temperature: 40 °C
Reaction time: 2 h
Yield: 50.9 %

Procedure:
4.56 g (40 mmol) of 3-methyl-hydantoin, 30 ml of acetic acid, and 2.0 ml (40 mmol) of bromine were mixed at room temperature. The reaction mixture was then vigorously stirred at a temperature of 40° C. for 2 hours. The reaction mixture was then allowed to cool to room temperature. To the reaction mixture was then added 5.7 g (60 mmol) of phenol. The reaction mixture was then allowed to undergo reaction at a temperature of 100° C. for 6 hours. The resulting precipitate was recovered by filtration, washed with water, and then dried to obtain 4.20 g (yield: 51%) of 5-(p-hydroxyphenyl)-3-methyl-hydantoin.
Reaction SMILES: [Cu][C:2]#[N:3].Br[C:5]1[CH:6]=[CH:7][C:8]2[CH:12]=[CH:11][S:10][C:9]=2[CH:13]=1.C(N)CN>CCOCC>[S:10]1[CH:11]=[CH:12][C:8]2[CH:7]=[CH:6][C:5]([C:2]#[N:3])=[CH:13][C:9]1=2
Reactant: N#C[Cu]
Reactant: Brc1ccc2ccsc2c1
Solvent: NCCN
Solvent: CCOCC
Product: N#Cc1ccc2ccsc2c1
Temperature: 0 °C
Yield: 77.5 %

Procedure:
Heat copper(I) cyanide (0.84 g, 9.4 mmol) and 6-bromobenzo[b]thiophene (prepared as described in WO 01/23381) (1.0 g, 4.7 mmol) at 160° C. for 13 h. Cool the mixture to 0° C., add 33% aqueous ethylenediamine (20 mL) and dilute with ether. Wash the organic mixture with brine, dry over Na2SO4 and evaporate. Purify by chromatography on silica gel eluting with EtOAc/hexane (0:1 to 1:3) to give the desired intermediate (0.58 g, 78%). GC-MS m/z: 159 (M+).
Reaction SMILES: Br[C:2]1[C:3]([F:31])=[CH:4][C:5]2[CH:11]3[CH2:12][CH:9]([CH2:10]3)[N:8]3[C:13]([CH:19]4[CH2:22][N:21]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:20]4)=[C:14]([C:16](=[O:18])[NH2:17])[N:15]=[C:7]3[C:6]=2[CH:30]=1.[CH3:32][C:33]([OH:37])([C:35]#[CH:36])[CH3:34]>>[C:16]([C:14]1[N:15]=[C:7]2[C:6]3[CH:30]=[C:2]([C:36]#[C:35][C:33]([OH:37])([CH3:34])[CH3:32])[C:3]([F:31])=[CH:4][C:5]=3[CH:11]3[CH2:12][CH:9]([CH2:10]3)[N:8]2[C:13]=1[CH:19]1[CH2:22][N:21]([C:23]([O:25][C:26]([CH3:27])([CH3:28])[CH3:29])=[O:24])[CH2:20]1)(=[O:18])[NH2:17]
Reactant: C#CC(C)(C)O
Reactant: CC(C)(C)OC(=O)N1CC(c2c(C(N)=O)nc3n2C2CC(C2)c2cc(F)c(Br)cc2-3)C1
Product: CC(C)(O)C#Cc1cc2c(cc1F)C1CC(C1)n1c-2nc(C(N)=O)c1C1CN(C(=O)OC(C)(C)C)C1

Procedure:
Similar to as described in General Procedure E, tert-butyl 3-(10-bromo-2-carbamoyl-9-fluoro-6,7-dihydro-5H-5,7-methanobenzo[c]imidazo[1,2-a]azepin-3-yl)azetidine-1-carboxylate was reacted with 2-methylbut-3-yn-2-ol to give the titled compound.
Reaction SMILES: [F:1][C:2]1[C:3]([F:15])=[C:4]([CH2:13]O)[C:5]2[O:9][C:8]([CH3:11])([CH3:10])[CH2:7][C:6]=2[CH:12]=1.O=S(Cl)[Cl:18]>ClCCl>[Cl:18][CH2:13][C:4]1[C:5]2[O:9][C:8]([CH3:11])([CH3:10])[CH2:7][C:6]=2[CH:12]=[C:2]([F:1])[C:3]=1[F:15]
Reactant: O=S(Cl)Cl
Reactant: CC1(C)Cc2cc(F)c(F)c(CO)c2O1
Solvent: ClCCl
Product: CC1(C)Cc2cc(F)c(F)c(CCl)c2O1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99 %

Procedure:
To a solution of (5,6-difluoro-2,2-dimethyl-3H-benzofuran-7-yl)methanol (736) (0.18 g, 0.84 mmol) in anhydrous dichloromethane (5 mL) was added SOCl2 dropwise at 0° C. The mixture was stirred at room temperature for 2 h. The solvent was removed in vacuo, and the residue was dissolved in EtOAc (100 mL). The solution was washed with water (30 mL), dried over anhydrous sodium sulfate, and evaporated in vacuo to give a solid 7-(chloromethyl)-5,6-difluoro-2,2-dimethyl-2,3-dihydrobenzofuran (737) (0.194 g, 99%).
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:9])[C@@H:5]([CH2:7][OH:8])[NH2:6].C(N(CC)CC)C.[C:17](Cl)(=[O:19])[CH3:18]>ClCCl>[CH3:2][O:3][C:4](=[O:9])[C@@H:5]([CH2:7][OH:8])[NH:6][C:17](=[O:19])[CH3:18]
Reactant: CC(=O)Cl
Reactant: COC(=O)[C@H](N)CO
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)[C@@H](CO)NC(C)=O
Temperature: -10 °C
Reaction time: 3 h
Yield: 90 %

Procedure:
D-Serine methyl ester hydrochloride (100 g, 0.6430 mole) was suspended in 500 ml dichloromethane. To this was added triethylamine (136.6 g, 1.35 mole) at 0-5° C., followed by acetyl chloride (53.06 g, 0.6751 mole) drop wise at −10° C. The reaction mixture was stirred at −10° C. for 3 hours, filtered to remove salts and the filtrate was evaporated. The resulting residue was suspended in 400 ml ethyl acetate and stirred for one hour. Salts were filtered and the ethyl acetate layer was concentrated under reduced pressure to get N-acetyl D-serine methyl ester as an oil (93.22 g, Yield: 90%, HPLC: 98.7%),
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:19]#[N:20])=[C:4]([CH:16]=[CH:17][CH:18]=1)[O:5][CH2:6][C:7]([CH3:15])([CH3:14])[C:8]([NH:10][CH2:11][CH2:12][CH3:13])=[O:9].[C:21]([N:29]=[C:30]=[O:31])(=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[C:19]([C:3]1[C:4]([O:5][CH2:6][C:7]([CH3:15])([CH3:14])[C:8](=[O:9])[NH:10][CH2:11][CH2:12][CH3:13])=[CH:16][CH:17]=[CH:18][C:2]=1[NH:1][C:30]([NH:29][C:21](=[O:28])[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)=[O:31])#[N:20]
Reactant: CCCNC(=O)C(C)(C)COc1cccc(N)c1C#N
Reactant: O=C=NC(=O)c1ccccc1
Product: CCCNC(=O)C(C)(C)COc1cccc(NC(=O)NC(=O)c2ccccc2)c1C#N
Yield: 85 %

Procedure:
Prepared as in Example 146a from 3-(3-amino-2-cyanophenoxy)-2,2-dimethyl-N-propyl-propanamide (Example 215b, Method A) and benzoyl isocyanate in 85% yield as a white solid. MS 423 (MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([C:14]3[O:18][C:17](=[O:19])[N:16]([CH2:20][CH3:21])[N:15]=3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[N+:22]([C:25]1[O:29][C:28]([CH:30]=O)=[CH:27][CH:26]=1)([O-:24])=[O:23]>CC(O)=O.CO>[CH2:20]([N:16]1[N:15]=[C:14]([CH:11]2[CH2:10][CH2:9][N:8]([C:5]3[CH:4]=[CH:3][C:2](/[N:1]=[CH:30]/[C:28]4[O:29][C:25]([N+:22]([O-:24])=[O:23])=[CH:26][CH:27]=4)=[CH:7][CH:6]=3)[CH2:13][CH2:12]2)[O:18][C:17]1=[O:19])[CH3:21]
Reactant: O=Cc1ccc([N+](=O)[O-])o1
Reactant: CCn1nc(C2CCN(c3ccc(N)cc3)CC2)oc1=O
Solvent: CO
Solvent: CC(=O)O
Product: CCn1nc(C2CCN(c3ccc(/N=C/c4ccc([N+](=O)[O-])o4)cc3)CC2)oc1=O
Yield: 87 %

Procedure:
5-[1-(4-Aminophenyl)-4-piperidyl]-3-ethyl-2,3-dihydro-1,3,4-oxadiazol-2-one (7c, 0.29 g, 1 mmol) on reacting with 5-nitro2-furaldehyde in the presence of catalytic amount of CH3COOH (3 drops) in methanol at 0° C. for 10 h and the obtained solid is filtered, washed with water and recrystallized in ethanol to obtain product 3-ethyl-5-[1-(4-[(E)-1-(5-nitro-2-furyl)methylidene]aminophenyl)-4-piperidyl]-2,3-dihydro-1,3,4-oxadiazol-2-one (9c, 357 mg, 87%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH2:27])=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[CH2:28]([CH2:35][C:36](=O)[CH3:37])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH:27][CH:36]([CH3:37])[CH2:35][CH2:28][C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)=[CH:17][CH:16]=3)=[CH:13][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CC(=O)CCc1ccccc1
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4N)cc3)cc2)CC1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4NC(C)CCc4ccccc4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 24, Step 1, using 1-[4′-(4-amino-3-methyl-isoxazol-5-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester and benzylacetone.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]([CH3:13])[CH3:12])=[CH:7][CH:6]=1)=O.[NH2:14][C:15]([NH2:17])=[S:16]>CO>[CH:11]([C:8]1[CH:9]=[CH:10][C:5]([C:3]2[N:14]=[C:15]([NH2:17])[S:16][CH:2]=2)=[CH:6][CH:7]=1)([CH3:13])[CH3:12]
Reactant: CC(C)c1ccc(C(=O)CBr)cc1
Reactant: NC(N)=S
Solvent: CO
Product: CC(C)c1ccc(-c2csc(N)n2)cc1

Procedure:
4-(4-Isopropyl-phenyl)-thiazol-2-ylamine was prepared (0.41 g) following general procedure B using 2-bromo-1-(4-isopropyl-phenyl)-ethanone (0.5 g, 2.07 mmol), thiourea (173 mg, 2.28 mmol) and MeOH (10 mL). LCMS m/z: 219 (M+1)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([OH:8])[C:3]=1[CH2:9][N:10]1[CH:14]=[CH:13][C:12]([NH:15][C:16](=[O:25])[C:17]2[C:22]([F:23])=[CH:21][CH:20]=[CH:19][C:18]=2[F:24])=[N:11]1.CC(C)([O-])C.[K+].Br[CH2:33][CH:34]1[CH2:37][CH2:36][CH2:35]1.C(Cl)(Cl)Cl>CS(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH2:33][CH:34]2[CH2:37][CH2:36][CH2:35]2)[C:3]=1[CH2:9][N:10]1[CH:14]=[CH:13][C:12]([NH:15][C:16](=[O:25])[C:17]2[C:22]([F:23])=[CH:21][CH:20]=[CH:19][C:18]=2[F:24])=[N:11]1
Reactant: O=C(Nc1ccn(Cc2c(O)cccc2Cl)n1)c1c(F)cccc1F
Reactant: BrCC1CCC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: CS(C)=O
Product: O=C(Nc1ccn(Cc2c(Cl)cccc2OCC2CCC2)n1)c1c(F)cccc1F
Temperature: 60 °C
Reaction time: 0.33 h

Procedure:
To a stirred solution of N-{1-[(2-chloro-6-hydroxyphenyl)methyl]-1H-pyrazol-3-yl}-2,6-difluorobenzamide (for a preparation see Intermediate 11)(0.047 g, 0.13 mmol) in dry DMSO (0.6 ml) in a reactivial was added potassium t-butoxide (0.0145 g, 0.13 mmol). The mixture was stirred for 20 min and then (bromomethyl)cyclobutane (0.023 g, 0.15 mmol, Aldrich) added. The mixture was stirred and heated at 60° C. for 24 h. The cooled reaction mixture was added to chloroform (about 20 ml) and this solution filtered through a hydrophobic frit and evaporated in vacuo. The residue was purified on MDAP (Method B) to give the title compound as a white solid (0.038 g); LCMS: (System 4) MH+=432, tRET=3.36 min.
Reaction SMILES: Br[C:2]1[C:3]([CH3:28])=[C:4]([N:8]([CH2:13][C:14]2[CH:26]=[CH:25][C:17]([O:18][CH2:19][C:20]([O:22]CC)=[O:21])=[C:16]([CH3:27])[CH:15]=2)[CH2:9][CH2:10][CH2:11][CH3:12])[CH:5]=[CH:6][CH:7]=1.[C:29]([C:31]1[CH:36]=[CH:35][C:34](B(O)O)=[CH:33][CH:32]=1)#[N:30]>>[CH2:9]([N:8]([CH2:13][C:14]1[CH:26]=[CH:25][C:17]([O:18][CH2:19][C:20]([OH:22])=[O:21])=[C:16]([CH3:27])[CH:15]=1)[C:4]1[C:3]([CH3:28])=[C:2]([C:34]2[CH:35]=[CH:36][C:31]([C:29]#[N:30])=[CH:32][CH:33]=2)[CH:7]=[CH:6][CH:5]=1)[CH2:10][CH2:11][CH3:12]
Reactant: N#Cc1ccc(B(O)O)cc1
Reactant: CCCCN(Cc1ccc(OCC(=O)OCC)c(C)c1)c1cccc(Br)c1C
Product: CCCCN(Cc1ccc(OCC(=O)O)c(C)c1)c1cccc(-c2ccc(C#N)cc2)c1C

Procedure:
Prepared from ethyl (4-{[(3-bromo-2-methylphenyl)(butyl)amino]methyl}-2-methylphenoxy)acetate and 4-cyanophenylboronic acid using the procedure described for Example 25 (Method A).
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:3]=1[CH2:4][N:5]1[C:17]2[CH:16]=[N:15][C:14]([CH2:18][OH:19])=[CH:13][C:12]=2[C:11]2[C:6]1=[CH:7][CH:8]=[CH:9][CH:10]=2.[CH:25]1([C:28](Cl)=[O:29])[CH2:27][CH2:26]1>C(Cl)Cl.CCOCC>[CH:25]1([C:28]([O:19][CH2:18][C:14]2[N:15]=[CH:16][C:17]3[N:5]([CH2:4][C:3]4[CH:20]=[C:21]([Cl:24])[CH:22]=[CH:23][C:2]=4[Cl:1])[C:6]4[C:11]([C:12]=3[CH:13]=2)=[CH:10][CH:9]=[CH:8][CH:7]=4)=[O:29])[CH2:27][CH2:26]1
Reactant: OCc1cc2c3ccccc3n(Cc3cc(Cl)ccc3Cl)c2cn1
Reactant: O=C(Cl)C1CC1
Solvent: ClCCl
Solvent: CCOCC
Product: O=C(OCc1cc2c3ccccc3n(Cc3cc(Cl)ccc3Cl)c2cn1)C1CC1
Reaction time: 0.17 h
Yield: 63.5 %

Procedure:
A solution of [9-(2,5-dichlorobenzyl)-9H-β-carbolin-3-yl]methanol (357 mg, 1.0 mmol) and cyclopropyl carbonyl chloride (133 mg, 1.27 mmol) in methylene chloride (5 mL) was allowed to stand for 10 minutes. The solvent was evaporated, and the residue partitioned between aqueous Na2CO3 and methylene chloride. The extract was dried over Na2SO4, filtered and evaporated, affording a resin. This was dissolved in ether and filtered through a plug of silica gel, treated with ethereal hydrogen chloride, evaporated, and the residue recrystallized from ethanol/ethyl acetate/ether, affording 270 mg (58%) of the title compound as a yellow solid. 1H NMR (CDCl3) δ8.85 (s, 1H), 8.44 (s, 1 H), 8.25 (d, J=7.9 Hz, 1H), 7.58 (t, J=7.5 Hz, 1H), 7.35-7.28 (m, 3H), 7.10 (dd, J=8, 2.3 Hz, 1H), 6.37 (d, J=2.3 Hz, 1H), 5.62 (s, 2H), 5.46 (s, 2H), 1.74 (m, 2H), 1.56 (m, 1H), 0.84-0.71 (m, 4H); MS (APCI; (M+H)+) m/z 425.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[C:4]([O:14][C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=2)[C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([O:12][CH3:13])=[CH:7][CH:6]=2.C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:35][CH2:36][CH2:37][C:38]([O:40][CH2:41][CH3:42])=[O:39]>CN(C=O)C>[CH3:1][C:2]1[C:3]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[C:4]([O:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:35][CH2:36][CH2:37][C:38]([O:40][CH2:41][CH3:42])=[O:39])=[CH:17][CH:16]=2)[C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([O:12][CH3:13])=[CH:7][CH:6]=2
Reactant: COc1ccc2c(Oc3ccc(O)cc3)c(-c3ccccc3)c(C)cc2c1
Reactant: CCOC(=O)CCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)CCCOc1ccc(Oc2c(-c3ccccc3)c(C)cc3cc(OC)ccc23)cc1
Temperature: 25 °C
Yield: 89.9 %

Procedure:
A round-bottomed flask was charged with 4-{[3-methyl-6-(methyloxy)-2-phenyl-1-naphthalenyl]oxy}phenol (233) (0.300 g, 0.842 mmol), Cs2CO3 (0.824 g, 2.53 mmol), DMF (4 mL), and ethyl 4-bromobutanoate (0.602 mL, 4.21 mmol) under N2. The reaction mixture was refluxed for 15 h and cooled at room temperature. Reaction mixture was partitioned between water and EtOAC (1:1, 100 mL) and the layers were separated. The aqueous phase was further extracted with EtOAc (2×30 mL). The combined organic layer was washed with brine (1×25 mL), dried (Na2SO4), and then concentrated under reduced pressure to afford the crude product. The product was purified by SiO2 column chromatography using hexanes:EtOAc (19:1 to 9:1) as an eluent to give 0.356 g (90%) of the title compound (288) as a colorless oil. LCMS (ESI) m/z 493.27 (M+Na)+.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][C:7]([C:13]#[N:14])=[C:6]2[O:15][CH2:16][CH2:17][O:18][CH2:19][CH2:20][O:21][CH3:22])=O.[CH:23]1([NH:26][C:27]2[S:28][CH2:29][C:30](=[O:32])[N:31]=2)[CH2:25][CH2:24]1.C([O-])(=O)C.[Na+]>C(O)(=O)C>[CH:23]1([NH:26][C:27]2[S:28]/[C:29](=[CH:1]\[C:3]3[CH:4]=[C:5]4[C:10](=[CH:11][CH:12]=3)[N:9]=[CH:8][C:7]([C:13]#[N:14])=[C:6]4[O:15][CH2:16][CH2:17][O:18][CH2:19][CH2:20][O:21][CH3:22])/[C:30](=[O:32])[N:31]=2)[CH2:25][CH2:24]1
Reactant: O=C1CSC(NC2CC2)=N1
Reactant: COCCOCCOc1c(C#N)cnc2ccc(C=O)cc12
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: COCCOCCOc1c(C#N)cnc2ccc(/C=C3\SC(NC4CC4)=NC3=O)cc12

Procedure:
Similar procedure as described in example 28c was used, starting from 6-formyl-4-[2-(2-methoxy-ethoxy)-ethoxy]-quinoline-3-carbonitrile (example 30b), 2-cyclopropylamino-thiazol-4-one, sodium acetate and acetic acid to give 6-[2-cyclopropylamino-4-oxo-4H-thiazol-(5Z)-ylidenemethyl]-4-[2-(2-methoxy-ethoxy)-ethoxy]-quinoline-3-carbonitrile. LC-MS m/e 439 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][CH:10]=[C:11]([CH3:13])[CH:12]=2)=[CH:4][CH:3]=1.[Li]C(C)(C)C.[C:19](=[O:21])=[O:20]>C1COCC1.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[S:9][C:10]([C:19]([OH:21])=[O:20])=[C:11]([CH3:13])[CH:12]=2)=[CH:6][CH:7]=1
Reactant: Cc1csc(-c2ccc(Cl)cc2)c1
Reactant: O=C=O
Agent: [Li]C(C)(C)C
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(-c2ccc(Cl)cc2)sc1C(=O)O
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 74.9 %

Procedure:
Dissolve 2-(4-chloro-phenyl)-4-methyl-thiophene (0.53 g, 1.85 mmol) in THF (25 mL) and cool to −78° C. Add t-BuLi (1.7 M, 2.3 mL, 3.88 mmol) dropwise. Stir the solution at −78° C. for 20 min. Cannulate the solution into a flask containing powdered dry ice (10 g). Stir the reaction and allow to warm to RT. Quench the reaction with saturated NH4Cl (10 mL), dilute with water (40 mL), and extract with EtOAc (2×50 mL). Dry the combined organic layers over Na2SO4, filter, and concentrate. Purify the crude material by washing with hexane (2×20 mL) to give 0.35 g (74%) of the title compound. LC-MS/ES m/z (35Cl) 251.0 [M−H]−.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[CH2:4][C:5]#[N:6].Cl.Cl[CH2:14][CH:15]1[CH2:20][CH2:19][CH2:18][N:17]([CH3:21])[CH2:16]1.[OH-].[Na+]>CS(C)=O>[Cl:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[CH:4]([CH2:14][CH:15]1[CH2:20][CH2:19][CH2:18][N:17]([CH3:21])[CH2:16]1)[C:5]#[N:6]
Reactant: N#CCc1ccc(Cl)cc1Cl
Reactant: CN1CCCC(CCl)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Product: CN1CCCC(CC(C#N)c2ccc(Cl)cc2Cl)C1

Procedure:
This intermediate (7.6 g.) was prepared using the procedure described in Example 14a except using 10 g. (0.054 mole) of 2,4-dichlorobenzyl cyanide, 10 g. (0.054 mole) of 3-chloromethyl-1-methylpiperidine hydrochloride, 11 g. (0.135 mole) of aqueous 50% sodium hydroxide, and 100 ml. of DMSO to yield an oil boiling 160°-165° C. at 5 mm of Hg.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[S:17][C:16]3[C:11](=[N:12][CH:13]=[CH:14][C:15]=3[O:18][C:19]3[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][C:20]=3[F:28])[CH:10]=2)=[N:7][CH:8]=1.C([O-])([O-])=O.[Cs+].[Cs+].[C:35]1(=[O:41])[NH:39][C:38](=[O:40])[CH2:37][CH2:36]1.O>CN(C=O)C>[F:28][C:20]1[CH:21]=[C:22]([N+:25]([O-:27])=[O:26])[CH:23]=[CH:24][C:19]=1[O:18][C:15]1[CH:14]=[CH:13][N:12]=[C:11]2[CH:10]=[C:9]([C:6]3[N:7]=[CH:8][C:3]([CH2:2][N:39]4[C:35](=[O:41])[CH2:36][CH2:37][C:38]4=[O:40])=[CH:4][CH:5]=3)[S:17][C:16]=12
Reactant: O=[N+]([O-])c1ccc(Oc2ccnc3cc(-c4ccc(CCl)cn4)sc23)c(F)c1
Reactant: O=C1CCC(=O)N1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C1CCC(=O)N1Cc1ccc(-c2cc3nccc(Oc4ccc([N+](=O)[O-])cc4F)c3s2)nc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 43.5 %

Procedure:
To a solution of 102 (200 mg, 0.481 mmol, scheme 26) in DMF (5 mL) was added Cs2CO3 (313 mg, 0.962 mmol) and succinimide (95 mg, 0.962 mmol) and the reaction mixture was stirred at RT for 4 hours. The reaction mixture was poured into water and extracted with EtOAc. The organic phase was collected, dried over anhydrous Na2SO4, filtered and concentrated to afford title compound 138 (100 mg, 43% yield) that was triturated with Et2O and used with no additional purification. MS (m/z)=479.50 (M+H)