Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+]([C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]=[C:6]([C:14]2[CH:20]=[CH:19][C:17]([NH2:18])=[CH:16][CH:15]=2)[CH:5]=1)([O-])=O.[F-:21].[K+]>>[F:21][C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]=[C:6]([C:14]2[CH:20]=[CH:19][C:17]([NH2:18])=[CH:16][CH:15]=2)[CH:5]=1
Reactant: [F-]
Reactant: Nc1ccc(-c2cc([N+](=O)[O-])c3ccccc3n2)cc1
Agent: [K+]
Product: Nc1ccc(-c2cc(F)c3ccccc3n2)cc1
Yield: 42 %

Procedure:
4-(4-Fluoroquinolin-2-yl)aniline T492 was prepared by using general procedure M from 4-(4-Nitroquinolin-2-yl)aniline (6 mg, 0.02 mmol) and KF (26 mg, 0.45 mmol), The crude product was purified by silica chromatography to afford 4-(4-fluoroquinolin-2-yl)aniline as a yellow solid (2 mg, 42%). 1H NMR (400 MHz, CDCl3): δ 8.11 (m, 1H), 8.03 (m, 1H), 8.00 (m, 2H), 7.72 (m, 1H), 7.51 (m, 1H), 7.48 (d, J=11.6 Hz, 1H), 6.80 (m, 2H), 3.93 (br s, 2H); MS (ESI): 239 (M+H+).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:18]=[C:7]([C:8]([NH:10][CH2:11][CH2:12][N:13]([CH2:16][CH3:17])[CH2:14][CH3:15])=[O:9])[C:6]([OH:19])=[CH:5][CH:4]=1.O1CC[CH2:23]OO1>FC(F)(F)C(O)=O>[Cl:2][C:3]1[CH:4]=[CH:5][C:6]2[O:19][CH2:23][N:10]([CH2:11][CH2:12][N:13]([CH2:16][CH3:17])[CH2:14][CH3:15])[C:8](=[O:9])[C:7]=2[CH:18]=1
Reactant: C1COOOC1
Reactant: CCN(CC)CCNC(=O)c1cc(Cl)ccc1O
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Product: CCN(CC)CCN1COc2ccc(Cl)cc2C1=O

Procedure:
8.00 Grammes (26.1 mmoles) of 5-chloro-N-[2-(diethylamino)ethyl]salicylamide hydrochloride are dissolvedin 100 ml of trifluoroacetic acid with 2.35 grammes (26.1 mmoles) of trioxane and left to react for 20 hours at a temperature of 50° C.
Reaction SMILES: Cl[C:2]1[N:24]=[C:5]2[C:6]([NH:10][C:11]3[CH:23]=[CH:22][CH:21]=[CH:20][C:12]=3[CH2:13][N:14]([CH3:19])[S:15]([CH3:18])(=[O:17])=[O:16])=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1.[N:25]1([CH2:30][CH2:31][O:32][C:33]2[CH:38]=[CH:37][C:36]([NH2:39])=[CH:35][CH:34]=2)[CH2:29][CH2:28][CH2:27][CH2:26]1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)CCCCC1>>[CH3:19][N:14]([CH2:13][C:12]1[CH:20]=[CH:21][CH:22]=[CH:23][C:11]=1[NH:10][C:6]1[C:5]2[N:4]([N:3]=[C:2]([NH:39][C:36]3[CH:37]=[CH:38][C:33]([O:32][CH2:31][CH2:30][N:25]4[CH2:29][CH2:28][CH2:27][CH2:26]4)=[CH:34][CH:35]=3)[N:24]=2)[CH:9]=[CH:8][CH:7]=1)[S:15]([CH3:18])(=[O:17])=[O:16]
Reactant: Nc1ccc(OCCN2CCCC2)cc1
Reactant: CN(Cc1ccccc1Nc1cccn2nc(Cl)nc12)S(C)(=O)=O
Agent: c1ccc(P(C2CCCCC2)C2CCCCC2)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c1
Product: CN(Cc1ccccc1Nc1cccn2nc(Nc3ccc(OCCN4CCCC4)cc3)nc12)S(C)(=O)=O

Procedure:
N-Methyl-N-(2-{2-[4-(2-pyrrolidin-1-yl-ethoxy)-phenylamino]-[1,2,4]triazolo[1,5-a]pyridin-8-ylamino}-benzyl)-methanesulfonamide was prepared from N-[2-(2-chloro-[1,2,4]triazolo[1,5-a]pyridin-8-ylamino)-benzyl]-N-methyl-methanesulfonamide (75.0 mg, 0.205 mmol) and 4-(2-pyrrolidin-1-yl-ethoxy)-phenylamine (47.0 mg, 0.228 mmol) with 2,2′-bis-dicyclohexylphosphanyl-biphenyl (25.0 mg, 0.0457 mmol) as the ligand in a manner analogous to Example 2d. Product isolated as a tan foam (0.017 g, 15%). 1H NMR (400 MHz, CDCl3, δ, ppm): 7.95 (d, J=6.7 Hz, 1H), 7.51 (d, J=8.9 Hz, 2H), 7.46-7.31 (m, 3H), 7.13 (t, J=7.4 Hz, 1H), 6.99 (s, 1H), 6.94 (d, J=8.9 Hz, 2H), 6.83 (d, J=7.7 Hz, 1H), 6.69 (t, J=7.1 Hz, 1H), 6.62 (s, 1H), 4.36 (s, 2H), 4.11 (t, J=6.0 Hz, 2H), 2.93-2.87 (m, 5H), 2.78 (s, 3H), 2.68-2.58 (m, 4H), 1.85-1.78 (m, 4H). MS=536 (MH)+.
Reaction SMILES: [CH2:1]([N:3]([CH2:20][CH3:21])[CH2:4][CH2:5][N:6]1[CH2:12][CH2:11][CH2:10][C:9]2[NH:13][C:14]([CH:17]=O)=[C:15]([CH3:16])[C:8]=2[C:7]1=[O:19])[CH3:2].[Br:22][C:23]1[CH:24]=[C:25]2[CH2:31][C:30](=[O:32])[NH:29][C:26]2=[N:27][CH:28]=1>>[Br:22][C:23]1[CH:24]=[C:25]2[C:26]([NH:29][C:30](=[O:32])/[C:31]/2=[CH:17]\[C:14]2[NH:13][C:9]3[CH2:10][CH2:11][CH2:12][N:6]([CH2:5][CH2:4][N:3]([CH2:20][CH3:21])[CH2:1][CH3:2])[C:7](=[O:19])[C:8]=3[C:15]=2[CH3:16])=[N:27][CH:28]=1
Reactant: O=C1Cc2cc(Br)cnc2N1
Reactant: CCN(CC)CCN1CCCc2[nH]c(C=O)c(C)c2C1=O
Product: CCN(CC)CCN1CCCc2[nH]c(/C=C3\C(=O)Nc4ncc(Br)cc43)c(C)c2C1=O
Yield: 33.8 %

Procedure:
The title compound was prepared under the same conditions as described in step 10 of Example 1 with 5-(2-diethylamino-ethyl)-3-methyl-4-oxo-1,4,5,6,7,8-hexahydro-pyrrolo[3,2-c]azepine-2-carbaldehyde 1j obtained from step 9 of Example 1 and 5-bromo-1,3-dihydro-pyrrolo[2,3-b]pyridin-2-one as starting materials to obtain (Z)-2-(5-bromo-2-oxo-1,2-dihydro-pyrrolo[2,3-b]pyridin-3-ylidenemethyl)-5-(2-diethylamino-ethyl)-3-methyl-5,6,7,8-tetrahydro-1H-pyrrolo[3,2-c]azepin-4-one 14 (23 mg, yield 33.8%) as an orange solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][CH:4]=1.Cl[C:12]([CH3:20])([CH2:14][CH2:15][C:16](Cl)([CH3:18])[CH3:17])[CH3:13].[Cl-].[Al+3].[Cl-].[Cl-]>ClCCCl>[CH3:1][O:2][C:3]1[C:8]2[C:16]([CH3:18])([CH3:17])[CH2:15][CH2:14][C:12]([CH3:20])([CH3:13])[C:7]=2[C:6]([O:9][CH3:10])=[CH:5][CH:4]=1
Reactant: COc1ccc(OC)cc1
Reactant: CC(C)(Cl)CCC(C)(C)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: COc1ccc(OC)c2c1C(C)(C)CCC2(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 65.7 %

Procedure:
To a solution, stirred at 0° C. under an inert atmosphere, of 165.5 g of 1,4-dimethoxybenzene and 218.7 g of 2,5-dichloro-2,5-dimethyl hexane, obtained in Example I(a), in 750 cm3 of anhydrous 1,2-dichloroethane, there are added, all at once, 31.9 g of powdered anhydrous aluminum chloride. The mixture is stirred for 1 hour at ambient temperature and then left to stand overnight. The next day after 4 hours stirring at this temperature, 600 cm3 of ice water are added. The organic phase is decanted and the aqueous phase is extracted three time with 400 cm3 of methylene chloride. The organic phases are combined, washed with water until neutral pH of the wash waters, then dried on sodium sulfate and concentrated. The resulting crude product is treated with animal charcoal in boiling ethanol, then recrystallized in this solvent. 195 g of 1,4-dimethoxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro naphthalene are obtained in the form of white needles having a melting point of 195° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)=[CH:5][CH:4]=1.C([O-])([O-])=O.[K+].[K+].[F:24][C:25]([F:39])([F:38])[C:26]1[CH:33]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:31]=[CH:30][C:27]=1[CH2:28]Br>O1CCOCC1>[F:24][C:25]([F:38])([F:39])[C:26]1[CH:33]=[C:32]([C:34]([F:37])([F:35])[F:36])[CH:31]=[CH:30][C:27]=1[CH2:28][N:11]([CH2:10][CH2:9][C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1
Reactant: COc1ccc(CCNc2ccccn2)cc1
Reactant: FC(F)(F)c1ccc(CBr)c(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: COc1ccc(CCN(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)c2ccccn2)cc1
Yield: 43.3 %

Procedure:
A solution of N-[2-(4-methoxyphenyl)ethyl]pyridin-2-amine (150 mg; 0.66 mmol) in 3 ml of dioxane, under nitrogen, was treated with K2CO3 (113 mg; 0.82 mmol) and 2,4-bis-trifluoromethyl-benzyl bromide (0.13 ml; 0.69 mmol) and heated in a pressure tube at 190–220C for 16 hours. Upon cooling, the reaction mixture was partitioned between ethyl acetate and saturated sodium bicarbonate. The organic phase was washed with saturated brine, dried over sodium sulfate and concentrated. Purification by radial chromatography on silica gel using an ethyl acetate-hexane gradient (5–50%) afforded N-[2,4-bis(trifluoromethyl)benzyl]-N-[2-(4-methoxyphenyl)ethyl]pyridin-2-amine (130 mg; 44% yield).
Reaction SMILES: [CH2:1]1[O:12][C:11]2[CH:10]=[CH:9][C:5]([CH2:6][CH2:7][NH2:8])=[CH:4][C:3]=2[O:2]1.Cl[C:14]1[C:15]2[C:28]([Cl:29])=[C:27]([CH3:30])[S:26][C:16]=2[N:17]=[C:18]([C:20]2[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=2)[N:19]=1>>[N:22]1[CH:23]=[CH:24][CH:25]=[C:20]([C:18]2[N:19]=[C:14]([NH:8][CH2:7][CH2:6][C:5]3[CH:9]=[CH:10][C:11]4[O:12][CH2:1][O:2][C:3]=4[CH:4]=3)[C:15]3[C:28]([Cl:29])=[C:27]([CH3:30])[S:26][C:16]=3[N:17]=2)[CH:21]=1
Reactant: NCCc1ccc2c(c1)OCO2
Reactant: Cc1sc2nc(-c3cccnc3)nc(Cl)c2c1Cl
Product: Cc1sc2nc(-c3cccnc3)nc(NCCc3ccc4c(c3)OCO4)c2c1Cl

Procedure:
With the procedure of Example 1, the reaction of 3,4-methylenedioxyphenethylamine with 4-chloro-2-(pyridin-3-yl)-5-chloro-6-methyl-thieno-[2,3-d]-pyrimidine yields 2-(pyridin-3-yl)-4-(3,4-methylenedioxyphenethylamino)-5-chloro-6-methyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][C:3]=1[C:11]#[C:12][C:13]1[CH:14]=[N:15][C:16]2[C:21]([CH:22]=1)=[CH:20][CH:19]=[CH:18][CH:17]=2.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.[Cl:45][C:46]1[CH:55]=[C:54]([Cl:56])[CH:53]=[C:52]([Cl:57])[C:47]=1[C:48]([NH:50][NH2:51])=[O:49]>CN(C)C=O>[Cl:45][C:46]1[CH:55]=[C:54]([Cl:56])[CH:53]=[C:52]([Cl:57])[C:47]=1[C:48]([N:50]([C:6](=[O:7])[C:5]1[CH:9]=[CH:10][C:2]([CH3:1])=[C:3]([C:11]#[C:12][C:13]2[CH:14]=[N:15][C:16]3[C:21]([CH:22]=2)=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH:4]=1)[NH2:51])=[O:49]
Reactant: Cc1ccc(C(=O)O)cc1C#Cc1cnc2ccccc2c1
Reactant: NNC(=O)c1c(Cl)cc(Cl)cc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: Cc1ccc(C(=O)N(N)C(=O)c2c(Cl)cc(Cl)cc2Cl)cc1C#Cc1cnc2ccccc2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 4-methyl-3-[(quinolin-3-yl)ethynyl]benzoic acid (0.15 g, 0.5 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.15 g, 0.7 mmol) and 1-hydroxybenzotriazole (0.1 g, 0.7 mmol) in N,N-dimethylformamide (15 ml) was stirred at ambient temperature for 1 hr. 2,4,6-Trichlorobenzohydrazide (0.125 g, 0.5 mmol) was added and the mixture stirred for 12 hrs at ambient temperature. Concentration and trituration of the residue with water produced a solid which was filtered, washed with water and the crude product was purified by flash chromatography on silica gel (elution with 10% methanol in dichloromethane) to get 2,4,6-trichloro-N-[4-methyl-3-[2-(3-quinolyl)ethynyl]benzoyl]benzohydrazide as a white solid.
Reaction SMILES: N[N:2]1[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[Cl:13])=[N:5][N:4]=[C:3]1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[Cl:20].N([O-])=O.[Na+]>C(O)(=O)C.O>[Cl:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[C:3]1[N:2]=[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[Cl:13])[NH:5][N:4]=1
Reactant: Nn1c(-c2ccccc2Cl)nnc1-c1ccccc1Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: Clc1ccccc1-c1n[nH]c(-c2ccccc2Cl)n1
Yield: 52.3 %

Procedure:
The product of stage (a) (19.5 g) was dissolved in glacial acetic acid (100 ml) and was treated with sodium nitrite (4.4 g) in water (15 ml) at 10° C. The precipitated solid was filtered off, washed, dried and recrystallised from methanol to yield 9.7 g of desired product, mp 159°-160° C.
Reaction SMILES: Br[C:2]1[C:6]([Cl:7])=[C:5]([CH3:8])[N:4]([CH2:9][O:10][CH2:11][CH2:12][Si:13]([CH3:16])([CH3:15])[CH3:14])[C:3]=1[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18].[Li]CCCC.C1C=CC(S(N(S(C2C=CC=CC=2)(=O)=O)[F:39])(=O)=O)=CC=1>C1COCC1>[Cl:7][C:6]1[C:2]([F:39])=[C:3]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[N:4]([CH2:9][O:10][CH2:11][CH2:12][Si:13]([CH3:16])([CH3:15])[CH3:14])[C:5]=1[CH3:8]
Reactant: O=S(=O)(c1ccccc1)N(F)S(=O)(=O)c1ccccc1
Reactant: Cc1c(Cl)c(Br)c(C(=O)OC(C)(C)C)n1COCC[Si](C)(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1c(Cl)c(F)c(C(=O)OC(C)(C)C)n1COCC[Si](C)(C)C
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
tert-butyl 3-bromo-4-chloro-5-methyl-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrole-2-carboxylate (Intermediate 265, 480 mg, 1.13 mmol) was dissolved in dry THF (8 ml), cooled down to −78° C., n-BuLi (2.5M in Hexane, 3.39 mmol) was added dropwise into the mixture via syringe and the mixture was stirred at −78° C. for 30 min followed by a quick addition of N-Fluorobenzensulfonimide (1.25 g, 3.96 mmol in 5 ml of THF/Toluene 1:1), the resulting mixture was then stirred at −78° C. for 30 min and slowly warmed up to room temperature during a period of 12 hrs. The reaction was quenched at 0° C. with drops of saturated NH4Cl solution and further diluted with EtOAc (50 ml). The organic phase was washed with brine and dried over anhydrous MgSO4, concentrated to an oil and purified by flash column chromatography eluted with 10% EtOAc in Hexanses. The desired product was obtained as an oil (125 mg).
Reaction SMILES: O[CH2:2][CH2:3][N:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7](=[O:14])[NH:6][C:5]1=[O:15].S(Cl)([Cl:18])=O>>[Cl:18][CH2:2][CH2:3][N:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7](=[O:14])[NH:6][C:5]1=[O:15]
Reactant: O=c1[nH]c(=O)n(CCO)c2ccccc12
Reactant: O=S(Cl)Cl
Product: O=c1[nH]c(=O)n(CCCl)c2ccccc12
Temperature: 25 °C
Yield: 86 %

Procedure:
A mixture of 3.6 parts of 1-(2-hydroxyethyl)-2,4(1H,3H)-quinazolinedione and 40 parts of thionyl chloride is stirred and refluxed overnight. The reaction mixture is allowed to cool to room temperature. The precipitated product is filtered off, washed with 2,2'-oxybispropane and dried, yielding 3.4 parts (86%) of 1-(2-chloroethyl)-2,4-(1H,3H)-quinazolinedione; mp. 215.3° C.
Reaction SMILES: [C:1]([NH:4][CH:5]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:6]([O:8][CH2:9][CH3:10])=[O:7])(=[O:3])[CH3:2].[O-]CC.[Na+].[CH2:20](Br)[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39].Cl>C(O)C>[C:1]([NH:4][C:5]([CH2:39][CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH3:20])([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:6]([O:8][CH2:9][CH3:10])=[O:7])(=[O:3])[CH3:2]
Reactant: CCOC(=O)C(NC(C)=O)C(=O)OCC
Reactant: CCCCCCCCCCCCCCCCCCCCBr
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CCCCCCCCCCCCCCCCCCCCC(NC(C)=O)(C(=O)OCC)C(=O)OCC
Temperature: 25 °C
Yield: 58.2 %

Procedure:
Diethyl 2-acetamidomalonate (3.0 g) was dissolved in 50 ml of dry ethanol and 1.3 g of sodium ethoxide was added thereto. A solution of 6.0 g of icosyl bromide in 20 ml of dry ethanol was added thereto while stirring at room temperature. The inside of the reaction vessel was displaced with nitrogen and the mixture was refluxed for about 15 hours. The mixture was neutralized with a 1 N aqueous hydrochloric acid solution and concentrated. The concentrate was purified by silica gel column chromatography to give 4 g of diethyl 2-acetamido-2-icosylmalonate.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][S:15]([C:18]3[CH:23]=[CH:22][C:21]([NH:24][C:25](=[O:27])[CH3:26])=[CH:20][CH:19]=3)(=[O:17])=[O:16])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.[NH2:28][CH2:29][C@H:30]([OH:39])[CH2:31][O:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>>[OH:39][C@H:30]([CH2:31][O:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[CH2:29][NH:28][CH:2]1[CH2:3][CH2:4][N:5]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][S:15]([C:18]3[CH:23]=[CH:22][C:21]([NH:24][C:25](=[O:27])[CH3:26])=[CH:20][CH:19]=3)(=[O:17])=[O:16])=[CH:10][CH:9]=2)[CH2:6][CH2:7]1
Reactant: CC(=O)Nc1ccc(S(=O)(=O)Nc2ccc(N3CCC(=O)CC3)cc2)cc1
Reactant: NC[C@H](O)COc1ccccc1
Product: CC(=O)Nc1ccc(S(=O)(=O)Nc2ccc(N3CCC(NC[C@H](O)COc4ccccc4)CC3)cc2)cc1

Procedure:
The title compound was prepared from N-{4-[4-(4-oxo-piperidine-1-yl)-phenylsulfamoyl]-phenyl}-acetamide (which was obtained in Example 216) and (2S)-1-amino-3-phenoxy-propan-2-ol (which was obtained in Example 3) according to the procedure of Example 255 as a white solid; 1H NMR (300 MHz, DMSO-d6) δ 1.40-1.65 (m, 2H), 1.95-2.10 (m, 2H), 2.06 (s, 3H), 2.50-3.20 (m, 5H), 3.55-3.75 (m, 2H), 3.96 (d, J=5.2 Hz, 2H), 4.15-4.25 (m, 1H), 5.70 (brs, 1H), 6.80 (d, J=9.0 Hz, 2H), 6.88 (d, J=9.0 Hz, 2H), 6.90-7.00 (m, 3H), 7.25-7.35 (m, 2H), 7.59 (d, J=9.0 Hz, 2H), 7.69 (d, J=9.0 Hz, 2H), 9.70 (s, 1H), 10.37 (s, 1H); MS (ES) m/z: 539.1 (MH+); HRMS Calcd. for C28H35N4O5S(MH+): 539.2328. Found: 539.2357.
Reaction SMILES: [CH:1]1([OH:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.N1C=CC=CC=1.Cl[C:15]([O:17][C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=1)=[O:16]>C1COCC1>[C:15](=[O:16])([O:17][C:18]1[CH:19]=[CH:20][C:21]([N+:24]([O-:26])=[O:25])=[CH:22][CH:23]=1)[O:7][CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: OC1CCCCC1
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: O=C(Oc1ccc([N+](=O)[O-])cc1)OC1CCCCC1
Reaction time: 0.08 h
Yield: 90.5 %

Procedure:
To a solution of cyclohexanol (1.0 g, 10 mmol) in THF (20 mL) at 0° C. was added pyridine (0.97 mL, 12 mmol). After 5 min stirring under N2, a solution of 4-nitrophenyl chloroformate (2.2 g, 11 mmol) in THF (15 mL) was added slowly. After addition, the reaction mixture was stirred at 0° C. for 30 min, and then at RT for 3 h. The precipitate was filtered, the filtrate was concentrated. The resulting residue was chromatographed (40 g silica gel) eluting with EtOAc (0-20%) in hexanes to give the title compound (2.4 g, 91%) as a white solid.
Reaction SMILES: [C:1]([O:5][C:6](/[CH:8]=[CH:9]\[C:10]1[CH:11]=[CH:12][C:13]([O:21][CH3:22])=[C:14]([CH2:16][C:17]([O:19]C)=[O:18])[CH:15]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>C(OCC)(=O)C.[Pd]>[C:1]([O:5][C:6](=[O:7])[CH2:8][CH2:9][C:10]1[CH:11]=[CH:12][C:13]([O:21][CH3:22])=[C:14]([CH2:16][C:17]([OH:19])=[O:18])[CH:15]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: [H][H]
Reactant: COC(=O)Cc1cc(/C=C\C(=O)OC(C)(C)C)ccc1OC
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COc1ccc(CCC(=O)OC(C)(C)C)cc1CC(=O)O

Procedure:
Methyl (Z)-5-t-butoxycarbonylvinyl-2-methoxyphenylacetate (250 mg, from above) in ethyl acetate (5 mL) in the presence of Pd/C (10% Pd content, 44 mg) was subjected to a Parr apparatus under 50 PSI of hydrogen gas for 1 hour. The mixture was filtered through celite and the filter cake washed with ethyl acetate. The filtrate and washing solution were combined and concentrated to give the desired product. 1H NMR (400 MHz, acetone-d6): δ 7.10 (d, 1H), 7.04 (s, 1H), 6.88 (d, 1H), 3.76 (s, 3H), 3.57 (s, 3H), 3.55 (s, 2H), 2.78 (t, 2H), 2.48 (t, 2H), 1.40 (s, 9H). This compound (100 mg) was then treated with LiOH monohydrate (27 mg) in ethanol/H2O (3:1, 4 mL) for 5 hours. The ethanol was evaporated on vacuo and the residual acidified to pH-1 and extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate and filtered. Concentration in vacuo afforded acid 10 (80 mg) as a white solid.
Reaction SMILES: [C:1]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH:10](O)[C:11]1[O:15][CH:14]=[CH:13][CH:12]=1)([OH:3])=[O:2].C(O)=[O:18].C([O-])=O.[Na+].C1(C=CC(O)=CC=1)O>O1CCOCC1.O>[C:1]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH:10]1[CH:11]([OH:15])[CH:12]=[CH:13][C:14]1=[O:18])([OH:3])=[O:2]
Reactant: O=C(O)CCCCCCC(O)c1ccco1
Reactant: O=CO
Agent: O=C[O-]
Agent: Oc1ccc(O)cc1
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)CCCCCCC1C(=O)C=CC1O

Procedure:
A stirred mixture of 65.0g (0.287 mol) of α-(6-carboxyhexyl)furfuryl alcohol (Example 6), 113 ml of 97% formic acid, 4.95g of sodium formate, 100 mg of hydroquinone, and 1430 ml of 3:2 dioxane-water is heated at reflux temperature for 19 hr. The solution is concentrated to volume of about 750 ml, diluted with water, saturated with salt, and extracted with ether. The extract is washed with brine, dried over magnesium sulfate, and evaporated with toluene chaser to give an amber solid.
Reaction SMILES: [CH3:1][N:2]([CH3:13])[C:3]1[CH:4]=[C:5]([S:9]([NH2:12])(=[O:11])=[O:10])[CH:6]=[CH:7][CH:8]=1.[OH-].[Na+].[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([N:23]=[C:24]=[O:25])=[CH:19][CH:18]=1>CC(C)=O>[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([NH:23][C:24]([NH:12][S:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([N:2]([CH3:13])[CH3:1])[CH:4]=2)(=[O:11])=[O:10])=[O:25])=[CH:19][CH:18]=1
Reactant: O=C=Nc1ccc(Cl)cc1
Reactant: CN(C)c1cccc(S(N)(=O)=O)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Product: CN(C)c1cccc(S(=O)(=O)NC(=O)Nc2ccc(Cl)cc2)c1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
The 3-(dimethylamino)benzenesulfonamide was dissolved in acetone (9.1 ml) to which was added 9.3 ml of 1N sodium hydroxide. To this mixture was added 4-chlorophenylisocyanate (1.43 g, 9.3 mmoles) dissolved in 9.1 ml of acetone. This mixture was stirred for 45 minutes at room temperature and then filtered. The filtrate was acidified using 1N hydrochloric acid (9.3 ml) and stirred for 2 hours, resulting in a precipitate. The solid was collected, washed thrice with water, and recrystallized using heated toluene (150 ml) and ethyl acetate (25 ml), followed by filtration and cooling.
Reaction SMILES: [CH3:1][N:2]([CH3:17])[C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[CH:6][CH:7]=[C:8]2[S:13](Cl)(=[O:15])=[O:14].[NH2:18][C:19]1[CH:20]=[CH:21][C:22]([Cl:25])=[N:23][CH:24]=1.N1C=CC=CC=1>CN(C)C1C=CN=CC=1.ClCCl>[CH3:1][N:2]([CH3:17])[C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[CH:6][CH:7]=[C:8]2[S:13]([NH:18][C:19]1[CH:20]=[CH:21][C:22]([Cl:25])=[N:23][CH:24]=1)(=[O:15])=[O:14]
Reactant: Nc1ccc(Cl)nc1
Reactant: CN(C)c1cccc2c(S(=O)(=O)Cl)cccc12
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CN(C)c1cccc2c(S(=O)(=O)Nc3ccc(Cl)nc3)cccc12
Reaction time: 72 h
Yield: 42.7 %

Procedure:
A solution of 5-dimethylamino-1-naphthalenesulphonyl chloride (1.35 g), 5-amino-2-chloropyridine (0.64 g), pyridine (0.4 g) and 4-dimethylaminopyridine (0.02 g) in dichloromethane (20 ml) was allowed to stand for three days. The solution was divided into two equal portions and each portion was applied to a separate silica gel Mega Bond Elut column. The columns were eluted with dichloromethane and the product-containing fractions were concentrated by evaporation. The residue was triturated with ether to give 5-(dimethylamino)-N-(2-chloro-5-pyridyl)-1-naphthalenesulphonamide (0.77 g); m.p. 145-146° C.; mass spectrum (+ve FAB, methanol/NBA): 362(M+H)+.
Reaction SMILES: [C:1]1([C:7]#[CH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:9][O:10][C:11](=[O:41])[CH2:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]#[C:23][C:24]2[CH:29]=[C:28]([C:30]#[C:31][CH2:32][N:33]3[CH2:38][CH2:37][O:36][CH2:35][CH2:34]3)[CH:27]=[C:26](Br)[CH:25]=2)=[CH:16][C:15]=1[CH3:40]>CN(C=O)C.C(N(CC)CC)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[CH3:9][O:10][C:11](=[O:41])[CH2:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]#[C:23][C:24]2[CH:25]=[C:26]([C:8]#[C:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH:27]=[C:28]([C:30]#[C:31][CH2:32][N:33]3[CH2:38][CH2:37][O:36][CH2:35][CH2:34]3)[CH:29]=2)=[CH:16][C:15]=1[CH3:40]
Reactant: C#Cc1ccccc1
Reactant: COC(=O)COc1ccc(OCC#Cc2cc(Br)cc(C#CCN3CCOCC3)c2)cc1C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)COc1ccc(OCC#Cc2cc(C#CCN3CCOCC3)cc(C#Cc3ccccc3)c2)cc1C
Temperature: 60 °C

Procedure:
A mixture of phenylacetylene (169 mg, 1.66 mmol), (4-{3-[3-bromo-5-(3-morpholin-4-yl-prop-1-ynyl)-phenyl]-prop-2-ynyloxy}-2-methyl-phenoxy)-acetic acid methyl ester (100 mg, 0.195 mmol, example 6), Pd(PPh3)2Cl2 (22 mg, 0.02 mmol), CuI (10 mg, 0.055 mmol) in dry DMF (2 ml) and triethylamine (2 ml) was heated in a microwave own for 1 hour at 60° C. in a sealed tube. The reaction mixture was filtered through Decalite and the filtrate was evaporated. The residue was purified on column chromatography using methylene chloride/THF mixtures to give (2-methyl-4-{3-[3-(3-morpholin-4-yl-prop-1-ynyl)-5-phenylethynylphenyl]-prop-2-ynyloxy}-phenoxy)-acetic acid methyl ester in 70 mg (67%) yield.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4](=[O:11])[C:5]2[CH:10]=[CH:9][S:8][C:6]=2[N:7]=1.C1C(=O)N([Cl:19])C(=O)C1>CC(O)=O>[Cl:19][C:9]1[S:8][C:6]2[N:7]=[C:2]([CH3:1])[NH:3][C:4](=[O:11])[C:5]=2[CH:10]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: Cc1nc2sccc2c(=O)[nH]1
Solvent: CC(=O)O
Product: Cc1nc2sc(Cl)cc2c(=O)[nH]1
Temperature: 40 °C
Reaction time: 48 h
Yield: 91.1 %

Procedure:
To a mixture of 2-methylthieno[2,3-d]pyrimidin-4(3H)-one (5.0 g) and AcOH (50 mL) was added NCS (4.8 g), followed by heating and stirring at 40° C. for 2 days. The reaction mixture was concentrated under reduced pressure. To the residue was added water, followed by stirring, and the precipitate was collected by filtration and then dried to obtain 6-chloro-2-methylthieno[2,3-d]pyrimidin-4(3H)-one (5.5 g).