Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH:10]([O:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]([OH:22])=O)=[CH:16][CH:15]=2)[CH2:9]1)=O)(C)(C)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.[CH:44]12[CH2:52][CH2:51][CH:48]([CH2:49][CH2:50]1)[CH2:47][NH:46][CH2:45]2.CCN(C(C)C)C(C)C>CN(C=O)C>[CH:44]12[CH2:52][CH2:51][CH:48]([CH2:49][CH2:50]1)[CH2:47][N:46]([C:20]([C:17]1[CH:16]=[CH:15][C:14]([O:13][CH:10]3[CH2:11][CH2:12][NH:8][CH2:9]3)=[CH:19][CH:18]=1)=[O:22])[CH2:45]2
Reactant: C1CC2CCC1CNC2
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(C(=O)O)cc2)C1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1ccc(OC2CCNC2)cc1)N1CC2CCC(CC2)C1
Reaction time: 0.17 h
Yield: 53.6 %

Procedure:
To a solution of 3-(4-carboxy-phenoxy)-pyrrolidine-1-carboxylic acid t-butyl ester (2.0 g, 6.53 mmol) in DMF (75 mL) was added HOBt (1.1 g, 7.83 mmol) and EDAC (1.5 g, 7.83 mmol) and the resulting mixture was stirred for 10 min. 3-Aza-bicyclo-[3.2.2]nonane (1 g, 7.83 mmol) and DIPEA (1.4 mL) were added and stirring was continued for 16 hrs at ambient temperature. The volatiles were evaporated in vacuo and to the residue was added water (50 mL) and diethyl ether (25 mL). A precipitate was forme, filtered off and redissolved in DCM (25 mL) followed by addition of TFA (10 mL). The mixture was stirred at room temperature for 16 hrs and the volatiles evaporated in vacuo. The residue was dissolved in water (50 mL) and washed with diethyl ether (2×10 mL). The pH of the aqueous phase was adjusted to ˜11 by addition of 32% NaOH followed by extraction with diethyl ether (2×50 mL). The combined organic phases were dried (Na2SO4), filtered and evaporated in vacuo. The crude residue was stirred with EtOAc (20 mL) and the precipitate formed was filtered off. The filtrate was evaporated to dryness affording crude 1.1 g (55%) of (3-aza-bicyclo[3.2.2]non-3-yl)-[4-(pyrrolidin-3-yloxy)-phenyl]-methanone which was used without further purification.
Reaction SMILES: [C:1]([O:5][C:6](=[O:29])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:15]=[N:16][C:17]([O:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:18][CH:19]=2)=[CH:10][C:9]=1[NH2:28])([CH3:4])([CH3:3])[CH3:2].[N:30]1([C:35]2[CH:36]=[C:37]([C:41]3[O:46]C(C)(C)[O:44][C:43](=O)[CH:42]=3)[CH:38]=[CH:39][CH:40]=2)[CH:34]=[CH:33][N:32]=[CH:31]1>>[C:1]([O:5][C:6](=[O:29])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:15]=[N:16][C:17]([O:20][CH2:21][C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)=[CH:18][CH:19]=2)=[CH:10][C:9]=1[NH:28][C:43](=[O:44])[CH2:42][C:41]([C:37]1[CH:38]=[CH:39][CH:40]=[C:35]([N:30]2[CH:34]=[CH:33][N:32]=[CH:31]2)[CH:36]=1)=[O:46])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2ccc(OCc3ccccc3)nc2)cc1N
Reactant: CC1(C)OC(=O)C=C(c2cccc(-n3ccnc3)c2)O1
Product: CC(C)(C)OC(=O)Nc1ccc(-c2ccc(OCc3ccccc3)nc2)cc1NC(=O)CC(=O)c1cccc(-n2ccnc2)c1
Yield: 69.2 %

Procedure:
Prepared from [2-amino-4-(6-benzyloxy-pyridin-3-yl)-phenyl]-carbamic acid tert.-butyl ester (Example G30) (196 mg, 0.5 mmol) and 6-(3-imidazol-1-yl-phenyl)-2,2-dimethyl-[1,3]dioxin-4-one (Example J10) (229 mg, 0.85 mmol) according to the general procedure K. Obtained as a yellow solid (209 mg).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12](=[O:16])[CH2:13][CH2:14][CH3:15])=[C:5]2Cl.[NH2:18][C:19]1[CH:20]=[CH:21][C:22]([N:25]2[CH2:30][CH2:29][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:27][CH2:26]2)=[N:23][CH:24]=1>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12](=[O:16])[CH2:13][CH2:14][CH3:15])=[C:5]2[NH:18][C:19]1[CH:20]=[CH:21][C:22]([N:25]2[CH2:30][CH2:29][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:27][CH2:26]2)=[N:23][CH:24]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(N)cn2)CC1
Reactant: CCCC(=O)c1cnc2ccc(Br)cc2c1Cl
Product: CCCC(=O)c1cnc2ccc(Br)cc2c1Nc1ccc(N2CCN(C(=O)OC(C)(C)C)CC2)nc1
Yield: 69 %

Procedure:
Following general procedure C, 1-(6-bromo-4-chloroquinolin-3-yl)butan-1-one (360 mg, 1.15 mmol) was reacted with tert-butyl 4-(5-aminopyridin-2-yl)piperazine-1-carboxylate (480 mg, 1.73 mmol) to afford the desired product (440 mg, 69%) as an orange solid: ESI MS m/z 554 [C27H32BrN5O3+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:29]=[C:30]([O:34][CH3:35])[C:31]=1[O:32][CH3:33])[C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C:10]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[C:23]([Cl:28])[CH:22]=2)([CH2:14][CH2:15]OS(C)(=O)=O)[CH2:9]1)=[O:7].[CH2:36]([O:38][CH2:39][CH2:40][N:41]1[C:45]2[CH:46]=[CH:47][CH:48]=[CH:49][C:44]=2[N:43]=[C:42]1[NH:50][CH:51]1[CH2:56][CH2:55][NH:54][CH2:53][CH2:52]1)[CH3:37].C(N(CC)C(C)C)(C)C.CO>C(#N)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:29]=[C:30]([O:34][CH3:35])[C:31]=1[O:32][CH3:33])[C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C:10]([CH2:14][CH2:15][N:54]2[CH2:53][CH2:52][CH:51]([NH:50][C:42]3[N:41]([CH2:40][CH2:39][O:38][CH2:36][CH3:37])[C:45]4[CH:46]=[CH:47][CH:48]=[CH:49][C:44]=4[N:43]=3)[CH2:56][CH2:55]2)([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[C:23]([Cl:28])[CH:22]=2)[CH2:9]1)=[O:7]
Reactant: CCOCCn1c(NC2CCNCC2)nc2ccccc21
Reactant: COc1cc(C(=O)N2CCCC(CCOS(C)(=O)=O)(c3ccc(Cl)c(Cl)c3)C2)cc(OC)c1OC
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: CCOCCn1c(NC2CCN(CCC3(c4ccc(Cl)c(Cl)c4)CCCN(C(=O)c4cc(OC)c(OC)c(OC)c4)C3)CC2)nc2ccccc21
Reaction time: 36 h

Procedure:
Combine 1-(3,4,5-trimethoxybenzoyl)-3-(3,4-dichlorophenyl)-3-(2-methanesulfonyloxyethyl)piperidine (0.71 g, 1.32 mmol) and (1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)(piperidin-4-yl)amine (0.38 g, 1.32 mmol), and N,N-diisopropylethylamine (0.37 g, 2.9 mmol) in acetonitrile (15 mL). Heat to reflux. After 36 hours, partition the residue between ethyl acetate and saturated aqueous sodium bicarbonate solution. Dry the organic layer over Na2SO4, filter, and concentrate in vacuo to obtain a residue. Chromatograph the residue on silica gel eluting with 15% methanol/2% triethylamine/ethyl acetate to give the title compound. Elemental Analysis calculated for C39H49Cl2N5O5: C 3.40; H 6.68; N 9.48; Found: C 63.68; H 6.69; N 9.57.
Reaction SMILES: FC(F)(F)S(OC1C=C(OC)C=CC=1CC1C=CC=C(OC)C=1)(=O)=O.C(OC1C=CC(B(O)O)=CC=1)C1C=CC=CC=1.C([O:50][C:51]1[CH:56]=[CH:55][C:54]([C:57]2[CH:62]=[C:61]([O:63][CH3:64])[CH:60]=[CH:59][C:58]=2[CH2:65][C:66]2[CH:71]=[CH:70][CH:69]=[C:68]([O:72][CH3:73])[CH:67]=2)=[CH:53][CH:52]=1)C1C=CC=CC=1>>[CH3:64][O:63][C:61]1[CH:60]=[CH:59][C:58]([CH2:65][C:66]2[CH:71]=[CH:70][CH:69]=[C:68]([O:72][CH3:73])[CH:67]=2)=[C:57]([C:54]2[CH:53]=[CH:52][C:51]([OH:50])=[CH:56][CH:55]=2)[CH:62]=1
Reactant: COc1cccc(Cc2ccc(OC)cc2-c2ccc(OCc3ccccc3)cc2)c1
Agent: COc1cccc(Cc2ccc(OC)cc2OS(=O)(=O)C(F)(F)F)c1
Agent: OB(O)c1ccc(OCc2ccccc2)cc1
Product: COc1cccc(Cc2ccc(OC)cc2-c2ccc(O)cc2)c1
Yield: 64.5 %

Procedure:
Synthesized from 5-methoxy-2-(3-methoxybenzyl)phenyl trifluoromethanesulfonate and 4-benzyloxyphenylboronic acid according to an analogous synthetic method to Example 24, 4′-benzyloxy-5-methoxy-2-(3-methoxybenzyl)biphenyl (332 mg) was used according to an analogous synthetic method to Example 22 to provide the title compound (167 mg).
Reaction SMILES: [CH2:1]([C:3]1[O:7][C:6]([CH:8]=[CH:9][C:10]([O-:12])=[O:11])=[CH:5][CH:4]=1)[CH3:2].[CH2:13](O)C>[Pd]>[CH2:1]([C:3]1[O:7][C:6]([CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])=[CH:5][CH:4]=1)[CH3:2]
Reactant: CCc1ccc(C=CC(=O)[O-])o1
Reactant: CCO
Agent: [Pd]
Product: CCc1ccc(CCC(=O)OC)o1

Procedure:
To a suspension of ethanol (200 mL) and 300 mg of 5% palladium on carbon was added 14.8 g (82.1 mmol) of 3-(5-ethyl-2-furanyl)propenoate at room temperature and the mixture was placed on a Paar hydrogenator and hydrogenated with H2. Palladium on carbon was filtered off bypassing the reaction mixture through a filter aid, Super-Cel™ and the residue was washed with ethanol several times. The filtrate was concentrated in vacuo, methylene chloride was added to the residue and the solvent was removed in vacuo to afford 14.9 g methyl 3-(5-ethyl-2-furanyl)propanoate. This ester was used without further purification.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:19][CH3:20])=[C:6]([C:8]([CH3:18])([CH3:17])[CH2:9][C:10]2([C:13]([F:16])([F:15])[F:14])[CH2:12][O:11]2)[CH:7]=1.[NH2:21][C:22]1[CH:31]=[CH:30][CH:29]=[C:28]2[C:23]=1[CH:24]=[CH:25][CH:26]=[N:27]2>CCCCCC.C(OCC)(=O)C>[N:27]1[C:28]2[C:23](=[C:22]([NH:21][CH2:12][C:10]([C:13]([F:16])([F:15])[F:14])([OH:11])[CH2:9][C:8]([C:6]3[CH:7]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=3[O:19][CH3:20])([CH3:18])[CH3:17])[CH:31]=[CH:30][CH:29]=2)[CH:24]=[CH:25][CH:26]=1
Reactant: Nc1cccc2ncccc12
Reactant: COc1ccc(F)cc1C(C)(C)CC1(C(F)(F)F)CO1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: COc1ccc(F)cc1C(C)(C)CC(O)(CNc1cccc2ncccc12)C(F)(F)F
Yield: 27.7 %

Procedure:
Analogously to Example 1, 200 mg (0.48 mmol) of 2-[2-(5-fluoro-2-methoxyphenyl)-2-methylpropyl]-2-(trifluoromethyl)oxirane is reacted with 99 mg (0.68 mmol) of 5-aminoquinoline. After chromatography on silica gel with hexane-ethyl acetate (0-70%), 58 mg of the product is obtained.
Reaction SMILES: CC1(C)CO[C:4]([C:7]2[CH:8]=[C:9]3[C:13](=[CH:14][CH:15]=2)[C:12](=[O:16])[O:11][CH2:10]3)=[N:3]1.CN(C)C=O.C1(C)C=CC=CC=1>S(Cl)(Cl)=O>[C:4]([C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[C:12](=[O:16])[O:11][CH2:10]2)#[N:3]
Reactant: CC1(C)COC(c2ccc3c(c2)COC3=O)=N1
Solvent: O=S(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: N#Cc1ccc2c(c1)COC2=O
Temperature: 25 °C

Procedure:
To a suspension of 4,4-dimethyl-2-(1-oxo-1,3-dihydroisobenzofuran-5-yl)oxazoline (23.1 g, 0.1 mol) in thionyl chloride (36 mL) is slowly added N,N-dimethylformamide (5 ml). The solution is heated at reflux for 1 hour and then allowed to cool to room temperature over 3 hours. Then toluene (150 mL) is added and the suspension is filtered and washed with toluene (2×50 mL). The wet crystals are taken into deionized water (150 mL) and the pH is adjusted to 8.0 with 25% aqueous ammonia. The solid is filtered and washed with deionized water (2×50 mL) and dried at 60° C. under reduced pressure. Yield: 11.9 g (75%) of an off-white product having a purity (HPLC, peak area)=92%. An analytical pure sample is obtained by crystallisation from acetic acid or toluene. 1H NMR (DMSO d-6, 500 MHz): 5.48 (2H, s), 8.04 (2H, s+s), 8.22 (1H, s).
Reaction SMILES: CN(C)C=O.[NH2:6][C:7]1[N:12]=[C:11]([N:13]2[C:22]3[C:17](=[CH:18][C:19]([F:25])=[C:20](F)[C:21]=3[Cl:23])[C:16](=[O:26])[C:15]([C:27]([OH:29])=[O:28])=[CH:14]2)[C:10]([F:30])=[CH:9][C:8]=1[F:31].Cl.Cl.[NH2:34][CH:35]1[CH2:38][NH:37][CH2:36]1.CN1CCCC1>C(O)C>[NH2:34][CH:35]1[CH2:38][N:37]([C:20]2[C:21]([Cl:23])=[C:22]3[C:17]([C:16](=[O:26])[C:15]([C:27]([OH:29])=[O:28])=[CH:14][N:13]3[C:11]3[C:10]([F:30])=[CH:9][C:8]([F:31])=[C:7]([NH2:6])[N:12]=3)=[CH:18][C:19]=2[F:25])[CH2:36]1
Reactant: Nc1nc(-n2cc(C(=O)O)c(=O)c3cc(F)c(F)c(Cl)c32)c(F)cc1F
Reactant: NC1CNC1
Agent: CN1CCCC1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCO
Product: Nc1nc(-n2cc(C(=O)O)c(=O)c3cc(F)c(N4CC(N)C4)c(Cl)c32)c(F)cc1F
Temperature: 90 °C
Reaction time: 1 h
Yield: 75.8 %

Procedure:
To 350 mg of N,N-dimethylformamide were added 100 mg of 1-(6-amino-3,5-difluoropyridin-2-yl)-8-chloro-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid, 80 mg of 3-aminoazetidine dihydrochloride and 150 mg of N-methylpyrrolidine, and the mixture was stirred at 90° C. for 1 hour. After adding 1 ml of ethanol, the mixture was allowed to cool, and the precipitate was collected by filtration and washed with ethanol and diisopropylether successively to obtain 86 mg of the title compound as a colorless powder.
Reaction SMILES: N1C=CC(NC[CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=CN=1.O=C1CCC(=O)N1[O:22][C:23](=O)[O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>CN(C=O)C>[CH2:25]([O:24][C:23]([N:12]1[CH2:11][CH2:10][CH2:9][CH2:14][CH2:13]1)=[O:22])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Reactant: c1cc(NCC2CCNCC2)cnn1
Solvent: CN(C)C=O
Product: O=C(OCc1ccccc1)N1CCCCC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of 4-[(pyridazin-4-ylamino)-methyl]-piperidine (0.20 g, 1.04 mmol), in DMF (3 mL) was added carbonic acid benzyl ester 2,5-dioxo-pyrrolidin-1-yl ester (0.26 g, 1.04 mmol). The resulting reaction solution was stirred at rt for 0.5 h, then concentrated in vacuo. The residue was purified by silica gel chromatography (1-7 (10% NH4OH in MeOH)/99-93 CH2Cl2) to give 4-(pyridazin-4-ylamino)-methyl]-piperidine-1-carboxylic acid benzyl ester.
Reaction SMILES: N1C=CC=C[C:2]=1C(C1C=CC=CN=1)=O.[Br-].[C:16]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([OH:18])=[O:17].CC([O-])(C)C.[K+]>C1COCC1>[C:16]([OH:18])(=[O:17])/[CH:19]=[CH:20]\[CH2:21][CH2:22][CH2:23][CH3:2]
Reactant: O=C(c1ccccn1)c1ccccn1
Reactant: O=C(O)CCCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCCC/C=C\C(=O)O
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 59.1 %

Procedure:
To a cooled (0° C.) solution of 293.6 mg (0.74 mmol) of the pyridyl ketone and 670.4 mg (1.48 mmol) of (5-carboxypentyl)-triphenylphosphonium bromide in 2.5 mL of THF was added dropwise 2.95 mL (2.95 mmol) of 1.0 M t-BuOK in THF over 10 min period. The dark brown solution was stirred at 0° C. for 1.5 h, and then the reaction was quenched with 20 mL of saturated aqueous NH4Cl. The mixture was extracted with 3× 50 ML of CH2Cl2. The combined extract was dried over MgSO4, concentrated and purified by preparative HPLC with MeOH--AcOH--CH2Cl2 (2:1:97) as the eluent to afford 56.1 mg (8.4%) of the less polar (Z)-heptenoic acid and 434.9 mg of the (E)-isomer containing a byproduct from the Wittig salt. In order to purify it, the (E)-isomer was therefore esterified with CH2N2 which was generated by a standard method from MNNG and aqueous NaOH in Et2O. The ester was isolated cleanly by flash chromatography with EtOAc-hexanes-CH2Cl2 (2:1:1) as the eluent. The ester (102.5 mg) was then hydrolyzed with 1 N NaOH in THF--MeOH (1:1). Flash chromatography with EtOAc--MeOH--AcOH--CH2Cl2 (50:1:1:48) yielded 92.5 mg (25%) of the pure (E)-heptenoic acid: mp 56-61° C.; 1H NMR (CDCl3) δ8.58 (s, 1H), 8.47 (d, J=4.1 Hz, 1H), 8.26 (s, 1H), 8.02 (d, J=8.2 Hz, 2H), 7.44 (dt, J=8.0, 1.5 Hz, 1H), 7.35-7.16 (m, 9H), 6.19 (t, J=7.4 Hz, 1H), 3.70 (dt, J=6.9, 6.7 Hz, 2H), 2.94 (t, J=7.2 Hz, 2H), 2.32 (t, J=7.8 Hz, 2H), 2.20 (ddd, J=7.3, 7.2, 7.0 Hz, 2H), 1.68-1.51 (m, 4H); FDMS 496 (M+1). Anal. (C30H29N3O4.0.1C2H4O2) C, H, N.
Reaction SMILES: [F:1]C1N=CC=CC=1C(O)=O.[C:11]([O:15][C:16](=[O:29])[NH:17][C:18]1[CH:19]=[N:20][C:21](C(F)(F)F)=[CH:22][C:23]=1[I:24])([CH3:14])([CH3:13])[CH3:12]>>[C:11]([O:15][C:16](=[O:29])[NH:17][C:18]1[C:19]([F:1])=[N:20][CH:21]=[CH:22][C:23]=1[I:24])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)OC(=O)Nc1cnc(C(F)(F)F)cc1I
Reactant: O=C(O)c1cccnc1F
Product: CC(C)(C)OC(=O)Nc1c(I)ccnc1F

Procedure:
The title product was prepared from 2-fluoronicotinic acid in the same manner as in the preparation of (4-iodo-6-trifluoromethylpyridin-3-yl)carbamic acid tert-butyl ester.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:14](=[S:15])[CH:13]2[CH:9]1[CH2:10][CH2:11][CH2:12]2)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH3:16]>CO>[C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:10][CH2:11][CH2:12][CH:13]1[C:14](=[S:15])[NH2:16])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: N
Reactant: CC(C)(C)OC(=O)N1C(=S)C2CCCC21
Solvent: CO
Product: CC(C)(C)OC(=O)NC1CCCC1C(N)=S
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
In 42 ml of 29% aqueous ammonia and 60 ml of methanol, 1.48 g of 6-tert-butoxycarbonyl-6-azabicyclo[3.2.0]heptane-7-thione was dissolved, followed by stirring at room temperature for 30 minutes. The solvent was azeotropically evaporated using benzene-ethanol, whereby 1.39 g of 2-(tert-butoxycarbonylamino)cyclopentanecarbothioamide was obtained as the crystal form.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[Cl:12])=[CH:9][CH:8]=[CH:7][CH:6]=2.[CH3:13][C:14]([CH3:19])([CH3:18])[C:15](Cl)=[O:16].ClC(Cl)C>ClCCl>[Cl:12][C:11]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=[CH:3][C:2]=1[NH:1][C:15](=[O:16])[C:14]([CH3:19])([CH3:18])[CH3:13]
Reactant: CC(C)(C)C(=O)Cl
Reactant: Nc1cnc2ccccc2c1Cl
Solvent: ClCCl
Solvent: CC(Cl)Cl
Product: CC(C)(C)C(=O)Nc1cnc2ccccc2c1Cl
Temperature: 70 °C

Procedure:
A mixture of 3-amino-4-chloroquinoline (8.00 g, 1 eq), trimethylacetyl chloride (11 mL g, 2 eq), and anhydrous dichloroethane (150 mL) was heated at 70° C. After 6 hours more trimethylacetyl chloride (2 eq) was added and heating was continued for a total of 23 hours. The reaction mixture was diluted with dichloromethane, washed sequentially with saturated aqueous potassium carbonate, water, and brine, dried over sodium sulfate, filtered, and then concentrated under reduced pressure. The residue was triturated with hexanes and then filtered to provide 7.16 g of N-(4-chloroquinolin-3-yl)trimethylacetamide as a solid. The filtrate was concentrated under reduced pressure to provide 5 g of crude N-(4-chloroquinolin-3-yl)trimethylacetamide.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[C:9]([C:10](O)=[O:11])=[CH:8][N:7]=[C:6]([S:13][CH3:14])[N:5]=1)[CH3:2].C(N(CC)CC)C.N1C(F)=NC(F)=NC=1[F:24]>C(Cl)Cl>[CH2:1]([NH:3][C:4]1[C:9]([C:10]([F:24])=[O:11])=[CH:8][N:7]=[C:6]([S:13][CH3:14])[N:5]=1)[CH3:2]
Reactant: Fc1nc(F)nc(F)n1
Reactant: CCNc1nc(SC)ncc1C(=O)O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCNc1nc(SC)ncc1C(=O)F
Temperature: 0 °C
Reaction time: 3 h
Yield: 99.6 %

Procedure:
To a solution containing 3.0 g (14.0 mmol) of 4-ethylamino-2-methylthio-5-pyrimidinecarboxylic acid and 2.1 mL (15.0 mmol) of triethylamine in 50 mL of CH2Cl2 are added 2.3 mL (28.0 mmol) of cyanuric fluoride. The mixture is stirred for 3 hours and the solution is diluted with 250 mL of CH2Cl2 and 75 mL of ice-cold water. After separation of the phases by settling, the organic phase is washed with 75 mL of ice-cold water and dried over MgSO4. The solvent is then evaporated off under reduced pressure. 3.0 g of expected product are obtained in the form of a greenish gum. The yield is quantitative.
Reaction SMILES: [Cl:1][C:2]1[N:9]=[C:8](Cl)[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[F:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[O:19][C:20]3[CH:30]=[C:29]([N:31]([CH3:36])[S:32]([CH3:35])(=[O:34])=[O:33])[C:28](B4OC(C)(C)C(C)(C)O4)=[CH:27][C:21]=3[C:22]=2[C:23]([NH:25][CH3:26])=[O:24])=[CH:14][CH:13]=1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O.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]>[Cl:1][C:2]1[N:9]=[C:8]([C:28]2[C:29]([N:31]([CH3:36])[S:32]([CH3:35])(=[O:34])=[O:33])=[CH:30][C:20]3[O:19][C:18]([C:15]4[CH:16]=[CH:17][C:12]([F:11])=[CH:13][CH:14]=4)=[C:22]([C:23]([NH:25][CH3:26])=[O:24])[C:21]=3[CH:27]=2)[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5]
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(C)S(C)(=O)=O)c(B3OC(C)(C)C(C)(C)O3)cc12
Reactant: O=Cc1ccc(Cl)nc1Cl
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(C)S(C)(=O)=O)c(-c3ccc(C=O)c(Cl)n3)cc12
Temperature: 80 °C
Reaction time: 8 h
Yield: 86.3 %

Procedure:
To a degassed solution of 2,6-dichloronicotinaldehyde (315 mg, 1.79 mmol) and 2-(4-fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-3-carboxamide (600 mg, 1.19 mmol) in 1,4-dioxane (8 mL) and water (300 μL) was added K2CO3 (330 mg, 2.40 mmol) and Pd(dppf)Cl2 (175 mg, 0.24 mmol) under N2 protection. The resulting mixture was heated to 80° C. and stirred at this temperature overnight. The reaction was cooled, filtered through a pad of celite and washed with ethyl acetate. The combined filtrate was evaporated in vacuo. The resulting residue was purified using column chromatography (eluted with 0-30% EtOAc/DCM) to provide 5-(6-chloro-5-formylpyridin-2-yl)-2-(4-fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide (530 mg, yield: 86%) MS (M+H)+: 516.
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([OH:10])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].C(=O)([O-])[O-].[K+].[K+].[I-].[K+].[N:19]1[CH:24]=[CH:23][C:22]([CH2:25]Cl)=[CH:21][CH:20]=1>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C(C(C)=O)C>[F:1][C:2]1[CH:9]=[C:8]([O:10][CH2:25][C:22]2[CH:23]=[CH:24][N:19]=[CH:20][CH:21]=2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: ClCc1ccncc1
Reactant: N#Cc1ccc(O)cc1F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [Br-]
Solvent: CCC(C)=O
Product: N#Cc1ccc(OCc2ccncc2)cc1F

Procedure:
A mixture of 2-fluoro-4-hydroxybenzonitrile (10.96 g; S. M. Kelly, Helv. Chim. Acta 1984, volume 67, p1572-1579), potassium carbonate (53.2 g), potassium iodide (6.64 g), tetra-n-butylammonium bromide (0.4 g) and 4-picolyl chloride (14.4 g) in methyl ethyl ketone (600 ml) was stirred at reflux for 3 hours. The reaction mixture was filtered and the insoluble material washed with methyl ethyl ketone. The combined filtrate plus washings were evaporated and the residue partitioned between ethyl acetate (300 ml) and water (150 ml). The aqueous phase was extracted twice with ethyl acetate (100 ml) and the combined ethyl acetate solutions washed with brine (100 ml), dried over magnesium sulphate and evaporated. The residue was recrystallized from a mixture of ethyl acetate and pentane to give the title compound (11.5 g) as a plum coloured solid, m.p. 132-133° C.
Reaction SMILES: C([O:9][C:10]1[CH:15]=[C:14]([Cl:16])[C:13]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([F:25])=[C:21]([O:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH:20]=2)=[C:12]([Cl:33])[CH:11]=1)(=O)C1C=CC=CC=1.[OH-].[K+].Cl>CO>[Cl:16][C:14]1[CH:15]=[C:10]([OH:9])[CH:11]=[C:12]([Cl:33])[C:13]=1[O:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([F:25])=[C:21]([O:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:20]=1
Reactant: O=C(Oc1cc(Cl)c(OCc2ccc(F)c(Oc3ccccc3)c2)c(Cl)c1)c1ccccc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: Oc1cc(Cl)c(OCc2ccc(F)c(Oc3ccccc3)c2)c(Cl)c1
Reaction time: 1 h
Yield: 90.9 %

Procedure:
A reaction vessel was charged with 1.36 g of 3,5-dichloro-4-(4-fluoro-3-phenoxybenzyloxy)phenyl benzoate and 10 ml of methanol, to which 4.2 g of 10% potassium hydroxide solution was slowly added dropwise under ice cooling. After stirring for 1 hour, the reaction mixture was made weakly acidic by the addition of 10% hydrochloric acid, and extracted twice with 50 ml of diethyl ether under salting out. The combined ether layer was washed with water, dried with anhydrous magnesium sulfate, and concentrated to obtain a crude product. The crude product was subjected to silica gel chromatography, which afforded 0.97 g of 3,5-dichloro-4-(4-fluoro-3-phenoxybenzyloxy)phenol (91% yield), m.p. 144.8° C.
Reaction SMILES: C([Mg]Br)C.[O:5]([CH2:12][C:13]#[CH:14])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.Br[CH2:16][C:17]#[C:18][CH2:19][C:20]#[CH:21].S(=O)(=O)(O)O>CCOCC.O1CCCC1>[O:5]([CH2:12][C:13]#[C:14][CH2:16][C:17]#[C:18][CH2:19][C:20]#[CH:21])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: C#CCC#CCBr
Reactant: C#CCOc1ccccc1
Agent: CC[Mg]Br
Agent: O=S(=O)(O)O
Solvent: C1CCOC1
Solvent: CCOCC
Product: C#CCC#CCC#CCOc1ccccc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
4.81 ml (1.92 g, 14.4 mmol) of a 3N solution of ethylmagnesium bromide in ether was added dropwise under argon to a solution of 2 g (15.15 mmol) of 3-phenoxy-1-propyne (G. Pourcelot, et al., Bull. Soc. Chim., France, (1966), pp 3016-24, in 15 ml of anhydrous tetrahydrofuran. The rate of addition was adjusted to maintain the temperature at 0° C. Thereafter, the reaction mixture was stirred for 1 hour further at 0°-5° C. Then, 77 mg of cuprous cyanide was added. After stirring 20 minutes more, a solution of 1.13 g (7.22 mmol) of 1-bromo-2,5-hexadiyne in 10 ml of anhydrous tetrahydrofuran was added dropwise. The temperature was maintained at between 0°-5° C.The resulting mixture was stirred at room temperature for 3 additional hours, then poured into 60 ml of 1N sulfuric acid and ice, and the resulting solution extracted with ether (3×100 ml). The combined organic extracts were concentrated in vacuo to a small volume, and washed several times with EDTA and water, dried over sodium sulfate and evaporated. The crude material was purified by TLC using hexane:methylene chloride (80:20) as the eluant, and the product crystallized from methylene chloride-hexane, to yield 9-phenoxy-1,4,7-nonatriyne, as an oil.The product was stored in dry ice.