Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[CH2:2][CH2:3][N:4]1[C:13](=[O:14])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]=[C:5]1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.S(Cl)([Cl:23])=O>ClC(Cl)Cl>[Cl:23][CH2:2][CH2:3][N:4]1[C:13](=[O:14])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]=[C:5]1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=c1c2ccccc2nc(-c2ccccc2)n1CCO
Reactant: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Product: O=c1c2ccccc2nc(-c2ccccc2)n1CCCl
Reaction time: 2 h

Procedure:
To a stirred mixture of 15 parts of 3-(2-hydroxyethyl)-2-phenyl-4(3H)-quinazolineone and 375 parts of trichloromethane are added dropwise 24 parts of thionyl chloride at room temperature. Upon completion, stirring is continued for 2 hours at reflux. The reaction mixture is evaporated. Water is added to the residue and the whole is neutralized with a sodium hydrogen carbonate solution. The product is extracted with trichloromethane. The extract is washed with water, dried, filtered and evaporated. The residue is crystallized from a mixture of 2,2'-oxybispropane and petroleumether. The product is filtered off and dried, yielding 11.6 parts of 3-(2-chloroethyl)-2-phenyl-4(3H)-quinazolinone.
Reaction SMILES: [CH2:1]([N:3]([CH2:37][CH3:38])[CH2:4][CH2:5][CH2:6][NH:7][C:8]1[N:9]=[C:10]([C:27]2[CH:28]=[C:29]([CH:33]=[CH:34][C:35]=2[CH3:36])[C:30]([OH:32])=O)[C:11]2[CH:17]=[CH:16][C:15](=[O:18])[N:14]([C:19]3[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:20]=3[F:26])[C:12]=2[N:13]=1)[CH3:2].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.Cl.[NH2:71][CH2:72][CH2:73][C:74]#[N:75]>CN(C=O)C>[C:72]([CH2:73][CH2:74][NH:75][C:30](=[O:32])[C:29]1[CH:33]=[CH:34][C:35]([CH3:36])=[C:27]([C:10]2[C:11]3[CH:17]=[CH:16][C:15](=[O:18])[N:14]([C:19]4[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:20]=4[F:26])[C:12]=3[N:13]=[C:8]([NH:7][CH2:6][CH2:5][CH2:4][N:3]([CH2:1][CH3:2])[CH2:37][CH3:38])[N:9]=2)[CH:28]=1)#[N:71]
Reactant: CCN(CC)CCCNc1nc(-c2cc(C(=O)O)ccc2C)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Reactant: N#CCCN
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCN(CC)CCCNc1nc(-c2cc(C(=O)NCCC#N)ccc2C)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 20.9 %

Procedure:
To the compound 3-[2-{[3-(diethylamino)propyl]amino}-8-(2,6-difluorophenyl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl]-4-methylbenzoic acid (26 mg, 0.05 mmol) in DMF (0.5 mL) were added HBTU (28 mg, 0.075 mmol), triethylamine (21.1 uL, 0.15 mmol) and 3-aminopropanenitrile hydrochloride (9.3 mg, 0.1 mmol). The mixture was stirred at rt overnight. Separation by HPLC with TFA, followed by neutralization with SPE amine cartridge afforded the title compound (6 mg, 21%). LC-MS m/z 560 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[S:10][CH:9]=[C:8]([CH2:11][CH2:12][CH3:13])[C:6]=2[N:7]=1.[CH3:15][NH2:16]>CN(C=O)C.CO>[Cl:1][C:2]1[N:3]=[C:4]([NH:16][CH3:15])[C:5]2[S:10][CH:9]=[C:8]([CH2:11][CH2:12][CH3:13])[C:6]=2[N:7]=1
Reactant: CCCc1csc2c(Cl)nc(Cl)nc12
Reactant: CN
Solvent: CO
Solvent: CN(C)C=O
Product: CCCc1csc2c(NC)nc(Cl)nc12
Temperature: 0 °C
Reaction time: 1 h
Yield: 51.5 %

Procedure:
To 10 ml of a solution of 100 mg (0.41 mmol) of 2,4-dichloro-7-propylthieno[3,2-d]pyrimidine in DMF was added 40% methylamine solution in methanol under ice cooling. The reaction mixture was stirred at the same temperature for one hour and then allowed to resume room temperature, followed by stirring for further 2 hours. After completion of the reaction, ice water was added to the reaction mixture, followed by extraction with ethyl acetate (50 ml×3). After the organic layer was washed successively with 1N hydrochloric acid, water and brine and dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (eluent: ethyl acetate-hexane=1/2) to give 50 mg (yield: 51.5%) of the title compound.
Reaction SMILES: [CH3:1][C:2]1([C:7]2[O:11][C:10]([CH2:12][N:13]3[CH:17]=[CH:16][C:15]([NH2:18])=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.C([SiH2][O:24][C:25](C)(C)[C:26]1[CH:27]=[C:28]([C:32]2[O:36][CH:35]=[N:34][C:33]=2[C:37](O)=[O:38])[CH:29]=[CH:30][CH:31]=1)(C)(C)C>>[C:2]([C:7]1[O:11][C:10]([CH2:12][N:13]2[CH:17]=[CH:16][C:15]([NH:18][C:37]([C:33]3[N:34]=[CH:35][O:36][C:32]=3[C:28]3[CH:29]=[CH:30][CH:31]=[C:26]([CH2:25][OH:24])[CH:27]=3)=[O:38])=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: CC1(c2ccc(Cn3ccc(N)n3)o2)OCCO1
Reactant: CC(C)(C)[SiH2]OC(C)(C)c1cccc(-c2ocnc2C(=O)O)c1
Product: CC(=O)c1ccc(Cn2ccc(NC(=O)c3ncoc3-c3cccc(CO)c3)n2)o1

Procedure:
Following general procedure B followed by C, starting from 1-[5-(2-methyl-[1,3]dioxolan-2-yl)-furan-2-ylmethyl]-1H-pyrazol-3-ylamine and 5-[3-(tert-butyl-dimethyl-silanyloxymethyl)-phenyl]-oxazole-4-carboxylic acid. LC-MS-conditions 02: tR=0.86 min; [M+H]+=407.37.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]1[CH2:16][CH2:15][N:14]([C@H:17]2[CH2:22][CH2:21][C@@H:20]([N:23]([CH:25]([CH3:27])[CH3:26])[CH3:24])[CH2:19][C@H:18]2[NH:28]C(=O)OCC[Si](C)(C)C)[C:13]1=[O:38])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>ClCCl>[NH2:28][C@@H:18]1[CH2:19][C@H:20]([N:23]([CH:25]([CH3:27])[CH3:26])[CH3:24])[CH2:21][CH2:22][C@@H:17]1[N:14]1[CH2:15][CH2:16][C@H:12]([NH:11][C:9](=[O:10])[O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:13]1=[O:38]
Reactant: CC(C)N(C)[C@@H]1CC[C@H](N2CC[C@H](NC(=O)OCc3ccccc3)C2=O)[C@H](NC(=O)OCC[Si](C)(C)C)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)N(C)[C@@H]1CC[C@H](N2CC[C@H](NC(=O)OCc3ccccc3)C2=O)[C@H](N)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 94.4 %

Procedure:
A stirring solution of 2-(trimethylsilyl)ethyl (1R,2S,5R)-2-((S)-3-benzyloxycarbonylamino-2-oxopyrrolidin-1-yl)-5-(isopropyl(methyl)amino)cyclohexylcarbamate (272 mg, 0.5 mmol) in dichloromethane (3 mL) was charged with trifluoroacetic acid (2 mL). The reaction was stirred for 2 h at room temperature and concentrated in vacuo. The residue was dissolved in dichloromethane (50 ml) and washed with saturated NaHCO3 (15 ml). the aqueous layer was extracted with dichloromethane (4×30 ml). Combined all the dichloromethane layers and dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to give benzyl (S)-1-((1S,2R,4R)-2-amino-4-(isopropyl(methyl)amino)cyclohexyl)-2-oxopyrrolidin-3-ylcarbamate (190 mg, 94.5%). LC/MS found [M+H]+=403.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:22]=[CH:21][C:10]([CH2:11][CH2:12][O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])=[C:9]([CH2:23][CH3:24])[CH:8]=1.[B:25](OC)([O:28]C)[O:26]C.Cl>C1COCC1>[Si:14]([O:13][CH2:12][CH2:11][C:10]1[CH:21]=[CH:22][C:7]([B:25]([OH:28])[OH:26])=[CH:8][C:9]=1[CH2:23][CH3:24])([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15]
Reactant: CCc1cc(Br)ccc1CCO[Si](C)(C)C(C)(C)C
Reactant: COB(OC)OC
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCc1cc(B(O)O)ccc1CCO[Si](C)(C)C(C)(C)C
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 0 %

Procedure:
n-Butyl Lithium (4.7 mL) was added to a solution of 46A (2.1 g, 6.1 mmol) in THF at −78° C. After stirring to 10 min at −78° C., trimethyl borate (1.0 mL, 12.3 mmol) was added dropwise. After warming to ambient temperature, the reaction mixture was stirred an additional 2 h. HCl (1.0 M, 30 mL, aqueous) was added to the mixture at −40° C. and stirred at −20° C. for 30 min. The solution was extracted with diethyl ether. The combined organics were washed with brine, dried over Na2SO4 and concentrated in vacuo. The resulting oil was purified by flash chromatography (0% to 20% MeOH in CH2Cl2) to yield 46B (0.90 mg, 48%) as a clear oil. MS (ESI) m/z 307.4 (M−H)−.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[C:7]([C:15]([F:18])([F:17])[F:16])[C:3]=1[C:4](O)=[O:5].C(Cl)(=O)C([Cl:22])=O>C(Cl)Cl.CN(C=O)C>[CH3:1][C:2]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[C:7]([C:15]([F:18])([F:17])[F:16])[C:3]=1[C:4]([Cl:22])=[O:5]
Reactant: O=C(Cl)C(=O)Cl
Reactant: Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1C(=O)O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1C(=O)Cl
Reaction time: 1 h

Procedure:
A solution of 2-methyl-4,6-bis(trifluoromethyl)benzoic acid D52 alternative method (400 mg, approximately 1.47 mmol) in DCM (5 ml), containing DMF (1 drop), was treated with oxalyl chloride (166 ul, 1.91 mmol) and stirred under argon for 1 hour. The solvent was carefully removed under reduced pressure and the residue re-evaporated from further DCM. The mixture of acid chlorides was then treated with methanol (3 ml) and kept at room temperature for 2 hours after which time the solvent was again carefully removed under reduced pressure. NMR data indicated this to be a mixture of the title product 2-methyl-4,6-bis(trifluoromethyl)benzoyl chloride and methyl 2,4-bis(trifluoromethyl)benzoate. The mixture was used without further purification.
Reaction SMILES: [Br:1][C:2]1[C:3]([F:14])=[CH:4][CH:5]=[C:6]2[C:11]=1[NH:10][C:9](=O)[C:8]([CH3:13])=[N:7]2.[C:15]([NH2:19])([CH3:18])([CH3:17])[CH3:16]>CS(C)=O.CCOC(C)=O.C([O-])(O)=O.[Na+]>[Br:1][C:2]1[C:3]([F:14])=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([NH:19][C:15]([CH3:18])([CH3:17])[CH3:16])[C:8]([CH3:13])=[N:7]2
Reactant: CC(C)(C)N
Reactant: Cc1nc2ccc(F)c(Br)c2[nH]c1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: Cc1nc2ccc(F)c(Br)c2nc1NC(C)(C)C
Temperature: 100 °C
Yield: 83 %

Procedure:
A mixture of 5-bromo-3-chloro-6-fluoro-2-methylquinoxaline (600) (5.00 g, 18.15 mmol) and tert-butylamine (Alfa-Aesar, Ward Hill, Ma) (9.62 mL, 91 mmol) in DMSO (50 mL) in a sealed tube was heated at 100° C. for 2 h. After cooling to RT, the mixture was diluted with EtOAc and saturated NaHCO3 (aq.). The layers were separated and the aq. layer was extracted with EtOAc (3×). The combined organic layers were washed with water and brine and dried over anhydrous Na2SO4, filtered and concentrated. The crude material was absorbed onto a plug of silica gel and purified by silica gel chromatography (0-20% EtOAc in hexanes) to provide 8-bromo-N-(tert-butyl)-7-fluoro-3-methylquinoxalin-2-amine (605a) (4.70 g, 15.06 mmol, 83% yield) as an orange solid. 1H NMR (400 MHz, CDCl3) δ ppm 7.71 (1H, dd, J=9.0, 5.7 Hz), 7.14 (1H, t, J=8.6 Hz), 4.82 (1H, br. s.), 2.51 (3H, s), 1.64 (9H, s). 19F NMR (376 MHz, CDCl3) δ ppm −103.85 (s, 1F). m/z (ESI, +ve) 312.0, 314.0 (M+H)+.
Reaction SMILES: Br[CH2:2][C:3]1[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[CH:10]=[C:9]2[C:4]=1[N:5]=[C:6]([O:18][CH3:19])[C:7]([O:16][CH3:17])=[N:8]2.[NH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[P:27](=[O:34])([O:31][CH2:32][CH3:33])[O:28][CH2:29][CH3:30].C(N(C(C)C)CC)(C)C>C(#N)C>[CH3:17][O:16][C:7]1[C:6]([O:18][CH3:19])=[N:5][C:4]2[C:9](=[CH:10][C:11]([N+:13]([O-:15])=[O:14])=[CH:12][C:3]=2[CH2:2][NH:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[P:27](=[O:34])([O:28][CH2:29][CH3:30])[O:31][CH2:32][CH3:33])[N:8]=1
Reactant: COc1nc2cc([N+](=O)[O-])cc(CBr)c2nc1OC
Reactant: CCOP(=O)(OCC)c1ccccc1N
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CCOP(=O)(OCC)c1ccccc1NCc1cc([N+](=O)[O-])cc2nc(OC)c(OC)nc12

Procedure:
190 mg (0.579 mmol) of 5-bromomethyl-7-nitro-2,3-dimethoxyquinoxaline, 159 mg (1.2 eq.) of diethyl 2-aminophenylphosphonate and 0.2 ml (2 eq.) of diisopropylethylamine are stirred at reflux for 20 hours in 8 ml of acetonitrile. The reaction mixture is evaporated and the residue is extracted with water and ethyl acetate. The combined organic phases are dried using brine and magnesium sulfate and evaporated. The title compound is obtained as a yellow solid.
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]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2Cl.[NH2:18][CH2:19][CH2:20][N:21]1[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][CH2:22]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]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[NH:18][CH2:19][CH2:20][N:21]1[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][CH2:22]1
Reactant: CC(C)(C)OC(=O)N1CCN(CCN)CC1
Reactant: O=C(c1cnc2ccc(Br)cc2c1Cl)C1CC1
Product: CC(C)(C)OC(=O)N1CCN(CCNc2c(C(=O)C3CC3)cnc3ccc(Br)cc23)CC1

Procedure:
Following general procedure B, (6-bromo-4-chloroquinolin-3-yl)(cyclopropyl)methanone (940 mg, 3.03 mmol) was reacted with tert-butyl 4-(2-aminoethyl)piperazine-1-carboxylate (830 mg, 86%) to afford the desired product as an orange solid: 1H NMR (300 MHz, CDCl3) δ 10.69 (s, 1H), 9.21 (s, 1H), 8.39 (d, J=2.0 Hz, 1H), 7.81 (d, J=8.9 Hz, 1H), 7.73 (dd, J=8.9, 2.0 Hz, 1H), 3.87 (dd, J=11.1, 5.5 Hz, 2H), 3.49 (t, J=4.9 Hz, 4H), 2.76-2.59 (m, 3H), 2.50 (t, J=4.9 Hz, 4H), 1.47 (s, J=11.3 Hz, 9H), 1.32-1.16 (m, 2H), 1.10-0.95 (m, 2H).
Reaction SMILES: [CH3:1][O-:2].[Na+].[O:4]1[C@@H:6]2[CH2:7][C:8]3[C:13]([C@H:5]12)=[CH:12][CH:11]=[CH:10][CH:9]=3.O.Cl>CO>[CH3:1][O:2][C@@H:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7][C@H:6]1[OH:4]
Reactant: C[O-]
Reactant: c1ccc2c(c1)C[C@H]1O[C@@H]21
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CO[C@@H]1c2ccccc2C[C@H]1O
Temperature: 30 °C
Reaction time: 1.5 h
Yield: 65.4 %

Procedure:
Into a 500 ml four-neck flask, 120 ml of methanol was introduced and 16.4 g (0.304 mol) of sodium methoxide powder was dissolved therein. At 30° C., 20.0 g (0.152 mol) of cis-(±)-1,2-epoxyindan (VI) dissolved in 80 ml of methanol was dropwise added thereto in a period of 90 minutes. After this mixture was stirred at 30° C. for 5 hours, 100 ml of water was added thereto. The resulting mixture was neutralized with 270 ml of 1N hydrochloric acid and then methanol was distilled off under reduced pressure. The remaining mixture was extracted twice with 200 ml of dichloromethane. The extracted phase was dried for one night with sodium sulfuric anhydride. The dichloromethane phase was concentrated under pressure to yield 28.5 g of an orange oily substance. When it was purified by a silica gel column chromatography in which chloroform was used as a developing solvent, 16.32 g (yield: 65.5%) of trans-(±)-1-methoxyindan-2-ol (I') was obtained as a pale yellow oil. Its purity determined by an HPLC analysis was 95.4%.
Reaction SMILES: Cl[CH2:2][CH2:3][CH:4]([C:12]1[C:20]2[C:15](=[C:16]([CH2:22][S:23][CH3:24])[CH:17]=[C:18]([F:21])[CH:19]=2)[NH:14][CH:13]=1)[C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][CH:6]=1.[C-:25]#[N:26].[K+]>CS(C)=O>[Cl:11][C:8]1[CH:9]=[CH:10][C:5]([CH:4]([C:12]2[C:20]3[C:15](=[C:16]([CH2:22][S:23][CH3:24])[CH:17]=[C:18]([F:21])[CH:19]=3)[NH:14][CH:13]=2)[CH2:3][CH2:2][C:25]#[N:26])=[CH:6][CH:7]=1
Reactant: CSCc1cc(F)cc2c(C(CCCl)c3ccc(Cl)cc3)c[nH]c12
Reactant: [C-]#N
Agent: [K+]
Solvent: CS(C)=O
Product: CSCc1cc(F)cc2c(C(CCC#N)c3ccc(Cl)cc3)c[nH]c12
Temperature: 120 °C
Reaction time: 8 h

Procedure:
180 mg (0.47 mmol) of 3-[3-chloro-1-(4-chlorophenyl)propyl]-5-fluoro-7-[(methylsulfanyl)methyl]-1H-indole and 61.3 mg (0.94 mmol) of potassium cyanide were dissolved in 11 ml of DMSO and stirred at 120° C. overnight. The mixture was concentrated, and the residue was taken up in ethyl acetate, washed with saturated aqueous sodium bicarbonate solution, water and saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered and concentrated. The crude product was purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient with addition of 0.1% formic acid) to result in a further 140 mg (80% of theory) of the title compound and thus in an overall yield of the title compound of 242 mg (64% of theory).
Reaction SMILES: C1(N(CC2C=C(C=CC=2)C(NC2SC3CCCCC=3C=2C(NC2C=CC(CC[C:37]3[CH:46]=[CH:45][C:40]([C:41]([O:43]C)=[O:42])=[CH:39][CH:38]=3)=CC=2)=O)=O)CCNCC(OCC)=O)CC1.[OH-].[Na+].CO.Cl>C1COCC1>[C:41]([OH:43])(=[O:42])[C:40]1[CH:45]=[CH:46][CH:37]=[CH:38][CH:39]=1
Reactant: CCOC(=O)CNCCN(Cc1cccc(C(=O)Nc2sc3c(c2C(=O)Nc2ccc(CCc4ccc(C(=O)OC)cc4)cc2)CCCC3)c1)C1CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 140 mg of methyl 4-{2-[4-({[2-({3-[(cyclopropyl {2-[(2-ethoxy-2-oxoethyl)amino]ethyl}amino)methyl]benzoyl}amino)-4,5,6,7-tetrahydro-1-benzothiophen-3-yl]carbonyl}amino)phenyl]ethyl}benzoate, 1.0 mL of a 1.0M aqueous sodium hydroxide solution, 1.0 mL of methanol, and 2.0 mL of THF was stirred overnight at room temperature. To the reaction mixture was added 1.0 mL of 1.0 M hydrochloric acid. The precipitated solid was collected by filtration, thereby obtaining 113 mg of 4-(2-{4-[({2-[(3-{[{2-[(carboxymethyl)amino]ethyl}(cyclopropyl)amino]methyl}benzoyl)amino]-4,5,6,7-tetrahydro-1-benzothiophen-3-yl}carbonyl)amino]phenyl)}ethyl)benzoic acid.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][CH2:7][NH2:8].[C:9](Cl)(=[O:18])[C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[CH:11]=1.C(N(CC)CC)C>C1COCC1>[CH3:17][O:16][C:12]1[CH:11]=[C:10]([CH:15]=[CH:14][CH:13]=1)[C:9]([NH:8][CH2:7][CH2:6][C:2]1[S:1][CH:5]=[CH:4][CH:3]=1)=[O:18]
Reactant: COc1cccc(C(=O)Cl)c1
Reactant: NCCc1cccs1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1cccc(C(=O)NCCc2cccs2)c1
Yield: 90.5 %

Procedure:
Reaction of-2-thiopheneethylamine (50 μL, 0.42 mmol) in THF (2.5 mL) with m-anisoyl chloride (74 μL, 0.57 mmol) in presence of triethylamine (78 μL, 0.55 mmol) according to method A gave 3-methoxy-N-(2-thiophen-2-yl-ethyl)-benzamide (100 mg, 0.38 mmol, 90% yield) as a yellow wax after purification on silica gel (eluent: EtOAc/hexane 5/95 to 20/80).
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([C:10](=[O:21])[NH:11][C:12]1([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)[CH2:14][CH2:13]1)[CH3:9])(C)(C)C.[ClH:23].O1CCOCC1>C(Cl)Cl>[ClH:23].[ClH:23].[NH2:7][C@@H:8]([CH3:9])[C:10]([NH:11][C:12]1([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)[CH2:14][CH2:13]1)=[O:21]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)NC1(c2ccccn2)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: C[C@H](N)C(=O)NC1(c2ccccn2)CC1
Reaction time: 4 h

Procedure:
A solution of [(S)-1-(1-pyridin-2-yl-cyclopropylcarbamoyl)-ethyl]-carbamic acid tert-butyl ester (120 mg, 0.39 mmol) in CH2Cl2 (5 mL) was added 4M HCl in dioxane (0.98 mL, 3.9 mmol). The solution stirred for 4 hours then was concentrated in vacuo to afford crude (S)-2-amino-N-(1-pyridin-2-yl-cyclopropyl)-propionamide dihydrochloride (100 mg, 0.36 mmol).
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:21])=[C:4]([CH:16]=[CH:17][C:18]=1[O:19][CH3:20])/[C:5](=[N:14]\[OH:15])/[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([F:12])[C:7]=1[F:13].[C:22](OC(=O)C)(=[O:24])[CH3:23]>>[C:22]([O:15]/[N:14]=[C:5](/[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([F:12])[C:7]=1[F:13])\[C:4]1[CH:16]=[CH:17][C:18]([O:19][CH3:20])=[C:2]([Cl:1])[C:3]=1[OH:21])(=[O:24])[CH3:23]
Reactant: CC(=O)OC(C)=O
Reactant: COc1ccc(/C(=N\O)c2cccc(F)c2F)c(O)c1Cl
Product: COc1ccc(/C(=N\OC(C)=O)c2cccc(F)c2F)c(O)c1Cl
Temperature: 60 °C

Procedure:
A mixture of 1.5 g of E-3-chloro-2',3'-difluoro-2-hydroxy-4-methoxybenzophenone oxime and 0.67 g of acetic anhydride are warmed at 60° C. for 30 minutes. The mixture is dissolved and then solidifies. The residue is partitioned between ethyl acetate and 10% NaHCO3. The ethyl acetate extract is washed, dried over Na2SO4 and evaporated to give E-3-chloro-2',3'-difluoro-2-hydroxy-4-methoxybenzophenone O-acetyl oxime, mp 136°-139° C.
Reaction SMILES: [OH:1][C:2]1[CH2:7][CH:6]([C:8]2[C:13]([CH3:14])=[CH:12][C:11]([CH3:15])=[C:10]([C:16](=[S:23])[NH:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:9]=2[CH3:24])[CH2:5][C:4](=[O:25])[C:3]=1[C:26](=O)[CH2:27][CH3:28].Cl.[CH2:31]([O:33][NH2:34])[CH3:32]>>[CH2:31]([O:33][N:34]=[C:26]([C:3]1[C:4](=[O:25])[CH2:5][CH:6]([C:8]2[C:13]([CH3:14])=[CH:12][C:11]([CH3:15])=[C:10]([C:16](=[S:23])[NH:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:9]=2[CH3:24])[CH2:7][C:2]=1[OH:1])[CH2:27][CH3:28])[CH3:32]
Reactant: CCOC(=O)NC(=S)c1c(C)cc(C)c(C2CC(=O)C(C(=O)CC)=C(O)C2)c1C
Reactant: CCON
Agent: Cl
Product: CCON=C(CC)C1=C(O)CC(c2c(C)cc(C)c(C(=S)NC(=O)OCC)c2C)CC1=O

Procedure:
Reaction of 3-hydroxy-5-(3-ethoxycarbonylthiocarbamoyl-2,4,6-trimethylphenyl)-2-propionylcyclohex-2-en-1-one with ethoxyamine hydrochloride following essentially the same procedure as that described in Example 1 part (v) gave 2-[1-(ethoxyimino)propyl]-3-hydroxy-5-(3-ethoxycarbonylthiocarbamoyl-2,4,6-trimethylphenyl)cyclohex-2-en-1-one (23) as a yellow oil. the compound was characterized by its proton nuclear magnetic resonance spectrum and the data are recorded in Table 3, Example 11.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([S:12][CH2:13][CH3:14])[CH:8]=[C:7]2[OH:15].C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:22][O:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28]Cl)=[CH:26][CH:25]=1>CN(C)C=O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([S:12][CH2:13][CH3:14])[CH:8]=[C:7]2[O:15][CH2:28][C:27]1[CH:30]=[CH:31][C:24]([O:23][CH3:22])=[CH:25][CH:26]=1
Reactant: CCSc1cc(O)c2cccc(Cl)c2n1
Reactant: COc1ccc(CCl)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCSc1cc(OCc2ccc(OC)cc2)c2cccc(Cl)c2n1
Temperature: 65 °C
Yield: 72.3 %

Procedure:
8-Chloro-2-ethylsulfanyl-quinolin-4-ol (10.26 g, 42.8 mmol) was dissolved in anhydrous dimethylformamide (100 mL). Cesium carbonate (27.9 g, 85.6 mmol) was added, followed by p-methoxybenzyl chloride (8.0 g, 51.36 mmol). The mixture was then heated at 65° C. for 2 hours and then cooled to room temperature and diluted with ethyl acetate. The diluted reaction mixture was washed with brine 2 times, dried over Mg2SO4 and concentrated in vacuo. The residue was recrystallized from EtOAc/Hexanes to afford 8-chloro-2-ethylsulfanyl-4-(4-methoxy-benzyloxy)-quinoline (11.14 g, 67% yield). LCMS found 360.21 [M+H]+.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:19]([C:28]3[N:32]([CH3:33])[CH:31]=[N:30][CH:29]=3)([C:21]3[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=3)[OH:20])[CH:8]=2)[N:3]=1.[N-:34]=[N+:35]=[N-:36].[Na+]>CN(C=O)C>[Cl:18][C:14]1[CH:13]=[C:12]([C:10]2[C:9]3[C:4](=[CH:5][CH:6]=[C:7]([C:19]([C:28]4[N:32]([CH3:33])[CH:31]=[N:30][CH:29]=4)([C:21]4[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=4)[OH:20])[CH:8]=3)[N:3]3[N:34]=[N:35][N:36]=[C:2]3[N:11]=2)[CH:17]=[CH:16][CH:15]=1
Reactant: Cc1ccc(C(O)(c2ccc3nc(Cl)nc(-c4cccc(Cl)c4)c3c2)c2cncn2C)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(C(O)(c2ccc3c(c2)c(-c2cccc(Cl)c2)nc2nnnn23)c2cncn2C)cc1
Temperature: 90 °C
Reaction time: 2 h
Yield: 72.7 %

Procedure:
A mixture of intermediate 24 (0.0105 mol) and sodium azide (0.031 mol) in DMF (70 ml) was stirred at 90° C. for 2 hours then cooled and poured out into ice water. The precipitate was filtered and taken up in DCM. The organic layer was washed with water, separated, dried (MgSO4), filtered, and the solvent was evaporated. The residue was purified by column chromatography over silica gel (15-40 μm) (eluent: DCM/MeOH/NH4OH; 95/5/0.1). The pure fractions were collected and the solvent was evaporated, yielding 3.68 g (quantitative) of 5-(3-chlorophenyl)-α-(1-methyl-1H-imidazol-5-yl)-α-(4-methylphenyl)-tetrazolo[1,5-a]quinazoline-7-methanol (intermediate 25), mp. 200° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[Br:14][C:15]1[CH:24]=[CH:23][CH:22]=[C:21]2[C:16]=1[CH2:17][CH2:18][NH:19][CH:20]2[CH3:25]>>[Br:14][C:15]1[CH:24]=[CH:23][CH:22]=[C:21]2[C:16]=1[CH2:17][CH2:18][N:19]([C:11]([C:9]1[CH:10]=[C:5]3[N:4]=[CH:3][C:2]([Br:1])=[CH:7][N:6]3[N:8]=1)=[O:13])[CH:20]2[CH3:25]
Reactant: CC1NCCc2c(Br)cccc21
Reactant: O=C(O)c1cc2ncc(Br)cn2n1
Product: CC1c2cccc(Br)c2CCN1C(=O)c1cc2ncc(Br)cn2n1

Procedure:
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 5-Bromo-1-methyl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.