Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][N:13]=2)[C:8]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]#[C:22][CH2:23][NH:24]C(OC(C)(C)C)=O)[CH:16]=2)=[C:7]([NH:32][C:33]([NH:35][C:36]2[C:41]([CH:42]([CH3:44])[CH3:43])=[CH:40][CH:39]=[CH:38][C:37]=2[CH:45]([CH3:47])[CH3:46])=[O:34])[C:6]1=[O:48])[CH2:2][CH2:3][CH3:4].FC(F)(F)C(O)=O>C(Cl)(Cl)Cl>[CH2:1]([N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][N:13]=2)[C:8]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]#[C:22][CH2:23][NH2:24])[CH:16]=2)=[C:7]([NH:32][C:33]([NH:35][C:36]2[C:37]([CH:45]([CH3:46])[CH3:47])=[CH:38][CH:39]=[CH:40][C:41]=2[CH:42]([CH3:44])[CH3:43])=[O:34])[C:6]1=[O:48])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCn1c(=O)c(NC(=O)Nc2c(C(C)C)cccc2C(C)C)c(-c2cccc(C#CCNC(=O)OC(C)(C)C)c2)c2cccnc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClC(Cl)Cl
Product: CCCCn1c(=O)c(NC(=O)Nc2c(C(C)C)cccc2C(C)C)c(-c2cccc(C#CCN)c2)c2cccnc21
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 75 %

Procedure:
To a solution of N-[1-butyl-4-{3-(3-tert-butoxycarbonylamino-1-propynyl)phenyl}-1,2-dihydro-2-oxo-1,8-naphthyridin-3-yl]-N'-(2,6-diisopropyl-phenyl)urea (104 mg, 0.16 mmol) in chloroform (5 ml) was added trifluoroacetic acid (1 ml) at under ice-cooling. The mixture was warmed to room temperature, and then stirred for 1.5 hour. The mixture was concentrated under reduced pressure to remove the solvent, and to the residue was added 5% aqueous sodium chloride solution. The mixture was treated with aqueous ammonia to be converted into a free form, and then extracted with ethyl acetate. The oily layer was washed with 5% aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. The resultant was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (4% methanol in chloroform) to give the title compound (64 mg, 0.12 mmol).
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[N:11]=[CH:12][C:13]3[C:19](=[O:20])[C:18]([C:21]([OH:23])=[O:22])=[CH:17][NH:16][C:14]=3[N:15]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].S(OCC)(O[CH2:28][CH3:29])(=O)=O.C(O)(=O)C>C(=O)([O-])[O-].[Na+].[Na+]>[C:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[N:11]=[CH:12][C:13]3[C:19](=[O:20])[C:18]([C:21]([OH:23])=[O:22])=[CH:17][N:16]([CH2:28][CH3:29])[C:14]=3[N:15]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CCOS(=O)(=O)OCC
Reactant: CC(=O)N1CCN(c2ncc3c(=O)c(C(=O)O)c[nH]c3n2)CC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CCn1cc(C(=O)O)c(=O)c2cnc(N3CCN(C(C)=O)CC3)nc21
Temperature: 25 °C

Procedure:
To a solution of 0.45 g of 2-(4-acetyl-1-piperazinyl)-5,8-dihydro-5-oxopyrido[2,3-d]pyrimidine-6-carboxylic acid in 30 ml of sodium carbonate was added two 0.5 ml portions of diethyl sulfate with stirring at room temperature. After the completion of the reaction the mixture was neutralized with acetic acid. The precipitate resulted was collected and recrystallized from dimthylformamide to yield 0.4 g of the product, m.p. 298° - 300°C.
Reaction SMILES: [CH3:1][CH:2]([SH:4])[CH3:3].Cl[C:6]1[C:7]2[CH:17]=[C:16]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH:15]=[CH:14][C:8]=2[S:9][C:10]=1[C:11]([NH2:13])=[O:12].C1(C2CCCCCCCCCC=2)CCCCCCCCNN=1.O>CN(C=O)C>[CH3:1][CH:2]([S:4][C:6]1[C:7]2[CH:17]=[C:16]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH:15]=[CH:14][C:8]=2[S:9][C:10]=1[C:11]([NH2:13])=[O:12])[CH3:3]
Reactant: CC(C)S
Reactant: NC(=O)c1sc2ccc(OCc3ccccc3)cc2c1Cl
Agent: C1=C(C2=NNCCCCCCCC2)CCCCCCCCC1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)Sc1c(C(N)=O)sc2ccc(OCc3ccccc3)cc12
Temperature: 55 °C
Reaction time: 1 h
Yield: 98 %

Procedure:
2-Propanethiol (0.8 mL, 8 mmol) is added to a solution of 3-chloro-5-(phenylmethoxy)benzo[b]thiophene-2-carboxamide (1.0 g, 3 mmol) and diazabicycloundecene (DBU) (2.6 mL, 17 mmol) in 10 mL of DMF and the mixture is warmed to 55° C. for 1 hour. The reaction mixture is allowed to cool and then poured into water and stirred. After 1 hour, the precipitate is filtered off, washed with water, and dried to provide 3-[(1-methylethyl)thio]-5-(phenylmethoxy)benzo[b]thiophene-2-carboxamide in 98% yield; mp=150°-152° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH2:8].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[C:30](O)(=[O:32])[CH3:31]>CN(C1C=CN=CC=1)C.CN(C=O)C>[NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:30](=[O:32])[CH3:31]
Reactant: Nc1ccccc1N
Reactant: CC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CC(=O)Nc1ccccc1N
Yield: 19.6 %

Procedure:
N-(2-aminophenyl)acetamide (59 mg, 57%) as a yellow solid was synthesized from 1,2-diaminobenzene (216 mg, 2.00 mmol), EDCI (764 mg, 4.00 mmol), HOBt (540 mg, 4.00 mmol), DMAP (488 mg, 4.00 mmol), acetic acid (120 mg, 2.00 mmol) and DMF (1 mL) using the procedure similar to that described for compound 1 (Example 1): LCMS: 531 [M+1]+. 1H-NMR (400 MHz. DMSO-d6) δ 2.03 (s, 3H), 4.85 (s, 2H), 6.52 (m, 1H), 6.70 (m, 1H), 6.89 (m, 1H), 7.15 (m, 1H), 9.11 (s, 1H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]3[O:17][CH2:16][CH2:15][C:14]([C:18](O)=[O:19])=[CH:13][C:12]=3[CH:21]=2)=[CH:4][CH:3]=1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.Cl.Cl.[NH2:46][CH:47]1[CH2:52][CH2:51][N:50]([CH2:53][CH2:54][N:55]([CH3:62])[CH:56]2[CH2:61][CH2:60][O:59][CH2:58][CH2:57]2)[CH2:49][CH2:48]1>C(#N)C.C(N(CC)CC)C>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]3[O:17][CH2:16][CH2:15][C:14]([C:18]([NH:46][CH:47]4[CH2:48][CH2:49][N:50]([CH2:53][CH2:54][N:55]([CH3:62])[CH:56]5[CH2:61][CH2:60][O:59][CH2:58][CH2:57]5)[CH2:51][CH2:52]4)=[O:19])=[CH:13][C:12]=3[CH:21]=2)=[CH:4][CH:3]=1
Reactant: CN(CCN1CCC(N)CC1)C1CCOCC1
Reactant: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCO3)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)NC2CCN(CCN(C)C4CCOCC4)CC2)CCO3)cc1
Reaction time: 1 h
Yield: 36.7 %

Procedure:
Into a solution of 7-(4-methylphenyl)-2,3-dihydro-1-benzooxepine-4-carboxylic acid (150 mg) and 1-hydroxybenzotriazole (0.14 g) in acetonitrile (10 ml) was added at room temperature 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride (0.20 g), and the resulting mixture was stirred for one hour. Into the reaction mixture was added a solution of 4-amino-1-[2-[N-methyl-N-(tetrahydropyran-4-yl)amino]ethyl]piperidine dihydrochloride (282 mg), triethylamine (0.15 ml.) and diazabicyclo[5,4,0]-7-undecene (0.37 g) in acetonitrile (15 ml), and the resulting mixture was stirred for 18 hours. After the reaction mixture was concentrated under reduced pressure, water was added to the residue and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with an aqueous saturated solution of sodium chloride and was dried with magnesium sulfate. The resulting organic layer was evaporated to remove the solvent, and then the residue was subjected to purification using column chromatography (triethylamine/ethanol/ethyl acetate 1:10:10) and further to recrystallization (ethyl acetate/hexane) to obtain 7-(4-methylphenyl)-N-[1-[2-[N-methyl-N-(tetrahydropyran-4-yl)amino]ethyl]piperidin-4-yl]-2,3-dihydro-1-benzooxepine-4-carboxamide (compound 62) (99 mg) as colorless crystals.
Reaction SMILES: [CH:1]1([NH2:4])[CH2:3][CH2:2]1.N1C=CC=CC=1.[C:11]1([CH2:17][C:18](Cl)=O)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>ClCCl.C1COCC1>[C:11]1([CH2:17][CH2:18][NH:4][CH:1]2[CH2:3][CH2:2]2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: NC1CC1
Reactant: O=C(Cl)Cc1ccccc1
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: c1ccc(CCNC2CC2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of cyclopropanamine (1 eq.) in dichloromethane (0.13 M) was added sequentially at 0° C. pyridine (1.5 eq.) and phenylacetyl chloride (9 eq.). The resulting mixture was slowly warmed to RT and stirred at RT for 3 h. After quenching with 1 N aq. HCl, the reaction mixture was extracted with EtOAc. The combined organic extracts were washed with sat. aq. NaHCO3 and brine, dried over MgSO4, filtered and the filtrate concentrated in vacuo. The crude amide thus obtained was taken up in THF (0.3 M) and added BH3.SMe2 complex (3 eq.). The reaction was heated to reflux and the volatiles were slowly distilled off. The resulting distillation residue was carefully quenched with 1 N aq. HCl and allowed to stir at 50° C. overnight. The reaction was cooled to 0° C. and the pH of the solution was brought to ˜12 with 1 N aq. NaOH before it was extracted with ether. The combined organic extracts were washed with brine, dried over MgSO4, filtered and the filtrate concentrated in vacuo. The crude product thus obtained could be further purified by way of column chromatography (SiO2, 2:1 (v/v) Hex:EtOAc→EtOAc) afforded the title compound as a colorless oil.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]=[C:5]1[C@@H:13]1[CH2:18][CH2:17][CH2:16][N:15]([C:19](=[O:41])[CH2:20][C@H:21]([NH:33][C:34](=[O:40])[O:35][C:36]([CH3:39])([CH3:38])[CH3:37])[CH2:22][C:23]2[CH:32]=[CH:31][C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH:24]=2)[CH2:14]1.ClCCl.[C:45](Cl)(=[O:47])[CH3:46].N1C=CC=CC=1>CO>[C:45]([NH:1][CH2:2][CH2:3][N:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]=[C:5]1[C@@H:13]1[CH2:18][CH2:17][CH2:16][N:15]([C:19](=[O:41])[CH2:20][C@H:21]([NH:33][C:34](=[O:40])[O:35][C:36]([CH3:37])([CH3:38])[CH3:39])[CH2:22][C:23]2[CH:32]=[CH:31][C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH:24]=2)[CH2:14]1)(=[O:47])[CH3:46]
Reactant: CC(=O)Cl
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)N1CCC[C@@H](c2nc3ccccc3n2CCN)C1)Cc1ccc2ccccc2c1
Solvent: c1ccncc1
Solvent: CO
Solvent: ClCCl
Product: CC(=O)NCCn1c([C@@H]2CCCN(C(=O)C[C@@H](Cc3ccc4ccccc4c3)NC(=O)OC(C)(C)C)C2)nc2ccccc21
Temperature: 0 °C
Yield: 36 %

Procedure:
tert-Butyl (R)-4-((R)-3-(1-(2-aminoethyl)-1H-benzo[d]imidazoI-2-yl)piperidin-1-yl)-1-(naphthalen-2-yl)-4-oxobutan-2-ylcarbamate (129D) was added to a 25 mL round-bottomed flask equipped for stirring under nitrogen. Dichloromethane (5 mL) was added and the solution was cooled to 0° C. with an ice/water bath. Acetyl chloride (0.703 mmoles; 0.050 mL) and pyridine (2.47 mmoles, 0.200 mL) were then added and the resultant solution was stirred at 0° C. for 10 min. Solution was allowed to warm to it and stirred for 1 hr. The reaction solution was subsequently concentrated in-vacuo, re-dissolved in methanol (3 mL), and then directly purified by preparative LC/MS (20-90% CH3CN in H2O) to afford tert-butyl (R)-4-((R)-3-(1-(2-acetamidoethyl)-1H-benzo[d]imidazol-2-yl)piperidin-1-yl)-1-(naphthalen-2-yl)-4-oxobutan-2-ylcarbamate (129E) as a clear oil (0.038 mmoles, 0.023 g, 36% yield over 2-steps). ESI-MS: m/z 598.5 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([N:12]([CH3:14])[CH3:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.Cl.[CH2:16]([O:23][C:24](=[O:34])[NH:25][C@H:26]1[CH2:31][CH2:30][C@H:29]([CH2:32][NH2:33])[CH2:28][CH2:27]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C([O-])(O)=O.[Na+]>CC(O)C.C(Cl)(Cl)Cl.CO>[CH2:16]([O:23][C:24](=[O:34])[NH:25][C@H:26]1[CH2:31][CH2:30][C@H:29]([CH2:32][NH:33][C:2]2[N:11]=[C:10]([N:12]([CH3:14])[CH3:13])[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[N:3]=2)[CH2:28][CH2:27]1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: CN(C)c1nc(Cl)nc2ccccc12
Reactant: NC[C@H]1CC[C@H](NC(=O)OCc2ccccc2)CC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CN(C)c1nc(NC[C@H]2CC[C@H](NC(=O)OCc3ccccc3)CC2)nc2ccccc12

Procedure:
A mixture of (2-chloro-quinazolin-4-yl)-dimethyl-amine (1.50 g, 7.22 mmol) and trans-(4-aminomethyl-cyclohexyl)-carbamic acid benzyl ester hydrochloride (2.59 g, 8.67 mmol) in 2-propanol (15 mL) was stirred at reflux for 8 days and dissolved in CHCl3 and MeOH. The mixture was poured into saturated aqueous NaHCO3, and the aqueous layer was extracted with CHCl3 (three times). The combined organic layer was dried over MgSO4, filtered, concentrated, and purified by flash chromatography (H-silica gel, 33% EtOAc in hexane) to give trans-{4-[(4-dimethylamino-quinazolin-2-ylamino)-methyl]-cyclohexyl}-carbamic acid benzyl ester (1.20 g, 38%) as a pale yellow solid.
Reaction SMILES: [C:1]([Si:5]([CH3:31])([CH3:30])[O:6][CH:7]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([O:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:18]=1)[CH2:8][CH2:9][CH:10]1[NH:14][C:13](=[O:15])[CH2:12][CH2:11]1)([CH3:4])([CH3:3])[CH3:2].C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[CH3:42][O:43][C:44](=[O:55])[C:45]1[CH:50]=[CH:49][C:48]([CH2:51][CH2:52][CH2:53]Br)=[CH:47][CH:46]=1>>[CH3:42][O:43][C:44](=[O:55])[C:45]1[CH:50]=[CH:49][C:48]([CH2:51][CH2:52][CH2:53][N:14]2[C:13](=[O:15])[CH2:12][CH2:11][CH:10]2[CH2:9][CH2:8][CH:7]([O:6][Si:5]([C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:31])[CH3:30])[CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([O:23][C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH:18]=2)=[CH:47][CH:46]=1
Reactant: COC(=O)c1ccc(CCCBr)cc1
Reactant: CC(C)(C)[Si](C)(C)OC(CCC1CCC(=O)N1)Cc1cccc(Oc2ccccc2)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Product: COC(=O)c1ccc(CCCN2C(=O)CCC2CCC(Cc2cccc(Oc3ccccc3)c2)O[Si](C)(C)C(C)(C)C)cc1
Yield: 61.8 %

Procedure:
Analogous to the procedure described for Example 1A, Step D, 5-[3-(tert-butyl-dimethyl-silanyloxy)-4-(3-phenoxy-phenyl)-butyl]-pyrrolidin-2-one (200 mg, 0.455 mmol) was alkylated with NaHMDS (1M in THF, 0.55 mL, 0.55 mmol) and 4-(3-bromo-propyl)-benzoic acid methyl ester (128 mg, 0.501 mmol) to yield 4-(3-{2-[3-(tert-butyl-dimethyl-silanyloxy)-4-(3-phenoxy-phenyl)-butyl]-5-oxo-pyrrolidin-1-yl}-propyl)-benzoic acid methyl ester (173.1 mg). 1H NMR (CDCl3) δ7.94 (d, 2H), 7.32 (m, 2H), 7.25-7.19 (m, 3H), 7.09 (m, 1H), 6.98 (d, 2H), 6.88-6.81 (m, 3H), 3.88 (s, 3H), 3.84 (m, 1H), 3.64 (m, 1H), 3.50 (m, 1H), 2.95 (m, 1H), 2.76-2.57 (m, 4H), 2.37 (m, 2H), 2.03 (m, 1H), 1.92-1.67 (m, 3H), 1.56 (m, 1H), 1.46-1.25 (m, 3H), 0.84 (s, 9H), −0.04 (d, 3H), −0.15 (d, 3H).
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[C:23]([C:24]#[N:25])=[CH:22][C:8]2[C:9]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[Cl:21])=[N:10][CH2:11][C:12](=[O:14])[NH:13][C:7]=2[CH:6]=1.[CH3:26][O:27][CH2:28][CH2:29][N:30](C)[CH2:31]CO.[I-].[Na+]>O1CCCC1>[Cl:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[C:9]1[C:8]2[CH:22]=[C:23]([C:24]#[N:25])[C:5]([O:4][CH2:3][CH2:2][N:30]([CH2:29][CH2:28][O:27][CH3:26])[CH3:31])=[CH:6][C:7]=2[NH:13][C:12](=[O:14])[CH2:11][N:10]=1
Reactant: N#Cc1cc2c(cc1OCCCl)NC(=O)CN=C2c1ccccc1Cl
Reactant: COCCN(C)CCO
Agent: [I-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCCN(C)CCOc1cc2c(cc1C#N)C(c1ccccc1Cl)=NCC(=O)N2
Temperature: 83 °C
Yield: 17.1 %

Procedure:
A mixture of 1.2 g (0.0032 mole) of 8-(2-chloroethoxy)-5-(2-chlorophenyl)-7-cyano-1,3-dihydro-2H-1,4-benzodiazepin-2-one (Iss, prepared in Example 35), 2.85 g (0.032 mole) of 2-((2-methoxyethyl)methylamino) ethanol, 20 mL of tetrahydrofuran and 4.8 g (0.032 mole) of sodium iodide was heated in an oil bath at 83° C. under an argon atmosphere for 20 hours. The mixture was cooled and then partitioned between ethyl acetate and 0.6 M sodium bicarbonate solution. The ethyl acetate layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was chromatographed on silica gel, eluting with acetonitrile-methanol (80:20) to give 0.233 g of 5-(2-chlorophenyl)-7-cyano-1,3-dihydro-8-(2-((2-methoxyethyl)methylamino)-ethoxy)-2H-1,4-benzodiazepin-2-one (Iv).
Reaction SMILES: Cl[C:2]([O:4][CH3:5])=[O:3].C([O-])([O-])=O.[K+].[K+].[C:12]([O:16][C:17](=[O:33])[N:18]([CH2:22][C:23]1[CH:28]=[C:27]([CH2:29][CH2:30][NH2:31])[CH:26]=[CH:25][C:24]=1[Cl:32])[CH:19]1[CH2:21][CH2:20]1)([CH3:15])([CH3:14])[CH3:13]>CC(C)=O>[CH3:5][O:4][C:2](=[O:3])[NH:31][CH2:30][CH2:29][C:27]1[CH:26]=[CH:25][C:24]([Cl:32])=[C:23]([CH2:22][N:18]([C:17]([O:16][C:12]([CH3:15])([CH3:13])[CH3:14])=[O:33])[CH:19]2[CH2:20][CH2:21]2)[CH:28]=1
Reactant: COC(=O)Cl
Reactant: CC(C)(C)OC(=O)N(Cc1cc(CCN)ccc1Cl)C1CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)NCCc1ccc(Cl)c(CN(C(=O)OC(C)(C)C)C2CC2)c1
Temperature: 25 °C
Yield: 67.2 %

Procedure:
Methyl chloroformate (1.72 mL, 21.9 mmol) and K2CO3 (7.65 g, 54.8 mmol) were added to a sol. of [5-(2-amino-ethyl)-2-chloro-benzyl]-cyclopropyl-carbamic acid tert-butyl ester (1.78 g, 5.48 mmol) in acetone (8.00 mL). The mixture was refluxed overnight, and was allowed to cool to rt. The mixture was partitioned between water and CH2Cl2, and the aq. layer was extracted with CH2Cl2 (3×). The combined org. extracts were dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the crude by FC (heptane/EtOAc 6:4) yielded the title compound (1.41 g, 67%). LC-MS: tR=1.03 min; ES+: 383.50.
Reaction SMILES: [CH3:1][C:2]1[N:11]=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([NH:6][CH3:7])=[O:5].C([N-]C(C)C)(C)C.[Li+].[CH3:20][O:21][C:22]1[CH:29]=[CH:28][C:25]([C:26]#N)=[CH:24][CH:23]=1.[O:30]1CCCC1>C1CCCCC1>[CH3:20][O:21][C:22]1[CH:29]=[CH:28][C:25]([C:26]([OH:30])=[CH:1][C:2]2[N:11]=[CH:10][CH:9]=[CH:8][C:3]=2[C:4]([NH:6][CH3:7])=[O:5])=[CH:24][CH:23]=1
Reactant: C1CCOC1
Reactant: COc1ccc(C#N)cc1
Reactant: CNC(=O)c1cccnc1C
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCCCC1
Product: CNC(=O)c1cccnc1C=C(O)c1ccc(OC)cc1
Temperature: -78 °C
Reaction time: 0.83 h

Procedure:
2-Methyl-N-methylnicotinamide (4.505 g) was dissolved in tetrahydrofuran (150 ml), followed by the dropwise addition of a solution of 1.5M lithium diisopropylamide in cyclohexane (40 ml) in nitrogen atmosphere at −30 to −20° C., and the mixture was stirred for 50 min. After cooling to −78° C., 4-methoxybenzonitrile (3.995 g)/tetrahydrofuran solution (20 ml) was added dropwise thereinto. After the mixture was stirred for 1 hr as it was, the cooling bath was removed, and then it was stirred overnight. An aqueous solution of saturated ammonium chloride was added thereto, and then the mixture was extracted with ethyl acetate. The resulting organic layer was washed with water, dried (over MgSO4) and evaporated. A small amount of ethyl acetate was added to the resulting residue, and then the resulting insoluble matters were collected by filtration, to give 5.395 g of the title compound as a yellow solid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[CH:5]=[CH:4][N:3]=1.[Cl:9][C:10]1[CH:15]=[CH:14][C:13](B(O)O)=[CH:12][CH:11]=1.C([O-])([O-])=O.[Na+].[Na+].CCOC(C)=O>C1COCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:8][C:6]1[CH:5]=[C:4]([C:13]2[CH:14]=[CH:15][C:10]([Cl:9])=[CH:11][CH:12]=2)[N:3]=[CH:2][N:7]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: Clc1ccnc(Cl)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: Clc1ccc(-c2cc(Cl)ncn2)cc1
Reaction time: 8 h
Yield: 71 %

Procedure:
To a solution of 2,4-dichloro-pyrimidine (1 eq) in THF/H2O (4:3) solution, was added 4-chloro phenyl boronic acid (1 eq), Pd(PPh3)4 (0.01 eq) and Na2CO3 (2 eq) under Ar. The reaction mixture was stirred at reflex for overnight. EtOAc (10 mL) was added. The organic phase was separated, dried over Na2SO4, and concentrated. The residue was purified by column chromatography (Ethyl acetate:Hexane:1:3) to give the desired product as a white powder (71% yield. MS: (ESI), MIZ, 225 (M+1). Retention time: 1.07 min (FA-non polar).
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[CH2:5]([O:12][C:13]1[CH:14]=[CH:15][C:16]([OH:22])=[C:17]([C:19](=[O:21])[CH3:20])[CH:18]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>C(O)(=O)C>[CH2:5]([O:12][C:13]1[CH:14]=[C:15]([N+:1]([O-:4])=[O:2])[C:16]([OH:22])=[C:17]([C:19](=[O:21])[CH3:20])[CH:18]=1)[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: CC(=O)c1cc(OCc2ccccc2)ccc1O
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Product: CC(=O)c1cc(OCc2ccccc2)cc([N+](=O)[O-])c1O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
18 mL of fuming nitric acid are added dropwise to a solution of 81.5 g (0.34 mol) 1-(5-benzyloxy-2-hydroxy-phenyl)-ethanone (known from U.S. Pat. No. 4,460,581) in 700 mL acetic acid, while cooling with the ice bath, such that the temperature does not exceed 20° C. Then the reaction mixture is stirred for two hours at ambient temperature, poured onto ice water and filtered. The product is recrystallised from isopropanol, suction filtered and washed with isopropanol and diisopropylether. Yield: 69.6 g (72%); mass spectroscopy [M+H]+=288.
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[C:10]2[C:5](=[CH:6][CH:7]=[C:8](OS(C(F)(F)F)(=O)=O)[CH:9]=2)[C:4](=[O:19])[CH2:3]1.[C:21]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1B(O)O)(=[O:23])[CH3:22]>>[C:21]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[C:4](=[O:19])[CH2:3][C:2]2([CH3:20])[CH3:1])(=[O:23])[CH3:22]
Reactant: CC1(C)CC(=O)c2ccc(OS(=O)(=O)C(F)(F)F)cc21
Reactant: CC(=O)c1ccccc1B(O)O
Product: CC(=O)c1ccccc1-c1ccc2c(c1)C(C)(C)CC2=O

Procedure:
The title compound was prepared from trifluoro-methanesulfonic acid 3,3-dimethyl-1-oxo-indan-5-yl ester and 2-acetylphenyl boronic acid according to the procedure described in example 21. MS (ESI) m/z 279; HRMS: calcd for C19H18O2+H+, 279.13796; found (ESI, [M+H]+), 279.1383.
Reaction SMILES: [Br:1][C:2]([F:18])([F:17])[C:3]([CH:6]1[CH2:10][CH:9]([C:11]([OH:13])=[O:12])[CH2:8][CH:7]1[C:14]([OH:16])=[O:15])([F:5])[F:4].[CH:19](O)([CH3:21])[CH3:20].[C:23]1(C)[CH:28]=CC(S(O)(=O)=O)=C[CH:24]=1>C1CCCCC1>[Br:1][C:2]([F:17])([F:18])[C:3]([CH:6]1[CH2:10][CH:9]([C:11]([O:13][CH:19]([CH3:21])[CH3:20])=[O:12])[CH2:8][CH:7]1[C:14]([O:16][CH:23]([CH3:28])[CH3:24])=[O:15])([F:5])[F:4]
Reactant: O=C(O)C1CC(C(=O)O)C(C(F)(F)C(F)(F)Br)C1
Reactant: CC(C)O
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1CCCCC1
Product: CC(C)OC(=O)C1CC(C(=O)OC(C)C)C(C(F)(F)C(F)(F)Br)C1
Yield: 209.9 %

Procedure:
Into a glass flask were charged 3.00 g (8.90 mmol) of 4-(2-bromo-1,1,2,2-tetrafluoroethyl)cyclopentane-1,3-dicarboxylic acid, 25 g of isopropanol, 25 g of cyclohexane and 0.300 g of p-toluenesulfonic acid, and the mixture was refluxed using a Dean and Stark apparatus for 10 hrs. Thereafter, the solvent was distilled off, and 100 mL of ethyl acetate was added thereto. The organic layer was washed with 50 mL of an aqueous sodium bicarbonate solution three times, and then with 50 mL of saturated brine once. After washing, the solvent of the organic layer was distilled off, and purification was carried out on column chromatography to obtain 1.54 g of diisopropyl 4-(2-bromo-1,1,2,2-tetrafluoroethyl)cyclopentane-1,3-dicarboxylate (precursor compound (a-6)) represented by the following formula (a-6) (yield: 41%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:11])[C:5]([O:8][CH2:9][CH3:10])=[N:6][CH:7]=1.[C:12]1([S:18](Cl)(=[O:20])=[O:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>N1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([NH:11][S:18]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)(=[O:20])=[O:19])[C:5]([O:8][CH2:9][CH3:10])=[N:6][CH:7]=1
Reactant: CCOc1ncc(Br)cc1N
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: c1ccncc1
Product: CCOc1ncc(Br)cc1NS(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A solution of 5-bromo-2-(ethyloxy)-3-pyridinamine (1.45 g) in anhydrous pyridine (15 ml) was treated with benzenesulfonyl chloride (1.03 ml) then stirred at RT for 20 hr. The reaction was evaporated to dryness and the residue was purified by column chromatography on silica, eluting with 30% hexanes in DCM, to give the title compound (1.86 g).