Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CO[C:3]([C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7][C:6]=1[O:15][CH3:16])=[O:4].[CH3:17][O:18][C:19]1[CH:20]=[C:21]([CH3:29])[CH:22]=[C:23]([O:27][CH3:28])[C:24]=1[O:25][CH3:26].O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O>ClCCl>[CH3:29][C:21]1[C:22]([C:3]([C:5]2[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH:8]=[CH:7][C:6]=2[O:15][CH3:16])=[O:4])=[C:23]([O:27][CH3:28])[C:24]([O:25][CH3:26])=[C:19]([O:18][CH3:17])[CH:20]=1
Reactant: COC(=O)c1c(OC)ccc2ccccc12
Reactant: COc1cc(C)cc(OC)c1OC
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: ClCCl
Product: COc1cc(C)c(C(=O)c2c(OC)ccc3ccccc23)c(OC)c1OC
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 5B (2.02 g, 10 mmol), 3,4,5-trimethoxytoluene (1.82 g; 10 mmol), P2O5 (10.0 g) and dichloromethane is stirred at room temperature for 16 hours. Subsequently, the dichloromethane is distilled off and the residue is diluted with ethyl acetate. The organic phase is washed with water and concentrated. The residue is purified by column chromatography (petrol ethers:ethyl acetate, 8:2 v/v) and recrystallized from petrol ether: diisopropylether (1:1 v/v). The solid material is collected by vacuum filtration, washed with cold petrol ether: diisopropylether (1:1 v/v) and dried, yielding white crystals, 0.9 g, (24.6%) mp 72° C.
Reaction SMILES: [NH2:1][C:2]1[CH:27]=[CH:26][CH:25]=[CH:24][C:3]=1[CH2:4][N:5]([S:13]([C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1)(=[O:15])=[O:14])[CH:6]([CH2:11]O)[C:7]([O:9][CH3:10])=[O:8].C(N(CC)CC)C.ClC(OCC1C=CC=CC=1)=O>C(Cl)Cl>[CH3:23][O:22][C:19]1[CH:20]=[CH:21][C:16]([S:13]([N:5]2[CH2:4][C:3]3[CH:24]=[CH:25][CH:26]=[CH:27][C:2]=3[NH:1][CH2:11][CH:6]2[C:7]([O:9][CH3:10])=[O:8])(=[O:15])=[O:14])=[CH:17][CH:18]=1
Reactant: COC(=O)C(CO)N(Cc1ccccc1N)S(=O)(=O)c1ccc(OC)cc1
Agent: O=C(Cl)OCc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)C1CNc2ccccc2CN1S(=O)(=O)c1ccc(OC)cc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 145.6 %

Procedure:
To a mixture of 5.0 g (12.68 mmol) of methyl 2-[(2-aminobenzyl)-(4-methoxybenzenesulfonyl)amino]-3-hydroxypropionate and 17.7 ml (26.8 mmol) of triethylamine in 50 ml of CH2Cl2 chilled to 0° C. was added 9.05 ml (63.4 mmol) of benzyl chloroformate. The mixture was stirred overnight and then cooled to 0° C. and 0.8 ml of triethylamine and 9.05 ml (63.4 mmol) of benzyl chloroformate were added thereto. The mixture was stirred overnight and then washed with H2O, 2 N citric acid, brine and dried with Na2SO4. The solvent was removed under vacuum to give 6.95 g of solid. The solid was chromatographed on silica gel with hexane-ethyl acetate (1:1) to give 2.7 g of product as a viscous yellow oil. From a similar 0.5 g run, there was obtained 0.178 g of an oil. Anal. for C18H20N2O5S: Calc'd: C, 57.4; H, 5.4; N, 7.4; S, 8.5; Found: C, 57.9; H, 5.4; N, 6.7; S, 7.9;
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:12][CH2:13][C@H:14]([NH2:16])[CH3:15])[N:5]=[C:4]([CH3:17])[C:3]=1[C:18]([O:20][CH2:21][CH3:22])=[O:19].[OH:23][C:24]1[CH:25]=[C:26]([CH:30]=[CH:31][CH:32]=1)[C:27](O)=[O:28]>>[NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:12][CH2:13][C@H:14]([NH:16][C:27](=[O:28])[C:26]2[CH:30]=[CH:31][CH:32]=[C:24]([OH:23])[CH:25]=2)[CH3:15])[N:5]=[C:4]([CH3:17])[C:3]=1[C:18]([O:20][CH2:21][CH3:22])=[O:19]
Reactant: O=C(O)c1cccc(O)c1
Reactant: CCOC(=O)c1c(C)nc2cccc(OC[C@@H](C)N)c2c1N
Product: CCOC(=O)c1c(C)nc2cccc(OC[C@@H](C)NC(=O)c3cccc(O)c3)c2c1N

Procedure:
Prepared as in Example 24a from (R)-ethyl 4-amino-5-(2-aminopropoxy)-2-methyl-quinoline-3-carboxylate (Example 86b) and 3-hydroxybenzoic acid as brown solid (36%). MS 424 (MH+).
Reaction SMILES: [C:1]([O:4][CH:5]1[C:9]2[N:10]=[CH:11][N:12]=[C:13](Cl)[C:8]=2[C@H:7]([CH3:15])[CH2:6]1)(=[O:3])[CH3:2].[C:16]([N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1)([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17]>CN1C(=O)CCC1.C(OCC)(=O)C>[C:1]([O:4][CH:5]1[C:9]2[N:10]=[CH:11][N:12]=[C:13]([N:26]3[CH2:25][CH2:24][N:23]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:28][CH2:27]3)[C:8]=2[C@H:7]([CH3:15])[CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: CC(=O)OC1C[C@@H](C)c2c(Cl)ncnc21
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: CC(=O)OC1C[C@@H](C)c2c1ncnc2N1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 110 °C
Yield: 72.4 %

Procedure:
To a solution of (5R)-4-chloro-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-7-yl acetate (0.5 g, 2.2 mmol) in NMP (10 mL) was added 1-Boc-piperazine (0.9 g, 4.8 mmol). The reaction mixture was heated to 110° C. for 12 hours. After cooling, the reaction mixture was diluted with ethyl acetate (200 mL) and washed with water (6×100 mL). The organic phase was dried and concentrated. The residue was purified by silica gel chromatography, eluting with ethyl acetate to give tert-butyl 4-((5R)-7-acetoxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]primidin-4-yl)piperazine-1-carboxylate (0.6 g, 72%). 1H NMR (CDCl3, 400 MHz) δ 8.60 (d, 1H), 6.05-5.90 (m, 1H), 3.80-3.30 (m, 9H), 2.84 (m, 1H), 2.20-(m, 1H), 1.49 (s, 9H), 1.29-1.20 (m, 3H). MS (APCI+) [M+H]+377. The resulting mixture of the diastereomers was purified by chiral separation HPLC (Chiralcel ODH column, 250×20 mm, Hexane/EtOH 60:40, 21 mL/min). The first peak (RT=3.73 min) gave the tert-butyl 4-((5R,7R)-7-acetoxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazine-1-carboxylate (0.144 g, 24%). The second peak (RT=5.66 min) gave the tert-butyl 4-((5R,7S)-7-acetoxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazine-1-carboxylate (0.172 g, 29%). MS (APCI+) [M+H]+377.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:13]3[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=O)=[CH:15][CH:14]=3)[O:12][CH2:11][CH2:10][O:9]2)=[CH:4][CH:3]=1.[I:22][C:23]1[CH:24]=[C:25]([CH2:29]C#N)[CH:26]=[CH:27][CH:28]=1.[OH-].[Na+]>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([C:13]3[CH:14]=[CH:15][C:16]4=[N:19][O:21][C:29]([C:25]5[CH:26]=[CH:27][CH:28]=[C:23]([I:22])[CH:24]=5)=[C:17]4[CH:18]=3)[O:9][CH2:10][CH2:11][O:12]2)=[CH:6][CH:7]=1
Reactant: N#CCc1cccc(I)c1
Reactant: O=[N+]([O-])c1ccc(C2(c3ccc(Cl)cc3)OCCO2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Clc1ccc(C2(c3ccc4noc(-c5cccc(I)c5)c4c3)OCCO2)cc1
Temperature: 25 °C
Yield: 81.9 %

Procedure:
2-(4-Chlorophenyl)-2-(4-nitrophenyl)-1,3-dioxolane (38.7 g, 127 mMol) was suspended in 190 mL of methanol (MeOH) under an atmosphere of dry N2. To this solution was added (3-iodophenyl)acetonitrile (46.3 g, 190 mMol) and 25.4 g (625 mMol) of sodium hydroxide (NaOH). The solution was then heated to reflux and reacted at this temperature for 2 hours. The reaction mixture was cooled to ambient temperature and the MeOH was removed under vacuum. The resulting red oil was partitioned between dichloromethane (DCM) and 0.1 N aqueous NaOH. The DCM layer was washed successively with 0.1 N aqueous NaOH and then brine. The DCM layer was dried over MgSO4, filtered and concentrated under vacuum to give a dark red oil. The oil was stirred in MeOH and the titled compound precipitated out as a yellow solid. The yellow solid was washed with MeOH and dried under vacuum to give 52.4 g of the titled compound which was used without further purification.
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:3].[F:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[S:22][C:21]([S:23]([N:26]3[CH2:31][CH2:30][NH:29][CH2:28][C@@H:27]3[C:32]([NH:34][O:35][CH:36]3[CH2:41][CH2:40][CH2:39][CH2:38][O:37]3)=[O:33])(=[O:25])=[O:24])=[CH:20][CH:19]=2)=[CH:14][CH:13]=1>C(Cl)(Cl)Cl.N1C=CC=CC=1>[F:11][C:12]1[CH:13]=[CH:14][C:15]([C:18]2[S:22][C:21]([S:23]([N:26]3[CH2:31][CH2:30][N:29]([C:2]([O:4][C:5]4[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=4)=[O:3])[CH2:28][C@@H:27]3[C:32]([NH:34][O:35][CH:36]3[CH2:41][CH2:40][CH2:39][CH2:38][O:37]3)=[O:33])(=[O:24])=[O:25])=[CH:20][CH:19]=2)=[CH:16][CH:17]=1
Reactant: O=C(NOC1CCCCO1)[C@H]1CNCCN1S(=O)(=O)c1ccc(-c2ccc(F)cc2)s1
Reactant: O=C(Cl)Oc1ccccc1
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: O=C(NOC1CCCCO1)[C@H]1CN(C(=O)Oc2ccccc2)CCN1S(=O)(=O)c1ccc(-c2ccc(F)cc2)s1
Yield: 107.2 %

Procedure:
Phenyl chloroformate (60 mg) in CHCl3 (1 ml) was added to (2R)-1-[5-(4-Fluorophenyl)thiophene-2-sulfonyl]-N-(2-tetrahydropyranyloxy)-2-piperazinecarboxamide (150 mg) in pyridine (0.5 ml) and CHCl3 (0.5 ml) dropwise with cooling on an ice bath. The reaction mixture was stirred at said temperature for 2 hours. The mixture was concentrated in vacuo, and the residue was partitioned between AcOEt and 5% aqueous citric acid. The organic layer was washed with 5% aqueous citric acid, saturated aqueous NaHCO3 solution and saturated aqueous NaCl solution, dried over MgSO4, and concentrated in vacuo to give 202 mg of (2R)-1-[5-(4-fluorophenyl)thiophene-2-sulfonyl]-4-phenoxycarbonyl-N-(2-tetrahydropyranyloxy)-2-piperazinecarboxamide.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:21])=[C:6]([C@@:8]([NH:14]S(C(C)(C)C)=O)([CH2:12][OH:13])[CH:9]([F:11])[F:10])[CH:7]=1.[ClH:22].CC(O)C>C(Cl)Cl>[NH2:14][C@@:8]([C:6]1[CH:7]=[C:2]([Br:1])[CH:3]=[CH:4][C:5]=1[F:21])([CH:9]([F:10])[F:11])[CH2:12][OH:13].[ClH:22]
Reactant: CC(C)(C)S(=O)N[C@@](CO)(c1cc(Br)ccc1F)C(F)F
Agent: Cl
Solvent: ClCCl
Solvent: CC(C)O
Product: N[C@@](CO)(c1cc(Br)ccc1F)C(F)F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2-methyl-propane-2-sulfinic acid [(R)-1-(5-bromo-2-fluoro-phenyl)-2,2-difluoro-1-hydroxymethyl-ethyl]-amide (10 g, 25.76 mmol) in DCM (100 ml) was added under argon a 30% HCl in IPA solution (10 ml, 91.6 mmol) below 25° C. After stirring for 30 min at 25° C., cooled down to −10° C., filtered and dried to provide the title compound HCl salt as white crystals: ESIMS: 284, 286 [(M+H)+], 1H NMR (400 MHz, DMSO-d6): δ 9.42 (b, 3H), 7.84 (m, 1H), 7.74 (m, 1H), 7.35 (dd, 1H), 6.68 (t, 1H), 4.03 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[C:5]([OH:7])=[O:6].[NH2:13][CH2:14][C:15]1[CH:16]=[C:17]([CH:31]=[CH:32][CH:33]=1)[C:18]([NH:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][N:28]([CH3:30])[CH3:29])=[CH:23][CH:22]=1)=[O:19].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[C:5]([NH:13][CH2:14][C:15]1[CH:33]=[CH:32][CH:31]=[C:17]([C:18](=[O:19])[NH:20][C:21]2[CH:22]=[CH:23][C:24]([CH2:27][N:28]([CH3:29])[CH3:30])=[CH:25][CH:26]=2)[CH:16]=1)=[O:7].[CH:5]([O-:7])=[O:6]
Reactant: CN(C)Cc1ccc(NC(=O)c2cccc(CN)c2)cc1
Reactant: COc1ccc(C(=O)O)cc1Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: COc1ccc(C(=O)NCc2cccc(C(=O)Nc3ccc(CN(C)C)cc3)c2)cc1Cl
Product: O=C[O-]
Temperature: 25 °C
Reaction time: 16 h
Yield: 423.1 %

Procedure:
A reaction vial was charged with 3-chloro-4-methoxybenzoic acid (40 mg, 0.21 mmol), 3-aminomethyl-N-(4-dimethylaminomethyl-phenyl)-benzamide (40 mg, 0.14 mmol), EDC (40 mg, 0.25 mmol) and HOBt (40 mg, 0.29 mmol). DMF (2 mL) was added followed by Hunig's base (0.11 mL, 0.57 mmol). The mixture was stirred at room temperature for 16 h. The product was purified by preparative HPLC using an acetonitrile/water/formic acid gradient providing the title compound as a formate salt (20 mg, 31% yield); MS, electrospray, 452 (M+H).
Reaction SMILES: [CH:1]1([NH:5][C:6]([C@@H:8]2[CH2:12][CH2:11][CH2:10][N:9]2[C:13](=[O:30])[CH2:14][O:15][C:16]2[N:20]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[N:19]=[C:18]([C:27](O)=[O:28])[CH:17]=2)=[O:7])[CH2:4][CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH2:64]([O:66][C:67]([N:69]1[CH2:74][CH2:73][N:72]([C:75](=[O:88])[C@@H:76]([NH2:87])[CH2:77][CH2:78][O:79][CH2:80][C:81]2[CH:86]=[CH:85][CH:84]=[CH:83][CH:82]=2)[CH2:71][CH2:70]1)=[O:68])[CH3:65]>CN(C=O)C.C(OCC)(=O)C>[CH2:64]([O:66][C:67]([N:69]1[CH2:74][CH2:73][N:72]([C:75](=[O:88])[C@@H:76]([NH:87][C:27]([C:18]2[CH:17]=[C:16]([O:15][CH2:14][C:13]([N:9]3[CH2:10][CH2:11][CH2:12][C@H:8]3[C:6](=[O:7])[NH:5][CH:1]3[CH2:4][CH2:3][CH2:2]3)=[O:30])[N:20]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[N:19]=2)=[O:28])[CH2:77][CH2:78][O:79][CH2:80][C:81]2[CH:86]=[CH:85][CH:84]=[CH:83][CH:82]=2)[CH2:71][CH2:70]1)=[O:68])[CH3:65]
Reactant: O=C(O)c1cc(OCC(=O)N2CCC[C@H]2C(=O)NC2CCC2)n(-c2ccccc2)n1
Reactant: CCOC(=O)N1CCN(C(=O)[C@@H](N)CCOCc2ccccc2)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)N1CCN(C(=O)[C@H](CCOCc2ccccc2)NC(=O)c2cc(OCC(=O)N3CCC[C@H]3C(=O)NC3CCC3)n(-c3ccccc3)n2)CC1
Reaction time: 12 h

Procedure:
To a solution of 355 mg 5-[2-((S)-2-cyclobutylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-1-phenyl-1H-pyrazole-3-carboxylic acid in 3 ml DMF were added 356 μl DIPEA, 328 mg HATU and 400 mg 4-((S)-2-amino-4-benzyloxy-butyryl)-piperazine-1-carboxylic acid ethyl ester hydrotrifluoroacetate. After stirring for 12 h the reaction mixture was diluted with ethyl acetate and subsequently washed with aqueous LiCl (4%), 0.1 M HCl and saturated NaHCO3. The crude product obtained after evaporation of the solvent was used without further purification. Yield: 543 mg.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH:13]([CH2:14][OH:15])[CH2:12][N:11]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:10][CH:9]2[OH:23])=[CH:4][CH:3]=1.[C:24]1([C:30]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)Cl)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(N(CC)CC)C>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH:13]([CH2:14][O:15][C:30]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)([C:38]3[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=3)[C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)[CH2:12][N:11]([C:16]([O:18][C:19]([CH3:20])([CH3:22])[CH3:21])=[O:17])[CH2:10][CH:9]2[OH:23])=[CH:6][CH:7]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CC(O)C(c2ccc(Br)cc2)C(CO)C1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CC(O)C(c2ccc(Br)cc2)C(COC(c2ccccc2)(c2ccccc2)c2ccccc2)C1
Yield: 84.1 %

Procedure:
A solution of 735 mg (1.91 mmol) of tert-butyl (3RS,4RS,5SR)-4-(4-bromo-phenyl)-3-hydroxy-5-hydroxymethyl-piperidine-1-carboxylate, 766 mg (2.75 mmol) of triphenylchloromethane and 324 mg (3.20 mmol) of triethylamine in 8 ml of methylene chloride was stirred at room temperature for 15 hours. For the working-up, the reaction mixture was evaporated under reduced pressure and the crude product was chromatographed directly on silica gel using methylene chloride as the eluent. There were obtained 1.01 g (84.5% of theory) of tert-butyl (3RS,4RS,5SR)-4-(4-bromo-phenyl)-3-hydroxy-5-trityloxymethyl-piperidine-1-carboxylate as a colourless foam; MS: 646 (M+NH4)+.
Reaction SMILES: [CH2:1]([C:3]1[CH:7]=[C:6]([CH2:8][CH3:9])[N:5]([C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)[N:4]=1)[CH3:2].C(=O)([O-])[O-].[K+].[K+].Cl[CH2:24][CH2:25][CH2:26][N:27]1[CH2:31][CH2:30][CH2:29][CH2:28]1>CC(=O)CC.O>[CH2:1]([C:3]1[CH:7]=[C:6]([CH2:8][CH3:9])[N:5]([C:10]2[CH:11]=[CH:12][C:13]([O:16][CH2:24][CH2:25][CH2:26][N:27]3[CH2:31][CH2:30][CH2:29][CH2:28]3)=[CH:14][CH:15]=2)[N:4]=1)[CH3:2]
Reactant: CCc1cc(CC)n(-c2ccc(O)cc2)n1
Reactant: ClCCCN1CCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCC(C)=O
Product: CCc1cc(CC)n(-c2ccc(OCCCN3CCCC3)cc2)n1
Temperature: 80 °C
Yield: 9.3 %

Procedure:
To a solution of 4-(3,5-diethylpyrazol-1-yl)phenol (50 mg, 0.23 mmol) in 2-butanone (2 mL) was added potassium carbonate (35 mg, 0.25 mmol) and 1-(3-chloropropyl)pyrrolidine (37 mg, 0.25 mmol). The vial was capped and the reaction was heated overnight at 80° C. After the reaction was diluted with water and extracted with methylene chloride, the organic layer was dried (MgSO4) and concentrated. The residue was purified by semi-prep LC-MS to give 7.0 mg of the desired product. LC-MS (C20H29N3O calculated 327) m/z 328 (M+H); 1H NMR (300 MHz, CDCl3) 7.29 (d, J=9.0 Hz, 2H), 6.94 (d, J=8.7 Hz, 2H), 6.02 (s, 1H), 4.05 (t, J=6.3 Hz, 2H), 2.73-2.54 (m, 10H), 2.06 (quint, J=6.3 Hz, 2H), 1.83 (s, 4H), 1.28 (t, J=7.5 Hz, 3H), 1.19 (t, J=7.5 Hz, 3H).
Reaction SMILES: C[CH:2]([CH:6]1[C:10]2=[C:11]([S:20][C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=3)[C:12]3[C:13](Br)=[CH:14][C:15]([F:18])=[CH:16][C:17]=3[N:9]2[CH2:8][CH2:7]1)[C:3]([O-:5])=[O:4].[CH:28]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:31]=[CH:30][C:29]=1B(O)O>>[Cl:27][C:24]1[CH:23]=[CH:22][C:21]([S:20][C:11]2[C:12]3[C:13]([C:30]4[CH:29]=[CH:28][C:37]5[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=5)[CH:31]=4)=[CH:14][C:15]([F:18])=[CH:16][C:17]=3[N:9]3[CH2:8][CH2:7][CH:6]([CH2:2][C:3]([OH:5])=[O:4])[C:10]=23)=[CH:26][CH:25]=1
Reactant: CC(C(=O)[O-])C1CCn2c1c(Sc1ccc(Cl)cc1)c1c(Br)cc(F)cc12
Reactant: OB(O)c1ccc2ccccc2c1
Product: O=C(O)CC1CCn2c1c(Sc1ccc(Cl)cc1)c1c(-c3ccc4ccccc4c3)cc(F)cc12

Procedure:
Staring from (+/−)-methyl[8-bromo-9-[(4-chlorophenyl)sulfanyl]-6-fluoro-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl]acetate (Example 7, Step 9) and 2-naphthylboronic acid, the title compound was synthesized following the procedures described in Example 108.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].I[CH2:8][CH2:9][CH3:10].[CH3:11][C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][C:13]=1[N+:19]([O-:21])=[O:20]>CN(C=O)C>[CH3:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:8][CH2:9][CH3:10])=[CH:14][C:13]=1[N+:19]([O-:21])=[O:20]
Reactant: CCCI
Reactant: Cc1ccc(O)cc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCOc1ccc(C)c([N+](=O)[O-])c1
Reaction time: 5 h

Procedure:
Potassium carbonate (13.5 g, 0.098 mol) followed by 1-iodopropane (9.56 mL, 0.098 mol) were added to a solution of 4-methyl-3-nitro-phenol (15 g, 0.098 mol) in DMF (100 mL). The mixture was stirred for 5 hours and then partitioned between H2O and EtOAc. The organic layer was washed with satd NaHCO3, brine, dried over Na2SO4 and concentrated to a clear oil (17.5 g).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]([C:17]2[O:18][C:19]3[CH:25]=[CH:24][C:23](I)=[CH:22][C:20]=3[N:21]=2)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:27]1([SH:37])[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:30]=[CH:29][CH:28]=1.C([O-])([O-])=O.[K+].[K+]>C(O)(C)C.CO.C(Cl)Cl.[Cu]I>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]([C:17]2[O:18][C:19]3[CH:25]=[CH:24][C:23]([S:37][C:27]4[C:36]5[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=5)[CH:30]=[CH:29][CH:28]=4)=[CH:22][C:20]=3[N:21]=2)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Sc1cccc2ccccc12
Reactant: O=C(OCc1ccccc1)N1CCN(c2nc3cc(I)ccc3o2)CC1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: ClCCl
Solvent: CC(C)O
Product: O=C(OCc1ccccc1)N1CCN(c2nc3cc(Sc4cccc5ccccc45)ccc3o2)CC1
Temperature: 90 °C
Yield: 31 %

Procedure:
A mixture of 4-(5-iodobenzoxazol-2-yl)piperazine-1-carboxylic acid benzyl ester, prepared in Example 2 (1.48 mmol theory), 1-napthalenethiol (0.237 g, 1.48 mmol), CuI (0.042 g, 0.22 mmol), and K2CO3 (0.409 g, 2.96 mmol) in isopropanol was heated at 90° C. overnight, diluted with 20% MeOH in CH2Cl2, and filtered through a pad of silica gel. The filtrate was concentrated to dryness. The resultant residue was purified by chromatography with 5% MeOH in CH2Cl2 to provide the title compound (230 mg, 31% overall yield from 4-benzoxazol-2-yl-piperazine-1-carboxylic acid benzyl ester), characterized by NMR and mass spectral analyses.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:13]=[C:14]=[O:15])[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].[Cl:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[N:23]1[CH2:28][CH2:27][N:26]([CH2:29][CH2:30][CH2:31][OH:32])[CH2:25][CH2:24]1>C1(C)C=CC=CC=1>[ClH:16].[Cl:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[N:23]1[CH2:24][CH2:25][N:26]([CH2:29][CH2:30][CH2:31][O:32][C:14](=[O:15])[NH:13][C:5]2[CH:6]=[C:7]([O:11][CH3:12])[C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=2)[CH2:27][CH2:28]1
Reactant: COc1cc(N=C=O)cc(OC)c1OC
Reactant: OCCCN1CCN(c2ccccc2Cl)CC1
Solvent: Cc1ccccc1
Product: COc1cc(NC(=O)OCCCN2CCN(c3ccccc3Cl)CC2)cc(OC)c1OC
Product: Cl
Yield: 40 %

Procedure:
A mixture of 3,4,5-trimethoxyphenylisocyanate (420 mg; 2.0 mmol) (produced as in Example 1) and 3-[4-(2-chloro-phenyl) -1-piperazinyl]propanol (500 mg; 20 mmol) in toluene (25 ml) was refluxed for 16 h. The solvent was evaporated and the residue taken up in ethanol, which was treated with hydrogen chloride in ether. Recrystallization from ethanol/ether afforded 400 mg of the title compound. M.p. 185°-187° C. MS (70 eV): m/z 463 (6%, M+), 254 (30), 209 (100), 194 (52), 166 (34), 70 (58).
Reaction SMILES: [Cl:1][C:2]1[C:13]([C:14](=[O:20])[C:15]2[S:19][CH:18]=[CH:17][CH:16]=2)=[CH:12][C:5]2[CH2:6][CH:7]([C:9](O)=[O:10])[O:8][C:4]=2[C:3]=1[Cl:21].S(Cl)([Cl:24])=O>C1C=CC=CC=1>[Cl:1][C:2]1[C:13]([C:14](=[O:20])[C:15]2[S:19][CH:18]=[CH:17][CH:16]=2)=[CH:12][C:5]2[CH2:6][CH:7]([C:9]([Cl:24])=[O:10])[O:8][C:4]=2[C:3]=1[Cl:21]
Reactant: O=S(Cl)Cl
Reactant: O=C(c1cccs1)c1cc2c(c(Cl)c1Cl)OC(C(=O)O)C2
Solvent: c1ccccc1
Product: O=C(c1cccs1)c1cc2c(c(Cl)c1Cl)OC(C(=O)Cl)C2

Procedure:
6,7-Dichloro-2,3-dihydro-5-(2-thenoyl)-2-benzofuran carboxylic acid (3.4 g.; 0.01M.) is combined with 2 ml. thionyl chloride and 50 ml. benzene. After 2 hours at reflux the excess thionyl chloride and benzene are removed by distillation at 20 mmHg to give 6,7-dichloro-2,3-dihydro-5-(2-thenoyl)-2-benzofuran carboxylic acid chloride as a yellow oil.
Reaction SMILES: O=[C:2]1[C:10]2[C:5](=[CH:6][C:7]([O:11][C:12]3[CH:20]=[CH:19][C:15]([C:16]([NH2:18])=[O:17])=[CH:14][N:13]=3)=[CH:8][CH:9]=2)[CH2:4][CH2:3]1.[S:21]1[CH:25]=[CH:24][CH:23]=[C:22]1[CH2:26][CH2:27][NH2:28].[BH3-]C#N.[Na+]>Cl[Ti](Cl)(Cl)Cl>[S:21]1[CH:25]=[CH:24][CH:23]=[C:22]1[CH2:26][CH2:27][NH:28][CH:2]1[C:10]2[C:5](=[CH:6][C:7]([O:11][C:12]3[CH:20]=[CH:19][C:15]([C:16]([NH2:18])=[O:17])=[CH:14][N:13]=3)=[CH:8][CH:9]=2)[CH2:4][CH2:3]1
Reactant: NCCc1cccs1
Reactant: NC(=O)c1ccc(Oc2ccc3c(c2)CCC3=O)nc1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: [BH3-]C#N
Agent: [Na+]
Product: NC(=O)c1ccc(Oc2ccc3c(c2)CCC3NCCc2cccs2)nc1
Yield: 51.7 %

Procedure:
Using a method similar to Example 1, using 6-(1-oxo-indan-5-yloxy)-nicotinamide (Intermediate 4, 268 mg, 1.00 mmol), 2-thiopheneethylamine (152 mg, 1.20 mmol), Ti(iPrO)4 (568 mg, 2.00 mmol), TiCl4 (1.0M/DCM, 2.00 ml, 2.00 mmol), and NaBH3CN (125 mg, 2.00 mmol) gives the title compound (196 mg) as a white solid. Mass spectrum (ion spray): m/z=380 (M+1); 1HNMR (CDCl3): 8.58 (s, 1H), 8.15 (d, 1H), 7.35 (d, 1H), 7.16 (d, 1H). 6.99 (s, 1H), 6.96-6.93 (m, 3H), 6.86 (d, 1H), 5.81 (br. s, 2H), 4.28 (t, 1H), 3.11-2.96 (m, 5H), 2.83 (m, 1H), 2.46 (m, 1H), 1.87 (m, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH2:7][CH2:6][CH:5]([CH3:8])[CH2:4][C:3]=1[C:9]([O:11]CC)=O.[C:14](OCC)(=[O:21])[CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17]>>[C:16]([C:15]1[C:14](=[O:21])[NH:1][C:2]2[CH2:7][CH2:6][CH:5]([CH3:8])[CH2:4][C:3]=2[C:9]=1[OH:11])([O:18][CH2:19][CH3:20])=[O:17]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: CCOC(=O)C1=C(N)CCC(C)C1
Product: CCOC(=O)c1c(O)c2c([nH]c1=O)CCC(C)C2

Procedure:
Condensation of ethyl 2-amino-5-methyl-cyclohex-1-ene-1-carboxylate (37 g; 0.202 mole) with diethyl malonate (32.4 g; 0.202 mole) at 110° C as described in Example 1 gave the title compound; m.p. (EtOH) 214° -216° C.