Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:20]2[CH:21]=[C:22]([CH:26]=[CH:27][CH:28]=2)[C:23]([OH:25])=O)[CH2:9][C:10]([C:12]2[CH:17]=[CH:16][C:15](=[O:18])[N:14]([CH3:19])[CH:13]=2)=[O:11])=[C:4]([F:29])[CH:3]=1.[CH3:30][NH:31][CH2:32][CH2:33][OH:34].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:20]2[CH:21]=[C:22]([CH:26]=[CH:27][CH:28]=2)[C:23]([N:31]([CH2:32][CH2:33][OH:34])[CH3:30])=[O:25])[CH2:9][C:10]([C:12]2[CH:17]=[CH:16][C:15](=[O:18])[N:14]([CH3:19])[CH:13]=2)=[O:11])=[C:4]([F:29])[CH:3]=1
Reactant: Cn1cc(C(=O)CC(c2cccc(C(=O)O)c2)c2ccc(Cl)cc2F)ccc1=O
Reactant: CNCCO
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Product: CN(CCO)C(=O)c1cccc(C(CC(=O)c2ccc(=O)n(C)c2)c2ccc(Cl)cc2F)c1

Procedure:
In analogy to example 207, step 2, 3-(1-(4-chloro-2-fluorophenyl)-3-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-3-oxopropyl)benzoic acid (example 320, step 4) was coupled with 2-(methylamino)ethanol using benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluoro-phosphate in tetrahydrofuran to give the title compound as a colourless foam, MS (ESI+): m/z=471.4 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:19]=[CH:18][C:5]2[CH2:6][CH:7]([CH2:13][C:14]([O:16][CH3:17])=[O:15])[C:8](=[O:12])[N:9]([CH3:11])[CH2:10][C:4]=2[CH:3]=1.[C:20]([NH:27][CH2:28][C:29](O)=[O:30])([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21]>>[C:23]([O:22][C:20]([NH:27][CH2:28][C:29]([NH:1][C:2]1[CH:19]=[CH:18][C:5]2[CH2:6][CH:7]([CH2:13][C:14]([O:16][CH3:17])=[O:15])[C:8](=[O:12])[N:9]([CH3:11])[CH2:10][C:4]=2[CH:3]=1)=[O:30])=[O:21])([CH3:26])([CH3:25])[CH3:24]
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: COC(=O)CC1Cc2ccc(N)cc2CN(C)C1=O
Product: COC(=O)CC1Cc2ccc(NC(=O)CNC(=O)OC(C)(C)C)cc2CN(C)C1=O
Yield: 55 %

Procedure:
Methyl (±)-8-amino-2-methyl-3-oxo-2,3,4,5-tetrahydro-1H-2-benzazepine-4-acetate was coupled with Boc-glycine according to the procedure of example 5(b). Purification by chromatography (silica gel, 2%-5% CH3OH/CH2Cl2) gave the title compound as a pale yellow foam (55%): 1H NMR (CDCl3) δ8.22 (br s, 1H), 7.48 (s, 1H), 7.20 (d, J=8.3 Hz, 1H), 7.04 (d, J=8.3 Hz, 1H), 5.27 (d, J=16.6 Hz, 1H), 5.25 (br s, 1H), 3.92 (d, J=5.4 Hz, 2H), 3.82 (m, 1H), 3.80 (d, J=16.6 Hz, 1H), 3.71 (s, 3H), 3.03 (s, 3H), 2.90 (m, 3H), 2.41 (dd, J=16.8, 5.5 Hz, 1H), 1.48 (s, 9H).
Reaction SMILES: [CH2:1]([N:8]([CH:12]1[CH2:17][CH2:16][N:15]([C:18]2[CH:23]=[CH:22][C:21]([C:24]3[NH:33][C:32](=[O:34])[C:31]4[C:26](=[CH:27][C:28]([O:37][CH3:38])=[CH:29][C:30]=4[O:35][CH3:36])[N:25]=3)=[CH:20][N:19]=2)[CH2:14][CH2:13]1)C(=O)C)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>Cl>[CH2:1]([NH:8][CH:12]1[CH2:13][CH2:14][N:15]([C:18]2[N:19]=[CH:20][C:21]([C:24]3[NH:33][C:32](=[O:34])[C:31]4[C:26](=[CH:27][C:28]([O:37][CH3:38])=[CH:29][C:30]=4[O:35][CH3:36])[N:25]=3)=[CH:22][CH:23]=2)[CH2:16][CH2:17]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cc(OC)c2c(=O)[nH]c(-c3ccc(N4CCC(N(Cc5ccccc5)C(C)=O)CC4)nc3)nc2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: COc1cc(OC)c2c(=O)[nH]c(-c3ccc(N4CCC(NCc5ccccc5)CC4)nc3)nc2c1
Yield: 59.8 %

Procedure:
A solution of N-benzyl-N-(1-(5-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)pyridin-2-yl)piperidin-4-yl)acetamide (0.200 g, 0.39 mmol) in 2 N HCl (15 mL) was refluxed for 3 days. The resulting mixture was basified with 2 N NaOH and extracted with CH2Cl2. The organics were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. Purification by flash chromatography on silica gel, eluting with 10% to 100% of 92:7:1 CHCl3/MeOH/concentrated NH4OH in CH2Cl2, afforded the title compound (0.110 g, 60%) as a white solid. 1H NMR (300 MHz, DMSO-d6): δ 11.11 (br s, 1H), 8.89 (d, J=2.3 Hz, 1H), 8.22-8.26 (m, 1H), 7.28-7.37 (m, 4H), 7.18-7.23 (m, 1H), 6.91 (d, J=7.2 Hz, 1H), 6.67 (d, J=2.2 Hz, 1H), 6.46 (d, J=2.2 Hz, 1H), 4.27-4.31 (m, 2H), 3.88 (s, 3H), 3.83 (s, 3H), 3.76 (s, 2H), 3.00-3.11 (m, 2H), 2.62-2.69 (m, 1H), 1.88-1.91 (m, 2H), 1.25-1.31 (m, 2H). ESI MS m/z 472 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:8])=[N:6][CH:7]=1.[N+:9]([O-])([OH:11])=[O:10]>S(=O)(=O)(O)O>[N+:9]([C:7]1[C:2]([OH:1])=[CH:3][CH:4]=[C:5]([CH3:8])[N:6]=1)([O-:11])=[O:10]
Reactant: O=[N+]([O-])O
Reactant: Cc1ccc(O)cn1
Agent: O=S(=O)(O)O
Product: Cc1ccc(O)c([N+](=O)[O-])n1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
5.45 g (50 mmol) of 5-hydroxy-2-methylpyridine are added to 20 ml of concentrated sulfuric acid while cooling in an ice bath. The temperature is maintained at +6° C. and 2.35 ml of fuming nitric acid are added with stirring. The mixture is left overnight at room temperature. 100 g of ice are added with stirring. The product is filtered off, rinsed with water and dried.
Reaction SMILES: [C:1]1([C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[CH3:16])([OH:9])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[CH3:19]I.Cl>O1CCCC1>[CH3:19][O:9][C:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH3:16])[CH3:8]
Reactant: CI
Reactant: Cc1ccccc1C(C)(O)c1ccccc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(C)(c1ccccc1)c1ccccc1C
Reaction time: 6 h

Procedure:
2 g of 1-Phenyl-1-tolylethanol are stirred overnight with 0.56 g of 80% NaH in 50 ml of tetrahydrofuran, 3.7 g of methyliodide added and stirring continued for 6 hours. The mixture is worked up with aq. HCl, extracted with dichloromethane and the oily product purified over a silica gel column with cyclohexane as eluant.
Reaction SMILES: [CH2:1]([N:5]([CH2:21][C:22]1[CH:23]=[CH:24][C:25]2[CH2:31][CH2:30][CH2:29][CH2:28][CH:27]([O:32]C3CCCCO3)[C:26]=2[CH:39]=1)[C:6]([CH:8]1[O:13][CH2:12][CH2:11][N:10]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:9]1)=[O:7])[CH:2]([CH3:4])[CH3:3].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>C(O)C>[OH:32][CH:27]1[C:26]2[CH:39]=[C:22]([CH2:21][N:5]([CH2:1][CH:2]([CH3:4])[CH3:3])[C:6]([CH:8]3[O:13][CH2:12][CH2:11][N:10]([C:14]([O:16][C:17]([CH3:18])([CH3:19])[CH3:20])=[O:15])[CH2:9]3)=[O:7])[CH:23]=[CH:24][C:25]=2[CH2:31][CH2:30][CH2:29][CH2:28]1
Reactant: CC(C)CN(Cc1ccc2c(c1)C(OC1CCCCO1)CCCC2)C(=O)C1CN(C(=O)OC(C)(C)C)CCO1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CCO
Product: CC(C)CN(Cc1ccc2c(c1)C(O)CCCC2)C(=O)C1CN(C(=O)OC(C)(C)C)CCO1
Temperature: 55 °C
Reaction time: 8 h

Procedure:
A mixture of 1.91 g (3.5 mmol) of (±)-tert-butyl 2-[(isobutyl {[9-(tetrahydro-2H-pyran-2-yloxy)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl]methyl}amino)carbonyl]morpholine-4-carboxylate and 0.088 g (0.35 mmol, 0.1 equiv) of pyridinium p-toluenesulfonate in 25 mL of ethanol was stirred under nitrogen at 55° C. overnight. The reaction mixture was concentrated under reduced pressure and the residue was purified by flash chromatography (10-50% ethyl acetate in hexanes) to give the product as a solid white foam. MS (m+1)=461.4; H NMR (400 MHz, CDCl3) 7.29 (m, 1H), 7.05 (m, 1H), 6.96 (m, 1H), 4.91 (t, 1H, J 8 Hz), 4.75 (m, 1H), 4.48 (d, 1H, J 16 Hz), 4.18-4.02 (m, 2H), 4.01-3.80 (m, 2H), 3.57-3.38 (m, 2H), 3.21 (m, 1H), 3.10-2.85 (m, 3H), 2.69 (m, 1H), 2.01 (m, 3H), 1.78 (m, 3H), 1.57 (m, 2H, obscured by H2O peak), 1.45 (d, 9H, J 15 Hz), 0.90 (m, 6H).
Reaction SMILES: [CH2:1]1[CH2:10][O:9][C:8]2[CH:7]=[CH:6][C:5]([CH:11]=[CH:12][C:13](=[O:15])[CH3:14])=[CH:4][C:3]=2[O:2]1.C(OCC)(=O)[CH2:17][C:18](OCC)=[O:19]>>[CH2:1]1[CH2:10][O:9][C:8]2[CH:7]=[CH:6][C:5]([CH:11]3[CH2:17][C:18](=[O:19])[CH:14]=[C:13]([OH:15])[CH2:12]3)=[CH:4][C:3]=2[O:2]1
Reactant: CCOC(=O)CC(=O)OCC
Reactant: CC(=O)C=Cc1ccc2c(c1)OCCO2
Product: O=C1C=C(O)CC(c2ccc3c(c2)OCCO3)C1

Procedure:
5-(3,4-Ethylenedioxyphenyl)-3-hydroxycyclohex-2-en-1-one was prepared from 1-(3,4-ethylenedioxyphenyl)but-1-en-3-one and diethyl malonate following essentially the same procedure as that described in Example 1 part (ii). The product was obtained as a crystalline solid, mp 188° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH2:18][CH2:17][C@H:16]([O:19][C:20]3[CH:21]=[N:22][C:23](Br)=[CH:24][CH:25]=3)[C:15]2=[O:27])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:28]([S:30]([O-:32])=[O:31])C.[Na+].[C@@H]1(N)CCCC[C@H]1N>CS(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH2:18][CH2:17][C@H:16]([O:19][C:20]3[CH:21]=[N:22][C:23]([S:30]([CH3:28])(=[O:32])=[O:31])=[CH:24][CH:25]=3)[C:15]2=[O:27])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(N2CC[C@H](Oc3ccc(Br)nc3)C2=O)CC1
Reactant: CCS(=O)[O-]
Agent: N[C@@H]1CCCC[C@H]1N
Agent: [Na+]
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CCC(N2CC[C@H](Oc3ccc(S(C)(=O)=O)nc3)C2=O)CC1
Temperature: 110 °C
Yield: 100.4 %

Procedure:
A solution of (S)-tert-butyl-4-(3-(6-bromopyridin-3-yloxy)-2-oxopyrrolidin-1-yl)piperidine-1-carboxylate (315 mg, 0.714 mmol) in degassed DMSO (5 mL) was added sodium ethanesulfinate (117 mg, 1.15 mmol), trans-cyclohexane-1,2-diamine (33 mg, 0.286 mmol) and Cu(I) triflate benzene complex (54 mg, 0.107 mmol). The reaction was heated to 110° C. for 12 hours at which point the reaction was cooled to ambient temperature and partitioned between water (5 mL) and EtOAc (10 mL). The organic layer was separated and the aqueous layer extracted with EtOAc (2×5 mL). The combined organic layers were dried over MgSO4, filtered and concentrated in vacuo. The resulting material was purified by silica gel chromatography eluting with 1:1 hexanes/EtOAc to yield (S)-tert-butyl-4-(3-(6-(methylsulfonyl)pyridine-3-yloxy)-2-oxopyrrolidin-1-yl)piperidine-1-carboxylate (315 mg, 94%) as a white solid.
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:10][CH2:9][C:8]2[N:11]([CH2:24][CH:25]3[CH2:27][O:26]3)[N:12]=[C:13]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=3)[C:7]=2[CH2:6]1)(=[O:4])=[O:3].[Cl:28][C:29]1[CH:37]=[C:36]2[C:32]([CH:33]=[CH:34][N:35]2[CH:38]2[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]2)=[CH:31][CH:30]=1>CCO>[Cl:28][C:29]1[CH:37]=[C:36]2[C:32]([CH:33]=[CH:34][N:35]2[CH:38]2[CH2:43][CH2:42][N:41]([CH2:27][CH:25]([OH:26])[CH2:24][N:11]3[C:8]4[CH2:9][CH2:10][N:5]([S:2]([CH3:1])(=[O:4])=[O:3])[CH2:6][C:7]=4[C:13]([C:14]4[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:21])[F:22])=[CH:16][CH:15]=4)=[N:12]3)[CH2:40][CH2:39]2)=[CH:31][CH:30]=1
Reactant: CS(=O)(=O)N1CCc2c(c(-c3ccc(C(F)(F)F)cc3)nn2CC2CO2)C1
Reactant: Clc1ccc2ccn(C3CCNCC3)c2c1
Solvent: CCO
Product: CS(=O)(=O)N1CCc2c(c(-c3ccc(C(F)(F)F)cc3)nn2CC(O)CN2CCC(n3ccc4ccc(Cl)cc43)CC2)C1
Temperature: 60 °C
Yield: 47.9 %

Procedure:
To a stirred solution of 86 mg (0.21 mmol) of 5-methanesulfonyl-1-oxiranylmethyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine in 4 mL of EtOH was added 50 mg (0.39 mmol) of 6-chloro-1-piperidin-4-yl-1H-indole. The solution was heated to 60° C. overnight. The solvent was then removed by rotary evaporation and the crude product was purified by column chromatography (silica, gradient elution from 0-5% 2 N NH3/MeOH in CH2Cl2) to afford 64 mg (48%) of a white solid. MS (electrospray), exact mass calculated for C30H33ClF3N5O3S: 635.19. m/z found, 636.2 [M+H]+. HPLC (reverse phase conditions 10-90%), tR=4.88 min. 1H NMR (CDCl3, 400 MHz): 7.72 and 7.67 (A and B of AB quartet, J=8.80 Hz, 4H), 7.52 (d, J=8.41, 1H), 7.34 (s, 1H), 7.18 (d, J=3.33 Hz, 1H), 7.07 (dd, J=8.41, 1.76 Hz, 1H), 6.50 (d, J=3.33 Hz, 1H), 4.59 and 4.54 (A and B of AB quartet, J=14.48 Hz, 2H), 4.24 (dd, J=13.69, 2.39 Hz, 1H), 4.21-4.14 (m, 2H), 4.05 (dd, J=13.69, 6.46 Hz, 1H), 3.69 (m, 2H), 3.15 (br d, J=11.54 Hz, 1H), 3.11-2.91 (m, 3H), 2.60-2.48 (m, 3H), 2.28 (dt, J=11.74, 2.15 Hz, 1H), 2.13-1.93 (m, 4H).
Reaction SMILES: [Si:1](Cl)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[OH:9][CH2:10][CH2:11][C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:13].N1C=CN=C1.CN(C)C=O>O>[Si:1]([O:9][CH2:10][CH2:11][C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:13])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: O=C(CCO)c1ccccc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCCC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Tert-butyldimethylsilyl chloride (150 g) was added to a mixture of 3-hydroxypropiophenone (125 g), imidazole (142 g) and dimethylformamide (330 ml) and the mixture was stirred at ambient temperature for 16 hours. The mixture was poured into water (600 ml) and extracted with diethyl ether (600 ml). The organic layer was separated, washed with water (4×30 ml), dried (Na2SO4) and evaporated to give 3-(tert-butyldimethylsilyloxy)propiophenone as an oil (186 g, b.p. 114°-118° C. at 0.01 mm Hg).
Reaction SMILES: Br.[CH:2]1([S:5][C:6]2[CH:11]=[CH:10][C:9]([C:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[C:16]([O:24]C)[N:15]=3)=[O:13])=[CH:8][CH:7]=2)[CH2:4][CH2:3]1.O>O1CCOCC1>[CH:2]1([S:5][C:6]2[CH:7]=[CH:8][C:9]([C:12]([C:14]3[NH:15][C:16](=[O:24])[C:17]([C:20]([F:23])([F:22])[F:21])=[CH:18][CH:19]=3)=[O:13])=[CH:10][CH:11]=2)[CH2:4][CH2:3]1
Reactant: COc1nc(C(=O)c2ccc(SC3CC3)cc2)ccc1C(F)(F)F
Agent: Br
Solvent: C1COCCO1
Solvent: O
Product: O=C(c1ccc(SC2CC2)cc1)c1ccc(C(F)(F)F)c(=O)[nH]1
Temperature: 65 °C
Reaction time: 1 h
Yield: 55 %

Procedure:
48% hydrobromic acid (2 mL) was added to a solution of [4-(cyclopropylsulfanyl)phenyl][6-methoxy-5-(trifluoromethyl)pyridin-2-yl]methanone obtained in Reference Example 1-68 (400 mg) in 1,4-dioxane (4 mL), and the mixture was stirred at 65° C. for one hour. Water was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, after which the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1→1:5) to give 6-{[4-(cyclopropylsulfanyl)phenyl]carbonyl}-3-(trifluoromethyl)pyridin-2(1H)-one (210 mg, 55%).
Reaction SMILES: C(OC(N1CCC(C([O:20][C:21]2[CH:43]=[CH:42][C:24]3[C:25]4[N:29]([CH2:30][CH2:31][O:32][C:23]=3[CH:22]=2)[CH:28]=[C:27]([C:33]2[N:34]([CH:39]([CH3:41])[CH3:40])[N:35]=[C:36]([CH3:38])[N:37]=2)[N:26]=4)CC)CC1)=O)C1C=CC=CC=1.[H-].[Na+].[CH2:46]([O:48][C:49](=[O:58])[C:50](Br)([CH3:56])[C:51]([O:53][CH2:54][CH3:55])=[O:52])[CH3:47]>CN(C=O)C>[CH2:46]([O:48][C:49](=[O:58])[C:50]([O:20][C:21]1[CH:43]=[CH:42][C:24]2[C:25]3[N:29]([CH2:30][CH2:31][O:32][C:23]=2[CH:22]=1)[CH:28]=[C:27]([C:33]1[N:34]([CH:39]([CH3:41])[CH3:40])[N:35]=[C:36]([CH3:38])[N:37]=1)[N:26]=3)([CH3:56])[C:51]([O:53][CH2:54][CH3:55])=[O:52])[CH3:47]
Reactant: CCC(Oc1ccc2c(c1)OCCn1cc(-c3nc(C)nn3C(C)C)nc1-2)C1CCN(C(=O)OCc2ccccc2)CC1
Reactant: CCOC(=O)C(C)(Br)C(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(Oc1ccc2c(c1)OCCn1cc(-c3nc(C)nn3C(C)C)nc1-2)C(=O)OCC
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 96.9 %

Procedure:
To a suspension of 2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulen-8-ol from Example 4 (100 mg, 0.307 mmol) in DMF (2 mL) was added sodium hydride (12.3 mg, 60% in oil, 0.307 mmol). The mixture was stirred at RT (room temperature) for 15 min, then 2-bromo-2-methylmalonic acid diethyl ester (88 μL, 0.461 mmol) was added. The reaction mixture was stirred at RT for 45 min, and then partitioned between water and EtOAc. The aqueous phase was extracted with EtOAc and the combined organic layers were washed with water, followed by brine, then dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si-PCC, gradient 2-8% MeOH in DCM) affording the title compound as a colourless gum (148 mg, 97%). LCMS (Method B): RT 3.46 min [M+H]+ 498.
Reaction SMILES: [CH3:1][NH:2][C:3](=O)[CH2:4][CH:5]([C:12]1[CH:20]=[C:19]2[C:15]([CH:16]=[CH:17][N:18]2[CH3:21])=[CH:14][CH:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.N1C2C(=CC=CC=2C(C2C=CC=CC=2)CCNC)C=C1>>[CH3:1][NH:2][CH2:3][CH2:4][CH:5]([C:12]1[CH:20]=[C:19]2[C:15]([CH:16]=[CH:17][N:18]2[CH3:21])=[CH:14][CH:13]=1)[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: CNC(=O)CC(c1ccccc1)c1ccc2ccn(C)c2c1
Agent: CNCCC(c1ccccc1)c1cccc2cc[nH]c12
Product: CNCCC(c1ccccc1)c1ccc2ccn(C)c2c1

Procedure:
Methyl-[3-(1-methyl-1H-indol-6-yl)-3-phenyl-propyl]-amine CXLVI was prepared as a hydrochloride salt from N-methyl-3-(1-methyl-1H-indol-6-yl)-3-phenyl-propionamide using the procedure described above for preparation of [3-(1H-Indol-7-yl)-3-phenyl-propyl]-methyl-amine XX (Example 4). MS (M+H)=279.
Reaction SMILES: [CH3:1][C@@H:2]([O:5][C:6]1[CH:7]=[C:8]([CH2:12]O)[CH:9]=[CH:10][CH:11]=1)[CH2:3][CH3:4].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Cl)(Cl)(Cl)[Cl:34]>>[Cl:34][CH2:12][C:8]1[CH:9]=[CH:10][CH:11]=[C:6]([O:5][C@H:2]([CH3:1])[CH2:3][CH3:4])[CH:7]=1
Reactant: ClC(Cl)(Cl)Cl
Reactant: CC[C@@H](C)Oc1cccc(CO)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CC[C@@H](C)Oc1cccc(CCl)c1

Procedure:
To a solution of (3-{[(1R)-1-methylpropyl]oxy}phenyl)methanol (1.01 g, 5.60 mmol) in carbon tetrachloride (18.7 ml) was added triphenylphosphine (1.40 g, 5.32 mmol). The reaction was heated to reflux overnight. The reaction was filtered through a fritted funnel and washed with carbon tetrachloride. The filtrate was concentrated. The residue was purified on a silica gel cartridge (0% EtOAc/hexanes to 10% EtOAc/hexanes) to give the desired product.
Reaction SMILES: C(N1CCOCC1)C.C1(N=C=NC2CCCCC2)CCCCC1.[NH2:24][C@H:25]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:26][C:27]1[CH:32]=[CH:31][C:30]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[CH:29][CH:28]=1.[NH:45]([C:53]([O:55][CH2:56][C:57]1[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=1)=[O:54])[C@H:46]([C:50](O)=[O:51])[CH:47]([CH3:49])[CH3:48].ON1C2C=CC=CC=2N=N1>CN(C)C=O>[NH:45]([C:53]([O:55][CH2:56][C:57]1[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=1)=[O:54])[C@H:46]([C:50]([NH:24][C@H:25]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:26][C:27]1[CH:28]=[CH:29][C:30]([O:33][C:34]([CH3:37])([CH3:35])[CH3:36])=[CH:31][CH:32]=1)=[O:51])[CH:47]([CH3:49])[CH3:48]
Reactant: CC(C)(C)OC(=O)[C@@H](N)Cc1ccc(OC(C)(C)C)cc1
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CCN1CCOCC1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@@H](Cc1ccc(OC(C)(C)C)cc1)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 1 h

Procedure:
13 ml (approx. 0.1 mole) of N-ethylmorpholine and 22 g (107 mmoles) of dicyclohexylcarbodiimide are added at 0° C. to a solution in 150 ml of dimethylformamide of 33 g (0.1 mole) of H-Tyr(But)-OBut, 25.1 g (0.1 mole) of Z-Val-OH and 13.5 g of 1-hydroxybenzotriazole. The mixture is stirred for one hour at 0° C. and allowed to stand overnight at room temperature. The precipitate is filtered off and the filtrate is concentrated. The residue is partitioned between 300 ml of ethyl acetate and 300 ml of water. The ethyl acetate phase is extracted by shaking successively with 100 ml of saturated NaHCO3 solution, 100 ml of KHSO4 /K2SO4 solution, 100 ml of saturated NaHCO3 solution and 100 ml of water. After drying over Na2SO4 the solution is concentrated. The residue is triturated with petroleum ether, cooled and filtered off. Yield 31.2 g (60%), melting point 82°-83°, [α]D21 =-20.9° (c=1, methanol).
Reaction SMILES: I[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][CH:6]([NH:11][S:12]([CH:15]([CH3:17])[CH3:16])(=[O:14])=[O:13])[CH2:5]2.[N+:18]([C:21]1[CH:22]=[C:23](B(O)O)[CH:24]=[CH:25][CH:26]=1)([O-:20])=[O:19].C(=O)([O-])[O-].[Cs+].[Cs+].O>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[N+:18]([C:21]1[CH:26]=[C:25]([C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[CH2:7][CH:6]([NH:11][S:12]([CH:15]([CH3:17])[CH3:16])(=[O:14])=[O:13])[CH2:5]3)[CH:24]=[CH:23][CH:22]=1)([O-:20])=[O:19]
Reactant: CC(C)S(=O)(=O)NC1Cc2ccc(I)cc2C1
Reactant: O=[N+]([O-])c1cccc(B(O)O)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)S(=O)(=O)NC1Cc2ccc(-c3cccc([N+](=O)[O-])c3)cc2C1
Temperature: 80 °C
Reaction time: 16 h
Yield: 109.1 %

Procedure:
A mixture of Intermediate 2 (800 mg, 2.19 mmol) and 3-nitrophenyl boronic acid (366 mg, 2.19 mmol, Sigma Aldrich Company Ltd.) in dioxane (60 ml) was treated with cesium carbonate (1.07 g, 3.29 mmol) and water (20 ml) and degassed with argon for 2 min. Palladium (II) acetate (25 mg, 0.11 mmol) and triphenylphosphine (58 mg, 0.22 mmol) were added and the mixture was stirred at 80° C. under argon for 16 h. The reaction mixture was cooled, then partitioned between ethyl acetate (100 ml) and water (100 ml). The organic layer was separated and dried over Na2SO4 and evaporated in vacuo to give a brown oil (861 mg). This crude oil was purified using flash chromatography to give the title compound as a yellow oil (500 mg, 63%); mass spectrum: (ES−): Found 359 (MH−). C18H20N2O4S requires 360; 1H-NMR (400 MHz, CDCl3) δ 1.38 (6H, m), 2.99 (2H, m), 3.18 (1H, m), 3.38 (2H, m), 4.35 (2H, m), 7.34 (1H, d J=8 Hz), 7.45 (2H, m), 7.60 (1H, m), 7.88 (1H, dd, J=8 Hz and 1 Hz), 8.19 (1H, m), 8.41 (1H, m).
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:13]=[C:12]([O:14][CH3:15])[C:11](=[O:16])[C:10]([C:17](N(OC)C)=[O:18])=[N:9]2)=[C:4]([O:23][CH3:24])[CH:3]=1.Cl.[CH2:26]1COCC1>>[C:17]([C:10]1[C:11](=[O:16])[C:12]([O:14][CH3:15])=[CH:13][N:8]([C:5]2[CH:6]=[CH:7][C:2]([I:1])=[CH:3][C:4]=2[O:23][CH3:24])[N:9]=1)(=[O:18])[CH3:26]
Reactant: COc1cc(I)ccc1-n1cc(OC)c(=O)c(C(=O)N(C)OC)n1
Reactant: C1CCOC1
Agent: Cl
Product: COc1cc(I)ccc1-n1cc(OC)c(=O)c(C(C)=O)n1
Reaction time: 0.33 h

Procedure:
To a solution of 1-(4-iodo-2-methoxyphenyl)-N,5-dimethoxy-N-methyl-4-oxo-1,4-dihydropyridazine-3-carboxamide (8.90 g) in THF (150 mL) was added dropwise 1M methylmagnesium bromide THF solution (30 mL) at −78° C., and the mixture was stirred for 20 min. To the reaction mixture was added 1M hydrochloric acid, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was washed with ethyl acetate, and recrystallized from methanol/water to give the title compound (5.12 g).
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([CH2:11][CH2:12][CH2:13][CH2:14][NH2:15])[CH:6]=1)[CH3:3].[N+](N[C:20]1[NH:25][C:24](=[O:26])[C:23]([CH2:27][C:28]2[CH:29]=[N:30][C:31]([CH3:34])=[CH:32][CH:33]=2)=[CH:22][N:21]=1)([O-])=O>N1C=CC=CC=1>[CH3:1][N:2]([CH2:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([CH2:11][CH2:12][CH2:13][CH2:14][NH:15][C:20]2[NH:25][C:24](=[O:26])[C:23]([CH2:27][C:28]3[CH:29]=[N:30][C:31]([CH3:34])=[CH:32][CH:33]=3)=[CH:22][N:21]=2)[CH:6]=1)[CH3:3]
Reactant: Cc1ccc(Cc2cnc(N[N+](=O)[O-])[nH]c2=O)cn1
Reactant: CN(C)Cc1ccnc(CCCCN)c1
Solvent: c1ccncc1
Product: Cc1ccc(Cc2cnc(NCCCCc3cc(CN(C)C)ccn3)[nH]c2=O)cn1
Yield: 43.9 %

Procedure:
A mixture of 4-(4-dimethylaminomethyl-2-pyridyl)butylamine (1 g) and 2-nitroamino-5-(6-methyl-3-pyridylmethyl)-4-pyrimidone (1.26 g) in pyridine (5 ml) was refluxed for 4.5 hours. The solvent was removed in vacuo, the residue chromatographed and then crystallised from ethanol:ether (1:10) to yield 2-[4(4-dimethylaminomethyl-2-pyridyl)butylamino]-5-(6-methyl-3-pyridylmethyl)-4-pyrimidone (0.86 g) m.p. 135°-137°.