Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Sn](CCCC)(CCCC)[C:6]1[O:7][CH:8]=[CH:9][CH:10]=1)CCC.[NH2:19][C:20]1[N:25]=[C:24](Cl)[CH:23]=[C:22]([Cl:27])[N:21]=1>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH2:19][C:20]1[N:21]=[C:22]([Cl:27])[CH:23]=[C:24]([C:6]2[O:7][CH:8]=[CH:9][CH:10]=2)[N:25]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccco1
Reactant: Nc1nc(Cl)cc(Cl)n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Product: Nc1nc(Cl)cc(-c2ccco2)n1
Temperature: 80 °C
Reaction time: 18 h
Yield: 56.7 %

Procedure:
A solution of 2-(tributylstannyl)furan (35.7 g, 100 mmol) in DMF (100 mL) was treated with 2-amino-4,6-dichloropyrimidine (16.4 g, 100 mmol) and dichlorobis(triphenylphosphine)palladium (II) (3.51 g, 5.0 mmol). The suspension was stirred at 80° C. for 18 h, allowed to cool to room temperature and poured onto ice (400 g). The solid precipitate was filtered off, washed with water, dried in air, and the filtrate was extracted with EtOAc (300 mL), washed with water (100 mL), mixed with the solid precipitate and concentrated. The crude product was purified by chromatography [SiO2; EtOAc:toluene (0:1-1:9-2:3)] and the material with Rf 0.23 (isopropyl ether) was triturated with isohexane to give the title compound (11.1 g, 57%) as a yellow solid; mp. 133-140° C.; NMR δH (400 MHz, DMSO) 6.70 (1H, q, J 2.0 Hz), 6.95 (1H, s), 7.16 (2H, br s), 7.27 (1H, d, J 3.6 Hz) and 7.92 (1H, t, J 1.0 Hz).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([S:14]([C:17]2[CH:26]=[CH:25][C:24]3[C:19](=[CH:20][CH:21]=[C:22]([Cl:27])[CH:23]=3)[CH:18]=2)(=[O:16])=[O:15])[CH2:10][CH:9]1[CH2:28][C:29](O)=[O:30])=O)(C)(C)C.[N:32]1C=CC=CC=1.C(=O)(O)[O-].[NH4+].C(=O)(OOC(C)(C)C)OOC(C)(C)C>CN(C)C=O.ClCCl>[ClH:27].[Cl:27][C:22]1[CH:23]=[C:24]2[C:19](=[CH:20][CH:21]=1)[CH:18]=[C:17]([S:14]([N:11]1[CH2:12][CH2:13][NH:8][CH:9]([CH2:28][C:29](=[O:30])[NH2:32])[CH2:10]1)(=[O:16])=[O:15])[CH:26]=[CH:25]2
Reactant: c1ccncc1
Reactant: CC(C)(C)OC(=O)N1CCN(S(=O)(=O)c2ccc3cc(Cl)ccc3c2)CC1CC(=O)O
Agent: CC(C)(C)OOC(=O)OOC(C)(C)C
Agent: O=C([O-])O
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cl
Product: NC(=O)CC1CN(S(=O)(=O)c2ccc3cc(Cl)ccc3c2)CCN1
Temperature: 25 °C
Reaction time: 7 h

Procedure:
In N,N-dimethylformamide (20 ml), 1-tert-butoxycarbonyl-2-carboxymethyl-4-[(6-chloronaphthalen-2-yl)sulfonyl]piperazine (800 mg) was dissolved, followed by the addition of pyridine (0.85 ml), ammonium bicarbonate (417 mg) and di-tert-butoxy carbonate (1.15 g). The resulting mixture was stirred at room temperature for 7 hours. After concentration of the reaction mixture under reduced pressure, the residue was added with dichloromethane, washed with 1N hydrochloric acid and a saturated aqueous solution of sodium bicarbonate, each once and then dried over anhydrous sodium sulfate. The solvent was then distilled off under reduced pressure. After the addition of saturated aqueous hydrochloric acid in ethanol (30 ml) to the residue, the resulting mixture was concentrated under reduced pressure. While washing with ethanol, the solid thus precipitated was removed by filtration. The filtrate was then concentrated under reduced pressure. The residue was crystallized in methanol, whereby the title compound (426 mg) was obtained as a colorless solid.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Cl[C:8]1[N:13]=[C:12]([NH2:14])[C:11]([N+:15]([O-:17])=[O:16])=[CH:10][CH:9]=1>CC#N>[N:1]1([C:8]2[N:13]=[C:12]([NH2:14])[C:11]([N+:15]([O-:17])=[O:16])=[CH:10][CH:9]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: Nc1nc(Cl)ccc1[N+](=O)[O-]
Reactant: C1COCCN1
Solvent: CC#N
Product: Nc1nc(N2CCOCC2)ccc1[N+](=O)[O-]
Temperature: 70 °C
Reaction time: 5 h

Procedure:
Morpholine (4 eq) was added to a suspension of 6-chloro-3-nitropyridin-2-amine (1 eq) in CH3CN, and the reaction mixture was stirred at 70° C. for 5 hours. The solvent was evaporated under reduced pressure, and the residue was triturated with ether to afford the desired compound as a bright yellow powder. LC/MS m/z 225.0 (MH+), Rt 1.79 minutes.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[OH:9].[Si:10](Cl)([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11].N1C=CN=C1.O>CN(C)C=O>[C:13]([Si:10]([O:9][C:3]1[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=1[F:1])([CH3:12])[CH3:11])([CH3:16])([CH3:15])[CH3:14]
Reactant: Oc1ccc(F)cc1F
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)Oc1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 2,4-difluoro-phenol (35, 5.00 g, 38.4 mmol) in N,N-dimethylformamide (100 mL) were added tert-butyldimethylsilyl chloride (7.00 g, 46.4 mmol) and imidazole (6.28 g, 92.2 mmol). The reaction was stirred at room temperature overnight. The reaction was poured into water and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and filtrated. The filtrate was concentrated and purified by silica gel column chromatography eluting with 10% ethyl acetate in hexane. The appropriate fractions were combined and concentrated to provide the compound (36, 7.50 g, 80.0%). MS (ESI) [M+H+]+=245.1.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][NH:8][C:7](=[O:11])[CH2:6]1.C(N(CC)CC)C.O1CCOCC1.Cl[C:26]1[CH:31]=[CH:30][C:29]([S:32]([NH2:35])(=[O:34])=[O:33])=[CH:28][C:27]=1[N+:36]([O-:38])=[O:37]>CN(C)C(=O)C>[N+:36]([C:27]1[CH:28]=[C:29]([S:32]([NH2:35])(=[O:33])=[O:34])[CH:30]=[CH:31][C:26]=1[NH:1][CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][NH:8][C:7](=[O:11])[CH2:6]1)([O-:38])=[O:37]
Reactant: NCCCN1CCNC(=O)C1
Reactant: NS(=O)(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Solvent: CC(=O)N(C)C
Product: NS(=O)(=O)c1ccc(NCCCN2CCNC(=O)C2)c([N+](=O)[O-])c1
Temperature: 90 °C

Procedure:
4-(3-Amino-propyl)-piperazin-2-one (3.45 g) and triethylamine (5.18 mL, 3.76 g) were added to 1,4-dioxane (100 mL) and N,N-dimethylacetamide (20 mL) and mixed until dissolved. 4-Chloro-3-nitrobenzenesulfonamide (4.00 g) was added, and the mixture was heated to 90° C. for 16 hours. The mixture was cooled and the solvent was removed under vacuum. The material purified by recrystallization from 20% methanol in dichloromethane with subsequent washing of the recrystallized solid with 10% methanol in dichloromethane followed by washing with 100% dichloromethane.
Reaction SMILES: [NH2:1][C:2]1[O:6][N:5]=[C:4]([CH3:7])[C:3]=1[Br:8].[Br:9][C:10]1[CH:15]=[CH:14][C:13]([S:16](Cl)(=[O:18])=[O:17])=[CH:12][CH:11]=1>>[Br:9][C:10]1[CH:15]=[CH:14][C:13]([S:16]([NH:1][C:2]2[O:6][N:5]=[C:4]([CH3:7])[C:3]=2[Br:8])(=[O:18])=[O:17])=[CH:12][CH:11]=1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Reactant: Cc1noc(N)c1Br
Product: Cc1noc(NS(=O)(=O)c2ccc(Br)cc2)c1Br
Yield: 74 %

Procedure:
4-Bromo-N-(4-bromo-3-methy l-5-isoxazolyl)benzenesulfonamide was prepared in the same manner as described in Example 30 from 5-amino-4-bromo-3-methylisoxazole and 4-bromobenzenesulfonyl chloride in 74% yield. Purification was achieved by recrystallization from ethyl acetate/hexanes to give a crystalline solid, m.p. 146-149° C.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[C:5]([CH2:14][C:15]2[O:16][CH:17]=[CH:18][CH:19]=2)=[N:4][N:3]=1.[NH:20]1[CH2:24][CH2:23][CH2:22][CH2:21]1>CN(C=O)C.C(OCC)(=O)C>[O:16]1[CH:17]=[CH:18][CH:19]=[C:15]1[CH2:14][C:5]1[C:6]2[C:11](=[CH:10][C:9]([O:12][CH3:13])=[CH:8][CH:7]=2)[C:2]([N:20]2[CH2:24][CH2:23][CH2:22][CH2:21]2)=[N:3][N:4]=1
Reactant: C1CCNC1
Reactant: COc1ccc2c(Cc3ccco3)nnc(Cl)c2c1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1ccc2c(Cc3ccco3)nnc(N3CCCC3)c2c1
Temperature: 60 °C
Yield: 74.6 %

Procedure:
A solution of 4-chloro-1-furan-2-ylmethyl-6-methoxy-phthalazine (500 mg, 1.82 mmoles), prepared as described in example 127, in DMF (10 ml) was added under stirring with pyrrolidine (0.91 ml, 10.92 mmoles), and heated at 60° C. overnight. The mixture was diluted with ethyl acetate, washed three times with water, anhydrified over Na2SO4 and dried. The residue was crystallised from ethyl ether/petrolatum 1:1 (10 ml) to give 420 mg of the title compound (yield: 75%). m.p.: 148-149° C.
Reaction SMILES: [F:1][C:2]1[C:3](=[O:9])[NH:4][C:5](=[O:8])[NH:6][CH:7]=1.NCC(O)=O.[O:15]1[CH:19]=[CH:18][CH2:17][CH2:16]1>CN(C)C=O>[O:15]1[CH2:19][CH2:18][CH2:17][CH:16]1[N:6]1[CH:7]=[C:2]([F:1])[C:3](=[O:9])[NH:4][C:5]1=[O:8]
Reactant: C1=COCC1
Reactant: O=c1[nH]cc(F)c(=O)[nH]1
Agent: NCC(=O)O
Solvent: CN(C)C=O
Product: O=c1[nH]c(=O)n(C2CCCO2)cc1F
Temperature: 145 °C

Procedure:
In 20 ml of dimethylformamide were dissolved 1.3 g of 5-fluorouracil and 0.75 g of glycin. 2.8 Grams of 2,3-dihydrofuran in several portions were added in 8 hours to the solution while heating it at 145° C. The mixture was then reacted for 5 hours at the same temperature. After completion of the reaction, the reaction liquid was treated in the same manner as described in Example 16. 0.9 g of 1-(2-tetrahydrofuryl)-5-fluorouracil was obtained and 1.0 g of 5-fluorouracil containing 0.75 g of glycin was recovered. The yield of the end product was 56% based on the consumed 5-fluorouracil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[C:17]3[C:12](=[CH:13][C:14]([O:18][CH2:19][CH2:20][CH2:21][N:22]4[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]4)=[CH:15][CH:16]=3)[C:11](=[O:28])[C:10]=2[C:29]2[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=2)[CH:5]=[C:6]([F:8])[CH:7]=1.N1C=CC=CC=1.[C:41](OC(=O)C)(=[O:43])[CH3:42]>C(Cl)Cl>[C:41]([N:25]1[CH2:26][CH2:27][N:22]([CH2:21][CH2:20][CH2:19][O:18][C:14]2[CH:13]=[C:12]3[C:17]([C:9]([C:4]4[CH:5]=[C:6]([F:8])[CH:7]=[C:2]([F:1])[CH:3]=4)=[C:10]([C:29]4[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=4)[C:11]3=[O:28])=[CH:16][CH:15]=2)[CH2:23][CH2:24]1)(=[O:43])[CH3:42]
Reactant: CC(=O)OC(C)=O
Reactant: O=C1C(c2cccnc2)=C(c2cc(F)cc(F)c2)c2ccc(OCCCN3CCNCC3)cc21
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)N1CCN(CCCOc2ccc3c(c2)C(=O)C(c2cccnc2)=C3c2cc(F)cc(F)c2)CC1
Temperature: 0 °C
Reaction time: 15 h
Yield: 59 %

Procedure:
To a 10 mL round-bottomed flask, 6-(3-(piperazin-1-yl)propoxy)-3-(3,5-difluorophenyl)-2-(pyridin-3-yl)-1H-inden-1-one (40 mg, 0.09 mmol) obtained in Step 1 of Example 66 and CH2Cl2 (2 mL, 0.05M) were charged. Pyridine (0.01 mL, 1.2 eq) was added and then the mixture was cooled to 0° C. and treated with acetic anhydride (0.01 mL, 1.2 eq). After being stirred for 15 h, the mixture was diluted with CH2Cl2 and washed with H2O and brine. The organic layer was dried over MgSO4 and concentrated in vacuo. The residue was purified by being purified by silica gel column chromatography (CH2Cl2/MeOH=9:1) and being purified by prep. HPLC (20% H2O/CH3CN) to provide the title compound (25.9 mg, 59%).
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:4]=[C:5]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[O:6][C:7]=1[CH:8]=[O:9].C(O)C.[BH4-].[Na+].O.[O:22]1[CH2:26]CC[CH2:23]1>>[CH3:23][O:22][CH2:26][O:1][CH2:2][C:3]1[N:4]=[C:5]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[O:6][C:7]=1[CH2:8][OH:9]
Reactant: C1CCOC1
Reactant: O=Cc1oc(-c2ccccc2)nc1CO
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: COCOCc1nc(-c2ccccc2)oc1CO
Temperature: 25 °C
Reaction time: 1 h
Yield: 76 %

Procedure:
To a solution of 4-hydroxymethyl-2-phenyloxazole-5-carbaldehyde (0.25 g) in tetrahydrofuran (5 mL)-ethanol (3 mL) was gradually added sodium borohydride (0.04 g) at 0° C. After stirring at room temperature for 1 hr, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated to give (4-methoxymethoxymethyl-2-phenyl-1,3-oxazol-5-yl)methanol as colorless crystals (0.19 g, yield 76%). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 70-71° C.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[C:8]3[C:38](=[CH:39][CH:40]=2)[C:16]2[N:17]([CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:36])[CH3:35])[C:18]([C:20]4[C:27]([C:28]#[N:29])=[CH:26][CH:25]=[CH:24][C:21]=4[C:22]#[N:23])=[N:19][C:15]=2[C:14]2[CH:13]=[CH:12][C:11]([CH2:41][C:42](=[O:44])[CH3:43])=[CH:10][C:9]3=2)[CH2:3][CH2:2]1.Cl[C:46]1C=C2C(=CC=1)C1N(COCC[Si](C)(C)C)C(C3C(C#N)=CC=CC=3C#N)=NC=1C1C=CC(CC(=O)C)=CC2=1>>[CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[C:8]3[C:38](=[CH:39][CH:40]=2)[C:16]2[N:17]([CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:35])([CH3:37])[CH3:36])[C:18]([C:20]4[C:27]([C:28]#[N:29])=[CH:26][CH:25]=[CH:24][C:21]=4[C:22]#[N:23])=[N:19][C:15]=2[C:14]2[CH:13]=[CH:12][C:11]([CH2:41][C:42]([OH:44])([CH3:46])[CH3:43])=[CH:10][C:9]3=2)[CH2:3][CH2:2]1
Reactant: CC(=O)Cc1ccc2c(c1)c1cc(Cl)ccc1c1c2nc(-c2c(C#N)cccc2C#N)n1COCC[Si](C)(C)C
Reactant: CC(=O)Cc1ccc2c(c1)c1cc(OCC3CC3)ccc1c1c2nc(-c2c(C#N)cccc2C#N)n1COCC[Si](C)(C)C
Product: CC(C)(O)Cc1ccc2c(c1)c1cc(OCC3CC3)ccc1c1c2nc(-c2c(C#N)cccc2C#N)n1COCC[Si](C)(C)C

Procedure:
This imidazole was prepared as described in Step 3, Example 135, substituting 2-(9-(cyclopropylmethoxy)-6-(2-oxopropyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-phenanthro[9,10-d]imidazol-2-yl)isophthalonitrile from Step 5 above for of 2-(9-chloro-6-(2-oxopropyl)-1-{[2-(trimethylsilyl)ethoxy]methyl)-1H-phenanthro[9,10-d]imidazol-2-yl)isophthalonitrile.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([C:8](=O)[CH3:9])[CH:7]=1.[O:12]1[CH2:17][CH2:16][N:15]([S:18]([C:21]2[CH:22]=[N:23][CH:24]=[C:25]([CH:30]=2)[C:26]([NH:28][NH2:29])=[O:27])(=[O:20])=[O:19])[CH2:14][CH2:13]1>CO.C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6](/[C:8](=[N:29]/[NH:28][C:26](=[O:27])[C:25]2[CH:30]=[C:21]([S:18]([N:15]3[CH2:14][CH2:13][O:12][CH2:17][CH2:16]3)(=[O:20])=[O:19])[CH:22]=[N:23][CH:24]=2)/[CH3:9])[CH:7]=1
Reactant: NNC(=O)c1cncc(S(=O)(=O)N2CCOCC2)c1
Reactant: CC(=O)c1cc(Cl)ccc1O
Solvent: CC(=O)O
Solvent: CO
Product: C/C(=N\NC(=O)c1cncc(S(=O)(=O)N2CCOCC2)c1)c1cc(Cl)ccc1O
Temperature: 70 °C
Yield: 65.7 %

Procedure:
1-(5-chloro-2-hydroxyphenyl)ethanone (6.55 mg, 0.038 mmol) and 5-(morpholinosulfonyl)nicotinohydrazide (10 mg, 0.035 mmol) was dissolved in Methanol (3 ml) in the presence of acetic acid as a catalyst and then the reaction mixture was refluxed for 12 h at 70° C. Reaction was monitored by TLC. After completion of the reaction, following cooling, the solvent was removed by vacuum and the resulting crude material was purified by flash column chromatography (2% CH3OH/CH2Cl2) afforded the title compound (E)-N′-(1-(5-chloro-2-hydroxyphenyl)ethylidene)-5-(morpholinosulfonyl)nicotinohydrazide (10 mg, 0.023 mmol, 65.2% yield) as a solid. 1HNMR (400 MHz, DMSO-d6): δ 11.82 (bs, 1H), 9.35 (s, 1H), 9.08 (s, 1H), 8.52 (s, 1H), 7.66 (s, 1H), 7.34 (d, 1H, J=8.4 Hz), 6.94 (d, 1H, J=8.8 Hz), 3.63 (m, 4H), 2.99 (m, 4H), 2.50 (s, 3H). ESI-MS: 439.1 [M+H]+
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:36]=[CH:35][CH:34]=[CH:33][C:9]=1[CH2:10][CH2:11][N:12]([CH2:22][C:23]1[CH:32]=[CH:31][C:26]([C:27]([O:29][CH3:30])=[O:28])=[CH:25][CH:24]=1)[CH2:13][CH2:14][CH2:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18].[C:37]1([N:43]2[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]2)[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.C(N(CC)CC)C>O1CCCC1>[CH2:20]([O:19][C:17](=[O:18])[CH2:16][CH2:15][CH2:14][CH2:13][N:12]([CH2:22][C:23]1[CH:32]=[CH:31][C:26]([C:27]([O:29][CH3:30])=[O:28])=[CH:25][CH:24]=1)[CH2:11][CH2:10][C:9]1[CH:33]=[CH:34][CH:35]=[CH:36][C:8]=1[O:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][N:46]1[CH2:47][CH2:48][N:43]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH2:44][CH2:45]1)[CH3:21]
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: CCOC(=O)CCCCN(CCc1ccccc1OCCCCCBr)Cc1ccc(C(=O)OC)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)CCCCN(CCc1ccccc1OCCCCCN1CCN(c2ccccc2)CC1)Cc1ccc(C(=O)OC)cc1

Procedure:
200.0 mg (0.355 mmol) of methyl 4-{[{2-[(5-bromopentyl)oxy]phenethyl}(5-ethoxy-5-oxopentyl)amino]methyl}benzoate from Ex. 107, 69.21 mg of N-phenylpiperazine and 71.95 mg (0.711 mmol) of triethylamine in 2 ml of tetrahydrofuran are heated at reflux for 18 hours. The reaction solution is washed with water, concentrated and chromatographed over silica gel using the mobile phase ethyl acetate/methanol 10/1.
Reaction SMILES: [CH3:1][N:2]1[C:9](=O)[CH2:8][C:6](=[O:7])[N:5]([CH3:11])[C:3]1=[O:4].P(Cl)(Cl)([Cl:14])=O>O>[Cl:14][C:9]1[N:2]([CH3:1])[C:3](=[O:4])[N:5]([CH3:11])[C:6](=[O:7])[CH:8]=1
Reactant: CN1C(=O)CC(=O)N(C)C1=O
Reactant: O=P(Cl)(Cl)Cl
Solvent: O
Product: Cn1c(Cl)cc(=O)n(C)c1=O
Temperature: 25 °C

Procedure:
To a stirred solution of 1,3-dimethylbarbituric acid (20.0 g, 128.09 mmol) in water (10 ml), phosphorous oxychloride (80 ml) was added slowly in externally cooling condition and then the reaction was slowly warmed to room temperature. After refluxing for 3 h the reaction mixture was allowed to cool to 0° C. and quenched with ice cold water (350 ml). The reaction mixture was extracted with chloroform (2×200 ml) and the combined organic extracts were washed with water (2×100 ml), dried over Na2SO4 and concentrated. The residue obtained was purified by silica gel column chromatography using 5% ethyl acetate in chloroform to obtain 21 g of the product as a pale brown solid; 1H NMR (300 MHz, CDCl3) δ 3.33 (s, 3H), 3.57 (s, 3H), 5.94 (s, 1H).
Reaction SMILES: [S:1]1[C:5]([NH:6][S:7]([C:10]2[C:40]([Cl:41])=[CH:39][C:13]3[N:14]([C@@H:18]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[C:26]4[CH2:31][CH2:30][N:29](C(OC(C)(C)C)=O)[CH2:28][CH:27]=4)[CH3:19])[C:15](=[O:17])[O:16][C:12]=3[CH:11]=2)(=[O:9])=[O:8])=[N:4][CH:3]=[N:2]1.C(Cl)Cl.Cl.CCOC(C)=O>CO>[ClH:41].[Cl:41][C:40]1[C:10]([S:7]([NH:6][C:5]2[S:1][N:2]=[CH:3][N:4]=2)(=[O:9])=[O:8])=[CH:11][C:12]2[O:16][C:15](=[O:17])[N:14]([C@@H:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[C:26]3[CH2:31][CH2:30][NH:29][CH2:28][CH:27]=3)[CH3:19])[C:13]=2[CH:39]=1
Reactant: C[C@H](c1ccccc1C1=CCN(C(=O)OC(C)(C)C)CC1)n1c(=O)oc2cc(S(=O)(=O)Nc3ncns3)c(Cl)cc21
Agent: Cl
Solvent: CO
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: C[C@H](c1ccccc1C1=CCNCC1)n1c(=O)oc2cc(S(=O)(=O)Nc3ncns3)c(Cl)cc21
Temperature: 25 °C

Procedure:
To a flask containing (R)-tert-butyl 4-(2-(1-(6-(N-(1,2,4-thiadiazol-5-yl)sulfamoyl)-5-chloro-2-oxobenzo[d]oxazol-3(2H)-yl)ethyl)phenyl)-5,6-dihydropyridine-1(2H)-carboxylate (34-5) (16 mg, 0.026 mmol) (prepared by a sequence analogous to the synthesis of 16-4, vide supra) was added DCM (2 ml) & MeOH (2), then added saturated HCl in EtOAc (˜4N) (64.7 μl, 0.26 mmol). The reaction mixture was capped (not under N2) & stirred at room temperature. Followed by LC/MS. After 3 hours the reaction mixture was concentrated to yield (R)-5-chloro-2-oxo-3-(1-(2-(1,2,3,6-tetrahydropyridin-4-yl)phenyl)ethyl)-N-(1,2,4-thiadiazol-5-yl)-2,3-dihydrobenzo[d]oxazole-6-sulfonamide hydrochloride (34-6). HRMS [M+H] calculated; 518.0718, observed; 518.0706. 1H NMR (499 MHz, DMSO): δ 9.15 (d, J=33.1 Hz, 2H); 8.51 (s, 1H); 7.95 (s, 1H); 7.79 (d, J=7.7 Hz, 1H); 7.63-7.46 (m, 2H); 7.46-7.36 (m, 2H); 7.23 (s, 1H); 7.09 (d, J=7.3 Hz, 1H); 5.74-5.68 (m, 1H); 5.42 (br s, 1H); 3.65-3.54 (m, 1H); 3.35-3.23 (m, 1H); 3.18-3.09 (m, 2H); 2.67-2.55 (m 1H); 2.18-2.08 (m, 1H); 1.83 (d, J=7.1 Hz, 3H). Note: NMR peaks overlapping with solvent or water could not be accurately accounted for.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:22]([CH2:29][CH3:30])[CH:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[C:5]([CH3:21])=[C:6]([CH:20]=1)[C:7]([NH:9][CH2:10][C:11]1[C:12](=[O:19])[NH:13][C:14]([CH3:18])=[CH:15][C:16]=1[CH3:17])=[O:8].[F:31][C:32]1[CH:33]=[C:34](B(O)O)[CH:35]=[CH:36][C:37]=1[CH:38]=[O:39].C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.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>[CH3:17][C:16]1[CH:15]=[C:14]([CH3:18])[NH:13][C:12](=[O:19])[C:11]=1[CH2:10][NH:9][C:7]([C:6]1[CH:20]=[C:2]([C:34]2[CH:35]=[CH:36][C:37]([CH:38]=[O:39])=[C:32]([F:31])[CH:33]=2)[CH:3]=[C:4]([N:22]([CH2:29][CH3:30])[CH:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[C:5]=1[CH3:21])=[O:8]
Reactant: O=Cc1ccc(B(O)O)cc1F
Reactant: CCN(c1cc(Br)cc(C(=O)NCc2c(C)cc(C)[nH]c2=O)c1C)C1CCOCC1
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: C1COCCO1
Solvent: O
Product: CCN(c1cc(-c2ccc(C=O)c(F)c2)cc(C(=O)NCc2c(C)cc(C)[nH]c2=O)c1C)C1CCOCC1
Temperature: 100 °C
Yield: 88 %

Procedure:
To a stirred solution of 5-bromo-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-3-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-2-methylbenzamide (300 mg, 0.63 mmol) and (3-fluoro-4-formylphenyl)boronic acid (160 mg, 0.94 mmol) in dioxane (6 mL), aqueous 2M Na2CO3 solution (1.15 mL, 2.3 mmol) was added and solution was purged with argon for 15 min. Then Pd(PPh3)4 (72 mg, 0.06 mmol) was added and argon was purged again for 15 min. Reaction mass was heated at 100° C. for 4 h. On completion, reaction mixture was diluted with water and extracted with 10% MeOH/DCM (3 times). Combined organic layer was dried over sodium sulphate. Removal of the solvent under reduced pressure followed by column chromatographic purification afforded the title compound (288 mg, 88%).
Reaction SMILES: [F:1][C:2]1[C:7]([S:8]([CH3:11])(=[O:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[C:12]1[CH2:13][CH2:14][N:15]([C:18]([O:20][CH3:21])=[O:19])[CH2:16][CH:17]=1.Cl>[Pd]>[F:1][C:2]1[C:7]([S:8]([CH3:11])(=[O:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:12]1[CH2:13][CH2:14][N:15]([C:18]([O:20][CH3:21])=[O:19])[CH2:16][CH2:17]1
Reactant: COC(=O)N1CC=C(c2cccc(S(C)(=O)=O)c2F)CC1
Agent: [Pd]
Agent: Cl
Product: COC(=O)N1CCC(c2cccc(S(C)(=O)=O)c2F)CC1

Procedure:
Preparation according to preparation 18: Methyl 4-[2-fluoro-3-(methylsulfonyl)-phenyl]-3,6-dihydropyridine-1(2H)-carboxylate (1.45 g, 4.6 mmol), palladium on carbon (0.2 g) and hydrochloric acid (0.5 ml, cone). Yield: 0.76 g. MS m/z (relative intensity, 70 eV) 315 (M+, 41), 256 (bp), 236 (54), 141 (43) 114 (50).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][C:13]([F:16])([F:15])[F:14])[C:7](=[O:17])[NH:6][C:5]2=O.C(N(CC)CC)C.C(OC([N:31]1[CH:36]2[CH2:37][CH2:38][CH:32]1[CH2:33][CH:34]([NH2:39])[CH2:35]2)=O)C>P(Cl)(Cl)(Cl)=O.CN(C=O)C>[CH:32]12[NH:31][CH:36]([CH2:37][CH2:38]1)[CH2:35][CH:34]([NH:39][C:5]1[C:4]3[C:9](=[CH:10][CH:11]=[C:2]([Cl:1])[CH:3]=3)[N:8]([CH2:12][C:13]([F:16])([F:15])[F:14])[C:7](=[O:17])[N:6]=1)[CH2:33]2
Reactant: CCOC(=O)N1C2CCC1CC(N)C2
Reactant: O=c1[nH]c(=O)n(CC(F)(F)F)c2ccc(Cl)cc12
Solvent: O=P(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=c1nc(NC2CC3CCC(C2)N3)c2cc(Cl)ccc2n1CC(F)(F)F
Temperature: 100 °C
Reaction time: 4 h

Procedure:
To a solution of 6-chloro-1-(2,2,2-trifluoro-ethyl)-1H-quinazoline-2,4-dione (1.10 g, 3.97 mmol) in phosphorous oxychloride (15 mL) was added 1 mL triethylamine. The reaction was heated to 100° C., stirred for 4 hrs and concentrated. The crude residue was dissolved in chloroform, washed with 1 N aq sodium hydroxide, dried over Na2SO4, filtered, and concentrated. To a solution of the crude residue in DMF (50 mL), was added triethylamine (1 mL) and 3-amino-8-aza-bicyclo[3.2.1]octane-8-carboxylic acid ethyl ester (1.0 g, 5.50 mmol). The solution was heated to 50° C. and stirred for 12 hrs. The reaction was partitioned between ethyl acetate and water and the organic phase was washed an additional 2× with water and brine, dried over Na2SO4, filtered, and concentrated. The resultant yellow foam was treated with HBr solution (6 mL, 30 weight % in AcOH) in a pressure vessel at 100° C. After 4 hrs the solution was cooled and concentrated (1.1 g). 1H NMR (300 MHz, CD3OD) δ ppm 2.20 (m, 8H), 4.16 (m, 2H), 4.65 (m, 1H), 5.04 (q, J=8.6 Hz, 2H), 7.62 (d, J=9.0 Hz, 1H), 7.83 (dd, J=2.2, 9.0 Hz, 1H), 8.47 (d, J=2.2 Hz, 1H); MS (ESI+Q1MS) m/z 388 [M+2H]+