Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3[CH:15]=[N:16][C:17]([C:20]#[N:21])=[C:18](O)[C:13]=3[C:12]3[CH:22]=[C:23]([Cl:26])[CH:24]=[N:25][C:11]2=3)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.P(Cl)(Cl)(Cl)(Cl)[Cl:28]>P(Cl)(Cl)(Cl)=O.ClCCl>[C:1]1([S:7]([N:10]2[C:14]3[CH:15]=[N:16][C:17]([C:20]#[N:21])=[C:18]([Cl:28])[C:13]=3[C:12]3[CH:22]=[C:23]([Cl:26])[CH:24]=[N:25][C:11]2=3)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: N#Cc1ncc2c(c1O)c1cc(Cl)cnc1n2S(=O)(=O)c1ccccc1
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClCCl
Product: N#Cc1ncc2c(c1Cl)c1cc(Cl)cnc1n2S(=O)(=O)c1ccccc1
Temperature: 25 °C
Yield: 58.7 %

Procedure:
A solution of 9-benzenesulfonyl-3-chloro-5-hydroxy-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile (1.9 g, 4.94 mmol) and phosphorus pentachloride (3.1 g, 14.8 mmol) in phosphorus oxychloride (8 mL) was heated at 105° C. for 2 hours. The reaction mixture was cooled to ambient temperature and then the solvent removed in-vacuo to afford a residue. The resultant residue was dissolved in dichloromethane (300 mL) and then the solution was diluted with ice/water (300 mL). The layers were separated and the aqueous layer further extracted with dichloromethane. The combined organic layer was washed with brine, dried (Na2SO4), filtered and evaporated. The resultant residue was triturated with diethyl ether and dried to afford the title compound as a tan solid (1.17 g, 59%). 1H NMR (400 MHz, CDCl3): 9.81 (s, 1H), 8.77 (d, J=2.4 Hz, 1H), 8.75 (d, J=2.4 Hz, 1H), 8.26-8.22 (m, 2H), 7.66-7.66 (m, 1H), 7.53-7.53 (m, 2H).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH:15]([F:17])[F:16])=[CH:10][CH:9]=2)=[CH:4][N:3]=1.[NH2:18][C:19]1[CH:20]=[C:21]([CH2:25][OH:26])[CH:22]=[CH:23][CH:24]=1.CC1C=CC(S(O)(=O)=O)=CC=1>O1CCOCC1.C([O-])([O-])=O.[Na+].[Na+]>[F:16][CH:15]([F:17])[O:14][C:11]1[CH:12]=[CH:13][C:8]([C:5]2[CH:4]=[N:3][C:2]([NH:18][C:19]3[CH:20]=[C:21]([CH2:25][OH:26])[CH:22]=[CH:23][CH:24]=3)=[N:7][CH:6]=2)=[CH:9][CH:10]=1
Reactant: Nc1cccc(CO)c1
Reactant: FC(F)Oc1ccc(-c2cnc(Cl)nc2)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: OCc1cccc(Nc2ncc(-c3ccc(OC(F)F)cc3)cn2)c1
Temperature: 105 °C

Procedure:
To a mixture of 2-chloro-5-(4-(difluoromethoxy)phenyl)pyrimidine 30 (0.40 mmol) and (3-aminophenyl)methanol (0.40 mmol) in 1,4-dioxane (0.5 mL) is added p-TSA (0.4 mmol). The reaction mixture is heated at 105° C. for 2 days. After this time, the reaction mixture is diluted with a solution of 2M Na2CO3 (30 mL) and extracted with DCM (3×30 mL). The organic layer is washed with brine, dried over Na2SO4 and concentrated. Purification by short silica gel chromatography using a hexane:EtOAc=1:2 affords (3-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)phenyl)methanol 36. 1H NMR (400 MHz, d4-MeOH) δ 8.56 (s, 2H), 7.65 (m, 1H), 7.48-7.52 (m, 1H), 7.42-7.46 (m, 2H), 7.29 (t, J=8 Hz, 1H), 7.15-7.18 (m, 3H), 6.99-7.03 (m, 1H), 6.49 (t, J=73.6 Hz, 1H), 4.67 (s, 2H). MS (m/z) (M+1)+ 344.1.
Reaction SMILES: [CH:1]1[C:11]2[CH:10]=[CH:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[C:6](=[C:16]3[CH2:21][CH2:20][N:19]([C:22](=[O:28])[CH2:23][CH2:24][C:25](O)=[O:26])[CH2:18][CH2:17]3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[C:29]([NH2:33])([CH3:32])([CH3:31])[CH3:30].Cl.C(N=C=NCCCN(C)C)C.C(N(CC)CC)C>CN(C)C1C=CN=CC=1.ClCCl>[C:29]([NH:33][C:25](=[O:26])[CH2:24][CH2:23][C:22]([N:19]1[CH2:18][CH2:17][C:16](=[C:6]2[C:7]3[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=3[CH:9]=[CH:10][C:11]3[CH:1]=[CH:2][CH:3]=[CH:4][C:5]2=3)[CH2:21][CH2:20]1)=[O:28])([CH3:32])([CH3:31])[CH3:30]
Reactant: CC(C)(C)N
Reactant: O=C(O)CCC(=O)N1CCC(=C2c3ccccc3C=Cc3ccccc32)CC1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)NC(=O)CCC(=O)N1CCC(=C2c3ccccc3C=Cc3ccccc32)CC1
Reaction time: 8 h

Procedure:
100 mg (0.268 mmol) of 4-[4-(5H-dibenzo[a,d][7]annulen-5-ylidene)-1-piperidinyl]-4-oxobutanoic acid, 23.5 mg (0.321 mmol) of t-butylamine, 3 mg (0.03 mmol) of 4-dimethylaminopyridine and 77.1 mg (0.402 mmol) of 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride were dissolved in 1 ml of dichloromethane. 35.2 mg (0.348 mmol) of triethylamine was added to the obtained solution, and they were stirred overnight. The obtained product was purified by the silica gel chromatography (hexane:ethyl acetate=2:1 to 4:6) to obtain the title compound.
Reaction SMILES: [OH:1][CH2:2][C:3]1([CH2:7][O:8][C:9]2[C:14]([O:15][CH3:16])=[C:13]([O:17][CH3:18])[CH:12]=[CH:11][C:10]=2[C:19]2[CH:27]=[CH:26][CH:25]=[C:24]3[C:20]=2[CH2:21][CH2:22][C:23]3=[O:28])[CH2:6][O:5][CH2:4]1.C(N(CC)CC)C.[CH2:36]([N:38]=[C:39]=[O:40])[CH3:37]>ClCCl>[CH3:16][O:15][C:14]1[C:13]([O:17][CH3:18])=[CH:12][CH:11]=[C:10]([C:19]2[CH:27]=[CH:26][CH:25]=[C:24]3[C:20]=2[CH2:21][CH2:22][C:23]3=[O:28])[C:9]=1[O:8][CH2:7][C:3]1([CH2:2][O:1][C:39](=[O:40])[NH:38][CH2:36][CH3:37])[CH2:4][O:5][CH2:6]1
Reactant: COc1ccc(-c2cccc3c2CCC3=O)c(OCC2(CO)COC2)c1OC
Reactant: CCN=C=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCNC(=O)OCC1(COc2c(-c3cccc4c3CCC4=O)ccc(OC)c2OC)COC1
Temperature: 50 °C

Procedure:
To a stirring solution of 4-[2-(3-Hydroxymethyl-oxetan-3-ylmethoxy)-3,4-dimethoxy-phenyl]-indan-1-one (Compound 104)(100 mg, 0.2604 mmol) in dichloromethane (15 mL), were added triethylamine (0.1 mL, 0.772 mmol) and ethyl isocyanate (55 mg, 0.78 mmol) and the resultant reaction mixture was heated to 50° C. for 16 h. The reaction mixture was quenched with sodium bi carbonate solution and extracted with dichloromethane (3×). The combined dichloromethane layer was washed with brine and dried over anhydrous sodium sulphate and concentrated under reduced pressure. Purification by column chromatography (silica gel, 0-25% ethyl acetate in pet ether) to afforded the title compound as a solid.
Reaction SMILES: [OH:1][C:2]1[C:11]([O:12][CH3:13])=[CH:10][C:9]([N+:14]([O-:16])=[O:15])=[C:8]2[C:3]=1[C:4]([CH3:17])=[CH:5][CH:6]=[N:7]2.Br[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C1OC1C.CCN(CC)CC>CN(P(N(C)C)(N(C)C)=O)C>[CH3:13][O:12][C:11]1[C:2]([O:1][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[C:3]2[C:8](=[C:9]([N+:14]([O-:16])=[O:15])[CH:10]=1)[N:7]=[CH:6][CH:5]=[C:4]2[CH3:17]
Reactant: COc1cc([N+](=O)[O-])c2nccc(C)c2c1O
Reactant: BrCCCCCCCc1ccccc1
Agent: CC1CO1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: CCN(CC)CC
Product: COc1cc([N+](=O)[O-])c2nccc(C)c2c1OCCCCCCCc1ccccc1
Reaction time: 1 h
Yield: 50 %

Procedure:
To a stirred mixture of 5-hydroxy-6-methoxy-4-methyl-8-nitroquinoline (18 g, 0.077 mol) and 1-bromo-7-phenyl heptane [Example 1a] (15 g, 0.059 mol) in HMPA (45 ml) at 130° C., was added, dropwise, during 1 h, a solution of propylene oxide (18 ml) and Et3N (1 ml). After six more hours, second portions of propylene oxide (4 ml) and Et3N (1 ml) were added and heating was continued for 4 h. The cooled mixture was extracted successively with pet ether, Et2O and Me2CO. The residue returned 2.5 g of starting material (i.e., 5-hydroxy-6-methoxy-4-methyl-8-nitroquinoline). The combined pet ether and Et2O extracts were washed (H2O, dil NaOH, H2O) dried (Na2SO4) and concentrated to a viscous oil. This material was dissolved in CHCl3, placed on a silica gel column (200 g) and eluted with CHCl3. Concentration of the eluates and crystallization of the residue from pet ether (Darco) gave 12 g, (50%) of 6-methoxy-4-methyl-8-nitro-5-(7-phenyl heptoxy) quinoline as yellow crystals, mp 53°-54° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15]([NH:17][C@H:18]4[CH2:23][CH2:22][CH2:21][C:20](=O)[CH2:19]4)[C:14]([F:25])=[CH:13][N:12]=3)=[CH:9][N:8]([S:26]([C:29]3[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][CH:30]=3)(=[O:28])=[O:27])[C:5]2=[N:6][CH:7]=1.Cl.[NH2:37][OH:38]>CCO>[Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15]([NH:17][C@H:18]4[CH2:23][CH2:22][CH2:21][C:20](=[N:37][OH:38])[CH2:19]4)[C:14]([F:25])=[CH:13][N:12]=3)=[CH:9][N:8]([S:26]([C:29]3[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][CH:30]=3)(=[O:28])=[O:27])[C:5]2=[N:6][CH:7]=1
Reactant: NO
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3ncc(F)c(N[C@H]4CCCC(=O)C4)n3)c3cc(Cl)cnc32)cc1
Agent: Cl
Solvent: CCO
Product: Cc1ccc(S(=O)(=O)n2cc(-c3ncc(F)c(N[C@H]4CCCC(=NO)C4)n3)c3cc(Cl)cnc32)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To solution of (3S)-3-[[2-[5-chloro-1-(p-tolylsulfonyl)pyrrolo[2,3-b]pyridin-3-yl]-5-fluoro-pyrimidin-4-yl]amino]cyclohexanone (0.41 g, 0.81 mmol) in EtOH (8.2 mL) was added hydroxylamine hydrochloride (0.11 g, 1.61 mmol). The reaction mixture was stirred at room temperature overnight. Then the mixture was warmed to 70° C. for 15 min. The reaction mixture was concentrated in vacuo, suspended in EtOAc-DCM, washed with half saturated brine (2×) and filtered through a SiO2 plug. The resulting residue was azeotroped with CH3CN (2×) to provide an off white powder which was used without further purification.
Reaction SMILES: [F:1][C:2]1[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[CH:11][C:3]=1[CH2:4][N:5]1[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1>CCOC(C)=O.[Pd]>[F:1][C:2]1[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][C:3]=1[CH2:4][N:5]1[CH2:6][CH2:7][O:8][CH2:9][CH2:10]1
Reactant: O=[N+]([O-])c1ccc(F)c(CN2CCOCC2)c1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Nc1ccc(F)c(CN2CCOCC2)c1
Yield: 55.2 %

Procedure:
A mixture of 4-(2-fluoro-5-nitrobenzyl)morpholine (414 mg, 1.723 mmol) in EtOAc (15 mL) was treated with 10% Pd/C (100 mg) and hydrogenated (1 atm) for 3 h. The solids were removed via filtration, rinsed with EtOAc and the filtrate concentrated to dryness to afford 4-fluoro-3-(morpholinomethyl)aniline (200 mg, 55% yield). MS (ESI) m/z: 211.1 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]2[CH2:15][CH2:14][C@@:13]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)([CH2:16][CH2:17][CH2:18][OH:19])[CH2:12][C:11]2=[O:27])[CH3:9])=[CH:4][CH:3]=1.CC(C)=[O:30].OS(O)(=O)=O.O=[Cr](=O)=O>CC(C)=O.CCOC(C)=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C@@H:8]([N:10]2[CH2:15][CH2:14][C@:13]([CH2:16][CH2:17][C:18]([OH:30])=[O:19])([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)[CH2:12][C:11]2=[O:27])[CH3:9])=[CH:6][CH:7]=1
Reactant: C[C@@H](c1ccc(Br)cc1)N1CC[C@](CCCO)(c2ccc(F)cc2)CC1=O
Reactant: CC(C)=O
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: CCOC(C)=O
Product: C[C@@H](c1ccc(Br)cc1)N1CC[C@](CCC(=O)O)(c2ccc(F)cc2)CC1=O
Reaction time: 0.5 h
Yield: 90 %

Procedure:
To a solution of (S)-1-((S)-1-(4-bromophenyl)ethyl)-4-(4-fluorophenyl)-4-(3-hydroxypropyl)piperidin-2-one (30 mg, 0.069 mmol) in acetone (2 mL) was added Jones reagent (0.3 mL, 2.5 M) at 0° C. The mixture was stirred for 0.5 h, diluted with EtOAc, and washed with water. The organic phase was concentrated to give the crude 3-((S)-1-((S)-1-(4-bromophenyl)ethyl)-4-(4-fluorophenyl)-2-oxopiperidin-4-yl)propanoic acid (28 mg, 90%), which was used for the next step without further purification.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].C(OS([C:15]1[CH:20]=[CH:19][C:18](C)=CC=1)(=O)=O)CCC.[CH:22]([N:25]1[C:30](=[O:31])[CH:29]=[C:28]([Cl:32])[NH:27][C:26]1=[O:33])([CH3:24])[CH3:23]>CN(C)C=O>[CH2:15]([N:27]1[C:28]([Cl:32])=[CH:29][C:30](=[O:31])[N:25]([CH:22]([CH3:24])[CH3:23])[C:26]1=[O:33])[CH2:20][CH2:19][CH3:18]
Reactant: CCCCOS(=O)(=O)c1ccc(C)cc1
Reactant: CC(C)n1c(=O)cc(Cl)[nH]c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCn1c(Cl)cc(=O)n(C(C)C)c1=O
Yield: 98.1 %

Procedure:
16.6 g (0.12 mole) of potassium carbonate and 24 g (0.105 mole) of butyl-p-toluene sulphonate are added to a solution of 19 g (0.10 mole) of 3-isopropyl-6-chlorouracil in 200 ml of dimethyl formamide. The mixture is heated for 1 hour to 80° C. After evaporation of the solvent, the residue is taken up in water, followed by extraction with CH2Cl2. The extract is dried over Na2SO4 and the solvent is evaporated, leaving 24 g of a pale yellow oily product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][N:12]([CH3:15])[C:11](=[O:16])[CH2:10]2)=[CH:5][C:4]=1[NH:17][C:18]([NH2:20])=[S:19].Br.CC(O)=O.CS(C)=O>CC(O)=O>[NH2:20][C:18]1[S:19][C:5]2[C:6]([N:9]3[CH2:14][CH2:13][N:12]([CH3:15])[C:11](=[O:16])[CH2:10]3)=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[C:4]=2[N:17]=1
Reactant: COc1ccc(N2CCN(C)C(=O)C2)cc1NC(N)=S
Agent: Br
Solvent: CC(=O)O
Solvent: CS(C)=O
Product: COc1ccc(N2CCN(C)C(=O)C2)c2sc(N)nc12

Procedure:
From [2-methoxy-5-(4-methyl-3-oxo-piperazin-1-yl)-phenyl]-thiourea with HBr—AcOH (4 equiv.) and DMSO (2.4 equiv.) in AcOH. ES-MS m/e (%): 293 (M+H+, 100).
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[NH:7][C:8]1[CH:13]=[CH:12][C:11](I)=[CH:10][C:9]=1[N+:15]([O-:17])=[O:16])([CH3:4])([CH3:3])[CH3:2].[F:19][C:20]1[CH:21]=[C:22](B(O)O)[CH:23]=[CH:24][CH:25]=1>>[C:1]([O:5][C:6](=[O:18])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:24]2[CH:23]=[CH:22][CH:21]=[C:20]([F:19])[CH:25]=2)=[CH:10][C:9]=1[N+:15]([O-:17])=[O:16])([CH3:4])([CH3:3])[CH3:2]
Reactant: OB(O)c1cccc(F)c1
Reactant: CC(C)(C)OC(=O)Nc1ccc(I)cc1[N+](=O)[O-]
Product: CC(C)(C)OC(=O)Nc1ccc(-c2cccc(F)c2)cc1[N+](=O)[O-]

Procedure:
Prepared from (4-iodo-2-nitro-phenyl)-carbamic acid tert.-butyl ester (Example A1) and 3-fluorobenzene boronic acid according to the general procedure B. Obtained as a yellow solid (3.87 g).
Reaction SMILES: [CH2:1]([C@@H:3]1[N:12]([C:13](=[O:22])[C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([F:23])[CH:10]=2)[NH:5][C:4]1=[O:24])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].C(=O)([O-])[O-].[K+].[K+].I[CH2:38][CH3:39]>CC(C)=O>[CH2:38]([N:5]1[C:6]2[C:11](=[CH:10][C:9]([F:23])=[CH:8][CH:7]=2)[N:12]([C:13](=[O:22])[C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[C@@H:3]([CH2:1][CH3:2])[C:4]1=[O:24])[CH3:39]
Reactant: CC[C@H]1C(=O)Nc2ccc(F)cc2N1C(=O)c1ccc(OC)cc1
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [K+]
Solvent: CC(C)=O
Product: CC[C@H]1C(=O)N(CC)c2ccc(F)cc2N1C(=O)c1ccc(OC)cc1
Temperature: 51 °C
Reaction time: 4 h
Yield: 70.1 %

Procedure:
To a stirred solution of (3S)-3-ethyl-6-fluoro-4-(4-methoxybenzoyl)-3,4-dihydroquinoxalin-2(1H)-one (0.25 g, 0.76 mmol) in acetone (6 mL) under nitrogen was added cesium carbonate (0.133 g, 0.41 mmol), potassium carbonate (0.057 g, 0.41 mmol) and iodoethane (0.20 mL, 0.39 g, 2.5 mmol). The reaction was stirred at 51° C. for 4 h. The solvent was evaporated, and the residue was partitioned between methylene chloride and water. The organic layer was separated and washed with water. The combined organic layers were dried over magnesium sulfate and concentrated in vacuo. The product was purified via Biotage Horizon® (SiO2, gradient from 4% EtOAc/hexane to 38% EtOAc/hexane) to yield 0.19 g (75%) of (3S)-1,3-diethyl-6-fluoro-4-(4-methoxybenzoyl)-3,4-dihydroquinoxalin-2(1H)-one. MS (ESI) m/z 357 ([M+H]+).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:18]([O:19][CH3:20])=[CH:17][C:6]2[CH2:7][C:8](=[O:16])[N:9]([CH2:12][CH2:13][CH2:14]Cl)[CH2:10][CH2:11][C:5]=2[CH:4]=1.[NH2:21][C:22]1[C:27]([Cl:28])=[CH:26][C:25]([NH:29][CH2:30][CH2:31][CH2:32][NH2:33])=[CH:24][C:23]=1[Cl:34]>>[CH3:1][O:2][C:3]1[C:18]([O:19][CH3:20])=[CH:17][C:6]2[CH2:7][C:8](=[O:16])[N:9]([CH2:12][CH2:13][CH2:14][NH:33][CH2:32][CH2:31][CH2:30][NH:29][C:25]3[CH:24]=[C:23]([Cl:34])[C:22]([NH2:21])=[C:27]([Cl:28])[CH:26]=3)[CH2:10][CH2:11][C:5]=2[CH:4]=1
Reactant: COc1cc2c(cc1OC)CC(=O)N(CCCCl)CC2
Reactant: NCCCNc1cc(Cl)c(N)c(Cl)c1
Product: COc1cc2c(cc1OC)CC(=O)N(CCCNCCCNc1cc(Cl)c(N)c(Cl)c1)CC2

Procedure:
The title compound is prepared from 3-(7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-on-3-yl)-1-chloropropane and 3-(4-amino-3,5-dichlorophenylamino)-propylamine analogously to Example 1. M.p.: 218°-220° C. (decomp.)
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][N:6]1[CH2:11][CH2:10][N:9]([S:12](=[O:35])(=[O:34])[NH:13][C:14]2[CH:19]=[C:18]([O:20][CH3:21])[N:17]=[C:16]([S:22]([CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[C:27]=3[F:33])(=[O:24])=[O:23])[N:15]=2)[CH2:8][CH2:7]1)C.[BH4-].[Li+]>C1COCC1>[F:33][C:27]1[C:28]([F:32])=[CH:29][CH:30]=[CH:31][C:26]=1[CH2:25][S:22]([C:16]1[N:15]=[C:14]([NH:13][S:12]([N:9]2[CH2:8][CH2:7][N:6]([CH2:5][CH2:4][OH:3])[CH2:11][CH2:10]2)(=[O:35])=[O:34])[CH:19]=[C:18]([O:20][CH3:21])[N:17]=1)(=[O:23])=[O:24]
Reactant: CCOC(=O)CN1CCN(S(=O)(=O)Nc2cc(OC)nc(S(=O)(=O)Cc3cccc(F)c3F)n2)CC1
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1cc(NS(=O)(=O)N2CCN(CCO)CC2)nc(S(=O)(=O)Cc2cccc(F)c2F)n1

Procedure:
The title compound was prepared according to the procedure outlined in example 24 using a mixture of {4-[2-(2,3-Difluoro-benzylsulfonyl)-6-methoxy-pyrimidin-4-ylsulfamoyl]-piperazin-1-yl}-acetic acid ethyl ester (the product from example 86 step i) (031 g) lithium borohydride (1M solution in THF) (1.2 mL) in THF (5 mL). Purification was by reverse phase HPLC (symmetry as the stationary phase and NH4OAc/acetonitrile as the mobile phase) then titurated with Toluene, MeOH followed by DCM to give the title compound as a white solid. Yield: 13 mg
Reaction SMILES: C[O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([S:10]([CH2:13][CH:14]2[CH2:16][CH2:15]2)(=[O:12])=[O:11])[CH2:7][N:6]1[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[O:4].[OH-].[Li+]>>[C:20]([O:19][C:17]([N:6]1[CH2:7][C@H:8]([S:10]([CH2:13][CH:14]2[CH2:15][CH2:16]2)(=[O:12])=[O:11])[CH2:9][C@H:5]1[C:3]([OH:4])=[O:2])=[O:18])([CH3:23])([CH3:21])[CH3:22]
Reactant: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)CC2CC2)CN1C(=O)OC(C)(C)C
Agent: [Li+]
Agent: [OH-]
Product: CC(C)(C)OC(=O)N1C[C@H](S(=O)(=O)CC2CC2)C[C@H]1C(=O)O

Procedure:
In analogy to the procedure described in example 253e, (2S,4R)-4-cyclopropylmethanesulfonyl-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester was saponified in the presence of lithium hydroxide to give the title compound as white solid. MS (ESI): m/z=333.6 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7](Cl)=[O:8])=[CH:5][CH:4]=1.C(N(CC)CC)C.[C:19]1([CH2:25][CH2:26][CH2:27][NH2:28])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(Cl)Cl>[C:19]1([CH2:25][CH2:26][CH2:27][NH:28][C:7](=[O:8])[C:6]2[CH:10]=[CH:11][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: NCCCc1ccccc1
Reactant: COc1ccc(C(=O)Cl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(C(=O)NCCCc2ccccc2)cc1
Temperature: 25 °C

Procedure:
To a solution of p-methoxybenzoyl chloride (37.8 g, 0.222 mol) in CH2Cl2 (200 ml) at 0°, is added triethylamine (22.5 g, 0.222 mol) followed by the slow addition of 3-phenylpropylamine (20 g, 0.148 mol) dissolved in CH2Cl2 (100 ml). The reaction is allowed to warm to room temperature over several hours. The solvent is removed in vacuo, and the residue is dissolved in EtOAc (500 ml) and 2N HCl (500 ml). The EtOAc is separated, washed with 2N HCl (350 ml), H2O (350 ml), saturated NaHCO3 solution (350 ml), and saturated NaCl solution (350 ml); dried over MgSO4 ; and evaporated. The resulting light brown solid is purified by chromatography (SiO2 ; 1:9 EtOAc/hexanes, 1:4 EtOAc/hexanes) yielding N-(3-phenylpropyl)-4-methoxybenzamide as creamy solid.
Reaction SMILES: [N+](=[CH2:3])=[N-].N(N(C)C(N)=O)=O.[OH-].[K+].[CH2:13]([C:16]1[C:21]([OH:22])=[CH:20][CH:19]=[C:18]([NH2:23])[C:17]=1[C:24]([C:26]1[CH:31]=[CH:30][C:29]([CH:32]([CH3:34])[CH3:33])=[CH:28][CH:27]=1)=[O:25])[CH:14]=[CH2:15]>C(OCC)C>[NH2:23][C:18]1[C:17]([C:24]([C:26]2[CH:27]=[CH:28][C:29]([CH:32]([CH3:34])[CH3:33])=[CH:30][CH:31]=2)=[O:25])=[C:16]([CH2:13][CH:14]2[CH2:3][CH2:15]2)[C:21]([OH:22])=[CH:20][CH:19]=1
Reactant: C=CCc1c(O)ccc(N)c1C(=O)c1ccc(C(C)C)cc1
Reactant: C=[N+]=[N-]
Agent: CN(N=O)C(N)=O
Agent: [K+]
Agent: [OH-]
Solvent: CCOCC
Product: CC(C)c1ccc(C(=O)c2c(N)ccc(O)c2CC2CC2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A diazomethane solution is freshly prepared by adding 515 mg (5 mmol) N-nitroso-N-methylurea in small portions to a stirred mixture of 50 ml diethyl ether and 17.5 ml 40% aqueous potassium hydroxide solution at 5° C. Ten minutes after the last addition, the organic layer is separated off and dried over solid potassium hydroxide. This diazomethane solution is added to a concentrated solution of 1.00 g (3.39 mmol) (2-allyl-6-amino-3-hydroxy-phenyl)-(4-isopropyl-phenyl)-methanone in diethyl ether containing 152 mg (0.68 mmol) Pd(OAc)2. After stirring for 16 h at r.t. the reaction mixture is filtered, evaporated to dryness and purified by flash column chromatography.
Reaction SMILES: [NH2:1][C:2](=[O:14])[CH2:3][S:4][C:5]1[CH:10]=[CH:9][C:8](B(O)O)=[CH:7][CH:6]=1.Br[C:16]1[N:21]=[CH:20][C:19]([O:22][CH2:23][CH:24]2[CH2:29][CH2:28][N:27]([C:30]([O:32][CH:33]([CH3:35])[CH3:34])=[O:31])[CH2:26][CH2:25]2)=[CH:18][CH:17]=1.C([O-])([O-])=O.[Na+].[Na+]>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.COCCOC>[NH2:1][C:2](=[O:14])[CH2:3][S:4][C:5]1[CH:10]=[CH:9][C:8]([C:16]2[N:21]=[CH:20][C:19]([O:22][CH2:23][CH:24]3[CH2:25][CH2:26][N:27]([C:30]([O:32][CH:33]([CH3:35])[CH3:34])=[O:31])[CH2:28][CH2:29]3)=[CH:18][CH:17]=2)=[CH:7][CH:6]=1
Reactant: CC(C)OC(=O)N1CCC(COc2ccc(Br)nc2)CC1
Reactant: NC(=O)CSc1ccc(B(O)O)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CC(C)OC(=O)N1CCC(COc2ccc(-c3ccc(SCC(N)=O)cc3)nc2)CC1
Yield: 74.6 %

Procedure:
1-Methylethyl 4-{[(6-{4-[(2-amino-2-oxoethyl)thio]phenyl}-3-pyridinyl)oxy]methyl}-1-piperidinecarboxylate (0.139 g, 75%) was prepared as a light yellow solid from {4-[(2-amino-2-oxoethyl)thio]phenyl}boronic acid (0.11 g, 0.50 mmol), 1-methylethyl 4-{[(6-bromo-3-pyridinyl)oxy]methyl}-1-piperidinecarboxylate (Example 81, Step 1, 0.15 g, 0.42 mmol), 2M Na2CO3 (2 mL), Pd(PPh3)2Cl2 (30 mg, 0.04 mmol) and DME (2 mL) in a manner similar to Example 21, Step 3. 1H NMR (400 MHz, CDCl3): δ 8.36 (d, 1H, J=2.5 Hz), 7.90 (d, 2H, J=8.2 Hz), 7.65 (d, 1H, J=8.8 Hz), 7.38 (d, 2H, J=8.2 Hz), 7.35-7.25 (m, 1H), 6.65 (bs, 1H), 5.41 (bs, 1H), 4.92 (septet, 1H, J=6.2 Hz), 4.23 (bs, 2H), 3.90 (d, 2H, J=6.3 Hz), 3.67 (s, 2H), 2.85-2.70 (m, 2H), 2.10-1.95 (m, 1H), 1.90-1.80 (m, 2H), 1.35-1.20 (m, 8H); LRMS (ESI), m/z 444 (M+H).
Reaction SMILES: [Br:1]Br.[CH3:3][C:4]1[O:5][CH:6]=[CH:7][C:8]=1[C:9]([O:11][CH3:12])=[O:10].S([O-])([O-])(=O)=S.[Na+].[Na+]>O1CCOCC1>[Br:1][C:6]1[O:5][C:4]([CH3:3])=[C:8]([C:9]([O:11][CH3:12])=[O:10])[CH:7]=1
Reactant: COC(=O)c1ccoc1C
Reactant: BrBr
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: C1COCCO1
Product: COC(=O)c1cc(Br)oc1C
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Bromine (2.0 ml) was added drop-wise to a mixture of methyl 2-methyl-3-furancarboxylate (5.0 g) in 1,4-dioxane (35 ml) stirred at 0° C. Stirring was continued at 0° C. for 2 hours and then at ambient temperature for 18 hours. Saturated aqueous sodium thiosulfate was added to the reaction mixture which was then extracted with ethyl acetate. The organic layer was dried with brine and over magnesium sulfate. The product isolated after evaporation of the solvent was further purified by flash column chromatography using cyclohexane:ethyl acetate (19:1) as eluent to give the title compound as a yellow oil.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([CH2:12][N:13]3[CH2:18][CH2:17][NH:16][CH:15]([CH2:19][O:20][CH2:21][CH3:22])[C:14]3=[O:23])=[CH:9][CH:10]=2)[N:5]=[CH:4][N:3]=1.[Cl:24][C:25]1[N:30]=[CH:29][C:28]([O:31][CH2:32][C:33](O)=[O:34])=[CH:27][CH:26]=1>>[NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([CH2:12][N:13]3[CH2:18][CH2:17][N:16]([C:33](=[O:34])[CH2:32][O:31][C:28]4[CH:29]=[N:30][C:25]([Cl:24])=[CH:26][CH:27]=4)[C@@H:15]([CH2:19][O:20][CH2:21][CH3:22])[C:14]3=[O:23])=[CH:9][CH:10]=2)[N:5]=[CH:4][N:3]=1
Reactant: CCOCC1NCCN(Cc2ccc3c(N)ncnc3c2)C1=O
Reactant: O=C(O)COc1ccc(Cl)nc1
Product: CCOC[C@H]1C(=O)N(Cc2ccc3c(N)ncnc3c2)CCN1C(=O)COc1ccc(Cl)nc1

Procedure:
The title compound is prepared as described in EXAMPLE 123, using 1-(4-aminoquinazoline-7-ylmethyl)-3-ethoxymethyl-piperazine-2-one, EXAMPLE 79 and, (6-chloro-pyridin-3-yloxy)-acetic acid, prepared similary to the procedure described in EXAMPLE 29. 1H NMR (d6-DMSO, 300 MHz) δ9.73 (bs, 2H), 8.81 (s, 1H), 8.37 (m, 1H), 8.10 (m, 1H), 7.61 (m, 2H), 7.40 (m, 2H), 4.98 (m, 2H), 4.65 (m, 2H), 4.50 (m, 1H), 3.91 (m, 1H), 3.75 (m, 1H), 3.59 (m, 2H), 3.31 (m, 2H), 1.07 (m, 3H). MS (ion spray), m/z, 485, 487 (M+H), (Cl pattern).