Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-:1].[CH:2]([O:15][C:16]([C:18]1([O:21]/[N:22]=[C:23](/[C:48]2[N:49]=[C:50]([NH:53][C:54]([O:56][C:57]([CH3:60])([CH3:59])[CH3:58])=[O:55])[S:51][CH:52]=2)\[C:24]([NH:26][C@@H:27]2[C:30](=[O:31])[NH:29][C@@H:28]2[CH2:32][N:33]2[N:37]=[C:36]([CH2:38][NH:39][CH2:40][C:41]3[CH:42]=[N+:43]([CH3:47])[CH:44]=[CH:45][CH:46]=3)[CH:35]=[N:34]2)=[O:25])[CH2:20][CH2:19]1)=[O:17])([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:61]([O-:64])(O)=[O:62].[Na+]>C(Cl)Cl>[Cl-:1].[CH:2]([O:15][C:16]([C:18]1([O:21]/[N:22]=[C:23](/[C:48]2[N:49]=[C:50]([NH:53][C:54]([O:56][C:57]([CH3:60])([CH3:59])[CH3:58])=[O:55])[S:51][CH:52]=2)\[C:24]([NH:26][C@@H:27]2[C:30](=[O:31])[NH:29][C@@H:28]2[CH2:32][N:33]2[N:37]=[C:36]([CH2:38][N:39]([CH2:40][C:41]3[CH:42]=[N+:43]([CH3:47])[CH:44]=[CH:45][CH:46]=3)[C:61]([O:64][C:3]([CH3:8])([CH3:4])[CH3:2])=[O:62])[CH:35]=[N:34]2)=[O:25])[CH2:19][CH2:20]1)=[O:17])([C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: O=C([O-])O
Reactant: C[n+]1cccc(CNCc2cnn(C[C@H]3NC(=O)[C@H]3NC(=O)/C(=N\OC3(C(=O)OC(c4ccccc4)c4ccccc4)CC3)c3csc(NC(=O)OC(C)(C)C)n3)n2)c1
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Product: C[n+]1cccc(CN(Cc2cnn(C[C@H]3NC(=O)[C@H]3NC(=O)/C(=N\OC3(C(=O)OC(c4ccccc4)c4ccccc4)CC3)c3csc(NC(=O)OC(C)(C)C)n3)n2)C(=O)OC(C)(C)C)c1

Procedure:
Prepared in an anologous manner to example 85, step 4 using 3-((((2-(((2R,3S)-3-((Z)-2-((1-((benzhydryloxy)carbonyl)cyclopropoxy)imino)-2-(2-((tert-butoxycarbonyl)amino)thiazol-4-yl)acetamido)-4-oxoazetidin-2-yl)methyl)-2H-1,2,3-triazol-4-yl)methyl)amino)methyl)-1-methylpyridin-1-ium chloride (50 mg, 0.058 mmol), Boc-anhydride (0.027 mL, 0.115 mmol), NaHCO3 (satd aq, 1.22 mL) and DCM (1.15 mL). LCMS: Rt=0.99 min, m/z=921.3 (M+) Method 2m_acidic.
Reaction SMILES: [C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH2:7]Br)=[C:5]([F:11])[CH:4]=1)#[N:2].[CH3:12][NH2:13]>C1COCC1>[F:11][C:5]1[CH:4]=[C:3]([CH:10]=[CH:9][C:6]=1[CH2:7][NH:13][CH3:12])[C:1]#[N:2]
Reactant: N#Cc1ccc(CBr)c(F)c1
Reactant: CN
Solvent: C1CCOC1
Product: CNCc1ccc(C#N)cc1F
Reaction time: 0.08 h
Yield: 95 %

Procedure:
A solution of 4-cyano-2-fluoro-benzylbromide (FluoroChem ltd, 16 g, 74 mmol) in dry THF (50 mL) was added to a 40% aqueous solution of methyl amine (700 mL) at 5-10° C. and allowed to stir for 5 min. The reaction mixture was extracted with DCM and the solvent was dried over Na2SO4 and concentrated under vacuum, affording (12.0 g, 95%) of the title compound as a brown liquid. 1H NMR (DMSO-d6, 400 MHz) δ 7.79-7.75 (m, 1H), 7.68-7.61 (m, 2H), 3.71 (s, 2H), 2.24 (s, 3H).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:18]3[C:17](=[O:19])[CH2:16][CH2:15][CH2:14][C:13]=3[N:12]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:21]=3)[C:11](=[O:30])[N:10]2[S:31]([CH2:34][CH2:35][CH2:36][C:37]([OH:39])=[O:38])(=[O:33])=[O:32])=[CH:5][CH:4]=1)#[N:2].C(C1C=CC(C2C(C#N)=C(C3C4C(=O)CCCC=4N(C4C=CC=C(C(F)(F)F)C=4)C(=O)N3[S:76]([C:79]3C=C(C(OC)=O)SC=3)(=O)=O)C=CC=2)=CC=1)#N>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:18]3[C:17](=[O:19])[CH2:16][CH2:15][CH2:14][C:13]=3[N:12]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:27])([F:29])[F:28])[CH:21]=3)[C:11](=[O:30])[N:10]2[S:31]([C:34]2[CH:35]=[C:36]([C:37]([OH:39])=[O:38])[S:76][CH:79]=2)(=[O:32])=[O:33])=[CH:5][CH:4]=1)#[N:2]
Reactant: N#Cc1ccc(C2C3=C(CCCC3=O)N(c3cccc(C(F)(F)F)c3)C(=O)N2S(=O)(=O)CCCC(=O)O)cc1
Reactant: COC(=O)c1cc(S(=O)(=O)N2C(=O)N(c3cccc(C(F)(F)F)c3)C3=C(C(=O)CCC3)C2c2cccc(-c3ccc(C#N)cc3)c2C#N)cs1
Product: N#Cc1ccc(C2C3=C(CCCC3=O)N(c3cccc(C(F)(F)F)c3)C(=O)N2S(=O)(=O)c2csc(C(=O)O)c2)cc1

Procedure:
The title compound is prepared in analogy to 4-(4-(4-cyanophenyl)-2,5-dioxo-1-(3-(tri-fluoromethyl)phenyl)-1,2,5,6,7,8-hexahydroquinazolin-3(4H)-ylsulfonyl)butanoic acid example 45), using methyl 4-(4-(4-cyanophenyl)-2,5-dioxo-1-(3-(trifluoromethyl)phenyl)-1,2,5,6,7,8-hexahydroquinazolin-3(4H)-ylsulfonyl)thiophene-2-carboxylate (example 44, 22 mg, 36 μmol) as starting material. Yield: 9 mg; ESI mass spectrum [M+H]+=602; Retention time HPLC: 0.94 min (Z018_S04).
Reaction SMILES: [N:1]1([C:7]2[N:8]=[C:9]([CH2:14][C:15]([O-:17])=O)[NH:10][C:11](=[O:13])[CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Na+].[F:19][C:20]1[C:26]([F:27])=[C:25]([F:28])[CH:24]=[CH:23][C:21]=1[NH2:22]>>[N:1]1([C:7]2[N:8]=[C:9]([CH2:14][C:15]([NH:22][C:21]3[CH:23]=[CH:24][C:25]([F:28])=[C:26]([F:27])[C:20]=3[F:19])=[O:17])[NH:10][C:11](=[O:13])[CH:12]=2)[CH2:2][CH2:3][O:4][CH2:5][CH2:6]1
Reactant: Nc1ccc(F)c(F)c1F
Reactant: O=C([O-])Cc1nc(N2CCOCC2)cc(=O)[nH]1
Agent: [Na+]
Product: O=C(Cc1nc(N2CCOCC2)cc(=O)[nH]1)Nc1ccc(F)c(F)c1F
Yield: 53.2 %

Procedure:
The product is prepared according to the procedure described in Example 5, using 260 mg of sodium [4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate and 294 mg of 2,3,4-trifluoroaniline in place of the 2,4-difluoroaniline. 195 mg of 2-[4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]-N-(2,3,4-trifluorophenyl)acetamide are obtained in the form of a white solid, the characteristics of which are the following:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([F:14])[C:5]2[O:9][C:8]([C:10]([OH:12])=O)=[CH:7][C:6]=2[CH:13]=1.Cl.Cl.[NH2:17][C@@H:18]1[CH:23]2[CH2:24][CH2:25][N:20]([CH2:21][CH2:22]2)[CH2:19]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C>[N:20]12[CH2:25][CH2:24][CH:23]([CH2:22][CH2:21]1)[C@@H:18]([NH:17][C:10]([C:8]1[O:9][C:5]3[C:4]([F:14])=[CH:3][C:2]([F:1])=[CH:13][C:6]=3[CH:7]=1)=[O:12])[CH2:19]2
Reactant: N[C@H]1CN2CCC1CC2
Reactant: O=C(O)c1cc2cc(F)cc(F)c2o1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(N[C@H]1CN2CCC1CC2)c1cc2cc(F)cc(F)c2o1
Reaction time: 0.33 h

Procedure:
55 mg (0.28 mmol) of 5,7-difluoro-1-benzofuran-2-carboxylic acid, 50 mg (0.25 mmol) of (R)-3-aminoquinuclidine dihydrochloride, 114.6 mg (0.3 mmol) of HATU, 117 mg (0.9 mmol) of N,N-diisopropylethylamine and 2.0 ml of DMF are reacted according to the general procedure (variant B). DMF is removed under reduced pressure and the crude product is dissolved in 1N aqueous sodium hydroxide solution. The aqueous phase is extracted with ethyl acetate. The combined organic phases are dried over magnesium sulfate and the solvent is removed under reduced pressure using a rotary evaporator. The crude product is taken up in methanol and, together with acidic ion exchange resin (Dowex WX2-200), shaken for about 20 min. The loaded ion exchanger is washed three times with in each case 30 ml of methanol, then with water, again with methanol, with dichloromethane and finally again with methanol. The product is eluted with methanol/triethylamine 95:5. The solvent is removed under reduced pressure using a rotary evaporator. 40 mg (52% of theory) of the title compound are isolated.
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([Cl:18])[CH:12]=2)[C:8]([NH2:10])=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:19]([N:21]=[C:22]=[O:23])[CH3:20]>C1(C)C=CC=CC=1>[CH:1]1([CH2:6][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([Cl:18])[CH:12]=2)[C:8]([NH:10][C:22]([NH:21][CH2:19][CH3:20])=[O:23])=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCN=C=O
Reactant: NC(=O)C(CC1CCCC1)c1ccc(Cl)c(Cl)c1
Solvent: Cc1ccccc1
Product: CCNC(=O)NC(=O)C(CC1CCCC1)c1ccc(Cl)c(Cl)c1
Yield: 24.6 %

Procedure:
A solution of 3-cyclopentyl-2-(3,4-dichloro-phenyl)-propionamide (98 mg, 0.33 mmol) in toluene (10 mL) was treated with ethyl isocyanate (0.03 mL, 0.42 mmol). The resulting solution was heated under reflux for 24 h. At this time, the reaction was concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230400 mesh, 90/10 hexanes/ethyl afforded 1-[3-cyclopentyl-2-(3,4-dichloro-phenyl)-propionyl]-3-ethyl-urea (29 mg, 26%) as a white foam: EI-HRMS m/e calcd for C17H22Cl2N2O2 (M+) 356.1058, found 356.1066.
Reaction SMILES: [CH2:1]([C:6]1([C:19]([O:21][CH3:22])=[O:20])[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]1)[CH2:2][CH2:3][CH:4]=C.CSC.C[OH:27]>>[O:27]=[CH:4][CH2:3][CH2:2][CH2:1][C:6]1([C:19]([O:21][CH3:22])=[O:20])[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:16])([CH3:18])[CH3:17])=[O:13])[CH2:8][CH2:7]1
Reactant: C=CCCCC1(C(=O)OC)CCN(C(=O)OC(C)(C)C)CC1
Reactant: CO
Solvent: CSC
Product: COC(=O)C1(CCCC=O)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C

Procedure:
A solution of methyl 4-(pent-4-en-1-yl)-1-(tert-butoxycarbonyl)piperidine-4-carboxylate (29.4 g, 0.0945 mol) from Step B in methanol (1000 mL) was cooled to −78° C. in a dry ice/methanol bath and ozone was bubbled into the solution until a blue color persisted. The excess ozone was removed with a stream of nitrogen and then methyl sulfide (69 mL, 0.95 mol) was added, the cooling bath was removed, and the reaction mixture was allowed to warm to room temperature over 1.5 h. The reaction mixture was then concentrated. The residue was then purified by flash chromatography eluting with 2:1 heptane/ethyl acetate to afford the title compound (23.0 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[N:8]([CH3:14])[CH:7]=[C:6]2[C:15]1[N:37](S(C2C=CC(C)=CC=2)(=O)=O)[C:18]2=[N:19][CH:20]=[CH:21][C:22]([CH2:23][NH:24][C:25]3[CH:30]=[CH:29][C:28]([N:31]4[CH2:36][CH2:35][O:34][CH2:33][CH2:32]4)=[CH:27][CH:26]=3)=[C:17]2[CH:16]=1.[OH-].[K+]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[N:8]([CH3:14])[CH:7]=[C:6]2[C:15]1[NH:37][C:18]2=[N:19][CH:20]=[CH:21][C:22]([CH2:23][NH:24][C:25]3[CH:26]=[CH:27][C:28]([N:31]4[CH2:32][CH2:33][O:34][CH2:35][CH2:36]4)=[CH:29][CH:30]=3)=[C:17]2[CH:16]=1
Reactant: COc1cc2c(-c3cc4c(CNc5ccc(N6CCOCC6)cc5)ccnc4n3S(=O)(=O)c3ccc(C)cc3)cn(C)c2cc1OC
Agent: [K+]
Agent: [OH-]
Product: COc1cc2c(-c3cc4c(CNc5ccc(N6CCOCC6)cc5)ccnc4[nH]3)cn(C)c2cc1OC
Yield: 55.7 %

Procedure:
[2-(5,6-Dimethoxy-1-methyl-1H-indol-3-yl)-1H-pyrrolo[2,3-b]pyrid-4-ylmethyl](4-morpholin-4-ylphenyl)amine is prepared as described in Example 179a starting with 0.16 g of [2-(5,6-dimethoxy-1-methyl-1H-indol-3-yl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyrid-4-ylmethyl](4-morpholin-4-ylphenyl)amine instead of the [2-(5,6-dimethoxy-1-methyl-1H-indol-3-yl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyrid-4-ylmethyl] (4-trifluoromethylsulfanylbenzyl)amine used in Example 179a and 1.08 cm3 of 5N potassium hydroxide. 0.068 g of [2-(5,6-dimethoxy-1-methyl-1H-indol-3-yl)-1H-pyrrolo[2,3-b]pyrid-4-ylmethyl](4-morpholin-4-ylphenyl)amine is obtained, the characteristics of which are as follows:
Reaction SMILES: Br[C:2]1[O:6][C:5]([C:7]([OH:9])=[O:8])=[CH:4][CH:3]=1.[CH2:10]([OH:28])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27].COCCOCCOC.[H-].[Na+]>C(O)(=O)C>[CH2:10]([O:28][C:2]1[O:6][C:5]([C:7]([OH:9])=[O:8])=[CH:4][CH:3]=1)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]
Reactant: CCCCCCCCCCCCCCCCCCO
Reactant: O=C(O)c1ccc(Br)o1
Agent: [H-]
Agent: [Na+]
Solvent: COCCOCCOC
Solvent: CC(=O)O
Product: CCCCCCCCCCCCCCCCCCOc1ccc(C(=O)O)o1
Temperature: 25 °C

Procedure:
A mixture of 30.0 g (0.157 mole) of 5-bromofuroic acid, 64.0 g (0.236 mole) of octadecanol and 500 ml of bis(2-methoxyethyl)ether is stirred at room temperature under nitrogen after which 9.45 g (0.393 mole) of sodium hydride is added. The mixture is refluxed about 22 hours, allowed to cool and poured into an ice-water mixture, acidified with acetic acid and extracted with ether. The ether layer is washed with water and salt water, dried over sodium sulfate, and filtered. The solvent is evaporated off replacing the ether with hexane. Upon cooling to room temperature a solid forms which is recrystallized from methanol to give 5-octadecyloxy-2-furoic acid, M.P. 117°-118° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([N:9]=[C:10]2[NH:14][CH2:13][CH2:12][NH:11]2)=[C:4]([Cl:15])[CH:3]=1.C([N:19]1[CH2:23][CH2:22][NH:21][C:20]1=O)(=O)C.[OH-].[Na+]>P(Cl)(Cl)(Cl)=O>[Cl:15][C:4]1[CH2:3][C:2](=[N:1][CH:20]2[NH:21][CH2:22][CH2:23][NH:19]2)[CH:7]=[C:6]([Cl:8])[C:5]=1[N:9]=[C:10]1[NH:14][CH2:13][CH2:12][NH:11]1
Reactant: Nc1cc(Cl)c(N=C2NCCN2)c(Cl)c1
Reactant: CC(=O)N1CCNC1=O
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Product: ClC1=CC(=NC2NCCN2)CC(Cl)=C1N=C1NCCN1

Procedure:
A mixture of 2-(4-amino-2,6-dichlorophenylimino)imidazolidine (3.7 g, 0.015M) and 1-acetyl-2-imidazolidone (2.2 g, 0.02M) in phosphoryl chloride (25 ml) was heated under reflux for 3 days. After cooling to room temperature the phosphoryl chloride was evaporated to give an oily residue. The residue was basified with sodium hydroxide (50%) and the insoluble solid was filtered off. This solid was hydrolysed with dilute sodium hydroxide in methanol. After evaporation of the mixture the product was extracted into methylene chloride. Evaporation of the extract gave 2-[2,6-dichloro-4-(2-imidazolidinylimino)phenylimino]imidazolidine.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:15]=[O:16])[C:5]2[C:10]([C:11]=1[OH:12])=[C:9]([CH2:13][CH3:14])[CH:8]=[CH:7][CH:6]=2.[CH3:17][O:18][CH2:19]Cl.C(N(CC)C(C)C)(C)C>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:15]=[O:16])[C:5]2[C:10]([C:11]=1[O:12][CH2:17][O:18][CH3:19])=[C:9]([CH2:13][CH3:14])[CH:8]=[CH:7][CH:6]=2
Reactant: COCCl
Reactant: CCc1cccc2c(C=O)cc(Cl)c(O)c12
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCc1cccc2c(C=O)cc(Cl)c(OCOC)c12

Procedure:
1.0 g of 3-chloro-5-ethyl-4-hydroxy-1-naphthalenecarbaldehyde, 0.91 ml of chloromethyl methyl ether and 3.5 ml of N,N-diisopropylethylamine were dissolved in 10 ml of dichloromethane, and reacted at room temperature for 4 hours.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.Br[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[O:15][C:16]3[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=3[N:18]=2)=[CH:10][C:9]=1[O:23][CH3:24].C(N(CC)CC)C>C(Cl)Cl>[CH3:24][O:23][C:9]1[CH:10]=[C:11]([C:14]2[O:15][C:16]3[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=3[N:18]=2)[CH:12]=[CH:13][C:8]=1[CH2:7][N:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1cc(-c2nc3ccccc3o2)ccc1CBr
Reactant: C1CCNC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc(-c2nc3ccccc3o2)ccc1CN1CCCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Pyrrolidine (226 μL, 2.83 mmol) was added to a stirring solution of 2-[4-(bromomethyl)-3-methoxyphenyl]-1,3-benzoxazole (300 mg, 0.94 mmol) and triethylamine (390 μL, 2.8 mmol) in CH2Cl2 (5 mL). The mixture was stirred at rt overnight. Crude mixture was adsorbed onto silica gel and purified by automated flash chromatography using an EtOAc/hexanes gradient to afford the desired 2-[3-methoxy-4-(pyrrolidin-1-ylmethyl)phenyl]-1,3-benzoxazole as a colorless solid: 1H NMR (CDCl3, 300 MHz) δ 7.82–7.80 (m, 1H), 7.77–7.74 (m, 1H), 7.71 (s, 1H), 7.56–7.50 (m, 2H), 7.35–7.30 (m, 2H), 3.94 (s, 3H), 3.71 (s, 2H), 2.59 (s, 4H), 1.81–1.78 (m, 4H). MS (ESI) 309 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[CH:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[CH:12][C:11]=1[O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1.CCCCCC>[CH:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[CH:12][C:11]=1[O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1
Reactant: OCCCCCCOc1ccc2ccccc2c1
Reactant: O=Cc1ccc(O)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCCCCC
Product: O=Cc1ccc(OCCCCCCOc2ccc3ccccc3c2)cc1
Temperature: 25 °C
Reaction time: 60 h
Yield: 57.5 %

Procedure:
Mitsunobu coupling is carried out as follows: 4-hydroxybenzaldehyde (0.92 g), 6-(2-naphthyloxy)hexanol (1.83 g), and triphenylphosphine (1.97 g) are dissolved in THF (25 ml) and cooled to 15° . Diethyl azodicarboxylate (1.2 ml) is added dropwise, and the mixture stirred at room temperature for 60 hrs. The reaction mixture is diluted with hexane and filtered to remove solids. The filtrate is concentrated and chromatographed with 25% v/v hexane in dichloromethane to provide 4-[6-(2-naphthyloxy)hexyloxy] benzaldehyde (1.5 g) as a white solid.
Reaction SMILES: [I:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][CH:3]=1.CC([O-])(C)C.[K+].[C:17]1([CH2:23]Br)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C1COCC1>[CH2:23]([N:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:2]([I:1])=[CH:3]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: Ic1c[nH]c2ccccc12
Reactant: BrCc1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: Ic1cn(Cc2ccccc2)c2ccccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 49.8 %

Procedure:
To a solution of 3-iodoindole (1, 2.9 g, 11.93 mmol) in THF (50 mL) is added t-BuOK (1.6 g, 14.26 mmol) at 0° C. After 1 h, PhCH2Br (3.0 g, 17.54 mmol) is added dropwise over 20 min at 0° C. The reaction is then warmed to room temperature and stirred for additional 4 h, then concentrated under reduced pressure. The residue is partitioned between EtOAc (60 mL) and H2O (30 mL). The organic layer is dried (MgSO4). The solvent is then removed and purification by flash column chromatography from EtOAc-n-hexane to give 1.98 g (52%) of 2: 1H NMR (CDCl3): δ7.94–7.98 (m, 1H), 7.41–7.45 (m, 2H), 7.13–7.35 (m, 5H), 6.47–6.54 (m, 2H), 5.33 (s, 2H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([F:10])[C:3]=1[CH:11]([O:15][CH3:16])[C:12]([OH:14])=O.[NH2:17][CH2:18][C:19]1[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[CH:21][C:20]=1[O:27][CH2:28][C:29]([F:32])([F:31])[F:30]>>[C:23]([C:22]1[CH:25]=[CH:26][C:19]([CH2:18][NH:17][C:12](=[O:14])[CH:11]([C:3]2[C:4]([F:10])=[CH:5][C:6]([O:8][CH3:9])=[CH:7][C:2]=2[F:1])[O:15][CH3:16])=[C:20]([O:27][CH2:28][C:29]([F:30])([F:32])[F:31])[CH:21]=1)#[N:24]
Reactant: N#Cc1ccc(CN)c(OCC(F)(F)F)c1
Reactant: COc1cc(F)c(C(OC)C(=O)O)c(F)c1
Product: COc1cc(F)c(C(OC)C(=O)NCc2ccc(C#N)cc2OCC(F)(F)F)c(F)c1

Procedure:
(RS)-(2,6-Difluoro-4-methoxy-phenyl)-methoxy-acetic acid (example 66.1) was coupled with 4-aminomethyl-3-(2,2,2-trifluoro-ethoxy)-benzonitrile according to general procedure B to give (RS)-N-[4-cyano-2-(2,2,2-trifluoro-ethoxy)-benzyl]-2-(2,6-difluoro-4-methoxy-phenyl)-2-methoxy-acetamide. Colorless solid. MS 445.0 ([M+H]+)
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1([C:12]([S:14]C)=S)[CH2:11][CH2:10][CH2:9][S:8]1.[CH2:16]([NH2:23])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]>C(O)C>[CH2:16]([NH:23][C:12]([C:7]1([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)[CH2:11][CH2:10][CH2:9][S:8]1)=[S:14])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: CCCCCCCN
Reactant: CSC(=S)C1(c2ccccn2)CCCS1
Solvent: CCO
Product: CCCCCCCNC(=S)C1(c2ccccn2)CCCS1
Yield: 102.7 %

Procedure:
A solution of methyl 2-(pyrid-2-yl)tetrahydrothiophene-2-carbodithioate (6.4 g) and n-heptylamine (2.9 g) in ethanol (75 cc) is heated under reflux for 2 hours 30 minutes. The reaction mixture is concentrated to dryness (20 mm Hg; 2.7 kPa) at 40° C. 6.8 g of a product prepared under the same conditions are added to the resulting residue (8.2 g) and the whole is chromatographed on neutral silica gel (150 g) contained in a column of diameter 3.5 cm. Elution is carried out with a cyclohexane-ethyl acetate mixture (98:2 by volume; 7300 cc), the following fractions of eluate being collected: fraction 1: 600 cc, fractions 2 to 8: 250 cc each and fractions 9 to 47: 100 cc each. Fractions 14 to 40 are combined and concentrated to dryness under reduced pressure (2 mm Hg; 0.27 kPa) at a temperature of 40° C. N-n-Heptyl-2-(pyrid-2-yl)tetrahydrothiophene-2-carbothioamide (8.3 g) is thus obtained in the form of a clear yellow liquid [Rf=0.40; chromatography on a thin layer of silica gel; solvent: cyclohexane-ethyl acetate (80:20 by volume)].
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:19]=[CH:20][C:21]=1[N:22]1[CH2:27][CH2:26][N:25]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[CH3:34])[CH2:24][CH2:23]1)[C:7]([NH:9][CH2:10][CH2:11][CH2:12][N:13]1[CH2:17][CH2:16][CH2:15][C:14]1=[O:18])=[O:8])([O-])=O>C(O)C.CO.[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]([CH:19]=[CH:20][C:21]=1[N:22]1[CH2:27][CH2:26][N:25]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[CH3:34])[CH2:24][CH2:23]1)[C:7]([NH:9][CH2:10][CH2:11][CH2:12][N:13]1[CH2:17][CH2:16][CH2:15][C:14]1=[O:18])=[O:8]
Reactant: Cc1ccccc1N1CCN(c2ccc(C(=O)NCCCN3CCCC3=O)cc2[N+](=O)[O-])CC1
Agent: [Pd]
Solvent: CO
Solvent: CCO
Product: Cc1ccccc1N1CCN(c2ccc(C(=O)NCCCN3CCCC3=O)cc2N)CC1
Reaction time: 8 h
Yield: 50.2 %

Procedure:
3-Nitro-N-[3-(2-oxo-pyrrolidin-1-yl)-propyl]-4-(4-o-tolyl-piperazin-1-yl)-benzamide (1.5 g, 3.2 mmol) was taken in a mixture of ethanol/methanol (50.0 mL/20.0 mL). This was added to a flask containing Pd/C (5 wt %) (0.15 g). The solution was evacuated and nitrogen purged and stirred under a balloon of hydrogen for 8 h. LC-MS indicated completion of reaction. Reaction was stopped, evacuated and nitrogen purged and filtered on celite. The solvent was rotavaped out to give 3-amino-N-[3-(2-oxo-pyrrolidin-1-yl)-propyl]-4-(4-o-tolyl-piperazin-1-yl)-benzamide (0.7 g, 47%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][CH2:7][C:8]2=[O:13].[N-:14]=[N+]=[N-].[Na+]>>[CH3:1][O:2][C:3]1[C:4]2[CH2:5][CH2:6][CH2:7][C:8](=[O:13])[NH:14][C:9]=2[CH:10]=[CH:11][CH:12]=1
Reactant: COc1cccc2c1CCCC2=O
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Product: COc1cccc2c1CCCC(=O)N2
Temperature: 25 °C
Reaction time: 16 h
Yield: 75.4 %

Procedure:
To a solution of 5-methoxy-3,4-dihydronaphthalen-1(2H)-one (8.3 g, 47.15 mmol) in polyphosphoric acid (100 mL) was added sodium azide (3.6 g, 55.4 mmol) in small portions at 0° C. within 30 minutes. Then the mixture was slowly warmed to room temperature and stirred for another 16 hours, and then poured into ice-water. The precipitate was collected and dried to afford the product 6-methoxy-4,5-dihydro-1H-benzo[b]azepin-2(3H)-one as a white solid (6.8 g, yield 75.5%). 1H NMR (400 MHz, DMSO-d6) δ ppm 9.48 (s, 1H), 7.13-7.17 (t, 1H, J=8.0 Hz), 6.77-6.79 (d, 1H, J=7.6 Hz), 6.58-6.60 (d, 1H, J=7.6 Hz), 3.78 (s, 3H), 2.68-2.72 (t, 2H, J=6.8 Hz), 2.11-2.14 (t, 2H, J=7.2 Hz), 1.99-2.05 (m, 2H).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH3:12])[N:3]=1.[CH3:13][O:14][C:15]1[CH:16]=[C:17]([CH:19]=[C:20]([O:24][CH3:25])[C:21]=1[O:22][CH3:23])[NH2:18].C([O-])(=O)C.[Na+]>>[CH3:12][C:4]1[N:3]=[C:2]([NH:18][C:17]2[CH:19]=[C:20]([O:24][CH3:25])[C:21]([O:22][CH3:23])=[C:15]([O:14][CH3:13])[CH:16]=2)[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=1
Reactant: COc1cc(N)cc(OC)c1OC
Reactant: Cc1nc(Cl)c2ccccc2n1
Agent: CC(=O)[O-]
Agent: [Na+]
Product: COc1cc(Nc2nc(C)nc3ccccc23)cc(OC)c1OC

Procedure:
The title compound was prepared from 4-chloro-2-methyl-quinazoline (179 mg, 1.0 mmol), 3,4,5-trimethoxy-aniline (183 mg, 1.0 mmol) and sodium acetate (98.4 mg, 1.2 mmol) similar to example 20 to give 239 mg (73.5%) of white solids. 1H NMR (CDCl3): 7.88 (t, J=7.2 Hz, 2H), 7.77 (t, J=7.2 Hz, 1H), 7.51 (t, J=8.1 Hz, 2H), 7.22 (s, 2H), 3.92-3.87 (m, 9H), 2.72 (s, 3H).