Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]([C:4]1[C:9]([C:10](=[O:44])[CH2:11][N:12]([CH2:35][C:36]2[CH:41]=[C:40]([F:42])[CH:39]=[C:38]([F:43])[CH:37]=2)[C:13]([C:15]2[CH:16]=[N:17][N:18]([C@H:24]3[CH2:29][CH2:28][C@H:27]([C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH2:26][CH2:25]3)[C:19]=2[C:20]([F:23])([F:22])[F:21])=[O:14])=[C:8]([Cl:45])[CH:7]=[CH:6][N:5]=1)=[N+]=[N-].P(C)(C)C.O>C1COCC1>[NH2:1][C:4]1[C:9]([C:10](=[O:44])[CH2:11][N:12]([CH2:35][C:36]2[CH:41]=[C:40]([F:42])[CH:39]=[C:38]([F:43])[CH:37]=2)[C:13]([C:15]2[CH:16]=[N:17][N:18]([C@H:24]3[CH2:29][CH2:28][C@H:27]([C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH2:26][CH2:25]3)[C:19]=2[C:20]([F:23])([F:22])[F:21])=[O:14])=[C:8]([Cl:45])[CH:7]=[CH:6][N:5]=1
Reactant: CCOC(=O)[C@H]1CC[C@H](n2ncc(C(=O)N(CC(=O)c3c(Cl)ccnc3N=[N+]=[N-])Cc3cc(F)cc(F)c3)c2C(F)(F)F)CC1
Agent: CP(C)C
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)[C@H]1CC[C@H](n2ncc(C(=O)N(CC(=O)c3c(Cl)ccnc3N)Cc3cc(F)cc(F)c3)c2C(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of compound 21-1 (60 mg, 0.09 mmol) in THF (5 mL) was added Me3P (1.0 M in THF, 0.18 mL, 0.18 mmol) at 0° C. and mixture was stirred at room temperature for 2 h. H2O (0.06 mL) was added to the reaction mixture at 0° C. and the mixture was stirred at room temperature for 16 h. The solvent was removed under reduced pressure and the residue was purified by column chromatography (silica gel, 30% EtOAc/hexane as eluent) to provide compound 21-2 (40 mg, 69%) as a yellow oil.
Reaction SMILES: O1CCOCC1.Cl[C:8]1[CH:13]=[C:12]([CH:14]([S:23][C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=2)[C:15]2[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:16]=2[F:22])[C:11]([Cl:31])=[CH:10][N:9]=1.[NH2:32][CH2:33][CH2:34][N:35]1[CH2:40][CH2:39][O:38][CH2:37][CH2:36]1>C(OCC)(=O)C>[Cl:31][C:11]1[C:12]([CH:14]([S:23][C:24]2[CH:25]=[CH:26][C:27]([Cl:30])=[CH:28][CH:29]=2)[C:15]2[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:16]=2[F:22])=[CH:13][C:8]([NH:32][CH2:33][CH2:34][N:35]2[CH2:40][CH2:39][O:38][CH2:37][CH2:36]2)=[N:9][CH:10]=1
Reactant: NCCN1CCOCC1
Reactant: Fc1ccc(F)c(C(Sc2ccc(Cl)cc2)c2cc(Cl)ncc2Cl)c1
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: Fc1ccc(F)c(C(Sc2ccc(Cl)cc2)c2cc(NCCN3CCOCC3)ncc2Cl)c1
Temperature: 25 °C
Yield: 10 %

Procedure:
A 1,4-dioxane (1.0 ml) solution of the 2,5-dichloro-4-[(4-chlorophenylthio)-(2,5-difluorophenyl)methyl]pyridine (100 mg, 0.24 mmol) obtained in Example 54 and 4-(2-aminoethyl)morpholine (200 μl) was stirred at 100° C. for 2 days under a nitrogen atmosphere. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate (40 ml). The diluted mixture was washed with water and brine, dried and concentrated under reduced pressure to give a residue. The resulting residue was purified by silica gel chromatography (3% methanol/chloroform) to give the title compound (12 mg, 10%) as an oil.
Reaction SMILES: [CH3:1][S:2]([O:5][CH2:6][C:7]([C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([Br:27])[CH:22]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([Br:20])[CH:15]=1)[CH2:8]OS(C)(=O)=O)(=[O:4])=[O:3].CN1C(=O)N(C)CCC1.[N-:37]=[N+:38]=[N-:39].[Na+]>CCOC(C)=O>[CH3:1][S:2]([O:5][CH2:6][C:7]([C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([Br:27])[CH:22]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([Br:20])[CH:15]=1)[CH2:8][N:37]=[N+:38]=[N-:39])(=[O:4])=[O:3]
Reactant: CS(=O)(=O)OCC(COS(C)(=O)=O)(c1cccc(Br)c1)c1cccc(Br)c1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN1CCCN(C)C1=O
Product: CS(=O)(=O)OCC(CN=[N+]=[N-])(c1cccc(Br)c1)c1cccc(Br)c1
Temperature: 110 °C
Yield: 40.1 %

Procedure:
To a solution of 2,2-bis(3-bromophenyl)propane-1,3-diyl dimethanesulfonate (3.6 g, 6.64 mmol) in DMPU (25 mL, 207 mmol) under N2 was added NaN3 (0.52 g, 7.97 mmol) with stirring. The mixture was heated to 110° C. for 5 h. After cooling to room temperature, the reaction mixture was diluted with EtOAc (100 mL), and washed with water (30 mL×2) and brine (25 mL), dried and concentrated. The residue was purified by column chromatography (on silica gel, eluent with Petroleum ether: EtOAc=3:1) to afford 1.3 g of the title compound (2.66 mmol, 40%). LC/MS: [M+18]=507. 1HNMR (CDCl3), 400 MHz: δ 2.83 (s, 3H), 4.07 (s, 2H), 4.77 (s, 2H), 7.07-7.09 (m, 2H), 7.21-7.31 (m, 4H), 7.44-7.46 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([NH:9][S:10]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)(=[O:12])=[O:11])[C:5]([Cl:8])=[N:6][CH:7]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].F[C:31]1[C:36]([C:37]2[N:42]=[C:41]([CH3:43])[N:40]=[C:39]([N:44]([CH2:54][C:55]3[CH:60]=[CH:59][C:58]([O:61][CH3:62])=[CH:57][CH:56]=3)[CH2:45][C:46]3[CH:51]=[CH:50][C:49]([O:52][CH3:53])=[CH:48][CH:47]=3)[N:38]=2)=[CH:35][CH:34]=[CH:33][N:32]=1>C1COCC1>[CH3:62][O:61][C:58]1[CH:57]=[CH:56][C:55]([CH2:54][N:44]([CH2:45][C:46]2[CH:47]=[CH:48][C:49]([O:52][CH3:53])=[CH:50][CH:51]=2)[C:39]2[N:40]=[C:41]([CH3:43])[N:42]=[C:37]([C:36]3[C:31]([NH:1][C:2]4[CH:3]=[C:4]([NH:9][S:10]([C:13]5[CH:14]=[CH:15][C:16]([F:19])=[CH:17][CH:18]=5)(=[O:11])=[O:12])[C:5]([Cl:8])=[N:6][CH:7]=4)=[N:32][CH:33]=[CH:34][CH:35]=3)[N:38]=2)=[CH:60][CH:59]=1
Reactant: Nc1cnc(Cl)c(NS(=O)(=O)c2ccc(F)cc2)c1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cccnc3F)n2)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cccnc3Nc3cnc(Cl)c(NS(=O)(=O)c4ccc(F)cc4)c3)n2)cc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 46.7 %

Procedure:
A mixture of N-(5-amino-2-chloropyridin-3-yl)-4-fluorobenzenesulfonamide (0.08 g, 0.265 mmol) in THF (5 mL) was cooled to 0° C. under N2. Lithium bis(trimethylsilyl)amide, 1.0 M solution in tetrahydrofuran (Aldrich) (0.795 mL, 0.795 mmol) was added dropwise and the mixture was stirred at 0° C. for 30 min before 4-(2-fluoropyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine (0.142 g, 0.318 mmol) was added. The resulting mixture was stirred at 0° C. for 10 min then removed from the ice bath and stirred for 3 h. The reaction mixture was quenched with water. The resulting mixture was partitioned between EtOAc and sat. NH4Cl. The aqueous layer was extracted with EtOAc (2×10 mL). The combined organic layers were washed with water, brine, dried over MgSO4 and concentrated. The crude product was purified by column chromatography (40 g, 20% to 30% acetone in hexanes) to give the product as a yellow solid (0.090 g). m/z (ESI, +ve ion) 727.1 (M+H)+. 1H NMR (300 MHz, CDCl3) δ 12.48 (s, 1H); 8.78-8.95 (m, 2H); 8.41 (d, J=3.51 Hz, 1H); 8.27 (s, 1H); 7.93 (dd, J=8.62, 4.97 Hz, 2H); 7.22 (d, J=6.58 Hz, 4H); 7.14 (t, J=8.48 Hz, 2H); 6.77-6.97 (m, 6H); 4.85 (d, J=3.36 Hz, 4H); 3.81 (d, J=5.12 Hz, 6H); 2.61 (s, 3H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])=[CH:4][CH:3]=1.[CH2:14]([S:26][CH2:27][CH2:28]O)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1C=CC=CC=1.C(OCC)(=O)C>[CH3:13][O:12][C:10](=[O:11])[CH2:9][CH2:8][C:5]1[CH:4]=[CH:3][C:2]([O:1][CH2:28][CH2:27][S:26][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[CH:7][CH:6]=1
Reactant: CCCCCCCCCCCCSCCO
Reactant: COC(=O)CCc1ccc(O)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: c1ccccc1
Product: CCCCCCCCCCCCSCCOc1ccc(CCC(=O)OC)cc1
Reaction time: 3 h
Yield: 84.6 %

Procedure:
A solution of methyl 3-[4-hydroxyphenyl)propionate (2.46 g, 13.6 mmol), 2-(dodecylthio)ethanol (3.40 g, 13.7 mmol) and triphenylphosphine (3.60 g, 13.8 mmol) in dry benzene (50 ml) was treated at 22° C. with diethyl azodicarboxylate (2.43 g, 13.9 mmol) added dropwise over 10 min. After 3 h at 22° C., the reaction mixture was diluted with ethyl acetate, washed with water, brine and dried (magnesium sulfate). Evaporation under reduced pressure gave an oil which was triturated with hexane to precipitate the triphenylphosphine oxide and the hydrazine side products. The filtrate was chromatographed on silica gel using a gradient of ethyl acetate (0-5%) in hexane as eluent to give 4.70 g(84%) of 3-[4-[2-(dodecylthio)ethoxy]phenyl]propanoic acid methyl ester as a white solid. Recrystallization from methanol gives white leaflets: m.p. 48° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=2[F:16])[CH:5]=[CH:4][C:3]=1[C:17]([C:19]1[CH:24]=[C:23](I)[CH:22]=[CH:21][C:20]=1[CH3:26])=[O:18].[OH:27][CH2:28][C:29]1[CH:30]=[C:31](B(O)O)[CH:32]=[CH:33][CH:34]=1.C([O-])(O)=O.[Na+].O>COCCOC.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.CCOC(C)=O>[Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=2[F:16])[CH:5]=[CH:4][C:3]=1[C:17]([C:19]1[CH:24]=[C:23]([C:33]2[CH:32]=[CH:31][CH:30]=[C:29]([CH2:28][OH:27])[CH:34]=2)[CH:22]=[CH:21][C:20]=1[CH3:26])=[O:18]
Reactant: Cc1ccc(I)cc1C(=O)c1ccc(Nc2ccc(F)cc2F)cc1Cl
Reactant: OCc1cccc(B(O)O)c1
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: CCOC(C)=O
Solvent: O
Solvent: COCCOC
Product: Cc1ccc(-c2cccc(CO)c2)cc1C(=O)c1ccc(Nc2ccc(F)cc2F)cc1Cl

Procedure:
Compound 495 (0.039 g, 0.081 mmol) was dissolved in 1,2-dimethoxyethane (0.8 mL) in a screw cap vessel. 3-(Hydroxymethyl)phenylboronic acid (0.015 g, 0.097 mmol) and saturated aqueous NaHCO3 (0.4 mL) were added. Argon was blown over the mixture and Pd(PPh3)4 (0.005 g, 0.004 mmol) was added. The reaction mixture was stirred at reflux temperature under an argon atmosphere for 2 h. H2O and EtOAc were added and the water phase was extracted with EtOAc (×2). The combined organic phases were dried (MgSO4), filtered and concentrated in vacuo. The crude product was purified by flash chromatography using EtOAc/petroleum ether (40-60) 1:1 as the eluent. This afforded the title compound as oil. 13C NMR (CDCl3) δ 196.3, 159.1 (dd), 155.5 (dd), 147.8, 141.5, 140.6, 139.6, 138.3, 137.0, 135.3, 133.7, 131.8, 129.4, 129.1, 128.0, 126.3, 126.0, 125.6, 124.4 (dd), 124.3 (dd), 116.3, 112.8, 111.6 (dd), 104.9 (dd), 65.3, 20.1
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH2:8][C:7](=O)[CH2:6][CH2:5]2.[BH3-]C#[N:15].[Na+].Cl>CO>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH2:8][CH:7]([NH2:15])[CH2:6][CH2:5]2
Reactant: O=C1CCc2cc(Br)ccc2C1
Reactant: [BH3-]C#N
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: NC1CCc2cc(Br)ccc2C1
Reaction time: 20 h
Yield: 276.4 %

Procedure:
This material is commercially available, however, it can be successfully prepared by the following procedure. To a solution of the 6-bromo 2-tetralone (0.288 g, 1.280 mmol) and NH4OAc (0.986 g, 10 eq.) in MeOH (40 mL) is added NaCNBH3 (0.097 g, 1.2 eq) at room temperature. The resulting yellow solution is stirred at that temperature for 20 hours, then acidified with 0.1 M HCl to pH 2.0. The mixture is extracted with CH2Cl2 twice. The aqueous layer is basified with 1.0 N NaOH to pH 10 then extracted with CH2Cl2 three times. The extracts are dried over anhydrous MgSO4 and concentrated in vacuo to afford 0.8 g (44% yield) of the desired product as a yellow oil which is used without further purification. 1H NMR (300 MHz, CD3OD) δ 7.27-7.35 (m, 8H), 7.05 (d, J=8.4 Hz, 4H), 3.56 (m, 1H), 3.17 (dd, J=3.9, 16.2 Hz, 1H), 2.95 (m, 2H), 2.81 (dd, J=9.9, 16.2 Hz, 1H), 2.19-2.29 (m, 1H), 1.79-1.92 (m, 1H); 13C NMR (75 MHz, CD3OD) δ 137.3, 131.5, 131.4, 130.9, 120.1, 47.4, 26.9, 26.7; LRMS: 226.1 (M+H), 209 (M+H−NH3).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[CH:7]=[CH:8][C:9]2[N:10]([CH:12]=[C:13]([C:15]([CH3:22])([CH3:21])[C:16]([O:18][CH2:19][CH3:20])=[O:17])[N:14]=2)[N:11]=1.[C:23]1([CH:29]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[N:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.[I-].[K+].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C>[C:36]1([CH:29]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[N:30]2[CH2:31][CH2:32][N:33]([CH2:2][CH2:3][CH2:4][CH2:5][C:6]3[CH:7]=[CH:8][C:9]4[N:10]([CH:12]=[C:13]([C:15]([CH3:22])([CH3:21])[C:16]([O:18][CH2:19][CH3:20])=[O:17])[N:14]=4)[N:11]=3)[CH2:34][CH2:35]2)[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1
Reactant: c1ccc(C(c2ccccc2)N2CCNCC2)cc1
Reactant: CCOC(=O)C(C)(C)c1cn2nc(CCCCCl)ccc2n1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(C)c1cn2nc(CCCCN3CCN(C(c4ccccc4)c4ccccc4)CC3)ccc2n1
Temperature: 60 °C
Reaction time: 5 h
Yield: 36.1 %

Procedure:
921 mg of ethyl 2-[6-(4-chlorobutyl)imidazo[1,2-b]pyridazin-2-yl]-2-methylpropionate was dissolved in 10 ml of N,N-dimethylformamide; 789 mg of 1-(diphenylmethyl)piperazine, 433 mg of potassium iodide and 520 mg of potassium carbonate were added, followed by stirring at 60° C. for 5 hours. After cooling, ethyl acetate was added; the mixture was washed with saturated saline and dried with magnesium sulfate. The dry product was concentrated under reduced pressure; the residue was subjected to silica gel column chromatography and eluted with ethyl acetate:triethylamine (50:1). The desired fraction was collected, concentrated under reduced pressure and crystallized from ethyl ether-hexane (1:1), collected by filtration, washed with hexane and dried to yield 554 mg of the title compound.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([OH:8])=[O:7].O[CH2:10][N:11]1[C:15](=[O:16])[C:14]2=[CH:17][CH:18]=[CH:19][CH:20]=[C:13]2[C:12]1=[O:21]>S(=O)(=O)(O)O>[O:21]=[C:12]1[C:13]2[C:14](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15](=[O:16])[N:11]1[CH2:10][C:5]1[O:1][C:2]([C:6]([OH:8])=[O:7])=[CH:3][CH:4]=1
Reactant: O=C1c2ccccc2C(=O)N1CO
Reactant: O=C(O)c1ccco1
Agent: O=S(=O)(O)O
Product: O=C(O)c1ccc(CN2C(=O)c3ccccc3C2=O)o1
Reaction time: 18 h
Yield: 52.8 %

Procedure:
2-Furoic acid (10.0 g) was dissolved in cold concentrated sulphuric acid (50 ml). The mixture was then added to N-hydroxy methylphthalimide (12.0 g) and the reaction mixture allowed to stand for 18 hrs at room temperature. The mixture was then poured into ice and the product extracted with dichloromethane, dried over magnesium sulphate and the solvent removed under reduced pressure. The crude product was triturated with diethyl ether and recrystallised from methanol to afford 5-[(1,3-dioxo-2,3-dihydro-1H-2-isoindolyl)methyl]-2-furoic acid (9.70 g) as a brown solid.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH:7]([C:9]1[CH:14]=[CH:13][C:12]([C:15]2[S:23][C:22]3[C:17](=[N:18][CH:19]=[C:20]([C:38]#[N:39])[C:21]=3[NH:24][C:25]3[CH:30]=[CH:29][C:28]([O:31][C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)=[CH:27][CH:26]=3)[CH:16]=2)=[CH:11][CH:10]=1)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl.CN(C)C=O.C(O)(=O)C>[N:1]1([CH2:7][C:9]2[CH:10]=[CH:11][C:12]([C:15]3[S:23][C:22]4[C:17](=[N:18][CH:19]=[C:20]([C:38]#[N:39])[C:21]=4[NH:24][C:25]4[CH:30]=[CH:29][C:28]([O:31][C:32]5[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=5)=[CH:27][CH:26]=4)[CH:16]=3)=[CH:13][CH:14]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: N#Cc1cnc2cc(-c3ccc(C=O)cc3)sc2c1Nc1ccc(Oc2ccccc2)cc1
Reactant: C1COCCN1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: N#Cc1cnc2cc(-c3ccc(CN4CCOCC4)cc3)sc2c1Nc1ccc(Oc2ccccc2)cc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 33.8 %

Procedure:
Morpholine (51 μL, 0.58 mmol) is added to a suspension of 2-(4-formylphenyl)-7-[(4-phenoxyphenyl)amino]thieno[3,2-b]pyridine-6-carbonitrile (200 mg, 0.45 mmol) in 8 mL of dichloromethane and 2 mL of N,N-dimethylformamide. The reaction mixture is cooled to 0° C. and sodium triacetoxyborohydride (474 mg, 2.24 mmol) is added. After stirring at 0° C. for 10 minutes, 2 drops of acetic acid are added and the reaction mixture is allowed to warm to room temperature and stirred for 4 hours. The reaction is quenched by the addition of water and then partitioned between saturated aqueous sodium bicarbonate and dichloromethane. The organic layer is washed with water, dried over sodium sulfate, filtered and concentrated in vacuo. The residue is purified by flash column chromatography eluting with ethyl acetate to provide 79 mg of 2-[4-(morpholin-4-ylmethyl)phenyl]-7-[(4-phenoxyphenyl)amino]thieno[3,2-b]pyridine-6-carbonitrile as white crystals, mp 254-256° C.; 1H NMR (DMSO-d6) δ 2.36 (s, 4H), 3.51 (s, 2H), 3.58 (s, 4H), 7.04-7.18 (m, 5H), 7.34-7.45 (m, 6H), 7.67 (d, J=8 Hz, 2H), 7.86 (s, 1H), 8.59 (s, 1H), 9.58 (s, 1H); MS 519.2 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[C:19]([C:20]([F:23])([F:22])[F:21])=[CH:18][C:5]2[N:6](C(OC(C)C)=O)[CH2:7][CH2:8][CH2:9][C:10](=[O:11])[C:4]=2[CH:3]=1.[Cl-].[Na+]>O.CS(C)=O>[CH3:1][C:2]1[C:19]([C:20]([F:23])([F:21])[F:22])=[CH:18][C:5]2[NH:6][CH2:7][CH2:8][CH2:9][C:10](=[O:11])[C:4]=2[CH:3]=1
Reactant: Cc1cc2c(cc1C(F)(F)F)N(C(=O)OC(C)C)CCCC2=O
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: Cc1cc2c(cc1C(F)(F)F)NCCCC2=O
Yield: 79.9 %

Procedure:
Heat a degassed mixture of isopropyl 7-methyl-5-oxo-8-trifluoromethyl-2,3,4,5-tetrahydrobenzo[b]azepine-1-carboxylate (6.68 g, 20.28 mmol) and sodium chloride (37.5 g) in water (7 mL) and dimethyl sulfoxide (180 mL) at reflux under nitrogen for 5 h. Dilute the cooled mixture with water (500 mL) and extract with ethyl acetate (2×300 mL). Wash the combined organic extracts with brine (200 mL), dry over anhydrous sodium sulfate and filter. Remove the solvents under reduced pressure and purify the residue by column chromatography on silica gel, eluting with ethyl acetate/hexanes (1:4), to afford the title compound as a yellow solid (3.94 g, 80%). ESI MS m/z 242 (M−H)−.
Reaction SMILES: [C:1]1([CH:7]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[N:8]2[CH2:11][CH:10]([CH:12]([C:17]3[CH:18]=C([CH:22]=[C:23]([F:25])[CH:24]=3)C#N)[C:13]([F:16])([CH3:15])[CH3:14])[CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-:32].[Na+].Cl.[CH3:35][CH2:36][OH:37]>>[C:1]1([CH:7]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[N:8]2[CH2:11][CH:10]([CH:12]([C:17]3[CH:18]=[C:35]([CH:22]=[C:23]([F:25])[CH:24]=3)[C:36]([OH:32])=[O:37])[C:13]([F:16])([CH3:15])[CH3:14])[CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCO
Reactant: [OH-]
Reactant: CC(C)(F)C(c1cc(F)cc(C#N)c1)C1CN(C(c2ccccc2)c2ccccc2)C1
Agent: Cl
Agent: [Na+]
Product: CC(C)(F)C(c1cc(F)cc(C(=O)O)c1)C1CN(C(c2ccccc2)c2ccccc2)C1

Procedure:
The reaction of mixture of 7.15 g (17.18 mmol) of 3-{1-[1(diphenylmethyl)azetidin-3-yl]-2-fluoro-2-methylpropyl}-5-fluorobenzonitrile (Step 1), 125 mL of EtOH, and 70 mL of 5N NaOH was refluxed for 3.5 h. Then it was adjusted to pH=4-5 with 12N HCl and concentrated to remove solvents. To the residue was added 200 mL of CH2Cl2 to dissolve the compound and it was filtered to remove the solid. The solid layer was washed with CH2Cl2 and the combined organic layers were concentrated to afford the title compound as white solid; Mass Spectrum: m/e=436 (M+1).
Reaction SMILES: [C:1]([O:5][CH:6]([C:12]1[C:16](B2OC(C)(C)C(C)(C)O2)=[C:15]([CH3:26])[S:14][C:13]=1[CH3:27])[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:4])([CH3:3])[CH3:2].FC(F)(F)S(OC1CCC2(OCCO2)CC=1)(=O)=O.C(OC(C1[C:61]([C:62]2[CH2:71][CH2:70][C:65]3(OCCO3)[CH2:64][CH:63]=2)=C(C)SC=1C)C(OCC)=O)(C)(C)C>>[C:1]([O:5][CH:6]([C:12]1[C:16]([C:61]2[CH2:62][CH2:71][CH2:70][CH2:65][CH2:64][CH:63]=2)=[C:15]([CH3:26])[S:14][C:13]=1[CH3:27])[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOC(=O)C(OC(C)(C)C)c1c(C)sc(C)c1C1=CCC2(CC1)OCCO2
Reactant: CCOC(=O)C(OC(C)(C)C)c1c(C)sc(C)c1B1OC(C)(C)C(C)(C)O1
Agent: O=S(=O)(OC1=CCC2(CC1)OCCO2)C(F)(F)F
Product: CCOC(=O)C(OC(C)(C)C)c1c(C)sc(C)c1C1=CCCCCC1

Procedure:
Using the procedure described in example 29, step 2, ethyl 2-(tert-butoxy)-2-[2,5-dimethyl-4-(tetramethyl-1,3,2-dioxaborolan-2-yl)thiophen-3-yl]acetate (28f) (100 mg, 0,246 mmol) is converted, by reaction with 1,4-dioxaspiro[4.5]dec-7-en-8-yl trifluoromethanesulfonate (34a) and after purification by flash chromatography on silica gel (cyclohexane/ethyl acetate 90/10), to ethyl 2-(tert-butoxy)-2-(4-{1,4-dioxaspiro[4.5]dec-7-en-8-yl}-2,5-dimethylthiophen-3-yl)acetate (34b) (39 mg, 0.10 mmol, 39%).
Reaction SMILES: [Br-].[C:2]1([CH2:8][CH2:9][N+:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16](=[O:18])[CH3:17])[CH:11]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.C(O)C>[Pd]>[C:2]1([CH2:8][CH2:9][N:10]2[CH2:15][CH2:14][CH2:13][C:12]([C:16]([CH3:17])=[O:18])=[CH:11]2)[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)c1ccc[n+](CCc2ccccc2)c1
Agent: [Pd]
Agent: [Br-]
Solvent: CCO
Solvent: CCN(CC)CC
Product: CC(=O)C1=CN(CCc2ccccc2)CCC1

Procedure:
A solution of 1-(2-phenylethyl)-3-acetylpyridinium bromide (30.6 g, 0.1 mole) and triethylamine (10.1 g, 0.1 mole) in ethyl alcohol (50 mole) over 5% palladium on carbon (5 g) was hydrogenated at room temperature and pressure. Upon cessation of hydrogen uptake, the catalyst was filtered and the filtrate concentrated at reduced pressure. The semi-solid filtered and the filtrate concentrated under reduced pressure to leave a pale brown oil, methyl 1-(2-phenyl ethyl)-1,4,5,6-tetrahydro-3-pyridyl ketone (6).
Reaction SMILES: [NH2:1][C:2]1[CH:21]=[CH:20][C:5]2[N:6]([CH3:19])[C:7]([CH2:9][CH2:10][C:11]3[CH:16]=[CH:15][C:14]([C:17]#[N:18])=[CH:13][CH:12]=3)=[N:8][C:4]=2[CH:3]=1.[CH3:22][N:23]([CH3:32])[C:24]1[CH:31]=[CH:30][C:27]([CH:28]=O)=[CH:26][CH:25]=1.CC(O)=O.[OH-].[Na+]>C(Cl)Cl.O>[C:17]([C:14]1[CH:15]=[CH:16][C:11]([CH2:10][CH2:9][C:7]2[N:6]([CH3:19])[C:5]3[CH:20]=[CH:21][C:2]([NH:1][CH2:28][C:27]4[CH:30]=[CH:31][C:24]([N:23]([CH3:32])[CH3:22])=[CH:25][CH:26]=4)=[CH:3][C:4]=3[N:8]=2)=[CH:12][CH:13]=1)#[N:18]
Reactant: CN(C)c1ccc(C=O)cc1
Reactant: Cn1c(CCc2ccc(C#N)cc2)nc2cc(N)ccc21
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Solvent: CC(=O)O
Product: CN(C)c1ccc(CNc2ccc3c(c2)nc(CCc2ccc(C#N)cc2)n3C)cc1

Procedure:
5-amino-2-[2-(4-cyanophenyl)-ethyl]-1-methyl-benzimidazole (1.0 g, 3.6 mmol) which is obtainable according to Example 2 (step c) and 4-dimethylamino-benzaldehyde (0.59 g, 3.0 mmol) in 25 mL of CH2Cl2 with 0.22 mL of AcOH are combined with Na[HB(OAc)3](2.2 g, 10.3 mmol) at ambient temperature with stirring. The mixture is stirred for 1 h at ambient temperature, covered with water, carefully acidified with conc hydrochloric acidaq and then made alkaline with 4N NaOH solution. The organic phase is separated off, dried and concentrated by evaporation. The product is chromatographed over silica gel (CH2Cl2/methanol=5/1) and crystallised from ethyl acetate.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([CH2:12][NH:13][C:14]([C@@H:16]3[CH2:20][CH2:19][CH2:18][N:17]3[C:21](=[O:40])[C@H:22]([NH:36][C:37](=[O:39])[CH3:38])[CH2:23][C:24]3[CH:29]=[CH:28][C:27](C4C=CC=CC=4)=[CH:26][CH:25]=3)=[O:15])=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1.[C:41](N[C@H](CC1C=CC(OC)=CC=1)C(N1CCC[C@H]1C(O)=O)=O)(=[O:43])C>>[NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([CH2:12][NH:13][C:14]([C@@H:16]3[CH2:20][CH2:19][CH2:18][N:17]3[C:21](=[O:40])[C@H:22]([NH:36][C:37](=[O:39])[CH3:38])[CH2:23][C:24]3[CH:25]=[CH:26][C:27]([O:43][CH3:41])=[CH:28][CH:29]=3)=[O:15])=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1
Reactant: CC(=O)N[C@H](Cc1ccc(-c2ccccc2)cc1)C(=O)N1CCC[C@H]1C(=O)NCc1ccc2c(N)nccc2c1
Reactant: COc1ccc(C[C@@H](NC(C)=O)C(=O)N2CCC[C@H]2C(=O)O)cc1
Product: COc1ccc(C[C@@H](NC(C)=O)C(=O)N2CCC[C@H]2C(=O)NCc2ccc3c(N)nccc3c2)cc1
Yield: 80 %

Procedure:
Using the procedure described for example 97f 0.140 g of 1-(2-(R)-acetylamino-3-(4-methoxyphenyl)-propionyl)-pyrrolidin-2-(S)-carboxylic acid was converted into 0.160 g (80%) of the title compound. (+)-APCI-MS: 490 (MH+).