Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]([CH3:29])([CH3:28])[CH2:3][NH:4][C:5]([C:7]1[N:11]2[CH:12]=[C:13]([CH3:26])[CH:14]=[C:15]([O:16][CH2:17][C:18]3[C:23]([F:24])=[CH:22][CH:21]=[CH:20][C:19]=3[F:25])[C:10]2=[N:9][C:8]=1[CH3:27])=[O:6].ClC(Cl)(Cl)S(O[CH2:36][C:37]([F:40])([F:39])[F:38])(=O)=O.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CN(C=O)C.O>[F:24][C:23]1[CH:22]=[CH:21][CH:20]=[C:19]([F:25])[C:18]=1[CH2:17][O:16][C:15]1[C:10]2[N:11]([C:7]([C:5]([NH:4][CH2:3][C:2]([CH3:29])([NH:1][CH2:36][C:37]([F:40])([F:39])[F:38])[CH3:28])=[O:6])=[C:8]([CH3:27])[N:9]=2)[CH:12]=[C:13]([CH3:26])[CH:14]=1
Reactant: O=S(=O)(OCC(F)(F)F)C(Cl)(Cl)Cl
Reactant: Cc1cc(OCc2c(F)cccc2F)c2nc(C)c(C(=O)NCC(C)(C)N)n2c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(OCc2c(F)cccc2F)c2nc(C)c(C(=O)NCC(C)(C)NCC(F)(F)F)n2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
100 mg (0.25 mmol) of N-(2-amino-2-methylpropyl)-8-[(2,6-difluorobenzyl)oxy]-2,6-dimethylimidazo[1,2-a]pyridine-3-carboxamide (Example 74) were initially charged in 2 ml of DMF, 0.041 ml (0.25 mmol) of 2,2,2-trifluoroethyl trichloromethanesulphonate, 69 mg (0.50 mmol) of potassium carbonate and 4.1 mg (0.025 mmol) of potassium iodide were added and the mixture was then stirred at RT overnight. 0.082 ml (0.50 mmol) of 2,2,2-trifluoroethyl trichloromethanesulphonate was then added, and the mixture was once more stirred at RT overnight. Another 0.123 ml (0.75 mmol) of 2,2,2-trifluoroethyl trichloromethanesulphonate were added, and the mixture was once more stirred at RT overnight. For work-up, 1 ml of water was added, the mixture was filtered through an Extrelut cartridge, eluted with dichloromethane, and the filtrate was concentrated. The crude product was purified by preparative HPLC (RP18 column, mobile phase: acetonitrile/water gradient with addition of 0.5% ammonium hydroxide). The product fractions were combined, evaporated and dried under high vacuum.
Reaction SMILES: C[O:2][C:3](=[O:30])[C:4]1[CH:9]=[C:8]([O:10][CH2:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:7]=[C:6]([O:20][CH2:21][CH2:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:5]=1.[OH-].[Na+]>CO.O1CCOCC1>[C:24]1([CH2:23][CH2:22][CH2:21][O:20][C:6]2[CH:5]=[C:4]([CH:9]=[C:8]([O:10][CH2:11][CH2:12][CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:7]=2)[C:3]([OH:30])=[O:2])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: COC(=O)c1cc(OCCCc2ccccc2)cc(OCCCc2ccccc2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1COCCO1
Product: O=C(O)c1cc(OCCCc2ccccc2)cc(OCCCc2ccccc2)c1

Procedure:
A solution of 3.0 g (7.4 mmol) of 3,5-bis(3-phenylpropoxy)benzoic acid methyl ester and 15 mL (15 mmol) of 1N NaOH in 100 mL of methanol and 40 mL of dioxane was stirred at reflux for 16 hours. The solvents were removed at reduced pressure, the residue was acidified and the product was extracted with ethyl acetate. The dried extract was concentrated to an oil which was crystallized from methanol-water to give 2.56 g, mp 107°-109°) of 3,5-bis(3-phenyl-propoxy)benzoic acid.
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1[C:9]2[CH2:10][C@H:11]3[CH2:23][C@H:12]3[C:13]=2[N:14]([C:16]2[CH:21]=[C:20](Br)[CH:19]=[CH:18][N:17]=2)[N:15]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:24]([Zn]C#N)#[N:25]>CC(N(C)C)=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>[C:1]([NH:5][C:6]([C:8]1[C:9]2[CH2:10][C@H:11]3[CH2:23][C@H:12]3[C:13]=2[N:14]([C:16]2[CH:21]=[C:20]([C:24]#[N:25])[CH:19]=[CH:18][N:17]=2)[N:15]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)NC(=O)c1nn(-c2cc(Br)ccn2)c2c1C[C@H]1C[C@@H]21
Reactant: N#C[Zn]C#N
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CC(=O)N(C)C
Product: CC(C)(C)NC(=O)c1nn(-c2cc(C#N)ccn2)c2c1C[C@H]1C[C@@H]21
Yield: 68.1 %

Procedure:
To a mixture of (1aR,5aR)-2-(4-bromo-pyridin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic acid tert-butylamide (100 mg, 0.265 mmol) and dicyanozinc (62.4 mg, 0.53 mmol) in DMA (2 mL), tetrakis(triphenylphosphine)palladium (61.4 mg, 0.051 mmol) was added. After degassing for 5 min with N2, the reaction mixture was heated under microwaved for 1 h at 130° C. in a heavy walled sealed tube. After removal of the volatile solvent, the residue was purified by preparative HPLC to give the title compound (58 mg). LCMS m/z=322.0 [M+H]+; 1H NMR (400 MHz, CDCl3) δ ppm 0.43-0.47 (m, 1H), 1.24 (td, J=7.8 and 5.0 Hz, 1H), 1.48 (s, 9H), 2.24-2.31 (m, 1H), 2.75-2.80 (m, 1H), 2.93 (d, J=16.8 Hz, 1H), 3.01 (dd, J=16.7 and 6.2 Hz, 1H), 6.73 (bs, 1H), 7.39 (dd, J=5.0 and 1.4 Hz, 1H), 8.16 (s, 1H), 8.61 (d, J=5.0 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][OH:10])[CH:5]=[N:6][C:7]=1Cl.[CH3:11][C@@H:12]1[CH2:17][NH:16][CH2:15][CH2:14][NH:13]1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][OH:10])[CH:5]=[N:6][C:7]=1[N:16]1[CH2:15][CH2:14][NH:13][C@H:12]([CH3:11])[CH2:17]1
Reactant: C[C@@H]1CNCCN1
Reactant: OCc1cnc(Cl)c(Cl)c1
Product: C[C@@H]1CN(c2ncc(CO)cc2Cl)CCN1

Procedure:
A mixture of 5,6-dichloro-3-pyridinemethanol (0.35 g, 2 mmol, TCI-US) and (R)-(−)-2-methylpiperazine (0.3 g. 3 mmol, Aldrich) reacted under the conditions of Example 43a to give the title compound as a light-brown solid. MS (ESI, pos. ion) m/z: 242 (M+1).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10](=[O:12])[CH3:11])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].CO[CH:15](OC)[N:16]([CH3:18])[CH3:17]>>[CH3:15][N:16]([CH3:18])/[CH:17]=[CH:11]/[C:10]([C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1)=[O:12]
Reactant: COC(OC)N(C)C
Reactant: CC(=O)c1cccc([N+](=O)[O-])c1
Product: CN(C)/C=C/C(=O)c1cccc([N+](=O)[O-])c1
Temperature: 115 °C
Reaction time: 15 h

Procedure:
To a sealed tube equipped with a magnetic stir bar, containing 1,1-dimethoxy-N,N-dimethylmethanamine (50 mL) was placed 1-(3-nitrophenyl)ethanone (5 g, 30 mmol, 1.0 equiv). The reaction was allowed to stir at 115° C. for 15 h. After the reaction was complete by LCMS, the solid product was filtered and washed with ether to yield 5.3 g (80%) of DHK-7-12 as an yellow solid. MS (ESI, Pos.) m/z: 221.1 [M+H]+.
Reaction SMILES: O.[CH:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([C:12]([OH:14])=O)[N:3]=1.[CH3:15][O:16][C:17]([C:19]1[C:27]2[O:26][C:25]([NH2:28])=[N:24][C:23]=2[CH:22]=[CH:21][CH:20]=1)=[O:18].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:15][O:16][C:17]([C:19]1[C:27]2[O:26][C:25]([NH:28][C:12]([C:4]3[N:3]=[CH:2][C:11]4[C:6]([CH:5]=3)=[CH:7][CH:8]=[CH:9][CH:10]=4)=[O:14])=[N:24][C:23]=2[CH:22]=[CH:21][CH:20]=1)=[O:18]
Reactant: O=C(O)c1cc2ccccc2cn1
Reactant: COC(=O)c1cccc2nc(N)oc12
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1cccc2nc(NC(=O)c3cc4ccccc4cn3)oc12

Procedure:
2-[(Isoquinoline-3-carbonyl)-amino]-benzooxazole-7-carboxylic acid methyl ester was prepared according to general procedure A using 1.052 g (5.5 mmol) of isoquinoline 3-carboxylic acid hydrate, 797 mg (4.15 mmol) of 2-amino-benzooxazole-7-carboxylic acid methyl ester, 2.09 g (5.5 mmol) of HBTU, 1.58 mL (9 mmol) of DIEA and 14 mL of DMF stirring at 90° C. for 3 h. 684 mg (1.97 mmol, 48%) of the product was obtained. LCMS: 348 (M+1)+.
Reaction SMILES: [N:1]1([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:6][CH2:5][CH:4]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:3][CH2:2]1.C[Si](C)(C)[N-][Si](C)(C)C.[K+].Br[CH2:30][C:31]([CH3:33])=[CH2:32].[Cl-].[NH4+]>O1CCCC1.O>[CH3:32][C:31](=[CH2:30])[CH2:33][C:4]1([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:3][CH2:2][N:1]([C:12]([O:14][C:15]([CH3:17])([CH3:16])[CH3:18])=[O:13])[CH2:6][CH2:5]1
Reactant: CCOC(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Reactant: C=C(C)CBr
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: C=C(C)CC1(C(=O)OCC)CCN(C(=O)OC(C)(C)C)CC1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 99.4 %

Procedure:
A solution of 1-(1,1-dimethylethyl) 4-ethyl 1,4-piperidinedicarboxylate (12.85 g, 50 mmol) in tetrahydrofuran (50 mL) was added slowly to a stirred, cooled (−78° C.) solution of potassium hexamethyldisilazide (14.96 g, 75 mmol) in tetrahydrofuran (75 mL), maintaining the internal temperature below −65° C. The mixture was stirred at −78° C. for 30 minutes, then 3-bromo-2-methylpropene (7.56 mL, 10.12 g, 75 mmol) was added dropwise over 5 minutes. The mixture was stirred at −78° C. for 1 hour, then saturated aqueous ammonium chloride (200 mL) was added and the mixture was warmed to room temperature. Water (100 mL) was added and the mixture was extracted with ethyl acetate (3×200 mL). The combined organic fractions were washed with aqueous citric acid (10%, 3×200 mL), saturated aqueous sodium hydrogen carbonate (200 mL) and brine (200 mL), dried (MgSO4) and the solvent was evaporated under reduced pressure to give the title compound as a pale yellow oil (15.48 g, 99%). m/z (ES+) 256 (M+1-C4H8).
Reaction SMILES: [C:1]([CH2:3][C:4]([O:6]CC)=O)#[N:2].[Cl:9][C:10]1[CH:18]=[CH:17][C:13]([CH2:14][CH2:15][NH2:16])=[CH:12][CH:11]=1>C(O)C>[Cl:9][C:10]1[CH:18]=[CH:17][C:13]([CH2:14][CH2:15][NH:16][C:4](=[O:6])[CH2:3][C:1]#[N:2])=[CH:12][CH:11]=1
Reactant: NCCc1ccc(Cl)cc1
Reactant: CCOC(=O)CC#N
Solvent: CCO
Product: N#CCC(=O)NCCc1ccc(Cl)cc1
Yield: 70.8 %

Procedure:
5.6 g of ethyl cyanoacetate and 7.8 g of 4-chlorophenethylamine are refluxed for 9 h in 50 ml of ethanol to give a solution. After concentration and cooling, this solution gives a residue which crystallizes. This is taken up with ether, filtered off and washed with ether to give 7.8 g of N-2-(4-chlorophenyl)ethylcyanoacetamide in the form of a white solid melting at 122° C. Yield 70%.
Reaction SMILES: O[CH2:2][C:3]1[N:4]=[C:5]([CH:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)[S:6][CH:7]=1.C(N(CC)CC)C.CS([Cl:32])(=O)=O>ClCCl>[Cl:32][CH2:2][C:3]1[N:4]=[C:5]([CH:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)[S:6][CH:7]=1
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCC(c2nc(CO)cs2)CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC(c2nc(CCl)cs2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 1-(1,1-dimethylethyl) 4-(4-hydroxymethyl-2-thiazolyl)-1-piperidinecarboxylate (i.e. the product of Example 1, Step B) (0.83 g, 2.8 mmol) and triethylamine (836 μL, 6.0 mmol) in dichloromethane (3 mL) was cooled to 0° C., and a solution of methanesulfonyl chloride (235 μL, 3.0 mmol) in dichloromethane (2 mL) was added dropwise. The reaction mixture was warmed to ambient temperature, stirred for 2 h, diluted with dichloromethane, washed with 1 N aqueous hydrochloric acid and brine, and dried (MgSO4). The organic layers were concentrated under reduced pressure and purified by silica gel chromatography using 25-50% ethyl acetate in hexanes as eluant to give 0.20 g of the title compound as a white solid.
Reaction SMILES: C[N:2]([C:8]1[S:9][CH:10]=[CH:11][N:12]=1)[CH2:3][CH2:4][CH2:5][NH:6]C.[C:13]1([C:19]#[C:20][C:21]([OH:23])=O)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>C1COCC1>[S:9]1[CH:10]=[CH:11][N:12]=[C:8]1[NH:2][CH2:3][CH2:4][CH2:5][NH:6][C:21](=[O:23])[C:20]#[C:19][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: O=C(O)C#Cc1ccccc1
Reactant: CNCCCN(C)c1nccs1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(C#Cc1ccccc1)NCCCNc1nccs1
Temperature: 25 °C
Reaction time: 2 h
Yield: 42.2 %

Procedure:
440 mg (2.37 mmol) N1,N3-dimethyl-N1-(thiazol-2-yl)propane-1,3-diamine was dissolved, together with 347 mg (2.37 mmol) 3-phenyl propiolic acid, 412 μl (2.37 mmol) DIPEA and 761 mg (2.37 mmol) TBTU, in THF (30 ml), and stirred for 2 h at RT. The reaction solution was concentrated in vacuo and the residue was taken up by chloroform, washed with water and brine, dried over MgSO4 and concentrated in vacuo. CC (DCE/EtOH 10:1) was carried out on the residue, yielding 314 mg (1.00 mmol, 42%) N-(3-((thiazol-2-yl)amino)propyl)-3-phenylpropiolamide. MS [MH+] 314.1
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:21])[CH2:15][CH2:16][CH2:17][CH:18]([CH3:20])[CH3:19])[CH2:10][C@@H:9]1[C@@H:22]([OH:45])[C@H:23]([N:31]=C(C1C=CC=CC=1)C1C=CC=CC=1)[CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:21])[CH2:15][CH2:16][CH2:17][CH:18]([CH3:20])[CH3:19])[CH2:10][C@@H:9]1[C@@H:22]([OH:45])[C@H:23]([NH2:31])[CH2:24][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)CCCC(=O)N1CCN(C(=O)OC(C)(C)C)[C@@H]([C@@H](O)[C@@H](Cc2ccccc2)N=C(c2ccccc2)c2ccccc2)C1
Agent: [Pd]
Solvent: CO
Product: CC(C)CCCC(=O)N1CCN(C(=O)OC(C)(C)C)[C@@H]([C@@H](O)[C@H](N)Cc2ccccc2)C1
Reaction time: 24 h

Procedure:
Dissolve 2-(R)-[2-(R)-(Benzhydrylideneamino)-1-(S)-hydroxy-3-phenyl-propyl]-4-(5-methylhexanoyl)-piperazine-1-carboxylic acid tert-butyl ester (103 mg, 0.17 mmol) in 2 ml of methanol and add palladium (10% on C, 30 mg). Stir under 1 atmosphere of H2 for 24 h and filter through celite, eluting with methanol. Concentrate to dryness to provide the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:29])[NH:10][CH:11]2[C:17](=[O:18])[NH:16][C:15]3[CH:19]=[CH:20][CH:21]=[CH:22][C:14]=3[CH:13]([CH:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)[CH2:12]2)[CH:5]=[CH:6][CH:7]=1.[C:30]([NH:34][C:35](=[O:38])[CH2:36]I)([CH3:33])([CH3:32])[CH3:31]>>[C:30]([NH:34][C:35](=[O:38])[CH2:36][N:16]1[C:17](=[O:18])[CH:11]([NH:10][C:9]([NH:8][C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)=[O:29])[CH2:12][CH:13]([CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)[C:14]2[CH:22]=[CH:21][CH:20]=[CH:19][C:15]1=2)([CH3:33])([CH3:32])[CH3:31]
Reactant: CC(C)(C)NC(=O)CI
Reactant: O=C(Nc1cccc(Cl)c1)NC1CC(C2CCCCC2)c2ccccc2NC1=O
Product: CC(C)(C)NC(=O)CN1C(=O)C(NC(=O)Nc2cccc(Cl)c2)CC(C2CCCCC2)c2ccccc21
Yield: 59 %

Procedure:
Following the previous expermental procedure, 3-[3-(3-chloro-phenyl)-ureido]-2-oxo-5-cyclohexyl-1,3,4,5-tetrahydro-benzo[b]azepine (0.4 g, 1 mmol) was alkylated with N-tert.-butyl iodoacetamide (0.28 g, 1.2 mmol) to provide the title compound as a white solid, 0.3 g, 59% yield. mp 222-5° C. 1H NMR (CDCl3) δ 8.03 (s, 1), 7.59 (t, 1), 7.34-7.15 (m, 3), 7.10 (d, 1),7.01 (t, 1), 6.91 (d, 1), 6.83 (d, 1), 6.43 (bd, 1), 6.43 (bd, 1), 6.31 (s, 1), 4.95 (d, 1), 4.54 (m, 1), 3.59 (d, 1), 2.66 (m, 1), 2.53 (t, 1), 2.18 (bd, 1), 1.78 (m, 1), 1.59 (m, 1), 1.4 (s, 9), 1.29-0.78 (m, 6), 0.58 (m, 1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:20])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([OH:16])=O)=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18].[CH3:21][N:22]([CH3:33])[CH2:23][CH2:24][O:25][C:26]1[CH:32]=[CH:31][C:29]([NH2:30])=[CH:28][CH:27]=1>>[Cl:20][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([Cl:1])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([NH:30][C:29]2[CH:28]=[CH:27][C:26]([O:25][CH2:24][CH2:23][N:22]([CH3:33])[CH3:21])=[CH:32][CH:31]=2)=[O:16])=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18]
Reactant: CN(C)CCOc1ccc(N)cc1
Reactant: O=C(O)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1
Product: CN(C)CCOc1ccc(NC(=O)c2cc([N+](=O)[O-])c(Sc3c(Cl)cncc3Cl)s2)cc1

Procedure:
Prepared according to the procedure described for example 44 from 5-[(3,5-dichloro-4-pyridyl)sulfanyl]-4-nitro-thiophene-2-carboxylic acid (35 mg, 0.1 mmol) and 4-(2-(dimethylamino)ethoxy)aniline (17.0 mg, 0.12 mmol). The title compound was obtained as a solid (17.5 mg, 34% yield). MS m/z: 513.02, 515.02 [M+H]+.
Reaction SMILES: [CH2:1](OC(=O)C1C=CN=C(C)C=1Cl)C.[CH3:14][O:15][N:16]=[C:17]1[C:25]2[C:20](=[CH:21][N:22]=[CH:23][C:24]=2Cl)[O:19][CH2:18]1>>[CH3:14][O:15][N:16]=[C:17]1[C:25]2[C:20](=[CH:21][N:22]=[CH:23][C:24]=2[CH3:1])[O:19][CH2:18]1
Reactant: CON=C1COc2cncc(Cl)c21
Reactant: CCOC(=O)c1ccnc(C)c1Cl
Product: CON=C1COc2cncc(C)c21

Procedure:
This compound was prepared using a method analogous to that of 3-chloro-2-methylisonicotinic acid ethyl ester (A.2.5.2), 4-chlorofuro[2,3-c]pyridin-3(2H)-one O-methyl oxime replacing 2,3-dichloroisonicotinic acid ethyl ester. Purification by CC using Hept/EtOAc (9/1 to 1/1) gives a white solid;
Reaction SMILES: [O:1]1[C@@H:5]2[O:6][CH2:7][CH2:8][C@@H:4]2[C@@H:3]([OH:9])[CH2:2]1.[C:10](O)(=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.N(C(OCC)=O)=NC(OCC)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1(C)C=CC=CC=1>[C:10]([O:9][C@H:3]1[C@@H:4]2[C@@H:5]([O:6][CH2:7][CH2:8]2)[O:1][CH2:2]1)(=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=C(O)c1ccccc1
Reactant: O[C@H]1CO[C@@H]2OCC[C@@H]21
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: O=C(O[C@@H]1CO[C@@H]2OCC[C@@H]21)c1ccccc1
Reaction time: 8 h
Yield: 5.3 %

Procedure:
(3R,3aR,6aS)-Hexahydrofuro[2,3-b]furan-3-ol (125 mg) obtained in Example 25 was dissolved in toluene (2 mL). Benzoic acid (214 mg), a 40 wt % solution (705 mg) of diethyl azodicarboxylate in toluene, and triphenylphosphine (416 mg) were added. The mixture was stirred overnight. After the reaction, 10% of the solution was purified by flash chromatography to give the title compound (12 mg) (88% ee), which was almost a pure anti-form.
Reaction SMILES: [NH2:1][C:2]1[C:28]([CH3:29])=[C:27]([CH3:30])[C:5]([O:6][CH2:7][C:8]([N:10]([CH:12]2[CH2:17][CH2:16][N:15]([CH2:18][C:19]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:20])[CH2:14][CH2:13]2)[CH3:11])=[O:9])=[C:4]([CH3:31])[C:3]=1[CH3:32].[BH4-].[Na+]>CO>[NH2:1][C:2]1[C:3]([CH3:32])=[C:4]([CH3:31])[C:5]([O:6][CH2:7][C:8]([N:10]([CH:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH:19]([OH:20])[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:14][CH2:13]2)[CH3:11])=[O:9])=[C:27]([CH3:30])[C:28]=1[CH3:29]
Reactant: Cc1c(C)c(OCC(=O)N(C)C2CCN(CC(=O)c3ccccc3)CC2)c(C)c(C)c1N
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Cc1c(C)c(OCC(=O)N(C)C2CCN(CC(O)c3ccccc3)CC2)c(C)c(C)c1N
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 58 %

Procedure:
To a mixture solution of the compound (10) obtained in the Example 10 in methanol was added 1.0 equivalent of sodium borohydride at 0° C., and the mixture was stirred for 1.5 hours at the room temperature. After the reaction, the solvent was removed under reduced pressure, and the resulting residue was purified by amine-coated silica gel (Fuji Silysia Chemical Ltd.) column chromatography (dichloromethane : methanol =20:1) to give the above-mentioned compound (11) in the yield of 58%.
Reaction SMILES: Cl[CH2:2][C:3]1[S:7][C:6]([CH:8]([CH3:10])[CH3:9])=[N:5][CH:4]=1.BrCC1CCCCO1.[F:19][C:20]([F:43])([F:42])[C:21]1[CH:22]=[CH:23][CH:24]=[C:25]2[C:29]=1[NH:28][C:27](=[O:30])[C:26]12[C:34]2=[CH:35][C:36]3[O:40][CH2:39][O:38][C:37]=3[CH:41]=[C:33]2[O:32][CH2:31]1>>[CH:8]([C:6]1[S:7][C:3]([CH2:2][N:28]2[C:29]3[C:25](=[CH:24][CH:23]=[CH:22][C:21]=3[C:20]([F:42])([F:19])[F:43])[C:26]3([C:34]4=[CH:35][C:36]5[O:40][CH2:39][O:38][C:37]=5[CH:41]=[C:33]4[O:32][CH2:31]3)[C:27]2=[O:30])=[CH:4][N:5]=1)([CH3:10])[CH3:9]
Reactant: O=C1Nc2c(C(F)(F)F)cccc2C12COc1cc3c(cc12)OCO3
Reactant: CC(C)c1ncc(CCl)s1
Agent: BrCC1CCCCO1
Product: CC(C)c1ncc(CN2C(=O)C3(COc4cc5c(cc43)OCO5)c3cccc(C(F)(F)F)c32)s1

Procedure:
Following the procedure as described in EXAMPLE 4 and making non-critical variations using 5-chloromethyl-2-(isopropyl)thiazole to replace 2-(bromomethyl)tetrahydro-2H-pyran, and 7′-(trifluoromethyl)spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one to replace 5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2″(1′H)-one, 1′-[(2-isopropyl-1,3-thiazol-5-yl)methyl]-7′-(trifluoromethyl)spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one was obtained (51%) as a colorless solid: mp 101-103° C.; 1H NMR (300 MHz, DMSO-d6) δ7.61 (d, J=8.1 Hz, 1H), 7.48 (d, J=6.8 Hz, 1H), 7.23 (dd J=7.8, 7.8 Hz, 1H), 7.18 (s, 1H), 6.69 (s, 1H), 6.48 (s, 1H), 5.91 (s, 2H), 5.08 (ABq, 2H), 4.77 (ABq, 2H), 3.21-3.16 (m, 1H), 1.22 (d, J=6.9 Hz, 6H); 13C NMR (75 MHz, DMSO-d6) δ178.7, 177.4, 156.0, 150.7, 149.0, 142.3, 140.7, 135.6, 128.7, 125.7, 124.5 (d), 123.6, 119.8, 113.3, 111.5 (m), 103.9, 101.9, 93.8, 80.8, 56.6, 43.3, 32.8, 23.3; MS (ES+) m/z 489.4 (M+1).
Reaction SMILES: [CH3:1][C:2]([CH3:9])=[CH:3][CH2:4][CH2:5][C:6](=[O:8])[CH3:7].[CH2:10]=[C:11]=[O:12].C=C1OC(=O)C1>ClCCl.N#N.B(F)(F)F.CCOCC.C1N2CN3CN(C2)CN1C3>[CH3:7][C:6]1([CH2:5][CH2:4][CH:3]=[C:2]([CH3:9])[CH3:1])[O:8][C:11](=[O:12])[CH2:10]1
Reactant: C=C=O
Reactant: CC(=O)CCC=C(C)C
Agent: C1N2CN3CN1CN(C2)C3
Agent: C=C1CC(=O)O1
Agent: FB(F)F
Solvent: ClCCl
Solvent: CCOCC
Product: CC(C)=CCCC1(C)CC(=O)O1
Temperature: -19 °C
Reaction time: 0.5 h
Yield: 80.9 %

Procedure:
128.8 g (1.0 mol) of 6-methyl-5-hepten-2-one were dissolved in 516 g of dichloromethane in an N2 atmosphere. The solution was cooled to −19° C. 0.71 g of boron trifluoride etherate (0.5 mol % relative to 6-methyl-5-hepten-2-one) were then added and ketene gas was metered in over a period of 4 h. The temperature ranged between −12° C. and −14° C. The ketene gas was drawn directly from a diketene cracker: approx. 1.25 mol of ketene were generated from 55 ml of diketene and used. The solution was stirred overnight at −15° C., during which time an N2 stream was passed through the solution to remove excess ketene. Finally, 350 mg (2.5 mmol) of urotropine were added, the solution stirred again for 30 minutes and heated to 0° C. The solvent was then evaporated off at 15 mbar and 20° C. The crude product was obtained in the form of an orange solution. Distillation by way of a thin-film evaporator at 1-2 mbar and with an overhead temperature of 88° C. yielded 136 g (80.9%) of the title product.
Reaction SMILES: [BH4-].[Na+].[CH2:3]([O:5][C:6]([C:8]1([C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:22]([C:24]3[CH:25]=[N:26][N:27]([C:30]4[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][CH:31]=4)[C:28]=3[CH3:29])=[O:23])=[CH:17][N:16]=2)[CH2:13][CH2:12][C:11](=[O:14])[CH2:10][CH2:9]1)=[O:7])[CH3:4]>CO.C(Cl)(Cl)Cl>[CH2:3]([O:5][C:6]([C:8]1([C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:22]([C:24]3[CH:25]=[N:26][N:27]([C:30]4[CH:31]=[CH:32][C:33]([CH3:36])=[CH:34][CH:35]=4)[C:28]=3[CH3:29])=[O:23])=[CH:17][N:16]=2)[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1)=[O:7])[CH3:4]
Reactant: CCOC(=O)C1(c2ccc(NC(=O)c3cnn(-c4ccc(C)cc4)c3C)cn2)CCC(=O)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CCOC(=O)C1(c2ccc(NC(=O)c3cnn(-c4ccc(C)cc4)c3C)cn2)CCC(O)CC1
Reaction time: 4 h
Yield: 70.7 %

Procedure:
Sodium borohydride (131 mg) was added at −78° C. to a solution of 1-[5({[5-methyl-1-(4-methylphenyl)-1H-pyrazol-4-yl]carbonyl}amino)pyridin-2-yl]-4-oxocyclohexanecarboxylic acid ethyl ester (400 mg) in methanol (6.0 ml) and chloroform (3.0 ml) and stirred at the same temperature for four hours. After the reaction, a saturated aqueous solution of ammonium chloride, the solvent was evaporated and extracted with chloroform three times. The organic solution was dried over anhydrous magnesium sulfate and concentrated. The resulting residue was recrystallized (n-hexane/ethanol) to give the titled compound (284 mg) as a white solid. MS (ESI) m/z: 463 (M+H)+.