Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH2:4])[CH:2]=[CH2:3].[S:5](Cl)([C:8]1[CH:14]=[CH:13][C:11]([CH3:12])=[CH:10][CH:9]=1)(=[O:7])=[O:6].C(N(CC)CC)C.Cl>ClCCl>[CH3:12][C:11]1[CH:13]=[CH:14][C:8]([S:5]([NH:4][CH2:1][CH:2]=[CH2:3])(=[O:7])=[O:6])=[CH:9][CH:10]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: C=CCN
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CCNS(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 1.25 h

Procedure:
Allylamine (10.6 mL, 0.14 mol) is added over a period of 4 minutes to a solution of tosyl chloride (25.1 g, 0.13 mol) in dichloromethane (250 mL) cooled in an ice bath. Triethylamine (24 mL, 0.18 mol) is added and then the solution is stirred at ambient temperature for 1.25 hours. Aqueous 3N HCl solution (60 mL) is added and the phases are then separated. The organic phase is washed with another amount of aqueous 3N HCl solution (60 mL) and then with 5% aqueous sodium bicarbonate solution (60 mL). The organic phase is dried over Na2SO4, filtered and concentrated to obtain the expected compound in the form of a solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:38])[NH:7][CH2:8][CH2:9][S:10][CH2:11][C:12]1[C:17]([S:18]SC2C(C(CCNC(OC(C)(C)C)=O)S)=NC=CC=2)=[CH:16][CH:15]=[CH:14][N:13]=1)([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+].[C:41]1([CH:47]([O:54][C:55]([C:57]2[N:58]3[CH:61]([CH2:62][CH2:63][C:64]=2Cl)[C@@H:60]([NH:66][C:67](=[O:97])/[C:68](/[C:90]2[N:91]=[C:92]([NH2:96])[S:93][C:94]=2[Cl:95])=[N:69]\[O:70][C:71]([C:84]2[CH:89]=[CH:88][CH:87]=[CH:86][CH:85]=2)([C:78]2[CH:83]=[CH:82][CH:81]=[CH:80][CH:79]=2)[C:72]2[CH:77]=[CH:76][CH:75]=[CH:74][CH:73]=2)[C:59]3=[O:98])=[O:56])[C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1>C(#N)C>[C:41]1([CH:47]([O:54][C:55]([C:57]2[N:58]3[CH:61]([CH2:62][CH2:63][C:64]=2[S:18][C:17]2[C:12]([CH2:11][S:10][CH2:9][CH2:8][NH:7][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:38])=[N:13][CH:14]=[CH:15][CH:16]=2)[C@@H:60]([NH:66][C:67](=[O:97])/[C:68](/[C:90]2[N:91]=[C:92]([NH2:96])[S:93][C:94]=2[Cl:95])=[N:69]\[O:70][C:71]([C:84]2[CH:85]=[CH:86][CH:87]=[CH:88][CH:89]=2)([C:78]2[CH:79]=[CH:80][CH:81]=[CH:82][CH:83]=2)[C:72]2[CH:77]=[CH:76][CH:75]=[CH:74][CH:73]=2)[C:59]3=[O:98])=[O:56])[C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1
Reactant: CC(C)(C)OC(=O)NCCSCc1ncccc1SSc1cccnc1C(S)CCNC(=O)OC(C)(C)C
Reactant: Nc1nc(/C(=N/OC(c2ccccc2)(c2ccccc2)c2ccccc2)C(=O)N[C@H]2C(=O)N3C(C(=O)OC(c4ccccc4)c4ccccc4)=C(Cl)CCC23)c(Cl)s1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)NCCSCc1ncccc1SC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)[C@H](NC(=O)/C(=N\OC(c3ccccc3)(c3ccccc3)c3ccccc3)c3nc(N)sc3Cl)C2CC1
Reaction time: 18 h
Yield: 47.8 %

Procedure:
To a solution of (2-{3-[2-(2-tert-butoxycarbonylaminoethyl-sulfanylmethyl)-pyridin-3-yldisulfanyl]-pyridin-2-ylmethylsulfanyl}ethyl)carbamic acid tert-butyl ester (1.3 g, 0.0022 mol) in acetonitrile (120 mL) was added sodium borohydride (0.12 g, 0.003 mol), and the mixture was stirred at room temp. for 18 hours. (7R)-7-[(Z)-2-(2-amino-5-chlorothiazol-4-yl)-2-(triphenylmethoxyimino]-acetamido]-3-chloro-8-oxo-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylate diphenylmethyl ester (3.6 g, 0.0043 mol) was added in portions and the mixture was heated at reflux for 6 hours. The solvent was evaporated and the residue was partitioned between ethyl acetate (50 mL) and water (50 mL). The organic layer was separated, dried over anhydrous MgSO4 and concentrated. The residue was treated with diethyl ether (50 mL), and the solid that formed was filtered and dried to give 3.6 g of crude product. The crude product was purified by column chromatography on silica gel (100 g), eluting with hexane: ethyl acetate 1:1, to give the title compound (1.15 g).
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:7][CH2:6][CH2:5][C@@H:4]1[NH:8][C:9](=[O:22])[C:10]1[CH:15]=[C:14]([CH3:16])[CH:13]=[CH:12][C:11]=1[N:17]1[N:21]=[CH:20][CH:19]=[N:18]1.Br[C:24]1[CH:25]=[CH:26][C:27]([C:30]([F:33])([F:32])[F:31])=[N:28][CH:29]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O>[CH3:16][C:14]1[CH:13]=[CH:12][C:11]([N:17]2[N:18]=[CH:19][CH:20]=[N:21]2)=[C:10]([CH:15]=1)[C:9]([NH:8][C@H:4]1[CH2:5][CH2:6][CH2:7][C@@H:3]1[NH:2][C:24]1[CH:29]=[N:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=1)=[O:22]
Reactant: FC(F)(F)c1ccc(Br)cn1
Reactant: Cc1ccc(-n2nccn2)c(C(=O)N[C@H]2CCC[C@@H]2N)c1
Agent: [Pd]
Agent: Cl
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1ccc(-n2nccn2)c(C(=O)N[C@H]2CCC[C@@H]2Nc2ccc(C(F)(F)F)nc2)c1
Temperature: 100 °C

Procedure:
N-[(1S,2S)-2-aminocyclopentyl]-5-methyl-2-(2H-1,2,3-triazol-2-yl)benzamide hydrochloride (Intermediate 7; 70 mg, 0.21 mmol), 5-bromo-2-(trifluoromethyl)pyridine (CAS number 436799-32-5; 73 mg, 0.32 mmol) and cesium carbonate (280 mg, 0.87 mmol) were suspended in toluene (3 ml). The reaction was degassed using nitrogen for 15 minutes. To this was then added BINAP (13 mg, 0.021 mmol) and tris(dibenzylideneacetone)dipalladium (0) (19 mg, 0.021 mmol) and the resulting reaction was heated to 100° C. overnight. The reaction mass was poured into water (20 ml) and the organics were extracted with ethyl acetate (3×20 ml). The combined organics were dried over sodium sulfate and concentrated in vacuo. This was then purified by reverse phase preparative HPLC (eluted with acetonitrile/water containing 0.1% ammonia) to afford the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]([C@@H:17]2[CH2:22][CH2:21][CH2:20][N:19]([C:23](=[O:44])[NH:24][C@@H:25]([CH2:38][CH2:39][C:40]([CH3:43])([CH3:42])[CH3:41])[CH2:26][N:27](C)[C:28](OCC[Si](C)(C)C)=O)[CH2:18]2)[O:9][CH2:10][CH2:11][NH:12][C:13](=[O:16])[O:14][CH3:15])[CH:5]=[CH:6][CH:7]=1.CCN(CC)CC.C(O)=O>CC#N>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]([C@@H:17]2[CH2:22][CH2:21][CH2:20][N:19]([C:23](=[O:44])[NH:24][C@@H:25]([CH2:38][CH2:39][C:40]([CH3:42])([CH3:41])[CH3:43])[CH2:26][NH:27][CH3:28])[CH2:18]2)[O:9][CH2:10][CH2:11][NH:12][C:13](=[O:16])[O:14][CH3:15])[CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)NCCO[C@@H](c1cccc(Cl)c1)[C@@H]1CCCN(C(=O)N[C@@H](CCC(C)(C)C)CN(C)C(=O)OCC[Si](C)(C)C)C1
Solvent: O=CO
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CNC[C@H](CCC(C)(C)C)NC(=O)N1CCC[C@@H]([C@@H](OCCNC(=O)OC)c2cccc(Cl)c2)C1
Temperature: 55 °C

Procedure:
Methyl 2-((R)-(3-chlorophenyl)((R)-1-((S)-5,5-dimethyl-1-(N-methyl-N-(2-trimethylsilylethoxycarbonyl)amino)hexan-2-ylcarbamoyl)piperidin-3-yl)methoxy)ethylcarbamate was dissolved in CH3CN and treated with 75 mg (0.504 mmol, 4.5 equiv) of TEAF and the mixture heated to 55° C. for 3 h. The solution was evaporated and purified by prep HPLC to afford methyl 2-((R)-(3-chlorophenyl)((R)-1-((S)-5,5-dimethyl-1-(methylamino)hexan-2-ylcarbamoyl)piperidin-3-yl)methoxy)ethylcarbamate.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6](B(O)O)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.Br[C:14]1[CH:19]=[N:18][CH:17]=[C:16]([CH:20]2[CH2:22][CH2:21]2)[N:15]=1.C([O-])([O-])=O.[Na+].[Na+]>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.O1CCOCC1>[CH:20]1([C:16]2[N:15]=[C:14]([C:6]3[CH:5]=[C:4]4[C:9](=[CH:8][CH:7]=3)[NH:1][CH:2]=[CH:3]4)[CH:19]=[N:18][CH:17]=2)[CH2:22][CH2:21]1
Reactant: OB(O)c1ccc2[nH]ccc2c1
Reactant: Brc1cncc(C2CC2)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: c1cc2cc(-c3cncc(C4CC4)n3)ccc2[nH]1
Temperature: 100 °C
Yield: 76.1 %

Procedure:
A reaction vessel was charged with indole-5-boronic acid (674 mg, 4.19 mmol, Sigma-Aldrich), 2-bromo-6-cyclopropylpyrazine (1.00 g, 5.02 mmol, Combi-Phos Catalysts Inc.) and Pd(PPh3)4 (242 mg, 0.21 mmol). The tube was sealed. Dioxane (14 mL) and 2 M Na2CO3 (aq.) (6.28 mL, 12.56 mmol) were added. The reaction was stirred and heated in at 100° C. for 7 h. After cooling to RT, the organic layer was separated and dried over anhydrous Na2SO4, filtered and concentrated. The crude was purified by silica gel chromatography, eluting with a gradient of 0-40% EtOAc in hexanes, to provide 5-(6-cyclopropylpyrazin-2-yl)-1H-indole (750 mg, 3.19 mmol, 76% yield) as a white solid. MS (ESI, pos. ion) m/z: 236.1 (M+1).
Reaction SMILES: [CH2:1]([NH:8][C:9]1[CH:14]=[C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([NH:22][S:23]([CH2:26][CH2:27][CH2:28]Cl)(=[O:25])=[O:24])=[CH:18][CH:17]=2)[N:12]=[CH:11][C:10]=1[CH2:30][C:31]([NH2:33])=[O:32])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].O>C(#N)C.C(NCC)C>[CH2:1]([NH:8][C:9]1[CH:14]=[C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([N:22]3[CH2:28][CH2:27][CH2:26][S:23]3(=[O:25])=[O:24])=[CH:18][CH:17]=2)[N:12]=[CH:11][C:10]=1[CH2:30][C:31]([NH2:33])=[O:32])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NC(=O)Cc1cnc(Nc2ccc(NS(=O)(=O)CCCCl)cc2)cc1NCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCNCC
Solvent: O
Solvent: CC#N
Product: NC(=O)Cc1cnc(Nc2ccc(N3CCCS3(=O)=O)cc2)cc1NCc1ccccc1
Temperature: 80 °C
Reaction time: 1 h
Yield: 108.1 %

Procedure:
12 mg of 4-(benzylamino)-6-({4-[(3-chloropropylsulfonyl)amino]phenyl}amino)pyridine-3-carboxyamide (the compound of Example 306) was dissolved in 1 mL of acetonitrile, to which 0.2 mL of diethylamine and 7 mg of potassium carbonate were added, and stirred at 80° C. for 1 hour. After cooling, water was added to the reaction mixture, extracted with chloroform, the extract was washed with saturated saline, and dried on anhydrous sodium sulfate. The solvent was evaporated, and the residue was purified by silica gel column chromatography (chloroform:methanol=10:1) to obtain 12 mg (100%) of the title compound as a brown crystalline powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1.Cl.[NH2:12][C@@H:13]([C:16]([O:18][CH3:19])=[O:17])[CH2:14][CH3:15].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)Cl>[CH3:19][O:18][C:16](=[O:17])[C@H:13]([NH:12][CH2:7][C:6]1[CH:9]=[CH:10][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)[CH2:14][CH3:15]
Reactant: COc1ccc(C=O)cc1
Reactant: CC[C@@H](N)C(=O)OC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: ClCCl
Product: CC[C@@H](NCc1ccc(OC)cc1)C(=O)OC
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 107.4 %

Procedure:
10.0 g of p-methoxybenzaldehyde and 12.98 g of methyl D-homoalaninate-hydrochloride were dissolved in 160 ml of DCM and at 0° C. 11.35 ml of TEA were added. After 10 min at 0° C. 23.36 g of sodium triacetoxyborohydride were added in small portions. The reaction was stirred at r.t. overnight. To the reaction was then added aqueous sodium carbonate solution (10%). The layers were separated and the organic layer was washed with water until neutral, dried over Na2SO4, filtered and concentrated in vacuo. 18.72 g of the title compound were obtained and used without further purification.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[N:4][N:5]([CH2:7][O:8][CH3:9])[N:6]=1.[C:10]1([CH:16]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:17](Cl)=[O:18])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[CH3:9][O:8][CH2:7][N:5]1[N:4]=[N:3][C:2]([NH:1][C:17](=[O:18])[CH:16]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[N:6]1
Reactant: O=C(Cl)C(c1ccccc1)c1ccccc1
Reactant: COCn1nnc(N)n1
Product: COCn1nnc(NC(=O)C(c2ccccc2)c2ccccc2)n1

Procedure:
The title compound, white solid, m.p. 127-128° and MS: (neg. ions): m/e=322.2 (M+−H) was prepared in accordance with the general method of example 1 from 5-amino-2-methoxymethyl-2H-tetrazole and diphenylacetyl chloride.
Reaction SMILES: [CH2:1]1[CH:6]([CH2:7][CH:8]2[CH2:13][CH2:12][CH:11]([NH2:14])[CH2:10][CH2:9]2)[CH2:5][CH2:4][CH:3]([NH2:15])[CH2:2]1.[C:16](=[O:27])([O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])N.N>>[CH2:19]([O:18][C:16]([NH:15][CH:3]1[CH2:2][CH2:1][CH:6]([CH2:7][CH:8]2[CH2:13][CH2:12][CH:11]([NH:14][C:16]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])=[O:27])[CH2:10][CH2:9]2)[CH2:5][CH2:4]1)=[O:27])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: NC1CCC(CC2CCC(N)CC2)CC1
Reactant: CCCCCCCCOC(N)=O
Agent: N
Product: CCCCCCCCOC(=O)NC1CCC(CC2CCC(NC(=O)OCCCCCCCC)CC2)CC1
Temperature: 100 °C

Procedure:
Agitated in a reaction vessel are 210 parts of 4,4'-diaminodicyclohexylmethane with 360 parts of O-octyl carbamate and 150 parts of n-octanol-(1) at a reflux temperature of 185° C.-205° C. for 2 hours while the ammonia is removed by means of distillation. At this point, an additional 650 parts of n-octanol are allowed to flow into the reaction mixture and the reaction is continued at reflux temperature for 10 hours. The reaction mixture, which has been cooled to 100° C., is filtered, and the product is allowed to crystallize by cooling the filtrate. By filtration, washing with octanol and drying, 468 parts of bis(4-octoxycarbonylaminocyclohexyl)methane, C31H58N2O4 (molecular weight 522) are obtained corresponding with 89.6 percent theory relative to 4,4'-bisaminodicyclohexylmethane. The melting point is 129° C.-130° C.
Reaction SMILES: [Cl:1][C:2]1[C:7](OS(C(F)(F)F)(=O)=O)=[N:6][C:5]2[N:16]([CH:19]([CH3:21])[CH3:20])[N:17]=[CH:18][C:4]=2[C:3]=1[C:22]([O:24][CH2:25][CH3:26])=[O:23].[CH3:27][C:28]1([CH3:45])[CH2:33][C:32](B2OC(C)(C)C(C)(C)O2)=[CH:31][C:30]([CH3:44])([CH3:43])[NH:29]1.C([O-])([O-])=O.[Na+].[Na+].CO.C(Cl)Cl>O1CCOCC1.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>[Cl:1][C:2]1[C:7]([C:32]2[CH2:31][C:30]([CH3:44])([CH3:43])[NH:29][C:28]([CH3:45])([CH3:27])[CH:33]=2)=[N:6][C:5]2[N:16]([CH:19]([CH3:21])[CH3:20])[N:17]=[CH:18][C:4]=2[C:3]=1[C:22]([O:24][CH2:25][CH3:26])=[O:23]
Reactant: CCOC(=O)c1c(Cl)c(OS(=O)(=O)C(F)(F)F)nc2c1cnn2C(C)C
Reactant: CC1(C)C=C(B2OC(C)(C)C(C)(C)O2)CC(C)(C)N1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CO
Solvent: ClCCl
Product: CCOC(=O)c1c(Cl)c(C2=CC(C)(C)NC(C)(C)C2)nc2c1cnn2C(C)C
Temperature: 100 °C
Reaction time: 1 h
Yield: 46.2 %

Procedure:
A solution of ethyl 5-chloro-1-isopropyl-6-(((trifluoromethyl)sulfonyl)oxy)-1H-pyrazolo[3,4-b]pyridine-4-carboxylate (0.2 g, 0.481 mmol), 2,2,6,6-tetramethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridine (0.127 g, 0.481 mmol) and Pd(PPh3)4 (0.027 g, 0.024 mmol) in 1,4-dioxane (3 mL) was purged with argon for 10 min. Then, 2M Na2CO3 solution (0.183 g, 1.734 mmol) was added to it and again argon was purged through it for 10 min. The reaction mixture was stirred at 100° C. for 1 h. After completion of the reaction, water was added to it and extraction was carried out using 10% MeOH/DCM. The combined organic layers were washed with water, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford crude material which was purified by column chromatography to give the desired compound (0.09 g, 45.6%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([OH:11])([CH3:10])[CH3:9])[CH:5]=[C:4]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)[N:3]=1.[CH3:22][C:23]1[O:24][C:25]([C:29]2[CH:34]=[CH:33][C:32]([NH2:35])=[CH:31][CH:30]=2)=[C:26]([CH3:28])[N:27]=1>>[CH3:22][C:23]1[O:24][C:25]([C:29]2[CH:34]=[CH:33][C:32]([NH:35][C:2]3[N:7]=[C:6]([C:8]([OH:11])([CH3:10])[CH3:9])[CH:5]=[C:4]([C:12]4[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=4)[N:3]=3)=[CH:31][CH:30]=2)=[C:26]([CH3:28])[N:27]=1
Reactant: CC(C)(O)c1cc(-c2ccc(C(F)(F)F)cc2)nc(Cl)n1
Reactant: Cc1nc(C)c(-c2ccc(N)cc2)o1
Product: Cc1nc(C)c(-c2ccc(Nc3nc(-c4ccc(C(F)(F)F)cc4)cc(C(C)(C)O)n3)cc2)o1
Yield: 51.2 %

Procedure:
Using in analogous manner the procedure described in example 1e), 2-[2-chloro-6-(4-trifluoromethyl-phenyl)-pyrimidin-4-yl]-propan-2-ol (95 mg, 0.3 mmol) was reacted with 4-(2,4-dimethyl-oxazol-5-yl)-phenylamine (56 mg, 0.3 mmol) to give the title compound as light yellow solid (72 mg, 51%). MS ISP (m/e): 469.2 [(M+H)+]. 1H NMR (CDCl3, 300 MHz): δ (ppm)=8.20, 7.78, 7.75 and 7.63 (4 d, 4×2H), 7.31 (s, 2H), 3.93 (s, 1H), 2.53 (s, 3H), 1.61 (s, 6H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:31]#[N:32])[CH2:13][CH2:12][C:11]([N:14]3[CH2:30][CH2:29][C:17]4([N:21]([C:22]5[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=5)[CH2:20][NH:19][C:18]4=[O:28])[CH2:16][CH2:15]3)=[CH:10][CH2:9]2)=[CH:4][CH:3]=1.C[O-].[Na+].[BH4-].[Na+]>C(O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:31]#[N:32])[CH2:9][CH2:10][CH:11]([N:14]3[CH2:30][CH2:29][C:17]4([N:21]([C:22]5[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=5)[CH2:20][NH:19][C:18]4=[O:28])[CH2:16][CH2:15]3)[CH2:12][CH2:13]2)=[CH:4][CH:3]=1
Reactant: N#CC1(c2ccc(F)cc2)CC=C(N2CCC3(CC2)C(=O)NCN3c2ccccc2)CC1
Agent: C[O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: N#CC1(c2ccc(F)cc2)CCC(N2CCC3(CC2)C(=O)NCN3c2ccccc2)CC1
Reaction time: 6 h

Procedure:
To a stirred mixture of 10.5 parts of 1-(4-fluorophenyl)-4-(4-oxo-1-phenyl-1,3,8-triazaspiro[4,5]dec-8-yl)-3-cyclohexene-1-carbonitrile, 1 part of sodium methoxide solution 30% and 320 parts of ethanol is added portionwise 1 part of sodium borohydride. Upon completion, starting at room temperature is continued for 6 hours. The reaction mixture is poured onto water and the product is extracted with trichloromethane. The extract is dried, filtered and evaporated. The residue is purified by column-chromatography over silica gel using a mixture of trichloromethane and 5% of methanol as eluent. The pure fractions are collected and the eluent is evaporated. The residue is crystallized from a mixture of methanol and 2-propanone, yielding 3.2 parts of 1-(4-fluorophenyl)-4-(4-oxo-1-phenyl-1,3,8-triazaspiro[4,5]dec-8-yl)cyclohexanecarbonitrile; mp. 236.1° C.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[N:8]=[N:7][C:6]([C:9]2[CH:14]=[CH:13][NH:12][C:11](=[O:15])[CH:10]=2)=[CH:5][CH:4]=1.Br[C:19]1[CH:20]=[CH:21][C:22]2[C:23]3[CH2:42][CH2:41][N:40]([C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[CH2:39][CH2:38][C:24]=3[N:25]([S:28]([C:31]3[CH:37]=[CH:36][C:34]([CH3:35])=[CH:33][CH:32]=3)(=[O:30])=[O:29])[C:26]=2[CH:27]=1.OC1C=CC=C2C=1N=CC=C2.C([O-])([O-])=O.[Cs+].[Cs+]>CS(C)=O.[Cu]I>[O:15]=[C:11]1[CH:10]=[C:9]([C:6]2[N:7]=[N:8][C:3]([C:2]([F:1])([F:16])[F:17])=[CH:4][CH:5]=2)[CH:14]=[CH:13][N:12]1[C:19]1[CH:20]=[CH:21][C:22]2[C:23]3[CH2:42][CH2:41][N:40]([C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[CH2:39][CH2:38][C:24]=3[N:25]([S:28]([C:31]3[CH:32]=[CH:33][C:34]([CH3:35])=[CH:36][CH:37]=3)(=[O:30])=[O:29])[C:26]=2[CH:27]=1
Reactant: Cc1ccc(S(=O)(=O)n2c3c(c4ccc(Br)cc42)CCN(C(=O)OC(C)(C)C)CC3)cc1
Reactant: O=c1cc(-c2ccc(C(F)(F)F)nn2)cc[nH]1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: Oc1cccc2cccnc12
Solvent: CS(C)=O
Product: Cc1ccc(S(=O)(=O)n2c3c(c4ccc(-n5ccc(-c6ccc(C(F)(F)F)nn6)cc5=O)cc42)CCN(C(=O)OC(C)(C)C)CC3)cc1
Temperature: 135 °C
Reaction time: 8 h
Yield: 43.7 %

Procedure:
A suspension of 4-(6-(trifluoromethyl)pyridazin-3-yl)pyridin-2(1H)-one (78 mg, 0.32 mmol), tert-butyl 8-bromo-6-tosyl-1,2,4,5-tetrahydroazepino[4,5-b]indole-3(6H)-carboxylate (183 mg, 0.353 mmol), CuI (73 mg, 0.39 mmol), 8-hydroxyquinoline (9 mg, 0.06 mmol) and Cs2CO3 (115 mg, 0.353 mmol) in DMSO (10 mL) was degassed under reduced pressure for 45 min. The suspension was put under N2 and stirred at 135° C. overnight. The suspension was cooled, 9:0.9:0.1 CH2Cl2/MeOH/NH4OH (10 mL) was added, and the resulting suspension was stirred at 25° C. for 30 min. The suspension was passed through a plug of silica gel, and the filtrate was washed with brine. The resulting solution was dried over Na2SO4 and concentrated under reduced pressure. Flash chromatography (silica gel, (1:1 EtOAc/hexanes)/(9:0.9:0.1 CH2Cl2/MeOH/NH4OH), 100:0 to 0:100) afforded the title compound (95 mg, 44%) as a yellow viscous oil: 1H NMR (300 MHz, CDCl3) δ 8.35 (br s, 1H), 8.12 (d, J=8.9 Hz, 1H), 7.99 (d, J=8.9 Hz, 1H), 7.71-7.63 (m, 4H), 7.54-7.47 (m, 1H), 7.39-7.22 (m, 4H), 3.73-3.58 (m, 4H), 3.44-3.31 (m, 2H), 2.95-2.86 (m, 2H), 2.37 (s, 3H), 1.47 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14](=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21]Cl)[CH:16]=1.[NH:24]1[CH2:28][CH2:27][CH2:26][CH2:25]1>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14](=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][N:24]2[CH2:28][CH2:27][CH2:26][CH2:25]2)[CH:16]=1
Reactant: C1CCNC1
Reactant: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1cccc(CCl)c1
Solvent: C1CCOC1
Product: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1cccc(CN2CCCC2)c1
Yield: 67.3 %

Procedure:
N-(2-(5-Chloro-1H-indol-3-yl)ethyl)-3-(pyrrolidin-1-ylmethyl)benzamide was prepared following Method C starting from N-(2-(5-chloro-1H-indol-3-yl)ethyl)-3-(chloromethyl)benzamide (0.050 g; 0.144 mmol) and pyrrolidine (0.042 mL; 0.5 mmol) in THF (3 mL), under a microwave irradiation at 150° C. for 5 minutes. Flash chromatography on silica gel (eluent 3 to 20% ethanol in dichloromethane) furnished 0.037 g (67%) of the title compound as a white solid.
Reaction SMILES: [CH:1]1([O:4][C:5]2[CH:6]=[C:7]([C:15]3[N:24](COCC[Si](C)(C)C)[C:18]4[CH:19]=[N:20][NH:21][C:22](=[O:23])[C:17]=4[C:16]=3[CH2:33][O:34][CH2:35][CH3:36])[CH:8]=[CH:9][C:10]=2[O:11][CH:12]([F:14])[F:13])[CH2:3][CH2:2]1.C1(OC2C=C(C3N(COCC[Si](C)(C)C)C4C=NNC(=O)C=4C=3)C=CC=2OC(F)F)CC1>O>[CH:1]1([O:4][C:5]2[CH:6]=[C:7]([C:15]3[NH:24][C:18]4[CH:19]=[N:20][NH:21][C:22](=[O:23])[C:17]=4[C:16]=3[CH2:33][O:34][CH2:35][CH3:36])[CH:8]=[CH:9][C:10]=2[O:11][CH:12]([F:13])[F:14])[CH2:2][CH2:3]1
Reactant: CCOCc1c(-c2ccc(OC(F)F)c(OC3CC3)c2)n(COCC[Si](C)(C)C)c2cn[nH]c(=O)c12
Agent: C[Si](C)(C)CCOCn1c(-c2ccc(OC(F)F)c(OC3CC3)c2)cc2c(=O)[nH]ncc21
Solvent: O
Product: CCOCc1c(-c2ccc(OC(F)F)c(OC3CC3)c2)[nH]c2cn[nH]c(=O)c12
Yield: 37.6 %

Procedure:
Reaction was carried out in the same manner as in Example 1-(b) except for using 184 mg (0.353 mmol) of 2-(3-cyclopropoxy-4-difluoromethoxyphenyl)-3-ethoxymethyl-1-(2-trimethylsilylethoxymethyl)-1,5-dihydropyrrolo[2,3-d]pyridazin-4-one obtained in Example 12-(a) in place of 2-(3-cyclopropoxy-4-difluoromethoxyphenyl)-1-(2-trimethylsilylethoxymethyl)-1,5-dihydropyrrolo[2,3-d]pyridazin-4-one. After completion of the reaction, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer after separation was washed successively with water and then with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. To the obtained concentrate was added a small amount of tetrahydrofuran to dissolve the concentrate, hexane was then added thereto, and the mixture was subjected to ultrasonic wave treatment whereby the precipitated solid was collected by filtration. The obtained solid was washed with water and dried under reduced pressure to obtain 52 mg of the title compound as a white solid. (Yield: 38%)
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:12]=[CH:11][C:10]([Br:13])=[CH:9][C:6]=1[CH:7]=[CH2:8])C=C.F[P-](F)(F)(F)(F)F>C1(C)C=CC=CC=1>[Br:13][C:10]1[CH:11]=[CH:12][C:5]2[O:4][CH2:1][CH:8]=[CH:7][C:6]=2[CH:9]=1
Reactant: C=CCOc1ccc(Br)cc1C=C
Agent: F[P-](F)(F)(F)(F)F
Solvent: Cc1ccccc1
Product: Brc1ccc2c(c1)C=CCO2
Reaction time: 16 h
Yield: 92.9 %

Procedure:
A solution of 2-allyloxy-5-bromostyrene (416 mg) in toluene (20 ml) is added dropwise to a solution of the allenylidene complex (p-cymene)RuCl(PCy3)(═C═C═CPh2)+PF6− (54 mg) in toluene (5 ml) over a period of 1.5 h at 80° C. After stirring at that temperature for another 16 h, the solvent is evaporated and the crude product purified by flash chromatography affording the title compound (341 mg, 93%). 1H NMR (200 MHz, CDCl3): d=7.15 (dd, 1H), 7.04 (d, 1H), 6.62 (d, 1H), 6.31 (dt, 1H), 5.77 (dt, 1H), 4.86 (dd, 2H).