Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:5]1[C:10](=[O:11])[C:9]([Cl:12])=[C:8]([OH:13])[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[CH2:14]([O:16][CH:17]([CH3:28])[CH2:18][O:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24]Br)=[CH:22][CH:21]=1)[CH3:15]>CN(C)C=O>[C:1]([N:5]1[C:10](=[O:11])[C:9]([Cl:12])=[C:8]([O:13][CH2:24][C:23]2[CH:22]=[CH:21][C:20]([O:19][CH2:18][CH:17]([O:16][CH2:14][CH3:15])[CH3:28])=[CH:27][CH:26]=2)[CH:7]=[N:6]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)n1ncc(O)c(Cl)c1=O
Reactant: CCOC(C)COc1ccc(CBr)cc1
Solvent: CN(C)C=O
Product: CCOC(C)COc1ccc(COc2cnn(C(C)(C)C)c(=O)c2Cl)cc1
Reaction time: 3 h
Yield: 37.6 %

Procedure:
In 15 ml of N,N-dimethylformamide were dissolved 1.5 g of 2-t-butyl-4-chloro-5-hydroxy-3(2H)-pyridazinone and 2.2 g of 4-(2-ethoxypropoxy)-benzyl bromide, and the resulting solution was heated under stirring on an oil bath at 80° to 90° C. for 3 hours. Then, similarly to the procedures in Preparation Example 2, 1.1 g of the aimed product was obtained as an oil.
Reaction SMILES: [C:1]([O:5][CH:6]([C:12]1[C:21]([CH3:22])=[CH:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]=1[OH:23])[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:4])([CH3:3])[CH3:2].C([O-])(O)=O.[Na+].[Br:29]Br.[O-]S([O-])(=S)=O.[Na+].[Na+]>C(Cl)(Cl)Cl.O>[Br:29][C:20]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]([OH:23])=[C:12]([CH:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])[C:7]([O:9][CH2:10][CH3:11])=[O:8])[C:21]=1[CH3:22]
Reactant: CCOC(=O)C(OC(C)(C)C)c1c(C)cc2ccccc2c1O
Reactant: BrBr
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: O
Product: CCOC(=O)C(OC(C)(C)C)c1c(C)c(Br)c2ccccc2c1O
Reaction time: 0.5 h
Yield: 96.8 %

Procedure:
A solution of ethyl 2-tert-butoxy-2-(1-hydroxy-3-methylnaphthalen-2-yl)acetate (1.24 g, 3.92 mmol) in CHCl3 (20 mL) was treated with solid NaHCO3 (843 mg, 9.80 mmol). Then a solution of Br2 (750 mg, 4.70 mmol) in CHCl3 (5.0 mL) was added dropwise over 2 min at 23° C. After 30 min, the reaction was treated with 10% Na2S2O3 solution (10 mL). After maximum decolorization was achieved, the reaction was diluted with H2O (10 mL) and extracted with DCM (3×10 mL). Combined organic phases were dried (Na2SO4), filtered, and concentrated. The residue was treated with DCM and wet-loaded onto a silica gel column and purified by flash chromatography (ethyl acetate/hexanes) giving the desired product (1.50 g, 97% yield). 1H NMR (400 MHz, CDCl3) δ 9.18 (s, 1H), 8.28 (d, J=8.6 Hz, 1H), 8.20 (d, J=8.6 Hz, 1H), 7.56 (dd, J=8.6, 8.6 Hz, 1H), 7.45 (dd, J=8.6, 8.6 Hz, 1H), 5.60 (s, 1H), 4.24-4.06 (m, 2H), 2.77 (s, 3H), 1.31 (s, 9H), 1.20 (t, J=7.0 Hz, 3H).
Reaction SMILES: [O:1]1CCO[CH:2]1[C:6]1[CH:7]=[C:8]([CH:19]=[CH:20][C:21]=1[F:22])[CH2:9][N:10]1[CH2:15][CH2:14][N:13]([CH:16]([CH3:18])[CH3:17])[CH2:12][CH2:11]1.Cl>C(Cl)Cl>[F:22][C:21]1[CH:20]=[CH:19][C:8]([CH2:9][N:10]2[CH2:11][CH2:12][N:13]([CH:16]([CH3:18])[CH3:17])[CH2:14][CH2:15]2)=[CH:7][C:6]=1[CH:2]=[O:1]
Reactant: CC(C)N1CCN(Cc2ccc(F)c(C3OCCO3)c2)CC1
Agent: Cl
Solvent: ClCCl
Product: CC(C)N1CCN(Cc2ccc(F)c(C=O)c2)CC1
Temperature: 25 °C
Reaction time: 0.83 h
Yield: 96.4 %

Procedure:
A mixture of 1-(3-[1,3] dioxolan-2-yl-4-fluoro-benzyl)-4-isopropyl-piperazine (695.2 mg, 2.25 mmol) and 6 N HCl (25 mL) was stirred at rt for 50 min, then was diluted with DCM (250 mL), and quenched slowly with 1 N NaOH. The organic layer was separated, dried (Na2SO4), and concentrated to give the desired product (573.5 mg, 96%). MS (ESI): mass calcd. for C15H21FN2O, 264.16; m/z found, 265.3 [M+H]+. 1H NMR (MeOD): 10.29 (s, 1H), 7.82-7.81 (m, 1H), 7.68-7.66 (m, 1H), 7.58-7.56 (m, 1H), 7.31-7.28 (m, 1H), 7.26-7.04 (m, 1H), 7.03-7.01 (t, J=8.4, 1H), 3.55 (s, 1H), 3.50 (s, 1H), 2.64-2.40 (br m, 9H), 1.07-1.06 (m, 6H).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([N+:8]([O-:10])=[O:9])=[N:6][CH:7]=1.[CH3:11][O:12][C:13]([O:17][Si](C)(C)C)=[C:14]([CH3:16])[CH3:15]>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].[F-].[Zn+2].[F-]>[CH3:11][O:12][C:13](=[O:17])[C:14]([CH3:16])([C:2]1[CH:7]=[N:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1)[CH3:15]
Reactant: O=[N+]([O-])c1ccc(Br)cn1
Reactant: COC(O[Si](C)(C)C)=C(C)C
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: [F-]
Product: COC(=O)C(C)(C)c1ccc([N+](=O)[O-])nc1
Yield: 24 %

Procedure:
5-Bromo-2-nitro-pyridine (7.0 g, 35 mmol), (1-methoxy-2-methyl-propenyloxy)-trimethyl-silane (12.0 g, 69 mmol), bis(dibenzylideneacetone)palladium (1.0 g, 1.75 mmol), and zinc fluoride (1.8 g, 17.5 mmol) were added to a round bottom flask and purged with nitrogen. Tri-tert-butylphosphine (3.5 ml of a 1.0 M solution in toluene) and 140 ml of DMF were added by syringe. The reaction mixture was heated at 80 degrees centigrade overnight. The reaction was diluted with ethyl acetate, water was added, and the layers were separated. The organic layer was washed with water and brine, dried and concentrated. The crude product was purified by flash chromatography using a gradient of 0% to 15% ethyl acetate in hexanes to yield 1.88 g (24%) of 2-methyl-2-(6-nitropyridin-3-yl)-propionic acid methyl ester.
Reaction SMILES: [C:1]1([N:7]=[C:8]=[S:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:10][C:11]1[CH:12]=[CH:13][C:14]2[S:18]N=N[C:15]=2[CH:19]=1>>[Cl:10][C:11]1[CH:12]=[CH:13][C:14]2[S:18][C:8](=[N:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[S:9][C:15]=2[CH:19]=1
Reactant: S=C=Nc1ccccc1
Reactant: Clc1ccc2snnc2c1
Product: Clc1ccc2sc(=Nc3ccccc3)sc2c1
Temperature: 220 °C
Yield: 24.6 %

Procedure:
Phenylisothiocyanate (8.8g) and 5-chloro-1,2,3-benzothiadiazole (3.75g) are combined under an inert atmosphere and heated at 220° C until nitrogen evolution ceases. Initial purification of the product is accomplished by dry column chromatography (600g alumina column, benzene solvent). The product is further purified with a methylene chloride wash and recrystallization (twice) from pentane to yield 1.5g of the title compound, melting point 71°-73° C.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([OH:11])[CH:9]=2)[C:4]([C:12](=[O:20])[C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)=[C:3]1[CH2:21][C:22]([CH3:28])([CH3:27])[C:23]([O:25][CH3:26])=[O:24].C([O-])([O-])=O.[K+].[K+].Br[CH2:36][C:37]1[CH:46]=[CH:45][C:44]2[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=2)[N:38]=1>CN(C=O)C>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:11][CH2:36][C:37]3[CH:46]=[CH:45][C:44]4[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=4)[N:38]=3)[CH:9]=2)[C:4]([C:12](=[O:20])[C:13]2[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=2)=[C:3]1[CH2:21][C:22]([CH3:28])([CH3:27])[C:23]([O:25][CH3:26])=[O:24]
Reactant: BrCc1ccc2ccccc2n1
Reactant: COC(=O)C(C)(C)Cc1c(C(=O)c2ccc(Cl)cc2)c2ccc(O)cc2n1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)C(C)(C)Cc1c(C(=O)c2ccc(Cl)cc2)c2ccc(OCc3ccc4ccccc4n3)cc2n1C
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 180 mg of the phenol from Step E in 5 mL of DMF were added 124 mg of milled K2CO3 followed by 150 mg of 2-(bromomethyl) quinoline. The mixture was stirred at R.T. for 18 h, poured onto 25% aq. NH4OAc and extracted with ethyl acetate. The extract was dried over Na2SO4 and evaporated to dryness to give an oil which was chromatographed on flash silica gel using ethyl acetate:hexane (30:70) as eluant to give the title compound as a foam.
Reaction SMILES: [Br:1][C:2]1[C:3]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][C:19]3[N:20]=[C:21]([CH:24]([CH3:26])[CH3:25])[S:22][CH:23]=3)[CH2:14][CH2:13]2)=[C:4]([N+:9]([O-])=O)[C:5]([NH2:8])=[N:6][CH:7]=1.CCO.[O:30]1[CH2:35][CH2:34][N:33]([CH2:36][C:37]2[CH:44]=[CH:43][C:40]([CH:41]=O)=[CH:39][CH:38]=2)[CH2:32][CH2:31]1.[O-]S(S([O-])=O)=O.[Na+].[Na+]>C(Cl)Cl.N.CN(C=O)C>[Br:1][C:2]1[C:3]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][C:19]3[N:20]=[C:21]([CH:24]([CH3:26])[CH3:25])[S:22][CH:23]=3)[CH2:14][CH2:13]2)=[C:4]2[N:9]=[C:41]([C:40]3[CH:39]=[CH:38][C:37]([CH2:36][N:33]4[CH2:34][CH2:35][O:30][CH2:31][CH2:32]4)=[CH:44][CH:43]=3)[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: O=Cc1ccc(CN2CCOCC2)cc1
Reactant: CC(C)c1nc(CN2CCN(c3c(Br)cnc(N)c3[N+](=O)[O-])CC2)cs1
Agent: N
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCO
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)c1nc(CN2CCN(c3c(Br)cnc4[nH]c(-c5ccc(CN6CCOCC6)cc5)nc34)CC2)cs1
Temperature: 85 °C
Yield: 39.1 %

Procedure:
To a mixture of 5-bromo-4-(4-((2-isopropylthiazol-4-yl)methyl)piperazin-1-yl)-3-nitropyridin-2-amine (0.066 g, 0.15 mmol), EtOH (2.6 mL) and DMF (0.35 mL), 4-(morpholinomethyl)-benzaldehyde (0.034 g, 0.165 mmol) was added, followed by a freshly prepared aqueous solution of Na2S2O4 (1M; 0.45 mL, 0.45 mmol). The reaction mixture was heated at 85° C. for 24 h, then allowed to cool to room temperature and diluted with DCM and a few drops of aqueous NH3 until complete dissolution was observed. This solution was deposited on two preparative silica TLC plates and eluted with DCM/MeOH (v/v; 96:4) to give the title compound as a solid (0.035 g, 39%); 1H-NMR (500 Mz, DMSO-d6): δ 1.33 (d, J=7.0 Hz, 6H, iPr—CH3), 2.34-2.42 (m, 4H), 2.68 (m, 4H), 3.22-3.32 (m, 1H), 3.54 (s, 2H), 3.59 (d, J=4.5 Hz, 4H), 3.62-3.70 (m, 6H), 7.35 (s, 1H, thiazole 5-H), 7.47 (d, J=8.5 Hz, 2H, ArH, C6H4), 8.14 (d, J=8.0 Hz, 2H, ArH, C6H4), 8.23 (s, 1H, imidazo[4,5-b]pyridine 5-H), 13.47 (br s, 1H, imidazo[4,5-b]pyridine N—H); LC (Method B)-MS (ESI, m/z) 2.55 min—596/598 [(M+H)+, Br isotopic pattern]. ESI-HRMS: Found: 596.18.07, calculated for C28H35BrN7OS (M+H)+: 596.1793.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:3]=1[C:4]([N:6]=[C:7]=[O:8])=[O:5].Cl.[CH3:15][O:16][C:17]1[O:21][C:20](=[O:22])[N:19]([C:23]2[CH:28]=[CH:27][C:26]([NH2:29])=[C:25]([O:30][CH3:31])[CH:24]=2)[N:18]=1.C(N(CC)CC)C>C(#N)C>[Cl:1][C:2]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:3]=1[C:4]([NH:6][C:7]([NH:29][C:26]1[CH:27]=[CH:28][C:23]([N:19]2[N:18]=[C:17]([O:16][CH3:15])[O:21][C:20]2=[O:22])=[CH:24][C:25]=1[O:30][CH3:31])=[O:8])=[O:5]
Reactant: COc1nn(-c2ccc(N)c(OC)c2)c(=O)o1
Reactant: O=C=NC(=O)c1ccc(F)cc1Cl
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COc1nn(-c2ccc(NC(=O)NC(=O)c3ccc(F)cc3Cl)c(OC)c2)c(=O)o1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The solution of equivalent amounts of 2-chloro-4-fluorobenzoyl isocyanate in acetonitrile was added dropwise to the solution of 0.39 g of 5-methoxy-3-(4-amino-3-methoxyphenyl)-3H-[1,3,4]oxadiazol-2-one hydrochloride and 0.2 ml of triethylamine in 5 ml of acetonitrile and the mixture is stirred at room temperature overnight. The solid formed was filtered off with suction and dried under reduced pressure.
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[S:6][C:5]2[CH:7]=[CH:8][CH:9]=[C:10]([S:11]([NH2:14])(=[O:13])=[O:12])[C:4]=2[S:3]1.C[Al](C)C.[CH3:20][O:21][C:22]1[N:27]=[C:26]([CH3:28])[N:25]=[C:24]([NH:29][C:30](=O)[O:31]C)[N:23]=1.C(O)(=O)C>C(Cl)Cl.Cl>[CH3:20][O:21][C:22]1[N:27]=[C:26]([CH3:28])[N:25]=[C:24]([NH:29][C:30]([NH:14][S:11]([C:10]2[C:4]3[S:3][C:2]([CH3:15])([CH3:1])[S:6][C:5]=3[CH:7]=[CH:8][CH:9]=2)(=[O:13])=[O:12])=[O:31])[N:23]=1
Reactant: CC1(C)Sc2cccc(S(N)(=O)=O)c2S1
Reactant: COC(=O)Nc1nc(C)nc(OC)n1
Agent: C[Al](C)C
Agent: Cl
Solvent: CC(=O)O
Solvent: ClCCl
Product: COc1nc(C)nc(NC(=O)NS(=O)(=O)c2cccc3c2SC(C)(C)S3)n1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 2.6 g 2,2-dimethyl-1,3-benzodithiole-4-sulfonamide prepared in Example 7, in 60 ml methylene chloride at room temperature under nitrogen is added 5.5 ml trimethylaluminum (2M in toluene). After stirring 15 minutes at room temperature, 2.0 g of methyl [4-methoxy-6-methyl-1,3,5-triazin-2-yl]carbamate, prepared according to the procedure of Example 5, was added and the reaction mixture was heated at reflux for 72 hours. The reaction mixture was cooled to room temperature and 75 ml ice, 3 ml glacial acetic acid, and 10 drops of hydrochloric acid were sequentially added. The organic phase was separated, dried and the solvent removed under reduced pressure to give an oil. Crystallization of the oil from an appropriate solvent gave a solid.
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[N:10]=[C:11]3[C:17]4[CH:18]=[CH:19][C:20]([CH2:22][C:23]([O:25]C)=[O:24])=[CH:21][C:16]=4[O:15][CH2:14][CH2:13][N:12]3[CH:27]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2].[OH-].[Li+].Cl.[CH3:31]O>>[CH:1]([N:4]1[C:8]([C:9]2[N:10]=[C:11]3[C:17]4[CH:18]=[CH:19][C:20]([CH2:22][C:23]([OH:25])=[O:24])=[CH:21][C:16]=4[O:15][CH2:14][CH2:13][N:12]3[CH:27]=2)=[N:7][C:6]([CH3:31])=[N:5]1)([CH3:3])[CH3:2]
Reactant: COC(=O)Cc1ccc2c(c1)OCCn1cc(-c3ncnn3C(C)C)nc1-2
Reactant: CO
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Product: Cc1nc(-c2cn3c(n2)-c2ccc(CC(=O)O)cc2OCC3)n(C(C)C)n1
Temperature: 50 °C
Reaction time: 3 h

Procedure:
A mixture of 98 mg (0.257 mmol) of methyl 2-(2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)acetate and 2.0 ml of 1.0 M of aqueous lithium hydroxide in 6 ml of methanol/tetrahydrofuram (1:1) mixture was stirred at 50° C. for 3 hours. The mixture was concentarted and acidified to pH 3 by careful addition of 1 N aqueous hydrogen chloride. The precipitate was collected and dried in high vacuum for 18 hours to give 2-(2-(1-isopropyl-3-methyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)acetic acid. Yield 58 mg. M/z 368.2, calc 367.16
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:16]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:18]=1)[O:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]([NH2:12])[C:7]=1[N+:13]([O-:15])=[O:14].[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([N:30]=[C:31]=[O:32])=[CH:26][C:25]=1[C:33]([F:36])([F:35])[F:34]>>[NH2:12][C:8]1[C:7]([N+:13]([O-:15])=[O:14])=[C:6]([O:5][C:4]2[CH:3]=[C:2]([NH:1][C:31]([NH:30][C:27]3[CH:28]=[CH:29][C:24]([Cl:23])=[C:25]([C:33]([F:35])([F:34])[F:36])[CH:26]=3)=[O:32])[CH:18]=[C:17]([C:19]([F:22])([F:20])[F:21])[CH:16]=2)[CH:11]=[CH:10][N:9]=1
Reactant: O=C=Nc1ccc(Cl)c(C(F)(F)F)c1
Reactant: Nc1cc(Oc2ccnc(N)c2[N+](=O)[O-])cc(C(F)(F)F)c1
Product: Nc1nccc(Oc2cc(NC(=O)Nc3ccc(Cl)c(C(F)(F)F)c3)cc(C(F)(F)F)c2)c1[N+](=O)[O-]
Yield: 98 %

Procedure:
Method G was used with 4-(3-amino-5-(trifluoromethyl)phenoxy)-3-nitropyridin-2-amine and 4-chloro-3-trifluoromethylphenyl isocyanate to afford the title compound as a yellow powder (262 mg, 98%). 1H-NMR (δ, ppm, DMSO-d6): 6.17 (d, 1H, HPy,4, J=5.6 Hz), 7.19 (m, 1H, Harom), 7.28 (bs, 2H, NHPy), 7.56 (s, 1H, Harom), 7.61 (d, 1H, Harom, J=8.7 Hz), 7.68 (dd, 1H, Harom, J=8.7 Hz, J=2.1 Hz), 7.80 (s, 1H, Harom), 8.07 (d, 1H, Harom, J=2.3 Hz), 8.08 (d, 1H, HPy,5, J=5.6 Hz), 9.43 (bs, 2H, NHurea). 13C-NMR (δ, ppm, DMSO-d6): 101.5 (C-4); 109.9 (C-11); 111.6 (C-9); 113.0 (C-7); 117.1 (C-15); 117.2 (C-2); 122.2 (C-17); 122.8 (C-16); 123.5 (C-19); 124.4 (C-10); 126.6 (C-20); 131.0 (C-12); 131.9 (C-18); 138.7 (C-14); 142.1 (C-8); 152.2 (C-13); 153.5 (C-5); 153.9 (C-1); 154.4 (C-6); 157.8 (C-3). LC-MS (m/z): 536 (M+H, 100).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10](Cl)(=[O:12])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[N+:14]([C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[NH:22][N:21]=[CH:20]2)([O-:16])=[O:15].C(N(CC)CC)C>C(#N)C>[N+:14]([C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[N:22]([S:10]([C:7]1[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1)(=[O:12])=[O:11])[N:21]=[CH:20]2)([O-:16])=[O:15]
Reactant: O=[N+]([O-])c1ccc2[nH]ncc2c1
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1ccc(S(=O)(=O)n2ncc3cc([N+](=O)[O-])ccc32)cc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 77 %

Procedure:
In 100 ml of acetonitrile were dissolved 10 g of 4-nitrophenylsulfonyl chloride and 8.8 g of 5-nitroindazole and the solution was cooled to 0° C. Then, 6.8 g of triethylamine was gradually added dropwise to the solution and the mixture was allowed to stand overnight to precipitate crystals. Then, 50 ml of water was added dropwise to the system and the crystals formed were collected by filtration, washed with water and then ethyl acetate, and dried to provide 12.1 g of the desired product having a melting point of from 196° C. to 197° C.
Reaction SMILES: [CH:1](=[N:8][N:9]1[CH2:13][CH2:12][N:11]=[C:10]1SC)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:16].N.C(#[N:20])C>CO>[NH2:20][C:10]1[N:9]([N:8]=[CH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:13][CH2:12][N:11]=1.[ClH:16]
Reactant: CSC1=NCCN1N=Cc1ccccc1
Reactant: CC#N
Agent: Cl
Agent: N
Solvent: CO
Product: NC1=NCCN1N=Cc1ccccc1

Procedure:
1 g of 1-benzylideneamino-2-methylthio-2-imidazoline in the form of a hydrochloride in 10 ml of methanol are treated with 0.33 ml of NH3 (28% in H2O). The mixture obtained is refluxed for ca. 5 hours and a precipitate obtained is filtrated off. From the filtrate obtained the solvent is evaporated off. The residue obtained is treated with acetonitrile. The precipitate obtained is filtrated off and dried. Solid 2-amino-1-benzylideneamino-4,5-dihydro-1H-imidazole in the form of a hydrochloride is obtained.
Reaction SMILES: [C:1]1([C:7]2([C:10]#[N:11])[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[C:1]1([C:7]2([CH2:10][NH2:11])[CH2:8][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: N#CC1(c2ccccc2)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: NCC1(c2ccccc2)CC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 1-phenylcyclopropanecarbonitrile (50 g, 0.34 mol, 1 eq.) in tetrahydrofuran (500 mL, 0.7 M) at 0° C. was added lithium aluminum hydride (23 g, 0.35 mol, 1.03 eq.). The reaction mixture was stirred at 0° C. for one hour and then at reflux for one hour. The reaction mixture was then cooled down and quenched with water (23 mL) and a 15% aqueous sodium hydroxide solution (69 mL). The mixture was filtered and concentrated in vacuo to afford #@1 (36 g, 72%). LC-MS: m/z 148.1 [M+H+], retention time=0.86 minutes; 1H NMR (400 MHz, CDCl3) δ 7.2-7.4 (m, 5H), 2.78 (s, 2H), 1.19 (br s, 2H), 0.72-0.84 (m, 4H).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][CH2:15][C:16](OCC)=[O:17])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O>O1CCCC1>[CH2:1]([N:8]1[CH2:9][CH2:10][CH:11]([O:14][CH2:15][CH2:16][OH:17])[CH2:12][CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)COC1CCN(Cc2ccccc2)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: OCCOC1CCN(Cc2ccccc2)CC1

Procedure:
A solution of (A) (14 g) in tetrahydrofuran (50 ml) was added to a solution of lithium aluminum hydride (2 g) in tetrahydrofuran (100 ml) under stirring. The mixture was refluxed for 3 hours and finally hydrolyzed by careful addition of water. After removal of inorganic salts by filtration, the filtrate was concentrated to give (B) as a viscous oil.
Reaction SMILES: [OH:1][CH:2]([C:5]1[CH:6]=[N:7][CH:8]=[CH:9][CH:10]=1)[C:3]#[CH:4].Br[C:12]1[CH:20]=[CH:19][CH:18]=[C:17]2[C:13]=1/[C:14](=[CH:22]/[C:23]1[NH:24][CH:25]=[CH:26][C:27]=1[O:28][CH3:29])/[C:15](=[O:21])[NH:16]2>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.CN(C=O)C.CCN(CC)CC>[OH:1][CH:2]([C:5]1[CH:6]=[N:7][CH:8]=[CH:9][CH:10]=1)[C:3]#[C:4][C:12]1[CH:20]=[CH:19][CH:18]=[C:17]2[C:13]=1/[C:14](=[CH:22]/[C:23]1[NH:24][CH:25]=[CH:26][C:27]=1[O:28][CH3:29])/[C:15](=[O:21])[NH:16]2
Reactant: COc1cc[nH]c1/C=C1\C(=O)Nc2cccc(Br)c21
Reactant: C#CC(O)c1cccnc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1cc[nH]c1/C=C1\C(=O)Nc2cccc(C#CC(O)c3cccnc3)c21

Procedure:
Using Method D above, 3-hydroxy-3-(3-pyridinyl)-1-propyne (150 mg, 1.13 mmol) (from Example 24 above) was coupled to (Z)-4-bromo-1,3-dihydro-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one (135 mg, 0.42 mmol) (Starting Material 1) using (Ph3P)2PdCl2 (32 mg) (Aldrich) and CuI (17 mg) (Aldrich) as catalyst in DMF (3 mL) and Et3N (3 mL) as solvent at 70° C. for 17 h, to yield rac-(Z)-1,3-dihydro-4-[3-hydroxy-3-(3-pyridinyl)-1-propynyl]-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one. (Yield 40 mg, 22%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH2:21][O:22][CH2:23][C:24]3[C:32]4[C:28](=[CH:29][N:30]([CH3:33])[N:31]=4)[CH:27]=[C:26]([C:34]([F:37])([F:36])[F:35])[CH:25]=3)[CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1>FC(F)(F)C(O)=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH2:21][O:22][CH2:23][C:24]3[C:32]4[C:28](=[CH:29][N:30]([CH3:33])[N:31]=4)[CH:27]=[C:26]([C:34]([F:35])([F:36])[F:37])[CH:25]=3)[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: Cn1cc2cc(C(F)(F)F)cc(COCC3(c4ccc(F)cc4)CCN(C(=O)OC(C)(C)C)CC3)c2n1
Solvent: O=C(O)C(F)(F)F
Product: Cn1cc2cc(C(F)(F)F)cc(COCC3(c4ccc(F)cc4)CCNCC3)c2n1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
tert-Butyl 4-(4-fluorophenyl)-4-(((2-methyl-5-(trifluoromethyl)-2H-indazol-7-yl)methoxy)methyl)piperidine-1-carboxylate (26 mg, 0.050 mmol) was dissolved in trifluoroacetic acid (25% in dichloromethane, 2 mL) and stirred at room temperature for 15 min. The reaction was concentrated, and loaded onto a strong cation exchange cartridge in methanol. The cartridge was flushed with several volumes of methanol which were discarded. The product was eluted with 2 M ammonia in methanol and concentrated to give 20.6 mg (98%) as a colorless film. 1H-NMR (CDCl3, 500 MHz) δ 7.98 (s, 1H), 7.86 (s, 1H), 7.35 (m, 2H), 7.23 (s, 1H), 7.00 (m, 2H), 4.82 (s, 2H), 4.21 (s, 3H), 3.54 (s, 2H), 2.90 (m, 2H), 2.74 (m, 2H), 2.14 (m, 2H), 1.60-2.05 (m, 3H); 13C-NMR (CDCl3, 126 MHz) δ 162.3, 160.3, 147.6, 140.2, 129.2, 128.9, 128.8, 125.6, 124.9 (q, J=272 Hz), 124.2 (q, J=32 Hz), 120.8, 118.8 (q, J=2.9 Hz), 117.6 (q, J=5.8 Hz), 115.0, 114.9, 79.9, 68.7, 42.7, 41.6, 40.7, 33.9. Mass spec.: 422.12 (MH)+. Accurate mass spec.: m/z 422.1836 [MH]+, Δ=4.6 ppm.
Reaction SMILES: [C:1]([C:4]12[CH2:11][CH2:10][C:7]([NH:12][CH2:13][C:14]([N:16]3[CH2:20][C@@H:19]([F:21])[CH2:18][C@H:17]3[C:22]#[N:23])=[O:15])([CH2:8][CH2:9]1)[CH2:6][CH2:5]2)([OH:3])=O.[CH2:24]([O:26][C:27](=[O:36])[CH2:28][S:29][C:30]1[S:31][C:32]([NH2:35])=[N:33][N:34]=1)[CH3:25]>>[CH2:24]([O:26][C:27]([CH2:28][S:29][C:30]1[S:31][C:32]([NH:35][C:1]([C:4]23[CH2:5][CH2:6][C:7]([NH:12][CH2:13][C:14]([N:16]4[CH2:20][C@@H:19]([F:21])[CH2:18][C@H:17]4[C:22]#[N:23])=[O:15])([CH2:10][CH2:11]2)[CH2:8][CH2:9]3)=[O:3])=[N:33][N:34]=1)=[O:36])[CH3:25]
Reactant: CCOC(=O)CSc1nnc(N)s1
Reactant: N#C[C@@H]1C[C@H](F)CN1C(=O)CNC12CCC(C(=O)O)(CC1)CC2
Product: CCOC(=O)CSc1nnc(NC(=O)C23CCC(NCC(=O)N4C[C@@H](F)C[C@H]4C#N)(CC2)CC3)s1
Yield: 20.2 %

Procedure:
In a similar manner to Example 87, (2S,4S)-1-[[N-(4-carboxybicyclo[2.2.2]oct-1-yl)amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (50.0 mg) and ethyl[(5-amino-1,3,4-thiadiazol-2-yl)thio]acetate (74.6 mg) were used to obtain (2S,4S)-1-[[N-[4-[N-(5-ethoxycarbonylmethylthio-1,3,4-thiadiazol-2-yl)amino]carbonylbicyclo[2.2.2]oct-1-yl]amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (16.4 mg).
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][N:12]1[C:20]([C:21]2[N:25]([CH3:26])[CH:24]=[C:23]([C:27]([OH:29])=O)[CH:22]=2)=[C:19]2[C:14]([N:15]([CH2:33][CH:34]([CH3:36])[CH3:35])[C:16](=[O:32])[N:17]([CH3:31])[C:18]2=[O:30])=[N:13]1.[CH:37]([NH2:40])([CH3:39])[CH3:38].C(P(=O)(OCC)OCC)#N>>[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][N:12]1[C:20]([C:21]2[N:25]([CH3:26])[CH:24]=[C:23]([C:27]([NH:40][CH:37]([CH3:39])[CH3:38])=[O:29])[CH:22]=2)=[C:19]2[C:14]([N:15]([CH2:33][CH:34]([CH3:36])[CH3:35])[C:16](=[O:32])[N:17]([CH3:31])[C:18]2=[O:30])=[N:13]1
Reactant: CC(C)N
Reactant: CC(C)Cn1c(=O)n(C)c(=O)c2c(-c3cc(C(=O)O)cn3C)n(Cc3c[nH]c4ccc(Cl)cc34)nc21
Agent: CCOP(=O)(C#N)OCC
Product: CC(C)Cn1c(=O)n(C)c(=O)c2c(-c3cc(C(=O)NC(C)C)cn3C)n(Cc3c[nH]c4ccc(Cl)cc34)nc21

Procedure:
This compound was synthesized by the reaction of 5-{2-[(5-chloro-1H-indol-3-yl)methyl]-7-isobutyl-5-methyl-4,6-dioxo-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-d]pyrimidin-3-yl}-1-methyl-1H-pyrrole-3-carboxylic acid and isopropylamine using diethyl cyanophosphonate as a coupling reagent. Mass: 550.14 (M+H).