Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH2:4][C:5]1[N:9]([CH:10]2[CH2:12][CH2:11]2)[C:8]2[CH:13]=[C:14]([N:18]3[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]3)[C:15]([F:17])=[CH:16][C:7]=2[N:6]=1)(=[O:3])[NH2:2].[C:31](N1C=CN=C1)(N1C=CN=C1)=[O:32].N12CCCN=C1CCCCC2>C1COCC1>[CH:10]1([N:9]2[C:8]3[CH:13]=[C:14]([N:18]4[CH2:19][CH2:20][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:22][CH2:23]4)[C:15]([F:17])=[CH:16][C:7]=3[N:6]3[C:31](=[O:32])[NH:2][C:1](=[O:3])[CH:4]=[C:5]23)[CH2:12][CH2:11]1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CC(C)(C)OC(=O)N1CCN(c2cc3c(cc2F)nc(CC(N)=O)n3C2CC2)CC1
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C)(C)OC(=O)N1CCN(c2cc3c(cc2F)n2c(=O)[nH]c(=O)cc2n3C2CC2)CC1
Yield: 85.7 %

Procedure:
tert-Butyl 4-[2-(carbamoylmethyl)-1-cyclopropyl-5-fluoro-6-benzimidazolyl]-1-piperazinecarboxylate (980 mg, 2.53 mmol) is suspended in THF (15 ml) and treated with 1,1'-carbonyldiimidazole (760 mg, 2 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (0.2 ml). The reaction mixture is heated to 60° for 2 hours, whereby white crystals separate. The suspension is then cooled to 0°. The crystals are filtered off and recrystallized from ethanol. There are obtained 760 mg (73%) of tert-butyl 4-[5-cyclopropyl-8-fluoro-1,2,3,5-tetrahydro-1,3-dioxopyrimido-[1,6-a]benzimidazol-7-yl]-1-piperazinecarboxylate.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][C:9](=[O:12])[CH2:8][CH2:7]1)=[O:5])[CH3:2].[CH2:13](O)[CH2:14][OH:15].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1.C(OCC)C>[CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][C:9]2([O:15][CH2:14][CH2:13][O:12]2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: OCCO
Reactant: CCOC(=O)C1CCC(=O)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: CCOC(=O)C1CCC2(CC1)OCCO2

Procedure:
A solution of 4-oxo-cyclohexanecarboxylic acid ethyl ester (5.0 g, 29.4 mmol), ethylene glycol (5.7 mL, 102 mmol) and p-toluenesulfonic acid (0.067 g, 0.35 mmol) in toluene (15 mL) was stirred at room temperature for 18 h. The resulting solution was diluted with ethyl ether (20 mL). The organic layer was washed successively with water and brine, separated and dried with sodium sulfate, filtered and concentrated to yield 1,4-dioxa-spiro[4.5]decane-8-carboxylic acid ethyl ester.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[C:5]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10](Br)[CH:9]=1)([CH3:7])[CH3:6])[CH3:2].C(N(CC)CC)C.[CH3:23][Si:24]([C:27]#[CH:28])([CH3:26])[CH3:25].C(OCC)(=O)C>CCCCCC.[Cu]I.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>[CH2:1]([O:3][C:4](=[O:15])[C:5]([CH3:7])([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:28]#[C:27][Si:24]([CH3:26])([CH3:25])[CH3:23])[CH:9]=1)[CH3:6])[CH3:2]
Reactant: C#C[Si](C)(C)C
Reactant: CCOC(=O)C(C)(C)c1cccc(Br)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCCCCC
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CCOC(=O)C(C)(C)c1cccc(C#C[Si](C)(C)C)c1
Yield: 90.3 %

Procedure:
Following General Procedure D and using 2-(3-bromo-phenyl)-2-methyl-propionic acid ethyl ester (Intermediate 130, 0.77 g, 2.84 mmol), triethyl amine (5 mL), copper(I)iodide (0.044 g, 0.23 mmol), trimethylsilyl acetylene (2 mL, 14.1 mmol) and dichlorobis(triphenylphosphine)palladium(II) (0.159 g, 0.23 mmol) followed by flash column chromatography over silica gel (230-400 mesh) using hexane to 5% ethyl acetate in hexane as the eluent, the title compound (0.74 g, 90%) was obtained as an orange oil.
Reaction SMILES: [Na][Na].[C:3]([C:5]([SH:10])=[C:6]([C:8]#[N:9])[SH:7])#[N:4].Br[CH:12]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:13]Br>>[C:8]([C:6]1[S:7][CH2:13][CH:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[S:10][C:5]=1[C:3]#[N:4])#[N:9]
Reactant: BrCC(Br)c1ccccc1
Reactant: N#CC(S)=C(S)C#N
Agent: [Na][Na]
Product: N#CC1=C(C#N)SC(c2ccccc2)CS1
Temperature: 40 °C

Procedure:
To a stirred suspension of 18.6 g of the disodium salt of 1,2-dicyano-1,2-dimercaptoethylene under nitrogen is added 26.4 g of 1,2-dibromo-1-phenylethane. After stirring at 40° C. for one-half hour, the mixture is heated under reflux for 1.5 hours, cooled, filtered, and the solvent removed under reduced pressure. The residue is crystallized by filtration with carbon tetrachloride to give the product, 2,3-dicyano-5,6-dihydro-5-phenyl-p-dithiin, as golden brown crystals, melting point 121.5° C. to 124° C. A purified sample had melting point 125° C. to 126.5° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([NH:8][S:9]([C:12]2[S:16][C:15]3[CH:17]=[CH:18][C:19]([F:21])=[CH:20][C:14]=3[C:13]=2[CH3:22])(=[O:11])=[O:10])=[C:4]([O:23][C:24]([F:27])([F:26])[F:25])[CH:3]=1.[N:28]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=1>COCCOC.C(O)C.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>[N:28]1[CH:33]=[CH:32][C:31]([C:2]2[CH:7]=[CH:6][C:5]([NH:8][S:9]([C:12]3[S:16][C:15]4[CH:17]=[CH:18][C:19]([F:21])=[CH:20][C:14]=4[C:13]=3[CH3:22])(=[O:10])=[O:11])=[C:4]([O:23][C:24]([F:27])([F:26])[F:25])[CH:3]=2)=[CH:30][CH:29]=1
Reactant: OB(O)c1ccncc1
Reactant: Cc1c(S(=O)(=O)Nc2ccc(Br)cc2OC(F)(F)F)sc2ccc(F)cc12
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: COCCOC
Solvent: CCO
Product: Cc1c(S(=O)(=O)Nc2ccc(-c3ccncc3)cc2OC(F)(F)F)sc2ccc(F)cc12
Yield: 73.6 %

Procedure:
This compound was prepared in analogy to example 2 starting from 5-fluoro-3-methyl-benzo[b]thiophene-2-sulfonic acid(4-bromo-2-trifluoromethoxy-phenyl)-amide (0.075 g) and 4-pyridineboronic acid (0.029 g) in 1,2-dimethoxyethane (1.5 ml), ethanol (0.25 ml) and 2 M aqueous sodium carbonate solution (0.6 ml) with tetrakis(triphenylphosphine)palladium (0.009 g) to obtain the title compound (0.055 g) as a colorless solid. MS (ISP): 483.0 (M+H)+
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][N:6]=[C:5]([N:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][CH2:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:16])[CH2:11][CH2:10]2)[CH:4]=1)#[N:2].[C:23](O)(=O)[CH3:24].[NH2:27][NH2:28].C(=O)([O-])[O-].[K+].[K+]>C(O)C.C(OCC)(=O)C>[CH3:24][C:23]1[NH:28][N:27]=[C:1]([C:3]2[CH:8]=[CH:7][N:6]=[C:5]([N:9]3[CH2:10][CH2:11][N:12]([C:15]([O:17][CH2:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:16])[CH2:13][CH2:14]3)[CH:4]=2)[N:2]=1
Reactant: CC(=O)O
Reactant: NN
Reactant: CC(C)(C)COC(=O)N1CCN(c2cc(C#N)ccn2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: CCOC(C)=O
Product: Cc1nc(-c2ccnc(N3CCN(C(=O)OCC(C)(C)C)CC3)c2)n[nH]1
Yield: 4.5 %

Procedure:
2,2-Dimethylpropyl 4-(4-cyanopyridin-2-yl)piperazine-1-carboxylate (143 mg) obtained in Example 2 was dissolved in ethanol (5 mL), and hydrazine acetate (140 mg) and potassium carbonate (328 mg) were added thereto and heated under reflux for 5 hours, then the reaction liquid was evaporated. Acetic anhydride (3 mL) was added to the resulting residue, and heated under reflux for 2 hours, then the reaction liquid was diluted with ethyl acetate, washed with water and saturated saline water, and dried with anhydrous sodium sulfate. The solvent was evaporated away, and the resulting residue was isolated and purified through thin-layer silica gel chromatography (chloroform/methanol=9/1) to obtain 7.6 mg of the entitled compound as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][O:16][C:17]3[CH:18]=[C:19]4[C:24](=[CH:25][CH:26]=3)[CH:23]=[C:22]([C:27](O)=[O:28])[CH:21]=[CH:20]4)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[NH2:30][C:31]([NH2:33])=[NH:32]>>[ClH:1].[ClH:1].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][O:16][C:17]3[CH:18]=[C:19]4[C:24](=[CH:25][CH:26]=3)[CH:23]=[C:22]([C:27]([NH:32][C:31]([NH2:33])=[NH:30])=[O:28])[CH:21]=[CH:20]4)[CH2:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: O=C(O)c1ccc2cc(OCCN3CCN(c4ccc(Cl)cc4)CC3)ccc2c1
Reactant: N=C(N)N
Product: Cl
Product: N=C(N)NC(=O)c1ccc2cc(OCCN3CCN(c4ccc(Cl)cc4)CC3)ccc2c1

Procedure:
2.4 g of 6-{2-[4-(4-chlorophenyl)-1-piperazinyl]-ethoxy}-2-naphthoic acid are reacted with CDl and guanidine according to the general procedure (variant 1 a). 1.4 g of 6-{2-[4-(4-chlorophenyl)-1-piperazinyl]-ethoxy}-2-naphthoylguanidine dihydrochloride are obtained; m.p.: 269-271° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=2)[CH:7]=[CH:8][CH:9]=1)([O-])=O.[H][H]>[Pd].C(O)C>[N:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[C:6]1[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=1)[NH2:1]
Reactant: O=[N+]([O-])c1cccc(-c2ccccn2)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: Nc1cccc(-c2ccccn2)c1
Yield: 87.9 %

Procedure:
To a solution of 2-(3-nitrophenyl)pyridine (prepared as described in J. Chem. Soc. 1958 p. 1759) (12.7g, 63.5mmol) in abs. ethanol is added palladium catalyst (1.3g 5% Pd on activated carbon) and the mixture is hydrogenated at ambient pressure until the hydrogen uptake has ceased. The mixture is filtered through celite and the filtrate is concentrated under reduced pressure. The residue is purified by column-chromatography on silica gel using a mixture of ethyl acetate and petroleum ether (9:1)as the eluent to afford 2f (9.5g, 88%) as a light brown oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:43])[CH2:9][CH2:10][CH:11]([C:29](N2C(C3C=CC=CC=3)COC2=O)=[O:30])[CH:12]([C:21]2[CH:28]=[CH:27][C:24](C#N)=[CH:23][CH:22]=2)[NH:13][C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)=[CH:4][CH:3]=1.O.O.O.[F-].[CH2:48]([N+:52](CCCC)(CCCC)CCCC)CCC.C[Si](C([Si](C)(C)C)C(N)=O)(C)C.C(O)(=O)C>COC(C)(C)C>[F:20][C:17]1[CH:18]=[CH:19][C:14]([N:13]2[C:29](=[O:30])[CH:11]([CH2:10][CH2:9][CH:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)[OH:43])[CH:12]2[C:21]2[CH:28]=[CH:27][CH:24]=[CH:23][C:22]=2[C:48]#[N:52])=[CH:15][CH:16]=1
Reactant: CCCC[N+](CCCC)(CCCC)CCCC
Reactant: N#Cc1ccc(C(Nc2ccc(F)cc2)C(CCC(O)c2ccc(F)cc2)C(=O)N2C(=O)OCC2c2ccccc2)cc1
Agent: C[Si](C)(C)C(C(N)=O)[Si](C)(C)C
Agent: [F-]
Solvent: CC(=O)O
Solvent: COC(C)(C)C
Solvent: O
Product: N#Cc1ccccc1C1C(CCC(O)c2ccc(F)cc2)C(=O)N1c1ccc(F)cc1
Temperature: 40 °C
Reaction time: 0.5 h

Procedure:
2 g of 4-[5-(4-Fluorophenyl)-1-(4-fluorophenylamino)-5-hydroxy-2-(2-oxo-4-phenyl-oxazolidine-3-carbonyl)-pentyl]-benzonitrile were dissolved in 20 ml of methyl-tert-butyl ether and, together with 100 mg of tetrabutylammonium fluoride trihydrate and 1.3 ml of bistrimethylsilyl acetamide, heated at 40° C. for about 1 h. The reaction was monitored by thin-layer chromatography. After the reaction ended, 0.2 ml of glacial acetic acid were initially added and the mixture was stirred for 30 min and then concentrated. 20 ml of a mixture of isopropanol/2N sulfuric acid=10:1 were added to the residue, and the mixture was stirred for 1 hour. Following addition of a spatula tip of solid sodium bicarbonate, the mixture was again concentrated under reduced pressure. The residue was taken up in ethyl acetate and the organic phase was washed with water and dried. The residue was, after removal of the solvent, purified by column chromatography (SiO2, CH2Cl2/methanol=100:1). This gave the product of molecular weight 418.45 (C25H20F2N2O2); MS (DCI+): 419 (M+H+).
Reaction SMILES: Cl.[CH3:2][C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][C:4]=1[CH2:12][NH:13][CH3:14].C(N(CC)CC)C.[C:22](Cl)(=[O:25])[CH:23]=[CH2:24].O>C(Cl)Cl>[CH3:14][N:13]([CH2:12][C:4]1[CH2:5][C:6]2[C:11]([C:3]=1[CH3:2])=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:22](=[O:25])[CH:23]=[CH2:24]
Reactant: C=CC(=O)Cl
Reactant: CNCC1=C(C)c2ccccc2C1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: C=CC(=O)N(C)CC1=C(C)c2ccccc2C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 101.3 %

Procedure:
To a solution of 3-methyl-2-(methylaminomethyl)indene hydrochloride (0.132 g, 0.63 mmole), from Preparation 19, and triethylamine (0.19 g, 1.89 mmole) in CH2Cl2 (6 mL) at 0° C. was added a solution of acryloyl chloride (0.06 mL, 0. 7 mmole) in CH2Cl2 (2 mL). The reaction was stirred at 0° C. for 1 hr, then was poured into water. The layers were separated, and the organic layer was washed with brine, dried over MgSO4 and concentrated in vacuo to yield the title compound (0.145 g, quantitative) as an oily solid: MS (ES) m/e 228.2 (M+H)+.
Reaction SMILES: C(O[CH:5]1[NH:8][C:7](=[O:9])[C@H:6]1[NH:10][C:11](=[O:20])[CH2:12][O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)(=O)C.C1C=CC([Se])=CC=1>C(Cl)Cl.B(F)(F)F.CCOCC.C(OCC)(=O)C>[O:13]([CH2:12][C:11]([NH:10][C@H:6]1[CH2:5][NH:8][C:7]1=[O:9])=[O:20])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CC(=O)OC1NC(=O)[C@H]1NC(=O)COc1ccccc1
Agent: FB(F)F
Agent: [Se]c1ccccc1
Solvent: CCOC(C)=O
Solvent: CCOCC
Solvent: ClCCl
Product: O=C(COc1ccccc1)N[C@H]1CNC1=O

Procedure:
Under a nitrogen atmosphere, 4-(R,S)-acetoxy-3-(S)-(phenoxyacetamido)azetidinone (1.32 g, 4.74 mmol) was dissolved in methylene chloride (9 ml). To this solution was added phenylselenol (1.5 ml, approximately 9.8 mmol), then boron trifluoride-etherate (10 drops). The resultant solution was stirred at room temperature for 20 minutes. The solution was diluted with ethyl acetate and extracted with saturated aqueous sodium bicarbonate solution (2×). The solution was dried over magnesium sulfate, filtered and concentrated in vacuo. The concentrate was absorbed onto silica gel (7 g) and then chromatographed over an additional amount of silica gel (15 g) using a gradient elution of toluene to ethyl acetate. The product-containing fractions gave 4-(R,S)-phenylselenyl)-3-(S)-(phenoxyacetamido)azetidinone.
Reaction SMILES: [CH:1]1[CH2:5][CH:4]=[CH:3][CH:2]=1.C([Li])CCC.[CH2:11]([C:18]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=O)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[Cl-].[NH4+]>O1CCCC1.CCOCC.CCCCCC>[CH2:20]([C:18]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[C:2]1[CH:1]=[CH:5][CH:4]=[CH:3]1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: C1=CCC=C1
Reactant: O=C(Cc1ccccc1)Cc1ccccc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: C1=CC(=C(Cc2ccccc2)Cc2ccccc2)C=C1
Temperature: 25 °C

Procedure:
Into a 100 ml Kjeldahl flask purged thoroughly with nitrogen, equipped with a dropping funnel and a magnetic stirrer, were introduced cyclopentadiene 2.40 g (36.2 mmol) which had been subjected to cracking, and dehydrated tetrahydrofuran 50 ml. With cooling in an ice bath, 1.57 mol/L n-hexane solution of n-butyllithium, 24.3 ml (38.1 mmol), was dropwise added to the solution by means of the dropping funnel. The resulting slurry was stirred all night at room temperature. With the flask cooled in an ice bath, a solution of dibenzyl ketone 9.16 g (43.6 mmol) in 20 ml of dehydrated tetrahydrofuran, was dropwise added into the flask by means of the dropping funnel. The resulting slurry was stirred all night at room temperature. After addition of a saturated aqueous solution of ammonium chloride 50 ml and ether 50 ml, the organic phase was recovered with a separatory funnel. The water phase was extracted with ether 30 ml. The organic phase was washed twice with water 50 ml and once with a saturated salt solution 50 ml, and dried over magnesium sulfate. The solution was filtered to remove the magnesium sulfate, and the solvent of the filtrate was distilled away to obtain a solid. The residue was subjected to column chromatography to obtain an objective brown oil in 1.10 g (12%) yield. The 1H NMR spectrum and the FD-MS spectrum as measured with respect to the brown oil are given below:
Reaction SMILES: C1(C(C2C=CC=CC=2)[N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]3([C:20]4[CH:21]=[C:22]([CH3:26])[C:23]([CH3:25])=[CH:24][C:19]=4[O:18][CH2:17]3)[C:9]2=[O:27])C=CC=CC=1.C1(C(C2C=CC=CC=2)N2C3C(=CC=CC=3)C3(C4C=C(C)C(OC)=CC=4OC3)C2=O)C=CC=CC=1>>[CH3:26][C:22]1[C:23]([CH3:25])=[CH:24][C:19]2[O:18][CH2:17][C:10]3([C:11]4[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=4)[NH:8][C:9]3=[O:27])[C:20]=2[CH:21]=1
Reactant: Cc1cc2c(cc1C)C1(CO2)C(=O)N(C(c2ccccc2)c2ccccc2)c2ccccc21
Agent: COc1cc2c(cc1C)C1(CO2)C(=O)N(C(c2ccccc2)c2ccccc2)c2ccccc21
Product: Cc1cc2c(cc1C)C1(CO2)C(=O)Nc2ccccc21

Procedure:
Following the procedure as described in EXAMPLE 3 and making non-critical variations using 1′-(diphenylmethyl)-5,6-dimethylspiro[1-benzofuran-3,3′-indol]-2′(1′H)-one to replace 1′-(diphenylmethyl)-6-methoxy-5-methylspiro[1-benzofuran-3,3′-indol]-2′(1′H)-one, 5,6-dimethylspiro[1-benzofuran-3,3′-indol]-2′(1′H)-one was obtained (88%) as a colorless solid: mp 206-207° C. (ethyl acetate/hexanes); 1H NMR (300 MHz, DMSO-d6) δ10.5 (s, 1H), 7.23-7.18 (m, 1H), 7.03-7.01 (m, 1H), 6.94-6.88 (m, 2H), 6.73 (s, 1H), 6.43 (s, 1H), 4.68 (ABq, 2H), 2.13 (s, 3H), 1.99 (s, 3H); 13C NMR (75 MHz, DMSO-d6) δ178.9, 159.1, 142.2, 138.0, 133.3, 129.1, 127.0, 124.2, 124.1, 122.7, 111.2, 110.2, 79.5, 58.2, 20.2, 19.1; MS (ES+) m/z 266.3 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][N:8]=[C:7]([O:10][CH2:11][CH:12]([NH:19]C(OC(C)(C)C)=O)[CH2:13][O:14][C:15](=[S:18])[NH:16][CH3:17])[C:6]=2[CH:27]=1.O1CCOCC1.Cl.CC(O)C>CO>[ClH:1].[NH2:19][CH:12]([CH2:13][O:14][C:15](=[S:18])[NH:16][CH3:17])[CH2:11][O:10][C:7]1[C:6]2[CH:27]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=2[O:9][N:8]=1
Reactant: CNC(=S)OCC(COc1noc2ccc(Cl)cc12)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Solvent: CC(C)O
Product: CNC(=S)OCC(N)COc1noc2ccc(Cl)cc12

Procedure:
To a solution of 0.4 g of 5-chloro-3-(2-tert-butoxycarbonylamino-3-methylthiocarbamoyloxypropoxy)-1,2-benzoisoxazole in 10 ml of methanol is added 5 ml of a dioxane solution (3.2N) of hydrogen chloride at room temperature, and they are subjected to reaction at the same temperature for three hours, after which the solvent is removed by distillation under reduced pressure. To the residue obtained is added 3 ml of 2-propanol, and the crystals precipitated are collected by filtration, to obtain 0.22 g of pale yellow, crystalline 3-(2-amino-3-methylthiocarbamoyloxypropoxy)-5-chloro-1,2-benzoisoxazole hydrochloride having a melting point of 198.8°-199.2° C. (decomp.).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8]C#C[Si](C)(C)C)=[CH:4][CH:3]=1.[CH2:15](N(CC)CC)[CH3:16].Br[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[O:29][C:30]([F:33])([F:32])[F:31].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1.[Cu]I>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH2:8])=[C:6]([C:15]#[C:16][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[O:29][C:30]([F:33])([F:32])[F:31])[CH:7]=1
Reactant: FC(F)(F)Oc1ccccc1Br
Reactant: C[Si](C)(C)C#CNc1ccc(Cl)cc1
Reactant: CCN(CC)CC
Agent: [Cu]I
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: Nc1ccc(Cl)cc1C#Cc1ccccc1OC(F)(F)F
Temperature: 70 °C
Reaction time: 1 h
Yield: 50.3 %

Procedure:
To a solution of 4-chloro-2-trimethylsilanylethynyl-phenylamine (300 mg, 1.34 mmol) in THF (10 ml) was added triethylamine (0.6 ml, 4.02 mmol), and 1-bromo-2-trifluoromethoxy-benzene (0.3 ml, 2.01 mmol). The mixture was purged with argon for 10 min and then PdCl2 (PPh3)2 (47 mg, 0.07 mmol) was added followed by CuI (7.7 mg, 0.04 mmol). The reaction mixture was then heated to 70° C. TBAF (1M solution in THF) (1.54 ml, 1.54 mmol) was added and the reaction mixture was stirred for 1 h at 70° C. After cooling, the mixture was filtered through celite bed, washed with ethyl acetate. The filtrate was concentrated in vacuo and the residue was purified by flash column chromatography (2-3% ethyl acetate in hexane) to obtain 4-chloro-2-(2-trifluoromethoxy-phenylethynyl)-phenylamine (210 mg, 50% yield) as a brown solid. GC-MS: 311 (M).
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[C@@H:5]([C:6]([N:8]2[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)=[O:7])[CH2:4][C@H:3]1[NH:14]C(=O)OC(C)(C)C.CCN(CC)CC>C(O)(C(F)(F)F)=O.C(Cl)Cl>[NH2:14][C@@H:3]1[CH2:4][C@H:5]([C:6]([N:8]2[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)=[O:7])[C:2]1([CH3:22])[CH3:1]
Reactant: CC(C)(C)OC(=O)N[C@@H]1C[C@H](C(=O)N2CCCCC2)C1(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1(C)[C@H](N)C[C@@H]1C(=O)N1CCCCC1
Yield: 100 %

Procedure:
A solution of tert-butyl (1R,3S)-2,2-dimethyl-3-(piperidine-1-carbonyl)cyclobutylcarbamate (step 1, 0.500 g, 1.612 mmol) in TFA:DCM (1:2) (3 ml) stirred at 0° C.-room temperature for about 1 hour. After completion of the reaction (monitored by TLC), the solvent was evaporated and the crude was dissolved in DCM and basified with Et3N (1.34 ml, 9.677 mmol) then the resulting solution as such used for the next reaction. Wt: 0.338 g (Based on 100% yield calculated and proceeded for next reaction).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([NH:10][C@H:11]([C:13]2[N:17]([CH3:18])[C:16]3[C:19](Br)=[C:20]([F:23])[CH:21]=[CH:22][C:15]=3[N:14]=2)[CH3:12])[N:5]=[CH:4][N:3]=1.[N:25]1[CH:30]=[CH:29][CH:28]=[C:27](B(O)O)[CH:26]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.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>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([NH:10][C@H:11]([C:13]2[N:17]([CH3:18])[C:16]3[C:19]([C:27]4[CH:26]=[N:25][CH:30]=[CH:29][CH:28]=4)=[C:20]([F:23])[CH:21]=[CH:22][C:15]=3[N:14]=2)[CH3:12])[N:5]=[CH:4][N:3]=1
Reactant: OB(O)c1cccnc1
Reactant: C[C@H](Nc1ncnc(N)c1C#N)c1nc2ccc(F)c(Br)c2n1C
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: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: C[C@H](Nc1ncnc(N)c1C#N)c1nc2ccc(F)c(-c3cccnc3)c2n1C
Temperature: 140 °C
Yield: 65.4 %

Procedure:
A mixture of 4-amino-6-[(S)-1-(7-bromo-6-fluoro-1-methyl-1H-benzoimidazol-2-yl)ethylamino]-pyrimidine-5-carbonitrile, (0.10 g, 0.26 mmol), 3-pyridylboronic acid (0.041 g, 0.33 mmol), tetrakis(triphenylphosphine)palladium(0) (0.015 g, 0.013 mmol) and caesium carbonate (0.17 g, 0.51 mmol) in dioxane (3 mL) and water (1.5 mL) was placed in a sealed tube and degassed with nitrogen for 5 min, then heated for 30 minutes at 140° C. by microwave irradiation. The resulting mixture was loaded onto an Isolute® SCX-2 cartridge then washed with MeOH and the product eluted with 2M NH3/MeOH and concentrated in vacuo. The resulting residue was purified by chromatography (SiO2, 0-10% (2M ammonia in methanol) in DCM) then by preparative HPLC (Phenomenex Gemini 5 μm C18 on a 78 min gradient 20-98% 0.1% HCO2H in acetonitrile/water) to give 425 as a white solid (0.066 g, 66%). LCMS (Method K): RT 2.50 min [M+H]+ 389.1. 1H NMR (DMSO-d6, 400 MHz): δ 8.72-8.64 (2H, m), 8.22-8.03 (1H, m), 7.97-7.90 (1H, m), 7.75-7.65 (2H, m), 7.57-7.53 (1H, m), 7.30 (2H, s), 7.21-7.17 (1H, m), 5.63 (1H, m), 3.19-3.17 (3H, m), 1.58 (3H, d, J=6.72 Hz)
Reaction SMILES: [C:1]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:24]=[C:23]3[C:19]([CH2:20][N:21]([C@@H:26]([CH:31]([CH3:33])[CH3:32])[C:27]([O:29][CH3:30])=[O:28])[C:22]3=[O:25])=[CH:18][CH:17]=2)=[CH:12][CH:11]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N[C:35]1C=CC(C2C=C3C(CN([C@@H](C(C)C)C(OC)=O)C3=O)=CC=2)=CC=1.CC1C=CC(C(Cl)=O)=CC=1.FC1C=C(F)C=CC=1C(NC1C=CC(C2C=C3C(CN([C@@H](C(C)C)C(O)=O)C3=O)=CC=2)=CC=1)=O>>[CH3:32][CH:31]([CH3:33])[C@H:26]([N:21]1[CH2:20][C:19]2[C:23](=[CH:24][C:16]([C:13]3[CH:12]=[CH:11][C:10]([NH:9][C:1](=[O:8])[C:2]4[CH:3]=[CH:4][C:5]([CH3:35])=[CH:6][CH:7]=4)=[CH:15][CH:14]=3)=[CH:17][CH:18]=2)[C:22]1=[O:25])[C:27]([O:29][CH3:30])=[O:28]
Reactant: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(N)cc3)cc2C1=O
Reactant: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)c4ccccc4)cc3)cc2C1=O
Agent: CC(C)[C@@H](C(=O)O)N1Cc2ccc(-c3ccc(NC(=O)c4ccc(F)cc4F)cc3)cc2C1=O
Agent: Cc1ccc(C(=O)Cl)cc1
Product: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)c4ccc(C)cc4)cc3)cc2C1=O

Procedure:
The compound of example 111 was prepared analogous to compound of example 97 by reaction of compound of example 6 with 4-methylbenzoyl chloride. The compound of example 111 was used directly without isolation for the preparation of compound of example 110.