Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH:2]([C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=1)[CH3:3].O[C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=1)[C:18]#[N:19].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(OC(N=NC(OC(C)C)=O)=O)(C)C>O1CCCC1.O>[C:18]([C:17]1[CH:20]=[CH:21][C:22]([O:1][CH:2]([C:4]2[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=2)[CH3:3])=[CH:15][CH:16]=1)#[N:19]
Reactant: N#Cc1cccc(O)c1
Reactant: COC(=O)c1ccc(C(C)O)cc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1ccc(C(C)Oc2ccc(C#N)cc2)cc1
Yield: 43.8 %

Procedure:
Methyl 4-(1-hydroxyethyl)benzoate (540 mg, 3 mmol), 3-hydroxybenzonitrile (360 mg, 3 mmol), triphenylphosphine (1.04 mg, 4 mmol), azodicarboxylic acid diisopropyl ester (800 mg, 4 mmol) in tetrahydrofuran (130 mL) were stirred at 20° C. for 12 hours. Water was added and the mixture was extracted with ethyl acetate (150 mL×3), the combined organic phase was dried by sodium sulfate, then filtered. The filtrate was evaporated in vacuum and the residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate=3:1) to give methyl 4-(1-(4-cyanophenoxy)ethyl)benzoate (370 mg, 45%) as colorless oil. LRMS (M+H+) m/z: calcd 281.11. found 281.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]1[CH2:17][C@H:16](OS(C)(=O)=O)[CH2:15][CH2:14][C@@H:13]1[C:23]([O:25][CH3:26])=[O:24])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N-:27]=[N+:28]=[N-:29].[Na+].C([O-])(O)=O.[Na+].O>CN(C)C=O>[N:27]([C@H:16]1[CH2:15][CH2:14][C@H:13]([C:23]([O:25][CH3:26])=[O:24])[C@H:12]([NH:11][C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:10])[CH2:17]1)=[N+:28]=[N-:29]
Reactant: COC(=O)[C@H]1CC[C@@H](OS(C)(=O)=O)C[C@H]1NC(=O)OCc1ccccc1
Reactant: [N-]=[N+]=[N-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)[C@H]1CC[C@H](N=[N+]=[N-])C[C@H]1NC(=O)OCc1ccccc1
Temperature: 80 °C
Reaction time: 2.5 h
Yield: 72.1 %

Procedure:
To a solution of methyl (1S,2R,4R)-2-{[(benzyloxy)carbonyl]amino}-4-[(methylsulfonyl)oxy]cyclohexanecarboxylate (0.30 g, 0.78 mmol) in N,N-dimethylformamide (2.6 mL) was added sodium azide (0.20 g, 3.1 mmol). The reaction was heated to 80° C. and stirred for 2.5 h. After cooling, the reaction mixture was poured into sat. NaHCO3/water and extracted with EtOAc (3 x). The combined extracts were washed with brine, dried (Na2SO4), and concentrated. The crude was purified on silica gel, eluting with 0-40% EtOAc in hexanes to give 187 mg (72%) of the desired product as a clear gum. LCMS calculated for C16H21N2O4 (M+H-28)+: m/z=305.2. Found: 305.1.
Reaction SMILES: [NH:1]1[C:5](=O)[CH2:4][C:3]2([CH2:18][CH2:17][N:9]3[C:10]4[C:15]([CH:16]=[C:8]3[CH2:7]2)=[CH:14][CH:13]=[CH:12][CH:11]=4)[C:2]1=O.[H-].[Al+3].[Li+].[H-].[H-].[H-].O>C1COCC1>[NH:1]1[CH2:5][CH2:4][C:3]2([CH2:18][CH2:17][N:9]3[C:10]4[C:15]([CH:16]=[C:8]3[CH2:7]2)=[CH:14][CH:13]=[CH:12][CH:11]=4)[CH2:2]1
Reactant: O=C1CC2(CCn3c(cc4ccccc43)C2)C(=O)N1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: c1ccc2c(c1)cc1n2CCC2(CCNC2)C1
Yield: 69.7 %

Procedure:
A solution of 100 mg of 7,9-dihydrospiro[pyrido[1,2-a]indole-8(6H),3'-pyrrolidine]-2',5'-dione in 10 ml of THF was added dropwise to a suspension of 152 mg of lithium aluminium hydride in 20 ml of THF. After completion of the addition the mixture was heated at reflux for 20 hours. 20 ml of water were added to the cooled mixture and the resulting mixture was extracted with diethyl ether. The etheral extracts were washed with water, dried and concentrated. There were obtained 62 mg of 7,9-dihydrospiro[pyrido[1,2-a]indole-8(6H),3'-pyrrolidine].
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]([C:12]1[CH:13]=[C:14](/[CH:29]=[CH:30]/[CH3:31])[C:15]([O:18][C:19]2[CH:20]=[C:21]([CH:26]=[CH:27][CH:28]=2)[C:22](OC)=[O:23])=[N:16][CH:17]=1)([O:8][CH2:9][O:10][CH3:11])[C:4]([F:7])([F:6])[F:5].[H-].[Al+3].[Li+].[H-].[H-].[H-].CO.O>O1CCCC1>[F:33][C:2]([F:1])([F:32])[C:3]([C:12]1[CH:13]=[C:14](/[CH:29]=[CH:30]/[CH3:31])[C:15]([O:18][C:19]2[CH:20]=[C:21]([CH2:22][OH:23])[CH:26]=[CH:27][CH:28]=2)=[N:16][CH:17]=1)([O:8][CH2:9][O:10][CH3:11])[C:4]([F:7])([F:6])[F:5]
Reactant: C/C=C/c1cc(C(OCOC)(C(F)(F)F)C(F)(F)F)cnc1Oc1cccc(C(=O)OC)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: C/C=C/c1cc(C(OCOC)(C(F)(F)F)C(F)(F)F)cnc1Oc1cccc(CO)c1
Yield: 95 %

Procedure:
To a solution of methyl (E)-3-(5-(1,1,1,3,3,3-hexafluoro-2-(methoxymethoxy)propan-2-yl)-3-(prop-1-enyl)pyridin-2-yloxy)benzoate (81 mg, 0.168 mmol) in tetrahydrofuran (2 mL), lithium aluminum hydride (9.6 mg, 0.252 mmol) was added under ice-cold conditions, and the resultant mixture was stirred at room temperature for 3 hours. The reaction solution was added with methanol and water, filtered using celite, and extracted with ethyl acetate. The organic layer was washed with brine, dried using anhydrous sodium sulfate, and concentrated in vacuo. The obtained residue was purified using silica-gel column chromatography (ethyl acetate), and the title compound (72 mg, yield 94.9%) was obtained as a yellow oil.
Reaction SMILES: C(NC(C)C)(C)C.[Li].[O:9]1[CH:13]=[CH:12][C:11]([C:14]([OH:16])=[O:15])=[CH:10]1.C([Si](C(C)C)(C(C)C)[O:21][CH2:22][C:23](=O)[CH2:24]O[Si](C(C)C)(C(C)C)C(C)C)(C)C.C(OC(=O)C)C>O1CCCC1>[OH:21][CH2:22][C:23]1[C:10]2[O:9][CH:13]=[CH:12][C:11]=2[C:14](=[O:16])[O:15][CH:24]=1
Reactant: O=C(O)c1ccoc1
Reactant: CC(C)[Si](OCC(=O)CO[Si](C(C)C)(C(C)C)C(C)C)(C(C)C)C(C)C
Agent: [Li]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CC(C)NC(C)C
Product: O=c1occ(CO)c2occc12
Temperature: -78 °C
Reaction time: 1 h
Yield: 42 %

Procedure:
Add lithium diisopropylamine (0.454 mole) as a solution in tetrahydrofuran (100) mL to a solution of 3-furoic acid (23.36 g, 0.208 mole) at −78° C. over 30 minutes and stir for 1 hour at −78° C. To the resulting di-anion add 1,3-Bis-triisopropylsilanyloxy-propan-2-one as a solution in tetrahydrofuran (250 mL) over 30 minutes and stir at −78° C. for 1 hour and allow to warm to room temperature overnight. Quench the reaction with saturated aqueous ammonium chloride, pour into ethylacetate (1 L), add 1N HCL (1 L) and separate the two layers. Wash the organic layer with 1N HCl, water, and brine, dry over magnesium sulfate, filter and concentrate to an oil. Dissolve the crude oil in 50% tetrahydrofuran and 50% 3N HCl (1 L) and heat a reflux over night Distill off tetrahydrofuran, concentrate under reduced pressure and, add acetonitrile remove it under reduced pressure to azeotrope off the remaining water. Dissolve the resulting crude oil in acetonitrile (250 mL) and add the solution to a solution of toluene containing a catalytic amount of p-toluenesulfonic acid at reflux that is fitted with a Dean Stark trap over 30 minutes. Toluene was added to replace the acetonitrile and water removed by distillation and azetroping (500 mL). Heat the solution at reflux until it appears no further water is being removed. The hot solution was poured into an erlenmeyer flask and allowed to cool. Triturate the brown remaining residue with ethylacetate and methanol and combine it with the toluene solution and concentrate. Dilute with ethylacetate and wash with saturated aqueous sodium bicarbonate and brine, dry over magnesium sulfate and concentrate to an off white solid. Purification by flash chromatography eluting with hexane:ethylacetate gives 13.27 g (42%) of the title compound as a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[CH2:5][NH:6][C:7]1[C:12]([NH2:13])=[CH:11][CH:10]=[CH:9][N:8]=1)[CH3:2].C(OC(=O)CNC1C([N+]([O-])=O)=CC=CN=1)C.C(N(CC)CC)C.[Br:38][C:39]1[CH:47]=[CH:46][C:42]([C:43](Cl)=[O:44])=[CH:41][CH:40]=1>O1CCCC1.[Pd].C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:14])[CH2:5][NH:6][C:7]1[C:12]([NH:13][C:43](=[O:44])[C:42]2[CH:46]=[CH:47][C:39]([Br:38])=[CH:40][CH:41]=2)=[CH:11][CH:10]=[CH:9][N:8]=1)[CH3:2]
Reactant: CCOC(=O)CNc1ncccc1N
Reactant: O=C(Cl)c1ccc(Br)cc1
Agent: [Pd]
Agent: CCOC(=O)CNc1ncccc1[N+](=O)[O-]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)CNc1ncccc1NC(=O)c1ccc(Br)cc1
Yield: 80 %

Procedure:
To a stirred and chilled (10°-20° C.) solution of N-(3-amino-2-pyridinyl)glycine ethyl ester (14.7 g, 0.075 mole) [freshly prepared by the hydrogenation of a solution of N-(3-nitro-2-pyridinyl) glycine ethyl ester in tetrahydrofuran over 5% palladium on carbon at room temperature], triethylamine 8.1 g, 0.080 mole), and tetrahydrofuran (150 ml) was added (rapid drop) 4-bromobenzoyl chloride (6.9 g, 0.077 mole), followed by 100 ml of methylene chloride. The reaction mixture was stirred at room temperature for 2 hr and was filtered. The filtrate was concentrated in vacuo and the residue combined with the filter cake. The combined mixture was twice suspended in water and filtered. The filter cake was recrystallized from ethanol, giving 22.7 g of crystals (80%). Recrystallization of a 1.6-g samples from ethanol gave 1.5 g of white flocculent solid, mp 153°-154° C.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[F:11][C:12]1([CH:15]([OH:27])[CH2:16][C:17]([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)([CH3:19])[CH3:18])[CH2:14][CH2:13]1.C(N(CC)CC)C>ClCCl>[F:11][C:12]1([C:15](=[O:27])[CH2:16][C:17]([C:20]2[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=2)([CH3:19])[CH3:18])[CH2:13][CH2:14]1
Reactant: CC(C)(CC(O)C1(F)CC1)c1ccc(F)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(CC(=O)C1(F)CC1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 51.8 %

Procedure:
2.2 mL of a 2 M solution of oxalyl chloride in dichloromethane was diluted with 2.5 mL of dichloromethane and cooled on dry ice/acetone bath. To this solution was added a dropwise a solution of 0.7 mL of DMSO in 2.5 mL of dichloromethane. After 10 minutes, a solution of the above crude 1-(1-fluorocyclopropyl)-3-(4-fluorophenyl)-3-methylbutan-1-ol (0.72 g, 3.0 mmol) in 2 mL of dichloromethane was added and the mixture was stirred for 15 minutes. 4 mL of triethylamine was added, the cooling bath was removed, the mixture was allowed to warm to room temperature and was then quenched with water and diluted with hexanes. The organic layer was separated, washed with water, dried, filtered, and concentrated in vacuo. The residue was purified by chromatography over silica gel (eluent: hexanes to hexanes-dichloromethane (4:1) gradient) to give 0.37 g of the title product as an oil.
Reaction SMILES: [N+:1]([O-:4])([O-])=[O:2].[K+].[Cl:6][C:7]1[CH:19]=[CH:18][C:10]([C:11]([C:13]2[S:14][CH:15]=[CH:16][N:17]=2)=[O:12])=[CH:9][CH:8]=1.S(=O)(=O)(O)O>>[N+:1]([C:19]1[CH:18]=[C:10]([CH:9]=[CH:8][C:7]=1[Cl:6])[C:11]([C:13]1[S:14][CH:15]=[CH:16][N:17]=1)=[O:12])([O-:4])=[O:2]
Reactant: O=[N+]([O-])[O-]
Reactant: O=C(c1ccc(Cl)cc1)c1nccs1
Agent: O=S(=O)(O)O
Agent: [K+]
Product: O=C(c1ccc(Cl)c([N+](=O)[O-])c1)c1nccs1
Reaction time: 1 h

Procedure:
Potassium nitrate (2.1 g., 0.02 mol) was added in one portion to a solution of 4.5 g. (0.02 mol) of 2-(4-chlorobenzoyl)thiazole in 25 ml. of concentrated sulfuric acid. After 1 hr. the mixture was cautiously poured into 250 ml. of ice water, the product collected, washed with water and dried to yield 2-(3-nitro-4-chlorobenzoyl)thiazole as pale-yellow prisms, mp. 118°-119° (acetone-water).
Reaction SMILES: ClC1C=C(Cl)C=CC=1C1C(N2C=CN=C2)=CN=C(CCN)N=1.Cl[C:24]1[N:29]=[C:28]([NH:30][CH3:31])[C:27]([N+:32]([O-:34])=[O:33])=[CH:26][CH:25]=1.[Cl:35][C:36]1[CH:41]=[C:40]([Cl:42])[CH:39]=[CH:38][C:37]=1[C:43]1[C:48]([C:49]2[NH:50][CH:51]=[CH:52][N:53]=2)=[CH:47][N:46]=[C:45]([NH:54][CH2:55][CH2:56][NH:57]C2C=CC([N+]([O-])=O)=C(OC)N=2)[N:44]=1>>[Cl:35][C:36]1[CH:41]=[C:40]([Cl:42])[CH:39]=[CH:38][C:37]=1[C:43]1[C:48]([C:49]2[NH:53][CH:52]=[CH:51][N:50]=2)=[CH:47][N:46]=[C:45]([NH:54][CH2:55][CH2:56][NH:57][C:24]2[CH:25]=[CH:26][C:27]([N+:32]([O-:34])=[O:33])=[C:28]([NH:30][CH3:31])[N:29]=2)[N:44]=1
Reactant: COc1nc(NCCNc2ncc(-c3ncc[nH]3)c(-c3ccc(Cl)cc3Cl)n2)ccc1[N+](=O)[O-]
Reactant: CNc1nc(Cl)ccc1[N+](=O)[O-]
Agent: NCCc1ncc(-n2ccnc2)c(-c2ccc(Cl)cc2Cl)n1
Product: CNc1nc(NCCNc2ncc(-c3ncc[nH]3)c(-c3ccc(Cl)cc3Cl)n2)ccc1[N+](=O)[O-]

Procedure:
[4-(2,4-dichlorophenyl)-5-imidazolylpyrimidin-2-yl](2-{[6-(methylamino)-5-nitro(2-pyridyl)]amino}ethyl)amine was prepared from [4-(2,4-dichlorophenyl)-5-imidazol-1-ylpyrimidin-2-ylethylamine and 6-chloro-2-methylamino-3-nitro-pyridine in accordance with the procedure described above for the preparation of [4-(2,4-dichlorophenyl)-5-imidazol-2-ylpyrimidin-2-yl]{2-[(6-methoxy-5-nitro(2-pyridyl))-amino]ethyl}amine.
Reaction SMILES: C1[C:6]([NH2:7])=[CH:5][CH:4]=C(O)C=1.O=[C:10]([CH2:16][CH2:17][C:18](O)=O)[CH2:11][CH2:12][C:13](O)=[O:14].O1C2(CCC(=O)O2)C[CH2:23][C:22]1=O>>[NH2:7][C:6]1[CH:5]=[CH:4][C:16]([C:10]2[CH:11]=[CH:12][C:13]([OH:14])=[CH:23][CH:22]=2)=[CH:17][CH:18]=1
Reactant: O=C(O)CCC(=O)CCC(=O)O
Reactant: Nc1ccc(O)cc1
Reactant: O=C1CCC2(CCC(=O)O2)O1
Product: Nc1ccc(-c2ccc(O)cc2)cc1

Procedure:
The hydroxy-containing primary amino compound and the spirodilactam precursor are typically contacted in a molar ratio of about 2:1 in the presence of an inert reaction diluent capable of dissolving at least a portion of each reactant at reaction temperature. A preferred class of reaction diluents comprises N-alkylamides such as N,N-dimethylacetamide or N-methyl-2-pyrrolidone. Reaction conditions include a reaction temperature from about 80° C. to about 200° C. and a reaction pressure sufficient to maintain the reaction mixture in the liquid phase. Such pressures are from about 0.8 atmosphere to about 20 atmospheres. Subsequent to reaction, the hydroxyaryl-substituted spirodilactam is recovered, if desired, by conventional methods such as extraction, solvent removal and precipitation. The isolation of the hydroxyaryl-substituted spirodilactam is not required, however, and the spirodilactam is further reacted in situ to form the cyanato derivative without isolation. By way of specific illustration, p-aminophenol reacts with either 4-oxoheptanedioic acid or 1,6-dioxaspiro[4.4]nonane-2,7-dione to produce 1,6-di(4-hydroxyphenyl)-1,6-diasaspiro[4.4]nonane-2,7-dione and 4-amino-4'-hydroxybiphenyl reacts with either di(2-carboxyphenyl)ketone or 3,4,8,9-dibenzo-1,6-dioxaspiro[4.4]nonane-2,7-dione to produce 1,6-di[4-(4'-hydroxybiphenyl)]-3,4,8,9-dibenzo-1,6diasaspiro[4.4]nonane-2,7-dione.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH2:8][N:9]=[C:10]=[O:11])[CH:5]=[CH:4][C:3]=1[C:12]([F:15])([F:14])[F:13].[NH2:16][C:17]1[CH:26]=[CH:25][CH:24]=[C:23]2[C:18]=1[CH:19]=[C:20]([NH:27]C(=O)C)[N:21]=[CH:22]2.CCN(C(C)C)C(C)C>C1(C)C=CC=CC=1>[NH2:27][C:20]1[N:21]=[CH:22][C:23]2[C:18]([CH:19]=1)=[C:17]([NH:16][C:10]([NH:9][CH2:8][C:6]1[CH:5]=[CH:4][C:3]([C:12]([F:13])([F:14])[F:15])=[C:2]([F:1])[CH:7]=1)=[O:11])[CH:26]=[CH:25][CH:24]=2
Reactant: O=C=NCc1ccc(C(F)(F)F)c(F)c1
Reactant: CC(=O)Nc1cc2c(N)cccc2cn1
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Product: Nc1cc2c(NC(=O)NCc3ccc(C(F)(F)F)c(F)c3)cccc2cn1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
2-Fluoro-4-(isocyanatomethyl)-1-(trifluoromethyl)benzene (2.59 mmol) in toluene (10 mL) was treated with N-(5-amino-3-isoquinolinyl)acetamide (400 mg, 1.99 mmol) and DIEA (1.8 mL). The mixture was heated at 80° C. for 5 hours, cooled to room temperature, and filtered. The solid was triturated with 97:3 CH2Cl2:CH3OH and stirred as a suspension in 48% aqueous HBr (8 mL) at 60° C. for 2 hours. After cooling to room temperature, the mixture was poured into concentrated NH4OH (20 mL). The solid was washed with water and air-dried to provide the title compound. The corresponding hydrochloride salt was prepared by treatment with methanolic HCl. 1H NMR (300 MHz, DMSO-d6) δ 8.81 (s, 1H), 8.68 (s, 1H), 7.94 (s, 1H), 7.76 (t, 1H, J=7.9 Hz), 7.35-7.49 (m, 3H), 7.26 (s, 1H), 7.09 (s, 1H), 6.92 (s, 1H), 6.84 (t, 1H, J=6.0 Hz), 6.62 (s, 1H), 4.41 (d, 2H, J=6.1 Hz).
Reaction SMILES: [NH:1]1[CH2:9][CH2:8][CH:4]([C:5]([OH:7])=[O:6])[CH2:3][CH2:2]1.Cl[C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12]>>[CH2:14]([O:13][C:11]([N:1]1[CH2:9][CH2:8][CH:4]([C:5]([OH:7])=[O:6])[CH2:3][CH2:2]1)=[O:12])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C(O)C1CCNCC1
Reactant: O=C(Cl)OCc1ccccc1
Product: O=C(O)C1CCN(C(=O)OCc2ccccc2)CC1
Yield: 88.6 %

Procedure:
The title compound (18 g, 88.6%) was prepared as a syrupy liquid from isonipecotic acid (10 g) and benzyl chloroformate (17 ml) in a similar manner to that described in preparation 1.
Reaction SMILES: [OH2:1].[CH2:2](Cl)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C]=O.CN1CCC[C:14]1=[O:18]>[Pd](Cl)Cl>[C:3]1([CH2:2][C:14]([OH:18])=[O:1])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: ClCc1ccccc1
Reactant: CN1CCCC1=O
Reactant: O
Agent: Cl[Pd]Cl
Agent: [C]=O
Product: O=C(O)Cc1ccccc1
Reaction time: 10 h
Yield: 87 %

Procedure:
11.6 g of a solution of 50% by weight of water [321 mmol] in N-methylpyrrolidone are added over a period of 1 hour to a solution of 36.9 g of benzyl chloride [291.5 mmol] and 26 mg of palladium chloride [0.145 mmol] in 76 g of N-methylpyrrolidone at a pressure of 30 bar of carbon monoxide with a temperature of 150° C. in a 300 ml HC4 autoclave. The pressure is kept constant during the addition at 30 bar. After approximately 10 hours of post-stirring, the carbon monoxide uptake is ended. After cooling, a GC yield of 87% phenylacetic acid is obtained. After fractional distillation, 32.1 g of phenylacetic acid [278.7 mmol], equivalent to a practical yield of 81%, are obtained. The melting point is 78° C.
Reaction SMILES: ClC(C[C:7]1[CH:12]=[C:11]([N:13]2[C:17](=[O:18])N(C(F)F)C(C)=N2)[C:10](Cl)=[CH:9][C:8]=1[Cl:24])C(O)=O.Cl[C:26]1C=CC(N)=C[CH:27]=1.O.ON1C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.C1(N=C=NC2CCCCC2)CCCCC1>O1CCCC1>[Cl:24][C:8]1[CH:7]=[CH:12][C:11]([NH:13][C:17](=[O:18])[CH2:26][CH3:27])=[CH:10][CH:9]=1
Reactant: Nc1ccc(Cl)cc1
Reactant: Cc1nn(-c2cc(CC(Cl)C(=O)O)c(Cl)cc2Cl)c(=O)n1C(F)F
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: C1CCOC1
Product: CCC(=O)Nc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A stirred solution of 0.50 g (0.0013 mole) of 2-chloro-3-[2,4-dichloro-5-(4-difluoromethyl-4,5-dihydro-3-methyl-5-oxo-1H-1,2,4-triazol-1-yl)phenyl]propionic acid (Compound 2), 0.16 g (0.0013 mole) of 4-chloroaniline, 0.17 g (0.0013 mole) of 1-hydroxybenzotriazole hydrate, and 0.18 g (0.0014 mole) of N,N-diisopropylethylamine in approximately 15 mL of tetrahydrofuran was cooled to 0° C. To this cold reaction mixture was added 0.26 g (0.0013 mole) of 1,3-dicyclohexylcarbodiimide. After complete addition, the reaction mixture was allowed to warm to room temperature and was stirred for approximately 18 hours. The reaction mixture was filtered. The filtrate was diluted with carbon tetrachloride and was washed in succession with a 1N hydrochloric acid solution, an aqueous 10% sodium hydroxide solution, water, and an aqueous saturated sodium chloride solution. The organic phase was dried over anhydrous magnesium sulfate, filtered, and the filtrate evaporated under reduced pressure to give 0.28 g of 2-chloro-3-[2,4-dichloro-5-(4-difluoromethyl)-4,5-dihydro-3-methyl-5-oxo-1H-1,2,4-triazol-1-yl)phenyl]-N-(4-chlorophenyl)propionamide as an oil, Compound 23 of Table 1.
Reaction SMILES: [F:1][C:2]1[C:3]([C:31]2[CH:36]=[CH:35][N:34]=[C:33]([C:37]([F:40])([F:39])[F:38])[CH:32]=2)=[N:4][CH:5]=[C:6]([CH2:8][NH:9][C:10]([C:12]2[N:17]=[CH:16][C:15]([N:18]3[CH2:23][CH2:22][N:21](C(OC(C)(C)C)=O)[CH2:20][CH2:19]3)=[CH:14][CH:13]=2)=[O:11])[CH:7]=1.C(O)(C(F)(F)F)=O>ClCCl>[F:1][C:2]1[C:3]([C:31]2[CH:36]=[CH:35][N:34]=[C:33]([C:37]([F:40])([F:38])[F:39])[CH:32]=2)=[N:4][CH:5]=[C:6]([CH2:8][NH:9][C:10](=[O:11])[C:12]2[CH:13]=[CH:14][C:15]([N:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)=[CH:16][N:17]=2)[CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(C(=O)NCc3cnc(-c4ccnc(C(F)(F)F)c4)c(F)c3)nc2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(NCc1cnc(-c2ccnc(C(F)(F)F)c2)c(F)c1)c1ccc(N2CCNCC2)cn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of tert-butyl 4-(6-((3-fluoro-2′-(trifluoromethyl)-2,4′-bipyridin-5-yl)methylcarbamoyl)pyridin-3-yl)piperazine-1-carboxylate 49-5 (106 mg, 0.21 mmol) in dichloromethane (2 mL) was added TFA (1 mL) dropwise. The mixture was stirred at room temperature for 2 hours, and the solvents were removed by rotary evaporation. The residue was dissolved in ethyl acetate (100 mL), washed with saturated aqueous NaHCO3 solution, H2O and brine, dried over Na2SO4 and concentrated to dryness by rotary evaporation to give N-((3-fluoro-2′-(trifluoromethyl)-2,4′-bipyridin-5-yl)methyl)-5-(piperazin-1-yl)picolinamide 49-6 as yellow solid. MS m/z 461.2 (M+1)
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N:8]([CH2:16][CH:17]1[CH2:21][CH2:20][O:19][CH2:18]1)[C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12].[F:22][C:23]1[CH:28]=[CH:27][C:26](B(O)O)=[C:25]([O:32][CH3:33])[CH:24]=1>>[F:22][C:23]1[CH:28]=[CH:27][C:26]([C:2]2[CH:7]=[CH:6][N:5]=[CH:4][C:3]=2[N:8]([CH2:16][CH:17]2[CH2:21][CH2:20][O:19][CH2:18]2)[C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[C:25]([O:32][CH3:33])[CH:24]=1
Reactant: COc1cc(F)ccc1B(O)O
Reactant: CC(C)(C)OC(=O)N(CC1CCOC1)c1cnccc1I
Product: COc1cc(F)ccc1-c1ccncc1N(CC1CCOC1)C(=O)OC(C)(C)C

Procedure:
The title compound was prepared in analogy to example 72, from tert-butyl 4-iodopyridin-3-yl((tetrahydrofuran-3-yl)methyl)carbamate and 4-fluoro-2-methoxyphenylboronic acid after a reaction time of 18 hours at 90° C. The compound was purified by silica gel chromatography on a 20 g column using an MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of n-heptane:EtOAc (100:0 to 0:100). Light yellow oil (79%). MS (ESI): m/z=403.203 [M+H]+.
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:22]3[C:17](=[N:18][CH:19]=[N:20][C:21]=3[NH2:23])[N:16]([C:24]3[CH:29]=[CH:28][C:27](Br)=[CH:26][N:25]=3)[N:15]=2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C)C=O.[H][H]>C(O)C.[Pd]>[O:1]([C:8]1[CH:9]=[CH:10][C:11]([C:14]2[C:22]3[C:17](=[N:18][CH:19]=[N:20][C:21]=3[NH2:23])[N:16]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=3)[N:15]=2)=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ncnc2c1c(-c1ccc(Oc3ccccc3)cc1)nn2-c1ccc(Br)cn1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Solvent: CN(C)C=O
Product: Nc1ncnc2c1c(-c1ccc(Oc3ccccc3)cc1)nn2-c1ccccn1

Procedure:
The more polar compound, 3-(4-phenoxyphenyl)-1-(5-bromo-2-pyridyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine, was suspended in absolute ethanol (10 mL) and N,N-dimethylformamide (5 mL) and 10% palladium on carbon (0.007 g) was added. The mixture was stirred under a balloon atmosphere of hydrogen for 18 hours. The mixture was filtered through pad of Celite® 521, washing with absolute ethanol. The solvent was removed in vacuo to give 3-(4-phenoxyphenyl)-1-(2-pyridyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.030 g, 0.00007 mol) as a white solid.
Reaction SMILES: Cl.Cl[C:3]1[C:12]2[C:7](=[CH:8][C:9]([O:15][CH3:16])=[C:10]([O:13][CH3:14])[CH:11]=2)[N:6]=[CH:5][C:4]=1[F:17].[CH3:18][O:19][C:20]1[CH:33]=[CH:32][CH:31]=[CH:30][C:21]=1[O:22][C:23]1[CH:29]=[CH:28][C:26]([NH2:27])=[CH:25][CH:24]=1>CCOCC.C1(O)CCCCC1>[CH3:18][O:19][C:20]1[CH:33]=[CH:32][CH:31]=[CH:30][C:21]=1[O:22][C:23]1[CH:29]=[CH:28][C:26]([NH:27][C:5]2[C:4]([F:17])=[CH:3][C:12]3[C:7](=[CH:8][C:9]([O:15][CH3:16])=[C:10]([O:13][CH3:14])[CH:11]=3)[N:6]=2)=[CH:25][CH:24]=1
Reactant: COc1cc2ncc(F)c(Cl)c2cc1OC
Reactant: COc1ccccc1Oc1ccc(N)cc1
Agent: Cl
Solvent: OC1CCCCC1
Solvent: CCOCC
Product: COc1cc2cc(F)c(Nc3ccc(Oc4ccccc4OC)cc3)nc2cc1OC
Temperature: 110 °C
Yield: 86.2 %

Procedure:
A solution of hydrogen chloride in ether (1 molar, 0.34 ml) was added to a mixture of 4-chloro-6,7-dimethoxy-3-fluoro-quinoline (80 mg) and 4-(2-methoxyphenoxy)-aniline (142 mg) in cyclohexanol (3 ml). The mixture was stirred and heated at 110° C. for 18 hours. The mixture was cooled to ambient temperature and then filtered. The crystals were washed with a small volume of diethyl ether and then dried to give 4-(2-methoxyphenoxy)-anilino-3-fluoro-6,7-dimethoxyquinoline (120 mg, 79%).