Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[CH:12]=[C:11]2[C:7]([C:8]([CH:14]([C:34]3[CH:42]=[CH:41][C:37]4[O:38][CH2:39][O:40][C:36]=4[CH:35]=3)[C:15]([NH:17][S:18]([C:21]3[CH:26]=[CH:25][C:24](/[CH:27]=[CH:28]/[C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:23][CH:22]=3)(=[O:20])=[O:19])=[O:16])=[CH:9][N:10]2[CH3:13])=[CH:6][CH:5]=1)(=[O:3])[NH2:2].[H][H]>C(O)C.[Pd]>[C:1]([C:4]1[CH:12]=[C:11]2[C:7]([C:8]([CH:14]([C:34]3[CH:42]=[CH:41][C:37]4[O:38][CH2:39][O:40][C:36]=4[CH:35]=3)[C:15]([NH:17][S:18]([C:21]3[CH:22]=[CH:23][C:24]([CH2:27][CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:25][CH:26]=3)(=[O:20])=[O:19])=[O:16])=[CH:9][N:10]2[CH3:13])=[CH:6][CH:5]=1)(=[O:3])[NH2:2]
Reactant: CCOC(=O)/C=C/c1ccc(S(=O)(=O)NC(=O)C(c2ccc3c(c2)OCO3)c2cn(C)c3cc(C(N)=O)ccc23)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)CCc1ccc(S(=O)(=O)NC(=O)C(c2ccc3c(c2)OCO3)c2cn(C)c3cc(C(N)=O)ccc23)cc1

Procedure:
Ethyl (E)-3-(4-[2-(6-carbamoyl-1-methyl-1H-3-indolyl)-2-(1,3-benzodioxol-5-yl)acetyl] sulfamoylphenyl)-2-propenoate (the compound of Example 41, 0.24 g, 0.40 mmol) was dissolved in ethanol (5 ml) and 5% palladium-on-carbon (24 mg) was added. The mixture was placed in a pressure vessel and a hydrogen pressure of 345 kPa (50 psi) was maintained for 48 h. The reaction mixture was filtered through Arbocel™ and concentrated in vacuo. Flash column chromatography (elution with 5% methanol/90% dichloromethane) gave the product (70 mg).
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH:14]=[C:13]2[C@@H:8]([CH2:9][C:10]3[C:11]4[C:18]([NH:19][CH:20]=3)=[CH:17][CH:16]=[CH:15][C:12]=42)[NH:7][CH2:6]1)=[O:4].[C:21]1([N:27]=[C:28]=[O:29])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>ClCCl.CO.C(Cl)Cl>[CH3:1][O:2][C:3]([C@@H:5]1[CH:14]=[C:13]2[C@@H:8]([CH2:9][C:10]3[C:11]4[C:18]([NH:19][CH:20]=3)=[CH:17][CH:16]=[CH:15][C:12]=42)[N:7]([C:28](=[O:29])[NH:27][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:6]1)=[O:4]
Reactant: COC(=O)[C@@H]1C=C2c3cccc4[nH]cc(c34)C[C@H]2NC1
Reactant: O=C=Nc1ccccc1
Solvent: CO
Solvent: ClCCl
Product: COC(=O)[C@@H]1C=C2c3cccc4[nH]cc(c34)C[C@H]2N(C(=O)Nc2ccccc2)C1

Procedure:
To a 100 ml round-bottom flask containing a solution of (6aR,9R)-4,6,6a,7,8,9-hexahydro-indolo[4,3-fg]quinoline-9-carboxylic acid methyl ester (0.89, 2.98 mmol) in dichloromethane (20 ml) is added phenylisocyanate (0.45 ml, 4.5 mmol, 1.5 eq.). The reaction mixture is stirred at room temperature for 16 hours by which time TLC in 10% methanol/DCM showed conversion of starting material to give product as a mixture of diastereomers. The volatiles are concentrated in vacuo and purified directly using Normal Phase Flash column chromatography (Biotage Flash 40, 90 g cartridge) using 30% ethyl acetate/hexane to isolate the product as a 1:1 diastereomeric mixture.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:15])=[C:11]([CH3:14])[N+:12]=2[O-])=[CH:4][C:3]=1[CH3:16].P(Cl)(Cl)([Cl:19])=O>C(Cl)(Cl)Cl>[Cl:19][CH2:14][C:11]1[N:12]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[C:3]([CH3:16])[CH:4]=2)[O:9][C:10]=1[CH3:15]
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1cc(-c2oc(C)c(C)[n+]2[O-])ccc1F
Solvent: ClC(Cl)Cl
Product: Cc1cc(-c2nc(CCl)c(C)o2)ccc1F

Procedure:
In analogy to the procedure described in example 2 b], 2-(4-fluoro-3-methyl-phenyl)-4,5-dimethyl-oxazole 3-oxide was treated with phosphorous oxychloride in chloroform to yield 4-chloromethyl-2-(4-fluoro-3-methyl-phenyl)-5-methyl-oxazole as colorless solid.
Reaction SMILES: Cl[C:2]1[N:11]=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[N+:12]([C:15]1[CH:16]=[C:17](B(O)O)[CH:18]=[CH:19][CH:20]=1)([O-:14])=[O:13].C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.C(OCC)(=O)C.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:7][O:6][C:4]([C:3]1[C:2]([C:19]2[CH:20]=[C:15]([N+:12]([O-:14])=[O:13])[CH:16]=[CH:17][CH:18]=2)=[N:11][CH:10]=[CH:9][CH:8]=1)=[O:5]
Reactant: COC(=O)c1cccnc1Cl
Reactant: O=[N+]([O-])c1cccc(B(O)O)c1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: COC(=O)c1cccnc1-c1cccc([N+](=O)[O-])c1
Temperature: 80 °C
Reaction time: 3 h
Yield: 27.6 %

Procedure:
To a suspension of methyl 2-chloronicotinate (1.89 g), 3-nitrophenylboronic acid (1.67 g) and tetrakis(triphenylphosphine)-palladium (578 mg) in 1,2-dimethoxyethane (20 ml) was added 2M aqueous solution of sodium carbonate (11 ml). The mixture was stirred at 80° C. for 3 hours under a nitrogen atmosphere, then cooled to room temperature and diluted with ethyl acetate. The organic layer was separated, washed with water and brine and dried over sodium sulfate. The solvent was evaporated under reduced pressure. The residue was triturated with 2-propanol, filtered, washed with 2-propanol and dried under reduced pressure to give 3-(3-methoxycarbonylpyridin-2-yl)-nitrobenzene (713 mg).
Reaction SMILES: [OH:1][N:2]1[C:7]([CH3:9])([CH3:8])[CH2:6][CH:5]([O:10][C:11](=[O:18])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:4][C:3]1([CH3:20])[CH3:19].[C:21](Cl)(=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[C:11]([O:10][CH:5]1[CH2:6][C:7]([CH3:9])([CH3:8])[N:2]([O:1][C:21](=[O:28])[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:3]([CH3:20])([CH3:19])[CH2:4]1)(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CC1(C)CC(OC(=O)c2ccccc2)CC(C)(C)N1O
Reactant: O=C(Cl)c1ccccc1
Product: CC1(C)CC(OC(=O)c2ccccc2)CC(C)(C)N1OC(=O)c1ccccc1
Yield: 83 %

Procedure:
Using 1-hydroxy-4-benzoyloxy-2,2,6,6-tetramethylpiperidine, prepared as described by: Kurumada T. et al., loc. cit., and benzoyl chloride in a procedure otherwise similar to that for preparing the compound 101 gives an 83% yield of the compound 111 which is obtained in the form of colourless crystals; melting point. 138–140° C. (toluene/hexane).
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][CH:26]=[CH:25][C:3]=1[C:4]([C:6]1[CH:14]=[C:13]2[C:9]([CH2:10][CH2:11][CH2:12]2)=[CH:8][C:7]=1[NH:15]C(=O)C1C=CC=CC=1Cl)=[O:5].N>OS(O)(=O)=O>[NH2:15][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][C:6]=1[C:4](=[O:5])[C:3]1[CH:25]=[CH:26][CH:27]=[CH:28][C:2]=1[Cl:1])[CH2:12][CH2:11][CH2:10]2
Reactant: O=C(Nc1cc2c(cc1C(=O)c1ccccc1Cl)CCC2)c1ccccc1Cl
Agent: N
Agent: O=S(=O)(O)O
Product: Nc1cc2c(cc1C(=O)c1ccccc1Cl)CCC2
Temperature: 120 °C
Yield: 94.4 %

Procedure:
A mixture of 6-(2-chlorobenzoyl)-5-(2-chlorobenzoylamino)indan (16.0 g) and 70% H2SO4 (100 ml) was heated at 120° C. for 30 minutes and, then, poured in ice-water (300 ml). The solution was alkalinized with concentrated aqueous ammonia and extracted with ethyl acetate. The extract was washed with water and dried (MgSO4) and the solvent was distilled off to give 5-amino-6-(2-chlorobenzoyl)indan as yellow oil (10.0 g, 94.3%). Recrystallization from hexane gave yellow prisms, m.p. 90°-92°.
Reaction SMILES: Br[C:2]1[CH:8]=[C:7]([F:9])[C:5]([NH2:6])=[C:4]([Cl:10])[CH:3]=1.[CH2:11]([O:13][C:14]1[CH:15]=[C:16](B(O)O)[CH:17]=[CH:18][CH:19]=1)[CH3:12]>>[Cl:10][C:4]1[CH:3]=[C:2]([C:18]2[CH:17]=[CH:16][CH:15]=[C:14]([O:13][CH2:11][CH3:12])[CH:19]=2)[CH:8]=[C:7]([F:9])[C:5]=1[NH2:6]
Reactant: Nc1c(F)cc(Br)cc1Cl
Reactant: CCOc1cccc(B(O)O)c1
Product: CCOc1cccc(-c2cc(F)c(N)c(Cl)c2)c1
Yield: 67.7 %

Procedure:
The title compound (0.360 g) was prepared from 4-bromo-2-chloro-6-fluoroaniline (0.5 g, 2.0 mmol) and 3-ethoxyphenylboronic acid (0.441 g, 2.65 mmol) as a yellow liquid. 1H-NMR (δ ppm, DMSO-d6, 400 MHz): 7.43-7.38 (m, 2H), 7.27 (t, J 7.9, 1H), 7.14 (d, J 7.9, 1H), 7.10 (s, 1H), 6.82 (dd, J 2.1, 8.1, 1H), 5.51 (s, 2H), 4.07 (q, J 7, 2H), 1.32 (t, J 7, 3H).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:27]/[O:28][C:29]([C:32]([O:34]CC2C=CC([N+]([O-])=O)=CC=2)=[O:33])([CH3:31])[CH3:30])/[C:8]([NH:10][C@@H:11]2[C:21](=[O:22])[N:20]3[C@@H:12]2[CH2:13][S:14][C@H:15]2[C@@:19]3([C:23]([O-:25])=[O:24])[O:18][C:17](=[O:26])[CH2:16]2)=[O:9])[N:6]=1.[Na+:45].P([O-])([O-])([O-])=O.C(O)C.[H][H]>O.[C].[Pd]>[NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:27]/[O:28][C:29]([C:32]([OH:34])=[O:33])([CH3:31])[CH3:30])/[C:8]([NH:10][C@@H:11]2[C:21](=[O:22])[N:20]3[C@@H:12]2[CH2:13][S:14][C@H:15]2[C@@:19]3([C:23]([O-:25])=[O:24])[O:18][C:17](=[O:26])[CH2:16]2)=[O:9])[N:6]=1.[Na+:45]
Reactant: CC(C)(O/N=C(\C(=O)N[C@@H]1C(=O)N2[C@@H]1CS[C@@H]1CC(=O)O[C@]12C(=O)[O-])c1csc(N)n1)C(=O)OCc1ccc([N+](=O)[O-])cc1
Reactant: [H][H]
Agent: [Pd]
Agent: O=P([O-])([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CC(C)(O/N=C(\C(=O)N[C@@H]1C(=O)N2[C@@H]1CS[C@@H]1CC(=O)O[C@]12C(=O)[O-])c1csc(N)n1)C(=O)O
Yield: 77 %

Procedure:
In 5 ml of water was dissolved 0.148 g of the compound obtained in Example 7. To this solution were added 5 ml of a 0.1M phosphate buffer solution, 5 ml of ethanol and 0.075 g of 10% palladium-carbon. Into the mixture was introduced hydrogen gas while stirring under ice-cooling. In 1.5 hour after starting of the reaction, 0.04 g of 10% palladium-carbon was added to the reaction system, followed by stirring for further one hour. The catalyst was filtered off, and the filtrate was concentrated under reduced pressure to a volume of about 5 ml. The residue was subjected to a Amberlite XAD-2 column chromatography. Fractions eluted with water were combined and freeze-dried to give 0.091 g of the subject compound as powders.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([O:13][C:14]2[CH:15]=[C:16]([N:20]3[CH2:37][CH2:36][C:23]4([CH2:27][N:26](C(O)=O)[C@H:25]([C:31]([O:33]CC)=[O:32])[CH2:24]4)[CH2:22][CH2:21]3)[N:17]=[N:18][CH:19]=2)[C:9]([F:12])([F:11])[F:10])=[C:4]([N:38]2[CH:42]=[CH:41][C:40]([CH3:43])=[N:39]2)[CH:3]=1.[Li+].[OH-]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([O:13][C:14]2[CH:15]=[C:16]([N:20]3[CH2:37][CH2:36][C:23]4([CH2:27][NH:26][C@H:25]([C:31]([OH:33])=[O:32])[CH2:24]4)[CH2:22][CH2:21]3)[N:17]=[N:18][CH:19]=2)[C:9]([F:10])([F:11])[F:12])=[C:4]([N:38]2[CH:42]=[CH:41][C:40]([CH3:43])=[N:39]2)[CH:3]=1
Reactant: CCOC(=O)[C@@H]1CC2(CCN(c3cc(O[C@H](c4ccc(Cl)cc4-n4ccc(C)n4)C(F)(F)F)cnn3)CC2)CN1C(=O)O
Agent: [Li+]
Agent: [OH-]
Product: Cc1ccn(-c2cc(Cl)ccc2[C@@H](Oc2cnnc(N3CCC4(CC3)CN[C@H](C(=O)O)C4)c2)C(F)(F)F)n1

Procedure:
Hydrolysis of (S)-8-(5-((R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyridazin-3-yl)-3-(ethoxycarbonyl)-2,8-diazaspiro[4.5]decane-2-carboxylic acid using the LiOH general method provided the title compound as an off-white solid.
Reaction SMILES: C[O:2][C:3](=[O:21])[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:15]([Cl:16])=[CH:14][N:13]=[C:12]([NH:17][CH:18]3[CH2:20][CH2:19]3)[N:11]=2)=[CH:6][CH:5]=1.O.[OH-].[Li+]>C1COCC1.O.Cl>[Cl:16][C:15]1[C:10]([C:7]2[CH:8]=[CH:9][C:4]([C:3]([OH:21])=[O:2])=[CH:5][CH:6]=2)=[N:11][C:12]([NH:17][CH:18]2[CH2:20][CH2:19]2)=[N:13][CH:14]=1
Reactant: COC(=O)c1ccc(-c2nc(NC3CC3)ncc2Cl)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1ccc(-c2nc(NC3CC3)ncc2Cl)cc1
Temperature: 50 °C
Yield: 90 %

Procedure:
4-(5-Chloro-2-cyclopropylaminopyrimidin-4-yl)-benzoic acid methyl ester (90 mg, 0.30 mmol) was dissolved in THF and 50 mg (1.2 mmol) of lithium hydroxide monohydrate dissolved in water was added. The reaction mixture was heated to 50° C. for 5 hours, cooled to room temperature, diluted with 1N HCl and extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated to afford 4-(5-chloro-2-cyclopropylaminopyrimidin-4-yl)-benzoic acid as a yellow solid, 78 mg, 0.27 mmol, 90% yield.
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]=C[CH:5]=[CH:4][CH:3]=1.[NH2:34]C1C=CC(C2C=C3C(CN([C@@H](C(C)C)C(OC)=O)C3=O)=CC=2)=CC=1.C(Cl)(=O)C1C=CC=NC=1>>[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][CH:5]=[N:34][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: O=C(Cl)c1cccnc1
Product: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)c4cccnc4)cc3)cc2C1=O
Yield: 91 %

Procedure:
The compound of example 206 was prepared analogous to compound of example 97 by reaction of compound of example 6 with nicotinoyl chloride.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([S:15]([C:18]([NH2:32])([CH2:23][C:24]#[C:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:19]([O:21]C)=[O:20])(=[O:17])=[O:16])=[C:11]([C:33]#[CH:34])[CH:10]=2)=[CH:5][CH:4]=1.IS(N)(=O)=O.COC1C=CC(C#C)=CC=1.CCN(CC)CC>CN(C=O)C.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>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([S:15]([C:18]([NH2:32])([CH2:23][C:24]#[C:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:19]([OH:21])=[O:20])(=[O:17])=[O:16])=[C:11]([C:33]#[CH:34])[CH:10]=2)=[CH:5][CH:4]=1
Reactant: C#Cc1cc(-c2ccc(OC)cc2)ccc1S(=O)(=O)C(N)(CC#Cc1ccccc1)C(=O)OC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: C#Cc1ccc(OC)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: C#Cc1cc(-c2ccc(OC)cc2)ccc1S(=O)(=O)C(N)(CC#Cc1ccccc1)C(=O)O
Temperature: 55 °C

Procedure:
Methyl 2-[4-(4-Methoxyphenyl)-acetylenylbenzenesulfonyl]-amino-5-phenylpent-4-ynoate: The starting iodo sulfonamide 3a (0.54 g, 1.15 mmol) and 4-methoxyphenylacetylene (0.2 g, 1.49 mmol) are taken in 10 mL of DMF in the presence of 0.32 mL of Et3N, Pd(PPh3)2Cl2 (40.4 mg, 0.058 mmol), and CuI (24 mg, 0.128 mmol). The mixture is then heated to 55° C. for 18 hr. and then partitioned between EtOAc and H2O. The organic layer is washed with 1N HCl, aqueous NaHCO3 and brine, dried over MgSO4, filtered and evaporated to give a residue which is adsorbed onto silica and eluted through a column of flash silica with hexane:EtOAc (4:1 to 2:1 ) to give the desired product.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([CH3:16])([CH3:15])[CH2:7][CH:8]([CH:13]=[O:14])[C:9]2=[O:12])=[CH:4][CH:3]=1.[CH3:17][C:18]([CH:20]=[CH2:21])=[O:19]>C(N(CC)CC)C.C(OCC)C>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([CH3:16])([CH3:15])[CH2:7][C:8]([CH:13]=[O:14])([CH2:21][CH2:20][C:18](=[O:19])[CH3:17])[C:9]2=[O:12])=[CH:4][CH:3]=1
Reactant: CC1(C)CC(C=O)C(=O)c2cc(Br)ccc21
Reactant: C=CC(C)=O
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CC(=O)CCC1(C=O)CC(C)(C)c2ccc(Br)cc2C1=O
Temperature: 0 °C
Yield: 87.2 %

Procedure:
7-Bromo-4,4-dimethyl-2-formyl-1-oxo- 1,2,3 ,4-tetrahydronaphthalene (1.0 g, 3.56 mmol) was dissoved in methylvinylketone (dist., 0.468 g, 6.7 mmol) and this mixture was cooled down to 0° C. Triethylamine (3 drops) was then added and the mixture was stirred at 0° C. for an hour and then at room temperature overnight. The reaction mixture was dissolved in ethyl ether and concentrated to give the title material (1.09 g, 87%) as a yellow oil.
Reaction SMILES: CS[C:3]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:10]=1)([CH3:8])[C:4]([O:6][CH3:7])=[O:5].C(OCC)C>C(O)(=O)C.S([O-])([O-])(=O)=O.[Cu+2].[Zn]>[O:15]([C:11]1[CH:10]=[C:9]([CH:3]([CH3:8])[C:4]([O:6][CH3:7])=[O:5])[CH:14]=[CH:13][CH:12]=1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: COC(=O)C(C)(SC)c1cccc(Oc2ccccc2)c1
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Agent: [Zn]
Solvent: CC(=O)O
Solvent: CCOCC
Product: COC(=O)C(C)c1cccc(Oc2ccccc2)c1
Yield: 97.3 %

Procedure:
Methyl α-methylthio-α-(m-phenoxyphenyl)propionate (302 mg) was dissolved in 2 ml of acetic acid, and 16 mg of anhydrous copper sulfate and 150 mg of zinc powder were added. With stirring, the mixture was heated under reflux for 9 hours. Furthermore, 50 mg of zinc powder was added, and the mixture was heated under reflux for 2 hours. Diethyl ether (60 mg) was added, and the insoluble matter was separated by filtration. The filtrate was washed twice with 10 ml of water and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was subjected to short-path distillation (bath temperature 140°-160° C./0.02 mmHg) to afford 249 mg of methyl α-(m-phenoxyphenyl)propionate as a colorless oil in a yield of 97%.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C@:8]2([CH3:17])[C:13]([F:15])([F:14])[CH2:12][O:11][C:10]([NH2:16])=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[C:18]([C:20]1[CH:21]=[CH:22][C:23]([C:26](O)=[O:27])=[N:24][CH:25]=1)#[N:19]>>[NH2:16][C:10]1[O:11][CH2:12][C:13]([F:15])([F:14])[C@:8]([C:4]2[CH:3]=[C:2]([NH:1][C:26]([C:23]3[CH:22]=[CH:21][C:20]([C:18]#[N:19])=[CH:25][N:24]=3)=[O:27])[CH:7]=[CH:6][CH:5]=2)([CH3:17])[N:9]=1
Reactant: N#Cc1ccc(C(=O)O)nc1
Reactant: C[C@]1(c2cccc(N)c2)N=C(N)OCC1(F)F
Product: C[C@]1(c2cccc(NC(=O)c3ccc(C#N)cn3)c2)N=C(N)OCC1(F)F

Procedure:
The condensation of (R)-4-(3-amino-phenyl)-5,5-difluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine (intermediate XI-4) and 5-cyano-pyridine-2-carboxylic acid following procedure I yielded the title compound as an off-white solid. MS (ISP): m/z=372.1 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10]2[C:14]([C:15]([OH:17])=O)=[CH:13][O:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].C(N(C(C)C)C(C)C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.Cl.Cl.[N:51]1[CH:56]=[CH:55][CH:54]=[C:53]([C:57]2([OH:62])[CH2:61][CH2:60][NH:59][CH2:58]2)[CH:52]=1>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:10]2[C:14]([C:15]([N:59]3[CH2:60][CH2:61][C:57]([C:53]4[CH:52]=[N:51][CH:56]=[CH:55][CH:54]=4)([OH:62])[CH2:58]3)=[O:17])=[CH:13][O:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: OC1(c2cccnc2)CCNC1
Reactant: COc1ccc(-c2nocc2C(=O)O)cc1Cl
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(-c2nocc2C(=O)N2CCC(O)(c3cccnc3)C2)cc1Cl
Yield: 50 %

Procedure:
A solution of 3-(3-chloro-4-methoxyphenyl)-isoxazole-4-carboxylic acid (10 mg, 0.04 mmol), N-ethyl-N-isopropylpropan-2-amine (14 μL, 0.08 mmol, 2 equ.) and TBTU (15 mg, 0.046 mmol, 1.2 equ.) in DMF (0.3 mL) was added to 3-pyridin-3-ylpyrrolidin-3-ol dihydrochloride (9 mg, 0.04 mmol). After 1 h at rt the crude product was purified by RP-HPLC. The pure fractions were basified (NaHCO3) and extracted with ethyl acetate, dried (Na2SO4), evaporated and dried in vacuum to yield the title compound (8 mg). MS (ESI, pos. ion) m/z: calcd for C20H18ClN3O4: 399.0986, found 399.0986.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[N:6][C:7]([S:30][CH2:31][C:32]3[N:33]=[C:34]([C:37]4[CH:42]=[CH:41][C:40]([Cl:43])=[CH:39][CH:38]=4)[S:35][CH:36]=3)=[C:8]([C:28]#[N:29])[C:9]=2[C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][O:20][Si](C(C)(C)C)(C)C)=[CH:13][CH:12]=2)[N:4]([CH2:44][C:45]([O:47][CH3:48])=[O:46])[C:3]=1[C:49]([O:51][CH3:52])=[O:50].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1.C(OCC)(=O)C>[NH2:1][C:2]1[C:10]2[C:5](=[N:6][C:7]([S:30][CH2:31][C:32]3[N:33]=[C:34]([C:37]4[CH:42]=[CH:41][C:40]([Cl:43])=[CH:39][CH:38]=4)[S:35][CH:36]=3)=[C:8]([C:28]#[N:29])[C:9]=2[C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][OH:20])=[CH:13][CH:12]=2)[N:4]([CH2:44][C:45]([O:47][CH3:48])=[O:46])[C:3]=1[C:49]([O:51][CH3:52])=[O:50]
Reactant: COC(=O)Cn1c(C(=O)OC)c(N)c2c(-c3ccc(OCCO[Si](C)(C)C(C)(C)C)cc3)c(C#N)c(SCc3csc(-c4ccc(Cl)cc4)n3)nc21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)Cn1c(C(=O)OC)c(N)c2c(-c3ccc(OCCO)cc3)c(C#N)c(SCc3csc(-c4ccc(Cl)cc4)n3)nc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
19 mg (0.024 mmol) of the compound from Example 33A were initially charged in 1 ml of THF, and 0.122 ml (0.122 mmol) of a 1N solution of tetrabutylammonium fluoride in THF were added. The reaction mixture was stirred at RT for 2 h and then diluted with ethyl acetate. The mixture was washed with saturated aqueous sodium bicarbonate solution. The organic phase was dried over sodium sulfate and concentrated, and the residue was purified by preparative HPLC (Chromasil, water/acetonitrile). This gave 15 mg of the product, which were purified by preparative thin-layer chromatography (dichloromethane/methanol=20/1).
Reaction SMILES: [CH2:1]([N:8]1[C:12]2=[N:13][CH:14]=[N:15][C:16](Cl)=[C:11]2[C:10]([NH:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C(O)C>[CH2:1]([N:8]1[C:12]2=[N:13][CH:14]=[N:15][C:16]([NH:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[C:11]2[C:10]([NH:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Clc1ncnc2c1c(Nc1ccccc1)nn2Cc1ccccc1
Reactant: Nc1ccccc1
Solvent: CCO
Product: c1ccc(Cn2nc(Nc3ccccc3)c3c(Nc4ccccc4)ncnc32)cc1

Procedure:
1 g of 1-benzyl-4-chloro-3-phenylamino-pyrazolo[3,4-d]pyrimidine is suspended in 8 ml of ethanol; 27 ml of aniline are added thereto and, under nitrogen, the reaction mixture is heated under reflux for 2.5 hours until, according to thin-layer chromatography, all the starting material has disappeared. The reaction mixture is concentrated to dryness by evaporation, the residue is suspended in water and the pH is adjusted to pH 8.5-9 with 0.1N NaOH. Extraction is then carried out with ethyl acetate and the ethyl acetate phase is then dried and concentrated by evaporation. The crude product is chromatographed on silica gel, mixtures of toluene/ethyl acetate being used as eluant. Product-containing column fractions are stirred with cyclohexane/hexane, yielding colorless crystals of 1-benzyl-3,4-diphenylamino-pyrazolo[3,4-d]pyrimidine; FAB-MS: (M+H)+ =393 (C24H20N6).
Reaction SMILES: [CH3:1][NH:2][NH2:3].[CH3:4][O:5][C:6]1[CH:14]=[CH:13][C:9]([C:10](Cl)=[O:11])=[CH:8][CH:7]=1>ClCCl>[CH3:1][N:2]([C:10](=[O:11])[C:9]1[CH:13]=[CH:14][C:6]([O:5][CH3:4])=[CH:7][CH:8]=1)[NH2:3]
Reactant: CNN
Reactant: COc1ccc(C(=O)Cl)cc1
Solvent: ClCCl
Product: COc1ccc(C(=O)N(C)N)cc1
Yield: 88.9 %

Procedure:
Methylhydrazine (2.76 g) was dissolved in dichloromethane (60 ml), and a solution of 4-methoxybenzoyl chloride (5.12 g) in dichloromethane (10 ml) was added thereto under an ice cooling and stirring. The mixture was further stirred at a room temperature for 1.5 hours, and then the reaction solution washed with water and a saturated saline solution in order. The washed product was dried over anhydrous sodium sulfate, concentrated under a reduced pressure, and dried to give the title compound (4.81 g, 89%).