Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13]3[C:14]([CH:23]=[CH2:24])=[CH:15][C:16]([NH:18][S:19]([CH3:22])(=[O:21])=[O:20])=[CH:17][C:12]=3[O:11][C:10]([CH3:26])([CH3:25])[C:9]2=[O:27])=[CH:4][CH:3]=1.[OH:28]O.[OH-].[Na+].[Cl-].[NH4+]>O1CCCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:13]3[C:14]([CH2:23][CH2:24][OH:28])=[CH:15][C:16]([NH:18][S:19]([CH3:22])(=[O:20])=[O:21])=[CH:17][C:12]=3[O:11][C:10]([CH3:26])([CH3:25])[C:9]2=[O:27])=[CH:6][CH:7]=1
Reactant: OO
Reactant: C=Cc1cc(NS(C)(=O)=O)cc2c1N(c1ccc(F)cc1)C(=O)C(C)(C)O2
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC1(C)Oc2cc(NS(C)(=O)=O)cc(CCO)c2N(c2ccc(F)cc2)C1=O
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of N-[4-(4-fluorophenyl)-2,2-dimethyl-3-oxo-5-vinyl-3,4-dihydro -2H-1,4-benzoxazin-7-yl]methanesulfonamide (compound obtained in Example 156, 200 mg) in tetrahydrofuran (5 mL) was added 10 M borane-dimethylsulfide complex in tetrahydrofuran (0.03 mL) under ice-cooling, and the mixture was stirred at room temperature for 5 hours. Thereto was further added 10 M borane-dimethylsulfide complex in tetrahydrofuran (0.03 mL), and the mixture was stirred for 15 hours. To the reaction mixture were added successively tetrahydrofuran (5 mL), an aqueous 30% hydrogen peroxide solution (0.6 mL) and an aqueous 2N sodium hydroxide solution (0.77 mL), and the mixture was stirred at room temperature for 3 hours. The reaction mixture was poured to an aqueous saturated ammonium chloride solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, dried over sodium sulfate and concentrated in vacuo. The resultant residue was purified by column chromatography on silica gel (Solvent; chloroform→chloroform/ethyl acetate=100/0→0/100) to give N-[4-(4-fluorophenyl)-5-(2-hydroxyethyl)-2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl]methanesulfonamide (113 mg) as a colorless powder.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:15]2[NH:19][N:18]=[N:17][N:16]=2)=[CH:5][CH:4]=1.[CH2:20]([CH2:24][C:25](=O)[CH3:26])[C:21]([CH3:23])=O.CC(O)=O>C(O)C>[CH3:26][C:25]1[N:1]([CH2:2][C:3]2[CH:8]=[CH:7][C:6]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[C:15]3[NH:19][N:18]=[N:17][N:16]=3)=[CH:5][CH:4]=2)[C:21]([CH3:23])=[CH:20][CH:24]=1
Reactant: NCc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Reactant: CC(=O)CCC(C)=O
Solvent: CC(=O)O
Solvent: CCO
Product: Cc1ccc(C)n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Yield: 54 %

Procedure:
2.8 g of (4a) (9.7 mmol), 1.1 g of acetonylacetone (9.7 mmol) and 0.5 mL of glacial AcOH in 50 mL of absolute ethanol are mixed under a nitrogen atmosphere. The mixture is heated to reflux for 6 h, the solvent is evaporated, the residue is redissolved with chloroform and water, the organic phase is washed with water, dried with Na2SO4 and evaporated. Product: 1.7 g. Formula: C20H19N5 (m.w. 329.41). Yield 54%.
Reaction SMILES: C([N:8]1[C:13]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)=[C:12]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=2)[C:11](=[O:28])[N:10](CC2C=CC=CC=2)[C:9]1=[O:36])C1C=CC=CC=1.[Al+3].[Cl-].[Cl-].[Cl-]>C1(C)C=CC=CC=1>[Cl:27][C:24]1[CH:23]=[CH:22][C:21]([C:12]2[C:11](=[O:28])[NH:10][C:9](=[O:36])[NH:8][C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)=[CH:26][CH:25]=1
Reactant: O=c1c(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2)n(Cc2ccccc2)c(=O)n1Cc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: Cc1ccccc1
Product: O=c1[nH]c(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 2 h
Yield: 90 %

Procedure:
To a solution of 1,3-dibenzyl-5,6-bis(4-chlorophenyl)pyrimidine-2,4(1H,3H)-dione (7.2 g, 14.0 mmol) in toluene (70 mL) was added AlCl3 (4.7 g, 35.2 mmol) under argon. The reaction mixture was stirred in an oil bath preheated at 85° C. for 2 h. The reaction mixture was cooled to room temperature and then poured onto crushed ice (100 g). The precipitate formed was collected by filtration, washed with water (30 mL×2) then ether (40 mL), and dried in a vacuum oven at 40° C. to obtain 4.2 g of the title compound as a brown solid. HPLC/MS (MeOH-water with 10 mM NH4OAc): retention time=3.433 min, [M+H]30 =333.
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C@@H:6]([CH:20]([CH3:22])[CH3:21])[C:7]([N:9]1[C@@H:13]([CH3:14])[CH2:12][CH2:11][C@H:10]1[C:15]([O:17]CC)=[O:16])=[O:8])=[O:4].[Li+].[OH-]>CO>[CH3:1][O:2][C:3]([NH:5][C@@H:6]([CH:20]([CH3:22])[CH3:21])[C:7]([N:9]1[C@@H:13]([CH3:14])[CH2:12][CH2:11][C@H:10]1[C:15]([OH:17])=[O:16])=[O:8])=[O:4]
Reactant: CCOC(=O)[C@@H]1CC[C@H](C)N1C(=O)[C@@H](NC(=O)OC)C(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: COC(=O)N[C@H](C(=O)N1[C@@H](C)CC[C@H]1C(=O)O)C(C)C
Yield: 56 %

Procedure:
(2S,5S)-Ethyl 1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)-5-methylpyrrolidine-2-carboxylate (39.3 mmol, assuming complete conversion from the previous transformation) was suspended in MeOH (200 mL) and aqueous LiOH (1.0 M, 100 mL, 100 mmol) was added. The reaction mixture was stirred o/n, then concentrated under reduced pressure to remove most of the MeOH. The aqueous solution was washed 2× with DCM before being acidified to pH˜1-2 with 10% HCl. The acidic aqueous phase was then extracted 5× with EtOAc. The combined EtOAc extracts were dried over MgSO4 filtered and concentrated under reduced pressure to afford (2S,5S)-1-((S)-2-(Methoxycarbonylamino)-3-methylbutanoyl)-5-methylpyrrolidine-2-carboxylic acid (6.89 g, 56% over 2 steps).
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@H:9]([O:10][C:11](=[O:13])[CH3:12])[C@@H:8]([CH2:14][OH:15])[O:7][C@H:6]1[O:16][C:17](=[O:19])[CH3:18])(=[O:3])[CH3:2].Cl[S:21]([NH2:24])(=[O:23])=[O:22]>>[C:1]([O:4][C@@H:5]1[C@H:9]([O:10][C:11](=[O:13])[CH3:12])[C@@H:8]([CH2:14][O:15][S:21](=[O:23])(=[O:22])[NH2:24])[O:7][C@H:6]1[O:16][C:17](=[O:19])[CH3:18])(=[O:3])[CH3:2]
Reactant: NS(=O)(=O)Cl
Reactant: CC(=O)O[C@@H]1O[C@H](CO)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Product: CC(=O)O[C@@H]1O[C@H](COS(N)(=O)=O)[C@@H](OC(C)=O)[C@H]1OC(C)=O

Procedure:
The title compound was prepared from (2S,3R,4R,5R)-2,4-diacetoxy-5-hydroxymethyl-tetrahydro-furan-3-yl acetate by reaction with chlorosulfonamide following a procedure analogous to that described in Example 43, step f.
Reaction SMILES: FC(F)(F)C(O)=O.[C:8]1([CH3:21])[CH:13]=[CH:12][C:11]([NH:14][CH:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)=[CH:10][CH:9]=1.Br[CH2:23][CH2:24][CH2:25][CH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1.C(=O)([O-])[O-].[K+].[K+].ClCCl>CN(C)C=O>[CH:26]1([CH2:25][CH2:24][CH2:23][N:18]2[CH2:19][CH2:20][CH:15]([NH:14][C:11]3[CH:10]=[CH:9][C:8]([CH3:21])=[CH:13][CH:12]=3)[CH2:16][CH2:17]2)[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1
Reactant: BrCCCC1CCCCC1
Reactant: Cc1ccc(NC2CCNCC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1ccc(NC2CCN(CCCC3CCCCC3)CC2)cc1
Temperature: 80 °C
Reaction time: 5 h

Procedure:
To a solution of 4-(p-toluidino)piperidine trifluoroacetate (0.7726 g) dissolved in N,N-dimethylformamide (10 mL) were added (3-bromopropyl)cyclohexane (0.57 g) and potassium carbonate (1.02 g). The reaction solution was heated with stirring at 80° C. for 5 hours. Dichloromethane was added to the reaction solution, and the insolubles were filtered off, and then, the solvent was distilled off under reduced pressure. The resulting residue was purified by chromatography [silica gel, dichloromethane-methanol-aqueous ammonia (95:5:0.3)] to give the title compound as a while solid (0.4879 g).
Reaction SMILES: [C:1]1(=[O:11])[O:6][C:4](=[O:5])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[Al+3].[Cl-].[Cl-].[Cl-].C([Zn]CC)C.[C:21]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)([CH2:24][CH3:25])([CH3:23])[CH3:22]>>[C:21]([C:26]1[CH:27]=[CH:28][C:29]([C:4]([C:3]2[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=2[C:1]([OH:6])=[O:11])=[O:5])=[CH:30][CH:31]=1)([CH2:24][CH3:25])([CH3:22])[CH3:23]
Reactant: O=C1OC(=O)c2ccccc21
Reactant: CCC(C)(C)c1ccccc1
Agent: CC[Zn]CC
Agent: [Al+3]
Agent: [Cl-]
Product: CCC(C)(C)c1ccc(C(=O)c2ccccc2C(=O)O)cc1
Yield: 79.8 %

Procedure:
74 g (0.5 mole) of phthalic anhydride were reacted with 128 g (1.05 moles) of AlCl3 and 25 g (0.2 mole) of diethylzinc in 74 g of tert-amylbenzene, similarly to Example 1. After the mixture had been worked up, 118 g (80% of theory) of pure 2-(4'-tert-amylbenzoyl)-benzoic acid were obtained.
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([S:15]([NH:18][C:19]3[C:20]([CH3:31])=[N:21][C:22]([N:25]4[CH2:29][CH2:28][O:27][C:26]4=[O:30])=[CH:23][CH:24]=3)(=[O:17])=[O:16])=[CH:11][CH:10]=2)=[C:5]([CH3:32])[O:4][N:3]=1.[CH3:33][C:34](N=C(N(C)C)N(C)C)([CH3:36])[CH3:35].BrCC(C)C>C(#N)C>[CH3:1][C:2]1[C:6]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([S:15]([N:18]([C:19]3[C:20]([CH3:31])=[N:21][C:22]([N:25]4[CH2:29][CH2:28][O:27][C:26]4=[O:30])=[CH:23][CH:24]=3)[CH2:33][CH:34]([CH3:36])[CH3:35])(=[O:16])=[O:17])=[CH:11][CH:10]=2)=[C:5]([CH3:32])[O:4][N:3]=1
Reactant: Cc1nc(N2CCOC2=O)ccc1NS(=O)(=O)c1ccc(OCc2c(C)noc2C)cc1
Reactant: CN(C)C(=NC(C)(C)C)N(C)C
Solvent: CC(C)CBr
Solvent: CC#N
Product: Cc1nc(N2CCOC2=O)ccc1N(CC(C)C)S(=O)(=O)c1ccc(OCc2c(C)noc2C)cc1
Temperature: 80 °C
Yield: 65 %

Procedure:
To a solution of 4-{[(3,5-dimethyl-4-isoxazolyl)methyl]oxy}-N-[2-methyl-6-(2-oxo-1,3-oxazolidin-3-yl)-3-pyridinyl]benzenesulfonamide (137 mg, 0.299 mmol) and N″-(1,1-dimethylethyl)-N,N,N′,N′-tetramethylguanidine (51 mg, 0.299 mmol) in acetonitrile (2 mL) was added 1-bromo-2-methylpropane (0.065 mL, 0.598 mmol). The reaction vessel was heated at 80° C. for 8 hours. The reaction mixture was then separated between ethyl acetate and saturated sodium bicarbonate solution. The organic phase was washed with brine, dried over magnesium sulphate then concentrated in vacuo. The crude was purified by flash silica (Si) chromatography (0-100% ethyl acetate-cyclohexane gradient) to give the title compound (100 mg) as a white foam. LCMS (2 min, formic) Rt 1.21 min, m/z (ES+) 515 (M+H).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:12]2[CH2:17][CH2:16][N:15]([CH:18]=[O:19])[CH2:14][CH2:13]2)[C:5]2[S:11][CH2:10][CH2:9][CH2:8][C:6]=2[N:7]=1.O.[CH3:21][NH2:22]>CO.C(O)C>[CH3:21][NH:22][C:2]1[N:3]=[C:4]([N:12]2[CH2:17][CH2:16][N:15]([CH:18]=[O:19])[CH2:14][CH2:13]2)[C:5]2[S:11][CH2:10][CH2:9][CH2:8][C:6]=2[N:7]=1
Reactant: CN
Reactant: O=CN1CCN(c2nc(Cl)nc3c2SCCC3)CC1
Solvent: CO
Solvent: CCO
Solvent: O
Product: CNc1nc2c(c(N3CCN(C=O)CC3)n1)SCCC2

Procedure:
7 g of 2-chloro-4-(N-formylpiperazino)-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidine was dissolved in 100 ml of a mixture of methanol-ethanol (1:1 by volume), and 50 ml of a 40% aqueous solution of methylamine was added thereto, followed by gently stirring while warming for 7 hours. A large amount of water was added to the mixture which was then extracted with chloroform. The organic layer was washed with water and dried over magnesium sulfate. The solvent was distilled off and PG,16 the resulting residue was purified by silica gel column chromatography (eluted with ethyl acetate-n-hexane, 1:1 by volume) to obtain 3 g of 2-methylamino-4-(N-formylpiperazino)-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidine as colorless prisms having a melting point of 149°-151° C.
Reaction SMILES: C([O:5][C:6](=[O:31])[C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH2:17][C:16]([C:22]3[CH:27]=[C:26]([Cl:28])[CH:25]=[C:24]([Cl:29])[CH:23]=3)([C:18]([F:21])([F:20])[F:19])[CH2:15][N:14]=2)=[CH:9][C:8]=1[Cl:30])CCC.O.[OH-].[Li+].Cl>C1COCC1.O>[Cl:30][C:8]1[CH:9]=[C:10]([C:13]2[CH2:17][C:16]([C:22]3[CH:23]=[C:24]([Cl:29])[CH:25]=[C:26]([Cl:28])[CH:27]=3)([C:18]([F:19])([F:21])[F:20])[CH2:15][N:14]=2)[CH:11]=[CH:12][C:7]=1[C:6]([OH:31])=[O:5]
Reactant: CCCCOC(=O)c1ccc(C2=NCC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1Cl
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1ccc(C2=NCC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1Cl
Temperature: 50 °C
Reaction time: 20 h
Yield: 107.9 %

Procedure:
To a solution of 2-chloro-4-[4-(3,5-dichloro-phenyl)-4-trifluoromethyl-4,5-dihydro-3H-pyrrol-2-yl]-benzoic acid butyl ester (Example I16) (0.48 g) in THF (16 ml) and water (8 ml) was added lithium hydroxide monohydrate (103 mg). The reaction mixture was stirred at 50° C. for 20 hours. The reaction mixture was cooled to ambient temperature and diluted with water, acidified by addition of aqueous hydrochloric acid (1M) and extracted twice with ethyl acetate. The combined organic phases were washed with brine, dried over sodium sulfate and concentrated to give 2-chloro-4-[4-(3,5-dichloro-phenyl)-4-trifluoromethyl-4,5-dihydro-3H-pyrrol-2-yl]-benzoic acid (459 mg). 1H-NMR (400 MHz, CDCl3): 8.15-7.40 (m, 6H), 4.95 (d, 1H), 4.30 (d, 1H), 3.85 (d, 1H), 3.35 (d, 1H) ppm.
Reaction SMILES: Cl.[NH2:2][CH:3]1[CH2:15][C:14]2[C:6](=[CH:7][C:8]3[CH2:12][CH2:11][O:10][C:9]=3[CH:13]=2)[CH2:5][CH2:4]1.C(N(CC)CC)C.[F:23][C:24]([F:31])([F:30])[C:25](OCC)=[O:26]>CO>[F:23][C:24]([F:31])([F:30])[C:25]([NH:2][CH:3]1[CH2:15][C:14]2[C:6](=[CH:7][C:8]3[CH2:12][CH2:11][O:10][C:9]=3[CH:13]=2)[CH2:5][CH2:4]1)=[O:26]
Reactant: NC1CCc2cc3c(cc2C1)OCC3
Reactant: CCOC(=O)C(F)(F)F
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CO
Product: O=C(NC1CCc2cc3c(cc2C1)OCC3)C(F)(F)F
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture containing 5 g of the compound of Example 2, 3.35 ml of triethylamine and 4 ml of ethyl trifluoroacetate in 7 ml of methanol is stirred for 4 hours at room temperature. The mixture is then evaporated to dryness and the dry residue obtained is recrystallized in isopropyl ether.
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:10][CH:9]([S:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[C:20]([F:23])([F:22])[F:21])(=[O:13])=[O:12])[CH2:8][N:7]1[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[C:30]([CH3:33])([CH3:32])[CH3:31])=[O:5])C.[OH-].[Li+]>>[C:30]([C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=1[N:7]1[CH2:8][CH:9]([S:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[C:20]([F:22])([F:23])[F:21])(=[O:13])=[O:12])[CH2:10][CH:6]1[C:4]([OH:5])=[O:3])([CH3:33])([CH3:31])[CH3:32]
Reactant: CCOC(=O)C1CC(S(=O)(=O)c2ccccc2C(F)(F)F)CN1c1ccccc1C(C)(C)C
Agent: [Li+]
Agent: [OH-]
Product: CC(C)(C)c1ccccc1N1CC(S(=O)(=O)c2ccccc2C(F)(F)F)CC1C(=O)O

Procedure:
In analogy to the procedure described in example 253e, 1-(2-tert-butyl-phenyl)-4-(2-trifluoromethyl-benzenesulfonyl)-pyrrolidine-2-carboxylic acid ethyl ester was saponified in the presence of lithium hydroxide to give the title compound as off-white solid which was used in the next step without further purification. MS (ESI): m/z=456.2 [M+H]+.
Reaction SMILES: [CH2:1]([O:8][NH:9][C:10](=[O:19])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH2:21]([O:23][C:24]1[CH:25]=[C:26]2[C:31](=[CH:32][C:33]=1[O:34][CH2:35][CH3:36])[CH2:30][NH:29][CH2:28][CH2:27]2)[CH3:22].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:1]([O:8][NH:9][C:10](=[O:19])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][N:29]1[CH2:28][CH2:27][C:26]2[C:31](=[CH:32][C:33]([O:34][CH2:35][CH3:36])=[C:24]([O:23][CH2:21][CH3:22])[CH:25]=2)[CH2:30]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOc1cc2c(cc1OCC)CNCC2
Reactant: O=C(CCCCCCCBr)NOCc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOc1cc2c(cc1OCC)CN(CCCCCCCC(=O)NOCc1ccccc1)CC2

Procedure:
In a manner analogous to that of example 1(b), 8-bromo-octanoic acid benzyloxy-amide (example 1(a); 0.38 g, 1.2 mmol) was reacted with 6,7-diethoxy-1,2,3,4-tetrahydroisoquinoline hydrochloride (0.3 g, 1.2 mmol) in the presence of potassium carbonate (0.16 g, 1.2 mmol) and DMF as solvent to give 8-(6,7-diethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-octanoic acid benzyloxyamide as an almost colorless wax (yield 0.15 g, 27%; purified by column chromatography using silica gel and ethyl acetate: methanol=9:1 as an eluent). MS (M+H+)=469.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4](Br)[C:5]2[N:6]([C:8]([I:11])=[CH:9][N:10]=2)[N:7]=1.[CH3:13][S-:14].[Na+].O>CN1C(=O)CCC1>[Br:1][C:2]1[CH:3]=[C:4]([S:14][CH3:13])[C:5]2[N:6]([C:8]([I:11])=[CH:9][N:10]=2)[N:7]=1
Reactant: C[S-]
Reactant: Brc1cc(Br)c2ncc(I)n2n1
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: O
Product: CSc1cc(Br)nn2c(I)cnc12
Yield: 81.6 %

Procedure:
To a stirred solution of 51.2 g (146.8 mmol) 6,8-dibromo-3-iodoimidazo[1,2-b]pyridazine which was prepared according to intermediate example 96c in NMP (450 mL) are added 12.35 g (176.2 mmol) sodium methanethiolate in one portion at 0° C. After reaction for 15 min, 700 mL water are added and the precipitate is filtered off and dried. Trituration with ether, filtration and drying in vaccuo. yields 44.3 g (65%) of the title compound
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][C:22]=1[O:23][CH3:24])[C:5]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([CH3:19])[CH:12]=1)([OH:10])[C:6]([O:8][CH3:9])=[O:7].[C@@:25]12(O)[N:32](C)[C@@H:29]([CH2:30][CH2:31]1)[CH2:28][CH:27]=[CH:26]2>>[CH3:19][C:13]1[CH:12]=[C:11]([CH:16]=[CH:15][C:14]=1[O:17][CH3:18])[C:5]([C:4]1[CH:20]=[CH:21][C:22]([O:23][CH3:24])=[C:2]([CH3:1])[CH:3]=1)([OH:10])[C:6]([O:8][C@@:9]12[N:32]([CH3:25])[C@@H:29]([CH2:30][CH2:31]1)[CH2:28][CH:27]=[CH:26]2)=[O:7]
Reactant: CN1[C@@H]2CC=C[C@@]1(O)CC2
Reactant: COC(=O)C(O)(c1ccc(OC)c(C)c1)c1ccc(OC)c(C)c1
Product: COc1ccc(C(O)(C(=O)O[C@]23C=CC[C@H](CC2)N3C)c2ccc(OC)c(C)c2)cc1C

Procedure:
4.17 is prepared analogously to the method according to II.1; the product is purified by recrystallizing from diethylether. Yield: 2.30 g (35% of theory) starting from 5.0 g (0.015 mol) of 3h and 4.21 g (0.03 mol) of tropenol; melting point: 126° C.
Reaction SMILES: Cl[C:2]([O:4][CH:5]1[CH2:9][CH2:8][CH2:7][CH2:6]1)=[O:3].FC(F)(F)C(O)=O.[NH:17]1[CH2:22][CH2:21][CH:20]([N:23]2[C:27]3=[N:28][CH:29]=[N:30][C:31]([O:32][C:33]4[CH:40]=[CH:39][CH:38]=[CH:37][C:34]=4[C:35]#[N:36])=[C:26]3[CH:25]=[N:24]2)[CH2:19][CH2:18]1.C(OC(N1CCC(N2C3=NC=NC(OC4C=CC=CC=4C#N)=C3C=N2)CC1)=O)(C)(C)C.FC(F)(F)C(O)=O.C(OC1C=CC(OC2N=CN=C3N(C4CCNCC4)N=CC=23)=C(F)C=1)C.C(N(C(C)C)CC)(C)C>ClCCl.O>[CH:5]1([O:4][C:2]([N:17]2[CH2:22][CH2:21][CH:20]([N:23]3[C:27]4=[N:28][CH:29]=[N:30][C:31]([O:32][C:33]5[CH:40]=[CH:39][CH:38]=[CH:37][C:34]=5[C:35]#[N:36])=[C:26]4[CH:25]=[N:24]3)[CH2:19][CH2:18]2)=[O:3])[CH2:9][CH2:8][CH2:7][CH2:6]1
Reactant: O=C(Cl)OC1CCCC1
Reactant: N#Cc1ccccc1Oc1ncnc2c1cnn2C1CCNCC1
Agent: CC(C)(C)OC(=O)N1CCC(n2ncc3c(Oc4ccccc4C#N)ncnc32)CC1
Agent: CCOc1ccc(Oc2ncnc3c2cnn3C2CCNCC2)c(F)c1
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1ccccc1Oc1ncnc2c1cnn2C1CCN(C(=O)OC2CCCC2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 72 %

Procedure:
Cyclopentyl chloroformate (51 mg, 0.344 mmol) was added to a mixture of 2-(1-piperidin-4-yl-1H-pyrazolo[3,4-d]pyrimidine-4-yloxy)-benzonitrile trifluoroacetate salt (which was prepared from 4-[4-(2-cyano-phenoxy)-pyrazolo[3,4-d]pyrimidin-1-yl]-piperidine-1-carboxylic acid tert-butyl ester [Example 45] following the procedure described for the preparation of Intermediate 29; 150 mg, 0.344 mmol), diisopropylethylamine (133 mg, 1.03 mmol) in dichloromethane (6 mL). The reaction was stirred at room temperature overnight. Water was added to quench the reaction and the aqueous layer was extracted three times with dichloromethane. The combined organic layers were dried (sodium sulfate), filtered, evaporated and purified by flash chromatography on silica gel, eluting with 4% methanol/dichloromethane to give 4-[4-(2-cyano-phenoxy)-pyrazolo[3,4-d]pyrimidin-1-yl]-piperidine-1-carboxylic acid cyclopentyl ester (107 mg, 72%) as a white solid. Mass spectrum MH+=433.
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:62])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([O:50][CH2:51][CH:52]([C:54]3[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=3)[OH:53])[CH:46]([O:60][CH3:61])[CH2:45]2)[CH:7]([CH3:63])[CH:6]([O:64][Si](C(C)(C)C)(C)C)[CH2:5][C:4]1=[O:72])[CH3:2].C1C=CN=CC=1.F>C1COCC1>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:62])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([O:50][CH2:51][CH:52]([C:54]3[CH:55]=[CH:56][CH:57]=[CH:58][CH:59]=3)[OH:53])[CH:46]([O:60][CH3:61])[CH2:45]2)[CH:7]([CH3:63])[CH:6]([OH:64])[CH2:5][C:4]1=[O:72])[CH3:2]
Reactant: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(OCC(O)c4ccccc4)C(OC)C3)C(C)C(O[Si](C)(C)C(C)(C)C)CC1=O)C(C)CC2OC
Agent: F
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(OCC(O)c4ccccc4)C(OC)C3)C(C)C(O)CC1=O)C(C)CC2OC
Temperature: 25 °C
Reaction time: 24 h
Yield: 42.7 %

Procedure:
To a solution of the product from Step A (29 mg) in THF (400 μl) was added hydrogen fluoride/pyridine and the reaction mixture stirred at room temperature for 24 hours. The reaction was then quenched by the addition of saturated aqueous sodium bicarbonate and extracted into ethyl acetate. The organic phase was dried with magnesium sulphate and concentrated. The crude material was purified by column chromatography on silica gel eluting with 70% hexane:30% ethyl acetate to give the title compound (11 mg).
Reaction SMILES: [CH3:1][O-:2].[Na+].Cl[C:5]1[C:6]([CH3:15])=[C:7]([NH2:14])[C:8]([N+:11]([O-:13])=[O:12])=[CH:9][CH:10]=1.Cl>CO>[CH3:1][O:2][C:5]1[C:6]([CH3:15])=[C:7]([NH2:14])[C:8]([N+:11]([O-:13])=[O:12])=[CH:9][CH:10]=1
Reactant: Cc1c(Cl)ccc([N+](=O)[O-])c1N
Reactant: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COc1ccc([N+](=O)[O-])c(N)c1C
Yield: 86 %

Procedure:
Sodium methoxide in methanol (110 mL of 25% solution, 0.49 mol, 20 equiv) was added to a stirred suspension of 3-chloro-2-methyl-6-nitrobenzenamine (4.0 g, 23.5 mmol) in methanol (250 mL) and the mixture was stirred at reflux for 18 hours. The solution was cooled, neutralized with methanolic hydrogen chloride, filtered to remove sodium chloride, and the solvent was removed under reduced pressure. The residual solid was partitioned between ethyl acetate and water. Evaporation of the ethyl acetate gave 3.7 g (86%) of 3-methoxy-2-methyl-6-nitrobenzenamine.
Reaction SMILES: C1(C2C3C(=CC=CC=3)C=CC=2)C2C(=CC=CC=2)C=CC=1P1C(C)(C)CC2(OCCO2)CC1(C)C.C(N(CC)CC)C.Br[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1.[CH2:49]([O:51][P:52]([O-:56])[O:53][CH2:54][CH3:55])[CH3:50]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(O)C>[C:43]1([P:52](=[O:56])([O:53][CH2:54][CH3:55])[O:51][CH2:49][CH3:50])[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1
Reactant: Brc1ccccc1
Reactant: CCOP([O-])OCC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)CC2(CC(C)(C)P1c1ccc3ccccc3c1-c1cccc3ccccc13)OCCO2
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCOP(=O)(OCC)c1ccccc1
Temperature: 80 °C
Reaction time: 24 h
Yield: 59 %

Procedure:
In a nitrogen-atmosphere glovebox, a microwave vial equipped with a magnetic stir bar was charged with palladium(II) acetate (1.4 mg, 0.00637 mmol, 0.02 equivalents), 8-(1,1′-binaphthyl-2-yl)-7,7,9,9-tetramethyl-1,4-dioxa-8-phosphaspiro[4.5]decane (3.6 mg, 0.00764 mmol, 0.024 equivalents) and ethanol (0.64 mL). To the slurry were added triethylamine (67 μL, 0.478 mmol, 1.5 equivalents), bromobenzene (34 μL, 0.318 mmol, 1 equivalent) and diethylphosphite (49 μL, 0.382 mmol, 1.2 equivalents). The vial was sealed with a crimp top and stirred at 80° C. After 24 hours, the vial was removed from the heating block, cooled to room temperature and brought out of the glovebox. The reaction solution was diluted with tetrahydrofuran (2 mL) and filtered into a tared 125-mL Erlenmeyer flask. The vial was rinsed with tetrahydrofuran (5×1 mL), followed by washing of the filter cake with tetrahydrofuran (5 mL). A wt % analysis was performed on the filtrate and an assay yield of 59% was measured versus commercially available diethyl phenylphosphonate.