Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[S:10][C:9]2[C:8](=[O:11])[NH:7][C:6]3([CH2:15][CH2:14][CH2:13][CH2:12]3)[N:5]([CH2:16][CH3:17])[C:4]=2[CH:3]=1.[CH3:18][C:19]1[C:23](B2OC(C)(C)C(C)(C)O2)=[CH:22][N:21](C(OC(C)(C)C)=O)[N:20]=1.C(=O)([O-])[O-].[Na+].[Na+].COCCOC>O>[CH2:16]([N:5]1[C:4]2[CH:3]=[C:2]([C:23]3[CH:22]=[N:21][NH:20][C:19]=3[CH3:18])[S:10][C:9]=2[C:8](=[O:11])[NH:7][C:6]21[CH2:15][CH2:14][CH2:13][CH2:12]2)[CH3:17]
Reactant: Cc1nn(C(=O)OC(C)(C)C)cc1B1OC(C)(C)C(C)(C)O1
Reactant: CCN1c2cc(Br)sc2C(=O)NC12CCCC2
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: CCN1c2cc(-c3cn[nH]c3C)sc2C(=O)NC12CCCC2
Temperature: 100 °C
Reaction time: 1 h
Yield: 54.4 %

Procedure:
A flask was charged with 6′-bromo-1′-ethyl-1′H-spiro [cyclopentane-1,2′-thieno[3,2-d]pyrimidin]-4′(3′H)-one (158 mg, 0.50 mmol), tert-butyl 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate (463 mg, 1.5 mmol), sodium carbonate (150 mg, 2.5 mmol), 1,2-dimethoxyethane (3.0 mL) and water (1.5 mL). The flask was purged with argon. Then, 1,1′-bis(diphenylphosphino)ferrocenepalladium (II) dichloride dichloromethane adduct (41 mg, 0.050 mmol) was added to the mixture. The flask was purged with argon again. After stirring at 100° C. for 1 h, 8 M aqueous NaOH (0.5 mL) was added. After stirring at 100° C. for 1 h, organic materials were extracted with EtOAc. The combined extracts were washed with brine, dried over Na2SO4 and filtered. After removal of the solvent at reduced pressure, the residue was purified by column chromatography (Purif, silica gel, 50:50 hexane/EtOAc to EtOAc), then crystallized from MeOH/EtOAc/hexane to give the title compound (86 mg, 54%) as a yellow solid:
Reaction SMILES: [NH2:1][CH2:2][C:3]([CH3:16])([CH3:15])[C:4]([NH:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[Cl:14])=[O:5].CCN(C(C)C)C(C)C.[CH2:26]([C:28]1[CH:33]=[CH:32][C:31]([N:34]=[C:35]=[O:36])=[CH:30][CH:29]=1)[CH3:27]>C(Cl)Cl>[Cl:14][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[CH2:7][NH:6][C:4](=[O:5])[C:3]([CH3:16])([CH3:15])[CH2:2][NH:1][C:35]([NH:34][C:31]1[CH:32]=[CH:33][C:28]([CH2:26][CH3:27])=[CH:29][CH:30]=1)=[O:36]
Reactant: CCc1ccc(N=C=O)cc1
Reactant: CC(C)(CN)C(=O)NCc1ccccc1Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCc1ccc(NC(=O)NCC(C)(C)C(=O)NCc2ccccc2Cl)cc1
Reaction time: 0.5 h
Yield: 17 %

Procedure:
To a solution of 3-amino-N-(2-chlorobenzyl)-2,2-dimethylpropanamide (0.45 mmol) in DCM (5 mL) was added DIEA (157 μL, 0.90 mmol, 2 equiv.) and 4-ethylphenyl isocyanate (97.0 μL, 0.675 mmol, 1.5 equiv.). The reaction mixture was stirred for 30 min. The mixture was concentrated and purified on RP-HPLC using a mixture of acetonitrile and H2O to give N-(2-chlorobenzyl)-3-(3-(4-ethylphenyl)ureido)-2,2-dimethylpropanamide (29.6 mg, 17% for two steps). LRMS (M+H+) m/z 388.1.
Reaction SMILES: Cl.Cl.[C:3]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][CH2:15][CH2:16][N:17]2[CH2:24][CH:23]3[O:25][CH:19]([CH2:20][NH:21][CH2:22]3)[CH2:18]2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)#[N:4].[O:26]1[C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=2[C:28]([CH2:35][CH2:36]OS(C)(=O)=O)=[N:27]1.C(=O)([O-])[O-].[K+].[K+].C(#N)C>O>[O:26]1[C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=2[C:28]([CH2:35][CH2:36][N:21]2[CH2:22][CH:23]3[O:25][CH:19]([CH2:18][N:17]([CH2:16][CH2:15][NH:14][S:11]([C:8]4[CH:9]=[CH:10][C:5]([C:3]#[N:4])=[CH:6][CH:7]=4)(=[O:13])=[O:12])[CH2:24]3)[CH2:20]2)=[N:27]1
Reactant: CS(=O)(=O)OCCc1noc2ccccc12
Reactant: N#Cc1ccc(S(=O)(=O)NCCN2CC3CNCC(C2)O3)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: N#Cc1ccc(S(=O)(=O)NCCN2CC3CN(CCc4noc5ccccc45)CC(C2)O3)cc1
Temperature: 160 °C
Yield: 41.5 %

Procedure:
To 4-cyano-N-[2-(9-oxa-3,7-diaza-bicyclo[3.3.1]non-3-yl)-ethyl]-benzenesulfonamide dihydrochloride (0.123 g, 0.30 mmol, from prep E above), methanesulfonic acid 2-benzo[d]isoxazol-3-yl-ethyl ester (0.076 g, 0.315 mmol, from prep AD above) and potassium carbonate (0.145 g, 1.05 mmol; from Prep ) was added acetonitrile (4 mL) and water (0.1 mL). The mixture was heated by microwave irradiation (10 minutes, 160° C.) and was then filtered and evaporated. The crude product was purified by chromatography on silica gel using methanol saturated with ammonia in dichloromethane as eluent, which afforded 60 mg (41.5%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[CH:9]=[CH:10][C:11]3[C:12]4[N:26](C5CCCCO5)[N:25]=[CH:24][C:13]=4[C:14](=[O:23])[N:15]([CH2:18][C:19]([F:22])([F:21])[F:20])[C:16]=3[CH:17]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.ClC1C(C2C=CC3C4NN(C5CCCCO5)CC=4C(=O)N(CC(F)(F)F)C=3C=2)=CC=CN=1.Cl.O1CCOCC1>C(Cl)Cl>[Cl:1][C:2]1[C:7]([C:8]2[CH:9]=[CH:10][C:11]3[C:12]4[NH:26][N:25]=[CH:24][C:13]=4[C:14](=[O:23])[N:15]([CH2:18][C:19]([F:22])([F:21])[F:20])[C:16]=3[CH:17]=2)=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: O=c1c2cnn(C3CCCCO3)c2c2ccc(-c3cccnc3Cl)cc2n1CC(F)(F)F
Agent: Cl
Agent: O=c1c2c(c3ccc(-c4cccnc4Cl)cc3n1CC(F)(F)F)NN(C1CCCCO1)C2
Solvent: ClCCl
Solvent: C1COCCO1
Product: O=c1c2cn[nH]c2c2ccc(-c3cccnc3Cl)cc2n1CC(F)(F)F
Temperature: 25 °C
Reaction time: 3 h
Yield: 15 %

Procedure:
To a solution of 7-(2-chloropyrid-3-yl)-1-(tetrahydro-2H-pyran-2-yl)-5-(2,2,2-trifluoroethyl)-1,5-dihydro-4H-pyrazolo[4,3-c]quinolin-4-one and 7-(2-chloropyrid-3-yl)-2-(tetrahydro-2H-pyran-2-yl)-5-(2,2,2-trifluoroethyl)-1,5-dihydro-4H-pyrazolo[4,3-c]quinolin-4-one (1.6 g, 3.46 mmol) in 34 mL of DCM, is added a 4M solution of hydrogen chloride in dioxane (8.5 mL, 34.6 mmol). The mixture is stirred for 3 hours at room temperature and concentrated to dryness. After purification by flash chromatography on amine phase (DCM/EtOH: 100/0 to 90/10), 189 mg of a white solid are obtained (yield=15%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=2[C:10]([OH:12])=O)=[CH:4][C:3]=1[C:17](=[O:25])[NH:18][C:19]1[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=1.[CH2:26]([NH:28][CH2:29][CH3:30])[CH3:27]>>[NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=2[C:10](=[O:12])[N:28]([CH2:29][CH3:30])[CH2:26][CH3:27])=[CH:4][C:3]=1[C:17]([NH:18][C:19]1[CH:20]=[CH:21][N:22]=[CH:23][CH:24]=1)=[O:25]
Reactant: CCNCC
Reactant: Nc1ncc(-c2ccccc2C(=O)O)cc1C(=O)Nc1ccncc1
Product: CCN(CC)C(=O)c1ccccc1-c1cnc(N)c(C(=O)Nc2ccncc2)c1

Procedure:
Reaction of 2-[6-amino-5-(pyridin-4-ylcarbamoyl)-pyridin-3-yl]-benzoic acid with diethyl amine gives “A100”; method 2: HPLC/MS: 1.35 min, [M+H]=390;
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:7]=[C:8]([O:12][CH3:13])[C:9]=1[O:10][CH3:11])[NH2:6].[H-].[Na+].[CH3:16][O:17][C:18]1[C:23]2[CH2:24][CH2:25][C:26]3[CH:27]=[N:28][C:29](SC)=[N:30][C:31]=3[C:22]=2[CH:21]=[CH:20][CH:19]=1.O>O1CCCC1>[CH3:16][O:17][C:18]1[C:23]2[CH2:24][CH2:25][C:26]3[CH:27]=[N:28][C:29]([NH:6][C:5]4[CH:7]=[C:8]([O:12][CH3:13])[C:9]([O:10][CH3:11])=[C:3]([O:2][CH3:1])[CH:4]=4)=[N:30][C:31]=3[C:22]=2[CH:21]=[CH:20][CH:19]=1
Reactant: COc1cccc2c1CCc1cnc(SC)nc1-2
Reactant: COc1cc(N)cc(OC)c1OC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COc1cccc2c1CCc1cnc(Nc3cc(OC)c(OC)c(OC)c3)nc1-2
Reaction time: 0.25 h
Yield: 77.4 %

Procedure:
To a solution of 3,4,5-trimethoxyaniline (0.401 g) in tetrahydrofuran at room temperature under nitrogen was added sodium hydride (60% oil dispersion, 0.16 g) in portions over 2-3 minutes. The mixture was stirred for 15 minutes, and then 7-methoxy-2-methylthio-5,6-dihydrobenzo[h]quinazoline (0.258 g) was added, and the mixture was refluxed for 4 hours. The reaction mixture was poured into 300 ml of water, and the resulting yellow precipitate filtered off, washed with pentane, and dried under vacuum, giving 7-methoxy-2-(3,4,5-trimethoxyanilino)-5,6-dihydrobenzo[h]quinazoline (0.3042 g).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9]O)=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[O:30]1[CH2:34][C:33](=[O:35])[NH:32][C:31]1=[O:36].N(C(OC(C)C)=O)=NC(OC(C)C)=O>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][N:32]2[C:33](=[O:35])[CH2:34][O:30][C:31]2=[O:36])=[CH:6][CH:7]=1
Reactant: OCCc1ccc(Br)cc1
Reactant: O=C1COC(=O)N1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: O=C1COC(=O)N1CCc1ccc(Br)cc1

Procedure:
The procedure described in Example 2 (step 2.1.) is used; starting from 4 g (19.89 mmol) of 2-(4-bromophenyl)ethanol, 6.3 g (23.87 mmol) of triphenylphosphine, 2.4 g (23.87 mmol) of 1,3-oxazolidine-2,4-dione and 4.8 g (23.87 mmol) of diisopropyl azodicarboxylate, 4.6 g of pure product are obtained in the form of a white solid, after chromatography on silica gel, eluting with dichloromethane.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=C(C=C)[N:6]2[C:11]1[CH:16]=[CH:15][C:14]([NH:17][C:18]([NH:20][C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[C:23]([C:28]([F:31])([F:30])[F:29])[CH:22]=2)=[O:19])=[CH:13][CH:12]=1.[OH:34]O.[O:36]1[CH2:40][CH2:39][CH2:38]C1>[Os](=O)(=O)(=O)=O>[NH2:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[C:38]([CH:39]([OH:34])[CH2:40][OH:36])[N:6]2[C:11]1[CH:16]=[CH:15][C:14]([NH:17][C:18]([NH:20][C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[C:23]([C:28]([F:31])([F:30])[F:29])[CH:22]=2)=[O:19])=[CH:13][CH:12]=1
Reactant: C1CCOC1
Reactant: C=Cc1nc2c(N)ncnc2n1-c1ccc(NC(=O)Nc2ccc(Cl)c(C(F)(F)F)c2)cc1
Reactant: OO
Agent: O=[Os](=O)(=O)=O
Product: Nc1ncnc2c1nc(C(O)CO)n2-c1ccc(NC(=O)Nc2ccc(Cl)c(C(F)(F)F)c2)cc1
Temperature: 25 °C
Reaction time: 14 h
Yield: 77 %

Procedure:
In 1 mL of tetrahydrofuran, 20 mg (0.04 mmol) of 1-[4-(6-amino-8-vinylpurin-9-yl)phenyl]-3-(4-chloro-3-(trifluoromethyl)phenyl)urea was dissolved, and 20 μL of a 0.1 M osmium tetraoxide aqueous solution and 143 μL of a 3% hydrogen peroxide aqueous solution were added thereto, and the mixture solution was stirred at room temperature for 14 hours. The reaction solution was concentrated under reduced pressure and purified by a silica gel column (dichloromethane:methanol=9:1) to obtain 16.4 mg (77%) of a target product as a white crystal.
Reaction SMILES: C(OC([NH:8][C:9]([NH:26]C(OC(C)(C)C)=O)=[N:10][C:11]1[CH:16]=[C:15]([C:17]2[CH:22]=[C:21]([O:23][CH3:24])[CH:20]=[CH:19][N:18]=2)[CH:14]=[CH:13][C:12]=1[CH3:25])=O)(C)(C)C.[ClH:34]>ClCCl.O1CCOCC1>[ClH:34].[ClH:34].[CH3:24][O:23][C:21]1[CH:20]=[CH:19][N:18]=[C:17]([C:15]2[CH:14]=[CH:13][C:12]([CH3:25])=[C:11]([NH:10][C:9]([NH2:26])=[NH:8])[CH:16]=2)[CH:22]=1
Reactant: COc1ccnc(-c2ccc(C)c(N=C(NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)c2)c1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: COc1ccnc(-c2ccc(C)c(NC(=N)N)c2)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of N,N′-bis(tert-butoxycarbonyl)-N″-(5-(4-methoxypyridin-2-yl)-2-methylphenyl)guanidine (200 mg) in dichloromethane (2 ml) was added a solution of hydrogen chloride in 1,4-dioxane (4N, 4 ml), and the mixture was stirred at room temperature for 18 hours. The solvent was evaporated under reduced pressure. To the residue was added 5% ethanol in ethyl acetate (100 ml), and the precipitate was collected by filtration and dried under reduced pressure to give (5-(4-methoxypyridin-2-yl)-2-methylphenyl)-guanidine dihydrochloride (127 mg).
Reaction SMILES: C(OC([NH:8][C@H:9]([C:13]([OH:15])=O)[CH:10]([CH3:12])[CH3:11])=O)(C)(C)C.[F:16][C:17]1([F:33])[C@H:21]([CH3:22])[N:20](C(=O)[C@H](CC(C)C)N)[C@H:19]([C:31]#[N:32])[CH2:18]1>>[F:16][C:17]1([F:33])[C@H:21]([CH3:22])[N:20]([C:13](=[O:15])[C@H:9]([CH:10]([CH3:11])[CH3:12])[NH2:8])[C@H:19]([C:31]#[N:32])[CH2:18]1
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: CC(C)C[C@H](N)C(=O)N1[C@H](C#N)CC(F)(F)[C@@H]1C
Product: CC(C)[C@H](N)C(=O)N1[C@H](C#N)CC(F)(F)[C@@H]1C

Procedure:
This compound was prepared from 51 mg (0.23 mmol) of (S)-N-tert-butoxycarbonylvaline and 50 mg (0.23 mmol) of (2,5-cis) 4,4-difluoro-5-methyl-pyrrolidine-2-carboxylic acid methyl ester hydrochloride (Example 95G) according to the same five step sequence as for (2S,5S)-4,4-difluoro-1-L-leucyl-5-methylpyrrolidine-2-carbonitrile (example 95H through example 95L) to give the titled compound as a colorless foam. 1H NMR (500 MHz, DMSO-d6) (mixture of rotamers, major rotamer only) δ ppm 0.99 (m, 6H) 1.37 (m, 3H) 2.11 (m, 1H) 2.96 (m, 1H) 3.09 (m, 1H) 4.09 (bs, 1H) 4.65 (m, 1H) 5.06 (t, J=8.6 Hz, 1H) 8.31 (bs, 3H) MS (ESI) m/z=246 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH2:23][CH2:24][N:25]2[CH2:30][CH2:29][C:28]([OH:37])([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH2:27][CH2:26]2)[C:10]([C:12]2[NH:16][N:15]=[N:14][C:13]=2[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8].[N-]=[N+]=[N-].[Na+].[Cl:42]C1C=C(C(CCN2CCC(O)(C3C=CC=CC=3)CC2)C(=O)C#CC2C=CC=CC=2)C=CC=1Cl>CN(C)C=O>[ClH:1].[ClH:42].[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH2:23][CH2:24][N:25]2[CH2:30][CH2:29][C:28]([OH:37])([C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)[CH2:27][CH2:26]2)[CH:10]([C:12]2[N:16]=[N:15][NH:14][C:13]=2[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[OH:11])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C(c1[nH]nnc1-c1ccccc1)C(CCN1CCC(O)(c2ccccc2)CC1)c1ccc(Cl)c(Cl)c1
Reactant: O=C(C#Cc1ccccc1)C(CCN1CCC(O)(c2ccccc2)CC1)c1ccc(Cl)c(Cl)c1
Agent: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cl
Product: OC(c1nn[nH]c1-c1ccccc1)C(CCN1CCC(O)(c2ccccc2)CC1)c1ccc(Cl)c(Cl)c1
Temperature: 35 °C
Reaction time: 3 h
Yield: 83 %

Procedure:
5-[2-(3,4-Dichlorophenyl)-4-(4-hydroxy-4-phenylpiperidino)butyroyl]-4-phenyl-(1H)-1,2,3-triazole. A suspension of sodium azide (38 mg) in N,N-dimethylformamide (1 mL) was treated dropwise with a solution of 4-(3,4-dichlorophenyl)-6-(4-hydroxy-4-phenyl-piperidino)-1-phenyl-1-hexyn-3-one (287 mg) in N,N-dimethylformamide (4 mL). The reaction mixture was warmed to 35° C. and was stirred for 3 hours. The reaction was quenched by addition of water and extracted with ethyl acetate. The organic extracts were combined, washed (water, brine) and evaporated to leave an orange syrup. The syrup was triturated with dichloromethane to afford the triazole as a pale tan powder (260 mg, 83%). NMR (d6-DMSO): 7.89 (m,2), 7.63 (d, J=1.8 Hz, 1), 7.57 (d, J=8.3 Hz, 1), 7.45-7.17 (m,9), 5.24 (t, J=7.3 Hz, 1H, H-C(2')), 4.91 (broad s, 1H, O), 2.86-2.50 (m,7), 1.95-1.49 (m,5H).
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][C:5]2[C:6](=[O:18])[C:7]3[C:14]([C:15]([OH:17])=O)=[N:13][NH:12][C:8]=3[C:9](=[O:11])[NH:10][C:4]=2[CH:3]=1.P(Cl)(Cl)(Cl)(Cl)Cl.[CH3:27][NH:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.O1CCOCC1>C(Cl)(Cl)(Cl)Cl.O>[Cl:1][C:2]1[CH:20]=[CH:19][C:5]2[C:6](=[O:18])[C:7]3[C:14]([C:15]([N:28]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[CH3:27])=[O:17])=[N:13][NH:12][C:8]=3[C:9](=[O:11])[NH:10][C:4]=2[CH:3]=1
Reactant: CNc1ccccc1
Reactant: O=C(O)c1n[nH]c2c(=O)[nH]c3cc(Cl)ccc3c(=O)c12
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: C1COCCO1
Solvent: ClC(Cl)(Cl)Cl
Solvent: O
Product: CN(C(=O)c1n[nH]c2c(=O)[nH]c3cc(Cl)ccc3c(=O)c12)c1ccccc1
Reaction time: 17 h
Yield: 15.3 %

Procedure:
To a suspension of 7-chloro-3-(carboxy)pyrazolo[3,4c][1]-benzazepine-4,10(1H,9H)-dione (500 mg, 1.72 mmol) (compound of Example 9) in carbon tetrachloride (5 mL) was added phosphorus pentachloride (358 mg, 1.72 mmol). The mixture was stirred for 17 hours, filtered and washed with carbon tetrachloride (3×10 mL). To the residue was added N-methylaniline (190 μL, 1.72 mmol) and dioxane (7 mL). The resulting mixture was stirred 17 hours. To this mixture was added water (50 mL). The aqueous layer was separated and extracted with ethyl acetate (3×100 mL). The organic layers were combined and concentrated by rotary evaporation to 50 mL. The insoluble material was removed by filtration and the organic solution was preabsorbed onto silica gel and purified by flash chromatography eluting with chloroform and chloroform:2-propanol (99:1, 98:2-90:10). The product fractions were combined and concentrated by rotarv evaporation to give the title compound as a light yellow solid (100 mg, 15.2%, m.p. 308° C.).
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:8]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH3:15].[Cl:16][C:17]1[CH:18]=[C:19]([CH:23]=[C:24]([C:26]([F:29])([F:28])[F:27])[N:25]=1)[C:20]([OH:22])=O>>[Cl:16][C:17]1[CH:18]=[C:19]([CH:23]=[C:24]([C:26]([F:29])([F:28])[F:27])[N:25]=1)[C:20]([N:2]([CH3:1])[C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:8]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH3:15])=[O:22]
Reactant: CNc1cnccc1-c1ccccc1C
Reactant: O=C(O)c1cc(Cl)nc(C(F)(F)F)c1
Product: Cc1ccccc1-c1ccncc1N(C)C(=O)c1cc(Cl)nc(C(F)(F)F)c1

Procedure:
The title compound was prepared in analogy to example 90, from N-methyl-4-o-tolylpyridin-3-amine (example 1, intermediate a) and 2-chloro-6-trifluoromethyl-isonicotinic acid (prepared in analogy to F. Cottet, M. Schlosser, Eur. J. Org. Chem. 2004, 18, 3793-3798) after a reaction time of 66 hours. The compound was purified by two silica gel chromatographies (10 g column each, gradient of n-heptane:EtOAc (100:0 to 50:50) for the first and EtOAc for the second chromatography), followed by preparative HPLC (phenomenex gemini column, gradient of acetonitrile:water (containing 0.05% formic acid) (10:90 to 98:2)). Colorless foam (49%). MS (ESI): m/z=406.09 [M+H]+.
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[O:3].N[C:6](N)=[O:7].C(O)(=O)C[CH2:11][CH2:12][C:13]([OH:15])=[O:14]>>[NH2:1][C:2]([NH2:4])=[O:3].[C:6]([OH:7])(=[O:3])[CH2:11][CH2:12][C:13]([OH:15])=[O:14]
Reactant: O=C(O)CCCC(=O)O
Agent: NC(N)=O
Product: O=C(O)CCC(=O)O
Reaction time: 5 h

Procedure:
35 g. of urea was further added to the mother liquor with the urea-glutaric acid adduct removed and dissolved at 50° C. The resulting solution was then cooled to and allowed to stand at 15° C. for 5 hours to crystallize a urea-succinic acid adduct out of the solution. By filtration, 47 g. of urea-succinic acid adduct (including 21 g. of succinic acid) was obtained. The obtained urea-succinic acid adduct was dissolved in 500 g. of methanol at 30° C. and the resulting solution was treated with AMBERLYST 15 as used in Example 3 to remove urea. After removal of 300 g. of methanol, the solution was cooled to and allowed to stand at 20° C. to precipitate succinic acid. By filtration, 18 g. of succinic acid having a purity of 97.9% was obtained.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11]/[C:12](=[CH:17]\[C:18]1[S:19][CH:20]=[C:21]([CH3:23])[CH:22]=1)/[C:13]([O:15][CH3:16])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[NH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[SH:38]>CO>[NH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[S:38][CH:17]([C:18]1[S:19][CH:20]=[C:21]([CH3:23])[CH:22]=1)[C@@H:12]([C:13]([O:15][CH3:16])=[O:14])[NH:11][C:9]([O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:10]
Reactant: COC(=O)/C(=C/c1cc(C)cs1)NC(=O)OCc1ccccc1
Reactant: Nc1ccccc1S
Solvent: CCN(CC)CC
Solvent: CO
Product: COC(=O)[C@@H](NC(=O)OCc1ccccc1)C(Sc1ccccc1N)c1cc(C)cs1

Procedure:
The title compound was prepared according to the method of Example 94b, employing methyl (2Z)-2-{[(benzyloxy)carbonyl]amino}-3-(4-methyl-2-thienyl)acrylate (95b) (3.38 g, 10.2 mmol), triethylamine (0.722 g, 7.14 mmol), and 2-aminothiophenol (6.43 g, 51.4 mmol) in anhydrous methanol (41 mL). The crude product was crystallized from 4:1 (v/v) petroleum ether/ether affording the title compound (2.74 g, 59%) as a pale yellow solid. 1H NMR (300 MHz, d6-DMSO) δ2.04 (s, 3H), 3.38 (s, 3H), 4.56 (t, 1H, J=8.3 Hz), 4.85 (d, 1H, J=7.9 Hz), 5.09 (m, 2H), 5.42 (bs, 2H), 6.36 (t, 1H, J=7.5 Hz), 6.56 (s, 1H), 6.65 (d, 1H, J=7.9 Hz), 6.94-7.02 (m, 3H), 7.30-7.42 (m, 5H), 8.21 (d, 1H, J=9.3 Hz). MS APCI, m/z=457 (M+1). LC/MS: 2.64 min.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C@@H:25]3[CH2:30][CH2:29][CH2:28][N:27]([C:31](=[O:35])[CH2:32][C:33]#[N:34])[CH2:26]3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=4)=[CH:13][CH:12]=3)[C:3]=12.[CH:36]1([CH:39]=O)[CH2:38][CH2:37]1.N1CCCCC1.ClCCl>CO>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C@@H:25]3[CH2:30][CH2:29][CH2:28][N:27]([C:31]([C:32](=[CH:39][CH:36]4[CH2:38][CH2:37]4)[C:33]#[N:34])=[O:35])[CH2:26]3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=4)=[CH:13][CH:12]=3)[C:3]=12
Reactant: O=CC1CC1
Reactant: N#CCC(=O)N1CCC[C@@H](n2nc(-c3ccc(Oc4cccc(F)c4)cc3)c3c(N)ncnc32)C1
Solvent: ClCCl
Solvent: CO
Solvent: C1CCNCC1
Product: N#CC(=CC1CC1)C(=O)N1CCC[C@@H](n2nc(-c3ccc(Oc4cccc(F)c4)cc3)c3c(N)ncnc32)C1
Temperature: 25 °C
Reaction time: 12 h
Yield: 27.5 %

Procedure:
Into a 50 mL round-bottom flask, was placed a solution of 3-[(3R)-3-[4-amino-3-[4-(3-fluorophenoxy)phenyl]-1H-pyrazolo[3,4-d]pyrimidin-1-yl]piperidin-1-yl]-3-oxopropanenitrile (120 mg, 0.25 mmol, 1.00 equiv) in methanol (20 mL), cyclopropanecarbaldehyde (54 mg, 0.77 mmol, 3.00 equiv), piperidine (11 mg, 0.13 mmol, 0.50 equiv), and dichloromethane (5 mL). The resulting solution was stirred for 12 h at room temperature and then concentrated under vacuum. The residue was loaded onto a silica gel column and eluted with dichloromethane/methanol (100:1) to give 36 mg (27%) of the title compounds as a white solid. LC-MS: (ES, m/z): 524 [M+H]+. H-NMR: (300MHz,CDCl3, ppm) 8.396 (1H, s), 7.721˜7.674 (2H, m), 7.393˜7.316 (1H, m), 7.237˜7.191 (2H, m), 6.923˜6.786 (3H,m),6.607˜6.570 (1H,d,J=11.1), 5.795 (2H, s), 5.018˜4.919 (1H, m), 4.8˜3.1 (4H,m), 2.465˜2.269 (5H,m),1.274 (2H m), 0.887 (2H,m).
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:12]1[C:21]([CH3:22])=[CH:20][C:19]2[C:14](=[CH:15][CH:16]=[C:17]([C:23]#[N:24])[CH:18]=2)[C:13]=1[O:25][S:26]([C:29]([F:32])([F:31])[F:30])(=[O:28])=[O:27])[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:4])([CH3:3])[CH3:2].[C:33](OC(CC)(C)C)(=O)C>>[C:23]([C:17]1[CH:18]=[C:19]2[C:14](=[CH:15][CH:16]=1)[C:13]([O:25][S:26]([C:29]([F:32])([F:30])[F:31])(=[O:27])=[O:28])=[C:12]([C@H:6]([O:5][C:1]([CH2:2][CH3:33])([CH3:3])[CH3:4])[C:7]([O:9][CH2:10][CH3:11])=[O:8])[C:21]([CH3:22])=[CH:20]2)#[N:24]
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2cc(C#N)ccc2c1OS(=O)(=O)C(F)(F)F
Reactant: CCC(C)(C)OC(C)=O
Product: CCOC(=O)[C@@H](OC(C)(C)CC)c1c(C)cc2cc(C#N)ccc2c1OS(=O)(=O)C(F)(F)F

Procedure:
(S)-ethyl 2-(6-cyano-3-methyl-1(trifluoromethylsulfonyloxy)-naphthalen-2-yl)-2-(tert-pentyloxy)acetate was prepared in a similar way to (S)-ethyl 2-tert-butoxy-2-(6-cyano-3-methyl-1-(trifluoromethylsulfonyloxy)naphthalen-2-yl)acetate in Example 5 except tert-amyl acetate was used instead of tert-butyl acetate. 1H NMR (400 MHz, CDCl3) 8.18 (s, 1H), 8.13 (d, J=8.7 Hz, 1H), 7.73 (s, 1H), 7.71 (d, J=8.9 Hz, 1H), 5.73 (s, 1H), 4.27-4.08 (m, 2H), 2.59 (s, 3H), 1.62-1.43 (m, 2H), 1.20 (s, 3H), 1.17 (t, J=7.2 Hz, 3H), 1.08 (s, 3H), 0.77 (t, J=7.4 Hz, 3H).