Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([Cl:30])[C:5]2[N:10]=[C:9]([C:11]3[N:15]([C:16]4[C:21]([Cl:22])=[CH:20][CH:19]=[CH:18][N:17]=4)[N:14]=[C:13]([O:23][S:24]([CH3:27])(=[O:26])=[O:25])[CH:12]=3)[O:8][C:7](=[O:28])[C:6]=2[CH:29]=1.[CH:31]([NH2:34])([CH3:33])[CH3:32]>C(#N)C>[Cl:22][C:21]1[C:16]([N:15]2[C:11]([C:9]([NH:10][C:5]3[C:6]([C:7]([NH:34][CH:31]([CH3:33])[CH3:32])=[O:28])=[CH:29][C:2]([Cl:1])=[CH:3][C:4]=3[Cl:30])=[O:8])=[CH:12][C:13]([O:23][S:24]([CH3:27])(=[O:26])=[O:25])=[N:14]2)=[N:17][CH:18]=[CH:19][CH:20]=1
Reactant: CC(C)N
Reactant: CS(=O)(=O)Oc1cc(-c2nc3c(Cl)cc(Cl)cc3c(=O)o2)n(-c2ncccc2Cl)n1
Solvent: CC#N
Product: CC(C)NC(=O)c1cc(Cl)cc(Cl)c1NC(=O)c1cc(OS(C)(=O)=O)nn1-c1ncccc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 6,8-dichloro-2-[1-(3-chloro-2-pyridinyl)-3-[(methylsulfonyl)oxy]-1H-pyrazol-5-yl]-4H-3,1-benzoxazin-4-one (i.e. the product of Example 1, step D) (0.05 g, 0.10 mmol) in acetonitrile (3 mL) was added isopropylamine (0.5 mL, 5.87 mmol) dropwise. The resulting solution was stirred at room temperature overnight. The reaction was concentrated to dryness to yield 0.038 g of the title compound, a compound of present invention, as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][OH:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cl:36][C:37]1[CH:42]=[CH:41][C:40]([N:43]([C@H:47]2[C:56]3[C:51](=[CH:52][CH:53]=[CH:54][CH:55]=3)[N:50]([C:57](=[O:65])[C:58]3[CH:63]=[CH:62][C:61](O)=[CH:60][CH:59]=3)[C@@H:49]([CH3:66])[CH2:48]2)[C:44](=[O:46])[CH3:45])=[CH:39][CH:38]=1.CCOC(/N=N/C(OCC)=O)=O>C1(C)C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][O:16][C:61]2[CH:60]=[CH:59][C:58]([C:57]([N:50]3[C:51]4[C:56](=[CH:55][CH:54]=[CH:53][CH:52]=4)[C@H:47]([N:43]([C:44](=[O:46])[CH3:45])[C:40]4[CH:41]=[CH:42][C:37]([Cl:36])=[CH:38][CH:39]=4)[CH2:48][C@@H:49]3[CH3:66])=[O:65])=[CH:63][CH:62]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(=O)N(c1ccc(Cl)cc1)[C@@H]1C[C@H](C)N(C(=O)c2ccc(O)cc2)c2ccccc21
Reactant: CC(C)(C)OC(=O)N1CCC(CCO)CC1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CC(=O)N(c1ccc(Cl)cc1)[C@@H]1C[C@H](C)N(C(=O)c2ccc(OCCC3CCN(C(=O)OC(C)(C)C)CC3)cc2)c2ccccc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 88.4 %

Procedure:
4-(2-Hydroxy-ethyl)-piperidine-1-carboxylic acid tert-butyl ester (0.119 g, 0.52 mmol) was dissolved in toluene at room temperature with PPh3 (0.136 g, 0.52 mmol), then added (2S,4R)-N-(4-chloro-phenyl)-N-[1-(4-hydroxy-benzoyl)-2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl]-acetamide (0.150 g, 0.35 mmol) and stirred for 5 min. DEAD (0.090 g, 0.52 mmol) was added and the reaction was stirred for 18 h at room temperature. The reaction was concentrated and purified by silica gel chromatography (45% CH2Cl2 /55% EtOAc) to afford (2S,4R)-4-[2-(4-{4-[acetyl(4-chloro-phenyl)-amino]-2-methyl-3,4-dihydro-2H-quinoline-1-carbonyl}-phenoxy)-ethyl]-piperidine-1-carboxylic acid tert-butyl ester (0.2 g, 90%)
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:12][C@H:13]3[CH2:17][CH2:16][CH2:15][N:14]3[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[N:9]=[C:10](I)[C:3]=12.OC[C@H]1CCCN1C(OC(C)(C)C)=O.[F:39][C:40]1[CH:41]=[C:42]([CH:59]=[CH:60][CH:61]=1)[O:43][C:44]1[CH:49]=[CH:48][C:47](B2OC(C)(C)C(C)(C)O2)=[CH:46][CH:45]=1.C(=O)([O-])[O-].[Na+].[Na+]>O.COCCOC>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:12][C@H:13]3[CH2:17][CH2:16][CH2:15][N:14]3[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[N:9]=[C:10]([C:47]3[CH:46]=[CH:45][C:44]([O:43][C:42]4[CH:59]=[CH:60][CH:61]=[C:40]([F:39])[CH:41]=4)=[CH:49][CH:48]=3)[C:3]=12
Reactant: CC1(C)OB(c2ccc(Oc3cccc(F)c3)cc2)OC1(C)C
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1Cn1nc(I)c2c(N)ncnc21
Agent: CC(C)(C)OC(=O)N1CCC[C@@H]1CO
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC[C@@H]1Cn1nc(-c2ccc(Oc3cccc(F)c3)cc2)c2c(N)ncnc21
Temperature: 80 °C
Reaction time: 12 h
Yield: 78.7 %

Procedure:
Into a 100-mL 3-necked round-bottom flask purged and maintained under an inert atmosphere of nitrogen, was placed tert-butyl (2R)-2-([4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl]methyl)pyrrolidine-1-carboxylate (300 mg, 0.68 mmol, 1.00 equiv), prepared as described in Example 1 except in the Mitsunobu reaction using (R)-tert-butyl 2-(hydroxymethyl)pyrrolidine-1-carboxylate instead of (S)-tert-butyl 3-hydroxypiperidine-1-carboxylate, 2-[4-(3-fluorophenoxy)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (254 mg, 0.81 mmol, 1.20 equiv), tetrakis(triphenylphosphane)palladium (47 mg, 0.04 mmol, 0.06 equiv), ethylene glycol dimethyl ether (50 mL), sodium carbonate (180 mg, 1.70 mmol, 2.50 equiv), and water (10 mL). The resulting solution was stirred for 12 h at 80° C. in an oil bath. The resulting mixture was concentrated under vacuum and extracted with dichloromethane. The organic layers were combined, dried and concentrated under vacuum. The residue was loaded on a silica gel column and eluted with dichloromethane/methanol (50/1) to give 0.27 g (79%) of tert-butyl (2R)-2-([4-amino-3-[4-(3-fluorophenoxy)phenyl]-1H-pyrazolo[3,4-d]pyrimidin-1-yl]methyl)pyrrolidine-1-carboxylate as a brown solid.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:11]=1)[C:6](Cl)=[O:7].[C:18]1([C@H:24]2[C@@H:29]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH2:28][CH2:27][NH:26][CH2:25]2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[F:1][C:2]([F:17])([F:16])[C:3]1[CH:4]=[C:5]([C:6]([N:26]2[CH2:27][CH2:28][C@H:29]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C@H:24]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:25]2)=[O:7])[CH:9]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:11]=1
Reactant: O=C(Cl)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: c1ccc([C@H]2CCNC[C@H]2c2ccccc2)cc1
Product: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CC[C@H](c2ccccc2)[C@H](c2ccccc2)C1

Procedure:
The title compound, MS: m/e=478.2 (M+H+), was prepared in accordance with the general method of example 1 from 3,5-bis(trifluoromethyl)benzoyl chloride and rac-cis-3,4-diphenylpiperidine.
Reaction SMILES: [C:1]1([NH:7][C:8]([C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[CH2:15][CH:14]([NH:19]C(OC(C)(C)C)=O)[CH2:13]3)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[ClH:27].O1CCOCC1>C(O)(=O)C>[ClH:27].[C:1]1([NH:7][C:8]([C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[CH2:15][CH:14]([NH2:19])[CH2:13]3)=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(C)OC(=O)NC1Cc2ccc(C(=O)Nc3ccccc3)cc2C1
Agent: Cl
Solvent: C1COCCO1
Solvent: CC(=O)O
Product: NC1Cc2ccc(C(=O)Nc3ccccc3)cc2C1

Procedure:
Using N-phenyl-2-(tert-butoxycarbonylamino)-5-indan carboxamide (27 mg, 0.077 mmol), 4N hydrochloric acid-dioxane (2.0 ml) and acetic acid (6.0 ml), a similar procedure to Production Example 213 was carried out to obtain N-phenyl-2-amino-5-indan carboxamide hydrochloride. Then using ethanol (1 ml), triethylamine (0.50 ml, 3.6 mmol), 4-chloro-5-methylthieno[2,3-d]pyrimidine (18 mg, 1.0 mmol), a similar procedure to b) in Production Example 208 was carried out. The product obtained was purified by silica gel chromatography (hexane:ethyl acetate=4:1 to 1:1) to obtain the title compound (8 mg, 0.020 mmol) having the following physical properties:
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[NH:4][C:3](=[O:11])[CH2:2]1.Br[CH2:13][C@@H:14]([CH3:24])[CH2:15][O:16][Si:17]([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18].C([O-])([O-])=O.[Cs+].[Cs+]>CC#N>[Si:17]([O:16][CH2:15][C@H:14]([CH3:24])[CH2:13][N:4]1[C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[O:1][CH2:2][C:3]1=[O:11])([C:20]([CH3:21])([CH3:22])[CH3:23])([CH3:18])[CH3:19]
Reactant: C[C@H](CBr)CO[Si](C)(C)C(C)(C)C
Reactant: O=C1COc2ccccc2N1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: C[C@@H](CO[Si](C)(C)C(C)(C)C)CN1C(=O)COc2ccccc21
Temperature: 25 °C
Reaction time: 168 h
Yield: 84.6 %

Procedure:
A reaction flask was charged with 4H-Benzo[1,4]oxazin-3-one (1.49 g, 10.0 mmol), (S)-(3-bromo-2-methylpropoxy)-tert-butyldimethylsilane (2.67 g, 10.0 mmol), and Cs2CO3 (4.89 g, 15.0 mmol) in MeCN (15 mL) and stirred at rt for 7 days. The reaction mixture was quenched with water and the product extracted into EtOAc. The combined organic layers were dried over Na2SO4, filtered, and concentrated. The product was purified by flash column chromatography (SiO2; n-heptane/EtOAc 2:1) to give the title compound (2.84 g, 85%).
Reaction SMILES: C([O:3][C:4](=O)[C:5]1[CH:10]=[C:9]([O:11][CH2:12][CH3:13])[C:8]([N:14]2[CH:18]=[CH:17][CH:16]=[CH:15]2)=[C:7]([O:19][CH2:20][CH3:21])[CH:6]=1)C.[H-].C([Al+]CC(C)C)C(C)C>C1(C)C=CC=CC=1>[CH2:20]([O:19][C:7]1[CH:6]=[C:5]([CH2:4][OH:3])[CH:10]=[C:9]([O:11][CH2:12][CH3:13])[C:8]=1[N:14]1[CH:15]=[CH:16][CH:17]=[CH:18]1)[CH3:21]
Reactant: CCOC(=O)c1cc(OCC)c(-n2cccc2)c(OCC)c1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Product: CCOc1cc(CO)cc(OCC)c1-n1cccc1
Reaction time: 0.5 h
Yield: 99.9 %

Procedure:
To a solution of 3,5-diethoxy-4-pyrrol-1-yl-benzoic acid ethyl ester (1.51 g, 4.98 mmol, 1.0 equiv) in toluene (5 mL) was added slowly over a time period of 15 min under slight cooling to 20° C. a solution of diisobutylaluminium hydride (8.9 mL, 12.45 mmol, 2.5 equiv; 20% solution in toluene). After 1 h the excess hydride was quenched by cautious addition of water (10 mL) and a 28% solution of NaOH (2 mL). The mixture was stirred for 30 min and the organic phase filtered over Hyflo Super Cel. The aqueous layer was extracted with toluene (2×50 mL), the combined organic phases washed with a sat. solution of NaCl (2×50 mL) and concentrated by evaporation under reduced pressure to afford 1.30 g (100%) of (3,5-diethoxy-4-pyrrol-1-yl-phenyl)-methanol. The crude alcohol (1.30 g, 4.98 mmol, 1.0 equiv) was dissolved in toluene (20 mL) and activated MnO2 (7.79 g, 89.5 mmol, 18.0 equiv) was added. The reaction mixture was heated to reflux for 7 h, after which time the reaction mixture was filtered through Hyflo Super Cel and concentrated yielding 1.15 g (89% yield) of the title compound. 1H NMR (300 MHz, DMSO): δ1.17 (t, J=7.0 Hz, 6H), 4.02 (q, J=7.0 Hz, 4H), 6.08-6.09 (m, 2H), 6.75-6.76 (m, 2H), 7.25 (s, 2H), 9.89 (s, 1H). MS (ISP): 260.1 [M+H]+.
Reaction SMILES: [CH2:1]([S:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([NH:13][C:14]([O:16][CH3:17])=[O:15])=[S:12])=[C:6]([N+:18]([O-])=O)[CH:5]=1)[CH3:2].O>CO>[NH2:18][C:6]1[CH:5]=[C:4]([S:3][CH2:1][CH3:2])[CH:9]=[CH:8][C:7]=1[NH:10][C:11]([NH:13][C:14]([O:16][CH3:17])=[O:15])=[S:12]
Reactant: CCSc1ccc(NC(=S)NC(=O)OC)c([N+](=O)[O-])c1
Solvent: O
Solvent: CO
Product: CCSc1ccc(NC(=S)NC(=O)OC)c(N)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 59.2 %

Procedure:
A mixture of 4-ethylthio-1-(3-methoxycarbonyl-2-thioureido)-2-nitrobenzene (14.0 g.), ferrous chloride tetrahydrate (3.04 g.), methanol (235 ml.) and water (50 ml.) was heated to reflux and treated with reduced iron powder (15.5 g.) portionwise during 5 minutes. The mixture was heated at reflux with stirring for one hour. Methanol (250 ml.) was added and the mixture was again heated to reflux. The hot mixture was filtered and the filtrate was allowed to cool to room temperature. The solid which crystallised on cooling was filtered off to give 2-amino-4-ethylthio-1-(3-methoxycarbonyl-2-thioureido)benzene (7.5 g.), m.p. 168° C.
Reaction SMILES: [OH:1][CH:2]1[C@@H:6]2[CH2:7][N:8](C(OCC3C=CC=CC=3)=O)[CH2:9][C@@H:5]2[CH2:4][CH2:3]1>C1COCC1.CO.[Pd]>[CH2:9]1[C@@H:5]2[CH2:4][CH2:3][CH:2]([OH:1])[C@@H:6]2[CH2:7][NH:8]1
Reactant: O=C(OCc1ccccc1)N1C[C@@H]2CCC(O)[C@@H]2C1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: OC1CC[C@H]2CNC[C@@H]12
Reaction time: 12 h

Procedure:
A mixture of benzyl (3aR,6aS)-6-hydroxy-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carboxylate (850 mg, 3.3 mmol) and Pd/C (200 mg) in THF (5.000 mL) was hydrogenated at 25-30 psi in a Parr shaker. After 12 h, the reaction mixture was diluted with MeOH and filtered through a plug of celite. The solvents were removed under reduced pressure to obtain (3aS,6aR)-1,2,3,3a,4,5,6,6a-octahydrocyclopenta[c]pyrrol-4-ol in quantitative yield.
Reaction SMILES: [C:1]1([C:7]2[CH:16]=[CH:15][C:14]3[C:9](=[CH:10][C:11]([CH:17]([OH:19])[CH3:18])=[CH:12][CH:13]=3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1C=C[NH+]=CC=1.[O-][Cr](Cl)(=O)=O>C(Cl)Cl>[C:1]1([C:7]2[CH:16]=[CH:15][C:14]3[C:9](=[CH:10][C:11]([C:17](=[O:19])[CH3:18])=[CH:12][CH:13]=3)[N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(O)c1ccc2ccc(-c3ccccc3)nc2c1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CC(=O)c1ccc2ccc(-c3ccccc3)nc2c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Into the CH2Cl2 (5 ml) solution of 1-(2-phenylquinolin-7-yl)-ethanol (236 mg, 0.947 mmol) was added PCC (408 mg, 2 eq.) under N2 at rt. After stirring for 18 h at rt, the reaction mixture was filtered through a silica pad and washed with EtOAc. After removing solvent, the title compound was obtained as brown oil. 1H NMR (CDCl3, 400 MHz): δ=2.78 (s, 3H), 7.48-7.58 (m, 3H), 7.87-7.89 (d, 1H, J=8.4 Hz), 7.96-7.98 (d, 1H, J=8.8 Hz), 8.09-8.12 (dd, 1H, J=1.6 & 8.4 Hz), 8.17-8.19 (m, 2H), 8.24-8.26 (d, 1H, J=8.8 Hz), 8.75 (s, 1H). MS (ES+): 248.3 [MH+]. HPLC: tR=3.6 min (MicromassZQ, polar—5 min).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12]=1[S:13](Cl)(=[O:15])=[O:14])[C:5]([O:7][CH2:8][CH3:9])=[O:6].[CH2:17]([N:19]1[C:27]2[C:22](=[CH:23][C:24]([CH2:28][NH2:29])=[CH:25][CH:26]=2)[CH:21]=[N:20]1)[CH3:18]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12]=1[S:13](=[O:15])(=[O:14])[NH:29][CH2:28][C:24]1[CH:23]=[C:22]2[C:27](=[CH:26][CH:25]=1)[N:19]([CH2:17][CH3:18])[N:20]=[CH:21]2)[C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: CCOC(=O)c1ccc(S(=O)(=O)Cl)c(Cl)c1
Reactant: CCn1ncc2cc(CN)ccc21
Product: CCOC(=O)c1ccc(S(=O)(=O)NCc2ccc3c(cnn3CC)c2)c(Cl)c1

Procedure:
The titled compound was prepared according to the procedure described in step-1 of Example 1 from ethyl 3-chloro-4-(chlorosulfonyl)benzoate and (1-ethyl-1H-indazol-5-yl)methanamine (step-3 of Example 14).
Reaction SMILES: [Cl-].[CH2:2]([O:4][C:5]([C:7]1[N:8]=[C:9]([CH:12]2[CH2:17][CH2:16][NH2+:15][CH2:14][CH2:13]2)[S:10][CH:11]=1)=[O:6])[CH3:3].[CH3:18][C:19]1[CH:23]=[C:22]([CH3:24])[N:21]([C:25]([CH3:30])([CH3:29])[C:26](O)=[O:27])[N:20]=1>>[CH3:18][C:19]1[CH:23]=[C:22]([CH3:24])[N:21]([C:25]([CH3:30])([CH3:29])[C:26]([N:15]2[CH2:16][CH2:17][CH:12]([C:9]3[S:10][CH:11]=[C:7]([C:5]([O:4][CH2:2][CH3:3])=[O:6])[N:8]=3)[CH2:13][CH2:14]2)=[O:27])[N:20]=1
Reactant: CCOC(=O)c1csc(C2CC[NH2+]CC2)n1
Reactant: Cc1cc(C)n(C(C)(C)C(=O)O)n1
Agent: [Cl-]
Product: CCOC(=O)c1csc(C2CCN(C(=O)C(C)(C)n3nc(C)cc3C)CC2)n1

Procedure:
4-[4-(Ethoxycarbonyl)-1,3-thiazol-2-yl]piperidinium chloride (VI-1, 8.23 g) is reacted analogously to Example IV-1 with 2-(3,5-dimethyl-1H-pyrazol-1-yl)-2-methylpropanoic acid (5.42 g). This gives, after chromatographic purification, ethyl 2-{1-[2-(3,5-dimethyl-1H-pyrazol-1-yl)-2-methylpropanoyl]piperidin-4-yl}-1,3-thiazole-4-carboxylate (9.64 g, 80%)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:25][CH:26]([F:28])[F:27])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:20][CH:21]([CH3:23])[CH3:22])[C:17]([OH:19])=O)[C:10](=[O:24])[CH:9]=2)[CH:7]=1.[NH2:29][C:30]1[CH:42]=[CH:41][C:33]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])=[CH:32][CH:31]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:25][CH:26]([F:28])[F:27])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:20][CH:21]([CH3:23])[CH3:22])[C:17]([NH:29][C:30]3[CH:42]=[CH:41][C:33]([C:34]([O:36][C:37]([CH3:38])([CH3:39])[CH3:40])=[O:35])=[CH:32][CH:31]=3)=[O:19])[C:10](=[O:24])[CH:9]=2)[CH:7]=1
Reactant: CC(C)(C)OC(=O)c1ccc(N)cc1
Reactant: COc1cn(C(CC(C)C)C(=O)O)c(=O)cc1-c1cc(Cl)ccc1OC(F)F
Product: COc1cn(C(CC(C)C)C(=O)Nc2ccc(C(=O)OC(C)(C)C)cc2)c(=O)cc1-c1cc(Cl)ccc1OC(F)F

Procedure:
319 mg (purity 91%, 0.70 mmol) of 2-{4-[5-chloro-2-(difluoromethoxy)phenyl]-5-methoxy-2-oxopyridin-1(2H)-yl}-4-methylpentanoic acid (racemate) and 148 mg (0.77 mmol, 1.1 eq.) of tert-butyl 4-aminobenzoate were reacted according to General Method 5A. Yield: 263 mg (purity 88%, 56% of theory)
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]2[C:14]([C:15]3[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][CH:16]=3)=[C:13]([CH3:22])[S:12][C:11]=2[CH:23]=1.[NH:24]1[CH2:27][CH2:26][CH2:25]1>>[Br:21][C:18]1[CH:19]=[CH:20][C:15]([C:14]2[C:10]3[CH:9]=[CH:8][C:7]([O:6][CH2:5][CH2:4][CH2:3][CH2:2][N:24]4[CH2:27][CH2:26][CH2:25]4)=[CH:23][C:11]=3[S:12][C:13]=2[CH3:22])=[CH:16][CH:17]=1
Reactant: C1CNC1
Reactant: Cc1sc2cc(OCCCCBr)ccc2c1-c1ccc(Br)cc1
Product: Cc1sc2cc(OCCCCN3CCC3)ccc2c1-c1ccc(Br)cc1

Procedure:
According to the method in example 31, 6-(4-Bromo-butoxy)-3-(4-bromo-phenyl)-2-methyl-benzo[b]thiophene and Azetidine were converted to yield 1-{4-[3-(4-Bromo-phenyl)-2-methyl-benzo[b]thiophen-6-yloxy]-butyl}-azetidine, MS: 430 (MH+,1Br).
Reaction SMILES: C1(C(C2C=CC=CC=2)(C2C=CC=CC=2)[N:8]2[CH:12]=[C:11]([CH2:13][CH2:14][C:15]([O:17][CH3:18])=[O:16])[N:10]=[CH:9]2)C=CC=CC=1.[C:31]([C:33]1[CH:40]=[CH:39][C:36]([CH2:37]Br)=[CH:35][C:34]=1[F:41])#[N:32]>CCOC(C)=O>[C:31]([C:33]1[CH:40]=[CH:39][C:36]([CH2:37][N:10]2[C:11]([CH2:13][CH2:14][C:15]([O:17][CH3:18])=[O:16])=[CH:12][N:8]=[CH:9]2)=[CH:35][C:34]=1[F:41])#[N:32]
Reactant: COC(=O)CCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reactant: N#Cc1ccc(CBr)cc1F
Solvent: CCOC(C)=O
Product: COC(=O)CCc1cncn1Cc1ccc(C#N)c(F)c1
Temperature: 50 °C
Reaction time: 3 h

Procedure:
A mixture of methyl 3-[1-(triphenylmethyl)-1H-imidazol-4-yl]propionate, as described above in Step C, (5.00 g, 12.6 mmol) and 4-cyano-3-fluorobenzyl bromide, as described in Example 1, Step D, (2.70 g, 12.6 mmol) in EtOAc (30 mL) was heated to 50° C. for 5 hours. The mixture was allowed to cool, and the solid collected by filtration. The EtOAc filtrate was concentrated in vacuo to a volume of approximately 15 mL and then reheated to 50° C. for 3 hours, cooled, and the solid removed by filtration. The two crops of precipitated imidazolium salts were combined in MeOH (120 mL) and CHCl3 (200 mL). The aqueous layer was extracted further with CHCl3 (2×100 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by flash column chromatography on silica, eluting with a gradient of CH2Cl2—1% MeOH—0.1% NH4OH to CH2Cl2—5% MeOH—0.5% NH4OH to yield the titled product.
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[NH:7][C:8]1[CH:13]=[C:12]([N:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)[C:11]([F:19])=[CH:10][C:9]=1[NH2:20])([CH3:4])([CH3:3])[CH3:2].C([O:26][C:27](=O)[CH2:28][C:29]([C:31]1[CH:36]=[CH:35][N:34]=[C:33]([C:37]#[N:38])[CH:32]=1)=[O:30])(C)(C)C>>[C:1]([O:5][C:6](=[O:21])[NH:7][C:8]1[CH:13]=[C:12]([N:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)[C:11]([F:19])=[CH:10][C:9]=1[NH:20][C:27](=[O:26])[CH2:28][C:29]([C:31]1[CH:36]=[CH:35][N:34]=[C:33]([C:37]#[N:38])[CH:32]=1)=[O:30])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1cc(N2CCCC2)c(F)cc1N
Reactant: CC(C)(C)OC(=O)CC(=O)c1ccnc(C#N)c1
Product: CC(C)(C)OC(=O)Nc1cc(N2CCCC2)c(F)cc1NC(=O)CC(=O)c1ccnc(C#N)c1

Procedure:
The title compound was prepared from (2-amino-4-fluoro-5-pyrrolidin-1-yl-phenyl)-carbamic acid tert.-butyl ester (Example J15) and 3-(2-cyano-pyridin-4-yl)-3-oxo-propionic acid tert.-butyl ester (Example K3) according to the general procedure M. Obtained as a yellow solid (196 mg).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C@@H:18]3[CH2:22][CH2:21][N:20]([C:23](OC(C)(C)C)=[O:24])[CH2:19]3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=3)[C:3]=12.[F:30][C:31]([F:42])([F:41])[C:32]1[CH:33]=[C:34]([N:38]=[C:39]=[O:40])[CH:35]=[CH:36][CH:37]=1.C(O)=O.Cl>C(Cl)Cl>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C@@H:18]3[CH2:22][CH2:21][N:20]([C:23]([NH:38][C:34]4[CH:35]=[CH:36][CH:37]=[C:32]([C:31]([F:30])([F:41])[F:42])[CH:33]=4)=[O:24])[CH2:19]3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:39]([NH:38][C:34]4[CH:35]=[CH:36][CH:37]=[C:32]([C:31]([F:41])([F:42])[F:30])[CH:33]=4)=[O:40])=[CH:13][CH:12]=3)[C:3]=12
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](n2nc(-c3ccc(N)cc3)c3c(N)ncnc32)C1
Reactant: O=C=Nc1cccc(C(F)(F)F)c1
Agent: Cl
Solvent: O=CO
Solvent: ClCCl
Product: Nc1ncnc2c1c(-c1ccc(NC(=O)Nc3cccc(C(F)(F)F)c3)cc1)nn2[C@@H]1CCN(C(=O)Nc2cccc(C(F)(F)F)c2)C1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A solution of (R)-tert-butyl 3-(4-amino-3-(4-aminophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pyrrolidine-1-carboxylate (0.090 g, 0.23 mmol) in CH2Cl2 (10 mL) was cooled in an ice-water bath. To this, 3-(trifluoromethyl)phenyl isocyanate (0.032 mL, 0.23 mmol) diluted in CH2Cl2 (5 mL) was added dropwise. The reaction was allowed to warm to room temperature and left stirring for 6 hours. After, formic acid (5 mL) and concentrated HCl (0.5 mL) were added dropwise directly to the reaction mixture. Three major species were observed by LC-MS corresponding to AD73a, AD73b, and AD73c. The reaction mixture was left stirring for 12 hours and then was concentrated in vacuo, resuspended in 50:50 H2O—CH3CN, and purified on a C18 column in CH3CN/H2O/0.1% TFA (1-100% gradient) to afford AD73a (ESI-MS m/z [M+H]+ found 483.5, calculated 483.2), AD73b (ESI-MS m/z [M+H]+ found 483.5, calculated 483.2), and AD73c (ESI-MS m/z [M+H]+ found 670.5, calculated 670.2).
Reaction SMILES: [OH-:1].[Na+].[CH2:3](Br)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C(Cl)Cl.CO>C(Cl)Cl.O.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C(Cl)Cl>[CH2:3]([O:1][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: [OH-]
Reactant: BrCc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Solvent: O
Product: c1ccc(COCc2ccccc2)cc1
Yield: 95 %

Procedure:
Compound 11 (Rb═H, 0.84 g, 2.66 mmol) was dissolved in DCM/water, 2/1, v/v (30 ml) and to this solution was added sodium hydroxide (2N, 4.2 ml). To this mixture was added tetrabutyl-ammonium bromide (0.09 g, 0.27 mmol, 0.1 eq) and benzyl bromide (0.35 ml, 2.93 mmol, 1.1 eg). The mixture was stirred for 16 hrs at room temperature after which time TLC analysis (DCM/MeOH, 98/2, v/v, Rf 0.8) showed complete reaction. The mixture was diluted with DCM (100 ml), the layers were separated and the water layer was extracted with DCM. The organic layers were dried on MgSO4, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (DCM/petroleum ether, 3/1 to 1/0, v/v) to give compound 12 (Ra═Rb═H, 1.03 g, 95%) as a white solid. 1H NMR (400 MHz, CDCl3) δ ppm 1.4 (s, 9H); 2.75 (bs, 2H); 3.75 (bs, 2H); 4.35 (bs, 2H); 5.05 (s, 2H); 6.35 (s, 1H); 6.98 (d, 2H); 7.30-7.55 (m, 7H).
Reaction SMILES: C(C1N=C(OCC)C(C2N(C(Cl)=O)[C@@](C3C=CC(Cl)=CC=3)(C)[C@@](C3C=CC(Cl)=CC=3)(C)N=2)=C[N:6]=1)(C)(C)C.[C:38]([C:42]1[N:47]=[CH:46][C:45]([C:48]2[N:49]([C:69]([N:71]3[CH2:76][CH2:75][CH:74]([CH2:77][S:78]([CH3:81])(=[O:80])=[O:79])[CH2:73][CH2:72]3)=[O:70])[C@@:50]([C:62]3[CH:67]=[CH:66][C:65]([Cl:68])=[CH:64][CH:63]=3)([CH3:61])[C@@:51]([C:54]3[CH:59]=[CH:58][C:57]([Cl:60])=[CH:56][CH:55]=3)([CH3:53])[N:52]=2)=[C:44]([O:82][CH2:83][CH3:84])C=1)([CH3:41])([CH3:40])[CH3:39]>>[C:38]([C:42]1[N:6]=[C:44]([O:82][CH2:83][CH3:84])[C:45]([C:48]2[N:49]([C:69]([N:71]3[CH2:72][CH2:73][CH:74]([CH2:77][S:78]([CH3:81])(=[O:80])=[O:79])[CH2:75][CH2:76]3)=[O:70])[C@@:50]([C:62]3[CH:67]=[CH:66][C:65]([Cl:68])=[CH:64][CH:63]=3)([CH3:61])[C@@:51]([C:54]3[CH:59]=[CH:58][C:57]([Cl:60])=[CH:56][CH:55]=3)([CH3:53])[N:52]=2)=[CH:46][N:47]=1)([CH3:40])([CH3:41])[CH3:39]
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(CS(C)(=O)=O)CC1
Reactant: CCOc1nc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)Cl
Product: CCOc1nc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(CS(C)(=O)=O)CC1

Procedure:
In a manner analogous to the method described in example 3, (4S,5R)-2-(2-tert-butyl-4-ethoxy-pyrimidin-5-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride (example 51) was reacted with 4-methanesulfonylmethyl-piperidine (example 52) to give the title compound. HR-MS (ES, m/z) calculated for C35H44Cl2N5O4S [(M+H)+] 700.2486, observed 700.2485.