Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:20][C@@H:19]([CH3:21])[N:18]2[C@H:10]([CH2:11][C:12]3[C:17]2=[N:16][C:15](Br)=[CH:14][CH:13]=3)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:23](=[NH:36])([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.CC(C)([O-])C.[Na+].C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:20][C@@H:19]([CH3:21])[N:18]2[C@H:10]([CH2:11][C:12]3[C:17]2=[N:16][C:15]([N:36]=[C:23]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[CH:14][CH:13]=3)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: N=C(c1ccccc1)c1ccccc1
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]2Cc3ccc(Br)nc3N21
Agent: CC(C)(C)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]2Cc3ccc(N=C(c4ccccc4)c4ccccc4)nc3N21
Temperature: 25 °C
Yield: 94.3 %

Procedure:
A mixture consisting of 0.20 g (0.54 mmol) (4R,9aR)-6-bromo-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylic acid tert-butyl ester, 91 μl (0.54 mmol) benzophenone imine, 73.0 mg (0.76 mmol) sodium tert-butoxide, 5.6 mg (0.01 mmol) tris(dibenzylideneacetone)dipalladium chloroform complex and 10.1 mg (0.02 mmol) R-(+)-2,2′-bis(diphenylphosphino)-1,1′-binaphthalene in 3 ml toluene was stirred at reflux for 1 h. The reaction mixture was cooled to room temperature, poured into 10% aqueous sodium bicarbonate solution and extracted twice with ethyl acetate. The combined organic layers were washed with brine, dried over magnesium sulfate, filtered and evaporated. The residue was purified by chromatography on silica gel (0.032–0.063 mm) with n-hexane:ethyl acetate (2:1) as eluant to afford the product as a yellow foam (94.3%).
Reaction SMILES: Cl.[CH2:2]([CH:9]1[CH2:14][CH2:13][N:12]([CH2:15][C:16]([OH:18])=O)[CH2:11][CH2:10]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[NH2:19][C@@H:20]([CH2:38][O:39][CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[C:21]([NH:23][C:24]1[CH:29]=[CH:28][C:27]([O:30][C:31]2[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=2)=[CH:26][CH:25]=1)=[O:22]>>[CH2:40]([O:39][CH2:38][C@H:20]([NH:19][C:16](=[O:18])[CH2:15][N:12]1[CH2:11][CH2:10][CH:9]([CH2:2][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:14][CH2:13]1)[C:21]([NH:23][C:24]1[CH:29]=[CH:28][C:27]([O:30][C:31]2[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=2)=[CH:26][CH:25]=1)=[O:22])[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1
Reactant: N[C@@H](COCc1ccccc1)C(=O)Nc1ccc(Oc2ccc(F)cc2)cc1
Reactant: O=C(O)CN1CCC(Cc2ccccc2)CC1
Agent: Cl
Product: O=C(CN1CCC(Cc2ccccc2)CC1)N[C@@H](COCc1ccccc1)C(=O)Nc1ccc(Oc2ccc(F)cc2)cc1
Yield: 44.9 %

Procedure:
Proceeding as in Example 1, but substituting 2-(4-benzylpiperidin-1-yl)acetic acid hydrochloride and (S)-2-amino-3-(benzyloxy)-N-(4-(4-fluorophenoxy)phenyl)propanamide, gave Compound 220, (S)-3-(benzyloxy)-2-(2-(4-benzylpiperidin-1-yl)acetamido)-N-(4-(4-fluorophenoxy)phenyl)propanamide (21.4 mg, 44.9%); Major isomer: 1H-NMR (400 MHz, DMSO-D6): σ 10.21 (s, 1H), 7.93 (d, 1H), 7.60 (d, 2H), 7.26-7.34 (m, 7H), 7.14-7.24 (m, 5H), 6.98-7.04 (m, 4H), 4.67-4.71 (m, 1H), 4.52 (s, 2H), 3.68-3.80 (m, 2H), 2.92 (d, 2H), 2.78-2.87 (m, 2H), 2.47-2.50 (m, 2H), 1.94-2.02 (m, 2H), 1.43-1.55 (m, 3H), 1.17-1.24 (m, 2H). MS (EI) for C36H38FN3O4. found 596.7 (MH+).
Reaction SMILES: [CH:1]1[N:2]=[CH:3][N:4]2[CH2:9][CH2:8][CH2:7][C:6](=[O:10])[C:5]=12.[C:11]1([Mg]Br)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[C:11]1([C:6]2([OH:10])[CH2:7][CH2:8][CH2:9][N:4]3[CH:3]=[N:2][CH:1]=[C:5]23)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=C1CCCn2cncc21
Reactant: Br[Mg]c1ccccc1
Product: OC1(c2ccccc2)CCCn2cncc21

Procedure:
In analogy to Example 3a 6,7-dihydro-5H-imidazo[1,5-a]pyridin-8-one [426219-51-4] and phenylmagnesium bromide solution [100-58-3] (1M in tetrahydrofuran) are reacted. The title compound is obtained as a beige solid. Rt=4.10 (Gradient I).
Reaction SMILES: [CH2:1]([NH:3][C:4](=[O:24])[NH:5][C:6]1[CH:16]=[C:15]([NH:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:9]([C:10]([O:12]CC)=[O:11])=[CH:8][N:7]=1)[CH3:2].[OH-].[Na+]>CO.O>[CH2:1]([NH:3][C:4](=[O:24])[NH:5][C:6]1[CH:16]=[C:15]([NH:17][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:9]([C:10]([OH:12])=[O:11])=[CH:8][N:7]=1)[CH3:2]
Reactant: CCNC(=O)Nc1cc(Nc2ccccc2)c(C(=O)OCC)cn1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCNC(=O)Nc1cc(Nc2ccccc2)c(C(=O)O)cn1
Temperature: 70 °C
Yield: 85.1 %

Procedure:
To a solution of iii (0.90 g, 2.74 mmol) in MeOH (25 mL) was added a solution of NaOH (0.55 g, 13.70 mmol) in H2O (5 mL). The resulting solution was heated at 70° C. for 3-4 h then cooled to RT and the solvent removed in vacuo. Water was added to the residue and this mixture extracted with EtOAc (2×50 mL). The organic layer was discarded, and the aqueous portion was carefully acidified (under ice-cooling) with 6N HCl till pH 5. The resulting precipitate was filtered, washed with ice-cold water and ether. The off-white solid thus obtained was dried under high vacuum to obtain compound iv (0.70 g, 85%). 1H-NMR (400 MHz, DMSO-d6): δ10.60 (br s, 1H), 9.07 (br s, 1H), 8.55 (s, 1H), 8.0 (br s, 1H), 7.13-7.42 (m, 6H), 3.12 (m, 2H), 1.05 (t, J=7.20 Hz, 3H); [M+H]+ m/z=301.21.
Reaction SMILES: CN(C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:16][CH:15]=2)[N:8]=1)=O.[F:26][C:27]([F:38])([F:37])[O:28][C:29]1[CH:30]=[C:31]([NH:35][NH2:36])[CH:32]=[CH:33][CH:34]=1>>[F:24][C:21]([F:22])([F:23])[O:20][C:17]1[CH:18]=[CH:19][C:14]([N:9]2[CH:10]=[CH:11][C:12](=[O:13])[C:7]([C:5]3[N:35]([C:31]4[CH:32]=[CH:33][CH:34]=[C:29]([O:28][C:27]([F:37])([F:38])[F:26])[CH:30]=4)[N:36]=[CH:3][CH:4]=3)=[N:8]2)=[CH:15][CH:16]=1
Reactant: NNc1cccc(OC(F)(F)F)c1
Reactant: CN(C)/C=C/C(=O)c1nn(-c2ccc(OC(F)(F)F)cc2)ccc1=O
Product: O=c1ccn(-c2ccc(OC(F)(F)F)cc2)nc1-c1ccnn1-c1cccc(OC(F)(F)F)c1

Procedure:
The product was obtained starting from 3-((E)-3-Dimethylamino-acryloyl)-1-(4-trifluoromethoxy-phenyl)-1H-pyridazin-4-one (A-8) and 3-trifluoromethoxy-phenylhydrazine according to the method described for example 91. MS: M=483.2 (M+H)+
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:8]2=[C:9]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[N:10]=[CH:11][CH:12]=[C:7]2[CH2:6][CH2:5]1.[F:28][C:29]1[CH:34]=[CH:33][C:32]([S:35](Cl)(=[O:37])=[O:36])=[CH:31][CH:30]=1>>[O:4]1[C:8]2=[C:9]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][S:35]([C:32]5[CH:33]=[CH:34][C:29]([F:28])=[CH:30][CH:31]=5)(=[O:37])=[O:36])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[N:10]=[CH:11][CH:12]=[C:7]2[CH2:6][CH2:5]1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3OCC4)CC2)CC1
Agent: Cl
Product: O=S(=O)(N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3OCC4)CC2)CC1)c1ccc(F)cc1

Procedure:
The title compound, white solid (119 mg, 97%), MS (ISP) m/z=489.3 [(M+H)+], mp 148° C., was prepared in accordance with the general method of example 26 from trans-4-{2-[4-(2,3-dihydro-furo[2,3-c]pyridin-7-yl)-piperazin-1-yl]-ethyl}-cyclohexylamine trihydrochloride (intermediate B) (110 mg, 0.25 mmol) and 4-fluoro-benzenesulfonyl chloride.
Reaction SMILES: C[O:2][C:3](=O)[C:4]([N:6]([CH:16]1[CH2:18][CH2:17]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N+:13]([O-])=[O:14])=[O:5]>CO.[Pd].C(OCC)(=O)C>[CH:16]1([N:6]2[C:7]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[N:13]([OH:14])[C:3](=[O:2])[C:4]2=[O:5])[CH2:18][CH2:17]1
Reactant: COC(=O)C(=O)N(c1ccccc1[N+](=O)[O-])C1CC1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: O=c1c(=O)n(C2CC2)c2ccccc2n1O
Temperature: 25 °C
Reaction time: 2 h
Yield: 84.1 %

Procedure:
To a solution of N-cyclopropyl-N-(2-nitro-phenyl)-oxalamic acid methyl ester (45.0 g, 0.17 mol, 1.0 equiv) in methanol (400 mL) was added palladium on carbon (4.52 g, 0.0043 mol, 0.025 equiv; 10% Pd/C; [CAS RN 7440-05-3]) and the reaction mixture stirred under an atmosphere of hydrogen (1.2 bar) at room temperature for 2 hours. The reaction mixture was diluted with ethyl acetate (400 mL), filtered over Celite® and the solvent mixture removed by evaporation under reduced pressure to give 31.2 g (84%) of the title compound as a light yellow solid. MS (ISN): m/z=219.1 [M+H]+.
Reaction SMILES: Cl[C:2]1[C:3](C)=[N+:4]([O-])[CH:5]=[CH:6][CH:7]=1.[N+:10]([O-])([OH:12])=[O:11]>>[N+:10]([C:7]1[CH:6]=[CH:5][N:4]=[CH:3][CH:2]=1)([O-:12])=[O:11]
Reactant: Cc1c(Cl)ccc[n+]1[O-]
Reactant: O=[N+]([O-])O
Product: O=[N+]([O-])c1ccncc1

Procedure:
3-Chloro-2-methylpyridine N-oxide may be nitrated with a mixture of nitric acid and sulphuric acids, and the 4-nitropyridine produced successively treated with sodium methoxide, heated in acetic anhydride, purified and deacetylated to give 2-hydroxymethyl-3-chloro-4-methoxypyridine, which may be substituted for 2-hydroxy-3-methoxypyridine in the procedure of Example 1(ii)-(v) to prepare N-cyano-N'-methyl-N"-[2-((3-chloro-4-methoxy-2-pyridyl)methylthio)ethyl]guanidine.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]2[NH:9][C:10]3[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=3[N:12]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.N.O1CCOC[CH2:19]1>>[CH:6]1[C:7]2[C:8]3[N:9]([CH:19]=[N:1][C:2]=2[N:3]=[CH:4][CH:5]=1)[C:10]1[C:11](=[CH:13][CH:14]=[CH:15][CH:16]=1)[N:12]=3
Reactant: C1COCCO1
Reactant: Nc1ncccc1-c1nc2ccccc2[nH]1
Agent: N
Product: c1ccc2c(c1)nc1c3cccnc3ncn21
Temperature: 80 °C
Reaction time: 3 h

Procedure:
A mixture of 100 mmol of the 2-(2-aminopyridin-3-yl)benzimidazole derivative (employed as equimolar mixture with the corresponding 2-tert-butylbenzimidazole derivative as obtained from synthesis 16)) and 1 mol of the corresponding carboxylic acid chloride is heated for 8 to 40 h under reflux in the case of carboxylic acid chlorides which boil below 150° C. or at 150° C. to 180° C. in the case of carboxylic acid chlorides which boil above 150° C., until the 2-(2-aminopyridin-3-yl)benzimidazole derivative has reacted. The reaction mixture is allowed to cool to 80° C., optionally diluted with 100 ml of dioxane, then stirred into a mixture of 500 ml of conc. ammonia solution and 500 g of ice and stirred for a further 3 h. The solid is subsequently filtered off with suction, washed twice with 100 ml of water in each case and dried in vacuo. The solid is taken up in 1000 ml of ethyl acetate, filtered through a short silica-gel column, rinsed with 500 ml of ethyl acetate, the ethylacetate is removed in vacuo, and the brown residue is recrystallised from methanol. The solids obtained in this way are freed from low-boiling components and non-volatile secondary components by sublimation (p about 1×10−5 mbar, T about 170-200° C.). Purity according to 1H-NMR typically >99.5%.
Reaction SMILES: [CH2:1]([CH:5]1[N:10](C(=O)CCC2NC=NC=2)[CH2:9][CH2:8][N:7]2[CH:20]=[C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[O:29][CH3:30])[N:22]=[C:6]12)[CH2:2]CC.N(C(OCC1C=CC=CC=1)=O)[C@H:32](C(O)=O)[C@H](CC)C>>[CH3:30][O:29][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=1[C:21]1[N:22]=[C:6]2[CH:5]([CH:1]([CH3:32])[CH3:2])[NH:10][CH2:9][CH2:8][N:7]2[CH:20]=1
Reactant: CC[C@H](C)[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: CCCCC1c2nc(-c3ccccc3OC)cn2CCN1C(=O)CCc1cnc[nH]1
Product: COc1ccccc1-c1cn2c(n1)C(C(C)C)NCC2

Procedure:
through 5.g. were carried out in a manner analogous to Steps 1.c. through 1.f of example 1, starting with Cbz-(L)-Ile-OH in place of Cbz-(L)-Nle-OH, and yielding 2-(2-methoxyphenyl)-8-(1-methylethyl)-5,6,7,8-tetrahydro-imidazo[1,2-a]pyrazine (compound vii, where R3 is isobutyl, R4 is 2-methoxyphenyl and R5, R6, and R7 are H,).
Reaction SMILES: C[O-].[Na+].[Si:4]([N:11]1[CH:14]([CH2:15][CH2:16][O:17]C(=O)C(F)(F)F)[CH:13]([N:24]=[N+:25]=[N-:26])[C:12]1=[O:27])([C:7]([CH3:10])([CH3:9])[CH3:8])([CH3:6])[CH3:5].C(O)(=O)C>CO>[Si:4]([N:11]1[CH:14]([CH2:15][CH2:16][OH:17])[CH:13]([N:24]=[N+:25]=[N-:26])[C:12]1=[O:27])([C:7]([CH3:9])([CH3:10])[CH3:8])([CH3:6])[CH3:5]
Reactant: CC(C)(C)[Si](C)(C)N1C(=O)C(N=[N+]=[N-])C1CCOC(=O)C(F)(F)F
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)(C)[Si](C)(C)N1C(=O)C(N=[N+]=[N-])C1CCO
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
A solution of sodium methoxide (0.02 mol) in methanol (20 ml) is added to an ice-cold solution of N-(t-butyldimethylsilyl)-3-azido-4-(2-trifluoroacetoxyethyl)-azetidin-2-one (0.1 mol) in methanol (100 ml). After stirring in the cold for 10 min, the solution is treated with acetic acid (2 ml) and concentrated under vacuum. The resdue is taken up in ethyl acetate, washed with water, 5% sodium bicarbonate solution, and brine, dried, and evaporated. The residue is chromatographed on silica gel to give N-(t-butyldimethylsilyl)-3-azido-4-(2-hydroxyethyl)-azetidin-2-one.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]([C@@H:18]2[CH2:24][CH2:23][C@@H:22]3[CH2:25][N:19]2[C:20](=[O:31])[N:21]3[O:26][S:27]([OH:30])(=[O:29])=[O:28])=[O:17])=[CH:11][CH:10]=1)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[NH2:7][CH2:8][C:9]1[CH:10]=[CH:11][C:12]([NH:15][C:16]([C@@H:18]2[CH2:24][CH2:23][C@@H:22]3[CH2:25][N:19]2[C:20](=[O:31])[N:21]3[O:26][S:27]([OH:30])(=[O:29])=[O:28])=[O:17])=[CH:13][CH:14]=1
Reactant: CC(C)(C)OC(=O)NCc1ccc(NC(=O)[C@@H]2CC[C@@H]3CN2C(=O)N3OS(=O)(=O)O)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NCc1ccc(NC(=O)[C@@H]2CC[C@@H]3CN2C(=O)N3OS(=O)(=O)O)cc1

Procedure:
To a mixture of the product of step 3 (34.8 mg, 0.074 mmol) in dry dichloromethane (3 mL) at 0° C. under nitrogen was added trifluoroacetic acid (1.0 mL, 13 mmol). All solids dissolved immediately upon addition of trifluoroacetic acid. the solution was stirred for 1.5 ours at which time LC-MS analysis showed reaction complete. The reaction was concentrated under vacuum and the residue was triturated with ether to remove excess trifluoroacetic acid and organic impurities. The resulting sticky solid was dried under vacuum and stored in the freezer overnight. The crude product was purified by HPLC on a Phenomenex Synergi Polar-RP 80A column to afford the impure title compound as a white solid after lyophilization. The solid was triturated with acetonitrile (3×) to afford the pure title compound as a white solid. LC-MS (negative ionization) m/e 369 (M−H); LC-MS (positive ionization) m/e 354 (M+H—NH3); 1H NMR (600 MHz, D2O; unreferenced) (δ, ppm) 7.53 (2H, d, J=8.5 Hz), 7.46 (2H, d, J=8.5 Hz), 4.23 (2H, br s), 4.11 (2H, s), 3.39 (1H, d, 3=12 Hz), 3.18 (1H, d, J=12 Hz), 2.27-2.31 (1H, m), 2.09-2.14 (1H, m), 1.90-2.00 (1H, m), 1.813-1.89 (1H, m).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8](/[C:11](/[C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([O:22][CH3:23])[N:16]=2)=[CH:12]\[CH2:13][OH:14])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[C:24]1(O)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(P(CCCC)CCCC)CCC>O1CCCC1>[C:1]([C:5]1[CH:10]=[CH:9][C:8](/[C:11](/[C:15]2[N:16]=[C:17]([O:22][CH3:23])[C:18]([Cl:21])=[CH:19][CH:20]=2)=[CH:12]\[CH2:13][O:14][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1nc(/C(=C/CO)c2ccc(C(C)(C)C)cc2)ccc1Cl
Reactant: Oc1ccccc1
Agent: CCCCP(CCCC)CCCC
Solvent: C1CCOC1
Product: COc1nc(/C(=C/COc2ccccc2)c2ccc(C(C)(C)C)cc2)ccc1Cl
Temperature: 25 °C
Reaction time: 20 h
Yield: 87 %

Procedure:
N,N,N′,N′-Tetramethylazodicarbodiimide (104 mg) was added to a solution of (2E)-3-(4-tert-butylphenyl)-3-(5-chloro-6-methoxypyridin-2-yl)prop-2-en-1-ol obtained in Reference Example 4-4 (199 mg), phenol (63 mg) and tributylphosphine (189 mg) in tetrahydrofuran (4 mL) under ice-cooling, and the mixture was stirred at room temperature for 20 hours. The solvent was evaporated from the reaction solution under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=19:1) to give 6-[(1E)-1-(4-tert-butylphenyl)-3-phenoxyprop-1-en-1-yl]-3-chloro-2-methoxypyridine as a yellow oil (212 mg, 87%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C@@H:26]3[CH2:31][CH2:30][CH2:29][N:28](C(OC(C)(C)C)=O)[CH2:27]3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[C:23]([F:24])=[CH:22][CH:21]=[CH:20][C:19]=4[F:25])=[CH:13][CH:12]=3)[C:3]=12.C(O)(C(F)(F)F)=O>ClCCl>[F:25][C:19]1[CH:20]=[CH:21][CH:22]=[C:23]([F:24])[C:18]=1[O:17][C:14]1[CH:13]=[CH:12][C:11]([C:10]2[C:3]3[C:4](=[N:5][CH:6]=[N:7][C:2]=3[NH2:1])[N:8]([C@@H:26]3[CH2:31][CH2:30][CH2:29][NH:28][CH2:27]3)[N:9]=2)=[CH:16][CH:15]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](n2nc(-c3ccc(Oc4c(F)cccc4F)cc3)c3c(N)ncnc32)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1ncnc2c1c(-c1ccc(Oc3c(F)cccc3F)cc1)nn2[C@@H]1CCCNC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 112.9 %

Procedure:
Into a 100 mL round-bottom flask, was placed a solution of tert-butyl (3R)-3-[4-amino-3-[4-(2,6-difluorophenoxy)phenyl]-1H-pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate (450 mg, 0.86 mmol, 1.00 equiv) in dichloromethane (40 mL). CF3COOH (10 mL) to added dropwise with stirring at 25° C. over 10 min and the resulting solution was stirred for 3 h at 25° C. and then concentrated under vacuum. The resulting solution was diluted with dichloromethane and washed with aqueous sodium bicarbonate and brine. The organics were dried over anhydrous sodium sulfate and concentrated under vacuum to give 410 mg of 3-[4-(2,6-difluorophenoxy)phenyl]-1-[(3R)-piperidin-3-yl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N+:9]([O-])=O)[CH:5]=[CH:6][C:7]=1[Cl:8].C(O[CH2:16][CH2:17][CH2:18]C)(=O)C>[Pt]>[CH:17]([NH:9][C:4]1[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=1)([CH3:18])[CH3:16]
Reactant: CCCCOC(C)=O
Reactant: O=[N+]([O-])c1ccc(Cl)c(Cl)c1
Agent: [Pt]
Product: CC(C)Nc1ccc(Cl)c(Cl)c1
Yield: 84.5 %

Procedure:
480.0 g (2.5 mol) of 3,4-dichloronitrobenzene were reacted in 2500 ml of butyl acetate under the reaction conditions described in Example 1 with 10 g of sulfited platinum catalyst F1OP. After the solvent had been distilled off in vacuo, the residue was fractionated to give 431.0 g of N-isopropyl-3,4-dichloroaniline at a purity of 98.9% (GC) in the boiling range 143° to 148° C. (13.33 to 16 bar), which corresponds to a yield of 84.5% of theory.
Reaction SMILES: Cl[C:2]1[C:3]([C:7]([OH:9])=[O:8])=[CH:4][S:5][CH:6]=1.[OH-].[Na+].[S:12](=[O:15])([OH:14])[O-:13].[Na+]>[Cu]Cl.O>[S:12]([C:2]1[C:3]([C:7]([OH:9])=[O:8])=[CH:4][S:5][CH:6]=1)([OH:15])(=[O:14])=[O:13]
Reactant: O=S([O-])O
Reactant: O=C(O)c1cscc1Cl
Agent: Cl[Cu]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)c1cscc1S(=O)(=O)O
Temperature: 0 °C

Procedure:
In a glass autoclave, 8.6 g. of 4-chlorothiophene-3-carboxylic acid are dissolved in 23 ml. of water containing 2.1 g. of sodium hydroxide, whereupon a solution of 5.6 g. of sodium bisulfite in 16 ml. of water is added and the solution make just alkaline with a 30% sodium hydroxide solution. The solution is treated with 0.43 g. of copper (I) chloride and heated at 143° C. for 16 hours. After cooling, the red copper oxide is filtered off under suction. The filtrate is acidified with 7 ml. of concentrated hydrochloric acid and the unreacted starting material precipitates out, the latter being removed by shaking out with ether. The acidic solution is treated with 12 g. of potassium chloride while warming and, after cooling to 0° C, the potassium salt of 4-sulfothiophene-3-carboxylic acid separates as colorless crystals. The crystals are dissolved in 50 ml. of water and the solution passed through an ion-exchange column which is charged with protons, after which the column is rinsed with water until the solution flowing out has a pH value of 5. The eluate is evaporated to dryness in vacuo. There is obtained 4-sulfothiophene-3-carboxylic acid as a crystalline residue of melting point 154° C (recrystallization from water).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([O:10][CH2:11][C:12]([F:15])([F:14])[F:13])[N:7]([C:16]3[CH:21]=[CH:20][N:19]=[C:18]([NH2:22])[N:17]=3)[C:6]=2[CH:23]=1.[N:24]1[CH:29]=[CH:28][CH:27]=[N:26][C:25]=1[C:30]([OH:34])([C:32]#[CH:33])[CH3:31].C(N(CC)CC)C>CS(C)=O.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>[NH2:22][C:18]1[N:17]=[C:16]([N:7]2[C:6]3[CH:23]=[C:2]([C:33]#[C:32][C:30]([C:25]4[N:24]=[CH:29][CH:28]=[CH:27][N:26]=4)([OH:34])[CH3:31])[CH:3]=[CH:4][C:5]=3[N:9]=[C:8]2[O:10][CH2:11][C:12]([F:15])([F:14])[F:13])[CH:21]=[CH:20][N:19]=1
Reactant: Nc1nccc(-n2c(OCC(F)(F)F)nc3ccc(Br)cc32)n1
Reactant: C#CC(C)(O)c1ncccn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CC(O)(C#Cc1ccc2nc(OCC(F)(F)F)n(-c3ccnc(N)n3)c2c1)c1ncccn1
Temperature: 90 °C
Reaction time: 1.5 h
Yield: 12.8 %

Procedure:
A mixture of 4-[6-bromo-2-(2,2,2-trifluoroethoxy)-1H-1,3-benzodiazol-1-yl]pyrimidin-2-amine (150 mg, 0.31 mmol, 80% purity), 2-(pyrimidin-2-yl)but-3-yn-2-ol (300 mg, 2.02 mmol), bis(triphenylphosphine)palladium(II) dichloride (220 mg, 0.31 mmol) and triethylamine (2 mL) in dimethylsulfoxide (3 mL) was stirred for 1.5 hr at 90° C. under nitrogen. The reaction mixture was cooled to room temperature then filtered through a frit filter to remove the catalyst. The filtrate was purified by preparative HPLC to afford 18 mg (13%) of 4-[1-(2-aminopyrimidin-4-yl)-2-(2,2,2-trifluoroethoxy)-1H-1,3-benzodiazol-6-yl]-2-(pyrimidin-2-yl)but-3-yn-2-ol as a light brown solid: 1H NMR (400 MHz, DMSO) delta 8.89 (d, J=4.8 Hz, 2H), 8.44 (d, J=5.6 Hz, 1H), 8.12 (s, 1H), 7.51-7.48 (m, 2H), 7.28 (d, J=8.0 Hz, 1H), 7.16 (s, 2H), 6.85 (d, J=5.2 Hz, 1H), 6.13 (s, 1H), 5.36-5.29 (m, 2H), 1.89 (s, 3H); LC-MS: m/z=+456 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][CH:18]=1)[O:5][CH2:6][CH2:7][NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12].[CH3:19][CH:20]([S:22](Cl)(=[O:24])=[O:23])[CH3:21]>>[CH3:19][CH:20]([S:22]([NH:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][CH:18]=1)[O:5][CH2:6][CH2:7][NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])(=[O:24])=[O:23])[CH3:21]
Reactant: CC(C)(C)OC(=O)NCCOc1cccc(N)c1
Reactant: CC(C)S(=O)(=O)Cl
Product: CC(C)S(=O)(=O)Nc1cccc(OCCNC(=O)OC(C)(C)C)c1

Procedure:
Sulfonation of tert-butyl 2-(3-aminophenoxy)ethylcarbamate (3) using propane-2-sulfonyl chloride following the method described in Example 1 gave tert-butyl 2-(3-(1-methylethylsulfonamido)phenoxy)ethylcarbamate (7) as a light yellow oil. 1H NMR (400 MHz, DMSO-d6) δ 9.70 (s, 1H), 7.17 (t, J=8.0 Hz, 1H), 6.97 (t, J=6.0 Hz, 1H), 6.76-6.79 (m, 2H), 6.60-6.62 (m, 1H), 3.16-3.30 (m, 3H), 1.35 (s, 9H), 1.19 (d, J=6.8 Hz, 6H).
Reaction SMILES: Br[CH:2]([CH2:19][CH3:20])[C:3]([NH:5][C:6]1[S:7][C:8]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:18])=[CH:9][N:10]=1)=[O:4].[CH2:21]([NH:23][CH2:24][CH3:25])[CH3:22]>CN(C)C=O>[Cl:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[CH2:11][C:8]1[S:7][C:6]([NH:5][C:3](=[O:4])[CH:2]([N:23]([CH2:24][CH3:25])[CH2:21][CH3:22])[CH2:19][CH3:20])=[N:10][CH:9]=1
Reactant: CCNCC
Reactant: CCC(Br)C(=O)Nc1ncc(Cc2ccccc2Cl)s1
Solvent: CN(C)C=O
Product: CCC(C(=O)Nc1ncc(Cc2ccccc2Cl)s1)N(CC)CC

Procedure:
2-Bromo-N-[5-(2-chloro-benzyl)-thiazol-2-yl]-butyramide (37 mg, 0.10 mmol) was dissolved in 0.5 mL of N,N-dimethylformamide containing diethylamine (146 mg, 2.00 mmol). The reaction vessel was sealed and then subjected to microwave irradiation for 5 minutes at 80° C. The crude mixture was evaporated to dryness and purified by reverse-phase preparative liquid chromatography (14 mg, 0.038, 38%). ESI-MS m/z calc. 365.1. found 366.2 (M+1)+ Retention time 2.18 minutes.