Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:28])[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][C:15]1[N:20]=[C:19]([N:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)[C:18]([Cl:27])=[CH:17][N:16]=1)([CH3:4])([CH3:3])[CH3:2].[N:29]([C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([C:38]([F:41])([F:40])[F:39])[CH:33]=1)=[C:30]=[O:31].C(N(CC)CC)C>C(Cl)Cl>[C:1]([O:5][C:6](=[O:28])[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][C:15]1[N:20]=[C:19]([N:21]2[CH2:26][CH2:25][N:24]([C:30](=[O:31])[NH:29][C:32]3[CH:37]=[CH:36][CH:35]=[C:34]([C:38]([F:39])([F:41])[F:40])[CH:33]=3)[CH2:23][CH2:22]2)[C:18]([Cl:27])=[CH:17][N:16]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ccccc1Nc1ncc(Cl)c(N2CCNCC2)n1
Reactant: O=C=Nc1cccc(C(F)(F)F)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)Nc1ccccc1Nc1ncc(Cl)c(N2CCN(C(=O)Nc3cccc(C(F)(F)F)c3)CC2)n1
Temperature: 23 °C
Reaction time: 16 h
Yield: 62.1 %

Procedure:
To a solution of tert-butyl(2-((5-chloro-4-(piperazin-1-yl)pyrimidin-2-yl)amino)phenyl)carbamate (28 mg, 0.068 mmol) in DCM (0.7 mL) was added 1-isocyanato-3-(trifluoromethyl)benzene (0.011 mL, 0.082 mmol) and triethylamine (0.015 mL, 0.1 mmol) and the mixture was stirred at 23° C. for 16 h. reaction. The crude reaction mixture was loaded onto silica gel and purified using 0-50% EtOAc/Hexanes gradient to give the title compound (25 mg, 62%). MS (ES+) C27H29ClF3N7O3 requires: 591. Found: 592 [M+H]+
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([CH3:24])[C:6]([N:9]2[CH2:14][CH2:13][N:12]([C:15]([C:17]3[CH:22]=[CH:21][C:20](I)=[CH:19][CH:18]=3)=[O:16])[CH2:11][CH2:10]2)=[N:7][CH:8]=1)[CH3:2].[O:25]1[CH2:29][CH:28]=[N:27][C:26]1=[O:30]>>[CH2:1]([C:3]1[CH:4]=[C:5]([CH3:24])[C:6]([N:9]2[CH2:14][CH2:13][N:12]([C:15]([C:17]3[CH:22]=[CH:21][C:20]([N:27]4[CH2:28][CH2:29][O:25][C:26]4=[O:30])=[CH:19][CH:18]=3)=[O:16])[CH2:11][CH2:10]2)=[N:7][CH:8]=1)[CH3:2]
Reactant: CCc1cnc(N2CCN(C(=O)c3ccc(I)cc3)CC2)c(C)c1
Reactant: O=C1N=CCO1
Product: CCc1cnc(N2CCN(C(=O)c3ccc(N4CCOC4=O)cc3)CC2)c(C)c1
Yield: 88 %

Procedure:
By reaction and treatment in the same manner as in Example 149 and using [4-(5-ethyl-3-methylpyridin-2-yl)piperazin-1-yl](4-iodophenyl)methanone (435 mg) described in Preparation Example 177 and oxazolin-2-one (104 mg), the title compound (347 mg) was obtained.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([Br:19])=[C:15]([Br:20])[CH:14]=2)=[S:11])[CH:5]=[CH:6][C:7]=1[Br:8].[C:21]([C:26](O)=[O:27])#[C:22][C:23]([OH:25])=[O:24]>>[O:27]=[C:26]1[C:21](=[CH:22][C:23]([OH:25])=[O:24])[S:11][C:10](=[N:9][C:4]2[CH:5]=[CH:6][C:7]([Br:8])=[C:2]([Br:1])[CH:3]=2)[N:12]1[C:13]1[CH:18]=[CH:17][C:16]([Br:19])=[C:15]([Br:20])[CH:14]=1
Reactant: O=C(O)C#CC(=O)O
Reactant: S=C(Nc1ccc(Br)c(Br)c1)Nc1ccc(Br)c(Br)c1
Product: O=C(O)C=C1SC(=Nc2ccc(Br)c(Br)c2)N(c2ccc(Br)c(Br)c2)C1=O
Yield: 13.1 %

Procedure:
Prepared by the method described in Example 21 from N,N'-bis(3,4-dibromophenyl)thiourea (13.7 g, 25 mmoles) and acetylenedicarboxylic acid (2.7 g, 25 mmoles). Recrystallization from methanol gave the product (2.1 g), mp 235°-237° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:9])=[CH:4][C:5]([NH2:8])=[N:6][CH:7]=1.[N+:10]([O-])([OH:12])=[O:11].[OH-].[NH4+]>S(=O)(=O)(O)O>[Cl:1][C:2]1[C:3]([CH3:9])=[C:4]([N+:10]([O-:12])=[O:11])[C:5]([NH2:8])=[N:6][CH:7]=1
Reactant: O=[N+]([O-])O
Reactant: Cc1cc(N)ncc1Cl
Agent: O=S(=O)(O)O
Agent: [NH4+]
Agent: [OH-]
Product: Cc1c(Cl)cnc(N)c1[N+](=O)[O-]
Temperature: -10 °C
Reaction time: 3 h
Yield: 58.6 %

Procedure:
5-chloro-4-methylpyridin-2-amine (30 g, 210 mmol) was dissolved in concentrated sulfuric acid (150 mL), and the solution was cooled to −10° C. Nitric acid (36 mL, 806 mmol) was added dropwise. The reaction mixture was stirred at 55° C. for 3 hours. The reaction mixture was poured into an ice/water mixture, and the pH was adjusted to 8 by addition of concentrated aqueous ammonium hydroxide (22%). The resulting suspension was filtered, and the solids were washed with water and dried under vacuum to provide the title compound (23 g, 123 mmol, 58.3% yield).
Reaction SMILES: CN1CCOCC1.[N+:8]([C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)([O-:10])=[O:9].[C:18](Cl)(=[O:26])[O:19][CH2:20][O:21][C:22](=[O:25])[CH2:23][CH3:24]>C(Cl)Cl>[C:18](=[O:26])([O:19][CH2:20][O:21][C:22](=[O:25])[CH2:23][CH3:24])[O:17][C:14]1[CH:15]=[CH:16][C:11]([N+:8]([O-:10])=[O:9])=[CH:12][CH:13]=1
Reactant: CCC(=O)OCOC(=O)Cl
Reactant: O=[N+]([O-])c1ccc(O)cc1
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CCC(=O)OCOC(=O)Oc1ccc([N+](=O)[O-])cc1
Yield: 60.7 %

Procedure:
4-Methylmorpholine (0.67 mL, 6.0 mmol) is added to a suspension of 4-nitrophenol (0.83 g, 6.0 mmol) in CH2Cl2 (10 mL) with stirring. A solution of 7c (1.27 g, 95% purity, 7.2 mmol) in CH2Cl2 (3 mL) is added during 20 min followed by stirring at 0° C. (30 min) and overnight at room temperature. After filtration the filtrate is evaporated and the residue partitioned between ice-cold Et2O (25 mL) and H2O (25 mL). The organic phase is extracted with ice-cold 0.5N NaOH (10 mL), H2O (3×15 mL), dried (MgSO4) and evaporated. The residue (1.50 g) is extracted with hexane (2×10 mL) to leave the title compound (0.98 g, 61%), mp 35°-36° C.
Reaction SMILES: [ClH:1].C(OCC)(=O)C.C([NH:15][C@@H:16]1[CH2:18][C@H:17]1[C:19]1[CH:24]=[CH:23][C:22]([NH:25][C:26](=[O:41])[C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([O:33][CH2:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[CH:28]=2)=[CH:21][CH:20]=1)C1C=CC=CC=1.C(=O)C1C=CC=CC=1>>[ClH:1].[NH2:15][C@@H:16]1[CH2:18][C@H:17]1[C:19]1[CH:24]=[CH:23][C:22]([NH:25][C:26](=[O:41])[C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([O:33][CH2:34][C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=3)[CH:28]=2)=[CH:21][CH:20]=1
Reactant: O=C(Nc1ccc([C@@H]2C[C@H]2NCc2ccccc2)cc1)c1cccc(OCc2ccccc2)c1
Agent: Cl
Solvent: O=Cc1ccccc1
Solvent: CCOC(C)=O
Product: N[C@@H]1C[C@H]1c1ccc(NC(=O)c2cccc(OCc3ccccc3)c2)cc1

Procedure:
By a method similar to Example 1, Step C, 4N hydrochloric acid/ethyl acetate solution was added to N-{4-[trans-2-(benzylamino)cyclopropyl]phenyl}-3-(benzyloxy)benzamide obtained from N-[4-(trans-2-aminocyclopropyl)phenyl]-3-(benzyloxy)benzamide hydrochloride (109 mg) and benzaldehyde (29.3 μL), and the resulting solid was collected by filtration to give the title compound (96.1 mg).
Reaction SMILES: C[O:2][C:3](=[O:21])[CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13](=[O:20])[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:8][CH:7]=1.[Li+].[OH-]>O.CO>[C:13]([NH:12][C:9]1[CH:10]=[CH:11][C:6]([CH:5]=[CH:4][C:3]([OH:21])=[O:2])=[CH:7][CH:8]=1)(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: COC(=O)C=Cc1ccc(NC(=O)c2ccccc2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)C=Cc1ccc(NC(=O)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 92 %

Procedure:
(Method H5) A mixture of 3-(4-benzoylamino-phenyl)-acrylic acid methyl ester (4b) (1.650 g, 5.87 mmol) and LiOH (0.630 g, 15 mmol) in water (30 ml) and methanol (30 ml) was stirred at ambient temperature for 24 hours. Methanol was evaporated and the residue was treated with hydrochloric acid to pH 4. The resulting precipitate was filtered off, washed with water (3×20 ml), and dried to give the title compound as a white solid (1.443 g, 92%). 1H NMR (DMSO-d6, HMDSO), δ: 6.44 (1H, d, J=16.0 Hz); 7.33-8.11 (10H, m); 10.40 (1H, s).
Reaction SMILES: [N+:1]([O-:4])([O-])=[O:2].[K+].FC(F)(F)C(O)=O.[NH2:13][C:14]1[CH:15]=[CH:16][C:17]([O:29][C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=2)=[C:18]([CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][N:21]2[C:26](=[O:28])[CH3:27])[CH:19]=1.C(=O)(O)[O-].[Na+]>>[NH2:13][C:14]1[C:15]([N+:1]([O-:4])=[O:2])=[CH:16][C:17]([O:29][C:30]2[CH:31]=[CH:32][C:33]([F:36])=[CH:34][CH:35]=2)=[C:18]([CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][N:21]2[C:26](=[O:28])[CH3:27])[CH:19]=1
Reactant: O=[N+]([O-])[O-]
Reactant: CC(=O)N1CCCCC1c1cc(N)ccc1Oc1ccc(F)cc1
Agent: O=C([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)N1CCCCC1c1cc(N)c([N+](=O)[O-])cc1Oc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
64 mg of potassium nitrate was added to a trifluoroacetic acid (1 ml) solution of 190 mg of 1-(2-(5-amino-2-(4-fluoro-phenoxy)-phenyl)-piperidin-1-yl)-ethanone, and the reaction liquid was stirred overnight at room temperature. Aqueous saturated sodium bicarbonate was added to the reaction liquid to neutralize it, and then extracted with ethyl acetate. The organic layer was washed with saturated saline, and dried with anhydrous sodium sulfate. The solvent was evaporated away under reduced pressure, and the resulting residue was purified through silica gel column chromatography (developing solvent: hexane/ethyl acetate=1/1) to obtain the entitled compound as a yellow solid.
Reaction SMILES: [CH3:1][O:2][C@H:3]1[O:8][C@H:7]([CH2:9][OH:10])[C@@H:6]([OH:11])[C@H:5]([OH:12])[C@H:4]1[OH:13].[OH-].[K+].O.[CH2:17](Cl)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[CH2:17]([O:13][C@@H:4]1[C@@H:5]([O:12][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C@H:6]([O:11][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C@@H:7]([CH2:9][O:10][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[O:8][C@@H:3]1[O:2][CH3:1])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: ClCc1ccccc1
Reactant: CO[C@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: CO[C@H]1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Methyl-α-D-glucopyranoside 9 (75 g) is dissolved in benzyl chloride (400 mL). To this solution is added potassium hydroxide (250 g). The resulting suspension is heated at 100° C. (water bath temp.) with stirring (mechanical) for 4 h, then cooled to r.t. The mixture is washed with saturated NaCl in ether (500 mL) and dried with MgSO4. The ether is evaporated. The residue is distilled under vacuum (~0.1 mm Hg) at a temperature of 120° C. until no more distillate is collected or the temperature at the distilling head begins to fall. The pot residue is used for the next reaction without further purification.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[N:9]=[CH:8][N:7]=[C:6]([C:10]([C:12]2[CH:21]=[CH:20][C:15]3[NH:16][C:17](=[O:19])[O:18][C:14]=3[CH:13]=2)=[O:11])[CH:5]=1.I[CH3:23]>CN(C=O)C>[Cl:3][C:4]1[N:9]=[CH:8][N:7]=[C:6]([C:10]([C:12]2[CH:21]=[CH:20][C:15]3[N:16]([CH3:23])[C:17](=[O:19])[O:18][C:14]=3[CH:13]=2)=[O:11])[CH:5]=1
Reactant: O=C(c1ccc2[nH]c(=O)oc2c1)c1cc(Cl)ncn1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1c(=O)oc2cc(C(=O)c3cc(Cl)ncn3)ccc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
135 mg (3.10 mmol) sodium hydride (55%, suspension in mineral oil) were added to 800 mg (2.90 mmol) 6-(6-chloro-pyrimidine-4-carbonyl)-3H-benzoxazol-2-one in 10 mL DMF and the mixture was stirred for 30 min at RT. Then 0.368 mL (5.80 mmol) iodomethane were added and the mixture was stirred for a further hour at RT. The mixture was mixed with ice water and extracted twice with EtOAc. The organic phases were combined, washed with water, dried and evaporated down. The residue was triturated with DIPE, suction filtered and dried.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:12][CH:11]([CH2:13][OH:14])[O:10][N:9]=2)=[CH:4][C:3]=1[F:15].C(N(CC)CC)C.[CH3:23][S:24](Cl)(=[O:26])=[O:25].C(=O)(O)[O-].[Na+]>ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:12][CH:11]([CH2:13][O:14][S:24]([CH3:23])(=[O:26])=[O:25])[O:10][N:9]=2)=[CH:4][C:3]=1[F:15]
Reactant: OCC1CC(c2ccc(Br)c(F)c2)=NO1
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCC1CC(c2ccc(Br)c(F)c2)=NO1
Temperature: 0 °C
Reaction time: 2 h
Yield: 97.8 %

Procedure:
[3-(4-Bromo-3-fluoro-phenyl)-4,5-dihydro-isoxazol-5-yl]-methanol (30 g, 112.4 mmol) was added to anhydrous dichloromethane (300 ml) followed by addition of triethylamine (21.8 ml, 157.3 mmol). The solution was cooled to 0° C. followed by drop wise addition of methane sulfonyl chloride (10.4 ml, 134.8 mmol). The reaction was stirred for 2 hours at 0° C. and then aqueous sodium bicarbonate (100 ml) was added. After further extraction with dichloromethane (2×100 ml), the organic layers were combined, dried over sodium sulfate, and concentrated in vacuo to give the desired product (38.7 g).
Reaction SMILES: Br[C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[C:11]([O:15][C:16](=[O:21])[NH:17][CH2:18][CH2:19][NH2:20])([CH3:14])([CH3:13])[CH3:12]>C(Cl)(Cl)Cl>[S:3]1[C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=[C:2]1[NH:20][CH2:19][CH2:18][NH:17][C:16](=[O:21])[O:15][C:11]([CH3:13])([CH3:12])[CH3:14]
Reactant: Brc1nc2ccccc2s1
Reactant: CC(C)(C)OC(=O)NCCN
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)NCCNc1nc2ccccc2s1

Procedure:
2-Bromo-1,3-benzothiazole (505.5 mg, 2.36 mmol) and N-(2-aminoethyl) carbamic acid tert-butyl ester (1.1356 g, 7.10 mmol) were stirred in a preheated oil bath (125° C.) for 5 h. The solid mass was dissolved in chloroform, and the resulting solution was washed with aqueous sodium bicarbonate then dried, filtered and concentrated to a yield a residue. The residue was purified by flash chromatography, eluting with 60% ethyl acetate in hexane to yield tert-butyl 2-(benzo[d]thiazol-2-ylamino)ethylcarbamate as a white amorphous solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[C:17]([I:18])=[CH:16][NH:15][C:4]=2[N:5]=[C:6]([NH:8][C:9](=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11])[N:7]=1.Cl.Cl[CH2:21][C:22]1[C:27]([CH3:28])=[C:26]([O:29][CH3:30])[C:25]([CH3:31])=[CH:24][N:23]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Cl:1][C:2]1[C:3]2[C:17]([I:18])=[CH:16][N:15]([CH2:21][C:22]3[C:27]([CH3:28])=[C:26]([O:29][CH3:30])[C:25]([CH3:31])=[CH:24][N:23]=3)[C:4]=2[N:5]=[C:6]([NH:8][C:9](=[O:14])[C:10]([CH3:11])([CH3:12])[CH3:13])[N:7]=1
Reactant: CC(C)(C)C(=O)Nc1nc(Cl)c2c(I)c[nH]c2n1
Reactant: COc1c(C)cnc(CCl)c1C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1c(C)cnc(Cn2cc(I)c3c(Cl)nc(NC(=O)C(C)(C)C)nc32)c1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.6 %

Procedure:
A mixture of N-(4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-2-yl)-2,2-dimethyl-propionamide (37.8 g, 0.1 mol), 2-chloromethyl-4-methoxy-3,5-dimethyl-pyridine hydrochloride (23.1 g, 0.104 mol), finely powdered K2CO3, (41.5 g, 0.3 mol, 3.0 eq.), and anhydrous DMF (200 mL) was stirred at rt overnight. The solvent was evaporated, and the residue taken up in CH2Cl2 (500 mL), washed with brine (200 mL×3), evaporated, and recrystallized from MeOH to give the title product as a white powder (42.0 g, 80% yield; HPLC purity 98%). tR: 6.49 min. 1H-NMR (DMSO-d6) δ 10.16 (br. s, 1H), 8.04 (s, 1H), 7.72 (s, 1H), 5.46 (s, 2H), 3.73 (s, 3H), 2.33 (s, 3H), 2.15 (s, 3H), 1.21 (s, 9H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[C:15]([F:23])[CH:14]=3)[N:11]=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[O:24]1[CH:28]=[CH:27][CH:26]=[C:25]1B(O)O>>[F:23][C:15]1[CH:14]=[C:13]([N:12]2[C:8]([C:5]3[CH:6]=[CH:7][C:2]([C:25]4[O:24][CH:28]=[CH:27][CH:26]=4)=[CH:3][CH:4]=3)=[CH:9][CH:10]=[N:11]2)[CH:18]=[CH:17][C:16]=1[S:19]([CH3:22])(=[O:21])=[O:20]
Reactant: OB(O)c1ccco1
Reactant: CS(=O)(=O)c1ccc(-n2nccc2-c2ccc(Br)cc2)cc1F
Product: CS(=O)(=O)c1ccc(-n2nccc2-c2ccc(-c3ccco3)cc2)cc1F

Procedure:
The title compound was prepared according to the procedure of Example 5 using 5-(4-bromophenyl)-1-[3-fluoro-4-(methylsulfonyl)phenyl]-1H-pyrazole instead of 4-[5-(4-bromophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]-1-phenylsulfonamide, 2-furanboronic acid instead of 3-thienylboronic acid.
Reaction SMILES: [CH2:1]([O:9][CH2:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH:7]=[CH2:8].Br[C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=1>>[CH:11]1([CH2:10][O:9][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:18]2[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=2)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]1
Reactant: C=CCCCCCCOCC1CCCCC1
Reactant: O=[N+]([O-])c1ccc(Br)cc1
Product: O=[N+]([O-])c1ccc(CCCCCCCCOCC2CCCCC2)cc1
Yield: 48 %

Procedure:
General procedure M was used to convert 4.56 mmol of 11c and 5.02 mmol of 1-bromo-4-nitrobenzene to 2.19 mmol (48%) of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:17]=[CH:16][C:6]([O:7][C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][CH:9]=2)=[C:5]([C:18]([F:21])([F:20])[F:19])[CH:4]=1.[H][H]>N.[Ni]>[CH3:1][O:2][C:3]1[CH:17]=[CH:16][C:6]([O:7][C:8]2[CH:15]=[CH:14][C:11]([CH2:12][NH2:13])=[CH:10][CH:9]=2)=[C:5]([C:18]([F:19])([F:20])[F:21])[CH:4]=1
Reactant: [H][H]
Reactant: COc1ccc(Oc2ccc(C#N)cc2)c(C(F)(F)F)c1
Agent: [Ni]
Agent: N
Product: COc1ccc(Oc2ccc(CN)cc2)c(C(F)(F)F)c1
Temperature: 25 °C

Procedure:
2.53 g (8.63 mmol) of 4-(4-methoxy-2-trifluoromethyl-phenoxy)-benzonitrile (from 82c) were dissolved in 100 ml 7M methanolic ammonia, then combined with 250 mg Raney nickel. The mixture was shaken at RT and 50 psi hydrogen pressure for 3 h. The catalyst was removed by suction filtering and the filtrate was evaporated down.
Reaction SMILES: C[O:2][C:3](=[O:33])[C@:4](C)([C:25](=[O:31])[C@@H:26]1[CH2:30][CH2:29][CH2:28][NH:27]1)[C@H:5]([NH:13][S:14]([C:17]1[CH:22]=[C:21]([Cl:23])[CH:20]=[C:19]([Cl:24])[CH:18]=1)(=[O:16])=[O:15])[C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1.C[CH2:35][N:36]([CH:40]([CH3:42])C)[CH:37]([CH3:39])C.C(=O)(O)[O-:44].[Na+]>C(Cl)Cl>[Cl:24][C:19]1[CH:18]=[C:17]([S:14]([NH:13][C@@H:5]([C:6]2[CH:7]=[CH:8][C:9]([O:12][C:35]([N:36]3[CH2:37][CH2:39][CH2:42][CH2:40]3)=[O:44])=[CH:10][CH:11]=2)[C@@H:4]([C:25](=[O:31])[C@@H:26]2[CH2:30][CH2:29][CH2:28][NH:27]2)[C:3]([OH:2])=[O:33])(=[O:15])=[O:16])[CH:22]=[C:21]([Cl:23])[CH:20]=1
Reactant: COC(=O)[C@](C)(C(=O)[C@@H]1CCCN1)[C@H](NS(=O)(=O)c1cc(Cl)cc(Cl)c1)c1ccc(O)cc1
Reactant: O=C([O-])O
Reactant: CCN(C(C)C)C(C)C
Agent: [Na+]
Solvent: ClCCl
Product: O=C(O)[C@H](C(=O)[C@@H]1CCCN1)[C@@H](NS(=O)(=O)c1cc(Cl)cc(Cl)c1)c1ccc(OC(=O)N2CCCC2)cc1
Reaction time: 1 h

Procedure:
N-(3,5-Dichlorobenzenesulfonyl)-2-methyl-2(S)-prolyl-3(R)-amino-3-(4-hydroxyphenyl)propionic acid methyl ester, as prepared in Example 28, Step F (50 mg, 0.11 mmol), was dissolved in 1 mL of methylene chloride and treated sequentially at 0° with DIPEA (56 μl, 0.3 mmol) and chlorocarbonyl-N-pyrrolidine (16 mg, 0.12 mmol). The mixture was stirred for 1 hour, then worked up with saturated sodium bicarbonate, extracted with methylene chloride and dried over magnesium sulphate. The solution was filtered, solvent removed in vacuo and the product chromatographed on flash silica gel (70/30 hexane/ethyl acetate) (Rf=0.3). The methyl ester was recovered (42 mg) and subsequently hydrolysed by the procedure described in Example 39, Step F to N-(3,5-dichlorobenzenesulfonyl)-2(S)-prolyl-3(R)-amino-3-(4-(N-pyrrolidinylcarbonyloxy)phenyl)propionic acid (35 mg).
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][C:5]2=[N:6][S:7][N:8]=[C:4]2[CH:3]=1.[N:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17]1[C:18](B(O)O)=[C:19]2[CH2:24][CH2:23][CH2:22][N:20]2[N:21]=1>>[N:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17]1[C:18]([C:2]2[CH:10]=[CH:9][C:5]3=[N:6][S:7][N:8]=[C:4]3[CH:3]=2)=[C:19]2[CH2:24][CH2:23][CH2:22][N:20]2[N:21]=1
Reactant: OB(O)c1c(-c2ccccn2)nn2c1CCC2
Reactant: Brc1ccc2nsnc2c1
Product: c1ccc(-c2nn3c(c2-c2ccc4nsnc4c2)CCC3)nc1
Yield: 24.5 %

Procedure:
In a similar fashion to Example 4, react 5-bromo-[2,1,3]-benzothiadiazole (Maybridge; 180 mg, 0.83 mmol) with 2-(pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-3-boronic acid (Preparation 5; 190 mg, 0.83 mmol) to provide the title compound (65 mg, 16%) as a tan solid. Melting Range: 184-186° C. MS ESI+ m/e 320 (M+1). 1H NMR (CDCl3) δ 8.61-8.52 (m, 1H), 7.94 (s, 1H), 7.89-7.82 (m, 1H), 7.70-7.62 (m, 2H), 7.52-7.49 (m, 1H), 7.29-7.17 (m, 1H), 4.33-4.22 (m, 2H), 3.12-3.02 (m, 2H), 2.72-2.60 (m, 2H). HPLC: >99%, Rt=15.41 min. TLC (SiO2): Rf0.3 (1:1 [80:18-2 chloroform/methanol/concentrated aqueous ammonium hydroxide]/dichloromethane).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C@@H:9]([CH3:15])[CH2:10][C:11](=[O:14])[NH:12][N:13]=2)=[CH:4][CH:3]=1.O1[CH:21]=[CH:20][C:19](=[O:22])[CH:18]=[CH:17]1.Cl>O>[CH3:15][C@@H:9]1[C:8]([C:5]2[CH:6]=[CH:7][C:2]([N:1]3[CH:21]=[CH:20][C:19](=[O:22])[CH:18]=[CH:17]3)=[CH:3][CH:4]=2)=[N:13][NH:12][C:11](=[O:14])[CH2:10]1
Reactant: C[C@H]1CC(=O)NN=C1c1ccc(N)cc1
Reactant: O=c1ccocc1
Agent: Cl
Solvent: O
Product: C[C@H]1CC(=O)NN=C1c1ccc(-n2ccc(=O)cc2)cc1

Procedure:
A mixture of (S)-6-(4-aminophenyl)-5-methyl-4,5-dihydro-3(2H)-pyridazinone (147 mg), 4H-pyran-4-one (78 mg) and hydrochloric acid (0.1 N, 1.5 ml) in water (2 ml) was stirred under reflux under nitrogen for 3 hours. The reaction mixture was cooled to afford the title compound, which was collected, washed with water and dried, 110 mg, m.p. 256-7° C. (softens 80° C.), [α]25D=+ 354° (1.03% in dimethylformamide).
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.[F:25][C:26]1[CH:27]=[C:28]([CH:45]=[C:46]([F:48])[CH:47]=1)[O:29][C:30]1[CH:35]=[CH:34][C:33](B2OC(C)(C)C(C)(C)O2)=[CH:32][CH:31]=1.O1CCOCC1.C(=O)([O-])[O-].[Na+].[Na+]>O>[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:33]3[CH:32]=[CH:31][C:30]([O:29][C:28]4[CH:45]=[C:46]([F:48])[CH:47]=[C:26]([F:25])[CH:27]=4)=[CH:35][CH:34]=3)[C:3]=12
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1Cn1nc(I)c2c(N)ncnc21
Reactant: CC1(C)OB(c2ccc(Oc3cc(F)cc(F)c3)cc2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCC[C@@H]1Cn1nc(-c2ccc(Oc3cc(F)cc(F)c3)cc2)c2c(N)ncnc21
Temperature: 80 °C
Reaction time: 12 h
Yield: 81 %

Procedure:
Into a 100 mL, 3-necked round-bottom flask purged and maintained with 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 (250 mg, 0.56 mmol, 1.00 equiv), 2-[4-(3,5-difluorophenoxy)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (226 mg, 0.68 mmol, 1.20 equiv), tetrakis(triphenylphosphane)palladium (39 mg, 0.03 mmol, 0.06 equiv), dioxane (50 mL), sodium carbonate (149 mg, 1.41 mmol, 2.50 equiv), and water (10 mL). The resulting solution was stirred for 12 h at 80° C. in an oil bath and then concentrated under vacuum. The resulting solution was extracted with dichloromethane and the organic layers combined, dried and concentrated under vacuum. The residue was loaded onto a silica gel column and eluted with dichloromethane/methanol (50/1) to give 0.237 g (81%) of tert-butyl (2R)-2-([4-amino-3-[4-(3,5-difluorophenoxy)phenyl]-1H-pyrazolo[3,4-d]pyrimidin-1-yl]methyl)pyrrolidine-1-carboxylate as a brown solid.