Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([S:3](=[N:29]C#N)([CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([NH:12][C:13]2[N:18]=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[O:26][CH3:27])[C:16]([F:28])=[CH:15][N:14]=2)[CH:7]=1)=[O:4])[CH3:2].C(OC(C(F)(F)F)=O)(C(F)(F)F)=O.C(=O)([O-])[O-].[K+].[K+]>C(Cl)Cl.C(OCC)(=O)C.C1COCC1>[CH2:1]([S:3]([CH2:5][C:6]1[CH:7]=[C:8]([NH:12][C:13]2[N:18]=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[O:26][CH3:27])[C:16]([F:28])=[CH:15][N:14]=2)[CH:9]=[CH:10][CH:11]=1)(=[NH:29])=[O:4])[CH3:2]
Reactant: CCS(=O)(Cc1cccc(Nc2ncc(F)c(-c3ccc(F)cc3OC)n2)c1)=NC#N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: CCS(=N)(=O)Cc1cccc(Nc2ncc(F)c(-c3ccc(F)cc3OC)n2)c1

Procedure:
To a stirring solution of (rac)-[ethyl(3-{[5-fluoro-4-(4-fluoro-2-methoxyphenyl)pyrimidin-2-yl]-amino}benzyl)oxido-λ6-sulfanylidene]cyanamide (230 mg; 0.52 mmol) in DCM (23.1 mL) at 0° C., TFAA (0.55 mL; 3.89 mmol) was added. The mixture was allowed to react at RT for 2 hours. The reaction mixture was concentrated, taken up in MeOH (3.6 mL) and treated with potassium carbonate (358 mg; 2.58 mmol). The mixture was allowed to react at RT for 2 hours. The reaction mixture was diluted with ethyl acetate and THF and washed with saturated aqueous sodium chloride solution. The organic phase was filtered using a Whatman filter and concentrated. The residue was purified by chromatography (DCM/EtOH 4:1).
Reaction SMILES: [I:1][C:2]1[CH:9]=[C:6]([CH:7]=O)[C:5]([OH:10])=[CH:4][CH:3]=1.CC1(C)O[C:17](=[O:18])[CH2:16][C:14](=[O:15])[O:13]1>O>[I:1][C:2]1[CH:9]=[C:6]2[C:5](=[CH:4][CH:3]=1)[O:10][C:17](=[O:18])[C:16]([C:14]([OH:15])=[O:13])=[CH:7]2
Reactant: O=Cc1cc(I)ccc1O
Reactant: CC1(C)OC(=O)CC(=O)O1
Solvent: O
Product: O=C(O)c1cc2cc(I)ccc2oc1=O
Temperature: 75 °C
Reaction time: 2 h
Yield: 68.7 %

Procedure:
5-iodosalicylaldehyde (344.2 mg, 1.39 mmol) and Meldrum's acid (200 mg, 1.39 mmol) were combined in H2O (2 mL). The solution was stirred at 75° C. for 2 h. After cooling to room temperature, the precipitate was filtered and dried at suction to give 302.0 mg of 6-iodo-3-carboxy-coumarin in 69% yield.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][NH:5][CH2:6][CH2:7][NH:8][CH2:9][CH2:10][CH2:11][NH2:12].[CH:13]([CH:15]=O)=O.O>C1(C)C=CC=CC=1>[CH2:11]1[N:12]2[C@@H:7]([C@@H:6]3[N:1]([CH2:13][CH2:15]2)[CH2:2][CH2:3][CH2:4][NH:5]3)[NH:8][CH2:9][CH2:10]1
Reactant: O=CC=O
Reactant: NCCCNCCNCCCN
Solvent: Cc1ccccc1
Solvent: O
Product: C1CN[C@@H]2[C@H]3NCCCN3CCN2C1

Procedure:
A solution of 87.2 g of 1,10-diamino-4,7-diazadecane in 500 ml of toluene was admixed with 72.3 g of a 40% aqueous glyoxal solution, and the mixture was refluxed, with a water separator fitted, for 3 hours. When the solution was cooled, a solid precipitated out which was filtered off with suction, washed three times with 50 ml of toluene each time and dried under reduced pressure. This gave 34.9 g of pale yellow needles.
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:29])[N:4]([C:19]2[CH:20]=[C:21]([CH:25]=[CH:26][C:27]=2[F:28])[C:22](O)=[O:23])[C:5]([CH3:18])=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17].O[N:31]1[C:35]2C=CC=CC=2N=N1.N=C=N.CN.CN=C=O>O1CCCC1.CN(C)C=O>[Cl:1][C:2]1[C:3](=[O:29])[N:4]([C:19]2[CH:20]=[C:21]([CH:25]=[CH:26][C:27]=2[F:28])[C:22]([NH:31][CH3:35])=[O:23])[C:5]([CH3:18])=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17]
Reactant: Cc1cc(OCc2ccc(F)cc2F)c(Cl)c(=O)n1-c1cc(C(=O)O)ccc1F
Reactant: On1nnc2ccccc21
Agent: CN
Agent: CN=C=O
Agent: N=C=N
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CNC(=O)c1ccc(F)c(-n2c(C)cc(OCc3ccc(F)cc3F)c(Cl)c2=O)c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a reaction vessel (borosilicate culture tube) was added 3-[3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]-4-fluorobenzoic acid (0.300 g, 0.708 mmol) and 1-hydroxybenzotriazole (0.048 g, 0.45 mmol). N,N-Dimethylformamide (3 mL) was added to the reaction vessel followed by approximately 1.2 g of the polymer bound carbodiimide resin (1.38 mmol/g). Additional N,N-dimethylformamide (2 mL) was then added to the reaction vessel. The parallel reaction apparatus was then orbitally shaken (Labline Benchtop Orbital Shaker) at approximately 200 RPM at room temperature for 15 minutes. N-Methyl amine (1 mL, 2 mmol) was then added to the reaction vessel and the reaction apparatus was orbitally shaken at room temperature overnight. At this time the reaction was diluted with tetrahydrofuran (20 mL) and treated with approximately 2.17 g of polyamine resin (2.63 mmol/g) and approximately 2.8 g of methylisocyanate functionalized polystyrene (1.5 mmol/9) and the orbital shaking was continued at 200 RPM at room temperature for 3 hours. The reaction vessel was then opened and the solution phase product was separated from the insoluble quenched byproducts by filtration and collection into a vial. After partially evaporation the insoluble byproducts were rinsed with tetrahydrofuran (2×10 mL). The filtrate was evaporated by blowing N2 over the vial and the resulting solid was triturated with diethyl ether to give an off-white solid. (0.168 g, 59%) 1H NMR (400 MHz, CD3OD) δ 8.02 (dddd, J=2, 4.4, 7.2 and 8.4 Hz, 1H), 7.80 (dd, J=2 and 6.8 Hz, 1H), 7.62 (q, J=8 and 14.4 Hz, 1H), 7.34 (t, J=8.8 Hz, 1H), 7.04 (m, 2H), 6.69 (s, 1H), 5.36 (s, 2H), 3.29 (s, 3H), 1.98 (s, 3H) ppm. 19F NMR (400 MHz, CD3OD) δ−108.94 (1 F), −113.55 (1 F), −117.76 (1 F) ppm. ES-HRMS m/z 437.0861 (M+H calcd for C21H17ClF3N2O3 requires 437.0874).
Reaction SMILES: [C:1]1([C:7]([CH2:23][CH3:24])=[C:8]([C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=2)[C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:25][N:26]1[CH2:30][CH2:29][CH2:28][CH:27]1[CH2:31]O>>[CH3:25][N:26]1[CH2:30][CH2:29][CH2:28][CH:27]1[CH2:31][O:22][C:19]1[CH:18]=[CH:17][C:16]([C:8]([C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)=[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:23][CH3:24])=[CH:21][CH:20]=1
Reactant: CCC(=C(c1ccc(O)cc1)c1ccc(O)cc1)c1ccccc1
Reactant: CN1CCCC1CO
Product: CCC(=C(c1ccc(O)cc1)c1ccc(OCC2CCCN2C)cc1)c1ccccc1
Yield: 33.2 %

Procedure:
Following same procedure of Mitsunobu reaction as described in example 16, step D, 4,4′-(2-phenylbut-1-ene-1,1-diyl)diphenol (220 mg, 0.473 mmol) was reacted with (1-methylpyrrolidin-2-yl)methanol (82 mg, 0.712 mmol, made from DL-proline Following Arch. Pharm. Phamz. Med. Chem. 1996, 329, 95-104.) to give 65 mg desired product (33% yield). m/z=414[M+1]+.
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[CH:5][N:6]=1.Cl[C:8]1[N:9]=[C:10]([NH:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([N+:29]([O-:31])=[O:30])[CH:24]=2)[C:11]2[CH:16]=[C:15]([C:17]([F:20])([F:19])[F:18])[S:14][C:12]=2[N:13]=1>>[CH3:1][C:2]1[N:3]([C:8]2[N:9]=[C:10]([NH:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([N+:29]([O-:31])=[O:30])[CH:24]=3)[C:11]3[CH:16]=[C:15]([C:17]([F:19])([F:20])[F:18])[S:14][C:12]=3[N:13]=2)[CH:4]=[CH:5][N:6]=1
Reactant: Cc1ncc[nH]1
Reactant: O=[N+]([O-])c1cccc(CNc2nc(Cl)nc3sc(C(F)(F)F)cc23)c1
Product: Cc1nccn1-c1nc(NCc2cccc([N+](=O)[O-])c2)c2cc(C(F)(F)F)sc2n1

Procedure:
Following the procedure of Example 97, the reaction of 2-methylimidazole with 2-chloro-6-trifluoromethyl-4-(3-nitrobenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(2-methylimidazol-1-yl)-6-trifluoromethyl-4-(3-nitrobenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [C:1]([C:3]1[N:8]=[CH:7][C:6]([N:9]2[C:16](=[O:17])[C:12]3([CH2:15][CH2:14][CH2:13]3)[N:11]([C:18]3[CH:26]=[CH:25][C:21]([C:22]([OH:24])=O)=[C:20]([F:27])[CH:19]=3)[C:10]2=[S:28])=[CH:5][C:4]=1[C:29]([F:32])([F:31])[F:30])#[N:2].[N:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[CH2:39][CH2:40][NH2:41].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[C:1]([C:3]1[N:8]=[CH:7][C:6]([N:9]2[C:16](=[O:17])[C:12]3([CH2:15][CH2:14][CH2:13]3)[N:11]([C:18]3[CH:26]=[CH:25][C:21]([C:22]([NH:41][CH2:40][CH2:39][C:34]4[CH:35]=[CH:36][CH:37]=[CH:38][N:33]=4)=[O:24])=[C:20]([F:27])[CH:19]=3)[C:10]2=[S:28])=[CH:5][C:4]=1[C:29]([F:32])([F:31])[F:30])#[N:2]
Reactant: NCCc1ccccn1
Reactant: N#Cc1ncc(N2C(=O)C3(CCC3)N(c3ccc(C(=O)O)c(F)c3)C2=S)cc1C(F)(F)F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1ncc(N2C(=O)C3(CCC3)N(c3ccc(C(=O)NCCc4ccccn4)c(F)c3)C2=S)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 59.8 %

Procedure:
A mixture of 4-(7-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-5-yl)-2-fluorobenzoic acid (Compound 224, 70 mg, 0.15 mmol), 2-(pyridin-2-yl)ethanamine (24 mg, 0.20 mmol), HATU (74 mg, 0.20 mmol), and DIEA (80 mL, 0.45 mmol) in DMF (3 mL) was stirred at room temperature overnight. The crude reaction mixture was purified by reverse phase HPLC (acetonitrile/water, 0.1% TFA). The fractions containing the desired compound were combined, acetonitrile was removed in vacuo, and the remaining aqueous layer was treated with a saturated solution of sodium bicarbonate. The aqueous layer was extracted with DCM (3×), the organics were combined, dried over sodium sulfate, and evaporated to dryness to afford 51 mg of 4-(7-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-5-yl)-2-fluoro-N-(2-(pyridin-2-yl)ethyl)benzamide as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 9.22 (d, 1H), 8.75 (d, 1H), 8.66 (t, 1H), 8.52 (d, 1H), 7.82-7.70 (m, 2H), 7.47-7.22 (m, 4H), 3.65 (q, 2H), 3.01 (t, 2H), 2.68-2.62 (m, 2H), 2.54-2.43 (m, 2H), 2.03-1.93 (m, 1H), 1.60-1.57 (m, 1H). LCMS [M+1]+ 569.5.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[C@H:4]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][CH:15]=1)[NH:5][C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7].C(N(C(C)C)CC)(C)C.[Cl:31][C:32]1[CH:40]=[CH:39][CH:38]=[C:37]([Cl:41])[C:33]=1[C:34](Cl)=[O:35]>ClCCl.O>[CH3:1][O:2][C:3](=[O:21])[C@H:4]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([NH:20][C:34]([C:33]2[C:32]([Cl:31])=[CH:40][CH:39]=[CH:38][C:37]=2[Cl:41])=[O:35])=[CH:16][CH:15]=1)[NH:5][C:6]([O:8][C:9]([CH3:12])([CH3:10])[CH3:11])=[O:7]
Reactant: COC(=O)[C@H](Cc1ccc(N)cc1)NC(=O)OC(C)(C)C
Reactant: O=C(Cl)c1c(Cl)cccc1Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: COC(=O)[C@H](Cc1ccc(NC(=O)c2c(Cl)cccc2Cl)cc1)NC(=O)OC(C)(C)C
Reaction time: 15 h
Yield: 100.3 %

Procedure:
To a solution of 4-(amino)-N-[(1,1-dimethylethoxy)carbonyl]-L-phenylalanine methyl ester (2.6 g, 8.6 mmol) in dichloromethane (20 mL) were added diisopropylethylamine (2.3 mL, 13 mmol) followed by 2,6-dichlorobenzoyl chloride (1.99 g, 9.5 mmol) at room temperature. The mixture was stirred for 15 h at which time a white precipitate was formed. The mixture was diluted with 30 mL of dichloromethane and 50 mL of water. The layers were separated and the aqueous layer was extracted with 100 mL (2×50 mL) of dichloromethane. The combined organic extracts were washed with brine and dried over anhydrous magnesium sulfate. Filtration and concentration of the solvent gave 4.03 g (quantitative) of 4-[[(2,6-dichlorophenyl)carbonyl]amino]-N-[(1,1-dimethylethoxy)-carbonyl]-L-phenylalanine methyl ester as a white solid, mp 148-151° C.
Reaction SMILES: [CH3:1][N:2]([C:22]1[CH:27]=[N:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][N:23]=1)[C@H:3]1[CH2:7][CH2:6][CH2:5][C@@H:4]1[NH:8][C:9](=[O:21])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[N:16]1[N:20]=[CH:19][CH:18]=[N:17]1.CN(C1C=NC(C(F)(F)[F:47])=CN=1)[C@H]1CCC[C@@H]1N.FC1C=CC=C(N2N=CC=N2)C=1C(O)=O>>[F:47][C:15]1[CH:14]=[CH:13][CH:12]=[C:11]([N:16]2[N:20]=[CH:19][CH:18]=[N:17]2)[C:10]=1[C:9]([NH:8][C@H:4]1[CH2:5][CH2:6][CH2:7][C@@H:3]1[N:2]([CH3:1])[C:22]1[CH:27]=[N:26][C:25]([C:28]([F:29])([F:31])[F:30])=[CH:24][N:23]=1)=[O:21]
Reactant: CN(c1cnc(C(F)(F)F)cn1)[C@H]1CCC[C@@H]1NC(=O)c1ccccc1-n1nccn1
Reactant: CN(c1cnc(C(F)(F)F)cn1)[C@H]1CCC[C@@H]1N
Agent: O=C(O)c1c(F)cccc1-n1nccn1
Product: CN(c1cnc(C(F)(F)F)cn1)[C@H]1CCC[C@@H]1NC(=O)c1c(F)cccc1-n1nccn1

Procedure:
Prepared according to the procedure for N-[(1S,2S)-2-{methyl[5-(trifluoromethyl)pyrazin-2-yl]amino}cyclopentyl]-2-(2H-1,2,3-triazol-2-yl)benzamide (Example 73) from (1S,2S)-1-N-methyl-1-N-[5-(trifluoromethyl)pyrazin-2-yl]cyclopentane-1,2-diamine (Intermediate 22; 59 mg, 0.23 mmol) and 2-fluoro-6-(2H-1,2,3-triazol-2-yl)benzoic acid (CAS number 1186050-58-7; 56 mg, 0.27 mmol) to afford the title compound.
Reaction SMILES: Cl.Cl[C:3]1[CH:4]=[CH:5][C:6]([C:10]2[N:11]=[N:12][C:13]([O:16][CH:17]3[CH2:22][C:21]([CH3:24])([CH3:23])[NH:20][C:19]([CH3:26])([CH3:25])[CH2:18]3)=[CH:14][CH:15]=2)=[C:7]([OH:9])[CH:8]=1.C([N:34]1[CH:38]=[C:37](B2OC(C)(C)C(C)(C)O2)[CH:36]=[N:35]1)(OC(C)(C)C)=O.C([O-])([O-])=O.[Cs+].[Cs+].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O.O1CCOCC1>[NH:34]1[CH:38]=[C:37]([C:3]2[CH:4]=[CH:5][C:6]([C:10]3[N:11]=[N:12][C:13]([O:16][CH:17]4[CH2:18][C:19]([CH3:25])([CH3:26])[NH:20][C:21]([CH3:23])([CH3:24])[CH2:22]4)=[CH:14][CH:15]=3)=[C:7]([OH:9])[CH:8]=2)[CH:36]=[N:35]1
Reactant: CC(C)(C)OC(=O)n1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: CC1(C)CC(Oc2ccc(-c3ccc(Cl)cc3O)nn2)CC(C)(C)N1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: Cl
Solvent: C1COCCO1
Solvent: O
Product: CC1(C)CC(Oc2ccc(-c3ccc(-c4cn[nH]c4)cc3O)nn2)CC(C)(C)N1
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
A 1-L flask was charged with 5-chloro-2-(6-((2,2,6,6-tetramethylpiperidin-4-yl)oxy)pyridazin-3-yl)phenol hydrochloride (9.2 g, 23 mmol), N-Boc-Pyrazole-4-boronic acid pinacol ester (10.2 g, 35 mmol), Cs2CO3 (15 g, 46 mmol), 1,4-dioxane (100 mL) and water (25 mL). The mixture was purged with nitrogen 3 times. X-Phos (0.88 g, 1.85 mmol) and Pd2 dba3 (0.845 g, 0.922 mmol) were added. The mixture was purged with nitrogen 3 times, then heated at 80° C. for 3 hrs. By HPLC analysis, the reaction was complete. 37% HCl (10 mL) was added slowly over 20 min. Ethanol (100 mL) and H2O (200 mL) were added and the reaction mixture was heated to 75-80° C. for 16 hours. The reaction mixture was cooled to 50-60° C., and the insoluble black solids were filtered. The filtrate was cooled to 30° C., and 2N NaOH (50 mL) was added to basify the solution to pH 8-9. The resulting precipitate was stirred for 30 min, then filtered and dried under vacuum at 50° C. to give 5-(1H-pyrazol-4-yl)-2-(6-((2,2,6,6-tetramethylpiperidin-4-yl)oxy)pyridazin-3-yl)phenol as yellow solid. HRMS m/z 394.2239 [M+H]; 1H-NMR: (DMSO-d6, 400 MHz) δ 13.2 (br, 1H), 13.0 (br, 1H), 8.44 (d, J=8 Hz, 1H), 8.14 (br, 2H), 7.93 (d, J=8 Hz, 1H), 7.39 (d, J=12 Hz, 1H), 7.24 (d, J=8 Hz, 2H), 5.64 (m, 1H), 2.10 (dd, Ja=4 Hz, Jb=12 Hz, 2H), 1.26-1.30 (m, J=8 Hz, 2H), 1.23 (s, 6H), 1.10 (s, 6H). 13C-NMR: (DMSO-d6, 100 MHz) δ 162.80, 158.55, 155.97, 136.13, 128.30, 127.71, 120.42, 120.01, 116.26, 115.13, 113.44, 71.32, 50.99, 43.20, 34.33, 29.14.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:28])=[C:6](/[CH:8]=[C:9](\[NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])/[C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:11])[CH:7]=1.[H][H]>C(O)C>[Br:1][C:2]1[CH:7]=[C:6]([C:5]([F:28])=[CH:4][CH:3]=1)[CH2:8][C@@H:9]([C:10]([O:12][CH2:13][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)=[O:11])[NH:20][C:21]([O:23][C:24]([CH3:26])([CH3:25])[CH3:27])=[O:22]
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)N/C(=C\c1cc(Br)ccc1F)C(=O)OCc1ccccc1
Solvent: CCO
Product: CC(C)(C)OC(=O)N[C@@H](Cc1cc(Br)ccc1F)C(=O)OCc1ccccc1
Reaction time: 0.5 h

Procedure:
6.0 g (13.3 mmol) of benzyl (2Z)-3-(5-bromo-2-fluorophenyl)-2-[(tert-butoxycarbonyl)amino]acrylate are dissolved in 100 ml of ethanol. Under an argon atmosphere, 40 mg (0.055 mmol) of (+)-1,2-bis((2S,5S)-2,5-diethylphospholano)benzene(cyclooctadiene)rhodium(I)trifluoromethanesulfonate are added, and argon is passed through the solution for 30 min. The mixture is then hydrogenated under a pressure of 3 bar of hydrogen for 4 days. The mixture is filtered through silica gel, which is carefully washed with ethanol. The filtrate is concentrated in vacuo, and the crude product is dried under high vacuum.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]([NH2:14])[CH2:10][N+:11]([O-:13])=[O:12].[O-:15][C:16]#[N:17].[K+]>O.CO>[Cl:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]([NH:14][C:16]([NH2:17])=[O:15])[CH2:10][N+:11]([O-:13])=[O:12]
Reactant: N#C[O-]
Reactant: NC(C[N+](=O)[O-])c1ccccc1Cl
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CO
Product: NC(=O)NC(C[N+](=O)[O-])c1ccccc1Cl
Temperature: 40 °C

Procedure:
At RT, 300 mg (about 93% pure, 1.18 mmol) of the compound of Example 25A were initially charged in 12 ml of water/methanol (1:1 v/v), and 287 mg (3.53 mmol) of potassium cyanate were added. The reaction mixture was warmed to 40° C. for 1 h. After cooling to RT, the mixture was directly separated into its components by preparative HPLC [Method 8]. This gave 120 mg (41% of theory) of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[C:6]([CH:7]=[O:8])[C:5]([OH:10])=[CH:4][CH:3]=1.[O:11]1[CH2:16][CH2:15][CH:14](OS(C)(=O)=O)[CH2:13][CH2:12]1.C([O-])([O-])=O.[K+].[K+]>CN(C)C=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH:14]2[CH2:15][CH2:16][O:11][CH2:12][CH2:13]2)=[C:6]([CH:9]=1)[CH:7]=[O:8]
Reactant: CS(=O)(=O)OC1CCOCC1
Reactant: O=Cc1cc(Br)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=Cc1cc(Br)ccc1OC1CCOCC1
Yield: 66.9 %

Procedure:
In a manner similar to the method described in example 4a, 5-bromosalicylaldehyde (3 g, 15 mmol) (Aldrich) reacted with methanesulfonic acid tetrahydropyran-4-yl ester (4 g, 22 mmol) prepared in Example 32a and K2CO3 in N,N-dimethylformamide to give 5-bromo-2-(tetrahydro-pyran-4-yloxy)-benzaldehyde as a yellow solid (Yield 2.86 g, 67%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[C:5]1[CH:10]=[CH:9][C:8]([N:11]=[CH:12][C:13]2[CH:14]=[N:15][CH:16]=[C:17]([Br:19])[CH:18]=2)=[CH:7][CH:6]=1)[CH3:2].O.[O-]S(C(F)(F)F)(=O)=O.[Yb+3].[O-]S(C(F)(F)F)(=O)=O.[O-]S(C(F)(F)F)(=O)=O.[CH:47](=[O:51])[CH:48]([CH3:50])[CH3:49].O>O1CCCC1>[CH2:1]([O:3][C:4]([C:5]1[CH:10]=[C:9]2[C:8](=[CH:7][CH:6]=1)[NH:11][CH:12]([C:13]1[CH:14]=[N:15][CH:16]=[C:17]([Br:19])[CH:18]=1)[C:48]([CH3:50])([CH3:49])[CH:47]2[OH:51])=[O:20])[CH3:2]
Reactant: CCOC(=O)c1ccc(N=Cc2cncc(Br)c2)cc1
Reactant: CC(C)C=O
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc2c(c1)C(O)C(C)(C)C(c1cncc(Br)c1)N2
Temperature: 25 °C
Reaction time: 12 h
Yield: 80.6 %

Procedure:
To a mixture of 4-[(5-bromo-pyridin-3-ylmethylene)-amino]-benzoic acid ethyl ester (16.3 g, 49 mmol) and ytterbium(III) triflate hydrate (3.1 g, 49 mmol) in dry tetrahydrofuran (100 mL) at 25° C. was added isobutyraldehyde (4.98 mL, 55 mmol) and water (0.89 mL, 49 mmol) dropwise. The reaction mixture was stirred at 25° C. for 12 h. Then the reaction mixture was concentrated in vacuo and the residue was extracted with ethyl acetate (2×200 mL), washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo to afford 2-(5-bromo-pyridin-3-yl)-4-hydroxy-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (16 g, 80%) as a light yellow oil which was used for next step without further purification: LC/MS m/e calcd for C19H21BrN2O3 (M+H)+: 406.29, observed: 405.1.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH2:11][C@H:10]([CH3:18])[NH:9]2)=[CH:4][CH:3]=1.[N:19]([C:22]1[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[CH:24][CH:23]=1)=[C:20]=[O:21]>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH2:11][C@H:10]([CH3:18])[N:9]2[C:20]([NH:19][C:22]2[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[CH:24][CH:23]=2)=[O:21])=[CH:4][CH:3]=1
Reactant: N#Cc1ccc(N=C=O)cc1
Reactant: C[C@H]1Cc2ccccc2[C@@H](c2ccc(Br)cc2)N1
Solvent: ClCCl
Product: C[C@H]1Cc2ccccc2[C@@H](c2ccc(Br)cc2)N1C(=O)Nc1ccc(C#N)cc1
Reaction time: 5 h

Procedure:
To a solution of (1R,3S)-1-(4-bromophenyl)-3-methyl-1,2,3,4-tetrahydroisoquinoline (50 mg, 165 example 81, step 2) in CH2Cl2 (1.0 mL) at RT was added 4-isocyanatobenzonitrile (37 mg, 256 μmol). The reaction was stirred 5 h and directly purified by reverse phase HPLC to give (1R,3S)-1-(4-bromophenyl)-N-(4-cyanophenyl)-3-methyl-3,4-dihydroisoquinoline-2(1H)-carboxamide as a white solid. MS (ESI pos. ion) m/z: 446, 448 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]([CH2:13][C:14](OC)=[O:15])=[CH:10][C:9]=2[C:18]2[CH:23]=[CH:22][C:21]([S:24]([CH3:27])(=[O:26])=[O:25])=[CH:20][CH:19]=2)=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].C(OCC)(=O)C.S(=O)(=O)(O)O>C(OCC)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[S:12][C:11]([CH2:13][CH2:14][OH:15])=[CH:10][C:9]=2[C:18]2[CH:23]=[CH:22][C:21]([S:24]([CH3:27])(=[O:25])=[O:26])=[CH:20][CH:19]=2)=[CH:6][CH:7]=1
Reactant: COC(=O)Cc1cc(-c2ccc(S(C)(=O)=O)cc2)c(-c2ccc(F)cc2)s1
Agent: O=S(=O)(O)O
Agent: [Al+3]
Agent: [H-]
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: CS(=O)(=O)c1ccc(-c2cc(CCO)sc2-c2ccc(F)cc2)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A mixture of methyl 5-(4-fluorophenyl)-4-[4-(methylsulfonyl)phenyl]thiophene-2-acetate (1.8 g) and lithium aluminum hydride (0.63 g) in diethyl ether (30 ml) was stirred at 0° C. for 1 hour. Ethyl acetate and 10% sulfuric acid (50 ml) were added, and the resulting mixture was filtered. The organic layer was separated, washed with water, dried and concentrated under reduced pressure. The residual pale yellow oil (1.6 g) was purified by column chromatography on silica gel eluting with a mixture of toluene and ethyl acetate (2:1). The obtained oil (1.4 g) was pulverized with hexane to give a yellow powder of 2-(4-fluorophenyl)-5-(2-hydroxyethyl)-3-[4-(methylsulfonyl)phenyl]thiophene.
Reaction SMILES: [CH2:1]([C:4]1(O)[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([B:14]3[O:18][C:17]([CH3:20])([CH3:19])[C:16]([CH3:22])([CH3:21])[O:15]3)[CH:12]=2)[O:7][CH2:6][CH2:5]1)[CH:2]=[CH2:3].C([SiH](CC)CC)C.C(O)(C(F)(F)F)=O>ClCCCl>[CH2:1]([CH:4]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([B:14]3[O:18][C:17]([CH3:20])([CH3:19])[C:16]([CH3:22])([CH3:21])[O:15]3)[CH:12]=2)[O:7][CH2:6][CH2:5]1)[CH:2]=[CH2:3]
Reactant: C=CCC1(O)CCOc2ccc(B3OC(C)(C)C(C)(C)O3)cc21
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCCl
Product: C=CCC1CCOc2ccc(B3OC(C)(C)C(C)(C)O3)cc21
Reaction time: 0.17 h
Yield: 55.2 %

Procedure:
A stirred solution of 4-allyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)chroman-4-ol (1.80 g, 5.69 mmol) and triethylsilane (7.27 ml, 45.5 mmol) in DCE (30 ml) was treated with TFA (14.03 ml, 182 mmol) by rapid addition at ambient temperature. The reaction was stirred for 10 min, then carefully quenched with sat'd. aq. NaHCO3 (200 mL). The organic layer was concentrated and the residue was purified by biotage (80 g SiO2, 0% (3 CV), 0-60% (15 CV), 60% (2 CV), EtOAc in hexanes) to afford the desired product (0.942 g, 3.14 mmol, 55.1% yield) as a viscous clear oil. 1H NMR (400 MHz, CDCl3) δ 7.64 (s, 1H), 7.56 (dd, J=8.2, 1.4 Hz, 1H), 6.80 (d, J=8.0 Hz, 1H), 5.90-5.76 (m, 1H), 5.15-5.04 (m, 2H), 4.23-4.14 (m, 2H), 2.89 (dq, J=10.0, 5.0 Hz, 1H), 2.75-2.62 (m, 1H), 2.35-2.22 (m, 1H), 2.09-1.96 (m, 1H), 1.92-1.81 (m, 1H), 1.34 (s, 12H). LCMS (M+H)=301.3.