Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([CH3:7])([CH3:6])[C:3](O)=[O:4].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C.[Cl:39][C:40]1[C:45]([CH2:46][NH2:47])=[CH:44][CH:43]=[C:42]([Cl:48])[C:41]=1[NH:49][C:50]1[N:54]([CH3:55])[C:53]2[CH:56]=[C:57]([N:63]3[CH2:68][CH2:67][CH:66]([C:69]([F:72])([F:71])[F:70])[CH2:65][CH2:64]3)[C:58]([C:60]([OH:62])=[O:61])=[CH:59][C:52]=2[N:51]=1>CN(C=O)C>[Cl:39][C:40]1[C:45]([CH2:46][NH:47][C:3](=[O:4])[C:2]([F:1])([CH3:7])[CH3:6])=[CH:44][CH:43]=[C:42]([Cl:48])[C:41]=1[NH:49][C:50]1[N:54]([CH3:55])[C:53]2[CH:56]=[C:57]([N:63]3[CH2:68][CH2:67][CH:66]([C:69]([F:72])([F:71])[F:70])[CH2:65][CH2:64]3)[C:58]([C:60]([OH:62])=[O:61])=[CH:59][C:52]=2[N:51]=1
Reactant: CC(C)(F)C(=O)O
Reactant: Cn1c(Nc2c(Cl)ccc(CN)c2Cl)nc2cc(C(=O)O)c(N3CCC(C(F)(F)F)CC3)cc21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cn1c(Nc2c(Cl)ccc(CNC(=O)C(C)(C)F)c2Cl)nc2cc(C(=O)O)c(N3CCC(C(F)(F)F)CC3)cc21
Reaction time: 0.17 h

Procedure:
A mixture of 2-fluoroisobutyric acid (191 mg, 1.80 mmol), TBTU (578 mg, 1.80 mmol), DIPEA (1.00 mL, 5.7 mmol) and 10 mL DMF is stirred for 10 min and then the mixture is added to 2-{2,6-dichloro-3-[aminomethyl]-phenylamino}-6-[4-trifluoromethyl-piperidinyl]-1-methyl-1H-benzimidazole-5-carboxylic acid (929 mg, 1.80 mmol) in 10 mL DMF and it is stirred overnight. Then the mixture is concentrated and purified via prep HPLC.
Reaction SMILES: I[C:2]1[C:6]2[CH2:7][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:9][CH2:10][C:5]=2[N:4](C(OCC)=O)[N:3]=1.[N:23]1[CH:24]=[CH:25][N:26]2[CH:31]=[C:30](B(O)O)[CH:29]=[CH:28][C:27]=12.C(O)C.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[N:23]1[CH:24]=[CH:25][N:26]2[CH:31]=[C:30]([C:2]3[C:6]4[CH2:7][N:8]([C:11]([O:13][C:14]([CH3:15])([CH3:16])[CH3:17])=[O:12])[CH2:9][CH2:10][C:5]=4[NH:4][N:3]=3)[CH:29]=[CH:28][C:27]=12
Reactant: OB(O)c1ccc2nccn2c1
Reactant: CCOC(=O)n1nc(I)c2c1CCN(C(=O)OC(C)(C)C)C2
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)N1CCc2[nH]nc(-c3ccc4nccn4c3)c2C1
Temperature: 160 °C

Procedure:
5-Tert-butyl 1-ethyl 3-iodo-6,7-dihydro-1H-pyrazolo[4,3-c]pyridine-1,5(4H)-dicarboxylate (1 g, 0.002 mol), (synthesized from patent procedure: WO 2004014374 A1) was added to a vial containing imidazo[1,2-a]pyridin-6-ylboronic acid (0.577 g, 0.00356 mol) and tetrakis(triphenylphosphine)palladium (0.1372 g, 0.00011 mol). After purging the vial with nitrogen gas, dioxane: ethanol: water solution (7:3:2, 7.125 mL) and 2M sodium carbonate (0.007125 mol) was added to the vial respectively. The reaction mixture was stirred and was heated in the microwave at 160° C. for 20 min. Upon completion, the mixture was concentrated under vacuo. The residue was dissolved in ethyl acetate, and filtered through a fitted reservoir. The ethyl acetate layer was concentrated and columned using flash chromatography (0-100% ethyl acetate in hexane and 0-20% methanol in dichloromethane. The remaining residue that didn't dissolve in ethyl acetate was dissolved in methanol and filtered through a fritted reservoir. The methanol layer was concentrated and submitted for reverse phase prep. Pure product (quantitative yield) was recovered.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([O:19][C:20]3[C:25]([CH3:26])=[CH:24][C:23]([NH:27][C:28]([NH:30][C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=4[O:37][CH3:38])=[O:29])=[C:22]([CH3:39])[CH:21]=3)=[CH:14][CH:15]=[N:16]2)=[CH:11][C:10]=1[O:40][CH3:41])[C:2]1C=CC=CC=1.[H][H].CN(C)[CH:46]=[O:47]>[OH-].[Pd+2].[OH-]>[CH3:41][O:40][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][C:9]=1[O:8][CH2:1][CH2:2][O:47][CH3:46])[N:16]=[CH:15][CH:14]=[C:13]2[O:19][C:20]1[C:25]([CH3:26])=[CH:24][C:23]([NH:27][C:28]([NH:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2[O:37][CH3:38])=[O:29])=[C:22]([CH3:39])[CH:21]=1
Reactant: COc1ccccc1NC(=O)Nc1cc(C)c(Oc2ccnc3cc(OCc4ccccc4)c(OC)cc23)cc1C
Reactant: CN(C)C=O
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Product: COCCOc1cc2nccc(Oc3cc(C)c(NC(=O)Nc4ccccc4OC)cc3C)c2cc1OC
Temperature: 70 °C
Reaction time: 8 h
Yield: 76 %

Procedure:
N-(4-{[7-(Benzyloxy)-6-methoxy-4-quinolyl]oxy}-2,5-dimethylphenyl)-N′-(2-methoxyphenyl)urea (363 mg) was dissolved in N,N-dimethylformamide (6 ml), and palladium hydroxide (363 mg) was added to the solution. The mixture was stirred in a hydrogen atmosphere at room temperature overnight. The solvent was removed by distillation under the reduced pressure, and the residue was dissolved in chloroform and methanol. The solution was filtered through Celite. Next, the solvent was removed by distillation under the reduced pressure. The residue (191 mg), potassium carbonate (110 mg), tetra-n-butylammonium iodide (12 mg), and 2-bromoethyl methyl ether (80 mg) were dissolved in N,N-dimethylformamide (5 ml), and the solution was stirred at 70° C. overnight. The solvent was removed by distillation under the reduced pressure. Water was added to the residue, and the mixture was extracted with chloroform. The chloroform layer was dried over sodium sulfate. The solvent was removed by distillation under the reduced pressure. The residue was purified by thin-layer chromatography on silica gel by development with chloroform/methanol (10/1) to give 128 mg (yield 76%) of the title compound.
Reaction SMILES: C[O:2][C:3](=[O:42])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[O:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:27]=[C:26]([O:28]CC3C=CC=CC=3)[C:25](Br)=[CH:24][C:23]=2[CH2:37][CH3:38])[C:12]=1[CH2:39][CH2:40][CH3:41].[O:43]1[CH:47]=[CH:46][C:45](B(O)O)=[CH:44]1.C(=O)([O-])[O-].[Na+:55].[Na+]>O1CCCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[OH2:2].[Na+:55].[CH2:37]([C:23]1[CH:24]=[C:25]([CH:45]2[CH2:46][CH2:47][O:43][CH2:44]2)[C:26]([OH:28])=[CH:27][C:22]=1[O:21][CH2:20][CH2:19][CH2:18][O:17][C:13]1[C:12]([CH2:39][CH2:40][CH3:41])=[C:11]([CH:16]=[CH:15][CH:14]=1)[O:10][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[C:3]([O-:42])=[O:2])[CH3:38].[CH2:37]([C:23]1[CH:24]=[C:25]([CH:45]2[CH2:46][CH2:47][O:43][CH2:44]2)[C:26]([OH:28])=[CH:27][C:22]=1[O:21][CH2:20][CH2:19][CH2:18][O:17][C:13]1[C:12]([CH2:39][CH2:40][CH3:41])=[C:11]([CH:16]=[CH:15][CH:14]=1)[O:10][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[C:3]([O-:42])=[O:2])[CH3:38].[Na+:55]
Reactant: OB(O)c1ccoc1
Reactant: CCCc1c(OCCCOc2cc(OCc3ccccc3)c(Br)cc2CC)cccc1Oc1ccccc1C(=O)OC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCCc1c(OCCCOc2cc(O)c(C3CCOC3)cc2CC)cccc1Oc1ccccc1C(=O)[O-]
Temperature: 100 °C
Yield: 65 %

Procedure:
A mixture of 2-{3-[3-(5-benzyloxy-4-bromo-2-ethylphenoxy)propoxy]-2-propylphenoxy}-benzoic acid methyl ester (3.00 g, 4.73 mmol), furan-3-boronic acid (1.06 g, 9.47 mmol), tetrakis(triphenylphosphine)palladium(0) (0.54 g, 0.47 mmol), and 2 M aqueous sodium carbonate solution (20 mL) in tetrahydrofuran (40 mL) was heated at 100° C. for 48 h. The mixture was cooled to room temperature, diluted with water, and extracted with ethyl acetate. The organic layer was separated, washed once with water, once with saturated sodium chloride solution, dried (sodium sulfate), filtered, and concentrated in vacuo. Chromatography (silica gel, 10% ethyl acetate/90% hexane) of the residue provided 1.9 g (65%) of the title compound as a yellow oil. 1H NMR (CDCl3) δ 7.88 (dd, J=8, 2 Hz, 1H), 7.87 (s, 1H), 7.40 (m, 7H), 7.26 (s 1H), 7.05 (m, 2H), 6.80 (d, J=9 Hz, 1H), 6.76 (d, J=2 Hz, 1H), 6.67 (d, J=9 Hz, 1H), 6.60 (s, 1H), 6.43 (d, J=9 Hz, 1H), 5.11 (s, 2H), 4.18 (m, 4H), 3.83 (s, 3H), 2.66 (t, J=8 Hz, 2H), 2.62 (q, J=7 Hz, 2H), 2.30 (quintet, J=6 Hz, 2H), 1.57 (hextet, J=8 Hz, 2H), 1.20 (t, J=7 Hz, 3H), 0.92 (t, J=7 Hz, 3H); MS ES+ m/z=621 (p+1); IR (CHCl3, cm−1) 3000, 1727, 1603, 1461.
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[CH2:23][CH2:22][C@:12]34[C:13]5[C:14]6[O:21][C@H:11]3[C@H:10]([N:24]([CH3:36])[C:25](=[O:35])[C:26]#[C:27][C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([CH3:34])[CH:29]=3)[CH2:9][CH2:8][C@@:7]4([OH:37])[C@H:6]2[CH2:19][C:18]=5[CH:17]=[CH:16][C:15]=6[OH:20])[CH2:3][CH2:2]1.[CH:38]1(CN2CC[C@]34C5C6O[C@H]3[C@@H](N(C)C(=O)CC3C=CC([Cl:70])=C(Cl)C=3)CC[C@@]4(O)[C@H]2CC=5C=CC=6O)CC1>>[ClH:70].[CH:1]1([CH2:4][N:5]2[CH2:23][CH2:22][C@:12]34[C:13]5[C:14]6[O:21][C@H:11]3[C@H:10]([N:24]([CH3:36])[C:25](=[O:35])[C:26]#[C:27][C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([CH3:34])[CH:29]=3)[CH2:9][CH2:8][C@@:7]4([OH:37])[C@H:6]2[CH2:19][C:18]=5[CH:17]=[CH:16][C:15]=6[O:20][CH3:38])[CH2:2][CH2:3]1
Reactant: Cc1cccc(C#CC(=O)N(C)[C@@H]2CC[C@@]3(O)[C@H]4Cc5ccc(O)c6c5[C@@]3(CCN4CC3CC3)[C@H]2O6)c1
Reactant: CN(C(=O)Cc1ccc(Cl)c(Cl)c1)[C@H]1CC[C@@]2(O)[C@H]3Cc4ccc(O)c5c4[C@@]2(CCN3CC2CC2)[C@H]1O5
Product: COc1ccc2c3c1O[C@H]1[C@H](N(C)C(=O)C#Cc4cccc(C)c4)CC[C@@]4(O)[C@@H](C2)N(CC2CC2)CC[C@]314
Product: Cl
Yield: 76 %

Procedure:
The procedure of Example 132 was repeated, except that 17-cyclopropylmethyl-4,5α-epoxy-3,14β-dihydroxy-6β-[N-methyl-trans-3-(3-furan)acrylamido]morphinan (free base of 78) and 17-cyclopropylmethyl-4,5α-epoxy-3,14β-dihydroxy-6β-[N-methyl-3-(3-methylphenyl)propiolamido]morphinan (free base of 172) were used instead of 17-cyclopropylmethyl-4,5α-epoxy-3,14β-dihydroxy-6α-(N-methyl-3,4-dichlorophenylacetamido)morphinan (free base of 1), thereby preparing 17-cyclopropylmethyl-4,5α-epoxy-14β-hydroxy-3-methoxy-6β-[N-methyl-trans-3-(3-furan)acrylamido]morphinan hydrochloride 217 (yield: 49%) and 17-cyclopropylmethyl-4,5α-epoxy-14β-hydroxy-3-methoxy-6β-[N-methyl-3-(3-methylphenyl)propiolamido]morphinan hydrochloride 218 (yield: 76%).
Reaction SMILES: C1([C:7]2[NH:8][C:9]3[CH:10]=[CH:11][CH:12]=[C:13]4[C:19](=[O:20])[NH:18][CH2:17][CH2:16][C:15]=2[C:14]=34)C=CC=CC=1.[Cl:21][C:22]1[CH:23]=[CH:24][C:25]([O:31][CH3:32])=[C:26](B(O)O)[CH:27]=1>>[Cl:21][C:22]1[CH:23]=[CH:24][C:25]([O:31][CH3:32])=[C:26]([C:7]2[NH:8][C:9]3[CH:10]=[CH:11][CH:12]=[C:13]4[C:19](=[O:20])[NH:18][CH2:17][CH2:16][C:15]=2[C:14]=34)[CH:27]=1
Reactant: COc1ccc(Cl)cc1B(O)O
Reactant: O=C1NCCc2c(-c3ccccc3)[nH]c3cccc1c23
Product: COc1ccc(Cl)cc1-c1[nH]c2cccc3c2c1CCNC3=O

Procedure:
In a manner similar to that described for Compound 12, the tricyclic bromide (129 mg, 0.49 mmol) and 5-chloro-2-methoxy-phenylboronic acid (100 mg, 0.54 mmol) were coupled to yield 2-(5-chloro-2-methoxy-phenyl)-3,4,5,6-tetrahydro-azepino[5,4,3-cd]indol-6-one, 100 mg (63%) as an off-white solid: m.p. 160-162° C.; 1H NMR (300 MHz, d6-DMSO) δ 2.81 (m, 2H), 3.34 (m, 2H), 3.84 (s, 3H), 7.20 (m, 2H), 7.46 (m, 2H), 7.55 (d, J=7.8 Hz, 1H), 7.68 (d, J=7.5 Hz, 1H), 8.05 (br t, 1H), 11.37 (br s, 1H). MS (FAB, MH+): 327. Anal. (C18H15ClN2O2) C, H, N, Cl.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[OH:12])[O:8][CH:7]=[C:6]([C:13]1[CH:14]=[C:15]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)[CH:16]=[CH:17][CH:18]=1)[C:5]2=O.O.[NH2:28][NH2:29]>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]2[C:6]([C:13]3[CH:14]=[C:15]([C:19]4[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=4)[CH:16]=[CH:17][CH:18]=3)=[CH:7][NH:29][N:28]=2)[C:9]([OH:8])=[CH:10][C:11]=1[OH:12]
Reactant: NN
Reactant: O=c1c(-c2cccc(-c3ccc(F)cc3)c2)coc2cc(O)c(Cl)cc12
Solvent: O
Solvent: CCO
Product: Oc1cc(O)c(-c2n[nH]cc2-c2cccc(-c3ccc(F)cc3)c2)cc1Cl

Procedure:
This compounds was synthesised in the same manner as described above. 6-Chloro-3-(4′-fluoro-biphenyl-3-yl)-7-hydroxy-chromen-4-one (0.2 g, 0.54 mmol), hydrazine hydrate (2.5 ml), ethanol (10 ml). The quenched solution was extracted into ethyl acetate, washed (water), dried (MgSO4), and the solvent removed under vacuum to give an oil which was purified by column chromatography to give 4-Chloro-6-[4-(4′-fluoro-biphenyl-3-yl)-1H-pyrazol-3-yl]-benzene-1,3-diol as an off white solid (0.13 g, 63.3%); Rf 0.2 cf SM 0.7 ethyl acetate/hexane (80/20).
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][C:10]([C@@H:13]3[O:18][CH2:17][CH2:16][N:15]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:14]3)=[CH:9][CH:8]=2)[CH:3]=1.N1C=CC=CC=1.[F:32][C:33]1[CH:41]=[CH:40][C:36]([C:37](Cl)=[O:38])=[CH:35][CH:34]=1>O1CCCC1.ClCCl.CN(C)C1C=CN=CC=1>[F:32][C:33]1[CH:41]=[CH:40][C:36]([C:37]([NH:1][C:2]2[NH:6][N:5]=[C:4]([C:7]3[CH:8]=[CH:9][C:10]([C@@H:13]4[O:18][CH2:17][CH2:16][N:15]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:14]4)=[CH:11][CH:12]=3)[CH:3]=2)=[O:38])=[CH:35][CH:34]=1
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(-c3cc(N)[nH]n3)cc2)C1
Reactant: O=C(Cl)c1ccc(F)cc1
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(-c3cc(NC(=O)c4ccc(F)cc4)[nH]n3)cc2)C1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
(S)-tert-Butyl 2-(4-(5-amino-1H-pyrazol-3-yl)phenyl)morpholine-4-carboxylate (100 mg, 0.29 mmol) was dissolved in a mixture of tetrahydrofurane/dichloromethane 2:3 (1.5 ml) then pyridine (46 mg, 0.047 ml, 0.58 mmol) and 4-dimethylaminopyridine (1.7 mg, 0.014 mmol) were added at 0° C. After 5 min, 4-fluorobenzoyl chloride (55.2 mg, 0.348 mmol) was addded and the reaction mixture was stirred at 0° C. for 1 h. The cooling bath was removed and the reaction mixture was allowed to stir at room temperature overnight. The reaction was quenched by addition of 1M citric acid (3 ml) and was extracted with ethyl acetate (5 ml). The organic layer was dried over MgSO4 and evaporated. The crude material was purified by flash chromatography (silica gel, hepatne/ethyl acetate 1:1). Isolation of an off-white solid (100 mg, 74%), MS (ISP): 411.2 (100%, [M-tBu+H]+), 467.2 (66%, [M+H]+).
Reaction SMILES: F[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=1.[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][NH:21][C@H:20]([CH3:24])[CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12].C([Mg]Cl)(C)C.Cl>O1CCCC1.O.CC(C)=O>[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][N:21]([C:2]2[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=2)[C@H:20]([CH3:24])[CH2:19]1)=[O:17])([CH3:14])([CH3:12])[CH3:13]
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)CCN1
Reactant: O=C(O)c1ccc(F)nc1
Agent: CC(C)[Mg]Cl
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Solvent: CC(C)=O
Product: C[C@@H]1CN(C(=O)OC(C)(C)C)CCN1c1ccc(C(=O)O)cn1
Temperature: -40 °C
Reaction time: 4 h
Yield: 96.3 %

Procedure:
A mixture of 6-fluoronicotinic acid (150 g, 1.063 mol) and (R)-3-methyl-piperazine-1-carboxylic acid tert-butyl ester (234.2 g, 1.169 mol) in tetrahydrofuran (1.75 L) was cooled to −40° C. and then 2 M isopropylmagnesium chloride in tetrahydrofuran (1.196 L, 2.39 mol) was added slowly maintaining the temperature at less than −20° C. The reaction mixture was slowly warmed to RT, stirred at RT for 4 h and then 1 N HCl (1.75 L) and water (1.175 L) were added. The reaction mixture was extracted with ethyl acetate (4 L). The organic phase was evaporated to provide crude solid (534 g). To the crude solid was added acetone (2 L) and water (200 mL). The resulting reaction mixture was heated to 50° C. and then water (2.8 L) was added slowly. Seed crystals from a previous run at smaller scale were added after ˜1 L of water. The reaction mixture was cooled to 20° C. over 3 h, stirred at 20° C. overnight and filtered. The solid was washed with 2:3 acetone:water (2×500 mL) and dried under vacuum to provide the title compound (329 g, 96% yield) as an off-white solid. HPLC Method A: Retention time 9.73 min.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]([C:11]#[N:12])[CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][NH:6]2.[F:13][C:14]1[CH:15]=[C:16](B(O)O)[CH:17]=[C:18]([F:28])[C:19]=1[O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[Br:1][C:2]1[CH:10]=[C:9]([C:11]#[N:12])[CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][N:6]2[C:16]1[CH:17]=[C:18]([F:28])[C:19]([O:20][CH2:21][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)=[C:14]([F:13])[CH:15]=1
Reactant: OB(O)c1cc(F)c(OCc2ccccc2)c(F)c1
Reactant: N#Cc1cc(Br)c2cn[nH]c2c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: N#Cc1cc(Br)c2cnn(-c3cc(F)c(OCc4ccccc4)c(F)c3)c2c1
Temperature: 25 °C
Reaction time: 144 h

Procedure:
To a solution of 4-bromo-1H-indazole-6-carbonitrile (1.0 g, 4.50 mmol) in dichloromethane (50 mL) was added {3,5-difluoro-4-[(phenylmethyl)oxy]phenyl}boronic acid {DE 4236105} (1.8 g, 6.82 mmol), pyridine (0.73 mL, 9.04 mmol), copper acetate (1.22 g, 6.74 mmol) and powdered 4A molecular sieves (5 g). The reaction mixture was stirred at room temperature in the presence of air for 6 days. Celite was added to the mixture and stirred for 5 mins then the mixture was filtered through a pad of celite and then the filtrate was washed with water, dried over magnesium sulphate, filtered and concentrated. The product was purified by silica gel chromatography eluting with 10-100% ethyl acetate in hexane to yield the title compound (D36) (944 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:41])[C:10]3([CH:15]([C:16]4[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=4[O:23][C:24]([C:27]([O:29][CH3:30])=[O:28])([CH3:26])[CH3:25])[CH2:14][C:13](=O)[NH:12][CH:11]3[C:32]3[CH:37]=[C:36]([F:38])[C:35]([F:39])=[CH:34][C:33]=3[CH3:40])[C:5]2=[CH:4][CH:3]=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:43]>C1COCC1.C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:41])[C:10]3([CH:15]([C:16]4[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=4[O:23][C:24]([C:27]([O:29][CH3:30])=[O:28])([CH3:26])[CH3:25])[CH2:14][C:13](=[S:43])[NH:12][CH:11]3[C:32]3[CH:37]=[C:36]([F:38])[C:35]([F:39])=[CH:34][C:33]=3[CH3:40])[C:5]2=[CH:4][CH:3]=1
Reactant: COC(=O)C(C)(C)Oc1ccc(Cl)cc1C1CC(=O)NC(c2cc(F)c(F)cc2C)C12C(=O)Nc1cc(Cl)ccc12
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: COC(=O)C(C)(C)Oc1ccc(Cl)cc1C1CC(=S)NC(c2cc(F)c(F)cc2C)C12C(=O)Nc1cc(Cl)ccc12
Temperature: 50 °C
Yield: 24.1 %

Procedure:
A mixture of racemic (2′S, 3S, 4′R)-6-chloro-4′-[5-chloro-2-(1-methoxycarbonyl-1-methyl-ethoxy)-phenyl]-2′-(4,5-difluoro-2-methyl-phenyl) spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (40 mg, 0.067 mmol) and P2S5 (45 mg, 0.20 mmol) in THF (2 mL) was heated at 50° C. for 2 h, and then diluted with toluene (10 mL). The mixture was concentrated in vacuo and the residue was washed with DCM twice. The DCM extracts were combined and concentrated. The residue was purified by flash chromatography to give the title compound as white solid (10 mg).
Reaction SMILES: C(OC([N:11]1[CH2:17][C@@H:16]2[C@@:13]([NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])([CH2:14][C@H:15]2[CH3:18])[CH2:12]1)=O)C1C=CC=CC=1.[H][H]>CO.O1CCCC1.[C].[Pd]>[C:23]([O:22][C:20]([NH:19][C@@:13]12[CH2:14][C@@H:15]([CH3:18])[C@@H:16]1[CH2:17][NH:11][CH2:12]2)=[O:21])([CH3:26])([CH3:24])[CH3:25]
Reactant: [H][H]
Reactant: C[C@@H]1C[C@@]2(NC(=O)OC(C)(C)C)CN(C(=O)OCc3ccccc3)C[C@@H]12
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: C[C@@H]1C[C@@]2(NC(=O)OC(C)(C)C)CNC[C@@H]12

Procedure:
(1S,5R,6R)-1-tert-Butoxycarbonylamino-6-methyl-3-azabicyclo[3.2.0]heptane-3-carboxylic acid benzyl ester (1.1 g, 3.1 mmol) was dissolved in a mixed solvent of methanol (20 mL) and tetrahydrofuran (10 mL). A small amount of 10% palladium-carbon (50% wet) was added, and the mixture was stirred in a hydrogen atmosphere for three hours. After removing the catalyst by filtration, the filtrate was concentrated under reduced pressure to give 0.70 g (quantitative) of the title compound as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:16]([SH:17])[C:15]3[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=3[C:9]2=[O:18])=[C:4]([F:19])[CH:3]=1.[C:20]1([N:26]=[C:27]=[O:28])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>ClCCl.C(N(CC)CC)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:16]([S:17][C:27](=[O:28])[NH:26][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:15]3[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=3[C:9]2=[O:18])=[C:4]([F:19])[CH:3]=1
Reactant: O=C=Nc1ccccc1
Reactant: O=C1C2=C(CCCC2)C(S)N1c1ccc(Cl)cc1F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Nc1ccccc1)SC1C2=C(CCCC2)C(=O)N1c1ccc(Cl)cc1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 71.4 %

Procedure:
In 20 ml of dichloromethane was dissolved 3.0 g of 2-(4-chloro-2-fluorophenyl)-2,3,4,5,6,7-hexahydro-3-mercapto-1H-isoindol-1-one, and 1.3 g of phenyl isocyanate, together with one drop of triethylamine, was added to the solution, followed by stirring at room temperature for 3 hours. The dichloromethane was distilled off under reduced pressure, and the residue was purified by means of column chromatography with the use of silica gel (developing solvent of acetonehexane), thereby producing 3.0 g (yield of 72%) of the subject compound in white crystals, m.p. 135°-136° C.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][N:12]=[CH:11][C:10]=1[NH:15][CH3:16])[CH3:2].[F:17][C:18]([F:33])([F:32])[C:19]1[CH:20]=[C:21]([CH:25]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:27]=1)[C:22](Cl)=[O:23]>>[CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][N:12]=[CH:11][C:10]=1[N:15]([CH3:16])[C:22](=[O:23])[C:21]1[CH:20]=[C:19]([C:18]([F:33])([F:32])[F:17])[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=1)[CH3:2]
Reactant: CCc1ccccc1-c1ccncc1NC
Reactant: O=C(Cl)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Product: CCc1ccccc1-c1ccncc1N(C)C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1

Procedure:
The title compound was prepared in analogy to example 72, intermediate, from [4-(2-ethyl-phenyl)-pyridin-3-yl]-methyl-amine and 3,5-bis(trifluoromethyl)benzoyl chloride (CAS RN 1271-19-8) and a gradient of n-heptane:EtOAc (100:0 to 40:60) for the chromatographic purification. Light yellow solid (54%). MS (ESI): m/z=453.139 [M+H]+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:8]=[CH:9][C:10](=O)[NH:11][N:12]=1.O=P(Cl)(Cl)[Cl:16]>>[Cl:16][C:10]1[N:11]=[N:12][C:7]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)=[CH:8][CH:9]=1
Reactant: O=c1ccc(-c2ccccn2)n[nH]1
Reactant: O=P(Cl)(Cl)Cl
Product: Clc1ccc(-c2ccccn2)nn1
Yield: 45 %

Procedure:
To a solid 6-pyridin-2-yl-2H-pyridazin-3-one (0.500 g, 2.900 mmol) was added 20 mL of POCl3 and the mixture was stirred at reflux for 4 hours. Excess POCl3 was removed in vacuo. The residue was poured on ice and neutralized using NaHCO3. The product was extracted with ether and ethyl acetate. The combined organic extracts were dried over MaSO4 and evaporated. The residue was purified by column chromatography to afford of 3-chloro-6-pyridin-2-ylpyridazine in 45% yield (0.250 g).
Reaction SMILES: [C:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[CH:6][CH:5]=1)(=O)[CH3:2].O.[C:14]([OH:18])(=O)[CH:15]=O.[CH3:19][NH:20][NH2:21]>C(O)(=O)C>[CH3:19][N:20]1[C:14](=[O:18])[CH:15]=[CH:2][C:1]([C:4]2[CH:12]=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[CH:6][CH:5]=2)=[N:21]1
Reactant: O=CC(=O)O
Reactant: CNN
Reactant: CC(=O)c1ccc(C(=O)O)cc1
Solvent: O
Solvent: CC(=O)O
Product: Cn1nc(-c2ccc(C(=O)O)cc2)ccc1=O
Temperature: 40 °C
Reaction time: 2 h

Procedure:
4-Acetylbenzoic acid (5.00 gram, 30.5 mmol) and 3.19 gram of glyoxalic acid monohydrate (34.7 mmol, 1.14 eq.) were stirred in 50 mL of acetic acid at 110° C. for 20 hours, and then cooled to 40° C. Solvent was removed with evaporator in vacuo. To the residue was added water (15 mL), and the mixture cooled with an ice bath. The resulting solution was titrated with ammonia solution until pH 9. Methyl hydrazine (3.00 mL 57.3 mmol, 1.88 eq.) was added, and the mixture was heated to reflux for 5 hours. The solution was concentrated in vacuo. To the solid residue was added 1 M cold aqueous hydrochloric acid until the solution had a pH 1˜2. The solid was filtrated and dried in vacuo over night. The solids were treated with diethyl ether (200 mL) and the mixture was ultrasonicated at room temperature for 3 hours and filtered. The solids were treated with 200 mL of diethyl ether and stirred for 2 hours before filtration, which after drying gave 4-(1-methyl-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzoic acid in 33% isolated yield.