Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-:1].[Na+].[Br:3][C:4]1[CH:5]=[C:6]2[C:11]([NH:12][C@@H:13]3[CH2:17][N:16]([C:18]([O:20][CH2:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[O:19])[CH2:15][C@@:14]3([F:29])[CH3:28])=[C:10]([C:30]#[N:31])[CH:9]=[N:8][N:7]2[CH:32]=1.OO>CS(C)=O.CO>[Br:3][C:4]1[CH:5]=[C:6]2[C:11]([NH:12][C@@H:13]3[CH2:17][N:16]([C:18]([O:20][CH2:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[O:19])[CH2:15][C@@:14]3([F:29])[CH3:28])=[C:10]([C:30](=[O:1])[NH2:31])[CH:9]=[N:8][N:7]2[CH:32]=1
Reactant: C[C@]1(F)CN(C(=O)OCc2ccccc2)C[C@H]1Nc1c(C#N)cnn2cc(Br)cc12
Reactant: [OH-]
Agent: OO
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CO
Product: C[C@]1(F)CN(C(=O)OCc2ccccc2)C[C@H]1Nc1c(C(N)=O)cnn2cc(Br)cc12
Reaction time: 1 h
Yield: 92.3 %

Procedure:
A 2.0 M aqueous NaOH (0.6 mL, 1.200 mmol) was added dropwise to a solution of (3S,4R)-benzyl 4-((6-bromo-3-cyanopyrrolo[1,2-b]pyridazin-4-yl)amino)-3-fluoro-3-methylpyrrolidine-1-carboxylate (120 mg, 0.254 mmol) in methyl sulfoxide (2 mL), methanol (2 mL) and hydrogen peroxide (0.3 mL, 2.94 mmol) at 0° C. After 1 h at 0° C., the mixture was quenched with saturated NaHCO3 (5 mL), diluted with ethyl acetate (80 mL), washed with water, brine, dried (MgSO4) and concentrated. The residue was purified by silica gel chromatography, eluting with 20 to 80% ethyl acetate in hexanes, to give (3S,4R)-benzyl 4-((6-bromo-3-carbamoylpyrrolo[1,2-b]pyridazin-4-yl)amino)-3-fluoro-3-methylpyrrolidine-1-carboxylate (115 mg, 92% yield). 1H NMR (400 MHz, chloroform-d) δ ppm 10.71 (d, J=8.4 Hz, 1H), 7.98-7.85 (m, 1H), 7.73-7.59 (m, 1H), 7.51-7.30 (m, 5H), 6.79 (d, J=7.5 Hz, 1H), 5.79-5.54 (m, 2H), 4.69-4.33 (m, 1H), 4.32-4.08 (m, 1H), 4.00-3.74 (m, 1H), 3.59-3.42 (m, 2H), 1.61-1.43 (m, 3H); MS (ES+) m/z: 490.1 (M+H).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[OH:6][CH2:7][CH2:8][C:9]1[CH:10]=[CH:11][C:12]2[O:16][C:15](=[O:17])[NH:14][C:13]=2[CH:18]=1.C(N(CC)CC)C>O1CCCC1>[O:17]=[C:15]1[NH:14][C:13]2[CH:18]=[C:9]([CH2:8][CH2:7][O:6][S:2]([CH3:1])(=[O:4])=[O:3])[CH:10]=[CH:11][C:12]=2[O:16]1
Reactant: CS(=O)(=O)Cl
Reactant: O=c1[nH]c2cc(CCO)ccc2o1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CS(=O)(=O)OCCc1ccc2oc(=O)[nH]c2c1
Reaction time: 3 h
Yield: 27.9 %

Procedure:
Methanesulfonyl chloride (0.23 ml, 2.93 mmol) was added dropwise, at room temperature, to a solution of alcohol (b) (0.5 g, 2.79 mmol) and triethylamine (0.41 ml, 3 mmol) in tetrahydrofuran (20 ml) and the mixture was stirred for 3 hours. More methane sulfonyl chloride (0.1 ml) and triethylamine (0.1 ml) were added and stirring was continued over night. The same amount of reagent was added yet again and stirring continued for 2 hours. The solvent was then concentrated, the residue was suspended in water and extracted with dichloromethane. The organic phase was dried over magnesium sulfate and concentrated. The solid residue was chromatographed on silica gel eluting with heptane-ethyl acetate (1-1) to give the product (0.2 g, 28%).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[F:6][C:7]([F:38])([F:37])[C:8]1[CH:9]=[C:10]([NH:14][C:15]([N:17]2[C:25]3[C:20](=[C:21]([F:35])[C:22]([O:26][C:27]4[CH:32]=[CH:31][N:30]=[C:29]([CH2:33]O)[N:28]=4)=[CH:23][CH:24]=3)[CH:19]=[C:18]2[CH3:36])=[O:16])[CH:11]=[CH:12][CH:13]=1.CCN(CC)CC.CS([O-])=O.[Na+]>C(Cl)Cl.CO>[F:6][C:7]([F:38])([F:37])[C:8]1[CH:9]=[C:10]([NH:14][C:15]([N:17]2[C:25]3[C:20](=[C:21]([F:35])[C:22]([O:26][C:27]4[CH:32]=[CH:31][N:30]=[C:29]([CH2:33][S:2]([CH3:1])(=[O:4])=[O:3])[N:28]=4)=[CH:23][CH:24]=3)[CH:19]=[C:18]2[CH3:36])=[O:16])[CH:11]=[CH:12][CH:13]=1
Reactant: CS(=O)(=O)Cl
Reactant: Cc1cc2c(F)c(Oc3ccnc(CO)n3)ccc2n1C(=O)Nc1cccc(C(F)(F)F)c1
Agent: CS(=O)[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Solvent: CCN(CC)CC
Product: Cc1cc2c(F)c(Oc3ccnc(CS(C)(=O)=O)n3)ccc2n1C(=O)Nc1cccc(C(F)(F)F)c1
Temperature: 23 °C
Reaction time: 0.17 h

Procedure:
Methanesulfonyl chloride (0.046 mL, 0.586 mmol) is added to a solution of 4-fluoro-5-(2-hydroxymethyl-pyrimidin-4-yloxy)-2-methyl-indole-1-carboxylic acid (3-trifluoromethyl-phenyl)-amide (180 mg, 0.391 mmol) and Et3N (0.109 mL, 0.782 mmol) in CH2Cl2 (5 mL) at 0° C. After 10 min, methanol is added, followed by sodium methanesulfinate (798 mg, 7.82 mmol). The resulting mixture is warmed to and stirred at 23° C. for 14 h. The mixture is concentrated and the residue is taken up in DMF (5 mL). The resulting mixture is stirred at 23° C. for 24 h, then partitioned between EtOAc (40 mL) and water (40 mL). The aqueous layer is extracted with EtOAc (2×40 mL). The combined organic layers are washed with brine (20 mL), dried (Na2SO4), and concentrated. The residue is purified by silica gel chromatography (0-100% EtOAc/heptane) to give 4-fluoro-5-(2-methanesulfonylmethyl-pyrimidin-4-yloxy)-2-methyl-indole-1-carboxylic acid (3-trifluoromethyl-phenyl)-amide. MS (ESI) m/z 474.0 (M+1); 1H NMR (400 MHz, DMSO-d6) δ ppm 10.98 (s, 1 H) 8.76 (d, J=5.81 Hz, 1 H) 8.12 (s, 1 H) 7.91 (d, J=8.34 Hz, 1 H) 7.64-7.69 (m, 1 H) 7.53 (d, J=8.84 Hz, 2 H) 7.18-7.25 (m, 2 H) 6.63 (s, 1 H) 4.55 (s, 2 H) 2.97 (s, 3 H) 2.59 (s, 3 H)
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][C:5]([CH2:6][NH:7][C:8]([C:10]2[CH:11]=[N:12][C:13]3[C:18]([C:19]=2[OH:20])=[CH:17][C:16](I)=[CH:15][CH:14]=3)=[O:9])=[CH:4][CH:3]=1.CN(C=O)C.[CH2:29]([OH:32])[C:30]#[CH:31]>N(CC)CC.[Cu]I.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>[Cl:1][C:2]1[CH:23]=[CH:22][C:5]([CH2:6][NH:7][C:8]([C:10]2[CH:11]=[N:12][C:13]3[C:18]([C:19]=2[OH:20])=[CH:17][C:16]([C:31]#[C:30][CH2:29][OH:32])=[CH:15][CH:14]=3)=[O:9])=[CH:4][CH:3]=1
Reactant: O=C(NCc1ccc(Cl)cc1)c1cnc2ccc(I)cc2c1O
Reactant: C#CCO
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CCNCC
Product: O=C(NCc1ccc(Cl)cc1)c1cnc2ccc(C#CCO)cc2c1O
Temperature: 25 °C
Reaction time: 48 h
Yield: 79 %

Procedure:
To a mixture of N-(4-chlorobenzyl)-4-hydroxy-6-iodo-3-quinolinecarboxamide from Preparation No. 1 (0.494 g) in Et2NH (12.9 mL) is added CuI (10.8 mg) and (Ph3P)2PdCl2 (39.7 mg). DMF (2 mL) is added to solubilize the reactants. To this solution is added propargyl alcohol (0.066 mL) and the reaction is stirred at room temperature for 2 days. The reaction mixture is concentrated to remove Et2NH. The resulting residue is partitioned between CH2Cl2 (3×) and H2O. A brown solid precipitated from the CH2Cl2 layer is filtered and collected to obtain pure product as indicated by NMR. The organic layers are combined, dried over Na2SO4, and concentrated to obtain a brown residue. The residue is placed under high vac to remove residual DMF. The residue is adsorbed onto silica and chromatographed eluting with 2% MeOH in CH2Cl2 and 3% MeOH in CH2Cl2. Fractions homogenous by TLC are combined, condensed and recrystallized with EtOAc/hexanes to obtain a creme solid. The two crops yielded 325.4 mg (79%) of the desired product as a tan solid.
Reaction SMILES: [CH2:1]([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C=O.[CH3:18]CCCC=C>>[CH3:18][N:8]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: c1ccc(CNCc2ccccc2)cc1
Reactant: C=CCCCC
Agent: C=O
Product: CN(Cc1ccccc1)Cc1ccccc1
Yield: 254.6 %

Procedure:
In a similar manner to Example 1, 197.3 g (1.0 mol) of dibenzylamine and 165.1 g (1.6 mol) of formaldehyde (29.1%) are reacted in a 1 l autoclave; a maximum pressure of 1.8 MPa is established at a temperature of 160° C. After the end of the reaction, 30 g of hexene-1 are added and the organic phase is removed from the aqueous phase. The remaining organic phase is subsequently distilled. 191.8 g of N-methyldibenzylamine having a purity of 93.8% are isolated, corresponding to a yield of 85.1% of theory.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][C:6](=O)[CH:7]1[CH2:11][CH2:10][O:9][CH2:8]1)C.Cl.[NH2:15][C:16]([NH2:18])=[NH:17].CC(C)([O-])C.[K+]>CO.O>[NH2:17][C:16]1[NH:18][C:4](=[O:3])[CH:5]=[C:6]([CH:7]2[CH2:11][CH2:10][O:9][CH2:8]2)[N:15]=1
Reactant: N=C(N)N
Reactant: CCOC(=O)CC(=O)C1CCOC1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CO
Product: Nc1nc(C2CCOC2)cc(=O)[nH]1
Temperature: 80 °C
Yield: 51.9 %

Procedure:
To a solution of 3-oxo-3-(tetrahydro-furan-3-yl)-propionic acid ethyl ester (4.0 g, 21.5 mmol) and guanidine hydrochloride (2.6 g, 27.2 mmol) in MeOH (125 mL) at 23° C. was added potassium tert-butoxide in portions (3.4 g, 30.3 mmol) over 5 min. The reaction was heated at 80° C. for 18 h. The mixture was filtered while warm to remove insoluble salts, and the filtrate was concentrated to afford an oil which was diluted with water (˜25 mL) and extracted with EtOAc (8×50 mL). The combined organic layers were washed with satd. aq. NaCl, dried, and concentrated to give a residue. The aqueous portion was concentrated to afford a solid residue that was collected and rinsed with MeOH. The residue and solid materials were combined and chromatographed (2 M NH3 in MeOH/EtOAc) to provide 2.02 g of product as a white solid (51%). MS (ESI): mass calcd. for: C8H11N3O2, 181.1; m/z found, 182.2 [M+H]+. 1H NMR (CD3OD): 5.66 (br s, 1H), 3.93-4.01 (m, 2H), 3.75-3.85 (m, 2H), 3.28-3.31 (m, 2H), 3.16-3.24 (m, 1H), 2.18-2.27 (m, 1H), 2.05-2.15 (m, 1H).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[CH:5][N:6]=1.Br[CH2:8][C:9]([C:11]1[CH:16]=[CH:15][C:14]([F:17])=[C:13]([O:18][CH3:19])[CH:12]=1)=O.[OH-].[NH4+]>C(O)C>[F:17][C:14]1[CH:15]=[CH:16][C:11]([C:9]2[N:1]=[C:2]3[N:6]([CH:8]=2)[CH:5]=[CH:4][S:3]3)=[CH:12][C:13]=1[O:18][CH3:19]
Reactant: COc1cc(C(=O)CBr)ccc1F
Reactant: Nc1nccs1
Agent: [NH4+]
Agent: [OH-]
Solvent: CCO
Product: COc1cc(-c2cn3ccsc3n2)ccc1F
Reaction time: 18 h
Yield: 65.8 %

Procedure:
To a mixture of 2-aminothiazole (0.976 g, 9.74 mmol) and 2-bromo-1-(4-fluoro-3-methoxy-phenyl)-ethanone (2.4 g, 9.74 mmol) was added absolute ethanol (100 ml). The reaction was allowed to reflux with vigorous stirring for 18 hours (checked by HPLC). The reaction mixture was reduced to half its original volume in vacuo. The remaining liquid was poured onto ice and the solution made basic by the addition of ammonium hydroxide solution (30%), until pH is 8. The mixture was extracted with ethyl acetate (2×100 ml). The combined extracts were washed with water (100 ml) and saturated aqueous sodium chloride solution (100 ml). The organic phase was dried with sodium sulfate, filtered and concentrated in vacuo, to give an orange solid. Purification by flash chromatography (gradient 25%-50% ethyl actetate in hexanes) afforded the title product as a pale yellow solid (1.59 g, 66%). 400 MHz 1H NMR (DMSO-d6) δ 8.26 (s, 1H), 7.95 (d, J=2.3 Hz, 1H), 7.61 (dd, J=8.6, 2.0 Hz, 1H), 7.39 (ddd, J=8.2, 4.3, 2.0 Hz, 1H); 7.28 (d, J=4.7 Hz, 1H), 7.22 (dd, J=11.3, 8.2 Hz, 1H), 3.91 (s, 3H). LCMS: 249 [M+H].
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](=[O:25])[C:5]([CH3:24])=[C:6]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][C:21](O)=[O:22])=[CH:15][CH:14]=2)[C:7](=[O:11])[C:8]=1[O:9][CH3:10].[CH2:26]([NH2:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[CH3:1][O:2][C:3]1[C:4](=[O:25])[C:5]([CH3:24])=[C:6]([CH2:12][C:13]2[CH:14]=[CH:15][C:16]([CH2:19][CH2:20][C:21]([NH:33][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[O:22])=[CH:17][CH:18]=2)[C:7](=[O:11])[C:8]=1[O:9][CH3:10]
Reactant: COC1=C(OC)C(=O)C(Cc2ccc(CCC(=O)O)cc2)=C(C)C1=O
Reactant: NCc1ccccc1
Product: COC1=C(OC)C(=O)C(Cc2ccc(CCC(=O)NCc3ccccc3)cc2)=C(C)C1=O
Yield: 13.8 %

Procedure:
3-[(4-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-ylmethyl)phenyl]propionic acid (200 mg, 0.58 mmol) obtained in Example 1 and benzylamine (80 mg, 0.75 mmol) were used, and a method similar to that described in Example 3 was employed to obtain the title compound (33 mg, 0.08 mmol, yield 13%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:15]C)=[C:6]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][C:13]=2N)[CH:7]=1.C1COCC1.O>C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:15][C:13]3[CH:12]=[CH:11][N:10]=[CH:9][C:8]=3[C:6]=2[CH:7]=1
Reactant: COc1ccc(Cl)cc1-c1cnccc1N
Solvent: CC(=O)O
Solvent: O
Solvent: C1CCOC1
Product: Clc1ccc2oc3ccncc3c2c1
Temperature: 25 °C

Procedure:
3-(5-chloro-2-methoxyphenyl)pyridin-4-amine (2 g, 8.5 mmol) was dissolved in 25 mL of acetic acid and 10 mL of THF at −10° C. To the solution t-butyl nitrile (2 ml, 17 mmol) was dropwisely added. The mixture was warmed to room temperature overnight. Water was added to the reaction mixture and was extracted by dichloromethane, the organic layer was then dried by MgSO4 and concentrated. The residue was then purified by column chromatography using THF:hexane (1:3, v/v) as the eluent. 0.8 g (46%) of product was collected as the product.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:22])=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:20][CH3:21])=[C:16]([OH:19])[CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1.CS(O[C@H:28]1[CH2:33][CH2:32][C@@H:31]([N:34]2[CH2:39][CH2:38][N:37]([CH3:40])[C:36](=[O:41])[CH2:35]2)[CH2:30][CH2:29]1)(=O)=O.C(=O)([O-])[O-].[K+].[K+]>CN1CCCC1=O>[Cl:1][C:2]1[C:3]([F:22])=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:20][CH3:21])=[C:16]([O:19][C@H:28]4[CH2:29][CH2:30][C@H:31]([N:34]5[CH2:39][CH2:38][N:37]([CH3:40])[C:36](=[O:41])[CH2:35]5)[CH2:32][CH2:33]4)[CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1O
Reactant: CN1CCN([C@H]2CC[C@@H](OS(C)(=O)=O)CC2)CC1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1O[C@H]1CC[C@H](N2CCN(C)C(=O)C2)CC1

Procedure:
Prepared by reacting 4-[(3-chloro-2-fluoro-phenyl)amino]-6-hydroxy-7-methoxy-quinazoline with (cis)-1-methanesulphonyloxy-4-(4-methyl-3-oxo-piperazin-1-yl)-cyclohexane in N-methyl-2-pyrrolidinone at 125° C. in the presence of potassium carbonate.
Reaction SMILES: [CH3:1][N:2]1[C:10]2([CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]2)[C:6]2=[CH:7][CH:8]=[CH:9][N:5]2[CH2:4][CH2:3]1.FC(F)(F)S([Cl:28])(=O)=O>ClCCl>[Cl:28][C:9]1[N:5]2[CH2:4][CH2:3][N:2]([CH3:1])[C:10]3([CH2:11][CH2:12][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:14][CH2:15]3)[C:6]2=[CH:7][CH:8]=1
Reactant: CN1CCn2cccc2C12CCN(C(=O)OC(C)(C)C)CC2
Reactant: O=S(=O)(Cl)C(F)(F)F
Solvent: ClCCl
Product: CN1CCn2c(Cl)ccc2C12CCN(C(=O)OC(C)(C)C)CC2
Reaction time: 8 h
Yield: 77.3 %

Procedure:
To tert-butyl 2-methylspiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4′-piperidine]-1′-carboxylate (5 g, 16.37 mmol) in dichloromethane (50.00 mL) at 0° C. was added trifluoromethanesulfonyl chloride (3.64 mL, 34.38 mmol) and the reaction was stirred from 0° C. to room temperature overnight. The reaction was diluted with dichloromethane and washed with water. The layers were separated and the organics were dried over sodium sulfate, filtered and concentrated. Purification of the residue by silica gel chromatography eluting with 10-100% ethylacetate in hexanes afforded tert-butyl 6-chloro-2-methyl-spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4′-piperidine]-1′-carboxylate (4.3 g, 77%), as a yellow solid. ESI-MS m/z calc. 339.2, found 340.3 (M+1)+; Retention time: 1.13 minutes (3 min run). 1H NMR (400 MHz, CDCl3) δ 6.01 (d, J=3.8 Hz, 1H), 5.91 (d, J=3.7 Hz, 1H), 3.77 (t, J=6.1 Hz, 2H), 3.34 (s, 2H), 3.24 (s, 2H), 2.34 (s, 3H), 2.03 (d, J=13.1 Hz, 2H), 1.74 (t, J=11.1 Hz, 2H), 1.47 (s, 9H).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[F:10].[BH4-].[Na+].CO>C1COCC1>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[CH:4][C:3]=1[F:10]
Reactant: O=Cc1ccc(Br)c(F)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: OCc1ccc(Br)c(F)c1
Yield: 96.8 %

Procedure:
To a solution of 4-bromo-3-fluorobenzaldehyde (10 g, 49.3 mmol) and NaBH4 (3.73 g, 99 mmol) in THF (100 mL) was added MeOH (100 mL) dropwise at 20° C. After LCMS analysis showed the starting material had disappeared, the solvent was removed in vacuo. The residue was dissolved in DCM (200 mL) and washed with H2O (60 mL) and brine (60 mL). The organic layer was dried over Na2SO4, filtered and concentrated to yield a white solid of (4-bromo-3-fluorophenyl)methanol (9.8 g, 47.7 mmol, 97.0% yield): 1H NMR (400 MHz, CD3OD) δ 7.54 (t, J=7.8 Hz, 1H), 7.18 (d, J=9.6 Hz, 1H), 7.06 (d, J=7.2 Hz, 1H), 4.56 (s, 2H); ES-LCMS m/z 188.9 (M−17).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:16][CH2:15][N:14]([C:17]([C:19]2[CH:23]=[C:22]([O:24][CH2:25][C:26]([O:28]C)=[O:27])[N:21]([CH3:30])[N:20]=2)=[O:18])[CH2:13][CH2:12]1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>O1CCCC1.CO>[C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:16][CH2:15][N:14]([C:17]([C:19]2[CH:23]=[C:22]([O:24][CH2:25][C:26]([OH:28])=[O:27])[N:21]([CH3:30])[N:20]=2)=[O:18])[CH2:13][CH2:12]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)COc1cc(C(=O)N2CCN(c3ccccc3C(C)(C)C)CC2)nn1C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cn1nc(C(=O)N2CCN(c3ccccc3C(C)(C)C)CC2)cc1OCC(=O)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 54.3 %

Procedure:
A mixture of methyl [(3-{[4-(2-tert-butylphenyl)piperazin-1-yl]carbonyl}-1-methyl-1H-pyrazol-5-yl)oxy]acetate (0.573 g, 1.38 mmol) and 1 M sodium hydroxide solution (5 mL) in tetrahydrofuran (20 mL) and methanol (20 mL) was stirred at room temperature for 3 h. Solvent was removed and 1 M hydrochloric acid solution added to the mixture. The mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to purify the residue by HPLC (Gilson Preparative HPLC System; column: YMC Combiprep ODS-A, S-5 μm, 50×20 mm; solvent: A; water containing 0.1% TFA, B; acetonitrile containing 0.1% TFA; gradient cycle: 0.00 min (A/B=90/10), 1.00 min (A/B=90/10), 4.20 min (A/B=10/90), 5.40 min (A/B=10/90), 5.50 min (A/B=90/10), 5.60 min (A/B=90/10); flow rate: 25 mL/min; detect: UV 220 nm). Solvent was removed to afford a solid (0.3 g, 54%).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])=[CH:5][CH:4]=1)#[CH:2].Br[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][N+:23]#[C-:24])[CH:17]=1>>[N+:23]([CH2:22][C:18]1[CH:17]=[C:16]([C:2]#[C:1][C:3]2[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])=[CH:5][CH:4]=2)[CH:21]=[CH:20][CH:19]=1)#[C-:24]
Reactant: C#Cc1ccc(CCC(=O)OC)cc1
Reactant: [C-]#[N+]Cc1cccc(Br)c1
Product: [C-]#[N+]Cc1cccc(C#Cc2ccc(CCC(=O)OC)cc2)c1

Procedure:
The title compound was prepared from methyl 3-(4-ethynylphenyl)propanoate (95 mg, 0.50 mmol) and 1-bromo-3-(isocyanomethyl)benzene (117 mg, 0.60 mmol) according to the general procedure IC to give 109 mg (71%) of a pale yellow oily product after purification by flash chromatography (SiO2, EtOAc:PE, 1:5). Rf=0.27 (EtOAc:PE, 1:2); 1H NMR (CDCl3) δ 7.51-7.44 (m, 4H), 7.36 (t, J=7.7 Hz, 1H), 7.31-7.27 (m, 1H), 7.19 (d, J=8.3 Hz, 2H), 3.73 (s, 2H), 3.67 (s, 3H), 2.97 (t, J=7.7 Hz, 2H), 2.64 (t, J=7.7 Hz, 2H); 13C NMR (CDCl3) δ 173.1, 141.2, 131.8, 131.2, 131.0, 130.2, 129.2, 128.4, 127.6, 124.5, 120.8, 117.5, 90.3, 88.1, 51.7, 35.4, 30.8, 23.4; ESI-MS m/z 326.1 (M+Na+).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[C:4](Cl)[N:3]=1.[C:10]1(B(O)O)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.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>[NH2:1][C:2]1[N:7]=[C:6]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:5]=[C:4]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:3]=1
Reactant: Nc1nc(Cl)cc(Cl)n1
Reactant: OB(O)c1ccccc1
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: COCCOC
Product: Nc1nc(-c2ccccc2)cc(-c2ccccc2)n1
Yield: 76.7 %

Procedure:
2-Amino-4,6-dichloropyrimidine 9.5 g (58 mmol), phenylboronic acid 17 g (140 mmol) and tetrakis(triphenylphosphine)palladium 2.7 g (2.3 mmol) were dissolved in 120 mL of 1,2-dimethoxyethane. A 2.0M sodium carbonate aqueous solution 60 mL was added thereto, and the solution was refluxed for 8 hours under argon atmosphere by heating. After finishing the reaction, the aqueous layer was removed. The organic layer was dried on anhydrous magnesium sulfate, and the solvent was removed by distillation under reduced pressure. The residue was refined by silica gel chromatography to obtain 11 g (yield: 77%) of 2-amino-4,6-diphenylpyrimidine.
Reaction SMILES: [F:1][C:2]1[C:14]([NH:15][CH2:16][C:17]2[CH:22]=[C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[CH:24]=3)[CH:20]=[CH:19][C:18]=2[F:30])=[C:13]([F:31])[CH:12]=[CH:11][C:3]=1[O:4][CH2:5][C:6]([O:8][CH2:9]C)=[O:7].C([O-])([O-])=O.[K+].[K+].Cl>CO.O>[F:1][C:2]1[C:14]([NH:15][CH2:16][C:17]2[CH:22]=[C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[CH:24]=3)[CH:20]=[CH:19][C:18]=2[F:30])=[C:13]([F:31])[CH:12]=[CH:11][C:3]=1[O:4][CH2:5][C:6]([O:8][CH3:9])=[O:7]
Reactant: CCOC(=O)COc1ccc(F)c(NCc2cc(-c3cccc(F)c3)ccc2F)c1F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: COC(=O)COc1ccc(F)c(NCc2cc(-c3cccc(F)c3)ccc2F)c1F

Procedure:
To a stirred solution of ethyl 2-[2,4-difluoro-3-[[2-fluoro-5-(3-fluorophenyl)phenyl]methylamino]phenoxy]acetate (II(a)) (290 mg, 0.7 mmol, 1.0 eq) in MeOH (30 mL) was added K2CO3 (28 mg, 0.2 mmol 0.3 eq). The reaction was heated at reflux overnight. The solvent was removed in vacuo and the residue obtained was diluted with water and neutralized by addition of 1M HCl. The aqueous layer was further extracted with EtOAc and the combined organic extracts were washed with brine, dried (Na2SO4), filtered and evaporated in vacuo. The residue was purified by chromatography (EtOAc:petroleum ether, 0:1 to 1:20) to give the title compound an oil (130 mg, 46%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[Cl:21])[N:12]([CH3:14])[CH3:13].[CH2:22]([N:24]([CH2:38][CH3:39])[C:25](=[O:37])[NH:26][C:27]1[CH:32]=[CH:31][C:30]([S:33](Cl)(=[O:35])=[O:34])=[CH:29][CH:28]=1)[CH3:23]>CCCCCC.CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([S:33]([C:30]1[CH:29]=[CH:28][C:27]([NH:26][C:25]([N:24]([CH2:38][CH3:39])[CH2:22][CH3:23])=[O:37])=[CH:32][CH:31]=1)(=[O:35])=[O:34])[C:6](=[O:11])[C:5]2([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[Cl:21])[N:12]([CH3:14])[CH3:13]
Reactant: CCN(CC)C(=O)Nc1ccc(S(=O)(=O)Cl)cc1
Reactant: CN(C)C1(c2ccccc2Cl)C(=O)Nc2ccc(Cl)cc21
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CCN(CC)C(=O)Nc1ccc(S(=O)(=O)N2C(=O)C(c3ccccc3Cl)(N(C)C)c3cc(Cl)ccc32)cc1

Procedure:
This compound is prepared according to the procedure described in EXAMPLE 1 from 0.500 g of 5-chloro-3-(2-chlorophenyl)-1,3-dihydro-3-(dimethylamino)indol-2-one and 0.453 g of 4-(N',N'-diethylureido)benzenesulfonyl chloride. Chromatography on silica using a gradient of a hexane/AcOEt mixture (80/20; v/v to 60/40; v/v) as the eluent gives the expected product after crystallization from a DCM/iso ether mixture. m=0.520 g. M.p.=146°-150° C.
Reaction SMILES: [C:1]12([C:11](=[O:21])[CH2:12][N:13]3[CH2:20][CH2:19][CH2:18][C@H:14]3[C:15](O)=[O:16])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.C(N(CC)CC)C.ClC(OCC(C)C)=O.[CH2:37]([NH:44][C:45](=[O:48])[CH2:46][NH2:47])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>C1COCC1>[C:1]12([C:11](=[O:21])[CH2:12][N:13]3[CH2:20][CH2:19][CH2:18][C@H:14]3[C:15]([N:44]([CH2:37][C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[C:45](=[O:48])[CH2:46][NH2:47])=[O:16])[CH2:2][CH:3]3[CH2:4][CH:5]([CH2:6][CH:7]([CH2:9]3)[CH2:8]1)[CH2:10]2
Reactant: O=C(O)[C@@H]1CCCN1CC(=O)C12CC3CC(CC(C3)C1)C2
Reactant: NCC(=O)NCc1ccccc1
Agent: CC(C)COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: NCC(=O)N(Cc1ccccc1)C(=O)[C@@H]1CCCN1CC(=O)C12CC3CC(CC(C3)C1)C2
Yield: 34.2 %

Procedure:
Using the procedure described in example 3, a solution of 1-(2-adamantan-1-yl-2-oxoethyl) L-proline (104.6 mg, 0.36 mmol, 1.0 eq), triethylamine (150 uL, 1.07 mmol, 3.0 eq), and THF (1.5 mL), was treated with isobutyl chloroformate (51 uL, 0.39 mL, 1.1 eq), then with glycine N-benzylamide (88.2 mg, 537 umol, 1.5 eq). Workup as before provided 53.9 mg (34%) of glycine, N-[1-(2-adamantan-1-yl-2-oxoethyl)-L-prolyl] benzylamide. as a white foam.