Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][N:11]([CH3:44])[C:12]([C:14]1[C:19]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[C:18]([OH:28])[N:17]=[C:16]([CH2:29][C:30]2([N:35]3[C:39]4=[N:40][CH:41]=[CH:42][CH:43]=[C:38]4[CH:37]=[CH:36]3)[CH2:34][CH2:33][CH2:32][CH2:31]2)[N:15]=1)=[O:13])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH2:45]([O:52][C:53]1C(C(O)=O)=NC(CC2(N3C4=NC=CC=C4C=C3)CCCC2)=NC=1O)C1C=CC=CC=1.[Si](OCCNC1COC1)(C(C)(C)C)(C)C>>[Si:1]([O:8][CH2:9][CH2:10][N:11]([CH:44]1[CH2:53][O:52][CH2:45]1)[C:12]([C:14]1[C:19]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[C:18]([OH:28])[N:17]=[C:16]([CH2:29][C:30]2([N:35]3[C:39]4=[N:40][CH:41]=[CH:42][CH:43]=[C:38]4[CH:37]=[CH:36]3)[CH2:31][CH2:32][CH2:33][CH2:34]2)[N:15]=1)=[O:13])([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:3])[CH3:2]
Reactant: O=C(O)c1nc(CC2(n3ccc4cccnc43)CCCC2)nc(O)c1OCc1ccccc1
Reactant: CN(CCO[Si](C)(C)C(C)(C)C)C(=O)c1nc(CC2(n3ccc4cccnc43)CCCC2)nc(O)c1OCc1ccccc1
Agent: CC(C)(C)[Si](C)(C)OCCNC1COC1
Product: CC(C)(C)[Si](C)(C)OCCN(C(=O)c1nc(CC2(n3ccc4cccnc43)CCCC2)nc(O)c1OCc1ccccc1)C1COC1

Procedure:
5-Benzyloxy-6-hydroxy-2-(1-pyrrolo[2,3-b]pyridin-1-yl-cyclopentylmethyl)-pyrimidine-4-carboxylic acid [2-(tert-butyl-dimethylsilanyloxy)-ethyl]oxetan-3-yl-amide (421) was prepared following the same method as described for 5-benzyloxy-6-hydroxy-2-(1-pyrrolo[2,3-b]pyridin-1-yl-cyclopentylmethyl)-pyrimidine-4-carboxylic acid [2-(tert-butyl-dimethylsilanyloxy)-ethyl]-methyl-amide (405) from 5-benzyloxy-6-hydroxy-2-(1-pyrrolo[2,3-b]pyridin-1-yl-cyclopentylmethyl)-pyrimidine-4-carboxylic acid (404) (125 mg, 0.28 mmol) and [2-(tert-butyl-dimethylsilanyloxy)-ethyl]-oxetan-3-yl-amine (98 mg, 0.42 mmol) (8 g) to get a white sticky solid (180 mg, 97%, mixture).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]([OH:10])=O)[CH:5]=[CH:4][C:3]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[CH3:17][N:18]([CH3:33])[CH2:19][CH2:20][N:21]([CH3:32])[C:22]1[S:23][C:24]2[CH:30]=[C:29]([NH2:31])[CH:28]=[CH:27][C:25]=2[N:26]=1>>[CH3:17][N:18]([CH3:33])[CH2:19][CH2:20][N:21]([CH3:32])[C:22]1[S:23][C:24]2[CH:30]=[C:29]([NH:31][C:8]([C:6]3[CH:5]=[CH:4][C:3]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)=[C:2]([CH3:1])[CH:7]=3)=[O:10])[CH:28]=[CH:27][C:25]=2[N:26]=1
Reactant: CN(C)CCN(C)c1nc2ccc(N)cc2s1
Reactant: Cc1cc(C(=O)O)ccc1-c1ccccc1
Product: Cc1cc(C(=O)Nc2ccc3nc(N(C)CCN(C)C)sc3c2)ccc1-c1ccccc1

Procedure:
The title compound is prepared by following General Method A, using 2-methyl-biphenyl-4-carboxylic acid (0.072 g, 0.34 mmol), and N*2*-(2-dimethylamino-ethyl)-N*2*-methyl-benzothiazole-2,6-diamine (0.065 g, 0.26 mmol) to give 0.036 g, (31%) of product. LC/MS: Retention time=4.80 min; (m/z): calcd for C2H28N4OS (M+H)+: 445.6; found: 445.0.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[CH3:9][C:10]1[N:15]=[C:14]([CH3:16])[C:13]([CH3:17])=[N:12][C:11]=1[CH3:18].[CH2:19]([C:25](=[CH:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[CH:26]=[O:27])[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]>O1CCCC1>[CH2:19]([C:25](=[CH:28][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)[CH:26]([OH:27])[CH2:18][C:11]1[C:10]([CH3:9])=[N:15][C:14]([CH3:16])=[C:13]([CH3:17])[N:12]=1)[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: CCCCCCC(C=O)=Cc1ccccc1
Reactant: Cc1nc(C)c(C)nc1C
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCCCCCC(=Cc1ccccc1)C(O)Cc1nc(C)c(C)nc1C
Temperature: 25 °C
Yield: 113.5 %

Procedure:
To a solution of lithium diisopropylamide (1.5 Molar, 73.3 mL, 0.11 mole) in 150 mL of tetrahydrofuran at -78° C. is added slowly a solution of tetramethylpyrazine (13.6 g, 0.1 mole) in 100 mL of tetrahydrofuran. The mixture is allowed to warm to room temperature and then cooled to -78° C. A solution of α-hexylcinnamaldehyde (23.7 g, 0.11 mole) in 100 mL of tetrahydrofuran is added dropwise over 15 minutes. The solution is allowed to warm to room temperature, and then poured into an ice/dilute hydrochloric acid mixture. The organic layer is separated and washed with saturated solutions of sodium bicarbonate and sodium chloride. The solution is dried over anhydrous magnesium sulfate. After filtration of drying agent and evaporation of solvent, a yield of 40 g of crude material is obtained. A volatile fraction in the crude material is removed by distillation at below 85° C. under 0.15 torr of mercury. The residue is crystallized from a mixture of ethyl acetate-hexane. The product is obtained as a fine needle, M.P. 61°-62° C. Yield 26 g (70%). NMR and IR confirm the structure.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][C:7]2[S:8][CH2:9][CH2:10][NH:11][C:6]=2[CH:5]=1)([O-:3])=[O:2].Cl.Cl[CH2:16][CH2:17][N:18]([CH3:20])[CH3:19].[OH-].[Na+]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.ClCCl.O>[CH3:19][N:18]([CH3:20])[CH2:17][CH2:16][N:11]1[CH2:10][CH2:9][S:8][C:7]2[CH:12]=[CH:13][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][C:6]1=2
Reactant: CN(C)CCCl
Reactant: O=[N+]([O-])c1ccc2c(c1)NCCS2
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [Br-]
Solvent: O
Solvent: ClCCl
Product: CN(C)CCN1CCSc2ccc([N+](=O)[O-])cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 11.7 %

Procedure:
To a stirred suspension of 6-nitro-3,4-dihydro-2H-benzo[b][1,4]thiazine (500 mg, 2.55 mmol), 2-chloro-N,N-dimethylethanamine hydrochloride (734 mg, 5.10 mmol), and tetrabutylammonium bromide (41.1 mg, 0.127 mmol) in dichloromethane (5 mL) was added 50% aqueous NaOH (5 mL). The reaction vessel was then sealed, and the mixture was stirred vigorously overnight at room temperature. The mixture was then diluted with water and extracted with dichloromethane (3×). The combined organics were dried, filtered, concentrated, and then chromatographed in 1:4:5 (2M NH3 in methanol):ethyl acetate:dichloromethane, giving the desired product (80 mg, 11.74%) and significant amounts of starting material. 1H NMR (DMSO-d6) δ 7.44 (d, J=2.4 Hz, 1H), 7.36 (dd, J=8.4, 2.4 Hz, 1H), 7.19 (d, J=8.4 Hz, 1H), 3.69-3.64 (m, 2H), 3.48 (t, J=6.9 Hz, 2H), 3.14-3.09 (m, 2H), 2.45 (t, J=6.9 Hz, 2H), 2.22 (s, 6H); ESI-MS (m/z, %): 268 (MH+, 100).
Reaction SMILES: [NH2:1][CH2:2][CH:3]([OH:9])[CH2:4][O:5][CH:6]([CH3:8])[CH3:7].Cl[C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12].C(N(C(C)C)CC)(C)C.CN(C=O)C>C1COCC1>[OH:9][CH:3]([CH2:4][O:5][CH:6]([CH3:8])[CH3:7])[CH2:2][NH:1][C:11](=[O:12])[O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CC(C)OCC(O)CN
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)OCC(O)CNC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
1 g of rac-1-amino-3-isopropoxypropan-2-ol (7.5 mmol, 1 equivalent) were initially charged in 25 ml of THF, and 1.16 ml of benzyl chloroformate (8.3 mmol, 1.1 equivalents), 3.9 ml of diisopropylethylamine (22.5 mmol, 3 equivalents) and 183 mg of N,N-dimethylaminopyridine (1.5 mmol, 0.2 equivalents) were added. The reaction mixture was stirred at RT, and after about 30 min 5 ml of DMF were added. After a further 2.5 h at RT, the mixture was concentrated to dryness. The residue was taken up in ethyl acetate and washed with saturated aqueous sodium bicarbonate solution and then with saturated aqueous sodium chloride solution. The organic phase was dried over magnesium sulphate, filtered and concentrated. The residue was used without further purification for the next reaction.
Reaction SMILES: [C:1]([C:3]1[C:4](F)=[C:5]([CH:19]=[C:20]([F:23])[C:21]=1[F:22])[C:6]([C:8](=[CH:14][NH:15][CH:16]1[CH2:18][CH2:17]1)[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[O:7])#[N:2].C([O-])([O-])=O.[K+].[K+]>CN(C)C=O>[C:1]([C:3]1[C:21]([F:22])=[C:20]([F:23])[CH:19]=[C:5]2[C:4]=1[N:15]([CH:16]1[CH2:18][CH2:17]1)[CH:14]=[C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:6]2=[O:7])#[N:2]
Reactant: CCOC(=O)C(=CNC1CC1)C(=O)c1cc(F)c(F)c(C#N)c1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(C2CC2)c2c(C#N)c(F)c(F)cc2c1=O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of the crude product from step f, 27,6 g of K2CO3, and 80 ml of dimethylformamide are stirred at room temperature for 16 hours. The reaction mixture is poured on 750 ml ice/water and the precipitate is filtered off with suction, washed with 80 ml of cold methanol and dried.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([N:6]=[CH:7][CH:8]=[N:9]2)=[C:4]([O:12][CH:13]2[CH2:18][CH2:17][CH:16]([N:19]3[C:27](=[O:28])[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[C:20]3=[O:29])[CH2:15][CH2:14]2)[CH:3]=1.[NH:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1.C([O-])([O-])=O.[Cs+].[Cs+].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>C1(C)C=CC=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[O:33]1[CH2:34][CH2:35][N:30]([C:2]2[CH:11]=[C:10]3[C:5]([N:6]=[CH:7][CH:8]=[N:9]3)=[C:4]([O:12][C@@H:13]3[CH2:18][CH2:17][C@H:16]([N:19]4[C:27](=[O:28])[C:26]5[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=5)[C:20]4=[O:29])[CH2:15][CH2:14]3)[CH:3]=2)[CH2:31][CH2:32]1
Reactant: O=C1c2ccccc2C(=O)N1C1CCC(Oc2cc(Br)cc3nccnc23)CC1
Reactant: C1COCCN1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: O=C1c2ccccc2C(=O)N1[C@H]1CC[C@@H](Oc2cc(N3CCOCC3)cc3nccnc23)CC1
Temperature: 110 °C

Procedure:
As shown in step 9-ii of Scheme 9, In a round bottom flask fitted with a condenser, a mixture of 2-[4-(7-bromoquinoxalin-5-yl)oxycyclohexyl]isoindoline-1,3-dione (6.2 g, 12.34 mmol), morpholine (1.61 g, 1.62 mL, 18.5 mmol), and Cs2CO3 (12.06 g, 37.0 mmol) in anhydrous toluene (73 mL) was treated with rac-BINAP (768.4 mg, 1.234 mmol) and Pd2(dba)3 (565 mg, 0.617 mmol). The reaction mixture was heated at 110° C. for 18 hours. After cooling to room temperature, the mixture was filtered through diatomaceous earth and concentrated under reduced pressure. The residue was triturated with Et2O and the solids collected by filtration and washed with Et2O to produce 2-((cis)-4-((7-morpholinoquinoxalin-5-yl)oxy)cyclohexyl)isoindoline-1,3-dione (compound 1029, 4.2 g) as yellow solid. The filterate was concentrated under reduced pressure and purified by medium pressure silica gel chromatography (0-100% EtOAc/hexanes gradient) to produce an additional 300 mg of compound 1029: 1H-NMR (300 MHz, CDCl3) δ 8.76-8.63 (m, 2H), 7.85 (dd, J=5.4, 3.1 Hz, 2H), 7.79-7.60 (m, 2H), 7.09 (d, J=2.6 Hz, 1H), 6.99 (d, J=2.5 Hz, 1H), 5.06 (t, J=2.8 Hz, 1H), 4.27 (tt, J=12.3, 3.8 Hz, 1H), 4.02-3.85 (m, 4H), 3.49-3.27 (m, 4H), 3.03-2.75 (m, 2H), 2.37 (d, J=14.0 Hz, 2H), 1.83-1.56 (m, 4H).
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[C:5]([CH3:31])=[C:6]([CH:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[C:7]([O:23][CH3:24])=[C:8]([CH:10]([N:12]2[C:16]3=[N:17][CH:18]=[N:19][C:20]([NH2:21])=[C:15]3[C:14]([CH3:22])=[N:13]2)[CH3:11])[CH:9]=1.[CH2:32]=O>>[Cl:3][C:4]1[C:5]([CH3:31])=[C:6]([CH:25]2[CH2:26][CH2:27][N:28]([CH3:32])[CH2:29][CH2:30]2)[C:7]([O:23][CH3:24])=[C:8]([CH:10]([N:12]2[C:16]3=[N:17][CH:18]=[N:19][C:20]([NH2:21])=[C:15]3[C:14]([CH3:22])=[N:13]2)[CH3:11])[CH:9]=1
Reactant: C=O
Reactant: COc1c(C(C)n2nc(C)c3c(N)ncnc32)cc(Cl)c(C)c1C1CCNCC1
Agent: Cl
Product: COc1c(C(C)n2nc(C)c3c(N)ncnc32)cc(Cl)c(C)c1C1CCN(C)CC1

Procedure:
This compound was prepared according to the procedure of Example 139 step 7, using of 1-[1-(5-chloro-2-methoxy-4-methyl-3-piperidin-4-ylphenyl)ethyl]-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine dihydrochloride and formaldehyde as the starting materials. The product was isolated as a racemic mixture. LCMS calculated for C22H30ClN6O (M+H)+: m/z=429.2; Found: 429.1.
Reaction SMILES: C(OC([N:11]1[CH2:14][CH2:13][C@H:12]1[C:15]1[N:19]([CH2:20][CH2:21][CH2:22][C:23]2[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=2)[N:18]=[N:17][N:16]=1)=O)C1C=CC=CC=1>C(O)C.[Pd]>[N:25]1[CH:26]=[CH:27][CH:28]=[C:23]([CH2:22][CH2:21][CH2:20][N:19]2[C:15]([C@@H:12]3[CH2:13][CH2:14][NH:11]3)=[N:16][N:17]=[N:18]2)[CH:24]=1
Reactant: O=C(OCc1ccccc1)N1CC[C@H]1c1nnnn1CCCc1cccnc1
Agent: [Pd]
Solvent: CCO
Product: c1cncc(CCCn2nnnc2[C@@H]2CCN2)c1
Reaction time: 26 h

Procedure:
(2S)-1-(Benzyloxycarbonyl)-2-(1-[3-(3-pyridyl)-1-propyl]-1H-tetrazol-5-yl)azetidine from Reference Example 17 (125.3 mg, 0.331 mmol, 1.0 eq) was dissolved in ethanol (20 mL) and 10% Pd/C (49.9 mg, 0.047 mmol, 0.14 eq) was carefully added. The mixture was flushed with vacuum and nitrogen three times and stirred under a hydrogen atmosphere at about room temperature for about 26 hours. After removing the solid matter by filtration, the solvent was removed under vacuum to give 80.8 mg (quantitative yield) of the product as a colorless oil. 1H NMR (CDCl3) δ 2.18-3.24 (series of m, 7H); 3.46-4.68 (series of m, 5H); 7.19-7.33 (m, 1H); 7.51-7.63 (m, 1H); 8.38-8.57 (m, 2H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:18]3[C:13](=[N:14][CH:15]=[N:16][C:17]=3[NH2:19])[S:12][N:11]=2)=[CH:6][CH:5]=1)([O-])=O.[NH4+].[Cl-]>[Fe].C(O)C.O>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:18]3[C:13](=[N:14][CH:15]=[N:16][C:17]=3[NH2:19])[S:12][N:11]=2)=[CH:6][CH:5]=1
Reactant: Nc1ncnc2snc(-c3ccc([N+](=O)[O-])cc3)c12
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: Nc1ccc(-c2nsc3ncnc(N)c23)cc1
Temperature: 25 °C
Yield: 96.3 %

Procedure:
A mixture of Example 96F (0.95 g, 3.5 mmol), iron (0.78 g, 13.9 mmol), and NH4Cl (0.19 g, 3.5 mmol) in 9:1 ethanol/water (80 mL) was heated to 60° C. for 4 hours, cooled to room temperature, and filtered through a pad of diatomaceous earth (Celite®). The pad was washed with THF and the filtrate was concentrated. The concentrate was suspended in water and filtered. The filter cake was washed with water and dried to provide 0.82 g (97% yield) of the desired product.
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][NH:7][CH2:8][C@H:9]1[O:14][CH2:13][C@H:12]([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:11][CH2:10]1)(=[O:3])[CH3:2].[C:23](OC(=O)C)(=[O:25])[CH3:24].N1C=CC=CC=1>ClCCl.[Cl-].[Na+].O>[C:1]([O:4][CH2:5][CH2:6][N:7]([C:23](=[O:25])[CH3:24])[CH2:8][C@H:9]1[O:14][CH2:13][C@H:12]([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:11][CH2:10]1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: CC(=O)OCCNC[C@@H]1CC[C@@H](NC(=O)OC(C)(C)C)CO1
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: c1ccncc1
Product: CC(=O)OCCN(C[C@@H]1CC[C@@H](NC(=O)OC(C)(C)C)CO1)C(C)=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 82 %

Procedure:
The compound (264 mg, 0.83 mmol) obtained in Step 4 above was dissolved in dichloromethane (8 ml), acetic anhydride (0.50 ml, 5.30 mmol) was added and the resulting mixture was stirred at room temperature for 1 hour. Then pyridine (0.10 ml, 1.24 mmol) was added and the resulting mixture was further stirred for 1 hour. Saturated brine (20 ml) was added to the reaction mixture and the resulting mixture was stirred for 1 hour, followed by extraction with dichloromethane. The organic layer was washed with saturated sodium bicarbonate solution and brine in that order and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue obtained was purified by silica gel column chromatography [chloroform:methanol=40:1 (v/v)] to give 244 mg (82%) of the title compound as a colorless amorphous solid.
Reaction SMILES: FC1C=CC(C=O)=CC=1.Cl[C:11]1[CH:20]=[C:19]2[C:14]([CH:15]=[CH:16][N:17]([CH2:22][C:23]3[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=3)[C:18]2=[O:21])=[CH:13][C:12]=1[F:31]>>[F:31][C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][CH:11]=1)[C:18](=[O:21])[N:17]([CH2:22][C:23]1[CH:24]=[CH:25][C:26]([O:29][CH3:30])=[CH:27][CH:28]=1)[CH:16]=[CH:15]2
Reactant: COc1ccc(Cn2ccc3cc(F)c(Cl)cc3c2=O)cc1
Agent: O=Cc1ccc(F)cc1
Product: COc1ccc(Cn2ccc3cc(F)ccc3c2=O)cc1

Procedure:
Starting from 4-fluoro benzaldehyde, the title compound was prepared following a similar sequence as described for 7-chloro-6-fluoro-2-(4-methoxy-benzyl)-2H-isoquinolin-1-one (62). Rt=1.72 min (Method B). Detected mass: 284.1 (M+H+).
Reaction SMILES: [H-].[Na+].Cl.[OH:4][CH2:5][C:6]1[C:7]([CH3:14])=[C:8]([OH:13])[C:9]([CH3:12])=[N:10][CH:11]=1.[Cl:15][C:16]1[CH:21]=[C:20]([N+]([O-])=O)[CH:19]=[CH:18][N:17]=1>CN(C=O)C.O>[Cl:15][C:16]1[CH:21]=[C:20]([O:13][C:8]2[C:7]([CH3:14])=[C:6]([CH2:5][OH:4])[CH:11]=[N:10][C:9]=2[CH3:12])[CH:19]=[CH:18][N:17]=1
Reactant: Cc1ncc(CO)c(C)c1O
Reactant: O=[N+]([O-])c1ccnc(Cl)c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ncc(CO)c(C)c1Oc1ccnc(Cl)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 78.7 %

Procedure:
A suspension of sodium hydride (5.27 g, 209 mmol) in DMF (100 mL) was carefully charged with 5-(hydroxymethyl)-2,4-dimethylpyridin-3-ol hydrochloride (18 g, 95 mmol). The mixture stirred at room temperature for 2 hours. 2-chloro-4-nitropyridine (15 g, 95 mmol) was then added and the reaction stirred overnight at room temperature. The material was diluted with water and extracted with ethylacetate. The organic layer was dried, and concentrated. Flash chromatography (dichloromethane/methanol 20:1) gave (5-(2-chloropyridin-4-yloxy)-4,6-dimethylpyridin-3-yl)methanol (19.8 g, 79%) as colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[S:9]([NH:12][C:13]1[C:14]([O:28][CH3:29])=[N:15][CH:16]=[C:17](B2OC(C)(C)C(C)(C)O2)[CH:18]=1)(=[O:11])=[O:10].Br[C:31]1[CH:39]=[C:38]2[C:34]([CH:35]=[N:36][N:37]2[S:40]([C:43]2[CH:48]=[CH:47][C:46]([CH3:49])=[CH:45][CH:44]=2)(=[O:42])=[O:41])=[C:33]([NH:50][C:51]([C:53]2[N:54]=[C:55]([CH2:58][N:59]3[CH2:64][C@H:63]([CH3:65])[O:62][C@H:61]([CH3:66])[CH2:60]3)[S:56][CH:57]=2)=[O:52])[CH:32]=1.C(=O)([O-])[O-].[Na+].[Na+].O1CCOCC1>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[S:9]([NH:12][C:13]1[CH:18]=[C:17]([C:31]2[CH:39]=[C:38]3[C:34]([CH:35]=[N:36][N:37]3[S:40]([C:43]3[CH:48]=[CH:47][C:46]([CH3:49])=[CH:45][CH:44]=3)(=[O:42])=[O:41])=[C:33]([NH:50][C:51]([C:53]3[N:54]=[C:55]([CH2:58][N:59]4[CH2:64][C@H:63]([CH3:65])[O:62][C@H:61]([CH3:66])[CH2:60]4)[S:56][CH:57]=3)=[O:52])[CH:32]=2)[CH:16]=[N:15][C:14]=1[O:28][CH3:29])(=[O:10])=[O:11]
Reactant: COc1ncc(B2OC(C)(C)C(C)(C)O2)cc1NS(=O)(=O)c1ccc(F)cc1F
Reactant: Cc1ccc(S(=O)(=O)n2ncc3c(NC(=O)c4csc(CN5C[C@@H](C)O[C@@H](C)C5)n4)cc(Br)cc32)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: COc1ncc(-c2cc(NC(=O)c3csc(CN4C[C@@H](C)O[C@@H](C)C4)n3)c3cnn(S(=O)(=O)c4ccc(C)cc4)c3c2)cc1NS(=O)(=O)c1ccc(F)cc1F
Temperature: 80 °C
Yield: 51.4 %

Procedure:
2,4-Difluoro-N-[2-(methyloxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridinyl]benzenesulfonamide (116 mg), N-{6-bromo-1-[(4-methylphenyl)sulfonyl]-1H-indazol-4-yl}-2-{[(2R,6S)-2,6-dimethyl-4-morpholinyl]methyl}-1,3-thiazole-4-carboxamide (150 mg), Pd(dppf)Cl2 (18 mg), sodium carbonate (79 mg), 1,4-dioxane (5 ml) and water (5 ml) were combined and heated at 80° C. for 3 hours. The cooled reaction mixture was filtered through a 1 g silica cartridge, washing with methanol, then evaporated to dryness. The residue was dissolved in DCM and washed with water. The DCM was passed through a hydrophobic frit and evaporated to dryness. The residue was purified by ISCO companion, 12 g Silica cartridge using 0-5% MeOH in DCM over 16 mins. Pure fractions were combined and evaporated to give title compound, (105 mg).
Reaction SMILES: [CH3:1][Mg]Br.[Cl:4][C:5]1[S:9][C:8]([S:10]([NH:13][C@H:14]([CH:20]=[O:21])[CH:15]([CH2:18][CH3:19])[CH2:16][CH3:17])(=[O:12])=[O:11])=[CH:7][CH:6]=1>C1(C)C=CC=CC=1.C1COCC1.C1COCC1>[Cl:4][C:5]1[S:9][C:8]([S:10]([NH:13][C@H:14]([CH:20]([OH:21])[CH3:1])[CH:15]([CH2:16][CH3:17])[CH2:18][CH3:19])(=[O:12])=[O:11])=[CH:7][CH:6]=1
Reactant: C[Mg]Br
Reactant: CCC(CC)[C@@H](C=O)NS(=O)(=O)c1ccc(Cl)s1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CCC(CC)[C@H](NS(=O)(=O)c1ccc(Cl)s1)C(C)O
Temperature: 25 °C
Yield: 84 %

Procedure:
A solution of methylmagnesium bromide (1.4 M, 7.0 mL, 9.7 mmol) in toluene/THF (75:25) was added to a 0° C. solution of 5-chloro-N-[(S)-2-ethyl-1-formylbutyl]thiophene-2-sulfonamide (Example 221, 1.0 g, 3.2 mmol) in THF (30 mL). The mixture was warmed to 25° C. and after 2 h was quenched carefully with saturated aqueous ammonium chloride (25 mL). The mixture was extracted with EtOAc (3×25 mL). The organic extract was dried over Na2SO4, filtered and concentrated to give a colorless oil. The product was purified by column chromatography (Biotage), eluant: 1:4 EtOAc-hexane, to afford 5-chloro-N-[(S)-2-ethyl-1-(1-hydroxyethyl)butyl]thiophene-2-sulfonamide as a white solid (876 mg, 83%). The product is a diastereomeric mixture with a ratio of 3:7. mp 95-98° C. Anal. Calc'd for C12H20ClNO3S2: C, 44.23; H, 6.19; N, 4.30. Found: C, 44.25 H, 6.35; N, 4.29. Mass Spectrum (−ESI): 324 (M−H)−.
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][C:10]([CH:13]=O)=[CH:9][C:3]=1[C:4]([N:6]([CH3:8])[CH3:7])=[O:5].[NH2:15][C:16]1[CH:24]=[CH:23][CH:22]=[C:21]2[C:17]=1[CH2:18][O:19][C:20]2=[O:25].S([O-])([O-])(=O)=O.[Mg+2]>C(#N)C>[F:1][C:2]1[CH:12]=[CH:11][C:10](/[CH:13]=[N:15]/[C:16]2[CH:24]=[CH:23][CH:22]=[C:21]3[C:17]=2[CH2:18][O:19][C:20]3=[O:25])=[CH:9][C:3]=1[C:4]([N:6]([CH3:7])[CH3:8])=[O:5]
Reactant: Nc1cccc2c1COC2=O
Reactant: CN(C)C(=O)c1cc(C=O)ccc1F
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: CC#N
Product: CN(C)C(=O)c1cc(/C=N/c2cccc3c2COC3=O)ccc1F
Yield: 37.7 %

Procedure:
A solution of 2-fluoro-5-formyl-N,N-dimethylbenzamide (2.38 g, 12.2 mmol), 4-aminoisobenzofuran-1(3H)-one (1.82 g, 12.2 mmol), anhydrous magnesium sulfate (14.67 g, 122 mmol) in acetonitrile (100 ml) was heated to reflux for 2 days. The solution was filtered and removed in vacuum. The crude product was re-crystal with isopropanol to give the title compound (1.5 g, yield: 37%) 1H-NMR (400 MHz, DMSO-d6) δ (ppm): 2.91-2.92 (d, J=0.4 Hz, 3H), 3.07 (s, 3H), 5.55 (s, 2H), 7.52-7.56 (t, J=8.8 Hz, 1H), 7.67-7.70 (m, 2H), 7.76-7.78 (m, 1H), 8.02-8.04 (m, 1H), 8.10-8.14 (m, 1H), 8.83 (s, 1H); LC-MS (ESI) m/z: 327 (M+1)+.
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[CH:5][C:6]([Cl:12])=[C:7]([CH:11]=1)[C:8]([OH:10])=[O:9].[C-:13]#[N:14].[K+]>CN(C=O)C.O>[Cl:12][C:6]1[CH:5]=[CH:4][C:3]([CH2:2][C:13]#[N:14])=[CH:11][C:7]=1[C:8]([OH:10])=[O:9]
Reactant: [C-]#N
Reactant: O=C(O)c1cc(CBr)ccc1Cl
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: N#CCc1ccc(Cl)c(C(=O)O)c1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A solution of 5-(bromomethyl)-2-chlorobenzoic acid [WO 2001044170] (1.75 g) in DMF (20 mL) was treated with a solution of potassium cyanide (0.91 g) in water (7 mL) and the resulting solution was stirred at room temperature over 3 days. The mixture was diluted with water and extracted twice with ethyl acetate. The organic phases were discarded, whilst the aqueous phase was carefully acidified with concentrated hydrochloric acid (5 mL), venting any liberated HCN through bleach solution via a stream of nitrogen. After being stirred for 20 minutes, the aqueous phase was extracted twice more with ethyl acetate. The combined organic phases were washed three times with water, once with brine, then dried over anhydrous magnesium sulphate and concentrated in vacuo to afford the crude subtitled compound as a brown solid. Yield 1.25 g.