Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][NH:2][S:3]([CH:6]1[CH2:11][CH2:10][N:9]([C:12](OCC2C=CC=CC=2)=O)[CH2:8][CH2:7]1)(=[O:5])=[O:4].ClC1[N:28]=[C:27]([N:29]2[CH2:34][CH2:33][O:32][CH2:31][CH2:30]2)[N:26]=[C:25]([N:35]2[C:39]3[CH:40]=[CH:41][CH:42]=[C:43]([O:44][CH3:45])[C:38]=3[N:37]=[C:36]2[CH:46]([F:48])[F:47])[N:24]=1.CCN(C(C)C)C(C)C>CO.C1COCC1.[Pd]>[F:48][CH:46]([F:47])[C:36]1[N:35]([C:25]2[N:26]=[C:27]([N:29]3[CH2:30][CH2:31][O:32][CH2:33][CH2:34]3)[N:28]=[C:12]([N:9]3[CH2:8][CH2:7][CH:6]([S:3]([NH:2][CH3:1])(=[O:4])=[O:5])[CH2:11][CH2:10]3)[N:24]=2)[C:39]2[CH:40]=[CH:41][CH:42]=[C:43]([O:44][CH3:45])[C:38]=2[N:37]=1
Reactant: COc1cccc2c1nc(C(F)F)n2-c1nc(Cl)nc(N2CCOCC2)n1
Reactant: CNS(=O)(=O)C1CCN(C(=O)OCc2ccccc2)CC1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: CNS(=O)(=O)C1CCN(c2nc(N3CCOCC3)nc(-n3c(C(F)F)nc4c(OC)cccc43)n2)CC1
Yield: 39 %

Procedure:
The above carbamate was hydrogenated over 5% Pd on carbon in MeOH. After removal of the solvent, the residue was combined with 0.19 g (0.48 mmol) 1-[4-chloro-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-2-(difluoromethyl)-4-methoxy-1H-benzimidazole (Example 2) and DIPEA in THF. The mixture was heated under reflux for 30 min and the solvent was concentrated. After dilution with water, the resulting solid was collected and dried. Chromatography on alumina, eluting with CH2Cl2/EtOAc (9:1), gave 0.127 g (39% yield) of 1-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-N-methyl-4-piperidinesulfonamide: mp (MeOH) 261-263° C.; 1H NMR (CDCl3) δ 7.87 (dd, J=8.4, 0.6 Hz, 1H), 7.46 (t, JHF=53.6 Hz, 1H), 7.35 (t, J=8.0 Hz, 1H), 6.82 (d, J=7.7 Hz, 1H), 4.93 (br d, J=13.5 Hz, 2H), 4.05 (s, 3H), 4.02 (q, J=5.3 Hz, 1H), 3.88 (m, 4H), 3.78 (m, 4H), 3.22 (tt, J=11.8, 3.7 Hz, 1H), 3.00 (m, 2H), 2.86 (d, J=5.3 Hz, 3H), 2.24 (br d, J=12.0 Hz, 2H), 1.85 (dq, J=12.5, 4.4 Hz, 2H); Anal. Calcd. for C22H28F2N8O4S: C, 49.1; H, 5.2; N, 20.8. Found: C, 49.2; H, 5.3; N, 21.0%.
Reaction SMILES: [C:1]([O:5][C:6](=[O:31])[NH:7][C@@H:8]([CH:12]=[N:13][C:14]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:15]=1[C:21](=[O:30])[NH:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH:9]([CH3:11])[CH3:10])([CH3:4])([CH3:3])[CH3:2].O.[OH-].[Li+].Cl>O1CCOCC1.C(O)CO>[C:1]([O:5][C:6](=[O:31])[NH:7][C@@H:8]([C:12]1[N:22]([CH2:23][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:21](=[O:30])[C:15]2[C:14](=[CH:19][C:18]([Cl:20])=[CH:17][CH:16]=2)[N:13]=1)[CH:9]([CH3:11])[CH3:10])([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)[C@H](C=Nc1cc(Cl)ccc1C(=O)NCc1ccccc1)NC(=O)OC(C)(C)C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Solvent: OCCO
Product: CC(C)[C@@H](NC(=O)OC(C)(C)C)c1nc2cc(Cl)ccc2c(=O)n1Cc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A dry 3-necked, round bottomed flask, equipped with a magnetic stirrer, nitrogen inlet, heating mantle and a water condenser, is charged with 60 mL of 1,4-dioxane/ethylene glycol (2:1), 4.60 g (10 mmol) of (R)-{1-[(2-benzylcarbamoyl-5-chloro-phenylimino)-methyl]-2-methyl-propyl}-carbamic acid tert-butyl ester (a compound of Formula 106, obtained as described in Example 5.3), and 0.46 g (11 mmol) of lithium hydroxide monohydrate. The mixture is heated to reflux and the reaction is monitored by TLC (hexanes/ethyl acetate 7:3). After 4 h of refluxing the reaction appears to be complete. The mixture is allowed to cool to room temperature and is slowly acidified to pH=5 by adding 1N hydrochloric acid. The mixture is stirred for 1 h and the white suspension is separated by filtration and dried in high vacuum to afford the title compound of Formula 107, (R)-[1-(3-benzyl-7-chloro-4-oxo-3,4-dihydro-quinazolin-2-yl)-2-methylpropyl]-carbamic acid tert-butyl ester.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12](/[CH:18]=[CH:19]/[C:20]([O:22][CH3:23])=[O:21])=[C:13]2[C:17]=1[NH:16][CH:15]=[CH:14]2)[C:2]1C=CC=CC=1.BrCC#[N:27].C(=O)([O-])[O-].[K+].[K+]>CO.C(OCC)(=O)C.[Pd].C(C(C)=O)C>[C:2]([CH2:1][O:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:18][CH2:19][C:20]([O:22][CH3:23])=[O:21])=[C:13]2[C:17]=1[NH:16][CH:15]=[CH:14]2)#[N:27]
Reactant: COC(=O)/C=C/c1ccc(OCc2ccccc2)c2[nH]ccc12
Reactant: N#CCBr
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CCC(C)=O
Solvent: CO
Product: COC(=O)CCc1ccc(OCC#N)c2[nH]ccc12

Procedure:
A suspension of 7-benzyloxy-4-(2(E)-methoxycarbonylethenyl)indole (0.50 g, 1.63 mmol) in methanol (40 ml) and ethyl acetate (10 ml) was hydrogenated at 60 p.s.i. over 10% palladium on charcoal (0.10 g) for 3 hours. The catalyst was filtered off and the filtrate was evaporated. A stirred solution of the residue and bromoacetonitrile (0.12 ml, 1.72 mmol) in methyl ethyl ketone was heated under reflux with solid anhydrous potassium carbonate (0.48 g, 3.4 mmol) for 3.5 hours, poured onto ice-hydrochloric acid and extracted with dichloromethane. The extract was dried and evaporated and the residue was chromatographed on silica in ethyl acetate-hexane (1:3) to give a pale solid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][C@@H:9]([C@H:11]2[CH2:15][NH:14][C:13](=[O:16])[CH2:12]2)[CH3:10])[C:5]2[N:17]([CH3:20])[CH:18]=[N:19][C:4]=2[CH:3]=1.[CH3:21][N:22]1[C:30]2[C:25](=[CH:26][C:27](B(O)O)=[CH:28][CH:29]=2)[C:24]([CH3:34])=[N:23]1>>[CH3:21][N:22]1[C:30]2[C:25](=[CH:26][C:27]([C:2]3[N:7]=[C:6]([O:8][C@@H:9]([C@H:11]4[CH2:15][NH:14][C:13](=[O:16])[CH2:12]4)[CH3:10])[C:5]4[N:17]([CH3:20])[CH:18]=[N:19][C:4]=4[CH:3]=3)=[CH:28][CH:29]=2)[C:24]([CH3:34])=[N:23]1
Reactant: C[C@@H](Oc1nc(Cl)cc2ncn(C)c12)[C@H]1CNC(=O)C1
Reactant: Cc1nn(C)c2ccc(B(O)O)cc12
Product: Cc1nn(C)c2ccc(-c3cc4ncn(C)c4c(O[C@H](C)[C@H]4CNC(=O)C4)n3)cc12

Procedure:
Following General Procedure B, beginning with crude (R)-4-((R)-1-(6-chloro-3-methyl-3H-imidazo[4,5-c]pyridin-4-yloxy)ethyl)pyrrolidin-2-one 2.06 (45 mg, 0.153 mmol) and 1,3-dimethyl-1H-indazol-5-ylboronic acid (35 mg, 0.183 mmol), (R)-4-((R)-1-(6-(1,3-dimethyl-1H-indazol-5-yl)-3-methyl-3H-imidazo[4,5-c]pyridin-4-yloxy)ethyl)pyrrolidin-2-one 3B.31 was isolated, following column chromatography.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@:8]2([OH:25])[CH2:13][CH2:12][CH:11]([C:14](=[O:22])[C@@H:15]([NH:19][CH:20]=O)[CH:16]([CH3:18])[CH3:17])[CH2:10][C:9]2([CH3:24])[CH3:23])=[CH:4][CH:3]=1.O=P(Cl)(Cl)Cl>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@@:8]2([OH:25])[CH2:13][CH2:12][CH:11]([C:14](=[O:22])[C@@H:15]([N+:19]#[C-:20])[CH:16]([CH3:18])[CH3:17])[CH2:10][C:9]2([CH3:23])[CH3:24])=[CH:6][CH:7]=1
Reactant: CC(C)[C@H](NC=O)C(=O)C1CC[C@](O)(c2ccc(Cl)cc2)C(C)(C)C1
Solvent: ClCCl
Solvent: O=P(Cl)(Cl)Cl
Product: [C-]#[N+][C@H](C(=O)C1CC[C@](O)(c2ccc(Cl)cc2)C(C)(C)C1)C(C)C
Temperature: 2.5 °C
Reaction time: 3 h
Yield: 81.9 %

Procedure:
To a mixture of N-((2S)-1-((4R)-4-(4-chlorophenyl)-4-hydroxy-3,3-dimethylcyclohexyl)-3-methyl-1-oxobutan-2-yl)formamide (109 mg, 0.298 mmol) and TEA (0.208 mL, 1.490 mmol) in CH2Cl2 (5 mL) was added POCl3 (0.027 mL, 0.298 mmol) at 0° under N2. The mixture was stirred at 0-5° C. for 3 h. The mixture was quenched with NaHCO3(aq), extracted into CH2Cl2, and dried over Na2SO4. After concentrating, the crude residue was purified via column chromatography (CH2Cl2) to give (2S)-1-((4R)-4-(4-chlorophenyl)-4-hydroxy-3,3-dimethylcyclohexyl)-2-isocyano-3-methylbutan-1-one (85 mg, 0.244 mmol, 82% yield) as a light yellow oil.
Reaction SMILES: [C:1]([C:4](C(OCC)=O)([CH2:19][CH:20]=[CH:21][CH:22]([O:28]C(=O)C)[CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH2:5][CH2:6][CH2:7][C:8]1[CH:18]=[CH:17][C:11]([C:12]([O:14]CC)=[O:13])=[CH:10][CH:9]=1)(=[O:3])[CH3:2].[OH-].[Na+]>O.C(O)C>[C:1]([CH:4]([CH2:19][CH:20]=[CH:21][CH:22]([OH:28])[CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH2:5][CH2:6][CH2:7][C:8]1[CH:9]=[CH:10][C:11]([C:12]([OH:14])=[O:13])=[CH:17][CH:18]=1)(=[O:3])[CH3:2]
Reactant: CCCCCC(C=CCC(CCCc1ccc(C(=O)OCC)cc1)(C(C)=O)C(=O)OCC)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCCCCC(O)C=CCC(CCCc1ccc(C(=O)O)cc1)C(C)=O

Procedure:
A solution of ethyl 4-(4-acetyl-4-ethoxycarbonyl-8-acetoxytridec-6-en-1-yl)benzoate (50.2 g., 0.1 mole) and sodium hydroxide (28.0 g., 0.7 mole) in water (300 ml.) and ethanol (350 ml.) is boiled under reflux for 3 hours. Solvents are removed under reduced pressure, the residue is dissolved in water, and the solution extracted with ether. The aqueous layer is acidified with concentrated hydrochloric acid to the Congo Red endpoint. The crude product separates as an oil. It is isolated in pure condition by column chromatography on silica gel with 4% methanol in chloroform as the eluant. 4-(4-Acetyl-8-hydroxytridec-6-en-1-yl)benzoic acid is obtained as a yellow, very viscous oil.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][N:15]([S:18]([CH3:21])(=[O:20])=[O:19])[CH2:14][CH2:13]3)=[CH:8][C:6]=2[N:7]=1.[CH3:28][O:29][C:30]1[N:35]=[CH:34][C:33](B(O)O)=[CH:32][N:31]=1>>[CH3:28][O:29][C:30]1[N:35]=[CH:34][C:33]([C:2]2[N:3]=[C:4]([N:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)[C:5]3[S:10][C:9]([CH2:11][N:12]4[CH2:17][CH2:16][N:15]([S:18]([CH3:21])(=[O:20])=[O:19])[CH2:14][CH2:13]4)=[CH:8][C:6]=3[N:7]=2)=[CH:32][N:31]=1
Reactant: CS(=O)(=O)N1CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1
Reactant: COc1ncc(B(O)O)cn1
Product: COc1ncc(-c2nc(N3CCOCC3)c3sc(CN4CCN(S(C)(=O)=O)CC4)cc3n2)cn1

Procedure:
2-Chloro-6-(4-methanesulfonyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidine, prepared via General Procedure B-3, was reacted with 2-methoxy-5-pyrimidine-boronic acid in General Procedure A. Purification on silica and ether trituration gave 246. NMR (CDCl3): 2.68-2.72 (4H, m), 2.82 (3H, s), 3.29-3.33 (4H, m), 3.90 (2H, s), 3.90-3.94 (4H, m), 4.05-4.10 (4H, m), 4.12 (3H, s), 7.32 (1H, br. s), 9.48 (2H, s). MS (ESI+): MH+506.2 (100%)
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:25])=[C:14]([C:20]([O:22]CC)=O)[C:15](=[O:19])[NH:16]3)=[N:11][CH:10]=2)=[CH:4][CH:3]=1.[N:26]1([CH2:32][CH2:33][NH2:34])[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:25])=[C:14]([C:20]([NH:34][CH2:33][CH2:32][N:26]4[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]4)=[O:22])[C:15](=[O:19])[NH:16]3)=[N:11][CH:10]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2[nH]c1=O
Reactant: NCCN1CCCCC1
Product: O=C(NCCN1CCCCC1)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2[nH]c1=O

Procedure:
This compound was prepared from ethyl 7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate and 2-(1-piperidinyl)ethylamine employing methods similar to those described in Example 2 and was obtained as a white solid: 1H NMR (d6-DMSO) δ 11.75 (1H, br), 10.70 (1H, br), 10.15 (1H, br), 8.20 (1H, m), 7.38-7.11 (5H, m), 4.01 (2H, s), 3.39 (2H, m), 2.38 (6H, m), 1.50 (4H, m), 1.39 (2H, m); ES +MS: 425 (M+H+, 100).
Reaction SMILES: [C:1]([C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7](=O)[NH:6][CH:5]=1)(=O)[CH3:2].[C:15](C1C=C(C2CCCCC2=O)C=CN=1)(=O)[CH3:16].[C:31]([CH2:33][C:34]([NH2:36])=[O:35])#[N:32]>>[C:31]([C:33]1[C:34](=[O:35])[NH:36][C:15]([CH3:16])=[C:1]2[C:4]=1[CH2:5][CH2:6][CH:7]([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][N:13]=1)[CH2:2]2)#[N:32]
Reactant: CC(=O)c1c[nH]c(=O)c2ccccc12
Reactant: N#CCC(N)=O
Reactant: CC(=O)c1cc(C2CCCCC2=O)ccn1
Product: Cc1[nH]c(=O)c(C#N)c2c1CC(c1ccccn1)CC2

Procedure:
Conventionally, these 4-acetyl isoquinolinone compounds have been prepared by condensing 2-acetyl-4-pyridyl cyclohexanone with cyanoacetamide to produce 4-cyano-1-methyl-7-pyridyl-5,6,7,8-tetrahydro-3(2H)-isoquinolinone and then reacting the obtained compound with a Grignard reagent such as methyl magnesium iodide and the like followed by decomposition by an acid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[C:10]([CH2:14][N:15]3[CH2:20][CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17][C@@H:16]3[CH3:28])[CH:11]=[N:12][CH:13]=2)[CH:5]=[CH:4][N:3]=1.[F:29][C:30]1[CH:31]=[C:32]([CH2:36][CH2:37][NH2:38])[CH:33]=[CH:34][CH:35]=1>>[F:29][C:30]1[CH:31]=[C:32]([CH:33]=[CH:34][CH:35]=1)[CH2:36][CH2:37][NH:38][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[N:12][CH:11]=[C:10]([CH2:14][N:15]3[CH2:20][CH2:19][NH:18][CH2:17][C@@H:16]3[CH3:28])[CH:9]=2)[CH:5]=[CH:4][N:3]=1
Reactant: NCCc1cccc(F)c1
Reactant: C[C@H]1CN(C(=O)OC(C)(C)C)CCN1Cc1cncc(-c2ccnc(Cl)n2)c1
Product: C[C@H]1CNCCN1Cc1cncc(-c2ccnc(NCCc3cccc(F)c3)n2)c1

Procedure:
Intermediate 148 from above was coupled with 2-(3-fluorophenyl)ethanamine following procedure F. The product was deprotected by procedure G2. LC-MS showed the product had the expected M+H+ of 407. 1H NMR (Varian 300 MHz, DMSO-d6, shifts relative to the solvent peak at 2.49 ppm) δ 9.4 (s, 1H) 9.0 (m, 2H) 8.5 (d, 1H) 7.4 (s, 1H), 7.2 (t, 1H), 7.1 (m, 2H), 6.9 (d, 1H), 3.71-3.65 (m, 4H) 3.57 (d, 2H), 3.47-3.44 (m, 1H), 3.39-3.31 (m, 4H), 2.9 (t, 2H), 1.6 (d, 3H).
Reaction SMILES: [CH3:1][N:2]([C@H:21]([CH3:26])[C:22]([O:24][CH3:25])=[O:23])[C:3](=[O:20])[CH:4]([C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=1)[CH2:5][C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7].[F:27][C:28]([F:42])([F:41])[C:29]1[CH:30]=[C:31]([CH:34]=[C:35]([C:37]([F:40])([F:39])[F:38])[CH:36]=1)[CH2:32]Br.C([O-])([O-])=O.[K+].[K+].CCOC(C)=O>CN(C=O)C>[CH3:1][N:2]([C@H:21]([CH3:26])[C:22]([O:24][CH3:25])=[O:23])[C:3](=[O:20])[CH:4]([C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:32][C:31]2[CH:34]=[C:35]([C:37]([F:39])([F:40])[F:38])[CH:36]=[C:29]([C:28]([F:27])([F:41])[F:42])[CH:30]=2)=[CH:15][CH:14]=1)[CH2:5][C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7]
Reactant: FC(F)(F)c1cc(CBr)cc(C(F)(F)F)c1
Reactant: COC(=O)[C@@H](C)N(C)C(=O)C(CC(=O)OC(C)(C)C)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)[C@@H](C)N(C)C(=O)C(CC(=O)OC(C)(C)C)c1ccc(OCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)cc1
Temperature: 25 °C
Yield: 60.2 %

Procedure:
A solution of methyl 2-UN-methyl-N-((R/S)-α-t-butoxycarbonylmethyl-4-hydroxyphenylacetyl)amino]-(R)-propionate 48d (1.5 g, 4.1 mmol) and 3,5-bistrifluoromethylbenzyl bromide (1.3 g, 4.2 mmol) in DMF (10 mL) was stirred at 60° C. overnight in the presence of K2CO3 (1.14 g, 8 mmol). After cooling to room temperature, EtOAc was added and the solution was washed with brine three times, dried over MgSO4, and concentrated. Purification on a silica gel column by eluting with 40% EtOAc/hexane afforded the product (1.46 g, 60%) as a solid. MS (CI—NH3): (M+H)+=592.
Reaction SMILES: [Mg].[CH3:2]I.CN(OC)[C:6]([C:8]1[C:16]2[S:15][N:14]=[N:13][C:12]=2[CH:11]=[CH:10][CH:9]=1)=[O:7].Cl>C(OCC)C.BrBr.O1CCCC1>[C:6]([C:8]1[C:16]2[S:15][N:14]=[N:13][C:12]=2[CH:11]=[CH:10][CH:9]=1)(=[O:7])[CH3:2]
Reactant: CON(C)C(=O)c1cccc2nnsc12
Reactant: CI
Agent: BrBr
Agent: Cl
Agent: [Mg]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(=O)c1cccc2nnsc12
Temperature: 75 °C
Reaction time: 1.5 h

Procedure:
0.59 g of magnesium turnings in 3 ml of diethyl ether are activated with 1 drop of bromine, and a solution of 1.5 ml of methyl iodide in 5.5 ml of diethyl ether is added dropwise with stirring. When the exothermic reaction has subsided, the mixture is heated and kept for a further 1.5 hours at bath temperature 55° C. The resulting solution is added dropwise under a nitrogen atmosphere and with stirring at -10° C. to the initially introduced solution of 4.9 g of N-methyl-N-methoxybenzo-1,2,3-thiadiazole-7-carboxamide in 150 ml of absolute tetrahydrofuran. After stirring has been continued for 1 hour at -10° C., the mixture is heated and refluxed at bath temperature 75° C. for 6 hours. The reaction mixture is then cooled, poured into ice-water, acidified with 2N hydrochloric acid and extracted several times using ethyl acetate. The extracts are washed with water, dried over sodium sulfate and evaporated. The residue is purified on silica gel (CHCl3), giving the title compound of m.p. 126°-127° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]1[C:10](=[CH:12][CH:13]=[CH:14][CH:15]=1)[NH2:11].[CH:16](OCC)(OCC)OCC.[CH2:26]([C:28]1([CH:33]([NH2:36])[CH2:34][CH3:35])OCCO1)[CH3:27]>[Ti](Cl)(Cl)(Cl)Cl>[CH2:34]([C:33]1[N:36]=[CH:16][N:11]([C:10]2[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=2[CH2:8][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[F:1])[C:28]=1[CH2:26][CH3:27])[CH3:35]
Reactant: CCOC(OCC)OCC
Reactant: Nc1ccccc1Cc1ccccc1F
Reactant: CCC(N)C1(CC)OCCO1
Agent: Cl[Ti](Cl)(Cl)Cl
Product: CCc1ncn(-c2ccccc2Cc2ccccc2F)c1CC

Procedure:
In the manner given in Example 3, α-(0-fluorophenyl)-0-toluidine is reacted with triethyl orthoformate, the resulting oil is heated with 2-ethyl-2-(1-aminopropyl)-1,3-dioxolane, and the resulting product treated with titanium tetrachloride to give 4,5-diethyl-1-[α-(0-fluorophenyl)-0-tolyl]imidazole.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([N:14]([CH3:19])[S:15]([CH3:18])(=[O:17])=[O:16])[CH:13]=1)[C:8](O)=[O:9])=[O:4].B.C1COCC1.C(O)(=O)C.O>C1COCC1>[OH:9][CH2:8][C:7]1[CH:6]=[C:5]([CH:13]=[C:12]([N:14]([CH3:19])[S:15]([CH3:18])(=[O:17])=[O:16])[CH:11]=1)[C:3]([O:2][CH3:1])=[O:4]
Reactant: COC(=O)c1cc(C(=O)O)cc(N(C)S(C)(=O)=O)c1
Agent: B
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: O
Product: COC(=O)c1cc(CO)cc(N(C)S(C)(=O)=O)c1
Temperature: 75 °C
Reaction time: 3 h
Yield: 85.8 %

Procedure:
To a stirring solution of 234 mg of 3-(methoxycarbonyl)-5-(N-methylmethylsulfonamido)benzoic acid in 10 mL of THF at r.t. was added 1.2 mL of BH3.THF (1.0 M in THF). After the solution was stirred at 75° C. for 3 h, 3 mL of acetic acid:H2O (1:1) was added and stirring was continued until bubbling ceased. Saturated NaHCO3 solution was added to a pH=7, and the solution was concentrated. Water was added, and the aqueous layer was extracted with EtOAc (2×). The combined extracts were washed with water and brine, dried over Na2SO4, filtered, and concentrated. Purification by flash silica gel chromatography (1.5% MeOH/CHCl3) provided 191 mg of methyl 3-(hydroxymethyl)-5-(N-methylmethylsulfonamido)benzoate as a pale yellow oil in 86% yield.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH2:9])[C:5]([NH2:8])=[CH:6][CH:7]=1.[C:10]([O:14][C:15]([N:17]1[CH2:22][CH2:21][CH:20]([C:23](O)=O)[CH2:19][CH2:18]1)=[O:16])([CH3:13])([CH3:12])[CH3:11].P(OC1C=CC=CC=1)(OC1C=CC=CC=1)OC1C=CC=CC=1>N1C=CC=CC=1.CCOC(C)=O>[C:10]([O:14][C:15]([N:17]1[CH2:22][CH2:21][CH:20]([C:23]2[NH:8][C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][C:4]=3[N:9]=2)[CH2:19][CH2:18]1)=[O:16])([CH3:13])([CH3:11])[CH3:12]
Reactant: Nc1ccc(F)cc1N
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Agent: c1ccc(OP(Oc2ccccc2)Oc2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N1CCC(c2nc3cc(F)ccc3[nH]2)CC1
Temperature: 25 °C
Yield: 32 %

Procedure:
This compound is synthesized as described by adaptation of the following reference: Lin et al, Tetrahedron Lett., 2006, 47, 17, 2883. To a stirred mixture of 4-fluorobenzene-1,2-diamine (1.0 g, 7.93 mmol) and 1-[(tert-butoxy)carbonyl]piperidine-4-carboxylic acid (1.82 g, 7.93 mmol) in pyridine (4 mL) is added triphenyl phosphite (2.49 mL, 9.51 mmol). The reaction mixture is heated under reflux for 18 h. The reaction mixture is cooled to room temperature and diluted with EtOAc (40 mL). The solution is washed with 1M aqueous HCl (8 mL) followed by saturated aqueous NaHCO3 (8 mL) and water (5 mL) to give an oily residue. The crude product is purified by column chromatography (Isolute column, eluent: DCM, 3% MeOH) to afford 0.81 g of tert-butyl-4-(5-fluoro-1H-1,3-benzodiazol-2-yl)piperidine-1-carboxylate.
Reaction SMILES: [C:1]([O:4][C:5]1[C:6]([CH3:37])=[C:7]2[C:12](=[C:13]([CH3:16])[C:14]=1[CH3:15])[O:11][C:10]([CH2:27][O:28][C:29]1[CH:34]=[CH:33][C:32](N)=[CH:31][CH:30]=1)([CH2:17][CH2:18][CH:19]([CH3:26])[CH2:20][CH2:21][CH2:22][CH:23]([CH3:25])[CH3:24])[CH2:9][C:8]2=[O:36])(=[O:3])[CH3:2].N([O-])=O.[Na+].[ClH:42].[C:43]([O:47][CH2:48][CH3:49])(=[O:46])[CH:44]=[CH2:45]>>[C:1]([O:4][C:5]1[C:6]([CH3:37])=[C:7]2[C:12](=[C:13]([CH3:16])[C:14]=1[CH3:15])[O:11][C:10]([CH2:27][O:28][C:29]1[CH:34]=[CH:33][C:32]([CH2:45][CH:44]([Cl:42])[C:43]([O:47][CH2:48][CH3:49])=[O:46])=[CH:31][CH:30]=1)([CH2:17][CH2:18][CH:19]([CH3:26])[CH2:20][CH2:21][CH2:22][CH:23]([CH3:25])[CH3:24])[CH2:9][C:8]2=[O:36])(=[O:3])[CH3:2]
Reactant: C=CC(=O)OCC
Reactant: CC(=O)Oc1c(C)c(C)c2c(c1C)C(=O)CC(CCC(C)CCCC(C)C)(COc1ccc(N)cc1)O2
Reactant: Cl
Agent: O=N[O-]
Agent: [Na+]
Product: CCOC(=O)C(Cl)Cc1ccc(OCC2(CCC(C)CCCC(C)C)CC(=O)c3c(C)c(OC(C)=O)c(C)c(C)c3O2)cc1

Procedure:
Following the same procedure as described in Preparation 18, 1.6 g of 6-acetoxy-2-(4-aminophenoxymethyl)-2-(3,7-dimethyloctyl)-5,7,8-trimethylchroman-4-one (prepared as described in Preparation 32), 0.28 g of sodium nitrite, 1.7 ml of concentrated hydrochloric acid, 3.3 ml of ethyl acrylate and 0.1 g of cuprous oxide were reacted, to give the title compound.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]=O.Cl.[NH2:10][OH:11].[OH-].[Na+].Cl>C(O)C.O>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1/[CH:7]=[N:10]\[OH:11]
Reactant: O=Cc1ccccn1
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O/N=C\c1ccccn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 78.1 %

Procedure:
To a suspension of 2-pyridinecarboxaldehyde (53.6 g, 500 mmol) and hydroxylamine hydrochloride (38.2 g, 544 mmol) in ethanol (36 mL) and water (69 mL) was added ice (205 g). Then an aqueous solution of sodium hydroxide (32%, 115 mL, 1.24 mol) was added dropwise within a 10 min period (temperature rises from −8° C. to +7° C.) whereupon most of the solid dissolves. After 1 h stirring at room temperature the resulting mixture was then acidified with HCl (5 N). The mixture was then extracted with dichloromethane to afford the title compound (47.7 g, 78%) which was obtained as an off white solid. MS: m/e=123.3 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH2:10])[CH3:9])=[CH:4][CH:3]=1.[CH:11](=O)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[H][H]>[Pd].CO>[CH2:11]([NH:10][CH:8]([C:5]1[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=1)[CH3:9])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=Cc1ccccc1
Reactant: Cc1ccc(C(C)N)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: Cc1ccc(C(C)NCc2ccccc2)cc1
Reaction time: 6 h

Procedure:
100 ml of methanol and 100 mmol of 4-methyl-1-phenylethylamine are initially taken, and 100 mmol of benzaldehyde are added dropwise at 24° C. in the course of 15 minutes. Stirring is effected for 6 hours at 24° C., the completeness of the iminization is checked by GC, 0.5 g of Pd/C (10% by weight) is added and the crude mixture is hydrogenated with hydrogen for 5 hours at atmospheric pressure. A sample is taken and the composition is investigated by GC analysis.
Reaction SMILES: [NH2:1][C:2]([O:4][CH2:5][C@H:6]1[O:10][CH2:9][C@@H:8]([S:11]C(=O)C)[CH2:7]1)=[O:3].C[O-].[Na+].CO.Cl.C(O)(C)C>O1CCCC1>[C:2]([O:4][CH2:5][C@H:6]1[CH2:7][C@@H:8]([SH:11])[CH2:9][O:10]1)(=[O:3])[NH2:1]
Reactant: CC(=O)S[C@@H]1CO[C@H](COC(N)=O)C1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(C)O
Solvent: C1CCOC1
Solvent: CO
Product: NC(=O)OC[C@H]1C[C@@H](S)CO1
Reaction time: 0.33 h

Procedure:
Under anhydrous conditions, 0.109 g of product from Example 10 dissolved in 1.75 ml of tetrahydrofuran, cooled in an ice bath, is treated, via syringe, with 120 microliter of sodium methoxide/methanol (25 wt % in methanol). The progress of the reaction is monitored by thin layer chromatography. After 20 minutes, 280 microliter of 1.86N hydrochloric acid/isopropyl alcohol is added and the reaction is stirred for 5 minutes. The reaction is concentrated in vacuo to give the desired product as a white solid which is used as is in the following reaction.