Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH:4]1[CH:8]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:7]([C:15](=[O:31])[CH2:16][NH:17][C:18]([NH:20][C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([O:29]C)=[O:28])[CH:22]=2)=[O:19])[CH:6]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:5]1)(=[O:3])[CH3:2].O.CO>[OH-].[K+]>[C:1]([CH:4]1[CH:8]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:7]([C:15](=[O:31])[CH2:16][NH:17][C:18](=[O:19])[NH:20][C:21]2[CH:22]=[C:23]([CH:24]=[CH:25][CH:26]=2)[C:27]([OH:29])=[O:28])[CH:6]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:5]1)(=[O:3])[CH3:2]
Reactant: COC(=O)c1cccc(NC(=O)NCC(=O)N2C(C(=O)OC(C)(C)C)CC(C(C)=O)C2c2ccccc2)c1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(=O)C1CC(C(=O)OC(C)(C)C)N(C(=O)CNC(=O)Nc2cccc(C(=O)O)c2)C1c1ccccc1
Yield: 23.5 %

Procedure:
A The reaction is carried out in a way analogous to that described in Example 3, but from 2.62 g of tert-butyl (2RS,4RS,5SR)-4-acetyl-1-{2-[3-(3-(methoxycarbonyl)phenyl)ureido]acetyl}-5-phenylpyrrolidine-2-carboxylate in a mixture of 5 cm3 of a normal aqueous potassium hydroxide solution, 25 cm3 of distilled water and 100 cm3 of methanol. After treatment, there is obtained 0.6 g of (2RS,4SR,5SR)-3-{3-[2-(4-acetyl-2-tert-butoxycarbonyl-5-phenyl-1-pyrrolidinyl)-2-oxoethyl]ureido}benzoic acid, melting at 145° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14](=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21]Cl)[CH:16]=1.[Cl:24][C:25]1[CH:26]=[C:27](B(O)O)[CH:28]=[CH:29][CH:30]=1.C(=O)([O-])[O-].[Na+].[Na+].[I-].[Na+]>C(COC)OC.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>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14](=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][C:29]2[CH:28]=[CH:27][CH:26]=[C:25]([Cl:24])[CH:30]=2)[CH:16]=1
Reactant: OB(O)c1cccc(Cl)c1
Reactant: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1cccc(CCl)c1
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: [I-]
Solvent: O
Solvent: COCCOC
Product: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1cccc(Cc2cccc(Cl)c2)c1
Yield: 47.8 %

Procedure:
N-(2-(5-Chloro-1H-indol-3-yl)ethyl)-3-(3-chlorobenzyl)benzamide was prepared according to method B with N-(2-(5-chloro-1H-indol-3-yl)ethyl)-3-(chloromethyl)benzamide (0.060 g; 0.173 mmol), 3-chlorophenylboronic acid (0.028 g; 0.181 mmol), tetrakis(triphenylphosphine)palladium(0) (0.010 g; 0.009 mmol), sodium carbonate (0.037 g; 0.345 mmol), sodium iodide (0.052 g; 0.345 mmol), in dimethoxyethane (3 mL) and water (1 mL), heated in a sealed tube at 130° C. for 18 hours. Flash chromatography on silica gel (eluent 1 to 10% ethyl acetate in dichloromethane) furnished 0.035 g (47%) of the title compound as a white solid.
Reaction SMILES: [C:1]([Si:5]([CH3:44])([CH3:43])[N:6]1[C:10]2=[N:11][CH:12]=[CH:13][C:14]([CH:15]([OH:42])[C:16]3[C:21]([N:22]([CH2:37][O:38][CH3:39])[S:23]([C:26]4[CH:31]=[CH:30][C:29]([Cl:32])=[C:28]([C:33]([F:36])([F:35])[F:34])[CH:27]=4)(=[O:25])=[O:24])=[CH:20][C:19]([Cl:40])=[C:18]([CH3:41])[N:17]=3)=[C:9]2[CH:8]=[CH:7]1)([CH3:4])([CH3:3])[CH3:2].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[C:1]([Si:5]([CH3:44])([CH3:43])[N:6]1[C:10]2[N:11]=[CH:12][CH:13]=[C:14]([C:15]([C:16]3[C:21]([N:22]([CH2:37][O:38][CH3:39])[S:23]([C:26]4[CH:31]=[CH:30][C:29]([Cl:32])=[C:28]([C:33]([F:36])([F:34])[F:35])[CH:27]=4)(=[O:25])=[O:24])=[CH:20][C:19]([Cl:40])=[C:18]([CH3:41])[N:17]=3)=[O:42])[C:9]=2[CH:8]=[CH:7]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COCN(c1cc(Cl)c(C)nc1C(O)c1ccnc2c1ccn2[Si](C)(C)C(C)(C)C)S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: COCN(c1cc(Cl)c(C)nc1C(=O)c1ccnc2c1ccn2[Si](C)(C)C(C)(C)C)S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of N-(2-{[1-(tert-Butyl-dimethyl-silanyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]-hydroxy-methyl}-5-chloro-6-methyl-pyridin-3-yl)-4-chloro-N-methoxymethyl-3-trifluoromethylbenzenesulfonamide (from above step), Dess-Martin periodinane (424 mg, 1.0 mmol) in 3 ml of DCM was stirred at room temperature for overnight. The mixture was directly purified by flash chromatography (25% ethyl acetate in hexane) to afford the desired title compound. MS (ES) (M++H) expect 687. found 686.9
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:4]=[C:5]([CH:20]=[CH:21][CH:22]=1)[CH2:6][N:7]1[CH2:11][CH2:10][C@H:9]([NH:12]C(=O)OC(C)(C)C)[CH2:8]1.[ClH:25].O1CCOCC1>CO>[ClH:25].[F:23][C:2]([F:1])([F:24])[C:3]1[CH:4]=[C:5]([CH:20]=[CH:21][CH:22]=1)[CH2:6][N:7]1[CH2:11][CH2:10][C@H:9]([NH2:12])[CH2:8]1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCN(Cc2cccc(C(F)(F)F)c2)C1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: N[C@H]1CCN(Cc2cccc(C(F)(F)F)c2)C1

Procedure:
A solution of product from Example 185A (0.32 g, 0.9 mmol) in methanol (10 mL) was treated with 4 N HCl/dioxane (2 mL) for 2 hours at room temperature. The reaction mixture was concentrated to yield the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 7.60 (m, 3H), 6.99 (m, 1H), 3.93 (m, 1H), 3.64 (dd, 2H), 2.69 (m, 1H), 2.45 (m, 2H), 2.26 (m, 1H), 1.99 (m, 1H), 1.60 (m, 1H); MS (ESI+) m/z 244 (M+H)+.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]([C:16](=[O:40])[NH:17][CH:18]1[CH2:23][CH2:22][CH2:21][CH:20]([N:24]2[C:33]3[CH:32]=[CH:31][CH:30]=[C:29]([Cl:34])[C:28]=3[C:27]3=[N:35][O:36][C:37]([CH3:38])=[C:26]3[C:25]2=[O:39])[CH2:19]1)[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)(C)(C)C>Cl>[NH2:7][CH:8]([CH2:9][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[C:16]([NH:17][CH:18]1[CH2:23][CH2:22][CH2:21][CH:20]([N:24]2[C:33]3[CH:32]=[CH:31][CH:30]=[C:29]([Cl:34])[C:28]=3[C:27]3=[N:35][O:36][C:37]([CH3:38])=[C:26]3[C:25]2=[O:39])[CH2:19]1)=[O:40]
Reactant: Cc1onc2c1c(=O)n(C1CCCC(NC(=O)C(Cc3ccccc3)NC(=O)OC(C)(C)C)C1)c1cccc(Cl)c21
Agent: Cl
Product: Cc1onc2c1c(=O)n(C1CCCC(NC(=O)C(N)Cc3ccccc3)C1)c1cccc(Cl)c21

Procedure:
A solution of {1-[3-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)-cyclohexylcarbamoyl]-2-phenyl-ethyl}-carbamic acid tert-butyl ester, 82 mg (0.14 mmol) in 15 mL of HCl-saturated acetic acid was stirred three hours at rt., then concentrated to dryness. The residue was slurried 3× in acetonitrile and concentrated to dryness to give a quantitative yield of the title compound as a tan foam. MS (ion spray) 479.2. (M+).
Reaction SMILES: Br[C:2]1[N:6]2[CH:7]=[CH:8][C:9]([C:11]([OH:14])([CH3:13])[CH3:12])=[N:10][C:5]2=[N:4][CH:3]=1.[F:15][C:16]1[C:21]([C:22]2[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=2)=[CH:20][CH:19]=[CH:18][C:17]=1B(O)O>>[F:15][C:16]1[C:21]([C:22]2[CH:23]=[CH:24][N:25]=[CH:26][CH:27]=2)=[CH:20][CH:19]=[CH:18][C:17]=1[C:2]1[N:6]2[CH:7]=[CH:8][C:9]([C:11]([OH:14])([CH3:13])[CH3:12])=[N:10][C:5]2=[N:4][CH:3]=1
Reactant: CC(C)(O)c1ccn2c(Br)cnc2n1
Reactant: OB(O)c1cccc(-c2ccncc2)c1F
Product: CC(C)(O)c1ccn2c(-c3cccc(-c4ccncc4)c3F)cnc2n1

Procedure:
2-(3-Bromoimidazo[1,2-α]pyrimidin-7-yl)propan-2-ol was coupled with 2-fluoro-3-(pyridin-4-yl)benzeneboronic acid as described in Example 1 to give 2-[3-(2-fluoro-3-(pyridin-4-yl)phenyl)imidazo[1,2-α]pyrimidin-7-yl]propan-2-ol as a white solid. Bis-hydrochloride salt (from ethyl acetate/ethanol): δH (360 MHz, DMSO) 1.56 (6H, s), 7.69 (1H, dd, J 8 and 8), 7.84-7.92 (2H, m), 7.99-8.04 (1H, m), 8.21 (2H, d, J 6), 8.53 (1H, s), 8.98 (2H, d, J 6),9.30 (1H, dd, J 7 and 3); m/z (ES+) 349 (M++H).
Reaction SMILES: O[Li].O.C([O:7][C:8]1[C:13]([CH3:14])=[C:12]([C:15]2[O:16][C:17]3[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=3[CH:19]=2)[O:11][C:10](=[O:24])[C:9]=1[CH3:25])(=O)C>CO>[O:16]1[C:17]2[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=2[CH:19]=[C:15]1[C:12]1[O:11][C:10](=[O:24])[C:9]([CH3:25])=[C:8]([OH:7])[C:13]=1[CH3:14]
Reactant: CC(=O)Oc1c(C)c(-c2cc3ccccc3o2)oc(=O)c1C
Agent: [Li]O
Solvent: CO
Solvent: O
Product: Cc1c(-c2cc3ccccc3o2)oc(=O)c(C)c1O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
An aqueous solution (30 ml) of LiOH-hydrate (465 mg) was added to a solution of 4-acetyloxy-6-(benzofuran-2-yl)-3,5-dimethyl-2H-pyran-2-one (3.00 g) in MeOH (100 ml) at 0° C., and after stirring at room temperature for 2 hours, the MeOH was distilled off under reduced pressure. The residue was rinsed with Et2O, and then a KHSO4 aqueous solution was added at 0° C. for adjustment to pH 2.0. The precipitated crystals were filtered off and thoroughly rinsed with water and Et2O in that order and then dried to obtain 6-(benzofuran-2-yl)-3,5-dimethyl-4-hydroxy-2H-pyran-2-one.
Reaction SMILES: S(Cl)(Cl)=O.[Cl:5][C:6]1[C:7]([CH2:53][C:54]2[CH:59]=[CH:58][C:57]([O:60][CH2:61][CH3:62])=[CH:56][CH:55]=2)=[CH:8][C:9]([C@H:14]2[C@H:19]([O:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C@@H:18]([O:28][CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C@H:17]([O:36][CH2:37][C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[C@@H:16]([CH2:44][O:45][CH2:46][C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=3)[O:15]2)=[C:10](CO)[CH:11]=1.[CH2:63]([Cl:65])Cl>>[CH2:37]([O:36][C@H:17]1[C@H:18]([O:28][CH2:29][C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[C@@H:19]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C@H:14]([C:9]2[CH:8]=[C:7]([CH2:53][C:54]3[CH:55]=[CH:56][C:57]([O:60][CH2:61][CH3:62])=[CH:58][CH:59]=3)[C:6]([Cl:5])=[CH:11][C:10]=2[CH2:63][Cl:65])[O:15][C@@H:16]1[CH2:44][O:45][CH2:46][C:47]1[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=1)[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: CCOc1ccc(Cc2cc([C@@H]3O[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)c(CO)cc2Cl)cc1
Reactant: ClCCl
Solvent: O=S(Cl)Cl
Product: CCOc1ccc(Cc2cc([C@@H]3O[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)c(CCl)cc2Cl)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Thionyl chloride (0.1 mL) was added dropwise into a solution of (5-chloro-4-(4-ethoxybenzyl)-2-((2S,3S,4R,5R,6R)-3,4,5-tris(benzyloxy)-6-(benzyloxymethyl)tetrahydro-2H-pyran-2-yl)phenyl)methanol (100 mg, 0.13 mmol) in methylene chloride (2 mL) at 0° C., and the mixture was allowed to stir for 2 hours at RT. The reaction mixture was evaporated to dryness, and the residual oil was used for the next step without further purification.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](Cl)[C:5]([S:9]([NH:12][C:13]([CH3:16])([CH3:15])[CH3:14])(=[O:11])=[O:10])=[CH:4][N:3]=1.[NH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH3:24])[CH:19]=1>COC>[NH2:1][C:2]1[N:7]=[C:6]([NH:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([CH3:24])[CH:19]=2)[C:5]([S:9]([NH:12][C:13]([CH3:16])([CH3:15])[CH3:14])(=[O:11])=[O:10])=[CH:4][N:3]=1
Reactant: Cc1cccc(N)c1
Reactant: CC(C)(C)NS(=O)(=O)c1cnc(N)nc1Cl
Agent: COC
Product: Cc1cccc(Nc2nc(N)ncc2S(=O)(=O)NC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 62.6 %

Procedure:
To a suspension of 2-amino-4-chloro-N-(1,1-dimethylethyl)-5-pyrimidinesulfonamide (2.64 g, 10 mmol) in 7 mL dimethylether was added meta-toluidine (2.46 g, 23 mmol) and the reaction stirred at room temperature for 1 hour and then at 60° C. for 1/2 hour. The solvent was removed and the residue taken up in ethyl acetate. The ethyl acetate was washed with water, saline, dried, and the solvent removed in vacuo. The residue was triturated with ether and the crystals collected by suction filtration and dried to give 2.10 g of the identical product obtained in Step 1.
Reaction SMILES: [CH:1]1([C:6]2[CH:11]=[C:10]([C:12]3[O:16][N:15]=[C:14]([C:17]4[CH:22]=[C:21]([CH3:23])[C:20]([OH:24])=[C:19]([CH2:25][CH3:26])[CH:18]=4)[N:13]=3)[CH:9]=[C:8]([O:27][CH3:28])[N:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[CH2:30][C@H:31]([OH:34])[CH2:32][OH:33]>C(O)(C)C.[OH-].[Na+].CC(=O)OCC>[CH:1]1([C:6]2[CH:11]=[C:10]([C:12]3[O:16][N:15]=[C:14]([C:17]4[CH:22]=[C:21]([CH3:23])[C:20]([O:24][CH2:30][C@H:31]([OH:34])[CH2:32][OH:33])=[C:19]([CH2:25][CH3:26])[CH:18]=4)[N:13]=3)[CH:9]=[C:8]([O:27][CH3:28])[N:7]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: OC[C@@H](O)CCl
Reactant: CCc1cc(-c2noc(-c3cc(OC)nc(C4CCCC4)c3)n2)cc(C)c1O
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CC(C)O
Product: CCc1cc(-c2noc(-c3cc(OC)nc(C4CCCC4)c3)n2)cc(C)c1OC[C@H](O)CO
Temperature: 60 °C
Reaction time: 15 h
Yield: 99.4 %

Procedure:
A mixture of 4-[5-(2-cyclopentyl-6-methoxy-pyridin-4-yl)-[1,2,4]oxadiazol-3-yl]-2-ethyl-6-methyl-phenol (250 mg, 659 μmol), (R)-3-chloro-1,2-propanediol (609 mg, 6.59 mmol) in isopropanol (8 mL) and 3 M aq. NaOH (2 mL) is stirred at 60° C. for 15 h. The mixture is diluted with EA and washed with brine, 1 M aq. NaOH and again with brine. The org. extract is dried over Na2SO4, filtered and concentrated. The crude product is purified on prep. TLC plates using DCM containing 10% of methanol to give the title compound (297 mg) as a pale yellow oil; LC-MS**: tR=0.87 min, [M+H]+=454.26.
Reaction SMILES: [CH:1]([OH:3])=O.C(OC(=O)C)(=O)C.[Br:11][C:12]1[N:17]=[C:16]([O:18][CH3:19])[C:15]([NH2:20])=[CH:14][CH:13]=1>CCCCCC>[Br:11][C:12]1[N:17]=[C:16]([O:18][CH3:19])[C:15]([NH:20][CH:1]=[O:3])=[CH:14][CH:13]=1
Reactant: O=CO
Reactant: COc1nc(Br)ccc1N
Solvent: CC(=O)OC(C)=O
Solvent: CCCCCC
Product: COc1nc(Br)ccc1NC=O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To formic acid (12 mL) was added acetic anhydride (12 mL) at 0° C., and the mixture was stirred at 0° C. for 30 min. 6-Bromo-2-methoxypyridin-3-amine (8.8 g) was gradually added to the reaction mixture at 0° C. over 10 min, and the mixture was stirred at 0° C. for 30 min. IPE (50 mL) and hexane (50 mL) were added to the reaction mixture, and the mixture was stirred at room temperature for 30 min. The obtained solid was collected by filtration to give the title compound (8.1 g).
Reaction SMILES: [I-:1].[Na+].Cl/[CH:4]=[CH:5]/[C:6](=[O:12])[CH2:7][CH2:8][CH2:9][CH2:10][CH3:11]>CC(C)=O>[I:1]/[CH:4]=[CH:5]/[C:6](=[O:12])[CH2:7][CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: [I-]
Reactant: CCCCCC(=O)/C=C/Cl
Agent: [Na+]
Solvent: CC(C)=O
Product: CCCCCC(=O)/C=C/I

Procedure:
A mixture of 54.5 g. (0.364 mole) of sodium iodide and 40 g. (0.249 mole) of 1-chloro-trans-1-octen 3-one (Example 723) in 360 ml. of acetone is stirred and refluxed for 24 hours. The reaction mixture is cooled, filtered and concentrated. The residue is partitioned between water and ether. The organic phase is washed with dilute sodium bicarbonate solution, brine, dried (MgSO4) and evaporated to an oil. This material is used directly without purification.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[F:11])[C:7](=[O:12])[NH:6][C:5]2=[O:13].[BH4-].[Na+].Cl>C(O)C>[F:11][C:10]1[CH:9]=[C:8]2[C:4](=[CH:3][C:2]=1[F:1])[C:5](=[O:13])[NH:6][CH:7]2[OH:12]
Reactant: O=C1NC(=O)c2cc(F)c(F)cc21
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: O=C1NC(O)c2cc(F)c(F)cc21
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
740 mg (4.04 mmol) of 5,6-difluoro-1H-isoindole-1,3(2H)-dione were dissolved in 6.6 ml of ethanol, the mixture was cooled to 0° C. and 76.4 mg (2.02 mmol) of sodium borohydride were added a little at a time. After the addition had ended, the reaction mixture was slowly warmed to RT and stirred at RT for another 30 min before the reaction mixture was adjusted to neutral with 1 N hydrochloric acid. The mixture was concentrated to dryness under reduced pressure, and the residue was dried further under high vacuum. This gave 800.8 mg of crude product which was used without further purification for the next reaction.
Reaction SMILES: C([NH:4][CH2:5][C:6]([NH:12][C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])([CH3:11])[C:7]([O:9][CH3:10])=[O:8])C=C>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.C(Cl)Cl>[NH2:4][CH2:5][C:6]([NH:12][C:13]([O:15][CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)=[O:14])([CH3:11])[C:7]([O:9][CH3:10])=[O:8]
Reactant: C=CCNCC(C)(NC(=O)OCc1ccccc1)C(=O)OC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COC(=O)C(C)(CN)NC(=O)OCc1ccccc1
Yield: 83.9 %

Procedure:
A solution of 0.22 g (1.42 mmol) of N,N-dimethylbarbituric acid, 0.02 g (0.017 mmol) of Pd(PPh3)4, 1.5 ml of DCM and 0.145 g (0.47 mmol) of methyl 3-allylamino-2-benzyloxycarbonylamino-2-methylpropionate is heated at 35° C. for 2 h. The reaction solution is subsequently concentrated in vacuo, and then 20 ml of diethyl ether are added, and the solution is washed 3 times with 20 ml of saturated Na2CO3 each time. A pH of 2 is adjusted by dropwise addition of 4N HCl. The aqueous phase is separated off and extracted with 2 ml of EtOAc, and the solvent is removed in vacuo. 0.105 g of the desired product are obtained. MW (calculated, monoisotopic)=266, measured value: (M+H)+ 267.
Reaction SMILES: Cl[C:2]1[C:7](=[O:8])[N:6]([CH3:9])[CH:5]=[C:4]2[CH2:10][N:11]([CH2:14][CH2:15][C:16]3[CH:25]=[CH:24][C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[N:17]=3)[C:12](=[O:13])[C:3]=12.[NH:26]1[CH:30]=[C:29](B(O)O)[CH:28]=[N:27]1>>[CH3:9][N:6]1[C:7](=[O:8])[C:2]([C:29]2[CH:30]=[N:26][NH:27][CH:28]=2)=[C:3]2[C:12](=[O:13])[N:11]([CH2:14][CH2:15][C:16]3[CH:25]=[CH:24][C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[N:17]=3)[CH2:10][C:4]2=[CH:5]1
Reactant: OB(O)c1cn[nH]c1
Reactant: Cn1cc2c(c(Cl)c1=O)C(=O)N(CCc1ccc3ccccc3n1)C2
Product: Cn1cc2c(c(-c3cn[nH]c3)c1=O)C(=O)N(CCc1ccc3ccccc3n1)C2

Procedure:
The title compound was prepared in analogy to the process of Example 13 starting from 7-chloro-5-methyl-2-(2-quinolin-2-yl-ethyl)-3,5-dihydro-2H-pyrrolo[3,4-c]pyridine-1,6-dione (see Example c4)) and 1H-pyrazol-4-ylboronic acid.
Reaction SMILES: [Si]([N:8]1[CH:12]=[CH:11][N:10]=[CH:9]1)(C(C)(C)C)(C)C.C([Li])CCC.[CH2:18]([N:21]([CH2:35][CH2:36][CH3:37])[C:22]([C:24]1[CH:25]=[C:26]([CH:31]=[C:32](I)[CH:33]=1)[C:27]([O:29][CH3:30])=[O:28])=[O:23])[CH2:19][CH3:20]>O1CCCC1.C(OCC)(=O)C.[Cl-].[Zn+2].[Cl-]>[CH2:35]([N:21]([CH2:18][CH2:19][CH3:20])[C:22]([C:24]1[CH:25]=[C:26]([CH:31]=[C:32]([C:9]2[NH:8][CH:12]=[CH:11][N:10]=2)[CH:33]=1)[C:27]([O:29][CH3:30])=[O:28])=[O:23])[CH2:36][CH3:37]
Reactant: CCCN(CCC)C(=O)c1cc(I)cc(C(=O)OC)c1
Reactant: CC(C)(C)[Si](C)(C)n1ccnc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [Zn+2]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCN(CCC)C(=O)c1cc(C(=O)OC)cc(-c2ncc[nH]2)c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a −70° C. stirred solution of 1-tert-butyldimethylsilylimidazole (602 mg, 3.3 mmol) in tetrahydrofuran (10 mL) is added n-butyllithium (1.6 M in hexanes, 2.3 mL, 3.63 mmol). After 30 min, zinc chloride (1 M in diethyl ether, 9.9 mL, 9.9 mmol) is added and the reaction mixture is warmed to 0° C. for 1 h. To this mixture is then added methyl 3-[(dipropylamino)carbonyl]-5-iodobenzoate prepared by the method in Example SP-281, step 2 (1.17 g, 3 mmol) followed by palladium(0)tetrakis(triphenylphosphine) (173 mg, 0.15 mmol). The reaction mixture is heated at reflux for 15 h. The reaction mixture is diluted with ethyl acetate (50 mL), washed with water, and brine, dried (sodium sulfate), filtered, and concentrated under reduced pressure. Purification by flash column chromatography (silica gel, 1-5% methanol/methylene chloride) provides the title compound in pure form. 1H NMR (300 MHz, CDCl3) δ 8.64 (s, 1H), 8.14 (s, 1H), 7.97 (s, 1H), 7.19 (s, 2H), 3.96 (s, 3H), 3.51 (m, 2H), 3.32 (m, 2H), 1.73 (m, 2H), 1.57 (m, 2H), 1.01 (m, 3H), 0.73 (m, 3H).
Reaction SMILES: Br[CH2:2][CH2:3][O:4][Si:5]([C:8]([CH3:11])([CH3:10])[CH3:9])([CH3:7])[CH3:6].[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][NH2:21])=[CH:16][CH:15]=1.C([O-])([O-])=O.[K+].[K+]>C(#N)C>[Si:5]([O:4][CH2:3][CH2:2][NH:21][CH2:20][C:17]1[CH:18]=[CH:19][C:14]([O:13][CH3:12])=[CH:15][CH:16]=1)([C:8]([CH3:11])([CH3:10])[CH3:9])([CH3:7])[CH3:6]
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Reactant: COc1ccc(CN)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1ccc(CNCCO[Si](C)(C)C(C)(C)C)cc1
Temperature: 80 °C
Reaction time: 16 h
Yield: 76.5 %

Procedure:
(2-bromoethoxy)(tert-butyl)dimethylsilane (20 g, 84 mmol) was added to a solution of (4-methoxyphenyl) methanamine (11.47 g, 84 mmol) in acetonitrile (200 mL) followed by K2CO3 (57.8 g, 418 mmol), and the mixture was stirred at 80° C. for 16 h. Insoluble solids were filtered off, filtrate was concentrated and partitioned between ethyl acetate and water. Organic layer was separated, washed with brine, dried over sodium sulphate and filtered. The filtrate was concentrated in vacuo and purified by flash chromatography using 30% ethyl acetate in hexane to afford title compound (19 g, 77%) as an oil. 1H NMR (300 MHz, DMSO-d6): δ 7.22 (d, J=8.4 Hz, 2H), 6.82 (d, J=8.7 Hz, 2H), 3.77 (s, 3H), 3.62 (m, 4H), 2.56 (t, J=5.7 Hz, 2H), 2.5 (m, 1H), 0.85 (s, 9H), 0.02 (s, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[C:8]([OH:10])=[O:9].[Si](C=[N+]=[N-])(C)(C)[CH3:12]>ClCCl.CO.CCOCC>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[C:8]([O:10][CH3:12])=[O:9]
Reactant: O=C(O)c1cnccc1Cl
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: ClCCl
Solvent: CO
Solvent: CCOCC
Product: COC(=O)c1cnccc1Cl
Temperature: 0 °C

Procedure:
To a suspension of 4-chloro-3-pyridinecarboxylic acid (3.630 g) in dichloromethane (20 mL) and methanol (8 mL) stirred under argon at 0° C. was added TMS-diazomethane 2M in Et2O (17.28 mL) dropwise. The reaction mixture was stirred at room temperature for 1 h. The solvents were evaporated in vacuo and the crude product was added to a silica gel column and was eluted with cyclohexane/EtOAc=7/3. The evaporation of the collected fractions gave 2.7 g of the title compound as a colourless solid.
Reaction SMILES: [CH3:1][NH:2][C@@H:3]([C:10]([CH3:13])([CH3:12])[CH3:11])[CH2:4][N:5]1[CH2:9][CH2:8][CH2:7][CH2:6]1.CN1CCOCC1.[Cl:21][C:22]1[CH:23]=[C:24]([CH:28]=[CH:29][C:30]=1[Cl:31])[C:25](Cl)=[O:26]>CN(C=O)C>[Cl:21][C:22]1[CH:23]=[C:24]([CH:28]=[CH:29][C:30]=1[Cl:31])[C:25]([N:2]([C@@H:3]([C:10]([CH3:13])([CH3:12])[CH3:11])[CH2:4][N:5]1[CH2:9][CH2:8][CH2:7][CH2:6]1)[CH3:1])=[O:26]
Reactant: O=C(Cl)c1ccc(Cl)c(Cl)c1
Reactant: CN[C@H](CN1CCCC1)C(C)(C)C
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CN(C(=O)c1ccc(Cl)c(Cl)c1)[C@H](CN1CCCC1)C(C)(C)C
Yield: 74.4 %

Procedure:
To a solution of (S)—N,3,3-trimethyl-1-(pyrrolidin-1-yl)butan-2-amine (Compound M1) (75 mg, 0.41 mmol) in DMF (1.5 mL) was NMM (0.049 mL, 0.45 mmol) and 3,4-dichlorobenzoyl chloride (0.074 mL, 0.53 mmol) added. The resultant mixture was stirred at rt overnight. The mixture was concentrated and the residue dissolved in DCM (5 mL). The organic phase was washed with NaHCO3 (saturated, 5 mL), filtered through a phase separator and concentrated under reduced pressure. The residue was purified by preparative HPLC to give the title compound (109 mg, 75%). Mixture of rotamers: 1H NMR (400 MHz, DMSO-d6) δ 0.97, 1.35-1.99, 2.07-2.43, 2.52-2.73, 2.93-3.18, 4.57, 6.86-7.18, 7.18-7.37, 7.37-7.61, 7.61-7.88. Total no of protons: 26. HRMS (M+H)+: calculated 357.1500. found 357.1470.