Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:8]2[CH:17]=[CH:16][C:11]3[NH:12][C:13](=[O:15])[O:14][C:10]=3[CH:9]=2)[CH2:6][CH2:5][C:4](=O)[CH2:3][CH2:2]1.[BH4-].[Na+].O.CCO[C:24]([CH3:26])=O>C1COCC1>[C:1]1([CH:24]([CH3:26])[CH2:10][CH2:11][NH:12][C@H:4]2[CH2:5][CH2:6][C@H:1]([C:8]3[CH:17]=[CH:16][C:11]4[NH:12][C:13](=[O:15])[O:14][C:10]=4[CH:9]=3)[CH2:2][CH2:3]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C1CCC(c2ccc3[nH]c(=O)oc3c2)CC1
Reactant: CCOC(C)=O
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(CCN[C@H]1CC[C@H](c2ccc3[nH]c(=O)oc3c2)CC1)c1ccccc1
Reaction time: 1 h

Procedure:
To a stirred solution of amine 14 (1.3 g, 6.2 mmol) in THF (75 mL) was added 5 (1.44 g, 6.22 mmol). The reaction mixture was stirred for 1 hour, NaBH4 (329 mg, 8.71 mmol) was added followed by water (30 mL). The reaction mixture was stirred for 45 minutes then diluted with EtOAc. The mixture was washed with 1N HCl and concentrated under reduced pressure. Purification by flash chromatography (silica, 95:5:1 CH2Cl2:MeOH:NH4OH) gave 6-[trans-4-(3-phenylbutylamino)cyclohexyl]-3H-benzoxazol-2-one (640 mg, 28%), as a white solid: 1H NMR (300 MHz, DMSO-d6): δ 7.31-7.11 (m, 7H), 6.94 (s, 1H), 2,78 (m, 1H), 2.45-2.35 (m, 5H), 1.87 (br d, J=10 Hz, 2H), 1.73 (br d, J=10 Hz, 2H), 1.68 (m, 2H), 1.44 (dddd, J=10, 10, 10, 2 Hz, 2H), 1.19 (d, J=4 Hz, 3H), 1.08 (dddd, J=10, 10, 10, 2 Hz, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([NH:8][NH2:9])=[O:7])=[CH:4][CH:3]=1.[NH2:12][C:13]1[CH:21]=[CH:20][C:16]([C:17](O)=[O:18])=[CH:15][C:14]=1[N+:22]([O-:24])=[O:23].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.C(N(CC)CC)C>CN(C=O)C.O>[NH2:12][C:13]1[CH:21]=[CH:20][C:16]([C:17]([NH:9][NH:8][C:6](=[O:7])[C:5]2[CH:10]=[CH:11][C:2]([Cl:1])=[CH:3][CH:4]=2)=[O:18])=[CH:15][C:14]=1[N+:22]([O-:24])=[O:23]
Reactant: NNC(=O)c1ccc(Cl)cc1
Reactant: Nc1ccc(C(=O)O)cc1[N+](=O)[O-]
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: Nc1ccc(C(=O)NNC(=O)c2ccc(Cl)cc2)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To 4-Chloro-benzoic acid hydrazide (5.0 g, 29 mmol) and 4-Amino-3-nitro-benzoic acid (5.3 g, 29 mmol) in DMF (100 mL) was added HOBT (3.9 g, 29 mmol), and EDCI (5.5 g, 29 mmol), followed by triethylamine (12.1 mL, 87 mmol). The mixture was stirred at ambient temperature for 18 hours. Water (50 mL) was added to the reaction mixture. The precipitate was collected by filtration, washed with water, and dried under vacuum to provide the title compound as a yellow solid. 1H NMR(DMSO-d6, 400MHz) δ ppm 7.08 (d, J=8.97 Hz, 1 H) 7.61 (m, 2 H) 7.82-7.97 (m, 5 H) 8.66 (d,J=2.15 Hz, 1 H) 10.52 (s, 1 H) 10.57 (s, 1 H; (M+H)+=335.0
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[N:7]1[CH:12]=[CH:11][C:10](B(O)O)=[CH:9][CH:8]=1.Br[C:17]1[CH:18]=[CH:19][C:20]([N:42]2[CH2:47][CH2:46][O:45][CH2:44][CH2:43]2)=[C:21]([NH:23][C:24]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[N:27]=[C:26]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=3[F:40])[C:25]=2[CH3:41])[CH:22]=1.CO>O.O1CCOCC1.C(Cl)Cl.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>[F:40][C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=1[C:26]1[C:25]([CH3:41])=[C:24]([NH:23][C:21]2[CH:22]=[C:17]([C:10]3[CH:11]=[CH:12][N:7]=[CH:8][CH:9]=3)[CH:18]=[CH:19][C:20]=2[N:42]2[CH2:47][CH2:46][O:45][CH2:44][CH2:43]2)[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[N:27]=1
Reactant: OB(O)c1ccncc1
Reactant: Cc1c(-c2ccccc2F)nc2ccccc2c1Nc1cc(Br)ccc1N1CCOCC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Solvent: O
Product: Cc1c(-c2ccccc2F)nc2ccccc2c1Nc1cc(-c2ccncc2)ccc1N1CCOCC1
Temperature: 130 °C
Reaction time: 1 h

Procedure:
A mixture of sodium carbonate (68 mg, 640 μmol), pyridin-4-ylboronic acid (40 mg, 329 μmol), N-(5-bromo-2-morpholinophenyl)-2-(2-fluorophenyl)-3-methylquinolin-4-amine (90 mg, 183 μmol) and dichlorobis(triphenylphosphine)-palladium(II) (13 mg, 18 μmol) in water (2.00 mL) and 1,4-dioxane (8.00 mL) was purged with nitrogen then heated in a microwave vessel with stirring at 130° C. for 60 min, after which time LC-MS indicated no starting material remained and desired product predominated. The reaction was diluted with 30 mL water and extracted with 3×15 mL EtOAc. The combined organic extracts were stirred over magnesium sulfate, filtered and the filtrate concentrated under reduced pressure to afford a dark brown oil. The desired product was isolated as a colorless solid by chromatography on silica gel eluting with a gradient of 1-5% MeOH in DCM. 1H NMR (400 MHz, chloroform-d) δ ppm 8.55 (2H, dd, J=4.3, 1.6 Hz), 8.21 (1H, d, J=8.2 Hz), 7.93 (1H, d, J=8.6 Hz), 7.61-7.79 (3H, m), 7.40-7.61 (3H, m), 7.10-7.40 (7H, m), 6.74 (1H, d, J=0.8 Hz), 3.98 (4H, t, J=4.5 Hz), 3.02-3.29 (4H, m), 2.26 (3H, d, J=2.3 Hz). Mass Spectrum (ESI) m/e=491.2 (M+1).
Reaction SMILES: CS(O[C@@H:6]1[CH2:10][CH2:9][N:8]([C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:12])[CH2:7]1)(=O)=O.[N-:21]=[N+:22]=[N-:23].[Na+]>CN(C)C=O>[N:21]([C@H:6]1[CH2:10][CH2:9][N:8]([C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:12])[CH2:7]1)=[N+:22]=[N-:23]
Reactant: [N-]=[N+]=[N-]
Reactant: CS(=O)(=O)O[C@@H]1CCN(C(=O)OCc2ccccc2)C1
Agent: [Na+]
Solvent: CN(C)C=O
Product: [N-]=[N+]=N[C@H]1CCN(C(=O)OCc2ccccc2)C1
Yield: 91.4 %

Procedure:
A solution of 20.5 g (72 mmol) of (R)-3-[(methylsulfonyl)oxy]-1-pyrrolidinecarboxylic acid, phenylmethyl ester in 100 ml of dry N,N-dimethylformamide was treated with 6.5 g (0.1 mol) of sodium azide and heated at 90° for four hours. The solvent was removed in high vacuo at 50° and the residue was partitioned between ethyl acetate/water (250 ml each). The aqueous layer was reextracted with ethyl acetate and the combined organic fractions were washed with water, dried (MgSO4) and evaporated in vacuo to give 16.2 g of the title compound.
Reaction SMILES: CS(O[CH2:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[C:13](=[O:17])[N:12]([CH2:18][CH:19]([CH3:21])[CH3:20])[C:11]([CH2:22][NH:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])=[C:10]2[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)(=O)=O.C[Si]([C:41]#[N:42])(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C(#N)C.O1CCCC1>[C:27]([O:26][C:24](=[O:25])[NH:23][CH2:22][C:11]1[N:12]([CH2:18][CH:19]([CH3:20])[CH3:21])[C:13](=[O:17])[C:14]2[C:9]([C:10]=1[C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)=[CH:8][C:7]([CH2:6][C:41]#[N:42])=[CH:16][CH:15]=2)([CH3:28])([CH3:29])[CH3:30]
Reactant: CC(C)Cn1c(CNC(=O)OC(C)(C)C)c(-c2ccccc2)c2cc(COS(C)(=O)=O)ccc2c1=O
Reactant: C[Si](C)(C)C#N
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CC#N
Product: CC(C)Cn1c(CNC(=O)OC(C)(C)C)c(-c2ccccc2)c2cc(CC#N)ccc2c1=O
Yield: 74.8 %

Procedure:
To a mixture of (3-{[(tert-butoxycarbonyl)amino]methyl}-2-isobutyl-1-oxo-4-phenyl-1,2-dihydroisoquinolin-6-yl)methyl methanesulfonate (39 g, 0.75 mmol) in acetonitrile (5 mL) and tetrahydrofuran (4 mL) were added trimethylsilyl cyanide (0.15 mL, 1.1 mmol) and a solution of 1.0 M tetrabutylammonium fluoride: in tetrahydrofuran (1.1 mL), and then the mixture was stirred at 80° C. for 30 min. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=5:2 (v/v)) to give tert-butyl[6-(cyanomethyl)-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-3-isoquinolinyl]methylcarbamate (0.25 g, 75%) as a colorless oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[S:9](Cl)(=[O:11])=[O:10].[NH2:13][C:14]1[C:27]([C:28]([O:30][CH3:31])=[O:29])=[C:26]2[C:17]([C:18]3[CH:19]=[CH:20][N:21]=[N:22][C:23]=3[CH2:24][O:25]2)=[CH:16][CH:15]=1>N1C=CC=CC=1.C(Cl)Cl>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[S:9]([NH:13][C:14]1[C:27]([C:28]([O:30][CH3:31])=[O:29])=[C:26]2[C:17]([C:18]3[CH:19]=[CH:20][N:21]=[N:22][C:23]=3[CH2:24][O:25]2)=[CH:16][CH:15]=1)(=[O:11])=[O:10]
Reactant: O=S(=O)(Cl)c1ccc(F)cc1Br
Reactant: COC(=O)c1c(N)ccc2c1OCc1nnccc1-2
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)c1c(NS(=O)(=O)c2ccc(F)cc2Br)ccc2c1OCc1nnccc1-2
Reaction time: 96 h
Yield: 53.8 %

Procedure:
2-Bromo-4-fluorobenzenesulfonyl chloride (0.631 g) was added to a solution of methyl 7-amino-10H-9-oxa-1,2-diazaphenanthrene-8-carboxylate (Intermediate 6, 0.395 g) in pyridine (20 mL) and DCM (20 mL) and the mixture was allowed to stand at room temperature for 4 days. The resulting solution was evaporated in vacuo, and the residue was partitioned between a mixture of DCM and water and filtered through a phase separator. The filtrate was evaporated to dryness, and the residue was azeotroped with toluene. The residue was purified by chromatography on silica, eluting with a mixture of ethyl acetate and cyclohexane with a gradient of 50-100% to give methyl 7-(2-bromo-4-fluorobenzenesulfonylamino)-10H-9-oxa-1,2-diaza-phenanthrene-8-carboxylate (0.408 g) as an off-white solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[CH2:7][CH:6]([CH2:8][C:9](O)=O)[CH2:5][C:4]([CH3:13])([CH3:12])[NH:3]1.[NH:15]([C:17](=[S:19])[NH2:18])[NH2:16].O=P(Cl)(Cl)Cl>>[CH3:1][C:2]1([CH3:14])[CH2:7][CH:6]([CH2:8][C:9]2[S:19][C:17]([NH2:18])=[N:15][N:16]=2)[CH2:5][C:4]([CH3:13])([CH3:12])[NH:3]1
Reactant: NNC(N)=S
Reactant: CC1(C)CC(CC(=O)O)CC(C)(C)N1
Solvent: O=P(Cl)(Cl)Cl
Product: CC1(C)CC(Cc2nnc(N)s2)CC(C)(C)N1
Temperature: 78 °C
Reaction time: 72 h
Yield: 22.5 %

Procedure:
A stirred mixture of 2-(2,2,6,6-tetramethylpiperidin-4-yl)acetic acid (410 mg, 2.057 mmol) and hydrazinecarbothioamide (281 mg, 3.09 mmol) was cooled under nitrogen in an ice bath. POCl3 (0.575 mL, 6.17 mmol) was added drop-wise and the mixture was heated at 78° C. for 3 hours. The reaction mixture was cooled in an ice bath and quenched by addition of ice water (20 mL). The resulting mixture was sonicated for 20 minutes and the resulting suspension was stirred at room temperature for 72 hours. The resulting solution was basified by addition of NaOH (pellets added portion-wise over ˜15 minutes). The resulting suspension was stirred at room temperature for 1 hour before filtering under vacuum and rinsing with water to afford the title compound as a pale brown solid (118 mg, 22% yield). LC-MS: Rt 0.44 min; MS m/z 255.3 [M+H]+ [Method A]. 1H NMR (400 MHz, DMSO-d6) δ ppm 6.98 (s, 2H), 2.66 (d, J=7.07 Hz, 2H), 2.03 (br. s., 1H), 1.49 (d, J=10.61 Hz, 2H), 1.08 (s, 6H), 0.99 (br. s., 6H), 0.78 (t, J=12.13 Hz, 2H).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([NH:8]C(=O)OC)[CH:5]=[CH:4][C:3]=1[Cl:13].[OH-].[K+]>CO.O>[Br:1][C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[CH:4][C:3]=1[Cl:13]
Reactant: COC(=O)Nc1ccc(Cl)c(Br)n1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Nc1ccc(Cl)c(Br)n1
Yield: 82.3 %

Procedure:
To a solution of methyl 6-bromo-5-chloropyridin-2-ylcarbamate (1.1 g, 4.1 mmol) in methanol (50 mL) was added KOH (700 mg, 13 mmol) at room temperature. The mixture was heated at reflux for 2 hr. The reaction mixture was diluted with water and extracted with ethyl acetate (20 mL×3). The combined organic layers were dried over anhydrous Na2SO4 and evaporated under vacuum. The residue was purified by column chromatography on silica gel (5% to 10% EtOAc in petroleum ether) to give 6-bromo-5-chloropyridin-2-amine (700 mg, 81%). 1H NMR (400 MHz, CDCl3) □ 7.54 (d, J=8.0 Hz, 1H), 6.41 (d, J=8.4 Hz, 1H).
Reaction SMILES: Cl.[NH2:2][C:3]1[C:4]2[C:14]([O:15][CH2:16][C@H:17]3[CH2:22][CH2:21][CH2:20][NH:19][CH2:18]3)=[CH:13][CH:12]=[CH:11][C:5]=2[NH:6][S:7](=[O:10])(=[O:9])[N:8]=1.C(N(CC)CC)C.[CH:30]1([CH2:33][C:34](O)=[O:35])[CH2:32][CH2:31]1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>O.C(#N)C>[NH2:2][C:3]1[C:4]2[C:14]([O:15][CH2:16][C@H:17]3[CH2:22][CH2:21][CH2:20][N:19]([C:34](=[O:35])[CH2:33][CH:30]4[CH2:32][CH2:31]4)[CH2:18]3)=[CH:13][CH:12]=[CH:11][C:5]=2[NH:6][S:7](=[O:9])(=[O:10])[N:8]=1
Reactant: NC1=NS(=O)(=O)Nc2cccc(OC[C@H]3CCCNC3)c21
Reactant: O=C(O)CC1CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CC#N
Solvent: CCN(CC)CC
Product: NC1=NS(=O)(=O)Nc2cccc(OC[C@H]3CCCN(C(=O)CC4CC4)C3)c21
Temperature: 25 °C
Reaction time: 8 h
Yield: 52.2 %

Procedure:
To a solution of (S)-4-amino-5(piperidine-3-ylmethoxy)-1H-benzo[c][1,2,6]thiadiazin 2,2-dioxide hydrochloride (Example 2a, 694 mg, 2.0 mmol) in H2O/ACN (5 mL, 1:1) was added triethylamine (228 uL, 2.0 mmol). After stirring at room temperature for 5 min a solution of 2-cyclopropylacetic acid (200 mg, 2.0 mmol), HOBt (272 mg, 2.0 mmol), and EDCI-HCl (382 mg, 2.0 mmol) in H2O/ACN (5 mL, 1:1) was added to the mixture. An additional equivalent of triethylamine (228 uL, 2.0 mmol) was added and the reaction mixture was stirred at room temperature overnight. The product crashed out of solution and is collected by vacuum filtration. The compound was purified via preparative RP HPLC (10 to 90% EtOH in water) then diluted with 10 mL water and 200 mg of NaHCO3 was added. The solution was heated at 90° C. for 20 minutes until all the compound was dissolved then cooled to 0° C. and neutralized with 1N HCl solution. The product precipitated out and was collected by filtration and dried to provide the title compound (410 mg, 52.3%). 1H NMR (DMSO-d6, 400 MHz, 80° C.): 0.12 (br s, 2H), 0.44 (m, 2H), 0.96 (br s, 1H), 1.42 (m, 2H), 1.70 (m, 1H), 1.88 (m, 1H), 1.98 (br s, 1H), 2.09 (m, 1H), 2.26 (br s, 2H), 2.91 (m, 2H), 3.67 (br s, 0.5H), 3.85 (br s, 0.5H), 4.09 (m, 3H), 6.65 (d, J=8.4 Hz, 1H), 6.71 (d, J=8.4 Hz, 1H), 7.46 (t, J=8.4 Hz, 1H), 7.75 (br s, 1H), 8.16 (br s, 1H), 10.79 (s, 1H). M+H=393.
Reaction SMILES: [CH:1]([N:4]1[C:9](=[O:10])[NH:8][CH:7](SC)[NH:6][C:5]1=[O:13])([CH3:3])[CH3:2].C(O)(=O)C.[CH:18]1([NH2:21])[CH2:20][CH2:19]1>O>[CH:1]([N:4]1[C:9](=[O:10])[NH:8][CH:7]([NH:21][CH:18]2[CH2:20][CH2:19]2)[NH:6][C:5]1=[O:13])([CH3:3])[CH3:2]
Reactant: NC1CC1
Reactant: CSC1NC(=O)N(C(C)C)C(=O)N1
Solvent: CC(=O)O
Solvent: O
Product: CC(C)N1C(=O)NC(NC2CC2)NC1=O
Temperature: 150 °C
Reaction time: 3 h

Procedure:
1-Isopropyl-4-methylthiotetrahydro-1,3,5-triazine-2,6-dione (6.0 g.) (obtained as described in U.K. patent specification No. 1,435,585) and cyclopropylamine acetate (17.85 g.) were heated together and stirred at 150° C. for 3 hours. The mixture was then cooled and water (150 ml.) was added. The white solid which formed was collected, washed with water and dried to give 1-isopropyl-4-cyclopropylaminotetrahydro-1,3,5-triazine-2,6-dione, m.p. 237°-239° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[C:9](=O)[NH:8][N:7]=[CH:6]2.P(Cl)(Cl)([Cl:18])=O>>[Cl:18][C:9]1[C:10]2[C:5](=[CH:4][C:3]([O:2][CH3:1])=[C:12]([O:13][CH3:14])[CH:11]=2)[CH:6]=[N:7][N:8]=1
Reactant: COc1cc2cn[nH]c(=O)c2cc1OC
Reactant: O=P(Cl)(Cl)Cl
Product: COc1cc2cnnc(Cl)c2cc1OC
Temperature: 25 °C

Procedure:
6,7-Dimethoxyphthalazin-1-one (20.6 g.) was heated under reflux with phosphoryl chloride (200 ml.) for 6 hours then cooled to room temperature and the excess phosphoryl chloride removed under reduced pressure. The resultant brown solid was suspended in acetone (150 ml.) and poured onto cold (5° C.) concentrated ammonium hydroxide (200 ml.). The crude product was filtered, washed with water (200 ml.) then petroleum ether (200 ml.). The pale yellow solid was dried (20 g.), dissolved in the minimum volume of chloroform and precipitated with excess petroleum ether, after which it was recovered by filtration, washed again with petroleum ether (100 ml.) and dried to give 1-chloro-6,7-dimethoxyphthalazine (13 g.), m.p. 195°-197° C. with decomposition.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[CH:3]=1.[Cl-].[Al+3].[Cl-].[Cl-].[Cl:13][CH:14]([CH3:18])[C:15](Cl)=[O:16].Cl>ClCCCl>[Cl:13][CH:14]([CH3:18])[C:15]([C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][C:4]=1[F:8])=[O:16]
Reactant: CC(Cl)C(=O)Cl
Reactant: Fc1cccc(F)c1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: CC(Cl)C(=O)c1ccc(F)cc1F
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Into the solution of 1,3-Difluorobenzene in 1,2-dicholoroethane (DCE) was added anhydrous aluminium chloride (1.2 mol eqnt.) at 25-30° C. and stirred for 30 minutes. The reaction mixture was then cooled to 0° C. and (±)2-chloropropionyl chloride (1.1 molar equivalent), diluted in DCE, was then added into it over a period of 30-60 min keeping the reaction temperature below 20° C. After the addition was over, reaction mixture was stirred at room temperature for 5-7 hours. For workup, reaction mixture was diluted with DCE and poured into chilled aq. hydrochloric acid solution (5%). The mixture was extracted with DCE and the combined organic layer was washed with 5% aq. sodium bicarbonate solution and water. The solvent was evaporated off under reduced pressure to afford an oil.
Reaction SMILES: [CH:1]1([CH2:4][NH:5][C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH2:3][CH2:2]1.[CH2:12]([N:15]1[C@H:20]([CH3:21])[CH2:19][N:18]([C@H:22]([C:37]2[CH:38]=[C:39]([CH:43]=[CH:44][CH:45]=2)[C:40](Cl)=[O:41])[C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([O:29][Si](C(C)(C)C)(C)C)[CH:24]=2)[C@@H:17]([CH3:46])[CH2:16]1)[CH:13]=[CH2:14]>>[CH2:12]([N:15]1[C@H:20]([CH3:21])[CH2:19][N:18]([C@H:22]([C:37]2[CH:38]=[C:39]([CH:43]=[CH:44][CH:45]=2)[C:40]([N:5]([CH2:4][CH:1]2[CH2:2][CH2:3]2)[C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)=[O:41])[C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([OH:29])[CH:24]=2)[C@@H:17]([CH3:46])[CH2:16]1)[CH:13]=[CH2:14]
Reactant: C=CCN1C[C@H](C)N([C@@H](c2cccc(O[Si](C)(C)C(C)(C)C)c2)c2cccc(C(=O)Cl)c2)C[C@H]1C
Reactant: c1ccc(NCC2CC2)cc1
Product: C=CCN1C[C@H](C)N([C@@H](c2cccc(O)c2)c2cccc(C(=O)N(CC3CC3)c3ccccc3)c2)C[C@H]1C

Procedure:
N-(Cyclopropyl)methylaniline was coupled with 3-((αR)-α-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-(tert-butyldimethylsilyloxy)benzyl)benzoyl chloride, deprotected and purified by the methods described in Example 10 to give 3-((αR)-α-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N-(cyclopropyl)methyl-N-phenylbenzamide as an off-white powder. NMR (200 MHz, DMSO-d6): δ0.09 (m, 2H); 0.39 (m, 2H); 0.92 (d, J=6.3 Hz,3H); 0.96 (d, J=6.2 Hz, 3H); 1.28 (m, 1H); 1.69 (dd, J1 =7.4 Hz, J2 =11.5 Hz, 1H); 2.04 (dd, J1 =6.6 Hz, J2 =11.0 Hz, 1H); 2.30 (br d, J=12.1 Hz, 1H); 2.40-2.54 (m, 2H); 2.67 (br d, J=9.8 Hz, 1H); 2.85 (dd, J1 =7.4 Hz, J2 =13.7 Hz, 1H); 3.16 (dd, J1 =4.5 Hz, J2 =14.7 Hz, 1H); 3.72 (d, J=7.0 Hz, 2H); 4.77 (s, 1H); 5.12 (d, J=10.0 Hz, 1H); 5.18 (d, J=15.6 Hz, 1H); 5.70-5.85 (m, 1H); 6.44 (d, J=7.3 Hz, 1H); 6.57 (s, 1H); 6.65 (d, J=8.0 Hz, 1H); 7.02-7.33 (m, 10H); 9.33 (s, 1H). Mass spectrum (CI--CH4) m/e: 510 (M+1, 61%), 356 (42%), 153 (100%). [α]D20 =+8.9° (abs. ethanol, c=1.1). The free amine was dissolved in ethanol and titrated with ethanolic hydrogen chloride to pH 3.75 followed by precipitation with diethyl ether from dichloromethane to give the monohydrochloride salt as a hygroscopic off-white powder. Calc. for C33H39N3O2HCl 1.25 H2O: C, 69.70; H, 7.53; N, 7.39; Cl, 6.23. Found: C, 69.82; H, 7.52; N, 7.36; Cl, 6.28.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:5]2[N:10]=[C:9]([C:11]([OH:13])=O)[S:8][C:6]=2[N:7]=1.C(Cl)(=O)C(Cl)=O.CCN(CC)CC.[NH:33]1[CH2:36][CH:35]([N:37]2[CH2:42][CH2:41][O:40][CH2:39][CH2:38]2)[CH2:34]1>C(Cl)Cl>[Cl:1][C:2]1[N:3]=[C:4]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:5]2[N:10]=[C:9]([C:11]([N:33]3[CH2:36][CH:35]([N:37]4[CH2:42][CH2:41][O:40][CH2:39][CH2:38]4)[CH2:34]3)=[O:13])[S:8][C:6]=2[N:7]=1
Reactant: O=C(O)c1nc2c(N3CCOCC3)nc(Cl)nc2s1
Reactant: C1CN(C2CNC2)CCO1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(c1nc2c(N3CCOCC3)nc(Cl)nc2s1)N1CC(N2CCOCC2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 63.3 %

Procedure:
To a suspension of 5-chloro-7-morpholin-4-ylthiazolo[5,4-d]pyrimidine-2-carboxylic acid (301 mg, 1.0 mmol) in DCM (6 mL) was added oxalyl chloride (847 μL, 10.00 mmol) and the resulting mixture allowed to stir at r.t. for 1 h then concentrated in vacuo and azeotroped with toluene. The resulting yellow solid was suspended in a mixture of DCM (6 mL) and NEt3 (418 μL, 3.00 mmol) at 0° C. before the addition of 4-azetidin-3-ylmorpholine (142 mg, 1.00 mmol). The resulting mixture was warmed to r.t. after 1 h then stirred for a further 30 min. The reaction mixture was partitioned between DCM and H2O, the organic phase dried (Na2SO4) and concentrated in vacuo. The resulting residue was triturated with EtOAc and dried in vacuo affording the title compound as an off-white solid (269 mg, 63%)._LCMS (method H): RT 2.19 min [M+H]+ 425.3
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([O:13][CH2:14][CH3:15])[C:9]([O:11]C)=[O:10])=[CH:4][CH:3]=1.[OH:16][C:17]1[C:29]([C:30]([F:33])([F:32])[F:31])=[CH:28][CH:27]=[C:26]([CH2:34][O:35][C:36]2[CH:41]=[CH:40][C:39](B3OC(C)(C)C(C)(C)O3)=[CH:38][CH:37]=2)[C:18]=1[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20]>>[C:22]([O:21][C:19]([C:18]1[C:17]([OH:16])=[C:29]([C:30]([F:31])([F:32])[F:33])[CH:28]=[CH:27][C:26]=1[CH2:34][O:35][C:36]1[CH:41]=[CH:40][C:39]([C:2]2[CH:7]=[CH:6][C:5]([CH:8]([O:13][CH2:14][CH3:15])[C:9]([OH:11])=[O:10])=[CH:4][CH:3]=2)=[CH:38][CH:37]=1)=[O:20])([CH3:25])([CH3:23])[CH3:24]
Reactant: CC(C)(C)OC(=O)c1c(COc2ccc(B3OC(C)(C)C(C)(C)O3)cc2)ccc(C(F)(F)F)c1O
Reactant: CCOC(C(=O)OC)c1ccc(Br)cc1
Product: CCOC(C(=O)O)c1ccc(-c2ccc(OCc3ccc(C(F)(F)F)c(O)c3C(=O)OC(C)(C)C)cc2)cc1

Procedure:
According to a method similar to Example (31) and Example (17-4), from methyl (4-bromophenyl)(ethoxy)acetate (110 mg, 0.4 mmol) and tert-butyl 2-hydroxy-6-{[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]methyl}-3-(trifluoromethyl)benzoate (170 mg, 0.34 mmol) obtained in Example (22-4), the title compound was obtained as a grayish white powder (35 mg, yield: 19%).
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:9]([NH:12][S:13]([CH3:16])(=[O:15])=[O:14])=[CH:8][C:3]=1[C:4]([O:6]C)=[O:5].[OH-].[K+]>O.CO>[F:1][C:2]1[CH:11]=[CH:10][C:9]([NH:12][S:13]([CH3:16])(=[O:15])=[O:14])=[CH:8][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: COC(=O)c1cc(NS(C)(=O)=O)ccc1F
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CS(=O)(=O)Nc1ccc(F)c(C(=O)O)c1
Yield: 92.8 %

Procedure:
Methyl 2-fluoro-5-methanesulfonylaminobenzoate (72 g) and 49 g of potassium hydroxide were dissolved in 400 ml of a 1:1 mixture of water and methanol and the solution was heated to reflux for 2 hours. Methanol was evaporated and the residue was acidified with hydrochloric acid. The crystals separated out therefrom were filtered followed by washing with water and drying to give 63 g of 2-fluoro-5-methanesulfonylaminobenzoic acid, m.p. 203°-205 ° C.
Reaction SMILES: [F:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][N:7]2[C:11]3=[N:12][C:13]([C:16]4[CH:23]=[CH:22][C:19]([CH:20]=[O:21])=[CH:18][CH:17]=4)=[CH:14][CH:15]=[C:10]3[N:9]=[N:8]2)=[CH:4][CH:3]=1.[BH4-].[Na+]>CO>[F:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][N:7]2[C:11]3=[N:12][C:13]([C:16]4[CH:23]=[CH:22][C:19]([CH2:20][OH:21])=[CH:18][CH:17]=4)=[CH:14][CH:15]=[C:10]3[N:9]=[N:8]2)=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(-c2ccc3nnn(Cc4ccc(F)cc4)c3n2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: OCc1ccc(-c2ccc3nnn(Cc4ccc(F)cc4)c3n2)cc1
Reaction time: 1 h
Yield: 46.2 %

Procedure:
To a solution of example 10 (0.095 g, 0.259 mmol) in methanol (2 ml) cooled to 0° C., sodium borohydride (0.010 g, 0.259 mmol) was added and stirred for 1 h. The reaction was quenched by the addition of ice-cold water, extracted with ethyl acetate, washed with brine, dried over sodium sulphate and concentrated. The crude product was purified by column chromatography with methanol:dichloromethane to afford the title compound as an off-white solid (0.040 g, 46%). M.P.: 210-213° C. 1H-NMR (δ ppm, DMSO-d6, 400 MHz): 8.61 (d, J=8.7 Hz, 1H), 8.22 (d, J=8.3 Hz, 2H), 8.11 (d, J=8.8 Hz, 1H), 7.53 (m, 4H), 7.21 (m, 2H), 5.98 (s, 2H), 5.32 (t, J=5.8 Hz, 1H), 4.59 (d, J=5.7 Hz, 2H). MS (m/z): 335.05 (M++1).