Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O)(C(F)(F)F)=O.[CH:8]1([NH:11][C:12](=[O:32])[C:13]([O:29][CH2:30][CH3:31])([O:26][CH2:27][CH3:28])[C@@H:14]([NH:18]C(=O)OC(C)(C)C)[CH2:15][CH2:16][CH3:17])[CH2:10][CH2:9]1.C([O-])(O)=O.[Na+]>C(Cl)Cl>[NH2:18][C@@H:14]([CH2:15][CH2:16][CH3:17])[C:13]([O:29][CH2:30][CH3:31])([O:26][CH2:27][CH3:28])[C:12]([NH:11][CH:8]1[CH2:9][CH2:10]1)=[O:32]
Reactant: CCC[C@H](NC(=O)OC(C)(C)C)C(OCC)(OCC)C(=O)NC1CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCC[C@H](N)C(OCC)(OCC)C(=O)NC1CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 87 %

Procedure:
TFA (2.45 mL, 32.1 mmol) was added to a solution of (S)-tert-butyl 1-(cyclopropylamino)-2,2-diethoxy-1-oxohexan-3-ylcarbamate (2.3 g, 6.41 mmol) in 45 mL CH2Cl2 and the mixture was stirred at room temperature for 18 hours. A saturated NaHCO3 solution was carefully added to the mixture, the aqueous phase was extracted with CH2Cl2 (2×30 mL) and the combined organic phases were dried over Na2SO4. Removal of the solvent in vacuo yielded 1.44 g (3S)-3-Amino-N-cyclopropyl-2,2-diethoxyhexanamide as a pale yellow oil.
Reaction SMILES: [CH2:1]1[C:6]2([CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]2)[CH2:5][CH2:4][O:3][C:2]1=[O:14].[H-].C([Al+]CC(C)C)C(C)C.O1CCCC1.[OH-].[Na+].S([O-])([O-])(=O)=O.[Mg+2]>O1CCCC1.C(OCC)C.O>[CH2:1]1[C:6]2([CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]2)[CH2:5][CH2:4][O:3][CH:2]1[OH:14]
Reactant: O=C1CC2(CCCCCCC2)CCO1
Agent: CC(C)C[Al+]CC(C)C
Agent: O=S(=O)([O-])[O-]
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOCC
Product: OC1CC2(CCCCCCC2)CCO1
Reaction time: 0.5 h
Yield: 82.9 %

Procedure:
To a solution of 3-oxaspiro[5.7]tridecan-2-one (0.74 g) in tetrahydrofuran (9 mL) cooled at −78° C. was added 1M diisobutylaluminum hydride/tetrahydrofuran (4.9 mL) dropwise over 5 minutes. The reaction solution was then stirred at that temperature for 30 minutes. Water (0.18 mL) was added to the reaction solution. After allowing the temperature to rise to room temperature, a 15% aqueous sodium hydroxide solution (0.18 mL) and water (0.54 mL) were successively added to the solution. After stirring the reaction solution at room temperature for 10 minutes, diethyl ether (9 mL) and anhydrous magnesium sulfate (0.17 g) were added, and the solution was stirred for additional 15 minutes. The reaction solution was filtered with Celite. The filtrate was concentrated under reduced pressure. The resulting residue was purified by chromatography [silica gel, hexane-ethyl acetate (3:1 to 2:1 to 1:1)] to give the title compound (0.62 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][C:19]=1[O:20][CH3:21])[C:5]([CH:7]1[CH2:12][CH2:11][N:10]([CH2:13][C:14]([OH:16])=O)[CH2:9][CH2:8]1)=[O:6].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C.[NH2:51][CH2:52][C:53]1[NH:54][C:55](=[O:63])[C:56]2[CH2:62][O:61][CH2:60][CH2:59][C:57]=2[N:58]=1>CN(C=O)C.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][C:19]=1[O:20][CH3:21])[C:5]([CH:7]1[CH2:8][CH2:9][N:10]([CH2:13][C:14]([NH:51][CH2:52][C:53]2[NH:54][C:55](=[O:63])[C:56]3[CH2:62][O:61][CH2:60][CH2:59][C:57]=3[N:58]=2)=[O:16])[CH2:11][CH2:12]1)=[O:6]
Reactant: COc1ccc(C(=O)C2CCN(CC(=O)O)CC2)cc1Cl
Reactant: NCc1nc2c(c(=O)[nH]1)COCC2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: COc1ccc(C(=O)C2CCN(CC(=O)NCc3nc4c(c(=O)[nH]3)COCC4)CC2)cc1Cl
Temperature: 25 °C
Reaction time: 15 h
Yield: 27.3 %

Procedure:
A solution of [4-(3-chloro-4-methoxy-benzoyl)-piperidin-1-yl]-acetic acid (0.41 g, 1.3 mmol), EDCl (0.25 g, 1.3 mmol), HOBT (0.18 g, 1.3 mmol) and triethylamine (0.56 g, 5.5 mmol) in 10 mL of DMF was stirred at ambient temperature for 20 min., then 2-aminomethyl-3,5,7,8-tetrahydro-pyrano[4,3-d]pyrimidin-4-one (0.20 g, 1.1 mmol) was added. The reaction mixture was stirred at ambient temperature for 15 hours. The reaction mixture was diluted with 50 mL of water, extracted with DCM (100 mL) and the combined organic layers were washed with saturated aqueous NaHCO3 solution. The organic layer was dried over Na2SO4, filtered and concentrated in vacuo to provide crude product. Purification by flash chromatography gave the title compound (155.2 mg, 0.3 mmol) as a white solid. MS (ESI) m/z 475.4 (M+H+); HPLC (Insertsil ODS3 100×3 mm C-18 column: mobile phase: 5-95% acetonitrile/water with 0.1% TFA, at 1 mL/min over 7.75 min.), t=0.97 min. 1H NMR (400 MHz, methanol-d4) δ ppm 2.01-2.19 (m, 6H) 2.65 (t, 4H) 3.31 (s, 2H) 3.63-3.80 (m, 3H) 3.93 (t, J=5.56 Hz, 1H) 3.98 (s, 3H) 4.07 (s, 1H) 4.38 (s, 1H) 4.47 (s, 1H) 7.20 (d, J=8.59 Hz, 1H) 7.98-8.02 (m, 1H) 8.03-8.06 (m, 1H) HRMS calculated for C23H28ClN4O5: 475.1748 (M+H). found (ESI, [M+H]+): 475.1755.
Reaction SMILES: [SH:1][C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[C:4]([NH:6][C:7](=[O:11])[CH2:8][CH2:9][NH2:10])=[O:5].[C:16]([N:20]=[C:21]=[O:22])([CH3:19])([CH3:18])[CH3:17]>CN(C=O)C>[C:16]([NH:20][C:21]([S:1][C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[C:4]([NH:6][C:7](=[O:11])[CH2:8][CH2:9][NH2:10])=[O:5])=[O:22])([CH3:19])([CH3:18])[CH3:17]
Reactant: CC(C)(C)N=C=O
Reactant: NCCC(=O)NC(=O)c1ccccc1S
Solvent: CN(C)C=O
Product: CC(C)(C)NC(=O)Sc1ccccc1C(=O)NC(=O)CCN
Yield: 89 %

Procedure:
To a well stirred mixture of N-(2-mercaptobenzoyl)-β-alaninamide (0.45 g, 2.0 mmol) in 8 ml DMF was added tert-butyl isocyanate (3.0 mmol). The reaction mixture was stirred for 8-10 h at room temp. After completion of the reaction, all of the DMF was removed in vacuo and the residue was treated with ethyl ether. The white precipitate that formed was washed with water, dried in vacuo/CaCl2 and crystallized from acetonitrile. Yield: 89%. 1H NMR (DMSO-d6): 1.30(s, 9H, 3CH3), 2.38(t, 2H, CH2), 3.40(q, 2H, CH2), 6.86(brs, 1H, NH2), 7.30-7.60(m, 5H, Ar—H, NH2), 8.06(s, 1H, NH), 8.26(t, 1H, NH).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10](O)[C:9]2[C:4](=[C:5]([Br:13])[CH:6]=[CH:7][CH:8]=2)[N:3]=1.P(Cl)(Cl)([Cl:16])=O>>[CH3:1][C:2]1[CH:11]=[C:10]([Cl:16])[C:9]2[C:4](=[C:5]([Br:13])[CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: Cc1cc(O)c2cccc(Br)c2n1
Reactant: O=P(Cl)(Cl)Cl
Product: Cc1cc(Cl)c2cccc(Br)c2n1
Temperature: 100 °C
Yield: 97 %

Procedure:
Part A: To a quantity of 4.76 g (20 mmol) of 2-methyl-4-hydroxy-8-bromo-quinoline (J.Org.Chem. 1964, pg 3548) 15 ml of phosphorous oxychloride was added under ice-cooling. After heating to 100° C. for 30 minutes and subsequent cooling residual phosphorous oxychloride was removed by evaporation. After addition of ice water to the residue the mixture was neutralized with ammonia and extracted with CH2Cl2. The organic layer was dried over magnesium sulphate and concentrated in vacuo. The resulting product was purified on a silicagel column using ethylacetate as eluent. A total of 5.0 g of 2-methyl-4-chloro-8-bromo-quinoline was obtained (97% yield)
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[C:19]2[C:14](=[CH:15][C:16]([N:20]3[CH2:24][CH:23]([CH2:25]O)[O:22][C:21]3=[O:27])=[CH:17][CH:18]=2)[CH2:13][CH:12]1[CH2:28][O:29][Si:30]([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([N:39](CC)CC)C.[N+](C1C=C(S(Cl)(=O)=O)C=CC=1)([O-])=O>C(Cl)Cl>[CH2:1]([O:8][C:9]([N:11]1[C:19]2[C:14](=[CH:15][C:16]([N:20]3[CH2:24][CH:23]([CH2:25][NH2:39])[O:22][C:21]3=[O:27])=[CH:17][CH:18]=2)[CH2:13][CH:12]1[CH2:28][O:29][Si:30]([C:33]([CH3:34])([CH3:35])[CH3:36])([CH3:31])[CH3:32])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCN(CC)CC
Reactant: CC(C)(C)[Si](C)(C)OCC1Cc2cc(N3CC(CO)OC3=O)ccc2N1C(=O)OCc1ccccc1
Agent: O=[N+]([O-])c1cccc(S(=O)(=O)Cl)c1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCC1Cc2cc(N3CC(CN)OC3=O)ccc2N1C(=O)OCc1ccccc1
Temperature: 55 °C
Reaction time: 16 h

Procedure:
An ice cold, stirred mixture of the product from Step 6 (6.03 g, 0.0117 mol) and triethylamine (4.55 ml) in methylene chloride (340 ml) is treated, portionwise during 10 min, with 3-nitrobenzenesulfonyl chloride (3.2 g) and kept in the ice bath for 15 min. It is then kept at ambient temperature for 16 h, diluted with CH2Cl2, washed with saturated NaHCO3 and brine, dried (MgSO4) and concentrated. A stirred solution of the residue (9.32 g) in a mixture of 2-propanol (250 ml), acetonitrile (250 ml), and concentrated ammonium hydroxide (250 ml) is warmed at 55° C. under a dry ice-acetone condenser for 3.5 h and kept at ambient temperature for 18 h. Additional ammonium hydroxide (50 ml) is added; the mixture is warmed at 55° C. for 30 min, kept at ambient temperature for 3 d and concentrated in vacuo. The aqueous residue is extracted with methylene chloride. The extract is washed water and brine, dried (Na2SO4) and concentrated to give 6.53 g of the titled product: 1H NMR (300 MHz, CDCl3) δ−0.11 (s, 3H), −0.06 (s, 3H), 0.76 (s, 9H), 3.03 (m, 3H), 3.24 (m, 1H), 3.79 (m, 2H), 4.02 (m, 2H), 4.52 (broad s, 1H), 4.65 (m, 1H), 5.27 (m, 2H), 7.08 (m, 1H), 7.38 (m, 5H), 7.62, 7.79 (broad s, 2H).
Reaction SMILES: Cl[C:2]([C:16]1[N:21]=[C:20]([O:22][CH3:23])[CH:19]=[C:18]([O:24][CH3:25])[N:17]=1)([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:3]([NH:5][S:6]([CH3:9])(=[O:8])=[O:7])=[O:4].[C:26]([O-:29])(=[O:28])[CH3:27].[Na+]>C(O)(=O)C>[C:26]([O:29][C:2]([C:16]1[N:21]=[C:20]([O:22][CH3:23])[CH:19]=[C:18]([O:24][CH3:25])[N:17]=1)([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:3]([NH:5][S:6]([CH3:9])(=[O:8])=[O:7])=[O:4])(=[O:28])[CH3:27]
Reactant: CC(=O)[O-]
Reactant: COc1cc(OC)nc(C(Cl)(C(=O)NS(C)(=O)=O)c2ccccc2)n1
Agent: [Na+]
Solvent: CC(=O)O
Product: COc1cc(OC)nc(C(OC(C)=O)(C(=O)NS(C)(=O)=O)c2ccccc2)n1
Yield: 98 %

Procedure:
2-Chloro-2-(4,6-dimethoxypyrimidin-2-yl)-N-methanesulfonyl-2-phenylacetamide (0.5 g) and anhydrous sodium acetate (0.25 g) were refluxed in glacial acetic acid (10 ml) for 7 hours. The acetic acid was evaporated off under vacuum, and the residue was taken into ether. The ether solution was washed with water (3 times), dried over magnesium sulfate, and evaporated under vacuum to give 0.52 g of a brown glass. Trituration with diisopropyl ether gave an off-white solid, which was filtered off, washed with diisopropyl ether and dried to give 0.3 g of the desired product, mp 141°-143° C.
Reaction SMILES: Br[C:2]1[C:3]([O:17][CH2:18][CH:19]2[CH2:23][CH2:22][CH2:21][O:20]2)=[CH:4][C:5]2[S:9][C:8]([NH:10][C:11]([NH:13][CH2:14][CH3:15])=[O:12])=[N:7][C:6]=2[CH:16]=1.C(NC(NC1SC2C(C3C=CC=CN=3)=CC([C:45]3[CH:46]=[N:47][C:48]([C:51]([OH:54])([CH3:53])[CH3:52])=[N:49][CH:50]=3)=CC=2N=1)=O)C.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.CO.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]>[CH2:14]([NH:13][C:11]([NH:10][C:8]1[S:9][C:5]2[CH:4]=[C:3]([O:17][CH2:18][CH:19]3[CH2:23][CH2:22][CH2:21][O:20]3)[C:2]([C:45]3[CH:46]=[N:47][C:48]([C:51]([OH:54])([CH3:53])[CH3:52])=[N:49][CH:50]=3)=[CH:16][C:6]=2[N:7]=1)=[O:12])[CH3:15]
Reactant: CCNC(=O)Nc1nc2cc(Br)c(OCC3CCCO3)cc2s1
Reactant: CCNC(=O)Nc1nc2cc(-c3cnc(C(C)(C)O)nc3)cc(-c3ccccn3)c2s1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: CO
Solvent: C1COCCO1
Product: CCNC(=O)Nc1nc2cc(-c3cnc(C(C)(C)O)nc3)c(OCC3CCCO3)cc2s1
Temperature: 80 °C
Yield: 43.7 %

Procedure:
To a solution of iv (0.303 g, 0.75 mmol) and the 4,4,5,5-tetramethyl-1,3,2-dioxaborolon-2-yl) ester of Precursor 1 (0.20 g, 0.75 mmol) in 1,4-dioxane:MeOH (5:3, 8.0 mL) was added potassium phosphate (0.24 g, 1.13 mmol) at RT. The mixture was degassed for 15-20 min by purging N2 followed by the addition of Pd(dppf)Cl2 (0.062 g, 0.075 mmol). The mixture was degassed for 15-20 min and heated at 80° C. for 5 h. The reaction mixture was cooled to RT, diluted with EtOAc (500 ml) and filtered through celite. The filtrate was evaporated in vacuo and the crude residue was purified over silica (5% MeOH-DCM) to obtain Compound 3 (0.15 g, 43%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][O:11][C:12]1[N:17]=[C:16]([C:18]([OH:20])=O)[CH:15]=[C:14]([N:21]2[CH2:26][CH2:25][CH:24]([NH:27][C:28]([C:30]3[NH:31][C:32]([CH3:37])=[C:33]([Cl:36])[C:34]=3[Cl:35])=[O:29])[CH2:23][CH2:22]2)[N:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[O:39]([NH2:41])[CH3:40]>>[Cl:35][C:34]1[C:33]([Cl:36])=[C:32]([CH3:37])[NH:31][C:30]=1[C:28]([NH:27][CH:24]1[CH2:23][CH2:22][N:21]([C:14]2[CH:15]=[C:16]([C:18]([NH:41][O:39][CH3:40])=[O:20])[N:17]=[C:12]([O:11][CH2:10][CH2:9][NH:8][C:6](=[O:7])[O:5][C:1]([CH3:3])([CH3:4])[CH3:2])[N:13]=2)[CH2:26][CH2:25]1)=[O:29]
Reactant: CON
Reactant: Cc1[nH]c(C(=O)NC2CCN(c3cc(C(=O)O)nc(OCCNC(=O)OC(C)(C)C)n3)CC2)c(Cl)c1Cl
Agent: Cl
Product: CONC(=O)c1cc(N2CCC(NC(=O)c3[nH]c(C)c(Cl)c3Cl)CC2)nc(OCCNC(=O)OC(C)(C)C)n1

Procedure:
The title compound was synthesized by an analogous method to Example 8 starting from 2-{2-[(tert-butoxycarbonyl)amino]ethoxy}-6-(4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}piperidin-1-yl)pyrimidine-4-carboxylic acid (Example 154) and methoxylamine hydrochloride.
Reaction SMILES: [SH:1][C:2]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[CH3:20][C:21](C)([O-])[CH3:22].[K+].O>CN(C)C=O>[CH2:22]([S:1][C:2]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:17])([F:18])[F:19])=[CH:12][CH:11]=2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5])[CH:21]=[CH2:20]
Reactant: N#Cc1ccc(-c2ccc(C(F)(F)F)cc2)cc1S
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: C=CCSc1cc(-c2ccc(C(F)(F)F)cc2)ccc1C#N
Yield: 43.5 %

Procedure:
1.0 g (3.6 mmol) of 2-mercapto-4-(4-trifluoromethylphenyl)benzonitrile, 0.45 g (4.0 mmol) of potassium tert-butoxide and 0.5 g (4.1 mmol) of 3-propenyl bromide were stirred in 20 ml of N,N-dimethylformamide at room temperature for 1 hour. The resulting reaction mixture was poured into 20 ml of water and extracted with 50 ml of ethyl acetate twice. The ethyl acetate layer was washed with 50 ml of water twice and dried over anhydrous magnesium sulfate, and the ethyl acetate was distilled off under reduced pressure. Purification of the residue by silica gel column chromatography afforded 0.5 g of 2-(2-propenylthio)-4-(4-trifluoromethylphenyl)benzonitrile (yield 43.0%) as yellow crystals (m.p. 89-90° C.).
Reaction SMILES: [NH2:1][CH:2]([C:10]1[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[CH:12][C:11]=1[O:18][CH3:19])[CH2:3][CH2:4][CH2:5][C:6]([O:8]C)=O.[C:20]1([C:26]2[N:31]=[C:30]([CH:32]=O)[CH:29]=[CH:28][CH:27]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[CH3:19][O:18][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]([O:16][CH3:17])[C:10]=1[CH:2]1[N:1]([CH2:32][C:30]2[CH:29]=[CH:28][CH:27]=[C:26]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[N:31]=2)[C:6](=[O:8])[CH2:5][CH2:4][CH2:3]1
Reactant: COC(=O)CCCC(N)c1c(OC)cccc1OC
Reactant: O=Cc1cccc(-c2ccccc2)n1
Product: COc1cccc(OC)c1C1CCCC(=O)N1Cc1cccc(-c2ccccc2)n1

Procedure:
Prepared according to the described general procedure 1 (GP1) by reaction of methyl 5-amino-5-(2,6-dimethoxyphenyl)pentanoate with 6-phenylpicolinaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.72 min.; [M+H]+: 403.01 g/mol.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:14](=O)[CH3:15])=[CH:4][CH:3]=1.[N:17]1([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1.[BH3-]C#N.[Na+].[OH-].[Na+]>ClCCl.CO.[Ti](Cl)(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[CH:14]([N:20]2[CH2:19][CH2:18][N:17]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:22][CH2:21]2)[CH3:15])=[CH:4][CH:3]=1
Reactant: CC(=O)c1ccccc1-c1ccc(Cl)cc1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: CC(c1ccccc1-c1ccc(Cl)cc1)N1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
A mixture of EXAMPLE 110A (1.9 g) in dichloromethane (3 mL) was treated with 1M titanium(IV) chloride in dichloromethane (9.06 mL), cooled to 0° C., treated with tert-butyl piperazine-1-carboxylate (3.07 g), stirred at ambient temperature for 3 hours, treated with NaCNBH3 (0.828 g) in methanol (5 ml), stirred at room temperature overnight, neutralized with aqueous NaOH and concentrated. The concentrate was treated with ethyl acetate and filtered. The organic filtrate was washed with water and concentrated. The concentrate was dissolved in methanol/trifluoroacetic acid/dimethylsulfoxide, loaded onto a reverse phase C18 column and eluted with 0-80% acetonitrile in 0.1% trifluoroacetic acid water over 70 minutes.
Reaction SMILES: [C:1]([O:5]C)(=O)[CH2:2][OH:3].[NH2:7][C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][N:9]=1>>[OH:3][CH2:2][C:1]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][N:9]=1)=[O:5]
Reactant: COC(=O)CO
Reactant: Cc1ccc(N)nc1
Product: Cc1ccc(NC(=O)CO)nc1

Procedure:
The title compound was prepared in a manner similar to that described for Intermediate A3, starting from methyl glycolate and 2-amino-5-picoline, 1H NMR (300 MHz, CDCl3) δ 9.24 (br s, 1H), 8.19 (d, 1H), 8.07 (d, 1H), 7.57 (dd, 1H), 5.59 (br s, 1H), 4.26 (s, 2H), 2.31 (s, 3H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[C@H:7]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1)[NH2:8])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:25]1([C:31](Cl)([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>CN(C=O)C>[C:1]([O:5][C:6](=[O:17])[C@H:7]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1)[NH:8][C:31]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)([C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1)[C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)OC(=O)[C@@H](N)Cc1ccc(O)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)[C@H](Cc1ccc(O)cc1)NC(c1ccccc1)(c1ccccc1)c1ccccc1

Procedure:
L-Tyrosine tert-butyl ester* was reacted at room temperature in DMF, in the presence of triethylamine, with an equimolar amount of triphenylmethylchloride. Through mixing of the DMF phase with the 4-fold amount of ice the raw product is precipitated and recrystallized from ethanol.
Reaction SMILES: [CH3:1][N:2](C(OC(C)(C)C)=O)[CH:3]([CH2:5]/[CH:6]=[CH:7]/[C:8]1[CH:13]=[CH:12][C:11]2[O:14][CH2:15][O:16][C:10]=2[CH:9]=1)[CH3:4].FC(F)(F)C(O)=O>C1(OC)C=CC=CC=1>[CH3:1][NH:2][CH:3]([CH2:5]/[CH:6]=[CH:7]/[C:8]1[CH:13]=[CH:12][C:11]2[O:14][CH2:15][O:16][C:10]=2[CH:9]=1)[CH3:4]
Reactant: CC(C/C=C/c1ccc2c(c1)OCO2)N(C)C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: CNC(C)C/C=C/c1ccc2c(c1)OCO2
Temperature: 2.5 °C
Reaction time: 1.5 h
Yield: 117.4 %

Procedure:
Under a nitrogen atmosphere, a cold (0-5° C.), stirring solution of (4E)-N-methyl-N-(tert-butoxycarbonyl)-5-(3,4-methylenedioxyphenyl)-4-penten-2-amine (1.08 g, 3.38 mmol) in anisole (11 mL) was treated drop-wise over 45 min with trifluoroacetic acid (16.28 g, 142.8 mmol). The resulting solution was stirred for 1.5 h at 0-5° C. The solution was then concentrated by rotary evaporation followed by further drying under high vacuum. The resulting red oil was cooled (0-5° C.), basified with 10% NaOH solution (15 mL), treated with saturated NaCI solution (10 mL) and extracted with CHCl3 (6×20 mL). The combined CHCl3 extracts were washed with saturated NaCl solution (25 mL), dried (Na2SO4), filtered, concentrated by rotary evaporation, followed by further drying under high vacuum to produce a brown oil (0.87 g). The crude product was purified by column chromatography on silica gel (50 g), eluting with CH3OH—Et3N (98:2, v/v). Selected fractions containing the product (Rf 0.37) were combined and concentrated on a rotary evaporator. The residue was dissolved in CHCl3. The CHCl3 solution was dried (Na2SO4), filtered, concentrated by rotary evaporation and dried under high vacuum to give 380.3 mg (51.3%) of a light-yellow oil.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][CH2:8][OH:9])[CH:2]=1.C(N(CC)CC)C.[CH3:17][S:18](Cl)(=[O:20])=[O:19]>C1COCC1>[CH3:17][S:18]([O:9][CH2:8][CH2:7][C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1)(=[O:20])=[O:19]
Reactant: CS(=O)(=O)Cl
Reactant: OCCc1cccnc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCCc1cccnc1

Procedure:
The 2-(3-pyridyl)ethan-1-ol (Maybridge, 0.15 g, 1.2 mmol), triethylamine (0.56 mL, 4.1 mmol), and methanesulfonyl chloride (0.15 mL, 1.9 mmol) in 10 mL THF were processed as described in Example 1C to give the title compound that was used directly in the next reaction.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:29]=[CH:28][C:7]([C:8]([C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[NH:16][C:15](=[O:20])[CH:14]=[C:13]3[C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[CH:22]=2)=[O:9])=[CH:6][CH:5]=1.[CH3:30][O:31][CH2:32][CH2:33]Cl>CS(C)=O>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([C:8]([C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]([CH2:33][CH2:32][O:31][CH3:30])[C:15](=[O:20])[CH:14]=[C:13]3[C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[CH:22]=2)=[O:9])=[CH:28][CH:29]=1
Reactant: COCCCl
Reactant: O=C(c1ccc(Cl)cc1)c1ccc2[nH]c(=O)cc(-c3cccc(Cl)c3)c2c1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: COCCn1c(=O)cc(-c2cccc(Cl)c2)c2cc(C(=O)c3ccc(Cl)cc3)ccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 36 %

Procedure:
Sodium hydride (601 g) was added portionwise under N2 flow to a solution of interm. (9-d) (15 g) in dimethyl sulfoxide (200 ml). The mixture was stirred at room temperature for 30 minutes. 2-Chloroethyl methyl ether (25.2 ml) was added. The mixture was stirred at 50° C. for 72 hours, poured out on ice and extracted with ethyl acetate. The organic layer was separated, washed with water, dried (MgSO4), filtered and the solvent was evaporated. The residue was purified by column chromatography over silica gel (eluent: cyclohexane/ethyl acetate 70/30). The pure fractions were collected and the solvent was evaporated, yielding 6.2 g (36%) of 6-(4-chlorobenzoyl)-4-(3-chlorophenyl)-1-(2-methoxyethyl)-2(1H)-quinolinone (interm. 9-e).
Reaction SMILES: COC([O:5][C@@H:6]1[C@H:10]([O:11]C(OC)=O)[C@@H:9]([CH3:16])[O:8][C@H:7]1[N:17]1[CH:32]=[C:31]([F:33])[C:21]([NH:22][C:23]([O:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])=[O:24])=[N:20][C:18]1=[O:19])=O.CO.[OH-].[Na+].Cl>O>[F:33][C:31]1[C:21]([NH:22][C:23]([O:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])=[O:24])=[N:20][C:18](=[O:19])[N:17]([CH:32]=1)[C@@H:7]1[O:8][C@H:9]([CH3:16])[C@@H:10]([OH:11])[C@H:6]1[OH:5]
Reactant: CCCCCOC(=O)Nc1nc(=O)n([C@@H]2O[C@H](C)[C@@H](OC(=O)OC)[C@H]2OC(=O)OC)cc1F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCCCCOC(=O)Nc1nc(=O)n([C@@H]2O[C@H](C)[C@@H](O)[C@H]2O)cc1F
Temperature: -2.5 °C
Yield: 88.2 %

Procedure:
42.9 g of the compound obtained in Example 3 was added to 215 ml of methanol, and the mixture was stirred and cooled to −5 to 0° C. 10.8 g of NaOH was dissolved in 107 ml of water, and NaOH solution was added thereto while maintaining the reaction mixture temperature at less than 0° C. The resulting mixture was stirred for 30 min, and 48 ml of 6 N HCl was added dropwise thereto until the pH of the reaction mixture became 5.3. The resulting mixture was successively washed twice with 215 ml of dichloromethane and once with 108 ml of dichloromethane, and the combined organic layer was washed with 215 ml of water, dried over anhydrous sodium sulfate, filtered and concentrated under a reduced pressure. After adding 129 ml of ethylacetate thereto, the residue was mixed with 97 ml of ethylacetate by stirring to be crystallized. 97 ml of hexane was added dropwise thereto to allow the crystal to be matured, and the resulting mixture was stirred for 1 hr, cooled to 0° C. and again stirred for 1 hr. The resulting solid was filtered, washed with 86 ml of a solid mixture of ethylacetate and hexane (1:1 (v/v)) cooled to 0° C., and dried in a 35° C. vacuum oven overnight, to obtain 28.6 g of the title compound as a light white solid.