Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Li])(C)(C)C.Br[C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[N:13]=[C:12]([O:17][CH3:18])[CH:11]=[CH:10]2.I[C:20]1[CH:29]=[CH:28][C:23]([C:24]([O:26][CH3:27])=[O:25])=[CH:22][CH:21]=1>CCCCC.O1CCCC1.[Cl-].[Zn+2].[Cl-].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>[CH3:18][O:17][C:12]1[CH:11]=[CH:10][C:9]2[C:14](=[CH:15][CH:16]=[C:7]([C:20]3[CH:29]=[CH:28][C:23]([C:24]([O:26][CH3:27])=[O:25])=[CH:22][CH:21]=3)[CH:8]=2)[N:13]=1
Reactant: COc1ccc2cc(Br)ccc2n1
Reactant: COC(=O)c1ccc(I)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Solvent: CCCCC
Product: COC(=O)c1ccc(-c2ccc3nc(OC)ccc3c2)cc1
Temperature: 25 °C

Procedure:
t-Butyllithium (30 cm3 of a 2.0M solution in n-pentane) was added dropwise at -70° to a stirred solution of 6-bromo-2-methoxyquinoline (7.14 g) in tetrahydrofuran (THF) (50 cm3) under nitrogen. After 10 minutes a solution of anhydrous zinc chloride (4.09 g) in THF (30 cm3) was added and the solution was allowed to warm to room temperature. A mixture of methyl 4-iodobenzoate (7.8 g) and tetrakis(triphenylphosphine)palladium (0) (0.32 g) was added and the mixture was heated under reflux for 1 hour. Volatile material was removed in vacuo and the residue was partitioned between chloroform (150 cm3) and a solution of ethylenediaminetetraacetic acid disodium salt (22.4 g) in water (400 cm3). The aqueous phase was further extracted with chloroform (2×100 cm3), and the combined and dried (MgSO4) organic extracts were evaporated to give a solid which was recrystallised from acetone to afford the title compound, m.p. 158°-161°, (6.81 g).
Reaction SMILES: C[O:2][C:3]1[C:8]2[C:9](=[O:14])[O:10][C:11](=[O:13])[NH:12][C:7]=2[CH:6]=[CH:5][CH:4]=1.[Al+3].[Cl-].[Cl-].[Cl-]>ClCCl.[Cl-].[Na+].O>[OH:2][C:3]1[C:8]2[C:9](=[O:14])[O:10][C:11](=[O:13])[NH:12][C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: COc1cccc2[nH]c(=O)oc(=O)c12
Agent: [Al+3]
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: O=c1[nH]c2cccc(O)c2c(=O)o1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A suspension of Example 385A (1.93 g, 10 mmol) in dichloromethane (100 mL) was treated with AlCl3 (2.6 g, 20 mmol), stirred at room temperature overnight, treated slowly with brine (100 mL) while vigorously stirring, and extracted with ethyl acetate. The desired product was obtained as a white solid after evaporation of the solvent. Yield: 1.74 g, 97.2%. 1H NMR (DMSO-d6) δ 6.55 (d, 1H), 6.65 (d, 1H), 7.50 (t, 1H), 10.35 (s, 1H), 11.62 (br s, 1H); MS (ESI(−)) m/e 178 (M−H)−.
Reaction SMILES: CN(C)C(=O)[S:4][C:5]1[C:13]([CH3:14])=[CH:12][C:11]([N+:15]([O-:17])=[O:16])=[C:10]2[C:6]=1[CH2:7][CH2:8][CH2:9]2.[OH-].[Na+].Cl>CO>[CH3:14][C:13]1[CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[C:10]2[CH2:9][CH2:8][CH2:7][C:6]=2[C:5]=1[SH:4]
Reactant: Cc1cc([N+](=O)[O-])c2c(c1SC(=O)N(C)C)CCC2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1cc([N+](=O)[O-])c2c(c1S)CCC2
Temperature: 90 °C
Reaction time: 6 h
Yield: 50.1 %

Procedure:
A suspension of S-(5-methyl-7-nitroindan-4-yl) dimethylthiocarbamate (5.0 g) in a 2 mol/L aqueous solution of sodium hydroxide (30 mL) and methanol (30 mL) was stirred at 90° C. under an argon atmosphere for 6 hours. The reaction mixture was cooled to room temperature. The reaction mixture was acidified by 1 mol/L hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: hexane/ethyl acetate=5/1−3/1) to give the title compound (1.87 g).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[C:7]([F:12])[CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:13]([O:15]CC)=O)[N:3]=1.[F:18][C:19]1[CH:24]=[CH:23][C:22]([Mg]Br)=[CH:21][CH:20]=1.C1COCC1.Cl.[Na+].[Cl-]>C1COCC1>[Cl:1][C:2]1[C:11]2[C:6](=[C:7]([F:12])[CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:13]([C:22]2[CH:23]=[CH:24][C:19]([F:18])=[CH:20][CH:21]=2)=[O:15])[N:3]=1
Reactant: CCOC(=O)c1nc(Cl)c2cccc(F)c2n1
Reactant: Fc1ccc([Mg]Br)cc1
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(c1ccc(F)cc1)c1nc(Cl)c2cccc(F)c2n1
Temperature: -40 °C
Reaction time: 3 h
Yield: 92.5 %

Procedure:
To a solution of ethyl 4-chloro-8-fluoroquinazoline-2-carboxylate (360 mg, 1.42 mmol) in THF (20 mL) at −40° C. was added 1M 4-fluorophenylmagnesium bromide/THF (1.7 mL, 1.7 mmol) and the mixture was stirred at −40° C. for 3 h. After this time, and additional portion of 1M 4-fluorophenylmagnesium bromide/THF (0.3 mL, 0.3 mmol) was added and the mixture was stirred at −40° C. for 2 h. To the mixture was added 0.5N HCl to give pH 2, and then saturated aq NaCl (50 mL) was added, and the mixture was extracted with EtOAc (3×50 mL). The combined organic layers were washed with brine (80 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to afford (4-chloro-8-fluoroquinazolin-2-yl)(4-fluorophenyl)methanone (0.4 g, 93%). 1H NMR (300 MHz, DMSO-d6) δ 7.04-7.25 (m, 1H), 7.31-7.58 (m, 2H), 7.70-8.36 (m, 4H); LC-MS (ESI) m/z 305 (M+H)+, 327 (M+Na)+.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH2:11][NH2:12])=[CH:5][CH:4]=1.CCN(CC)CC.[CH:20]1([C:27]2[CH:36]=[CH:35][C:30]3[NH:31][C:32](=[O:34])[O:33][C:29]=3[CH:28]=2)[CH2:25][CH2:24][C:23](=O)[CH2:22][CH2:21]1.[BH4-].[Na+]>CC(O)C.C1COCC1>[Cl:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][CH2:10][CH2:11][NH:12][C@H:23]2[CH2:24][CH2:25][C@H:20]([C:27]3[CH:36]=[CH:35][C:30]4[NH:31][C:32](=[O:34])[O:33][C:29]=4[CH:28]=3)[CH2:21][CH2:22]2)=[CH:7][CH:8]=1
Reactant: O=C1CCC(c2ccc3[nH]c(=O)oc3c2)CC1
Reactant: NCCCc1ccc(Cl)cc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CC(C)O
Product: O=c1[nH]c2ccc([C@H]3CC[C@H](NCCCc4ccc(Cl)cc4)CC3)cc2o1
Temperature: 25 °C
Reaction time: 2.25 h

Procedure:
To a solution of 3-(4-Chlorophenyl)-1-propylamine hydrochloride (1.5 g, 7.3 mmol) in 2-propanol (50 mL) was added Et3N (1.1 mL, 8.0 mmol), ketone 5 (1.7 g, 7.3 mmol), THF (25 mL), and 3 Å molecular sieves. The reaction mixture was warmed to dissolve ketone 5 and then stirred at room temperature for 2.25 hours. Sodium borohydride (550 mg, 14.5 mmol) was added, and the reaction mixture was stirred for 12 hours. The reaction was quenched with MeOH, and the mixture was filtered through a pad of Celite and concentrated under reduced pressure. Purification by flash chromatography (silica, 90:10 CH2Cl2/MeOH) followed by trituration/recrystallization with MeOH gave 6-{trans-4-[3-(4-chlorophenyl)propylamino]cyclohexyl}-3H-benzoxazol-2-one (683 mg, 24%), as a white solid: 1H NMR (500 MHz, DMSO-d6): δ 7.32 (d, J=8 Hz, 2H), 7.23 (d, J=8 Hz, 2H), 7.12 (s, 1H), 6.98-6.93 (m, 2H), 2.61 (t, J=7 Hz, 2H), 2.56 (t, J=7 Hz, 2H), 2.48-2.38 (m, 2H), 1.94 (br d, J=10 Hz, 2H), 1.77 (br d, J=10 Hz, 2H), 1.72-1.66 (m, 2H), 1.44 (dddd, J=12, 12, 12, 3 Hz, 2H), 1.12 (dddd, J=12, 12, 12, 3 Hz, 2H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:19]=[CH:18][CH:17]=[C:13]([C:14]([OH:16])=O)[C:12]=2[C:20]([OH:22])=O)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].Cl.[NH2:24][CH:25]1[CH2:31][CH2:30][C:29](=[O:32])[NH:28][C:26]1=[O:27]>N1C=CC=CC=1>[O:27]=[C:26]1[CH:25]([N:24]2[C:20](=[O:22])[C:12]3[C:13](=[CH:17][CH:18]=[CH:19][C:11]=3[NH:10][C:4]3[CH:5]=[CH:6][C:7]([O:8][CH3:9])=[C:2]([OH:1])[CH:3]=3)[C:14]2=[O:16])[CH2:31][CH2:30][C:29](=[O:32])[NH:28]1
Reactant: COc1ccc(Nc2cccc(C(=O)O)c2C(=O)O)cc1O
Reactant: NC1CCC(=O)NC1=O
Agent: Cl
Solvent: c1ccncc1
Product: COc1ccc(Nc2cccc3c2C(=O)N(C2CCC(=O)NC2=O)C3=O)cc1O
Yield: 56.9 %

Procedure:
A mixture of 3-(3-hydroxy-4-methoxyphenylamino)phthalic acid (0.60 g, 2.0 mmol) and rac-α-aminoglutarimide hydrochloride (0.33 g, 2.0 mmol) in pyridine (10 mL) was heated to reflux for 16 hours. The mixture was cooled and evaporated under vacuum. The residue was dissolved in ethyl acetate (150 mL), washed with dilute aqueous HCl (2×100 mL) and water (2×100 mL), was dried (MgSO4) and evaporated. The residue was triturated in 1:1 acetonitrile-water (15 mL) and filtered, and the resulting solid was washed with additional 1:1 acetonitrile-water and dried under high vacuum, providing 0.45 g of the product, in 58% yield: mp 225-227° C.; 1H NMR (DMSO-d6) δ 2.03-2.08 (m, 1H), 2.52-2.63 (m, 2H), 2.83-2.92 (m, 1H), 3.77 (s, 3H), 5.11 (dd, J=12.5 Hz, J=5.4 Hz, 1H), 6.69-6.76 (m, 2H), 6.94 (d, J=8.5 Hz, 1H), 7.14-7.23 (m, 2H), 7.56 (t, J=7.8 Hz, 1H), 8.15 (s, 1H), 9.21 (s, 1H), 11.13 (s, 1H); 13C NMR (DMSO-d6) δ 22.1, 31.0, 48.6, 55.9, 110.7, 111.5, 112.5, 113.0, 114.2, 118.8, 132.1, 132.3, 136.1, 144.2, 145.2, 147.2, 167.1, 168.4, 170.0, 172.8; Anal. calcd for C20H17N3O6: C, 60.76; H, 4.33; N, 10.63. Found: C, 60.76; H, 4.11; N, 10.42.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[N:11]=[C:10]([C@@H:12]3[CH2:16][CH2:15][C@H:14]([CH2:17][OH:18])[CH2:13]3)[O:9][N:8]=2)=[CH:3][CH:2]=1.[H-].[Na+].Br[CH2:22][CH2:23][CH2:24][CH3:25]>C1COCC1.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH2:22]([O:18][CH2:17][C@@H:14]1[CH2:15][CH2:16][C@H:12]([C:10]2[O:9][N:8]=[C:7]([C:4]3[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=3)[N:11]=2)[CH2:13]1)[CH2:23][CH2:24][CH3:25]
Reactant: OC[C@H]1CC[C@@H](c2nc(-c3ccncc3)no2)C1
Reactant: CCCCBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [H-]
Agent: [I-]
Solvent: C1CCOC1
Product: CCCCOC[C@@H]1CC[C@H](c2nc(-c3ccncc3)no2)C1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A solution of cis-[3-(3-pyridin-4-yl-[1,2,4]oxadiazol-5-yl)cyclopentyl]methanol (Preparation 5, 40 mg, 0.116 mmol) in anhydrous THF (2 ml) was treated with sodium hydride (23 mg of a 60% dispersion in oil, 0.57 mmol) and tetrabutylammonium iodide (6 mg, 16 μmol). After stirring the mixture at rt for 10 min, 1-bromobutane (59 μl, 0.65 mmol) was introduced and stirring continued for 72 h. The solvent was removed in vacuo, the residue dissolved in CH2Cl2 (20 ml) and washed with water (2×5 ml). The organic phase was dried (MgSO4) and evaporated. Flash chromatography (IH-EtOAc, 7:3) afforded the title compound: RT=3.99 min, m/z (ES−)=302.3 [M+H]+.
Reaction SMILES: [C:1]([CH:8]([NH2:12])[CH2:9][CH2:10]Br)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[NH:13]1[CH2:18][CH2:17][S:16][CH2:15][CH2:14]1>C(Cl)Cl>[C:1]([CH:8]([NH2:12])[CH2:9][CH2:10][SH:16]1[CH2:17][CH2:18][NH:13][CH2:14][CH2:15]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CC(C)(C)OC(=O)C(N)CCBr
Reactant: C1CSCCN1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)C(N)CC[SH]1CCNCC1
Temperature: 25 °C
Yield: 92.7 %

Procedure:
A solution of 3-BOC-aminopropyl bromide (3.07 g; 12.9 mmol) and thiamorpholine (2.6 mL; 25.8 mmol) in CH2Cl2 (25 mL) is heated at the reflux temperature for 24 h. The mixture is cooled at r.t., filtered, washed with water (2×50 mL), dried over Na2SO4 and evaporated to dryness in vacuum. Purification by flash chromatography on silica gel (eluent CHCl3/CH3OH 9:1) yields 1-(3-BOC-aminopropyl)-thiamorpholine (3.1 g; 11.96 mmol), as a transparent oil.
Reaction SMILES: F[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.[OH:12][CH2:13][CH2:14][CH:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1.O>CN1CCCC1=O>[CH3:9][O:8][C:6]([C:5]1[CH:10]=[CH:11][C:2]([N:18]2[CH2:19][CH2:20][CH:15]([CH2:14][CH2:13][OH:12])[CH2:16][CH2:17]2)=[CH:3][CH:4]=1)=[O:7]
Reactant: COC(=O)c1ccc(F)cc1
Reactant: OCCC1CCNCC1
Solvent: CN1CCCC1=O
Solvent: O
Product: COC(=O)c1ccc(N2CCC(CCO)CC2)cc1
Reaction time: 72 h
Yield: 70.7 %

Procedure:
A solution of 9.84 grams of methyl 4-fluorobenzoate (63.9 mmol) and 12.40 grams of 4-(2-hydroxyethyl)piperdine (96 mmol) in 50 mL N-methylpyrrolidin-2-one was heated to 110°-120° C. and stirred for 72 hours. The dark solution was cooled and poured into 400 mL water. The tan precipitate was filtered off and washed well with water to yield 11.89 grams of crude product as a tan powder (71%). The crude material was recrystallized once from 100 mL ethanol which gave 4.75 grams (40% recovery) of a tan powder. Melting point 110°-115° C. 2H NMR δ (acetone-d6): 1.27 (2H, quad of doub, J=3.8 hz & 12.2 hz); 1.47 (2H, quad, J=6.6 hz); 1.71 (1H, mult); 1.80 (2H, br doub); 2.83 (2H, trip of doub, J=2.5 hz & 12.6 hz); 3.62 (2H, trip, J=6.6 hz); 3.78 (3H, s); 3.92 (2H, br doub); 6.93 (2H, doub); 7.81 (2H, doub). 13C NMR δ (acetone-d6): 32.59, 33.36, 40.30, 48.61, 51.55, 59.81, 114.30, 119.26, 132.0, 155.29, 167.18.
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[N:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:4](=[O:18])[C:3]=1[C:19](=O)[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([N+:27]([O-:29])=[O:28])[CH:22]=1.O.[NH2:32][NH2:33]>CN(C=O)C>[N+:27]([C:23]1[CH:22]=[C:21]([CH:26]=[CH:25][CH:24]=1)[CH2:20][C:19]1[C:3]2[C:4](=[O:18])[N:5]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:6]3[N:7]=[CH:8][CH:9]=[CH:10][C:11]=3[C:2]=2[NH:33][N:32]=1)([O-:29])=[O:28]
Reactant: O=C(Cc1cccc([N+](=O)[O-])c1)c1c(O)c2cccnc2n(-c2ccccc2)c1=O
Reactant: NN
Solvent: CN(C)C=O
Solvent: O
Product: O=c1c2c(Cc3cccc([N+](=O)[O-])c3)n[nH]c2c2cccnc2n1-c1ccccc1
Yield: 70.4 %

Procedure:
To a suspension of 4-hydroxy-3-[1-oxo-2-(3-nitrophenyl)ethyl]-1-phenyl-1,8-naphthyridin-2 (1H)-one (568 mg, 1.42 mmol, prepared in Synthetic Example 19) in DMF (14 ml) was added hydrazine monohydrate (80%, 203 μl, 5.07 mmol, 3.6 eq.), and the mixture was treated in the same manner as in Example 24 to give 3-(3-nitrobenzyl)-5-phenyl-1H-pyrazolo[4,3-c][1,8]naphthyridin-4 (5H)-one (397 mg, 71%).
Reaction SMILES: C([O:8][C@H:9]1[C@H:14]([O:15]CC2C=CC=CC=2)[C@@H:13]([O:23]CC2C=CC=CC=2)[C@H:12]([C:31]2[CH:36]=[CH:35][C:34]([Cl:37])=[C:33]([CH2:38][C:39]3[CH:44]=[CH:43][C:42]([CH2:45][CH2:46][O:47][CH:48]([F:50])[F:49])=[CH:41][CH:40]=3)[CH:32]=2)[O:11][C@@H:10]1[CH2:51][O:52]CC1C=CC=CC=1)C1C=CC=CC=1.CO.O1CCCC1>[Pd].ClC1C=CC=CC=1Cl>[Cl:37][C:34]1[CH:35]=[CH:36][C:31]([C@H:12]2[C@H:13]([OH:23])[C@@H:14]([OH:15])[C@H:9]([OH:8])[C@@H:10]([CH2:51][OH:52])[O:11]2)=[CH:32][C:33]=1[CH2:38][C:39]1[CH:44]=[CH:43][C:42]([CH2:45][CH2:46][O:47][CH:48]([F:50])[F:49])=[CH:41][CH:40]=1
Reactant: FC(F)OCCc1ccc(Cc2cc([C@@H]3O[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)ccc2Cl)cc1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Solvent: Clc1ccccc1Cl
Product: OC[C@H]1O[C@@H](c2ccc(Cl)c(Cc3ccc(CCOC(F)F)cc3)c2)[C@H](O)[C@@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 64 %

Procedure:
(2R,3R,4R,5S,6S)-3,4,5-tris(benzyloxy)-2-(benzyloxymethyl)-6-(4-chloro-3-(4-(2-(difluoromethoxy)ethyl)benzyl)phenyl)tetrahydro-2H-pyran (intermediate BM) was taken up in a mixture of 4:1 methanol:tetrahydrofuran (0.5 mL) and 9.6 μL of 1,2-dichlorobenzene was added followed by palladium on charcoal (10%, 5 mg). The mixture was stirred at room temperature under a hydrogen balloon for 30 min. The mixture was passed through a short Celite® pad to remove the catalyst, and the pad was washed with methanol (1 mL). Solvent was evaporated and the product was purified by TLC using 8:1 dichloromethane:methanol to obtain compound BN (2.5 mg, yield 64%). 1H NMR (300 MHz, CDCl3): δ 7-33-7.11 (m, 7H), 6.30 (t, JC-F=75.6 Hz, 1H), 4.13 (d, J=9 Hz, 1H), 4.04 (m, 4H), 3.86-3.80 (m, 3H), 3.64 (t, J=4.5, 6.6 Hz, 2H), 3.47-3.41 (m, 2H), 2.90 (t, J=6.9, 7.2 Hz, 2H); LC-ESI-MS (m/z): 457 (M−H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([O:15][CH3:16])[C:9]=1[O:10][CH2:11][CH2:12][O:13][CH3:14])[CH:5]=[O:6].C1COCC1.[C:22]1([Mg]Br)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C(OCC)C>[Br:1][C:2]1[CH:3]=[C:4]([CH:5]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[OH:6])[CH:7]=[C:8]([O:15][CH3:16])[C:9]=1[O:10][CH2:11][CH2:12][O:13][CH3:14]
Reactant: Br[Mg]c1ccccc1
Reactant: COCCOc1c(Br)cc(C=O)cc1OC
Solvent: CCOCC
Solvent: C1CCOC1
Product: COCCOc1c(Br)cc(C(O)c2ccccc2)cc1OC
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a 1l round bottomed flask with a stirring bar and an argon inlet was added 3-bromo-4-(2-methoxyethoxy)-5-methoxybenzaldehyde (12.00 g, 41.50 mmol) and dry THF (150 mL). This solution was cooled in an ice bath and phenylmagnesiumbromide in diethyl ether (16.6 mL of a 3.0 M solution, 49.81 mmol) was added with a syringe. The resulting solution was stirred for 1 h at 0° C. The reaction was quenched with aqueous NH4Cl solution. The mixture was diluted with EtOAc and the layers were separated. The organic phase was washed with brine, dried (MgSO4), filtered and concentrated in vacuo. This material was chromatographed on 400g of silica gel using 30/70 EtOAc-hexane as eluant. There was obtained 1-(3-bromo-4-(2-methoxyethoxy)-5-methoxyphenyl)-1-phenylmethanol as an oil. 1H NMR (CDCl3): δ2.29 (d, j=4Hz, 1H); 3.44 (s, 3H); 3.74 (t, j=4 Hz, 2H); 3.82 (s, 3H); 4.13 (t, j=4 Hz, 2H); 5.75 (d, j=4Hz, 1H); 6.88 (s, 1H); 7.12 (s, 1H); 7.35 (m, 5H).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([O:12][CH3:13])=[O:11])=[CH:5][CH:4]=1)#[N:2].Cl.[NH2:15][OH:16].C([O-])(O)=O.[Na+]>CO>[OH:16][NH:15][C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([O:12][CH3:13])=[O:11])=[CH:5][CH:4]=1)=[NH:2]
Reactant: COC(=O)Cc1ccc(C#N)cc1
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: COC(=O)Cc1ccc(C(=N)NO)cc1
Temperature: 60 °C
Reaction time: 18 h
Yield: 63.4 %

Procedure:
To a solution of methyl (4-cyanophenyl)acetate (4.00 g, 27.8 mmol) in MeOH (20 mL), hydroxylamine hydrochloride (3.17 g, 45.7 mmol) and NaHCO3 (3.84 g, 45.7 mmol) is added. The suspension is stirred at 60° C. for 18 h before it is filtered and the filtrate is concentrated. The residue is dissolved in DCM, washed with water followed by brine, dried over MgSO4, filtered, concentrated and dried to give methyl [4-(N-hydroxycarbamimidoyl)-phenyl]-acetate (3.67 g) as a colourless oil; LC-MS: tR=0.50 min, [M+1]+=209.05.
Reaction SMILES: CC1C=CC=C(C)N=1.[N+](C1C=CC(C=O)=CC=1)([O-])=[O:10].[N+:20]([C:23]1[CH:47]=[CH:46][C:26]([CH:27]=[CH:28][C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([CH:35]=[CH:36][C:37]3[CH:42]=[CH:41][C:40]([N+:43]([O-:45])=[O:44])=[CH:39][CH:38]=3)[N:30]=2)=[CH:25][CH:24]=1)([O-:22])=[O:21].ClC1C=CC=C(C(OO)=O)C=1>ClCCl>[N+:20]([C:23]1[CH:47]=[CH:46][C:26]([CH:27]=[CH:28][C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([CH:35]=[CH:36][C:37]3[CH:42]=[CH:41][C:40]([N+:43]([O-:45])=[O:44])=[CH:39][CH:38]=3)[N+:30]=2[O-:10])=[CH:25][CH:24]=1)([O-:22])=[O:21]
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Reactant: O=[N+]([O-])c1ccc(C=Cc2cccc(C=Cc3ccc([N+](=O)[O-])cc3)n2)cc1
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc(C=Cc2cccc(C=Cc3ccc([N+](=O)[O-])cc3)[n+]2[O-])cc1

Procedure:
More specifically, the synthesizing procedure is as follows. 2,6-dimethylpyridine or a substituted product thereof, is reacted with p-nitrobenzenealdehyde or a substituted product according to a method described, for example, in Journal of Organic Chemistry, vol. 15, P. 1184 (1950) to synthesize 2,6-di(p-nitrostyryl)pyridine (K). 30 g of this nitro compound is reacted wtih 27 g of m-chloroperbenzoic acid in three liter of dichloromethane to obtain 24 g of 2,6-di(p-nitrostyryl)pyridine-N-oxide. 24 g of this pyridine-N-oxide is reacted with 90 g of sodium sulfide in a solution mixed four liter of water with four liter of ethanol to reduce nitro group selectively and form 18 g of 2,6-di(p-aminostyryl)pyridine-N-oxide (M). The N-oxide amino compound is converted into a diazo compound according to a conventional method, and thereby tetrazonium salt is isolated as 15 g of hydroborofluoric salt (N). 5.0 g of the tetrazonium salt (N) and 5.0 g of 2-hydroxy-3-phenylcarbamoylnaphthalene (O) were dissolved in one liter of DMF, to which aqueous sodium acetate solution (7 g/100 ml) was added to perform coupling reaction. After two hours of stirring, the resultant crystals were separated by filtration, and the crystals were rinsed three times respectively with five liter water, three times respectively with five liter THF, then dried, to obtain 4.0 g of the final product, azo compound (P - 1).
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:10][CH:9]([CH3:11])[NH:8][CH:7]([CH3:12])[CH2:6]1)(=[O:4])=[O:3].Br[CH2:14][C:15]1[S:23][C:22]2[C:21]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)=[N:20][C:19]([Cl:30])=[N:18][C:17]=2[C:16]=1[CH3:31].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Cl:30][C:19]1[N:20]=[C:21]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[C:22]2[S:23][C:15]([CH2:14][N:8]3[C@H:9]([CH3:11])[CH2:10][N:5]([S:2]([CH3:1])(=[O:3])=[O:4])[CH2:6][C@@H:7]3[CH3:12])=[C:16]([CH3:31])[C:17]=2[N:18]=1
Reactant: Cc1c(CBr)sc2c(N3CCOCC3)nc(Cl)nc12
Reactant: CC1CN(S(C)(=O)=O)CC(C)N1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Cc1c(CN2[C@H](C)CN(S(C)(=O)=O)C[C@@H]2C)sc2c(N3CCOCC3)nc(Cl)nc12
Temperature: 25 °C

Procedure:
To a mixture of 1-methanesulfonyl-3,5-dimethylpiperazine and 6-bromomethyl-2-chloro-7-methyl-4-morpholin-4-yl-thieno[3,2-d]pyrimidine in acetonitrile was added potassium carbonate and the mixture refluxed overnight. After cooling to room temperature, the acetonitrile was removed under reduced pressure. DCM/sat. aq.NaHCO3 extraction and purification on silica gave 2-chloro-6-((2S,6R)-4-methanesulfonyl-2,6-dimethyl-piperazin-1-ylmethyl)-7-methyl-4-morpholin-4-yl-thieno[3,2-d]pyrimidine.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:4]([F:23])=[CH:5][C:6]([Cl:22])=[C:7]([N:9]2[C:13](=[O:14])[NH:12][C:11]([C:15]3[CH:20]=[CH:19][C:18]([I:21])=[CH:17][CH:16]=3)=[N:10]2)[CH:8]=1.[C:24](Cl)(=[O:29])[C:25]([CH3:28])([CH3:27])[CH3:26].CCN(C(C)C)C(C)C>C1COCC1>[Cl:22][C:6]1[C:7]([N:9]2[C:13](=[O:14])[NH:12][C:11]([C:15]3[CH:16]=[CH:17][C:18]([I:21])=[CH:19][CH:20]=3)=[N:10]2)=[CH:8][C:3]([CH2:2][NH:1][C:24](=[O:29])[C:25]([CH3:28])([CH3:27])[CH3:26])=[C:4]([F:23])[CH:5]=1
Reactant: NCc1cc(-n2nc(-c3ccc(I)cc3)[nH]c2=O)c(Cl)cc1F
Reactant: CC(C)(C)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(C)(C)C(=O)NCc1cc(-n2nc(-c3ccc(I)cc3)[nH]c2=O)c(Cl)cc1F
Yield: 63 %

Procedure:
The title compound was prepared according to the procedure described in step-2 of Intermediate-83 by using 2-(5-(aminomethyl)-2-chloro-4-fluorophenyl)-5-(4-iodophenyl)-2H-1,2,4-triazol-3(4H)-one (0.400 g, 0.900 mmol), pivaloyl chloride (0.2 mL, 1.35 mmol), DIPEA (2 mL), and THF (10 mL) to afford 0.300 g of the desired product. 1H NMR (300 MHz, DMSO d6): δ 1.10 (s, 9H), 4.30 (d, J=5.4 Hz, 2H), 7.42-7.44 (m, 1H), 7.62-7.66 (m, 3H), 7.88-7.91 (br d, 1H), 8.14 (m, 1H); MS (m/z): 529.42 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@:8]2([C:26]#[N:27])[C@H:12]([CH2:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH2:11][NH:10][C@@H:9]2[C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[C:19]=2[Cl:25])=[C:4]([F:28])[CH:3]=1.[CH3:29][O:30][C:31](=[O:41])[C:32]1[CH:37]=[CH:36][C:35]([N:38]=[C:39]=[O:40])=[CH:34][CH:33]=1>C(Cl)Cl>[CH3:29][O:30][C:31](=[O:41])[C:32]1[CH:33]=[CH:34][C:35]([NH:38][C:39]([N:10]2[CH2:11][C@@H:12]([CH2:13][C:14]([CH3:17])([CH3:16])[CH3:15])[C@@:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][C:4]=3[F:28])([C:26]#[N:27])[C@H:9]2[C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[C:19]=2[Cl:25])=[O:40])=[CH:36][CH:37]=1
Reactant: CC(C)(C)C[C@@H]1CN[C@H](c2cccc(Cl)c2Cl)[C@@]1(C#N)c1ccc(Cl)cc1F
Reactant: COC(=O)c1ccc(N=C=O)cc1
Solvent: ClCCl
Product: COC(=O)c1ccc(NC(=O)N2C[C@@H](CC(C)(C)C)[C@](C#N)(c3ccc(Cl)cc3F)[C@H]2c2cccc(Cl)c2Cl)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 79.9 %

Procedure:
A mixture of rac-4-{[(2S,3S,4S)-3-(4-chloro-2-fluoro-phenyl)-2-(2,3-dichloro-phenyl)-4-(2,2-dimethyl-propyl)-pyrrolidine-3-carbonitrile (88.0 mg, 0.20 mmol) and 4-isocyanato-benzoic acid methyl ester (Aldrich, 42.5 mg, 0.22 mmol) in CH2Cl2 (2 mL) was stirred at rt for 1 h. The reaction mixture was then concentrated and purified by flash column to give rac-4-{[(2S,3S,4S)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-2-(2,3-dichloro-phenyl)-4-(2,2-dimethyl-propyl)-pyrrolidine-1-carbonyl]-amino}-benzoic acid methyl ester (98.6 mg, 79.9%) which was used in the next step without further purification.