Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][C:9](=[O:34])[CH2:10][N:11]1[CH2:33][CH2:32][CH2:31][C@H:12]1[C:13]([N:15]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:16](=[O:23])[C@H:17]([C@H:19]([CH2:21][CH3:22])[CH3:20])[NH2:18])=[O:14])C1C=CC=CC=1.[H][H]>[Pd].CO>[C:9]([CH2:10][N:11]1[CH2:33][CH2:32][CH2:31][C@H:12]1[C:13]([N:15]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:16](=[O:23])[C@H:17]([C@H:19]([CH2:21][CH3:22])[CH3:20])[NH2:18])=[O:14])([OH:34])=[O:8]
Reactant: CC[C@H](C)[C@H](N)C(=O)N(Cc1ccccc1)C(=O)[C@@H]1CCCN1CC(=O)OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CC[C@H](C)[C@H](N)C(=O)N(Cc1ccccc1)C(=O)[C@@H]1CCCN1CC(=O)O
Temperature: 22 °C
Reaction time: 8 h
Yield: 96 %

Procedure:
Using the hydrogenation conditions described in example 4, a solution of L-isoleucine, N-[1-(2-benzyloxy-2-oxoethyl)-L-prolyl] benzylamide (14.80 g, 31.76 mmol), 10% palladium on carbon (0.80 g), and methanol (350 mL), was purged with hydrogen, and stirred under an atmosphere of hydrogen at 22° C. After 8 hrs, the solution was purged with argon, filtered through a plug of celite, and concentrated in vacuo to provide 11.47 g, (96%) of L-isoleucine, N-[1-(carboxymethyl)-L-prolyl] benzylamide as a white solid.
Reaction SMILES: C[CH2:2][N:3](CC)[CH2:4]C.N(C)C.Cl.[Cl:12][C:13]1[CH:33]=[C:32]([CH:34]=O)[CH:31]=[C:30]([Cl:36])[C:14]=1[C:15]([NH:17][C:18]1[CH:23]=[CH:22][N:21]=[C:20]([NH:24][C:25]([CH:27]2[CH2:29][CH2:28]2)=[O:26])[CH:19]=1)=[O:16].[BH4-].[Na+]>CO.CCOC(C)=O>[Cl:36][C:30]1[CH:31]=[C:32]([CH2:34][N:3]([CH3:4])[CH3:2])[CH:33]=[C:13]([Cl:12])[C:14]=1[C:15]([NH:17][C:18]1[CH:23]=[CH:22][N:21]=[C:20]([NH:24][C:25]([CH:27]2[CH2:29][CH2:28]2)=[O:26])[CH:19]=1)=[O:16]
Reactant: O=Cc1cc(Cl)c(C(=O)Nc2ccnc(NC(=O)C3CC3)c2)c(Cl)c1
Reactant: CCN(CC)CC
Agent: CNC
Agent: Cl
Agent: [BH4-]
Solvent: CCOC(C)=O
Solvent: CO
Product: CN(C)Cc1cc(Cl)c(C(=O)Nc2ccnc(NC(=O)C3CC3)c2)c(Cl)c1
Temperature: 25 °C
Reaction time: 9 h
Yield: 36.8 %

Procedure:
To a solution of Et3N (121 mg, 1.2 mmol) in absolute methanol (1 mL) was added Me2NH HCl (103 mg, 1.2 mmol), Ti(O-iPr)4 (114 mg, 0.40 mmol), and 2,6-dichloro-N-(2-(cyclopropanecarboxamido)pyridin-4-yl)-4-formylbenzamide (80 mg, 0.20 mmol). The reaction was stirred at room temperature for 9 hours and then NaBH4 (12 mg, 0.30 mmol) was added. The resulting mixture was stirred for 10 hours and then diluted with EtOAc (20 mL). The organic solution was washed with water (3×10 ml) and then concentrated under reduced pressure. The residue was purified by prep-HPLC (Gilson GX 281, Shim-pack PRC-ODS 250 mm×20 mm×2, gradient: CH3CN/10 mm/L NH4HCO3, 17 min) to afford the desired product (30 mg, 31% yield). 1H NMR (500 MHz, MeOH-d4): δ 8.31 (s, 1H), 8.24 (s, 1H), 7.60 (m, 1H), 7.48 (s, 2H), 3.52 (s, 2H), 2.28 (s, 6H), 1.91 (m, 1H), 1.02-0.98 (m, 2H), 0.94-0.90 (m, 2H). LCMS (ESI) m/z: 407.1 [M+H+].
Reaction SMILES: C1(C2C=CC=CC=2)C=CC(C(=O)CC2C=CC=CC=2)=CC=1.CON(C)[C:25](=[O:35])[CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([O:33][CH3:34])[CH:28]=1.Br[C:38]1[CH:43]=[CH:42][C:41]([F:44])=[CH:40][CH:39]=1>>[F:44][C:41]1[CH:42]=[CH:43][C:38]([C:25](=[O:35])[CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([O:33][CH3:34])[CH:28]=2)=[CH:39][CH:40]=1
Reactant: Fc1ccc(Br)cc1
Reactant: COc1cccc(CC(=O)N(C)OC)c1
Agent: O=C(Cc1ccccc1)c1ccc(-c2ccccc2)cc1
Product: COc1cccc(CC(=O)c2ccc(F)cc2)c1
Yield: 37 %

Procedure:
Followed the procedure described in Synthesis of Intermediate 14 using N-methoxy-2-(3-methoxyphenyl)-N-methylacetamide and 1-bromo-4-fluorobenzene to give desired Intermediate 53 (260 mg, 37% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([C:9]([OH:11])=O)[CH:6]=[CH:5][C:4]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH3:18].C(Cl)(=O)C(Cl)=O.[CH:25]1[CH:26]=[CH:27][N:28]2[CH2:34][C:33]3[CH:35]=[CH:36][CH:37]=[CH:38][C:32]=3[NH:31][CH2:30][C:29]=12.C(N(CC)CC)C>ClCCl.CN(C)C=O>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([C:9]([N:31]2[C:32]3[CH:38]=[CH:37][CH:36]=[CH:35][C:33]=3[CH2:34][N:28]3[CH:27]=[CH:26][CH:25]=[C:29]3[CH2:30]2)=[O:11])[CH:6]=[CH:5][C:4]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH3:18]
Reactant: COc1cc(C(=O)O)ccc1-c1ccccc1C
Reactant: c1ccc2c(c1)Cn1cccc1CN2
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1cc(C(=O)N2Cc3cccn3Cc3ccccc32)ccc1-c1ccccc1C
Yield: 93.3 %

Procedure:
To a solution of 2-methoxy-2′-methyl-biphenyl-4-carboxylic acid of step D (23 mmol) in dichloromethane (50 mL) was added a drop of N,N-dimethylformamide. Oxalyl chloride (36 mmol) then was added dropwise to the solution, which then was stirred at reflux temperature for 2 hours. The solvents were evaporated and the resulting acid chloride was dissolved in 20 mL dichloromethane. This was added dropwise to a stirred mixture of 10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine (25 mmol) and triethylamine (34 mmol) in dichloromethane (30 mL) at 0° C. under nitrogen atmosphere. After 20 hours the mixture was quenched with water and washed with 0.5 N hydrochloric acid, 1.0 N sodium hydroxide, and brine. The solution was dried over anhydrous sodium sulfate, and evaporated to a solid. The product was purified by flash chromatography using ethyl acetate/hexane (1:3) to yield 8.77 g (95%) of the title compound as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:29]=[C:30]([N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)[CH:31]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21](S(C)(=O)=O)[N:20]=2)=[CH:10][CH:9]=1)=[O:6].[CH3:38][NH:39][C:40]([NH2:42])=[NH:41]>>[NH2:42][C:40]([N:39]([CH3:38])[C:21]1[N:20]=[C:19]([O:18][C:11]2[C:12]3[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:8]([NH:7][C:5](=[O:6])[C:4]3[CH:29]=[C:30]([N:32]4[CH2:37][CH2:36][O:35][CH2:34][CH2:33]4)[CH:31]=[C:2]([F:1])[CH:3]=3)=[CH:9][CH:10]=2)[CH:24]=[CH:23][N:22]=1)=[NH:41]
Reactant: CNC(=N)N
Reactant: CS(=O)(=O)c1nccc(Oc2ccc(NC(=O)c3cc(F)cc(N4CCOCC4)c3)c3ccccc23)n1
Product: CN(C(=N)N)c1nccc(Oc2ccc(NC(=O)c3cc(F)cc(N4CCOCC4)c3)c3ccccc23)n1

Procedure:
Compound is prepared from 3-fluoro-N-(4-{[2-(methylsulfonyl)pyrimidin-4-yl]oxy}-1-naphthyl)-5-morpholin-4-ylbenzamide and N-methylguanidine according to conditions described in general procedure C. Mp: 155-157° C.; 1H NMR (400 MHz, DMSO-d6) δ 3.19-3.33 (m, 7 H), 3.75-3.78 (m, 4 H), 6.50 (d, J=5.5 Hz, 1 H), 7.04 (d, J=12.0 Hz, 1 H), 7.27 (d, J=9.1Hz, 1 H), 7.34-7.68 (m, 7 H), 7.80 (d, J=8.8 Hz, 1 H), 7.99 (d, J=8.2 Hz, 1 H), 8.29 (d, J=5.5 Hz, 1 H), 10.47 (s, 1 H).
Reaction SMILES: O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[CH:24]1([C:27]([C:29]2[CH:53]=[CH:52][C:32]([O:33][C@@H:34]([C:37]3[O:41][N:40]=[C:39]([C:42]4[CH:50]=[CH:49][C:45]([C:46](O)=[O:47])=[C:44]([F:51])[CH:43]=4)[N:38]=3)[CH2:35][CH3:36])=[CH:31][CH:30]=2)=[O:28])[CH2:26][CH2:25]1.[NH2:54][C@H:55]1[C@@H:59]([OH:60])[CH2:58][O:57][C:56]1=[O:61]>C(OCC)(=O)C.O.CN(C)C=O>[CH:24]1([C:27]([C:29]2[CH:30]=[CH:31][C:32]([O:33][C@@H:34]([C:37]3[O:41][N:40]=[C:39]([C:42]4[CH:50]=[CH:49][C:45]([C:46]([NH:54][C@H:55]5[C@@H:59]([OH:60])[CH2:58][O:57][C:56]5=[O:61])=[O:47])=[C:44]([F:51])[CH:43]=4)[N:38]=3)[CH2:35][CH3:36])=[CH:52][CH:53]=2)=[O:28])[CH2:25][CH2:26]1
Reactant: N[C@@H]1C(=O)OC[C@@H]1O
Reactant: CC[C@@H](Oc1ccc(C(=O)C2CC2)cc1)c1nc(-c2ccc(C(=O)O)c(F)c2)no1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: CC[C@@H](Oc1ccc(C(=O)C2CC2)cc1)c1nc(-c2ccc(C(=O)N[C@@H]3C(=O)OC[C@@H]3O)c(F)c2)no1
Reaction time: 0.5 h
Yield: 18 %

Procedure:
1-Hydroxybenzotriazole monohydrate (44.6 mg, 0.291 mmol) and N-(3-dimethylaminopropyl) -N′-ethylcarbodiimide hydrochloride (55.8 mg, 0.291 mmol) were added to an N,N-dimethylformamide (0.5 mL) solution of the 4-(5-{(1R)-1-[4 -(cyclopropylcarbonyl) phenoxy]propyl}-1,2,4-oxadiazol-3-yl)-2-fluorobenzoic acid synthesized in Reference Example 8 (99.6 mg, 0.243 mmol) at room temperature, and the mixture was stirred at the same temperature for 30 minutes. Subsequently, an N,N-dimethylformamide (1.0 mL) solution of the crude (3S,4R)-3-amino-4-hydroxydihydrofuran-2-(3H)-one synthesized in Reference Example 14 (85.4 mg) was added, and the mixture was further stirred at the same temperature for 30 minutes. Water was added to the reaction mixture, and the mixture was subjected to extraction twice with ethyl acetate. The organic layer thus obtained was washed with a saturated aqueous solution of sodium hydrogen carbonate and brine, and then was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=70:30→30:70, v/v) to give the title compound (22.5 mg, yield: 18%).
Reaction SMILES: [C:1]([CH2:4][NH:5][C:6]([NH:8][CH2:9][C:10]1[CH:28]=[CH:27][C:13]([C:14]([N:16]2[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[CH2:20][CH2:19][CH2:18][CH2:17]2)=[O:15])=[CH:12][C:11]=1[CH3:29])=[O:7])([OH:3])=O.C[CH2:31][N:32](C(C)C)C(C)C.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.Cl.CN>ClCCl>[CH3:31][NH:32][C:1](=[O:3])[CH2:4][NH:5][C:6]([NH:8][CH2:9][C:10]1[CH:28]=[CH:27][C:13]([C:14]([N:16]2[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[CH2:20][CH2:19][CH2:18][CH2:17]2)=[O:15])=[CH:12][C:11]=1[CH3:29])=[O:7]
Reactant: Cc1cc(C(=O)N2CCCCc3ccccc32)ccc1CNC(=O)NCC(=O)O
Reactant: CCN(C(C)C)C(C)C
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: CN
Agent: Cl
Solvent: ClCCl
Product: CNC(=O)CNC(=O)NCc1ccc(C(=O)N2CCCCc3ccccc32)cc1C
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of the carboxylic acid from Example 33 (0.10 g, 0.25 mmol) in dichloromethane (25 ml) was added DIEA (0.221 ml, 1.26 mmol) and PyBroP (0.129 g, 0.278 mmol). The mixture was stirred at room temperature for 10 min and then methylamine hydrochloride (0.085 g, 1.26 mmol) was added. Stirring was continued for a further 3 h. The mixture was then washed with 1M KHSO4 (3 times), saturated sodium bicarbonate solution (3 times) and brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by flash chromatography on silica (eluant dichloromethane:methanol 96:4) to give a white solid; yield 0.018 g (17%).
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH2:11])[N:4]([C@H:12]2[CH2:17][CH2:16][C@@H:15]([N:18]3[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]3)[CH2:14][CH2:13]2)[N:3]=1.[O:25]([C:32]1[N:37]=[CH:36][C:35](B2OC(C)(C)C(C)(C)O2)=[CH:34][N:33]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.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>[CH3:24][N:21]1[CH2:22][CH2:23][N:18]([C@@H:15]2[CH2:16][CH2:17][C@H:12]([N:4]3[C:5]4=[N:6][CH:7]=[N:8][C:9]([NH2:11])=[C:10]4[C:2]([C:35]4[CH:34]=[N:33][C:32]([O:25][C:26]5[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=5)=[N:37][CH:36]=4)=[N:3]3)[CH2:13][CH2:14]2)[CH2:19][CH2:20]1
Reactant: CC1(C)OB(c2cnc(Oc3ccccc3)nc2)OC1(C)C
Reactant: CN1CCN([C@H]2CC[C@@H](n3nc(I)c4c(N)ncnc43)CC2)CC1
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: [Na+]
Solvent: COCCOC
Solvent: O
Product: CN1CCN([C@H]2CC[C@@H](n3nc(-c4cnc(Oc5ccccc5)nc4)c4c(N)ncnc43)CC2)CC1
Yield: 56.5 %

Procedure:
A mixture of cis-3-iodo-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (Intermediate AC) (0.297 g, 0.000674 mol), 2-phenoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine (int AV) (0.221 g, 0.000741 mol), sodium carbonate (0.179 g, 0.001684 mol) in 1,2-dimethoxyethane (10 mL) and water (20 mL) was stirred rapidly and tetrakis(triphenylphosphine)palladium(0) (0.047 g, 0.000040 mol) added. The reaction mixture was stirred 18 hours at 80° C. The solvents were removed in vacuo and the residue was partitioned between ethyl acetate (50 mL) and saturated aqueous sodium bicarbonate (50 mL). The phases were separated and the aqueous phase was extracted with ethyl acetate (3×25 mL). The combined organic phases were dried over magnesium sulfate, and the solvent was removed in vacuo. The product was purified by flash column chromatography on silica using dichloromethane/methanol/ammonium hydroxide (95:5:0.5). The solvent was removed in vacuo to give cis-1-[4-(4-methylpiperazino)cyclohexyl]-3-(2-phenoxy-5-pyrimidinyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine as a white solid (0.185 g, 0.000381 mol): 1H NMR (DMSO-d6, 400 MHz) 8.79 (s, 2H), 8.24 (s, 1H), 7.48 (t, 2H), 7.28 (t, 1H), 7.27 (d, 2H), 4.81 (m, 1H), 1.55-2.56 (m, 20H); TLC (dichloromethane/methanol/ammonium hydroxide=90:10:0.5) Rf 0.23.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([P:9](=[O:22])([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:6]=[CH:7][CH:8]=1.C([N-]C(C)C)(C)C.[Li+].[I:31]I.O.O.O.O.O.S([O-])([O-])(=O)=S.[Na+].[Na+]>O1CCCC1.O>[I:31][C:4]1[C:3]([O:2][CH3:1])=[CH:8][CH:7]=[CH:6][C:5]=1[P:9](=[O:22])([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: II
Reactant: COc1cccc(P(=O)(c2ccccc2)c2ccccc2)c1
Agent: CC(C)[N-]C(C)C
Agent: O=S([O-])([O-])=S
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: COc1cccc(P(=O)(c2ccccc2)c2ccccc2)c1I
Temperature: -78 °C
Reaction time: 8 h
Yield: 75.5 %

Procedure:
db) 52.5 g (0.170 mol) of (m-metho xyphenyl)-diphenylphosphine oxide were placed in a 1.5 l four-necked sulphonation flask as described under da) and the apparatus was placed under argon by 3-fold evacuation/filling. Then, 350 ml of dry tetrahydrofuran were allowed to flow in and the solution was cooled to -78° C. 313 ml (0.186 mol) of the lithium diisopropylamide solution prepared under da) were added dropwise within 20 minutes while stirring well, with the temperature being held at ≤-70° C. The reaction mixture became reddish-brown in colour at the beginning of the addition and formed a beige suspension towards the end of the addition. After an additional period of stirring of 15 minutes at -78° C. a solution of 47.4 g of iodine in 170 ml of tetrahydrofuran was added dropwise to the solution within 20 minutes, with the reaction mixture being held at ≤-70° C. (The iodine solution had been prepared previously in a separate 250 ml Schlenk tube under argon and had been transferred into the dropping funnel via a steel cannula). Towards the end of the addition there resulted a red solution and there set in the formation of a reddish-brown viscous material which settled on the walls and on the bottom of the reaction vessel. At this point the mechanical stirrer was shut off, the cooling bath was removed and the reaction mixture was left to warm. At about -30° C. there again resulted a clear red solution, the stirring operation was resumed and the mixture was allowed to warm to 0° C. The reaction solution was treated at 0° C. with a solution of 12 g of sodium thiosulphate pentahydrate in 100 ml of deionized water, the mixture was stirred well and the phases were separated. The now yellowish organic phase was washed three times with 200 ml of saturated NaCl solution, dried over about 50 g of magnesium sulphate, filtered and concentrated to dryness on a rotary. evaporator at 40° C. The brown residue was treated with 300 ml of tert.-butyl methyl ether and the mixture was boiled at reflux, whereby the product began to crystallize out. After standing overnight at room temperature the beige crystallizate was filtered off under suction, washed with 100 ml of tert.-butyl methyl ether and dried for 1 hour in a high vacuum at 70° C. There were obtained 55.7 g of (2-iodo-3-metho xyphenyl)diphenylphosphine oxide as a beige powder of m.p. 186°-189° C.
Reaction SMILES: [CH2:1]([C:4]1([CH2:16][CH2:17][CH3:18])[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:14]#[CH:15])[CH:12]=2)[S:7][CH2:6][CH2:5]1)[CH2:2][CH3:3].C(N(CC)CC)C.I[C:27]1[CH:37]=[CH:36][C:30]([C:31]([O:33][CH2:34][CH3:35])=[O:32])=[CH:29][CH:28]=1>[Cu]I.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[CH2:16]([C:4]1([CH2:1][CH2:2][CH3:3])[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:14]#[C:15][C:27]3[CH:37]=[CH:36][C:30]([C:31]([O:33][CH2:34][CH3:35])=[O:32])=[CH:29][CH:28]=3)[CH:12]=2)[S:7][CH2:6][CH2:5]1)[CH2:17][CH3:18]
Reactant: CCOC(=O)c1ccc(I)cc1
Reactant: C#Cc1ccc2c(c1)C(CCC)(CCC)CCS2
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: CCCC1(CCC)CCSc2ccc(C#Cc3ccc(C(=O)OCC)cc3)cc21
Temperature: 55 °C
Reaction time: 16 h

Procedure:
A mixture of 0.338 g (1.47 mmol) of 4,4-dipropylthiochroman-6-yl)acetylene (Compound 31), 24 mg, (0.13 mmol) of copper (I) iodide, and 2.54 g (25 mmol of triethylamine were degassed with argon for 15 minutes. To the suspension was added 0.57 g (2.07 mmol) of ethyl 4-iodobenzoate (Compound 22) and then 0.12 g (0.17 mmol) of bis(triphenylphosphine)palladium (II) chloride. The suspension was degassed with argon for an additional 5 minutes, the tube was sealed and the mixture stirred at 55° C. for 16 hours.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:17])[C:5](=[O:16])[N:6]2[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].C(N1C2C(=CC=CC=2)C(=O)C1=O)CCCC.O1C2C=CC(O)=CC=2OC1.[Br:44][C:45]1[CH:50]=[CH:49][C:48]([OH:51])=[CH:47][CH:46]=1>>[Br:44][C:45]1[CH:46]=[CH:47][C:48]([OH:51])=[C:49]([C:4]2([OH:17])[C:3]3[C:7](=[CH:8][CH:9]=[CH:10][CH:2]=3)[N:6]([CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[C:5]2=[O:16])[CH:50]=1
Reactant: CCCCCN1C(=O)C(=O)c2c(Br)cccc21
Reactant: Oc1ccc(Br)cc1
Agent: CCCCCN1C(=O)C(=O)c2ccccc21
Agent: Oc1ccc2c(c1)OCO2
Product: CCCCCN1C(=O)C(O)(c2cc(Br)ccc2O)c2ccccc21

Procedure:
Following the procedure as described in PREPARATION 1C, and making non-critical variations to replace 4-bromo-1-pentyl-1H-indole-2,3-dione with 1-pentyl-1H-indole-2,3-dione, and 1,3-benzodioxol-5-ol with 4-bromophenol, the title compound was obtained (41%): 1H NMR (300 MHz, CDCl3) δ 9.46-9.25 (br, 1H), 7.51-6.80 (m, 7H), 4.73-4.51 (br, 1H), 3.79-3.56 (m, 2H), 1.76-1.60 (m, 2H), 1.41-1.22 (m, 4H), 0.87 (t, 3H); MS (ES+) m/z 377 (M−17), 379 (M−17), 412 (M+23), 414 (M+23).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([C:11](O)=O)[CH3:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:14][C:15]1[C:20]([Cl:21])=[CH:19][CH:18]=[CH:17][C:16]=1[SH:22]>O1CCCC1>[C:1]([O:5][C:6]([NH:8][C@@H:9]([C:11]1[S:22][C:16]2[CH:17]=[CH:18][CH:19]=[C:20]([Cl:21])[C:15]=2[N:14]=1)[CH3:10])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: Nc1c(S)cccc1Cl
Solvent: C1CCOC1
Product: C[C@@H](NC(=O)OC(C)(C)C)c1nc2c(Cl)cccc2s1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 52 %

Procedure:
18.4 g of N,N'-carbonyldiimidazole was gradually added to a solution containing 20.5 g of N-tert-butoxycarbonyl-D-alanine dissolved in 200 mL of tetrahydrofuran, and the reaction mixture was stirred for 30 minutes at room temperature. 16.5 g of 2-amino-3-chlorothiophenol was added to the reaction mixture, and the whole mixture was refluxed for 3 hours. After completion of the reaction, the resulting mixture was poured into ice-cold water. The organic layer was extracted with ethyl acetate, washed using water, and then dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel, thus yielding 16.8 g of (R)-N-tert-butoxycarbonyl-1-(4-chloro-2-benzothiazolyl)ethylamine (melting point: 95°~96° C.). Furthermore, a hydrogen chloride gas was bubbled into a solution containing 10 g of the crystals obtained above dissolved in 50 mL of methylene chloride, for 3 hours at room temperature. After completion of the reaction, the reaction mixture was extracted with water, and was made basic using a saturated aqueous solution of sodium bicarbonate. The solution was extracted with ethyl acetate, washed with water, and then dried over anhydrous magnesium sulfate, followed by concentration under reduced pressure. The residue was purified by column chromatography on silica gel to afford 5.7 g (yield 84%) of the desired product.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]=1[CH2:12][C:13]([OH:15])=[O:14].S(=O)(=O)(O)O.[CH3:21][CH2:22]O>>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]=1[CH2:12][C:13]([O:15][CH2:21][CH3:22])=[O:14]
Reactant: O=C(O)Cc1cc([N+](=O)[O-])c(F)cc1Br
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)Cc1cc([N+](=O)[O-])c(F)cc1Br
Temperature: 85 °C
Yield: 49 %

Procedure:
A solution of 2-(2-bromo-4-fluoro-5-nitrophenyl)acetic acid (5.00 g, 17.98 mmol) in EtOH (100 mL) was treated with concentrated sulfuric acid (0.999 mL, 17.98 mmol) and heated at 85° C. overnight. The mixture was cooled to RT and the EtOH was removed under reduced pressure. The resulting oil was dissolved in MTBE, washed with water (2×) then brine (2×), dried (MgSO4), and concentrated to dryness. The material was purified by silica gel chromatography (EtOAc/Hex) to afford ethyl 2-(2-bromo-4-fluoro-5-nitrophenyl)acetate (2.679 g, 49% yield) as a yellow oil. 1H NMR (400 MHz, DMSO-d6): δ 8.33 (d, 1H), 8.08 (d, 1H), 4.12 (q, 2H), 3.96 (s, 2H), 1.20 (t, 3H); MS (ESI) m/z: 308.0 [M+H]+.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].Cl[C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][C:9]=1[N+:15]([O-:17])=[O:16].[CH3:18][SH:19]>CN(C=O)C>[CH3:18][S:19][C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][C:9]=1[N+:15]([O-:17])=[O:16]
Reactant: Cc1ccc(Cl)c([N+](=O)[O-])c1
Reactant: CS
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CSc1ccc(C)cc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 3 h
Yield: 80 %

Procedure:
138 g (1 mol) of K2CO3 are added to a solution of 171.6 g (1 mol) of 4-chloro-3-nitrotoluene in 500 ml of DMF. 1 molar equivalent of methyl mercaptan is passed through, and stirring is continued at 50° C. for 3 h. The reaction mixture is poured on a large amount of ice-water and the precipitate is filtered off under suction, washed with water and dried; 146.3 g (80%) of 4-methylthio-3-nitrotoluene of melting point 71-73° C. are obtained.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C:11]2[NH:20][C:19](=[O:21])[C:18]3[C:13](=[CH:14][C:15]([O:24][CH3:25])=[C:16]([O:22][CH3:23])[CH:17]=3)[N:12]=2)[CH:10]=1)=[O:5])C.[OH-].[K+]>C1COCC1>[CH3:23][O:22][C:16]1[CH:17]=[C:18]2[C:13](=[CH:14][C:15]=1[O:24][CH3:25])[N:12]=[C:11]([N:9]1[CH:10]=[C:6]([C:4]([OH:5])=[O:3])[CH:7]=[N:8]1)[NH:20][C:19]2=[O:21]
Reactant: CCOC(=O)c1cnn(-c2nc3cc(OC)c(OC)cc3c(=O)[nH]2)c1
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1cc2nc(-n3cc(C(=O)O)cn3)[nH]c(=O)c2cc1OC
Reaction time: 4 h
Yield: 89.8 %

Procedure:
A mixture of 1-(6,7-dimethoxy-4-oxo-3,4-dihydro-quinazolin-2-yl)-1H-pyrazole-4-carboxylic acid ethyl ester (0.28 g, 0.81 mmol), 1M aq. KOH (3.0 mL) and THF (3.0 mL) was stirred for 4 h. The mixture was concentrated to remove the THF and the aqueous residue was acidified to pH 2 with 1M aq. HCl. The resulting precipitate was collected by filtration to provide the titled compound (0.23 g, 89%). MS (ESI): mass calcd. for C14H12N4O5, 316.3; m/z found, 317.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6): 13.32-12.29 (br m, 2H), 8.90 (s, 1H), 8.22 (s, 1H), 7.47 (s, 1H), 7.19 (s, 1H), 3.93 (s, 3H), 3.89 (s, 3H).