Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][CH:2]([F:18])[CH2:3][O:4][C:5]1[CH:13]=[C:12]([NH2:14])[C:11]([N+:15]([O-])=O)=[CH:10][C:6]=1[C:7]([OH:9])=[O:8]>[Pd]>[F:1][CH:2]([F:18])[CH2:3][O:4][C:5]1[CH:13]=[C:12]([NH2:14])[C:11]([NH2:15])=[CH:10][C:6]=1[C:7]([OH:9])=[O:8]
Reactant: Nc1cc(OCC(F)F)c(C(=O)O)cc1[N+](=O)[O-]
Agent: [Pd]
Product: Nc1cc(OCC(F)F)c(C(=O)O)cc1N
Yield: 99 %

Procedure:
The subtitle compound is prepared from 2-(2,2-difluoro-ethoxy)-4-amino-5-nitro-benzoic acid (example 2c) with Pd/C and H2 in analogy to example 1f.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[Cl:9][C:10]1[CH:11]=[C:12]([CH:15]=[CH:16][C:17]=1[Cl:18])[CH2:13]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(C)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:13][C:12]2[CH:15]=[CH:16][C:17]([Cl:18])=[C:10]([Cl:9])[CH:11]=2)=[CH:4][CH:3]=1
Reactant: Oc1ccc(Br)cc1
Reactant: OCc1ccc(Cl)c(Cl)c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: Clc1ccc(COc2ccc(Br)cc2)cc1Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
4-Bromophenol (1.07 g, 6.18 mmol), 3,4-dichlorobenzyl alcohol (1.42 g, 8.02 mmol), and triphenylphosphine (2.10 g, 8.01 mmol) were dissolved in tetrahydrofuran (30 mL), and a diethyl azodicarboxylate toluene solution (2.2M, 3.65 mL, 8.03 mmol) was slowly added dropwise thereto at room temperature, and then, the resulting mixture was stirred under a nitrogen atmosphere at room temperature for 2 hours. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=100:0 to 95:5 (v/v)), whereby the objective title compound was obtained as a white solid (2.25 g, quantitative).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5](Cl)(=[O:7])[CH3:6].[Cl:9][CH2:10][CH2:11][CH2:12][CH2:13][N:14]1[C:20](=[O:21])[C:19]2[CH:22]=[CH:23][S:24][C:18]=2[S:17][CH2:16][CH2:15]1.O>C(Cl)Cl>[C:5]([C:23]1[S:24][C:18]2[S:17][CH2:16][CH2:15][N:14]([CH2:13][CH2:12][CH2:11][CH2:10][Cl:9])[C:20](=[O:21])[C:19]=2[CH:22]=1)(=[O:7])[CH3:6]
Reactant: CC(=O)Cl
Reactant: O=C1c2ccsc2SCCN1CCCCCl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: ClCCl
Product: CC(=O)c1cc2c(s1)SCCN(CCCCCl)C2=O
Reaction time: 0.25 h

Procedure:
To a suspension of 13 g of aluminum chloride in 150 ml of methylene chloride was added 4.6 ml of acetyl chloride under ice-cooling and the mixture was stirred for 15 minutes. To the mixture was added a solution of 9.0 g of 4-(4-chlorobutyl)-2,3-dihydrothieno[3,2-f]-1,4-thiazepin-5(4H)-one in 20 ml of methylene chloride and the mixture was stirred at room temperature of 2 hours. Then, the mixture was poured into chilled water and extracted with chloroform. The extract was washed with water, dried over magnesium sulfate and the solvent was distilled off. The resulting crystals were recrystallized from ethyl acetate to give 6.9 g of 7-acetyl-4-(4-chlorobutyl)-2,3-dihydrothieno-[3,2-f]-1,4-thiazepin-5(4H)-one as white crystals, melting at 132°-134° C.
Reaction SMILES: [SH:1][C:2]1[C:3]2[C:13](=[O:14])[N:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:11](=[O:21])[N:10]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:4]=2[N:5]([CH3:9])[C:6](=[O:8])[N:7]=1.[CH3:28]N(C)C=O.C(=O)([O-])[O-].[K+].[K+].CI>O>[CH3:9][N:5]1[C:4]2[N:10]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:11](=[O:21])[N:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:13](=[O:14])[C:3]=2[C:2]([S:1][CH3:28])=[N:7][C:6]1=[O:8]
Reactant: CN(C)C=O
Reactant: Cn1c(=O)nc(S)c2c(=O)n(-c3ccccc3)c(=O)n(-c3ccccc3)c21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: O
Product: CSc1nc(=O)n(C)c2c1c(=O)n(-c1ccccc1)c(=O)n2-c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 89 %

Procedure:
To crude 5-mercapto-8-methyl-1,3-diphenyl-1H,8H-pyrimido[4,5-d]pyrimidine-2,4,7-trione 24 (100 mg) obtained in Step 5 was added N,N-dimethylformamide (0.5 ml). Under a nitrogen atmosphere, potassium carbonate (44 mg) and methyl iodide 25 (20 μl) were successively added, and the mixture was stirred at room temperature for 3 hrs. Water was added, and the mixture was extracted with chloroform. The organic layer was washed with water and brine, and dried over anhydrous sodium sulfate. Anhydrous sodium sulfate was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (hexane:ethyl acetate=4:1→3:1) to give 8-methyl-5-methylsulfanyl-1,3-diphenyl-1H,8H-pyrimido[4,5-d]pyrimidine-2,4,7-trione 26 (91 mg, yield 89%) as brown crystals.
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:8][CH:7]1[C:9]1[C:10]([CH3:21])=[N:11][O:12][C:13]=1[C:14]1[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][CH:15]=1)=[O:5])C.CO.[OH-].[Na+].Cl>C1COCC1>[Br:20][C:17]1[CH:16]=[CH:15][C:14]([C:13]2[O:12][N:11]=[C:10]([CH3:21])[C:9]=2[CH:7]2[CH2:8][CH:6]2[C:4]([OH:5])=[O:3])=[CH:19][CH:18]=1
Reactant: CCOC(=O)C1CC1c1c(C)noc1-c1ccc(Br)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1noc(-c2ccc(Br)cc2)c1C1CC1C(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-[5-(4-Bromo-phenyl)-3-methyl-isoxazol-4-yl]-cyclopropanecarboxylic acid ethyl ester (more polar isomer, 0.164 g, 0.468 mmol) was dissolved in THF (3 mL) then MeOH (1 mL) and NaOH (1N aq., 1 mL) were added. The reaction stirred at room temperature overnight and was then acidified with 1N aq. HCl and submitted to standard aqueous workup to afford the title compound.
Reaction SMILES: [Br:1][C:2]1[C:22]([OH:23])=[CH:21][C:5]2[C:6]([CH3:20])([CH3:19])[C:7]3[NH:8][C:9]4[C:14]([C:15]=3[C:16](=[O:17])[C:4]=2[CH:3]=1)=[CH:13][CH:12]=[C:11]([Cl:18])[CH:10]=4.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:43][C:44]1([CH3:51])[O:48][C@@H:47]([CH2:49]O)[CH2:46][O:45]1.C1(C)C=CC=CC=1.C(OC(N=NC(OCC)=O)=O)C>C(OCC)(=O)C.C1COCC1>[Cl:18][C:11]1[CH:10]=[C:9]2[C:14]([C:15]3[C:16](=[O:17])[C:4]4[CH:3]=[C:2]([Br:1])[C:22]([O:23][CH2:49][C@H:47]5[CH2:46][O:45][C:44]([CH3:51])([CH3:43])[O:48]5)=[CH:21][C:5]=4[C:6]([CH3:20])([CH3:19])[C:7]=3[NH:8]2)=[CH:13][CH:12]=1
Reactant: CC1(C)c2cc(O)c(Br)cc2C(=O)c2c1[nH]c1cc(Cl)ccc21
Reactant: CC1(C)OC[C@H](CO)O1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC1(C)OC[C@H](COc2cc3c(cc2Br)C(=O)c2c([nH]c4cc(Cl)ccc24)C3(C)C)O1
Temperature: 50 °C
Reaction time: 2 h
Yield: 52.5 %

Procedure:
Under nitrogen atmosphere, 9-bromo-3-chloro-8-hydroxy-6,6-dimethyl-5,6-dihydro-benzo[b]carbazol-11-one (Compound S2-4, 76 mg, 0.2 mmol) and triphenylphosphine (69 mg, 1.3 eq.) were added with THF (2 ml), and ((S)-2,2-dimethyl-[1,3]dioxolan-4-yl)-methanol (35 mg, 1.3 eq.) and 2.19 N toluene solution (118 μL, 1.3 eq.) of diethyl azodicarboxylic acid were added dropwise thereto, followed by stirring at 50° C. for 2 hr. After cooling, the reaction solution was added with ethyl acetate, washed with brine, dried over sodium sulfate and filtered. The residues obtained after concentration under reduced pressure were purified by silica gel column chromatography (ethyl acetate/dichloromethane) to give a solid, which was then washed with dichloromethane to obtain the title compound (brown powder, 53 mg).
Reaction SMILES: [C:1]1([O:7][C:8](=[O:23])[NH:9][C@H:10]([C:14]2[C:19]([F:20])=[CH:18][CH:17]=[C:16]([Cl:21])[C:15]=2[F:22])[CH2:11][CH:12]=C)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.ClC(OC1C=CC=CC=1)=[O:27]>CO.C(#N)C.CCOC(C)=O>[C:1]1([O:7][C:8](=[O:23])[NH:9][C@H:10]([C:14]2[C:19]([F:20])=[CH:18][CH:17]=[C:16]([Cl:21])[C:15]=2[F:22])[CH2:11][CH:12]=[O:27])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: C=CC[C@H](NC(=O)Oc1ccccc1)c1c(F)ccc(Cl)c1F
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: CO
Product: O=CC[C@H](NC(=O)Oc1ccccc1)c1c(F)ccc(Cl)c1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 40 %

Procedure:
(S)-Phenyl(1-(3-chloro-2,6-difluorophenyl)but-3-en-1-yl)carbamate: To a solution of crude Intermediate 17B (1.17 g, 3.64 mmol) in MeOH (10 mL) was added HCl (5 mL, 20.00 mmol) and the reaction was stirred at rt for 1 h. After 1 h, the reaction mixture was concentrated and dried under vacuum to obtain a pale yellow solid. The solid was dissolved in ACN (25 mL) followed by addition of TEA (1.520 mL, 10.91 mmol). The above reaction mixture was cooled to 0° C. To this mixture was added phenyl chloroformate (0.502 mL, 4.00 mmol) dropwise and the resulting reaction was stirred at 0° C. for 1 h. The reaction mixture was then diluted with EtOAc and washed with water followed by brine. The crude product was then purified by silica gel chromatography to give the desired product (490 mg, 40%) as clear oil. MS (ESI) m/z: 338.1 (M+H)+.
Reaction SMILES: C[O:2][C:3](=[O:21])[C@H:4]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[NH:5][C:6](=[O:13])[C@H:7]([CH2:9][C:10](=[O:12])[OH:11])[NH2:8].Cl.[CH:23](N[C@@H]1C(=O)OC(=O)C1)=[O:24].N[C@H](C(O)=O)CC1C=CC=CC=1>O>[CH:23]([NH:8][C@H:7]([C:6]([NH:5][C@H:4]([C:3]([OH:2])=[O:21])[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:13])[CH2:9][C:10](=[O:12])[OH:11])=[O:24]
Reactant: O=CN[C@H]1CC(=O)OC1=O
Reactant: COC(=O)[C@H](Cc1ccccc1)NC(=O)[C@@H](N)CC(=O)O
Agent: Cl
Agent: N[C@@H](Cc1ccccc1)C(=O)O
Solvent: O
Product: O=CN[C@@H](CC(=O)O)C(=O)N[C@@H](Cc1ccccc1)C(=O)O

Procedure:
This invention relates to a preparation process of α-L-aspartyl-L-phenylalanine methyl ester or its hydrochloride. More specifically, this invention provides a process for preparing α-L-aspartyl-L-phenylalanine methyl ester or its hydrochloride which process comprises: condensating N-formyl-L-aspartic acid anhydride and L-phenylalanine in water at a pH in the range of 7-12 to form N-formyl-α-L-aspartyl-L-phenylalanine; acidifying the reaction mixture with hydrochloric acid in the presence of methanol without isolating the N-formyl-α-L-aspartyl-L-phenylalanine so as to bring it into contact with hydrochloric acid in the presence of methanol for reaction and thereby to precipitate α-L-aspartyl-L-phenylalanine methyl ester hydrochloride; separating the α-L-aspartyl-L-phenylalanine methyl ester hydrochloride; and neutralizing said hydrochloride as required. Further, this invention provides another process for preparing α-L-aspartyl-L-phenylalanine methyl ester or its hydrochloride which process comprises: condensating N-formyl-L-aspartic acid anhydride and L-phenylalanine in water containing methanol in an amount of 6 moles or less per mol of the L-phenylalanine at a pH in the range of 7-12 to form N-formyl-α-L-aspartyl-L-phenylalanine; acidifying the reaction mixture with hydrochloric acid without isolating the N-formyl-α-L-aspartyl-L-phenylalanine so as to bring it into contact with hydrochloric acid in the presence of methanol for reaction and thereby to precipitate α-L-aspartyl-L-phenylalanine methyl ester hydrochloride; separating the α-L-aspartyl-L-phenylalanine methyl ester hydrochloride; and neutralizing said hydrochloride as required.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:10]=[C:9]2[C:17]([OH:19])=[O:18])=[CH:4][CH:3]=1.C(=O)(O)[O-].[Na+].[F:25][C:26]([F:39])([F:38])[O:27][C:28]1[CH:33]=[CH:32][C:31]([S:34](Cl)(=[O:36])=[O:35])=[CH:30][CH:29]=1>ClCCl>[F:39][C:26]([F:25])([F:38])[O:27][C:28]1[CH:33]=[CH:32][C:31]([S:34]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([N:8]3[C:16]4[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=4)[CH:10]=[C:9]3[C:17]([OH:19])=[O:18])=[CH:6][CH:7]=2)(=[O:36])=[O:35])=[CH:30][CH:29]=1
Reactant: Nc1ccc(-n2c(C(=O)O)cc3ccccc32)cc1
Reactant: O=S(=O)(Cl)c1ccc(OC(F)(F)F)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: O=C(O)c1cc2ccccc2n1-c1ccc(NS(=O)(=O)c2ccc(OC(F)(F)F)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 14.4 %

Procedure:
To a stirred solution of 1-(4-aminophenyl)-1H-indole-2-carboxylic acid (0.4 g, 1.59 mmol) in 10 mL of 1:1 of dichloromethane/sat. aqueous sodium bicarbonate was added 4-trifluoromethoxy-benzenesulfonyl chloride (0.40 g, 1.53 mmol). After being stirred at room temperature for 1 hour the solid was collected and purified by semi-preparative HPLC (Column: Phenomenex C18 Luna 21.6 mm×60 mm, 5 μM; Solvent A: Water (0.1% TFA buffer); Solvent B: Acetonitrile (0.1% TFA buffer); Solvent Gradient: Time 0: 0% B; 10 min: 100% B; Hold 100% B 5 min. Flow Rate: 22.5 mL/min) to afford 0.105 g (15%) of the title compound as a pale yellow solid: 1H NMR (DMSO-d6) δ 6.89(d, J=8.3 Hz, 1H), 7.10-7.30 (m, 6H), 7.39 (d, J=2.1 Hz, 1H), 7.60 (d, J=7.2 Hz, 2H), 7.71 (d, J=6.0 Hz, 1H), 7.90-8.00 (m, 2H), 10.63 (br s, 1H), 12.74 (br s, 1H); MS (ESI) m/z 477 (MH+); MS (ESI) m/z 475 ([M−H]−); HRMS calcd for C22H16F3N2O5S: 477.0721; found (ESI+): 477.0719; Anal. calcd for C22H15F3N2O5S.0.2H2O: C, 55.05; H, 3.23; N, 5.84. Found: C, 54.97; H, 3.41; N, 5.82.
Reaction SMILES: [C:1]([NH2:10])([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)([CH3:3])[CH3:2].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.[C:33]([O:37][C:38]([NH:40][C@H:41]1[CH2:46][CH2:45][CH2:44][CH2:43][C@H:42]1[NH:47][C:48]1[C:56]([F:57])=[CH:55][C:51]([C:52](O)=[O:53])=[C:50]([Cl:58])[N:49]=1)=[O:39])([CH3:36])([CH3:35])[CH3:34].[Cl-].[NH4+]>C(OCC)(=O)C.CN(C=O)C.O>[Cl:58][C:50]1[N:49]=[C:48]([NH:47][C@H:42]2[CH2:43][CH2:44][CH2:45][CH2:46][C@H:41]2[NH:40][C:38](=[O:39])[O:37][C:33]([CH3:36])([CH3:34])[CH3:35])[C:56]([F:57])=[CH:55][C:51]=1[C:52]([NH:10][C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)([CH3:3])[CH3:2])=[O:53]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCC[C@H]1Nc1nc(Cl)c(C(=O)O)cc1F
Reactant: CC(C)(N)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N[C@@H]1CCCC[C@@H]1Nc1nc(Cl)c(C(=O)NC(C)(C)c2ccccc2)cc1F
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Cumylamine (1.97 ml), WSC.HCl (2.62 g), and HOBt.H2O (2.10 g) were added to a DMF (60 ml) solution containing 6-(cis-2-(tert-butoxycarbonylamino)cyclohexylamino)-2-chloro-5-fluoronicotinic acid obtained in the 1st step, followed by stirring at room temperature for 4 hours. A saturated aqueous ammonium chloride solution and ethyl acetate were added to the reaction mixture. The organic layer was collected, washed with a saturated aqueous sodium hydrogen carbonate solution and then with saturated saline, and dried over anhydrous magnesium sulfate, and the solvent was distilled away under reduced pressure. Diisopropylether and hexane were added to the obtained residue, solid matter was collected by filtration, and a white solid of tert-butyl cis-2-(6-chloro-3-fluoro-5-(2-phenylpropan-2-ylaminocarbonyl)pyridin-2-ylamino)cyclohexylcarbamate (4.41 g) was thus obtained.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:19]=[C:20]([F:22])[CH:21]=1)[CH2:5][C@H:6]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[C@H:7]([OH:10])[CH2:8][OH:9].[C:23](Cl)(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>ClCCl>[C:23]([O:9][CH2:8][C@@H:7]([OH:10])[C@@H:6]([NH:11][C:12]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:18])[CH2:5][C:4]1[CH:3]=[C:2]([F:1])[CH:21]=[C:20]([F:22])[CH:19]=1)(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1cc(F)cc(F)c1)[C@H](O)CO
Reactant: O=C(Cl)c1ccccc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H](Cc1cc(F)cc(F)c1)[C@H](O)COC(=O)c1ccccc1

Procedure:
BOC-Protected aminodiol 28 was dissolved in dichloromethane with tritethyamine and cooled to 0°. Benzoylchloride (1.0 eq.) was added and the solution stirred until all of the starting material was consumed. After extraction, the benzoyl ester (29) was purified using silica gel chromatography.
Reaction SMILES: [NH2:1][C@@H:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([Br:12])[CH:10]=2)[CH2:5][CH2:4][C@H:3]1[NH2:13].[C:14](=S)=[S:15]>C(O)C>[Br:12][C:9]1[CH:10]=[C:11]2[C:6]([CH2:5][CH2:4][C@H:3]3[NH:13][C:14](=[S:15])[NH:1][C@@H:2]32)=[CH:7][CH:8]=1
Reactant: N[C@@H]1CCc2ccc(Br)cc2[C@H]1N
Reactant: S=C=S
Solvent: CCO
Product: S=C1N[C@@H]2c3cc(Br)ccc3CC[C@H]2N1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 70 %

Procedure:
Trans-1,2-diamino-7-bromo-1,2,3,4-tetrahydronaphthalene (6.75 g, 28.0 m mol) was dissolved in ethanol (70 ml) and carbon disulfide (1.9 ml, 31.7 m mol) was added to the solution. After stirring at room temperature for 20 minutes, they were heated under reflux for 5.5 hours. The reaction mixture was cooled in an ice bath and crystals precipitated were collected by filtration, whereby trans-8-bromo-3a,4,5,9b-tetrahydronaphth[1,2-d]imidazoline-2-thione (5.57 g) was obtained in 70% yield. The crystals were recrystallized from methanol-acetonitrile to give pale-yellow crystals melting at 259.5°-260.5° C. (decomposition). The product gave the following data on spectroscopy and elemental analysis.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[S:15][CH2:16][C:17]2[C:22]([O:23][CH3:24])=[CH:21][C:20]([O:25][CH3:26])=[CH:19][C:18]=2[O:27][CH3:28])O1.[OH2:30]>C1COCC1.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][O:23][C:22]1[CH:21]=[C:20]([O:25][CH3:26])[CH:19]=[C:18]([O:27][CH3:28])[C:17]=1[CH2:16][S:15][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([OH:30])[CH:10]=1
Reactant: O
Reactant: COc1cc(OC)c(CSc2ccccc2B2OC(C)(C)C(C)(C)O2)c(OC)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1cc(OC)c(CSc2ccccc2-c2cccc(O)c2)c(OC)c1

Procedure:
A mixture of 4,4,5,5-tetramethyl-2-(2-(2,4,6-trimethoxybenzylthio)phenyl)-1,3,2-dioxaborolane (1.2 g, 2.9 mmol), 3-lodophenol (0.65 g, 2.9 mmol), Ag2CO3 (0.82 g, 2.9 mmol) and Pd(PPh3)4 (0.16 g, 0.15 mmol) in 6 ml of THF was refluxed in the dark for 12 h. The reaction mixture was poured into H2O and the resulting mixture extracted with ether. The organic layer was washed with brine (3×20 ml) and dried over MgSO4 and concentrated. The residue was purified by silica flash chromatography (40/60, ethylacetate/hexane) to afford 2′-(2,4,6-trimethoxybenzylthio)biphenyl-3-ol.
Reaction SMILES: [NH:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]1=[O:7].Br[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:13]([O:12][C:10]([CH2:9][N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]1=[O:7])=[O:11])[CH3:14]
Reactant: CCOC(=O)CBr
Reactant: O=c1cccc[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)Cn1ccccc1=O
Yield: 83.9 %

Procedure:
2-Pyridone (4.76 g, 50 mmol) and ethyl bromoacetate (10.02 g, 60 mmol) were dissolved in acetone (100 ml). Potassium carbonate (8.28 g, 60 mmol) was added to the solution and the mixture was refluxed for two hours with stirring. After being cooled, insoluble substances were removed by filtration and the filtrate was evaporated to dryness. The residue was purified by silica gel column chromatography, to thereby obtain N-ethoxycarbonylmethyl-2-pyridone (7.60 g, yield 84%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:14](=[CH:15][CH:16]=1)[O:13][C:7]1[CH:8]=[N:9][C:10]([Cl:12])=[CH:11][C:6]=1[C:5]2([CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])O.[N:24]([Si](C)(C)C)=[N+:25]=[N-:26].C([O+]([B-](F)(F)F)CC)C>C1(C)C=CC=CC=1>[N:24]([C:5]1([CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:6]2[CH:11]=[C:10]([Cl:12])[N:9]=[CH:8][C:7]=2[O:13][C:14]2[C:4]1=[CH:3][C:2]([Br:1])=[CH:16][CH:15]=2)=[N+:25]=[N-:26]
Reactant: CCOC(=O)CC1(O)c2cc(Br)ccc2Oc2cnc(Cl)cc21
Reactant: C[Si](C)(C)N=[N+]=[N-]
Agent: CC[O+](CC)[B-](F)(F)F
Solvent: Cc1ccccc1
Product: CCOC(=O)CC1(N=[N+]=[N-])c2cc(Br)ccc2Oc2cnc(Cl)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 99 %

Procedure:
To a solution of ethyl 2-(7-bromo-3-chloro-5-hydroxy-5H-chromeno[2,3-c]pyridin-5-yl)acetate (20 g, 50.2 mmol) in toluene (300 ml) was added azidotrimethylsilane (19.93 ml, 151 mmol, followed by (diethyloxonio)trifluoroborate (12.72 ml, 100 mmol). The mixture was stirred overnight at RT. The reaction mixture was quenched with MeOH (200 mL) and diluted with EtOAc. The organic phase was separated, washed with saturated aqueous sodium bicarbonate solution and brine. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure to afford ethyl 2-(5-azido-7-bromo-3-chloro-5H-chromeno[2,3-c]pyridin-5-yl)acetate (21 g, 49.6 mmol, 99% yield).
Reaction SMILES: [CH3:1][C:2]1[C:14]2[CH:13]([CH2:15][CH2:16][C:17]([OH:19])=O)[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1.O=S(Cl)[Cl:22]>>[CH3:1][C:2]1[C:14]2[CH:13]([CH2:15][CH2:16][C:17]([Cl:22])=[O:19])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: Cc1cccc2c1C(CCC(=O)O)c1ccccc1-2
Product: Cc1cccc2c1C(CCC(=O)Cl)c1ccccc1-2
Reaction time: 2 h

Procedure:
3-(1-Methylfluoren-9-yl)propionic acid (2.5 g, 9.9 mmol) was charged with SOCl2 (20 mL, in excess) at room temperature. The reaction mixture was boiled for 2 hr. Excess of thionyl chloride was removed under reduced pressure. The residual oil was used for the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[C:9]([C:10]#[C:11][Si](C)(C)C)=[C:8](F)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[NH2:17][C@@H:18]([CH3:23])[C:19]([CH3:22])([OH:21])[CH3:20].C([O-])([O-])=O.[K+].[K+].CN1C(=O)CCC1>[Cu]I.CCOC(C)=O.O>[Cl:1][C:2]1[C:3]([C:4]#[N:5])=[CH:6][CH:7]=[C:8]2[C:9]=1[CH:10]=[CH:11][N:17]2[C@H:18]([C:19]([OH:21])([CH3:22])[CH3:20])[CH3:23]
Reactant: C[Si](C)(C)C#Cc1c(F)ccc(C#N)c1Cl
Reactant: C[C@H](N)C(C)(C)O
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: C[C@H](n1ccc2c(Cl)c(C#N)ccc21)C(C)(C)O
Temperature: 60 °C
Reaction time: 2 h
Yield: 61.9 %

Procedure:
A mixture of 2-chloro-4-fluoro-3-((trimethylsilyl)ethynyl)benzonitrile, (0.229 g, 0.91 mmol), (S)-3-amino-2-methylbutan-2-ol (Example 21E) (0.113 g, 1.092 mmol), and K2CO3 (0.252 g, 1.820 mmol) in anhyd NMP (3 mL) was stirred in a heating block at 60° C. under N2 for 2 h. CuI (0.017 g; 0.091 mmol) was added and the mixture was subjected to microwave heating (140° C.) for 30 min. The reaction mixture was poured into EtOAc/water and the whole was filtered through a pad of Celite. Layers of the filtrate were separated and the aqueous layer was extracted with EtOAc (×2). Combined organics were filtered (Whatman #2), washed (water, brine), dried over Na2SO4 and concentrated in vacuo. The residue was purified by low pressure liquid chromatography (silica gel, EtOAc/hexanes, gradient elution) affording (S)-4-chloro-1-(3-hydroxy-3-methylbutan-2-yl)-1H-indole-5-carbonitrile (0.148 g, 62% yield) as a pale yellow solid: 1H NMR (400 MHz, CDCl3) δ 7.50 (d, 1H), 7.42-7.39 (m, 1H), 7.39-7.34 (m, 1H), 6.74 (d, J=3.3 Hz, 1H), 4.41 (q, J=7.0 Hz, 1H), 1.60 (d, J=7.1 Hz, 3H), 1.41 (s, 1H), 1.33 (s, 3H), 1.09 (s, 3H); MS (LCMS ES+) m/z 263 ([M+H]+, 88%), 304 ({[M+H]+MeCN}+, 100%).
Reaction SMILES: O=[C:2]1[CH2:6][CH2:5][CH2:4][CH:3]1[C:7]([O:9][CH2:10][CH3:11])=[O:8].[CH3:12][C:13]([CH3:18])([CH3:17])[CH2:14][CH2:15][NH2:16]>C(O)C>[CH2:10]([O:9][C:7]([C:3]1[CH2:4][CH2:5][CH2:6][C:2]=1[NH:16][CH2:15][CH2:14][C:13]([CH3:18])([CH3:17])[CH3:12])=[O:8])[CH3:11]
Reactant: CCOC(=O)C1CCCC1=O
Reactant: CC(C)(C)CCN
Solvent: CCO
Product: CCOC(=O)C1=C(NCCC(C)(C)C)CCC1
Temperature: 25 °C
Yield: 89 %

Procedure:
To a solution of ethyl 2-oxocyclopentanecarboxylate (4.10 mL, 26.3 mmol) in ethanol (50 mL) was added 3,3-dimethylbutylamine (2.80 g, 26.8 mmol) at 25° C. The mixture was heated at reflux for 12 h. The reaction mixture was allowed to cool to 25° C. and concentrated in vacuo. The crude material was purified by flash column chromatography (Teledyne Isco RediSep Flash Column; 0-20% ethyl acetate in hexanes) to afford the desired product, 2-(3,3-dimethylbutylamino)-cyclopent-1-enecarboxylic acid ethyl ester (5.59 g, 23.4 mmol, 89%), as a yellowish oil. 1H NMR (400 MHz, CDCl3) δ 0.94 (9H, s), 1.28 (3H, t, J=7.0 Hz), 1.46-1.50 (2H, m), 1.80-1.88 (2H, m), 2.51-2.58 (4H, m), 3.16-3.21 (2H, m), 4.14 (2H, q, J=7.0 Hz).