Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@H:2]([C:8]([OH:10])=O)[CH2:3][CH2:4][C:5]([OH:7])=[O:6].C1(C)C(S(O)(=O)=O)=CC=CC=1.[C:22]([O:26][C:27](=[O:37])[C@H:28]([C:30]([S:33][C:34](=[O:36])[CH3:35])([CH3:32])[CH3:31])[NH2:29])([CH3:25])([CH3:24])[CH3:23].C(N1CCOCC1)C.C1(N=C=NC2CCCCC2)CCCCC1>ClCCl.CN(C=O)C.ClCCl>[C:22]([O:26][C:27](=[O:37])[C@H:28]([C:30]([S:33][C:34](=[O:36])[CH3:35])([CH3:31])[CH3:32])[NH:29][C:8](=[O:10])[C@H:2]([CH2:3][CH2:4][C:5](=[O:6])[OH:7])[NH2:1])([CH3:23])([CH3:24])[CH3:25]
Reactant: CC(=O)SC(C)(C)[C@H](N)C(=O)OC(C)(C)C
Reactant: N[C@@H](CCC(=O)O)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CCN1CCOCC1
Agent: Cc1ccccc1S(=O)(=O)O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(=O)SC(C)(C)[C@H](NC(=O)[C@@H](N)CCC(=O)O)C(=O)OC(C)(C)C

Procedure:
A solution of 20 mmoles of pyro-L-glutamic acid and 20 mmoles S-acetyl-penicillamine t-butyl ester toluene sulfonic acid, neutrallized with N-ethyl morpholine, in dichloromethane: DMF (4:1) is cooled in an ice bath with stirring. A solution of 20 mmoles of dicyclohexylcarbodiimide in dichloromethane is added to the above reaction mixture. The reaction mixture is stirred in an ice water bath for 1 hour and then at room temperature overnight. Dicyclohexylurea is removed by filtration and the product is washed in ethyl acetate. Solvents of the combined filtrates are removed under reduced pressure with a rotary evaporator at 40° C. Ethyl acetate is added to the residue and the organic solution is washed until neutral. The organic phase is dried over anhydrous MgSO4, filtered and then the solvent is removed with a rotary evaporator. The material is crystallized from isopropanol and ether, yielding the named product.
Reaction SMILES: Br[C:2]1[C:3]2[C:4]3[CH:17]=[CH:16][S:15][C:5]=3[C:6](=[O:14])[NH:7][C:8]=2[CH:9]=[CH:10][C:11]=1[O:12][CH3:13].[F:18][C:19]1[CH:24]=[C:23](B2OC(C)(C)C(C)(C)O2)[CH:22]=[CH:21][C:20]=1[CH:34]([CH3:44])[CH2:35][NH:36][C:37](=[O:43])[O:38][C:39]([CH3:42])([CH3:41])[CH3:40]>>[F:18][C:19]1[CH:24]=[C:23]([C:2]2[C:3]3[C:4]4[CH:17]=[CH:16][S:15][C:5]=4[C:6](=[O:14])[NH:7][C:8]=3[CH:9]=[CH:10][C:11]=2[O:12][CH3:13])[CH:22]=[CH:21][C:20]=1[CH:34]([CH3:44])[CH2:35][NH:36][C:37](=[O:43])[O:38][C:39]([CH3:41])([CH3:40])[CH3:42]
Reactant: COc1ccc2[nH]c(=O)c3sccc3c2c1Br
Reactant: CC(CNC(=O)OC(C)(C)C)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1F
Product: COc1ccc2[nH]c(=O)c3sccc3c2c1-c1ccc(C(C)CNC(=O)OC(C)(C)C)c(F)c1
Yield: 49.4 %

Procedure:
Following General Procedure B, 9-bromo-8-methoxythieno[2,3-c]quinolin-4(5H)-one (1.2 g, 3.8 mmol) was reacted with tert-butyl 2-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propylcarbamate (2.2 g, 5.8 mmol) to afford the desired product (905 mg, 51%) as a brown solid: ESI MS m/z 483 [C26H27FN2O4S+H]+.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[NH:5]1[CH:9]=[CH:8][CH:7]=[C:6]1[C:10]([O:12][CH3:13])=[O:11].Cl[C:15]([CH3:18])([CH3:17])[CH3:16]>ClC(Cl)C>[C:15]([C:9]1[NH:5][C:6]([C:10]([O:12][CH3:13])=[O:11])=[CH:7][CH:8]=1)([CH3:18])([CH3:17])[CH3:16]
Reactant: CC(C)(C)Cl
Reactant: COC(=O)c1ccc[nH]1
Agent: [Al+3]
Agent: [Cl-]
Solvent: CC(Cl)Cl
Product: COC(=O)c1ccc(C(C)(C)C)[nH]1
Reaction time: 2 h
Yield: 91.2 %

Procedure:
Aluminum chloride (0.710 g, 5.33 mmol, 2.2 equiv) is added in one portion to a solution of methyl pyrrole-2-carboxylate (0.30 g, 2.42 mmol) in dry dichloroethane (12 mL) under N2 at rt. Subsequently, 2-chloro-2-methylpropane (0.26 mL, 2.42 mmol, 1.0 equiv) is added in one portion via syringe. After 2 h, the orange solution is quenched by slowly pouring into a saturated sodium bicarbonate solution. The resulting white suspension is extracted with diethyl ether (2×). The combined organic layers are dried (Na2SO4) and concentrated in vacuo to give 0.40 g of methyl 5-t-butylpyrrole-2-carboxylate as an off-white solid. Flash chromatography (40% hexane in dichloromethane) gives 0.3 6 g of the desired material as a white amorphous solid (81%). 1H NMR (CDCl3) d 8.82 (br s, 1H), 6.81 (t, 1H, J=3.3 Hz), 6.00 (t, 1H, J=3.3 Hz), 3.83 (s, 3H), 1.31 (s, 9H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][CH:4]=1.[Li:12]CCCC>CCCCCC>[CH3:1][O:2][C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]([Li:12])[CH:4]=1
Reactant: [Li]CCCC
Reactant: COC1=CCc2ccccc21
Solvent: CCCCCC
Product: [Li]C1C=C(OC)c2ccccc21
Yield: 97 %

Procedure:
3-Methoxy-1H-indene (9.65 g, 66.04 mmol) was dissolved in 150 mL of hexane. To this solution 50 mL of a 1.6 M solution of n-BuLi was added (80 mmol) within 10 minutes After 20 hours of stirring the off-white solid was collected on a medium-size frit, washed with hexane (3×30 mL) and dried under reduced pressure to give 9.72 g of product. Yield 97 percent.
Reaction SMILES: C1C=C(O[C:8](OC2N=CC=CC=2)=[S:9])N=CC=1.[C:17]([C:21]1[CH:28]=[CH:27][C:24]([CH2:25][NH2:26])=[CH:23][CH:22]=1)([CH3:20])([CH3:19])[CH3:18].C(N(CC)CC)C>C(Cl)Cl>[C:17]([C:21]1[CH:22]=[CH:23][C:24]([CH2:25][N:26]=[C:8]=[S:9])=[CH:27][CH:28]=1)([CH3:20])([CH3:18])[CH3:19]
Reactant: S=C(Oc1ccccn1)Oc1ccccn1
Reactant: CC(C)(C)c1ccc(CN)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)c1ccc(CN=C=S)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 71.3 %

Procedure:
Di-2-pyridyl thionocarbonate (45 mg) was dissolved in methylenechloride (2 ml) and to the solution were added 4-t-butylbenzylamine (29 mg) and triethylamine (20 μl), followed by stirring at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure and the obtained residue was chromatographed on a silica gel column eluting with ethyl acetate/hexane (1/10) to yield 4-t-butylbenzylisothiocyanate (26 mg, 71%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([N+:20]([O-])=O)[CH:18]=3)[N:13]=[CH:12][C:11]=2[C:23]#[N:24])[CH:6]=[CH:7][CH:8]=1.NN>[Pd].C(O)C>[NH2:20][C:17]1[CH:18]=[C:19]2[C:14](=[CH:15][CH:16]=1)[N:13]=[CH:12][C:11]([C:23]#[N:24])=[C:10]2[NH:9][C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=1
Reactant: COc1cccc(Nc2c(C#N)cnc3ccc([N+](=O)[O-])cc23)c1
Agent: [Pd]
Agent: NN
Solvent: CCO
Product: COc1cccc(Nc2c(C#N)cnc3ccc(N)cc23)c1
Reaction time: 1.5 h
Yield: 96.2 %

Procedure:
325 mg of 10% palladium on carbon was added to a round bottom flask under N2 and covered with 165 ml ethanol. Added 3.29 g (10.3 mmol) 4-[(3-methoxyphenyl)amino]-6-nitro-3-quinolinecarbonitrile and 800 μl anhydrous hydrazine and heated mixture to reflux. At 1.5 hours, filtered hot through celite, stripped solvent and dried in vacuo, giving 2.876 g of yellow solid: mass spectrum (electrospray m/e): M+H=291.2.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][CH:7]=[C:6]2[OH:13].[CH3:14][C:15]1([CH3:25])[O:19][C@H:18]([CH2:20]/[CH:21]=[CH:22]/[CH2:23]O)[CH2:17][O:16]1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[CH3:14][C:15]1([CH3:25])[O:19][C@H:18]([CH2:20][CH:21]=[CH:22][CH2:23][O:13][C:6]2[C:5]3[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[CH:4]=3)[N:9]=[CH:8][CH:7]=2)[CH2:17][O:16]1
Reactant: CC1(C)OC[C@@H](C/C=C/CO)O1
Reactant: COc1ccc2nccc(O)c2c1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1ccc2nccc(OCC=CC[C@@H]3COC(C)(C)O3)c2c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 73.9 %

Procedure:
A solution of 6-methoxy-quinolin-4-ol (0.54 g, 3 mmol) and (E)-4-((R)-2,2-dimethyl-[1,3]dioxolan-4-yl)-but-2-en-1-ol (prepared according to J. Am. Chem. Soc. (2001), 123, 9525; 0.53 g, 3 mmol) in THF was treated with PPh3 (977 mg, 1.2 eq.) and dropwise with DIAD (0.77 mL, 1.2 eq.). The mixture was stirred at rt for 3 days, concentrated in vacuo and purified by FC (EA) to give the product as a yellowish oil (0.73 g, 72% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@:9]2([C:14]#N)[CH2:11][CH:10]2[CH2:12][OH:13])[CH:5]=[CH:6][C:7]=1[Cl:8].C([OH:18])C.[OH-].[Na+].Cl>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([C@@:9]23[CH2:11][C@@H:10]2[CH2:12][O:13][C:14]3=[O:18])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: N#C[C@]1(c2ccc(Cl)c(Cl)c2)CC1CO
Reactant: CCO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: O=C1OC[C@H]2C[C@@]12c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 55 %

Procedure:
(1R)-1-(3,4-Dichloro-phenyl)-2-hydroxymethyl cyclopropanecarbonitrile (24 g, 9.9 mmol), ethanol (48 mL) and 25N sodium hydroxide solution (24 mL) were heated under reflux for 18 hours. The reaction is monitored by TLC (dichloromethane (100%)). The reaction mixture was cooled to room temperature and ice cold water (24 mL) was added to the reaction mass followed by concentrated hydrochloric acid drop wise to adjust the pH of the reaction mass to 1-2 and stirred for overnight at room temperature. The aqueous layer was extracted with dichloromethane (100 mL).The organic layer was washed with 3% sodium bicarbonate solution, dried over anhydrous sodium sulphate, filtered and evaporated under reduced pressure to yield 13 g (55%) of product. 1H NMR δ(300 MHz,CDCl3): 1.41-1.43 (1H,t,J=4.9 Hz), 1.58-1.63 (1H,dd,J=7.8,5.0 Hz), 2.56-2.59 (1H,m), 4.28-4.31 (1H, d, J=9.3 Hz), 4.44-4.48 (1H, dd, J=9.4, 4.6 Hz), 7.26-7.30 (1H,dd,J=8.4,2.1 Hz), 7.40-7.43 (1H,d,J=8.4 Hz) 7.52-7.53 (1H,d,J=2 Hz).
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:22])[CH:6]([NH2:21])[C:7](=[O:20])[CH2:8][CH2:9][C:10]12[CH2:19][CH:14]3[CH2:15][CH:16]([CH2:18][CH:12]([CH2:13]3)[CH2:11]1)[CH2:17]2)[CH3:3].[CH3:23][C:24]1[CH:32]=[CH:31][CH:30]=[CH:29][C:25]=1[C:26](Cl)=[O:27]>CN(C=O)C.C1COCC1>[CH2:2]([O:4][C:5](=[O:22])[CH:6]([NH:21][C:26](=[O:27])[C:25]1[CH:29]=[CH:30][CH:31]=[CH:32][C:24]=1[CH3:23])[C:7](=[O:20])[CH2:8][CH2:9][C:10]12[CH2:17][CH:16]3[CH2:18][CH:12]([CH2:13][CH:14]([CH2:15]3)[CH2:19]1)[CH2:11]2)[CH3:3]
Reactant: Cc1ccccc1C(=O)Cl
Reactant: CCOC(=O)C(N)C(=O)CCC12CC3CC(CC(C3)C1)C2
Agent: Cl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CCOC(=O)C(NC(=O)c1ccccc1C)C(=O)CCC12CC3CC(CC(C3)C1)C2
Temperature: 25 °C

Procedure:
5-Adamantan-1-yl-2-amino-3-oxo-pentanoic acid ethyl ester hydrochloride (prepared using the method of T. W. von Geldem & C. Hutchins et al, J. Med. Chem. 1996, 39, 957) (3.30 g, 10.0 mmol) was suspended in DMF (15 ml) and a solution of 2-methylbenzoyl chloride (1.55 g 10.0 mmol) in THF (15 ml) was added. The mixture was stirred at room temperature and a solution of N,N-diispropylethylamine (3.48 ml 20.0 mmol) in THF (10 ml) was added dropwise over 30 min. After stirring for 2 h the THF was evaporated and the residue was partitioned between ethyl acetate and saturated sodium bicarbonate. The organic layer was separated, washed with water, 2M HCl, brine, dried (MgSO4), and the solvent was evaporated. The residue was purified by flash column chromatography (silica, DCM/hexane/ethyl acetate 9:9:2) to afford the product as a pale yellow oil. (2.08 g, 60%). 1NMR (300 MHz, CDCl3) 7.49-7.23 (4H, m), 6.97 (1H, d), 5.45 (1H, d), 4.30 (2H, m), 2.77 (2H, m), 2.47 (3H, s), 1.97 (3H, s) 1.67 (6H, m), 1.47 (8H, m), 1.34 (3H, t).
Reaction SMILES: C([SiH](CC)CC)C.[CH2:8]([O:10][C:11]([C:13]1[NH:14][CH:15]=[C:16]([C:18](=O)[CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[Br:26])[CH:17]=1)=[O:12])[CH3:9]>FC(F)(F)C(O)=O>[CH2:8]([O:10][C:11]([C:13]1[NH:14][CH:15]=[C:16]([CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[Br:26])[CH:17]=1)=[O:12])[CH3:9]
Reactant: CCOC(=O)c1cc(C(=O)Cc2ccccc2Br)c[nH]1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1cc(CCc2ccccc2Br)c[nH]1
Temperature: 25 °C
Reaction time: 3 h
Yield: 57.3 %

Procedure:
Triethylsilane (2.25 mL, 14.1 mmol) was added to a stirring, room temperature solution of 63 (1.5291 g, 4.55 mmol) in trifluoroacetic acid (TFA) (10.8 mL, 0.42 M) under N2. After stirring at room temperature for 3 hours, the reaction was heated to 35° C. for 35 min, then the TFA was removed under vacuum, and the crude product was taken up in EtOAc, washed with brine, dried with Na2SO4, filtered, concentrated, and purified by preparative reverse phase HPLC with the following conditions: 0 to 12 min, 35:65 H2O:CH3CN; 14-15 min, 35:65 to 0:100 H2O:CH3CN; 20 mL/min.; λ=254 nM; 3.67 g/mL, 0.2 mL/injection. 0.8402 g (57.3%) of 64 was obtained as a fluffy white solid. (Note: An undesired impurity has a retention time of 12.281 min by HPLC.) 1H (CDCl3, 400 MHz): δ 9.07 (1H, broad s), 7.55 (1H, dd, J=8.0, 1.3 Hz), 7.21 (1H, td, J=7.3, 1.3 Hz), 7.17 (1H, dd, J=7.6, 2.4 Hz), 7.06 (1H, ddd, J=7.9, 7.0, 2.3 Hz), 6.82 (1H, s), 6.72 (1H, s), 4.32 (2H, t, J=7.2 Hz), 2.99 (2H, t, J=8.0 Hz), 2.78 (2H, t, J=7.9 Hz), 1.36 (3H, t, J=7.2 Hz) ppm. 13C (CDCl3, 100 MHz): δ 161.21, 141.03, 132.75, 130.41, 127.63, 127.32, 125.31, 124.43, 122.66, 120.68, 114.83, 60.22, 37.78, 27.03, 14.48 ppm. DEPT (CDCl3, 100 MHz): CH3 carbons: 14.48; CH2 carbons: 60.22, 37.78, 27.03; CH carbons: 132.75, 130.41, 127.63, 127.32, 120.68, 114.83 ppm. HPLC: 11.355 min.
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[C:10]([CH2:15][CH2:16][CH3:17])[CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:24](Br)[CH:25]=[CH2:26].Cl>CN(C=O)C>[CH2:26]([O:14][C:11]1[CH:12]=[CH:13][C:8]([O:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:9][C:10]=1[CH2:15][CH2:16][CH3:17])[CH:25]=[CH2:24]
Reactant: CCCc1cc(Oc2ccccc2)ccc1O
Reactant: C=CCBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=CCOc1ccc(Oc2ccccc2)cc1CCC
Temperature: 50 °C
Reaction time: 5 h

Procedure:
To a solution of 4-phenoxy-2-propylphenol (PCT Application WO97/28115) in DMF was added potassium carbonate and allyl bromide. The reaction was stirred for 5 h at 50° C., and after cooling was neutralized with 1N HCl and extracted with ethyl acetate. The organic extract was washed with brine, dried over magnessium sulphate, filtered and concentrated to afford an oil which was chromatographed on silica gel (15% ethyl acetate:hexanes) to afford 2-propyl-4-phenoxyphenyl allyl ether.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.[H-].[Na+].[CH3:11][Si:12]([CH3:17])([CH3:16])[CH2:13][CH2:14][OH:15].Cl>C1COCC1.O>[Cl:1][C:2]1[N:7]=[C:6]([O:15][CH2:14][CH2:13][Si:12]([CH3:17])([CH3:16])[CH3:11])[CH:5]=[CH:4][N:3]=1
Reactant: Clc1ccnc(Cl)n1
Reactant: C[Si](C)(C)CCO
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: C[Si](C)(C)CCOc1ccnc(Cl)n1
Reaction time: 16 h
Yield: 79.2 %

Procedure:
2,4-Dichloro-pyrimidine (2.00 g, 13.4 mmol) in THF (30 mL) was treated with sodium hydride (670 mg, 60% oil dispersion, 16.8 mmol) followed by 2-trimethylsilanyl-ethanol (2.01 mL, 14.1 mmol) in portions over 15 minutes. The reaction mixture was stirred for 16 hours and treated with 1 M HCl (20 mL). Water (20 mL) was added and the mixture was extracted with 1:1 ethyl acetate:hexanes (100 mL) followed by ethyl acetate (100 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated. Purification by flash chromatography (10-30% EtOAc:hexanes, 80 g column), afforded 2.45 g (79% yield) of 2-chloro-4-(2-trimethylsilanyl-ethoxy)-pyrimidine as a mixture of regioisomers.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@@H:10]([CH2:13][C:14]([OH:16])=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:17][C:18]1[CH:19]=[C:20]([NH:28][C:29]2[N:38]=[CH:37][C:36]3[N:35]([CH3:39])[C:34](=[O:40])[CH2:33][N:32]([CH:41]([CH3:43])[CH3:42])[C:31]=3[N:30]=2)[CH:21]=[C:22]([S:24]([CH3:27])(=[O:26])=[O:25])[CH:23]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@@H:10]([CH2:13][C:14](=[O:16])[NH:17][C:18]2[CH:23]=[C:22]([S:24]([CH3:27])(=[O:25])=[O:26])[CH:21]=[C:20]([NH:28][C:29]3[N:38]=[CH:37][C:36]4[N:35]([CH3:39])[C:34](=[O:40])[CH2:33][N:32]([CH:41]([CH3:43])[CH3:42])[C:31]=4[N:30]=3)[CH:19]=2)[CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)N1CC(=O)N(C)c2cnc(Nc3cc(N)cc(S(C)(=O)=O)c3)nc21
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](CC(=O)O)C1
Product: CC(C)N1CC(=O)N(C)c2cnc(Nc3cc(NC(=O)C[C@@H]4CCN(C(=O)OC(C)(C)C)C4)cc(S(C)(=O)=O)c3)nc21
Yield: 82 %

Procedure:
The (S)-enantiomer was prepared with the same procedure used for the (R)-enantiomer and described in Scheme 12 starting from (S)-3-carboxymethyl-pyrrolidine-1-carboxylic acid tert butyl ester (132 mg; 0.576 mmol) and 2-(3-Amino-5-(methylsulfonyl)-phenylamino)-8-isopropyl-5-methyl-7,8-dihydro-5H-pteridin-6-one (150 mg; 0.384 mmol), 190 mg (0.316 mmol; 82% yield) of product were obtained.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6](=[O:18])[C:7](=[O:17])[C:8]3[C:13]([C:14]=2[CH:15]=1)=[CH:12][C:11]([OH:16])=[CH:10][CH:9]=3.C(=O)([O-])[O-].[K+].[K+].[I-].[K+].Br[CH2:28][CH:29]1[CH2:31][CH2:30]1>CC(C)=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6](=[O:18])[C:7](=[O:17])[C:8]3[C:13]([C:14]=2[CH:15]=1)=[CH:12][C:11]([O:16][CH2:28][CH:29]1[CH2:31][CH2:30]1)=[CH:10][CH:9]=3
Reactant: O=C1C(=O)c2ccc(Br)cc2-c2cc(O)ccc21
Reactant: BrCC1CC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=C1C(=O)c2ccc(OCC3CC3)cc2-c2cc(Br)ccc21

Procedure:
A solution of 3-bromo-6-hydroxyphenanthrene-9,10-dione from Step 4 in acetone was treated with excess potassium carbonate, potassium iodide and (bromomethyl)cyclopropane. The mixture was heated at reflux overnight, followed by standard workup to yield 3-bromo-6-(cyclopropylmethoxy)phenanthrene-9,10-dione.
Reaction SMILES: [NH2:1][C:2]1[C:22]([F:23])=[CH:21][C:20]([F:24])=[CH:19][C:3]=1[NH:4][C:5]1[S:9][C:8]2[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=2[C:6]=1[C:14](OCC)=O.[CH3:25][N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1.C1(OC)C=CC=CC=1>[Ti](Cl)(Cl)(Cl)Cl>[F:24][C:20]1[CH:21]=[C:22]([F:23])[C:2]2[N:1]=[C:14]([N:29]3[CH2:30][CH2:31][N:26]([CH3:25])[CH2:27][CH2:28]3)[C:6]3[C:7]4[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=4[S:9][C:5]=3[NH:4][C:3]=2[CH:19]=1
Reactant: CN1CCNCC1
Reactant: CCOC(=O)c1c(Nc2cc(F)cc(F)c2N)sc2ccccc12
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: COc1ccccc1
Product: CN1CCN(C2=Nc3c(F)cc(F)cc3Nc3sc4ccccc4c32)CC1

Procedure:
In the same manner as in Example 1 and using ethyl 2-(2-amino-3,5-difluoroanilino)benzo[b]thiophene-3-carboxylate, 1-methylpiperazine, anisole and titanium tetrachloride, 8,10-difluoro-12-(4-methylpiperazin-1-yl)-6H-[1]benzothieno[2,3-b][1,5]benzodiazepine is obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([C:18]([C:35]4[CH:36]=[N:37][C:38]([Cl:41])=[CH:39][CH:40]=4)([N:25]=CC4C=CC(OC)=CC=4)[C:19]4[N:20]([CH3:24])[CH:21]=[N:22][CH:23]=4)[CH:16]=3)[N:11]([CH2:42][CH:43]3[CH2:45][CH2:44]3)[C:10](=[O:46])[CH:9]=2)[CH:5]=[CH:6][CH:7]=1.Cl.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>C1COCC1>[NH2:25][C:18]([C:35]1[CH:36]=[N:37][C:38]([Cl:41])=[CH:39][CH:40]=1)([C:19]1[N:20]([CH3:24])[CH:21]=[N:22][CH:23]=1)[C:15]1[CH:16]=[C:17]2[C:12](=[CH:13][CH:14]=1)[N:11]([CH2:42][CH:43]1[CH2:44][CH2:45]1)[C:10](=[O:46])[CH:9]=[C:8]2[C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=1
Reactant: COc1ccc(C=NC(c2ccc(Cl)nc2)(c2ccc3c(c2)c(-c2cccc(Cl)c2)cc(=O)n3CC2CC2)c2cncn2C)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cn1cncc1C(N)(c1ccc(Cl)nc1)c1ccc2c(c1)c(-c1cccc(Cl)c1)cc(=O)n2CC1CC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 91.4 %

Procedure:
To a solution of the title compound of Example 45, the slower moving enantiomer of 4-(3-chloro-phenyl)-6-[(6-chloro-pyridin-3-yl)-[(4-methoxy-benzylidene)amino]-(3-methyl-3H-imidazol-4-yl)-methyl]-1-cyclopropylmethyl-1H-quinolin-2-one (1.41 g, 1.74 mmol) in THF (200 ml) was added 2N hydrochloric acid (20 ml) slowly. The reaction mixture was stirred at ambient temperature for 1.5 hour after which time it was cooled to 0° C. An aqueous solution of potassium carbonate was added followed by addition of ethyl acetate. After separation, the organic layer was washed with brine, dried over MgSO4 and concentrated under vacuum to give the crude product. It was chromatographed on silica gel with MeOH—CHCl3—NH4OH (1:99:0.1 to 2:98:0.1) as the eluents to afford the title compound as a white solid ( 0.844 g, 1.59 mmol, 90% yield). It is the faster eluting enantiomer of 6-[amino-(6-chloro-pyridin-3-yl)-(3-methyl-3H-imidazol-4-yl)-methyl]-4-(3-chloro-phenyl)-1-cyclopropylmethyl-1H-quinolin-2-one with >99% optical purity.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=O)[CH:9]([C:12]1[N:17]=[C:16]2[S:18][C:19]([NH:21][CH:22]([CH3:24])[CH3:23])=[N:20][C:15]2=[CH:14][CH:13]=1)[C:10]#[N:11].[NH2:26][NH2:27]>CCO.CC(O)=O>[NH2:11][C:10]1[NH:27][N:26]=[C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:2]=2)[C:9]=1[C:12]1[N:17]=[C:16]2[S:18][C:19]([NH:21][CH:22]([CH3:24])[CH3:23])=[N:20][C:15]2=[CH:14][CH:13]=1
Reactant: CC(C)Nc1nc2ccc(C(C#N)C(=O)c3ccccc3F)nc2s1
Reactant: NN
Solvent: CCO
Solvent: CC(=O)O
Product: CC(C)Nc1nc2ccc(-c3c(-c4ccccc4)n[nH]c3N)nc2s1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 1.4 %

Procedure:
To a solution of 3-(2-fluorophenyl)-2-(2-(isopropylamino)thiazolo[5,4-b]pyridin-5-yl)-3-oxopropanenitrile (0.10 g, 0.282 mmol, 1.0 eq.) in EtOH (1 mL) and HOAc (2 mL) at 0° C. was added hydrazine (0.1 mL, 3.19 mmol, 11.3 eq.). After 10 min., the cold bath was removed, and the reaction mixture was stirred to room temperature for 10 min. It was then heated at 88° C. for 5 hr and at 100° C. overnight. After cooling to room temperature and then to 0° C., water was added followed by concentrated aqueous NH4OH until pH was 10 by litmus paper. The aqueous layer was extracted with EtOAc (3×). The organic layers were combined, dried over Na2SO4, filtered, and concentrated in vacuo. MeOH was added to the residue, and the mixture was subjected to autoprep. The appropriate fractions were collected, and NaHCO3 (s) was added. The solution was then concentrated in vacuo not to dryness and extracted with CH2Cl2 (3×). The organic layers were combined, dried over Na2SO4, filtered, and concentrated in vacuo to give 5-(5-amino-3-phenyl-1H-pyrazol-4-yl) -N-isopropylthiazolo[5,4-b]pyridin-2-amine as a light yellow solid (0.0014 g, 1.3% yield). LC/MS (MH)=369.14.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:9][C:10]2[C:19]3[C:14](=[C:15]([CH3:49])[CH:16]=[C:17]([S:20]([C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([N:31]5[CH2:36][CH2:35][N:34]([C:37](=[O:48])[C:38]6[CH:43]=[CH:42][CH:41]=[C:40](CC(=O)C)[CH:39]=6)[CH2:33][CH2:32]5)=[O:30])[CH:24]=4)(=[O:22])=[O:21])[CH:18]=3)[N:13]=[CH:12][C:11]=2[C:50]([NH2:52])=[O:51])[CH:6]=[CH:7][CH:8]=1.[CH2:53]([O:60][C:61]1[CH:62]=[CH:63][C:64]([C@@H:72]([O:88][Si:89]([C:92]([CH3:95])([CH3:94])[CH3:93])([CH3:91])[CH3:90])[CH2:73][NH:74][C:75]([CH3:87])([CH3:86])[CH2:76]C2C=C(C=CC=2)C(O)=O)=[C:65]2[C:70]=1[NH:69][C:68](=[O:71])[CH:67]=[CH:66]2)[C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1>>[CH2:53]([O:60][C:61]1[CH:62]=[CH:63][C:64]([C@@H:72]([O:88][Si:89]([C:92]([CH3:95])([CH3:94])[CH3:93])([CH3:90])[CH3:91])[CH2:73][NH:74][C:75]([CH3:86])([CH3:87])[CH2:76][C:40]2[CH:39]=[C:38]([CH:43]=[CH:42][CH:41]=2)[C:37]([N:34]2[CH2:35][CH2:36][N:31]([C:29]([C:25]3[CH:24]=[C:23]([S:20]([C:17]4[CH:18]=[C:19]5[C:14](=[C:15]([CH3:49])[CH:16]=4)[N:13]=[CH:12][C:11]([C:50]([NH2:52])=[O:51])=[C:10]5[NH:9][C:5]4[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=4)(=[O:22])=[O:21])[CH:28]=[CH:27][CH:26]=3)=[O:30])[CH2:32][CH2:33]2)=[O:48])=[C:65]2[C:70]=1[NH:69][C:68](=[O:71])[CH:67]=[CH:66]2)[C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1
Reactant: CC(C)(Cc1cccc(C(=O)O)c1)NC[C@H](O[Si](C)(C)C(C)(C)C)c1ccc(OCc2ccccc2)c2[nH]c(=O)ccc12
Reactant: COc1cccc(Nc2c(C(N)=O)cnc3c(C)cc(S(=O)(=O)c4cccc(C(=O)N5CCN(C(=O)c6cccc(CC(C)=O)c6)CC5)c4)cc23)c1
Product: COc1cccc(Nc2c(C(N)=O)cnc3c(C)cc(S(=O)(=O)c4cccc(C(=O)N5CCN(C(=O)c6cccc(CC(C)(C)NC[C@H](O[Si](C)(C)C(C)(C)C)c7ccc(OCc8ccccc8)c8[nH]c(=O)ccc78)c6)CC5)c4)cc23)c1

Procedure:
The title compound was synthesized in a manner analogous to that described for Intermediate 97, using Intermediate 101 in place of 3-(2-oxopropyl)benzoic acid. ES/MS calcd. for C64H72N7O9SSi+ 1142.5. Found m/z=1142.5 (M+H)+.