Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I:1][C:2]1[C:10]2[C:9](=[S:11])[NH:8][CH:7]=[N:6][C:5]=2[NH:4][N:3]=1.[C:12](O)(=O)[CH3:13]>[OH-].[K+].O>[CH2:12]([S:11][C:9]1[N:8]=[CH:7][N:6]=[C:5]2[NH:4][N:3]=[C:2]([I:1])[C:10]=12)[CH3:13]
Reactant: CC(=O)O
Reactant: S=c1[nH]cnc2[nH]nc(I)c12
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: CCSc1ncnc2[nH]nc(I)c12
Temperature: 25 °C

Procedure:
Compound 5 (43.5 g, 157 mmol) was stirred in potassium hydroxide solution (38.6 g KOH in 350 mL of water) for 30 min. The mixture was filtered and the filtrate was acidified to pH 10 by addition of acetic acid and then diluted with 350 mL of absolute ethanol. Iodoethane (10 mL) was added and the solution was stirred at room temperature. Additional 10 mL aliquots of iodoethane were added after 30 min. and 1.0 h. The reaction was complete after a total of 90 min. Other runs required further addition of iodoethane to complete the reaction. The reaction solution was diluted with 700 mL of water and 20 mL of acetic acid. The mixture was cooled in an ice-bath and the solid was filtered, rinsed with water and dried. This crude product was dissolved in 300 of DMF and stirred at 90° C. for 15 min. Insoluble material was filtered away and the filtrate was diluted with 1 L of water and cooled in an ice-water bath. The solid was filtered, rinsed with water and dried: 19 g (40%) yield.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1.[N:12]1([CH2:17][C:18]2[CH:19]=[CH:20][C:21](Br)=[N:22][CH:23]=2)[CH:16]=[CH:15][N:14]=[CH:13]1>>[N:12]1([CH2:17][C:18]2[CH:19]=[CH:20][C:21]([C:6]3[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)=[N:22][CH:23]=2)[CH:16]=[CH:15][N:14]=[CH:13]1
Reactant: COc1ccc(B(O)O)cc1
Reactant: Brc1ccc(Cn2ccnc2)cn1
Product: COc1ccc(-c2ccc(Cn3ccnc3)cn2)cc1

Procedure:
Synthesized using 4-methoxyphenylboronic acid (380 mg, 3.35 mmol) and 1a (400 mg, 1.68 mmol) according to Method C. Yellow solid. Yield: 400 mg, 1.51 mmol, 90%. 1H NMR (CDCl3, 500 MHz): δH (ppm)=3.86 (s, 3H), 5.16 (s, 2H), 6.92 (t, J=1.3 Hz, 1H), 6.99 (d, J=9.1 Hz, 2H), 7.11 (s, 1H), 7.46 (dd, J=8.2, 2.5 Hz, 1H), 7.59 (s, 1H), 7.66 (d, J=8.2 Hz, 1H), 7.94 (d, J=9.1 Hz, 2H), 8.54 (d, J=2.5 Hz, 1H); 13C NMR (CDCl3, 125 MHz): δC (ppm)=48.1, 55.4, 114.2, 119.0, 119.8, 128.2, 129.2, 130.3, 131.2, 135.7, 137.3, 148.5, 157.4, 160.8; MS (ESI): m/z=266.22 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[C:3]=1[O:10][CH3:11].[Li]C(C)(C)C.CO[B:19]1[O:23][C:22]([CH3:25])([CH3:24])[C:21]([CH3:27])([CH3:26])[O:20]1>C(OCC)C>[Cl:9][C:4]1[C:3]([O:10][CH3:11])=[C:2]([B:19]2[O:23][C:22]([CH3:25])([CH3:24])[C:21]([CH3:27])([CH3:26])[O:20]2)[CH:7]=[C:6]([Cl:8])[CH:5]=1
Reactant: COB1OC(C)(C)C(C)(C)O1
Reactant: COc1c(Cl)cc(Cl)cc1Br
Agent: [Li]C(C)(C)C
Solvent: CCOCC
Product: COc1c(Cl)cc(Cl)cc1B1OC(C)(C)C(C)(C)O1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
1-Bromo-3,5-dichloro-2-methoxybenzene (Preparation 25, 4.4 g, 17.5 mmol) in 95 ml diethylether was cooled to −78° C. under nitrogen. tBuLi (10 ml, 35.16 mmol) was added dropwise and the reaction stirred for 15 minutes. 2-Methoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (4.58 g, 29 mmol) was added and the reaction stirred at −78° C. for 1 hour before pouring the reaction into 50 ml ice cold ammonium chloride (aqueous). The product was extracted with diethylether (3×30 ml), the combined organic layers were washed with water (50 ml) and brine (2×25 ml), dried over sodium sulphate, and concentrated in vacuo to afford a yellow oil. This was purified using silica gel column chromatography (heptane:ethyl acetate 9:1) to furnish a yellow oil, 4.5 g
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[C:10]=1[N:9]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:8](=S)[C:7]=3[CH:19]=[CH:20][CH:21]=2.[N:22]1([CH2:27][CH2:28][CH2:29][NH2:30])[CH:26]=[CH:25][N:24]=[CH:23]1.C(O)C>CN(C)C=O>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[C:10]=1[N:9]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:8](=[N:30][CH2:29][CH2:28][CH2:27][N:22]1[CH:26]=[CH:25][N:24]=[CH:23]1)[C:7]=3[CH:19]=[CH:20][CH:21]=2
Reactant: NCCCn1ccnc1
Reactant: Cc1ccc2cccc3c2c1N(Cc1ccccc1)C3=S
Solvent: CN(C)C=O
Solvent: CCO
Product: Cc1ccc2cccc3c2c1N(Cc1ccccc1)C3=NCCCn1ccnc1

Procedure:
A mixture of 2.9 g of (8-methyl-1-(phenylmethyl)benz[cd]indole-2(1H)-thione (Cq), 1.4 g of 1H-imidazole-1-propanamine, 250 ml of ethanol, 50 ml of dimethylformamide, and 3.5 g of mercuric acetate is reacted as described in Example 3, giving I.6 g of the desired product, mp 107°-109° C.
Reaction SMILES: [NH:1]1[CH2:4][CH2:3][CH2:2]1.[CH3:5][O:6][CH:7]([O:12][CH3:13])[CH2:8][CH2:9][CH2:10]Cl.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[CH3:5][O:6][CH:7]([O:12][CH3:13])[CH2:8][CH2:9][CH2:10][N:1]1[CH2:4][CH2:3][CH2:2]1
Reactant: COC(CCCCl)OC
Reactant: C1CNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(CCCN1CCC1)OC

Procedure:
A mixture of azetidine (2.0 g, 35.0 mmol), 4-chlorobutanal dimethylacetal (5.88 g, 39.0 mmol) and K2CO3 (5.38 g, 39.0 mmol), in anhydrous DMF (100ml), was stirred at room temperature for 72 h. Water (50 ml) was added and the mixture extracted with EtOAc (3×150 ml). The combined extracts were washed with H2O (3×50ml), dried (Na2SO4) and evaporated. The crude product was purified by distillation (1.2 g). δ (360 MHz, CDCl3) 1.35-1.42 (2H, m, CH2), 1.57-1.64 (2H, m, CH2), 2.00-2.40 (2H, m, CH2), 2.36 (2H, t, J=9.0 Hz, CH2), 3.15 (4H, m, t, J=7.0 Hz, 2 of CH2), 3.33 (6H, s, 2 of OMe), 4.35 (1H, t, J=5.7 Hz, CH).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:23])=[C:4]([C:7]([OH:22])=[C:8]([CH:11]([OH:21])[CH2:12][CH:13]([CH3:20])[CH2:14][CH2:15][CH:16]=[C:17]([CH3:19])[CH3:18])[C:9]=1[OH:10])[CH:5]=[O:6].[H][H]>[Pd].C(O)C>[Cl:1][C:2]1[C:3]([CH3:23])=[C:4]([C:7]([OH:22])=[C:8]([CH:11]([OH:21])[CH2:12][CH:13]([CH3:20])[CH2:14][CH2:15][CH2:16][CH:17]([CH3:18])[CH3:19])[C:9]=1[OH:10])[CH:5]=[O:6]
Reactant: [H][H]
Reactant: CC(C)=CCCC(C)CC(O)c1c(O)c(Cl)c(C)c(C=O)c1O
Agent: [Pd]
Solvent: CCO
Product: Cc1c(Cl)c(O)c(C(O)CC(C)CCCC(C)C)c(O)c1C=O

Procedure:
An ethanol solution (1.5 ml) of 3-chloro-5-(1-hydroxy-3,7-dimethyl-6-octenyl)-4,6-dihydroxy-2-methylbenzaldehyde (220) (196 mg, 0.57 mmol) was stirred at 0° C. in the presence of 5% Pd/C (50 mg) in a hydrogen atmosphere for 2 hours. After the catalyst was separated by filtration with the use of Celite, the filtrate was concentrated to obtain a crude product (188 mg). This crude product was purified by silica gel column chromatography (hexane:ethyl acetate=20:1) to obtain 3-chloro-5-(1-hydroxy-3,7-dimethyloctyl)-4,6-dihydroxy-2-methylbenzaldehyde (222, a diastereomeric mixture, red syrup 69 mg, crude yield 35%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[C:5](Br)=[N:6][NH:7][C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1)[CH3:2].O1CCN([C:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH:24]=2)CC1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4]([C:5]1[C:24]2[CH2:25][CH2:26][CH2:27][CH2:28][C:23]=2[N:7]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=2)[N:6]=1)=[O:16])[CH3:2]
Reactant: C1=C(N2CCOCC2)CCCC1
Reactant: CCOC(=O)C(Br)=NNc1ccc(Cl)cc1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCOC(=O)c1nn(-c2ccc(Cl)cc2)c2c1CCCC2
Yield: 54.9 %

Procedure:
A solution of bromo-(4-chlorophenyl)hydrazonoacetic acid ethyl ester (18.24 g, 60 mmol) in toluene (390 ml) and 10.02 g (60 mmol) of morpholinocyclohexene (10.02 g, 60 mmol) was cooled to 0° C. and triethylamine (12.6 ml, 90 mmol) was added. The solution was reacted for 1.5 hours at 0° C. and at ambient temperature for 48 hours. Triethylamine hydrochloride was filtered, the filtrate was washed with 10% hydrochloric acid, dried and evaporated. The crude product was crystallized from methanol to yield pure title compound (10.04 g), m.p. 139°-140° C. (lit 139°-141° C.).
Reaction SMILES: [NH2:1][C:2]1[C:7]([S:8]([N:11]2[CH2:15][CH2:14][C@@H:13]([NH:16]C(=O)OC(C)(C)C)[CH2:12]2)(=[O:10])=[O:9])=[CH:6][C:5](Br)=[CH:4][N:3]=1.[CH3:25][C:26]1([CH3:51])[C:35]([CH3:36])=[CH:34][C:33]2[N:32]=[CH:31][N:30]=[C:29]([N:37]3[CH2:43][C:42]4[CH:44]=[C:45](B(O)O)[CH:46]=[CH:47][C:41]=4[O:40][CH2:39][CH2:38]3)[C:28]=2[CH2:27]1>>[NH2:16][C@@H:13]1[CH2:14][CH2:15][N:11]([S:8]([C:7]2[C:2]([NH2:1])=[N:3][CH:4]=[C:5]([C:45]3[CH:46]=[CH:47][C:41]4[O:40][CH2:39][CH2:38][N:37]([C:29]5[C:28]6[CH2:27][C:26]([CH3:25])([CH3:51])[C:35]([CH3:36])=[CH:34][C:33]=6[N:32]=[CH:31][N:30]=5)[CH2:43][C:42]=4[CH:44]=3)[CH:6]=2)(=[O:9])=[O:10])[CH2:12]1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCN(S(=O)(=O)c2cc(Br)cnc2N)C1
Reactant: CC1=Cc2ncnc(N3CCOc4ccc(B(O)O)cc4C3)c2CC1(C)C
Product: CC1=Cc2ncnc(N3CCOc4ccc(-c5cnc(N)c(S(=O)(=O)N6CC[C@@H](N)C6)c5)cc4C3)c2CC1(C)C

Procedure:
Prepared as in example 5 using (R)-tert-butyl 1-(2-amino-5-bromopyridin-3-ylsulfonyl)pyrrolidin-3-ylcarbamate (reagent preparation 25) and [4-(6,6,7-trimethyl-5,6-dihydroquinazolin-4-yl)-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl]boronic acid (reagent preparation 23) in step 1 and BOC group deprotection. 1H NMR (400 MHz, d6-DMSO) δ 8.54 (s, 1H), 8.37 (s, 1H), 8.01 (d, 1H), 7.57 (d, 1H), 7.48 (dd, 1H), 7.02 (d, 1H), 6.76 (s, 2H), 6.13 (d, 1H), 4.62 (s, 2H), 4.33 (s, 2H), 3.84 (s, 2H), 3.44-3.20 (m, 3H), 2.89 (d, 1H), 2.69 (s, 2H), 1.88 (d, 5H), 1.53 (s, 1H), 0.92 (s, 6H); MS (ES) for C29H35N7O3S: 562.2 (MH+).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]([O:11]C)=O)[CH2:4][CH2:3]1.O.[NH2:14][NH2:15]>C(O)C>[CH3:1][N:2]1[CH2:3][CH2:4][N:5]([CH2:8][C:9]([NH:14][NH2:15])=[O:11])[CH2:6][CH2:7]1
Reactant: COC(=O)CN1CCN(C)CC1
Reactant: NN
Solvent: CCO
Solvent: O
Product: CN1CCN(CC(=O)NN)CC1

Procedure:
A solution of 2-(4-methyl-1-piperazinyl)acetic acid, methyl ester (16.3 g., 0.0946 mole) and hydrazine monohydrate (7.0 ml., 0.142 mole) in ethanol (100 ml.) was refluxed for 17 hours and the solvent was removed under vacuum. The residue was triturated with ether with cooling at -78° and the resulting solid was filtered. The product was triturated again with ether-ethyl acetate to give 2-(4-methyl-1-piperazinyl)acetic acid, hydrazide as a solid melting at 87°-89° C. (8.94 g., 55%).
Reaction SMILES: C(O[C:4]([CH:6]1[CH2:11][CH2:10][CH2:9][N:8]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)[CH2:7]1)=[O:5])C.C1COCC1.Cl.[CH3:27][NH:28][O:29][CH3:30].C([Mg]Cl)(C)C>C(OCC)(=O)C>[CH3:30][O:29][N:28]([CH3:27])[C:4]([CH:6]1[CH2:11][CH2:10][CH2:9][N:8]([CH2:12][C:13]2[CH:14]=[CH:15][C:16]([O:19][CH3:20])=[CH:17][CH:18]=2)[CH2:7]1)=[O:5]
Reactant: CNOC
Reactant: CCOC(=O)C1CCCN(Cc2ccc(OC)cc2)C1
Agent: CC(C)[Mg]Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1ccc(CN2CCCC(C(=O)N(C)OC)C2)cc1
Temperature: 25 °C
Yield: 93.2 %

Procedure:
Combine 1-(4-Methoxy-benzyl)-piperidine-3-carboxylic acid ethyl ester (9.3 g, 33.5 mmol), THF (200 mL), N,O-Dimethylhydroxylamine hydrochloride (4.9 g, 50.3 mmol) at −10° C. (Acetone/ice bath) under a Nitrogen atmosphere. By dropwise addition, add Isopropylmagnesium chloride (50.3 mL, 100.6 mmol). Stir the reaction for 6 hours allowing the reaction mixture to warm to room temperature. Quench the reaction mixture with sat NH4Cl (aq) and extract product from the water using Ethyl acetate. Wash the organic layer with brine and then dry over Na2SO4. Concentrate under reduced pressure and flash chromatograph using 1:1 Hexanes:Ethyl acetate and then 1:1 Hexanes:Ethyl acetate with 3% 1N NH3MeOH to give 9.13 g (93% yield) of the title compound: 1H NMR (500 MHz, CDCl3); 1.4-1.7 (3H, m), 1.8 (1H, d), 1.9 (1H, t), 2.1 (1H, t), 2.8-3.0 (3H, m), 3.1 (3H, s), 3.5 (2H, d), 3.6 (3H, s), 3.8 (3H, s), 6.8 (2H, d), 7.2 (2H, d); MS m/z 293 (M+1).
Reaction SMILES: [O:1]([CH2:8][C@H:9]1[CH2:11][O:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:12][C@@H:13]([C@@H:16]([O:42][CH2:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)[C@@H:17]([N:27]([CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[CH2:18][C:19]1[CH:24]=[C:23]([F:25])[CH:22]=[C:21]([F:26])[CH:20]=1)[CH2:14][OH:15]>C(O)C>[CH2:43]([O:42][C@@H:16]([C@@H:17]([N:27]([CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[CH2:28][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)[CH2:18][C:19]1[CH:20]=[C:21]([F:26])[CH:22]=[C:23]([F:25])[CH:24]=1)[C@H:13]([NH:12][CH2:11][C@@H:9]([OH:10])[CH2:8][O:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH2:14][OH:15])[C:44]1[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=1
Reactant: N[C@H](CO)[C@@H](OCc1ccccc1)[C@H](Cc1cc(F)cc(F)c1)N(Cc1ccccc1)Cc1ccccc1
Reactant: c1ccc(OC[C@H]2CO2)cc1
Solvent: CCO
Product: OC[C@@H](NC[C@@H](O)COc1ccccc1)[C@@H](OCc1ccccc1)[C@H](Cc1cc(F)cc(F)c1)N(Cc1ccccc1)Cc1ccccc1
Temperature: 80 °C
Yield: 57 %

Procedure:
Add (R)-2-phenoxymethyl-oxirane (0.189 g, 1.258 mmol) to a solution of (2R,3R,4S)-2-amino-3-benzyloxy-4-dibenzylamino-5-(3,5-difluorophenyl)-pentan-1-ol (0.205 g, 0.434 mmol) in ethanol (2.1 mL). Heat in a sealed vessel at 80° C. overnight. Concentrate and purify (silica gel chromatography, eluting with 1-1.5% 2 M ammonia in methanol/dichloromethane) to give the desired compound as a clear semi-solid (0.165 g, 56.9%).
Reaction SMILES: [C:1]1([CH2:7][C:8]2[CH:17]=[CH:16][C:15]([OH:18])=[C:14]3[C:9]=2[CH:10]=[CH:11][CH:12]=[N:13]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>CO.C(OCC)(=O)C.[Pt]=O>[C:1]1([CH2:7][C:8]2[CH:17]=[CH:16][C:15]([OH:18])=[C:14]3[C:9]=2[CH2:10][CH2:11][CH2:12][NH:13]3)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Oc1ccc(Cc2ccccc2)c2cccnc12
Agent: O=[Pt]
Solvent: CO
Solvent: CCOC(C)=O
Product: Oc1ccc(Cc2ccccc2)c2c1NCCC2
Reaction time: 4 h
Yield: 102.6 %

Procedure:
To a solution of 702.8 mg (2.99 mmol) of 5-(phenylmethyl)-8-quinolinol in 40 ml of methanol and 8 ml of ethyl acetate under nitrogen was added 200 mg of platinum oxide and the mixture was hydrogenated at 40 PSI for four hours. Filtration through a 0.4 μm polyester membrane filter followed by evaporation yielded 733.8 mg of a dark tan solid. Recrystallization from dichloromethane:hexane and then flash chromatography on 50 g of silica eluted with 3:7 ethyl acetate:petroleum ether provided 534.5 mg: melting point 135°-136° C.
Reaction SMILES: [C:1]1([C:7]2([C:10]3[N:15]=[C:14]4[S:16][C:17]([C:19]5[CH:20]=[C:21]6[C:26](=[CH:27][CH:28]=5)[CH2:25][NH:24][CH2:23][CH2:22]6)=[N:18][C:13]4=[CH:12][CH:11]=3)[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.Br[CH2:37][C:38]([O:40][CH3:41])=[O:39]>C(Cl)Cl>[C:1]1([C:7]2([C:10]3[N:15]=[C:14]4[S:16][C:17]([C:19]5[CH:20]=[C:21]6[C:26](=[CH:27][CH:28]=5)[CH2:25][N:24]([CH2:37][C:38]([O:40][CH3:41])=[O:39])[CH2:23][CH2:22]6)=[N:18][C:13]4=[CH:12][CH:11]=3)[CH2:9][CH2:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: c1ccc(C2(c3ccc4nc(-c5ccc6c(c5)CCNC6)sc4n3)CC2)cc1
Reactant: COC(=O)CBr
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)CN1CCc2cc(-c3nc4ccc(C5(c6ccccc6)CC5)nc4s3)ccc2C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 5-(1-phenylcyclopropyl)-2-(1,2,3,4-tetrahydroisoquinolin-6-yl)thiazolo[5,4-b]pyridine (97 mg, 0.252 mmol), triethylamine (0.053 mL, 0.377 mmol), and methyl 2-bromoacetate (0.024 mL, 0.254 mmol) in DCM (2.0 mL) was stirred at 25° C. for 30 min. Additional methyl 2-bromoacetate (0.024 mL, 0.254 mmol) was then added, and the resulting mixture was stirred at 25° C. for 30 min. The resulting suspension was then concentrated onto silica gel and chromatographically purified (0-100% EtOAc/hexanes) to provide methyl 2-(6-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridin-2-yl)-3,4-dihydroisoquinolin-2(1H)-yl)acetate as a white solid. MS (ESI) m/z: Calculated: 455.2; Observed: 456.0 (M++1).
Reaction SMILES: O[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:13][C:12](=[O:14])[CH:11]([C:15](=[O:18])[CH2:16][CH3:17])[C:10](=[O:19])[CH:9]1[C:20]([O:22]CC)=[O:21].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[C:15]([CH:11]1[C:12](=[O:14])[CH2:13][CH:8]2[C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[O:22][C:20](=[O:21])[CH:9]2[C:10]1=[O:19])(=[O:18])[CH2:16][CH3:17]
Reactant: CCOC(=O)C1C(=O)C(C(=O)CC)C(=O)CC1c1ccccc1O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CCC(=O)C1C(=O)CC2c3ccccc3OC(=O)C2C1=O
Yield: 92.9 %

Procedure:
A solution of 5-(2-hydroxyphenyl)-4-ethoxycarbonyl-2-propionylcyclohexane-1,3-dione (100 mg) and p-toluenesulphonic acid (10 mg) in toluene (5 ml) was heated under reflux for 1 hour. The solution was washed with dilute aqueous sodium bicarbonate and the toluene layer was dried (MgSO4) and evaporated to give 8-propionyl-10,10a-dihydro-6H-dibenzo[b,d]-pyran-6,7,9-(6aH,8H)trione (80 mg) as a pale yellow oil, proton magnetic resonance spectrum (CDCl3 ; δ in ppm): 0.8-1.3 (3H,m); 2.8-4.0 (6H,m); 6.9 (4H,bs); 18.1 (1H,bs).
Reaction SMILES: Br.[NH2:2][C:3]1[S:4][C:5](Br)=[CH:6][N:7]=1.C(=O)([O-])[O-].[K+].[K+].[NH:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1>CN(C=O)C>[N:15]1([C:5]2[S:4][C:3]([NH2:2])=[N:7][CH:6]=2)[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1
Reactant: C1COCCN1
Reactant: Nc1ncc(Br)s1
Agent: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Nc1ncc(N2CCOCC2)s1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 66.7 %

Procedure:
To a mixture of 2-amino-5- bromothiazole monohydrobromide (2 gm, 7.69 mmol) and powdered potassium carbonate (2.1 gm, 15.38 mmol) in DMF (20 mL) was added morpholine (1.34 ml, 15.38 mmol) under argon atmosphere and heated at 60° C. for 3 hr. Reaction mixture was cooled to rt and poured over ice cold water (100 ml), extracted with ethylacetate (3×100 ml), washed with brine solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. To the residue, diisopropyl ether (50 mL) was added, after stirring for 30 minutes product precipitated out, which was filtered and dried under vacuum to provide 5-morpholin-4-yl-thiazol-2-ylamine (0.95 gm).
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@H:13]([CH2:14][O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:12][C@@H:11]([OH:23])[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[Cl:26][C:27]1[CH:32]=[C:31](Cl)[N:30]=[CH:29][N:28]=1>O1CCCC1>[CH2:1]([O:8][C@@H:9]1[C@H:13]([CH2:14][O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:12][C@@H:11]([O:23][C:31]2[CH:32]=[C:27]([Cl:26])[N:28]=[CH:29][N:30]=2)[CH2:10]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Clc1cc(Cl)ncn1
Reactant: O[C@@H]1C[C@@H](COCc2ccccc2)[C@@H](OCc2ccccc2)C1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Clc1cc(O[C@@H]2C[C@@H](COCc3ccccc3)[C@@H](OCc3ccccc3)C2)ncn1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
At 0° C., under a blanket of nitrogen, to a solution of (1R,3S,4S)-3-(benzyloxy)-4-(benzyloxymethyl)cyclopentanol (24) (226.500 g, 725.026 mmol) in tetrahydrofuran (1150 mL) was added NaH, 60% in mineral oil (86.995 g, 2175.1 mmol) portionwise, maintaining a temperature of less than 10° C. A solution of 4,6-dichloropyrimidine (118.81 g, 797.53 mmol) in tetrahydrofuran (1150 mL) was then added over 30 minutes maintaining a temperature of less than 5° C. The mixture was allowed to warm to ambient temperature and stirred for 24 hours. HPLC analysis indicated that the reaction mixture contained 74% starting material. The reaction mixture was quenched with a mixture of water (1150 mL) and saturated ammonium chloride in water (1150 ml), maintaining a temperature of less than 10° C. The tetrahydrofuran layer was separated and concentrated to ˜2 volumes (500 mL). The aqueous layer was extracted twice with ethyl acetate (1150 mL). The organic layers were combined and washed twice with water (1150 mL) and once with saturated sodium chloride in water (1150 mL). The organics were then concentrated. The residue was taken up in tetrahydrofuran (2300 mL) and cooled to 0° C. under a blanket of nitrogen. NaH, 60% in mineral oil (86.995 g, 2175.1 mmol) was added portionwise maintaining a temperature of less than 10° C. Mixture was allowed to warm to ambient temperature and stirred for 16 hours. HPLC analysis indicated reaction was complete. The reaction mixture was quenched with a mixture of water (1150 mL) and saturated ammonium chloride in water (1150 mL). The tetrahydrofuran layer was separated and concentrated to ˜2 volumes (500 mL). The aqueous layer was extracted twice with ethyl acetate (1150 mL). The organic layers were combined and washed twice with water (1150 mL) and once with saturated sodium chloride in water (1150 ml). The organics were then concentrated to give the crude intermediate 4-((1R,3S,4S)-3-(benzyloxy)-4-(benzyloxymethyl)cyclopentyloxy)-6-chloropyrimidine. This crude reaction mixture was taken in to the next step without further purification.
Reaction SMILES: [C:1]1([CH2:7][N:8]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:9][C@@H:10]([C:12]2[CH:13]=[CH:14][C:15]([OH:21])=[C:16]([NH:18][CH:19]=[O:20])[CH:17]=2)[OH:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[CH3:31][Si:32]([CH3:39])([CH3:38])[CH2:33][CH2:34][O:35][CH2:36]Cl.P([O-])([O-])([O-])=O>CN(C=O)C.O>[C:1]1([CH2:7][N:8]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:9][C@@H:10]([C:12]2[CH:13]=[CH:14][C:15]([O:21][CH2:36][O:35][CH2:34][CH2:33][Si:32]([CH3:39])([CH3:38])[CH3:31])=[C:16]([NH:18][CH:19]=[O:20])[CH:17]=2)[OH:11])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: C[Si](C)(C)CCOCCl
Reactant: O=CNc1cc([C@@H](O)CN(Cc2ccccc2)Cc2ccccc2)ccc1O
Agent: O=P([O-])([O-])[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C[Si](C)(C)CCOCOc1ccc([C@@H](O)CN(Cc2ccccc2)Cc2ccccc2)cc1NC=O
Reaction time: 0.17 h

Procedure:
A solution of (5-{(1R)2-[bis(phenylmethyl)amino]-1-hydroxyethyl}-2-hydroxyphenyl)formamide (354 mg) in DMF (10 ml) under nitrogen was treated with sodium hydride (60% dispersion in mineral oil, 38 mg) and the mixture stirred at 20° for 10 min. 2-(Trimethylsilyl)ethoxymethyl chloride (0.17 ml) was added and the mixture was stirred at 20° for 3 h. Phosphate buffer solution (pH 6.5) and water were added and the mixture was extracted with EtOAc. The extract was washed with water and dried (Na2SO4). Solvent evaporation in vacuo gave a residue which was purified on a silica SPE bond elut cartridge (20 g) using a gradient of 0% to 2% MeOH in DCM (Gradmaster™). The appropriate fractions were evaporated in vacuo to give the title compound (286 mg). LCMS RT=3.08 min.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[OH:17])[CH2:10][CH2:9]1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+].Cl[CH:27](Cl)[C:28]([OH:30])=[O:29]>C(O)(C)C>[CH:4]1[C:3]2[C:8]3([CH2:10][CH2:9]3)[C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[O:17][CH:27]([C:28]([OH:30])=[O:29])[O:1][C:2]=2[CH:7]=[CH:6][CH:5]=1
Reactant: O=C(O)C(Cl)Cl
Reactant: Oc1ccccc1C1(c2ccccc2O)CC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)O
Product: O=C(O)C1Oc2ccccc2C2(CC2)c2ccccc2O1
Reaction time: 24 h

Procedure:
An 18.5 g (0.082 mole) sample of unpurified 1,1-bis(2-hydroxyphenyl)cyclopropane was combined with 44.0 g (0.32 mole) of potassium carbonate, 2.0 g (0.012 mole) of potassium iodide, 8.0 ml of dichloroacetic acid, and 400 ml of isopropyl alcohol. The mixture was heated at reflux with stirring for 24 hours. Another 8.0 ml of dichloroacetic acid was added and the mixture heated at reflux with stirring for another 48 hours. The volatiles were then removed by evaporation under reduced pressure. The solid that remained was dissolved in 300 ml of water. The resulting solution was extracted with 500 ml of ether, acidified with concentrated hydrochloric acid (carefully due to foaming), and then extracted with three 500 ml portions of ether. The latter ether extracts were dried over magnesium sulfate, filtered, and concentrated under reduced pressure to obtain the title compound in crude form as a solid.
Reaction SMILES: [NH:1]([C:8]1[S:9][C:10]2[N:18]=[CH:17][CH:16]=[CH:15][C:11]=2[C:12](=[O:14])[N:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Li+].[CH3:21]I>>[CH3:21][N:13]1[C:12](=[O:14])[C:11]2[CH:15]=[CH:16][CH:17]=[N:18][C:10]=2[S:9][C:8]1=[N:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=c1nc(Nc2ccccc2)sc2ncccc12
Reactant: CI
Agent: [H-]
Agent: [Li+]
Product: Cn1c(=Nc2ccccc2)sc2ncccc2c1=O

Procedure:
The reaction procedure of Example 11 was followed except that 255 mg of 2-anilino-4H-pyrido[3,2-e]-1,3-thiazin-4-one, 9 mg of lithium hydride and 0.063 ml of methyl iodide were used. As a result, 113 mg of 3-methyl-2-phenylimino-2,3-dihydro-4H-pyrido[3,2-e]-1,3-thiazin-4-one was obtained.