Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:20]3[CH:21]=[N:22][NH:23][CH:24]=3)=[CH:7][N:8]2[S:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)(=[O:13])=[O:12])=[CH:4][CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].Cl[CH2:32][CH2:33][N:34]1[CH2:38][CH2:37][CH2:36][CH2:35]1>CN(C=O)C.[NH4+].[Cl-]>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:20]3[CH:24]=[N:23][N:22]([CH2:32][CH2:33][N:34]4[CH2:38][CH2:37][CH2:36][CH2:35]4)[CH:21]=3)=[CH:7][N:8]2[S:11]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)(=[O:12])=[O:13])=[CH:4][CH:3]=1
Reactant: O=S(=O)(c1ccccc1)n1cc(-c2cn[nH]c2)c2ccc(F)cc21
Reactant: ClCCN1CCCC1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: O=S(=O)(c1ccccc1)n1cc(-c2cnn(CCN3CCCC3)c2)c2ccc(F)cc21
Temperature: 65 °C
Reaction time: 2 h
Yield: 97.7 %

Procedure:
To a solution of 6-fluoro-1-(phenylsulfonyl)-3-(1H-pyrazol-4-yl)-1H-indole (Intermediate 5; 240 mg; 0.70 mmol) and Cs2CO3 (688 mg; 2.11 mmol) in DMF (20 mL) was added 1-(2-chloroethyl)-pyrrolidine (186 mg; 1.39 mmol). The reaction mixture was stirred at 65° C. for 2 hours, cooled to r.t., diluted with 10% aqueous NH4Cl (20 mL), and extracted with EtOAc (20 mL×3). The combined organic layers were washed with water (20 mL), brine (20 mL), dried over Na2SO4 anhydrous, and concentrated to afford 300 mg (98%) of the title compound as a yellow solid, which was used directly without further purification.
Reaction SMILES: N#N.Br[C:4]1[C:5]([O:13][CH3:14])=[CH:6][C:7]([OH:12])=[C:8]([CH:11]=1)[CH:9]=[O:10].[S:15]1[CH:19]=[CH:18][CH:17]=[C:16]1B(O)O.C([O-])([O-])=O.[Na+].[Na+]>COCCOC>[S:15]1[C:19]([C:4]2[C:5]([O:13][CH3:14])=[CH:6][C:7]([OH:12])=[C:8]([CH:11]=2)[CH:9]=[O:10])=[CH:18][C:17]2[CH:5]=[CH:4][CH:11]=[CH:8][C:16]1=2
Reactant: OB(O)c1cccs1
Reactant: COc1cc(O)c(C=O)cc1Br
Agent: N#N
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: COc1cc(O)c(C=O)cc1-c1cc2ccccc2s1
Yield: 170.1 %

Procedure:
Ex-62B: A stream of N2 was bubbled through a solution of 5-bromo-2-hydroxy-4-methoxybenzaldehyde (1 g, 4.3 mmol) from Ex-62A in 30 mL of ethylene glycol dimethyl ether for 15 min. Tetrakis-triphenylphosphine palladium (0) (0.5 g, 0.4 mmol) was added along with thiophene-2-boronic acid (1.2 g, 6.5 mmol) and 10 mL of Na2CO3 (2M aqueous solution). The resulting mixture was stirred under reflux overnight. The solvent was removed by rotary evaporation and the residue was treated with saturated NaHCO3 and extracted with dichloromethane. The organic phase was washed with brine, dried over MgSO4, and filtered to remove drying agent. Solvent was removed by rotary evaporation. Purification of the crude material by silica gel chromatography (hexanes/EtOAc, 2:1) gave 1.04 g of the desired 5-benzo[b]thien-2-yl-2-hydroxy-4-methoxybenzaldehyde.
Reaction SMILES: [C:1]1([S:7]([O:10][C:11]2[C:20]([Br:21])=[C:19]3[C:14]([CH:15]=[CH:16][C:17]([CH:22]([OH:26])[CH2:23][C:24]#[N:25])=[N:18]3)=[CH:13][CH:12]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>C1COCC1>[C:1]1([S:7]([O:10][C:11]2[C:20]([Br:21])=[C:19]3[C:14]([CH:15]=[CH:16][C:17]([CH:22]([OH:26])[CH2:23][CH2:24][NH2:25])=[N:18]3)=[CH:13][CH:12]=2)(=[O:8])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: N#CCC(O)c1ccc2ccc(OS(=O)(=O)c3ccccc3)c(Br)c2n1
Solvent: C1CCOC1
Product: NCCC(O)c1ccc2ccc(OS(=O)(=O)c3ccccc3)c(Br)c2n1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a stirred solution of 8-Bromo-2-(2-cyano-1-hydroxyethyl)quinolin-7-yl benzenesulfonate (890 mg, 2.05 mmol) in THF (2 mL) were slowly added 1 M BH3-THF complex (4.1 mL, 4.10 mmol) at 0° C. And the reaction mixture was slowly warmed to room temperature. The mixture was then refluxed for 1 h, then cooled to 0° C. and quenched with MeOH. After the removal of solvents in vacuo, the mixture was stirred with 1.2N HCl in MeOH for 10 min. After the removal of solvents in vacuo again, the residue was dissolved in CHCl3 extracted with and washed twice with saturated aq. NaHCO3 and then dried over anhydrous Na2SO4. Solvent was removed in vacuo to yield 895 mg SO190 as a yellow oil and was used for next step without further purification.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]([N:5]1[CH2:10][CH2:9][CH2:8][CH:7]([C:11]2[CH:19]=[CH:18][CH:17]=[C:16]3[C:12]=2[CH:13]=[CH:14][NH:15]3)[CH2:6]1)=[O:4].O1CCOCC1.[Cl:28]N1C(=O)CCC1=O>O>[Cl:28][C:13]1[C:12]2[C:16](=[CH:17][CH:18]=[CH:19][C:11]=2[CH:7]2[CH2:8][CH2:9][CH2:10][N:5]([C:3](=[O:4])[C:2]([F:1])([F:20])[F:21])[CH2:6]2)[NH:15][CH:14]=1
Reactant: O=C(N1CCCC(c2cccc3[nH]ccc23)C1)C(F)(F)F
Reactant: O=C1CCC(=O)N1Cl
Solvent: O
Solvent: C1COCCO1
Product: O=C(N1CCCC(c2cccc3[nH]cc(Cl)c23)C1)C(F)(F)F
Temperature: 20 °C
Reaction time: 20 h
Yield: 98.5 %

Procedure:
A mixture of 10 g of the product of Step A, 300 ml of dioxane and 5 g of N-chlorosuccinimide was stirred at 20° C. for 20 hours and was then diluted with water. The mixture was extracted with ethyl acetate and the organic phase was washed with water and aqueous sodium chloride solution, was dried and evaporated to dryness. The residue was chromatographed over silica gel and was eluted with a 6-3-1 cyclohexane-chloroform-triethylamine mixture to obtain 11 g of 3-chloro-4-(1-trifluoroacetyl-piperidin-3-yl)-1H-indole which was used as is for the next step.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:8][OH:9])[CH:5]=[N:6][CH:7]=1.[Cl:10][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[C:17](=[O:21])[NH:16][CH2:15][CH2:14]2.C([O-])([O-])=O.[Cs+].[Cs+].N[C@H]1CCCC[C@@H]1N>O1CCOCC1.[Cu]I.O>[Cl:10][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[C:17](=[O:21])[N:16]([C:2]1[CH:7]=[N:6][CH:5]=[C:4]([CH2:8][OH:9])[CH:3]=1)[CH2:15][CH2:14]2
Reactant: O=C1NCCc2cc(Cl)ccc21
Reactant: OCc1cncc(Br)c1
Agent: [Cu]I
Agent: N[C@H]1CCCC[C@@H]1N
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: O=C1c2ccc(Cl)cc2CCN1c1cncc(CO)c1
Temperature: 150 °C
Yield: 86.6 %

Procedure:
In a 25 mL sealed tube, (5-bromo-pyridin-3-yl)-methanol (900 mg, 4.8 mmol), 6-chloro-3,4-dihydro-2H-isoquinolin-1-one (intermediate A-2) (800 mg, 4.4 mmol), CuI (200 mg, 1.1 mmol), Cs2CO3 (3.0 g, 9.2 mmol) and (+)-(S,S)-1,2-diaminocyclohexane (0.4 mL, 3.2 mmol) were dissolved in dioxane (8.0 mL). The resulting reaction mixture was heated at 150° C. for 3 hours before it was poured into H2O (50 mL) and extracted with EtOAc (2×125 mL). The organic layer was washed with brine, dried over anhy. Na2SO4, filtered and concentrated in vacuo to give a crude product which was purified by silica gel flash chromatography (30-100% EtOAc-hexane gradient) to yield the title compound (1.1 g, 90%) as a light yellow solid. MS: 289.2 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:11][N:10]([C@@H:12]3[CH2:16][CH2:15][NH:14][CH2:13]3)[CH2:9][C:8](=[O:17])[N:7]([CH2:18][CH3:19])[C:6]=2[CH:20]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:28][CH2:29][CH:30]=[C:31]1[C:37]2[CH:38]=[CH:39][CH:40]=[N:41][C:36]=2[CH2:35][O:34][C:33]2[CH:42]=[CH:43][C:44]([C:46]([OH:49])([CH3:48])[CH3:47])=[CH:45][C:32]1=2>C(#N)C.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:11][N:10]([C@@H:12]3[CH2:16][CH2:15][N:14]([CH2:28][CH2:29][CH:30]=[C:31]4[C:37]5[CH:38]=[CH:39][CH:40]=[N:41][C:36]=5[CH2:35][O:34][C:33]5[CH:42]=[CH:43][C:44]([C:46]([OH:49])([CH3:48])[CH3:47])=[CH:45][C:32]4=5)[CH2:13]3)[CH2:9][C:8](=[O:17])[N:7]([CH2:18][CH3:19])[C:6]=2[CH:20]=1
Reactant: CC(C)(O)c1ccc2c(c1)C(=CCCBr)c1cccnc1CO2
Reactant: CCN1C(=O)CN([C@@H]2CCNC2)Cc2ccc(Cl)cc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CCN1C(=O)CN([C@@H]2CCN(CCC=C3c4cc(C(C)(C)O)ccc4OCc4ncccc43)C2)Cc2ccc(Cl)cc21
Temperature: 25 °C
Reaction time: 48 h
Yield: 20.8 %

Procedure:
To a solution of (R)-8-chloro-1-ethyl-4-pyrrolidin-3-yl-1,3,4,5-tetrahydro-benzo[e][1,4]diazepin-2-one (0.121 g, 0.32 mmol) in acetonitrile/water (8:2) (3.2 mL) was added K2CO3 (0.368 g, 2.6 mmol) and 2-[5-(3-bromo-propylidene)-5,11-dihydro-10-oxa-1-aza-dibenzo[a,d]cyclohepten-7-yl]-propan-2-ol (0.102 g, 0.27 mmol). The solution was allowed to stir at room temperature for 48 h. The reaction was concentrated down and partitioned between EtOAc/H2O, extracted with EtOAc (3×). The organics were collected together dried over Mg2SO4, filtered and evaporated in vacuo, then purified by Biotage flash chromatography (5% methanol/95% methylene chloride to 10% methanol/90% methylene chloride to 15% methanol/85% methylene chloride) to yield the title compound (0.033 g, 21%). 1H-NMR (CDCl3): 1.17 (t, 3H), 1.55 (s, 6H), 1.73 (septet, 1H), 2.08 (m, 1H), 2.34(pentet, 2H), 2.43–2.61 (m, 4H), 2.85 (t, 1H), 2.92 (d, 1H), 3.10 (q, 1H), 3.22 (m, 1H), 3.52 (q, 2H), 3.91 (septet, 2H), 5.29 (bs, 2H), 6.12 (t, 1H), 6.79 (dd, 1H), 7.15–7.28 (m, 5H), 7.44 (s, 1H), 7.56 (d, 1H), 8.47 (d, 1H). ESI-MS m/z: 587 (M+1), retention time 1.37.
Reaction SMILES: [C:1]([Si:5]([O:18][C@@H:19]1[CH2:25][C@H:24](C(C)=C)[CH2:23][C@@H:22]2[C@@:20]1([CH3:29])[O:21]2)([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)([CH3:4])([CH3:3])[CH3:2].C([O-])(O)=[O:31].[Na+].O=[O+][O-].[N+](C1C=CC(C(Cl)=O)=CC=1)([O-])=O.C([O-])([O-])=O.[K+].[K+]>ClCCl.CO.O>[Si:5]([O:18][C@H:19]1[C@@:20]2([CH3:29])[C@H:22]([O:21]2)[CH2:23][C@@H:24]([OH:31])[CH2:25]1)([C:1]([CH3:2])([CH3:4])[CH3:3])([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: C=C(C)[C@@H]1C[C@H]2O[C@@]2(C)[C@H](O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)C1
Reactant: O=C([O-])O
Agent: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Agent: O=C([O-])[O-]
Agent: O=[O+][O-]
Solvent: O
Solvent: CO
Solvent: ClCCl
Product: CC(C)(C)[Si](O[C@@H]1C[C@H](O)C[C@H]2O[C@]21C)(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 69 %

Procedure:
A mixture of the compound of Example 13A (34 g, 92 wt %, 77 mmol) and NaHCO3 (3.3 g, 39 mmol) in 300 mL dichloromethane and 60 mL methanol was cooled to ←70° C. and treated with ozone (7-8 psi, 90 volts, 4 slpm) until a persistent blue color was observed. After purging with nitrogen to remove the color, the reaction was warmed to ˜0° C., then filtered through paper and concentrated. After chasing with 2×100 mL benzene, 300 mL of dichloromethane and 60 mL of pyridine were added and the reaction was cooled to <5° C. p-Nitrobenzoyl chloride (22.2 g, 120 mmol) was added and stirred for 1 hour, then the bath was removed and the reaction stirred at ambient temperature overnight. The resulting suspension was concentrated in vacuo to a thick slurry, and then diluted with ethyl acetate, and the solids were removed by filtration. The filtrate was washed with 250 mL of saturated aqueous sodium bicarbonate, then with 100 mL each of 2 N HCl, 1 N HCl, and 2 N HCl, and with 200 mL each of 1 N HCl, saturated aqueous sodium bicarbonate, and brine. The organic layer was dried over MgSO4, filtered and concentrated to yield the crude ester. A sample of this product (20.6 g, 32 mmol) was dissolved in 115 mL methanol; 15 mL water was added, followed by 11.0 g of K2CO3. After 2 hours, the reaction was quenched with 6.5 mL of acetic acid, and then concentrated in vacuo. The residue was treated with 100 mL water, and then extracted sequentially with 150 mL and 100 mL of ethyl acetate. The combined organic layers were washed with 100 mL each of saturated aqueous sodium bicarbonate, then 10% aqueous NaCl, then 20% aqueous NaCl. The ethyl acetate layer was dried over MgSO4, filtered and concentrated. Chromatography (Isco CombiFlash® system, Analogix RS 300 300 g column, 1:9 ethyl acetate: dichloromethane for 5 minutes, then to 12:88 over 35 minutes, then hold for 10 minutes) provided the title compound (10.3 g, 91 wt %, 76%).
Reaction SMILES: Cl.[O:2]1[C:10]2[CH2:9][CH2:8][NH:7][CH2:6][C:5]=2[CH:4]=[CH:3]1.[C:11]1(/[CH:20]=[CH:21]\[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:16]=[CH:15][C:14]([C:17](O)=[O:18])=[CH:13][CH:12]=1.C(N(CC)CC)C.C(P(=O)(OCC)OCC)#N>ClCCl.O>[C:11]1(/[CH:20]=[CH:21]\[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:12]=[CH:13][C:14]([C:17]([N:7]2[CH2:8][CH2:9][C:10]3[O:2][CH:3]=[CH:4][C:5]=3[CH2:6]2)=[O:18])=[CH:15][CH:16]=1
Reactant: O=C(O)c1ccc(/C=C\c2ccccc2)cc1
Reactant: c1cc2c(o1)CCNC2
Agent: CCOP(=O)(C#N)OCC
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: O=C(c1ccc(/C=C\c2ccccc2)cc1)N1CCc2occc2C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 0.160 g (1.000 mmol) of 4,5,6,7-tetrahydrofuro[3,2-c]pyridine hydrochloride, 0.269 g (1.2 mmol) of (Z)-4-stilbenecarboxylic acid and 0.55 ml (4.0 mmol) of triethylamine in 30 ml of dichloromethane, 0.24 g (1.5 mmol) of diethyl cyanophosphonate was added dropwise under ice-cooling, followed by overnight stirring at room temperature. The reaction mixture was poured into water and extracted with dichloromethane 2 times. The combined organic layer was washed with water and dried over anhydrous sodium sulfate; the solvent was distilled off under reduced pressure. The resulting crude product was purified by silica gel column chromatography (hexane/ethyl acetate=6/1) to yield the desired product.
Reaction SMILES: [CH:1]([C:3]1[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][C:4]=1[O:5][CH2:6][C:7]([O:9][CH3:10])=[O:8])=[O:2].[BH4-].[Na+]>C[O-].[Na+].CO>[OH:2][CH2:1][C:3]1[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][C:4]=1[O:5][CH2:6][C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)COc1cc(C)ccc1C=O
Agent: C[O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)COc1cc(C)ccc1CO
Yield: 82.9 %

Procedure:
By the method of Example 1, Step G, 11.27 g (0.054 mole) of methyl (2-formyl-5-methylphenoxy)acetate was reacted with 0.54 g (0.014 mole) of sodium borohydride and 0.10 g (0.0018 mole) of sodium methoxide in 30 of methanol, yielding 9.41 g of methyl (2-hydroxymethyl-5-methylphenoxy)acetate as a yellow oil. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [F:1][CH:2]([F:42])[C:3]1[N:7]([C:8]2[N:13]=[C:12]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[N:11]=[C:10]([N:20]([CH2:27][CH2:28][CH2:29][N:30]3[CH2:35][CH2:34][O:33][CH2:32][CH2:31]3)[CH:21]3[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)[N:9]=2)[C:6]2[CH:36]=[CH:37][CH:38]=[C:39]([O:40][CH3:41])[C:5]=2[N:4]=1.[CH3:43][S:44](Cl)(=[O:46])=[O:45]>C(Cl)Cl>[F:42][CH:2]([F:1])[C:3]1[N:7]([C:8]2[N:13]=[C:12]([N:14]3[CH2:15][CH2:16][O:17][CH2:18][CH2:19]3)[N:11]=[C:10]([N:20]([CH:21]3[CH2:22][CH2:23][N:24]([S:44]([CH3:43])(=[O:46])=[O:45])[CH2:25][CH2:26]3)[CH2:27][CH2:28][CH2:29][N:30]3[CH2:31][CH2:32][O:33][CH2:34][CH2:35]3)[N:9]=2)[C:6]2[CH:36]=[CH:37][CH:38]=[C:39]([O:40][CH3:41])[C:5]=2[N:4]=1
Reactant: COc1cccc2c1nc(C(F)F)n2-c1nc(N2CCOCC2)nc(N(CCCN2CCOCC2)C2CCNCC2)n1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Product: COc1cccc2c1nc(C(F)F)n2-c1nc(N2CCOCC2)nc(N(CCCN2CCOCC2)C2CCN(S(C)(=O)=O)CC2)n1
Yield: 90 %

Procedure:
Reaction of 4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-N-[3-(4-morpholinyl)propyl]-N-(4-piperidinyl)-1,3,5-triazin-2-amine with methanesulfonyl chloride in CH2Cl2 gave 4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-N-[1-(methylsulfonyl)-4-piperidinyl]-6-(4-morpholinyl)-N-[3-(4-morpholinyl)propyl]-1,3,5-triazin-2-amine in 90% yield.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.Cl[C:7]1[N:8]=[C:9]([NH:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH:26]3C(C(C)C)CCC(C)C3)=[C:21]([O:36][CH:37]3C(C(C)C)CCC(C)C3)[CH:20]=2)[C:10]2[CH:15]=[C:14]([CH3:16])[S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:36][CH3:37])[CH:20]=3)[C:10]3[CH:15]=[C:14]([CH3:16])[S:13][C:11]=3[N:12]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: Cc1cc2c(NCc3ccc(OC4CC(C)CCC4C(C)C)c(OC4CC(C)CCC4C(C)C)c3)nc(Cl)nc2s1
Reactant: c1c[nH]cn1
Product: COc1ccc(CNc2nc(-n3ccnc3)nc3sc(C)cc23)cc1OC

Procedure:
Following the procedure of Example 97, the reaction of imidazole with 2-chloro-6-methyl-4-(3,4-dimenthoxybenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(imidazol-1-yl)-6-methyl-4-(3,4-dimethoxybenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1Cl)=[CH:13][CH:12]=[CH:11][C:10]=2[O:17][CH3:18])(=[O:5])[CH2:2][CH2:3][CH3:4].[NH2:19][C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][C:27]=1[CH3:28])[CH2:23][OH:24]>O1CCOCC1>[C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:19][C:20]1[CH:21]=[C:22]([CH2:23][OH:24])[CH:25]=[CH:26][C:27]=1[CH3:28])=[CH:13][CH:12]=[CH:11][C:10]=2[O:17][CH3:18])(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: Cc1ccc(CO)cc1N
Reactant: CCCC(=O)c1cnc2c(OC)cccc2c1Cl
Solvent: C1COCCO1
Product: CCCC(=O)c1cnc2c(OC)cccc2c1Nc1cc(CO)ccc1C
Yield: 59.5 %

Procedure:
A solution of 3-butyryl-4-chloro-8-methoxyquinoline (0.80 g, 3 mmol) and 3-amino-4-methylbenzyl alcohol (0.48 g, 3.5 mmol) in dioxan (I0 ml) was heated at reflux for 1.5 hours, then the solvent evaporated. Aqueous sodium bicarbonate was added, the product extracted into dichloromethane, dried and evaporated. Recrystallisation from methanol gave 3-butyryl-4-(5-hydroxymethyl-2-methylphenylamino)-8-methoxyquinoline (0.65 g, 59%) 180°-181°.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[CH:7][C:6]([CH2:11][C:12]#[N:13])=[C:5]([N+:14]([O-])=O)[CH:4]=1.[Sn](Cl)(Cl)(Cl)Cl>C(O)C>[CH3:10][O:9][C:8]1[CH:7]=[C:6]2[C:5](=[CH:4][C:3]=1[O:2][CH3:1])[N:14]=[C:12]([NH2:13])[CH2:11]2
Reactant: COc1cc(CC#N)c([N+](=O)[O-])cc1OC
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: CCO
Product: COc1cc2c(cc1OC)N=C(N)C2
Temperature: 70 °C
Yield: 6.2 %

Procedure:
A solution of 2-(4,5-dimethoxy-2-nitrophenyl)acetonitrile (0.22 g, 1 mmol) in ethanol (15 ml) was treated with tin chloride (0.50 g, 2.2 mmol) and heated to 70° C. for 72 hours. The reaction mixture was allowed to cool to room temperature, extracted with EtOAc and washed with 1N NaOH and water. The combined organic extracts were dried over MgSO4, filtered and concentrated. HPLC purification provided 5,6-dimethoxy-3H-indol-2-amine (12 mg, 6.2%). 1H NMR (400 MHz, DMSO) δ 11.82 (s, 1H), 9.80 (s, 1H), 9.54 (s, 1H), 7.11 (s, 1H), 6.82 (s, 1H), 4.10 (s, 2H), 3.77 (s, 3H), 3.73 (s, 3H). MS (APCI) m/z 193 (M+H)+.
Reaction SMILES: Cl[CH:2]([CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)[C:3]1[O:4][C:5]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][C:6]=2[C:7]=1[CH3:8].[NH2:20][C:21]1[CH:30]=[CH:29][C:24]([C:25]([O:27]C)=[O:26])=[CH:23][CH:22]=1.[I-].[Na+].C(=O)([O-])[O-].[Na+].[Na+].Cl.[OH-].[Na+]>C(O)C.O1CCCC1.CN(C)C=O>[CH:14]1([CH:2]([NH:20][C:21]2[CH:30]=[CH:29][C:24]([C:25]([OH:27])=[O:26])=[CH:23][CH:22]=2)[C:3]2[O:4][C:5]3[CH:12]=[CH:11][C:10]([F:13])=[CH:9][C:6]=3[C:7]=2[CH3:8])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: Cc1c(C(Cl)C2CCCCC2)oc2ccc(F)cc12
Reactant: COC(=O)c1ccc(N)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: CCO
Product: Cc1c(C(Nc2ccc(C(=O)O)cc2)C2CCCCC2)oc2ccc(F)cc12
Temperature: 80 °C
Reaction time: 8 h
Yield: 54.2 %

Procedure:
To a mixture of 2-[chloro(cyclohexyl)methyl]-5-fluoro-3-methyl-1-benzofuran (1.44 g) synthesized in Example A37(3), methyl 4-aminobenzoate (776 mg), sodium iodide (1.54 g) and N,N-dimethylformamide (30 mL) was added sodium carbonate (1.09 g), and the mixture was stirred at 80° C. overnight. 1N Hydrochloric acid was added to quench the reaction, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (20% ethyl acetate/hexane) to give a yellow solid. To a mixture of the obtained solid, tetrahydrofuran (20 mL) and ethanol (20 mL) was added 1N aqueous sodium hydroxide solution (20 mL), and the mixture was stirred overnight with heating under reflux, and concentrated under reduced pressure. The residue was dissolved in water (40 mL), and 1N hydrochloric acid (20 mL) was added at 0° C. The resulting precipitate was collected by filtration to give the title object compound (1.06 g, 54%) as a yellow solid.
Reaction SMILES: C([O:3][C:4]([C@H:6]1[CH2:11][CH2:10][C@H:9]([CH2:12][NH:13][C:14]([N:16]2[CH2:21][CH2:20][C:19]3([C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[C:23](=[O:30])[O:22]3)[CH2:18][CH2:17]2)=[O:15])[CH2:8][CH2:7]1)=[O:5])C.O.O[Li].O>C1COCC1>[C:4]([C@H:6]1[CH2:7][CH2:8][C@H:9]([CH2:12][NH:13][C:14]([N:16]2[CH2:17][CH2:18][C:19]3([C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[C:23](=[O:30])[O:22]3)[CH2:20][CH2:21]2)=[O:15])[CH2:10][CH2:11]1)([OH:5])=[O:3]
Reactant: CCOC(=O)[C@H]1CC[C@H](CNC(=O)N2CCC3(CC2)OC(=O)c2ccccc23)CC1
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Product: O=C1OC2(CCN(C(=O)NC[C@H]3CC[C@H](C(=O)O)CC3)CC2)c2ccccc21

Procedure:
Dissolve 1′-(trans-4-ethoxycarbonyl-cyclohexylmethyl)carbamoyl-spiro[isobenzofuran-1,4′piperidin]-3-one (21 mg, 0.05 mmol) in THF (2 mL) and add an equal volume of water. Add LiOH•H2O (11 mg, 0.26 mmol) to this mixture and heat at 60° C. for 3 hours with stirring. Evaporate the THF under reduced pressure, dilute the residue with water and acidify with 3N HCL. Extract the aqueous mixture with EtOAc, wash with brine, dry (Na2SO4) and concentrate under reduced pressure to obtain 1′-(trans-4-carboxy-cyclohexylmethyl)carbamoyl-spiro[isobenzofuran-1,4′piperidin]-3-one as a white solid.
Reaction SMILES: [CH:1]([N:4]([CH:10]([CH3:12])[CH3:11])[C:5](=[O:9])[O:6][CH2:7]Cl)([CH3:3])[CH3:2].[OH:13][C@@H:14]([C@H:16]1[C:36](=[O:37])[N:18]2[C:19]([C:33]([O-:35])=[O:34])=[C:20]([S:23]/[CH:24]=[CH:25]\[C:26]3[S:30][CH:29]=[N:28][C:27]=3[CH2:31][OH:32])[C@H:21]([CH3:22])[C@H:17]12)[CH3:15].[Na+]>[Cl-].C([N+](CC)(CC)CC1C=CC=CC=1)C.CN(C)C(=O)C>[OH:13][C@@H:14]([C@H:16]1[C:36](=[O:37])[N:18]2[C:19]([C:33]([O:35][CH2:7][O:6][C:5]([N:4]([CH:10]([CH3:12])[CH3:11])[CH:1]([CH3:3])[CH3:2])=[O:9])=[O:34])=[C:20]([S:23]/[CH:24]=[CH:25]\[C:26]3[S:30][CH:29]=[N:28][C:27]=3[CH2:31][OH:32])[C@H:21]([CH3:22])[C@H:17]12)[CH3:15]
Reactant: CC(C)N(C(=O)OCCl)C(C)C
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)[O-])=C(S/C=C\c3scnc3CO)[C@H](C)[C@H]12
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: CC(C)N(C(=O)OCOC(=O)C1=C(S/C=C\c2scnc2CO)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12)C(C)C
Temperature: 30 °C
Reaction time: 5 h
Yield: 92.1 %

Procedure:
Chloromethyl N,N-diisopropylcarbamate (2.81 g) and 2.76 g of triethyl benzyl ammonium chloride were added to 50 ml of a solution of 4.89 g of sodium (1R,5S,6S)-6-((1R)-1-hydroxyethyl)-2-[[(Z)-2-(4-hydroxymethylthiazol-5-yl)ethen-1-yl]thio]-1-methyl-1-carbapen-2-em-3-carboxylate in N,N-dimethylacetamide, and the mixture was stirred at 30° C. for 5 hr. The reaction solution was washed twice with 180 ml of heptane. Thereafter, 125 ml of ethyl acetate and 125 ml of 20% brine were added thereto, followed by separation. The organic layer was washed three times with 125 ml of 10% brine, was dried over anhydrous magnesium sulfate, and was filtered, and ethyl acetate was removed by distillation under the reduced pressure to give 6.01 g of the title compound.
Reaction SMILES: [F:1][C:2]1[C:3]([N:9]=CN(C)C)=[N:4][C:5]([OH:8])=[N:6][CH:7]=1.[CH:14]1([N:19]=[C:20]=[O:21])[CH2:18][CH2:17][CH2:16][CH2:15]1>C(Cl)Cl>[NH2:9][C:3]1[C:2]([F:1])=[CH:7][N:6]([C:20]([NH:19][CH:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)=[O:21])[C:5](=[O:8])[N:4]=1
Reactant: O=C=NC1CCCC1
Reactant: CN(C)C=Nc1nc(O)ncc1F
Solvent: ClCCl
Product: Nc1nc(=O)n(C(=O)NC2CCCC2)cc1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 5.6 %

Procedure:
To a suspension of N′-(5-fluoro-2-hydroxy-pyrimidin-4-yl)-N,N-dimethylformamidine (0.25 g, 1.35 mmol) in CH2Cl2 (5 mL) was added cyclopentyl isocyanate (0.168 mL, 1.49 mmol) forming a solution that was stirred at room temperature for 3 h. The solvent was removed to give a solid residue that was purified by reverse phase chromatography (gradient, CH3CN/H2O) to yield 4-amino-N-cyclopentyl-5-fluoro-2-oxopyrimidine-1(2H)-carboxamide (0.018 g, 5%) as a white solid: mp 294-297° C.; 1H NMR (300 MHz, DMSO-d6) δ 10.37 (d, J=6.59 Hz, 1H), 8.43 (s, 1H), 8.32 (d, J=7.58 Hz, 1H), 8.18 (s, 1H), 4.03 (sext, J=6.92 Hz, 1H), 1.94-1.85 (m, 2H), 1.68-1.39 (m, 6H); ESIMS m/z 239.1 ([M−H]−)