Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:14][CH2:15][CH3:16])[CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10](F)=[N:11][CH:12]=1)[CH3:2].CC(C)([O-])C.[K+].CN(C)C(=O)C.[CH3:29][N:30]1[CH:34]=[CH:33][C:32]([NH:35][C:36]2[C:45]3[C:40](=[CH:41][CH:42]=[C:43]([OH:46])[CH:44]=3)[N:39]=[CH:38][N:37]=2)=[N:31]1>O>[CH2:1]([O:3][CH:4]([O:14][CH2:15][CH3:16])[CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]([O:46][C:43]2[CH:44]=[C:45]3[C:40](=[CH:41][CH:42]=2)[N:39]=[CH:38][N:37]=[C:36]3[NH:35][C:32]2[CH:33]=[CH:34][N:30]([CH3:29])[N:31]=2)=[N:11][CH:12]=1)[CH3:2]
Reactant: Cn1ccc(Nc2ncnc3ccc(O)cc23)n1
Reactant: CCOC(COc1ccc(F)nc1)OCC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: CCOC(COc1ccc(Oc2ccc3ncnc(Nc4ccn(C)n4)c3c2)nc1)OCC
Temperature: 170 °C
Reaction time: 15 h
Yield: 64.8 %

Procedure:
5-(2,2-diethoxyethoxy)-2-fluoropyridine (502 mg, 2.19 mmol) and potassium tert-butoxide (279 mg, 2.49 mmol) were added to an N,N-dimethylacetamide solution (1 ml) of 4-[(1-methyl-1H-pyrazol-3-yl)amino]quinazolin-6-ol (240 mg, 1.00 mmol), and stirred at 170° C. for 15 hours under a nitrogen atmosphere in a sealed tube. The reaction solution was cooled to room temperature, then water was added, and extracted with chloroform. The organic layer was washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (Biotage, chloroform:methanol=100:3) to obtain 6-{[5-(2,2-diethoxyethoxy)pyridin-2-yl]oxy}-N-(1-methyl-1H-pyrazol-3-yl)quinazoline-4-amine (292 mg, yield: 65%) as a brown oil.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][C:7]([O:17][CH3:18])=[C:8]([O:15][CH3:16])[C:9]=2[O:13][CH3:14])[N:4]=1.[NH:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1>>[CH3:14][O:13][C:9]1[C:8]([O:15][CH3:16])=[C:7]([O:17][CH3:18])[CH:6]=[C:5]2[C:10]=1[CH:11]=[CH:12][C:3]([CH2:2][N:19]1[CH2:24][CH2:23][N:22]([CH2:2][C:3]3[CH:12]=[CH:11][C:10]4[C:5](=[CH:6][C:7]([O:17][CH3:18])=[C:8]([O:15][CH3:16])[C:9]=4[O:13][CH3:14])[N:4]=3)[CH2:21][CH2:20]1)=[N:4]2
Reactant: COc1cc2nc(CCl)ccc2c(OC)c1OC
Reactant: C1CNCCN1
Product: COc1cc2nc(CN3CCN(Cc4ccc5c(OC)c(OC)c(OC)cc5n4)CC3)ccc2c(OC)c1OC

Procedure:
2-Chloromethyl-5,6,7-trimethoxyquinoline (400 mg) and piperazine (65 mg) were reacted in the same manner as in Example 1 to obtain the title compound as a free base.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([S:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1.C1C=C(Cl)C=C(C(OO)=[O:28])C=1.C([O-])(O)=O.[Na+].CO>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([S:13]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)=[O:28])=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COc1ccc2c(Sc3ccccc3)ccnc2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: COc1ccc2c(S(=O)c3ccccc3)ccnc2c1
Temperature: 25 °C
Yield: 93.7 %

Procedure:
To 7-methoxy-4-(phenylthio)quinoline (1.38 g, 5.16 mmol) in CH2Cl2 (50 mL) at −78° C. was added m-CPBA (77%) (1.25 g, 7.23 mmol) portionwise. The mixture was allowed to slowly warm to RT (3 hrs). The reaction mixture was diluted with CH2Cl2 then neutralized with NaHCO3 (sat.). The aqueous phase was extracted three times with CH2Cl2 then the organic layer was dried over Na2SO4, filtered, and concentrated in vacuo. The crude mixture was purified by silica gel chromatography using 0-10% CH2Cl2:MeOH to afford 7-methoxy-4-(phenylsulfinyl)quinoline (1.37 g, 94% yield) as a off-white foam. MH+=284.0.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[N:12]3[CH:13]=[CH:14][C:15]([C:17]([CH3:27])([O:19][Si:20]([CH2:25][CH3:26])([CH2:23][CH3:24])[CH2:21][CH3:22])[CH3:18])=[N:16][C:11]3=[N:10][CH:9]=2)[CH:5]=[CH:4][N:3]=1.CC1(C)C(C)(C)OB([C:36]2[S:37][CH:38]=[CH:39][C:40]=2[C:41]#[N:42])O1.BrC1SC=CC=1C#N>>[CH3:18][C:17]([C:15]1[CH:14]=[CH:13][N:12]2[C:8]([C:6]3[CH:5]=[CH:4][N:3]=[C:2]([C:36]4[S:37][CH:38]=[CH:39][C:40]=4[C:41]#[N:42])[N:7]=3)=[CH:9][N:10]=[C:11]2[N:16]=1)([O:19][Si:20]([CH2:25][CH3:26])([CH2:23][CH3:24])[CH2:21][CH3:22])[CH3:27]
Reactant: CC1(C)OB(c2sccc2C#N)OC1(C)C
Reactant: CC[Si](CC)(CC)OC(C)(C)c1ccn2c(-c3ccnc(Cl)n3)cnc2n1
Agent: N#Cc1ccsc1Br
Product: CC[Si](CC)(CC)OC(C)(C)c1ccn2c(-c3ccnc(-c4sccc4C#N)n3)cnc2n1

Procedure:
3-(2-Chloropyrimidin-4-yl)-7-(1-methyl-1-triethylsilanyloxyethyl)imidazo[1,2-α]pyrimidine was reacted with 2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)thiophene-3-carbonitrile (synthesised from 2-bromothiophene-3-carbonitrile following the procedure in Example 21) by the method of Example 35 to afford 2-{4-[7-(1-methyl-1-triethylsilanyloxyethyl)imidazo[1,2-α]pyrimidin-3-yl]pyrimidin-2-yl}thiophene-3-carbonitrile as a white solid: δH (400 MHz, CDCl3) 0.67 (6H, q, J 8.1), 0.99 (9H, t, J 8.0), 1.71 (6H, s), 7.66 (2H, m), 7.97 (1H, d, J 5.5), 8.51 (1H, s), 8.79 (1H, d, J 5.5), 9.71 (1H, m), 10.34 (1H, d, J 7.0); m/z (ES+) 477 (M++H).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]([F:13])([F:12])[F:11])=[CH:7][C:6]=2[CH:14]=1.C([Li])CCC.CN(C)[CH:22]=[O:23].[Cl-].[NH4+]>C(OCC)(=O)C.O1CCCC1>[F:11][C:10]([F:13])([F:12])[C:8]1[O:9][C:5]2[CH:4]=[CH:3][C:2]([CH:22]=[O:23])=[CH:14][C:6]=2[CH:7]=1
Reactant: FC(F)(F)c1cc2cc(Br)ccc2o1
Reactant: CN(C)C=O
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=Cc1ccc2oc(C(F)(F)F)cc2c1
Temperature: 25 °C
Yield: 38 %

Procedure:
To a tetrahydrofuran solution (12 mL) of 5-bromo-2(trifluoromethyl)benzofuran (587 mg, 2.21 mmol), n-butyl lithium (hexane solution, 1.59 mol/L) (1.70 mL, 2.66 mmol) was added at −78° C. and the resultant solution was stirred for 40 minutes. To the reaction solution, N,N-dimethylformamide (257 μL, 3.32 mmol) was added and the resultant mixture was stirred for 3 hours while the temperature of the mixture was raised to room temperature. After completion of the reaction, saturated ammonium chloride aqueous solution was added to the reaction solution and extraction with ethyl acetate from the resultant mixture was performed. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain the title compound (180 mg, yield 39%).
Reaction SMILES: [C:1]([N:5]1[C:9]([CH2:10][CH2:11][CH3:12])=[CH:8][C:7]([CH2:13][CH2:14][CH:15]=O)=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[F:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1.CCN(C(C)C)C(C)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[C:1]([N:5]1[C:9]([CH2:10][CH2:11][CH3:12])=[CH:8][C:7]([CH2:13][CH2:14][CH2:15][N:27]2[CH2:26][CH2:25][N:24]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=3[F:17])[CH2:29][CH2:28]2)=[N:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Fc1ccccc1N1CCNCC1
Reactant: CCCc1cc(CCC=O)nn1C(C)(C)C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Product: CCCc1cc(CCCN2CCN(c3ccccc3F)CC2)nn1C(C)(C)C

Procedure:
93 mg (97%) of target compound was obtained by using a method same as in Example 1 by using 3-(1-tert-butyl-5-propyl-1H-pyrazol-3-yl)propanal (50 mg, 0.225 mmol), 1-(2-fluorophenyl)piperazine (41 mg, 0.225 mmol), DIPEA (0.060 mL, 0.338 mmol) and NaBH(OAc)3 (143 mg, 0.675 mmol).
Reaction SMILES: Br[CH2:2][CH:3]1[CH2:5][O:4]1.C([O-])([O-])=O.[K+].[K+].[CH2:12]([N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(Cl)Cl.CO>C(#N)C>[CH2:12]([N:19]1[CH2:24][CH2:23][N:22]([CH2:2][CH:3]2[CH2:5][O:4]2)[CH2:21][CH2:20]1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: BrCC1CO1
Reactant: c1ccc(CN2CCNCC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CC#N
Solvent: ClCCl
Product: c1ccc(CN2CCN(CC3CO3)CC2)cc1
Reaction time: 24 h
Yield: 83.8 %

Procedure:
To a solution of 2-bromomethyl-oxirane (2.3 mL, 27.5 mmol) in 40 mL of ACN are added K2CO3 (3.8 g, 27.5 mmol) and a solution of 1-benzyl-piperazine (5.81 g, 25 mmol) in 60 mL of ACN. After 24 hr at rt the reaction is judged to be completed by tlc monitoring (SiO2, DCM:MeOH 20:1). The reaction mixture is filtered off and the filtrate is concentrated in vacuo. Flash chromatography on a 7×15 cm2 column of SiO2 using DCM:MeOH (20:1) as eluting solvent and removal of the solvent gives the title compound (4.87 g, 84%) as a colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13]3[CH:14]=[CH:15][C:16]([NH:18][S:19]([CH3:22])(=[O:21])=[O:20])=[CH:17][C:12]=3[O:11][C:10]([CH3:24])([CH3:23])[C:9]2=O)=[CH:4][CH:3]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:35])=CC=1>O1CCOCC1.C(Cl)(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13]3[CH:14]=[CH:15][C:16]([NH:18][S:19]([CH3:22])(=[O:21])=[O:20])=[CH:17][C:12]=3[O:11][C:10]([CH3:24])([CH3:23])[C:9]2=[S:35])=[CH:4][CH:3]=1
Reactant: CC1(C)Oc2cc(NS(C)(=O)=O)ccc2N(c2ccc(F)cc2)C1=O
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: C1COCCO1
Solvent: ClC(Cl)Cl
Product: CC1(C)Oc2cc(NS(C)(=O)=O)ccc2N(c2ccc(F)cc2)C1=S
Temperature: 25 °C
Reaction time: 2 h
Yield: 13.2 %

Procedure:
To a suspension of N-[4-(4-fluorophenyl)-2,2-dimethyl-3-oxo-3,4-dihydro-2H -1,4-benzoxazin-7-yl]methanesulfonamide (compound of Example 9, 182 mg) in dioxane (10 mL) was added Lawesson's reagent (202 mg), and the mixture was stirred at room temperature for 2 hours and then stirred at 40° C. for 24 hours. The reaction mixture was diluted with chloroform and the mixture was filtered through a NH-silica gel pad and washed with ethyl acetate. The filtrate and the washings were combined and concentrated in vacuo. The resultant residue was purified by column chromatography on silica gel (solvent; n-hexane/ethyl acetate=19/1→3/2) to give N-[4-(4-fluorophenyl)-2,2-dimethyl-3-thioxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl]methanesulfonamide (25 mg) as a yellow powder.
Reaction SMILES: C[S-].[Na+].[Cl:4][C:5]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[C:7]([O:13]C)[CH:6]=1>>[Cl:4][C:5]1[CH:6]=[C:7]([OH:13])[CH:8]=[C:9]([O:11][CH3:12])[CH:10]=1
Reactant: COc1cc(Cl)cc(OC)c1
Agent: C[S-]
Agent: [Na+]
Product: COc1cc(O)cc(Cl)c1
Temperature: 140 °C
Yield: 90.4 %

Procedure:
To sodium methanethiolate (12.32 g, 173.80 mmol) was added 1-methyl-2-pyrrolidine (75 mL) followed by 1-chloro-3,5-dimethoxy-benzene (20.00 g, 115.87 mmol) and the reaction heated in a 140° C. bath for 2.5 hours then stirred at room temperature over night. The 1-methyl-2-pyrrolidine was removed under reduced pressure and the material partitioned between ethyl acetate/water/1N hydrochloric acid. The organic layer was washed with twice with 1N hydrochloric acid, once with aqueous saturated sodium chloride, dried over magnesium sulfate and solvent removed under reduced pressure to give a yellowish solid. The solid was chromatographed on 400 mL plug of silica gel eluting with dichloromethane. The combined purified fractions were removed of solvent to give the title compound as a yellow solid (16.62 g, 90%). 1H NMR (300 MHz, DMSO-d6) δ 6.43 (t, J=2.0 Hz, 1 H), 6.40 (t, J=1.9 Hz, 1 H), 6.28 (t, J=2.1 Hz, 1 H), 3.71 (s, 3 H); MS (APCI+) m/z 159 [M+1]+; tR=2.04 min.
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:36])[C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([C:13]3[CH:14]=[C:15]4[C:20](=[CH:21][CH:22]=3)[C:19](=[O:23])[N:18]([CH2:24][CH:25]3[CH2:27][CH2:26]3)[CH:17]=[C:16]4[CH2:28][N:29]3[CH2:35][CH2:34][CH2:33][NH:32][CH2:31][CH2:30]3)[CH:7]=2)[CH2:3][CH2:2]1.[CH3:37][C:38]([CH3:40])=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[CH:1]1([NH:4][C:5](=[O:36])[C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([C:13]3[CH:14]=[C:15]4[C:20](=[CH:21][CH:22]=3)[C:19](=[O:23])[N:18]([CH2:24][CH:25]3[CH2:26][CH2:27]3)[CH:17]=[C:16]4[CH2:28][N:29]3[CH2:35][CH2:34][CH2:33][N:32]([CH:38]([CH3:40])[CH3:37])[CH2:31][CH2:30]3)[CH:7]=2)[CH2:2][CH2:3]1
Reactant: CC(C)=O
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc2c(=O)n(CC3CC3)cc(CN3CCCNCC3)c2c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc2c(=O)n(CC3CC3)cc(CN3CCCN(C(C)C)CC3)c2c1
Reaction time: 0.03 h

Procedure:
The product of Example 70 (50 mg) was dissolved in dichloromethane (10 mL) and acetone (0.15 mL) added. The mixture was stirred for 2 minutes then sodium triacetoxyborohydride (109 mg) added. The mixture was stirred at room temperature for 12 hours. The volatiles were removed under reduced pressure and the residue purified by HPLC to give the title compound as a solid (33 mg).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:21]=[C:14]3[CH2:15][N:16]([CH3:20])[C:17](=[O:19])[CH2:18][N:13]3[N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.[C:22]([O:25][CH2:26][C:27]1[C:28]([N:42]2[CH2:53][CH2:52][N:51]3[C:44](=[CH:45][C:46]4[CH2:47][C:48]([CH3:55])([CH3:54])[CH2:49][C:50]=43)[C:43]2=[O:56])=[N:29][CH:30]=[CH:31][C:32]=1B1OC(C)(C)C(C)(C)O1)(=[O:24])[CH3:23].[O-]P([O-])([O-])=O.[K+].[K+].[K+].C([O-])(=O)C.[Na+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O.C(#N)C>[C:22]([O:25][CH2:26][C:27]1[C:28]([N:42]2[CH2:53][CH2:52][N:51]3[C:44](=[CH:45][C:46]4[CH2:47][C:48]([CH3:55])([CH3:54])[CH2:49][C:50]=43)[C:43]2=[O:56])=[N:29][CH:30]=[CH:31][C:32]=1[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:21]=[C:14]3[CH2:15][N:16]([CH3:20])[C:17](=[O:19])[CH2:18][N:13]3[N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1)(=[O:24])[CH3:23]
Reactant: CN1Cc2cc(Nc3cc(Br)cn(C)c3=O)nn2CC1=O
Reactant: CC(=O)OCc1c(B2OC(C)(C)C(C)(C)O2)ccnc1N1CCn2c(cc3c2CC(C)(C)C3)C1=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: O
Solvent: CC#N
Product: CC(=O)OCc1c(-c2cc(Nc3cc4n(n3)CC(=O)N(C)C4)c(=O)n(C)c2)ccnc1N1CCn2c(cc3c2CC(C)(C)C3)C1=O
Temperature: 100 °C
Yield: 48.8 %

Procedure:
A 25-mL single-neck round-bottomed flask equipped with a magnetic stirrer and a reflux condenser was charged with 313e (150 mg, 0.43 mmol), {3-[(acetoxy)methyl]-2-{4,4-dimethyl-9-oxo-1,10-diazatricyclo[6.4.0.02,6]dodeca-2(6),7-dien-10-yl}pyridin-4-yl}boronic acid 199e (170 mg, 0.43 mmol), K3PO4 (183 mg, 0.86 mmol), sodium acetate (71 mg, 0.86 mmol), Pd(dppf)Cl2 (35 mg, 0.043 mmol), acetonitrile (10 mL), and water (0.5 mL). The system was subjected to three cycles of vacuum/nitrogen flush and heated at 100° C. for 3 h. After this time the reaction was cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica-gel column chromatography eluting with 30:1 dichloromethane/methanol to afford 313f (131 mg, 49%) as a yellow solid. MS-ESI: [M+H]+ 625.3.
Reaction SMILES: F[C:2](F)(F)[C:3]([OH:5])=O.O[CH:9]1[CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10]1>>[NH:11]1[CH2:10][CH:9]([O:5][C:3]2[CH:2]=[CH:12][CH:9]=[CH:10][N:11]=2)[CH2:12]1
Reactant: O=C(O)C(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CC(O)C1
Product: c1ccc(OC2CNC2)nc1

Procedure:
Preparation of compound P21. Compound P21 was prepared by deprotection of C73 with trifluoroacetic acid as described for t-butyl 3-hydroxyazetidine-1-carboxylate in the preparation of C19 in Example 3, before being used in the coupling step.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:15](=[O:17])[N:14]([CH2:18][CH2:19][CH2:20][O:21][Si](C(C)(C)C)(C)C)[C:13](=[O:29])[N:12](COCC[Si](C)(C)C)[C:11]=2[N:10]=[C:9]1[Cl:38])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:39]>C(O)C>[Cl:38][C:9]1[N:8]([CH2:1][C:2]2[CH:7]=[CH:6][C:5]([Cl:39])=[CH:4][CH:3]=2)[C:16]2[C:15](=[O:17])[N:14]([CH2:18][CH2:19][CH2:20][OH:21])[C:13](=[O:29])[NH:12][C:11]=2[N:10]=1
Reactant: CC(C)(C)[Si](C)(C)OCCCn1c(=O)c2c(nc(Cl)n2Cc2ccccc2)n(COCC[Si](C)(C)C)c1=O
Reactant: Cl
Solvent: CCO
Product: O=c1[nH]c2nc(Cl)n(Cc3ccc(Cl)cc3)c2c(=O)n1CCCO
Temperature: 80 °C
Reaction time: 8 h
Yield: 87.5 %

Procedure:
To a solution of 7-benzyl-1-(3-(tert-butyldimethylsilyloxy)propyl)-8-chloro-3-((2-(trimethylsilyl)ethoxy)methyl)-1H-purine-2,6(3H,7H)-dione (340 mg, 0.56 mmol) in ethyl alcohol (20 mL) was added concentrated HCl (2 mL). The mixture was stirred at 80° C. overnight. The reaction was concentrated, neutralized with saturated sodium bicarbonate, extracted with ethyl acetate. The organic phase was washed with brine, dried over sodium sulfate, and concentrated to give 8-chloro-7-(4-chlorobenzyl)-1-(3-hydroxypropyl)-1H-purine-2,6(3H,7H)-dione (180 mg, 87.5% yield) as colorless oil. LCMS retention time 1.990 min; LCMS MH+ 369.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([OH:21])[CH:16]=2)=[O:14])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].C1C(C=O)=CC2OCOC=2C=1>>[OH:21][C:17]1[CH:16]=[C:15]([CH:20]=[CH:19][CH:18]=1)[C:13](=[O:14])[CH:12]=[CH:11][C:5]1[CH:6]=[CH:7][C:8]2[O:9][CH2:10][O:2][C:3]=2[CH:4]=1
Reactant: COc1ccc(C=CC(=O)c2cccc(O)c2)cc1OC
Agent: O=Cc1ccc2c(c1)OCO2
Product: O=C(C=Cc1ccc2c(c1)OCO2)c1cccc(O)c1

Procedure:
Prepared in a similar manner as (4) from piperonal. Crude solids (26.7 g, 100%) were carried on directly to the next reaction step without chromatographic purification or characterization.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH:8]=[C:9]([N+]([O-])=O)[CH3:10])[CH:5]=[CH:4][C:3]=1[S:14]([CH3:17])(=[O:16])=[O:15].Cl.C1C[O:22]CC1>O.[Fe]>[F:1][C:2]1[CH:7]=[C:6]([CH2:8][C:9](=[O:22])[CH3:10])[CH:5]=[CH:4][C:3]=1[S:14]([CH3:17])(=[O:16])=[O:15]
Reactant: CC(=Cc1ccc(S(C)(=O)=O)c(F)c1)[N+](=O)[O-]
Reactant: C1CCOC1
Agent: [Fe]
Agent: Cl
Solvent: O
Product: CC(=O)Cc1ccc(S(C)(=O)=O)c(F)c1
Temperature: 60 °C
Reaction time: 20 h

Procedure:
Iron powder (25 g, 0.45 mol) is added to a stirred mixture of freshly prepared 2-fluoro-1-methanesulfonyl-4-(2-nitro-propenyl)-benzene (Example 64b) (29 g, 0.112 mol) in THF (50 ml). Water (110 ml) is added and the mixture is heated to 60° C. Concentrated hydrochloric acid (50 ml) is added slowly over 1 h at 60-90° C. The reaction is then stirred at 100° C. for 20 hours then diluted with cold water (500 ml) and filtered through Celite™ filter material washing with chloroform (500 ml). The organic extract is washed with water (200 ml) followed by brine (200 ml). After drying (MgSO4) the mixture is absorbed on silica and purified by chromatography, eluting with hexane-ethyl acetate (1:1) to give the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)[C:9]([OH:11])=O)=[CH:4][CH:3]=1.[NH2:19][CH2:20][CH2:21][CH2:22][N:23]1[CH2:28][CH2:27][CH:26]([C:29]2[CH:30]=[C:31]([NH:35][C:36](=[O:41])[O:37][CH:38]([CH3:40])[CH3:39])[CH:32]=[CH:33][CH:34]=2)[CH2:25][CH2:24]1>>[CH3:18][C:15]1[CH:16]=[CH:17][C:12]([CH:8]([C:5]2[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=2)[C:9]([NH:19][CH2:20][CH2:21][CH2:22][N:23]2[CH2:28][CH2:27][CH:26]([C:29]3[CH:30]=[C:31]([NH:35][C:36](=[O:41])[O:37][CH:38]([CH3:39])[CH3:40])[CH:32]=[CH:33][CH:34]=3)[CH2:25][CH2:24]2)=[O:11])=[CH:13][CH:14]=1
Reactant: Cc1ccc(C(C(=O)O)c2ccc(C)cc2)cc1
Reactant: CC(C)OC(=O)Nc1cccc(C2CCN(CCCN)CC2)c1
Product: Cc1ccc(C(C(=O)NCCCN2CCC(c3cccc(NC(=O)OC(C)C)c3)CC2)c2ccc(C)cc2)cc1

Procedure:
Example 145 was prepared from bis(4-methylphenyl)acetic acid and isopropyl 3-[1-(3-aminopropyl)-4-piperidinyl]phenylcarbamate according to the procedures described in Scheme 9: 1H NMR (400 MHz, CDCl3) δ 7.24 (s, 1H), 7.18–7.06 (m, 4H), 7.06–7.00 (m, 6H), 6.82–6.78 (m, 2H), 6.62 (s, 1H), 4.92 (septet, 1H, J=6.7 Hz), 4.72 (s, 1H), 4.04 (q, 1H, J=6.8 Hz), 3.32–3.26 (m, 2H), 2.88–2.81 (m, 2H), 2.41–2.27 (m, 3H), 2.21 (s, 6H), 1.92–1.83 (m, 2H), 1.74–1.66 (m, 2H), 1.62–1.46 (m, 3H), 1.21 (d, 6H, J=6.7 Hz); ESMS m/e: 542.3 (M+H)+.
Reaction SMILES: [Cl:1][CH:2]([Cl:6])[C:3](Cl)=[O:4].[CH:7]([NH2:10])([CH3:9])[CH3:8]>C(Cl)Cl>[CH:7]([NH:10][C:3](=[O:4])[CH:2]([Cl:6])[Cl:1])([CH3:9])[CH3:8]
Reactant: O=C(Cl)C(Cl)Cl
Reactant: CC(C)N
Solvent: ClCCl
Product: CC(C)NC(=O)C(Cl)Cl
Temperature: 0 °C
Yield: 98 %

Procedure:
Dichloroacetyl chloride, 442.5 grams (3.0 mole), was dissolved in a flask containing 900 milliliters of methylene chloride and the solution cooled to 0° C. in an ice/acetone bath. 354 grams (5.98 mole) of isopropyl amine was added dropwise with vigorous stirring and the addition rate was adjusted to maintain the reaction temperature below 5° C. When the addition was complete, the mixture was allowed to stir at ambient temperature for one hour then washed with 2×500 milliliters water, the organic phase separated, dried over magnesium sulfate and stripped of solvent at reduced pressure giving 499 grams (98% yield) of the desired product, a white solid, m.p. 45°-48° C.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1.C([Li])CCC.[N:11]1[O:12][CH2:13][CH:14]2[CH2:18][N:17]([C:19]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[O:20])[CH2:16][C:15]=12>O1CCCC1>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:15]12[CH2:16][N:17]([C:19]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[O:20])[CH2:18][CH:14]1[CH2:13][O:12][NH:11]2
Reactant: c1ccsc1
Reactant: O=C(OCc1ccccc1)N1CC2=NOCC2C1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=C(OCc1ccccc1)N1CC2CONC2(c2cccs2)C1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 65.9 %

Procedure:
A −78° C. solution of thiophene (17 g, 203 mmol) in tetrahydrofuran (250 mL) under nitrogen is treated drop wise with a solution of n-butyl lithium (81 mL, 203 mmol, 1.6 M in hexanes) and the reaction is stirred at −78° C. for 10 minutes. In a separate flask, a −78° C. solution of benzyl 3,3a,4,6-tetrahydropyrrolo[3,4-c]isoxazole-5-carboxylate (25 g, 101 mmol) in tetrahydrofuran (500 mL) under nitrogen is treated with boron trifluoride ether complex (19 mL, 152 mmol) and the mixture is stirred for 10 minutes. The solution is added by cannula to the organolithium solution generated above at −78° C. and the resulting mixture is stirred for 1 hour at −78° C. The reaction is quenched with saturated ammonium chloride and warmed to room temperature. The aqueous layer is separated, the organic layer is dried over magnesium sulfate and the solvent is removed under vacuum. The crude product is purified over silica gel using a 5 to 50% gradient of ethyl acetate/hexanes gradient to give the title compound (22 g, 65%). ES/MS (m/e): 331 (M+H).
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.[NH:16]1[CH2:20][CH2:19][CH2:18][C:17]1=O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C1C=CC=CC=1>O>[N:16]1([C:2]2[CH2:7][CH2:6][N:5]([C:8]3[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][CH:9]=3)[CH2:4][CH:3]=2)[CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: O=C1CCCN1
Reactant: N#Cc1ccc(N2CCC(=O)CC2)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: c1ccccc1
Product: N#Cc1ccc(N2CC=C(N3CCCC3)CC2)cc1
Yield: 66 %

Procedure:
A solution of 24 g (0.1199 mol) of the compound of (b), 15 ml (12.78 g/0.1796 mol) of pyrrolidone, 240 mg of p-toluenesulfonic acid, and 100 ml of benzene is stirred at reflux with the azeotropic removal of water for 6 hours. After cooling, the resulting precipitate is collected and triturated with ethyl ether to afford 20 g (66%) of title compound: m.p. 126°-129° C.; IR (KBr) 2200, 1635, and 1600 cm-1 ; 'H NMR (CDCl3) δ 7.48 (d, 2H), 6.7 (d, 2H), 4.3-4.1 (m, 1H), 3.95-3.45 (m, 4H), 3.2-2.85 (m, 4H), 2.65-2.25 (m, 2H), and 1.95-1.75 (m, 4H).