Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:14]2[CH2:18][C@H:17]([CH2:19]O)[O:16][C:15]2=[O:21])[CH:5]=[CH:6][C:7]=1[N:8]1[CH:12]=[C:11]([CH3:13])[N:10]=[N:9]1.[CH3:22][C:23]1[N:24]=[N:25][NH:26][N:27]=1.CO>ClCCl>[F:1][C:2]1[CH:3]=[C:4]([N:14]2[CH2:18][C@H:17]([CH2:19][N:25]3[N:26]=[N:27][C:23]([CH3:22])=[N:24]3)[O:16][C:15]2=[O:21])[CH:5]=[CH:6][C:7]=1[N:8]1[CH:12]=[C:11]([CH3:13])[N:10]=[N:9]1
Reactant: Cc1cn(-c2ccc(N3C[C@H](CO)OC3=O)cc2F)nn1
Reactant: Cc1nn[nH]n1
Solvent: CO
Solvent: ClCCl
Product: Cc1cn(-c2ccc(N3C[C@H](Cn4nnc(C)n4)OC3=O)cc2F)nn1
Yield: 44.1 %

Procedure:
This compound was prepared from (5R)-3-[3-Fluoro-4-(4-methyl-1H-1,2,3-triazol-1-yl)phenyl]-5-(hydroxymethyl)oxazolidin-2-one (Intermediate 19) (1.054 g, 3.61 mmol) and 5-methyl-2H-tetrazole (0.608 g, 7.23 mmol), as described for Example 29. Chromatography on silica gel with 5% methanol in dichloromethane gave the crude product (0.72 g) which was purified further by trituration with dichloromethane and diethyl ether to afford the title product (0.571 g). The regioisomeric product (5R)-3-[3-fluoro-4-(4-methyl-1H-1,2,3-triazol-1-yl)phenyl]-5-[(5-methyl-1H-tetrazol-1-yl)methyl]-1,3-oxazolidin-2-one was also isolated (0.228 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[F:10])[CH:5]=O.FC1C=C2C(=CC=1)C=[N:17][CH:16]=[CH:15]2>>[Br:1][C:2]1[CH:3]=[C:4]2[C:7]([CH:15]=[CH:16][N:17]=[CH:5]2)=[CH:8][C:9]=1[F:10]
Reactant: O=Cc1ccc(F)c(Br)c1
Reactant: Fc1ccc2cnccc2c1
Product: Fc1cc2ccncc2cc1Br

Procedure:
Starting from 3-bromo-4-fluoro-benzaldehyde, the title compound was prepared by the same reaction sequence as used for the synthesis of 6-fluoro-isoquinoline (3). Rt=0.91 min (Method B). Detected mass: 226.0/228.0 (M+H+).
Reaction SMILES: [CH3:1][C:2]12[CH2:8][CH:5]([CH2:6][CH2:7]1)[C:4]([CH3:10])([CH3:9])[CH:3]2[NH:11][CH2:12][C:13]([N:15]([CH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=O.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:37])=CC=1>ClC1C=CC=CC=1>[CH3:1][C:2]12[CH2:8][CH:5]([CH2:6][CH2:7]1)[C:4]([CH3:10])([CH3:9])[CH:3]2[NH:11][CH2:12][C:13]([N:15]([CH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[S:37]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CC12CCC(C1)C(C)(C)C2NCC(=O)N(c1ccccc1)C1CCCCC1
Solvent: Clc1ccccc1
Product: CC12CCC(C1)C(C)(C)C2NCC(=S)N(c1ccccc1)C1CCCCC1
Temperature: 120 °C
Reaction time: 2 h

Procedure:
To a stirred solution of 2-[(1,3,3-trimethylbicyclo[2.2.1]hept-2-yl)amino]-N-cyclohexyl-N-phenylacetamide (110 mg, 0.272 mmol) in chlorobenzene (3 mL) was added Lawesson's reagent (70 mg, 0.17 mmol). The solution was stirred at 120° C. for 2 hours. The solvent was removed under reduced pressure, and the residue purified on preparatory plate using 15% ethyl acetate/hexanes to furnish 2-[(1,3,3-trimethylbicyclo[2.2.1]hept-2-yl)amino]-N-cyclohexyl-N-phenylthioacetamide as a yellow solid. (M+1)=385.0]
Reaction SMILES: O[C:2]([C:10]([CH3:13])([CH3:12])[CH3:11])=[CH:3][C:4](=[O:9])[CH:5]=[CH:6][O:7]C.C(O)(C(F)(F)F)=O>C1C=CC=CC=1>[C:10]([C:2]1[O:7][CH:6]=[CH:5][C:4](=[O:9])[CH:3]=1)([CH3:11])([CH3:12])[CH3:13]
Reactant: COC=CC(=O)C=C(O)C(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: c1ccccc1
Product: CC(C)(C)c1cc(=O)cco1
Temperature: 25 °C
Reaction time: 14 h
Yield: 102.2 %

Procedure:
A mixture of 5-hydroxy-1-methoxy-6,6-dimethyl-hepta-1,4-dien-3-one (Step 1.7) (6.8 g, 36.9 mmol) and TFA (5.65 mL, 74 mmol, 2 eq) in benzene (250 mL) is stirred for 14 h at rt and concentrated. Purification of the residue by silica gel column chromatography (Hex/EtOAc, 1:0→75:25) provides 5.74 g of the title compound as a yellow oil: ESI-MS: 153.1 [M+H]+; tR=3.21 min (System 1); TLC: Rf=0.22 (Hex/EtOAc, 1:1).
Reaction SMILES: [Mg].BrCCBr.Br[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH:13]1[CH2:15][CH2:14]1.[C:16](=[O:18])=[O:17]>O1CCCC1>[CH:13]1([CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][C:16]([OH:18])=[O:17])[CH2:15][CH2:14]1
Reactant: O=C=O
Reactant: BrCCCCCCC1CC1
Agent: [Mg]
Solvent: BrCCBr
Solvent: C1CCOC1
Product: O=C(O)CCCCCCC1CC1

Procedure:
0.684 g. Magnesium metal is covered with 2 ml. anhydrous tetrahydrofuran and 0.2 ml. 1,2-dibromoethane is added with stirring and heating. 1-Bromo-6-cyclopropylhexane (4.8 g.) and tetrahydrofuran (25 ml.) are added portionwise. An additional 0.207 ml. of 1,2-dibromethane is added and the reaction mixture refluxed for 3 hours. The solution is then maintained at 24°-28° while anhydrous carbon dioxide is bubbled through it for 11/2 hours. After stirring overnight under carbon dioxide, dry ether, water and 2N sulfuric acid are added until the pH is less than 7. The solution is extracted with ether and washed with water and brine, dried over calcium sulfate, filtered and the solvent removed to yield 7-cyclopropylheptanoic acid.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[F:9].[NH2:10][C:11]1[S:12][CH:13]=[CH:14][N:15]=1.N1C2C(=CC=CC=2)C=C1.[NH:25]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:27]([C:34](OC)=[O:35])=[CH:26]1>>[S:12]1[CH:13]=[CH:14][N:15]=[C:11]1[NH:10][C:34]([C:27]1[C:28]2[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=2)[N:25]([CH2:2][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[F:9])[CH:26]=1)=[O:35]
Reactant: Fc1ccccc1CBr
Reactant: COC(=O)c1c[nH]c2ccccc12
Reactant: Nc1nccs1
Agent: c1ccc2[nH]ccc2c1
Product: O=C(Nc1nccs1)c1cn(Cc2ccccc2F)c2ccccc12

Procedure:
R5X=1-Bromomethyl-2-fluoro-benzene, NH2A=2-aminothiazole; Indole starting material=methyl indole 3-carboxylate
Reaction SMILES: O[CH2:2][C:3]1[CH:4]=[C:5]([C:15]([CH3:19])([CH3:18])[C:16]#[N:17])[CH:6]=[C:7]([CH2:9][N:10]2[CH:14]=[N:13][CH:12]=[N:11]2)[CH:8]=1.S(Cl)([Cl:22])=O>ClCCl>[ClH:22].[Cl:22][CH2:2][C:3]1[CH:4]=[C:5]([C:15]([CH3:19])([CH3:18])[C:16]#[N:17])[CH:6]=[C:7]([CH2:9][N:10]2[CH:14]=[N:13][CH:12]=[N:11]2)[CH:8]=1
Reactant: CC(C)(C#N)c1cc(CO)cc(Cn2cncn2)c1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: CC(C)(C#N)c1cc(CCl)cc(Cn2cncn2)c1
Product: Cl

Procedure:
A solution of the product from Example 27 (1 g) and thionyl chloride (0.4 ml) in dichloromethane (5 ml) was heated under reflux for 0.5 h, then evaporated to dryness under reduced pressure, to give 2-[3-chloromethyl-5-(1H-1,2,4-triazol-1-ylmethyl)phenyl]-2-methylpropiononitrile hydrochloride, mp. 189°-190° after trituration with ethyl acetate.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:22]=[CH:21][CH:20]=[C:19]3[C:15]=2[CH:16]=[CH:17][NH:18]3)[CH2:10][CH2:9]1)(OC(C)(C)C)=O.[Cl:23][C:24]1[CH:25]=[CH:26][C:27]2[S:31][C:30]([S:32](Cl)(=[O:34])=[O:33])=[C:29]([CH3:36])[C:28]=2[CH:37]=1>>[ClH:23].[Cl:23][C:24]1[CH:25]=[CH:26][C:27]2[S:31][C:30]([S:32]([N:18]3[C:19]4[C:15](=[C:14]([N:11]5[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]5)[CH:22]=[CH:21][CH:20]=4)[CH:16]=[CH:17]3)(=[O:34])=[O:33])=[C:29]([CH3:36])[C:28]=2[CH:37]=1
Reactant: Cc1c(S(=O)(=O)Cl)sc2ccc(Cl)cc12
Reactant: CC(C)(C)OC(=O)N1CCN(c2cccc3[nH]ccc23)CC1
Product: Cc1c(S(=O)(=O)n2ccc3c(N4CCNCC4)cccc32)sc2ccc(Cl)cc12
Product: Cl

Procedure:
The title compound was prepared 4-(4-boc-piperazinyl)-indole and 1-[(5-chloro-3-methyl-1-benzothien-2-yl)sulfonyl chloride according to Method 4 to afford the hydrochloride salt (yield 45%), HPLC purity >95%; 1HNMR (DMSO-d6) δ 2.65 (s, 3H), 3.26 (bs, 8H), 6.82 (app d, 1H), 7.00 (appd, 1H), 7.28 (app t, 1H), 7.60 (app dd, 2H), 7.87 (app d, 1H), 8.08-8.12 (m, 2H); 13C NMR (DMSO-d6) δ 145.05, 139.82, 139.35, 137.46, 135.14, 133.31, 130.96, 128.70 (2C), 125.62, 124.89, 124.12, 123.52, 111.42, 107.91, 107.71, 47.87 (2C), 43.03 (2C), 12.27; MS (posES-FIA) m/z 446 (M+H).
Reaction SMILES: C(O[C:4]([C:6]1[C:11](=O)[NH:10][C:9]([S:13][CH3:14])=[N:8][C:7]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:5])C.O=P(Cl)(Cl)Cl.[SH:26][CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29]>CCCCCCC.C(OCC)(=O)C>[OH:5][C:4]1[C:6]2[C:7]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)=[N:8][C:9]([S:13][CH3:14])=[N:10][C:11]=2[S:26][C:27]=1[C:28]([O:30][CH2:31][CH3:32])=[O:29]
Reactant: CCOC(=O)c1c(-c2ccccc2)nc(SC)[nH]c1=O
Reactant: CCOC(=O)CS
Solvent: CCCCCCC
Solvent: O=P(Cl)(Cl)Cl
Solvent: CCOC(C)=O
Product: CCOC(=O)c1sc2nc(SC)nc(-c3ccccc3)c2c1O

Procedure:
Treatment of 5-ethyloxycarbonyl-2-methylthio-4-phenyl-6-oxopyrimidine (63 mg) with POCl3 (304 μl) and subsequent reaction of the product with ethyl 2-mercaptoacetate were performed according to the methods described in example 1. The pure title compound was obtained after chromatography on silicagel in heptane/ethyl acetate 100/0=>60/40 (v/v) as eluent.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[C:12](=[CH:13][C:14]([OH:18])=[CH:15][CH:16]=3)[CH2:11][CH2:10][N:9]=2)=[CH:4][CH:3]=1.Br[CH2:20]/[CH:21]=[CH:22]/[CH2:23]Br.[CH2:25]([NH:28][CH3:29])[CH:26]=[CH2:27]>>[CH2:25]([N:28]([CH2:20]/[CH:21]=[CH:22]/[CH2:23][O:18][C:14]1[CH:13]=[C:12]2[C:17](=[CH:16][CH:15]=1)[C:8]([C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=1)=[N:9][CH2:10][CH2:11]2)[CH3:29])[CH:26]=[CH2:27]
Reactant: BrC/C=C/CBr
Reactant: Oc1ccc2c(c1)CCN=C2c1ccc(Br)cc1
Reactant: C=CCNC
Product: C=CCN(C)C/C=C/COc1ccc2c(c1)CCN=C2c1ccc(Br)cc1

Procedure:
Analogously to Example 25, from 1-(4-bromo-phenyl)-3,4-dihydro-isoquinolin-6-ol and (E)-1,4-dibromo-2-butene and after reaction with N-allyl-methyl-amine there is obtained (E)-allyl-[4-[1-(4-bromo-phenyl)-3,4-dihydro-isoquinolin-6-yloxy]-but-2-enyl]-methyl-amine, which is converted into the fumarate, MS: m/e 425 (M+H+, 1 Br).
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].C(NC(=O)[O-])C.[OH:21][C:22]1[CH:23]=[CH:24][C:25]2[CH:26]([CH3:34])[CH:27]3[CH2:31][NH:30][CH2:29][CH:28]3[C:32]=2[CH:33]=1>CC#N>[CH2:1]([O:21][C:22]1[CH:23]=[CH:24][C:25]2[CH:26]([CH3:34])[CH:27]3[CH2:31][NH:30][CH2:29][CH:28]3[C:32]=2[CH:33]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC1c2ccc(O)cc2C2CNCC12
Reactant: BrCc1ccccc1
Agent: CCNC(=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC1c2ccc(OCc3ccccc3)cc2C2CNCC12
Temperature: 80 °C
Reaction time: 8 h

Procedure:
Benzyl bromide (15 μL, 0.12 mmol) and K2CO3 (70 mg, 0.5 mmol) were added to a solution of N-ethylcarbamate-5-hydroxy-8-methyl-1,2,3,3a,8,8a-hexahydro indeno[1,2-c]pyrrole (26 mg, 0.1 mmol) in CH3CN (2 mL). The resulting mixture was stirred overnight at 80° C. The reaction was cooled to room temperature, concentrated by rotary evaporation and taken up in H2O (2.5 mL). The product was extracted with ethyl acetate (3×5 mL). The combined organic extracts were dried over MgSO4 and concentrated to afford the subtitle compound, which was used without further purification. MS calculated for C22H25NO3+H: 352, observed: 352.
Reaction SMILES: C(OC(C1C=C(C2C=CC(C[Br:19])=CC=2)C=CC=1)=O)C.[CH2:20]([O:22][C:23]([C:25]1[CH:30]=[CH:29][C:28]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2[CH3:37])=[CH:27][CH:26]=1)=[O:24])[CH3:21].BrN1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.N(C(C)(C)C#N)=NC(C)(C)C#N>[CH2:20]([O:22][C:23]([C:25]1[CH:30]=[CH:29][C:28]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2[CH2:37][Br:19])=[CH:27][CH:26]=1)=[O:24])[CH3:21]
Reactant: CCOC(=O)c1cccc(-c2ccc(CBr)cc2)c1
Reactant: CCOC(=O)c1ccc(-c2ccccc2C)cc1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)c1ccc(-c2ccccc2CBr)cc1
Yield: 99 %

Procedure:
2′-Bromomethyl-biphenyl4-carboxylic acid ethyl ester was synthesized as described for 4′-bromomethyl-biphenyl-3-carboxylic acid ethyl ester. 2′-Methyl-biphenyl-4-carboxylic acid ethyl ester (4.4 g, 18.31 mmol, 1 eq.) in carbon tetrachloride was treated with N-bromosuccinimide (3.58 g, 20.14 mmol, 1.1 eq.), and 2,2′-azobisisobutyronitrile (0.15 g, 0.92 mmol, 5 mol %). When complete, the reaction was worked up as described leaving 2′-bromomethyl-biphenyl-4-carboxylic acid ethyl ester (5.77 g, 99% yield) as a yellow oil.
Reaction SMILES: [CH:1]1[C:11]2[CH2:10][CH2:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[C:6](=[CH:16][C:17]3[CH:18]=[C:19]([NH2:23])[CH:20]=[CH:21][CH:22]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH3:24][CH:25]([CH3:31])[CH2:26][S:27](Cl)(=[O:29])=[O:28]>>[CH:1]1[C:11]2[CH2:10][CH2:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[C:6](=[CH:16][C:17]3[CH:18]=[C:19]([NH:23][S:27]([CH2:26][CH:25]([CH3:31])[CH3:24])(=[O:29])=[O:28])[CH:20]=[CH:21][CH:22]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: Nc1cccc(C=C2c3ccccc3CCc3ccccc32)c1
Reactant: CC(C)CS(=O)(=O)Cl
Product: CC(C)CS(=O)(=O)Nc1cccc(C=C2c3ccccc3CCc3ccccc32)c1
Yield: 21.4 %

Procedure:
Following procedures essentially as described in Example 90, 3-(10,11-dihydro-dibenzo[a,d]cyclohepten-5-ylidenemethyl)-phenylamine (50 mg, 0.168 mmol) and 2-methyl-propane-1-sulfonyl chloride (53 mg, 0.336 mmol) (prepared as described in Quast, H., Synthesis (1974), (7), 489-90) affords 15 mg (21%) of the title compound as a brown oil. MS (ES) 435 (M+NH4), 416 (M−H); HPLC shows 100% purity.
Reaction SMILES: [CH3:1][C:2]([CH3:21])([CH3:20])[C@H:3]([NH:9][C:10](=[O:19])[O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:4]1[N:5]=[N:6][NH:7][N:8]=1.[C:22](=O)([O-])[O-].[K+].[K+].CI>CC(C)=O>[CH3:1][C:2]([CH3:21])([CH3:20])[C@H:3]([NH:9][C:10](=[O:19])[O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:4]1[N:5]=[N:6][N:7]([CH3:22])[N:8]=1.[CH3:1][C:2]([CH3:21])([CH3:20])[C@H:3]([NH:9][C:10](=[O:19])[O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:4]1[N:8]([CH3:22])[N:7]=[N:6][N:5]=1
Reactant: CC(C)(C)[C@H](NC(=O)OCc1ccccc1)c1nn[nH]n1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: Cn1nnc([C@@H](NC(=O)OCc2ccccc2)C(C)(C)C)n1
Product: Cn1nnnc1[C@@H](NC(=O)OCc1ccccc1)C(C)(C)C
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 28 %
Yield: 57 %

Procedure:
To a suspension of benzyl [(1S)-2,2-dimethyl-1-(2H-tetrazol-5-yl)propyl]carbamate (280 mg, 0.96 mmol), potassium carbonate (660 mg, 4.8 mmol) and methyl iodide (0.24 mL, 3.8 mmol) in acetone (5 mL) was stirred at 0° C. for 10 min and warmed to rt. After 4 h, the mixture was filtered and concentrated. The residue was purified by column chromatography on silica gel eluting with hexane/ethyl acetate (8/1-4/1-1/1) to afford 166 mg (57%) of benzyl [(1S)-2,2-dimethyl-1-(2-methyl-2H-tetrazol-5-yl)propyl]carbamate and 82 mg (28%) of benzyl [(1S)-2,2-dimethyl-1-(1-methyl-1H-tetrazol-5-yl)propyl]carbamate.
Reaction SMILES: [Cl:1][Pt:2][Cl:3].[NH2:4][CH2:5][CH2:6][CH2:7][C:8](=[O:10])[CH3:9].C(O)C.OO.[OH2:16]>>[OH:16][Pt:2]([OH:10])([Cl:3])[Cl:1].[NH2:4][CH2:5][CH2:6][CH2:7][C:8](=[O:10])[CH3:9]
Reactant: O
Reactant: Cl[Pt]Cl
Agent: CC(=O)CCCN
Agent: OO
Solvent: CCO
Product: O[Pt](O)(Cl)Cl

Procedure:
Thirty-eight grams (0.099 moles) of cis ammino-5-aminopentan-2-one dichloro platinum (II) were suspended in 350 ml of water. Five milliliters of ethanol were added to wet the solid. Next 49 ml of a 30% solution of hydrogen peroxide (0.49 moles) was added with stirring.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[CH2:4][CH:5]([C:8]1[CH:13]=[CH:12][C:11]([O:14]C2CCCCO2)=[CH:10][CH:9]=1)[CH:6]=[O:7].C12(CS(O)(=O)=O)C(C)(C)C(CC1)C[C:23]2=[O:24].[OH-].[Na+].[CH3:39]O>>[CH3:1][O:2][C:3](=[O:21])[CH2:4][CH:5]([C:8]1[CH:9]=[CH:10][C:11]([OH:14])=[CH:12][CH:13]=1)[CH:6]([O:7][CH3:39])[O:24][CH3:23]
Reactant: CO
Reactant: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Reactant: COC(=O)CC(C=O)c1ccc(OC2CCCCO2)cc1
Agent: [Na+]
Agent: [OH-]
Product: COC(=O)CC(c1ccc(O)cc1)C(OC)OC
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of 4-oxo-3-[4-(tetrahydropyran-2-yloxy)-phenyl]-butyric acid methyl ester (1.29 g) obtained in Step 3 in methanol (13 mL) was added camphorsulfonic acid (98 mg), followed by stirring the reaction mixture at room temperature for 6 hours. Then, after addition of 1N aqueous sodium hydroxide solution (0.42 mL), the reaction mixture was concentrated. To the residue was added water, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, dried and concentrated. The residue was purified by column chromatography on silica gel (ethyl acetate:hexane (volume ratio)=1:2 to 2:3) to give 3-(4-hydroxyphenyl)-4,4-dimethoxy butyric acid methyl ester (0.99 g).
Reaction SMILES: NC1C2N=C(COCC)N(CC(C)(O)C)C=2C2N=CC(Br)=CC=2N=1.[NH2:25][C:26]1[CH:27]=[N:28][C:29]2[C:34]([C:35]=1[NH:36][CH2:37][C:38]([NH:41][C:42](=[O:48])[O:43][C:44]([CH3:47])([CH3:46])[CH3:45])([CH3:40])[CH3:39])=[N:33][CH:32]=[C:31]([Br:49])[CH:30]=2.[CH2:50]([O:52][CH2:53][C:54]([Cl:56])=[O:55])[CH3:51]>C(#N)C>[ClH:56].[Br:49][C:31]1[CH:30]=[C:29]2[C:34]([C:35]([NH:36][CH2:37][C:38]([NH:41][C:42](=[O:48])[O:43][C:44]([CH3:47])([CH3:46])[CH3:45])([CH3:40])[CH3:39])=[C:26]([NH:25][C:54](=[O:55])[CH2:53][O:52][CH2:50][CH3:51])[CH:27]=[N:28]2)=[N:33][CH:32]=1
Reactant: CCOCC(=O)Cl
Reactant: CC(C)(CNc1c(N)cnc2cc(Br)cnc12)NC(=O)OC(C)(C)C
Agent: CCOCc1nc2c(N)nc3cc(Br)cnc3c2n1CC(C)(C)O
Solvent: CC#N
Product: CCOCC(=O)Nc1cnc2cc(Br)cnc2c1NCC(C)(C)NC(=O)OC(C)(C)C
Product: Cl
Yield: 66.9 %

Procedure:
The method described in Part C of the preparation of 1-[4-amino-7-bromo-2-(ethoxymethyl)-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl]-2-methylpropan-2-ol was used to treat tert-butyl 2-[(3-amino-7-bromo[1,5]naphthyridin-4-yl)amino]-1,1-dimethylethylcarbamate (64.0 g, 0.156 mol) with ethoxyacetyl chloride (21.0 g, 0.171 mol) in acetonitrile (640 mL). At the completion of the reaction, additional acetonitrile (200 mL) was added, and the solid product was isolated by filtration, washed with a small volume of acetonitrile, and dried for four hours to provide 55.6 g of tert-butyl 2-({7-bromo-3-[(ethoxyacetyl)amino][1,5]naphthyridin-4-yl}amino)-1,1-dimethylethylcarbamate hydrochloride.
Reaction SMILES: CO[C:3]([C:5]1[N:13]=[C:12]2[C:8]([N:9]=[CH:10][N:11]2[C@@H:14]2[CH2:18][C@H:17]([NH:19][C:20](=[O:23])[CH2:21][CH3:22])[C@@H:16]([OH:24])[C@H:15]2[OH:25])=[C:7]([NH:26][CH2:27][CH:28]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[N:6]=1)=[O:4].Cl.COC(C1N=C2[C:49]([N:50]=CN2)=[C:48]([NH:55][CH2:56][CH:57]([C:64]2C=CC=CC=2)C2C=CC=CC=2)N=1)=O.Cl.NCCNC(C1N=C2C(N=CN2[C@@H]2C[C@H](N)[C@@H](O)[C@H]2O)=C(NCC(C2C=CC=CC=2)C2C=CC=CC=2)N=1)=[O:76]>>[C:56]([NH:55][CH2:48][CH2:49][NH:50][C:3]([C:5]1[N:13]=[C:12]2[C:8]([N:9]=[CH:10][N:11]2[C@@H:14]2[CH2:18][C@H:17]([NH:19][C:20](=[O:23])[CH2:21][CH3:22])[C@@H:16]([OH:24])[C@H:15]2[OH:25])=[C:7]([NH:26][CH2:27][CH:28]([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)[N:6]=1)=[O:4])(=[O:76])[CH2:57][CH3:64]
Reactant: NCCNC(=O)c1nc(NCC(c2ccccc2)c2ccccc2)c2ncn([C@@H]3C[C@H](N)[C@@H](O)[C@H]3O)c2n1
Reactant: CCC(=O)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(C(=O)OC)nc32)[C@H](O)[C@@H]1O
Reactant: COC(=O)c1nc(NCC(c2ccccc2)c2ccccc2)c2nc[nH]c2n1
Agent: Cl
Product: CCC(=O)NCCNC(=O)c1nc(NCC(c2ccccc2)c2ccccc2)c2ncn([C@@H]3C[C@H](NC(=O)CC)[C@@H](O)[C@H]3O)c2n1

Procedure:
The title compound is prepared analogously to 9-((1R,2S,3R,4S)-2,3-dihydroxy-4-propionylamino-cyclopentyl)-6-(2,2-diphenyl-ethylamino)-9H-purine-2-carboxylic acid methyl ester (Example 48 step 7) by replacing 9-(1R,2S,3R,4S)-,4-amino-2,3-dihydroxy-cyclopentyl)-6-(2,2-diphenyl-ethylamino)-9H-purine-2-carboxylic acid methyl ester hydrochloride with 9-((1R,2S,3R,4S)-4-amino-2,3-dihydroxy-cyclopentyl)-6-(2,2-diphenyl-ethylamino)-9H-purine-2-carboxylic acid (2-amino-ethyl)-amide hydrochloride. (MH+ 629.5)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:13][C:12](=O)[CH2:11][C:10](=[O:15])[CH2:9]1.C([O-])(=O)C.[NH4+:20]>C(O)C>[NH2:20][C:12]1[CH2:13][CH:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])[CH2:9][C:10](=[O:15])[CH:11]=1
Reactant: [NH4+]
Reactant: O=C1CC(=O)CC(c2ccccc2Cl)C1
Agent: CC(=O)[O-]
Solvent: CCO
Product: NC1=CC(=O)CC(c2ccccc2Cl)C1
Yield: 88.4 %

Procedure:
A solution of 5-(2-chlorophenyl)cyclohexane-1,3-dione (2.5 g) and ammonium acetate (2.6 g) in ethanol (50 ml) was heated under reflux for 12 hours. The solvent was distilled off under reduced pressure, and aqueous sodium hydrogen carbonate was added and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and the resultant crystal was recrystallized from ethyl acetate-hexane to obtain 1-amino-5-(2-chlorophenyl)cyclohexen-3-one (2.2 g) as a pale yellow crystal.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[C:7]1[CH:12]=[CH:11][C:10]([NH:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)=[CH:9][CH:8]=1)([CH3:4])([CH3:3])[CH3:2].[C:23]1([S:29](Cl)(=[O:31])=[O:30])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.N1C=CC=CC=1>ClCCl>[C:1]([O:5][C:6](=[O:22])[C:7]1[CH:12]=[CH:11][C:10]([N:13]([S:29]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)(=[O:31])=[O:30])[CH2:14][C:15]2[CH:16]=[CH:17][C:18]([Cl:21])=[CH:19][CH:20]=2)=[CH:9][CH:8]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)c1ccc(NCc2ccc(Cl)cc2)cc1
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)c1ccc(N(Cc2ccc(Cl)cc2)S(=O)(=O)c2ccccc2)cc1
Temperature: 25 °C
Yield: 76.3 %

Procedure:
A mixture of 4-(4-chloro-benzylamino)-benzoic acid tert-butyl ester (6 g, 6.3 mmol), phenylsulfonylchloride (2.9 ml, 21 mmol) and pyridine (1.86 mL, 23 mmol) in dichloromethane (25 mL) was heated to reflux for 16 hours. The reaction mixture was cooled to room temperature, diluted with dichloromethane (25 ml) and washed with water (2×25 ml). The organics were collected, dried over magnesium sulfate and concentrated in vacuo to afford a yellow oil which was purified by flash chromatography (hexanes/ethyl acetate 9:1) to afford the title compound as a white solid (2.2 g, 76% yield). HPLC retention time 8.54 min.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[N+:14]([O-:16])=[O:15])[C:5]1=[O:17].C(N(CC)C(C)C)(C)C.[C:27](Cl)(=[O:29])[CH3:28]>ClCCl.CN(C)C=O>[C:27]([O:1][CH2:2][CH2:3][N:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[N+:14]([O-:16])=[O:15])[C:5]1=[O:17])(=[O:29])[CH3:28]
Reactant: CC(=O)Cl
Reactant: O=c1c2cccc([N+](=O)[O-])c2ccn1CCO
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)OCCn1ccc2c([N+](=O)[O-])cccc2c1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 99.7 %

Procedure:
2-(2-Hydroxyethyl)-5-nitroisoquinolin-1(2H)-one (2.2 g, 0.0089 mol) was dissolved in the mixture of dichloromethane (20 mL) and dimethylformamide (10 mL), N,N-diisopropylethylamine (2.33 mL, 0.0134 mol) and acetyl chloride (1.06 g, 0.0134 mol) were added and the reaction mixture was stirred at room temperature for 30 min. The volatiles were removed, the residue was washed with water and then with diethyl ether to obtain a light yellow solid (2.45 g). MS m/z=276.5 (M+H).
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][C:8]([NH:10][C:11]3[O:12][CH2:13][C:14](=[O:21])[C:15]=3[C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:9][C:4]=2[NH:3][CH:2]=1.[NH:22]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][N:29]=2)[C:24]([CH:31]=O)=[CH:23]1.N1CCCCC1>C(O)C>[NH:22]1[C:30]2=[N:29][CH:28]=[CH:27][CH:26]=[C:25]2[C:24]([CH:31]=[C:13]2[O:12][C:11]([NH:10][C:8]3[CH:7]=[CH:6][C:5]4[N:1]=[CH:2][NH:3][C:4]=4[CH:9]=3)=[C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:14]2=[O:21])=[CH:23]1
Reactant: O=Cc1c[nH]c2ncccc12
Reactant: CCOC(=O)C1=C(Nc2ccc3nc[nH]c3c2)OCC1=O
Solvent: C1CCNCC1
Solvent: CCO
Product: CCOC(=O)C1=C(Nc2ccc3nc[nH]c3c2)OC(=Cc2c[nH]c3ncccc23)C1=O
Temperature: 25 °C
Yield: 3.6 %

Procedure:
To a solution of ethyl 2-[(5-benzimidazolyl)amino]-4-oxo-4,5-dihydrofuran-3-carboxylate (0.30 g, 1.0 mmol) which similarly prepared according to the procedure described in the Example 74, Fourth step and 7-azaindole-3-carboxaldehyde (0.15 g, 1.0 mmol) in ethanol (5.0 mL), piperidine (0.20 mL, 3.1 mmol) was added at ambient temperature. The mixture was refluxed for 24 h. Cooled to ambient temperature, the precipitate was collected by filtration, washed with methanol then dried to afford the titled compound as solid (0.015 g, y. 4%).