Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:31])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:23]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[CH:22][N:21]=[C:20]([NH2:30])[N:19]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].Br[CH2:33][C:34]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)=O>C(O)C.C(Cl)Cl>[C:1]([O:5][C:6](=[O:31])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:23]([C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=4)=[CH:22][N:21]4[CH:33]=[C:34]([C:36]5[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=5)[N:30]=[C:20]4[N:19]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc(N)ncc3-c3ccccc3)cc2)CCC1
Reactant: O=C(CBr)c1ccccc1
Solvent: CCO
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4nc(-c5ccccc5)cn4cc3-c3ccccc3)cc2)CCC1
Temperature: 100 °C
Reaction time: 0.75 h
Yield: 48.4 %

Procedure:
A mixture of 5-1 (150 mg, 0.36 mmol) and 2-Bromo-1-phenyl-ethanone (110 mg, 0.54 mmol) in ethanol (2 mL) was heated to 100° C. and stirred for 45 mins under microwave radiation. The mixture was cooled to r.t. and diluted with 20 mL of DCM. The organic phase was washed with brine, dried over anhydrous Na2SO4 and concentrated. The residue was purified by prep.TLC to give 90 mg of 5-2.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[CH:11]=[CH:10][C:7]([C:8]#[N:9])=[CH:6][CH:5]=1.[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([Mg]Br)=[CH:16][CH:15]=1.[BH4-].[Na+].Cl>C1COCC1>[CH3:1][O:2][CH2:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]([C:17]2[CH:18]=[CH:19][C:14]([O:13][CH3:12])=[CH:15][CH:16]=2)[NH2:9])=[CH:6][CH:5]=1
Reactant: COCc1ccc(C#N)cc1
Reactant: COc1ccc([Mg]Br)cc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCc1ccc(C(N)c2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
To the product of Step A (1.5 g, 10.19 mmol) in THF (15 mL) was added 4-methoxyphenylmagnesium bromide (11.21 mL, 11.21 mmol, 1.0 M). The reaction aged at rt for 3.5 h and was concentrated. The residue was dissolved in MeOH (20 mL) and then slowly treated with NaBH4 (0.386 g, 10.19 mmol). The reaction was stirred at rt overnight, concentrated and treated with aq. HCl (15 mL, 30 mmol, 2.0 M). The aqueous portion was extracted with EtOAc (2×) and the combined organic layers were washed with a 1:1 solution of aq. 2.0 M NaOH/brine, dried (MgSO4), filtered and concentrated. The residue was purified by flash chromatography on silica gel gradient eluted with 0-100% EtOAc/hexane to afford the title compound. HPLC/MS: 241.0 (M—NH2)+; Rt=1.91 min.
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([O:9][CH3:10])[C:5]([NH2:8])=[N:6][CH:7]=1.[I:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[S:18](Cl)(=[O:20])=[O:19]>>[Br:1][C:2]1[N:3]=[C:4]([O:9][CH3:10])[C:5]([NH:8][S:18]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[I:11])(=[O:20])=[O:19])=[N:6][CH:7]=1
Reactant: O=S(=O)(Cl)c1ccccc1I
Reactant: COc1nc(Br)cnc1N
Product: COc1nc(Br)cnc1NS(=O)(=O)c1ccccc1I

Procedure:
Prepared by the method of Example 1 (reaction performed at room temperature) using 5-bromo-3-methoxy-2-pyrazinamine and 2-iodobenzenesulphonyl chloride.
Reaction SMILES: N([O-])=O.[Na+].[CH2:5]([O:7][C:8]([C:10]1[C:19](N)=[CH:18][C:17]2[C:12](=[C:13]([O:21][CH3:22])[CH:14]=[CH:15][CH:16]=2)[CH:11]=1)=[O:9])[CH3:6].C([O-])(O)=O.[Na+].[ClH:28]>O>[CH2:5]([O:7][C:8]([C:10]1[C:19]([Cl:28])=[CH:18][C:17]2[C:12](=[C:13]([O:21][CH3:22])[CH:14]=[CH:15][CH:16]=2)[CH:11]=1)=[O:9])[CH3:6]
Reactant: Cl
Reactant: CCOC(=O)c1cc2c(OC)cccc2cc1N
Agent: O=C([O-])O
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: CCOC(=O)c1cc2c(OC)cccc2cc1Cl
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of NaNO2 (884 mg, 12.81 mmol, 1.45 equiv) in water (20 ml) was added dropwise at 0° C. to a solution of 3-amino-8-methoxy-naphthalene-2-carboxylic acid ethyl ester (2.165 g, 8.83 mmol) in 18% aqueous HCl (50 ml). After it was stirred for 30 minutes at 0° C., this mixture was added dropwise at −20° C. to a solution of freshly prepared Cu(I)CI (2.62 g, 26.50 mmol, 3.0 equiv) in concentrated aqueous HCl (90 ml). After 1 hour at −10° C. and 1 hour at rt, solid NaHCO3 was carefully added to the reaction mixture until pH was >7.0. After dilution with water (200 ml), the aqueous phase was extracted with EtOAc (2 liters in total). The combined organic layers were washed with water (300 ml) and concentrated aqueous NH4Cl solution (100 ml), dried over Na2SO4, filtered and concentrated in vacuo. Purification via flash chromatography (gradient of hexane/EtOAc 10:0 to 9:1) afforded the title compound (1.36 g, 58%, inseparable ˜1:1 mixture of regioisomers A:B) as a slightly yellow oil. 1H NMR (400 MHz, CDCl3): δ=8.76 (s, 1H isomer A/B), 8.31 (s, 1H isomer A/B), 7.85 (s, 1H isomer A/B), 7.50-7.40 (m, 3H isomer A/B), 7.32 (d, J=8.6 Hz, 1H isomer A/B), 6.90 (dd, J=6.6/2.0 Hz, 1H isomer A/B), 6.83 (d, J=7.6 Hz, 1H isomer A/B), 4.44 (q, J=7.1 Hz, 2H), 4.01 (s, 3H isomer A/B), 4.00 (s, 3H isomer A/B). 1.44 (t, J=7.1 Hz, 3H isomer A/B), 1.44 (t, J=7.1 Hz, 3H isomer A/B). MS (ES+): 265 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[CH2:5][S:6]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][CH2:18][CH3:19])=[CH:11][CH:10]=1)(=[O:8])=[O:7])[CH3:2].[Cl:21][C:22]1[CH:23]=[C:24]([CH:33]=[CH:34][C:35]=1[Cl:36])[CH2:25][N:26]([CH2:30][CH2:31]Cl)[CH2:27][CH2:28]Cl>>[CH2:1]([O:3][C:4]([C:5]1([S:6]([C:9]2[CH:10]=[CH:11][C:12]([O:15][CH2:16][CH2:17][CH2:18][CH3:19])=[CH:13][CH:14]=2)(=[O:7])=[O:8])[CH2:28][CH2:27][N:26]([CH2:25][C:24]2[CH:33]=[CH:34][C:35]([Cl:36])=[C:22]([Cl:21])[CH:23]=2)[CH2:30][CH2:31]1)=[O:20])[CH3:2]
Reactant: CCCCOc1ccc(S(=O)(=O)CC(=O)OCC)cc1
Reactant: ClCCN(CCCl)Cc1ccc(Cl)c(Cl)c1
Product: CCCCOc1ccc(S(=O)(=O)C2(C(=O)OCC)CCN(Cc3ccc(Cl)c(Cl)c3)CC2)cc1

Procedure:
4-(4-Butoxy-benzenesulfonyl)-1-(3,4-dichloro-benzyl)-piperidine-4-carboxylic acid ethyl ester was prepared according to the general method outlined in example 83. Starting from (4-butoxy-benzenesulfonyl)acetic acid ethyl ester (13.2 g 44 mmol) (3,4-dichloro-benzyl)-bis-(2-chloro-ethyl)-amine (14.3 g, mmol). Yield 14.1 g (60%), white solid, MP 86° C.; MS: 527.9 (M+H)+
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[C:14]([OH:16])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:17][C:18]1[CH:19]=[C:20]([NH:28][C:29]2[N:38]=[CH:37][C:36]3[N:35]([CH3:39])[C:34](=[O:40])[CH2:33][N:32]([CH:41]([CH3:43])[CH3:42])[C:31]=3[N:30]=2)[CH:21]=[C:22]([S:24]([CH3:27])(=[O:26])=[O:25])[CH:23]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[C:14](=[O:16])[NH:17][C:18]1[CH:23]=[C:22]([S:24]([CH3:27])(=[O:25])=[O:26])[CH:21]=[C:20]([NH:28][C:29]2[N:38]=[CH:37][C:36]3[N:35]([CH3:39])[C:34](=[O:40])[CH2:33][N:32]([CH:41]([CH3:43])[CH3:42])[C:31]=3[N:30]=2)[CH:19]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)N1CC(=O)N(C)c2cnc(Nc3cc(N)cc(S(C)(=O)=O)c3)nc21
Reactant: CC(C)(C)OC(=O)N1CCCCC1C(=O)O
Product: CC(C)N1CC(=O)N(C)c2cnc(Nc3cc(NC(=O)C4CCCCN4C(=O)OC(C)(C)C)cc(S(C)(=O)=O)c3)nc21
Yield: 15 %

Procedure:
Starting from piperidine-1,2-dicarboxylic acid 1-tert-butyl ester (176 mg; 0.768 mmol) and 2-(3-amino-5-(methylsulfonyl)-phenylamino)-8-isopropyl-5-methyl-7,8-dihydro-5H-pteridin-6-one (200 mg; 0.512 mmol), 45 mg (0.074 mmol; 15% yield) of the desired compound were obtained.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([S:16][C:17]2[CH:28]=[CH:27][C:20]3[NH:21][C:22](=[O:26])[C@@H:23]([CH3:25])[O:24][C:19]=3[CH:18]=2)[CH:5]=[C:6]([C:8]2([O:14][CH3:15])[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[CH:7]=1.[CH3:29]I>>[F:1][C:2]1[CH:3]=[C:4]([S:16][C:17]2[CH:28]=[CH:27][C:20]3[N:21]([CH3:29])[C:22](=[O:26])[C@@H:23]([CH3:25])[O:24][C:19]=3[CH:18]=2)[CH:5]=[C:6]([C:8]2([O:14][CH3:15])[CH2:9][CH2:10][O:11][CH2:12][CH2:13]2)[CH:7]=1
Reactant: COC1(c2cc(F)cc(Sc3ccc4c(c3)O[C@H](C)C(=O)N4)c2)CCOCC1
Reactant: CI
Product: COC1(c2cc(F)cc(Sc3ccc4c(c3)O[C@H](C)C(=O)N4C)c2)CCOCC1
Yield: 42 %

Procedure:
Using a similar procedure to that described in Example 16, (R)(-)-4-[5-fluoro-3-(2-methyl-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-7-ylthio)phenyl]-4-methoxytetrahydropyran was reacted with methyl iodide to give (R)-(-)-4-[5-fluoro-3-(2,4-dimethyl-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-7-ylthio)phenyl]-4-methoxytetrahydropyran in 42% yield,
Reaction SMILES: [CH:1]1([CH2:7][N:8]2[C:16](=[O:17])[C:15]3[N:14]=[C:13]([C:18]4[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=4C(O)=O)[NH:12][C:11]=3[N:10]([CH2:27][CH:28]3[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]3)[C:9]2=[O:34])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(OC(=O)C(Br)C(C1C=CC([C:48]2[NH:49][C:50]3N(CC4CCCCC4)C(=O)N(CC4CCCCC4)C(=O)[C:55]=3[N:56]=2)=CC=1)Br)C>>[CH:1]1([CH2:7][N:8]2[C:16](=[O:17])[C:15]3[N:14]=[C:13]([C:18]4[CH:19]=[CH:23][CH:24]=[C:25](/[CH:11]=[CH:15]/[C:16]([N:49]5[CH:50]=[CH:55][N:56]=[CH:48]5)=[O:17])[CH:26]=4)[NH:12][C:11]=3[N:10]([CH2:27][CH:28]3[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]3)[C:9]2=[O:34])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C(O)c1ccccc1-c1nc2c(=O)n(CC3CCCCC3)c(=O)n(CC3CCCCC3)c2[nH]1
Reactant: CCOC(=O)C(Br)C(Br)c1ccc(-c2nc3c(=O)n(CC4CCCCC4)c(=O)n(CC4CCCCC4)c3[nH]2)cc1
Product: O=C(/C=C/c1cccc(-c2nc3c(=O)n(CC4CCCCC4)c(=O)n(CC4CCCCC4)c3[nH]2)c1)n1ccnc1
Reaction time: 18 h

Procedure:
A slurry of (E)-3-[(1,3-bis(cyclohexylmethyl)-1,2,3,6-tetrahydro-2,6-dioxo-9H-purin-8-yl]benzoic acid (from part (a) of this example, 0.500 g) in anhydrous N,N-dimethylfonnamide (10 mL) was heated briefly to near reflux under nitrogen. N,N′-Carbonyldiimidazole (Aldrich, 0.213 g) was added to the pale yellow slurry, which thinned and turned orange as a gas evolved. Within minutes the slurry turned bright yellow and yellow solid precipitated. The mixture was stirred for 18 h, diluted with dichloromethane (30 mL), and filtered. The solid was washed with dichloromethane (30 mL) and dried at 40° C. to provide (E)-1,3-bis(cyclohexylmethyl)-8-[3-(2-(1H-imidazol-1-ylcarbonyl)vinyl)phenyl]-9H-purin-2,6(1H,3H)-dione as a yellow powder (0.46 g). A mixture of this solid (0.45 g), nonaethylene glycol monomethyl ether, (from part (a) of example 10, 0.393 g) and anhydrous potassium carbonate (0.242 g) in acetonitrile (10 mL) was stirred at reflux for 20 h. Chloroform (50 mL) was added and the solution was washed with 1N HCl, (20 mL). The organic layer was washed with brine, dried (magnesium sulfate), and chromatographed on silica gel. Elution with 10% methanolchloroform evaporation of solvents gave (E)-3-[1,3-bis(cyclohexylmethyl)-1,2,3,6-tetrahydro-2,6-dioxo-9H-purin-8-yl]benzoic acid nonaethylene glycol methyl ether ester as a waxy white solid (0.262 g, 38%); 1H-NMR (DMSO-d6)6: 8.79 (s) and 8.43 (d, J=7.9), 8.11 (d, J=8.0), and 7.57 (m, each 1, C6H4), 4.50 (m, 2, CH2O), 3.99 (d,J=7.1, 2, CH2N), 3.83 (m, 4, CH2N and CH2O), 3.70-3.40 (m, 32, 16 CH2), 3.28 (s, 3, CH3), 2.1-1.6 and 1.4-1.0 (both m, 22, cyclohexyl CH2 and CH).
Reaction SMILES: [Cl-].[CH3:2][O:3][CH2:4][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CC([O-])(C)C.[K+].[CH2:30]([C@H:33]1[CH2:38][CH2:37][C@H:36]([C@H:39]2[CH2:44][CH2:43][C@H:42]([CH2:45][CH2:46][CH:47]=O)[CH2:41][CH2:40]2)[CH2:35][CH2:34]1)[CH2:31][CH3:32]>C1COCC1>[CH3:2][O:3][CH:4]=[CH:47][CH2:46][CH2:45][C@H:42]1[CH2:43][CH2:44][C@H:39]([C@H:36]2[CH2:37][CH2:38][C@H:33]([CH2:30][CH2:31][CH3:32])[CH2:34][CH2:35]2)[CH2:40][CH2:41]1
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCC[C@H]1CC[C@H]([C@H]2CC[C@H](CCC=O)CC2)CC1
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCC[C@H]1CC[C@H]([C@H]2CC[C@H](CCC=COC)CC2)CC1
Temperature: -30 °C
Reaction time: 1 h

Procedure:
A mixture of 57.3 g (167 mmol) of methoxymethyl-triphenylphosphonium chloride and 500 ml of THF was cooled to −30° C. under a nitrogen gas stream with a refrigeration medium. 17.3 g (154 mmol) of t-BuOK was added to this mixture, followed by stirring for 1 hour. To this mixture, 300 ml of THF containing 34.0 g (129 mmol) of 3-(trans-4-(trans-4-propylcyclohexyl)cyclohexyl)propanal was added dropwise, while a temperature of −30° C. or less was maintained. After the dropping, a reaction temperature was gradually raised to room temperature, followed by stirring for 5 hours. The reaction mixture was filtered through Celite, and the solvent was then distilled off under reduced pressure. The resulting residue was purified through silica gel column chromatography (a developing solvent: heptane) to obtain 30.3 g of crude 1-methoxy-4-(trans-4-(trans-4-propylcyclohexyl)cyclohexyl)-1-butene.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[C:12]([CH3:14])[N:11]=[C:10]([C:15]([O:17][CH3:18])=[O:16])[CH:9]=2)[CH2:4][C@H:3]1[O:19][CH3:20].[Cl:21][C:22]1[N:23]=[C:24]([C:29](O)=[O:30])[NH:25][C:26]=1[CH2:27][CH3:28].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>>[Cl:21][C:22]1[N:23]=[C:24]([C:29]([NH:1][C@H:2]2[CH2:7][CH2:6][N:5]([C:8]3[CH:13]=[C:12]([CH3:14])[N:11]=[C:10]([C:15]([O:17][CH3:18])=[O:16])[CH:9]=3)[CH2:4][C@H:3]2[O:19][CH3:20])=[O:30])[NH:25][C:26]=1[CH2:27][CH3:28]
Reactant: CCc1[nH]c(C(=O)O)nc1Cl
Reactant: COC(=O)c1cc(N2CC[C@H](N)[C@H](OC)C2)cc(C)n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Product: CCc1[nH]c(C(=O)N[C@H]2CCN(c3cc(C)nc(C(=O)OC)c3)C[C@H]2OC)nc1Cl

Procedure:
The same operation as in Example (1g) was performed using methyl cis(±)-4-(4-amino-3-methoxypiperidin-1-yl)-6-methylpyridine-2-carboxylate obtained in Example (168b) (129 mg, 0.44 mmol), 4-chloro-5-ethyl-1H-imidazole-2-carboxylic acid obtained by the method described in Example (1d) (64 mg, 0.37 mmol), WSC hydrochloride (211 mg, 1.1 mmol) and HOBt (49.7 mg, 0.37 mmol), to obtain 174 mg of the title compound as a pale yellow oily substance.
Reaction SMILES: N1CC[CH2:3][CH2:2]1.[Cl:6][C:7]1[CH:8]=[C:9]([N:13]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15](=[CH:22][N:23]([CH3:25])[CH3:24])[C:14]2=[O:26])[CH:10]=[CH:11][CH:12]=1>C(O)C>[Cl:6][C:7]1[CH:8]=[C:9]([N:13]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15](=[CH:22][N:23]3[CH2:24][CH2:3][CH2:2][CH2:25]3)[C:14]2=[O:26])[CH:10]=[CH:11][CH:12]=1
Reactant: C1CCNC1
Reactant: CN(C)C=C1C(=O)N(c2cccc(Cl)c2)c2ccccc21
Solvent: CCO
Product: O=C1C(=CN2CCCC2)c2ccccc2N1c1cccc(Cl)c1
Reaction time: 3 h

Procedure:
Pyrrolidine (0.42 ml, 5.0 mmoles) was added to a solution of the title product of Example A3 (0.3 g, 1.0 mmole) in 10 ml of ethanol. The mixture was stirred 3 hours and then allowed to stand for 16 hours at 25°. The reaction mixture was evaporated to dryness in vacuo. The residue was triturated with ether and filtered with pentane wash to yield purified title product, 0.253 g; m.p. 108°-112°.
Reaction SMILES: Br[CH2:2][C:3]1[N:4]([CH3:22])[C:5](=[O:21])[C:6]2[C:11]([C:12]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[CH:10][C:9]([O:19][CH3:20])=[CH:8][CH:7]=2.[OH:23][CH2:24][CH2:25][SH:26].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[OH:23][CH2:24][CH2:25][S:26][CH2:2][C:3]1[N:4]([CH3:22])[C:5](=[O:21])[C:6]2[C:11]([C:12]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[CH:10][C:9]([O:19][CH3:20])=[CH:8][CH:7]=2
Reactant: COc1ccc2c(=O)n(C)c(CBr)c(-c3ccccc3)c2c1
Reactant: OCCS
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COc1ccc2c(=O)n(C)c(CSCCO)c(-c3ccccc3)c2c1
Reaction time: 1 h

Procedure:
To a solution of 3-(bromomethyl)-6-methoxy-2-methyl-4-phenylisoquinolin-1(2H)-one (125 mg, 0.349 mmol) in 5 mL of dimethylformamide was added 2-hydroxyethanethiol (0.027 mL, 0.38 mmol) and cesium carbonate (227 mg, 0.698 mmol). After one hour, the reaction mixture was partitioned between EtOAc and water, and the organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The crude residue was purified by recrystallization from EtOAc/hexane to provide the titled product. 1H-NMR (500 MHz, CDCl3) δ 8.41 (d, J=9.0 Hz, 1H), 7.45-7.54 (m, 3H), 7.34-7.36 (m, 2H), 7.04 (dd, J=9.0, 2.5 Hz, 1H), 6.35 (d, J=2.5 Hz, 1H), 3.83, (s, 3H), 3.68 (s, 3H), 3.63 (s, 2H), 3.41 (m, 2H), 2.58 (t, J=5.6 Hz, 2H) ppm. ESI+ MS: 356.14 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][N:7]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)[C:6](=[O:17])[C:5]=1[C:18]([O:20]CC)=[O:19])[CH3:2].[Li+].[OH-]>CCO.O>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][N:7]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)[C:6](=[O:17])[C:5]=1[C:18]([OH:20])=[O:19])[CH3:2]
Reactant: CCOC(=O)c1c(OCC)ccn(-c2ccc(F)cc2)c1=O
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCOc1ccn(-c2ccc(F)cc2)c(=O)c1C(=O)O
Temperature: 25 °C
Reaction time: 16 h
Yield: 79.1 %

Procedure:
A mixture of ethyl 4-ethoxy-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxylate (60 g, 0.196 mol) and LiOH (30 g, 0.6 mol) in EtOH (200 mL) and water (100 mL) was stirred at RT for 16 h. The mixture was concentrated to remove EtOH, the aqueous residue diluted with additional water (300 mL), washed with EtOAc (1×) and acidified to pH<2 with conc. HCl. The mixture was extracted with EtOAc (3×) and the combined organics were washed with brine, dried over Na2SO4 and concentrated to dryness. The residue was treated with pet ether and the resulting solid collected via filtration to afford 4-ethoxy-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxylic acid (43 g, 79%). 1H NMR (400 MHz, DMSO-d6): δ 7.95 (d, J=8.0 Hz, 1H), 7.48 (m, 2H), 7.35 (m, 2H), 6.58 (d, J=7.6 Hz, 1H), 4.28 (q, J=7.2 Hz, 2H), 1.32 (t, J=7.2 Hz, 3H).
Reaction SMILES: Cl.[C:2]([O:5][C@@H:6]1[C@@H:10]([C:11]2ON=C(CC)C=2)[O:9][C@@H:8]([N:18]2[CH:26]=[N:25][C:24]3[C:19]2=[N:20][C:21]([Cl:38])=[N:22][C:23]=3[NH:27][C@@H:28]([CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH2:29][OH:30])[C@@H:7]1[O:39][C:40](=[O:42])[CH3:41])(=[O:4])[CH3:3].C(O[C@@H]1[C@@H](C2[N:53]=[N:54][N:55]([CH2:57][CH3:58])[N:56]=2)O[C@@H](N2C=NC3C2=NC(Cl)=NC=3Cl)[C@@H]1OC(=O)C)(=O)C>>[C:2]([O:5][C@@H:6]1[C@@H:10]([C:11]2[N:53]=[N:54][N:55]([CH2:57][CH3:58])[N:56]=2)[O:9][C@@H:8]([N:18]2[CH:26]=[N:25][C:24]3[C:19]2=[N:20][C:21]([Cl:38])=[N:22][C:23]=3[NH:27][C@@H:28]([CH2:31][C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH2:29][OH:30])[C@@H:7]1[O:39][C:40](=[O:42])[CH3:41])(=[O:4])[CH3:3]
Reactant: CCc1cc([C@H]2O[C@@H](n3cnc4c(N[C@H](CO)Cc5ccccc5)nc(Cl)nc43)[C@H](OC(C)=O)[C@@H]2OC(C)=O)on1
Reactant: CCn1nnc([C@H]2O[C@@H](n3cnc4c(Cl)nc(Cl)nc43)[C@H](OC(C)=O)[C@@H]2OC(C)=O)n1
Agent: Cl
Product: CCn1nnc([C@H]2O[C@@H](n3cnc4c(N[C@H](CO)Cc5ccccc5)nc(Cl)nc43)[C@H](OC(C)=O)[C@@H]2OC(C)=O)n1

Procedure:
The title compound is prepared analogously to acetic acid (2R,3R,4R,5S)-4-acetoxy-2-[6-((S)-1-benzyl-2-hydroxy-ethyl amino)-2-chloro-purin-9-yl]5-(3-ethyl-isoxazol-5-yl)-tetrahydro-furan-3-yl ester hydrochloride (Step CA1) by replacing acetic acid (2R,3R,4R,5S)-4-acetoxy-2-(2,6-dichloro-purin-9-yl)-5-(3-ethyl-isoxazol-5-yl)-tetrahydro-furan-3-yl ester (WO 99/38877) with acetic acid (2R,3R,4R,5R)-4-acetoxy-2-(2,6-dichloro-purin-9-yl)-5-(2-ethyl-2H-tetrazol-5-yl)-tetrahydro-furan-3-yl ester (WO 98/28319).
Reaction SMILES: C(N(CC)CC)C.[CH:8]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH:17]([CH3:19])[CH3:18])[C:12]=1[NH2:20])([CH3:10])[CH3:9].[Cl:21][CH2:22][C:23](Cl)=[O:24]>ClCCl>[Cl:21][CH2:22][C:23]([NH:20][C:12]1[C:11]([CH:8]([CH3:10])[CH3:9])=[CH:16][CH:15]=[CH:14][C:13]=1[CH:17]([CH3:19])[CH3:18])=[O:24]
Reactant: CC(C)c1cccc(C(C)C)c1N
Reactant: O=C(Cl)CCl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)c1cccc(C(C)C)c1NC(=O)CCl
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
222 mL (1.59 mol) of triethylamine are added to a solution of 300 mL (1.59 mol) of 2,6-diisopropyl-phenylamine (Starting material 3) in 1 litre of dichloromethane. The reaction mixture is cooled to 0° C., and 127 mL (1.59 mol) of chloroacetyl chloride are then added dropwise. Once the addition is complete, the ice bath is removed and the medium is stirred for 20 minutes. It is then poured into water and extracted with dichloromethane. The organic phases are combined and washed with water. They are dried over sodium sulfate. The solvents are evaporated off. The residue is filtered through silica gel (eluent: dichloromethane). The filtrate is evaporated and then triturated in heptane. 2-Chloro-N-(2,6-diisopropyl-phenyl)acetamide is obtained in the form of a white solid.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH2:6]2)[CH3:2].C([OH:15])C.[OH-].[K+]>O>[CH2:1]([C:3]1[CH:11]=[CH:10][C:9]([NH2:8])=[C:5]([CH2:6][C:7]([OH:12])=[O:15])[CH:4]=1)[CH3:2]
Reactant: CCc1ccc2c(c1)CC(=O)N2
Reactant: CCO
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: CCc1ccc(N)c(CC(=O)O)c1

Procedure:
5-Ethyloxindole (˜54 g, ˜335 mmol), ethanol (750 ml), water (150 ml) and potassium hydroxide (65 g, 1.62 mol) are combined and heated at reflux for 3 days. The mixture is allowed to cool and then filtered through a bed of Celite. The filtrate is concentrated under reduced pressure, water is added and the pH adjusted to 6.5. The precipitate is filtered off, washed with water and dried in an oven overnight to yield 5-ethyl-2-aminophenylacetic acid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:25]=[CH:24][C:6]([C:7]([C:9]2[O:10][C:11]3[C:18]([CH2:19][CH:20]=[CH2:21])=[CH:17][C:16]([Cl:22])=[C:15]([OH:23])[C:12]=3[C:13]=2[CH3:14])=[O:8])=[CH:5][CH:4]=1>C(O)C.[Pd]>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:7]([C:9]2[O:10][C:11]3[C:18]([CH2:19][CH2:20][CH3:21])=[CH:17][C:16]([Cl:22])=[C:15]([OH:23])[C:12]=3[C:13]=2[CH3:14])=[O:8])=[CH:24][CH:25]=1
Reactant: C=CCc1cc(Cl)c(O)c2c(C)c(C(=O)c3ccc(OC)cc3)oc12
Agent: [Pd]
Solvent: CCO
Product: CCCc1cc(Cl)c(O)c2c(C)c(C(=O)c3ccc(OC)cc3)oc12
Yield: 98.9 %

Procedure:
A solution of 2-(p-methoxybenzoyl)-3-methyl-4-hydroxy-5-chloro-7-allylbenzofuran (110 mg; 0.31mmole) in ethanol (15 mL) was hydrogenated in a Parr apparatus at 20 psi in the presence of 5% palladium on charcoal. The catalyst was filtered off and the filtrate was evaporated in vacuo to yield 110 mg of 2-(p-methoxybenzoyl)-3-methyl-4-hydroxy-5-chloro-7-propylbenzofuran.
Reaction SMILES: [CH2:1]([C:8]1[C:16]2[C:15](=[O:17])[NH:14][N:13]=[CH:12][C:11]=2[N:10](COCC2C=CC=CC=2)[C:9]=1[C:27]1[CH:32]=[CH:31][C:30]([O:33][CH:34]([F:36])[F:35])=[C:29]([O:37][CH:38]2[CH2:40][CH2:39]2)[CH:28]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[H][H]>[Pd].C(O)C>[CH2:1]([C:8]1[C:16]2[C:15](=[O:17])[NH:14][N:13]=[CH:12][C:11]=2[NH:10][C:9]=1[C:27]1[CH:32]=[CH:31][C:30]([O:33][CH:34]([F:35])[F:36])=[C:29]([O:37][CH:38]2[CH2:40][CH2:39]2)[CH:28]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: [H][H]
Reactant: O=c1[nH]ncc2c1c(Cc1ccccc1)c(-c1ccc(OC(F)F)c(OC3CC3)c1)n2COCc1ccccc1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: O=c1[nH]ncc2[nH]c(-c3ccc(OC(F)F)c(OC4CC4)c3)c(Cc3ccccc3)c12
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.1 %

Procedure:
To 20 ml of ethanol solution containing 198 mg (0.364 mmol) of 3-benzyl-1-benzyloxymethyl-2-(3-cyclopropoxy-4-difluoromethoxyphenyl)-1,5-dihydropyrrolo[2,3-d]pyridazin-4-one obtained in Example 19-(b), then, 28 mg of 5% palladium-active carbon and 0.36 ml of 1N hydrochloric acid were added thereto, and the mixture was stirred under 1 atm hydrogen atmosphere at 50° C. for 3.8 hours. After completion of the reaction, the reaction mixture was filtered, the filtrate was concentrated under reduced pressure, 8.6 ml of methanol and 4.3 ml of 28% aqueous ammonia were added to the obtained solid and the mixture was stirred at room temperature for 1 hour. Then, the solution was concentrated under reduced pressure, water was added to the obtained concentrate, and the precipitated solid was collected by filtration. The obtained solid was washed successively with water and then with diisopropyl ether and dried under reduced pressure to obtain 128 mg of the title compound as a white solid. (Yield: 84%)