Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN(C)[CH:3]=[O:4].O=P(Cl)(Cl)Cl.[CH2:11]([N:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:21][CH2:20][CH2:19]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C([O-])(=O)C.[Na+]>ClCCCl.O>[CH2:11]([N:18]1[C:27]2[C:22](=[CH:23][C:24]([CH:3]=[O:4])=[CH:25][CH:26]=2)[CH2:21][CH2:20][CH2:19]1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: c1ccc(CN2CCCc3ccccc32)cc1
Reactant: CN(C)C=O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: ClCCCl
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Product: O=Cc1ccc2c(c1)CCCN2Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To dimethylformamide (1.7 ml, 0.022 mol) at 0° C. was added dropwise POCl3 (2.0 ml, 0.022 mol) and the mixture allowed to warm and stirred at ambient temperature for 20 minutes, then diluted with 1,2-dichloroethane (5 ml). 1-Benzyl-1,2,3,4-tetrahydroquinoline (4.5 g, 0.020 mol) dissolved in 5 ml of 1,2-dichloroethane was then added and the mixture refluxed 1 hour, then cooled to room temperature. Sodium acetate (9.0g, 0.11 mol), dissolved in the minimum necessary water, was added and the mixture refluxed for 15 minutes. The layers were separated and the aqueous layer extracted 2×10 ml ether.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[N:8][CH2:7][CH2:6]2.O.[BH4-].[Na+]>CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH2:9][NH:8][CH2:7][CH2:6]2
Reactant: COc1ccc2c(c1)CCN=C2
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COc1ccc2c(c1)CCNC2

Procedure:
In methanol (100 ml), 6-methoxy-3,4-dihydroisoquinoline (10.4 g) was dissolved. After the addition of water (10 ml) and then sodium borohydride (6.10 g), the resulting mixture was stirred at room temperature for 15 minutes. The reaction mixture was concentrated under reduced pressure and the residue was dissolved in dichloromethane. The resulting solution was washed with water. The organic layer so separated was dried over anhydrous sodium sulfate. The solvent was then distilled off under reduced pressure. The residue was purified by chromatography on a silica gel column (dichloromethane˜dichloromethane:methanol=100:15), whereby the title compound (7.95 g, 76%) was obtained.
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[CH3:11][C:12]1[C:22](C(O)=O)=[N:21][C:20]2[C:19]3[S:26][CH:27]=[CH:28][C:18]=3[CH2:17][CH2:16][O:15][C:14]=2[CH:13]=1.CC[O:31]C(C)=O>C1(C)C=CC=CC=1>[OH:31][CH2:11][C:12]1[CH:22]=[N:21][C:20]2[C:19]3[S:26][CH:27]=[CH:28][C:18]=3[CH2:17][CH2:16][O:15][C:14]=2[CH:13]=1
Reactant: Cc1cc2c(nc1C(=O)O)-c1sccc1CCO2
Reactant: CCOC(C)=O
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Product: OCc1cnc2c(c1)OCCc1ccsc1-2
Temperature: 0 °C

Procedure:
To a solution of 1.00 M of diisobutylaluminum hydride in toluene (4.02 mL) at 0° C. was added 3-methylcarboxy-6,7-dihydropyrido[3,2-b]thieno[2,3-d]oxepine (0.420 g, 1.61 mmol) in toluene (17.8 mL, 167 mmol). The reaction mixture was stirred at 0° C. 2 h. The reaction is diluted with EtOAc then quenched with 1M HCl. The organic layer was dried Na2SO4, concentrated to give 3-hydroxymethyl-6,7-dihydropyrido[3,2-b]thieno[2,3-d]oxepine which was dissolved in triethylamine (0.336 mL, 2.41 mmol) and N,N-dimethylformamide (10.5 mL, 136 mmol). Tert-butyldimethylsilyl chloride (0.291 g, 1.93 mmol) was added. The reaction was stirred at room temperature 20 min. The reaction was diluted with EtOAc then wash with water and brine, dried and concentrated to give 3-tert-butyldimethylsilyloxymethyl-6,7-dihydropyrido[3,2-b]thieno[2,3-d]oxepine which was dissolved in DCM/Acetic acid at 0° C. N-Bromosuccinimide (315 mg, 1.77 mmol) was added. The reaction was stirred overnight at room temperature. The reaction was concentrated and purified by flash chromatography (EtOAc/Hex) (eluted 10%) to give 3-tert-butyldimethylsilyloxymethyl-9-bromo-6,7-dihydropyrido[3,2-b]thieno[2,3-d]oxepine (61.3% yield). MS: (ESI+) 426.1
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:22][CH2:23][CH3:24])[N:14]([CH2:15][C:16]3([OH:21])[CH2:20][CH2:19][CH2:18][CH2:17]3)[C:10]=2[C:9]2[N:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1.FC(F)(F)C(O)=O>[Pt]=O>[NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:22][CH2:23][CH3:24])[N:14]([CH2:15][C:16]3([OH:21])[CH2:17][CH2:18][CH2:19][CH2:20]3)[C:10]=2[C:9]2[NH:8][CH2:7][CH2:6][CH2:5][C:4]=2[N:3]=1
Reactant: CCCc1nc2c(N)nc3cccnc3c2n1CC1(O)CCCC1
Agent: O=[Pt]
Solvent: O=C(O)C(F)(F)F
Product: CCCc1nc2c(N)nc3c(c2n1CC1(O)CCCC1)NCCC3
Temperature: 25 °C
Reaction time: 2 h
Yield: 32.3 %

Procedure:
A mixture of 1-[(4-amino-2-propyl-1H-imidazo[4,5-c][1,5]napthyridin-1-yl)methyl]cyclopentanol (511 mg), platinum oxide (511 mg), and trifluoroacetic acid was placed under hydrogen pressure (50 psi, 3.4×105 Pa) overnight on a Parr apparatus. The mixture was filtered through a layer of CELITE filter aid and the filter cake was rinsed with methanol. The filtrate was concentrated under reduced pressure. The residue was combined with concentrated hydrochloric acid (2 mL) and stirred at ambient temperature for 2 hours. The mixture was diluted with water (10 mL) and then cooled to 0° C. The pH was adjusted to 12 with 6N sodium hydroxide and then the mixture was extracted with dichloromethane (3×50 mL). The combined organics were washed with brine (20 mL), dried over sodium sulfate, filtered, and then concentrated under reduced pressure. The residue was triturated with acetonitrile, purified by HPFC eluting with a gradient of 0-35% CMA in chloroform, and then triturated with acetonitrile to provide 167 mg of 1-[(4-amino-2-propyl-6,7,8,9-tetrahydro-1H-imidazo[4,5-c][1,5]napthyridin-1-yl)methyl]cyclopentanol as a white powder, mp 207.0-208.0° C. Anal. Calcd for C18H27N5O.0.25H2O C, 64.74; H, 8.30; N, 20.97. Found: C, 64.71; H, 8.29; N, 20.98.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([N+:18]([O-:20])=[O:19])[CH:5]=[C:6]([CH3:17])[C:7]=1[O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=1.[Br:21]N1C(=O)CCC1=O.FC(F)(F)C(O)=O>C(Cl)(Cl)Cl>[Br:21][C:13]1[CH:14]=[C:9]([CH:10]=[CH:11][C:12]=1[O:15][CH3:16])[O:8][C:7]1[C:6]([CH3:17])=[CH:5][C:4]([N+:18]([O-:20])=[O:19])=[CH:3][C:2]=1[CH3:1]
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1ccc(Oc2c(C)cc([N+](=O)[O-])cc2C)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClC(Cl)Cl
Product: COc1ccc(Oc2c(C)cc([N+](=O)[O-])cc2C)cc1Br
Yield: 97.2 %

Procedure:
To a solution of 3,5-dimethyl-4-(4′-methoxyphenoxy)nitrobenzene (4.0 g) (J. Med. Chem. 1995, 38, 703) in chloroform (150 ml) were added N-bromosuccinimide (2.6 g) and trifluoroacetic acid (1.1 ml), and the resulting mixture was heated under reflux for 90 min. Additional portions of N-bromosuccinimide (2.6 g) and trifluoroacetic acid (1.1 ml) were added, followed by further heating for 18 h. The reaction was washed with sodium bicarbonate, dried (Na2SO4) and concentrated to afford the title compound as an orange solid (5.0 g). MS Calc: 351; Found: 352 (M+1).
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:9]([C:10]2[NH:11][C:12](=[O:28])[C:13]3[C:14](=[C:16]([CH2:26][CH3:27])[N:17]([CH2:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=4)[N:18]=3)[N:15]=2)=[CH:8][C:7]([S:29]([N:32]2[CH2:37][CH2:36][N:35]([CH2:38][CH3:39])[CH2:34][CH2:33]2)(=[O:31])=[O:30])=[CH:6][N:5]=1)[CH3:2].C[Si]([N-][Si](C)(C)C)(C)C.[K+].[CH2:50](O)[CH2:51]CC>>[CH2:1]([O:3][C:4]1[C:9]([C:10]2[NH:11][C:12](=[O:28])[C:13]3[C:14](=[C:16]([CH2:26][CH3:27])[N:17]([CH2:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=4)[N:18]=3)[N:15]=2)=[CH:8][C:7]([S:29]([N:32]2[CH2:37][CH2:36][N:35]([CH2:38][CH3:39])[CH2:34][CH2:33]2)(=[O:30])=[O:31])=[CH:6][N:5]=1)[CH2:2][CH2:50][CH3:51]
Reactant: CCCCO
Reactant: CCOc1ncc(S(=O)(=O)N2CCN(CC)CC2)cc1-c1nc2c(CC)n(Cc3ccccn3)nc2c(=O)[nH]1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Product: CCCCOc1ncc(S(=O)(=O)N2CCN(CC)CC2)cc1-c1nc2c(CC)n(Cc3ccccn3)nc2c(=O)[nH]1
Temperature: 100 °C
Reaction time: 18 h
Yield: 69 %

Procedure:
A mixture of the title compound of Example 1 (200 mg, 0.36 mmol), potassium bis(trimethylsilyl)amide (360 mg, 1.81 mmol) and n-butanol (5 ml) was stirred at 100° C. for 18 hours, then allowed to cool. The resulting mixture was evaporated under reduced pressure and the residue partitioned between water (5 ml) and dichloromethane (5 ml). The phases were separated and the aqueous layer extracted with dichloromethane (2×10 ml), then the combined organic solutions dried (MgSO4) and evaporated under reduced pressure. The residual yellow solid was purified by column chromatography on silica gel, using dichloromethane: methanol (97.5:2.5) as eluant, to yield the title compound (145 mg, 69%) as a white solid. Found: C, 57.43; H, 6.29; N, 18.82. C28H36N8O4S; 0.20 H2O requires C, 57.56; H, 6.28; N, 19.18%. δ (CDCl3): 1.03 (6H,2xt), 1.30 (3H,t), 1.55 (2H,m), 1.94 (2H,m), 2.40 (2H,q), 2.55 (4H,m), 3.03 (2H,q), 3.13 (4H,m), 4.67 (2H,t), 5.68 (2H,s), 7.10 (1H,d), 7.22 (1H,m), 7.62 (1H,m), 8.56 (1H,d), 8.62 (1H,s), 9.01 (1H,s), 10.64 (1H,s). LRMS: m/z 581 (M+1)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([S:9](Cl)(=[O:11])=[O:10])[CH:5]=[CH:6][C:7]=1[F:8].C(Cl)Cl.[OH-].[NH4+:17].Cl>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([S:9]([NH2:17])(=[O:11])=[O:10])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: [NH4+]
Reactant: O=S(=O)(Cl)c1ccc(F)c(Br)c1
Agent: Cl
Agent: [OH-]
Solvent: ClCCl
Solvent: C1CCOC1
Product: NS(=O)(=O)c1ccc(F)c(Br)c1
Temperature: 0 °C
Reaction time: 3.5 h
Yield: 60 %

Procedure:
A solution of 3-bromo-4-fluorobenzenesulfonyl chloride (1 g, 3.3 mmol, 90% pure) stirred at 0° C. in THF (15 ml) and DCM (5 ml) was treated with aqueous ammonium hydroxide (28%) by dropwise addition over 15 min. After stirring at 0° C. for 210 min, the mixture was acidified (pH=1) by addition of 1 N HCl (aq). After the mixture was concentrated in vacuo to near dryness, it was treated with water (50 ml), sonicated for 3 min and filtered. After the filter cake was washed sequentially with water (50 ml) and hexanes (100 ml), it was dried in vacuo to afford the title compound (503 mg, 60%) as a white solid which was carried forward without purification. LCMS (M−H)−=253.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[NH:9][N:8]=2)[CH2:3][CH2:2]1.Cl[CH2:17][CH2:18][CH2:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([C:27](=[O:29])[CH3:28])=[CH:23][C:22]=1[O:30][CH3:31].C(#N)C>O>[NH:9]1[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:7]([CH:4]2[CH2:3][CH2:2][N:1]([CH2:17][CH2:18][CH2:19][O:20][C:21]3[CH:26]=[CH:25][C:24]([C:27](=[O:29])[CH3:28])=[CH:23][C:22]=3[O:30][CH3:31])[CH2:6][CH2:5]2)=[N:8]1
Reactant: COc1cc(C(C)=O)ccc1OCCCCl
Reactant: c1ccc2c(C3CCNCC3)n[nH]c2c1
Solvent: O
Solvent: CC#N
Product: COc1cc(C(C)=O)ccc1OCCCN1CCC(c2n[nH]c3ccccc23)CC1
Yield: 83.4 %

Procedure:
A mixture of 3-(4-piperidinyl)-1H-indazole (3.0 g, 15 mmol), K2 CO3 (1.6 g), 1-[4-(3-chloropropoxy)-3-methoxyphenyl]ethanone (5.3 g, 22 mmol), a few crystals of KI and acetonitrile (100 ml) was stirred and refluxed for 16 hours. The reaction was poured into water and a white solid separated from solution. The solid was collected, dried and afforded 5.1 g of product. Recrystallization from ethanol yielded 3.6 g of the compound, which upon chromatography (preparative HPLC on silica gel, eluting with methylene chloride/methanol--9:1) gave 3.0 g (49%) of an off-white solid. Recrystallization from ethanol afforded the analytically pure 1-[4-[3-[4-(1H-indazol-1 3-yl)-1-piperidinyl]-propoxy]-3-methoxyphenyl]ethanone as a white solid, m.p.=171°-173° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][CH2:18][N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)=[CH:11][CH:10]=2)[C:5]([F:25])=[CH:4][N:3]=1.[CH3:26][O:27][C:28]1[CH:29]=[C:30]([CH:32]=[CH:33][C:34]=1[O:35][CH3:36])[NH2:31]>>[CH3:26][O:27][C:28]1[CH:29]=[C:30]([NH:31][C:2]2[N:7]=[C:6]([NH:8][C:9]3[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][CH2:18][N:19]4[CH2:24][CH2:23][O:22][CH2:21][CH2:20]4)=[CH:11][CH:10]=3)[C:5]([F:25])=[CH:4][N:3]=2)[CH:32]=[CH:33][C:34]=1[O:35][CH3:36]
Reactant: Fc1cnc(Cl)nc1Nc1ccc(OCCCN2CCOCC2)cc1
Reactant: COc1ccc(N)cc1OC
Product: COc1ccc(Nc2ncc(F)c(Nc3ccc(OCCCN4CCOCC4)cc3)n2)cc1OC

Procedure:
In like manner to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine, the reaction of 2-chloro-5-fluoro-N4-[4-[3-(N-morpholinyl)propyl]oxyphenyl]-4-pyrimidineamine with 3,4-dimethoxyaniline gave N2-(3,4-dimethoxyphenyl)-5-fluoro-N4-[4-[3-(N-morpholinyl)propyl]oxyphenyl]-2,4-pyrimidinediamine. LCMS: retn, time: 14.72 min.; purity: 94%; MS (m/e): 484 (MH+); 1H NMR (CDCl3): δ 7.89 (1H, d, J=3.3 Hz), 7.47 (2H, d, J=9 Hz), 7.22 (1H, d, J=2.2 Hz), 6.93-6.76 (5H, m), 6.64 (1H, d, J=2.2 Hz), 4.01 (2H, t, J=5.6 Hz), 3.86 (3H, s), 3.72 (3H, s), 3.71 (4H, m), 2.58-2.44 (6H, m), 1.97 (2H, m).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]2=[N:6][C:7](=[O:9])[N:8]=[C:4]2[CH:3]=1.C([O-])(=O)C.[Na+].[OH:17][C:18]1[C:19]([C:28](Cl)=[O:29])=[CH:20][C:21]2[C:26]([CH:27]=1)=[CH:25][CH:24]=[CH:23][CH:22]=2.OC1C(C(O)=O)=CC2C(C=1)=CC=CC=2>ClC1C=CC=CC=1.CN(C=O)C>[OH:17][C:18]1[C:19]([C:28]([NH:1][C:2]2[CH:11]=[CH:10][C:5]3=[N:6][C:7](=[O:9])[N:8]=[C:4]3[CH:3]=2)=[O:29])=[CH:20][C:21]2[C:26]([CH:27]=1)=[CH:25][CH:24]=[CH:23][CH:22]=2
Reactant: O=C(Cl)c1cc2ccccc2cc1O
Reactant: Nc1ccc2c(c1)=NC(=O)N=2
Agent: CC(=O)[O-]
Agent: O=C(O)c1cc2ccccc2cc1O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: Clc1ccccc1
Product: O=C1N=c2ccc(NC(=O)c3cc4ccccc4cc3O)cc2=N1
Temperature: 20 °C
Reaction time: 3 h
Yield: 82.1 %

Procedure:
75.0 g (0.5 mol) of 5-aminobenzimidazolone and 41 g of anhydrous sodium acetate are initially introduced into 700 ml of N,N'-dimethylformamide and 776.8 g of 3-hydroxy-2-naphthoyl chloride (from 99.0 g (0.52 mol) of 3-hydroxy-2-naphthoic acid) in chlorobenzene are metered in at 5°-10° C. in the course of 30 min. After addition is complete, the mixture is subsequently stirred at 20° C. for 3 h, warmed to 50° C. and filtered. The filter cake does not filter off with suction very well (suction time: 14 h). For purification, the filter cake is taken up in 1 ml of methanol, the mixture is stirred and filtered off with suction, and the filter cake is washed with 250 ml of methanol and subsequently several times with a total of 1 l of boiling water. After drying, 130.3 g of 3-hydroxy-N-benzimidazolon-5-yl-2-naphthamide are obtained; this corresponds to 81.7% of theory.
Reaction SMILES: [CH3:1][C:2](/[CH:4]=[N:5]/[OH:6])=O.[F:7][C:8]([F:18])([F:17])[C:9]1[CH:14]=[CH:13][C:12]([NH:15][NH2:16])=[CH:11][CH:10]=1.C(OCC)(=O)C>C(OCC)C.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Cu+2]>[CH3:1][C:2]1[CH:4]=[N+:5]([O-:6])[N:15]([C:12]2[CH:13]=[CH:14][C:9]([C:8]([F:7])([F:18])[F:17])=[CH:10][CH:11]=2)[N:16]=1
Reactant: NNc1ccc(C(F)(F)F)cc1
Reactant: CC(=O)/C=N/O
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Solvent: CCOCC
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1c[n+]([O-])n(-c2ccc(C(F)(F)F)cc2)n1
Temperature: 23 °C
Reaction time: 2 h
Yield: 78.2 %

Procedure:
To a stirred solution of anti-pyruvic aldehyde 1-oxime (2.67 g, 30.7 mmol) in diethyl ether (50 mL) was added 4-(trifluoromethyl)phenylhydrazine (5.40 g, 30.7 mmol). The reaction mixture was stirred at 23° C. for 2 h, then concentrated under reduced pressure. The crude residue was dissolved in 15% aqueous pyridine (150 mL). A solution of copper(II) sulfate pentahydrate (15.31 g, 61.3 mmol) in water (75 mL) was added at once. The resulting mixture was stirred at reflux for 17 h, then cooled to 0° C. Ethyl acetate (100 mL) was added and the mixture was filtered through Celite® diatomaceaous filter aid. The layers were separated, and the aqueous layer was extracted with ethyl acetate (2×100 mL). The combined organic layers were washed with 1.0 M aqueous hydrochloric acid (3×50 mL). The organic layer was dried (MgSO4), filtered, and evaporated under reduced pressure. The residue was purified by chromatography on silica gel, eluting with 0 to 50% ethyl acetate in hexanes, to afford the title compound (5.84 g) as a colorless solid.
Reaction SMILES: Cl[C:2]1[C:7]2[CH2:8][N:9]([CH:12]([C:14]3[CH:19]=[C:18]([CH3:20])[C:17]([O:21][CH2:22][C:23]([F:26])([F:25])[F:24])=[CH:16][N:15]=3)[CH3:13])[C:10](=[O:11])[C:6]=2[CH:5]=[CH:4][N:3]=1.[CH:27]([O:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:28]>>[CH3:20][C:18]1[C:17]([O:21][CH2:22][C:23]([F:26])([F:25])[F:24])=[CH:16][N:15]=[C:14]([CH:12]([N:9]2[C:10](=[O:11])[C:6]3[CH:5]=[CH:4][N:3]=[C:2]([C:27]([O:29][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)=[O:28])[C:7]=3[CH2:8]2)[CH3:13])[CH:19]=1
Reactant: Cc1cc(C(C)N2Cc3c(ccnc3Cl)C2=O)ncc1OCC(F)(F)F
Reactant: O=COc1ccccc1
Product: Cc1cc(C(C)N2Cc3c(ccnc3C(=O)Oc3ccccc3)C2=O)ncc1OCC(F)(F)F
Yield: 63 %

Procedure:
The title compound is prepared in 63% yield (120 mg, yellow oil) from 4-chloro-2-(1-(4-methyl-5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (150 mg, 0.40 mmol, Intermediate-66, single enantiomer) and phenyl formate (95 mg, 0.78 mmol) in a similar manner to Intermediate-91.
Reaction SMILES: N[C@@H:2]([CH2:6][CH:7]([CH3:9])[CH3:8])[C:3]([OH:5])=O.[CH:10]1([NH:17][C:18]([NH2:20])=[S:19])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1>>[CH:10]1([NH:17][C:18]2[S:19][CH:2]([CH2:6][CH:7]([CH3:9])[CH3:8])[C:3](=[O:5])[N:20]=2)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: CC(C)C[C@H](N)C(=O)O
Reactant: NC(=S)NC1CCCCCC1
Product: CC(C)CC1SC(NC2CCCCCC2)=NC1=O

Procedure:
Synthesis was performed from (2S)-2-amino-4-methylpentanoic acid and N-cycloheptylthiourea according to Method E and C.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4]([Cl:11])[N:3]=1.[C:12]([O:20][CH2:21][CH2:22][O:23][CH2:24]Cl)(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH2:24][O:23][CH2:22][CH2:21][O:20][C:12](=[O:19])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:4]([Cl:11])[N:3]=1
Reactant: Clc1nc(Cl)c2[nH]cnc2n1
Reactant: O=C(OCCOCCl)c1ccccc1
Product: O=C(OCCOCn1cnc2c(Cl)nc(Cl)nc21)c1ccccc1
Yield: 41 %

Procedure:
Following the procedure of Example 1, 2,6-dichloropurine was condensed with 1-benzoyloxy-2-chloromethoxyethane to give a 41% yield of 2,6-dichloro-9-(2-benzoyloxy ethoxymethyl)purine, m.p. 121°-125° C. This was treated according to the procedure of Example 2 to give simultaneous ammonolysis of the 6-chloro and benzoyloxy groups yielding 2-chloro-9-(hydroxyethoxymethyl)adenine, in 94% yield, m.p. 188°-190° C. after recrystallization from isopropanol.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]([CH2:6][NH:7][C:8]([C:10]2([C:13]([F:16])([F:15])[F:14])[CH2:12][CH2:11]2)=[O:9])=[CH:4][C:3]=1[N:19]=[C:20]=S.[Cl:22][C:23]1[C:24]([N:32]2[CH2:37][CH2:36][CH:35]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[CH2:34][CH2:33]2)=[CH:25][C:26]([NH:30][CH3:31])=[C:27]([CH:29]=1)[NH2:28].CC(C)N=C=NC(C)C>CN(C=O)C.O>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]([CH2:6][NH:7][C:8]([C:10]2([C:13]([F:16])([F:15])[F:14])[CH2:12][CH2:11]2)=[O:9])=[CH:4][C:3]=1[NH:19][C:20]1[N:30]([CH3:31])[C:26]2[CH:25]=[C:24]([N:32]3[CH2:37][CH2:36][CH:35]([C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=4)[CH2:34][CH2:33]3)[C:23]([Cl:22])=[CH:29][C:27]=2[N:28]=1
Reactant: O=C(NCc1ccc(Cl)c(N=C=S)c1)C1(C(F)(F)F)CC1
Reactant: CNc1cc(N2CCC(c3ccccc3)CC2)c(Cl)cc1N
Agent: CC(C)N=C=NC(C)C
Solvent: O
Solvent: CN(C)C=O
Product: Cn1c(Nc2cc(CNC(=O)C3(C(F)(F)F)CC3)ccc2Cl)nc2cc(Cl)c(N3CCC(c4ccccc4)CC3)cc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of N-(4-chloro-3-isothiocyanatobenzyl)-1-(trifluoromethyl)cyclopropane carboxamide (200 mg; 0.60 mmol) and 5-chloro-2-methylamino-4-(4-phenyl-piperidin-1-yl)aniline (190 mg; 0.60 mmol) in DMF (4 mL) was stirred overnight at rt. DIC (76 mg; 0.60 mmol) was added and the mixture was heated at 90° C. for 1.5 h. The mixture was poured in water, extracted with EtOAc and the combined organic layer was dried over Na2SO4, filtered and concentrated and the residue was purified by column chromatography.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[CH2:9][S:10]([C:12]1[C:17]([CH3:18])=[CH:16][CH:15]=[CH:14][N+:13]=1[O-:19])=[O:11].[OH-:20].[Na+].[CH3:22]I>CN(C)C=O>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[CH:9]([S:10]([C:12]1[C:17]([CH3:18])=[CH:16][CH:15]=[CH:14][N+:13]=1[O-:19])(=[O:20])=[O:11])[CH3:22]
Reactant: CI
Reactant: [OH-]
Reactant: Cc1ccc(C)c(CS(=O)c2c(C)ccc[n+]2[O-])c1
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(C)c(C(C)S(=O)(=O)c2c(C)ccc[n+]2[O-])c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred suspension of 3 g (0.01 mol) of sulfone (described in Example 3) in 15 mL of dry dimethylformamide cooled in an ice bath, is added 0.5 g sodium hydroxide powder. To this mixture is slowly added 0.75 mL methyl iodide. The reaction mixture is warmed to room temperature and stirred for 2 hours. 100 mL ice-water is slowly added with stirring. After filtration the white solid is recrystallized from toluene. Melting point: 146°-147° C. Structure confirmed by NMR. I.R. N→O 1250 cm-1, SO2 1350, 1140 cm-1.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][C:8](=O)[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[C-:12]#[N:13].[K+].Cl.[NH:16]1[CH2:19][CH2:18][CH2:17]1>O.CO>[N:16]1([C:8]2([C:12]#[N:13])[CH2:9][CH2:10][C:5]3([O:4][CH2:3][CH2:2][O:1]3)[CH2:6][CH2:7]2)[CH2:19][CH2:18][CH2:17]1
Reactant: O=C1CCC2(CC1)OCCO2
Reactant: C1CNC1
Reactant: [C-]#N
Agent: Cl
Agent: [K+]
Solvent: CO
Solvent: O
Product: N#CC1(N2CCC2)CCC2(CC1)OCCO2
Temperature: 25 °C
Reaction time: 120 h

Procedure:
1,4-Dioxaspiro[4,5]decan-8-one (4.84 g, 31 mmol) followed by potassium cyanide (4.85 g, 74.4 mmol) in water (15 ml) were added with ice cooling to a mixture of 4 N hydrochloric acid (8.1 ml), methanol (4.9 ml) and azetidine (8.5 g, 10 ml, 149 mmol). The mixture was stirred at room temperature for 5 days, then water (50 ml) was added and the mixture was extracted with diethyl ether (3×50 ml). The combined organic phases were dried with sodium sulfate and concentrated to small volume under vacuum. Yield: 6.77 g (98%), oil
Reaction SMILES: C1CCC(N=C=NC2CCCCC2)CC1.C(Cl)Cl.[Br:19][C:20]1[CH:28]=[CH:27][CH:26]=[CH:25][C:21]=1[C:22]([OH:24])=[O:23].[C:29](O)([CH3:32])([CH3:31])[CH3:30]>CN(C1C=CN=CC=1)C>[C:29]([O:23][C:22](=[O:24])[C:21]1[CH:25]=[CH:26][CH:27]=[CH:28][C:20]=1[Br:19])([CH3:32])([CH3:31])[CH3:30]
Reactant: O=C(O)c1ccccc1Br
Reactant: CC(C)(C)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)c1ccccc1Br
Temperature: 25 °C
Reaction time: 16 h
Yield: 101.8 %

Procedure:
To a solution of DCC (32.8 g, 159 mmol) in DCM (200 mL, 2 mol) was added 2-bromobenzoic acid (32.0 g, 159 mmol) followed by DMAP (1.8 g, 15 mmol) and t-butyl alcohol (15.2 mL, 159 mmol). The mixture was stirred at room temperature for 16 hours, then filtered. The organic was washed with saturated NaHCO3 (200 mL), saturated aqueous NaCl, dried over MgSO4, filtered and concentrated under reduced pressure to yield compound A as an oil (41.6 g).