Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]([CH:9]([C:13]1[N:22]([CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:21](=[O:30])[C:20]2[C:15](=[CH:16][C:17]([Cl:31])=[CH:18][CH:19]=2)[N:14]=1)[CH:10]([CH3:12])[CH3:11])[C:5](=[O:8])[CH:6]=[CH2:7].C(OC(=O)NCCN(C(=O)C=C)C(C1N(CC2C=CC=CC=2)C(=O)C2C(=CC(Cl)=CC=2)N=1)C(C)C)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:23]([N:22]1[C:21](=[O:30])[C:20]2[C:15](=[CH:16][C:17]([Cl:31])=[CH:18][CH:19]=2)[N:14]=[C:13]1[CH:9]([N:4]1[C:5](=[O:8])[CH2:6][CH2:7][NH:1][CH2:2][CH2:3]1)[CH:10]([CH3:12])[CH3:11])[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: C=CC(=O)N(CCN)C(c1nc2cc(Cl)ccc2c(=O)n1Cc1ccccc1)C(C)C
Agent: C=CC(=O)N(CCNC(=O)OC(C)(C)C)C(c1nc2cc(Cl)ccc2c(=O)n1Cc1ccccc1)C(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)C(c1nc2cc(Cl)ccc2c(=O)n1Cc1ccccc1)N1CCNCCC1=O

Procedure:
N-(2-Amino-ethyl)—N-[1-(3-benzyl-7-chloro-4-oxo-3,4-dihydro-quinazolin-2-yl)-2-methyl-propyl]-acrylamide: (2-{Acryloyl-[1-(3-benzyl-7-chloro-4-oxo-3,4-dihydro-quinazolin-2-yl)-2-methyl-propyl]-amino}-ethyl)-carbamic acid tert-butyl ester (300 mg, 0.56 mmol) was treated with 50% TFA in CH2Cl2 (3 mL at room temperature. After 2 h the mixture was concentrated under vacuum, redissolved in CH2Cl2, washed with 10% NaHCO3, brine, dried and concentrated to give the title compound (240 mg) as a white solid: MS (ES) m/e 439.2 (M+H)+.
Reaction SMILES: Cl.[OH:2][C:3]12[CH2:36][CH2:35][C@@:34]3([CH3:37])[C:29](=[C:30]([CH3:38])[CH2:31][CH2:32][CH2:33]3)[C@H:4]1[O:5][C:6](=[O:28])[CH:7]2[CH2:8][NH:9][CH2:10][CH:11]1[C:15](=[O:16])[O:14][C@H:13]2[C:17]3[C@@:22]([CH3:25])([CH2:23][CH2:24][C:12]12[OH:27])[CH2:21][CH2:20][CH2:19][C:18]=3[CH3:26].[C:39](OC(=O)C)(=[O:41])[CH3:40]>C(#N)C>[OH:2][C:3]12[CH2:36][CH2:35][C@:34]3([CH3:37])[C:29](=[C:30]([CH3:38])[CH2:31][CH2:32][CH2:33]3)[C@@H:4]1[O:5][C:6](=[O:28])[CH:7]2[CH2:8][N:9]([CH2:10][CH:11]1[C:15](=[O:16])[O:14][C@@H:13]2[C:17]3[C@:22]([CH3:25])([CH2:23][CH2:24][C:12]12[OH:27])[CH2:21][CH2:20][CH2:19][C:18]=3[CH3:26])[C:39](=[O:41])[CH3:40]
Reactant: CC1=C2[C@H]3OC(=O)C(CNCC4C(=O)O[C@H]5C6=C(C)CCC[C@]6(C)CCC45O)C3(O)CC[C@]2(C)CCC1
Reactant: CC(=O)OC(C)=O
Agent: Cl
Solvent: CC#N
Product: CC(=O)N(CC1C(=O)O[C@@H]2C3=C(C)CCC[C@@]3(C)CCC12O)CC1C(=O)O[C@H]2C3=C(C)CCC[C@]3(C)CCC12O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The compound obtained in step 1 of example 55 (200 mg, 0.389 mmole) was dissolved in dry acetonitrile (4 mL) and to it acetic anhydride (43.78 mg, 0.426 mmole) and TEA (59.04 mg, 0.58 mmole) were added. The reaction mixture was stirred at room temperature (25° C.) for 2 hours. Reaction mixture was concentrated and crude product was purified by column chromatography (silica gel, 30% ethyl acetate in petroleum ether) to obtain the title compound.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[N:8]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=2)[C:7](=[O:19])[NH:6][C:5]=1[C:20]1[N:24]([C:25]2[CH:32]=[CH:31][C:28]([C:29]#[N:30])=[CH:27][CH:26]=2)[N:23]=[CH:22][CH:21]=1.Cl[C:34]([O:36][CH2:37][CH3:38])=[O:35].O>CN(C=O)C>[CH2:37]([O:36][C:34]([N:6]1[C:5]([C:20]2[N:24]([C:25]3[CH:26]=[CH:27][C:28]([C:29]#[N:30])=[CH:31][CH:32]=3)[N:23]=[CH:22][CH:21]=2)=[C:4]([CH3:3])[N:8]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=2)[C:7]1=[O:19])=[O:35])[CH3:38]
Reactant: Cc1c(-c2ccnn2-c2ccc(C#N)cc2)[nH]c(=O)n1-c1cccc(C(F)(F)F)c1
Reactant: CCOC(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)n1c(-c2ccnn2-c2ccc(C#N)cc2)c(C)n(-c2cccc(C(F)(F)F)c2)c1=O
Reaction time: 0.08 h
Yield: 55.2 %

Procedure:
Sodium hydride (38 mg of a 60% dispersion in mineral oil, 0.95 mmol) was added to a solution of 4-(5-{5-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-2,3-dihydro-1H-imidazol-4-yl}-1H-pyrazol-1-yl)benzonitrile (Example 1) (300 mg, 0.73 mmol) in DMF under a nitrogen atmosphere. The mixture was stirred for 5 minutes and the resultant yellow solution was treated with ethyl chloroformate (104 mg, 0.091 mL, 0.95 mmol). The mixture was stirred for 1 h then treated with water and extracted with EtOAc. The organic phase was washed with water and brine then dried (sodium sulfate) and concentrated in vacuo. The residue was purified by chromatography using silica gel eluting with 25%-50% ethyl acetate in cyclohexane. The product thus obtained was freeze-dried from acetonitrile-water to afford the title compound (194 mg) a white solid.
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: CCn1nnc([C@H]2O[C@@H](n3cnc4c(Cl)nc(Cl)nc43)[C@H](OC(C)=O)[C@@H]2OC(C)=O)n1
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
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:1]1([CH3:11])[CH:6]=[CH:5][C:4](S(Cl)(=O)=O)=[CH:3][CH:2]=1.O.N1C=C[CH:16]=[CH:15][CH:14]=1>>[CH2:5]1[C:6]2[C:1](=[CH:11][CH:14]=[CH:15][CH:16]=2)[CH2:2][CH2:3][CH2:4]1
Reactant: c1ccncc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: O
Product: c1ccc2c(c1)CCCC2
Reaction time: 15 h

Procedure:
To a solution of the above compound (11 g; 57.6 mmol) in pyridine (20 ml) at 0° C. was added, dropwise a solution of p-toluenesulfonyl chloride (11 g; 57.7 mmol) in pyridine (20 ml). The mixture was left at ambient temperature for 15 hours, then poured into water and extracted with CH2Cl2. The organic phase was washed with 2N HCl and 0.5N NaHC3, dried over MgSO4 and evaporated to give -methoxy-1-tosyloxyimino-,1,2,3,4-tetrahydronaphthalene as a brown solid (16 g; 100%).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[S:4][CH:5]=[C:6]([C:8](=[O:11])[CH2:9]Br)[N:7]=1.[OH:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH:22]([NH:24][CH2:25][CH2:26]O)[CH3:23])=[CH:17][CH:16]=1>>[OH:14][C:15]1[CH:16]=[CH:17][C:18]([CH2:21][CH:22]([N:24]2[CH2:25][CH2:26][O:11][CH:8]([C:6]3[N:7]=[C:3]([C:2]([F:13])([F:12])[F:1])[S:4][CH:5]=3)[CH2:9]2)[CH3:23])=[CH:19][CH:20]=1
Reactant: O=C(CBr)c1csc(C(F)(F)F)n1
Reactant: CC(Cc1ccc(O)cc1)NCCO
Product: CC(Cc1ccc(O)cc1)N1CCOC(c2csc(C(F)(F)F)n2)C1

Procedure:
Prepared by analogy to Example 22 by reaction of 2-trifluoromethyl-4-bromoacetyl-thiazole with N-[2-(4-hydroxyphenyl)-1-methylethyl]-2-hydroxyethanamine followed by purification of the base on a silica gel column using chloroform/ethyl acetate=3:1 as eluant.
Reaction SMILES: C1([C@H]2[C@H](C3C4C(=CC=CC=4)NC=3)C(=O)NC2=O)C2=C3C(=CC=C2)CCCN3C=1.[NH:29]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:31]=[CH:30]1.[Br:38][C:39]1[C:40](=[O:52])[N:41]([C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)[C:42](=[O:45])[C:43]=1Br.C[Mg]Br>>[Br:38][C:39]1[C:40](=[O:52])[N:41]([C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)[C:42](=[O:45])[C:43]=1[C:31]1[C:32]2[C:37](=[CH:36][CH:35]=[CH:34][CH:33]=2)[NH:29][CH:30]=1
Reactant: c1ccc2[nH]ccc2c1
Reactant: O=C1C(Br)=C(Br)C(=O)N1c1ccccc1
Agent: C[Mg]Br
Agent: O=C1NC(=O)[C@@H](c2cn3c4c(cccc24)CCC3)[C@@H]1c1c[nH]c2ccccc12
Product: O=C1C(Br)=C(c2c[nH]c3ccccc23)C(=O)N1c1ccccc1

Procedure:
(±)-Trans-3-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-4(1H-indol-3-yl)pyrrolidine-2,5-dione may be prepared by reacting 1H-indole and 3,4-dibromo-1-phenyl-pyrrole-2,5-dione in the presence of methyl magnesium bromide to yield 3-bromo-4-(1H-indol-3-yl)-1-phenyl-pyrrole-2,5-dione. The 3-bromo-4-(1H-indol-3-yl)-1-phenyl-pyrrole-2,5-dione is subsequently reacted with 5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinoline and LiHMDS (lithium hexamethyldisilane) in toluene or (5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-boranediol and Pd(PPh3)4(tetrakis(triphenylphosphine)palladium) to yield 3-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)-1-phenyl-pyrrole-2,5-dione, which is reduced and deprotected by treatment with Mg in methanol, as in Example 2 procedure C, followed by catalytic hydrogenation over palladium on carbon to yield (±)-trans-3-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-4(1H-indol-3-yl)pyrrolidine-2,5-dione. Bnz is benzyl.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]([S:8]([CH3:11])(=[O:10])=[O:9])=[CH:6][CH:7]=1.[N:12]([O-])=O.[Na+].O.O.[Sn](Cl)[Cl:19].[OH-].[Na+]>Cl.O.O1CCCC1>[ClH:19].[NH:1]([C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH3:11])(=[O:10])=[O:9])=[N:4][CH:3]=1)[NH2:12]
Reactant: Cl[Sn]Cl
Reactant: O=N[O-]
Reactant: CS(=O)(=O)c1ccc(N)cn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CS(=O)(=O)c1ccc(NN)cn1
Temperature: -7.5 °C
Reaction time: 2 h
Yield: 66.2 %

Procedure:
To a solution of 3-amino-6-(methylsulfonyl)pyridine (3.72 g, 21.6 mmol) in concentrated hydrochloric acid (30 mL), sodium nitrite (1.78 g, 25.7 mmol) in water (20 mL) was added dropwise at −10 to −15° C. and the mixture was stirred for 2 hours at −10 to −5° C. (note: the reaction was monitored by thin layer chromatography to make sure all the starting material was consumed). Tin(II) chloride dihydrate (20 g, 88.6 mmol) in concentrated hydrochloric acid (30 mL) was added dropwise at −5° C. The mixture was stirred 1 hour at −5° C. and then left overnight. The mixture was basified with aqueous sodium hydroxide (pH=9) with ice cooling and tetrahydrofuran (200 mL) was added and stirred for 30 minutes. The mixture was filtered through Celite® and the filtrate was extracted with tetrahydrofuran (200 mL×3). The organic extraction was combined and dried over magnesium sulfate and concentrated under reduced pressure to provide the title compound (3.2g, 78.8%).
Reaction SMILES: [C:1]1([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:6]=[CH:5][C:4]([O:7][CH2:8][C:9]2[CH:10]=[C:11]([C:15](O)=[O:16])[O:12][C:13]=2[CH3:14])=[CH:3][CH:2]=1.[CH3:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[S:31]([NH2:34])(=[O:33])=[O:32].Cl.CN(C)CCCN=C=NCC>CN(C1C=CN=CC=1)C.O1CCCC1.C(#N)C>[C:1]1([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:2]=[CH:3][C:4]([O:7][CH2:8][C:9]2[CH:10]=[C:11]([C:15]([NH:34][S:31]([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=3[CH3:24])(=[O:32])=[O:33])=[O:16])[O:12][C:13]=2[CH3:14])=[CH:5][CH:6]=1
Reactant: Cc1oc(C(=O)O)cc1COc1ccc(-c2ccccc2)cc1
Reactant: Cc1ccccc1S(N)(=O)=O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CC#N
Solvent: C1CCOC1
Product: Cc1ccccc1S(=O)(=O)NC(=O)c1cc(COc2ccc(-c3ccccc3)cc2)c(C)o1
Temperature: 25 °C
Reaction time: 16 h
Yield: 26.7 %

Procedure:
A stirred solution of 4-(biphenyl-4-yloxymethyl)-5-methyl-furan-2-carboxylic acid (18) (50 mg, 0.162 mmoles), 2-methyl-benzenesulphonamide (42 mg, 0.243 mmoles) and 4-(N,N-dimethylamino)-pyridine (2.5 mg) in a mixture of tetrahydrofuran (8 ml) and acetonitrile (2 ml) was treated with 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (38 mg, 0.194 mmoles). The mixture was stirred at room temperature for 16 hours under an argon atmosphere. The reaction mixture was concentrated in vacuo and the residue was purified by HPLC to afford compound 60 (20 mg) as a white solid. LC/MS System D; Rt=11.09 mins, m/z (ES+)=462 (M+H for C26H23NO5S).
Reaction SMILES: [C:1]([O-:4])(=[O:3])[CH3:2].[Na+].[Cl:6][C:7]([Cl:23])([Cl:22])[CH:8](Cl)[CH:9]([N:16]1[CH:20]=[N:19][CH:18]=[N:17]1)[C:10](=[O:15])[C:11]([CH3:14])([CH3:13])[CH3:12].O>C(O)(=O)C>[Cl:23][C:7]([Cl:6])([Cl:22])[CH:8]([O:3][C:1](=[O:4])[CH3:2])[CH:9]([N:16]1[CH:20]=[N:19][CH:18]=[N:17]1)[C:10](=[O:15])[C:11]([CH3:13])([CH3:12])[CH3:14]
Reactant: CC(=O)[O-]
Reactant: CC(C)(C)C(=O)C(C(Cl)C(Cl)(Cl)Cl)n1cncn1
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CC(=O)OC(C(C(=O)C(C)(C)C)n1cncn1)C(Cl)(Cl)Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 78 %

Procedure:
16.4 g (0.2 mol) of anhydrous sodium acetate were added to 31.5 g (0.1 mol) of 1,1,1,2-tetrachloro-3-(1,2,4-triazol-1-yl)-5,5-dimethyl-hexan-4-one in 150 ml of glacial acetic acid. The mixture was stirred at room temperature overnight and then heated to 40° C. for about 4 hours. The reaction mixture was then added to 1,000 ml of water and extracted twice with 250 ml of chloroform each time. The combined organic phases were dried over sodium sulphate and concentrated by distilling off the solvent in vacuo. The solid residue was recrystallized from ethanol and rinsed with a little hexane. 27.8 g (77.8% of theory) of 1,1,1-trichloro-2-acetoxy-3-(1,2,4-triazol-1-yl)-5,5-dimethylhexan-4-one were obtained as a diastereomer mixture of melting point 115°-119° C.
Reaction SMILES: [CH2:1]([S:6]([Cl:9])(=[O:8])=[O:7])[CH2:2][CH2:3][CH2:4][CH3:5].[F:10][C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:12]=1[N:18]([S:28]([C:31]1[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=1)(=[O:30])=[O:29])[C@H](C)CCCS(O)(=O)=O.P(Cl)(Cl)(Cl)(Cl)Cl>>[F:10][C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:12]=1[N:18]([S:28]([C:31]1[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=1)(=[O:30])=[O:29])[C@H:4]([CH3:5])[CH2:3][CH2:2][CH2:1][S:6]([Cl:9])(=[O:8])=[O:7]
Reactant: C[C@H](CCCS(=O)(=O)O)N(c1cc(F)ccc1F)S(=O)(=O)c1ccc(Cl)cc1
Reactant: CCCCCS(=O)(=O)Cl
Agent: ClP(Cl)(Cl)(Cl)Cl
Product: C[C@H](CCCS(=O)(=O)Cl)N(c1cc(F)ccc1F)S(=O)(=O)c1ccc(Cl)cc1
Yield: 88 %

Procedure:
(4R)-4-[N-[2,5-difluorophenyl][(4-chlorophenyl)sulfonyl]amino]pentylsulfonyl chloride was prepared analogous to (4R)-4-[2,5-dichlorophenyl][4-chlorophenyl)sulfonyl]-amino]pentylsulfonyl chloride by reacting (4R)-4-[N-[2,5-difluorophenyl][(4-chlorophenyl)sulfonyl]amino]pentylsulfonic acid with phosphorus pentachloride. Yield=88%; MS (ESI) 434 (M+1).
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:6]=[C:7]([S:16][C@@H:17]2[CH2:21][CH2:20][CH2:19][C@H:18]2[S:22][CH2:23][C:24]([OH:26])=[O:25])[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])[CH3:3].[CH3:27]O>>[CH3:4][C:2]([C:5]1[CH:6]=[C:7]([S:16][C@@H:17]2[CH2:21][CH2:20][CH2:19][C@H:18]2[S:22][CH2:23][C:24]([O:26][CH3:27])=[O:25])[CH:8]=[C:9]([C:12]([CH3:13])([CH3:14])[CH3:15])[C:10]=1[OH:11])([CH3:1])[CH3:3]
Reactant: CO
Reactant: CC(C)(C)c1cc(S[C@@H]2CCC[C@H]2SCC(=O)O)cc(C(C)(C)C)c1O
Product: COC(=O)CS[C@@H]1CCC[C@H]1Sc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1

Procedure:
The compound of Example 5 (1.0 g, 0.0025 mole) was dissolved in methanol (35 ml) and hydrogen chloride gas was bubbled into the solution for 10 minutes. Nitrogen gas was bubbled into the reaction solution to remove most of the dissolved hydrogen chloride, and then the reaction mixture was poured into water (150 ml). The mixture was extracted twice with 100 ml of diethyl ether, and the combined extracts were dried over anhydrous magnesium sulfate, filtered and concentrated to an oil with a rotary evaporator. The product was purified by silica gel chromatography. The structure was supported by NMR, infrared spectroscopy and elemental analysis.
Reaction SMILES: [NH2:1][C:2]1[N:9]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[O:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)[CH:7]=[C:6]([C:26]2[CH:31]=[CH:30][C:29]([N:32]([CH3:34])[CH3:33])=[C:28]([NH2:35])[CH:27]=2)[C:3]=1[C:4]#[N:5].[Cl:36][CH2:37][C:38](Cl)=[O:39]>C1COCC1>[NH2:1][C:2]1[C:3]([C:4]#[N:5])=[C:6]([C:26]2[CH:31]=[CH:30][C:29]([N:32]([CH3:34])[CH3:33])=[C:28]([NH:35][C:38](=[O:39])[CH2:37][Cl:36])[CH:27]=2)[CH:7]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[O:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)[N:9]=1
Reactant: O=C(Cl)CCl
Reactant: COc1ccc(COc2ccccc2-c2cc(-c3ccc(N(C)C)c(N)c3)c(C#N)c(N)n2)cc1
Solvent: C1CCOC1
Product: COc1ccc(COc2ccccc2-c2cc(-c3ccc(N(C)C)c(NC(=O)CCl)c3)c(C#N)c(N)n2)cc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 70 %

Procedure:
To a cooled (0° C.), stirred solution of 2-amino-4-[3-amino-4-(dimethylamino)phenyl]-6-{2-[(4-methoxybenzyl)-oxy]phenyl}nicotinonitrile (starting compound 4, 0.500 g, 1.724 mmol) in THF (7 mL) under an argon atmosphere was added chloroacetyl chloride (0.121 g, 1.074 mmol). The mixture was stirred at 0° C. for 15 minutes and then partitioned between ethyl acetate and saturated aqueous NaHCO3. The separated organic phase was washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was suspended in ethyl acetate and ethanol. The resulting solid was collected by filtration, washed with ethanol, and dried under reduced pressure to give N-[5-(2-amino-3-cyano-6-{2-[(4-methoxybenzyl)oxy]-phenyl}-4-pyridinyl)-2-(dimethylamino)phenyl]-2-chloroacetamide as a yellow solid. (0.410 g, yield 70%)
Reaction SMILES: COC1[CH:26]=[CH:25][C:6]([CH2:7][NH:8][C:9]2[C:14]([NH2:15])=[CH:13][N:12]=[C:11]([NH:16][C:17]3[N:18]=[CH:19][C:20]([C:23]#[N:24])=[N:21][CH:22]=3)[CH:10]=2)=CC=1.C1(C=O)CC1.S(S([O-])=O)([O-])(=O)=O.[Na+].[Na+]>CN(C=O)C>[CH:6]1([C:7]2[NH:8][C:9]3[CH:10]=[C:11]([NH:16][C:17]4[N:18]=[CH:19][C:20]([C:23]#[N:24])=[N:21][CH:22]=4)[N:12]=[CH:13][C:14]=3[N:15]=2)[CH2:25][CH2:26]1
Reactant: COc1ccc(CNc2cc(Nc3cnc(C#N)cn3)ncc2N)cc1
Agent: O=CC1CC1
Agent: O=S([O-])S(=O)(=O)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1cnc(Nc2cc3[nH]c(C4CC4)nc3cn2)cn1
Temperature: 100 °C
Yield: 16.1 %

Procedure:
A mixture of crude 5-(4-(4-methoxybenzylamino)-5-aminopyridin-2-ylamino)pyrazine-2-carbonitrile (0.083 mmol), cyclopropane carboxaldehyde (5.9 mg, 0.083 mmol) and sodium metabisulfite (16 mg, 0.083 mmol) in DMF (1 mL) was heated at 100° C. for 4 hours. Upon cooling, the mixture was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried (Na2SO4) and concentrated to a light brown solid. The solid was stirred at 65° C. with trifluoroacetic acid. Upon completion of the reaction, the mixture was concentrated. Preparative HPLC gave the title compound (3.7 mg, 16%). 1H NMR (d6-DMSO, 400 MHz) δ 12.60 (br s, 1H), 10.75 (br s, 1H), 8.80 (s, 1H), 8.75 (s, 1H), 8.50 (s, 1H), 8.10 (s, 1H), 2.10-2.20 (m, 1H), 1.00-1.20 (m, 4H). LCMS (2) Rt=1.68 min; m/z (ESI−) 276 (M−H); (ESI+) 278 (MH+).
Reaction SMILES: C(OC1C=C(C=CC=1OC)C[N:13]1[C:21]2[N:20]=[C:19](C(OCC3C=CC=CC=3)(C)C)[NH:18][C:17]=2[C:16](=[O:33])[NH:15][C:14]1=S)C1C=CC=CC=1.C(OC1C=C(C=CC=1OC)CN1C2N=C(C(OCC3C=CC=CC=3)(C)C)NC=2C(=O)N=C1)C1C=CC=CC=1.CO>C(O)CC.[Ni]>[NH:15]1[C:16](=[O:33])[C:17]2[NH:18][CH:19]=[N:20][C:21]=2[N:13]=[CH:14]1
Reactant: COc1ccc(Cn2c(=S)[nH]c(=O)c3[nH]c(C(C)(C)OCc4ccccc4)nc32)cc1OCc1ccccc1
Agent: [Ni]
Agent: COc1ccc(Cn2cnc(=O)c3[nH]c(C(C)(C)OCc4ccccc4)nc32)cc1OCc1ccccc1
Solvent: CO
Solvent: CCCO
Product: O=c1[nH]cnc2nc[nH]c12
Yield: 35.1 %

Procedure:
3-(3-Benzyloxy-4-methoxy-benzyl)-8-(1-benzyloxy-1-methyl-ethyl)-2-thioxanthine (26.05 g, 48 mmole) was heated under reflux in 1-propanol (700 ml) with Raney-nickel (29 g) (treated with 0.1% aqueous acetic acid) for 1.5 hours. The nickel was filtered off and the solvent evaporated in vacuo. The residue was dissolved in dichloromethane (300 ml), extracted with sodium carbonate solution and evaporated again to dryness. The residue was dissolved in methanol (150 ml), treated with charcoal, filtered, concentrated and crystallized to give 3-(3-benzyloxy-4-methoxy-benzyl)-8-(1-benzyloxy-1-methyl-ethyl)-hypoxanthine (15.81 g, 64.5%), mp 78-86° C. (containing methanol). A second crop gave 2.29 g (9.3%) of hypoxanthine.
Reaction SMILES: C([O-])=O.[NH4+].[N+:5]([C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH:18]=[N:17][CH:16]=[N:15]2)=[CH:10][C:9]=1[O:19][CH:20]([CH3:22])[CH3:21])([O-])=O>CO.[Pd]>[CH3:22][CH:20]([O:19][C:9]1[CH:10]=[C:11]([N:14]2[CH:18]=[N:17][CH:16]=[N:15]2)[CH:12]=[CH:13][C:8]=1[NH2:5])[CH3:21]
Reactant: CC(C)Oc1cc(-n2cncn2)ccc1[N+](=O)[O-]
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: CC(C)Oc1cc(-n2cncn2)ccc1N
Temperature: 80 °C
Yield: 96.9 %

Procedure:
A mixture of 1 g of 4-bromo-1-nitro-2-(propan-2-yloxy)benzene, 319 mg of triazole, 110 mg of copper (I) iodide, 585 mg of potassium carbonate and 84 mg of 8-hydroxyquinoline in 8 ml of DMSO is stirred overnight at ambient temperature and then heated at 120° C. for 3 hours. The reaction medium is poured into 10 ml of an aqueous 25% NH4OH solution, 40 ml of water and 10 ml of ethyl acetate. The mixture is stirred for 30 minutes at ambient temperature and then the two phases are separated. The aqueous phase is washed with twice 40 ml of ethyl acetate. The combined organic phases are dried over magnesium sulfate, filtered and evaporated. Purification is carried out by flash chromatography on silica gel (40-63 μm), elution being carried out with a mixture of dichloromethane and acetone (100/0 to 95/5). 695 mg of 1-[4-nitro-3-(propan-2-yloxy)phenyl]-1H-1,2,4-triazole are obtained in the form of a beige solid. 965 mg of ammonium formate and 172 mg of Pd/C (10%) are added to a solution of 691 mg of 1-[4-nitro-3-(propan-2-yloxy)phenyl]-1H-1,2,4-triazole in 14 ml of methanol. The reaction medium is microwave-heated at 80° C. for 5 minutes. The mixture is filtered on Clarcel, and the Clarcel is rinsed with methanol. The filtrate is concentrated under reduced pressure. The residue is taken up with 20 ml of ethyl acetate, 2 ml of water and 8 ml of a saturated aqueous sodium chloride solution. The two phases are separated and the aqueous phase is washed with 3 times 10 ml of ethyl acetate. The combined organic phases are dried over magnesium sulfate, filtered and evaporated, so as to give 589 mg of 2-(propan-2-yloxy)-4-(1H-1,2,4-triazol-1-yl)aniline in the form of a brown oil.
Reaction SMILES: O[CH:2]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:3]1[C:12]2[C:11](=[O:13])[N:10]([CH2:14][CH2:15][CH2:16][O:17][CH:18]3CCCC[O:19]3)[C:9](=[O:24])[N:8]([CH3:25])[C:7]=2[N:6]=[CH:5][C:4]=1[O:26][CH:27]([CH3:29])[CH3:28]>C(O)=O.[Zn]>[CH:18]([O:17][CH2:16][CH2:15][CH2:14][N:10]1[C:11](=[O:13])[C:12]2[C:3]([CH2:2][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[C:4]([O:26][CH:27]([CH3:28])[CH3:29])[CH:5]=[N:6][C:7]=2[N:8]([CH3:25])[C:9]1=[O:24])=[O:19]
Reactant: CC(C)Oc1cnc2c(c1C(O)c1ccccc1)c(=O)n(CCCOC1CCCCO1)c(=O)n2C
Agent: [Zn]
Solvent: O=CO
Product: CC(C)Oc1cnc2c(c1Cc1ccccc1)c(=O)n(CCCOC=O)c(=O)n2C
Temperature: 80 °C
Yield: 82.2 %

Procedure:
To a solution of 5-(hydroxy(phenyl)methyl)-6-isopropoxy-1-methyl-3-(3-(tetrahydro-2H-pyran-2-yloxy)propyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (100 mg, 0.207 mmol) in HCOOH (2 mL) was added Zn dust (67.2 mg, 1.034 mmol). The reaction was heated at 80° C. for 1 h then cooled to RT and filtered. The filtrate was concentrated and dried to a residue which was purified by Prep TLC eluted with PE/EA (2:1) to give 3-(5-benzyl-6-isopropoxy-1-methyl-2,4-dioxo-1,2-dihydropyrido[2,3-d]pyrimidin-3(4H)-yl)propyl formate (70 mg, 85% yield) as a white solid.