Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1C=CN=C1.[I:25]I.O[CH2:28][C:29]1[CH:44]=[CH:43][C:32]([CH2:33][NH:34][C:35]([C:37]2[N:38]=[CH:39][N:40]([CH3:42])[CH:41]=2)=[O:36])=[CH:31][CH:30]=1>ClCCl>[I:25][CH2:28][C:29]1[CH:44]=[CH:43][C:32]([CH2:33][NH:34][C:35]([C:37]2[N:38]=[CH:39][N:40]([CH3:42])[CH:41]=2)=[O:36])=[CH:31][CH:30]=1
Reactant: II
Reactant: Cn1cnc(C(=O)NCc2ccc(CO)cc2)c1
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Cn1cnc(C(=O)NCc2ccc(CI)cc2)c1
Reaction time: 0.5 h
Yield: 73.5 %

Procedure:
Gently stir for 30 min a mixture of polymer supported triphenylphosphine (1.0 g, 3 mmol/g, 3.0 mmol), 1H-imidazole (208 mg, 3.06 mmol), and iodine (776 mg; 3.06 mmol) in anhydrous dichloromethane (12 mL). To the reaction mixture, add a mixture of N-(4-(hydroxymethyl)benzyl)-1-methyl-1H-imidazole-4-carboxamide (500 mg, 2.04 mmol) in anhydrous dichloromethane (5.0 mL). Gently stir the reaction mixture for 5 hrs at room temperature. Filter the reaction mixture and wash the filtrate with an aqueous 10% sodium thiosulfate solution. Separate the aqueous layer. Wash the organic layer with water, dry over magnesium sulfate, and concentrate to the title compound (532 mg, 1.50 mmol). MS (m/z): 356 (M+1).
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].CS(O[CH:10]1[CH2:18][CH2:17][C:16]2[N:12]([C:13]3[N:32]=[CH:31][N:30]=[C:29]([NH2:33])[C:14]=3[C:15]=2[C:19]2[CH:20]=[N:21][C:22]3[C:27]([CH:28]=2)=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:11]1)(=O)=O.O>CN(C=O)C>[N:1]([CH:10]1[CH2:18][CH2:17][C:16]2[N:12]([C:13]3[N:32]=[CH:31][N:30]=[C:29]([NH2:33])[C:14]=3[C:15]=2[C:19]2[CH:20]=[N:21][C:22]3[C:27]([CH:28]=2)=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:11]1)=[N+:2]=[N-:3]
Reactant: CS(=O)(=O)OC1CCc2c(-c3cnc4ccccc4c3)c3c(N)ncnc3n2C1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: [N-]=[N+]=NC1CCc2c(-c3cnc4ccccc4c3)c3c(N)ncnc3n2C1
Temperature: 80 °C
Reaction time: 4 h
Yield: 77 %

Procedure:
Sodium azide (361 mg) was added to a solution of 4-amino-5-(quinolin-3-yl)-6,7,8,9-tetrahydropyrimido[5,4-b]indolizin-8-yl methanesulfonate (758 mg) obtained in Step 9 in DMF (9 ml) at room temperature, and the mixture was stirred at 80° C. for 4 hours. After cooling, the reaction mixture was poured into water, followed by extraction with ethyl acetate. The organic layer was washed with water and a saturated sodium chloride solution, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound as a yellow solid (508 mg).
Reaction SMILES: [C:1]([CH:3]=[C:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:15]=[CH:14][C:13]([N:16]3[CH2:20][C@H:19]([CH2:21][NH2:22])[O:18][C:17]3=[O:23])=[CH:12][C:11]=2[F:24])[CH2:6][CH2:5]1)#[N:2].C(Cl)(=O)C(Cl)=O.[F:31][CH:32]([F:36])[C:33](O)=[O:34].C(N(CC)CC)C>ClCCl>[C:1]([CH:3]=[C:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:15]=[CH:14][C:13]([N:16]3[CH2:20][C@H:19]([CH2:21][NH:22][C:33](=[O:34])[CH:32]([F:36])[F:31])[O:18][C:17]3=[O:23])=[CH:12][C:11]=2[F:24])[CH2:6][CH2:5]1)#[N:2]
Reactant: O=C(O)C(F)F
Reactant: N#CC=C1CCN(c2ccc(N3C[C@H](CN)OC3=O)cc2F)CC1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: N#CC=C1CCN(c2ccc(N3C[C@H](CNC(=O)C(F)F)OC3=O)cc2F)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 48 %

Procedure:
The mixture of (S)-N-{3-[4-(4-cyanomethylidene-piperidin-1-yl)-3-fluorophenyl]-2-oxo-oxazolidin-5-ylmethyl}-amine (0.5 g, 1.45 mmol), oxalyl chloride (0.150 ml, 1.74 mmol), difluoroacetic acid (0.1 ml, 1.74 mmol) and triethylamine (0.242 ml, 1.74 mmol) in dichloromethane (20 ml) was stirred for 1 hour at room temperature. The reaction mixture was extracted with the dichloromethane water mixture. The combined organic layer was dried and removal of the solvent afforded a residue which was chromatographed over silica gel to give title compound in 48% yield.
Reaction SMILES: [NH2:1][C:2]1[N:3]([CH3:24])[C:4](=[O:23])[C:5]2([C:15]3[C:10](=[CH:11][CH:12]=[C:13](Br)[CH:14]=3)[O:9][CH:8]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:7]2)[N:6]=1.[CH3:25][S:26]([C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1)(=[O:28])=[O:27]>O1CCOCC1.C([O-])([O-])=O.[Cs+].[Cs+].Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH2:1][C:2]1[N:3]([CH3:24])[C:4](=[O:23])[C:5]2([C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:32]4[CH:33]=[CH:34][C:29]([S:26]([CH3:25])(=[O:28])=[O:27])=[CH:30][CH:31]=4)[CH:14]=3)[O:9][CH:8]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:7]2)[N:6]=1
Reactant: CN1C(=O)C2(CC(c3ccccc3)Oc3ccc(Br)cc32)N=C1N
Reactant: CS(=O)(=O)c1ccc(B(O)O)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: CN1C(=O)C2(CC(c3ccccc3)Oc3ccc(-c4ccc(S(C)(=O)=O)cc4)cc32)N=C1N
Temperature: 120 °C
Yield: 75 %

Procedure:
Pd(PPh3)2Cl2 (10 mg) in a 10 mL tube under Ar was treated sequentially with 2′-amino-6-bromo-1′-methyl-2-phenylspiro[chroman-4,4′-imidazol]-5′(1′H)-one (20 mg, 0.052 mmol) in 1,4-dioxane (1 mL), Cs2CO3 (2 N, 0.3 mL) and 4-(methylsulfonyl)phenylboronic acid (20.8 mg, 0.1 mmol). The mixture was heated in a microwave reactor at 120° C. for 30 min. The reaction mixture was concentrated in vacuo to give the residue, which was purified by preparative TLC to give pure 2′-amino-1′-methyl-6-(4-(methylsulfonyl)phenyl)-2-phenylspir-o[chroman-4,4′-imidazol]-5′(1′H)-one (18 mg, 80%). 1H-NMR (CDCl3+MeOD): 2.07 (dd, 1H), 2.41 (t, 1H), 3.01 (s, 3H), 3.12 (s, 3H), 5.25 (d, 0.5H), 5.89 (d, 1H), 6.90 (d, 1H), 7.31 (s, 2H), 7.32 (t, 2H), 7.39 (d, 3H), 7.60 (t, 2H), 7.87 (d, 2H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N+:25]([O-])=O)[CH:5]=[C:6]2[C:11]=1[N:10]([CH2:12][CH2:13][N:14]([CH3:24])[C:15](=[O:23])[O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:9][CH2:8][CH2:7]2.[H][H]>[Pd]>[NH2:25][C:4]1[CH:5]=[C:6]2[C:11](=[C:2]([F:1])[CH:3]=1)[N:10]([CH2:12][CH2:13][N:14]([CH3:24])[C:15](=[O:23])[O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:9][CH2:8][CH2:7]2
Reactant: CN(CCN1CCCc2cc([N+](=O)[O-])cc(F)c21)C(=O)Oc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Product: CN(CCN1CCCc2cc(N)cc(F)c21)C(=O)Oc1ccccc1
Reaction time: 3 h
Yield: 87.2 %

Procedure:
To a stirred solution of phenyl 2-(8-fluoro-6-nitro-3,4-dihydroquinolin-1(2H)-yl)ethyl(methyl)carbamate (560 mg, 1.500 mmol) was added palladium on activated carbon, 10 wt % (160 mg, 0.150 mmol). The resulting suspension was stirred at room temperature in a balloon pressure atmosphere of hydrogen. After 3 h, most of the starting material was consumed, and the reaction was stopped due to the presence of a minor impurity. The reaction mixture was filtered through a pad of celite, then concentrated to give a brown oil. The residue was dried and use directly in the subsequent reaction. Crude product obtained was phenyl 2-(6-amino-8-fluoro-3,4-dihydroquinolin-1(2H)-yl)ethyl(methyl)carbamate (449 mg, 1.308 mmol, 87% yield). 1 H NMR (DMSO-d6) δ 7.40-7.35 (m, 2H); 7.23-7.17 (m, 1H); 7.10-7.05 (m, 2H); 6.19 (d, J=14 Hz, 1H); 6.06 (s, 1H); 4.85-4.72 (m, 2H); 3.57-3.53 (m, 1H); 3.46-3.42 (m, 1H); 3.13-2.93 (m, 4H); 3.07, 2.95 (2s, 3H); 2.57 (t, J=6.3 Hz, 1H); 1.74-1.65 (m, 2H). ESI-MS (m/z, %): 344 (MH+).
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]([O:27]C(=O)C)=[C:8]2[C:16]([Cl:17])=[CH:15][N:14]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([F:25])=[C:21]([F:26])[CH:20]=3)[C:9]2=[C:10]([C:12]#[N:13])[N:11]=1)=O)C.[NH2:31][CH2:32][C:33]([OH:35])=[O:34].C[O-].[Na+].CO>>[Cl:17][C:16]1[C:8]2[C:9](=[C:10]([C:12]#[N:13])[N:11]=[C:6]([C:4]([NH:31][CH2:32][C:33]([OH:35])=[O:34])=[O:3])[C:7]=2[OH:27])[N:14]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([F:25])=[C:21]([F:26])[CH:20]=2)[CH:15]=1
Reactant: CCOC(=O)c1nc(C#N)c2c(c(Cl)cn2Cc2ccc(F)c(F)c2)c1OC(C)=O
Reactant: NCC(=O)O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: N#Cc1nc(C(=O)NCC(=O)O)c(O)c2c(Cl)cn(Cc3ccc(F)c(F)c3)c12

Procedure:
Prepared in analogy to that of Example 1(e) from 4-acetoxy-3-chloro-7-cyano-1-(3,4-difluoro-benzyl)-1H-pyrrolo[2,3-c]pyridine-5-carboxylic acid ethyl ester, glycine and NaOMe/HOMe. The title compound, ESI MS (m/z): 421 (M+H)+.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([O:10][C:11]2[CH:19]=[CH:18][C:17]3[N:16]4[C@H:20]([CH3:25])[CH2:21][NH:22][C:23](=[O:24])[C:15]4=[CH:14][C:13]=3[CH:12]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2].[CH2:26](Br)[CH3:27].[H-].[Na+]>>[CH2:26]([N:22]1[CH2:21][C@@H:20]([CH3:25])[N:16]2[C:17]3[CH:18]=[CH:19][C:11]([O:10][CH:7]4[CH2:8][CH2:9][N:4]([CH:1]([CH3:3])[CH3:2])[CH2:5][CH2:6]4)=[CH:12][C:13]=3[CH:14]=[C:15]2[C:23]1=[O:24])[CH3:27]
Reactant: CC(C)N1CCC(Oc2ccc3c(c2)cc2n3[C@H](C)CNC2=O)CC1
Reactant: CCBr
Agent: [H-]
Agent: [Na+]
Product: CCN1C[C@@H](C)n2c(cc3cc(OC4CCN(C(C)C)CC4)ccc32)C1=O
Yield: 76 %

Procedure:
The title compound was synthesized in analogy to example 17, from (R)-8-(1-isopropyl-piperidin-4-yloxy)-4-methyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (example 8), ethyl bromide and sodium hydride, to give the desired product as a colorless oil (76%).
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH:11](O)[CH2:12][CH2:13][CH3:14])=[CH:4][C:5]2[O:9][CH2:8][O:7][C:6]=2[CH:10]=1.[SH:16][CH2:17][C:18]([OH:20])=[O:19].CC1(C)C2(CS(O)(=O)=O)C(CC1CC2)=O.C(OCC)(=O)C>C1C=CC=CC=1>[CH3:1][C:2]1[C:3]([CH:11]([S:16][CH2:17][C:18]([OH:20])=[O:19])[CH2:12][CH2:13][CH3:14])=[CH:4][C:5]2[O:9][CH2:8][O:7][C:6]=2[CH:10]=1
Reactant: CCCC(O)c1cc2c(cc1C)OCO2
Reactant: O=C(O)CS
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: CCOC(C)=O
Solvent: c1ccccc1
Product: CCCC(SCC(=O)O)c1cc2c(cc1C)OCO2
Yield: 54 %

Procedure:
A solution of 5.6 g of (6-methyl-1,3-benzodioxol-5-yl)butan-1-ol, 4.8 g of mercaptoacetic acid and a catalytic amount of D-10-camphorsulfonic acid in 60 ml of benzene was heated under reflux for 3 hours, followed by the addition of ethyl acetate. The obtained mixture was washed with water and extracted with a 1N aqueous solution of sodium hydroxide. The aqueous layer was washed with ethyl acetate, acidified with 1N hydrochloric acid and extracted with chloroform. The organic layer was dried over magnesium sulfate and distilled to remove the solvent. The obtained residue was chromatographed over silica gel column and eluted with chloroform to obtain a colorless crystal. This crystal was recrystallized from isopropyl ether/hexane to obtain 4.1 g of the title compound as a colorless prismatic crystal.
Reaction SMILES: [N+:1]([C:4]1[CH:17]=[CH:16][C:7]([CH2:8][N:9]2[CH2:14][CH2:13][CH:12]([OH:15])[CH2:11][CH2:10]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].C(N(CC)CC)C.[C:25]1([CH3:34])[CH:30]=[CH:29][C:28]([C:31](Cl)=[O:32])=[CH:27][CH:26]=1>C1(C)C=CC=CC=1>[CH3:34][C:25]1[CH:30]=[CH:29][C:28]([C:31]([O:15][CH:12]2[CH2:11][CH2:10][N:9]([CH2:8][C:7]3[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:17][CH:16]=3)[CH2:14][CH2:13]2)=[O:32])=[CH:27][CH:26]=1
Reactant: O=[N+]([O-])c1ccc(CN2CCC(O)CC2)cc1
Reactant: Cc1ccc(C(=O)Cl)cc1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: Cc1ccc(C(=O)OC2CCN(Cc3ccc([N+](=O)[O-])cc3)CC2)cc1
Yield: 82.9 %

Procedure:
0.5 g (0.00212 mol) of 1-(4-nitro-benzyl)-piperidin-4-ol and 0.595 ml (0.00424 mol) of triethylamine were dissolved in 15 ml of toluene, treated with 0.561 ml (0.00424 mol) of p-toluoyl chloride and boiled at reflux for 18 hrs. The reaction mixture was concentrated and the residue was chromatographed over silica gel with ethyl acetate/hexane (1:2). 0.623 g (83%) of 1-(4-nitro-benzyl)-piperidin-4-yl 4-methyl-benzoate was obtained as yellow crystals. MS: me/e=355 (C20H23N2 O4+).
Reaction SMILES: [O:1]1[CH2:5][CH2:4][C@@H:3]([O:6][C:7]2[C:12]([NH2:13])=[CH:11][CH:10]=[CH:9][N:8]=2)[CH2:2]1.[CH3:14][O:15][C:16]([C:18]1[S:27][C:21]2[N:22]=[CH:23][N:24]=[C:25](Cl)[C:20]=2[C:19]=1[CH3:28])=[O:17].Cl>O1CCOCC1>[CH3:14][O:15][C:16]([C:18]1[S:27][C:21]2[N:22]=[CH:23][N:24]=[C:25]([NH:13][C:12]3[C:7]([O:6][C@@H:3]4[CH2:4][CH2:5][O:1][CH2:2]4)=[N:8][CH:9]=[CH:10][CH:11]=3)[C:20]=2[C:19]=1[CH3:28])=[O:17]
Reactant: Nc1cccnc1O[C@@H]1CCOC1
Reactant: COC(=O)c1sc2ncnc(Cl)c2c1C
Agent: Cl
Solvent: C1COCCO1
Product: COC(=O)c1sc2ncnc(Nc3cccnc3O[C@@H]3CCOC3)c2c1C
Temperature: 100 °C
Reaction time: 36 h

Procedure:
A mixture of 166 mg (0.92 mmol) 2-[(R)-(tetrahydro-furan-3-yl)oxy]-pyridin-3-ylamine, 364 mg (1.5 mmol) 4-chloro-5-methyl-thieno[2,3-d]pyrimidine-6-carboxylic acid methyl ester and 39 μl hydrochloric acid (4M in dioxane) and 30 ml dioxane was stirred at 100° C. for 1.5 days. The reaction mixture was concentrated and used for the next synthesis step without further purification.
Reaction SMILES: [SH:1][C:2]1[N:6]([CH3:7])[CH:5]=[N:4][N:3]=1.Cl[CH2:9][CH2:10][CH2:11][N:12]1[CH2:17][CH2:16][N:15]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=2)[CH2:14][CH2:13]1.C(N(CC)CC)C.Cl>CN(C=O)C>[CH3:7][N:6]1[CH:5]=[N:4][N:3]=[C:2]1[S:1][CH2:9][CH2:10][CH2:11][N:12]1[CH2:17][CH2:16][N:15]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:25])[F:26])[CH:19]=2)[CH2:14][CH2:13]1
Reactant: FC(F)(F)c1cccc(N2CCN(CCCCl)CC2)c1
Reactant: Cn1cnnc1S
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cn1cnnc1SCCCN1CCN(c2cccc(C(F)(F)F)c2)CC1
Yield: 54.5 %

Procedure:
1.15 g (10 mmol) of 3-mercapto-4-methyl-4H-1,2,4-triazole, 3.1 g (10.1 mmol) of 1-(3-chloropropyl)-4-(3-trifluoromethylphenyl)piperazine and 1.5 g (15 mmol) of triethylamine in 5 ml of DMF were stirred at 100° C. for 1 hour. The mixture was then poured into 5% strength hydrochloric acid and extracted with ethyl acetate. The aqueous phase was made alkaline with sodium hydroxide solution and then extracted again with ethyl acetate, and the organic phase was dried over MgSO4 and concentrated. The residue was purified by chromatography (mobile phase: CH2Cl2/CH3OH=95/5). 2.1 g of product were obtained as a yellowish oil (=55% yield).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:11](=[O:12])[N:10]2[CH:13]=[CH:14][CH:15]=[C:16]([SH:17])[C:9]2=[N:8][CH:7]=1)=[O:5])[CH3:2].[CH2:18]=[O:19]>>[CH2:1]([O:3][C:4]([C:6]1[C:11](=[O:12])[N:10]2[CH:13]=[CH:14][CH:15]=[C:16]([S:17][CH2:18][OH:19])[C:9]2=[N:8][CH:7]=1)=[O:5])[CH3:2]
Reactant: C=O
Reactant: CCOC(=O)c1cnc2c(S)cccn2c1=O
Product: CCOC(=O)c1cnc2c(SCO)cccn2c1=O
Temperature: 100 °C
Reaction time: 2 h
Yield: 27.8 %

Procedure:
A mixture of 1.0 g of 3-ethoxycarbonyl-9-mercapto-4-oxo-4H-pyrido[1,2-a]pyrimidine (II-1) and 325 mg of 27% formaldehyde is stirred at 100° C. for 2 hours in a nitrogen atmosphere. The reaction mixture is washed with methylene chloride and recrystallized from methylene chloride-methanol (19:1 v/v) to give 311 mg (Yield: 27.8%) of 3-ethoxycarbonyl-9-(hydroxymethylthio)-4-oxo-4H-pyrido[1,2-a]pyrimidine (III).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6](=[O:26])[C:7]3[C:14](=[O:15])[N:13]([NH:16][C:17]4[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=4)[C:12](=[O:25])[C:8]=3[NH:9][C:10]=2[CH:11]=1.CS(O)(=O)=O>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6](=[O:26])[C:7]3[C:14]([OH:15])=[N:13][N:16]([C:17]4[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=4)[C:12](=[O:25])[C:8]=3[NH:9][C:10]=2[CH:11]=1
Reactant: COc1ccc(NN2C(=O)c3[nH]c4cc(Cl)ccc4c(=O)c3C2=O)cc1
Agent: CS(=O)(=O)O
Solvent: CO
Product: COc1ccc(-n2nc(O)c3c(=O)c4ccc(Cl)cc4[nH]c3c2=O)cc1
Temperature: 25 °C
Yield: 43.7 %

Procedure:
6-Chloro-2-(4-methoxyanilino)-2,3,4,9-tetrahydro-1H-pyrrolo[3,4-b]-quinoline-1,3,9-trione (2.72 g, 7.40 mM) was stirred in methanol (200 mL), and methanesulfonic acid (50 mL) was added. The tan suspension was heated to reflux for 16 hours during which it turned yellow. This yellow suspension was cooled to room temperature and filtered (the filtrate was saved for use in Example 8). The collected solids were washed with methanol to give the title compound as a yellow powder (1.19 g, 44%), mp 371-373° C.; MS(CI): 370 (M+H). Analysis for C18H12ClN3O4: Calculated: C, 58.50; H, 3.27; N, 11.36; Found: C, 58.30; H, 3.41; N, 10.92;
Reaction SMILES: [CH:1]1([C:6]2[CH:12]=[CH:11][C:9]([NH2:10])=[CH:8][CH:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C1C(=O)N([Br:20])C(=O)C1.O>CN(C=O)C>[Br:20][C:11]1[CH:12]=[C:6]([CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5]2)[CH:7]=[CH:8][C:9]=1[NH2:10]
Reactant: O=C1CCC(=O)N1Br
Reactant: Nc1ccc(C2CCCC2)cc1
Solvent: O
Solvent: CN(C)C=O
Product: Nc1ccc(C2CCCC2)cc1Br
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 80.4 %

Procedure:
4-Cyclopentylaniline (210 mg, 1.30 mmol) was dissolved in cold (0° C.) DMF (8 mL) and treated with NBS (232 mg, 1.30 mmol). The reaction was stirred at 0° C. for 5 min and then warmed to room temperature for 1 h. The reaction mixture was poured into water (40 mL) and extracted with ethyl acetate (3×20 mL). The combined organic extracts dried over MgSO4, filtered and concentrated in vacuo. Purification by silica gel chromatography (0-50% ethyl acetate/hexanes) yielded 2-bromo-4-cyclopentylaniline (251 mg, 80% yield). LC/MS m/z 242.0 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][NH:11][CH2:12][CH:13]([OH:24])[CH2:14][O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[O:22][CH3:23])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(C(C)C)CC)(C)C.[Cl:34][CH2:35][C:36](Cl)=[O:37]>C(Cl)Cl>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][N:11]([CH2:12][CH:13]([OH:24])[CH2:14][O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[O:22][CH3:23])[C:36](=[O:37])[CH2:35][Cl:34])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccccc1OCC(O)CNCCNC(=O)OC(C)(C)C
Reactant: O=C(Cl)CCl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1ccccc1OCC(O)CN(CCNC(=O)OC(C)(C)C)C(=O)CCl
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Compound 11 (1.0 g, 3.0 mmol) was dissolved in 20 mL DCM and treated with diisopropylethyl amine (0.76 g, 4.5 mmol). The mixture was cooled to ° C. To the cold mixture was added dropwise chloroacetyl chloride in 5 mL DCM. The reaction mixture was allowed to stir at RT for 24 h. The mixture was diluted with 50 mL DCM and washed with 50 mL of water and 10% citric acid. The organic layer was dried over MgSO4 and filtered. The solvent was evaporated under reduced pressure and the residue was crystallized from ethylether to afford compound 12.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[CH2:8][CH2:9][CH2:10][OH:11].[O:12]1[CH:17]=[CH:16][CH2:15][CH2:14][CH2:13]1.C(=O)([O-])O.[Na+]>C1COCC1>[OH:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[CH2:8][CH2:9][CH2:10][O:11][CH:13]1[CH2:14][CH2:15][CH2:16][CH2:17][O:12]1
Reactant: C1=COCCC1
Reactant: OCCCc1ccncc1O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: Oc1cnccc1CCCOC1CCCCO1

Procedure:
3-(3-Hydroxypyridin-4-yl)-1-propanol (1.00 g, 6.53 mmol) obtained in Example 62 is dissolved in THF, and thereto are added dihydropyrane (5.0 ml, 55 mmol), D,L-camphore-10-sulfonic acid (1.00 g, 4.30 mmol), and the mixture is heated under reflux for 20 minutes. The reaction solution is poured into an aqueous sodium hydrogen carbonate solution, and the mixture is extracted with ethyl acetate (200 ml×2), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue is purified by silica gel column chromatography (eluent: hexane/ethyl acetate) to give 3-hydroxy-4-(3-tetrahydropyranyloxypropyl)pyridine as colorless oil.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[CH:11][C:12]2[C:13]3[N:21]([CH2:22][C:23]([NH:26][S:27]([CH3:30])(=[O:29])=[O:28])([CH3:25])[CH3:24])[C:20]([CH2:31][O:32][CH2:33][CH3:34])=[N:19][C:14]=3[CH:15]=[N:16][C:17]=2[CH:18]=1)C1C=CC=CC=1>C(O)C.[Pd]>[CH2:33]([O:32][CH2:31][C:20]1[N:21]([CH2:22][C:23]([NH:26][S:27]([CH3:30])(=[O:29])=[O:28])([CH3:25])[CH3:24])[C:13]2[C:12]3[CH:11]=[CH:10][C:9]([OH:8])=[CH:18][C:17]=3[N:16]=[CH:15][C:14]=2[N:19]=1)[CH3:34]
Reactant: CCOCc1nc2cnc3cc(OCc4ccccc4)ccc3c2n1CC(C)(C)NS(C)(=O)=O
Agent: [Pd]
Solvent: CCO
Product: CCOCc1nc2cnc3cc(O)ccc3c2n1CC(C)(C)NS(C)(=O)=O
Reaction time: 8 h
Yield: 96.3 %

Procedure:
A solution of N-[2-(7-benzyloxy-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)-1,1-dimethylethyl]methanesulfonamide (9.38 g, 19.5 mmol) in ethanol (150 mL) was added to a Parr vessel containing 10% palladium on carbon (0.83 g). The reaction was placed under hydrogen pressure (50 psi, 3.4×105 Pa) over two nights. Starting material remained as evidenced by a TLC analysis, and additional 10% palladium on carbon (1.02 g) was added. The reaction was continued for an additional eight hours. The reaction mixture was filtered through a layer of CELITE filter aid, and the filter cake was washed with ethanol and methanol. The filtrate was concentrated under reduced pressure, and the residue was several times dissolved in toluene and concentrated under reduced pressure to yield a yellow powder, which was dried under high vacuum to provide 7.37 g of N-[2-(2-ethoxymethyl-7-hydroxy-1H-imidazo[4,5-c]quinolin-1-yl)-1,1-dimethylethyl]methanesulfonamide as a yellow solid.
Reaction SMILES: [H-].[Na+].[I:3][C:4]1[CH:5]=[N:6][NH:7][CH:8]=1.Cl[C:10]1[C:15]([C:16]([F:19])([F:18])[F:17])=[CH:14][CH:13]=[CH:12][N:11]=1.O>CN(C)C=O>[I:3][C:4]1[CH:5]=[N:6][N:7]([C:10]2[C:15]([C:16]([F:19])([F:18])[F:17])=[CH:14][CH:13]=[CH:12][N:11]=2)[CH:8]=1
Reactant: Ic1cn[nH]c1
Reactant: FC(F)(F)c1cccnc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: FC(F)(F)c1cccnc1-n1cc(I)cn1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 82 %

Procedure:
Sodium hydride (60% dispersion in mineral oil, 243 mg, 6.07 mmol) was suspended in 4 mL anhydrous N,N-dimethylformamide. To this solution was added 4-iodo-1H-pyrazole (982 mg, 5.06 mmol) in 4 mL anhydrous N,N-dimethylformamide at 0° C. under nitrogen. The mixture was stirred at 0° C. for 15 min, and then allowed to warm to ambient temperature and stirred at the same temperature for 2 hrs. After this period of time, a solution of 2-chloro-3-trifluoromethyl-pyridine (1.01 g, 5.56 mmol) in 4 mL N,N-dimethylformamide was added and the mixture was heated at 90° C. for 5 hrs. After cooling off, the mixture was poured into water and extracted with ethyl acetate three times. The combined extract was washed with brine, dried over sodium sulfate, and concentrated in vacuo to give 2-(4-iodo-pyrazol-1-yl)-3-trifluoromethyl-pyridine as a white solid (1.406 g, 74% yield). The product was used for the next step without purification. 1H-NMR (400 MHz, CDCl3): δ 7.48 (dd, 1H, J=4.80, J=8.08), 7.79 (s, 1H), 8.21 (dd, 1H, J=1.52, J=8.08), 8.27 (s, 1H), 8.67 (dd, 1H, J=1.52, J=4.80).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][N:17]=[C:16](Cl)[N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:21][C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=1)[CH2:25][NH2:26].C(=O)([O-])[O-].[K+].[K+].O>C(O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][N:17]=[C:16]([NH:26][CH2:25][C:24]3[CH:27]=[CH:28][CH:29]=[C:22]([Cl:21])[CH:23]=3)[N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: NCc1cccc(Cl)c1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccnc(Cl)n2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCN(c2ccnc(NCc3cccc(Cl)c3)n2)CC1
Temperature: 25 °C
Yield: 36.4 %

Procedure:
A mixture of 4-(2-chloro-pyrimidin-4-yl)-piperazine-1-carboxylic acid tert-butyl ester (100 mg, 0.33 mmol), 3-chlorobenzylamine (0.65 mL, 5.3 mmol) and potassium carbonate (71 mg, 0.67 mmol) in ethanol (5 mL) was heated at reflux for 7 days. The reaction mixture was cooled to room temperature, poured into H2O (15 mL) and extracted with EtOAc (2×20 mL). The combined organic extracts were washed with H2O (3×15 mL), brine, dried (Na2SO4) and concentrated in vacuo. The residue was purified by preparative TLC (10% MeOH in CH2Cl2) to give a yellow solid. The yellow solid was triturated with MeOH (1 mL) and the solid was collected by filtration to give intermediate (I-3a) as a white solid (48.5 mg).