Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([O:13][CH3:14])=[O:12])=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:15]([O:17][CH3:18])=[O:16].C(O)[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36].CO>C(O)(C)C>[CH:6]1[C:5]2[C:10](=[CH:1][C:2]([C:15]([O:17][CH2:18][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH3:20])=[O:16])=[CH:3][CH:4]=2)[CH:9]=[CH:8][C:7]=1[C:11]([O:13][CH2:14][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH3:20])=[O:12]
Reactant: COC(=O)c1ccc2cc(C(=O)OC)ccc2c1
Reactant: CCCCCCCCCCCCCCCCCCO
Solvent: CC(C)O
Solvent: CO
Product: CCCCCCCCCCCCCCCCCCOC(=O)c1ccc2cc(C(=O)OCCCCCCCCCCCCCCCCCC)ccc2c1
Temperature: 160 °C
Yield: 85.8 %

Procedure:
To a 3 neck 100 mL round bottomed flask equipped with a Dean Stark trap and condenser, thermocouple and argon inlet was added dimethyl naphthalene-2,6-dicarboxylate (10 grams, 40.94 mmoles, available from Sigma Aldrich), stearyl alcohol (22.15 grams, 81.89 mmoles, available from Spectrum Chemical), Fascat 4100 (0.03 grams, 0.1 wt %, available from Arkema Inc) and Xylenes (50 ml, available from Sigma Aldrich). The mixture was slowly heated under argon to 160° C. during which reagents melted/dissolved. The temperature was raised to 180° C. The reaction mixture was stirred at 180° C. overnight (˜20 hours) during which 46 mL of a mixture of xylenes and methanol was collected. Vacuum was applied (1-2 mm-Hg) for about 10 minutes during which an additional 5 mL of a mixture of Xylenes and methanol was collected. The solution was cooled under argon to about 140° C. and discharged in an aluminum tray where it was allowed to cool to room temperature to give product as an off-white solid. The product was transferred to a 1 L Erlenmeyer flask, about 100 mL of isopropyl alcohol was added, heated to about 100° C. during which product dissolved. The solution was cooled to room temperature during which product crystallized out, filtered and dried on a vacuum pump overnight to give 25.33 grams product as an off-white solid (86% yield). The product was shown to be pure by 1H NMR with trace amounts of the mono-ester. Physical properties of this compound are shown in Table 2 above. The FIGURE shows the rheological profile.
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:20]=[C:19]([NH:21]/[C:22](/[NH:34][CH2:35][CH:36]([CH3:38])[CH3:37])=[N:23]\[C:24](=[O:33])[C:25]3[CH:30]=[CH:29][C:28]([F:31])=[C:27]([F:32])[CH:26]=3)[NH:18][N:17]=2)=[CH:12][CH:11]=1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[F:32][C:27]1[CH:26]=[C:25]([CH:30]=[CH:29][C:28]=1[F:31])[C:24](/[N:23]=[C:22](\[NH:21][C:19]1[NH:18][N:17]=[C:16]([C:13]2[CH:14]=[CH:15][C:10]([CH2:9][OH:8])=[CH:11][CH:12]=2)[CH:20]=1)/[NH:34][CH2:35][CH:36]([CH3:38])[CH3:37])=[O:33]
Reactant: CC(C)CN/C(=N/C(=O)c1ccc(F)c(F)c1)Nc1cc(-c2ccc(CO[Si](C)(C)C(C)(C)C)cc2)n[nH]1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC(C)CN/C(=N/C(=O)c1ccc(F)c(F)c1)Nc1cc(-c2ccc(CO)cc2)n[nH]1
Temperature: 25 °C
Reaction time: 1 h
Yield: 48.6 %

Procedure:
To a solution of (Z)—N-(((3-(4-(((tert-butyldimethylsilyl)oxy)methyl)phenyl)-1H-pyrazol-5-yl)amino)(isobutylamino)methylene)-3,4-difluorobenzamide (60 mg) in THF (2 mL) was added tetrabutylammonium fluoride (TBAF) (1 M in THF, 0.122 mL, 1.1 equiv). The solution was stirred at room temperature for one hour, and partitioned between water and EtOAc. The organic phase was dried over sodium sulfate, concentrated onto silica gel, and purified by silica chromatography to provide the title compound (23 mg, 49% yield). 1HNMR (400 MHz, DMSO-d6) δ 13.18 (s, 1H), 12.60 (s, 1H), 8.96 (t, 1H), 8.00 (m, 2H), 7.70 (d, 2H), 7.48 (m, 1H), 7.40 (d, 2H), 6.60 (s, 1H), 5.23 (t, 1H), 4.50 (d, 2H), 3.43 (m, 2H), 1.92 (m, 1H), 1.00 (d, 6H); MS (EI+) m/z: 428.07; HPLC (Method B): 4.67 min.
Reaction SMILES: [N+:1]([O-:4])([O-])=[O:2].[K+].S(=O)(=O)(O)O.[CH2:11]([O:13][C:14]([C:16]1([CH3:35])[C:24]2[C:19](=[CH:20][C:21]([NH:25][C:26]([C:28]3[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=3)=[O:27])=[CH:22][CH:23]=2)[NH:18][C:17]1=[O:34])=[O:15])[CH3:12].N>>[CH2:11]([O:13][C:14]([C:16]1([CH3:35])[C:24]2[C:19](=[CH:20][C:21]([NH:25][C:26]([C:28]3[CH:29]=[CH:30][N:31]=[CH:32][CH:33]=3)=[O:27])=[C:22]([N+:1]([O-:4])=[O:2])[CH:23]=2)[NH:18][C:17]1=[O:34])=[O:15])[CH3:12]
Reactant: CCOC(=O)C1(C)C(=O)Nc2cc(NC(=O)c3ccncc3)ccc21
Reactant: O=[N+]([O-])[O-]
Agent: N
Agent: O=S(=O)(O)O
Agent: [K+]
Product: CCOC(=O)C1(C)C(=O)Nc2cc(NC(=O)c3ccncc3)c([N+](=O)[O-])cc21
Reaction time: 1 h

Procedure:
A solution of 3.9 g. (0.038 mol) potassium nitrate in 30 ml. concentrated sulphuric acid is added dropwise, while cooling, to a solution of 13 g. (0.038 mol) 3-ethoxycarbonyl-3-methyl-6-(4-pyridinoylamino)-indolin-2-one in 90 ml. concentrated sulphuric acid. The reaction mixture is further stirred for about 1 hour, poured on to ice, adjusted to pH 8 with a concentrated aqueous solution of ammonia, while cooling, and the crystals obtained are filtered off with suction and recrystallised from ethanol/methylen chloride. Yield: 12.81 g. (82% of theory); m.p. 217°-219° C.
Reaction SMILES: C[N:2](C)[CH:3]=[C:4]([C:10]1[CH:11]=[N:12][CH:13]=[C:14]([Br:16])[CH:15]=1)[C:5]([O:7]CC)=O.[NH:18]([C:20]1[N:25]=[CH:24][N:23]=[C:22]([N:26]2[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)[CH:21]=1)N.C1(C)C=CC(S(O)(=O)=O)=CC=1.[ClH:43]>C(O)C.O1CCOCC1>[ClH:43].[Br:16][C:14]1[CH:15]=[C:10]([C:4]2[C:5](=[O:7])[N:18]([C:20]3[CH:21]=[C:22]([N:26]4[CH2:31][CH2:30][O:29][CH2:28][CH2:27]4)[N:23]=[CH:24][N:25]=3)[NH:2][CH:3]=2)[CH:11]=[N:12][CH:13]=1
Reactant: CCOC(=O)C(=CN(C)C)c1cncc(Br)c1
Reactant: NNc1cc(N2CCOCC2)ncn1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: CCO
Solvent: C1COCCO1
Product: O=c1c(-c2cncc(Br)c2)c[nH]n1-c1cc(N2CCOCC2)ncn1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
At 100° C., 500 mg (1.7 mmol) of the compound from Example 11A, 326 mg (1.7 mmol) of the compound from Example 9A and 58 mg (0.3 mmol) of p-toluenesulfonic acid are stirred in 4 ml of ethanol for 16 h. After cooling to RT, 0.5 ml of a 4 N solution of hydrogen chloride in dioxane is added, and the mixture is stirred at RT for 30 min. The precipitate is filtered off, washed first with ethanol and then with diethyl ether and dried under reduced pressure.
Reaction SMILES: [CH3:1][N:2]([CH3:19])[S:3]([C:6]1[CH:14]=[CH:13][C:9]([C:10](N)=[O:11])=[C:8]([C:15]([F:18])([F:17])[F:16])[CH:7]=1)(=[O:5])=[O:4].C(O)(=[O:22])C.S(=O)(=O)(O)O.N(OCCC(C)C)=O>O>[CH3:1][N:2]([CH3:19])[S:3]([C:6]1[CH:14]=[CH:13][C:9]([C:10]([OH:22])=[O:11])=[C:8]([C:15]([F:18])([F:17])[F:16])[CH:7]=1)(=[O:5])=[O:4]
Reactant: CN(C)S(=O)(=O)c1ccc(C(N)=O)c(C(F)(F)F)c1
Reactant: CC(=O)O
Agent: CC(C)CCON=O
Agent: O=S(=O)(O)O
Solvent: O
Product: CN(C)S(=O)(=O)c1ccc(C(=O)O)c(C(F)(F)F)c1
Temperature: 70 °C

Procedure:
A mixture of 4-(N,N-dimethylsulphamoyl)-2-trifluoromethylbenzamide (1.38 g), acetic acid (10 ml) and concentrated sulphuric acid (0.5 ml) were heated to 70° C. and isoamyl nitrite (15 ml) was added over 4 hours. After cooling the mixture was poured into water and extracted with ethyl acetate and washed with water. The organic phase was extracted with 2M sodium carbonate and the aqueous layer acidified to pH 1 with 2M HCl. This was extracted with ethyl acetate, washed with water, dried (anhydrous magnesium sulphate) and filtered. The filtrate was evaporated to dryness and the residue passed through a short silica column eluting with dichloromethane-ethyl acetate to give 4-(N,N-dimethylsulphamoyl)-2-trifluoromethylbenzoic acid (0.98 g) as a white solid, m.p. 188.8°-189.4° C.
Reaction SMILES: C([N:4]1[CH2:8][CH2:7][N:6]([C:9]2[CH:18]=[CH:17][C:12]([C:13]([O:15]C)=O)=[CH:11][CH:10]=2)[C:5]1=[O:19])(=O)C.[CH3:20][C:21]1[CH:26]=[C:25]([CH3:27])[CH:24]=[CH:23][C:22]=1[N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1>>[CH3:20][C:21]1[CH:26]=[C:25]([CH3:27])[CH:24]=[CH:23][C:22]=1[N:28]1[CH2:29][CH2:30][N:31]([C:13]([C:12]2[CH:11]=[CH:10][C:9]([N:6]3[CH2:7][CH2:8][NH:4][C:5]3=[O:19])=[CH:18][CH:17]=2)=[O:15])[CH2:32][CH2:33]1
Reactant: COC(=O)c1ccc(N2CCN(C(C)=O)C2=O)cc1
Reactant: Cc1ccc(N2CCNCC2)c(C)c1
Product: Cc1ccc(N2CCN(C(=O)c3ccc(N4CCNC4=O)cc3)CC2)c(C)c1
Yield: 45.3 %

Procedure:
Using methyl 4-(3-acetyl-2-oxoimidazolidin-1-yl)benzoate (290 mg) described in Preparation Example 59 and 1-(2,4-dimethylphenyl)piperazine (209 mg) and by the reaction and treatment in the same manner as in Example 109, the title compound (188.5 mg) was obtained.
Reaction SMILES: [CH3:1][CH:2]([OH:4])[CH3:3].[H-].[Na+].Br[CH2:8][C@@H:9]1[O:28][CH2:27][C@:12]2([C:29]3[CH:34]=[CH:33][C:32]([F:35])=[CH:31][C:30]=3[F:36])[N:13]=[C:14]([NH:18][C:19](=[O:26])[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[S:15][C@H:16]([CH3:17])[C@@H:11]2[CH2:10]1>O1CCCC1>[F:36][C:30]1[CH:31]=[C:32]([F:35])[CH:33]=[CH:34][C:29]=1[C@:12]12[CH2:27][O:28][C@@H:9]([CH2:8][O:4][CH:2]([CH3:3])[CH3:1])[CH2:10][C@H:11]1[C@@H:16]([CH3:17])[S:15][C:14]([NH:18][C:19](=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[N:13]2
Reactant: C[C@H]1SC(NC(=O)c2ccccc2)=N[C@@]2(c3ccc(F)cc3F)CO[C@@H](CBr)C[C@@H]12
Reactant: CC(C)O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)OC[C@H]1C[C@H]2[C@@H](C)SC(NC(=O)c3ccccc3)=N[C@@]2(c2ccc(F)cc2F)CO1
Temperature: 55 °C
Reaction time: 0.5 h

Procedure:
2-Propanol (139 μL, 1.82 mmol) was added to a suspension of sodium hydride (60% in mineral oil, 29 mg, 0.73 mmol) in tetrahydrofuran (3 mL), and the mixture was stirred for 30 minutes. A solution of N-[(4R,4aR,6R,8aS)-6-(bromomethyl)-8a-(2,4-difluorophenyl)-4-methyl-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazin-2-yl]benzamide (C26) (90 mg, 0.18 mmol) in tetrahydrofuran (0.5 mL) was added, and the reaction mixture was heated at 55° C. for 6 hours. After cooling to room temperature, it was partitioned between saturated aqueous ammonium chloride solution (20 mL) and ethyl acetate (25 mL). The aqueous layer was extracted with ethyl acetate (2×25 mL), and the combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. Silica gel chromatography (Gradient: 0% to 70% ethyl acetate in heptane) provided the product as a white solid. Yield: 39.2 mg, 82.4 μmol, 46%. 1H NMR (400 MHz, CD3OD) δ 8.12 (br d, J=7 Hz, 2H), 7.51-7.57 (m, 1H), 7.39-7.49 (m, 3H), 7.01-7.11 (m, 2H), 4.14 (br d, J=12 Hz, 1H), 3.89 (d, J=11.9 Hz, 1H), 3.78-3.85 (m, 1H), 3.67 (septet, J=6.0 Hz, 1H), 3.48-3.58 (m, 2H), 3.19-3.28 (br m, 1H), 2.96-3.04 (m, 1H), 1.75-1.82 (m, 1H), 1.51-1.64 (m, 1H), 1.25 (d, J=7.0 Hz, 3H), 1.14 (d, J=6.0 Hz, 3H), 1.14 (d, J=6.0 Hz, 3H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][C:17]=1[O:18][CH3:19])[CH2:5][NH:6][CH:7]1[CH2:13][CH2:12][CH2:11][CH2:10][NH:9][C:8]1=[O:14].CCN(C(C)C)C(C)C.[Cl:29][C:30]1[S:34][C:33]([S:35](Cl)(=[O:37])=[O:36])=[CH:32][CH:31]=1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[F:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][C:17]=1[O:18][CH3:19])[CH2:5][N:6]([CH:7]1[CH2:13][CH2:12][CH2:11][CH2:10][NH:9][C:8]1=[O:14])[S:35]([C:33]1[S:34][C:30]([Cl:29])=[CH:31][CH:32]=1)(=[O:37])=[O:36]
Reactant: COc1ccc(CNC2CCCCNC2=O)cc1F
Reactant: O=S(=O)(Cl)c1ccc(Cl)s1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(CN(C2CCCCNC2=O)S(=O)(=O)c2ccc(Cl)s2)cc1F
Reaction time: 8 h

Procedure:
rac-3-(3-Fluoro-4-methoxy-benzylamino)-azepan-2-one (213 mg, 0.80 mmol) was dissolved in CH2Cl2 (7.7 ml) and treated with DMAP (30 mg, 0.24 mmol), Hünig's base (0.30 ml, 1.76 mmol) and ⅛ of the cooled (0° C.) reaction mixture was reacted with 5-chloro-thiophene-2-sulfonyl chloride (48 mg, 0.22 mmol) and shaken overnight in a parallel reaction block. Solvent was removed under reduced pressure and the residue dissolved in aqueous acetonitrile solution and purified using high throughput preparative RP(C18) chromatography: lyophilisate 13 mg;
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH2:12][N:13]3[CH:17]=[C:16]([C:18]([OH:20])=O)[N:15]=[N:14]3)[CH:8]=2)[N:3]=1.[NH2:21][CH2:22][C:23]1[C:24]([Cl:31])=[CH:25][C:26]([NH2:30])=[N:27][C:28]=1[CH3:29]>>[NH2:30][C:26]1[N:27]=[C:28]([CH3:29])[C:23]([CH2:22][NH:21][C:18]([C:16]2[N:15]=[N:14][N:13]([CH2:12][C:7]3[CH:8]=[C:9]4[C:4](=[CH:5][CH:6]=3)[N:3]=[C:2]([CH3:1])[CH:11]=[CH:10]4)[CH:17]=2)=[O:20])=[C:24]([Cl:31])[CH:25]=1
Reactant: Cc1nc(N)cc(Cl)c1CN
Reactant: Cc1ccc2cc(Cn3cc(C(=O)O)nn3)ccc2n1
Product: Cc1ccc2cc(Cn3cc(C(=O)NCc4c(Cl)cc(N)nc4C)nn3)ccc2n1

Procedure:
The title compound was prepared from 1-((2-Methylquinolin-6-yl)methyl)-1H-1,2,3-triazole-4-carboxylic acid and 5-(aminomethyl)-4-chloro-6-methylpyridin-2-amine in analogy to Example 20c). HPLC-MS (Method F) Rt=0.44 min. [M+H]+=422.1.
Reaction SMILES: [F:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][NH:7][C:8]([C:10]2[N:11]=[C:12]3[N:27]([CH3:28])[C:26](=[O:29])[CH2:25][N:13]3[C:14](=[O:24])[C:15]=2[O:16]CC2C=CC=CC=2)=[O:9])=[C:4]([C:32](=[O:35])[NH:33][CH3:34])[CH:3]=1>FC(F)(F)C(O)=O>[F:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][NH:7][C:8]([C:10]2[N:11]=[C:12]3[N:27]([CH3:28])[C:26](=[O:29])[CH2:25][N:13]3[C:14](=[O:24])[C:15]=2[OH:16])=[O:9])=[C:4]([C:32](=[O:35])[NH:33][CH3:34])[CH:3]=1
Reactant: CNC(=O)c1cc(F)ccc1CNC(=O)c1nc2n(c(=O)c1OCc1ccccc1)CC(=O)N2C
Solvent: O=C(O)C(F)(F)F
Product: CNC(=O)c1cc(F)ccc1CNC(=O)c1nc2n(c(=O)c1O)CC(=O)N2C
Yield: 79.1 %

Procedure:
A solution of intermediate 15, N-{4-fluoro-2-(methylcarbamoyl)benzyl}-6-benzyloxy-1-methyl-2,5-dioxo-1,2,3,5-tetrahydroimidazo[1,2-a]pyrimidine-7-carboxamide, (0.179 g, 0.37 mmol) in trifluoroacetic acid (10 ml) was stirred at 22° C. for 2 h. The solvent was then evaporated in vacuo and the residue recrystallized from ethyl acetate to give 0.114 g (78% yield) of the title amide as a white solid. 1HNMR 400 MHz (DMSO-d6) δ (ppm): 2.79 (3H, d, J=4.3 Hz, NCH3), 3.12 (3H, s, NCH3), 4.48 (2H, s, CH2), 4.58 (2H, d, J=6.3 Hz, NCH2), 7.25–7.4 (3H, m, aromatics), 8.55 (1H, broad q, NH), 9.36 (1H, broad t, NH), 12.1 (1H, s, OH). MS (ESI+) m/z 390 [M+H+].
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]([O:14][C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[NH:20][CH:19]=[C:18]2[CH2:24][CH:25]([N+:27]([O-])=O)[CH3:26])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>C(OCC)C>[CH2:7]([O:14][C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[NH:20][CH:19]=[C:18]2[CH2:24][CH:25]([NH2:27])[CH3:26])[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CC(Cc1c[nH]c2ccc(OCc3ccccc3)cc12)[N+](=O)[O-]
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: CC(N)Cc1c[nH]c2ccc(OCc3ccccc3)cc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 51.1 %

Procedure:
To a stirred suspension of lithium aluminum hydride (700 mg) in diethyl ether (25 mL) was slowly added a solution of 5-benzyloxy-3-(2-nitro-propyl)-1H-indole (650 mg) in diethyl ether (10 mL). The mixture was refluxed for 2 h. After cooling to rt, the reaction was quenched sequentially with 0.7 mL water, 0.7 mL 3 M aqueous sodium hydroxide, followed by 1.4 mL of water. The mixture was stirred at rt for 30 min and filtered. The filtrate was evaporated to afford 2-(5-benzyloxy-1H-indol-3-yl)-1-methyl-ethylamine (300 mg).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]#[C:11][C:12]1[CH:13]=[C:14]2[C:19]3=[C:20]([CH2:22][CH2:23][CH2:24][N:18]3[CH:17]=[C:16]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[C:15]2=[O:30])[CH:21]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>ClCCl>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][C:12]1[CH:13]=[C:14]2[C:19]3=[C:20]([CH2:22][CH2:23][CH2:24][N:18]3[CH:17]=[C:16]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[C:15]2=[O:30])[CH:21]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)c1cn2c3c(cc(C#CCNC(=O)OC(C)(C)C)cc3c1=O)CCC2
Solvent: ClCCl
Product: CCOC(=O)c1cn2c3c(cc(CCCNC(=O)OC(C)(C)C)cc3c1=O)CCC2

Procedure:
Ethyl 9-(3-tert-butoxycarbonylamino-prop-1-ynyl)-1-oxo-6,7-dihydro-1H,5H-pyrido[3,2,1-ij]quinoline-2-carboxylate (318 mg, 0.77 mmol) was dissolved in dichloromethane (50 mL), treated with 10% palladiun on carbon (200 mg) and hydrogenated at room temperature and atmospheric pressure overnight. The reaction mixture was filtered and concentrated to provide a brown oil which was purified by chromatography on silica gel eluting with 0-1% (9:1 MeOH/20 M NH3) in dichloromethane to yield the title compound as a brown oil. ESMS m/z 415 (MH+). 1H NMR (CDCl3) δ 8.34 (s, 1H), 8.11 (bs, 1H), 7.25 (bs, 1H), 4.60 (m, 1H), 4.37 (q, 2H), 4.17 (t, 2H), 3.13 (q, 2H), 3.02 (t, 2H), 2.71 (t,2H), 2.20 (tt, 2H), 1.85 (tt, 2H), 1.44 (s, 9H), 1.40 (t, 3H).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:13]=[C:14]3[C:19]([CH3:20])=[CH:18][CH:17]=[CH:16][N:15]3[CH:21]=2)=[CH:8][CH:7]=1.[NH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1.C(NCCCC)CCC>>[N:22]1([CH2:2][CH2:3][CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([C:12]3[N:13]=[C:14]4[C:19]([CH3:20])=[CH:18][CH:17]=[CH:16][N:15]4[CH:21]=3)=[CH:8][CH:7]=2)[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: C1CCNCC1
Reactant: Cc1cccn2cc(-c3ccc(OCCCCl)cc3)nc12
Solvent: CCCCNCCCC
Product: Cc1cccn2cc(-c3ccc(OCCCN4CCCCC4)cc3)nc12

Procedure:
This compound was prepared according to the procedure described in Example 1 of U.S. Pat. No. 4,727,145 or J. Med. Chem. 188, 31, 2221 et seq., above using 2-(4-chloropropoxyphenyl)-8-methylimidazo[1,2-a]pyridine and piperidine instead of 2-(4-chloropropoxyphenyl)-imidazo[1,2-a]pyridine and dibutylamine respectively. Analysis: Calc'd for C22H27N3O 3HCl 1H2O; C, 6.76; H, 55.41; N, 8.81. Found: C, 6.63; H, 55.02; N, 8.55.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([N:5]2[C:9]3[CH:10]=[C:11]([F:14])[CH:12]=[CH:13][C:8]=3[N:7]=[C:6]2[C@@H:15]([NH:17][C:18]2[N:26]=[CH:25][N:24]=[C:23]3[C:19]=2[N:20]=[CH:21][NH:22]3)[CH3:16])[CH2:2]1.[CH3:27][N:28]1[CH2:33]C[O:31][CH2:30][CH2:29]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH3:27][N:28]([CH3:33])[CH2:29][C:30]([N:1]1[CH2:2][CH:3]([N:5]2[C:9]3[CH:10]=[C:11]([F:14])[CH:12]=[CH:13][C:8]=3[N:7]=[C:6]2[CH:15]([NH:17][C:18]2[N:26]=[CH:25][N:24]=[C:23]3[C:19]=2[N:20]=[CH:21][NH:22]3)[CH3:16])[CH2:4]1)=[O:31]
Reactant: CN1CCOCC1
Reactant: C[C@H](Nc1ncnc2[nH]cnc12)c1nc2ccc(F)cc2n1C1CNC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: CC(Nc1ncnc2[nH]cnc12)c1nc2ccc(F)cc2n1C1CN(C(=O)CN(C)C)C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 21.8 %

Procedure:
A mixture of [(S)-1-(1-azetidin-3-yl-6-fluoro-1H-benzoimidazol-2-yl)ethyl]-(9H-purin-6-yl)amine (75 mg, 0.21 mmol) dimethylaminoacetic acid (25 mg. 0.23 mmol), 4-methylmorpholine (70 μL, 0.64 mmol) and HATU (93 mg, 0.24 mmol) in DMF (2 mL) was stirred at RT for 4 h. The crude mixture was partitioned between EtOAc and a saturated aqueous solution of NaHCO3. The aqueous phase was further extracted with EtOAc and the combined organic fractions washed with water, followed by brine, dried (MgSO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, gradient 0-10% 2N NH3/MeOH in DCM) followed by reverse phase HPLC (Phenomenex Gemini 5 μm C18 on a gradient 5-60%, 0.1% NH4OH in acetonitrile/water) to afford 381 as a white solid (20 mg, 22%). LCMS (Method K): RT 1.86 min [M+H]+ 438.1. 1H NMR (DMSO-d6, 400 MHz): δ 8.30-7.92 (3H, m), 7.71-7.63 (1H, m), 7.45-7.34 (1H, m), 7.11 (1H, t, J=9.36 Hz), 5.93-5.58 (2H, m), 4.82-4.69 (1H, m), 4.67-4.56 (1H, m), 4.49-4.34 (1H, m), 4.25-4.26 (1H, m), 3.14 (1H, d, J=14.18 Hz), 2.89 (1H, dd, J=14.18, 3.84 Hz), 2.23 (3H, s), 2.22 (3H, s), 1.67 (3H, d, J=6.66 Hz)
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][C:13]=1[OH:14])[C:8]([OH:10])=[O:9])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].[I-:17].[Na+].Cl[O-].[Na+].S([O-])([O-])(=O)=S.[Na+].[Na+]>CO>[C:1]([C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([I:17])[C:13]=1[OH:14])[C:8]([OH:10])=[O:9])([CH3:4])([CH3:2])[CH3:3]
Reactant: [I-]
Reactant: CC(C)(C)c1cc(C(=O)O)ccc1O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Agent: [O-]Cl
Solvent: CO
Product: CC(C)(C)c1cc(C(=O)O)cc(I)c1O
Temperature: 0 °C
Reaction time: 2 h
Yield: 75 %

Procedure:
20 g (103 mmol) of 3-tert-butyl-4-hydroxybenzoic acid are dissolved in 400 mL of methanol. 4.12 g (103 mmol) of sodium hydroxide and 15.4 g (103 mmol) of sodium iodide are added. The reaction medium is cooled to 0° C., and 234 g (113 mmol) of 3.6% sodium hypochlorite are added slowly. The medium is stirred at 0° C. for 2 hours and is then treated with saturated sodium thiosulfate solution. The aqueous phase is acidified and extracted with ethyl ether. A pale yellow solid is obtained (m=24.7 g; yield=75%; m.p.=178° C.).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][N:11](C=O)[CH:12]=[O:13])=[N:6][C:5]=1[Cl:16].O.C(O)=O>CO>[CH3:1][O:2][C:3](=[O:17])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][NH:11][CH:12]=[O:13])=[N:6][C:5]=1[Cl:16]
Reactant: COC(=O)c1ccc(CN(C=O)C=O)nc1Cl
Solvent: O=CO
Solvent: O
Solvent: CO
Product: COC(=O)c1ccc(CNC=O)nc1Cl

Procedure:
To a solution of 2-chloro-6-diformylaminomethylnicotinic acid methyl ester (53.0 g, 0.21 mol) in methanol (300 mL) was added water (3.72 mL, 0.21 mol) and formic acid (15.6 mL, 0.42 mol) before the reaction mixture was heated at reflux for 16 hours. The reaction mixture was concentrated in vacuo and the residue dissolved in ethyl acetate (200 mL). The resultant solution was washed with water (200 mL) and the aqueous layer extracted with ethyl acetate (2×100 mL). The combined organic extracts were washed with brine (100 mL), dried (MgSO4) and concentrated in vacuo to yield the title compound as an orange oil which solidified on standing (42.6 g, 90%). 1H NMR (CDCl3, 400 MHz) 8.34 (1H, s), 8.17 (1H, d, J=8.0 Hz), 7.31 (1H, d, J=7.8 Hz), 6.63 (1H, br s), 4.63 (2H, d, J=5.6 Hz), 3.96 (3H, s).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([Br:8])[N:5]=[C:4]([CH3:9])[C:3]=1[OH:10].C([Li])CCC.CCCCCC>O1CCCC1>[Br:8][C:6]1[N:5]=[C:4]([CH3:9])[C:3]([OH:10])=[CH:2][CH:7]=1
Reactant: Cc1nc(Br)cc(Br)c1O
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Cc1nc(Br)ccc1O
Temperature: -78 °C
Reaction time: 2 h
Yield: 93.3 %

Procedure:
4,6-Dibromo-2-methyl-pyridin-3-ol (14.32 g, 53.65 mmol) was dissolved in tetrahydrofuran (181 mL). The solution was cooled to −78° C. and n-butyllithium in hexane (45.16 mL of 2.5 M, 112.9 mmol) was added drop-wise keeping the temperature at −78° C. The mixture was stirred for 2 hours before it was quenched with water (45 mL) and neutralized with 1 N HCl. The aqueous mixture was extracted with dichloromethane (3×100 mL). The organic layers were combined and dried over sodium sulfate, filtered and the solvent was evaporated under reduced pressure to yield 6-bromo-2-methyl-pyridin-3-ol (9.41 g, 93%). 1H NMR (400 MHz, DMSO) δ 10.10 (s, 1H), 7.24 (d, J=8.4 Hz, 1H), 7.08 (d, J=8.4 Hz, 1H), 2.29 (s, 3H). ESI-MS m/z calc. 187.0, found 188.3 (M+1)+; Retention time: 0.85 minutes (3 min run).