Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([O:4][CH2:5][CH2:6][NH:7][C:8]1[CH:30]=[CH:29][C:11]([C:12]([N:14]2[CH2:19][CH2:18][N:17]([CH2:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=3)[CH2:16][CH2:15]2)=[O:13])=[CH:10][CH:9]=1)([CH3:3])[CH3:2].[Cl:31][CH2:32][C:33](Cl)=[O:34]>C(Cl)Cl>[CH:1]([O:4][CH2:5][CH2:6][N:7]([C:8]1[CH:30]=[CH:29][C:11]([C:12]([N:14]2[CH2:15][CH2:16][N:17]([CH2:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=3)[CH2:18][CH2:19]2)=[O:13])=[CH:10][CH:9]=1)[C:33](=[O:34])[CH2:32][Cl:31])([CH3:3])[CH3:2]
Reactant: CC(C)OCCNc1ccc(C(=O)N2CCN(CCc3ccc(Cl)cc3)CC2)cc1
Reactant: O=C(Cl)CCl
Solvent: ClCCl
Product: CC(C)OCCN(C(=O)CCl)c1ccc(C(=O)N2CCN(CCc3ccc(Cl)cc3)CC2)cc1

Procedure:
In a manner analogous to that described in Example 6, the oily 1-{4-[N-(2-isopropyloxyethyl)-N-chloroacetylamino]benzoyl}-4-[2-(4-chlorophenyl)ethyl]piperazine is prepared from 1.35 g of 1-[4-(2-isopropyloxyethyl)aminobenzoyl]-4-[2-(4-chlorophenyl)ethyl]piperazine by reaction with chloroacetyl chloride; IR (CH2Cl2): 1650 cm-1 (broad); NMR (CDCl3): 1.15 (t, 3H), 1.8 (m, 2H), 2.5 (m) and 2.6 (t) (together 6H), 2.8 (t, 2H), 3.4 (m, 6H), 3.85 (m, 6H), 7.15 (d, 2H), 7.3 (m, 4H), 7.5 ppm (d, 2H).
Reaction SMILES: [CH3:1][CH:2]([NH2:5])[CH2:3][OH:4].[OH:6][CH2:7][C:8](=O)[CH3:9]>CO.[Pt](=O)=O>[OH:4][CH2:3][CH:2]([NH:5][CH:8]([CH3:9])[CH2:7][OH:6])[CH3:1]
Reactant: CC(N)CO
Reactant: CC(=O)CO
Agent: O=[Pt]=O
Solvent: CO
Product: CC(CO)NC(C)CO
Reaction time: 18 h

Procedure:
Platinum dioxide (40 mg) was added to a solution of dl-2-amino-1-propanol (6.4 ml) and hydroxyacetone (7.0 g) in methanol (75 ml) over 3A molecular sieves. The reaction mixture was hydrogenated at 60 psi. for 18 hours, after which time the catalyst was filtered off and the solvent removed under reduced pressure. The crude product was purified by distillation, b.pt. 94° C. @ 0.2 mbar to afford 2-[(2-hydroxy-1-methylethyl)amino]-1-propanol (3.66 g) as a yellow oil.
Reaction SMILES: CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.Cl[C:36]1[N:44]=[C:43]2[C:39]([N:40]=[C:41]([CH:46]=[O:47])[N:42]2[CH3:45])=[C:38]([N:48]2[CH2:53][CH2:52][O:51][CH2:50][CH2:49]2)[N:37]=1.[CH2:54]([C:56]1[NH:60][C:59]2[CH:61]=[CH:62][CH:63]=[CH:64][C:58]=2[N:57]=1)C.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:45][N:42]1[C:41]([CH:46]=[O:47])=[N:40][C:39]2[C:43]1=[N:44][C:36]([N:57]1[C:58]3[CH:64]=[CH:63][CH:62]=[CH:61][C:59]=3[N:60]=[C:56]1[CH3:54])=[N:37][C:38]=2[N:48]1[CH2:53][CH2:52][O:51][CH2:50][CH2:49]1
Reactant: Cn1c(C=O)nc2c(N3CCOCC3)nc(Cl)nc21
Reactant: CCc1nc2ccccc2[nH]1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C=O)n(C)c2n1
Temperature: 145 °C
Yield: 48.9 %

Procedure:
A mixture of Pd2(dba)3 (161 mg, 0.18 mmol), Xphos (CAS Reg. No. 564483-18-7, 336 mg, 0.72 mmol), 2-chloro-9-methyl-6-morpholin-4-yl-9H-purine-8-carbaldehyde (1.0 g, 3.52 mmol), 2-ethyl-1H-benzoimidazole (500 mg, 3.73 mmol), cesium carbonate (2.3 g, 7 mmol) in dioxane (15 mL) was degassed for 5 min and heated at 145° C. for 30 min under microwave irradiation. The reaction mixture was filtered while still hot through a pad of celite, and the pad was washed with hot dioxane. The product precipitated immediately as a pale yellow solid. The solid was filtered and dried at 50° C. under vacuum to give 9-Methyl-2-(2-methylbenzoimidazol-1-yl)-6-morpholin-4-yl-9H-purine-8-carbaldehyde (650 mg, 50%). Additional material could be recovered from the mother liquors. LCMS (Method H): RT 3.39 min; [M+MeOH]+ 410
Reaction SMILES: C[N:2](C)[CH:3]=[C:4]([C:7]1[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=1)[C:5]#[N:6].N[OH:19].Cl>C(O)C>[F:14][C:13]([F:16])([F:15])[C:10]1[CH:11]=[CH:12][C:7]([C:4]2[CH:5]=[N:6][O:19][C:3]=2[NH2:2])=[CH:8][CH:9]=1
Reactant: NO
Reactant: CN(C)C=C(C#N)c1ccc(C(F)(F)F)cc1
Agent: Cl
Solvent: CCO
Product: Nc1oncc1-c1ccc(C(F)(F)F)cc1

Procedure:
3-Dimethylamino-2-(4-(trifluoromethyl)phenyl)-acrylonitrile (2.5 g), and NH2OH.HCl (1.5 g) were refluxed in ethanol for 2 hours. After evaporation of the solvent, water was added and the final product was filtered, recrystallized from methylene chloride, and identified by NMR analysis.
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[O:15])[CH2:10][C@H:9]2[CH3:22])=[C:4]2[N:23]=[CH:24][CH:25]=[CH:26][C:3]=12.[Cl:27][C:28]1[CH:33]=[CH:32][C:31](B(O)O)=[C:30]([F:37])[CH:29]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:27][C:28]1[CH:33]=[CH:32][C:31]([C:2]2[N:7]=[N:6][C:5]([N:8]3[CH2:13][CH2:12][N:11]([C:14]([C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=4)=[O:15])[CH2:10][C@H:9]3[CH3:22])=[C:4]3[N:23]=[CH:24][CH:25]=[CH:26][C:3]=23)=[C:30]([F:37])[CH:29]=1
Reactant: C[C@@H]1CN(C(=O)c2ccccc2)CCN1c1nnc(Cl)c2cccnc12
Reactant: OB(O)c1ccc(Cl)cc1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: C[C@@H]1CN(C(=O)c2ccccc2)CCN1c1nnc(-c2ccc(Cl)cc2F)c2cccnc12

Procedure:
Using methods described in Example 6, and starting with (R)-(4-(5-chloropyrido[2,3-d]pyridazin-8-yl)-3-methylpiperazin-1-yl)(phenyl)methanone 79 (180 mg, 489 μmol), 4-chloro-2-fluorophenylboronic acid (128 mg, 734 μmol), tetrakis(triphenylphosphine)palladium (28 mg, 24 μmol), and 2 M sodium carbonate (489 μl, 979 μmol) afforded ((R)-4-(5-(4-chloro-2-fluorophenyl)pyrido[2,3-d]pyridazin-8-yl)-3-methylpiperazin-1-yl)(phenyl)methanone 83 after chromatographic purification. MS 461.1 (calc'd) 462.1 (M+H, found).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[C:5]([CH3:20])([O:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)[CH:9]=1)[CH3:6])C.Cl.[H][H]>CO.[Pt]>[CH3:1][O:3][C:4](=[O:21])[C:5]([CH3:6])([O:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([CH:14]2[CH2:19][CH2:18][CH2:17][NH:16][CH2:15]2)[CH:9]=1)[CH3:20]
Reactant: CCOC(=O)C(C)(C)Oc1cccc(-c2cccnc2)c1
Reactant: [H][H]
Agent: [Pt]
Agent: Cl
Solvent: CO
Product: COC(=O)C(C)(C)Oc1cccc(C2CCCNC2)c1
Yield: 82.3 %

Procedure:
2-methyl-2-(3-pyridin-3-yl-phenoxy)-propionic acid ethyl ester (6.0 g, 21.03 mmol) was dissolved in methanol (70 mL) and followed by the addition of 37% HCl (5.3 mL) and 10% Pt/C (0.60 g). The mixture was shaken with hydrogen under 50 psi at 50° C. in a Parr bottle for 5 h, filtered through a pad of Celite, and rinsed with methanol. GC/MS showed complete hydrogenation and only 50% of methyl ester conversion. Concentrated H2SO4 (2.0 mL) was added to the filtrate and the resulting solution was allowed to reflux under nitrogen overnight. After removal of excess methanol, the residue was treated with saturated Na2CO3 (150 mL) and extracted with ethyl acetate (2×200 mL). The organic extract was washed with water, dried over sodium sulfate, and concentrated to give 4.80 g (82%) of 2-methyl-2-(3-piperidin-3-yl-phenoxy)-propionic acid methyl ester as a yellow oil: 1H NMR (CDCl3) δ 1.59 (s, 6H), 1.78 (br, 1H), 1.97 (br d, 1H), 2.02 (br, 2H), 2.61 (m, 3H), 3.06 –3.13 (m, 2H), 3.76 (s, 3H), 6.61 (dd, 1H), 6.70 (s, 1H), 6.83 (d, 1H), 7.14 (t, 1H); MS m/z (relative intensity) 277 (M+, 2), 218 (6), 176 (100).
Reaction SMILES: BrC1C=C(C(Cl)=O)C=CC=1.[CH3:11][O:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][C:22]=1[O:23][CH3:24])[N:19]=[CH:18][N:17]=[C:16]2[O:25][C:26]1[CH:32]=[CH:31][C:29]([NH2:30])=[CH:28][CH:27]=1.[Br:33][C:34]1[CH:35]=[C:36]([C:40]([N:42]=[C:43]=[S:44])=[O:41])[CH:37]=[CH:38][CH:39]=1>C1(C)C=CC=CC=1.C(O)C>[Br:33][C:34]1[CH:35]=[C:36]([C:40]([N:42]=[C:43]=[S:44])=[O:41])[CH:37]=[CH:38][CH:39]=1.[Br:33][C:34]1[CH:35]=[C:36]([CH:37]=[CH:38][CH:39]=1)[C:40]([NH:42][C:43]([NH:30][C:29]1[CH:31]=[CH:32][C:26]([O:25][C:16]2[C:15]3[C:20](=[CH:21][C:22]([O:23][CH3:24])=[C:13]([O:12][CH3:11])[CH:14]=3)[N:19]=[CH:18][N:17]=2)=[CH:27][CH:28]=1)=[S:44])=[O:41]
Reactant: COc1cc2ncnc(Oc3ccc(N)cc3)c2cc1OC
Agent: O=C(Cl)c1cccc(Br)c1
Agent: O=C(N=C=S)c1cccc(Br)c1
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1cc2ncnc(Oc3ccc(NC(=S)NC(=O)c4cccc(Br)c4)cc3)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 70 %

Procedure:
3-Bromo-1-benzenecarbonyl isothiocyanate was prepared using commercially available 3-bromo-1-benzenecarbonyl chloride (80 mg) as a starting compound according to the description of the literature. 4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]aniline (50 mg) was dissolved in toluene (5 ml) and ethanol (1 ml) to prepare a solution. A solution of 3-bromo-1-benzenecarbonyl isothiocyanate in ethanol (1 ml) was then added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (61 mg, yield 70%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH3:9])[N:3]=1.C([Li])CCC.CCCCCC.[O:21]1[CH:25]=[CH:24][CH:23]=[C:22]1[C:26]1[N:27]=[C:28]([NH:37][C:38]([C:40]2[CH:45]=[CH:44][N:43]=[CH:42][CH:41]=2)=[O:39])[S:29][C:30]=1[C:31](=[O:36])N(OC)C.[Cl-].[NH4+]>C1COCC1>[O:21]1[CH:25]=[CH:24][CH:23]=[C:22]1[C:26]1[N:27]=[C:28]([NH:37][C:38]([C:40]2[CH:41]=[CH:42][N:43]=[CH:44][CH:45]=2)=[O:39])[S:29][C:30]=1[C:31]([C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH3:9])[N:3]=1)=[O:36]
Reactant: CON(C)C(=O)c1sc(NC(=O)c2ccncc2)nc1-c1ccco1
Reactant: COc1cccc(Br)n1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COc1cccc(C(=O)c2sc(NC(=O)c3ccncc3)nc2-c2ccco2)n1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 34 %

Procedure:
2-Bromo-6-methoxypyridine (0.274 mL, 2.23 mmol) was dissolved in THF (1 mL), and a 1.58 mol/L solution of n-butyllithium in n-hexane (1.42 mL, 2.23 mmol) was added thereto in a stream of argon at −78° C., followed by stirring for 15 minutes at −78° C. A solution of Compound 98 (200 mg, 0.558 mmol) in THF (2 mL) was added dropwise to the reaction mixture, followed by stirring at room temperature for 1.5 hours. The reaction mixture was poured into a saturated aqueous solution of ammonium chloride, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and then the solvent was distilled away under reduced pressure. The resulting residue was purified through silica gel column chromatography (hexane:ethyl acetate=1:9) to afford the entitled Compound 283 (77.0 mg, 34%).
Reaction SMILES: [CH:1]1([N:7]([CH3:29])[C:8]([C:10]2[CH:11]=[N:12][N:13]([C:18]3[CH:28]=[CH:27][C:21]([C:22]([O:24]CC)=[O:23])=[CH:20][CH:19]=3)[C:14]=2[CH2:15][CH2:16][CH3:17])=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+]>CO>[CH:1]1([N:7]([CH3:29])[C:8]([C:10]2[CH:11]=[N:12][N:13]([C:18]3[CH:19]=[CH:20][C:21]([C:22]([OH:24])=[O:23])=[CH:27][CH:28]=3)[C:14]=2[CH2:15][CH2:16][CH3:17])=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCCc1c(C(=O)N(C)C2CCCCC2)cnn1-c1ccc(C(=O)OCC)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCc1c(C(=O)N(C)C2CCCCC2)cnn1-c1ccc(C(=O)O)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Ethyl 4-[4-(cyclohexyl-methyl-carbamoyl)-5-propyl-pyrazol-1-yl]benzoate (Intermediate #23, 105 mg, 0.26 mmol) was dissolved in methanol (10 mL) and treated at ambient temperature with 2M aqueous sodium hydroxide solution (2.5 mL). The mixture was stirred at ambient temperature for 18 h and then methanol was removed by evaporation under reduced pressure. The remaining aqueous solution was acidified with 2M aqueous hydrochloric acid to pH=2. A white solid precipitated out of solution, it was filtered, dried under vacuum and identified as the desired product (96 mg, quantitative reaction).
Reaction SMILES: [O:1]=[C:2]1[CH2:11][CH:10]([C:12]2[CH:13]=[C:14]([CH:17]=[CH:18][CH:19]=2)[C:15]#[N:16])[C:9]2[C:4](=[C:5]3[CH:23]=[CH:22][CH:21]=[CH:20][C:6]3=[CH:7][CH:8]=2)[NH:3]1.[N-:24]=[N+:25]=[N-:26].[Na+].[Cl-].[NH4+]>CN(C)C=O>[NH:24]1[C:15]([C:14]2[CH:13]=[C:12]([CH:10]3[C:9]4[C:4](=[C:5]5[CH:23]=[CH:22][CH:21]=[CH:20][C:6]5=[CH:7][CH:8]=4)[NH:3][C:2](=[O:1])[CH2:11]3)[CH:19]=[CH:18][CH:17]=2)=[N:16][N:26]=[N:25]1
Reactant: [N-]=[N+]=[N-]
Reactant: N#Cc1cccc(C2CC(=O)Nc3c2ccc2ccccc32)c1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1CC(c2cccc(-c3nnn[nH]3)c2)c2ccc3ccccc3c2N1
Temperature: 130 °C
Reaction time: 18 h
Yield: 39.9 %

Procedure:
A mixture of 3-(2-Oxo-1,2,3,4-tetrahydro-benzo[h]quinolin-4-yl)-benzonitrile (0.50 g, 1.68 mmol), sodium azide (0.13 g, 2.0 mmol) and ammonium chloride (0.11 g, 2.01 mmol) in dimethylformamide (3.5 ml) was heated with stirring at 130° C. for 18 hr. The solvent was removed in vacuo and water was added. The solution was acidified with dilute hydrochloric acid to afford a precipitate which was separated by filtration. Crystallization from methanol afforded the title compound (0.23 g, 0.67 mmol).
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH:15][C:16]1[CH:17]=[CH:18][CH:19]=[C:20]2[C:25]=1[N:24]=[C:23]([CH:26]=O)[CH:22]=[CH:21]2.[NH2:28][CH2:29][CH2:30][C:31]1[N:35]=[CH:34][NH:33][CH:32]=1>ClC(Cl)C>[NH:33]1[CH:32]=[C:31]([CH2:30][CH2:29][NH:28][CH2:26][C:23]2[CH:22]=[CH:21][C:20]3[C:25](=[C:16]([OH:15])[CH:17]=[CH:18][CH:19]=3)[N:24]=2)[N:35]=[CH:34]1
Reactant: O=Cc1ccc2cccc(O)c2n1
Reactant: NCCc1c[nH]cn1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Product: Oc1cccc2ccc(CNCCc3c[nH]cn3)nc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 61.5 %

Procedure:
Sodium triacetoxyborohydride (225 mg, 1.061 mmol) was added to a stirred solution of 8-hydroxy-quinoline-2-carboxaldehyde 4 (200 mg, 1.156 mmol) and histamine (128 mg, 1.152 mmol) in dichloroethane (10 mL). The mixture was left to stir at RT for 16 h, neutralized (aqueous NaHCO3), and concentrated. The resulting residue, after column chromatography on silica (ethyl acetate/i-PrOH/2 N NH4OH, 6:2:1), afforded 2-{[2-(1H-imidazol-4-yl)-ethylamino]-methyl}-quinolin-8-ol F1 as a straw-colored solid (190 mg, 61%). The above method was repeated using other amines: 2-(aminomethyl)pyridine gave F2 and 2-(2-methylaminoethyl)pyridine gave F3, data given in Table 2.
Reaction SMILES: [O:1]=[C:2]1[N:25]([CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][C:34]([O:36]CC)=[O:35])[C:6]2=[N:7][C:8]([C:18]3[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=3)=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=3)[N:10]=[C:5]2[CH2:4][CH2:3]1.[OH-].[Na+]>CO>[O:1]=[C:2]1[N:25]([CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][C:34]([OH:36])=[O:35])[C:6]2=[N:7][C:8]([C:18]3[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=3)=[C:9]([C:11]3[CH:12]=[CH:13][C:14]([CH3:17])=[CH:15][CH:16]=3)[N:10]=[C:5]2[CH2:4][CH2:3]1
Reactant: CCOC(=O)CCCCCCCCN1C(=O)CCc2nc(-c3ccc(C)cc3)c(-c3ccc(C)cc3)nc21
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1ccc(-c2nc3c(nc2-c2ccc(C)cc2)N(CCCCCCCCC(=O)O)C(=O)CC3)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of ethyl 9-(6-oxo-2,3-di-p-tolyl-7,8-dihydropyrido[2,3-b]pyrazin-5(6H)-yl)nonanoate (step 1)(392.5 mg, 0.764 mmol) in MeOH (10 ml) was treated with 1M NaOH (2.292 ml, 2.292 mmol) and stirred at RT overnight. The mixture was concentrated under reduced pressure to remove MeOH and acidified using 1M HCl. The resulting mixture was extracted with DCM and the organic extracts were concentrated under reduced pressure to afford the titled compound;
Reaction SMILES: [C:1]([O:5][C:6](=[O:28])[NH:7][C@H:8]([C:10](=O)[NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[NH:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([C:25]#[N:26])[CH:20]=1)[CH3:9])([CH3:4])([CH3:3])[CH3:2]>CC(O)=O>[C:1]([O:5][C:6](=[O:28])[NH:7][C@H:8]([C:10]1[N:18]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([C:25]#[N:26])[CH:20]=2)[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[N:11]=1)[CH3:9])([CH3:4])([CH3:3])[CH3:2]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)Nc1ccccc1Nc1cccc(C#N)c1
Solvent: CC(=O)O
Product: C[C@H](NC(=O)OC(C)(C)C)c1nc2ccccc2n1-c1cccc(C#N)c1
Temperature: 25 °C
Yield: 85.4 %

Procedure:
A solution of {(S)-1-[2-(3-cyanophenylamino)phenylcarbamoyl]ethyl}carbamic acid tert-butyl ester (289 mg, 0.75 mmol) in AcOH (3 mL) was heated at 80° C. for 16 h. After cooling to RT, the volatiles were removed in vacuo and the residue dissolved in DCM and washed with a saturated aqueous solution of NaHCO3. The aqueous phase was further extracted with DCM (×3) and the combined organic fractions were dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, gradient 0-2% 2M NH3/MeOH in DCM) to afford the title compound (232 mg, 86%). The material was still impure and taken forward in the next step without further purification. LCMS (Method C): RT 3.54 min [M+H]+ 363.4
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][C:5]1[N:6]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([OH:25])=O)[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[CH:9][C:8]=2[N:17]=1.C(Cl)(=O)C(Cl)=O.[NH:32]1[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1>>[CH3:1][O:2][CH2:3][CH2:4][C:5]1[N:6]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)=[O:25])[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[CH:9][C:8]=2[N:17]=1
Reactant: C1COCCN1
Reactant: COCCc1nc2cnc3ccccc3c2n1CCCCCC(=O)O
Agent: O=C(Cl)C(=O)Cl
Product: COCCc1nc2cnc3ccccc3c2n1CCCCCC(=O)N1CCOCC1
Reaction time: 2 h
Yield: 92.4 %

Procedure:
6-[2-(2-Methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]hexanoic acid (4.1 g, 12 mmol) was treated with oxalyl chloride (1.89 mL, 21.6 mmol) and morpholine (3.15 mL, 36.0 mmol) according to a modification of the method described in Part F of Example 6. The reaction with oxalyl chloride was carried out at ambient temperature, and the reaction with morpholine was complete after two hours. Following the work-up procedure, 4.55 g of 2-(2-methoxyethyl)-1-(6-morpholin-4-yl-6-oxohexyl)-1H-imidazo[4,5-c]quinoline were obtained.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][O:9][C:10](=[O:60])[C@@H:11]([NH:52]C(OC(C)(C)C)=O)[C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][C:21]([C:24]([C:29]3[CH:34]=[CH:33][C:32]([CH2:35][CH2:36][CH:37]([O:42][Si](C(C)(C)C)(C)C)[C:38]([CH3:41])([CH3:40])[CH3:39])=[C:31]([CH3:50])[CH:30]=3)([CH2:27][CH3:28])[CH2:25][CH3:26])=[CH:20][C:19]=2[CH3:51])=[CH:14][CH:13]=1>ClCCl>[CH3:8][O:9][C:10](=[O:60])[C@@H:11]([NH2:52])[C:12]1[CH:13]=[CH:14][C:15]([C:18]2[CH:23]=[CH:22][C:21]([C:24]([CH2:25][CH3:26])([C:29]3[CH:34]=[CH:33][C:32]([CH2:35][CH2:36][CH:37]([OH:42])[C:38]([CH3:39])([CH3:40])[CH3:41])=[C:31]([CH3:50])[CH:30]=3)[CH2:27][CH3:28])=[CH:20][C:19]=2[CH3:51])=[CH:16][CH:17]=1
Reactant: CCC(CC)(c1ccc(CCC(O[Si](C)(C)C(C)(C)C)C(C)(C)C)c(C)c1)c1ccc(-c2ccc([C@H](NC(=O)OC(C)(C)C)C(=O)OC)cc2)c(C)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCC(CC)(c1ccc(CCC(O)C(C)(C)C)c(C)c1)c1ccc(-c2ccc([C@H](N)C(=O)OC)cc2)c(C)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 83 %

Procedure:
Trifluoroacetic acid (0.25 mL) was added to a solution of (S)-t-butoxycarbonylamino-[4′-(1-{4-[3-(t-butyl-dimethyl-silanyloxy)-4,4-dimethyl-pentyl]-3-methyl-phenyl}-1-ethyl-propyl)-2′-methyl-biphenyl-4-yl]acetic acid methyl ester (Example 166-(2); 20.3 mg, 0.0273 mmol) in dichloromethane (1.3 mL) at room temperature, and the mixture was stirred at room temperature for 30 minutes. The solvent in the reaction solution was distilled off under reduced pressure, and the residue was diluted with diethyl ether. The mixture was adjusted to pH 7 with aqueous sodium bicarbonate solution, followed by extraction with diethyl ether. The extract was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane/ethyl acetate=2/1) to give the title compound (12.0 mg, 83%).
Reaction SMILES: [CH2:1]([O:4][CH:5]([C:10]1[N:11]=[N:12][N:13]([CH2:15][C:16]2[CH:47]=[C:19]3[N:20]=[C:21]([CH3:46])[C:22]([C@H:35]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])[C:36]([O:38]CC)=[O:37])=[C:23]([N:24]4[CH2:29][CH2:28][C:27]([O:31][CH2:32][CH:33]=C)([CH3:30])[CH2:26][CH2:25]4)[N:18]3[N:17]=2)[CH:14]=1)[CH2:6][CH:7]([CH3:9])[CH3:8])[CH:2]=C.[OH-].[Na+]>ClCCCl.CC1C=C(C)C(N2C(=[Ru](Cl)(Cl)=CC3C=CC=CC=3OC(C)C)N(C3C(C)=CC(C)=CC=3C)CC2)=C(C)C=1.CO>[C:42]([O:41][C@@H:35]([C:22]1[C:21]([CH3:46])=[N:20][C:19]2=[CH:47][C:16]3=[N:17][N:18]2[C:23]=1[N:24]1[CH2:29][CH2:28][C:27]([CH3:30])([O:31][CH2:32][CH:33]=[CH:2][CH2:1][O:4][CH:5]([CH2:6][CH:7]([CH3:8])[CH3:9])[C:10]2[N:11]=[N:12][N:13]([CH:14]=2)[CH2:15]3)[CH2:26][CH2:25]1)[C:36]([OH:38])=[O:37])([CH3:45])([CH3:43])[CH3:44]
Reactant: C=CCOC(CC(C)C)c1cn(Cc2cc3nc(C)c([C@H](OC(C)(C)C)C(=O)OCC)c(N4CCC(C)(OCC=C)CC4)n3n2)nn1
Agent: Cc1cc(C)c(N2CCN(c3c(C)cc(C)cc3C)C2=[Ru](Cl)(Cl)=Cc2ccccc2OC(C)C)c(C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCCl
Solvent: CO
Product: Cc1nc2cc3nn2c(c1[C@H](OC(C)(C)C)C(=O)O)N1CCC(C)(CC1)OCC=CCOC(CC(C)C)c1cn(nn1)C3
Reaction time: 2 h
Yield: 119 %

Procedure:
To a stirred solution of (2S)-ethyl 2-(2-((4-(1-(allyloxy)-3-methylbutyl)-1H-1,2,3-triazol-1-yl)methyl)-7-(4-(allyloxy)-4-methylpiperidin-1-yl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetate (0.080 g, 0.123 mmol) in 1,2-dichloroethane (30 mL) was added Hoveyda-Grubbs catalyst 2nd generation (3.85 mg, 6.14 μmol) at 70° C. After 2 h at 75° C., the reaction mixture was filtered through a plug of silica gel (washed with 10 mL of EtOAC), concentrated and used in the next step without purification. A solution of above crude ester and NaOH (0.491 ml, 0.491 mmol) in MeOH (4 mL) was refluxed for 2 h. Then, cooled and purified by prep-HPLC to afford mixture of diastereomers (0.087 g, 0.146 mmol, 119% yield) as white solid. LCMS (M+H)=596.7.
Reaction SMILES: [NH2:1][C:2]1[C:3]([S:9]([NH2:12])(=[O:11])=[O:10])=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1.[CH:13]([O-])([O-])OCC>>[CH3:8][C:6]1[CH:5]=[N:4][C:3]2[S:9](=[O:11])(=[O:10])[N:12]=[CH:13][NH:1][C:2]=2[CH:7]=1
Reactant: Cc1cnc(S(N)(=O)=O)c(N)c1
Reactant: CCOC([O-])[O-]
Product: Cc1cnc2c(c1)NC=NS2(=O)=O

Procedure:
A suspension of 1.3 g of 3-amino-5-methylpyridine-2-sulfonamide (Preparation 25) in 13 cm3 of ethyl orthoformate is brought to reflux for 2 hours. After cooling, the precipitate obtained is collected on a filter, washed with diethyl ether and dried.