Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:4]([CH2:7][CH3:8])[CH2:5][CH3:6])[CH:2]=[CH2:3].[C:9]1([PH:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(N(CC)C(C)CP(C1C=CC=CC=1)C1C=CC=CC=1)C>>[CH2:5]([N:4]([CH2:1][CH2:2][CH2:3][P:15]([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH2:7][CH3:8])[CH3:6]
Reactant: C=CCN(CC)CC
Reactant: c1ccc(Pc2ccccc2)cc1
Agent: CCN(CC)C(C)CP(c1ccccc1)c1ccccc1
Product: CCN(CC)CCCP(c1ccccc1)c1ccccc1

Procedure:
A mixture of 17 g (0.15 mole) allyl diethyl amine and 30.7 g (0.165 mole, 10% excess) of diphenyl phosphine is reacted in the usual manner with u.v. irradiation for 17 hours. A subsequent analysis of the reaction mixture indicated that about one third of the reactants was converted. The only product formed was the desired adduct, 2-diethylaminopropyl diphenylphosphine. It was isolated as a clear colorless liquid (Table 3).
Reaction SMILES: Cl[C:2]1[C:3]([F:18])=[CH:4][C:5]([N+:15]([O-:17])=[O:16])=[C:6]([N:8]2[CH2:13][CH2:12][CH:11]([CH3:14])[CH2:10][CH2:9]2)[CH:7]=1.[CH3:19][N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1>CO.ClCCl>[F:18][C:3]1[CH:4]=[C:5]([N+:15]([O-:17])=[O:16])[C:6]([N:8]2[CH2:13][CH2:12][CH:11]([CH3:14])[CH2:10][CH2:9]2)=[CH:7][C:2]=1[N:23]1[CH2:24][CH2:25][N:20]([CH3:19])[CH2:21][CH2:22]1
Reactant: CN1CCNCC1
Reactant: CC1CCN(c2cc(Cl)c(F)cc2[N+](=O)[O-])CC1
Solvent: ClCCl
Solvent: CO
Product: CC1CCN(c2cc(N3CCN(C)CC3)c(F)cc2[N+](=O)[O-])CC1
Yield: 93.9 %

Procedure:
The procedure of Example 4, step (b) was followed using 88 mg (0.19 mmol based on 60% purity by 1H-NMR) of 1-(5-chloro-4-fluoro-2-nitro-phenyl)-4-methyl-piperidine (as prepared in the previous step) and 105 μL (0.950 mmol) of 1-methylpiperazine at 150° C. for 16 h. Chromatography on a 10-g silica SPE column with 24% MeOH-dichloromethane afforded 60 mg (94%) of the title compound as a crystalline orange solid: Mass spectrum (ESI, m/z): Calcd. for C17H25FN4O2, 337.2 (M+H), found 337.2.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[N:2]1.[H-].[Na+].CS(O[CH:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]1)(=O)=O>CN(C=O)C>[N:1]1([CH:13]2[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: CC(C)(C)OC(=O)N1CCC(OS(C)(=O)=O)CC1
Reactant: c1cn[nH]c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(n2cccn2)CC1
Reaction time: 0.08 h

Procedure:
To a solution of pyrazole (100 mg, 1.50 mmol) in DMF (10.0 ml) under nitrogen atmosphere was added sodium hydride (60 mg, 1.65 mmol) and the solution stirred for 5 min. After bubbling ceased, the title compound from Step A (204 mg, 1.50 mmol) in 2.5 mL of DMF was added to the solution. The mixture was placed in a microwave reaction vessel and nitrogen was blown into it before closing.
Reaction SMILES: [CH3:1][C:2]([CH3:31])([CH3:30])[CH2:3][C:4]([NH:6][C:7]1[C:8]([CH3:29])=[C:9](B(O)O)[C:10]2[O:14][CH2:13][CH:12]([C:15]3[CH:20]=[CH:19][C:18]([CH:21]([CH3:23])[CH3:22])=[CH:17][CH:16]=3)[C:11]=2[C:24]=1[CH3:25])=[O:5].Br[C:33]1[CH:34]=[C:35]([CH:39]=[CH:40][CH:41]=1)[N:36]([CH3:38])[CH3:37]>>[CH3:37][N:36]([CH3:38])[C:35]1[CH:34]=[C:33]([C:9]2[C:10]3[O:14][CH2:13][CH:12]([C:15]4[CH:20]=[CH:19][C:18]([CH:21]([CH3:22])[CH3:23])=[CH:17][CH:16]=4)[C:11]=3[C:24]([CH3:25])=[C:7]([NH:6][C:4](=[O:5])[CH2:3][C:2]([CH3:31])([CH3:30])[CH3:1])[C:8]=2[CH3:29])[CH:41]=[CH:40][CH:39]=1
Reactant: CN(C)c1cccc(Br)c1
Reactant: Cc1c(NC(=O)CC(C)(C)C)c(C)c2c(c1B(O)O)OCC2c1ccc(C(C)C)cc1
Product: Cc1c(NC(=O)CC(C)(C)C)c(C)c2c(c1-c1cccc(N(C)C)c1)OCC2c1ccc(C(C)C)cc1
Yield: 77 %

Procedure:
Using (5-((3,3-dimethylbutanoyl)amino)-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-7-yl)boronic acid obtained in Example 116 and 3-bromo-N,N-dimethylaniline, the title compound was obtained in the same manner as in Example 107. Yield: 77%. Melting point: 197-199° C. (ethyl acetate-hexane).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([O:12][C:13]3[C:14]([C:23]([O:25][CH2:26][CH2:27][CH3:28])=[O:24])=[CH:15][C:16]4[C:21]([CH:22]=3)=[CH:20][CH:19]=[CH:18][CH:17]=4)=[CH:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[O:29][CH3:30].Br[CH2:32][CH2:33][Cl:34].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Cl:34][CH2:33][CH2:32][O:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([O:12][C:13]3[C:14]([C:23]([O:25][CH2:26][CH2:27][CH3:28])=[O:24])=[CH:15][C:16]4[C:21]([CH:22]=3)=[CH:20][CH:19]=[CH:18][CH:17]=4)=[CH:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[O:29][CH3:30]
Reactant: CCCOC(=O)c1cc2ccccc2cc1Oc1ccnc2cc(O)c(OC)cc12
Reactant: ClCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCOC(=O)c1cc2ccccc2cc1Oc1ccnc2cc(OCCCl)c(OC)cc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 91 %

Procedure:
Propyl 3-(7-hydroxy-6-methoxy-quinolin-4-yloxy)-naphthalene-2-carboxylate (80 mg) and 1-bromo-2-chloroethane (0.082 ml) were dissolved in N,N-dimethylformamide (2 ml) to prepare a solution. Potassium carbonate (274 mg) was added to the solution, and the mixture was stirred at room temperature overnight. Water was then added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by column chromatography using acetone-chloroform to give the title compound (85 mg, yield 91%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][CH2:15][C:16]([OH:18])=[O:17])=[N:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH2:25](Br)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>CN(C=O)C>[CH2:25]([O:17][C:16](=[O:18])[CH2:15][CH2:14][CH2:13][C:10]1[CH:11]=[CH:12][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[N:9]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CC(C)(C)OC(=O)n1ccc(CCCC(=O)O)n1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)n1ccc(CCCC(=O)OCc2ccccc2)n1
Reaction time: 24 h
Yield: 68.4 %

Procedure:
To a stirred solution of 60.0 g (236 mmol) of 4-[1-(tert-butoxycarbonyl)-1H-pyrazol-3-yl]butanoic acid from step C above in 400 mL of DMF was added 48.9 g (354 mmol) of potassium carbonate followed by dropwise addition of 40.0 mL (300 mmol) of benzyl bromide. The resulting mixture was stirred for 24 h, quenched with water, and extracted with ethyl acetate (3×300 mL). The combined organic layers were washed with brine, dried over magnesium sulfate, filtered and evaporated to dryness in vacuo. The crude residue was purified by silica gel chromatography eluting with 30% ethyl acetate in hexanes to afford the title compound as a yellow oil (55.6 g. 68.4%). LC-MS: m/z (ES) 345 (MH)+.
Reaction SMILES: N[C@@H]1C2C(=CC=CC=2)C[C@@H]1O.O1CCCC1.[F:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[C:36]([CH:37]([F:49])[C:38]3[CH:43]=[CH:42][C:41]([O:44][C:45]([F:48])([F:47])[F:46])=[CH:40][CH:39]=3)=[C:35]([CH:50]([CH3:52])[CH3:51])[CH:34]=[C:33]3[C:25]=2[C:26](=[O:53])[CH2:27][C:28]2([O:32]3)[CH2:31][CH2:30][CH2:29]2)=[CH:20][CH:19]=1>CO>[F:17][C:18]1[CH:19]=[CH:20][C:21]([C:24]2[C:36]([CH:37]([F:49])[C:38]3[CH:43]=[CH:42][C:41]([O:44][C:45]([F:47])([F:48])[F:46])=[CH:40][CH:39]=3)=[C:35]([CH:50]([CH3:51])[CH3:52])[CH:34]=[C:33]3[C:25]=2[C@@H:26]([OH:53])[CH2:27][C:28]2([O:32]3)[CH2:31][CH2:30][CH2:29]2)=[CH:22][CH:23]=1
Reactant: CC(C)c1cc2c(c(-c3ccc(F)cc3)c1C(F)c1ccc(OC(F)(F)F)cc1)C(=O)CC1(CCC1)O2
Agent: N[C@@H]1c2ccccc2C[C@@H]1O
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)c1cc2c(c(-c3ccc(F)cc3)c1C(F)c1ccc(OC(F)(F)F)cc1)[C@@H](O)CC1(CCC1)O2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Under argon, 0.6 mg (0.004 mmol) of (1R,2S)-1-aminoindan-2-ol is dissolved in 0.5 ml of abs. tetrahydrofuran, 27.5 μl (0.15 mmol) of borane/N,N-diethylaniline complex are added and the mixture is stirred at room temperature for 30 min. After this time, 20 mg (0.04 mmol) of 5-(4-fluorophenyl)-6-{fluoro[4-(trifluoromethoxy)phenyl]methyl}-7-isopropylspiro[chromen-2,1′-cyclobutan]-4(3H)-one (Example 59A), dissolved in 1 ml of abs. tetrahydrofuran, are then added at room temperature over a period of 10 min, and the mixture is then stirred at room temperature overnight. 3 ml of methanol are added, and the mixture is stirred for 15 min and then concentrated to dryness. The residue is taken up in ethyl acetate and washed twice with 1 N hydrochloric acid, twice with saturated sodium bicarbonate solution and twice with saturated sodium chloride solution. The organic phase is dried over sodium sulfate, filtered and concentrated. The crude product is purified by thick-layer chromatography (mobile phase: cyclohexane→cyclohexane/ethyl acetate 5:1). This is followed by further purification by preparative HPLC. This gives 5.3 mg (26% of theory) of the title compound as a mixture of diastereomers.
Reaction SMILES: OC1C(C2(CO)C3C(=CC=CC=3)N(CC[CH2:22][N:23]3[C:31](=[O:32])[C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[C:24]3=[O:33])C2=O)=CC2OCOC=2C=1.C1([CH2:40][CH2:41][N:42]2[C:50]3[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=3)[C:44]([C:53]3[C:61]([OH:62])=[CH:60][C:56]4[O:57][CH2:58][O:59][C:55]=4[CH:54]=3)([CH2:51]O)[C:43]2=[O:63])CC1>>[O:63]=[C:43]1[C:44]2([C:53]3=[CH:54][C:55]4[O:59][CH2:58][O:57][C:56]=4[CH:60]=[C:61]3[O:62][CH2:51]2)[C:45]2[C:50](=[CH:49][CH:48]=[CH:47][CH:46]=2)[N:42]1[CH2:41][CH2:40][CH2:22][N:23]1[C:31](=[O:32])[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:24]1=[O:33]
Reactant: O=C1c2ccccc2C(=O)N1CCCN1C(=O)C(CO)(c2cc3c(cc2O)OCO3)c2ccccc21
Reactant: O=C1N(CCC2CC2)c2ccccc2C1(CO)c1cc2c(cc1O)OCO2
Product: O=C1c2ccccc2C(=O)N1CCCN1C(=O)C2(COc3cc4c(cc32)OCO4)c2ccccc21
Yield: 45 %

Procedure:
Following the procedure as described in EXAMPLE 1, and making non-critical variations using 2-{3-[3-(6-hydroxy-1,3-benzodioxol-5-yl)-3-(hydroxymethyl)-2-oxo-2,3-dihydro-1H-indol-1-yl]propyl}-1H-isoindole-1,3(2H)-dione to replace 1-(2-cyclopropylethyl)-3-(6-hydroxy-1,3-benzodioxol-5-yl)-3-(hydroxymethyl)-1,3-dihydro-2H-indol-2-one, the title compound was obtained in 45% yield: 1H NMR (300 MHz, CDCl3) δ 7.83-7.80 (m, 2H), 7.70-7.68 (m, 2H), 7.28-7.26 (m, 1H), 7.15 (d, 1H), 7.05-7.00 (m, 1H), 6.86 (d, 1H), 6.48 (s, 1H), 6.23 (s, 1H), 5.85-5.83 (m, 2H), 4.91 (d, 1H), 4.65 (d, 1H), 3.94-3.68-(m, 4H), 2.15-2.10-(m, 2H); 13C NMR (75 MHz, CDCl3) δ 177.4, 168.2, 155.9, 148.8, 142.4, 141.9, 134.0, 132.5, 132.0, 128.9, 124.1, 123.4, 123.3, 119.4, 108.4, 103.2, 101.5, 93.6, 80.4, 58.2, 38.0, 35.6, 26.8; MS (ES+) m/z 469.3 (M+1), 491.3 (M+23).
Reaction SMILES: CO[C:3]([C:5]1[N:6]([CH3:24])[N:7]=[C:8]([O:10][CH2:11][C:12]2[C:13]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)=[N:14][O:15][C:16]=2[CH3:17])[CH:9]=1)=[O:4].C[O:26][C:27]([C:29]1[NH:30]N=C(OCC2C(C3C=CC=CC=3)=NOC=2C)[CH:33]=1)=O.N[C@H](CO)C>>[OH:26][CH2:27][C@@H:29]([NH:30][C:3]([C:5]1[N:6]([CH3:24])[N:7]=[C:8]([O:10][CH2:11][C:12]2[C:13]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)=[N:14][O:15][C:16]=2[CH3:17])[CH:9]=1)=[O:4])[CH3:33]
Reactant: COC(=O)c1cc(OCc2c(-c3ccccn3)noc2C)nn1C
Reactant: COC(=O)c1cc(OCc2c(-c3ccccc3)noc2C)n[nH]1
Agent: C[C@H](N)CO
Product: Cc1onc(-c2ccccn2)c1COc1cc(C(=O)N[C@@H](C)CO)n(C)n1
Yield: 89 %

Procedure:
As described for example 6, 2-methyl-5-(5-methyl-3-pyridin-2-yl-isoxazol-4-ylmethoxy)-2H-pyrazole-3-carboxylic acid methyl ester (90 mg, 0.27 mmol), instead of 5-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-2H-pyrazole-3-carboxylic acid methyl ester, was converted, using L-alaninol instead of ethanolamine, to the title compound (91 mg, 89%) which was obtained as a colorless oil. MS: m/e=372.2 [M+H]+.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][CH2:5][O:6][C:7]1[C:8]([CH3:29])=[C:9]2[C:14](=[C:15]([CH3:18])[C:16]=1[CH3:17])[O:13][C:12]([CH2:27][OH:28])([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH2:11][CH2:10]2.CN(C)C=O.Cl[C:36]1[CH:41]=[CH:40][C:39]([N+:42]([O-:44])=[O:43])=[CH:38][CH:37]=1>C1C=CC=CC=1>[CH3:3][O:4][CH2:5][O:6][C:7]1[C:8]([CH3:29])=[C:9]2[C:14](=[C:15]([CH3:18])[C:16]=1[CH3:17])[O:13][C:12]([CH2:27][O:28][C:36]1[CH:41]=[CH:40][C:39]([N+:42]([O-:44])=[O:43])=[CH:38][CH:37]=1)([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH2:11][CH2:10]2
Reactant: O=[N+]([O-])c1ccc(Cl)cc1
Reactant: CCCCCCCCC1(CO)CCc2c(C)c(OCOC)c(C)c(C)c2O1
Agent: [H-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: CN(C)C=O
Product: CCCCCCCCC1(COc2ccc([N+](=O)[O-])cc2)CCc2c(C)c(OCOC)c(C)c(C)c2O1
Temperature: 50 °C

Procedure:
0.38 g of a 55% w/w suspension of sodium hydride in mineral oil was added to a mixture of 3 g of 6-methoxymethoxy-5,7,8-trimethyl-2-octylchroman-2-ylmethanol (prepared as described in Preparation 13) and 25 ml of dimethylformamide under a nitrogen stream at room temperature, and the resulting mixture was heated for 2 hours at 50° C. A mixture of 1.4 g of p-chloronitrobenzene and 2 ml of benzene was then added dropwise, whilst ice-cooling, and the resulting mixture was heated for 2 hours at 50° C. The reaction mixture was then poured into ice-water and extracted with benzene. The extract was washed with water and dried over anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure, and the residue was purified by silica gel column chromatography eluted with benzene, to give the title compound.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[NH:17][C@H:18]1[CH2:23][CH2:22][C@H:21]([N:24]([CH3:32])[C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[CH2:20][CH2:19]1.[Cl:33][C:34]1[CH:39]=[C:38](B2OC(C)(C)C(C)(C)O2)[CH:37]=[C:36]([Cl:49])[C:35]=1[OH:50]>>[CH:14]1([C:12]([C:6]2[CH:7]=[N:8][C:9]3[C:4]([C:5]=2[NH:17][C@H:18]2[CH2:23][CH2:22][C@H:21]([N:24]([CH3:32])[C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:28])[CH3:29])[CH2:20][CH2:19]2)=[CH:3][C:2]([C:38]2[CH:39]=[C:34]([Cl:33])[C:35]([OH:50])=[C:36]([Cl:49])[CH:37]=2)=[CH:11][CH:10]=3)=[O:13])[CH2:16][CH2:15]1
Reactant: CN(C(=O)OC(C)(C)C)[C@H]1CC[C@H](Nc2c(C(=O)C3CC3)cnc3ccc(Br)cc23)CC1
Reactant: CC1(C)OB(c2cc(Cl)c(O)c(Cl)c2)OC1(C)C
Product: CN(C(=O)OC(C)(C)C)[C@H]1CC[C@H](Nc2c(C(=O)C3CC3)cnc3ccc(-c4cc(Cl)c(O)c(Cl)c4)cc23)CC1

Procedure:
Following general procedure F, tert-butyl {trans-4-[6-bromo-3-(cyclopropanecarbonyl)quinolin-4-ylamino]cyclohexyl}(methyl)carbamate (61 mg, 0.120 mmol) was reacted with 2,6-dichloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (52 mg, 0.180 mmol) to afford the crude product (65 mg) as a brown oil: ESI MS m/z 584 [C31H35Cl2N3O4+H]+.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:8][C:9]([N:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1)=[O:10].[OH:17][C:18]1[CH:27]=[CH:26][C:25]2[N:24]=[C:23]([NH2:28])[C:22]3[N:29]=[C:30]([CH2:35][O:36][CH3:37])[N:31]([CH2:32][CH2:33][CH3:34])[C:21]=3[C:20]=2[CH:19]=1.CN(C=O)C>ClCCl>[CH3:37][O:36][CH2:35][C:30]1[N:31]([CH2:32][CH2:33][CH3:34])[C:21]2[C:20]3[CH:19]=[C:18]([O:17][CH2:8][C:9]([N:11]4[CH2:16][CH2:15][O:14][CH2:13][CH2:12]4)=[O:10])[CH:27]=[CH:26][C:25]=3[N:24]=[C:23]([NH2:28])[C:22]=2[N:29]=1
Reactant: O=C(CBr)N1CCOCC1
Reactant: CCCn1c(COC)nc2c(N)nc3ccc(O)cc3c21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCCn1c(COC)nc2c(N)nc3ccc(OCC(=O)N4CCOCC4)cc3c21
Temperature: 70 °C
Yield: 49.2 %

Procedure:
Cesium carbonate (1.7 g, 5.25 mmol, 3 eq) was added to a mixture of 2-bromo-1-morpholin-4-yl-ethanone (400 mg, 1.92 mmol, 1.1 eq), 8-hydroxy-2-methoxymethyl-1-propyl-1H-imidazo[4,5-c]quinolin-4-amine (500 mg, 1.75 mmol, 1.0 eq), and anhydrous DMF. The reaction mixture was heated to 70° C. and maintained overnight. The reaction mixture was then cooled to ambient temperature, filtered, and concentrated under reduced pressure to yield a dark oil. The dark oil was dissolved in dichloromethane, filtered, purified by chromatography on a HORIZON HPFC system (eluting with a gradient of methanol/dichloromethane (20:80) in dichloromethane from 0:100 to 40:60), and crystallized from acetonitrile to afford 356 mg of 2-(methoxymethyl)-8-(2-morpholin-4-yl-2-oxoethoxy)-1-propyl-1H-imidazo[4,5-c]quinolin-4-amine as an off white powder, mp 201-204° C.
Reaction SMILES: CN(P(N(C)C)N(C)C)C.[C:11]([O:14][CH:15]([C:24](=[O:26])[CH3:25])[CH2:16][CH:17]1[C:19]([CH3:21])([CH3:20])[CH:18]1[CH:22]=O)(=[O:13])[CH3:12].[C:27](Cl)(Cl)([Cl:29])[Cl:28].O>C(OCC)C>[C:11]([O:14][CH:15]([C:24](=[O:26])[CH3:25])[CH2:16][C@H:17]1[C:19]([CH3:21])([CH3:20])[C@H:18]1[CH:22]=[C:27]([Cl:29])[Cl:28])(=[O:13])[CH3:12]
Reactant: ClC(Cl)(Cl)Cl
Reactant: CC(=O)OC(CC1C(C=O)C1(C)C)C(C)=O
Agent: CN(C)P(N(C)C)N(C)C
Solvent: O
Solvent: CCOCC
Product: CC(=O)OC(C[C@@H]1[C@H](C=C(Cl)Cl)C1(C)C)C(C)=O
Reaction time: 0.08 h
Yield: 52.8 %

Procedure:
Tri(dimethylamino)phosphine (40 mmol) was added with stirring at -20° C. to a solution of 1-(2-formyl-3,3-dimethylcyclopropyl)-3-oxo-2-butyl acetate (14.2 mmol) and carbon tetrachloride (40 mmol) in diethyl ether (160 ml) kept under nitrogen. Then, the temperature of the mixture was allowed to rise to 20° C. Water (50 ml) was added, the mixture was stirred for 5 minutes and, after settling, the organic phase was isolated. The organic phase was washed with two 50-ml portions of water. The washed organic phase was dried over anhydrous magnesium sulphate and the solvent was evaporated from the dried solution to leave a residue (2.2 g) containing 1-[2-(2,2-dichlorovinyl)-3,3-dimethylcyclopropyl]-3-oxo-2-butyl acetate (100% (1R,cis), yield 54%).
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6](C)[C:7](=[O:16])[N:8]2[CH:11]([CH2:14][CH3:15])[CH2:12][CH3:13])=[CH:4][N:3]=1.CC1C=CC(S(O)(=O)=O)=CC=1.[NH2:29][C:30]1[CH:35]=[CH:34][C:33]([N:36]2[CH2:41][CH2:40][N:39]([C:42](=[O:44])[CH3:43])[CH2:38][CH2:37]2)=[CH:32][CH:31]=1>CN(C=O)C.CCOC(C)=O>[C:42]([N:39]1[CH2:38][CH2:37][N:36]([C:33]2[CH:34]=[CH:35][C:30]([NH:29][C:2]3[N:10]=[C:9]4[C:5]([NH:6][C:7](=[O:16])[N:8]4[CH:11]([CH2:12][CH3:13])[CH2:14][CH3:15])=[CH:4][N:3]=3)=[CH:31][CH:32]=2)[CH2:41][CH2:40]1)(=[O:44])[CH3:43]
Reactant: CC(=O)N1CCN(c2ccc(N)cc2)CC1
Reactant: CCC(CC)n1c(=O)n(C)c2cnc(Cl)nc21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCC(CC)n1c(=O)[nH]c2cnc(Nc3ccc(N4CCN(C(C)=O)CC4)cc3)nc21
Temperature: 140 °C
Yield: 29.5 %

Procedure:
To a mixture of 2-chloro-9-(1-ethyl-propyl)-7-methyl-7,9-dihydro-purin-8-one (102 mg, 0.4 mmol) and TsOH (1.6 mL, 0.2 M in 1,4-dioxane) in DMF (0.25 mL) is added 1-[4-(4-amino-phenyl)-piperazin-1-yl]-ethanone (105 mg, 0.5 mmol). The reaction mixture is sealed in a microwave reactor and heated at 140° C. for 30 min. The mixture is diluted with EtOAc and washed with NaHCO3 aqueous solution and brine. The organics are dried over Na2SO4, filtered and concentrated. The crude product is purified by preparative HPLC to give 50 mg of 2-[4-(4-acetyl-piperazin-1-yl)-phenylamino]-9-(1-ethyl-propyl)-7,9-dihydro-purin-8-one.
Reaction SMILES: C[N:2]([CH3:12])[CH:3]=[CH:4][C:5]([C:7]1[S:8][CH:9]=[CH:10][CH:11]=1)=O.Cl.NC1[N:16]=[CH:17][NH:18][C:19]=1[C:20]([NH2:22])=[O:21].C([O-])(=O)C.[Na+]>C(O)(=O)C>[S:8]1[CH:9]=[CH:10][CH:11]=[C:7]1[C:5]1[N:16]2[CH:17]=[N:18][C:19]([C:20]([NH2:22])=[O:21])=[C:12]2[N:2]=[CH:3][CH:4]=1
Reactant: NC(=O)c1[nH]cnc1N
Reactant: CN(C)C=CC(=O)c1cccs1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Product: NC(=O)c1ncn2c(-c3cccs3)ccnc12

Procedure:
A mixture of 0.01 mol of 3-dimethylamino-1-(2-thienyl)-2-propen-1-one (prepared as described in Example 1, Part A), 0.01 mol of 4amino-5-imidazolecarboxamide hydrochloride and 0.01 mol of anhydrous sodium acetate in 25 ml. of glacial acetic acid can be refluxed for 16 hours. The reaction mixture can be cooled and the crystalline precipitate collected by filtration and washed with water to produce 4-(2-thienyl)imidazo[1,5-a]pyrimidine-8-carboxamide.
Reaction SMILES: [NH2:1][C:2]1[N:7]2[CH:8]=[C:9]([CH2:11][CH3:12])[N:10]=[C:6]2[C:5]([C:13]([OH:15])=O)=[CH:4][C:3]=1[Cl:16].[NH2:17][CH2:18][CH:19]1[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]1.CCOC(OC(OCC)=O)=O.C(N(C(C)C)CC)(C)C>CN(C)C=O>[NH2:1][C:2]1[N:7]2[CH:8]=[C:9]([CH2:11][CH3:12])[N:10]=[C:6]2[C:5]([C:13]([NH:17][CH2:18][CH:19]2[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]2)=[O:15])=[CH:4][C:3]=1[Cl:16]
Reactant: CC(C)(C)OC(=O)N1CCC(CN)CC1
Reactant: CCc1cn2c(N)c(Cl)cc(C(=O)O)c2n1
Agent: CCOC(=O)OC(=O)OCC
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCc1cn2c(N)c(Cl)cc(C(=O)NCC3CCN(C(=O)OC(C)(C)C)CC3)c2n1
Yield: 90 %

Procedure:
A mixture of 5-amino-6-chloro-2-ethylimidazo[1,2-a]pyridine-8-carboxylic acid (EXAMPLE 3, Step 2, 10.00 g, 41.72 mmol), tert-butyl 4-(aminomethyl)piperidine-1-carboxylate (J. Prugh, L. A. Birchenough and M. S. Egbertson, Synth. Commun., 1992, 22, 2357–60, 15.20 g, 70.93 mmol), DEPC (10.76 mL, 70.93 mmol) and diisopropylethylamine (18.17 mL, 104.4 mmol) in N,N-dimethylformamide (267 mL) was stirred at room temperature for 43 h. The solvent was removed by evaporation. The residue was basified with aqueous sodium bicarbonate (40 mL), and extracted with dichloromethane (5×100 mL). The combined extract was washed with brine, dried over magnesium sulfate, and concentrated in vacuo. Flash chromatography of the residue eluting with dichloromethane/methanol (100:1 to 20:1) afforded 19.08 g (90%) of the title compound as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N+:10]([O-:11])=[N:9][C:8](=[O:12])[N:7]([CH2:13][CH:14]=C)[C:6]=2[CH:16]=1.I([O-])(=O)(=O)=[O:18].[Na+]>O1CCOCC1.O.[Os](=O)(=O)(=O)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N+:10]([O-:11])=[N:9][C:8](=[O:12])[N:7]([CH2:13][CH:14]=[O:18])[C:6]=2[CH:16]=1
Reactant: C=CCn1c(=O)n[n+]([O-])c2ccc(Cl)cc21
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: O=CCn1c(=O)n[n+]([O-])c2ccc(Cl)cc21
Temperature: 25 °C
Reaction time: 6 h
Yield: 84.8 %

Procedure:
6-Chloro-4-(2-propen-1-yl)-1,2,4-benzotriazin-3(4H)-one 1-oxide (104 mg, 0.438 mmol) was dissolved in 1,4-dioxane (4 ml) and water (2 ml). Sodium periodate (234 mg, 1.096 mmol) was added, followed by osmium tetroxide (0.09 ml of 4% aqueous solution). The mixture stirred at rt for 6 h, and then extracted with 20% MeOH/DCM (3×100 ml). The organic extracts were combined, dried over anhydrous magnesium sulphate, filtered and evaporated under reduced pressure to give (6-Chloro-1-oxido-3-oxo-1,2,4-benzotriazin-4(3H)-yl)acetaldehyde as an impure yellow oil (89 mg, 85%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([NH:10][C@@:11]2([C:21]3[CH:26]=[CH:25][C:24]([O:27][C:28]([F:31])([F:30])[F:29])=[C:23]([F:32])[CH:22]=3)[C:16]3=[N:17][CH:18]=[CH:19][CH:20]=[C:15]3[O:14][CH2:13][CH2:12]2)=[O:9])=[N:6][CH:7]=1.[CH3:33][S:34](Cl)(=[O:36])=[O:35].CCN(C(C)C)C(C)C>C(Cl)Cl.[OH-].[Na+]>[F:32][C:23]1[CH:22]=[C:21]([C@:11]2([NH:10][C:8](=[O:9])[C:5]3[CH:4]=[CH:3][C:2]([NH:1][S:34]([CH3:33])(=[O:36])=[O:35])=[CH:7][N:6]=3)[C:16]3=[N:17][CH:18]=[CH:19][CH:20]=[C:15]3[O:14][CH2:13][CH2:12]2)[CH:26]=[CH:25][C:24]=1[O:27][C:28]([F:31])([F:30])[F:29]
Reactant: CS(=O)(=O)Cl
Reactant: Nc1ccc(C(=O)N[C@]2(c3ccc(OC(F)(F)F)c(F)c3)CCOc3cccnc32)nc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)Nc1ccc(C(=O)N[C@]2(c3ccc(OC(F)(F)F)c(F)c3)CCOc3cccnc32)nc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (S)-5-amino-N-(4-(3-fluoro-4-(trifluoromethoxy)phenyl)-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl)picolinamide (44 mg, 0.098 mmol) in DCM (0.6 mL) were added methanesulfonyl chloride (8.40 μl, 0.128 mmol) and DIEA (0.022 mL, 0.128 mmol). The resulting mixture was stirred at room temperature overnight. A solution of NaOH (10 N, 2 drops) was added, and the resulting mixture was stirred at room temperature for 2 h. The reaction mixture was filtered and the filtrate concentrated in vacuo. The residue was purified by prep HPLC (0-100% MeCN 0.1% TFA/H2O 0.1% TFA) to give the title compound as a white solid. MS (ESI, positive ion) m/z: 527.0 (MH+). 1H NMR (400MHz, d4-MeOH) δ: 8.48 (d, J=2.3 Hz, 1H), 8.30 (dd, J=4.5, 1.4 Hz, 1H), 8.05 (d, J=8.6 Hz, 1H), 7.83 (dd, J=8.6, 2.5 Hz, 1H), 7.37-7.62 (m, 4H), 7.25 (d, J=8.6 Hz, 1H), 4.47 (dt, J=11.9, 4.4 Hz, 1H), 4.05-4.26 (m, 1H), 3.12-3.25 (m, 2H), 3.10 (s, 3H).