Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]([CH2:16][C:17]1[C:22]([C:23]([O:26][C:27](=[O:29])[CH3:28])([CH3:25])[CH3:24])=[CH:21][CH:20]=[CH:19][N:18]=1)[CH2:7][C:8]1[C:13]([CH3:14])=[CH:12][C:11]([CH3:15])=[CH:10][N:9]=1.C[Si]([N:34]=[C:35]=[O:36])(C)C>CC(O)C>[CH3:14][C:13]1[C:8]([CH2:7][N:6]([CH2:16][C:17]2[C:22]([C:23]([O:26][C:27](=[O:29])[CH3:28])([CH3:25])[CH3:24])=[CH:21][CH:20]=[CH:19][N:18]=2)[CH2:5][CH2:4][CH2:3][CH2:2][NH:1][C:35]([NH2:34])=[O:36])=[N:9][CH:10]=[C:11]([CH3:15])[CH:12]=1
Reactant: C[Si](C)(C)N=C=O
Reactant: CC(=O)OC(C)(C)c1cccnc1CN(CCCCN)Cc1ncc(C)cc1C
Solvent: CC(C)O
Product: CC(=O)OC(C)(C)c1cccnc1CN(CCCCNC(N)=O)Cc1ncc(C)cc1C
Yield: 91.8 %

Procedure:
A solution of acetic acid 1-(2-{[(4-amino-butyl)-(3,5-dimethyl-pyridin-2-ylmethyl)-amino]-methyl}-pyridin-3-yl)-1-methyl-ethyl ester (223 mg, 0.56 mmol) in i-PrOH (3.7 mL) and treated with trimethylsilylisocyanate (110 μL, 0.78 mmol) at room temperature for 16 hours. The solution was then concentrated under reduced pressure and dried in vacuo. The crude material was then purified by column chromatography with silica gel (20:1:1 CH2Cl2/MeOH/NH4OH) to give almost pure acetic acid 1-(2-{[(3,5-dimethyl-pyridin-2-ylmethyl)-(4-ureido-butyl)-amino]-methyl}-pyridin-3-yl)-1-methyl-ethyl ester as a colorless oil (227 mg, 92%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[CH:11][CH:10]=[N:9]2)=[CH:4][CH:3]=1.[CH:13](=[O:17])[CH:14]([CH3:16])[CH3:15]>>[CH3:15][CH:14]([CH3:16])[CH:13]([C:12]1[N:8]([C:5]2[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=2)[N:9]=[CH:10][CH:11]=1)[OH:17]
Reactant: Cc1ccc(-n2cccn2)cc1
Reactant: CC(C)C=O
Product: Cc1ccc(-n2nccc2C(O)C(C)C)cc1
Yield: 54 %

Procedure:
This compound was prepared from 1-(4-methylphenyl)-1H-pyrazole (Tetrahedron Lett. 39(19): 2941 (1998)) and isobutyraldehyde using the method described in example 10B and isolated as a clear oil in 54% yield.
Reaction SMILES: C1(C2[O:12][CH2:11][CH:10]([O:13][C:14]([C:16]3[N:17]=[CH:18][C:19]4[NH:20][C:21]5[C:26]([C:27]=4[C:28]=3[CH2:29][O:30][CH3:31])=[CH:25][C:24]([O:32][CH2:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)=[CH:23][CH:22]=5)=[O:15])[CH2:9][O:8]2)C=CC=CC=1>Cl>[OH:8][CH2:9][CH:10]([O:13][C:14]([C:16]1[N:17]=[CH:18][C:19]2[NH:20][C:21]3[C:26]([C:27]=2[C:28]=1[CH2:29][O:30][CH3:31])=[CH:25][C:24]([O:32][CH2:33][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)=[CH:23][CH:22]=3)=[O:15])[CH2:11][OH:12]
Reactant: COCc1c(C(=O)OC2COC(c3ccccc3)OC2)ncc2[nH]c3ccc(OCc4ccccc4)cc3c12
Agent: Cl
Product: COCc1c(C(=O)OC(CO)CO)ncc2[nH]c3ccc(OCc4ccccc4)cc3c12
Yield: 89 %

Procedure:
135 mg of 6-benzyloxy-4-methoxymethyl-β-carboline-3carboxylic acid-(2-phenyl-1,3-dioxan-5-yl)-ester under 10 ml of acetone and 100 ml of 4N hydrochloric acid is stirred for 1 hour at 80° C. bath temperature. The batch is concentrated by evaporation, taken up in aqueous ammonia and suctioned off. 100 mg of 6-benzyloxy-4-methoxymethyl-β-carboline-3-carboxylic acid-(1,3-dihydroxy-propan-2-yl)-ester of a melting point of 190°-192° C. is obtained.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([C:12]3([CH3:17])[O:16][CH2:15][CH2:14][O:13]3)=[CH:8][C:7]=2[C:18]2[C:19]3[N:26]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:34])([CH3:33])[CH3:32])[C:25]([CH3:35])=[C:24]([C:36](O)=[O:37])[C:20]=3[N:21]=[CH:22][N:23]=2)[CH2:3][CH2:2]1.[NH2:39][CH:40]1[CH2:45][CH2:44][N:43]([C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47])[CH2:42][CH2:41]1>>[CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([C:12]3([CH3:17])[O:13][CH2:14][CH2:15][O:16]3)=[CH:8][C:7]=2[C:18]2[C:19]3[N:26]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:33])([CH3:32])[CH3:34])[C:25]([CH3:35])=[C:24]([C:36]([NH:39][CH:40]4[CH2:41][CH2:42][N:43]([C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47])[CH2:44][CH2:45]4)=[O:37])[C:20]=3[N:21]=[CH:22][N:23]=2)[CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: Cc1c(C(=O)O)c2ncnc(-c3cc(C4(C)OCCO4)ccc3OCC3CC3)c2n1COCC[Si](C)(C)C
Product: Cc1c(C(=O)NC2CCN(C(=O)OC(C)(C)C)CC2)c2ncnc(-c3cc(C4(C)OCCO4)ccc3OCC3CC3)c2n1COCC[Si](C)(C)C

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-5-(2-methyl-1,3-dioxolan-2-yl)phenyl]-6-methyl-5-{[2-(trimethylsilyl)ethoxy]methyl}-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (example D.c13) and commercially available tert-butyl 4-amino-piperidine-1-carboxylate the title compound is obtained as pale yellow viscous oil.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[CH2:7])=[CH:4][CH:3]=1.Br[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1OC>>[CH:6]([C:5]1[CH:8]=[CH:9][CH:2]=[CH:3][C:4]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[CH2:7]
Reactant: C=Cc1ccc(Br)cc1
Reactant: COc1ccccc1Br
Product: C=Cc1ccccc1-c1ccccc1

Procedure:
A vinylbiphenyl polymer was prepared in the same manner as in Example 10 except that poly-p-bromostyrene obtained as in Example 10 by using p-bromostyrene instead of p-chlorostyrene, and o-bromoanisol were used. The polymer gave a peak of OCH3 through 1H-NMR measurement in the same manner as in Example 10.
Reaction SMILES: [Na].[OH:2][N:3]=[C:4]([C:10]#[N:11])[C:5]([O:7][CH2:8][CH3:9])=[O:6].Cl[C:13]([O:15][CH2:16][CH:17]=[CH2:18])=[O:14].C(=O)([O-])O.[Na+]>O.C(OCC)(=O)C>[CH2:16]([O:15][C:13]([O:2][N:3]=[C:4]([C:10]#[N:11])[C:5]([O:7][CH2:8][CH3:9])=[O:6])=[O:14])[CH:17]=[CH2:18]
Reactant: C=CCOC(=O)Cl
Reactant: CCOC(=O)C(C#N)=NO
Agent: O=C([O-])O
Agent: [Na+]
Agent: [Na]
Solvent: O
Solvent: CCOC(C)=O
Product: C=CCOC(=O)ON=C(C#N)C(=O)OCC
Reaction time: 1 h
Yield: 62.4 %

Procedure:
To a solution of sodium salt of ethyl 2-hydroxyimino-2-cyanoacetate (23.1 g) in water (100 ml), a solution of allyl chloroformate (17.0 g) in ethyl acetate (30 ml) is dropwise added at 5° to 10°C. The resulting mixture is stirred for 1 hour while adjusting pH to 7 with the addition of an aqueous solution of sodium hydrogencarbonate. The reaction mixture is extracted with ethyl acetate, and the organic layer is washed with water, dried and concentrated. The residue is distilled under reduced pressure to give ethyl 2-allyloxycarbonyloxyimino-2-cyanoacetate (19.9 g) as an oil. B.P. 122 to 124°C/0.9 mmHg.
Reaction SMILES: [F:1][C@H:2]1[C@H:8]([NH:9]C(=O)OC(C)(C)C)[CH2:7][CH2:6][C@@H:5]([C:17]2[N:21]([CH3:22])[N:20]=[CH:19][C:18]=2[N+:23]([O-])=O)[O:4][CH2:3]1.[F:26][C:27]1[CH:32]=[C:31]([CH2:33][O:34][CH3:35])[CH:30]=[C:29]([F:36])[C:28]=1[C:37]1[N:42]=[C:41]([C:43](O)=[O:44])[CH:40]=[CH:39][C:38]=1[F:46]>>[NH2:9][C@H:8]1[C@H:2]([F:1])[CH2:3][O:4][C@H:5]([C:17]2[N:21]([CH3:22])[N:20]=[CH:19][C:18]=2[NH:23][C:43](=[O:44])[C:41]2[CH:40]=[CH:39][C:38]([F:46])=[C:37]([C:28]3[C:29]([F:36])=[CH:30][C:31]([CH2:33][O:34][CH3:35])=[CH:32][C:27]=3[F:26])[N:42]=2)[CH2:6][CH2:7]1
Reactant: COCc1cc(F)c(-c2nc(C(=O)O)ccc2F)c(F)c1
Reactant: Cn1ncc([N+](=O)[O-])c1[C@@H]1CC[C@@H](NC(=O)OC(C)(C)C)[C@H](F)CO1
Product: COCc1cc(F)c(-c2nc(C(=O)Nc3cnn(C)c3[C@@H]3CC[C@@H](N)[C@H](F)CO3)ccc2F)c(F)c1

Procedure:
Following the procedure for Example 111 starting from tert-butyl ((3S,4R,7S)-3-fluoro-7-(1-methyl-4-nitro-1H-pyrazol-5-yl)oxepan-4-yl)carbamate (Intermediate 80), and replacing 5-((tert-butoxycarbonyl)amino)-2-(2,6-difluorophenyl)thiazole-4-carboxylic acid with 6-(2,6-difluoro-4-(methoxymethyl)phenyl)-5-fluoropicolinic acid (see US2012/225062) gave 199. 1H NMR (400 MHz, DMSO-d6) δ 10.20 (s, 1H), 8.29 (dd, J=8.6, 4.0 Hz, 1H), 8.15 (t, J=8.8 Hz, 1H), 7.91 (s, 1H), 7.24 (d, J=9.0 Hz, 2H), 4.81 (dd, J=10.3, 3.7 Hz, 1H), 4.53 (s, 2H), 4.31-4.07 (m, 1H), 4.02-3.83 (m, 2H), 3.75 (s, 3H), 3.36 (s, 3H), 3.11-2.98 (m, 1H), 2.10-2.00 (m, 1H), 1.82-1.57 (m, 3H). LCMS (ES+) m/z 508 (M+1).
Reaction SMILES: N1C=CN=C1CN1C(=O)C[O:10][C:9]2N=C(C3C=CC(C4(N)CCC4)=CC=3)C(C3C=CC=CC=3)=CC1=2.C(OC(=O)[NH:41][C:42]1([C:46]2[CH:51]=[CH:50][C:49]([C:52]3[C:53]([C:69]4[CH:74]=[CH:73][CH:72]=[CH:71][CH:70]=4)=[CH:54][C:55]4[N:60]([CH2:61][C:62]5([CH3:66])C[O:64][CH2:63]5)[C:59](=[O:67])[CH2:58][O:57][C:56]=4[N:68]=3)=[CH:48][CH:47]=2)[CH2:45][CH2:44][CH2:43]1)(C)(C)C>>[NH2:41][C:42]1([C:46]2[CH:47]=[CH:48][C:49]([C:52]3[C:53]([C:69]4[CH:70]=[CH:71][CH:72]=[CH:73][CH:74]=4)=[CH:54][C:55]4[N:60]([CH2:61][C:62]([CH2:9][OH:10])([CH3:66])[CH2:63][OH:64])[C:59](=[O:67])[CH2:58][O:57][C:56]=4[N:68]=3)=[CH:50][CH:51]=2)[CH2:45][CH2:44][CH2:43]1
Reactant: CC1(CN2C(=O)COc3nc(-c4ccc(C5(NC(=O)OC(C)(C)C)CCC5)cc4)c(-c4ccccc4)cc32)COC1
Reactant: NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)N(Cc3ncc[nH]3)C(=O)CO4)cc2)CCC1
Product: CC(CO)(CO)CN1C(=O)COc2nc(-c3ccc(C4(N)CCC4)cc3)c(-c3ccccc3)cc21
Yield: 79 %

Procedure:
Following the procedure for 1-((1H-imidazol-2-yl)methyl)-6-(4-(1-aminocyclobutyl)phenyl)-7-phenyl-1H-pyrido[2,3-b][1,4]oxazin-2(3H)-one, tert-butyl(1-(4-(1-((3-methyloxetan-3-yl)methyl)-2-oxo-7-phenyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6-yl)phenyl)cyclobutyl)carbamate (16 mg, 0.03 mmol) was reacted to afford the title compound (16 mg, 79%). LCMS (Method D): RT=0.721 min, M+1=474. 1H NMR (500 MHz, MeOD): 8.03 (1H,S), 7.44-7.38 (4H,m), 7.30-7.24 (5H, m), 4.96 (2H, s), 4.11 (2H, s), 3.47-3.41 (4H, m), 2.77-2.72 (2H, m), 2.59-2.53 (2H, m), 2.25-2.21 (1H, m), 1.98-1.94 (1H, m), 0.92 (3H, s).
Reaction SMILES: [OH:1][CH:2]([C:5]1[N:6]=[C:7]([C:10]2[N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH:12]=[CH:13][CH:14]=2)[S:8][CH:9]=1)[CH2:3][OH:4].[Br:22]N1C(=O)CCC1=O.O>O1CCCC1>[Br:22][C:12]1[N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C:10]([C:7]2[S:8][CH:9]=[C:5]([CH:2]([OH:1])[CH2:3][OH:4])[N:6]=2)=[CH:14][CH:13]=1
Reactant: CC(C)(C)OC(=O)n1cccc1-c1nc(C(O)CO)cs1
Reactant: O=C1CCC(=O)N1Br
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)n1c(Br)ccc1-c1nc(C(O)CO)cs1
Temperature: 0 °C
Reaction time: 14 h
Yield: 48.4 %

Procedure:
t-Butyl 2-[4-(1,2-dihydroxyethyl)-1,3-thiazol-2-yl]-1H-pyrrole-1-carboxylate (868 mg, 2.80 mmol) synthesized in Example (9c) was dissolved in tetrahydrofuran (30 mL), and cooled to 0° C. N-Bromosuccinimide (498 mg, 2.80 mmol) was added, and stirring was carried out at room temperature for 14 hours under nitrogen atmosphere. Water (20 mL) was added, and extraction was carried out with diethyl ether (20 mL). The organic layer was washed with saturated brine, and subsequently dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate/hexane=0%-30%) to afford the desired compound (527 mg, yield 48%) as a pale yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[N:12]1[C:17](=[O:18])[CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[N:14]([CH3:23])[C:13]1=[O:24])[NH:8][C:7](=[O:25])[C:6]([C:26]([F:29])([F:28])[F:27])=[CH:5]2.Br[CH2:31][C:32]#[CH:33].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:33]([N:8]1[C:9]2[C:4](=[CH:3][C:2]([F:1])=[C:11]([N:12]3[C:17](=[O:18])[CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[N:14]([CH3:23])[C:13]3=[O:24])[CH:10]=2)[CH:5]=[C:6]([C:26]([F:29])([F:27])[F:28])[C:7]1=[O:25])[C:32]#[CH:31]
Reactant: C#CCBr
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2cc3[nH]c(=O)c(C(F)(F)F)cc3cc2F)c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C#CCn1c(=O)c(C(F)(F)F)cc2cc(F)c(-n3c(=O)cc(C(F)(F)F)n(C)c3=O)cc21
Yield: 86.7 %

Procedure:
These compounds were prepared in a manner analogous to that of Step I of Example 1, using 1.0 gram (0.002 mole) of 3-(6-fluoro-3-trifluoromethylquinolin-2-on-7-yl)-1-methyl-6-trifluoromethyluracil, 0.7 gram (0.005 mole) of 80% 3-bromopropyne, and 0.7 gram (0.005 mole) of potassium carbonate in 40 mL of N,N-dimethylformamide. The crude reaction product was subjected to column chromatography on silica gel. Elution was accomplished using 1:4 ethyl acetate-hexane and 1:1 ethyl acetatehexane. The appropriate product-containing fractions were combined and concentrated under reduced pressure, yielding 0.8 gram of 3-[1-(2-propyn-1-yl)-3-trifluoromethyl-6-fluoroquinolin-2-on-7-yl]-1-methyl-6-trifluoromethyluracil (Compound 42), mp 248°-250° C. Other product-containing fractions were combined and concentrated under reduced pressure, yielding 0.1 gram of the O-alkylated product, 3-[2-(2-propyn-1-yloxy)-3-trifluoromethyl-6-fluoroquinolin-2-on-7-yl]-1-methyl-6-trifluoromethyluracil (Compound 26A). The NMR spectra were consistent with the proposed structures.
Reaction SMILES: CS(O[CH2:6][C@H:7]1[CH2:12][N:11]([S:13]([C:16]2[S:17][CH:18]=[CH:19][CH:20]=2)(=[O:15])=[O:14])[CH2:10][CH2:9][N:8]1[C:21]1[CH:26]=[CH:25][C:24]([C:27]([OH:33])([CH3:32])[C:28]([F:31])([F:30])[F:29])=[CH:23][CH:22]=1)(=O)=O.[CH:34]1([CH:37]2[CH2:42][S:41](=[O:44])(=[O:43])[CH2:40][CH2:39][NH:38]2)[CH2:36][CH2:35]1>>[CH:34]1([CH:37]2[CH2:42][S:41](=[O:43])(=[O:44])[CH2:40][CH2:39][N:38]2[CH2:6][C@H:7]2[CH2:12][N:11]([S:13]([C:16]3[S:17][CH:18]=[CH:19][CH:20]=3)(=[O:14])=[O:15])[CH2:10][CH2:9][N:8]2[C:21]2[CH:22]=[CH:23][C:24]([C:27]([OH:33])([CH3:32])[C:28]([F:30])([F:31])[F:29])=[CH:25][CH:26]=2)[CH2:36][CH2:35]1
Reactant: CC(O)(c1ccc(N2CCN(S(=O)(=O)c3cccs3)C[C@@H]2COS(C)(=O)=O)cc1)C(F)(F)F
Reactant: O=S1(=O)CCNC(C2CC2)C1
Product: CC(O)(c1ccc(N2CCN(S(=O)(=O)c3cccs3)C[C@@H]2CN2CCS(=O)(=O)CC2C2CC2)cc1)C(F)(F)F

Procedure:
This compound was synthesized following the procedure outlined for Example 84. The reaction of ((2R)-4-(2-thiophenylsulfonyl)-1-(4-(2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-2-piperazinyl)methyl methanesulfonate (Intermediate B) and 3-cyclopropylthiomorpholine 1,1-dioxide followed by purification via column chromatography on silica gel (0 to 75% EtOAc in hexanes) delivered 2-(4-((2S)-2-((3-cyclopropyl-1,1-dioxido-4-thiomorpholinyl)methyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-1,1,1-trifluoro-2-propanol as a mixture of four isomers.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([N:8]([CH:16]2[CH2:18][CH2:17]2)[C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[N:5]2[N:19]=[CH:20][C:21]([CH:22]=[O:23])=[C:4]2[N:3]=1.[OH:24][C:25]1[CH:26]=[C:27](B(O)O)[CH:28]=[CH:29][CH:30]=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.COCCOC.CCO>[CH:16]1([N:8]([C:6]2[N:5]3[N:19]=[CH:20][C:21]([CH:22]=[O:23])=[C:4]3[N:3]=[C:2]([C:29]3[CH:28]=[CH:27][CH:26]=[C:25]([OH:24])[CH:30]=3)[CH:7]=2)[C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH2:18][CH2:17]1
Reactant: OB(O)c1cccc(O)c1
Reactant: CC(C)(C)OC(=O)N(c1cc(Cl)nc2c(C=O)cnn12)C1CC1
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+]
Solvent: COCCOC
Solvent: CCO
Product: CC(C)(C)OC(=O)N(c1cc(-c2cccc(O)c2)nc2c(C=O)cnn12)C1CC1
Temperature: 85 °C
Reaction time: 1 h
Yield: 52.5 %

Procedure:
To tert-butyl 5-chloro-3-formylpyrazolo[1,5-a]pyrimidin-7-yl(cyclopropyl)carbamate (650 mg, 1.93 mmol) in 14 mL of a 2:1 mixture of 1,2-dimethoxyethane/EtOH was added 3-hydroxyphenyl boronic acid (399 mg, 2.89 mmol), tetrakis(triphenylphosphine)palladium(0) (112 mg, 0.096 mmol), and 2M aqueous solution of Na2CO3 (2.9 mL, 5.79 mmol). The mixture was stirred at 85° C. for 1 h. The volatiles were removed by rotary evaporation and the residue was purified by silica gel chromatography (0%-30% EtOAc/Hexanes) to provide 400 mg of tert-butyl cyclopropyl(3-formyl-5-(3-hydroxyphenyl)pyrazolo[1,5-a]pyrimidin-7-yl)carbamate. (52%). LCMS (M+1=395)
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[CH:13][N:14]([CH2:15][C:16]([CH3:19])([OH:18])[CH3:17])[C:10]=2[C:9]2[CH:8]=[C:7](Br)[CH:6]=[CH:5][C:4]=2[N:3]=1.[C:21]([O:25][CH3:26])(=[O:24])[CH:22]=[CH2:23]>>[NH2:1][C:2]1[C:11]2[N:12]=[CH:13][N:14]([CH2:15][C:16]([OH:18])([CH3:19])[CH3:17])[C:10]=2[C:9]2[CH:8]=[C:7](/[CH:23]=[CH:22]/[C:21]([O:25][CH3:26])=[O:24])[CH:6]=[CH:5][C:4]=2[N:3]=1
Reactant: C=CC(=O)OC
Reactant: CC(C)(O)Cn1cnc2c(N)nc3ccc(Br)cc3c21
Product: COC(=O)/C=C/c1ccc2nc(N)c3ncn(CC(C)(C)O)c3c2c1

Procedure:
The method described in Example 15 Part E can be used to couple 1-(4-amino-8-bromo-1H-imidazo[4,5-c]quinolin-1-yl)-2-methylpropan-2-ol with methyl acrylate to provide Methyl(2E)-3-[4-amino-1-(2-hydroxy-2-methylpropyl)-1H-imidazo[4,5-c]quinolin-8-yl]prop-2-enoate.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([N+:10]([O-])=O)[CH:7]=[C:6]([N+:13]([O-])=O)[C:5]=1[C:16]1[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=1)([O-])=O.Cl>>[NH2:1][C:4]1[CH:9]=[C:8]([NH2:10])[CH:7]=[C:6]([NH2:13])[C:5]=1[C:16]1[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=1
Reactant: Cc1ccc(-c2c([N+](=O)[O-])cc([N+](=O)[O-])cc2[N+](=O)[O-])cc1
Agent: Cl
Product: Cc1ccc(-c2c(N)cc(N)cc2N)cc1

Procedure:
2′,4′,6′-trinitro-4-methylbiphenyl (1) is reacted with stannous chloride and hydrochloric acid to yield 2′,4′,6′-triamino-4-methylbiphenyl (2).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:10]=2[CH:11]=1.CC([O-])(C)C.[K+].[N:18](OC(C)(C)C)=[O:19]>C1COCC1>[Cl:1][C:2]1[N:3]=[CH:4][C:5]2[CH2:6][CH2:7][CH2:8][C:9](=[N:18][OH:19])[C:10]=2[CH:11]=1
Reactant: CC(C)(C)ON=O
Reactant: Clc1cc2c(cn1)CCCC2
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: ON=C1CCCc2cnc(Cl)cc21
Reaction time: 12 h

Procedure:
3-Chloro-5,6,7,8-tetrahydro-isoquinoline (Chemische Berichte 1948, 81, 279) (8.82 g; 52.6 mmol) dissolved in THF (65 ml) is added under stirring at room temperature to a solution of KOtBu (11.78 g; 105.2 mmol) in THF (100 ml). The red turbid solution is stirred for 12 hours and then cooled to 0° C. tert-Butyl nitrite (18.7 ml; 157.8 mmol) is added dropwise, the reaction mixture is stirred at room temperature for 4 hours and poured on brine. The reaction mixture is extracted with ethyl acetate three times, the organic phases are combined, dried over Na2SO4 and evaporated to dryness, yielding the desired product as brownish crystals. 1H-NMR (400 MHz; DMSO-d6): 11.83 (s, 1H); 8.28 (s, 1H); 7.66 (s, 1H); 2.72 (m, 2H); 2.66 (m, 2H); 1.77 (m, 2H). MS (m/z) ES+: (197, MH+).
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6](=[O:27])[N:7]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][C:18]=2[O:25][CH3:26])[CH:8]=[CH:9][C:10]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[O:4].[Li+].[I-]>N1C=CC=CC=1>[CH2:14]([O:13][C:11]([C:10]1[CH:9]=[CH:8][N:7]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][C:18]=2[O:25][CH3:26])[C:6](=[O:27])[C:5]=1[C:3]([OH:4])=[O:2])=[O:12])[CH3:15]
Reactant: CCOC(=O)c1ccn(Cc2ccc(OC)cc2OC)c(=O)c1C(=O)OC
Agent: [I-]
Agent: [Li+]
Solvent: c1ccncc1
Product: CCOC(=O)c1ccn(Cc2ccc(OC)cc2OC)c(=O)c1C(=O)O
Temperature: 25 °C
Yield: 74.6 %

Procedure:
A solution of 1-(2,4-dimethoxy-benzyl)-2-oxo-1,2-dihydro-pyridine-3,4-dicarboxylic acid 4-ethyl ester 3-methyl ester (18.4 g, 49.0 mmol) in 30 mL of pyridine was added to a refluxing mixture of LiI (26.2 g, 196 mmol) in 190 mL of pyridine. The resulting mixture was refluxed for 1 h. After the mixture was cooled to r.t., solvent was evaporated in vacuo. The residue was dissolved in water (200 mL) and acidified with 6M HCl to pH about 2. The resulting precipitate was collected by filtration. The crude product was purified by chromatography (100% EtOAc) to give 13.2 g of the title compound. MS: (+) m/z 384.29 (M+Na).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([NH2:7])[CH2:3][CH2:2]1.C1(S([N:17]2[C:21]3=[N:22][CH:23]=[CH:24][CH:25]=[C:20]3[C:19]([C:26]3[CH:31]=[CH:30][N:29]=[C:28](Cl)[N:27]=3)=[CH:18]2)(=O)=O)C=CC=CC=1>>[NH:17]1[C:21]2=[N:22][CH:23]=[CH:24][CH:25]=[C:20]2[C:19]([C:26]2[CH:31]=[CH:30][N:29]=[C:28]([N:1]3[CH2:6][CH2:5][CH:4]([NH2:7])[CH2:3][CH2:2]3)[N:27]=2)=[CH:18]1
Reactant: O=S(=O)(c1ccccc1)n1cc(-c2ccnc(Cl)n2)c2cccnc21
Reactant: NC1CCNCC1
Product: NC1CCN(c2nccc(-c3c[nH]c4ncccc34)n2)CC1
Yield: 71.8 %

Procedure:
Using the procedure of example 1, piperidin-4-ylamine (540 mg) was reacted with compound 1f (500 mg) to provide compound 62 (285 mg, 72%). 1H NMR (400MHz, DMSO) δ 8.70 (d, 1 H), 8.40 (s, 1 H), 8.25 (m, 1 H), 8.20 (d, 1 H), 7.20 (m, 1 H), 7.05 (d, 1 H), 4.60 (d, 2 H), 3.05 (m, 2 H), 2.85 (m, 1 H), 1.85 (m, 2 H), 1.25 (m, 2 H). MS (ESI) m/z: 295 (M+H)+.
Reaction SMILES: [CH:1]1([CH:6]2[C:15]3[C:14](=[O:16])[CH2:13][C:12]([CH3:18])([CH3:17])[CH2:11][C:10]=3[NH:9][C:8]([CH:19]([CH3:21])[CH3:20])=[C:7]2[C:22](=[O:33])[C:23]2[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>ClCCl>[CH:1]1([C:6]2[C:15]3[C:14](=[O:16])[CH2:13][C:12]([CH3:17])([CH3:18])[CH2:11][C:10]=3[N:9]=[C:8]([CH:19]([CH3:21])[CH3:20])[C:7]=2[C:22](=[O:33])[C:23]2[CH:28]=[CH:27][C:26]([C:29]([F:30])([F:31])[F:32])=[CH:25][CH:24]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CC(C)C1=C(C(=O)c2ccc(C(F)(F)F)cc2)C(C2CCCC2)C2=C(CC(C)(C)CC2=O)N1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: ClCCl
Product: CC(C)c1nc2c(c(C3CCCC3)c1C(=O)c1ccc(C(F)(F)F)cc1)C(=O)CC(C)(C)C2
Temperature: 25 °C

Procedure:
4.0 g (8.7 mmol) of the compound from Example 1A are dissolved in 100 ml of dichloro-methane, and 2.17 g (9.6 mmol, 1.1 eq.) of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) are added a little at a time at 0° C. With stirring, the mixture is warmed to room temperature over a period of 3 h. The mixture is concentrated on a rotary evaporator and the residue is purified by chromatography (silica gel, mobile phase: isohexane/ethyl acetate 100:0→50:50).
Reaction SMILES: [F:1][C:2]1[C:10]([O:11][C:12]2[C:17]3=[C:18]([CH3:26])[C:19]([O:21][CH2:22][CH:23]4[CH2:25][O:24]4)=[CH:20][N:16]3[N:15]=[CH:14][N:13]=2)=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH3:27])[NH:6]2.[CH3:28][S:29]([O-:31])=[O:30].[Na+]>CS(C)=O>[F:1][C:2]1[C:10]([O:11][C:12]2[C:17]3=[C:18]([CH3:26])[C:19]([O:21][CH2:22][CH:23]([OH:24])[CH2:25][S:29]([CH3:28])(=[O:31])=[O:30])=[CH:20][N:16]3[N:15]=[CH:14][N:13]=2)=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH3:27])[NH:6]2
Reactant: Cc1cc2c(F)c(Oc3ncnn4cc(OCC5CO5)c(C)c34)ccc2[nH]1
Reactant: CS(=O)[O-]
Agent: [Na+]
Solvent: CS(C)=O
Product: Cc1cc2c(F)c(Oc3ncnn4cc(OCC(O)CS(C)(=O)=O)c(C)c34)ccc2[nH]1
Yield: 45.4 %

Procedure:
A mixture of Example 2 (10 mg, 0.027 mmol) and sodium methanesulfinate (120 mg, 85%, 1.0 mmol) in DMSO was heated at 105° C. for 1 hr. The mixture was concentrated and purified by chromatography on silica gel eluting with 5% methanol in ethyl acetate to provide the title compound (5.5 mg, 45%) as a white solid. MS: (M+H)+=449.3
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[CH:3]([CH2:8][CH3:9])[CH2:4][C:5]([OH:7])=[O:6].[CH3:12][Si](C=[N+]=[N-])(C)C>ClCCl.CO>[CH3:12][O:6][C:5](=[O:7])[CH2:4][CH:3]([C:2]([F:10])([F:11])[F:1])[CH2:8][CH3:9]
Reactant: CCC(CC(=O)O)C(F)(F)F
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Solvent: ClCCl
Product: CCC(CC(=O)OC)C(F)(F)F
Yield: 92.3 %

Procedure:
To a stirred solution of Example 1D (250 mg, 1.47 mmol) in dichloromethane (10 mL) and methanol (0.25 mL), under nitrogen atmosphere, trimethylsilyldiazomethane (2.0 M solution in diethyl ether) (2.1 mL, 4.19 mmol) was added drop wise at 0° C. The reaction mixture was stirred keeping the temperature below 5° C. for 1 h. The solvent was removed (40° C., 25 bar) yielding 250 mg (75.4%) of a yellow oil that was used in the next step without further purification.