Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([O:4][C:5]1[N:10]=[C:9]([C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([C:20]4[S:21][C:22](S(C)(=O)=O)=[N:23][N:24]=4)[CH:18]=3)[N:13]([S:29]([C:32]3[CH:38]=[CH:37][C:35]([CH3:36])=[CH:34][CH:33]=3)(=[O:31])=[O:30])[CH:12]=2)[CH:8]=[CH:7][CH:6]=1)([CH3:3])[CH3:2].[NH2:39][C@@H:40]1[CH2:45][CH2:44][CH2:43][N:42]([C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47])[CH2:41]1>O1CCOCC1.CN1CCCC1=O.C(Cl)Cl>[CH:1]([O:4][C:5]1[N:10]=[C:9]([C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([C:20]4[S:21][C:22]([NH:39][C@@H:40]5[CH2:45][CH2:44][CH2:43][N:42]([C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47])[CH2:41]5)=[N:23][N:24]=4)[CH:18]=3)[N:13]([S:29]([C:32]3[CH:38]=[CH:37][C:35]([CH3:36])=[CH:34][CH:33]=3)(=[O:31])=[O:30])[CH:12]=2)[CH:8]=[CH:7][CH:6]=1)([CH3:2])[CH3:3]
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cccc(OC(C)C)n3)c3cc(-c4nnc(S(C)(=O)=O)s4)ccc32)cc1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](N)C1
Solvent: ClCCl
Solvent: CN1CCCC1=O
Solvent: C1COCCO1
Product: Cc1ccc(S(=O)(=O)n2cc(-c3cccc(OC(C)C)n3)c3cc(-c4nnc(N[C@@H]5CCCN(C(=O)OC(C)(C)C)C5)s4)ccc32)cc1
Temperature: 120 °C
Yield: 50 %

Procedure:
A yellow solution of 2-(3-(6-isopropoxypyridin-2-yl)-1-tosyl-1H-indol-5-yl)-5-(methylsulfonyl)-1,3,4-thiadiazole (177.5 mg, 0.284 mmol) and (R)-tert-butyl 3-aminopiperidine-1-carboxylate (Small Molecules, Inc., Hoboken, N.J.; 0.251 mL, 1.296 mmol) in dioxane (2.0 mL) was heated in an open microwave vial at 90° C. for 2 d. The resulting solid residue was taken up in N-methyl-2-pyrrolidinone (0.4 mL) and heated under argon at 120° C. for 2.5 days. The mixture was then diluted with DCM (10 mL), concentrated onto silica gel, and chromatographically purified (silica gel, 0-100% EtOAc/Hex) to provide (R)-tert-butyl 3-(5-(3-(6-isopropoxypyridin-2-yl)-1-tosyl-1H-indol-5-yl)-1,3,4-thiadiazol-2-ylamino)piperidine-1-carboxylate (98.0 mg, 0.142 mmol, 50%) as a yellow oil: MS (ESI, pos. ion) m/z: 689.2 (M+1). 1H NMR (400 MHz, CDCl3) δ ppm 8.80 (1H, s), 8.07 (1H, s), 8.06 (1H, d, J=8.2 Hz), 7.93 (1H, d, J=8.7 Hz), 7.82 (2H, d, J=8.4 Hz), 7.62 (1H, t, J=7.8 Hz), 7.28 (2H, d, J=8.0 Hz), 7.24 (2H, s), 6.63 (1H, d, J=8.2 Hz), 5.55 (1H, dt, J=12.0, 5.9 Hz), 4.40 (1H, d, J=6.1 Hz), 3.61-3.74 (2H, m), 3.47-3.57 (2H, m), 3.36-3.45 (2H, m), 3.30 (2H, m), 2.35 (3H, s), 1.47 (9H, s), 1.44 (6H, br. s.).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]=[C:4]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][CH3:19])=[CH:12][CH:11]=2)[N:3]=1>[Zn].O1CCOCC1>[C:8]([C:7]1[CH:6]=[N:5][C:4]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][CH3:19])=[CH:12][CH:11]=2)=[N:3][CH:2]=1)#[N:9]
Reactant: CCCOc1ccc(-c2ncc(C#N)c(Cl)n2)cc1
Agent: [Zn]
Solvent: C1COCCO1
Product: CCCOc1ccc(-c2ncc(C#N)cn2)cc1

Procedure:
4.7 G. of 4-chloro-5-cyano-2-(4-n--propoxyphenyl)-pyrimidine are reacted in 230 ml. of 50% dioxane with 20.0 g. of pre-treated zinc dust and worked up after the reaction in a manner analogous to that described in Example 13. There is obtained 5-cyano-2-(4-n-propoxyphenyl)-pyrimidine as colorless crystals having a melting point of 146.2°-146.6° C, which on cooling are nematic (monotropic) at 137.0° C.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[C:34]1([S:40][CH2:41][C@H:42]([NH:47][C:48]2[CH:53]=[CH:52][C:51]([S:54](=[O:57])(=[O:56])[NH2:55])=[CH:50][C:49]=2[S:58]([C:61]([F:64])([F:63])[F:62])(=[O:60])=[O:59])[CH2:43][C:44](O)=[O:45])[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.[Si:65]([O:82][CH2:83][CH2:84][N:85]1[CH2:90][CH2:89][NH:88][CH2:87][CH2:86]1)([C:78]([CH3:81])([CH3:80])[CH3:79])([C:72]1[CH:77]=[CH:76][CH:75]=[CH:74][CH:73]=1)[C:66]1[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=1>CC(N(C)C)=O.CCOC(C)=O>[Si:65]([O:82][CH2:83][CH2:84][N:85]1[CH2:90][CH2:89][N:88]([C:44](=[O:45])[CH2:43][C@@H:42]([NH:47][C:48]2[CH:53]=[CH:52][C:51]([S:54]([NH2:55])(=[O:56])=[O:57])=[CH:50][C:49]=2[S:58]([C:61]([F:64])([F:62])[F:63])(=[O:60])=[O:59])[CH2:41][S:40][C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH2:87][CH2:86]1)([C:78]([CH3:79])([CH3:80])[CH3:81])([C:72]1[CH:73]=[CH:74][CH:75]=[CH:76][CH:77]=1)[C:66]1[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=1
Reactant: NS(=O)(=O)c1ccc(N[C@@H](CSc2ccccc2)CC(=O)O)c(S(=O)(=O)C(F)(F)F)c1
Reactant: CC(C)(C)[Si](OCCN1CCNCC1)(c1ccccc1)c1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: CC(C)(C)[Si](OCCN1CCN(C(=O)C[C@H](CSc2ccccc2)Nc2ccc(S(N)(=O)=O)cc2S(=O)(=O)C(F)(F)F)CC1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 117.2 %

Procedure:
HATU (0.915 g, 2.41 mmol) and DIPEA (0.701 ml, 4.01 mmol) were added sequentially to a solution of (R)-4-(phenylthio)-3-(4-sulfamoyl-2-(trifluoromethylsulfonyl)phenylamino) butanoic acid (INTERMEDIATE 8, 1.0 g, 2.01 mmol) and 1-(2-(tert-butyldiphenylsilyloxy)ethyl)piperazine (INTERMEDIATE 20, 0.894 g, 2.21 mmol) in DMA (2.0 ml). Additional DMA (1.7 ml) was added and the resulting mixture was stirred at room temperature for 2 hrs. The mixture was diluted with EtOAc and the organic layer was washed with H2O (2×), 1N NaHSO4 (aq.) and saturated aq. NaHCO3. The organic layer was dried (Na2SO4), and concentrated under reduced pressure to provide the title product (2.0 g, yield: quantitative), which was used in the preparation of INTERMEDIATE 22 without further purification.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([C:15](=[O:19])[CH2:16][C:17]#[N:18])([CH3:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+]>CO>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([CH:15]([OH:19])[CH2:16][C:17]#[N:18])([CH3:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(C)(C(=O)CC#N)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(C)(C(O)CC#N)CC1
Reaction time: 1 h

Procedure:
To 4-(2-cyanoacetyl)-4-methylpiperidine-1-carboxylic acid tert-butyl ester (6.20 g, 23.3 mmol) dissolved in dry MeOH (95 mL) is added sodium borohydride (1.76 g, 46.6 mmol) portion wise over 10 minutes. The ice bath is removed after 1 hour and stirring is continued for 1 hour. The reaction mixture is concentrated, then dissolved in EtOAc (50 mL) and some MeOH. The mixture is washed with 1N HCl (25 mL). Saturated aqueous sodium chloride (25 mL) is added and the organic layer is dried over Na2SO4, then concentrated. The residue is dissolved in dichloromethane, loaded onto a silica gel column, and chromatographed. After pooling fractions and concentrating, the mixture is dissolved in MeOH and concentrated again to give the title compound as a slightly yellow oil (5.89 g, 95% yield).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[NH:4][C:5]1[S:6][C:7]2[C:13]([C:14]3[CH2:15][CH2:16][O:17][CH2:18][CH:19]=3)=[CH:12][CH:11]=[C:10]([O:20][CH3:21])[C:8]=2[N:9]=1>CO.[Pd]>[CH3:1][O:2][C:3](=[O:22])[NH:4][C:5]1[S:6][C:7]2[C:13]([CH:14]3[CH2:15][CH2:16][O:17][CH2:18][CH2:19]3)=[CH:12][CH:11]=[C:10]([O:20][CH3:21])[C:8]=2[N:9]=1
Reactant: COC(=O)Nc1nc2c(OC)ccc(C3=CCOCC3)c2s1
Agent: [Pd]
Solvent: CO
Product: COC(=O)Nc1nc2c(OC)ccc(C3CCOCC3)c2s1
Temperature: 25 °C
Reaction time: 72 h
Yield: 65 %

Procedure:
To a stirred solution of 200 mg (0.62 mmol) [7-(3,6-dihydro-2H-pyran-4-yl)-4-methoxy-benzothiazol-2-yl]-carbamic acid methyl ester in 20 ml methanol was added a spatula end of 10% palladium on charcoal and the mixture was then stirred for 72 h at room temperature under an atmosphere of hydrogen. The mixture was then filtered, washing with dichloromethane, and the filtrate concentrated in vacuo to afford 130 mg (64%) [4-methoxy-7-(tetrahydro-pyran-4-yl)-benzothiazol-2-yl]-carbamic acid methyl ester as an off-white foam. ES-MS m/e (%): 345 (M+Na+, 9), 323 (M+H+, 100).
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:22])([F:21])[CH2:17]2)[C:8]2[C:9](=[N:11][N:12]([CH2:14][CH3:15])[N:13]=2)[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C(C1N=C(N2CCC(F)(F)C2)C2N=NNC=2N=1)(C)(C)C.[Cl:43][C:44]1C(CCl)=[N:46][CH:47]=[CH:48][CH:49]=1>>[C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:21])([F:22])[CH2:17]2)[C:8]2[C:9](=[N:11][N:12]([CH2:14][C:15]3[C:44]([Cl:43])=[CH:49][CH:48]=[CH:47][N:46]=3)[N:13]=2)[N:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: ClCc1ncccc1Cl
Reactant: CCn1nc2nc(C(C)(C)C)nc(N3CCC(F)(F)C3)c2n1
Agent: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn[nH]c2n1
Product: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn(Cc3ncccc3Cl)nc2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoro-pyrrolidin-1-yl)-2-ethyl-2H-[1,2,3]triazolo[4,5-d]pyrimidine (example 3, step b), the title compound was prepared from 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 3-chloro-2-(chloromethyl)pyridine and isolated as light brown gum. MS (m/e): 408.3 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:4]=1[S:11][C:12]1[NH:13][C:14]2[C:19]([N:20]=1)=[C:18]([NH2:21])[N:17]=[CH:16][N:15]=2.Cl[CH2:23][CH2:24][C:25]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:26]=1[F:32]>>[F:32][C:26]1[CH:27]=[C:28]([F:31])[CH:29]=[CH:30][C:25]=1[CH2:24][CH2:23][N:13]1[C:12]([S:11][C:4]2[CH:5]=[C:6]([O:9][CH3:10])[CH:7]=[CH:8][C:3]=2[O:2][CH3:1])=[N:20][C:19]2[C:14]1=[N:15][CH:16]=[N:17][C:18]=2[NH2:21]
Reactant: COc1ccc(OC)c(Sc2nc3c(N)ncnc3[nH]2)c1
Reactant: Fc1ccc(CCCl)c(F)c1
Product: COc1ccc(OC)c(Sc2nc3c(N)ncnc3n2CCc2ccc(F)cc2F)c1

Procedure:
The title compound was prepared from 8-(2,5-dimethoxy-phenylsulfanyl)-9H-purin-6-ylamine and 1-(2-chloro-ethyl)-2,4-difluoro-benzene by a procedure similar to examples 1 and 2. The compound was purified by preparative HPLC. LC-MS [M+H]+ 444.1.
Reaction SMILES: [OH:1][C:2]1[C:7]2[C@@:8]3([OH:45])[C@@:21]([O:25][CH3:26])([C@H:22]([OH:24])[CH2:23][C:6]=2[CH:5]=[C:4]([CH3:46])[C:3]=1[C:47]([O:49][CH3:50])=[O:48])[C:20](=[O:27])[C:19]1[C:10](=[CH:11][C:12]2[C:13](=[O:43])[C:14]([NH:30][C@@H:31]4[C@H:36]([O:37][CH3:38])[C@H:35]([OH:39])[C@@H:34]([O:40][CH3:41])[C@H:33]([CH3:42])[O:32]4)=[CH:15][C:16](=O)[C:17]=2[C:18]=1[OH:28])[C:9]3=[O:44].Cl.[NH2:52][OH:53]>CO.N1C=CC=CC=1.C(OCC)(=O)C>[OH:1][C:2]1[C:7]2[C@@:8]3([OH:45])[C@@:21]([O:25][CH3:26])([C@H:22]([OH:24])[CH2:23][C:6]=2[CH:5]=[C:4]([CH3:46])[C:3]=1[C:47]([O:49][CH3:50])=[O:48])[C:20](=[O:27])[C:19]1[C:10](=[CH:11][C:12]2[C:13](=[O:43])[C:14]([NH:30][C@@H:31]4[C@H:36]([O:37][CH3:38])[C@H:35]([OH:39])[C@@H:34]([O:40][CH3:41])[C@H:33]([CH3:42])[O:32]4)=[CH:15]/[C:16](=[N:52]\[OH:53])/[C:17]=2[C:18]=1[OH:28])[C:9]3=[O:44]
Reactant: COC(=O)c1c(C)cc2c(c1O)[C@]1(O)C(=O)c3cc4c(c(O)c3C(=O)[C@]1(OC)[C@H](O)C2)C(=O)C=C(N[C@H]1O[C@@H](C)[C@H](OC)[C@@H](O)[C@H]1OC)C4=O
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Solvent: CO
Solvent: CCOC(C)=O
Product: COC(=O)c1c(C)cc2c(c1O)[C@]1(O)C(=O)c3cc4c(c(O)c3C(=O)[C@]1(OC)[C@H](O)C2)/C(=N/O)C=C(N[C@H]1O[C@@H](C)[C@H](OC)[C@@H](O)[C@H]1OC)C4=O
Reaction time: 8 h
Yield: 16.7 %

Procedure:
To a solution of (6R,6aS,14aR)-methyl 1,6,8,14a-tetrahydroxy-11-((2S,3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-6a-methoxy-3-methyl-7,9,12,14-tetraoxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxylate (100 mg, 0.143 mmol) in methanol (1 mL) and pyridine (1 mL) was added hydroxylamine hydrochloride (100 mg, 1.43 mmol) at room temperature, and the mixture was stirred under nitrogen overnight. The mixture was diluted with ethyl acetate, washed with 1N HCl and brine, dried (Na2SO4), filtered and concentrated. The residue was purified by preparative TLC (silica gel, 95:5 chloroform/methanol) to afford (6R,6aS,14aR,E)-methyl 1,6,8,14a-tetrahydroxy-11-((2S,3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-9-(hydroxyimino)-6a-methoxy-3-methyl-7,12,14-trioxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxylate (17 mg, 16%) as an orange solid: 1H NMR (500 MHz, CDCl3) δ 12.02 (s, 1H), 8.45 (s, 1H), 6.93 (s, 1H), 6.54 (s, 1H), 6.52 (d, J=9.0 Hz, 1H), 5.33 (br s, 1H), 5.00 (br s, 1H), 4.84-4.82 (m, 2H), 3.83 (s, 3H), 3.80 (s, 3H), 3.78-3.68 (m, 3H), 3.62 (s, 3H), 3.54 (dd, J=19.5, 6.5 Hz, 1H), 3.45-3.42 (m, 1H), 3.43 (s, 3H), 3.36 (d, J=19.5 Hz, 1H), 3.13 (t, J=9.5 Hz, 1H), 2.46 (d, J=5.0 Hz, 1H), 2.39 (s, 3H), 1.38 (d, J=6.0 Hz, 3H); MS (ESI+) m/z 713 (M+H); HPLC 95.0% (AUC), tR 12.31 min.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[N:4][CH:5]=[C:6]([CH3:13])[C:7]=1[C:8]([O:10]CC)=[O:9].[OH-].[Na+].Cl>C(O)C.O>[CH3:1][C:2]1[N:3]=[N:4][CH:5]=[C:6]([CH3:13])[C:7]=1[C:8]([OH:10])=[O:9]
Reactant: CCOC(=O)c1c(C)cnnc1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1cnnc(C)c1C(=O)O
Temperature: 50 °C

Procedure:
To a solution of ethyl 3,5-dimethylpyridazine-4-carboxylate (600 mg, 3.3 mmol) in ethanol (1 mL) was added a solution of NaOH (166 mg, 4.16 mmol) in water (5 mL). The mixture was heated at 50° C. for 1 hour and a clear solution was obtained. The solution was acidified by addition of aq. HCl until pH 5 and all volatiles were removed in vacuo. The residue was extracted with DCM/MeOH 4/1. The extract was concentrated to dryness to afford Intermediate 50: 3,5-dimethylpyridazine-4-carboxylic acid (550 mg) as an off-white solid.
Reaction SMILES: [CH:1]1([N:6]2[C:11]3=[N:12][C:13]([NH:16][C:17]4[CH:22]=[CH:21][C:20]([N:23]5[CH2:28][CH2:27][CH2:26][CH:25]([OH:29])[CH2:24]5)=[CH:19][CH:18]=4)=[N:14][CH:15]=[C:10]3[CH2:9][NH:8][C:7]2=[O:30])[CH2:5][CH2:4][CH2:3][CH2:2]1.CC(C)([O-])C.[K+]>C1COCC1>[CH:1]1([N:6]2[C:11]3=[N:12][C:13]([NH:16][C:17]4[CH:18]=[CH:19][C:20]([N:23]5[CH2:28][CH2:27][CH2:26][CH:25]([OH:29])[CH2:24]5)=[CH:21][CH:22]=4)=[N:14][CH:15]=[C:10]3[CH:9]=[N:8][C:7]2=[O:30])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=C1NCc2cnc(Nc3ccc(N4CCCC(O)C4)cc3)nc2N1C1CCCC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: O=c1ncc2cnc(Nc3ccc(N4CCCC(O)C4)cc3)nc2n1C1CCCC1
Yield: 47.8 %

Procedure:
Prepared from 75 mg (0.18 mmol) of 1-cyclopentyl-7-[4-(3-hydroxypiperidin-1-yl)phenylamino]-3,4-dihydro-pyrimido[4,5-d]pyrimidin-2(1H)-one and 82 mg (0.73 mmol) of potassium tert-butoxide in 4.0 mL of THF. The semi-solid residue is triturated in diethyl ether, and the orange amorphous solid is collected and dried to give 35 mg (45%) of the title compound: mp>135° C. (dec).
Reaction SMILES: B(F)(F)[O:2][C:3]([C:5]1[C:14](=[O:15])[C:13]2[C:8](=[C:9]([O:18][CH3:19])[C:10](F)=[C:11]([F:16])[CH:12]=2)[N:7]([CH2:20][C:21]([F:24])([F:23])[F:22])[CH:6]=1)=[O:4].[NH:27]1[CH2:32][CH2:31][CH:30]([C:33]([O:35][CH2:36][CH3:37])=[O:34])[CH2:29][CH2:28]1>>[CH2:36]([O:35][C:33]([CH:30]1[CH2:31][CH2:32][N:27]([C:10]2[C:9]([O:18][CH3:19])=[C:8]3[C:13]([C:14](=[O:15])[C:5]([C:3]([OH:2])=[O:4])=[CH:6][N:7]3[CH2:20][C:21]([F:23])([F:22])[F:24])=[CH:12][C:11]=2[F:16])[CH2:28][CH2:29]1)=[O:34])[CH3:37]
Reactant: CCOC(=O)C1CCNCC1
Reactant: COc1c(F)c(F)cc2c(=O)c(C(=O)OB(F)F)cn(CC(F)(F)F)c12
Product: CCOC(=O)C1CCN(c2c(F)cc3c(=O)c(C(=O)O)cn(CC(F)(F)F)c3c2OC)CC1

Procedure:
According to the same method as for Example 46A, from 800 mg (2.08 mmol) of [6,7-difluoro-8-methoxy-4-oxo-1-(2,2,2-trifluoroethyl)-1,4-dihydroquinolin-3-yl]carbonyl difluoroborate (Example 38A) and 653 mg (4.15 mmol) of ethyl piperidine-4-carboxylate, 625 mg (63% of theory) of the title compound are obtained.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:8]2[C:12]3[CH:13]=[CH:14][C:15]([CH:17]([N:19]4[C:27](=[O:28])[C:26]5[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=5)[C:20]4=[O:29])[CH3:18])=[CH:16][C:11]=3[N:10]=[CH:9]2)[CH:5]=[CH:6][CH:7]=1.[N:30]1[CH:35]=[CH:34][CH:33]=[C:32](B(O)O)[CH:31]=1>>[N:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C:2]2[CH:3]=[C:4]([N:8]3[C:12]4[CH:13]=[CH:14][C:15]([CH:17]([N:19]5[C:20](=[O:29])[C:21]6[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=6)[C:27]5=[O:28])[CH3:18])=[CH:16][C:11]=4[N:10]=[CH:9]3)[CH:5]=[CH:6][CH:7]=2)[CH:31]=1
Reactant: OB(O)c1cccnc1
Reactant: CC(c1ccc2c(c1)ncn2-c1cccc(Br)c1)N1C(=O)c2ccccc2C1=O
Product: CC(c1ccc2c(c1)ncn2-c1cccc(-c2cccnc2)c1)N1C(=O)c2ccccc2C1=O

Procedure:
This was prepared analogously from 2-{1-[1-(3-bromo-phenyl)-1H-benzoimidazol-5-yl]-ethyl}-isoindole-1,3-dione and 3-pyridineboronic acid
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[CH:4][C:3]=1[C:17]1[N:18]=[CH:19][C:20]([NH2:23])=[N:21][CH:22]=1.[F:24][C:25]([F:36])([F:35])[CH2:26][O:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1Br>>[F:1][C:2]1[CH:7]=[C:6]([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=2[O:27][CH2:26][C:25]([F:24])([F:36])[F:35])[CH:5]=[CH:4][C:3]=1[C:17]1[N:18]=[CH:19][C:20]([NH2:23])=[N:21][CH:22]=1
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)cn3)c(F)c2)OC1(C)C
Reactant: FC(F)(F)COc1ccccc1Br
Product: Nc1cnc(-c2ccc(-c3ccccc3OCC(F)(F)F)cc2F)cn1

Procedure:
The title compound was prepared using analogous conditions to those described in Example 1 utilizing what 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrazin-2-amine and 2-(2,2,2-trifluoroethoxy)bromobenzene. MS (ESI): mass calcd. for C18H13F4N3O, 363.10; m/z found, 363.9 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.39 (s, 1H), 8.03 (s, 1H), 7.91 (m, 1H), 7.56-7.34 (m, 4H), 7.25 (d, J=8.0, 1H), 7.16 (m, 1H), 6.71 (s, 2H), 4.82 (q, J=8.8, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[CH3:14][CH:15]1[C:24]2[C:19](=[C:20]3[CH:27]=[CH:26][O:25][C:21]3=[CH:22][CH:23]=2)[CH2:18][CH2:17][NH:16]1>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:16]3[CH2:17][CH2:18][C:19]4[C:24](=[CH:23][CH:22]=[C:21]5[O:25][CH:26]=[CH:27][C:20]5=4)[CH:15]3[CH3:14])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: O=C(O)c1cc2ncc(Br)cn2n1
Reactant: CC1NCCc2c1ccc1occc21
Product: CC1c2ccc3occc3c2CCN1C(=O)c1cc2ncc(Br)cn2n1

Procedure:
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 6-Methyl-6,7,8,9-tetrahydro-furo[3,2-f]isoquinoline to provide the title compound in moderate yield.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([OH:13])[C:11]=1[CH3:12])[C:5]([O:7][CH3:8])=[O:6].C(=O)([O-])[O-].[K+].[K+].[CH2:20](Br)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CN(C=O)C>[CH2:20]([O:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([OH:13])[C:11]=1[CH3:12])[C:5]([O:7][CH3:8])=[O:6])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: COC(=O)c1cc(O)c(C)c(O)c1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1cc(O)c(C)c(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Methyl 3,5-dihydroxy-4-methylbenzoate (3.5 g, 19.22 mmol, 1.0 eq) was dissolved in 300 ml of DMF. To this solution potassium carbonate (2.52 g, 18.26 mmol, 0.95 eq) was added. To this stirred suspension, benzyl bromide (3.12 g, 18.26 mmol, 0.95 eq) (diluted with 50 ml of DMF) was added dropwise over a period of 3 h. The solution was stirred overnight at ambient temperature. Then DMF was evaporated under reduced pressure. The residue was washed with water and the product was extracted thrice with DCM. The combined DCM layers was dried over sodium sulphate and evaporated under vacuum. The required product was purified by silica gel (240-400) column chromatography using 10% ethyl acetate/hexane as the eluent. Yield: 1.6 g (30%). 1H NMR (400 MHz, DMSO-d6): δ 2.07 (s, 3H), 3.81 (s, 3H), 5.14 (s, 2H), 7.08 (s, 1H), 7.14 (s, 1H), 7.33-7.35 (d, 1H, J=7.04 Hz), 7.39-7.42 (t, 2H, J=7.40 Hz), 7.46-7.48 (d, 2H, J=7.48 Hz), 9.78 (s, 1H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Br[C:8]1[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=1>CC1C=CC=CC=1C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[N:10]1[CH:11]=[CH:12][CH:13]=[C:8]([N:1]2[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]2)[CH:9]=1
Reactant: C1CNCCN1
Reactant: Brc1cccnc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1C
Product: c1cncc(N2CCNCC2)c1
Temperature: 120 °C
Yield: 86 %

Procedure:
A 500 ml Kjeldahl flask equipped with a cooling condenser and a thermometer was charged with a solution of 44.6 g of piperazine in 45 ml of o-xylene, a solution of 13.44 g of 3-bromopyridine in 45 ml of o-xylene, and a solution of 11.3 g of NaOBut in 45 ml of o-xylene, and further with a solution of 19 mg of palladium acetate in 10 ml of o-xylene (the ratio of palladium atom/heterocyclic aromatic halide=0.1% by mole). The flask was flushed with nitrogen for about 20 minutes while the content was stirred, and 0.26 ml of a solution in toluene of tri-tert.-butylphosphine having a concentration of 0.256 g/ml was added. Then the mixture was heated to 120° C., and maintained at that temperature for 3 hours with stirring. After completion of the reaction, the same treatment as employed in Example 1 was conducted to give colorless oily 1-(3-pyridyl)piperazine. The yield was 86% by mole.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH:15][C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[C:23]([C:26]#[C:27][CH2:28][OH:29])[CH:24]=3)[N:19]=[CH:18][N:17]=2)[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=1.C1(C)C=CC=CC=1.[H-].COCCO[Al+]OCCOC.[Na+].[H-].COCCO[AlH2-]OCCOC.[Na+]>O1CCCC1>[CH3:1][C:2]1[CH:3]=[C:4]([NH:15][C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[C:23]([CH:26]=[CH:27][CH2:28][OH:29])[CH:24]=3)[N:19]=[CH:18][N:17]=2)[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=1
Reactant: Cc1cc(Nc2ncnc3ccc(C#CCO)cc23)ccc1Oc1cccnc1
Agent: COCCO[Al+]OCCOC
Agent: COCCO[AlH2-]OCCOC
Agent: [H-]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: Cc1cc(Nc2ncnc3ccc(C=CCO)cc23)ccc1Oc1cccnc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 47.4 %

Procedure:
To a solution of 0.56 g (1.47 mmol) of 3-{4-[3-methyl-4-(pyridin-3-yloxy)-phenylamino]-quinazolin-6-yl}-prop-2-yn-1-ol (prepared by Method B) in 6 mL of dry tetrahydrofuran at 0° C. was added 0.73 mL of a 65% weight toluene solution of sodium bis(2-methoxyethoxy)aluminum hydride (Red-Al, 2.35 mmol) in 1 mL of THF. The reaction was stirred at room temperature for 3 hours. Upon recooling to 0° C. an additional 0.73 mL of the Red-Al solution in 1 mL of THF was added. After stirring for 1 hour at room temperature, the mixture was quenched with the dropwise addition of 10% aqueous potassium carbonate and extracted with ethyl acetate. The organic extracts were dried over sodium sulfate, filtered and evaporated to give 650 mg. Chromatography on 90 g silica gel, eluting with 96:4:0.1 chloroform/methanol/concentrated ammonium hydroxide afforded 268 mg of the title compound. 1H NMR (d6 DMSO): δ 9.79 (s, 1), 8.57 (m, 2), 8.35 (m, 2), 8.01 (m, 1), 7.80 (m, 3), 7.41 (m, 1), 7.29 (m, 1), 7.07 (d, J=8.7 Hz, 1), 6.77 (d, J=16.2 Hz, 1), 6.67 (m, 1), 5.04 (t, J=5.6 Hz, 1), 4.23 (m, 2), 2.23 (s, 3).
Reaction SMILES: [C:1]1([CH2:11][CH2:12][OH:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.ClCCl.[C:24](Cl)(=[O:28])[C:25]([CH3:27])=[CH2:26]>CN(C)C1C=CN=CC=1.C(OCC)C>[C:24]([O:13][CH2:12][CH2:11][C:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1)(=[O:28])[C:25]([CH3:27])=[CH2:26]
Reactant: C=C(C)C(=O)Cl
Reactant: OCCc1cccc2ccccc12
Agent: CN(C)c1ccncc1
Solvent: CCOCC
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=C(C)C(=O)OCCc1cccc2ccccc12

Procedure:
A solution of 2-(1-naphthy)ethanol (30.0 g, 174 mmol), triethylamine (24.2 g, 239 mmol), 4-(dimethylamino)pyridine (1.1 g, 9.1 mmol), and dichloromethane (500 mL) was treated dropwise under nitrogen with methacryloyl chloride (18.9 g, 181 mmol), and then heated at refluxed for 4 h. The reaction mixture was cooled to ambient and diluted with diethyl ether. The solution was filtered and the filtrate was washed twice with water, once with NaHCO3, and once with brine. The solution was dried (Na2SO4) and concentrated to deposit a yellow oil. The product was purified by distillation at reduced pressure, collecting the fraction bp 120-125° C./0.08 mm to provide a colorless oil, mass: 36.0 g (86% theory). 1H (CDCl3): δ 2.00 (s, 3H), 3.50 (t, 2H), 4.55 (t, 2H), 5.60 (s, 1H), 6.15 (s, 1H), 7.50 (m, 4H), 7.8 (d, 1H), 7.9 (d, 1H), 8.2 (d, 1H).