Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[CH:5]2[CH2:6][CH:7]([NH2:8])[CH:3]([CH2:4]2)[CH2:2]1.[OH-].[Na+].Cl[CH2:12][CH:13]([OH:19])[CH2:14][S:15]([OH:18])(=[O:17])=[O:16].[Na]>O1CCOCC1.O>[CH:3]12[CH2:4][CH:5]([CH2:1][CH2:2]1)[CH2:6][CH:7]2[NH:8][CH2:12][CH:13]([OH:19])[CH2:14][S:15]([OH:18])(=[O:17])=[O:16]
Reactant: O=S(=O)(O)CC(O)CCl
Reactant: NC1CC2CCC1C2
Agent: [Na+]
Agent: [Na]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: O=S(=O)(O)CC(O)CNC1CC2CCC1C2
Temperature: 80 °C
Reaction time: 5 h
Yield: 17 %

Procedure:
To an 80° C. solution of exo-2-aminonorbornane (910 mg, 8.2 mmol) and sodium hydroxide (242 mg, 6.1 mmol) in 1,4-dioxane (4 mL) and water (4 mL) was added via syringe pump (1 hour addition) a solution of 3-chloro-2-hydroxy-propane sulfonic acid, sodium salt (1.09 g, 5.5 mmol) in 1,4-dioxane (0.5 mL) and water (5.5 mL). The solution was stirred at 80° C. for an additional 5 hours. The reaction was cooled to room temperature. The solvent was evaporated under reduced pressure. The solid was suspended in EtOH (25 mL). The mixture was heated to reflux for 1 minute. The solid was recovered by filtration and it was passed through an ion exchange column (Dowex 50×8, 100 g, solvent: water). The product was recrystallized in EtOH/water (99/1). Yield: 17%. 1H NMR (D2O, 500 MHz) δ ppm 4.25 (m, 1H), 3.25 (m, 2H), 3.01 (m, 4H), 2.39 (m, 1H), 2.27 (m, 1H), 1.69 (m, 1H), 1.51 (m, 1H), 1.38 (m, 3H), 1.19 (m, 1H), 1.07 (m, 2H). 13C (D2O, 125 MHz) δ ppm 63.66, 63.50, 62.21, 61.98, 54.94, 50.11, 50.04, 39.26, 39.21, 36.02, 35.97, 35.91, 35.80, 34.70, 34.61, 27.11, 27.08, 26.50, 26.45. ES-MS 250 (M−1).
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:14]=[C:13]([F:15])[C:12]([C:16]2([C:36]#[N:37])[CH:20]([CH2:21][C:22]([CH3:25])([CH3:24])[CH3:23])[NH:19][CH:18]([C:26]([OH:28])=O)[CH:17]2[C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([Cl:35])[CH:30]=2)=[C:11]([F:38])[CH:10]=1.CC1(C)[O:44][C@@H:43]([CH2:45][CH2:46][NH2:47])[CH2:42][O:41]1.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.Cl>C(Cl)Cl.O1CCCC1>[OH:44][C@H:43]([CH2:42][OH:41])[CH2:45][CH2:46][NH:47][C:26]([CH:18]1[CH:17]([C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([Cl:35])[CH:30]=2)[C:16]([C:12]2[C:11]([F:38])=[CH:10][C:9]([Cl:8])=[CH:14][C:13]=2[F:15])([C:36]#[N:37])[CH:20]([CH2:21][C:22]([CH3:23])([CH3:24])[CH3:25])[NH:19]1)=[O:28]
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2)C1(C#N)c1c(F)cc(Cl)cc1F
Reactant: CC1(C)OC[C@H](CCN)O1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(C)(C)CC1NC(C(=O)NCC[C@H](O)CO)C(c2cccc(Cl)c2)C1(C#N)c1c(F)cc(Cl)cc1F
Yield: 80.8 %

Procedure:
In a manner similar to the method described in Examples 42c, 42d, rac-(2R,3R,4R,5S)-4-(4-chloro-2,6-difluoro-phenyl)-3-(3-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid prepared in Example 108c (0.4 g, 0.67 mmol) was reacted with 2-((S)-2,2-dimethyl-[1,3]dioxolan-4-yl)-ethylamine (0.29 g, 2 mmol), HATU (0.46 g, 1.2 mmol) and iPr2NEt (0.58 mL, 3.3 mmol) in CH2Cl2 at room temperature for 20 h, then reacted with aqueous HCl solution in tetrahydrofuran at room temperature for 2 h to give rac-(2R,3R,4R,5S)-4-(4-chloro-2,6-difluoro-phenyl)-3-(3-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide as a white solid (0.3 g, 77%).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[C:7]2[OH:12].[H-].[Na+].[CH3:15][O:16][CH2:17]Cl.O>CN(C)C=O>[Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[C:7]2[O:12][CH2:15][O:16][CH3:17]
Reactant: COCCl
Reactant: Oc1cccc2c(Br)cccc12
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COCOc1cccc2c(Br)cccc12
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
6.0 g of 5-bromo-1-naphthol was dissolved in 50 ml of N,N-dimethylformamide, to which 1.2 g of 60% sodium hydride was added. After stirring at a room temperature for 10 min, it was cooled to 0° C., to which 3.5 ml of chloromethyl methyl ether was added and stirred for 10 min. Water was added to the reaction solution, which was extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and then the solvent was distilled off. When the resultant residue was purified on silica gel column chromatography (10% ethyl acetate/hexane), 7.2 g of the above-captioned compound was obtained as red acicular crystals.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][N:3]=1.[C:9]([C:11]1[CH:16]=[CH:15][C:14](B(O)O)=[CH:13][CH:12]=1)#[N:10]>>[OH:8][C:5]1[CH:6]=[CH:7][C:2]([C:14]2[CH:15]=[CH:16][C:11]([C:9]#[N:10])=[CH:12][CH:13]=2)=[N:3][CH:4]=1
Reactant: Oc1ccc(Br)nc1
Reactant: N#Cc1ccc(B(O)O)cc1
Product: N#Cc1ccc(-c2ccc(O)cn2)cc1
Yield: 26 %

Procedure:
The title compound was prepared according to the method described for Preparation 17 using 2-bromo-5-hydroxypyridine and 4-cyanophenylboronic acid to afford the title compound as a yellow solid (300 mg, 26%)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](Cl)=[C:8]([C:11]([NH2:13])=[O:12])[CH:7]=[N:6][N:5]2[CH:14]=1.[CH:15]1([C@H:18]([NH2:20])[CH3:19])[CH2:17][CH2:16]1.CCN(C(C)C)C(C)C.O>CN1C(=O)CCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:9]([NH:20][C@@H:18]([CH:15]3[CH2:17][CH2:16]3)[CH3:19])=[C:8]([C:11]([NH2:13])=[O:12])[CH:7]=[N:6][N:5]2[CH:14]=1
Reactant: NC(=O)c1cnn2cc(Br)cc2c1Cl
Reactant: C[C@@H](N)C1CC1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: C[C@@H](Nc1c(C(N)=O)cnn2cc(Br)cc12)C1CC1
Reaction time: 0.17 h
Yield: 84.2 %

Procedure:
A solution of 6-bromo-4-chloropyrrolo[1,2-b]pyridazine-3-carboxamide (Preparation 5, 474.3 mg, 1.728 mmol), (R)-1-cyclopropylethylamine (162 mg, 1.901 mmol) and DIPEA (0.453 mL, 2.59 mmol) in NMP (Volume: 5 mL) was heated to 100° C. for 4 hr. The reaction was cooled and 10 mL of water was added and the resulting mixture was stirred for 10 minutes. The solid was collected by vacuum filtration and dried to afford the title compound (470 mg, 80%). HPLC (Method N): retention time=3.258 min. LC/MS (M+H)+=325.1. 1H NMR (400 MHz, CD3OD) δ 8.11 (s, 1H), 7.60 (dd, J=1.8, 0.7 Hz, 1H), 6.94 (d, J=1.8 Hz, 1H), 4.12-3.73 (m, 1H), 1.39 (d, J=6.4 Hz, 3H), 1.18-1.04 (m, 1H), 0.64-0.49 (m, 2H), 0.41-0.27 (m, 2H).
Reaction SMILES: [N:1]1([C@H:10]2[CH2:13][C@H:12]([NH2:14])[CH2:11]2)[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[CH:2]1.C(N(CC)C(C)C)(C)C.Cl[C:25]1[S:26][C:27]2[CH:33]=[CH:32][CH:31]=[CH:30][C:28]=2[N:29]=1>CN(C)C1C=CN=CC=1.CS(C)=O>[N:1]1([C@H:10]2[CH2:11][C@H:12]([NH:14][C:25]3[S:26][C:27]4[CH:33]=[CH:32][CH:31]=[CH:30][C:28]=4[N:29]=3)[CH2:13]2)[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[CH:2]1
Reactant: Clc1nc2ccccc2s1
Reactant: N[C@H]1C[C@H](n2ccc3cccnc32)C1
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: c1cnc2c(c1)ccn2[C@H]1C[C@H](Nc2nc3ccccc3s2)C1
Temperature: 110 °C

Procedure:
trans-3-(1H-pyrrolo[2,3-b]pyridin-1-yl)cyclobutanamine (78 mg, 0.42 mmol), 4-dimethylaminopyridine (3.56 mg, 0.029 mmol), N,N-diisopropylethylamine (159 μl, 0.916 mmol) and 2-chlorobenzothiazole (81 μl, 0.625 mmol) were added in a round bottomed flask, followed by dry DMSO (833 μl). The mixture was sealed and heated at 110° C. for 16 h. The reaction mixture was partitioned between water, saturated ammonium chloride and ethyl acetate. The organic was dried with magnesium sulfate and evaporated to dryness under reduced pressure. Purification using ISCO (0-60% EtOAc in hexane), gave N-(trans-3-(1H-pyrrolo[2,3-b]pyridin-1-yl)cyclobutyl)benzo[d]thiazol-2-amine (23 mg, 0.072 mmol, 17% yield) as off-white solid. 1H NMR (400 MHz, CHLOROFORM-d) δ: ppm 2.77 (ddd, J=14.04, 8.46, 3.72 Hz, 2 H) 2.96-3.14 (m, 2 H) 4.56 (dt, J=7.43, 3.72 Hz, 1 H) 5.59-5.76 (m, 1 H) 6.54 (d, J=3.52 Hz, 1 H) 7.04-7.17 (m, 2 H) 7.28-7.36 (m, 1 H) 7.45 (d, J=3.72 Hz, 1 H) 7.60 (t, J=8.51 Hz, 2 H) 7.92 (dd, J=7.82, 1.37 Hz, 1 H) 8.32 (dd, J=4.69, 1.37 Hz, 1 H).
Reaction SMILES: C(OC(N([CH2:16][C:17]1[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:18]=1[Br:24])C(OC(C)(C)C)=O)=O)(C)(C)C.[Br:25]C1C=CC(Cl)=CC=1C.C1C(=O)N(Br)C(=O)C1>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:24][C:18]1[CH:19]=[CH:20][C:21]([Cl:23])=[CH:22][C:17]=1[CH2:16][Br:25]
Reactant: Cc1cc(Cl)ccc1Br
Reactant: CC(C)(C)OC(=O)N(Cc1cc(Cl)ccc1Br)C(=O)OC(C)(C)C
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Agent: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: Clc1ccc(Br)c(CBr)c1
Temperature: 80 °C

Procedure:
N,N-bis(tert-butoxycarbonyl)-2-bromo-5-chlorobenzylamine: To 1-bromo-4-chloro-2-methylbenzene (3.3 g, 16.06 mmol) in CCl4 (30 mL) were added NBS (3.43 g, 19.27 mmol) and benzoyl peroxide (10 mg, 0.041 mmol). The reaction was heated 80° C. overnight, then filtered and purified by flash chromatography to give 1-bromo-2-bromomethyl-4-chloro-benzene (4.5 g). 1HNMR (400 MHz, CDCl3) δ: 4.53 (s, 2 H) 7.15 (dd, J=8.59, 2.27 Hz, 1 H), 7.40-7.47 (m, 1 H), 7.49 (d, J=8.59 Hz, 1 H). This intermediate was combined with di-tert-butyl imidodicarbonate (3.49 g, 16.06 mmol) and cesium carbonate (5.23 g, 16.06 mmol) in DMF (16 mL) and stirred overnight. The reaction was partitioned with EtOAc/water and extracted with EtOAc. The combined organic layers were washed with water and brine, dried (MgSO4), and evaporated. The resulting residue was purified by flash chromatography to give 126A (3.4 g). 1HNMR (400 MHz, CDCl3) δ: 1.43-1.51 (m, 18 H), 4.82 (s, 2 H), 7.08-7.18 (m, 1 H), 7.39-7.53 (m, 2 H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][C@@H:8]([C@@H:16]1[CH2:18][O:17]1)[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:22][NH:21]1>>[C:1]([O:5][C:6](=[O:19])[NH:7][C@H:8]([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C@@H:16]([OH:17])[CH2:18][N:21]1[CH2:22][C:23]2[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:20]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccccc1)[C@@H]1CO1
Reactant: c1ccc2c(c1)CNC2
Product: CC(C)(C)OC(=O)N[C@H](Cc1ccccc1)[C@@H](O)CN1Cc2ccccc2C1

Procedure:
Using general procedure 1 with [(1R)-1-{(2R)-oxiran-2-yl}-2-phenyl-ethyl]carbamic acid tert-butylester (0.132 g, 0.50 mmol) and 2,3-dihydro-1H-isoindole (0.114 mL, 1.0 mmol) gives the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]3[CH:18]=[CH:17][CH:16]=[CH:15][C:10]=3[O:11][C:12]=2[C:13]#[N:14])=[CH:4][CH:3]=1.[Br:19]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.N(C(C)(C)C#N)=NC(C)(C)C#N>[Br:19][CH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]3[CH:18]=[CH:17][CH:16]=[CH:15][C:10]=3[O:11][C:12]=2[C:13]#[N:14])=[CH:4][CH:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(-c2c(C#N)oc3ccccc23)cc1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: N#Cc1oc2ccccc2c1-c1ccc(CBr)cc1
Temperature: 25 °C
Yield: 94 %

Procedure:
A mixture of 3-(4-methylphenyl)benzo[b]furan-2-carbonitrile (239 mg), N-bromosuccinimide (182 mg), and 2,2'-azobisisobutyronitrile (10 mg) in carbon tetrachloride (5 ml) was refluxed for 5 hours and cooled to ambient temperature. The precipitates were filtered off. The filtrate was washed with aqueous sodium bicarbonate solution (×3), dried, and concentrated in vacuo to give a yellow oil, which was crystallized from n-hexane to yield 3-(4-bromomethylphenyl)benzo[b]furan-2-carbonitrile (300 mg) as a yellow solid.
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:16]=[C:17]([C:22]3[CH:31]=[CH:30][C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[CH:23]=3)[C:18]([NH2:21])=[N:19][CH:20]=2)=[CH:11][CH:10]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Si:32]([O:39][C:40]1[CH:45]=[CH:44][C:43]([CH2:46][C:47](Cl)=[O:48])=[CH:42][CH:41]=1)([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:34])[CH3:33].O>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[Si:32]([O:39][C:40]1[CH:41]=[CH:42][C:43]([CH2:46][C:47]([NH:21][C:18]2[C:17]([C:22]3[CH:31]=[CH:30][C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[CH:23]=3)=[N:16][C:15]([C:12]3[CH:11]=[CH:10][C:9]([O:8][Si:1]([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2])=[CH:14][CH:13]=3)=[CH:20][N:19]=2)=[O:48])=[CH:44][CH:45]=1)([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:34])[CH3:33]
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(CC(=O)Cl)cc1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(-c2cnc(N)c(-c3ccc4ccccc4c3)n2)cc1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: O
Product: CC(C)(C)[Si](C)(C)Oc1ccc(CC(=O)Nc2ncc(-c3ccc(O[Si](C)(C)C(C)(C)C)cc3)nc2-c2ccc3ccccc3c2)cc1
Temperature: 50 °C
Reaction time: 16 h
Yield: 58.2 %

Procedure:
Under an argon atmosphere, to a mixture of 5-[4-(tert-butyldimethylsilyloxy)phenyl]-3-(naphthalen-2-yl)pyrazin-2-amine (7e) (500 mg, 1.17 mmol) and 4-(dimethylamino)pyridine (15.0 mg, 123 μmol) dissolved in anhydrous pyridine (20 mL) was added 2-[4-(tert-butyldimethylsilyloxy)phenyl]acetyl chloride (10) prepared above at 0° C., and the mixture was heated with stirring at 50° C. for 16 hours. After cooling to room temperature, to this was added water and the product was extracted with ethyl acetate (200 mL×3). The combined organic extract was washed successively with water (200 mL) and brine (200 mL), followed by drying over anhydrous sodium sulfate. After filtration and concentration under reduced pressure, the residue was purified by column chromatography (silica gel 50 g, n-hexane/ethyl acetate=3/1) to give Compound 11e (460 mg, 681 μmol, 58.2%) as a yellow foamy solid. Rf=0.26 (n-hexane/diethyl ether=2/3); 1H NMR (400 MHz, DMSO-d6) δ 0.12 (s, 6H), 0.21 (s, 6H), 0.91 (s, 9H), 0.94 (s, 9H), 3.46 (s, 2H), 6.55-6.65 (AA′BB′, 2H), 6.91-6.97 (AA′BB′, 2H), 6.97-7.03 (AA′BB′, 2H), 7.47-7.58 (m, 2H), 7.75-8.00 (m, 4H), 8.08-8.14 (AA′BB′, 2H), 8.23 (s, 1H), 9.00 (s, 1H), 10.63 (s, 1H); 13C NMR (75.5 MHz, DMSO-d6) 8-4.6 (4C), 17.8, 17.9, 25.5 (6C), 119.4 (2C), 120.3 (2C), 125.5, 126.1, 126.6, 127.1, 127.2, 127.3, 127.5, 127.9, 128.2 (2C), 128.5, 130.2 (2C), 132.6, 132.8, 135.3, 137.6, 143.0, 147.5, 148.0, 153.7, 156.7, 169.4 (one carbon at the benzyl position was unobservable due to overlapping with the septet peak of DMSO); IR (KBr, cm−1) 478, 527, 687, 718, 746, 781, 804, 839, 914, 1009, 1082, 1103, 1128, 1169, 1261, 1362, 1415, 1445, 1472, 1508, 1605, 1670, 2857, 2886, 2928, 2955, 3057, 3221; HRMS (ESI+) m/z 698.3194 ([M+Na]+, C40H49N3NaO3Si2+ requires 698.3205).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:17]=[C:16]([C:18]([O:20]CC)=[O:19])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]=2)=[CH:4][CH:3]=1.[Li+].[OH-].O1CCCC1.O>C(O)(=O)C>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:17]=[C:16]([C:18]([OH:20])=[O:19])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1nc(-c2ccc(N)cc2)nc2ccccc12
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: Nc1ccc(-c2nc(C(=O)O)c3ccccc3n2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Into a 50-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed ethyl 2-(4-aminophenyl)quinazoline-4-carboxylate (300 mg, 1.02 mmol, 1.00 equiv), LiOH (85 mg, 3.55 mmol, 2.00 equiv), tetrahydrofuran (5 mL) and water (5 mL). The resulting solution was stirred for 2 h at room temperature. To this was added 122.4 mg of acetic acid. The resulting solution was concentrated under vacuum. This resulted in 25.3 mg (9%) of 2-(4-aminophenyl)quinazoline-4-carboxylic acid as a yellow solid. MS (ESI) m/z 266 ([M+H]+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([C:11]2[C:16]([NH:17][C:18]3[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=3)=[CH:15][CH:14]=[C:13]([CH3:24])[N:12]=2)=[O:10])=[N:6][CH:7]=1.Br[C:26]1C=NC=CC=1C>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([C:11]2[C:16]([NH:17][C:18]3[CH:19]=[N:20][CH:21]=[CH:22][C:23]=3[CH3:26])=[CH:15][CH:14]=[C:13]([CH3:24])[N:12]=2)=[O:10])=[N:6][CH:7]=1
Reactant: Cc1ccncc1Br
Reactant: Cc1ccc(Nc2cccnc2)c(C(=O)Nc2ccc(F)cn2)n1
Product: Cc1ccc(Nc2cnccc2C)c(C(=O)Nc2ccc(F)cn2)n1

Procedure:
The title compound, was prepared from 3-Amino-6-methyl-pyridine-2-carboxylic acid (5-fluoro-pyridin-2-yl)-amide (example 8) in accordance with the general method of example 5, step 6 using 3-Bromo-4-methylpyridine instead of 3-Bromopyridine to yield the final compound as a light yellow crystalline solid, MS (ISP): m/e=338.3 (M+H+).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:15]([CH3:21])=[N:16][C:17]([CH3:20])=[CH:18][CH:19]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.Cl.C(OCC)(=O)C.C(=O)([O-])[O-].[K+].[K+]>C(Cl)(Cl)Cl>[CH3:21][C:15]1[C:14]([N:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)=[CH:19][CH:18]=[C:17]([CH3:20])[N:16]=1
Reactant: Cc1ccc(N2CCN(C(=O)OC(C)(C)C)CC2)c(C)n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: CCOC(C)=O
Product: Cc1ccc(N2CCNCC2)c(C)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 141.8 %

Procedure:
To a mixture of 3-bromo-2,6-dimethylpyridine (2.0 g), t-Boc-piperazine (2 g), palladium(II) acetate (0.12 g), rac-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (0.31 g) and sodium tert-butoxide (1.34 g) was added toluene (35 mL), and the mixture was stirred with heating under reflux for 9 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and the solvent was evaporated. The obtained residue was purified by column chromatography (chloroform:methanol) to give 4-(2,6-dimethylpyridin-3-yl)piperazine-1-carboxylic acid tert-butyl ester (3.06 g). The obtained 4-(2,6-dimethylpyridin-3-yl)piperazine-1-carboxylic acid tert-butyl ester (2.16 g) was dissolved in chloroform (21 mL), 4N hydrogen chloride/ethyl acetate solution (10 mL) was added, and the mixture was stirred at room temperature overnight. The reaction mixture was neutralized with aqueous potassium carbonate solution, the mixture was extracted with ethyl acetate, and the solvent was evaporated to give the title compound (2.01 g).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[NH2:14])=[CH:4][CH:3]=1.[C:15]1([C@@H:21]2[CH2:23][C@H:22]2[C:24](=O)[CH3:25])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[NH:14][CH:24]([C@@H:22]2[CH2:23][C@H:21]2[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH3:25])=[CH:6][CH:7]=1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1N
Reactant: CC(=O)[C@@H]1C[C@H]1c1ccccc1
Product: Cc1noc(-c2ccc(Br)cc2)c1NC(C)[C@@H]1C[C@H]1c1ccccc1

Procedure:
Prepared according to the procedure described in Example 1, Step 12, using 5-(4-bromo-phenyl)-3-methyl-isoxazol-4-ylamine and trans-1-(2-phenyl-cyclopropyl)-ethanone.
Reaction SMILES: [CH3:1][O:2][CH2:3][C@H:4]([CH3:32])[O:5][C:6]1[CH:7]=[C:8]([CH:19]=[C:20]([C:22]2[NH:23][C:24]([C:27]3[S:28][CH:29]=[CH:30][N:31]=3)=[CH:25][CH:26]=2)[CH:21]=1)[O:9][C:10]1[N:11]=[CH:12][C:13]([C:16](O)=[O:17])=[N:14][CH:15]=1.[CH3:33][N:34]1[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>O1CCCC1.O>[CH3:1][O:2][CH2:3][C@H:4]([CH3:32])[O:5][C:6]1[CH:7]=[C:8]([CH:19]=[C:20]([C:22]2[NH:23][C:24]([C:27]3[S:28][CH:29]=[CH:30][N:31]=3)=[CH:25][CH:26]=2)[CH:21]=1)[O:9][C:10]1[CH:15]=[N:14][C:13]([C:16]([N:37]2[CH2:38][CH2:39][N:34]([CH3:33])[CH2:35][CH2:36]2)=[O:17])=[CH:12][N:11]=1
Reactant: CN1CCNCC1
Reactant: COC[C@H](C)Oc1cc(Oc2cnc(C(=O)O)cn2)cc(-c2ccc(-c3nccs3)[nH]2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: COC[C@H](C)Oc1cc(Oc2cnc(C(=O)N3CCN(C)CC3)cn2)cc(-c2ccc(-c3nccs3)[nH]2)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 98.8 %

Procedure:
5-{3-[(1S)-2-Methoxy-1-methylethoxy]-5-[5-(1,3-thiazol-2-yl)-1H-pyrrol-2-yl]phenoxyl}pyrazine-2-carboxylic acid (40.4 mg, 0.089 mmol) synthesized in Example (63a) was dissolved in tetrahydrofuran (5 mL), and 1-methylpiperazine (30 μL, 0.27 mmol), HATU (67.9 mg, 0.18 mmol) and N,N-diisopropylethylamine (93 μL, 0.54 mmol) were added, followed by stirring at room temperature for 12 hours under nitrogen atmosphere. To the reaction solution, water (15 mL) was added, and extraction was carried out with ethyl acetate (15 mL), followed by drying over sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: methanol/dichloromethane=0%-5%) to afford the desired compound (47 mg, yield 98%) as a pale yellow solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:5]=[CH:6][C:7]=1[NH2:8].Cl.N([O-])=O.[Na+].[I-:20].[K+].S([O-])([O-])(=O)=S.[Na+].[Na+]>C(O)(=O)C.O>[I:20][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:5]=[CH:6][C:7]=1[NH2:8]
Reactant: [I-]
Reactant: Nc1ccc(-c2ccccc2)cc1Br
Agent: Cl
Agent: O=N[O-]
Agent: O=S([O-])([O-])=S
Solvent: O
Solvent: CC(=O)O
Product: Nc1ccc(-c2ccccc2)cc1I
Temperature: 15 °C
Reaction time: 0.5 h

Procedure:
A solution of 7.3 g (29.4 mmol) of 3-bromobiphenyl-4-ylamine in 120 mL of acetic acid is mixed with 6 mL of concentrated hydrochloric acid at ambient temperature, cooled to 15° C., and stirred for 30 minutes. A solution of 2 g (28.9 mmol) of sodium nitrite in 7 mL of water is slowly added dropwise to this reaction mixture at 15° C. and stirred for 30 minutes. Then at 5° C., a solution of 5.4 g (32.5 mmol) of potassium iodide in 28 mL of water is slowly added dropwise and the mixture is stirred. After 30 minutes, 2.95 g of sodium thiosulfate is added and the mixture is stirred for a further 30 minutes. Then the reaction mixture is evaporated down and combined with water/ethyl acetate. The aqueous phase is again extracted with ethyl acetate, the combined aqueous phases are extracted once with water and dried over sodium sulfate. The purification is carried out by column chromatography on silica gel (eluant: petroleum ether). Yield: 6.6 g (85% of theory); C12H8BrI (M=359.00); calc.: molecular ion peak (M)+: 358/360 (Br); found: molecular ion peak (M)+: 358/360 (Br).
Reaction SMILES: [O:1]1[CH2:6][CH2:5]C[O:3][CH:2]1[CH2:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][OH:17])=[CH:12][CH:11]=1.N1C=CN=C1.[C:23]([Si:27](Cl)([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)([CH3:26])([CH3:25])[CH3:24]>C(Cl)Cl.C(OCC)(=O)C>[Si:27]([O:17][CH2:16][C:13]1[CH:12]=[CH:11][C:10]([CH2:9][CH2:8][CH2:7][CH:2]2[O:1][CH2:6][CH2:5][O:3]2)=[CH:15][CH:14]=1)([C:23]([CH3:26])([CH3:25])[CH3:24])([C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: OCc1ccc(CCCC2OCCCO2)cc1
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)(C)[Si](OCc1ccc(CCCC2OCCO2)cc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 102.9 %

Procedure:
To a solution of 2.58 g (11.6 mmol) of alcohol 170 and 1.19 g (17.5 mmol) of imidazole in 50 mL of CH2Cl2 was added 3.4 mL (13.1 mmol) of tert-butylchlorodiphenyl silane and the resulting mixture was allowed to stir at room temperature for 1 h. The mixture was then diluted with ethyl acetate and washed with 0.5N HCl. The organic layer was dried over MgSO4, filtered and concentrated. Flash chromatography (elution with 5% ethyl acetate in hexane) afforded 5.5 g of 171. 1H NMR consistent with the product.