Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]([CH2:19][CH3:20])[CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][C:9]2[NH:12][C:13]([CH:16]=O)=[C:14]([CH3:15])[C:8]=2[C:7]1=[O:18])[CH3:2].[Cl:21][C:22]1[CH:23]=[C:24]2[C:28](=[CH:29][CH:30]=1)[NH:27][C:26](=[O:31])[CH2:25]2>>[Cl:21][C:22]1[CH:23]=[C:24]2[C:28](=[CH:29][CH:30]=1)[NH:27][C:26](=[O:31])[C:25]2=[CH:16][C:13]1[NH:12][C:9]2[CH2:10][CH2:11][N:6]([CH2:5][CH2:4][N:3]([CH2:19][CH3:20])[CH2:1][CH3:2])[C:7](=[O:18])[C:8]=2[C:14]=1[CH3:15].[CH3:15][C:14]1[C:8]2[C:7](=[O:18])[NH:6][CH2:11][CH2:10][C:9]=2[NH:12][CH:13]=1
Reactant: O=C1Cc2cc(Cl)ccc2N1
Reactant: CCN(CC)CCN1CCc2[nH]c(C=O)c(C)c2C1=O
Product: CCN(CC)CCN1CCc2[nH]c(C=C3C(=O)Nc4ccc(Cl)cc43)c(C)c2C1=O
Product: Cc1c[nH]c2c1C(=O)NCC2
Yield: 91.7 %

Procedure:
The title compound was prepared under the same conditions as described in Example 1 with 5-(2-diethylamino-ethyl)-3-methyl-4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine-2-carbaldehyde and 5-chloro-1,3-dihydro-indole-2-one (commercially available from Aldrich) as starting materials to give 2-(5-chloro-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-5-2-diethylamino-ethyl)-3-methyl-1,5,6,7-tetrahydro-pyrrolo[3,2-c]pyridin-4-one (55 mg, 91.7%) as a yellow solid.
Reaction SMILES: [Ga:1].[N+:2]([O-:5])([OH:4])=[O:3]>>[N+:2]([O-:5])([O-:4])=[O:3].[Ga+3:1].[N+:2]([O-:5])([O-:4])=[O:3].[N+:2]([O-:5])([O-:4])=[O:3]
Reactant: O=[N+]([O-])O
Reactant: [Ga]
Product: O=[N+]([O-])[O-]
Product: [Ga+3]
Reaction time: 8 h

Procedure:
A solution of gallium nitrate was prepared as follows: 57.45 parts of gallium were dissolved in 400 ml conc. nitric acid. The mixture was heated until brown fumes appeared, when the heat was removed and the container covered. After standing overnight, the resultant green solution was alternately heated and cooled until it turned yellow, and then clear. Deionized water was added to form 1000 ml of solution.
Reaction SMILES: [Br:1][C:2]1[C:10]2[O:9][N:8]=[C:7]([Cl:11])[C:6]=2[CH:5]=[CH:4][C:3]=1[O:12][CH3:13].[NH:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1>CO>[ClH:11].[Br:1][C:2]1[C:10]2[O:9][N:8]=[C:7]([N:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[C:6]=2[CH:5]=[CH:4][C:3]=1[O:12][CH3:13]
Reactant: COc1ccc2c(Cl)noc2c1Br
Reactant: C1CNCCN1
Solvent: CO
Product: COc1ccc2c(N3CCNCC3)noc2c1Br
Product: Cl
Temperature: 140 °C

Procedure:
To a sealed tube was added 7-bromo-3-chloro-6-methoxy-1,2-benzisoxazole (2.0 g) and piperazine (2.6 g). The reaction was heated to 140° C. over 30 minutes and then cooled to room temperature. The residue was dissolved in MeOH and concentrated in vacuo. Flash column chromatography (silica gel) eluting with 30% MeOH/EtOAc provided a residue upon evaporation (1.0 g) which was recrystallized from MeOH/CH2Cl2 /pet. ether to yield 1.0 g, m.p. 268-269° C.
Reaction SMILES: [OH:1][N:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=[N:3]1.[CH3:11][N:12]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:13](Cl)=[O:14]>>[N:2]1([O:1][C:13](=[O:14])[N:12]([CH3:11])[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=[N:3]1
Reactant: On1nnc2ccccc21
Reactant: CN(C(=O)Cl)c1ccccc1
Product: CN(C(=O)On1nnc2ccccc21)c1ccccc1

Procedure:
The title compound was prepared from 1-hydroxybenzotriazole and N-methyl-N-phenylcarbamoyl chloride applying the general procedure 8. The crude product was purified by flash chromatography (Quad flash 12, EtOAc-heptane) (98%, crystallizes slowly).
Reaction SMILES: C(OC(=O)[N:7]([CH2:12][C:13]1[N:17]([CH3:18])[C:16]([C:19]2[S:27][C:26]3[C:21](=[N:22][CH:23]=[CH:24][C:25]=3[O:28][C:29]3[CH:34]=[CH:33][C:32]([NH:35][C:36](=[O:48])[CH2:37][C:38]([NH:40][C:41]4[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=4[F:47])=[O:39])=[CH:31][C:30]=3[F:49])[CH:20]=2)=[N:15][CH:14]=1)[CH2:8][CH2:9][O:10][CH3:11])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:49][C:30]1[CH:31]=[C:32]([NH:35][C:36](=[O:48])[CH2:37][C:38]([NH:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=2[F:47])=[O:39])[CH:33]=[CH:34][C:29]=1[O:28][C:25]1[CH:24]=[CH:23][N:22]=[C:21]2[CH:20]=[C:19]([C:16]3[N:17]([CH3:18])[C:13]([CH2:12][NH:7][CH2:8][CH2:9][O:10][CH3:11])=[CH:14][N:15]=3)[S:27][C:26]=12
Reactant: COCCN(Cc1cnc(-c2cc3nccc(Oc4ccc(NC(=O)CC(=O)Nc5ccccc5F)cc4F)c3s2)n1C)C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COCCNCc1cnc(-c2cc3nccc(Oc4ccc(NC(=O)CC(=O)Nc5ccccc5F)cc4F)c3s2)n1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 40.6 %

Procedure:
To a solution of 354 (230 mg, 0.325 mmol) in DCM (3 mL) was added TFA (0.5 mL). The reaction mixture was stirred at room temperature overnight then concentrated. The residue was partitioned between EtOAc and NaHCO3 saturated solution. The organic layer was collected, dried and concentrated. The residue was purified via Biotage (0-50% MeOH/EA; 10 g SNAP column) to afford a reddish solid which was purified again by flash column chromatography (eluent MeOH/EA, 20-25%) to give a yellowish solid which was triturated with ether to afford the title compound 355 (80 mg, 0.132 mmol, 40.5% yield) as an off-white solid. HNMR (dmso) d(ppm) 1H: 10.53 (s, 1H), 10.01 (s, 1H), 8.47 (d, 1H, J=5.5 Hz), 7.95 (m, 1H), 7.85-7.81 (m, 2H), 7.46 (t, 1H, J=8.8 Hz), 7.39 (d, 1H, J=10.9 Hz), 7.15-7.09 (m, 2H), 6.91 (s, 1H), 6.65 (d, 1H, J=5.5 Hz), 3.81 (s, 3H), 3.72 (s, 2H), 3.58 (s, 2H), 3.35 (t, 2H, J=5.6 Hz), 3.20 (s, 3H), 2.64 (t, 2H, J=5.6 Hz). MS: 607.2 (MH)+.
Reaction SMILES: [C:1](=[O:21])(OC1C=CC([N+]([O-])=O)=CC=1)[O:2][CH2:3][CH:4]1[CH2:9][CH2:8][N:7]([CH3:10])[CH2:6][CH2:5]1.CCN(C(C)C)C(C)C.Cl.Cl.[CH3:33][C:34]1[CH:35]=[C:36]([N:40]2[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]2)[CH:37]=[CH:38][CH:39]=1>CN(C=O)C>[CH3:33][C:34]1[CH:35]=[C:36]([N:40]2[CH2:45][CH2:44][N:43]([C:1]([O:2][CH2:3][CH:4]3[CH2:5][CH2:6][N:7]([CH3:10])[CH2:8][CH2:9]3)=[O:21])[CH2:42][CH2:41]2)[CH:37]=[CH:38][CH:39]=1
Reactant: CN1CCC(COC(=O)Oc2ccc([N+](=O)[O-])cc2)CC1
Reactant: Cc1cccc(N2CCNCC2)c1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cccc(N2CCN(C(=O)OCC3CCN(C)CC3)CC2)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 13.4 %

Procedure:
(1-Methylpiperidin-4-yl)methyl 4-nitrophenyl carbonate (Intermediate 1; 4.30 g, 14.6 mmol) was dissolved in DMF (50 mL). DIPEA (8.91 mL, 51.1 mmol) and 4-(3-methylphenyl)piperazine dihydrochloride (3.64 g, 14.6 mmol) were added. The reaction mixture was stirred at room temperature for 4 hours and then concentrated in vacuo. The residue was dissolved in EtOAc (500 mL) and then washed sequentially with 1 M aq NaOH solution (6×200 mL), brine (50 mL), dried (MgSO4) and concentrated in vacuo. The residue was dissolved in DCM (150 mL) and methyl isocyanate resin (1.0 g) was added and the reaction mixture shaken for 14 h, filtered and then concentrated in vacuo. The residue was purified by reverse phase chromatography (gradient eluting with MeOH in water, with 1% formic acid in each solvent, 0-30%). The resulting residue was dissolved in DCM (70 mL) and stirred with solid K2CO3 for 20 minutes, filtered and concentrated in vacuo to give (1-methylpiperidin-4-yl)methyl 4-(3-methylphenyl)piperazine-1-carboxylate (0.65 g, 13.3%) as a pale yellow oil.
Reaction SMILES: C[O:2][C:3](=[O:22])[C@H:4]([N:6]([S:8]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]#[C:20][CH3:21])=[CH:13][CH:12]=1)(=[O:10])=[O:9])[CH3:7])[CH3:5].O.[OH-].[Li+].Cl>C1COCC1.CO>[CH2:18]([O:17][C:14]1[CH:13]=[CH:12][C:11]([S:8]([N:6]([CH3:7])[CH:4]([CH3:5])[C:3]([OH:22])=[O:2])(=[O:9])=[O:10])=[CH:16][CH:15]=1)[C:19]#[C:20][CH3:21]
Reactant: CC#CCOc1ccc(S(=O)(=O)N(C)[C@H](C)C(=O)OC)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CC#CCOc1ccc(S(=O)(=O)N(C)C(C)C(=O)O)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 97.9 %

Procedure:
To a solution of 0.273 g (0.840 mmol) of (2R)-2-[(4-but-2-ynyloxy-benzenesulfonyl)-methyl-amino]-propionic acid methyl ester in 6 mL of THF/methanol (1/1) was added 0.123 g (2.94 mmol) of lithium hydroxide monohydrate and the resulting solution was stirred at room temperature for 3 h. The reaction was then acidified with 5% HCl solution and extracted with chloroform. The combined organics were dried over MgSO4, filtered and concentrated in vacuo to give 0.256 g of 2-[(4-but-2-ynyloxy-benzenesulfonyl)-methyl-amino]-propionic acid as a white solid. Electrospray Mass Spec 310.2 (M−H)−.
Reaction SMILES: [OH:1][N:2]=[C:3]([NH2:10])[C:4]1[CH:9]=[CH:8][CH:7]=[N:6][CH:5]=1.[F:11][C:12]1[CH:13]=[C:14]([CH:18]=[CH:19][C:20]=1[F:21])[C:15](O)=O.N>>[F:11][C:12]1[CH:13]=[C:14]([C:15]2[O:1][N:2]=[C:3]([C:4]3[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=3)[N:10]=2)[CH:18]=[CH:19][C:20]=1[F:21]
Reactant: NC(=NO)c1cccnc1
Reactant: O=C(O)c1ccc(F)c(F)c1
Agent: N
Product: Fc1ccc(-c2nc(-c3cccnc3)no2)cc1F

Procedure:
The title compound was prepared according to the procedure of Example 8 using N′-hydroxynicotinimidamide (Aldrich) and 3,4-difluorobenzoic acid (Aldrich). 1H NMR (300 MHz, CD3OD) δ 7.52-7.67 (m, 2H), 8.12 (ddd, J=8.7, 4.3, 1.5 Hz, 1H), 8.19 (ddd, J=10.8, 7.5, 2.0 Hz, 1H), 8.55 (dt, J=8.1, 1.9 Hz, 1H), 8.74 (dd, J=5.1, 1.7 Hz, 1H), 9.29 (dd, J=2.0, 0.7 Hz, 1H) ppm; MS (DCl/NH3) m/z 260 (M+H)+.
Reaction SMILES: [F:1][CH:2]([F:28])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12]([OH:14])=O)=[C:7]2[N:6]=[C:5]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[C:17]([O:25][CH2:26][CH3:27])[CH:16]=2)[CH:4]=1.[N:29]1([S:35]([C:38]2[CH:39]=[C:40]([NH2:44])[CH:41]=[CH:42][CH:43]=2)(=[O:37])=[O:36])[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1>>[N:29]1([S:35]([C:38]2[CH:39]=[C:40]([NH:44][C:12]([C:11]3[CH:10]=[N:9][N:8]4[C:3]([CH:2]([F:28])[F:1])=[CH:4][C:5]([C:15]5[CH:20]=[CH:19][C:18]([C:21]([F:22])([F:23])[F:24])=[C:17]([O:25][CH2:26][CH3:27])[CH:16]=5)=[N:6][C:7]=34)=[O:14])[CH:41]=[CH:42][CH:43]=2)(=[O:37])=[O:36])[CH2:30][CH2:31][O:32][CH2:33][CH2:34]1
Reactant: CCOc1cc(-c2cc(C(F)F)n3ncc(C(=O)O)c3n2)ccc1C(F)(F)F
Reactant: Nc1cccc(S(=O)(=O)N2CCOCC2)c1
Product: CCOc1cc(-c2cc(C(F)F)n3ncc(C(=O)Nc4cccc(S(=O)(=O)N5CCOCC5)c4)c3n2)ccc1C(F)(F)F

Procedure:
The title compound was prepared from 7-difluoromethyl-5-(3-ethoxy-4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.12) and 3-(morpholine-4-sulfonyl)-phenylamine [CAS 22184-97-0; commercially available] according to general procedure II. Light yellow solid. MS (ISP) 624.3 [(M−H)−]; mp 231° C.
Reaction SMILES: [S:1]([CH2:6][C:7](O)=O)[CH2:2][C:3](O)=O.[C:10]1([NH2:17])[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[NH2:16].[NH4+:18].[OH-]>Cl>[NH:16]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:17]=[C:3]1[CH2:2][S:1][CH2:6][C:7]1[NH:16][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:18]=1
Reactant: O=C(O)CSCC(=O)O
Reactant: Nc1ccccc1N
Reactant: [NH4+]
Agent: Cl
Agent: [OH-]
Product: c1ccc2[nH]c(CSCc3nc4ccccc4[nH]3)nc2c1

Procedure:
A solution of 4.1 g (27.3 mmol) thiodiacetic acid and 4.9 g (27.3 mmol) o-phenylene diamine in 40 ml 4N HCl was stirred at reflux for 4 hours. The reaction mixture was cooled to room temperature an neutralised with conc. NH4OH. The formed precipitate was filtered, washed with water (3×40 ml) and dried under vacuum. Yield—2.4g (25.2%).
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C@@H:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C@H:17]([O:24][C:25]3[CH:26]=[CH:27][C:28]4[N:29]([C:31]([N:34]5[CH2:39][CH2:38][CH2:37][CH2:36][C@@H:35]5[CH3:40])=[N:32][N:33]=4)[CH:30]=3)[CH2:16][CH2:15]2)=[O:12])[N:7]([C:41]2[CH:42]=[C:43]([CH:50]=[CH:51][CH:52]=2)[CH2:44][O:45]S(C)(=O)=O)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.[CH3:62][O:63][CH:64]1[CH2:69][CH2:68][NH:67][CH2:66][CH2:65]1>C1COCC1>[CH:44]([OH:45])=[O:63].[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C@@H:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C@H:17]([O:24][C:25]3[CH:26]=[CH:27][C:28]4[N:29]([C:31]([N:34]5[CH2:39][CH2:38][CH2:37][CH2:36][C@@H:35]5[CH3:40])=[N:32][N:33]=4)[CH:30]=3)[CH2:16][CH2:15]2)=[O:12])[N:7]([C:41]2[CH:52]=[CH:51][CH:50]=[C:43]([CH2:44][N:67]3[CH2:68][CH2:69][CH:64]([O:63][CH3:62])[CH2:65][CH2:66]3)[CH:42]=2)[N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COC1CCNCC1
Reactant: C[C@H]1CCCCN1c1nnc2ccc(O[C@@H]3CC[C@H](NC(=O)Nc4cc(C(C)(C)C)nn4-c4cccc(COS(C)(=O)=O)c4)c4ccccc43)cn12
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COC1CCN(Cc2cccc(-n3nc(C(C)(C)C)cc3NC(=O)N[C@H]3CC[C@@H](Oc4ccc5nnc(N6CCCC[C@@H]6C)n5c4)c4ccccc43)c2)CC1
Product: O=CO
Temperature: 50 °C
Reaction time: 24 h
Yield: 26.6 %

Procedure:
To a solution of Intermediate 167b (0.19 mmol) in THF (2 mL) was added DIPEA (130 μL, 0.75 mmol) and 4-methoxypiperidine (86 mg, 0.75 mmol) and the reaction stirred at 50° C. for 24 h. The crude reaction mixture was cooled and partitioned between EtOAc and water. The aqueous phase was extracted with EtOAc (×3) and the combined organic layers were washed with brine, dried (MgSO4) and concentrated in vacuo. The resulting residue was purified by FCC on silica, using a gradient of 0-10% (2M NH3 in MeOH) in DCM, followed by MDAP (Method 7) purification, to give the title compound (20 mg, 14%). LCMS (Method 5): Rt 3.66 min, m/z 746 [MH+]. 1H NMR (400 MHz, d6-DMSO): 0.86 (3H, d, J=6.2 Hz), 1.23 (9H, s), 1.30-1.40 (2H, m), 1.42-1.50 (2H, m), 1.58-1.67 (2H, m), 1.70-1.83 (5H, m), 1.83-1.93 (1H, m), 1.96-2.12 (4H, m), 2.56-2.64 (2H, m), 2.86 (1H, ddd, J=12.7, 9.0, 3.9 Hz), 3.05-3.12 (3H, m), 3.13 (3H, s), 3.45 (2H, s), 4.77 (1H, td, J=8.4, 5.7 Hz), 5.47 (1H, t, J=4.2 Hz), 6.28 (1H, s), 7.00 (1H, d, J=8.6 Hz), 7.14 (1H, dd, J=9.8, 2.1 Hz), 7.20-7.30 (4H, m), 7.30-7.37 (3H, m), 7.40 (1H, t, J=7.7 Hz), 7.59 (1H, d, J=10.0 Hz), 7.64 (1H, d, J=1.8 Hz), 8.07 (1H, s), 8.23 (0.3H, s).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:21]=[CH:20][C:6]([O:7][CH2:8][C:9]2[N:10]=[C:11]([C:15]3[O:16][CH:17]=[CH:18][CH:19]=3)[O:12][C:13]=2[CH3:14])=[C:5]([O:22][CH3:23])[CH:4]=1.[OH:24][C:25]1[C:29]([C:30]([O:32][CH2:33][CH3:34])=[O:31])=[CH:28][N:27]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[N:26]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[O:16]1[CH:17]=[CH:18][CH:19]=[C:15]1[C:11]1[O:12][C:13]([CH3:14])=[C:9]([CH2:8][O:7][C:6]2[CH:20]=[CH:21][C:3]([CH2:2][O:24][C:25]3[C:29]([C:30]([O:32][CH2:33][CH3:34])=[O:31])=[CH:28][N:27]([C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)[N:26]=3)=[CH:4][C:5]=2[O:22][CH3:23])[N:10]=1
Reactant: CCOC(=O)c1cn(-c2ccccc2)nc1O
Reactant: COc1cc(CCl)ccc1OCc1nc(-c2ccco2)oc1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cn(-c2ccccc2)nc1OCc1ccc(OCc2nc(-c3ccco3)oc2C)c(OC)c1
Temperature: 90 °C
Reaction time: 3 h
Yield: 68.8 %

Procedure:
A mixture of 4-[(4-chloromethyl-2-methoxyphenoxy)methyl]-2-(2-furyl)-5-methyl-1,3-oxazole (3.07 g), ethyl 3-hydroxy-1-phenyl-1H-pyrazole-4-carboxylate (2.04 g), potassium carbonate (1.22 g) and N,N-dimethylformamide (50 mL) was stirred at 90° C. for 3 hrs. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to give ethyl 3-[(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-methoxybenzyl)oxy]-1-phenyl-1H-pyrazole-4-carboxylate as colorless crystals (3.20 g, 69%) from a fraction eluted with ethyl acetate-hexane (1:1, v/v). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 150-151° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:11][CH2:12][C:13]([F:16])([F:15])[F:14])=[CH:4][C:5]([C:8]([OH:10])=O)=[N:6][CH:7]=1.CCN(C(C)C)C(C)C.[NH2:26][C@@H:27]([C:32]([CH3:35])([CH3:34])[CH3:33])[C:28]([NH:30][CH3:31])=[O:29]>CN(C=O)C>[CH3:33][C:32]([CH3:35])([CH3:34])[C@H:27]([NH:26][C:8]([C:5]1[CH:4]=[C:3]([O:11][CH2:12][C:13]([F:16])([F:15])[F:14])[C:2]([Cl:1])=[CH:7][N:6]=1)=[O:10])[C:28](=[O:29])[NH:30][CH3:31]
Reactant: CNC(=O)[C@@H](N)C(C)(C)C
Reactant: O=C(O)c1cc(OCC(F)(F)F)c(Cl)cn1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)[C@@H](NC(=O)c1cc(OCC(F)(F)F)c(Cl)cn1)C(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 5-Chloro-4-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylic acid (Example 24c, 72 mg, 282 μmol) in DMF (1 mL) was added 4-(4,6-dimethoxyl-1,3,5-triazin-2-yl)-4-methylmorpholininium chloride (CAN 3945-69-5, 82 mg, 296 μmol) and DIEA (34.5 μL, 296 μmol). The reaction mixture was then stirred at room temperature for 30 min, followed by addition of (S)-2-amino-N,3,3-trimethylbutanamide (CAN 89226-12-0, 43 mg, 296 μmol). The reaction mixture was stirred for 3 h. The crude reaction mixture was directly purified by preparative HPLC to deliver the desired compound (65 mg, 60%) as white solid. MS (ESI, m/z): 382.4 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[CH3:11].[Mn]([O-])(=O)(=O)=[O:13].[K+].[OH2:18]>>[F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[C:11]([OH:13])=[O:18]
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: Cc1ccc([N+](=O)[O-])cc1F
Reactant: O
Agent: [K+]
Product: O=C(O)c1ccc([N+](=O)[O-])cc1F

Procedure:
A solution of 2-fluoro-4-nitrotoluene (3.95 g, 25.5 mmol, Janssen) in water (200 mL) was treated portionwise with potassium permanganate (24.6 g, 0.15 mmol) at 80° C. After 2 h the reaction mixture was filtered hot, acidified with 5N hydrochloric acid and extracted with ethyl acetate (2×100 mL). The extract was dried over anhydrous sodium sulfate and concentrated in vacuo to give 1.15 g (Y: 24%) of the title compound; 1H-NMR (DMSO-d6): δ 8.21 (d, J=10.5 Hz, 1H), 8.16-8.08 (m, 2H); MS (DCI) m/e: 186 (MH+).
Reaction SMILES: CN1C(C2C=CC(O)=CC=2)=C(C2C=CN=CC=2)N=N1.ClCCl.C[O:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]2[N:32]([C:36]3[CH:41]=[CH:40][N:39]=[CH:38][CH:37]=3)[CH:33]=[CH:34][N:35]=2)=[CH:27][CH:26]=1.B(Br)(Br)Br>CC(O)C>[N:39]1[CH:38]=[CH:37][C:36]([N:32]2[CH:33]=[CH:34][N:35]=[C:31]2[C:28]2[CH:29]=[CH:30][C:25]([OH:24])=[CH:26][CH:27]=2)=[CH:41][CH:40]=1
Reactant: COc1ccc(-c2nccn2-c2ccncc2)cc1
Agent: BrB(Br)Br
Agent: Cn1nnc(-c2ccncc2)c1-c1ccc(O)cc1
Solvent: ClCCl
Solvent: CC(C)O
Product: Oc1ccc(-c2nccn2-c2ccncc2)cc1
Yield: 75.9 %

Procedure:
According to the procedure for preparation of 4-(3-methyl-5-(pyridin-4-yl)-3H-1,2,3-triazol-4-yl)phenol, except that 4:1 dichloromethane:2-propanol was used in place of ethyl acetate to extract the product, 4-(2-(4-methoxyphenyl)-1H-imidazol-1-yl)pyridine (125 mg, 0.5 mmol) was treated with 1.25 mmol of boron tribromide to give 90 mg of a colorless solid. 1H NMR (CDCl3, 400 mHz) δ 8.52 (d, 2H, J=6 Hz), 7.14 (m, 2H), 7.11-7.08 (m, 4H), 6.79 (m, 2H), 2.94 (br, 1 H).
Reaction SMILES: [H-].[Na+].[O:3]=[C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:14]([O:16][CH3:17])=[O:15])[CH:12]=2)[CH:7]=[CH:6][NH:5]1.[Br:18][CH2:19][CH2:20][CH2:21]Br>CN(C=O)C>[Br:18][CH2:19][CH2:20][CH2:21][N:5]1[CH:6]=[CH:7][C:8]2[C:13](=[CH:12][C:11]([C:14]([O:16][CH3:17])=[O:15])=[CH:10][CH:9]=2)[C:4]1=[O:3]
Reactant: COC(=O)c1ccc2cc[nH]c(=O)c2c1
Reactant: BrCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2ccn(CCCBr)c(=O)c2c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 144.6 %

Procedure:
To a stirred suspension of sodium hydride (60% in mineral oil, 0.30 g, 7.4 mmol) in DMF (15 mL) under an atmosphere of nitrogen cooled to 0° C. was added methyl 1-oxo-1,2-dihydroisoquinoline-7-carboxylate (1.0 g, 4.9 mmol) in DMF (15 mL) dropwise. The mixture was stirred for 30 mins, then 1,3-dibromopropane (80 μL, 1.28 mmol) was added quickly and the resulting solution was stirred overnight warming to rt slowly. The reaction was quenched with water and extracted with EtOAc (2×). The combined organic phases were then washed with water, and brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by flash silica gel chromatography (0% to 30% EtOAc/hexanes) to afford methyl 2-(3-bromopropyl)-1-oxo-1,2-dihydroisoquinoline-7-carboxylate (0.60 g, 38%). LC-MS: (FA) ES+ 326.
Reaction SMILES: [Cl:1][C:2]1[C:12]2[N:11]3[CH2:13][CH2:14][CH2:15][C@@H:16]([NH:17]CCOC)[C@H:10]3[C:9]3[CH:22]=[CH:23][CH:24]=[CH:25][C:8]=3[O:7][C:6]=2[CH:5]=[CH:4][C:3]=1[Cl:26].[CH:27](OCC)=[O:28]>>[Cl:1][C:2]1[C:12]2[N:11]3[CH2:13][CH2:14][CH2:15][C@@H:16]([NH:17][CH:27]=[O:28])[C@H:10]3[C:9]3[CH:22]=[CH:23][CH:24]=[CH:25][C:8]=3[O:7][C:6]=2[CH:5]=[CH:4][C:3]=1[Cl:26]
Reactant: CCOC=O
Reactant: COCCN[C@@H]1CCCN2c3c(ccc(Cl)c3Cl)Oc3ccccc3[C@H]12
Product: O=CN[C@@H]1CCCN2c3c(ccc(Cl)c3Cl)Oc3ccccc3[C@H]12
Yield: 30 %

Procedure:
A solution of trans-6,7-dichloro-2,3,4,14b-tetrahydro-N-(2-methoxyethyl)-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepine-1-amine (122 mg, 0.36 mmol) in ethyl formate was stirred overnight at reflux temperature. After removal of the solvent under reduced pressure, the remaining product was purified with preparative LC-MS to give the title compound (40 mg, 30%). Data (m/z)=397 (M+H)+.
Reaction SMILES: N[C:2]1[CH:3]=[CH:4][C:5]([Cl:8])=[N:6][CH:7]=1.N([O-])=O.[Na+].[S:13](=[O:15])=[O:14].[ClH:16]>>[Cl:8][C:5]1[C:4]([S:13]([Cl:16])(=[O:15])=[O:14])=[CH:3][CH:2]=[CH:7][N:6]=1
Reactant: O=S=O
Reactant: Nc1ccc(Cl)nc1
Reactant: Cl
Agent: O=N[O-]
Agent: [Na+]
Product: O=S(=O)(Cl)c1cccnc1Cl
Yield: 42 %

Procedure:
Under ice-cooling, thionyl chloride (24 mL) was added dropwise over 1 hr to water (140 mL) and the mixture was stirred at room temperature for 12 hr to give a sulfur dioxide-containing solution. Under ice-cooling, 5-amino-2-chloropyridine (10 g) was added to concentrated hydrochloric acid (80 mL) and the mixture was stirred. An aqueous solution (25 mL) of sodium nitrite (5.75 g) was added dropwise while keeping the inside temperature at not higher than 5° C., and the mixture was further stirred for 15 min. The reaction mixture was gradually added at 5° C. to the above-mentioned sulfur dioxide-containing solution added with cuprous chloride (140 mg). Under ice-cooling, the mixture was further stirred for 30 min, and the precipitate was collected by filtration and washed with water and ethanol to give the title compound (yield 6.99 g, 42%).
Reaction SMILES: C[O:2][C:3](=[O:16])[CH2:4][CH:5]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH3:15])[CH2:6][CH2:7][CH3:8].[OH-].[K+]>CO.O>[C:10]1([CH3:15])[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[CH:5]([CH2:6][CH2:7][CH3:8])[CH2:4][C:3]([OH:16])=[O:2]
Reactant: CCCC(CC(=O)OC)c1ccccc1C
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCCC(CC(=O)O)c1ccccc1C

Procedure:
32 g of 3-o-tolyl-hexanoic acid methyl ester obtained from step (b) in 200 ml methanol are boiled under reflux with 9.8 g KOH in 20 ml H2O for 2 hours. Isolation of the acid product yields 3-o-tolyl-hexanoic acid as an oil.