Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1.[NH:14]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C@@H:15]([C:24](O)=[O:25])[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=1.CCN=C=NCCCN(C)C.CI.C1C=NC2N(O)N=NC=2C=1>CN(C=O)C>[Cl:23][C:20]1[CH:21]=[CH:22][C:17]([CH2:16][C@@H:15]([NH:14][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C:24](=[O:25])[N:11]2[CH2:12][CH2:13][N:8]([CH2:7][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=3)[CH2:9][CH2:10]2)=[CH:18][CH:19]=1
Reactant: c1ccc(CN2CCNCC2)nc1
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccc(Cl)cc1)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: CI
Product: CC(C)(C)OC(=O)N[C@H](Cc1ccc(Cl)cc1)C(=O)N1CCN(Cc2ccccn2)CC1

Procedure:
N-{(1R)-1-[(4-Chlorophenyl)methyl]-2-oxo-2-[4-(2-pyridylmethyl)piperazinyl]ethyl}(tert-butoxy)carboxamide was prepared according to the procedure for Preparation XIX using (2-pyridylmethyl)piperazine (650 mg. 3.7 mmol) (Array), Boc-p-Cl-D-Phe-OH (1.1 g, 3.7 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide methiodide (2.2 g, 7.2 mmol), HOAT (560 mg, 4.10 mmol) and DMF (15 mL) (730 mg). MS (ESI, pos. ion) m/z: 459 (M+H), (ESI, neg. ion) m/z: 457 (M−H). Calc'd for C24H31ClN4O3: 458.98.
Reaction SMILES: C(OC([NH:8][CH:9]([C:32]([O:34][CH3:35])=[O:33])[CH2:10][C:11]1[CH:31]=[CH:30][C:14]([O:15][C:16]2[CH:29]=[CH:28][C:19]([CH:20]=[C:21]3[S:25][C:24](=[O:26])[NH:23][C:22]3=[O:27])=[CH:18][CH:17]=2)=[CH:13][CH:12]=1)=O)(C)(C)C.Cl>C(Cl)Cl>[NH2:8][CH:9]([C:32]([O:34][CH3:35])=[O:33])[CH2:10][C:11]1[CH:31]=[CH:30][C:14]([O:15][C:16]2[CH:29]=[CH:28][C:19]([CH:20]=[C:21]3[S:25][C:24](=[O:26])[NH:23][C:22]3=[O:27])=[CH:18][CH:17]=2)=[CH:13][CH:12]=1
Reactant: COC(=O)C(Cc1ccc(Oc2ccc(C=C3SC(=O)NC3=O)cc2)cc1)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: ClCCl
Product: COC(=O)C(N)Cc1ccc(Oc2ccc(C=C3SC(=O)NC3=O)cc2)cc1
Reaction time: 1 h
Yield: 97.5 %

Procedure:
A solution of 5-[4-(4-(2-t-butoxycarbonylamino-2-methoxycarbonylethyl)phenoxy)benzilidene]thiazolidin-2,4-dione (2 g, 4.0 mmol) in DCM (100 ml) at 0° C. was bubbled with HCl gas. After stirring for 1 hour, the yellow precipitate was filtered and 1.7 g (3.9 mmol) of HCl-Tyr (C6H4-CH=TDZ)-OMe was collected with 97.5% yield, mp: 187-190° C. The HPLC purity of product was 94.5%. Compound 1.
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[C:11](=[C:12](OS(C(F)(F)F)(=O)=O)[N:13]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[N:14]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[Cl:32][C:33]1[CH:38]=[CH:37][C:36](B(O)O)=[CH:35][CH:34]=1>>[Cl:32][C:33]1[CH:38]=[CH:37][C:36]([C:12]2[N:13]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:14]=[C:15]3[C:11]=2[CH2:10][CH2:9][NH:8][CH2:17][CH2:16]3)=[CH:35][CH:34]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: CC(C)(C)OC(=O)N1CCc2nn(-c3ccccc3)c(OS(=O)(=O)C(F)(F)F)c2CC1
Product: Clc1ccc(-c2c3c(nn2-c2ccccc2)CCNCC3)cc1
Yield: 8.1 %

Procedure:
The title compound (9.3 mg) was prepared from 164.0 mg of 2-phenyl-3-trifluoromethanesulfonyloxy-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 176, Step B) and 63.8 mg of 4-chlorophenylboronic acid as in Example 196. MS (ESI): exact mass calculated for C19H18ClN3, 323.12; found, m/z 324.1 [M+H]+. 1H NMR (500 MHz, CDCl3): 7.33-7.25 (m, 4H), 7.23-7.16 (m, 3H), 7.09-7.06 (m, 2H), 3.10-3.07 (m, 2H), 3.03-3.00 (m, 2H), 2.99-2.96 (m, 2H), 2.66-2.63 (m, 2H).
Reaction SMILES: [N:1]([O-])=O.[Na+].[Br:5][C:6]1[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[CH:10]=[C:9]([CH3:16])[C:7]=1[NH2:8].CC(O)=O>O>[Br:5][C:6]1[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[CH:10]=[C:9]2[C:7]=1[NH:8][N:1]=[CH:16]2
Reactant: Cc1cc([N+](=O)[O-])cc(Br)c1N
Reactant: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: O=[N+]([O-])c1cc(Br)c2[nH]ncc2c1
Reaction time: 1 h
Yield: 72 %

Procedure:
NaNO2 (65.00 g, 942.0 mmol) in H2O (140 mL) was added via addition funnel to a 5 L 3-neck round bottom flask, equipped with a mechanical stirrer and a thermometer, containing a mixture of crude 2-bromo-6-methyl-4-nitroaniline (145.0 g, 627.6 mmol) and glacial HOAc (2.5 L). During the addition, the reaction mixture was cooled with an ice bath to to maintain the internal reaction temperature below 25° C. About 1 hour after the addition was complete, additional NaNO2 (21.65 g, 313.8 mmol) in H2O (50 mL) was added to the reaction mixture relatively rapidly (<5 min) with no evidence of an exotherm. After an additional 1 hour, the reaction mixture was concentrated under reduced pressure. The resulting solid was triturated with MeOH/H2O (1:1, 1 L) then filtered, washed with additional MeOH/H2O (1:1, 500 mL), and dried in a vacuum oven at about 50-60° C. for about 16 hours to give 7-bromo-5-nitro-1H-indazole (109.4 g, 72%, 90% pure by HPLC); 1H NMR (DMSO-d6, 400 MHz) 14.28 (br s, 1H), 8.87 (d, J=1.9 Hz, 1H), 8.57 (s, 1H), 8.40 (d, J=1.9 Hz, 1H); LC/MS (Table 1, Method e) Rt 1.75 min; m/z (ESI−) 241.7.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C@@H:9]([OH:39])[CH2:10][N:11]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:12][CH2:13][O:14][C:15]2[CH:23]=[C:22]3[C:18]([C:19]([Cl:31])=[N:20][N:21]3[C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])=[CH:17][CH:16]=2)[CH:5]=[CH:6][C:7]=1[F:8].N1C=CN=C1.Cl[Si:46]([CH2:51][CH3:52])([CH2:49][CH3:50])[CH2:47][CH3:48].C(=O)([O-])O.[Na+]>CN(C=O)C>[NH2:1][C:2]1[CH:3]=[C:4]([C@@H:9]([O:39][Si:46]([CH2:51][CH3:52])([CH2:49][CH3:50])[CH2:47][CH3:48])[CH2:10][N:11]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:12][CH2:13][O:14][C:15]2[CH:23]=[C:22]3[C:18]([C:19]([Cl:31])=[N:20][N:21]3[C:24]([O:26][C:27]([CH3:28])([CH3:29])[CH3:30])=[O:25])=[CH:17][CH:16]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CC[Si](Cl)(CC)CC
Reactant: CC(C)(C)OC(=O)N(CCOc1ccc2c(Cl)nn(C(=O)OC(C)(C)C)c2c1)C[C@H](O)c1ccc(F)c(N)c1
Agent: O=C([O-])O
Agent: [Na+]
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC[Si](CC)(CC)O[C@@H](CN(CCOc1ccc2c(Cl)nn(C(=O)OC(C)(C)C)c2c1)C(=O)OC(C)(C)C)c1ccc(F)c(N)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
(R)-Tert-butyl 6-(2-((2-(3-amino-4-fluorophenyl)-2-hydroxyethyl)(tert-butoxycarbonyl)amino)ethoxy)-3-chloroindazole-1-carboxylate (601.2 mg) which can be prepared according to the method described in Reference example 69, etc. and imidazole (290.3 mg; Tokyo Chemical Industry Co., Ltd) were dissolved in dehydrated DMF (5 mL), added with chlorotriethylsilane (705 μL; manufactured by Shin-Etsu Chemical Co., Ltd.), and then the mixture was stirred for three hours at room temperature. The reaction solution was added to saturated solution of sodium hydrogen carbonate solution and extracted twice with ethyl acetate. The organic layer was washed twice with water and once with brine, dried over anhydrous sodium sulfate, and then the solvent was evaporated under reduced pressure. The resulting residue was purified by column chromatography (“COLUMN-B”; n-hexane:ethyl acetate=84:16→64:36) to obtain the title compound (480 mg).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:9]=[N:10][N:11]([CH2:13][CH2:14][N:15]3[CH2:20][CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17][CH2:16]3)[CH:12]=2)=[CH:4][C:3]=1[C:28]1[O:29][C:30]2[CH:36]=[CH:35][CH:34]=[CH:33][C:31]=2[N:32]=1.N>C(O)(C(F)(F)F)=O.CO>[O:29]1[C:30]2[CH:36]=[CH:35][CH:34]=[CH:33][C:31]=2[N:32]=[C:28]1[C:3]1[C:2]([NH2:1])=[N:7][CH:6]=[C:5]([C:8]2[CH:9]=[N:10][N:11]([CH2:13][CH2:14][N:15]3[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)[CH:12]=2)[CH:4]=1
Reactant: CC(C)(C)OC(=O)N1CCN(CCn2cc(-c3cnc(N)c(-c4nc5ccccc5o4)c3)cn2)CC1
Agent: N
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: Nc1ncc(-c2cnn(CCN3CCNCC3)c2)cc1-c1nc2ccccc2o1
Yield: 68.4 %

Procedure:
A solution of tert-butyl 4-[2-[4-[6-amino-5-(1,3-benzoxazol-2-yl)-3-pyridyl]pyrazol-1-yl]ethyl]piperazine-1-carboxylate (90 mg) in TFA (3 ml) was stirred at 25° C. for 1 hour. A solution 7N ammonia in methanol (20 ml) was added to the mixture and adsorbed on silica gel. The crude product was purified by flash chromatography on silica gel eluting with 2 to 8% methanolic ammonia (7 N) in dichloromethane. The solvent was evaporated to dryness to afford 3-(1,3-benzoxazol-2-yl)-5-[1-(2-piperazin-1-ylethyl)pyrazol-4-yl]pyridin-2-amine (49.0 mg). NMR Spectrum: (DMSOd6) 2.29-2.42 (m, 4H), 2.64-2.70 (m, 4H), 2.71 (t, 2H), 4.23 (t, 2H), 7.41-7.49 (m, 2H), 7.65 (bs, 2H), 7.77-7.82 (m, 1H), 7.82-7.87 (m, 1H), 7.90 (s, 1H), 8.24 (s, 1H), 8.40 (d, 1H), 8.51 (d, 1H); Mass spectrum: M+H+ 390.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:11][O:12][C:13]2[CH:18]=[CH:17][C:16]([F:19])=[C:15]([F:20])[CH:14]=2)=[C:6]([CH:10]=1)[C:7]([OH:9])=O.Cl.[NH2:22][C@H:23]([C:25]1[CH:34]=[CH:33][C:28]([C:29]([O:31][CH3:32])=[O:30])=[CH:27][CH:26]=1)[CH3:24]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:11][O:12][C:13]2[CH:18]=[CH:17][C:16]([F:19])=[C:15]([F:20])[CH:14]=2)=[C:6]([CH:10]=1)[C:7]([NH:22][C@H:23]([C:25]1[CH:34]=[CH:33][C:28]([C:29]([O:31][CH3:32])=[O:30])=[CH:27][CH:26]=1)[CH3:24])=[O:9]
Reactant: COC(=O)c1ccc([C@H](C)N)cc1
Reactant: O=C(O)c1cc(Cl)ccc1COc1ccc(F)c(F)c1
Agent: Cl
Product: COC(=O)c1ccc([C@H](C)NC(=O)c2cc(Cl)ccc2COc2ccc(F)c(F)c2)cc1

Procedure:
The title compound was prepared according to the procedure described in step 6 of Example 1 from 5-chloro-2-[(3,4-difluorophenoxy)methyl] benzoic acid (step 2) and methyl 4-[(1S)-1-aminoethyl]benzoate hydrochloride (step 5 of Example 1):
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:8]=[CH:7][C:6]([NH:9][CH:10]2[CH2:15][CH2:14][N:13]([CH:16]3[CH2:21][CH2:20][CH2:19][CH2:18][C:17]3=[O:22])[CH2:12][CH2:11]2)=[CH:5][CH:4]=1.[CH3:25][O:26][C:27]1[CH:32]=[CH:31][C:30]([S:33](Cl)(=[O:35])=[O:34])=[CH:29][CH:28]=1>>[F:24][C:2]([F:1])([F:23])[C:3]1[CH:4]=[CH:5][C:6]([N:9]([CH:10]2[CH2:11][CH2:12][N:13]([CH:16]3[CH2:21][CH2:20][CH2:19][CH2:18][C:17]3=[O:22])[CH2:14][CH2:15]2)[S:33]([C:30]2[CH:29]=[CH:28][C:27]([O:26][CH3:25])=[CH:32][CH:31]=2)(=[O:35])=[O:34])=[CH:7][CH:8]=1
Reactant: O=C1CCCCC1N1CCC(Nc2ccc(C(F)(F)F)cc2)CC1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Product: COc1ccc(S(=O)(=O)N(c2ccc(C(F)(F)F)cc2)C2CCN(C3CCCCC3=O)CC2)cc1

Procedure:
The title compound, MS (ISP): m/e=589.4 (M+H+), was prepared as for example 99, steps (A) to (F). Step (B) was performed using 4-trifluoromethyl-aniline, and yielded (+/−)-trans-2-[4-(4-trifluoromethyl-phenylamino)-piperidin-1-yl]-cyclohexanol, which was oxidized to (+/−)-2-[4-(4-trifluoromethyl-phenylamino)-piperidin-1-yl]-cyclohexanone in step (C). This was then reacted with 4-methoxy-benzensulfonyl chloride in step (D), yielding (+/−)-N-(4-trifluoromethyl-phenyl)-4-methoxy-N-[1-(2-oxo-cyclohexyl)-piperidin-4-yl]-benzenesulfonamide. The final step (F) was performed with bromobenzene.
Reaction SMILES: [CH:1]1([CH:7]([OH:9])[CH3:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:10](O)=[O:11]>>[CH:10]([O:9][CH:7]([CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)[CH3:8])=[O:11]
Reactant: O=CO
Reactant: CC(O)C1CCCCC1
Product: CC(OC=O)C1CCCCC1
Temperature: 25 °C

Procedure:
A mixture of 12.8 g. (0.1 moles) 1-cyclohexyl-1-ethanol and 13.8 g. (0.3 moles) formic acid was refluxed for two hours and then cooled to room temperature. It was poured in 200 ml. cold water, the organic material extracted in ether and the ether extract washed thoroughly with water, sodium bicarbonate, water and brine and dried over molecular sieves. 15.4 g. crude product of 97.9% purity was recovered--major impurity is residual solvent. The crude product was distilled through a short Vigreux-column. The product is a mobile, colorless liquid, b.p. 94° C./16 mm., nD25 =1.4437. Yield 13.6 g.=87.1%, purity 99.2% (by GLC) of 1-cyclohexyl-1-ethyl formate.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[C:5]2[O:11][CH:10]([CH:12]3[CH2:14][CH2:13]3)[CH2:9][O:8][C:6]=2[N:7]=1.CC1(C)C(C)(C)OB([C:29]2[CH:30]=[N:31][C:32]([NH2:35])=[N:33][CH:34]=2)O1.C(=O)([O-])[O-].[Na+].[Na+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(#N)C>[CH:12]1([CH:10]2[CH2:9][O:8][C:6]3[N:7]=[C:2]([C:29]4[CH:30]=[N:31][C:32]([NH2:35])=[N:33][CH:34]=4)[N:3]=[C:4]([N:15]4[CH2:20][CH2:19][O:18][CH2:17][CH2:16]4)[C:5]=3[O:11]2)[CH2:14][CH2:13]1
Reactant: Clc1nc2c(c(N3CCOCC3)n1)OC(C1CC1)CO2
Reactant: CC1(C)OB(c2cnc(N)nc2)OC1(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: Nc1ncc(-c2nc3c(c(N4CCOCC4)n2)OC(C2CC2)CO3)cn1
Temperature: 120 °C
Yield: 9.2 %

Procedure:
A microwave vial was charged with 2-chloro-6-cyclopropyl-4-morpholin-4-yl-6,7-dihydro-[1,4]dioxino[2,3-d]pyrimidine (191 mg, 0.64 mmol), 5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrimidin-2-ylamine (283 mg, 1.28 mmol), Pd(PPh3)2Cl2 (45 mg, 0.06 mmol), sodium carbonate (2.11 mL, 2.11 mmol, 1M aqueous solution) and acetonitrile (2.5 mL). The vessel was sealed then evacuated and refilled with argon (×3) before being heated at 120° C. for 30 minutes using microwave irradiation. The reaction mixture was filtered before being purified by column chromatography (SiO2, gradient 0-4% methanol in DCM). The resultant residue was triturated with diethyl ether to give 107 as a white solid (21 mg, 9%). LCMS: RT=3.54 min, [M+H]+=357. 1H NMR (400 MHz, DMSO-d6): δ 8.89 (2H, s), 7.00 (2H, s), 4.53 (1H, dd, J=11.48, 2.34 Hz), 4.22 (1H, dd, J=11.50, 7.87 Hz), 3.75-3.67 (8H, m), 3.65-3.58 (1H, m), 1.01-0.99 (1H, m), 0.63-0.55 (2H, m), 0.51-0.42 (2H, m).
Reaction SMILES: [NH2:1][C@H:2]([C:4]([C@@H:6]1[C@@H:11]([OH:12])[C@H:10]([OH:13])[C@@H:9]([CH2:14][OH:15])[O:8][C@@:7]1([NH2:50])[N:16]([CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH3:49])[C:17](=[O:35])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]/[CH:25]=[CH:26]\[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])=[O:5])[CH3:3].[C:51]([O:55][C:56]([NH:58][C@H:59]([C:61](O)=[O:62])[CH3:60])=[O:57])([CH3:54])([CH3:53])[CH3:52]>O1CCCC1>[C:51]([O:55][C:56]([NH:58][C@H:59]([C:61]([NH:1][C@H:2]([C:4]([C@@H:6]1[C@@H:11]([OH:12])[C@H:10]([OH:13])[C@@H:9]([CH2:14][OH:15])[O:8][C@@:7]1([NH2:50])[N:16]([CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH3:49])[C:17](=[O:35])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]/[CH:25]=[CH:26]\[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])=[O:5])[CH3:3])=[O:62])[CH3:60])=[O:57])([CH3:53])([CH3:54])[CH3:52]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)N(CCCCCCCCCCCCCC)[C@]1(N)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1C(=O)[C@H](C)N
Solvent: C1CCOC1
Product: CCCCCCCC/C=C\CCCCCCCC(=O)N(CCCCCCCCCCCCCC)[C@]1(N)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1C(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)OC(C)(C)C
Yield: 59 %

Procedure:
from N-(2-L-alanyl-amino-2-deoxy-β-D-glucopyranosyl)-N-tetradecyl-oleamide and N-tert-butyloxycarbonyl-L-alanine. Yield 59%. [α]D =+0.2° (c=0.86, tetrahydrofuran).
Reaction SMILES: [CH2:1]([S:6][C:7]1[N:12]=[C:11]([C:13]2[S:14][C:15]3[CH:23]=[CH:22][CH:21]=[CH:20][C:16]=3[C:17](=[O:19])[N:18]=2)[CH:10]=[CH:9][CH:8]=1)[CH2:2][CH2:3][CH2:4][CH3:5].ClC1C=CC=C(C(OO)=[O:32])C=1>C(Cl)(Cl)Cl>[CH2:1]([S:6]([C:7]1[N:12]=[C:11]([C:13]2[S:14][C:15]3[CH:23]=[CH:22][CH:21]=[CH:20][C:16]=3[C:17](=[O:19])[N:18]=2)[CH:10]=[CH:9][CH:8]=1)=[O:32])[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCCSc1cccc(-c2nc(=O)c3ccccc3s2)n1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: CCCCCS(=O)c1cccc(-c2nc(=O)c3ccccc3s2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 47.5 %

Procedure:
2-[6-(n-Pentylthio)-2-pyridyl]-4H-1,3-benzothiazine-4-one (0.15 g, 0.44 mmol) was dissolved in chloroform (50 ml), and a solution of 3-chloroperbenzoic acid (ca. 77%, 0.10 g, 0.46 mmol) in chloroform (10 ml) was added dropwise thereto. The reaction mixture was stirred at room temperature for 1 hr. The solvent was evaporated, and the residue was recrystallized from ethanol to give the titled compound (0.075 g, 48%) as white crystals.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH:10]([C:13](=[O:38])[NH:14][C:15]2[CH:20]=[CH:19][C:18]([N:21]3[CH:26]=[CH:25][C:24]4[CH:27]=[C:28]([C:30]5[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=5)[S:29][C:23]=4[C:22]3=[O:37])=[CH:17][CH:16]=2)[CH2:9]1)=O)(C)(C)C>C(Cl)Cl>[Cl:36][C:33]1[CH:34]=[CH:35][C:30]([C:28]2[S:29][C:23]3[C:22](=[O:37])[N:21]([C:18]4[CH:17]=[CH:16][C:15]([NH:14][C:13]([CH:10]5[CH2:11][CH2:12][NH:8][CH2:9]5)=[O:38])=[CH:20][CH:19]=4)[CH:26]=[CH:25][C:24]=3[CH:27]=2)=[CH:31][CH:32]=1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)Nc2ccc(-n3ccc4cc(-c5ccc(Cl)cc5)sc4c3=O)cc2)C1
Solvent: ClCCl
Product: O=C(Nc1ccc(-n2ccc3cc(-c4ccc(Cl)cc4)sc3c2=O)cc1)C1CCNC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 889 %

Procedure:
Add trifluoroacetic (1.06 mL, 14.1 mmol) to a solution of 3-{4-[2-(4-chloro-phenyl)-7-oxo-7H-thieno[2,3-c]pyridin-6-yl]-phenylcarbamoyl}-pyrrolidine-1-carboxylic acid tert-butyl ester (0.12 g, 0.21 mmol) in CH2Cl2 (2 mL). Stir the mixture at RT for 2 h, and concentrate in vacuo. Dissolve the crude residue in CH2Cl2, filter through an SCX column with CH2Cl2 and MeOH, then elute the product with 2 N NH3 in MeOH. Concentrate the solution, then filter the solid with Et2O to give 0.84 g (88%) of the title compound. LC-ES/MS m/z (35Cl) 450.0 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:28])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=2[O:21][CH2:22][O:23][CH3:24])=[CH:10][C:9]=1[N+:25]([O-])=O)([CH3:4])([CH3:3])[CH3:2]>[Pd]>[C:1]([O:5][C:6](=[O:28])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=2[O:21][CH2:22][O:23][CH3:24])=[CH:10][C:9]=1[NH2:25])([CH3:4])([CH3:2])[CH3:3]
Reactant: COCOc1cc(F)ccc1-c1ccc(NC(=O)OC(C)(C)C)c([N+](=O)[O-])c1
Agent: [Pd]
Product: COCOc1cc(F)ccc1-c1ccc(NC(=O)OC(C)(C)C)c(N)c1

Procedure:
Prepared from (4′-fluoro-2′-methoxymethoxy-3-nitro-biphenyl-4-yl)-carbamic acid tert.-butyl ester (Example B14) by catalytic hydrogenation with Pd/C according to the general procedure G (method a). Obtained as a light purple foam (577 mg).
Reaction SMILES: [F:1][C:2]1([F:11])[O:6][C:5](Cl)([Cl:7])[C:4](Cl)([Cl:9])[O:3]1>[Zn].[Cl-].[Zn+2].[Cl-].C(O)CC>[F:1][C:2]1([F:11])[O:6][C:5]([Cl:7])=[C:4]([Cl:9])[O:3]1
Reactant: FC1(F)OC(Cl)(Cl)C(Cl)(Cl)O1
Agent: [Cl-]
Agent: [Zn+2]
Agent: [Zn]
Solvent: CCCO
Product: FC1(F)OC(Cl)=C(Cl)O1
Reaction time: 2.47 h

Procedure:
A 300 mL, 3-neck glass flask equipped with magnetic stirrer, thermometer, Vigreux column with a water condenser to receiver, trap to a nitrogen tee and bubbler was charged with 1-propanol, 175 mL; zinc dust, 59.3 g; zinc chloride, 2.0 g. After heating to reflux, the 2,2-difluoro-4,4,5,5-tetrachloro-1,3-dioxolane (4j), 74.3 g, was added by syringe pump at 0.33 mL/minute. The addition was complete in 148 minutes. Distillation was begun 40 minutes after the start of the addition and continued for 6 hours until 72 mL of distillate was collected. The product was 98.7% pure desired dioxole, (3j), at 100% conversion of the dioxolane; the distillate which contained some propanol was redistilled through a 0.51 m spinning band column to separate the dioxole, (3j), b.p. 64°-65° C., at a purity of 98.6%. A 3.66 m×0.0064 m diameter 30% "Krytox" perfluoroether (Du Pont Co.) column at 60° C. was used in the analysis. The infrared spectrum was consistent with the structure.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][C:7]([O:10][C:11]3[CH:12]=[C:13]([NH:17][C:18]([C:20]4[C:25]([CH3:26])=[CH:24][CH:23]=[CH:22][N:21]=4)=[O:19])[CH:14]=[CH:15][CH:16]=3)=[CH:6][N:5]2[CH:27]=1.[CH3:28][O:29][CH2:30][C:31](Cl)=[O:32].CO.C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C(=O)C.O1CCCC1>[CH3:28][O:29][CH2:30][C:31]([NH:1][C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][C:7]([O:10][C:11]3[CH:12]=[C:13]([NH:17][C:18]([C:20]4[C:25]([CH3:26])=[CH:24][CH:23]=[CH:22][N:21]=4)=[O:19])[CH:14]=[CH:15][CH:16]=3)=[CH:6][N:5]2[CH:27]=1)=[O:32]
Reactant: COCC(=O)Cl
Reactant: Cc1cccnc1C(=O)Nc1cccc(Oc2ccc3nc(N)cn3c2)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: C1CCOC1
Solvent: CO
Product: COCC(=O)Nc1cn2cc(Oc3cccc(NC(=O)c4ncccc4C)c3)ccc2n1
Temperature: 25 °C
Reaction time: 81 h
Yield: 22.8 %

Procedure:
To a solution of N-{3-[(2-aminoimidazo[1,2-a]pyridin-6-yl)oxy]phenyl}-3-methylpyridine-2-carboxamide (148 mg, 0.412 mmol) in N,N-dimethylacetamide (5 mL) was added methoxyacetyl chloride (37.8 μL, 0.413 mmol), and the mixture was stirred at room temperature for 81 hr. Methanol, tetrahydrofuran and aqueous sodium carbonate solution were added to the reaction mixture, and the mixture was stirred at 60° C. for 8 hr. The reaction mixture was concentrated under reduced pressure, diluted with aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The organic layer was washed with aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate and filtrated. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (0%→90% ethyl acetate-hexane) to give the title compound (40.6 mg, 23%) as a pale-yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([N:12]2[CH2:19][CH:18]([OH:20])[CH2:17][C@H:13]2[C:14](O)=[O:15])=[O:11])[CH:5]=[C:6]([Cl:8])[CH:7]=1.Cl>>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:14](=[O:15])[C@@H:13]3[CH2:17][C@@H:18]([OH:20])[CH2:19][N:12]3[C:10]2=[O:11])[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: O=C(O)[C@@H]1CC(O)CN1C(=O)Nc1cc(Cl)cc(Cl)c1
Agent: Cl
Product: O=C1[C@@H]2C[C@@H](O)CN2C(=O)N1c1cc(Cl)cc(Cl)c1
Yield: 50.6 %

Procedure:
1-(3,5-dichloro-phenylcarbamoyl)-4-hydroxy-L-proline (6.8 g) (0.021 mol) (Preparation 1) was combined with 35 mL of 1 N HCl and refluxed for 11 hrs. The organic oil was separated from the reaction mixture and dissolved in EtOAc. The organic layer was washed with water, dried over MgSO4, and evaporated under reduced pressure. The resulting residue was purified on a SiO2 column (eluent: DCM/acetone-90/10) to afford the titled compound as a white solid (3.2 g). NMR (CDCl3, 200 MHz): 7.4 (2H, d), 7.35 (1H, m), 4.75 (1H, m), 4.60 (1H, dd), 3.95 (1H, dd), 3.35 (1H, d), 2.75 (1H, m, OH), 2.40 (1H, dd), 1.80-1.95 (1H, m).
Reaction SMILES: C1(O[C:8](=[O:29])[NH:9][C:10]2[CH:11]=[N:12][C:13]([O:16][C:17]3[C:22]4[C:23]([CH3:27])([CH3:26])[CH2:24][O:25][C:21]=4[C:20]([CH3:28])=[CH:19][CH:18]=3)=[CH:14][CH:15]=2)C=CC=CC=1.O.[NH2:31][NH2:32].O>O1CCOCC1>[CH3:26][C:23]1([CH3:27])[C:22]2[C:17]([O:16][C:13]3[N:12]=[CH:11][C:10]([NH:9][C:8]([NH:31][NH2:32])=[O:29])=[CH:15][CH:14]=3)=[CH:18][CH:19]=[C:20]([CH3:28])[C:21]=2[O:25][CH2:24]1
Reactant: NN
Reactant: Cc1ccc(Oc2ccc(NC(=O)Oc3ccccc3)cn2)c2c1OCC2(C)C
Solvent: O
Solvent: C1COCCO1
Product: Cc1ccc(Oc2ccc(NC(=O)NN)cn2)c2c1OCC2(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 63.1 %

Procedure:
Phenyl{6-[(3,3,7-trimethyl-2,3-dihydro-1-benzofuran-4-yl)oxy]-3-pyridinyl}carbamate (Intermediate 1, 640 mg, 1.64 mmol) was dissolved in dioxane (7 mL) and hydrazine monohydrate (8.2 mmol) was added. The reaction mixture was stirred for 30 minutes at room temperature and then at 70° C. for 1 hour. Water was added and the resulting suspension was stirred for 1 hour and then filtered. The solid was collected, washed with water and dried under vacuum at 25° C. affording the title compound (340 mg) as off-white solid.