Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[C:7]([CH3:14])[C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[N:5]=[C:4]([N:15]2[CH:19]=[CH:18][C:17]([CH:20]([CH3:22])[CH3:21])=[N:16]2)[CH:3]=1.COC1C(C)=C2C(C(O[CH:42]3[CH2:59][CH:58]4[CH:44]([C:45](=[O:65])[N:46]([CH3:64])[CH2:47][CH2:48][CH2:49][CH2:50][CH:51]=[CH:52][CH:53]5[C:55]([C:61]([OH:63])=[O:62])([NH:56][C:57]4=[O:60])[CH2:54]5)[CH2:43]3)=CC(C3SC=CN=3)=N2)=CC=1>>[CH:20]([C:17]1[CH:18]=[CH:19][N:15]([C:4]2[CH:3]=[C:2]([O:1][CH:42]3[CH2:59][CH:58]4[CH:44]([C:45](=[O:65])[N:46]([CH3:64])[CH2:47][CH2:48][CH2:49][CH2:50][CH:51]=[CH:52][CH:53]5[C:55]([C:61]([OH:63])=[O:62])([NH:56][C:57]4=[O:60])[CH2:54]5)[CH2:43]3)[C:11]3[C:6](=[C:7]([CH3:14])[C:8]([O:12][CH3:13])=[CH:9][CH:10]=3)[N:5]=2)[N:16]=1)([CH3:22])[CH3:21]
Reactant: COc1ccc2c(O)cc(-n3ccc(C(C)C)n3)nc2c1C
Reactant: COc1ccc2c(OC3CC4C(=O)NC5(C(=O)O)CC5C=CCCCCN(C)C(=O)C4C3)cc(-c3nccs3)nc2c1C
Product: COc1ccc2c(OC3CC4C(=O)NC5(C(=O)O)CC5C=CCCCCN(C)C(=O)C4C3)cc(-n3ccc(C(C)C)n3)nc2c1C

Procedure:
The title compound was prepared from 4-hydroxy-2-(3-isopropylpyrazol-1-yl)-7-methoxy-8-methylquinoline (64) and intermediate 26 following the procedure (Step D-F) reported for the preparation of 17-[7-methoxy-8-methyl-2-(thiazol-2-yl)quinolin-4-yloxy]-13-methyl-2,14-dioxo-3,13-diazatricyclo[13.3.0.04,6]octadec-7-ene-4-carboxylic acid (29): m/z=630 (M+H)+.
Reaction SMILES: Cl.[NH2:2][C@H:3]([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[CH:18]=2)=[CH:13][CH:12]=1)[CH2:4][C:5]([O:7]CC)=[O:6].[N:24]([CH2:27][C:28]([O:30]CC)=[O:29])=[C:25]=[O:26].N1C=CC=CC=1.[OH-].[Na+].Cl>CN(C=O)C>[C:28]([CH2:27][NH:24][C:25](=[O:26])[NH:2][C@H:3]([CH2:10][C:11]1[CH:12]=[CH:13][C:14]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[CH:18]=2)=[CH:15][CH:16]=1)[CH2:4][C:5]([OH:7])=[O:6])([OH:30])=[O:29]
Reactant: CCOC(=O)CN=C=O
Reactant: CCOC(=O)C[C@H](N)Cc1ccc(-c2cccc(Cl)c2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: O=C(O)CNC(=O)N[C@@H](CC(=O)O)Cc1ccc(-c2cccc(Cl)c2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of Intermediate 8-1 (90 mg, 0.254 mmol) and ethyl isocyanatoacetate (Intermediate 16-1: 39.4 mg, 0.305 mmol) in DMF (3 mL) is added pyridine (2.93 g, 37.1 mmol) and the mixture is stirred at room temperature for 2 hours. The solvent is removed under reduced pressure and the residue is used directly in the next step. Next, the above residue is dissolved in EtOH (1 mL) and 1N NaOH (3 mL, 3 mmol) is added. The mixture is stirred at room temperature for 2 hours then is acidified with 1N HCl. The mixture is extracted with EtOAc and the organic phase is washed with water, brine then dried over sodium sulfate. The solvent is removed under reduced pressure and the residue purified by preparative HPLC using a gradient of 10% MeCN/water to 100% MeCN (+0.1% TFA). Lyophilization of the proper fractions gives the title compound; HPLC Retention time 0.98 minutes (condition C); MS 391.3 (M+1); 1H NMR (400 MHz, DMSO-d6): δ ppm 2.34 (d, J=7.33 Hz, 2H), 2.79 (d, J=6.57 Hz, 2H), 3.67 (d, J=5.56 Hz, 2H), 4.04-4.12 (m, 1H), 6.15 (t, J=5.81 Hz, 1H), 6.23 (d, J=8.34 Hz, 1H), 7.28-7.30 (m, 2H), 7.39-7.42 (m, 1H), 7.48 (t, J=7.83 Hz, 1H), 7.62-7.65 (m, 3H), 7.71 (t, J=1.77 Hz, 1H), 12.32 (s, br, 2H).
Reaction SMILES: [O:1]([CH2:8][C:9]([NH:11][C:12]1[NH:13][C:14](=[O:36])[C:15]2[N:16]=[CH:17][N:18]([C:34]=2[N:35]=1)[C@@H:19]1[O:33][C@H:30]([CH2:31][OH:32])[C@@H:28]([OH:29])[C@H:20]1[O:21][CH2:22][O:23][CH2:24][CH2:25][C:26]#[N:27])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.[CH3:43][O:44][C:45]1[CH:66]=[CH:65][C:48]([C:49](Cl)([C:58]2[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=2)[C:50]2[CH:55]=[CH:54][C:53]([O:56][CH3:57])=[CH:52][CH:51]=2)=[CH:47][CH:46]=1>CO>[O:1]([CH2:8][C:9]([NH:11][C:12]1[NH:13][C:14](=[O:36])[C:15]2[N:16]=[CH:17][N:18]([C:34]=2[N:35]=1)[C@@H:19]1[O:33][C@H:30]([CH2:31][O:32][C:49]([C:58]2[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=2)([C:50]2[CH:55]=[CH:54][C:53]([O:56][CH3:57])=[CH:52][CH:51]=2)[C:48]2[CH:47]=[CH:46][C:45]([O:44][CH3:43])=[CH:66][CH:65]=2)[C@@H:28]([OH:29])[C@H:20]1[O:21][CH2:22][O:23][CH2:24][CH2:25][C:26]#[N:27])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(C(Cl)(c2ccccc2)c2ccc(OC)cc2)cc1
Reactant: N#CCCOCO[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1n1cnc2c(=O)[nH]c(NC(=O)COc3ccccc3)nc21
Solvent: c1ccncc1
Solvent: CO
Product: COc1ccc(C(OC[C@H]2O[C@@H](n3cnc4c(=O)[nH]c(NC(=O)COc5ccccc5)nc43)[C@H](OCOCCC#N)[C@@H]2O)(c2ccccc2)c2ccc(OC)cc2)cc1
Reaction time: 0.17 h
Yield: 75.5 %

Procedure:
N2-Phenoxyacetyl-2′-O-(2-cyanoethoxymethyl)guanosine (660 mg, 1.32 mmol) was subjected to azeotropic distillation with pyridine, and then was dried with a vacuum pump for 30 minutes. The residue was dissolved in 9 mL of THF, and 2.1 g of pyridine (26.4 mmol) and 600 mg of molecular sieve 4 A were added under an argon atmosphere, and the reaction solution was stirred for 10 minutes. To the solution was added 540 mg of 4,4′-dimethoxytritylchloride (1.58 mmol) by 3 portions every 1 hour, and the reaction solution was further stirred for 1 hour. After 2 mL of methanol was added and the reaction solution was stirred for 2 minutes, the reaction solution was filtrated with a celite, and was washed with ethyl acetate. After concentrating the filtrate with evaporation, the residue was dissolved in ethyl acetate, and was separated with a saturated aqueous sodium bicarbonate solution. After the organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, the solvent was distilled off. The obtained residue was purified by silica gel chromatography to obtain the objective compound (800 mg, yield 75%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:16])=[C:4]([CH:9]=[CH:10][C:11]=1[C:12]([F:15])([F:14])[F:13])[C:5]([O:7][CH3:8])=[O:6].[Br:17]N1C(=O)CCC1=O.O>CN(C=O)C>[Br:17][C:10]1[C:11]([C:12]([F:14])([F:15])[F:13])=[C:2]([Cl:1])[C:3]([OH:16])=[C:4]([CH:9]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1ccc(C(F)(F)F)c(Cl)c1O
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cc(Br)c(C(F)(F)F)c(Cl)c1O
Temperature: 15 °C
Reaction time: 16 h
Yield: 84.8 %

Procedure:
To a solution of methyl 3-chloro-2-hydroxy-4-(trifluoromethyl)benzoate (6.30 g) in DMF (65.0 mL) was added N-bromosuccinimide (4.41 g), and the mixture was stirred at 15° C. for 16 hr. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (7.00 g).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[C:5]([O:13][CH3:14])[C:6]([O:11][CH3:12])=[CH:7][C:8]=1[CH2:9]Cl.[OH-].[Na+].C1(C)C=CC=CC=1.[NH2:24][C:25]1[CH:30]=[CH:29][C:28]([CH2:31][CH2:32][NH2:33])=[CH:27][CH:26]=1>O>[CH3:14][O:13][C:5]1[CH:4]=[C:3]2[C:8](=[CH:7][C:6]=1[O:11][CH3:12])[CH2:9][N:33]([CH2:32][CH2:31][C:28]1[CH:29]=[CH:30][C:25]([NH2:24])=[CH:26][CH:27]=1)[CH2:2]2
Reactant: COc1cc(CCl)c(CCl)cc1OC
Reactant: NCCc1ccc(N)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O
Product: COc1cc2c(cc1OC)CN(CCc1ccc(N)cc1)C2
Temperature: 25 °C
Reaction time: 16 h

Procedure:
4,5-Bischloromethyl veratrol (2.35 g: S. H. Wood, M. A. Peny and C. C. Tung, J. A. C. S. (1950), 72, 2989-2991) was added at room temperature to a stirred suspension of 50% aqueous sodium hydroxide (5 ml), toluene (25 ml), 4-aminophenylethylamine (1.5 g) and Aliquat (0.2 g). The heterogeneous mixture was stirred at room temperature for 16 hours, poured in water and extracted with methylene chloride. The organic layer was dried and the solvent evaporated in vacuo. The residue was purified by column chromatography on silica gel eluting with methylene dichloride/methanol (95:5) to give the title compound as a solid (0.6 g), MP: 150°. NMR includes signals at d 2.7(4H,m,Ph--CH2 --CH2 --N); 4.6(2H,bs,NH2); 3.7(6H,s,2×OCH3); 3.8(4H,s,2×N--CH2Ph); 6.2-7.0(6H,m,aromatics).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH3:13])[C:5]([CH2:8][CH2:9][CH2:10][CH2:11][NH2:12])=[N:6][CH:7]=1.Cl[C:15]1[C:19]2[CH:20]=[CH:21][C:22]([N+:24]([O-:26])=[O:25])=[CH:23][C:18]=2[S:17](=[O:28])(=[O:27])[N:16]=1>C(#N)C>[Br:1][C:2]1[CH:3]=[C:4]([CH3:13])[C:5]([CH2:8][CH2:9][CH2:10][CH2:11][NH:12][C:15]2[C:19]3[CH:20]=[CH:21][C:22]([N+:24]([O-:26])=[O:25])=[CH:23][C:18]=3[S:17](=[O:27])(=[O:28])[N:16]=2)=[N:6][CH:7]=1
Reactant: O=[N+]([O-])c1ccc2c(c1)S(=O)(=O)N=C2Cl
Reactant: Cc1cc(Br)cnc1CCCCN
Solvent: CC#N
Product: Cc1cc(Br)cnc1CCCCNC1=NS(=O)(=O)c2cc([N+](=O)[O-])ccc21
Yield: 39 %

Procedure:
A mixture of 4-(5-bromo-3-methyl-2-pyridinyl)butylamine (318 mg, 1.31 mmol) and 3-chloro-6-nitrobenzisothiazole 1,1-dioxide (U.S. Pat. No. 4,490,527) (357 mg, 1.45 mmol) in 15 ml acetonitrile was stirred under dry nitrogen at room temperature then heated to reflux for several minutes until the material dissolved. The solvent was removed under reduced pressure and the residue recrystallized from ethanol and triturated with hot ethanol, yielding 250 mg (39%) of the title compound as the hydrochloride salt, m.p. 235°-242° C. IR(KBr) 1620, 1345, 1300, 1160 cm-1.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:6][N:5]=[C:4]2[N:14]([CH3:24])[N:15]=[C:16](C3C=CC=CC=3Cl)[C:3]=12.[Cl:25][C:26]1[CH:31]=[CH:30][C:29](C2C=C(N)N(C)N=2)=[CH:28][CH:27]=1>>[Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:6][N:5]=[C:4]2[N:14]([CH3:24])[N:15]=[C:16]([C:29]3[CH:30]=[CH:31][C:26]([Cl:25])=[CH:27][CH:28]=3)[C:3]=12
Reactant: Cn1nc(-c2ccc(Cl)cc2)cc1N
Reactant: Cn1nc(-c2ccccc2Cl)c2c(Cl)c(-c3ccccc3)nnc21
Product: Cn1nc(-c2ccc(Cl)cc2)c2c(Cl)c(-c3ccccc3)nnc21

Procedure:
Compound 26 was synthesised following similar procedures outlined in Example 1 (Compound 37), starting from Step 2 using 3-(4-chlorophenyl)-1-methyl-1H-pyrazol-5-amine instead of 3-(2-chlorophenyl)-1-methyl-1H-pyrazol-5-amine.
Reaction SMILES: [F:1][C:2]1[CH:31]=[CH:30][CH:29]=[CH:28][C:3]=1[CH2:4][NH:5][C:6]1[C:11]([C:12]([NH2:14])=[O:13])=[CH:10][N:9]=[C:8]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([CH:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)=[CH:18][CH:17]=2)[CH:7]=1.Cl.CCN(C(C)C)C(C)C.[CH3:42][N:43]([CH3:47])[C:44]([Cl:46])=[O:45]>CN1C(=O)CCC1>[CH3:42][N:43]([CH3:47])[C:44]([N:25]1[CH2:26][CH2:27][CH:22]([C:19]2[CH:18]=[CH:17][C:16]([NH:15][C:8]3[CH:7]=[C:6]([NH:5][CH2:4][C:3]4[CH:28]=[CH:29][CH:30]=[CH:31][C:2]=4[F:1])[C:11]([C:12]([NH2:14])=[O:13])=[CH:10][N:9]=3)=[CH:21][CH:20]=2)[CH2:23][CH2:24]1)=[O:45].[ClH:46]
Reactant: NC(=O)c1cnc(Nc2ccc(C3CCNCC3)cc2)cc1NCc1ccccc1F
Reactant: CN(C)C(=O)Cl
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: CN(C)C(=O)N1CCC(c2ccc(Nc3cc(NCc4ccccc4F)c(C(N)=O)cn3)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Compound 4-(2-fluorobenzylamino)-6-(4-(piperidin-4-yl)phenylamino)nicotinamide (Example 106) HCl salt (100 mg, 0.2 mmol) was stirred in 5 mL NMP. To the solution were added DIEA (0.18 mL, 1.0 mmol) and dimethylcarbamylchloride (0.055 mL, 0.6 mmol). The mixture was stirred at RT for 1 h and quenched with Me2NH. The mixture was concentrated in vacuo and subjected to reverse phase prep HPLC to isolate the title compound as HCl salt. UV=259 nm. M+H found for C27H31FN6O2: 491.5. NMR (CD3OD): 8.12 (1H, s), 7.37 (1H, m), 7.34 (2H, d, J=8.4 Hz), 7.28 (1H, m), 7.17 (1H, m), 7.16-7.10 (3H, m), 5.88 (1H, s), 4.51 (2H, s), 3.82 (2H, m), 2.94 (2H, m), 2.88 (6H, s), 2.80 (1H, m), 1.86 (2H, m), 1.72 (2H, m) ppm.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([OH:11])[C:5](=[CH:9][CH:10]=1)[C:6]([OH:8])=[O:7].[C:12](OC(=O)C)(=[O:14])[CH3:13]>C(O)C>[C:12]([NH:1][C:2]1[CH:3]=[C:4]([OH:11])[C:5](=[CH:9][CH:10]=1)[C:6]([OH:8])=[O:7])(=[O:14])[CH3:13]
Reactant: Nc1ccc(C(=O)O)c(O)c1
Reactant: CC(=O)OC(C)=O
Solvent: CCO
Product: CC(=O)Nc1ccc(C(=O)O)c(O)c1
Temperature: 40 °C
Reaction time: 3 h
Yield: 92 %

Procedure:
30.6 grs (0.2 mol) p-aminosalicylic acid and 100 cc ethanol were introduced into a 250 ml flask, and the mixture was heated to 40° C. 20.4 grs (0.2 mol) acetic anhydride was then added at such a rate that the temperature did not exceed 50° C. When the addition was complete, the mixture was stirred at 50° C. for 3 hours. The product was filtered. Weight: 36 grs m.p. = 235° C. Yield = 92%.
Reaction SMILES: [CH3:1][N:2]([CH3:20])[C:3]([C:5]1[CH:6]=[C:7]([CH2:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18])[CH:8]=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])=[O:4].C(=O)([O-])[O-].[K+].[K+].[CH2:27](Br)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.O>CN(C=O)C>[CH2:27]([O:18][C:17](=[O:19])[CH2:16][CH2:15][CH2:14][C:7]1[CH:8]=[CH:9][C:10]([N+:11]([O-:13])=[O:12])=[C:5]([C:3](=[O:4])[N:2]([CH3:1])[CH3:20])[CH:6]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: BrCc1ccccc1
Reactant: CN(C)C(=O)c1cc(CCCC(=O)O)ccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CN(C)C(=O)c1cc(CCCC(=O)OCc2ccccc2)ccc1[N+](=O)[O-]
Temperature: 60 °C
Reaction time: 3.5 h
Yield: 76.8 %

Procedure:
To a solution of 4-(3-dimethylcarbamoyl-4-nitrophenyl)butanoic acid (1.37 g) in DMF (10 mL) were added potassium carbonate (880 mg) and benzyl bromide (922 mg). The mixture was stirred at 60° C. for 3.5 hours under heating and then allowed to stand for cooling down to room temperature. After addition of water thereto, the mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate=1:1, v/v) to give the title compound (1.39 g).
Reaction SMILES: Cl.[NH2:2][C@H:3]([C:6]([OH:8])=[O:7])[CH2:4][SH:5].[CH3:9][C:10]1[C:15]([OH:16])=[C:14]([CH:17]=O)[C:13]([CH2:19][OH:20])=[CH:12][N:11]=1.Cl.C(=O)([O-])O.[Na+].O>C(O)C>[OH:16][C:15]1[C:10]([CH3:9])=[N:11][CH:12]=[C:13]([CH2:19][OH:20])[C:14]=1[CH:17]1[NH:2][CH:3]([C:6]([OH:8])=[O:7])[CH2:4][S:5]1
Reactant: Cc1ncc(CO)c(C=O)c1O
Reactant: N[C@@H](CS)C(=O)O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Cc1ncc(CO)c(C2NC(C(=O)O)CS2)c1O
Reaction time: 48 h
Yield: 91.8 %

Procedure:
L-Cysteine hydrochloride (8.00 g, 45.6 mmol), pyridoxal hydrochloride (8.80 g, 43.25 mmol), and sodium hydrogen carbonate (7.60 g, 90.5 mmol) were added to a mixed solvent of water (60 ml) and ethanol (120 ml), and the mixture was at stored −20° C. for 2 days. The precipitated solid was collected by filtration, and dried under reduced pressure to give 2-[3-hydroxy-5-(hydroxymethyl)-2-methylpyridin-4-yl]thiazolidine-4-carboxylic acid as a pale-yellow solid (10.73 g).
Reaction SMILES: [CH3:1][CH:2]1[CH2:6][CH2:5][CH:4]([CH3:7])[NH:3]1.C(N(CC)CC)C.[Cl:15][CH2:16][C:17](Cl)=[O:18]>C1C=CC=CC=1>[Cl:15][CH2:16][C:17]([N:3]1[CH:4]([CH3:7])[CH2:5][CH2:6][CH:2]1[CH3:1])=[O:18]
Reactant: O=C(Cl)CCl
Reactant: CC1CCC(C)N1
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: CC1CCC(C)N1C(=O)CCl
Reaction time: 0.25 h

Procedure:
A solution of 2,5-dimethylpyrrolidine (15 grams; 0.15 mol) and triethylamine (15 grams) in benzene (150 ml) was charged into a 250 ml glass reaction flask equipped with stirrer, reflux condenser and addition funnel. Chloroacetyl chloride (18 grams; 0.15 mol) was then slowly added, with vigorous stirring, over a period of several minutes. After the addition was completed stirring was continued for about 15 minutes. After this time the reaction mixture was filtered to remove the triethylamine hydrochloride which had formed. The filtered reaction mixture was then stripped of benzene under reduced pressure to yield a dark colored oil. The oil was distilled under vacuum to yield 1-(α-chloroacetyl)-2,5-dimethylpyrrolidine as a colorless oil having a boiling point of 89° to 90° C. at 0.1 mm of mercury pressure, and a refractive index at 25° C. of 1.4863.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.[C:12]1([CH3:21])[C:13]([N:18]=[C:19]=[O:20])=[CH:14][CH:15]=[CH:16][CH:17]=1.C(N(CC)CC)C>C(Cl)Cl>[C:12]1([CH3:21])[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[NH:18][C:19](=[O:20])[NH:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:6][CH:7]=1
Reactant: Nc1ccc(CC(=O)O)cc1
Reactant: Cc1ccccc1N=C=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccccc1NC(=O)Nc1ccc(CC(=O)O)cc1

Procedure:
To a stirred mixture of 4-aminophenylacetic acid (15.0 g) and o-tolylisocyanate (10.2 ml) in CH2Cl2 (200 ml) was added triethylamine (13.8 ml). After 1 h the resulting homogeneous solution was concentrated under reduced pressure, dissolved in water (100 ml) and acidified to pH 2 with 1N HCl. The off-white ppt was filtered, suspended in THF (200 ml) and 10 ml conc. HCl was added. The resulting homogeneous solution was concentrated under reduced pressure and recrystallized from EtOAc (800 ml) to give 22 g of the title compound as a white solid. MP 221-20° C.; MS [M+1]+285.2; Analysis calcd. for C16H16N203: C (67.59), H (5.67), N (9.85). Found: C (67.22), H (5.78), N (9.69).
Reaction SMILES: Cl.Cl.[NH:3]1[C:11]2[CH2:10][CH2:9][NH:8][CH2:7][C:6]=2[N:5]=[C:4]1[CH:12]([CH3:18])[C:13]([O:15][CH2:16][CH3:17])=[O:14].C(N(CC)C(C)C)(C)C.Cl[C:29]([O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:30].[O-]CC.[Na+].Cl>C(#N)C>[CH2:16]([O:15][C:13]([CH:12]([C:4]1[NH:3][C:11]2[CH2:10][CH2:9][N:8]([C:29]([O:31][CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)=[O:30])[CH2:7][C:6]=2[N:5]=1)[CH3:18])=[O:14])[CH3:17]
Reactant: CCOC(=O)C(C)c1nc2c([nH]1)CCNC2
Reactant: O=C(Cl)OCc1ccccc1
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C(C)c1nc2c([nH]1)CCN(C(=O)OCc1ccccc1)C2
Temperature: 0 °C
Yield: 72.7 %

Procedure:
A solution comprising ethyl 2-(4,5,6,7-tetrahydroimidazo[4,5-c]pyridin-2-yl)propionate dihydrochloride (60.2 g, 0.20 mol) in acetonitrile (400 mL) was cooled to 0° C. under nitrogen, treated with N,N-diisopropylethylamine (35 mL, 0.20 mol), further cooled to ˜−5° C. (ice/acetone) and then treated with benzyl chloroformate (58 mL, 0.41 mol) and N,N-diisopropylethylamine (70 mL, 0.40 mol) in alternating portions over 30 minutes. The mixture was cooled at −5° C. for 1 hour and allowed to warm to 20° C. and, after 16 hours, concentrated under reduced pressure. The residue was suspended in ether and the suspension was washed successively with sodium bicarbonate, sodium chloride, 0.1M hydrochloric acid and sodium chloride, dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was dissolved in ethanol (320 mL) and the solution was cooled to −5° C. under nitrogen and then sodium ethoxide (21 wt %, 85 mL, 0.22 mol) was added dropwise over 1 hour while the reaction temperature was maintained below 0° C. The mixture was cooled at −5° C. for 1 hour, adjusted to neutral pH with 50 mL of 4M hydrochloric acid and concentrated under reduced pressure. The residue was dissolved in ethyl acetate and the solution was washed with sodium bicarbonate and sodium chloride, dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexanes/ethyl acetate) to provide benzyl 2-(1-ethoxycarbonylethyl)-1,4,6,7-tetrahydroimidazo[4,5-c]pyridine-5-carboxylate (52 g, 72%) as a pale yellow oil; 1H-NMR (300 MHz, DMSO-d6) d ppm: 11.72 (br s, 1H), 7.32 (s, 5H), 5.07 (s, 2H), 4.32 (br s, 2H), 4.02 (q, 2H, J=9.3 Hz), 3.77 (q, 1H, J=8.3 Hz), 3.66 (s, 2H), 2.55 (s, 2H), 1.38 (d, 3H, J=8.3 Hz), 1.13 (t, 3H, J=9.3 Hz).
Reaction SMILES: [CH2:1]([N:4]1[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1)[C:2]#[CH:3].[CH3:10][O:11][C:12](=[O:34])[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]#[C:24][C:25]2[CH:30]=[C:29]([Br:31])[CH:28]=[C:27](Br)[CH:26]=2)=[CH:17][C:16]=1[CH3:33]>CN(C=O)C.C(N(CC)CC)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I>[CH3:10][O:11][C:12](=[O:34])[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]#[C:24][C:25]2[CH:26]=[C:27]([C:3]#[C:2][CH2:1][N:4]3[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]3)[CH:28]=[C:29]([Br:31])[CH:30]=2)=[CH:17][C:16]=1[CH3:33]
Reactant: COC(=O)COc1ccc(OCC#Cc2cc(Br)cc(Br)c2)cc1C
Reactant: C#CCN1CCCCC1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)COc1ccc(OCC#Cc2cc(Br)cc(C#CCN3CCCCC3)c2)cc1C
Temperature: 60 °C

Procedure:
A mixture of 1-prop-2-ynyl-piperidine (53 mg, 0.44 mmol), {4-[3-(3,5-dibromo-phenyl)-prop-2-ynyloxy]-2-methyl-phenoxy}-acetic acid methyl ester (204 mg, 0.44 mmol, intermediate 2), Pd(PPh3)4 (50 mg, 0.044 mmol), CuI (23 mg, 0.12 mmol) in dry DMF (2 ml) and triethylamine (2 ml) was heated in a microwave own for 30 min at 60° C. in a sealed tube. The reaction mixture was filtered through Decalite and the filtrate was evaporated. The residue was purified on column chromatography using ethyl acetate/methanol mixtures to give (4-{3-[3-bromo-5-(3-piperidin-1-yl-prop-1-ynyl)-phenyl]-prop-2-ynyloxy}-2-methyl-phenoxy)-acetic acid methyl ester in 105 mg (47%) yield.
Reaction SMILES: [F:1][CH:2]([F:12])[O:3][C:4]1[C:5]([CH3:11])=[C:6]([CH:8]=[CH:9][CH:10]=1)[NH2:7].Cl[C:14](Cl)([O:16]C(=O)OC(Cl)(Cl)Cl)Cl>C1(C)C=CC=CC=1>[F:1][CH:2]([F:12])[O:3][C:4]1[CH:10]=[CH:9][CH:8]=[C:6]([N:7]=[C:14]=[O:16])[C:5]=1[CH3:11]
Reactant: Cc1c(N)cccc1OC(F)F
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: Cc1c(N=C=O)cccc1OC(F)F
Yield: 200.1 %

Procedure:
At room temperature, to a mixture of 3-difluoromethoxy-2-methylaniline 6.4 g and toluene 100 ml was added triphosgene 5.48 g, and the resulting mixture was stirred with heating under reflux for one hour. The reaction mixture was concentrated under reduced pressure to give 1-difluoromethoxy-3-isocyanato-2-methylbenzene 7.36 g.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([CH2:24][OH:25])[CH2:10][O:11][C:12]1[C:16]2[CH:17]=[C:18]([N:21]([CH3:23])[CH3:22])[CH:19]=[CH:20][C:15]=2[O:14][N:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].ClC(Cl)(Cl)[C:28]([N:30]=C=O)=[O:29].O>C(Cl)Cl>[C:28]([O:25][CH2:24][CH:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:10][O:11][C:12]1[C:16]2[CH:17]=[C:18]([N:21]([CH3:22])[CH3:23])[CH:19]=[CH:20][C:15]=2[O:14][N:13]=1)(=[O:29])[NH2:30]
Reactant: O=C=NC(=O)C(Cl)(Cl)Cl
Reactant: CN(C)c1ccc2onc(OCC(CO)NC(=O)OC(C)(C)C)c2c1
Solvent: O
Solvent: ClCCl
Product: CN(C)c1ccc2onc(OCC(COC(N)=O)NC(=O)OC(C)(C)C)c2c1

Procedure:
To a solution of 0.58 g of 3-(2-tert-butoxycarbonylamino-3-hydroxypropoxy)-5-dimethylamino-1,2-benzoisoxazole in 12 ml of methylene chloride is added 0.26 g of trichloroacetyl isocyanate at -35° to -30° C., and the temperature is elevated to 0° C., after which they are subjected to reaction at the same temperature for one hour. To the reaction mixture is added 10 ml of water, and they are subjected to reaction at 20°-25° C. for one hour, after which the organic layer is separated. The separated organic layer is dried over anhydrous magnesium sulfate and thereafter the solvent is removed by distillation under reduced pressure, to obtain 0.94 g of brown, oily 3-(3-carbamoyloxy-2-tert-butoxycarbonylaminopropoxy)-5-dimethylamino-1,2-benzoisoxazole.