Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[CH:9]=[C:8]([NH:10][C:11]([C:13]3[CH:18]=[CH:17][C:16]([CH:19]4[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]4)=[CH:15][CH:14]=3)=[O:12])[CH:7]=[CH:6][C:5]=12.[Cl:32]N1C(=O)CCC1=O>C(Cl)(Cl)Cl.CO>[Cl:32][C:3]1[N:4]2[CH:9]=[C:8]([NH:10][C:11]([C:13]3[CH:14]=[CH:15][C:16]([CH:19]4[CH2:20][CH2:21][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:23][CH2:24]4)=[CH:17][CH:18]=3)=[O:12])[CH:7]=[CH:6][C:5]2=[N:1][CH:2]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(C(=O)Nc3ccc4nccn4c3)cc2)CC1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(C(=O)Nc3ccc4ncc(Cl)n4c3)cc2)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of tert-butyl 4-(4-(imidazo[1,2-a]pyridin-6-ylcarbamoyl)phenyl)piperidine-1-carboxylate (0.015 g, 0.036 mmol) in chloroform (0.618 ml) and methanol (0.095 ml) was treated with N-chlorosuccinimide (5.24 mg, 0.039 mmol) and the reaction was stirred at ambient temperature for 16 hours. The reaction mixture was concentrated under a stream of warm nitrogen. The residue was purified by normal phase flash chromatography to provide the title compound. 1H NMR (500 MHz, methanol-d4) δ ppm 9.23 (s, 1H), 7.93 (d, J=8.3 Hz, 2H), 7.62-7.51 (m, 3H), 7.42 (d, J=8.3 Hz, 2H), 4.27-4.19 (m, 2H), 2.96-2.76 (m, 3H), 1.90-1.82 (m, 2H), 1.70-1.57 (m, 2H), 1.48 (s, 9H); MS (ESI(+)) m/e 455 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:10]([NH:13][S@](C(C)(C)C)=O)[CH2:11][CH3:12])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[ClH:20].CO>CCOCC>[ClH:20].[F:1][C:2]1[CH:3]=[C:4]([C@H:10]([NH2:13])[CH2:11][CH3:12])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: CC[C@@H](N[S@@](=O)C(C)(C)C)c1ccc(OC)c(F)c1
Agent: Cl
Solvent: CO
Solvent: CCOCC
Product: CC[C@@H](N)c1ccc(OC)c(F)c1
Reaction time: 1.5 h
Yield: 78.8 %

Procedure:
To a solution of 68 (1.5 g, 5.2 mmol) in Et2O (20 mL) at 0° C. was added 3N HCl/MeOH (5.0 mL, 15 mmol). After being stirred for 1.5 h, the solid was filtered and dried in vacuo to afford 900 mg (80%) of 70a. 1H NMR (500 MHz, DMSO-d6) δ 8.56 (s, 3H), 7.44 (dd, J=12.5, 2.0 Hz, 1H), 7.29-7.20 (m, 2H), 4.08 (m, 1H), 3.84 (s, 3H), 1.97 (m, 1H), 1.78 (m, 1H), 0.73 (t, J=7.0 Hz, 3H). LCMS (ESI) m/z: 167.1 [M+H−17]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[OH:24])[CH:5]=[CH:6][C:7]=1[C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9].C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:32][C:33]([CH3:42])([CH3:41])[C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35]>CN(C)C=O>[C:37]([O:36][C:34](=[O:35])[C:33]([CH3:42])([CH3:41])[CH2:32][O:24][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[C:4]1[CH:5]=[CH:6][C:7]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])=[C:2]([F:1])[CH:3]=1)([CH3:40])([CH3:39])[CH3:38]
Reactant: O=C(OCc1ccccc1)c1ccc(-c2ccccc2O)cc1F
Reactant: CC(C)(C)OC(=O)C(C)(C)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)C(C)(C)COc1ccccc1-c1ccc(C(=O)OCc2ccccc2)c(F)c1
Reaction time: 0.5 h
Yield: 68.3 %

Procedure:
To an N,N-dimethylformamide solution (200 ml) of benzyl 3-fluoro-2′-hydroxybiphenyl-4-carboxylate (14.8 g) was added at room temperature cesium carbonate (37.5 g), followed by stirring for 30 minutes. To this was added an N,N-dimethylformamide solution (200 ml) of tert-butyl 3-bromo-2,2-dimethylpropanoate (27.2 g), followed by stirring at 60° C. for 3 days. After the reaction solution was concentrated under reduced pressure, water and ethyl acetate were added to the residue, and the solution was separated. The organic layer was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to afford benzyl 2′-(3-tert-butoxy-2,2-dimethyl-3-oxopropoxy)-3-fluorobiphenyl-4-carboxylate (15.0 g).
Reaction SMILES: C(OC([N:8]1[CH:17]([CH:18]([OH:36])[CH:19]([O:21][C:22](=[O:35])[CH:23]([NH:27]C(OC(C)(C)C)=O)[CH:24]([CH3:26])[CH3:25])[CH3:20])[CH2:16][NH:15][C:14]2[NH:13][C:12]([NH2:37])=[N:11][C:10](=[O:38])[C:9]1=2)=O)(C)(C)C.[ClH:39].O1CCOCC1>O1CCOCC1>[ClH:39].[ClH:39].[NH2:37][C:12]1[NH:11][C:10](=[O:38])[C:9]2[NH:8][CH:17]([CH:18]([OH:36])[CH:19]([O:21][C:22](=[O:35])[CH:23]([NH2:27])[CH:24]([CH3:25])[CH3:26])[CH3:20])[CH2:16][NH:15][C:14]=2[N:13]=1
Reactant: CC(C)C(NC(=O)OC(C)(C)C)C(=O)OC(C)C(O)C1CNc2[nH]c(N)nc(=O)c2N1C(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: CC(C)C(N)C(=O)OC(C)C(O)C1CNc2nc(N)[nH]c(=O)c2N1
Temperature: 25 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
The product of step d) (1.75 g, 3.24 mmol) was dissolved in dioxane (10 ml) and treated with 4N HCl/dioxane (80 mL, 320 mmol). The reaction mixture was stirred at room temperature under an atmosphere of nitrogen for 2 h. The product was isolated by filtration and dried in nitrogen purged vacuum oven at 45° C. to give 1.34 g (100%) of the title compound as a white solid. 1H NMR (CD3OD) δ 5.11 (t, J=6.6 Hz, 1H), 4.22 (dd, J=2.4 Hz, J=6.9 Hz, 1H), 4.02 (d, J=4.5 Hz, 1H), 3.73 (d, J=11.4 Hz, 1H), 3.66 (s, 2H), 3.61-3.57 (m, 2H), 2.4-2.3 (m, 1H), 1.43 (d, J=6.3 Hz, 3H), 1.12-1.05 (dd, J=7.0 Hz, J=12 Hz, 6H). MS: ESI (positive): 341 (M+H).
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][CH:13]=1)[O:7][CH2:8][CH:9]=O.FC(F)(F)C(O)=O.[CH3:21][C:22]1[S:23][CH:24]=[C:25]([C:27]([N:29]2[CH2:34][C:33]3([CH2:39][CH2:38][NH:37][CH2:36][CH2:35]3)[O:32][CH2:31][CH2:30]2)=[O:28])[N:26]=1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO>[OH:1][CH2:2][CH2:3][C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][CH:13]=1)[O:7][CH2:8][CH2:9][N:37]1[CH2:38][CH2:39][C:33]2([O:32][CH2:31][CH2:30][N:29]([C:27]([C:25]3[N:26]=[C:22]([CH3:21])[S:23][CH:24]=3)=[O:28])[CH2:34]2)[CH2:35][CH2:36]1
Reactant: Cc1nc(C(=O)N2CCOC3(CCNCC3)C2)cs1
Reactant: O=CCOc1cccc(CCO)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CC(=O)O
Solvent: CO
Product: Cc1nc(C(=O)N2CCOC3(CCN(CCOc4cccc(CCO)c4)CC3)C2)cs1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A suspension of 2-(3-(2-hydroxyethyl)phenoxy)acetaldehyde (example 24, step b) (0.143 g) and (2-methylthiazol-4-yl)(1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)methanone trifluoroacetate (example 4, step h) (0.314 g) in methanol (10 mL) was treated with acetic acid (0.045 mL) and stirred at room temperature for 30 minutes. The mixture was cooled in ice-water, treated with sodium triacetoxyborohydride (0.254 g) and stirred over 3 days, allowing the ice-bath to expire. The resulting solution was purified by flash chromatography on silica eluted with 1:15:84 triethylamine:methanol:dichloromethane to afford the crude product (0.243 g). A second purification by flash chromatography on silica eluted with 1:5:94 triethylamine:methanol:dichloromethane afforded the slightly impure subtitled compound as a brown gum. Yield 0.122 g.
Reaction SMILES: [CH3:1][N:2]([CH3:18])[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][C:8]2[NH:11][C:12]([CH:15]=O)=[C:13]([CH3:14])[C:7]=2[C:6]1=[O:17].[Cl:19][C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][CH:28]=1)[NH:25][C:24](=[O:29])[CH2:23]2>>[Cl:19][C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][CH:28]=1)[NH:25][C:24](=[O:29])[C:23]2=[CH:15][C:12]1[NH:11][C:8]2[CH2:9][CH2:10][N:5]([CH2:4][CH2:3][N:2]([CH3:18])[CH3:1])[C:6](=[O:17])[C:7]=2[C:13]=1[CH3:14]
Reactant: O=C1Cc2cc(Cl)ccc2N1
Reactant: Cc1c(C=O)[nH]c2c1C(=O)N(CCN(C)C)CC2
Product: Cc1c(C=C2C(=O)Nc3ccc(Cl)cc32)[nH]c2c1C(=O)N(CCN(C)C)CC2
Yield: 65.5 %

Procedure:
The title compound was prepared under the same conditions as described in Example 112 with 5-(2-dimethylamino-ethyl)-3-methyl-4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine-2-carbaldehyde and 5-chloro-1,3-dihydro-indol-2-one as starting materials to give 2-(5-chloro-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-5-(2-dimethylamino-ethyl)-3-methyl-1,5,6,7-tetrahydro-pyrrolo[3,2-c]pyridin-4-one (40 mg, 65.5%) as a yellow solid.
Reaction SMILES: COC(C1N=CC2C(C=1)=CC(OC)=C(OC)C=2)=O.[CH3:19][O:20][C:21]([CH:23]1[CH2:32][C:31]2[C:26](=[CH:27][CH:28]=[CH:29][C:30]=2[Br:33])[CH2:25][NH:24]1)=[O:22].ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>O1CCCC1>[Br:33][C:30]1[CH:29]=[CH:28][CH:27]=[C:26]2[C:31]=1[CH:32]=[C:23]([C:21]([O:20][CH3:19])=[O:22])[N:24]=[CH:25]2
Reactant: COC(=O)C1Cc2c(Br)cccc2CN1
Agent: COC(=O)c1cc2cc(OC)c(OC)cc2cn1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: C1CCOC1
Product: COC(=O)c1cc2c(Br)cccc2cn1
Yield: 91.4 %

Procedure:
methyl-5-bromo-isoquinoline-3-carboxylate was prepared using the following procedure describe in US054777252 for methyl-6,7-dimethoxy-isoquinoline-3-carboxylate: 5-bromo-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid methyl ester (880 mg, 3.26 mmol) was treated with 2,3-Dichloro-5,6-dicyanobenzoquinone (1.62 mg, 7.19 mmol) in dry tetrahydrofuran (19 ml) at reflux temperature for 18 hours. The cooled dark mixture was filtered and the solid washed with dichloromethane. The filtrate was treated with a 1M aqueous sodium hydroxide solution and the aqueous layer was extracted twice with dichloromethane. The organic layer was washed with water, brine, dried over sodium sulfate and concentrated to dryness. The residue was purified by flash chromatography over silica gel (gradient cyclohexane/ethyl acetate: 0-100%) to yield methyl 5-bromo-isoquinoline-3-carboxylate (793 mg, 91%) as beige solid.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5]([N:8]2[C:12]([NH2:13])=[C:11]([C:14]#[N:15])[CH:10]=[N:9]2)=[CH:6][CH:7]=1.S(=O)(=O)(O)[OH:17]>>[Cl:1][C:2]1[N:3]=[N:4][C:5]([N:8]2[C:12]([NH2:13])=[C:11]([C:14](=[O:17])[NH2:15])[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: O=S(=O)(O)O
Reactant: N#Cc1cnn(-c2ccc(Cl)nn2)c1N
Product: NC(=O)c1cnn(-c2ccc(Cl)nn2)c1N

Procedure:
A mixture of 3 g. of 3-chloro-6-(4-cyano-5-amino-1-pyrazolyl)-pyridazine (prepared according to Example 24) and 10.5 ml. of concentrated sulphuric acid is stirred at room temperature for one hour. Then the mixture is poured onto ice, the precipitate filtered, washed with water and triturated with 15 ml. of hot ethanol, filtered and dried. Yield: 3.05 g. (93.5%); m.p.: 314°-317° C.
Reaction SMILES: [OH:1][C:2]1[N:6]([C:7]2[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=2)[N:5]=[CH:4][CH:3]=1.[C:15]1([CH2:21]O)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1.O>[CH2:21]([O:1][C:2]1[N:6]([C:7]2[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=2)[N:5]=[CH:4][CH:3]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: N#Cc1ccnc(-n2nccc2O)c1
Reactant: OCc1ccccc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: N#Cc1ccnc(-n2nccc2OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 21.7 %

Procedure:
To a solution of 2-(5-hydroxy-1H-pyrazol-1-yl)pyridine-4-carbonitrile (186 mg, 1 mmol), phenylmethan-1-ol (216 mg, 2 mmol), and PPh3 (523 mg, 2 mmol) in THF (10 mL) was added dropwise DIAD (402 mg, 2 mmoL) at 0° C. under N2. Then the mixture was stirred at rt overnight. Water was added, and the reaction mixture was extracted with EtOAc, then washed with water and brine. The organic phase was dried, concentrated, and purified by prep-HPLC to afford the title compound (60 mg). 1H NMR (400 MHz, CDCl3): δ 5.25 (2H, s), 5.75 (1H, d, J=2.0 Hz), 7.36-7.44 (5H, m), 7.57 (1H, d, J=2.0 Hz), 8.04 (1H, s), 8.71 (1H, d, J=5.2 Hz). [M+H] Calc'd for C16H12N4O, 277; Found, 277.
Reaction SMILES: [CH:1]([NH:3][C@@H:4]1[C:19](=[O:20])[N:6]2[C:7]([C:16]([OH:18])=[O:17])=[C:8]([CH2:11]OC(=O)C)[CH2:9][S:10][C@H:5]12)=[O:2].[CH3:21][C:22]1[S:26][C:25]([SH:27])=[N:24][N:23]=1.P(=O)(O)(O)O>P([O-])([O-])([O-])=O>[CH:1]([NH:3][C@@H:4]1[C:19](=[O:20])[N:6]2[C:7]([C:16]([OH:18])=[O:17])=[C:8]([CH2:11][S:27][C:25]3[S:26][C:22]([CH3:21])=[N:23][N:24]=3)[CH2:9][S:10][C@H:5]12)=[O:2]
Reactant: Cc1nnc(S)s1
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](NC=O)[C@H]2SC1
Agent: O=P(O)(O)O
Agent: O=P([O-])([O-])[O-]
Product: Cc1nnc(SCC2=C(C(=O)O)N3C(=O)[C@@H](NC=O)[C@H]3SC2)s1
Yield: 31.5 %

Procedure:
A solution of 7β-formamido-3-acetoxymethylceph-3-em-4-carboxylic acid (24.0 g) and 5-methyl-1,3,4-thiadiazole-2-thiol (10.56 g) in M. pH 6.4 phosphate buffer (600 ml.) was heated at 60° for 41/2 hours. The solution was cooled to 20° and the pH was adjusted from 6 to 5 with phosphoric acid. The solution was extracted with ethyl acetate the pH of the aqueous layer was taken to 2 with phosphoric acid and the product was extracted into ethyl acetate. The extract was washed with brine, dried and concentrated to a low volume under reduced pressure and added to stirred petroleum. The resulting solid was collected and dried to give the title compound (9.36 g.) [α]D -98° (c 1 DMSO), λmax. (pH 6 buffer) 271 nm (ε11,400), τ values (D2O+NaHCO3) include 1.74 (s; CHO), 4.30 (d, J 4.5 Hz; C-7 H), 4.88 (d, J 4.5 Hz; C-6 H) and 7.25 (s; CH3).
Reaction SMILES: [N:1]1([C:6]2[CH:7]=[C:8]([OH:12])[CH:9]=[CH:10][CH:11]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[S:13](Cl)(=[O:16])(=[O:15])[NH2:14].ClS(N=C=O)(=O)=O.C(N(CC)CC)C>C(#N)C>[N:1]1([C:6]2[CH:7]=[C:8]([O:12][S:13](=[O:16])(=[O:15])[NH2:14])[CH:9]=[CH:10][CH:11]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: NS(=O)(=O)Cl
Reactant: Oc1cccc(-n2ccnc2)c1
Agent: O=C=NS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: NS(=O)(=O)Oc1cccc(-n2ccnc2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 3(1H-imidazol-1-yl)phenol (8 g, 0.05 mole) in acetonitrile was treated in an ice bath with sulfamoyl chloride generated from 0.075 mole of chlorosulfonyl isocyanate (Preparation 19) followed by 0.075 mole of triethylamine. After stirring overnight at room temperature, TLC, and 1H NMR of a sample showed starting material still present. The reaction was then treated with another 0.075 mole each of sulfamoyl chloride and triethylamine for another night.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[H-].[Na+].Cl[C:12]1[CH:17]=[CH:16][N:15]=[C:14]([CH3:18])[CH:13]=1>CN1CCCC1=O.C(OCC)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:12]2[CH:17]=[CH:16][N:15]=[C:14]([CH3:18])[CH:13]=2)=[CH:4][CH:3]=1
Reactant: Oc1ccc(Br)cc1
Reactant: Cc1cc(Cl)ccn1
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CN1CCCC1=O
Product: Cc1cc(Oc2ccc(Br)cc2)ccn1
Temperature: 250 °C
Reaction time: 0.17 h

Procedure:
4-Bromophenol (1.0 g, 5.78 mmol) was added to a solution of sodium hydride (0.3 g, 7.51 mmol) in N-methylpyrrolidone (10 ml). After stiffing for 10 minutes, 4-chloro-2-methylpyridine (0.96 g, 7.51 mmol) was added. The reaction mixture was heated at 250° C. for 45 minutes under microwave irradiation. After cooling to room temperature the mixture was diluted with diethyl ether and washed with water. The solution was then extracted with additional diethyl ether, the organic layer dried (Na2SO4) and the solvent evaporated in vacuo. The crude product was purified by column chromatography (silica gel; DCM as eluent). The desired fractions were collected and evaporated in vacuo to yield intermediate D10 (1.34 g, 88%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:14][CH3:15])[C:11]=2[Cl:13])[NH:6][CH:5]=1>C(OC(=O)CC)(=O)CC>[C:10]([CH:2]([NH2:1])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:14][CH3:15])[C:11]=2[Cl:13])[NH:6][CH:5]=1)(=[O:14])[CH2:9][CH3:8]
Reactant: COc1ccc2[nH]cc(CCN)c2c1Cl
Agent: CCC(=O)OC(=O)CC
Product: CCC(=O)C(N)Cc1c[nH]c2ccc(OC)c(Cl)c12
Yield: 200.6 %

Procedure:
A solution of 3-(2-aminoethyl)-4-chloro-5-methoxy-indole (260 mg, 1.03 mmol) in propionic anhydride (4 ml) was evaporated to dryness in vacuo at 40° C. Purification by chromatography (SiO2 ; EtOAc) gave 3-(2-propionyl-aminoethyl)-4-chloro-5-methoxyindole (290 mg).
Reaction SMILES: [C:1](Cl)(Cl)=[S:2].[F:5][C:6]1[CH:7]=[C:8]([CH:10]=[CH:11][CH:12]=1)[NH2:9]>>[F:5][C:6]1[CH:12]=[CH:11][CH:10]=[C:8]([N:9]=[C:1]=[S:2])[CH:7]=1
Reactant: S=C(Cl)Cl
Reactant: Nc1cccc(F)c1
Product: Fc1cccc(N=C=S)c1

Procedure:
A solution of thiophosgene and 3-fluoroaniline were processed as described in Example 55A to provide the desired product.
Reaction SMILES: [OH:1][CH:2]1[C:7]([O:10][CH3:11])([O:8][CH3:9])[CH2:6][CH2:5][N:4]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:3]1.N1C=CC=CC=1.[C:25](OC(=O)C)(=[O:27])[CH3:26]>C(OCC)(=O)C>[C:25]([O:1][CH:2]1[C:7]([O:8][CH3:9])([O:10][CH3:11])[CH2:6][CH2:5][N:4]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:3]1)(=[O:27])[CH3:26]
Reactant: COC1(OC)CCN(C(=O)OC(C)(C)C)CC1O
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: COC1(OC)CCN(C(=O)OC(C)(C)C)CC1OC(C)=O
Temperature: 25 °C
Yield: 83 %

Procedure:
A mixture of tert-butyl 3-hydroxy-4,4-dimethoxypiperidine-1-carboxylate [synthesized by the method described in Tetrahedron Lett., 46(3), 447-450 (2005)] (10 g, 38.3 mmol), pyridine (100 mL) and acetic anhydride (18.1 mL, 192 mmol) was stirred at 70° C. overnight. The reaction solution was cooled to room temperature, diluted with ethyl acetate, washed with 1 N hydrochloric acid and brine, and dried over magnesium sulfate. Thereafter, the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (Elution solvent: hexane/ethyl acetate=4/1) to obtain 9.65 g of the title compound as a colorless oil (83%).
Reaction SMILES: Cl[CH:2]([C@H:8]([OH:16])[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:3]([O:5]CC)=[O:4].[O-]CC.[Na+].C(O)C>C(O)C>[CH2:9]([C@H:8]1[O:16][C@@H:2]1[C:3]([OH:5])=[O:4])[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: CCOC(=O)C(Cl)[C@H](O)Cc1ccccc1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: O=C(O)[C@H]1O[C@@H]1Cc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 74.1 %

Procedure:
Ethyl (3R)-2-chloro-3-hydroxy-4-phenylbutyrate (122 mg, 0.5 mmol) was dissolved in ethanol (3 ml), and 20 wt % sodium ethoxide/ethanol solution (254 mg) was gradually added. The mixture was stirred at room temperature for 3 hours, and the solvent was evaporated away under reduced pressure. Water (5 ml) was added, and the pH was adjusted to 13 with 30 wt % aqueous solution of sodium hydroxide. The mixture was washed with toluene (5 ml), and the pH was adjusted to 1.5 with concentrated hydrochloric acid. The mixture was extracted with ethyl acetate (15 ml), and drying was carried out with anhydrous magnesium sulfate. The solvent was evaporated away under reduced pressure to obtain the title compound as a brown oil (66 mg, yield: 74%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]=[C:16]([N:22]=[N+]=[N-])[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[C:11]([Cl:25])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C1(C)C=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]2[C:12]([CH:15]=[C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[NH:22]2)=[C:11]([Cl:25])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(=Cc1ccc(OCc2ccccc2)cc1Cl)N=[N+]=[N-]
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cc2c(Cl)cc(OCc3ccccc3)cc2[nH]1
Yield: 89.8 %

Procedure:
A solution of 4.50 g (12.6 mmols) of ethyl 3-(4-benzyloxy-2-chlorophenyl)-2-azidopropenoate in 100 ml of toluene was refluxed for 3 hours. The reaction mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to give 3.73 g (89.8%) of ethyl 6-benzyloxy-4-chloro-2-indolecarboxylate.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]([C:7]1[C:15]2[C:10](=[CH:11][C:12]([Br:16])=[CH:13][CH:14]=2)[NH:9][CH:8]=1)=[O:6].Br[CH2:18][CH2:19][O:20][CH3:21]>CN(C=O)C>[CH3:3][O:4][C:5]([C:7]1[C:15]2[C:10](=[CH:11][C:12]([Br:16])=[CH:13][CH:14]=2)[N:9]([CH2:18][CH2:19][O:20][CH3:21])[CH:8]=1)=[O:6]
Reactant: COCCBr
Reactant: COC(=O)c1c[nH]c2cc(Br)ccc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCCn1cc(C(=O)OC)c2ccc(Br)cc21
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 62.8 %

Procedure:
Sodium hydride (60% in mineral oil, 87 mg, 2.2 mmol) is added to a solution of 6-bromo-1H-indole-3-carboxylic acid methyl ester (500 mg, 1.97 mmol) in DMF (5 mL) at room temperature and the mixture is stirred for 30 minutes. To the reaction mixture is added 1-bromo-2-methoxy-ethane (222 μL, 2.36 mmol). After one hour, sodium hydride (20 mg) is added. Thirty minutes later, 1-bromo-2-methoxy-ethane (60 μL) is added. The mixture is heated to 60° C. for one hour. The cooled mixture is quenched with a small amount of water and concentrated under reduced pressure. The residue is taken up in ethyl acetate and filtered. The filtrate is concentrated under reduced pressure and the resulting residue is purified by column chromatography (gradient: 10 to 60% ethyl acetate/heptane) followed by purification via radial chromatography (gradient: 0 to 1% MeOH/CH2Cl2) to provide the title compound (386 mg, 63%). ES/MS m/e 314.0 (M+2).
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:15]=[CH:14][C:10]3[O:11][CH2:12][O:13][C:9]=3[C:8]=2[C:16]2[C:17]3[NH:24][C:23]([CH3:25])=[C:22]([C:26]([NH:28][C@H:29]4[C@H:33]([OH:34])[CH2:32][NH:31][CH2:30]4)=[O:27])[C:18]=3[N:19]=[CH:20][N:21]=2)[CH2:4][CH2:3]1.[C:35](Cl)(=[O:38])[CH2:36][CH3:37]>>[CH:2]1([CH2:5][O:6][C:7]2[CH:15]=[CH:14][C:10]3[O:11][CH2:12][O:13][C:9]=3[C:8]=2[C:16]2[C:17]3[NH:24][C:23]([CH3:25])=[C:22]([C:26]([NH:28][C@H:29]4[C@H:33]([OH:34])[CH2:32][N:31]([C:35](=[O:38])[CH2:36][CH3:37])[CH2:30]4)=[O:27])[C:18]=3[N:19]=[CH:20][N:21]=2)[CH2:4][CH2:3]1
Reactant: CCC(=O)Cl
Reactant: Cc1[nH]c2c(-c3c(OCC4CC4)ccc4c3OCO4)ncnc2c1C(=O)N[C@@H]1CNC[C@H]1O
Agent: Cl
Product: CCC(=O)N1C[C@@H](O)[C@H](NC(=O)c2c(C)[nH]c3c(-c4c(OCC5CC5)ccc5c4OCO5)ncnc23)C1

Procedure:
Starting from 4-[5-(cyclopropylmethoxy)-1,3-benzodioxol-4-yl]-N-[(3R*,4R*)-4-hydroxypyrrolidin-3-yl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f5) and commercially available propionyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [Se](=O)=O.[OH:4]O.[CH2:6]([S:9][C:10]1[N:15]=[CH:14][C:13]([Cl:16])=[CH:12][N:11]=1)[C:7]#[CH:8].[Na+].[Cl-]>O.CO>[CH2:6]([S:9]([C:10]1[N:15]=[CH:14][C:13]([Cl:16])=[CH:12][N:11]=1)=[O:4])[C:7]#[CH:8]
Reactant: C#CCSc1ncc(Cl)cn1
Reactant: OO
Agent: O=[Se]=O
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: C#CCS(=O)c1ncc(Cl)cn1
Yield: 63 %

Procedure:
A mixture of selenium dioxide (4 mmol) and 35% H2O2 (4 mmol) in water (2.5 ml) was added to a solution of 2-propargylthio-5-chloropyrimidine in methanol (10 ml). The mixture was stirred at room temperature for 18 h before water (50 ml), saturated with NaCl, was added and the mixture extracted with chloroform (3×20 ml). The dried (MgSO4) chloroform solution was evaporated and the residue recrystallized from chloroform: pet. ether; yield 63%, m.p. 92° C. 1H NMR (CDCl3): δ2.28 (HC≡t, J 2 Hz), 3.87 and 4.09 (CH2J 15 Hz), 8.85 (H-4, H-6), IR (KBr): 3235 (CH≡), 2110 and 2100 (--C≡C--). MS [70 eV; m/e (% rel. int)]: 200 (13, M) 199 (19), 173 (33), 171 (100), 146 (25), 114 (30), 113 (31), 111 (47).
Reaction SMILES: [CH2:1]([C:4]1[C:8]2[CH:9]=[C:10]([C:13]([O:15]C)=[O:14])[CH:11]=[CH:12][C:7]=2[O:6][N:5]=1)[CH2:2][CH3:3].O1CCCC1.O.[OH-].[Li+]>CO>[CH2:1]([C:4]1[C:8]2[CH:9]=[C:10]([C:13]([OH:15])=[O:14])[CH:11]=[CH:12][C:7]=2[O:6][N:5]=1)[CH2:2][CH3:3]
Reactant: CCCc1noc2ccc(C(=O)OC)cc12
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CCCc1noc2ccc(C(=O)O)cc12
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 88.9 %

Procedure:
To a solution of methyl 3-propyl-1,2-benzisoxazole-5-carboxylate (90 mg, 0.4 mmol) in a 2:1:1 mixture of tetrahydrofuran, water, and methanol (4 mL) was added lithium hydroxide (50 mg, 1.2 mmol) and the resulting reaction mixture stirred at room temperature for 2.5 h. The reaction mixture was concentrated under reduced pressure, and partitioned between water and ethyl ether. The aqueous layer was washed twice with ether and acidified to pH 1 with 6 M hydrochloric acid. The resulting aqueous layer was extracted with ethyl acetate, dried (sodium sulfate), and concentrated under reduced pressure to afford 3-propyl-1,2-benzisoxazole-5-carboxylic acid (73 mg): 1H NMR (300 MHz, CD3OD): δ 8.28–8.27 (m, 1H), 8.09–8.06 (m, 1H), 7.64–7.61 (m, 1H), 2.99–2.94 (m, 2H), 1.96–1.86 (m, 2H), 1.08–1.02 (m, 3H).