Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N:9]1[CH2:14][CH2:13][C:12]2([CH2:23][C:22](=[O:24])[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([NH:25][S:26]([CH3:29])(=[O:28])=[O:27])[CH:20]=3)[O:15]2)[CH2:11][CH2:10]1)(=O)C1C=CC=CC=1.C(O)C.[ClH:33].CO>ClCCl>[ClH:33].[O:24]=[C:22]1[C:21]2[C:16](=[CH:17][CH:18]=[C:19]([NH:25][S:26]([CH3:29])(=[O:28])=[O:27])[CH:20]=2)[O:15][C:12]2([CH2:11][CH2:10][NH:9][CH2:14][CH2:13]2)[CH2:23]1
Reactant: CS(=O)(=O)Nc1ccc2c(c1)C(=O)CC1(CCN(C(=O)c3ccccc3)CC1)O2
Agent: Cl
Solvent: ClCCl
Solvent: CCO
Solvent: CO
Product: CS(=O)(=O)Nc1ccc2c(c1)C(=O)CC1(CCNCC1)O2
Temperature: 87.5 °C
Reaction time: 3.5 h
Yield: 114 %

Procedure:
N-(1′-Benzoyl-4-oxospiro[chroman-2,4′-piperidine]-6-yl)methanesulfonamide (10, 0.81 g, 1.95 mmol) was suspended in a mixture of absolute ethanol (10 mL) and 6 M aqueous hydrochloric acid (10 mL) and stirred at 85-90° C. in an oil bath. After 1 hour the oil bath temperature was increased to 95° C. After ˜3.5 hours at 95° C. the reaction was allowed to cool to room temperature. TLC (silica gel, 10% methanol in dichloromethane, UV visualization) showed no remaining starting material [Rf (10)=0.65−0.7]. Solvent was removed under reduced pressure on a rotary evaporator. Ethanol was added to the residue and then evaporated to dryness under reduced pressure on a rotary evaporator. The ethanol addition and evaporation to dryness was repeated two more times. The residue was dried in vacuo to afford 0.77 g (114% yield) of N-(4-oxospiro[chroman-2,4′-piperidine]-6-yl)methanesulfonamide hydrochloride (11) as a light yellow solid that was homogeneous by TLC [silica gel, 10% methanol in dichloromethane containing a small amount of concentrated aqueous ammonium hydroxide, UV visualization, Rf (11)=0.12−0.19]. Mass spec: m/z=311.2 [M+H]+
Reaction SMILES: [O:1]=[C:2]1[N:7]2[CH2:8][CH2:9][CH2:10][C:6]2=[N:5][CH:4]=[C:3]1[C:11]([O:13]CC)=[O:12].[OH-].[Na+].Cl>>[O:1]=[C:2]1[N:7]2[CH2:8][CH2:9][CH2:10][C:6]2=[N:5][CH:4]=[C:3]1[C:11]([OH:13])=[O:12]
Reactant: CCOC(=O)c1cnc2n(c1=O)CCC2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)c1cnc2n(c1=O)CCC2
Yield: 66.7 %

Procedure:
10.4 g. of ethyl 4-oxo-4,6,7,8-tetrahydro-pyrrolo[1,2-a]pyrimidine-3-carboxylate are dissolved in 50 ml. of a 5% by W/V sodium hydroxide solution and after two hours the pH of the reaction mixture is adjusted to 2.5 with 36% by W/V hydrochloric acid solution. The precipitated crystals are filtered and washed with a small amount of cold water. 6.0 g. (66.7%) of 4-oxo-4,6,7,8-tetrahydro-pyrrolo[1,2-a]pyrimidine-3-carboxylic acid are obtained melting at 146° to 148° C. (decomposition).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:19]=[CH:18][C:17]([C:20]3[CH:21]=[N:22][CH:23]=[C:24]([C:26]4[C:35]5[C:30](=[N:31][CH:32]=[CH:33][CH:34]=5)[N:29]=[C:28]([C:36]5[CH:41]=[C:40]([Cl:42])[CH:39]=[CH:38][C:37]=5[F:43])[CH:27]=4)[CH:25]=3)=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.Cl>O1CCOCC1>[ClH:42].[Cl:42][C:40]1[CH:39]=[CH:38][C:37]([F:43])=[C:36]([C:28]2[CH:27]=[C:26]([C:24]3[CH:25]=[C:20]([C:17]4[CH:18]=[N:19][C:14]([N:11]5[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]5)=[CH:15][CH:16]=4)[CH:21]=[N:22][CH:23]=3)[C:35]3[C:30](=[N:31][CH:32]=[CH:33][CH:34]=3)[N:29]=2)[CH:41]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(-c3cncc(-c4cc(-c5cc(Cl)ccc5F)nc5ncccc45)c3)cn2)CC1
Agent: Cl
Solvent: C1COCCO1
Product: Fc1ccc(Cl)cc1-c1cc(-c2cncc(-c3ccc(N4CCNCC4)nc3)c2)c2cccnc2n1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A solution of 438 mg (0.734 mmol) 4-{5′-[2-(5-Chloro-2-fluoro-phenyl)-[1,8]naphthyridin-4-yl]-[3,3′]bipyridinyl-6-yl}-piperazine-1-carboxylic acid tert-butyl ester in 5 ml dioxane was treated with 6 ml of a 4 N solution of hydrochlorid acid in dioxane. The mixture was stirred for 20 minutes at room temperature. The resulting precipitate was filtered off, washed with dioxane and dried under vacuum yielding 2-(5-chloro-2-fluoro-phenyl)-4-(6′-piperazin-1-yl-[3,3′]bipyridinyl-5-yl)-[1,8]naphthyridine hydrochloride as light yellow solid; HPLC-MS: 1.66 min, [M+H] 497.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[C:10]([N:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)=[C:11]3[CH:17]=[CH:16][NH:15][C:12]3=[N:13][CH:14]=2)[CH:6]=[CH:7][CH:8]=1.[C:24]([O:28][C:29]([NH:31][C@H:32]([CH2:36][C:37]1[CH:42]=[CH:41][C:40]([Cl:43])=[CH:39][CH:38]=1)[C:33](O)=[O:34])=[O:30])([CH3:27])([CH3:26])[CH3:25].C1C=CC2N(O)N=NC=2C=1.O.CCN=C=NCCCN(C)C.CCN(C(C)C)C(C)C>C(Cl)Cl>[Cl:43][C:40]1[CH:41]=[CH:42][C:37]([CH2:36][C@@H:32]([NH:31][C:29](=[O:30])[O:28][C:24]([CH3:26])([CH3:25])[CH3:27])[C:33]([N:21]2[CH2:22][CH2:23][N:18]([C:10]3[C:9]([C:5]4[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=4)=[CH:14][N:13]=[C:12]4[NH:15][CH:16]=[CH:17][C:11]=34)[CH2:19][CH2:20]2)=[O:34])=[CH:38][CH:39]=1
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccc(Cl)cc1)C(=O)O
Reactant: COc1cccc(-c2cnc3[nH]ccc3c2N2CCNCC2)c1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: ClCCl
Product: COc1cccc(-c2cnc3[nH]ccc3c2N2CCN(C(=O)[C@@H](Cc3ccc(Cl)cc3)NC(=O)OC(C)(C)C)CC2)c1
Reaction time: 2 h
Yield: 54.6 %

Procedure:
5-(3-Methoxyphenyl)-4-(piperazin-1-yl)-1H-pyrrolo[2,3-b]pyri dine (0.045 g, 0.118 mmol) and (R)-2-(tert-butoxycarbonylamino)-3-(4-chlorophenyl)propanoic acid (0.0425 g, 0.142 mmol) were placed in DCM (3 mL). HOBT-H2O (0.0253 g, 0.165 mmol), EDCI (0.0294 g, 0.153 mmol), and DIEA (d 0.742; 0.103 mL, 0.591 mmol) were then added, and the reaction was stirred for 2 hours. The reaction was then quenched with saturated Na2CO3 and extracted with DCM. The product was dried, filtered, and concentrated to give the crude product. The crude product was purified (500:5 DCM:MeOH) to yield (R)-tert-butyl 3-(4-chlorophenyl)-1-(4-(5-(3-methoxyphenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazin-1-yl)-1-oxopropan-2-ylcarbamate (0.038 g, 54.6% yield).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[CH2:4][NH:5][C:6]1[CH:7]=[N:8][CH:9]=[CH:10][C:11]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[O:18][C:19]([F:22])([F:21])[F:20].FC1C=CC=C(OC)C=1C1C=CN=CC=1N(CC(F)(F)F)[C:40](=[O:55])[C:41]1[CH:46]=[C:45]([C:47]([F:50])([F:49])[F:48])[CH:44]=[C:43]([S:51]([CH3:54])(=[O:53])=[O:52])[CH:42]=1>>[CH3:1][O:2][C:3](=[O:23])[CH2:4][N:5]([C:40](=[O:55])[C:41]1[CH:46]=[C:45]([C:47]([F:50])([F:48])[F:49])[CH:44]=[C:43]([S:51]([CH3:54])(=[O:53])=[O:52])[CH:42]=1)[C:6]1[CH:7]=[N:8][CH:9]=[CH:10][C:11]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[O:18][C:19]([F:20])([F:21])[F:22]
Reactant: COC(=O)CNc1cnccc1-c1ccccc1OC(F)(F)F
Reactant: COc1cccc(F)c1-c1ccncc1N(CC(F)(F)F)C(=O)c1cc(C(F)(F)F)cc(S(C)(=O)=O)c1
Product: COC(=O)CN(C(=O)c1cc(C(F)(F)F)cc(S(C)(=O)=O)c1)c1cnccc1-c1ccccc1OC(F)(F)F

Procedure:
The title compound was prepared in analogy to example 284, from [4-(2-trifluoromethoxy-phenyl)-pyridin-3-ylamino]-acetic acid methyl ester and 3-methanesulfonyl-5-trifluoromethyl-benzoyl chloride (example 223, intermediate d). The crude product was used in the next step without further purification. Brown sticky liquid. MS (ESI): m/z=577.2 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:15]3[C:20](=O)[NH:19]C(=O)C3(CCC)C=CC=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O.NN>C(O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][CH2:20][NH2:19])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCC12C=CC=C(C3CCN(C(=O)OC(C)(C)C)CC3)C1C(=O)NC2=O
Agent: NN
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(CCCN)CC1
Temperature: 25 °C

Procedure:
To a solution of 20.24 g (54.34 mM) of 3-(1-tert-butoxycarbonyl-4-piperidyl)-1-propylphthalimide in 350 ml of ethanol was added 7.9 ml (163 mM) of hydrazine monohydrate and the mixture was refluxed for one hour. After cooling to room temperature, the resulting precipitate (phthalide) was filtered off and washed with a small amount of ethanol. The filtrate and washes were pooled and the solvent was distilled off under reduced pressure. The residue was extracted with chloroform and the organic layer was washed with saturated aqueous solution of sodium chloride and dried over MgSO4. The solvent was then distilled off under reduced pressure to provide the title compound. Light-yellow oil. Yield 13.08 g (99%)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10](=[O:12])[CH3:11])=[CH:5][CH:4]=1.C(O[CH:16](OCC)[N:17]([CH3:19])[CH3:18])C>>[CH3:16][N:17]([CH3:19])[CH:18]=[C:9]([C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)[C:10](=[O:12])[CH3:11]
Reactant: COc1ccc(CC(C)=O)cc1
Reactant: CCOC(OCC)N(C)C
Product: COc1ccc(C(=CN(C)C)C(C)=O)cc1

Procedure:
A stirred mixture of 1-(4-methoxyphenyl)-2-propanone (8.2 g) and dimethylformamide diethyl acetal (9.5 ml) was heated on an oil bath at 95°-100° C. for 30 minutes. Volatile material was removed under vacuum and the residue was crystallised from ether-petroleum spirit (40°-60° C.) to give the title compound (mp 56°-58° C.).
Reaction SMILES: [NH2:1][C:2]([CH2:9][C:10](=[O:12])[O-:11])([CH2:4][N+:5]([CH3:8])([CH3:7])[CH3:6])O.[CH2:13]([C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([N:26]=[C:27]=[O:28])[CH:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[CH2:13]([C:20]1[CH:21]=[C:22]([NH:26][C:27](=[O:28])[NH:1][C@@H:2]([CH2:4][N+:5]([CH3:8])([CH3:7])[CH3:6])[CH2:9][C:10]([O-:11])=[O:12])[CH:23]=[CH:24][CH:25]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: O=C=Nc1cccc(Cc2ccccc2)c1
Reactant: C[N+](C)(C)CC(N)(O)CC(=O)[O-]
Product: C[N+](C)(C)C[C@@H](CC(=O)[O-])NC(=O)Nc1cccc(Cc2ccccc2)c1
Yield: 93.4 %

Procedure:
According to the method described in example S11, aminocarnitine (1.28 HBr salt, 68 mg, 0.31 mmol) was reacted with 1-benzyl-3-isocyanatobenzene (132 mg, 0.63 mmol) to yield the title compound as a white solid (107 mg, 92%). NMR (400 MHz, CD3OD) δ=ppm 7.11-7.29 (m, 8H), 6.83 (d, J=7.33 Hz, 1H), 4.58 (br. s, 1 H), 3.89 (s, 2 H), 3.71 (dd, J=13.64, 9.35 Hz, 1 H), 3.50 (d, J=13.39 Hz, 1 H), 3.17 (s, 9 H), 2.40-2.58 (m, 2 H). MS ESI [M+H]+, calcd for [C21H27N3O3+H]+ 370.46 found m/z 370.2 (100).
Reaction SMILES: [Cl:1][C:2]1[N:3]([C@@H:15]2[O:21][C@H:20]([CH2:22][OH:23])[C@@H:18]([OH:19])[C@H:16]2[OH:17])[C:4]2[C:9]([C:10]=1[CH:11]=O)=[CH:8][C:7]([Cl:13])=[C:6]([Cl:14])[CH:5]=2.[NH:24]([C:26]([O:28][CH3:29])=[O:27])[NH2:25].O>CO>[Cl:1][CH:2]1[C:10](=[C:11]=[N:25][NH:24][C:26]([O:28][CH3:29])=[O:27])[C:9]2[C:4](=[CH:5][C:6]([Cl:14])=[C:7]([Cl:13])[CH:8]=2)[N:3]1[C@@H:15]1[O:21][C@H:20]([CH2:22][OH:23])[C@@H:18]([OH:19])[C@H:16]1[OH:17]
Reactant: COC(=O)NN
Reactant: O=Cc1c(Cl)n([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c2cc(Cl)c(Cl)cc12
Solvent: O
Solvent: CO
Product: COC(=O)NN=C=C1c2cc(Cl)c(Cl)cc2N([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)C1Cl
Temperature: 25 °C
Yield: 84.9 %

Procedure:
2,5,6-Trichloro-3-formyl-1-(β-D-ribofuranosyl)indole (4.3, 122 mg, 0.32 mmol) was dissolved in MeOH (10 mL) to which was added methyl hydrazinocarboxylate (115 mg, 1.3 mmol). The resulting solution was heated on a 60 C oil bath for 16 h, then cooled to room temperature and poured into 100 mL of water, and the solvent evaporated to approx 50 mL. The resulting suspension was cooled to 4 C, then filtered and the solids rinsed with cold water (25 mL). The solids were recrystallized from boiling EtOAc/hexane to yield 123 mg (85%) of 4.31 as a pale pink crystalline solid: mp 217-219 C; Rf 0.2 (10% MeOH/CHCl3); 1H-NMR (500 MHz, DMSO-d6): δ 11.17 (b, 1H, D2O exch.), 8.54 (s, 1H), 8.42 (s, 1H), 8.22 (b, 1H), 5.92 (d, 1H), 5.42-5.37 (m, 2H, D2O exch.), 5.25 (d, 1H, D2O exch.), 4.43 (q, 1H), 4.15 (d, 1H), 3.98 (d, 1H), 3.72 (b, 5H). 13C-NMR (125 MHz, DMSO-d6): δ 153.88, 133.17, 129.33, 126.08, 124.96, 124.06, 122.17, 115.34, 108.59, 88.76, 86.03, 71.30, 69.73, 69.62, 61.07, 52.04. HRMS (ES) m/z calcd. for C16H16Cl3N3O6.Na 474.0002. found 473.9999. Anal calcd for C16H16Cl3N3O6.¼H2O: C, 42.03; H, 3.64; N, 9.19. Found: C, 42.11; H, 3.92; N, 9.18.
Reaction SMILES: [NH2:1][C:2]1[C:6]2[C:7]([Cl:13])=[C:8]([O:11][CH3:12])[CH:9]=[CH:10][C:5]=2[O:4][C:3]=1[C:14](=[O:25])/[CH:15]=[CH:16]/[C:17]1[S:21][C:20]([CH:22]([CH3:24])[CH3:23])=[N:19][CH:18]=1.CC#N.OP(O)(O)=O>[Cl-].[Cl-].[Zn+2].CC(O)=O>[Cl:13][C:7]1[C:6]2[C:2]3[NH:1][CH:16]([C:17]4[S:21][C:20]([CH:22]([CH3:23])[CH3:24])=[N:19][CH:18]=4)[CH2:15][C:14](=[O:25])[C:3]=3[O:4][C:5]=2[CH:10]=[CH:9][C:8]=1[O:11][CH3:12]
Reactant: COc1ccc2oc(C(=O)/C=C/c3cnc(C(C)C)s3)c(N)c2c1Cl
Agent: O=P(O)(O)O
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CC(=O)O
Solvent: CC#N
Product: COc1ccc2oc3c(c2c1Cl)NC(c1cnc(C(C)C)s1)CC3=O
Temperature: 25 °C
Yield: 68.6 %

Procedure:
9A (3.5 g, 9.28 mmol) was added to MeCN (50 mL) and stirred at room temperature. To the mixture was added ZnCl2 (1.91 g, 13.93 mmol, 1.5 eq), followed by AcOH (50 mL) and H3PO4 (50 mL) The reaction mixture was heated to 80° C. and stirred overnight. After reaction completed, the mixture was cooled and poured into crushed ice under stirring, neutralized to pH=7˜8, extracted with ethyl acetate, dried and concentrated to give 2.4 g of product (9B).
Reaction SMILES: [ClH:1].Cl.[NH2:3][C@H:4]1[CH2:9][CH2:8][N:7]([CH2:10][CH2:11][N:12]2[C:21]3[C:16](=[N:17][CH:18]=[C:19]([O:22][CH3:23])[CH:20]=3)[CH:15]=[CH:14][C:13]2=[O:24])[CH2:6][C@H:5]1[OH:25].C(N(CC)CC)C.[O:33]1[C:42]2[CH:41]=[C:40]([CH:43]=O)[N:39]=[CH:38][C:37]=2[O:36][CH2:35][CH2:34]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(Cl)Cl.CO.C(Cl)(Cl)Cl>[ClH:1].[O:33]1[C:42]2[CH:41]=[C:40]([CH2:43][NH:3][C@H:4]3[CH2:9][CH2:8][N:7]([CH2:10][CH2:11][N:12]4[C:21]5[C:16](=[N:17][CH:18]=[C:19]([O:22][CH3:23])[CH:20]=5)[CH:15]=[CH:14][C:13]4=[O:24])[CH2:6][C@H:5]3[OH:25])[N:39]=[CH:38][C:37]=2[O:36][CH2:35][CH2:34]1
Reactant: COc1cnc2ccc(=O)n(CCN3CC[C@H](N)[C@H](O)C3)c2c1
Reactant: O=Cc1cc2c(cn1)OCCO2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: O=C([O-])O
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CO
Product: COc1cnc2ccc(=O)n(CCN3CC[C@H](NCc4cc5c(cn4)OCCO5)[C@H](O)C3)c2c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
1-{2-[(3R,4S)-4-amino-3-hydroxy-1-piperidinyl]ethyl}-7-(methyloxy)-1,5-naphthyridin-2(1H)-one dihydrochloride (100 mg, 0.2556 mmol) was stirred in 9:1 v:v chloroform:MeOH (5 mL) at rt under argon and triethylamine (125 uL, 3.5 eq.) was added. The mixture was stirred at rt for 10 mins., then 2,3-dihydro[1,4]dioxino[2,3-c]pyridine-7-carboxaldehyde (for a synthesis see WO2004058144, Example 2(c) or WO03/087098, Example 19(d)) was added and the mixture was stirred at rt for 1 h before being treated with sodium triacetoxyborohydride (163 mg) added in one portion. The mixture was then stirred at rt over the weekend. Saturated aqueous sodium hydrogen cabonate (3 ml) was then added and the organic phase was diluted with DCM to bring the total volume to ca. 20 ml. The organic phase was separated using a hydrophobic frit and the aqueous phase was extracted with DCM (2×20 ml). The combined DCM extracts were evaporated under reduced pressure and purified by MDAP to give the free base of the title compound as an off-white foam (45 mg).
Reaction SMILES: [C:1](OC1C=CC(C)=CC=1O)(=O)C1C=CC=CC=1.C(O[C:27]1[CH:28]=[CH:29][C:30]([OH:39])=[C:31]([CH:38]=1)[O:32][CH2:33][C:34]([NH:36][CH3:37])=[O:35])(=O)C1C=CC=CC=1.C(OC1C=CC(OCC2C=CC=CC=2)=CC=1O)(=O)C1C=CC=CC=1>>[OH:39][C:30]1[CH:29]=[CH:28][C:27]([CH3:1])=[CH:38][C:31]=1[O:32][CH2:33][C:34]([NH:36][CH3:37])=[O:35]
Reactant: CNC(=O)COc1cc(OC(=O)c2ccccc2)ccc1O
Reactant: Cc1ccc(OC(=O)c2ccccc2)c(O)c1
Agent: O=C(Oc1ccc(OCc2ccccc2)cc1O)c1ccccc1
Product: CNC(=O)COc1cc(C)ccc1O

Procedure:
2-Hydroxy-N,5-dimethylphenoxyacetamide, m.p. 163°-165°C. is prepared from 2-benzoyloxy-5-methylphenol by a similar process to that described in Example 12 for the preparation of 5-benzoyloxy-2-hydroxy-N-methylphenoxyacetamide from 2-benzoyloxy-5-benzyloxyphenol.
Reaction SMILES: N#N.[N+:3]([C:6]1[CH:10]=[N:9][N:8]([CH2:11][C:12]2[O:16][C:15]([C:17](=[O:19])[CH3:18])=[CH:14][CH:13]=2)[N:7]=1)([O-])=O.[NH4+].[Cl-]>CCO.O.[Fe]>[NH2:3][C:6]1[CH:10]=[N:9][N:8]([CH2:11][C:12]2[O:16][C:15]([C:17](=[O:19])[CH3:18])=[CH:14][CH:13]=2)[N:7]=1
Reactant: CC(=O)c1ccc(Cn2ncc([N+](=O)[O-])n2)o1
Agent: [Fe]
Agent: N#N
Agent: [Cl-]
Solvent: O
Solvent: CCO
Product: CC(=O)c1ccc(Cn2ncc(N)n2)o1
Temperature: 85 °C
Reaction time: 0.5 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a mixture of 1-(5-((4-nitro-2H-1,2,3-triazol-2-yl)methyl)furan-2-yl)ethanone (WO2009077990A1) (500 mg, 2.12 mmol), iron powder (358 mg, 6.35 mmol) and NH4Cl (572 mg, 10.59 mmol) in a mixture of EtOH (8.0 mL) and water (4.0 mL) was stirred at 85° C. for 30 min. The reaction mixture was filtered while hot and concentrated under reduced pressure. CH2Cl2 (15 mL) was added followed by 1N NaOH (15 mL). The aq. layer was extracted with CH2Cl2 (2×15 mL) and the combined org. extracts were dried over MgSO4, filtered, and the solvents were removed under reduced pressure to give the title compound as a yellow oil. LC-MS-conditions 02: tR=0.64 min; [M+H]+=207.49.
Reaction SMILES: [CH2:1]([C:3]1[S:4][C:5]([CH:10]2[CH2:15][CH2:14][S:13][CH2:12][CH2:11]2)=[CH:6][C:7]=1[CH2:8][OH:9])[CH3:2]>O1CCCC1.[O-2].[O-2].[Mn+4]>[CH2:1]([C:3]1[S:4][C:5]([CH:10]2[CH2:15][CH2:14][S:13][CH2:12][CH2:11]2)=[CH:6][C:7]=1[CH:8]=[O:9])[CH3:2]
Reactant: CCc1sc(C2CCSCC2)cc1CO
Agent: [Mn+4]
Agent: [O-2]
Solvent: C1CCOC1
Product: CCc1sc(C2CCSCC2)cc1C=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.6 %

Procedure:
To a solution of [2-ethyl-5-(tetrahydro-2H-thiopyran-4-yl)thiophen-3-yl]methanol (2.76 g) synthesized above in tetrahydrofuran (50 mL) was added activated manganese dioxide (15.0 g), and the mixture was stirred at room temperature overnight. Activated manganese dioxide (8.00 g) was added again, and the mixture was further stirred at room temperature for 5 hr. Manganese dioxide was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (15% ethyl acetate/hexane) to give the title compound (1.85 g, 68%) as a colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:22]=[CH:21][C:20]([C:23]([NH:25][C:26]2[CH:31]=[C:30]([CH3:32])[CH:29]=[CH:28][C:27]=2[F:33])=[O:24])=[CH:19][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([C:11]2[NH:15][CH:14]=[C:13]([C:16](O)=[O:17])[CH:12]=2)[CH:6]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.[NH2:67][CH2:68][CH2:69][CH:70]([O:74][CH2:75][CH3:76])[O:71][CH2:72][CH3:73]>CN(C=O)C.O>[CH2:72]([O:71][CH:70]([O:74][CH2:75][CH3:76])[CH2:69][CH2:68][NH:67][C:16]([C:13]1[CH:12]=[C:11]([C:7]2[CH:6]=[C:5]([O:4][C:3]3[CH:19]=[C:20]([C:23]([NH:25][C:26]4[CH:31]=[C:30]([CH3:32])[CH:29]=[CH:28][C:27]=4[F:33])=[O:24])[CH:21]=[CH:22][C:2]=3[F:1])[CH:10]=[CH:9][N:8]=2)[NH:15][CH:14]=1)=[O:17])[CH3:73]
Reactant: CCOC(CCN)OCC
Reactant: Cc1ccc(F)c(NC(=O)c2ccc(F)c(Oc3ccnc(-c4cc(C(=O)O)c[nH]4)c3)c2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(CCNC(=O)c1c[nH]c(-c2cc(Oc3cc(C(=O)Nc4cc(C)ccc4F)ccc3F)ccn2)c1)OCC
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a stirred solution of 5-[4-(2-fluoro-5-{[(2-fluoro-5-methylphenyl)amino]carbonyl}phenoxy)pyridin-2-yl]-1H-pyrrole-3-carboxylic acid (200 mg, 0.45 mmol) in 10 ml of anhydrous DMF were added HATU (205 mg, 0.54 mmol) and N,N-diisopropylethylamine (128 mg, 0.99 mmol). The mixture was stirred at room temperature for 10 minutes, followed by addition of 1-amino-3,3-diethoxypropane (100 mg, 0.68 mmol), and stirring was continued for another 10 minutes. The mixture was poured into 100 ml of water with vigorous stirring. The precipitates were filtered, washed with water and dried in vacuo to give N-(3,3-diethoxypropyl)-5-[4-(2-fluoro-5-{[(2-fluoro-5-methylphenyl)amino]carbonyl}phenoxy)pyridin-2-yl]-1H-pyrrole-3-carboxamide as white solid.
Reaction SMILES: C([C:4]1[C:5](=[O:12])[O:6][C:7]([CH3:11])=[CH:8][C:9]=1[OH:10])(=O)C.S(=O)(=O)(O)O>>[CH3:11][C:7]1[O:6][C:5](=[O:12])[CH:4]=[C:9]([OH:10])[CH:8]=1
Reactant: CC(=O)c1c(O)cc(C)oc1=O
Agent: O=S(=O)(O)O
Product: Cc1cc(O)cc(=O)o1

Procedure:
3-Acetyl-6-methyl-4-hydroxypyran-2-one may be deacylated by reaction with 90% sulphuric acid at 130° C. to give 6-methyl-4-hydroxy pyran-2-one;
Reaction SMILES: [F:1][CH:2]([F:24])[C@H:3]1[O:11][C@H:10]2[C@H:6]([N:7]=[C:8]([N:12]([CH2:20][CH3:21])[C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[S:9]2)[C@@H:5]([OH:22])[C@@H:4]1[OH:23].N1C=CN=C1.[CH3:30][C:31]([Si:34](Cl)([CH3:36])[CH3:35])([CH3:33])[CH3:32]>CN(C=O)C>[Si:34]([O:22][C@@H:5]1[C@H:6]2[N:7]=[C:8]([N:12]([CH2:20][CH3:21])[C:13](=[O:19])[O:14][C:15]([CH3:16])([CH3:17])[CH3:18])[S:9][C@H:10]2[O:11][C@H:3]([CH:2]([F:1])[F:24])[C@H:4]1[OH:23])([C:31]([CH3:33])([CH3:32])[CH3:30])([CH3:36])[CH3:35]
Reactant: CCN(C(=O)OC(C)(C)C)C1=N[C@@H]2[C@@H](O)[C@H](O)[C@@H](C(F)F)O[C@@H]2S1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CCN(C(=O)OC(C)(C)C)C1=N[C@@H]2[C@@H](O[Si](C)(C)C(C)(C)C)[C@H](O)[C@@H](C(F)F)O[C@@H]2S1
Temperature: 25 °C
Yield: 66.9 %

Procedure:
A solution of tert-butyl (-(3aR,5S,6S,7R,7aR)-5-(difluoromethyl)-6,7-dihydroxy-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-2-yl)(ethyl)carbamate (500 mg, 1.3 mmol) and imidazole (277 mg, 4 mmol) in DMF (20 mL) was treated with TBDMSCl (611 mg, 4 mmol) for 3 h at 40° C. The resulting solution was then cooled to room temperature, quenched by satd. aqueous NaHCO3 (50 mL) solution, extracted with DCM (3×20 mL), washed with brine (3×10 mL), dried over anhydrous MgSO4, and concentrated under vacuum to give a residue, which was purified by a silica gel column, eluted with 5%10% EtOAc in petroleum ether to afford tert-butyl(3 aR,5S,6R,7R,7aR)-7-(tert-butyldimethylsilyloxy)-5-(difluoromethyl)-6-hydroxy-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-2-yl(ethyl)carbamate as a light yellow syrup (420 mg, 64%). (ES, m/z): [M+1]+ 483.0; 1H NMR (300 MHz, CDCl3) δ 5.87 (d, J=5.4 Hz, 1H), 5.98 (td, J=55.2 Hz, 3.6 Hz, 1H), 4.10-3.91 (m, 5H), 3.77-3.70 (m, 1H), 1.56 (s, 9H), 1.21 (t, J=6.9 Hz, 3H), 0.94 (s, 9H), 0.19 (s, 3H), 0.15 (s, 3H).
Reaction SMILES: [Si]([O:8][C:9]1[CH:10]=[C:11]([C:15]2([CH2:34][CH2:35][CH2:36][NH:37][C:38](=[O:44])[O:39][C:40]([CH3:43])([CH3:42])[CH3:41])[N:19]([C:20]3[S:21][C:22]([CH3:25])=[N:23][N:24]=3)[N:18]=[C:17]([C:26]3[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:27]=3[F:33])[S:16]2)[CH:12]=[CH:13][CH:14]=1)(C(C)(C)C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[F:33][C:27]1[CH:28]=[CH:29][C:30]([F:32])=[CH:31][C:26]=1[C:17]1[S:16][C:15]([CH2:34][CH2:35][CH2:36][NH:37][C:38](=[O:44])[O:39][C:40]([CH3:43])([CH3:42])[CH3:41])([C:11]2[CH:12]=[CH:13][CH:14]=[C:9]([OH:8])[CH:10]=2)[N:19]([C:20]2[S:21][C:22]([CH3:25])=[N:23][N:24]=2)[N:18]=1
Reactant: Cc1nnc(N2N=C(c3cc(F)ccc3F)SC2(CCCNC(=O)OC(C)(C)C)c2cccc(O[Si](C)(C)C(C)(C)C)c2)s1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: Cc1nnc(N2N=C(c3cc(F)ccc3F)SC2(CCCNC(=O)OC(C)(C)C)c2cccc(O)c2)s1
Temperature: 0 °C
Yield: 82.4 %

Procedure:
t-Butyl 3-(2-(3-(tert-butyldimethylsilyloxy)phenyl)-5-(2,5-difluorophenyl)-3-(5-methyl-1,3,4-thiadiazol-2-yl)-2,3-dihydro-1,3,4-thiadiazol-2-yl)propylcarbamate (75 mg, 0.113 mmol) was weighed into a 25 mL flask and dissolved in 10.0 mL of THF, then cooled to 0° C. TBAF (0.39 mL, 0.39 mmol) was added dropwise and the reaction mixture was allowed to warm to room temperature overnight. The reaction mixture was concentrated to dryness, then re-dissolved in DCM, washed with saturated NaHCO3 solution, dried over Na2SO4, and concentrated in vacuo. The residue was purified by removal of tributylamine via successive washes with 1N HCl. The organic layer was concentrated in vacuo, and the yellow oil subject to purification by flash column chromatography (25-60% ethyl acetate/hexanes) to afford the desired product (51 mg, 82% yield) as a yellow foam.