Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[S:5][C:4]([C:12]2[N:17]=[C:16]([CH2:18][CH2:19][C:20]([N:22]3[CH2:26][CH2:25][CH2:24][CH:23]3[C:27]([O:29]C(C)(C)C)=[O:28])=[O:21])[CH:15]=[CH:14][CH:13]=2)=[N:3]1.C(OC(C)C)(C)C>FC(F)(F)C(O)=O>[O:1]=[C:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[S:5][C:4]([C:12]2[N:17]=[C:16]([CH2:18][CH2:19][C:20]([N:22]3[CH2:26][CH2:25][CH2:24][C@H:23]3[C:27]([OH:29])=[O:28])=[O:21])[CH:15]=[CH:14][CH:13]=2)=[N:3]1
Reactant: CC(C)(C)OC(=O)C1CCCN1C(=O)CCc1cccc(-c2nc(=O)c3ccccc3s2)n1
Solvent: O=C(O)C(F)(F)F
Solvent: CC(C)OC(C)C
Product: O=C(O)[C@@H]1CCCN1C(=O)CCc1cccc(-c2nc(=O)c3ccccc3s2)n1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 46.7 %

Procedure:
tert-Butyl 1-{3-[6-(4-oxo-4H-1,3-benzothiazin-2-yl)-2-pyridyl]propanoyl}-2-pyrrolidinecarboxylate (0.25 g, 0.68 mmol) was dissolved in trifluoroacetic acid (2 ml), and the mixture was stirred at room temperature for 2.5 hrs. Isopropyl ether was added to the reaction mixture to precipitate crystals, which were collected by filtration and recrystallized from ethanol-hexane to give the titled compound (0.13 g, 45%) as white crystals.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:29]=[CH:28][C:10]2[C:11]([CH2:14][O:15][C:16]3[CH:24]=[CH:23][CH:22]=[C:21]4[C:17]=3[CH:18]=[C:19]([C:25]([OH:27])=O)[NH:20]4)=[CH:12][O:13][C:9]=2[CH:8]=1.[NH2:30][CH:31]1[CH2:36][CH2:35][C:34]([CH2:38][CH2:39][N:40]2[CH2:45][CH2:44][C@H:43]([OH:46])[C@@H:42]([CH3:47])[CH2:41]2)([OH:37])[CH2:33][CH2:32]1>>[OH:37][C:34]1([CH2:38][CH2:39][N:40]2[CH2:45][CH2:44][C@H:43]([OH:46])[C@@H:42]([CH3:47])[CH2:41]2)[CH2:35][CH2:36][CH:31]([NH:30][C:25]([C:19]2[NH:20][C:21]3[C:17]([CH:18]=2)=[C:16]([O:15][CH2:14][C:11]2[C:10]4[CH:28]=[CH:29][C:7]([O:6][CH2:5][CH2:4][CH2:3][O:2][CH3:1])=[CH:8][C:9]=4[O:13][CH:12]=2)[CH:24]=[CH:23][CH:22]=3)=[O:27])[CH2:32][CH2:33]1
Reactant: C[C@H]1CN(CCC2(O)CCC(N)CC2)CC[C@@H]1O
Reactant: COCCCOc1ccc2c(COc3cccc4[nH]c(C(=O)O)cc34)coc2c1
Product: COCCCOc1ccc2c(COc3cccc4[nH]c(C(=O)NC5CCC(O)(CCN6CC[C@H](O)[C@@H](C)C6)CC5)cc34)coc2c1

Procedure:
This compound is synthesized analogously to example 1 from 4-[6-(3-methoxy-propoxy)-benzofuran-3-ylmethoxy]-1H-indole-2-carboxylic acid 30f and amine 14.
Reaction SMILES: [NH2:1][CH2:2][C:3]([N:5]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:4].[CH3:18][O:19][C:20]1[CH:21]=[C:22]([N:26]=[C:27]=[O:28])[CH:23]=[CH:24][CH:25]=1>>[CH3:18][O:19][C:20]1[CH:21]=[C:22]([NH:26][C:27](=[O:28])[NH:1][CH2:2][C:3]([N:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)=[O:4])[CH:23]=[CH:24][CH:25]=1
Reactant: NCC(=O)N(c1ccccc1)c1ccccc1
Reactant: COc1cccc(N=C=O)c1
Product: COc1cccc(NC(=O)NCC(=O)N(c2ccccc2)c2ccccc2)c1
Yield: 79.5 %

Procedure:
Working in a manner similar to that described in Example 1, but starting with 2-amino-N,N-diphenylacetamide (2 g) and 3-methoxyphenyl isocyanate (1.3 g), and after recrystallization in acetonitrile, 2-[3-(3-methoxyphenyl)ureido]-N,N-diphenylacetamide (2.6 g), m.p. 182° C., is obtained.
Reaction SMILES: [Cl:1][C:2]1[O:3][C:4]([CH2:14][CH2:15][C:16](OCC)=[O:17])=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=2)[N:6]=1.[H-].C([Al+]CC(C)C)C(C)C>O1CCCC1.C1(C)C=CC=CC=1>[Cl:1][C:2]1[O:3][C:4]([CH2:14][CH2:15][CH2:16][OH:17])=[C:5]([C:7]2[CH:8]=[CH:9][C:10]([Cl:13])=[CH:11][CH:12]=2)[N:6]=1
Reactant: CCOC(=O)CCc1oc(Cl)nc1-c1ccc(Cl)cc1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: OCCCc1oc(Cl)nc1-c1ccc(Cl)cc1
Temperature: -78 °C
Yield: 89.8 %

Procedure:
Ethyl 2-chloro-4-(4-chlorophenyl)-5-oxazolepropionate (9.00 g) was dissolved in tetrahydrofuran (100 ml), the solution was cooled to −78° C., and a 1 N solution of diisobutylaluminum hydride in toluene (65 ml) was added dropwise with stirring. After completion of the dropping, the cooling bath was removed to raise the inner temperature to −20° C. Sodium sulfate decahydrate (10.0 g) was added to the reaction mixture, and the temperature was raised to room temperature. The reaction mixture was filtered, and the residue on the filter paper was washed with ethyl acetate. The filtrate was concentrated to give crystals of 2-chloro-4-(4-chlorophenyl)-5-oxazolepropanol (7.00 g, 86%).
Reaction SMILES: [NH2:1][C@H:2]([C:8]([NH:10][C@H:11]([C:19]([N:21]1[CH2:109][CH2:108][CH2:107][C@H:22]1[C:23]([NH:25][C@H:26]([C:34]([NH:36][C@H:37]([C:42]([NH:44][C@H:45]([C:48]([NH:50][C@H:51]([C:58]([NH:60][C@H:61]([C:67]([NH:69][CH2:70][C:71]([N:73]1[CH2:106][CH2:105][CH2:104][C@H:74]1[C:75]([NH:77][C@H:78]([C:83]([N:85]1[CH2:103][CH2:102][CH2:101][C@H:86]1[C:87]([NH:89][C@H:90]([C:98]([OH:100])=[O:99])[CH2:91][C:92]1[CH:97]=[CH:96][CH:95]=[CH:94][CH:93]=1)=[O:88])=[O:84])[CH2:79][CH2:80][S:81][CH3:82])=[O:76])=[O:72])=[O:68])[CH2:62][CH2:63][CH2:64][CH2:65][NH2:66])=[O:59])[CH2:52][C:53]1[N:57]=[CH:56][NH:55][CH:54]=1)=[O:49])[CH2:46][OH:47])=[O:43])[CH2:38][CH:39]([CH3:41])[CH3:40])=[O:35])[CH2:27][CH2:28][CH2:29][NH:30][C:31](=[NH:33])[NH2:32])=[O:24])=[O:20])[CH2:12][CH2:13][CH2:14][NH:15][C:16](=[NH:18])[NH2:17])=[O:9])[CH2:3][CH2:4][C:5](=[O:7])[NH2:6].[NH:110]([C:132]([O:134]C(C)(C)C)=O)[C@H:111]([C:129]([OH:131])=O)[CH2:112][CH2:113][CH2:114][NH:115][C:116](=[NH:128])[NH:117]S(C1C=CC(C)=CC=1)(=O)=O>>[NH2:10][C@H:11]([C:132]([NH:110][C@H:111]([C:129]([NH:1][C@H:2]([C:8]([NH:10][C@H:11]([C:19]([N:21]1[CH2:109][CH2:108][CH2:107][C@H:22]1[C:23]([NH:25][C@H:26]([C:34]([NH:36][C@H:37]([C:42]([NH:44][C@H:45]([C:48]([NH:50][C@H:51]([C:58]([NH:60][C@H:61]([C:67]([NH:69][CH2:70][C:71]([N:73]1[CH2:106][CH2:105][CH2:104][C@H:74]1[C:75]([NH:77][C@H:78]([C:83]([N:85]1[CH2:103][CH2:102][CH2:101][C@H:86]1[C:87]([NH:89][C@H:90]([C:98]([OH:100])=[O:99])[CH2:91][C:92]1[CH:93]=[CH:94][CH:95]=[CH:96][CH:97]=1)=[O:88])=[O:84])[CH2:79][CH2:80][S:81][CH3:82])=[O:76])=[O:72])=[O:68])[CH2:62][CH2:63][CH2:64][CH2:65][NH2:66])=[O:59])[CH2:52][C:53]1[N:57]=[CH:56][NH:55][CH:54]=1)=[O:49])[CH2:46][OH:47])=[O:43])[CH2:38][CH:39]([CH3:41])[CH3:40])=[O:35])[CH2:27][CH2:28][CH2:29][NH:30][C:31](=[NH:32])[NH2:33])=[O:24])=[O:20])[CH2:12][CH2:13][CH2:14][NH:15][C:16](=[NH:17])[NH2:18])=[O:9])[CH2:3][CH2:4][C:5](=[O:7])[NH2:6])=[O:131])[CH2:112][CH2:113][CH2:114][NH:115][C:116](=[NH:128])[NH2:117])=[O:134])[CH2:12][CH2:13][CH2:14][NH:15][C:16](=[NH:17])[NH2:18]
Reactant: CSCC[C@H](NC(=O)[C@@H]1CCCN1C(=O)CNC(=O)[C@H](CCCCN)NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@H](CO)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCNC(=N)N)NC(=O)[C@@H]1CCCN1C(=O)[C@H](CCCNC(=N)N)NC(=O)[C@@H](N)CCC(N)=O)C(=O)N1CCC[C@H]1C(=O)N[C@@H](Cc1ccccc1)C(=O)O
Reactant: Cc1ccc(S(=O)(=O)NC(=N)NCCC[C@H](NC(=O)OC(C)(C)C)C(=O)O)cc1
Product: CSCC[C@H](NC(=O)[C@@H]1CCCN1C(=O)CNC(=O)[C@H](CCCCN)NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@H](CO)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCNC(=N)N)NC(=O)[C@@H]1CCCN1C(=O)[C@H](CCCNC(=N)N)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CCCNC(=N)N)NC(=O)[C@@H](N)CCCNC(=N)N)C(=O)N1CCC[C@H]1C(=O)N[C@@H](Cc1ccccc1)C(=O)O

Procedure:
The resin of Example 26 was further condensed with Boc-Arg(Tos) two times, followed by the same treatment and purification procedure, to give 17 mg of a white powder.
Reaction SMILES: [CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([CH2:10][CH2:11][CH:12]([CH:14]3[CH2:16][CH2:15]3)O)=[CH:4][C:3]=2[O:2]1.P(Br)(Br)[Br:18].[Br-].[Li+]>[Br-].[Zn+2].[Br-]>[CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([CH2:10][CH2:11][CH:12]=[CH:14][CH2:15][CH2:16][Br:18])=[CH:4][C:3]=2[O:2]1
Reactant: BrP(Br)Br
Reactant: OC(CCc1ccc2c(c1)OCO2)C1CC1
Agent: [Br-]
Agent: [Li+]
Agent: [Zn+2]
Product: BrCCC=CCCc1ccc2c(c1)OCO2

Procedure:
6-(3,4-Methylenedioxyphenyl)-3-hexenyl bromide [V; Ar is 3,4-methylenedioxyphenyl, R is H] was prepared from 11.5 g. of 2-(3,4-methylenedioxyphenyl)ethyl cyclopropyl carbinol (Preparation B2), 12 g. of phosphorus tribromide, 10 g. of lithium bromide and 12.7 g. of zinc bromide according to the procedure given above in Preparation C1,affording 12.5 g. of product as an oil.
Reaction SMILES: Br[C:2]1[CH:32]=[CH:31][CH:30]=[CH:29][C:3]=1[CH2:4][N:5]1[C:9]2([CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[C:8](=[O:15])[N:7]([C:16]2[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[C:18]([C:24]([F:27])([F:26])[F:25])[CH:17]=2)[C:6]1=[O:28].[NH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>>[O:28]=[C:6]1[N:7]([C:16]2[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[C:18]([C:24]([F:26])([F:25])[F:27])[CH:17]=2)[C:8](=[O:15])[C:9]2([CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[N:5]1[CH2:4][C:3]1[CH:29]=[CH:30][CH:31]=[CH:32][C:2]=1[NH:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: N#Cc1ccc(N2C(=O)N(Cc3ccccc3Br)C3(CCCCC3)C2=O)cc1C(F)(F)F
Reactant: Nc1ccccc1
Product: N#Cc1ccc(N2C(=O)N(Cc3ccccc3Nc3ccccc3)C3(CCCCC3)C2=O)cc1C(F)(F)F

Procedure:
To prepare the compound of example 28, the procedure may be according to process “A”. Analogously to the process described in example 1.2, 28.2 and aniline were reacted. 28: Molecular weight 518.19 (C29H25F3N4O2); retention time Rt=3.19 min. [C]; MS (ESI): 519.24 (MH+).
Reaction SMILES: [OH:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[O:26][CH3:27])=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:28]([O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[O:29])[CH2:3]1.[Br:38][C:39]1[CH:46]=[CH:45][CH:44]=[CH:43][C:40]=1[CH2:41]Br>>[Br:38][C:39]1[CH:46]=[CH:45][CH:44]=[CH:43][C:40]=1[CH2:41][O:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[O:26][CH3:27])=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:28]([O:30][CH2:31][C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)=[O:29])[CH2:3]1
Reactant: BrCc1ccccc1Br
Reactant: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OCc3ccccc3)CC2O)cc1
Product: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OCc3ccccc3)CC2OCc2ccccc2Br)cc1

Procedure:
Analogously to Method D, 3.0 g of benzyl 3-hydroxy-4-{4-[3-(2-methoxybenzyloxy)propoxy]-phenyl}piperidine-1-carboxylate (Example 10f) and 2-bromobenzyl bromide are reacted. The title compound is obtained as a colourless oil. Rf=0.58 (1:1 EtOAc-heptane); Rt=6.36.
Reaction SMILES: [Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.[OH:12][CH2:13][C:14]1[C:19]2[CH:20]=[CH:21][O:22][C:18]=2[C:17]([NH:23][S:24]([CH3:27])(=[O:26])=[O:25])=[CH:16][CH:15]=1>ClCCl>[CH:13]([C:14]1[C:19]2[CH:20]=[CH:21][O:22][C:18]=2[C:17]([NH:23][S:24]([CH3:27])(=[O:26])=[O:25])=[CH:16][CH:15]=1)=[O:12]
Reactant: CS(=O)(=O)Nc1ccc(CO)c2ccoc12
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CS(=O)(=O)Nc1ccc(C=O)c2ccoc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 86.1 %

Procedure:
Pyridinium chlorochromate (7.55 g, 35.0 mmole) was added into a solution of N-(4-hydroxymethyl-benzofuran-7-yl)-methanesulfonamide (5.69 g, 23.3 mmole) in dichloromethane (350 mL). The reaction mixture was stirred at room temperature for 16 hr and was partitioned between dichloromethane and water. The organic extract was dried (anhydrous sodium sulfate) and concentrated under reduced pressure. The residue was purified by flash column chromatography over silica gel eluting with 50% ethyl acetate in hexane to give N-(4-formyl-benzofuran-7-yl)-methanesulfonamide as solid (4.8 g, 86%). 1H NMR (DMSO-d6) δ: 3.26 (s, 3H), 7.48 (d, 1H, J=8.20 Hz), 7.51 (d, 1H, J=2.10 Hz), 7.88 (d, 1H, J=8.20 Hz), 8.29 (d, 1H, J=2.1 Hz), 10.12 (s, 1H), 10.63 (s, 1H). M−H: 238.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[SH:8].CC(C)([O-])C.[K+].[CH3:15][O:16][CH:17]([O:20][CH3:21])[CH2:18]Cl.O>C1COCC1>[CH3:15][O:16][CH:17]([O:20][CH3:21])[CH2:18][S:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[F:1]
Reactant: COC(CCl)OC
Reactant: Fc1ccccc1S
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: COC(CSc1ccccc1F)OC
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
2-Fluorothiophenol (4.14 g, 32.6 mmol) was dissolved in anhydrous THF (100 mL). Potassium tert-butoxide (1.0 M in THF, 35.8 mL) was added and the suspension was stirred at room temperature for 15 minutes. 2-Chloroacetaldehyde dimethyl acetal was added and the mixture was stirred for 3 days. Water (100 mL) was added and the solution was extracted with diethyl ether (3×100 mL). The extracts were concentrated to a yellow oil and chromatographed (5 to 20% ethyl acetate in hexane) to yield 1-(2,2-dimethoxy-ethylsulfanyl)-2-fluoro-benzene (6.42 g) as a colorless oil. Chlorobenzene (25 mL) was heated to reflux and polyphosphoric acid (1 mL) was added. The 1-(2,2-dimethoxy-ethylsulfanyl)-2-fluoro-benzene was then added slowly turning the solution dark. After 3 hours of heating, the reaction was cooled to room temperature and diluted with water (50 mL). The solution was extracted with benzene (2×50 mL). The extracts were concentrated and chromatographed (0 to 15% ethyl acetate in hexane) to yield 7-fluorobenzothiophenyl (0.77 g). The 7-fluorobenzothiophenyl (0.77 g, 5.1 mmol) and dichloromethyl methyl ether (0.872 g, 7.6 mmol) were dissolved in anhydrous DCM (25 mL). Titanium tetrachloride (1.0 M in DCM, 7.6 mL, 7.6 mmol) was added, turning the solution dark. After 30 minutes at room temperature, the reaction was poured into a mixture of saturated aqueous NaHCO3 and ice. The mixture was stirred for about 30 minutes and then was extracted with DCM (2×50 mL). The extracts were concentrated and chromatographed (0 to 15% ethyl acetate in hexane) to yield 7-fluorobenzothiophene-3-carboxaldehyde (0.642 g). The 7-fluorobenzothiophene-3-carboxaldehyde (0.642 g, 3.77 mmol) and sulfamide (1.7 g, 18 mmol) were combined in anhydrous ethanol (20 mL) and heated to reflux for three days. The reaction was cooled to room temperature and sodium borohydride (0.148 g, 3.92 mmol) was added. After two hours, water (25 ml) was added and the solution was extracted with chloroform (3×25 mL). The extracts were concentrated, suspended in a minimal amount of DCM, and filtered to yield the title compound as a yellow solid.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([C:24]3[CH:29]=[CH:28][N:27]=[C:26](Cl)[N:25]=3)[CH:19]=2)[CH2:15][CH3:16])[CH2:10][CH2:9]1)=O)(C)(C)C.[N:31]1[CH:36]=[CH:35][C:34]([CH2:37][CH2:38][NH2:39])=[CH:33][CH:32]=1>>[CH2:15]([N:14]([CH2:17][C:18]1[CH:19]=[C:20]([C:24]2[CH:29]=[CH:28][N:27]=[C:26]([NH:39][CH2:38][CH2:37][C:34]3[CH:35]=[CH:36][N:31]=[CH:32][CH:33]=3)[N:25]=2)[CH:21]=[CH:22][CH:23]=1)[CH:11]1[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1)[CH3:16]
Reactant: CCN(Cc1cccc(-c2ccnc(Cl)n2)c1)C1CCN(C(=O)OC(C)(C)C)CC1
Reactant: NCCc1ccncc1
Product: CCN(Cc1cccc(-c2ccnc(NCCc3ccncc3)n2)c1)C1CCNCC1

Procedure:
Intermediate 84 was coupled with 2-Pyridin-4-yl-ethylamine following procedure F. The resulting product was deprotected following procedure G. LC-MS showed the product had the expected M+H+ of 417. 1H NMR (Varian 300 MHz, CD3OD, shifts relative to the solvent peak at 3.30 ppm) δ 8.72 (d, 2H) 88.3-8.5 (m, 2H) 8.06 (d, 2H) 7.88 (d, 1H) 7.72 (m, 1H) 7.58 (d, 1H) 4.59 (d, 2H) 4.12 (br s, 2H) 3.85 (m, 1H) 3.62 (m, 2H) 3.1-3.45 (m, 6H) 2.48 (m, 2H) 2.18-2.24 (m, 2H) 1.35 (t, 3H).
Reaction SMILES: [OH:1][C:2]1[C:11]2[N:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:5]([CH:12]=[O:13])=[CH:4][CH:3]=1.C[O-].[Na+].S(OC)(O[CH3:21])(=O)=O>CS(C)=O>[CH3:21][O:1][C:2]1[C:11]2[N:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:5]([CH:12]=[O:13])=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(O)c2ncccc12
Reactant: COS(=O)(=O)OC
Agent: C[O-]
Agent: [Na+]
Solvent: CS(C)=O
Product: COc1ccc(C=O)c2cccnc12
Reaction time: 0.08 h
Yield: 74.2 %

Procedure:
To a solution of 0.76 g (4.39 mmol) of 8-hydroxyquinoline-5-carboxaldehyde (G. R. Clemo and R. Howe, J. Chem. Soc., 1955, 3552) in 5 mL of dimethyl sulfoxide was added 0.24 g (4.4 mmol) of sodium methoxide, while keeping the mixture under nitrogen. After stirring for 5 min, 0.56 g (4.4 mmol) of dimethyl sulfate was added. The reaction was stirred for 1 hr and the solvent removed under vacuum. The residue was partitioned between dichloromethane (100 mL) and 0.5N sodium hydroxide (50 mL); the organic layer was washed with water (100 mL), dried over anhydrous magnesium sulfate, and concentrated to give 0.61 g (74%) of 8-methoxyquinoline-5-carboxaldehyde, mp 121°-122° after recrystallization from ethanol-hexane (2:25). Anal. Calcd for C11H9NO2 : C, 70.58; H, 4.85; N, 7.48. Found: C, 70.55; H, 4.91; N, 7.44.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[CH:5][N:4]=1.C(O[CH:13]=[C:14]([C:20](=[O:23])[CH2:21][CH3:22])[C:15]([O:17][CH2:18][CH3:19])=[O:16])C>>[CH3:1][O:2][C:3]1[N:4]=[CH:5][C:6]([NH:9][CH:13]=[C:14]([C:20](=[O:23])[CH2:21][CH3:22])[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:7][CH:8]=1
Reactant: CCOC=C(C(=O)CC)C(=O)OCC
Reactant: COc1ccc(N)cn1
Product: CCOC(=O)C(=CNc1ccc(OC)nc1)C(=O)CC

Procedure:
Ethyl 2-(((6-methoxypyridin-3-yl)amino)methylene)-3-oxopentanoate was prepared with conditions described in Example 99 using 2-methoxy-5-aminopyridine and ethyl 2-(ethoxymethylene)-3-oxopentanoate.
Reaction SMILES: C([O:4][C:5]1[CH:6]=[C:7]([CH:15]([CH3:21])[C:16]([O:18]CC)=O)[CH:8]=[CH:9][C:10]=1[O:11]C(=O)C)(=O)C.[NH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[C:23]1([NH:22][C:16](=[O:18])[CH:15]([C:7]2[CH:8]=[CH:9][C:10]([OH:11])=[C:5]([OH:4])[CH:6]=2)[CH3:21])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CCOC(=O)C(C)c1ccc(OC(C)=O)c(OC(C)=O)c1
Reactant: Nc1ccccc1
Product: CC(C(=O)Nc1ccccc1)c1ccc(O)c(O)c1

Procedure:
Ethyl 3,4-diacetoxyphenylpropionate and aniline were used to obtain N-Phenyl-3,4-dihydroxyphenylpropionamide by carrying out the same procedures as described in Example 1 as an oily product.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9](O)=[O:10])=[CH:7][C:6]=1[CH3:14])([CH3:3])[CH3:2].S(Cl)([Cl:17])=O>C(Cl)(Cl)Cl>[CH:1]([O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([Cl:17])=[O:10])=[CH:7][C:6]=1[CH3:14])([CH3:3])[CH3:2]
Reactant: O=S(Cl)Cl
Reactant: Cc1cc(C(=O)O)ccc1OC(C)C
Solvent: ClC(Cl)Cl
Product: Cc1cc(C(=O)Cl)ccc1OC(C)C

Procedure:
To a solution of 4-isopropoxy-3-methyl-benzoic acid (1.35 g, 6.95 mmol) in chloroform (20 mL), thionylchloride (2.48 g, 20.9 mmol) is added. The mixture is refluxed for 2 h before the solvents are removed in vacuo to give crude 4-isopropoxy-3-methyl-benzoic acid chloride; LC-MS: tR=1.00 min.
Reaction SMILES: [O:1]1[CH2:18][CH:2]1[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH2:12][CH2:13][C:14](=[O:17])[NH:15][N:16]=2)=[CH:7][CH:6]=1.[CH:19]([NH2:22])([CH3:21])[CH3:20]>CO>[OH:1][CH:2]([CH2:18][NH:22][CH:19]([CH3:21])[CH3:20])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH2:12][CH2:13][C:14](=[O:17])[NH:15][N:16]=2)=[CH:7][CH:6]=1
Reactant: O=C1CCC(c2ccc(OCC3CO3)cc2)=NN1
Reactant: CC(C)N
Solvent: CO
Product: CC(C)NCC(O)COc1ccc(C2=NNC(=O)CC2)cc1
Yield: 99.9 %

Procedure:
A mixture of the 6-[4-(2,3-epoxypropoxy)phenyl]-4,5dihydro-3(2H)-pyridazinone (38.37 g, 0.156 mole), isopropylamine (80 ml, 0.94 mole), and methanol (380 ml) was stirred under reflux for one hour, and then evaporated under reduced pressure to give 6-[4-(2-hydroxy-3-isopropylaminopropoxy)phenyl]-4,5-dihydro-3(2H)-pyridazinone (47.59 g, 100%), m.p. 108°-113° C. The hydrochloride, crystallised from a mixture of 2-propanol, ethanol and ether, had m.p. 195°-200° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[C@H:7]2[CH2:8][C@@H:3]1[CH2:4][CH2:5][C@@H:6]2[CH2:9][OH:10].[H-].[Na+].[F:14][C:15]1[CH:22]=[CH:21][CH:20]=[C:19](F)[C:16]=1[C:17]#[N:18]>CN(C)C=O>[F:14][C:15]1[CH:22]=[CH:21][C:20]([O:10][CH2:9][C@H:6]2[CH2:5][CH2:4][C@H:3]3[CH2:8][C@@H:7]2[C:2]3([CH3:11])[CH3:1])=[CH:19][C:16]=1[C:17]#[N:18]
Reactant: N#Cc1c(F)cccc1F
Reactant: CC1(C)[C@H]2CC[C@H](CO)[C@@H]1C2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1(C)[C@H]2CC[C@H](COc3ccc(F)c(C#N)c3)[C@@H]1C2
Temperature: 25 °C
Reaction time: 1 h
Yield: 76.8 %

Procedure:
A solution of (1S,2S,5S)-(−)-myrtanol (1.0 g, 6.48 mmol) in dimethylformamide was added to a cooled (0° C.) slurry of sodium hydride (310 mg, 7.78 mmol) in dimethylformamide under nitrogen atmosphere. The reaction mixture was slowly warmed to room temperature, stirred for 1 hour. Again, cooled (0° C.), then a solution of 2,6-difluorobenzonitrile (1.08 g, 7.78 mmol) in dimethylfomamide was added, stirred overnight at room temperature. The reaction mixture was poured on crushed-ice water, stirred. The reaction mixture was extracted with ethyl acetate, dried, filtered and concentrated. Purification by silica gel chromatography (1:1 hexanes in dichloromethane) yielded 1.36 g of 2-fluoro-5-((1S,2S,5S)-6,6-dimethylbicyclo[3.1.1]hept-2-ylmethoxy)benzonitrile.
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([C:7]([OH:9])=O)=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([NH2:25])=[CH:21][C:20]=1[N:26]1[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]1>S(Cl)(Cl)=O>[Br:1][C:2]1[S:6][C:5]([C:7]([NH:25][C:22]2[CH:23]=[CH:24][C:19]([O:18][CH3:17])=[C:20]([N:26]3[CH2:27][CH2:28][N:29]([CH3:32])[CH2:30][CH2:31]3)[CH:21]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccc(Br)s1
Reactant: COc1ccc(N)cc1N1CCN(C)CC1
Solvent: CCN(CC)CC
Solvent: O=S(Cl)Cl
Product: COc1ccc(NC(=O)c2ccc(Br)s2)cc1N1CCN(C)CC1
Reaction time: 18 h

Procedure:
5-Bromo-2-thiophenecarboxylic acid (0.375;1.8 mmol) was heated at reflux in thionyl chloride (8 ml) for 30 minutes, cooled, evaporated in vacuo and the residue azeotroped with toluene. The residue was redissolved in CH2Cl2 (10 ml) and treated with dry triethylamine (0.25 ml;1.81 mmol) and 4-methoxy-3-(4-methyl-1-piperazinyl)benzenamine (0.4 g;1.81 mmol). The solution was stirred under Ar (18 hours), evaporated in vacuo and partitioned satd. K2CO3 (aq)/EtOAc. The organic phases were combined, dried over Na2SO4, filtered and the filtrate evaporated in vacuo to a brown gum. The gum was purified by flash silica-gel chromatography and eluted with 3%MeOH/CHCl3 to yield the title compound as a brown gum which crystallised on standing (0.388 g;52%), and was converted to the oxalate salt, mp=114°-115° C.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[C:3]=1[C:4]([OH:6])=O.[NH2:12][CH2:13][CH2:14][CH2:15][C@H:16]1[O:20][C:19](=[O:21])[N:18]([C:22]2[CH:23]=[CH:24][C:25]3[S:30][CH2:29][C:28](=[O:31])[NH:27][C:26]=3[CH:32]=2)[CH2:17]1>>[NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[C:3]=1[C:4]([NH:12][CH2:13][CH2:14][CH2:15][C@H:16]1[O:20][C:19](=[O:21])[N:18]([C:22]2[CH:23]=[CH:24][C:25]3[S:30][CH2:29][C:28](=[O:31])[NH:27][C:26]=3[CH:32]=2)[CH2:17]1)=[O:6]
Reactant: Nc1cccc(Cl)c1C(=O)O
Reactant: NCCC[C@@H]1CN(c2ccc3c(c2)NC(=O)CS3)C(=O)O1
Product: Nc1cccc(Cl)c1C(=O)NCCC[C@@H]1CN(c2ccc3c(c2)NC(=O)CS3)C(=O)O1
Yield: 46 %

Procedure:
Starting from 2-amino-6-chlorobenzoic acid and 6-[(R)-5-(3-amino-propyl)-2-oxo-oxazolidin-3-yl]-4H-benzo[1,4]thiazin-3-one (described in WO 2010/041219) and using Procedure D, the title compound was obtained as a beige solid (100 mg; 46% yield).
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[NH:16][C:15](=[O:17])[C:14]([C:18]([OH:20])=[O:19])=[CH:13][CH:12]=1)[CH2:2][CH3:3].[CH3:21]O>S(=O)(=O)(O)O.C(Cl)(Cl)Cl>[CH2:1]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[NH:16][C:15](=[O:17])[C:14]([C:18]([O:20][CH3:21])=[O:19])=[CH:13][CH:12]=1)[CH2:2][CH3:3]
Reactant: CCCOc1ccccc1-c1ccc(C(=O)O)c(=O)[nH]1
Reactant: CO
Agent: O=S(=O)(O)O
Solvent: ClC(Cl)Cl
Product: CCCOc1ccccc1-c1ccc(C(=O)OC)c(=O)[nH]1

Procedure:
A stirred mixture of 6-(2-propoxyphenyl)-1,2-dihydro-2-oxopyridine-3-carboxylic acid, (0.9 g) dry methanol (30 ml) and 3 drops of concentrated sulphuric acid was heated under reflux for ca 24 hours. The cooled mixture was evaporated to yield a pale yellow solid which was dissolved in chloroform, extracted with dilute aqueous potassium carbonate (2×10 ml), washed with water and brine, dried (magnesium sulphate) and evaporated to yield a yellow solid, 0.8 g, m.p. 126°-7° C. This was recrystallised from aqueous methanol (20 ml) to yield the pure title compound, 0.65 g, m.p. 126.5°-127.5° C.