Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][CH3:11])=[CH:4][CH:3]=1.[CH3:12][C:13]([OH:17])([CH3:16])[C:14]#[CH:15]>C(N(CC)CC)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:12][C:13]([OH:17])([CH3:16])[C:14]#[C:15][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][CH3:11])=[CH:4][CH:3]=1
Reactant: C#CC(C)(C)O
Reactant: CCCCc1ccc(Br)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: CCCCc1ccc(C#CC(C)(C)O)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 41.9 %

Procedure:
1-Bromo-4-butylbenzene (235 g), 3-methyl-1-butyne-3-ol (139 g), triphenylphosphine (4.8 g) and bis(triphenylphosphine)palladium(II) chloride (2.8 g) were dissolved in triethylamine (1,000 ml), and then copper(I) iodide (0.8 g) was added thereto. After stirring at room temperature for 1 hour, the reaction mixture was further stirred at 90° C. for 5 hours. The resulting precipitated crystals were filtered, and then triethylamine was distilled off therefrom, followed by extracting with chloroform. The resultant was washed with 10% hydrochloric acid twice, and further with water twice, and then chloroform was distilled off therefrom. The residue was purified using silica gel-chloroform column chromatography to give 3-methyl-1-(4'-butylphenyl)-1-butyne-3-ol (100 g).
Reaction SMILES: [CH3:1][O:2][C:3]([N:5]=[C:6]=[S:7])=[O:4].[O:8]([S:15]([C:18]1[CH:19]=[CH:20][C:21]([NH:25][C:26]([NH2:28])=[O:27])=[C:22]([CH:24]=1)[NH2:23])(=[O:17])=[O:16])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>O1CCOCC1>[CH3:1][O:2][C:3]([NH:5][C:6]([NH:23][C:22]1[CH:24]=[C:18]([S:15]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)(=[O:16])=[O:17])[CH:19]=[CH:20][C:21]=1[NH:25][C:26]([NH2:28])=[O:27])=[S:7])=[O:4]
Reactant: COC(=O)N=C=S
Reactant: NC(=O)Nc1ccc(S(=O)(=O)Oc2ccccc2)cc1N
Solvent: C1COCCO1
Product: COC(=O)NC(=S)Nc1cc(S(=O)(=O)Oc2ccccc2)ccc1NC(N)=O

Procedure:
25 ml of methoxycarbonyl isothiocyanate are added dropwise to 23.5 g of 5-phenoxysulfonyl-2-ureidoaniline in 100 ml of dioxane, with stirring, the temperature rising to about 35° C. The mixture is stirred for a further four hours without cooling, the dioxane is distilled off, the residue is stirred with diisopropyl ether and the solid is filtered off with suction.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:12]([F:15])([F:14])[F:13])=[C:6]([S:8](Cl)(=[O:10])=[O:9])[CH:7]=1.[NH:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:12]([F:15])([F:14])[F:13])=[C:6]([S:8]([N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)(=[O:10])=[O:9])[CH:7]=1
Reactant: O=S(=O)(Cl)c1cc(Cl)ccc1C(F)(F)F
Reactant: C1COCCN1
Solvent: ClCCl
Product: O=S(=O)(c1cc(Cl)ccc1C(F)(F)F)N1CCOCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
5-Chloro-2-trifluoromethyl-benzenesulfonyl chloride (0.17 g, 0.62 mmol) is added to a solution of morphline (0.114 ml, 1.3 mol) in DCM (5 ml) and the resulting white suspension is stirred at room temperature overnight. The reaction mixture is diluted with DCM (5 ml), and washed with 0.1M HCl, dried (MgSO4) and concentrated in vacuo to yield the title compound. [M+H]+ 330.
Reaction SMILES: C(O)(=O)C.[F:5][C:6]([F:26])([F:25])[O:7][C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH2:18][CH2:17][C:16]3([CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)[C:15]2=[O:24])=[CH:10][CH:9]=1.[N:27]1[CH:32]=[CH:31][CH:30]=[C:29]([S:33](Cl)(=[O:35])=[O:34])[CH:28]=1.Cl>>[N:27]1[CH:32]=[CH:31][CH:30]=[C:29]([S:33]([N:21]2[CH2:20][CH2:19][C:16]3([C:15](=[O:24])[N:14]([C:11]4[CH:12]=[CH:13][C:8]([O:7][C:6]([F:5])([F:25])[F:26])=[CH:9][CH:10]=4)[CH2:18][CH2:17]3)[CH2:23][CH2:22]2)(=[O:35])=[O:34])[CH:28]=1
Reactant: O=S(=O)(Cl)c1cccnc1
Reactant: O=C1N(c2ccc(OC(F)(F)F)cc2)CCC12CCNCC2
Agent: Cl
Solvent: CC(=O)O
Product: O=C1N(c2ccc(OC(F)(F)F)cc2)CCC12CCN(S(=O)(=O)c1cccnc1)CC2

Procedure:
The title compound was prepared in analogy to example 180 step D from 2-(4-trifluoromethoxy-phenyl)-2,8-diaza-spiro[4.5]decan-1-one acetic acid salt (described in example 180 step C) and pyridine-3-sulfonyl chloride; hydrochloride. White solid. MS (ESI): 456.2 (MH+).
Reaction SMILES: [CH2:1]1[CH2:6][CH:5]([C:7]2([NH:20][C:21]([NH:23][C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([NH:30][C:31]4[NH:35][N:34]=[N:33][N:32]=4)[CH:25]=3)=[O:22])[N:13]=[CH:12][C:11]3[CH:14]=[CH:15][CH:16]=[CH:17][C:10]=3[N:9]([CH3:18])[C:8]2=[O:19])[CH2:4][CH2:3][CH2:2]1.N1C(NC2C=C(C=CC=2)N)=NN=N1>C(#N)C>[CH2:3]1[CH2:4][CH:5]([C@@:7]2([NH:20][C:21]([NH:23][C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([NH:30][C:31]4[NH:35][N:34]=[N:33][N:32]=4)[CH:25]=3)=[O:22])[N:13]=[CH:12][C:11]3[CH:14]=[CH:15][CH:16]=[CH:17][C:10]=3[N:9]([CH3:18])[C:8]2=[O:19])[CH2:6][CH2:1][CH2:2]1
Reactant: CN1C(=O)C(NC(=O)Nc2cccc(Nc3nnn[nH]3)c2)(C2CCCCC2)N=Cc2ccccc21
Agent: Nc1cccc(Nc2nnn[nH]2)c1
Solvent: CC#N
Product: CN1C(=O)[C@@](NC(=O)Nc2cccc(Nc3nnn[nH]3)c2)(C2CCCCC2)N=Cc2ccccc21

Procedure:
The title compound was prepared from Intermediate 3 and 3-[(tetrazol-5-yl)amino]aniline using a similar method to that described for Example 4, except that anhydrous acetonitrile was used as the reaction solvent; the crude product was purified by flash chromatography (silica gel, dichloromethane-methanol, 93:7 to 80:20) and recrystallized from methanol; mp 190°-193° C.; [α]D25 +8.4° (c=0.50, dimethylformamide); the spectroscopic properties (1H-NMR and MS spectra) of this material were identical to those described for its racemate (Example 2). (Found: C, 59.78; H, 5.98; N, 25.68.C24H27N9O2 ×0.6H2O requires: C, 59.52; H, 5.87; N, 26.03%).
Reaction SMILES: [O:1]1[C:5]([C:6]2[C:14]3[C:9](=[CH:10][CH:11]=[C:12]([C:15]([O:17]C)=[O:16])[CH:13]=3)[NH:8][N:7]=2)=[CH:4][C:3]2[CH:19]=[CH:20][CH:21]=[CH:22][C:2]1=2.[OH-].[Na+]>CO.O1CCCC1>[O:1]1[C:5]([C:6]2[C:14]3[C:9](=[CH:10][CH:11]=[C:12]([C:15]([OH:17])=[O:16])[CH:13]=3)[NH:8][N:7]=2)=[CH:4][C:3]2[CH:19]=[CH:20][CH:21]=[CH:22][C:2]1=2
Reactant: COC(=O)c1ccc2[nH]nc(-c3cc4ccccc4o3)c2c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1ccc2[nH]nc(-c3cc4ccccc4o3)c2c1
Temperature: 25 °C
Reaction time: 120 h
Yield: 122.2 %

Procedure:
To a solution of 275 mg of methyl 3-benzo[b]furan-2-yl-1H-5-indazolecarboxylate in 3 ml methanol and 3 ml tetrahydrofuran was added 1.5 ml of 5 N aqueous sodium hydroxide solution, and the mixture was stirred at room temperature for five days. After removing the solvent by distillation, the residue was added with 9 ml of 1 N hydrochloric acid, and the mixture was extracted with 200 ml of ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and the solvent was evaporated, to give 320 mg of the title compound as pale yellow crystals.
Reaction SMILES: C([O:14][C:15]([C:17]1[N:18]2[CH:21]([S:22][CH2:23][C:24]=1[CH:25]=[C:26]1[CH2:30][CH2:29][N:28]([CH:31]3[CH2:35][CH2:34][N:33]([C:36]([O:38][CH2:39][C:40]4[O:41][C:42](=[O:46])[O:43][C:44]=4[CH3:45])=[O:37])[CH2:32]3)[C:27]1=[O:47])[CH:20]([NH:48][C:49](=[O:78])[C:50]([C:72]1[N:76]=[C:75]([NH2:77])[S:74][N:73]=1)=[N:51][O:52]C(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[C:19]2=[O:79])=[O:16])(C1C=CC=CC=1)C1C=CC=CC=1.C([SiH](CC)CC)C>FC(F)(F)C(O)=O>[NH2:77][C:75]1[S:74][N:73]=[C:72](/[C:50](=[N:51]/[OH:52])/[C:49]([NH:48][C@@H:20]2[C:19](=[O:79])[N:18]3[C@@H:21]2[S:22][CH2:23][C:24](/[CH:25]=[C:26]2/[C:27](=[O:47])[N:28]([C@@H:31]4[CH2:35][CH2:34][N:33]([C:36]([O:38][CH2:39][C:40]5[O:41][C:42](=[O:46])[O:43][C:44]=5[CH3:45])=[O:37])[CH2:32]4)[CH2:29][CH2:30]/2)=[C:17]3[C:15]([OH:16])=[O:14])=[O:78])[N:76]=1
Reactant: Cc1oc(=O)oc1COC(=O)N1CCC(N2CCC(=CC3=C(C(=O)OC(c4ccccc4)c4ccccc4)N4C(=O)C(NC(=O)C(=NOC(c5ccccc5)(c5ccccc5)c5ccccc5)c5nsc(N)n5)C4SC3)C2=O)C1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: Cc1oc(=O)oc1COC(=O)N1CC[C@@H](N2CC/C(=C\C3=C(C(=O)O)N4C(=O)[C@@H](NC(=O)/C(=N\O)c5nsc(N)n5)[C@H]4SC3)C2=O)C1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 91.5 %

Procedure:
A mixture of 40 mg 7-[2-(5-amino-[1,2,4]thiadiazol-3-yl)-2-trityloxyimino-acetylamino]-3-[1′-(5-methyl-2-oxo-[1,3]dioxol-4-ylmethoxycarbonyl)-2-oxo-[1,3′]bipyrrolidinyl-3-ylidenemethyl]-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid benzhydryl ester and 20 mg triethylsilane is dissolved in 0.30 ml trifluoroacetic acid. The resulting solution is stirred at 0° C. for 15 min. The solvent is evaporated under aspirator vacuum and the residue is triturated with diethyl ether. The solid is collected by filtration and washed with diethyl ether to yield 23 mg of the title compound as beige powder. MS: M−H=689.3. 1H-NMR (d6-DMSO): 13.8 (s, 1H, COOH); 11.9 (s, 1H, OH); 9.45 (d, J=8.4, 1H, NH); 8.05 (s, 2H, NH2); 7.31(s, 1H, HC═C); 5.86 (dd, J=8.4; 4.8, 1H CH); 5.17 (d, J=8.4, 1H CH); 4.61 (m, 1H CH); 3.85 (m, 2H CH2); 3.55-3.35 (m, 6H 3×CH2); 3.1 (m, 1H); 2.9 (m, 1H); 2.15 (s, 3H, CH3); 2.05 (m, 2H CH2).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7]3([CH2:16][CH2:15][CH:14]([O:17][CH3:18])[CH2:13][CH2:12]3)[C:8]2=O)=[CH:4][C:3]=1[F:19].[CH3:20][C:21]([S:24]([NH2:26])=[O:25])([CH3:23])[CH3:22].O>CCOC(C)=O.[O-]CC.[Ti+4].[O-]CC.[O-]CC.[O-]CC>[Br:1][C:2]1[CH:10]=[C:9]2[C:5](=[CH:4][C:3]=1[F:19])[CH2:6][C:7]1([CH2:16][CH2:15][CH:14]([O:17][CH3:18])[CH2:13][CH2:12]1)[C:8]2=[N:26][S:24]([C:21]([CH3:23])([CH3:22])[CH3:20])=[O:25]
Reactant: COC1CCC2(CC1)Cc1cc(F)c(Br)cc1C2=O
Reactant: CC(C)(C)S(N)=O
Agent: [Ti+4]
Agent: CC[O-]
Solvent: O
Solvent: CCOC(C)=O
Product: COC1CCC2(CC1)Cc1cc(F)c(Br)cc1C2=NS(=O)C(C)(C)C
Temperature: 25 °C
Yield: 57 %

Procedure:
6′-Bromo-5′-fluoro-4-methoxyspiro[cyclohexane-1,2′-inden]-1′(3′H)-one (Intermediate 8, 2.0 g, 6.11 mmol), 2-methylpropane-2-sulfinamide (1.11 g, 9.17 mmol) and titanium ethoxide (2.52 mL, 12.2 mmol) were dissolved in 2-Me THF (31 mL) and heated to reflux for 48 h. The reaction was allowed to cool to r.t. whereafter it was diluted with EtOAc (75 mL). Water (25 mL) was added dropwise over 10 min under vigorous stirring and then the mixture was left standing without stirring for 1.5 h. The solids were filtered off and the organics were concentrated. The was purified by silica gel chromatography using a stepwise gradient of heptane/EtOAC (5:1-4:1-3:1-1:1), to give the title compound (1.5 g, 57% yield) as a diasteromer mixture in the ratio ˜4:1 (established by HPLC and NMR analysis) (1.50 g, 57% yield). The was used in the next step. 1H NMR (500 MHz, CDCl3, signals for both isomers) δ ppm 1.20-1.29 (m, 1 H) 1.30-1.41 (m, 14 H) 1.50-1.60 (m, 4 H) 1.60-1.68 (m, 1 H) 1.97-2.08 (m, 1 H) 2.08-2.20 (m, 2.5 H) 2.24-2.32 (m, 0.3 H) 2.95-3.02 (m, 2.5 H) 3.22-3.32 (m, 1 H) 3.35 (s, 0.9 H) 3.40 (s, 3 H) 3.48-3.53 (m, 0.3 H) 7.09-7.11 (m, 0.3 H) 7.13 (d, 1 H) 8.64-8.88 (m, 1 H); MS (ES+) m/z 430, 432 [M+H]+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[C:9]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=3[Cl:21])=[N:10][N:11]([CH3:13])[CH:12]=2)[CH:5]=[CH:4][N:3]=1.[CH3:22][O:23][C:24]1[CH:25]=[C:26]([NH2:32])[CH:27]=[CH:28][C:29]=1[O:30][CH3:31]>>[Cl:21][C:15]1[CH:16]=[C:17]([Cl:20])[CH:18]=[CH:19][C:14]=1[C:9]1[C:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:32][C:26]3[CH:27]=[CH:28][C:29]([O:30][CH3:31])=[C:24]([O:23][CH3:22])[CH:25]=3)[N:7]=2)=[CH:12][N:11]([CH3:13])[N:10]=1
Reactant: Cn1cc(-c2ccnc(Cl)n2)c(-c2ccc(Cl)cc2Cl)n1
Reactant: COc1ccc(N)cc1OC
Product: COc1ccc(Nc2nccc(-c3cn(C)nc3-c3ccc(Cl)cc3Cl)n2)cc1OC

Procedure:
The title compound is prepared as described in Example 1 but using 2-chloro-4-[3-(2,4-dichloro-phenyl)-1-methyl-1H-pyrazol-4-yl]-pyrimidine and 3,4-dimethoxy-phenylamine.
Reaction SMILES: [N+]([O-])([O-])=O.[NH4+].[Ce].[CH2:7]([C:9]1[C:10](=[O:23])[NH:11][C:12]2[C:17]([CH:18]=1)=[C:16]([O:19]C)[CH:15]=[CH:14][C:13]=2[O:21]C)[CH3:8]>O.C(#N)C>[CH2:7]([C:9]1[C:10](=[O:23])[NH:11][C:12]2[C:13](=[O:21])[CH:14]=[CH:15][C:16](=[O:19])[C:17]=2[CH:18]=1)[CH3:8]
Reactant: CCc1cc2c(OC)ccc(OC)c2[nH]c1=O
Agent: O=[N+]([O-])[O-]
Agent: [Ce]
Agent: [NH4+]
Solvent: CC#N
Solvent: O
Product: CCc1cc2c([nH]c1=O)C(=O)C=CC2=O
Reaction time: 0.08 h
Yield: 108.3 %

Procedure:
Cerium ammonium nitrate (284 mg, 0.5 mmol) was added in small portions to a stirred suspension of 3-ethyl-5,8-dimethoxy-1H-quinolin-2-one(50 mg, 0.2 mmol) in water (0.5 ml) and acetonitrile (1 ml). After 5 minutes at room temperature, water (3 ml) was added and the reaction mixture was extracted with chloroform (3×20 ml), yielding 3-ethyl-1H-quinoline-2,5,8-trione (44 mg, 100 %). The analytical sample was obtained by rapid silica gel chromatography, eluting with ethyl ether.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:19])=[C:6]([C@:8]2([CH:16]([F:18])[F:17])[CH2:14][CH2:13]S[CH2:11][C:10]([NH2:15])=[N:9]2)[CH:7]=1.[S:20]([O-:25])(O[O-])(=O)=[O:21].[K+].[K+]>CO>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:19])=[C:6]([C@:8]2([CH:16]([F:17])[F:18])[CH2:14][CH2:13][S:20](=[O:25])(=[O:21])[CH2:11][C:10]([NH2:15])=[N:9]2)[CH:7]=1
Reactant: NC1=N[C@@](c2cc(Br)ccc2F)(C(F)F)CCSC1
Reactant: O=S(=O)([O-])O[O-]
Agent: [K+]
Solvent: CO
Product: NC1=N[C@@](c2cc(Br)ccc2F)(C(F)F)CCS(=O)(=O)C1
Temperature: 23 °C
Reaction time: 5 h
Yield: 81.2 %

Procedure:
A solution of (S)-5-(5-bromo-2-fluoro-phenyl)-5-difluoromethyl-2,5,6,7-tetrahydro-[1,4]thiazepin-3-ylamine (364 mg, 1.03 mmol) in methanol (20 ml) was treated in two portions with potassium peroxymonosulfate (Oxone) (1.27 g, 2.06 mmol) at 23° C. The white suspension was stirred at 23° C. for 5 hours. For the workup, the reaction mixture was quenched at 0° C. under vigorous stirring with water (10 ml), then treated with a diluted solution of sodium hydrogensulfite, a saturated solution of sodium and with dichloromethane. The vigorous stirring was continued for 10 minutes. The organic layer was separated, washed with water, dried over sodium sulfate and evaporated to give a colorless oil. The crude product was purified by chromatography on silica gel using a gradient of dichloromethane and methanol 100:0 to 90:10 as the eluent. The (S)-5-(5-bromo-2-fluoro-phenyl)-5-difluoromethyl-1,1-dioxo-2,5,6,7-tetrahydro-1H-1λ6-[1,4]thiazepin-3-ylamine (322 mg, 81% yield) was obtained as a white solid. MS (ISP): m/z=384.9 [M+H]+and =386.9 [M+2+H]+.
Reaction SMILES: [Cl:1][CH2:2][C:3]([NH:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][C:15]=1[O:16][CH2:17][CH2:18][O:19]CCF)[N:12]=[CH:11][N:10]=[C:9]2[NH:23][C:24]1[CH:29]=[C:28]([Cl:30])[C:27]([Cl:31])=[CH:26][C:25]=1[F:32])=[O:4].ClC1C(Cl)=CC(NC2C3C(=CC(OCCO[CH2:57][CH2:58][O:59][CH2:60][CH2:61][O:62][CH2:63][CH2:64][O:65][CH2:66][CH2:67][O:68][CH2:69][CH2:70][F:71])=C(N)C=3)N=CN=2)=C(F)C=1.CCN(C(C)C)C(C)C.ClCC(Cl)=O>C1COCC1>[Cl:1][CH2:2][C:3]([NH:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][C:15]=1[O:16][CH2:17][CH2:18][O:19][CH2:57][CH2:58][O:59][CH2:60][CH2:61][O:62][CH2:63][CH2:64][O:65][CH2:66][CH2:67][O:68][CH2:69][CH2:70][F:71])[N:12]=[CH:11][N:10]=[C:9]2[NH:23][C:24]1[CH:29]=[C:28]([Cl:30])[C:27]([Cl:31])=[CH:26][C:25]=1[F:32])=[O:4]
Reactant: O=C(CCl)Nc1cc2c(Nc3cc(Cl)c(Cl)cc3F)ncnc2cc1OCCOCCF
Reactant: Nc1cc2c(Nc3cc(Cl)c(Cl)cc3F)ncnc2cc1OCCOCCOCCOCCOCCOCCF
Agent: O=C(Cl)CCl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(CCl)Nc1cc2c(Nc3cc(Cl)c(Cl)cc3F)ncnc2cc1OCCOCCOCCOCCOCCOCCF

Procedure:
Compound 1c was prepared as described hereinabove for Compound 1a, using Compound 38c (0.13 gram, 0.21 mmol), DIPEA (0.43 mmol, 75.1 μl) and chloroacetylchloride (0.43 mmol, 34.3 μl in THF (18 ml), yielding 0.03 gram of the product (21% yield).
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([NH2:10])[CH:3]=1.C(N(CC)CC)C.[C:18](Cl)(=[O:27])[C:19]1[C:20]([O:25][CH3:26])=[CH:21][CH:22]=[CH:23][CH:24]=1.O>C(Cl)Cl.CN(C1C=CC=CN=1)C.CCCCCC>[C:6]([C:5]1[CH:8]=[CH:9][C:2]([CH3:1])=[CH:3][C:4]=1[NH:10][C:18](=[O:27])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[O:25][CH3:26])#[N:7]
Reactant: COc1ccccc1C(=O)Cl
Reactant: Cc1ccc(C#N)c(N)c1
Agent: CN(C)c1ccccn1
Solvent: CCCCCC
Solvent: ClCCl
Solvent: O
Product: COc1ccccc1C(=O)Nc1cc(C)ccc1C#N
Temperature: 2.5 °C
Reaction time: 3 h
Yield: 90.1 %

Procedure:
To a stirred solution of 4-methyl-2-aminobenzonitrile (100 g, 0.75 mol) in 800 mL CH2Cl2 was added triethylamine (77.4 g, 0.76 mol) and dimethylaminopyridine (4.62 g, 0.037 mol). The solution was cooled to 0-5° C., and o-anisoyl chloride (129 g, 0.75 mol) was added over 1 h while maintaining the reaction temperature at 0-5° C. The reaction was then stirred at 30-40° C. for 3 h. Water (400 mL) was added, and the mixture was stirred for 15 minutes. The organic layer was separated, and the aqueous solution was extracted with CH2Cl2 (600 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo to yield a solid residue, to which 800 mL hexane were added. The slurry was stirred and filtered to give N-(2-cyano-5-methyl-phenyl)-2-methoxy-benzamide as a yellow powder (180 g, 90%). mp 147-149° C. 1H NMR (CDCl3) δ 2.429 (s, 3H), 4.2 (s, 3H), 6.8-7.2 (m, 3H), 7.4-7.6 (m, 2H), 8.2-8.4 (d, 1H), 8.6 (s, 1H), 10.8 (bs, 1H) ppm; 13C NMR (CDCl3) δ 22.68, 55.7, 99, 111.27, 116.7, 120.3, 121.1, 124.15, 131.7, 132.25, 133.67, 141.32, 141.1, 157.2, 163. M/z (obs., [m+H]+)=268.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[N:20]=[C:19]([C:21](OC)=O)[CH:18]=[CH:17][CH:16]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.O.O.O.O.O.O.O.O.O.[O-]S([O-])(=O)=O.[Na+].[Na+].S(Cl)([Cl:50])=O>O1CCCC1>[Cl:50][CH2:21][C:19]1[CH:18]=[CH:17][CH:16]=[C:15]([O:14][CH2:13][C:3]2[N:4]=[C:5]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)[O:6][C:2]=2[CH3:1])[N:20]=1
Reactant: O=S(Cl)Cl
Reactant: COC(=O)c1cccc(OCc2nc(-c3ccccc3)oc2C)n1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1oc(-c2ccccc2)nc1COc1cccc(CCl)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a mixture of methyl 6-(5-methyl-2-phenyl-4-oxazolyl)methoxy-2-pyridinecarboxylate (6.49 g) and tetrahydrofuran (60 mL) was added lithium aluminum hydride (0.759 g) under ice-cooling, and the mixture was stirred at room temperature for 30 min. To the mixture was added sodium sulfate 10 hydrate (6.44 g) and further stirred at room temperature for 30 min. The insoluble materials were removed by filtration, and the filtrate was concentrated to give crystals. The obtained crystals were added to thionyl chloride (20 mL) under ice-cooling, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was concentrated, saturated aqueous sodium hydrogencarbonate was added to the residue and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The obtained residue was subjected to silica gel column chromatography to give crystals of 2-chloromethyl-6-(5-methyl-2-phenyl-4-oxazolylmethoxy)pyridine from a fraction eluted with ethyl acetate-hexane (1:3, v/v). Recrystallization from ethyl acetate-hexane gave colorless plate crystals (2.74 g, 44%). melting point: 85-86° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]=[O:10])=[CH:4][C:3]=1[Cl:11].[NH2:12][C@H:13]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[CH2:14][CH2:15][N:16]1[CH2:21][CH2:20][CH:19]([C:22]2[CH:23]=[C:24]([NH:28][C:29](=[O:33])[CH:30]([CH3:32])[CH3:31])[CH:25]=[CH:26][CH:27]=2)[CH2:18][CH2:17]1>>[Cl:11][C:3]1[CH:4]=[C:5]([CH:6]=[CH:7][C:2]=1[Cl:1])[NH:8][C:9]([NH:12][C@H:13]([C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)[CH2:14][CH2:15][N:16]1[CH2:21][CH2:20][CH:19]([C:22]2[CH:23]=[C:24]([NH:28][C:29](=[O:33])[CH:30]([CH3:32])[CH3:31])[CH:25]=[CH:26][CH:27]=2)[CH2:18][CH2:17]1)=[O:10]
Reactant: O=C=Nc1ccc(Cl)c(Cl)c1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CC[C@H](N)c3ccccc3)CC2)c1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CC[C@H](NC(=O)Nc3ccc(Cl)c(Cl)c3)c3ccccc3)CC2)c1

Procedure:
Prepared by Procedure P and Scheme AB using 1,2-dichloro-4-isocyanatobenzene and N-(3-{1-[(3S)-3-amino-3-phenylpropyl]-4-piperidinyl}phenyl)-2-methylpropanamide: ESMS m/e: 567.1 (M+H)+.
Reaction SMILES: [C:1]1([S:7]([NH:10][C:11]2[S:15][C:14]3[CH2:16][CH2:17]C[CH2:19][C:13]=3[C:12]=2[C:20]([O:22][CH2:23]C)=[O:21])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.NC1SC(CC)=C(C)C=1C(OC)=O.C1(S(Cl)(=O)=O)C=CC=CC=1>>[C:1]1([S:7]([NH:10][C:11]2[S:15][C:14]([CH2:16][CH3:17])=[C:13]([CH3:19])[C:12]=2[C:20]([O:22][CH3:23])=[O:21])(=[O:8])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)c1c(NS(=O)(=O)c2ccccc2)sc2c1CCCC2
Agent: CCc1sc(N)c(C(=O)OC)c1C
Agent: O=S(=O)(Cl)c1ccccc1
Product: CCc1sc(NS(=O)(=O)c2ccccc2)c(C(=O)OC)c1C

Procedure:
Prepared by proceeding in a similar manner to Intermediate 1, starting from methyl 2-amino-5-ethyl-4-methylthiophene-3-carboxylate and benzenesulphonyl chloride.
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:5](=[CH:6][N:7]=[CH:8][CH:9]=2)[S:4][C:3]=1[CH3:11].ClC1C=CC=C(C(OO)=[O:20])C=1>C(Cl)Cl.[OH-].[Na+]>[Br:1][C:2]1[C:10]2[C:5](=[CH:6][N+:7]([O-:20])=[CH:8][CH:9]=2)[S:4][C:3]=1[CH3:11]
Reactant: Cc1sc2cnccc2c1Br
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: Cc1sc2c[n+]([O-])ccc2c1Br
Reaction time: 4 h

Procedure:
3-Bromo-2-methylthieno[2,3-c]pyridine (0.500 g, 2.19 mmol) was dissolved in DCM (10 ml) and cooled down to 0° C. m-Chloroperbenzoic acid (0.737 g, 3.29 mmol) was added to the reaction portionwise while stirring. After 4 hours, the reaction wad diluted with 1N NaOH (10 ml) and DCM (10 ml). The layers were separated and the organic layer was washed (2×) with an aqueous saturated solution of sodium bicarbonate, then with water and then brine. The organic layer was then dried with sodium sulfate, reduced in vacuo and dried to give the title compound as a yellow solid. MS (M+H)+ 245
Reaction SMILES: C(N(CC)CC)C.[Cl:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]([NH2:15])[CH:10]=1.[CH3:16][C:17]([CH3:22])([CH3:21])[C:18](Cl)=[O:19]>ClCCl>[Cl:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]([NH:15][C:18](=[O:19])[C:17]([CH3:22])([CH3:21])[CH3:16])[CH:10]=1
Reactant: Nc1cc(Cl)ccn1
Reactant: CC(C)(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)C(=O)Nc1cc(Cl)ccn1
Reaction time: 18 h
Yield: 67 %

Procedure:
Triethylamine (6.8 mL, 48.6 mmol) was added to a stirred solution of 4-chloro-2-aminopyridine, 11, (Townsend, L. B. et al Synthetic Commun. 1997 27, 861-870) (5 g, 38.9 mmol) in dichloromethane (75 mL). After cooling to 0° C. a solution of trimethylacetyl chloride (5.3 mL, 42.8 mmol) in dichloromethane (10 mL) was added dropwise over 15 min. The mixture was allowed to warm to 23° and stirred for 18 h then washed with saturated sodium bicarbonate. The organic layer was dried (Na2SO4) and evaporated in vacuo to give an off-white solid. This was recrystallised from isopropyl ether to afford the title compound as white crystals (5.5 g, 67%). MS(EI) m/e 213, 215 [M+H]+.
Reaction SMILES: Cl.[CH3:2][N:3]([CH3:12])[C:4]([C@@H:6]1[CH2:10][C@@H:9]([OH:11])[CH2:8][NH:7]1)=[O:5].Cl[C:14]1([C:25]2[C:26]([O:33][CH3:34])=[N:27][C:28]([O:31][CH3:32])=[N:29][CH:30]=2)[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([Cl:23])[CH:21]=2)[NH:16][C:15]1=[O:24].C1COCC1.CCN(C(C)C)C(C)C>ClCCl.O>[CH3:2][N:3]([CH3:12])[C:4]([C@@H:6]1[CH2:10][C@@H:9]([OH:11])[CH2:8][N:7]1[C:14]1([C:25]2[C:26]([O:33][CH3:34])=[N:27][C:28]([O:31][CH3:32])=[N:29][CH:30]=2)[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([Cl:23])[CH:21]=2)[NH:16][C:15]1=[O:24])=[O:5]
Reactant: CN(C)C(=O)[C@@H]1C[C@@H](O)CN1
Reactant: COc1ncc(C2(Cl)C(=O)Nc3ccc(Cl)cc32)c(OC)n1
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Solvent: ClCCl
Product: COc1ncc(C2(N3C[C@H](O)C[C@H]3C(=O)N(C)C)C(=O)Nc3ccc(Cl)cc32)c(OC)n1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
(2S,4R)-4-Hydroxy-pyrrolidine-2-carboxylic acid dimethylamide hydrochloride (0.39 g, 2.0 mmol) was added to a solution of the intermediate from Step B in a mixture of dichloromethane (4 ml), THF (1 ml) and DIPEA (1 ml). The reaction mixture was stirred at room temperature for 18 h. After addition of water, the mixture was extracted four times with ethyl acetate. The combined organic phase was dried over magnesium sulfate, filtered and concentrated under reduced pressure. Purification by chromatography (silica gel, 7% MeOH in dichloromethane) resulted in 0.45 g of the mixture of diastereomers (ratio about 2:1).