Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C@:2]12[C@@H:11]3[CH2:12][CH2:13][C@@H:14]4[C:16]([CH2:18][C@@:10]3([CH2:15]4)[CH2:9][CH2:8][C@@H:7]1[C@@:6]([C:20]([OH:22])=[O:21])([CH3:19])[CH2:5][CH2:4][CH2:3]2)=[CH2:17].C(Cl)(C(Cl)=O)=O.[CH:29]1([NH2:35])[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1>C(Cl)Cl.CN(C=O)C>[CH:29]1([NH-:35])[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1.[CH3:1][C@:2]12[C@@H:11]3[CH2:12][CH2:13][C@@H:14]4[C:16]([CH2:18][C@@:10]3([CH2:15]4)[CH2:9][CH2:8][C@@H:7]1[C@@:6]([C:20]([OH:22])=[O:21])([CH3:19])[CH2:5][CH2:4][CH2:3]2)=[CH2:17]
Reactant: NC1CCCCC1
Agent: C=C1C[C@@]23CC[C@H]4[C@@](C)(CCC[C@@]4(C)C(=O)O)[C@@H]2CC[C@H]1C3
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: [NH-]C1CCCCC1

Procedure:
Kaurenoic acid can be dissolved in dry CH2Cl2 and treated with 10 equivalents of (COCl)2 followed by two drops of DMF. When the reaction stops bubbling, the CH2Cl2 solvent and (COCl)2 can be evaporated under vacuum and the reaction residue can be redissolved in dry benzene and then treated with 5 equivalents of cyclohexylamine to yield N-cyclohexylamide derivative of kaurenoic acid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:37])[C:4]1[CH:9]=[CH:8][C:7]([C:10]([C:17]2[N:26](S(C3C=CC=CC=3)(=O)=O)[C:20]3=[N:21][CH:22]=[C:23]([CH3:25])[CH:24]=[C:19]3[CH:18]=2)=[CH:11][CH:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)=[CH:6][C:5]=1[F:36].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O1CCCC1>[Cl-].[Na+].O>[CH3:1][O:2][C:3](=[O:37])[C:4]1[CH:9]=[CH:8][C:7]([C:10]([C:17]2[NH:26][C:20]3=[N:21][CH:22]=[C:23]([CH3:25])[CH:24]=[C:19]3[CH:18]=2)=[CH:11][CH:12]2[CH2:13][CH2:14][CH2:15][CH2:16]2)=[CH:6][C:5]=1[F:36]
Reactant: COC(=O)c1ccc(C(=CC2CCCC2)c2cc3cc(C)cnc3n2S(=O)(=O)c2ccccc2)cc1F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1ccc(C(=CC2CCCC2)c2cc3cc(C)cnc3[nH]2)cc1F
Yield: 99.6 %

Procedure:
A mixture of 4-[1-(1-benzenesulfonyl-5-methyl-1H-pyrrolo[2,3-b]pyridin-2-yl)-2-cyclopentyl-vinyl]-2-fluoro-benzoic acid methyl ester (470 mg, 1.99 mmol) and a solution of tetrabutylammonium fluoride in tetrahydrofuran (1 M, 39.8 mL, 39.8 mmol) was stirred for 12 h at room temperature. The mixture was poured into brine (15 mL), extracted with ethyl acetate (2×50 mL), washed with a saturated aqueous ammonium chloride solution (3×30 mL), dried over anhydrous sodium sulfate and then concentrated in vacuo to give 4-[2-cyclopentyl-1-(5-methyl-1H-pyrrolo[2,3-b]pyridin-2-yl)-vinyl]-2-fluoro-benzoic acid methyl ester (0.75 g, 100%) as a solid which was used in the next step without purification: LC/MS m/e calcd for C23H23FN2O2 [M+H]+ 379.45, observed 378.9.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[CH3:8][O:9][CH2:10][CH2:11][N:12]([C:14]1[CH:15]=[C:16]([CH:38]=[CH:39][CH:40]=1)[C:17]([NH:19][C:20]1[CH:21]=[CH:22][C:23]([CH3:37])=[C:24]([NH:26][C:27](=[O:36])[C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([CH2:34]Cl)[CH:29]=2)[CH:25]=1)=[O:18])[CH3:13]>>[CH3:8][O:9][CH2:10][CH2:11][N:12]([C:14]1[CH:15]=[C:16]([CH:38]=[CH:39][CH:40]=1)[C:17]([NH:19][C:20]1[CH:21]=[CH:22][C:23]([CH3:37])=[C:24]([NH:26][C:27](=[O:36])[C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([CH2:34][N:5]3[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]3)[CH:29]=2)[CH:25]=1)=[O:18])[CH3:13]
Reactant: CN1CCNCC1
Reactant: COCCN(C)c1cccc(C(=O)Nc2ccc(C)c(NC(=O)c3cccc(CCl)c3)c2)c1
Product: COCCN(C)c1cccc(C(=O)Nc2ccc(C)c(NC(=O)c3cccc(CN4CCN(C)CC4)c3)c2)c1
Temperature: 80 °C

Procedure:
A mixture of N-methylpiperazine (3 ml) and N-(5-{3-[N-(2-methoxyethyl)-N-methylamino]benzamido}-2-methylphenyl)-3-chloromethylbenzamide (0.21 g) was stirred and heated to 80° C. for 3 hours. The mixture was cooled to ambient temperature and partitioned between ethyl acetate and water. The organic phase was evaporated and the residue was triturated under diethyl ether. There was thus obtained the title compound (0.17 g); NMR Spectrum: (DMSOd6) 2.17 (d, 6H), 2.33 (m, 8H), 2.98 (s, 3H), 3.23 (s, 3H), 3.50 (m, 6H), 6.87 (d, 1H), 7.2 (m, 4H), 7.46 (m, 2H), 7.57 (m, 1H), 7.8 (s, 1H), 7.86 (m, 2H), 9.87 (s, 1H), 10.06 (s, 1H); Mass Spectrum: M+H+ 530.
Reaction SMILES: C(C1C=CC([S:9]([Cl:12])(=[O:11])=[O:10])=CC=1OCC)#N.[Cl:16][C:17]1[CH:22]=[C:21]([F:23])[C:20]([N+]([O-])=O)=[CH:19][C:18]=1[O:27][CH3:28]>>[Cl:16][C:17]1[C:18]([O:27][CH3:28])=[CH:19][C:20]([S:9]([Cl:12])(=[O:11])=[O:10])=[C:21]([F:23])[CH:22]=1
Reactant: CCOc1cc(S(=O)(=O)Cl)ccc1C#N
Reactant: COc1cc([N+](=O)[O-])c(F)cc1Cl
Product: COc1cc(S(=O)(=O)Cl)c(F)cc1Cl

Procedure:
The titled compound was prepared analogously to 4-cyano-3-ethoxy-benzenesulfonyl chloride (Intermediate 127c) by replacing 2-ethoxy-4-nitro-benzonitrile with 1-chloro-5-fluoro-2-methoxy-4-nitro-benzene.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:26]=[CH:25][C:6]([CH2:7][N:8]2[CH:12]=[C:11]([C:13]3[N:14]=[C:15]([NH:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=4)[S:16][CH:17]=3)[CH:10]=[N:9]2)=[CH:5][CH:4]=1.[Br:27]N1C(=O)CCC1=O>CN(C=O)C.C([O-])([O-])=O.[Na+].[Na+].O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]2[CH:12]=[C:11]([C:13]3[N:14]=[C:15]([NH:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=4)[S:16][C:17]=3[Br:27])[CH:10]=[N:9]2)=[CH:25][CH:26]=1
Reactant: COc1ccc(Cn2cc(-c3csc(Nc4ccccn4)n3)cn2)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(Cn2cc(-c3nc(Nc4ccccn4)sc3Br)cn2)cc1
Yield: 95.7 %

Procedure:
According to Scheme 5 Step 1: A solution of N-(4-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)thiazol-2-yl)pyridin-2-amine (4.20 mmol, 1.53 g) and N-bromosuccinimide (4.40 mmol, 782 mg) in DMF (76 mL) was stirred for 1.5 hour at 50° C. The reaction mixture was diluted with a saturated solution of Na2CO3 and water. The precipitate formed was recovered and washed with DCM. The aqueous phase was extracted with DCM and the organic phase was washed. The organic phase was dried over MgSO4, was filtered and was concentrated to yield with the addition of the precipitate N-(4-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)-5-bromothiazol-2-yl)pyridin-2-amine (4.02 mmol, 1.78 g, 96%) as a beige solid.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH2:11][C@H:10]([NH:14][CH2:15][C:16]2[CH:21]=[C:20]([C:22]([CH3:26])([CH3:25])[C:23]#[CH:24])[CH:19]=[CH:18][C:17]=2[O:27][CH3:28])[C@@H:9]1[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=O)(C)(C)C.C(C(C1C=CC(OC)=C(C=1)CN[C@H]1CCCN[C@H]1C1C=CC=CC=1)C)#N>>[CH3:28][O:27][C:17]1[CH:18]=[CH:19][C:20]([C:22]([CH3:26])([CH3:25])[C:23]#[CH:24])=[CH:21][C:16]=1[CH2:15][NH:14][C@H:10]1[CH2:11][CH2:12][CH2:13][NH:8][C@H:9]1[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: C#CC(C)(C)c1ccc(OC)c(CN[C@H]2CCCN(C(=O)OC(C)(C)C)[C@H]2c2ccccc2)c1
Agent: COc1ccc(C(C)C#N)cc1CN[C@H]1CCCN[C@H]1c1ccccc1
Product: C#CC(C)(C)c1ccc(OC)c(CN[C@H]2CCCN[C@H]2c2ccccc2)c1

Procedure:
This compound was prepared from Compound 23 in the same manner of Compound 19.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[CH2:3][CH2:4][CH2:5][S:6][C:7]1[C:8]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)=[N:9][NH:10][CH:11]=1.[CH3:20]SC1C(C2C=NC=CC=2)=NNC=1>>[F:19][C:2]([F:1])([F:18])[CH2:3][CH2:4][CH2:5][S:6][C:7]1[C:8]([C:12]2[CH2:13][N:14]([CH3:20])[CH2:15][CH2:16][CH:17]=2)=[N:9][NH:10][CH:11]=1
Reactant: FC(F)(F)CCCSc1c[nH]nc1-c1cccnc1
Reactant: CSc1c[nH]nc1-c1cccnc1
Product: CN1CCC=C(c2n[nH]cc2SCCCC(F)(F)F)C1

Procedure:
Compound 21B (0.3 g, 1.49 mmol) was converted to compound 22B, using the methodology described for the conversion of 21A to 22A. Yield 0.131 g (amorphous, 72% overall). LCMS (method A); Rt: 1.64 min, ([M+H]+=306). 1H-NMR (400 MHz, CDCl3): δ 7.57 (s, 1H), 6.67-6.60 (bs, 1H), 3.43-3.39 (m, 2H), 2.71-2.62 (m, 4H), 2.49 (s, 3H), 2.48-2.43 (m, 2H), 2.28-2.19 (m, 2H), 1.81-1.75 (m, 2H).
Reaction SMILES: S(Cl)(Cl)=O.C([NH:8][C:9]1[C:17]([Cl:18])=[CH:16][C:12]([C:13]([OH:15])=O)=[C:11]([O:19][CH3:20])[CH:10]=1)(=O)C.[NH2:21][CH:22]1[CH2:26][N:25]([CH2:27][CH3:28])[N:24]([CH2:29][CH3:30])[CH2:23]1>C(Cl)(Cl)Cl>[NH2:8][C:9]1[C:17]([Cl:18])=[CH:16][C:12]([C:13]([NH:21][CH:22]2[CH2:26][N:25]([CH2:27][CH3:28])[N:24]([CH2:29][CH3:30])[CH2:23]2)=[O:15])=[C:11]([O:19][CH3:20])[CH:10]=1
Reactant: CCN1CC(N)CN1CC
Reactant: COc1cc(NC(C)=O)c(Cl)cc1C(=O)O
Solvent: ClC(Cl)Cl
Solvent: O=S(Cl)Cl
Product: CCN1CC(NC(=O)c2cc(Cl)c(N)cc2OC)CN1CC
Reaction time: 0.17 h

Procedure:
To 75 ml. of thionyl chloride was added 12 g. (0.05 mole) of 4-acetamido-5-chloro 2-methoxy-benzoic acid and the stirred suspension refluxed one hour. The resulting solution was concentrated and 100 ml. of chloroform added to the residue which was concentrated to remove traces of thionyl chloride. The residue was dissolved in 100 ml. of chloroform and the solution added at a rapid drop to 7 g. (0.05 mole) of 4-amino-1,2-diethylpyrazolidine in 100 ml. of chloroform while stirring and cooling to 20°-25° C. with an ice bath. After 30 minutes the chloroform solution was extracted two times with 100 ml. of 3 N hydrochloric acid and the chloroform solution retained. The acid extract was boiled 10 minutes, cooled with ice, made basic with concentrated sodium hydroxide while cooling and extracted with chloroform. The chloroform was dried (sodium sulfate), concentrated and the residue crystallized from isopropyl ether-isooctane to give 3 g. of material which melted at 116°-118° C. The retained chloroform solution was extracted with dilute sodium hydroxide and concentrated. The residue was dissolved in 3 N hydrochloric acid and extracted with isopropyl ether. The acid solution was refluxed for 10 minutes, cooled with ice bath, made basic with sodium hydroxide while cooling and extracted with chloroform. The chloroform was dried (sodium sulfate) and concentrated. The residue was crystallized three times from isopropyl ether to give 0.7 g. of material which melted at 117°-119° C. A mixture melting point of both materials gave no depression of the melting point. The combined yield was 3.7 g. (23%).
Reaction SMILES: [CH3:1][N:2]([C@@H:4]1[C:27](=[O:28])[C:26]([C:29]([NH2:31])=[O:30])=[C:25]([OH:32])[C@:24]2([OH:33])[C@H:5]1[CH2:6][C@H:7]1[C:21]([C:22]2=[O:23])=[C:20]([OH:34])[C:10]2[C:11]([OH:19])=[C:12]([NH2:18])[CH:13]=[C:14]([N:15]([CH3:17])[CH3:16])[C:9]=2[CH2:8]1)[CH3:3].[C:35]([N:39]([C:51]([O:53][CH3:54])=[O:52])[CH2:40][C:41](OC(OCC(C)C)=O)=[O:42])([CH3:38])([CH3:37])[CH3:36]>>[NH2:31][C:29]([C:26]1[C:25](=[O:32])[C@:24]2([OH:33])[C@@H:5]([CH2:6][C@H:7]3[C:21](=[C:22]2[OH:23])[C:20](=[O:34])[C:10]2[C:11]([OH:19])=[C:12]([NH:18][C:41](=[O:42])[CH2:40][N:39]([C:35]([CH3:37])([CH3:36])[CH3:38])[C:51](=[O:52])[O:53][CH3:54])[CH:13]=[C:14]([N:15]([CH3:16])[CH3:17])[C:9]=2[CH2:8]3)[C@H:4]([N:2]([CH3:1])[CH3:3])[C:27]=1[OH:28])=[O:30]
Reactant: CN(C)c1cc(N)c(O)c2c1C[C@H]1C[C@H]3[C@H](N(C)C)C(=O)C(C(N)=O)=C(O)[C@@]3(O)C(=O)C1=C2O
Reactant: COC(=O)N(CC(=O)OC(=O)OCC(C)C)C(C)(C)C
Product: COC(=O)N(CC(=O)Nc1cc(N(C)C)c2c(c1O)C(=O)C1=C(O)[C@]3(O)C(=O)C(C(N)=O)=C(O)[C@@H](N(C)C)[C@@H]3C[C@@H]1C2)C(C)(C)C

Procedure:
The title compound is prepared by the procedure of Example 42, using 1 equivalent of 9-amino-minocycline and 2 equivalents of isobutoxycarbonyl N-(tert-butyl)-N-(methoxycarbonyl)glycinate Reference Example 120 to give the product of the example.
Reaction SMILES: C(OC(C1C=CC=CC=1O[C:9]1[C:23]([O:24][C:25]2[CH:30]=[CH:29][C:28]([S:31]([CH3:34])(=[O:33])=[O:32])=[CH:27][CH:26]=2)=[CH:22][C:12]2[NH:13][C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)=[N:15][C:11]=2[CH:10]=1)=O)C.[F:39][C@@H:40]1[CH2:44][CH2:43][NH:42][CH2:41]1>>[F:39][C@@H:40]1[CH2:44][CH2:43][N:42]([C:9]2[C:23]([O:24][C:25]3[CH:26]=[CH:27][C:28]([S:31]([CH3:34])(=[O:32])=[O:33])=[CH:29][CH:30]=3)=[CH:22][C:12]3[N:13]=[C:14]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=4)[NH:15][C:11]=3[CH:10]=2)[CH2:41]1
Reactant: F[C@@H]1CCNC1
Reactant: CCOC(=O)c1ccccc1Oc1cc2nc(-c3ccccn3)[nH]c2cc1Oc1ccc(S(C)(=O)=O)cc1
Product: CS(=O)(=O)c1ccc(Oc2cc3nc(-c4ccccn4)[nH]c3cc2N2CC[C@@H](F)C2)cc1

Procedure:
The entitled compound was obtained as a yellow oily substance in the same method as in Example 15 or in accordance with the method or by combining it with an ordinary method but using 5-fluoro-4-(4-methanesulfonyl-phenoxy)-2-nitro-phenylamine obtained in Example 14, and (R)-3-fluoropyrrolidine.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([Cl:11])[N:5]=[C:4]([S:12][CH2:13][CH2:14][CH3:15])[N:3]=1.[NH2:16][C@@H:17]1[CH2:21][C@H:20]([O:22][CH2:23][CH2:24][OH:25])[C@@H:19]([OH:26])[C@H:18]1[OH:27].C(N(CC)CC)C>O1CCCC1.CN1CCCC1=O.C(OCC)(=O)C>[Cl:11][C:6]1[N:5]=[C:4]([S:12][CH2:13][CH2:14][CH3:15])[N:3]=[C:2]([NH:16][C@@H:17]2[CH2:21][C@H:20]([O:22][CH2:23][CH2:24][OH:25])[C@@H:19]([OH:26])[C@H:18]2[OH:27])[C:7]=1[N+:8]([O-:10])=[O:9]
Reactant: N[C@@H]1C[C@H](OCCO)[C@@H](O)[C@H]1O
Reactant: CCCSc1nc(Cl)c([N+](=O)[O-])c(Cl)n1
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCCSc1nc(Cl)c([N+](=O)[O-])c(N[C@@H]2C[C@H](OCCO)[C@@H](O)[C@H]2O)n1
Temperature: 0 °C
Reaction time: 3 h
Yield: 70.1 %

Procedure:
To a stirring solution of 4,6-dichloro-5-nitro-2-(propylthio)pyrimidine (CLIN; 0.80 g, 3 mmol) in tetrahydrofuran (30 mL) at 0° C. was slowly added a solution of (1S,2S,3R,5S)-3-amino-5-(2-hydroxyethoxy)cyclopentane-1,2-diol (OLA; 0.53 g, 3 mmol) in N-methylpyrrolidin-2-one (5 mL). After 10 min there was added triethylamine (0.42 mL, 3 mmol) and the mixture left stirring for 3 h at 0° C. and then 16 h at 20° C. The reaction mixture was diluted with ethyl acetate (60 mL), washed with water (2×60 mL) and evaporated under reduced pressure. The obtained crude product was triturated under diisopropyl ether (10 mL) and filtered to give OLACIN as a yellow powder (0.86 g, 70% yield): 98 area % by HPLC; mp 94-98° C.; 13C NMR (CDCl3, 125 MHz) δ13.2, 22.3, 32.7, 33.6, 55.7, 60.3, 70.7, 74.0, 74.6, 82.5, 124.5, 151.6, 153.9, 171.9.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]([C:13](Cl)=[O:14])=[CH:10][C:9]=2[C:16]2[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:18][CH:17]=2)=[CH:4][CH:3]=1.[CH3:26][NH2:27].O1CCCC1.O>C(OCC)(=O)C>[CH3:26][NH:27][C:13]([C:11]1[S:12][C:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)=[C:9]([C:16]2[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:18][CH:17]=2)[CH:10]=1)=[O:14]
Reactant: CS(=O)(=O)c1ccc(-c2cc(C(=O)Cl)sc2-c2ccc(F)cc2)cc1
Reactant: CN
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: CNC(=O)c1cc(-c2ccc(S(C)(=O)=O)cc2)c(-c2ccc(F)cc2)s1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
5-(4-Fluorophenyl)-4-[4-(methylsulfonyl)phenyl]thiophene-2-carbonyl chloride (1.4 g) was added to a stirred mixture of methylamine (25% in water, 2 ml), tetrahydrofuran (15 ml) and water (5 ml) at 5° C. The mixture was stirred at room temperature for 2 hours, diluted with ethyl acetate, washed with water, and concentrated to dryness. The residue was purified by column chromatography on silica gel (20 g) eluting with a mixture of chloroform and ethyl acetate (1:1). The purified powder (1.1 g) was crystallized from diethyl ether to give colorless crystals of N-methyl-5-(4-fluorophenyl)-4-[4-(methylsulfonyl)phenyl]thiophene-2-carboxamide (1.0 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[NH:9][C:10](N)=[S:11]>ClC1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]=[C:10]=[S:11]
Reactant: NC(=S)Nc1c(Cl)cccc1Cl
Solvent: Clc1ccccc1
Product: S=C=Nc1c(Cl)cccc1Cl

Procedure:
A solution of 156.9 g. of 1-(2,6-dichlorophenyl)thiourea in 1 l. of chlorobenzene was refluxed for 20 hours and concentrated. The resulting oil was triturated with 1 l. of hot hexane which was filtered. On cooling overnight, 52 g. (36%) of 2,6-dichlorophenylisothiocyanate, m.p. 41°-42° separated. Concentration of the filtrate gave an additional 64.2 g. (44%), m.p. 41°-43° in two crops. Recrystallization of a sample from hexane gave the analytical sample, m.p. 41°-42°.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[CH2:5][CH:6]1[C:10]2[CH:11]=[CH:12][C:13]([OH:15])=[CH:14][C:9]=2[S:8][CH2:7]1)[CH3:2].[Cl:17][C:18]1[CH:25]=[C:24]([Cl:26])[CH:23]=[CH:22][C:19]=1[CH2:20]Cl.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CCOC(C)=O>[CH2:1]([O:3][C:4](=[O:16])[CH2:5][CH:6]1[C:10]2[CH:11]=[CH:12][C:13]([O:15][CH2:20][C:19]3[CH:22]=[CH:23][C:24]([Cl:26])=[CH:25][C:18]=3[Cl:17])=[CH:14][C:9]=2[S:8][CH2:7]1)[CH3:2]
Reactant: ClCc1ccc(Cl)cc1Cl
Reactant: CCOC(=O)CC1CSc2cc(O)ccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)CC1CSc2cc(OCc3ccc(Cl)cc3Cl)ccc21
Temperature: 20 °C
Reaction time: 72 h
Yield: 68.3 %

Procedure:
To a solution of ethyl(6-hydroxy-2,3-dihydro-1-benzothiophen-3-yl)acetate (17.2 g) in DMF (300 mL) were added 2,4-dichlorobenzyl chloride (17.0 g) and K2CO3 (15.0 g) and the resulting solution was stirred at 20° C. for 72 h. The mixture was diluted with EtOAc, washed successively with water and brine. The organic layer was dried over Na2SO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE/EtOAc) to give the title compound (19.6 g).
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([CH2:10][NH2:11])[N:7]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[F:19][C:20]1[CH:21]=[C:22]([CH:31]([CH3:35])[C:32](O)=[O:33])[CH:23]=[CH:24][C:25]=1[CH2:26][O:27][CH2:28][CH2:29][OH:30].C1C=CC2N(O)N=NC=2C=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>C1COCC1.CN(C=O)C>[C:1]([C:5]1[CH:9]=[C:8]([CH2:10][NH:11][C:32](=[O:33])[CH:31]([C:22]2[CH:23]=[CH:24][C:25]([CH2:26][O:27][CH2:28][CH2:29][OH:30])=[C:20]([F:19])[CH:21]=2)[CH3:35])[N:7]([C:12]2[CH:13]=[CH:14][C:15]([F:18])=[CH:16][CH:17]=2)[N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C(=O)O)c1ccc(COCCO)c(F)c1
Reactant: CC(C)(C)c1cc(CN)n(-c2ccc(F)cc2)n1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(C(=O)NCc1cc(C(C)(C)C)nn1-c1ccc(F)cc1)c1ccc(COCCO)c(F)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 78.9 %

Procedure:
To a stirred solution of (3-tert-butyl-1-(4-fluorophenyl)-1H-pyrazol-5-yl)methanamine (60 mg, 0.25 mmol, 1.0 eq) in THF/DMF (1/20, v/v, 2 mL) was added 2-(3-fluoro-4-((2-hydroxyethoxy)methyl)phenyl)propanoic acid (61 mg, 0.25 mmol, 1 equiv.), HOBt (35 mg. 0.25 mmol, 1 equiv.), TBTU (80 mg, 0.25 mmo, 1 equiv.) and DIPEA (0.168 mL, 127 mg, 1.01 mmol, 4 equiv.) and the mixture was stirred for 3 d at room temperature. The reaction mixture was evaporated and the residue was purified by column chromatography (EtOAc/cyclohexane (1:2) as eluent) to give N-((3-tert-butyl-1-(4-fluorophenyl)-1H-pyrazol-5-yl)methyl)-2-(3-fluoro-4-((2-hydroxyethoxy)methyl)phenyl)propanamide (93 mg, 78%).
Reaction SMILES: [CH:1]1([CH2:7][NH:8][CH:9]([C:13]2[CH:18]=[C:17]([C:19]([CH3:22])([CH3:21])[CH3:20])[C:16]([OH:23])=[C:15]([C:24]([CH3:27])([CH3:26])[CH3:25])[CH:14]=2)[C:10](O)=[O:11])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:28]([NH2:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.ON1C2C=CC=CC=2N=N1.C>CO.C(Cl)Cl>[CH2:28]([NH:35][C:10](=[O:11])[CH:9]([NH:8][CH2:7][CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1)[C:13]1[CH:18]=[C:17]([C:19]([CH3:21])([CH3:20])[CH3:22])[C:16]([OH:23])=[C:15]([C:24]([CH3:25])([CH3:27])[CH3:26])[CH:14]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: CC(C)(C)c1cc(C(NCC2CCCCC2)C(=O)O)cc(C(C)(C)C)c1O
Reactant: NCc1ccccc1
Agent: On1nnc2ccccc21
Solvent: CO
Solvent: ClCCl
Product: CC(C)(C)c1cc(C(NCC2CCCCC2)C(=O)NCc2ccccc2)cc(C(C)(C)C)c1O
Temperature: 25 °C
Reaction time: 24 h
Yield: 22.4 %

Procedure:
To a methylene chloride (5 mL) solution of Example 22 (0.36 g, 0.96 mmol) was added benzyl amine (110 mg, 1.0 mmol), N,N1 -dicyclohexylcarbodiimide (DCC) (206 mg, 1.0 mmol), and 1-hydroxybenzotriazole (HOBT) (135 mg, 1.0 mmol). The solution was stirred at room temperature for 24 hours. The mixture was filtered free of insolubles and the filtrate evaporated to give an oil. The oil was dissolved in methanol (30 mL) treated with charcoal and evaporated to a foam. The foam was dissolved in ethyl acetate (75 mL) and washed with saturated sodium bicarbonate (50 mL) and then dried over magnesium sulfate. This was purified by chromatography (125 g silica gel, 2% methanol in methylene chloride). The appropriate fractions were combined and evaporated in vacuo to give 0.10 g (22%) of product.
Reaction SMILES: C(N(CC)CC)C.N1C(=O)CC[C@H]1C(O)=O.[CH3:17][O:18][C:19]1[CH:20]=[C:21]2[C:26](=[CH:27][CH:28]=1)[N:25]=[CH:24][N:23]=[C:22]2[O:29][CH2:30][CH:31]1[CH2:36][CH2:35][CH:34]([OH:37])[CH2:33][CH2:32]1.O>CS(C)=O>[CH3:17][O:18][C:19]1[CH:20]=[C:21]2[C:26](=[CH:27][CH:28]=1)[N:25]=[CH:24][N:23]=[C:22]2[O:29][CH2:30][CH:31]1[CH2:36][CH2:35][C:34](=[O:37])[CH2:33][CH2:32]1
Reactant: COc1ccc2ncnc(OCC3CCC(O)CC3)c2c1
Agent: O=C1CC[C@@H](C(=O)O)N1
Solvent: CCN(CC)CC
Solvent: O
Solvent: CS(C)=O
Product: COc1ccc2ncnc(OCC3CCC(=O)CC3)c2c1
Reaction time: 0.25 h

Procedure:
Triethylamine (10 ml, 71 mmol) and then, in portions, Pyr.SO3 (5.8 g, 36 mmol), were added at 0° C. to a solution of 4-(6-methoxy-quinazolin-4-yloxymethyl)-cyclohexanol (2.88 g, 10 mmol) in DMSO (30 ml). The reaction mixture was stirred at that temperature for 15 minutes and then allowed to come to room temperature. After 2 hours, water (300 ml) was added. The aqueous phase was extracted with ether (3×150 ml). The combined organic phases were washed with saturated sodium chloride solution, dried over MgSO4 and concentrated. The crude product was purified by chromatography on silica gel (EtOAc/hex 1/2).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=[O:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl-].[Al+3].[Cl-].[Cl-].[Br:19]Br>O1CCCC1.C(OCC)C>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][C:11](=[O:14])[CH:12]([Br:19])[CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: BrBr
Agent: [Al+3]
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1CCC(=O)C(Br)C1
Temperature: 2.5 °C
Reaction time: 24 h
Yield: 71.9 %

Procedure:
A solution of 4-Oxo-piperidin-1-carboxylic acid tert-butyl ester (10 grams, 50 mmol) and aluminium chloride (0.67 grams, 5 mmol) in tetrahydrofuran (30 mL) and diethyl ether (30 mL) was cooled to 0° C., and then treated with bromine (2.6 mL, 50 mmol) over a period of 30 minutes. Stirred the reaction mass for 24 hours at 0-5° C. After completion of reaction, the obtain solids were filtered and the mother liquor was concentrated under vacuum. The obtain crude was triturated with diethyl ether and solids were filtered and dried under vacuum to obtain the title compound (10 grams).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].Cl.[CH3:12][N:13]([CH3:17])[CH2:14][CH2:15]Cl.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:12][N:13]([CH3:17])[CH2:14][CH2:15][O:10][C:7]1[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1
Reactant: CN(C)CCCl
Reactant: O=[N+]([O-])c1ccc(O)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CN(C)CCOc1ccc([N+](=O)[O-])cc1
Yield: 57 %

Procedure:
A mixture of 4-nitrophenol (3.5 g, 25 mmol), 2-(dimethylamino)ethyl chloride hydrochloride (3.6 g, 25 mmol), and potassium carbonate (13.2 g, 125 mmol) in acetone (100 mL) was heated to reflux for 30 hours. The solvent was removed under vacuum. The residue was partitioned between water (150 mL) and ethyl acetate (150 mL), and the aqueous phase was extracted with ethyl acetate (100 mL). The combined organic layers were washed with water (3×150 mL) and extracted with dilute aqueous HCl (2×125 mL). These extracts were washed with CH2Cl2 (2×150 mL), made basic (NaOH) and extracted into ethyl acetate (3×75 mL). These organic extracts were washed with water (3×75 mL), dried (MgSO4), and evaporated, providing 3.0 g as a pale yellow solid, in 57% yield; 1H NMR (CDCl3) δ 2.35 (s, 6H), 2.76 (t, J=5.6 Hz, 2H), 4.15 (t, J=5.6 Hz, 2H), 6.96-7.00 (m, 2H), 8.17-8.22 (m, 2H).