Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:10]([C:11](O)=[O:12])=[C:9]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)[S:8][C:7]=2[CH:22]=1.S(Cl)([Cl:25])=O.CN(C)C=O>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:10]([C:11]([Cl:25])=[O:12])=[C:9]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)[S:8][C:7]=2[CH:22]=1
Reactant: COc1ccc(-c2sc3cc(OC)ccc3c2C(=O)O)cc1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1ccc(-c2sc3cc(OC)ccc3c2C(=O)Cl)cc1
Yield: 97.2 %

Procedure:
To a slurry of 6-methoxy -2-(4-methoxyphenyl)benzo[b]thiophene-3-carboxylic acid (0.0484 g, 0.154 mmol) in methylene chloride (5 ml) is added thionyl chloride (0.025 ml, 0.356 mmol), and a catalytic amount of N,N-dimethylformamide. The reaction is heated to reflux for 2 hours, then cooled and concentrated in vacuo. The residual material is dissolved in toluene (10 ml), and reconcentrated in vacuo. This dissolution/reconcentration procedure is repeated two more times to afford 0.0498 g (97%) of title compound as a solid: mp 135.5-137.9° C. IR (KBr) 2965, 1678, 1610, 1525, 1478, 1253, 815; 1H NMR (CDCl3): δ8.13 (d, 1 H, J=9 Hz), 7.48 (d, 2 H, J=8.7 Hz), 7.27 (d, 1 H, J=2.4 Hz), 7.13 (dd, 1 H, J=9.0, 2.4 Hz), 7.00 (d, 2 H, J=8.7 Hz); 13C NMR (CDCl3): d 163.4, 161.0, 158.2, 139.1, 131.3, 131.2, 129.1, 128.3, 125.1, 124.6, 115.9, 114.2, 104.4, 55.7, 55.5; Exact mass calcd. for C18H16O4S (in situ-derived methyl ester): 328.0769. Found: 328.0760.
Reaction SMILES: [CH:1]([C:4]1[N:8]([C:9]2[CH:10]=[C:11]([C:22]([OH:24])=O)[CH:12]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=3)[CH:14]=2)[N:7]=[CH:6][N:5]=1)([CH3:3])[CH3:2].[N:25]1[CH:30]=[CH:29][N:28]=[CH:27][C:26]=1[CH:31]([NH2:33])[CH3:32]>>[N:25]1[CH:30]=[CH:29][N:28]=[CH:27][C:26]=1[CH:31]([NH:33][C:22]([C:11]1[CH:12]=[C:13]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)[CH:14]=[C:9]([N:8]2[C:4]([CH:1]([CH3:2])[CH3:3])=[N:5][CH:6]=[N:7]2)[CH:10]=1)=[O:24])[CH3:32]
Reactant: CC(N)c1cnccn1
Reactant: Cc1ccc(-c2cc(C(=O)O)cc(-n3ncnc3C(C)C)c2)cc1
Product: Cc1ccc(-c2cc(C(=O)NC(C)c3cnccn3)cc(-n3ncnc3C(C)C)c2)cc1

Procedure:
5-(5-Isopropyl-[1,2,4]triazol-1-yl)-4′-methyl-biphenyl-3-carboxylic acid was subject to the amide coupling reaction described in step 4 of Example 6, but replacing 2-amino-propan-1-ol with 1-pyrazin-2-yl-ethylamine, to give 5-(5-isopropyl-[1,2,4]triazol-1-yl)-4′-methyl-biphenyl-3-carboxylic acid (1-pyrazin-2-yl-ethyl)-amide, MS (M+H)=427.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:13]=[C:12]([O:14][CH:15]([CH3:17])[CH3:16])[NH:11][N:10]=2)[C:5]([N+:18]([O-:20])=[O:19])=[CH:4][N:3]=1.Cl.[F:22][C:23]1[CH:24]=[CH:25][C:26]([C@@H:29]([NH2:31])[CH3:30])=[N:27][CH:28]=1.C(N(C(C)C)CC)(C)C>CCCCO.C(OCC)(=O)C>[F:22][C:23]1[CH:24]=[CH:25][C:26]([C@@H:29]([NH:31][C:2]2[N:7]=[C:6]([NH:8][C:9]3[CH:13]=[C:12]([O:14][CH:15]([CH3:17])[CH3:16])[NH:11][N:10]=3)[C:5]([N+:18]([O-:20])=[O:19])=[CH:4][N:3]=2)[CH3:30])=[N:27][CH:28]=1
Reactant: CC(C)Oc1cc(Nc2nc(Cl)ncc2[N+](=O)[O-])n[nH]1
Reactant: C[C@H](N)c1ccc(F)cn1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)Oc1cc(Nc2nc(N[C@@H](C)c3ccc(F)cn3)ncc2[N+](=O)[O-])n[nH]1
Temperature: 70 °C
Reaction time: 4 h
Yield: 74.2 %

Procedure:
A mixture of 2-chloro-N-(5-isopropoxy-1H-pyrazol-3-yl)-5-nitropyrimidin-4-amine (Intermediate 30, 1.0 g) and [(1S)-1-(5-fluoropyridin-2-yl)ethyl]amine hydrochloride (Intermediate 5, 0.8 g) in n-BuOH (5 mL) with diisopropylethylamine (1 mL) was stirred at 70° C. for 4 hours. The resulting mixture was diluted with ethyl acetate (20 mL), and washed with brine (10 mL×3). The organic layer was dried and concentrated. The resulting residue was separated by silica gel column (Hexane/Ethyl acetate) to yield 1.0 g of the title compound. MS (electrospray): 403 (M+1) for C17H19FN8O3. 1H NMR (300 MHz, CD3OD) δ ppm 9.10 (s, 1H) 8.50 (s, 1H) 7.60 (m, 1H) 7.40 (m, 1H) 5.80 (s, 1H) 5.20 (m, 1H) 4.70 (m, 2H) 1.60 (d, 3H) 1.40 (d, 6H).
Reaction SMILES: [C:1](OC(=O)C)(=O)C.C(O)=O.[Cl:11][C:12]1[C:13]([NH:45]S(C)(=O)=O)=[CH:14][C:15]2[N:19]=[C:18]([CH2:20][CH3:21])[N:17]([C:22]3[CH:27]=[CH:26][C:25]([CH2:28][CH2:29][NH:30][C:31]([NH:33][S:34]([C:37]4[CH:42]=[CH:41][C:40]([CH3:43])=[CH:39][CH:38]=4)(=[O:36])=[O:35])=[O:32])=[CH:24][CH:23]=3)[C:16]=2[CH:44]=1>C1COCC1>[Cl:11][C:12]1[C:13]([NH:45][CH3:1])=[CH:14][C:15]2[N:19]=[C:18]([CH2:20][CH3:21])[N:17]([C:22]3[CH:27]=[CH:26][C:25]([CH2:28][CH2:29][NH:30][C:31]([NH:33][S:34]([C:37]4[CH:38]=[CH:39][C:40]([CH3:43])=[CH:41][CH:42]=4)(=[O:36])=[O:35])=[O:32])=[CH:24][CH:23]=3)[C:16]=2[CH:44]=1
Reactant: CC(=O)OC(C)=O
Reactant: CCc1nc2cc(NS(C)(=O)=O)c(Cl)cc2n1-c1ccc(CCNC(=O)NS(=O)(=O)c2ccc(C)cc2)cc1
Solvent: C1CCOC1
Solvent: O=CO
Product: CCc1nc2cc(NC)c(Cl)cc2n1-c1ccc(CCNC(=O)NS(=O)(=O)c2ccc(C)cc2)cc1
Temperature: 60 °C
Reaction time: 2 h
Yield: 67 %

Procedure:
A solution of acetic anhydride (0.14 ml) in THF (5 ml) was added formic acid (0.06 ml, 1.65 mmol) at 0° C. under nitrogen and the mixture was stirred at 60° C. for 2 h. Then the mixture was recooled to 0° C. and was added 6-Chloro-1-[4-(2-chloroethyl)phenyl]-2-ethyl-1H-benzimidazol-5-ylamine (Example 110, step 6, 100 mg, 0.3 mmol) in THF (2 ml). The mixture was stirred at room temperature for 2 h. The volatile component was removed under reduced pressure, and the residue was dissolved with ethyl acetate (100 ml). The organic layer was washed with 2N aqueous NaOH (50 ml), brine (50 ml), then dried (Na2SO4). After removal of solvent, the crude product was purified by flash column chromatography eluting with hexane/ethyl acetate (1:10) to afford 68 mg (67%) of the title compound as pale yellow solids.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:15]([NH2:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>ClCCl>[CH2:15]([NH:22][CH:11]1[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9][CH2:10]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: NCc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCC(NCc2ccccc2)CC1
Reaction time: 72 h
Yield: 92.3 %

Procedure:
To a solution of 1-(tert-butoxycarbonyl)-4-piperidone (10.0 g, 50.2 mmol), benzylamine (5.4 g, 50.2 mmol), and acetic acid (3.01 g, 50.2 mmol) in 200 mL of dry dichloromethane was added sodium triacetoxyborohydride (21.2 g, 100 mmol) under nitrogen. The mixture was stirred for three days, and then aqueous 1 N NaOH (200 mL) solution was added. After 1 h of stirring, the layers were separated, and the aqueous layer was extracted twice with dichloromethane (100 mL). The organic extracts were combined, washed twice with 1 N NaOH (100 mL), dried (Na2SO4), and concentrated to give 13.46 g of 4-benzylamino-1-(tert-butoxycarbonyl)piperidine as a cream-colored waxy solid. MS (ES), m/z 291 (MH+). 300 MHz 1H NMR (CDCl3) δ1.22-1.39 (br q, 2H), 1.45 (s, 9H), 1.86 (br d, J=11.3 Hz, 2H), 2.60-2.93 (m, 4H), 3.82 (s, 2H), 3.85-4.20 (br m, 2H), 7.19-7.37 (m, 5H).
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][C:11](=[O:35])[CH2:12][CH:13]1[CH:22]([S:23]([C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=2)(=[O:25])=[O:24])[C:21]2[C:16](=[C:17]([F:34])[CH:18]=[CH:19][C:20]=2[F:33])[O:15][CH2:14]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:36](O)[CH2:37][OH:38].C1(C)C(S(O)(=O)=O)=CC=CC=1.O>C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH2:1]([O:8][CH2:9][CH2:10][C:11]1([CH2:12][CH:13]2[CH:22]([S:23]([C:26]3[CH:27]=[CH:28][C:29]([Cl:32])=[CH:30][CH:31]=3)(=[O:25])=[O:24])[C:21]3[C:16](=[C:17]([F:34])[CH:18]=[CH:19][C:20]=3[F:33])[O:15][CH2:14]2)[O:38][CH2:37][CH2:36][O:35]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(CCOCc1ccccc1)CC1COc2c(F)ccc(F)c2C1S(=O)(=O)c1ccc(Cl)cc1
Reactant: OCCO
Agent: Cc1ccccc1S(=O)(=O)O
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: O
Product: O=S(=O)(c1ccc(Cl)cc1)C1c2c(F)ccc(F)c2OCC1CC1(CCOCc2ccccc2)OCCO1
Temperature: 25 °C

Procedure:
4-Benzyloxy-1-[4-(4-chloro-benzenesulfonyl)-5,8-difluoro-chroman-3-yl]-butan-2-one (10 g, 19.2 mmole), ethylene glycol (20 ml) and toluene sulfonic acid (1 g) were dissolved in 300 ml toluene. The reaction was refluxed for four hours with a Dean-Stark trap. The reaction was cooled to room temperature and 200 ml water and 200 ml EtOAc were added. The organic layer washed with brine (2×50 ml), dried over Na2SO4 and concentrated. The residue was purified by column chromatography (EtOAc/hexane from 0/100 to 50/50 in 55 minute). Yield: 6.3 g, 58%. 1H NMR (CDCl3 400 MHz δ 7.74 (d, J=8.1 Hz, 2H), 7.51 (d, J=8.8 Hz, 2H), 7.20-7.39 (m, 5H), 7.02 (m, 1H), 6.42 (m, 1H), 4.89 (dd, J=11.0 and 2.9 Hz, 1H), 4.84 (s, 1H), 4.40 (d, J=2.0 Hz, 2H), 4.21 (d, J=11.7 Hz, 1H), 3.85 (m, 4H), 3.46 (t, J=5.9 Hz, 2H), 3.03 (d, J=8.1 Hz, 1H), 1.75-1.90 (m, 3H), 1.54-1.61 (m, 1H).
Reaction SMILES: O[C:2]([CH:16]([CH3:18])[CH3:17])([CH:6]([CH:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1)[C:7]([OH:9])=[O:8])[C:3](O)=[O:4].CCCCCC.C(OCC)(=O)C>C(OC(=O)C)(=O)C>[CH:16]([C:2]1=[C:6]([CH:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[C:7]([O:9][C:3]1=[O:4])=[O:8])([CH3:18])[CH3:17]
Reactant: CC(C)C(O)(C(=O)O)C(C(=O)O)C1CCOCC1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: CC(=O)OC(C)=O
Product: CC(C)C1=C(C2CCOCC2)C(=O)OC1=O
Reaction time: 10 h
Yield: 62.8 %

Procedure:
2-Hydroxy-2-isopropyl-3-(tetrahydropyran-4-yl)succinic acid (70 mg, 0.27 mmol) was dissolved in acetic anhydride (1 mL), and the solution was left standing at 120° C. for 10 h. The acetic anhydride was evaporated under reduced pressure and the residue thus obtained was subjected to silica gel column chromatography (hexane-ethyl acetate 3:1) to give 38 mg of the title compound as a solid (yield: 67%).
Reaction SMILES: [Li].[Br:2][C:3]1[CH:8]=[CH:7][N:6]=[CH:5][C:4]=1[CH:9]=[O:10].[Cl-:11].[NH4+:12]>COCCOC.C1CCCCC1>[Br:2][C:3]1[CH:8]=[CH:7][N:6]=[CH:5][C:4]=1[CH:9]([C:4]1[CH:5]=[N:12][CH:7]=[CH:8][C:3]=1[Cl:11])[OH:10]
Reactant: [Cl-]
Reactant: O=Cc1cnccc1Br
Reactant: [NH4+]
Agent: [Li]
Solvent: C1CCCCC1
Solvent: COCCOC
Product: OC(c1cnccc1Cl)c1cnccc1Br
Temperature: -70 °C
Reaction time: 8 h

Procedure:
Five grams (g) of 4-chloropyridine hydrochloride were placed into a 30 milliliters (ml) of diethyl ether in a 200 ml beaker equipped with a magnetic stirrer. 1.8 grams of sodium hydroxide in 30 ml of water were added at 0° C. and the mixture stirred for 15 minutes. The diethyl ether layer was separated, washed with water, dried over magnesium sulfate, filtered, and concentrated in vacuo. The 1.6 grams of the 4-chloropyridine produced were placed into a 3-necked flask and dissolved in 45 ml of ethylene glycol dimethyl ether (DME). After cooling to -70° C., 10 ml of 1.5 molar (M) solution of lithium dlisopropyl amide (LDA) in cyclohexane were added over a period of 30 minutes while maintaining the temperature below -60° C. Upon completion of the addition, the reaction mixture was stirred for an additional hour at -70° C. To this cooled mixture were then added 2.6 grams of 4-bromopyridine-3-carboxaldehyde that was dissolved in 10 ml of DME. The reaction mixture was stirred in a dry-ice bath for 2 hours and then left at room temperature overnight. 35 ml of saturated ammonium chloride solution were added to the reaction mixture, and the mixture was stirred for 15 minutes at room temperature. The mixture was then extracted twice with ethyl ether. The combined ether extracts were then washed with water, dried over magnesium sulfate, filtered, and concentrated in vacuo to afford 2.9 g of the crude product as a viscous oil. This oil was then chromatographed on a silica gel column using ethyl acetate as the eluant to afford 0.5 g of 1-(4-bromopyrid-3-yl)-1-(4-chloropyrid-3-yl)methanol as a waxy solid.
Reaction SMILES: [C:1]1([CH3:51])[CH:6]=[CH:5][C:4]([S:7]([NH:10][CH2:11][CH2:12][N:13]([S:41]([C:44]2[CH:49]=[CH:48][C:47]([CH3:50])=[CH:46][CH:45]=2)(=[O:43])=[O:42])[CH2:14][CH2:15][CH2:16][N:17]([S:31]([C:34]2[CH:39]=[CH:38][C:37]([CH3:40])=[CH:36][CH:35]=2)(=[O:33])=[O:32])[CH2:18][CH2:19][NH:20][S:21]([C:24]2[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][CH:25]=2)(=[O:23])=[O:22])(=[O:9])=[O:8])=[CH:3][CH:2]=1.[H-].[Na+].[CH3:54][N:55]([CH2:59][CH2:60]Cl)[CH2:56][CH2:57]Cl>CN(C=O)C>[CH3:54][N:55]1[CH2:59][CH2:60][N:10]([S:7]([C:4]2[CH:5]=[CH:6][C:1]([CH3:51])=[CH:2][CH:3]=2)(=[O:8])=[O:9])[CH2:11][CH2:12][N:13]([S:41]([C:44]2[CH:45]=[CH:46][C:47]([CH3:50])=[CH:48][CH:49]=2)(=[O:43])=[O:42])[CH2:14][CH2:15][CH2:16][N:17]([S:31]([C:34]2[CH:39]=[CH:38][C:37]([CH3:40])=[CH:36][CH:35]=2)(=[O:32])=[O:33])[CH2:18][CH2:19][N:20]([S:21]([C:24]2[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][CH:25]=2)(=[O:23])=[O:22])[CH2:57][CH2:56]1
Reactant: CN(CCCl)CCCl
Reactant: Cc1ccc(S(=O)(=O)NCCN(CCCN(CCNS(=O)(=O)c2ccc(C)cc2)S(=O)(=O)c2ccc(C)cc2)S(=O)(=O)c2ccc(C)cc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)N2CCCN(S(=O)(=O)c3ccc(C)cc3)CCN(S(=O)(=O)c3ccc(C)cc3)CCN(C)CCN(S(=O)(=O)c3ccc(C)cc3)CC2)cc1
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 34 %

Procedure:
To a stirred solution of 1,4,8,11-tetra(p-toluenesulfonyl)-1,4,8,11-tetraazaundecane prepared in Example 16A (80.7 g, 0.104 mole) in anhydrous DMF (1 l) was added sodium hydride (6.24 g-80% in mineral oil, 0.208 mole) in portions under a dry nitrogen blanket. The resulting mixture was stirred for 30 minutes under a dry argon atmosphere. The solution was then heated to 100° C. and a solution of N-methylbis(2-chloroethyl)amine freshly prepared as in Example 15A (16.2 g, 0.104 mole) in anhydrous DMF (200 ml) was added dropwise over a 45 minute period, maintaining the temperature at 100° C. After stirring, an additional 45 minutes at 100° C., the solution was concentrated in vacuo to a volume of 900 ml. H2O (1200 ml) was added at room temperature to crystallize the product. The solid was dried in vacuo over P2O5 to give 83.2 g (93% yield) of the crude product as a brown solid. A portion (50 g) of the crude product was purified by flash chromatography (silica gel, CHCl3 --95:5 (v/v) --CHCl3 --MeOH gradient) to give 16.8 g (34% yield) of the product as a light yellow solid. An analytical sample was recrystallized from CH2Cl2 -hexane: mp 183°-5° C.; Rf =0.60, silica gel--95:5 (v/v) CHCl3 -MeOH; 1H NMR (CDCl3) δ 1.91 (quint, J=6.0 Hz, 2 H), 2.19 (s, 3 H), 2.44 (s, 12 H), 2.52 (t, J=6.2 Hz, 4 H), 3.18 (m, 12 H), 3.31 (m, 4 H), 7.33 (m, 8 H), 7.68 (m, 8 H).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[S:6](Cl)(=[O:8])=[O:7].[NH4+:10].[OH-]>>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[S:6]([NH2:10])(=[O:8])=[O:7]
Reactant: O=S(=O)(Cl)c1ccco1
Reactant: [NH4+]
Agent: [OH-]
Product: NS(=O)(=O)c1ccco1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Twenty-three g of 2-furansulfonyl chloride (138 mm) was added dropwise into 200 ml of conc. NH4OH at 0°-5°. After stirring overnight at room temperature, the water was removed under vacuum and the precipitate washed with ice water and dried. Yield: 14 g 2-furansulfonamide m.p. 120-122°. (literature m.p. 120°-122°: JOC 18, 894 (1953)). IR (Nujol) 3250 cm-1, 3100 cm-1, 1600 cm-1 (W), 1550 cm-1, 1310 cm-1, 1190 cm-1, 1140 cm-1 1120 cm-1, 1055 cm-1, 1005 cm-1, 930 cm-1, 880 cm-1, 843 cm-1 (S).
Reaction SMILES: [C:1]([O:5][CH3:6])(=[O:4])[CH2:2][OH:3].[CH2:7]([O:9][CH:10]=[CH2:11])[CH3:8].CC1C=CC(S(O)(=O)=O)=CC=1>C1COCC1.C(OCC)C>[CH2:7]([O:9][CH:10]([O:3][CH2:2][C:1]([O:5][CH3:6])=[O:4])[CH3:11])[CH3:8]
Reactant: COC(=O)CO
Reactant: C=COCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCOC(C)OCC(=O)OC
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 87.8 %

Procedure:
A solution of methyl glycolate (0.193 g, 2.15 mmol) in THF (21 ml) was treated with ethylvinyl ether (EVE) (1.03 ml, 10.7 mmol) and a catalytic amount of p-TsOH (41 mg). After stirring for 15 min at 0° C., the mixture was diluted with ethyl ether, washed with saturated NaHCO3 aqueous solution, brine, dried (Na2SO4) and evaporated to give methyl (1-ethoxyethoxy)acetate (0.306 g, 87%).
Reaction SMILES: [Li+].[OH-].C[O:4][C:5]([CH:7]1[CH2:12][CH2:11][N:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:9][CH2:8]1)=[O:6]>C1COCC1.CO.O>[C:13]1([N:10]2[CH2:11][CH2:12][CH:7]([C:5]([OH:6])=[O:4])[CH2:8][CH2:9]2)[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: COC(=O)C1CCN(c2ccccc2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)C1CCN(c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.3 %

Procedure:
LiOH (43 mg, 1.03 mmol) was added at room temperature to a stirred solution of 1-phenyl-piperidine-4-carboxylic acid methyl ester (150 mg, 0.68 mmol) in THF:MeOH:H2O (3:1:1, 3.2 mL). The resulting mixture was stirred at room temperature overnight. The MeOH and THF were evaporated and the residue was diluted with water (2 mL), acidified with citric acid solution and extracted with EtOAc. The organic layer was washed with saturated brine, dried over Na2SO4 and concentrated under reduced pressure to afford 94 mg (67.14% yield) of 1-phenyl-piperidine-4-carboxylic acid. LCMS purity: 95.98%.
Reaction SMILES: O[O:2][S:3]([O-:5])=O.[K+].[NH2:7][C:8]1[N:9]=[C:10](SC)[S:11][C:12]=1[C:13]([O:15][CH3:16])=[O:14].[CH3:19]O>O>[NH2:7][C:8]1[N:9]=[C:10]([S:3]([CH3:19])(=[O:5])=[O:2])[S:11][C:12]=1[C:13]([O:15][CH3:16])=[O:14]
Reactant: COC(=O)c1sc(SC)nc1N
Reactant: CO
Reactant: O=S([O-])OO
Agent: [K+]
Solvent: O
Product: COC(=O)c1sc(S(C)(=O)=O)nc1N
Temperature: 5 °C
Reaction time: 3 h

Procedure:
5.12 g (8.32 mmol) of Oxone® are dissolved in 170 ml of water and cooled to 5° C. A solution of 1 g (4.90 mmol) of methyl 4-amino-2-(methylsulphanyl)-1,3-thiazole-5-carboxylate in 18 ml of methanol is then added dropwise, and the solution is stirred at RT for 3 h. The major amount of methanol is removed and extracted three times with dichloromethane. The combined organic phases are dried with sodium sulphate. After removal of the solvent and drying of the residue under high vacuum, the resulting solid (824 mg (43% of theory)) is employed without further purification.
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[C:5]([C:14]#[N:15])=[C:4]1[C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[NH:21][CH:20]=[CH:19]2)[CH3:2].[CH3:25][S:26](Cl)(=[O:28])=[O:27]>N1C=CC=CC=1.O>[CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[C:5]([C:14]#[N:15])=[C:4]1[C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[N:21]([S:26]([CH3:25])(=[O:28])=[O:27])[CH:20]=[CH:19]2)[CH3:2]
Reactant: CCn1c(-c2ccc3[nH]ccc3c2)c(C#N)c2ccc(OC)cc21
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: O
Product: CCn1c(-c2ccc3c(ccn3S(C)(=O)=O)c2)c(C#N)c2ccc(OC)cc21
Reaction time: 8 h
Yield: 80.9 %

Procedure:
A solution of 1-ethyl-6-methoxy-1H,1′H-[2,5′]biindolyl-3-carbonitrile (70 mg, 0.22 mmol), prepared as described in Example 1Gb, in pyridine (2 mL) is treated with methanesulfonyl chloride (0.034 mL, 0.44 mmol) and stirred overnight. The reaction mixture is then diluted with H2O and extracted with ethyl acetate (3×). The organic phase is washed with H2O and saturated NaCl, dried and concentrated and purified by flash chromatography using EtOAc/hexanes (30-80%) to afford 70 mg (81%) of 1-ethyl-1′-methanesulfonyl-6-methoxy-1H,1′H-[2,5′]biindolyl-3-carbonitrile as a tan solid.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)=O)(C)(C)C.[CH2:14]([S:16](Cl)(=[O:18])=[O:17])[CH3:15].CC1C(C(N2CCNCC2)=O)=C(C)ON=1>>[CH2:14]([S:16]([N:8]1[CH2:9][CH2:10][NH:11][CH2:12][CH2:13]1)(=[O:18])=[O:17])[CH3:15]
Reactant: CCS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: Cc1noc(C)c1C(=O)N1CCNCC1
Product: CCS(=O)(=O)N1CCNCC1

Procedure:
Ethanesulfonyl-piperazine was prepared from 1-tert-butyloxycarbonyl-piperazine and ethylsulfonyl chloride in an analogous manner as described for the preparation of (3,5-dimethyl-isoxazol-4-yl)-piperazin-1-yl-methanone in example 41.
Reaction SMILES: S(Cl)([Cl:3])=O.[Cl:5][C:6]1[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[C:7]=1[CH:8]=[CH:9][C:10](O)=[O:11]>C1(C)C=CC=CC=1>[Cl:5][C:6]1[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[C:7]=1[CH:8]=[CH:9][C:10]([Cl:3])=[O:11]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)C=Cc1c(Cl)cccc1Cl
Solvent: Cc1ccccc1
Product: O=C(Cl)C=Cc1c(Cl)cccc1Cl

Procedure:
A solution of 20% thionyl chloride in toluene is added dropwise to a magnetically stirred, warmed mixture of 2,6-dichlorocinnamic acid (20.74 g) in toluene (119 ml) and the mixture brought to reflux for 6 hrs after it clears to a yellow haze. The reaction mixture is cooled overnight, filtered and concentrated in vacuo to afford a pale yellow solid, M.P. 64.5°-66° C.
Reaction SMILES: F[C:2]1[CH:16]=[CH:15][C:5]2[C:6](=[O:14])[NH:7][C:8]3[C:13]([C:4]=2[CH:3]=1)=[CH:12][CH:11]=[CH:10][N:9]=3.Cl[C:18]1[CH:19]=[C:20]([OH:24])[CH:21]=[CH:22][CH:23]=1.[C:25](=O)([O-])[O-:26].[K+].[K+]>CN(C=O)C>[CH3:25][O:26][C:23]1[CH:22]=[CH:21][C:20]([O:24][C:2]2[CH:16]=[CH:15][C:5]3[C:6](=[O:14])[NH:7][C:8]4[C:13]([C:4]=3[CH:3]=2)=[CH:12][CH:11]=[CH:10][N:9]=4)=[CH:19][CH:18]=1
Reactant: O=C([O-])[O-]
Reactant: Oc1cccc(Cl)c1
Reactant: O=c1[nH]c2ncccc2c2cc(F)ccc12
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(Oc2ccc3c(=O)[nH]c4ncccc4c3c2)cc1
Temperature: 180 °C
Reaction time: 0.33 h
Yield: 82.7 %

Procedure:
9-Fluoro-5H-benzo[c][1,8]naphthyridin-6-one (40 mg, 0.19 mmol), 3-chlorophenol (72 mg, 0.56 mmol), and potassium carbonate (129 mg, 0.93 mmol) were suspended in DMF (1.5 mL), and stirred for 20 minutes at 180° C. in the microwave. The reaction mixture was quenched with H2O. The resulting precipitate was filtered, washed with H2O, and dried under vacuum to provide 73 (50 mg, 83% yield) as a tan solid. LC-MS (M+H=323, obsd.=323). 1H NMR (400 MHz, d6-DMSO): δ 12.05 (s, 1H), 8.78 (dd, 1H), 8.51 (dd, 1H), 8.35 (d, 1H), 8.19 (d, 1H), 7.49 (t, 1H), 7.29 (m, 4H), 7.12 (dd, 1H).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([P:19]([CH3:22])([CH3:21])=[O:20])=[CH:15][CH:14]=2)[N:3]=1.C([N:25](CC)CC)C.NC[CH2:32][N:33]1[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1>C(O)C>[CH3:21][P:19]([C:16]1[CH:17]=[CH:18][C:13]([NH:12][C:4]2[N:3]=[C:2]([NH:25][CH2:32][N:33]3[CH2:38][CH2:37][O:36][CH2:35][CH2:34]3)[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=2)=[CH:14][CH:15]=1)([CH3:22])=[O:20]
Reactant: CCN(CC)CC
Reactant: NCCN1CCOCC1
Reactant: CP(C)(=O)c1ccc(Nc2ncc(C(F)(F)F)c(Cl)n2)cc1
Solvent: CCO
Product: CP(C)(=O)c1ccc(Nc2ncc(C(F)(F)F)c(NCN3CCOCC3)n2)cc1
Yield: 81 %

Procedure:
To a solution of 4-chloro-N-[4-(dimethylphosphoryl)phenyl]-5-(trifluoromethyl)pyrimidin-2-amine (prepared as in Example 1: 40 mg, 0.12 mmol) in 2 mL of ethanol was added 50 L of triethylamine and 4-(2-aminoethyl) morpholine (15 mg, 0.12 mmol). The mixture was microwave at 120 degrees for 20 minutes. The reaction mixture was filtered through a syringe filter and purified by prep-HPLC (Waters Sunfire C18 column with ACN/water mobile phases) to yield a white solid as product (42 mg, 81% yield.) MS/ES+: m/z=430.