Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=1.[NH2:10][C:11]1[C:27]([Cl:28])=[CH:26][C:14]([C:15]([NH:17][C@H:18]2[CH2:23][CH2:22][NH:21][CH2:20][C@H:19]2[O:24][CH3:25])=[O:16])=[C:13]([O:29][CH3:30])[CH:12]=1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O>[NH2:10][C:11]1[C:27]([Cl:28])=[CH:26][C:14]([C:15]([NH:17][C@H:18]2[CH2:23][CH2:22][N:21]([CH2:3][C:4]3[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=3)[CH2:20][C@H:19]2[O:24][CH3:25])=[O:16])=[C:13]([O:29][CH3:30])[CH:12]=1
Reactant: ClCc1cccnc1
Reactant: COc1cc(N)c(Cl)cc1C(=O)N[C@H]1CCNC[C@H]1OC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc(N)c(Cl)cc1C(=O)N[C@H]1CCN(Cc2cccnc2)C[C@H]1OC
Temperature: 60 °C
Reaction time: 5 h
Yield: 64.2 %

Procedure:
A mixture of 2.8 parts of 3-(chloromethyl)pyridine hydrochloride, 4.7 parts of cis-4-amino-5-chloro-2-methoxy-N-(3-methoxy-4-piperidinyl)benzamide, 5.3 parts of sodium carbonate and 68 parts of N,N-dimethylformamide was stirred for 5 hours at about 60° C. The reaction mixture was cooled to room temperature and filtered. The filtrate was evaporated. The solid residue was purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (90:10 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from ethanol. The product was filtered off and dried, yielding 3.84 parts (64.2%) of cis-4-amino-5-chloro-2-methoxy-N-[3-methoxy-1-(3-pyridinylmethyl)-4-piperidinyl]benzamide; mp. 188.9° C. (compound 91).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]2[CH:15]=[CH:16][C:17]3[NH:22][C:21](=[O:23])[O:20][C:19]([CH3:25])([CH3:24])[C:18]=3[CH:26]=2)=[CH:4][CH:3]=1.[OH:27]O>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]2[CH:15]=[CH:16][C:17]3[NH:22][C:21](=[O:23])[O:20][C:19]([CH3:24])([CH3:25])[C:18]=3[CH:26]=2)=[O:27])=[CH:4][CH:3]=1
Reactant: CC1(C)OC(=O)Nc2ccc(OCCCCSc3ccc(Cl)cc3)cc21
Reactant: OO
Product: CC1(C)OC(=O)Nc2ccc(OCCCCS(=O)c3ccc(Cl)cc3)cc21

Procedure:
Prepared analogously to Example 2 from 6-[4-(4-chlorophenylmercapto)-butoxy]-4,4-dimethyl-4H-3,1-benzoxazin-2-one and hydrogen peroxide.
Reaction SMILES: [NH2:1][CH:2]1[C:8](=[O:9])[N:7]([CH3:10])[C:6]2[CH:11]=[CH:12][CH:13]=[CH:14][C:5]=2[C:4]2[CH:15]=[CH:16][CH:17]=[CH:18][C:3]1=2.[CH3:19][CH:20]([C:24]([NH:26][CH2:27][C:28]1[CH:33]=[C:32]([O:34][CH3:35])[CH:31]=[C:30]([O:36][CH3:37])[CH:29]=1)=[O:25])[C:21](O)=[O:22]>>[CH3:37][O:36][C:30]1[CH:29]=[C:28]([CH:33]=[C:32]([O:34][CH3:35])[CH:31]=1)[CH2:27][NH:26][C:24](=[O:25])[CH:20]([CH3:19])[C:21]([NH:1][CH:2]1[C:8](=[O:9])[N:7]([CH3:10])[C:6]2[CH:11]=[CH:12][CH:13]=[CH:14][C:5]=2[C:4]2[CH:15]=[CH:16][CH:17]=[CH:18][C:3]1=2)=[O:22]
Reactant: CN1C(=O)C(N)c2ccccc2-c2ccccc21
Reactant: COc1cc(CNC(=O)C(C)C(=O)O)cc(OC)c1
Product: COc1cc(CNC(=O)C(C)C(=O)NC2C(=O)N(C)c3ccccc3-c3ccccc32)cc(OC)c1

Procedure:
The title compound, MS: m/e=488.3 (M+H+), was prepared in analogy to example 16 from 7-amino-5-methyl-5H,7H-dibenzo[b,d]azepin-6-one and 2-methyl-N-(3,5-dimethoxy-benzyl)-malonamic acid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:36])[C@@H:4]([NH:25][C:26](=[O:35])[C:27]1[CH:32]=[C:31]([Cl:33])[CH:30]=[CH:29][C:28]=1[NH2:34])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:14][CH:13]=2)=[CH:8][CH:7]=1.[CH3:37][O:38][C:39](=[O:46])[CH2:40][CH2:41][CH2:42][CH2:43][CH:44]=O.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH3:37][O:38][C:39](=[O:46])[CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][NH:34][C:28]1[CH:29]=[CH:30][C:31]([Cl:33])=[CH:32][C:27]=1[C:26](=[O:35])[NH:25][C@H:4]([C:3]([O:2][CH3:1])=[O:36])[CH2:5][C:6]1[CH:7]=[CH:8][C:9]([C:12]2[CH:13]=[CH:14][C:15]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:16][CH:17]=2)=[CH:10][CH:11]=1
Reactant: COC(=O)CCCCC=O
Reactant: COC(=O)[C@H](Cc1ccc(-c2ccc(Oc3ccccc3)cc2)cc1)NC(=O)c1cc(Cl)ccc1N
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: COC(=O)CCCCCNc1ccc(Cl)cc1C(=O)N[C@@H](Cc1ccc(-c2ccc(Oc3ccccc3)cc2)cc1)C(=O)OC

Procedure:
(S)-6-{4-Chloro-2-[1-methoxycarbonyl-2-(4′-phenoxy-biphenyl-4-yl)-ethylcarbamoyl]-phenylamino}-hexanoic acid methyl ester was prepared following Procedure G using (S)-2-(2-amino-5-chloro-benzoylamino)-3-(4′-phenoxy-biphenyl-4-yl)propionic acid methyl ester (401 mg, 0.8 mmol), 6-oxo-hexanoic acid methyl ester (231 mg, 1.6 mmol), acetic acid (2.4 mmol), sodium triacetoxyborohydride (437 mg, 97%, 2 mmol) and DCE (6 mL). Purification by flash chromatography (ethyl acetate/hexanes 1:3) gave the title compound as yellow oil (418 mg).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]1[CH:14]=[CH:13][CH:12]=[CH:11]1)([O-:3])=[O:2].P(Cl)(Cl)(Cl)=O.[OH-].[Na+].CN(C)[CH:24]=[O:25]>>[N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]1[CH:14]=[CH:13][CH:12]=[C:11]1[CH:24]=[O:25])([O-:3])=[O:2]
Reactant: CN(C)C=O
Reactant: O=[N+]([O-])c1ccccc1-n1cccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Product: O=Cc1cccn1-c1ccccc1[N+](=O)[O-]
Temperature: 90 °C
Reaction time: 0.5 h

Procedure:
To a solution of 3.76 g of 1-(2-nitrophenyl)pyrrole in 20 ml of N,N-dimethylformamide at 0° C. is added dropwise with stirring 3 ml of phosphorus oxychloride. Stirring is continued for 30 minutes and the reaction mixture is heated at 90° C. for 1 hour. After cooling to room temperature the mixture is treated with crushed ice and the pH adjusted to 12 with 2N sodium hydroxide. The resulting suspension is filtered, washed with water and dried to give 5.81 g of the desired product as a light yellow solid m.p. 119°-122° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[CH2:10][C@:9]3([CH:15]4[CH2:16][CH2:17][N:12]([CH2:13][CH2:14]4)[CH2:11]3)[O:8][C:5]2=[N:6][CH:7]=1.[CH3:18][Si:19]([C:22]#[CH:23])([CH3:21])[CH3:20].C(N(CC)CC)C>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(#N)C>[CH3:18][Si:19]([CH3:21])([CH3:20])[C:22]#[C:23][C:2]1[CH:3]=[C:4]2[CH2:10][C@:9]3([CH:15]4[CH2:16][CH2:17][N:12]([CH2:13][CH2:14]4)[CH2:11]3)[O:8][C:5]2=[N:6][CH:7]=1
Reactant: Brc1cnc2c(c1)C[C@@]1(CN3CCC1CC3)O2
Reactant: C#C[Si](C)(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: C[Si](C)(C)C#Cc1cnc2c(c1)C[C@@]1(CN3CCC1CC3)O2
Temperature: 100 °C
Yield: 90 %

Procedure:
(R)-(-)-5'-Bromospiro[1-azabicyclo[2.2.2]octane-3,2'(3'H)-furo[2,3-b]pyridine](295 mg, 1 mmol), trimethylsilylacetylene (0.355 mL, 2.5 mmol), tetrakis(triphenylphosphine)palladium (230 mg, 0.2 mmol), triethylamine (2 mL) and anhydrous acetonitrile (2 mL) were combined in a heavy-walled threaded glass tube containing a magnetic stir bar, purged with argon and sealed with a Teflon plug and FETFE O-ring. The mixture was stirred and heated at 100° C. for 4 hours, cooled to room temperature, dissolved in chloroform (25 mL), washed with saturated aqueous sodium carbonate (2 mL), dried (MgSO4), and evaporated under reduced pressure. Purification by flash chromatography through silica gel (eluting with ammoniated ether/methanol, 9:1) afforded the title compound (280 mg, 0.90 mmol, 90%): chemical ionization MS (m/z, relative intensity) 313 ([MH]+, 30).
Reaction SMILES: [C:1]([C:5]1[N:9]([CH2:10][CH:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[C:8]2[CH:17]=[CH:18][C:19]([S:21](Cl)(=[O:23])=[O:22])=[CH:20][C:7]=2[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1>CN(C1C=CN=CC=1)C.CC#N>[C:1]([C:5]1[N:9]([CH2:10][CH:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[C:8]2[CH:17]=[CH:18][C:19]([S:21]([N:25]3[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]3)(=[O:23])=[O:22])=[CH:20][C:7]=2[N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: C1CCNCC1
Reactant: CC(C)(C)c1nc2cc(S(=O)(=O)Cl)ccc2n1CC1CCOCC1
Agent: CN(C)c1ccncc1
Solvent: CC#N
Product: CC(C)(C)c1nc2cc(S(=O)(=O)N3CCCCC3)ccc2n1CC1CCOCC1
Yield: 43.5 %

Procedure:
Following the same procedure in Example 1, Step A, using 2-tert-butyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazole-5-sulfonyl chloride (61 mg, 0.17 mmol), piperidine (0.2 mL, 2.0 mmol) and DMAP (50 mg, 0.41 mmol) in MeCN (5 mL). The crude product was purified by MPLC using Hex/EtOAc (1:1) on silica gel to give 31 mg (45%) of a white solid as the title compound. 1H NMR (400 MHz, METHANOL-D4) δ 1.40 (m, 2 H), 1.47-1.64 (m, 8 H), 1.65 (s, 9 H), 2.25-2.48 (m, 1 H), 2.92-3.05 (m, 4 H), 3.29-3.39 (m, 2 H), 3.88-3.98 (m, 2 H), 4.50 (d, J=7.62 Hz, 2 H), 7.82 (dd, J=8.69, 1.66 Hz, 1 H), 8.01 (d, J=8.79 Hz, 1 H), 8.06 (d, J=1.56 Hz, 1 H); MS (ESI) (M+H)+=420.0; Anal. Calcd for C22H33N3O3S+1.10 TFA+0.50H2O+0.10 CH3OH (557.23): C, 52.38; H, 6.42; N, 7.54. Found: C, 52.38; H, 6.43; N, 7.58.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[NH:8][N:9]=[C:10]([C:11]3[CH:16]=[CH:15][N:14]=[C:13]([S:17][CH3:18])[N:12]=3)[C:5]2=[CH:4][N:3]=1.[NH2:19][CH2:20][CH2:21][OH:22].C(N(CC)CC)C>CC(O)C>[CH3:18][S:17][C:13]1[N:12]=[C:11]([C:10]2[C:5]3[C:6](=[N:7][C:2]([NH:19][CH2:20][CH2:21][OH:22])=[N:3][CH:4]=3)[NH:8][N:9]=2)[CH:16]=[CH:15][N:14]=1
Reactant: CSc1nccc(-c2n[nH]c3nc(Cl)ncc23)n1
Reactant: NCCO
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: CSc1nccc(-c2n[nH]c3nc(NCCO)ncc23)n1

Procedure:
To a solution of 6-chloro-3-(2-methylsulfanyl-pyrimidin-4-yl)-1H-pyrazolo[3,4-d]pyrimidine (from Example 7 supra) (590 mg, 2.12 mmol) in 2-propanol (20 mL) was added 2-aminoethanol (142 mg, 2.33 mmol) followed by triethylamine (235 mg, 2.33 mmol). The reaction mixture was stirred at reflux for 16 hours and the solvent was then removed under reduced pressure. The residue was washed with 2-propanol (1 mL) and dried by evaporation to afford 2-[3-(2-methylsulfanyl-pyrimidin-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-ylamino]-ethanol. (Yield 0.7 g, crude). LC-MS: [M+H]+ 304.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([Br:10])[CH:9]=1)[CH:5]=[O:6].[CH2:11](O)[CH2:12][OH:13]>C1(C)C=CC=CC=1.C(OCC)(=O)C.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([CH:5]2[O:13][CH2:12][CH2:11][O:6]2)[CH:7]=[C:8]([Br:10])[CH:9]=1
Reactant: O=Cc1cc(Br)cc(Br)c1
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: O
Product: Brc1cc(Br)cc(C2OCCO2)c1
Temperature: 25 °C
Yield: 99.9 %

Procedure:
A mixture of 3,5-dibromobenzaldehyde (5.37 g, 20.37 mmol), ethylene glycol (3.40 mL, 61.10 mmol) and p-toluenesulfonic acid monohydrate (78 mg, 0.41 mmol) in anhydrous toluene (30 mL) was heated at reflux under Dean-Stark conditions for 5 h. The reaction mixture was cooled to room temperature and diluted with ethyl acetate (25 mL). The ethyl acetate layer was washed with a saturated NaHCO3 solution (25 mL). The organic layer was removed and washed with water (1×25 mL) and dried with anhydrous MgSO4, filtered and evaporated in vacuo to give a colorless viscous liquid (6.27 g). GC-MS (Cl/methane) analysis of the liquid shows the desired product's mass: m/z 306 (79Br,79BrM+), m/z 308 (79Br,81BrM+), and m/z 310 (81Br,81BrM+); Calcd for C9H8Br2O2: 307.96. 1H NMR (400 MHz, CDl3): δ 3.97-4.10 (M, 4H, 2×—CH2—O—), 5.74 (s, 1H, O—CH-0), 7.53 (d, J=1.80 Hz, 2H), 7.63 (appt, J=1.80 Hz, 1H). 1H NMR spectrum of the liquid was consistent with the suggested structure of the product.
Reaction SMILES: C([O:5][C:6](=[O:50])[C@@H:7]([NH:13][C:14]([O:16][CH2:17][C:18]([CH3:49])([CH3:48])[CH2:19][CH:20]1[CH2:22][CH:21]1[C:23]1[CH:24]=[C:25]2[C:30](=[CH:31][C:32]=1[O:33][CH3:34])[N:29]=[C:28]([O:35][CH2:36][CH3:37])[CH:27]=[C:26]2[O:38][C@H:39]1[CH2:43][NH:42][C@H:41]([C:44]([O:46][CH3:47])=[O:45])[CH2:40]1)=[O:15])[CH:8]1[CH2:12][CH2:11][CH2:10][CH2:9]1)(C)(C)C.[ClH:51]>O1CCOCC1>[ClH:51].[ClH:51].[CH:8]1([C@H:7]([NH:13][C:14]([O:16][CH2:17][C:18]([CH3:48])([CH3:49])[CH2:19][CH:20]2[CH2:22][CH:21]2[C:23]2[CH:24]=[C:25]3[C:30](=[CH:31][C:32]=2[O:33][CH3:34])[N:29]=[C:28]([O:35][CH2:36][CH3:37])[CH:27]=[C:26]3[O:38][C@@H:39]2[CH2:40][C@@H:41]([C:44]([O:46][CH3:47])=[O:45])[NH:42][CH2:43]2)=[O:15])[C:6]([OH:50])=[O:5])[CH2:9][CH2:10][CH2:11][CH2:12]1
Reactant: CCOc1cc(O[C@H]2CN[C@H](C(=O)OC)C2)c2cc(C3CC3CC(C)(C)COC(=O)N[C@H](C(=O)OC(C)(C)C)C3CCCC3)c(OC)cc2n1
Agent: Cl
Solvent: C1COCCO1
Product: CCOc1cc(O[C@H]2CN[C@H](C(=O)OC)C2)c2cc(C3CC3CC(C)(C)COC(=O)N[C@H](C(=O)O)C3CCCC3)c(OC)cc2n1

Procedure:
A solution of the product from Step 5 (25.2 g, 31.6 mmol) in 4.0 N HCl in dioxane (400 mL) was stirred for 6 hours. N2 was bubbled through the solution for 15 minutes, and the solvent was concentrated in vacuo to give 20.3 g of the title compound as a thick oil. LRMS ESI+ (M+H−2(HCl))+ 642.3, calcd for C34H48N3O9: 642.3.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[CH3:14][CH:15]1[C:24]2[C:19](=[CH:20][CH:21]=[N:22][CH:23]=2)[CH2:18][CH2:17][NH:16]1>>[Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:16]3[CH2:17][CH2:18][C:19]4[C:24](=[CH:23][N:22]=[CH:21][CH:20]=4)[CH:15]3[CH3:14])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: O=C(O)c1cc2ncc(Cl)cn2n1
Reactant: CC1NCCc2ccncc21
Product: CC1c2cnccc2CCN1C(=O)c1cc2ncc(Cl)cn2n1

Procedure:
In close analogy to the procedure described in Example 1, 6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 1-methyl-1,2,3,4-tetrahydro-[2,7]naphthyridine to provide the title compound in moderate yield.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[C:6]([CH3:12])[C:5]=1[NH2:13].[CH3:15][C:16]1[CH:17]=[CH:18][C:19]([C:22](O)=[O:23])=[N:20][CH:21]=1.P(Cl)(Cl)(Cl)=O.[OH-].[Na+]>ClCCl.N1C=CC=CC=1>[CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[C:6]([CH3:12])[C:5]=1[NH:13][C:22]([C:19]1[CH:18]=[CH:17][C:16]([CH3:15])=[CH:21][N:20]=1)=[O:23]
Reactant: COC(=O)c1ccc(OC)c(C)c1N
Reactant: Cc1ccc(C(=O)O)nc1
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccncc1
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClCCl
Product: COC(=O)c1ccc(OC)c(C)c1NC(=O)c1ccc(C)cn1
Reaction time: 1 h
Yield: 65.2 %

Procedure:
2-Amino-4-methoxy-3-methyl-benzoic acid methyl ester (400 mg, 2 mmol) and 5-methyl-pyridine-2-carboxylic acid (280 mmol, 2 mmol) where dissolved in dichloro-methane (8 ml) and pyridine (1 ml). Phosphorous oxychloride (0.37 ml) was added while cooling on ice-bath. The mixture was left at 0° C. for 1 h then allowed to attain room temperature. Aqueous sodium hydroxide (20 ml, 1M) was added and the mixture were extracted with dichloromethane. Purification by column chromatography on silica gel (ether-pentane 1:1) gave pure title compound (410 mg, 65%). MS (M−H)+ 315.1
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[C:5]([CH2:7][N:8]2[C:16]3[C:11](=[C:12]([C:19]([F:22])([F:21])[F:20])[C:13]([C:17]#[N:18])=[CH:14][CH:15]=3)[CH:10]=[C:9]2[CH3:23])[N:6]=1.[F:24][C:25]([F:40])([F:39])[C:26]1[CH:27]=[C:28](B(O)O)[CH:29]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:31]=1>>[F:24][C:25]([F:39])([F:40])[C:26]1[CH:27]=[C:28]([C:2]2[S:3][CH:4]=[C:5]([CH2:7][N:8]3[C:16]4[C:11](=[C:12]([C:19]([F:22])([F:21])[F:20])[C:13]([C:17]#[N:18])=[CH:14][CH:15]=4)[CH:10]=[C:9]3[CH3:23])[N:6]=2)[CH:29]=[C:30]([C:32]([F:33])([F:34])[F:35])[CH:31]=1
Reactant: Cc1cc2c(C(F)(F)F)c(C#N)ccc2n1Cc1csc(Br)n1
Reactant: OB(O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Product: Cc1cc2c(C(F)(F)F)c(C#N)ccc2n1Cc1csc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)n1

Procedure:
Synthesized as described in Example 310D using 1-[(2-bromo-1,3-thiazol-4-yl)methyl]-2-methyl-4-(trifluoromethyl)-1H-indole-5-carbonitrile (Example 311B) and [3,5-bis(trifluoromethyl)phenyl]boronic acid: MS (ES) m/z 534 (M+1).
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=4[Cl:22])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:23]([CH2:30][CH3:31])[CH2:24][C:25](OCC)=[O:26])=[CH:4][CH:3]=1.[OH-].[Na+].ClC(OCC)=O.[NH3:40]>O1CCCC1.C(OCC)(=O)C>[Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=4[Cl:22])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:23]([CH2:30][CH3:31])[CH2:24][C:25]([NH2:40])=[O:26])=[CH:4][CH:3]=1
Reactant: CCOC(=O)CC(CC)c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl
Reactant: N
Agent: CCOC(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCC(CC(N)=O)c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 37 %

Procedure:
A solution of ethyl 3-[9-chloro-1-(2,4-dichlorophenyl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazol-6-yl]pentanoate (173 mg, 0.360 mmol) and aqueous sodium hydroxide (8 M, 0.09 mL) in tetrahydrofuran (1.8 mL) was stirred for 24 h at reflux. The reaction mixture was concentrated in vacuo. To the residue was added tetrahydrofuran (3.0 mL) and ethyl chloroformate (74.3 μL, 0.780 mmol) at 0° C. After being stirred for 1.5 h at room temperature, the reaction mixture was cooled down to 0° C. And then aqueous ammonia solution (28%, 150 μL) was added. After 2 h, the reaction mixture was diluted with ethyl acetate, washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography on NH silica gel eluting with ethyl acetate to give the title compound as a colorless solid (60.1 mg, 0.133 mmol, 37%).
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:41])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([C:24]3[CH:29]=[CH:28][C:27]([O:30][CH2:31][C:32](=[O:37])[C:33]([CH3:36])([CH3:35])[CH3:34])=[C:26]([CH3:38])[CH:25]=3)([CH2:22][CH3:23])[CH2:20][CH3:21])=[CH:15][C:14]=2[CH3:39])=[CH:9][C:8]=1[F:40].[Cl-].[NH4+]>CO>[CH3:36][C:33]([CH3:34])([CH3:35])[C:32](=[O:37])[CH2:31][O:30][C:27]1[CH:28]=[CH:29][C:24]([C:19]([C:16]2[CH:17]=[CH:18][C:13]([C:10]3[CH:11]=[CH:12][C:7]([CH2:6][C:5]([OH:41])=[O:4])=[C:8]([F:40])[CH:9]=3)=[C:14]([CH3:39])[CH:15]=2)([CH2:20][CH3:21])[CH2:22][CH3:23])=[CH:25][C:26]=1[CH3:38]
Reactant: CCC(CC)(c1ccc(OCC(=O)C(C)(C)C)c(C)c1)c1ccc(-c2ccc(CC(=O)OC)c(F)c2)c(C)c1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Product: CCC(CC)(c1ccc(OCC(=O)C(C)(C)C)c(C)c1)c1ccc(-c2ccc(CC(=O)O)c(F)c2)c(C)c1
Reaction time: 4 h
Yield: 103.1 %

Procedure:
A 2 N sodium hydroxide aqueous solution (0.25 mL) was added to a solution of (4′-{1-[4-(3,3-dimethyl-2-oxo-butoxy)-3-methyl-phenyl]-1-ethyl-propyl}-3-fluoro-2′-methyl-biphenyl-4-yl)acetic acid methyl ester (Example 103-(1); 38.6 mg, 0.0724 mmol) in methanol (2.4 mL), and the mixture was stirred for four hours. A saturated aqueous ammonium chloride solution was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the title compound (38.7 mg, 99%).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][S:5]([CH2:8][CH:9]=[CH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)(=[O:7])=[O:6].C1(C)C=CC(S(O)(=O)=O)=CC=1.[O:28]1[CH:33]=[CH:32][CH2:31][CH2:30][CH2:29]1>ClCCl>[CH2:8]([S:5]([CH2:4][CH2:3][CH2:2][O:1][CH:29]1[CH2:30][CH2:31][CH2:32][CH2:33][O:28]1)(=[O:7])=[O:6])[CH:9]=[CH:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: O=S(=O)(CC=Cc1ccccc1)CCCO
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Product: O=S(=O)(CC=Cc1ccccc1)CCCOC1CCCCO1
Reaction time: 24 h

Procedure:
Cinnamylthiopropionic acid, m.p. 87° C., was prepared from cinnamyl bromide and mercaptopropionic acid and oxidised by the method described in Example 23(a) to cinnamylsulphonylpropionic acid, m.p. 160° C. This acid was reduced by addition to a stirred suspension of lithium aluminium hydride (2 equivalents) in tetrahydrofuran at -20° to -25° C. and the product formed isolated by ethyl acetate extraction to give cinnamyl 3-hydroxypropyl sulphone, m.p. 86° C. A solution of cinnamyl 3-hydroxylpropyl sulphone, para-toluene sulphonic acid (catalytic) and dihydropyran (2 equivalents) in dichloromethane was allowed to stand at room temperature for 24 hours, evaporated, and recrystallised from diethyl ether to give the title compound, m.p. about 45° C.
Reaction SMILES: [CH2:1]([C:3]1([CH2:16][CH3:17])[CH2:15][CH2:14][C:6]2=[C:7]([C:11]([OH:13])=O)[S:8][C:9]([CH3:10])=[C:5]2[CH2:4]1)[CH3:2].Cl.[CH2:19]([C:21]1[CH:22]=[C:23]([CH:28]=[C:29]([CH3:31])[N:30]=1)[C:24]([NH:26][NH2:27])=O)[CH3:20]>>[CH2:16]([C:3]1([CH2:1][CH3:2])[CH2:15][CH2:14][C:6]2=[C:7]([C:11]3[O:13][C:24]([C:23]4[CH:28]=[C:29]([CH3:31])[N:30]=[C:21]([CH2:19][CH3:20])[CH:22]=4)=[N:26][N:27]=3)[S:8][C:9]([CH3:10])=[C:5]2[CH2:4]1)[CH3:17]
Reactant: CCC1(CC)CCc2c(C(=O)O)sc(C)c2C1
Reactant: CCc1cc(C(=O)NN)cc(C)n1
Agent: Cl
Product: CCc1cc(-c2nnc(-c3sc(C)c4c3CCC(CC)(CC)C4)o2)cc(C)n1

Procedure:
4-[5-(5,5-Diethyl-3-methyl-4,5,6,7-tetrahydro-benzo[c]thiophen-1-yl)-[1,3,4]oxadiazol-2-yl]-2-ethyl-6-methyl-pyridine is synthesized from 5,5-diethyl-3-methyl-4,5,6,7-tetrahydro-benzo[c]thiophene-1-carboxylic acid and 2-ethyl-6-methyl-isonicotinic acid hydrazide hydrochloride in analogy to Example 9; LC-MS: tR=0.98 min, [M+1]=396.39.
Reaction SMILES: [Cl:1][C:2]([Cl:14])([F:13])[S:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.[O:15]1CCC[CH2:16]1.C=O>O.[OH-].C([N+](CCCC)(CCCC)CCCC)CCC>[Cl:14][C:2]([Cl:1])([F:13])[S:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]([CH2:16][OH:15])[CH:5]=1
Reactant: C1CCOC1
Reactant: FC(Cl)(Cl)Sc1c[nH]c2ccccc12
Agent: C=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [OH-]
Solvent: O
Product: OCn1cc(SC(F)(Cl)Cl)c2ccccc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
0.50 g of 3-{[dichlorofluoromethyl]thio}-1H-indole was dissolved to 10 ml of tetrahydrofuran. 10 ml of formaldehyde 36% in water and 0.4 ml of tetrabutylammonium hydroxide 10% in water were added to the solution, followed by stirring at room temperature for 30 minutes. Water was added to the reaction mixture, and extracted with MTBE. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain 0.54 g of 3-{[dichlorofluoromethyl]thio}-1H-indole-1-ylmethanol.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:15]=[CH:14][C:6]([CH2:7][S:8][C:9]2[N:13]=[CH:12][NH:11][N:10]=2)=[CH:5][CH:4]=1.[N+](=[CH2:18])=[N-]>CO.CCOCC>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][S:8][C:9]2[N:10]([CH3:18])[N:11]=[CH:12][N:13]=2)=[CH:14][CH:15]=1
Reactant: C=[N+]=[N-]
Reactant: COc1ccc(CSc2nc[nH]n2)cc1
Solvent: CCOCC
Solvent: CO
Product: COc1ccc(CSc2ncnn2C)cc1
Reaction time: 1 h

Procedure:
To a solution of 3-p-methoxybenzylthio-1,2,4-triazole (10.0 g : 45.2 mMol.) in methanol (100 ml) is added under ice cooling a solution of diazomethane in ether (prepared from 15 g of N-nitrosomethylurea), and the mixture is stirred for 1 hour. The reaction mixture is concentrated and purified by Lobar column chromatography (toluene : ethyl acetate=1:2 to 1:3) to give 3-p-methoxybenzylthio-2-methyl- 1,2,4-triazole [5.17 g : NMR δ(CDCl3) ppmi 3.63(s, 3H), 3.79(s, 3H), 4.34(s, 2H), 6.80-6.84, 7.19-7.24(A2B2, 4H), 7.88(s, 1H). IR ν(CHCl3) cm-1 : 1611, 1511, 1476, 1464, 1440, 1360, 1302 Yield: 49%]and 3-p- methoxybenzylthio-1-methyl-1,2,4-triazole [3.60 g : NMR δ(CDCl3) ppmi 3.78(s, 3H), 3.87(s, 3H), 4.31(s, 2H), 6.80-6.85, 7.30- 7.34(A2B2, 4H), 7.99(s, 1H). IR ν(CHCl ) cm-1 : 1612, 1512, 1465, 1440, 1421, 1356, 1302. Yield : 34%].
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.Cl[C:12]1[C:13](=[O:26])[NH:14][C:15]2[C:20]([N:21]=1)=[CH:19][C:18]([C:22]([O:24][CH3:25])=[O:23])=[CH:17][CH:16]=2>CN1C(=O)CCC1>[O:26]=[C:13]1[C:12]([N:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH2:4][CH2:3][CH2:2]2)=[N:21][C:20]2[C:15](=[CH:16][CH:17]=[C:18]([C:22]([O:24][CH3:25])=[O:23])[CH:19]=2)[NH:14]1
Reactant: COC(=O)c1ccc2[nH]c(=O)c(Cl)nc2c1
Reactant: c1ccc2c(c1)CCCN2
Solvent: CN1CCCC1=O
Product: COC(=O)c1ccc2[nH]c(=O)c(N3CCCc4ccccc43)nc2c1
Reaction time: 3 h
Yield: 74.3 %

Procedure:
To a solution of 1,2,3,4-tetrahydroquinoline (1.0 g, 7.51 mmol) in NMP (20 ml) was added methyl 3-chloro-2-oxo-1,2-dihydroquinoxaline-6-carboxylate (670 mg, 2.81 mmol) with stifling 3 h at 130° C. in an oil bath. The product was precipitated with water (80 ml), collected by filtration to afford methyl 2-oxo-3-(1,2,3,4-tetrahydroquinolin-1-yl)-1,2-dihydroquinoxaline-6-carboxylate as a yellow solid (700 mg, 28%).