Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:18][CH2:19][C:20](O)=[O:21])([O:3][CH2:4][CH:5]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]2[C:6]1=[CH:7][CH:8]=[CH:9][CH:10]=2)=[O:2].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:56][C@H:57]([C:65]([NH:67][CH2:68][C:69]([OH:71])=[O:70])=[O:66])[CH2:58][C:59]1[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=1>CN(C=O)C.C(OCC)(=O)C>[CH:7]1[C:6]2[CH:5]([CH2:4][O:3][C:1]([NH:18][CH2:19][C:20]([NH:56][C@H:57]([C:65]([NH:67][CH2:68][C:69]([OH:71])=[O:70])=[O:66])[CH2:58][C:59]3[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=3)=[O:21])=[O:2])[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]=2[CH:10]=[CH:9][CH:8]=1
Reactant: N[C@@H](Cc1ccccc1)C(=O)NCC(=O)O
Reactant: O=C(O)CNC(=O)OCC1c2ccccc2-c2ccccc21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: O=C(O)CNC(=O)[C@H](Cc1ccccc1)NC(=O)CNC(=O)OCC1c2ccccc2-c2ccccc21
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a solution of Fmoc-glycine (297 mg, 1.00 mmol) in DMF (5 mL) at 0° C. was added DIEA (348 μL, 2.00 mmol) and HBTU (379 mg, 1.00 mmol). After stirring for 10 min at 0° C., the resulting activated ester solution was added to crude dipeptide 73 (1.00 mmol) and the reaction mixture was stirred for 2 h at 0° C. It was diluted with ethyl acetate, washed with H2O, 1N HCl solution, saturated NaHCO3 solution and saturated NaCl solution. The organic layer was dried over MgSO4, filtered and concentrated to dryness. The crude product was purified by silica gel chromatography on a Biotage™ flash chromatography system using a gradient of 0-75% ethyl acetate in CH2Cl2. Tripeptide 74 was obtained as a white solid (546 mg, 98%). 1H NMR (400 MHz, CDCl3) δ 1.44 (s, 9H), 3.10 (d, J=6.8 Hz, 2H), 3.74-3.95 (m, 4H), 4.21 (t, J=7.0 Hz, 1H), 4.40 (d, J=7.2 Hz, 2H), 4.70 (q, J=7.5 Hz, 1H), 5.36 (bs, 1H), 6.31 (bs, 1H), 6.53 (d, J=7.4 Hz, 1H), 7.17-7.22 (m, 3H), 7.24-7.28 (m, 2H), 7.30-7.34 (m, 2H), 7.41 (t, J=7.4 Hz, 2H), 7.59 (d, J=7.3 Hz, 2H), 7.77 (d, J=7.3 Hz, 2H).
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([CH3:14])[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br-].[Na+].C(O)(=[O:19])C>O.O.O.O.C([O-])(=O)C.[Co+2].C([O-])(=O)C>[O:1]([C:8]1[CH:9]=[C:10]([CH:11]=[CH:12][CH:13]=1)[CH:14]=[O:19])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cccc(Oc2ccccc2)c1
Reactant: CC(=O)O
Agent: [Co+2]
Agent: CC(=O)[O-]
Agent: [Br-]
Solvent: O
Product: O=Cc1cccc(Oc2ccccc2)c1

Procedure:
Experiments were carried out under such condition that the mixing ratio of m-phenoxytoluene to acetic acid was varied. Using as catalysts 3 mol% of cobalt acetate tetrahydrate and 3 mol% of sodium bromide to m-phenoxytoluene and limiting the total volume of the reaction liquid to 150 ml, the experiments were carried out in the same manner as described in Example 17. The results obtained are shown in Table 21. No substantial intermediate oxidation product was obtained when the amount of acetic acid was zero. When the amount of acetic acid was 0.5 mol per mol of m-phenoxytoluene, m-phenoxybenzaldehyde was obtained at a rate of selection of 20 mol% at a conversion rate of 30%. However, this experiment showed bad reproducibility.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([Cl:15])=[N:10][CH:11]=[N:12][C:13]=2Cl)=[CH:4][CH:3]=1.[K+].[CH2:17]([NH:24][S:25]([NH-:28])(=[O:27])=[O:26])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CS(C)=O.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>[Cl:15][C:9]1[N:10]=[CH:11][N:12]=[C:13]([NH:28][S:25](=[O:26])(=[O:27])[NH:24][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:8]=1[C:5]1[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=1
Reactant: Clc1ncnc(Cl)c1-c1ccc(Br)cc1
Reactant: [NH-]S(=O)(=O)NCc1ccccc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [K+]
Solvent: CS(C)=O
Product: O=S(=O)(NCc1ccccc1)Nc1ncnc(Cl)c1-c1ccc(Br)cc1
Yield: 102.7 %

Procedure:
A solution of 5-(4-bromophenyl)-4,6-dichloro-pyrimidine (4.00 g, 13.2 mmol) and benzylsulfamide potassium salt (7.38 g, 32.9 mmol) in DMSO (30 mL) was stirred at it for 24 h before being diluted with a 10% aq. citric acid solution (200 mL). The suspension that formed was filtered. The collected solid was washed well with water and dried under HV at 40° C. for 48 h to give the expected product as a white powder (6.15 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([N+:23]([O-])=O)=[C:7]([S:9]([NH:12][C:13]2[CH:14]=[CH:15][CH:16]=[C:17]3[C:22]=2[N:21]=[CH:20][CH:19]=[CH:18]3)(=[O:11])=[O:10])[CH:8]=1.Cl[Sn]Cl>Cl.CCO>[NH2:23][C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][C:7]=1[S:9]([NH:12][C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[N:21]=[CH:20][CH:19]=[CH:18]2)(=[O:11])=[O:10]
Reactant: COc1ccc([N+](=O)[O-])c(S(=O)(=O)Nc2cccc3cccnc23)c1
Agent: Cl
Agent: Cl[Sn]Cl
Solvent: CCO
Product: COc1ccc(N)c(S(=O)(=O)Nc2cccc3cccnc23)c1
Yield: 71.9 %

Procedure:
In a similar fashion using route 1 general procedure 4, 5-methoxy-2-nitro-N-quinolin-8-yl-benzenesulfonamide (Intermediate 264) (690 mg, 1.9 mmol), SnCl2 (1.45 g, 7.68 mmol), 6N HCl (2 drops) and EtOH (12 ml) at 85° C. for 6 h gave the title compound (450 mg, 71%) which was used in the next step without further purification.
Reaction SMILES: CC1SC(C([O-])=S)=CC=1.[NH2:10][C:11](=[S:22])[C:12]1[CH:13]=[C:14]([C:18]([O:20][CH3:21])=[S:19])[S:15][C:16]=1[CH3:17].[F:23][C:24]([F:40])([F:39])[C:25]1[CH:26]=[C:27]([C:35](=O)[CH2:36]Br)[CH:28]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:30]=1>>[F:23][C:24]([F:39])([F:40])[C:25]1[CH:26]=[C:27]([C:35]2[N:10]=[C:11]([C:12]3[CH:13]=[C:14]([C:18]([O:20][CH3:21])=[S:19])[S:15][C:16]=3[CH3:17])[S:22][CH:36]=2)[CH:28]=[C:29]([C:31]([F:32])([F:33])[F:34])[CH:30]=1
Reactant: COC(=S)c1cc(C(N)=S)c(C)s1
Reactant: O=C(CBr)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: Cc1ccc(C([O-])=S)s1
Product: COC(=S)c1cc(-c2nc(-c3cc(C(F)(F)F)cc(C(F)(F)F)c3)cs2)c(C)s1
Yield: 5 %

Procedure:
Methyl 4-{4-[3,5-bis(trifluoromethyl)phenyl]1,3-thiazol-2-yl)}-5-methylthiothiophene-2-carboxylate: A solution of 75 mg (0.3 mmol) of methyl 4-(aminothioxomethyl)-5-methylthiothiophene-2-carboxylate (Maybridge, Cornwall, UK) was reacted with 101 mg (0.3 mmol) of 1-[3,5-bis(trifluoromethyl)phenyl]-2-bromoethane-1-one in a manner similar Example 8, step (a) to give methyl 4-{4-[3,5-bis(trifluoromethyl)phenyl](1,3-thiazol-2-yl)}-5-methylthiothiophene-2-carboxylate (7 mg, 5%) as a solid. 1H-NMR (DMSO-d6; 300 MHz) δ 8.75 (s, 1H), 8.73 (m, 2H), 8.29 (s, 1H), 8.13 (m, 1H), 3.87 (s, 3H), 2.79 (s, 3H). Mass spectrum (MALDI-TOF, CHCA matrix, m/z): Calcd. for C18H11NO2S3F6, 484.0 (M+H), found 484.0.
Reaction SMILES: CS(O[CH2:6][CH2:7][N:8]1[C:16]2[CH2:15][CH2:14][C:13]3[C:17]4[C:23]([NH:24][C:25]5[CH:30]=[CH:29][C:28]([F:31])=[C:27]([Cl:32])[CH:26]=5)=[N:22][CH:21]=[N:20][C:18]=4[S:19][C:12]=3[C:11]=2[CH:10]=[N:9]1)(=O)=O.[NH:33]1[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1.C(N(C(C)C)CC)(C)C>CN(C=O)C.O>[Cl:32][C:27]1[CH:26]=[C:25]([NH:24][C:23]2[N:22]=[CH:21][N:20]=[C:18]3[S:19][C:12]4[C:11]5[CH:10]=[N:9][N:8]([CH2:7][CH2:6][N:33]6[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]6)[C:16]=5[CH2:15][CH2:14][C:13]=4[C:17]=23)[CH:30]=[CH:29][C:28]=1[F:31]
Reactant: C1CNCCN1
Reactant: CS(=O)(=O)OCCn1ncc2c1CCc1c-2sc2ncnc(Nc3ccc(F)c(Cl)c3)c12
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Fc1ccc(Nc2ncnc3sc4c(c23)CCc2c-4cnn2CCN2CCNCC2)cc1Cl
Temperature: 80 °C
Reaction time: 16 h
Yield: 38.8 %

Procedure:
2-{6-[(3-chloro-4-fluorophenyl)amino]-4,5-dihydro-3H-pyrimido[5′,4′:4,5]thieno[2,3-e]indazol-3-yl}ethyl methanesulfonate (80 mg, 0.1 mmol), piperazine (25.1 mg, 0.29 mmol) and diisopropylethylamine (25 mg, 0.19 mmol) were mixed in 2 mL DMF. The reaction mixture was stirred at 80° C. for 16 h. The reaction mixture was diluted with water and extracted with EtOAc. The combined organic layer was concentrated under reduced pressure and purified by prep HPLC. The combined fractions were treated with saturated Na2CO3 and dried to afford free base product N-(3-chloro-4-fluorophenyl)-3-(2-piperazin-1-ylethyl)-4,5-dihydro-3H-pyrimido[5′,4′:4,5]thieno[2,3-e]indazol-6-amine (18.8 mg, 40%). 1H-NMR (DMSO-d6) δ 8.65 (broad s, 1H), 8.30 (s, 1H), 7.86 (dd, 1H), 7.60 (s, 1H), 7.56 (m, 1H), 7.35 (t, 1H), 4.19 (t, 2H), 4.34 (t, 2H), 3.20 (broad, 1H), 3.08 (t, 2H), 2.62 (m, 6H), 2.31 (m, 4H). LCMS RT=2.35 min, [M+H]+=484.1
Reaction SMILES: C(O[C@H](C)[C@H](NC(OCC1C2C=CC=CC=2C2C1=CC=CC=2)=O)C(O)=O)C1C=CC=CC=1.[C:33]([O:37][C:38]([NH:40][C@H:41]([C:45]1[CH:50]=[CH:49][C:48]([O:51][CH2:52][CH2:53][O:54][CH:55]2CCCCO2)=[CH:47][CH:46]=1)[C:42]([OH:44])=[O:43])=[O:39])([CH3:36])([CH3:35])[CH3:34]>>[C:33]([O:37][C:38]([NH:40][C@H:41]([C:45]1[CH:46]=[CH:47][C:48]([O:51][CH2:52][CH2:53][O:54][CH3:55])=[CH:49][CH:50]=1)[C:42]([OH:44])=[O:43])=[O:39])([CH3:36])([CH3:35])[CH3:34]
Reactant: CC(C)(C)OC(=O)N[C@@H](C(=O)O)c1ccc(OCCOC2CCCCO2)cc1
Agent: C[C@@H](OCc1ccccc1)[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Product: COCCOc1ccc([C@@H](NC(=O)OC(C)(C)C)C(=O)O)cc1

Procedure:
Prepared by the same method as described in example 3 except that (i) 2-chloro-4-iodo-aniline was used in place of 4-bromo-2-chloro-aniline in step 1, and (ii) (R)-tert-butoxycarbonylamino-[4-(2-methoxy-ethoxy)-phenyl]-acetic acid was used in place of (R)-tert-butoxycarbonylamino-[4-(2-tert-butoxy-ethoxy)-phenyl]-acetic acid in step 2. (R)-tert-Butoxycarbonylamino-[4-(2-methoxy-ethoxy)-phenyl]-acetic acid was prepared as described in example 80.
Reaction SMILES: [C:1]1([C:7]2[C:8]([CH2:13][C:14]#[N:15])=[N:9][CH:10]=[CH:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:16][OH:17].C(OCC)(=O)C>C(O)C.CCCCCC>[OH:17][NH:16][C:14](=[NH:15])[CH2:13][C:8]1[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[CH:12][CH:11]=[CH:10][N:9]=1
Reactant: NO
Reactant: N#CCc1ncccc1-c1ccccc1
Solvent: CCCCCC
Solvent: CCO
Solvent: CCOC(C)=O
Product: N=C(Cc1ncccc1-c1ccccc1)NO
Temperature: 60 °C
Yield: 92.3 %

Procedure:
To a stirred solution of (3-phenyl-pyridin-2-yl)-acetonitrile (159) (4.9 g, 25.26 mmol) in ethanol (250 mL) was added 50% aqueous NH2OH (3.4 mL, 50.51 mmol) and the mixture was heated at 60° C. for 16 h. Silica thin layer chromatography was performed (40% ethyl acetate in hexane, Rf=0.2). Ethanol was evaporated, water (50 mL) was added, the mixture was extracted with etylacetate (3×50 mL), dried and concentrated to get N-hydroxy-2-(3-phenyl-pyridin-2-yl)-acetamidine (160) (5.3 g, 92.33%, crude) as a yellow solid.
Reaction SMILES: [C:1]([N:8]1[CH2:11][C:10](=O)[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].Cl.[CH3:14][NH2:15]>CO.[C].[Pd]>[CH3:14][NH:15][CH:10]1[CH2:11][N:8]([C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CC(=O)C1
Reactant: CN
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CNC1CN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 60 h
Yield: 82.7 %

Procedure:
To a solution of 1-Boc-azetidin-3-on (240 mg) in methanol (20 ml) were added methylamine hydrochloride (1.42 g) and 10% palladium carbon (1.0 g), followed by stirring under hydrogen atmosphere at room temperature for 60 hours. The reaction mixture was filtered to remove the catalyst. To the filtrate was added again 10% palladium carbon (1.0 g), followed by stirring under hydrogen atmosphere (0.40 MPa) at room temperature for 9 hours. The reaction mixture was filtered to remove the catalyst, and the filtrate was concentrated under reduced pressure. To the resultant residue were added a saturated aqueous solution of sodium hydrogencarbonate, ethyl acetate and potassium carbonate, followed by partition. The aqueous layer was extracted with ethyl acetate. The combined organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure to provide a crude product of the title compound (216 mg) as a pale yellow oil.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([OH:11])=[O:10])[CH:5]=[CH:6][CH:7]=1.Br[CH2:13][C:14]1[CH:15]=[CH:16][C:17]2[O:21][C:20]([N+:22]([O-:24])=[O:23])=[C:19]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:18]=2[CH:31]=1>>[N+:22]([C:20]1[O:21][C:17]2[CH:16]=[CH:15][C:14]([CH2:13][O:1][C:2]3[CH:3]=[C:4]([CH2:8][C:9]([OH:11])=[O:10])[CH:5]=[CH:6][CH:7]=3)=[CH:31][C:18]=2[C:19]=1[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)([O-:24])=[O:23]
Reactant: O=C(O)Cc1cccc(O)c1
Reactant: O=[N+]([O-])c1oc2ccc(CBr)cc2c1-c1ccccc1
Product: O=C(O)Cc1cccc(OCc2ccc3oc([N+](=O)[O-])c(-c4ccccc4)c3c2)c1

Procedure:
Using the method of Example 10 and starting with 3-hydroxyphenylacetic acid and 5-bromomethyl-2-nitro-3-phenylbenzofuran the product obtained is recrystallized from ethanol to provide 3-[(2-nitro-3-phenylbenzofuran-5-yl)methoxy]phenylacetic acid, m.p. 144°-145° C.
Reaction SMILES: Cl[CH2:2][CH2:3][S:4][C:5]1[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=1[NH2:7].C(=O)([O-])[O-].[K+].[K+].[I-].[Na+]>CN(C=O)C.C(OCC)(=O)C>[S:4]1[CH2:3][CH2:2][NH:7][C:6]2[CH:8]=[CH:9][CH:10]=[CH:11][C:5]1=2
Reactant: Nc1ccccc1SCCCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: c1ccc2c(c1)NCCS2
Temperature: 90 °C
Reaction time: 8 h
Yield: 98.5 %

Procedure:
To a stirred solution of 2-(2-chloroethylthio)aniline (850 mg, 4.53 mmol) in DMF (10 mL) was added potassium carbonate (1878 mg, 13.59 mmol) followed by sodium iodide (67.9 mg, 0.453 mmol). The resulting mixture was heated to 90° C. and stirred overnight. The reaction mixture was then cooled to room temperature, diluted with ethyl acetate, and washed with water (3×) and brine. The organic phase was dried, filtered, concentrated, and then chromatographed in 9:1 hexanes:ethyl acetate, giving an orange oil (675 mg, 99%). 1H NMR (DMSO-d6) δ 6.85-6.75 (m, 2H), 6.51-6.39 (m, 2H), 6.00 (brs, 1H), 3.49-3.44 (m, 2H), 2.98-2.93 (m, 2H); ESI-MS (m/z, %): 152 (MH+, 100), 124 (44).
Reaction SMILES: C([O:3][C:4](=[O:31])[C@H:5]([CH3:30])[CH2:6][C@H:7]([NH:22][C:23](=[O:29])[CH2:24][CH2:25][C:26]([OH:28])=[O:27])[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[CH:16]=2)=[CH:11][CH:10]=1)C.[OH-].[Na+].Cl>CCO>[C:26]([CH2:25][CH2:24][C:23]([NH:22][C@H:7]([CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[CH:16]=2)=[CH:11][CH:10]=1)[CH2:6][C@@H:5]([CH3:30])[C:4]([OH:31])=[O:3])=[O:29])([OH:28])=[O:27]
Reactant: CCOC(=O)[C@H](C)C[C@@H](Cc1ccc(-c2cccc(Cl)c2)cc1)NC(=O)CCC(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: C[C@H](C[C@@H](Cc1ccc(-c2cccc(Cl)c2)cc1)NC(=O)CCC(=O)O)C(=O)O
Yield: 53.2 %

Procedure:
To a stirred solution of (2R,4S)-4-(3-carboxy-propionylamino)-5-(3′-chloro-biphenyl-4-yl)-2-methyl-pentanoic acid ethyl ester (20 mg, 0.045 mmol) in 2 ml EtOH was added 1 ml of aqueous 1M NaOH and the solution was stirred for an hour. The reaction mixture was acidified to pH=2 to 3 with aqueous 1M HCl. Solvent was removed under reduced pressure and the residue was purified by RP-HPLC to give 10 mg (2R,4S)-4-(3-carboxy-propionylamino)-5-(3′-chloro-biphenyl-4-yl)-2-methyl-pentanoic acid. LC/MS m/z 418.3 (M+H), 419.4 (M−H). LC/MS (Condition A): 1.21 min. 1H NMR (400 MHz, DMSO-d6): 1.04-1.05 (d, J=7.07 Hz, 3H), 1.30-1.37 (m, 1H), 1.73-1.80 (m, 1H), 2.24-2.39 (m, 5H), 2.66-2.73 (m, 2H), 3.90-3.98 (m, 1H), 7.25-7.27 (d, J=8.08 Hz, 2H), 7.39-7.41 (m, 1H), 7.45-7.49 (t, J=7.83 Hz, 1H), 7.60-7.64 (m, 3H), 7.70-7.71 (t, J=2.02 Hz, 1H), 7.75-7.77 (d, J=8.59 Hz, 1H), 12.04 (br s, 2H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[N:5]=[C:4]([O:9][CH3:10])[N:3]=1.[C:11]1([SH:17])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(=O)(O)[O-].[Na+]>CC(C)=O>[Cl:1][C:2]1[N:3]=[C:4]([O:9][CH3:10])[N:5]=[C:6]([S:17][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:7]=1
Reactant: Sc1ccccc1
Reactant: COc1nc(Cl)nc(Cl)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Product: COc1nc(Cl)nc(Sc2ccccc2)n1
Reaction time: 2 h

Procedure:
The 2,4-dichloro-6-methoxy-s-triazine obtained according to Example A-3 is suspended, with partial solution, in 1000 parts by volume of acetone, 110 parts of thiophenol and 90 parts of sodium bicarbonate are added, and the reaction is carried out at about 20° C. After about 2 hours, the synthesis mixture is evaporated. The compound 2-chloro-4-methoxy-6-phenylthio-s-triazine is obtained as a powder containing electrolyte salt. It serves as a monochloro-triazine starting compound for the synthesis of dyestuffs according to the invention.
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[CH2:7][CH:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[C:5]2[CH:14]=[CH:15][CH:16]=[CH:17][C:4]=2[O:3]1.N1C=CC=CC=1.[Cl:25]Cl>C(Cl)(Cl)(Cl)Cl>[Cl:25][C:15]1[CH:16]=[CH:17][C:4]2[O:3][C:2]([CH3:18])([CH3:1])[CH2:7][CH:6]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=3)[C:5]=2[CH:14]=1
Reactant: CC1(C)CC(c2ccccn2)c2ccccc2O1
Reactant: ClCl
Solvent: c1ccncc1
Solvent: ClC(Cl)(Cl)Cl
Product: CC1(C)CC(c2ccccn2)c2cc(Cl)ccc2O1

Procedure:
1 g of 3,4-dihydro-2,2-dimethyl-4-(2-pyridyl)-2H-1-benzopyran was dissolved in 20 ml of carbon tetrachloride at room temperature and 0.25 ml of pyridine and 10 ml of a 0.42M solution of chlorine in carbon tetrachloride were added. After 30 minutes the mixture was washed with sodium bicarbonate solution, the organic phase was separated, dried over sodium sulphate and evaporated. The residue was chromatographed on silica gel using 1% (v/v) methanol/dichloromethane and then 2% (v/v) methanol/dichloromethane for the elution. The product was recrystallized from t-butyl methyl ether to give 200 mg of 6-chloro-3,4-dihydro-2,2-dimethyl-4-(2-pyridyl)-2H-1-benzopyran of melting point 124°-125° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][C:13]2[N:14]=[C:15]3[CH:21]=[C:20]([C:22]4[CH:23]=[N:24][NH:25][CH:26]=4)[N:19](S(C4C=CC=CC=4)(=O)=O)[C:16]3=[N:17][CH:18]=2)[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.[CH3:36][C@H:37]1[CH2:39][O:38]1.C(N(CC)CC)C.C(=O)([O-])[O-].[K+].[K+]>C(O)(C)C.CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][C:13]2[N:14]=[C:15]3[CH:21]=[C:20]([C:22]4[CH:26]=[N:25][N:24]([CH2:36][C@@H:37]([OH:38])[CH3:39])[CH:23]=4)[NH:19][C:16]3=[N:17][CH:18]=2)[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1
Reactant: C[C@H]1CO1
Reactant: COc1cc(CCc2cnc3c(cc(-c4cn[nH]c4)n3S(=O)(=O)c3ccccc3)n2)cc(OC)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: CC(C)O
Solvent: CN(C)C=O
Product: COc1cc(CCc2cnc3[nH]c(-c4cnn(C[C@H](C)O)c4)cc3n2)cc(OC)c1
Temperature: 90 °C
Reaction time: 2 h
Yield: 15.2 %

Procedure:
To a stirred solution of 2-[2-(3,5-dimethoxyphenyl)ethyl]-5-(phenylsulfonyl)-6-(1H-pyrazol-4-yl)-5H-pyrrolo[2,3-b]pyrazine (from Example 35, Step 1, 30.0 mg, 0.0613 mmol) and (S)-(−)-methyloxirane (8.56 μL, 0.122 mmol) in isopropyl alcohol (2 mL)/N,N-dimethylformamide (0.5 mL), triethylamine (17.1 μL, 0.122 mmol) was added at ambient temperature. The reaction mixture was then warmed up to 90° C. After 2 hours, the volatiles were removed and the residue was dissolved in methanol (2 mL). Potassium carbonate (16.9 mg, 0.122 mmol) was added and the reaction mixture was warmed up to 60° C. After 30 minutes, the crude mixture was purified on RP-HPLC (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.05% TFA, at flow rate of 30 mL/min) to give the desired product (3.8 mg) as its TFA salt. LCMS calculated for C22H26N5O3 (M+H)+: m/z=408.2. Found: 408.2.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]2[C:12](=[C:13]([N:15]([CH3:25])[S:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=3)(=[O:18])=[O:17])[CH:14]=1)[NH:11][C:10]([C:26]([OH:28])=O)=[CH:9]2.Cl.[CH3:30][O:31][C:32](=[O:44])[C@H:33]([CH2:35][S:36][CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[NH2:34].N1(O)C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>CN(C)C=O.C(N(CC)CC)C>[CH3:30][O:31][C:32](=[O:44])[C@H:33]([CH2:35][S:36][CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[NH:34][C:26]([C:10]1[NH:11][C:12]2[C:8]([CH:9]=1)=[CH:7][C:6]([O:5][CH2:4][CH2:3][O:2][CH3:1])=[CH:14][C:13]=2[N:15]([CH3:25])[S:16]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=1)(=[O:18])=[O:17])=[O:28]
Reactant: COC(=O)[C@@H](N)CSCc1ccccc1
Reactant: COCCOc1cc(N(C)S(=O)(=O)c2ccccn2)c2[nH]c(C(=O)O)cc2c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COCCOc1cc(N(C)S(=O)(=O)c2ccccn2)c2[nH]c(C(=O)N[C@@H](CSCc3ccccc3)C(=O)OC)cc2c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 96.7 %

Procedure:
A mixture of 5-(2-methoxyethoxy)-7-[methyl(pyridin-2-ylsulfonyl)amino]-1H-indole-2-carboxylic acid (3.00 g), S-benzyl-L-cysteine methyl ester hydrochloride (1.90 g), 1H-1,2,3-benzotriazol-1-ol (1.70 g), N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (2.10 g), triethylamine (1.50 mL) and N,N-dimethylformamide (40 mL) was stirred at room temperature for 18 hr. The reaction mixture was concentrated, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with 1N hydrochloric acid, saturated aqueous sodium hydrogencarbonate solution and saturated brine, dried (MgSO4), and concentrated. The obtained residue was subjected to silica gel column chromatography, and eluted with hexane-ethyl acetate (1:1-1:2, volume ratio) to give the title compound (4.30 g, yield 94%) as a colorless amorphous solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:18]=[CH:19][CH:20]=[C:21]4[C:25]=3[N:24]([CH3:26])[CH:23]=[C:22]4[CH2:27][CH2:28][OH:29])[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].CCN(CC)CC.[CH3:37][C:38]1[CH:43]=[CH:42][C:41]([S:44](Cl)(=[O:46])=[O:45])=[CH:40][CH:39]=1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH3:37][C:38]1[CH:43]=[CH:42][C:41]([S:44]([O:29][CH2:28][CH2:27][C:22]2[C:21]3[C:25](=[C:17]([C:14]4[N:13]=[C:12]([C:4]5[CH:5]=[CH:6][C:7]([O:8][CH:9]([CH3:10])[CH3:11])=[C:2]([Cl:1])[CH:3]=5)[O:16][N:15]=4)[CH:18]=[CH:19][CH:20]=3)[N:24]([CH3:26])[CH:23]=2)(=[O:46])=[O:45])=[CH:40][CH:39]=1
Reactant: CC(C)Oc1ccc(-c2nc(-c3cccc4c(CCO)cn(C)c34)no2)cc1Cl
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)OCCc2cn(C)c3c(-c4noc(-c5ccc(OC(C)C)c(Cl)c5)n4)cccc23)cc1
Temperature: 20 °C
Reaction time: 12 h
Yield: 242.5 %

Procedure:
To a stirred solution of 2-[7-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1-methyl-1H-indol-3-yl]ethanol (D126) (30 mg), Et3N (0.1 mL) and DMAP (10 mg) in DCM (5 mL) was added 4-methylbenzenesulfonyl chloride (42 mg) in DCM (5 mL). The reaction mixture was stirred at 20° C. for 12 h. The reaction mixture was quenched with water, partitioned between DCM (25 mL) and water (25 mL). The organic phase was washed with water, saturated aqueous sodium carbonate and brine, dried over sodium sulphate and evaporated to give the crude product 2-[7-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1-methyl-1H-indol-3-yl]ethyl 4-methylbenzenesulfonate (D127) (100 mg). MS (ES): C29H28ClN3O5S requires 565; found 566.2 (M+H+).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[N:18]([CH2:19][CH3:20])[N:17]=[C:16]([CH2:21][O:22][CH3:23])[C:15]=2[CH3:24])[CH2:10][CH2:9]1)=O)(C)(C)C.N1CCCCC1>>[CH2:19]([N:18]1[C:14]([CH:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)=[C:15]([CH3:24])[C:16]([CH2:21][O:22][CH3:23])=[N:17]1)[CH3:20]
Reactant: CCn1nc(COC)c(C)c1C1CCN(C(=O)OC(C)(C)C)CC1
Solvent: C1CCNCC1
Product: CCn1nc(COC)c(C)c1C1CCNCC1

Procedure:
The title compound was prepared from 1-(tert-butoxycarbonyl)-4-(1-ethyl-3-methoxymethyl-4-methyl-(1H)-pyrazol-5-yl)piperidine (from Step A) using a procedure analogous to that described for Piperidine 8, Step F. 1H-NMR (500 MHz) δ 1.36 (t, J=7.2, 3H), 1.71–1.74 (m, 2H), 1.97–2.09 (m, 2H), 2.11 (s, 3H), 2.72–2.80 (m, 3H), 3.25–3.35 (m, 2H), 3.37 (s, 3H), 4.11 (q, J=7.2, 2H), 4.37 (s, 2H).