Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]#[N:4].C(N(C(C)C)C(C)C)C.[C:14]([S:18][S:19][CH2:20][C@H:21]([NH:25][C:26](=[O:31])[CH2:27][CH2:28][CH:29]=[CH2:30])[C:22]([OH:24])=[O:23])([CH3:17])([CH3:16])[CH3:15].C(O)(=O)CCC=C.[Cl-].[NH4+]>CN(C)C=O>[C:14]([S:18][S:19][CH2:20][C@H:21]([NH:25][C:26](=[O:31])[CH2:27][CH2:28][CH:29]=[CH2:30])[C:22]([O:24][CH2:2][C:3]#[N:4])=[O:23])([CH3:17])([CH3:16])[CH3:15]
Reactant: N#CCBr
Reactant: C=CCCC(=O)N[C@@H](CSSC(C)(C)C)C(=O)O
Agent: C=CCCC(=O)O
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C=CCCC(=O)N[C@@H](CSSC(C)(C)C)C(=O)OCC#N
Temperature: 25 °C
Reaction time: 0.83 h
Yield: 62 %

Procedure:
2-Bromoacetonitrile (0.957 ml, 13.74 mmol) and N-ethyl-N-isopropylpropan-2-amine (1.76 ml, 10.1 mmol) were added to a solution of the mixed crude product C (1.75 g, 8.70 mmol) of (R)-3-(tert-butyldisulfanyl)-2-(pent-4-enamido)propanoic acid (Compound 2k-C) and pent-4-enoic acid (1:0.9) in N,N-dimethylformamide (11 ml), and the mixture was stirred at room temperature for 50 minutes. A saturated aqueous ammonium chloride solution (6 ml) was added to the reaction mixture, after which the mixture was extracted with ethyl acetate and the organic layer was washed with water. The organic extract was then dried over magnesium sulfate. Following concentration under reduced pressure, the resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate=100/0→50/50) to afford (R)-cyanomethyl 3-(tert-butyldisulfanyl)-2-(pent-4-enamido)propanoate (Compound 21-C) (940 mg, 62%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:25]([OH:27])=O)[CH2:10][C:11]1[CH:16]=[CH:15][C:14](OCC2C=CC=CC=2)=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].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.[C:61]([NH2:65])([CH3:64])([CH3:63])[CH3:62]>CN(C=O)C.CCOCC>[CH3:4][C:1]([O:5][C:6](=[O:7])[NH:8][C@@H:9]([CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[C:25]([NH:65][C:61]([CH3:64])([CH3:63])[CH3:62])=[O:27])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(OCc2ccccc2)cc1)C(=O)O
Reactant: CC(C)(C)N
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOCC
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)NC(=O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 153.7 %

Procedure:
A solution of N-(tert-Butyloxycarbonyl)-O-benzyl-L-tyrosine (Bachem, 2.00 g, 5.38 mmol) in 20 mL of DMF was cooled to 0C and treated with iPr2NEt (1.5 mL) followed by HBTU (2.04 g, 5.38 mmol). The resulting suspension was stirred for 30 minutes at 0° C. and then treated with tert-butylamine (0.48 g, 6.56 mmol). The reaction mixture was stirred for 1 hour at 0° C. and warmed to room temperature. The reaction mixture was poured into Et2O and washed sequentially with saturated aqueous NaHCO3 solution, and saturated aqueous NaCl solution. The organic phase was dried (MgSO4), filtered, and concentrated. The crude residue was purified by chromatography (silica gel, 3:1 heptane/ethyl acetate) to give the product (2.65 g).
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][SH:5].[Na].Cl.[CH2:8]([N:12]=[C:13]([NH2:22])[NH:14][C:15]1[S:16][CH:17]=[C:18]([CH2:20][Cl:21])[N:19]=1)[CH2:9][CH2:10][CH3:11].Cl>C(O)C.O>[ClH:21].[CH2:8]([N:12]=[C:13]([NH2:22])[NH:14][C:15]1[S:16][CH:17]=[C:18]([CH2:20][S:5][CH2:4][CH2:3][NH2:2])[N:19]=1)[CH2:9][CH2:10][CH3:11]
Reactant: NCCS
Reactant: CCCCN=C(N)Nc1nc(CCl)cs1
Agent: Cl
Agent: [Na]
Solvent: O
Solvent: CCO
Product: CCCCN=C(N)Nc1nc(CSCCN)cs1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 2-aminoethanethiol hydrochloride (1.85 g.) in ethanol (30 ml.) was added to a stirred solution of sodium (0.90 g.) in ethanol (50 ml.) under a nitrogen atmosphere. A solution of 2-(2-n-butylguanidino)-4-chloromethylthiazole hydrochloride (2.20 g.) in ethanol (50 ml.) was added dropwise to the mixture, which was then stirred for 3 hours while warming to room temperature. A mixture of concentrated hydrochloric acid (5 ml.) and water (15 ml.) was then added, and the mixture evaporated to dryness. The residual gummy solid was extracted with boiling ethanol (3×20 ml.) and the residual white solid discarded. The combined ethanolic extracts were filtered and the filtrate evaporated to dryness to give 2-(2-n-butylguanidino)-4-(2-aminoethyl)thiomethylthiazole hydrochloride as a thick gum which was used without further purification.
Reaction SMILES: C([Li])CCC.Br[C:7]1[C:12]([O:13][CH3:14])=[CH:11][C:10]([CH2:15][O:16][CH3:17])=[CH:9][C:8]=1[O:18][CH3:19].C[O:21][B:22]([O:25]C)[O:23]C.[Cl-].[NH4+]>O1CCCC1>[CH3:19][O:18][C:8]1[CH:9]=[C:10]([CH2:15][O:16][CH3:17])[CH:11]=[C:12]([O:13][CH3:14])[C:7]=1[O:21][B:22]([OH:25])[OH:23]
Reactant: COB(OC)OC
Reactant: COCc1cc(OC)c(Br)c(OC)c1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: COCc1cc(OC)c(OB(O)O)c(OC)c1
Temperature: -10 °C
Reaction time: 0.33 h

Procedure:
n-Butyllithium (2.64M hexane solution; 182 mL) was added dropwise to a solution of 2-bromo-1,3-dimethoxy-5-(methoxymethyl)benzene (121.3 g) in tetrahydrofuran (730 mL) at −78° C., and the mixture was stirred for 20 minutes. A solution of trimethoxyborane (61.7 mL) in tetrahydrofuran (20 mL) was then added to the reaction mixture at −78° C. When internal temperature was raised to −10° C., to the reaction mixture was added saturated aqueous ammonium chloride (730 mL), and stirring was continued for 15 minutes. The obtained reaction mixture was extracted with ethyl acetate, the extract was washed with brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography and the title compound (90.4 g) was obtained as a white solid from the n-hexane:ethyl acetate (2:3) fraction.
Reaction SMILES: Cl.[CH2:2]([N:9]([CH2:11][C:12]([OH:14])=O)[CH3:10])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(Cl)CCl.Cl.[CH3:20][NH:21][O:22][CH3:23].CN1CCOCC1>CN(C=O)C>[CH2:2]([N:9]([CH3:10])[CH2:11][C:12]([N:21]([O:22][CH3:23])[CH3:20])=[O:14])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CNOC
Reactant: CN(CC(=O)O)Cc1ccccc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: ClCCCl
Solvent: CN1CCOCC1
Product: CON(C)C(=O)CN(C)Cc1ccccc1
Reaction time: 16 h
Yield: 101.2 %

Procedure:
(Benzyl-methyl-amino)-acetic acid hydrochloride salt (12 g, 56 mmol, 1.0 equiv) was mixed in DMF (200 mL) along with EDC (10.6 g, 56 mmol, 1.0 equiv) for 15 min. N,O-Dimethylhydroxylamine hydrochloride (6.52 g, 67 mmol, 1.2 equiv) was added to the reaction followed by N-methylmorpholine (34 mL, 334 mmol, 6.0 equiv). The reaction was stirred for 16 h. The DMF was removed in vacuo and the residue was redissolved in 200 mL of EtOAc. The solution was washed once with 200 mL brine. The organic layer was dried over Na2SO4, decanted and concentrated to yield the desired product as a free-flowing oil (12.6 g, 80%) that was used in the next step without further purification; MS, m/z 223=M+1.
Reaction SMILES: [CH3:1][CH:2]([CH3:7])[CH2:3][C:4](Cl)=[O:5].[C:8]([O:12][C:13](=[O:35])[CH2:14][N:15]1[C:19]2[CH:20]=[CH:21][C:22]([NH:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[CH:23][C:18]=2[N:17]=[C:16]1[CH2:32][CH2:33][CH3:34])([CH3:11])([CH3:10])[CH3:9].CCN(C(C)C)C(C)C>CN(C1C=CN=CC=1)C.C(Cl)Cl.Cl>[C:8]([O:12][C:13](=[O:35])[CH2:14][N:15]1[C:19]2[CH:20]=[CH:21][C:22]([N:24]([CH2:25][C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)[C:4](=[O:5])[CH2:3][CH:2]([CH3:7])[CH3:1])=[CH:23][C:18]=2[N:17]=[C:16]1[CH2:32][CH2:33][CH3:34])([CH3:11])([CH3:10])[CH3:9]
Reactant: CC(C)CC(=O)Cl
Reactant: CCCc1nc2cc(NCc3ccccc3)ccc2n1CC(=O)OC(C)(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCCc1nc2cc(N(Cc3ccccc3)C(=O)CC(C)C)ccc2n1CC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3-Methyl-butyryl chloride (44 μL, 0.36 mmol) was added to a solution of (5-benzylamino-2-propyl-benzoimidazol-1-yl)-acetic acid tert-butyl ester (45 mg, 0.12 mmol), DIEA (41 μL, 0.24 mmol) and DMAP (15 mg, 0.12 mmol) in CH2Cl2 (1 mL), and stirred overnight at room temperature. The reaction solution was diluted with aqueous HCl (1.0 M) and filtered through an Extrelut column. The Extrelut column was washed with CH2Cl2, and the filtrate was concentrated to afford the subtitle compound that was used without further purification. MS calculated for C28H37N3O3+H: 464, observed: 464.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]([N:5]1[CH2:11][CH:10]([CH3:12])[C:9]2[CH:13]=[CH:14][C:15](O)=[CH:16][C:8]=2[CH2:7][CH2:6]1)=[O:4].[CH3:20][N:21]1[C:25]([Sn](CCCC)(CCCC)CCCC)=[CH:24][CH:23]=[N:22]1.[Li+].[Cl-]>CN(C)C=O.CCOC(C)=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:1][C:2]([F:19])([F:18])[C:3]([N:5]1[CH2:11][CH:10]([CH3:12])[C:9]2[CH:13]=[CH:14][C:15]([C:25]3[N:21]([CH3:20])[N:22]=[CH:23][CH:24]=3)=[CH:16][C:8]=2[CH2:7][CH2:6]1)=[O:4]
Reactant: CC1CN(C(=O)C(F)(F)F)CCc2cc(O)ccc21
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccnn1C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC1CN(C(=O)C(F)(F)F)CCc2cc(-c3ccnn3C)ccc21
Reaction time: 4 h

Procedure:
To a solution of N-trifluoroacetyl-7-hydroxy-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine, O-trifluoromethanesulfonate (100 mg, 0.25 mmol) in dimethylformamide (2 mL) was treated with (2-methyl-2H-pyrazol-3-yl)-tri-n-butyltin (138 mg, 0.37 mmol), LiCl (21 mg, 0.50 mmol), Pd(PPh3)2Cl2 (35 mg, 0.05 mmol) and stirred at 100 C for 4 hours. The product mixture was diluted with EtOAc (20 mL), washed twice with water (10 mL), once with brine (10 mL), dried with Na2SO4 and concentrated. Flash chromatography (30% EtOAc in hexane, silica) resulted in 80 mg of a clear oil. MS calculated for C17H18F3N3O+H: 338, observed: 338.
Reaction SMILES: C([C:3]1[CH:8]=[CH:7][N+:6]([O-:9])=[C:5](CC)[C:4]=1[NH2:12])C.C(O[CH:16]=[C:17]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[C:18]([O:20][CH2:21][CH3:22])=[O:19])C>C(O)C>[CH2:21]([O:20][C:18](=[O:19])[C:17]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:16][NH:12][C:4]1[CH:5]=[N+:6]([O-:9])[CH:7]=[CH:8][CH:3]=1)[CH3:22]
Reactant: CCc1cc[n+]([O-])c(CC)c1N
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Solvent: CCO
Product: CCOC(=O)C(=CNc1ccc[n+]([O-])c1)C(=O)OCC
Temperature: 130 °C
Yield: 78.4 %

Procedure:
A mixture of diethyl 3-aminopyridine 1-oxide (3.0 g, 27.3 mmol) and diethyl 2-(ethoxymethylene)malonate (11.8 g, 54.6 mmol) was heated to 130° C. under a Dean-Stark trap for 2 hours. After cooling to room temperature, the mixture was stirred with ethanol (100 mL). The solid was collected by filtration, washed with petroleum ether (100 mL) and dried in vacuo to afford the title compound (6.0 g). 1H NMR (400 MHz, MeOD) δ 8.40-8.39 (t, J=1.6 Hz, 1H), 8.36 (s, 1H), 8.01 (d, J=6.4 Hz, 1H), 7.49 (d, J=1.2 Hz, 1H), 7.46-7.44 (m, 1H), 4.22 (q, J=7.2 Hz, 2H), 4.14 (q, J=7.2 Hz, 2H), 1.08 (t, J=7.2 Hz, 6H).
Reaction SMILES: P(Br)(Br)[Br:2].N1C=CC=CC=1.[Cl:11][C:12]1[CH:13]=[C:14]([CH2:21][CH2:22]O)[CH:15]=[C:16]([O:19][CH3:20])[C:17]=1[Cl:18]>C1(C)C=CC=CC=1>[Cl:18][C:17]1[C:12]([Cl:11])=[CH:13][C:14]([CH2:21][CH2:22][Br:2])=[CH:15][C:16]=1[O:19][CH3:20]
Reactant: BrP(Br)Br
Reactant: COc1cc(CCO)cc(Cl)c1Cl
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: COc1cc(CCBr)cc(Cl)c1Cl
Temperature: -5 °C
Reaction time: 0.25 h

Procedure:
In a four-necked flask fitted with a stirrer, internal thermometer, dropping funnel and calcium chloride tube is placed freshly distilled phosphorous tribromide (9.6 g., 0.036 mole) and dry toluene (50 ml.). To this is added dry pyridine (1.5 g.). The mixture is stirred for 15 minutes and then cooled to -5° C. A mixture of 2-(3,4-dichloro-5-methoxyphenyl)ethanol (22.1 g., 0.1 mole) and dry pyridine (0.5 g.) in toluene (50 ml.) is added dropwise with stirring at -5° to -3° C. over a one hour period. The reaction mixture is stirred at -5° to -3° C. for an additional hour and then allowed to warm up to 20°-25° C. The mixture is kept for 48 hours and then added to ice water (ca. 500 ml.). The toluene layer is separated and washed with water, dilute hydrochloric acid, sodium bicarbonate solution and again with water. After drying over Na2SO4 and evaporation of the toluene under reduced pressure there is obtained 2,3-dichloro-5-(2-bromoethyl)anisole.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][C:17]=1[F:18])[O:5][C:6]1[CH:7]=[CH:8][C:9]([C:12]([OH:14])=O)=[N:10][CH:11]=1.CN.C1COCC1.C1C=CC2N(O)N=[N:32][C:30]=2C=1.Cl.C(N=C=NCCCN(C)C)C>CN(C=O)C.C(OCC)(=O)C>[NH2:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][C:17]=1[F:18])[O:5][C:6]1[CH:7]=[CH:8][C:9]([C:12]([NH:32][CH3:30])=[O:14])=[N:10][CH:11]=1
Reactant: Nc1cc(Oc2ccc(C(=O)O)nc2)ccc1F
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: CN
Agent: Cl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CNC(=O)c1ccc(Oc2ccc(F)c(N)c2)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 101 %

Procedure:
In DMF (5 mL) was placed 5-(3-amino-4-fluorophenoxy)picolinic acid from Example A12 (500 mg, 2.01 mmol), 2.0 M methylamine solution/THF (10 mL, 20.1 mmol) and HOBt (324 mg, 2.12 mmol). To this was added N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (772 mg, 4.03 mmol) and the solution stirred overnight at RT. The solution was treated with an additional equiv of N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (775 mg) and warmed to 40° C., then cooled to RT and stirred overnight. The solution was diluted with ethyl acetate (30 mL) and washed with water (30 mL), brine (30 mL), dried (Na2SO4) and concentrated in vacuo to yield 5-(3-amino-4-fluorophenoxy)-N-methylpicolinamide (530 mg, 101% yield) as a thick oil, which was used without further purification. MS (ESI) m/z: 262.0 (M+H+).
Reaction SMILES: [CH3:1][C:2]1[N:6]=[C:5]([C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:10]=[CH:9][CH:8]=2)[NH:4][C:3]=1[CH2:17]O.O=S(Cl)Cl.[CH:23]1([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[CH2:27][CH2:26][CH2:25][CH2:24]1.CCN(CC)CC>C(Cl)Cl>[CH:23]1([N:28]2[CH2:29][CH2:30][N:31]([CH2:17][C:3]3[NH:4][C:5]([C:7]4[C:16]5[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=5)[CH:10]=[CH:9][CH:8]=4)=[N:6][C:2]=3[CH3:1])[CH2:32][CH2:33]2)[CH2:24][CH2:25][CH2:26][CH2:27]1
Reactant: Cc1nc(-c2cccc3ccccc23)[nH]c1CO
Reactant: C1CCC(N2CCNCC2)C1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: Cc1nc(-c2cccc3ccccc23)[nH]c1CN1CCN(C2CCCC2)CC1

Procedure:
(5-Methyl-2-naphthalen-1-yl-3H-imidazol-4-yl)-methanol (40 mg) is treated with SOCl2, followed by N-cyclopentylpiperazine (60 mg) and Et3N (0.04 ml) in CH2Cl2 (2 ml). The crude is purified by column (2% Et3N, 3% MeOH in EtOAc) to afford the title compound as a white solid. LCMS 375.5 (M+1).
Reaction SMILES: Cl.Cl.[NH:3]1[CH2:7][CH2:6][CH2:5][C@@H:4]1[CH2:8][O:9][C:10]1[C:11]([C:16]([NH2:18])=[O:17])=[N:12][CH:13]=[CH:14][CH:15]=1.[F:19][C:20]([F:31])([F:30])[C:21]1[CH:22]=[C:23]([CH:27]=[CH:28][CH:29]=1)[C:24](O)=[O:25].COC1C=C(OC[C@H]2CCCN2C([C@H]2CC[C@H](C(F)(F)F)CC2)=O)C(C(O)=O)=NC=1>>[F:19][C:20]([F:30])([F:31])[C:21]1[CH:22]=[C:23]([CH:27]=[CH:28][CH:29]=1)[C:24]([N:3]1[CH2:7][CH2:6][CH2:5][C@@H:4]1[CH2:8][O:9][C:10]1[C:11]([C:16]([NH2:18])=[O:17])=[N:12][CH:13]=[CH:14][CH:15]=1)=[O:25]
Reactant: NC(=O)c1ncccc1OC[C@H]1CCCN1
Reactant: O=C(O)c1cccc(C(F)(F)F)c1
Agent: COc1cnc(C(=O)O)c(OC[C@H]2CCCN2C(=O)[C@H]2CC[C@H](C(F)(F)F)CC2)c1
Agent: Cl
Product: NC(=O)c1ncccc1OC[C@H]1CCCN1C(=O)c1cccc(C(F)(F)F)c1

Procedure:
The title compound was prepared according to the procedure described in Step 5 of EXAMPLE 31 using (R)-3-(pyrrolidin-2-ylmethoxy)picolinamide dihydrochloride (EXAMPLE 1 Step 3) and 3-(trifluoromethyl)benzoic acid instead of ammonium chloride and 5-methoxy-3-(((R)-1-(trans-4-(trifluoromethyl)cyclohexanecarbonyl)pyrrolidin-2-yl)methoxy)picolinic acid.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[C:4]([O:14][C:15]2[CH:21]=[CH:20][C:18]([NH2:19])=[CH:17][CH:16]=2)[C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([O:12][CH3:13])=[CH:7][CH:6]=2.CCN(CC)CC.[CH3:35][S:36](Cl)(=[O:38])=[O:37]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH3:13][O:12][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[C:4]([O:14][C:15]1[CH:21]=[CH:20][C:18]([NH:19][S:36]([CH3:35])(=[O:38])=[O:37])=[CH:17][CH:16]=1)=[C:3]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:2]([CH3:1])=[CH:11]2
Reactant: CS(=O)(=O)Cl
Reactant: COc1ccc2c(Oc3ccc(N)cc3)c(-c3ccccc3)c(C)cc2c1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc2c(Oc3ccc(NS(C)(=O)=O)cc3)c(-c3ccccc3)c(C)cc2c1
Reaction time: 8 h
Yield: 46 %

Procedure:
To a flask containing a solution of 29, Et3N (0.26 g, 2.55 mmol) and DMAP (0.032, 0.26 mmol) in CH2Cl2 (5 mL) was added methanesulfonyl chloride (0.24 g, 2.13 mmol), dropwise at RT and the reaction allowed to stir overnight. After 18 h the reaction was diluted with CH2Cl2 (15 mL) and the reaction rinsed with 10% aqueous HCl (25 mL). The CH2Cl2 layer was dried (MgSO4) and concentrated to a dark amber oil. The crude product was purified by silica gel column chromatography to afford 170 mg (46%) of the title compound (269) as a colorless oil. An additional 90 mg of a mixture of 269 and N,N-bissulfonylated product was also isolated. 1H NMR (400 MHz, DMSO-d6): δ 2.15 (s, 3H), 2.82 (s, 3H), 3.85 (s, 3H), 6.54 (d, J=8.9 Hz, 2H), 6.94 (d, J=8.8 Hz, 2H), 6.97 (dd, J1=2.4 Hz, J2=9.1 Hz, 1H), 6.96 (d, J=6.6 Hz, 1H), 7.15-7.32 (m, 5H), 7.58 (d, J=9.1 Hz, 1H), 7.67 (s, 1H), 9.32 (s, 1H).
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7]([O-:10])(=[O:9])=[O:8])=[CH:3][CH:2]=1.[CH3:12][NH+:13]1[C:17]2=[N:18][CH:19]=[CH:20][N:21]=[C:16]2[N:15]([CH3:22])[CH:14]1[CH3:23].[CH:24]([C:26]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[N:28]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[N:27]=1)=O.CCOCC>C(OC(=O)C)(=O)C>[C:1]1([CH3:11])[CH:2]=[CH:3][C:4]([S:7]([O-:10])(=[O:8])=[O:9])=[CH:5][CH:6]=1.[CH3:22][NH+:15]1[C:16]2=[N:21][CH:20]=[CH:19][N:18]=[C:17]2[N:13]([CH3:12])[CH:14]1[CH:23]=[CH:24][C:26]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[N:28]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[N:27]=1
Reactant: CC1N(C)c2nccnc2[NH+]1C
Reactant: O=Cc1nn(-c2ccccc2)c2ccccc12
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Solvent: CC(=O)OC(C)=O
Solvent: CCOCC
Product: CN1c2nccnc2[NH+](C)C1C=Cc1nn(-c2ccccc2)c2ccccc12

Procedure:
A mixture of 1,2,3-trimethyl-1H-imidazo[4,5-b]-pyrazinium p-toluenesulfonate (1.67 g, 0.050 mole) and 3-formyl-1-phenylindazole (1.11 g, 0.050 mole) is heated together in acetic anhydride (15 ml) at reflux for 30 minutes. After chilling, ether (500 ml) is added and the solid which separates is filtered off and dried. Yield 1.92 g, (72%). After recrystallization from water the yield of dye is 0.55 g (41%).
Reaction SMILES: [Br-].[NH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH2:11][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[N:3]1.[O:31]=[C:32]1[NH:36][CH2:35][C:34](=[O:37])[N:33]1[CH2:38][CH2:39][O:40][C:41]1[CH:48]=[CH:47][C:44]([CH:45]=O)=[C:43]([N+:49]([O-:51])=[O:50])[C:42]=1[O:52][CH3:53].C(=O)([O-])[O-].[K+].[K+].O>CO>[NH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](/[CH:11]=[CH:45]/[C:44]2[CH:47]=[CH:48][C:41]([O:40][CH2:39][CH2:38][N:33]3[C:34](=[O:37])[CH2:35][NH:36][C:32]3=[O:31])=[C:42]([O:52][CH3:53])[C:43]=2[N+:49]([O-:51])=[O:50])=[N:3]1
Reactant: COc1c(OCCN2C(=O)CNC2=O)ccc(C=O)c1[N+](=O)[O-]
Reactant: c1ccc([P+](Cc2n[nH]c3ccccc23)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Br-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: COc1c(OCCN2C(=O)CNC2=O)ccc(/C=C/c2n[nH]c3ccccc23)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h
Yield: 28.6 %

Procedure:
(1H-indazol-3-ylmethyl)triphenylphosphonium bromide (0.12 g, 0.26 mmol), 4-[2-(2,5-dioxoimidazolidin-1-yl)ethoxy]-3-methoxy-2-nitrobenzaldehyde (0.08 g, 0.24 mmol) obtained in Step 1 and potassium carbonate (0.07 g, 0.47 mmol) were dissolved in methanol (3.0 mL), followed by stirring at room temperature for 1.0 hour. The reaction mixture was added with water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform/methanol=9/1) to obtain (E)-3-(2-{4-[2-(1H-indazol-3-yl)vinyl]-2-methoxy-3-nitrophenoxy}ethyl)imidazolidine 2,4-dione (0.03 g, 32%).
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]([CH2:7][C:8]1([CH3:18])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11][CH2:10][CH2:9]1)([OH:6])[CH2:4][OH:5].C(N(CC)CC)C.[Cl-].[NH4+]>ClCCl.CS(C)=O>[F:1][C:2]([F:19])([F:20])[C:3]([OH:6])([CH2:7][C:8]1([CH3:18])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11][CH2:10][CH2:9]1)[CH:4]=[O:5]
Reactant: CC1(CC(O)(CO)C(F)(F)F)CCCc2ccccc21
Agent: [Cl-]
Agent: [NH4+]
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1(CC(O)(C=O)C(F)(F)F)CCCc2ccccc21
Temperature: 21 °C
Reaction time: 17 h
Yield: 78 %

Procedure:
To a solution of 3,3,3-trifluoro-2-[(1-methyl-1,2,3,4-tetrahydro-1-naphthalenyl)methyl]-1,2-propanediol (Intermediate 5) (1.6 g, 5.55 mmol) in anhydrous dichloromethane (36 ml), anhydrous dimethylsulphoxide (12 ml) and triethylamine (4.9 ml, 35 mmol) stirred under nitrogen in a bath at 8.5° C., was added pyridine-sulphur trioxide complex (4.45 g, 28 mmol) portionwise over 20 min. The solution was stirred in the ice-water bath for a further 1.5 h and then allowed to warm to 21° C. and stirred for 17 h. The reaction mixture was added to aqueous ammonium chloride solution (100 ml) and dichloromethane (100 ml) and the layers were separated. The aqueous layer was re-extracted with dichloromethane (100 ml) and the combined organic layers were washed successively with water (6×100 ml) and saturated brine (100 ml), dried over anhydrous magnesium sulphate and evaporated. The yellow oil obtained was purified by flash chromatography on a 90 g Biotage cartridge eluting with 5% ether in cyclohexane to give the title compound as an oil (1.24 g, 78%).
Reaction SMILES: [F:1][C:2]1[CH:19]=[CH:18][C:5]2[N:6]=[C:7]([C:9](=O)[CH2:10][C:11](=O)[C:12]([F:15])([F:14])[F:13])[S:8][C:4]=2[CH:3]=1.[CH3:20][S:21][C:22]1[CH:27]=[CH:26][C:25]([NH:28][NH2:29])=[CH:24][CH:23]=1>C(O)(=O)C>[F:1][C:2]1[CH:19]=[CH:18][C:5]2[N:6]=[C:7]([C:9]3[N:28]([C:25]4[CH:26]=[CH:27][C:22]([S:21][CH3:20])=[CH:23][CH:24]=4)[N:29]=[C:11]([C:12]([F:15])([F:14])[F:13])[CH:10]=3)[S:8][C:4]=2[CH:3]=1.[F:1][C:2]1[CH:19]=[CH:18][C:5]2[N:6]=[C:7]([C:9]3[CH:10]=[C:11]([C:12]([F:15])([F:14])[F:13])[N:28]([C:25]4[CH:26]=[CH:27][C:22]([S:21][CH3:20])=[CH:23][CH:24]=4)[N:29]=3)[S:8][C:4]=2[CH:3]=1
Reactant: O=C(CC(=O)C(F)(F)F)c1nc2ccc(F)cc2s1
Reactant: CSc1ccc(NN)cc1
Solvent: CC(=O)O
Product: CSc1ccc(-n2nc(-c3nc4ccc(F)cc4s3)cc2C(F)(F)F)cc1
Product: CSc1ccc(-n2nc(C(F)(F)F)cc2-c2nc3ccc(F)cc3s2)cc1
Temperature: 100 °C
Reaction time: 13 h
Yield: 43 %
Yield: 5 %

Procedure:
The mixture of 1-(6-fluorobenzothiazol-2-yl)-4,4,4-trifluorobutane-1,3-dione (820 mg, 2.82 mmol) and 4-methylthio-phenylhydrazine (529.5 mg, 3.43 mmol) in acetic acid (23 ml) was stirred at 100° C. for 13 hours, allowed to cool and then concentrated. The resulting residue was subjected to purification using column chromatography on silica gel to afford 6-fluoro-2-[1-(4-methylthiophenyl)-3-trifluoromethyl-1H-pyrazol-5-yl]benzothiazole (500 mg, 43%) and 6-fluoro-2-[1-(4-methylthiophenyl)-5-trifluoromethyl-1H-pyrazol-3-yl]-benzothiazole (58 mg, 5%).