Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([C:13]2[S:14][C:15]3[CH:16]=[N:17][CH:18]=[CH:19][C:20]=3[N:21]=2)[CH:12]=1)[C:7](O)=[O:8])([O-:3])=[O:2].CN1CCOCC1.ClC(OCC(C)C)=O.[BH4-].[Na+]>C1COCC1.O>[N+:1]([C:4]1[CH:5]=[C:6]([CH2:7][OH:8])[CH:10]=[C:11]([C:13]2[S:14][C:15]3[CH:16]=[N:17][CH:18]=[CH:19][C:20]=3[N:21]=2)[CH:12]=1)([O-:3])=[O:2]
Reactant: O=C(O)c1cc(-c2nc3ccncc3s2)cc([N+](=O)[O-])c1
Agent: CC(C)COC(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: O=[N+]([O-])c1cc(CO)cc(-c2nc3ccncc3s2)c1
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 17.9 %

Procedure:
3-Nitro-5-thiazolo[5,4-c]pyridin-2-yl-benzoic acid (880 mg, 2.92 mmol) was suspended in 50 mL of anhydrous THF along with NMM (0.32 mL, 2.92 mmol). The reaction mixture was cooled in an ice bath and isobutyl chloroformate (0.38 mL, 2.92 mmol) was added. The reaction mixture was stirred at 0° C. for 40 min. NaBH4 (110 mg, 2.92 mmol) was then added as a solution in 5 mL of water. The reaction mixture was stirred at 0° C. for 30 min and then warmed to room temperature. It was concentrated and then extracted with CH2Cl2. The combined organic layers were dried (Na2SO4) and concentrated to afford the crude product. Purification by chromatography (Isco, gradient elution, CH2Cl2 to 9:1 CH2Cl2/MeOH) afford 150 mg of (3-nitro-5-thiazolo[5,4-c]pyridin-2-yl-phenyl)-methanol.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:9])=[C:6]([CH:8]=1)[NH2:7].[C:10]([O:13]C(=O)C)(=O)[CH3:11].[Br:17]Br>C1(C)C=CC=CC=1.C(O)(=O)C.O>[Br:17][C:3]1[C:2]([F:1])=[CH:8][C:6]([NH:7][C:10](=[O:13])[CH3:11])=[C:5]([CH3:9])[CH:4]=1
Reactant: Cc1ccc(F)cc1N
Reactant: BrBr
Reactant: CC(=O)OC(C)=O
Solvent: CC(=O)O
Solvent: O
Solvent: Cc1ccccc1
Product: CC(=O)Nc1cc(F)c(Br)cc1C
Temperature: 25 °C
Reaction time: 12 h
Yield: 87.4 %

Procedure:
A solution of 5-fluoro-2-methylaniline (24A, 25 g, 200 mmol) in toluene (250 mL) was treated with acetic anhydride (25 mL. 226 mmol) heated at reflux for 1 hour. The reaction mixture was cooled when a colorless solid precipitated out which was filtered and washed with a mixture of ether and hexanes. The colorless solid was taken in acetic acid (150 mL) and treated dropwise with a solution of bromine (9.6 mL, 186 mmol) in acetic acid (20 mL) and stirred at room temperature. for 12 hours. The solution was diluted with water and the solid separating out was filtered and washed to provide N-(4-bromo-5-fluoro-2-methylphenyl)acetamide (24B, 40 g) as a colorless solid.
Reaction SMILES: [F:1][C:2]1[CH:16]=[C:15](B2OC(C)(C)C(C)(C)O2)[CH:14]=[CH:13][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([CH3:11])[C:6]=1[CH3:12].C([O-])(O)=O.[Na+].Br[C:32]1[CH:37]=[CH:36][N:35]([CH2:38][CH:39]2[CH2:41][CH2:40]2)[C:34](=[O:42])[C:33]=1[C:43]#[N:44]>O1CCOCC1.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>[CH:39]1([CH2:38][N:35]2[CH:36]=[CH:37][C:32]([C:15]3[CH:14]=[CH:13][C:3]([O:4][C:5]4[CH:10]=[CH:9][N:8]=[C:7]([CH3:11])[C:6]=4[CH3:12])=[C:2]([F:1])[CH:16]=3)=[C:33]([C:43]#[N:44])[C:34]2=[O:42])[CH2:40][CH2:41]1
Reactant: N#Cc1c(Br)ccn(CC2CC2)c1=O
Reactant: Cc1nccc(Oc2ccc(B3OC(C)(C)C(C)(C)O3)cc2F)c1C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: Cc1nccc(Oc2ccc(-c3ccn(CC4CC4)c(=O)c3C#N)cc2F)c1C

Procedure:
To a solution of intermediate 24 (1.769 mmol) in 1,4-dioxane (7 ml) and a saturated solution of NaHCO3 (7 ml) was added intermediate 5 (0.38 g, 1.504 mmol). The resulting solution was degassed using a stream of nitrogen and to this was added Pd(PPh3)4 (0.2 mg, 0.176 mmol). The reaction was then microwaved in a sealed tube at 150° C. for 10 minutes. The resulting cooled reaction mixture was filtered through a pad of diatomaceous earth. The filtrate was diluted with EtOAc, and then it was washed with water, dried (Na2SO4) and concentrated in vacuo. The crude reaction mixture was then purified by column chromatography (silica gel; DCM to DCM/MeOH up to 5% as eluent). The desired fractions were collected and evaporated in vacuo to yield compound 11 precipitated from diisopropylether (0.190 g, 32%).
Reaction SMILES: [N:1]([C:4]1[CH:5]=[C:6]([C:12]([F:15])([F:14])[F:13])[C:7]([C:10]#[N:11])=[N:8][CH:9]=1)=[C:2]=[S:3].[C:16]([C:18]1([NH:22][C:23]2[CH:32]=[CH:31][C:26]([C:27]([NH:29][CH3:30])=[O:28])=[C:25]([F:33])[CH:24]=2)[CH2:21][CH2:20][CH2:19]1)#N.C[OH:35].Cl>CN(C=O)C>[C:10]([C:7]1[N:8]=[CH:9][C:4]([N:1]2[C:16](=[O:35])[C:18]3([CH2:21][CH2:20][CH2:19]3)[N:22]([C:23]3[CH:32]=[CH:31][C:26]([C:27]([NH:29][CH3:30])=[O:28])=[C:25]([F:33])[CH:24]=3)[C:2]2=[S:3])=[CH:5][C:6]=1[C:12]([F:15])([F:13])[F:14])#[N:11]
Reactant: N#Cc1ncc(N=C=S)cc1C(F)(F)F
Reactant: CNC(=O)c1ccc(NC2(C#N)CCC2)cc1F
Reactant: CO
Agent: Cl
Solvent: CN(C)C=O
Product: CNC(=O)c1ccc(N2C(=S)N(c3cnc(C#N)c(C(F)(F)F)c3)C(=O)C23CCC3)cc1F
Temperature: 80 °C
Reaction time: 2 h
Yield: 35 %

Procedure:
5-isothiocyanato-3-(trifluoromethyl)pyridine-2-carbonitrile, 9, A is reacted with 4-(1-cyanocyclobutylamino)-2-fluoro-N-methylbenzamide B in DMF solution by heating in a microwave at 80° C. for 20 hours. Methanol and hydrochloric acid are then added and the reaction allowed to proceed for 2 hours to produce 4-(7-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-5-yl)-2-fluoro-N-methylbenzamide, A52 (yield 35 to 87%).
Reaction SMILES: [C:1]([O:4][CH2:5][CH:6]1[N:11]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:10][CH:9]2[C:19]3[CH:25]=[C:24](Br)[CH:23]=[C:22]([Cl:27])[C:20]=3[O:21][CH:8]2[CH2:7]1)(=[O:3])[CH3:2].[C:28]1([S:34]([O-:36])=[O:35])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.[Na+]>>[C:1]([O:4][CH2:5][CH:6]1[N:11]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:10][C:9]2[C:19]3[CH:25]=[C:24]([S:34]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)(=[O:36])=[O:35])[CH:23]=[C:22]([Cl:27])[C:20]=3[O:21][C:8]=2[CH2:7]1)(=[O:3])[CH3:2]
Reactant: O=S([O-])c1ccccc1
Reactant: CC(=O)OCC1CC2Oc3c(Cl)cc(Br)cc3C2CN1C(=O)OC(C)(C)C
Agent: [Na+]
Product: CC(=O)OCC1Cc2oc3c(Cl)cc(S(=O)(=O)c4ccccc4)cc3c2CN1C(=O)OC(C)(C)C
Yield: 84 %

Procedure:
The product from step J and sodium benzenesulfinate were coupled following the procedure of Example 29 step C. The crude product was purified by flash column chromatography (SiO2, 9:1 to 7:3, hexanes/ethyl acetate) to give tert-butyl 3-(acetoxymethyl)-6-chloro-8-(phenylsulfonyl)-3,4-dihydrobenzofuro[3,2-c]pyridine-2(1H)-carboxylate (110 mg, 84%) as a white solid: 1H NMR (CDCl3, 300 MHz) δ 7.98-7.95 (m, 3H), 7.86 (s, 1H), 7.58-7.49 (m, 3H), 5.10 (br s, 2H), 4.20-4.04 (m, 3H), 3.22-3.14 (m, 1H), 2.81 (d, J=17.4 Hz, 1H), 2.04 (s, 3H), 1.53 (s, 9H).
Reaction SMILES: [C:1]([C:4]1[O:5][CH:6]=[CH:7][CH:8]=1)(=[O:3])[CH3:2].[CH2:9](O)[CH2:10][OH:11].C(OCC)(OCC)OCC.C(OCC)(=O)C>O>[CH3:2][C:1]1([C:4]2[O:5][CH:6]=[CH:7][CH:8]=2)[O:11][CH2:10][CH2:9][O:3]1
Reactant: CC(=O)c1ccco1
Reactant: OCCO
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCOC(OCC)OCC
Product: CC1(c2ccco2)OCCO1
Yield: 46.4 %

Procedure:
A mixture of 4 mL (139.6 mmol) 2-acetylfuran, 8.7 mL (156 mmol) of ethylene glycol, 198 mg (1 mmol) of ptoluenesulfonic acid monohydrate, and 22 mL (132.3 mmol) of triethyl orthoformate was reacted at room temperature under N2 for 3 days. The reaction mixture was poured into a mixture of ethyl acetate (100 mL) and water (100 mL). The aqueous layer was extracted with ethyl acetate (3×50 mL), and the combined organic layer was washed with water (100 mL), sodium bicarbonate solution (150 mL), and brine (100 mL). The organic layer was dried over MgSO4, concentrated in vacuo, and the residue was distilled under reduced pressure (1.5 tort) to afford 9.98 g (50%) of 2-(2-methyl-1,3-dioxolan-2-yl)-furan, as a clear oil, b.p. 24° C./1.5 min.
Reaction SMILES: [N:1]1[C:6]2[NH:7][CH:8]=[CH:9][C:5]=2[C:4]([N:10]2[CH2:15][CH2:14][CH:13]([NH2:16])[CH2:12][CH2:11]2)=[N:3][CH:2]=1.[N:17]1[CH:22]=[C:21]([C:23](O)=[O:24])[CH:20]=[N:19][CH:18]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1C=NC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CN(C=O)C>[NH:1]1[C:6]2=[N:7][CH:8]=[CH:9][C:5]2=[C:4]([N:10]2[CH2:11][CH2:12][CH:13]([NH:16][C:23]([C:21]3[CH:22]=[N:17][CH:18]=[N:19][CH:20]=3)=[O:24])[CH2:14][CH2:15]2)[N:3]=[CH:2]1
Reactant: NC1CCN(c2ncnc3[nH]ccc23)CC1
Reactant: O=C(O)c1cncnc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2cccnc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(NC1CCN(c2nc[nH]c3nccc2-3)CC1)c1cncnc1
Temperature: 25 °C

Procedure:
To a mixture of 1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-4-piperidinamine D2 (65.2 mg), 5-pyrimidinecarboxylic acid (37.2 mg, 0.300 mmol), HATU (137 mg, 0.360 mmol) and HOAt (24.50 mg, 0.180 mmol) in DMF (1.5 mL) was added DIPEA (252 μL, 1.440 mmol). The reaction mixture was stirred at room temperature until reaction was complete then solvent was removed in vacuo. The crude mixture was purified by MDAP using a high pH method to afford E14 (21 mg), 1H NMR (d6-DMSO) δ 11.70 (1H, brs), 9.30 (1H, s), 9.15 (2H, s), 8.65 (1H, d), 8.17 (1H, s), 7.17 (1H, d), 6.60 (1H, d), 4.65 (2H, dt), 4.15 (1H, m), 3.25 (2H, dt), 1.90 (2H, m), 1.55 (2H, m), MS(ES+) 324 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19]([OH:20])=[C:18]3[C:13]([CH:14]=[CH:15][CH:16]=[N:17]3)=[C:12]([S:21][CH2:22][C:23]([OH:25])=O)[N:11]=2)=[O:9])=[CH:4][CH:3]=1.Cl.[CH3:29][NH:30][CH3:31].ON1C2N=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.C(N(C(C)C)CC)(C)C.Cl>CN(C=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19]([OH:20])=[C:18]3[C:13]([CH:14]=[CH:15][CH:16]=[N:17]3)=[C:12]([S:21][CH2:22][C:23]([N:30]([CH3:31])[CH3:29])=[O:25])[N:11]=2)=[O:9])=[CH:26][CH:27]=1
Reactant: O=C(O)CSc1nc(C(=O)NCc2ccc(F)cc2)c(O)c2ncccc12
Reactant: CNC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN(C)C(=O)CSc1nc(C(=O)NCc2ccc(F)cc2)c(O)c2ncccc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of the carboxylic acid from Step 1 (0.18 g, 0.46 mmol), dimethylamine hydrochloride (56 mg, 0.69 mmol), 1-hydroxy-7-azabenzotriazole (62 mg, 0.46 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (106 mg, 0.55 mmol), and diisopropylethylamine (0.2 mL, 0.46 mmol) in DMF (2.3 mL) was stirred at room temperature overnight. The product mixture was treated with 1 M aq HCl at 0° C. The resulting yellow solid was filtered, washed with diethyl ether. The solid was dissolved in DMSO and subjected to HPLC purification on C-18 stationary phase eluted with water/acetonitrile/TFA mobile phase. Collection and lyophilization of appropriate fractions provide the title compound as yellow solid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:29][C:30]1[CH:35]=[C:34]([F:36])[C:33]([F:37])=[CH:32][C:31]=1[F:38])[CH2:10][C:11]([N:13]1[CH2:18][CH2:17][N:16]2[C:19]([C:25]([F:28])([F:27])[F:26])=[N:20][C:21]([C:22]([OH:24])=O)=[C:15]2[CH2:14]1)=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].[N:39]1([C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46])[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]1.O=C1N([ClH]P([ClH]N2CCOC2=O)=O)CCO1.C(N(CC)CC)C>ClCCl>[C:48]([O:47][C:45]([N:39]1[CH2:44][CH2:43][N:42]([C:22]([C:21]2[N:20]=[C:19]([C:25]([F:27])([F:28])[F:26])[N:16]3[CH2:17][CH2:18][N:13]([C:11](=[O:12])[CH2:10][C@H:9]([NH:8][C:6]([O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[O:7])[CH2:29][C:30]4[CH:35]=[C:34]([F:36])[C:33]([F:37])=[CH:32][C:31]=4[F:38])[CH2:14][C:15]=23)=[O:24])[CH2:41][CH2:40]1)=[O:46])([CH3:51])([CH3:49])[CH3:50]
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)N1CCn2c(C(F)(F)F)nc(C(=O)O)c2C1)Cc1cc(F)c(F)cc1F
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H](CC(=O)N1CCn2c(C(F)(F)F)nc(C(=O)N3CCN(C(=O)OC(C)(C)C)CC3)c2C1)Cc1cc(F)c(F)cc1F
Yield: 103.1 %

Procedure:
(R)-7-[3-tert-Butoxycarbonylamino-4-(2,4,5-trifluoro-phenyl)-butyryl]-3-trifluoromethyl-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazine-1-carboxylic acid 2a (150 mg, 0.27 mmol), tert-butyl piperazine-1-carboxylate (100.6 mg, 0.54 mmol), bis(2-oxo-3-oxazolidinyl)phosphonic chloride (0.138 g, 0.54 mmol) and triethylamine (0.25 mL, 1.62 mmol) were dissolved in 6 mL of dichloromethane under stirring. The reaction mixture was reacted at room temperature overnight and monitored by thin layer chromatography until the disappearance of the starting materials. The reaction mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (R)-4-{7-[3-tert-butoxycarbonylamino-4-(2,4,5-trifluoro-phenyl)-butyryl]-3-trifluoromethyl-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazine-1-carbonyl}-piperazine-1-carboxylic acid tert-butyl ester 13a (200 mg, yield 99%) as a white solid.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9](I)[CH:10]=2)[N:5]=[CH:4][N:3]=1.[N:13]1[C:21]2[C:16](=[N:17][CH:18]=[CH:19][CH:20]=2)[S:15][C:14]=1[NH2:22].[N:23]1[CH:27]=[C:26]([SH:28])[NH:25][N:24]=1>>[N:23]1[CH:27]=[C:26]([S:28][C:9]2[CH:10]=[C:11]3[C:6](=[CH:7][CH:8]=2)[N:5]=[CH:4][N:3]=[C:2]3[NH:22][C:14]2[S:15][C:16]3[C:21]([N:13]=2)=[CH:20][CH:19]=[CH:18][N:17]=3)[NH:25][N:24]=1
Reactant: Clc1ncnc2ccc(I)cc12
Reactant: Sc1cnn[nH]1
Reactant: Nc1nc2cccnc2s1
Product: c1cnc2sc(Nc3ncnc4ccc(Sc5cnn[nH]5)cc34)nc2c1

Procedure:
The compound of Example 16 was manufactured by the same method as in Example 1, by a similar method thereto or by a combination of such a method with a conventional method using 4-chloro-6-iodo-quinazoline, thiazolo[5,4-b]pyridin-2-yl-amine and 3H-[1,2,3]triazole-4-thiol.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[NH:12][C@H:11]([C:13]([OH:15])=[O:14])[CH2:10][S:9]2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[C:22]([S:30][CH2:31][C@H:32]([CH3:36])[C:33](Cl)=[O:34])(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.Cl>O>[C:22]([S:30][CH2:31][C@@H:32]([CH3:36])[C:33]([N:12]1[C@H:11]([C:13]([OH:15])=[O:14])[CH2:10][S:9][CH:8]1[C:5]1[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=1)=[O:34])(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: Cc1ccc(C2N[C@H](C(=O)O)CS2)cc1
Reactant: C[C@@H](CSC(=O)c1ccccc1)C(=O)Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: Cc1ccc(C2SC[C@@H](C(=O)O)N2C(=O)[C@H](C)CSC(=O)c2ccccc2)cc1

Procedure:
4.5 g of (4R)-2-(4-methylphenyl)-4-thiazolidinecarboxylic acid and 4.3 g of sodium carbonate are dissolved in 25 ml of water and 4.9 g of (2S)-S-benzoyl-3-mercapto-2-methylpropanoyl chloride is added dropwise while stirring under ice-cooling. After the addition, the mixture is stirred under ice-cooling for 1 hour and acidified with dilute hydrochloric acid. The produced oil is extracted with ethyl acetate. The ethyl acetate layer is washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated to dryness in vacuo to give oil. The produced oil is purified by silica gel column chromatography to give the titled compound, yield 4.0 g (48%), mp. 131°-132° C. (ethyl acetatehexane), [α]D26 +117.6° (c=1.0, methanol).
Reaction SMILES: O[C@@H:2]1[CH2:6][CH2:5][N:4]([C:7](/[N:9]=[C:10]2\[S:11][C:12]([CH3:29])=[CH:13][N:14]\2[C:15]2[CH:28]=[CH:27][C:18]3[O:19][C:20]([F:26])([F:25])[C:21]([F:24])([F:23])OC=3[CH:16]=2)=[O:8])[CH2:3]1.COCCN(S(F)(F)[F:40])CCOC.[C:43](=[O:46])(O)[O-].[Na+]>C(Cl)Cl>[F:40][C@H:2]1[CH2:6][CH2:5][N:4]([C:7](/[N:9]=[C:10]2\[S:11][C:12]([CH3:29])=[CH:13][N:14]\2[C:15]2[CH:28]=[CH:27][C:18]3[O:19][C:20]([F:26])([F:25])[C:21]([F:24])([F:23])[O:46][C:43]=3[CH:16]=2)=[O:8])[CH2:3]1
Reactant: Cc1cn(-c2ccc3c(c2)OC(F)(F)C(F)(F)O3)/c(=N/C(=O)N2CC[C@@H](O)C2)s1
Reactant: COCCN(CCOC)S(F)(F)F
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1cn(-c2ccc3c(c2)OC(F)(F)C(F)(F)O3)/c(=N/C(=O)N2CC[C@H](F)C2)s1

Procedure:
A solution of (3R)-3-hydroxy-N-[(2Z)-5-methyl-3-(2,2,3,3-tetrafluoro-2,3-dihydro-1,4-benzodioxin-6-yl)-1,3-thiazol-2(3H)-ylidene]pyrrolidine-1-carboxamide (Example 109, 0.1 g, 0.23 mmol) in dry CH2Cl2 (5 mL) was treated with bis(2-methoxyethyl)aminosulfur trifluoride (0.056 g, 0.25 mmol) After 2 hours at room temperature, the mixture was neutralized by dropwise addition of a saturated solution of sodium bicarbonate. The mixture was washed with water and brine, dried over sodium sulfate, filtered, and evaporated under reduced pressure. The residue was purified over silica using CH2Cl2 as eluant. 1H NMR (CDCl3) δ ppm 2.00 (2 H), 2.25 (3 H), 3.35-3.85 (4 H), 5.15-5.30 (1 H), 6.60 (1 H), 7.20 (1 H), 7.35 (1 H), 7.45 (1 H); MS (ESI) m/z 436(M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[CH3:9].[Cl:10][CH2:11][C:12](Cl)=[O:13].[Cl-].[Al+3].[Cl-].[Cl-].Cl>ClCCl>[Cl:10][CH:11]([C:5]1[CH:4]=[C:3]([CH3:9])[C:2]([Cl:1])=[CH:7][C:6]=1[CH3:8])[C:12]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:13]
Reactant: O=C(Cl)CCl
Reactant: Cc1ccc(C)c(Cl)c1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: Cc1cc(C(Cl)C(=O)c2ccccc2)c(C)cc1Cl
Temperature: 0 °C
Yield: 134.3 %

Procedure:
A mixture of 2-chloro-1,4-dimethyl-benzene (5 g, 35.56 mmol) and chloroacetylchloride (4.0 g, 35.6 mmol) was cooled to 0° C. and treated with aluminum chloride (4.74 g, 35.6 mmol) in small portions. The reaction slurry was diluted with dichloromethane and allowed to warm to room temperature. After 30 min the reaction was poured onto a mixture of ice and 10 mL of concentrated aqueous hydrochloric acid solution. The mixture was extracted with ethyl acetate and the organic layers were combined and washed with saturated aqueous sodium bicarbonate solution. The organic layer was separated, dried (Na2SO4) and concentrated to give approximately 7 g of pure product as a white powder.
Reaction SMILES: I[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([NH:11][C:12]([CH:14]3[CH2:16][CH2:15]3)=[O:13])[N:10]=2)[N:7]=1.[NH2:17][C:18]1[C:19]([Cl:26])=[C:20]([OH:25])[C:21]([CH3:24])=[CH:22][CH:23]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[NH2:17][C:18]1[C:19]([Cl:26])=[C:20]([C:21]([CH3:24])=[CH:22][CH:23]=1)[O:25][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([NH:11][C:12]([CH:14]3[CH2:16][CH2:15]3)=[O:13])[N:10]=2)[N:7]=1
Reactant: O=C(Nc1cn2nc(I)ccc2n1)C1CC1
Reactant: Cc1ccc(N)c(Cl)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(N)c(Cl)c1Oc1ccc2nc(NC(=O)C3CC3)cn2n1
Temperature: 140 °C
Reaction time: 12 h
Yield: 64.1 %

Procedure:
To a solution of N-(6-iodoimidazo[1,2-b]pyridazin-2-yl)cyclopropanecarboxamide (2.0 g, 6.1 mmol) in N,N-dimethylformamide (20 mL) were added 3-amino-2-chloro-6-methylphenol (1.9 g, 12 mmol) and potassium carbonate (2.1 g, 15 mmol), and the mixture was stirred at 140° C. for 12 hr. After cooling the mixture to room temperature, the mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with 5% aqueous sodium hydrogencarbonate solution and saturated brine, dried over anhydrous sodium sulfate, and filtrated. The solvent was evaporated under reduced pressure, and the residue was purified by NH silica gel column chromatography (ethyl acetate/hexane=50/50→80/20) and precipitated from methanol/diisopropyl ether to give the title compound (1.4 g, 64%) as a pale-yellow powder.
Reaction SMILES: C([O:3][C:4](=O)[C:5](Br)=[C:6](Br)[C:7]1[CH:12]=[CH:11][C:10]([CH:13]([CH3:15])[CH3:14])=[CH:9][CH:8]=1)C.Cl.[NH2:20][OH:21].[OH-].[Na+]>>[OH:3][C:4]1[CH:5]=[C:6]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([CH3:15])[CH3:14])=[CH:9][CH:8]=2)[O:21][N:20]=1
Reactant: CCOC(=O)C(Br)=C(Br)c1ccc(C(C)C)cc1
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CC(C)c1ccc(-c2cc(O)no2)cc1
Yield: 70.1 %

Procedure:
α,β-Dibromo-4-isopropylcinnamic acid ethyl ester (9.5 g), hydroxylamine hydrochloride (2.2 g) and sodium hydroxide (5.2 g) were subjected to reaction and post-treatment in a similar manner to that described in Reference example 10(c) to obtain the title compound (3.6 g, 71%) as colorless crystals.
Reaction SMILES: [CH3:1][S:2]([CH3:5])(=[O:4])=[O:3].[H-].[Na+].CS(C)=O.C[O:13][C:14](=O)[C:15]1[CH:20]=[C:19]([O:21][CH3:22])[C:18]([N:23]([CH3:25])[CH3:24])=[C:17]([O:26][CH3:27])[CH:16]=1>C(O)(=O)C.O>[CH3:25][N:23]([CH3:24])[C:18]1[C:17]([O:26][CH3:27])=[CH:16][C:15]([C:14](=[O:13])[CH2:1][S:2]([CH3:5])(=[O:4])=[O:3])=[CH:20][C:19]=1[O:21][CH3:22]
Reactant: COC(=O)c1cc(OC)c(N(C)C)c(OC)c1
Reactant: CS(C)(=O)=O
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CC(=O)O
Solvent: O
Product: COc1cc(C(=O)CS(C)(=O)=O)cc(OC)c1N(C)C
Temperature: 30 °C
Reaction time: 4 h

Procedure:
A suspension of 21.6 g. of dimethylsulfone and 7.7 g. of sodium hydride (50% dispersion in oil) in 80 ml. of absolute dimethylsulfoxide was stirred at 50° C. for 3 hours under an atmosphere of nitrogen and the exclusion of moisture. The mixture was cooled to 30° C. and 15.6 g. of 4-(dimethylamino)-3,5-dimethoxybenzoic acid methyl ester were added. After stirring at room temperature for 4 hours, 500 ml. of water were added and the solution was made neutral with glacial acetic acid. The precipitate was removed by filtration with suction, washed with water, dried, recrystallized from ethyl acetate/cyclohexane, whereby there was obtained 4'-(dimethylamino)-3',5'-dimethoxy-2-(methylsulfonyl)-acetophenone having a melting point of 111°-112° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:13][C:14](Cl)(Cl)Cl)=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([CH3:12])=[CH:5]2.C[O-:19].[Na+].OS(O)(=O)=O.[C:26]([O-])(O)=[O:27].[Na+]>CO>[CH3:26][O:27][C:14](=[O:19])[CH2:13][C:3]1[C:2]([Cl:1])=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[C:6]([CH3:12])[CH:7]=[N:8]2
Reactant: C[O-]
Reactant: O=C([O-])O
Reactant: Cc1cnc2ccc(Cl)c(CC(Cl)(Cl)Cl)c2c1
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Product: COC(=O)Cc1c(Cl)ccc2ncc(C)cc12
Temperature: 70 °C
Yield: 67 %

Procedure:
To a solution of 6-chloro-3-methyl-5-(2,2,2-trichloro-ethyl)quinoline (4.11 g, 13.3 mmol) in anhydrous methanol (35 mL) was added a 30% solution of NaOMe in methanol (10.7 mL) under an argon atmosphere. The resulting brown solution was heated for 4 h at 70° C. After cooling to 0° C., concentrated H2SO4 (7 mL) was carefully added and the resulting reaction mixture was heated for 1 h at 70° C. After cooling the reaction mixture was rendered basic (pH=9) with a saturated aqueous NaHCO3 solution and extracted three times with TBDM. The combined organic layers were dried over Na2SO4, filtered and concentrated at reduced pressure to afford a brown solid. Purification by flash column chromatography (silica gel, gradient of cyclohexane/EtOAc 100:0 to 80:20) afforded the title compound as a white powder (2.22 g, 8.90 mmol, 67%). 1H NMR (400 MHz, CDCl3, 298 K): δ=8.80 (s, 1H), 8.09 (s, 1H), 8.05 (d, J=9.2 Hz, 1H), 7.69 (d, J=9.2 Hz, 1H), 4.29 (s, 2H), 3.73 (s, 3H), 2.59 (s, 3H). MS (ES+): 250 (M(C13H1235ClNO2)+H)+.
Reaction SMILES: [Br:1][C:2]1[S:3][CH:4]=[C:5]([C:7]([OH:9])=O)[N:6]=1.C(N1CCOCC1)C.[B-](F)(F)(F)F.CCOC(C(C#N)=NOC(N(C)C)=[N+](C)C)=O.[NH2:40][CH:41]([C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][C:48]=1[CH3:53])[CH2:42][C:43]([O:45][CH3:46])=[O:44]>CN(C=O)C>[CH3:46][O:45][C:43](=[O:44])[CH2:42][CH:41]([NH:40][C:7]([C:5]1[N:6]=[C:2]([Br:1])[S:3][CH:4]=1)=[O:9])[C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][C:48]=1[CH3:53]
Reactant: COC(=O)CC(N)c1ccccc1C
Reactant: O=C(O)c1csc(Br)n1
Agent: CCN1CCOCC1
Agent: CCOC(=O)C(C#N)=NOC(N(C)C)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Product: COC(=O)CC(NC(=O)c1csc(Br)n1)c1ccccc1C
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
100 mg (0.48 mmol) of 2-bromo-1,3-thiazole-4-carboxylic acid are dissolved in 10 ml of DMF, N-ethylmorpholine (122 mg, 2.2 Eq) and TOTU (174 mg, 1.1 Eq) are added and the mixture is stirred at RT for 5 minutes. Then 93 mg (1 Eq) of methyl 3-amino-3-(2-methylphenyl)propanoate are added and the mixture is stirred overnight. The solvent is removed in vacuo and the residue subjected to preparative HPLC delivering 3-[(2-bromo-thiazole-4-carbonyl)-amino]-3-o-tolyl-propionic acid methyl ester yields in yields below 80%