Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH:7]([C:8]([O:10]C)=O)[C:6](=[O:12])[C:5]2[CH:13]=[CH:14][CH:15]=[CH:16][C:4]=2[S:3]1(=[O:18])=[O:17].[NH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=1>>[CH3:1][N:2]1[S:3](=[O:18])(=[O:17])[C:4]2[CH:16]=[CH:15][CH:14]=[CH:13][C:5]=2[C:6]([OH:12])=[C:7]1[C:8]([NH:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=1)=[O:10]
Reactant: COC(=O)C1C(=O)c2ccccc2S(=O)(=O)N1C
Reactant: Nc1ccccn1
Product: CN1C(C(=O)Nc2ccccn2)=C(O)c2ccccc2S1(=O)=O
Temperature: 140 °C
Reaction time: 28 h

Procedure:
To a five liter flask equipped with thermometer, packed distillation column, condenser, and stirrer, under a nitrogen atmosphere is added 3300 ml mixed xylenes, 80 g (0.297 mole) methyl 3,4-dihydro-2-methyl-4-oxo-2H-1,2-benzothiazine-3-carboxylate-1,1-dioxide, 32 g (0.340 mole) 2-aminopyridine and 8 g of activated carbon (Darco G-60* or Darco KBB*). The mixture is heated at reflux (ca. 140° C.) for 28 hours while slowly distilling off methanol and xylene at a rate of about 25 ml per hour for the first 8 hours, then at a rate of 5-10 ml per hour for the remaining reflux period, while adding fresh xylene to maintain a reaction volume of about 3500 ml. After 28 hours, the reaction mixture is cooled slightly (~100° C.) and filtered to remove carbon. The carbon cake was washed with warm xylene (100 ml), the filtrate and washings cooled slowly under a nitrogen atmosphere with rapid stirring to 25°-50° C. Stirring was continued for one hour to allow for complete crystallization. The crystals were collected by filtration, the mother liquor concentrated to about 1500 ml, cooled under nitrogen to 0°-5° C., filtered, the cake washed with 100 ml cold xylene and the crystals dried under vacuum below 60° C. for several hours. The yield is 76.7-84.6 g (78-86% of theory). Average throughput 24.4 g/liter of solvent.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][S:11]([CH3:14])(=[O:13])=[O:12])=[C:6]([F:15])[CH:5]=1.[F:16][C:17]([F:30])([F:29])[C:18]1[N:23]=[CH:22][C:21]([O:24][CH2:25][C:26](O)=[O:27])=[CH:20][CH:19]=1>>[F:15][C:6]1[CH:5]=[C:4]([CH:9]=[CH:8][C:7]=1[NH:10][S:11]([CH3:14])(=[O:13])=[O:12])[CH2:3][NH:2][C:26](=[O:27])[CH2:25][O:24][C:21]1[CH:22]=[N:23][C:18]([C:17]([F:16])([F:29])[F:30])=[CH:19][CH:20]=1
Reactant: CS(=O)(=O)Nc1ccc(CN)cc1F
Reactant: O=C(O)COc1ccc(C(F)(F)F)nc1
Agent: Cl
Product: CS(=O)(=O)Nc1ccc(CNC(=O)COc2ccc(C(F)(F)F)nc2)cc1F
Yield: 12.8 %

Procedure:
N-(4-Aminomethyl-2-fluoro-phenyl)-methanesulfonamide HCl salt (270 mg, 1.00 mmol) was reacted with (6-trifluoromethyl-pyridin-3-yloxy)-acetic acid (221 mg) to give N-(3-fluoro-4-methanesulfonylamino-benzyl)-2-(6-trifluoromethyl-pyridin-3-yloxy)-acetamide (54 mg, 88%) after recrystallization from Hex/EtOAc.
Reaction SMILES: [OH:1][C:2]1[CH:8]=[C:7]([C:9]#[N:10])[CH:6]=[CH:5][C:3]=1[NH2:4].CC(C)=O.[C:15](Cl)(=[O:19])[C:16]([CH3:18])=[CH2:17]>COC1C=CC(O)=CC=1.N1C=CC=CC=1>[OH:1][C:2]1[CH:8]=[C:7]([C:9]#[N:10])[CH:6]=[CH:5][C:3]=1[NH:4][C:15](=[O:19])[C:16]([CH3:18])=[CH2:17]
Reactant: N#Cc1ccc(N)c(O)c1
Reactant: C=C(C)C(=O)Cl
Agent: COc1ccc(O)cc1
Solvent: c1ccncc1
Solvent: CC(C)=O
Product: C=C(C)C(=O)Nc1ccc(C#N)cc1O
Yield: 58 %

Procedure:
400 g of o-hydroxy-p-cyanoaniline, 4 g of hydroquinone monomethyl ether, 4 litres of acetone, and 360 g of pyridine were mixed and the mixture was cooled externally with a freezing medium. At a point when the internal temperature of the solution had dropped to -10° C., 420 g of methacrylic acid chloride was added dropwise to the mixture with stirring. Thereafter the mixture was treated in the same way as in Synthesis Example 1 to obtain 350 g of o-hydroxy-p-cyanomethacrylanilide. 76.8 g (0.38 mol) of this o-hydroxy-p-cyanomethacrylanilide was dissolved together with 68.4 g (0.60 mol) of ethyl methacrylate, 1.44 g (0.02 mol) of acrylic acid and 0.7 g of α,α'-azobisisobutyronitrile in 300 ml of an acetone/ethanol (1/2) mixed solvent. After replacing the atmosphere with nitrogen gas, the solution was heated at 65° C. for 4 hours to obtain a polymer solution. This polymer solution was poured into 3 litres of aqueous 5% HCl solution and the produced white precipitate was filtered and dried, giving 75 g of a white polymer. Determination of molecular weight of this polymer by the GPC method showed Mn=4,700 and Mw=33,000.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:11]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[CH:13]=2)[C:10]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[C:9]([NH2:26])[NH:8][C:7]=1[NH2:27])=[O:5])[CH3:2].[CH3:28]C[O-].[Na+].CI>C(O)C>[CH2:24]([O:23][C:21]([C:10]1([CH3:28])[CH:11]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[CH:13]=2)[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])=[C:7]([NH2:27])[N:8]=[C:9]1[NH2:26])=[O:22])[CH3:25]
Reactant: CC[O-]
Reactant: CCOC(=O)C1=C(N)NC(N)=C(C(=O)OCC)C1c1cccc([N+](=O)[O-])c1
Agent: [Na+]
Solvent: CCO
Solvent: CI
Product: CCOC(=O)C1=C(N)N=C(N)C(C)(C(=O)OCC)C1c1cccc([N+](=O)[O-])c1

Procedure:
A solution of 37.5 g of 2,6-diamino-4-(3'-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid diethyl ester and 6.8 g of sodium ethylate in 500 ml of ethanol was treated with 15 g of methyl iodide at the boil. After a further 60 minutes under reflux, the mixture was concentrated by distillation. The residue is taken up in 300 ml of chloroform and extracted by shaking twice with 100 ml of water, and the organic phase is concentrated. Recrystallization of the residue from ethanol gave 2,6-diamino-3-methyl-4-(3'-nitrophenyl)-3,4-dihydropyridine-3,5-dicarboxylic acid diethyl ester of melting point 142°C (18 g, 41.5% of theory).
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([CH:7]([OH:13])[CH:8]([NH2:12])[C:9]([OH:11])=[O:10])=[CH:3][CH:2]=1.[C:14]1([CH2:20][C:21](O)=O)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[CH2:20]([C:21]1[O:13][C:7]([C:4]2[CH:3]=[CH:2][CH:1]=[CH:6][CH:5]=2)=[C:8]([C:9]([OH:11])=[O:10])[N:12]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: NC(C(=O)O)C(O)c1ccccc1
Reactant: O=C(O)Cc1ccccc1
Product: O=C(O)c1nc(Cc2ccccc2)oc1-c1ccccc1

Procedure:
Prepared starting from DL-3-phenylserine hydrate following sequentially general procedures W, X with phenyl-acetic acid, Y and Z. LC-MS-conditions 02: tR=0.95 min; [M+H]+=220.18.
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:14][S:15]([C:17]2[NH:21][C:20]3[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=3[N:18]=2)=[O:16])=[N:4][CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]([F:13])([F:12])[F:11].[H-].[Na+].Cl[S:29]([C:32]1[CH:33]=[CH:34][C:35]([O:53][CH3:54])=[C:36]([CH:52]=1)[C:37]([O:39][CH2:40][CH2:41][S:42]([C:45]1[CH:50]=[CH:49][C:48]([CH3:51])=[CH:47][CH:46]=1)(=[O:44])=[O:43])=[O:38])(=[O:31])=[O:30].O>C(Cl)Cl>[C:48]1([CH3:51])[CH:49]=[CH:50][C:45]([S:42]([CH2:41][CH2:40][O:39][C:37](=[O:38])[C:36]2[CH:52]=[C:32]([S:29]([N:21]3[C:20]4[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=4[N:18]=[C:17]3[S:15]([CH2:14][C:3]3[C:2]([CH3:1])=[C:7]([O:8][CH2:9][C:10]([F:13])([F:11])[F:12])[CH:6]=[CH:5][N:4]=3)=[O:16])(=[O:31])=[O:30])[CH:33]=[CH:34][C:35]=2[O:53][CH3:54])(=[O:44])=[O:43])=[CH:46][CH:47]=1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1C(=O)OCCS(=O)(=O)c1ccc(C)cc1
Reactant: Cc1c(OCC(F)(F)F)ccnc1CS(=O)c1nc2ccccc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: COc1ccc(S(=O)(=O)n2c(S(=O)Cc3nccc(OCC(F)(F)F)c3C)nc3ccccc32)cc1C(=O)OCCS(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 65.3 %

Procedure:
To a clear solution of 2-[3-methyl-4-(2,2,2-trifluoroethoxy)pyridin-2-ylmethanesulfinyl]-1H-benzimidazole (740 mg, 2.0 mmol) and NaH (60 mg, 2.5 mmol) in 10 mL of CH2Cl2 was added 2-(p-toluenesulfonyl)ethyl 5-chlorosulfonyl-2-methoxybenzoate (Intermediate 7, 1.0 g, 2.3 mmol). The resulting mixture was stirred at room temperature for 1.5 h. Thereafter water was added and the mixture was extracted with CH2Cl2. The dichloromethane layer was dried over anhydrous magnesium sulfate, and evaporated under reduced pressure to give a thick oil. The oil was purified by column chromatography (silica gel, CH2Cl2 to 2% MeOH in CH2Cl2) to give 1.0 g (65%) of 2-methoxy-5-{2-[3-methyl-4-(2,2,2-trifluoro-ethoxy)-pyridin-2-ylmethanesulfinyl]-benzimidazole-1-sulfonyl}benzoic acid 2-(toluene-4-sulfonyl)ethyl ester (Intermediate 8).
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:6][C@H:5]([N:7]2[C:11]3=[N:12][CH:13]=[CH:14][N:15]=[C:10]3[N:9]([CH:16]3[CH2:18][CH2:17]3)[C:8]2=[O:19])[CH2:4]1.Cl[C:21]1[S:22][C:23]2[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:24]=2[N:25]=1.C(NC(C)C)(C)C>CN(C1C=CN=CC=1)C.CS(C)=O>[CH:16]1([N:9]2[C:10]3=[N:15][CH:14]=[CH:13][N:12]=[C:11]3[N:7]([C@H:5]3[CH2:6][C@H:3]([NH:2][C:21]4[S:22][C:23]5[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:24]=5[N:25]=4)[CH2:4]3)[C:8]2=[O:19])[CH2:17][CH2:18]1
Reactant: N[C@H]1C[C@H](n2c(=O)n(C3CC3)c3nccnc32)C1
Reactant: Fc1ccc2nc(Cl)sc2c1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CC(C)NC(C)C
Solvent: CS(C)=O
Product: O=c1n(C2CC2)c2nccnc2n1[C@H]1C[C@H](Nc2nc3ccc(F)cc3s2)C1
Temperature: 90 °C

Procedure:
A glass microwave reaction vessel was charged with 1-(trans-3-aminocyclobutyl)-3-cyclopropyl-1H-imidazo[4,5-b]pyrazin-2(3H)-one hydrochloride (Intermediate 79, 0.1283 g, 0.455 mmol), 2-chloro-6-fluorobenzo[d]thiazole (0.094 g, 0.501 mmol, Step 1), DMAP (0.056 g, 0.455 mmol, Sigma-Aldrich Chemical Company, Inc.), and diisopropylamine (0.238 ml, 1.366 mmol, Sigma-Aldrich Chemical Company, Inc.) in DMSO (1.518 ml) and heated to 90° C. for 20 h. The crude product was purified by reverse-phase preparative HPLC using a Phenomenex Gemini column, 10 micron, C18, 110 Å, 100×50 mm, 0.1% TFA in CH3CN/H2O, gradient 10% to 90% over 12 min. Fractions containing product peak were concentrated in vacuo. The product was taken up in DCM and loaded onto a Silicyle Si-carbonate cartridge to remove any salts to give the title compound (61.2 mg, 0.154 mmol, 33.9% yield). LCMS showed product peak at 1.732 min (m+1=397.0).
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[NH:7][C:8]1([CH:14]=O)[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[Br:17][C:18]1[CH:24]=[CH:23][C:21]([NH2:22])=[CH:20][CH:19]=1.C(O)(=O)C.C([BH3-])#N.[Na+]>C(OCC)(=O)C>[C:1]([O:5][C:6](=[O:16])[NH:7][C:8]1([CH2:14][NH:22][C:21]2[CH:23]=[CH:24][C:18]([Br:17])=[CH:19][CH:20]=2)[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Nc1ccc(Br)cc1
Reactant: CC(C)(C)OC(=O)NC1(C=O)CCOCC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NC1(CNc2ccc(Br)cc2)CCOCC1
Temperature: 25 °C

Procedure:
A solution of (4-formyl-tetrahydro-pyran-4-yl)-carbamic acid tert-butyl ester (4.48 g, 19.5 mmol), 4-bromoaniline (3.38 g, 19.7 mmol), and acetic acid (1.2 mL, 21.2 mmol) in ethyl acetate (50 mL) contained in a 250 mL round bottom flask fitted with a reflux condenser and a Dean and Stark trap was heated at reflux under N2 blanket for 2 h then cooled to ambient temperature. Sodium cyanoborohydride (1.29 g, 19.5 mmol) was added and the mixture stirred over night. The reaction mixture was then washed with water (50 mL), saturated aqueous sodium chloride (50 mL), dried (MgSO4), preabsorbed on silica gel and flash chromatographed (elution solvent: 10% (v/v) ethyl acetate/hexane) to isolate the desired product as 3.1 g of white solid foam. LRMS (ESI) m/z 385.0, 387.0 [(M+H)+, calcd for C17H26N2O3Br 386.3].
Reaction SMILES: Cl.[Cl:2][C:3]1[C:8]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([F:21])=[CH:17][C:18]=3F)[N:13]=[CH:12][N:11]=2)=[C:7]2[O:22][CH2:23][O:24][C:6]2=[CH:5][CH:4]=1.CCC([O-])(C)C.[Na+].CN1CCCC1=O.[OH:39][CH:40]1[CH2:45][CH2:44][O:43][CH2:42][CH2:41]1>O>[Cl:2][C:3]1[C:8]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([F:21])=[CH:17][C:18]=3[O:39][CH:40]3[CH2:45][CH2:44][O:43][CH2:42][CH2:41]3)[N:13]=[CH:12][N:11]=2)=[C:7]2[O:22][CH2:23][O:24][C:6]2=[CH:5][CH:4]=1
Reactant: Fc1cc(F)c2c(Nc3c(Cl)ccc4c3OCO4)ncnc2c1
Reactant: OC1CCOCC1
Agent: CCC(C)(C)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: O
Product: Fc1cc(OC2CCOCC2)c2c(Nc3c(Cl)ccc4c3OCO4)ncnc2c1
Temperature: 60 °C

Procedure:
4-(6-Chloro-2,3-methylenedioxyanilino)-5,7-difluoroquinazoline hydrochloride salt (80 g) was added portionwise to a stirred mixture of sodium tert-pentoxide (90.2 g) and N-methylpyrrolidin-2-one (500 ml) under an atmosphere of nitrogen gas. 4-Hydroxytetrahydropyran (23.5 ml) and N-methylpyrrolidin-2-one (35 ml) were added and the resultant mixture was heated to 60° C. for 3 hours. Water (764 ml) was added to the heated reaction mixture during 3 hours and the mixture was stirred and heated to 60° C. for a further 3 hours. The warm reaction mixture was filtered and the isolated solid was washed with water (2×230 ml) and dried in vacuo to constant weight. There was thus obtained 4-(6-chloro-2,3-methylenedioxyanilino)-7-fluoro-5-tetrahydropyran-4-yloxyquinazoline (68.6 g, 95% HPLC purity using Method A, retention time 4.6 minutes); m.p. 209-212° C.; NMR Spectrum: (DMSOd6) 1.9-2.0 (m, 2H), 2.1-2.2 (m, 2H), 3.5-3.6 (m, 2H), 3.8-3.95 (m, 2H), 5.05 (m, 1H), 6.1 (s, 2H), 6.95 (d, 1H), 7.05 (d, 1H), 7.1 (d, 1H), 7.3 (d, 1H), 8.4 (s, 1H), 9.3 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@:8]2([CH3:41])[C@:12]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)([CH3:13])[N:11]([C:21]([N:23]3[CH2:28][CH2:27][NH:26][C:25](=[O:29])[CH2:24]3)=[O:22])[C:10]([C:30]3[C:31]([O:38][CH2:39][CH3:40])=[N:32][C:33](SC)=[N:34][CH:35]=3)=[N:9]2)=[CH:4][CH:3]=1.ClC1C=C(C=CC=1)C(OO)=O.S(=O)(O)[O-].[Na+].[NH:58]1[CH2:63][CH2:62][O:61][CH2:60][CH2:59]1>C(Cl)Cl.O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@:8]2([CH3:41])[C@:12]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)([CH3:13])[N:11]([C:21]([N:23]3[CH2:28][CH2:27][NH:26][C:25](=[O:29])[CH2:24]3)=[O:22])[C:10]([C:30]3[C:31]([O:38][CH2:39][CH3:40])=[N:32][C:33]([N:58]4[CH2:63][CH2:62][O:61][CH2:60][CH2:59]4)=[N:34][CH:35]=3)=[N:9]2)=[CH:4][CH:3]=1
Reactant: C1COCCN1
Reactant: CCOc1nc(SC)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCNC(=O)C1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: CCOc1nc(N2CCOCC2)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCNC(=O)C1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 55.2 %

Procedure:
To a solution of rac-4-[(4S*,5R*)-4,5-bis-(4-chloro-phenyl)-2-(4-ethoxy-2-methylsulfanyl-pyrimidin-5-yl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl]-piperazin-2-one (160 mg, 0.261 mmol) in methylene chloride cooled to 0° C. was added 100 mg of m-chloroperoxybenzoic acid (≦77%, Aldrich). After 10 min, sodium bisulfite solution was added to quench the reaction. The product was extracted with methylene chloride. The organic layer was washed with saturated solution of sodium bicarbonate, brine, dried over Na2SO4 and concentrated to give the crude sulphoxide as light yellow foam. The crude sulphoxide/sulphone was taken in 20 mL of tetrahydrofuran, and morpholine (200 uL, 3.34 mmol, Aldrich) was added. The mixture was heated at reflux overnight. Upon cooling to room temperature, the reaction mixture was concentrated under reduced pressure. Purification of the crude residue by flash column chromatography (silica gel, eluting with 50-100% ethyl acetate in hexanes, then with 0-5% methanol in ethyl acetate) gave the tittle compound (94 mg, 55%). HR-MS (ES, m/z) calculated for C32H36N7O4Cl2 [(M+H)+] 652.2201, observed 652.2202.
Reaction SMILES: CI.[CH3:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([Br:12])=[CH:8][C:7]=1[OH:13])=O.[C:14](=O)([O-])[O-].[K+].[K+].NN.[OH-].[K+]>CC(C)=O>[Br:12][C:9]1[CH:10]=[CH:11][C:6]([CH2:4][CH3:3])=[C:7]([O:13][CH3:14])[CH:8]=1
Reactant: O=C([O-])[O-]
Reactant: CC(=O)c1ccc(Br)cc1O
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: CI
Product: CCc1ccc(Br)cc1OC
Temperature: 25 °C
Reaction time: 18 h
Yield: 1.4 %

Procedure:
Methyl iodide (3 mL, 47.3 mmol) was added to a solution of 4-bromo-2-hydroxyacetophenone (9.25 g, 43 mmol) and potassium carbonate (6.54 g, 47.3 mmol) in acetone (20 mL) and the mixture was stirred at room temperature for 18 hours. The reaction mixture was concentrated in vacuo to low volume and diluted with water. The aqueous mixture was extracted with dichloromethane (3×50 mL) and the combined organic solution was washed with water, dried over sodium sulfate and concentrated in vacuo. The residue was dissolved in 1,2-ethanediol (10 mL), hydrazine (19.47 mL, 400 mmol) and potassium hydroxide (7.86 g, 140 mmol) were added and the reaction mixture was heated at 150° C. for 60 hours. The reaction mixture was then quenched with 1M hydrochloric acid and extracted with ethyl acetate (3×20 mL). The combined organic solution was dried over sodium sulfate, concentrated in vacuo and the residue was purified by Kugel Rohr fractional distillation (150° C./0.05 mbar) to provide the title compound as a yellow oil (128 mg).
Reaction SMILES: CO[C:3](=[O:23])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([S:18]([CH3:21])(=[O:20])=[O:19])=[CH:14][CH:13]=2)=[CH:6][C:5]=1[F:22].[CH3:24][C@@H:25]1[CH2:29][CH2:28][CH2:27][N:26]1[CH2:30][C@@H:31]1[CH2:35][CH2:34][CH2:33][NH:32]1>>[F:22][C:5]1[CH:6]=[C:7]([O:10][CH2:11][C:12]2[CH:13]=[CH:14][C:15]([S:18]([CH3:21])(=[O:19])=[O:20])=[CH:16][CH:17]=2)[CH:8]=[CH:9][C:4]=1[C:3]([N:32]1[CH2:33][CH2:34][CH2:35][C@H:31]1[CH2:30][N:26]1[CH2:27][CH2:28][CH2:29][C@H:25]1[CH3:24])=[O:23]
Reactant: C[C@@H]1CCCN1C[C@@H]1CCCN1
Reactant: COC(=O)c1ccc(OCc2ccc(S(C)(=O)=O)cc2)cc1F
Product: C[C@@H]1CCCN1C[C@@H]1CCCN1C(=O)c1ccc(OCc2ccc(S(C)(=O)=O)cc2)cc1F

Procedure:
The title compound is prepared in a manner substantially analogous to Procedure F from 2-fluoro-4-(4-methanesulfonyl-benzyloxy)-benzoic acid methyl ester and 2-(R)-Methyl-1-(2-(S)-pyrrolidinylmethyl)pyrrolidine. MS (ES+) 475.2
Reaction SMILES: [CH2:1]1[O:5][C@@H:4]2[C@H:6]([OH:9])[CH2:7][O:8][C@@H:3]2[C@@H:2]1[OH:10].[C:11](O)(=[O:17])[CH2:12][CH2:13][CH2:14][CH:15]=[CH2:16].CCN=C=NCCCN(C)C>CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:11]([O:10][C@@H:2]1[CH2:1][O:5][C@@H:4]2[C@H:6]([OH:9])[CH2:7][O:8][C@H:3]12)(=[O:17])[CH2:12][CH2:13][CH2:14][CH:15]=[CH2:16]
Reactant: C=CCCCC(=O)O
Reactant: O[C@@H]1CO[C@H]2[C@@H]1OC[C@H]2O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: C=CCCCC(=O)O[C@@H]1CO[C@H]2[C@@H]1OC[C@H]2O
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a stirred solution of 1,4:3,6-dianhydro-D-mannitol (isommanide) (2.00 g, 13.68 mmol), 5-hexenoic acid (1.60 g, 13.68 mmol) and DMAP (0.17 g, 1.4 mmol) in DCM (50 mL) cooled at 0° C., EDAC (3.1 g, 16.42 mmol) was added. The solution was stirred at room temperature for 6 hrs. The solution was diluted with DCM (30 mL), washed with a solution of NaHPO4 5% (2×40 mL) and brine. The organic layer was dried over sodium sulfate and concentrated under vacuo. The residue was purified by flash chromatography (Biotage SP1, 40+M column, TLC method: n-Hexane/EtOAc −8:2, Rf product: 0.35) yielding the title compound.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:13])=[C:4]([CH:9]=[C:10]([F:12])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].C1C(=O)N([Br:21])C(=O)C1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:1][C:2]1[C:3]([CH2:13][Br:21])=[C:4]([CH:9]=[C:10]([F:12])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1cc(F)cc(Br)c1C
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1cc(F)cc(Br)c1CBr
Temperature: 0 °C

Procedure:
A suspension of (E4), NBS (1.2 eq.) and benzoyl peroxide (0.1 eq.) in CCl4 (0.28 M) was heated to reflux for 4.5 h. Afterwards, the reaction mixture was cooled down to 0° C. and the solid filtered off. The solid was washed with Et2O and the filtrate was washed sequentially with 1 M Na2S2O3, brine and dried (Na2SO4). Evaporation of the solvent under reduced pressure afforded the title compound that was used without further purification in the next step. 1H NMR (400 MHz, CDCl3, 300 K) δ 7.63 (1H, dd, J=8.6 and 2.8 Hz), 7.52 (1H, dd, J=7.4 and 2.8 Hz), 5.10 (2H, s), 3.97 (3H, s).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:16](Cl)(=[O:21])[C:17]([CH3:20])([CH3:19])[CH3:18]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[N:7]=[C:6]([NH:8][C:16](=[O:21])[C:17]([CH3:20])([CH3:19])[CH3:18])[CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)C(=O)Cl
Reactant: Nc1cccc(Cl)n1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CC(C)(C)C(=O)Nc1cccc(Cl)n1
Temperature: 25 °C

Procedure:
To 6-chloropyridin-2-amine (20.0 g, 156 mmol) and triethylamine (23.7 mL, 171 mmol) in 100 mL toluene at 50° C. was added pivaloyl chloride (19.6 mL, 163 mmol) dropwise via syringe. The reaction mixture was allowed to stir, and eventually became a solid mass. 50 mL toluene was added. The reaction mixture was heated overnight, and cooled to ambient temperature. The reaction mixture was quenched with 400 mL 2N aq. HCl, and diluted with 300 mL EtOAc. The organic layer was washed with water, brine, dried over sodium sulfate, filtered, and concentrated to a solid. The solid was dissolved in a min. volume of hot MTBE (50° C.), and approx. 300 mL hexanes was added with swirling. On standing, crystals form, which were collected by filtration, rinsing with hexanes to give a total of N-(6-chloropyridin-2-yl)pivalamide. MS (ESI) m/z: calculated: 212.1; Observed: 213.2 (M++1).
Reaction SMILES: O[C:2]1[N:3]=[N:4][C:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][CH:7]=1.OC1N=NC(C(O)=O)=CC=1.P(Cl)(Cl)([Cl:25])=O>>[Cl:25][C:2]1[N:3]=[N:4][C:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1ccc(O)nn1
Reactant: O=P(Cl)(Cl)Cl
Agent: O=C(O)c1ccc(O)nn1
Product: CCOC(=O)c1ccc(Cl)nn1

Procedure:
Ethyl 3-hydroxypyridazine-6-carboxylate [22.00 g, 0.13 mol, prepared from 3-hydroxypyridazine-6-carboxylic acid according to the procedure of Libermann, D. and Rouaix, A. (Bull. Soc. Chim . Fr. 1959, 1793-1798)] and phosphorous oxychloride (122 mL, 1.31 mol) were heated at 110° C. (via an oil bath) for 1 h. The mixture was cooled and concentrated under reduced pressure, which removed the excess phosphorous oxychloride. The residue was dissolved into chloroform, cooled, and carefully washed with saturated sodium bicarbonate solution. The chloroform extract was dried (MgSO4) , filtered, concentrated and recrystallized from ethyl acetate-diisopropyl ether to afford ethyl 6-chloro-3-pyridazinecarboxylate as tan needles, mp 145°-150° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]3[C:11](=[O:29])[N:12]([C:17]4[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][CH:25]=O)=[C:19]([O:27][CH3:28])[CH:18]=4)[CH:13]=[CH:14][C:15]=3[N:16]=2)=[CH:4][CH:3]=1.[NH:30]1[CH2:34][CH2:33][CH2:32][CH2:31]1.CC(O)=O.[OH-].[Na+]>ClCCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]3[C:11](=[O:29])[N:12]([C:17]4[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][CH2:25][N:30]5[CH2:34][CH2:33][CH2:32][CH2:31]5)=[C:19]([O:27][CH3:28])[CH:18]=4)[CH:13]=[CH:14][C:15]=3[N:16]=2)=[CH:4][CH:3]=1
Reactant: COc1cc(-n2ccc3nc(-c4ccc(Cl)cc4)sc3c2=O)ccc1CCC=O
Reactant: C1CCNC1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: COc1cc(-n2ccc3nc(-c4ccc(Cl)cc4)sc3c2=O)ccc1CCCN1CCCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 71 %

Procedure:
Dissolve 3-{4-[2-(4-chloro-phenyl)-4-oxo-4H-thiazolo[5,4-c]pyridin-5-yl]-2-methoxy-phenyl}-propionaldehyde (94 mg, 0.22 mmol) in 1,2-dichloroethane (2.2 mL) and add pyrrolidine (20 μL, 0.24 mmol), AcOH (19 μL, 0.33 mmol), and NaHB(OAc)3 (70 mg, 0.33 mmol). Stir the yellow solution at room temperature for 1 h, then add 1N NaOH (5 mL), and extract the mixture with CH2Cl2 (2×10 mL). Combine the organic portions, then dry, filter, and concentrate. Purify the crude material by flash chromatography, using 8% 2N NH3 in MeOH/CHCl3 as eluent, to give the title compound (75 mg, 71%). MS (ES+) 480.1 (M+1)+. 1H NMR (400 MHz, CDCl3): δ 8.03 (d, 2H, J=8.3 Hz), 7.48 (d, 2H, J=8.8 Hz), 7.43 (d, 1H, J=7.5 Hz), 7.25 (t, 1H, J=3.7 Hz), 6.97 (d, 1H, J=7.5 Hz), 6.93-6.88 (m, 2H), 3.83 (s, 3H), 2.70 (t, 2H, J=7.7 Hz), 2.60 (br s, 6H), 1.96-1.79 (m, 6H).