Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:7]2[S:8][CH:9]=[CH:10][C:6]=2[CH:5]=[CH:4][CH:3]=1.[Cl:11][C:12]1[CH:17]=[C:16](B2OC(C)(C)C(C)(C)O2)[CH:15]=[CH:14][N:13]=1.ClCCl.C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)(Cl)Cl.C(O)(C)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1)(C)(C)C.C1COCC1>[S:8]1[CH:9]=[CH:10][C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([C:16]3[CH:15]=[CH:14][N:13]=[C:12]([Cl:11])[CH:17]=3)[C:7]1=2
Reactant: CC1(C)OB(c2ccnc(Cl)c2)OC1(C)C
Reactant: Brc1cccc2ccsc12
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Solvent: CC(C)O
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: Clc1cc(-c2cccc3ccsc23)ccn1
Temperature: 100 °C
Yield: 66.3 %

Procedure:
In a flask, combine 7-bromo-benzo[b]thiophene (1.7 g, 12 mmol), 2-chloro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine (1.6 g, 7 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane (1:1) (285 mg, 0.3 mmol), 2-(di-tert-butylphosphino)biphenyl (63 mg, 0.2 mmol), sodium carbonate (2 M, 8 mL, 16 mmol) and THF (20 mL). Heat the mixture at 100° C. for 3 hours. Dilute the mixture with chloroform/isopropanol (3/1). Wash the solution with saturated aqueous sodium chloride. Dry over sodium sulfate. Concentrate the solution in vacuo to a dark residue. Purify by column chromatography (dichloromethane to 20% THF in dichloromethane) to afford the title compound (1.14 g, 66%) as a yellow solid. MS (ES) m/z 246 [M+1]+.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]2[S:8][C:9]3[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=3[C:5]2=[C:4]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)[C:3]=1[CH2:22][C:23]([O:25][CH3:26])=[O:24].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.C1COCC1.I[CH:43]([CH3:49])[CH2:44][C:45]([F:48])([F:47])[F:46]>CN(C=O)C>[CH3:1][C:2]1[N:7]=[C:6]2[S:8][C:9]3[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=3[C:5]2=[C:4]([C:15]2[CH:16]=[CH:17][C:18]([CH3:21])=[CH:19][CH:20]=2)[C:3]=1[CH:22]([CH2:49][CH2:43][CH2:44][C:45]([F:48])([F:47])[F:46])[C:23]([O:25][CH3:26])=[O:24]
Reactant: CC(I)CC(F)(F)F
Reactant: COC(=O)Cc1c(C)nc2sc3c(c2c1-c1ccc(C)cc1)CCCC3
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COC(=O)C(CCCC(F)(F)F)c1c(C)nc2sc3c(c2c1-c1ccc(C)cc1)CCCC3
Yield: 72.3 %

Procedure:
This compound was prepared according to the procedure C from methyl [2-methyl-4-(p-tolyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]acetate (0.183 g; 0.5 mmol), LHMDS 1N in THF (0.55 mL; 0.55 mmol), 3-iodo-1,1,1-trifluorobutane (0.127 mL; 1 mmol) in DMF (2.5 mL) for 18 h. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (3-30%) in heptane furnished 0.172 g (72%) of the title compound as a yellow oil.
Reaction SMILES: C([O:4][C@H:5]1[C@H:10]([O:11]C(=O)C)[C@@H:9]([O:15]C(=O)C)[C@H:8]([C:19]2[S:20][C:21]([Cl:33])=[C:22]([CH2:24][C:25]3[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=3)[CH:23]=2)[O:7][C@@H:6]1[CH2:34][O:35]C(=O)C)(=O)C.C[O-].[Na+].CC(O)=O>CO>[Cl:33][C:21]1[S:20][C:19]([C@H:8]2[C@H:9]([OH:15])[C@@H:10]([OH:11])[C@H:5]([OH:4])[C@@H:6]([CH2:34][OH:35])[O:7]2)=[CH:23][C:22]=1[CH2:24][C:25]1[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=1
Reactant: COc1ccc(Cc2cc([C@@H]3O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]3OC(C)=O)sc2Cl)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: COc1ccc(Cc2cc([C@@H]3O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)sc2Cl)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 62.5 %

Procedure:
To a suspension of acetate 19 (1.37 g, 2.41 mmol) in MeOH (20 mL) was added NaOMe (25 wt % in MeOH, 0.3 mL) at room temperature. The mixture was stirred at room temperature for 1 hour. Glacial AcOH was added to the mixture to acidify the mixture. The mixture was concentrated under reduced pressure. The residue was purified by prep HPLC (C18) to provide the title compound 20 (604 mg, 63%).
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]1[C:10]([OH:12])=[O:11].S(=O)(=O)(O)O.[C:18](=O)(O)[O-].[Na+]>CO>[CH2:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH2:1][CH:2]1[C:10]([O:12][CH3:18])=[O:11]
Reactant: O=C(O)C1Cc2ccccc2C1
Reactant: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Product: COC(=O)C1Cc2ccccc2C1

Procedure:
A solution of 50 g. of indan-2-carboxylic acid (prepared according to the procedure reported by E. D. Bergmann and E. Hoffman, J. Org. Chem., 26, 3555 (1961)) and 5 ml. of con d sulfuric acid in 500 ml. of methanol is heated at reflux for 3.0 hours then is cooled in ice. The cooled solution is neutralized (pH~5) with saturated sodium bicarbonate, is concentrated, and the aqueous layer is extracted with methylene chloride. The combined organic extracts are washed with saturated bicarbonate, with saturated brine, are dried (anhydrous magnesium sulfate), and are concentrated. Distillation of the crude residue in vacuo provides the desired methyl indan-2-carboxylate.
Reaction SMILES: [NH:1](C(OCC1C=CC=CC=1)=O)[C@H:2]([C:8]([NH:10][C@H:11]([C:19]([NH:21][C@H:22]([C:24]([NH:26][C@H:27]([C:32]([NH:34][CH2:35][C:36]([OH:38])=[O:37])=[O:33])[C@H:28]([CH2:30][CH3:31])[CH3:29])=[O:25])[CH3:23])=[O:20])[C@@H:12]([CH3:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:9])[CH2:3][CH2:4][C:5](=[O:7])[NH2:6].Cl>CN(C)C=O.[Pd]>[NH2:1][C@H:2]([C:8]([NH:10][C@H:11]([C:19]([NH:21][C@H:22]([C:24]([NH:26][C@H:27]([C:32]([NH:34][CH2:35][C:36]([OH:38])=[O:37])=[O:33])[C@H:28]([CH2:30][CH3:31])[CH3:29])=[O:25])[CH3:23])=[O:20])[C@@H:12]([CH3:18])[O:13][C:14]([CH3:15])([CH3:16])[CH3:17])=[O:9])[CH2:3][CH2:4][C:5](=[O:7])[NH2:6]
Reactant: CC[C@H](C)[C@H](NC(=O)[C@H](C)NC(=O)[C@@H](NC(=O)[C@H](CCC(N)=O)NC(=O)OCc1ccccc1)[C@@H](C)OC(C)(C)C)C(=O)NCC(=O)O
Agent: [Pd]
Agent: Cl
Solvent: CN(C)C=O
Product: CC[C@H](C)[C@H](NC(=O)[C@H](C)NC(=O)[C@@H](NC(=O)[C@@H](N)CCC(N)=O)[C@@H](C)OC(C)(C)C)C(=O)NCC(=O)O
Temperature: 25 °C

Procedure:
3.40 g of Z-Gln-Thr(tBu)-Ala-Ile-Gly-OH are dissolved in 70 ml of warm dimethylformamide. After cooling to room temperature, 5 ml of 1 N hydrochloric acid and 500 mg of Pd on charcoal (10%) are added and the product hydrogenated. After completion of the hydrogenation the catalyst is filtered off by filtering through 1 g of Norite and the filtrate is concentrated to about 10 ml in a high vacuum at 40° C. This solution is added dropwise to 100 ml of ether and the precipitated material is filtered off and washed with ether. The product is dried in a high vacuum at room temperature and on potentiometric titration with 0.1 N sodium hydroxide solution in 80% methanol proves to have a content of 91%.
Reaction SMILES: N1[C:6]([CH3:7])=[CH:5][CH:4]=[CH:3][C:2]=1[CH3:8].C1C[O:12][CH2:11]C1>[Pd]>[CH3:8][CH:2]1[CH2:7][CH2:6][CH:5]([CH:11]=[O:12])[CH2:4][CH2:3]1
Reactant: Cc1cccc(C)n1
Reactant: C1CCOC1
Agent: [Pd]
Product: CC1CCC(C=O)CC1
Temperature: 25 °C
Reaction time: 15.5 h

Procedure:
A mixture of the compound prepared in step 115.6 (8.8 g, 54.7 mmol) and Pd/C 10% (5.8 g, 54.7 mmol) in THF (150 mL) and 2,6-lutidine (11.7 g, 109 mmol) was stirred for 15.5 h at rt, under a hydrogen atmosphere. The reaction mixture was filtered through a pad of celite. The crude was dissolved in CH2Cl2 and extracted with 1N HCl then with a saturated aqueous NaHCO3 solution. The organic layer was dried (Na2SO4), filtered and concentrated.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:11])[CH3:10])=[C:4]([F:12])[CH:3]=1.O.[C:14](OC(=O)C)(=[O:16])[CH3:15]>C(O)(=O)C>[C:9]([NH:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:14](=[O:16])[CH3:15])=[CH:3][C:4]=1[F:12])(=[O:11])[CH3:10]
Reactant: CC(=O)OC(C)=O
Reactant: CC(=O)Nc1ccc(N)cc1F
Solvent: O
Solvent: CC(=O)O
Product: CC(=O)Nc1ccc(NC(C)=O)c(F)c1
Temperature: 15 °C

Procedure:
134.5 g (0.8 mol) of the 1-amino-4-acetylamino-3-fluorobenzene prepared above under A. are heated at 85° C. together with 800 ml of water and 34 g of acetic acid. 86.5 g of acetic anhydride are added to this mixture in the course of one hour. The reaction mixture is subsequently stirred at the same temperature for a further hour and cooled to 15° C. The product which has precipitated is then filtered off, washed twice with 150 ml of water each time and dried.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([CH3:14])[C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:10]=2[C:11]=1[CH:12]=O.[OH-].[Na+].O.[CH3:18][C:19]([CH3:21])=[O:20]>>[Cl:1][C:2]1[N:3]=[C:4]([CH3:14])[C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:10]=2[C:11]=1[CH:12]=[CH:18][C:19](=[O:20])[CH3:21]
Reactant: CC(C)=O
Reactant: Cc1nc(Cl)c(C=O)c2c1CCCC2
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(=O)C=Cc1c(Cl)nc(C)c2c1CCCC2

Procedure:
3-Chloro-1-methyl-5,6,7,8-tetrahydroisoquinoline-4-carboxaldehyde (4.0 g) was stirred with a few drops of a 2% aqueous sodium hydroxide solution in aqueous acetone (1:2 v/v; 20 ml) at room temperature for 4 hr. The mixture was poured into water which was then extracted with diethyl ether. The residue obtained after evaporation of the dried (MgSO4) organic extract was purified by column chromatography over silica with dichloromethane elution to give 1-(3-chloro-1-methyl-5,6,7,8-tetrahydroisoquinolin-4-yl)-but-1-en-3-one as white crystals, mp 90° C.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].C[O:8][C:9](=O)[C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:12][C:11]=1[OH:24]>C1COCC1>[CH2:17]([O:16][C:13]1[CH:14]=[CH:15][C:10]([CH2:9][OH:8])=[C:11]([OH:24])[CH:12]=1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: COC(=O)c1ccc(OCc2ccccc2)cc1O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCc1ccc(OCc2ccccc2)cc1O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a 1.0M solution of LiAlH4 (22 mL) in THF at 0° C. is added dropwise a solution of 4-(benzyloxy)-2-hydroxybenzoic acid methyl ester (2.84 g, 11 mmol) in THF (15 mL). The mixture is stirred for 2 h, then quenched by the careful addition of 1 mL of saturated Na2SO4 solution. The mixture is warmed to ambient temperature and extracted with Et2O. The organic layer is washed with water, sat. NaCl and dried over sodium sulfate. The solvent is removed under reduced pressure to afford 5-benzyloxy-2-hydroxymethylphenol as a white solid: 1H NMR (DMSO-d6) δ 9.28 (s, 1H), 7.42-7.31 (m, 5H), 7.11 (d, J=8.34 Hz, 1H), 6.44-6.40 (m, 2H), 5.01 (s, 2H), 4.75-4.72 (m, 1H), 4.38 (d, J=5.56 Hz, 2H); (M−H)−=229.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:27][CH:28]([C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([Cl:36])[CH:31]=1)[OH:29])[CH:9]([CH3:26])[CH2:10][C:11]1[CH:25]=[CH:24][C:14]2[O:15][C:16]([C:21]([OH:23])=[O:22])([C:18]([OH:20])=[O:19])[O:17][C:13]=2[CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[CH:38]([CH3:44])[C:39]([O:41][CH2:42][CH3:43])=[O:40]>>[CH2:42]([O:41][C:39]([CH:38]([O:19][C:18]([C:16]1([C:21]([O:23][CH:38]([C:39]([O:41][CH2:42][CH3:43])=[O:40])[CH3:44])=[O:22])[O:15][C:14]2[CH:24]=[CH:25][C:11]([CH2:10][CH:9]([N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:27][CH:28]([C:30]3[CH:35]=[CH:34][CH:33]=[C:32]([Cl:36])[CH:31]=3)[OH:29])[CH3:26])=[CH:12][C:13]=2[O:17]1)=[O:20])[CH3:44])=[O:40])[CH3:43]
Reactant: CCOC(=O)C(C)Br
Reactant: CC(Cc1ccc2c(c1)OC(C(=O)O)(C(=O)O)O2)N(CC(O)c1cccc(Cl)c1)C(=O)OC(C)(C)C
Product: CCOC(=O)C(C)OC(=O)C1(C(=O)OC(C)C(=O)OCC)Oc2ccc(CC(C)N(CC(O)c3cccc(Cl)c3)C(=O)OC(C)(C)C)cc2O1

Procedure:
The title compound was prepared from 5-(2-{tert-butoxycarbonyl-[2-(3-chloro-phenyl)-2-hydroxy-ethyl]-amino}-propyl)-benzo[1,3]dioxole-2,2-dicarboxylic acid and ethyl 2-bromopropionate according to the procedure of Example 24, Step 3 as a colorless oil; 1H NMR (300 MHz, CDCl3): δ 1.15-1.30 (complex m, 9H), 1.40 (brs, 9H), 1.52-1.69 (m, 6H), 2.47-2.58 (m, 1H), 2.58-2.70 (m, 1H), 3.05-3.16 (m, 1H), 3.42-3.54 (m, 1H), 4.05-4.30 (complexm, 5H), 4.77 (m, 1H), 5.19-5.30 (m, 2H), 5.49 (brs, 1H), 6.57-6.67 (m, 1H), 6.71-6.80 (m, 1H), 6.82-6.91 (m, 2H), 7.20-7.35 (m, 2H), 7.41 (brs, 1H); MS (ES) m/z (relative intensity): 722 (M+, 100).
Reaction SMILES: Br[CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=1.[C-:12]#[N:13].[Na+].[OH-].[Na+]>C(#N)C.O>[C:12]([CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=1)#[N:13]
Reactant: [C-]#N
Reactant: O=C(O)c1ccc(CBr)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC#N
Product: N#CCc1ccc(C(=O)O)cc1
Temperature: 25 °C
Yield: 26.4 %

Procedure:
A solution of 4-bromomethyl-benzoic acid (4.0 g, 18.6 mmol) in acetonitrile (186 mL) was treated with a solution of sodium cyanide (1.0 g, 20.4 mmol) and sodium hydroxide (0.74 g, 18.6 mmol) in water (24 mL). The reaction mixture was heated at reflux for 2 h. At this time, the reaction was cooled to 25° C. and concentrated in vacuo. The resulting solution was washed with chloroform (1×50 mL). The aqueous layer was acidified to pH=3 with a 1N aqueous hydrochloric acid solution. The aqueous layer was extracted with a solution of chloroform/methanol (9:1, 3×100 mL). The organics were dried over sodium sulfate, filtered, and concentrated in vacuo to afford 4-cyanomethyl-benzoic acid (0.79 g, 26.3%) as a white solid: mp 193-195° C.; EI-HRMS m/e calcd for C9H7NO2 (M+) 161.0476, found 161.0483.
Reaction SMILES: [CH3:1][C:2]([CH3:9])([CH2:6][CH:7]=O)[CH2:3][CH:4]=O.S([O-])([O-])(=O)=O.[Mg+2].[C:16]1([NH:22][C:23]([NH2:25])=[O:24])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C1COCC1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH3:1][C:2]1([CH3:9])[CH:6]=[CH:7][N:25]([C:23]([NH:22][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:24])[CH:4]=[CH:3]1
Reactant: CC(C)(CC=O)CC=O
Reactant: NC(=O)Nc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: C1CCOC1
Solvent: O
Product: CC1(C)C=CN(C(=O)Nc2ccccc2)C=C1
Reaction time: 0.67 h
Yield: 100.1 %

Procedure:
A mixture of 4.57 g (0.036 mole) of 3,3-dimethylglutaraldehyde, 0.20 g (0.001 mole) of p-toluenesulfonic acid monohydrate and 8.64 g (0.072 mole) of anhydrous magnesium sulfate in 300 ml of dry THF was heated to reflux under nitrogen. 4.89 g (0.036 mole) of phenylurea in 125 ml of dry THF was added over a period of 1 hour. Refluxing was continued for an additional 40 minutes before the reaction mixture was filtered and the filtrate evaporated in vacuo to yield 8.23 g of a brown oil. The crude product was purified by silica gel column chromatography on 410 g of CC-7 silica gel eluting with a 7.5% ethyl acetate/hexane solution. The eluate was evaporated in vacuo to yield 4.74 g of the title compound, a white solid, mp 128°-130° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[CH2:5]P(OCC)(OCC)=O)[CH3:2].[H-].[Na+].[CH2:17]([N:24]1[CH2:28][CH2:27][CH:26]([NH:29][C:30]2[CH:37]=[CH:36][C:33]([CH:34]=O)=[CH:32][N:31]=2)[CH2:25]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(OCC)(C)=O.O>C1COCC1>[CH2:17]([N:24]1[CH2:28][CH2:27][CH:26]([NH:29][C:30]2[N:31]=[CH:32][C:33](/[CH:34]=[CH:5]/[C:4]([O:3][CH2:1][CH3:2])=[O:14])=[CH:36][CH:37]=2)[CH2:25]1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: O=Cc1ccc(NC2CCN(Cc3ccccc3)C2)nc1
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)/C=C/c1ccc(NC2CCN(Cc3ccccc3)C2)nc1
Temperature: 15 °C
Yield: 88.6 %

Procedure:
A solution of diethylphosphonoacetic acid ethyl ester (896 mg) in THF (10 ml) was added dropwise to a mixture of 60% sodium hydride in oil (170 mg) in THF (20 mL) with stirring at 10-20° C. under atmospheric pressure of nitrogen, and the reaction mixture was stirred at ambient temperature for 30 minutes. A solution of 6-[(1-benzyl-3-pyrrolidinyl)amino]nicotinaldehyde (0.75 g) in THF (10 ml) solution was added the above mixture, and resultant mixture was stirred at ambient temperature for 1.5 hour. The reaction mixture was poured into a mixture of AcOEt-H2O and the organic layer was washed with brine and dried over MgSO4. The solvent was evaporated in vacuo and the residue was chromatographed on silicagel eluting with AcOEt-MeOH (95:5). The eluted fractions containing the desired product were collected and evaporated in vacuo to give ethyl (2E)-3-{6-[(1-benzyl-3-pyrrolidinyl)amino]-3-pyridyl}acrylate (0.83 g).
Reaction SMILES: Cl.[CH3:2][C:3]1([CH3:9])[NH:8][CH2:7][CH2:6][S:5][CH2:4]1.[N:10]([O-])=[O:11].[Na+].C(=O)([O-])[O-].[K+].[K+]>O>[N:10]([N:8]1[CH2:7][CH2:6][S:5][CH2:4][C:3]1([CH3:9])[CH3:2])=[O:11]
Reactant: O=N[O-]
Reactant: CC1(C)CSCCN1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CC1(C)CSCCN1N=O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
12 ml of 10N HCl are added with cooling to a mixture of 15.7 g of 3,3-dimethyltetrahydro-1,4-thiazine (step c) and 60 ml of ice-water. A solution of 12.4 g of sodium nitrite in 40 ml of water is then added dropwise at 4° to 6° C. The mixture is subsequently stirred at room temperature for 4 hours, rendered alkaline with potassium carbonate and extracted by shaking with ethyl acetate. The organic phase is dried and concentrated in a water jet vacuum. Yield: 17.5 g; M.p.: yellow oil.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.[NH2:12][C:13]1[CH:18]=[C:17]([CH3:19])[CH:16]=[CH:15][C:14]=1[S:20][C:21]1[CH:26]=[CH:25][C:24]([NH:27][C:28](=[O:30])[CH3:29])=[CH:23][CH:22]=1>>[CH3:19][C:17]1[CH:16]=[CH:15][C:14]([S:20][C:21]2[CH:22]=[CH:23][C:24]([NH:27][C:28](=[O:30])[CH3:29])=[CH:25][CH:26]=2)=[C:13]([NH:12][C:2]2[C:11]3[C:6](=[N:7][CH:8]=[CH:9][CH:10]=3)[N:5]=[CH:4][CH:3]=2)[CH:18]=1
Reactant: Clc1ccnc2ncccc12
Reactant: CC(=O)Nc1ccc(Sc2ccc(C)cc2N)cc1
Product: CC(=O)Nc1ccc(Sc2ccc(C)cc2Nc2ccnc3ncccc23)cc1

Procedure:
The product from Example 16c (50 mg, 0.304 mmol) was reacted with the product from Example 18b (83 mg, 0.304 mmol) for 16 h following the procedure from Example 1g giving the crude title compound which was purified by HPLC with TFA providing the trifluoroacetic acid salt (29 mg, 24%). 1H NMR (300 MHz, DMSO-d6) δ ppm: 2.04 (s, 3H), 2.35 (s, 3H), 6.34 (d, J=6.99 Hz, 1H), 7.17 (d, J=7.72 Hz, 1H), 7.23 (d, J=8.46 Hz, 2H), 7.28-7.34 (m, 2H), 7.49 (d, J=8.82 Hz, 2H), 7.90 (dd, J=8.46, 4.41 Hz, 1H),8.48 (d, J=6.99 Hz, 1H),9.11 (dd, J=8.46, 1.47 Hz, 1H),9.17 (dd, J=4.41, 1.47 Hz, 1H), 10.04 (s, 1H), 11.12 (s, 1H); MS (ESI+) m/z 401 (M+H)+, (ESI−) m/z 399 (M−H)−.
Reaction SMILES: [CH2:1]([NH2:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[C:12]1(=[O:17])[O:16][CH2:15][CH2:14][CH2:13]1>[Cl-].[Zn+2].[Cl-].C1(C)C=CC=CC=1>[CH2:1]([NH:11][C:15](=[O:16])[CH2:14][CH2:13][CH2:12][OH:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCCCCCN
Reactant: O=C1CCCO1
Agent: [Cl-]
Agent: [Zn+2]
Solvent: Cc1ccccc1
Product: CCCCCCCCCCNC(=O)CCCO
Yield: 44.6 %

Procedure:
A mixture of 15 g of decylamine, 5.48 g of gamma butyrolactone, 100 ml of toluene, and 20 mg of zinc chloride was refluxed under nitrogen for 4 days. Upon cooling the reaction mixture formed a precipitate which was recrystallized from toluene to yield 6.91 g (44.6%) of N-decyl-4-hydroxybutyramide, m.p. 74-75° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]2[S:8][C:9](SC)=[N:10][C:5]2=[CH:4][CH:3]=1.[CH3:13][O-:14].[Na+].C(Cl)Cl.CO>C(OCC)(=O)C.C(O)(=O)C>[Cl:1][C:2]1[N:7]=[C:6]2[S:8][C:9]([O:14][CH3:13])=[N:10][C:5]2=[CH:4][CH:3]=1
Reactant: C[O-]
Reactant: CSc1nc2ccc(Cl)nc2s1
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Solvent: CCOC(C)=O
Product: COc1nc2ccc(Cl)nc2s1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a round bottom flask was added 5-chloro-2-(methylthio)[1,3]thiazolo[5,4-b]pyridine (1-2) (11.5 g, 53.3 mmol), sodium methoxide (10.8 g, 200 mmol), anhydrous DCM (200 mL) and anhydrous MeOH (200 mL). The reaction mixture was then permitted to stir at room temperature under an atmosphere of nitrogen for 18 hours. The reaction mixture was then acidified to pH 5 with glacial acetic acid, then suspended in ethyl acetate and washed with water, then brine, dried over sodium sulfate, filtered, and concentrated. The resulting residue was purified by silica gel chromatography (0-6% IPA/DCM) to give 5-chloro-2-methoxy[1,3]thiazolo[5,4-b]pyridine (1-3) as an off-white solid. HRMS (M+H)+: observed=198.9998, calculated=198.9994.
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH3:7])=[C:5]([C:8]2[CH:9]=[C:10]([CH:19]=[CH:20][CH:21]=2)[CH2:11][CH2:12][O:13][CH2:14][CH2:15][C:16]([OH:18])=O)[CH:4]=[N:3]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:55][O:56][CH:57]([O:66][CH3:67])[CH2:58][NH:59][CH:60]1[CH2:65][CH2:64][CH2:63][CH2:62][CH2:61]1>CN(C=O)C>[CH:60]1([N:59]([CH2:58][CH:57]([O:66][CH3:67])[O:56][CH3:55])[C:16](=[O:18])[CH2:15][CH2:14][O:13][CH2:12][CH2:11][C:10]2[CH:19]=[CH:20][CH:21]=[C:8]([C:5]3[CH:4]=[N:3][N:2]([CH3:1])[C:6]=3[CH3:7])[CH:9]=2)[CH2:65][CH2:64][CH2:63][CH2:62][CH2:61]1
Reactant: Cc1c(-c2cccc(CCOCCC(=O)O)c2)cnn1C
Reactant: COC(CNC1CCCCC1)OC
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(CN(C(=O)CCOCCc1cccc(-c2cnn(C)c2C)c1)C1CCCCC1)OC
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 3-(3-(1,5-dimethyl-1H-pyrazol-4-yl)phenethoxy)propanoic acid [Example 37 Step ii)] (0.3 g) and DIPEA (0.545 mL) in DMF (4 mL) was added HATU (0.475 g) and the mixture was stirred at ambient temperature for 10 min. To this solution was added N-(2,2-dimethoxyethyl)cyclohexanamine (0.214 g) and the reaction mixture was stirred at ambient temperature for 2.5 h. The reaction mixture was poured onto water and extracted with ethyl acetate (2×100 mL). The organics were washed well with water, then brine and dried over anhydrous sodium sulfate, filtered and evaporated. The crude product was purified by flash silica chromatography, elution gradient 20-70% ethyl acetate in isohexane to afford the titled compound (0.185 g) as an oil. MS [M+H-MeOH]+=426 (MultiMode+) 1H NMR (400 MHz, CDCl3) δ 7.54 (s, 1H), 7.33-7.27 (m, 1H), 7.22-7.17 (m, 2H), 7.12 (d, 1H), 3.84 (s, 3H), 3.79 (dt, 2H), 3.70 (dt, 2H), 3.40 (s, 6H), 3.37 (d, 1H), 3.30 (d, 1H), 2.94-2.88 (m, 2H), 2.74-2.65 (m, 2H), 2.38 (s, 3H), 1.86-1.73 (m, 2H), 1.73-1.59 (m, 3H), 1.53-1.19 (m, 5H), 1.14-1.02 (m, 1H).