Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:11](=[O:12])[CH:10]=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[I-].[K+].[Cl:21][C:22]1[C:23]([CH3:44])=[C:24]([CH:33]2[CH2:36][N:35]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:34]2)[C:25]([O:31][CH3:32])=[C:26]([CH:28](Cl)[CH3:29])[CH:27]=1>CN(C)C=O.O>[NH2:1][C:2]1[C:3]2[C:11](=[O:12])[CH:10]=[CH:9][N:8]([CH:28]([C:26]3[C:25]([O:31][CH3:32])=[C:24]([CH:33]4[CH2:34][N:35]([C:37]([O:39][C:40]([CH3:42])([CH3:41])[CH3:43])=[O:38])[CH2:36]4)[C:23]([CH3:44])=[C:22]([Cl:21])[CH:27]=3)[CH3:29])[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: Nc1ncnc2[nH]ccc(=O)c12
Reactant: COc1c(C(C)Cl)cc(Cl)c(C)c1C1CN(C(=O)OC(C)(C)C)C1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [I-]
Solvent: CN(C)C=O
Solvent: O
Product: COc1c(C(C)n2ccc(=O)c3c(N)ncnc32)cc(Cl)c(C)c1C1CN(C(=O)OC(C)(C)C)C1
Temperature: 140 °C
Reaction time: 1 h

Procedure:
To a mixture of 4-aminopyrido[2,3-d]pyrimidin-5(8H)-one (from VWR) (8.6 mg, 0.053 mmol), cesium carbonate (26 mg, 0.080 mmol) and potassium iodide (0.89 mg, 0.0053 mmol) in N,N-dimethylformamide (0.2 mL) was added tert-butyl 3-[3-chloro-5-(1-chloroethyl)-6-methoxy-2-methylphenyl]azetidine-1-carboxylate (20 mg, 0.05 mmol, from Example 1, step 5, racemic intermediate). The mixture was stirred at 140° C. for 1 hour, then cooled and was diluted with water, extracted with ether. The organic layers were dried over MgSO4 and concentrated to afford the crude product which was used in the next step directly. LCMS calculated for C25H31ClN5O4 (M+H)+: m/z=500.2; Found: 500.1.
Reaction SMILES: C([N:8]1[CH2:12][C@H:11]2[C@@H:13]([NH:16][C:17](=[O:31])[CH:18]([CH:25]3[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]3)[CH:19]3[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)[CH2:14][CH2:15][C@H:10]2[CH2:9]1)C1C=CC=CC=1>[OH-].[OH-].[Pd+2].CO>[CH:25]1([CH:18]([CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[C:17]([NH:16][C@@H:13]2[C@H:11]3[C@H:10]([CH2:9][NH:8][CH2:12]3)[CH2:15][CH2:14]2)=[O:31])[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]1
Reactant: O=C(N[C@H]1CC[C@H]2CN(Cc3ccccc3)C[C@H]21)C(C1CCCCC1)C1CCCCC1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: O=C(N[C@H]1CC[C@H]2CNC[C@H]21)C(C1CCCCC1)C1CCCCC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
N-[(3aS,4S,6aR)-2-benzyloctahydrocyclopenta[c]pyrrol-4-yl]-2,2-dicyclohexylacetamide (2.65 g, 6.27 mmol) from Example 15 and methanol (60 mL) were added to 20% palladium hydroxide on carbon (wet, 0.530 g, 3.77 mmol) in a 250 mL pressure bottle. The reaction was stirred for 16 hours under hydrogen (30 psi) at room temperature. The mixture was filtered through a nylon membrane and the solvent removed in vacuo. The crude material was chromatographed on a silica gel cartridge (Analogix®, Burlington, Wis., RS25-25) eluting with 1-10% methanol (2 N ammonia)/dichloromethane to give the title compound: 1H NMR (500 MHz, pyridine-d5) δ ppm 7.97 (d, J=7.1, 1H), 4.57 (dt, J=7.0, 13.8, 1H), 3.03 (dd, J=3.2, 10.1, 1H), 2.89 (dd, J=7.8, 9.7, 1H), 2.78 (dd, J=7.4, 10.1, 1H), 2.71 (ddd, J=3.2, 7.5, 16.7, 1H), 2.58 (dd, J=3.2, 9.8, 1H), 2.50-2.39 (m, J=8.3, 1H), 1.98-1.89 (m, 3H), 1.89-1.80 (m, 3H), 1.79-1.67 (m, J=6.4, 14.9, 7H), 1.66-1.56 (m, 3H), 1.49-1.36 (m, 2H), 1.36-1.28 (m, 1H), 1.28-1.02 (m, 8H); MS (ESI+) m/z 333 (M+H)+.
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([CH2:6][CH:7]1[C:12](=O)[CH2:11][CH2:10][CH2:9][CH2:8]1)=[O:5].Cl.[CH2:15]([O:22][NH2:23])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C(O)C>[CH2:2]([O:3][C:4](=[O:5])[CH2:6][CH:7]1[CH2:8][CH2:9][CH2:10][CH2:11][C:12]1=[N:23][O:22][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH3:1]
Reactant: CCOC(=O)CC1CCCCC1=O
Reactant: NOCc1ccccc1
Agent: Cl
Solvent: CCO
Product: CCOC(=O)CC1CCCCC1=NOCc1ccccc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 72 %

Procedure:
Ethyl 2-cyclohexanoneacetate (4.28 g, 23.3 mmol) and O-benzyl hydroxylamine hydrochloride were combined in 100 mL of ethanol (EtOH) and 2.59 g (25.6 mmol, 3.55 mL) of triethyl amine(Et3N) was added. The reaction was stirred at room temperature for 12 hours at which point it was concentrated in vacuo. The residue was taken up in EtOAc and washed with 1N HCl (2×20 mL), saturated NaHCO3 (1×20 mL), dried over Na2SO4, filtered, and concentrated. Purification by chromatography (SiO2, 90:1 hexanes-EtOAc) afforded (2-benzyloxyimino-cyclohexyl)-acetic acid ethyl ester (4.76 g, 72%) as a mixture of oxime isomers.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:16][CH2:17][CH3:18])[C:5]1[N:6]=[C:7]2[C:12]([CH2:13][OH:14])=[CH:11][CH:10]=[CH:9][N:8]2[CH:15]=1)[CH3:2]>C(Cl)(Cl)(Cl)Cl>[CH2:1]([O:3][CH:4]([O:16][CH2:17][CH3:18])[C:5]1[N:6]=[C:7]2[C:12]([CH:13]=[O:14])=[CH:11][CH:10]=[CH:9][N:8]2[CH:15]=1)[CH3:2]
Reactant: CCOC(OCC)c1cn2cccc(CO)c2n1
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(OCC)c1cn2cccc(C=O)c2n1
Yield: 98 %

Procedure:
From 3i: reaction time 15 h (yield: 98%) as an oil; IR (CCl4) 1693, 1056 cm−1; 1H NMR (400 MHz, CDCl3) δ 1.30 (t, 6H, J=7 Hz), 3.73 (m, 4H), 5.79 (s, 1H), 6.96 (t, 1H, J=7 Hz), 7.80 (s, 1H), 7.83 (d, 1H, J=7 Hz), 8.34 (d, 1H, J=7 Hz), 10.82 (s, 1H); 13C NMR (100 MHz, CDCl3) δ 15.3, 62.0, 98.6, 111.0, 112.0, 124.1, 125.7, 130.6, 144.1, 146.8, 189.1; MS m/z 248 (M+, 1), 204 (17), 175 (100).
Reaction SMILES: Cl.[CH3:2][N:3]([CH3:12])[C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH2:6]Cl.[CH3:13][C:14]1([CH3:21])[NH:18][C:17](=[S:19])[NH:16][C:15]1=[S:20]>C(Cl)(Cl)Cl>[CH3:2][N:3]([CH3:12])[C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH2:6][S:19][C:17]1[NH:18][C:14]([CH3:21])([CH3:13])[C:15](=[S:20])[N:16]=1
Reactant: CC1(C)NC(=S)NC1=S
Reactant: CN(C)c1ccccc1CCl
Agent: Cl
Solvent: ClC(Cl)Cl
Product: CN(C)c1ccccc1CSC1=NC(=S)C(C)(C)N1
Reaction time: 0.5 h

Procedure:
Initially, 11 g of 2-dimethylaminobenzylchloride hydrochloride was added to a solution of 8 g of 5,5-dimethyl-2,4-dithiohydantoin in 200 mL of chloroform (CHCl3) at about 60° C. The reaction mixture was stirred for 30 minutes and washed with an aqueous solution of NaHCO3, dried over MgSO4, and concentrated in vacuo. The residue was treated following the procedure used for the compound (a). As a result, the desired compound of 2-(2-dimethylaminobenzylthio)-5,5-dimethylimidazolin-4-thione was isolated by column chromatography. The yield of this compound was 9.1 g with a yield ratio of 62.1%. Further, the desired compound of 2,4-bis(2-dimethylaminobenzylthio)-5,5-dimethyl-5H-imidazole was isolated. The yield of this compound was 1.2 g with a yield ratio of 5.6%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[NH:8][CH:9]=[CH:10][C:3]=12.C1N2CN3CN(C2)CN1C3.[C:21](O)(=[O:23])C>>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[NH:8][CH:9]=[C:10]([CH:21]=[O:23])[C:3]=12
Reactant: CC(=O)O
Reactant: Clc1ccnc2[nH]ccc12
Agent: C1N2CN3CN1CN(C2)C3
Product: O=Cc1c[nH]c2nccc(Cl)c12
Temperature: 100 °C

Procedure:
A mixture of 4-chloro-1H-pyrrolo[2,3-b]pyridine (15 g, 98 mmol) and hexamethylenetetramine (25.00 g, 178 mmol) in aqueous acetic acid (33%, 15 mL) was heated at 100° C. overnight. After cooling, the mixture was poured into ice-water and stirred for several minutes. The solid material was collected by filtration, washed with water, and dried in vacuo to provide the title compound. MS (ESI+) m/z 181 (M+H)+.
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([CH:14]([NH2:16])[CH3:15])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[O:18][C:19](=O)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH2:26]Br.C([O-])([O-])=O.[K+].[K+].C(OCC)(=O)C>C1(C)C=CC=CC=1>[O:1]([C:8]1[CH:9]=[CH:10][C:11]([CH:14]([N:16]2[CH2:26][C:21]3[C:20](=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:19]2=[O:18])[CH3:15])=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(N)c1ccc(Oc2ccccc2)cc1
Reactant: COC(=O)c1ccccc1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CC(c1ccc(Oc2ccccc2)cc1)N1Cc2ccccc2C1=O
Reaction time: 16 h
Yield: 44.3 %

Procedure:
A mixture of 1-(4-phenoxyphenyl)ethylamine (213 mg, 1 mmol), 2-bromomethyl-benzoic acid methyl ester (250 mg, 1.1 mmol), and K2CO3 (1 g, 7.2 mmol) in toluene (10 mL) was heated at reflux with stirring for 16 h. Workup and silica gel column chromatography using a gradient of hexanes to 30% ethyl acetate in hexanes afforded 2-[1-(4-phenoxyphenyl)-ethyl]-2,3-dihydroisoindol-1-one (146 mg, 44%). GC/MS gave: m/z (rel.int.) 329 (M+, 46), 314 (100), 196 (8) and 77 (8). 1H NMR (300 MHz, CDCl3): δ 1.68 (d, 3H), 4.03 (d, 1H), 4.34 (d, 1H), 5.80 (q, 1H), 6.98 (br t, 4H), 7.10 (t, 1H), 7.49 (dt, 2H), 7.33 (br m, 5H), 7.88 (dd, 1H).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:25]=[CH:24][C:8]2[N:9]([CH3:23])[C:10]([NH:12][C:13]3[S:14][C:15]4[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:16]=4[N:17]=3)=[N:11][C:7]=2[CH:6]=1)=[O:4].[Li+].[OH-]>>[F:22][C:20]1[CH:19]=[CH:18][C:16]2[N:17]=[C:13]([NH:12][C:10]3[N:9]([CH3:23])[C:8]4[CH:24]=[CH:25][C:5]([C:3]([OH:4])=[O:2])=[CH:6][C:7]=4[N:11]=3)[S:14][C:15]=2[CH:21]=1
Reactant: COC(=O)c1ccc2c(c1)nc(Nc1nc3ccc(F)cc3s1)n2C
Agent: [Li+]
Agent: [OH-]
Product: Cn1c(Nc2nc3ccc(F)cc3s2)nc2cc(C(=O)O)ccc21
Yield: 87.1 %

Procedure:
2-(6-Fluoro-benzothiazol-2-ylamino)-1-methyl-1H-benzimidazole-5-carboxylic acid (1.49 g) was prepared by following General Procedure E starting from 2-(6-fluoro-benzothiazol-2-ylamino)-1-methyl-1H-benzimidazole-5-carboxylic acid methyl ester (1.78 g), and LiOH (10.0 ml, 2.0 N solution in water). LC/MS: m/z 344.
Reaction SMILES: C([O:8][C:9]1[C:14]2[CH:15]=[C:16]([C:18]3[N:19]=[C:20]4[N:24]([CH:25]=3)[N:23]=[C:22]([C@@H:26]([F:28])[CH3:27])[S:21]4)[O:17][C:13]=2[CH:12]=[C:11]([O:29][CH3:30])[CH:10]=1)C1C=CC=CC=1.CC1C(C)=C(C)C(C)=C(C)C=1.ClCCl.B(Cl)(Cl)Cl>>[F:28][C@H:26]([C:22]1[S:21][C:20]2=[N:19][C:18]([C:16]3[O:17][C:13]4[C:14](=[C:9]([OH:8])[CH:10]=[C:11]([O:29][CH3:30])[CH:12]=4)[CH:15]=3)=[CH:25][N:24]2[N:23]=1)[CH3:27]
Reactant: COc1cc(OCc2ccccc2)c2cc(-c3cn4nc([C@H](C)F)sc4n3)oc2c1
Agent: Cc1cc(C)c(C)c(C)c1C
Agent: ClB(Cl)Cl
Solvent: ClCCl
Product: COc1cc(O)c2cc(-c3cn4nc([C@H](C)F)sc4n3)oc2c1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
A mixture of (S)-6-(4-(benzyloxy)-6-methoxybenzofuran-2-yl)-2-(1-fluoroethyl)imidazo[2,1-b][1,3,4]thiadiazole (Example 40B, 0.152 g, 0.359 mmol) and pentamethylbenzene (0.374 g, 2.52 mmol) in dichloromethane (24 ml, 373 mmol) was cooled to −78° C. under nitrogen atmosphere and then treated immediately (to avoid crystallization) with boron trichloride 1.0M in dichloromethane (1 ml, 1.000 mmol) added dropwise over 3 min. The resulting mixture was stirred at −78° C. for 1 h. The reaction mixture was quenched by addition of a solution of sodium bicarbonate (0.71 g) in water (12 mL) added in one portion. The cooling bath was removed and the resulting mixture was stirred at room temperature for 1 h. The solid formed was filtered, washed successively with water (8 mL) and dichloromethane (8 mL). The filter cake was soaked with anh. ethanol and suck dried. The white solid obtained was dried under vacuum on P2O5 for 36 h. LC (Method B): 2.038 min. MS (ESI) calcd. for C15H13FN3O3S [M+H]+ m/z: 334.0656. found: 334.0680. 1H NMR (400 MHz, DMSO-d6) δ ppm 10.06 (s, 1H) 8.56 (s, 1H) 7.09 (s, 1H) 6.67 (s, 1H) 6.26-6.28 (m, 1H) 6.16 (dq, J=46.9, 6.4 Hz, 1H) 3.76 (s, 3H) 1.80 (dd, J=24.7, 6.3 Hz, 3H).
Reaction SMILES: [C:1]([CH2:4][CH2:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([OH:12])=[O:11])=[CH:8][CH:7]=1)([OH:3])=O.[Al+3].[Cl-].[Cl-].[Cl-].[Na+].[Cl-].Cl>C(OCC)(=O)C>[O:3]=[C:1]1[C:14]2[C:6](=[CH:7][CH:8]=[C:9]([C:10]([OH:12])=[O:11])[CH:13]=2)[CH2:5][CH2:4]1
Reactant: O=C(O)CCc1ccc(C(=O)O)cc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCOC(C)=O
Product: O=C(O)c1ccc2c(c1)C(=O)CC2
Temperature: 190 °C
Yield: 77 %

Procedure:
A mixture of 4-(2-carboxyethyl)benzoic acid (20.0 g, 103.09 mmol, 1.0 eq.), AlCl3 (164.0 g, 1237.11 mmol, 12.0 eq.) and NaCl (16.4 g, 10% mass weight of AlCl3) was heated for 12 hours at 190° C. The mixture was poured onto ice (500 g), and 6 M HCl (500 ml) and ethyl acetate (800 ml) were added. The phases were separated and the aqueous phase was extracted with ethyl acetate (3×400 ml). The combined org. phases were washed with 2 M HCl solution (2×400 ml), water (2×400 ml) and sat. NaCl solution (500 ml), dried over sodium sulfate and concentrated under reduced pressure. The crude product was used in the next stage without being purified further. Yield: 77% (14.0 g, 79.545 mmol)
Reaction SMILES: Cl.[Cl:2][C:3]1[N:4]=[C:5]([C:10]([NH:12][C@H:13]2[CH2:18][CH2:17][NH:16][CH2:15][C@H:14]2[O:19][CH:20]([CH3:22])[CH3:21])=[O:11])[NH:6][C:7]=1[CH2:8][CH3:9].C(N(C(C)C)CC)(C)C.Cl[C:33]1[S:34][C:35]([C:45]([O:47][CH2:48][CH3:49])=[O:46])=[C:36]([C:38](=[O:44])[NH:39][CH2:40][CH2:41][O:42][CH3:43])[N:37]=1>>[Cl:2][C:3]1[N:4]=[C:5]([C:10]([NH:12][C@H:13]2[CH2:18][CH2:17][N:16]([C:33]3[S:34][C:35]([C:45]([O:47][CH2:48][CH3:49])=[O:46])=[C:36]([C:38](=[O:44])[NH:39][CH2:40][CH2:41][O:42][CH3:43])[N:37]=3)[CH2:15][C@H:14]2[O:19][CH:20]([CH3:21])[CH3:22])=[O:11])[NH:6][C:7]=1[CH2:8][CH3:9]
Reactant: CCc1[nH]c(C(=O)N[C@H]2CCNC[C@H]2OC(C)C)nc1Cl
Reactant: CCOC(=O)c1sc(Cl)nc1C(=O)NCCOC
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1sc(N2CC[C@H](NC(=O)c3nc(Cl)c(CC)[nH]3)[C@H](OC(C)C)C2)nc1C(=O)NCCOC
Yield: 73.8 %

Procedure:
The same operation as in Example (1h) was performed using cis(±)-4-chloro-N-(3-isopropoxypiperidin-4-yl)-5-ethyl-1H-imidazole-2-carboxamide hydrochloride obtained in Example (148a) (0.150 g, 0.427 mmol), diisopropylethylamine (0.186 mL, 1.07 mmol) and ethyl 2-chloro-4-[(2-methoxyethyl)carbamoyl]-1,3-thiazole-5-carboxylate obtained in Example (149a) (0.167 g, 0.572 mmol), to obtain 0.180g of the title compound as a yellow solid (74%).
Reaction SMILES: Cl[CH2:2][C:3](=[O:5])[CH3:4].[Cl:6][C:7]1[CH:8]=[C:9]([CH:14]=[CH:15][CH:16]=1)[C:10]([NH2:13])([CH3:12])[CH3:11].C(N(CC)CC)C.O>CN(C)C(=O)C>[Cl:6][C:7]1[CH:8]=[C:9]([CH:14]=[CH:15][CH:16]=1)[C:10]([NH:13][CH2:2][C:3](=[O:5])[CH3:4])([CH3:12])[CH3:11]
Reactant: CC(=O)CCl
Reactant: CC(C)(N)c1cccc(Cl)c1
Solvent: CCN(CC)CC
Solvent: O
Solvent: CC(=O)N(C)C
Product: CC(=O)CNC(C)(C)c1cccc(Cl)c1
Temperature: 80 °C
Yield: 30.6 %

Procedure:
27.8 g (0.3 mol) of chloroacetone, 16.0 g (0.1 mol) of 3-chloro-α,α-dimethylbenzylamine and 11.2 g (0.11 mol) of triethylamine were dissolved in 200 ml of N,N-dimethylacetamide, and the mixture was heated at 80° C. for 3 hours under stirring. The reaction solution was cooled, then poured into a large amount of water and extracted with toluene. The toluene layer was washed with water and then dried over anhydrous magensium sulfate. Then, the toluene layer was distilled off under reduced pressure to obtain 6.9 g (yield: 30.6%) of the desired compound.
Reaction SMILES: [CH:1]1([C:4]([OH:6])=O)[CH2:3][CH2:2]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.C(O)(C(F)(F)F)=O.[N:47]1([C:53]2[CH:54]=[CH:55][C:56]([C:59]3[CH:60]=[C:61]([O:68][C@@H:69]([C@H:71]4[CH2:75][NH:74][C:73](=[O:76])[CH2:72]4)[CH3:70])[C:62]4[S:66][CH:65]=[N:64][C:63]=4[CH:67]=3)=[N:57][CH:58]=2)[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1>CN(C=O)C>[CH:1]1([C:4]([N:50]2[CH2:49][CH2:48][N:47]([C:53]3[CH:54]=[CH:55][C:56]([C:59]4[CH:60]=[C:61]([O:68][C@@H:69]([C@H:71]5[CH2:75][NH:74][C:73](=[O:76])[CH2:72]5)[CH3:70])[C:62]5[S:66][CH:65]=[N:64][C:63]=5[CH:67]=4)=[N:57][CH:58]=3)[CH2:52][CH2:51]2)=[O:6])[CH2:3][CH2:2]1
Reactant: O=C(O)C1CC1
Reactant: C[C@@H](Oc1cc(-c2ccc(N3CCNCC3)cn2)cc2ncsc12)[C@H]1CNC(=O)C1
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
Solvent: O=C(O)C(F)(F)F
Product: C[C@@H](Oc1cc(-c2ccc(N3CCN(C(=O)C4CC4)CC3)cn2)cc2ncsc12)[C@H]1CNC(=O)C1
Reaction time: 0.17 h

Procedure:
Cyclopropanecarboxylic acid (9.6 μL, 0.12 mmol) was dissolved in DMF (0.5 mL) along with iPr2NEt (30 μL, 0.17 mmol). To this mixture was added HATU (46 mg, 0.12 mmol). After 10 min, a mixture of the crude TFA salt of 4.23 (0.06 mmol) and iPr2NEt (50 μL, 0.29 mmol) in DMF (0.5 mL) was added. Additional DMF (2×0.25 mL) was used to ensure complete transfer. After 1.5 h, the reaction mixture was partitioned between EtOAc, water, and sat. aq. NaHCO3. The phases were separated, and the aqueous phase was extracted with EtOAc. The combined organic phase was dried over Na2SO4, filtered, and concentrated. The crude product was purified by silica gel chromatography (0-25% MeOH in DCM) to afford (R)-4-((R)-1-((5-(5-(4-(cyclopropanecarbonyl)piperazin-1-yl)pyridin-2-yl)benzo[d]thiazol-7-yl)oxy)ethyl)pyrrolidin-2-one (4.33).
Reaction SMILES: [Br-].[C:2]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([OH:4])=[O:3].[OH:29][CH:30]([CH3:40])[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][C:37](=O)[CH3:38]>O1CCCC1>[OH:29][CH:30]([CH3:40])[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][C:37]([CH3:38])=[CH:9][CH2:8][CH2:7][CH2:6][CH2:5][C:2]([OH:4])=[O:3]
Reactant: O=C(O)CCCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(=O)CCCCCCC(C)O
Agent: [Br-]
Solvent: C1CCOC1
Product: CC(=CCCCCC(=O)O)CCCCCCC(C)O
Yield: 98.3 %

Procedure:
325 g (0.7 mol) of (5-carboxypentyl)triphenylphosphonium bromide were dissolved in 1500 ml of tetrahydrofuran. After the addition of 180 g (1.6 mol) of potassium t-butylate in 700 ml of tetrahydrofuran the mixture was treated with 175 g (0.71 mol) of 9-hydroxy-2-decanone (70% purity). After usual work up 186 g of crude 14-hydroxy-7-methyl-pentadec-6-enoic acid were obtained. This product was dissolved in 400 ml of methanol and, after the addition of 5 ml of concentrated sulphuric acid, heated to reflux for 2 hours. After work up, bulb-tube distillation and chromatography 102 g (50%) of methyl 14-hydroxy-7-methyl- pentadec-6-enoate were obtained having the following characteristics:
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([CH:6]=[CH:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:2]1.[CH3:13][N+:14]([O-:16])=[O:15]>>[N+:14]([CH2:13][CH:6]([C:3]1[CH:4]=[CH:5][S:1][CH:2]=1)[CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])([O-:16])=[O:15]
Reactant: C[N+](=O)[O-]
Reactant: CCOC(=O)C=Cc1ccsc1
Product: CCOC(=O)CC(C[N+](=O)[O-])c1ccsc1
Yield: 65 %

Procedure:
To a solution of ethyl 3-(thiophen-3-yl)acrylate (5 g, 27.5 mmol) in CH3NO2 (20 mL) was added Triton B (5 mL) under N2 and the resulting reaction mixture was refluxed overnight. The reaction mixture was concentrated and then diluted with water. The mixture was extracted with EtOAc, washed with brine, and dried over anhydrous Na2SO4. After filtration and concentration, the crude product was purified by column chromatography to give the title compound (4.3 g, 65%).
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1([NH:15][C:16]2[C:17](=[O:35])[N:18]([C:22]3[CH:23]=[C:24]([CH:31]=[CH:32][C:33]=3[CH3:34])[C:25]([NH:27][CH:28]3[CH2:30][CH2:29]3)=[O:26])[CH:19]=[CH:20][N:21]=2)[CH2:14][CH2:13][CH2:12]1.[CH2:36]([NH2:38])[CH3:37]>>[CH:28]1([NH:27][C:25](=[O:26])[C:24]2[CH:31]=[CH:32][C:33]([CH3:34])=[C:22]([N:18]3[CH:19]=[CH:20][N:21]=[C:16]([NH:15][C:11]4([C:6]5[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=5[O:4][CH2:3][CH2:2][NH:38][CH2:36][CH3:37])[CH2:14][CH2:13][CH2:12]4)[C:17]3=[O:35])[CH:23]=2)[CH2:30][CH2:29]1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-n1ccnc(NC2(c3ccccc3OCCCl)CCC2)c1=O
Reactant: CCN
Product: CCNCCOc1ccccc1C1(Nc2nccn(-c3cc(C(=O)NC4CC4)ccc3C)c2=O)CCC1

Procedure:
The title product was prepared from 3-(3-(1-(2-(2-chloroethoxy)phenyl)cyclobutylamino)-2-oxopyrazin-1(2H)-yl)-N-cyclopropyl-4-methylbenzamide (Example 268g) and ethylamine using a similar method to that described for example 167f.
Reaction SMILES: [Br:1][CH:2]1[CH:12]([Br:13])[CH2:11][CH2:10][CH:4]2[C:5]([NH:7][C:8](=[O:9])[CH:3]12)=[O:6].N1C=CC=CC=1.[Br:20][C:21]1[CH:29]=[CH:28][C:27]([Br:30])=[CH:26][C:22]=1[C:23](Cl)=[O:24]>C1C=CC=CC=1>[Br:20][C:21]1[CH:29]=[CH:28][C:27]([Br:30])=[CH:26][C:22]=1[C:23]([N:7]1[C:8](=[O:9])[CH:3]2[CH:2]([Br:1])[CH:12]([Br:13])[CH2:11][CH2:10][CH:4]2[C:5]1=[O:6])=[O:24]
Reactant: O=C(Cl)c1cc(Br)ccc1Br
Reactant: O=C1NC(=O)C2C1CCC(Br)C2Br
Solvent: c1ccccc1
Solvent: c1ccncc1
Product: O=C(c1cc(Br)ccc1Br)N1C(=O)C2CCC(Br)C(Br)C2C1=O
Temperature: 25 °C

Procedure:
3,4-Dibromohexahydrophthalimide (0.10 mole), benzene (300 ml) and pyridine (0.11 mole) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. 2,5-Dibromobenzoyl chloride (0.10 mole) is then added dropwise to the flask with stirring at room temperature. After the addition is completed the reaction mixture is heated at reflux with continued stirring for a period of about 1 hour. After this time the reaction mixture is filtered and the filtrate is washed with water. The washed filtrate is then dried over anhydrous magnesium sulfate, filtered and stripped of solvent under reduced pressure to yield the desired product N-(2,5-dibromobenzoyl)-3,4-dibromohexahydrophthalimide.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:13])[CH2:9][CH2:10][CH2:11][OH:12])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:21][C:22]1[CH:26]=[CH:25][S:24][C:23]=1[C:27]([O:29][CH3:30])=[O:28]>[I-].[K+].CC(=O)CC>[C:27]([C:23]1[S:24][CH:25]=[CH:26][C:22]=1[CH2:21][O:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([CH3:13])[CH2:9][CH2:10][CH2:11][OH:12])=[CH:6][CH:7]=1)([O:29][CH3:30])=[O:28]
Reactant: COC(=O)c1sccc1CBr
Reactant: CC(CCCO)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCC(C)=O
Product: COC(=O)c1sccc1COc1ccc(C(C)CCCO)cc1
Yield: 75.7 %

Procedure:
A stirred suspension of 8.0 g of 4-(4-hydroxyphenyl)pentanol, 18.41 g of anhydrous potassium carbonate, 0.4 g of potassium iodide, 10.44 g of methyl 3-bromomethyl-2-thiophenecarboxylate, and 225 ml of 2-butanone was heated under reflux overnight, with exclusion of moisture. The mixture was filtered while hot and the filter cake was washed with 2-butanone. The combined filtrate was concentrated, and a solution of the residue and dichloromethane was washed with 10% sodium hydroxide solution, water and saturated brine. The dried (over anhydrous sodium sulfate) organic phase was filtered and the filtrate was concentrated to an oil. Purification by high-pressure liquid chromatography (Waters Associates Prep LC/System 500A; two silica gel columns; 0.2 l/min flow rate; Gow Mac model 80-800 UV detector; 30% V/V ethyl acetate in hexane) gave 11.23 g (75.6%) of product as an oil, dried at 60° C. for 2 hours.