Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:3]([O:20][CH3:21])=[CH:4][C:5]2[O:19][CH2:18][C:8]3([C:16]4[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=4)[NH:10][C:9]3=[O:17])[C:6]=2[CH:7]=1.CC1C2C=C3[C:34]4([C:42]5[C:37](=[CH:38]C=C[CH:41]=5)N[C:35]4=[O:43])COC3=CC=2ON=1.BrCC1CCOCC1.BrCC1OC(C(F)(F)F)=CC=1>>[F:1][C:2]1[C:3]([O:20][CH3:21])=[CH:4][C:5]2[O:19][CH2:18][C:8]3([C:16]4[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=4)[N:10]([CH2:41][CH:42]4[CH2:37][CH2:38][O:43][CH2:35][CH2:34]4)[C:9]3=[O:17])[C:6]=2[CH:7]=1
Reactant: COc1cc2c(cc1F)C1(CO2)C(=O)Nc2ccccc21
Reactant: Cc1noc2cc3c(cc12)C1(CO3)C(=O)Nc2ccccc21
Agent: BrCC1CCOCC1
Agent: FC(F)(F)c1ccc(CBr)o1
Product: COc1cc2c(cc1F)C1(CO2)C(=O)N(CC2CCOCC2)c2ccccc21

Procedure:
Following the procedure as described in EXAMPLE 9 and making non-critical variations using 5-fluoro-6-methoxyspiro[1-benzofuran-3,3′-indol]-2′(1′H)-one to replace 3-methylspiro[furo[3,2-f][1,2]benzisoxazole-5,3′-indol]-2′(1′H)-one, and 4-(bromomethyl)tetrahydropyran to replace 2-(bromomethyl)-5-(trifluoromethyl)furan, 5-fluoro-6-methoxy-1′-(tetrahydro-2H-pyran-4-ylmethyl)spiro[1-benzofuran-3,3′-indol]-2′(1′H)-one was obtained (82%) as a colorless solid: 1H NMR (300 MHz, CDCl3) δ7.30 (ddd, J=7.7, 7.7, 1.3 Hz, 1H), 7.16-7.00 (m, 2H), 6.89 (d, J=7.8 Hz, 1H), 6.59 (d, J=6.8 Hz, 1H), 6.38 (d, J=10.0 Hz, 1H), 4.90 (d, J=9.0 Hz, 1H), 4.65 (d, J=9.0 Hz, 1H), 4.02-3.92 (m, 2H), 3.85 (s, 3H), 3.76-3.51 (m, 2H), 3.35 (t, J=11.5 Hz, 2H), 2.18-2.00 (m, 1H), 1.65-1.37 (m, 4H); 13C NMR (75 MHz, CDCl3) δ177.4, 157.3 (d, J=1.7 Hz), 149.3, 149.1, 149.0, 146.1, 142.7, 131.9, 129.1, 123.7 (d, J=49.0 Hz), 118.9 (d, J=6.4 Hz), 110.3 (d, J=21.7 Hz), 96.4, 80.7, 67.41, 67.39, 57.9, 56.4, 46.1, 33.9, 30.8, 30.7; MS (ES+) m/z 384.2 (M+1).
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]2[N:8]=[CH:9][CH:10]=[N:11][C:12]=2[C:13]([C:16]2[C:21]([F:22])=[C:20]([O:23][CH3:24])[CH:19]=[C:18]([O:25][CH3:26])[C:17]=2[Cl:27])=[CH:14][CH:15]=1)=O)C.[O:28]=[S:29]1(=[O:43])[CH2:34][CH2:33][N:32]([CH2:35][C:36]2[CH:37]=[CH:38][C:39]([NH2:42])=[N:40][CH:41]=2)[CH2:31][CH2:30]1.C[Al](C)C.C([O-])(O)=O.[Na+]>C(Cl)Cl.CO.C(Cl)Cl>[O:43]=[S:29]1(=[O:28])[CH2:30][CH2:31][N:32]([CH2:35][C:36]2[CH:37]=[CH:38][C:39]([NH:42][C:4]([C:6]3[C:7]4[N:8]=[CH:9][CH:10]=[N:11][C:12]=4[C:13]([C:16]4[C:21]([F:22])=[C:20]([O:23][CH3:24])[CH:19]=[C:18]([O:25][CH3:26])[C:17]=4[Cl:27])=[CH:14][CH:15]=3)=[O:3])=[N:40][CH:41]=2)[CH2:33][CH2:34]1
Reactant: CCOC(=O)c1ccc(-c2c(F)c(OC)cc(OC)c2Cl)c2nccnc12
Reactant: Nc1ccc(CN2CCS(=O)(=O)CC2)cn1
Agent: C[Al](C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: COc1cc(OC)c(Cl)c(-c2ccc(C(=O)Nc3ccc(CN4CCS(=O)(=O)CC4)cn3)c3nccnc23)c1F
Temperature: 80 °C
Reaction time: 6 h

Procedure:
The title compound was prepared in analogy to the procedure described in Example 115 but using 8-(2-chloro-6-fluoro-3,5-dimethoxy-phenyl)-quinoxaline-5-carboxylic acid ethyl ester (Step 144.1), 5-(1,1-dioxothiomorpholin-4-ylmethyl)-pyridin-2-ylamine (Step 104.1), 2 equiv of trimethyl aluminum, stirring the reaction mixture for 6 h at 80° C., pouring it onto a saturated aqueous solution of NaHCO3 and DCM. Title compound: ESI-MS: 585.9 [M+H]+; tR=3.96 min (System 1); TLC: Rf=0.39 (DCM/MeOH/NH3aq, 94:5:1).
Reaction SMILES: O[CH:2]([C:22]1[CH:23]=[C:24]2[C:29](=[CH:30][CH:31]=1)[C:28](=[O:32])[O:27][C@H:26]([CH3:33])[CH2:25]2)[CH2:3][N:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:11])[CH2:6][C@H:5]1[CH2:20]O.S(Cl)(Cl)=O.[CH2:38]([NH2:41])[CH:39]=[CH2:40].[I-].[Na+]>C(OCC)(=O)C>[CH2:38]([N:41]1[CH:2]([C:22]2[CH:23]=[C:24]3[C:29](=[CH:30][CH:31]=2)[C:28](=[O:32])[O:27][C@H:26]([CH3:33])[CH2:25]3)[CH2:3][N:4]2[CH2:9][CH2:8][N:7]([C:10]([O:12][CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[O:11])[CH2:6][C@H:5]2[CH2:20]1)[CH:39]=[CH2:40]
Reactant: C[C@@H]1Cc2cc(C(O)CN3CCN(C(=O)OCc4ccccc4)C[C@H]3CO)ccc2C(=O)O1
Reactant: C=CCN
Agent: [I-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O=S(Cl)Cl
Product: C=CCN1C[C@@H]2CN(C(=O)OCc3ccccc3)CCN2CC1c1ccc2c(c1)C[C@@H](C)OC2=O
Temperature: 90 °C

Procedure:
A solution of (3S)-benzyl 4-(2-hydroxy-2-((R)-3-methyl-1-oxoisochroman-6-yl)ethyl)-3-(hydroxymethyl)piperazine-1-carboxylate (2.07 g, 4.55 mmol) in thionyl chloride (30.0 mL, 411 mmol) was heated at reflux for 1 h. After removing the volatiles, the residue was dissolved in N,N-dimethylformamide (20 mL) and treated with allylamine (1.879 mL, 25.05 mmol) at 0° C. The resulting solution was treated with sodium iodide (0.0680 g, 0.455 mmol) and heated at 90° C. for 1 h. The solution was diluted in ethyl acetate (300 mL) and was washed with saturated sodium bicarbonate three times, dried over sodium sulphate concentrated and the residue was purified on Biotage using 40-100% ethyl acetate/hexane to give the title compound: LC/MS: (M+1)+: 476.14.
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:12])=[CH:4][C:5]2[CH:9]=[CH:8][S:7][C:6]=2[C:10]=1[Cl:11].C([Li])CCC.[CH:18](=[O:21])[CH2:19][CH3:20]>O1CCCC1.CCCCCC>[Cl:1][C:2]1[C:3]([OH:12])=[CH:4][C:5]2[CH:9]=[C:8]([CH:18]([CH2:19][CH3:20])[OH:21])[S:7][C:6]=2[C:10]=1[Cl:11]
Reactant: Oc1cc2ccsc2c(Cl)c1Cl
Reactant: CCC=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCC(O)c1cc2cc(O)c(Cl)c(Cl)c2s1
Reaction time: 4 h

Procedure:
A solution of 7.0 g of 6,7-dichloro-5-hydroxybenzo[b]thiophene in 50 ml of dry tetrahydrofuran is cooled to -30°, using a dry ice-carbon tetrachloride bath and to the mixture is added dropwise, 35 ml of 2.2M n-butyllithium in hexane while the temperature is maintained below -20°. Following the addition, the bath is replaced with an ice-water bath and the reaction is stirred for 4 hrs at a temperature of 0°-5°. To the mixture is added dropwise solution of 3 ml of freshly distilled proprionaldehyde in 5 ml of tetrahydrofuran. The bath is removed. The reaction mixture is stirred for 20 mins and poured onto cold 10% hydrochloric acid. The mixture is extracted 3 times with ethyl ether. The combined ether extracts are washed, dried and the solvent is removed to give a solid. Recrystallization from ethyl ether and hexane gives 5.9 g of 6,7-dichloro-5-hydroxy-α-ethylbenzo[b]thiophene-2-methanol, mp 145°-145.5°.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[NH:7]1[CH:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[N:8]1.[NH2:15][C:16]([CH3:20])([CH3:19])[CH2:17][OH:18].C([O-])(O)=O.[Na+]>CN(C=O)C.C(Cl)Cl>[OH:18][CH2:17][C:16]([NH:15][C:12]([C:10]1[CH:9]=[N:8][NH:7][CH:11]=1)=[O:14])([CH3:20])[CH3:19]
Reactant: O=C(O)c1cn[nH]c1
Reactant: CC(C)(N)CO
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)(CO)NC(=O)c1cn[nH]c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 44.9 %

Procedure:
A solution of DMF (2 drops) and oxalyl chloride (0.88 g, 4.5 mmol) in methylene chloride (4 ml) was added to a suspension of 4-pyrazolecarboxylic acid (0.50 g, 4.5 mmol) in methylene chloride (6 ml) and stirred at room temperature for 1 hour. The reaction mixture was concentrated and dried under a reduced pressure. To a suspension of the obtained solid in methylene chloride (5 ml) cooled in an ice-bath, 2-amino-2-methyl-1-propanol (1.33 g, 15 mmol) was added. The mixture was stirred at room temperature for 1 hour, added saturated aqueous NaHCO3 to, and concentrated and dried under a reduced pressure. The residue was extracted with warm chloroform and the solvent was evaporated under a reduced pressure. The residue was subjected to silica gel chromatography (chloroform/methanol/triethylamine=100/10/1) to give the title compound (0.37 g, 45%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:20]2[CH:28]=[CH:27][C:23]([C:24](O)=[O:25])=[CH:22][CH:21]=2)[CH2:9][C:10]([C:12]2[CH:17]=[CH:16][C:15](=[O:18])[N:14]([CH3:19])[CH:13]=2)=[O:11])=[C:4]([F:29])[CH:3]=1.[CH3:30][S:31]([CH2:34][CH2:35][NH2:36])(=[O:33])=[O:32].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:20]2[CH:21]=[CH:22][C:23]([C:24]([NH:36][CH2:35][CH2:34][S:31]([CH3:30])(=[O:33])=[O:32])=[O:25])=[CH:27][CH:28]=2)[CH2:9][C:10]([C:12]2[CH:17]=[CH:16][C:15](=[O:18])[N:14]([CH3:19])[CH:13]=2)=[O:11])=[C:4]([F:29])[CH:3]=1
Reactant: Cn1cc(C(=O)CC(c2ccc(C(=O)O)cc2)c2ccc(Cl)cc2F)ccc1=O
Reactant: CS(=O)(=O)CCN
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Product: Cn1cc(C(=O)CC(c2ccc(C(=O)NCCS(C)(=O)=O)cc2)c2ccc(Cl)cc2F)ccc1=O

Procedure:
In analogy to example 207, step 2, 4-[1-(4-chloro-2-fluoro-phenyl)-3-(1-methyl-6-oxo-1,6-dihydro-pyridin-3-yl)-3-oxo-propyl]-benzoic acid (example 311, step 4) was coupled with 2-methanesulfonyl-ethylamine using benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate in tetrahydrofuran to give the title compound as a colourless foam, MS (ESI+): m/z=519.2 [M+H]+.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:17]([O:19][C:20](=[O:25])[C:21](Br)([CH3:23])[CH3:22])[CH3:18].C(=O)([O-])[O-].[K+].[K+]>>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]([C:21]([C:20]([O:19][CH2:17][CH3:18])=[O:25])([CH3:23])[CH3:22])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(OCc1ccccc1)N1CCNCC1
Reactant: CCOC(=O)C(C)(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCOC(=O)C(C)(C)N1CCN(C(=O)OCc2ccccc2)CC1
Temperature: 150 °C
Reaction time: 24 h
Yield: 77 %

Procedure:
A mixture of piperazine-1-carboxylic acid benzyl ester (8.8 g, 40 mmol), 2-bromo-2-methylpropionic acid ethyl ester and potassium carbonate was stirred at 150° C. for 24 h. On cooling, the resulting mixture was partitioned between dichloromethane and water. The organic layer was washed with brine, dried (MgSO4) and evaporated under reduced pressure to give 4-(1-Ethoxycarbonyl-1-methyl-ethyl)-piperazine-1-carboxylic acid benzyl ester (10.2 g, 77%) as an oil.
Reaction SMILES: [OH-].[Na+].[CH2:3]([NH:10][C:11](=[O:36])[N:12]([C:14]1[CH:15]=[C:16]([C:20]2[CH:25]=[CH:24][C:23]([CH2:26][CH2:27][C:28]([O:30]C)=[O:29])=[CH:22][C:21]=2[O:32][CH2:33][CH2:34][CH3:35])[CH:17]=[CH:18][CH:19]=1)[CH3:13])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]>O1CCCC1.CO>[CH2:3]([NH:10][C:11](=[O:36])[N:12]([C:14]1[CH:15]=[C:16]([C:20]2[CH:25]=[CH:24][C:23]([CH2:26][CH2:27][C:28]([OH:30])=[O:29])=[CH:22][C:21]=2[O:32][CH2:33][CH2:34][CH3:35])[CH:17]=[CH:18][CH:19]=1)[CH3:13])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: CCCCCCCNC(=O)N(C)c1cccc(-c2ccc(CCC(=O)OC)cc2OCCC)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCCCCCCNC(=O)N(C)c1cccc(-c2ccc(CCC(=O)O)cc2OCCC)c1
Yield: 59 %

Procedure:
In a manner similar to that of Example (19g), by reaction of 200 mg (5.0 mmol, ˜8 eq) of sodium hydroxide and methyl 3-[3′-(3-heptyl-1-methylureido)-2-propoxybiphenyl-4-yl]propanoate, prepared in the preceding step, in 6 ml of a tetrahydrofuran/methanol mixture (8/2), and after crystallization from pentane, 180 mg of 3-[3′-(3-heptyl-1-methylureido)-2-propoxybiphenyl-4-yl]propanoic acid are obtained in the form of a white powder (m.p.=79-80° C.). Yield=59% over the two steps b and c.
Reaction SMILES: [CH2:1]([N:3]1[C:7]([OH:8])=[C:6]([C:9](=[O:22])[C:10]2[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[C:12](Cl)[C:11]=2[Cl:21])[CH:5]=[N:4]1)[CH3:2].[CH3:23][NH:24][CH3:25]>>[CH2:1]([N:3]1[C:7]([OH:8])=[C:6]([C:9](=[O:22])[C:10]2[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[C:12]([N:24]([CH3:25])[CH3:23])[C:11]=2[Cl:21])[CH:5]=[N:4]1)[CH3:2]
Reactant: CCn1ncc(C(=O)c2ccc(S(C)(=O)=O)c(Cl)c2Cl)c1O
Reactant: CNC
Product: CCn1ncc(C(=O)c2ccc(S(C)(=O)=O)c(N(C)C)c2Cl)c1O
Temperature: 110 °C

Procedure:
A mixture of 0.60 g (1.7 mmol) of 1-ethyl-4-(2,3-dichloro-4-methylsulfonylbenzoyl)-5-hydroxypyrazole and 8 mL of 40 percent aqueous dimethylamine was placed in a pressure reactor and heated at 110° C. for 24 hours. It was then allowed to cool and was concentrated by evaporation under reduced pressure. The residue was dissolved in dichloromethane and the solution obtained was washed with 1N aqueous hydrochloric acid, dried over sodium sulfate, and concentrated by evaporation under reduced pressure to obtain about 0.50 g of a yellow foam. This was crystallized from ethanol to obtain, after drying for 24 hours at 50° C., 0.17 g of the title compound as an off-white solid melting at 227-228° C. with decomposition.
Reaction SMILES: N1C=CC=CC=1.[OH:7][CH2:8][C@H:9]1[C@@H:14]([CH2:15]/[CH:16]=[CH:17]\[CH2:18][CH2:19][CH2:20][C:21]([O:23][CH3:24])=[O:22])[CH2:13][O:12][C@@H:11]([CH3:25])[O:10]1>ClCCl.CCOCC.[O-2].[O-2].[O-2].[Cr+6]>[CH:8]([C@H:9]1[C@@H:14]([CH2:15]/[CH:16]=[CH:17]\[CH2:18][CH2:19][CH2:20][C:21]([O:23][CH3:24])=[O:22])[CH2:13][O:12][C@@H:11]([CH3:25])[O:10]1)=[O:7]
Reactant: COC(=O)CCC/C=C\C[C@H]1CO[C@@H](C)O[C@H]1CO
Agent: [Cr+6]
Agent: [O-2]
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: CCOCC
Product: COC(=O)CCC/C=C\C[C@H]1CO[C@@H](C)O[C@H]1C=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 67.7 %

Procedure:
To a solution of pyridine (1.64 ml) in dichloromethane (45 ml) was added chromium trioxide (1.07 g) at 10° C. and the solution was stirred at room temperature for 1 hour. The solution was cooled in an ice bath and was added (2R,4R,5S)-4-hydroxymethyl-5-[(Z)-6-methoxycarbonyl-2-hexenyl]-2-methyl-1,3-dioxane (500 mg) in dichloromethane (3 ml). After being stirred at room temperature for 2 hours, the solution was diluted with ether (100 ml) and passed through a silica gel column. The eluate was evaporated in vacuo and the residue was chromatographed on a silica gel column (20 g) with a mixture of n-hexane and ethyl acetate (1:1) as an eluent to give (2R,4R,5S)-4-formyl-5-[(Z)-6-methoxycarbonyl-2-hexenyl]-2-methyl-1,3-dioxane (336 mg) as a colorless oil.
Reaction SMILES: Cl[CH:2]1[C:7](=[O:8])[CH2:6][C:5]([CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([Cl:24])[CH:17]=2)([CH:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)[O:4][C:3]1=[O:25].[SH:26][C:27]1[NH:28][CH:29]=[CH:30][N:31]=1>O>[Cl:24][C:18]1[CH:17]=[C:16]([CH2:15][CH2:14][C:5]2([CH:9]3[CH2:13][CH2:12][CH2:11][CH2:10]3)[O:4][C:3](=[O:25])[C:2]([S:26][C:27]3[NH:28][CH:29]=[CH:30][N:31]=3)=[C:7]([OH:8])[CH2:6]2)[CH:21]=[CH:20][C:19]=1[O:22][CH3:23]
Reactant: COc1ccc(CCC2(C3CCCC3)CC(=O)C(Cl)C(=O)O2)cc1Cl
Reactant: Sc1ncc[nH]1
Solvent: O
Product: COc1ccc(CCC2(C3CCCC3)CC(O)=C(Sc3ncc[nH]3)C(=O)O2)cc1Cl

Procedure:
The title compound was prepared as described in Example C(70), where 3-chloro-6-[2-(3-chloro-4-methoxyphenyl)ethyl]-6-cyclopentyldihydro-2H-pyran-2,4(3H)-dione was used in place of 3-chloro-6-[2-(5-chloro-2,4-dimethoxyphenyl)ethyl]6-cyclopentyldihydro-2H-pyran-2,4(3H)-dione and 2-mercaptoimidazole was used in place of 6-hydroxy-8-mercaptopurine monohydrate. 1H NMR (500 MHz, DMSO-d6, WET suppression of DMSO-h6 (2.5 ppm) and H2O (3.35 ppm) peak areas) δ 1.50-1.64 (m, 8H) 1.89 (m, 2H) 2.71 (d, J=15.0 Hz, 1H) 3.80 (s, 3H) 7.03 (d, J=8.5 Hz, 1H) 7.08 (d, J=5.0 Hz, 1H) 7.21 (d, J=1.9 Hz, 1H) 7.46 (s, 2H). MS (APCI) calcd for C22H25ClN2O4S: 448.97; found M=449.0.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:29]=[C:30]([O:34][CH3:35])[C:31]=1[O:32][CH3:33])[C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C:10]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[C:23]([Cl:28])[CH:22]=2)([CH2:14][CH2:15]OS(C)(=O)=O)[CH2:9]1)=[O:7].[CH2:36]([O:38][CH2:39][CH2:40][N:41]1[C:45]2[CH:46]=[CH:47][CH:48]=[CH:49][C:44]=2[N:43]=[C:42]1[NH:50][CH:51]1[CH2:56][CH2:55][NH:54][CH2:53][CH2:52]1)[CH3:37].C(N(CC)C(C)C)(C)C.CO>C(#N)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:29]=[C:30]([O:34][CH3:35])[C:31]=1[O:32][CH3:33])[C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C:10]([CH2:14][CH2:15][N:54]2[CH2:53][CH2:52][CH:51]([NH:50][C:42]3[N:41]([CH2:40][CH2:39][O:38][CH2:36][CH3:37])[C:45]4[CH:46]=[CH:47][CH:48]=[CH:49][C:44]=4[N:43]=3)[CH2:56][CH2:55]2)([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[C:23]([Cl:28])[CH:22]=2)[CH2:9]1)=[O:7]
Reactant: COc1cc(C(=O)N2CCCC(CCOS(C)(=O)=O)(c3ccc(Cl)c(Cl)c3)C2)cc(OC)c1OC
Reactant: CCOCCn1c(NC2CCNCC2)nc2ccccc21
Solvent: CO
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CCOCCn1c(NC2CCN(CCC3(c4ccc(Cl)c(Cl)c4)CCCN(C(=O)c4cc(OC)c(OC)c(OC)c4)C3)CC2)nc2ccccc21
Reaction time: 36 h

Procedure:
Combine 1-(3,4,5-trimethoxybenzoyl)-3-(3,4-dichlorophenyl)-3-(2-methanesulfonyloxyethyl)piperidine (0.71 g, 1.32 mmol) and (1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)(piperidin-4-yl)amine (0.38 g, 1.32 mmol), and N,N-diisopropylethylamine (0.37 g, 2.9 mmol) in acetonitrile (15 mL). Heat to reflux. After 36 hours, partition the residue between ethyl acetate and saturated aqueous sodium bicarbonate solution. Dry the organic layer over Na2SO4, filter, and concentrate in vacuo to obtain a residue. Chromatograph the residue on silica gel eluting with 15% methanol/2% triethylamine/ethyl acetate to give the title compound. Elemental Analysis calculated for C39H49Cl2N5O5: C 3.40; H 6.68; N 9.48; Found: C 63.68; H 6.69; N 9.57.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:15]=[C:14]([O:16]C2C=NC(C(=O)N(C)C)=CC=2)[C:8]2[CH2:9][C:10]([CH3:13])([CH3:12])[O:11][C:7]=2[CH:6]=1)=[O:4].Br[C:29]1[CH:36]=[CH:35][C:32]([C:33]#[N:34])=[C:31]([Cl:37])[CH:30]=1.COC(C1C=C(O)C2CC(C)(C)OC=2C=1)=O>>[CH3:1][O:2][C:3]([C:5]1[CH:15]=[C:14]([O:16][C:29]2[CH:36]=[CH:35][C:32]([C:33]#[N:34])=[C:31]([Cl:37])[CH:30]=2)[C:8]2[CH2:9][C:10]([CH3:13])([CH3:12])[O:11][C:7]=2[CH:6]=1)=[O:4]
Reactant: COC(=O)c1cc(Oc2ccc(C(=O)N(C)C)nc2)c2c(c1)OC(C)(C)C2
Reactant: N#Cc1ccc(Br)cc1Cl
Agent: COC(=O)c1cc(O)c2c(c1)OC(C)(C)C2
Product: COC(=O)c1cc(Oc2ccc(C#N)c(Cl)c2)c2c(c1)OC(C)(C)C2

Procedure:
The title compound was prepared in a similar manner as described for Intermediate 161b, from 4-bromo-2-chlorobenzonitrile (292 mg, 1.35 mmol) and 4-hydroxy-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid methyl ester (3e) (300 mg, 1.35 mmol) to give a white foam (116 mg, 24% yield). 1H NMR (400 MHz, CDCl3) δ 7.62 (d, J=8.59 Hz, 1 H) 7.25-7.34 (m, 1 H) 7.23 (d, J=1.01 Hz, 1 H) 7.04 (d, J=2.27 Hz, 1 H) 6.90 (dd, J=8.72, 2.40 Hz, 1 H) 3.88 (s, 3 H) 2.87 (s, 2 H) 1.48 (s, 6 H); LCMS for C19H16ClNO4 m/z 380.00 (M+Na+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:28][CH:29]([F:31])[F:30])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:20][C@@H:21]3[CH2:26][CH2:25][CH2:24][CH2:23][O:22]3)[C:17](O)=[O:18])[C:10](=[O:27])[CH:9]=2)[CH:7]=1.[NH2:32][C:33]1[CH:43]=[CH:42][C:36]([C:37]([O:39][CH2:40][CH3:41])=[O:38])=[CH:35][CH:34]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:28][CH:29]([F:30])[F:31])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:20][C@@H:21]3[CH2:26][CH2:25][CH2:24][CH2:23][O:22]3)[C:17]([NH:32][C:33]3[CH:34]=[CH:35][C:36]([C:37]([O:39][CH2:40][CH3:41])=[O:38])=[CH:42][CH:43]=3)=[O:18])[C:10](=[O:27])[CH:9]=2)[CH:7]=1
Reactant: CCOC(=O)c1ccc(N)cc1
Reactant: COc1cn(C(C[C@@H]2CCCCO2)C(=O)O)c(=O)cc1-c1cc(Cl)ccc1OC(F)F
Product: CCOC(=O)c1ccc(NC(=O)C(C[C@@H]2CCCCO2)n2cc(OC)c(-c3cc(Cl)ccc3OC(F)F)cc2=O)cc1

Procedure:
Two fractions, 312 mg (purity 87%, 0.59 mmol) and 86 mg (0.19 mmol) of 2-{4-[5-chloro-2-(difluoromethoxy)phenyl]-5-methoxy-2-oxopyridin-1(2H)-yl}-3-[(2S)-tetrahydro-2H-pyran-2-yl]propanoic acid (mixture of enantiomerically pure diastereomers 1 and 2), were reacted with in total 202 mg (1.23 mmol, 1.6 eq.) of ethyl 4-aminobenzoate according to General Method 5B. Yield: 315 mg (83% of theory)
Reaction SMILES: I[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][N:6]=[C:5]2OC.[CH3:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][C:17]=1[C:24]#[CH:25].[CH2:26](N(CC)CC)[CH3:27]>CN(C)C=O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cu]I>[CH3:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][C:17]=1[C:24]#[C:25][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][N:6]=[C:5]2[CH2:26][CH3:27]
Reactant: C#Cc1cc(OC)ccc1OC
Reactant: CCN(CC)CC
Reactant: COc1ncnc2ccc(I)cc12
Agent: [Cu]I
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: CCc1ncnc2ccc(C#Cc3cc(OC)ccc3OC)cc12

Procedure:
Argon is passed through a solution of 200 mg of 6-iodo-4-methoxy-quinazoline in 12 ml of dry dimethylformamide for 15 minutes. Then 40 mg of tetrakis(triphenylphosphine)-palladium, 113 mg of (2,5-dimethoxyphenyl)acetylene, 11 mg of copper(I)iodide and 220 mg of triethylamine are added, and the mixture is heated to 60° for 2 hours. The solvent is distilled off in vacuo and the residue partitioned between water and ethyl acetate. The organic layer is separated, dried and concentrated in vacuo. The pure title compound is obtained after chromatography (silica gel, cyclohexane/ethyl acetate=2/1) as colourless crystals. mp: 103-105°.
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[CH2:10][CH2:9][CH2:8][CH2:7][CH:6]2[C:11]([NH2:13])=O)[CH2:3][CH2:2]1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>>[CH:1]1([CH2:4][N:5]2[CH2:10][CH2:9][CH2:8][CH2:7][C@@H:6]2[CH2:11][NH2:13])[CH2:2][CH2:3]1.[NH3:5]
Reactant: NC(=O)C1CCCCN1CC1CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: N
Product: NC[C@H]1CCCCN1CC1CC1

Procedure:
The title compound was prepared by a similar method to preparation 60 from (2R-1-(cyclopropylmethyl-2-piperidinecarboxamide [see preparation 69] and lithium aluminium hydride. The crude product was purified by column chromatography on silica gel using dichloromethane:methanol:0.88 ammonia (90:10:0.1) as the eluant, to afford the product as a yellow oil, (71%).
Reaction SMILES: [CH:1]1([C@@H:4]2[O:25][CH2:24][C@:7]3([C:26]4[CH:31]=[CH:30][C:29]([F:32])=[CH:28][C:27]=4[F:33])[N:8]=[C:9]([NH:15]C(=O)C4C=CC=CC=4)[S:10][C@H:11]([CH2:12][O:13][CH3:14])[C@@H:6]3[CH2:5]2)[CH2:3][CH2:2]1.FC1C=C(F)C=CC=1[C@]12CO[C@@H](C3CCO3)C[C@H]1CSC(N)=N2.[ClH:57]>ClCCl.C(OCC)C>[ClH:57].[CH:1]1([C@@H:4]2[O:25][CH2:24][C@:7]3([C:26]4[CH:31]=[CH:30][C:29]([F:32])=[CH:28][C:27]=4[F:33])[N:8]=[C:9]([NH2:15])[S:10][C@H:11]([CH2:12][O:13][CH3:14])[C@@H:6]3[CH2:5]2)[CH2:3][CH2:2]1
Reactant: COC[C@H]1SC(NC(=O)c2ccccc2)=N[C@@]2(c3ccc(F)cc3F)CO[C@@H](C3CC3)C[C@@H]12
Agent: Cl
Agent: NC1=N[C@@]2(c3ccc(F)cc3F)CO[C@@H](C3CCO3)C[C@H]2CS1
Solvent: CCOCC
Solvent: ClCCl
Product: COC[C@H]1SC(N)=N[C@@]2(c3ccc(F)cc3F)CO[C@@H](C3CC3)C[C@@H]12

Procedure:
Conversion of rel-N-[(4S,4aR,6R,8aS)-6-cyclopropyl-8a-(2,4-difluorophenyl)-4-(methoxymethyl)-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazin-2-yl]benzamide (C42) to the free base of the product was carried out via the method described for synthesis of (4aR,6R,8aS)-8a-(2,4-difluorophenyl)-6-(oxetan-2-yl)-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazin-2-amine (4) in Example 4. In this case, purification was effected using silica gel chromatography (Gradient: 0% to 15% methanol in dichloromethane), affording an oil. This was dissolved in dichloromethane and treated with a 1 M solution of hydrogen chloride in diethyl ether; removal of volatiles under reduced pressure provided the product as a solid. Yield: 8.6 mg, 21 μmol, 58%. LCMS m/z 369.2 [M+H+]. 1H NMR, free base of 5: (400 MHz, CDCl3) δ 7.33 (ddd, J=9.0, 9.0, 6.6 Hz, 1H), 6.74-6.87 (m, 2H), 4.03 (dd, J=10.9, 2.3 Hz, 1H), 3.80 (d, J=11.3 Hz, 1H), 3.58-3.65 (m, 1H), 3.32-3.39 (m, 2H), 3.30 (s, 3H), 2.79-2.87 (m, 2H), 1.63-1.74 (m, 1H), 1.50-1.57 (m, 1H), 0.91-1.04 (m, 1H), 0.47-0.61 (m, 2H), 0.38-0.46 (m, 1H), 0.19-0.27 (m, 1H).