Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]([NH:31][S@@:32]([C:34]([CH3:37])([CH3:36])[CH3:35])=[O:33])([C:17]2[CH:22]=[C:21]([O:23][C:24]([F:29])([F:28])[CH:25]([F:27])[F:26])[CH:20]=[C:19]([F:30])[CH:18]=2)[CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:5]=[CH:6][C:7]=1[OH:8].C([O-])([O-])=O.[K+].[K+].I[CH:45]([CH3:47])[CH3:46]>CN(C=O)C.CCOCC>[F:1][C:2]1[CH:3]=[C:4]([C:9]([NH:31][S@@:32]([C:34]([CH3:37])([CH3:36])[CH3:35])=[O:33])([C:17]2[CH:22]=[C:21]([O:23][C:24]([F:28])([F:29])[CH:25]([F:26])[F:27])[CH:20]=[C:19]([F:30])[CH:18]=2)[CH2:10][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:45]([CH3:47])[CH3:46]
Reactant: CC(C)(C)[S@@](=O)NC(Cc1ccccc1)(c1cc(F)cc(OC(F)(F)C(F)F)c1)c1ccc(O)c(F)c1
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CC(C)Oc1ccc(C(Cc2ccccc2)(N[S@](=O)C(C)(C)C)c2cc(F)cc(OC(F)(F)C(F)F)c2)cc1F
Yield: 125.2 %

Procedure:
At rt to a solution of 4:1 diastereomeric mixture (R)—N-(1-(3-fluoro-4-hydroxyphenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethyl)-2-methylpropane-2-sulfinamide (578 mg, 1.06 mmol) in DMF (10 mL) was added K2CO3 (800 mg, 5.80 mmol) and the slurry was stirred vigorously. 2-Iodopropane (220 mg, 1.27 mmol) was added and the reaction mixture was stirred at rt for 16 h. The reaction mixture was diluted with ether (50 mL), washed successively with 10% LiCl (2×20 mL) and water (20 mL). The organic portion was dried over Na2SO4, filtered and concentrated to yield (R)—N-(1-(3-fluoro-4-isopropoxyphenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethyl)-2-methylpropane-2-sulfinamide as a pale orange foam (780 mg, 100% yield).
Reaction SMILES: Br[C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.B([O-])([O-])O[C:15]1[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=1.C(=O)([O-])O.[Na+].COCCOC>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.O>[N:18]1[CH:19]=[CH:20][C:15]([C:2]2[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=2)=[CH:16][CH:17]=1
Reactant: [O-]B([O-])Oc1ccncc1
Reactant: CCOC(=O)c1ccc(Br)cc1
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: COCCOC
Solvent: O
Product: CCOC(=O)c1ccc(-c2ccncc2)cc1
Reaction time: 3 h
Yield: 56.3 %

Procedure:
To a mixture of ethyl 4-bromobenzoate (2.29 g), 4-pyridyl borate (1.23 g), 1 M sodium hydrogen carbonate solution (30 ml) and 1,2-dimethoxyethane (40 ml) was added tetrakis(triphenylphosphine)palladium (0.3 g) and the mixture was stirred for 3 hours with reflux under nitrogen atmosphere. To the mixture was added water and the solution was extracted with ethyl acetate. The extract was washed with water, dried (MgSO4) and concentrated. The residue was subjected to silica gel chromatography, and eluted with hexane-ethyl acetate (2:1) to give the title compound as crystals (1.15 g, 50.7%).
Reaction SMILES: C[C:2]1[N:7]=[C:6]2[N:8](CC3C=CC(NCCC)=CC=3)[C:9](CC)=[N:10][C:5]2=[C:4](C)[CH:3]=1.BrC1C=CC=CC=1CC(OC)=O>>[NH:10]1[C:5]2[C:6](=[N:7][CH:2]=[CH:3][CH:4]=2)[N:8]=[CH:9]1
Reactant: CCCNc1ccc(Cn2c(CC)nc3c(C)cc(C)nc32)cc1
Agent: COC(=O)Cc1ccccc1Br
Product: c1cnc2nc[nH]c2c1

Procedure:
Using the general procedure for the phenylaminophenylacetic, acid synthesis described in Step F of Example 25, the product of Step B was alkylated with methyl 2-bromophenylacetate. Standard workup and purification by flash chromatography afforded the title compound.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=3)[C:6]=2[N:7]=1.C[CH2:20][N:21](C(C)C)C(C)C>CO>[Cl:1][C:2]1[N:3]=[C:4]([NH:21][CH3:20])[C:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=3)[C:6]=2[N:7]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: Clc1ccc(C2CCc3c(Cl)nc(Cl)nc32)cc1
Solvent: CO
Product: CNc1nc(Cl)nc2c1CCC2c1ccc(Cl)cc1
Yield: 34.3 %

Procedure:
A solution of 2,4-dichloro-7-(4-chlorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine (300 mg, 1.001 mmol), methanamine, HCl salt (135 mg, 2.003 mmol) and DIPEA (0.700 mL, 4.01 mmol) in MeOH (6 mL) was stirred at rt for 30 min. The solvent was removed in vacuum and the crude product was purified by column chromatography on silica gel to afford 2-chloro-7-(4-chlorophenyl)-N-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-amine (101 mg, 0.343 mmol, 34.3% yield). LC-MS (M+H)+=294.2.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][C:13]([OH:15])=[O:14])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[CH3:16]O>S(=O)(=O)(O)O>[CH3:16][O:14][C:13](=[O:15])[CH:12]=[CH:11][C:5]1[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=1
Reactant: COc1ccc(C=CC(=O)O)cc1OC
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)C=Cc1ccc(OC)c(OC)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
3-(3,4-Dimethoxy-phenyl)-acrylic acid (compound of Example 2 (Step 1); 1.0 g, 4.8 mmol) was dissolved in methanol (10 mL) in the presence of catalytic amount of sulfuric acid. The reaction mixture was stirred at room temperature for 4 h. The reaction mixture was cooled at 5° C. and quenched with saturated sodium carbonate solution (2 mL). The solid obtained was filtered and dried.
Reaction SMILES: [C:1]([CH2:3][N:4]([S:33]([CH3:36])(=[O:35])=[O:34])[NH:5][C:6](=[O:32])[C@@H:7]([C@@H:12]([C:22](=[O:31])[NH:23][O:24]C1CCCCO1)[CH2:13]/[CH:14]=[CH:15]/[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:8][CH:9]([CH3:11])[CH3:10])#[N:2].BrCC#N>>[C:1]([CH2:3][N:4]([S:33]([CH3:36])(=[O:35])=[O:34])[NH:5][C:6](=[O:32])[C@@H:7]([C@@H:12]([C:22](=[O:31])[NH:23][OH:24])[CH2:13]/[CH:14]=[CH:15]/[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:8][CH:9]([CH3:11])[CH3:10])#[N:2]
Reactant: CC(C)C[C@@H](C(=O)NN(CC#N)S(C)(=O)=O)[C@H](C/C=C/c1ccccc1)C(=O)NOC1CCCCO1
Agent: N#CCBr
Product: CC(C)C[C@@H](C(=O)NN(CC#N)S(C)(=O)=O)[C@H](C/C=C/c1ccccc1)C(=O)NO

Procedure:
The (E)-2′-(cyanomethyl)-2(R)-[1(S)-[(tetrahydro-2(RS)-pyranyloxy)carbamoyl]-4-phenyl-3-butenyl]-2′-(methanesulphonyl)-4-methylvalerohydrazide used as the starting material was prepared in an analogous manner to that described in Example 15, part (iii), starting from (E)-(2R)-[1(S)-[(tetrahydro-2(RS)-pyranyloxy)cambamoyl]-4-phenyl-3-butenyl]-2′-(methanesulphonyl)-4-methylvalerohydrazide by reaction with bromoacetonitrile.
Reaction SMILES: [C:1]([C:3]1[C:4]([N+:23]([O-])=O)=[CH:5][C:6]([O:21][CH3:22])=[C:7]([CH:20]=1)[O:8][CH:9]1[CH2:14][CH2:13][N:12]([CH2:15][C:16]([NH:18][CH3:19])=[O:17])[CH2:11][CH2:10]1)#[N:2].S(S([O-])=O)([O-])=O.[Na+].[Na+].Cl.[OH-].[Na+].CC1CCCO1>O.CO>[NH2:23][C:4]1[C:3]([C:1]#[N:2])=[CH:20][C:7]([O:8][CH:9]2[CH2:10][CH2:11][N:12]([CH2:15][C:16]([NH:18][CH3:19])=[O:17])[CH2:13][CH2:14]2)=[C:6]([O:21][CH3:22])[CH:5]=1
Reactant: CNC(=O)CN1CCC(Oc2cc(C#N)c([N+](=O)[O-])cc2OC)CC1
Agent: Cl
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC1CCCO1
Solvent: CO
Product: CNC(=O)CN1CCC(Oc2cc(C#N)c(N)cc2OC)CC1
Temperature: 60 °C
Reaction time: 3 h
Yield: 87.5 %

Procedure:
2-[4-(5-Cyano-2-methoxy-4-nitrophenoxy)piperidin-1-yl]-N-methylacetamide (5, 7.42 g, 19.38 mmoles) was suspended in water (44.52 g) and methanol (5.35 g). To this was added sodium dithionite (11.91 g, 58.15 mmoles) and the resulting reaction mixture was heated to 60° C. To the reaction mixture was added hydrochloric acid (46.98 g, 463.89 mmoles)), resulting in a solution, which was held at 60° C. for 3 hours. The reaction mixture was then allowed to cool to 20° C. Aqueous sodium hydroxide (15.51 g 182.2 mmoles) was charged followed by 2-methyltetrahydrofuran (58.0 g). The reaction mixture was heated to 60° C., which upon settling gave two layers and the lower aqueous layer was discarded. The volume of the reaction mixture was reduced by vacuum distillation and methyl tert-butyl ether (18.54 g) was added to give a slurry which was cooled to 10° C. and then the solid was collected by filtration. The solid was washed with 2-methyltetrahydrofuran (5.8 g) and dried to give the title compound (5.4 g, 78% yield); 1H NMR (400 MHz, DMSO-d6) δ ppm 1.62 (m, 2H) 1.82 (m, 2H) 2.20 (m, 2H) 2.60 (d, J=4.7 Hz, 3H) 2.65 (m, 2H) 2.86 (s, 2H) 3.72 (s, 3H) 4.00 (tt, J=8.3, 4.0 Hz, 1H) 5.66 (br. s, 2H) 6.39 (s, 1H) 6.94 (s, 1H) 7.65 (q, J=4.7 Hz, 1H)
Reaction SMILES: [Cl:1][CH2:2][CH2:3][NH:4][C:5]([N:7]([CH2:17][CH2:18][CH3:19])[CH:8]1[O:16][CH2:15][C@@H:13]([OH:14])[C@H:11]([OH:12])[C@H:9]1[OH:10])=[O:6].C(=O)([O-])[O-].[Na+].[Na+].[N+:26]([O-])([N+]([O-])=O)=[O:27]>O1CCCC1.C(Cl)Cl>[Cl:1][CH2:2][CH2:3][N:4]([N:26]=[O:27])[C:5]([N:7]([CH2:17][CH2:18][CH3:19])[CH:8]1[O:16][CH2:15][C@@H:13]([OH:14])[C@H:11]([OH:12])[C@H:9]1[OH:10])=[O:6]
Reactant: CCCN(C(=O)NCCCl)C1OC[C@@H](O)[C@H](O)[C@H]1O
Reactant: O=[N+]([O-])[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: CCCN(C(=O)N(CCCl)N=O)C1OC[C@@H](O)[C@H](O)[C@H]1O
Yield: 79 %

Procedure:
3.0 g of 1-(2-chloroethyl)-3-n-propyl-3-D-xylopyranosylurea are dissolved in a mixture of 80 ml of tetrahydrofuran and 80 ml of methylene chloride, and 15 g of sodium carbonate anhydrate are added thereto. 5 g of nitrogen tetroxide gas are introduced into the mixture for 10 minutes under ice-cooling. The mixture is treated in the same manner as described in Example 2. 2.6 g of 1-(2-chloroethyl)-1-nitroso-3-n-propyl-3-D-xylopyranosylurea are thereby obtained as yellow caramel.
Reaction SMILES: [C:1]([C:4]1[C:5]([CH2:28]Br)=[N:6][C:7]2[C:12]([C:13]=1[C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH3:23])[CH:15]=1)=[CH:11][C:10]([O:24][CH3:25])=[C:9]([O:26][CH3:27])[CH:8]=2)(=[O:3])[CH3:2].[CH2:30]([NH:32][CH2:33][CH3:34])[CH3:31]>ClCCl>[C:1]([C:4]1[C:5]([CH2:28][N:32]([CH2:33][CH3:34])[CH2:30][CH3:31])=[N:6][C:7]2[C:12]([C:13]=1[C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH3:23])[CH:15]=1)=[CH:11][C:10]([O:24][CH3:25])=[C:9]([O:26][CH3:27])[CH:8]=2)(=[O:3])[CH3:2]
Reactant: CCNCC
Reactant: COc1ccc(-c2c(C(C)=O)c(CBr)nc3cc(OC)c(OC)cc23)cc1OC
Solvent: ClCCl
Product: CCN(CC)Cc1nc2cc(OC)c(OC)cc2c(-c2ccc(OC)c(OC)c2)c1C(C)=O
Yield: 70.2 %

Procedure:
A mixture of 3-acetyl-2-bromomethyl-4-(3,4-dimethoxyphenyl)-6,7-dimethoxyquinoline (3.0 g), diethylamine (4.76 g) and dichloromethane (50 ml) was stirred under reflux for 14 hours. The reaction mixture was washed with water, dried over magnesium sulfate, and the solvent was evaporated. The residue was subjected to column chromatography on silica gel. The fractions eluted with chloroform gave 3-acetyl-2-(N,N-diethylaminomethyl)-4-(3,4-dimethoxyphenyl)-6,7-dimethoxyquinoline (2.07 g, 73%). This compound was recrystallized from ethyl acetate-hexane to give colorless prisms, mp. 146°-148° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]([C:14]([OH:16])=O)[CH:11]=[CH:10][C:9]=2[O:17][CH2:18][CH:19]2[CH2:21][CH2:20]2)=[CH:4][CH:3]=1.[CH:22]1([C:25]2[S:26][CH:27]=[C:28]([CH2:30][NH2:31])[N:29]=2)[CH2:24][CH2:23]1>>[CH:22]1([C:25]2[S:26][CH:27]=[C:28]([CH2:30][NH:31][C:14]([C:12]3[CH:11]=[CH:10][C:9]([O:17][CH2:18][CH:19]4[CH2:21][CH2:20]4)=[C:8]([C:5]4[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=4)[N:13]=3)=[O:16])[N:29]=2)[CH2:24][CH2:23]1
Reactant: O=C(O)c1ccc(OCC2CC2)c(-c2ccc(Cl)cc2)n1
Reactant: NCc1csc(C2CC2)n1
Product: O=C(NCc1csc(C2CC2)n1)c1ccc(OCC2CC2)c(-c2ccc(Cl)cc2)n1

Procedure:
The title compound was synthesized in analogy to Example 41 using 6-(4-Chloro-phenyl)-5-cyclopropylmethoxy-pyridine-2-carboxylic acid (example AW) and 2-cyclopropyl-4-thiazolemethanamine (CAN. 1083299-53-9) as starting materials, LC-MS (UV peak area/ESI) 95.5%, 440.2 (M+H)+.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]([C:18]1[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][C:19]=1[CH2:25][C:26]1[C:31]([F:32])=[CH:30][CH:29]=[CH:28][C:27]=1[F:33])[S:5]([C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([O:16][CH3:17])[CH:9]=1)(=[O:7])=[O:6].[CH2:34]([N:41]=[C:42]=[O:43])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>C1COCC1>[CH2:34]([NH:41][C:42]([NH:1][CH2:2][CH2:3][N:4]([C:18]1[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][C:19]=1[CH2:25][C:26]1[C:31]([F:32])=[CH:30][CH:29]=[CH:28][C:27]=1[F:33])[S:5]([C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([O:16][CH3:17])[CH:9]=1)(=[O:6])=[O:7])=[O:43])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: O=C=NCc1ccccc1
Reactant: COc1ccc(S(=O)(=O)N(CCN)c2ccc(C)cc2Cc2c(F)cccc2F)cc1OC
Solvent: C1CCOC1
Product: COc1ccc(S(=O)(=O)N(CCNC(=O)NCc2ccccc2)c2ccc(C)cc2Cc2c(F)cccc2F)cc1OC
Yield: 53.4 %

Procedure:
To 1 g of N-(2-aminoethyl)-N-[2-(2,6-difluorobenzyl)-4-methylphenyl]-3,4-dimethoxybenzenesulfonamide (compound 215) dissolved in 20 ml of THF is added 0.266 g of benzyl isocyanate, and, after refluxing for 3 hours, the medium is evaporated to dryness. The residue is chromatographed on a column of silica gel, eluting with an 8/2 (v/v) toluene/ethyl acetate mixture to give 0.65 g of the expected product.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][NH2:9])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Cl[C:11]1[N:16]=[CH:15][C:14]2[C:17](=[C:22]3[C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[NH:24][C:23]3=[O:31])[O:18][CH:19]([CH2:20][CH3:21])[C:13]=2[C:12]=1Cl>O1CCOCC1>[CH2:20]([CH:19]1[C:13]2[CH:12]=[C:11]([NH:9][CH2:8][CH2:7][N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)[N:16]=[CH:15][C:14]=2[C:17](=[C:22]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[NH:24][C:23]2=[O:31])[O:18]1)[CH3:21]
Reactant: NCCN1CCOCC1
Reactant: CCC1OC(=C2C(=O)Nc3ccccc32)c2cnc(Cl)c(Cl)c21
Solvent: C1COCCO1
Product: CCC1OC(=C2C(=O)Nc3ccccc32)c2cnc(NCCN3CCOCC3)cc21
Temperature: 100 °C
Yield: 27.7 %

Procedure:
A solution of 2-morpholin-4-yl-ethylamine (320 mg, 2.46 mmol) in 3 mL of dioxane is treated with 3-(6,7-Dichloro-1-ethyl-1H-furo[3,4-c]pyridin-3-ylidene)-1,3-dihydro-indol-2-one (100 mg, 0.32 mmol) in one portion and the reaction mixture is heated at 100° C. until no starting material remains. The reaction mixture is cooled to room temperature and concentrated. The residue is purified by chromatography (silica gel, 5% MeOH-EtOAc) to give the title compound as a solid (36 mg, 28%).
Reaction SMILES: COC[O:4][C:5]1[CH:10]=[C:9]([O:11]COC)[CH:8]=[CH:7][C:6]=1[CH:15]1[CH2:20][CH2:19][CH2:18][CH:17]([NH:21][C:22](=[O:24])[CH3:23])[CH2:16]1>CO>[OH:4][C:5]1[CH:10]=[C:9]([OH:11])[CH:8]=[CH:7][C:6]=1[CH:15]1[CH2:20][CH2:19][CH2:18][CH:17]([NH:21][C:22](=[O:24])[CH3:23])[CH2:16]1
Reactant: COCOc1ccc(C2CCCC(NC(C)=O)C2)c(OCOC)c1
Solvent: CO
Product: CC(=O)NC1CCCC(c2ccc(O)cc2O)C1
Yield: 33.8 %

Procedure:
(±)-N-{3-[2,4-bis(methoxymethoxy)phenyl]cyclohexyl}acetamide (20 mg), methanol (2 ml) and acidic ion exchange resin (300 mg) were heated under reflux for 3 hr. The reaction mixture was filtered and the resin was washed with methanol. The combined filtrate and washings were evaporated in vacuo and the crude residue was purified by preparative HPLC to furnish the title compound as a solid (5 mg, 34%). δH(CD3OD) 1.10-200 (1H, m), 2.90 (0.3H, tt), 3.08 (0.7H, tt), 3.70-380 (0.3H, m), 4.16 (0.7H, m), 6.20-6.26 (2H, m), 6.84-6.90 (1H, m); m/z (ES+) 250 (M+H)+.
Reaction SMILES: C(O[C:4](=[O:11])[CH2:5][C:6]([O:8]CC)=O)C.Cl.[CH3:13][O:14][CH2:15][C:16]([NH2:18])=[NH:17].C[O-].[Na+].CO>CO>[CH3:13][O:14][CH2:15][C:16]1[N:18]=[C:4]([OH:11])[CH:5]=[C:6]([OH:8])[N:17]=1
Reactant: CCOC(=O)CC(=O)OCC
Reactant: COCC(=N)N
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COCc1nc(O)cc(O)n1

Procedure:
Reflux a mixture of malonic acid diethyl ester (7.96 g, 50 mmol), 2-methoxy-acetamidine hydrochloride (6.2 g, 50 mmol), and NaOMe MeOH solution (4.37 M, 22.7 mL, 100 mmol) in MeOH (30 mL) for 24 hours. Concentrate, dilute with H2O (50 mL), wash with EtOAc, and concentrate the aqueous layer. Extract with MeOH and concentrate to yield 2-methoxymethyl-pyrimidine-4,6-diol.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[CH:7][CH:8]=1.F[C:11]1[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][N:12]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CS(C)=O>[CH3:17][C:14]1[CH:15]=[CH:16][C:11]([O:9][C:5]2[CH:4]=[C:3]([CH2:2][OH:1])[CH:8]=[CH:7][CH:6]=2)=[N:12][CH:13]=1
Reactant: Cc1ccc(F)nc1
Reactant: OCc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: Cc1ccc(Oc2cccc(CO)c2)nc1
Temperature: 110 °C
Reaction time: 16 h
Yield: 52.7 %

Procedure:
3-Hydroxymethyl-phenol (5.04 g, 40.6 mmol), 2-fluoro-5-methyl-pyridine (4.1 g, 37 mmol,) and cesium carbonate (15.0 g, 46.1 mmol) were suspended in dimethylsulfoxide (50 mL) and heated to 110° C. After stirring for 16 h, the reaction was partitioned between water (500 mL) and ethyl acetate (500 mL). The organic layer was separated and the aqueous was extracted again with ethyl acetate. The combined organic layer was dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (10-20%, EtOAc:heptane) to afford the title compound (4.2 g, 53% yield) as a thick oil.
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][O:11][C:12]1[CH:46]=[CH:45][C:15]([O:16][CH2:17][C:18]#[C:19][CH:20]2[C:29]3[C:24](=[CH:25][C:26]([O:30][CH2:31][O:32][CH3:33])=[CH:27][CH:28]=3)[S:23][CH2:22][C:21]2([C:35]2[CH:40]=[CH:39][C:38]([O:41][CH2:42][O:43][CH3:44])=[CH:37][CH:36]=2)[CH3:34])=[CH:14][CH:13]=1)(C(C)(C)C)(C)C>C(O)C.O1CCCC1.[OH-].[OH-].[Pd+2]>[OH:8][CH2:9][CH2:10][O:11][C:12]1[CH:46]=[CH:45][C:15]([O:16][CH2:17][CH2:18][CH2:19][CH:20]2[C:29]3[C:24](=[CH:25][C:26]([O:30][CH2:31][O:32][CH3:33])=[CH:27][CH:28]=3)[S:23][CH2:22][C:21]2([C:35]2[CH:40]=[CH:39][C:38]([O:41][CH2:42][O:43][CH3:44])=[CH:37][CH:36]=2)[CH3:34])=[CH:14][CH:13]=1
Reactant: COCOc1ccc(C2(C)CSc3cc(OCOC)ccc3C2C#CCOc2ccc(OCCO[Si](C)(C)C(C)(C)C)cc2)cc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: COCOc1ccc(C2(C)CSc3cc(OCOC)ccc3C2CCCOc2ccc(OCCO)cc2)cc1
Reaction time: 17 h
Yield: 70.8 %

Procedure:
4-{3-[4-(2-t-Butyldimethylsilyloxyethoxy)phenoxy]-1-propynyl}-7-methoxymethoxy-3-[4-(methoxymethoxy)phenyl]-3-methylthiochroman (6) prepared in Step 4 (408 mg) was dissolved in a solvent mixture of ethanol (6 ml) and tetrahydrofuran (2 ml), 20% palladium hydroxide/carbon (130 mg) washed with ethanol was added, and the resulting mixture was stirred under hydrogen for 17 hours. The reaction solution was filtered through cellite, concentrated, and subjected to silica gel column chromatography to give 4-(3-[4-(2-hydroxyethoxy)phenoxy]propyl}-7-methoxymethoxy-3-[4-(methoxymethoxy)phenyl]-3-methylthiochroman (7) (241 mg, yield 71%) as a yellow oily substance.
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:8])[C:4]#[C:5][CH2:6][OH:7].Br[CH2:10][C:11]1[CH:12]=[C:13]([C:17]2[CH:21]=[CH:20][S:19][CH:18]=2)[CH:14]=[CH:15][CH:16]=1.C(OCC)C>CN(C)C=O.O>[S:19]1[CH:20]=[CH:21][C:17]([C:13]2[CH:12]=[C:11]([CH:16]=[CH:15][CH:14]=2)[CH2:10][O:7][CH2:6][C:5]#[C:4][CH2:3][OH:8])=[CH:18]1
Reactant: BrCc1cccc(-c2ccsc2)c1
Reactant: OCC#CCO
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOCC
Product: OCC#CCOCc1cccc(-c2ccsc2)c1
Yield: 79.7 %

Procedure:
Under a nitrogen atmosphere, 0.47 g of 60% oily sodium hydride was suspended in 10 ml of dimethylformamide, and a dimethylformamide solution (10 ml) of 1.0 g of 2-butyn-1,4-diol was added dropwise with stirring and ice cooling. After the mixture was stirred for 10 minutes, a dimethylformamide solution (5 ml) of 0.59 g of 3-(3-bromomethylphenyl)thiophene was added. The mixture was stirred at room temperature for 1 hour and then ethyl ether and water were added. The organic layer separated was worked up in a customary manner, and the product was purified by silica gel column chromatography [hexane/ethyl acetate=3/1] to give 0.48 g of 4-[3-(3-thienyl)benzyloxy]-2-butyn-1-ol as a colorless oil.
Reaction SMILES: [CH2:1]([CH:3]([NH:6][C:7]1[CH:12]=[C:11]([CH3:13])[N:10]=[C:9]([O:14][C:15]2[C:20]([CH3:21])=[CH:19][C:18]([CH3:22])=[CH:17][C:16]=2[CH3:23])[C:8]=1[NH2:24])[CH2:4][CH3:5])[CH3:2].[Cl:25][CH2:26][C:27](Cl)=[O:28].C(N(CC)CC)C>C1COCC1>[Cl:25][CH2:26][C:27]([NH:24][C:8]1[C:9]([O:14][C:15]2[C:20]([CH3:21])=[CH:19][C:18]([CH3:22])=[CH:17][C:16]=2[CH3:23])=[N:10][C:11]([CH3:13])=[CH:12][C:7]=1[NH:6][CH:3]([CH2:4][CH3:5])[CH2:1][CH3:2])=[O:28]
Reactant: O=C(Cl)CCl
Reactant: CCC(CC)Nc1cc(C)nc(Oc2c(C)cc(C)cc2C)c1N
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCC(CC)Nc1cc(C)nc(Oc2c(C)cc(C)cc2C)c1NC(=O)CCl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of N4-(1-ethyl-propyl)-6-methyl-2-(2,4,6-trimethyl-phenoxy)-pyridine-3,4-diamine (250 mg, 0.763 mmol) in dry THF was added chloroacetyl chloride (86 mg, 0.763 mmol) and triethylamine (77 mg, 0.763 mmol) at 0° C. The resulting mixture was warmed to room temperature and stirred for 1 hr. The mixture was quenched with water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated to dryness to give the title compound as a solid. The solid was purified through silica gel column chromatography to give 280 mg(91%) of tan crystals, mp. 152–154° C.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([OH:10])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].C(=O)([O-])[O-].[Cs+].[Cs+].Cl[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=1>C(#N)C>[OH:1][C:2]1[CH:9]=[C:8]([O:10][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5]
Reactant: O=Cc1ccc(O)cc1O
Reactant: ClCc1ccccn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: O=Cc1ccc(OCc2ccccn2)cc1O
Reaction time: 11 h
Yield: 27 %

Procedure:
Separately, 13.8 g (100 mmol) of 2,4-dihydroxybenzaldehyde was dissolved in 250 mL of acetonitrile and 32.5 g (100 mmol) of cesium carbonate was added at room temperature. To this solution, the solution of 2-chloromethylpyridine in acetonitrile prepared in advance was added dropwise at 50° C. over 4 hours and the mixture was stirred for 11 hours. After filtration, the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=80/20 to 50/50) to give 6.10 g (27% yield) of the title compound as a white solid.
Reaction SMILES: S(Cl)([Cl:3])=O.[CH2:5]([O:15][C:16]1[CH:24]=[CH:23][C:19]([C:20](O)=[O:21])=[CH:18][CH:17]=1)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]>CN(C)C=O>[CH2:5]([O:15][C:16]1[CH:24]=[CH:23][C:19]([C:20]([Cl:3])=[O:21])=[CH:18][CH:17]=1)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: O=S(Cl)Cl
Reactant: CCCCCCCCCCOc1ccc(C(=O)O)cc1
Solvent: CN(C)C=O
Product: CCCCCCCCCCOc1ccc(C(=O)Cl)cc1
Yield: 99 %

Procedure:
A 3,000 ml two-necked flask equipped with a stirrer and a reflux condenser was charged with 500 ml of thionyl chloride and 277 g of 4-n-decyloxybenzoic acid obtained by a conventional method, and stirred together with 0.1 g of dimethylformamide at room temperature over one night. Thereafter, the mixture was heated for 1 hour under reflux. Then, unreacted thionyl chloride was removed under reduced pressure to obtain 293 g of 4-decyloxybenzoyl chloride as a colorless to yellow oily product (yield: 99%, boiling point: 175° to 180° C./0.5 mmHg).
Reaction SMILES: S1[CH:5]=[CH:4][C:3]([CH:6]([OH:11])[CH2:7][CH2:8][CH2:9][OH:10])=C1.[O:12]1C=CC=[C:13]1C=O>O1CCCC1>[O:12]1[CH:13]=[CH:5][CH:4]=[C:3]1[CH:6]([OH:11])[CH2:7][CH2:8][CH2:9][OH:10]
Reactant: O=Cc1ccco1
Reactant: OCCCC(O)c1ccsc1
Solvent: C1CCOC1
Product: OCCCC(O)c1ccco1

Procedure:
The Grignard reagent prepared in Example 26 step (a) (0.7 M, 28 ml, 19.6 mmol), and furan-2-carboxaldehyde (1.92 g, 20 mmol) in anhydrous tetrahydrofuran (15 ml) were used to prepare the sub-title compound, using the procedure described in Example 26 step (a). The product was a colourless oil (2.69 g, 88%).