Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1(=[O:8])[CH:7]=[CH:6][CH2:5][CH2:4][CH:3]=[CH:2]1.[F:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2([CH2:21][CH2:22][CH2:23][NH2:24])[O:20][CH2:19][CH2:18][O:17]2)=[CH:12][CH:11]=1>CO>[F:9][C:10]1[CH:11]=[CH:12][C:13]([C:16]2([CH2:21][CH2:22][CH2:23][N:24]3[CH:6]4[CH2:5][CH2:4][CH:3]3[CH2:2][C:1](=[O:8])[CH2:7]4)[O:17][CH2:18][CH2:19][O:20]2)=[CH:14][CH:15]=1
Reactant: NCCCC1(c2ccc(F)cc2)OCCO1
Reactant: O=C1C=CCCC=C1
Solvent: CO
Product: O=C1CC2CCC(C1)N2CCCC1(c2ccc(F)cc2)OCCO1

Procedure:
To a flask equipped with a nitrogen gas inlet, addition funnel and magnetic stirrer is charged 2.7 g. (0.025 mol) of 2,6-cycloheptadienone and 90 ml. of methanol. The solution is stirred and 5.63 g. (0.025 mol) of 2-(4-fluorophenyl)-1,3-dioxolane-2-propanamine in 90 ml. of methanol is added over 30 minutes. After the addition, the reaction is allowed to stir for 20 hrs. The solution is then concentrated in vacuo to afford an oil. Chromatography on 500 g. of silica gel gives, after evaporation of solvent, 8-{3-[2-(4-fluorophenyl)1,3-dioxolan-2-yl]-propyl}-8-azabicyclo-[3.2.1]octan-3-one as an oil.
Reaction SMILES: [CH3:1][Si:2]([CH3:7])([CH3:6])[C:3]#[C:4][CH3:5].[Li]CCCC.CCCCCC.Cl[CH2:20][C:21]1[N:22]=[C:23]2[C:28]([CH3:29])=[CH:27][CH:26]=[CH:25][N:24]2[CH:30]=1>C1COCC1>[CH3:29][C:28]1[C:23]2[N:24]([CH:30]=[C:21]([CH2:20][CH2:5][C:4]#[C:3][Si:2]([CH3:7])([CH3:6])[CH3:1])[N:22]=2)[CH:25]=[CH:26][CH:27]=1
Reactant: Cc1cccn2cc(CCl)nc12
Reactant: CC#C[Si](C)(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: Cc1cccn2cc(CCC#C[Si](C)(C)C)nc12
Temperature: -78 °C
Reaction time: 1.5 h
Yield: 99.6 %

Procedure:
To a solution of trimethyl(prop-1-ynyl)silane (259 mg, 2.31 mmol) in THF (7.5 mL) at −78° C. was added n-BuLi 2.5M in hexane (1.1 mL, 2.8 mmol). After 90 min at −78° C. 2-(chloromethyl)-8-methyl-imidazo[1,2-a]pyridine (500 mg, 2.8 mmol) in THF (5 mL) was added dropwise. The solution became blue-green at −78° C. The solution was stirred at −78° C. for an additional 1 h. The reaction was quenched with water and the solvent was removed under reduced pressure. The crude product was purified over silicagel chromatography (prepacked 25 g silicagel column, DCM/MeOH from 100/0 to 99/1 as eluent) to afford 590 mg of 8-methyl-2-(4-(trimethylsilyl)but-3-ynyl)-imidazo[1,2-a]pyridine (Yield: 100%) as an yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[N:11][C:12](Cl)=[CH:13][C:14]=2[C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)=[CH:5][CH:4]=1.[F:24][C:25]1[C:30]([F:31])=[C:29]([F:32])[C:28]([F:33])=[C:27]([F:34])[C:26]=1[OH:35]>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[N:11][C:12]([O:35][C:26]3[C:27]([F:34])=[C:28]([F:33])[C:29]([F:32])=[C:30]([F:31])[C:25]=3[F:24])=[CH:13][C:14]=2[C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(-c2cc(Cl)nnc2-c2ccc(OC)cc2)cc1
Reactant: Oc1c(F)c(F)c(F)c(F)c1F
Product: COc1ccc(-c2cc(Oc3c(F)c(F)c(F)c(F)c3F)nnc2-c2ccc(OC)cc2)cc1

Procedure:
In a similar manner as in Example 2, 3,4-bis(4-methoxyphenyl)-6-chloropyridazine (200 mg, 0.613 mmol) and 2,3,4,5,6-pentafluorophenol were reacted as starting materials at 150° C. for 24 hours and post-treatment was then conducted, whereby the title compound was obtained as a colorless amorphous solid (175.6 mg, 60.5%).
Reaction SMILES: O[CH:2]([CH2:7][CH2:8][S:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[CH:11]=1)[CH2:3][C:4](=[O:6])[CH3:5].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH3:17][O:16][C:12]1[CH:11]=[C:10]([S:9][CH2:8][CH2:7][CH:2]=[CH:3][C:4](=[O:6])[CH3:5])[CH:15]=[CH:14][CH:13]=1
Reactant: COc1cccc(SCCC(O)CC(C)=O)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: COc1cccc(SCCC=CC(C)=O)c1
Yield: 90.3 %

Procedure:
1.00 Gram of 4-hydroxy-6-(3-methoxyphenylthio)-2-hexanone was dissolved in 100 ml of toluene, and 0.02 g of p-toluene sulfonic acid was added thereto. The resulting mixture was refluxed for 2.5 hours with stirring. After having been cooled, the mixture was washed with a saturated aqueous sodium hydrogencarbonate solution and then saturated aqueous sodium chloride solution. Then the mixture was dried over anhydrous magnesium sulfate. Removing the solvent from the mixture under reduced pressure gave 0.96 g of 6-(3-methoxyphenylthio)-3-hexen-2-one. (trans : cis =4.2 : 1) (purity: 87.2%). The yield was 90.3%.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][N:13]([C:15]([N:17]3[CH2:22][CH2:21][CH:20]([OH:23])[CH2:19][CH2:18]3)=[O:16])[CH2:12][CH:11]([C:24](O)=O)[CH2:10]2)=[CH:5][CH:4]=1)[CH3:2].[F:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[C:34](=[N:36][OH:37])[NH2:35]>>[CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:10][CH:11]([C:24]3[O:37][N:36]=[C:34]([C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=4[F:27])[N:35]=3)[CH2:12][N:13]([C:15]([N:17]3[CH2:18][CH2:19][CH:20]([OH:23])[CH2:21][CH2:22]3)=[O:16])[CH2:14]2)=[CH:5][CH:4]=1)[CH3:2]
Reactant: NC(=NO)c1ccccc1F
Reactant: CCc1ccc(C2CC(C(=O)O)CN(C(=O)N3CCC(O)CC3)C2)cc1
Product: CCc1ccc(C2CC(c3nc(-c4ccccc4F)no3)CN(C(=O)N3CCC(O)CC3)C2)cc1

Procedure:
80 mg (0.22 mmol) of 5-(4-ethylphenyl)-1-[(4-hydroxypiperidin-1-yl)carbonyl]piperidine -3-carboxylic acid (Example 59A) and 51 mg (0.33 mmol) of 2-fluoro-N′-hydroxybenzene-carboximidamide were reacted according to the General Method 2. Yield: 71 mg (67% of theory)
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[CH:10]=[C:9]([CH:11]=O)[S:8][C:6]=2[N:7]=1.[CH3:19][N:20]([CH3:29])[C:21]([N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1)=[O:22]>>[Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[CH:10]=[C:9]([CH2:11][N:26]3[CH2:25][CH2:24][N:23]([C:21]([N:20]([CH3:29])[CH3:19])=[O:22])[CH2:28][CH2:27]3)[S:8][C:6]=2[N:7]=1
Reactant: CN(C)C(=O)N1CCNCC1
Reactant: O=Cc1cc2c(N3CCOCC3)nc(Cl)nc2s1
Product: CN(C)C(=O)N1CCN(Cc2cc3c(N4CCOCC4)nc(Cl)nc3s2)CC1

Procedure:
Reaction between 2-chloro-4-morpholin-4-yl-thieno[2,3-d]pyrimidine-6-carbaldehyde (General Procedure D-2) and piperazine-1-carboxylic acid dimethylamide (Example 26) using General Procedure B-3 yielded 4-((2-chloro-4-morpholinothieno[2,3-d]pyrimidin-6-yl)methyl)-N,N-dimethylpiperazine-1-carboxamide.
Reaction SMILES: [C:1]([O:4][CH2:5][C@H:6]1[NH:9][C:8](=[O:10])[C@H:7]1[NH2:11])(=[O:3])[CH3:2].C(=O)([O-])O.[Na+].[Cl:17][CH2:18][C:19]([NH:21][C:22]1[S:23][CH:24]=[C:25]([C:27](=[N:31][O:32][CH3:33])[C:28](Cl)=[O:29])[N:26]=1)=[O:20].O>O1CCCC1>[C:1]([O:4][CH2:5][C@H:6]1[NH:9][C:8](=[O:10])[C@H:7]1[NH:11][C:28](=[O:29])[C:27]([C:25]1[N:26]=[C:22]([NH:21][C:19](=[O:20])[CH2:18][Cl:17])[S:23][CH:24]=1)=[N:31][O:32][CH3:33])(=[O:3])[CH3:2]
Reactant: CC(=O)OC[C@H]1NC(=O)[C@H]1N
Reactant: CON=C(C(=O)Cl)c1csc(NC(=O)CCl)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CON=C(C(=O)N[C@@H]1C(=O)N[C@@H]1COC(C)=O)c1csc(NC(=O)CCl)n1

Procedure:
Under ice-cooling and stirring, 12 ml of an aqueous solution containing 632 mg of cis-4-acetoxymethyl-3-amino-2-oxoazetidine and 1.122 g of sodium hydrogen carbonate is added to a suspension of 2.36 g of 2-(2-chloroacetamido-4-thiazolyl)-2-methoxyiminoacetyl chloride (syn-isomer) in 20 ml of tetrahydrofuran. The mixture is stirred for 2 hours at room temperature and the solvent is then distilled off in vacuo to leave the residue, which solidifies. Water is added to the solidified residue, followed by filtration. The collected crystals are washed successively with an aqueous sodium hydrogen carbonate solution, water and ether and dried to give cis-4-acetoxymethyl-3-[2-(2-chloroacetamido-4-thiazolyl)-2-methoxyiminoacetamido]-2-oxoazetidine (syn-isomer), m.p. 180°-190° C. (dec.).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][S:5](=[O:38])([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[N:6][C:7](=[O:31])[C:8]1[CH:13]=[C:12]([C:14]#[C:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([NH:22][C:23]([C:25]3[O:26][CH:27]=[CH:28][C:29]=3[CH3:30])=[O:24])[CH:17]=2)[CH:11]=[N:10][CH:9]=1.[CH3:39][NH:40][CH2:41][CH:42]([OH:45])[CH2:43][OH:44]>>[OH:45][CH:42]([CH2:43][OH:44])[CH2:41][N:40]([CH3:39])[CH2:2][CH2:3][CH2:4][S:5](=[O:38])([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[N:6][C:7](=[O:31])[C:8]1[CH:13]=[C:12]([C:14]#[C:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([NH:22][C:23]([C:25]3[O:26][CH:27]=[CH:28][C:29]=3[CH3:30])=[O:24])[CH:17]=2)[CH:11]=[N:10][CH:9]=1
Reactant: CNCC(O)CO
Reactant: Cc1ccoc1C(=O)Nc1cccc(C#Cc2cncc(C(=O)N=S(=O)(CCCBr)c3ccccc3)c2)c1
Product: Cc1ccoc1C(=O)Nc1cccc(C#Cc2cncc(C(=O)N=S(=O)(CCCN(C)CC(O)CO)c3ccccc3)c2)c1

Procedure:
In a manner similar to that described for Example 508, N-[(3-bromopropyl)(oxido)phenyl--sulfanylidene]-5-({3-[(3-methyl-2-furoyl)amino]phenyl}ethynyl)nicotinamide and 3-methylamino-1,2-propanediol were converted to the title compound.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH3:12])=[N:7]2.[NH2:13][C:14]1[CH:19]=[C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([Br:28])[CH:23]=2)[CH:17]=[CH:16][C:15]=1[S:29][C:30]1[CH:35]=[CH:34][C:33]([NH:36][C:37](=[O:39])[CH3:38])=[CH:32][CH:31]=1>C(O)C>[Br:28][C:24]1[CH:23]=[C:22]([CH:27]=[CH:26][CH:25]=1)[CH2:21][O:20][C:18]1[CH:17]=[CH:16][C:15]([S:29][C:30]2[CH:31]=[CH:32][C:33]([NH:36][C:37](=[O:39])[CH3:38])=[CH:34][CH:35]=2)=[C:14]([NH:13][C:2]2[C:3]3[C:8](=[N:7][C:6]([CH3:12])=[CH:5][CH:4]=3)[N:9]=[CH:10][CH:11]=2)[CH:19]=1
Reactant: CC(=O)Nc1ccc(Sc2ccc(OCc3cccc(Br)c3)cc2N)cc1
Reactant: Cc1ccc2c(Cl)ccnc2n1
Solvent: CCO
Product: CC(=O)Nc1ccc(Sc2ccc(OCc3cccc(Br)c3)cc2Nc2ccnc3nc(C)ccc23)cc1

Procedure:
The product from Example 1d (18 mg, 0.085 mmol) was reacted in ethanol (1 mL) with the product from Example 154a (37 mg, 0.085 mmol) for 18 h following the procedure from Example 1g giving the crude title compound which was purified by HPLC with TFA providing the product as a trifluoroacetic acid salt (15 mg, 30%). 1H NMR (300 MHz, DMSO-d6) δ ppm: 0.97 (t, J=7.35 Hz, 3H) 1.65-1.90 (m, 2H) 2.02 (s, 3H) 2.99 (t, J=7.54 Hz, 2H) 5.17 (s, 2H) 6.29 (d, J=6.99 Hz, 1H) 7.14 (d, J=8.82 Hz, 2H) 7.17-7.27 (m, 2H) 7.28-7.40 (m, 3H) 7.42 (d, J=8.46 Hz, 2H) 7.55 (d, J=7.72 Hz, 1H) 7.66 (s, 1H) 7.80 (d, J=8.46 Hz, 1H) 8.37 (d, J=6.99 Hz, 1H) 8.97 (d, J=8.82 Hz, 1H) 9.98 (s, 1H) 11.00 (s, 1H) 14.37 (s, 1H); MS (ESI+) m/z 613 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[CH2:3][O:4][CH:5]1[CH:7]([C:8]([OH:10])=[O:9])[C:6]1([CH3:12])[CH3:11].C(=O)([O-])[O-].[K+].[K+].[O:21]([C:28]1[CH:29]=[C:30]([CH:33]=[CH:34][CH:35]=1)[CH2:31]Br)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CN(C=O)C>[F:1][C:2]([F:13])([F:14])[CH2:3][O:4][CH:5]1[CH:7]([C:8]([O:10][CH2:31][C:30]2[CH:33]=[CH:34][CH:35]=[C:28]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:29]=2)=[O:9])[C:6]1([CH3:11])[CH3:12]
Reactant: BrCc1cccc(Oc2ccccc2)c1
Reactant: CC1(C)C(OCC(F)(F)F)C1C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC1(C)C(OCC(F)(F)F)C1C(=O)OCc1cccc(Oc2ccccc2)c1
Reaction time: 15 h

Procedure:
To 10 ml DMF is added 0.88 g 3-(2,2,2-trifluoroethoxy)-2,2-dimethylcyclopropanecarboxylic acid (4.l4 mmol) and 1.146 g potassium carbonate (8.29 mmol), after which is added 12 g m-phenoxybenzyl bromide. This mixture is stirred under nitrogen for 15 hr. The reaction mixture is extracted with ether and the ether phase is washed with water (3X) and brine, and dried over sodium sulfate. The solvent is then removed to yield m-phenoxybenzyl 3-(2,2,2-trifluoroethoxy)-2,2-dimethylcyclopropanecarboxylate, MS m/e 394.1 (M+).
Reaction SMILES: Br.[Br-].[CH3:3][N:4]([CH3:27])[CH2:5][CH2:6][CH2:7][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C([Li])CCC.[Br:33][C:34]1[CH:49]=[CH:48][C:37]2[C:38](=O)[C:39]3[CH:46]=[CH:45][CH:44]=[CH:43][C:40]=3[O:41][CH2:42][C:36]=2[CH:35]=1>CCCCCC.O1CCCC1>[Br:33][C:34]1[CH:49]=[CH:48][C:37]2/[C:38](=[CH:7]/[CH2:6][CH2:5][N:4]([CH3:27])[CH3:3])/[C:39]3[CH:46]=[CH:45][CH:44]=[CH:43][C:40]=3[O:41][CH2:42][C:36]=2[CH:35]=1
Reactant: O=C1c2ccc(Br)cc2COc2ccccc21
Reactant: CN(C)CCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Br
Agent: [Br-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CN(C)CC/C=C1/c2ccc(Br)cc2COc2ccccc21

Procedure:
Anhydrous 3-(dimethylamino)propyltriphenylphosphonium bromide hydrobromide (24.5 g, 48 mmole), 96 mmole of n-butyl lithium in hexane, and 8-bromo-6,11-dihydrodibenz[b,e]oxepin-11-one (10 g, 34.6 mmole) were reacted in 580 mL dry tetrahydrofuran by the procedure of Example I, step b. This provided an E/Z (1:3.5) isomeric mixture of bromoamines. Recrystallization of the mixture from diethyl ether gave 0.17 g of Z-isomer and 1.8 g of an E/Z (1:4) (assayed by HPLC on C18) isomeric mixture which was used in the next step without further purification. pmr (Z-isomer) (CDCl3) δ: 7.38-7.44 (m, 2H, H7 and H9); 7.13-7.18 (m, 3H, aromatic H); 6.84-6.93 (m, 2H, H2 and H4); 5.70 (t, 1H, CH=); 5.15 (br s, 2H, ArCH2O); 2.55 (q, 2H, CH2); 2.43 (t, 2H, NCH2 ); 2.22 (s, 6H, NMe2).
Reaction SMILES: [F:1][C:2]([F:43])([F:42])[C@H:3]([N:29]1[CH2:33][CH2:32][C@H:31]([NH:34]C(=O)OC(C)(C)C)[CH2:30]1)[C:4]1[CH:5]=[CH:6][C:7]2[N:8]([C:10]([C:13]3[CH:22]=[CH:21][C:20]4[C:15](=[C:16]([O:23][C@H:24]([CH3:28])[CH2:25][O:26][CH3:27])[CH:17]=[CH:18][CH:19]=4)[N:14]=3)=[N:11][N:12]=2)[CH:9]=1.[ClH:44]>ClCCl>[ClH:44].[ClH:44].[F:42][C:2]([F:1])([F:43])[C@H:3]([N:29]1[CH2:33][CH2:32][C@H:31]([NH2:34])[CH2:30]1)[C:4]1[CH:5]=[CH:6][C:7]2[N:8]([C:10]([C:13]3[CH:22]=[CH:21][C:20]4[C:15](=[C:16]([O:23][C@H:24]([CH3:28])[CH2:25][O:26][CH3:27])[CH:17]=[CH:18][CH:19]=4)[N:14]=3)=[N:11][N:12]=2)[CH:9]=1
Reactant: COC[C@@H](C)Oc1cccc2ccc(-c3nnc4ccc([C@@H](N5CC[C@H](NC(=O)OC(C)(C)C)C5)C(F)(F)F)cn34)nc12
Agent: Cl
Solvent: ClCCl
Product: COC[C@@H](C)Oc1cccc2ccc(-c3nnc4ccc([C@@H](N5CC[C@H](N)C5)C(F)(F)F)cn34)nc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 177.2 %

Procedure:
To a solution of tert-butyl (S)-1-((R)-2,2,2-trifluoro-1-(3-(8-((R)-1-methoxypropan-2-yloxy)quinolin-2-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)ethyl)pyrrolidin-3-ylcarbamate (0.37 g, 0.61 mmol) in dichloromethane (1 mL) was added hydrochloric acid (5-6M in 2-propanol; 8.7 mL, 0.61 mmol). The reaction mixture was stirred at ambient temperature for 30 minutes. The solvent was removed under reduced pressure, and the resulting solid was suspended in acetonitrile (3 mL) and stirred at ambient temperature for 5 minutes. The solid was collected by vacuum filtration to give the title compound (0.31 g, 87%). LCMS APCI (+) m/z 501 (M+H). Specific rotation: [α]25D=0.48° (c=1.03, MeOH).
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:15])=[N:4][C:5]2[C:10]([C:11]=1C(O)=O)=[CH:9][CH:8]=[CH:7][CH:6]=2.[CH2:16]([O:23][C:24]1[CH:33]=[C:32]2[C:27]([C:28](Cl)=[CH:29][CH:30]=[N:31]2)=[CH:26][C:25]=1[O:35][CH3:36])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CN(C1C=CN=CC=1)C.ClC1C=CC=CC=1Cl>[CH2:16]([O:23][C:24]1[CH:33]=[C:32]2[C:27]([C:28]([O:1][C:2]3[C:3]([CH3:15])=[N:4][C:5]4[C:10]([CH:11]=3)=[CH:9][CH:8]=[CH:7][CH:6]=4)=[CH:29][CH:30]=[N:31]2)=[CH:26][C:25]=1[O:35][CH3:36])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: Cc1nc2ccccc2c(C(=O)O)c1O
Reactant: COc1cc2c(Cl)ccnc2cc1OCc1ccccc1
Agent: CN(C)c1ccncc1
Solvent: Clc1ccccc1Cl
Product: COc1cc2c(Oc3cc4ccccc4nc3C)ccnc2cc1OCc1ccccc1
Temperature: 150 °C
Reaction time: 8 h
Yield: 85.1 %

Procedure:
3-Hydroxy-2-methyl-4-quinoline carboxylic acid (1.5 g), 7-benzyloxy-4-chloro-6-methoxyquinoline (2 g), and 4-(N,N-dimethylamino)-pyridine (2.4 g) were dissolved in 1,2-dichlorobenzene (70 ml) to prepare a solution which was then stirred at 150° C. overnight. The reaction solution was cooled to room temperature, and the solvent was then removed by distillation under the reduced pressure. Water was added to the residue, and the mixture was extracted with chloroform and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure. The residue was purified by column chromatography using hexane-acetone to give the title compound (2.4 g, yield 85%).
Reaction SMILES: [C:1]1([C:7]2[N:11]=[C:10]([S:12]([NH2:15])(=[O:14])=[O:13])[S:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:16](OCC)(OCC)([O:18][CH2:19][CH3:20])[CH3:17]>CCCCCC>[CH2:16]([O:18][C:19](=[N:15][S:12]([C:10]1[S:9][N:8]=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:11]=1)(=[O:14])=[O:13])[CH3:20])[CH3:17]
Reactant: NS(=O)(=O)c1nc(-c2ccccc2)ns1
Reactant: CCOC(C)(OCC)OCC
Solvent: CCCCCC
Product: CCOC(C)=NS(=O)(=O)c1nc(-c2ccccc2)ns1
Temperature: 25 °C

Procedure:
A mixture of 3.0 g of 3-phenyl-1,2,4-thiadiazole-5-sulfonamide and 10 ml of triethyl orthoacetate was warmed at reflux for 4 hours. The mixture was cooled to room temperature and diluted with hexane (30 ml) and the precipitated solid was collected, washed with hexane and dried to give 3.25 g of solid, m.p. 120°-122°.
Reaction SMILES: [C:1]12([CH2:12][C:11](=O)[O:10][C:8](=[O:9])[CH2:7]1)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2.[BH4-].[Na+].O.Cl>C1COCC1>[CH2:7]1[C:1]2([CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[CH2:12][CH2:11][O:10][C:8]1=[O:9]
Reactant: O=C1CC2(CCCCC2)CC(=O)O1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: O=C1CC2(CCCCC2)CCO1
Temperature: 25 °C
Reaction time: 3 h
Yield: 92 %

Procedure:
To a solution of 1,1-cyclohexane diacetic acid anhydride (20.1 g) in THF (150 mL) was added sodium borohydride (3.78 g, 100 mmol) under ice cooling. The reaction solution was stirred at room temperature for additional 3 hours. Water was added to the solution, and it was made acidic with conc. hydrochloric acid. The solution was extracted with ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate and filtered. The filtrate was then concentrated under reduced pressure to give the title compound (17.07 g). This product was subjected to the subsequent step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[O:13][CH:14]([C:16]1[N:17]=[C:18]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[O:19][C:20]=1[CH3:21])[CH3:15])[CH:6]=[CH:7][CH:8]=O.[O:28]1[CH2:32][C:31](=[O:33])[NH:30][C:29]1=[O:34]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:6][CH2:7][CH2:8][CH:32]2[O:28][C:29](=[O:34])[NH:30][C:31]2=[O:33])[CH:10]=[CH:11][C:12]=1[O:13][CH:14]([C:16]1[N:17]=[C:18]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[O:19][C:20]=1[CH3:21])[CH3:15]
Reactant: O=C1COC(=O)N1
Reactant: COc1cc(C=CC=O)ccc1OC(C)c1nc(-c2ccccc2)oc1C
Product: COc1cc(CCCC2OC(=O)NC2=O)ccc1OC(C)c1nc(-c2ccccc2)oc1C

Procedure:
In substantially the same manner as in Working Example 11, 3-methoxy-4-[1-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]cinnamaldehyde was condensed with 2,4-oxazolidinedione. The condensate was subjected to catalytic hydrogenation to yield 5-[3-[3-methoxy-4-[1-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]phenyl]propyl]-2,4-oxazolidinedione.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([CH:11]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]([NH:27][CH2:28][CH2:29][C:30]([O:32]CC)=[O:31])=[O:26])=[CH:21][CH:20]=3)[CH2:12][CH2:13][CH2:14][CH2:15][S:16][CH3:17])=[C:8]([CH3:35])[C:7]=2[CH:36]=1.O1CCCC1.[OH-].[Na+]>C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([CH:11]([NH:18][C:19]3[CH:20]=[CH:21][C:22]([C:25]([NH:27][CH2:28][CH2:29][C:30]([OH:32])=[O:31])=[O:26])=[CH:23][CH:24]=3)[CH2:12][CH2:13][CH2:14][CH2:15][S:16][CH3:17])=[C:8]([CH3:35])[C:7]=2[CH:36]=1
Reactant: CCOC(=O)CCNC(=O)c1ccc(NC(CCCCSC)c2oc3ccc(OC)cc3c2C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: COc1ccc2oc(C(CCCCSC)Nc3ccc(C(=O)NCCC(=O)O)cc3)c(C)c2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 55.6 %

Procedure:
To a mixture of ethyl 3-{[(4-{[1-(5-methoxy-3-methyl-1-benzofuran-2-yl)-5-(methylsulfanyl)pentyl]amino}phenyl)carbonyl]amino}propanoate (253 mg) synthesized above, tetrahydrofuran (5 mL) and ethanol (5 mL) was added 1N aqueous sodium hydroxide solution (2.00 mL), and the mixture was stirred at room temperature for 3 hr, and concentrated under reduced pressure. The residue was dissolved in water (10 mL), and 1N hydrochloric acid (2.00 mL) was added at 0° C. The resulting precipitate was collected by filtration to give the title object compound (133 mg, 56%) as a pale-brown solid.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[CH2:6][N:5]2[N:9]=[C:10]([N+:12]([O-])=O)[CH:11]=[C:4]2[CH2:3]1.[H][H]>C(O)C.[Pd]>[NH2:12][C:10]1[CH:11]=[C:4]2[CH2:3][N:2]([CH3:1])[C:7](=[O:8])[CH2:6][N:5]2[N:9]=1
Reactant: [H][H]
Reactant: CN1Cc2cc([N+](=O)[O-])nn2CC1=O
Agent: [Pd]
Solvent: CCO
Product: CN1Cc2cc(N)nn2CC1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 83.7 %

Procedure:
A solution of 313c (450 mg, 2.3 mmol) in ethanol (30 mL) was added Pd/C (10%, 400 mg). The reaction was charged with hydrogen gas (via balloon) and stirred at room temperature for 2 h. After reaction was complete, the mixture was filtered through a plug of CELITE® and the filtrate was concentrated under reduced pressure to afford 313d as a yellow solid (320 mg, 84%), which was used without further purification in the next step. MS-ESI: [M+H]+ 167.1
Reaction SMILES: B.O1CCCC1.[F:7][C:8]1[CH:13]=[C:12]([OH:14])[CH:11]=[CH:10][C:9]=1[CH2:15][C:16](O)=[O:17].O>C1COCC1>[F:7][C:8]1[CH:13]=[C:12]([OH:14])[CH:11]=[CH:10][C:9]=1[CH2:15][CH2:16][OH:17]
Reactant: O=C(O)Cc1ccc(O)cc1F
Agent: B
Solvent: O
Solvent: C1CCOC1
Product: OCCc1ccc(O)cc1F
Temperature: -10 °C
Reaction time: 2 h

Procedure:
Borane-tetrahydrofuran complex (1.0 M solution in THF, 22 ml, 0.02200 mol) was added dropwise to the solution of (2-fluoro-4-hydroxyphenyl)acetic acid (P. C. Belanger et al. EP 106565 B1, 2.27 g, 0.01145 mol) in dry THF (40 ml) under nitrogen at −10° C., and the resulting solution was stirred for 2 h at −10° C. Water was added and the product was extracted into ethyl acetate. The combined extracts were washed with water, dried and evaporated in vacuo to give the product. 1H NMR (400 MHz, DMSO-d6): 2.62 (2H, t, 3J=7.2 Hz), 3.50 (2H, m), 4.63 (1H, t, 3J=5.4 Hz, —CH2OH), 6.47-6.53 (2H, m), 7.06 (1H, t, 3JHH=4JHF=8.5 Hz), 9.60 (1H, s, ArOH).
Reaction SMILES: CI.[Cl:3][C:4]1[CH:9]=[C:8]([O:10][C:11]2[CH:12]=[C:13]([CH:17]=[CH:18][C:19]=2[CH3:20])[C:14]([OH:16])=[O:15])[CH:7]=[CH:6][N:5]=1.[C:21](=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:3][C:4]1[CH:9]=[C:8]([O:10][C:11]2[CH:12]=[C:13]([CH:17]=[CH:18][C:19]=2[CH3:20])[C:14]([O:16][CH3:21])=[O:15])[CH:7]=[CH:6][N:5]=1
Reactant: O=C([O-])[O-]
Reactant: Cc1ccc(C(=O)O)cc1Oc1ccnc(Cl)c1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)c1ccc(C)c(Oc2ccnc(Cl)c2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
At ambient temperature 1.6 ml methyl iodide are added to a mixture of 6.21 g 3-(2-chloro-pyridin-4-yloxy)-4-methyl-benzoic acid, 4.88 g potassium carbonate to and 30 ml N,N-dimethylformamide. The mixture is stirred overnight at ambient temperature. Then the mixture is added to ice-cold water, and the precipitate is filtered off and dried at 45° C.