Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][C@H:6]([NH:14][C:15](=[O:34])[NH:16][C@@H:17]([CH2:25][CH2:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8].[CH:35]1[C:47]2[CH:46]([CH2:48][O:49][C:50]([NH:52][CH:53]([CH2:57][CH2:58][CH2:59][CH2:60][N:61]([CH2:88][C:89]3[N:90]([CH2:94][C:95]([N:97]([CH2:106][C:107]([O:109][C:110]([CH3:113])([CH3:112])[CH3:111])=[O:108])[CH2:98][C:99](=[O:105])[O:100][C:101]([CH3:104])([CH3:103])[CH3:102])=[O:96])[CH:91]=[CH:92][N:93]=3)[CH2:62][C:63]3[N:64]([CH2:68][C:69](=[O:87])[N:70]([CH2:79][C:80](=[O:86])[O:81][C:82]([CH3:85])([CH3:84])[CH3:83])[CH2:71][C:72](=[O:78])[O:73][C:74]([CH3:77])([CH3:76])[CH3:75])[CH:65]=[CH:66][N:67]=3)[C:54](O)=[O:55])=[O:51])[C:45]3[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=3)[C:39]=2[CH:38]=[CH:37][CH:36]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>C(Cl)Cl>[C:110]([O:109][C:107](=[O:108])[CH2:106][N:97]([CH2:98][C:99](=[O:105])[O:100][C:101]([CH3:104])([CH3:103])[CH3:102])[C:95](=[O:96])[CH2:94][N:90]1[CH:91]=[CH:92][N:93]=[C:89]1[CH2:88][N:61]([CH2:62][C:63]1[N:64]([CH2:68][C:69](=[O:87])[N:70]([CH2:79][C:80](=[O:86])[O:81][C:82]([CH3:83])([CH3:84])[CH3:85])[CH2:71][C:72](=[O:78])[O:73][C:74]([CH3:75])([CH3:76])[CH3:77])[CH:65]=[CH:66][N:67]=1)[CH2:60][CH2:59][CH2:58][CH2:57][C@@H:53]([C:54](=[O:55])[NH:1][CH2:2][CH2:3][CH2:4][CH2:5][C@@H:6]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[NH:14][C:15](=[O:34])[NH:16][C@H:17]([C:18]([O:20][C:21]([CH3:22])([CH3:23])[CH3:24])=[O:19])[CH2:25][CH2:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[NH:52][C:50](=[O:51])[O:49][CH2:48][CH:46]1[C:45]2[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=2[C:39]2[C:47]1=[CH:35][CH:36]=[CH:37][CH:38]=2)([CH3:111])([CH3:112])[CH3:113]
Reactant: CC(C)(C)OC(=O)CC[C@H](NC(=O)N[C@@H](CCCCN)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Reactant: CC(C)(C)OC(=O)CN(CC(=O)OC(C)(C)C)C(=O)Cn1ccnc1CN(CCCCC(NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O)Cc1nccn1CC(=O)N(CC(=O)OC(C)(C)C)CC(=O)OC(C)(C)C
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)CC[C@H](NC(=O)N[C@@H](CCCCNC(=O)[C@H](CCCCN(Cc1nccn1CC(=O)N(CC(=O)OC(C)(C)C)CC(=O)OC(C)(C)C)Cc1nccn1CC(=O)N(CC(=O)OC(C)(C)C)CC(=O)OC(C)(C)C)NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C

Procedure:
A solution of (S)-di-tert-butyl 2-(3-((S)-6-amino-1-tert-butoxy-1-oxohexan-2-yl)ureido)pentanedioate (97 mg, 0.20 mmol), 2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-6-(bis((1-(2-(bis(2-tert-butoxy-2-oxoethyl)amino)-2-oxoethyl)-1H-imidazol-2-yl)methyl)amino)hexanoic acid (132 mg, 0.12 mmol), EDCI (38 mg, 0.20 mmol), HOBt (26 mg, 0.20) and DIPEA (0.30 mL) in DCM (5.0 mL) was stirred at rt for 2 days. The reaction mixture was purified by biotage eluting with 1% MeOH in DCM to afford (5S,12S,16S)-tri-tert-butyl 5-(4-(bis((1-(2-(bis(2-tert-butoxy-2-oxoethyl)amino)-2-oxoethyl)-1H-imidazol-2-yl)methyl)amino)butyl)-1-(9H-fluoren-9-yl)-3,6,14-trioxo-2-oxa-4,7,13,15-tetraazaoctadecane-12,16,18-tricarboxylate (impure) as an oil.
Reaction SMILES: C([O:3][C:4](=[O:29])[C:5]1[C:10]([NH:11][C:12]2[C:13]3[CH2:28][O:27][CH2:26][C:14]=3[N:15]=[C:16]([C:18]3[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:19]=3[F:25])[N:17]=2)=[CH:9][CH:8]=[N:7][CH:6]=1)C.[OH-].[Na+]>CO>[Cl:24][C:22]1[CH:21]=[CH:20][C:19]([F:25])=[C:18]([C:16]2[N:17]=[C:12]([NH:11][C:10]3[C:5]([C:4]([OH:29])=[O:3])=[CH:6][N:7]=[CH:8][CH:9]=3)[C:13]3[CH2:28][O:27][CH2:26][C:14]=3[N:15]=2)[CH:23]=1
Reactant: CCOC(=O)c1cnccc1Nc1nc(-c2cc(Cl)ccc2F)nc2c1COC2
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1cnccc1Nc1nc(-c2cc(Cl)ccc2F)nc2c1COC2
Temperature: 25 °C
Yield: 92.3 %

Procedure:
To a suspension of 4-[2-(5-chloro-2-fluoro-phenyl)-5,7-dihydro-furo[3,4-d]pyrimidin-4-ylamino]-nicotinic acid ethyl ester (60 mg, 0.14 mmol, 1 eq) in MeOH (5 ml) was added a 1N NaOH(aq) solution (300 μl, 0.30 mmol, 2 eq) and the reaction mixture was heated to reflux for 2 h. The solution was cooled to rt and concentrated in vacuo. Water (20 ml) was added to the crude material and the aqueous layer was acidified to pH 4. The solid was filtered, washed with water (2×5 ml) and dried overnight to afford 4-[2-(5-Chloro-2-fluoro-phenyl)-5,7-dihydro-furo[3,4-d]pyrimidin-4-ylamino]-nicotinic acid (50 mg, 90%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])=[N:10][C:9]=2[C:17]2[C:18]([F:35])=[C:19]([NH:23][S:24]([C:27]3[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:28]=3[F:34])(=[O:26])=[O:25])[CH:20]=[CH:21][CH:22]=2)[CH:5]=[CH:4][N:3]=1.[NH2:36][CH2:37][CH2:38][NH:39][C:40](=[O:46])[O:41][C:42]([CH3:45])([CH3:44])[CH3:43]>>[F:34][C:28]1[CH:29]=[CH:30][C:31]([F:33])=[CH:32][C:27]=1[S:24]([NH:23][C:19]1[C:18]([F:35])=[C:17]([C:9]2[N:10]=[C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])[S:12][C:8]=2[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:36][CH2:37][CH2:38][NH:39][C:40](=[O:46])[O:41][C:42]([CH3:44])([CH3:43])[CH3:45])[N:7]=2)[CH:22]=[CH:21][CH:20]=1)(=[O:26])=[O:25]
Reactant: CC(C)(C)c1nc(-c2cccc(NS(=O)(=O)c3cc(F)ccc3F)c2F)c(-c2ccnc(Cl)n2)s1
Reactant: CC(C)(C)OC(=O)NCCN
Product: CC(C)(C)OC(=O)NCCNc1nccc(-c2sc(C(C)(C)C)nc2-c2cccc(NS(=O)(=O)c3cc(F)ccc3F)c2F)n1
Yield: 88 %

Procedure:
Following a procedure analogous to the procedure described in Example 1 using N-{3-[5-(2-chloro-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,5-difluorobenzenesulfonamide (0.30 g, 0.56 mmol), 1,1-dimethylethyl (2-aminoethyl)carbamate (0.089 g, 0.56 mmol) the title compound of Step A was obtained (0.34 g, 88% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.75 (s, 1H), 8.03 (d, J=5.1 Hz, 1H), 7.13-7.67 (m, 7H), 6.85 (br. s., 1H), 5.80-6.02 (m, 1H), 3.16-3.28 (m, 2H), 2.99-3.13 (m, 2H), 1.40 (s, 9H), 1.37 (s, 9H); m/z (ES+): 663 [M+H]+.
Reaction SMILES: [C:1]1([CH3:15])[CH:6]=[CH:5][C:4]([NH:7][C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=2)=[CH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].Br[C:23]1[CH:24]=[C:25]2[C:42]3[C:39]([C:40]=1Br)=[CH:38][CH:37]=[CH:36][C:35]=3[C:34]1[C:43]3[C:30]([CH:31]=[C:32]4[CH:47]=[CH:46][CH:45]=[CH:44][C:33]4=1)=[CH:29][CH:28]=[CH:27][C:26]2=3>O.[Cu]>[C:11]1([CH3:14])[CH:12]=[CH:13][C:8]([N:7]([C:23]2[CH:24]=[C:25]3[C:42]4[C:39]([C:40]=2[N:7]([C:8]2[CH:9]=[CH:10][C:11]([CH3:14])=[CH:12][CH:13]=2)[C:4]2[CH:3]=[CH:2][C:1]([CH3:15])=[CH:6][CH:5]=2)=[CH:38][CH:37]=[CH:36][C:35]=4[C:34]2[C:43]4[C:30]([CH:31]=[C:32]5[CH:47]=[CH:46][CH:45]=[CH:44][C:33]5=2)=[CH:29][CH:28]=[CH:27][C:26]3=4)[C:4]2[CH:3]=[CH:2][C:1]([CH3:15])=[CH:6][CH:5]=2)=[CH:9][CH:10]=1
Reactant: Brc1cc2c3cccc4cc5ccccc5c(c5cccc(c1Br)c25)c43
Reactant: Cc1ccc(Nc2ccc(C)cc2)cc1
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: Cc1ccc(N(c2ccc(C)cc2)c2cc3c4cccc5cc6ccccc6c(c6cccc(c2N(c2ccc(C)cc2)c2ccc(C)cc2)c36)c54)cc1

Procedure:
Then, two equivalents of di-p-tolylamine, potassium carbonate, and copper power were added to the thus obtained dibromobenzo[a]perylene. This mixture stood still for reaction at 200 degrees centigrade for thirty hours. After reactant solution was diluted with water, reactant was extracted by chloroform. Thereafter, the reactant was refined in a conventional manner to thereby obtain bis(di-p-tolylamino)benzo[a]perylene.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])=[O:3].[OH:13][C:14]1[CH:21]=[CH:20][C:17]([CH:18]=[O:19])=[CH:16][CH:15]=1>N1C=CC=CC=1>[CH2:5]([O:4][C:2]([O:13][C:14]1[CH:21]=[CH:20][C:17]([CH:18]=[O:19])=[CH:16][CH:15]=1)=[O:3])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCOC(=O)Cl
Reactant: O=Cc1ccc(O)cc1
Solvent: c1ccncc1
Product: CCCCCCCCOC(=O)Oc1ccc(C=O)cc1
Reaction time: 8 h
Yield: 99.4 %

Procedure:
Octyl chloroformate (23.1 g, 0.12 mol) was added to and reacted with a solution of p-hydroxybenzaldehyde (III) (16 g, 0.18 mol) dissolved in dry pyridine (100 ml), followed by allowing the reaction mixture to stand overnight, thereafter extracting it with toluene, washing the organic layer with 6N-hydrochloric acid, then with 2N-NaOH aqueous solution and further with water until the washing water became neutral, and distilling off toluene to obtain p-octyloxycarbonyloxybenzaldehyde (IV) (33.2 g), dissolving this compound (20.5 g, 0.07 mol) in acetic acid (60 ml), dropwise adding a solution of anhydrous chromic acid (14 g, 0.14 mol) dissolved in water (11 ml) and acetic (17 ml) to the above solution being agitated, keeping the inner temperature at 40° C. on a water bath for 4 hours after completion of the dropwise addition, thereafter cooling the reaction mixture, adding water (300 ml), filtering the deposited crystals, recrystallizing from ethanol to obtain p-hexyloxycarbonyloxybenzoic acid (V) (7 g), adding thereto thionyl chloride (10 ml), heating the mxiture under reflux for one hour, and distilling off excess thionyl chloride to obtain the objective p-hexyloxycarbonyloxybenzoic acid chloride (VI) (7.5 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=O.[NH2:11][C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[N:15][C:16]([Cl:22])=[CH:17][CH:18]=2)[N:13]=1.C(#N)C>O>[Cl:22][C:16]1[N:15]=[C:14]2[C:19]([CH:20]=[CH:21][C:12]([NH:11][C:5](=[O:7])[C:4]3[CH:8]=[CH:9][CH:10]=[C:2]([F:1])[CH:3]=3)=[N:13]2)=[CH:18][CH:17]=1
Reactant: Nc1ccc2ccc(Cl)nc2n1
Reactant: O=C(O)c1cccc(F)c1
Solvent: O
Solvent: CC#N
Product: O=C(Nc1ccc2ccc(Cl)nc2n1)c1cccc(F)c1
Temperature: 4 °C
Yield: 75.4 %

Procedure:
The procedure is similar to that described in Example 1, but starting with 3-fluorobenzoic acid (20 g), N,N'-carbonyldiimidazole (23 g) and 2-amino-7-chloro-1,8-naphthyridine (16.9 g). The product produced by precipitation in water (25 g; m.p. 201° C.) is dissolved in boiling acetonitrile (230 cc). After 4 hours' cooling at 4° C., the crystallised solid is separated by filtration, washed with acetonitrile (2×20 cc) and dried at 40° C. under reduced pressure (0.067 kPa). N-(7-chloro-1,8-naphthyridin-2-yl)-3-fluorobenzamide (21.4 g) is produced, m.p. 202° C. EXAMPLE 15
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:18]2[C:13](=[CH:14][C:15]([F:21])=[C:16](F)[C:17]=2[F:19])[C:12](=[O:22])[C:11]([C:23]([OH:25])=[O:24])=[CH:10]1.[Cl:26][C:27]1[CH:35]=[CH:34][CH:33]=[C:32]2[C:28]=1[CH2:29][NH:30][CH2:31]2.C1CCN2C(=NCCC2)CC1>CN(C=O)C>[Cl:26][C:27]1[CH:35]=[CH:34][CH:33]=[C:32]2[C:28]=1[CH2:29][N:30]([C:16]1[C:17]([F:19])=[C:18]3[C:13]([C:12](=[O:22])[C:11]([C:23]([OH:25])=[O:24])=[CH:10][N:9]3[C:3]3[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=3[F:1])=[CH:14][C:15]=1[F:21])[CH2:31]2
Reactant: O=C(O)c1cn(-c2ccc(F)cc2F)c2c(F)c(F)c(F)cc2c1=O
Reactant: Clc1cccc2c1CNC2
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: O=C(O)c1cn(-c2ccc(F)cc2F)c2c(F)c(N3Cc4cccc(Cl)c4C3)c(F)cc2c1=O
Yield: 24.5 %

Procedure:
178 mg of 1-(2,4-difluorophenyl)-6,7,8-trifluoro-1,4- dihydro-4-oxoquinoline-3-carboxylic acid, 89 mg of 4-chloroisoindoline, 137 mg of DBU, and 1.5 ml of anhydrous DMF were processed in the same manner as in Example 20 to produce 60 mg of the target compound.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([N:8]2[C:12]([CH3:13])=[N:11][C:10]([CH3:14])=[N:9]2)[N:5]=[C:4]([CH3:15])[N:3]=1.[IH:16]>O>[CH3:14][C:10]1[N:11]=[C:12]([CH3:13])[N:8]([C:6]2[CH:7]=[C:2]([I:16])[N:3]=[C:4]([CH3:15])[N:5]=2)[N:9]=1
Reactant: Cc1nc(Cl)cc(-n2nc(C)nc2C)n1
Reactant: I
Solvent: O
Product: Cc1nc(I)cc(-n2nc(C)nc2C)n1
Temperature: 70 °C

Procedure:
To a mixture of 4-chloro-6-(3,5-dimethyl-1H-1,2,4-triazol-1-yl)-2-methylpyrimidine (2.00 g, 8.9 mmol), KI (4.44 g, 26.8 mmol) was added 57% aq. HI solution (20 mL, 89.2 mmol). After heating at 70° C. for 5 min, water (20 mL) was added to the reaction mixture. The white solid was filtered, rinsed with water, and dried under vacuum to give Intermediate 2 as a white solid. 1H NMR (400 MHz, DMSO) δ 8.06 (s, 1H), 2.78 (s, 3H), 2.62 (s, 3H), 2.30 (s, 3H). MS: m/z=316.1 (M+H).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([N+:15]([O-:17])=[O:16])=[C:6]([N:8]2[CH2:13][CH2:12][CH:11]([CH3:14])[CH2:10][CH2:9]2)[CH:7]=1.[OH:18][CH2:19][CH2:20][N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1>>[CH3:14][CH:11]1[CH2:12][CH2:13][N:8]([C:6]2[CH:7]=[C:2]([N:24]3[CH2:25][CH2:26][N:21]([CH2:20][CH2:19][OH:18])[CH2:22][CH2:23]3)[CH:3]=[CH:4][C:5]=2[N+:15]([O-:17])=[O:16])[CH2:9][CH2:10]1
Reactant: OCCN1CCNCC1
Reactant: CC1CCN(c2cc(Cl)ccc2[N+](=O)[O-])CC1
Product: CC1CCN(c2cc(N3CCN(CCO)CC3)ccc2[N+](=O)[O-])CC1
Yield: 100.2 %

Procedure:
The procedure of Example 4, step (b) was followed using 810 mg (3.18 mmol) of 1-(5-chloro-2-nitro-phenyl)-4-methyl-piperidine (as prepared in the Example 12, step (a)) and 1.95 mL (15.9 mmol) of 1-(2-hydroxyethyl)piperazine for 14 h to afford 1.11 g (100%) of the title compound as a yellow solid: Mass spectrum (ESI, m/z): Calcd. for C18H28N4O3, 349.2 (M+H), found 349.2.
Reaction SMILES: [CH2:1]=[C:2]1[C@H:6]([OH:7])[C@@H:5]([CH2:8][OH:9])[O:4][C@H:3]1[N:10]1[CH:17]=[CH:16][C:14]([NH2:15])=[N:13][C:11]1=[O:12].C[Si](Cl)(C)C.[C:23](Cl)(=[O:33])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32].O.N>N1C=CC=CC=1.O>[CH2:1]=[C:2]1[C@H:6]([OH:7])[C@@H:5]([CH2:8][OH:9])[O:4][C@H:3]1[N:10]1[CH:17]=[CH:16][C:14]([NH:15][C:23](=[O:33])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])=[N:13][C:11]1=[O:12]
Reactant: CCCCCCCCCC(=O)Cl
Reactant: C=C1[C@H](n2ccc(N)nc2=O)O[C@H](CO)[C@H]1O
Agent: C[Si](C)(C)Cl
Agent: N
Solvent: O
Solvent: c1ccncc1
Product: C=C1[C@H](n2ccc(NC(=O)CCCCCCCCC)nc2=O)O[C@H](CO)[C@H]1O
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 45.6 %

Procedure:
2'-Deoxy-2'-methylidenecytidine, 239 mg, was dissolved in 5 ml of pyridine, and to the solution was added dropwise 0.63 ml of trimethylsilyl chloride under ice cooling. The mixture was stirred at room temperature for 5 minutes and then 0.83 ml of decanoyl chloride was added dropwise to the mixture under ice cooling, followed by stirring at room temperature for 2 hours. After the reaction, 2 ml of water was added to the reaction solution, stirring was conducted at room temperature for 5 minutes, and then 2 ml of concentrated ammonia water was added to the solution, followed by stirring for 15 minutes. After the reaction, the solution was partitioned with chloroform, and the chloroform layer was distilled off under reduced pressure. The residue was treated with a silica gel chromatography (elution solvent-chloroform: methanol=25:1) to give 179 mg of the objective compound as an oleaginous product. Yield: 45.6%
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[CH:9])=[CH:4][CH:3]=1.[Cl:10][C:11]1[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=1[CH2:13][SH:14].[Na]>>[CH3:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]\[CH:13]([S:14][CH:13](/[CH:9]=[CH:8]\[C:5]2[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=2)[C:12]2[CH:15]=[CH:16][CH:17]=[CH:18][C:11]=2[Cl:10])[C:12]2[CH:15]=[CH:16][CH:17]=[CH:18][C:11]=2[Cl:10])=[CH:4][CH:3]=1
Reactant: C#Cc1ccc(C)cc1
Reactant: SCc1ccccc1Cl
Agent: [Na]
Product: Cc1ccc(/C=C\C(SC(/C=C\c2ccc(C)cc2)c2ccccc2Cl)c2ccccc2Cl)cc1

Procedure:
A solution of 4-methylphenylacetylene (0.02 mol) and 2-chlorobenzyl mercaptan (0.02 mol) and metallic sodium (0.02 g atom) was subjected to the General Procedure to form Z-4-methylstyryl 2-chlorobenzylsulfide. The title compound was obtained in 76% yield following oxidation. 1HNMR (CDC13) δ2.50 (3H, s), 4.58 (2H, s), 6.80 (1H, d, JH,H=11.88), 7.20-7.63 (9H aromatic+1H ethylenic).
Reaction SMILES: Cl[C:2]1[C:3]2[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][C:4]=2[S:5](=[O:8])(=[O:7])[CH:6]=1.[NH:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1.ClS(Cl)(=O)=O>ClCCl>[Cl:13][C:10]1[CH:11]=[CH:12][C:3]2[C:2]([N:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)=[CH:6][S:5](=[O:8])(=[O:7])[C:4]=2[CH:9]=1
Reactant: O=S1(=O)C=C(Cl)c2ccc(Cl)cc21
Reactant: C1CNCCN1
Solvent: O=S(=O)(Cl)Cl
Solvent: ClCCl
Product: O=S1(=O)C=C(N2CCNCC2)c2ccc(Cl)cc21
Reaction time: 1 h
Yield: 66.5 %

Procedure:
A mixture of 3,6-dichlorobenzo[b]thiophene-1,1-dioxide (16.00 g, 0.0681 mol), piperazine (20.52 g, 0.238 mol) and dichloromethane (300 ml) was heated to reflux. After 1 hour, TLC analysis showed the dichlorosulfone (Rf =0.47, 30% ethyl acetate in hexanes, silica gel) to be consumed. The cloudy mixture was washed with 0.25 N NaOH (400 ml), H2O (300 ml), brine (250 ml), dried (Na2SO4), and the solvent removed under reduced pressure. The residue was chromatographed on silica gel, eluting with 50% methanol in dichloromethane, to afford 12.90 g (66.5%) of a yellow solid. A 1.60 g sample was recrystallized from dichloromethane/ether yielding 0.480 g of light yellow crystals: m.p. 154° C. dec.
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([OH:23])[CH:10]([NH2:22])[CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)=[CH:5][CH:4]=1.[C:24](Cl)(=[O:33])[C:25]1[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=1.C(=O)([O-])O.[Na+]>C(OCC)(=O)C.O>[F:2][C:3]1[CH:4]=[CH:5][C:6]([CH:9]([OH:23])[CH:10]([NH:22][C:24](=[O:33])[C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=2)[CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)=[CH:7][CH:8]=1
Reactant: NC(Cc1ccc(C(F)(F)F)cc1)C(O)c1ccc(F)cc1
Reactant: COc1ccc(C(=O)Cl)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: COc1ccc(C(=O)NC(Cc2ccc(C(F)(F)F)cc2)C(O)c2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.5 %

Procedure:
To a solution of (1RS,2SR)-1-(4-fluorophenyl)-1-hydroxy-3-(4-(trifluoromethyl)phenyl)-2-propylamine hydrochloride (200 mg, 0.57 mmol) in ethyl acetate (5 ml) were added 4-anisoyl chloride (146 mg, 0.86 mmol) and saturated aqueous sodium hydrogen carbonate (5 ml) and the mixture was stirred overnight at room temperature. The reaction solution was diluted with water (50 ml), and extracted with ethyl acetate (50 ml×2). The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1) and recrystallized from ethyl acetate-hexane to give the title compound (185 mg, 72%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][CH2:11][NH2:12].[CH:13]1([C:20]2[CH:29]=[CH:28][C:23]3[NH:24][C:25](=[O:27])[O:26][C:22]=3[CH:21]=2)[CH2:18][CH2:17][C:16](=O)[CH2:15][CH2:14]1>>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][CH2:11][NH:12][C@H:16]1[CH2:17][CH2:18][C@H:13]([C:20]2[CH:29]=[CH:28][C:23]3[NH:24][C:25](=[O:27])[O:26][C:22]=3[CH:21]=2)[CH2:14][CH2:15]1
Reactant: O=C1CCC(c2ccc3[nH]c(=O)oc3c2)CC1
Reactant: NCCCc1ccc(F)cc1Cl
Product: O=c1[nH]c2ccc([C@H]3CC[C@H](NCCCc4ccc(F)cc4Cl)CC3)cc2o1

Procedure:
Condensation of 3-(2-Chloro-4-fluorophenyl)-1-propylamine (1.5 g, 6.5 mmol) and ketone 5 (1.5 g, 6.5 mmol), following the procedure described in Example 1, gave 6-{trans-4-[3-(2-chloro-4-fluorophenyl)-propylamino]cyclohexyl}-3H-benzoxazol-2-one (535 mg, 21%), as a white solid: 1H NMR (500 MHz, DMSO-d6): δ 7.41-7.35 (m, 2H), 7.17-7.13 (m, 2H), 6.99-6.94 (m, 2H), 3.60-2.90 (br s, 2H), 2.72 (t, J=8 Hz, 2H), 2.59 (t, J=8 Hz, 2H), 2.49-2.40 (m, 2H), 1.95 (br d, J=12 Hz, 2H), 1.77 (br d, J=12 Hz, 2H), 1.69-1.66 (m, 2H), 1.44 (dddd, J=13, 13, 13, 3 Hz, 2H), 1.13 (dddd, J=13, 13, 13, 3 Hz, 2H).
Reaction SMILES: [O-:1][Mn](=O)(=O)=O.[K+].[F:7][C:8]1[C:9]([CH:18]=[O:19])=[CH:10][C:11]2[O:16][CH2:15][CH2:14][O:13][C:12]=2[CH:17]=1>O>[F:7][C:8]1[C:9]([C:18]([OH:1])=[O:19])=[CH:10][C:11]2[O:16][CH2:15][CH2:14][O:13][C:12]=2[CH:17]=1
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: O=Cc1cc2c(cc1F)OCCO2
Agent: [K+]
Solvent: O
Product: O=C(O)c1cc2c(cc1F)OCCO2
Temperature: 100 °C
Reaction time: 24 h
Yield: 55.1 %

Procedure:
To a solution of KMnO4 (0.35 g, 2.2 mmol) in H2O (11 mL) at 80° C. was added 7-fluoro-2,3-dihydro-benzo[1,4]dioxine-6-carbaldehyde (0.20 g, 1.1 mmol). The resulting suspension was stirred at 100° C. for 24 h. The reaction mixture was filtered and the solids were washed with H2O (30 mL). The filtrate was acidified with concentrated HCl, which led to the formation of a white precipitate, which was collected, washed with H2O and dried in vacuo to provide 0.12 g (57%) of the title compound as a white solid. MS (ESI): exact mass calculated for C9H7FO4, 198.03; m/z not found. 1H NMR (400 MHz, DMSO-d6): 12.95 (s, 1H), 7.29 (d, J=7.2, 1H), 6.87 (d, J=11.6, 1H), 4.34-4.31 (m, 2H), 4.27-4.24 (m, 2H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[N:11]([CH2:18][CH2:19][CH2:20][N:21]3[CH2:26][CH2:25][N:24](C(OC(C)(C)C)=O)[CH2:23][CH2:22]3)[S:10]2(=[O:35])=[O:34])[CH:5]=[CH:6][C:7]=1[F:8].Cl>ClCCl.O1CCOCC1>[F:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[N:11]([CH2:18][CH2:19][CH2:20][N:21]3[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)[S:10]2(=[O:34])=[O:35])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CC(C)(C)OC(=O)N1CCN(CCCN2c3ccccc3N(c3ccc(F)c(F)c3)S2(=O)=O)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: O=S1(=O)N(CCCN2CCNCC2)c2ccccc2N1c1ccc(F)c(F)c1
Yield: 89.8 %

Procedure:
A solution of tert-butyl 4-{3-[3-(3,4-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]propyl}piperazine-1-carboxylate (0.16 g, 0.3 mmol) in dichloromethane (10 mL) was treated with hydrogen chloride (6.0 mL of a 4 M solution in dioxane), resulting in a white precipitate that was evaporated and dried under vacuum to provided 1-(3,4-difluorophenyl)-3-(3-piperazin-1-ylpropyl)-1,3-dihydro-2,1,3-benzothiadiazole2,2-dioxide (0.11 g, 81%) as a white solid:
Reaction SMILES: [O:1]=[C:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[S:4][N:3]1[C:11]1[CH:16]=[CH:15][C:14]([S:17]([NH2:20])(=[O:19])=[O:18])=[CH:13][CH:12]=1.[C:21]([OH:30])(=[O:29])[C:22]1[C:23](=[CH:25][CH:26]=[CH:27][CH:28]=1)[SH:24]>CO.O1CCCC1>[S:17]([C:14]1[CH:15]=[CH:16][C:11]([NH:3][C:2]([C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[S:4][S:24][C:23]2[CH:25]=[CH:26][CH:27]=[CH:28][C:22]=2[C:21]([OH:30])=[O:29])=[O:1])=[CH:12][CH:13]=1)(=[O:19])(=[O:18])[NH2:20]
Reactant: NS(=O)(=O)c1ccc(-n2sc3ccccc3c2=O)cc1
Reactant: O=C(O)c1ccccc1S
Solvent: C1CCOC1
Solvent: CO
Product: NS(=O)(=O)c1ccc(NC(=O)c2ccccc2SSc2ccccc2C(=O)O)cc1
Yield: 95.5 %

Procedure:
This compound was prepared according to the method of Example 132 using a suspension of 0.46 g (1.5 mmol) of 4-(3-oxo-3H-benzo[d]isothiazol-2-yl)benzene sulfonamide in a mixture of 15 mL of methanol and 15 mL of tetrahydrofuran, and 0.23 g (1.5 mmol) of thiosalicylic acid. The product was washed with ether and dried in vacuo to give 0.66 g of the title compound, mp 276°-278° C.
Reaction SMILES: [CH:1]1([CH:7]([CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)[C:8]([OH:10])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:17][C@H:18]1[CH2:22][CH2:21][N:20]([CH2:23][CH2:24][C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)[CH2:19]1>>[F:31][C:28]1[CH:29]=[CH:30][C:25]([CH2:24][CH2:23][N:20]2[CH2:21][CH2:22][C@H:18]([NH:17][C:8](=[O:10])[CH:7]([CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]3)[CH:11]3[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]3)[CH2:19]2)=[CH:26][CH:27]=1
Reactant: O=C(O)C(C1CCCCC1)C1CCCCC1
Reactant: N[C@H]1CCN(CCc2ccc(F)cc2)C1
Product: O=C(N[C@H]1CCN(CCc2ccc(F)cc2)C1)C(C1CCCCC1)C1CCCCC1
Yield: 26.5 %

Procedure:
Dicyclohexylacetic acid (0.45 g) and (S)-3-amino-1-(2-(4-fluorophenyl)ethyl)pyrrolidine (0.42 g) were reacted under the same conditions as in Example 23 to give (S)-N-(1-(2-(4-fluorophenyl)ethyl)pyrrolidin-3-yl)dicyclohexylacetamide (0.22 g), melting point 122-124° C.