Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][CH:3]([CH2:16][C:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[NH:19][CH:18]=1)[C:4]([O:6][CH2:7][C:8]1[CH:13]=[C:12]([CH3:14])[CH:11]=[C:10]([CH3:15])[CH:9]=1)=[O:5].C[Si]([N:30]=[C:31]=[O:32])(C)C>>[NH:2]([CH:3]([CH2:16][C:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[NH:19][CH:18]=1)[C:4]([O:6][CH2:7][C:8]1[CH:9]=[C:10]([CH3:15])[CH:11]=[C:12]([CH3:14])[CH:13]=1)=[O:5])[C:31]([NH2:30])=[O:32]
Reactant: Cc1cc(C)cc(COC(=O)C(N)Cc2c[nH]c3ccccc23)c1
Reactant: C[Si](C)(C)N=C=O
Agent: Cl
Product: Cc1cc(C)cc(COC(=O)C(Cc2c[nH]c3ccccc23)NC(N)=O)c1

Procedure:
Following the method of Example 16, 3,5-dimethylbenzyl 2-amino-3-(3-indolyl)propionate hydrochloride and trimethylsilyl isocyanate gave the title compound after recrystallisation from ethyl acetate/petroleum ether, m.p. 154°-156° C. (dec.). 1H NMR (360 MHz, CDCl3) δ7.99 (1H, s), 7.52 (1H, d, J=8 Hz), 7.30 (1H, d, J=8 Hz), 7.16 (1H, t. J=8 Hz), 7.08 (1H, t, J=8 Hz), 6.97 (1H, s), 6.88 (2H, s), 6.77 (1H, s), 5.21 (1H, d, J=8 Hz), 5.01 (2H, s), 4.85 (1H, m), 4.34 (2H, s), 3.28 (2H, J=5 Hz), 2.30 (6H, s).
Reaction SMILES: C([Li])CCC.CC1(C)CCCC(C)(C)N1.[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=1.CN(C)[CH:26]=[O:27]>CCCCCC.O1CCCC1>[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([F:23])=[C:19]([CH:18]=1)[CH:26]=[O:27]
Reactant: Fc1ccc(Cl)cc1
Reactant: CN(C)C=O
Agent: CC1(C)CCCC(C)(C)N1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: O=Cc1cc(Cl)ccc1F
Temperature: 0 °C
Reaction time: 2 h
Yield: 64.6 %

Procedure:
To a solution of 1.6M butyllithium in hexane (32 ml) was added anhydrous tetrahydrofuran (100 ml), and then added dropwise 2,2,6,6-tetramethylpiperidine (8.4 ml) at −70° C. or less. To the mixture was added dropwise a solution of 1-chloro-4-fluorobenzene (6.5 g) in anhydrous tetrahydrofuran (20 ml), and the mixture was stirred at −70° C. or less for 2 hours. To the mixture was added dropwise a solution of dimethylformamide (6.5 g) in tetrahydrofuran (15 ml), and the mixture was allowed to stand to warm up to 0° C. The reaction solution was poured into ice-water and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried with magnesium sulfate. Under reduced pressure, the solvent was evaporated to give oil of 5-chloro-2-fluorobenzaldehyde (5.1 g).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][C:15](OC)=O)=[CH:10][CH:9]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].[O:25]1CCCC1>>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14]([OH:25])[CH3:15])=[CH:10][CH:9]=1
Reactant: COC(=O)Cc1ccc(OC2CCCCO2)cc1
Reactant: C1CCOC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: CC(O)c1ccc(OC2CCCCO2)cc1

Procedure:
A solution of 57 g. of methyl 4-(tetrahydropyran-2-yloxy)phenylacetate, in 2 l. of anhydrous tetrahydrofuran is added dropwise, over a 30 minute period to a stirred suspension of 20 g. of lithium aluminum hydride in 1 l. of anhydrous tetrahydrofuran, under nitrogen atmosphere. The mixture is refluxed for 90 minutes, cooled and cautiously treated with 20 ml. of ethyl acetate, to destroy the excess reagent. Solid sodium sulfate is added, the inorganic material filtered off and thoroughly washed with hot ethyl acetate. Upon evaporation of the combined organic filtrates there is obtained 4-(tetrahydropyran-2-yloxy)phenylethanol.
Reaction SMILES: O1[C:5]2([CH2:10][CH2:9][N:8]([C:11]3[N:16]=[C:15]([C:17]([NH2:19])=[O:18])[CH:14]=[CH:13][N:12]=3)[CH2:7][CH2:6]2)[O:4]CC1.Cl>C(O)(=O)C>[O:4]=[C:5]1[CH2:10][CH2:9][N:8]([C:11]2[N:16]=[C:15]([C:17]([NH2:19])=[O:18])[CH:14]=[CH:13][N:12]=2)[CH2:7][CH2:6]1
Reactant: NC(=O)c1ccnc(N2CCC3(CC2)OCCO3)n1
Agent: Cl
Solvent: CC(=O)O
Product: NC(=O)c1ccnc(N2CCC(=O)CC2)n1
Yield: 87.9 %

Procedure:
A mixture of 4.1 g (0.0155 mol) of 2-(1,4-dioxa-8-azaspiro[4.5]decan-8-yl]pyrimidine-4-carboxamide, 41 ml of acetic acid and 4.1 ml of concentrated hydrochloric acid is heated at reflux temperature for 30 minutes. The mixture is concentrated under reduced pressure, the residue is then taken up in a mixture of dichloromethane and water, is alkalified with aqueous ammonia solution, extracted with dichloromethane, the organic phase is dried over magnesium sulphate, filtered and the solvent evaporated under reduced pressure. 3 g of compound are obtained.
Reaction SMILES: [CH:1]1([C:4]2[N:5]=[CH:6][N:7]([C:9]3[CH:10]=[CH:11][C:12]([O:21][CH3:22])=[C:13]([CH:20]=3)[C:14]([O:16]C(C)C)=[O:15])[CH:8]=2)[CH2:3][CH2:2]1>Cl>[CH:1]1([C:4]2[N:5]=[CH:6][N:7]([C:9]3[CH:10]=[CH:11][C:12]([O:21][CH3:22])=[C:13]([CH:20]=3)[C:14]([OH:16])=[O:15])[CH:8]=2)[CH2:2][CH2:3]1
Reactant: COc1ccc(-n2cnc(C3CC3)c2)cc1C(=O)OC(C)C
Agent: Cl
Product: COc1ccc(-n2cnc(C3CC3)c2)cc1C(=O)O
Yield: 100 %

Procedure:
A solution of isopropyl 5-(4-cyclopropyl-1H-imidazol-1-yl)-2-methoxybenzoate (0.720 g, 2.4 mmol) in 2N hydrochloric acid (10 ml) was heated to 100° C. for 10 hours. The solvent was removed under reduced pressure to give 5-(4-cyclopropyl-1H-imidazol-1-yl)-2-methoxybenzoic acid (HCl salt) as a brown powder. (0.715 g, 2.4 mmol). 100% yield. 259 (M+1).
Reaction SMILES: [I:1][C:2]1[C:3]([O:23][CH3:24])=[CH:4][C:5]([CH:20]([CH3:22])[CH3:21])=[C:6]([CH:19]=1)[O:7][C:8](=[CH:11]NC1C=CC=CC=1)[C:9]#[N:10].C(=O)(O)O.[NH2:29][C:30]([NH2:32])=[NH:31].CN(C=O)C.C(OCC)(=O)C>O>[I:1][C:2]1[C:3]([O:23][CH3:24])=[CH:4][C:5]([CH:20]([CH3:22])[CH3:21])=[C:6]([CH:19]=1)[O:7][C:8]1[C:9]([NH2:10])=[N:31][C:30]([NH2:32])=[N:29][CH:11]=1
Reactant: N=C(N)N
Reactant: COc1cc(C(C)C)c(OC(C#N)=CNc2ccccc2)cc1I
Agent: O=C(O)O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: COc1cc(C(C)C)c(Oc2cnc(N)nc2N)cc1I
Temperature: 60 °C
Yield: 99.1 %

Procedure:
A solution of 2-(5-iodo-2-isopropyl-4-methoxy-phenoxy)-3-phenylamino-acrylonitrile (280 g, 0.64 mol), guanidine carbonate (110 g, 0.61 mol), and 560 ml of DMF was heated to 120° C. for 18 hours. After cooling the mixture to 60° C., 140 ml of ethyl acetate was added. Water (1.12 L) was then added to the mixture at a rate to maintain an internal temperature of 50° C. The resulting slurry was cooled to 20° C. and aged. Precipitated solids were collected by filtration, washed with water (300 ml) followed by isopropanol (500 ml), and dried in a vacuum oven (50° C., 24 inches Hg) to give 242 g of 5-(5-iodo-2-isopropyl-4-methoxy-phenoxy)-pyrimidine-2,4-diamine, 94% yield: m.p. 204.4-205.9 degrees C.; 1HNMR (DMSO) δ=1.2 (d, 6H), 3.3 (m, 1H), 3.8 (s, 3H), 5.85 (s, 2H), 6.4 (s, 2H), 6.9 (d, 2H), 7.35 (s, 1H)
Reaction SMILES: C([O:3][C:4](=[O:18])[CH2:5][CH2:6][N:7]1[CH2:13][C:12]2([CH3:15])[CH2:14][CH:8]1[CH2:9][C:10]([CH3:17])([CH3:16])[CH2:11]2)C.[ClH:19]>>[ClH:19].[CH3:15][C:12]12[CH2:14][CH:8]([N:7]([CH2:6][CH2:5][C:4]([OH:18])=[O:3])[CH2:13]1)[CH2:9][C:10]([CH3:17])([CH3:16])[CH2:11]2
Reactant: CCOC(=O)CCN1CC2(C)CC1CC(C)(C)C2
Agent: Cl
Product: CC1(C)CC2CC(C)(CN2CCC(=O)O)C1

Procedure:
16.8 g of 3-(1,3,3-trimethyl-6-aza-bicyclo[3,2,1]oct-6-yl)-propionic acid ethyl ester (0.066 mol) are heated under reflux with 300 ml of 4N hydrochloric acid for 24 hours. The mixture is then completely concentrated by evaporation under reduced pressure and the crystalline residue is triturated with acetone. After filtering the crystals with suction, washing and drying, 3-(1,3,3-trimethyl-6-aza-bicyclo[3,2,1]oct-6-yl)-propionic acid hydrochloride, m.p. 183°-185° C. (decomposition) is obtained.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH:10]([O:13][CH3:14])[O:11][CH3:12])[CH:4]=1.[C-:15]#[N:16].[Na+]>CO>[CH3:12][O:11][CH:10]([O:13][CH3:14])[C:5]1[CH:4]=[C:3]([CH2:2][C:15]#[N:16])[CH:8]=[C:7]([CH3:9])[CH:6]=1
Reactant: [C-]#N
Reactant: COC(OC)c1cc(C)cc(CBr)c1
Agent: [Na+]
Solvent: CO
Product: COC(OC)c1cc(C)cc(CC#N)c1
Temperature: 25 °C
Yield: 52.1 %

Procedure:
A mixture of 1-bromomethyl-3-dimethoxymethyl-5-methyl-benzene (6 g, 23 mmol) and sodium cyanide (1.7 g, 34 mmol) in methanol (30 ml) and distilled water (15 ml) was refluxed for 1.5 hr. After cooling to room temperature, the mixture was evaporated in vacuo and the residue was dissolved in ether, washed with water, dried with anhydrous magnesium sulfate, filtered, and evaporated in vacuo. The residue was then purified by silica gel column chromatography (eluent, ether:hexanes (1:3)) to afford 2.46 g (52%) of a colorless oil 1H NMR (300 MHz, CDCl3) δ 2.37 (3H, s), 3.33 (6H, s), 3.71 (2H, s), 5.33 (1H, s), 7.12 (1H, s), 7.20 (1H, s), 7.22 (1H, s).
Reaction SMILES: [C:1]([O:4][CH:5]([CH2:41][O:42][C:43](=[O:45])[CH3:44])[CH2:6][NH:7][C:8]([C:10]1[C:15]([I:16])=[C:14]([NH:17][C:18]([CH:20]2[CH2:24][CH2:23][CH2:22][O:21]2)=[O:19])[C:13]([I:25])=[C:12]([C:26]([NH:28][CH2:29][CH:30]([O:36][C:37](=[O:39])[CH3:38])[CH2:31][O:32][C:33](=[O:35])[CH3:34])=[O:27])[C:11]=1[I:40])=[O:9])(=[O:3])[CH3:2].C(N(CC)CC)C>C(Cl)Cl>[C:1]([O:4][CH:5]([CH2:41][O:42][C:43](=[O:45])[CH3:44])[CH2:6][NH:7][C:8]([C:10]1[C:15]([I:16])=[C:14]([N:17]2[CH2:22][CH2:23][CH2:24][CH:20]([OH:21])[C:18]2=[O:19])[C:13]([I:25])=[C:12]([C:26]([NH:28][CH2:29][CH:30]([O:36][C:37](=[O:39])[CH3:38])[CH2:31][O:32][C:33](=[O:35])[CH3:34])=[O:27])[C:11]=1[I:40])=[O:9])(=[O:3])[CH3:2]
Reactant: CC(=O)OCC(CNC(=O)c1c(I)c(NC(=O)C2CCCO2)c(I)c(C(=O)NCC(COC(C)=O)OC(C)=O)c1I)OC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)OCC(CNC(=O)c1c(I)c(C(=O)NCC(COC(C)=O)OC(C)=O)c(I)c(N2CCCC(O)C2=O)c1I)OC(C)=O

Procedure:
To a stirred solution of N,N'-bis[2,3-bis(acetyloxy)propyl]-2,4,6-triiodo-5-[[(tetrahydro-2-furanyl)carbonyl]amino]-1,3-benzenedicarboxamide (0.25 g, 0.26 mmol) (the title compound of Example 19) in dry CH2Cl2 (5 mL) was added triethyl amine (0.01 mL). The solution was cooled to 0°-5°, and to this was added dropwise a solution of dimethylboron bromide in CH2Cl2 (0.12 g, 0.5 mL/2 mMol solution in CH2CL2). After stirring the mixture at 0°-5° for 6-8 hours, the mixture was added to a vigorously stirred solution of aqueous saturated sodium bicarbonate (5 mL). After stirring for 5 minutes, ethyl acetate (50 mL) and water (10 mL) were added. The organic layer was separated, washed with water, dried over anhydrous sodium sulfate, and concentrated in vacuo to yield the omega-bromo-alpha-hydroxypentanoyl anilide as an off-white fluffy solid (260 mg).
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:20])=[C:11]([N:14]4[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]4)[CH:12]=3)[C:7](=[O:21])[C:6]([C:22]([OH:24])=[O:23])=[CH:5]2)[CH2:3][CH2:2]1.[N:25]([CH2:28][CH2:29][CH2:30][C:31]([O:33][CH3:34])=[O:32])=[C:26]=[O:27].Cl>[OH-].[Na+].O.O1CCOCC1>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:20])=[C:11]([N:14]4[CH2:19][CH2:18][N:17]([C:26](=[O:27])[NH:25][CH2:28][CH2:29][CH2:30][C:31]([O:33][CH3:34])=[O:32])[CH2:16][CH2:15]4)[CH:12]=3)[C:7](=[O:21])[C:6]([C:22]([OH:24])=[O:23])=[CH:5]2)[CH2:2][CH2:3]1
Reactant: O=C(O)c1cn(C2CC2)c2cc(N3CCNCC3)c(F)cc2c1=O
Reactant: COC(=O)CCCN=C=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)CCCNC(=O)N1CCN(c2cc3c(cc2F)c(=O)c(C(=O)O)cn3C2CC2)CC1
Reaction time: 2 h
Yield: 63.2 %

Procedure:
6.6 g (0.02 mol) of 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-(piperazin-1-yl)-quinoline-3-carboxylic acid are dissolved in a solution of 0.4 g of sodium hydroxide in 40 ml of water, and a solution of 3.2 g (0.022 mol) of methyl 4-isocyanato-butyrate in 12 ml of dioxane is added, while cooling with ice. Thereafter, stirring is continued for 2 hours at room temperature, the pH is adjusted to 5 with 2N hydrochloric acid and the precipitate is filtered off under suction and recrystallised from methanol. 6 g (63% of theory) of 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-{4-[(3-methoxycarbonylpropyl)-carbamoyl]-piperazin-1-yl}-quinoline-3-carboxylic acid of melting point 198°-200° C. are obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:51]=[C:50]([O:52][CH3:53])[CH:49]=[C:48]([O:54][CH3:55])[C:4]=1/[CH:5]=[CH:6]/[CH:7]([S:19]([CH:22](/[CH:34]=[CH:35]/[C:36]1[C:41]([O:42][CH3:43])=[CH:40][C:39]([O:44][CH3:45])=[CH:38][C:37]=1[O:46][CH3:47])[C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25]([N+:31]([O-])=O)[CH:24]=1)(=[O:21])=[O:20])[C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([N+:16]([O-])=O)[CH:9]=1.S(S([O-])=O)([O-])=O.[Na+].[Na+].O>CC(C)=O.O>[CH3:55][O:54][C:48]1[CH:49]=[C:50]([O:52][CH3:53])[CH:51]=[C:3]([O:2][CH3:1])[C:4]=1/[CH:5]=[CH:6]/[CH:7]([S:19]([CH:22](/[CH:34]=[CH:35]/[C:36]1[C:37]([O:46][CH3:47])=[CH:38][C:39]([O:44][CH3:45])=[CH:40][C:41]=1[O:42][CH3:43])[C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25]([NH2:31])[CH:24]=1)(=[O:21])=[O:20])[C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([NH2:16])[CH:9]=1
Reactant: COc1cc(OC)c(/C=C/C(c2ccc(OC)c([N+](=O)[O-])c2)S(=O)(=O)C(/C=C/c2c(OC)cc(OC)cc2OC)c2ccc(OC)c([N+](=O)[O-])c2)c(OC)c1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: COc1cc(OC)c(/C=C/C(c2ccc(OC)c(N)c2)S(=O)(=O)C(/C=C/c2c(OC)cc(OC)cc2OC)c2ccc(OC)c(N)c2)c(OC)c1
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
A solution of (E)-2,4,6-trimethoxystyryl-4-methoxy-3-nitrobenzylsulfone (1.3 mmol) in acetone-water (10:5) was heated to 50° C. After 30 min, sodium hydrosulfite (Na2S2O4) (26.3 mmol) was added slowly, and the mixture was heated at reflux (50° C., 1 h.), cooled to room temperature and water was added. The product was rinsed with NaHCO3, and then isolated by extraction with ethyl acetate. The organic layer was dried over anhydrous Na2SO4. The solvent was removed under reduced pressure and the crude product was recrystallized from 2-propanol, m.p. 148-150° C.
Reaction SMILES: C([O:4][C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:6]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)C=C.[C:24]1(C)[CH:29]=C(C)C=C(C)[CH:25]=1>>[CH2:29]([C:10]1[CH:9]=[C:8]([F:11])[CH:7]=[C:6]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:5]=1[OH:4])[CH:24]=[CH2:25]
Reactant: Cc1cc(C)cc(C)c1
Reactant: C=CCOc1ccc(F)cc1-c1ccccc1-c1ccccc1
Product: C=CCc1cc(F)cc(-c2ccccc2-c2ccccc2)c1O
Yield: 96 %

Procedure:
A solution of 2-allyloxy-5-fluoro-2′-phenylbiphenyl (6.4 g, 21.0 mmol) in mesitylene (200 mL) was refluxed for 72 h. The solvent was removed under reduced pressure. Purification by ISCO using a solvent gradient of 0 to 20% ethyl acetate in hexanes afforded 6.2 g (96%) of 3-allyl-5-fluoro-2′-phenylbiphenyl-2-ol as a pale yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:9](OC)=[O:10])[CH:5]=[N:6][C:7]=1[CH3:8].CC(C[AlH]CC(C)C)C.C(C(C(C([O-])=O)O)O)([O-])=O>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([CH2:9][OH:10])[CH:5]=[N:6][C:7]=1[CH3:8]
Reactant: COC(=O)c1cnc(C)c(Br)c1
Agent: CC(C)C[AlH]CC(C)C
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Solvent: ClCCl
Product: Cc1ncc(CO)cc1Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 84 %

Procedure:
To a solution of methyl 5-bromo-6-methyl-3-pyridinecarboxylate (76 mg, 0.330 mmol) in DCM (1.5 ml), DIBAL-H (1.5 M solution in toluene, 0.661 ml, 0.991 mmol) was added dropwise at −78° C. under N2. The reaction mixture was allowed to warm to rt and stirred overnight. To this solution was added saturated, aqueous NaK-tartrate solution followed by DCM. The organic phase was separated, dried and concentrated to afford 56 mg of (5-bromo-6-methyl-3-pyridinyl)methanol (56 mg, 84%) pure enough to be used in the next step.
Reaction SMILES: [CH:1]1[C:14]2[C:5](=[C:6]([CH:17]=O)[C:7]3[C:12]([C:13]=2[CH:15]=O)=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH:4]=[CH:3][CH:2]=1.[NH2:19][NH:20][C:21]([NH2:23])=[S:22].C(O)C>C(O)(=O)C>[N:19](=[CH:15][C:13]1[C:14]2[C:5]([C:6]([CH:17]=[N:19][NH:20][C:21]([NH2:23])=[S:22])=[C:7]3[C:12]=1[CH:11]=[CH:10][CH:9]=[CH:8]3)=[CH:4][CH:3]=[CH:2][CH:1]=2)[NH:20][C:21]([NH2:23])=[S:22]
Reactant: O=Cc1c2ccccc2c(C=O)c2ccccc12
Reactant: NNC(N)=S
Solvent: CC(=O)O
Solvent: CCO
Product: NC(=S)NN=Cc1c2ccccc2c(C=NNC(N)=S)c2ccccc12
Reaction time: 8 h

Procedure:
A mixture of 2.34 g. of 9,10-anthracenedicarboxaldehyde and 3.65 g. of thiosemicarbazide in 250 ml. of absolute ethanol containing 2.0 ml. of glacial acetic acid is heated on a steam bath for 24 hours, allowed to cool and then let stand overnight. The solid is collected, washed with absolute ethanol, dried and recrystallized from aqueous dimethylformamide giving the desired product as orange crystals, m.p. 275°-277° C.
Reaction SMILES: [CH:1]1([N:6]2[CH2:11][CH2:10][N:9]([C:12]([C:14]3[CH:15]=[C:16]4[C:20](=[CH:21][CH:22]=3)[NH:19][C:18]([C:23]([N:25]3[CH2:30][CH2:29][C:28]([F:32])([F:31])[CH2:27][CH2:26]3)=[O:24])=[CH:17]4)=[O:13])[CH2:8][CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[F:33][C:34]([F:45])([F:44])[C:35]1[CH:40]=[CH:39][C:38](B(O)O)=[CH:37][CH:36]=1.N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH:1]1([N:6]2[CH2:7][CH2:8][N:9]([C:12]([C:14]3[CH:15]=[C:16]4[C:20](=[CH:21][CH:22]=3)[N:19]([C:38]3[CH:39]=[CH:40][C:35]([C:34]([F:45])([F:44])[F:33])=[CH:36][CH:37]=3)[C:18]([C:23]([N:25]3[CH2:26][CH2:27][C:28]([F:31])([F:32])[CH2:29][CH2:30]3)=[O:24])=[CH:17]4)=[O:13])[CH2:10][CH2:11]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(c1ccc2[nH]c(C(=O)N3CCC(F)(F)CC3)cc2c1)N1CCN(C2CCCC2)CC1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(c1ccc2c(c1)cc(C(=O)N1CCC(F)(F)CC1)n2-c1ccc(C(F)(F)F)cc1)N1CCN(C2CCCC2)CC1
Yield: 51 %

Procedure:
The title compound was synthesized in analogy to example 66, from [5-(4-cyclopentyl-piperazine-1-carbonyl)-1H-indol-2-yl]-(4,4-difluoro-piperidin-1-yl)-methanone (example 8), 4-(trifluoromethyl)phenylboronic acid, copper(II) acetate and pyridine in dichloromethane, to give the desired product as a white foam (51%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:18])=[C:6]([C@@:8]2([CH3:17])[NH:13][C:12](=O)[CH2:11][S:10](=[O:16])(=[O:15])[CH2:9]2)[CH:7]=1.F[C:20](F)(F)C(O)=O.FC(F)(F)S(O)(=O)=O.[C:34]([O-:37])([O-])=O.[Na+].[Na+]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:18])=[C:6]([C@@:8]2([CH3:17])[NH:13][C:34](=[O:37])[C:11]([CH3:20])([CH3:12])[S:10](=[O:16])(=[O:15])[CH2:9]2)[CH:7]=1
Reactant: O=C(O)C(F)(F)F
Reactant: C[C@@]1(c2cc(Br)ccc2F)CS(=O)(=O)CC(=O)N1
Reactant: O=C([O-])[O-]
Agent: O=S(=O)(O)C(F)(F)F
Agent: [Na+]
Product: CC1(C)C(=O)N[C@](C)(c2cc(Br)ccc2F)CS1(=O)=O
Temperature: 23 °C
Reaction time: 2 h
Yield: 94.2 %

Procedure:
A mixture of (R)-5-(5-bromo-2-fluoro-phenyl)-5-methyl-1,1-dioxo-1λ6-thio morpholin-3-one (2.1 g, 4.08 mmol, Eq: 1.00) and trifluoroacetic acid (46.5 g, 31.5 ml, 408 mmol, Eq: 100) was stirred at 23° C. After 1 hour trifluoromethanesulfonic acid (1.23 g, 725 μl, 8.16 mmol, Eq: 2.0) was added and stirring continued for 2 hours. Poured into 1 M Na2CO3-sol. and extracted twice with ethyl acetate. The combined organic layers were dried over Na2SO4, filtered and evaporated. The residue was chromatographed on 70 g silica gel with heptane/ethyl acetate 1:1 to give (R)-5-(5-bromo-2-fluoro-phenyl)-2,2,5-trimethyl-1,1-dioxo-1λ6-thio morpholin-3-one (1.4 g, 3.84 mmol, 94.2% yield) as an off-white solid. MS (ISP): m/z=364.0 [M+H]+ and 366.3 [M+2+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[SH:8].Br[CH:10]1[CH2:12][CH2:11]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C.C1(C(C2C=CC=CC=2)(C2C=CC=CC=2)S)C=CC=CC=1.C(OCC)(=O)C>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][CH:10]1[CH2:12][CH2:11]1
Reactant: BrC1CC1
Reactant: Sc1ccccc1Br
Agent: O=C([O-])[O-]
Agent: SC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: Brc1ccccc1SC1CC1
Temperature: 80 °C
Reaction time: 24 h
Yield: 81.4 %

Procedure:
To a solution of 2-bromobenzenethiol (50 g) in DMF (500 mL) were added bromocyclopropane (41.6 g), potassium carbonate (54.8 g), and triphenylmethanethiol (1.46 g), followed by stirring at an internal temperature of 80° C. for 24 hours. After cooling to room temperature, water and ethyl acetate were added thereto, and the organic layer was then separated. The organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 1-bromo-2-(cyclopropylsulfanyl)benzene (49.3 g).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4]([N+:9]([O-])=O)[CH:3]=1.C1C(=O)N([Br:19])C(=O)C1>C(O)(=O)C.O.[Zn]>[Br:19][C:7]1[CH:6]=[C:5]([NH2:8])[C:4]([NH2:9])=[CH:3][C:2]=1[CH3:1]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(N)c([N+](=O)[O-])c1
Agent: [Zn]
Solvent: O
Solvent: CC(=O)O
Product: Cc1cc(N)c(N)cc1Br
Reaction time: 2.5 h
Yield: 83.2 %

Procedure:
To the solution of 4-methyl-2-nitro-phenylamine (1 g, 1 eq.) in 15 mL of acetic acid was added NBS (1.4 g, 1.2 eq.). The reaction was allowed to stir for 2.5 hours. Reaction was then diluted with 15 mL of water and Zn dust (1.29 g, 3 eq.) was added. Reaction was stirred for 1 hour, filtered and then pH was adjusted to ˜7 with ammonia. The aqueous layer was extracted with CH2Cl2 twice, dried over Na2SO4, concentrated and adsorbed on silica. Purification by flash column chromatography (60:40 hexanes/EtOAc) afforded 1.1 g (83 %) of product as off-white solid. MS (electrospray): mass calculated for C7H9BrN2, 201.06; m/z found 202.2, [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5](O)=O.C(Cl)(=O)C(Cl)=O.C[N:19]1CCOCC1.N>C1(C)C=CC=CC=1.CN(C=O)C.C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]#[N:19]
Reactant: CN1CCOCC1
Reactant: Cc1ccc(C(=O)O)cc1Br
Agent: N
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: Cc1ccc(C#N)cc1Br
Reaction time: 3 h

Procedure:
3-Bromo-4-methyl-benzoic acid (3 g) in toluene (75 ml) was treated with oxalyl chloride (10 ml) and DMF (4 drops). The mixture was then stirred at 20 C for 3 h. and then the solvent evaporated giving a yellow solid. This in turn was dissolved in THF (30 ml) containing N-methyl-morpholine (1.5 ml). Aqueous ammonia (0.880, 40 ml) was then added and the mixture stirred for 18 h. The THF was then evaporated and the resulting amide intermediate collected by filtration as a colourless solid (2.9 g). This material was then suspended in thionyl chloride (35 ml) and was heated to 85 C for 6 h. The excess reagent was then evaporated and the residue purified on silica gel. Elution with 5-50% ethyl acetate in hexane gave the title compound as a white solid (1.4 g)