Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([CH:21]=[CH:22][C:23]=1[O:24][CH3:25])[C:12]([N:14]1[CH2:18][CH2:17][C@H:16]([OH:19])[C:15]1=[O:20])=[O:13])C1C=CC=CC=1.[H][H]>O1CCCC1.[Pd]>[OH:8][C:9]1[CH:10]=[C:11]([CH:21]=[CH:22][C:23]=1[O:24][CH3:25])[C:12]([N:14]1[CH2:18][CH2:17][C@H:16]([OH:19])[C:15]1=[O:20])=[O:13]
Reactant: [H][H]
Reactant: COc1ccc(C(=O)N2CC[C@H](O)C2=O)cc1OCc1ccccc1
Agent: [Pd]
Solvent: C1CCOC1
Product: COc1ccc(C(=O)N2CC[C@H](O)C2=O)cc1O

Procedure:
2.40 g of (S)-1-(3-benzyloxy-4-methoxybenzoyl)-3-hydroxy-2-pyrrolidinone are hydrogenated in 100 ml of tetrahydrofuran over 2.00 g of 5% palladium/carbon with hydrogen at atmospheric pressure. After removal of the catalyst by filtration, concentration of the filtrate and crystallization from ethyl acetate/diethyl ether, there is obtained (S)-1-(3-hydroxy-4-methoxybenzoyl)-3-hydroxy-2-pyrrolidinone of melting point 131°-132°; [α]D20 =-180°; [α]54620 =-223°; [α]43620 =-464° (chloroform, c=1.0).
Reaction SMILES: [N-:1]=[C:2]=[S:3].[Na+].N1C=CC=CC=1.CS(O[N:16]=[C:17](Cl)[C@H:18]1[CH2:22][O:21][C:20]2([CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)[O:19]1)(=O)=O.[CH2:29]([N:31]1[C:35]([O:36][C:37]2[C:38]([NH2:50])=[N:39][CH:40]=[C:41]([S:43][C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][N:45]=3)[CH:42]=2)=[CH:34][CH:33]=[N:32]1)[CH3:30]>CCOC(C)=O.[OH-].[Na+]>[CH2:29]([N:31]1[C:35]([O:36][C:37]2[C:38]([NH:50][C:2]3[S:3][N:16]=[C:17]([C@H:18]4[CH2:22][O:21][C:20]5([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]5)[O:19]4)[N:1]=3)=[N:39][CH:40]=[C:41]([S:43][C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][N:45]=3)[CH:42]=2)=[CH:34][CH:33]=[N:32]1)[CH3:30]
Reactant: CCn1nccc1Oc1cc(Sc2ccccn2)cnc1N
Reactant: [N-]=C=S
Reactant: CS(=O)(=O)ON=C(Cl)[C@H]1COC2(CCCCC2)O1
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CCn1nccc1Oc1cc(Sc2ccccn2)cnc1Nc1nc([C@H]2COC3(CCCCC3)O2)ns1
Temperature: 50 °C
Reaction time: 65 h
Yield: 6470.6 %

Procedure:
To 75 mL of EtOAc was added sodium isothiocyanate (0.579 g, 7.15 mmol), pyridine (0.874 ml, 10.7 mmol) and (R)-N-(methylsulfonyloxy)-1,4-dioxaspiro[4.5]decane-2-carbimidoyl chloride (2.13 g, 7.15 mmol) and the reaction was heated to 50° C. for 30 minutes. The reaction mixture was added to 3-(1-ethyl-1H-pyrazol-5-yloxy)-5-(pyridin-2-ylthio)pyridin-2-amine (1.12 g, 3.57 mmol) and the reaction was stirred for 65 hours at 75° C. The reaction was cooled and diluted with 50 ml EtOAc and 75 ml 1N NaOH. The aqueous layer was extracted with EtOAc. The organic layer was dried over Na2SO4, filtered and concentrated. The residue was purified over silica gel (75% EtOAc/Hexanes) to afford (S)-N-(3-(1-ethyl-1H-pyrazol-5-yloxy)-5-(pyridin-2-ylthio)pyridin-2-yl)-3-(1,4-dioxaspiro[4.5]decane-2-yl)-1,2,4-thiadiazol-5-amine (1.24 g, 231 mmol, 64.5% yield) as a tan solid.
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:7][CH2:6][CH2:5][C@@H:4]1[NH:8][C:9](=[O:20])[C:10]1[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[CH:12][C:11]=1[O:18][CH3:19].N[C@H]1CCC[C@@H]1NC(=O)OC(C)(C)C.COC1C=CC=C(OC)C=1C([Cl:41])=O>>[ClH:41].[NH2:2][C@H:3]1[CH2:7][CH2:6][CH2:5][C@@H:4]1[NH:8][C:9](=[O:20])[C:10]1[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[CH:12][C:11]=1[O:18][CH3:19]
Reactant: COc1cccc(OC)c1C(=O)Cl
Reactant: COc1cccc(OC)c1C(=O)N[C@H]1CCC[C@H]1N
Agent: CC(C)(C)OC(=O)N[C@H]1CCC[C@@H]1N
Agent: Cl
Product: COc1cccc(OC)c1C(=O)N[C@H]1CCC[C@@H]1N

Procedure:
Prepared according to the procedure for N-[(1S,2R)-2-aminocyclopentyl]-2,6-dimethoxybenzamide hydrochloride (Intermediate 3) from tert-butyl N-[(1S,2S)-2-aminocyclopentyl]carbamate (CAS number 586961-34-4; 1.0 g, 4.99 mmol) and 2,6-dimethoxybenzoyl chloride (CAS number 1989-53-3; 1.50 g, 7.99 mmol) except that after the reaction was complete it was partitioned between DCM and a saturated solution of sodium bicarbonate, filtered through a hydrophobic frit and concentrated in vacuo. The Boc protected intermediate was purified by column chromatography (silica, 0-100% ethyl acetate/petrol) to give a white solid. After deprotection with HCl in 1,4-dioxane, azeotropic distillation from toluene afforded the title compound.
Reaction SMILES: CO[C:3](=[O:38])[C:4]1[CH:9]=[C:8]([C:10]2[CH:11]=[C:12]3[C:18]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[O:25][CH3:26])=[CH:17][N:16](S(C4C=CC(C)=CC=4)(=O)=O)[C:13]3=[N:14][CH:15]=2)[CH:7]=[CH:6][C:5]=1[OH:37].[CH3:39][N:40]([CH3:45])[CH2:41][CH2:42][NH:43][CH3:44].N=C=N.CN(C=O)C>N1C=CC=CC=1>[CH3:39][N:40]([CH3:45])[CH2:41][CH2:42][N:43]([CH3:44])[C:3](=[O:38])[C:4]1[CH:9]=[C:8]([C:10]2[CH:11]=[C:12]3[C:18]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[O:25][CH3:26])=[CH:17][NH:16][C:13]3=[N:14][CH:15]=2)[CH:7]=[CH:6][C:5]=1[OH:37]
Reactant: CNCCN(C)C
Reactant: COC(=O)c1cc(-c2cnc3c(c2)c(-c2ccccc2OC)cn3S(=O)(=O)c2ccc(C)cc2)ccc1O
Agent: N=C=N
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: COc1ccccc1-c1c[nH]c2ncc(-c3ccc(O)c(C(=O)N(C)CCN(C)C)c3)cc12
Temperature: 100 °C
Reaction time: 16 h
Yield: 12 %

Procedure:
To a solution of 2-hydroxy-5-[3-(2-methoxy-phenyl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-benzoic acid methyl ester (52 mg, 0.10 mmol) in pyridine (0.5 mL) was added an excess of N,N,N′-trimethylethylenediamine (0.5 mL). The reaction was stirred for 16 hours at 100° C. in a scintillation vial. There appeared to be ˜50% product formation and ˜50% hydrolysis of the methyl ester to the carboxylic acid. PS-carbodiimide resin (244 mg, 0.29 mmol, 1.21 mmol/g load capacity) and DMF (1 mL) were added to the reaction solution and heating was continued for 16 hours at 70° C. The resin was filtered off and rinsed well with THF and MeOH. The filtrate was concentrated down to a yellow oil and then redissolved in a 1:1 MeOH/acetone solution (4 mL total). The solution was treated with 200 uL of a 50% KOH (aq) solution and stirred at ambient temperature for 3 hours. Glacial acetic acid was added dropwise until the pH=7. The product was extracted into ethyl acetate, whereupon the organic layer was washed with H2O, dried over Na2SO4, filtered, and concentrated under vacuum. The material was dissolved in MeOH and filtered through a 0.45 μm syringe filter. The solution was purified by reverse phase chromatography using a gradient of H2O and acetonitrile (with 0.1% formic acid as a modifier). Clean fractions were lyophilized, affording the title compound as a white powder (5.2 mg, 12% yield). 1H NMR (500 MHz, d6-DMSO) δ 11.80 (d, J=2.5 Hz, 1H), 8.49 (s, 1H), 8.19 (s, 1H), 8.10 (s, 1H), 7.74 (d, J=2.5 Hz, 1H), 7.63 (dd, J=2.0, 6.0 Hz, 1H), 7.51 (d, J=8.5 Hz, 1H), 7.43 (s, 1H), 7.33 (m, 1H), 7.17 (d, J=8.5 Hz, 1H), 7.09 (t, J=6.5 Hz, 1H), 7.01 (d, J=9.0 Hz, 1H), 3.85 (s, 3H), 3.01 (br s, 3H), 2.90 (br s, 2H), 2.59 (m, 2H), 2.36 (br s, 3H), 2.00 (br s, 3H). MS: m/z 445.1 (M+H+).
Reaction SMILES: [CH2:1]([CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][C:16]#[C:17][C:18]2[CH:19]=[C:20]([NH2:25])[C:21]([NH2:24])=[CH:22][CH:23]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:26](C1NC=CN=1)(C1NC=CN=1)=[O:27]>C1COCC1.CCOCC>[CH2:1]([CH:8]1[CH2:9][CH2:10][N:11]([CH2:14][CH2:15][C:16]#[C:17][C:18]2[CH:23]=[CH:22][C:21]3[NH:24][C:26](=[O:27])[NH:25][C:20]=3[CH:19]=2)[CH2:12][CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(c1ncc[nH]1)c1ncc[nH]1
Reactant: Nc1ccc(C#CCCN2CCC(Cc3ccccc3)CC2)cc1N
Solvent: CCOCC
Solvent: C1CCOC1
Product: O=c1[nH]c2ccc(C#CCCN3CCC(Cc4ccccc4)CC3)cc2[nH]1
Temperature: 25 °C
Reaction time: 1 h
Yield: 64.8 %

Procedure:
A mixture of 4-[4-(4-benzyl-piperidin-1-yl)-but-1-ynyl]-benzene-1,2-diamine (Example 70) (333 mg, 1 mmol) and carbonyl diimidazole (243 mg, 1.5 mmol) in THF (5 mL) is stirred at room temperature for 1 hr. A precipitate forms; the mixture is diluted with ether (10 mL), filtered and the solid washed with ether to give the title compound as a white powder (233 mg): mp 221-223° C.
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:27])[F:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:29][C:30]1[CH:31]=[CH:32][C:33]([N+:38]([O-:40])=[O:39])=[C:34]([CH:37]=1)[CH:35]=O>>[CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH:24][CH2:35][C:34]3[CH:37]=[C:30]([OH:29])[CH:31]=[CH:32][C:33]=3[N+:38]([O-:40])=[O:39])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:26])[F:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=Cc1cc(O)ccc1[N+](=O)[O-]
Reactant: Nc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Product: O=[N+]([O-])c1ccc(O)cc1CNc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1

Procedure:
The title compound was prepared from {3-[3-benzyl-8-(trifluoromethyl)quinolin-4-yl]phenyl}amine and 5-hydroxy-2-nitro-benzaldehyde according to the procedure of Example 66. MS (ES) m/z 528.0.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Cl[CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:22]=[C:21]2[C:16]([CH2:17][CH2:18][C:19](=[O:23])[NH:20]2)=[CH:15][CH:14]=1.Cl.[Cl:25][C:26]1[C:31]([Cl:32])=[CH:30][CH:29]=[CH:28][C:27]=1[N:33]1[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1>O>[CH:29]1[CH:28]=[C:27]([N:33]2[CH2:38][CH2:37][N:36]([CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]3[CH:14]=[CH:15][C:16]4[CH2:17][CH2:18][C:19](=[O:23])[NH:20][C:21]=4[CH:22]=3)[CH2:35][CH2:34]2)[C:26]([Cl:25])=[C:31]([Cl:32])[CH:30]=1
Reactant: O=C1CCc2ccc(OCCCCCl)cc2N1
Reactant: Clc1cccc(N2CCNCC2)c1Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: O=C1CCc2ccc(OCCCCN3CCN(c4cccc(Cl)c4Cl)CC3)cc2N1
Temperature: 92.5 °C
Reaction time: 4 h
Yield: 92.8 %

Procedure:
In 600 ml of water was dissolved 36.0 g of potassium carbonate, to which were added 60.0 g of 7-(4-chlorobutoxy)-3,4-dihydrocarbostyril and 69.6 g of 1-(2,3-dichlorophenyl)piperazine monohydrochloride. The mixture was heated with stirring at 90 to 95° C. for about 4 hours. Then, the reaction mixture was cooled to about 40° C., and the deposited crystals were collected by filtration. The crystals thus obtained were washed with 240 ml of water and dissolved in 900 ml of ethyl acetate, and an azeotropic mixture of water/ethyl acetate (about 300 ml) was distilled out under reflux. The remaining solution was cooled to 0 to 5° C., and the deposited crystals were collected by filtration. The crystals thus obtained were washed with 120 ml of ethyl acetate and dried under a reduced pressure of 50 Torr, at 50 to 60° C. for 3 hours to obtain 98.4 g of aripiprazole (yield 92.8%, purity 99%). mp. 140° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1)[CH:6]=[C:5]2[CH:18]1[CH2:23][CH2:22][N:21]([CH2:24][CH2:25][N:26]2[CH2:30][CH2:29][NH:28][C:27]2=[O:31])[CH2:20][CH2:19]1.[CH2:32]=[O:33]>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]1[CH:12]=[CH:13][C:14]([F:17])=[CH:15][CH:16]=1)[CH:6]=[C:5]2[CH:18]1[CH2:23][CH2:22][N:21]([CH2:24][CH2:25][N:26]2[CH2:30][CH2:29][N:28]([CH2:32][OH:33])[C:27]2=[O:31])[CH2:20][CH2:19]1
Reactant: O=C1NCCN1CCN1CCC(c2cn(-c3ccc(F)cc3)c3ccc(Cl)cc23)CC1
Reactant: C=O
Solvent: C1CCOC1
Product: O=C1N(CO)CCN1CCN1CCC(c2cn(-c3ccc(F)cc3)c3ccc(Cl)cc23)CC1
Temperature: 50 °C

Procedure:
To a solution of 5-chloro-1-(4-fluorophenyl)-3-[1-[2-(2-imidazolidinon-1-yl)ethyl]-4-piperidyl]-1H-indole (4.4 g) in tetrahydrofuran (25 ml) at room temperature was added dropwise a 30% aqueous solution of formaldehyde (800 mg). The mixture was heated at 50 ° C. for 2 h. Solvents were evaporated in vacuo and excess H2O was removed by evaporation with toluene. By addition of acetone the title compound crystallized. Recrystallization from acetone afforded 3.2 g of pure 5a. Mp: 118°-119 ° C. 1H NMR: δ1.85 (2H, dq), 2.05 (2H, broad d), 2.20 (2H, t), 2.60 (2H, t), 2.85 (1H, tt), 3.10 (2H, broad d), 3.40 (2H, t), 3.50 (4H), 4.80 (2H, s), 7.0-7.7 (8H).
Reaction SMILES: S(=O)(=O)(O)O.[N:6]([O-])=O.[Na+].[S:10]([C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][S:22]([C:25]2[CH:31]=[C:30]([N+:32]([O-:34])=[O:33])[CH:29]=[CH:28][C:26]=2[NH2:27])(=[O:24])=[O:23])=[CH:16][CH:15]=1)([OH:13])(=[O:12])=[O:11].[O:35]1[CH2:40][CH2:39][N:38]([S:41]([NH:44][C:45]2[CH:54]=[CH:53][CH:52]=[C:51]3[C:46]=2[CH:47]=[CH:48][CH:49]=[C:50]3[OH:55])(=[O:43])=[O:42])[CH2:37][CH2:36]1.C([O-])(=O)C.[Na+]>O.C(O)C.C(O)(=O)C>[S:10]([C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][S:22]([C:25]2[CH:31]=[C:30]([N+:32]([O-:34])=[O:33])[CH:29]=[CH:28][C:26]=2[N:27]=[N:6][C:47]2[C:46]3[C:51](=[CH:52][CH:53]=[CH:54][C:45]=3[NH:44][S:41]([N:38]3[CH2:39][CH2:40][O:35][CH2:36][CH2:37]3)(=[O:43])=[O:42])[C:50]([OH:55])=[CH:49][CH:48]=2)(=[O:23])=[O:24])=[CH:16][CH:15]=1)([OH:13])(=[O:12])=[O:11]
Reactant: O=N[O-]
Reactant: O=S(=O)(Nc1cccc2c(O)cccc12)N1CCOCC1
Reactant: Nc1ccc([N+](=O)[O-])cc1S(=O)(=O)CCc1ccc(S(=O)(=O)O)cc1
Agent: CC(=O)[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Solvent: O
Product: O=[N+]([O-])c1ccc(N=Nc2ccc(O)c3cccc(NS(=O)(=O)N4CCOCC4)c23)c(S(=O)(=O)CCc2ccc(S(=O)(=O)O)cc2)c1
Temperature: 5 °C
Reaction time: 3 h

Procedure:
To 3 ml. of conc. sulfuric acid under cooling was added 0.43 g. of sodium nitrite, dissolved by heating and, after cooling, 5.5 ml. of acetic acid were added thereto. The resulting solution was cooled to 5° C. and 2.32 g. of 2[2(4-sulfophenyl)ethylsulfonyl]-4-nitroaniline were added thereto with stirring. Stirring was continued at room temperature for 3 hours to prepare a diazonium salt solution. Separately, a solution of 1.85 g. of 5-morpholinosulfonamido-1-naphthol in 250 ml. of ethanol and 30 ml. of water was prepared, and a solution of 15 g. of sodium acetate in 40 ml. of water was added thereto with stirring. To the resulting solution, the diazonium salt solution as prepared above was added dropwise under ice-cooling. The reaction mixture was stirred at about 50° C. for 2 hours. Thereafter, the mixture was concentrated to about 100 ml., the precipitate thus separated was recovered by filtration and dried to give 4.3 g. of the desired product.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12](C=O)=[CH:11][C:10]=1[Cl:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1C=C(Cl)C=C(C(OO)=[O:26])C=1>C(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([OH:26])=[CH:11][C:10]=1[Cl:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(OCc2ccccc2)c(Cl)c1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: Oc1ccc(OCc2ccccc2)c(Cl)c1
Temperature: 25 °C
Reaction time: 120 h

Procedure:
To a solution of 4-benzyloxy-3-chlorobenzaldehyde (4 g, 16.2 mmol) in CH2Cl2 (65 mL), m-CPBA (3.63 g, 77% max, 21.05 mmol) was added and stirred at RT for 5 days. The mixture was washed with a Na2S2O3 solution, then NaHCO3 (sat), and evaporated. The residue was suspended in MeOH (150 mL), NaOMe (0.5 M in MeOH, 60 mL) was added and the mixture was stirred for 1 h. The mixture was concentrated, and the residue was dissolved in water, and extracted with Et2O/EtOAc. The aqueous layer was acidified, and extracted with EtOAc. The combined organic portions were dried with Na2SO4, filtered and evaporated. The mixture was purified by column chromatography using CH2Cl2 as the eluent to yield an off-white solid. MS(MH+)=NA; Calc'd 361.09 for C22H16ClNO2.
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([C:15]3[O:16][C:17]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=4)=[CH:18][CH:19]=3)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1.C(NC(C)C)(C)C.C1C(=O)N([Br:40])C(=O)C1>C(Cl)Cl>[Br:40][C:19]1[CH:18]=[C:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[O:16][C:15]=1[C:9]1[CH:10]=[CH:11][C:12]([O:13][CH3:14])=[C:7]([O:6][CH:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)[CH:8]=1
Reactant: COc1ccc(-c2ccc(-c3ccccn3)o2)cc1OC1CCCC1
Reactant: O=C1CCC(=O)N1Br
Solvent: CC(C)NC(C)C
Solvent: ClCCl
Product: COc1ccc(-c2oc(-c3ccccn3)cc2Br)cc1OC1CCCC1
Yield: 63 %

Procedure:
A mixture of 2-(3-cyclopentyloxy-4-methoxyphenyl)-5-(2-pyridyl)furan, (0.5 g) example 2, in CH2Cl2 (3 ml) and diisopropylamine(21 ul) and NBS (0.320 g) were stirred for 20 mins. at room temperature. The reaction mixture was quenched with Na2CO3, extracted with CH2Cl2 dried with sodium sulfate and evaporated in vacuo to afford the title compound as a beige solid in 63% yield. 1H NMR (300 MHz, CDCl3): δ 1.6 (m, 2H), 2.0-1.8 (m, 6H), 3.90 (s, 3H), 4.95 (m, 1H), 7.05 (dd, 1H), 7.23 (m, 2H), 7.43 (m, 2H), 7.85 (dd, 2H), 8.5 (dd, 1H).
Reaction SMILES: [NH2:1][CH:2]1[CH:7]2[CH2:8][CH2:9][N:4]([CH2:5][CH2:6]2)[CH2:3]1.[CH:10]([O:13][C:14]1[CH:24]=[CH:23][CH:22]=[CH:21][C:15]=1[C:16]([N:18]=[C:19]=[O:20])=[O:17])([CH3:12])[CH3:11].C([O-])(=O)/C=C/C([O-])=O>>[N:4]12[CH2:9][CH2:8][CH:7]([CH2:6][CH2:5]1)[CH:2]([NH:1][C:19]([NH:18][C:16](=[O:17])[C:15]1[CH:21]=[CH:22][CH:23]=[CH:24][C:14]=1[O:13][CH:10]([CH3:11])[CH3:12])=[O:20])[CH2:3]2
Reactant: NC1CN2CCC1CC2
Reactant: CC(C)Oc1ccccc1C(=O)N=C=O
Agent: O=C([O-])/C=C/C(=O)[O-]
Product: CC(C)Oc1ccccc1C(=O)NC(=O)NC1CN2CCC1CC2

Procedure:
The above compound was prepared, following the procedure of Example 1, from 3-aminoquinuclidine (0.31 g, 2.46 mmol) and crude 2-isopropoxybenzoyl isocyanate (0.58 g, ca 2.5 mmol). The product (0.51 g) was converted to the 1:1 fumarate, mp 171°-175° C.
Reaction SMILES: [Si]([O:8][C@@H:9]1[C:17]2[C:12](=[C:13]([C:18]3[S:22][C:21]([C:23]4[CH:24]=[CH:25][C:26]([O:31][CH:32]([CH3:34])[CH3:33])=[C:27]([CH:30]=4)[C:28]#[N:29])=[N:20][N:19]=3)[CH:14]=[CH:15][CH:16]=2)[CH2:11][CH2:10]1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1.CC(=O)OCC>[OH:8][C@@H:9]1[C:17]2[C:12](=[C:13]([C:18]3[S:22][C:21]([C:23]4[CH:24]=[CH:25][C:26]([O:31][CH:32]([CH3:34])[CH3:33])=[C:27]([CH:30]=4)[C:28]#[N:29])=[N:20][N:19]=3)[CH:14]=[CH:15][CH:16]=2)[CH2:11][CH2:10]1
Reactant: CC(C)Oc1ccc(-c2nnc(-c3cccc4c3CC[C@@H]4O[Si](C)(C)C(C)(C)C)s2)cc1C#N
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)Oc1ccc(-c2nnc(-c3cccc4c3CC[C@@H]4O)s2)cc1C#N
Temperature: 25 °C
Reaction time: 8 h
Yield: 35.3 %

Procedure:
To a stirred solution of (S)-5-(5-(1-((tert-butyldimethylsilyl)oxy)-2,3-dihydro-1H-inden-4-yl)-1,3,4-thiadiazol-2-yl)-2-isopropoxybenzonitrile (21 mg, 0.06 mmol) in anhydrous THF (1 mL) was added 1M tetrabutyl ammonium fluoride (0.3 mL, 0.3 mmol) and the reaction mixture stirred at room temperature overnight. The reaction mixture was diluted with EA (10 mL), washed with saturated NaHCO3 and brine, and dried over MgSO4. The product was purified by chromatography (EA/hexanes) to afford 8 mg (81%) of (S)-5-(5-(1-hydroxy-2,3-dihydro-1H-inden-4-yl)-1,3,4-thiadiazol-2-yl)-2-isopropoxybenzonitrile 1 as a white solid. LCMS-ESI (m/z) calculated for C21H19N3O2S: 377.1; found 378.1 [M+H]+, tR=3.67 min. 1H NMR (400 MHz, CDCl3) δ 8.28-8.07 (m, 2H), 7.86 (d, J=7.5 Hz, 1H), 7.57 (d, J=7.5 Hz, 1H), 7.40 (t, J=7.6 Hz, 1H), 7.08 (d, J=9.0 Hz, 1H), 5.41-5.18 (m, 1H), 4.74 (dd, J=12.2, 6.0 Hz, 1H), 3.48 (ddd, J=17.1, 8.7, 4.6 Hz, 1H), 3.30-3.06 (m, 1H), 2.72-2.40 (m, 1H), 2.04 (ddd, J=13.6, 8.7, 6.5 Hz, 1H), 1.64 (s, 2H), 1.44 (d, J=6.1 Hz, 5H). 13C NMR (101 MHz, CDCl3) δ 167.61, 166.22, 162.23, 147.58, 142.93, 134.04, 133.83, 129.81, 128.30, 127.45, 127.09, 123.37, 116.14, 114.45, 104.34, 77.23, 76.71, 73.09, 36.24, 31.69, 22.32.
Reaction SMILES: [Br:1][CH2:2][C:3]1[CH:4]=[C:5]([N:9]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])=[CH:16][CH:15]=2)[C:10](=[O:12])[CH3:11])[CH:6]=[CH:7][CH:8]=1.[N:35]1[CH:40]=[CH:39][C:38]([CH3:41])=[C:37]([CH3:42])[CH:36]=1>C(#N)C>[Br-:1].[C:10]([N:9]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])=[CH:16][CH:15]=1)[C:5]1[CH:4]=[C:3]([CH2:2][N+:35]2[CH:40]=[CH:39][C:38]([CH3:41])=[C:37]([CH3:42])[CH:36]=2)[CH:8]=[CH:7][CH:6]=1)(=[O:12])[CH3:11]
Reactant: Cc1ccncc1C
Reactant: CCCCCCCCCCCCCCOc1ccc(CN(C(C)=O)c2cccc(CBr)c2)cc1
Solvent: CC#N
Product: CCCCCCCCCCCCCCOc1ccc(CN(C(C)=O)c2cccc(C[n+]3ccc(C)c(C)c3)c2)cc1
Product: [Br-]

Procedure:
A mixture of 1.6 g of N-[3-(bromomethyl)phenyl]-N-[[4-(tetradecyloxy)phenyl]methyl]acetamide and 1.29 g of 3,4-lutidine in 25 ml of acetonitrile is refluxed under argon for 5 hours. The solvent is evaporated and the residue stirred with ether. The solid is collected by centrifugation, washed several times with ether and vacuum dried to give the desired product as a solid, m.p. 100°-103° C.
Reaction SMILES: [NH2:1][C:2]1[CH:21]=[CH:20][C:5]([CH2:6][NH:7][C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][C:9]=2[N+:17]([O-])=[O:18])=[CH:4][CH:3]=1.C[O-].[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CCO.CN(C=O)C.O>[N+:14]([C:11]1[CH:12]=[CH:13][C:8]2[N:7]=[C:6]([C:5]3[CH:20]=[CH:21][C:2]([NH2:1])=[CH:3][CH:4]=3)[N:17]([OH:18])[C:9]=2[CH:10]=1)([O-:16])=[O:15]
Reactant: Nc1ccc(CNc2ccc([N+](=O)[O-])cc2[N+](=O)[O-])cc1
Agent: C[O-]
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Solvent: CCO
Solvent: CN(C)C=O
Solvent: O
Product: Nc1ccc(-c2nc3ccc([N+](=O)[O-])cc3n2O)cc1
Temperature: 60 °C
Yield: 90 %

Procedure:
To a solution of N-(4-aminobenzyl)-2,4-dinitroaniline (7) (21.6 g, 74.9 mmol) in anhydrous EtOH (300 mL) and anhydrous DMF (75 mL) was slowly added sodium methoxide (30% w/w) (69.1 g, 375 mmol) at room temperature under argon atmosphere, followed by heating to 60° C. for 2 hours. After cooling to ambient termperature, the solution was diluted with water (700 mL) and then acidified with saturated citric acid. The resulting precipitate was collected on a sintered funnel while rinsing with water. The crude product was recrystallized in hot EtOH to afford 18.1 g as a brown solid in 90% yield.
Reaction SMILES: CO[C:3]([C:5]1[N:6]([CH3:22])[S:7](=[O:21])(=[O:20])[C:8]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=[CH:12][C:9]=2[C:10]=1[OH:11])=[O:4].[CH3:23][O:24][C:25]1[CH:31]=[CH:30][CH:29]=[CH:28][C:26]=1[NH2:27]>>[OH:11][C:10]1[C:9]2[CH:12]=[CH:13][C:14]3[C:19]([C:8]=2[S:7](=[O:21])(=[O:20])[N:6]([CH3:22])[C:5]=1[C:3]([NH:27][C:26]1[CH:28]=[CH:29][CH:30]=[CH:31][C:25]=1[O:24][CH3:23])=[O:4])=[CH:18][CH:17]=[CH:16][CH:15]=3
Reactant: COC(=O)C1=C(O)c2ccc3ccccc3c2S(=O)(=O)N1C
Reactant: COc1ccccc1N
Product: COc1ccccc1NC(=O)C1=C(O)c2ccc3ccccc3c2S(=O)(=O)N1C
Yield: 31 %

Procedure:
4-Hydroxy-N-(2-methoxyphenyl)-2-methyl-2H-naphtho[2,1-e]-1,2-thiazine-3-carboxamide-1,1-dioxide was prepared analogous to Example 1 from 4-hydroxy-2-methyl-2H-naphtho[2,1-e]-1,2-thiazine-3-carboxylic acid methylester-1,1-dioxide and 2-methyoxy-aniline. Yield: 31% of theory; m.p. 198°-200° C (from ethylene chloride/petroleum ether).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[CH:10]=[N:9][N:8](C3CCCCO3)[C:5]2=[N:6][CH:7]=1.[CH3:17][C:18]1([CH3:42])[CH2:27][CH2:26][C:25]2[N:24]=[CH:23][N:22]=[C:21]([N:28]3[CH2:34][C:33]4[CH:35]=[C:36](B(O)O)[CH:37]=[CH:38][C:32]=4[O:31][CH2:30][CH2:29]3)[C:20]=2[CH2:19]1>>[CH3:17][C:18]1([CH3:42])[CH2:27][CH2:26][C:25]2[N:24]=[CH:23][N:22]=[C:21]([N:28]3[CH2:34][C:33]4[CH:35]=[C:36]([C:2]5[CH:3]=[C:4]6[CH:10]=[N:9][NH:8][C:5]6=[N:6][CH:7]=5)[CH:37]=[CH:38][C:32]=4[O:31][CH2:30][CH2:29]3)[C:20]=2[CH2:19]1
Reactant: Brc1cnc2c(cnn2C2CCCCO2)c1
Reactant: CC1(C)CCc2ncnc(N3CCOc4ccc(B(O)O)cc4C3)c2C1
Product: CC1(C)CCc2ncnc(N3CCOc4ccc(-c5cnc6[nH]ncc6c5)cc4C3)c2C1

Procedure:
Prepared according to the method of example 5 by using 5-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridine (reagent preparation 32) and [4-(6,6-dimethyl-5,6,7,8-tetrahydroquinazolin-4-yl)-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl]boronic acid (reagent preparation 23) in step 1. 1H NMR (400 MHz, d6-DMSO): 13.71 (s, 1H), 8.82 (d, 1H), 8.43 (d, 1H), 8.38 (s, 1H), 8.18 (d, 1H), 7.74 (d, 1H), 7.58 (dd, 1H), 7.07 (d, 1H), 4.66 (s, 2H), 4.34 (m, 2H), 3.85 (m, 2H), 2.71 (m, 2H), 2.45 (s, 2H), 1.59 (m, 2H), 0.84 (s, 6H); MS (EI) for C25H26N6O: 427 (MH+).