Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:5]2[N:6]([CH3:19])[C:7](=[O:18])[CH2:8][C:9](=[O:17])[N:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:4]=2[CH:3]=1.CC([O-])(C)C.[K+].[N:28](OC(CC)(C)C)=[O:29]>C(O)(C)(C)C>[Cl:1][C:2]1[CH:21]=[CH:20][C:5]2[N:6]([CH3:19])[C:7](=[O:18])[C:8](=[N:28][OH:29])[C:9](=[O:17])[N:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:4]=2[CH:3]=1
Reactant: CCC(C)(C)ON=O
Reactant: CN1C(=O)CC(=O)N(c2ccccc2)c2cc(Cl)ccc21
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Product: Cn1c(=O)c(=NO)c(=O)n(-c2ccccc2)c2cc(Cl)ccc21
Temperature: 20 °C
Reaction time: 16 h
Yield: 85 %

Procedure:
3 g of 7-chloro-1-methyl-5-phenyl-1H-1,5-benzodiazepine-2,4(3H,5H)-dione were suspended in 30 ml of tert-butanol and 1.12 g of potassium tert-butylate were added in small fractions. While maintaining the temperature at 20° C. with a water bath, 2.3 ml of tert-amyl nitrite were added and the solution thickened and a precipitate formed. After standing for 16 hours at ambient temperature, the precipitate formed was separated off (potassium salt of the oxime) and dissolved in 20 ml of water and acidified by acetic acid. The precipitate formed was extracted and the organic phase was washed with water, dried and concentrated to obtain 2.8 g of the expected product (yield=85%) melting at approx. 50° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]#[N:9])[C:5]([C:10]#[N:11])=[CH:4][C:3]=1[NH2:12].C(O)CCCC.[CH2:19]([CH:25]([CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[CH:26]=O)[CH2:20][CH2:21][CH2:22]CC.O=O>CN1C(=O)CCC1>[C:10]([C:5]1[C:6]([C:8]#[N:9])=[CH:7][C:2]2[N:1]=[C:26]([CH:25]([CH2:19][CH2:20][CH2:21][CH3:22])[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[NH:12][C:3]=2[CH:4]=1)#[N:11]
Reactant: N#Cc1cc(N)c(N)cc1C#N
Reactant: CCCCCCC(C=O)CCCCCC
Agent: O=O
Solvent: CN1CCCC1=O
Solvent: CCCCCO
Product: CCCCCCC(CCCC)c1nc2cc(C#N)c(C#N)cc2[nH]1
Temperature: 120 °C
Reaction time: 2 h
Yield: 87.8 %

Procedure:
A 100 mL round-bottom flask was charged with 3 (1.32 g, 8.37 mmol), pentanol (42 mL), 2-hexyl-1-octanal (1.77 g, 8.37 mmol), and a magnetic stirring bar. The flask was fitted with a Hickman still and placed in an oil bath heated to 120° C. NMP (4.0 mL) was added to fully dissolve the solid material. The mixture was heated and stirred for 2 h. Then FeCl3.6H2O (113 mg, 0.42 mmol) was added to the reaction vessel and oxygen was bubbled through the mixture as it was heated and stirred for an additional 12 h. The reaction mixture was then removed from heat and added to 200 mL diethyl ether. The ether solution was washed three times with water, then washed with brine, dried over Na2SO4, filtered, and concentrated to dryness. The residue was chromatographed (silica, CHCl3), yielding a tan solid (2.37 g, 81%): 1H NMR δ 0.82 (t, J=7.6 Hz, 6H), 1.10-1.30 (m, 16H), 1.77-1.87 (m, 2H), 2.90-3.04 (m, 1H), 8.07 (br s, 2H), 10.36 (br s, 1H); 13C NMR δ 14.2, 22.8, 27.7, 29.4, 31.8, 34.9, 41.3, 108.4, 117.0, 165.3; FAB-MS obsd 351.2551, calcd 351.2549 (C22H30N4).
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([Cl:11])[N:3]=1.C(=O)([O-])[O-].[K+].[K+].[Cl:18][C:19]1[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[C:20]=1[CH2:21][NH2:22]>CC#N>[Cl:18][C:19]1[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[C:20]=1[CH2:21][NH:22][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([Cl:11])[N:3]=1
Reactant: NCc1c(Cl)cccc1Cl
Reactant: O=[N+]([O-])c1ccc(Cl)nc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=[N+]([O-])c1ccc(Cl)nc1NCc1c(Cl)cccc1Cl
Temperature: 0 °C
Reaction time: 1 h
Yield: 29.7 %

Procedure:
To a mixture of 2,6-dichloro-3-nitropyridine (1.0 g, 5.18 mmol) and potassium carbonate (848 mg, 6.14 mmol) in 15 mL MeCN was added 2,6-dichlorobenzylamine (0.63 mL, 5.18 mmol) at 0° C. The reaction mixture was stirred for one hour at 0° C. and then for 10 hours at room temperature. The organic solvent was evaporated and the residue was purified by silica gel chromatography (EtOAc:Hex=1:10) giving 16 [511 mg].
Reaction SMILES: [CH2:1]([N:3]1[CH:8]=[CH:7][C:6](=[O:9])[C:5]([O:10]CC2C=CC=CC=2)=[C:4]1[CH2:18][O:19]C)[CH3:2].CO.C(OCC)C.[ClH:28]>>[ClH:28].[CH2:1]([N:3]1[CH:8]=[CH:7][C:6](=[O:9])[C:5]([OH:10])=[C:4]1[CH2:18][OH:19])[CH3:2]
Reactant: CCn1ccc(=O)c(OCc2ccccc2)c1COC
Agent: Cl
Solvent: CCOCC
Solvent: CO
Product: CCn1ccc(=O)c(O)c1CO
Yield: 73 %

Procedure:
2.0 g (7.33 mmol) 1-ethyl-2-methoxymethyl-3-benzyloxy-pyridin-4(1H)-one was dissolved in 50 ml of 4N hydrochloric acid and refluxed for 6 hours. Concentration to dryness in vacuo afforded the crude product. Recrystalissaion from methanol/diethyl ether gave the pure title compound (1.1 g, 73%) as a white crystalline solid. m.p. 168-169° C.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH3:12])[N:3]=1.[NH2:13][C:14]1[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=1>>[CH3:12][C:4]1[N:3]=[C:2]([NH:13][C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=1
Reactant: Cc1nc(Cl)c2ccccc2n1
Reactant: Nc1ccncc1
Product: Cc1nc(Nc2ccncc2)c2ccccc2n1

Procedure:
The title compound was prepared from 4-chloro-2-methyl-quinazoline and 4-amino-pyridine by a procedure similar to examples 100. 1H NMR (CDCl3): 8.58 (m, 1H), 7.79-7.93 (m, 5H), 7.70 (s, broad, 1H), 7.55 (ddd, J=1.2, 6.9, 8.1, 1H), 2.79 (s, 3H).
Reaction SMILES: O=P(Cl)(Cl)[Cl:3].[Cl:6][C:7]1[C:16]2[C:11](=[CH:12][C:13]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([C:23]#[N:24])[CH:18]=3)=[CH:14][CH:15]=2)[C:10](=O)[NH:9][CH:8]=1>CC#N>[Cl:3][C:10]1[C:11]2[C:16](=[CH:15][CH:14]=[C:13]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([C:23]#[N:24])[CH:18]=3)[CH:12]=2)[C:7]([Cl:6])=[CH:8][N:9]=1
Reactant: N#Cc1cccc(-c2ccc3c(Cl)c[nH]c(=O)c3c2)c1
Reactant: O=P(Cl)(Cl)Cl
Solvent: CC#N
Product: N#Cc1cccc(-c2ccc3c(Cl)cnc(Cl)c3c2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 88.3 %

Procedure:
A solution of POCl3 (8.36 kg, 54.5 mol) in MeCN (11.5 L) was added to a suspension of 4-chloro-7-(3-cyanophenyl)isoquinolinone (7.65 kg, 27.3 mol) in boiling MeCN (65 L) under N2 over 1 hour. The mixture was heated at reflux for 11 hours and then cooled to room temperature. The mixture was slowly quenched with 1N aqueous HCl (38.3 L) and the resultant slurry stirred for 1 hour. The solid was collected by filtration, washed with MeCN (7.6 L) and dried in vacuo at 50° C. to give 1,4-dichloro-7-(3-cyanophenyl)isoquinoline (7.20 kg, 24.1 mol, 88%) as a creamy coloured solid.
Reaction SMILES: [Cl:1][C:2]1[CH:36]=[CH:35][C:5]([CH2:6][C:7]2[N:8]=[C:9]([C:25]3[C:26]([CH3:34])=[N:27][N:28]4[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=34)[S:10][C:11]=2[C:12]2[N:16]=[CH:15][N:14](COCC[Si](C)(C)C)[N:13]=2)=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][C:7]2[N:8]=[C:9]([C:25]3[C:26]([CH3:34])=[N:27][N:28]4[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=34)[S:10][C:11]=2[C:12]2[NH:16][CH:15]=[N:14][N:13]=2)=[CH:35][CH:36]=1
Reactant: Cc1nn2ccccc2c1-c1nc(Cc2ccc(Cl)cc2)c(-c2ncn(COCC[Si](C)(C)C)n2)s1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1nn2ccccc2c1-c1nc(Cc2ccc(Cl)cc2)c(-c2nnc[nH]2)s1
Temperature: 25 °C
Reaction time: 3 h
Yield: 64.1 %

Procedure:
To a solution of 3-[4-(4-chlorobenzyl)-5-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-1,2,4-triazol-3-yl)-1,3-thiazol-2-yl]-2-methylpyrazolo[1,5-a]pyridine (0.182 g, 0.339 mmol) in dichloromethane (3.3 mL) at room temperature was added trifluoroacetic acid (5.1 mL, 66 mmol). The mixture was then stirred at room temperature for 3 hours. The solvent was evaporated and the excess trifluoroacetic acid was removed by azeotroping with toluene. The crude product was purified by column chromatography (SiO2, elution with hexane to 100% ethyl acetate) to yield the title compound (0.0884 g, 64%). LCMS: (FA) ES+, 407. 1H NMR (400 MHz, d6-DMSO) δ: 8.76-8.70 (m, 2H), 8.28-8.22 (m, 1H), 7.53-7.46 (m, 1H), 7.45-7.40 (m, 2H), 7.37-7.31 (m, 2H), 7.07-7.01 (m, 1H), 5.55-5.50 (m, 1H), 4.64 (s, 2H), 2.65 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][C:8]=2[CH3:14])[N:5]=[C:4]([CH3:15])[CH:3]=1.[C:16]([N:19]1[CH2:23][C:22](=O)[N:21]=[CH:20]1)(=[O:18])[CH3:17]>>[C:16]([N:19]1[CH2:23][CH2:22][N:21]=[C:20]1[NH:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][C:8]=2[CH3:14])[N:5]=[C:4]([CH3:15])[CH:3]=1)(=[O:18])[CH3:17]
Reactant: CC(=O)N1C=NC(=O)C1
Reactant: Cc1cc(N)n(-c2ccc(Cl)cc2C)n1
Product: CC(=O)N1CCN=C1Nc1cc(C)nn1-c1ccc(Cl)cc1C

Procedure:
5-Amino-3-methyl-1-(4-chloro-2-methylphenyl) pyrazole (22.16 g.) and 1-acetyl-2-imidazolinone (15.4 g.) were reacted as described in Example I to give 13.1 g. of product, mp 195°-195°.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][CH:10]=[C:11]([C:13]([F:16])([F:15])[F:14])[N:12]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:24][S:25](Cl)(=[O:27])=[O:26]>CC(C)=O>[CH3:24][S:25]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][CH:10]=[C:11]([C:13]([F:16])([F:15])[F:14])[N:12]=2)=[CH:4][CH:3]=1)(=[O:27])=[O:26]
Reactant: CS(=O)(=O)Cl
Reactant: Nc1ccc(-c2nc(C(F)(F)F)c[nH]2)cc1
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: CS(=O)(=O)Nc1ccc(-c2nc(C(F)(F)F)c[nH]2)cc1
Reaction time: 20 h

Procedure:
To a solution of 2-(p-aminophenyl)-4-trifluoromethylimidazole (3.0 g.) in acetone (50 ml.) and triethylamine (2.7 g.) is added methanesulfonyl chloride (1.5 g.). After refluxing for four hours, a second portion of methanesulfonyl chloride (1.5 g.) is added. Reflux is continued 20 hours, a third portion of methanesulfonyl chloride (1.5 g.) is added and reflux continued another four hours. The reaction mixture is filtered and concentrated to an oil which, upon trituration with water, affords a solid. After chromatography on silica gel and recrystallization from a mixture of acetonitrile and water 1.3 g. of 2-(p-methylsulfonamidophenyl)-4-trifluoromethylimidazole, m.p. 253°-255° C. is obtained.
Reaction SMILES: CN(C)C=O.[H-].[Na+].[OH:8][C:9]1[C:26]([OH:27])=[CH:25][C:24]2[C:23]3[C:18](=[CH:19][C:20]([OH:29])=[C:21]([OH:28])[CH:22]=3)[C:17]3[C:12](=[CH:13][C:14]([OH:31])=[C:15]([OH:30])[CH:16]=3)[C:11]=2[CH:10]=1.C1(C)C=CC(S(O[CH2:42][CH2:43][CH2:44][CH:45]([CH3:48])[CH2:46][CH3:47])(=O)=O)=CC=1>O>[CH3:48][CH:45]([CH2:46][CH3:47])[CH2:44][CH2:43][CH2:42][O:8][C:9]1[C:26]([O:27][CH2:42][CH2:43][CH2:44][CH:45]([CH3:48])[CH2:46][CH3:47])=[CH:25][C:24]2[C:23]3[C:18](=[CH:19][C:20]([O:29][CH2:15][CH2:16][CH2:17][CH:18]([CH3:23])[CH2:19][CH3:20])=[C:21]([O:28][CH2:42][CH2:43][CH2:44][CH:45]([CH3:48])[CH2:46][CH3:47])[CH:22]=3)[C:17]3[C:12](=[CH:13][C:14]([O:31][CH2:42][CH2:43][CH2:44][CH:45]([CH3:48])[CH2:46][CH3:47])=[C:15]([O:30][CH2:26][CH2:9][CH2:10][CH:11]([CH3:12])[CH2:24][CH3:25])[CH:16]=3)[C:11]=2[CH:10]=1
Reactant: Oc1cc2c3cc(O)c(O)cc3c3cc(O)c(O)cc3c2cc1O
Reactant: CCC(C)CCCOS(=O)(=O)c1ccc(C)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCC(C)CCCOc1cc2c3cc(OCCCC(C)CC)c(OCCCC(C)CC)cc3c3cc(OCCCC(C)CC)c(OCCCC(C)CC)cc3c2cc1OCCCC(C)CC
Temperature: 25 °C
Reaction time: 1 h
Yield: 56.8 %

Procedure:
At room temperature, 3 ml of N,N-dimethylformamide (DMF) was placed in a flask, and 0.27 g of NaH (60% in oil) was added thereto. Then, 0.3 g (0.925 mmol) of 2,3,6,7,10,11-hexahydroxytriphenylene was added thereto, and after 1 hour of stirring, a mixture liquid of 1.96 g (6.84 mmol) of 4-methylhexyl p-toluenesulfonate and 2 ml of DMF was added dropwise thereto, followed by 5 hours of stirring at 70° C. After the reaction, the system was cooled to room temperature, and water was added thereto to precipitate a crystal, which was recovered by filtration. The crystal was then purified by silica gel chromatography (with toluene) and re-cystallized from acetone/methanol to obtain 0.24 g of 2,3,6,7,10,11-hexa(4-methylhexyloxy)triphenylene.
Reaction SMILES: N1C2C(=CC=C3C=2N=CC=C3)C=CC=1.N#N.[C:17]1([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[CH:22]=[CH:21][C:20]([NH:23][C:24]2[CH:36]=[CH:35][C:34]3[C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[C:27]([CH3:38])([CH3:37])[C:26]=3[CH:25]=2)=[CH:19][CH:18]=1.[Br:45][C:46]1[CH:51]=[CH:50][C:49](I)=[CH:48][CH:47]=1>C1(C)C=CC=CC=1.[Cu]Cl.O>[C:17]1([C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=2)[CH:22]=[CH:21][C:20]([N:23]([C:49]2[CH:50]=[CH:51][C:46]([Br:45])=[CH:47][CH:48]=2)[C:24]2[CH:36]=[CH:35][C:34]3[C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[C:27]([CH3:38])([CH3:37])[C:26]=3[CH:25]=2)=[CH:19][CH:18]=1
Reactant: Brc1ccc(I)cc1
Reactant: CC1(C)c2ccccc2-c2ccc(Nc3ccc(-c4ccccc4)cc3)cc21
Agent: Cl[Cu]
Agent: N#N
Agent: c1cnc2c(c1)ccc1cccnc12
Solvent: O
Solvent: Cc1ccccc1
Product: CC1(C)c2ccccc2-c2ccc(N(c3ccc(Br)cc3)c3ccc(-c4ccccc4)cc3)cc21
Temperature: 130 °C

Procedure:
A degassed solution of 490 mg (0.16 mmol) of copper(I) chloride and 906 mg (5 mmol) of 1,10-phenanthroline in 100 ml of toluene is saturated with N2 for 1 h and heated to 130° C. 18 g (50 mmol) of N-[1,1-biphenyl]-4-yl-9,9-dimethyl-9H-fluoren-2-amine and 14 g (50 mmol) of 1-bromo-4-iodobenzene are subsequently added to the solution, which is then heated at 180° C. for 2 h. After cooling, 180 ml of water are added to the mixture, the organic phase is separated off, and the solvent is removed in vacuo. The product is recrystallised from n-hexane.
Reaction SMILES: [O-]P([O-])([O-])=O.[K+].[K+].[K+].[F:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:17]=[N:18][C:19]3[N:20]([N:22]=[CH:23][C:24]=3B3OC(C)(C)C(C)(C)O3)[CH:21]=2)=[CH:12][CH:11]=1.Cl[C:35]1[CH:40]=[C:39]([NH:41][C:42]([NH:44][CH2:45][CH3:46])=[O:43])[CH:38]=[CH:37][N:36]=1.N#N>O.O1CCOCC1>[CH2:45]([NH:44][C:42]([NH:41][C:39]1[CH:38]=[CH:37][N:36]=[C:35]([C:24]2[CH:23]=[N:22][N:20]3[CH:21]=[C:16]([C:13]4[CH:12]=[CH:11][C:10]([F:9])=[CH:15][CH:14]=4)[CH:17]=[N:18][C:19]=23)[CH:40]=1)=[O:43])[CH3:46]
Reactant: CC1(C)OB(c2cnn3cc(-c4ccc(F)cc4)cnc23)OC1(C)C
Reactant: CCNC(=O)Nc1ccnc(Cl)c1
Agent: N#N
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CCNC(=O)Nc1ccnc(-c2cnn3cc(-c4ccc(F)cc4)cnc23)c1
Temperature: 90 °C
Yield: 18.6 %

Procedure:
A solution of K3PO4 (640 mg, 3 mmol) in H2O (2 ml) was added to a stirred mixture of 6-(4-fluoro-phenyl)-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrazolo[1,5-a]pyrimidine (330 mg, 0.97 mmol) and 1-(2-chloro-pyridin-4-yl)-3-ethyl-urea (procedure U4, 420 mg, 2.1 mmol) in dioxane (8 ml) at RT under N2. The mixture was deoxygenated by evacuate/fill N2 (×2), PdCl2dppf (40 mg, 0.05 mmol) was added and the mixture was deoxygenated again (×3). The reaction was stirred and heated at 90° C. for 18 h. After cooling to RT the reaction was partitioned between CH2Cl2/H2O. The aqueous layer was extracted with CH2Cl2 (×1). The combined extracts were dried, then evaporated. The residue was purified by preparative HPLC to give the title compound (68 mg) as a yellow solid.
Reaction SMILES: [CH2:1]([N:8]1[CH:12]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=2)[CH:11]([CH2:21][OH:22])[CH2:10][C:9]1=[O:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[K].[C:25]1([CH3:35])[CH:30]=[CH:29][C:28]([S:31](Cl)(=[O:33])=[O:32])=[CH:27][CH:26]=1.Cl>>[CH2:1]([N:8]1[CH:12]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=2)[CH:11]([CH2:21][O:22][S:31]([C:28]2[CH:29]=[CH:30][C:25]([CH3:35])=[CH:26][CH:27]=2)(=[O:33])=[O:32])[CH2:10][C:9]1=[O:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COc1cccc(C2C(CO)CC(=O)N2Cc2ccccc2)c1
Agent: Cl
Agent: [K]
Product: COc1cccc(C2C(COS(=O)(=O)c3ccc(C)cc3)CC(=O)N2Cc2ccccc2)c1
Reaction time: 3 h

Procedure:
To 21.4 gm. of 1-benzyl-4-hydroxymethyl-5-(3methoxyphenyl)pyrrolidin-2-one in 40 ml. of potassium dried pyridine was slowly added at -4° to -7°, 14.4 gm of p-toluenesulfonyl chloride. The reaction mixture was stirred for 3 hours at 15° and then diluted with 180 ml. of 10% hydrochloric acid. The gum was extracted with chloroform, dried (Na2SO4), filtered and concentrated in vacuo to provide 24.6 gm. of the desired product as an oil. ir (CHCl3): 1165-1195 cm-1 ; 1335-1375 cm-1
Reaction SMILES: [CH3:1][Li].[NH2:3][C:4]1[C:15]([Cl:16])=[CH:14][CH:13]=[C:12]([Cl:17])[C:5]=1[C:6](N(OC)C)=[O:7]>O1CCCC1.O>[NH2:3][C:4]1[C:15]([Cl:16])=[CH:14][CH:13]=[C:12]([Cl:17])[C:5]=1[C:6](=[O:7])[CH3:1]
Reactant: [Li]C
Reactant: CON(C)C(=O)c1c(Cl)ccc(Cl)c1N
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)c1c(Cl)ccc(Cl)c1N
Temperature: 25 °C
Reaction time: 3 h
Yield: 28.9 %

Procedure:
At −78° C. a solution of methyl lithium (1.6M in diethyl ether, 25 ml, 40 mmol) was added dropwise to a solution of 2-amino-3,6-dichloro-N-methoxy-N-methyl-benzamide (2.5 g, 10 mmol) in tetrahydrofurane (100 ml). After complete addition, the reaction was warmed to r.t. The dark solution was stirred for 3 hours at room temperature. Under ice cooling 2N aqueous hydrochloride solution (25 ml) was added dropwise and stirred at r.t. for 30 minutes. The reaction was diluted with water, extracted twice with ethyl acetate. The combined organic layers were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered, and the solvent was evaporated. The residue was purified by column chromatography (silica gel, solvent gradient n-heptan/ethyl acetate=3/7) to yield the title compound as an orange oil (0.59 g, 29%).
Reaction SMILES: [CH2:1]1[O:9][CH:2]1[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH2:10]([CH2:12][NH2:13])[OH:11]>O>[OH:9][CH:2]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1)[CH2:1][NH:13][CH2:12][CH2:10][OH:11]
Reactant: c1ccc(C2CO2)cc1
Reactant: NCCO
Solvent: O
Product: OCCNCC(O)c1ccccc1
Reaction time: 24 h
Yield: 30.9 %

Procedure:
Styrene oxide (1.2 g.), ethanolamine (0.6 g.) and water (0.05 g.) were heated at 70° with stirring for 24 hours. The mixture was cooled, evacuated and the oil formed triturated with ether to give title compound (550 mg.) m.p 93.5° - 95°.
Reaction SMILES: CCC(C[O:7][C:8](C(N(CC[NH+](C)C)C)=O)([C:15]1[CH:20]=CC=CC=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)CC.[Cl-].C1C2C(=CC=CC=2)C=C1.[Br:40]Br.OO>ClC1C=CC=CC=1Cl.O>[Br:40][C@@H:15]1[CH2:20][C:10]2[C:9](=[CH:14][CH:13]=[CH:12][CH:11]=2)[C@H:8]1[OH:7]
Reactant: BrBr
Reactant: CCC(CC)COC(C(=O)N(C)CC[NH+](C)C)(c1ccccc1)c1ccccc1
Agent: C1=Cc2ccccc2C1
Agent: OO
Agent: [Cl-]
Solvent: Clc1ccccc1Cl
Solvent: O
Product: O[C@@H]1c2ccccc2C[C@H]1Br
Temperature: 20 °C
Reaction time: 3 h
Yield: 69 %

Procedure:
100 ml of water and 0.70 g of Triton X-100 were put into a 300-ml 4-mouthed flask, and mixed as 80 ml of ortho-dichlorobenzene and 60.0 g of indene (95 wt %; 0.491 mol) were added. At 20° C., 41.54 g of bromine (0.259 mol) was added with strong stirring and air cooling over approximately 5 minutes. After dropwise addition the temperature of the reaction mixture became 52° C. After mixing at 60° C. for 13 hours, 23.8 g of hydrogen peroxide (35 wt %; 0.245 mol) was added dropwise at the same temperature, requiring 3 hours, followed by mixing for a further 3 hours at 60° C. and then separation into an aqueous layer and a slurry layer. The aqueous layer was extracted with 120 ml of ortho-dichlorobenzene, and the extract layer was bulked with the earlier slurry layer. The warm slurry layer was cooled gradually to 20° C. under stirring, the crystals which came down were isolated by centrifugation and washed with 30 ml of ortho-dichlorobenzene. The wet crystals were dried at 65°-70° C. under decreased pressure to obtain 72.18 g of white crystals of trans-2-bromoindan-1-ol (yield 69.0%).
Reaction SMILES: [CH3:1][N:2]([CH3:29])[C:3]1[CH:4]=[C:5]([CH:26]=[CH:27][CH:28]=1)[C:6]([NH:8][C:9]1[CH:10]=[CH:11][C:12]([CH3:25])=[C:13]([NH:15][C:16](=[O:24])[C:17]2[CH:22]=[CH:21][C:20](F)=[CH:19][CH:18]=2)[CH:14]=1)=[O:7].[O:30]1[CH2:35][CH2:34][N:33]([CH2:36][CH2:37][CH2:38][NH2:39])[CH2:32][CH2:31]1>>[CH3:1][N:2]([CH3:29])[C:3]1[CH:4]=[C:5]([CH:26]=[CH:27][CH:28]=1)[C:6]([NH:8][C:9]1[CH:10]=[CH:11][C:12]([CH3:25])=[C:13]([NH:15][C:16](=[O:24])[C:17]2[CH:22]=[CH:21][C:20]([NH:39][CH2:38][CH2:37][CH2:36][N:33]3[CH2:34][CH2:35][O:30][CH2:31][CH2:32]3)=[CH:19][CH:18]=2)[CH:14]=1)=[O:7]
Reactant: Cc1ccc(NC(=O)c2cccc(N(C)C)c2)cc1NC(=O)c1ccc(F)cc1
Reactant: NCCCN1CCOCC1
Product: Cc1ccc(NC(=O)c2cccc(N(C)C)c2)cc1NC(=O)c1ccc(NCCCN2CCOCC2)cc1
Yield: 3 %

Procedure:
Using an analogous procedure to that described in Example 20, N-[5-(3-dimethylaminobenzamido)-2-methylphenyl]4-fluorobenzamide was reacted with 3-morpholinopropylamine to give the title compound in 3% yield; NMR Spectrum: (DMSOd6) 1.77 (m, 2H), 2.24 (s, 3H), 2.46 (m, 6H), 3.02 (s, 6H), 3.16 (q, 2H), 3.65 (t, 4H), 6.33 (t, 1H), 6.67 (d, 2H), 6.97 (m, 1H), 7.28 (m, 2H), 7.36 (t, 1H), 7.62 (m, 1H), 7.83 (m, 3H), 9.45 (s, 1H), 10.06 (s, 1H); Mass Spectrum: M+H+ 516.
Reaction SMILES: [CH2:1]1[CH:9]2[N:4]([CH2:5][CH2:6][CH:7]([C:10]3[C:18]4[C:13](=[CH:14][CH:15]=[N:16][CH:17]=4)[NH:12][CH:11]=3)[CH2:8]2)[CH2:3][CH2:2]1.[C:19]1([S:29](Cl)(=[O:31])=[O:30])[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[CH:21][CH:20]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+]>C1COCC1>[CH2:1]1[CH:9]2[N:4]([CH2:5][CH2:6][CH:7]([C:10]3[C:18]4[C:13](=[CH:14][CH:15]=[N:16][CH:17]=4)[N:12]([S:29]([C:19]4[C:28]5[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=5)[CH:22]=[CH:21][CH:20]=4)(=[O:31])=[O:30])[CH:11]=3)[CH2:8]2)[CH2:3][CH2:2]1
Reactant: O=S(=O)(Cl)c1cccc2ccccc12
Reactant: c1cc2[nH]cc(C3CCN4CCCC4C3)c2cn1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: O=S(=O)(c1cccc2ccccc12)n1cc(C2CCN3CCCC3C2)c2cnccc21

Procedure:
from 3-(octahydro-7-indolizinyl)-1-H-5-azaindole (10 mg, 0.0415 mmol), 1-naphthalenesulfonyl chloride (17.2 mg, 0.0828 mmol) and 1M NaN(TMS)2 (100 μL, 0.10 mmol) in THF (0.5 mL) at RT.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:17])[C@@H:5]([CH2:7][C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[NH:10][CH:9]=1)[NH2:6].C(N(CC)CC)C.[C:25](Cl)(=[O:35])[C:26]1[CH:34]=[CH:33][C:32]2[O:31][CH2:30][O:29][C:28]=2[CH:27]=1>C(Cl)Cl>[CH3:2][O:3][C:4](=[O:17])[C@@H:5]([CH2:7][C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[NH:10][CH:9]=1)[NH:6][C:25]([C:26]1[CH:34]=[CH:33][C:32]2[O:31][CH2:30][O:29][C:28]=2[CH:27]=1)=[O:35]
Reactant: COC(=O)[C@H](N)Cc1c[nH]c2ccccc12
Reactant: O=C(Cl)c1ccc2c(c1)OCO2
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)[C@@H](Cc1c[nH]c2ccccc12)NC(=O)c1ccc2c(c1)OCO2
Temperature: 0 °C
Reaction time: 2 h
Yield: 100.2 %

Procedure:
To a suspension of D-tryptophan methyl ester hydrochloride (10.2 g) in anhydrous CH2Cl2 (150 ml) cooled at 0° C. was added dropwise triethylamine (12.3 ml). To the resulting solution solid piperonyloyl chloride (8.16 g) was added portionwise at the same temperature, and the mixture was stirred at room temperature for 2 h. The mixture was washed successively with water, 0.5N hydrochloric acid, water, a saturated aqueous solution of NaHCO3 and again with water. After drying over Na2SO4 and evaporation of the solvent under reduced pressure, the resulting oil on trituration from hot cyclohexane afforded the title compound as a white solid (14.7 g).
Reaction SMILES: [CH2:1]([N:5]1[C:9]([CH:10]=[O:11])=[CH:8][N:7]=[C:6]1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4].[CH3:18][Li]>C(OCC)C>[CH2:1]([N:5]1[C:9]([CH:10]([OH:11])[CH3:18])=[CH:8][N:7]=[C:6]1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCn1c(C=O)cnc1-c1ccccc1
Reactant: [Li]C
Solvent: CCOCC
Product: CCCCn1c(C(C)O)cnc1-c1ccccc1
Reaction time: 0.17 h

Procedure:
A solution of aldehyde 102 (230 mg) in diethyl ether (30 mL) is placed in a separatory funnel and treated with a solution of methyl lithium (1.4 M in THF, 1.5 mL). After 10 min, the solution is washed with ammonium chloride solution (1 M, 20 mL), dried (Na2SO4) and concentrated. The resulting dark oil is purified by preparative TLC (10% MeOH/CHCl3) to provide compound 107 as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 7.56 (d, J=2 Hz, 2H), 7.4 (m, 3H), 7.01 (s, 1H), 4.86 (q, J=7 Hz, 1H), 4.18 (m, 1H), 4.0 (m, 1H), 1.63 (d, J=6.6 Hz, 3H), 1.63 (m, 2H), 1.23 (m, 2H), 0.81 (t, J=7 Hz, 3H).