Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C@H:2]1[CH2:8][CH2:7][C@@H:6]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[O:5][C:3]1=[O:4].O[C:16]1[CH:24]=[CH:23][C:19]([C:20]([OH:22])=[O:21])=[CH:18][CH:17]=1>>[CH2:8]([O:22][C:20]([C:19]1[CH:23]=[CH:24][C:16]([O:1][C@@H:2]2[CH2:8][CH2:7][C@@H:6]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[O:5][C:3]2=[O:4])=[CH:17][CH:18]=1)=[O:21])[CH2:7][CH2:6][CH2:9][CH3:10]
Reactant: O=C(O)c1ccc(O)cc1
Reactant: CCCCCC[C@@H]1CC[C@H](O)C(=O)O1
Product: CCCCCC[C@@H]1CC[C@@H](Oc2ccc(C(=O)OCCCCC)cc2)C(=O)O1

Procedure:
A crude product was obtained in the same manner as described in Example 22 except that (2S,5R)-2-hydroxy-5-hexyl-δ-valerolactone was used in an amount of 125 mg and 125 mg of p-hydroxybenzoic acid was used instead of 120 mg of 4-octyloxy-3-cyanobenzoic acid. The crude product was purified by the silica gel column chromatography to obtain 20 mg of (2R,5R)-2-(4'-pentyloxycarbonylphenoxy)-5-hexyl-δ-valerolactone.
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6](Cl)[C:5]([CH3:12])=[C:4]([CH3:13])[N:3]=1.C(N(CC)CC)C.[NH2:21][C@H:22]([CH2:24][OH:25])[CH3:23]>CN(C=O)C>[Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([NH:21][C@@H:22]([CH3:23])[CH2:24][OH:25])[C:5]([CH3:12])=[C:4]([CH3:13])[N:3]=1
Reactant: Cc1nc(Cl)c([N+](=O)[O-])c(Cl)c1C
Reactant: C[C@H](N)CO
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1nc(Cl)c([N+](=O)[O-])c(N[C@@H](C)CO)c1C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 61.7 %

Procedure:
A solution of 2,4-dichloro-5,6-dimethyl-3-nitropyridine (5.0 g, 22.6 mmol) in 50 mL of dry DMF was cooled to 0° C. under an atmosphere of N2. Triethylamine (6.3 mL, 45.2 mmol) and L-alaninol (2.1 mL, 27.1 mmol) were added sequentially. After approximately 15 minutes, the reaction was allowed to warm to ambient temperature, and then heated to 35° C. for 3 days. The reaction mixture was concentrated under reduced pressure to give an orange-brown solid. The resulting solid was partitioned between 50 mL of ethyl acetate and 50 mL of H2O. The layers were separated and the organic portion was washed sequentially with H2O and brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. Chromatography (SiO2, 40-60% ethyl acetate/hexanes) afforded (2S)-2-[(2-chloro-5,6-dimethyl-3-nitropyridin-4-yl)amino]propan-1-ol (3.62 g) as an orange solid.
Reaction SMILES: [OH:1][C@@H:2]([CH2:18][N:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1)[CH2:3][N:4]1[CH2:10][CH2:9][CH2:8][C:7]2[NH:11][C:12](C=O)=[C:13]([CH3:14])[C:6]=2[C:5]1=[O:17].N1CCCCC1>C(O)C>[OH:1][CH:2]([CH2:18][N:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1)[CH2:3][N:4]1[CH2:10][CH2:9][CH2:8][C:7]2[NH:11][CH:12]=[C:13]([CH3:14])[C:6]=2[C:5]1=[O:17]
Reactant: Cc1c(C=O)[nH]c2c1C(=O)N(C[C@@H](O)CN1CCOCC1)CCC2
Solvent: CCO
Solvent: C1CCNCC1
Product: Cc1c[nH]c2c1C(=O)N(CC(O)CN1CCOCC1)CCC2
Temperature: 25 °C
Yield: 87.3 %

Procedure:
(S)-5-(2-Hydroxy-3-morpholin-4-yl-propyl)-3-methyl-4-oxo-1,4,5,6,7,8-hexahydro-pyrrolo[3,2-c]azepine-2-carbaldehyde 78f (50 mg, 0.149 mmol) was dissolved in 261 μl of ethanol under stirring, and added with 5-fluoro-1,3-dihyrdro-indole-2-one (20.28 mg, 0.134 mmol) and piperidine (7.3 μl, 0.074 mmol) to the solution at room temperature. Upon the completion of the addition, the reaction mixture was stirred for 2 hours in dark at 80° C. in an oil bath. After thin lay chromatography showed the disappearance of starting materials, the reaction was stopped, and the oil bath was removed. The reaction system was cooled to room temperature, the reaction solution was filtered and the filter cake was dried to obtain the title compound (S,Z)-2-(5-fluoro-2-oxoindolin-3-ylidene)methyl)-5-(2-hydroxy-3-morpholinopropyl)-3-methyl-5,6,7,8-tetrahydropyrrolo[3,2-c]azepin-4(1H)-one 78(40 mg, yield 57%) as a yellow solid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]([CH3:19])[C:16]([OH:18])=O)=[CH:11][CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].S(Cl)(Cl)=O.[C:24]([O:28][C:29]([N:31]1[C:35]([NH2:36])=[CH:34][C:33]([CH:37]2[CH2:39][CH2:38]2)=[N:32]1)=[O:30])([CH3:27])([CH3:26])[CH3:25].C(O)C(N)(CO)CO>O1CCCC1.C(N(CC)CC)C>[C:1]([O:5][C:6]([NH:8][C:9]1[CH:10]=[CH:11][C:12]([CH:15]([CH3:19])[C:16]([NH:36][C:35]2[N:31]([C:29]([O:28][C:24]([CH3:26])([CH3:27])[CH3:25])=[O:30])[N:32]=[C:33]([CH:37]3[CH2:39][CH2:38]3)[CH:34]=2)=[O:18])=[CH:13][CH:14]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C(=O)O)c1ccc(NC(=O)OC(C)(C)C)cc1
Reactant: CC(C)(C)OC(=O)n1nc(C2CC2)cc1N
Agent: NC(CO)(CO)CO
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O=S(Cl)Cl
Product: CC(C(=O)Nc1cc(C2CC2)nn1C(=O)OC(C)(C)C)c1ccc(NC(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 69.9 %

Procedure:
265 mg (1 mmol) of 2-{4-[(tert-butoxycarbonyl)amino]phenyl}propanoic acid were treated at 4° C. under nitrogen with 146 μl (2 mmol) of thionylchloride. The reaction mixture was stirred for 2.5 hours and the temperature was gradually raised to room temperature. The mixture was taken up with tetrahydrofuran and evaporated thoroughly. The resulting acyl chloride, without any further purification, was dissolved in 3 ml of dry tetrahydrofuran and added dropwise to a solution of 178 mg (0.8 mmol) of tert-butyl-5-amino-3-cyclopropyl-1H-pyrazole-1-carboxylate in 3 ml of tetrahydrofuran. 312 mg (1 mmol, loading 3.2 mmol/g) of polymer supported triethylamine were then added under stirring. After 2.5 hours 80 mg (loading 3.2 mmol/g) of polymer supported trisamine were finally added in order to quench the excess of acyl chloride. After 2 hours, the resins were filtered and washed with methanol and dichloromethane. Evaporation of the filtrate afforded 263 mg of the title compound as a foam (70% yield).
Reaction SMILES: [CH3:1][CH:2]1[CH2:8][C:7](=O)[C:6]2[CH:10]=[C:11]([CH2:14][C:15]([OH:17])=[O:16])[CH:12]=[CH:13][C:5]=2[CH2:4][CH2:3]1.[BH4-].[Na+].Cl>CO.O>[CH3:1][CH:2]1[CH:8]=[CH:7][C:6]2[CH:10]=[C:11]([CH2:14][C:15]([OH:17])=[O:16])[CH:12]=[CH:13][C:5]=2[CH2:4][CH2:3]1
Reactant: CC1CCc2ccc(CC(=O)O)cc2C(=O)C1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC1C=Cc2cc(CC(=O)O)ccc2CC1
Temperature: 25 °C

Procedure:
6,7,8,9-tetrahydro-7-methyl-9-oxo-5H-benzocycloheptene-2-acetic acid (6.3 g) is dissolved in 90 cc of methanol, and 4.1 g of sodium borohydride are added in small portions within 10 minutes while stirring at room temperature. The solution is stirred for a further 30 minutes, is diluted with water, acidified with 1 N hydrochloric acid, and the crude 6,7,8,9-tetrahydro-9-hydroxy-7-methyl-5H-benzocycloheptene-2-acetic acid is filtered off. The crude product has a M.P. of 161°-163°.
Reaction SMILES: ClCCl.[Cl:4][C:5]1[N:10]=[C:9]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]#[N:19])=[CH:14][CH:13]=2)[N:8]=[C:7]([NH:20][C:21](=[O:28])[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:6]=1.[Br:29]Br.S(S([O-])(=O)=O)([O-])(=O)=O>O.C(O)(=O)C>[Br:29][C:6]1[C:7]([NH:20][C:21](=[O:28])[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)=[N:8][C:9]([NH:11][C:12]2[CH:13]=[CH:14][C:15]([C:18]#[N:19])=[CH:16][CH:17]=2)=[N:10][C:5]=1[Cl:4]
Reactant: BrBr
Reactant: N#Cc1ccc(Nc2nc(Cl)cc(NC(=O)c3ccccc3)n2)cc1
Agent: O=S(=O)([O-])S(=O)(=O)[O-]
Solvent: O
Solvent: ClCCl
Solvent: CC(=O)O
Product: N#Cc1ccc(Nc2nc(Cl)c(Br)c(NC(=O)c3ccccc3)n2)cc1
Reaction time: 11 h

Procedure:
1500 ml of dichloromethane and 150 g of N-[6-chloro-2-(4-cyanophenylamino)pyrimidin-4-yl]benzamide were added to a reaction vessel and to this was added 750 ml of acetic acid and 44.2 mL of liquid bromine solution at 27±3° C. and stirred for 11 hrs. After completion of the reaction, to the reaction mixture was added 375 ml of water under stirring and maintained for 45 mins. To the reaction mixture was further added metabisulphate solution (60 g in 375 ml of water) and stirred further for 30 mins. The solid was filtered and washed with 300 ml of water and suck dried. The wet cake and 1500 ml of water were charged into a clean RB and adjusted pH 9.0±0.5 with 50% potassium carbonate solution. The reaction mass was stirred and filtered; the solid was washed with 150 ml of water followed by 150 ml of dichloromethane. The obtained solid was dried under vacuum at 73±2° C. to yield the title compound.
Reaction SMILES: COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:10])=CC=1.[Cl:23][C:24]1[C:40]([C:41]([F:44])([F:43])[F:42])=[CH:39][CH:38]=[CH:37][C:25]=1[CH2:26][N:27]1[C@@H:32]([CH2:33][CH3:34])[CH2:31][NH:30][C:29](=O)[C:28]1=[O:36]>C1COCC1>[Cl:23][C:24]1[C:40]([C:41]([F:44])([F:43])[F:42])=[CH:39][CH:38]=[CH:37][C:25]=1[CH2:26][N:27]1[C@@H:32]([CH2:33][CH3:34])[CH2:31][NH:30][C:29](=[S:10])[C:28]1=[O:36]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CC[C@H]1CNC(=O)C(=O)N1Cc1cccc(C(F)(F)F)c1Cl
Solvent: C1CCOC1
Product: CC[C@H]1CNC(=S)C(=O)N1Cc1cccc(C(F)(F)F)c1Cl
Temperature: 55 °C
Yield: 181.3 %

Procedure:
To a heterogeneous mixture of Lawesson's reagent (346 mg, 0.83 mmol) in THF (16 mL) was added (6S)-1-(2-chloro-3-(trifluoromethyl)benzyl)-6-ethylpiperazine-2,3-dione (555 mg, 1.7 mmol) at once. The mixture was heated at 55° C. for 20 minutes and then concentrated to remove the solvent. Purification by chromatography (SiO2; hexanes—100% EtOAc) afforded the desired product as a yellow oil (528 mg, 91%). MS (ESI): mass calcd. for C14H14ClF3N2OS, 350.1; m/z found, 335.1 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 8.99 (s, 1H), 7.69 (dd, J=15.9, 7.8 Hz, 2H), 7.38 (t, J=7.8 Hz, 1H), 5.24 (d, J=15.3 Hz, 1H), 4.50 (d, J=15.3 Hz, 1H), 3.67 (dd, J=13.7, 3.9 Hz, 1H), 3.45 (dd, J=12.8, 5.4 Hz, 2H), 1.91-1.75 (m, 2H), 1.00 (t, J=7.5 Hz, 3H).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][O:7][CH2:8][CH2:9][NH:10][OH:11].[C:12](Cl)(=[O:14])[CH3:13].C(N(CC)CC)C.[Li+].[OH-]>CC(O)C>[OH:11][N:10]([CH2:9][CH2:8][O:7][CH2:6][C:2]1[S:1][CH:5]=[CH:4][CH:3]=1)[C:12](=[O:14])[CH3:13]
Reactant: CC(=O)Cl
Reactant: ONCCOCc1cccs1
Agent: [Li+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: CC(=O)N(O)CCOCc1cccs1

Procedure:
The title compound is prepared from 2-(thien-2-ylmethoxy)ethyl hydroxylamine from Example 19 by first reaction with 3 equivalents of acetyl chloride and 3.3 equivalents of triethylamine followed by treatment with LiOH in 2-propanol.
Reaction SMILES: C1CCN2C(=NCCC2)CC1.[CH:12](=[O:21])/[CH:13]=[CH:14]/[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[N:22]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:23]>ClCCl>[OH:23][N:22]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:12](=[O:21])/[CH:13]=[CH:14]/[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C/C=C/c1ccccc1
Reactant: O=Nc1ccccc1
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Product: O=C(/C=C/c1ccccc1)N(O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
DBU (15 mg, 0.1 mmol) was added under argon to a solution of (E)-cinnamaldehyde (132 mg, 1 mmol), nitrosobenzene (107 mg, 1 mmol) and catalyst (36.4 mg, 0.1 mmol) in dichloromethane (5 mL). The reaction mixture was stirred at room temperature for 10 min. The solvent was removed under vacuum, and the residue was purified by flash silica gel column chromatography using hexane and ethyl acetate as the eluents.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[CH2:14][CH:13]=[C:12]2[CH2:18][C:19]([N:21]1[CH2:26][CH2:25][N:24]([C:27]2[C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[CH:30]=[CH:29][CH:28]=2)[CH2:23][CH2:22]1)=O.C(C(C(C([O-])=O)O)O)([O-])=O.[K+].[Na+]>CCOCC>[CH3:7][O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[CH2:14][CH:13]=[C:12]2[CH2:18][CH2:19][N:21]1[CH2:22][CH2:23][N:24]([C:27]2[C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[CH:30]=[CH:29][CH:28]=2)[CH2:25][CH2:26]1
Reactant: COc1ccc2c(c1)C(CC(=O)N1CCN(c3cccc4ccccc34)CC1)=CC2
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: CCOCC
Product: COc1ccc2c(c1)C(CCN1CCN(c3cccc4ccccc34)CC1)=CC2

Procedure:
0.76 g (0.02 mol) of lithium aluminum hydride are placed under an argon atmosphere in a 500 ml round-bottomed flask and covered with diethyl ether. A Soxhlet extractor containing 2.0 g (0.005 mol) of 4-[(5-methoxy-1H-inden-3-yl)acetyl]-1-(naphth-1-yl)piperazine is placed on top of the flask, and the mixture is reacted with refluxing of the ether for 30 h. The reaction mixture is treated with 1.6 ml of 10% aqueous sodium potassium tartrate solution and filtered. The solid is washed with diethyl ether and then with tetrahydrofuran, and the filtrate is evaporated under reduced pressure.
Reaction SMILES: Cl.[F:2][C:3]1[CH:25]=[CH:24][C:6]([C:7]([NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH:17]3[CH2:22][CH2:21][N:20](C)[CH2:19][CH2:18]3)[N:11]=2)=[O:8])=[CH:5][CH:4]=1.[Cl:26]CCCl.ClC(OC(Cl)C)=O.[Cl-].[NH4+]>CO>[ClH:26].[F:2][C:3]1[CH:4]=[CH:5][C:6]([C:7]([NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH:17]3[CH2:18][CH2:19][NH:20][CH2:21][CH2:22]3)[N:11]=2)=[O:8])=[CH:24][CH:25]=1
Reactant: ClCCCl
Reactant: CN1CCC(Oc2cccc(NC(=O)c3ccc(F)cc3)n2)CC1
Agent: CC(Cl)OC(=O)Cl
Agent: Cl
Agent: [Cl-]
Solvent: CO
Product: O=C(Nc1cccc(OC2CCNCC2)n1)c1ccc(F)cc1
Temperature: 80 °C
Yield: 29 %

Procedure:
Combine 4-fluoro-N-[6-(1-methyl-piperidin-4-yloxy)-pyridin-2-yl]-benzamide hydrochloride (example 161, 365 mg, 1.11 mmol) and 1,2-dichloroethane (10 mL) and add 1-chloroethyl chloroformate (1.20 mL, 11.1 mmol). Heat the reaction to 80° C. for 18 hr. Add additional 1-chloroethyl chloroformate (600 μL, 5.5 mmol) and continue to heat at 80° C. for 5 hr. Cool reaction to ambient temperature and add methanol. Load solution onto an SCX column and wash with methanol. Flush off product with 2 M ammonia in methanol and concentrate in vacuo. Purify by column chromatography (2%-8% 2 M NH3 in methanol/CH2Cl2). Make the hydrogen chloride salt by sonication with one equivalent of ammonium chloride dissolved in methanol to yield of the title compound (115 mg, 29%). Mass spectrum (ion spray): m/z 316.3 (M+1); Analysis calculated for C17H19N3O2FCl.0.5H2O. Theory: C, 56.59; H, 5.59; N, 11.65. Found: C, 56.83; H, 5.38; N, 11.74. mp=251-3° C.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][S:10]([CH3:13])(=[O:12])=[O:11])=[C:5]([F:14])[CH:4]=1.C(N(CC)CC)C.[F:22][S:23]([F:37])([F:36])([F:35])([F:34])[C:24]1[CH:33]=[CH:32][C:27]([CH2:28][N:29]=[C:30]=[S:31])=[CH:26][CH:25]=1>CN(C)C=O>[F:22][S:23]([F:34])([F:35])([F:36])([F:37])[C:24]1[CH:25]=[CH:26][C:27]([CH2:28][NH:29][C:30](=[S:31])[NH:1][CH2:2][C:3]2[CH:8]=[CH:7][C:6]([NH:9][S:10]([CH3:13])(=[O:12])=[O:11])=[C:5]([F:14])[CH:4]=2)=[CH:32][CH:33]=1
Reactant: CS(=O)(=O)Nc1ccc(CN)cc1F
Reactant: FS(F)(F)(F)(F)c1ccc(CN=C=S)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CS(=O)(=O)Nc1ccc(CNC(=S)NCc2ccc(S(F)(F)(F)(F)F)cc2)cc1F
Temperature: 25 °C

Procedure:
N-(4-aminomethyl-2-fluoro-phenyl)-methane sulphonamide (237 mg, 1.09 mmol) was dissolved in dimethylformamide (1 ml) and to this was added triethylamine (132 mg, 1.30 mmol) and 4-(pentafluorosulphanyl)benzylisothiocyanate (300 mg, 1.09 mmol) dissolved in dimethylformamide (1 ml). The reaction mixture was stirred over night at room temperature, the solvent removed under vacuum and the residue dissolved in a little methanol. Following column chromatographic cleaning (silica gel, hexane/ethyl acetate 1:5), the product was obtained as a solid (305 mg, 57% of the theoretical amount).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:34])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19](B5OC(C)(C)C(C)(C)O5)[CH:20]=[CH:21][C:22]=4[F:24])[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1.Br[C:36]1[C:41]([CH3:42])=[CH:40][C:39]([C:43]2[C:48]([CH3:49])=[CH:47][CH:46]=[CH:45][N:44]=2)=[CH:38][C:37]=1[CH3:50].BrC1C=CC(F)=C2C=1CC[C@H]2OC1C=CC2[C@H](CC(OC)=O)COC=2C=1>>[CH3:1][O:2][C:3](=[O:34])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19]([C:36]5[C:37]([CH3:50])=[CH:38][C:39]([C:43]6[C:48]([CH3:49])=[CH:47][CH:46]=[CH:45][N:44]=6)=[CH:40][C:41]=5[CH3:42])[CH:20]=[CH:21][C:22]=4[F:24])[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1
Reactant: Cc1cccnc1-c1cc(C)c(Br)c(C)c1
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(B5OC(C)(C)C(C)(C)O5)ccc(F)c43)ccc21
Agent: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(Br)ccc(F)c43)ccc21
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(-c5c(C)cc(-c6ncccc6C)cc5C)ccc(F)c43)ccc21

Procedure:
The title compound is prepared from {(S)-6-[(R)-7-fluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester and 2-(4-bromo-3,5-dimethyl-phenyl)-3-methyl-pyridine following a procedure analogous to that described in Step 5 of Intermediate 1. LC (method 7): tR=1.07 min; Mass spectrum (ESI+): m/z=538 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][CH:15]=1)[C:12]([NH:16][CH2:17][CH2:18][CH2:19][NH2:20])=[C:11]1[C:6]([CH2:7][CH2:8][CH2:9][CH2:10]1)=[N:5]2.[NH:21]1[C:30]2[CH2:29][CH2:28][C:27](=O)[CH2:26][C:25]=2[CH:24]=[CH:23][C:22]1=[O:32].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][CH:15]=1)[C:12]([NH:16][CH2:17][CH2:18][CH2:19][NH:20][CH:27]1[CH2:28][CH2:29][C:30]3[NH:21][C:22](=[O:32])[CH:23]=[CH:24][C:25]=3[CH2:26]1)=[C:11]1[C:6]([CH2:7][CH2:8][CH2:9][CH2:10]1)=[N:5]2
Reactant: O=C1CCc2[nH]c(=O)ccc2C1
Reactant: NCCCNc1c2c(nc3cc(Cl)ccc13)CCCC2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: O=c1ccc2c([nH]1)CCC(NCCCNc1c3c(nc4cc(Cl)ccc14)CCCC3)C2
Reaction time: 24 h
Yield: 36.6 %

Procedure:
To a mixture of N1-(6-Chloro-1,2,3,4-tetrahydro-acridin-9-yl)-propane-1,3-diamine (50 mg, 0.17 mmoL), 1,5,7,8-Tetrahydro-quinoline-2,6-dione (31 mg, 0.19 mmoL) in 5 mL methylene chloride, was added sodium triacetoxyborohydride (110 mg, 0.52 mmoL) and a catalytic amount of acetic acid. After stiring at room temperature for 24 h, the reaction was stopped by adding saturated sodium bicarbonate. The mixture was extracted with methylene chloride three times. The combined methylene chloride extract was dried, filtered and concentrated. Purification by column chromatography on silica gel column with 10% MeOH/1% ammonium hydroxide in methylene chloride provided the desired product (27.6 mg, 0.063 mmoL, 37%).
Reaction SMILES: [Cl:1][C:2]1[NH:7][C:6]2=[N:8][CH:9]=[CH:10][C:5]2=[C:4]([C:11]2[O:12][CH:13]=[CH:14][CH:15]=2)[N:3]=1.[H-].[Na+].[F:18][C:19]1[CH:26]=[CH:25][CH:24]=[CH:23][C:20]=1[CH2:21]Br>CN(C=O)C>[Cl:1][C:2]1[N:3]=[C:4]([C:11]2[O:12][CH:13]=[CH:14][CH:15]=2)[C:5]2[CH:10]=[CH:9][N:8]([CH2:21][C:20]3[CH:23]=[CH:24][CH:25]=[CH:26][C:19]=3[F:18])[C:6]=2[N:7]=1
Reactant: Fc1ccccc1CBr
Reactant: Clc1nc(-c2ccco2)c2ccnc-2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Fc1ccccc1Cn1ccc2c(-c3ccco3)nc(Cl)nc21
Reaction time: 0.33 h
Yield: 76.3 %

Procedure:
A solution of 2-chloro-4-(2-furyl)-1H-pyrrolo[2,3-d]pyrimidine (219 mg, 1 mmol) in DMF (2 mL) at 0° C. was treated with NaH (40 mg, 60%, 1 mmol), stirred for 20 min, treated with 2-fluorobenzyl bromide (120 μL, 1 mmol), stirred at room temperature for 1 h, quenched with water, extracted with EtOAc, dried (MgSO4), concentrated in vacuo and purified by chromatography (EtOAc:Heptane, 1:4) to give the title compound (250 mg, 76%) as a cream solid.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5](N2C(CO)=NN=C2C)=[C:6]([CH:15]=1)[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:8].CS(Cl)(=O)=O.CNC.[I-].[K+]>C(N(CC)CC)C>[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=[O:8])[C:6]1[CH:15]=[CH:2][CH:3]=[CH:4][CH:5]=1
Reactant: Cc1nnc(CO)n1-c1ccc(Cl)cc1C(=O)c1ccccc1
Agent: CNC
Agent: CS(=O)(=O)Cl
Agent: [I-]
Solvent: CCN(CC)CC
Product: O=C(c1ccccc1)c1ccccc1

Procedure:
In the manner given in Example 21, 5-chloro-[3-methyl-5-(hydroxymethyl)-4H-1,2,4-triazol-4-yl]benzophenone was reacted with methanesulfonyl chloride in the presence of triethylamine and the resulting solution, treated with gaseous dimethylamine in the presence of potassium iodide, to give 5-chloro-2-[3-methyl-5-(dimethylamino)methyl]-4H-1,2,4-triazol-4-yl]benzophenone of melting point 171°-172°.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[C:5]([O:10][CH2:11][CH2:12][CH2:13][O:14][C:15]3[CH:27]=[CH:26][C:18]4[C:19]([C:22]([F:25])([F:24])[F:23])=[N:20][O:21][C:17]=4[C:16]=3[CH2:28][CH2:29][CH3:30])[CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[CH3:31][O:32][C:33](=[O:36])[CH2:34]Br.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>C(#N)C>[CH3:31][O:32][C:33](=[O:36])[CH2:34][N:1]1[C:9]2[C:4](=[C:5]([O:10][CH2:11][CH2:12][CH2:13][O:14][C:15]3[CH:27]=[CH:26][C:18]4[C:19]([C:22]([F:24])([F:23])[F:25])=[N:20][O:21][C:17]=4[C:16]=3[CH2:28][CH2:29][CH3:30])[CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: CCCc1c(OCCCOc2cccc3[nH]ccc23)ccc2c(C(F)(F)F)noc12
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: CCCc1c(OCCCOc2cccc3c2ccn3CC(=O)OC)ccc2c(C(F)(F)F)noc12
Temperature: 25 °C
Yield: 75.6 %

Procedure:
A mixture of 6-[3-(1H-indol-4-yloxy)-propoxy]-7-propyl-3-trifluoromethyl-benzo[d]isoxazole (0.100 g, 0.24 mmol), methyl-2-bromoacetate (0.109 g, 0.72 mmol), potassium carbonate (0.050 g, 0.36 mmol), potassium iodide (0.008 g, 0.05 mmol), and acetonitrile (15 mL) was stirred and refluxed for 12 hours. The mixture was cooled to room temperature and filtered to remove suspended salts. The solvent was removed in vacuo and the residue partitioned between dichloromethane and water. The organic layer was collected, washed with water (2×20 mL) and brine (2×20 mL), and then dried over anhydrous Na2SO4. The solvent was removed and the residue was purified by flash chromatograph over silica gel using hexane/ethyl acetate (95/5) as an eluant to afford {4-[3-(7-propyl-3-trifluoromethyl-benzo[d]isoxazol-6-yloxy)-propoxy]-indol-1-yl}-acetic acid methyl ester (0.089 g, yield: 76%).
Reaction SMILES: [CH2:1]([C@:3]12[CH2:11][CH2:10][C:9]3[C:12]4[CH:13]=[CH:14][C:15]([O:21][CH3:22])=[CH:16][C:17]=4[CH:18]([CH3:20])[CH2:19][C:8]=3[C@@H:7]1[CH2:6][CH2:5][C:4]12[O:26][CH2:25][CH2:24][O:23]1)[CH3:2].N.NC1C=CC=CC=1.[Li]>O1CCCC1>[CH2:1]([C@:3]12[CH2:11][CH2:10][C@@H:9]3[C:12]4[CH:13]=[CH:14][C:15]([O:21][CH3:22])=[CH:16][C:17]=4[CH:18]([CH3:20])[CH2:19][C@H:8]3[C@@H:7]1[CH2:6][CH2:5][C:4]12[O:23][CH2:24][CH2:25][O:26]1)[CH3:2]
Reactant: CC[C@]12CCC3=C(CC(C)c4cc(OC)ccc43)[C@@H]1CCC21OCCO1
Agent: N
Agent: [Li]
Solvent: C1CCOC1
Solvent: Nc1ccccc1
Product: CC[C@]12CC[C@@H]3c4ccc(OC)cc4C(C)C[C@H]3[C@@H]1CCC21OCCO1
Yield: 85.9 %

Procedure:
Add dl-13-ethyl-3-methoxy-6-methyl-17,17-ethylenedioxygona-1,3,5(10),8-tetraene (11.0 g) in tetrahydrofuran (160 ml) to liquid ammonia (600 ml) containing tetrahydrofuran (170 ml) and aniline (30 ml). Then add lithium (0.6 g) in small portions and stir for 2 hours. Work up in the usual way to obtain dl-13-ethyl-3-methoxy-6-methyl-17,17-ethylenedioxygona-1,3,5-(10)-triene as a gum (9.5 g) that will crystallize on scratching. Recrystallize from isopronanol to obtain a product with m.p. 130°-134°; ultaviolet absorption peak at 280 mμ (ε1,976), no infrared absorption in the ketone region.