Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:20]=[CH:19][C:5]([CH2:6][C:7]([CH3:18])([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:4][CH:3]=1.Cl[CH2:22][CH2:23][NH:24][CH2:25][CH2:26]Cl.Cl>C1(C)C(C)=CC=CC=1>[N:1]1([C:2]2[CH:3]=[CH:4][C:5]([CH2:6][C:7]([CH3:18])([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:19][CH:20]=2)[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1
Reactant: CCOC(=O)C(C)(Cc1ccc(N)cc1)C(=O)OCC
Reactant: ClCCNCCCl
Agent: Cl
Solvent: Cc1ccccc1C
Product: CCOC(=O)C(C)(Cc1ccc(N2CCNCC2)cc1)C(=O)OCC
Yield: 76.3 %

Procedure:
A solution of diethyl 2-(4-aminobenzyl)-2-methylmalonate (2.00 g, 7.17 mmol) and Bis-(2-chloroethyl) amine.HCl (1.90 g, 10.8 mmol) in xylene (10 ml) were heated at reflux for 48 h. The reaction mixture was concentrated and the residue was partitioned between saturated sodium bicarbonate solution and ethyl acetate. The separated organic layer was washed with water, brine solution, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give the crude product. Purification by column chromatography over neutral alumina using 5% methanol in CHCl3 as eluent afforded 1.90 g (76.3%) of diethyl 2-(4-(piperazin-1-yl)benzyl)-2-methylmalonate as brown oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[N:11]3[N:18]=[CH:19][C:20]([C:21]#[CH:22])=[C:10]3[N:9]=2)=[CH:4][C:3]=1[CH3:23].Br[C:25]1[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]([F:15])([F:17])[F:16])[N:11]3[N:18]=[CH:19][C:20]([C:21]#[C:22][C:25]4[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=4)=[C:10]3[N:9]=2)=[CH:4][C:3]=1[CH3:23]
Reactant: Brc1cccnc1
Reactant: C#Cc1cnn2c(C(F)(F)F)cc(-c3ccc(Cl)c(C)c3)nc12
Product: Cc1cc(-c2cc(C(F)(F)F)n3ncc(C#Cc4cccnc4)c3n2)ccc1Cl

Procedure:
The title compound was prepared from 5-(4-chloro-3-methyl-phenyl)-3-ethynyl-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine (example C.11) (336 mg, 1.0 mmol) and commercially available 3-bromopyridine (158 mg, 1.0 mmol) according to general procedure II. Obtained as a yellow solid (90 mg, 22%). MS (ISP) 413.0 [(M+H)+]; mp 196° C.
Reaction SMILES: [OH-].[Na+].[C:3]([C:7]1[CH:8]=[C:9]([C:18]2[CH:19]=[C:20]([C:30]3[CH:35]=[CH:34][C:33]([C:36]([O:38]CC)=[O:37])=[CH:32][CH:31]=3)[CH:21]=[CH:22][C:23]=2[O:24][CH2:25][CH2:26][CH2:27][CH2:28][OH:29])[CH:10]=[CH:11][C:12]=1[N:13]([CH2:16][CH3:17])[CH2:14][CH3:15])([CH3:6])([CH3:5])[CH3:4].Cl>O1CCCC1.O.CCCCCCC>[C:3]([C:7]1[CH:8]=[C:9]([C:18]2[CH:19]=[C:20]([C:30]3[CH:31]=[CH:32][C:33]([C:36]([OH:38])=[O:37])=[CH:34][CH:35]=3)[CH:21]=[CH:22][C:23]=2[O:24][CH2:25][CH2:26][CH2:27][CH2:28][OH:29])[CH:10]=[CH:11][C:12]=1[N:13]([CH2:14][CH3:15])[CH2:16][CH3:17])([CH3:5])([CH3:6])[CH3:4]
Reactant: CCOC(=O)c1ccc(-c2ccc(OCCCCO)c(-c3ccc(N(CC)CC)c(C(C)(C)C)c3)c2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCCCCCC
Product: CCN(CC)c1ccc(-c2cc(-c3ccc(C(=O)O)cc3)ccc2OCCCCO)cc1C(C)(C)C
Temperature: 25 °C
Reaction time: 12 h
Yield: 82.8 %

Procedure:
0.9 mL of aqueous 1N sodium hydroxide solution is added to a solution of 300 mg of ethyl 3″-tert-butyl-4″-diethylamino-4′-(4-hydroxybutoxy)-[1,1′;3′,1″]terphenyl-4-carboxylate (Example 2b) in a mixture of 10 mL of tetrahydrofuran and 3 mL of water. The reaction medium is stirred at room temperature for 12 hours. 0.5 mL of aqueous 1N sodium hydroxide solution is then added. After 12 hours at room temperature, the reaction medium is heated to 50° C. and then left at room temperature for 3 days. The reaction is stopped by adding 5 mL of water. The reaction medium is acidified to pH 5 by adding aqueous 1N hydrochloric acid solution and is then extracted with ethyl acetate. The organic phase is dried over magnesium sulfate. The solid obtained is taken up in heptane and then filtered. 235 mg of 3″-tert-butyl-4″-diethylamino-4′-(4-hydroxybutoxy)-[1,1′;3′,1″]terphenyl-4-carboxylic acid are obtained in the form of a white solid (yield=83%, m.p.=165° C.).
Reaction SMILES: [NH2:1][C:2]1[C:3]([OH:13])=[C:4]([S:9]([NH2:12])(=[O:11])=[O:10])[C:5]([Cl:8])=[CH:6][CH:7]=1.[Cl:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[N:21]=[C:22]=[O:23]>CN(C)C=O.C(OCC)(=O)C>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:22]([NH:21][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[Cl:14])=[O:23])=[C:3]([OH:13])[C:4]=1[S:9]([NH2:12])(=[O:11])=[O:10]
Reactant: O=C=Nc1ccccc1Cl
Reactant: Nc1ccc(Cl)c(S(N)(=O)=O)c1O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: NS(=O)(=O)c1c(Cl)ccc(NC(=O)Nc2ccccc2Cl)c1O
Yield: 44.3 %

Procedure:
A solution of 3-amino-6-chloro-2-hydroxybenzenesulfonamide (40mg, 0.18mmol) and 2-chlorophenylisocyanate (33 mg, 0.22 mmol) in 1 mL of N,N-dimethyl-formamide was stirred at room temperature for 18 hours. The mixture was diluted with ethyl acetate and washed with water to give the crude material. Purification by column chromatography on silica gel, eluting with ethyl acetate/hexane (30/70, v/v), followed by recrystallization from acetone and hexane, gave the desired product (30 mg, 44%). EI-MS (m/z) 374.3, 376.1 (M−).
Reaction SMILES: [NH:1]([C:8]([N:10]1[CH2:15][CH2:14][N:13]([CH2:16][C@@H:17]2[CH2:22][CH2:21][CH2:20][N:19](C(OC(C)(C)C)=O)[CH2:18]2)[CH2:12][CH2:11]1)=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>ClCCl>[C:2]1([NH:1][C:8]([N:10]2[CH2:11][CH2:12][N:13]([CH2:16][C@@H:17]3[CH2:22][CH2:21][CH2:20][NH:19][CH2:18]3)[CH2:14][CH2:15]2)=[O:9])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](CN2CCN(C(=O)Nc3ccccc3)CC2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(Nc1ccccc1)N1CCN(C[C@@H]2CCCNC2)CC1
Reaction time: 2 h

Procedure:
tert-Butyl (3S)-3-{[4-(anilinocarbonyl)piperazin-1-yl]methyl}piperidine-1-carboxylate (4.0 g) was added to a mixture of dichloromethane (20 ml) and TFA (20 ml) and the reaction mixture stirred for 2 h. The solvent was removed in-vacuo and the residue dissolved in dichloromethane (20 ml) and subsequently poured into hydrochloric acid solution (1N, 20 ml). The aqueous layer was basified using potassium carbonate and extracted with dichloromethane (3×15 ml). The organic layer was dried using a phase separation cartridge and the solvent removed under reduced pressure to afford the desired compound as a white foam white (2.0 g), which was used without further purification.
Reaction SMILES: [OH:1][CH2:2][C:3]#[C:4][C:5]1[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][CH:6]=1>CO.[Pd].CC([O-])=O.CC([O-])=O.[Pb+2]>[OH:1][CH2:2][CH:3]=[CH:4][C:5]1[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][CH:6]=1
Reactant: COC(=O)c1ccc(C#CCO)cc1
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Pb+2]
Solvent: CO
Product: COC(=O)c1ccc(C=CCO)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 74.2 %

Procedure:
To a solution of methyl 4-(3-hydroxy-1-propinyl)benzoate (2 g) in methanol (32 mL) is added Lindlar catalyst (238 mg) and the mixture is stirred under hydrogen gas atmosphere at room temperature for 18 hours. To the reaction mixture is added Lindlar catalyst (90 mg) and the mixture is stirred for 1 hour. The reaction mixture is filtered to remove insoluble materials through Celite. The filtrate is concentrated in vacuo and the residue is purified by column chromatography on silica gel (Solvent; n-hexane:ethyl acetate=100:0→50:50) to give methyl 4-(3-hydroxy-1-propenyl)-benzoate (1.5 g, yield; 75%) as an amorphous powder. MS (APCI) m/z; 175 [M+H−H2O]+
Reaction SMILES: Br.[CH2:2]([C@@H:4]1[NH:9][C@@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C@@H:7]([N+:16]([O-])=O)[CH2:6][CH2:5]1)[CH3:3]>CO.[Ni]>[CH2:2]([CH:4]1[NH:9][CH:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:7]([NH2:16])[CH2:6][CH2:5]1)[CH3:3]
Reactant: CC[C@H]1CC[C@H]([N+](=O)[O-])[C@H](c2ccccc2)N1
Agent: [Ni]
Agent: Br
Solvent: CO
Product: CCC1CCC(N)C(c2ccccc2)N1
Reaction time: 4 h
Yield: 72.3 %

Procedure:
To a 250 ml Parr bottle was charged 1 gm (3.18 mmol) of the (2S,3S,6S)-6-Ethyl-3-nitro-2-phenyl-piperidine HBr salt prepared above in 60 ml of methanol. To the resulting solutionwas added an excess of commercial Raney nickel which had been exhaustively washed with deionized water until the supernatant was pH 7.00. The reaction mixture was placed under 50 p.s.i. in a Parr Hydrogenator and shaken for 4 hrs. The reaction mixture was filtered through celite and the filtrate was evaporated in vacuo. The residue was partitioned between methylene chloride and 1N NaOH. The combined organics were washed with brine and then dried and evaporated to afford 0.47 gm (72%) of crude racemic 6-Ethyl-2-phenyl-piperidin-3-ylamine. Such racemate was resolved through the formation of a salt with (−)-O,O′-dibenzoyl-L-tartaric acid in isopropanol water. 1H NMR (CDCl3, 400 MHz) δ 7.4–7.2 (br.m, 5H), 4.05 (d), 3.0 (br.t), 2.90 (m), 1.98 (m), 1.75 (m), 1.6–1.4 (m), 0.80 (t, 3H), ppm. Mass spectra m/z=205 (p+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][CH2:15][N:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1)[N:9]=[CH:8][N:7]=[C:6]2[O:22][C:23]1[CH:24]=[C:25]([CH:27]=[CH:28][CH:29]=1)[NH2:26].[F:30][C:31]([C:34]1[CH:38]=[C:37]([NH:39][C:40](=O)[O:41]C2C=CC=CC=2)[O:36][N:35]=1)([CH3:33])[CH3:32]>CN(C)C1C=CN=CC=1>[F:30][C:31]([C:34]1[CH:38]=[C:37]([NH:39][C:40]([NH:26][C:25]2[CH:27]=[CH:28][CH:29]=[C:23]([O:22][C:6]3[C:5]4[C:10](=[CH:11][C:12]([O:13][CH2:14][CH2:15][N:16]5[CH2:21][CH2:20][O:19][CH2:18][CH2:17]5)=[C:3]([O:2][CH3:1])[CH:4]=4)[N:9]=[CH:8][N:7]=3)[CH:24]=2)=[O:41])[O:36][N:35]=1)([CH3:32])[CH3:33]
Reactant: CC(C)(F)c1cc(NC(=O)Oc2ccccc2)on1
Reactant: COc1cc2c(Oc3cccc(N)c3)ncnc2cc1OCCN1CCOCC1
Agent: CN(C)c1ccncc1
Product: COc1cc2c(Oc3cccc(NC(=O)Nc4cc(C(C)(C)F)no4)c3)ncnc2cc1OCCN1CCOCC1
Yield: 49 %

Procedure:
Using the procedure described in Example 229B by using 3-(6-methoxy-7-(2-morpholinoethoxy)quinazolin-4-yloxy)aniline described in Example 251A Step 3 (146 mg, 0.37 mmol) was reacted with phenyl 3-(2-fluoropropan-2-yl)isoxazol-5-ylcarbamate from Example 42A (117 mg, 0.44 mmol) and 4-(dimethylamino)pyridine (45 mg, 0.37 mmol) to give 1-(3-(2-fluoropropan-2-yl)isoxazol-5-yl)-3-(3-(6-methoxy-7-(2-morpholinoethoxy)quinazolin-4-yloxy)phenyl)urea (101.6 mg, 49%) as a solid. 1H NMR (300 MHz, DMSO-d6) δ 10.41 (s, 1H), 9.11 (s, 1H), 8.56 (s, 1H), 7.57 (s, 2H), 7.44-7.40 (m, 2H), 7.32 (d, 1H), 7.00 (d, 1H), 6.15 (s, 1H), 4.35-4.33 (m, 2H), 3.98 (s, 3H), 3.62-3.60 (m, 4H), 2.85-2.70 (m, 2H), 2.52-2.50 (m, 4H), 1.70 (s, 3H), 1.63 (s, 3H); LC-MS (ESI) m/z 567 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][F:9])[N:3]=1.[N:10]1[NH:11][N:12]=[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=12>>[F:9][CH2:8][C:4]1[N:3]=[C:2]([C:8]#[C:4][CH2:5][CH2:6][N:11]2[N:12]=[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]3=[N:10]2)[CH:7]=[CH:6][CH:5]=1
Reactant: c1ccc2n[nH]nc2c1
Reactant: FCc1cccc(Br)n1
Product: FCc1cccc(C#CCCn2nc3ccccc3n2)n1
Yield: 75.9 %

Procedure:
The title compound was prepared in accordance with the general method of Example 1, from 2-bromo-6-(fluoromethyl)-pyridine (111 mg, 0.58 mmol, Example 190(E)) and 2-but-3-ynyl)-2H-benzo[d][1,2,3]triazole (100 mg, 0.58 mmol, Example 109(D)). Reaction time: 3 hours. The crude residue was purified by flash chromatography (DCM/MeOH 99:1) to yield 61 mg (0.22 mmol, 37%) of 2-(4-(6-(fluoromethyl)pyridin-2-yl)but-3-ynyl)-2H-benzo[d][1,2,3]triazole as a grey solid.
Reaction SMILES: Cl.[CH3:2][N:3]([CH3:11])[CH:4]1[CH2:9][CH2:8][C:7](=O)[CH2:6][CH2:5]1.Cl.[CH2:13]([O:20][C:21]1[CH:22]=[C:23]([NH:27]N)[CH:24]=[CH:25][CH:26]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(O)C>O>[CH3:2][N:3]([CH3:11])[CH:4]1[CH2:9][C:8]2[C:24]3[C:23](=[CH:22][C:21]([O:20][CH2:13][C:14]4[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=4)=[CH:26][CH:25]=3)[NH:27][C:7]=2[CH2:6][CH2:5]1
Reactant: NNc1cccc(OCc2ccccc2)c1
Reactant: CN(C)C1CCC(=O)CC1
Agent: Cl
Solvent: O
Solvent: CCO
Product: CN(C)C1CCc2[nH]c3cc(OCc4ccccc4)ccc3c2C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 15.8 g. of 4-dimethylaminocyclohexanone hydrochloride and 20.3 g. of 3-benzyloxyphenylhydrazine hydrochloride (m.p. 165°-168° C.) in 225 ml. of absolute ethyl alcohol was heated under reflux for three hours, cooled to room temperature, and diluted with 50 ml. of water. After standing for three hours the resulting crystals were collected by filtration and washed with ethyl alcohol to give, after recrystallization from ethyl alcohol, 6.1 g. of 3-(dimethylamino)-7-(benzyloxy)-1,2,3,4-tetrahydrocarbazole hydrochloride, m.p. 237°-239° C.
Reaction SMILES: [Cl:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][N:7]2[C:12](=[O:13])[C:11]([CH2:14]OS(C)(=O)=O)=[CH:10][C:9]([C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([F:28])[CH:21]=3)=[N:8]2)=[CH:4][CH:3]=1.[CH3:31][N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:12](=[O:13])[C:11]([CH2:14][N:35]3[CH2:36][CH2:37][N:32]([CH3:31])[CH2:33][CH2:34]3)=[CH:10][C:9]([C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([F:28])[CH:21]=3)=[N:8]2)=[CH:29][CH:30]=1
Reactant: CN1CCNCC1
Reactant: COc1ccc(-c2cc(COS(C)(=O)=O)c(=O)n(Cc3ccc(Cl)cc3)n2)cc1F
Product: COc1ccc(-c2cc(CN3CCN(C)CC3)c(=O)n(Cc3ccc(Cl)cc3)n2)cc1F
Yield: 39.5 %

Procedure:
Following the procedure of Example 1(10), 2-(4-chlorobenzyl)-6-(3-fluoro-4-methoxyphenyl)-4-methanesulfonyloxymethyl-2H-pyridazin-3-one and 1-methylpiperazine were reacted to yield the title compound as pale brown prisms (yield: 39.5%).
Reaction SMILES: [CH2:1]([OH:5])[C:2](=[CH2:4])[CH3:3].Cl[C:7]1[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=1.[OH-].[K+].O>S1(CCCC1)(=O)=O>[F:14][C:13]([F:16])([F:15])[C:10]1[CH:11]=[CH:12][C:7]([O:5][CH:1]=[C:2]([CH3:3])[CH3:4])=[CH:8][CH:9]=1
Reactant: FC(F)(F)c1ccc(Cl)cc1
Reactant: C=C(C)CO
Agent: [K+]
Agent: [OH-]
Solvent: O=S1(=O)CCCC1
Solvent: O
Product: CC(C)=COc1ccc(C(F)(F)F)cc1
Reaction time: 21 h

Procedure:
A mixture of 50.48 g of methallyl alcohol, 63.2 g of 4-chlorobenzotrifluoride and 69 g of 85% flake potassium hydroxide in 175 ml sulpholane was stirred under nitrogen at 120°-145° C. for 21 hours. The mixture was then cooled, added to 200 ml water and extracted twice with 60°/80° petroleum ether. The solvent was removed and the residue was purified by fractionation to give isobutenyl 4-trifluoromethylphenyl ether, b.p.: 77°-77.5° C. at 8 Torr.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[S:11](Cl)(=[O:13])=[O:12].[NH:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1>C(OCC)(=O)C>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[S:11]([N:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1)(=[O:13])=[O:12]
Reactant: O=C(O)c1ccc(Br)c(S(=O)(=O)Cl)c1
Reactant: C1COCCN1
Solvent: CCOC(C)=O
Product: O=C(O)c1ccc(Br)c(S(=O)(=O)N2CCOCC2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 88 %

Procedure:
4-Bromo-3-chlorosulfonyl-benzoic acid (2.2, 1.1 g) was dissolved in 20 mL of ethyl acetate and morpholine (Aa, 1.48 mL, 3 eq) was added. The mixture was stirred at room temperature for 2 hours, then extracted with 15 mL of 0.5M HCl. The organic layer was washed with H2O and brine and the solvent evaporated to yield 4-bromo-3-(morpholinosulfonyl)-benzoic acid (2.3.Aa) as an off-white powder (1.13 mg, 88% yield). MS analysis (m−1)=348.
Reaction SMILES: [CH3:1][N:2]1[C:8](=[O:9])[C:7]2[CH:10]=[CH:11][CH:12]=[CH:13][C:6]=2[N:5]2[CH:14]=[N:15][C:16]([C:17]([OH:19])=O)=[C:4]2[CH2:3]1.C(N1C=CN=C1)(N1C=CN=C1)=O.C(=O)=O.Cl.[CH3:36][O:37][C:38](=[O:43])[C@H:39]([CH2:41][OH:42])[NH2:40].C(N(CC)CC)C>CN(C)C=O.O>[OH:42][CH2:41][C@H:39]([NH:40][C:17]([C:16]1[N:15]=[CH:14][N:5]2[C:6]3[CH:13]=[CH:12][CH:11]=[CH:10][C:7]=3[C:8](=[O:9])[N:2]([CH3:1])[CH2:3][C:4]=12)=[O:19])[C:38]([O:37][CH3:36])=[O:43]
Reactant: CN1Cc2c(C(=O)O)ncn2-c2ccccc2C1=O
Reactant: COC(=O)[C@@H](N)CO
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Agent: O=C=O
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)[C@H](CO)NC(=O)c1ncn2c1CN(C)C(=O)c1ccccc1-2
Temperature: 25 °C
Reaction time: 70 h
Yield: 68.3 %

Procedure:
A suspension of 11.3 g (0.0437 mol) of 5-methyl-6-oxo-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylic acid in 220 ml of dimethylformamide was treated portionwise with 7.80 g (0.048 mol) of carbonyldiimidazole while gassing with argon. After completion of the CO2 evolution the mixture was stirred at 55° for 2 hrs. After cooling to 0°-5° the pale yellow solution obtained was treated with 7.48 g (0.0532 mol) of L-serine methyl ester hydrochloride and with 6.7 ml (0.048 mol) of triethylamine and stirred at room temperature for 70 hrs. The light suspension was completely freed from the solvents. The residue was dissolved in hot water and extracted continuously with ethyl acetate. The yellow oily residue was chromatographed over silica gel with ethyl acetate as the eluent. There were obtained 10.7 g (68%) of methyl (S)-3-hydroxy-2-(5-methyl-6-oxo-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepin-3-ylcarbonylamino)-propionate as a white solid. An analytical sample was recrystallized from ethyl acetate/diethyl ether and gave white crystals; m.p. 180°-181°. [α]D20 =+12.9° (CHCl3, c=1%).
Reaction SMILES: ClC(OCC)=O.[Br:7][C:8]1[C:13]([C:14](O)=[O:15])=[CH:12][CH:11]=[CH:10][N:9]=1.CCN(CC)CC.[H-].[H-].[H-].[H-].[Li+].[Al+3].C1COCC1>C1(C)C=CC=CC=1>[Br:7][C:8]1[C:13]([CH2:14][OH:15])=[CH:12][CH:11]=[CH:10][N:9]=1
Reactant: O=C(O)c1cccnc1Br
Agent: CCOC(=O)Cl
Agent: [Al+3]
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: OCc1cccnc1Br
Reaction time: 1 h

Procedure:
Add ethyl chloroformate (3.17 g, 29.28 mmol) to a solution of 2-bromo-3-pyridinecarboxylic acid (5.63 g, 27.89 mmol) and Et3N (2.96 g, 29.28 mmol) in toluene (150 ml) at RT and stir for 1 h., filter and concentrate. Dissolve the residue in THF (93 ml), add to a suspension of LiAlH4 (1.11 g, 29.28 mmol) in THF (37 mmol) dropwise at −78° C. and stir for 30 min. Quench the reaction with saturated aqueous NH4Cl, stir at RT for 1 h, filter through celite, extract with EtOAc, dry over Na2SO4 and concentrate. Purify the residue by column chromatography to produce the desired compound.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]3[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=3[C:9]=2[CH2:17][C:18]2[CH:31]=[CH:30][C:21]([O:22][CH2:23][CH2:24][N:25]3[CH2:29][CH2:28][CH2:27][CH2:26]3)=[CH:20][CH:19]=2)=[CH:4][CH:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[K+].Br[CH2:43][CH2:44][CH2:45][CH2:46][N:47]1C(=O)C2=CC=CC=C2C1=O>C1COCC1.C1(C)C=CC=CC=1.C(OCC)(=O)C>[NH2:47][CH2:46][CH2:45][CH2:44][CH2:43][O:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]3[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=3[C:9]=2[CH2:17][C:18]2[CH:19]=[CH:20][C:21]([O:22][CH2:23][CH2:24][N:25]3[CH2:26][CH2:27][CH2:28][CH2:29]3)=[CH:30][CH:31]=2)=[CH:4][CH:3]=1
Reactant: O=C1c2ccccc2C(=O)N1CCCCBr
Reactant: Oc1ccc(-c2sc3ccccc3c2Cc2ccc(OCCN3CCCC3)cc2)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: NCCCCOc1ccc(-c2sc3ccccc3c2Cc2ccc(OCCN3CCCC3)cc2)cc1
Temperature: 25 °C
Reaction time: 1.33 h
Yield: 87.7 %

Procedure:
To a solution of 1-[2-[4-[[2-(4-hydroxyphenyl)benzo[b]thiophen-3-yl]methyl]phenoxy]ethyl]pyrrolidine (53 mg, 0.123 mmol) in THF (1 mL) was added a solution of potassium bis(trimethylsilyl)amide (0.271 mL of 0.5 M, 1.36 mmol, 1.1 eq.) in toluene at ambient temperature. After 80 min, N-(4-bromobutyl)phthalimide (75 mg, 0.265 mmol, 2.2 eq) was added and the reaction heated at reflux for 18 h. The reaction was cooled to ambient temperature, diluted with ethyl acetate (50 mL) then washed with 10% aqueous sodium bicarbonate (20 mL). The solvent was removed under reduced pressure then the residue purified by flash chromatography (20:1 CHCl3: MeOH then 5:1 CHCl3: MeOH) to give the protected amine as a tan solid (54 mg, 70%) and recovered starting material (8 mg).
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[NH:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH:13](O)[CH:14]=[CH:15][C:16]1[CH:17]=[N:18][C:19]([CH3:22])=[N:20][CH:21]=1)([CH3:4])([CH3:3])[CH3:2].C(O)(=O)CC.Cl.[C:31](OCC)([O:36]CC)([O:33][CH2:34][CH3:35])[CH3:32]>[Cl-].[Na+].O>[CH2:34]([O:33][C:31](=[O:36])[CH2:32][CH:15]([C:16]1[CH:17]=[N:18][C:19]([CH3:22])=[N:20][CH:21]=1)[CH:14]=[CH:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][NH:7][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:24])[CH3:35]
Reactant: Cc1ncc(C=CC(O)CCCCCNC(=O)OC(C)(C)C)cn1
Reactant: CCOC(C)(OCC)OCC
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CCC(=O)O
Solvent: O
Product: CCOC(=O)CC(C=CCCCCCNC(=O)OC(C)(C)C)c1cnc(C)nc1
Temperature: 150 °C

Procedure:
A solution of 24-4 (1.00 g, 2.98 mmol) in triethyl orthoacetate (50 mL) was treated with propionic acid (2.5 mg, 0.034 mmol) and heated to 150° C. for 3 h. The reaction mixture was cooled to room temperature and treated with 1 N HCl and brine (75 mL each). The mixture was extracted with two portions of ethyl acetate. The combined organics were washed with brine and dried (Na2SO4). Purification via PCTLC (SiO2, 4 mm, 10% EtOH; 90% CH2Cl2) afforded 24-5 (650 mg).
Reaction SMILES: C[C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[CH2:4][C:5]1[O:9][C:8](C(O)=O)=[CH:7][CH:6]=1.[C:17](=O)=O>>[CH3:17][C:16]1[CH:15]=[CH:14][CH:13]=[C:3]([CH:2]=1)[CH2:4][C:5]1[O:9][CH:8]=[CH:7][CH:6]=1
Reactant: Cc1ccccc1Cc1ccc(C(=O)O)o1
Reactant: O=C=O
Product: Cc1cccc(Cc2ccco2)c1

Procedure:
A mixture of 5-(2-methylbenzyl)-2-furoic acid [prepared as described in (d) or (f) above; 26.2 g.] and cupric oxide (1 g.) was heated at 200° C. for 4 hours until evolution of carbon dioxide almost ceased. The residue was cooled and distilled to give 2-(5-methylbenzyl)furan (16.5 g.), b.p. 118° C./20 mm.Hg, in the form of a pale yellow coloured oil.
Reaction SMILES: [Li]CCCC.CCCCCC.Br[C:13]1[CH:14]=[CH:15][C:16]2[C:17]([CH:28]=1)=[C:18]([C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[CH:22]=1)[O:19][N:20]=2.[F:29][C:30]1[CH:37]=[CH:36][C:33]([CH:34]=[O:35])=[CH:32][CH:31]=1>C1COCC1>[Cl:27][C:23]1[CH:22]=[C:21]([C:18]2[O:19][N:20]=[C:16]3[CH:15]=[CH:14][C:13]([CH:34]([C:33]4[CH:36]=[CH:37][C:30]([F:29])=[CH:31][CH:32]=4)[OH:35])=[CH:28][C:17]=23)[CH:26]=[CH:25][CH:24]=1
Reactant: Clc1cccc(-c2onc3ccc(Br)cc23)c1
Reactant: O=Cc1ccc(F)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: OC(c1ccc(F)cc1)c1ccc2noc(-c3cccc(Cl)c3)c2c1
Temperature: -70 °C
Reaction time: 0.25 h
Yield: 26.8 %

Procedure:
nBuLi 1.6M in hexane (0.112 mol) was added dropwise at −70° C. under N2 flow to a mixture of 5-bromo-3-(3-chlorophenyl)-2,1-benzisoxazole (0.097 mol) in THF (300 ml). The mixture was stirred at −70° C. for 15 min. A mixture of 4-fluoro-benzaldehyde (0.112 mol) in THF (100 ml) was added dropwise. The mixture was stirred at −70° C. for 30 min, then hydrolized and extracted with EtOAc. The organic layer was separated, dried (MgSO4), filtered and the solvent was evaporated till dryness. The residue was taken up in diethyl ether and DIPE. The precipitate was filtered off, washed and dried, yielding 9.2 g (26.8%) of 3-(3-chlorophenyl)-α-(4-fluorophenyl)-2,1-benzisoxazole-5-methanol (intermediate 1), mp. 171° C.