Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[CH:9]=[C:8]([C:10]#[C:11][C:12]2[N:13]=[C:14]([CH3:17])[NH:15][CH:16]=2)[CH:7]=[CH:6][N:5]=1.Br.Br[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=1.O>C1COCC1>[N:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[CH2:20][N:15]1[CH:16]=[C:12]([C:11]#[C:10][C:8]2[CH:7]=[CH:6][N:5]=[C:4]([CH3:3])[CH:9]=2)[N:13]=[C:14]1[CH3:17]
Reactant: Cc1cc(C#Cc2c[nH]c(C)n2)ccn1
Reactant: BrCc1ccccn1
Agent: Br
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(C#Cc2cn(Cc3ccccn3)c(C)n2)ccn1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Sodium hydride (69 mg, 55%, 1.59 mmol) was suspended in 2 mL dry THF. A solution of 2-methyl-4-(2-methyl-1H-imidazol-4-ylethynyl)-pyridine (95 mg, 0.48 mmol) in 8 mL dry THF was added and the reaction mixture was stirred at room temperature for 30 min. 2-(Bromomethyl)pyridine hydrobromide (162 mg, 0.63 mmol) was added and stirring was continued overnight. The reaction mixture was poured into 70 mL water and extracted three times with ethyl acetate (70 mL each). The combined organic extracts were dried with sodium sulfate, filtered and evaporated. The crude product was purified by flash chromatography on silica gel (dichloromethane/methanol 100:0→90:10 gradient) and a mixture of two regioisomers was obtained. This mixture could be separated by crystallization from diethylether and the desired compound was obtained as a white solid (35 mg, 25%), MS: m/e=289.1 (M+H30).
Reaction SMILES: [CH2:1]([O:8][C@@H:9]([CH2:18][O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH2:10][C:11]1([S:14](O)(=[O:16])=[O:15])[CH2:13][CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C=O)C.O=S(Cl)[Cl:34]>>[CH2:1]([O:8][C@@H:9]([CH2:18][O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH2:10][C:11]1([S:14]([Cl:34])(=[O:16])=[O:15])[CH2:13][CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: O=S(=O)(O)C1(C[C@H](COCc2ccccc2)OCc2ccccc2)CC1
Solvent: CN(C)C=O
Product: O=S(=O)(Cl)C1(C[C@H](COCc2ccccc2)OCc2ccccc2)CC1
Reaction time: 0.08 h
Yield: 52 %

Procedure:
A mixture of (R)-1-(2,3-bis(benzyloxy)propyl)cyclopropane-1-sulfonic acid (630 g) and DMF (30 mL) in SOCl2 (1.5 L) was refluxed for 2 hours until HPLC analysis showed the reaction had gone to completion. The reaction mixture was concentrated to dryness and the residue purified on silica gel chromoatography with eluent: heptane for 5 minutes, then IPAC: heptanes=1:30; heptanes 1:10 resulting in the product as a red oil (298.5 g; 52% yield; 95% purity). 1H NMR (CDCl3, 400 MHz): δ 7.34 (m, 10H), 4.68 (d, 1H), 4.56 (bs, 1H), 4.53 (d, 1H), 4.16 (m, 1H), 3.54-3.62 (m, 2H), 2.63 (dd, 1H), 2.01 (q, 1H), 1.52-1.81 (m, 3H), 1.16 (m, 1H), 2.22 (bs, 1H), 1.75 (t, 2H), 1.38-1.40 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][NH:13][C:14](=[O:24])[CH2:15][NH:16][C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O.Cl[C:37]([O:39][CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)=[O:38]>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][NH:13][C:14](=[O:24])[CH2:15][N:16]([C:37]([O:39][CH2:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)=[O:38])[C:17]2[CH:18]=[CH:19][C:20]([CH3:23])=[CH:21][CH:22]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(CCNC(=O)CNc2ccc(C)cc2)cc1OC
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: COc1ccc(CCNC(=O)CN(C(=O)OCc2ccccc2)c2ccc(C)cc2)cc1OC
Temperature: 0 °C
Yield: 84.8 %

Procedure:
A mixture of N-[2-(3,4-dimethoxyphenyl)ethyl]-2-(p-toluidino)acetamide (3.6 g) and anhydrous potassium carbonate (2.5 g) was added to anhydrous dimethylformamide (25 ml). The mixture was vigorously stirred under ice cooling and to the solution was dropwise added over 20 minutes an anhydrous chloroform solution (5 ml) containing benzyl chloroformate (2.04 g). The reaction mixture was poured into ice-water and extracted with chloroform. The extract was washed with water, dried and the solvent was distilled off. The residue was crystallized by treating with ether to give N-[2-(3,4-dimethoxyphenyl)ethyl]-2-(N-benzyloxycarbonyl-p-toluidino)-acetamide (4.3 g), mp 81° to 85° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O-:11])(=[O:10])=[O:9])=[CH:4][CH:3]=1.C(OC([NH:22][C:23]([CH3:39])([CH3:38])[CH2:24][CH2:25][N+:26]([CH2:29][CH2:30][O:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])([CH3:28])[CH3:27])=O)C1C=CC=CC=1>[Pd].CO>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([O-:11])(=[O:10])=[O:9])=[CH:6][CH:7]=1.[NH2:22][C:23]([CH3:38])([CH3:39])[CH2:24][CH2:25][N+:26]([CH2:29][CH2:30][O:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])([CH3:28])[CH3:27]
Reactant: CCCCCCOCC[N+](C)(C)CCC(C)(C)NC(=O)OCc1ccccc1
Agent: [Pd]
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Solvent: CO
Product: CCCCCCOCC[N+](C)(C)CCC(C)(C)N
Temperature: 25 °C
Reaction time: 18 h
Yield: 99 %

Procedure:
Under a nitrogen atmosphere, 10% palladium on carbon (200 mg) was added to a solution of 3-(((benzyloxy)carbonyl)amino)-N-(2-(hexyloxy)ethyl)-N,N,3-trimethylbutan-1-aminium 4-methylbenzenesulfonate (0.95 g, 1.7 mmol) in 7 mL of methanol. The flask was degassed and placed under a hydrogen atmosphere, stirring for 18 hours at room temperature. The suspension was filtered through a pad of celite, washing with methanol, and the filtrate was concentrated under reduced pressure to give 725 mg of clear viscous oil (quantitative yield). 1H NMR (400 MHz, D2O) δ 0.75-78 (t, J=6.4 Hz, 3H), 1.09 (s, 6H), 1.7-1.26 (m, 6H), 1.47-1.51 (m, 2H), 1.80-1.84 (m, 2H), 2.30 (s, 3H), 3.03 (s, 6H), 3.36-3.40 (m, 2H), 3.44-3.48 (m, 4H), 3.81 (br s, 2H), 7.27-7.28 (d, J=8.1 Hz, 2H), 7.58-7.60 (d, J=8.1 Hz, 2H). LRMS (ESI/APCI) m/z 259 [M]+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[CH2:10][C@@:9]3([CH:15]4[CH2:16][CH2:17][N:12]([CH2:13][CH2:14]4)[CH2:11]3)[O:8][C:5]2=[N:6][CH:7]=1.[CH2:18]=[CH:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(N(CC)CC)C>C(#N)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>[C:20]1(/[CH:19]=[CH:18]/[C:2]2[CH:3]=[C:4]3[CH2:10][C@@:9]4([CH:15]5[CH2:16][CH2:17][N:12]([CH2:13][CH2:14]5)[CH2:11]4)[O:8][C:5]3=[N:6][CH:7]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: Brc1cnc2c(c1)C[C@]1(CN3CCC1CC3)O2
Reactant: C=Cc1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Solvent: CC#N
Product: C(=C/c1cnc2c(c1)C[C@]1(CN3CCC1CC3)O2)\c1ccccc1
Temperature: 100 °C
Yield: 54.9 %

Procedure:
A solution of (S)-(+)-5′-bromospiro[1-azabicyclo[2.2.2]octane-3,2′(3′H)-furo[2,3-b]pyridine] (150 mg, 0.51 mmol), styrene (0.07 mL, 0.61 mmol), palladium(II)acetate (1.2 mg, 0.0053 mmol), tri-o-tolylphosphine (6.4 mg, 0.021 mmol), and triethylamine (0.5 mL, 3.6 mmol) in anhydrous acetonitrile (0.5 mL), in a heavy-walled threaded glass tube containing a magnetic stir bar, was purged with argon and sealed with a Teflon plug and FETFE O-ring. The mixture was stirred and heated at 100° C. for 2 hours, cooled to room temperature, dissolved in chloroform (10 mL), washed with saturated aqueous sodium carbonate (1 mL), dried (MgSO4), and evaporated under reduced pressure. Recrystallization from ethyl acetate afforded the title compound (90 mg, 0.28 mmol, 55%) as a light tan solid: electrospray MS (m/z, relative intensity) 319 ([MH]+, 100).
Reaction SMILES: C([NH:4][C:5]([CH2:16][C:17]1[CH:22]=[C:21]([Cl:23])[CH:20]=[C:19]([CH3:24])[C:18]=1[N+:25]([O-:27])=O)(C(OCC)=O)[C:6](OCC)=[O:7])(=O)C.C(NC(CC1C=CC(Br)=CC=1[N+]([O-])=O)(C(OCC)=O)C(OCC)=O)(=O)C.BrCC1C=C(Cl)C=C(C)C=1[N+]([O-])=O>>[NH2:4][CH:5]1[CH2:16][C:17]2[C:18](=[C:19]([CH3:24])[CH:20]=[C:21]([Cl:23])[CH:22]=2)[N:25]([OH:27])[C:6]1=[O:7]
Reactant: CCOC(=O)C(Cc1cc(Cl)cc(C)c1[N+](=O)[O-])(NC(C)=O)C(=O)OCC
Agent: CCOC(=O)C(Cc1ccc(Br)cc1[N+](=O)[O-])(NC(C)=O)C(=O)OCC
Agent: Cc1cc(Cl)cc(CBr)c1[N+](=O)[O-]
Product: Cc1cc(Cl)cc2c1N(O)C(=O)C(N)C2

Procedure:
Diethyl acetamido(5-chloro-3-methyl-2-nitrobenzyl)malonate (39) Following the procedure for the preparation of diethyl acetamido(4-bromo-2-nitrobenzyl)malonate (24) in Example 5,1-(bromomethyl)-5-chloro-3-methyl-2-nitrobenzene (38) was converted to the title product, which was obtained as a solid (65%). LCMS m/z 401.0 (M+1). 1H NMR (400 MHz, DMSO-d6) δ 1.15 (t, J=7.1 Hz, 6H), 1.90 (s, 3H), 2.24 (br s, 3H), 3.53 (s, 2H), 4.10-4.17 (m, 4H), 7.05 (br d, J=2.2 Hz, 1H), 7.56 (apparent dd, J=2.3, 0.7 Hz, 1H), 8.31 (br s, 1H).
Reaction SMILES: [C:1]1([C@H:7]([NH:10][C:11]([C:13]2[CH:14]=[C:15]([C:22]([N:24]3[CH2:28][CH2:27][CH2:26][C@@H:25]3[CH3:29])=[O:23])[N:16]3[CH2:21][CH2:20][O:19][CH2:18][C:17]=23)=[O:12])[CH2:8][CH3:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:30]N1C(=O)CCC1=O>>[C:1]1([C@H:7]([NH:10][C:11]([C:13]2[C:14]([Cl:30])=[C:15]([C:22]([N:24]3[CH2:28][CH2:27][CH2:26][C@@H:25]3[CH3:29])=[O:23])[N:16]3[CH2:21][CH2:20][O:19][CH2:18][C:17]=23)=[O:12])[CH2:8][CH3:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: CC[C@@H](NC(=O)c1cc(C(=O)N2CCC[C@@H]2C)n2c1COCC2)c1ccccc1
Product: CC[C@@H](NC(=O)c1c(Cl)c(C(=O)N2CCC[C@@H]2C)n2c1COCC2)c1ccccc1

Procedure:
The compound was prepared from 6-((S)-2-methyl-pyrrolidine-1-carbonyl)-3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazine-8-carboxylic acid ((R)-1-phenyl-propyl)-amide (Comp. No. 16a) and N-chloro-succinimide in analogy to the synthesis of comp. no. 16ru. LC/MS (method 3): Rt=1.86 min; m/z=430.22 (M+H+).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH:11]=O)=[C:3]1Cl.C([O-])([O-])=O.[K+].[K+].[SH:20][CH2:21][C:22]([O:24][CH3:25])=[O:23]>>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]2[CH:11]=[C:21]([C:22]([O:24][CH3:25])=[O:23])[S:20][C:3]1=2
Reactant: COC(=O)CS
Reactant: Cn1c(Cl)c(C=O)c2ccccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COC(=O)c1cc2c3ccccc3n(C)c2s1

Procedure:
Prepared from (3) (9.6 g), K2CO3 (15 g) and methyl 2-mercaptoacetate (10 ml) yielding (6) (9.3 g), m.p. 133.5°-133.8° C.
Reaction SMILES: C[O:2][C:3](=[O:35])[CH2:4][CH2:5][NH:6][C:7]([CH:9]1[CH2:14][CH2:13][CH2:12][N:11]([C:15](=[O:34])[CH2:16][O:17][CH:18]2[CH2:23][CH2:22][N:21]([C:24]([O:26][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[O:25])[CH2:20][CH2:19]2)[CH2:10]1)=[O:8].[OH-].[Na+].OS([O-])(=O)=O.[K+]>CO.O.O1CCCC1>[CH2:27]([O:26][C:24]([N:21]1[CH2:22][CH2:23][CH:18]([O:17][CH2:16][C:15]([N:11]2[CH2:12][CH2:13][CH2:14][CH:9]([C:7]([NH:6][CH2:5][CH2:4][C:3]([OH:35])=[O:2])=[O:8])[CH2:10]2)=[O:34])[CH2:19][CH2:20]1)=[O:25])[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: COC(=O)CCNC(=O)C1CCCN(C(=O)COC2CCN(C(=O)OCc3ccccc3)CC2)C1
Agent: O=S(=O)([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)CCNC(=O)C1CCCN(C(=O)COC2CCN(C(=O)OCc3ccccc3)CC2)C1
Temperature: 0 °C
Yield: 94.4 %

Procedure:
To a solution of N-[l-{2-(1-benzyloxycarbonyl4-piperidyloxy)acetyl}-3-piperidylcarbonyl]-β-alanine methyl ester (1.33 g) in methanol (10 ml), H2O (10 ml) and tetrahydrofuran (10 ml) was added 1N NaOH (8.55 ml) under stirring at 0° C. After stirring at ambient temperature for 3 hours, the mixture was acidified with 10% KHSO4 aqueous solution, and extracted with ethyl acetate. The extract was washed with water and brine, and dried over MgSO4, and evaporated in vacuo to give N-[1-{2-(1-benzyloxycarbonyl-4-piperidyloxy)acetyl}-3-piperidylcarbonyl]-β-alanine (1.22 g) as an oil.
Reaction SMILES: [CH:1]1([CH:6]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]I)[C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2]1.[C-:26]#[N:27].[Na+]>CS(C)=O>[C:26]([CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH:6]([CH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1)[C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8])#[N:27]
Reactant: O=C(OCc1ccccc1)C(CCCCCCCCI)C1CCCC1
Reactant: [C-]#N
Agent: [Na+]
Solvent: CS(C)=O
Product: N#CCCCCCCCCC(C(=O)OCc1ccccc1)C1CCCC1
Temperature: 0 °C
Yield: 93.4 %

Procedure:
A mixture of the iodoester from step 2, (3.99 g, 8.7 mmol) and sodium cyanide (0.47 g, 9.6 mmol) in 15 mL of anhyd. DMSO was heated at 70°-75° C. for 30 min. After cooling, the reaction mixture was poured over ice (~ 40 g), extracted into ether and washed successively with water and saturated brine. The organic layer was concentrated to yield an oil (2.89 g). 1H NMR (300 MHz, CDCl3). δ: 7.35 (m, 5H), 5.15 (s, 2H), 2.30(t, 8 Hz, 2H), 2.20(m, 1H), 2.00(m, 1H), 1.3-1.8 (m, 22H).
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24](C(=O)C(F)(F)F)[CH2:23][CH2:22][C:21]([C:31]([NH:33][C:34]4[CH:39]=[CH:38][C:37]([CH:40]([OH:49])[C:41]5[CH:46]=[CH:45][C:44]([Cl:47])=[CH:43][N+:42]=5[O-:48])=[CH:36][CH:35]=4)=[O:32])=[CH:20][C:19]=3[CH:50]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].[BH4-].[Na+].O>C(O)C>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[NH:24][CH2:23][CH2:22][C:21]([C:31]([NH:33][C:34]4[CH:39]=[CH:38][C:37]([CH:40]([OH:49])[C:41]5[CH:46]=[CH:45][C:44]([Cl:47])=[CH:43][N+:42]=5[O-:48])=[CH:36][CH:35]=4)=[O:32])=[CH:20][C:19]=3[CH:50]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(C(O)c4ccc(Cl)c[n+]4[O-])cc2)CCN3C(=O)C(F)(F)F)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(C(O)c4ccc(Cl)c[n+]4[O-])cc2)CCN3)cc1
Reaction time: 2.5 h
Yield: 30.6 %

Procedure:
To a solution of 7-[4-(2-butoxyethoxy)phenyl]-N-[4-[hydroxy(5-chloro-1-oxidopyridin-2-yl)methyl]phenyl]-1-trifluoroacetyl-2,3-dihydro-1H-1-benzazepine-4-carboxamide (0.20 g) in ethanol (30 ml), sodium borohydride (50 mg) was added at room temperature and the mixture was stirred for 2.5 hours. To the reaction solution was added sodium borohydride (50 mg), and the mixture was stirred for 2.5 hours. Sodium borohydride (50 mg) was further added to the mixture and the mixture was stirred for 1 hour. Sodium borohydride (50 mg) was further added to the mixture, and the mixture was stirred for 13 hours. Water was added to the mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The obtained residue was separated and purified by column chromatography (ethyl acetate:hexane 4:1→ethyl acetate) to give 7-[4-(2-butoxyethoxy)phenyl]-N-[4-[hydroxy(5-chloro-1-oxidopyridin-2-yl)methyl]phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (Compound 109) (53 mg) as yellow amorphous.
Reaction SMILES: [C:1]1([C:7]2[NH:16][C:15](=O)[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.P(Br)(Br)([Br:27])=O.C1C=CC2N=CNC(=O)C=2C=1>C1(C)C=CC=CC=1>[Br:27][C:15]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]=[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[N:16]=1
Reactant: O=P(Br)(Br)Br
Reactant: O=c1[nH]c(-c2ccccc2)nc2ccccc12
Agent: O=c1[nH]cnc2ccccc12
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: Brc1nc(-c2ccccc2)nc2ccccc12
Yield: 46.3 %

Procedure:
Into a mixture of 5 g of 2-phenylquinazolin-4(3H)-one and 1.82 g of triethylamine in 100 ml of toluene was added a solution of 25.8 g of phosphorus oxybromide in 50 ml of toluene. The mixture was warmed slightly and the insoluble quinazolinone dissolved slowly, with a new solid appearing. The reaction mixture was heated at 80°-85° for approximately 24 hours. The reaction mixture was cooled and the solid which separated was collected on a filter. The collected solid was dissolved in chloroform, was washed twice with 100-ml portions of water and the washed solution dried over magnesium sulfate. The solution was concentrated to dryness to leave a light orange solid, m.p. 131°-132°. This solid was recrystallized from cyclohexane to give 2.97 g of light yellow 4-bromo-2-phenylquinazoline, m.p. 131.5°-132.5°; ir and nmr spectra were consistent with the assigned structure.
Reaction SMILES: [CH:1]12[N:8]([C:9]3[CH:18]=[N:17][C:16]4[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=4)[N:10]=3)[CH2:7][CH:6]1[CH2:5][CH2:4][NH:3][CH2:2]2.[C@@H]12N(C3C=NC4C(=CC=CC=4)N=3)C[C@@H]1CCNC2.[CH3:37][O:38][C:39]1[CH:47]=[CH:46][CH:45]=[C:44]([O:48][CH3:49])[C:40]=1[C:41](Cl)=[O:42].C1(C2C=CC=CC=2)C(C(Cl)=O)=CC=CC=1>>[CH3:49][O:48][C:44]1[CH:45]=[CH:46][CH:47]=[C:39]([O:38][CH3:37])[C:40]=1[C:41]([N:3]1[CH2:4][CH2:5][CH:6]2[CH:1]([N:8]([C:9]3[CH:18]=[N:17][C:16]4[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=4)[N:10]=3)[CH2:7]2)[CH2:2]1)=[O:42]
Reactant: COc1cccc(OC)c1C(=O)Cl
Reactant: c1ccc2nc(N3CC4CCNCC43)cnc2c1
Agent: O=C(Cl)c1ccccc1-c1ccccc1
Agent: c1ccc2nc(N3C[C@@H]4CCNC[C@@H]43)cnc2c1
Product: COc1cccc(OC)c1C(=O)N1CCC2CN(c3cnc4ccccc4n3)C2C1

Procedure:
The title compound was prepared in a manner analogous to Example 5, substituting the trifluoro acetic acid salt of 2-(3,8-diaza-bicyclo[4.2.0]oct-8-yl)-quinoxaline (Intermediate 2) for (1R,6S)-2-(3,8-diaza-bicyclo[4.2.0]oct-8-yl)-quinoxaline and 2,6-dimethoxy benzoyl chloride for biphenyl-2-carbonyl chloride. MS (ESI) mass calcd. for C23H24N4O3, 404.46; m/z found, 405.3 [M+H]+. 1H NMR (400 MHz, CDCl3): 8.25 (s, 0.25H), 7.98 (s, 0.75H), 7.90-7.80 (m, 1H), 7.60-7.47 (m, 1H), 7.44-7.30 (m, 2H), 7.23 (t, J=8.4, 0.25H), 7.13 (t, J=8.4, 0.75H), 6.58-6.44 (m, 1.25H), 6.03 (d, J=8.4, 0.75H), 4.90-4.56 (m, 1H), 4.32-3.84 (m, 3H), 3.81 (s, 6H), 3.78-3.56 (m, 1H), 3.50-3.30 (m, 1H), 3.17-2.91 (m, 1H), 2.41-1.53 (m, 3H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1OCCC.[Cl-].[Al+3].[Cl-].[Cl-].[C:16](Cl)(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>ClCCl>[C:16]([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CCCOc1ccccc1Br
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: O=C(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
69.7 g (324.2 mmol) of 1-bromo-2-propoxybenzene was added dropwise to a dichloromethane (350 ml) solution containing 51.8 g (388.6 mmol) of aluminum chloride and 45.6 g (324.3 mmol) of benzoyl chloride which was cooled to 0° C. After addition, the resulting solution was stirred for 2 hours. After a reaction, the reaction solution was washed with water, the solvent was removed, and the obtained product was purified by column chromatography to obtain a benzophenone derivative represented by the following formula (40) as 67.3 g (210.7 mmol, yield of 65%) of a yellow solid.
Reaction SMILES: [NH2:1][C@H:2]([C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15])[CH2:3][C:4]([O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:5].[CH3:24][Si:25]([CH3:28])([CH3:27])Cl.C(N(CC)CC)C>C(OCC)C>[CH3:24][Si:25]([CH3:28])([CH3:27])[NH:1][C@H:2]([C:14]([O:16][CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)=[O:15])[CH2:3][C:4]([O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:5]
Reactant: N[C@@H](CC(=O)OCc1ccccc1)C(=O)OCc1ccccc1
Reactant: C[Si](C)(C)Cl
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: C[Si](C)(C)N[C@@H](CC(=O)OCc1ccccc1)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The dibenzyl (S)-aspartate in anhydrous diethyl ether (200 ml) is cooled in an ice-bath under a nitrogen atmosphere. Trimethylchlorosilane (12.7 ml, 0.1 mole) is added to the stirred solution to give a white precipitate. Triethylamine (14.0 ml, 0.1 mole) is then added to the mixture. The cooling bath is removed and the mixture is stirred at room temperature (22°-25° C.) for 2 hrs. The mixture is then filtered directly into a 3-neck, 1.0 liter, round bottom flask fitted with a sintered glass funnel, magnetic stirrer, and a vacuum-nitrogen inlet. This operation is carried out under a blanket of nitrogen, care being taken to exclude atmospheric moisture. The sintered glass funnel is replaced by a stopper and the ether is evaporated under vacuum with stirring to provide dibenzyl (S)-N-trimethylsilylaspartate (35.5 g, 0.092 mole) as a slightly hazy oil.
Reaction SMILES: [OH:1][C:2]([CH3:35])([CH3:34])[CH2:3][C@@:4]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16](B3OC(C)(C)C(C)(C)O3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1.Br[C:37]1[CH:38]=[CH:39][C:40]([C:43]2([C:49]([NH2:51])=[O:50])[CH2:48][CH2:47][CH2:46][CH2:45][CH2:44]2)=[N:41][CH:42]=1>>[OH:1][C:2]([CH3:34])([CH3:35])[CH2:3][C@@:4]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:14]=[CH:15][C:16]([C:37]3[CH:38]=[CH:39][C:40]([C:43]4([C:49]([NH2:51])=[O:50])[CH2:48][CH2:47][CH2:46][CH2:45][CH2:44]4)=[N:41][CH:42]=3)=[CH:17][CH:18]=2)[CH3:12])[CH2:6][CH2:5]1
Reactant: NC(=O)C1(c2ccc(Br)cn2)CCCCC1
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Product: C[C@@H](c1ccc(-c2ccc(C3(C(N)=O)CCCCC3)nc2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Yield: 58 %

Procedure:
The title compound was prepared from (S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-{(S)-1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-ethyl}-1,3-oxazinan-2-one and 1-(5-bromo-pyridin-2-yl)-cyclohexanecarboxylic acid amide following a procedure analogous to that described in Example 1. Yield: 58% of theory; LC (method 1): tR=2.08 min; Mass spectrum (ESI+): m/z=556 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]2[CH:18]=[C:17]([CH2:19][CH2:20][C:21]3[CH:26]=[CH:25][C:24]([CH2:27][CH2:28][CH2:29][CH3:30])=[CH:23][CH:22]=3)[S:16][C:10]=2[NH:11][C:12](=O)[CH2:13][N:14]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:40])=CC=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]2[CH:18]=[C:17]([CH2:19][CH2:20][C:21]3[CH:26]=[CH:25][C:24]([CH2:27][CH2:28][CH2:29][CH3:30])=[CH:23][CH:22]=3)[S:16][C:10]=2[NH:11][C:12](=[S:40])[CH2:13][N:14]=1
Reactant: CCCCc1ccc(CCc2cc3c(s2)NC(=O)CN=C3c2ccccc2Cl)cc1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Product: CCCCc1ccc(CCc2cc3c(s2)NC(=S)CN=C3c2ccccc2Cl)cc1
Yield: 121.2 %

Procedure:
A suspension of 5 g of 5-(2-chlorophenyl)-7-[2-(4-n-butylphenyl)ethyl]-1,3-dihydro-2H-thieno[2,3-e]-1,4-diazepin-2-one, melting at 152°-154° C. and 2.8 g of Lawesson reagent in 100 ml of toluene is stirred at 40°-45° C. for an hour. The resultant solution is concentrated under reduced pressure, and the residue is subjected to chromatography on silica gel and then eluted with chloroform-methanol (100:1 to 100:2). The objective fraction is concentrated under reduced pressure to give 3.8 g of 5-(2-chlorophenyl)-7-[2-(4-n-butylphenyl)ethyl]-1,3-dihydro-2H-thieno[2,3-e]-1,4-diazepine-2-thione, melting at 186°-188° C. with decomposition.
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]2([CH2:14][C:13]3[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=3[O:11]2)[CH2:3][NH:2]1.C(N(CC)CC)C.[C:26](Cl)(=[O:28])[CH3:27]>ClCCl>[C:26]([N:2]1[CH2:3][C:4]2([CH2:14][C:13]3[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=3[O:11]2)[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH2:1]1)(=[O:28])[CH3:27]
Reactant: CC(=O)Cl
Reactant: c1ccc2c(c1)CC1(CNCc3ccccc31)O2
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)N1Cc2ccccc2C2(Cc3ccccc3O2)C1
Temperature: 25 °C
Reaction time: 20 h
Yield: 65.8 %

Procedure:
To a cooled solution of spiro[benzofuran-2(3H),4'(2'H)-isoquinoline] (8.0 g) and triethylamine (4.1 g) in dichloromethane (35 ml) is added dropwise acetyl chloride (3.2 g) in dichloromethane (20 ml). After stirring at ambient temperature for 20 hours, the reaction mixture is washed with water (2x), saturated sodium chloride solution and dried over anhydrous magnesium sulfate. Removal of the solvent yields a solid (6.2 g), of which 2.5 g is recrystallized from ethyl acetate to yield 1.4 g (56%) of product as a powder, mp 141°-142°.