Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[CH:10]=[CH:9][N:8]([S:11]([C:14]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=3)(=[O:13])=[O:12])[C:6]=2[N:7]=1.[NH2:22][C:23]1[CH:31]=[C:30]([CH3:32])[CH:29]=[CH:28][C:24]=1[C:25]([NH2:27])=[O:26]>>[Cl:1][C:2]1[N:3]=[C:4]([NH:22][C:23]2[CH:31]=[C:30]([CH3:32])[CH:29]=[CH:28][C:24]=2[C:25]([NH2:27])=[O:26])[C:5]2[CH:10]=[CH:9][N:8]([S:11]([C:14]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=3)(=[O:13])=[O:12])[C:6]=2[N:7]=1
Reactant: Cc1ccc(C(N)=O)c(N)c1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(Cl)nc(Cl)nc32)cc1
Product: Cc1ccc(S(=O)(=O)n2ccc3c(Nc4cc(C)ccc4C(N)=O)nc(Cl)nc32)cc1

Procedure:
Using General Protocol II and starting with 2,4-dichloro-7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidine (3.0 g, 8.8 mmol) and 2-amino-4-methylbenzamide (2.0 g, 13.2 mmol), 2-({2-chloro-7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}amino)-4-methylbenzamide was isolated as a white solid (2.81 g, 70% Yield): 1H NMR (400 MHz, DMSO-d6) δ ppm 2.34 (s, 3 H), 2.36 (s, 3 H), 6.65 (d, J=3.84 Hz, 1 H), 6.98 (s, 1 H), 7.47 (d, J=8.05 Hz, 2 H), 7.70 (s, 1 H), 7.74 (s, 1 H), 7.75 (d, J=2.93 Hz, 1 H), 7.98 (d, J=8.42 Hz, 2 H), 8.25 (s, 1 H), 8.33 (s, 1 H), 12.52 (s, 1 H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[C@H:9]([CH3:14])[N:8]=[C:7]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[F:21])[C:6]=2[CH:22]=1.[Cl:23]Cl>>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[C@H:9]([CH3:14])[N:8]=[C:7]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[F:21])[C:6]=2[C:22]=1[Cl:23]
Reactant: C[C@@H]1N=C(c2ccccc2F)c2cc(N)ccc2N(C)C1=O
Reactant: ClCl
Product: C[C@@H]1N=C(c2ccccc2F)c2c(ccc(N)c2Cl)N(C)C1=O
Temperature: 0 °C

Procedure:
4 g (0.011 M) of (S)-7-amino-5-(o-fluorophenyl)-1,3-dihydro-1,3-dimethyl-2H-1,4-benzodiazepin-2-one are dissolved in 35 ml of ice-cold concentrated hydrochloric acid at -10° C. and chlorine gas is conducted in at -10° C. for 1 hour. The mixture is concentrated at 0°-5° C. using a high vacuum cooling trap and a soda lime tower under a high vacuum (1-2 mmHg). The residue is made alkaline with a mixture of ice and 10% sodium bicarbonate solution. The mixture is extracted with methylene chloride and the extract is dried over sodium sulphate, filtered and concentrated. The remaining oil is purified on a 300 g silica gel column using methylene chloride and then methylene chloride/ethyl acetate (20:1) as the eluting agent. This operation is repeated once on a 120 g silica gel column using methylene chloride and then methylene chloride/ethyl acetate (20:1) as the eluting agent. After crystallisation from ethyl acetate/ether, there is obtained (S)-7-amino-6-chloro-5-(o-fluorophenyl)-1,3-dihydro-1,3-dimethyl-2H-1,4-benzodiazepin-2-one which melts at 222°-226° C.; [α]25D =+92° (in methylene chloride; 0.5%).
Reaction SMILES: [CH3:1][N:2]1[C:10]([CH2:11][CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[N:9][C:8]2[C:3]1=[N:4][C:5]([N:24]1[C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=3[N:26]=[C:25]1[CH3:33])=[N:6][C:7]=2[N:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1.[CH3:34][C:35]1([O:38][CH2:37]1)[CH3:36]>>[CH3:34][C:35]([OH:38])([CH3:37])[CH2:36][N:15]1[CH2:16][CH2:17][CH:12]([CH2:11][C:10]2[N:2]([CH3:1])[C:3]3[C:8]([N:9]=2)=[C:7]([N:18]2[CH2:19][CH2:20][O:21][CH2:22][CH2:23]2)[N:6]=[C:5]([N:24]2[C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=4[N:26]=[C:25]2[CH3:33])[N:4]=3)[CH2:13][CH2:14]1
Reactant: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CC3CCNCC3)n(C)c2n1
Reactant: CC1(C)CO1
Product: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CC3CCN(CC(C)(C)O)CC3)n(C)c2n1

Procedure:
Following General Procedure C, 4-(9-methyl-2-(2-methyl-1H-benzo[d]imidazol-1-yl)-8-(piperidin-4-ylmethyl)-9H-purin-6-yl)morpholine and isobutylene oxide were reacted to give 542. LCMS m/z: 519.3 (MH+)
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH2:11][CH:12]([NH:21][C:22](=[O:31])[O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:13]([NH:15][CH2:16][C:17]([CH3:20])([CH3:19])[CH3:18])=O)[CH:5]=[C:6]2[C:10]=1[NH:9][N:8]=[CH:7]2.P(Cl)(Cl)(Cl)(Cl)Cl.N1C2C(=CC=CC=2)C=CC=1.[N-:48]=[N+:49]=[N-:50].[Na+]>C(Cl)(Cl)Cl>[CH3:1][C:2]1[CH:3]=[C:4]([CH2:11][CH:12]([NH:21][C:22](=[O:31])[O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:13]2[N:15]([CH2:16][C:17]([CH3:20])([CH3:19])[CH3:18])[N:50]=[N:49][N:48]=2)[CH:5]=[C:6]2[C:10]=1[NH:9][N:8]=[CH:7]2
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1cc(CC(NC(=O)OCc2ccccc2)C(=O)NCC(C)(C)C)cc2cn[nH]c12
Agent: ClP(Cl)(Cl)(Cl)Cl
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: c1ccc2ncccc2c1
Product: Cc1cc(CC(NC(=O)OCc2ccccc2)c2nnnn2CC(C)(C)C)cc2cn[nH]c12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of benzyl 3-(7-methyl-1H-indazol-5-yl)-1-(neopentylamino)-1-oxopropan-2-ylcarbamate (0.17 g, 0.402 mmol) in chloroform (0.5 mL) was added to a mixture of phosphorus pentachloride (0.17 g, 0.802 mmol) and quinoline (0.2 mL) in chloroform (1.0 mL). After stirring at room temperature for 2 h, the solvents were removed in vacuo. The crude mixture was dissolved in acetonitrile (2.0 mL) and treated with sodium azide (78 mg, 3.0 equiv). After stirring the mixture at 40° C. overnight, the solvents were removed and the crude mixture dissolved in methylene chloride which was washed with water (2×), brine (2×), dried over sodium sulfate, and concentrated. Column chromatography afforded 73 mg (40%, 2 steps). 1H-NMR (CD3OD, 500 MHz) δ 0.82 (s, 9H), 2.46 (s, 3H), 2.30-3.46 (m, 2H), 3.69 (d, J=14.3, 1H), 3.93 (d, J=14.3, 1H), 4.98-5.13 (m, 2H), 5.30 (m, 1H), 6.02 (d, J=8.9, 1H), 6.86 (s, 1H), 7.25-7.35 (m, 5H), 7.94 (s, 1H). Mass spec.: 448.19 (MH)+.
Reaction SMILES: [CH3:1][S:2]([NH:5][CH2:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]=[C:10]2[C:16](=O)[C:17](OCC)=[O:18])(=[O:4])=[O:3].[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[OH:18][CH2:17][CH2:16][C:10]1[C:9]2[C:13](=[CH:14][CH:15]=[C:7]([CH2:6][NH:5][S:2]([CH3:1])(=[O:4])=[O:3])[CH:8]=2)[NH:12][CH:11]=1
Reactant: CCOC(=O)C(=O)c1c[nH]c2ccc(CNS(C)(=O)=O)cc12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CS(=O)(=O)NCc1ccc2[nH]cc(CCO)c2c1
Yield: 72.5 %

Procedure:
Ethyl 5-[[(methylsulphonyl)amino]methyl]-α-oxo-1H-indole-3-acetate (0.50 g) was added portionwise under nitrogen to a stirred suspension of lithium aluminium hydride (0.59 g) in dry THF (30 ml). The mixture was heated under reflux for 6 h, then cooled in an ice bath and treated dropwise with aqueous THF (15%, 20 ml) and then with water (20 ml) and extracted with ethyl acetate (6×25 ml). The extract was washed with brine (3×25 ml) and dried (Na2SO4). Removal of the solvent gave a dark brown oil which was purified by chromtography on a silica column (Merck Kieselgel 60; 10 g) eluted with cyclohexane then ethyl acetate to give the title compound as a gum (0.3 g) which failed to crystallise
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]([CH:5]1[CH2:10][CH2:9][N:8](C(OCC2C=CC=CC=2)=O)[CH2:7][CH2:6]1)=[O:4].N>CCOC(C)=O.CO>[F:22][C:2]([F:1])([F:21])[C:3]([CH:5]1[CH2:6][CH2:7][NH:8][CH2:9][CH2:10]1)=[O:4]
Reactant: O=C(OCc1ccccc1)N1CCC(C(=O)C(F)(F)F)CC1
Agent: N
Solvent: CCOC(C)=O
Solvent: CO
Product: O=C(C1CCNCC1)C(F)(F)F

Procedure:
The product was obtained analogously to IP 2b starting from 900 mg (2.85 mmol) of benzyl 4-(2,2,2-trifluoroacetyl)piperidine-1-carboxylate. Yield: 516 mg (quant. yield); C7H10F3NO (M=181.156); calc.: molpeak (M+H)+: 182; found: molpeak (M+H)+: 182; Rf value: 0.18 (silica gel, EtOAc/MeOH/conc. aqueous ammonia 5:5:0.5).
Reaction SMILES: [C:1]([O:4][CH:5]([C:9]1[CH:14]=[CH:13][C:12]([Br:15])=[CH:11][CH:10]=1)[C:6]([OH:8])=O)(=[O:3])[CH3:2].C(Cl)(=O)C(Cl)=O.[F:22][C:23]([F:32])([F:31])[C:24]1[CH:30]=[CH:29][C:27]([NH2:28])=[CH:26][CH:25]=1.C(N(CC)CC)C>ClCCl>[Br:15][C:12]1[CH:13]=[CH:14][C:9]([CH:5]([O:4][C:1](=[O:3])[CH3:2])[C:6](=[O:8])[NH:28][C:27]2[CH:29]=[CH:30][C:24]([C:23]([F:22])([F:31])[F:32])=[CH:25][CH:26]=2)=[CH:10][CH:11]=1
Reactant: CC(=O)OC(C(=O)O)c1ccc(Br)cc1
Reactant: Nc1ccc(C(F)(F)F)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)OC(C(=O)Nc1ccc(C(F)(F)F)cc1)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 62.3 %

Procedure:
To a cooled solution (0 degrees Celcius) of acetoxy-(4-bromo-phenyl)-acetic acid (6.1 g, 22 mmol) in dichloromethane (30 mL) was added oxalyl chloride (4.2 g, 33 mmol) dropwise. After stirring for an additional 1 hour at room temperature, the reaction mixture was concentrated in vacuo and dried under vacuum. The acid chloride intermediate was dissolved in dichloromethane (20 mL) and then added over 1 hr to a solution of 4-trifluoromethylaniline (4.0 g, 25 mmol) and triethylamine (3.6 mL, 25 mmol) in dichloromethane (10 mL) at 0 degrees Celcius. The reaction was then allowed to warm to room temperature and stirred for 30 minutes. The reaction was diluted with dichloromethane and then washed twice with 1N HCl, twice with saturated sodium bicarbonate, and twice with brine. The organic layer was then dried over magnesium sulfate, filtered, and concentrated in vacuo to furnish a yellow solid. The solid was washed with ether to obtain a white solid (5.7 g, 61%).
Reaction SMILES: I[C:2]1[CH:11]=[CH:10][C:5]([O:6][CH2:7][CH2:8][OH:9])=[C:4]([CH:12]=[CH2:13])[CH:3]=1.[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:22]=[CH:23][C:24]([C:27]#[CH:28])=[N:25][CH:26]=2)=[CH:17][CH:16]=1>>[Cl:14][C:15]1[CH:16]=[CH:17][C:18]([C:21]2[CH:22]=[CH:23][C:24]([C:27]#[C:28][C:2]3[CH:11]=[CH:10][C:5]([O:6][CH2:7][CH2:8][OH:9])=[C:4]([CH:12]=[CH2:13])[CH:3]=3)=[N:25][CH:26]=2)=[CH:19][CH:20]=1
Reactant: C=Cc1cc(I)ccc1OCCO
Reactant: C#Cc1ccc(-c2ccc(Cl)cc2)cn1
Product: C=Cc1cc(C#Cc2ccc(-c3ccc(Cl)cc3)cn2)ccc1OCCO

Procedure:
The product was obtained analogously to Example 7.1e starting from 2-(4-iodo-2-vinylphenoxy)ethanol and 5-(4-chlorophenyl)-2-ethynylpyridine. Yield: 0.66 g (96% of theoretical); C23H18ClNO2 (M=375.847); calc.: molpeak (M+H)+: 376/378 (Cl); found: molpeak (M+H)+: 376/378 (Cl); HPLC-MS: 6.21 minutes (method B).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:28][CH:29]=O)[CH:9]([C:13]2[CH:27]=[CH:26][C:16]([C:17]([NH:19][CH2:20][CH2:21][C:22]([O:24][CH3:25])=[O:23])=[O:18])=[CH:15][CH:14]=2)[CH2:10][CH2:11][CH3:12])=[CH:4][CH:3]=1.Cl.[F:32][C:33]1[CH:38]=[C:37]([CH3:39])[CH:36]=[CH:35][C:34]=1[NH:40]N>[Cl-].[Cl-].[Zn+2].C(O)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([C:28]2[C:35]3[C:34](=[C:33]([F:32])[CH:38]=[C:37]([CH3:39])[CH:36]=3)[NH:40][CH:29]=2)[C@@H:9]([C:13]2[CH:14]=[CH:15][C:16]([C:17]([NH:19][CH2:20][CH2:21][C:22]([O:24][CH3:25])=[O:23])=[O:18])=[CH:26][CH:27]=2)[CH2:10][CH2:11][CH3:12])=[CH:4][CH:3]=1
Reactant: CCCC(c1ccc(C(=O)NCCC(=O)OC)cc1)C(CC=O)c1ccc(Cl)cc1
Reactant: Cc1ccc(NN)c(F)c1
Agent: Cl
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CC(=O)O
Product: CCC[C@H](c1ccc(C(=O)NCCC(=O)OC)cc1)[C@H](c1ccc(Cl)cc1)c1c[nH]c2c(F)cc(C)cc12

Procedure:
An acetic acid solution (10 ml) of methyl N-{4-[2-(4-chlorophenyl)-4-oxo-1-propylbutyl]benzoyl}-β-alaninate, INTERMEDIATE 4, (757 mg, 1.76 mmol), ZnCl2 (3.1M in AcOH, 1.7 ml, 5.27 mol) and 2-fluoro-4-methylphenylhydrazine hydrochloride (374 mg, 2.1 mmol) was heated at 80° C. for 45 minutes. The solution was concentrated and the residue partitioned between EtOAc and water. The organic phase was washed with water (2×), brine (2×) and dried over Na2SO4. The solution was filtered, concentrated and the residue purified by silica gel chromatography using a hexanes/ethyl acetate gradient to give the title compound. Data for the major diastereomer: 1H NMR (500 MHz, CD3CN): δ 9.11 (s, 1 H); 7.54 (d, J=8.2 Hz, 2 H); 7.48 (d, J=8.5 Hz, 2H); 7.38 (d, J=8.2 Hz, 2 H); 7.30 (d, J=8.4 Hz, 2 H); 7.15 (d, J=2.5 Hz, 1 H); 7.11 (s, 1 H); 7.02-6.97 (m, 1 H); 6.59 (d, J=12.3 Hz, 1 H); 4.49 (d, J=11.6 Hz, 1 H); 3.60 (s, 3H); 3.56-3.48 (m, 3 H); 2.52 (t, J=6.8 Hz, 2 H); 2.32 (s, 3 H); 1.49-1.35 (m, 2 H); 1.04-0.90 (m, 2 H); 0.69 (t, J=7.4 Hz, 3 H). LC1=3.94 min. (M+H)=535. Chiral LC1 (1% to 15% EtOH/heptane over 25 min, 15% EtOH/heptane isocratic >25 min) retention time=28.38 minutes. The material also contains ca 2% by area of the enantiomer. Chiral LC1 (1% to 15% EtOH/heptane over 25 min, 15% EtOH/heptane isocratic >25 min) retention time=26.88 minutes.
Reaction SMILES: C(O[CH:4](OCC)[CH2:5][S:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH3:14])[CH:8]=1)C.B(F)(F)F.CCOCC.C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH3:14][O:13][C:9]1[CH:10]=[CH:11][C:12]2[CH:4]=[CH:5][S:6][C:7]=2[CH:8]=1
Reactant: CCOC(CSc1cccc(OC)c1)OCC
Agent: FB(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: ClCCl
Product: COc1ccc2ccsc2c1
Reaction time: 0.5 h
Yield: 66.6 %

Procedure:
A solution of 1-[(2,2-diethoxy)ethylthio]-3-methoxybenzene (13.0 g, 0.051 mol) in CH2Cl2 (100 ml) was added dropwise to a solution of BF3.Et2O (6.7 ml, 0.054 mol) in CH2Cl2 (1000 ml) at room temperature under a nitrogen atmosphere. The reaction mixture was stirred for 0.5 hours, treated with aqueous NaHCO3 solution, and stirred until both phases were clear. The CH2Cl2 layer was separated, and the aqueous layer was extracted with CH2Cl2. The combined organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo to give 8.68 g of an approximately 10:1 mixture of 6- and 4-methoxybenzo[b]thiophene as a dark brown oil. Purification by vacuum distillation (bp=65°-7° C. at 0.3 mmHg) gave 5.58 g of pale yellow oil. Major isomer: 'H NMR, δ :(CDCl3):3.85 (3H, s, --OCH3); 6.98 (1H, dd, J=4.5, H5); 7.23 (2H, s, H2, H3); 7.35 (1H, d, J=1.5, H7); 7.68 (1H, d, J=4.5, H4).
Reaction SMILES: [CH2:1]1[O:5][C:4]2[CH:6]=[C:7]([CH:10]=O)[CH:8]=[CH:9][C:3]=2[O:2]1.[NH:12]([CH2:19][CH2:20][C:21]#[N:22])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.CS(C)=O.C[O-].[Na+]>CO>[NH:12]([CH:19]=[C:20]([CH2:10][C:7]1[CH:8]=[CH:9][C:3]2[O:2][CH2:1][O:5][C:4]=2[CH:6]=1)[C:21]#[N:22])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=Cc1ccc2c(c1)OCO2
Reactant: N#CCCNc1ccccc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CS(C)=O
Product: N#CC(=CNc1ccccc1)Cc1ccc2c(c1)OCO2
Temperature: 5 °C

Procedure:
Piperonaldehyde (45 g.), β-anilinopropionitrile (52 g.) and dimethylsulfoxide (96 ml.) were heated together to 120° C and a solution of sodium methylate (2.5 g.) in methanol (12 ml.) was added over a 5 min. period. The temperature was maintained at 115°-120° C for 1 hr. and the mixture was then poured into ice-water. The resulting gum was collected by decantation and was likewise washed with water (2 × 100 ml.). Methanol (100 ml.) was then added and the mixture was heated until solution was complete. Cooling to 5° C gave β-anilino-α-piperonylacrylonitrile as a crystalline solid which was collected, and washed with cold methanol, ether, and pentane. Wt=45 g. (54%) m.p. 150.5°-151° C (recrystallised from methanol).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][N:11]2[CH2:20][CH2:19][C:18]3[C:13](=[CH:14][CH:15]=[C:16]([O:21][CH2:22][CH2:23][NH:24][OH:25])[CH:17]=3)[C:12]2=[O:26])=[CH:4][CH:3]=1.C[Si]([N:31]=[C:32]=[O:33])(C)C>O1CCOCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][CH2:10][N:11]2[CH2:20][CH2:19][C:18]3[C:13](=[CH:14][CH:15]=[C:16]([O:21][CH2:22][CH2:23][N:24]([C:32]([NH2:31])=[O:33])[OH:25])[CH:17]=3)[C:12]2=[O:26])=[CH:6][CH:7]=1
Reactant: O=C1c2ccc(OCCNO)cc2CCN1CCCc1ccc(F)cc1
Reactant: C[Si](C)(C)N=C=O
Solvent: C1COCCO1
Product: NC(=O)N(O)CCOc1ccc2c(c1)CCN(CCCc1ccc(F)cc1)C2=O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a stirred solution of 2-[3-(4-fluorophenyl)-propyl]-6-[2-(N-hydroxyamino)-ethoxy]-1-oxo-1,2,3,4-tetrahydroisoquinoline (3.0 g, 8.4 mmol) in dioxane (100 mL) is added trimethylsilyl isocyanate (1.06 g, 9.2 mmol). The reaction is stirred at room temperature for 24 hours and subsequently poured into H20 (350 mL). The resulting suspension is extracted with EtOAc (1×500 mL) and the organic phase washed with 2M HCl (1×250 mL), H2O (5×500 mL), saturated NaCl solution (2×500 mL), dried over MgSO4 and concentrated in vacuo. The resulting material is triturated with hexanes, and recrystallized from EtOAc to give 2-[3-(4-fluorophenyl)-propyl]-6-[2-(N-aminocarbonyl-N-hydroxyamino)ethoxy]-1-oxo-1,2,3,4-tetrahydroisoquinoline, m.p. 138°-140°.
Reaction SMILES: Cl.Cl.[C@H]1(C[N:14]2[CH2:19][CH2:18][CH:17]([NH:20][C:21]([C:23]3[NH:24][C:25]4[C:30]([CH:31]=3)=[C:29]([O:32][CH2:33][C:34]3[C:38]5[CH:39]=[CH:40][C:41]([Cl:43])=[CH:42][C:37]=5[O:36][CH:35]=3)[CH:28]=[CH:27][CH:26]=4)=[O:22])[CH2:16][CH2:15]2)[C@@H]2N(CCCC2)CCC1.Cl.Cl.Cl.NC1CCN([CH2:54][CH2:55][N:56]2[CH2:61][CH2:60][C@H:59]([OH:62])[C@@H:58]([CH3:63])[CH2:57]2)CC1>>[OH:62][C@H:59]1[CH2:60][CH2:61][N:56]([CH2:55][CH2:54][N:14]2[CH2:15][CH2:16][CH:17]([NH:20][C:21]([C:23]3[NH:24][C:25]4[C:30]([CH:31]=3)=[C:29]([O:32][CH2:33][C:34]3[C:38]5[CH:39]=[CH:40][C:41]([Cl:43])=[CH:42][C:37]=5[O:36][CH:35]=3)[CH:28]=[CH:27][CH:26]=4)=[O:22])[CH2:18][CH2:19]2)[CH2:57][C@@H:58]1[CH3:63]
Reactant: O=C(NC1CCN(C[C@@H]2CCCN3CCCC[C@H]23)CC1)c1cc2c(OCc3coc4cc(Cl)ccc34)cccc2[nH]1
Reactant: C[C@H]1CN(CCN2CCC(N)CC2)CC[C@@H]1O
Agent: Cl
Product: C[C@H]1CN(CCN2CCC(NC(=O)c3cc4c(OCc5coc6cc(Cl)ccc56)cccc4[nH]3)CC2)CC[C@@H]1O

Procedure:
This compound is synthesized from 4-(6-chloro-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid (117, see example 72) and amine 14 analogously to the method described in example 1.
Reaction SMILES: [Cl-].[F:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][C:4]=1[O:13][CH2:14][CH2:15][NH3+:16].[Cl:17][C:18]1[O:22][C:21]([CH:23]=O)=[CH:20][CH:19]=1>>[Cl:17][C:18]1[O:22][C:21]([CH2:23][NH:16][CH2:15][CH2:14][O:13][C:4]2[CH:5]=[CH:6][C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[C:3]=2[F:2])=[CH:20][CH:19]=1
Reactant: O=Cc1ccc(Cl)o1
Reactant: [NH3+]CCOc1ccc2ccccc2c1F
Agent: [Cl-]
Product: Fc1c(OCCNCc2ccc(Cl)o2)ccc2ccccc12
Yield: 70 %

Procedure:
Prepared from 2-[(1-fluoronaphthalen-2-yl)oxy]ethanaminium chloride and 5-chlorofuran-2-carbaldehyde in 70% yield as a yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([NH:9][C:10]2[N:17]=[CH:16][CH:15]=[CH:14][C:11]=2[CH:12]=O)=[CH:5][CH:4]=1.[C:18](OCC)(=[O:25])[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21].N1CCCCC1>C(O)C>[CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([N:9]2[C:10]3[C:11](=[CH:14][CH:15]=[CH:16][N:17]=3)[CH:12]=[C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:18]2=[O:25])=[CH:5][CH:4]=1
Reactant: COc1ccc(Nc2ncccc2C=O)cn1
Reactant: CCOC(=O)CC(=O)OCC
Solvent: CCO
Solvent: C1CCNCC1
Product: CCOC(=O)c1cc2cccnc2n(-c2ccc(OC)nc2)c1=O
Temperature: 100 °C
Reaction time: 4 h
Yield: 45 %

Procedure:
6.4 g (28 mmol) of 2-(6-methoxy-3-pyridinylamino)nicotinaldehyde was dissolved in ethanol (50 mL), and 6.7 g (42 mmol) of diethyl malonate and 0.95 g (11 mmol) of piperidine were added thereto. The resulting mixture was stirred for 4 hours at 100° C. The solvent was distilled off under reduced pressure from the reaction mixture, and the residue was washed with a mixed solution of ethyl acetate and diisopropyl ether. Thus, 4.1 g of the title compound was obtained as a pale yellow solid (yield: 45%).
Reaction SMILES: [CH3:1][N:2]([CH2:12][CH2:13][CH2:14][N:15]1[C:24]2[C:19](=[CH:20][C:21]([N+:25]([O-])=O)=[CH:22][CH:23]=2)[CH2:18][CH2:17][CH2:16]1)[C:3](=[O:11])[O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>C1COCC1.C(O)C.[Pd]>[NH2:25][C:21]1[CH:20]=[C:19]2[C:24](=[CH:23][CH:22]=1)[N:15]([CH2:14][CH2:13][CH2:12][N:2]([CH3:1])[C:3](=[O:11])[O:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)[CH2:16][CH2:17][CH2:18]2
Reactant: CN(CCCN1CCCc2cc([N+](=O)[O-])ccc21)C(=O)Oc1ccccc1
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: CN(CCCN1CCCc2cc(N)ccc21)C(=O)Oc1ccccc1
Reaction time: 3 h
Yield: 88.6 %

Procedure:
To a stirred solution of phenyl methyl(3-(6-nitro-3,4-dihydroquinolin-1(2H)-yl)propyl)carbamate (1.02 g, 2.76 mmol) in THF (15.00 ml) and ethanol (15 ml) was added palladium 10 wt. % on activated carbon (0.294 g, 0.276 mmol). The reaction mixture was stirred under an atmosphere of hydrogen (balloon pressure) for 3 h. The mixture was then filtered through celite and concentrated, giving a dark oil. The crude product (phenyl 3-(6-amino-3,4-dihydroquinolin-1(2H)-yl)propyl(methyl)carbamate (830 mg, 2.445 mmol, 89% yield)) was used directly in the subsequent reaction. ESI-MS (m/z, %) 340 (MH+, 100).
Reaction SMILES: [Li]CCCC.[C:6]([Si:10]([O:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][C:37]#[CH:38])([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([CH3:9])([CH3:8])[CH3:7].[CH2:39]=[O:40]>C1COCC1>[Si:10]([O:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][C:37]#[C:38][CH2:39][OH:40])([C:6]([CH3:9])([CH3:8])[CH3:7])([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: C#CCCCCCCCCCCCCCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Reactant: C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)[Si](OCCCCCCCCCCCCCC#CCO)(c1ccccc1)c1ccccc1
Temperature: -50 °C
Reaction time: 0.5 h
Yield: 67.5 %

Procedure:
n-BuLi (2.5 M solution in hexanes, 1.29 g, 8 mL, 20.24 mmol) was added to a stirring, −40° C. solution of tert-butyl(pentadec-14-ynyloxy)diphenylsilane (8.5 g, 18.40 mmol) in THF (175 mL) under an argon atmosphere. After 30 min, the reaction mixture was gradually warmed over 3 h to −10° C., held at this temperature for 20 min, then re-cooled to −50° C. Then, a solution of paraformaldehyde (3.05 g, 92.2 mmol) in THF (30 mL) was cannulated into the stirring reaction mixture. After 30 min, the temperature was gradually warmed over 3 h to room temperature. Following 1 h at room temperature, the reaction mixture was quenched with sat. aq. NH4Cl (10 mL), diluted with ether (100 mL), and washed with water (2×75 mL). The combined aqueous washes were back-extracted with ether (2×50 mL). The combined All of the organic extracts were combined, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by SiO2 column chromatography using 5% EtOAc/hexanes as eluent to give 16-(tert-butyldiphenylsilyloxy)hexadec-2-yn-1-ol (6.12 g, 68%). TLC: 30% EtOAc/hexanes, Rf≈0.5; 1H NMR (CDCl3, 300 MHz) δ 7.70-7.74 (m, 4H), 7.34-7.44 (m, 6H), 4.3 (t, 2H, J=2.1 Hz), 3.65 (t, 2H, J=7.3 Hz), 2.12-2.17 (m, 2H), 1.20-1.61 (m, 22H), 1.04 (s, 9H).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH:11]=[CH:12][C:13]([NH:15][NH2:16])=[O:14].C(N(CC)CC)C.[C:24](C1NC=CN=1)(C1NC=CN=1)=[O:25]>O1CCCC1>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH:11]=[CH:12][C:13]1[O:14][C:24](=[O:25])[NH:16][N:15]=1
Reactant: NNC(=O)C=Cc1ccc2ccccc2c1
Reactant: O=C(c1ncc[nH]1)c1ncc[nH]1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=c1[nH]nc(C=Cc2ccc3ccccc3c2)o1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred suspension of 3-naphthalen-2-yl-acrylic acid hydrazide (1.0 g, 4.71 mmol, prepared as described in example 5) and triethylamine (0.64 g, 6.28 mmol) in dry tetrahydrofuran (15 ml) was added carbonyl diimidazole (1.02 g, 6.28 mmol) at 0° C. The reaction mixture was stirred at room temperature for 1 h. The resulting reaction mixture was evaporated in vacuo and to the residue was added water (25 ml). The precipitate was filtered off and washed with water (2×10 ml) and diethyl ether (2×10 ml) and recrystallised from ethyl acetate (100 ml) affording after drying in vacuo at 50° C. 0.5 g (45%) of the title compound as a solid.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[C:7](Cl)=[O:8])([O-:3])=[O:2].[NH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20](=[O:27])[CH2:21][CH2:22][C:23]([O:25]C)=[O:24])=[CH:16][CH:15]=1>>[N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[C:7]([NH:13][C:14]1[CH:15]=[CH:16][C:17]([C:20](=[O:27])[CH2:21][CH2:22][C:23]([OH:25])=[O:24])=[CH:18][CH:19]=1)=[O:8])([O-:3])=[O:2]
Reactant: O=C(Cl)c1cccc([N+](=O)[O-])c1
Reactant: COC(=O)CCC(=O)c1ccc(N)cc1
Product: O=C(O)CCC(=O)c1ccc(NC(=O)c2cccc([N+](=O)[O-])c2)cc1
Yield: 25.7 %

Procedure:
In a manner similar to that described in Example 3, 3-nitro-benzoyl chloride (0.064 g, 0.00035 mol) was allowed to react with 4-(4-amino-phenyl)-4-oxo-butyric acid, methyl ester (0.052 g, 0.00025 mol), and the resulting intermediate was hydrolyzed to give 0.022 g of 4-[4-(3-nitro-benzoylamino)-phenyl]-4-oxo-butyric acid as a yellow solid; MS-(AP+) MH+343.