Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH2:6][C@H:7]([CH2:11][N:12]([CH:21]=[O:22])[O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:8]([OH:10])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:23][C@@H:24]1[N:29]([CH3:30])[CH2:28][CH2:27][N:26]([C:31]2[C:36]([F:37])=[C:35]([NH:38][NH2:39])[N:34]=[C:33]([CH3:40])[N:32]=2)[CH2:25]1.CN1CCOCC1.C1C=NC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C=O)C>[CH:1]1([CH2:6][C@@H:7]([C:8]([NH:39][NH:38][C:35]2[C:36]([F:37])=[C:31]([N:26]3[CH2:27][CH2:28][N:29]([CH3:30])[C@@H:24]([CH3:23])[CH2:25]3)[N:32]=[C:33]([CH3:40])[N:34]=2)=[O:10])[CH2:11][N:12]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:21]=[O:22])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=CN(C[C@@H](CC1CCCC1)C(=O)O)OCc1ccccc1
Reactant: Cc1nc(NN)c(F)c(N2CCN(C)[C@@H](C)C2)n1
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Solvent: CN1CCOCC1
Product: Cc1nc(NNC(=O)[C@H](CC2CCCC2)CN(C=O)OCc2ccccc2)c(F)c(N2CCN(C)[C@@H](C)C2)n1
Reaction time: 8 h
Yield: 67.4 %

Procedure:
(2R)-3-Cyclopentyl-2-({formyl[(phenylmethyl)oxy]amino}methyl)propanoic acid (0.184 g, 0.60 mmol), 4-[(3S)-3,4-dimethyl-1-piperazinyl]-5-fluoro-6-hydrazino-2-methylpyrimidine (0.161 g, 0.63 mmol), NMM (0.21 mL, 1.89 mmol), HOAt (0.086 g, 0.63 mmol), and EDC (0.121 g, 0.63 mmol) were dissolved in DMF (4 mL), and the reaction was stirred overnight. Purified by RP-HPLC to provide [(2R)-2-(cyclopentylmethyl)-3-(2-{6-[(3S)-3,4-dimethyl-1-piperazinyl]-5-fluoro-2-methyl-4-pyrimidinyl}hydrazino)-3-oxopropyl][(phenylmethyl)oxy]formamide (0.219 g, 64%). LCMS: (M+H)+=542.7.
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@H:2]([C:7]([NH:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5].[NH:23]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[C@H:24]([C:29]([OH:31])=O)[C@H:25]([CH2:27][CH3:28])[CH3:26]>>[NH:23]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[C@H:24]([C:29]([NH:1][C@H:2]([C:7]([NH:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[O:8])[CH2:3][CH:4]([CH3:5])[CH3:6])=[O:31])[C@H:25]([CH2:27][CH3:28])[CH3:26]
Reactant: CC[C@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: CCOC(=O)CNC(=O)[C@H](CC(C)C)NC(=O)OC(C)(C)C
Product: CCOC(=O)CNC(=O)[C@H](CC(C)C)NC(=O)[C@@H](NC(=O)OC(C)(C)C)[C@@H](C)CC
Yield: 73.3 %

Procedure:
By using 2.00 g of Boc-Leu-Gly-OEt and 1.67 g of Boc-Ile-OH.1/2H2O and the same procedure as in Reference Example 15 was repeated to obtain 1.99 g (yield: 73.3%) of the above-mentioned objective product.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[NH:12][C:13](=[O:26])[N:14]([C:15]4[CH:20]=[CH:19][C:18]([C:21]([CH3:25])([CH3:24])[C:22]#[N:23])=[CH:17][CH:16]=4)[C:5]=3[C:4]=2[CH:3]=1.C(N(CC)CC)C.[F:34][C:35]1[CH:36]=[C:37]([S:41](Cl)(=[O:43])=[O:42])[CH:38]=[CH:39][CH:40]=1.O>ClCCl>[Br:1][C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([S:41]([C:37]4[CH:38]=[CH:39][CH:40]=[C:35]([F:34])[CH:36]=4)(=[O:43])=[O:42])[C:13](=[O:26])[N:14]([C:15]4[CH:20]=[CH:19][C:18]([C:21]([CH3:24])([CH3:25])[C:22]#[N:23])=[CH:17][CH:16]=4)[C:5]=3[C:4]=2[CH:3]=1
Reactant: CC(C)(C#N)c1ccc(-n2c(=O)[nH]c3cnc4ccc(Br)cc4c32)cc1
Reactant: O=S(=O)(Cl)c1cccc(F)c1
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CC(C)(C#N)c1ccc(-n2c(=O)n(S(=O)(=O)c3cccc(F)c3)c3cnc4ccc(Br)cc4c32)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 2-(4-(8-bromo-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl)phenyl)-2-methylpropanenitrile (Intermediate 1, 50 mg, 0.12 mmol) and triethylamine (24.4 mg, 0.36 mmol) in dichloromethane (6 ml) was added 3-fluoro benzenesulfonyl chloride (35 mg, 0.18 mmol) at 0° C. The reaction was stirred at RT for 3 hours. The reaction mixture was poured into cold water and organic layer was separated. The aqueous layer was extracted with dichloromethane. The combined organic layer was washed with brine, dried over sodium sulfate and evaporated to dryness. The crude product was purified by column chromatography (silica gel, 2% acetone in chloroform) to obtain the title compound. Yield: 50 mg (44.99%); 1H NMR (CDCl3, 300 MHz): δ 9.57 (s, 1H), 8.025-8.051 (d, 1H, J=7.8 Hz), 7.952-7.980 (d, 1H, J=8.4 Hz), 7.94 (m 1H,), 7.75 (d, 2H, J=9 Hz,), 7.63 7.674 (dd, 1H, J=9, 2.1 Hz), 7.56-7.61 (m, 1H), 7.438-7.466 (d, 2H, J=8.4 Hz), 7.38-7.42 (m, 1H), 6.99-6.996 (d, 1H, J=1.8 Hz), 1.80 (s, 6H); MS: m/z 565 (M+).
Reaction SMILES: [C:1](=[O:4])([O-])[O-].[K+].[K+].[CH2:7](Br)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[Br:15][C:16]1C=[CH:20][C:19](O)=[C:18]([CH2:23][CH3:24])[CH:17]=1>CN(C=O)C>[CH2:7]([O:4][C:1]1[CH:20]=[CH:19][C:18]([CH2:23][CH3:24])=[CH:17][C:16]=1[Br:15])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: BrCc1ccccc1
Reactant: CCc1cc(Br)ccc1O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCc1ccc(OCc2ccccc2)c(Br)c1
Reaction time: 20 h
Yield: 569.5 %

Procedure:
Potassium carbonate (21.6 g, 0.16 mol) followed by benzyl bromide (6.2 mL, 52 mmol) were added to a solution of 4-bromo-2-ethyl-phenol (1.6 g, 7.9 mmol, from step 1 of Example B(98)) in DMF (75 mL). The mixture was stirred for 20 hours and then partitioned between 1N HCl and EtOAc. The organic layers were washed with brine, dried over Na2SO4 and concentrated. The crude yellow oil was purified by flash column chromatography (hexanes) to give the desired product (13.1 g, 87%). 1H NMR (400 MHz, CDCl3): δ 1.20 (t, J=7.6 Hz, 3 H), 2.56 (q, J=7.8 Hz, 2 H), 5.13 (s, 2 H), 6.84 (d, J=8.3 Hz, 1 H), 7.04 (dd, J=8.3, 2.3 Hz, 1 H), 7.32 (m, 1 H), 7.38 (m, 3 H), 7.47 (d, J=7.9 Hz, 2 H).
Reaction SMILES: C[O:2][C:3]([C:5]1[S:6][CH:7]=[CH:8][C:9]=1[Br:10])=[O:4]>CO.O1CCCC1.[OH-].[Na+]>[Br:10][C:9]1[CH:8]=[CH:7][S:6][C:5]=1[C:3]([OH:4])=[O:2]
Reactant: COC(=O)c1sccc1Br
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1sccc1Br
Temperature: 25 °C
Reaction time: 2 h
Yield: 97.3 %

Procedure:
3-Bromo-2-thiophenecarboxylic acid methyl ester (7.74 g) was dissolved in a mixture of methanol (35 ml) and tetrahydrofuran (35 ml), and 1N aqueous sodium hydroxide (53 ml) was added. The mixture was stirred at room temperature for 2 hours and washed with diethyl ether. The aqueous layer was acidified with 1N hydrochloric acid and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 3-bromo-2-thiophenecarboxylic acid (7.05 g) as crystals.
Reaction SMILES: [Br-].[CH2:2]([O:9][CH2:10][CH2:11][CH2:12][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[CH:42]([CH:44]1[CH2:49][CH2:48][N:47]([C:50]([O:52][C:53]([CH3:56])([CH3:55])[CH3:54])=[O:51])[CH2:46][CH2:45]1)=O>C1COCC1>[CH2:2]([O:9][CH2:10][CH2:11]/[CH:12]=[CH:42]\[CH:44]1[CH2:49][CH2:48][N:47]([C:50]([O:52][C:53]([CH3:54])([CH3:56])[CH3:55])=[O:51])[CH2:46][CH2:45]1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: c1ccc(COCCC[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(C=O)CC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Br-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(/C=C\CCOCc2ccccc2)CC1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
(3-Benzyloxypropyl)triphenylphosphonium bromide (2.88 g, 5.86 mmol) was suspended in 15 mL THF and cooled to 0° C. Sodium bis(trimethylsily)amide (1M in THF, 5.63 mL, 5.63 mmol) was added drop wise. The mixture turned deep orange. tert-Butyl 4-formylpiperidine-1-carboxylate (1 g, 4.69 mmol) in 3 mL THF was added after 5 minutes. Color faded to slight yellow. The reaction was stirred at room temperature for 1.5 hours, before quenching with saturated aqueous ammonium chloride solution. The aqueous layer was extracted twice with ethyl acetate. The organic layers were combined, washed with water and brine, dried over sodium sulfate, filtered, concentrated and purified by passing through a 40 gram Biotage™ silica gel cartridge using 20% EtOAc/hexanes to afford the product as colorless oil. NMR integration indicated >20:1 Z/E selectivity. LRMS calc: 345.2; obs: 346.5 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([O:13][CH3:14])=[CH:5][C:4]=1[CH2:15][CH2:16][C:17](OC)=[O:18].[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[CH3:1][O:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([O:13][CH3:14])=[CH:5][C:4]=1[CH2:15][CH2:16][CH2:17][OH:18]
Reactant: COC(=O)CCc1cc(OC)c2ccccc2c1OC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1cc(CCCO)c(OC)c2ccccc12
Yield: 92.4 %

Procedure:
Following a procedure similar to that described in Preparation 20(b), but using 0.41 g of methyl 3-(1,4-dimethoxy-2-naphthyl)propionate [prepared as described in step (c) above], 68 mg of lithium aluminum hydride and 6 ml of tetrahydrofuran, 0.34 g of the title compound was obtained as a colorless oil.
Reaction SMILES: [CH2:1]([N:8]([CH2:29][CH2:30][CH2:31][CH2:32][C:33]1[CH:34]=[N:35][CH:36]=[CH:37][CH:38]=1)[CH2:9][CH2:10][C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([NH2:20])[CH:18]=2)[NH:13][C:12]=1[C:21]1[CH:26]=[C:25]([CH3:27])[CH:24]=[C:23]([CH3:28])[CH:22]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:40](Cl)([O:42]C(=O)OC(Cl)(Cl)Cl)Cl>N1C=CC=CC=1>[CH2:1]([N:8]([CH2:9][CH2:10][C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([N:20]=[C:40]=[O:42])[CH:18]=2)[NH:13][C:12]=1[C:21]1[CH:22]=[C:23]([CH3:28])[CH:24]=[C:25]([CH3:27])[CH:26]=1)[CH2:29][CH2:30][CH2:31][CH2:32][C:33]1[CH:34]=[N:35][CH:36]=[CH:37][CH:38]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: Cc1cc(C)cc(-c2[nH]c3ccc(N)cc3c2CCN(CCCCc2cccnc2)Cc2ccccc2)c1
Solvent: c1ccncc1
Product: Cc1cc(C)cc(-c2[nH]c3ccc(N=C=O)cc3c2CCN(CCCCc2cccnc2)Cc2ccccc2)c1
Reaction time: 0.83 h
Yield: 253.2 %

Procedure:
To a solution of 3-{2-[benzyl-(4-pyridin-3-yl-butyl)amino]ethyl} -2-(3,5-dimethylphenyl)-1H-indol-5-ylamine (120 mg in 8 mL dry methylene chloride) at 0° C. was added 26.6 mg triphosgene followed by 0.050 mL pyridine and the mixture stirred at low temperature. After 50 minutes, the mixture was concentrated in vacuo to give the crude title compound (120 mg).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:6]=1/[CH:12]=[CH:13]/[C:14]([OH:16])=O)(=[O:3])[CH3:2].[Cl:17][C:18]1[CH:31]=[CH:30][C:21]([CH2:22][N:23]2[CH2:28][CH2:27][NH:26][CH:25]([CH3:29])[CH2:24]2)=[CH:20][CH:19]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C>[Cl:11][C:9]1[CH:8]=[CH:7][C:6](/[CH:12]=[CH:13]/[C:14]([N:26]2[CH2:27][CH2:28][N:23]([CH2:22][C:21]3[CH:30]=[CH:31][C:18]([Cl:17])=[CH:19][CH:20]=3)[CH2:24][CH:25]2[CH3:29])=[O:16])=[C:5]([NH:4][C:1](=[O:3])[CH3:2])[CH:10]=1
Reactant: CC(=O)Nc1cc(Cl)ccc1/C=C/C(=O)O
Reactant: CC1CN(Cc2ccc(Cl)cc2)CCN1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CC(=O)Nc1cc(Cl)ccc1/C=C/C(=O)N1CCN(Cc2ccc(Cl)cc2)CC1C
Reaction time: 8 h
Yield: 63.2 %

Procedure:
0.10 g (0.42 mmol) (E)-3-(2-Acetylamino-4-chloro-phenyl)-acrylic acid, 85 mg 1-(4-Chloro-benzyl)-3-methyl-piperazine (0.38 mmol), 87 mg EDCI (0.45 mmol) and 61 mg HOBt (0.45 mmol) were dissolved in 5 ml DMF. The reaction mixture was stirred overnight, then partitioned between ethylacetate and aq. sodiumbicarbonate solution. The organic phase was further washed with water and brine. Removal of the solvent gave a crude product which was further purified by prep. HPLC (Waters XT column, acetonitrile/water). 0.11 mg (0.24 mmol, 63%) of the title compound was obtained as an pale yellow solid.
Reaction SMILES: [C:1]([N:4]([C:13]1[CH:49]=[CH:48][C:16]([CH:17]=[CH:18][C:19]([NH:21][CH2:22][C:23]([N:25]([C:27]2[C:28]([Cl:47])=[C:29]([C:43]([Cl:46])=[CH:44][CH:45]=2)[CH2:30][O:31][C:32]2[CH:33]=[CH:34][CH:35]=[C:36]3[C:41]=2[N:40]=[C:39]([CH3:42])[CH:38]=[CH:37]3)[CH3:26])=[O:24])=[O:20])=[CH:15][CH:14]=1)[CH2:5][C:6]([O:8]C(C)(C)C)=[O:7])(=[O:3])[CH3:2].FC(F)(F)C(O)=O>ClCCl>[C:1]([N:4]([C:13]1[CH:14]=[CH:15][C:16]([CH:17]=[CH:18][C:19]([NH:21][CH2:22][C:23]([N:25]([C:27]2[C:28]([Cl:47])=[C:29]([C:43]([Cl:46])=[CH:44][CH:45]=2)[CH2:30][O:31][C:32]2[CH:33]=[CH:34][CH:35]=[C:36]3[C:41]=2[N:40]=[C:39]([CH3:42])[CH:38]=[CH:37]3)[CH3:26])=[O:24])=[O:20])=[CH:48][CH:49]=1)[CH2:5][C:6]([OH:8])=[O:7])(=[O:3])[CH3:2]
Reactant: CC(=O)N(CC(=O)OC(C)(C)C)c1ccc(C=CC(=O)NCC(=O)N(C)c2ccc(Cl)c(COc3cccc4ccc(C)nc34)c2Cl)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)N(CC(=O)O)c1ccc(C=CC(=O)NCC(=O)N(C)c2ccc(Cl)c(COc3cccc4ccc(C)nc34)c2Cl)cc1
Reaction time: 1 h
Yield: 94.2 %

Procedure:
To a solution of 8-[3-[N-[4-(N-acetyl-N-tert-butoxycarbonylmethylamino)cinnamoylglycyl]-N-methylamino]-2,6-dichlorobenzyloxy]-2-methylquinoline (143 mg) in dichloromethane (1.4 ml) was added trifluoroacetic acid (0.05 ml) at ambient temperature and the mixture was stirred at the same temperature. After 1 hour, to the solution was added trifluoroacetic acid (1 ml). After 5 hours the solvent was removed in vacuo to give 8-[3-[N-[4-(N-acetyl-N-carboxymethylamino)cinnamoylglycyl]-N-methylamino]-2,6-dichlorobenzyloxy]-2-methylquinoline (124 mg) as amorphous solid.
Reaction SMILES: [C:1]1([OH:8])[C:5](=O)[C:3](=[O:4])[C:2]=1[OH:7].[CH3:9][C:10]([C:13]1[Se:14][C:15]([C:28]([CH3:31])([CH3:30])[CH3:29])=[CH:16][C:17](=[CH:19]C2C(Cl)(Cl)C(=O)C=2Cl)[CH:18]=1)([CH3:12])[CH3:11].FC(F)(F)S(O)(=O)=O.[OH-].[Na+]>O>[CH3:12][C:10]([C:13]1[Se:14][C:15]([C:28]([CH3:31])([CH3:30])[CH3:29])=[CH:16][C:17](=[CH:19][C:5]2[C:3](=[O:4])[C:2](=[O:7])[C:1]=2[OH:8])[CH:18]=1)([CH3:9])[CH3:11]
Reactant: O=c1c(O)c(O)c1=O
Reactant: CC(C)(C)C1=CC(=CC2=C(Cl)C(=O)C2(Cl)Cl)C=C(C(C)(C)C)[Se]1
Agent: O=S(=O)(O)C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(C)(C)C1=CC(=Cc2c(O)c(=O)c2=O)C=C(C(C)(C)C)[Se]1
Temperature: 25 °C
Yield: 94 %

Procedure:
This Example illustrates the preparation, by the reaction D→E shown in FIG. 1, of the squaric acid derivative of Formula II in which Q1 is a 2,6-bis(1,1-dimethylethyl)-4-selenopyrylidene grouping and R1 is a hydrogen atom. 3-[[2,6-bis(1,1-dimethylethyl)-4H-selenopyran-4-ylidene]methyl]-2,4,4-trichlorocyclobut-2-en-1-one (23 g, 52.4 mmole, prepared in Examples 48 and 49 above), trifluoromethane sulfonic acid (80 mL) and water (3 mL) were heated at 105° C. for three hours under nitrogen in a vessel fitted with an outlet connected to a gas-washing bottle containing 10% aqueous sodium hydroxide solution. The resultant dark solution was cooled to room temperature and added slowly to an ice/water mixture with rapid agitation. The resultant red solid was collected by filtration, washed with water and air dried, causing. its color to change to an iridescent green. The crude product so obtained was purified by trituration with cyclohexane for three hours. The pure 3-[[2,6-bis(1,1-dimethylethyl)-4H-selenopyran-4-ylidene]methyl]-4-hydroxycyclobut-3-ene-1,2-dione was collected by filtration, washed with cyclohexane, and dried to afford a red material (18 g, 94% yield). The structure of this compound was confirmed by mass spectroscopy and by 1H and 13C NMR spectroscopy.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[CH2:4][C:5]1[N:14]=[C:13]2[C:8]([CH2:9][CH2:10][CH2:11][N:12]2C(OC(C)(C)C)=O)=[CH:7][CH:6]=1.[ClH:23]>CO>[ClH:23].[N:14]1[C:13]2[NH:12][CH2:11][CH2:10][CH2:9][C:8]=2[CH:7]=[CH:6][C:5]=1[CH2:4][C:3]([O:2][CH3:1])=[O:22]
Reactant: COC(=O)Cc1ccc2c(n1)N(C(=O)OC(C)(C)C)CCC2
Agent: Cl
Solvent: CO
Product: COC(=O)Cc1ccc2c(n1)NCCC2
Reaction time: 1 h
Yield: 99 %

Procedure:
tert-Butyl 7-(2-methoxy-2-oxoethyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxylate (1 eq.) (CAS [925889-81-2], available commercially from Fluorochem, for example) was dissolved in methanol (1.6 ml); hydrogen chloride in methanol (1.25 M, 5 equiv.) was added, and the mixture was heated to boiling temperature. After 1 h, the solvent was removed in vacuo and the residue so obtained was used directly in the following stage. Yield: >99%
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:11](C)=O)[C:5]([F:10])=[C:6]([O:8][CH3:9])[CH:7]=1.C(OC(C(F)(F)F)=O)(C(F)(F)F)=O>CC#N>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([F:10])=[C:4]([SH:11])[CH:3]=1
Reactant: COc1cc(Cl)cc(S(C)=O)c1F
Solvent: CC#N
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: COc1cc(Cl)cc(S)c1F
Temperature: 0 °C
Reaction time: 1 h
Yield: 69.9 %

Procedure:
To a mixture of 5-chloro-2-fluoro-1-methoxy-3-(methylsulfinyl)benzene (501 mg) and CH3CN (20 mL) was added TFAA (0.953 mL) at 0° C. The mixture was stirred at 0° C. for 1 h and then at room temperature for 1 h. The mixture was concentrated. The residue was dissolved in a mixture of MeOH (3.5 mL) and TEA (3.5 mL) at 0° C. The solution was stirred at 0° C. for 10 min, and concentrated in vacuo. The mixture was diluted with saturated aqueous NH4Cl and extracted with EtOAc. The organic layer was extracted with 1N NaOH. The aqueous layer was acidified with 1N HCl and extracted with EtOAc. The organic layer was washed with brine, dried over MgSO4, and concentrated in vacuo to give the title compound (303 mg).
Reaction SMILES: C1(=O)[N:5]([C:6]2[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[NH:8][N:7]=2)[C:4](=O)[C:3]2=[CH:16]C=CC=C12.Br.Br[CH2:23][CH2:24][CH2:25][N:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1.[C:32]1(=O)[N:36](C2C3C(=CC=CC=3Cl)NN=2)[C:35](=O)[C:34]2=CC=CC=[C:33]12.Br.BrCCCN(CC)CC>>[O:29]1[CH2:30][CH2:31][N:26]([CH2:25][CH2:24][CH2:23][N:8]2[C:9]3[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:6]([NH:5][CH2:4][CH2:3][CH2:16][N:36]([CH2:32][CH3:33])[CH2:35][CH3:34])=[N:7]2)[CH2:27][CH2:28]1
Reactant: O=C1c2ccccc2C(=O)N1c1n[nH]c2cccc(Cl)c12
Reactant: O=C1c2ccccc2C(=O)N1c1n[nH]c2ccccc12
Reactant: BrCCCN1CCOCC1
Agent: Br
Agent: CCN(CC)CCCBr
Product: CCN(CC)CCCNc1nn(CCCN2CCOCC2)c2ccccc12

Procedure:
The same procedures as described in Example 89 were repeated except that 8.0 g of 3-phthalimido-indazole and 10.1 g of 3-bromopropylmorpholine hydrobromide were employed instead of the 3-phthalimido-4-chloroindazole and the 4.83 g of 3-bromopropyldiethylamine hydrobromide, respectively. As a result, 8.7 g of 1-(3-morpholinopropyl)-3-(3-diethylaminopropylamino)indazole was obtained.
Reaction SMILES: [C:1]([C:3]1[CH:24]=[CH:23][C:6]([CH2:7][NH:8][C:9](=[O:22])[CH:10]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([OH:21])[CH:14]=2)[O:11][CH3:12])=[CH:5][CH:4]=1)#[N:2].C([O-])([O-])=O.[K+].[K+].Br[CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34]>CN(C=O)C.CCOC(C)=O>[CH2:36]([O:35][C:33](=[O:34])[CH2:32][O:21][C:15]1[CH:14]=[C:13]([CH:10]([C:9](=[O:22])[NH:8][CH2:7][C:6]2[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:24][CH:23]=2)[O:11][CH3:12])[CH:18]=[CH:17][C:16]=1[O:19][CH3:20])[CH3:37]
Reactant: COc1ccc(C(OC)C(=O)NCc2ccc(C#N)cc2)cc1O
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)COc1cc(C(OC)C(=O)NCc2ccc(C#N)cc2)ccc1OC
Temperature: 25 °C
Reaction time: 5 h
Yield: 89.3 %

Procedure:
To a stirred solution of (RS)-N-(4-cyano-benzyl)-2-(3-hydroxy-4-methoxy-phenyl)-2-methoxy-acetamide (0.303 g) at rt in DMF (3 ml) were added K2CO3 (0.14 g) and ethyl bromoacetate (0.169 g). The reaction mixture was then stirred at rt under an argon atmosphere for 5 h 45. The mixture was diluted with EtOAc (25 ml), washed with water (25 ml) and brine (25 ml), dried (MgSO4), filtered and concentrated (rotavapor) to leave the crude product as a light yellow gum. The product was purified by chromatography (Silicagel (20 g) using a gradient profile: cyclohexane to cyclohexane/EtOAc 35:65) to give (RS)-{5-[(4-cyano-benzylcarbamoyl)-methoxy-methyl]-2-methoxy-phenoxy}-acetic acid ethyl ester (0.342 g) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([F:11])[C:9]=1F)[C:5]#[N:6].[NH:12]([CH2:16][CH2:17][OH:18])[CH2:13][CH2:14][OH:15]>CN(C)C(=O)C>[F:11][C:8]1[CH:7]=[C:4]([CH:3]=[C:2]([F:1])[C:9]=1[N:12]([CH2:16][CH2:17][OH:18])[CH2:13][CH2:14][OH:15])[C:5]#[N:6]
Reactant: OCCNCCO
Reactant: N#Cc1cc(F)c(F)c(F)c1
Solvent: CC(=O)N(C)C
Product: N#Cc1cc(F)c(N(CCO)CCO)c(F)c1

Procedure:
A solution of 3,4,5-trifluorobenzonitrile (5 g, 32 mmol) and diethanolamine (6 ml, 85 mmol) in N,N-dimethylacetamide was stirred for 10 days. The solvent was then evaporated, the residue partitioned between CH2Cl2 (200 ml) and H2O (200 ml), the organic layer dried (MgSO4) and evaporated to dryness. The residue was chromatographed using CH2Cl2-EtOAc as eluent to give, after recrystallization from toluene, 2.7 g (35%) of pure white crystals: mp 63-65° C.; 1H NMR δ3.33 (t, 4H, NCH2, J=6 Hz), 3.48 (t, 4H, OCH2, J=6 Hz), 4.43 (bs, 2H, OH), 7.57 (dd, 2H, H2+6, JH2, F3 and H6, F5=8.5 Hz, JH2, F5 and H6, F3=2Hz=22 Hz); 19F NMR δ −116.0 (d, 2F, F3+5, JF3, H2 and F5, 6=7.5 Hz); MS m/z 265 (M+Na+, 10), 243 (M+H+, 100), 211 (M-CH2OH, 85). Anal. (C11H12N2O2F2) C,H,N.
Reaction SMILES: [CH3:1][C:2]1([CH3:34])[C:11]2[CH:10]=[C:9]([Se:12][C:13]#[C:14][C:15]3[CH:24]=[CH:23][C:18]([C:19]([O:21]C)=[O:20])=[C:17]([O:25][CH3:26])[CH:16]=3)[CH:8]=[CH:7][C:6]=2[C:5]([C:27]2[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=2)=[CH:4][CH2:3]1.[OH-].[Na+].Cl>O1CCCC1.O>[CH3:1][C:2]1([CH3:34])[C:11]2[CH:10]=[C:9]([Se:12][C:13]#[C:14][C:15]3[CH:24]=[CH:23][C:18]([C:19]([OH:21])=[O:20])=[C:17]([O:25][CH3:26])[CH:16]=3)[CH:8]=[CH:7][C:6]=2[C:5]([C:27]2[CH:28]=[CH:29][C:30]([CH3:33])=[CH:31][CH:32]=2)=[CH:4][CH2:3]1
Reactant: COC(=O)c1ccc(C#C[Se]c2ccc3c(c2)C(C)(C)CC=C3c2ccc(C)cc2)cc1OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(C#C[Se]c2ccc3c(c2)C(C)(C)CC=C3c2ccc(C)cc2)ccc1C(=O)O
Reaction time: 15 h

Procedure:
0.55 g (1.1 mmol) of methyl 4-(8,8-dimethyl-5-p-tolyl-7,8-dihydro-2-naphthylselanylethynyl)-2-methoxybenzoate is dissolved in 15 ml of tetrahydrofuran and 2 drops of water. 0.26 g (6.4 mmol) of sodium hydroxide is added. The medium is stirred for 15 hours, acidified with 2N hydrochloric acid solution and then extracted with ethyl acetate. The solid obtained is purified by chromatography (eluent: 3/7 heptane/ethyl acetate). A white solid is obtained (0.53 g; yield=99%; m.p.=150° C.).
Reaction SMILES: [C:1]([C:5]1[CH:14]=[CH:13][C:8]2[NH:9][C:10](=[O:12])[O:11][C:7]=2[CH:6]=1)(=[O:4])[CH2:2][CH3:3].C(=O)([O-])[O-].[K+].[K+].[CH2:21](Br)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CC(C)=O>[CH2:21]([N:9]1[C:8]2[CH:13]=[CH:14][C:5]([C:1](=[O:4])[CH2:2][CH3:3])=[CH:6][C:7]=2[O:11][C:10]1=[O:12])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CCC(=O)c1ccc2[nH]c(=O)oc2c1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCC(=O)c1ccc2c(c1)oc(=O)n2Cc1ccccc1
Temperature: 50 °C
Reaction time: 4 h

Procedure:
94 g (492 mmol) 6-propionyl-3H-benzoxazol-2-one is placed in 1000 mL acetone and 160 g (1.157 mol) potassium carbonate and then 65 ml (546 mol) benzylbromide are added and the mixture is stirred for 4 h at 50° C. The reaction mixture is suction filtered hot and then the filtrate is slowly cooled. The solid is suction filtered and washed with acetone/diethyl ether.
Reaction SMILES: [CH3:1][N:2]1[CH:7]2[CH2:8][CH2:9][CH:3]1[CH2:4][CH:5]([OH:10])[CH2:6]2.F[C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][C:13]=1[CH3:21]>>[CH3:1][N:2]1[CH:7]2[CH2:8][CH2:9][CH:3]1[CH2:4][CH:5]([O:10][C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][C:13]=1[CH3:21])[CH2:6]2
Reactant: CN1C2CCC1CC(O)C2
Reactant: Cc1cc([N+](=O)[O-])ccc1F
Product: Cc1cc([N+](=O)[O-])ccc1OC1CC2CCC(C1)N2C

Procedure:
8-Methyl-8-aza-bicyclo[3.2.1]octan-3-ol was reacted with 1-Fluoro-2-methyl-4-nitrobenzene according to method D. The product with the molecular weight of 276.34 (C15H20N2O3) was obtained in this way; MS (ESI) 277 (M+H+).