Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:19])[N:7]([CH3:18])[C:8]([CH2:12]OS(C)(=O)=O)=[N:9]2)=[CH:4][C:3]=1[CH2:20][N:21]([C:25]1[CH:37]=[CH:36][C:28]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])=[CH:27][CH:26]=1)[CH2:22][C:23]#[CH:24].[NH:38]1[CH2:43][CH2:42][O:41][CH2:40][CH2:39]1>ClCCl>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:19])[N:7]([CH3:18])[C:8]([CH2:12][N:38]3[CH2:43][CH2:42][O:41][CH2:40][CH2:39]3)=[N:9]2)=[CH:4][C:3]=1[CH2:20][N:21]([C:25]1[CH:26]=[CH:27][C:28]([C:29]([O:31][C:32]([CH3:33])([CH3:35])[CH3:34])=[O:30])=[CH:36][CH:37]=1)[CH2:22][C:23]#[CH:24]
Reactant: C#CCN(Cc1cc2c(=O)n(C)c(COS(C)(=O)=O)nc2cc1Cl)c1ccc(C(=O)OC(C)(C)C)cc1
Reactant: C1COCCN1
Solvent: ClCCl
Product: C#CCN(Cc1cc2c(=O)n(C)c(CN3CCOCC3)nc2cc1Cl)c1ccc(C(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A mixture of tert-butyl 4-[N-[7-chloro-2-methanesulphonyloxymethyl-3-methyl-4-oxo-3,4-dihydroquinazolin-6-ylmethyl]-N-(prop-2-ynyl )amino]benzoate (0.193 g, 0.35 mmol), dichloromethane (7 ml), and morpholine (0.304 g, 3.5 mmol) was stirred at room temperature for 6 h under argon. The cloudy reaction mixture was then partitioned between ethyl acetate (200 ml) and 5% aqueous sodium carbonate (80 ml). The organic layer was washed more 5% sodium carbonate (2×80 ml), and brine (80 ml), dried (Na2SO4) and concentrated in vacuo. Purification by column chromatography, on elution with 10% ethyl acetate in dichloromethane, afforded a solid which was triturated with 5% dichloromethane in hexanes. The white solid was collected by filtration, dried in vacuo over P2O5 (0.174 g, 82%), mp 140-143° C.; 1H-NMR (DMSO-d6) 1.50 (s, 9H, But), 2.48, (br s obscured) and 3.55 (br s) (8H, N(CH2CH2)2O), 3.62 (s, 5H, 2-CH2, N3-Me), 3.20 (s(poorly resolved triplet), 1H, C≡CH), 4.39 (s, 2H, CH2C≡C), 4.79 (s, 2H, 6-CH2), 6.78 (d, J=8.7 Hz, 2H, 3′,5′-ArH), 7.72 (d, J=8.7 Hz, 2H, 2′,6′-ArH), 7.80, 7.89 (2×s, 2H, 5-H, 8-H). MS (ESI, m/z) 537, 539 [(M+H)+, 100%, 38% respectively; Cl isotopic pattern].
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([OH:17])=O)[CH3:14])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1.Cl.[CH3:19][O:20][C:21](=[O:31])[C@H:22]([CH2:24][CH2:25][CH2:26][CH2:27][N:28]([CH3:30])[CH3:29])[NH2:23]>CO.C(Cl)Cl>[F:8][C:6]1[CH:5]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([NH:23][C@@H:22]([CH2:24][CH2:25][CH2:26][CH2:27][N:28]([CH3:30])[CH3:29])[C:21]([O:20][CH3:19])=[O:31])=[O:17])[CH3:14])=[O:11])[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: COC(=O)[C@@H](N)CCCCN(C)C
Reactant: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)O
Agent: Cl
Solvent: ClCCl
Solvent: CO
Product: COC(=O)[C@H](CCCCN(C)C)NC(=O)[C@H](C)NC(=O)Cc1cc(F)cc(F)c1

Procedure:
Following General Procedure A and using N-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) and Nε,Nε-dimethyl-L-lysine methyl ester hydrochloride (Bachem), the title compound was prepared as a solid (mp=123-126° C.). The reaction was monitored by tlc (Rf=0.22 in 10% MeOH/DCM+1% TEA) and the product was purified by silica gel column chromatography.
Reaction SMILES: C([O:3][C:4]([C:6]1([S:19]([C:22]2[CH:27]=[CH:26][C:25]([O:28][CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[CH:24][CH:23]=2)(=[O:21])=[O:20])[CH2:11][CH2:10][N:9]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:8][CH2:7]1)=O)C.C(OC1C=CC(S(C2(C(O)=O)CCN(CC3C=CC=CC=3)CC2)(=O)=O)=CC=1)C1C=CC=CC=1.[OH:69][NH:70]C(C1CCN(CC2C=CC=CC=2)C(S(C2C=CC(OCC3C=CC=CC=3)=CC=2)(=O)=O)C1)=O>CO.C1COCC1>[OH:69][NH:70][C:4]([C:6]1([S:19]([C:22]2[CH:23]=[CH:24][C:25]([O:28][CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[CH:26][CH:27]=2)(=[O:21])=[O:20])[CH2:7][CH2:8][N:9]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:10][CH2:11]1)=[O:3]
Reactant: O=C(NO)C1CCN(Cc2ccccc2)C(S(=O)(=O)c2ccc(OCc3ccccc3)cc2)C1
Reactant: CCOC(=O)C1(S(=O)(=O)c2ccc(OCc3ccccc3)cc2)CCN(Cc2ccccc2)CC1
Agent: O=C(O)C1(S(=O)(=O)c2ccc(OCc3ccccc3)cc2)CCN(Cc2ccccc2)CC1
Solvent: C1CCOC1
Solvent: CO
Product: O=C(NO)C1(S(=O)(=O)c2ccc(OCc3ccccc3)cc2)CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
4-(4-Benzyloxy-benzenesulfonyl)-1-benzyl-piperidine-4-carboxylic acid ethyl ester (5.0 g, 10.1 mmol) was dissolved in MeOH/THF (1:1, 200 ml) and stirred at room temperature for 72 hrs. At the end reaction mixture was concentrated and the product was nuetralised with con. HCl by dissolving it in water (200 mL). After the neutralization reaction mixture was concentrated to dryness. Ice cold water (100 mL) was added to the solid and filtered. The product 4-(4-Benzyloxy-benzenesulfonyl)-1-benzyl-piperidine-4-carboxylic acid was dried at 50° C. and taken to next step with out any purification. Colorless solid. MP: 66-68; Yield: 4.3 g, 91% ; MS: 466 (M+H) Starting from 4-(4-Benzyloxy-benzenesulfonyl)-1-benzyl-piperidine-4-carboxylic acid (4.65 g, 10.0 mmol) and following the procedure outlined in example 83, 1.1 g of 4-(4-Benzyloxy-benzenesulfonyl-1-benzyl-piperidine-4-carboxylic acid hydroxyamide was isolated as a colurless solid. Yield 21%; mp 89° C.; MS: 481.1 1H NMR (300 MHz, DMSO-d6): δ2.27 (m, 3H), 2.76-2.79 (m, 2H), 3.43 (m, 4H),4.30 (s, 2H), 7.14-7.17 (d,2H), 7.50-7.73 (m, 5H), 9.37 (s, 1H), 10.53 (s, 1H), 11.18 (s, 1H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][N:8]([CH3:11])[CH2:7][CH2:6]1.Cl[C:13]1[C:18]([N+:19]([O-:21])=[O:20])=[CH:17][CH:16]=[CH:15][N:14]=1>C(O)C>[CH3:11][N:8]1[CH2:7][CH2:6][N:5]([CH2:4][CH2:3][CH2:2][NH:1][C:13]2[C:18]([N+:19]([O-:21])=[O:20])=[CH:17][CH:16]=[CH:15][N:14]=2)[CH2:10][CH2:9]1
Reactant: CN1CCN(CCCN)CC1
Reactant: O=[N+]([O-])c1cccnc1Cl
Solvent: CCO
Product: CN1CCN(CCCNc2ncccc2[N+](=O)[O-])CC1
Temperature: 25 °C

Procedure:
In a 2 liter, three-necked flask fitted with condenser, dropping funnel, thermometer, magnetic stirrer and nitrogen inlet was placed 71.8 g. (0.456 mole) 1-(3-aminopropyl)-4-methyl piperazine and 150 ml. of ethanol. The solution was heated at reflux and a solution of 65.0 g. 2-chloro-3-nitropyridine dissolved in 500 ml. of warm ethanol was added dropwise over 90 minutes. The dark yellow reaction mixture was maintained at reflux of an additional hour then cooled to ambient temperature. The solvent was then removed in vacuo to obtain a yellow-brown semi-solid residue. The residue was partitioned between 200 ml. each of aqueous 1N HCl and methylene chloride, and aqueous phase washed with 100 ml. CH2Cl2. The aqueous portion was made basic with 6N NaOH and extracted with 3 × 250 ml. CH2Cl2. The combined organic layers were dried over Na2SO4 and the solvent evaporated to afford 2-[3-(4-methyl-1-piperazinyl)propylamino]- 3-nitropyridine as a red-yellow oil which crystallized on standing at room temperature; yield 82.9 g. (72%).
Reaction SMILES: [CH2:1]1[CH:5]2[CH2:6][NH:7][CH2:8][CH:4]2[CH2:3][N:2]1[C:9]1[CH:18]=[N:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=1.[CH3:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[C:27]([C:32](O)=[O:33])=[CH:28][CH:29]=[CH:30][CH:31]=2)=[CH:22][CH:21]=1>>[CH3:19][C:20]1[CH:21]=[CH:22][C:23]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[C:32]([N:7]2[CH2:8][CH:4]3[CH:5]([CH2:1][N:2]([C:9]4[CH:18]=[N:17][C:16]5[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=5)[N:10]=4)[CH2:3]3)[CH2:6]2)=[O:33])=[CH:24][CH:25]=1
Reactant: Cc1ccc(-c2ccccc2C(=O)O)cc1
Reactant: c1ccc2nc(N3CC4CNCC4C3)cnc2c1
Product: Cc1ccc(-c2ccccc2C(=O)N2CC3CN(c4cnc5ccccc5n4)CC3C2)cc1

Procedure:
The title compound was prepared in a manner analogous to Example 15 utilizing Intermediate 35 and 4′-methyl-biphenyl-2-carboxylic acid. MS (ESI): mass calculated for C28H26N4O, 434.55; m/z found 435.3 [M+H]+.
Reaction SMILES: [Br:1]Br.[O:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[CH2:5][CH2:4]1>O1CCOCC1>[Br:1][C:10]1[CH:9]=[CH:8][C:7]2[O:3][CH2:4][CH2:5][C:6]=2[CH:11]=1
Reactant: c1ccc2c(c1)CCO2
Reactant: BrBr
Solvent: C1COCCO1
Product: Brc1ccc2c(c1)CCO2
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 70.3 %

Procedure:
To an ice-cooled dioxane (30 ml) was slowly added liquid bromine (2.66 g) and this mixture was stirred for 30 minutes at said temperature. To the mixture was added dropwise 2,3-dihydrobenzofuran (2 g), and the resulting mixture was stirred for 3 hours at room temperature. The solvent was removed under reduced pressure. The residue was dissolved in AcOEt (50 ml) and the solution was washed with saturated aqueous NaHCO3 solution and brine, and dried over MgSO4. The solvent was evaporated to give an orange oil as a crude product. The crude product was purified on an SiO2 column (hexane-AcOEt 20:1) to give 2.33 g of 5-bromo-2,3 dihydrobenzofuran as white crystals (yield 70.3%).
Reaction SMILES: C([O:8][C:9]1[CH:19]=[CH:18][C:12]([C:13]([N:15]([CH3:17])[CH3:16])=[O:14])=[CH:11][C:10]=1[C:20]([NH:22][C:23]1[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[C:25]([C:33]([F:36])([F:35])[F:34])[CH:24]=1)=[O:21])C1C=CC=CC=1.C(O)C>[Pd].C(OCC)(=O)C>[F:30][C:29]([F:31])([F:32])[C:27]1[CH:28]=[C:23]([NH:22][C:20](=[O:21])[C:10]2[CH:11]=[C:12]([CH:18]=[CH:19][C:9]=2[OH:8])[C:13]([N:15]([CH3:17])[CH3:16])=[O:14])[CH:24]=[C:25]([C:33]([F:35])([F:34])[F:36])[CH:26]=1
Reactant: CN(C)C(=O)c1ccc(OCc2ccccc2)c(C(=O)Nc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CN(C)C(=O)c1ccc(O)c(C(=O)Nc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.1 %

Procedure:
A solution of 4-benzyloxy-N3-[3,5-bis(trifluoromethyl)phenyl]-N1,N1-dimethyl-isophthalamide (141 mg, 0.28 mmol) and 5% Pd—C (14 mg) in the mixture of ethanol (5 ml) and ethyl acetate (5 ml) was stirred at room temperature for 1 hour under hydrogen atmosphere. The reaction mixture was filtered and the filtrate was evaporated under reduced pressure to give the title compound (106 mg, 91.2%) as a white solid.
Reaction SMILES: [CH:1]([C:3]1[C:4]([O:20][CH3:21])=[C:5]([CH:17]=[CH:18][CH:19]=1)[O:6][C:7]1[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][C:8]=1[C:9]#[N:10])=O.CN.[C:24]([BH3-])#[N:25].[Na+].[C:28]([OH:35])(=[O:34])/[CH:29]=[CH:30]/[C:31]([OH:33])=[O:32]>C(O)(=O)C.CO>[C:28]([OH:35])(=[O:34])/[CH:29]=[CH:30]/[C:31]([OH:33])=[O:32].[CH3:16][O:15][C:13]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[C:7]([O:6][C:5]2[CH:17]=[CH:18][CH:19]=[C:3]([CH2:1][NH:25][CH3:24])[C:4]=2[O:20][CH3:21])[CH:14]=1
Reactant: [BH3-]C#N
Reactant: COc1ccc(C#N)c(Oc2cccc(C=O)c2OC)c1
Agent: CN
Agent: O=C(O)/C=C/C(=O)O
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CNCc1cccc(Oc2cc(OC)ccc2C#N)c1OC
Yield: 60.5 %

Procedure:
2-(3-Formyl-2-methoxy-phenoxy)-4-methoxy-benzonitrile (0.38 g, 1.3 mmol), methylamine (2M in methanol, 3.0 mL, 6.0 mmol) and sodium cyanoborohydride (10 mg, 1.8 mmol) were stirred at ambient temperature in a 1% acetic acid/methanol solution (50 mL) for 17 h. The solvent was removed in vacuo. The residue was treated with 10% sodium carbonate solution and extracted with ethyl acetate. The ethyl acetate layer was separated and fumaric acid (0.15 g, 1.3 mmol) was added. After the solvent was removed in vacuo, the residue was triturated with ethyl acetate overnight, collected by filtration, and dried to give 4-methoxy-2-(2-methoxy-3-methylaminomethyl-phenoxy)-benzonitrile fumarate (326 mg, 58%) as an off-white solid.
Reaction SMILES: [O:1]=[CH:2][C@H:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[OH:4].[Br:13][CH2:14][CH2:15]O>CO.ClCCl>[Br:13][CH2:14][CH2:15][C:2]([C@H:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[OH:4])=[O:1]
Reactant: O=C[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Reactant: OCCBr
Solvent: CO
Solvent: ClCCl
Product: O=C(CCBr)[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Temperature: 25 °C
Reaction time: 4 h

Procedure:
DOWEX 50Wx4 resin (Alfa Aesar, Ward Hill, Mass.) is washed with deionized water to remove color. A mixture of 225 gm D-mannose (1.25 mol; 1 equiv., Alfa Aesar) and 140 gm DOWEX 50Wx4 is treated with 2.2 L 2-bromoethanol (30.5 mol, 25 equiv.; 124.97 gm/mol; 1.762 gm/mL; BP=150 C; Alfa Aesar) and the stirred mixture heated to 80 C for 4 hours. The reaction is monitored by TLC (20% methanol/dichloromethane (DCM)). Reaction is complete after about four hours, and then allowed to cool to room temperature. The solution is filtered to remove the resin, and the resin washed with ethyl acetate and DCM. The resulting filtrate is stripped to an amber oil in a rotory evaporator.
Reaction SMILES: [OH:1][CH2:2][C:3]1O[CH:5]=[C:6]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[C:7](=[O:9])[CH:8]=1.[NH3:20]>>[OH:1][CH2:2][C:3]1[NH:20][CH:5]=[C:6]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[C:7](=[O:9])[CH:8]=1
Reactant: COc1ccc(COc2coc(CO)cc2=O)cc1
Reactant: N
Product: COc1ccc(COc2c[nH]c(CO)cc2=O)cc1
Temperature: 90 °C

Procedure:
2-(hydroxymethyl)-5-(4-methoxybenzyloxy)-4H-pyran-4-one (Intermediate 63, 6.44 g, 24.56 mmol) and ammonia (7N in MeOH) (59.6 ml, 417.45 mmol) were combined in a pressure reactor vessel and heated at 90° C. for 5 hours. The reaction mixture was cooled overnight then concentrated. The solid was suspended in water then collected by filtration. The title compound was obtained as a brown solid (3.48 g, 54%).
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:31]=[CH:30][C:16]([CH2:17][NH:18][C:19]3[CH:20]=[CH:21][C:22]([F:29])=[C:23]([CH:28]=3)[C:24]([O:26][CH3:27])=[O:25])=[CH:15][CH:14]=2)=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].[CH2:32](O)[CH3:33]>>[CH2:1]([C:5]1[CH:6]=[CH:7][C:8]([C:11]#[C:12][C:13]2[CH:14]=[CH:15][C:16]([CH2:17][N:18]([CH2:32][CH3:33])[C:19]3[CH:20]=[CH:21][C:22]([F:29])=[C:23]([CH:28]=3)[C:24]([O:26][CH3:27])=[O:25])=[CH:30][CH:31]=2)=[CH:9][CH:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCO
Reactant: CCCCc1ccc(C#Cc2ccc(CNc3ccc(F)c(C(=O)OC)c3)cc2)cc1
Product: CCCCc1ccc(C#Cc2ccc(CN(CC)c3ccc(F)c(C(=O)OC)c3)cc2)cc1

Procedure:
The title compound was prepared following the procedure described in Example 23 step b) using methyl 5-({4-[(4-butylphenyl)ethynyl]benzyl}amino)-2-fluorobenzoate (prepared in Example 23, step a) and ethanol. The title compound was obtained as a pale yellow oil (215 mg). HPLC, Rt: 5.8 min (purity: 98.9%).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[NH2:15][CH2:16][CH2:17][C:18]([OH:20])=[O:19].C(=O)([O-])[O-].[K+].[K+].Cl>CN(C)C=O.O>[N+:12]([C:3]1[CH:4]=[C:5]([C:8]([F:11])([F:10])[F:9])[CH:6]=[CH:7][C:2]=1[NH:15][CH2:16][CH2:17][C:18]([OH:20])=[O:19])([O-:14])=[O:13]
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1Cl
Reactant: NCCC(=O)O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(O)CCNc1ccc(C(F)(F)F)cc1[N+](=O)[O-]
Temperature: 0 °C
Yield: 97.2 %

Procedure:
60 g (0.27 mol) of 2-chloro-1-nitro-5-trifluoromethylbenzene, 50 g (0.56 mol) of β-alanine and 41 g (0.3 mol) of potassium carbonate were refluxed in a mixture of 300 ml of dimethylformamide and 50 ml of water for 6 h. The mixture was then poured into ice-water, the aqueous phase was acidified with hydrochloric acid, and the precipitate was filtered off with suction to yield 73 g (99%) of the product.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[CH2:5][CH2:6][OH:7].[S:11]1[CH:15]=[CH:14][C:13](B(O)O)=[CH:12]1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[S:11]1[CH:15]=[CH:14][C:13]([C:2]2[CH:3]=[C:4]([CH2:5][CH2:6][OH:7])[CH:8]=[CH:9][CH:10]=2)=[CH:12]1
Reactant: OB(O)c1ccsc1
Reactant: OCCc1cccc(Br)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: OCCc1cccc(-c2ccsc2)c1
Temperature: 25 °C

Procedure:
A mixture of 3-bromo-phenethyl-alcohol (1 g, 4.97 mmol), 3-thiophene-boronic-acid (1.9 g, 14.9 mmol, 3.0 equiv), Pd(PPh3)4 (172 mg, 0.149 mmol, 0.03 equiv), and 2M Na2CO3 (10.8 mL, 22.4 mmol, 4.5 equiv) in toluene (40 mL) is heated to reflux 1 h, under an argon atmosphere. The resulting suspension is allowed to cool to RT and filtered through a pad of celite, washing the filter cake with CH2Cl2 and water. The layers are separated. The organic phase is washed with brine, dried (Na2SO4), filtered and concentrated. Purification of the crude material by silica gel column chromatography (CH2Cl2/Et2O, 95/5) affords the title compound: ES-MS: 205.0 [M+H]+; single peak at tR=4.27 min (System 2); Rf=0.32 (CH2Cl2/Et2O, 95/5).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([NH:8][N:9]=[C:10](OCC)[CH2:11][CH2:12][CH2:13][CH3:14])=O.[N+:18]([C:21]1[CH:28]=[CH:27][C:24]([CH2:25][NH2:26])=[CH:23][CH:22]=1)([O-:20])=[O:19].Cl>C(O)C>[CH2:11]([C:10]1[N:26]([CH2:25][C:24]2[CH:23]=[CH:22][C:21]([N+:18]([O-:20])=[O:19])=[CH:28][CH:27]=2)[C:6]([C:2]2[O:1][CH:5]=[CH:4][CH:3]=2)=[N:8][N:9]=1)[CH2:12][CH2:13][CH3:14]
Reactant: NCc1ccc([N+](=O)[O-])cc1
Reactant: CCCCC(=NNC(=O)c1ccco1)OCC
Agent: Cl
Solvent: CCO
Product: CCCCc1nnc(-c2ccco2)n1Cc1ccc([N+](=O)[O-])cc1

Procedure:
To 678 mg (2.85 mmole) of ethyl valerate 2-furoylhydrazone dissolved in 3 ml of ethanol was added a solution of 514 mg (2.16 mmole ) of 4-nitrobenzylamine (generated from the hydrochloride by partitioning between ether and saturated Na2CO3 solution) in 3 ml of ethanol. The resulting solution was heated at 45°-50° C. for two hours and then at 70° C. overnight. The solution was cooled and concentrated. Column chromatography of the residue on silica gel (gradient elution with 0.5-2.5% methanol in CH2Cl2) afforded some recovered starting material (ester hydrazone) followed by 432 mg (61%) of the product as a yellow oil which upon standing at 5° C. crystallized to a solid having mp 91°-92.5° C., homogeneous by TLC in 97:3 CH2Cl2 --MeOH; mass spectrum (FAB) m/e 327 (M+1)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][N:5]2[CH:10]=[CH:9][C:8]([CH2:11][CH3:12])=[CH:7][C:6]=12.C1C(=O)N([Br:20])C(=O)C1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.O>C(Cl)(Cl)(Cl)Cl>[Br:1][C:2]1[CH:3]=[N:4][N:5]2[CH:10]=[CH:9][C:8]([CH:11]([Br:20])[CH3:12])=[CH:7][C:6]=12
Reactant: O=C1CCC(=O)N1Br
Reactant: CCc1ccn2ncc(Br)c2c1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Solvent: O
Product: CC(Br)c1ccn2ncc(Br)c2c1
Temperature: 77 °C
Reaction time: 2 h
Yield: 28697.2 %

Procedure:
To a stirred solution of 3-bromo-5-ethylpyrazolo[1,5-a]pyridine (I-17, 2.1 g, 0.0094 mmol) in CCl4 (20 mL) at rt was added NBS (2 g, 0.01 mmol) followed by benzoyl peroxide (1.1 g, 0.004 mmol). The resulting reaction mixture was heated to 77° C. After 2 h, the reaction mixture was allowed to cool to rt and subsequently water (20 mL) was added followed by extraction with dichloromethane (2×20 mL). The combined organic layers were washed with water (1×20 mL), sat NaHCO3 solution (1×10 mL), brine (1×10 mL), dried over Na2SO4 and the solvent was removed under reduced pressure. The resulting crude product was purified by column chromatography over silica gel (petroleum ether/EtOAc, 0-5% EtOAc) to afford 820 mg (29%) of 3-bromo-5-(1-bromoethyl)pyrazolo[1,5-a]pyridine (I-18) as a brown solid. 1H NMR (400 MHz, CDCl3) δ 8.45 (d, J=7.91 Hz, 1H), 7.93 (s, 1H), 7.46 (d, J=1.32 Hz, 1H), 6.90-6.92 (dd, J=1.76, 5.71 Hz, 1H), 5.19-5.24 (m, 2H), 2.08 (d, J=7.04 Hz, 3H); ESI-LC/MS (m/z): [M+H]+ 302.9, [(M+2)+H]+ 304.9, [(M+4)+H]+ 306.9, RT 2.65 min
Reaction SMILES: [Br:1][C:2]1[C:3]([F:13])=[CH:4][C:5]2[O:10][CH2:9][C:8](=[O:11])[NH:7][C:6]=2[CH:12]=1.C([O-])([O-])=O.[K+].[K+].Br[CH:21]([CH3:27])[C:22]([O:24][CH2:25][CH3:26])=[O:23]>CC(C)=O>[CH2:25]([O:24][C:22](=[O:23])[CH:21]([N:7]1[C:6]2[CH:12]=[C:2]([Br:1])[C:3]([F:13])=[CH:4][C:5]=2[O:10][CH2:9][C:8]1=[O:11])[CH3:27])[CH3:26]
Reactant: CCOC(=O)C(C)Br
Reactant: O=C1COc2cc(F)c(Br)cc2N1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)C(C)N1C(=O)COc2cc(F)c(Br)cc21
Temperature: 25 °C
Yield: 74.4 %

Procedure:
To a mixture of 6-bromo-7-fluoro-4H-benzo[1,4]oxazin-3-one (41.0 g, 167 mmol) and K2CO3 (23.0 g, 167 mmol) in acetone (300 mL) was added ethyl 2-bromopropanoate (75.0 g, 53.8 mL, 417 mmol) drop-wise at ambient temperature and the mixture was heated at reflux overnight. The mixture was cooled to ambient temperature and filtered. The filtrate was evaporated in vacuo and the residue was purified by column chromatography on silica gel (eluting with 10% EtOAc in petroleum ether) to give 2-(6-bromo-7-fluoro-3-oxo-2,3-dihydro-benzo[1,4]oxazin-4-yl)-propionic acid ethyl ester (43.0 g, 75%). 1H NMR (CDCl3, 400 MHz): δ 6.97 (d, J=6.4 Hz, 1H), 6.85 (d, J=8.4 Hz, 1H), 5.25 (q, J=7.2 Hz, 1H), 4.59 (dd, J=15.2 Hz, 2H), 4.27 (m, 2H), 1.63 (d, J=7.2 Hz, 3H), 1.23 (t, J=7.2 Hz, 3H).
Reaction SMILES: N12CCN(CC1)CC2.[Br:9][C:10]1[CH:18]=[CH:17][C:13]([CH2:14][CH2:15][OH:16])=[CH:12][CH:11]=1.[S:19](Cl)([C:22]1[CH:28]=[CH:27][C:25]([CH3:26])=[CH:24][CH:23]=1)(=[O:21])=[O:20].O>ClCCl>[CH3:26][C:25]1[CH:27]=[CH:28][C:22]([S:19]([O:16][CH2:15][CH2:14][C:13]2[CH:17]=[CH:18][C:10]([Br:9])=[CH:11][CH:12]=2)(=[O:21])=[O:20])=[CH:23][CH:24]=1
Reactant: OCCc1ccc(Br)cc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: C1CN2CCN1CC2
Solvent: O
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCCc2ccc(Br)cc2)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
1,4-Diazabicyclo[2.2.2]octane (5.61 g, 0.050 mol) and 4-bromophenethyl alcohol (5.0 g, 0.025 mol) were combined in dichloromethane (100 mL). The resulting mixture was cooled to 0° C. in an ice bath and a solution of tosyl chloride (5.67 g, 0.029 mol) in dichloromethane (50 mL) was added via an addition funnel over 15 min. After stirring for about 1 h at 0° C., water (30 mL) was added and stirring was continued for another 30 min. The aqeuous layer was then separated and discarded. The organic layer was dried (NaSO2), filtered, and concentrated under reduced pressure to give the title compound as a white solid.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[N:2]1.Cl[C:7]1[N:8]=[C:9]([NH:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([Cl:27])[CH:21]=2)[C:10]2[C:15]([CH3:16])=[C:14]([CH3:17])[S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:18][CH2:19][C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([Cl:27])[CH:21]=3)[C:10]3[C:15]([CH3:16])=[C:14]([CH3:17])[S:13][C:11]=3[N:12]=2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: c1cn[nH]c1
Reactant: Cc1sc2nc(Cl)nc(NCc3ccc(Cl)c(Cl)c3)c2c1C
Product: Cc1sc2nc(-n3cccn3)nc(NCc3ccc(Cl)c(Cl)c3)c2c1C

Procedure:
Following the procedure of Example 97, the reaction of pyrazole with 2-chloro-5,6-dimethyl-4-(3,4-dichlorobenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(pyrazol-1-yl)-5,6-dimethyl-4-(3,4-dichlorobenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [OH:1][N:2]=[C:3]([NH2:14])[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[C:6]([O:12][CH3:13])[CH:5]=1.[H-].[Na+].[Cl:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[C:19]=1[NH:25][C:26]1[NH:30][C:29]2[C:31]3[CH2:32][C:33]([CH3:43])([CH3:42])[O:34][C:35]=3[C:36]([C:38](OC)=O)=[CH:37][C:28]=2[N:27]=1>C1COCC1>[Cl:24][C:20]1[CH:21]=[CH:22][CH:23]=[C:18]([Cl:17])[C:19]=1[NH:25][C:26]1[NH:30][C:29]2[C:31]3[CH2:32][C:33]([CH3:43])([CH3:42])[O:34][C:35]=3[C:36]([C:38]3[O:1][N:2]=[C:3]([C:4]4[CH:5]=[C:6]([O:12][CH3:13])[CH:7]=[C:8]([O:10][CH3:11])[CH:9]=4)[N:14]=3)=[CH:37][C:28]=2[N:27]=1
Reactant: COC(=O)c1cc2nc(Nc3c(Cl)cccc3Cl)[nH]c2c2c1OC(C)(C)C2
Reactant: COc1cc(OC)cc(C(N)=NO)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cc(OC)cc(-c2noc(-c3cc4nc(Nc5c(Cl)cccc5Cl)[nH]c4c4c3OC(C)(C)C4)n2)c1
Yield: 20.6 %

Procedure:
The title compound was prepared by following the procedure as described for Example-156 using N′-hydroxy-3,5-dimethoxybenzimidamide (Intermediate-54, 0.075 g, 0.30 mmol), sodium hydride (0.021 g, 0.51 mmol), methyl 2-((2-chloro-6-chlorophenyl)amino)-7,7-dimethyl-7,8-dihydro-1H-benzofuro[4,5-d]imidazole-5-carboxylate (Step-1 of Intermediate-6, 0.100 g, 0.255 mmol) and THF to afford 0.029 g of the desired product. 1HNMR (DMSO-d6): δ 1.29 (d, J=7.8 Hz, 6H), 3.09 (s, 2H), 3.85 (s, 6H), 6.58 (s, 1H), 7.30 (m, 3H), 7.44 (d, 1H), 7.78 (s, 1H). MS [M+H]+: 552.09.