Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[CH3:5][O:6][C:7](=[O:17])[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[O:15]C.[C:18](Cl)(=[O:20])[CH3:19].N>ClCCl.C.O>[CH3:5][O:6][C:7](=[O:17])[CH2:8][C:9]1[CH:14]=[C:13]([C:18](=[O:20])[CH3:19])[CH:12]=[CH:11][C:10]=1[OH:15]
Reactant: CC(=O)Cl
Reactant: COC(=O)Cc1ccccc1OC
Agent: C
Agent: N
Agent: [Al+3]
Solvent: O
Solvent: ClCCl
Product: COC(=O)Cc1cc(C(C)=O)ccc1O

Procedure:
To a solution of aluminum chloride (35.0 g, 262.5 mmol) in dichloromethane (75 mL) was added a solution of (2-Methoxy-phenyl)-acetic acid methyl ester (13.5 g, 75.0 mmol) and acetyl chloride (5.86 mL, 82.5 mmol)in dichloromethane (75 mL) dropwise. After the addition was complete the reaction was heated to reflux for 5 hours. The reaction mixture was then cooled and carefully poured onto a mixture of ice and water. The aqueous layer was then extracted with ethyl acetate (2×400 mL). The combined extracts were then washed with saturated sodium chloride (1×100 mL), dried over magnesium sulfate, filtered, and concentrated under reduced pressure to yield a solid. 1H NMR (400 MHz, DMSO): δ 10.51 (s, 1H), 7.79 (m, 2H), 6.88 (d, 1H), 3.63 (s, 2H), 3.59 (s, 3H), 2.47 (s, 3H). Mass Spectrum (Chemical Ionization, 1% NH3 in CH4) m/z 209 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.[N:12]([O-])=O.[Na+].[Sn](Cl)Cl>Cl.O>[ClH:1].[Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][NH2:12])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1
Reactant: Nc1ccc(Cl)cc1[N+](=O)[O-]
Reactant: O=N[O-]
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [Na+]
Solvent: O
Product: NNc1ccc(Cl)cc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 116.4 %

Procedure:
4-Chloro-2-nitroaniline (40 g, 0.23 mol) prepared in Preparation 13 was dissolved in 12N hydrochloric acid (100 mL). Sodium nitrite (16 g, 0.23 mol) dissolved in water (50 mL) was slowly added in drops thereto at 0° C., and the mixture was stirred for 30 min at 0° C. to room temperature. The reaction mixture was cooled to 0° C., tin (II) chloride (132 g, 0.70 mol) dissolved in 12N hydrochloric acid (100 mL) was slowly added in drops thereto, and the mixture was stirred for 3 h at 0° C. to room temperature. The resulting yellow solid was filtered, washed with a small amount of 6N HCl, and dried to give the title compound (30 g, Yield 63%).
Reaction SMILES: O[CH2:2][C:3]1[N:4]([CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:5]2[C:10]([C:11]=1[C:12](=[O:16])[C:13]([OH:15])=[O:14])=[CH:9][C:8]([C:17]1[CH:22]=[CH:21][C:20]([O:23][C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=1)=[CH:7][CH:6]=2.[K].Cl>>[CH2:28]([N:4]1[C:5]2[C:10](=[CH:9][C:8]([C:17]3[CH:22]=[CH:21][C:20]([O:23][C:24]([F:26])([F:25])[F:27])=[CH:19][CH:18]=3)=[CH:7][CH:6]=2)[C:11]2[C:12](=[O:16])[C:13](=[O:14])[O:15][CH2:2][C:3]1=2)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: O=C(O)C(=O)c1c(CO)n(Cc2ccccc2)c2ccc(-c3ccc(OC(F)(F)F)cc3)cc12
Agent: Cl
Agent: [K]
Product: O=C1OCc2c(c3cc(-c4ccc(OC(F)(F)F)cc4)ccc3n2Cc2ccccc2)C1=O

Procedure:
The title compound was prepared from {2-(Hydroxymethyl)-1-benzyl-5-[4-(trifluoromethoxy)phenyl]-1H-indol-3-yl}(oxo)acetic acid, potassium salt and aqueous HCl in substantially the same manner, as described in step 7 of Example 1. The product was obtained as an off-white solid; mp: 239–240° C. Mass spectrum (ESI, [M+H]+) m/z 452. 1H NMR (400 MHz, DMSO-d6) δ 8.24 (s, 1H), 7.81 (dd, 2H, J=8.86 and 2.14 Hz), 7.74 (d, 1H, J=8.56 Hz), 7.68 (dd, 1H, J=8.54 and 1.83 Hz), 7.46 (d, 2H, J=7.94 Hz), 7.37–7.26 (m, 5H,), 5.93 (s, 2H), and 5.56 ppm (s, 2H).
Reaction SMILES: O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[Cl:13][C:14]1[CH:20]=[C:19]([Cl:21])[CH:18]=[C:17]([Cl:22])[C:15]=1N.N([O-])=O.[Na+].[I-:27].[K+].C(=O)([O-])O.[Na+].S([O-])([O-])(=O)=S.[Na+].[Na+]>C(#N)C.O>[Cl:13][C:14]1[CH:20]=[C:19]([Cl:21])[CH:18]=[C:17]([Cl:22])[C:15]=1[I:27]
Reactant: Nc1c(Cl)cc(Cl)cc1Cl
Reactant: [I-]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: O=N[O-]
Solvent: CC#N
Solvent: O
Product: Clc1cc(Cl)c(I)c(Cl)c1
Temperature: 12.5 °C
Reaction time: 0.17 h
Yield: 80.4 %

Procedure:
To a solution of paratoluene sulfonic acid monohydrate (14.5 g; 76.4 mmol) in acetonitrile (100 ml) was added the 2,4,6-trichloroaniline (5.0 g; 25.5 mmol). The resulting white suspension was cooled to 10-15° C. and to this was added, gradually a solution of sodium nitrite (3.5 g; 51.0 mmol) and potassium iodide (10.6 g; 63.6 mmol) in water (15 ml), the suspension became dark brown, thick and gas release was observed. The thick mixture was stirred for 10 min at 10° C. and then temperature was allowed to increase to 20° C. The solution obtained was stirred for 1 h. The solution was poured in water, 1M sodium hydrogen carbonate solution was added (pH adjusted to 9-10) and 2M solution of sodium thiosulfate was added. The mixture was extracted three times with dichloromethane. Organics were combined, dried over sodium sulfate and the solvent was removed in vacuo to provide a resin which was subject to flash column chromatography (eluant: c-hexane). 6.3 g (80% of theory) of 1,3,5-trichloro-2-iodo-benzene was obtained as a white solid.
Reaction SMILES: Cl.Cl.[CH3:3][N:4]1[CH2:9][CH2:8][N:7]([CH:10]2[CH2:19][CH2:18][C:17]3[CH:16]=[C:15]([C:20]([OH:22])=O)[CH:14]=[CH:13][C:12]=3[CH2:11]2)[CH2:6][CH2:5]1.[NH:23]1[CH2:27][CH2:26][CH2:25][C@@H:24]1[CH2:28][N:29]1[CH2:33][CH2:32][CH2:31][CH2:30]1>>[CH3:3][N:4]1[CH2:5][CH2:6][N:7]([CH:10]2[CH2:19][CH2:18][C:17]3[CH:16]=[C:15]([C:20]([N:23]4[CH2:27][CH2:26][CH2:25][CH:24]4[CH2:28][N:29]4[CH2:33][CH2:32][CH2:31][CH2:30]4)=[O:22])[CH:14]=[CH:13][C:12]=3[CH2:11]2)[CH2:8][CH2:9]1
Reactant: CN1CCN(C2CCc3cc(C(=O)O)ccc3C2)CC1
Reactant: C1CN[C@@H](CN2CCCC2)C1
Agent: Cl
Product: CN1CCN(C2CCc3cc(C(=O)N4CCCC4CN4CCCC4)ccc3C2)CC1

Procedure:
[6-(4-methyl-piperazin-1-yl)-5,6,7,8-tetrahydro-naphthalen-2-yl]-(2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl)-methanone is prepared from 6-(4-methyl-piperazin-1-yl)-5,6,7,8-tetrahydro-naphthalene-2-carboxylic acid dihydrochloride and (R)-(+)-1-(2-pyrrolidinylmethyl)-pyrrolidine in a manner substantially analogous to Procedure C (See herein Example 13). Observed mass 411 (M++1).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([NH2:13])[CH:8]=[CH:7]2)([O-:3])=[O:2].Cl.[Cl:15][C:16]1[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=1.O.C(=O)([O-])[O-].[Na+].[Na+]>C(O)(C)C>[ClH:15].[N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([NH:13][C:16]1[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=1)[CH:8]=[CH:7]2)([O-:3])=[O:2]
Reactant: Nn1ccc2cc([N+](=O)[O-])ccc21
Reactant: Clc1ccncc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)O
Solvent: O
Product: O=[N+]([O-])c1ccc2c(ccn2Nc2ccncc2)c1
Yield: 51.5 %

Procedure:
A solution of 5-nitro-1H-indol-1-amine (4.5 g) and 4-chloropyridine hydrochloride (4.5 g) in 175 ml of isopropanol was stirred at reflux for two hours, another equivalent of 4-chloropyridine hydrochloride was added and the mixture was refluxed for two additional hours. The reaction mixture was then cooled, stirred with water, basified with sodium carbonate and extracted with ethyl acetate. The organic extract was washed with water and saturated sodium chloride solution, was dried (MgSO4), filtered and concentrated to 9 g of dark oil. This oil was purified by flash chromatography (silica, ethyl acetate) to give 3.8 g of light brown solid, m.p. 183°-184° . This material was converted to the hydrochloride salt and recrystallized twice from methanol/ether to give 3.5 g of orange needles, m.p. 300°-302° (dec.).
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][CH2:5][N:4]=1.C(NC(=O)C(F)(F)F)CC1C=CC=CC=1.C(O)(C(F)(F)F)=O>O1CCCC1.[Ru]>[F:14][C:2]([F:1])([F:13])[CH:3]1[CH:12]2[CH:7]([CH2:8][CH2:9][CH2:10][CH2:11]2)[CH2:6][CH2:5][NH:4]1
Reactant: FC(F)(F)C1=NCCc2ccccc21
Agent: [Ru]
Agent: O=C(NCCc1ccccc1)C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: FC(F)(F)C1NCCC2CCCCC21

Procedure:
20 g (0,101 mol) of 1-(Trifluoromethyl)-3,4-dihydroisoquinoline [prepared from N-(phenethyl)trifluoroacetamide analogously to U.S. Pat. No. 3,956,333 (11.5.76; Sterling Drug Inc.)] were hydrogenated in 100 ml of tetrahydrofuran on 5 g of ruthenium on alumina (about 10% Ru content) at 150° C. for 8 h at an H 2 pressure of 100 bar in a 0.3 1 V4A autoclave. After filtration, the THF was stripped off and the crude product was fractionareal in a water pump vacuum by means of a microdistillation apparatus. B.p.16 (main fraction): 94°-96° C. Yield: 19 g (0.092 mol) (91% of theory) The product was obtained as a diastereomer mixture. 19F--NMR: δ=+5.9 ppm(d, JH-F =8.5 Hz)(according to integral about 99%) 19F--NMR: δ=+14.2 ppm(d, JH-F =8.5 Hz) (according to integral <1%) (against external CF3COOH).
Reaction SMILES: [NH2:1][C:2]1[C:11]([C:12]([O:14]N2C3C=C(Cl)C=CC=3N=N2)=O)=[C:5]2[N:6]=[CH:7][C:8]([F:10])=[CH:9][N:4]2[N:3]=1.[NH2:25][C:26]1[CH:27]=[N:28][CH:29]=[C:30]([F:45])[C:31]=1[N:32]1[CH2:37][CH2:36][CH:35]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:34][CH2:33]1.C(O)C>N1C=CC=CC=1>[NH2:1][C:2]1[C:11]([C:12]([NH:25][C:26]2[CH:27]=[N:28][CH:29]=[C:30]([F:45])[C:31]=2[N:32]2[CH2:37][CH2:36][CH:35]([C:38]([O:40][C:41]([CH3:43])([CH3:42])[CH3:44])=[O:39])[CH2:34][CH2:33]2)=[O:14])=[C:5]2[N:6]=[CH:7][C:8]([F:10])=[CH:9][N:4]2[N:3]=1
Reactant: Nc1nn2cc(F)cnc2c1C(=O)On1nnc2ccc(Cl)cc21
Reactant: CC(C)(C)OC(=O)C1CCN(c2c(N)cncc2F)CC1
Solvent: CCO
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)C1CCN(c2c(F)cncc2NC(=O)c2c(N)nn3cc(F)cnc23)CC1
Temperature: 95 °C
Yield: 77.9 %

Procedure:
6-chloro-1H-benzo[d][1,2,3]triazol-1-yl 2-amino-6-fluoropyrazolo[1,5-a]pyrimidine-3-carboxylate 6a* (45 g, 129.4 mmol) and tert-butyl 1-(3-amino-5-fluoropyridin-4-yl)piperidine-4-carboxylate 27 (40.1 g, 135.9 mmol) were slurried in pyridine (675 ml). The mixture was heated at 95° C. under nitrogen until the reaction was complete (determined by HPLC analysis). The mixture was cooled and ethanol (450 ml) was added dropwise. The mixture was filtered and the filter cake washed with ethanol (2×70 ml). The damp cake was dried to give the product 28 as a yellow crystalline solid (47.7 g, 78%); 1H NMR (500 MHz, DMSO-d6) δ 10.45 (s, 1H), 9.58 (s, 1H), 9.51 (dd, 1H), 8.72 (dd, 1H), 8.25 (d, 1H), 6.81 (s, 2H), 3.15-2.93 (m, 4H), 2.55-2.47 (masked signal, 1H), 2.02-1.91 (m, 4H), 1.47 (s, 9H); 19F NMR (500 MHz, DMSO-d6) δ −153.5, −136.3; MS (ES+) 474.2.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[N:28]=[CH:27][C:13]2[N:14]([CH3:26])[C:15](=[O:25])[N:16]([CH2:19][CH2:20][C:21](OC)=[O:22])[C:17](=[O:18])[C:12]=2[CH:11]=1)([CH3:3])[CH3:2].[H-].C([Al+]CC(C)C)C(C)C>C1COCC1>[OH:22][CH2:21][CH2:20][CH2:19][N:16]1[C:17](=[O:18])[C:12]2[CH:11]=[C:10]([C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[CH:1]([CH3:3])[CH3:2])[N:28]=[CH:27][C:13]=2[N:14]([CH3:26])[C:15]1=[O:25]
Reactant: COC(=O)CCn1c(=O)c2cc(-c3ccccc3C(C)C)ncc2n(C)c1=O
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: C1CCOC1
Product: CC(C)c1ccccc1-c1cc2c(=O)n(CCCO)c(=O)n(C)c2cn1
Temperature: -55 °C
Reaction time: 1 h
Yield: 15.4 %

Procedure:
To a solution of methyl 3-(6-(2-isopropylphenyl)-1-methyl-2,4-dioxo-1,2-dihydropyrido[3,4-d]pyrimidin-3(4H)-yl)propanoate (140 mg, 0.367 mmol) in THF (3.7 mL) at −55° C. was added diisobutylaluminium hydride (1.1 mL, 1.58 mmol, 1.5M in toluene) dropwise. The reaction was stirred at −55° C. for 1 h, warmed to 0° C., quenched with aq. NH4Cl (10 mL) and diluted with EA (20 mL). The organic layer was washed with brine (10 mL), dried over Na2SO4 and concentrated to give 3-(3-hydroxypropyl)-6-(2-isopropylphenyl)-1-methylpyrido[3,4-d]pyrimidine-2,4(1H,3H)-dione (20 mg, 15% yield) as a white solid. 1H NMR (DMSO-d6) δ: 8.99 (s, 1H), 7.85 (s, 1H), 7.49-7.43 (m, 2H), 7.29-7.28 (m, 2H), 4.51-4.49 (m, 1H), 4.03-4.00 (m, 2H), 3.633 (s, 3H), 3.49-3.45 (m, 2H), 3.17-3.14 (m, 1H), 1.77-1.73 (m, 1H), 1.15-1.14 (m, 6H). LCMS: MH+ 354 and TR=2.246 min.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[CH:10][C:9]=2[CH2:13][CH2:14][C:15]([OH:17])=[O:16])=[CH:4][CH:3]=1.S(=O)(=O)(O)O.[CH3:23]O>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:12][N:11]=[CH:10][C:9]=2[CH2:13][CH2:14][C:15]([O:17][CH3:23])=[O:16])=[CH:6][CH:7]=1
Reactant: CO
Reactant: O=C(O)CCc1cnoc1-c1ccc(Cl)cc1
Agent: O=S(=O)(O)O
Product: COC(=O)CCc1cnoc1-c1ccc(Cl)cc1
Yield: 94 %

Procedure:
A mixture of 3-[5-(4-chlorophenyl)-4-isoxazolyl]propionic acid (6.57 g), conc. sulfuric acid (0.5 ml) and methanol (100 ml) was refluxed for 4 hr. The reaction mixture was concentrated, water was added to the residue and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and methyl 3-[5-(4-chlorophenyl)-4-isoxazolyl]propionate (6.51 g, yield 94%) was obtained as colorless crystals from a fraction eluted with ethyl acetate-hexane (1:3, volume ratio). The crystals were recrystallized from ethyl acetate-hexane. melting point: 51–52° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:14]([C:16]2[CH:21]=[CH:20][C:19]([S:22][CH3:23])=[CH:18][CH:17]=2)=O)[C:9](OCC)=[O:10])=[CH:4][CH:3]=1.O.[NH2:25][NH2:26].C(O)(=O)C.O>O1CCOCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([OH:10])=[N:25][NH:26][C:14]=2[C:16]2[CH:21]=[CH:20][C:19]([S:22][CH3:23])=[CH:18][CH:17]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(C(=O)c1ccc(SC)cc1)c1ccc(F)cc1
Reactant: NN
Solvent: CC(=O)O
Solvent: C1COCCO1
Solvent: O
Product: CSc1ccc(-c2[nH]nc(O)c2-c2ccc(F)cc2)cc1
Yield: 95.7 %

Procedure:
A mixture of ethyl 2-(4-fluorophenyl)-3-(4-(methylthio)phenyl)-3-oxopropanoate(1.33 g, 4 mmol), prepared according to the method of Example 1A(ii), hydrazine hydrate (0.25 mL, 4.2 mmol), and acetic acid (0.25 mL, 4.2 mmol) in dioxane (50 mL), and water (5 mL) was refluxed for 24 hours and then concentrated in vacuo. Water was added to the residue, and the solid was filtered and dried in vacuo to provide the desired product (yield: 1.15 g; 95%). MS (DCI-NH3) m/z 301 (M+H)+, 318 (M+NH4)+; 1H NMR (300 MHz, DMSO-d6) δ2.47 (s, 3H), 7.12 (t, J=9 Hz, 2H), 7.26 (m, 6H).
Reaction SMILES: [O-]CC.[K+].[CH2:5]([O:12][C:13]1[CH:14]=[CH:15][C:16]([N:24]2[C:28]([CH3:29])=[N:27][N:26]=[N:25]2)=[C:17]([CH:23]=1)[C:18]([O:20]CC)=O)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.O.[Cl-].[NH4+]>CN(C=O)C>[CH2:5]([O:12][C:13]1[CH:23]=[C:17]2[C:16](=[CH:15][CH:14]=1)[N:24]1[N:25]=[N:26][N:27]=[C:28]1[CH:29]=[C:18]2[OH:20])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: CCOC(=O)c1cc(OCc2ccccc2)ccc1-n1nnnc1C
Agent: CC[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Oc1cc2nnnn2c2ccc(OCc3ccccc3)cc12
Reaction time: 1 h
Yield: 100.3 %

Procedure:
Potassium ethoxide (57.5 g, 0.682 mol) was added portionwise to a solution of ethyl 5-benzyloxy-2-(5-methyltetrazol-1-yl)benzoate (115.6 g, 0.341 mol) in 550 mL of DMF. The reaction exothermed and the temperature increased by 35 degrees. The reaction mixture was cooled in an ice bath and stirred for 1 hour. The solution was then poured into 6 L of water containing 500 g of ammonium chloride. A yellow-orange precipitate formed. After stirring overnight, the reaction was filtered. The recovered solid was dried at 50° C. in a vacuum oven to provide 100 g of 7-(benzyloxy)tetraazolo[1,5-a]quinolin-5-ol.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C@H:3]1[CH2:8][CH2:7][C@H:6]([C:9](O)=[O:10])[CH2:5][CH2:4]1.S(Cl)([Cl:16])=O>>[F:1][C:2]([F:13])([F:12])[C@H:3]1[CH2:8][CH2:7][C@H:6]([C:9]([Cl:16])=[O:10])[CH2:5][CH2:4]1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)[C@H]1CC[C@H](C(F)(F)F)CC1
Product: O=C(Cl)[C@H]1CC[C@H](C(F)(F)F)CC1

Procedure:
trans-4-Trifluoromethyl-cyclohexanecarboxylic acid (2.0 g, 10.2 mmol) is stirred in thionyl chloride (30 mL) for 1 h at reflux. The reaction mixture is concentrated and used directly in the next step without further purification.
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:4].[CH3:13][O:14][CH2:15][CH2:16][NH:17][CH2:18][CH2:19][O:20][CH3:21]>ClCCl>[CH3:13][O:14][CH2:15][CH2:16][N:17]([CH2:2][C:3]([O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:4])[CH2:18][CH2:19][O:20][CH3:21]
Reactant: COCCNCCOC
Reactant: O=C(CBr)OCc1ccccc1
Solvent: ClCCl
Product: COCCN(CCOC)CC(=O)OCc1ccccc1
Reaction time: 0.5 h

Procedure:
A solution of benzyl bromoacetate (28.9 g; 96.7 mmol) in dichloromethane (100 mL) at room temperature was treated with 2-methoxy-N-(2-methoxyethyl)ethanamine (40.6 g; 305 mmol), stirred for 30 minutes, diluted with dichloromethane, washed sequentially with saturated NH4Cl, water, and brine, dried (Na2SO4), filtered, and concentrated. The concentrate was purified by flash column chromatography on silica gel with 40% diethyl ether/dichloromethane to provide the desired product.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][CH2:13][C:14]1[CH:15]=[C:16]([S:20]([CH3:28])(=[N:22]C(OCC)=O)=[O:21])[CH:17]=[CH:18][CH:19]=1)[N:8]=[CH:7][N:6]=[C:5]2[NH:29][CH2:30][C@H:31]([OH:33])[CH3:32].[O-]CC.[Na+].C(=O)(O)[O-].[Na+]>C(O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][CH2:13][C:14]1[CH:15]=[C:16]([S:20]([CH3:28])(=[NH:22])=[O:21])[CH:17]=[CH:18][CH:19]=1)[N:8]=[CH:7][N:6]=[C:5]2[NH:29][CH2:30][C@H:31]([OH:33])[CH3:32]
Reactant: CCOC(=O)N=S(C)(=O)c1cccc(COc2cc3ncnc(NC[C@@H](C)O)c3cc2Br)c1
Agent: CC[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: C[C@@H](O)CNc1ncnc2cc(OCc3cccc(S(C)(=N)=O)c3)c(Br)cc12
Temperature: 60 °C
Reaction time: 6 h
Yield: 88 %

Procedure:
According to GWP 6, (RS)-S-(3-{[(6-bromo-4-{[(R)-2-hydroxypropyl]amino}quinazolin-7-yl)oxy]methyl}phenyl)-N-(ethoxycarbonyl)-S-methylsulphoximide (38 mg, 0.071 mmol) is dissolved in ethanol (5 mL), admixed with sodium ethoxide (17 mg, 0.25 mmol) and stirred at 60° C. for 6 hours. The reaction solution is admixed with saturated sodium bicarbonate solution and extracted with ethyl acetate. Drying of the organic phase over sodium sulphate and removal of the solvent and also chromatographic purification of the residue (silica gel, dichloromethane/methanol: 0→10% methanol) gives the desired product in 88% yield (29 mg).
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:15]=[N:16][CH:17]=[C:18]([C:20]#[N:21])[CH:19]=2)[CH2:10][CH2:9]1)(C)(C)C.Cl>O1CCOCC1>[NH2:7][CH:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:15]=[N:16][CH:17]=[C:18]([C:20]#[N:21])[CH:19]=2)[CH2:10][CH2:9]1
Reactant: CC(C)(C)OC(=O)NC1CCN(c2cncc(C#N)c2)CC1
Agent: Cl
Solvent: C1COCCO1
Product: N#Cc1cncc(N2CCC(N)CC2)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of (5′-cyano-3,4,5,6-tetrahydro-2H-(1,3′)bipyridinyl-4-yl)-carbamic acid tert-butyl ester (0.45 g, 1.49 mmol) in dioxane (3.0 mL) at room temperature was added 4M HCl in dioxane (8 mL). The reaction mixture was stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure, and the residue was treated with ether. The solid obtained by filtration provided the titled compound. MS (CI) m/z 203 (M+1)+; 1H NMR (300 MHz, methanol-d4) δ ppm 8.68 (d, 1H), 8.52 (s, 1H), 8.35 (m, 1H), 4.15-4.10 (m, 2H), 3.51-3.40 (m, 1H), 3.12 (t, 2H), 2.20-2.15 (m, 2H), 1.82-1.69 (m, 2H).
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([C@H:6]1[CH2:10][CH2:9][C:8](=[O:11])[N:7]1[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[O:5].[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([Mg]Br)=[CH:22][CH:21]=1.O>O1CCCC1>[C:15]([O:14][C:12]([NH:7][C@H:6]([CH2:10][CH2:9][C:8]([C:23]1[CH:24]=[CH:25][C:20]([Cl:19])=[CH:21][CH:22]=1)=[O:11])[C:4]([O:3][CH2:2][CH3:1])=[O:5])=[O:13])([CH3:18])([CH3:17])[CH3:16]
Reactant: Clc1ccc([Mg]Br)cc1
Reactant: CCOC(=O)[C@H]1CCC(=O)N1C(=O)OC(C)(C)C
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)[C@@H](CCC(=O)c1ccc(Cl)cc1)NC(=O)OC(C)(C)C
Reaction time: 1 h

Procedure:
To a solution of (R)-5-oxopyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-ethyl ester (CAS No. 128811-48-3; 4.0 g) in tetrahydrofuran (100 mL), 4-chlorophenylmagnesium bromide (1.0 M solution in diethyl ether; 17.1 mL) was added dropwise at −40° C. over 20 minutes, and the reaction solution was stirred at −40° C. to 0° C. for one hour. Water was added to the solution in small portions at 0° C., followed by extraction with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (heptane-ethyl acetate system) to obtain 5.6 g of the title compound as a colorless oil. The property values of the compound are as follows.
Reaction SMILES: [CH3:1][N:2]([CH3:22])[C:3]([NH:5][C:6]1[CH:11]=[C:10]([O:12][C:13]2[CH:14]=[N:15][C:16]([N+:19]([O-])=O)=[CH:17][CH:18]=2)[CH:9]=[CH:8][N:7]=1)=[O:4].[NH4+].[Cl-]>CO.C1COCC1.CCOC(C)=O.[Zn]>[NH2:19][C:16]1[N:15]=[CH:14][C:13]([O:12][C:10]2[CH:9]=[CH:8][N:7]=[C:6]([NH:5][C:3](=[O:4])[N:2]([CH3:1])[CH3:22])[CH:11]=2)=[CH:18][CH:17]=1
Reactant: CN(C)C(=O)Nc1cc(Oc2ccc([N+](=O)[O-])nc2)ccn1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CO
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CN(C)C(=O)Nc1cc(Oc2ccc(N)nc2)ccn1
Temperature: 0 °C

Procedure:
A solution of 1,1-dimethyl-3-(4-((6-nitropyridin-3-yl)oxy)pyridin-2-yl)urea (6.2 g, 20.4 mmol) in MeOH (100 mL) and THF (100 mL) was treated with NH4Cl (332.8 g, 613 mmol) and cooled to 0° C. with stirring. Zinc dust (13.37 g, 204 mmol) was added portion-wise over 10 min and the mixture was stirred overnight as the cooling bath expired. The mixture was diluted with EtOAc and the solids were removed via filtration, and washed with EtOAc. The filtrate was concentrated to dryness, then suspended in EtOAc. The solids were removed by filtration and the filtrate was concentrated to dryness. The resultant brown solid was suspended in MeCN and sonicated for a few minutes. The light brown solid was collected to afford a first crop of 3-(4-((6-aminopyridin-3-yl)oxy)pyridin-2-yl)-1,1-dimethylurea. The MeCN filtrate was concentrated to dryness and again suspended in MeCN. The light brown solid was collected and dried to afford a second crop of 3-(4-((6-aminopyridin-3-yl)oxy)pyridin-2-yl)-1,1-dimethylurea (5.57 g combined, 100%). 1H NMR (400 MHz, DMSO-d6) δ 8.81 (s, 1H), 8.05 (d, J=5.7 Hz, 1H), 7.77 (d, J=2.9 Hz, 1H), 7.33 (d, J=2.4 Hz, 1H), 7.24 (dd, J=8.9, 2.9 Hz, 1H), 6.53-6.49 (m, 2H), 6.00 (br s, 2H), 2.88 (s, 6H); MS (ESI) m/z: 274.1 (M+H+).
Reaction SMILES: [CH2:1]([NH:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([N+:15]([O-:17])=[O:16])[CH:13]=2)[N:8]=[C:7](Cl)[N:6]=1)[CH:2]=[CH2:3].Cl.[CH3:20][C:21]([CH3:25])=[CH:22][CH2:23][NH2:24].C(N(CC)CC)C>C(#N)C>[CH2:1]([NH:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([N+:15]([O-:17])=[O:16])[CH:13]=2)[N:8]=[C:7]([NH:24][CH2:23][CH:22]=[C:21]([CH3:25])[CH3:20])[N:6]=1)[CH:2]=[CH2:3]
Reactant: C=CCNc1nc(Cl)nc2ccc([N+](=O)[O-])cc12
Reactant: CC(C)=CCN
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: C=CCNc1nc(NCC=C(C)C)nc2ccc([N+](=O)[O-])cc12
Temperature: 25 °C
Yield: 74.5 %

Procedure:
To 10 ml of a solution of 150 mg (0.57 mmol) of 4-allylamino-2-chloro-6-nitroquinazoline in acetonitrile were added 137 mg (1.13 mmol) of 3-methyl-2-butenylamine hydrochloride and 288 mg (2.85 mmol) of triethylamine, followed by heating at room temperature for 4.5 hours. After completion of the reaction, ice water was added to the reaction mixture, followed by extraction with chloroform (10 ml×3). After the organic layer was washed with brine and then dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The residue was purified by a silica gel chromatography to give 133 mg (yield: 75.1%) of the title compound.