Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:11]([OH:13])=O)[CH3:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH3:15][NH:16][O:17][CH3:18].O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>ClCCl.C(N(CC)CC)C>[CH3:18][O:17][N:16]([CH3:15])[C:11](=[O:13])[C@@H:9]([NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH3:10]
Reactant: CNOC
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CON(C)C(=O)[C@H](C)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 53.4 %

Procedure:
To 20.0 g of N-(tert-butoxycarbonyl)-L-alanine in 352 ml of dichloromethane, 12.4 g of N,O-dimethylhydroxylamine hydrochloride, 15.7 g of 1-hydroxybenzotriazole monohydrate, 24.3 g of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 42.7 g of triethylamine were added, and the mixture was stirred at room temperature for 1.5 hours. After completion of the reaction, the reaction mixture was washed with 500 ml of saturated aqueous sodium hydrogen carbonate, 500 ml of 1N aqueous hydrochloric acid and 500 ml of water in this order, the resulting organic layer was dried over saturated aqueous sodium chloride and then anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was washed with 200 ml of hexane to obtain 13.1 g of the desired product as white crystals.
Reaction SMILES: [C:1]1([S:7]([C:10]([CH:29]2[CH2:41][C:32]3[NH:33][C:34]4[CH:35]=[CH:36][C:37]([Cl:40])=[CH:38][C:39]=4[C:31]=3[CH2:30]2)([F:28])[C:11]2[O:15][N:14]=[C:13]([CH2:16][N:17]3C(=O)C4C(=CC=CC=4)C3=O)[N:12]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.NN>CCO>[C:1]1([S:7]([C:10]([CH:29]2[CH2:41][C:32]3[NH:33][C:34]4[CH:35]=[CH:36][C:37]([Cl:40])=[CH:38][C:39]=4[C:31]=3[CH2:30]2)([F:28])[C:11]2[O:15][N:14]=[C:13]([CH2:16][NH2:17])[N:12]=2)(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C1c2ccccc2C(=O)N1Cc1noc(C(F)(C2Cc3[nH]c4ccc(Cl)cc4c3C2)S(=O)(=O)c2ccccc2)n1
Agent: NN
Solvent: CCO
Solvent: O
Product: NCc1noc(C(F)(C2Cc3[nH]c4ccc(Cl)cc4c3C2)S(=O)(=O)c2ccccc2)n1
Temperature: 80 °C
Yield: 64.2 %

Procedure:
To a stirred suspension of 420 mg (0.71 mmol) of (RS,SR)-2-{5-[benzenesulfonyl-(7-chloro-1,2,3,4-tetrahydro-cyclopenta[b]indol-2-yl)-fluoro-methyl]-[1,2,4]oxadiazol-3-ylmethyl}-isoindole-1,3-dione in 50 mL of EtOH, was added 0.10 mL (2.13 mmol, 3 eq) of hydrazine hydrate. The reaction mixture was heated to 80° C. for 3 hours, before it was partitioned between EtOAc and aqueous HCl 1N. The organic phases were dried over Na2SO4, filtered and evaporated. Column chromatography on silica gel with CH2Cl2/MeOH 95:5 afforded 210 mg (64%) of (RS,SR)-C-{5-[benzenesulfonyl-(7-chloro-1,2,3,4-tetrahydro-cyclopenta[b]indol-2-yl)-fluoro-methyl]-[1,2,4]oxadiazol-3-yl}-methylamine light brown solid, MS: 461 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][OH:10])=[CH:4][CH:3]=1.[H-].[Na+].I[CH3:14]>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][O:10][CH3:14])=[CH:4][CH:3]=1
Reactant: OCCc1ccc(Br)cc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCCc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 93 %

Procedure:
To a solution of 2-(4-bromophenyl)ethanol (1 g, 5 mmol) in anhydrous THF (10 mL) was added NaH (60% oil dispersion, 0.2 g, 5 mmol). The mixture was stirred at room temperature for 30 min and cooled to −0° C. Iodomethane (920 mg, 6.5 mmole) was added slowly to the mixture and stirred for 8 h. The reaction mixture was then quenched by adding water, extracted with ethyl acetate. The combined organic extracts were dried over MgSO4, filtered, and concentrated. The residue was purified by flash chromatography (silica gel, 5% ethyl acetate in hexane) to give the title compound as a colorless (1 g, 93% yield). 1H NMR (CDCl3, 400 MHz): 7.39 (d, 2H), 7.08 (d, 2H), 3.56 (t, 2H), 3.33 (s, 3H), 2.82 (t, 2H); MS (ESI) m/z. Calc. 215.1 (M+). Found: 216.3 (M′+1), 218.1 (M++3).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][OH:10])=[CH:4][CH:3]=1.[H-].[Na+].[CH3:13]I.O>CN(C)C=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][O:10][CH3:13])=[CH:4][CH:3]=1
Reactant: CI
Reactant: OCCc1ccc(Br)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COCCc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 56.1 %

Procedure:
2-(4-Bromophenyl)ethanol (2.0 g) was dissolved in N,N-dimethylformamide (50 mL), and sodium hydride (60% in oil) (0.44 g) was added under ice-cooling. After gradually warming to room temperature, the mixture was stirred for 2 hr, and methyl iodide (2.1 g) was added again under ice-cooling. After gradually warming to room temperature, the mixture was stirred overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent; hexane:ethyl acetate=20:1 to 10:1) to give the title compound (1.2 g) as a colorless oil.
Reaction SMILES: C([O:3][C:4](=[O:27])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][N:11]([CH2:16][CH2:17][O:18][C:19]1[CH:24]=[C:23]([Cl:25])[CH:22]=[C:21]([Cl:26])[CH:20]=1)[S:12]([CH3:15])(=[O:14])=[O:13])C.[OH-].[Na+]>>[Cl:26][C:21]1[CH:20]=[C:19]([CH:24]=[C:23]([Cl:25])[CH:22]=1)[O:18][CH2:17][CH2:16][N:11]([S:12]([CH3:15])(=[O:13])=[O:14])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][C:4]([OH:27])=[O:3]
Reactant: CCOC(=O)CCCCCCN(CCOc1cc(Cl)cc(Cl)c1)S(C)(=O)=O
Agent: [Na+]
Agent: [OH-]
Product: CS(=O)(=O)N(CCCCCCC(=O)O)CCOc1cc(Cl)cc(Cl)c1

Procedure:
The title compound was prepared from 7-{[2-(3,5-dichloro-phenoxy)-ethyl]-methanesulfonyl-amino}-heptanoic acid ethyl ester using the procedure described in Step B of Example 1 with 2N NaOH. Purification by flash chromatography (1% MeOH in CH2Cl2) provided the title acid. 1HNMR (400 MHz, CDCl3) δ6.95 (m, 1H), 6.75 (m, 2H), 4.07 (t, 2H), 3.56 (t, 2H), 3.23 (t, 2H), 2.86 (s, 3H), 2.33 (t, 2H), 1.61 (m, 4H), 1.33 (m, 4H); MS 411 (M−1). Example numbers 112-122 are not used in this specification.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.[NH2:9][C:10]1[CH:11]=[N:12][C:13]2[C:18]([CH:19]=1)=[CH:17][CH:16]=[CH:15][CH:14]=2.C(N(C(C)C)C(C)C)C>CC(O)C>[Cl:1][C:2]1[N:7]=[C:6]([NH:9][C:10]2[CH:11]=[N:12][C:13]3[C:18]([CH:19]=2)=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:5]=[CH:4][N:3]=1
Reactant: Nc1cnc2ccccc2c1
Reactant: Clc1ccnc(Cl)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: Clc1nccc(Nc2cnc3ccccc3c2)n1
Temperature: 0 °C
Yield: 68.7 %

Procedure:
50 g (0.34 mol) of 2,4-dichloropyrimidine and 50 g (0.35 mol) of 3-amino-quinoline are combined and kept at the boil under reflux for 50 h in 400 ml of 2-propanol with 100 ml of ethyldiisopropylamine. The reaction mixture is poured into 3 l of ice-water, the precipitate is filtered off with suction and washed with water. The residue is recrystallised from acetone, giving 60 g of pale-grey crystals (m.p.: 140-143° C.) (2-chloropyrimidin-4-yl)quinolin-3-ylamine.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH3:14])[CH2:10][C:11]([OH:13])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.Cl.[CH3:38][NH:39][O:40][CH3:41]>C(#N)C.C(N(CC)CC)C>[C:1]([O:5][C:6](=[O:7])[NH:8][C@H:9]([CH3:14])[CH2:10][C:11]([N:39]([O:40][CH3:41])[CH3:38])=[O:13])([CH3:2])([CH3:3])[CH3:4]
Reactant: C[C@H](CC(=O)O)NC(=O)OC(C)(C)C
Reactant: CNOC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CON(C)C(=O)C[C@@H](C)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A solution of (3R)-3-[(tert-butoxycarbonyl)amino]butanoic acid (1 g, 5 mmol) in acetonitrile (40 mL) was treated with 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (EDC; 1.05 g, 5.5 mmol), 1-hydroxybenzotriazole (HOBt; 810 mg, 6 mmol), N,O-dimethylhydroxylamine hydrochloride (1.0 g, 10 mmol) and triethylamine (1.4 mL) and stirred at room temperature for 2 d. The solution was evaporated and the residue purified by flash chromatography on a Biotage® system (silica gel, 40-90% ethyl acetate/hexane gradient) to yield the desired product as a colorless viscous oil. MS 269.1 (M+Na).
Reaction SMILES: Cl[C:2]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3].[OH:12][C@H:13]1[CH2:17][NH:16][C@H:15]([C:18]([OH:20])=[O:19])[CH2:14]1.C([O-])(O)=O.[Na+].O>CCOCC>[CH2:5]([O:4][C:2]([N:16]1[CH2:17][C@H:13]([OH:12])[CH2:14][C@H:15]1[C:18]([OH:20])=[O:19])=[O:3])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: O=C(O)[C@@H]1C[C@@H](O)CN1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Product: O=C(O)[C@@H]1C[C@@H](O)CN1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 76.7 %

Procedure:
A solution of benzyl chloroformate (50 mL, 0.35 mol) in Et2O (160 mL) was added dropwise, during 10 min, to a rapidly stirred mixture of trans-4-hydroxy-L-proline (39.8 g, 0.308 mol), NaHCO3 (63.7 g, 0.758 mol) and H2O (660 mL). The reaction mixture was stirred at room temperature for 20 h. The layers were separated, and the aqueous layer was washed with Et2O (4×200 mL), cooled, and then acidified to pH 1-2 with concentrated hydrochloric acid The resulting emulsion was extracted with EtOAc (5×200 mL). Combined EtOAc extracts were washed in succession with H2O (3×500 mL) and brine (3×500 mL), dried over MgSO4, and then concentrated in vacuo to give intermediate (4) as a colorless foam (62.7 g, 78%). Additional reactions were carried out to give a total of 284 g of product suitable for further transformation.
Reaction SMILES: C1([C@@H]2C(C3C=CC=CC=3)(C3C=CC=CC=3)OB(C)N2)CCCCC1.[Br:25][CH2:26][C:27]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:28].CO>O1CCCC1.C(OCC)(=O)C>[Br:25][CH2:26][C@@H:27]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[OH:28]
Reactant: O=C(CBr)c1ccccc1
Agent: CB1N[C@H](C2CCCCC2)C(c2ccccc2)(c2ccccc2)O1
Solvent: CCOC(C)=O
Solvent: CO
Solvent: C1CCOC1
Product: O[C@@H](CBr)c1ccccc1
Temperature: 25 °C

Procedure:
A 0.25 M tetrahydrofuran solution of (R)-4-cyclohexyl-5,5-diphenyl-2-methyl-1,3,2-oxazaborolidine (0.4 mL) (prepared as in example 12) was added to a dry flask containing borane dimethylsulfide complex (0.05 mL, 0.5 mmol) under nitrogen. The mixture was stirred at room temperature for I hour and then, a solution of bromoacetophenone (99.5 mg, 0.5 mmol) in dry tetrahydrofuran (3 mL) was added to the borane/(R)-4-cyclohexyl-5,5-diphenyl-2-methyl-1,3,2-oxazaborolidine complex over 20 minutes via a syringe pump. The reaction was stirred at room temperature for 2 hours. Methanol was added to quench the reaction and then the solvents were removed by evaporation. The residue obtained was dissolved in ethyl acetate, washed with 1M hydrochloric acid and filtered through a silica gel plug. The filtrate was concentrated to provide (R)-2-bromo-1-phenylethanol. The enantiomeric excess=96.2% and was measured by HPLC (Chiralcel OD-H column, mobile phase, hexane/isopropyl alcohol 9:1, flow rate=0.6 mL/min).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]1[CH2:18][CH2:17][C@@H:16]2[CH2:19][C@H:13]1[C:14](=[O:27])[N:15]2[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].C([Al+]CC(C)C)C(C)C.CO.O>ClCCl>[CH2:1]([O:8][C:9]([NH:11][C@H:12]1[CH2:18][CH2:17][C@@H:16]2[CH2:19][C@H:13]1[CH:14]([OH:27])[N:15]2[C:20]([O:22][C:23]([CH3:25])([CH3:24])[CH3:26])=[O:21])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1C(=O)[C@@H]2C[C@H]1CC[C@@H]2NC(=O)OCc1ccccc1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: O
Solvent: CO
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1C(O)[C@@H]2C[C@H]1CC[C@@H]2NC(=O)OCc1ccccc1
Reaction time: 0.08 h

Procedure:
A solution of (1R,2S,5R)-tert-butyl 2-(benzyloxycarbonylamino)-7-oxo-6-aza-bicyclo[3.2.1]octane-6-carboxylate (2.62 g, 7.0 mmol) in dichloromethane (50 mL) was stirred on an ice bath and treated dropwise with diisobutylaluminum hydride (1.0 M in tetrahydrofuran, 21 mL, 21 mmol) over ca. 10 min. The solution was stirred on ice for 4 h 5 min, then was treated dropwise over 10 min with methanol (1.75 mL). The mixture was stirred on ice for 10 min, then was treated with water (2.75 mL) over ca. 1 min. The mixture was stirred at rt for 35 min, then was filtered and the gelatinous solid was triturated 3× with dichloromethane and filtered. The combined filtrates were combined and concentrated under vacuum to provide (1R,2S,5R)-tert-butyl 2-(benzyloxycarbonylamino)-7-hydroxy-6-aza-bicyclo[3.2.1]octane-6-carboxylate as a sticky semicrystalline solid (2.41 g). MS found: (M+H—H2O)+=359.3.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[N+:14]([O-:16])=[O:15])=[CH:4][CH:3]=1.[Br:17]N1C(=O)CCC1=O.CC(N=NC(C#N)(C)C)(C#N)C.[I-].[K+]>C(Cl)(Cl)(Cl)Cl>[Br:17][CH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[N+:14]([O-:16])=[O:15])=[CH:6][CH:7]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(-c2ccccc2[N+](=O)[O-])cc1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: [I-]
Agent: [K+]
Solvent: ClC(Cl)(Cl)Cl
Product: O=[N+]([O-])c1ccccc1-c1ccc(CBr)cc1
Yield: 102.1 %

Procedure:
A solution of 4-methyl-2'-nitro-1,1'-biphenyl (Step J) (6.0 g, 28.2 mmol), N-bromosuccinimide (4.99 g, 28.2 mmol) and AIBN (653 mg) in 75 mL of carbon tetrachloride was heated at reflux until a negative potassium iodide test was obtained (1.5 h). The reaction mixture was cooled and filtered. The filtrate was evaporated under vacuum to yield 8.41 g of crude product. 1H NMR revealed the product composition was approximatly 75% monobromo and 10% dibromo, in addition to 15% of unreacted starting material. 1H NMR (200 MHz,CDCl3): 4.53 (s, 2H), 7.2-7.7 (m, 7H), 7.85 (m, 1H). EI-MS: calculated for C14H10BrN 272; found 272,274 (M+).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[C:5]2[N:10]=[CH:9][S:8][C:6]=2[N:7]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.CN([CH:30]=[O:31])C.Cl>C1COCC1>[Cl:1][C:2]1[N:3]=[C:4]([N:11]2[CH2:12][CH2:13][O:14][CH2:15][CH2:16]2)[C:5]2[N:10]=[C:9]([CH:30]=[O:31])[S:8][C:6]=2[N:7]=1
Reactant: Clc1nc(N2CCOCC2)c2ncsc2n1
Reactant: CN(C)C=O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Product: O=Cc1nc2c(N3CCOCC3)nc(Cl)nc2s1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 87.7 %

Procedure:
5-Chloro-7-morpholin-4-yl-thiazolo[5,4-d]pyrimidine (5.1 g, 0.02 mol) was suspended in THF (200 mL) and the resulting solution was cooled to −78° C. whereupon the starting material precipitated from solution. LiHMDS (1M in THF, 25 mL, 1.25 equiv) was added dropwise to the stirred suspension. After addition was complete, the mixture was stirred for 30 min, then DMF (9 mL, 6 equiv) was added and the resulting solution was stirred for 15 min at −78° C. and then warmed to 0° C. and stirred for 15 min. The solution was re-cooled to −78° C. and then cannulated (via a wide-bore double-ended needle) into a stirred solution of ˜0.5M HCl (600 mL) The product precipitated from solution as a pale yellow powder. This was isolated by filtration through a sintered glass funnel, washed with water and dried in vacuo overnight to give 5 g of 5-Chloro-7-morpholin-4-yl-thiazolo[5,4-d]pyrimidine-2-carbaldehyde (87.7%). 1H NMR (400 MHz, CDCl3): δ 3.83-3.88 (m, 4 H), 4.06-4.15 (m, 2 H), 4.72 (m, 2 H) and 9.95 (s, 1 H).
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([N:9](C=O)[CH2:10][C@@H:11]2[O:15][C:14](=[O:16])[N:13]([C:17]3[CH:22]=[CH:21][C:20]([N:23]4[CH2:28][CH2:27][O:26][CH2:25][C:24]4=[O:29])=[CH:19][CH:18]=3)[CH2:12]2)=[O:8])=[CH:4][CH:3]=1.ClCCl.Cl>CO>[CH:19]1[C:20]([N:23]2[C:24](=[O:29])[CH2:25][O:26][CH2:27][CH2:28]2)=[CH:21][CH:22]=[C:17]([N:13]2[C:14](=[O:16])[O:15][C@@H:11]([CH2:10][NH:9][C:7]([C:5]3[S:6][C:2]([Cl:1])=[CH:3][CH:4]=3)=[O:8])[CH2:12]2)[CH:18]=1
Reactant: O=CN(C[C@H]1CN(c2ccc(N3CCOCC3=O)cc2)C(=O)O1)C(=O)c1ccc(Cl)s1
Agent: Cl
Solvent: ClCCl
Solvent: CO
Product: O=C(NC[C@H]1CN(c2ccc(N3CCOCC3=O)cc2)C(=O)O1)c1ccc(Cl)s1

Procedure:
In four neck round bottom flask charge 5-chloro-N-formyl-N-({(5S)-2-oxo-3-[4-(3-oxomorpholin-4-yl)phenyl]-1,3-oxazolidin-5-yl}methyl)thiophene-2-carboxamide (120 g), dichloromethane (2400 ml) and hydrochloric acid OR sulphuric acid (120 ml) at 25-30° C. Obtained reaction mixture is heated to reflux for 4 to 5 h. After completion of reaction, concentrate reaction mass under reduced pressure to obtain residue. Added Dichloromethane (120 ml) and slowly added Methanol (600 ml) to the residue. The precipitated solid is filtered off and washed by methanol (240 ml)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:17]=[C:18]([CH:20]=[CH:21][CH:22]=1)[NH2:19].[OH:23][CH2:24][C:25]([C:28]1[O:32][N:31]=[C:30]([NH:33][C:34](=O)[O:35]C2C=CC=CC=2)[CH:29]=1)([CH3:27])[CH3:26].C(C1C=C(NC(=O)N)ON=1)(C)C>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:17]=[C:18]([NH:19][C:34]([NH:33][C:30]2[CH:29]=[C:28]([C:25]([CH3:27])([CH3:26])[CH2:24][OH:23])[O:32][N:31]=2)=[O:35])[CH:20]=[CH:21][CH:22]=1
Reactant: COc1cc2ncnc(Oc3cccc(N)c3)c2cc1OC
Reactant: CC(C)(CO)c1cc(NC(=O)Oc2ccccc2)no1
Agent: CC(C)c1cc(NC(N)=O)on1
Product: COc1cc2ncnc(Oc3cccc(NC(=O)Nc4cc(C(C)(C)CO)on4)c3)c2cc1OC
Yield: 61 %

Procedure:
Prepared from 3-(6,7-dimethoxyquinazolin-4-yloxy)aniline from Example 113A (30 mg, 0.10 mmol) and phenyl 5-(1-hydroxy-2-methylpropan-2-yl)isoxazol-3-ylcarbamate from the previous step (41 mg, 0.15 mmol) according to the method described for 14346,7-dimethoxyquinazolin-4-yloxy)phenyl)-3-(3-isopropylisoxazol-5-yl)urea in Example 122B. Purification via preparative TLC eluting with 10% methanol in dichloromethane afforded 1-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)-3-(5-(1-hydroxy-2-methylpropan-2-yl)isoxazol-3-yl)urea as a colorless solid (30 mg, 61%). 1H NMR (300 MHz, DMSO-d6) δ 9.57 (brs, 1H), 8.99 (brs, 1H), 8.56 (s, 1H), 7.56-7.58 (m, 2H), 7.38-7.42 (m, 2H), 7.23-7.26 (m, 1H), 6.95-6.98 (m, 1H), 6.49 (s, 1H), 4.95 (brs, 1H), 3.98-3.99 (2×s, 6H), 3.43 (s, 2H), 1.20 (s, 6H); LC-MS (ESI) m/z 480 (M+H)+.
Reaction SMILES: Cl[CH2:2][C:3](Cl)=[O:4].[Br:6][C:7]1[CH:12]=[CH:11][C:10]([C@H:13]([OH:24])[CH2:14][NH:15][C@@H:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH3:17])=[CH:9][CH:8]=1.C(N(CC)CC)C.[OH-].[K+]>ClCCl.C(O)(C)C>[Br:6][C:7]1[CH:8]=[CH:9][C:10]([C@H:13]2[CH2:14][N:15]([C@@H:16]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH3:17])[C:3](=[O:4])[CH2:2][O:24]2)=[CH:11][CH:12]=1
Reactant: C[C@@H](NC[C@@H](O)c1ccc(Br)cc1)c1ccccc1
Reactant: O=C(Cl)CCl
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@H](c1ccccc1)N1C[C@H](c2ccc(Br)cc2)OCC1=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 90.6 %

Procedure:
A solution of chloroacetyl chloride (24.3 g, 215 mmol) in dichloromethane (100 ml) was dropped into the ice-cooled solution of (1S)-1-(4-bromophenyl)-2-((1R)-1-phenylethylamino)ethanol (62.6 g, 215 mmol) and triethylamine (21.8 g, 215 mmol) in dichloromethane (600 ml) over 30 minutes and the mixture was stirred for one hour at the same temperature. Resulting solution was washed with 0.5 M hydrochloric acid, saturated sodium hydrogen carbonate, brine and dried over anhydrous magnesium sulfate. The solvents were removed under reduced pressure and potassium hydroxide (85%, 16.1 g, 244 mmol) was added to a solution of resulting pale brown oil in isopropyl alcohol (600 ml) and stirred for 16 hours. The solvent was removed in vacuo and the residue was partitioned between water and ethyl acetate. The organic layer was washed with 0.5 M hydrochloric acid, saturated sodium hydrogen carbonate, brine and dried over anhydrous magnesium sulfate. Removal of the solvent under reduced pressure furnished (6S)-6-(4-bromophenyl)-4-((1R)-1-phenyethyl)morpholin-3-one (70.2 g) as a brown oil.
Reaction SMILES: S(=O)(O)O.[CH:5]1([CH:11]=O)[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1.CCN(CC)CC.[CH3:20][NH:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClC(Cl)C.CCOC(C)=O>[CH2:11]([N:21]([CH2:22][CH:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1)[CH3:20])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: CNCc1ccccc1
Reactant: O=CC1CCCCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=S(O)O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(Cl)Cl
Solvent: CCN(CC)CC
Product: CN(Cc1ccccc1)CC1CCCCC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A suspension of cyclohexanecarboxaldehyde bisulfite adduct (5.0 mmol) and Et3N (5.5 mmol) in dichloroethane (20 mL) was stirred at room temperature for 15 min. The suspension was treated with N-methylbenzylamine (5.5 mmol) and was stirred for 45 min. NaBH(OAc)3 (7.0 mmol) was added portion-wise over approximately 30 min. After 16 h, the reaction mixture was diluted with EtOAc (80 mL), and was washed with 1 N NaOH (25 mL) followed by brine (25 mL). The organic layer was dried (MgSO4) and concentrated to yield benzyl-cyclohexylmethyl-methyl-amine as an oil. The crude material was purified by the General Purification Method as described above.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]([S:13][CH3:14])[N:3]=1.Cl.[Cl:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][C:24]=1[O:25][CH3:26])[CH2:20][NH2:21].C(N(CC)CC)C>C(Cl)Cl>[Cl:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][C:24]=1[O:25][CH3:26])[CH2:20][NH:21][C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]([S:13][CH3:14])[N:3]=1
Reactant: CCOC(=O)c1cnc(SC)nc1Cl
Reactant: COc1ccc(CN)cc1Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cnc(SC)nc1NCc1ccc(OC)c(Cl)c1
Temperature: 25 °C
Reaction time: 10 h
Yield: 75.7 %

Procedure:
In DCM (100 mL) were dissolved ethyl 4-chloro-2-(methylthio)pyrimidine-5-carboxylate (5.0 g, 21.55 mmol), 3-chloro-4-methoxybenzylamine hydrochloride salt (4.0 g, 23.4 mmol) and triethylamine (4.35 g, 43.1 mmol). The reaction mixture was stirred at ambient temperature for 10 h and washed with water. The organic phase was dried over magnesium sulfate and concentrated to give ethyl 4-((3-chloro-4-methoxybenzyl)amino)-2-(methylthio)pyrimidine-5-carboxylate as a solid (6.0 g, 76% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[Sn](CCCC)(CCCC)(Cl)Cl.Br[CH2:20][C:21](=O)[C:22]([O:24][CH2:25][CH3:26])=[O:23].C([O-])([O-])=O.[K+].[K+]>COCCOC.C(OCC)(=O)C>[CH3:26][CH2:25][O:24][C:22]([C:21]1[N:1]=[C:2]2[N:3]([CH:4]=[CH:5][CH:6]=[CH:7]2)[CH:20]=1)=[O:23]
Reactant: Nc1ccccn1
Reactant: CCOC(=O)C(=O)CBr
Agent: CCCC[Sn](Cl)(Cl)CCCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: CCOC(=O)c1cn2ccccc2n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 61.7 %

Procedure:
To a solution of 2-aminopyridine (292, 1.1022 g; 11.71 mmol) and Bu2SnCl2 (431 mg; 1.3 mmol) in DME (20 mL), ethyl 3-bromopyruvate (1.56 mL; 11.16 mmol) was added to give an instant yellow precipitate. The suspension was stirred at room temperature for 2 h, then solid K2CO3 (2.6 g; 18.8 mmol) was added and the mixture stirred for additional 20 h at the same temperature. The reaction mixture was then diluted with ethyl acetate (200 mL) and washed with saturated aqueous sodium chloride. The organic layer was dried (MgSO4), filtered and concentrated. The residue was purified by flash chromatography on silica gel (eluent 50% ethyl acetate in dichloromethane), to afford the title compound 293 (1.31 g, 59% yield) as a white crystalline material. 1H NMR (400.2 MHz, DMSO) δ (ppm): 8.54 (m, 1H); 8.53 (d; J=0.9 Hz; 1H); 7.59 (ddd; J=1.3, 2.0, 9.2 Hz; 1H); 7.33 (ddd; J=1.3, 6.7, 9.2 Hz; 1H); 6.98 (dt; J=0.9, 7.8 Hz; 1H); 4.30 (q; J=7.0 Hz; 2H); 1.32 (t; J=7.0 Hz; 3H). MS: calc: 190.0; found: 191.1 (M+H).