Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][CH:13]=1)[CH2:6][NH:7][C:8](=[O:10])[CH3:9])#N.C[Mg]Br.O.Cl.CC[O:21][CH2:22][CH3:23]>C(Cl)Cl.O1CCCC1>[C:8]([NH:7][CH2:6][C:5]1[CH:4]=[C:3]([C:22](=[O:21])[CH3:23])[CH:13]=[CH:12][CH:11]=1)(=[O:10])[CH3:9]
Reactant: CC(=O)NCc1cccc(C#N)c1
Reactant: CCOCC
Agent: C[Mg]Br
Agent: Cl
Solvent: ClCCl
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)NCc1cccc(C(C)=O)c1

Procedure:
To a solution of N-(3-cyanobenzyl)acetamide (7.7 g) in methylene dichloride (150 ml) and tetrahydrofuran (50 ml) was added dropwise a solution of methyl magnesium bromide in ether (3 mol/l, 52 ml) at 10° to 20° C. under stirring and the resulting mixture was stirred at the same condition for 6 hours. The reaction mixture was poured into water and the resultant mixture was adjusted to pH 7 with 6N hydrochloric acid and extracted with ethyl acetate. The extract was washed with brine and magnesium sulfate. The solvent was evaporated in vacuo and the residue was subjected to column chromatography on silica gel. The fractions eluted with a mixture of chloroform and ethyl acetate (8:2) were collected and the solvent was evaporated in vacuo to give 3'-(acetylaminomethyl)acetophenone (4.7 g) (oil).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[CH:10]=O)[CH:3]=[CH:2]1.[NH2:12][OH:13].[OH-].[Na+]>CCO.O>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2/[CH:10]=[N:12]\[OH:13])[CH:3]=[CH:2]1
Reactant: O=Cc1cccc2cc[nH]c12
Reactant: NO
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O/N=C\c1cccc2cc[nH]c12
Yield: 80 %

Procedure:
1H-indole-7-carbaldehyde (1 g, 6.9 mmol) in EtOH (30 mL), hydroxylamine (527 mg, 7.6 mmol) in water (10 mL) was added followed by 50% NaOH (1.38 g in 1.38 mL water) was added. After refluxing for 2 h, ethanol was removed under reduced pressure. Resultant slurry was extracted with ethylacetate. Organic layer was washed with water, brine and dried. Crude residue was column chromatographed on a silica gel eluting with (30% EtOAc/hexanes) to afford (Z)-1H-indole-7-carbaldehyde oxime in 80% yield.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11](=O)[C:10]([CH3:20])([CH3:19])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+]>CO>[C:1]([O:5][C:6]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11][C:10]([CH3:20])([CH3:19])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC(C)(C)C(=O)c2ccccc21
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC1(C)Cc2ccccc2N(C(=O)OC(C)(C)C)C1
Temperature: 0 °C
Reaction time: 3 h
Yield: 81.4 %

Procedure:
To a solution of 1-tert-butyloxycarbonyl-1,2,3,4-tetrahydro-3,3-dimethyl-4-quinolinone (128 mg, 0.47 mmol) in methanol (2 mL) at 0° C. was added portionwise sodium borohydride (18 mg, 0.47 mmol) and the reaction mixture was stirred at 0° C. for 3 h. The reaction mixture was then quenched with sat'd NH4Cl (2 mL), extracted with ethyl acetate (2×5 mL), dried (Na2SO4) and concentrated. A solution of this crude material in ethyl acetate (3 mL) was hydrogenated under an atmosphere of hydrogen with 10% Pd/C (20 mg) and a trace of cone. H2SO4 at rt for 16 h. Filtration over Celite™ afforded 100 mg (84%) of 1-tert-butyloxycarbonyl-1,2,3,4-tetrahydro-3,3-dimethylquinoline. Data for 1-tert-butyloxycarbonyl-1,2,3,4-tetrahydro-3,3-dimethylquinoline: 1H NMR (400 MHz, CDCl3) 7.68 (d, J=8.3, 1H), 7.12 (ddd, J=8.8, 8.8, 1.5, 1H), 7.02 (d, J=7.0, 1H), 6.97 (ddd, J=7.4, 7.4, 1.0, 1H), 3.46 (s, 2H), 2.58 (s, 2H), 1.51 (s, 9H), 1.01 (6H).
Reaction SMILES: [N:1]1([C@H:7]2[CH2:12][CH2:11][C@H:10]([OH:13])[CH2:9][CH2:8]2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[H-].[Na+].Cl[C:17]1[CH:18]=[CH:19][CH:20]=[C:21]2[C:28]=1[C:27]1[CH2:26][CH2:25][CH2:24][C:23]=1[S:22]2>CN(C)C=O>[C:28]12[C:21](=[CH:20][CH:19]=[CH:18][C:17]=1[O:13][CH:10]1[CH2:9][CH2:8][CH:7]([N:1]3[CH2:2][CH2:3][O:4][CH2:5][CH2:6]3)[CH2:12][CH2:11]1)[S:22][C:23]1[CH2:24][CH2:25][CH2:26][C:27]2=1
Reactant: Clc1cccc2sc3c(c12)CCC3
Reactant: O[C@H]1CC[C@H](N2CCOCC2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: c1cc(OC2CCC(N3CCOCC3)CC2)c2c3c(sc2c1)CCC3
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 30.8 %

Procedure:
To a solution of trans-4-(morpholin-4-yl)cyclohexan-1-ol (213 mg, 1.15 mmol, 2.00 equiv) in distilled N,N-dimethylformamide (10 mL) was added sodium hydride (69 mg, 2.88 mmol, 3.00 equiv, 60% dispersion in mineral oil) at room temperature and the resulting solution was stirred for 0.5 h at 80° C. in an oil bath under nitrogen. Then a solution of 12-chloro-7-thiatricyclo[6.4.0.0^[2,6]]dodeca-1(12),2(6),8,10-tetraene (120 mg, 0.57 mmol, 1.00 equiv) in 3 mL of DMF was added via syringe and the resulting mixture was stirred at 80° C. for 3 hours. After cooling, the reaction was quenched with water and extracted with 5×50 mL of dichloromethane. The combined organic layers were dried over sodium sulfate and concentrated under vacuum. The crude product (100 mg) was purified by preparative HPLC under the following conditions (Waters): Column: Xbridge Prep C18, 5 μm, 19*50 m; water (with 0.05% NH4HCO3) and CH3CN (10% CH3CN up to 40% CH3CN in 10 min); flow rate: 20 mL/min; UV detection at 254 nm. The product-containing fractions were collected and partially evaporated to remove water and CH3CN under reduced pressure. The residue was lyophilized overnight to give the desired 4-(4-[7-thiatricyclo[6.4.0.0^[2,6]]dodeca-1(12),2(6),8,10-tetraen-12-yloxy]cyclohexyl)morpholine (62.7 mg) as a white solid. MS (ES): m/z 359 (M+H)+. 1H NMR (300 MHz, CDCl3): δ 1.51-1.72 (4H, m), 1.82-2.06 (2H, m), 2.22-2.30 (3H, m), 2.42-2.50 (2H, m), 2.68 (4H, m), 2.78-3.06 (4H, m), 3.51-3.96 (4H, m), 4.30-4.48 (1H, m), 6.63 (1H, d, J=5.4 Hz), 8.25 (1H, d, J=5.4 Hz).
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[C:13]([O:15]C)[CH:12]=[C:11]([C:17]3[CH:26]=[CH:25][C:24]4[C:19](=[CH:20][CH:21]=[C:22]([O:27]C)[CH:23]=4)[CH:18]=3)[CH:10]=2)=[CH:5][CH:4]=1.B(Br)(Br)Br>O>[OH:27][C:22]1[CH:23]=[C:24]2[C:19](=[CH:20][CH:21]=1)[CH:18]=[C:17]([C:11]1[CH:12]=[C:13]([OH:15])[CH:14]=[C:9]([C:6]3[CH:7]=[CH:8][C:3]([OH:2])=[CH:4][CH:5]=3)[CH:10]=1)[CH:26]=[CH:25]2
Reactant: COc1ccc(-c2cc(OC)cc(-c3ccc4cc(OC)ccc4c3)c2)cc1
Agent: BrB(Br)Br
Solvent: O
Product: Oc1ccc(-c2cc(O)cc(-c3ccc4cc(O)ccc4c3)c2)cc1
Yield: 92 %

Procedure:
The compound is prepared by reaction of 2-(4′,5-dimethoxy-1,1′-biphenyl-3-yl)-6-methoxynaphthalene (40 mg, 0.11 mmol, 1 eq) with boron tribromide solution (1.35 ml, 1.35 mmol, 12 eq) according to method G. After the addition of water, the desired product was obtained as a precipitate in a yield of 92%, 34 mg.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:36])[C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH:15]=[C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[O:22]CC3C=CC=CC=3)[C:13]([C:30]#[N:31])=[CH:12]2)=[CH:7][C:6]=1[O:32][CH2:33][O:34][CH3:35])[CH3:2].C(OCC)(=O)C>[C].[Pd].CO>[CH2:1]([O:3][C:4](=[O:36])[C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH:15]=[C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[OH:22])[C:13]([C:30]#[N:31])=[CH:12]2)=[CH:7][C:6]=1[O:32][CH2:33][O:34][CH3:35])[CH3:2]
Reactant: CCOC(=O)c1ccc(-n2cc(C#N)c(-c3ccccc3OCc3ccccc3)c2)cc1OCOC
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: CCOC(=O)c1ccc(-n2cc(C#N)c(-c3ccccc3O)c2)cc1OCOC
Temperature: 25 °C
Reaction time: 5 h
Yield: 74.8 %

Procedure:
To a solution of 4-[4-(2-benzyloxyphenyl)-3-cyanopyrrole-1-yl]-2-methoxymethoxy-benzoic acid ethyl ester (2.3 g) in a mixed solvent of ethyl acetate (20 mL) and methanol (20 mL) was added palladium-carbon powder under an argon atmosphere, and this mixture was stirred at room temperature under a hydrogen atmosphere for 5 hours. The insoluble material was removed by filtration, and this filtrate was concentrated under reduced pressure to give the title compound (1.4 g)
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21]O)=[CH:17][CH:16]=1.C(Br)(Br)(Br)[Br:24].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[Br:24][CH2:21][C:18]1[CH:19]=[CH:20][C:15]([O:14][CH2:13][C:3]2[N:4]=[C:5]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)[O:6][C:2]=2[CH3:1])=[CH:16][CH:17]=1
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc(CO)cc1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Cc1oc(-c2ccccc2)nc1COc1ccc(CBr)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of the title C compound, [4-(5-methyl-2-phenyl-oxazol-4-ylmethoxy)-phenyl]-methanol (1.5 g, 5.08 mmol), carbon tetrabromide (2.53 g, 7.62 mmol), and triphenylphosphine (2.0 g, 7.62 mmol) in DCM is stirred at RT overnight. The mixture is then concentrated under vacuum, and chromatographed on a silica gel column using 8% EtOAc in hexane as the eluent to give 4-(4-bromomethyl-phenoxymethyl)-5-methyl-2-phenyl-oxazole as a white solid.
Reaction SMILES: [Si:1]([O:8][CH:9]1[CH2:14][CH2:13][CH:12]([N:15]2[CH:19]=[C:18]([I:20])[CH:17]=[N:16]2)[CH2:11][CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Li+].CC([N-]C(C)C)C.C1CCCCC1.[Cl:35]C(Cl)(Cl)C(Cl)(Cl)Cl.[NH4+].[Cl-]>C1COCC1>[Si:1]([O:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([N:15]2[C:19]([Cl:35])=[C:18]([I:20])[CH:17]=[N:16]2)[CH2:11][CH2:10]1)([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OC1CCC(n2cc(I)cn2)CC1
Reactant: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Agent: CC(C)[N-]C(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCCCC1
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)O[C@H]1CC[C@H](n2ncc(I)c2Cl)CC1
Reaction time: 0.08 h

Procedure:
A solution of 1-[4-(tert-butyldimethylsilyloxy)cyclohexyl]-4-iodo-1H-pyrazole (50.0 mg, 0.123 mmol) in THF (3 mL, 40 mmol) was cooled to −78° C. and added 1.5 M of LDA in cyclohexane (0.107 mL, 0.160 mmol). After stirring for 5 min, a solution of hexachloroethane (35.0 mg, 0.148 mmol) in THF was added, and the mixture was stirred at −78° C. for 30 min. Sat. NH4Cl was added to quench, and the organic solvent was removed in vacuo. The material was extracted with DCM and water, and the organic layer was dry-loaded onto silica gel for column chromatography, eluting with 1-3% EtOAc/heptane. The fractions containing the pure product were concentrated in vacuo to afford the title compound as a clear oil. 1H NMR (400 MHz, CD3OD): δ=0.11 (s, 6H), 0.93 (s, 9H), 1.46-1.60 (m, 2H), 1.88-2.08 (m, 6H), 3.69-3.80 (m, 1H), 4.32-4.43 (m, 1H), 7.58 (s, 1H).
Reaction SMILES: [CH2:1]([N:8]1[C:12](=[O:13])[CH2:11][CH2:10][C@@H:9]1[C:14]([NH:16][CH:17]([CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH:18]([OH:24])[C:19]([O:21]CC)=[O:20])=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].O>C(O)C>[CH2:1]([N:8]1[C:12](=[O:13])[CH2:11][CH2:10][C@@H:9]1[C:14]([NH:16][CH:17]([CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH:18]([OH:24])[C:19]([OH:21])=[O:20])=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(O)C(Cc1ccccc1)NC(=O)[C@H]1CCC(=O)N1Cc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)C(O)C(Cc1ccccc1)NC(=O)[C@H]1CCC(=O)N1Cc1ccccc1
Temperature: 50 °C

Procedure:
Ethyl 3-((R)-1-benzyl-5-oxopyrrolidine-2-carboxamido)-2-hydroxy-4-phenylbutanoate (4550 mg raw material from previous step 22.1; max. 10.72 mmol) dissolved in 13 ml of ethanol was treated with 6.43 ml 2N aq. NaOH overnight at room temperature. To complete the reaction, the mixture was then heated to 50° C. for 2 h. Water was added followed by extraction with MTBE (3×). The aqueous layer was acidified to pH 3 using 2M HCl and extracted three times with dichloromethane. The combined dichloromethane layers were then successively washed with water and brine, dried over Na2SO4 and the solvent was removed under reduced pressure. The title compound was obtained as a pale brown powder (2450 mg, yield: 58%). ESI-MS [M+H]+=397.2.
Reaction SMILES: CC(C)([O-])C.[K+].[NH:7]1[CH2:11][CH2:10][CH:9]([CH2:12][OH:13])[CH2:8]1.Cl[C:15]1[N:20]=[N:19][C:18]([C:21]2[CH:26]=[CH:25][C:24]([N:27]3[CH:31]=[CH:30][CH:29]=[N:28]3)=[CH:23][C:22]=2[OH:32])=[CH:17][CH:16]=1>C1COCC1>[N:27]1([C:24]2[CH:25]=[CH:26][C:21]([C:18]3[N:19]=[N:20][C:15]([O:13][CH2:12][CH:9]4[CH2:10][CH2:11][NH:7][CH2:8]4)=[CH:16][CH:17]=3)=[C:22]([OH:32])[CH:23]=2)[CH:31]=[CH:30][CH:29]=[N:28]1
Reactant: Oc1cc(-n2cccn2)ccc1-c1ccc(Cl)nn1
Reactant: OCC1CCNC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: Oc1cc(-n2cccn2)ccc1-c1ccc(OCC2CCNC2)nn1
Temperature: 50 °C
Reaction time: 0.17 h

Procedure:
Potassium tert-butoxide (1.0 M in THF, 0.7 mL, 0.7 mmol) was added to pyrrolidin-3-ylmethanol (0.06 g, 0.64 mmol) in THF (1.4 mL) and the mixture was stirred for 10 min at 50° C. 2-(6-Chloropyridazin-3-yl)-5-(1H-pyrazol-1-yl)phenol Intermediate 2-2 (0.05 g, 0.18 mmol) was added to the reaction at 0° C. and the mixture was stirred for 1 h at RT. Solvent was evaporated under reduced pressure. The crude material was purified via reverse phase preparative HPLC (5 to 95% acetonitrile in water, 5 mM NH4OH as modifier). Enantiomer 1 and Enantiomer 2 were isolated via preparative SFC. Two solids (11 mg (17%), and 12 mg (20%) were afforded.
Reaction SMILES: [CH2:1]([O:3][C:4]1([O:18][CH2:19][CH3:20])[CH2:7][C@@H:6]([C:8]([O:10]CC)=[O:9])[C@@H:5]1[C:13]([O:15]CC)=[O:14])[CH3:2].CO.[OH-].[K+]>O1CCCC1>[CH2:19]([O:18][C:4]1([O:3][CH2:1][CH3:2])[CH2:7][C@@H:6]([C:8]([OH:10])=[O:9])[C@@H:5]1[C:13]([OH:15])=[O:14])[CH3:20]
Reactant: CCOC(=O)[C@@H]1CC(OCC)(OCC)[C@H]1C(=O)OCC
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCOC1(OCC)C[C@@H](C(=O)O)[C@@H]1C(=O)O
Reaction time: 72 h

Procedure:
A solution of trans-3,3-diethoxy-1,2-cyclobutanedicarboxylic acid, diethyl ester (100 g) in 1400 ml of tetrahydrofuran under argon was treated with 1400 ml of methanol and 1400 ml of 1N potassium hydroxide solution. The resulting mixture was allowed to stand for 3 days at room temperature and then was evaporated in vacuo to an aqueous solution. The pH was adjusted to 2.3 with 3N hydrochloric acid and the solution was saturated with sodium chloride. The resulting suspension was extracted with ethyl acetate (3×1000 ml). The combined extracts were washed with 250 ml of water and 250 ml of brine, dried over sodium sulfate, and evaporated to afford the product as solid, 78.8 g, m.p. 118°-120° C.
Reaction SMILES: [NH3:1].CO[C:4](=[O:38])[CH:5]([NH:30][C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH2:17][CH2:18][NH:19][C:20]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:21])=[CH:11][CH:10]=1>CO>[CH2:23]([O:22][C:20](=[O:21])[NH:19][CH2:18][CH2:17][CH2:16][CH2:15][C:12]1[CH:13]=[CH:14][C:9]([O:8][CH2:7][CH2:6][CH:5]([NH:30][C:31]([O:33][C:34]([CH3:37])([CH3:35])[CH3:36])=[O:32])[C:4](=[O:38])[NH2:1])=[CH:10][CH:11]=1)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: N
Reactant: COC(=O)C(CCOc1ccc(CCCCNC(=O)OCc2ccccc2)cc1)NC(=O)OC(C)(C)C
Solvent: CO
Product: CC(C)(C)OC(=O)NC(CCOc1ccc(CCCCNC(=O)OCc2ccccc2)cc1)C(N)=O
Temperature: 25 °C
Reaction time: 40 h
Yield: 63 %

Procedure:
Ammonia (7 M in methanol, 20 mL) was added to a solution of N-Boc methyl ester 31(718 mg, 1.40 mmol) in methanol (5 mL) and the mixture was stirred at room temperature in a sealed tube for 40 h. The mixture was concentrated by rotary evaporation and purified by flash silica gel column chromatography using methanol/dichloromethane (1:30, 1:20, v/v) to give the desired amide 32 as a white solid (436 mg, 63% yield). 1H NMR (300 MHz, CDCl3) δ 1.45 (s, 9H), 1.48-1.68 (m, 4H), 2.09-2.32 (m, 2H), 2.48-2.61 (m, 2H), 3.08-3.25 (m, 2H), 3.97-4.20 (m, 2H), 4.30-4.45 (m, 1H), 4.75 (br s, 1H), 5.09 (s, 2H), 5.48-5.58 (m, 1H), 5.62 (br s, 1H), 6.38 (br s, 1H), 6.75-6.85 (m, 2H), 6.99-7.10 (m, 2H), 7.28-7.40 (m, 5H). m/z (ESI) 500 [C27H37N3O6+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=2F)[CH:5]=[CH:4][C:3]=1[C:17]([C:19]1[CH:24]=[C:23]([C:25]2[N:26]=[N:27][N:28]([CH2:30][CH2:31][O:32]C3CCCCO3)[CH:29]=2)[CH:22]=[CH:21][C:20]=1[CH3:39])=[O:18].ClC1C=C([NH:47]C2C=CC(F)=CC=2)C=CC=1C(C1C=C(C#C)C=CC=1C)=O.N(CC(N)=O)=[N+]=[N-]>>[Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)[CH:5]=[CH:4][C:3]=1[C:17]([C:19]1[CH:24]=[C:23]([C:25]2[N:26]=[N:27][N:28]([CH2:30][C:31]([NH2:47])=[O:32])[CH:29]=2)[CH:22]=[CH:21][C:20]=1[CH3:39])=[O:18]
Reactant: Cc1ccc(-c2cn(CCOC3CCCCO3)nn2)cc1C(=O)c1ccc(Nc2ccc(F)cc2F)cc1Cl
Reactant: C#Cc1ccc(C)c(C(=O)c2ccc(Nc3ccc(F)cc3)cc2Cl)c1
Agent: [N-]=[N+]=NCC(N)=O
Product: Cc1ccc(-c2cn(CC(N)=O)nn2)cc1C(=O)c1ccc(Nc2ccc(F)cc2)cc1Cl

Procedure:
The reaction was carried out similarly as described in the preparation of compound 101, using compound 432 (1.04 mmol) and compound 411 (1.5 mmol). The crude product was purified by continuous gradient flash chromatography using EtOAc/DCM/petroleum ether (40-60) 0:80:20, 0:100:0 and 10:90:0 as the eluent to afford the title compound as yellow solid.
Reaction SMILES: [CH3:1][C@H:2]1[N:15]2[C:6]([CH2:7][O:8][C:9]3[C:14]2=[CH:13][C:12](B2OC(C)(C)C(C)(C)O2)=[CH:11][CH:10]=3)=[N:5][NH:4][C:3]1=[O:25].[C:26]([O:30][C:31]([N:33]1[CH2:36][C:35]([CH3:47])([C:37](OS(C(F)(F)F)(=O)=O)=[CH2:38])[CH2:34]1)=[O:32])([CH3:29])([CH3:28])[CH3:27].C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.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>[C:26]([O:30][C:31]([N:33]1[CH2:36][C:35]([CH3:47])([C:37]([C:12]2[CH:13]=[C:14]3[C:9](=[CH:10][CH:11]=2)[O:8][CH2:7][C:6]2[N:15]3[C@H:2]([CH3:1])[C:3](=[O:25])[NH:4][N:5]=2)=[CH2:38])[CH2:34]1)=[O:32])([CH3:29])([CH3:28])[CH3:27]
Reactant: C[C@@H]1C(=O)NN=C2COc3ccc(B4OC(C)(C)C(C)(C)O4)cc3N21
Reactant: C=C(OS(=O)(=O)C(F)(F)F)C1(C)CN(C(=O)OC(C)(C)C)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: C1COCCO1
Solvent: O
Product: C=C(c1ccc2c(c1)N1C(=NNC(=O)[C@H]1C)CO2)C1(C)CN(C(=O)OC(C)(C)C)C1
Temperature: 90 °C
Reaction time: 8 h
Yield: 25.4 %

Procedure:
A mixture of (R)-4-methyl-6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-2,10-dihydro-9-oxa-1,2,4a-triaza-phenanthren-3-one (Preparation #11, Step E, 2 g, 5.83 mmol), 3-methyl-3-(1-trifluoromethanesulfonyloxy-vinyl)-azetidine-1-carboxylic acid tert-butyl ester (Preparation #20 3.02 g, 8.74 mmol), Na2CO3 (1.235 g, 11.66 mmol) and Pd(Ph3P)4 (3.37 g, 2.91 mmol) in dioxane (20 mL) and water (5 mL) was stirred at 90° C. overnight. The reaction mixture was cooled to ambient temperature. The solvent was removed in vacuo and the residue was purified by column chromatography on silica gel (eluting with 0-30% EtOAc in petroleum ether) to give 3-methyl-3-[1-((R)-4-methyl-3-oxo-2,3,4,10-tetrahydro-9-oxa-1,2,4a-triaza-phenanthren-6-yl)-vinyl]-azetidine-1-carboxylic acid tert-butyl ester (0.610 g, 25%) as a solid. LC/MS (Table 1, Method 25) Rt=0.867 min.; MS m/z: 413 [M+H]+ and 357 [M+H−56]+. 1H NMR (CDCl3, 400 MHz): δ 8.10 (br. s., 1H), 6.98 (d, J=8.4 Hz, 1H), 6.83 (d, J=8.4 Hz, 1H), 6.78 (s, 1H), 5.33 (s, 1H), 5.10 (s, 1H), 4.74 (m, 1H), 4.67-4.56 (d, J=15.2 Hz, 2H), 4.11 (m, 2H), 3.79 (m, 2H), 1.61 (d, J=15.2 Hz, 3H), 1.55 (m, 3H). 1.46 (s, 9H).
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5](/[CH:8]=[CH:9]/[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[N:6][CH:7]=1.Cl.Cl.[F:17][C:18]1[CH:30]=[CH:29][C:21]([CH2:22][N:23]2[CH2:27][CH2:26][C@@H:25]([NH2:28])[CH2:24]2)=[CH:20][CH:19]=1.C(N(CC)CC)C>>[F:17][C:18]1[CH:19]=[CH:20][C:21]([CH2:22][N:23]2[CH2:27][CH2:26][C@@H:25]([NH:28][C:2]3[N:3]=[CH:4][C:5](/[CH:8]=[CH:9]/[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[N:6][CH:7]=3)[CH2:24]2)=[CH:29][CH:30]=1
Reactant: N[C@@H]1CCN(Cc2ccc(F)cc2)C1
Reactant: CCOC(=O)/C=C/c1cnc(Cl)cn1
Agent: Cl
Solvent: CCN(CC)CC
Product: CCOC(=O)/C=C/c1cnc(N[C@@H]2CCN(Cc3ccc(F)cc3)C2)cn1
Temperature: 100 °C
Reaction time: 6 h
Yield: 46.9 %

Procedure:
A mixture of ethyl (2E)-3-(5-chloro-2-pyrazinyl)acrylate (300 mg, 1.41 mmol), (3R)-1-(4-fluorobenzyl)-3-pyrrolidinamine dihydrochloride (565 mg, 2.11 mmol) and triethylamine (928 mg, 9.17 mmol) was stirred at 100° C. for 6 hrs. The reaction mixture was evaporated in vacuo and the residue was partitioned between water and EtOAc. The organic layer was separated, washed water and brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by silica gel column chromatography (35% EtOAc/hexane-50% EtOAc/hexane) to give ethyl (2E)-3-(5-{[(3R)-1-(4-fluorobenzyl)-3-pyrrolidinyl]amino}-2-pyrazinyl)acrylate (245 mg, 47%) as an oil.
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].[NH2:5][C:6]1[S:7][C:8]2[C:14]([Br:15])=[CH:13][CH:12]=[CH:11][C:9]=2[N:10]=1>C(OCC)(=O)C>[Br:15][C:14]1[C:8]2[S:7][C:6]([N:5]=[C:1]=[O:2])=[N:10][C:9]=2[CH:11]=[CH:12][CH:13]=1
Reactant: Nc1nc2cccc(Br)c2s1
Reactant: O=C(Cl)Cl
Solvent: CCOC(C)=O
Product: O=C=Nc1nc2cccc(Br)c2s1

Procedure:
A saturated solution of phosgene in ethyl acetate (200 ml) is charged into a glass reaction vessel equipped with a mechanical stirrer, the thermometer and reflux condenser. 2-Amino-7-bromobenzothiazole (0.1 mole) is added with stirring. After this time the mixture is cooled, and the solid product formed is recovered by filtration. The solid is then dried to yield the desired product 7-bromobenzothiazol-2-yl isocyanate dimer.
Reaction SMILES: [CH2:1]([C:4]1[C:13]([OH:14])=[C:12]([O:15][CH3:16])[CH:11]=[C:10]2[C:5]=1[C:6]([NH:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([Br:24])[CH:19]=1)=[N:7][CH:8]=[N:9]2)[CH:2]=[CH2:3].[C:25]([O-])([O-])=O.[K+].[K+].CI>CC(C)=O>[CH2:1]([C:4]1[C:13]([O:14][CH3:25])=[C:12]([O:15][CH3:16])[CH:11]=[C:10]2[C:5]=1[C:6]([NH:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([Br:24])[CH:19]=1)=[N:7][CH:8]=[N:9]2)[CH:2]=[CH2:3]
Reactant: C=CCc1c(O)c(OC)cc2ncnc(Nc3cccc(Br)c3)c12
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: C=CCc1c(OC)c(OC)cc2ncnc(Nc3cccc(Br)c3)c12
Temperature: 90 °C
Reaction time: 4 h

Procedure:
To a solution of 5-allyl-4-(3-bromo-phenylamino)-7-methoxy-quinazolin-6-ol (0.27 g, 0.7 mmol) (from Example 17, Step D, supra) in acetone (30 mL) was added K2CO3 (0.48 g, 3.5 mmol) and methyl iodide (0.4 g, 2.8 mmol) (Aldrich). The reaction mixture was heated with stirring at 90° C. for 4 hours. The mixture was cooled to room temperature, filtered, and the filtrate was concentrated. The residue was purified by chromatography using EtOAc/CH2Cl2/Et3N (1:3:0.01) as eluent to give the desired (5-allyl-6,7-dimethoxy-quinazolin-4-yl)-(3-bromo-phenyl)-amine as a yellow solid. (Yield 0.14 g, 50%).
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[CH:13](/B(O)O)=[CH:14]\[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Pd]>[F:12][C:10]1[CH:9]=[CH:8][C:3]([C:4]([O:6][CH3:7])=[O:5])=[C:2]([CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:11]=1
Reactant: OB(O)/C=C/c1ccccc1
Reactant: COC(=O)c1ccc(F)cc1Br
Agent: [Pd]
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: COC(=O)c1ccc(F)cc1CCc1ccccc1
Reaction time: 96 h

Procedure:
Methyl 2-bromo-4-fluorobenzoate (1.00 g), (E)-styrylboronic acid (0.89 g), tetrakis(triphenylphosphine)palladium(O) (0.50 g), and K3PO4 (2.28 g) were stirred in dioxane (17 mL) at 90° C. for 24 hours. The reaction mixture chromatographed on silica gel with 1-5% ethyl acetate/hexanes. The product in methanol (10 ml) was added to 20 wt % of fresh dry 5% Pd—C and stirred 4 days with H2 in a pressure bottle. The mixture was filtered through a nylon membrane and concentrated.