Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:18]=[CH:17][CH:16]=[CH:15][C:10]=2[C:11]([NH:13][CH3:14])=[O:12])[C:5]([Br:19])=[CH:4][N:3]=1.[CH3:20][O:21][C:22]1[C:23]([NH2:37])=[CH:24][C:25]2[CH2:31][CH2:30][N:29]([CH2:32][CH2:33][O:34][CH3:35])[CH2:28][CH2:27][C:26]=2[CH:36]=1.Cl>C(O)CCC.O1CCOCC1>[Br:19][C:5]1[C:6]([NH:8][C:9]2[CH:18]=[CH:17][CH:16]=[CH:15][C:10]=2[C:11]([NH:13][CH3:14])=[O:12])=[N:7][C:2]([NH:37][C:23]2[C:22]([O:21][CH3:20])=[CH:36][C:26]3[CH2:27][CH2:28][N:29]([CH2:32][CH2:33][O:34][CH3:35])[CH2:30][CH2:31][C:25]=3[CH:24]=2)=[N:3][CH:4]=1
Reactant: COCCN1CCc2cc(N)c(OC)cc2CC1
Reactant: CNC(=O)c1ccccc1Nc1nc(Cl)ncc1Br
Agent: Cl
Solvent: C1COCCO1
Solvent: CCCCO
Product: CNC(=O)c1ccccc1Nc1nc(Nc2cc3c(cc2OC)CCN(CCOC)CC3)ncc1Br
Yield: 25 %

Procedure:
2-(2-chloro-5-bromo-pyrimidin-4-ylamino)-N-methyl-benzamide (52 mg, 0.15 mmol) and 8-methoxy-3-(2-methoxyethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamine (48 mg, 0.19 mmol) were combined in 5 mL n-butanol. Two drops of a solution of 4N hydrochloric acid in dioxane was added and the mixture was refluxed for eight hours. The mixture was concentrated and the organics were partitioned between dichloromethane and saturated sodium bicarbonate solution (100 mL each). The organic layer was separated, was dried (sodium sulfate), and was concentrated to afford an oil which was purified on silica (methanol:dichloromethane gradient elution) to afford 2-{5-bromo-2-[8-methoxy-3-(2-methoxy-ethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamino]-pyrimidin-4-ylamino}-N-methyl-benzamide as a tan foam (25%). Mp: 171-5° C.; MS: 556.78 (M+H); 1H NMR (chloroform-d): δ 10.81 (s, 1H), δ 8.60 (d, J=8 Hz, 1H), δ 8.21 (s, 1H), δ 8.08 (s, 1H), δ 7.53-7.41 (m, 3H), δ 6.92 (t, J=8 Hz, 1H), δ 6.66 (s, 1H), δ 6.24 (br s, 1H), δ 3.78 (s, 3H), δ 3.57 (t, J=5 Hz, 35), δ 3.39 (s, 3H), δ 3.06 (dd, J=2.4 Hz, 2H), δ 2.91 (m, 2H), δ 2.82-2.67 (m, 8H).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([O:11][CH2:12][CH2:13][CH2:14][CH3:15])[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH2:16][C:17]1[CH:18]=[C:19]([CH2:23][P:24](=[O:31])([O:28][CH2:29][CH3:30])[O:25][CH2:26][CH3:27])[CH:20]=[CH:21][CH:22]=1.[Br:32]Br>C(Cl)(Cl)Cl>[NH2:1][C:2]1[N:10]=[C:9]([O:11][CH2:12][CH2:13][CH2:14][CH3:15])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([Br:32])[N:6]2[CH2:16][C:17]1[CH:18]=[C:19]([CH2:23][P:24](=[O:31])([O:25][CH2:26][CH3:27])[O:28][CH2:29][CH3:30])[CH:20]=[CH:21][CH:22]=1
Reactant: BrBr
Reactant: CCCCOc1nc(N)c2ncn(Cc3cccc(CP(=O)(OCC)OCC)c3)c2n1
Solvent: ClC(Cl)Cl
Product: CCCCOc1nc(N)c2nc(Br)n(Cc3cccc(CP(=O)(OCC)OCC)c3)c2n1
Yield: 49 %

Procedure:
To a solution of 61 (134.9 mg, 0.30 mmol) in CHCl3 (5 mL) was added a 10% (v) solution of Br2 in chloroform. The reaction was stopped when starting material was consumed, monitored by HPLC. Bromine was quenched with a saturated Na2SO3 solution and product extracted with DCM (2×10 mL). Organics were washed with water (2×10 mL) and brine (1×10 mL) and dried over Na2SO4. Purified by flash column eluting 100% ethyl acetate. Evaporation of solvent gave 76.0 mg (49%) of 62 as a yellow solid. LCMS: m/z for C21H29BrN5O4P++H observed 526.1 and 528.1 at 2.37 minutes of a 3.5 minute run, eluting 5-95% CH3CN in H2O.
Reaction SMILES: [Cl-].[NH2:2][C:3]1[N:8]=[CH:7][CH:6]=[CH:5][N+:4]=1[CH2:9][S:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[Br:17]>CC(O)C>[Br:17][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[S:10][CH2:9][N:4]1[CH:5]=[CH:6][CH:7]=[N:8][C:3]1=[NH:2]
Reactant: Nc1nccc[n+]1CSc1ccccc1Br
Agent: [Cl-]
Solvent: CC(C)O
Product: N=c1ncccn1CSc1ccccc1Br

Procedure:
To a suspension of 2.05 g of sodium 2-propoxide in 200 ml of 2-propanol is added 8.3 g of 2-amino-1-[[(o-bromophenyl)thio]methyl]pyrimidinium chloride, and the mixture is stirred and heated under reflux for about 5 hours. During this time the flocculent sodium 2-propoxide is replaced by a granular precipitate. The mixture is filtered hot, the insoluble solid is washed repeatedly with warm 2-propanol, and the combined filtrate and washings are concentrated to a volume of about 25 ml in vacuo. The solution is cooled, the solid that separates is filtered, and then is recrystallized from cyclohexane to give 1-[(o-bromophenylthio)methyl]-2-iminopyrimidine.
Reaction SMILES: [CH3:1][N:2]([CH2:10][CH2:11][O:12][C:13]1[C:18]([C:19]([F:22])([F:21])[F:20])=[CH:17][C:16](B2OC(C)(C)C(C)(C)O2)=[CH:15][N:14]=1)[C:3](=[O:9])[O:4][C:5]([CH3:8])([CH3:7])[CH3:6].[NH2:32][C:33]1[C:34]([C:42]#[N:43])=[N:35][C:36](Cl)=[CH:37][C:38]=1[NH:39][CH3:40].C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[NH2:32][C:33]1[C:38]([NH:39][CH3:40])=[CH:37][C:36]([C:16]2[CH:15]=[N:14][C:13]([O:12][CH2:11][CH2:10][N:2]([CH3:1])[C:3](=[O:9])[O:4][C:5]([CH3:6])([CH3:7])[CH3:8])=[C:18]([C:19]([F:20])([F:21])[F:22])[CH:17]=2)=[N:35][C:34]=1[C:42]#[N:43]
Reactant: CNc1cc(Cl)nc(C#N)c1N
Reactant: CN(CCOc1ncc(B2OC(C)(C)C(C)(C)O2)cc1C(F)(F)F)C(=O)OC(C)(C)C
Agent: [Pd]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: O
Product: CNc1cc(-c2cnc(OCCN(C)C(=O)OC(C)(C)C)c(C(F)(F)F)c2)nc(C#N)c1N
Temperature: 100 °C
Reaction time: 2 h
Yield: 49 %

Procedure:
A suspension of tert-butyl methyl(2-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-(trifluoromethyl)pyridin-2-yloxy)ethyl)carbamate (440 mg), 3-amino-6-chloro-4-(methylamino)picolinonitrile (135 mg), tris(dibenzylideneacetone)dipalladium (0) (34.9 mg), tricyclohexylphosphine (25.7 mg) and potassium phosphate (327 mg) in 1,4-dioxane (10 ml) and water (5 ml) was stirred at 100° C. for 2 h. The reaction mixture was cooled and partitioned between water and ethyl acetate, washed with water, brine, dried over sodium sulfate, filtered and concentrated. Purified by Biotage SNAP cartridge KP-Sil column (25 g, heptane:ethyl acetate=1:0, 3:1, 2:1, 1:1 to 1:2) to give 170 mg orange amorphous as tert-butyl 2-(5-amino-6-cyano-4-(methylamino)-5′-(trifluoromethyl)-2,3′-bipyridin-6′-yloxy)ethyl(methyl)carbamate (49%).
Reaction SMILES: [CH2:1]([CH:3]([CH2:6][CH2:7][CH2:8][CH3:9])[CH:4]=[O:5])[CH3:2].[CH2:10]=[O:11]>C(N(CC)CC)C>[CH2:1]([C:3]([CH2:10][OH:11])([CH2:6][CH2:7][CH2:8][CH3:9])[CH:4]=[O:5])[CH3:2]
Reactant: CCCCC(C=O)CC
Reactant: C=O
Solvent: CCN(CC)CC
Product: CCCCC(C=O)(CC)CO
Temperature: 100 °C

Procedure:
A one liter Parr autoclave was charged with 2-ethylhexanal (334 g, 406 mL, 2.6 mole), 44% aqueous formaldehyde (136.4 g, 122 mL, 2.0 mole) and varying amounts of triethylamine to determine the effect of increasing triethylamine concentration on reaction rate. After purging with nitrogen, the autoclave was sealed and heated at 100° C. for one hour. The autoclave was cooled and the contents were analyzed for formaldehyde (HCHO) by calorimetric analysis and for 2-ethyl2-(hydroxymethyl)hexanal (EHMH) by gas chromatography analysis. The yield of EHMH was calculated based on the 2-ethylhexanal consumed which was determined after correcting the gas chromatograph area for methanol and excess 2-ethylhexanal. Table I sets forth the amount of triethylamine (TEA, g/mL), the concentration by weight of triethylamine based on the total weight of the materials charged (TEA, %), the mole percent of formaldehyde converted (HCHO Conv.) and the percent yield of EHMH obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][CH2:10][C:11]([OH:13])=O)[CH:5]=[C:6]([F:8])[CH:7]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.[NH:35]1[CH2:40][CH2:39][CH2:38][C@@H:37]([NH:41][C:42]2[N:47]=[CH:46][N:45]=[C:44]3[NH:48][N:49]=[CH:50][C:43]=23)[CH2:36]1.CCN(C(C)C)C(C)C>CN(C=O)C.CCOC(C)=O>[NH:48]1[C:44]2=[N:45][CH:46]=[N:47][C:42]([NH:41][C@@H:37]3[CH2:38][CH2:39][CH2:40][N:35]([C:11](=[O:13])[CH2:10][NH:9][C:4]4[CH:5]=[C:6]([F:8])[CH:7]=[C:2]([Cl:1])[CH:3]=4)[CH2:36]3)=[C:43]2[CH:50]=[N:49]1
Reactant: O=C(O)CNc1cc(F)cc(Cl)c1
Reactant: c1nc(N[C@@H]2CCCNC2)c2cn[nH]c2n1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(CNc1cc(F)cc(Cl)c1)N1CCC[C@@H](Nc2ncnc3[nH]ncc23)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 10.2 %

Procedure:
To a cooled solution of 2-(3-chloro-5-fluorophenylamino)acetic acid (70 mg, 0.34 mmol) at 0° C. in DMF (5 mL), HOBt (69 mg, 0.51 mmol) was added and the reaction mixture was stirred for 10 min. before EDCI (101 mg 0.51 mmol), (R)—N-(piperidin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (75 mg, 0.34 mmol) and DIEA (104 mg, 0.80 mmol) were added in succession. The reaction mixture was allowed to warm to rt and was stirred overnight. After completion of the reaction as indicated by TLC the reaction mixture was diluted with EtOAc (50 mL) and was washed with water (3×20 mL). The EtOAc layer was then dried over Na2SO4 and evaporated in vacuo to give a residue that was purified by column chromatography (silica gel, gradient MeOH in CH2Cl2) to afford the titled compound (14 mg, 10%). 1H NMR (400 MHz, CD3OD): δ 8.52-8.43 (m, 1H), 6.45-6.08 (m, 4H), 4.49-3.82 (m, 5H), 3.31-2.95 (m, 2H), 1.96-1.63 (m, 4H). LC-MS: m/z [M+1]=404.
Reaction SMILES: [CH3:1][NH:2][C:3]1[N:8]=[C:7]([C:9]2[NH:10][C:11]3[C:16]([CH:17]=2)=[CH:15][C:14]([C:18]([OH:20])=[O:19])=[CH:13][CH:12]=3)[CH:6]=[CH:5][N:4]=1.[F:21][C:22]1[C:27](O)=[C:26]([F:29])[C:25]([F:30])=[C:24]([F:31])[C:23]=1[F:32].Cl.C(N=C=NCCCN(C)C)C>C1COCC1>[CH3:1][NH:2][C:3]1[N:8]=[C:7]([C:9]2[NH:10][C:11]3[C:16]([CH:17]=2)=[CH:15][C:14]([C:18]([O:20][C:27]2[C:26]([F:29])=[C:25]([F:30])[C:24]([F:31])=[C:23]([F:32])[C:22]=2[F:21])=[O:19])=[CH:13][CH:12]=3)[CH:6]=[CH:5][N:4]=1
Reactant: Oc1c(F)c(F)c(F)c(F)c1F
Reactant: CNc1nccc(-c2cc3cc(C(=O)O)ccc3[nH]2)n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: C1CCOC1
Product: CNc1nccc(-c2cc3cc(C(=O)Oc4c(F)c(F)c(F)c(F)c4F)ccc3[nH]2)n1
Temperature: 25 °C
Reaction time: 15 h
Yield: 45.5 %

Procedure:
6.38 g (23.78 mmol) of the acid 20 were suspended in 100 ml of THF. 5.25 g (28.54 mmol) of pentafluorophenol and 5.47 g (28.54 mmol) of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC*HCl) were then added. The mixture was stirred at RT for 15 h, after which the solvent was removed i.v. and the residue was partitioned between 300 ml of a sat. solution of NaHCO3 and 300 ml of ethyl acetate. The solids were filtered off through kieselguhr and the residue was washed twice with in each 100 ml of ethyl acetate. The phases were separated and the aqueous phase was extracted twice within each case 100 ml of ethyl acetate. The combined organic phases were washed with 200 ml of a sat. solution of NaCl and then dried with MgSO4. After the solvents had been removed i.v., the residue was chromatographed on silica gel using heptane/ethyl acetate 1:1. 4.7 g (46%) of the pentafluorophenyl ester 55 was obtained.
Reaction SMILES: [CH2:1]([Li])CCC.[CH3:6][N:7]1[C:11]([S:12][C:13]2[CH:18]=[C:17]([CH3:19])[CH:16]=[C:15]([CH3:20])[CH:14]=2)=[C:10]([CH2:21][C:22]#[N:23])[N:9]=[C:8]1[CH3:24].CN(C)P(=O)(N(C)C)N(C)C.CI>CCCCCC>[CH3:6][N:7]1[C:11]([S:12][C:13]2[CH:18]=[C:17]([CH3:19])[CH:16]=[C:15]([CH3:20])[CH:14]=2)=[C:10]([CH:21]([CH3:1])[C:22]#[N:23])[N:9]=[C:8]1[CH3:24]
Reactant: Cc1cc(C)cc(Sc2c(CC#N)nc(C)n2C)c1
Reactant: [Li]CCCC
Solvent: CI
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: CCCCCC
Product: Cc1cc(C)cc(Sc2c(C(C)C#N)nc(C)n2C)c1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 57 %

Procedure:
To this, 0.3 ml of 1.62 M hexane solution of n-butyllithium was added under a stream of nitrogen, and the mixture was stirred for 10 minutes. The mixture was cooled to -78° C., and 85 mg (0.31 mmol) of [1,2-dimethyl-5-(3,5-dimethylphenylthio)imidazol-4-yl]acetonitrile (42d) was added, and the mixture was stirred for 15 minutes. Then, 86 mg (0.48 mmol) of hexamethylphosphoric triamide and 68 mg (0.48 mmol) of methyl iodide were added dropwise, and the mixture was stirred at -78° C. for 30 minutes. The reaction mixture was poured into ice-water, extracted with diethyl ether, and the extract was washed with water and dried over sodium sulfate. The solvent was distilled off under reduced pressure, the residue was purified by silica gel chromatography (ethyl acetate) to give 51 mg of 2-[1,2-dimethyl-5-(3,5-dimethylphenylthio)-1H-imidazol-4-yl]propiononitrile (43a) as oil (yield 57%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([NH:14]C(=O)OC(C)(C)C)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:9][CH2:10][CH:11]([NH2:14])[CH2:12][CH2:13]2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)NC1CCN(c2ccc(Br)cc2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NC1CCN(c2ccc(Br)cc2)CC1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
tert-Butyl 1-(4-bromophenyl)piperidin-4-ylcarbamate (365 mg) is dissolved in dichloromethane (10 mL), treated with trifluoroacetic acid (780 μL) and stirred for 6 hours at room temperature. Then the mixture is partitioned between dichloromethane and saturated aqueous K2CO3 solution and stirred vigorously for 30 minutes. The phases are separated and the organic phase is washed with saturated aqueous K2CO3 solution. The organic phase is dried (MgSO4) and concentrated to give the title compound. LC (method 2): tR=0.93 min; Mass spectrum (ESI+): m/z=255 [M+H]+.
Reaction SMILES: CO[CH:3](OC)[N:4]([CH3:6])[CH3:5].[NH2:9][C:10]1[CH:15]=[C:14]([CH2:16][C:17]2[C:22]([Cl:23])=[CH:21][CH:20]=[CH:19][C:18]=2[Cl:24])[N:13]=[C:12]([NH:25][C:26]2[CH:33]=[CH:32][C:29]([C:30]#[N:31])=[CH:28][CH:27]=2)[N:11]=1>>[C:30]([C:29]1[CH:32]=[CH:33][C:26]([NH:25][C:12]2[N:11]=[C:10]([N:9]=[CH:3][N:4]([CH3:6])[CH3:5])[CH:15]=[C:14]([CH2:16][C:17]3[C:22]([Cl:23])=[CH:21][CH:20]=[CH:19][C:18]=3[Cl:24])[N:13]=2)=[CH:27][CH:28]=1)#[N:31]
Reactant: N#Cc1ccc(Nc2nc(N)cc(Cc3c(Cl)cccc3Cl)n2)cc1
Reactant: COC(OC)N(C)C
Product: CN(C)C=Nc1cc(Cc2c(Cl)cccc2Cl)nc(Nc2ccc(C#N)cc2)n1
Temperature: 25 °C
Reaction time: 48 h
Yield: 44.1 %

Procedure:
1,1-Dimethoxy-N,N-dimethylmethanamine (0.152 mol) was added to 4-[[4-amino-6-[(2,6-dichlorophenyl)methyl]-2-pyrimidinyl]amino]benzonitrile (0.0008 mol). The mixture was stirred at room temperature for 2 days and then concentrated. The crude product was purified by flash chromatography over silica gel (eluent: CH2Cl2/CH3OH 99/1). The desired fraction was collected and the solvent was evaporated. The resulting residue was triturated with hexane, yielding 0.15 g (42%) of N′-[2-[(4-cyano-phenyl)amino]-6-[(2,6-dichlorophenyl)methyl]-4-pyrimidinyl]-N,N-dimethyl-methanimidamide (comp. 26; mp. 175-180° C.).
Reaction SMILES: F[C:2]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[Br:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][CH:23]=1)[CH:20]=[C:19]([OH:24])[CH:18]=[CH:17]2.C1OCCOCCOCCOCCOCCOC1>C(#N)C>[Br:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][CH:23]=1)[CH:20]=[C:19]([O:24][C:2]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5])[CH:18]=[CH:17]2
Reactant: Oc1ccc2cc(Br)ccc2c1
Reactant: N#Cc1ccc([N+](=O)[O-])cc1F
Agent: C1COCCOCCOCCOCCOCCO1
Solvent: CC#N
Product: N#Cc1ccc([N+](=O)[O-])cc1Oc1ccc2cc(Br)ccc2c1
Temperature: 25 °C
Yield: 64.3 %

Procedure:
After heating to reflux 2-fluoro-4-nitrobenzonitrile (1 g), 6-bromo-2-naphthol (1.41 g), potassium fluoride/alumina (0.7 g) and 18-crown-6 (0.16 g) in acetonitrile, the mixture was reacted for 12 hours. It was then cooled to room temperature, the insoluble portion was filtered using celite, the ethyl acetate layer was washed with water and saturated saline and then dried over magnesium sulfate, and the solvent was distilled off. Methanol was added to the residue for crystallization to obtain 1.43 g of 2-(6-bromo-2-naphthyloxy)-4-nitrobenzonitrile.
Reaction SMILES: C(O)(C(F)(F)F)=O.C(OC(=O)[NH:14][CH2:15][CH2:16][CH2:17][O:18][C:19]1[CH:20]=[C:21]2[C:26](=[CH:27][C:28]=1[O:29][CH3:30])[N:25]=[CH:24][N:23]=[C:22]2[NH:31][C:32]1[CH:37]=[CH:36][C:35]([O:38][CH2:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][N:41]=2)=[C:34]([Cl:46])[CH:33]=1)(C)(C)C>C(Cl)Cl.C([O-])(O)=O.[Na+]>[NH2:14][CH2:15][CH2:16][CH2:17][O:18][C:19]1[CH:20]=[C:21]2[C:26](=[CH:27][C:28]=1[O:29][CH3:30])[N:25]=[CH:24][N:23]=[C:22]2[NH:31][C:32]1[CH:37]=[CH:36][C:35]([O:38][CH2:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][N:41]=2)=[C:34]([Cl:46])[CH:33]=1
Reactant: COc1cc2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c2cc1OCCCNC(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cc2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c2cc1OCCCN
Reaction time: 1 h
Yield: 94.5 %

Procedure:
TFA (3 mL) was added drop wise to a suspension of (3-{4-[3-Chloro-4-(pyridin-2-ylmethoxy)-phenylamino]-7-methoxy-quinazolin-6-yloxy}-propyl)-carbamic acid tert-butyl ester (0.9 g, 1.59 mmol) in DCM (3 mL). Stir for 1 hour and the reaction mixture was diluted with DCM (20 ml) and sat. NaHCO3 (20 mL). Phases were separated and organic layer was extracted with DCM (20 mL). Organic layers were combined, dried (Na2SO4), and concentrated to give 0.7 g (95%) of desired product.
Reaction SMILES: Cl.C(O[N:6]1[CH2:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([Cl:17])[C:13]=2[Cl:16])[N:8](CC)[C:7]1=[N:20]C#N)(=O)C.C(=O)([O-])[O-].[K+].[K+].[CH2:29]([OH:32])[CH2:30]O>>[Cl:16][C:13]1[C:12]([Cl:17])=[CH:11][CH:10]=[C:9]2[C:14]=1[CH2:15][N:6]1[CH2:30][C:29](=[O:32])[NH:20][C:7]1=[N:8]2
Reactant: CCN1C(=NC#N)N(OC(C)=O)Cc2c1ccc(Cl)c2Cl
Reactant: OCCO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: O=C1CN2Cc3c(ccc(Cl)c3Cl)N=C2N1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 93 %

Procedure:
To a solution of 150 ml of ethylene glycol and 15 ml (0.15 moles) of cc. hydrochloric acid 24.5 g (0.075 moles) of ethyl-(2-cyanoimino-5,6-dichloro-1,2,3,4-tetrahydroquinazolin-3-yl) acetate are added in small portions, within about 10 minutes, at 115° C., and the mixture is kept at the same temperature for further 20 minutes. Then it is cooled to room temperature and made neutral by the dropwise addition of 10% potassium carbonate solution. The separated crystals are filtered off. Thus 17.75 g (93.0%) of 6,7-dichloro-1,5-dihydroimidazo[2,1-b]quinazolin-2[3H]-one base are obtained (m.p.>300° C., HPLC content: 99.5%), which is dissolved in a hot mixture of 150 ml of methanol and 150 ml of cc. ethanolic hydrogen chloride (hydrogen chloride content: 0.75 moles/1000 ml). The mixture is then cooled, the separated product is filtered off and washed with a slight amount of ethanol.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C@H:15]2[CH2:32][C@@:30]3([CH3:31])[C@@H:26]([CH2:27][CH2:28][C:29]3=[O:33])[C@H:25]3[C:16]2=[C:17]2[C:22]([CH2:23][CH2:24]3)=[CH:21][C:20](=[O:34])[CH2:19][CH2:18]2)=[CH:11][CH:10]=1.C(OC(=O)C)(=O)C.C(Br)(=O)C>>[OH:34][C:20]1[CH:19]=[CH:18][C:17]2[C@@H:16]3[C@H:25]([C@H:26]4[C@@:30]([CH2:32][C@@H:15]3[C:12]3[CH:11]=[CH:10][C:9]([O:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][Cl:1])=[CH:14][CH:13]=3)([CH3:31])[C:29](=[O:33])[CH2:28][CH2:27]4)[CH2:24][CH2:23][C:22]=2[CH:21]=1
Reactant: C[C@]12C[C@H](c3ccc(OCCCCCCCl)cc3)C3=C4CCC(=O)C=C4CC[C@H]3[C@@H]1CCC2=O
Agent: CC(=O)Br
Solvent: CC(=O)OC(C)=O
Product: C[C@]12C[C@H](c3ccc(OCCCCCCCl)cc3)[C@@H]3c4ccc(O)cc4CC[C@H]3[C@@H]1CCC2=O
Yield: 100.4 %

Procedure:
The operation is carried out as in Stages B and C of Example 3 starting with 481 mg of the product obtained in Stage A above using 0.5 cm3 of acetic anhydride and 0.25 cm3 of acetyl bromide. 483 mg of desired product is obtained.
Reaction SMILES: [OH-].[Na+].[NH:3]([C:56]([O:58][C:59]([CH3:62])([CH3:61])[CH3:60])=[O:57])[C@H:4]([C:9]([NH:11][C@H:12]([C:17]([NH:19][C@H:20]([C:36]([NH:38][C@H:39]([C:44]([NH:46][C@H:47]([C:52]([O:54]C)=[O:53])[CH2:48][CH:49]([CH3:51])[CH3:50])=[O:45])[CH2:40][CH:41]([CH3:43])[CH3:42])=[O:37])[CH2:21][CH2:22][CH2:23][CH2:24][NH:25][C:26]([O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:27])=[O:18])[CH2:13][CH:14]([CH3:16])[CH3:15])=[O:10])[CH2:5][CH:6]([CH3:8])[CH3:7].C1COCC1.C(O)=O>O.C(OCC)(=O)C>[NH:3]([C:56]([O:58][C:59]([CH3:62])([CH3:61])[CH3:60])=[O:57])[C@H:4]([C:9]([NH:11][C@H:12]([C:17]([NH:19][C@H:20]([C:36]([NH:38][C@H:39]([C:44]([NH:46][C@H:47]([C:52]([OH:54])=[O:53])[CH2:48][CH:49]([CH3:50])[CH3:51])=[O:45])[CH2:40][CH:41]([CH3:42])[CH3:43])=[O:37])[CH2:21][CH2:22][CH2:23][CH2:24][NH:25][C:26]([O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:27])=[O:18])[CH2:13][CH:14]([CH3:16])[CH3:15])=[O:10])[CH2:5][CH:6]([CH3:8])[CH3:7]
Reactant: COC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCCNC(=O)OCc1ccccc1)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(C)C)NC(=O)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: O=CO
Product: CC(C)C[C@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCCNC(=O)OCc1ccccc1)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(C)C)NC(=O)OC(C)(C)C)C(=O)O
Temperature: 62.5 °C
Reaction time: 2 h
Yield: 97.5 %

Procedure:
A solution of NaOH(1.44 g, 36.0 mmol) in H2O (15.0 g) was added at 20-25° C. over 5 min to a mixture of Boc-Leu-Leu-Lys(Z)-Leu-Leu-OMe (SEQ. ID No. 2) (12.0 g, 14.16 mmol) THF (48.0 g) and H2O (18.0 g). The resulting mixture was stirred for 2 h. 98% Formic acid (5 g) was added, followed by ethyl acetate (30.0 g). The resulting organic phase was washed with H2O, concentrated in vacuo and the residue was dissolved in MeOH (60.0 g). The solids were filtered and rinsed with an additional portion of MeOH (8.0 g). The combined MeOH solution was heated to 60-65° C. and H2O (30.0 g) was added over 10 min. This mixture was cooled to 20-25° C., the solid product began to crystallize. An additional portion of H2O (35.0 g) was added and the mixture was stirred for 1 h. The solid product was filtered, washed with H2O and dried in vacuo to give Boc-Leu-Leu-Lys(Z)-Leu-Leu-OH (SEQ. ID No. 2) (11.5 g, 97.5%).
Reaction SMILES: [OH:1][CH:2]([C:4](=[CH2:10])[C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH3:3].N1C=CC=CC=1.[C:17](Cl)(=[O:19])[CH3:18]>ClCCl>[C:17]([O:1][CH:2]([C:4](=[CH2:10])[C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH3:3])(=[O:19])[CH3:18]
Reactant: CC(=O)Cl
Reactant: C=C(C(=O)OCC)C(C)O
Solvent: c1ccncc1
Solvent: ClCCl
Product: C=C(C(=O)OCC)C(C)OC(C)=O
Reaction time: 1 h

Procedure:
To a solution of ethyl 2-(1-hydroxyethyl)acrylate (40 g) and pyridine (26.9 ml) in dichloromethane (277 ml) was added dropwise acetyl chloride (23.7 ml) at 0° C. The reaction mixture was stirred for 1 hour and quenched with water (200 ml). The aqueous layer was separated and extracted twice with dichloromethane. The combined organic layers were washed with 1N hydrochloric acid, saturated aqueous sodium hydrogen carbonate water and an aqueous sodium chloride in turn, and then, dried over magnesium sulfate. After the resultant solution was evaporated, the residue was distilled in vacuo to give ethyl 2-(1-acetoxyethyl)acrylate (41.44 g) as a colorless oil.
Reaction SMILES: [CH:1]([C@H:3]1[C@H:10]([O:11][C:12](=[O:19])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:9][C@H:8]2[C@@H:4]1[CH2:5][C:6](=[O:20])[O:7]2)=O.[O:21]=[C:22]([CH2:43][C:44]#[C:45][CH2:46][CH3:47])[CH:23]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>C1(C)C=CC=CC=1>[C:12]([O:11][C@@H:10]1[CH2:9][C@H:8]2[C@H:4]([CH2:5][C:6](=[O:20])[O:7]2)[C@H:3]1/[CH:1]=[CH:23]/[C:22](=[O:21])[CH2:43][C:44]#[C:45][CH2:46][CH3:47])(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C[C@@H]1[C@H]2CC(=O)O[C@H]2C[C@H]1OC(=O)c1ccccc1
Reactant: CCC#CCC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Product: CCC#CCC(=O)/C=C/[C@@H]1[C@H]2CC(=O)O[C@H]2C[C@H]1OC(=O)c1ccccc1
Yield: 98.1 %

Procedure:
A solution of 7.4 g of (1S,5R,6R,7R)-6-formyl-7-benzoyloxy-2-oxabicyclo[3.3.0]octan-3-one (E. J. Corey et al., J. Chem. Soc., 91, 5675 (1969)) and 10.3 g of the phosphorane prepared in Example (23b) in 200 ml of absolute toluene is stirred at room temperature for 5.5 hours. The reaction solution is concentrated in vacuo and the residue is chromatographed over silica gel by gradient elution in hexane/40% ethyl acetate. 9.7 g of the title compound are obtained.