Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]=O)[CH:2]=1.Cl.[NH2:10][OH:11].[OH-].[Na+]>C(O)C.O>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]=[N:10][OH:11])[CH:2]=1
Reactant: O=Cc1cccnc1
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: ON=Cc1cccnc1

Procedure:
3-Pyridinecarboxaldehyde oxime was prepared by treating 3-pyridinecarboxaldehyde (10 mL, 106 mmol) with hydroxylamine hydrochloride (8.10 g, 117 mmol) and 50% aqueous sodium hydroxide (2 mL) in ethanol (100 mL) and water (200 mL) for 17 hours. The solution was adjusted to pH 14 with the addition of 50% (w/w) aqueous sodium hydroxide. The solution was extracted with several portions of dichloromethane. The combined organic layers were washed with brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure to yield 8.3 g of a white solid. The aqueous layers were combined and back-extracted with chloroform (5×1 L) to yield additional product. The total amount of 3-pyridinecarboxaldehyde oxime obtained was 12.24 g.
Reaction SMILES: [C:1]([O:5][C:6](=[O:39])[NH:7][CH2:8][C:9]1[CH:38]=[CH:37][C:12]2[N:13]([CH2:32]CC(C)C)[C:14]([CH2:16][N:17]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[C:20](=[O:27])[N:19]([CH:28]4[CH2:30][CH2:29]4)[C:18]3=[O:31])=[N:15][C:11]=2[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].C1(N2C(=O)C3C(=CC=CC=3)NC2=O)CC1.C(OC(NCC1C=CC2N(C[CH2:74][CH2:75][CH2:76][O:77][C:78](=[O:83])[C:79]([CH3:82])([CH3:81])[CH3:80])C(C[Cl:72])=NC=2C=1)=O)(C)(C)C>>[ClH:72].[C:1]([O:5][C:6]([NH:7][CH2:8][C:9]1[CH:38]=[CH:37][C:12]2[N:13]([CH2:32][CH2:74][CH2:75][CH2:76][O:77][C:78](=[O:83])[C:79]([CH3:82])([CH3:81])[CH3:80])[C:14]([CH2:16][N:17]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[C:20](=[O:27])[N:19]([CH:28]4[CH2:30][CH2:29]4)[C:18]3=[O:31])=[N:15][C:11]=2[CH:10]=1)=[O:39])([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)(C)OC(=O)NCc1ccc2c(c1)nc(CCl)n2CCCCOC(=O)C(C)(C)C
Reactant: CC(C)CCn1c(Cn2c(=O)n(C3CC3)c(=O)c3ccccc32)nc2cc(CNC(=O)OC(C)(C)C)ccc21
Agent: O=c1[nH]c2ccccc2c(=O)n1C1CC1
Product: CC(C)(C)OC(=O)NCc1ccc2c(c1)nc(Cn1c(=O)n(C3CC3)c(=O)c3ccccc31)n2CCCCOC(=O)C(C)(C)C
Product: Cl
Yield: 81 %

Procedure:
The procedure for [2-(3-cyclopropyl-2,4-dioxo-3,4-dihydro-2H-quinazolin-1-ylmethyl)-1-(3-methyl-butyl)-1H-benzoimidazol-5-ylmethyl]-carbamic acid tert-butyl ester was followed using 3-cyclopropyl-1H-quinazoline-2,4-dione (44 mg, 0.22 mmol) and 2,2-dimethyl-propionic acid 4-[5-(tert-butoxycarbonylamino-methyl)-2-chloromethyl-benzoimidazol-1-yl]-butyl ester; HCl salt (107 mg, 0.219 mmol) to give 2,2-Dimethyl-propionic acid 4-[5-(tert-butoxycarbonylamino-methyl)-2-(3-cyclopropyl-2,4-dioxo-3,4-dihydro-2H-quinazolin-1-ylmethyl)-benzoimidazol-1-yl]-butyl ester (110 mg, 81%) as a white solid:
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][CH:20]=1)[C:5]([C:7](=[CH:10]NC1C=CC=CC=1)[C:8]#[N:9])=[O:6].Cl.[NH:22]([C:24]1[CH:25]=[C:26]([CH:30]=[CH:31][C:32]=1[CH3:33])[C:27]([OH:29])=[O:28])[NH2:23].C(N(CC)CC)C.[CH2:41]([OH:43])C>>[NH2:9][C:8]1[N:22]([C:24]2[CH:25]=[C:26]([CH:30]=[CH:31][C:32]=2[CH3:33])[C:27]([OH:29])=[O:28])[N:23]=[CH:10][C:7]=1[C:5](=[O:6])[C:4]1[CH:18]=[CH:19][CH:20]=[C:2]([O:43][CH3:41])[CH:3]=1
Reactant: Cc1ccc(C(=O)O)cc1NN
Reactant: N#CC(=CNc1ccccc1)C(=O)c1cccc(Cl)c1
Reactant: CCO
Agent: Cl
Solvent: CCN(CC)CC
Product: COc1cccc(C(=O)c2cnn(-c3cc(C(=O)O)ccc3C)c2N)c1

Procedure:
A solution of 2-(3-chlorobenzoyl)-3-phenylaminoacrylonitrile (63 mg, 0.22 mmol, 1.0 eq), 3-hydrazino-4-methylbenzoic acid hydrochloride (72 mg, 0.22 mmol, 1 eq), and triethylamine (31 μL, 0.22 mmol, 1.0 eq) in 10 mL of ethanol was heated to 65° C. for 20 h. After cooling, the mixture was concentrated and the residue purified by flash chromatography on silica gel packed and eluted with 7/3 hexanes/ethyl acetate to remove byproducts followed by 3/2 ethyl acetate/hexanes to elute the title compound (15 mg, 32%) as a brown solid. HPLC (4 minute 10-90 gradient) tR 2.13 min; MS m/z 352.2 [M+H]+.
Reaction SMILES: [F:1][C:2]1[C:3]([N+:13]([O-])=O)=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH3:12])[CH:6]=[CH:5]2.[H][H].[CH2:18]([OH:20])[CH3:19]>C(OCC)(=O)C.C(OC(=O)C)(=O)C.[Pd]>[C:18]([NH:13][C:3]1[C:2]([F:1])=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[CH:6][C:7]([CH3:12])=[N:8]2)(=[O:20])[CH3:19]
Reactant: Cc1ccc2c([N+](=O)[O-])c(F)ccc2n1
Reactant: [H][H]
Reactant: CCO
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CC(=O)OC(C)=O
Product: CC(=O)Nc1c(F)ccc2nc(C)ccc12

Procedure:
To a mixture of 20 g (0.1 mole) of 6-fluoro-5-nitroquinaldine in 180 ml of ethyl acetate and 20 ml of acetic anhydride were added 3 g of ten percent palladium on charcoal. The mixture was hydrogenated with hydrogen gas at 50 psi on a Paar apparatus for 20 minutes. The theoretical amount of hydrogen (25 psi) was used. On cooling, the mixture solidified to a yellow mass. About 200 ml of ethanol was added, and the mixture was heated to dissolve the product. The catalyst was filtered off through celite, and the filtrate was evaporated to dryness, leaving a yellow solid. This solid was triturated with 200 ml of water and neutralized with ten percent sodium hydroxide solution. Filtration and drying provided white crystals of 5-acetamido-6-fluoroquinaldine, m.p. 232°-235° C. The structural assignment was confirmed by infrared spectral analysis.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][C:8]([C@H:10]3[C@H:15]4[CH2:16][C@H:12]([CH2:13][CH2:14]4)[C@H:11]3[C:17]([N:19]([CH3:21])[CH3:20])=[O:18])=[CH:9][C:4]=2[CH:3]=[CH:2]1.[CH:22]([N-]C(C)C)(C)C.[Li+].IC.O>O1CCCC1>[CH3:22][C:2]1[S:1][C:5]2[CH:6]=[CH:7][C:8]([C@H:10]3[C@H:15]4[CH2:16][C@H:12]([CH2:13][CH2:14]4)[C@H:11]3[C:17]([N:19]([CH3:21])[CH3:20])=[O:18])=[CH:9][C:4]=2[CH:3]=1
Reactant: CN(C)C(=O)[C@@H]1[C@H]2CC[C@H](C2)[C@@H]1c1ccc2sccc2c1
Reactant: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CI
Solvent: O
Product: Cc1cc2cc([C@H]3[C@@H]4CC[C@@H](C4)[C@H]3C(=O)N(C)C)ccc2s1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 66.7 %

Procedure:
To a stirred solution of (1S,2R,3S,4R)-3-(1-benzothien-5-yl)-N,N-dimethylbicyclo[2,2,1]heptane-2-carboxamide (200 mg, 0.67 mmol) in dry tetrahydrofuran (5 mL) at −78° C. was added lithium diisopropylamide (1.67 mL, 3.35 mmol). The mixture was stirred at this temperature for 1 hour before iodomethane (2.3 mL, 3.35 mmol) was added. The mixture was stirred for another 10 minutes at this temperature before it was allowed to warm to room temperature. After 1 hour, water was added and the layers were separated. The aqueous phase was extracted with ethyl acetate (2×10 mL) and the extracts were washed with water (2×10 mL) dried over magnesium sulphate and evaporated in-vacuo. Column chromatography with 20% ethyl acetate in hexane provided the (1S,2R,3S,4R)-3-(2-methyl-1-benzothien-5-yl)-N,N-dimethylbicyclo [2,2,1]heptane-2-carboxamide as a glass (140 mg, 66%). M/e 314 (M+H+).
Reaction SMILES: Cl[CH:2]1[C:7](SC)([N+:8]([O-:10])=O)[C:6](Cl)=[N:5]C=N1.Cl[C:15]1[N:20]=[C:19]([S:21][CH3:22])[N:18]=[C:17]([NH:23][CH:24]2[CH2:26][CH2:25]2)[C:16]=1[N+:27]([O-])=O.C([N:32](CC)CC)C.O1CCCC1.C1(N)CC1>C(O)C>[CH:24]1([N:23]2[C:2]([C:7]3[C:6]([NH2:32])=[N:5][O:10][N:8]=3)=[N:27][C:16]3[C:17]2=[N:18][C:19]([S:21][CH3:22])=[N:20][CH:15]=3)[CH2:25][CH2:26]1
Reactant: CSc1nc(Cl)c([N+](=O)[O-])c(NC2CC2)n1
Reactant: CCN(CC)CC
Reactant: CSC1([N+](=O)[O-])C(Cl)=NC=NC1Cl
Agent: NC1CC1
Solvent: C1CCOC1
Solvent: CCO
Product: CSc1ncc2nc(-c3nonc3N)n(C3CC3)c2n1
Temperature: -60 °C
Reaction time: 3 h
Yield: 97 %

Procedure:
(6-Chloro-2-methylsulfanyl-5-nitro-pyrimidine-4-yl)-cyclopropyl-amine 4,6-Dichloro-5-methylsulfanyl-5-nitro-pyrimidine (PCT Int. Appl. (2003), WO 0302544 (14.1 g, 59 mmol), and triethylamine (8.2 ml, 59 mmol) were dissolved in ethanol (400 ml) containing tetrahydrofuran (50 ml) at −60° C. Cycloproplyamine (4.06 ml, 59 mmol) was added dropwise maintaining an internal temperature of −60° C. and stirred slowly to room temperature over 3 hours. The solution was concentrated in vacuo and the residue slurried in diethyl ether. Solid triethylamine hydrochloride was filtered, washed with diethyl ether and the filtrate concentrated in vacuo to afford a crude solid. The solid was purified by column chromatography eluting with a gradient of 40% dichloromethane in hexane to dichloromethane, to afford the title compound (17.89 g, 97%); MS (ES+) m/e 260/262 [M+H]+. Step 2. 6-chloro-N4-cyclopropyl-2-methansulfanyl-pyrimidine-4,5-diamine
Reaction SMILES: [CH2:1](/[C:3](=[CH:11]\[CH3:12])/[CH:4]=[CH:5]/[C:6]([O:8]CC)=[O:7])[CH3:2].[OH-].[Na+]>CO>[CH2:11](/[C:3](=[CH:1]\[CH3:2])/[CH:4]=[CH:5]/[C:6]([OH:8])=[O:7])[CH3:12]
Reactant: C/C=C(/C=C/C(=O)OCC)CC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: C/C=C(/C=C/C(=O)O)CC
Temperature: 25 °C
Reaction time: 20 h
Yield: 96.7 %

Procedure:
Ethyl (E,E)-4-ethyl-2,4-hexadienoate (134 g) was dissolved in methanol (200 ml) and 1N aqueous sodium hydroxide (880 ml) was added to the solution. The resulting mixtute was stirred at room temperature for 20 hours under nitrogen atmosphere. After removal of methanol, the residual aqueous solution was washed with ether. The aqueous layer was acidified with conc. hydrochloric acid and then extracted with three portions of ethyl acetate (500 ml×3). The combined extracts were washed with brine, dried over magnesium sulfate and then evaporated to dryness to give a white powder which was crystallized from ether to give (E,E)-4-ethyl-2,4-hexadienoic acid (108 g).
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([NH:17][C:18]3[C:27]4[C:22](=[CH:23][CH:24]=[C:25](I)[CH:26]=4)[N:21]=[CH:20][N:19]=3)=[CH:14][CH:15]=2)[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Sn](CCCC)(CCCC)[C:34]1[N:38]([CH3:39])[CH:37]=[N:36][CH:35]=1)CCC>>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([NH:17][C:18]3[C:27]4[C:22](=[CH:23][CH:24]=[C:25]([C:34]5[N:38]([CH3:39])[CH:37]=[N:36][CH:35]=5)[CH:26]=4)[N:21]=[CH:20][N:19]=3)=[CH:14][CH:15]=2)[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Ic1ccc2ncnc(Nc3ccc4c(cnn4Cc4ccccc4)c3)c2c1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cncn1C
Product: Cn1cncc1-c1ccc2ncnc(Nc3ccc4c(cnn4Cc4ccccc4)c3)c2c1

Procedure:
Prepared in an analogous manner to Example 6 according to Procedure B from (1-Benzyl-1H-indazol-5-yl)-(6-iodoquinazolin-4-yl)-amine and 5-(tributylstannyl)-1-methylimidazole; δH [2H6]DMSO 9.98(1H, s), 8.62(1H, s), 8.55(1H, s), 8.20(1H, s), 8.15(1H, s), 7.99(1H, dd), 7.83(2H, m), 7.70(2H, m), 7.28(6H, m), 5.70(2H, s), 3.70(3H, s); m/z (M+1)+ 432.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5](B2OC(C)(C)C(C)(C)O2)=[CH:4][CH:3]=1.Cl[C:17]1[N:22]=[N:21][C:20]([N:23]2[CH2:28][CH2:27][CH:26]([N:29]3[C:37]4[C:32](=[CH:33][CH:34]=[C:35]([F:38])[CH:36]=4)[CH2:31][CH2:30]3)[CH2:25][CH2:24]2)=[CH:19][CH:18]=1>>[F:38][C:35]1[CH:36]=[C:37]2[C:32]([CH2:31][CH2:30][N:29]2[CH:26]2[CH2:27][CH2:28][N:23]([C:20]3[N:21]=[N:22][C:17]([C:5]4[S:6][C:2]([CH3:1])=[CH:3][CH:4]=4)=[CH:18][CH:19]=3)[CH2:24][CH2:25]2)=[CH:33][CH:34]=1
Reactant: Cc1ccc(B2OC(C)(C)C(C)(C)O2)s1
Reactant: Fc1ccc2c(c1)N(C1CCN(c3ccc(Cl)nn3)CC1)CC2
Product: Cc1ccc(-c2ccc(N3CCC(N4CCc5ccc(F)cc54)CC3)nn2)s1

Procedure:
The title compound was prepared following the procedure as described in Example 1, Method A, STEP 4, reacting 5-methylthiophene-2-boronic acid pinacol ester and 1-(1-(6-chloropyridazin-3-yl)piperidin-4-yl)-6-fluoroindoline.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][C@@H:8]1[C@@:41]2([CH3:42])[C:12](=[CH:13][CH2:14][C@@H:15]3[C@@H:40]2[CH2:39][CH2:38][C@@:37]2([CH3:43])[C@H:16]3[CH2:17][CH2:18][C@@H:19]2[C@H:20]([CH2:35]I)[CH2:21][CH2:22][C:23]([F:34])([F:33])[C:24]([O:27][CH:28]([O:30][CH2:31][CH3:32])[CH3:29])([CH3:26])[CH3:25])[CH2:11][C@@H:10]([O:44][CH:45]2[CH2:50][CH2:49][CH2:48][CH2:47][O:46]2)[CH2:9]1.C([SnH](CCCC)CCCC)CCC>O1CCCC1>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][C@@H:8]1[C@@:41]2([CH3:42])[C:12](=[CH:13][CH2:14][C@@H:15]3[C@@H:40]2[CH2:39][CH2:38][C@@:37]2([CH3:43])[C@H:16]3[CH2:17][CH2:18][C@@H:19]2[C@H:20]([CH3:35])[CH2:21][CH2:22][C:23]([F:33])([F:34])[C:24]([O:27][CH:28]([O:30][CH2:31][CH3:32])[CH3:29])([CH3:26])[CH3:25])[CH2:11][C@@H:10]([O:44][CH:45]2[CH2:50][CH2:49][CH2:48][CH2:47][O:46]2)[CH2:9]1
Reactant: CCOC(C)OC(C)(C)C(F)(F)CC[C@@H](CI)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](OC5CCCCO5)C[C@H](OC5CCCCO5)[C@]4(C)[C@H]3CC[C@]12C
Agent: CCCC[SnH](CCCC)CCCC
Solvent: C1CCOC1
Product: CCOC(C)OC(C)(C)C(F)(F)CC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](OC5CCCCO5)C[C@H](OC5CCCCO5)[C@]4(C)[C@H]3CC[C@]12C
Temperature: 25 °C
Reaction time: 18 h

Procedure:
By an alternative procedure, a mixture of 0.205 g (0.00025 mol) of [1α,3β]-1,3-bis[(tetrahydro-2H-pyran-2-yl)oxy]-25-(1-ethoxyethoxy)-24,24-difluoro-21-iodocholest-5-ene, 0.987 g (0.00030 mol) of tri-n-butyltin hydride and 3 ml of tetrahydrofuran were stirred at 25° C. for 18 hr under an argon atmosphere. The mixture was evaporated to dryness and the residue was purified by chromatography on 0.06-0.20 mm silica gel to yield [1α,3β]-1,3-bis[(tetrahydro-2H-pyran-2-yl)oxy]-25-(1-ethoxyethoxy)-24,24-difluorocholest-5-ene, [α]D18 +2° (c 1, CHCl3).
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:5]=[CH:6][C:7](O)=[CH:8][CH:9]=1)=[O:3].CS(O)(=O)=[O:13].[O:16]1[CH:21]=[CH:20][CH2:19][CH2:18][CH2:17]1>C(OCC)(=O)C>[O:16]1[CH2:17][CH2:18][CH:19]([O:13][CH2:1][C:2]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=2)=[O:3])[CH2:20][CH2:21]1
Reactant: CC(=O)c1ccc(O)cc1
Reactant: CS(=O)(=O)O
Reactant: C1=COCCC1
Solvent: CCOC(C)=O
Product: O=C(COC1CCOCC1)c1ccccc1

Procedure:
4-Hydroxyacetophenone (75.00 g, 0.55 mol) was dissolved in ethyl acetate (300 ml) and a catalytic amount of methanesulfonic acid, and cooled to 0-4° C. Dihydropyran (204 ml, 2.20 moles, 4.0 eq) was slowly added. At room temperature, a white precipitate was formed, washed with water, and recrystallized from hexane. The yield was quantitative.
Reaction SMILES: [CH2:1]([N:3]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][C:5]([CH3:12])=[N:4]1)[CH3:2].[B-](F)(F)(F)[F:14].[B-](F)(F)(F)F.C1[N+]2(CCl)CC[N+](F)(CC2)C1.CCOC(C)=O>C(#N)C.O>[CH2:1]([N:3]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[C:6]([F:14])[C:5]([CH3:12])=[N:4]1)[CH3:2]
Reactant: CCn1nc(C)cc1C(=O)OC
Reactant: F[B-](F)(F)F
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Solvent: CC#N
Solvent: O
Solvent: CCOC(C)=O
Product: CCn1nc(C)c(F)c1C(=O)OC
Yield: 26.9 %

Procedure:
To a flask, methyl 1-ethyl-3-methylpyrazol-5-ylcarboxylate (1.70 g, 0.010 mol, Ref. CN1626520A) was dissolved in 30 mL of acetonitrile and the selectfluor (1-chloromethyl-4-fluoro-1,4-diazabicyclo[2.2.2]octanium bis(tetrafluoroborate)) (5.30 g, 0.015 mol) was added in batches. After heating to reflux for 1.5 h, the mixture was diluted with 50 mL of water, and then extracted with ethyl acetate (3×50 mL). The combined organic layer was washed with 150 mL of saturated aqueous sodium bicarbonate solution and 150 mL of saturated brine, dried over anhydrous MgSO4 and concentrated under reduced pressure. Column chromatography (EtOAc:P.E.=1:20 as eluent) gave 0.50 g of the title compound as a yellow oil (yield 26%).
Reaction SMILES: CNC(NC)=O.[P:7]([O:22]C1C=CC=CC=1)([O:15]C1C=CC=CC=1)[O:8]C1C=CC=CC=1.CCCC=S.[CH3:34][N:35]1[C:39](=[O:40])[N:38]([CH3:41])[CH:37]([CH2:42][CH2:43][S:44][CH3:45])P1(=O)OC1C=CC=CC=1.C1(O)C=CC=CC=1>C1(C)C=CC=CC=1>[CH3:41][N:38]([CH:37]([P:7](=[O:8])([OH:15])[OH:22])[CH2:42][CH2:43][S:44][CH3:45])[C:39]([NH:35][CH3:34])=[O:40]
Reactant: c1ccc(OP(Oc2ccccc2)Oc2ccccc2)cc1
Reactant: CSCCC1N(C)C(=O)N(C)P1(=O)Oc1ccccc1
Agent: CCCC=S
Agent: CNC(=O)NC
Solvent: Cc1ccccc1
Solvent: Oc1ccccc1
Product: CNC(=O)N(C)C(CCSC)P(=O)(O)O

Procedure:
When a mixture of 0.5 mole each of 1,3-dimethylurea, triphenyl phosphite, and 3-methylthiopropionaldehyde in 100g of toluene is warmed to 75°, a reaction is initiated and the temperature increases rapidly to 120°. After further warming at 105° for 1 hr, the resulting yellow product has a 31P nmr signal at -28.2 ppm for the cyclic ester, 1,4-dimethyl-3-(2-methylthioethyl)-2-phenoxy-1,4,2-diazaphospholidin-5-one-2-oxide. The above product is then employed in a toluene solution from which byproduct phenol is removed by stripping to 110° /1 mm, after which one-third of the residue is dissolved in 75ml of acetonitrile and 10g of water, and this solution is refluxed for 3 hr. The reaction mixture is allowed to evaporate to dryness, and the residue is extracted with ether and then with hot acetonitrile and recrystallized twice from acetic acid to give a white solid: mp 164.5°-167°; 31P nmr (DMSO-d6) -21.4 ppm; 1H nmr 9.6 (broad, 2, OH), 4.5 (m, 1, PCH), 2.8 (s, NCH3), 2.6 (s, NCH3), 2.0 (s, SCH3), 1.9-2.6 (m, CH2CH2S).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.Br[C:9]([F:16])([F:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11].C(OC(C)C)(=O)C>[Cu].CN(C=O)C>[F:15][C:9]([F:16])([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1)[C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: Brc1ccccn1
Reactant: CCOC(=O)C(F)(F)Br
Agent: [Cu]
Solvent: CN(C)C=O
Solvent: CC(=O)OC(C)C
Product: CCOC(=O)C(F)(F)c1ccccn1
Temperature: 75 °C
Reaction time: 0.17 h

Procedure:
2-Bromopyridine (20 g), ethyl bromodifluoroacetate (27.2 g) and DMF (120 mL) were added and stirred for 10 minutes under nitrogen. Copper powder was added to the reaction mixture and heated to 70-80° C. for 45 minutes. The reaction mixture was cooled to RT and 400 mL of isopropyl acetate (IPAc) was added. The reaction mixture was quenched with the aqueous potassium dihydrogen phosphate at 0-10° C. and stirred for 30 minutes. The reaction mixture was filtered off and the residue obtained was washed with ethyl acetate. The organic layer was collected and washed with brine solution and dried over sodium sulphate then distilled under vacuum. (Crude weight=20 g).
Reaction SMILES: [C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]3[C:30]4[C:25](=[CH:26][C:27]([O:33][CH2:34][CH2:35][CH2:36]Cl)=[C:28]([O:31][CH3:32])[CH:29]=4)[N:24]=[CH:23][N:22]=3)[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:38][N:39]1[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]1.C(N(C(C)C)CC)(C)C>CN(C=O)C.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]3[C:30]4[C:25](=[CH:26][C:27]([O:33][CH2:34][CH2:35][CH2:36][N:42]5[CH2:43][CH2:44][N:39]([CH3:38])[CH2:40][CH2:41]5)=[C:28]([O:31][CH3:32])[CH:29]=4)[N:24]=[CH:23][N:22]=3)[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1cc2c(Oc3cccc(NC(=O)Nc4cc(C(C)(C)C)on4)c3)ncnc2cc1OCCCCl
Reactant: CN1CCNCC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3cccc(NC(=O)Nc4cc(C(C)(C)C)on4)c3)ncnc2cc1OCCCN1CCN(C)CC1
Temperature: 60 °C
Yield: 18.3 %

Procedure:
To a solution of (1-(5-tert-butyl-isoxazol-3-yl)-3-{3-[7-(3-chloro-propoxy)-6-methoxy-quinazolin-4-yloxy]-phenyl}-urea (225 mg, 0.427 mmol) from Example 27B in DMF (3 mL) was added N-methyl piperazine (0.142 mL, 1.281 mmol) followed by diisopropyl ethylamine (0.223 mL, 1.281 mmol) and tetrabutyl ammonium iodide (157.72 mg, 0.427 mmol). The reaction mixture was heated at 60° C. for 15 h. Formation of the product was determined by LCMS. The crude reaction mixture was purified by preparative HPLC (using a phenyl-hexyl reverse phase column eluted with gradient of solvent A=0.05% HOAc/H2O and solvent B=0.05% HOAc/CH3CN). The appropriate fractions were concentrated followed by trituration with ether to afford 1-(5-tert-butylisoxazol-3-yl)-3-(3-(6-methoxy-7-(3-(4-methylpiperazin-1-yl)propoxy)quinazolin-4-yloxy)phenyl)urea (46 mg, 18%) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 9.68 (s, 1H), 9.25 (s, 1H), 8.55 (s, 1H), 7.60 (d, 2H), 7.40 (m, 2H), 7.25 (d, 1H), 6.95 (d, 1H), 6.50 (s, 1H), 4.25 (m, 2H), 3.98 (s, 3H), 2.55-2.30 (m, 10H), 2.15 (s, 3H), 1.98 (m, 2H), 1.28 (s, 9H); LC-MS (ESI)m/z 590 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:36]=[CH:37][CH:38]=1)[CH2:5][O:6][C:7]1[C:12]([Br:13])=[CH:11][C:10]([CH:14]2[C:23]3[C:22](=[O:24])[CH2:21][CH:20]([CH2:25][CH2:26][CH3:27])[CH2:19][C:18]=3[NH:17][C:16]([CH3:28])=[C:15]2[C:29]#[N:30])=[CH:9][C:8]=1[NH:31][S:32]([CH3:35])(=[O:34])=[O:33].N1C=CC=CC=1.[CH3:45][S:46](Cl)(=[O:48])=[O:47]>ClCCl.C(OCC)(=O)C>[Br:13][C:12]1[C:7]([O:6][CH2:5][C:4]2[CH:36]=[CH:37][CH:38]=[C:2]([NH:1][S:46]([CH3:45])(=[O:48])=[O:47])[CH:3]=2)=[C:8]([NH:31][S:32]([CH3:35])(=[O:34])=[O:33])[CH:9]=[C:10]([CH:14]2[C:23]3[C:22](=[O:24])[CH2:21][CH:20]([CH2:25][CH2:26][CH3:27])[CH2:19][C:18]=3[NH:17][C:16]([CH3:28])=[C:15]2[C:29]#[N:30])[CH:11]=1
Reactant: CS(=O)(=O)Cl
Reactant: CCCC1CC(=O)C2=C(C1)NC(C)=C(C#N)C2c1cc(Br)c(OCc2cccc(N)c2)c(NS(C)(=O)=O)c1
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCCC1CC(=O)C2=C(C1)NC(C)=C(C#N)C2c1cc(Br)c(OCc2cccc(NS(C)(=O)=O)c2)c(NS(C)(=O)=O)c1
Reaction time: 18 h

Procedure:
To a solution of N-[2-(3-amino-benzyloxy)-3-bromo-5-(3-cyano-2-methyl-5-oxo-7-propyl-1,4,5,6,7,8-hexahydro-quinolin-4-yl)-phenyl]-methanesulfonamide (709 mg) and pyridine (286 μl) in dichloromethane (20 ml) was added methanesulfonyl chloride (138 μl). After stirring for 18 h, the mixture was diluted with ethyl acetate and washed with water. The organic layer was dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by preparative HPLC (Method B).
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]3([CH2:14][CH2:13]3)[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([OH:28])=O)=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[NH2:64][N:65]1[CH2:70][CH2:69][N:68]([CH2:71][CH2:72][OH:73])[CH2:67][CH2:66]1>C(Cl)Cl>[CH:1]1([N:6]2[CH2:12][C:11]3([CH2:14][CH2:13]3)[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([NH:64][N:65]5[CH2:70][CH2:69][N:68]([CH2:71][CH2:72][OH:73])[CH2:67][CH2:66]5)=[O:28])=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC1(CC1)C(=O)N2C
Reactant: NN1CCN(CCO)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(C(=O)NN2CCN(CCO)CC2)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC1(CC1)C(=O)N2C
Temperature: 25 °C
Reaction time: 16 h
Yield: 38.6 %

Procedure:
4-(9′-Cyclopentyl-5′-methyl-6′-oxo-5′,6′,8′,9′-tetrahydrospiro[cyclopropane-1,7′-pyrimido[4,5-b][1,4]diazepine]-2′-ylamino)-3-methoxybenzoic acid (Intermediate 5) (48 mg, 0.11 mmol, 1 eq), DIPEA (36 μL, 0.22 mmol, 2 eq) and TBTU (39 mg, 0.12 mmol, 1.1 eq) were added to 5 mL DCM and the resulting solution stirred at rt for 15 min before the addition of 2-(4-aminopiperazin-1-yl)ethanol (19 mg, 0.13 mmol, 1.2 eq). The RM was then stirred at rt for 16 hours before concentrating in vacuo and purifying by preparative RP-HPLC-MS (Preparative 1) to provide 4-(9′-cyclopentyl-5′-methyl-6′-oxo-5′,6′,8′,9′-tetrahydrospiro[cyclopropane-1,7′-pyrimido[4,5-b][1,4]diazepine]-2′-ylamino)-N-(4-(2-hydroxyethyl)piperazin-1-yl)-3-methoxybenzamide (24 mg, 39%).