Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[OH:20])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].Cl[CH2:24][C:25]([N:27]([CH2:30][CH3:31])[CH2:28][CH3:29])=[O:26]>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[O:20][CH2:24][C:25](=[O:26])[N:27]([CH2:30][CH3:31])[CH2:28][CH3:29])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCN(CC)C(=O)CCl
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccccc2O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCN(CC)C(=O)COc1ccccc1N1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 80 °C
Reaction time: 0.17 h
Yield: 56.1 %

Procedure:
4-(2-hydroxy-phenyl)-piperazine-1-carboxylic acid tert-butyl ester (500 mg, 1.8 mmol) was dissolved in DMF (2 mL), and sodium hydride (1.98 mmol) was added. The mixture was stirred for about 10 minutes and 2-chloro-N,N-diethyl-acetamide (269 mg, 1.8 mmol) was added. The mixture was heated to 80° C. for about 2 hours. The mixture was concentrated and deprotected, which was then chromatographed to give about 395 mg of the final compound as a clear oil (75%). MS found 292.2
Reaction SMILES: [C:1]([N:5]1[CH2:11][CH:10]([N:12]2[C:16]3[C:17]([Cl:21])=[CH:18][CH:19]=[CH:20][C:15]=3[N:14]=[C:13]2[NH:22][C:23](=[O:31])[C:24]2[CH:29]=[CH:28][N:27]=[C:26]([CH3:30])[CH:25]=2)[CH2:9][N:8](C(OC(C)(C)C)=O)[CH2:7][CH2:6]1)(=[O:4])[CH:2]=[CH2:3].FC(F)(F)C(O)=O>C(Cl)Cl>[C:1]([N:5]1[CH2:11][CH:10]([N:12]2[C:16]3[C:17]([Cl:21])=[CH:18][CH:19]=[CH:20][C:15]=3[N:14]=[C:13]2[NH:22][C:23](=[O:31])[C:24]2[CH:29]=[CH:28][N:27]=[C:26]([CH3:30])[CH:25]=2)[CH2:9][NH:8][CH2:7][CH2:6]1)(=[O:4])[CH:2]=[CH2:3]
Reactant: C=CC(=O)N1CCN(C(=O)OC(C)(C)C)CC(n2c(NC(=O)c3ccnc(C)c3)nc3cccc(Cl)c32)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C=CC(=O)N1CCNCC(n2c(NC(=O)c3ccnc(C)c3)nc3cccc(Cl)c32)C1
Reaction time: 1.5 h

Procedure:
A solution of Example 12 (150 mg, 0.278 mmol) in CH2Cl2 (2 mL) was treated with a 1:1 solution of 2,2,2-trifluoroacetic acid in CH2Cl2 (4 mL) and stirred for 90 min. The volatiles were removed under reduced pressure, the residue partitioned between CH2Cl2 and saturated aqueous Na2CO3, the layers separated, and the aqueous phase extracted with CH2Cl2 (2×). The combined organics were washed with brine, dried over Na2SO4, and concentrated under reduced pressure to afford the title compound (Example 13). 1H NMR (400 MHz, MeOD) δ 8.58 (d, J=5.2 Hz, 1H), 7.96 (d, J=8.8 Hz, 1H), 7.88 (s, 1H), 7.60-7.47 (m, 1H), 7.31 (s, 1H), 7.30-7.21 (m, 1H), 6.83 (dd, J=10.6, 16.8 Hz, 1H), 6.31 (d, J=16.7 Hz, 1H), 6.17-5.85 (m, 1H), 5.78 (dd, J=10.5, 34.2 Hz, 1H), 4.79-4.39 (m, 1H), 4.37-4.12 (m, 1H), 4.12-3.56 (m, 1H), 3.55-3.34 (m, 1H), 3.25-2.97 (m, 3H), 2.96-2.82 (m, 1H), 2.65 (s, 3H); MS calculated for C22H24ClN6O2 (M+H+) 439.16. found 439.2.
Reaction SMILES: C(OC([NH:8][C@H:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]1[NH:15][C:16]1[N:21]=[C:20](Cl)[C:19]2[C:23](=[O:33])[N:24](C(OC(C)(C)C)=O)[CH2:25][C:18]=2[C:17]=1[F:34])=O)(C)(C)C.C([Sn](CCCC)(CCCC)[C:40]1[CH:41]=[C:42]2[N:47]([CH:48]=1)[CH2:46][CH2:45][O:44][CH2:43]2)CCC.[C:57]([OH:63])([C:59]([F:62])([F:61])[F:60])=[O:58]>C1(C)C=CC=CC=1.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:57]([OH:63])([C:59]([F:62])([F:61])[F:60])=[O:58].[NH2:8][C@H:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]1[NH:15][C:16]1[N:21]=[C:20]([C:40]2[CH:41]=[C:42]3[N:47]([CH:48]=2)[CH2:46][CH2:45][O:44][CH2:43]3)[C:19]2[C:23](=[O:33])[NH:24][CH2:25][C:18]=2[C:17]=1[F:34]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cc2n(c1)CCOC2
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCC[C@H]1Nc1nc(Cl)c2c(c1F)CN(C(=O)OC(C)(C)C)C2=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Product: N[C@H]1CCCC[C@H]1Nc1nc(-c2cc3n(c2)CCOC3)c2c(c1F)CNC2=O
Temperature: 90 °C
Reaction time: 1 h
Yield: 6.3 %

Procedure:
In a 30 mL sealed cap glass tube, tert-butyl 6-((1R,2S)-2-(tert-butoxycarbonylamino)cyclohexylamino)-4-chloro-7-fluoro-3-oxo-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate (150 mg, 0.301 mmol), 7-(tributylstannyl)-3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazine (124 mg, 0.301 mmol) and tetrakis(triphenylphosphine)palladium(0) (174 mg, 0.150 mmol) were dissolved in toluene (5 mL). The cap was sealed and the reaction mixture was heated at 90° C. in an oil bath for 2 hours. Following work-up, the intermediate, tert-butyl 6-(((1R,2S)-2-((tert-butoxycarbonyl)amino)cyclohexyl)amino)-4-(3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazin-7-yl)-7-fluoro-3-oxo-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate, was purified by preparative HPLC eluting with a gradient of 55-95% ACN (0.035% TFA) and H2O (0.05% TFA). The pure fractions were combined and the solvent stripped by rotary evaporation to give a solid intermediate. The intermediate was subsequently dissolved in TFA (3 mL) and the reaction mixture was stirred for 1 hour. The mixture was concentrated, dissolved in DMSO (5 mL), and purified via preparatory HPLC eluting with a gradient of 20-50% ACN (0.035% TFA) and H2O (0.05% TFA). The pure fractions were combined, evaporated to a minimal volume, and lyophilized to give a TFA salt of the title compound as a pale yellow solid (7.3 mg, 6.3%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.44 (d, J=7.33 Hz, 2H), 1.59 (br s, 1H), 1.63-1.92 (m, 4H), 3.98 (d, J=1.77 Hz, 3H), 4.26-4.46 (m, 3H), 4.74 (s, 2H), 6.54-6.71 (m, 2H), 7.74 (br s, 3H), 8.17-8.36 (m, 2H). ESI-MS m/z [M+H]+ calc'd for C20H24FN5O2, 386. found, 386.
Reaction SMILES: [CH:1]([OH:4])([CH3:3])[CH3:2].[Cl:5][C:6](=[C:10]([Cl:12])[Cl:11])[C:7](Cl)=[O:8]>C(Cl)Cl>[Cl:11][C:10]([Cl:12])=[C:6]([Cl:5])[C:7]([O:4][CH:1]([CH3:3])[CH3:2])=[O:8]
Reactant: O=C(Cl)C(Cl)=C(Cl)Cl
Reactant: CC(C)O
Solvent: ClCCl
Product: CC(C)OC(=O)C(Cl)=C(Cl)Cl

Procedure:
A solution of 6.5 gms (0.108 moles) isopropyl alcohol, 20 gms (0.013 moles) trichloro acryloyl chloride and 100 ml methylene chloride was stirred for 72 hours. The solvent was stripped and the product was used in subsequent reactions without further purification.
Reaction SMILES: [Cl:1][C:2]1[C:20]([N:21](OCC)[C:22](=[O:38])[CH:23](C=C=O)[N:24]2C(=O)C3=CC=CC=[C:26]3[C:25]2=[O:34])=[CH:19][CH:18]=[C:17]([Cl:42])[C:3]=1[CH2:4][O:5][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:15]=1[N:14]=[C:13]([CH3:16])[CH:12]=[CH:11]2.CN>ClCCl.CO>[Cl:1][C:2]1[C:20]([N:21]2[CH2:26][C:25](=[O:34])[NH:24][CH2:23][C:22]2=[O:38])=[CH:19][CH:18]=[C:17]([Cl:42])[C:3]=1[CH2:4][O:5][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:15]=1[N:14]=[C:13]([CH3:16])[CH:12]=[CH:11]2
Reactant: CCON(C(=O)C(C=C=O)N1C(=O)c2ccccc2C1=O)c1ccc(Cl)c(COc2cccc3ccc(C)nc23)c1Cl
Agent: CN
Solvent: CO
Solvent: ClCCl
Product: Cc1ccc2cccc(OCc3c(Cl)ccc(N4CC(=O)NCC4=O)c3Cl)c2n1
Reaction time: 24 h
Yield: 49.8 %

Procedure:
To the solution of 8-[2,6-dichloro-3-[N-ethoxy-carbonylmethyl-N-(phthalimidoacetyl)amino]benzyloxy]-2-methylquinoline (527 mg) in dichloromethane (5.3 ml) was added 30% solution of methylamine in methanol (2 ml) at ambient temperature. After stirring for 24 hours, the reaction mixture was evaporated in vacuo. The residue was, purified by flash column chromatography (silica gel 50 ml) eluting with dichloromethane/methanol (20/1, V/V) and by crystallizing from isopropyl ether to give 8-[2,6-dichloro-3-(2,5-dioxopiperazin-1-yl)benzyloxy]-2-methylquinoline (187 mg) as colorless crystals.
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([CH2:8][C:9]#[N:10])=O)=[CH:4][CH:3]=1.C([O-])(=O)C.[Na+].[NH2:18][OH:19].Cl>O.C(O)C>[F:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]2[CH:8]=[C:9]([NH2:10])[O:19][N:18]=2)=[CH:4][CH:3]=1
Reactant: N#CCC(=O)c1ccc(F)cc1
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Nc1cc(-c2ccc(F)cc2)no1
Temperature: 25 °C

Procedure:
(4-Fluorobenzoyl)acetonitrile (10 g., 0.063 mol) and 200 ml. of ethyl alcohol were placed in a 500 ml. 1-neck flask. To the reaction mixture was added in portionwise fashion a solution comprised of 24 g. of sodium acetate and 18.3 g. of hydroxylamine.HCl in 200 ml. of H2O. After refluxing for three days, the reaction mixture was cooled to room temperature. About half the solvent was removed and then an oily layer formed. The residue was extracted thoroughly in ether and then the combined ether extracts were washed in water, brine, and then dried over MgSO4. When the ether was removed orange crystals formed which were recrystallized from diethyl ether/hexane, m.p., 98°-99° C.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[C:8]([O:14][CH3:15])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[C:16](Cl)(Cl)=[O:17]>C(Cl)(Cl)Cl.O1CCCC1>[CH3:15][O:14][C:8]1[C:9]([N+:11]([O-:13])=[O:12])=[CH:10][C:2]2[NH:1][C:16](=[O:17])[O:5][C:4](=[O:6])[C:3]=2[CH:7]=1
Reactant: O=C(Cl)Cl
Reactant: COc1cc(C(=O)O)c(N)cc1[N+](=O)[O-]
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: COc1cc2c(=O)oc(=O)[nH]c2cc1[N+](=O)[O-]
Temperature: 60 °C
Reaction time: 12 h
Yield: 100 %

Procedure:
2.0 g (9.4 mmol) of 2-amino-5-methoxy-4-nitrobenzoic acid were dissolved in 20 ml of chloroform and 10 ml of tetrahydrofuran, and 20 ml of 20% strength phosgene solution (1.8 M in toluene) were added. After 3 hours under reflux, a further 10 ml of phosgene solution were added at 60° C., and the mixture was stirred at 60° C. for a further 12 hours. The phosgene was distilled off and the residue was concentrated in vacuo after addition of toluene several times. 2.2 g (100%) of the desired product were obtained.
Reaction SMILES: [F:1][C:2]1[C:10]([F:11])=[C:9]([F:12])[C:8]([F:13])=[CH:7][C:3]=1[C:4](O)=[O:5].S(Cl)([Cl:16])=O>CCCCCC.CN(C)C=O>[F:1][C:2]1[C:10]([F:11])=[C:9]([F:12])[C:8]([F:13])=[CH:7][C:3]=1[C:4]([Cl:16])=[O:5]
Reactant: O=C(O)c1cc(F)c(F)c(F)c1F
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: O=C(Cl)c1cc(F)c(F)c(F)c1F
Yield: 100.8 %

Procedure:
In a 500 ml round bottom flask equipped with a magnetic stirrer, a reflux condenser and an inert gas supply 97.05 g of 2,3,4,5-tetrafluorobenzoic acid (2, 500 mmol) were suspended under argon and with stirring in 100 ml of n-hexane and 0.5 ml of N,N-dimethyl formamide. To this suspension 44 ml of thionyl chloride (d=1.64, 600 mmol) were added at room temperature, and the mixture was heated to reflux for 15 hours. The light yellowish solution was evaporated in a rotary evaporator at 50° C. reducing the pressure first to 200 torr until distillation ceased, then to 30 torr holding this pressure for 3 minutes to yield 107.1 g of the crude acid chloride 2a as a pale yellow liquid, which was kept under argon and directly used for step 3).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Br:8])[CH:5]=[CH:4][C:3]=1[OH:9].C([O-])(O)=O.[Na+].Cl[CH2:16][C:17](Cl)=[O:18]>O.COCCOC>[Br:8][C:6]1[CH:5]=[CH:4][C:3]2[O:9][CH2:16][C:17](=[O:18])[NH:1][C:2]=2[CH:7]=1
Reactant: O=C(Cl)CCl
Reactant: Nc1cc(Br)ccc1O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: O=C1COc2ccc(Br)cc2N1
Temperature: 15 °C
Reaction time: 0.5 h
Yield: 97.3 %

Procedure:
To a mixture of 2-amino-4-bromophenol (50 g, 266 mmol) and NaHCO3 (67.0 g, 798 mmol) in water (200 mL) and DME (200 mL) was added 2-chloroacetyl chloride (45.1 g, 399 mmol) at 0° C. The mixture was stirred at 15° C. for 0.5 h and then stirred at 80° C. overnight. The mixture was cooled to ambient temperature and quenched with water (400 mL). The precipitate was collected by suction filtration, washed with water (200 mL) and petroleum ether (300 mL) in turn, and dried to give 6-bromo-4H-benzo[1,4]oxazin-3-one (59 g, 97%) as a gray solid. 1H NMR (DMSO-d6, 400 MHz): δ 7.07 (d, J=8.4 Hz, 1H), 7.02 (s, 1H), 6.90 (d, J=8.4 Hz, 1H), 4.59 (s, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@@H:18]([C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=3)[N:11]3[C:12](=[O:17])[C:13](I)=[CH:14][CH:15]=[C:10]3[N:9]2[S:26]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[F:35])(=[O:28])=[O:27])=[CH:4][CH:3]=1.[CH3:36][C:37]([CH3:42])=[CH:38]B(O)O>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@@H:18]([C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=3)[N:11]3[C:12](=[O:17])[C:13]([CH:36]=[C:37]([CH3:42])[CH3:38])=[CH:14][CH:15]=[C:10]3[N:9]2[S:26]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[F:35])(=[O:28])=[O:27])=[CH:4][CH:3]=1
Reactant: CC(C)=CB(O)O
Reactant: O=c1c(I)ccc2n1[C@H](c1ccc(Cl)cc1)[C@H](c1ccc(Cl)cc1)N2S(=O)(=O)c1ccccc1F
Product: CC(C)=Cc1ccc2n(c1=O)[C@H](c1ccc(Cl)cc1)[C@H](c1ccc(Cl)cc1)N2S(=O)(=O)c1ccccc1F

Procedure:
rac-cis-2,3-Bis-(4-chloro-phenyl)-1-(2-fluoro-benzenesulfonyl)-6-(2-methyl-propenyl)-2,3-dihydro-1H-imidazo[1,2-a]pyridin-5-one was prepared according to general method D by reaction of rac-cis-2,3-bis-(4-chloro-phenyl)-1-(2-fluoro-benzenesulfonyl)-2,3-dihydro-6-iodo-1H-imidazo[1,2-a]pyridin-5-one with 2,2-dimethylethenylboronic acid. The compound was isolated by preparative HPLC. The expected product was characterized by LC/MS (M+H) where the mass was observed as 569.06; the expected mass is 568. LC/MS indicated a purity of 100% as measured by UV 214 nM.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[CH:8][C:4]=1[C:5](Cl)=[O:6].[CH2:12]([N:14]1[CH2:18][CH:17]([NH2:19])[CH2:16][N:15]1[CH2:20][CH3:21])[CH3:13]>C1(C)C=CC=CC=1>[CH2:12]([N:14]1[CH2:18][CH:17]([NH:19][C:5](=[O:6])[C:4]2[CH:8]=[CH:9][CH:10]=[CH:11][C:3]=2[O:2][CH3:1])[CH2:16][N:15]1[CH2:20][CH3:21])[CH3:13]
Reactant: CCN1CC(N)CN1CC
Reactant: COc1ccccc1C(=O)Cl
Solvent: Cc1ccccc1
Product: CCN1CC(NC(=O)c2ccccc2OC)CN1CC
Temperature: 25 °C
Reaction time: 2 h
Yield: 77.9 %

Procedure:
A solution of 2-methoxybenzoyl chloride (3.41 g, 0.020 mole) in 50 ml of toluene was added dropwise to a stirred solution of 1,2-diethyl-4-aminopyrazolidine (2.86 g. 0.020 mole) in 100 ml of toluene. The mixture was stirred at ambient temperature for 2 hrs, and then at reflux temperature for 2 hrs. After standing for 16 hrs, the mixture was extracted with 100 ml of 10% sodium bicarbonate solution. The toluene layer was dried over magnesium sulfate and concentrated to give 4.32 g (81.6%) of oil. The liquid was distilled over magnesium sulfate, b.p. 160° C./0.020 mm Hg, to give 2.52 g of a clear, yellow oil.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[C:9]3([CH2:15][CH2:14]3)[CH2:8][N:7]([CH:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)[C:6]=2[N:21]=1.[NH2:22][C:23]1[CH:47]=[CH:46][C:26]([C:27]([NH:29][C@H:30]2[CH2:35][CH2:34][C@H:33]([N:36]3[CH2:41][CH2:40][N:39]([CH2:42][CH:43]4[CH2:45][CH2:44]4)[CH2:38][CH2:37]3)[CH2:32][CH2:31]2)=[O:28])=[CH:25][C:24]=1[O:48][CH3:49].C(O)(C(F)(F)F)=O>>[CH:16]1([N:7]2[CH2:8][C:9]3([CH2:15][CH2:14]3)[C:10](=[O:13])[N:11]([CH3:12])[C:5]3[CH:4]=[N:3][C:2]([NH:22][C:23]4[CH:47]=[CH:46][C:26]([C:27]([NH:29][C@H:30]5[CH2:31][CH2:32][C@H:33]([N:36]6[CH2:41][CH2:40][N:39]([CH2:42][CH:43]7[CH2:45][CH2:44]7)[CH2:38][CH2:37]6)[CH2:34][CH2:35]5)=[O:28])=[CH:25][C:24]=4[O:48][CH3:49])=[N:21][C:6]2=3)[CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: COc1cc(C(=O)N[C@H]2CC[C@H](N3CCN(CC4CC4)CC3)CC2)ccc1N
Reactant: CN1C(=O)C2(CC2)CN(C2CCCC2)c2nc(Cl)ncc21
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(C(=O)N[C@H]2CC[C@H](N3CCN(CC4CC4)CC3)CC2)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC1(CC1)C(=O)N2C

Procedure:
2′-Chloro-9′-cyclopentyl-5′-methyl-8′,9′-dihydrospiro[cyclopropane-1,7′-pyrimido[4,5-b][1,4]diazepin]-6′(5′H)-one (Intermediate 2) (0.14 g, 0.45 mmol, 1 eq), 4-amino-N-(trans-4-(4-(cyclopropylmethyl)piperazin-1-yl)cyclohexyl)-3-methoxybenzamide (Intermediate 11) (0.26 g, 0.67 mmol, 1.5 eq) and TFA (0.17 mL, 2.2 mmol, 5 eq) in TFE (3 mL) were heated together at 80° C. for 18 hours. Further quantity of Intermediate 2 (0.14 g) was added and the reaction further heated for 48 hours. RM was concentrated in vacuo and the residue was purified by flash column chromatography on silica eluting with 0→20% ammonia/MeOH in DCM gradient followed by preparative HPLC (Preparative—4) then finally preparative RP-HPLC-MS (Preparative 1) to give 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-((trans)-4-(4-(cyclopropylmethyl)piperazin-1-yl)cyclohexyl)-3-methoxybenzamide (0.11 g, 25%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]([O:8][CH3:9])=[CH:6][CH:7]=1.[CH2:10]([O:12][C:13](=[O:24])[C:14](=[CH:20]OCC)[C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH3:11].C(O)C>C1(C)C=CC=CC=1>[CH2:10]([O:12][C:13](=[O:24])[C:14](=[CH:20][NH:1][C:2]1[CH:3]=[N:4][C:5]([O:8][CH3:9])=[CH:6][CH:7]=1)[C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH3:11]
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: COc1ccc(N)cn1
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCOC(=O)C(=CNc1ccc(OC)nc1)C(=O)OCC
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 91.5 %

Procedure:
A solution of 3-amino-6-methoxy-pyridine (200.0 g, 1611.05 mmol, 1.0 eq) and 2-ethoxymethylene-malonic acid diethyl ester (348.4 g, 1611.05 mmol, 1.0 eq) in toluene (650 mL) is heated to reflux and the ethanol formed is removed by azeotropic distillation. After 2.5 hours at 115° C., the reaction mixture is cooled to room temperature, the solvent is removed and the resulting solid is washed with 500 mL of hexane then dried under vacuum to afford 2-[(6-methoxy-pyridin-3-ylamino)-methylene]-malonic acid diethyl ester as a red solid (434.0 g, 90% yield).
Reaction SMILES: O[CH2:2][C:3]1[N:7]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][C:9]=2[C:15]2([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[F:26])[S:19][CH2:18][CH2:17][S:16]2)[C:6]([CH3:27])=[N:5][CH:4]=1.S(Cl)([Cl:30])=O>C(Cl)(Cl)Cl>[Cl:30][CH2:2][C:3]1[N:7]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][C:9]=2[C:15]2([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[F:26])[S:19][CH2:18][CH2:17][S:16]2)[C:6]([CH3:27])=[N:5][CH:4]=1
Reactant: Cc1ncc(CO)n1-c1ccc(Cl)cc1C1(c2ccccc2F)SCCS1
Reactant: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Product: Cc1ncc(CCl)n1-c1ccc(Cl)cc1C1(c2ccccc2F)SCCS1
Reaction time: 0.5 h

Procedure:
The hydroxy derivative of formula VIII (4 gm) was stirred in 20 ml of chloroform at 0° to 5° C. and to this was added thionyl chloride (2.5 gm) and stirred at 5°-10° C. for 30 minutes, and then for 1 hr. at 20°-25° C. Chloroform was recovered completely and to this was added 20 ml of THF. The precipitated solid was filtered under nitrogen atmosphere and washed well with THF (20 ml). The title compound was obtained as an off-white powder (4.6 gm) as its hydrochloride. Melting point 147°-150° C.; NMR (DMSO, 200 MHz): δ 2.19 (S, 3H, CH3), 3.2-3.5 (m, 4H, S--CH2 ×CH2 --S), 4.5-4.9 (dd, 2H, CH2,Cl) 7.19-8.34 (m, 3H, aromatic-H); IR (KBr): 3500, 1610, 1480, 1100, 780 cm-1.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[C:7](Br)[CH:6]=[CH:5][C:4]=1[NH:10][S:11]([NH2:14])(=[O:13])=[O:12])#[N:2].[CH3:15][C:16]([CH3:21])=[CH:17]B(O)O>>[C:1]([C:3]1[CH:8]=[C:7]([CH:15]=[C:16]([CH3:21])[CH3:17])[CH:6]=[CH:5][C:4]=1[NH:10][S:11]([NH2:14])(=[O:13])=[O:12])#[N:2]
Reactant: CC(C)=CB(O)O
Reactant: N#Cc1cc(Br)ccc1NS(N)(=O)=O
Product: CC(C)=Cc1ccc(NS(N)(=O)=O)c(C#N)c1

Procedure:
Prepared as in Example 77a from N-(2-cyano-4-bromophenyl)sulfamide (Example 83b) and 2-methylprop-1-enylboronic acid.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([C:16](=[O:18])[CH3:17])[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])([CH3:3])[CH3:2].[Br:19]Br>CCOCC.C(Cl)(Cl)Cl>[Br:19][CH2:17][C:16]([C:7]1[CH:6]=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[C:10]([OH:11])=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[CH:8]=1)=[O:18]
Reactant: BrBr
Reactant: CC(=O)c1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Solvent: CCOCC
Solvent: ClC(Cl)Cl
Product: CC(C)(C)c1cc(C(=O)CBr)cc(C(C)(C)C)c1O
Reaction time: 1 h

Procedure:
A mixture of (3,5-Di-t-butyl-4-hydroxyphenyl)ethanone (EXAMPLE 58, 800 mg) in ether (15 ml) and chloroform (10 ml) is cooled to 0° and then treated in a dropwise manner with a mixture containing 0. 17 ml of bromine dissolved in 5 ml of chloroform. The reaction mixture is allowed to warm to 20°-25° and stirred for 1 hr. Standard work-up gives the crude product (1.21 g) which is chromatographed on 180 g of silica gel. The column is packed and eluted with chloroform. An initial fraction of 200 ml is collected, followed by 7 ml fractions. Based on their TLC homogeneity, fractions 36-65 are combined and concentrated. Recrystallization from hexane gives the title compound, mp 105°-106°; IR (mineral oil) 3590, 2955, 2925, 2871, 2856, 1685, 1594, 1581, 1466, 1459, 1451, 1438, 1426, 1366, 1328, 1302, 1282, 1242, 1194, 1153, 1139, 1121, 860 and 615 cm-1 ; NMR (CDCl3 ; TMS) 7.88, 5.85, 4.40 and 1.47δ; CMR (CDCl3 ; TMS) 190.6, 159.0, 135.9, 126.8, 125.6, 34.2, 30.6 and 29.9δ; MS (m/z) M+ found=327, other ions at m/z 326, 311,233, 219, 203, 189, 175, 115, 101, 87, 57 and 40.
Reaction SMILES: C([Li])(C)(C)C.[OH:6][CH:7]([C:20]1[CH:21]=[C:22]([Si:25]([CH3:28])([CH3:27])[CH3:26])[O:23][CH:24]=1)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19].[Br:29][CH2:30][CH2:31][CH2:32][C:33](Cl)=[O:34]>CCCCC.O1CCCC1>[Br:29][CH2:30][CH2:31][CH2:32][C:33]([O:6][CH:7]([C:20]1[CH:21]=[C:22]([Si:25]([CH3:28])([CH3:27])[CH3:26])[O:23][CH:24]=1)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])=[O:34]
Reactant: CCCCCCCCCCCCC(O)c1coc([Si](C)(C)C)c1
Reactant: O=C(Cl)CCCBr
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Solvent: CCCCC
Product: CCCCCCCCCCCCC(OC(=O)CCCBr)c1coc([Si](C)(C)C)c1
Reaction time: 0.33 h

Procedure:
tert-Butyl lithium (a 1.7 M solution in pentane; 0.25 ml, 0.43 mmol) was added dropwise to a solution of 4-(1-hydroxytridecyl)-2-trimethylsilylfuran (120.4 mg, 0.36 mmol) in tetrahydrofuran (6 ml) at 0° under argon. After 20 minutes, a solution of 4-bromobutyryl chloride (66 mg, 0.43 mmol) in tetrahydrofuran (1 ml) was added. Stirring was continued at room temperature for 16 hours and the mixture was quenched with water. Extraction (ethyl ether) and evaporation of the dried (magnesium sulphate) extracts gave an oil, which was purified by preparative TLC (20×20 cm, 500μ silica plate; developed with 10% ethyl ether/hexane). The title ester was obtained as a yellow oil.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][Cl:5].[NH:6]1[CH2:11][CH2:10][O:9][CH2:8][CH2:7]1.Cl>C1(C)C=CC=CC=1>[ClH:5].[Cl:5][CH2:4][CH2:3][CH2:2][N:6]1[CH2:11][CH2:10][O:9][CH2:8][CH2:7]1
Reactant: ClCCCBr
Reactant: C1COCCN1
Agent: Cl
Solvent: Cc1ccccc1
Product: ClCCCN1CCOCC1
Temperature: 84 °C
Reaction time: 3 h

Procedure:
To a solution of 1-bromo-3-chloropropane (45 g, 0.29 mol) in toluene (100 mL) was added morpholine (38 g, 0.44 mol). The solution was stirred at 84° C. for 3 h, during which time a precipitate formed. After cooling to rt, the precipitate was isolated by vacuum filtration, washed with ether, and the solid was discarded. The mother liquor was acidified with HCl (4 M in dioxane, 72 mL, 0.29 mol), which caused the desired product to precipitate as an HCl salt. Solvent was removed under reduced pressure, and the resultant solid was dried to afford the title compound (53 g, 90%): 1H NMR (DMSO-d6) δ: 11.45 (1H, br s), 3.94-3.77 (4H, m), 3.74 (2H, t), 3.39 (2H, m), 3.15 (2H, m), 3.03 (2H, m), 2.21 (2H, m).