Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:3]([CH2:10][C@:11]([OH:35])([CH3:34])[CH2:12][N:13]2[CH2:18][CH2:17][N:16]([C:19]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([O:29][C:30]([F:33])([F:32])[F:31])=[CH:25][CH:24]=3)=[O:20])[CH2:15][CH2:14]2)[CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1.[H-].[Na+].C(OCC)(=O)C.O>CN(C=O)C>[CH3:34][C@@:11]1([CH2:12][N:13]2[CH2:18][CH2:17][N:16]([C:19]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([O:29][C:30]([F:33])([F:32])[F:31])=[CH:25][CH:24]=3)=[O:20])[CH2:15][CH2:14]2)[O:35][C:2]2=[N:6][C:5]([N+:7]([O-:9])=[O:8])=[CH:4][N:3]2[CH2:10]1
Reactant: C[C@](O)(CN1CCN(C(=O)OCc2ccc(OC(F)(F)F)cc2)CC1)Cn1cc([N+](=O)[O-])nc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C[C@]1(CN2CCN(C(=O)OCc3ccc(OC(F)(F)F)cc3)CC2)Cn2cc([N+](=O)[O-])nc2O1
Reaction time: 2 h
Yield: 78.8 %

Procedure:
4-Trifluoromethoxybenzyl (S)-4-[3-(2-chloro-4-nitroimidazol-1-yl)-2-hydroxy-2-methylpropyl]-piperazine-1-carboxylate prepared in Example 390 (4.3 g, 8.24 mmol) was dissolved in DMF (13 ml). To the solution, sodium hydride (430 mg, 10.7 mmol) was added followed by stirring at the same temperature for 2 hours with cooling on ice-bath. To the reaction mixture, ethyl acetate (4.3 ml) and water (30 ml) were added in this order, and the solution was stirred for 30 minutes. The precipitates were filtered off and washed with water. The solids obtained were recrystallized from ethyl acetate/isopropyl ether and then recrystallized from isopropyl alcohol to afford 4-trifluoromethoxybenzyl (S)-4-(2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazol-2-ylmethyl)piperazine-1-carboxylate (3.15 g, yield 79%) as a white powder.
Reaction SMILES: [F:1][C:2]1[C:10]([F:11])=[C:9]([F:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[N+:13]([O-])([O-:15])=[O:14].[K+]>S(=O)(=O)(O)O>[F:1][C:2]1[C:10]([F:11])=[C:9]([F:12])[C:8]([N+:13]([O-:15])=[O:14])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: O=C(O)c1ccc(F)c(F)c1F
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: O=C(O)c1cc([N+](=O)[O-])c(F)c(F)c1F
Temperature: 0 °C
Reaction time: 48 h
Yield: 97.5 %

Procedure:
2,3,4-Trifluorobenzoic acid (2.5 g) was dissolved in concentrated sulfuric acid (15 ml). Potassium nitrate (1.62 g) was added to the solution under ice cooling. The temperature of the reaction mixture was (given back to room temperature to conduct stirring for 2 days. The reaction mixture was poured into ice water (300 ml) and extracted with ether (200 ml). An organic layer was dried and concentrated. Hexane was added to the residue to conduct filtration, thereby obtaining the title compound (3.06 g) as a pale yellow powder.
Reaction SMILES: CC(C)([O-])C.[K+].[CH:7]1[C:19]2[NH:18][C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]=2[CH:10]=[CH:9][CH:8]=1.[NH2:20][O:21][S:22]([OH:25])(=[O:24])=[O:23].C[N:27]1CCCC1=O.CC(C)([O-])C.[K+].CN1CCCC1=O>CN1CCCC1=O.CC(C)([O-])C.[K+].CN1CCCC1=O>[NH2:20][O:21][S:22]([OH:25])(=[O:24])=[O:23].[CH:16]1([NH2:27])[C:17]2[C:12]([C:11]3[C:19]([N:18]=2)=[CH:7][CH:8]=[CH:9][CH:10]=3)=[CH:13][CH:14]=[CH:15]1
Reactant: CN1CCCC1=O
Reactant: c1ccc2c(c1)[nH]c1ccccc12
Agent: CC(C)(C)[O-]
Agent: NOS(=O)(=O)O
Agent: [K+]
Product: NC1C=CC=C2C1=Nc1ccccc12
Reaction time: 1.43 h
Yield: 85 %

Procedure:
A solution of 10.0 g (9.7 g corrected for 97% purity) of hydroxylamine-O-sulfonic acid (HOSA) in 35.9 g of N-methylpyrrolidinone (NMP) is prepared and chilled to 0–5° C. A second solution is prepared from 20.3 g (19.3 g corrected for 95% purity) of potassium tert-butoxide and 35.3 g of NMP. An amination vessel is charged with 7.0 g (6.7 g corrected for 99% purity) of carbazole, 21.7 g of NMP and an initial charge of 1.3 g of the potassium tert-butoxide/NMP solution. The HOSA/NMP solution and the remaining potassium tert-butoxide/NMP solution are then simultaneously and proportionally metered into the amination vessel over a period of 86 minutes while maintaining a reaction temperature of 22–30° C. to yield a solution containing an 85% yield of 1H-carbazol-1-amine as determined by HPLC.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14](=[N:20][OH:21])[CH2:15][CH2:16][C:17]([OH:19])=O)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.O.CC1C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1.ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[CH:10][C:11]([C:14]3[CH2:15][CH2:16][C:17](=[O:19])[O:21][N:20]=3)=[CH:12][CH:13]=2)=[CH:6][CH:7]=1
Reactant: O=C(O)CCC(=NO)c1ccc(-c2ccc(Cl)cc2)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: ClCCl
Solvent: O
Product: O=C1CCC(c2ccc(-c3ccc(Cl)cc3)cc2)=NO1
Yield: 31.5 %

Procedure:
A stirred suspension of 4-(4′-chloro-biphenyl-4-yl)-4-hydroxyimino-butyric acid (2.126 g, 0.00700 mol) and (4-methylphenyl)sulfonic acid monohydrate (0.067 g, 0.00035 mol) in toluene (22 mL) was heated under nitrogen at reflux over a Dean-Stark trap for 7 hours, and allowed to cool. The volatiles were rotary evaporated. The residue was dissolved/suspended in dichloromethane and chromatographed on silica gel (221 g, 230-400 mesh), eluting with dichloromethane (20×200 mL) to give 0.63 g of 3-(4′-chloro-biphenyl-4-yl)-4,5-dihydro-6-oxo-6H-1,2-oxazine as a light purple solid; mp 190-192° C.
Reaction SMILES: Cl.O1CCCC1.[C:7]([C:11]1[CH:16]=[CH:15][C:14]([CH2:17][CH:18]([O:26][Si](C(C)(C)C)(C)C)[CH2:19][CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)=[CH:13][C:12]=1[NH:34][C:35](=[O:51])[CH2:36][CH:37]1[C:50]2[CH:49]=[CH:48][CH:47]=[CH:46][C:45]=2[O:44][C:43]2[C:38]1=[CH:39][CH:40]=[CH:41][CH:42]=2)([CH3:10])([CH3:9])[CH3:8].C(OCC)(=O)C>O>[C:7]([C:11]1[CH:16]=[CH:15][C:14]([CH2:17][CH:18]([OH:26])[CH2:19][CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)=[CH:13][C:12]=1[NH:34][C:35](=[O:51])[CH2:36][CH:37]1[C:50]2[CH:49]=[CH:48][CH:47]=[CH:46][C:45]=2[O:44][C:43]2[C:38]1=[CH:39][CH:40]=[CH:41][CH:42]=2)([CH3:10])([CH3:8])[CH3:9]
Reactant: CC(C)(C)c1ccc(CC(CC2CCCCC2)O[Si](C)(C)C(C)(C)C)cc1NC(=O)CC1c2ccccc2Oc2ccccc21
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)c1ccc(CC(O)CC2CCCCC2)cc1NC(=O)CC1c2ccccc2Oc2ccccc21
Temperature: 50 °C
Reaction time: 2.5 h

Procedure:
1.5 ml of 2N aqueous hydrochloric acid were added to 15 ml of a tetrahydrofuran solution containing 813 mg (1.30 mmol) of N-[2-t-butyl-5-(3-cyclohexyl-2-t-butyl-dimethylsilyloxypropyl)phenyl]-2-(9H-xanthen-9-yl)-acetamide (prepared by a procedure similar to that described in Preparation 11), and the mixture was stirred for 2.5 hours at 50° C. The reaction mixture was then allowed to return to room temperature. Addition of a mixture of ethyl acetate and water caused the title compound to be distributed between the organic solvent and water. The organic layer was separated and washed with a saturated aqueous solution of sodium hydrogen carbonate, and then with a saturated aqueous solution of sodium chloride. The solvent was removed by distillation under reduced pressure. The resulting residue was subjected to column chromatography through 50 g of silica gel. Elution with mixtures of ethyl acetate and hexane ranging from 1:2 to 2:3 by volume afforded 650 mg (yield 98%) of the title compound as crystals, melting at 177°-178° C. (after recrystallization from diisopropyl ether).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:5]=[CH:6][CH:7]=1.[C:16]1([P:22](Cl)(Cl)=[O:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[C:16]1([P:22]2(=[O:23])[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[CH2:9][N:8]2[C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[CH:3]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=P(Cl)(Cl)c1ccccc1
Reactant: Cc1cccc(NCc2ccccc2)c1
Product: Cc1cccc(N2Cc3ccccc3P2(=O)c2ccccc2)c1

Procedure:
The procedure of Example 1 was employed utilizing N-3-methylphenyl-N-benzylamine and phenyl phosphonic dichloride. The reaction of the dilithio compound and the phenyl phosphonic dichloride was conducted at 0° C. The crude product produced as a result of the chromatographic separation was crystallized from diethyl ether then recrystallized from carbon tetrachloride to yield 1-phenyl-2-(3-methylphenyl)-2,3-dihydro-1H-2,1-benzazaphosphole-1-oxide as a yellow solid. A second crop was obtained to give a total yield of 1.2 g (12% yield) of 1-phenyl-2-(3-methylphenyl)-2,3-dihydro-1H-2,1-benzazaphosphole-1-oxide having a melting point of 190°-192° C. and the following analysis:
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[N:11][N:12](C(OC(C)(C)C)=O)[CH:13]=2)O1.C(=O)([O-])[O-].[Na+].[Na+].Br[C:29]1[CH:30]=[CH:31][C:32]([O:44][CH2:45][C:46]2[CH:51]=[CH:50][C:49]([F:52])=[CH:48][CH:47]=2)=[C:33]([CH:43]=1)[C:34]([NH:36][C:37]1[CH:42]=[CH:41][N:40]=[N:39][CH:38]=1)=[O:35]>COCCOC.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>[F:52][C:49]1[CH:48]=[CH:47][C:46]([CH2:45][O:44][C:32]2[CH:31]=[CH:30][C:29]([C:9]3[CH:13]=[N:12][NH:11][CH:10]=3)=[CH:43][C:33]=2[C:34]([NH:36][C:37]2[CH:42]=[CH:41][N:40]=[N:39][CH:38]=2)=[O:35])=[CH:51][CH:50]=1
Reactant: CC(C)(C)OC(=O)n1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: O=C(Nc1ccnnc1)c1cc(Br)ccc1OCc1ccc(F)cc1
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: COCCOC
Product: O=C(Nc1ccnnc1)c1cc(-c2cn[nH]c2)ccc1OCc1ccc(F)cc1
Temperature: 120 °C

Procedure:
1,1-Dimethylethyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate (110 mg, 0.37 mmol), sodium carbonate (0.75 ml, 0.75 mmol) and tetrakis(triphenylphosphine)palladium(0) (25.9 mg, 0.02 mmol) were added to a solution of 5-bromo-2-{[(4-fluorophenyl)methyl]oxy}-N-4-pyridazinylbenzamide (may be prepared as described in Example 77; 150 mg, 0.37 mmol) in 1,2-dimethoxyethane (5 ml). The reaction was heated at 120° C. for one hour. The solvent was removed in vacuo, triturated with 1:1 DMSO/methanol and washed with methanol (1 ml) and ethyl acetate (2 ml) to give a white solid. Recrystallisation with hot 1:1 DMSO/ethyl acetate yielded the title compound as a white solid. 48.6 mg.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][C@H:12]([C:14]([O:16][CH3:17])=[O:15])[CH2:11][C@H:10](C(O)=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1(P([N:35]=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.C(N(CC)CC)C.C(O)C1C=CC=CC=1>C1(C)C=CC=CC=1>[NH2:35][C@@H:10]1[CH2:9][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:13][C@H:12]([C:14]([O:16][CH3:17])=[O:15])[CH2:11]1
Reactant: COC(=O)[C@@H]1C[C@H](C(=O)O)CN(C(=O)OC(C)(C)C)C1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Solvent: OCc1ccccc1
Product: COC(=O)[C@@H]1C[C@H](N)CN(C(=O)OC(C)(C)C)C1
Temperature: 100 °C
Reaction time: 1 h

Procedure:
(3S,5R)-1-(tert-Butoxycarbonyl)-5-(methoxycarbonyl)piperidine-3-carboxylic acid (2.83 g) was suspended in toluene (36 ml), diphenylphosphoryl azide (2.60 ml) and triethylamine (1.70 ml) were added and the mixture was stirred at 100° C. for 1 hr. The reaction mixture was cooled to room temperature, benzyl alcohol (1.53 ml) and triethylamine (7.00 ml) were added and the mixture was stirred at 80° C. for 3 hr. The reaction mixture was concentrated, and the residue was dissolved in ethyl acetate. The mixture was washed with water, 0.5 M hydrochloric acid, saturated aqueous sodium hydrogen carbonate and saturated brine in this order, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography. The fraction eluted with ethyl acetate-hexane (1:3-3:1) was concentrated under reduced pressure. The obtained residue was dissolved in methanol (60 ml), 10% palladium-carbon (50% containing water) (150 mg) was added, and the mixture was subjected to catalytic reduction at ambient temperature under a hydron atmosphere (1 atm) for 5 hr. The catalyst was filtered off, and the filtrate was concentrated under reduced pressure to give the object compound (1.83 g) as an oil.
Reaction SMILES: [CH:1]([O:4][CH:5]([O:12][CH:13]([CH3:15])[CH3:14])[C:6]([CH3:11])([CH3:10])[C:7](=[O:9])[CH3:8])([CH3:3])[CH3:2].C([N-]C(C)C)(C)C.[Li+].[CH3:24][C@@H:25]([CH2:28][CH:29]=[CH2:30])[CH:26]=[O:27].O>CCOCC.C1COCC1>[CH:13]([O:12][CH:5]([O:4][CH:1]([CH3:2])[CH3:3])[C:6]([CH3:11])([CH3:10])[C:7](=[O:9])[CH2:8][C@@H:26]([OH:27])[C@@H:25]([CH3:24])[CH2:28][CH:29]=[CH2:30])([CH3:15])[CH3:14]
Reactant: CC(=O)C(C)(C)C(OC(C)C)OC(C)C
Reactant: C=CC[C@H](C)C=O
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: O
Product: C=CC[C@H](C)[C@H](O)CC(=O)C(C)(C)C(OC(C)C)OC(C)C
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
A solution of 1,1-diisopropoxy-2,2,-dimethyl-3-butanone (3.08 g) in 15 mL of ether is added slowly to a solution of lithium diisopropylamide (15.7 mmol) in 20 mL of ether cooled to −78° C., the mixture is stirred for 30 minutes, warmed to −40° C. and stirred for 30 minutes, then recooled to −78° C. A solution of bis(1,2:5,6-di-O-isopropylidene-α-D-glucofuranos-3-O-yl)cyclopentadienyltitanium chloride (17.4 mmol) in 180 mL of ether is added dropwise over 40 minutes, and the reaction is stirred for an additional 30 minutes at −78° C., warmed to −30° C. and kept for 45 minutes, then recooled to −78° C. A solution of (2S)-2-methyl-4-pentenal (16.36 mmol) in 30 mL of ether is added over 10 minutes and the mixture is stirred for 2 hours at −78° C. A 5 M solution of water in THF (28 mL) is added, the mixture is stirred for 1 hour and then filtered through Celite. The filtrate is washed with sat. aq. NaCl, and the brine layer is back extracted with ether. The organic phases are combined, dried with Na2SO4, filtered, and evaporated. The product is purified by chromatography on SiO2.
Reaction SMILES: [CH:1]([CH:4]1[CH:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:8]([CH3:15])[CH:7]=[CH:6][CH2:5]1)([CH3:3])[CH3:2]>[Pd].C(O)C>[CH:1]([CH:4]1[CH2:5][CH2:6][CH2:7][CH:8]([CH3:15])[CH:9]1[C:10]([O:12][CH2:13][CH3:14])=[O:11])([CH3:2])[CH3:3]
Reactant: CCOC(=O)C1C(C)C=CCC1C(C)C
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)C1C(C)CCCC1C(C)C
Reaction time: 1 h
Yield: 88.7 %

Procedure:
0.5 g of 5% palladium on charcoal as a catalyst was added to 10.5 g of ethyl 6-isopropyl-2-methyl-3-cyclohexene-1-carboxylate (mixture of isomers obtained according to Example 1) dissolved in 100 ml of ethanol, after which the mixture was hydrogenated at 20° C. for 1 hour under a hydrogen pressure of 100 kPa. The catalyst was then filtered off, the filtrate evaporated down and the evaporation residue distilled. 9.4 g of the desired compound were obtained as a mixture of the cis-trans and the trans-trans isomer. b.p.: 96°-97° C./1 kPa; NMR (of the mixture): 0.7-1.0 (9H); 1.24 (3H, t); 1.0-2.5 (10H); 3.9-4.2 (2H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8](B(O)O)=[CH:7][CH:6]=1)=[O:4].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+].Cl/[CH:40]=[CH:41]/[C:42]#[C:43][C:44]1[CH:51]=[CH:50][C:47]([CH:48]=[O:49])=[CH:46][CH:45]=1>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(OCC)(=O)C.C(O)C.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3](=[O:4])[C:5]1[CH:10]=[CH:9][C:8](/[CH:40]=[CH:41]/[C:42]#[C:43][C:44]2[CH:45]=[CH:46][C:47]([CH:48]=[O:49])=[CH:50][CH:51]=2)=[CH:7][CH:6]=1
Reactant: O=Cc1ccc(C#C/C=C/Cl)cc1
Reactant: COC(=O)c1ccc(B(O)O)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: CCO
Product: COC(=O)c1ccc(/C=C/C#Cc2ccc(C=O)cc2)cc1
Temperature: 25 °C
Yield: 81.2 %

Procedure:
4-Methoxycarbonylphenylboronic acid (1.0 g), PdCl2(PPh3)2 (0.18 g), triphenylphosphine (0.13 g) and potassium carbonate (1.4 g) were added to a toluene (5.0 mL)-ethanol (2.5 mL) solution of 4-((E)-4-chlorobut-3-en-1-yn-1-yl)benzaldehyde (0.97 g) as obtained in Example 22-(1), and the mixture was heated and refluxed for 3 hours in a nitrogen atmosphere. After the reaction mixture was cooled to room temperature, ethyl acetate was added, the insolubles were filtered out, and the filtrate was concentrated under reduced pressure. IPE was added to the resulting residue, and the solids were filtered out, whereafter chloroform and OH type silica gel (10 g) were added. The insolubles were filtered out, and the filtrate was concentrated under reduced pressure to obtain 4-[(1E)-4-(4-formylphenyl)but-1-en-3-yn-1-yl]benzoic acid methyl ester (light brown solid) (1.2 g, 78%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([O:14][C:15]2[CH:16]=[C:17]3[C:22](=[CH:23][C:24]=2[O:25][CH3:26])[N:21]=[CH:20][N:19]=[C:18]3[NH:27][C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([Cl:34])[C:29]=2[F:35])[CH2:10][C@H:9]1[C:36]([OH:38])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C[N:40]1CCOCC1.N>C1COCC1.C(Cl)Cl>[NH2:40][C:36]([C@@H:9]1[CH2:10][C@@H:11]([O:14][C:15]2[CH:16]=[C:17]3[C:22](=[CH:23][C:24]=2[O:25][CH3:26])[N:21]=[CH:20][N:19]=[C:18]3[NH:27][C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([Cl:34])[C:29]=2[F:35])[CH2:12][CH2:13][N:8]1[C:6]([O:5][C:1]([CH3:3])([CH3:4])[CH3:2])=[O:7])=[O:38]
Reactant: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1O[C@H]1CCN(C(=O)OC(C)(C)C)[C@H](C(=O)O)C1
Reactant: CN1CCOCC1
Agent: N
Solvent: ClCCl
Solvent: C1CCOC1
Product: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1O[C@H]1CCN(C(=O)OC(C)(C)C)[C@H](C(N)=O)C1
Temperature: 25 °C
Reaction time: 0.12 h
Yield: 100 %

Procedure:
A stirred solution of (2S,4S)-1-(tert-butoxycarbonyl)-4-({4-[(3-chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}oxy)piperidine-2-carboxylic acid (3) (5 g, 9.16 mmol) in THF (50 ml) was cooled to −15° C. (acetone/ice). NMM (1.5 ml, 13.7 mmol) was added to the solution followed by IBCF (1.54 ml, 11.9 mmol). The reaction mixture was held at −15° C. (the formation of the mixed anhydride was monitored by TLC (THF)). After 5-10 minutes, the reaction mixture was treated with concentrated aqueous ammonia (3 ml) at −15° C. and allowed to warm to room temperature. The reaction mixture was diluted with DCM (250 ml), washed with water (2×20 ml) and concentrated to give tert-butyl (2S,4S)-2-(aminocarbonyl)-4-({4-[(3-chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}oxy)piperidine-1-carboxylate (4) (5 g, 100%) as a pale yellow foam which was used without further purification; Mass Spectrum: (M+H)+ 546.1.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:9]([O:11]CC)=[O:10])=[N:4][O:5][C:6]=1[CH:7]=[CH2:8].CO.[OH-].[Na+]>C1COCC1>[CH3:1][C:2]1[C:3]([C:9]([OH:11])=[O:10])=[N:4][O:5][C:6]=1[CH:7]=[CH2:8]
Reactant: C=Cc1onc(C(=O)OCC)c1C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: C=Cc1onc(C(=O)O)c1C
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Ethyl 4-methyl-5-vinylisoxazole-3-carboxylate (250 mg, 0.993 mmol) was dissolved in THF (5.3 mL) and MeOH (3.2 mL) and to this was added 2M NaOH (aq) (497 μl, 0.993 mmol). The reaction mixture was stirred at room temperature for 15 minutes. The resulting mixture was concentrated under reduced pressure and treated with 2M HCl (5 mL) and water (5 mL). DCM was added to the aqueous resulting in the formation of an emulsion. The solvent was removed under reduced pressure. The resulting residue was suspended in DCM (25 mL) and passed through a phase separating column. The organic solvent was removed under reduced pressure to afford the title compound;
Reaction SMILES: Cl.Cl.Cl.[NH2:4][CH2:5][CH2:6][NH:7][C:8]1[C:34]([Cl:35])=[CH:33][C:11]([C:12]([NH:14][C:15]2[S:16][C:17]([CH2:26][N:27]([CH2:29][CH2:30][CH2:31][CH3:32])[CH3:28])=[C:18]([C:20]3[S:21][CH:22]=[C:23]([Cl:25])[CH:24]=3)[N:19]=2)=[O:13])=[CH:10][N:9]=1.C(N(CC)CC)C.[CH3:43][S:44](Cl)(=[O:46])=[O:45].O>C1COCC1>[CH2:29]([N:27]([CH2:26][C:17]1[S:16][C:15]([NH:14][C:12](=[O:13])[C:11]2[CH:33]=[C:34]([Cl:35])[C:8]([NH:7][CH2:6][CH2:5][NH:4][S:44]([CH3:43])(=[O:46])=[O:45])=[N:9][CH:10]=2)=[N:19][C:18]=1[C:20]1[S:21][CH:22]=[C:23]([Cl:25])[CH:24]=1)[CH3:28])[CH2:30][CH2:31][CH3:32]
Reactant: CS(=O)(=O)Cl
Reactant: CCCCN(C)Cc1sc(NC(=O)c2cnc(NCCN)c(Cl)c2)nc1-c1cc(Cl)cs1
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: CCCCN(C)Cc1sc(NC(=O)c2cnc(NCCNS(C)(=O)=O)c(Cl)c2)nc1-c1cc(Cl)cs1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
100 mg of 6-[(2-aminoethyl)amino]-N-[5-{[butyl(methyl)amino]methyl}-4-(4-chlorothiophen-2-yl)thiazol-2-yl]-5-chloronicotinamide trihydrochloride was suspended in 5 ml of THF, and 85 μl of triethylamine was added, followed by cooling to 0° C. 13 μl of methanesulfonyl chloride was added to the solution, and the mixture was stirred at room temperature for 2 hours. The reaction solution was poured into water, and extracted with chloroform. The organic layer was washed with water and with brine, and then dried over magnesium sulfate. After the solvent was distilled off, the residue was purified by silica gel column chromatography (chloroform:MeOH =10:1) to obtain 75 mg of N-[5-{[butyl(methyl)amino]methyl}-4-(4-chlorothiophen-2-yl)thiazol-2-yl]-5-chloro-6-({2-[(methylsulfonyl)amino]ethyl}amino)nicotinamide.
Reaction SMILES: [N+:1]([C:4]1[C:13]2[C:12](=[O:14])O[C:10]([CH3:15])=[N:9][C:8]=2[CH:7]=[CH:6][CH:5]=1)([O-:3])=[O:2].Cl.[NH2:17][CH:18]1[CH2:23][CH2:22][C:21](=[O:24])[NH:20][C:19]1=[O:25].CO>N1C=CC=CC=1>[CH3:15][C:10]1[N:17]([CH:18]2[CH2:23][CH2:22][C:21](=[O:24])[NH:20][C:19]2=[O:25])[C:12](=[O:14])[C:13]2[C:8](=[CH:7][CH:6]=[CH:5][C:4]=2[N+:1]([O-:3])=[O:2])[N:9]=1
Reactant: NC1CCC(=O)NC1=O
Reactant: Cc1nc2cccc([N+](=O)[O-])c2c(=O)o1
Agent: Cl
Solvent: CO
Solvent: c1ccncc1
Product: Cc1nc2cccc([N+](=O)[O-])c2c(=O)n1C1CCC(=O)NC1=O
Temperature: 170 °C
Reaction time: 2 h
Yield: 53.2 %

Procedure:
Step 4: Two vials each with a suspension of 5-nitro-2-methyl-benzo[d][1,3]oxazin-4-one (0.60 g, 2.91 mmol) and 3-amino-piperidine-2,6-dione hydrogen chloride (0.48 g, 2.91 mmol) in pyridine (15 mL) were heated at 170° C. for 10 minutes in a microwave oven. The suspension was filtered and washed with pyridine (5 mL). The filtrate was concentrated in vacuo. The resulting mixture was stirred in HCl (30 mL, 1N), ethyl acetate (15 mL) and ether (15 mL) for 2 hrs. The suspension was filtered and washed with water (30 mL) and ethyl acetate (30 mL) to give a dark brown solid, which was stirred with methanol (50 mL) at room temperature overnight. The suspension was filtered and washed with methanol to give 3-(2-methyl-5-nitro-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione as a black solid (490 mg, 27% yield). The solid was used in the next step without further purification.
Reaction SMILES: C([N:8]1[CH2:26][CH2:25][C:10]2([CH2:14][N:13]([C:15]3[CH:24]=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][N:16]=3)[CH2:12][CH2:11]2)[CH2:9]1)C1C=CC=CC=1>CCO.[OH-].[OH-].[Pd+2]>[CH2:14]1[C:10]2([CH2:25][CH2:26][NH:8][CH2:9]2)[CH2:11][CH2:12][N:13]1[C:15]1[CH:24]=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][N:16]=1
Reactant: COC(=O)c1ccc(N2CCC3(CCN(Cc4ccccc4)C3)C2)nc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: COC(=O)c1ccc(N2CCC3(CCNC3)C2)nc1
Reaction time: 20 h

Procedure:
A mixture of 2-benzyl-2,7-diazaspiro[4.4]nonane (1.00 g, 4.68 mmol), methyl 6-chloronicotinate (800 mg, 4.68 mmol) and K2CO3 (700 mg, 5.07 momol) in 5 mL of DMSO was stirred under microwave irradiation for 20 min at a temperature of 150° C. The mixture was poured into EtOAc and washed with sat'd NaHCO3, dried (Na2SO4), filtered and concentrated, giving methyl 6-(7-benzyl-2,7-diazaspiro[4.4]non-2-yl)nicotinate. A bottle containing a suspension of the benzyl amine and 20% Pd(OH)2/C (600 mg, 0.857 mmol) in 20 mL of EtOH was evacuated and purged with H2 gas three times. Using a Parr shaker apparatus, the suspension was agitated under 50 psi of H2 for 20 h. The pressure was released and the mixture filtered through a pad of Celite and concentrated, giving methyl 6-(2,7-diazaspiro[4.4]non-2-yl)nicotinate: 1H NMR (600 MHz, DMSO-d6) δ 8.59 (d, J=2.1 Hz, 1H), 7.89 (dd, J=9.1, 2.3 Hz, 1H), 7.27 (d, J=4.4 Hz, 1H), 6.44 (d, J=8.8 Hz, 1H), 3.74 (s, 3H), 3.13 (br s, 4H), 2.89 (t, J=7.3 Hz, 2H), 2.72 (AB, J=7.6 Hz, 2H), 1.92 (br m, 2H), 1.69 (AB, J=7.3 Hz, 2H).