Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:30])[NH:7][C:8]([CH:12]([NH:18][CH2:19][CH2:20][CH2:21][NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[C:13]([N:15]([CH3:17])[CH3:16])=[O:14])=[N:9]2)=[CH:4][CH:3]=1.[CH3:31][C:32]1[CH:40]=[CH:39][C:35]([C:36](Cl)=[O:37])=[CH:34][CH:33]=1.C(N([CH2:46][CH3:47])CC)C>>[CH3:31][C:32]1[CH:40]=[CH:39][C:35]([C:36]([O:30][CH:6]2[C:5]3[C:10](=[CH:11][C:2]([Cl:1])=[CH:3][CH:4]=3)[N:9]=[C:8]([CH:12]([N:18]([CH2:19][CH2:20][CH2:21][NH:22][C:23]([O:24][C:25]([CH3:27])([CH3:26])[CH3:28])=[O:29])[C:6](=[O:30])[C:5]3[CH:10]=[CH:11][C:46]([CH3:47])=[CH:3][CH:4]=3)[C:13]([N:15]([CH3:16])[CH3:17])=[O:14])[NH:7]2)=[O:37])=[CH:34][CH:33]=1
Reactant: Cc1ccc(C(=O)Cl)cc1
Reactant: CCN(CC)CC
Reactant: CN(C)C(=O)C(NCCCNC(=O)OC(C)(C)C)c1nc2cc(Cl)ccc2c(=O)[nH]1
Product: Cc1ccc(C(=O)OC2NC(C(C(=O)N(C)C)N(CCCNC(=O)OC(C)(C)C)C(=O)c3ccc(C)cc3)=Nc3cc(Cl)ccc32)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of tert-butyl 3-{[1-(7-chloro-4-oxo-3,4-dihydroquinazolin-2-yl)-2-(dimethylamino)-2-oxoethyl]amino}propylcarbamate (1.2 g, 1 eq.) methylene chloride 920 ml) at 0° C., was added 4-methyl benzoyl chloride (1.1 ml, 3 eq.) and triethylamine (1.9 ml, 5 eq.). The reaction was allowed to warm up to room temperature and stirred at room temperature overnight. The solvent was evaporated and the crude product was dissolved in ethyl acetate. Ethyl acetate layer was washed with water, saturated sodium carbonate, saturated sodium chloride, dried over magnesium sulfate, filtered, and evaporated to yield 2-[1-[{3-[(tert-butoxycarbonyl)amino]propyl} (4-methylbenzoyl)amino]-2-(dimethylamino)-2-oxoethyl]-7-chloro-3,4-dihydroquinazolin-4-yl 4-methylbenzoate (2.3 g) as a brown oil.
Reaction SMILES: [Li][CH2:2][CH2:3][CH2:4][CH3:5].[Li+].CC([N-]C(C)C)C.[Br:14][C:15]1[CH:16]=[N:17][CH:18]=[CH:19][C:20]=1[Cl:21].C1([CH:25]=[N:26][S:27]([CH3:30])(=[O:29])=[O:28])CC1.CI>C1COCC1.O>[Br:14][C:15]1[C:20]([Cl:21])=[C:19]([CH:2]([CH:3]2[CH2:5][CH2:4]2)[N:26]([CH3:25])[S:27]([CH3:30])(=[O:29])=[O:28])[CH:18]=[N:17][CH:16]=1
Reactant: Clc1ccncc1Br
Reactant: CS(=O)(=O)N=CC1CC1
Reactant: [Li]CCCC
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CI
Solvent: O
Solvent: C1CCOC1
Product: CN(C(c1cncc(Br)c1Cl)C1CC1)S(C)(=O)=O
Temperature: -78 °C
Reaction time: 2 h

Procedure:
To a solution of DIPA (1.71 mL, 12 mmol) in THF (50 mL) at −78° C. was added 1.6M BuLi (7.5 mL, 12.0 mmol) and the mixture was stirred at −78° C. for 2 h. The LDA solution was cannulated into a solution of 3-bromo-4-chloropyridine (2.117 g, 11 mmol) in THF (50 mL) at −78° C., and the mixture was stirred at −78° C. for 1 h. A solution of N-(cyclopropylmethylene)methanesulfonamide (10 mmol, crude mixture) in THF (50 mL) was added and the mixture was stirred at −78° C. for 1 h. A solution of MeI (0.625 mL, 10 mmol) in THF (10 mL) was added, and the mixture was warmed to room temperature and stirred overnight. Water (0.5 mL) was added and the mixture was concentrated in vacuo. The residue was purified by silica gel chromatography eluting with a 0-50% EtOAc-heptane gradient to give N-((5-bromo-4-chloropyridin-3-yl)(cyclopropyl)methyl)-N-methylmethanesulfonamide. MS (ESI): m/z 353.0, 355.0 (M+H)+.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[C:12]([F:14])[CH:11]=[C:10]([F:15])[CH:9]=2)[N:5]2[N:16]=[C:17]([CH3:20])[C:18]([I:19])=[C:4]2[N:3]=1.CCN(C(C)C)C(C)C.[NH:30]1[CH2:34][CH2:33][CH2:32][C@H:31]1[CH2:35][OH:36]>C(#N)C>[F:15][C:10]1[CH:9]=[C:8]([C:6]2[N:5]3[N:16]=[C:17]([CH3:20])[C:18]([I:19])=[C:4]3[N:3]=[C:2]([N:30]3[CH2:34][CH2:33][CH2:32][C@H:31]3[CH2:35][OH:36])[CH:7]=2)[CH:13]=[C:12]([F:14])[CH:11]=1
Reactant: OC[C@@H]1CCCN1
Reactant: Cc1nn2c(-c3cc(F)cc(F)c3)cc(Cl)nc2c1I
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: Cc1nn2c(-c3cc(F)cc(F)c3)cc(N3CCC[C@H]3CO)nc2c1I

Procedure:
5-Chloro-7-(3,5-difluorophenyl)-3-iodo-2-methylpyrazolo[1,5-a]pyrimidine obtained in Step 3, DIPEA (0.35 mL) and (S)-2-pyrrolidinemethanol (401 mg) are stirred in an acetonitrile (60 mL) solvent for 2.5 hours at 90° C. The reaction solvent is removed by distillation under reduced pressure. The remainder is purified by column chromatography to yield the target compound. 1H NMR (CDCl3, 300 MHz); δ 7.46 (m, 2H), 6.98 (m, 1H), 6.13 (s, 1H), 4.45 (br, 1H), 3.85-3.57 (m, 5H), 2.38 (s, 3H), 2.08-2.04 (m, 3H), 1.77 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:26])[N:9]3[CH2:25][CH2:24][CH2:23][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16](N3C=CN=C3)=[O:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1.[OH2:27]>CN(C)C=O>[Cl:1][C:2]1[C:7]2[C:8](=[O:26])[N:9]3[CH2:25][CH2:24][CH2:23][CH:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]([O:27][C:7]([CH3:8])([CH3:2])[CH3:6])=[O:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: O=C1c2c(Cl)cccc2-n2cnc(C(=O)n3ccnc3)c2[C@@H]2CCCN12
Reactant: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)c1ncn2c1C1CCCN1C(=O)c1c(Cl)cccc1-2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A suspension of 1.1 g (3 mmol) of (S)-1-[(8-chloro-11,12,13,13a-tetrahydro-9-oxo-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepin-1-yl)carbonyl]imidazole in 10 ml of dry dimethylformamide is treated while stirring with 0.34 g (3 mmol) of potassium t-butylate, the mixture is stirred at room temperature for a further 30 minutes, then poured into 200 ml of water and extracted three times with chloroform. The chloroform solution is washed three times with water, dried over magnesium sulphate and evaporated. After crystallization from ethyl acetate, there is obtained t-butyl 8-chloro-11,12,13,13a-tetrahydro-9-oxo-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepine-1-carboxylate of melting point 223°-225°.
Reaction SMILES: [SH:1][CH2:2][C:3]([N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8][CH2:7][CH:6]1[C:15]([OH:17])=[O:16])=[O:4].[OH-:18].[Na+].II>O.C(O)C>[O:18]=[C:3]([N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8][CH2:7][CH:6]1[C:15]([OH:17])=[O:16])[CH2:2][S:1][S:1][CH2:2][C:3]([N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8][CH2:7][CH:6]1[C:15]([OH:17])=[O:16])=[O:4]
Reactant: O=C(O)C1CCc2ccccc2N1C(=O)CS
Reactant: [OH-]
Agent: II
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: O=C(O)C1CCc2ccccc2N1C(=O)CSSCC(=O)N1c2ccccc2CCC1C(=O)O

Procedure:
(±)-1,2,3,4-Tetrahydro-1-(2-mercapto-1-oxoethyl)-2-quinolinecarboxylic acid (3 g) was suspended in water (40 ml) and the pH was adjusted to 6.5 with 2 N sodium hydroxide. A saturated solution of iodine in ethanol was then added dropwise while maintaining the pH at 6.5 by the slow addition of 2 N sodium hydroxide. When a yellow color remained for at least five minutes, addition of the iodine solution was terminated and the yellow color was discharged with saturated aqueous sodium thiosulfate. The mixture was then acidified with concentrated hydrochloric acid and extracted with ethyl acetate. The combined extracts were washed with 10% hydrochloric acid and water, dried over magnesium sulfate, and concentrated under reduced pressure. The (±) 1,1'-[dithiobis(1-oxo-2,1-ethanediyl)]-bis-1,2,3,4-tetrahydro-2-quinolinecarboxylic acid was recrystallized from ethyl acetate; yield 0.7 g, m.p. 172°-174°.
Reaction SMILES: O[C:2]1[CH:17]=[C:16]([OH:18])[CH:15]=[CH:14][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][C:7]=1[OH:13])=O.C([O-])(=O)C.[Na+].Cl.[F:25][C:26]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][C:27]=1[NH:33][NH2:34]>>[F:25][C:26]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][C:27]=1[N:33]1[C:2]2[C:3](=[CH:14][CH:15]=[C:16]([OH:18])[CH:17]=2)[C:4]([C:6]2[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][C:7]=2[OH:13])=[N:34]1
Reactant: O=C(c1ccc(O)cc1O)c1ccc(O)cc1O
Reactant: NNc1cc(F)ccc1F
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Product: Oc1ccc(-c2nn(-c3cc(F)ccc3F)c3cc(O)ccc23)c(O)c1
Yield: 18.9 %

Procedure:
Prepared according to Method B from 2,2′,4,4′-tetrahydroxybenzophenone (0.4 g, 1.6 mmol), sodium acetate (0.27 g, 3 mmol) and 2,5-difluorophenylhydrazine hydrochloride (0.45 g, 3 mmol) to give 0.107 g of product as an off-white colored solid.
Reaction SMILES: [NH2:1][C@@H:2]1[C@@H:7]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C@H:6]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C@@H:5]([CH2:24][F:25])[CH2:4][C@@H:3]1[OH:26].C(S[N:30]=[C:31]=O)C.CI.[CH2:35]1[CH2:39]OCC1>CC(C)=O.C([O-])(O)=O.[Na+]>[CH2:9]([O:8][C@@H:7]1[C@H:2]2[N:1]=[C:31]([NH:30][CH2:39][CH3:35])[O:26][C@H:3]2[CH2:4][C@H:5]([CH2:24][F:25])[C@H:6]1[O:16][CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: C1CCOC1
Reactant: CCSN=C=O
Reactant: N[C@@H]1[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@@H](CF)C[C@@H]1O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CI
Solvent: CC(C)=O
Product: CCNC1=N[C@@H]2[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@@H](CF)C[C@@H]2O1
Temperature: 25 °C
Reaction time: 18 h
Yield: 100 %

Procedure:
To a solution of (1S,2S,3R,4R,5S)-2-amino-3,4-bis(benzyloxy)-5-(fluoromethyl)cyclohexanol (182 mg, 0.507 mmol) in THF (4 mL) at room temperature was added a solution of ethylthioisocyanate (55 mg, 0.63 mmol) in THF (1 mL). The mixture was stirred at room temperature for 18 h. The solvent was evaporated to give a colorless syrup. This was dissolved in acetone (3 mL) and MeI (144 mg, 1.01 mmol) was added. The mixture was stirred at room temperature for 6 h. The reaction was diluted with saturated aqueous NaHCO3 (20 mL) and extracted with DCM (3×10 mL). The extracts were dried with Na2SO4 and the solvents were evaporated to give (3aS,4R,5R,6S,7aS)-4,5-bis(benzyloxy)-N-ethyl-6-(fluoromethyl)-3a,4,5,6,7,7a-hexahydrobenzo[d]oxazol-2-amine as a white solid (209 mg, 100%) which was pure enough for next reaction. MS m/z 413.2 (M+1, 100%); 1H NMR (400 MHz, CDCl3) δ 7.27-7.39 (m, 10H), 4.86 (d, J=11.7 Hz, 1H), 4.80 (d, J=11.2 Hz, 1H), 4.70 (d, J=11.6 Hz, 1H), 4.69-4.73 (m, 1H), 4.64 (dd, J=9.0 Hz, 4.5 Hz, 0.5H), 4.45-4.53 (m, 1H), 4.48 (d, J=11.2 Hz, 1H), 4.35 (dd, J=8.9 Hz, 2.9 Hz, 0.5H), 4.09 (dd, J=8.0 Hz, 5.2 Hz, 1H), 3.67 (t, J=5.6 Hz, 1H), 3.46 (dd, J=9.3 Hz, 6.1 Hz, 1H), 3.16-3.29 (m, 2H), 2.12 (dt, J=14.6 Hz, 2.9 Hz, 1H), 1.91-2.06 (m, 1H), 1.79-1.87 (m, 1H), 1.15 (t, J=7.2 Hz, 3H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH2:23][CH3:24])=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[C:4]([N:25]2[CH2:29][CH2:28][CH2:27][S:26]2(=[O:31])=[O:30])[CH:3]=1.[CH3:32][C:33]1([CH3:39])[O:37][C:36](=[O:38])[N:35]=[CH:34]1>>[O:30]=[S:26]1(=[O:31])[CH2:27][CH2:28][CH2:29][N:25]1[C:4]1[CH:3]=[C:2]([N:35]2[CH2:34][C:33]([CH3:39])([CH3:32])[O:37][C:36]2=[O:38])[CH:7]=[CH:6][C:5]=1[C:8]([N:10]1[CH2:15][CH2:14][N:13]([C:16]2[C:21]([CH3:22])=[CH:20][C:19]([CH2:23][CH3:24])=[CH:18][N:17]=2)[CH2:12][CH2:11]1)=[O:9]
Reactant: CC1(C)C=NC(=O)O1
Reactant: CCc1cnc(N2CCN(C(=O)c3ccc(Br)cc3N3CCCS3(=O)=O)CC2)c(C)c1
Product: CCc1cnc(N2CCN(C(=O)c3ccc(N4CC(C)(C)OC4=O)cc3N3CCCS3(=O)=O)CC2)c(C)c1
Yield: 48.3 %

Procedure:
By reaction and treatment in the same manner as in Example 110 and using [4-bromo-2-(1,1-dioxoisothiazolidin-2-yl)phenyl][4-(5-ethyl-3-methylpyridin-2-yl)piperazin-1-yl]methanone (761 mg) described in Preparation Example 180 and 5,5-dimethyloxazolin-2-one (207 mg) described in Preparation Example 43, the title compound (392 mg) was obtained.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]([CH3:15])=[C:13]([CH3:16])[C:12]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[C:11]([CH3:25])[C:10]=1[CH2:26][CH2:27][CH2:28][CH2:29][OH:30])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.C([O-])(O)=O.[Na+].CCOC(C)=O>C(Cl)Cl>[CH2:1]([O:8][C:9]1[C:14]([CH3:15])=[C:13]([CH3:16])[C:12]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[C:11]([CH3:25])[C:10]=1[CH2:26][CH2:27][CH2:28][CH:29]=[O:30])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1c(C)c(OCc2ccccc2)c(CCCCO)c(C)c1OCc1ccccc1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: Cc1c(C)c(OCc2ccccc2)c(CCCC=O)c(C)c1OCc1ccccc1
Temperature: 25 °C
Reaction time: 1.25 h

Procedure:
A stirred solution of 4-(2,5-bis(benzyloxy)-3,4,6-trimethylphenyl)butan-1-ol (640 mg, 1.58 mmol) in 10 mL CH2Cl2 at 0° C. was treated with a suspension of Dess-martin periodonate (860 mg, 2.03 mmol) in CH2Cl2 (4 mL) and the pale yellow cloudy solution stirred at room temperature for 1.25 h. The cloudy white solution was poured over a solution of 10 mL 1.0 M NaHCO3 containing ˜0.5 g Na2S2O3 and 20 mL EtOAc added, the layers separated and the aqueous phase extracted 3×20 mL EtOAc. The combined organics were washed with 20 mL saturated aqueous NaCl, dried over Na2SO4 and concentrated to a yellow-white solid. The solid was dissolved into 5 mL EtOAc, filtered and the residual solids rinsed with EtOAc. The combined washings were stored overnight at 2° C., concentrated and purified by flash chromatography (gradient elution, 0-20% EtOAc/heptanes) collecting 530 mg of 4-(2,5-bis(benzyloxy)-3,4,6-trimethylphenyl)butanal. MS M++H at 403 m/z; 1H NMR (400 MHz, CDCl3) δ=9.67 (t, 1 H), 7.52-7.48 (m, 2 H), 7.45-7.36 (m, 6 H), 4.75 (s, 2 H), 4.74 (s, 2 H), 2.69 (t, 2 H), 2.44 (td, 2 H), 2.27 (s, 3 H), 2.24 (s, 6 H), 1.84 (pent, 2 H) ppm.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH:7]=O)=[CH:3][CH:2]=1.CO.[NH2:11][CH2:12][CH2:13][CH2:14][O:15][C:16]1[CH:33]=[CH:32][C:19]2[N:20]([CH2:30][CH3:31])[C:21](=[O:29])[C:22]([CH3:28])([CH3:27])[C:23](=[O:26])[N:24]([CH3:25])[C:18]=2[CH:17]=1.[BH4-].[Na+]>C(OCC)(=O)C.O>[CH2:30]([N:20]1[C:21](=[O:29])[C:22]([CH3:28])([CH3:27])[C:23](=[O:26])[N:24]([CH3:25])[C:18]2[CH:17]=[C:16]([O:15][CH2:14][CH2:13][CH2:12][NH:11][CH2:7][C:4]3[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=3)[CH:33]=[CH:32][C:19]1=2)[CH3:31]
Reactant: CCN1C(=O)C(C)(C)C(=O)N(C)c2cc(OCCCN)ccc21
Reactant: O=Cc1ccncc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: CCOC(C)=O
Product: CCN1C(=O)C(C)(C)C(=O)N(C)c2cc(OCCCNCc3ccncc3)ccc21
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 84.2 %

Procedure:
4-Pyridinecarbaldehyde (0.64 ml, 6.8 mmol) was added to a methanol solution (10 ml) of 7-(3-aminopropoxy)-1-ethyl-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione (2.18 g, 6.8 mmol), and stirred under a nitrogen atmosphere at room temperature for 1.5 hours. The reaction mixture was cooled in an ice water bath, and sodium borohydride (257 mg, 6.8 mmol) was added thereto at 0° C. The mixture was then stirred at room temperature overnight. Water was added to the reaction mixture, and extraction with ethyl acetate was performed. The organic layer was washed with water and a saturated sodium chloride aqueous solution, in this order, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:methanol=9:1→3:2). The purified product was concentrated under reduced pressure to thereby obtain 2.35 g (yield: 84%) of 1-ethyl-3,3,5-trimethyl-7-{3-[(pyridin-4-ylmethyl)amino]propoxy}-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione as a pale yellow oil.
Reaction SMILES: C([N:11]1[CH2:16][CH2:15][NH:14][CH:13]([C:17]([OH:19])=O)[CH2:12]1)(OCC1C=CC=CC=1)=O.[F:20][C:21]1[CH:26]=[C:25]([N+:27]([O-])=O)[C:24](F)=[CH:23][C:22]=1[F:31]>>[F:20][C:21]1[CH:26]=[C:25]2[C:24](=[CH:23][C:22]=1[F:31])[N:14]1[CH2:15][CH2:16][NH:11][CH2:12][CH:13]1[C:17](=[O:19])[NH:27]2
Reactant: O=[N+]([O-])c1cc(F)c(F)cc1F
Reactant: O=C(O)C1CN(C(=O)OCc2ccccc2)CCN1
Product: O=C1Nc2cc(F)c(F)cc2N2CCNCC12
Yield: 16.7 %

Procedure:
By the same procedure described for example 2 method 2B, from 1.5 g of racemic 4-carbobenzyloxypiperazine-2-carboxylic acid and 1,2,4-trifluoro-5-nitrobenzene, there was obtained 0.4 g (16.7%) of title compound as an orange-red residue.
Reaction SMILES: [CH:1]1([NH:11][CH2:12][CH2:13][CH2:14][N:15]2[C:19](=[O:20])[C:18]3=[CH:21][CH:22]=[CH:23][CH:24]=[C:17]3[C:16]2=[O:25])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[CH2:26]([CH:31]=O)[CH2:27][C:28]([OH:30])=[O:29].CC(O)=O.[BH3-]C#N.[Na+]>CO.O>[C:19]1(=[O:20])[N:15]([CH2:14][CH2:13][CH2:12][N:11]([CH:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH2:4][CH2:3][CH2:2]2)[CH2:31][CH2:26][CH2:27][C:28]([OH:30])=[O:29])[C:16](=[O:25])[C:17]2=[CH:24][CH:23]=[CH:22][CH:21]=[C:18]12
Reactant: O=C1c2ccccc2C(=O)N1CCCNC1CCCc2ccccc21
Reactant: O=CCCC(=O)O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: CO
Product: O=C(O)CCCN(CCCN1C(=O)c2ccccc2C1=O)C1CCCc2ccccc21
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 82 %

Procedure:
To a solution of N-[3-(1,2,3,4-tetrahydro-1-naphthylamino)propyl]phthalimide (200 mg, 0.60 mmol) in MeOH (10 ml) were added succinic semialdehyde (15 wt. % solution in water, 0.45 ml, 0.72 mmol), HOAc (41 μl, 0.72 mmol) and NaBH3CN (45 mg, 0.72 mmol), and the mixture was stirred at RT for 2.5 h. After adding water, the mixture was extracted with chloroform, washed with water and brine, dried over sodium sulfate, and filtered. The filtrate was concentrated under vacuum to dryness, and the residue was chromatographed on silica gel (eluting with 5% methanol/chloroform) to afford 4-[[(3-phthalimido)propyl](1,2,3,4-tetrahydro-1-naphthyl)amino]butanoic acid (207 mg, 82%): MS(ES+) m/e 421 [M+H]+; 1H NMR (400 MHz, CDCl3) δ 7.83 (dd, J=5.6, 2.9 Hz, 2H), 7.72 (m, 2H), 7.65 (d, J=7.6 Hz, 1H), 7.15 (m, 1H), 7.08 (m, 1H), 7.00 (d, J=7.3 Hz, 1H), 4.28 (m, 1H) 3.75 (m, 1H), 3.65 (m, 1H), 2.80-2.55 (m, 6H), 2.47 (m, 1H), 2.30 (m, 1H), 2.06-1.86 (m, 5H), 1.74-1.66 (m, 3H).
Reaction SMILES: [C:1]([C:4]1[C:5](=[O:23])[CH2:6][CH2:7][C:8]2([CH2:19][CH2:20][CH2:21][CH3:22])[C:16]=1[C:15]1[C:10](=[CH:11][C:12]([NH2:18])=[C:13]([F:17])[CH:14]=1)[CH2:9]2)(=[O:3])[CH3:2].N#N.[Br:26]N1C(=O)CCC1=O>CN(C)C=O>[C:1]([C:4]1[C:5](=[O:23])[CH2:6][CH2:7][C:8]2([CH2:19][CH2:20][CH2:21][CH3:22])[C:16]=1[C:15]1[C:10](=[C:11]([Br:26])[C:12]([NH2:18])=[C:13]([F:17])[CH:14]=1)[CH2:9]2)(=[O:3])[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCCCC12CCC(=O)C(C(C)=O)=C1c1cc(F)c(N)cc1C2
Agent: N#N
Solvent: CN(C)C=O
Product: CCCCC12CCC(=O)C(C(C)=O)=C1c1cc(F)c(N)c(Br)c1C2
Reaction time: 1 h
Yield: 74.6 %

Procedure:
A solution of 4-acetyl-7-amino-9a-butyl-6-fluoro-1,2,9,9a-tetrahydro-3H-fluoren-3-one (157 mg, 0.5 mmol) in anhydrous N,N-dimethylformamide (1.5 mL) was purged with N2, cooled in an ice bath, and treated with N-bromosuccinimide (89 mg, 0.5 mmol). The resulting solution was stirred at 0–5° C. for one hour, and then partitioned between EtOAc and water. The aqueous portion was extracted with more EtOAc. The combined organics were washed with water and brine, dried over MgSO4, filtered, and concentrated under vacuum. The oily residue was purified by flash chromatography on a Biotage 12M column, eluting with 4:1 hexanes-EtOAc. The product containing fractions were evaporated under vacuum to afford 4-acetyl-7-amino-8-bromo-9a-butyl-6-fluoro-1,2,9,9a-tetrahydro-3H-fluoren-3-one (147 mg, 75%) as a yellow oil.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[O:9][C@H:10]([CH2:12][CH:13]=[CH2:14])[CH3:11].CC(O)C.C(=O)=O.[Li]CCCC.[B:27](OC(C)C)([O:32]C(C)C)[O:28]C(C)C.Cl>C1COCC1.CCCCCC>[F:8][C:5]1[CH:6]=[CH:7][C:2]([B:27]([OH:32])[OH:28])=[C:3]([O:9][C@H:10]([CH2:12][CH:13]=[CH2:14])[CH3:11])[CH:4]=1
Reactant: C=CC[C@H](C)Oc1cc(F)ccc1Br
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: Cl
Agent: O=C=O
Agent: [Li]CCCC
Solvent: CC(C)O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: C=CC[C@H](C)Oc1cc(F)ccc1B(O)O
Reaction time: 0.75 h
Yield: 101.5 %

Procedure:
A solution of (S)-1-bromo-4-fluoro-2-(pent-4-en-2-yloxy)benzene (0.66 mL, 2.55 mmol, 1 equiv) in THF (13 mL) was cooled to −78° C. (IPA/dry ice). nBuLi (1.9 mL of a 1.6 M solution in hexane, 3.06 mmol, 1.2 equiv) was added slowly. No color change observed. After 45 min, triisopropyl borate (0.70 mL, 3.06 mmol, 1.2 equiv) was added. The reaction was stirred 30 min. 1 N HCl (5 mL) was added and the reaction was removed from the cold bath. After 10 min, the reaction was added to water and extracted with DCM (×3). The combined DCM extracts were dried (Na2SO4) and concentrated in vacuo to provide the crude boronic acid (0.58 g, 100%) as a viscous pale yellow oil. Purity is ˜80%. The crude boronic acid was for used as is for the Suzuki coupling. 1H NMR (500 MHz, CDCl3) δ 7.85 (t, J=8.0 Hz, 1H), 6.74 (td, J=8.3, 2.2 Hz, 1H), 6.66-6.62 (m, 1H), 5.87 (ddt, J=17.1, 10.1, 7.1 Hz, 1H), 5.24-5.18 (m, 2H), 4.63-4.54 (m, 1H), 2.60-2.45 (m, 2H), 1.43 (d, J=6.1 Hz, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[NH:23][C:17]3[N:18]=[CH:19][N:20]=[C:21](Cl)[C:16]=3[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:24][C:25]1[C:33]2[C:28](=[CH:29][CH:30]=[C:31]([NH2:34])[CH:32]=2)[NH:27][N:26]=1>CC(O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[NH:23][C:17]3[N:18]=[CH:19][N:20]=[C:21]([NH:34][C:31]4[CH:32]=[C:33]5[C:28](=[CH:29][CH:30]=4)[NH:27][N:26]=[C:25]5[CH3:24])[C:16]=3[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CC=C(c2cc3c(Cl)ncnc3[nH]2)CC1
Reactant: Cc1n[nH]c2ccc(N)cc12
Solvent: CC(C)O
Product: Cc1n[nH]c2ccc(Nc3ncnc4[nH]c(C5=CCN(C(=O)OC(C)(C)C)CC5)cc34)cc12
Temperature: 90 °C

Procedure:
A mixture of 4-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (50.1 mg, 0.150 mmol) and 3-methyl-1H-indazol-5-ylamine (25.0 mg, 0.170 mmol) in iPrOH (2.5 mL) in a sealed tube was heated to 90° C. (bath temp.) for 16 h. The solvent was evaporated, water/NaHCO3 solution was added, the mixture was extracted with CH2Cl2 (3×30 mL), and the combined extracts were washed with brine and dried over MgSO4. The extracts were filtered through a pad of silica gel, washing with 5% MeOH in CH2Cl2 until no more product eluted as indicated by TLC. Concentration in vacuo gave a light brown solid. The solid was triturated with MeOH, filtered, washed with more MeOH, and dried in vacuo overnight. One obtained the title compound as white solid, mp. 245-250° C. (decomp.). 1H NMR (DMSO-d6, 400 MHz): δ=1.43 (s, 9H), 2.42-2.50 (brs, 2H), 2.47 (s, 3H), 3.53-3.59 (me, 2H), 3.99-4.08 (m, 2H), 6.38 (brs, 1H), 6.73 (brs, 1H), 7.43 (d, J=8.8 Hz, 1H), 7.69 (dd, J=1.6, 8.8 Hz, 1H), 8.15 (s, 1H), 8.23 (s, 1H), 9.32 (s, 1H), 11.88 (brs, 1H), 12.54 (s, 1H). MS (ES+): m/z 446.0 (100) [MH+]. HPLC: tR=2.4 min (ZQ2000, polar—5 min).
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:8]2[C:12]([C:13]3[O:26][C:25](=[O:27])[C:24]4[C:23]5[C:18](=[CH:19][CH:20]=[CH:21][N:22]=5)[CH:17]=[CH:16][C:15]=4[N:14]=3)=[CH:11][C:10]([C:28]([F:31])([F:30])[F:29])=[N:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.C(#N)C.O.[CH:36]([NH2:39])([CH3:38])[CH3:37]>[Cl-].[Na+].O>[CH:36]([NH:39][C:25]([C:24]1[C:15]([NH:14][C:13]([C:12]2[N:8]([C:3]3[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][N:4]=3)[N:9]=[C:10]([C:28]([F:31])([F:29])[F:30])[CH:11]=2)=[O:26])=[CH:16][CH:17]=[C:18]2[C:23]=1[N:22]=[CH:21][CH:20]=[CH:19]2)=[O:27])([CH3:38])[CH3:37]
Reactant: O=c1oc(-c2cc(C(F)(F)F)nn2-c2ncccc2Cl)nc2ccc3cccnc3c12
Reactant: CC(C)N
Agent: [Cl-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: CC(C)NC(=O)c1c(NC(=O)c2cc(C(F)(F)F)nn2-c2ncccc2Cl)ccc2cccnc12
Temperature: 25 °C
Reaction time: 6 h
Yield: 71 %

Procedure:
To a suspension of 140 mg (0.28 mmol) of the above 2-[2-(3-chloro-pyridin-2-yl)-5-trifluoromethyl-2H-pyrazol-3-yl]-3-oxa-1,5-diaza-phenanthren-4-one in 5.60 mL of a mixture acetonitrile: H2O 4:1 (v/v) is added 73 μL (0.85 mmol) of isopropylamine. The reaction mixture is stirred for 6 hours at ambient temperature. Brine is then added to the mixture and the product is extracted with ethyl acetate (3 times). The regrouped organic phases are dried on Na2SO4, filtrated and evaporated. The purification of the residue by flash chromatography (SiO2, heptane and ethyl acetate as eluants) affords 100 mg (70%) of a white solid; LC/MS: 503/505 (M+H)+, m.p.: 225-226° C.