Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)CC)C.Cl.[CH3:9][C:10]1([OH:15])[CH2:14][CH2:13][NH:12][CH2:11]1.Cl[C:17]1[N:25]2[C@@H:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=3)[CH2:27][O:28][C:23]3=[C:24]2[C:19](=[CH:20][CH:21]=[C:22]3[C:35]2[C:36]([CH3:41])=[N:37][O:38][C:39]=2[CH3:40])[N:18]=1>CN1CCCC1=O.CO>[CH3:41][C:36]1[C:35]([C:22]2[C:23]3[O:28][CH2:27][C@H:26]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=4)[N:25]4[C:17]([N:12]5[CH2:13][CH2:14][C:10]([CH3:9])([OH:15])[CH2:11]5)=[N:18][C:19]([C:24]=34)=[CH:20][CH:21]=2)=[C:39]([CH3:40])[O:38][N:37]=1
Reactant: Cc1noc(C)c1-c1ccc2nc(Cl)n3c2c1OC[C@@H]3c1ccccn1
Reactant: CC1(O)CCNC1
Agent: Cl
Solvent: CO
Solvent: CCN(CC)CC
Solvent: CN1CCCC1=O
Product: Cc1noc(C)c1-c1ccc2nc(N3CCC(C)(O)C3)n3c2c1OC[C@@H]3c1ccccn1
Temperature: 150 °C

Procedure:
Triethylamine (0.76 mL, 5.5 mmol) and 3-methylpyrrolidin-3-ol hydrochloride (563 mg, 4.09 mmol) were added to (4S)-2-chloro-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazine (100 mg, 0.27 mmol) in N-methylpyrrolidinone (3 mL) and the resulting mixture was heated in a microwave at 150° C. for 20 min. The mixture was then diluted with methanol and purified by preparative LCMS at pH 2 buffer followed by preparative LCMC at pH 10 buffer to give the title compound as a mixture of diastereomers (47.1 mg, 40%). LCMS calc. for C24H26N5O3 (M+H)+: m/z=432.2. found: 432.2. The isomers were separated by prep chiral column chromatography: Column: phenomenex Lux Cellulose C-2 5 μm, 21, 2×250 mm, Mobile phase: 20% EtOH/Hexanes, gradient condition: isocratic at 18 mL/min, run time: 30 min, peak time: 23.0 and 25.7 min.
Reaction SMILES: Cl.[C:2]([NH:6][NH2:7])([CH3:5])([CH3:4])[CH3:3].[OH-:8].[Na+].[C:10](Cl)(=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C1(C)C=CC=CC=1>[C:2]([N:6]([C:10](=[O:8])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[NH:7][C:10](=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([CH3:5])([CH3:4])[CH3:3]
Reactant: O=C(Cl)c1ccccc1
Reactant: CC(C)(C)NN
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CC(C)(C)N(NC(=O)c1ccccc1)C(=O)c1ccccc1
Temperature: 5 °C
Reaction time: 0.25 h

Procedure:
To a stirred suspension of t-butylhydrazine hydrochloride (1.24 g, 10 mmoles) in toluene (50 ml) at room temperature, was added dropwise a solution of 50% aqueous sodium hydroxide (0.8 g, 10 ml). After 15 minutes, the reaction mixture was cooled to 5° C. and solutions of benzoyl chloride (2.82 gm, 20 ml) in toluene (7 ml) and 50% aqueous sodium hydroxide (1.6 g) were added dropwise and simultaneously from separate addition funnels while maintaining the temperature below 10° C. Following the addition, the reaction mixture was warmed to room temperature and stirred for 1 hr. The reaction mixture was diluted with ether and the product isolated by filtration. The product was washed with water and ether and dried. The product was recrystallized from ether-methanol to afford N'-t-butyl-N,N'-dibenzoylhydrazine as a white powder: m.p. 174°-176° C.
Reaction SMILES: [NH:1]1[C:10]2[C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[NH:7][CH2:6][CH2:5][C:4]=2[CH:3]=[N:2]1.[C:15]1([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:20]=[CH:19][C:18]([C:21](Cl)=[O:22])=[CH:17][CH:16]=1.[OH-].[Na+]>CO>[C:15]1([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:16]=[CH:17][C:18]([C:21]([N:7]2[C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=3[C:10]3[NH:1][N:2]=[CH:3][C:4]=3[CH2:5][CH2:6]2)=[O:22])=[CH:19][CH:20]=1
Reactant: c1ccc2c(c1)NCCc1cn[nH]c1-2
Reactant: O=C(Cl)c1ccc(-c2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(c1ccc(-c2ccccc2)cc1)N1CCc2cn[nH]c2-c2ccccc21

Procedure:
As described for Example 26, 2 mmol of 1,4,5,6-tetrahydropyrazolo[4,3-d][1]benzazepine is reacted with 5 mmol of [1,1'-biphenyl]-4-carbonyl chloride. The product is stirred in methanol with 2N NaOH for 16 hours and the mixture concentrated and extracted with ethyl acetate. The extract is washed with 1M citric acid, NaHCO3, H2O, dried (Na2SO4) and the solvent removed to give the product of the example as a solid.
Reaction SMILES: [C:1]12([OH:13])[CH2:10][C:5]3([OH:11])[CH2:6][CH:7]([CH2:9][C:3]([OH:12])([CH2:4]3)[CH2:2]1)[CH2:8]2.C(N(CC)CC)C.[O:21]1C[CH2:24][CH2:23][CH2:22]1.C(Cl)(=O)C=C>O>[C:22]([O:13][C:1]12[CH2:10][C:5]3([OH:11])[CH2:6][CH:7]([CH2:9][C:3]([OH:12])([CH2:4]3)[CH2:2]1)[CH2:8]2)(=[O:21])[CH:23]=[CH2:24]
Reactant: OC12CC3CC(O)(C1)CC(O)(C3)C2
Reactant: C1CCOC1
Agent: C=CC(=O)Cl
Solvent: O
Solvent: CCN(CC)CC
Product: C=CC(=O)OC12CC3CC(O)(CC(O)(C3)C1)C2
Temperature: 25 °C
Reaction time: 6 h

Procedure:
10 mmol of 1,3,5-adamantanetriol, 10 mmol of triethylamine, and 40 ml of tetrahydrofuran were mixed, and 10 mmol of acrylic acid chloride was added dropwise to this mixture for about 30 minutes. After completion of the dropwise addition, the mixture was stirred at room temperature for 6 hours. After the reaction had been completed, to the reaction mixture was added water and the resultant mixture was purified by column chromatography to give 1-acryloyloxy-3,5-dihydroxyadamantane.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[B:8]1[O:12]CC[O:9]1.[NH:13]([C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24])[CH2:14][C:15]([NH:17][C@H:18]([C:20]([OH:22])=[O:21])[CH3:19])=[O:16].C(N(CC)CC)C.C(P(=O)(OCC)OCC)#N>CN(C)C=O>[NH:13]([C:23]([O:25][CH2:26][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)=[O:24])[CH2:14][C:15]([NH:17][C@H:18]([C:20]([OH:22])=[O:21])[CH3:19])=[O:16].[NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[B:8]([OH:12])[OH:9]
Reactant: Nc1ccccc1B1OCCO1
Agent: CCOP(=O)(C#N)OCC
Agent: C[C@H](NC(=O)CNC(=O)OCc1ccccc1)C(=O)O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Nc1ccccc1B(O)O

Procedure:
To a solution of o-aminophenylboronic acid (13.7 g, 100 mmoles) in dichloromethane (200 ml) is added ethylene glycol (6.30 g, 102 mmoles). The solution is shaken for 20 minutes, and then stirred over solid sodium sulfate. Removal of the volatiles affords ethylene o-aminophenylboronate. To a flame dried three neck round bottom flask equipped with septum, stopper and gas inlet, is added ethylene o-aminophenylboronate (0.36 g, 2.20 mmoles) in dry dimethylformamide (10 ml). To this solution is added Z-Gly-Ala (0.62 g, 2.21 mmoles), triethylamine (0.62 ml, 4.45 mmoles), and finally diethyl cyanophosphonate (0.37 ml, 2.44 mmoles). After stirring the reaction at room temperature for 17 hours, the DMF is removed under reduced pressure. The remaining residue is dissolved in ethyl acetate, and washed sequentially with 10% HCl, saturated sodium bicarbonate, and brine. After drying the organic phase over magnesium sulfate, the salts are removed by filtration and filtrate concentrated in vacuum to leave (0.63 g) of Z-Gly-Ala-o- aminophenylboronic acid. This compound can be used "as is" in the present invention, or the benzyloxycarbonyl (Z) group can be removed by hydrogenolysis (see first step of Example 4).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3](=O)[CH:4]=[CH:5][NH:6][CH:7]=[CH:8][C:9]#[N:10].[OH-].[K+].CCCCCC.CC(C)=[O:24]>CO>[F:1][C:2]([F:13])([F:12])[C:3]1[C:8]([C:9]([NH2:10])=[O:24])=[CH:7][N:6]=[CH:5][CH:4]=1
Reactant: N#CC=CNC=CC(=O)C(F)(F)F
Reactant: CC(C)=O
Agent: [K+]
Agent: [OH-]
Solvent: CCCCCC
Solvent: CO
Product: NC(=O)c1cnccc1C(F)(F)F
Yield: 52.6 %

Procedure:
3-[(4,4,4-Trifluoro-3-oxo-1-butenyl)amino]-2-propenenitrile (a mixture of IIa and IIb; 1.90 g, 10 mmol) was dissolved in methanol (15 ml), and potassium hydroxide (990 mg, 15 mmol) was added. The mixture was heated under reflux for 6 hours. The reaction solution was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (a eluting solvent: hexane/acetone=1/1) to obtain 1.03 g (yield 52.6%) of the title compound.
Reaction SMILES: C1C=CC(P(C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CN=2)C2C=CC=CC=2)=CC=1.[CH:34]([O:37][C:38]([C@@H:40]1[CH2:44][C@H:43]([C:45](=[O:47])[CH3:46])[C@H:42]([C:48]2[CH:53]=[CH:52][C:51]([O:54][CH3:55])=[C:50]([O:56][CH2:57][CH2:58][CH2:59][O:60][CH3:61])[CH:49]=2)[NH:41]1)=[O:39])([CH3:36])[CH3:35]>>[CH:34]([O:37][C:38]([C@H:40]1[CH2:44][C@@H:43]([C:45](=[O:47])[CH3:46])[C@@H:42]([C:48]2[CH:53]=[CH:52][C:51]([O:54][CH3:55])=[C:50]([O:56][CH2:57][CH2:58][CH2:59][O:60][CH3:61])[CH:49]=2)[NH:41]1)=[O:39])([CH3:35])[CH3:36]
Reactant: COCCCOc1cc([C@@H]2N[C@H](C(=O)OC(C)C)C[C@@H]2C(C)=O)ccc1OC
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2nccc3ccccc23)cc1
Product: COCCCOc1cc([C@H]2N[C@@H](C(=O)OC(C)C)C[C@H]2C(C)=O)ccc1OC

Procedure:
In a similar fashion using (R)-QUINAP, (2S,4S,5R)-4-Acetyl-5-[4-methoxy-3-(3-methoxypropoxy)-phenyl]-pyrrolidine-2-carboxylic acid isopropyl ester, 1H-NMR, δ CDCl3: 6.89-6.79 (3H, m, Ph), 5.15 (1H, m, CHO), 4.52 (1H, d, PHCHN), 4.11 (2H, t, CH2O), 3.85 (3H, s, MeO), 3.60 (2H, t, CH2O), 3.41 (1H, m, CHCO), 3.48 (3H, s, MeO), 2.39 (1H, ddd, CH), 2.29 (1H, ddd, CH), 2.12 (2H, m, CH2), 1.30 (6H, 2 overlapping d, 2×Me), can be prepared. The epimer (2R,4R,5S)-4-Acetyl-5-[4-methoxy-3-(3-methoxy-propoxy)-phenyl]-pyrrolidine-2-carboxylic acid isopropyl ester, can also be isolated; 1H-NMR, δ CDCl3: 6.89-6.79 (3H, m, Ph), 5.15 (1H, m, CHO), 4.52 (1H, d, PHCHN), 4.11 (2H, t, CH2O), 3.85 (3H, s, MeO), 3.60 (2H, t, CH2O), 3.41 (1H, m, CHCO), 3.48 (3H, s, MeO), 2.39 (1H, ddd, CH), 2.29 (1H, ddd, CH), 2.12 (2H, m, CH2), 1.30 (6H, 2 overlapping d, 2×Me).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:25]=[CH:26][CH:27]=1)[CH:7]=[C:8]([C:22]([CH3:24])=[O:23])[C:9]([O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[O:10])([O-:3])=[O:2].[C:28]([CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])#[N:29].N1CCCCC1>C(O)C>[NH2:29][C:28]1[O:23][C:22]([CH3:24])=[C:8]([C:9]([O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[O:10])[CH:7]([C:6]2[CH:25]=[CH:26][CH:27]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[C:30]=1[C:31]([O:33][CH2:34][CH3:35])=[O:32]
Reactant: CCCCCCCCCCOC(=O)C(=Cc1cccc([N+](=O)[O-])c1)C(C)=O
Reactant: CCOC(=O)CC#N
Solvent: CCO
Solvent: C1CCNCC1
Product: CCCCCCCCCCOC(=O)C1=C(C)OC(N)=C(C(=O)OCC)C1c1cccc([N+](=O)[O-])c1

Procedure:
A solution of 5.7 g (15 mmol) of decyl 2-(3-nitrobenzylidene)acetoacetate and 1.8 g (15 mmol) of ethyl cyanoacetate in 15 ml of ethanol was heated to boiling in the presence of 0.3 ml of piperidine, for 4 hours. The solvent was then removed by distillation and the oily residue was purified by column chromatography (SiO2, chloroform) and brought to crystalli ation, melting point: 100° C., yield: 3.3 g (45%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[O:15][CH2:16][CH2:17][CH2:18]O)[CH:5]=[CH:4][C:3]=1[C:20]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[CH3:28])=[O:21].C1(C)C=CC(S(Cl)(=O)=O)=CC=1.[NH:40]1[CH2:45][CH2:44][O:43][CH2:42][CH2:41]1.O>N1C=CC=CC=1.CCOC(C)=O>[Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[O:15][CH2:16][CH2:17][CH2:18][N:40]2[CH2:45][CH2:44][O:43][CH2:42][CH2:41]2)[CH:5]=[CH:4][C:3]=1[C:20]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[CH3:28])=[O:21]
Reactant: C1COCCN1
Reactant: Cc1ccccc1C(=O)c1ccc(Nc2ccccc2OCCCO)cc1Cl
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1ccccc1C(=O)c1ccc(Nc2ccccc2OCCCN2CCOCC2)cc1Cl
Temperature: 25 °C
Reaction time: 48 h

Procedure:
Compound 198 (100 mg, 0.25 mmol) was dissolved in dry pyridine (130 μL) under an argon atmosphere. The solution was cooled on an ice bath and 4-toluenesulfonyl chloride (48 mg, 0.25 mmol) was added. The reaction mixture was quenched with water after 45 min at room temperature. The aqueous phase was extracted twice with EtOAc. The combined organic phases were washed with brine, dried (MgSO4), filtered and concentrated in vacuo. The crude product was purified by flash chromatography using petroleum ether/EtOAc 4:1 as the eluent. The tosylate was dissolved in dry DMF (2.0 mL) and morpholine (17 μL, 0.19 mmol) was added. The reaction mixture was stirred for 48 h at room temperature and then poured into a mixture of water and EtOAc. The aqueous phase was extracted with more EtOAc (×2). The combined organic phases were washed with water, dried (MgSO4), filtered and concentrated in vacuo. The crude product was purified by flash chromatography using DCM/MeOH 100:4 as the eluent to afford the title compound as a yellow oil.
Reaction SMILES: [F:1][C:2]([F:46])([F:45])[C:3]1[CH:4]=[C:5]([CH:38]=[C:39]([C:41]([F:44])([F:43])[F:42])[CH:40]=1)[CH2:6][N:7]1[C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:10]([C:18]2[O:22][N:21]=[C:20]([CH2:23][CH:24](OC)[O:25]C)[C:19]=2[C:29]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2[Cl:37])=[O:30])[N:9]=[N:8]1.C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(C)=O.O>[F:45][C:2]([F:1])([F:46])[C:3]1[CH:4]=[C:5]([CH:38]=[C:39]([C:41]([F:44])([F:42])[F:43])[CH:40]=1)[CH2:6][N:7]1[C:11]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[C:10]([C:18]2[O:22][N:21]=[C:20]([CH2:23][CH:24]=[O:25])[C:19]=2[C:29](=[O:30])[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2[Cl:37])[N:9]=[N:8]1
Reactant: COC(Cc1noc(-c2nnn(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)c2-c2ccccc2)c1C(=O)c1ccccc1Cl)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)=O
Solvent: O
Product: O=CCc1noc(-c2nnn(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)c2-c2ccccc2)c1C(=O)c1ccccc1Cl
Temperature: 60 °C
Reaction time: 8 h

Procedure:
Combine [5-[1-(3,5-bis-trifluoromethyl-benzyl)-5-phenyl-1H-[1,2,3]triazol-4-yl]-3-(2,2-dimethoxy-ethyl)-isoxazol-4-yl]-(2-chloro-phenyl)-methanone (1 eq) in acetone/H2O (4:1) and p-toluenesulfonic acid (1 eq) with stirring. Attach a reflux condensor and stir overnight in a 60° C. oil bath. Neutralize with saturated aqueous NaHCO3, extract with ethyl acetate, dry over MgSO4, filter, and concentrate under vacuum. 1H NMR (CDCl3): δ 9.84 (s, 1H), 7.83 (s, 1H), 7.56–7.09 (m, 11H), 5.43 (s, 2H), 4.09 (s, 2H).
Reaction SMILES: [CH3:1][C:2]1[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][C:3]=1[C:4]([C:20]#[CH:21])([OH:19])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH2:13][N:14]([CH2:17][CH3:18])[CH2:15][CH3:16])=[CH:7][CH:6]=1.[H][H]>[Pd].CO>[CH3:1][C:2]1[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][C:3]=1[C:4]([CH2:20][CH3:21])([OH:19])[C:5]1[CH:6]=[CH:7][C:8]([O:11][CH2:12][CH2:13][N:14]([CH2:15][CH3:16])[CH2:17][CH3:18])=[CH:9][CH:10]=1
Reactant: C#CC(O)(c1ccc(OCCN(CC)CC)cc1)c1cc(C)ccc1C
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CCN(CC)CCOc1ccc(C(O)(CC)c2cc(C)ccc2C)cc1

Procedure:
10.5 g. of 2,5-dimethyl-4'-[2-(diethylamino)-ethoxy]-α-ethinyl-benzhydrol are dissolved in 110 ml. of methanol, and 0.5 g. of a 10% palladium-on-charcoal catalyst are added to the mixture. The reaction mixture is hydrogenated until the uptake of the calculated amount of hydrogen is complete. Thereafter the catalyst is filtered off, and the solvent is evaporated in vacuo. Recrystallization of the solid residue obtained from a mixture of n-hexane and ethyl acetate yields 9.1 g. of the title compound, melting at 89° to 90° C.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][C:9]1[S:10][CH:11]=[C:12]([C:14]([N:16]2[CH2:27][CH2:26][C:20]3([CH2:25][CH2:24][NH:23][CH2:22][CH2:21]3)[O:19][CH2:18][CH2:17]2)=[O:15])[N:13]=1.C(N(CC)CC)C.Br[CH2:36][C:37]1[CH:38]=[C:39]([CH2:43][CH2:44][OH:45])[CH:40]=[CH:41][CH:42]=1>C(#N)C>[OH:45][CH2:44][CH2:43][C:39]1[CH:38]=[C:37]([CH:42]=[CH:41][CH:40]=1)[CH2:36][N:23]1[CH2:24][CH2:25][C:20]2([CH2:26][CH2:27][N:16]([C:14]([C:12]3[N:13]=[C:9]([CH3:8])[S:10][CH:11]=3)=[O:15])[CH2:17][CH2:18][O:19]2)[CH2:21][CH2:22]1
Reactant: OCCc1cccc(CBr)c1
Reactant: Cc1nc(C(=O)N2CCOC3(CCNCC3)CC2)cs1
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cc1nc(C(=O)N2CCOC3(CCN(Cc4cccc(CCO)c4)CC3)CC2)cs1
Temperature: 20 °C
Reaction time: 3 h

Procedure:
A solution of (2-methylthiazol-4-yl)(7-oxa-3,10-diazaspiro[5.6]dodecan-10-yl)methanone trifluoroacetate (example 89, step g) (0.21 g) in acetonitrile (15 mL) was treated with triethylamine (0.214 mL) followed by 2-(3-(bromomethyl)phenyl)ethanol (example 6, step a) (0.121 g). The reaction mixture was stirred for 3 hours at 20° C. The solvent was evaporated under reduced pressure and the residue was partitioned between DCM and saturated sodium bicarbonate solution. The aqueous layer was re-extracted twice with DCM and the combined organics were dried over sodium sulphate, filtered and the solvent removed under reduced pressure. The crude product was purified by flash silica chromatography using 6% methanol in dichloromethane with 1% triethylamine as solvent. Pure fractions were evaporated to dryness to afford the subtitled compound. Yield 0.21 g.
Reaction SMILES: [C:1]([NH:5][C:6]1[C:15]2[C:10](=[C:11]([NH2:16])[CH:12]=[CH:13][CH:14]=2)[N:9]=[CH:8][N:7]=1)([CH3:4])([CH3:3])[CH3:2].[Cl:17][C:18]1[C:23]([C:24](O)=[O:25])=[C:22]([F:27])[C:21]([CH2:28][NH:29][C:30](=[O:34])[CH:31]([CH3:33])[CH3:32])=[CH:20][CH:19]=1.S(Cl)(Cl)=O.CCN(C(C)C)C(C)C>C1COCC1>[C:1]([NH:5][C:6]1[C:15]2[C:10](=[C:11]([NH:16][C:24](=[O:25])[C:23]3[C:18]([Cl:17])=[CH:19][CH:20]=[C:21]([CH2:28][NH:29][C:30](=[O:34])[CH:31]([CH3:32])[CH3:33])[C:22]=3[F:27])[CH:12]=[CH:13][CH:14]=2)[N:9]=[CH:8][N:7]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)Nc1ncnc2c(N)cccc12
Reactant: CC(C)C(=O)NCc1ccc(Cl)c(C(=O)O)c1F
Solvent: C1CCOC1
Solvent: O=S(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)C(=O)NCc1ccc(Cl)c(C(=O)Nc2cccc3c(NC(C)(C)C)ncnc23)c1F
Yield: 6 %

Procedure:
The title compound was prepared following the procedure described in Example-1 using N4-(tert-butyl)quinazoline-4,8-diamine (Intermediate-55, 100 mg, 0.46 mmol), 6-chloro-2-fluoro-3-(isobutyramidomethyl)benzoic acid (Intermediate-60, 188 mg, 0.69 mmol), thionyl chloride (1 mL), and DIPEA (238 mg, 1.80 mmol) in THF (2 mL) to afford 13 mg of the title product. 1H NMR (300 MHz, DMSO-d6): δ 10.42 (s, 1H), 8.69 (d, 1H), 8.50 (s, 1H), 8.37 (t, 1H), 8.15 (d, 1H), 7.52-7.40 (m, 4H), 4.32 (d, 2H), 1.55 (s, 9H), 1.03 (d, J=6.3 Hz, 6H); MS [M+H]+: 474.34.
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[C:12]2[C:7](=[CH:8][C:9]([Cl:14])=[CH:10][C:11]=2[Cl:13])[NH:6][C@@H:5]([C:15]([O:17][CH3:18])=[O:16])[CH2:4]1.C(N(CC)CC)C.[C:26]1([N:32]=[C:33]=[O:34])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>ClCCl>[Cl:13][C:11]1[CH:10]=[C:9]([Cl:14])[CH:8]=[C:7]2[C:12]=1[C@@H:3]([NH:2][C:33]([NH:32][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:34])[CH2:4][C@H:5]([C:15]([O:17][CH3:18])=[O:16])[NH:6]2
Reactant: COC(=O)[C@H]1C[C@H](N)c2c(Cl)cc(Cl)cc2N1
Reactant: O=C=Nc1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)[C@H]1C[C@H](NC(=O)Nc2ccccc2)c2c(Cl)cc(Cl)cc2N1
Yield: 73.1 %

Procedure:
To a suspension of trans-4-amino-5,7-dichloro-2-methoxycarbonyl-1,2,3,4-tetrahydroquinoline hydrochloride (0.200 g, 0.642 mmol) in anhydrous dichloromethane (20 ml) under an atmosphere of nitrogen was added dry triethylamine (0.098 ml, 0.706 mmol) and the mixture was stirred until dissolution was complete. To this solution was then added phenyl isocyanate (0.077 ml, 0.706 mmol) and the resulting mixture was stirred at room temperature for 2 h. The solvent was removed under vacuum and the residue was partitioned between ethyl acetate (150 ml) and 1M aqueous citric acid (75 ml). The organic layer was successively washed with 1M aqueous citric acid (1×75 ml), saturated sodium bicarbonate solution (2×75 ml) and saturated brine (1×75 ml), then dried (MgSO4) and evaporated. The crude product was recrystallised from methanol to give the title compound as colourless crystals (0.185 g), m.p. 228°-229° C. (dec). δ (DMSO, 360 MHz) 1.67 (1H, ddd, J=12.7, 12.4 and 3.5 Hz, CHACHBHCCHD), 2.34 (1H, dm, J=12.7 Hz, CHACHBHCCHD), 3.73 (3H, s, CO2CH3), 4.00 (1H, dd, J=12.4 and 2.9 Hz, CH ACHBHCCHD), 4.94 (1H, m, CHACHBHCCHDNHCO), 6.53 (1H, d, J=6.4 Hz, CHDNHCONAr), 6.72 (1H, d, J=2.0 Hz, 6-H or 8-H), 6.88-6.93 (3H, m, 6-H or 8-H, ArH and ArNH), 7.20-7.25 (2H, m, ArH) 7.39 (2H, d, J=8.0 Hz, ArH), 8.15 (1H, s, CHDNHCONHAr); m/e 393 (M+), 198 (100%, M-NHCONHPh, CO2CH3 and H); Found C, 54.76; H, 4.39; N, 10.48; C18H17Cl2N3O3 requires C, 54.84; H, 4.35; N, 10.66%.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C@H:4]1[CH2:8][O:7][C:6]([CH3:10])([CH3:9])[N:5]1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12].C(N(C(C)C)C(C)C)C.[CH3:27][S:28](Cl)(=[O:30])=[O:29].O>ClCCl>[C:14]([O:13][C:11]([N:5]1[C@@H:4]([CH2:3][CH2:2][O:1][S:28]([CH3:27])(=[O:30])=[O:29])[CH2:8][O:7][C:6]1([CH3:10])[CH3:9])=[O:12])([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(C)(C)OC(=O)N1[C@@H](CCO)COC1(C)C
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1[C@@H](CCOS(C)(=O)=O)COC1(C)C

Procedure:
To a stirred solution of tert-butyl (S)-4-(2-hydroxyethyl)-2,2-dimethyl-oxazolidine-3-carboxylate (1.0 g) at 0° C. (ice cooling) in dichloromethane (25 ml) under an argon atmosphere were added N-ethyldiisopropylamine (3.5 ml) and methanesulfonyl chloride (0.56 g). The mixture was stirred at 0° C. for 2.5 hours Water was added and the mixture was extracted 3 times with dichloromethane. The combined organic layers were dried (MgSO4) and evaporated to yield crude (S)-4-(2-methanesulfonyloxy-ethyl)-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester. To a stirred solution of this compound (1.4 g) at room temperature in tetrahydrofuran (15 ml) under an argon atmosphere were added 4-fluorothiophenol (1.11 g) and triethylamine (0.88 g). The mixture was stirred at room temperature overnight. The solvent was evaporated and the residue was purified by column chromatography (SiO2; heptane/EtOAc=4:1) to give (S)-4-[2-(4-fluoro-phenylsulfanyl)-ethyl]-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester (1.0 g) as a colourless oil which was used for the next step.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[C:9]([O:17][CH2:18][CH2:19][O:20][CH2:21][N:22]1[CH:29]=[C:28]([CH:30]=[CH2:31])[C:26](=[O:27])[NH:25][C:23]1=[O:24])(=[O:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[N-:32]=[N+:33]=[N-:34].[Na+]>COCCOC.O>[C:9]([O:17][CH2:18][CH2:19][O:20][CH2:21][N:22]1[CH:29]=[C:28]([CH:30]([N:32]=[N+:33]=[N-:34])[CH2:31][Br:1])[C:26](=[O:27])[NH:25][C:23]1=[O:24])(=[O:16])[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: [N-]=[N+]=[N-]
Reactant: C=Cc1cn(COCCOC(=O)c2ccccc2)c(=O)[nH]c1=O
Reactant: O=C1CCC(=O)N1Br
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: [N-]=[N+]=NC(CBr)c1cn(COCCOC(=O)c2ccccc2)c(=O)[nH]c1=O
Reaction time: 0.5 h
Yield: 45.4 %

Procedure:
N-Bromosuccinimide (NBS, 350 mg, 1.96 mmol) was added in aliquots to a precooled (−5° C.) suspension prepared by mixing a solution of 3 (61 mg, 1.95 mmol) in 1,2-dimethoxyethane (25 ml) with a solution of sodium azide (510 mg, 7.84 mmol) in water (1.2 ml). The initial yellow color faded away after each addition. When all the NBS was consumed, the reaction mixture was allowed to stand at 0° C. for 30 min., prior to pouring onto ice-water (25 ml), and extraction with dichloromethane (3×50 ml). The dichloromethane extract was washed with cold water (25 ml), dried (Na2SO4), the solvent was removed in vacuo to yield a residue which was purified by elution from a silica gel column using chloroform:methanol (98:2, v/v) as eluent to yield 4 (388 mg, 45.5%) as a viscous oil which was used in the next reaction.