Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:45])([F:44])[C:3]1[CH:4]=[C:5]([CH:37]=[C:38]([C:40]([F:43])([F:42])[F:41])[CH:39]=1)[CH2:6][N:7]([C@H:14]1[CH2:20][CH2:19][CH2:18][N:17]([CH2:21][CH:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)[C:16]2[CH:28]=[C:29]([C:33]([F:36])([F:35])[F:34])[C:30]([CH3:32])=[CH:31][C:15]1=2)[C:8]1[N:9]=[N:10][N:11]([CH3:13])[N:12]=1.[CH2:46]([O:48][C:49](=[O:52])[CH2:50]Br)[CH3:47].C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C>[CH2:46]([O:48][C:49](=[O:52])[CH2:50][N:25]1[CH2:24][CH2:23][CH:22]([CH2:21][N:17]2[CH2:18][CH2:19][CH2:20][C@H:14]([N:7]([CH2:6][C:5]3[CH:4]=[C:3]([C:2]([F:1])([F:44])[F:45])[CH:39]=[C:38]([C:40]([F:41])([F:42])[F:43])[CH:37]=3)[C:8]3[N:9]=[N:10][N:11]([CH3:13])[N:12]=3)[C:15]3[CH:31]=[C:30]([CH3:32])[C:29]([C:33]([F:34])([F:35])[F:36])=[CH:28][C:16]2=3)[CH2:27][CH2:26]1)[CH3:47]
Reactant: Cc1cc2c(cc1C(F)(F)F)N(CC1CCNCC1)CCC[C@@H]2N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1nnn(C)n1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CN1CCC(CN2CCC[C@H](N(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)c3nnn(C)n3)c3cc(C)c(C(F)(F)F)cc32)CC1
Temperature: 50 °C

Procedure:
To a solution of (S)-(3,5-Bis-trifluoromethyl-benzyl)-(7-methyl-1-piperidin-4-ylmethyl-8-trifluoromethyl-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl)-(2-methyl-2H-tetrazol-5-yl)-amine (Example 120) (0.18 mmol) in DMF (3 mL), add bromo-acetic acid ethyl ester (0.54 mmol) and cesium carbonate (0.90 mmol). After heating the mixture at 50° C. for 30 minutes, cool to room temperature and dilute the reaction with water (15 mL) and extract with ethyl acetate (3×10 mL). Dry the combined organic phases over sodium sulfate, filter, and remove solvent under vacuum. Chromatograph the product over silica gel, eluting with ethyl acetate/hexane (5-50%), to give the title compound as a colorless foam. MS (ES+): 736 (M+H).
Reaction SMILES: C[O:2][C:3]([C:5]1[N:6]=[C:7]2[CH:16]=[CH:15][C:14]([N:17]3[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]3)=[CH:13][N:8]2[C:9](=[O:12])[C:10]=1[OH:11])=O.[Cl:23][C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][C:31]=1[Cl:32])[CH2:27][NH2:28]>>[Cl:23][C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][C:31]=1[Cl:32])[CH2:27][NH:28][C:3]([C:5]1[N:6]=[C:7]2[CH:16]=[CH:15][C:14]([N:17]3[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]3)=[CH:13][N:8]2[C:9](=[O:12])[C:10]=1[OH:11])=[O:2]
Reactant: NCc1ccc(Cl)c(Cl)c1
Reactant: COC(=O)c1nc2ccc(N3CCCCC3)cn2c(=O)c1O
Product: O=C(NCc1ccc(Cl)c(Cl)c1)c1nc2ccc(N3CCCCC3)cn2c(=O)c1O

Procedure:
Using the product of Example 2.6, the procedure described in Example 6 was adapted (except only 1.3 eq. of 3,4-dichlorobenzylamine was used) to afford the desired compound.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([B:8]([OH:10])[OH:9])[CH:5]=[CH:6][CH:7]=1.[CH3:11][S:12](Cl)(=[O:14])=[O:13].O.C(OCC)(=O)C>N1C=CC=CC=1>[CH3:11][S:12]([O:1][C:2]1[CH:3]=[C:4]([B:8]([OH:10])[OH:9])[CH:5]=[CH:6][CH:7]=1)(=[O:14])=[O:13]
Reactant: OB(O)c1cccc(O)c1
Reactant: CS(=O)(=O)Cl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Solvent: O
Product: CS(=O)(=O)Oc1cccc(B(O)O)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 3-hydroxyphenylboronic acid (10 g) stirred in pyridine (40 mL) at 0° C. was added methanesulfonyl chloride (8 mL). The reaction mixture was stirred for 1 h at room temperature and then water and ethyl acetate was added. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with dilute HCl washed with brine, dried over magnesium sulfate. The resulting solid was recrystallizated from petroleum ether and ethyl acetate to give the sub-titled compound (12 g).
Reaction SMILES: FC(F)(F)S([O:6][S:7]([C:10]([F:13])([F:12])[F:11])(=[O:9])=[O:8])(=O)=O.[CH2:16]([O:18][C:19]1[CH:20]=[C:21]([C:28]2[S:29][CH:30]=[C:31]([C:33]3[CH:38]=[CH:37][C:36](O)=[C:35]([C:40]([O:42][CH3:43])=[O:41])[CH:34]=3)[N:32]=2)[CH:22]=[CH:23][C:24]=1[O:25][CH2:26][CH3:27])[CH3:17].C(N(CC)CC)C.O>ClCCl>[CH2:16]([O:18][C:19]1[CH:20]=[C:21]([C:28]2[S:29][CH:30]=[C:31]([C:33]3[CH:38]=[CH:37][C:36]([O:6][S:7]([C:10]([F:11])([F:12])[F:13])(=[O:8])=[O:9])=[C:35]([C:40]([O:42][CH3:43])=[O:41])[CH:34]=3)[N:32]=2)[CH:22]=[CH:23][C:24]=1[O:25][CH2:26][CH3:27])[CH3:17]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: CCOc1ccc(-c2nc(-c3ccc(O)c(C(=O)OC)c3)cs2)cc1OCC
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CCOc1ccc(-c2nc(-c3ccc(OS(=O)(=O)C(F)(F)F)c(C(=O)OC)c3)cs2)cc1OCC
Yield: 95.4 %

Procedure:
8.5 g of trifluoromethanesulfonic acid anhydride was added to a solution of 10 g of 2-(3,4-diethoxyphenyl)-4-(3-methoxycarbonyl-4-hydroxyphenyl)-thiazole dissolved in 100 ml of dichloromethane. Thereto was dropwise added 6 ml of triethylamine with stirring under ice-cooling. The reaction mixture was stirred at room temperature for 2 hours. Thereto was added 40 ml of water for phase separation. The organic layer was dried and subjected to distillation to remove the solvent. The residue was recrystallized from ethanol to obtain 12.7 g of 2-(3,4-diethoxyphenyl)-4-(3-methoxycarbonyl-4-trifluoromethanesulfonyloxyphenyl)thiazole as a white powder.
Reaction SMILES: [Br:1][C:2]1[C:17]([Cl:18])=[CH:16][C:5]([O:6][C:7]2[C:12]([C:13]([OH:15])=O)=[CH:11][N:10]=[CH:9][CH:8]=2)=[C:4]([Cl:19])[CH:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.[CH:53]1([N:56]2[C:65]3[C:60](=[CH:61][CH:62]=[CH:63][CH:64]=3)[NH:59][CH2:58][CH2:57]2)[CH2:55][CH2:54]1>CN(C)C=O.C(OCC)(=O)C.O>[Br:1][C:2]1[C:17]([Cl:18])=[CH:16][C:5]([O:6][C:7]2[CH:8]=[CH:9][N:10]=[CH:11][C:12]=2[C:13]([N:59]2[C:60]3[C:65](=[CH:64][CH:63]=[CH:62][CH:61]=3)[N:56]([CH:53]3[CH2:55][CH2:54]3)[CH2:57][CH2:58]2)=[O:15])=[C:4]([Cl:19])[CH:3]=1
Reactant: c1ccc2c(c1)NCCN2C1CC1
Reactant: O=C(O)c1cnccc1Oc1cc(Cl)c(Br)cc1Cl
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: O=C(c1cnccc1Oc1cc(Cl)c(Br)cc1Cl)N1CCN(C2CC2)c2ccccc21
Temperature: 25 °C
Reaction time: 17 h

Procedure:
To a suspension of 5.0 g (13.77 mmol) 4-(4-bromo-2,5-dichloro-phenoxy)-nicotinic acid in 30 mL N,N-dimethylformamide were added 5.50 g (14.46 mmol) 0-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU, commercially available, CAS RN 148893-10-1) and 7.03 mL (41.32 mmol) N,N-diisopropylethylamine. To this brown solution was added 2.52 g (14.46 mmol) 1-cyclopropyl-1,2,3,4-tetrahydro-quinoxaline (Example 8, intermediate a), the resulting clear brown solution was stirred at room temperature for 17 hours and then poured on 120 mL water and 120 mL ethyl acetate. The resulting mixture was filtered, the filter cake was thoroughly washed with water and a very small amount of ethyl acetate to give after drying 6.55 g (92%) of the title compound as a brown solid. MS (ESI): m/z=520.1 [M+H]+.
Reaction SMILES: [K].C1(=O)[NH:6]C(=O)C2=CC=CC=C12.[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][CH2:22]Br)=[CH:16][CH:15]=1.O.NN>CN(C=O)C.C(O)C.C(Cl)Cl.O>[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][CH2:22][NH2:6])=[CH:16][CH:15]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: Clc1ccc(CCCBr)cc1
Agent: NN
Agent: [K]
Solvent: CN(C)C=O
Solvent: CCO
Solvent: ClCCl
Product: NCCCc1ccc(Cl)cc1
Temperature: 80 °C
Reaction time: 16 h

Procedure:
The potassium salt of phthalimide (4.4 g, 24 mmol) was dissolved in DMF (20 ml) and 1-chloro-4-(3-bromopropyl)benzene (4.67 g, 20 mmol) was added. The mixture was stirred at 80° C. for 16 hours. Water (50 ml) and DCM (50 ml) were added, the phases were separated and the aqueous phase extracted with DCM (2×50 ml). The combined organic phases were washed with sodium hydroxide (0.2 M, 50 ml), dried (magnesium sulphate), filtered and concentrated in vacuo. Ethanol (75 ml) and hydrazine hydrate (2 equiv.) were added and the mixture was heated to reflux for 2 hours. After cooling the mixture was filtrated and the filter cake washed with DCM (2×50 ml). The filtrate and washings were evaporated and dissolved in ethyl acetate (40 ml). Washing of the organic phase with sodium hydroxide (0.4 M, 2×25 ml) and water (2×25 ml) followed by drying (magnesium sulphate), filtration and evaporation gave 3-(4-chlorophenyl)propylamine.
Reaction SMILES: [C:1]([NH:3][C:4]([NH:6][C@@H:7]([CH2:20][CH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1)[CH2:8][N:9]([CH3:19])[C:10]([O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])=[O:11])=S)#[N:2].Cl[C:28]1[CH:29]=[C:30]([C@:34]([C@@H:42]2[CH2:47][CH2:46][CH2:45][NH:44][CH2:43]2)([OH:41])[CH2:35][CH2:36][CH2:37][CH2:38][O:39][CH3:40])[CH:31]=[CH:32][CH:33]=1.C(Cl)CCl>CN(C=O)C.CCOCC>[C:1]([N:3]=[C:4]([N:44]1[CH2:45][CH2:46][CH2:47][C@@H:42]([C@:34]([OH:41])([C:30]2[CH:29]=[CH:28][CH:33]=[CH:32][CH:31]=2)[CH2:35][CH2:36][CH2:37][CH2:38][O:39][CH3:40])[CH2:43]1)[NH:6][C@@H:7]([CH2:20][CH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1)[CH2:8][N:9]([CH3:19])[C:10]([O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])=[O:11])#[N:2]
Reactant: COCCCC[C@@](O)(c1cccc(Cl)c1)[C@@H]1CCCNC1
Reactant: CN(C[C@H](CC1CCCCC1)NC(=S)NC#N)C(=O)OCC[Si](C)(C)C
Solvent: CCOCC
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: COCCCC[C@@](O)(c1ccccc1)[C@@H]1CCCN(C(=NC#N)N[C@@H](CC2CCCCC2)CN(C)C(=O)OCC[Si](C)(C)C)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 38.9 %

Procedure:
To a stirred solution of 1-cyano-3-((S)-3-cyclohexyl-1-(N-methyl-N-(2-(trimethylsilyl)ethoxycarbonyl)amino)propan-2-yl)thiourea (230 mg, 0.58 mmol) and (S)-1-(3-chlorophenyl)-5-methoxy-1-((R)-piperidin-3-yl)pentan-1-ol (180 mg, 0.58 mmol) in DMF (5 mL) was added EDC (0.17 g, 0.87 mmol). The mixture was stirred for 16 h at rt, diluted with ether (175 mL) and washed with 5% aq HCl (2×50 mL) and brine (50 mL). The combined aqueous washes were back extracted with ether. The combined ether extracts were concentrated to afford crude product (290 mg). The mixture was purified by prep HPLC to afford (3R)—N′-cyano-N—((S)-3-cyclohexyl-1-(N-methyl-N-(2-(trimethylsilyl)ethoxycarbonyl)amino)propan-2-yl)-3-((S)-1-hydroxy-5-methoxy-1-phenylpentyl)piperidine-1-carboxamidine (145 mg, 37%).
Reaction SMILES: [I:1][C:2]1[C:10]2[C:9]([C:11]#[N:12])=[CH:8][CH:7]=[CH:6][C:5]=2[NH:4][N:3]=1.[CH2:13]1[CH2:18][O:17][CH:16]=[CH:15][CH2:14]1.CC1C=CC(S(O)(=O)=O)=CC=1>C1COCC1>[I:1][C:2]1[C:10]2[C:9]([C:11]#[N:12])=[CH:8][CH:7]=[CH:6][C:5]=2[N:4]([CH:16]2[CH2:15][CH2:14][CH2:13][CH2:18][O:17]2)[N:3]=1
Reactant: C1=COCCC1
Reactant: N#Cc1cccc2[nH]nc(I)c12
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1CCOC1
Product: N#Cc1cccc2c1c(I)nn2C1CCCCO1
Temperature: 85 °C
Yield: 84.4 %

Procedure:
A mixture of 3-iodo-1H-indazole-4-carbonitrile (3.0 g, 11.1 mmol), DHP (1.84 g, 22.2 mmol), and TsOH (212 mg, 1.1 mmol) in THF (40 mL) under nitrogen was heated at 85° C. overnight. The reaction mixture was quenched with water (40 mL) and extracted with EtOAc (50 mL×3). The combined extracts were washed with brine, dried (MgSO4), filtered, and concentrated in vacuo. The residue was purified by SiO2 chromatography using petroleum ether/EtOAc (5:1) to afford 3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-4-carbonitrile as white solid (3.31 g, 84.0%). MS (ESI): m/z=354 [M+1]+.
Reaction SMILES: [CH2:1]([N:4]1[C:12](=[O:13])[C:11]2[N:10]=[C:9]([CH:14]([C:17]3[CH:27]=[CH:26][C:20]([O:21][CH2:22][C:23](O)=[O:24])=[CH:19][CH:18]=3)[CH2:15][CH3:16])[NH:8][C:7]=2[N:6]([CH2:28][CH2:29][CH3:30])[C:5]1=[O:31])[CH2:2][CH3:3].ON1C(=O)CCC1=O.Cl.CN(C)CCCN=C=NCC.[CH2:52]([NH2:55])[CH2:53][NH2:54]>CN(C)C=O.CO.[Cl-].[Na+].O>[NH2:54][CH2:53][CH2:52][NH:55][C:23](=[O:24])[CH2:22][O:21][C:20]1[CH:19]=[CH:18][C:17]([CH:14]([C:9]2[NH:8][C:7]3[N:6]([CH2:28][CH2:29][CH3:30])[C:5](=[O:31])[N:4]([CH2:1][CH2:2][CH3:3])[C:12](=[O:13])[C:11]=3[N:10]=2)[CH2:15][CH3:16])=[CH:27][CH:26]=1
Reactant: CCCn1c(=O)c2nc(C(CC)c3ccc(OCC(=O)O)cc3)[nH]c2n(CCC)c1=O
Reactant: NCCN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C1CCC(=O)N1O
Solvent: CO
Solvent: CN(C)C=O
Solvent: O
Product: CCCn1c(=O)c2nc(C(CC)c3ccc(OCC(=O)NCCN)cc3)[nH]c2n(CCC)c1=O
Reaction time: 1.5 h

Procedure:
Dissolve 2-[4-[1-(2,3,6,9-tetrahydro-1,3-dipropyl-2,6-dioxo-1H-purin-8-yl)propyl]phenoxy]acetic acid (720 mg, 1.68 mmol) in dimethylformamide (10 mL) and treat with N-hydroxysuccinimide (192 mg, 1.68 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (676 mg, 3.53 mmol). Stir for 1.5 hours and add to a solution of ethylenediamine (10 mL of a 10% solution in methanol). Stir for 1.5 hours, pour into brine (300 mL) and extract with ethyl acetate (3×200 mL) and chloroform (3×300 mL). Dry (MgSO4) and evaporate the solvent in vacuo. Purify by radial chromatography (5→10→20% methanol chloroform with 1% ammonium hydroxide) and recrystallize (10% isopropanol/pentane to give the title compound (51 mg) as a white solid; mp 139-40° C.
Reaction SMILES: [C:1](=O)([O-])[O-].[Li+].[Li+].[C:7]1([CH:15]=[CH:14][CH:13]=[C:11]([OH:12])[C:9]=1[OH:10])[OH:8].CI.O>CN(C)C=O>[CH3:1][O:10][C:9]1[C:7]([OH:8])=[CH:15][CH:14]=[CH:13][C:11]=1[OH:12]
Reactant: Oc1cccc(O)c1O
Reactant: O=C([O-])[O-]
Agent: [Li+]
Solvent: CI
Solvent: O
Solvent: CN(C)C=O
Product: COc1c(O)cccc1O
Temperature: 50 °C
Reaction time: 0.08 h
Yield: 39.9 %

Procedure:
Lithium carbonate (281 mg, 1.98 mmol) was added to pyrogallol (100 mg, 0.79 mmol) in N,N-dimethylformamide (3.0 mL) at room temperature. After five minutes, methyl iodide (130 μL, 1.98 mmol) was added and the resulting solution was heated to 50° C. for 48 hours. Upon cooling to room temperature, water (20 mL) was added and the solution was extracted with EtOAc (3×20 mL). Combined organic fractions were dried (Na2SO4), filtered, and concentrated. The residue was purified via column chromatography (SiO2, 5:1→1:1 Hexane:EtOAc) to afford 19 as a colorless amorphous solid (44.2 mg, 34%): 1H NMR (CDCl3, 400 MHz) δ 6.89 (td, J=8.0, 0.9 Hz, ′H), 6.53 (dd, J=8.2, 0.8 Hz, 2H), 5.83 (bs, 2H), 3.90 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([OH:11])=[CH:4][C:3]=1[CH3:12].C(=O)([O-])[O-].[K+].[K+].[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[OH-].[Na+]>CN(C=O)C>[CH2:19]([O:11][C:5]1[CH:6]=[C:7]([N+:8]([O-:10])=[O:9])[C:2]([NH2:1])=[C:3]([CH3:12])[CH:4]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: BrCc1ccccc1
Reactant: Cc1cc(O)cc([N+](=O)[O-])c1N
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc(OCc2ccccc2)cc([N+](=O)[O-])c1N
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
0.84 g (5.00 mmol) 4-amino-3-methyl-5-nitrophenol was placed in 10 mL DMF, combined with 0.78 g (5.50 mmol) potassium carbonate and stirred for 10 min at RT. Then 0.65 mL (5.50 mmol) benzylbromide were added and the mixture was stirred for a further 30 min at RT and for 1 h at 60° C. Another 0.33 mL benzylbromide were added and the mixture was stirred for 1 h at 60° C. The reaction mixture was poured onto ice water, extracted with ethyl acetate and evaporated down i.vac. The residue was purified by chromatography. The fractions containing product were combined and evaporated down i.vac. to leave the aqueous residue. This was neutralised with a 1M aqueous NaOH solution and extracted with ethyl acetate. The organic phase was evaporated down i.vac.
Reaction SMILES: C([O:8][NH:9][C:10](=[O:38])[CH2:11][CH:12]([C:27]1[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[C:29]([O:35][CH2:36][CH3:37])[CH:28]=1)[N:13]1[C:17](=[O:18])[C:16]2=[C:19]([N+:23]([O-])=O)[CH:20]=[CH:21][CH:22]=[C:15]2[C:14]1=[O:26])C1C=CC=CC=1.CCOCC>C(OCC)(=O)C.CO.[Pd]>[NH2:23][C:19]1[CH:20]=[CH:21][CH:22]=[C:15]2[C:14]([N:13]([CH:12]([C:27]3[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[C:29]([O:35][CH2:36][CH3:37])[CH:28]=3)[CH2:11][C:10]([NH:9][OH:8])=[O:38])[C:17](=[O:18])[C:16]=12)=[O:26]
Reactant: CCOc1cc(C(CC(=O)NOCc2ccccc2)N2C(=O)c3cccc([N+](=O)[O-])c3C2=O)ccc1OC
Agent: [Pd]
Solvent: CCOCC
Solvent: CO
Solvent: CCOC(C)=O
Product: CCOc1cc(C(CC(=O)NO)N2C(=O)c3cccc(N)c3C2=O)ccc1OC
Reaction time: 72 h
Yield: 64.1 %

Procedure:
A mixture of N-benzyloxy-3-(3-ethoxy-4-methoxyphenyl)-3-(3-nitrophthalimido)-propionamide (1.32 g, 2.54 mmol) and 10% Pd/C (230 mg) in ethyl acetate/methanol (150 mL each) was shaken under 50–60 psi of H2. After 3 days, the suspension was filtered through a pad of Celite, and the pad washed with methanol (75 mL) and methylene chloride (75 mL). The filtrate was concentrated in vacuo to give an oil. The oil was stirred with ether (20 mL) to afford 3-(3-aminophthalimido)-3-(3-ethoxy-4-methoxyphenyl)-N-hydroxypropionamide as a yellow solid (650 mg, 64% yield): mp, 143.0–145.0° C.; 1H NMR (DMSO-d6) δ 1.39 (t, J=6.9 Hz, 3H, CH3), 3.16 (d, J=7.8 Hz, 2H, CH2), 3.79 (s, 3H, CH3), 4.05 (q, J=6.9 Hz, 2H, CH2), 5.68 (t, J=7.8 Hz, 1H, NCH), 6.55 (br s, 2H, NH2), 6.98–7.08 (m, 5H, Ar), 7.47–7.53 (m, 1H, Ar), 8.88 (br s, 1H, OH), 10.66 (1H, NH); 13C NMR (DMSO-d6) δ 14.70, 34.37, 49.65, 55.47, 63.75, 108.64, 110.68, 111.77, 112.39, 119.61, 121.40, 131.69, 132.03, 135.19, 146.48, 147.65, 148.47, 166.14, 167.81, 169.18; Anal Calcd for C20H21N3O6: C, 60.14; H, 5.30; N, 10.52. Found: C, 59.76; H, 5.21; N, 10.30.
Reaction SMILES: [F:1][C:2]1[N:7]=[CH:6][C:5]([NH2:8])=[CH:4][CH:3]=1.C([Mg]Cl)(C)C.[CH:14]([C:17]1[NH:21][CH:20]=[C:19]([NH:22][C:23]2[C:32]3[CH2:31][CH2:30][CH2:29][CH2:28][C:27]=3[N:26]=[C:25]([N:33]3[CH2:37][CH2:36][CH2:35][CH:34]3[C:38](OC)=[O:39])[N:24]=2)[CH:18]=1)([CH3:16])[CH3:15]>C1COCC1>[F:1][C:2]1[N:7]=[CH:6][C:5]([NH:8][C:38]([CH:34]2[CH2:35][CH2:36][CH2:37][N:33]2[C:25]2[N:24]=[C:23]([NH:22][C:19]3[CH:18]=[C:17]([CH:14]([CH3:16])[CH3:15])[NH:21][CH:20]=3)[C:32]3[CH2:31][CH2:30][CH2:29][CH2:28][C:27]=3[N:26]=2)=[O:39])=[CH:4][CH:3]=1
Reactant: Nc1ccc(F)nc1
Reactant: COC(=O)C1CCCN1c1nc2c(c(Nc3c[nH]c(C(C)C)c3)n1)CCCC2
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: CC(C)c1cc(Nc2nc(N3CCCC3C(=O)Nc3ccc(F)nc3)nc3c2CCCC3)c[nH]1
Temperature: 25 °C
Reaction time: 2 h
Yield: 51.9 %

Procedure:
To a solution of 6-fluoropyridin-3-amine (1.41 g, 12.5 mmol) in THF (30 mL) was added 2M solution of isopropylmagnesium chloride in THF (6.2 mL, 12.4 mmol) dropwise at 0° C. The resultant mixture was stirred at the same temperature for 20 min followed by the dropwise addition of a solution of methyl 1-(4-(5-isopropyl-1H-pyrrol-3-ylamino)-5,6,7,8-tetrahydroquinazolin-2-yl)pyrrolidine-2-carboxylate (1.2 g, 3.12 mmol) in THF (10 mL) at 0° C. The reaction mixture was stirred at RT for 2 h. The progress of reaction was monitored by TLC and LCMS. The reaction mixture was quenched with saturated aqueous NH4Cl (40 mL) and was extracted with EtOAc (3×50 mL). The organic layer was washed with water (50 mL), dried over anhydrous sodium sulfate and concentrated under vacuum to obtain a crude product which was purified by column chromatography on silica (100-200 mesh using 1% MeOH-DCM system as eluent to afford N-(6-fluoropyridin-3-yl)-1-(4-(5-isopropyl-1H-pyrrol-3-ylamino)-5,6,7,8-tetrahydroquinazolin-2-yl)pyrrolidine-2-carboxamide (750 mg) as racemate. The enantiomers were separated by chiral HPLC to afford (R)—N-(6-fluoropyridin-3-yl)-1-(4-(5-isopropyl-1H-pyrazol-3-ylamino)-5,6,7,8 tetrahydroquinazolin-2-yl)pyrrolidine-2-carboxamide (200 mg), and its (S) enantiomer. 1H NMR (400 MHz, CDCl3, freebase) δ (ppm): 1.10-1.30 (m, 6H), 1.80-2.20 (m, 7H), 2.35-2.46 (m, 2H), 2.58-2.80 (m, 3H), 2.81-2.99 (m, 1H), 3.58-3.77 (m, 2H), 4.75 (brs, 1H), 6.20 (s, 1H), 6.83 (dd, 1H), 6.95 (s, 1H), 7.91 (s, 1H), 8.18 (s, 1H), 10.80 (brs, 1H).
Reaction SMILES: [C:1](=O)([O-])[O-].[K+].[K+].CI.[F:9][C:10]([F:21])([F:20])[C:11]1[C:16]([C:17]([OH:19])=[O:18])=[CH:15][N:14]=[CH:13][CH:12]=1.O>CN(C)C=O>[F:21][C:10]([F:9])([F:20])[C:11]1[C:16]([C:17]([O:19][CH3:1])=[O:18])=[CH:15][N:14]=[CH:13][CH:12]=1
Reactant: O=C([O-])[O-]
Reactant: O=C(O)c1cnccc1C(F)(F)F
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Solvent: O
Product: COC(=O)c1cnccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 12 h
Yield: 56 %

Procedure:
6.7 g (48.6 mmoles) of anhydrous potassium carbonate and 6.9 g (48.6 mmoles) of methyl iodide were added to a solution of 4.6 g (24.1 mmoles) of 4-trifluoromethylnicotinic acid dissolved in 70 ml of N,N-dimethylformamide. The mixture was stirred at room temperature for 12 hours to give rise to a reaction. After confirmation of the completion of the reaction, the reaction mixture was poured into water, followed by extraction with ethyl acetate. The resulting organic layer was washed with water and an aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to vacuum distillation to remove the solvent contained therein. The residue was purified by silica gel column chromatography (developing solvent: hexane-ethyl acetate mixed solvent) to obtain 2.77 g (yield: 56.1%) of methyl 4-trifluoromethylnicotinate as a yellow oily substance.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][CH2:6][N:7]2[C:12]([C:14]1([C:17](O)=[O:18])[CH2:16][CH2:15]1)=[O:13].C(Cl)(=O)C(Cl)=O.[H-].C(O[Al](OC(C)(C)C)OC(C)(C)C)(C)(C)C.[Li+]>C(Cl)Cl.C1COCC1.CN(C)C=O>[Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][CH2:6][N:7]2[C:12]([C:14]1([CH2:17][OH:18])[CH2:15][CH2:16]1)=[O:13]
Reactant: O=C(O)C1(C(=O)N2CCCc3c(Br)cccc32)CC1
Agent: CC(C)(C)O[Al](OC(C)(C)C)OC(C)(C)C
Agent: O=C(Cl)C(=O)Cl
Agent: [H-]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: ClCCl
Product: O=C(N1CCCc2c(Br)cccc21)C1(CO)CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 81.1 %

Procedure:
To a solution of 1-(5-bromo-1,2,3,4-tetrahydroquinoline-1-carbonyl)cyclopropanecarboxylic acid (0.58 g, 1.789 mmol) in CH2Cl2 (17 mL) at 0° C. was added N,N-dimethylformamide (2.78 μL, 0.036 mmol) and oxalyl chloride (0.187 mL, 2.147 mmol) slowly. The reaction mixture was stirred at 0° C. for 60 min, and then at room temperature for 16 h. The solvent was removed under reduced pressure and the crude acyl chloride (0.610 g, 1.78 mmol) was re-dissolved in THF (17.8 mL) and cooled to 0° C. Lithium tri-tert-butoxyaluminum hydride (7.12 mL, 7.12 mmol) was added, and the reaction mixture was stirred at 0° C. for 2 h. The reaction mixture was quenched with saturated NH4Cl (10 mL) and then stirred at room temperature for 30 min. After this time, the mixture was extracted with EtOAc (2×40 mL). The combined organic layer was dried, filtered and concentrated. The resulting residue was purified by flash chromatography (0 to 100% ethyl acetate:hexanes) to afford the title compound (0.45 g, 82% yield) as an oil. LCMS, [M+H]+=310.0. 1H NMR (400 MHz, CDCl3) δ 7.47 (d, J=8.7 Hz, 1H), 7.35 (d, J=8.0 Hz, 1H), 7.01 (dd, J=8.7, 8.0 Hz, 1H), 3.88-3.81 (m, 2H), 3.56 (d, J=5.8 Hz, 2H), 2.81 (t, J=6.9 Hz, 2H), 2.04-1.93 (m, 3H), 1.06 (dd, J=6.7, 4.9 Hz, 2H), 0.81 (dd, J=6.7, 4.9 Hz, 2H).