Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:5][N:6]=[C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH2:18][CH2:19][Cl:20])[CH:15]=2)[O:10][C:9]([C:21]2[N:26]=[CH:25][N:24]3[CH:27]=[CH:28][CH:29]=[C:23]3[CH:22]=2)=[CH:8]1)(C)(C)C.[CH3:30][CH:31]1[CH2:35][CH2:34][CH2:33][NH:32]1>>[ClH:20].[CH3:30][CH:31]1[CH2:35][CH2:34][CH2:33][N:32]1[CH2:19][CH2:18][O:17][C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][CH:13]=1)[O:10][C:9]([C:21]1[N:26]=[CH:25][N:24]3[CH:27]=[CH:28][CH:29]=[C:23]3[CH:22]=1)=[CH:8][C:7]2=[N:6][OH:5]
Reactant: CC1CCCN1
Reactant: CC(C)(C)ON=c1cc(-c2cc3cccn3cn2)oc2ccc(OCCCl)cc12
Product: CC1CCCN1CCOc1ccc2oc(-c3cc4cccn4cn3)cc(=NO)c2c1
Product: Cl

Procedure:
6-[2-(2-methyl-pyrrolidin-1-yl)-ethoxy]-2-pyrrolo[1,2-c]pyrimidin-3-yl-chromen-4-one oxime, hydrochloride was prepared in 22% overall yield using the method described in example 87, starting from 6-(2-chloro-ethoxy)-2-pyrrolo[1,2-c]pyrimidin-3-yl-chromen-4-one O-tert-butyl oxime (example 87B) and 2-methylpyrrolidine.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]([O:13]CC)=O)=[N:9][N:10]=2)[CH:7]=1.Cl.Cl.[F:18][C:19]1[CH:20]=[CH:21][C:22]([C:31]([F:34])([F:33])[F:32])=[C:23]([CH:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[CH:24]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>C1COCC1.O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]([N:28]3[CH2:29][CH2:30][CH:25]([C:23]4[CH:24]=[C:19]([F:18])[CH:20]=[CH:21][C:22]=4[C:31]([F:34])([F:32])[F:33])[CH2:26][CH2:27]3)=[O:13])=[N:9][N:10]=2)[CH:7]=1
Reactant: CCOC(=O)c1nnc2ccc(Br)cn12
Reactant: Fc1ccc(C(F)(F)F)c(C2CCNCC2)c1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: O=C(c1nnc2ccc(Br)cn12)N1CCC(c2cc(F)ccc2C(F)(F)F)CC1
Reaction time: 0.33 h
Yield: 64.3 %

Procedure:
To a solution of ethyl 6-bromo-[1,2,4]triazolo[4,3-a]pyridine-3-carboxylate (85 mg, 0.32 mmol) in THF (2.6 mL) was added a solution of LiOH monohydrate (15 mg, 0.35 mmol) in H2O (1.8 mL). The mixture stirred for 20 min and was neutralized with 2 N HCl. The mixture was concentrated under reduced pressure. The obtained residue was diluted in DMF (3.0 mL) under an atmosphere of N2. To this mixture was added 4-(5-fluoro-2-trifluoromethyl)phenylpiperidine hydrochloride (11, 89 mg, 0.32 mmol), benzotriazole-1-yl-oxy-tris-(dimethylamino)-phosphonium hexafluorophosphate (280 mg, 0.63 mmol), and diisopropylethylamine (0.17 mL, 0.95 mmol). The mixture was stirred at ambient temperature for 18 h. The resulting mixture was diluted with H2O (20 mL). The solution was extracted with EtOAc (3×20 mL). The combined organic layers were washed with a saturated brine solution (3×20 mL) and concentrated under reduced pressure. The resulting residue was chromatographed over silica gel (Isco CombiFlash Rf unit, 12 g Redisep column, 0% to 50% EtOAc in hexanes) to provide to provide (6-bromo-[1,2,4]triazolo[4,3-a]pyridin-3-yl)(4-(5-fluoro-2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone as a white solid (97 mg, 65%): 1H NMR (500 MHz, DMSO-d6) δ 9.16-9.14 (m, 1H), 7.98 (dd, J=10.0, 1.0 Hz, 1H), 7.77 (dd, J=8.5, 5.5 Hz, 1H), 7.72 (dd, J=9.5, 1.5 Hz, 1H), 7.52 (dd, J=11.0, 3.5 Hz, 1H), 7.29-7.23 (m, 1H), 5.31-5.24 (m, 1H), 4.76-4.70 (m, 1H), 3.42-3.32 (m, 1H), 3.27-3.19 (m, 1H), 3.06-2.96 (m, 1H), 1.98-1.75 (m, 4H).
Reaction SMILES: C(O[C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[CH:10]([CH3:24])[CH2:9]1)=[O:7])(C)(C)C.FC(F)(F)C(O)=O.[I:32][C:33]1[CH:41]=[CH:40][C:39]([S:42]([CH3:45])(=[O:44])=[O:43])=[CH:38][C:34]=1C(O)=O.C(N(C(C)C)C(C)C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>ClCCl>[I:32][C:33]1[CH:41]=[CH:40][C:39]([S:42]([CH3:45])(=[O:44])=[O:43])=[CH:38][C:34]=1[C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:21])[F:22])=[CH:16][CH:15]=2)[CH:10]([CH3:24])[CH2:9]1)=[O:7]
Reactant: CS(=O)(=O)c1ccc(I)c(C(=O)O)c1
Reactant: CC1CN(C(=O)OC(C)(C)C)CCN1c1ccc(C(F)(F)F)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC1CN(C(=O)c2cc(S(C)(=O)=O)ccc2I)CCN1c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 97.8 %

Procedure:
To a solution of rac-3-Methyl-4-(4-trifluoromethyl-phenyl)-piperazine-1-carboxylic acid tert-butyl ester (95 mg, 0.27 mmol) in dichloromethane (2 ml) was added trifluoroacetic acid (1 ml) and the reaction mixture was stirred at room temperature for 30 min. After such time the reaction mixture was concentrated in vacuo, and the residue was dissolved in dimethylformamide (3 ml). To the solution were added 2-Iodo-5-methanesulfonyl-benzoic acid (81 mg, 0.25 mmol), N-ethyldiisopropylamine (0.29 ml, 1.7 mmol), and TBTU (99 mg, 0.3 mmol). The reaction mixture was then allowed to stir at room temperature for 2 hours. The reaction mixture was then concentrated in vacuo and the residue was purified by column chromatography (SiO2, 20 g, Heptane/EtOAc 0-100%) to give the title compound as a light brown solid (135 mg, 90%). MS (m/e): 553.1 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[CH:4][CH:3]=1.[CH:11]([C@H:13]1[CH2:17][CH2:16][CH2:15][N:14]1[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=O.[NH:25]1[C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=2[N:27]=[N:26]1.C1(C)C=CC(S(O)(=O)=O)=CC=1>>[N:25]1([CH:11]([NH:8][C:6](=[O:7])[C:5]2[CH:9]=[CH:10][C:2]([Cl:1])=[CH:3][CH:4]=2)[C@H:13]2[CH2:17][CH2:16][CH2:15][N:14]2[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=2[N:27]=[N:26]1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1C=O
Reactant: c1ccc2[nH]nnc2c1
Reactant: NC(=O)c1ccc(Cl)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: CC(C)(C)OC(=O)N1CCC[C@@H]1C(NC(=O)c1ccc(Cl)cc1)n1nnc2ccccc21

Procedure:
4-Chlorobenzamide, tert-butyl (2R)-formyl-1-pyrrolidinecarboxylate, benzotriazole, and p-toluenesulfonic acid were processed as described in Example 53A to provide the desired product.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:14](=[CH:15][CH:16]=1)[O:13][C:7]1[CH:8]=[N:9][C:10]([Cl:12])=[CH:11][C:6]=1[C:5]2([CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])O.[N:24]([Si](C)(C)C)=[N+:25]=[N-:26].C([O+]([B-](F)(F)F)CC)C>C1(C)C=CC=CC=1>[N:24]([C:5]1([CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:6]2[CH:11]=[C:10]([Cl:12])[N:9]=[CH:8][C:7]=2[O:13][C:14]2[C:4]1=[CH:3][C:2]([Br:1])=[CH:16][CH:15]=2)=[N+:25]=[N-:26]
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: CCOC(=O)CC1(O)c2cc(Br)ccc2Oc2cnc(Cl)cc21
Agent: CC[O+](CC)[B-](F)(F)F
Solvent: Cc1ccccc1
Product: CCOC(=O)CC1(N=[N+]=[N-])c2cc(Br)ccc2Oc2cnc(Cl)cc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 99.3 %

Procedure:
To a solution of ethyl 2-(7-bromo-3-chloro-5-hydroxy-5H-chromeno[2,3-c]pyridin-5-yl)acetate (38.5 g, 97 mmol) in toluene (400 ml) was added azidotrimethylsilane (38.4 ml, 290 mmol) followed by (diethyloxonio)trifluoroborate (24.48 ml, 193 mmol) under an atmosphere of nitrogen. The reaction mixture was stirred at RT for 16 hours. The reaction mixture was quenched with MeOH (200 mL) and diluted with EtOAc. The organic phase was separated, washed with saturated aqueous sodium bicarbonate solution and brine. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure to afford ethyl 2-(5-azido-7-bromo-3-chloro-5H-chromeno[2,3-c]pyridin-5-yl)acetate (40.82 g) which was used in the next step without further purification.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10](/[CH:17]=[CH:18]/[C:19](O)=[O:20])=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:22]([NH:25][NH:26][C:27](=[O:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)([CH3:24])[CH3:23].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>CN(C=O)C.CCOC(C)=O>[C:27]([NH:26][N:25]([C:19](=[O:20])/[CH:18]=[CH:17]/[C:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:8]([C:6]([O:5][C:1]([CH3:3])([CH3:4])[CH3:2])=[O:7])[CH:9]=1)[CH:22]([CH3:24])[CH3:23])(=[O:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: CC(C)NNC(=O)c1ccccc1
Reactant: CC(C)(C)OC(=O)n1cc(/C=C/C(=O)O)c2ccccc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)N(NC(=O)c1ccccc1)C(=O)/C=C/c1cn(C(=O)OC(C)(C)C)c2ccccc12
Temperature: 25 °C
Reaction time: 12 h
Yield: 62.3 %

Procedure:
To solution containing (E)-3-(1-(tert-butoxycarbonyl)-1H-indol-3-yl)acrylic acid (1000 mg, 3.48 mmol), N′-isopropylbenzohydrazide (930.51 mg, 5.22 mmol) and HATU (1985.12 mg, 5.22 mmol) dissolved in DMF (15.0 ml), N,N-diisopropylethylamine (DIPEA)(0.90943 ml, 5.22 mmol) was slowly drop-wise added and stirred at room temperature for 12 hr. The reaction mixture was diluted with EtOAc, washed with water and brine, dried with anhydrous MgSO4 filtered, and concentrated under reduced pressure. The residue was separated through silica gel chromatography (n-hexane:EtOAc=3:1) and dried so that ivory (E)-tert-butyl 3-(3-(2-benzoyl-1-isopropylhydrazinyl)-3-oxoprop-1-enyl)-1H-indole-1-carboxylate was obtained as white solid (970 mg, 62.3%).
Reaction SMILES: Br.[CH3:2][O:3][CH2:4][CH2:5][N:6]1[C:10]2[CH2:11][CH2:12][CH2:13][CH2:14][C:9]=2[S:8][C:7]1=[NH:15].[CH2:16]1[CH:23]2[C:19]3([C:25](O)=[O:26])[CH2:20][CH:21]([CH2:24][CH:17]1[CH2:18]3)[CH2:22]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>CN(C=O)C>[CH3:2][O:3][CH2:4][CH2:5][N:6]1[C:10]2[CH2:11][CH2:12][CH2:13][CH2:14][C:9]=2[S:8]/[C:7]/1=[N:15]\[C:25]([C:19]12[CH2:20][CH:21]3[CH2:24][CH:17]([CH2:16][CH:23]1[CH2:22]3)[CH2:18]2)=[O:26]
Reactant: O=C(O)C12CC3CC(CC1C3)C2
Reactant: COCCn1c2c(sc1=N)CCCC2
Agent: Br
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COCCn1c2c(s/c1=N\C(=O)C13CC4CC(CC1C4)C3)CCCC2

Procedure:
A mixture of the product of Example 68A (293 mg, 1.00 mmol), hexahydro-2,5-methano-pentalene-3a-carboxylic acid (199 mg, 1.20 mmol), HATU (570 mg, 1.50 mmol) and triethylamine (836 mL, 6.00 mmol) in 15 mL of DMF was processed according to the method of Example 3B to afford the title compound: 1H NMR (500 MHz, DMSO-d6) δ 1.53-1.62 (m, 4 H) 1.67-1.82 (m, 8 H) 2.07-2.12 (m, 2 H) 2.23-2.27 (m, 2 H) 2.45-2.49 (m, 3 H) 2.54-2.59 (m, 2 H) 3.23 (s, 3 H) 3.63 (t, J=5.3 Hz, 2 H) 4.16 (t, J=5.5 Hz, 2 H); MS (DCI/NH3) m/z 361 (M+H)+.
Reaction SMILES: [NH2:1][CH2:2][C:3]([N:5]([CH2:12][C:13]([N:15]([C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=1)[CH3:16])=[O:14])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:4].[CH3:24][C:25]1[CH:26]=[C:27]([N:31]=[C:32]=[O:33])[CH:28]=[CH:29][CH:30]=1>>[F:23][C:20]1[CH:19]=[CH:18][C:17]([N:15]([CH3:16])[C:13](=[O:14])[CH2:12][N:5]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:3](=[O:4])[CH2:2][NH:1][C:32]([NH:31][C:27]2[CH:28]=[CH:29][CH:30]=[C:25]([CH3:24])[CH:26]=2)=[O:33])=[CH:22][CH:21]=1
Reactant: Cc1cccc(N=C=O)c1
Reactant: CN(C(=O)CN(C(=O)CN)c1ccccc1)c1ccc(F)cc1
Product: Cc1cccc(NC(=O)NCC(=O)N(CC(=O)N(C)c2ccc(F)cc2)c2ccccc2)c1
Yield: 48.7 %

Procedure:
The procedure is analogous to that described in Example 1, but 2.6 g of 2-(2-amino-N-phenylacetamido)-N-(4-fluorophenyl)-N-methylacetamide and 1.1 g of 3-methylphenyl isocyanate are used as the starting material. The crude product obtained is purified by chromatography on 60 g of silica (0.065-0.200 mm) contained in a column 2.0 cm in diameter [eluent: ethyl acetate/cyclohexane (50-50 by volume)], collecting 30 cm3 fractions. Fractions 6 to 10 are combined and concentrated to dryness under reduced pressure (2.7 kPa) at 40° C. After recrystallization from ethyl acetate, 1.8 g of N-(4-fluorophenyl)-N-methyl-2-{2-[3-(3-methylphenyl)ureido]-N-phenylacetamido}acetamide melting at 135° C is obtained.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5](Cl)=[N:6][OH:7].[CH3:12][O:13][C:14](=[O:18])[CH2:15][C:16]#[N:17].C[O-].[Na+]>CO>[NH2:17][C:16]1[O:7][N:6]=[C:5]([C:4]2[CH:9]=[CH:10][CH:11]=[C:2]([F:1])[CH:3]=2)[C:15]=1[C:14]([O:13][CH3:12])=[O:18]
Reactant: COC(=O)CC#N
Reactant: ON=C(Cl)c1cccc(F)c1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1c(-c2cccc(F)c2)noc1N
Yield: 77.3 %

Procedure:
In a similar manner as described in Preparation Example 17, by using methanol (160 mL), 3-fluoro-N-hydroxybenzimidoyl chloride (8.00 g, 46.09 mmol), methylcyanoacetate (5.94 g, 59.92 mmol) and sodium methoxide (4.98 g, 92.18 mmol), a white solid required compound (8.42 g, 35.64 mmol, 77%) was obtained.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=S)[CH2:6][CH2:5]2.[C:13]([NH:16][NH2:17])(=O)[CH3:14].C1(O)CCCCC1>O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]1[C:13]([CH3:14])=[N:16][N:17]=[C:7]1[CH2:6][CH2:5]2
Reactant: CC(=O)NN
Reactant: S=C1CCc2cc(Br)ccc2N1
Solvent: OC1CCCCC1
Solvent: O
Product: Cc1nnc2n1-c1ccc(Br)cc1CC2

Procedure:
A flask containing the title compound from Example 22 Step A (100 mg, 0.413 mmol), acetic hydrazide (40.8 mg, 0.496 mmol) and cyclohexanol (2.00 ml, 0.413 mmol) was heated at reflux for 2 days. The reaction was then poured into water and extracted with ethyl acetate. The organic extracts were combined, washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. Purification by flash chromatography on silica gel (0-15% methanol in ethyl acetate) provided the title compound: LCMS m/z 265.99 [M+2+H]+; 1H NMR (500 MHz, CDCl3) δ 7.53 (br s, 1H), 7.50 (d, J=8.57 Hz, 1H), 7.35 (d, J=8.57 Hz, 1H), 3.13-3.11 (m, 2H), 3.00-2.98 (m, 2H), 2.74 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([Cl:26])[C:9]=1[O:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[C:13]([S:18]([N:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)(=[O:20])=[O:19])[CH:12]=1)[C:5]#[N:6].[N-:27]=[N+:28]=[N-:29].[Na+].[Cl-].[NH4+]>>[Cl:26][C:8]1[CH:7]=[C:4]([C:5]2[N:27]=[N:28][NH:29][N:6]=2)[CH:3]=[C:2]([Cl:1])[C:9]=1[O:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[C:13]([S:18]([N:21]2[CH2:22][CH2:23][CH2:24][CH2:25]2)(=[O:20])=[O:19])[CH:12]=1
Reactant: [N-]=[N+]=[N-]
Reactant: N#Cc1cc(Cl)c(Oc2ccc(O)c(S(=O)(=O)N3CCCC3)c2)c(Cl)c1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Product: O=S(=O)(c1cc(Oc2c(Cl)cc(-c3nn[nH]n3)cc2Cl)ccc1O)N1CCCC1
Temperature: 143 °C

Procedure:
4-[2,6-Dichloro-4-(2H-tetrazol-5-yl)-phenoxy]-2-(pyrrolidine-1-sulfonyl)-phenol was prepared from 3,5-dichloro-4-[4-hydroxy-3-(pyrrolidine-1-sulfonyl)-phenoxy]-benzonitrile according to a procedure analogous to that described in EXAMPLE 1, Step C. Sodium azide (4.0 equiv) and ammonium chloride (4.0 equiv) were used, and the reaction was heated to 143° C. for 40 hours. After the reaction had been acidified and the crude product collected by filtration, the solid was dissolved in MeOH, filtered, and the filtrate was concentrated. The residue was purified by preparative TLC (methanol:water:chloroform=19:1:47) to afford the title product of Example 2. MS (APCI−) Calc.: 455.0, Found: 454.2 (M−1).
Reaction SMILES: [C:1]1([NH2:10])[CH:6]=[CH:5][C:4]([O:7][CH2:8][CH3:9])=[CH:3][CH:2]=1.C(N(CC)CC)C.[C:18](Cl)(=[O:20])[CH3:19]>C(Cl)Cl>[C:18]([NH:10][C:1]1[CH:6]=[CH:5][C:4]([O:7][CH2:8][CH3:9])=[CH:3][CH:2]=1)(=[O:20])[CH3:19]
Reactant: CCOc1ccc(N)cc1
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOc1ccc(NC(C)=O)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
5.0 g of phenetylamine was dissolved in 50 ml of methylene chloride, and 7.0 ml of triethylamine and 3.6 ml of acetyl chloride were added to the solution at 0° C. The solution was stirred at room temperature for 2 hours, washed with water, aqueous solution of citric acid, and saturated aqueous solution of sodium chloride, and dried with anhydrous magnesium sulfate. After separating the desiccant by filtration, the solution was purified by silica gel column chromatography to obtain 5.52 g of N-acetylphenetylamine, which was white crystal (yield: 82%).
Reaction SMILES: Cl[C:2]([O:4][CH3:5])=[O:3].[CH3:6][O:7][N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11][C@@H:10]([NH2:18])[C:9]1=[O:19].C(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl.O.CCCCC>[CH3:6][O:7][N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11][C@@H:10]([NH:18][C:2](=[O:3])[O:4][CH3:5])[C:9]1=[O:19]
Reactant: COC(=O)Cl
Reactant: CON1C(=O)[C@H](N)Cc2ccccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCCCC
Solvent: O
Solvent: ClC(Cl)Cl
Product: COC(=O)N[C@@H]1Cc2ccccc2N(OC)C1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.6 %

Procedure:
A solution of methyl chloroformate (42.8 g, 0.453 mol) in chloroform (50 ml) was added to a mixture of (R)-1,2,3,4-tetrahydro-1-methoxy-2-oxo-3-quinolinamine 1 (M. Kawase, T. Kitamura, Y. Kilugawa, J. Org. Chem., 54, 1989 3394–3403)(0.15 mol) and sodium bicarbonate (50.4 g, 0.600 mol) in chloroform (250 ml) and water (100 ml) over a period of 10 minutes at 0° C. The mixture was stirred overnight at room temperature, diluted with pentane, and the layers were separated. The aqueous layer was extracted with diethylether, and the combined organic extracts were washed with brine and dried (MgSO4). The solvent was removed under vacuum to leave an amber oil. Purification by flash chromatography (230–400 mesh silica gel, 35–40% ethyl acetate in hexane) gave the title compound as a light yellow oil (37.0 g, 99%).
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][C:22]([OH:24])=O)=[CH:16][CH:15]=3)=[CH:11][CH:12]=2)[C@H:7]([NH:25][C:26]2[CH:31]=[CH:30][C:29]([C:32]#[N:33])=[CH:28][N:27]=2)[CH2:6][C@@H:5]1[CH3:34])(=[O:3])[CH3:2].[CH3:35][N:36]([CH3:40])[CH2:37][CH2:38][NH2:39].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][C:22]([NH:39][CH2:38][CH2:37][N:36]([CH3:40])[CH3:35])=[O:24])=[CH:16][CH:15]=3)=[CH:11][CH:12]=2)[C@H:7]([NH:25][C:26]2[CH:31]=[CH:30][C:29]([C:32]#[N:33])=[CH:28][N:27]=2)[CH2:6][C@@H:5]1[CH3:34])(=[O:3])[CH3:2]
Reactant: CN(C)CCN
Reactant: CC(=O)N1c2ccc(-c3ccc(CCC(=O)O)cc3)cc2[C@H](Nc2ccc(C#N)cn2)C[C@@H]1C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N1c2ccc(-c3ccc(CCC(=O)NCCN(C)C)cc3)cc2[C@H](Nc2ccc(C#N)cn2)C[C@@H]1C
Reaction time: 0.5 h
Yield: 48 %

Procedure:
To a solution of 3-(4-((2S,4R)-1-acetyl-4-((5-cyanopyridin-2-yl)amino)-2-methyl-1,2,3,4-tetrahydroquinolin-6-yl)phenyl)propanoic acid (for a preparation See Intermediate 10)(58 mg, 0.128 mmol) and N1,N1-dimethylethane-1,2-diamine (22.50 mg, 0.255 mmol) in DMF (3 mL) were added HATU (72.8 mg, 0.191 mmol) and DIPEA (0.067 mL, 0.383 mmol). The resulting mixture was stirred for 30 min, then reaction mixture partitioned between water and EtOAc. The aqueous phase was extracted with EtOAc (×3), the combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The crude residue was dissolved in 1:1 MeOH/DMSO and was purified by MDAP (formate). The appropriate fractions were combined and concentrated in vacuo to give 3-(4-((2S,4R)-1-acetyl-4-((5-cyanopyridin-2-yl)amino)-2-methyl-1,2,3,4-tetrahydroquinolin-6-yl)phenyl)-N-(2-(dimethylamino)ethyl)propanamide (34.6 mg, 48%) as a viscous colourless oil. LCMS (Formate, 2 min), Rt=0.71 min, MH+=525.
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[O:7][C:6](=[O:8])[CH2:5][CH2:4]1.C(N(CC)CC)C.[C:16](Cl)([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:16]([O:1][CH2:2][C@H:3]1[O:7][C:6](=[O:8])[CH2:5][CH2:4]1)([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)([C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: O=C1CC[C@@H](CO)O1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C1CC[C@@H](COC(c2ccccc2)(c2ccccc2)c2ccccc2)O1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 76 %

Procedure:
The product from step 2 was dissolved in dry CH2Cl2 and the solution was cooled to 0° C. Triethylamine (1.5 molar equiv) was added. After 10 min, trityl chloride (1.1 molar equiv) followed by DMAP (0.2 molar equiv) were added and stirred over night at room temperature. The reaction was then quenched with saturated NH4Cl solution, the organic layer was separated and the aqueous layer was extracted with EtOAc. The combined organic extracts were washed with water, brine, dried (Na2SO4) and concentrated in vacuo. Purification by column chromatography afforded (5S)-5-(trityloxymethyl)-2-oxo-tetrahydrofuran in 76% yield.
Reaction SMILES: C([O:5]C(N1CCC[C@H]1CO)=O)(C)(C)C.[C:15]1([P:21]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.N1C=CC(=O)NC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C(Cl)Cl>[C:28]1([P:21](=[O:5])([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1CO
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: O=c1ccnc[nH]1
Solvent: ClCCl
Product: O=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 48 h

Procedure:
To a stirred solution of N-tert-butoxycarbonyl-L-prolinol (0.81 g, 4 mmol) 18 in dry DCM (10 mL) was added triphenylphosphine (5.24 g, 20 mmol) followed by 4(3H)-pyrimidone (0.77 g, 8 mmol). The solution was cooled in an ice bath and DIAD (3.24 g, 16 mmol) added dropwise over 10 min. After 48 h GC-MS indicated complete conversion of 18 and the reaction mixture was poured onto water (30 mL), the organic fraction collected and the aqueous phase washed with further DCM (2×20 mL). The combined organic fractions were washed with 1M NaOH (2×15 mL) then brine (1×15 mL) and dried over Na2SO4. Removal of bulk solvent yielded an orange gum, addition of hexanes/diethyl ether (1:1) resulted in formation of a precipitate of triphenylphosphine oxide, which was removed by filtration. Chromatography (ethyl acetate) afforded the desired product as a colorless oil (0.77 g, 69%). HRMS (ESI)=280.1655 (M+H)+. Calcd. for C14H22N3O3 280.1656. 1H NMR (600 MHz, CDCl3) δ 8.71 (s, 1H), 8.39 (d, J=6 Hz, 1H), 6.69 (d, J=6 Hz, 1H), 4.45-3.91 (m, 3H), 3.40-3.33 (m, 2H), 2.00-1.82 (m, 4H), 1.42 (s, 9H). TLC (UV254) Rf=0.49 (ethyl acetate).
Reaction SMILES: C(N(CC)CC)C.[CH:8]1([N:11]2[C:19]3[C:14](=[C:15]([O:23][CH3:24])[CH:16]=[C:17]([C:20]([OH:22])=O)[CH:18]=3)[CH:13]=[CH:12]2)[CH2:10][CH2:9]1.Cl.[O:26]=[C:27]1[C:41]2[C:36](=[CH:37][CH:38]=[C:39]([C:42]3[CH:43]=[N:44][CH:45]=[C:46]([CH:50]=3)[C:47]([OH:49])=[O:48])[CH:40]=2)[O:35][C:29]2([CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)[CH2:28]1.Cl>CN(C=O)C.O>[CH:8]1([N:11]2[C:19]3[C:14](=[C:15]([O:23][CH3:24])[CH:16]=[C:17]([C:20]([N:32]4[CH2:33][CH2:34][C:29]5([CH2:28][C:27](=[O:26])[C:41]6[C:36](=[CH:37][CH:38]=[C:39]([C:42]7[CH:43]=[N:44][CH:45]=[C:46]([CH:50]=7)[C:47]([OH:49])=[O:48])[CH:40]=6)[O:35]5)[CH2:30][CH2:31]4)=[O:22])[CH:18]=3)[CH:13]=[CH:12]2)[CH2:9][CH2:10]1
Reactant: O=C(O)c1cncc(-c2ccc3c(c2)C(=O)CC2(CCNCC2)O3)c1
Reactant: COc1cc(C(=O)O)cc2c1ccn2C1CC1
Agent: Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1cc(C(=O)N2CCC3(CC2)CC(=O)c2cc(-c4cncc(C(=O)O)c4)ccc2O3)cc2c1ccn2C1CC1
Temperature: 70 °C
Reaction time: 20 h

Procedure:
N,N′-carbonyldiimidazole (130 mg) and triethylamine (0.446 mL) were added to a solution of 1-cyclopropyl-4-methoxy-1H-indole-6-carboxylic acid (185 mg) in DMF (4 mL), and stirred at 70° C. for 20 hours. To the reaction mixture was added 5-(4-oxo-spiro[chroman-2,4′-piperidin]-6-yl)nicotinic acid hydrochloride (370 mg), which was further stirred at that temperature for 6 hours. 1 N hydrochloric acid and water were added to the reaction mixture, and the formed solid was collected by filtration. The solid was purified through silica gel column chromatography (chloroform/methanol) to obtain the intended compound. 1H-NMR (400 MHz, DMSO-d6) δ: 9.04-9.00 (2H, m), 8.40 (1H, s), 8.06-8.00 (2H, m), 7.30-7.22 (3H, m), 6.58 (1H, s), 6.40 (1H, d, J=3.2 Hz), 4.47-4.01 (1H, m), 3.88 (3H, s), 3.79-3.09 (4H, m), 2.96 (2H, s), 2.15-1.71 (4H, m), 1.09-1.01 (2H, m), 0.96-0.89 (2H, m); MS [M+H]+=552.