Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].CN1CCOCC1.[C:16]1(=[O:35])[N:20]([C@@H:21]([CH2:25][CH2:26][CH2:27][CH2:28]O)[C:22](O)=[O:23])[C:19](=[O:30])[C:18]2=[CH:31][CH:32]=[CH:33][CH:34]=[C:17]12.OC1C2N=NNC=2C=CC=1>CN(C)C=O>[C:19]1(=[O:30])[N:20]([C@@H:21]([CH2:25][CH2:26][CH2:27][CH3:28])[C:22]([NH:2][CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])=[O:23])[C:16](=[O:35])[C:17]2=[CH:34][CH:33]=[CH:32][CH:31]=[C:18]12
Reactant: CCOC(=O)CN
Reactant: O=C(O)[C@H](CCCCO)N1C(=O)c2ccccc2C1=O
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CCCC[C@@H](C(=O)NCC(=O)OCC)N1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A slurry of glycine, ethyl ester, hydrochloride salt (2.718 g, 19.5 mmol.) in dimethylformamide (36 ml.) was treated with 4-methyl morpholine (2.60 ml., 2.39 g., 23.6 mmol.) and stirred at room temperature for 5 minutes. The mixture was then treated with (S)-2-phthalimido-6-hydroxyhexanoic acid (4.50 g., 16.2 mmol.) and hydroxybenzotriazole (2.225 g., 16.5 mmol.), cooled to 0° C., and then treated with ethyl-3-(3-dimethylamino)-propyl carbodiimide, hydrochloride salt (3.438 g., 17.9 mmol.). After stirring at 0° C. for 1 hour and at room temperature for 2 hours, the mixture was partitioned between ethyl acetate and 0.5N hydrochloric acid and subsequently extracted three times with ethyl acetate. The pooled ethyl acetate extracts were washed in succession with water, saturated sodium bicarbonate, and brine, then dried (sodium sulfate), filtered and stripped to give 5.77 g. of title product as a colorless oil. TLC (ethyl acetate) Rf =0.34.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[N:10]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=3)[NH:8][C:5]2=[N:6][CH:7]=1.Br[CH2:19][CH2:20][CH2:21][Cl:22]>>[Br:1][C:2]1[CH:3]=[C:4]2[N:10]=[C:9]([C:11]3[CH:12]=[CH:13][C:14]([O:17][CH2:19][CH2:20][CH2:21][Cl:22])=[CH:15][CH:16]=3)[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: ClCCCBr
Reactant: Oc1ccc(-c2nc3cc(Br)cnc3[nH]2)cc1
Product: ClCCCOc1ccc(-c2nc3cc(Br)cnc3[nH]2)cc1

Procedure:
The title compound was prepared from 4-(6-bromo-3H-imidazo[4,5-b]pyridin-2-yl)phenol and 1-bromo-3-chloropropane using the method described in Example 41.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[NH:9][N:8]=[CH:7][C:6]=2[C:5]2[CH2:11][N:12]([CH2:21][C:22]([F:25])([F:24])[F:23])[C:13](=[O:20])[C@H:14]([CH2:16][C:17](O)=[O:18])[CH2:15][C:4]=2[CH:3]=1.[NH:26]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:29]2([CH2:40][CH2:39][NH:38][CH2:37][CH2:36]2)[NH:28][C:27]1=[O:41].F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C>ClCCl>[Cl:1][C:2]1[C:10]2[NH:9][N:8]=[CH:7][C:6]=2[C:5]2[CH2:11][N:12]([CH2:21][C:22]([F:24])([F:23])[F:25])[C:13](=[O:20])[C@H:14]([CH2:16][C:17](=[O:18])[N:38]3[CH2:37][CH2:36][C:29]4([C:30]5[C:35](=[CH:34][CH:33]=[CH:32][CH:31]=5)[NH:26][C:27](=[O:41])[NH:28]4)[CH2:40][CH2:39]3)[CH2:15][C:4]=2[CH:3]=1
Reactant: O=C(O)C[C@@H]1Cc2cc(Cl)c3[nH]ncc3c2CN(CC(F)(F)F)C1=O
Reactant: O=C1Nc2ccccc2C2(CCNCC2)N1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C1Nc2ccccc2C2(CCN(C(=O)C[C@@H]3Cc4cc(Cl)c5[nH]ncc5c4CN(CC(F)(F)F)C3=O)CC2)N1
Reaction time: 12 h
Yield: 79.8 %

Procedure:
To a solution of (S)-2-(4-chloro-8-oxo-9-(2,2,2-trifluoroethyl)-3,6,7,8,9,10-hexahydroazepino[3,4-e]indazol-7-yl)acetic acid (50 mg, 0.133 mmol) in dichloromethane (25 mL) was added 1′H-spiro[piperidine-4,4′-quinazolin]-2′(3′H)-one (31 mg, 0.14 mmol) followed by 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (47 mg, 0.15 mmol) and triethylamine (1.0 mL). After 12 h, the reaction mixture was washed with aqueous NaHCO3 followed by 1.0 M HCl and dried (Na2SO4). The solvent was removed and the crude product was purified by flash chromatography using 7% MeOH in dichloromethane to give (S)-4-chloro-7-(2-oxo-2-(2′-oxo-2′,3′-dihydro-1′H-spiro[piperidine-4,4′-quinazoline]-1-yl)ethyl)-9-(2,2,2-trifluoroethyl)-6,7,9,10-tetrahydroazepino[3,4-e]indazol-8(3H)-one (61 mg, 79%) as a white powder. MS (ESI) 575 (M+H); Rf=2.133.
Reaction SMILES: [Na].Cl[C:3]1[CH:8]=[C:7](Cl)[N:6]=[C:5]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)[N:4]=1.[CH:17]([OH:20])([CH3:19])[CH3:18]>>[C:13]1([CH3:16])[CH:14]=[CH:15][C:10]([C:5]2[N:6]=[C:7]([O:20][CH:17]([CH3:19])[CH3:18])[CH:8]=[C:3]([O:20][CH:17]([CH3:19])[CH3:18])[N:4]=2)=[CH:11][CH:12]=1
Reactant: CC(C)O
Reactant: Cc1ccc(-c2nc(Cl)cc(Cl)n2)cc1
Agent: [Na]
Product: Cc1ccc(-c2nc(OC(C)C)cc(OC(C)C)n2)cc1

Procedure:
21.16 g of sodium are dissolved in anhydrous isopropanol and to this solution are added 95.64 g of 4,6-dichloro-2-p-tolylpyrimidine at 60°-65° C. over 15 minutes. The mixture is then heated to the boil and refluxed for a further 4 hours to bring the reaction to completion. Excess isopropanol is then distilled off and the residual oil is taken up in chloroform. The chloroform layer is washed with water, dried over sodium sulfate, and filtered. The solvent is then distilled off, affording 112 g of 2-p-tolyl-4,6-bis-isopropoxypyrimidine in the form of a yellowish oil which is purified by high vacuum distillation. The boiling point is 123° C./5.332 Pascal.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:5]=[CH:6][C:7]([N:12]2[CH2:16][CH2:15][CH2:14][CH:13]2[CH3:17])=[C:8]([CH2:10][OH:11])[CH:9]=1.[CH3:18]I>CN(C=O)C>[Br:3][C:4]1[CH:5]=[CH:6][C:7]([N:12]2[CH2:16][CH2:15][CH2:14][CH:13]2[CH3:17])=[C:8]([CH2:10][O:11][CH3:18])[CH:9]=1
Reactant: CC1CCCN1c1ccc(Br)cc1CO
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCc1cc(Br)ccc1N1CCCC1C
Reaction time: 0.5 h
Yield: 98.1 %

Procedure:
To a solution of sodium hydride (2.84 g, 119 mmol) in anhydrous DMF (80 mL) was added a solution of [5-Bromo-2-(2-methylpyrrolidin-1-yl)phenyl]methanol (16 g, 59.2 mmol) in DMF (50 mL) drop wise at 0° C. After 30 minutes, methyl iodide (7.3 mL, 119 mmol) was added drop wise at 0° C. The reaction mixture was quenched with a saturated aqueous solution of NH4Cl (20 mL), then diluted with water (200 mL) and extracted with EtOAc (150 ml). The organic layer was dried (Na2SO4) and concentrated under reduced pressure to afford the title compound as a yellow oil (16.5 g, 98%). 1H NMR (CDCl3, 400 MHz) δ 7.55 (1H, s), 7.29 (1H, m), 6.86 (1H, d), 4.45 (2H, s), 3.55 (1H, m), 3.41 (1H, m), 2.82 (1H, m), 2.12-2.51 (1H, m), 1.91 (1H, m) 1.81 (1H, m), 1.58 (1H, m), 0.99 (3H, d).
Reaction SMILES: [CH2:1]([N:3]([CH2:18][CH3:19])[CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13](=[O:17])[CH2:14][CH2:15][CH3:16])=[CH:9][CH:8]=1)[CH3:2].Cl.ClCCN1CC[O:27]CC1>>[O:27]1[CH2:2][CH2:1][N:3]([CH2:4][CH2:5][O:6][C:7]2[CH:8]=[CH:9][C:10]([C:13](=[O:17])[CH2:14][CH2:15][CH3:16])=[CH:11][CH:12]=2)[CH2:18][CH2:19]1
Reactant: ClCCN1CCOCC1
Reactant: CCCC(=O)c1ccc(OCCN(CC)CC)cc1
Agent: Cl
Product: CCCC(=O)c1ccc(OCCN2CCOCC2)cc1

Procedure:
The title compound was prepared by using a similar procedure as described for the preparation of 21 except that N-(2-chloroethyl)morpholine hydrochloride was used instead of 2-(diethylamino)ethyl chloride hydrochloride. This produced a crude oil, which was purified by silica gel column chromatography, eluting with 1:1 hexanes/ethyl acetate, to give 24 (550 mg, quantitative) as a clear oil: MS (ES+) m/z 278.1 (M+H)+.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.C1(C)C=CC(S(O[CH2:16][CH2:17][O:18][CH2:19][CH2:20][O:21][CH2:22][CH2:23][O:24][CH3:25])(=O)=O)=CC=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>C(OCC)(=O)C>[CH3:25][O:24][CH2:23][CH2:22][O:21][CH2:20][CH2:19][O:18][CH2:17][CH2:16][N:1]1[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: c1c[nH]cn1
Reactant: COCCOCCOCCOS(=O)(=O)c1ccc(C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COCCOCCOCCn1ccnc1
Temperature: 100 °C
Reaction time: 16 h
Yield: 76.2 %

Procedure:
In a nitrogen atmosphere, a mixture of 68.0 g of imidazole, 318 g of 2-[2-(2-methoxyethoxy)ethoxy]ethyl p-toluenesulfonate, 276 g of potassium carbonate, and 1,000 g of N,N-dimethylformamide was heated and stirred at 100° C. for 16 hours. To the reaction solution was added ethyl acetate. The precipitate was filtered off, after which the solvent was distilled off in vacuo. The residue was purified by distillation in vacuo, obtaining 163 g of 1-[2-[2-(2-methoxyethoxy)ethoxy]ethyl]-1H-imidazole (boiling point 121° C./16 Pa, yield 76%).
Reaction SMILES: [C:1]([NH:5][CH2:6][CH:7]([OH:43])[CH2:8][O:9][C:10]1[CH:19]=[C:18]2[C:13]([C:14](=[O:42])[CH:15]=[C:16]([C:20]3[CH:25]=[CH:24][C:23]([O:26]CC4C=CC=CC=4)=[C:22]([O:34]CC4C=CC=CC=4)[CH:21]=3)[O:17]2)=[CH:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2]>CO.[Pd]>[C:1]([NH:5][CH2:6][CH:7]([OH:43])[CH2:8][O:9][C:10]1[CH:19]=[C:18]2[C:13]([C:14](=[O:42])[CH:15]=[C:16]([C:20]3[CH:25]=[CH:24][C:23]([OH:26])=[C:22]([OH:34])[CH:21]=3)[O:17]2)=[CH:12][CH:11]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)NCC(O)COc1ccc2c(=O)cc(-c3ccc(OCc4ccccc4)c(OCc4ccccc4)c3)oc2c1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)NCC(O)COc1ccc2c(=O)cc(-c3ccc(O)c(O)c3)oc2c1

Procedure:
7-(3-tert-Butylamino-2-hydroxy-propoxy)-3′,4′-dibenzyloxy-flavone, 37 (1.4 g, 2.4 mmol) was debenzylated in dry methanol (40 mL) with 10% Pd/C (30 mg) under hydrogen atmosphere as described for 48 to provide 50. Yield 930 mg (97%); mp 165° C. (decomposes); MS (FAB) 400 (M++1); IR (KBr) 3274, 1623; 1H NMR (200 MHz, DMSO-d6) δ 7.95 (d, J=8.8 Hz, 1H), 7.47 (s, 1H), 7.44 (d, J=9.4 Hz, 1H), 7.29 (s, 1H), 7.10 (d, J=8.8 Hz, 1H), 6.95 (d, J=8.1 Hz, 1H), 6.68 (s, 1H), 4.28-4.19 (m, 3H), 3.18-3.14 (m, 1H), 2.97-2.94 (m, 1H), 1.34 (s, 9H). Analysis Calcd for C22H25NO6: C, 66.15; H, 6.31; N, 3.51. Found: C, 66.26; H, 6.27; N, 3.27.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH:10]2[CH2:15][C@H:14]([CH3:16])[O:13][C@H:12]([CH3:17])[CH2:11]2)[CH:5]=[CH:4][CH:3]=1.[Cl:18][C:19]1[C:20](B(O)O)=[CH:21][C:22]([F:25])=[N:23][CH:24]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC>[Cl:18][C:19]1[C:20]([C:2]2[CH:3]=[CH:4][CH:5]=[C:6]([NH:8][CH2:9][CH:10]3[CH2:15][C@H:14]([CH3:16])[O:13][C@H:12]([CH3:17])[CH2:11]3)[N:7]=2)=[CH:21][C:22]([F:25])=[N:23][CH:24]=1
Reactant: OB(O)c1cc(F)ncc1Cl
Reactant: C[C@@H]1CC(CNc2cccc(Br)n2)C[C@H](C)O1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: C[C@@H]1CC(CNc2cccc(-c3cc(F)ncc3Cl)n2)C[C@H](C)O1
Temperature: 95 °C

Procedure:
A mixture of 6-bromo-N-(((2R,6S)-2,6-dimethyltetrahydro-2H-pyran-4-yl)methyl)pyridin-2-amine (110 mg, 0.36 mmol), 5-chloro-2-fluoro-pyridine-4-boronic acid (193 mg, 1.10 mmol), 0.55 ml 2.0M saturated sodium carbonate aqueous solution in 2 ml DME was purged with Argon for 3 min, PdCl2(dppf)CH2Cl2 (30 mg, 0.037 mmol) was added to this purged. The resulting mixture was heated at about 95° C. in an oil bath for 3.5 hours. Formation of the desired product was confirmed by LCMS: MH+ 350, 0.70 min. The preceding reaction mixture was diluted with ethyl acetate, washed with water, brine, dried over sodium sulfate and concentrated. The resulting residue was purified by ISCO eluting with 10% ethyl acetate in heptane to give 90 mg desired product as colorless oil. LCMS (m/z): 350 (MH+), retention time=0.70 min.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:14]([OH:16])=O)[CH2:10][CH:9]2[C:11](O)=[O:12])=[CH:4][CH:3]=1.[NH3:17]>>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]23[CH2:10][CH:9]2[C:11](=[O:12])[NH:17][C:14]3=[O:16])=[CH:4][CH:3]=1
Reactant: Nc1ccc(C2(C(=O)O)CC2C(=O)O)cc1
Reactant: N
Product: Nc1ccc(C23CC2C(=O)NC3=O)cc1

Procedure:
In a glass bomb tube, 2.3 g of 1-(4-aminophenyl)-1,2-cyclopropanedicarboxylic acid are stirred in 80 ml of approx. 1N methanolic ammonia solution for 7 days at 100° C. The reaction mixture is evaporated to dryness and the residue is chromatographed over silica gel with hexane/ethyl acetate (4:6). Recrystallisation from ethanol affords white crystals of the title compound, which is identical with the title compound of Example 1.
Reaction SMILES: [CH:1]1[CH:2]=[C:3]2[C:8]3=[C:9]([C:11]([O:13][C:14](=[O:15])[C:7]3=[CH:6][CH:5]=[CH:4]2)=O)[CH:10]=1.[C:16]([O:20][C:21](=[O:32])[NH:22][CH2:23][CH2:24][CH2:25][N:26]([CH2:28][CH2:29][CH2:30][NH2:31])[CH3:27])([CH3:19])([CH3:18])[CH3:17]>C(O)C>[C:16]([O:20][C:21](=[O:32])[NH:22][CH2:23][CH2:24][CH2:25][N:26]([CH2:28][CH2:29][CH2:30][N:31]1[C:11](=[O:13])[CH:9]2[CH:10]=[CH:1][CH:2]=[C:3]3[CH:8]2[C:7](=[CH:6][CH:5]=[CH:4]3)[C:14]1=[O:15])[CH3:27])([CH3:19])([CH3:17])[CH3:18]
Reactant: O=C1OC(=O)c2cccc3cccc1c23
Reactant: CN(CCCN)CCCNC(=O)OC(C)(C)C
Solvent: CCO
Product: CN(CCCNC(=O)OC(C)(C)C)CCCN1C(=O)C2=CC=CC3=CC=CC(C1=O)C32
Yield: 90 %

Procedure:
1,8-naphthalic anhydride (0.18 g, 0.9 mmol) was added to a solution of [3-[(3-aminopropyl)methylamino]propyl]carbamic acid tert-butyl ester previously prepared (Spicer at el., Bioorg. Med. Chem. 2002, vol. 10, p. 19) (0.2 g, 0.8 mmol) in absolute ethanol (20 ml). The reaction mixture was heated at reflux overnight. Removal of the solvent and purification by chromatography on alumina (CH2Cl2/MeOH, 50:1) yielded [3-[[3-(1,3-dioxo-3a,9b-dihydro-1H,3H-benzo[de]isoquinolin-2-yl)propyl]methylamino]propyl]carbamic acid tert-butyl ester (0.37 g, 90%) as a foam.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH3:13])=[C:11]([C:14](Cl)=[O:15])[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[NH2:17][C:18]1[CH:19]=[CH:20][C:21]([N:26]2[CH2:31][CH2:30][CH:29]([N:32](C(OC(C)(C)C)=O)[CH2:33][CH2:34][OH:35])[CH2:28][CH2:27]2)=[C:22]([CH:25]=1)[C:23]#[N:24].[OH-].[Na+]>FC(F)(F)C(O)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH3:13])=[C:11]([C:14]([NH:17][C:18]3[CH:19]=[CH:20][C:21]([N:26]4[CH2:31][CH2:30][CH:29]([NH:32][CH2:33][CH2:34][OH:35])[CH2:28][CH2:27]4)=[C:22]([C:23]#[N:24])[CH:25]=3)=[O:15])[CH:10]=[N:9]2)=[CH:4][CH:3]=1
Reactant: Cc1c(C(=O)Cl)cnn1-c1ccc(Cl)cc1
Reactant: CC(C)(C)OC(=O)N(CCO)C1CCN(c2ccc(N)cc2C#N)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Product: Cc1c(C(=O)Nc2ccc(N3CCC(NCCO)CC3)c(C#N)c2)cnn1-c1ccc(Cl)cc1

Procedure:
The reaction and treatment in the same manner as in Example 150 were conducted using 1-(4-chlorophenyl)-5-methylpyrazole-4-carboxylic chloride (1.19 g) and 5-amino-2-[4-(N-tert-butoxycarbonyl-N-(2-hydroxyethyl)amino)piperidin-1-yl]benzonitrile and the resulting mixture was further stirred in trifluoroacetic acid (10 ml) under ice-cooling for 1 h. The reaction mixture was treated with aqueous sodium hydroxide solution and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was recrystallized from ethanol to give the title compound (0.29 g), melting point: 181° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:17]([C:18](O)=[O:19])[CH2:16][C:15]2[C:10](=[CH:11][C:12]([NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])=[CH:13][CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN=C=NCCCN(C)C.Cl.C1C=NC2N(O)N=NC=2C=1.C(N(CC)CC)C.[NH2:58][C:59]1[C:67]([NH2:68])=[CH:66][CH:65]=[CH:64][C:60]=1[C:61]([NH2:63])=[O:62]>CN(C=O)C>[NH2:58][C:59]1[C:60]([C:61](=[O:62])[NH2:63])=[CH:64][CH:65]=[CH:66][C:67]=1[NH:68][C:18]([CH:17]1[CH2:16][C:15]2[C:10](=[CH:11][C:12]([NH:21][C:22]([O:24][C:25]([CH3:26])([CH3:28])[CH3:27])=[O:23])=[CH:13][CH:14]=2)[CH2:9][N:8]1[C:6]([O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[O:7])=[O:19]
Reactant: CC(C)(C)OC(=O)Nc1ccc2c(c1)CN(C(=O)OC(C)(C)C)C(C(=O)O)C2
Reactant: NC(=O)c1cccc(N)c1N
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)Nc1ccc2c(c1)CN(C(=O)OC(C)(C)C)C(C(=O)Nc1cccc(C(N)=O)c1N)C2
Temperature: 80 °C
Reaction time: 0.17 h

Procedure:
Step-2: To a solution of 2-(tert-butoxycarbonyl)-7-((tert-butoxycarbonyl)amino)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (200 mg, 0.51 mmol) in anhydrous DMF (3 mL) was added EDC.HCl (293 mg, 1.53 mmol), HOAt (105 mg, 0.77 mmol) and triethylamine (0.107 ml, 0.77 mmol) at RT and the mixture was stirred for 10 min. To this reaction mixture, 2,3-diaminobenzamide (77 mg, 0.51 mmol) was added and heated to 80° C. over night. The reaction mixture was concentrated and purified by preparative TLC to afford tert-butyl 3-((2-amino-3-carbamoylphenyl)carbamoyl)-7-((tert-butoxycarbonyl)amino)-3,4-dihydroisoquinoline-2(1H)-carboxylate. MS (ES+): m/z 526.30 [M+H]+
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][S:10][C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:24][S:25](Cl)(=[O:27])=[O:26]>CC(C)=O.ClCCl>[CH3:24][S:25]([O:17][C:14]1[CH:15]=[CH:16][C:11]([S:10][CH2:9][S:8][C:5]2[CH:4]=[CH:3][C:2]([O:1][S:25]([CH3:24])(=[O:27])=[O:26])=[CH:7][CH:6]=2)=[CH:12][CH:13]=1)(=[O:27])=[O:26]
Reactant: CS(=O)(=O)Cl
Reactant: Oc1ccc(SCSc2ccc(O)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CC(C)=O
Product: CS(=O)(=O)Oc1ccc(SCSc2ccc(OS(C)(=O)=O)cc2)cc1
Temperature: 70 °C
Reaction time: 4 h
Yield: 90.4 %

Procedure:
In 200 g of acetone was dissolved 23 g (0.1 mol) of the bis(4-hydroxyphenylthio)methane crude product in Synthesis Example 1. To this were added 35 g (0.25 mol) of potassium carbonate and 28 g (0.24 mol) of methanesulfonylchloride. While refluxing in an oil bath at 70° C., the solution was ripened for 4 hours. After cooling, the inorganic salt was filtered and washed with 50 g of acetone. The filtrate and wash liquid combined was concentrated, yielding an oily product, which was dissolved in 150 g of dichloromethane. This solution was washed with 100 g of water, and concentrated again. There was yielded 38 g of a concentrated oily residue, which was used in the subsequent reaction without further purification. It is noted that this oily matter crystallized when kept at room temperature.
Reaction SMILES: [Na].CO.[Cl:4][C:5]1[CH:6]=[C:7]([N:11]2[C:15]([CH3:16])=[N:14][C:13]([OH:17])=[N:12]2)[CH:8]=[CH:9][CH:10]=1.Br[CH:19]([CH3:25])[C:20]([O:22][CH2:23][CH3:24])=[O:21]>CS(C)=O>[Cl:4][C:5]1[CH:6]=[C:7]([N:11]2[C:15]([CH3:16])=[N:14][C:13]([O:17][CH:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH3:25])=[N:12]2)[CH:8]=[CH:9][CH:10]=1
Reactant: CCOC(=O)C(C)Br
Reactant: Cc1nc(O)nn1-c1cccc(Cl)c1
Agent: [Na]
Solvent: CS(C)=O
Solvent: CO
Product: CCOC(=O)C(C)Oc1nc(C)n(-c2cccc(Cl)c2)n1
Yield: 68 %

Procedure:
The process was carried out as was Example 9 above, starting with 0.8 g of sodium, 20 ml of methanol, 75 ml of dimethylsulfoxide, 7.8 g of 1-(3-chlorophenyl)-3-hydroxy-5-methyl-1,2,4-1H-triazole and 6.7 g of ethyl 2-bromopropionate. The yield was 7.8 g of the desired product, an oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:38][CH3:39])=[C:16]([O:19][CH2:20][CH2:21][CH2:22][N:23]4[CH2:27][CH:26]5[CH2:28][N:29](C(OC(C)(C)C)=O)[CH2:30][CH:25]5[CH2:24]4)[CH:17]=3)[N:12]=[CH:11][N:10]=2)=[CH:4][CH:3]=1.Cl>C(Cl)Cl.CCOC(C)=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:38][CH3:39])=[C:16]([O:19][CH2:20][CH2:21][CH2:22][N:23]4[CH2:24][CH:25]5[CH:26]([CH2:28][NH:29][CH2:30]5)[CH2:27]4)[CH:17]=3)[N:12]=[CH:11][N:10]=2)=[CH:4][CH:3]=1
Reactant: COc1cc2ncnc(Nc3ccc(F)cc3)c2cc1OCCCN1CC2CN(C(=O)OC(C)(C)C)CC2C1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COc1cc2ncnc(Nc3ccc(F)cc3)c2cc1OCCCN1CC2CNCC2C1
Temperature: 25 °C
Reaction time: 6 h
Yield: 89.5 %

Procedure:
To a solution of tert-butyl 5-(3-((4-((4-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)oxy) propyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (1.14 g) in DCM (30 mL) was added a solution of HCl in EtOAc. The reaction mixture was stirred for 6 h at room temperature and filtered to give crude product. The crude product was recrystallized from a mixture of MeOH and EA to give the title compound as a white solid (0.83 g, 89.50%), HPLC: 95.23%. The compound was characterized by the following spectroscopic data: MS (ESI, pos. ion) m/z: 438.2 (M+1); 1H NMR (400 MHz, CDCl3) δ: 1.83-1.88 (m, 4H), 2.32-2.45 (m, 6H), 2.66-2.76 (m, 4H), 4.03 (s, 3H), 4.15 (t, J=7.2 Hz, 2H), 7.15 (s, 1H), 7.23 (s, 1H), 7.40 (s, 1H), 7.53-7.60 (m, 2H), 7.90-7.93 (m, 1H), 8.66 (s, 1H) ppm.
Reaction SMILES: [O:1]=[C:2]1[N:6]2[CH2:7][CH2:8][NH:9][CH2:10][C@H:5]2[CH2:4][N:3]1[CH2:11][C:12]([CH3:17])(C)[C:13]([OH:15])=[O:14].N[C@@H:19]1CCC[C@H:20]1C(OCC)=O>>[O:1]=[C:2]1[N:6]2[CH2:7][CH2:8][NH:9][CH2:10][C@H:5]2[CH2:4][N:3]1[C@@H:11]1[CH2:20][CH2:19][CH2:17][C@H:12]1[C:13]([OH:15])=[O:14]
Reactant: CCOC(=O)[C@@H]1CCC[C@H]1N
Reactant: CC(C)(CN1C[C@@H]2CNCCN2C1=O)C(=O)O
Product: O=C(O)[C@@H]1CCC[C@H]1N1C[C@@H]2CNCCN2C1=O

Procedure:
Compound 49-A was prepared in analogy to compound Q in Example 19 by using ethyl (1R,2R)-2-aminocyclopentanecarboxylate (Accela Chembio Co., Ltd, SY024586) instead of ethyl 3-amino-2,2-dimethyl-propanoate hydrochloride salt.
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][N:6]([C:9]2[CH:14]=[C:13]([N+:15]([O-])=O)[CH:12]=[CH:11][N:10]=2)[CH2:5][CH2:4]1)[CH3:2].[H][H]>CO.[Pd]>[CH2:1]([N:3]1[CH2:4][CH2:5][N:6]([C:9]2[CH:14]=[C:13]([NH2:15])[CH:12]=[CH:11][N:10]=2)[CH2:7][CH2:8]1)[CH3:2]
Reactant: CCN1CCN(c2cc([N+](=O)[O-])ccn2)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CCN1CCN(c2cc(N)ccn2)CC1

Procedure:
A solution of 2.03 g (9 mmol) 1-ethyl-4-(4-nitro-pyridin-2-yl)-piperazine in 30 ml methanol was hydrogenated over 0.052 g Pd/C with 1 bar hydrogen for 3 h at room temperature. The mixture was filtered and evaporated to dryness to yield the title compound as yellow solid which was used without further purification (m/e): 207.1 (MH+; 100%).
Reaction SMILES: C(NC(C)C)(C)C.[Li].[Cl:9][CH:10]1[CH2:19][CH2:18][C:17]2[C:12](=[CH:13][CH:14]=[C:15]([O:20][CH3:21])[CH:16]=2)[C:11]1=[O:22].[NH4+].[Cl-].[CH3:25][CH2:26][O:27][C:28]([CH3:30])=[O:29]>C1COCC1>[CH2:26]([O:27][C:28](=[O:29])[CH2:30][C:11]1([OH:22])[C:12]2[C:17](=[CH:16][C:15]([O:20][CH3:21])=[CH:14][CH:13]=2)[CH2:18][CH2:19][CH:10]1[Cl:9])[CH3:25]
Reactant: COc1ccc2c(c1)CCC(Cl)C2=O
Reactant: CCOC(C)=O
Agent: [Cl-]
Agent: [Li]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CCOC(=O)CC1(O)c2ccc(OC)cc2CCC1Cl
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
A solution of EtOAc (7.2 ml, 73.96 mmol) in THF (20 ml) is slowly added under an atmosphere of argon at −78° C. to a solution of lithium diisopropylamine (prepared from 10.5 ml of diisopropylamine (73.96 mmol) and 46.2 ml of 1.6 M n-BuLi in hexane (73.96 mmol)) in THF (20 ml). After stirring at −78° C. for 30 minutes, a solution of 2-chloro-6-methoxy-3,4-dihydro-2H-naphthalen-1-one (7.79 g, 36.98 mmol) in THF (20 ml) is slowly added during 30 minutes. The reaction mixture is stirred at −78° C. for 24 h. TLC analysis indicates complete conversion of starting material. The reaction mixture is diluted with EtOAc and poured into a sat aqueous solution of NH4Cl. The organic layer is separated and washed with brine. After drying over Na2SO4, the solvent is removed. Purification by FCC (hexane/EtOAc 920:80 to 880:120) yields the title compound. 1H NMR (CDCl3, 400 MHz): δ 1.22 (t, J=9 Hz, 3H), 2.33-2.41 (m, 2H), 2.80-3.12 (m, 4H); 3.12 (s, 1H), 3.78 (s, 3H), 4.12 (q, J=9 Hz, 2H), 5.01-5.04 (m, 1H), 6.60-6.62 (m, 1H), 6.78-6.82 (m, 1H), 7.52 (d. J=10 Hz, 1H).
Reaction SMILES: C([O:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH2:13][C:14]([C:21]3[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[N:24]=[C:23]([C:31]([F:34])([F:33])[F:32])[CH:22]=3)([C:17]([F:20])([F:19])[F:18])[CH2:15][N:16]=2)=[CH:8][C:7]=1[Br:35])(=O)C.C[O-].[Na+]>CO.C(OC)(C)(C)C>[F:34][C:31]([F:32])([F:33])[C:23]1[CH:22]=[C:21]([C:14]2([C:17]([F:18])([F:19])[F:20])[CH2:13][C:12]([C:9]3[CH:10]=[CH:11][C:6]([CH2:5][OH:4])=[C:7]([Br:35])[CH:8]=3)=[N:16][CH2:15]2)[CH:26]=[C:25]([C:27]([F:28])([F:29])[F:30])[N:24]=1
Reactant: CC(=O)OCc1ccc(C2=NCC(c3cc(C(F)(F)F)nc(C(F)(F)F)c3)(C(F)(F)F)C2)cc1Br
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: COC(C)(C)C
Product: OCc1ccc(C2=NCC(c3cc(C(F)(F)F)nc(C(F)(F)F)c3)(C(F)(F)F)C2)cc1Br

Procedure:
4-{3-[2,6-bis(trifluoromethyl)pyridin-4-yl]-3-(trifluoromethyl)-3,4-dihydro-2H-pyrrol-5-yl}-2-bromobenzyl acetate (0.5 g) and Sodium methoxide (0.005 g) in MeOH (10 ml) were stirred at room temperature for 30 minutes. The mixture was diluted with t-BuOMe, and washed with brine, and the organic layer was dried over MgSO4. After the solvent was evaporated under reduced pressure, the targeted product was obtained (0.4 g).