Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH2:2]([NH:4][C:5]([N:7]1[CH2:11][C:10]([CH3:13])([CH3:12])[CH:9]=[N:8]1)=[NH:6])[CH3:3].CCN(P1(N(C)CCCN1C)=NC(C)(C)C)CC.[Br:32][C:33]1[CH:34]=[C:35]([S:46](Cl)(=[O:48])=[O:47])[CH:36]=[CH:37][C:38]=1[NH:39][C:40](=[O:45])[C:41]([F:44])([F:43])[F:42].Cl>C1COCC1>[Br:32][C:33]1[CH:34]=[C:35]([S:46](=[O:48])(=[O:47])[N:6]=[C:5]([N:7]2[CH2:11][C:10]([CH3:12])([CH3:13])[CH:9]=[N:8]2)[NH:4][CH2:2][CH3:3])[CH:36]=[CH:37][C:38]=1[NH:39][C:40](=[O:45])[C:41]([F:43])([F:44])[F:42]
Reactant: CCNC(=N)N1CC(C)(C)C=N1
Reactant: O=C(Nc1ccc(S(=O)(=O)Cl)cc1Br)C(F)(F)F
Agent: CCN(CC)P1(=NC(C)(C)C)N(C)CCCN1C
Agent: Cl
Solvent: C1CCOC1
Product: CCNC(=NS(=O)(=O)c1ccc(NC(=O)C(F)(F)F)c(Br)c1)N1CC(C)(C)C=N1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 78.4 %

Procedure:
To a solution of 1.20 g N-ethyl-4,4-dimethyl-4,5-dihydro-pyrazole-1-carboxamidine hydrochloride in 35 mL dry THF was added 5.1 mL (3.0 equiv.) BEMP and the reaction mixture was stirred for 10 minutes at room temperature. 2.15 g (1.0 equiv.) 3-Bromo-4-(2,2,2-trifluoro-acetylamino)-benzenesulfonyl chloride was added in one portion and the resulting bright yellow solution was stirred overnight at room temperature. The reaction mixture was acidified with 1N HCl and extracted twice with EA. The combined organic layers were dried over Na2SO4, filtered and evaporated under reduced pressure. Purification by flash chromatography (Et2O/PA 1:1→Et2O) afforded 2.29 g (78%) of product. 1H NMR (400 MHz, CDCl3) δ 1.18 (t, J=7.3 Hz, 3H), 1.24 (s, 6H), 3.43-3.51 (m, 2H), 3.79 (br.s, 2H), 6.78 (s, 1H), 7.93 (dd, J=8.6, 2.0 Hz, 1H), 8.19 (d, J=2.0 Hz, 1H), 8.39 (d, J=8.6 Hz, 1H), 8.61 (br.s., 1H).
Reaction SMILES: [CH2:1]([NH2:9])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C[O:11][C:12]([C:14]1[O:15][C:16]([S:19]([N:22]2[CH2:27][CH2:26][CH:25]([NH:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:24][CH2:23]2)(=[O:21])=[O:20])=[CH:17][CH:18]=1)=O>CO>[C:32]([O:31][C:29](=[O:30])[NH:28][CH:25]1[CH2:26][CH2:27][N:22]([S:19]([C:16]2[O:15][C:14]([C:12](=[O:11])[NH:9][CH2:1][CH2:2][C:3]3[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=3)=[CH:18][CH:17]=2)(=[O:21])=[O:20])[CH2:23][CH2:24]1)([CH3:35])([CH3:33])[CH3:34]
Reactant: COC(=O)c1ccc(S(=O)(=O)N2CCC(NC(=O)OC(C)(C)C)CC2)o1
Reactant: NCCc1ccccc1
Solvent: CO
Product: CC(C)(C)OC(=O)NC1CCN(S(=O)(=O)c2ccc(C(=O)NCCc3ccccc3)o2)CC1
Temperature: 45 °C
Reaction time: 8 h
Yield: 96.3 %

Procedure:
Phenethylamine (0.5 g, 4.1 mmol) was added in one portion to a stirred solution of 5-(4-tert-butoxycarbonylamino-piperidine-1-sulfonyl)-furan-2-carboxylic acid methyl ester (0.4 g, 1.0 mmol) in methanol (10 ml) at room temperature. The reaction mixture was then heated to 45° C. and stirred at this temperature overnight, after which time the mixture was concentrated. The resulting residue was dissolved in DCM (100 ml), washed sequentially with HCl (1M solution, 50 ml), NaOH (1M solution, 50 ml) and brine (50 ml). The organic layer was separated, dried (MgSO4), filtered and concentrated to give the title compound (0.46 g, 94% yield) as a light brown solid which was taken on without further purification. δH (500 MHz, DMSO) 8.71 (t, J=5.79 Hz, 1 H) 7.13-7.38 (m, 8 H) 6.93 (d, J=7.61 Hz, 1 H) 5.75 (s, 1 H) 3.41-3.63 (m, 5 H) 2.66-2.91 (m, 5 H) 1.66-1.87 (m, 2 H) 1.25-1.47 (m, 12 H).
Reaction SMILES: [N+]([C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:12]=1[NH:11][C:10]([C:13]([O:15][CH3:16])=[O:14])=[CH:9]2)([O-])=O.[N+:17](C1C=C2C(=CC=1)NC(C(OC)=O)=C2)([O-:19])=[O:18].[N+](C1C=CC(C=O)=CC=1)([O-])=O.N(CC(OC)=O)=[N+]=[N-]>C1(C)C(C)=CC=CC=1.C(Cl)Cl>[N+:17]([C:5]1[CH:4]=[C:12]2[C:8]([CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[NH:11]2)=[CH:7][CH:6]=1)([O-:19])=[O:18]
Reactant: COC(=O)c1cc2cccc([N+](=O)[O-])c2[nH]1
Reactant: COC(=O)c1cc2cc([N+](=O)[O-])ccc2[nH]1
Agent: COC(=O)CN=[N+]=[N-]
Agent: O=Cc1ccc([N+](=O)[O-])cc1
Solvent: Cc1ccccc1C
Solvent: ClCCl
Product: COC(=O)c1cc2ccc([N+](=O)[O-])cc2[nH]1

Procedure:
Condensation of 3-nitrobenzaldehyde with methyl 2-azidoacetate (8 equiv, 6 equiv NaOCH3, CH3OH, −23 to 0° C., 6 h, 88%) both reagents commercially available from Aldrich, followed by thermolysis of the resulting methyl 2-azidocinnamate (xylene, reflux, 4.5 h, 81%) provided a readily separable mixture (4:1) of methyl 5- and 7-nitroindole-2-carboxylate. For methyl 7-nitroindole-2-carboxylate (164): mp 122-125° C. (CH2Cl2, light yellow fine needles); 1H NMR (CDCl3, 400 MHz) 10.37 (br s, 1H, NH), 8.31 (d, 1H, J=8.0 Hz, C4-H), 8.06 (d, 1H, J=8.0 Hz, C6-H), 7.36 (d, 1H, J=2.4 Hz, C3-H), 7.28 (t, 1H, J=8.0 Hz, C5-H), 3.99 (s, 3H, CO2CH3); IR (film)max 3372, 1727, 1531, 1445, 1344, 1298, 1249, 1188, 1107, 830, 763 cm−1; FABHRMS (NBA) m/e 221.0560 (M++H, C10H8N2O4 requires 221.0562). For methyl 5-nitroindole-2-carboxylate (168): 1H NMR (DIMETHYLSULFOXIDE-d6, 400 MHz) 12.65 (br s, 1H, NH), 8.73 (d, 1H, J=2.3 Hz, C4-H), 8.14 (dd, 1H, J=2.0, 8.0 Hz, C6-H), 7.60 (d, 1H, J=8.0 Hz, C7-H), 7.45 (d, 1H, J=0.7 Hz, C3-H), 3.90 (s, 3H, CO2CH3); IR (film)max 3316, 1701, 1614, 1531, 1435, 1343, 1261, 1203, 992, 746 cm−1. Similarly, condensation of 4-nitrobenzaldehyde with methyl 2-azidoacetate (8 equiv, 6 equiv NaOCH3, CH3OH, −23 to 0° C., 7 h, 84%) followed by thermolysis (xylene, reflux, 4 h, 83%) provided methyl 6-nitroindole-2-carboxylate (166): 1H NMR (CDCl3, 400 MHz) 9.27 (br s, 1H, NH), 8.39 (d, 1H, J=2.0 Hz, C7-H), 8.04 (dd, 1H, J=2.0, 8.0 Hz, C5-H), 7.78 (d, 1H, J=8.0Hz, C4-H), 7.28 (d, 1H, J=2.3 Hz, C3-H), 4.00 (s, 3H, CO2CH3).
Reaction SMILES: [NH:1]=[C:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH3:7].[C:8]1([CH3:17])[CH:13]=[CH:12][CH:11]=[C:10]([N:14]=[C:15]=[O:16])[CH:9]=1>>[CH3:17][C:8]1[CH:9]=[C:10]([NH:14][C:15]([N:1]=[C:2]2[CH2:6][CH2:5][CH2:4][N:3]2[CH3:7])=[O:16])[CH:11]=[CH:12][CH:13]=1
Reactant: Cc1cccc(N=C=O)c1
Reactant: CN1CCCC1=N
Product: Cc1cccc(NC(=O)N=C2CCCN2C)c1

Procedure:
Conversion of the hydrochloride salt of 2-imino-1-methylpyrrolidine (6.73 g.; 0.05 mole) to the free base (4.9 g. assuming 100% conversion) is carried out in the usual manner. After drying over K2CO3, the benzene layer is stirred, and 6.66 g. (0.05 mole) of m-tolylisocyanate is added (solid forms). The reaction mixture is stirred at room temperature overnight. The solid is collected, m.p. = 148°-149° C. The benzene filtrate, after removal of solvent, yields a further crop of solid material, m.p. 137°-142° C. Recrystallizations of the combined solids from acetone gives the pure product, 1-m-methylphenyl-3-(1-methyl-2-pyrrolidylidene)urea, m.p. = 149°-151° C.
Reaction SMILES: [F:1][C:2]1[CH:41]=[C:40]([F:42])[CH:39]=[CH:38][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][C:6]=1[C:15]1[N:16](COCC[Si](C)(C)C)[C:17]([CH3:29])=[C:18]2[C:23]=1[CH:22]=[C:21]([C:24]([NH:26][CH3:27])=[O:25])[NH:20][C:19]2=[O:28].C(O)(C(F)(F)F)=O.C([O-])(=O)C.[Na+]>ClCCl>[F:1][C:2]1[CH:41]=[C:40]([F:42])[CH:39]=[CH:38][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:12])[F:13])=[CH:7][C:6]=1[C:15]1[NH:16][C:17]([CH3:29])=[C:18]2[C:23]=1[CH:22]=[C:21]([C:24]([NH:26][CH3:27])=[O:25])[NH:20][C:19]2=[O:28]
Reactant: CNC(=O)c1cc2c(-c3cc(C(F)(F)F)ccc3Oc3ccc(F)cc3F)n(COCC[Si](C)(C)C)c(C)c2c(=O)[nH]1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CNC(=O)c1cc2c(-c3cc(C(F)(F)F)ccc3Oc3ccc(F)cc3F)[nH]c(C)c2c(=O)[nH]1
Temperature: 25 °C
Reaction time: 1 h
Yield: 22.1 %

Procedure:
To a solution of Example 34d (0.023 g, 0.038 mmol) in dichloromethane was added TFA (0.5 mL, 6.49 mmol). The reaction mixture was stirred at ambient temperature for 1 hour and then concentrated by rotary evaporation. The residue was concentrated down from toluene (2×), then taken up in methanol/tetrahydrofuran. Sodium acetate (0.124 g, 1.514 mmol) was added, and the reaction mixture was heated at reflux for 2 hours. The reaction mixture was concentrated by rotary evaporation. The residue was partitioned between ethyl acetate and water. The layers were separated, and the organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated. The crude material was purified by flash chromatography (silica gel, 20-80% ethyl acetate in hexanes) to give the title compound (0.004 g, 22% yield). 1H NMR (300 MHz, DMSO-d6) δ 12.20-12.46 (m, 1 H), 9.06 (s, 1 H), 8.41-8.52 (m, 1 H), 7.82 (d, J=2.03 Hz, 1 H), 7.66 (dd, J=8.82, 1.70 Hz, 1 H), 7.44-7.54 (m, 2 H), 7.15-7.23 (m, 2 H), 6.99 (d, J=8.48 Hz, 1 H), 2.74 (d, J=4.41 Hz, 3 H), 2.65 (s, 3H). MS (ESI+) m/z 478.0)+.
Reaction SMILES: [N:1]1([C:7]2[N:8]=[C:9]([CH2:14][C:15]([O-:17])=O)[NH:10][C:11](=[O:13])[CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Na+].[NH:19]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:21][CH:20]1[CH2:28][OH:29].Cl.CN(C)CCCN=C=NCC>N1C=CC=CC=1.CN(C)C=O>[OH:29][CH2:28][CH:20]1[CH2:21][C:22]2[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:19]1[C:15](=[O:17])[CH2:14][C:9]1[NH:10][C:11](=[O:13])[CH:12]=[C:7]([N:1]2[CH2:2][CH2:3][O:4][CH2:5][CH2:6]2)[N:8]=1
Reactant: OCC1Cc2ccccc2N1
Reactant: O=C([O-])Cc1nc(N2CCOCC2)cc(=O)[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: O=C(Cc1nc(N2CCOCC2)cc(=O)[nH]1)N1c2ccccc2CC1CO
Yield: 57.3 %

Procedure:
The product is prepared according to the procedure described in example 5, using 261 mg of sodium [4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate, 298 mg of 2,3-dihydro-1H-indol-2-ylmethanol and 249 mg of N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride in a mixture of 322 μl of pyridine and 4.0 ml of N,N-dimethylformamide. 212 mg of 2-{2-[2-(hydroxymethyl)-2,3-dihydro-1H-indol-1-yl]-2-oxoethyl}-6-(morpholin-4-yl)pyrimidin-4(3H)-one are obtained in the form of a pale pink crystalline powder, the characteristics of which are the following:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][C:3]=1[C:11]1[C:16]([F:17])=[CH:15][C:14]([F:18])=[CH:13][N:12]=1.Br[C:20]1[N:24]2[CH:25]=[CH:26][C:27]([C:29]([F:32])([F:31])[F:30])=[N:28][C:23]2=[N:22][CH:21]=1>>[F:17][C:16]1[C:11]([C:3]2[CH:4]=[C:5]([C:20]3[N:24]4[CH:25]=[CH:26][C:27]([C:29]([F:30])([F:31])[F:32])=[N:28][C:23]4=[N:22][CH:21]=3)[CH:6]=[CH:7][C:2]=2[F:1])=[N:12][CH:13]=[C:14]([F:18])[CH:15]=1
Reactant: OB(O)c1ccc(F)c(-c2ncc(F)cc2F)c1
Reactant: FC(F)(F)c1ccn2c(Br)cnc2n1
Product: Fc1cnc(-c2cc(-c3cnc4nc(C(F)(F)F)ccn34)ccc2F)c(F)c1

Procedure:
4-Fluoro-3-(3,5-difluoropyridin-2-yl)phenylboronic acid was coupled with 3-bromo-7-trifluoromethylimidazo[1,2-α]pyrimidine by the method of Example 78. Purification by chromatography on silica gel eluting with dichloromethane containing 2% methanol and crystallisation from toluene/isohexane gave 3-[3-(3,5-difluoropyridin-2-yl)-4-fluorophenyl]-7-trifluoromethylimidazo[1,2-α]pyrimidine: δH (400 MHz, CDCl3) 8.80 (1H, d, J 7), 8.50 (1H, d, J 2), 8.12 (1H, s), 7.79 (1H, dd, J 7 and 2), 7.64 (1H, m), 7.36-7.43 (2H, m), 7.26 (1H, d, J 7); m/z (ES+) 395 (MH+).
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[N:7]([S:13]([C:16]1[CH:21]=[C:20]([Cl:22])[C:19](F)=[CH:18][C:17]=1[F:24])(=[O:15])=[O:14])[C:8]1[N:9]=[CH:10][S:11][CH:12]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:26]([N:28]1[C:32]([C@H:33]2[CH2:38][CH2:37][CH2:36]C[C@@H:34]2[OH:39])=[CH:31][CH:30]=[N:29]1)[CH3:27].[H-].[Na+]>CN(C=O)C>[C:1]([O:5][C:6](=[O:25])[N:7]([S:13]([C:16]1[CH:21]=[C:20]([Cl:22])[C:19]([O:39][C@H:34]2[CH2:36][CH2:37][CH2:38][C@@H:33]2[C:32]2[N:28]([CH2:26][CH3:27])[N:29]=[CH:30][CH:31]=2)=[CH:18][C:17]=1[F:24])(=[O:15])=[O:14])[C:8]1[N:9]=[CH:10][S:11][CH:12]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CCn1nccc1[C@H]1CCCC[C@@H]1O
Reactant: CC(C)(C)OC(=O)N(c1cscn1)S(=O)(=O)c1cc(Cl)c(F)cc1F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCn1nccc1[C@H]1CCC[C@@H]1Oc1cc(F)c(S(=O)(=O)N(C(=O)OC(C)(C)C)c2cscn2)cc1Cl
Yield: 42.5 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 1a by using the tert-butyl[(5-chloro-2,4-difluorophenyl)sulfonyl](1,3-thiazol-4-yl)carbamic acid (WO 2010/079443; 222 mg, 0.540 mmol), (1S*,2R*)-2-(1-ethyl-1H-pyrazol-5-yl)cyclohexanol (100 mg, 0.515 mmol) prepared in Example 12a, sodium hydride (63%; 39.2 mg, 1.03 mmol) and DMF (5.0 mL), to yield the title compound (125 mg, 41%) as a colorless oil.
Reaction SMILES: C([NH:8][CH:9]1[CH2:13][CH2:12][C:11]([CH3:15])([OH:14])[C:10]1([F:17])[CH3:16])C1C=CC=CC=1.Cl>[Pd].CO>[NH2:8][C@@H:9]1[CH2:13][CH2:12][C@@:11]([CH3:15])([OH:14])[C@@:10]1([F:17])[CH3:16]
Reactant: CC1(O)CCC(NCc2ccccc2)C1(C)F
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: C[C@@]1(O)CC[C@@H](N)[C@@]1(C)F
Reaction time: 15 h

Procedure:
A mixture of 3-(benzylamino)-2-fluoro-1,2-dimethylcyclopentanol (415 mg, 1.749 mmol, from Step 3), 10% palladium on carbon (93 mg) in methanol (10 mL) and 4 N aqueous hydrochloric acid (0.481 mL, 1.924 mmol) was stirred under hydrogen at 34 psi for 15 h. After removal of catalyst by filtration, the filtrate was concentrated to give (1R,2R,3R)-3-amino-2-fluoro-1,2-dimethylcyclopentanol (racemic mixture) as a hydrochloride salt. 1H NMR (400 MHz, methanol-d4) δ ppm 3.51-3.85 (1 H, m), 2.21-2.55 (1 H, m), 1.95-2.15 (1 H, m), 1.59-1.83 (2 H, m), 1.13-1.57 (6H, m).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:18]([O:19][CH3:20])=[CH:17][C:12]2[N:13]=[C:14](Br)[S:15][C:11]=2[C:10]=1[O:21][CH3:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:23][CH2:24][C:25]1[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=1>O>[CH2:1]([O:8][C:9]1[C:18]([O:19][CH3:20])=[CH:17][C:12]2[N:13]=[C:14]([NH:23][CH2:24][C:25]3[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=3)[S:15][C:11]=2[C:10]=1[O:21][CH3:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCc1cccnc1
Reactant: COc1cc2nc(Br)sc2c(OC)c1OCc1ccccc1
Solvent: O
Product: COc1cc2nc(NCc3cccnc3)sc2c(OC)c1OCc1ccccc1
Temperature: 120 °C
Reaction time: 4 h
Yield: 88.4 %

Procedure:
A mixture of 0.38 g of 6-benzyloxy-2-bromo-5,7-dimethoxybenzothiazole and 0.32 g of 3-aminomethylpyridine was heated and stirred at 120° C. for 4 hours. After adding water, the mixture was extracted with ethyl acetate and the organic layer was dried over magnesium sulfate. After distilling off the solvent, the obtained crude product was crystallized from ether. Thus 0.36 g of the title compound was obtained.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=1)[C:6]([C:19]([OH:21])=O)=[CH:5]2.[NH2:22][C:23]1[CH:24]=[C:25]2[N:31]=[CH:30][S:29][C:26]2=[N:27][CH:28]=1>>[N:31]1[C:25]2[C:26](=[N:27][CH:28]=[C:23]([NH:22][C:19]([C:6]3[N:7]([CH2:11][C:12]4[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=4)[C:8]4[C:4]([CH:5]=3)=[CH:3][C:2]([F:1])=[CH:10][CH:9]=4)=[O:21])[CH:24]=2)[S:29][CH:30]=1
Reactant: Nc1cnc2scnc2c1
Reactant: O=C(O)c1cc2cc(F)ccc2n1Cc1cccc(F)c1
Product: O=C(Nc1cnc2scnc2c1)c1cc2cc(F)ccc2n1Cc1cccc(F)c1
Yield: 72.9 %

Procedure:
The process is performed according to a method similar to that of Example 1.2, starting with 0.32 g (1.11 mmol) of 5-fluoro-1-(3-fluorobenzyl)-1H-indole-2-carboxylic acid prepared in step 1.1 and 0.2021 g (1.34 mmol) of 6-amino-thiazolo[5,4-b]pyridine (WO2007/100758). At the end of the reaction, the product is concentrated under reduced pressure and then taken up in 100 mL of water. A precipitate is collected by filtration, and is purified by chromatography on a column of alumina, eluting with a mixture of dichloromethane and methanol. The resulting product is recrystallized from methanol, and a solid is collected by filtration and dried under reduced pressure. 340 mg of the expected product are thus isolated.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]=1[C:13]([OH:15])=O.C(Cl)(=O)C(Cl)=O.[CH3:22][NH:23][CH3:24].C(N(CC)CC)C>ClCCl.CN(C)C=O.O1CCCC1.O>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]=1[C:13]([N:23]([CH3:24])[CH3:22])=[O:15]
Reactant: CNC
Reactant: COc1ccc2ccccc2c1C(=O)O
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1ccc2ccccc2c1C(=O)N(C)C
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
To a solution of 2-methoxynaphthoic acid (268 mg, 1.3 mmol) in dry dichloromethane (5 mL) at 0° C. under a N2 atmosphere was added oxalyl chloride (0.8 mL of a 2M solution in dichloromethane, 1.6 mmol) and 4 drops of N,N-dimethyl formamide. The mixture was stirred at 0° C. for 20 minutes, allowed to warm to room temperature, and stirred for one hour. This solution was added dropwise to a solution of dimethylamine (3.3 mL, 6.5 mmol) and triethylamine (0.92 mL, 6.5 mmol) in tetrahydrofuran (20 mL) and H2O (2 mL), and stirring was continued at room temperature under a N2 atmosphere for 16 hours. The mixture was concentrated in vacuo and the product was purified by column chromatography using 20% ethyl acetate in hexane. The title compound was obtained as a colorless oil (385 mg, 92%). 1H NMR (300 MHz, CDCl3): δ 7.85 (d, 1H), 7.78 (d, 1H), 7.61 (d, 1H), 7.47 (t, 1H), 7.36 (t, 1H), 7.30 (d, 1H), 3.96 (s, 3H), 3.27 (s, 3H), 2.81 (s, 3H). MS (ESI) m/z=230 [M+H].
Reaction SMILES: [CH2:1]1[CH:9]2[CH:4]3[CH:5]([CH2:10][C:11](=[O:12])[N:3]3[C:2]1=[O:13])[CH2:6][CH2:7][CH2:8]2.Cl.C([OH:22])C1C=CC=CC=1>C(OCC)C>[O:12]=[C:11]1[CH2:10][CH:5]2[CH:4]([CH:9]([CH2:1][C:2]([OH:13])=[O:22])[CH2:8][CH2:7][CH2:6]2)[NH:3]1
Reactant: OCc1ccccc1
Reactant: O=C1CC2CCCC3CC(=O)N1C23
Agent: Cl
Solvent: CCOCC
Product: O=C(O)CC1CCCC2CC(=O)NC12
Temperature: 100 °C

Procedure:
A solution of 9.5 grams (0.053 mol) hexahydropyrrolo [3,2,1-hi]-indole-2,4(1H, 5H)-dione (5aα, 8aα, 8bα) in 50 ml of benzyl alcohol is treated with four drops of drops of concentrated hydrochloric acid. The solution is heated to 100° C. for 72 hours, cooled, and diluted with 250 ml of anhydrous diethyl ether. A white crystalline precipitate of octahydro-2-oxo-1H-indole-7-acetic acid (3aα, 7β, 7aα) is isolated by filtration with a melting point of 238°-240° C. The filtrate is cooled and octahydro-2-oxo-1H-indole-7acetic acid benzyl ester (3aα, 7β, 7aα). This is purified by chromatography over silica gel using methylene chloride for elution. The eluate is concentrated at reduced pressure. The resulting solid is triturated with anhydrous diethyl ether and filtered. The filtrate is concentrated at reduced pressure to yield octahydro-2-oxo-1H-indole-7-acetic acid benzyl ester (3aα, 7β, 7aα) with a melting point of 89°-90° C.
Reaction SMILES: P(Br)(Br)[Br:2].[CH:5]1([CH:8]([CH:12]2[CH2:14][CH2:13]2)[CH2:9][CH2:10]O)[CH2:7][CH2:6]1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>CCOCC>[Br:2][CH2:10][CH2:9][CH:8]([CH:12]1[CH2:14][CH2:13]1)[CH:5]1[CH2:7][CH2:6]1
Reactant: OCCC(C1CC1)C1CC1
Reactant: BrP(Br)Br
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: BrCCC(C1CC1)C1CC1
Temperature: 0 °C
Yield: 60 %

Procedure:
15.5 g of phosphorus tribromide are slowly added to a solution, cooled to -30° C., of 22 g of 3,3-dicyclopropylpropanol (obtained by reduction of the compound described in preparation A in the presence of lithium aluminum hydride) in 85 ml of anhydrous ether, and the mixture is poured, after returning to room temperature, into 7 ml of ice cold water. The organic phase is then washed with a saturated solution of sodium bicarbonate and then with water until neutral and finally dried and evaporated. The expected product is obtained after distillation under vacuum.
Reaction SMILES: Br[CH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([Br:11])[CH:9]=2)[C:4](=[O:12])[O:3]1.[OH-].[K+].S(=O)(=O)(O)[O-:16].[K+]>O>[Br:11][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[C:4](=[O:12])[O:3][CH:2]2[OH:16]
Reactant: O=C1OC(Br)c2cc(Br)ccc21
Reactant: O=S(=O)([O-])O
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: O=C1OC(O)c2cc(Br)ccc21

Procedure:
To a suspension of EXAMPLE 1A (5 g, 17.1 mmol) in water (40 mL) was added powdered potassium hydroxide (1.92 g, 34.3 mmol), and the mixture was refluxed for 1 hour. After cooling, potassium bisulfate (2 g) was added, and the mixture extracted with ethyl acetate (150 mL). The organics were concentrated on a rotary evaporator and dried under vacuum to yield the title compound. MS (ESI) m/z 230 (M+H)+.
Reaction SMILES: [NH2:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Cl.[P:14](=[O:18])([OH:17])([OH:16])[OH:15].[CH3:19]O>>[P:14]([OH:18])([OH:17])([OH:16])=[O:15].[CH3:19][O:11][C:10](=[O:12])[C@H:2]([CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[NH2:1]
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Reactant: CO
Agent: Cl
Agent: O=P(O)(O)O
Product: COC(=O)[C@@H](N)Cc1ccccc1
Reaction time: 8 h
Yield: 61.1 %

Procedure:
The same esterification procedure as in Example 1 was followed with the exception that 165.2 g of L-phenylalanine and 165.2 g of methanol were used and that hydrochloric acid was replaced with 132.1 g of 89% phosphoric acid. The reaction was conducted at 60 ° C. for 8 hours, followed by cooling in order to deposit the crystals, which were collected by filtration and then dried to obtain 169.4 g (58.1% yield) of L-phenylalanine methyl ester phosphate having a purity of 95.1% and containing 0.3% of water and 3.0% of L-phenylalanine.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:6][CH3:7])[C:3]([NH2:5])=[O:4].Cl.N.C(O)(C)C.O[C:15]1[O:19][C:18](=O)[CH2:17][C:16]=1[CH2:21][CH2:22][CH3:23]>C(O)(C)C>[O:19]=[C:18]1[CH2:17][C@@H:16]([CH2:21][CH2:22][CH3:23])[CH2:15][N:1]1[C@@H:2]([CH2:6][CH3:7])[C:3]([NH2:5])=[O:4]
Reactant: CC[C@H](N)C(N)=O
Reactant: CCCC1=C(O)OC(=O)C1
Agent: Cl
Agent: N
Solvent: CC(C)O
Product: CCC[C@@H]1CC(=O)N([C@@H](CC)C(N)=O)C1

Procedure:
Example 1 is repeated except that in step 1.1 a solution of (2S)-2-aminobutyramide.HCl in isopropanol is used (27.72 g, 1.2 equivalent), which is neutralised with a NH3/isopropanol solution (3.4-3.7 mol/L). The resulting ammonium chloride is removed from this solution by filtration and the solution is directly used for reaction with 5-hydroxy-4-n-propyl-furan-2-one (23.62 g, 1.0 equivalent) without intermediate drying of the (2S)-2-aminobutyramide solution. Yield after separation of the two diastereoisomers and recrystallisation: approximately 84%.
Reaction SMILES: [Br:1][C:2]1[C:7]2[O:8][C:9](SC)=[N:10][C:6]=2[CH:5]=[CH:4][N:3]=1.[CH3:13][O:14][C:15]1[CH:16]=[C:17]([CH:19]=[C:20]([O:24][CH3:25])[C:21]=1[O:22][CH3:23])[NH2:18]>>[Br:1][C:2]1[C:7]2[O:8][C:9]([NH:18][C:17]3[CH:19]=[C:20]([O:24][CH3:25])[C:21]([O:22][CH3:23])=[C:15]([O:14][CH3:13])[CH:16]=3)=[N:10][C:6]=2[CH:5]=[CH:4][N:3]=1
Reactant: COc1cc(N)cc(OC)c1OC
Reactant: CSc1nc2ccnc(Br)c2o1
Product: COc1cc(Nc2nc3ccnc(Br)c3o2)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
0.6 g (2.61 mmol) 4-bromo-2-methylsulfanyl-oxazolo[5,4-c]pyridine are heated to 100° C. until it liquefies, then 0.977 g (5.23 mmol) 3,4,5-trimethoxyanilin is added in small portions with stirring. Stirring is continued for 2 h. The reaction mixture is cooled to room temperature and purified by chromatography (silicagel, hexane=>EtOAc) to afford the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[N:17][N:18]([CH2:20][CH2:21][CH2:22][OH:23])[CH:19]=2)=[CH:11][C:3]=1[C:4]([N:6](CC)CC)=[O:5].NC1C=CC(Br)=CC=1[C:27](NOC)=[O:28]>>[NH2:1][C:2]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[N:17][N:18]([CH2:20][CH2:21][CH2:22][OH:23])[CH:19]=2)=[CH:11][C:3]=1[C:4]([NH:6][O:28][CH3:27])=[O:5]
Reactant: CCN(CC)C(=O)c1cc(-c2cnn(CCCO)c2)ccc1N
Reactant: CONC(=O)c1cc(Br)ccc1N
Product: CONC(=O)c1cc(-c2cnn(CCCO)c2)ccc1N
Yield: 14 %

Procedure:
Prepared analogously to Compound 3C replacing Compound 3D with 2-amino-5-bromo-N-methoxybenzamide (Compound 26D, 1 g, 4.08 mmol) to afford 169 mg of the title compound (14%). 1H NMR (400 MHz, CD3OD) δ=7.85 (d, J=0.5 Hz, 1H), 7.74 (d, J=0.8 Hz, 1H), 7.54 (d, J=2.0 Hz, 1H), 7.41 (dd, J=2.2, 8.5 Hz, 1H), 6.79 (d, J=8.6 Hz, 1H), 4.25 (t, J=7.0 Hz, 2H), 3.81 (s, 3H), 3.54 (t, J=6.2 Hz, 2H), 2.06 (t, J=6.4 Hz, 2H). MS (ESI): m/z=291.13 [MH]. UPLC: tR=0.85 min (UPLC-TOF: polar—3 min).