Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][C:10]([CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)([CH2:13][CH2:14]OS(C)(=O)=O)[C:9]1=[O:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:28][C:29]1[CH:51]=[CH:50][C:32]([CH2:33][N:34]2[C:38]3[CH:39]=[CH:40][CH:41]=[CH:42][C:37]=3[N:36]=[C:35]2[NH:43][CH:44]2[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]2)=[CH:31][CH:30]=1>>[CH2:1]([N:8]1[CH2:12][CH2:11][C:10]([CH2:13][CH2:14][N:47]2[CH2:48][CH2:49][CH:44]([NH:43][C:35]3[N:34]([CH2:33][C:32]4[CH:50]=[CH:51][C:29]([F:28])=[CH:30][CH:31]=4)[C:38]4[CH:39]=[CH:40][CH:41]=[CH:42][C:37]=4[N:36]=3)[CH2:45][CH2:46]2)([CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:9]1=[O:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Fc1ccc(Cn2c(NC3CCNCC3)nc3ccccc32)cc1
Reactant: CS(=O)(=O)OCCC1(Cc2ccccc2)CCN(Cc2ccccc2)C1=O
Product: O=C1N(Cc2ccccc2)CCC1(CCN1CCC(Nc2nc3ccccc3n2Cc2ccc(F)cc2)CC1)Cc1ccccc1

Procedure:
Prepare by the method of Example 2.6 using 1-benzyl-3-(phenylmethyl)-3-(2-methanesulfonyloxyethyl)-2-oxopyrrolidine (0.99 g, 2.6 mmol) and (1-(4-fluorobenzyl)-1H-benzimidazol-2-yl)(piperidin-4-yl)amine (0.80 g, 2.6 mmol) to give the title compound: Rf=0.22 (silica gel, 5% methanol/ethyl acetate/2% triethylamine).
Reaction SMILES: C[O:2][C:3]([CH2:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13]2[N:22]=[C:21]([NH:23][C:24]3[NH:25][N:26]=[C:27]([CH3:29])[CH:28]=3)[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]=2)=[CH:8][C:7]=1[CH3:30])=[O:4].[OH-].[Na+].Cl>O.CCO>[C:3]([CH2:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13]2[N:22]=[C:21]([NH:23][C:24]3[NH:25][N:26]=[C:27]([CH3:29])[CH:28]=3)[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]=2)=[CH:8][C:7]=1[CH3:30])([OH:4])=[O:2]
Reactant: COC(=O)Cc1ccc(Nc2nc(Nc3cc(C)n[nH]3)c3ccccc3n2)cc1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1cc(Nc2nc(Nc3ccc(CC(=O)O)c(C)c3)nc3ccccc23)[nH]n1
Temperature: 70 °C
Yield: 95.3 %

Procedure:
A solution of [2-(4-methoxycarbonylmethyl-3-methylphenylamino)-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine (IIc-64, 200 mg, 0.5 mmol) in a mixture of methanol/water (3/1, 8 mL) was treated with 1M NaOH (2 mL, 2 mmol). The mixture was heated at 70° C. for 2 hours and then neutralised with 1M HCl (2 mL, 2 mmol). The solid that formed was collected by filtration to afford the title compound (185 mg, 95%) as a pale yellow solid, mp 245° C. (dec.); 1H NMR (DMSO) δ2.27 (6H, 2×s), 3.55 (2H, s), 6.49 (1H, s), 7.13 (1H, d), 7.26 (1H, t), 7.50 (1H, d), 7.62-7.78 (3H, m), 8.42 (1H, d), 9.34 (1H,d), 10.26 (1H, s), 12.36 (1H, s); IR (solid) 1660, 1590, 1562, 1504, 1427, 1385, 810, 776, 751, 693; MS 389.4 (M+H)+
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.[C:9]1([NH:15][N:16]=[CH:17][C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>CN(C=O)C>[Cl:1][N:15]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[N:16]=[CH:17][C:18]1[CH:19]=[CH:20][N:21]=[CH:22][CH:23]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: C(=NNc1ccccc1)c1ccncc1
Solvent: CN(C)C=O
Product: ClN(N=Cc1ccncc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 52.4 %

Procedure:
N-Chlorosuccinimide (2.11 g, 16 mmol) was added portionwise to a solution of compound 1 (2.97 g, 15 mmol) in DMF (15 mL). The reaction mixture was stirred for 10 min at room temperature. The resulting precipitates were collected and washed with petroleum ether to afford 1.82 g (52%) of 2 as a solid.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([C:11]#[N:12])[C:9]=1[OH:10])[CH:5]=O.[CH3:13][CH2:14][C:15](=[O:19])[CH2:16][CH:17]=[O:18].N1CCCCC1.C(O)(=O)C>C1(C)C=CC=CC=1>[OH:1][C:2]1[CH:3]=[C:4]([CH:5]=[C:16]([CH:17]=[O:18])[C:15](=[O:19])[CH2:14][CH3:13])[CH:7]=[C:8]([C:11]#[N:12])[C:9]=1[OH:10]
Reactant: N#Cc1cc(C=O)cc(O)c1O
Reactant: CCC(=O)CC=O
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Solvent: C1CCNCC1
Product: CCC(=O)C(C=O)=Cc1cc(O)c(O)c(C#N)c1

Procedure:
A mixture 1.6 g of 3,4-dihydroxy-5-cyanobenzaldehyde, 2.0 g of 3,5-pentanedione, 0.2 ml of piperidine and 0.6 ml of acetic acid in 70 ml of toluene was refluxed for 2 h with Dean-Stark separator. The solvent was evaporated in vacuo and the residue was crystallized from acetone-cyclohexane. mp 228°-232° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]([N:11]2[CH2:14][CH:13]([O:15][C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[CH2:12]2)=[C:6]([CH:10]=1)[C:7](O)=[O:8].Cl.C(N=C=NCCCN(C)C)C.Cl.[NH2:36][C@H:37]([C:39]1[CH:48]=[CH:47][C:42]([C:43]([O:45][CH3:46])=[O:44])=[CH:41][CH:40]=1)[CH3:38].C(N(CC)CC)C.C([O-])(O)=O.[Na+]>ClCCl>[Cl:1][C:2]1[CH:3]=[N:4][C:5]([N:11]2[CH2:12][CH:13]([O:15][C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[CH2:14]2)=[C:6]([CH:10]=1)[C:7]([NH:36][C@H:37]([C:39]1[CH:48]=[CH:47][C:42]([C:43]([O:45][CH3:46])=[O:44])=[CH:41][CH:40]=1)[CH3:38])=[O:8]
Reactant: O=C(O)c1cc(Cl)cnc1N1CC(Oc2ccc(F)cc2)C1
Reactant: COC(=O)c1ccc([C@H](C)N)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc([C@H](C)NC(=O)c2cc(Cl)cnc2N2CC(Oc3ccc(F)cc3)C2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.1 %

Procedure:
A mixture of 5-chloro-2-(3-(4-fluorophenoxy)azetidin-1-yl)nicotinic acid (D102) (75 mg, 0.232 mmol) 1-Hydroxybenzotriazole hydrate (31.34 mg, 0.232 mmol) and 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (66.8 mg, 0.35 mmol) in dichloromethane (3 ml) was stirred 1 h at room temperature. A solution (S)-methyl 4-(1-aminoethyl)benzoate (D3) (50 mg, 0.232 mmol) and triethylamine (0.03 ml, 0.232 mmol) in dichloromethane (1 ml) was added and the resulting mixture was stirred overnight at room temperature. NaHCO3 sat. sol. (5 ml) was added and the mixture was extracted with dichloromethane (3×10 ml). Collected organics, after solvent evaporation were purified by SPE-Si (10 g) eluting with a mixture Cyclohexane/ethylacetate from 95/05 to 60/40. Collected fractions, after solvent evaporation, afforded the title compound (D146) (100 mg).
Reaction SMILES: Br[CH2:2][C:3]1[N:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[N:6]=[C:5]([C:13]([O:15]CC)=[O:14])[CH:4]=1.[CH2:18]([NH:20][CH2:21][CH3:22])[CH3:19].O.[OH-].[Li+]>C(Cl)Cl.O1CCCC1.O>[CH2:18]([N:20]([CH2:2][C:3]1[N:8]=[C:7]([C:9]([F:10])([F:11])[F:12])[N:6]=[C:5]([C:13]([OH:15])=[O:14])[CH:4]=1)[CH2:21][CH3:22])[CH3:19]
Reactant: CCOC(=O)c1cc(CBr)nc(C(F)(F)F)n1
Reactant: CCNCC
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: ClCCl
Product: CCN(CC)Cc1cc(C(=O)O)nc(C(F)(F)F)n1
Reaction time: 0.5 h

Procedure:
To a solution of ethyl 6-(bromomethyl)-2-(trifluoromethyl)pyrimidine-4-carboxylate (0.15 g, 0.32 mmol, prepared as in Example 5, Step A) in methylene chloride (3.0 mL) was added N-ethylethanamine (0.13 mL, 1.3 mmol). After 30 minutes, the solvent was removed in vacuo. The ester was hydrolyzed by stirring with lithium hydroxide monohydrate (0.12 g, 3.0 mmol) in a mixture of tetrahydrofuran (5 mL) and water (2 mL). After 1 hour, 1N HCl was added dropwise to neutralize. Purification via preparative HPLC-MS (C18 eluting with a gradient of MeCN/H2O containing 0.15% NH4OH) afforded product as a light yellow solid. Yield: 0.050 g (60%); LC-MS: 278.0 (M+H)+. 1H NMR (400 MHz, DMSO-d6): δ 7.97 (s, 1H), 3.74 (s, 2H), 2.52 (q, 4H), 0.99 (t, 6H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[S:9](=[O:17])(=[O:16])[C:8]=2[CH:18]=1)([O-])=O.C(O)(=O)C>CN(C)C=O.[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[S:9](=[O:17])(=[O:16])[C:8]=2[CH:18]=1
Reactant: O=[N+]([O-])c1ccc2c(c1)S(=O)(=O)c1ccccc1-2
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: Nc1ccc2c(c1)S(=O)(=O)c1ccccc1-2

Procedure:
A 10 g portion of 3-nitrodibenzothiophene S,S-dioxide in 180 ml of dimethylformamide and 20 ml of glacial acetic acid containing 1.0 g of 5% palladium on carbon was hydrogenated for 1.75 hours, then filtered through diatomaceous earth and the filtrate evaporated. The residue was dissolved in 250 ml of acetonitrile, filtered through diatomaceous earth and concentrated to 150 ml. The solid was collected, giving 6.95 g of the desired product mp 261°-264° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[N+:9]([O-])=O.C(=O)=O.[C:15](#N)[CH3:16].C([Mg]Br)=C.[NH4+].[Cl-].Cl>C1COCC1.CCOC(C)=O>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[C:3]2[C:4]=1[CH:15]=[CH:16][NH:9]2
Reactant: O=[N+]([O-])c1cc(Br)ccc1Br
Reactant: CC#N
Agent: C=C[Mg]Br
Agent: Cl
Agent: O=C=O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Brc1ccc(Br)c2[nH]ccc12
Temperature: -40 °C
Reaction time: 1.5 h
Yield: 47 %

Procedure:
To a solution of 1,4-dibromo-2-nitrobenzene (18 g, 64.1 mmol) in THF (200 mL) at −40° C. (dry ice-acetonitrile) was added slowly a solution of vinylmagnesium bromide (1.0 M in THF, 199 mL, 199 mmol). The resulting mixture was stirred at −40° C. for 1.5 h, then was then treated with saturated aqueous NH4Cl (500 mL) and stirred at room temperature for 1 h. HCl (1M) was added to adjust the pH to 7. EtOAc was added and the organic phase was separated, washed with brine, dried and concentrated. The residue was subjected to column chromatography on silica gel (330 g), eluting with EtOAc-hexane (5:95) to provide a light yellow oil which solidified on standing under vacuum. The desired product was obtained as a solid (8.35 g, 47% yield. LCMS showed one major peak with no ionization.
Reaction SMILES: [C:1]([C@H:4]([C@@H:6]([C:8]([O-:10])=[O:9])[OH:7])[OH:5])([O-:3])=[O:2].S([O-])([O-])(=O)=O.[NH4+].[NH4+].[Cl-].[Ca+2].[Cl-]>O>[C:8]([OH:10])(=[O:9])[C@H:6]([C@@H:4]([C:1]([OH:3])=[O:2])[OH:5])[OH:7]
Reactant: O=C([O-])[C@@H](O)[C@H](O)C(=O)[O-]
Agent: O=S(=O)([O-])[O-]
Agent: [Ca+2]
Agent: [Cl-]
Solvent: O
Product: O=C(O)[C@@H](O)[C@H](O)C(=O)O
Reaction time: 8 h

Procedure:
The cells of Ach. tartarogenes nov. sp. TORAY 1246 (FERM-P 2507), obtained from 3 liters of the culture broth prepared as described in Example 1, were suspended in 10 mM tris-HCl buffer (pH 7.6) to make 200 ml. The suspension contained 5.3 g of the cells and 34200 units of d-tartrate epoxidase activity. One hundred ml of the suspension were treated by a French Press and a sonic oscillator. To the supernatant fluid resulting from centrifugation at 7000 r.p.m. for 15 minutes of the treated cell suspension, 16.2 g (30% saturation) of ammonium sulfate were added. After being kept at 5° C overnight, the precipitates then formed were removed and discarded by centrifugation. To the resulting clear supernatant fluid, 25.9 g (0.70% saturation) of ammonium sulfate were added. After 7 hours, the precipitates formed were collected by centrifugation and dissolved in tris-HCl buffer (10 mM, pH 7.6) to make 46 ml. The solution was dialyzed to remove dialyzable salts to the buffer overnight at 4° C using a Visking cellophane tube. Eighty-one ml of the partially purified enzyme solution thus obtained contained 1.07 g of protein and 13500 units of d-tartrate epoxidase activity. Fifty ml of 20 (w/v)% disodium cis-epoxysuccinate solution buffered by 50 mM tris-HCl buffer to pH 8.0 were mixed with 17 ml of the enzyme solution and water to make a total volume of 100 ml. The mixture was incubated at 40° C for 24 hours without shaking. After the reaction was completed, 14 ml of 4.5 M calcium chloride was added. Precipitates were collected after overnight maturation and 7.77 g of d-tartaric acid was obtained by the same method as in Example 1, yielding 91 - 92%.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1.C(=O)([O-])[O-].[K+].[K+].[F:24][C:25]([F:40])([F:39])[C:26]1[CH:27]=[C:28]([CH:31]=[C:32]([C:35]([F:38])([F:37])[F:36])[C:33]=1Cl)[CH:29]=[O:30]>CS(C)=O>[CH:12]1([CH2:11][C:5]2[C:4]3[C:8](=[CH:9][CH:10]=[C:2]([O:1][C:33]4[C:32]([C:35]([F:38])([F:37])[F:36])=[CH:31][C:28]([CH:29]=[O:30])=[CH:27][C:26]=4[C:25]([F:24])([F:39])[F:40])[CH:3]=3)[NH:7][CH:6]=2)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]1
Reactant: Oc1ccc2[nH]cc(CC3CCCCC3)c2c1
Reactant: O=Cc1cc(C(F)(F)F)c(Cl)c(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: O=Cc1cc(C(F)(F)F)c(Oc2ccc3[nH]cc(CC4CCCCC4)c3c2)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Analogously to the procedure of Example V, 2.0 g (8.72 mmol) of 5-hydroxy-3-cyclohexylmethyl-indole are dissolved in 50 ml of DMSO, 1.33 g (9.59 mmol) of potassium carbonate are added, the mixture is stirred for 10 min at room temperature and afterwards 2.41 g (8.72 mmol) of 3,5-bis-trifluoromethyl-4-chlorobenzaldehyde are introduced in portions. After stirring overnight at 50° C., the batch is worked up analogously to Example V and the crude product is chromatographed on silica gel 60 by means of toluene.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[C:7]([Cl:9])[CH:6]=[CH:5][C:4]=1[C:10]1[O:11][C:12]([CH:27]([CH3:29])[CH3:28])=[C:13]([CH2:15][CH2:16][C:17]([C:19]2[CH:24]=[CH:23][C:22]([OH:25])=[C:21]([CH3:26])[CH:20]=2)=[O:18])[N:14]=1.B(Cl)(Cl)Cl.C(Cl)(Cl)Cl.C(=O)([O-])O.[Na+]>C(Cl)Cl>[OH:2][C:3]1[CH:8]=[C:7]([Cl:9])[CH:6]=[CH:5][C:4]=1[C:10]1[O:11][C:12]([CH:27]([CH3:29])[CH3:28])=[C:13]([CH2:15][CH2:16][C:17]([C:19]2[CH:24]=[CH:23][C:22]([OH:25])=[C:21]([CH3:26])[CH:20]=2)=[O:18])[N:14]=1
Reactant: COc1cc(Cl)ccc1-c1nc(CCC(=O)c2ccc(O)c(C)c2)c(C(C)C)o1
Agent: ClB(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: Cc1cc(C(=O)CCc2nc(-c3ccc(Cl)cc3O)oc2C(C)C)ccc1O
Temperature: 0 °C
Reaction time: 72 h
Yield: 64.2 %

Procedure:
The obtained 3-[2-(2-methoxy4-chlorophenyl)-5-isopropyl-4-oxazolyl]-1-(3-methyl-4-hydroxyphenyl)propan-1-one (621 mg, 1.50 mmol) was suspended in methylene chloride (30 mL) and cooled with ice. To the suspension, a 1M methylene chloride solution of boron trichloride (BCl3) (3.0 mL, 3.00 mmol) was dropwise added for 1 minute. The mixture was allowed to room temperature, stirred for 72 hours, and poured into ice water. Chloroform and saturated sodium hydrogen carbonate were added to the mixture. The organic layer was washed with water, and a saline, dried over anhydrous sodium sulfate. The chloroform was removed under reduced pressure. The residue was purified by column chromatography on silica gel with hexane/ethyl acetate (3/1) to give the desired compound (385 mg) as colorless oil (yield 64%).
Reaction SMILES: OOS([O-])=O.[K+].C(=O)([O-])[O-:8].[K+].[K+].[NH2:13][C:14]1[CH:23]=[CH:22][C:17]([NH:18][C:19](=[O:21])[CH3:20])=[CH:16][CH:15]=1>O>[N:13]([C:14]1[CH:15]=[CH:16][C:17]([NH:18][C:19](=[O:21])[CH3:20])=[CH:22][CH:23]=1)=[O:8]
Reactant: O=C([O-])[O-]
Reactant: CC(=O)Nc1ccc(N)cc1
Agent: O=S([O-])OO
Agent: [K+]
Solvent: O
Product: CC(=O)Nc1ccc(N=O)cc1
Reaction time: 0.17 h
Yield: 64.6 %

Procedure:
After oxone (potassium peroxymonosulfate, from Sigma-Aldrich®; 12.28 g, 20.0 mmol) had dissolved completely in water (100 mL), potassium carbonate (4.14 g, 30 mmol) was added slowly to neutralize the solution to a weak acidity. The solution was added quickly into a solution of 4′-aminoacetanilide (from Sigma-Aldrich®; 1.50 g, 10.0 mmol) in water (150 mL). The mixture immediately turned green, and greenish-gray solids started to fall out of solution. After the mixture had been stirred for another 10 minutes, the precipitates were collected on a filter funnel, air dried, and recrystallized from hot ethanol. Two batches of products were collected to give a total yield of 1.06 g (65%) greenish crystals, mp 179-180° C. (lit. 179-180° C.).
Reaction SMILES: C[O:2][C:3](=O)[CH:4]([C:6]([F:9])([F:8])[F:7])[OH:5].O.[NH2:12][NH2:13]>C(O)CCC>[F:7][C:6]([F:9])([F:8])[CH:4]([OH:5])[C:3]([NH:12][NH2:13])=[O:2]
Reactant: COC(=O)C(O)C(F)(F)F
Reactant: NN
Solvent: O
Solvent: CCCCO
Product: NNC(=O)C(O)C(F)(F)F

Procedure:
As described for example 112a, methyl-3,3,3-trifluoro-DL-lactate in butanol was reacted with hydrazine hydrate (1.2 equivalents) at rt for 16 h. The mixture was concentrated and the title compound was obtained as a light yellow oil (yield: 81%). MS: m/e=158.0 [M]+.
Reaction SMILES: C(O[C:4]([C:6]1[NH:7][CH:8]=[CH:9][C:10]=1[NH:11][CH2:12][C:13]1[C:18]([O:19][CH2:20][CH2:21][O:22][CH2:23][CH3:24])=[CH:17][CH:16]=[CH:15][N:14]=1)=[O:5])C.C(OC([N:30]=[C:31]=[S:32])=O)C>>[CH2:23]([O:22][CH2:21][CH2:20][O:19][C:18]1[C:13]([CH2:12][N:11]2[C:10]3[CH:9]=[CH:8][NH:7][C:6]=3[C:4](=[O:5])[NH:30][C:31]2=[S:32])=[N:14][CH:15]=[CH:16][CH:17]=1)[CH3:24]
Reactant: CCOCCOc1cccnc1CNc1cc[nH]c1C(=O)OCC
Reactant: CCOC(=O)N=C=S
Product: CCOCCOc1cccnc1Cn1c(=S)[nH]c(=O)c2[nH]ccc21
Yield: 28.3 %

Procedure:
The title compound (0.051 g, 28%) was prepared in accordance with general method B using 3-({[3-(2-ethoxyethoxy)pyridin-2-yl]methyl}amino)-1H-pyrrole-2-carboxylic acid ethyl ester (0.17 g, 0.52 mmol) and ethoxycarbonyl isothiocyanate (0.07 mL, 0.62 mmol).
Reaction SMILES: Cl.C([O:4][C:5](=[O:33])[C:6]([NH:29]C(=O)C)([CH:12]1[CH2:20][C:19]2[C:14](=[CH:15][CH:16]=[C:17]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[CH:18]=2)[CH2:13]1)C(OCC)=O)C>CO>[NH2:29][CH:6]([CH:12]1[CH2:20][C:19]2[C:14](=[CH:15][CH:16]=[C:17]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[CH:18]=2)[CH2:13]1)[C:5]([OH:33])=[O:4]
Reactant: CCCCCCCCc1ccc2c(c1)CC(C(NC(C)=O)(C(=O)OCC)C(=O)OCC)C2
Agent: Cl
Solvent: CO
Product: CCCCCCCCc1ccc2c(c1)CC(C(N)C(=O)O)C2
Yield: 46 %

Procedure:
To 10 mL of 12 M hydrochloric acid was added 5 (0.2 g, 0.451 mmol). Methanol was added until mix became homogenous and solution was allowed to reflux for 2 hours. The resulting mix was concentrated and co-evaporated with methanol and ether (3×10 mL). The reaction provided 10 (63 mg, 0.2076 mmol, 46%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[C:11]([F:14])([F:13])[F:12])[CH2:7][N:6](C(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH2:5]2.CO.[F:36][C:37]([F:42])([F:41])[C:38]([OH:40])=[O:39]>C(Cl)(Cl)Cl>[F:36][C:37]([F:42])([F:41])[C:38]([OH:40])=[O:39].[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[C:11]([F:13])([F:12])[F:14])[CH2:7][NH:6][CH2:5]2
Reactant: Fc1cc2c(cc1C(F)(F)F)CN(C(c1ccccc1)(c1ccccc1)c1ccccc1)C2
Solvent: ClC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: Fc1cc2c(cc1C(F)(F)F)CNC2
Temperature: 25 °C
Reaction time: 3 h
Yield: 100 %

Procedure:
To a mixture of 0.33 mmol 5-fluoro-6-trifluoromethyl-2-trityl-2,3-dihydro-1H-isoindole in 1.5 methanol and 1.5 ml chloroform at 0° C. was added dropwise 1.63 mmol trifluoroacetic acid and the mixture was then stirred at RT for 3 h before being concentrated in vacuo to afford the title compound as a yellow solid (100% yield). EI-MS (m/e): 206.1 ([M+H]+, 100%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:10]([CH3:11])=[C:9]([CH3:12])[NH:8][C:5]2=[N:6][CH:7]=1.BrC1N=C2NC(C)=C(C)C2=CC=1.[CH2:25](Br)[C:26]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:27]>CC#N>[Br:1][C:2]1[CH:3]=[C:4]2[C:10]([CH3:11])=[C:9]([CH3:12])[N:8]=[C:5]2[N:6]([CH2:25][C:26]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[O:27])[CH:7]=1
Reactant: O=C(CBr)c1ccccc1
Reactant: Cc1[nH]c2ncc(Br)cc2c1C
Agent: Cc1[nH]c2nc(Br)ccc2c1C
Solvent: CC#N
Product: Cc1nc2n(CC(=O)c3ccccc3)cc(Br)cc-2c1C

Procedure:
A solution of 5-bromo-2,3 -dimethyl-pyrrolo [2,3 -b]pyridine (prepared in a similar manner as 6-bromo-2,3-dimethyl-pyrrolo[2,3-b]pyridine (200 mg, 0.9 mmol) and phenacyl bromide (200 mg, 1.3 mmol) in 15 ml CH3CN was refluxed for 16 h. The mixture was allowed to cool and the precipitated product filtered off and washed with a small volume of diethyl ether affording 243 mg (72%) pure title compound as the hydrochloride.
Reaction SMILES: [C:1]([O:5][C:6]([N:8](C)[C@@H:9](C)C(N[C@@H](C1C=CC=CC=1)C(N1C2C(=CC=CC=2)C[C@H]1C(O)=O)=O)=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].FC1C=CC(C)=C(CN)C=1.C(P1(=O)OP(=O)(CCC)OP(=O)(CCC)O1)CC.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[C:1]([O:5][C:6](=[O:7])[NH:8][CH3:9])([CH3:4])([CH3:3])[CH3:2]
Reactant: C[C@@H](C(=O)N[C@H](C(=O)N1c2ccccc2C[C@H]1C(=O)O)c1ccccc1)N(C)C(=O)OC(C)(C)C
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: Cc1ccc(F)cc1CN
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CNC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 359.2 %

Procedure:
To a solution of (S)-1-{(S)-2-[(S)-2-(tert-butoxycarbonyl-methyl-amino)-propionylamino]-2-phenyl-acetyl}-2,3-dihydro-1H-indole-2-carboxylic acid (50 mg, 104 μmol, Eq: 1) and (5-fluoro-2-methylphenyl)methanamine (28.9 mg, 208 μmol, Eq: 2) in DCM (3 mL) cooled to 0° C. was added 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphorinane-2,4,6-trioxide (50% weight solution in EtOAc, volume added: 150 μL, Eq: 2) and diisopropylethylamine (54 μL, Eq: 3). The reaction mixture was stirred at 0° C. for 20 min and then at 23° C. for 1 h. The reaction was quenched with saturated aqueous NaHCO3 to pH=8. The two phases were separated and aqueous phase was re-extracted with DCM. The organic layers were combined and concentrated in vacuo. The mixture was purified by flash chromatography (silica gel, 0% to 70% EtOAc in hexanes) to give ((S)-1-{(S)-2-[(S)-2-(5-fluoro-2-methyl-benzylcarbamoyl)-2,3-dihydro-indol-1-yl]-2-oxo-1-phenyl-ethylcarbamoyl})-ethyl)-methyl-carbamic acid tert-butyl ester as a white powder (49 mg), m/z=603 (M+H).
Reaction SMILES: [BH4-].[Na+].[CH3:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]([N:13]=[CH:14][CH2:15][CH3:16])[CH:5]=1.C(O)(=O)C.[H][H]>CN1C(=O)CCC1.CCCCCCC.O>[CH3:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]([NH:13][CH2:14][CH2:15][CH3:16])[CH:5]=1
Reactant: CCC=Nn1cc(C)c2ccccc21
Reactant: [H][H]
Agent: [BH4-]
Agent: [Na+]
Solvent: CCCCCCC
Solvent: O
Solvent: CN1CCCC1=O
Product: CCCNn1cc(C)c2ccccc21
Temperature: 30 °C

Procedure:
Prepare a solution of sodium borohydride (4.54 kg, 120 mol) in 38 kg of NMP. Add to this solution, a solution of 3-methyl-N-(propylidene)-1H-indol-1-amine (38.6 kg, 190 mol) in 78 kg of n-heptane. Prepare a solution of 6.8 kg (120 mol) glacial acetic acid in 32 kg n-heptane. Add the acetic acid solution over a period of about 30 min at 30° C. to the sodium borohydride solution using a pump. Immediately hydrogen evolution occurs. Rinse the pump with 3 kg n-heptane and add the rinse to the reaction mixture. Stir the reaction mixture at 30° C. until completion of the reaction (˜1 h). The reaction mixture is then worked-up by adding 76 L water. No or only minimal foaming is observed during the addition of water. Stir the mixture over night and separate the phases. Add 2.82 kg HCl (30%) and 4.75 kg water to the n-heptane phase, check the pH, if the pH is above 1, add more HCl. Heat this mixture to 75° C. internal temperature for ˜2 h. Cool the mixture to 25° C. in order to control the evolution of hydrogen. If no more residual hydrogen is evolved, adjust pH level to 7, add additional 30 kg water, separate the phases and wash the n-Heptane phase twice with 37 kg water. Evaporate the n-heptane phase to dryness. This results in 37.5 kg 3-methyl-N-propyl-1H-indol-1-amine (98%) as a brown liquid.
Reaction SMILES: C(OC(=O)[N:7]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]#[N:14])(C)(C)C.BrCCCCCC#N>Cl.CCO>[CH2:16]([O:15][N:7]1[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]1=[NH:14])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CC(C)(C)OC(=O)N(CCCCCC#N)OCc1ccccc1
Agent: Cl
Agent: N#CCCCCCBr
Solvent: CCO
Product: N=C1CCCCCN1OCc1ccccc1
Reaction time: 0.75 h

Procedure:
Tert-butyl-(benzyloxy)-(5-cyanopentyl)-carbamate (synthesized following the procedure described in EXAMPLE 1-Step 1a starting from 6-bromohexanenitrile) was dissolved in a saturated solution of HCl in EtOH and the mixture was stirred for 45 minutes. Nitrogen was bubbled into the solution to remove HCl in excess. The solvent was removed under reduced pressure and the residue, dissolved in 1,4-dioxane, was treated with triethylamine to adjust pH at 10. Ethanol was removed and the title compound containing an excess of triethylammonium chloride and ethyl 6-[(benzyloxy)amino]hexanoate was used without further purification. The analytical sample was purified by preparative RP-HPLC, using water (0.1% TFA) and acetonitrile (0.1% TFA) as eluents (column C18). The pooled product fractions were lyophilized.