Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[CH2:4][C:5]1[CH:14]=[C:13]([O:15]CC2C=CC=CC=2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:23])[CH:11]=2)[C:6]=1[Br:24]>C(OCC)(=O)C.[Pd].[Br-].[Zn+2].[Br-]>[CH3:1][O:2][C:3](=[O:25])[CH2:4][C:5]1[CH:14]=[C:13]([OH:15])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:23])[CH:11]=2)[C:6]=1[Br:24]
Reactant: COC(=O)Cc1cc(OCc2ccccc2)c2cc(F)ccc2c1Br
Agent: [Pd]
Agent: [Br-]
Agent: [Zn+2]
Solvent: CCOC(C)=O
Product: COC(=O)Cc1cc(O)c2cc(F)ccc2c1Br
Temperature: 25 °C
Reaction time: 1 h
Yield: 64.4 %

Procedure:
To a solution of (4-benzyloxy-1-bromo-6-fluoro-naphthalen-2-yl)-acetic acid methyl ester (400 mg, 0.992 mmol) in ethyl acetate (10 mL) was added zinc bromide (670 mg, 2.978 mmol) and 10% palladium on carbon (40 mg) under a hydrogen atmosphere (balloon). After being stirred at room temperature for 1 hour, the resulting mixture was filtered. The filtrate was concentrated in vacuo. The residue was purified by preparative HPLC (gradient elution with 50-80% 0.1% trifluoroacetic acid in water in acetonitrile, 8 minutes) to afford (1-bromo-6-fluoro-4-hydroxy-naphthalen-2-yl)acetic acid methyl ester (200 mg, 64.4%) as a white solid.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[S:3]([O:6][C:7]1[CH:12]=[CH:11][C:10]([CH:13]=[O:14])=[C:9]([CH:15]([CH3:17])[CH3:16])[CH:8]=1)(=[O:5])=[O:4].[BH4-].[Na+]>CO>[F:18][C:2]([F:1])([F:19])[S:3]([O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][OH:14])=[C:9]([CH:15]([CH3:17])[CH3:16])[CH:8]=1)(=[O:4])=[O:5]
Reactant: CC(C)c1cc(OS(=O)(=O)C(F)(F)F)ccc1C=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)c1cc(OS(=O)(=O)C(F)(F)F)ccc1CO
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of 4-formyl-3-isopropyl-phenyl 1,1,1-trifluoro-methansulfonate (Intermediate 148, 540.0 mg, 1.82 mmols) in 7 mL MeOH at 0° C. was added NaBH4(72.0 mg, 1.91 mmols). After stirring 2 hours at 0° C. the reaction was carefully quenched with H2O and extracted with Et2O. The combined organic layers were washed with H2O and saturated aqueous NaCl, dried (MgSO4), and concetrated under reduced pressure. The title compound was isolated by column chromatography (5-10% EtOAc-hexanes) as a colorless oil, 355.0 mg (90%).
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([NH:11][C:12](=[O:19])[C:13]3[CH:18]=[CH:17][CH:16]=[N:15][CH:14]=3)[N:10]=[C:6]2[CH:5]=[CH:4][CH:3]=1.[CH:20]1([NH2:28])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1>>[CH:20]1([NH:28][C:2]2[N:7]3[N:8]=[C:9]([NH:11][C:12](=[O:19])[C:13]4[CH:18]=[CH:17][CH:16]=[N:15][CH:14]=4)[N:10]=[C:6]3[CH:5]=[CH:4][CH:3]=2)[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: O=C(Nc1nc2cccc(Cl)n2n1)c1cccnc1
Reactant: NC1CCCCCCC1
Product: O=C(Nc1nc2cccc(NC3CCCCCCC3)n2n1)c1cccnc1

Procedure:
The title compound was prepared following procedure described for example 30 but starting from N-(5-chloro[1,2,4]triazolo[1,5-a]pyridin-2-yl)nicotinamide ((B4), 58 mg; 0.21 mmol; 1.0 eq.) and cyclooctylamine (440 μL) as a white powder (4 mg, 4%). HPLC, Rt: 3.25 min. (purity 97.9%). LC/MS, M+(ESI): 365.4, M−(ESI): 363.4.
Reaction SMILES: C[Si]([C:5]1[NH:10][C:9](=[O:11])[N:8]([Si](C)(C)C)[C:7](=[O:16])[C:6]=1[F:17])(C)C.FC1C(=O)NC(=O)NC=1.[CH2:27]([CH:29]1[O:33][CH2:32][CH2:31][O:30]1)[CH3:28].C(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl.CO.C(O)CO>[OH:33][CH2:32][CH2:31][O:30][CH:29]([N:10]1[CH:5]=[C:6]([F:17])[C:7](=[O:16])[NH:8][C:9]1=[O:11])[CH2:27][CH3:28]
Reactant: C[Si](C)(C)c1[nH]c(=O)n([Si](C)(C)C)c(=O)c1F
Reactant: CCC1OCCO1
Agent: O=C([O-])O
Agent: O=c1[nH]cc(F)c(=O)[nH]1
Agent: [Na+]
Solvent: OCCO
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CCC(OCCO)n1cc(F)c(=O)[nH]c1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Bis(trimethylsilyl)-5-fluorouracil which had been prepared by treating 5-fluorouracil (10 g) as in Example 1 was dissolved in chloroform (20 ml). Separately prepared 2-ethyl-1,3-dioxolan (15 ml) from propionyldehyde (25 ml) and ethylene glycol (25 ml) was added to the above solution. Then, to the mixture was added dropwise a solution of anhydrous stannic chloride (6 ml) in chloroform (15 ml) under cooling in an ice bath for one hour. Following stirring at room temperature for one hour, the reaction mixture was poured into methanol (100 ml) containing sodium bicarbonate (30 g) and, after removing the resulting precipitate by filtration, the filtrate was evaporated under reduced pressure. The residue was dissolved in water (10 ml), purified by column chromatography with use of Amberlite XAD-4 (Rohm and Haas Co.), and then treated with benzene to give 8.7 of crystalline 1-[1-(2-hydroxyethoxy)propyl]-5-fluorouracil.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13]2[N:18]=[C:17]([C:19]3[S:23][C:22]([CH3:24])=[N:21][C:20]=3[CH3:25])[CH:16]=[CH:15][N:14]=2)=[CH:8][CH:7]=1)=[O:4].[NH:26]1[CH:30]=[N:29][CH:28]=[N:27]1>>[CH3:24][C:22]1[S:23][C:19]([C:17]2[CH:16]=[CH:15][N:14]=[C:13]([NH:12][C:9]3[CH:10]=[CH:11][C:6]([NH:5][C:3](=[O:4])[CH2:2][N:26]4[CH:30]=[N:29][CH:28]=[N:27]4)=[CH:7][CH:8]=3)[N:18]=2)=[C:20]([CH3:25])[N:21]=1
Reactant: Cc1nc(C)c(-c2ccnc(Nc3ccc(NC(=O)CCl)cc3)n2)s1
Reactant: c1nc[nH]n1
Product: Cc1nc(C)c(-c2ccnc(Nc3ccc(NC(=O)Cn4cncn4)cc3)n2)s1

Procedure:
By treatment of 2-chloro-N-{4-[4-(2,4-dimethyl-thiazol-5-yl)-pyrimidin-2-ylamino]-phenyl}-acetamide with 1H-[1,2,4]triazole. 1H-NMR (DMSO-D6) δ: 2.61 (s, 3H, CH3), 2.63 (s, 3H, CH3), 5.10 (s, 2H, CH2), 7.05 (d, 1H, J=5.4 Hz, pyrimidinyl-H), 7.50 (d, 2H, J=8.3 Hz, pyrimidinyl-H), 7.69 (d, 2H, J=8.9 Hz, Ph-H), 7.98 (s, 1H, Aryl-H), 8.48 (d, 1H, J=4.9 Hz, pyrimidinyl-H), 8.53 (s, 1H, Aryl-H), 9.62 (brs, 1H, NH), 10.30 (brs, 1H, NH). MS (ESI+) m/z 406.97 (C19H18N8OS requires 406.47).
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([SH:10])[CH2:7][N:6]1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[O:4].[CH:18]1([CH2:21]Br)[CH2:20][CH2:19]1>>[CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([S:10][CH2:21][CH:18]2[CH2:20][CH2:19]2)[CH2:7][N:6]1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[O:4]
Reactant: BrCC1CC1
Reactant: COC(=O)[C@@H]1C[C@@H](S)CN1C(=O)OC(C)(C)C
Product: COC(=O)[C@@H]1C[C@@H](SCC2CC2)CN1C(=O)OC(C)(C)C

Procedure:
In analogy to the procedure described in example 409b, (2S,4R)-4-mercapto-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (example 409a) was reacted with cyclopropylmethyl bromide (CAS Reg. No. 7051-34-5) to give the title compound as colorless liquid. MS (ESI): m/z=316.2 [M+H]+.
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]([C:6]1[S:10][C:9]2[CH2:11][CH2:12][CH2:13][CH2:14][C:8]=2[CH:7]=1)=[O:5].S(=O)(=O)(O)O>>[CH2:2]1[C:7]2[C:8]3[CH2:14][CH2:13][CH2:12][CH2:11][C:9]=3[S:10][C:6]=2[C:4](=[O:5])[CH2:3]1
Reactant: O=C(CCCl)c1cc2c(s1)CCCC2
Agent: O=S(=O)(O)O
Product: O=C1CCc2c1sc1c2CCCC1
Temperature: 95 °C
Reaction time: 16 h
Yield: 47 %

Procedure:
A 50-mL single-necked round-bottomed flask equipped with a magnetic stirrer was charged with 103b (800 mg, 3.51 mmol) and 98% sulfuric acid (8 mL). After stirring at 95° C. for 16 h, the reaction mixture was poured into ice (50 g), and the resulting suspension was extracted with ethyl acetate (3×50 mL). The organic extracts were combined, dried over sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by flash chromatography to afford 103c in 47% yield (320 mg) as an off-white solid: mp 75-76° C.; 1H NMR (500 MHz, CDCl3) δ 2.89 (m, 2H), 2.87-2.83 (m, 4H), 2.56 (t, 2H, J=6.5 Hz), 1.84 (m, 4H)
Reaction SMILES: [CH:1]1([C:7]2[C:15]3[CH:14]=[CH:13][C:12]([C:16]([O:18]C)=[O:17])=[CH:11][C:10]=3[N:9]3[CH2:20][C:21](=O)[C:22]4[C:23]5[C:28]([NH:29][CH:30]=4)=[CH:27][CH:26]=[CH:25][C:24]=5[C:8]=23)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.S(C)C.[OH-].[Na+]>C1COCC1>[CH:1]1([C:7]2[C:15]3[CH:14]=[CH:13][C:12]([C:16]([OH:18])=[O:17])=[CH:11][C:10]=3[N:9]3[CH2:20][CH2:21][C:22]4[C:23]5[C:28]([NH:29][CH:30]=4)=[CH:27][CH:26]=[CH:25][C:24]=5[C:8]=23)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CC(=O)c1c[nH]c2cccc-3c12
Agent: [Na+]
Agent: [OH-]
Solvent: CSC
Solvent: C1CCOC1
Product: O=C(O)c1ccc2c(C3CCCCC3)c3n(c2c1)CCc1c[nH]c2cccc-3c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 12 %

Procedure:
To a solution of methyl 13-cyclohexyl-6-oxo-6,7-dihydro-4H -indolo[4′,3′:3,4,5]azepino[1,2-a]indole-10-carboxylate in THF (0.15 M), 20 eq of BH3.Me2S (2 M solution in THF) were added and the mixture was stirred overnight at RT. The solution was carefully quenched by adding 1.25 N HCl in MeOH until effervescence subsided. Then the volatiles were driven off by boiling the mixture to dryness. The residue was dissolved in MeOH (0.06 M) and 10 eq of 1N NaOH (aq) were added. The solution stirred at 60° C. for 2 h before removing volatiles in vacuo. The crude was then purified by prep RP-HPLC (stationary phase: column WATERS X-TERRA prep. C18, 5 microns. Mobile phase: MeCN/H2O buffered with 0.1% TFA). Fractions containing the pure compound were combined and freeze dried to afford the title compound (12% yield from methyl 3-cyclohexyl-1-[2-(dimethylamino)-2-oxoethyl]-1H,1′H-2,4′-biindole-6-carboxylate). 1H NMR (400 MHz, DMSO-d6+TFA, 300 K) δ 8.20 (s, 1H), 7.85 (d, J 8.4, 1H), 7.65 (d, J 8.4, 1H), 7.45 (d, J 7.9, 1H), 7.30-7.10 (m, 3H), 5.20-5.00 (m, 1H), 4.10-3.90 (m, 1H), 3.30-3.10 (m, 2H), 2.80-2.70 (m, 1H), 2.10-1.80 (m, 3H), 1.70-1.50 (m, 2H), 1.50-1.30 (m, 3H), 1.30-1.00 (m, 2H); MS (ES+) m/z 385 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[N:7]2N=N[N:10]=[C:6]2[C:5]2[N:11]=[C:12]([CH2:24][O:25][N:26]=[C:27]([CH3:29])[CH3:28])[N:13]([CH2:14][CH2:15][CH2:16][CH2:17][NH:18][C:19](=[O:23])[CH:20]([CH3:22])[CH3:21])[C:4]=2[C:3]=1[CH3:30].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClC1C=CC=CC=1Cl>[NH2:10][C:6]1[C:5]2[N:11]=[C:12]([CH2:24][O:25][N:26]=[C:27]([CH3:29])[CH3:28])[N:13]([CH2:14][CH2:15][CH2:16][CH2:17][NH:18][C:19](=[O:23])[CH:20]([CH3:22])[CH3:21])[C:4]=2[C:3]([CH3:30])=[C:2]([CH3:1])[N:7]=1
Reactant: CC(C)=NOCc1nc2c(c(C)c(C)n3nnnc23)n1CCCCNC(=O)C(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Clc1ccccc1Cl
Product: CC(C)=NOCc1nc2c(N)nc(C)c(C)c2n1CCCCNC(=O)C(C)C
Temperature: 125 °C
Reaction time: 72 h

Procedure:
A mixture of N-{4-[5,6-dimethyl-8-({[(1-methylethylidene)amino]oxy}methyl)-7H-imidazo[4,5-c]tetraazolo[1,5-a]pyridin-7-yl]butyl}-2-methylpropanamide (from Part C, approximately 9.71 mmol), triphenylphosphine (5.1 g, 19 mmol), and 1,2-dichlorobenzene (97 mL) was heated at 125° C. for 2 days, then stirred at room temperature for 3 days, then heated at 130° C. for 5 hours. The reaction was allowed to cool to room temperature and was concentrated under reduced pressure. The residue was dissolved in methanol (80 mL) and 1 M aqueous hydrochloric acid (40 mL) and heated at 40° C. for 6 hours. The reaction was allowed to stir at room temperature overnight and a white precipitate formed that was removed by filtration. The filtrate was concentrated under reduced pressure and the residue was partitioned between 1 M aqueous hydrochloric acid (20 mL) and chloroform (10 mL). The aqueous layer was extracted with chloroform (3×10 mL). The organic layers were combined, washed with saturated aqueous sodium bicarbonate, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The solid was purified by chromatography using a HORIZON HPFC system (silica gel, gradient elution with 5-55% CMA in chloroform). The appropriate fractions were combined and concentrated under reduced pressure. The resulting solid was triturated with acetonitrile and then was recrystallized from acetonitrile to provide N-{4-[4-amino-6,7-dimethyl-2-({[(1-methylethylidene)amino]oxy}methyl)-1H-imidazo[4,5-c]pyridin-1-yl]butyl}-2-methylpropanamide as a white powder, mp 180.0-181.0° C. Anal. Calcd for C20H32N6O2: C, 61.83; H, 8.30; N, 21.63. Found: C, 61.65; H, 8.65; N, 21.70.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([N+:9]([O-:11])=[O:10])[C:3]=1[OH:12].C(=O)([O-])[O-].[K+].[K+].[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.CN(C=O)C>C1COCC1>[CH2:19]([O:12][C:3]1[C:4]([N+:9]([O-:11])=[O:10])=[CH:5][CH:6]=[C:7]([F:8])[C:2]=1[F:1])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: BrCc1ccccc1
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc(F)c(F)c1OCc1ccccc1
Temperature: 60 °C
Reaction time: 6 h
Yield: 27.5 %

Procedure:
In THF (200 ml) was dissolved 2,3-difluoro-6-nitrophenol (10.0 g, 57.1 mmol), followed by the addition of potassium carbonate (15.8 g, 114.2 mmol) and benzyl bromide (7.47 ml, 62.8 mmol) at room temperature. The reaction mixture was stirred at 60° C. for 6 hours. DMF (100 ml) was added to the reaction mixture and the mixture was stirred at 60° C. for 24 hours. After cooling to room temperature, the reaction mixture was distilled under reduced pressure to remove the solvent. The residue was diluted with ether (100 ml), washed with saturated brine, dried over anhydrous sodium sulfate and distilled under reduced pressure to remove the solvent. The residue was purified by chromatography on a silica gel column (silica gel: 100 g), whereby from the hexane/ethyl acetate (4/1) eluate fractions, the title compound (4.17 g, 28%) was obtained as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:10]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18](=[N:26][C:27]#[N:28])OC4C=CC=CC=4)=[CH:13][CH:12]=3)=[C:9]([CH3:29])[S:8][C:4]=2[N:5]=[CH:6][N:7]=1.[CH3:30][C:31]1[CH:32]=[C:33]([CH:35]=[CH:36][CH:37]=1)[NH2:34]>CN(C=O)C>[NH2:1][C:2]1[C:3]2[C:10]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]([NH:34][C:33]4[CH:35]=[CH:36][CH:37]=[C:31]([CH3:30])[CH:32]=4)=[N:26][C:27]#[N:28])=[CH:13][CH:12]=3)=[C:9]([CH3:29])[S:8][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: Cc1cccc(N)c1
Reactant: Cc1sc2ncnc(N)c2c1-c1ccc(NC(=NC#N)Oc2ccccc2)cc1
Solvent: CN(C)C=O
Product: Cc1cccc(NC(=NC#N)Nc2ccc(-c3c(C)sc4ncnc(N)c34)cc2)c1
Yield: 362.8 %

Procedure:
A solution of Example 132 (40 mg, 0.01 mmol) and 3-methylaniline (0.012 mL, 0.01 mmol) in DMF (1 mL) was heated in a Smith synthesizer microwave to 180° C. for 22 minutes and partitioned between water and ethyl acetate. The aqueous phase was extracted three times with ethyl acetate and the combined extracts were washed with water and brine, dried (Na2SO4), filtered and concentrated. The concentrate was purified by flash column chromatography on silica gel with 8% methanol/dichloromethane to provide the desired product (15 mg). MS(ESI(+)) m/e 414 (M+H)+; 1H NMR (300 MHz, DMSO-d6) δ 9.65 (s, 1H); 9.48 (s, 1H); 8.26 (s, 1H); 7.45 (d, J=8.4 Hz, 2H); 7.35 (d, J=8.4 Hz, 2H); 7.23 (t, J=7.8 Hz, 1H); 7.15-7.10 (m, 2H); 6.96 (d, J=7.8 Hz, 1H); 2.29 (s, 6H).
Reaction SMILES: [CH2:1]([N-]CC)[CH3:2].[Li+].[Li].C(NCC)C.[CH3:13][C:14]1[O:18][C:17]([CH2:19][CH2:20][CH2:21][C:22]#[N:23])=[CH:16][CH:15]=1.C(I)C>C1C=CC=CC=1.CN(C)P(=O)(N(C)C)N(C)C.O.CCOCC.O1CCCC1>[CH2:1]([CH:21]([CH2:20][CH2:19][C:17]1[O:18][C:14]([CH3:13])=[CH:15][CH:16]=1)[C:22]#[N:23])[CH3:2]
Reactant: Cc1ccc(CCCC#N)o1
Reactant: CC[N-]CC
Agent: [Li+]
Agent: [Li]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCC(C#N)CCc1ccc(C)o1
Temperature: -70 °C
Reaction time: 1 h
Yield: 58 %

Procedure:
A solution of lithium diethyl amide prepared from 0.7 g (0.1 mol) lithium and 7.3 g (0.1 mol) diethyl amine in 44 ml benzene/hexamethyl phosphoric acid triamide 1:1 (2 hours at 25° C.) was added dropwise under nitrogen to a mixture which had been cooled down to -70° C. of 14.9 g (0.1 mol) 4-(5-methyl-2-furyl)-butane nitrile, 15.6 g (0.1 mol) ethyl iodide, 20 ml dry tetrahydrofurane and 140 ml dry ether. The mixture obtained was stirred for one hour at -70° C., was slowly heated up to 10° C. and then poured into cold water. The organic layer was separated off, washed with water and dried on anhydrous magnesium sulphate. The solvent was evaporated off under reduced pressure and the residue was subjected to chromatography over 300 g silicagel with hexane/ethyl acetate 95:5. Initially 2.3 g dl-2,2-diethyl-4-(5-methyl-2-furyl)-butane nitrile was eluated, followed by 9.5 g (58% yield) dl-2-ethyl-4-(5-methyl-2-furyl)-butane nitrile.
Reaction SMILES: COC(=O)C(O)=CC(=O)N(CC1C=CC(F)=CC=1)C.C=O.[CH:22]([NH2:25])([CH3:24])[CH3:23].[F:26][C:27]1[CH:45]=[CH:44][C:30]([CH2:31][N:32]([CH3:43])[C:33]([C:35]2[CH2:36]N(C)[C:38](=[O:41])[C:39]=2[OH:40])=[O:34])=[CH:29][CH:28]=1>>[F:26][C:27]1[CH:45]=[CH:44][C:30]([CH2:31][N:32]([CH3:43])[C:33]([C:35]2[CH2:36][N:25]([CH:22]([CH3:24])[CH3:23])[C:38](=[O:41])[C:39]=2[OH:40])=[O:34])=[CH:29][CH:28]=1
Reactant: CC(C)N
Reactant: CN1CC(C(=O)N(C)Cc2ccc(F)cc2)=C(O)C1=O
Agent: C=O
Agent: COC(=O)C(O)=CC(=O)N(C)Cc1ccc(F)cc1
Product: CC(C)N1CC(C(=O)N(C)Cc2ccc(F)cc2)=C(O)C1=O

Procedure:
3-[(4-Fluoro-benzyl)-methyl-carbamoyl]-2-hydroxy-acrylic acid methyl ester (compound 1-D) was treated with paraformaldehyde and isopropylamine as described in the preparation of Compound 1. 1H NMR (500 MHz, CDCl3) δ: 1.23 (d, 6, J=7), 3.02 (s, 3), 4.10 (s, 2), 4.45 (heptet, 1, J=7), 4.62 (s, 2), 7.03 (m, 2), 7.24 (m, 2). 13C NMR (125 MHz, CDCl3) δ: 20.61, 34.72, 44.09, 44.34, 110.21, 115.57, 115.75, 129.43, 129.50, 132.28, 132.30, 149.92, 161.35, 163.31, 164.76, 165.80.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:10]([O:12][CH3:13])=[O:11])[CH:8]=2)[CH:3]=[CH:2]1.[N:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][C:15]=1[CH2:24][O:25][C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=1)[CH2:29]Cl.COC(C1C=C2C(C(CC3C=CC(OCC4C=CC5C(=CC=CC=5)N=4)=CC=3)=CN2C)=CC=1)=O>>[CH3:13][O:12][C:10]([C:7]1[CH:8]=[C:9]2[C:4]([C:3]([CH2:29][C:28]3[CH:31]=[CH:32][CH:33]=[C:26]([O:25][CH2:24][C:15]4[CH:16]=[CH:17][C:18]5[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=5)[N:14]=4)[CH:27]=3)=[CH:2][NH:1]2)=[CH:5][CH:6]=1)=[O:11]
Reactant: COC(=O)c1ccc2cc[nH]c2c1
Reactant: ClCc1cccc(OCc2ccc3ccccc3n2)c1
Agent: COC(=O)c1ccc2c(Cc3ccc(OCc4ccc5ccccc5n4)cc3)cn(C)c2c1
Product: COC(=O)c1ccc2c(Cc3cccc(OCc4ccc5ccccc5n4)c3)c[nH]c2c1

Procedure:
This compound was prepared from methyl indole-6-carboxylate and 3-(quinolin-2-ylmethoxy)benzyl chloride (Example 5a) by the method described in Example 10, part ii.
Reaction SMILES: Cl.[CH:2]12[CH:7]([CH2:8][OH:9])[CH:6]1[CH2:5][NH:4][CH2:3]2.CCN(CC)CC.[O:17](C(OC(C)(C)C)=O)[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=O>C(Cl)Cl>[C:21]([O:20][C:18]([N:4]1[CH2:5][CH:6]2[CH:2]([CH:7]2[CH2:8][OH:9])[CH2:3]1)=[O:17])([CH3:24])([CH3:23])[CH3:22]
Reactant: OCC1C2CNCC12
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC2C(CO)C2C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 92.9 %

Procedure:
To a solution of (3-Aza-bicyclo[3.1.0]hex-6-yl)-methanol-HCl (11.8 gm, 78.7 mmol) in 350 mL of anhydrous CH2Cl2 at room temperature was added Et3N (32.9 mL, 236 mmol), followed by (BOC)2O (18.9 gm, 86.6 mmol) in portions. The reaction was stirred at room temperature for 18 hours. The mixture was washed with saturated NaHCO3, water, brine and dried over anhydrous MgSO4. The mixture was filtered and concentrated under reduced pressure to yield the crude material, which was purified via flash chromatography with 10% MeOH/CH2Cl2. The product containing fractions were collected and concentrated to yield 6-Hydroxymethyl-3-aza-bicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester (15.6 gm). 400 MHz 1H NMR (CDCl3) δ 3.4-3.6 (m, 4H), 3.2-3.7 (m, 2H), 1.72 (brs, 1H), 1.4-1.4 (m, 10H), 0.9-0.9 (m, 1H); MS (M+1) 213.2.
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([C:9]([O:11][CH3:12])=[O:10])[CH2:5][CH2:4]1.C(N(CC)CC)C.[Cl:20][CH2:21][CH2:22][CH2:23][S:24](Cl)(=[O:26])=[O:25].Cl>C(Cl)(Cl)Cl>[Cl:20][CH2:21][CH2:22][CH2:23][S:24]([NH:2][C@H:3]1[CH2:4][CH2:5][C@H:6]([C:9]([O:11][CH3:12])=[O:10])[CH2:7][CH2:8]1)(=[O:26])=[O:25]
Reactant: O=S(=O)(Cl)CCCCl
Reactant: COC(=O)[C@H]1CC[C@H](N)CC1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: COC(=O)[C@H]1CC[C@H](NS(=O)(=O)CCCCl)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Methyl trans-4-aminocyclohexanecarboxylate hydrochloride (4.08 g) obtained in Reference Example 2(1) is suspended in chloroform (50 ml), and thereto is added triethylamine (8.8 ml) under ice-cooling. Subsequently, a solution of 3-chloropropanesulfonyl chloride (3.35 ml) in chloroform (20 ml) is added dropwise over 20 minutes under the same temperature. After stirring for 2 hours at room temperature, 5% hydrochloric acid is added to the reaction solution and the mixture is extracted with chloroform. The organic layer is washed with saturated brine, dried over sodium sulfate and evaporated to remove the solvent under reduced pressure. The resulting residue is suspended in diisopropylamine, and filtered to collect precipitates to give methyl trans-4-{[(3-chloropropyl)sulfonyl]amino}cyclohexanecarboxylate (6.14 g).
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].Cl[CH2:8][C:9]([O:11][C:12]([CH:15]1[CH2:20][CH2:19][CH2:18][C:17]([CH3:22])([CH3:21])[CH2:16]1)([CH3:14])[CH3:13])=[O:10].[C:23]([OH:27])(=[O:26])[CH2:24][CH3:25].CCOCC>CC(C)=O>[C:23]([O:27][CH2:8][C:9]([O:11][C:12]([CH:15]1[CH2:20][CH2:19][CH2:18][C:17]([CH3:22])([CH3:21])[CH2:16]1)([CH3:14])[CH3:13])=[O:10])(=[O:26])[CH2:24][CH3:25]
Reactant: CCC(=O)O
Reactant: CC1(C)CCCC(C(C)(C)OC(=O)CCl)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CCOCC
Product: CCC(=O)OCC(=O)OC(C)(C)C1CCCC(C)(C)C1
Yield: 73.8 %

Procedure:
K2CO3 (6.2 g, 45 mmol) and 1-(3,3-dimethylcyclohexyl)-1-methylethyl chloroacetate (2,5 g, 10 mmol) are added successively to a solution of propionic acid (1.8 g, 30 mmol) in acetone (20 ml). After the suspension has been heated under reflux for 36 hours, it is allowed to cool and ether (80 ml) and 10% K2CO3 solution (50 ml) are added. After phase separation has taken place, the aqueous phase is freed from residual acetone and the aqueous phase is also extracted twice with 50 ml diethyl ether. The combined organic phases are also washed once with water and once with saturated NaCl solution, then dried, filtered off and freed from solvent in a rotary evaporator. After purification by flash chromatography (cyclohexane/EtOAc=10:1, Rf=0.23) and subsequent bulb tube distillation, (BTD: 215° C., 0.9 mbar) 2.1 g (78%) 2-[1-(3,3-dimethylcyclohexyl)-1-methylethoxy]-2-oxoethyl propionate is obtained as a colorless liquid.
Reaction SMILES: [CH3:1][N:2]1[CH:6]2[CH2:7][C:8]3[C:16]4[C:15]([CH:5]2[CH:4]([C:17]([OH:19])=[O:18])[CH2:3]1)=[CH:14][CH:13]=[CH:12][C:11]=4[NH:10][CH:9]=3.S(=O)(=O)(O)O.[CH3:25]O>>[C:17]([CH:4]1[CH:5]2[CH:6]([CH2:7][C:8]3[C:16]4[C:15]2=[CH:14][CH:13]=[CH:12][C:11]=4[NH:10][CH:9]=3)[N:2]([CH3:1])[CH2:3]1)([O:19][CH3:25])=[O:18]
Reactant: CO
Reactant: CN1CC(C(=O)O)C2c3cccc4[nH]cc(c34)CC21
Agent: O=S(=O)(O)O
Product: COC(=O)C1CN(C)C2Cc3c[nH]c4cccc(c34)C12
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a solution of the free indole 9-carboxylic acid (Example 13) (0.203 g) in methanol (5 cm3) was added with stirring concentrated sulphuric acid (0.15 cm3) and the reaction heated to reflux. After 2 hours further concentrated sulphuric acid (0.1 cm3) was added, reaction was indicated to be complete after 15 hours. The resultant solution was allowed to cool to room temperature to give after evaporation under vacuum and trituration with chloroform a dark orange solid (0.329 g).