Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:19])=[C:4]([CH:16]=[CH:17][CH:18]=1)[CH2:5][NH:6][C:7](=[NH:15])[CH:8](OCC)OCC.S(=O)(=O)(O)O>>[Cl:1][C:2]1[C:3]([F:19])=[C:4]2[C:16]([CH:8]=[C:7]([NH2:15])[N:6]=[CH:5]2)=[CH:17][CH:18]=1
Reactant: CCOC(OCC)C(=N)NCc1cccc(Cl)c1F
Agent: O=S(=O)(O)O
Product: Nc1cc2ccc(Cl)c(F)c2cn1
Temperature: 40 °C
Yield: 87.8 %

Procedure:
To N-(3-chloro-2-fluorobenzyl)-2,2-diethoxyacetimidamide (0.97 g, 3.36 mmol) was added sulfuric acid (4 mL, 75 mmol). The reaction was heated to 40° C. for 28 hours. The reaction was cooled to room temperature and quenched with aq. sodium hydroxide (˜15 M) until the reaction mixture was ˜pH 7. The crude product was extracted with ethyl acetate (2×50 mL) and the organics were dried with MgSO4, filtered, and concentrated in vacuo. The crude product was purified by chromatography (Biotage: 100% ethyl acetate to 90/10% ethyl acetate/MeOH) to yield 7-chloro-8-fluoroisoquinolin-3-amine (0.58 g, 2.95 mmol, 88% yield) as a powder. 1H NMR (500 MHz, DMSO-d6) d ppm 8.97 (s, 1H), 7.47-7.57 (m, 1H), 7.38-7.45 (m, 1H), 6.67 (s, 1H), 6.33 (s, 2H). MS (LC/MS) R.T.=1.18; [M+H]+=196.95.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][CH2:6][CH2:5]2.[F:11][C:12]([F:22])([F:21])[C:13]1[CH:14]=[CH:15][C:16]([CH:19]=[CH2:20])=[N:17][CH:18]=1>>[CH2:7]1[C:8]2[C:4](=[CH:3][C:2]([NH:1][CH2:20][CH2:19][C:16]3[CH:15]=[CH:14][C:13]([C:12]([F:22])([F:11])[F:21])=[CH:18][N:17]=3)=[CH:10][CH:9]=2)[CH2:5][CH2:6]1
Reactant: Nc1ccc2c(c1)CCC2
Reactant: C=Cc1ccc(C(F)(F)F)cn1
Product: FC(F)(F)c1ccc(CCNc2ccc3c(c2)CCC3)nc1

Procedure:
In analogy to the procedure described for the synthesis example 25 (step 1), the title compound Indan-5-yl-[2-(5-trifluoromethyl-pyridin-2-yl)-ethyl]-amine (MS m/e: 307.2 [M+H]+) was prepared from 5-amino-indan instead of 3,4-dimethylaniline and 5-trifluoromethyl-2-vinyl-pyridine.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:12]3[N:13]=[C:14]4[C:20]([C:21]([OH:23])=O)=[CH:19][NH:18][C:15]4=[N:16][CH:17]=3)=[N:7][N:8]2[CH3:11])=[CH:4][CH:3]=1.[ClH:24].[NH2:25][C:26]1([CH3:38])[CH2:29][CH:28]([NH:30][C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34])[CH2:27]1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CN(C1C=CN=CC=1)C.CN(C=O)C>[ClH:24].[F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:12]3[N:13]=[C:14]4[C:20]([C:21]([NH:25][C:26]5([CH3:38])[CH2:29][CH:28]([NH:30][C:31](=[O:37])[O:32][C:33]([CH3:35])([CH3:34])[CH3:36])[CH2:27]5)=[O:23])=[CH:19][NH:18][C:15]4=[N:16][CH:17]=3)=[N:7][N:8]2[CH3:11])=[CH:4][CH:3]=1
Reactant: Cn1nc(-c2cnc3[nH]cc(C(=O)O)c3n2)c2ccc(F)cc21
Reactant: CC1(N)CC(NC(=O)OC(C)(C)C)C1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cn1nc(-c2cnc3[nH]cc(C(=O)NC4(C)CC(NC(=O)OC(C)(C)C)C4)c3n2)c2ccc(F)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 64.9 %

Procedure:
A mixture of 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (0.1 g, 0.32 mmol), tert-butyl 3-amino-3-methylcyclobutylcarbamate hydrochloride (0.1 g, 0.42 mmol), EDCI (0.092 g, 0.48 mmol), DMAP (0.059 g, 0.48 mmol), HOBT (0.065 g, 0.48 mmol) and DIPEA (0.248 g, 1.92 mmol) in 25 mL of DMF was stirred at room temperature overnight. The solvent was removed under reduced pressure and the residue was passed through a pad of silica gel (200-300 mesh, eluting with a mixture of petroleum ether and ethyl acetate (4:1, v/v) to give tert-butyl 3-(2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamido)-3-methylcyclobutylcarbamate hydrochloride (0.11 g, 69%) as crude white solid which was used for the next step without further purification. MS: (M+H)+=494.2.
Reaction SMILES: [C:1]([O:5][O:6][C:7]([C:9]1[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=1[C:11](Cl)=[O:12])=[O:8])([CH3:4])([CH3:3])[CH3:2].N1C=CC=CC=1.[CH2:24]([OH:28])[CH:25]([OH:27])[CH3:26]>C(OC)(C)(C)C>[C:7]([O:6][O:5][C:1]([CH3:4])([CH3:3])[CH3:2])(=[O:8])[C:9]1[C:10](=[CH:14][CH:15]=[CH:16][CH:17]=1)[C:11]([O:28][CH2:24][CH:25]([OH:27])[CH3:26])=[O:12]
Reactant: CC(C)(C)OOC(=O)c1ccccc1C(=O)Cl
Reactant: CC(O)CO
Solvent: COC(C)(C)C
Solvent: c1ccncc1
Product: CC(O)COC(=O)c1ccccc1C(=O)OOC(C)(C)C
Temperature: 25 °C
Reaction time: 4 h
Yield: 91.4 %

Procedure:
A 300 mL 3-neck round-bottom flask, equipped with a magnetic stirrer, a thermometer, a cold water condenser and an addition funnel, was charged with 100 mL of methyl t-butyl ether, 16.7 g (0.06 mole) of 91.3% of 2-(t-butylperoxycarbonyl)benzoyl chloride and 5.5 g (0.07 mole) of pyridine. To this vigorously stirred solution at 20° C. was added 22.8 g (0.30 mole) of 1,2-propanediol over a period of 20 minutes. During the addition there was a slight exotherm and a white precipitate formed. The reaction mass was warmed to 25° C. and stirred at 25° C. for 240 minutes. The precipitate was separated by filtration and the white solid was washed with about 25 mL of methyl t-butyl ether. The methyl t-butyl ether washings were combined with the filtrate and the filtrate was washed twice with 50 mL portions of 5% aqueous HCl solution, then twice with 50 mL portions of 3% aqueous NaHCO3 solution. The methyl t-butyl ether solution was then dried over 10% by weight of anhydrous MgSO4 and, after separation of the spent desiccant by filtration, the solvent was removed in vacuo leaving 17.4 g (98.3% of theory, uncorrected) of a straw-color liquid. An infrared spectrum of the product showed a strong OH band at ca. 3500 cm-1 and two carbonyl bands at ca. 1720 cm-1 and 1770 cm-1. The product had a peroxyester Act[O] content of 5.02%. Based on a theoretical Act[O] of 5.40% for the desired title product, the assay was 93.0% and the corrected yield was 91.4%.
Reaction SMILES: [N:1]1[C:9]([NH2:10])=[C:8]2[C:4]([N:5]=[CH:6][NH:7]2)=[N:3][CH:2]=1.C1OCCOCCOCCOCCOCCOC1.CC1C=CC(S(O[C@@H:40]2[CH2:44][O:43][C@@H:42]([CH2:45][OH:46])[CH2:41]2)(=O)=O)=CC=1>CN(C=O)C>[NH2:10][C:9]1[N:1]=[CH:2][N:3]=[C:4]2[C:8]=1[N:7]=[CH:6][N:5]2[C@H:40]1[CH2:44][O:43][C@@H:42]([CH2:45][OH:46])[CH2:41]1
Reactant: Nc1ncnc2nc[nH]c12
Reactant: Cc1ccc(S(=O)(=O)O[C@@H]2CO[C@@H](CO)C2)cc1
Agent: C1COCCOCCOCCOCCOCCO1
Solvent: CN(C)C=O
Product: Nc1ncnc2c1ncn2[C@H]1CO[C@@H](CO)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 29 %

Procedure:
To a flame-dried argon blanketed round bottom flask equipped with a magnetic stir bar and condenser was added adenine (50 mg, 0.37 mmole) K2CO3 (100 mg, 0.73 mmole), 18-crown-6 (97 mg, 0.37 mmole) and DMF (10 mL). This mixture was allowed to stir at room temperature for 30 minutes under a stream of argon. A solution of (2R-trans)-tetrahydro-4-[[(4-methylphenyl)sulfonyl]oxy]-2-furanmethanol, Compound IV(c), (100 mg, 0.37 mmole) in 2 mL DMF was then added dropwise to the stirring mixture. The resultant mixture was warmed to 80° C., and stirred at that temperature overnight. After removal of the solvent in vacuo, the solid residue was purified by flash chromatorgraphy using a 10% MeOH/90% CH2Cl2 solution as eluant. This isolated material was further purified by reverse-phase HPLC using a gradient elution system of CH3CN/H2O to yield 25 mg (29%) of Compound I as a white solid. An analytical sample was crystallized from methanol: mp 183°-185°, [α]D +47.91 (c 0.67, MeOH).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[CH:7]2)([O-:3])=[O:2].[CH3:13][N:14]1[CH2:19][CH2:18][C:17](=O)[CH2:16][CH2:15]1.C[O-].[Na+]>CO>[CH3:13][N:14]1[CH2:15][CH:16]=[C:17]([C:7]2[C:6]3[C:10](=[CH:11][CH:12]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=3)[NH:9][CH:8]=2)[CH2:18][CH2:19]1
Reactant: CN1CCC(=O)CC1
Reactant: O=[N+]([O-])c1ccc2[nH]ccc2c1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CN1CC=C(c2c[nH]c3ccc([N+](=O)[O-])cc23)CC1

Procedure:
5-Nitroindole (2.6 g) was dissolved in 100 mL anhydrous MeOH, followed by 5 g N-methyl-4-piperidone and NaOMe (5 g) powder. The mixture was heated to reflux under N2 overnight. The mixture was concentrated in vacuo, and was extracted between saturated NaHCO3 solution and EtOAc. The resulting organic layer was dried over MgSO4, filtered and concentrated in vacuo to afford a yellow solid. This solid was washed with 5 mL EtOAc and 2 mL MeOH to afford a bright yellow solid. MS: 258 (M+1). Calc'd. for C14H15N3O2−257.29.
Reaction SMILES: ClC1C2C=C(C(NC3C=CC(N4CCN([C:26](=[O:34])[CH2:27][C:28]([CH3:33])([CH3:32])[C:29]([OH:31])=[O:30])CC4)=NC=3)=O)SC=2C=CC=1.[NH:35]1[CH2:40][CH2:39][N:38]([C:41]2[CH:46]=[CH:45][C:44]([NH:47][C:48]([C:50]3[N:51]([CH2:62][CH3:63])[C:52]4[C:57]([CH:58]=3)=[C:56]([O:59][CH2:60][CH3:61])[CH:55]=[CH:54][CH:53]=4)=[O:49])=[CH:43][CH:42]=2)[CH2:37][CH2:36]1>>[CH2:60]([O:59][C:56]1[CH:55]=[CH:54][CH:53]=[C:52]2[C:57]=1[CH:58]=[C:50]([C:48]([NH:47][C:44]1[CH:45]=[CH:46][C:41]([N:38]3[CH2:39][CH2:40][N:35]([C:26](=[O:34])[CH2:27][C:28]([CH3:33])([CH3:32])[C:29]([OH:31])=[O:30])[CH2:36][CH2:37]3)=[CH:42][CH:43]=1)=[O:49])[N:51]2[CH2:62][CH3:63])[CH3:61]
Reactant: CCOc1cccc2c1cc(C(=O)Nc1ccc(N3CCNCC3)cc1)n2CC
Reactant: CC(C)(CC(=O)N1CCN(c2ccc(NC(=O)c3cc4c(Cl)cccc4s3)cn2)CC1)C(=O)O
Product: CCOc1cccc2c1cc(C(=O)Nc1ccc(N3CCN(C(=O)CC(C)(C)C(=O)O)CC3)cc1)n2CC

Procedure:
With a method similar to that used for the preparation of 4-(4-{5-[(4-chloro-benzo[b]thiophene-2-carbonyl)-amino]-pyridin-2-yl}-piperazin-1-yl)-2,2-dimethyl-4-oxo-butyric acid, 4-(4-{4-[(4-ethoxy-1-ethyl-1,1-indole-2-carbonyl)-amino]-phenyl}-piperazin-1-yl)-2,2-dimethyl-4-oxo-butyric acid was prepared from 4-ethoxy-1-ethyl-1H-indole-2-carboxylic acid (4-piperazin-4-yl-phenyl)-amide. LCMS for C29H36N4O5 calcd. (m/e) 520, observed 521 (M+H).
Reaction SMILES: O[CH:2]=[C:3]1[C:15]2[N:14]3[CH:16]=[CH:17][N:18]=[C:13]3[C:12](=[O:19])[NH:11][C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]1=2.CN(C)C=O>[Pd].CO>[CH3:2][CH:3]1[C:15]2[N:14]3[CH:16]=[CH:17][N:18]=[C:13]3[C:12](=[O:19])[NH:11][C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]1=2
Reactant: O=c1[nH]c2c3ccccc3c(=CO)c2n2ccnc12
Agent: [Pd]
Solvent: CO
Solvent: CN(C)C=O
Product: CC1c2ccccc2-c2[nH]c(=O)c3nccn3c21
Yield: 37.1 %

Procedure:
10-Methyl-5H,10H-imidazo[1,2-a]indeno-[1,2-e]pyrazin-4-one may be obtained in the following way: a mixture of 1 g of 10-hydroxymethylene-5H,10H-imidazo[1,2-a]indeno[1,2-e]pyrazin-4-one, 80 ml of dimethylformamide and 20 ml of methanol is hydrogenated at a temperature in the region of 20° C. and at normal pressure for 4 hours in the presence of 10% palladium-on-charcoal. After filtration of the catalyst under an inert atmosphere, the solvents are evaporated off and the beige-coloured solid obtained (1.25 g) is purified by chromatography on a column of silica (100 g) with a mixture of dichloromethane and methanol (95/5 by volume). After drying at 90° C., 0.35 g of 10-methyl-5H,10H-imidazo[1,2-a]indeno[1,2-e]pyrazin-4-one is obtained in the form of a cream-coloured solid melting above 260° C. (Analysis, % calculated C: 70.87, H: 4.67, N: 17.71, O: 6.74, % found C: 70.5, H: 4.4, N: 17.4).
Reaction SMILES: BrC1C=C(F)C(F)=CC=1O.C(O[CH:14](OCC)[CH2:15][O:16][C:17]1[CH:22]=[C:21]([F:23])[C:20]([F:24])=[CH:19][C:18]=1[Br:25])C>>[F:23][C:21]1[C:22]2[CH:14]=[CH:15][O:16][C:17]=2[C:18]([Br:25])=[CH:19][C:20]=1[F:24]
Reactant: CCOC(COc1cc(F)c(F)cc1Br)OCC
Agent: Oc1cc(F)c(F)cc1Br
Product: Fc1cc(Br)c2occc2c1F

Procedure:
Beginning with 5 gm (23.9 mMol) 2-bromo-4,5-difluorophenol, 7.05 gm (91%) 2-(2-bromo-4,5-difluorophenoxy)acetaldehyde diethyl acetal were prepared essentially as described in Preparation IV.
Reaction SMILES: [NH3:1].Cl[C:3]([CH2:5][CH2:6][CH2:7][C:8]([O:10][CH3:11])=[O:9])=[O:4]>C1COCC1>[NH2:1][C:3]([CH2:5][CH2:6][CH2:7][C:8]([O:10][CH3:11])=[O:9])=[O:4]
Reactant: N
Reactant: COC(=O)CCCC(=O)Cl
Solvent: C1CCOC1
Product: COC(=O)CCCC(N)=O

Procedure:
6.1 Ammonia is passed into 350 ml of cold THF for 30 minutes. 30 g of methyl 4-chlorocarbonylbutyrate are then added dropwise, with ammonia continuing to be passed in at the same time. The crystals which deposit are separated off, and the residue is boiled a number of times with ethyl acetate. The combined filtrates are distilled off, and the residue is recrystallised from ethyl acetate, giving 23.4 g of methyl 4-aminocarbonylbutyrate (“FA”), m.p. 80°.
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@H:13](OC(=O)C)[C@@H:12]([CH2:27][O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[O:11][C@:10]1(C)[O:36][CH2:37][C@H:38]1[O:45][C@H:42]([O:43][CH3:44])[C@H:41]([O:46][CH2:47][C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)[C@@H:40]([O:54][CH2:55][C:56]2[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=2)[C@@H:39]1[O:62][CH2:63][C:64]1[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:71][OH:72].C[O-].[Na+]>C1(C)C=CC=CC=1>[CH2:1]([O:8][C@@H:9]1[C@@H:14]([O:15][CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C@H:13]([CH2:71][OH:72])[C@@H:12]([CH2:27][O:28][CH2:29][C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[O:11][C@@H:10]1[O:36][CH2:37][C@H:38]1[O:45][C@H:42]([O:43][CH3:44])[C@H:41]([O:46][CH2:47][C:48]2[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=2)[C@@H:40]([O:54][CH2:55][C:56]2[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=2)[C@@H:39]1[O:62][CH2:63][C:64]1[CH:65]=[CH:66][CH:67]=[CH:68][CH:69]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CO[C@H]1O[C@H](CO[C@@]2(C)O[C@H](COCc3ccccc3)[C@@H](OC(C)=O)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Reactant: CO
Agent: C[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CO[C@H]1O[C@H](CO[C@H]2O[C@H](COCc3ccccc3)[C@@H](CO)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
Methyl 6-O-(2,3,6-tri-O-benzyl-4-deoxy-4-acetyloxy-methyl-α-D-glucopyranosyl) -2,3,4-tri-O-benzyl-α-D-glucopyranoside (2.469 g, 2.593 mmol) was dissolved in hot toluene (20 mL) and methanol (80 mL) was added, followed by a few drops of 1M. methanolic sodium methoxide. The mixture was stirred at room temperature during 2 h. The reaction mixture was made neutral with Amberlite IR 120 (H+) resin, filtered and concentrated under reduced pressure to afford methyl 6-O-(2,3,6-tri-O-benzyl-4-deoxy-4-hydroxymethyl -α-D-glucopyranosyl)-2,3,4-tri-O-benzyl-α-D-glucopyranoside (2.36 g, 100%) as an amorphous solid.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8]([C:10]2[C:14]3[N:15]=[CH:16][N:17]=[C:18]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[O:25][CH2:26][CH:27]4[CH2:29][CH2:28]4)[C:13]=3[NH:12][CH:11]=2)=[O:9])[CH2:3][CH2:2]1.Cl[C:31]([O:33][CH2:34][CH3:35])=[O:32]>>[CH2:34]([O:33][C:31]([N:1]1[CH2:2][CH2:3][CH:4]([NH:7][C:8]([C:10]2[C:14]3[N:15]=[CH:16][N:17]=[C:18]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[O:25][CH2:26][CH:27]4[CH2:28][CH2:29]4)[C:13]=3[NH:12][CH:11]=2)=[O:9])[CH2:5][CH2:6]1)=[O:32])[CH3:35]
Reactant: O=C(NC1CCNCC1)c1c[nH]c2c(-c3ccccc3OCC3CC3)ncnc12
Reactant: CCOC(=O)Cl
Product: CCOC(=O)N1CCC(NC(=O)c2c[nH]c3c(-c4ccccc4OCC4CC4)ncnc23)CC1

Procedure:
Starting from 4-(2-cyclopropylmethoxy-phenyl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid piperidin-4-ylamide (example A162) and ethyl chloroformate the title compound is obtained as colorless solid.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:8]=[C:9]([CH:26]=[O:27])[C:10]3[N:14]=[C:13]([O:15]CC)[N:12](C(OC(C)(C)C)=O)[C:11]=3[CH:25]=2)=[C:5]([CH3:28])[O:4][N:3]=1.[F:29][C:30]([F:36])([F:35])[C:31]([F:34])([F:33])I.CN(C=O)C.CN(C(N(C)C)=C(N(C)C)N(C)C)C>C(OCC)(=O)C>[CH3:1][C:2]1[C:6]([C:7]2[CH:8]=[C:9]([CH:26]([OH:27])[C:31]([F:34])([F:33])[C:30]([F:36])([F:35])[F:29])[C:10]3[NH:14][C:13](=[O:15])[NH:12][C:11]=3[CH:25]=2)=[C:5]([CH3:28])[O:4][N:3]=1
Reactant: CCOc1nc2c(C=O)cc(-c3c(C)noc3C)cc2n1C(=O)OC(C)(C)C
Reactant: FC(F)(F)C(F)(F)I
Agent: CN(C)C(=C(N(C)C)N(C)C)N(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1noc(C)c1-c1cc(C(O)C(F)(F)C(F)(F)F)c2[nH]c(=O)[nH]c2c1
Temperature: 70 °C
Reaction time: 0.5 h

Procedure:
A solution of tert-butyl 6-(3,5-dimethylisoxazol-4-yl)-2-ethoxy-4-formyl-1H-benzo[d]imidazole-1-carboxylate (100 mg, 0.26 mmol), pentafluoroiodoethane (350 mg, 1.42 mmol) and DMF was cooled to −15° C. under nitrogen. Tetra(dimethlamino)ethylene was added (0.33 mL, 1.42 mmol) and the reaction mixture was irradiated with a sun lamp. A thick precipitate formed, and after 30 minutes, the reaction mixture was diluted with ethyl acetate filtered. The filtrate was washed with water and the organic layer was concentrated and dissolved in ethanol (3 mL) and 4M HCl in dioxane (1 mL) and heated to 70° C. for 1 h. The reaction mixture was concentrated and purified by reverse-phase HPLC to give the desired product as a white powder.
Reaction SMILES: [C:1]([C:9]1[CH:14]=[C:13]([C:15]#[N:16])[CH:12]=[CH:11][C:10]=1[OH:17])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:18].[CH2:19]([O:21]CC)C>CO>[ClH:18].[C:1]([C:9]1[CH:14]=[C:13]([CH:15]=[N:16][O:21][CH3:19])[CH:12]=[CH:11][C:10]=1[OH:17])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOCC
Reactant: N#Cc1ccc(O)c(C(=O)c2ccccc2)c1
Agent: Cl
Solvent: CO
Product: CON=Cc1ccc(O)c(C(=O)c2ccccc2)c1

Procedure:
A suspension of 214 g of 2-benzoyl-4-cyanophenol in 1.7 liters of anhydrous methanol was saturated with anhydrous hydrogen chloride, while being cooled in ice and stirred. After having been stirred overnight at room temperature, the mixture was mixed with a large volume of ethyl ether. The precipitated crystals were collected by filtration and dried to yield 156 g of 2-benzoyl-4-methoxyiminomethylphenol hydrochloride.
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][CH2:5][N:4]([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])[CH2:3]1.[C:17](OC(=O)C)(=[O:19])[CH3:18].N1C=CC=CC=1.CO>CN(C)C1C=CN=CC=1.ClCCl>[C:17]([O:1][C@H:2]1[CH2:6][CH2:5][N:4]([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])[CH2:3]1)(=[O:19])[CH3:18]
Reactant: CC(=O)OC(C)=O
Reactant: O=C(OCc1ccccc1)N1CC[C@H](O)C1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: CO
Solvent: ClCCl
Product: CC(=O)O[C@H]1CCN(C(=O)OCc2ccccc2)C1
Reaction time: 72 h

Procedure:
A mixture of 2.87 g of (S)-3-hydroxy-1-pyrrolidinecarboxylic acid, phenylmethyl ester, 2.0 ml of acetic anhydride, 2.0 ml of pyridine and 20 mg of 4-dimethylaminopyridine in 25 ml of dichloromethane was stirred for 72 hours. Methanol (2 ml) and dichloromethane (50 ml) were added. The dichloromethane solution was washed with 40 ml each of 1N hydrochloric acid and 5% sodium bicarbonate solution, dried, filtered and concentrated in vacuo. The residue was purified by chromatography (silica gel), giving 3.1 g of (S)-3-(acetyloxy)-1-pyrrolidinecarboxylic acid, phenylmethyl ester as a colorless oil, [α]D26 =+17° (dichloromethane).
Reaction SMILES: [F:1][CH:2]([F:20])[CH2:3][C@@:4]1([C:16]([O:18]C)=[O:17])[CH2:8][C@H:7]([N:9]2[C:13]([CH3:14])=[CH:12][CH:11]=[C:10]2[CH3:15])[CH:6]=[CH:5]1.[OH-].[Na+]>CO>[F:20][CH:2]([F:1])[CH2:3][C@@:4]1([C:16]([OH:18])=[O:17])[CH2:8][C@H:7]([N:9]2[C:10]([CH3:15])=[CH:11][CH:12]=[C:13]2[CH3:14])[CH:6]=[CH:5]1
Reactant: COC(=O)[C@@]1(CC(F)F)C=C[C@@H](n2c(C)ccc2C)C1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1ccc(C)n1[C@@H]1C=C[C@](CC(F)F)(C(=O)O)C1
Temperature: 25 °C
Reaction time: 22 h
Yield: 92 %

Procedure:
A solution of methyl (1S,4S)-1-(2,2-difluoroethyl)-4-(2,5-dimethyl-1H-pyrrol-1-yl)cyclopent-2-ene-1-carboxylate (7.54 g, 26.6 mmol) in methanol (60 ml) was treated with 2.5N NaOH (15 ml, 37.5 mmol) and stirred at room temperature for 22 hours. The methanol was removed under reduced pressure and the residue partitioned between diethyl ether and water. The layers were separated and the aqueous was acidified with 4N HCl, extracted with ethyl acetate, washed with brine, dried over MgSO4, and concentrated under reduced pressure to give (1S,4S)-1-(2,2-difluoroethyl)-4-(2,5-dimethyl-1H-pyrrol-1-yl)cyclopent-2-ene-1-carboxylic acid as a brown oil (6.59 g, 92%). 1H NMR (400 MHz, CDCl3) δ ppm 6.12-6.09 (1H), 6.07-6.05 (0.25H), 5.99-5.96 (1H), 5.93-5.91 (0.5H), 5.79-5.76 (0.25H), 5.74 (2H), 5.38-5.32 (1H), 2.54-2.46 (2H), 2.43-2.25 (2H), 2.20 (6H).
Reaction SMILES: C[O:2][C:3](=[O:19])[C:4]1[CH:9]=[CH:8][C:7]([CH:10]([CH2:17][OH:18])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])=[CH:6][CH:5]=1.[OH-].[Na+].Cl>O1CCCC1.C(OCC)C.O>[OH:18][CH2:17][CH:10]([C:7]1[CH:6]=[CH:5][C:4]([C:3]([OH:19])=[O:2])=[CH:9][CH:8]=1)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCC(CO)c1ccc(C(=O)OC)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOCC
Product: CCCCCCC(CO)c1ccc(C(=O)O)cc1
Reaction time: 8 h

Procedure:
4-(1-Hydroxymethyl-heptyl)-benzoic acid methyl ester (3.46 g, 12.1 mmol) is dissolved in tetrahydrofuran (40 mL) and 5N sodium hydroxide (10 mL) is added. The reaction may be monitored by HPLC and is complete within 8 h. The reaction is neutralized with 5N HCl (10 mL), and diluted with diethyl ether and water. The two phases are separated, and the organic layer is washed, dried, and concentrated to provide the title compound which is used without further purification. MS (ES): 249.3 [M+H]−.
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[CH2:3][CH2:4][CH:5]([NH:23][C:24]1[CH:33]=[CH:32][C:27]([C:28]([O:30]C)=[O:29])=[CH:26][CH:25]=1)[C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][N:13]=2)=[CH:8][C:7]=1[CH3:22].[OH-].[Na+].C1COCC1.Cl>CO>[F:35][C:2]([F:1])([F:34])[CH2:3][CH2:4][CH:5]([NH:23][C:24]1[CH:25]=[CH:26][C:27]([C:28]([OH:30])=[O:29])=[CH:32][CH:33]=1)[C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:13]=[CH:14][C:15]([C:18]([F:19])([F:20])[F:21])=[CH:16][N:17]=2)=[CH:8][C:7]=1[CH3:22]
Reactant: COC(=O)c1ccc(NC(CCC(F)(F)F)c2ccc(-c3ncc(C(F)(F)F)cn3)cc2C)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cc(-c2ncc(C(F)(F)F)cn2)ccc1C(CCC(F)(F)F)Nc1ccc(C(=O)O)cc1
Temperature: 70 °C
Reaction time: 8 h
Yield: 99.7 %

Procedure:
A reaction mixture of methyl 4-((4,4,4-trifluoro-1-(2-methyl-4-(5-(trifluoromethyl)pyrimidin-2-yl)phenyl)butyl)amino)benzoate (0.259 g), 1M aqueous sodium hydroxide solution (2.08 mL), THF (2 mL) and methanol (2 mL) was stirred at 70° C. overnight. The reaction mixture was neutralized with 1M hydrochloric acid at 0° C., and extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give the title compound (0.251 g). This compound was used in step C without further purification.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[N:5]([CH2:12][CH2:13][CH:14]([CH3:16])[CH3:15])[C:4](=[O:17])[C:3]=1[C:18]1[NH:23][C:22]2[CH:24]=[CH:25][C:26]([NH:28][S:29](=[O:43])(=[O:42])[N:30](C)[C:31](OCC3C=CC=CC=3)=O)=[CH:27][C:21]=2[S:20](=[O:45])(=[O:44])[N:19]=1>CO.[Pd]>[OH:1][C:2]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[N:5]([CH2:12][CH2:13][CH:14]([CH3:16])[CH3:15])[C:4](=[O:17])[C:3]=1[C:18]1[NH:23][C:22]2[CH:24]=[CH:25][C:26]([NH:28][S:29]([NH:30][CH3:31])(=[O:43])=[O:42])=[CH:27][C:21]=2[S:20](=[O:45])(=[O:44])[N:19]=1
Reactant: CC(C)CCn1c(=O)c(C2=NS(=O)(=O)c3cc(NS(=O)(=O)N(C)C(=O)OCc4ccccc4)ccc3N2)c(O)c2cccnc21
Agent: [Pd]
Solvent: CO
Product: CNS(=O)(=O)Nc1ccc2c(c1)S(=O)(=O)N=C(c1c(O)c3cccnc3n(CCC(C)C)c1=O)N2
Reaction time: 2 h
Yield: 71.8 %

Procedure:
A solution of the product of Example 441 (14 mg, 0.0214 mmol) in methanol (3 mL) was reacted with 10% palladium on carbon (10 mg) under a hydrogen atmosphere at 25° C. with stirring for 2 hours. The solution was filtered and concentrated under reduced pressure to provide the title compound (8 mg, 73%). 1H NMR (300 MHz, DMSO-d6) δ 0.94 (d, J=6.6 Hz, 6H), 1.57 (m, 2H), 1.69 (m, 1H), 2.49 (s, 3H), 4.45 (m, 2H), 7.50 (m, 2H), 7.62 (m, 2H), 8.57 (m, 1H), 8.84 (m, 1H), 10.18 (bs, 1H). MS (ESI−) m/z 519 (M−H)−.