Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4](=[O:15])[C:5]([C:13]#[N:14])=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[N:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl.Cl[CH2:24][C:25]1[CH:34]=[CH:33][C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[N:26]=1>CN(C=O)C>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4]([O:15][CH2:24][C:25]2[CH:34]=[CH:33][C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[N:26]=2)[N:3]=1
Reactant: ClCc1ccc2ccccc2n1
Reactant: N#Cc1c(-c2ccco2)nc(N)[nH]c1=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: N#Cc1c(OCc2ccc3ccccc3n2)nc(N)nc1-c1ccco1
Reaction time: 16 h
Yield: 16.2 %

Procedure:
To a stirred solution of 400 mg (1.98 mmol) 2-amino-4-furan-2-yl-6-oxo-1,6-dihydro-pyrimidine-5-carbonitrile in 15 ml DMF were added 1.93 g (5.94 mmol) cesium carbonate and 847 mg (3.96 mmol) 2-(chloromethyl)quinoline hydrochloride and stirring continued for 16 h ours at 100° C. The reaction mixture was then concentrated in vacuo and the residue partitioned between ethyl acetate and water. The organic phase was dried over sodium sulfate and concentrated in vacuo. The residue was triturated in ether/methanol to afford 110 mg (16%) 2-amino-4-furan-2-yl-6-(quinolin-2-ylmethoxy)-pyrimidine-5-carbonitrile as an orange crystalline solid. ES-MS m/e (%): 344 (M+H+, 100).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([O:14][CH2:15][C:16]#[CH:17])[C:9]=1[O:10][CH2:11][C:12]#[CH:13])[CH:5]=[O:6].[BH4-].[Na+].Cl>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([O:14][CH2:15][C:16]#[CH:17])[C:9]=1[O:10][CH2:11][C:12]#[CH:13])[CH2:5][OH:6]
Reactant: C#CCOc1cc(C=O)cc(Cl)c1OCC#C
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: C#CCOc1cc(CO)cc(Cl)c1OCC#C
Temperature: 25 °C
Reaction time: 2 h
Yield: 105.3 %

Procedure:
3-Chloro-4,5-dipropargyloxybenzaldehyde (14.7 g) was added to a solution of sodium borohydride (3.6 g) in ethanol (150 ml) at a temperature below 30° C. After stirring at room temperature for 2 hours, the resultant mixture was poured into dilute hydrochloric acid under cooling and extracted with ethyl acetate. The extract was washed with water, dried over magnesium sulfate and concentrated under reduced pressure to give 3-chloro-4,5-dipropargyloxybenzyl alcohol (15.60 g). nD17.0 1.5713.
Reaction SMILES: C([N:4]1[CH2:9][CH2:8][N:7]([CH:10]([CH3:12])[CH3:11])[CH2:6][CH2:5]1)(=O)C.[OH-].[K+]>CO>[CH:10]([N:7]1[CH2:8][CH2:9][NH:4][CH2:5][CH2:6]1)([CH3:12])[CH3:11]
Reactant: CC(=O)N1CCN(C(C)C)CC1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CC(C)N1CCNCC1
Yield: 105.7 %

Procedure:
A mixture of 7.26 g of 1-acetyl-4-isopropylpiperazine, 100 ml of methanol and 10 g of potassium hydroxide was heated under reflux for 17 hours. After the solvent was distilled off, water and chloroform were added to perform extraction with chloroform and the extract was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to afford 5.78 g of the title compound as an oily substance.
Reaction SMILES: [CH:1]1[C:6]([OH:7])=[CH:5][CH:4]=[C:3]([Br:8])[CH:2]=1.[N:9]#[C:10]Br>>[Br:8][C:3]1[CH:4]=[CH:5][C:6]([O:7][C:10]#[N:9])=[CH:1][CH:2]=1
Reactant: Oc1ccc(Br)cc1
Reactant: N#CBr
Product: N#COc1ccc(Br)cc1
Yield: 63 %

Procedure:
Analogous to Example 1, p-bromophenol was reacted with cyanogen bromide to obtain the title compound as white crystals. The yield was 63% of theory. The product was identified by its NMR spectrum as well as by the absorption of the cyanato group at 2260 cm-1 and the absence of phenolic hydroxy absorption in the IR spectrum.
Reaction SMILES: [CH:1]1[C:13]2[C:12]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[NH:6][C:5]=2[CH:4]=[CH:3][N:2]=1.I[C:15]1[CH:24]=[CH:23][CH:22]=[CH:21][C:16]=1[C:17]([O:19][CH3:20])=[O:18].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.[Cu]>[CH:1]1[C:13]2[C:12]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[N:6]([C:15]3[CH:24]=[CH:23][CH:22]=[CH:21][C:16]=3[C:17]([O:19][CH3:20])=[O:18])[C:5]=2[CH:4]=[CH:3][N:2]=1
Reactant: c1ccc2c(c1)[nH]c1ccncc12
Reactant: COC(=O)c1ccccc1I
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccccc1-n1c2ccccc2c2cnccc21
Temperature: 130 °C
Reaction time: 24 h

Procedure:
A mixture of 16.8 g (100 mmol) of 5H-pyrido[4,3-b]indole [244-69-9], 28.8 g (110 mmol) of methyl 2-iodobenzoate [610-97-9], 34.6 g (250 mmol) of potassium carbonate, 6.4 g (100 mmol) of copper powder and 100 g of glass beads (diameter 3 mm) in 300 ml of DMF is stirred at 130° C. for 24 h. After cooling, the mixture is filtered through a short Celite bed, the bed is rinsed with DMF, and the latter is removed in vacuo. The residue is dissolved in 500 ml of dichloromethane, and the solution is washed three times with 200 ml of 0.5 N sodium hydroxide solution each time and dried over magnesium sulfate. After removal of the dichloromethane in vacuo, the residue is recrystallised once from ethyl acetate and dried in vacuo (p=0.1 mbar, T=60° C.). Yield: 19.3 g (64 mmol), 64%; purity: 97% (1H-NMR).
Reaction SMILES: [Br-:1].[Br-].[Br-].C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1.[CH2:34]([O:36][C:37](=[O:55])[C:38]1[CH:43]=[C:42]([C:44](=[O:46])[CH3:45])[CH:41]=[CH:40][C:39]=1[O:47][CH2:48][C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1)C.O>O1CCCC1>[CH3:34][O:36][C:37](=[O:55])[C:38]1[CH:43]=[C:42]([C:44](=[O:46])[CH2:45][Br:1])[CH:41]=[CH:40][C:39]=1[O:47][CH2:48][C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1
Reactant: [Br-]
Reactant: CCOC(=O)c1cc(C(C)=O)ccc1OCc1ccccc1
Agent: C[N+](C)(C)c1ccccc1
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1cc(C(=O)CBr)ccc1OCc1ccccc1
Reaction time: 18 h
Yield: 72 %

Procedure:
Phenyltrimethyl ammonium tribromide (10.60 g, 28.20 mmol) was added in 7 portions to a stirring solution of acetophenone 44 (8.00 g, 28.10 mmol) in anhydrous tetrahydrofuran (50 mL). After 18 h, the reaction mixture was poured into water (250 mL) and stirred for 1 h. The formed precipitate was collected by vacuum filtration. Re-crystallization of the collected solid from ethanol gave the α-bromide 45 (7.35 g, 72%) as a white, needle solid: 1H NMR (500 MHz, DMSO-d6) δ 3.85 (s, 3H), 4.89 (s, 1H), 5.38 (s, 2H), 7.22 (d, 1H), 7.31-7.51 (m, 6H), 8.17-8.31 (m, 2H).
Reaction SMILES: [CH:1]([N:5]1[C:10]2[N:11]=[C:12](S(C)(=O)=O)[N:13]=[C:14]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=3[CH3:22])[C:9]=2[CH:8]=[CH:7][C:6]1=[O:27])([CH2:3][CH3:4])[CH3:2].[NH2:28][CH:29]([CH2:32][OH:33])[CH2:30][OH:31]>>[CH:1]([N:5]1[C:10]2[N:11]=[C:12]([NH:28][CH:29]([CH2:32][OH:33])[CH2:30][OH:31])[N:13]=[C:14]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=3[CH3:22])[C:9]=2[CH:8]=[CH:7][C:6]1=[O:27])([CH2:3][CH3:4])[CH3:2]
Reactant: CCC(C)n1c(=O)ccc2c(-c3ccc(F)cc3C)nc(S(C)(=O)=O)nc21
Reactant: NC(CO)CO
Product: CCC(C)n1c(=O)ccc2c(-c3ccc(F)cc3C)nc(NC(CO)CO)nc21

Procedure:
The product of Example 55, and serinol were reacted by the procedure of Example 60 to afford the title compound 8-sec-butyl-4-(4-fluoro-2-methyl-phenyl)-2-(2-hydroxy-1-hydroxymethyl ethylamino)-8H-pyrido[2,3-d]pyrimidin-7-one. 1H-NMR: δ 0.80 (m, 3H), 1.37 (m, 3H), 2.21 (m, 3H), 2.73 (m, 2H), 3.96 (m, 4H), 4.20 (m, 1H), 5.52 (m, 1H), 6.29 (m, 1H), 6.59 (br s, 1H), 6.91-7.40 (m, 4H); LC MS (m/e)=401 (MH+).
Reaction SMILES: [CH:1](=[C:8]1[NH:12][C:11](=[O:13])[C:10]([N:14]=[O:15])=[C:9]1OC)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CO>[CH:1](=[C:8]1[NH:12][C:11](=[O:13])[C:10]([N:14]=[O:15])=[C:9]1[NH:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC1=C(N=O)C(=O)NC1=Cc1ccccc1
Reactant: Nc1ccccc1
Solvent: CO
Product: O=NC1=C(Nc2ccccc2)C(=Cc2ccccc2)NC1=O
Yield: 30 %

Procedure:
A solution of 0.11 g (0.5 mmol) 5-benzylidene-4-methoxy-3-nitroso-1,5-dihydropyrrol-2-one (prepared by the method of H. Poschenrieder et al (Arch. Pharm. Pharm. Med. Chem. 1998, vol. 331, pp. 389-394) and Stachel et al (J. Heterocycl. Chem. 1980, vol. 17, pp. 1195-1199 and Liebigs Ann. Chem. 1985, pp. 1692-1696)) in methanol was boiled under reflux with 0.25 mol (0.25 mmol) aniline for two minutes. The compound 5-benzylidene-3-nitroso-4-phenylamino-1,5-dihydropyrrol-2-one was obtained in a yield of 30% after recrystallization from methanol. The compound decomposes at 230° C.
Reaction SMILES: C(OC([N:8]1[CH2:12][C@@H:11]([CH2:13][NH2:14])[CH2:10][C@H:9]1[C:15]([N:17]1[CH2:21][CH2:20][S:19][CH2:18]1)=[O:16])=O)(C)(C)C.C(N(CC)C(C)C)(C)C.Cl[C:32]([O:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:33]>C1COCC1>[C:35]1([O:34][C:32](=[O:33])[NH:14][CH2:13][C@H:11]2[CH2:10][C@@H:9]([C:15]([N:17]3[CH2:21][CH2:20][S:19][CH2:18]3)=[O:16])[NH:8][CH2:12]2)[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: CC(C)(C)OC(=O)N1C[C@@H](CN)C[C@H]1C(=O)N1CCSC1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: O=C(NC[C@@H]1CN[C@H](C(=O)N2CCSC2)C1)Oc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of Example 17D (32 mg, 0.1 mmol) in anhydrous THF (5 mL) was added N,N-diisopropylethylamine (0.035 mL, 0.2 mmol), followed by phenyl chloroformate (17.22 mg, 0.11 mmol). The mixture was stirred for 8 hours at room temperature and concentrated under reduced pressure. The residue was taken up in anhydrous dichloromethane (3 mL) and trifluoracetic acid (0.075 mL) in dichloromethane (0.075 mL) were added. The mixture was stirred for 5 hours at room temperature, concentrated under reduced pressure and purified using RP-HPLC to provide the titled compound. MS (ESI) m/e 336 (M+H)+; 1H NMR (400 MHz, CD3OD) δ ppm 1.77 (m, 1 H) 2.69 (m, 2 H) 3.07 (m, 1 H) 3.17 (m, 2 H) 3.25 (m, 1 H) 3.52 (m, 2 H) 3.75 (m, 1 H) 3.88 (m, 1 H) 4.52 (m, 1 H) 4.66 (m, 2 H) 7.10 (d, 2 H) 7.21 (t, 1 H) 7.37 (t, 2 H).
Reaction SMILES: [CH3:1][N:2]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([NH2:19])[CH:13]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:20].[CH3:21][S:22](Cl)(=[O:24])=[O:23].Cl.C([O-])(O)=O.[Na+]>C(Cl)Cl.N1C=CC=CC=1>[CH3:1][N:2]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([NH:19][S:22]([CH3:21])(=[O:24])=[O:23])[CH:13]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:20]
Reactant: CS(=O)(=O)Cl
Reactant: Cn1nc(-c2ccc(Cl)c(N)c2)c2ccccc2c1=O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cn1nc(-c2ccc(Cl)c(NS(C)(=O)=O)c2)c2ccccc2c1=O
Reaction time: 8 h
Yield: 78 %

Procedure:
To a mixture of 2-methyl-4-(3-amino-4-chlorophenyl)-1-(2H)-phthalazinone (38.72 g, 0,136 mol), CH2Cl2 (380 mL) and pyridine (75 mL) at 0° C. was added methanesulfonyl chloride (15.75 mL) in CH2Cl2 (75 mL). The reaction mixture was stirred overnight, poured into 1N HCl (400 mL) and stirred for 45 minutes. The mixture was filtered and the filtrate layers were separated. The solid thus obtained was treated with saturated NaHCO3, filtered, stirred with hexane, then filtered, stirred with hot methanol, then filtered and finally stirred with hot ethyl acetate and filtered to afford 38.8 g (78%) of 2-methyl-4-(3-methylsulfonylamino-4-chlorophenyl)-1-(2H)-phthalazinone, m.p. 234°-236° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:41])[C:5]([CH3:40])([O:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][CH:16]2[CH2:20][N:19]([CH2:21][C:22]3[CH:31]=[CH:30][C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[CH:23]=3)[C:18](=[O:32])[NH:17]2)=[CH:9][CH:8]=1)[CH3:2].[H-].[Na+].I[CH3:45]>CN(C=O)C>[CH2:1]([O:3][C:4](=[O:41])[C:5]([CH3:40])([O:33][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][CH2:14][CH2:15][CH:16]2[CH2:20][N:19]([CH2:21][C:22]3[CH:31]=[CH:30][C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[CH:23]=3)[C:18](=[O:32])[N:17]2[CH3:45])=[CH:11][CH:12]=1)[CH3:2]
Reactant: CCOC(=O)C(C)(Cc1ccc(OCCC2CN(Cc3ccc4ccccc4c3)C(=O)N2)cc1)Oc1ccccc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(Cc1ccc(OCCC2CN(Cc3ccc4ccccc4c3)C(=O)N2C)cc1)Oc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 95 %

Procedure:
A solution of a diasteriomeric mixture of 2-methyl-3-{4-[2-(1-naphthalen-2-ylmethyl-2-oxo-imidazolidin-4-yl)-ethoxy]-phenyl}-2-phenoxy-propionic acid ethyl ester (0.275 g, 0.498 mmol) in DMF (7 mL) is treated with NaH (60% oil suspension, 0.030 g, 0.750 mmol) and stirred at room temperature under N2 for 30 minutes. The reaction is cooled to 0° C. and treated with iodomethane (0.141 g, 0.996 mmol) and then warmed to room temperature and stirred for 3 hours. The reaction is quenched with 1 N HCl (5 mL) and worked up extractively with Et2O and water. The organic layer is dried and the solvent removed in vacuo to afford crude product that is purified by flash chromatography using 4:1 hexanes:acetone to afford 0.268 g (95%) 2-methyl-3-{4-[2-(3-methyl-1-naphthalen-2-ylmethyl-2-oxo-imidazolidin-4-yl)-ethoxy]-phenyl}-2-phenoxy-propionic acid ethyl ester. The diasteriomeric products are separated by chiral HPLC (8×32 cm Chiralpak AD, 100% IPA, 350 mL/min, 270 nm, to give products in>99% de 1H NMR. Rf=0.35 (1:1 acetone:hexanes). MS (ES+) Calc'd for C35H39N2O5 (M+1) 567. Found m/z 567 (100%).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C@H:11]1[CH2:14][C@H:13]([NH:15][C:16]2[C:21]([NH2:22])=[CH:20][CH:19]=[CH:18][N:17]=2)[CH2:12]1.[C:23](Cl)(=O)[CH2:24][CH3:25].C(N(CC)CC)C>ClCCl>[CH2:24]([C:25]1[N:15]([C@H:13]2[CH2:12][C@H:11]([NH:10][C:2]3[S:1][C:5]4[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=4[N:3]=3)[CH2:14]2)[C:16]2=[N:17][CH:18]=[CH:19][CH:20]=[C:21]2[N:22]=1)[CH3:23]
Reactant: Nc1cccnc1N[C@H]1C[C@H](Nc2nc3ccccc3s2)C1
Reactant: CCC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCc1nc2cccnc2n1[C@H]1C[C@H](Nc2nc3ccccc3s2)C1
Temperature: 100 °C
Reaction time: 1 h

Procedure:
N2-(Trans-3-(benzo[d]thiazol-2-ylamino)cyclobutyl)pyridine-2,3-diamine (0.075 g, 0.241 mmol) was suspended in dichloromethane (20 mL) and treated with propionyl chloride (0.03 ml, 0.357 mmol). Triethylamine (0.050 ml, 0.359 mmol) was added and the reaction stirred for 1 hour. The mixture was evaporated to dryness under reduced pressure and the crude redissolved in propionic acid (5 mL). The solution was heated at 100° C. for 16 hours. The mixture was evaporated to dryness under reduced pressure and purified using silica chromatography (0-10% methanol in dichloromethane gradient) followed by reverse phase HPLC gave the desired N-(trans-3-(2-ethyl-3H-imidazo[4,5-b]pyridin-3-yl)cyclobutyl)benzo[d]thiazol-2-amine (0.045 g, 0.129 mmol, 53.5% yield). M+1: 350.1. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.31 (t, J=7.53 Hz, 3 H) 2.46 (br. s., 1 H) 2.52-2.68 (m, 2 H) 2.79 (q, J=7.63 Hz, 2 H) 3.61-3.84 (m, 2 H) 4.47-4.68 (m, 1 H) 5.12 (quin, J=8.20 Hz, 1 H) 7.03 (t, J=7.53 Hz, 1 H) 7.12 (dd, J=7.92, 4.79 Hz, 1 H) 7.18-7.32 (m, 1 H) 7.52 (dd, J=21.91, 8.00 Hz. 2 H) 7.88 (dd, J=8.02, 1.37 Hz. 1 H) 8.26 (dd, J=4.69, 1.37 Hz. 1 H).
Reaction SMILES: [CH2:1]([C@@H:8]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH2:9]Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[C:25]([C:27]1[CH:28]=[C:29]([OH:33])[CH:30]=[CH:31][CH:32]=1)#[N:26]>CN(C)C=O>[CH2:1]([C@@H:8]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH2:9][O:33][C:29]1[CH:30]=[CH:31][CH:32]=[C:27]([C:25]#[N:26])[CH:28]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](CCl)Cc1ccccc1
Reactant: N#Cc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@@H](COc1cccc(C#N)c1)Cc1ccccc1

Procedure:
8.52 g (31.6 mmol) of t-butyl N-[(1R)-1-benzyl-2-chloroethyl]carbamate, 12.1 g (87.5 mmol) of potassium carbonate and 5 g (41.9 mmol) of 3-cyanophenol were reacted in 120 ml of dimethylformamide as the solvent at 70° C. overnight. After the treatment in an ordinary manner followed by the silica gel column chromatography, the title compound was obtained.
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[C:12]([CH3:15])[C:11]([O:16][C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[C:19]([CH:24]([C:26]3[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=3)[OH:25])[CH:18]=1)=[C:10]([CH3:33])[CH:9]=2)=[O:5])C>CO.O.[OH-].[K+]>[F:32][C:29]1[CH:30]=[CH:31][C:26]([CH:24]([OH:25])[C:19]2[CH:18]=[C:17]([CH:22]=[CH:21][C:20]=2[OH:23])[O:16][C:11]2[C:12]([CH3:15])=[C:13]3[C:8](=[CH:9][C:10]=2[CH3:33])[NH:7][C:6]([C:4]([OH:5])=[O:3])=[CH:14]3)=[CH:27][CH:28]=1
Reactant: CCOC(=O)c1cc2c(C)c(Oc3ccc(O)c(C(O)c4ccc(F)cc4)c3)c(C)cc2[nH]1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1cc2[nH]c(C(=O)O)cc2c(C)c1Oc1ccc(O)c(C(O)c2ccc(F)cc2)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 79.1 %

Procedure:
To a solution of 5-{3-[(4-Fluoro-phenyl)-hydroxy-methyl]-4-hydroxy-phenoxy}-4,6-dimethyl-1H-indole-2-carboxylic acid ethyl ester (17.5 mg, 0.039 mmol) in a mixture of methanol (0.5 mL) and water (0.5 mL) at room temperature was added potassium hydroxide (3M, 0.078 mL), and the resulting solution was stirred at room temperature for 20 hours. The reaction solution was diluted with 0.1M potassium hydroxide (10 mL) and washed with ethyl acetate (3 times 5 mL). The aqueous solution was acidified with hydrochloric acid and then extracted with ethyl acetate (3 times 10 mL). The combined organic extracts were washed with brine, dried over Na2SO4, filtered, and concentrated to afford the title compound (13 mg) as a solid. 1H NMR (400 MHz, CD3OD) δ11.0 (s, 1H), 7.30-7.26 (m, 2H), 7.12 (s, 2H), 6.93 (t, 2H), 6.73 (d, 1H), 6.60 (d, 2H), 6.43-6.40 (dd, H), 5.97 (s, 1H), 2.23 (s, 3H), 2.13 (s, 3H). MS (APCI−) Calc:421. 1, Found: 420.1 (M−1).
Reaction SMILES: [CH:1]1([NH:6][C@@H:7]2[CH2:12][C:11]3[C:13]([O:18][CH3:19])=[CH:14][CH:15]=[C:16]([F:17])[C:10]=3[O:9][CH2:8]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.CC(O)=O.[C:24]1(=O)[CH2:27][CH2:26][CH2:25]1.[BH3-]C#N.[Na+]>CO>[CH:1]1([N:6]([C@@H:7]2[CH2:12][C:11]3[C:13]([O:18][CH3:19])=[CH:14][CH:15]=[C:16]([F:17])[C:10]=3[O:9][CH2:8]2)[CH:24]2[CH2:27][CH2:26][CH2:25]2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COc1ccc(F)c2c1C[C@@H](NC1CCCC1)CO2
Reactant: O=C1CCC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: COc1ccc(F)c2c1C[C@@H](N(C1CCCC1)C1CCC1)CO2
Reaction time: 144 h
Yield: 48.8 %

Procedure:
To a solution of (R)-3-(N-cyclopentylamino)-8-fluoro-5- methoxy-3,4-dihydro-2H-1-benzopyran (0.9 g, 3.4 mmol), HOAc (0.22 g, 3.6 mmol) and cyclobutanone (2g, 30 mmol) in methanol (25 mL), were NaCNBH3 (1 g, 16 mmol) added in portions at room temperature. After stirring for four days GC indicated 37% product. pH was adjusted to 5 (HOAc)and additional (1 g, 15 mmol) cyclobutanone was added. After stirring for further 6 days, GC indicated 64% conversion. The solvent was evaporated and the residue worked up by extraction. Flash chromatography (EtOAc/P-ether, 1+1), gave 0.53 g (53% yield) of the title compound as a colourless oil. GC/MS (70 eV) M=319 (3%).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].C[O:9][C:10](=[O:24])[C@@H:11]1[CH2:15][C@H:14]([OH:16])[CH2:13][N:12]1[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18]>ClCCl>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[C:20]([O:19][C:17]([N:12]1[CH2:13][C@@H:14]([OH:16])[CH2:15][C@H:11]1[C:10]([OH:24])=[O:9])=[O:18])([CH3:23])([CH3:21])[CH3:22]
Reactant: COC(=O)[C@@H]1C[C@H](O)CN1C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1C[C@@H](O)C[C@H]1C(=O)O
Temperature: 0 °C
Reaction time: 3 h

Procedure:
Trifluoroacetic acid (10 mL) was added to a solution of N-tert-butoxycarbonyl-cis-4-hydroxy-L-proline methyl ester (Compound D101 (J), 1.10 g) in dichloromethane (10 mL) at 0° C. After stirring at 0° C. for 10 min and at room temperature for 3 hr, the mixture was evaporated in vacuo to give a crude N-tert-butoxycarbonyl-cis-4-hydroxy-L-proline trifluoroacetate. The crude N-tert-butoxycarbonyl-cis-4-hydroxy-L-proline trifluoroacetate was dissolved in dichloromethane (20 mL), and N-tert-butoxycarbonyl-sarcosine (844 mg), triethylamine (1.25 mL), 1-hydroxybenzotriazole (663 mg), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (856 mg) were added at 0° C. After stirring at 0° C. for 30 min and at room temperature for 17 hr, the solvent was removed in vacuo. The residue was diluted with 1 N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with saturated sodium hydrogen carbonate, water, and brine, dried over anhydrous sodium sulfate, and evaporated in vacuo. The residue as purified by silica gel column chromatography (chloroform then chloroform-methanol=50:1 to 30:1, v/v) to afford the title compound (452 mg) as a colorless oil. The compound appears as a mixture of rotamers: 1H NMR (400 MHz, CDCl3) δ 1.42 and 1.46 (each s, total 9H), 2.04-2.14 (m, 1H), 2.26-2.39 (m, 1H), 2.94 (s, 3H), 3.52-4.17 (m, 4H), 3.75 and 3.77 (each s, total 3H), 4.17-4.28 (m, 1H), and 4.38-4.62 (m, 2H).
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[CH2:7][CH2:6][C@@H:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH2:4]1.[H-].[Na+].[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.O>C1COCC1>[CH2:18]([O:1][CH2:2][C@H:3]1[CH2:7][CH2:6][C@@H:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:12])([CH3:14])[CH3:13])[CH2:4]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CC[C@H](CO)C1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N[C@@H]1CC[C@H](COCc2ccccc2)C1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 74.8 %

Procedure:
To a solution of 1.4 g (6.7 mmol) of tert-butyl [(1R,3S)-3-(hydroxymethyl)cyclopentyl]carbamate in 20 mL of anhydrous THF are added portionwise under argon, at room temperature, 0.27 g (6.7 mmol) of sodium hydride at 60% in oil. After stirring for 45 minutes, the medium is cooled to 0° C. and 0.8 mL (6.7 mmol) of benzyl bromide is added. After stirring for 1 hour at room temperature, the medium is hydrolysed with 30 mL of water and extracted with 2×100 mL of EtOAc, dried over Na2SO4, concentrated under reduced pressure and then purified by chromatography on a column of silica gel, eluting with a 99/1 DCM/MeOH mixture. 1.53 g of tert-butyl {(1R,3S)-3-[(benzyloxy)methyl]cyclopentyl}carbamate are obtained in the form of an oil.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([C:11]([OH:13])=O)[N:2]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[CH3:47][O:48][C:49]([C:51]1[C:59]2[N:58]=[C:57]([NH2:60])[NH:56][C:55]=2[C:54]([F:61])=[C:53]([O:62][CH3:63])[C:52]=1[F:64])=[O:50]>CN(C=O)C>[CH3:47][O:48][C:49]([C:51]1[C:59]2[NH:58][C:57]([NH:60][C:11]([C:3]3[N:2]=[CH:1][C:10]4[C:5]([CH:4]=3)=[CH:6][CH:7]=[CH:8][CH:9]=4)=[O:13])=[N:56][C:55]=2[C:54]([F:61])=[C:53]([O:62][CH3:63])[C:52]=1[F:64])=[O:50]
Reactant: O=C(O)c1cc2ccccc2cn1
Reactant: COC(=O)c1c(F)c(OC)c(F)c2[nH]c(N)nc12
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)c1c(F)c(OC)c(F)c2nc(NC(=O)c3cc4ccccc4cn3)[nH]c12
Yield: 48.7 %

Procedure:
0.4 g (2.0 mmol) of isoquinoline-3-carboxylic acid and 800 mg (2.1 mmol) HBTU were dissolved in 3.0 mL of DMF and 0.6 mL of DIEA and treated with 0.35 g (1.5 mmol) of 2-amino-5,7-difluoro-6-methoxy-1H-benzoimidazole-4-carboxylic acid methyl ester as described in general procedure A to produce 0.3 g (0.73 mmol, 49%) of 5,7-difluoro-2-[(isoquinoline-3-carbonyl)-amino]-6-methoxy-3H-benzoimidazole-4-carboxylic acid methyl ester. LCMS: 413 (M+1)+.