Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:32])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][S:18][C:19]3[CH:24]=[CH:23][C:22]([C:25](=[O:27])[CH3:26])=[C:21]([OH:28])[C:20]=3[CH2:29][CH2:30][CH3:31])[CH:12]=2)[CH:5]=1.O.[OH-].[Li+].Cl>O1CCCC1.CO.O>[C:25]([C:22]1[CH:23]=[CH:24][C:19]([S:18][CH2:17][C:13]2[CH:12]=[C:11]([CH:16]=[CH:15][CH:14]=2)[CH2:10][C:6]2[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=2)[C:3]([OH:32])=[O:2])=[C:20]([CH2:29][CH2:30][CH3:31])[C:21]=1[OH:28])(=[O:27])[CH3:26]
Reactant: CCCc1c(SCc2cccc(Cc3cccc(C(=O)OC)c3)c2)ccc(C(C)=O)c1O
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CCCc1c(SCc2cccc(Cc3cccc(C(=O)O)c3)c2)ccc(C(C)=O)c1O
Temperature: 0 °C
Yield: 85.1 %

Procedure:
Dissolve 3-[3-(4-Acetyl-3-hydroxy-2-propyl-phenylsulfanylmethyl)-benzyl]-benzoic acid methyl ester (238 mg, 0.53 mmol) in tetrahydrofuran (5 ml) and methanol (4 ml). Add lithium hydroxide monohydrate (89 mg, 2.1 mmol) and water (1.5 ml), then stir at room temperature for 18 hours. Cool at 0° C. and adjust to pH 3 with 1 N hydrochloric acid. Dilute with water (35 ml) and extract with ethyl acetate (2×20 ml). Combine the organic extracts, dry over sodium sulfate, filter and concentrate to a solid. Purify the crude product via reverse phase HPLC using a gradient of 90:10 to 20:80 (water/0.1% TFA):acetonitrile as eluent to give the title compound (196 mg, 85%).
Reaction SMILES: [N+](C1C=CC(O[C:11]([C:13]2[C:14]3[CH:25]=[C:24]([CH2:26][CH3:27])[O:23][C:15]=3[C:16]([O:19][CH:20]([F:22])[F:21])=[N:17][CH:18]=2)=[O:12])=CC=1)([O-])=O.[NH2:28][C:29]1[C:36]([Cl:37])=[CH:35][C:32]([C:33]#[N:34])=[CH:31][C:30]=1[Cl:38]>>[Cl:37][C:36]1[CH:35]=[C:32]([C:33]#[N:34])[CH:31]=[C:30]([Cl:38])[C:29]=1[NH:28][C:11]([C:13]1[C:14]2[CH:25]=[C:24]([CH2:26][CH3:27])[O:23][C:15]=2[C:16]([O:19][CH:20]([F:21])[F:22])=[N:17][CH:18]=1)=[O:12]
Reactant: N#Cc1cc(Cl)c(N)c(Cl)c1
Reactant: CCc1cc2c(C(=O)Oc3ccc([N+](=O)[O-])cc3)cnc(OC(F)F)c2o1
Product: CCc1cc2c(C(=O)Nc3c(Cl)cc(C#N)cc3Cl)cnc(OC(F)F)c2o1
Yield: 10.7 %

Procedure:
Starting from 7-difluromethoxy-2-ethylfuro[2,3-c]pyridine-4-carboxylic acid 4-nitrophenyl ester (100 mg) and 4-amino-3,5-dichlorobenzonitrile (99 mg). Purification by column chromatography on silica eluting with 1% methanol in dichloromethane afforded the title compound as a white solid (12 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[N:17]2[C:12]([CH:13]=[N:14][C:15](SC)=[N:16]2)=[CH:11][CH:10]=1.OO.[O-:22][S:23]([O-:26])(=S)=O.[Na+].[Na+].[CH3:29]O>O.O.[O-][W]([O-])(=O)=O.[Na+].[Na+]>[CH3:29][S:23]([C:15]1[N:14]=[CH:13][C:12]2=[CH:11][CH:10]=[C:9]([C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[O:2][CH3:1])[N:17]2[N:16]=1)(=[O:26])=[O:22]
Reactant: CO
Reactant: O=S([O-])([O-])=S
Reactant: COc1ccccc1-c1ccc2cnc(SC)nn12
Agent: O=[W](=O)([O-])[O-]
Agent: OO
Agent: [Na+]
Solvent: O
Product: COc1ccccc1-c1ccc2cnc(S(C)(=O)=O)nn12
Temperature: 60 °C
Reaction time: 5 h
Yield: 87.7 %

Procedure:
Sodium Tungstate Dihydrate (62 mg, 0.19 mmol) and 7-(2-Methoxy-phenyl)-2-methylsulfanyl-pyrrolo[2,1-f][1,2,4]triazine (1.02 g, 3.76 mmol) were combined in Methanol (40.0 mL) and 50% Hydrogen Peroxide (0.65 mL, 11 mmol) was added and the reaction was stirred under an atmosphere of nitrogen at 60° C. for 5 h. The mixture was treated with 5 mL 10% Na2S2O3, generating a ppt, then allowed to cool to rt before being stored in a freezer for 30 min. The resultant solids were collected on a Buchner, washing with water (25 mL). Further drying in vacuo afforded 2-Methanesulfonyl-7-(2-methoxy-phenyl)-pyrrolo[2,1-f][1,2,4]triazine (1.00 g; Yield=87.7%). 1H-NMR (DMSO-d6): 9.38 (s, 1H), 7.75 (dd, 1H, J=1.6, 7.6 Hz), 7.51 (m, 2H), 7.40 (d, 1H, J=4.7 Hz), 7.25 (d, 1H, J=8.3 Hz), 7.13 (m, 1H), 3.83 (s, 3H), 3.37 (s, 3H).
Reaction SMILES: [CH3:1][C:2](=[CH2:34])[C@@H:3]([N:20]1[C:26](=[O:27])[C@H:25]2[C@@H:21]1[O:22][C:23]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[N:24]2)[C:4]([O:6][CH:7]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:5].[Cl:35]Cl.N1C=CC=CC=1>C(OCC)(=O)C.C(Cl)(Cl)(Cl)Cl>[C:28]1([C:23]2[O:22][C@H:21]3[C@H:25]([C:26](=[O:27])[N:20]3[C@H:3]([C:2]([CH2:1][Cl:35])=[CH2:34])[C:4]([O:6][CH:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=3)=[O:5])[N:24]=2)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: ClCl
Reactant: C=C(C)[C@H](C(=O)OC(c1ccccc1)c1ccccc1)N1C(=O)[C@@H]2N=C(c3ccccc3)O[C@@H]21
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Solvent: ClC(Cl)(Cl)Cl
Product: C=C(CCl)[C@H](C(=O)OC(c1ccccc1)c1ccccc1)N1C(=O)[C@@H]2N=C(c3ccccc3)O[C@@H]21

Procedure:
A solution of 100 mg of Compound (1a) in ethyl acetate is reacted with a solution (2.0 molar equivalents) of chlorine in carbon tetrachloride at room temperature. The obtained product is treated with 1.2 equivalents of pyridine for 45 minutes under ice cooling, instead of chromatography of silica gel, to yield 110 mg of Compound (7).
Reaction SMILES: C1C2[CH:12]([CH2:14][O:15][C:16]([NH:18][C@@H:19]([CH2:23][S:24][CH2:25][C@H:26]([O:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH3:53])[CH2:27][O:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])[C:20](O)=[O:21])=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)C=2C=CC=1.CN(C(ON1N=N[C:64]2[CH:65]=[CH:66][CH:67]=[CH:68][C:63]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH2:87][CH2:88][CH2:89][O:90][CH2:91][CH2:92][O:93][CH2:94][CH2:95][O:96][CH2:97][CH2:98][C:99]([O:101][C:102]([CH3:105])([CH3:104])[CH3:103])=[O:100]>C(Cl)Cl>[CH:65]1[C:64]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C@@H:19]([CH2:23][S:24][CH2:25][C@H:26]([O:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH3:53])[CH2:27][O:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])[C:20](=[O:21])[NH:87][CH2:88][CH2:89][O:90][CH2:91][CH2:92][O:93][CH2:94][CH2:95][O:96][CH2:97][CH2:98][C:99]([O:101][C:102]([CH3:105])([CH3:104])[CH3:103])=[O:100])=[O:17])[C:11]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[C:63]=2[CH:68]=[CH:67][CH:66]=1
Reactant: CC(C)(C)OC(=O)CCOCCOCCOCCN
Reactant: CCCCCCCCCCCCOC[C@H](CSC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O)OCCCCCCCCCCCC
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCCCCCCCCCCCOC[C@H](CSC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)NCCOCCOCCOCCC(=O)OC(C)(C)C)OCCCCCCCCCCCC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (R)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(((R)-2,3-bis(dodecyloxy)propyl)thio)propanoic acid (1 eq, from example 20, step 5) and HBTU (1.2 eq) in DCM (0.06 M) was added DIEA (3.5 eq), followed by tert-butyl 3-(2-(2-(2-aminoethoxy)ethoxy)ethoxy)propanoate (1.2 eq). The reaction was stirred at room temperature for 2 hours. The crude mixture was purified by flash chromatography on a COMBIFLASH® system (ISCO) using 0-5% MeOH/DCM to give the title product as a white solid.
Reaction SMILES: [OH:1][C:2]1[N:7]2[N:8]=[CH:9][CH:10]=[C:6]2[N:5]=[C:4]([CH2:11][CH2:12][C:13](=[O:15])[CH3:14])[CH:3]=1.[BH4-].[Na+].Cl>CO>[OH:1][C:2]1[N:7]2[N:8]=[CH:9][CH:10]=[C:6]2[N:5]=[C:4]([CH2:11][CH2:12][CH:13]([OH:15])[CH3:14])[CH:3]=1
Reactant: CC(=O)CCc1cc(O)n2nccc2n1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(O)CCc1cc(O)n2nccc2n1
Temperature: 0 °C
Reaction time: 2 h
Yield: 72.3 %

Procedure:
The crystals obtained in step (2) (5.7 g) were dissolved in 120 ml of methanol. Sodium borohydride (0.53 g) was added under ice-cooling and stirred at 0° C. for 2 hours. After completion of the reaction, the reaction mixture was acidified by adding dilute aqueous hydrochloric acid dropwise and then extracted with chloroform. The organic layer was collected, washed with a saturated saline solution, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was recrystallized from ethanol-n-hexane to provide 4.16 g of 7-hydroxy-5-(3-hydroxybutyl) pyrazolo[1,5-a]pyrimidine as colorless crystals.
Reaction SMILES: [I:1][C:2]1[N:3]=[C:4]([NH2:20])[C:5]2[N:6]=[CH:7][N:8]([C:18]=2[N:19]=1)[C@@H:9]1[O:17][C@H:14]([CH2:15][OH:16])[C@@H:12]([OH:13])[C@H:10]1[OH:11].Cl(O)(=O)(=O)=O.C([O-])([O-])=O.[Na+].[Na+].[CH3:32][C:33]([CH3:35])=O>>[NH2:20][C:4]1[N:3]=[C:2]([I:1])[N:19]=[C:18]2[C:5]=1[N:6]=[CH:7][N:8]2[C@H:9]1[C@H:10]2[C@H:12]([O:13][C:33]([CH3:35])([CH3:32])[O:11]2)[C@@H:14]([CH2:15][OH:16])[O:17]1
Reactant: Nc1nc(I)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Reactant: CC(C)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Agent: [O-][Cl+3]([O-])([O-])O
Product: CC1(C)O[C@@H]2[C@H](O1)[C@@H](CO)O[C@H]2n1cnc2c(N)nc(I)nc21
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 93 %

Procedure:
To a suspension of 2-iodoadenosine 1 (10.0 g, 25.4 mmol) in acetone (200 ml) cooled to 0° C. was added dropwise 70% perchloric acid (4.0 mL), resulting in an exotherm of about 5° C. The resultant colorless solution was allowed to warm to room temperature over 30 minutes, then stirred for a further 45 minutes. 1M Na2CO3 (50 mL) was added, resulting in solids precipitating. This was followed by the careful portionwise addition of water (300 mL) with stirring until all solids had dissolved. The mixture was extracted with three portions of CH2Cl2. The combined organics were washed with brine, dried (Na2SO4), filtered, and evaporated to afford Compound 2 (10.26 g, 93%) as a colorless solid. 1H-NMR (600 MHz, DMSO d6): 1.32 (s, 3H), 1.54 (s, 3H), 3.54 (m, 2H), 4.19 (m, 1H), 4.93 (dd, 1H), 5.05 (t, 1H), 5.27 (dd, 1H), 6.05 (d, 1H), 7.74 (bs, 2H), 8.28 (s, 1H); 13C-NMR (150 MHz, DMSO d6): 25.45, 27.08, 85.69, 86.09, 88.44, 92.59, 114.92, 120.39, 142.47, 151.08, 157.20, 173.14. LRMS (ES): m/z=434.0 (M+H, 100%).
Reaction SMILES: C1C=CC=CC=1.[CH3:7][C:8]1[NH:9][C:10]([CH2:33][OH:34])=[C:11]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH:12]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[N+:25]([O-:27])=[O:26])[C:13]=1[C:14]([O:16][CH2:17][CH3:18])=[O:15].[C:35](Cl)(=[O:37])[CH3:36]>N1C=CC=CC=1.C(Cl)Cl>[CH3:7][C:8]1[NH:9][C:10]([CH2:33][O:34][C:35](=[O:37])[CH3:36])=[C:11]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH:12]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[N+:25]([O-:27])=[O:26])[C:13]=1[C:14]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: CC(=O)Cl
Reactant: CCOC(=O)C1=C(C)NC(CO)=C(C(=O)OCC)C1c1ccccc1[N+](=O)[O-]
Solvent: c1ccncc1
Solvent: c1ccccc1
Solvent: ClCCl
Product: CCOC(=O)C1=C(C)NC(COC(C)=O)=C(C(=O)OCC)C1c1ccccc1[N+](=O)[O-]
Yield: 68.4 %

Procedure:
((5) To a mixture of diethyl 2-methyl-4-(2-nitrophenyl)-6-hydroxymethyl-1,4-dihydropyridine-3,5-dicarboxylate (2.35 g) in pyridine (30 ml), was dropwise added a solution of acetyl chloride (942 mg) in methylene chloride (5 ml) under stirring and ice-cooling over the period of 7 minutes. The mixture was further stirred for 70 minutes at room temperature. The pyridine was distilled off under reduced pressure and ethyl acetate was added to the residue. The resultant mixture was washed twice with water adjusted to pH 4 with hydrochloric acid and then an aqueous solution of sodium chloride, dried and concentrated under reduced pressure to give an oily substance. This oily substance was crystallized by treating with a mixture of diethyl ether and a small amaunt of n-hexane, and collected crude crystals (2.5 g) were washed with n-hexane and thus obtained crystals were recrystallized from diethyl ether to give pure crystals (1.78 g) of diethyl 2-methyl-4-(2-nitrophenyl)-6-acetoxymethyl-1,4-dihydropyridine-3,5-dicarboxylate, m.p. 89° to 90° C.
Reaction SMILES: [P:1](=[O:5])([OH:4])([OH:3])[OH:2].[OH-].[Ca+2:7].[OH-]>>[O-:3][P:1]([O-:5])([O-:4])=[O:2].[O-:3][P:1]([O-:5])([O-:4])=[O:2].[Ca+2:7].[Ca+2:7].[Ca+2:7]
Reactant: O=P(O)(O)O
Agent: [Ca+2]
Agent: [OH-]
Product: O=P([O-])([O-])[O-]

Procedure:
As aqueous solution of phosphoric acid was reacted with a suspension of calcium hydroxide by a conventional method. The reaction product was dried and calcined at 1,200° C. to obtain α-tricalcium phosphate in powder form. 2 grams of this powder was mixed with 1 g of a setting solution having a viscosity at room temperature of 6,000 cp prepared by dissolving 0.1 g of chitosan ("Flonac N" made by Kyowa Yushi Kogyo K. K.) in 10 g of an aqueous solution of 40% citric acid. A plastic gum-like composition was obtained and this composition set in about 7 minutes to produce a setting material having a high strength.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9](Cl)=[O:10])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[C:14]([C:16]1[CH:21]=[CH:20][C:19]([SH:22])=[CH:18][CH:17]=1)#[N:15].N1C=CC=CC=1>ClCCl>[C:1]([O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([S:22][C:19]2[CH:20]=[CH:21][C:16]([C:14]#[N:15])=[CH:17][CH:18]=2)=[O:10])=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: N#Cc1ccc(S)cc1
Reactant: CC(=O)Oc1ccc(C(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)Oc1ccc(C(=O)Sc2ccc(C#N)cc2)cc1
Temperature: 5 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
A solution of 4-acetoxybenzoyl chloride (3.33 g) in dry dichloromethane (20 ml) was added over 10 minutes to a cool (5° C.), stirred solution of 4-cyanothiophenol (2.06 g), pyridine (1.45 ml) and 4-N,N-dimethylaminopyridine (25 mg) in dry dichloromethane (30 ml). The stirred solution was allowed to reach room temperature overnight and the organic solution was washed successively with aqueous 2M hydrochloric acid, a saturated sodium bicarbonate solution and water. Evaporation of the extracts, which had been dried over magnesium sulphate, afforded the desired thioester (4.53 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[C:5]([F:11])=[CH:4][C:3]=1[NH:12][C:13](=O)[CH3:14].CO>O1CCCC1>[CH2:13]([NH:12][C:3]1[CH:4]=[C:5]([F:11])[C:6]([N+:8]([O-:10])=[O:9])=[CH:7][C:2]=1[F:1])[CH3:14]
Reactant: CC(=O)Nc1cc(F)c([N+](=O)[O-])cc1F
Solvent: CO
Solvent: C1CCOC1
Product: CCNc1cc(F)c([N+](=O)[O-])cc1F
Temperature: 0 °C
Reaction time: 48 h
Yield: 95.5 %

Procedure:
To a cold (0°C.), stirred solution of 6.3 g (0.029 mole) of N-(2,5-difluoro-4-nitrophenyl)acetamide in 100 ml of dry tetrahydrofuran was added dropwise 8.8 ml of a 10M boranedimethyl sulfide complex in tetrahydrofuran. The reaction mixture was heated until a gentle reflux was maintained with no external heating. When this reflux subsided, the mixture was reheated at reflux for three hours. The reaction mixture was cooled to 0° C., and methanol was added dropwise until no gas evolution was seen upon subsequent addition. This mixture was allowed to stand at room temperature for two days. The solvent was removed from the mixture by distillation under reduced pressure, leaving a residue. This residue was purified by column chromatography on silica gel, eluting with methylene chloride to yield 5.6 g of N-ethyl-2,5-difluoro-4-nitroaniline as a solid. The nmr spectrum was consistent with the proposed structure.
Reaction SMILES: [F:1][C:2]1[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][C:3]=1[O:4][C:5]1[C:14]2[CH:13]=[CH:12][CH:11]=[C:10]([NH2:15])[C:9]=2[CH:8]=[CH:7][N:6]=1.[Cl:24][C:25]1[CH:33]=[CH:32][C:31]([CH2:34][NH:35][C:36](=[O:41])[C:37]([CH3:40])([CH3:39])[CH3:38])=[CH:30][C:26]=1[C:27](O)=[O:28].C(Cl)(=O)C(Cl)=O.CCN(C(C)C)C(C)C>CN(C=O)C.C(Cl)Cl>[Cl:24][C:25]1[CH:33]=[CH:32][C:31]([CH2:34][NH:35][C:36](=[O:41])[C:37]([CH3:39])([CH3:38])[CH3:40])=[CH:30][C:26]=1[C:27]([NH:15][C:10]1[CH:11]=[CH:12][CH:13]=[C:14]2[C:9]=1[CH:8]=[CH:7][N:6]=[C:5]2[O:4][C:3]1[CH:16]=[C:17]([C:20]([F:21])([F:23])[F:22])[CH:18]=[CH:19][C:2]=1[F:1])=[O:28]
Reactant: CC(C)(C)C(=O)NCc1ccc(Cl)c(C(=O)O)c1
Reactant: Nc1cccc2c(Oc3cc(C(F)(F)F)ccc3F)nccc12
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)C(=O)NCc1ccc(Cl)c(C(=O)Nc2cccc3c(Oc4cc(C(F)(F)F)ccc4F)nccc23)c1
Yield: 25.4 %

Procedure:
The title compound was prepared following the procedure described in Example-1 using 1-(2-fluoro-5-(trifluoromethyl)phenoxy)isoquinolin-5-amine (Intermediate-36, 80 mg, 0.24 mmol), 2-chloro-5-(pivalamidomethyl)benzoic acid (Intermediate-5, 134 mg, 0.49 mmol), oxalyl chloride (93 mg, 0.74 mmol), DMF (1 drop) and DIPEA (93 mg, 0.72 mmol) in CH2Cl2 (5 mL) to afford 35 mg of the title product. 1H NMR (300 MHz, DMSO-d6): δ 10.77 (s, 1H), 8.32 (d, 1H), 8.11 (t, 1H), 8.09 (d, 1H), 8.00-7.96 (m, 2H), 7.75-7.69 (m, 4H), 7.55 (m, 2H), 7.38 (d, 1H), 4.32 (d, J=5.4 Hz, 2H), 1.14 (s, 9H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][N:12]([C:15]([C@H:17]([C@H:22]3[O:26]C(C)(C)[O:24][C:23]3=O)[CH2:18][CH:19]([CH3:21])[CH3:20])=[O:16])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.[NH2:30][OH:31]>CC(O)C>[OH:31][NH:30][C:23](=[O:24])[C@H:22]([OH:26])[C@@H:17]([C:15]([N:12]1[CH2:11][CH2:10][N:9]([C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[CH2:14][CH2:13]1)=[O:16])[CH2:18][CH:19]([CH3:20])[CH3:21]
Reactant: NO
Reactant: COc1ccc(N2CCN(C(=O)[C@@H](CC(C)C)[C@H]3OC(C)(C)OC3=O)CC2)cc1
Solvent: CC(C)O
Product: COc1ccc(N2CCN(C(=O)[C@@H](CC(C)C)[C@@H](O)C(=O)NO)CC2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 55 %

Procedure:
To a suspension of (5R)-5-((1S)-1-{[4-(4-methoxyphenyl)piperazin-1-yl]carbonyl}-3-methylbutyl)-2,2-dimethyl-1,3-dioxolan-4-one (108 mg, 0.27 mmol) in iPrOH (4 mL) was added a 50% aqueous solution of hydroxylamine (80 μL) and the resulting mixture was stirred at RT for 2 hours. Then the white solid was filtered off, washed with water and dried under reduced pressure to give 56 mg (55%) of the title compound as a white powder. HPLC, Rt: 1.57 min (purity: 99.1%). LC/MS, M+(ESI): 380.2, M−(ESI): 378.2. 1H NMR (CD3OD, 300 MHz) δ 7.01 (d, J=9.1 Hz, 2H), 6.89 (d, J=9.1 Hz, 2H), 4.05 (d, J=6.8 Hz, 1H), 3.96 (m, 2H), 3.80 (m, 1H), 3.78 (s, 3H), 3.68 (m, 1H), 3.49 (m, 1H), 3.15-2.99 (m, 4H), 1.72 (m, 1H), 1.54 (m, 1H), 1.29 (m, 1H), 0.96 (d, J=6.5 Hz, 3H), 0.95 (d, J=6.4 Hz, 3H).
Reaction SMILES: [CH3:1][C:2]([CH3:22])([CH3:21])[CH2:3][N:4]([CH2:13][C:14]1[CH:19]=[CH:18][C:17](I)=[CH:16][CH:15]=1)[C:5]1[CH:10]=[CH:9][N:8]=[C:7]([C:11]#[N:12])[N:6]=1.[C:23]([Si:25]([CH3:28])([CH3:27])[CH3:26])#[CH:24].C(N(CC)CC)C.O>CN(C=O)C.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:1][C:2]([CH3:22])([CH3:21])[CH2:3][N:4]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:24]#[C:23][Si:25]([CH3:28])([CH3:27])[CH3:26])=[CH:16][CH:15]=1)[C:5]1[CH:10]=[CH:9][N:8]=[C:7]([C:11]#[N:12])[N:6]=1
Reactant: C#C[Si](C)(C)C
Reactant: CC(C)(C)CN(Cc1ccc(I)cc1)c1ccnc(C#N)n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)CN(Cc1ccc(C#C[Si](C)(C)C)cc1)c1ccnc(C#N)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 330.6 %

Procedure:
At room temperature, a soln. of 4-[(2,2-Dimethyl-propyl)-(4-iodo-benzyl)-amino]-pyrimidine-2-carbonitrile (2 g, 4.9 mmoles) and ethynyl-trimethyl-silane (3.47 ml, 24.7 mmoles) in 20 ml of DMF is treated with triethylamine (2.6 ml, 14.8 mmoles), CuI (93 mg, 0.5 mmoles) and (Ph3P)2PdCl2 (0.2 g, 0.2 mmoles). The mixture is stirred at rt for overnight. Water is added and the organic layer is extracted with AcOEt, washed with brine, dried over magnesium sulfate and concentrated. The crude product is purified by silica gel column chromatography to give 6.1 g of desired 4-[(2,2-dimethyl-propyl)-(4-trimethylsilanylethynyl-benzyl)-amino]-pyrimidine-2-carbonitrile in 82% yield. Rf=0.52 (Hexane:AcOEt=1:1)
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][CH2:6][C:7]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=1[O:14][CH3:15])C.CC(C[AlH]CC(C)C)C.CO.Cl>C1(C)C=CC=CC=1>[F:13][C:11]1[CH:10]=[CH:9][C:8]([O:14][CH3:15])=[C:7]([CH2:6][CH2:5][CH:4]=[O:3])[CH:12]=1
Reactant: CCOC(=O)CCc1cc(F)ccc1OC
Agent: CC(C)C[AlH]CC(C)C
Agent: Cl
Solvent: CO
Solvent: Cc1ccccc1
Product: COc1ccc(F)cc1CCC=O
Temperature: 0 °C
Reaction time: 2 h
Yield: 66.2 %

Procedure:
To a solution of ethyl-3-(5′-fluoro-2′-methoxyphenyl)propionate (5.8 g, 25.7 mmol) in dry toluene (40 mL) under Ar was added DIBAL solution (1 M in toluene, 30 mL, 30 mmol) at −78° C. The reaction was stirred at this temperature for 2 h. Methanol (2 mL) was added to the reaction mixture and the reaction was allowed to warm to 0° C. The reaction mixture was then poured into a separatory funnel containing HCl solution (1 N, 150 mL). The organic function was extracted with ethyl acetate (3×100 mL) and the combined organic layers were washed with brine (80 mL) and dried over sodium sulfate. The crude product that was obtained after removal of the solvent in vacuo was purified by flash column chromatography (20% EtOAc in hexane, Rf=0.20) to give the product (3.1 g, 66%).
Reaction SMILES: [CH2:1]([N:8]1[C:12]([C:13]([F:16])([F:15])[F:14])=[CH:11][C:10]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)=[C:9]1[C:24]([N:26]([CH2:28][C:29]([C:32](=O)[NH2:33])([CH3:31])[CH3:30])[CH3:27])=[O:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OC(C(F)(F)F)=O)(C(F)(F)F)=O.Cl.C(Cl)Cl>N1C=CC=CC=1>[CH2:1]([N:8]1[C:12]([C:13]([F:14])([F:15])[F:16])=[CH:11][C:10]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)=[C:9]1[C:24]([N:26]([CH2:28][C:29]([C:32]#[N:33])([CH3:30])[CH3:31])[CH3:27])=[O:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(CC(C)(C)C(N)=O)C(=O)c1c(-c2ccc(Cl)cc2)cc(C(F)(F)F)n1Cc1ccccc1
Agent: Cl
Solvent: ClCCl
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: c1ccncc1
Product: CN(CC(C)(C)C#N)C(=O)c1c(-c2ccc(Cl)cc2)cc(C(F)(F)F)n1Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 82.5 %

Procedure:
To a stirred solution of SC-174 (235 mg, 0.478 mmol) in pyridine (4.83 mL) was added at 0° C. TFAA (0.153 mL, 1.099 mmol) under a nitrogen atmosphere. The reaction mixture was stirred at room temperature for 30 min. Aqueous 1 M HCl (20 mL) and DCM (10 mL) were added and the aqueous layer was set to pH 2 with aqueous 5 M HCl (10 mL). The layers were separated and extracted twice with DCM (10 mL). The combined organic layers were concentrated in vacuo. Purification was performed with flash chromatography (silica, gradient heptane/EtOAc, 1:0→0:1). The appropriate fractions were combined and solvents removed in vacuo to give SC-187 (187 mg, 82%) as a yellow foam.
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[C@@H:4]2[CH2:5][C:6]3[C:10]([C@H:3]12)=[C:9]([CH3:11])[S:8][C:7]=3[C:12]([OH:14])=O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)C(C)C)C.Cl.[NH2:48][CH2:49][C:50]1[CH:55]=[CH:54][C:53]([OH:56])=[CH:52][CH:51]=1>CN(C=O)C.C(O)=O>[OH:56][C:53]1[CH:54]=[CH:55][C:50]([CH2:49][NH:48][C:12]([C:7]2[S:8][C:9]([CH3:11])=[C:10]3[C:6]=2[CH2:5][C@H:4]2[C:2]([CH3:1])([CH3:15])[C@H:3]23)=[O:14])=[CH:51][CH:52]=1
Reactant: Cc1sc(C(=O)O)c2c1[C@H]1[C@@H](C2)C1(C)C
Reactant: NCc1ccc(O)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O=CO
Product: Cc1sc(C(=O)NCc2ccc(O)cc2)c2c1[C@H]1[C@@H](C2)C1(C)C
Reaction time: 0.33 h
Yield: 27.5 %

Procedure:
A solution of (1aS,5aR)-1,1,2-trimethyl-1,1a,5,5a-tetrahydro-3-thia-cyclopropa[a]pentalene-4-carboxylic acid (111 mg, 0.50 mmol), TBTU (177 mg, 0.55 mmol) and ethyl-diisopropylamine (282 μL, 1.65 mmol) in DMF (15 mL) is allowed to stand at rt for 20 min. A solution of 4-aminomethyl-phenol hydrochloride (88 mg, 0.55 mmol) and ethyl-diisopropylamine (94 μL, 0.55 mmol) in DMF (1.5 mL) is added and the mixture is allowed to stand at rt for 3 h. After the addition of formic acid (0.2 mL), the mixture is separated by HPLC to afford (1aS,5aR)-1,1,2-trimethyl-1,1a,5,5a-tetrahydro-3-thia-cyclopropa[a]pentalene-4-carboxylic acid 4-hydroxy-benzylamide (45 mg) as a colourless oil. LC-MS: tR=0.96 min, [M+1]+=328.17.