Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]=[CH:16][CH2:17][CH2:18][OH:19])=[CH:11][CH:10]=1)C1C=CC=CC=1.[H][H]>CO.C1COCC1.[C].[Pd]>[OH:19][CH2:18][CH2:17][CH2:16][CH2:15][C:12]1[CH:11]=[CH:10][C:9]([OH:8])=[CH:14][CH:13]=1
Reactant: OCCC=Cc1ccc(OCc2ccccc2)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: OCCCCc1ccc(O)cc1
Yield: 99 %

Procedure:
4-(4-benzyloxyphenyl)-3-buten-1-ol (1.70 g) was dissolved in a mixture of methanol-THF (1:1, 20 ml); 10% palladium carbon (0.17 g) was added, followed by vigorous stirring in a hydrogen atmosphere for 1.5 hours. The catalyst was filtered off; the filtrate was concentrated under reduced pressure to yield the titled compound (1.1 g) as a colorless crystalline powder.
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH3:7])=[C:5]([C:8]([F:11])([F:10])[F:9])[C:4]([C:12]([OH:14])=O)=[CH:3]1.C(Cl)(=O)C(Cl)=O.CN(C=O)C.[C:26]1([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:27]([NH2:32])=[CH:28][CH:29]=[CH:30][CH:31]=1>C(Cl)Cl.C(N(CC)CC)C>[C:26]1([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[NH:32][C:12]([C:4]1[C:5]([C:8]([F:9])([F:10])[F:11])=[C:6]([CH3:7])[N:2]([CH3:1])[CH:3]=1)=[O:14]
Reactant: Cc1c(C(F)(F)F)c(C(=O)O)cn1C
Reactant: Nc1ccccc1-c1ccccc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1c(C(F)(F)F)c(C(=O)Nc2ccccc2-c2ccccc2)cn1C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 1,5-dimethyl-4-trifluoromethylpyrrol-3-carboxylic acid (1.9 g) and oxalyl chloride (0.9 ml) in methylene chloride (20 ml) is stirred at room temperature in the presence of a catalytic amount of DMF. The solvent is evaporated under reduced pressure to give a crystalline solid. This solid is dissolved in methylene chloride (1 ml) and added to a solution of 2-biphenylamine (1.7 g) and triethylamine (4.2 ml) in methylene chloride (20 ml) at 0° C. The reaction mixture is stirred at room temperature for 2 hours. Evaporation of the solvent under reduced pressure, addition of water and filtering gives the N-(2-biphenylyl)-1,5-dimethyl-4-trifluoromethylpyrrol-3-carboxamide.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](=[O:32])[NH:20][C:21]3[CH:30]=[N:29][C:28]4[C:23](=[CH:24][CH:25]=[C:26]([Cl:31])[CH:27]=4)[N:22]=3)=[CH:15][CH:14]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:33]([O:35]CC)=[O:34].[OH-].[Na+].C(O)C>C1COCC1.C(OCC)(=O)C.Cl>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:14]=[CH:15][C:16]([C:19](=[O:32])[NH:20][C:21]3[CH:30]=[N:29][C:28]4[C:23](=[CH:24][CH:25]=[C:26]([Cl:31])[CH:27]=4)[N:22]=3)=[CH:17][CH:18]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:33]([OH:35])=[O:34]
Reactant: CCOC(=O)C1CCOc2cc(Oc3ccc(C(=O)Nc4cnc5cc(Cl)ccc5n4)cc3)c(Cl)cc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCO
Product: O=C(Nc1cnc2cc(Cl)ccc2n1)c1ccc(Oc2cc3c(cc2Cl)C(C(=O)O)CCO3)cc1
Reaction time: 2 h
Yield: 82.3 %

Procedure:
Ethyl 6-chloro-7-(4-(6-chloroquinoxalin-2-ylcarbamoyl)phenoxy)chroman-4-carboxylate (540 mg, 1.00 mmol) was diluted with THF (8 mL) followed by the addition of NaOH (5015 μL, 5.02 mmol) and ethanol (4 mL). After stirring for 2 hours, the reaction was diluted with ethyl acetate and 0.5 M HCl. The layers were separated and the organic layer was dried over MgSO4, filtered and concentrated. The material was triturated with DCM to provide the desired product (420 mg, 0.823 mmol, 82.1% yield). MS (ESI)=510.1 (M+1).
Reaction SMILES: C(OC(=O)[NH:10][C:11]1([CH2:16][CH3:17])[CH2:15][CH:14]=[CH:13][CH2:12]1)C1C=CC=CC=1.[ClH:19]>CO.[Pd]>[ClH:19].[CH2:16]([C:11]1([NH2:10])[CH2:15][CH2:14][CH2:13][CH2:12]1)[CH3:17]
Reactant: CCC1(NC(=O)OCc2ccccc2)CC=CC1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CCC1(N)CCCC1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
To a solution of benzyl(1-ethylcyclopent-3-en-1-yl)carbamate (1.3 g, 5.3 mmol) in methanol (20 mL) was added palladium on charcoal (130 mg, 10%). The reaction mixture was stirred at 50° C. under hydrogen atmosphere overnight. A solution of hydrochloric acid (20 mL, 1 mol/L in methanol) was added to the reaction and the reaction mixture was filtered through celite. The filtrate was concentrated under reduced pressure to give the crude product (900 mg), which was used for the next step without further purification. MS (ESI) m/z=114.2 [M+H]+
Reaction SMILES: [N:1]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7][C:2]=1[CH2:3][C:4]([OH:6])=O.O.ON1C2C=CC=CC=2N=N1.C1(N=C=NC2CCCCC2)CCCCC1.[NH2:41][CH:42]([C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1)[CH2:43][CH2:44][N:45]1[CH2:50][CH2:49][CH2:48][CH2:47][CH2:46]1>C(OCC)(=O)C>[C:51]1([CH:42]([NH:41][C:4]([CH2:3][C:2]2[CH:7]=[CH:8][C:9]3[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=3)[N:1]=2)=[O:6])[CH2:43][CH2:44][N:45]2[CH2:50][CH2:49][CH2:48][CH2:47][CH2:46]2)[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=1
Reactant: NC(CCN1CCCCC1)c1ccccc1
Reactant: O=C(O)Cc1ccc2ccccc2n1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(Cc1ccc2ccccc2n1)NC(CCN1CCCCC1)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 79.2 %

Procedure:
To a solution of 1.73 g (10 mmol.) of quinaldinic acid and 1.53 g (10 mmol.) of 1-hydroxybenzotriazole monohydrate in 50 ml of ethyl acetate was dropwise added over a period of 20 min. under chilling with ice a solution of 2.06 g (10 mmol.) of N,N'-dicyclohexylcarbodiimide in 10 ml of ethyl acetate. After the addition was complete, the resulting mixture was stirred for 2 hours at room temperature and chilled with ice. To the chilled mixture was dropwise added over a period of 30 min. a solution of 2.18 g (10 mmol.) of 1-(3-amino-3-phenylpropyl)piperidine in 8 ml of ethyl acetate. After the addition was complete, the mixture was stirred overnight at room temperature. Precipitated insolubles were filtered off and then the insolubles were washed with ethyl acetate. The filtrate and the washings were combined and washed twice with a saturated aqueous sodium hydrogencarbonate solution and once with a saturated aqueous sodium chloride solution. The mixture was then dried over sodium sulfate, and was evaporated under reduced pressure to remove the solvent. The residue was crystallized after addition of n-hexane. The resulting crystals were washed three times with n-hexane and dissolved in 35 ml of ethyl acetate. The resulting solution was allowed to stand overnight in a refrigerator. Precipitated insolubles were filtered off and the insolubles were washed with ethyl acetate. The filtrate and the washings were combined and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (silica gel: 40 g, CHCl3 and CHCl3 /CH3OH (30:1)) to obtain 3.07 g (yield: 82%) of the subject compound as a pale yellow crystalline product.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][C:13]1([C:28]([OH:30])=O)[CH2:18][CH2:17][CH2:16][N:15]([C:19]([O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25])=[O:20])[CH2:14]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClCCCl.CCN(C(C)C)C(C)C.[C:44]1([NH2:50])[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1>C(Cl)Cl>[CH2:1]([O:8][C:9]([NH:11][CH2:12][C:13]1([C:28](=[O:30])[NH:50][C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[CH2:18][CH2:17][CH2:16][N:15]([C:19]([O:21][CH2:22][CH2:23][Si:24]([CH3:26])([CH3:27])[CH3:25])=[O:20])[CH2:14]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)CCOC(=O)N1CCCC(CNC(=O)OCc2ccccc2)(C(=O)O)C1
Reactant: Nc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Solvent: ClCCl
Product: C[Si](C)(C)CCOC(=O)N1CCCC(CNC(=O)OCc2ccccc2)(C(=O)Nc2ccccc2)C1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 90.1 %

Procedure:
To a solution of 3-((((benzyloxy)carbonyl)amino)methyl)-1-((2-(trimethylsilyl)ethoxy)carbonyl)piperidine-3-carboxylic acid (2462.00 mg; 5.64 mmol; 1.00 eq.) in DCE (4.0 ml) bis(2-oxo-1,3-oxazolidin-3-yl)phosphinic chloride (1435.59 mg; 5.64 mmol; 1.00 eq.) was added. After stirring for 15 mins at RT, DIEA (1.52 ml; 8.46 mmol; 1.50 eq.) and Phenylamine (525.18 mg; 5.64 mmol; 1.00 eq.) were added. The reaction mixture was stirred overnight at RT. The reaction mixture was added 50 ml of DCM, washed with brine, dried and concentrated. The residue was subjected to SNAP column (100 g) for purification, eluted with 20-50% EtOAc in hexane to yield the title compound (2600 mg, yield 90.1%)
Reaction SMILES: [NH2:1][C:2]1[S:6][N:5]=[N:4][CH:3]=1.[C:7]1([N:13]=[C:14]=[O:15])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>C(N(CC)CC)C.O1CCCC1>[C:7]1([NH:13][C:14]([NH:1][C:2]2[S:6][N:5]=[N:4][CH:3]=2)=[O:15])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=C=Nc1ccccc1
Reactant: Nc1cnns1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(Nc1ccccc1)Nc1cnns1
Reaction time: 8 h

Procedure:
Combine 10.1 g (0.1 mole) 5-amino-1,2,3-thiadiazole, 75 ml of tetrahydrofurane and 11.5 ml (0.106 mole) of phenyl isocyanate. Further add 0.1 ml of triethylamine as catalyst. After standing overnight, the first crystals will have precipitated. The solvent is removed by evaporation under vacuum, and the residue is recrystallized from isopropanol.
Reaction SMILES: [C:1]([C:3]1[CH:15]=[CH:14][C:6]([O:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:5][CH:4]=1)#[CH:2].I[C:17]1[CH:18]=[C:19]([OH:23])[CH:20]=[CH:21][CH:22]=1.CCN(C(C)C)C(C)C.[Cl-].[NH4+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I.O.CN(C=O)C>[OH:23][C:19]1[CH:18]=[C:17]([C:2]#[C:1][C:3]2[CH:15]=[CH:14][C:6]([O:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:5][CH:4]=2)[CH:22]=[CH:21][CH:20]=1
Reactant: Oc1cccc(I)c1
Reactant: C#Cc1ccc(OCC(=O)OCC)cc1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)COc1ccc(C#Cc2cccc(O)c2)cc1

Procedure:
To a dried Schlenk flask filled with nitrogen was added Pd(PPh3)4 (17.3 mg, 0.015 mmol), CuI (6.6 mg, 0.035 mmol), ethyl 2-(4-ethynylphenoxy)acetate (60.6 mg, 0.294 mmol), and 3-iodophenol (78.4 mg, 0.352 mmol) was added. The flask was evacuated, equipped with a septum, and filled with nitrogen. DMF (5 mL) and DIPEA (0.1 mL, 0.6 mmol) were added through the septum. The reaction was stirred over night and was neutralized with saturated aqueous ammonium chloride (5 mL). Water (5 mL) was added and the mixture was extracted with EtOAc (3×10 mL). The combined EtOAc phases was washed with brine, dried over MgSO4, and concentrated under reduced pressure. The product was purified on a dry silica column (EtOAc:hexanes 1:90→90:1 v/v). The final product was yellow/orange and solid (52 mg, 60%). Rf=0.46 (EtOAc:hexanes 1:1 v/v). 1H-NMR (DMSO-d6): □ 1.22 (t, 3H, J=7.7 Hz, CH2CH3); 4.18 (q, 2H, J=7.5 Hz, CH2CH3); 4.84 (s, 2H, OCH2); 6.9 (m, 5H, Ph); 7.20 (t, 1H, J=8.0 Hz, Ph); 7.49 (m, 2H, Ph); 9.67 (s, 1H, OH). 13C-NMR (DMSO-d6): □ 14.0 (CH2CH3); 60.7 (CH2CH3); 64.7 (OCH2); 88.3 (CC); 88.6 (CC); 115.0, 116.0, 117.6, 122.1, 123.4, 128.4, 129.8, 132.9, 157.3, 157.8 (Ph); 168.5 (COO).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:38]#[N:39])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:30][CH:31]3[CH2:36][CH2:35][CH2:34][CH2:33][O:32]3)[C:17]([NH:19][C:20]3[CH:29]=[CH:28][CH:27]=[CH:26][C:21]=3[C:22]([O:24]C)=[O:23])=[O:18])[C:10](=[O:37])[CH:9]=2)[CH:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CO.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:38]#[N:39])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:30][CH:31]3[CH2:36][CH2:35][CH2:34][CH2:33][O:32]3)[C:17]([NH:19][C:20]3[CH:29]=[CH:28][CH:27]=[CH:26][C:21]=3[C:22]([OH:24])=[O:23])=[O:18])[C:10](=[O:37])[CH:9]=2)[CH:7]=1
Reactant: COC(=O)c1ccccc1NC(=O)C(CC1CCCCO1)n1cc(OC)c(-c2cc(Cl)ccc2C#N)cc1=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CO
Solvent: O
Product: COc1cn(C(CC2CCCCO2)C(=O)Nc2ccccc2C(=O)O)c(=O)cc1-c1cc(Cl)ccc1C#N

Procedure:
1.24 g (2.25 mmol) of methyl ({2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-[tetrahydro-2H-pyran-2-yl]propanoyl}amino)benzoate (mixture of racemic diastereomers) in 30 ml of methanol/water (4/1) were reacted with 1.47 g (4.51 mmol) of caesium carbonate according to General Method 4. Yield: 1.17 g (85% of theory)
Reaction SMILES: [CH2:1]1[O:10][C:9]2[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=2[O:2]1.[C:11]1([C:17]([CH:19]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)O)=O)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C1(C)C(C)=CC=CC=1>C(Cl)(Cl)Cl.C1(C)C=CC(S(O)(=O)=O)=CC=1>[C:11]1([C:17]2[NH:6][C:5]3[CH:4]=[C:3]4[O:2][CH2:1][O:10][C:9]4=[CH:8][C:7]=3[C:19]=2[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Nc1ccc2c(c1)OCO2
Reactant: O=C(c1ccccc1)C(O)c1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1C
Solvent: ClC(Cl)Cl
Product: c1ccc(-c2[nH]c3cc4c(cc3c2-c2ccccc2)OCO4)cc1
Temperature: 25 °C
Yield: 91.6 %

Procedure:
A flask equipped with a Dean-Stark apparatus was charged with 3,4-(methylenedioxy)aniline (5.0 g, 36.4 mmol), p-toluenesulfonic acid (245 mg, 1.2 mmol), benzoin (5.20 g, 24.4 mmol), and xylene (30 mL). The mixture was heated to reflux for 10 hours, then cooled to room temperature. The reaction mixture was diluted with chloroform, then washed twice with 10% sulfuric acid, once with water, and once with brine. The organic layer was concentrated to a minimum volume and petroleum ether was added. The mixture was stirred well and then the precipitated solid was filtered off and dried to give Intermediate 3A (7.0 g, 92%). HPLC: RT=2.261 min (H2O/MeCN with NH4OAc, PUROSPHER® Star RP-18 3 μM, 4×55 mm, gradient=3 min, wavelength=220 nm); MS(ES, negative ionization): m/z=312 [M−H]−.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][N:7]=[CH:6][CH:5]=1.[H][H].[C:12]([OH:15])(=[O:14])[CH3:13]>[Pt]=O>[C:12]([OH:15])(=[O:14])[CH3:13].[OH:1][CH2:2][CH2:3][CH:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1
Reactant: [H][H]
Reactant: OCCc1ccncc1
Agent: O=[Pt]
Solvent: CC(=O)O
Product: OCCC1CCNCC1
Yield: 100 %

Procedure:
Combined 4-(2-hydroxyeth-1-yl)pyridine (25 g, 0.2 mol) and platinum oxide (1 g, 4.4 mmol) in 400 mL acetic acid. Placed under 45 psi hydrogen at 60° C. for 24 h. Decanted, then filtered through Celite and removed the solvent to afford 38 g (100%) of the crude product, which was used without further purification.
Reaction SMILES: [C:1]([O:5][C:6](=[O:29])[NH:7][CH:8]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH2:16][CH:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[CH:30]([C:32]1[CH:48]=[CH:47][C:35]([C:36]([O:38][CH2:39][CH2:40][CH2:41][CH:42]2[O:46][CH2:45][CH2:44][O:43]2)=[O:37])=[CH:34][CH:33]=1)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[C:1]([O:5][C:6]([NH:7][CH:8]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:9]1[CH:10]=[C:11]([CH:12]=[CH:13][CH:14]=1)[O:15][CH2:16][CH:17]1[CH2:18][CH2:19][N:20]([CH2:30][C:32]2[CH:33]=[CH:34][C:35]([C:36]([O:38][CH2:39][CH2:40][CH2:41][CH:42]3[O:43][CH2:44][CH2:45][O:46]3)=[O:37])=[CH:47][CH:48]=2)[CH2:21][CH2:22]1)=[O:29])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC(c1ccccc1)c1cccc(OCC2CCNCC2)c1
Reactant: O=Cc1ccc(C(=O)OCCCC2OCCO2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC(c1ccccc1)c1cccc(OCC2CCN(Cc3ccc(C(=O)OCCCC4OCCO4)cc3)CC2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 52.4 %

Procedure:
To a stirred solution of tert-butyl(phenyl(3-(piperidin-4-ylmethoxy)phenyl)-methyl)carbamate (0.335 g, 0.84 mmol) and 3-(1,3-dioxolan-2-yl)propyl 4-formylbenzoate (0.706 g, 2.67 mmol) in DCM (5 mL), was added sodium triacetoxyborohydride (0.213 g, 1.01 mmol). The reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was diluted with DCM and washed with water, saturated aqueous sodium hydrogen carbonate, and brine. The organic phase was dried with anhydrous magnesium sulfate, and the solvent evaporated at reduced pressure. The residue was triturated with iso-hexane/diethyl ether (3:1) to afford the title compound (0.286 g, 0.44 mmol).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.O.O.[F:11][C:12]([F:20])([F:19])[C:13]([C:15]([F:18])([F:17])[F:16])=[O:14]>C(OCC)(=O)C.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:13]([OH:14])([C:15]([F:18])([F:17])[F:16])[C:12]([F:20])([F:19])[F:11])=[CH:4][CH:3]=1
Reactant: Nc1ccccc1
Reactant: O=C(C(F)(F)F)C(F)(F)F
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CCOC(C)=O
Product: Nc1ccc(C(O)(C(F)(F)F)C(F)(F)F)cc1
Temperature: 90 °C
Reaction time: 18 h
Yield: 45.2 %

Procedure:
A neat solution of aniline (4.3 mL, 47 mmol) and p-toluenesulfonic acid monohydrate (85 mg, 0.45 mmol) in a round bottom flask equipped with a reflux condenser was heated to 90° C. and hexafluoroacetone trihydrate (7 mL, 50 mmol) added over 15 minutes via syringe. Following addition, the temperature was increased to 130° C. and the resulting solution stirred over 18 h. The reaction mixture was cooled to room temperature and diluted with ethyl acetate. The organics were washed with saturated NaHCO3 solution then brine. The solution was dried over MgSO4 and the solvent removed in vacuo. The residue was purified by flash chromatography (4:1 hexanes/EtOAc) to give the title product as a white crystalline solid (5.5 g, 45%). MS (ES+) m/z 260 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:38][CH3:39])=[C:6]([CH:8]([O:30][Si](C(C)(C)C)(C)C)[C:9]2[C:10]([F:29])=[N:11][C:12]([F:28])=[C:13]([Sn:15]([CH2:24][CH2:25][CH2:26][CH3:27])([CH2:20][CH2:21][CH2:22][CH3:23])[CH2:16][CH2:17][CH2:18][CH3:19])[CH:14]=2)[CH:7]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C(OCC)C.[Cl-].[NH4+]>C1COCC1.C(Cl)Cl.O.[Ru]([O-])(=O)(=O)=O.C([N+](CCC)(CCC)CCC)CC>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:38][CH3:39])=[C:6]([C:8]([C:9]2[C:10]([F:29])=[N:11][C:12]([F:28])=[C:13]([Sn:15]([CH2:16][CH2:17][CH2:18][CH3:19])([CH2:20][CH2:21][CH2:22][CH3:23])[CH2:24][CH2:25][CH2:26][CH3:27])[CH:14]=2)=[O:30])[CH:7]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cc(C(O[Si](C)(C)C(C)(C)C)c2cc(Br)ccc2OC)c(F)nc1F
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: CCC[N+](CCC)(CCC)CCC
Solvent: ClCCl
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1cc(C(=O)c2cc(Br)ccc2OC)c(F)nc1F
Reaction time: 0.08 h

Procedure:
3-((5-Bromo-2-methoxyphenyl)(tert-butyldimethylsilyloxy)methyl)-2,6-difluoro-5-(tributylstannyl)pyridine (1.17 g, 1.595 mmol) was dissolved in dry THF (10 mL). Tetrabutylammonium fluoride (2.2 mL, 2.200 mmol) was added and the reaction stirred for 5 minutes. Water (100 mL), diethyl ether (100 mL) and saturated ammonium chloride (10 mL) were added. The phases were mixed and separated and the organic dried with magnesium sulfate before evaporating to dryness under reduced pressure. The crude alcohol was dissolved in DCM (50 mL) and treated with 4-methylmorpholine n-oxide (0.467 g, 3.99 mmol) followed by tetrapropylammonium perruthenate (0.056 g, 0.160 mmol). The dark yellow solution was stirred for 15 minutes until it turned black. The solution was diluted with DCM (50 mL) and water (100 mL). The phases were mixed, filtered through a pad of celite and separated and the organic dried with magnesium sulfate before evaporating to dryness under reduced pressure. The crude was purified using silica chromatography (hexane to DCM gradient) to give (5-bromo-2-methoxyphenyl)(2,6-difluoro-5-(tributylstannyl)pyridin-3-yl)methanone.
Reaction SMILES: O[CH2:2][C@@H:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])O)[OH:4].S(=O)(=O)(O)O.[OH-].[Na+].S(OC)(OC)(=O)=O>C1(C)C(C)=CC=CC=1>[CH2:11]1[O:12][C@@H:5]2[C@@H:3]([OH:4])[CH2:2][O:8][C@@H:7]2[C@@H:9]1[OH:10]
Reactant: OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)CO
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: COS(=O)(=O)OC
Solvent: Cc1ccccc1C
Product: O[C@@H]1CO[C@H]2[C@@H]1OC[C@@H]2O
Yield: 83.5 %

Procedure:
1.548 g (8.5 mol) of sorbitol, 3,000 ml of xylene and 20 ml of concentrated sulfuric acid were heated to reflux with stirring and about 306 ml of water were removed. The xylene was then removed by distillation (the last amount under vacuum) and the residue was taken up in 3,000 ml of tert.-butanol, heated to 55° to 65° C., 2,432 ml (30.4 mol) of an aqueous solution of sodium hydroxide and 2,682 g (21.25 mol) of dimethyl sulfate were added dropwise simultaneously at this temperature while keeping the mixture always alkaline. When the addition is completed, the mixture was stirred for three hours at 60° C. and the alcohol was then removed up to a distillation temperature of 97° to 98° C. The residue was taken up in 8,500 ml of water and the aqueous solution was extracted three times with 1,000 ml portions of ethylene chloride. The solvent was evaporated from the combined organic phases and was fractioned in a column to recover the fraction in the boiling range of 118° to 120° C. mbar which was 1,037 g (70% yield) of dimthyl isosorbide.
Reaction SMILES: [CH3:1][C:2]([NH:4][C@@H:5]1[C:21]2[C:14](=[CH:15][CH:16]=[C:17](OC)[C:18]([CH:20]=2)=[O:19])[C:13]2[C:12]([O:24][CH3:25])=[C:11]([O:26][CH3:27])[C:10]([O:28][CH3:29])=[CH:9][C:8]=2[CH2:7][CH2:6]1)=[O:3].[CH3:30][S-:31].[Na+]>O>[CH3:1][C:2]([NH:4][C@@H:5]1[C:21]2[C:14](=[CH:15][CH:16]=[C:17]([S:31][CH3:30])[C:18]([CH:20]=2)=[O:19])[C:13]2[C:8](=[CH:9][C:10]([O:28][CH3:29])=[C:11]([O:26][CH3:27])[C:12]=2[O:24][CH3:25])[CH2:7][CH2:6]1)=[O:3]
Reactant: C[S-]
Reactant: COc1cc2c(c(OC)c1OC)-c1ccc(OC)c(=O)cc1[C@@H](NC(C)=O)CC2
Agent: [Na+]
Solvent: O
Product: COc1cc2c(c(OC)c1OC)-c1ccc(SC)c(=O)cc1[C@@H](NC(C)=O)CC2
Reaction time: 24 h

Procedure:
Colchicine (1.25 mmole) was dissolved in 10.0 mL of water to which was added sodium methanethiolate (7.13 mmol). The yellow solution was stirred for 24 hours, then extracted 3× with ETOH:Chloroform (1:1), then evaporated to yield the desired compound as yellow crystals.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:24]2[CH2:29][CH2:28][CH2:27][C@H:26]([NH:30]C(=O)OC(C)(C)C)[CH2:25]2)=[N:4][C:5]([N:8]2[C:16]3[CH:15]=[C:14]([C:17]4[CH:22]=[N:21][CH:20]=[C:19]([CH3:23])[N:18]=4)[N:13]=[CH:12][C:11]=3[CH:10]=[N:9]2)=[CH:6][N:7]=1.FC(F)(F)C(O)=O>ClCCl>[Cl:1][C:2]1[C:3]([N:24]2[CH2:29][CH2:28][CH2:27][C@H:26]([NH2:30])[CH2:25]2)=[N:4][C:5]([N:8]2[C:16]3[CH:15]=[C:14]([C:17]4[CH:22]=[N:21][CH:20]=[C:19]([CH3:23])[N:18]=4)[N:13]=[CH:12][C:11]=3[CH:10]=[N:9]2)=[CH:6][N:7]=1
Reactant: Cc1cncc(-c2cc3c(cn2)cnn3-c2cnc(Cl)c(N3CCC[C@H](NC(=O)OC(C)(C)C)C3)n2)n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cncc(-c2cc3c(cn2)cnn3-c2cnc(Cl)c(N3CCC[C@H](N)C3)n2)n1
Yield: 49.9 %

Procedure:
A solution of tert-butyl N-[(3S)-1-[3-chloro-6-[6-(6-methylpyrazin-2-yl)pyrazolo[4,3-c]pyridin-1-yl]pyrazin-2-yl]-3-piperidyl]carbamate (30 mg, 0.057 mmol) in dichloromethane 4.0 ml and trifluoroacetic acid (0.80 ml, 10 mmol) was stirred at RT 3 h. The reaction was concentrated and diluted with water then extracted with EtOAc. The aqueous layer was basified with 1M NaOH to pH 10 then extracted with EtOAc. The organic layers was dried with sodium sulfate, filtered, and concentrated in vacuum. The crude product was submitted for reverse phase HPLC to give 226 (12 mg, 49% yield). MS (ESI) m/z: 422.1.