Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([OH:9])=[CH:4][C:3]=1[N:10]1[C:14](=[O:15])[N:13]([CH2:16][CH2:17][CH3:18])[N:12]=[N:11]1.C(=O)([O-])[O-].[K+].[K+].I[CH:26]([CH3:28])[CH3:27]>CC(C)=O>[F:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([O:9][CH:26]([CH3:28])[CH3:27])=[CH:4][C:3]=1[N:10]1[C:14](=[O:15])[N:13]([CH2:16][CH2:17][CH3:18])[N:12]=[N:11]1
Reactant: CCCn1nnn(-c2cc(O)c(F)cc2F)c1=O
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCn1nnn(-c2cc(OC(C)C)c(F)cc2F)c1=O
Yield: 37.5 %

Procedure:
A stirred mixture of 0.87 g (0.0034 mole) of 1-(2,4-difluoro-5-hydroxyphenyl)-1,4-dihydro-4-propyl-5H-tetrazol-5-one, 0.7 g (0.0051 mole) of potassium carbonate, and 1.2 g (0.007 mole) of 2-iodopropane in 40 mL of acetone was heated at reflux for approximately 18 hours. The mixture was cooled, filtered, and the solvent evaporated under reduced pressure to leave an oil. The oil was purified by filtration through a small amount of silica gel followed by crystallization from heptane to yield 0.38 g of 1-[2,4-difluoro-5-(1-methylethoxy)phenyl]-1,4-dihydro-4-propyl-5H-tetrazol-5-one, mp 76.5°-77° C..
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].C[O:8][C:9]([C:11]1[CH:12]=[CH:13][C:14]2[O:19][C:18]([F:21])([F:20])[O:17][C:16]([F:23])([F:22])[C:15]=2[CH:24]=1)=O.O.[OH-].[Na+]>C1COCC1>[F:21][C:18]1([F:20])[O:17][C:16]([F:22])([F:23])[C:15]2[CH:24]=[C:11]([CH2:9][OH:8])[CH:12]=[CH:13][C:14]=2[O:19]1
Reactant: COC(=O)c1ccc2c(c1)C(F)(F)OC(F)(F)O2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: OCc1ccc2c(c1)C(F)(F)OC(F)(F)O2
Temperature: 0 °C
Reaction time: 1 h
Yield: 96.8 %

Procedure:
To a suspension of LAH (2.14 g, 56.4 mmol) in dry THF (200 mL) was added dropwise a solution of 2,2,4,4-tetrafluoro-4H-benzo[1,3]dioxine-6-carboxylic acid methyl ester (7.50 g, 28.2 mmol) in dry THF (50 mL) at 0° C. After being stirred at 0° C. for 1 h, the reaction mixture was treated with water (2.14 g) and 10% NaOH (2.14 mL). The slurry was filtered and washed with THF. The combined filtrates were evaporated to dryness to give the crude (2,2,4,4-tetrafluoro-4H-benzo[1,3]dioxin-6-yl)-methanol (6.5 g), which was used directly in the next step. 1H NMR (CDCl3, 300 MHz) δ 7.64 (s, 1 H), 7.57-7.60 (m, 1 H), 7.58 (d, J=8.7 Hz, 1 H), 4.75 (s, 2 H).
Reaction SMILES: [F:1][C:2]([F:30])([F:29])[C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][CH:7]=[C:6]2[O:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][O:19][C:20]1[C:21](=[O:28])[CH:22]=[C:23]([CH2:26][OH:27])[O:24][CH:25]=1.C(N(CC)CC)C.[CH3:38][S:39](Cl)(=[O:41])=[O:40]>C(Cl)Cl>[CH3:38][S:39]([O:27][CH2:26][C:23]1[O:24][CH:25]=[C:20]([O:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][O:13][C:6]2[C:5]3[C:10](=[CH:11][CH:12]=[C:3]([C:2]([F:1])([F:29])[F:30])[CH:4]=3)[N:9]=[CH:8][CH:7]=2)[C:21](=[O:28])[CH:22]=1)(=[O:41])=[O:40]
Reactant: O=c1cc(CO)occ1OCCCCCOc1ccnc2ccc(C(F)(F)F)cc12
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCc1cc(=O)c(OCCCCCOc2ccnc3ccc(C(F)(F)F)cc23)co1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 90.5 %

Procedure:
To a solution of 5-(5-(6-(trifluoromethyl)quinolin-4-yloxy)pentyloxy)-2-(hydroxymethyl)-4H-pyran-4-one 11 (93 mg, 0.22 mmol) in CH2Cl2 (5 mL) was added at 0° C. triethylamine (37 μL, 0.26 mmol), methanesulfonyl chloride (20.5 μL, 0.26 mmol). The solution was stirred at RT for 1.5 h. Dichloromethane (50 mL) was added and the solution was washed with water (2×100 mL), dried over MgSO4, filtered and evaporated. (5-(5-(6-(Trifluoromethyl)quinolin-4-yloxy)pentyloxy)-4-oxo-4H-pyran-2-yl)methyl methanesulfonate 16 was obtained (100 mg, 90.5% yield) as a pale yellow oil.
Reaction SMILES: C([O:4][C:5]1[CH:14]=[C:13]2[C:8]([CH2:9][CH2:10][N:11]3[CH:17]=[N:16][CH:15]=[C:12]32)=[CH:7][C:6]=1[O:18][CH3:19])(C)C.CS(O)(=O)=O>C(Cl)(Cl)Cl>[CH3:19][O:18][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][C:5]=1[OH:4])[C:12]1=[CH:15][N:16]=[CH:17][N:11]1[CH2:10][CH2:9]2
Reactant: COc1cc2c(cc1OC(C)C)-c1cncn1CC2
Agent: CS(=O)(=O)O
Solvent: ClC(Cl)Cl
Product: COc1cc2c(cc1O)-c1cncn1CC2
Temperature: 63 °C

Procedure:
To a 50 mL round bottom flask was added 9-isopropoxy-8-methoxy-5,6-dihydroimidazo[5,1-a]isoquinoline (180 mg, 0.70 mmol), chloroform (13 mL), and methanesulfonic acid (1.3 mL, 20.02 mmol). The resulting mixture was heated at 63° C. for 2 h then cooled to RT and concentrated in vacuo. To the resulting oil was added H2O and aqueous saturated sodium carbonate. The solution was extracted with EtOAc (2×), and the organic extracts were combined, dried with sodium sulfate and concentrated in vacuo to afford 8-methoxy-5,6-dihydroimidazo[5,1-a]isoquinolin-9-ol. (151 mg) MS [M+H+]=217.4.
Reaction SMILES: Cl[CH2:2][C:3](=[O:7])[CH2:4][CH2:5][CH3:6].[CH3:8][C:9]1[N:14]=[C:13]([NH:15][C:16](=[S:18])[S-:17])[CH:12]=[CH:11][CH:10]=1.C([NH+](CC)CC)C.C1CCCCC1>C(#N)C>[OH:7][C:3]1([CH2:4][CH2:5][CH3:6])[CH2:2][S:18][C:16](=[S:17])[N:15]1[C:13]1[CH:12]=[CH:11][CH:10]=[C:9]([CH3:8])[N:14]=1
Reactant: CCCC(=O)CCl
Reactant: Cc1cccc(NC(=S)[S-])n1
Agent: CC[NH+](CC)CC
Solvent: C1CCCCC1
Solvent: CC#N
Product: CCCC1(O)CSC(=S)N1c1cccc(C)n1
Temperature: 10 °C
Reaction time: 2 h
Yield: 80.6 %

Procedure:
1-Chloropentan-2-one (12.1 g) is added to a suspension of triethylammonium (6-methylpyrid-2-yl)dithiocarbamate (28.5 g) in anhydrous acetonitrile (200 cc) at a temperature between 15° and 25° C. The reaction is continued for 2 hours at 20°-25° C. The insoluble triethylamine hydrochloride is removed by filtration and washed twice with diethyl ether (60 cc. total). The solvents are evaporated under reduced pressure (20 mm.Hg) at 40° C. The residual oil is dissolved in a mixture of diethyl ether (100 cc) and methylene chloride (50 cc); the organic solution is washed twice with distilled water (total 100 cc), dried over sodium sulphate and evaporated. The crystals obtained (25.4 g; m.p. about 70° C.) are dissolved in boiling cyclohexane (500 cc) and the boiling solution is filtered. After cooling for 1 hour at about 10° C., the resulting crystals are separated by filtration, washed twice with cyclohexane (total 120 cc) cooled to 10° C., and dried under reduced pressure (0.1 mm.Hg) at 40° C. 4-Hydroxy-3-(6-methylpyrid-2-yl)-4-propylthiazolidine-2-thione (21.6 g), melting at 83° C., is thus obtained.
Reaction SMILES: [C-]#N.[Na+].Br[C:5]1[CH:10]=[CH:9][C:8]([C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:12])=[CH:7][CH:6]=1.[CH3:19][NH:20]CCNC.[OH-].[NH4+]>[Cu]I.O.C(OCC)(=O)C.C1(C)C=CC=CC=1>[C:11]([C:8]1[CH:9]=[CH:10][C:5]([C:19]#[N:20])=[CH:6][CH:7]=1)(=[O:12])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C(c1ccccc1)c1ccc(Br)cc1
Reactant: CNCCNC
Agent: [Cu]I
Agent: [C-]#N
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: Cc1ccccc1
Product: N#Cc1ccc(C(=O)c2ccccc2)cc1
Temperature: 110 °C
Reaction time: 24 h

Procedure:
An oven dried screw cap test tube was charged with NaCN (91 mg, 1.857 mmol), dried KI (51 mg, 0.307 mmol, 20 mol %), CuI (30 mg, 0.157 mmol, 10 mol %), (4-bromophenyl)-phenyl-methanon (404 mg, 1.548 mmol), evacuated and backfilled with argon three times. N,N′-dimethylethylenediamine (165 μL, 1.550 mmol) and anhydrous toluene (1 mL) were added under argon. The tube was sealed and the reaction mixture was stirred magnetically at 110° C. for 24 h. The resulting suspension was cooled to room temperature, 2 mL of ethyl acetate, 1 mL of ammonium hydroxide (30%) and 1 mL of water were added. The mixture was stirred at 25° C. for 10 min then the organic layer was washed with 1 mL of water and dried over MgSO4. The GC analysis showed complete conversion of starting material with formation of title product (confirmed by GC-MS).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][NH2:14].[C:15]1([C:21]2[O:25][C:24]([C:26](Cl)=[O:27])=[N:23][N:22]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(N(CC)CC)C.C(OCC)(=O)C>ClCCl>[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][NH:14][C:26]([C:24]1[O:25][C:21]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)=[N:22][N:23]=1)=[O:27]
Reactant: NCCc1c[nH]c2ccc(Cl)cc12
Reactant: O=C(Cl)c1nnc(-c2ccccc2)o1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1nnc(-c2ccccc2)o1
Yield: 34.3 %

Procedure:
This compound was obtained following Method B starting from 2-(5-chloro-1H-indol-3-yl)ethanamine hydrochloride (0.0417 g, 0.177 mmol), 5-phenyl-1,3,4-oxadiazole-2-carbonyl chloride (0.041 g; 0.177 mmol), and triethylamine (0.0621 mL; 0.442 mmol) in dichloromethane (3 mL). Flash chromatography on silica gel eluting with 2 to 16% of ethyl acetate in dichloromethane gave 0.0223 g (34%) of N-(2-(5-chloro-1H-indol-3-yl)ethyl)-5-phenyl-1,3,4-oxadiazole-2-carboxamide as a solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]#[C:9][C@@H:10]2[CH2:15][CH2:14][C@@H:13]([CH3:16])[N:12](CC3C=CC(OC)=CC=3)[CH2:11]2)=[N:6][CH:7]=1.C(N(CC)CC)C.ClC(OC(Cl)C)=O.ClC(OCCCl)=O>C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]#[C:9][C@@H:10]2[CH2:15][CH2:14][C@@H:13]([CH3:16])[NH:12][CH2:11]2)=[N:6][CH:7]=1
Reactant: COc1ccc(CN2C[C@H](C#Cc3ccc(F)cn3)CC[C@H]2C)cc1
Agent: CC(Cl)OC(=O)Cl
Agent: O=C(Cl)OCCCl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@@H]1CC[C@@H](C#Cc2ccc(F)cn2)CN1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 5-fluoro-2-{[(3S,6R)-1-(4-methoxybenzyl)-6-methylpiperidin-3-yl]ethynyl}pyridine (276 mg, 0.82 mmol) and triethylamine (0.23 mL, 1.6 mmol) in CH2Cl2 (5 mL) was cooled at 0° C. and treated with 1-chloroethyl chloroformate (0.18 mL, 1.6 mmol) and allowed to warm to ambient temperature. After stirring overnight, additional triethylamine (0.20 mL) and chloroethyl chloroformate (0.15 mL) was added and the reaction stirred overnight again. The reaction was quenched by addition of 1N NaOH. The layers were separated and the aqueous phase was extracted with CH2Cl2. The organics were washed with brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. The crude residue was taken up in MeOH and heated at reflux for 2 h. The reaction was concentrated in vacuo. The crude material was purified by silica gel flash chromatography eluting with 0-10% MeOH in CH2Cl2 to provide 5-fluoro-2-{[(3S,6R)-6-methylpiperidin-3-yl]ethynyl}pyridine as an orange solid which gave a proton NMR spectra consistent with theory and a mass ion (ES+) of 219.3 for M+H+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:11]O)[CH:5]=[C:6]([F:10])[C:7]=1[S:8][CH3:9].CS([Cl:17])(=O)=O.C(N(C(C)C)CC)(C)C.Cl>ClCCl>[Cl:17][CH2:11][C:4]1[CH:5]=[C:6]([F:10])[C:7]([S:8][CH3:9])=[C:2]([F:1])[CH:3]=1
Reactant: CS(=O)(=O)Cl
Reactant: CSc1c(F)cc(CO)cc1F
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CSc1c(F)cc(CCl)cc1F
Temperature: 25 °C
Reaction time: 18 h
Yield: 94.7 %

Procedure:
To a solution of [3,5-difluoro-4-(methylthio)-phenyl]-methanol (24.0 g, 0.126 mol) in dichloromethane (300 mL) cooled in an ice bath was added methanesulfonylchloride (16.9 g, 0.147 mol) in portions followed by diisopropyl-ethylamine in portions. The mixture was allowed to warm to room temperature, and stirred for 18 hours. 4-dimethyl-aminopyridine was added and the mixture was heated to reflux for 2 hours, cooled, and stirred at room temperature for 18 hours. The mixture was poured into dilute HCl and extracted with dichloromethane once (75 mL) after separating. The combined extracts were washed with dilute sodium chloride, dried using magnesium sulfate, and concentrated. Purification by silica gel chromatography using 5% ethyl acetate in hexanes gave 5-(chloromethyl)-1,3-difluoro-2-(methylthio)benzene as a clear colorless liquid (24.9 g, 95%). 1H NMR (CDCl3/400 MHz) 6.92-6.96 (m, 2H), 4.49 (s, 2H), 2.44 (s, 3H). HRMS m/z 207.9893 (M+, calcd 207.9925).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:15]([NH:23][C:24]([CH:26]2[CH2:29][CH2:28][CH2:27]2)=[O:25])[C:16]2[C:21]([Cl:22])=[N:20][CH:19]=[CH:18][N:17]=2)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:30]1(C(O)=O)CCC1>>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:15]([NH:23][C:24]([CH:26]2[CH2:27][CH2:28][CH2:29][CH2:30]2)=[O:25])[C:16]2[C:21]([Cl:22])=[N:20][CH:19]=[CH:18][N:17]=2)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(NC(c1cccc(OCc2ccccc2)c1)c1nccnc1Cl)C1CCC1
Reactant: O=C(O)C1CCC1
Product: O=C(NC(c1cccc(OCc2ccccc2)c1)c1nccnc1Cl)C1CCCC1

Procedure:
Cyclopentanecarboxylic acid [(3-benzyloxy-phenyl)-(3-chloro-pyrazin-2-yl)-methyl]-amide (compound of Formula II where R1=cyclopentyl and Q1=Ph-(3-OBn)) was prepared according to the procedures described for the synthesis of cyclobutanecarboxylic acid [(3-benzyloxy-phenyl)-(3-chloro-pyrazin-2-yl)-methyl]amide (compound of Formula III where R1=cyclobutyl and Q1=Ph-(3-OBn)) above except for the substitution of cyclopentane carboxylic acid for cyclobutanecarboxylic acid; MS (ES) 422.2 (M+1), 424.2 (M+3).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]([CH3:24])[C:10]([C:13]([CH3:23])([CH3:22])[CH:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[OH:15])=[N:11][N:12]=1>[O-2].[O-2].[Mn+4].C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]([CH3:24])[C:10]([C:13]([CH3:22])([CH3:23])[C:14]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[O:15])=[N:11][N:12]=1
Reactant: Cn1c(-c2ccccc2Cl)nnc1C(C)(C)C(O)c1ccccc1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: Cn1c(-c2ccccc2Cl)nnc1C(C)(C)C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 73.7 %

Procedure:
Manganese dioxide (955 mg) was gradually added to a methylene chloride (4.8 ml) solution of 2-[5-(2-chlorophenyl)-4-methyl-4H-1,2,4-triazol-3-yl]-2-methyl-1-phenylpropan-1-ol (191 mg) under ice cooling. The reaction mixture was stirred at room temperature for 3 hours and then manganese dioxide (955 mg) was added thereto, followed by stirring at room temperature for another 18.5 hours. Then, the mixture was subjected to filtration through celite. The filtrate was subjected to evaporation under reduced pressure and then purified by silica gel column chromatography (chloroform:methanol=50:1) to obtain 2-[5-(2-chlorophenyl)-4-methyl-4H-1,2,4-triazol-3-yl]-2-methyl-1-phenylpropan-1-one (140 mg).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]1([C:16]#N)[CH2:15][CH2:14][CH2:13][CH2:12]1.ClC1C=CC(Cl)=CC=1C1(C=[O:32])CCCC1>>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]1([CH:16]=[O:32])[CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: O=CC1(c2cc(Cl)ccc2Cl)CCCC1
Reactant: N#CC1(c2ccc3ccccc3c2)CCCC1
Product: O=CC1(c2ccc3ccccc3c2)CCCC1
Yield: 82.77 %

Procedure:
1-Naphthalen-2-yl-cyclopentanecarbaldehyde (212) (21.0 g, 82.77%) was synthesized as a colourless liquid from 1-naphthalen-2-yl-cyclopentanecarbonitrile (211) (25.0 g, 113.12 mmol) following the procedure described for 1-(2,5-dichlorophenyl)-cyclopentanecarbaldehyde (199).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]([C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1)=[O:11].F[C:20]1[C:25]([C:26]2([F:32])[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)=[N:24][CH:23]=[CH:22][N:21]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN1CCCC1=O>[NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]([C:12]1[CH:17]=[CH:16][C:15]([O:18][C:20]2[C:25]([C:26]3([F:32])[CH2:27][CH2:28][O:29][CH2:30][CH2:31]3)=[N:24][CH:23]=[CH:22][N:21]=2)=[CH:14][CH:13]=1)=[O:11]
Reactant: Fc1nccnc1C1(F)CCOCC1
Reactant: O=C(c1ccc(O)cc1)c1nc2ccccc2[nH]1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Product: O=C(c1ccc(Oc2nccnc2C2(F)CCOCC2)cc1)c1nc2ccccc2[nH]1

Procedure:
A solution of (1H-benzo[d]imidazol-2-yl)(4-hydroxyphenyl)methanone (0.543 g, 2.278 mmol),2-fluoro-3-(4-fluorotetrahydro-2H-pyran-4-yl)pyrazine (0.304 g, 1.519 mmol), cesium carbonate (0.990 g, 3.04 mmol), and N-Methyl-2-pyrrolidinone (3.04 mL) in a sealed tube was heated to 100° C. overnight. Aqueous work up with DCM and washing with alternating water and brine washes. The organic layer was rotovapped and loaded onto a Biotage samplet. Purification by Biotage (0-100% EtOAc/hexane, slow gradient, over 12 CV). The product containing fractions were concentrated by rotovap. The residue was further purified by trituration with EtOH at room temperature overnight to produce product. MS (ESI, pos. ion) m/z: 419.1 (M+1). IC50 (uM) +++++.
Reaction SMILES: C1(CCCN)C=CC=CC=1.[CH2:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:13][N:12]1[C:20]([NH:22][C:23]1[N:28]=[N:27][C:26]([C:29]([OH:31])=O)=[CH:25][CH:24]=1)=[O:21].C1C2C(=CC=CC=2)CN1C([NH:43][C:44]1C=C[C:47]([C:48]([OH:50])=O)=[CH:46][CH:45]=1)=O>>[O:50]1[CH2:48][CH2:47][CH2:46][C@@H:45]1[CH2:44][NH:43][C:29]([C:26]1[N:27]=[N:28][C:23]([NH:22][C:20]([N:12]2[CH2:11][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:13]2)=[O:21])=[CH:24][CH:25]=1)=[O:31]
Reactant: O=C(O)c1ccc(NC(=O)N2Cc3ccccc3C2)cc1
Reactant: O=C(O)c1ccc(NC(=O)N2Cc3ccccc3C2)nn1
Agent: NCCCc1ccccc1
Product: O=C(NC[C@H]1CCCO1)c1ccc(NC(=O)N2Cc3ccccc3C2)nn1

Procedure:
The title compound was prepared as described in Example 1C, substituting (R)-(tetrahydrofuran-2-yl)methamine for 3-phenylpropan-1-amine and 6-(isoindoline-2-carboxamido)pyridazine-3-carboxylic acid for 4-(isoindoline-2-carboxamido)benzoic acid. 1H NMR (300 MHz, DMSO-d6) δ 10.02 (s, 1H), 8.85 (t, J=6.1 Hz, 1H), 8.32 (d, J=9.3 Hz, 1H), 8.12 (d, J=9.3 Hz, 1H), 7.41-7.28 (m, 4H), 5.00-4.71 (m, 4H), 4.04 (p, J=6.2 Hz, 1H), 3.85-3.74 (m, 1H), 3.70-3.58 (m, 1H), 3.44-3.33 (m, 3H), 1.99-1.71 (m, 2H), 1.69-1.54 (m, 1H); MS (ESI(+)) m/e 368 (M+H)+.
Reaction SMILES: C[C:2]1([CH3:9])[O:6][C@@H:5]([CH2:7][OH:8])[CH2:4][O:3]1.[I:10][C:11]1[CH:18]=[CH:17]C(CBr)=[CH:13][CH:12]=1.[OH-].[K+].O>C1(C)C=CC=CC=1>[I:10][C:11]1[CH:18]=[CH:17][C:9]([CH2:2][O:3][CH2:4][C@H:5]([OH:6])[CH2:7][OH:8])=[CH:13][CH:12]=1
Reactant: CC1(C)OC[C@H](CO)O1
Reactant: BrCc1ccc(I)cc1
Agent: [K+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O
Product: OC[C@@H](O)COCc1ccc(I)cc1
Yield: 88.9 %

Procedure:
(S)-(+)-2,2-Dimethyl-1,3-dioxolane-4-methanol (6, 1.17 g, 8.9 mmol) and 4-iodobenzylbromide (2.5 g, 8.4 mmol) were refluxed under Dean-Stark conditions in toluene (80 mL) in the presence of KOH (8.8 g, 154.0 mmol) for 12 h. The reaction mixture was allowed to cool down and H2O (30 mL) was added. After separation of the phases the water layer was washed with toluene (2×15 mL). Combined organic layers were washed with H2O (30 mL) and concentrated in vacuo. The residue was treated with 80% aq. AcOH (25 mL) for 48 h at rt. The solvent was removed in vacuo and the residue was co-evaporated twice with toluene/EtOH (30 mL, 5:1, v/v). The residue was dried under diminished pressure to afford (R)-3-(4-iodobenzyloxy)propane-1,2-diol (7, 100%, 2.3 g) as yellowish oil that was used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][CH:17]=1)[CH2:5][O:6][CH2:7][C:8]1[N:13]=[C:12]([NH2:14])[CH:11]=[CH:10][CH:9]=1.[Cl:18][C:19]1[CH:24]=[C:23]([Cl:25])[CH:22]=[C:21]([CH3:26])[C:20]=1[S:27](Cl)(=[O:29])=[O:28]>>[Cl:18][C:19]1[CH:24]=[C:23]([Cl:25])[CH:22]=[C:21]([CH3:26])[C:20]=1[S:27]([NH:14][C:12]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:7][O:6][CH2:5][C:4]2[CH:15]=[CH:16][CH:17]=[C:2]([Cl:1])[CH:3]=2)[N:13]=1)(=[O:29])=[O:28]
Reactant: Cc1cc(Cl)cc(Cl)c1S(=O)(=O)Cl
Reactant: Nc1cccc(COCc2cccc(Cl)c2)n1
Product: Cc1cc(Cl)cc(Cl)c1S(=O)(=O)Nc1cccc(COCc2cccc(Cl)c2)n1

Procedure:
This material was prepared in analogy to example 1 from 6-(3-chloro-benzyloxymethyl)-pyridin-2-ylamine (0.08 g) and 2,4-dichloro-6-methyl-benzenesulfonyl chloride (0.092g) as a light yellow gum (0.039 g). MS (ESI−): 469.0 ([M−H]−).
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10]O)[CH2:2][CH2:3][CH3:4].[CH2:12]([O:19][C:20]1[CH:29]=[CH:28][CH:27]=[C:26]2[C:21]=1[CH2:22][CH2:23][CH2:24][CH:25]2[C:30]([N:32]([C:39]1[CH:40]=[N:41][C:42]([CH:45]([CH3:47])[CH3:46])=[CH:43][CH:44]=1)[CH2:33][C:34]1[CH:35]=[N:36][NH:37][CH:38]=1)=[O:31])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[CH2:12]([O:19][C:20]1[CH:29]=[CH:28][CH:27]=[C:26]2[C:21]=1[CH2:22][CH2:23][CH2:24][CH:25]2[C:30]([N:32]([CH2:33][C:34]1[CH:35]=[N:36][N:37]([CH2:10][CH2:9][O:8][CH2:7][CH2:6][O:5][CH2:1][CH2:2][CH2:3][CH3:4])[CH:38]=1)[C:39]1[CH:40]=[N:41][C:42]([CH:45]([CH3:47])[CH3:46])=[CH:43][CH:44]=1)=[O:31])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CC(C)c1ccc(N(Cc2cn[nH]c2)C(=O)C2CCCc3c(OCc4ccccc4)cccc32)cn1
Reactant: CCCCOCCOCCO
Product: CCCCOCCOCCn1cc(CN(C(=O)C2CCCc3c(OCc4ccccc4)cccc32)c2ccc(C(C)C)nc2)cn1

Procedure:
By the reaction and treatment of diethylene glycol monobutyl ether (1.0 mL) and 5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-[(pyrazol-4-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.96 g) in the same manner as in Example 394, 5-benzyloxy-N-({1-[2-(2-butoxyethoxy)ethyl]pyrazol-4-yl}methyl)-N-(6-isopropylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (1.94 g) was obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:9]2[N:10]=[C:11]([NH2:20])[S:12][C:13]=2[C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)[CH:5]=[C:6]([CH3:8])[CH:7]=1.[CH2:21]([N:24]=[C:25]=[O:26])[CH2:22][CH3:23].C(=O)([O-])O.[Na+]>CN(C)C(=O)C>[CH3:1][C:2]1[CH:3]=[C:4]([C:9]2[N:10]=[C:11]([NH:20][C:25]([NH:24][CH2:21][CH2:22][CH3:23])=[O:26])[S:12][C:13]=2[C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)[CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: Cc1cc(C)cc(-c2nc(N)sc2-c2ccncc2)c1
Reactant: CCCN=C=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: CCCNC(=O)Nc1nc(-c2cc(C)cc(C)c2)c(-c2ccncc2)s1
Temperature: 80 °C
Reaction time: 14 h
Yield: 34.9 %

Procedure:
To a solution of [4-(3,5-dimethylphenyl)-5-(4-pyridyl)-1,3-thiazol-2-yl]amine (0.51 g, 1.8 mmol) in N,N-dimethylacetamide (15 mL) was added propyl isocyanate (0.23 g, 2.67 mmol) and the mixture was stirred at 80° C. for 14 h. To the reaction mixture was poured aqueous sodium hydrogencarbonate solution and the precipitated solid was collected by filtration. The obtained solid was washed with water and dried. The crude crystals were recrystallized from ethanol to give the title compound (0.23 g, yield 33%).
Reaction SMILES: F[C:2]1(OC#CC)[CH:7]=C(F)C=C[CH2:3]1.[Br:13][C:14]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=1[OH:21]>>[Br:13][C:14]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=1[O:21][CH2:7][C:2]#[CH:3]
Reactant: Oc1ccc(F)cc1Br
Reactant: CC#COC1(F)C=C(F)C=CC1
Product: C#CCOc1ccc(F)cc1Br

Procedure:
This compound was prepared analogously to 2,4-difluoro-2-prop-ynyloxy-benzene but using 2-bromo-4-fluoro-phenol (15 g, 78 mmol) to give 2-bromo-4-fluoro-1-prop-2-ynyloxy-benzene 15. g (84%).
Reaction SMILES: [CH3:1][S@@:2]([C:4]([CH3:7])([CH3:6])[CH3:5])=[O:3].[C:8]([Mg]Cl)(C)([CH3:10])[CH3:9].C[Mg]Br>C1COCC1>[CH2:1]([S@:2]([C:4]([CH3:7])([CH3:6])[CH3:5])=[O:3])[CH:8]([CH3:10])[CH3:9]
Reactant: C[S@](=O)C(C)(C)C
Reactant: CC(C)(C)[Mg]Cl
Agent: C[Mg]Br
Solvent: C1CCOC1
Product: CC(C)C[S@@](=O)C(C)(C)C
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 83 %

Procedure:
Preparation of (S)-t-butyl methyl sulfoxide from (2S,4S,5R)-3-(2,4,6-mesitylsulfonyl)-3,3a,8,8a-tetrahydro-1-oxa-2-thia-3-aza-cyclopenta[a]indene 2-oxide (one pot procedure): A solution of (2S,4S,5R)-3-(2,4,6-mesitylsulfonyl)-3,3a,8,8a-tetrahydro-1-oxa-2-thia-3-aza-cyclopenta[a]indene 2-oxide (1.44 g, 3.82 mmol) in THF at −15° C. was slowly added to t-BuMgCl (4.0 mL, 1.0M) in THF, and the reaction mixture was stirred (1-2 hours) until the reaction complete as monitored by TLC. Methyl magnesium bromide (4.4 mL, 1.0 M) in THF was then added, the reaction mixture was warmed to room temperature and stirred for 1-2 hours. The reaction was monitored by TLC. After the reaction mixture was cooled to 0° C., the reaction was quenched by addition of saturated aq. NH4Cl (5 mL), stirred and diluted with EtOAc (5 mL). The aqueous phase was extracted with EtOAc (5 mL×2) and the organic solvent was evaporated. The residue was purified on silica gel eluted with EtOAc/MeOH (8:2) to give the title product (0.38 g, 83%).