Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si:1]([O:8][CH:9]([CH2:27][O:28][Si](C(C)(C)C)(C)C)[CH:10]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[C@H:11]([F:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C1COCC1>N1C=CC=CC=1>[Si:1]([O:8][CH:9]([CH2:27][OH:28])[CH:10]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[C@H:11]([F:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NC(C(CO[Si](C)(C)C(C)(C)C)O[Si](C)(C)C(C)(C)C)[C@H](F)c1ccccc1
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC(C(CO)O[Si](C)(C)C(C)(C)C)[C@H](F)c1ccccc1
Reaction time: 6 h

Procedure:
To a plastic bottle containing (R)-tert-butyl 3,4-bis(tert-butyldimethylsilyloxy)-1-fluoro-1-phenylbutan-2-ylcarbamate was added 10 ml THF, 3 ml pyridine, 1 ml HF-pyr at 0° C. The mixture was stirred for 6 h and then carefully quench with sodium bicarbonate. The aq. layer was extracted with DCM (4×25 ml). The combined organics were washed with brine, dried with sodium sulfate, filtered, concentrated and the crude purified on a 40 g ISCO column to give 225 mg of the title compound.
Reaction SMILES: S(=O)(=O)(O)O.[CH3:6][N:7]1[CH2:12][CH2:11][N:10]([CH:13]2[CH2:19][CH2:18][C:17]3[CH:20]=[CH:21][CH:22]=[CH:23][C:16]=3[CH:15](O)[CH2:14]2)[CH2:9][CH2:8]1>O1CCOCC1>[CH3:6][N:7]1[CH2:8][CH2:9][N:10]([CH:13]2[CH:14]=[CH:15][C:16]3[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=3[CH2:18][CH2:19]2)[CH2:11][CH2:12]1
Reactant: CN1CCN(C2CCc3ccccc3C(O)C2)CC1
Agent: O=S(=O)(O)O
Solvent: C1COCCO1
Product: CN1CCN(C2C=Cc3ccccc3CC2)CC1
Temperature: 20 °C
Yield: 74 %

Procedure:
18 ml of 18 N sulfuric acid were added to a refluxing solution of 9 g of the product of Step B in 180 ml of dioxane and the mixture was refluxed for 30 minutes and then was concentrated and cooled to 20° C. 100 ml of ice-water were added thereto and the mixture was extracted with ethyl acetate. The aqueous phase was made alkaline with concentrated ammonium hydroxide and was extracted with methylene chloride. The organic phase was dried and evaporated to dryness to obtain 6.2 g of 7-(4-methylpiperazin-1-yl)-6,7-dihydro [5H] benzocycloheptene.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[CH:6]=[CH:7][CH:8]=[N+:9]([O-])[C:10]=2[CH:11]=1.C1(C)C=CC(S(Cl)(=O)=[O:20])=CC=1.C(=O)([O-])[O-].[K+].[K+].O>C(Cl)(Cl)Cl>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](=[O:20])[NH:9]2)=[N:4][CH:3]=1
Reactant: [O-][n+]1cccc2ncc(Br)cc21
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClC(Cl)Cl
Product: O=c1ccc2ncc(Br)cc2[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 78 %

Procedure:
To a solution of 0.50 g of 3-bromo-1,5-naphthyridin-5-oxide in 10 mL of chloroform, 0.51 g of p-toluenesulfonyl chloride, 1.04 g of potassium carbonate and 3 mL of water were added, and the mixture was stirred at room temperature overnight. Thereto were added water and chloroform, and the solid was filtered off to obtain 0.39 g of 7-bromo-1,5-naphthyridin-2(1H)-one as a white solid.
Reaction SMILES: CC([S@@]([NH:7][C@H:8]([C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][N:20]=2)=[CH:15][CH:14]=1)[CH2:9][CH:10]([CH3:12])[CH3:11])=O)(C)C.Cl.C(OCC)C>CO>[CH3:11][CH:10]([CH3:12])[CH2:9][C@@H:8]([C:13]1[CH:14]=[CH:15][C:16]([C:19]2[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:26])[F:27])=[CH:21][N:20]=2)=[CH:17][CH:18]=1)[NH2:7]
Reactant: CC(C)C[C@H](N[S@@](=O)C(C)(C)C)c1ccc(-c2ccc(C(F)(F)F)cn2)cc1
Agent: Cl
Solvent: CCOCC
Solvent: CO
Product: CC(C)C[C@H](N)c1ccc(-c2ccc(C(F)(F)F)cn2)cc1
Reaction time: 1 h

Procedure:
A cooled solution (0° C. by internal thermometer) of (S,S)-2-methyl-N-(3-methyl-1-{4-[5-(trifluoromethyl)pyridin-2-yl]phenyl}butyl)propane-2-sulfinamide (74.0 g, 179 mmol) in methanol (0.90 L) was treated with 2.0M hydrochloric acid in diethylether (233 ml, 466 mmol) dropwise while maintaining the reaction temperature below 15° C. Following 1 hour, the solvent was removed in vacuo and the resulting oil was treated with diethylether to precipitate the product as a fine white solid. The solid was collected via filtration, and washed with diethylether (3×100 ml). The remaining solid was dried in vacuo. The crude material was used for further transformations.
Reaction SMILES: [O:1]=[C:2]1[CH:7]=[C:6]([C:8]([OH:10])=[O:9])[O:5][C:4]2[C:11]([CH2:19][C:20](=O)[CH3:21])=[C:12]3[C:17](=[CH:18][C:3]1=2)[CH2:16][CH2:15][CH2:14][CH2:13]3.[OH-].[Na+].[BH4-].[Na+].Cl>O>[O:1]=[C:2]1[CH:7]=[C:6]([C:8]([OH:10])=[O:9])[O:5][C:4]2[C:11]([CH2:19][CH2:20][CH3:21])=[C:12]3[C:17](=[CH:18][C:3]1=2)[CH2:16][CH2:15][CH2:14][CH2:13]3
Reactant: CC(=O)Cc1c2c(cc3c(=O)cc(C(=O)O)oc13)CCCC2
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Product: CCCc1c2c(cc3c(=O)cc(C(=O)O)oc13)CCCC2

Procedure:
To a refluxing solution of 4-oxo-10-(2-oxopropyl)-6,7,8,9-tetrahydro-4H-naphtho[2,3-b]pyran-2-carboxylic acid (3.1 g) in water (100 ml) containing sodium hydroxide (0.12 g) was added portion-wise sodium borohydride (3.04 g). The resulting mixture was heated under reflux for 2 hours. After cooling the solution was acidified with concentrated hydrochloric acid and the precipitate filtered off, washed with water and dried giving the title compound as a white solid, mp 235°.
Reaction SMILES: [C:1]([O-])(=[O:3])[CH3:2].[O:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[N:7]=[C:6]1[N:14]([CH2:16][CH2:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][C:26](=[N+]=[N-])[C:27]([O:29][CH3:30])=[O:28])=[CH:21][CH:20]=1)[CH3:15].C(O)C>C1C=CC=CC=1>[O:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[N:7]=[C:6]1[N:14]([CH2:16][CH2:17][O:18][C:19]1[CH:20]=[CH:21][C:22]([CH2:25][CH:26]([O:3][CH2:1][CH3:2])[C:27]([O:29][CH3:30])=[O:28])=[CH:23][CH:24]=1)[CH3:15]
Reactant: CC(=O)[O-]
Reactant: COC(=O)C(Cc1ccc(OCCN(C)c2nc3ccccc3o2)cc1)=[N+]=[N-]
Solvent: c1ccccc1
Solvent: CCO
Product: CCOC(Cc1ccc(OCCN(C)c2nc3ccccc3o2)cc1)C(=O)OC
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Rodium (II) acetate dimer (33 mg) was added to a mixture of methyl 3-[4-[2- [N-(2-benzoxazolyl)-N-methylamino]ethoxy]phenyl]-2-diazopropanoate (2.80 g), ethanol (2.16 mL) and benzene (50 mL). The mixture was stirred at room temperature under a nitrogen atmosphere for 15 minutes, heated at reflux for a further 15 minutes, then cooled and evaporated in vacuo. The residue was chromotographed on silica gel using 1.5% methanol in dichloromethane as eluent to afford the title compound as a gum. 1H NMRδ(CDCl3) 1.14 (3H,t); 2.93 (2H,app d); 3.31 (1H,complex); 3.32 (3H,s); 3.57 (1H,complex); 3.69 (3H,s); 3.93 (3H,complex); 4.23 (2H,t);6.79 (2H,d); 7.00 (1H,t); 7.14 (3H,complex); 7.25 (1H,d); and 7.36 (1H,d).
Reaction SMILES: [N:1]1([CH2:6][CH:7]2[CH2:12][CH2:11][N:10]([C:13]3[CH:20]=[CH:19][C:16]([CH:17]=O)=[CH:15][CH:14]=3)[CH2:9][CH2:8]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:21][N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1>>[CH3:21][N:22]1[CH2:27][CH2:26][N:25]([CH2:17][C:16]2[CH:19]=[CH:20][C:13]([N:10]3[CH2:11][CH2:12][CH:7]([CH2:6][N:1]4[CH2:5][CH2:4][CH2:3][CH2:2]4)[CH2:8][CH2:9]3)=[CH:14][CH:15]=2)[CH2:24][CH2:23]1
Reactant: O=Cc1ccc(N2CCC(CN3CCCC3)CC2)cc1
Reactant: CN1CCNCC1
Product: CN1CCN(Cc2ccc(N3CCC(CN4CCCC4)CC3)cc2)CC1

Procedure:
Prepared from the product of Example 9 and N-methylpiperazine.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[NH:21][CH:20]=[CH:19]2.C([SiH](CC)CC)C.O.C(=O)(O)O>FC(F)(F)C(O)=O.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[NH:21][CH2:20][CH2:19]2
Reactant: COc1cc2nccc(Oc3ccc4[nH]ccc4c3)c2cc1OC
Agent: CC[SiH](CC)CC
Agent: O=C(O)O
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Solvent: O
Product: COc1cc2nccc(Oc3ccc4c(c3)CCN4)c2cc1OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 79.5 %

Procedure:
After dissolving 6,7-dimethoxy-4-(5-indolyloxy)quinoline (30 mg, 0.0780 mmol, described in WO9717329, p. 52) in trifluoroacetic acid (0.9 ml), triethylsilane (45 ml, 0.2808 mmol, 3.0 eqM) was added while cooling on ice, and the mixture was stirred for 4 hours and 30 minutes at room temperature under a nitrogen atmosphere. After cooling, the reaction solution was diluted with ethyl acetate, neutralized with saturated bicarbonate water, extracted with ethyl acetate, washed with saturated saline and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/ethanol system) to obtain the title compound (20 mg, 0.0620 mmol, 66.28%) as light yellow crystals.
Reaction SMILES: [Cl-].[CH:2]([S:4]([NH:7][CH2:8][CH2:9][NH3+:10])(=[O:6])=[O:5])=[CH2:3].C(N(CC)CC)C>CO>[S:4]1(=[O:6])(=[O:5])[CH2:2][CH2:3][NH:10][CH2:9][CH2:8][NH:7]1
Reactant: C=CS(=O)(=O)NCC[NH3+]
Agent: [Cl-]
Solvent: CO
Solvent: CCN(CC)CC
Product: O=S1(=O)CCNCCN1
Reaction time: 28 h

Procedure:
A solution of 2-[(vinylsulfonyl)amino]ethanaminium chloride (1.17 g, 6.24 mmol) in methanol (50 ml) at room temperature, was treated with triethylamine (0.87 mL, 6.24 mmol) and then stirred for 28 hr. Silica gel (10 g) was added to the solution. The solvent was evaporated in vacuo and the remaining silica gel was applied to a column of silica gel and chromatographed eluting with 4% ammonium hydroxide in acetonitrile to afford the title compound as an oil.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][N:7]1[C:19]2[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[N:12]=[C:11]([NH2:20])[C:10]=2[N:9]=[C:8]1[CH2:21][CH2:22][O:23][CH3:24].CCN(CC)CC.[CH3:32][S:33](Cl)(=[O:35])=[O:34]>C(Cl)Cl.CO.CCOCC>[NH2:20][C:11]1[C:10]2[N:9]=[C:8]([CH2:21][CH2:22][O:23][CH3:24])[N:7]([CH2:6][CH2:5][O:4][CH2:3][CH2:2][NH:1][S:33]([CH3:32])(=[O:35])=[O:34])[C:19]=2[C:18]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N:12]=1
Reactant: COCCc1nc2c(N)nc3ccccc3c2n1CCOCCN
Reactant: CS(=O)(=O)Cl
Solvent: CCOCC
Solvent: CO
Solvent: CCN(CC)CC
Product: COCCc1nc2c(N)nc3ccccc3c2n1CCOCCNS(C)(=O)=O
Temperature: 0 °C
Yield: 41.4 %

Procedure:
1-[2-(2-Aminoethoxy)ethyl]-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-4-amine (750 mg, 2.28 mmol) was dissolved in 30 mL of anhydrous CH2Cl2 and cooled to 0° C. under N2. To the stirred solution were added Et3N (0.64 mL, 4.56 mmol) and methanesulfonyl chloride (176 μL, 2.28 mmol) and the reaction was allowed to warm to room temperature over 2 h. The reaction mixture was then quenched by addition of saturated NaHCO3 solution (30 mL). The organic layer was separated and washed with H2O (3×25 mL) and brine, dried over Na2SO4 and concentrated under reduced pressure to give a tan foam. The foam was dissolved in a minimum amount of MeOH and Et2O was added and a solid percipitated from the solution. The off-white solid was isolated by filtration and dried to yield 385 mg of N-(2-{2-[4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]ethoxy}ethyl)methanesulfonamide. m.p. 114.0-117.0° C.;
Reaction SMILES: [CH2:1]([N:8]1[CH2:20][C@@H:19]2[C@H:10]([NH:11][CH2:12][C:13]3[C:14]([CH3:21])=[CH:15][CH:16]=[CH:17][C:18]=32)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:29](Cl)(=[O:31])[CH3:30]>C(Cl)Cl>[CH2:1]([N:8]1[CH2:20][C@@H:19]2[C@H:10]([N:11]([C:29](=[O:31])[CH3:30])[CH2:12][C:13]3[C:14]([CH3:21])=[CH:15][CH:16]=[CH:17][C:18]=32)[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)Cl
Reactant: Cc1cccc2c1CN[C@@H]1CN(Cc3ccccc3)C[C@@H]21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)N1Cc2c(C)cccc2[C@@H]2CN(Cc3ccccc3)C[C@H]21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (±)-trans-2-benzyl-6-methyl-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,4-c]isoquinoline from Example 105, Part A (28 mg, 0.1 mmol) in 1 mL of methylene chloride was added triethylamine (0.021 mL, 0.15 mmol) and acetyl chloride (0.009 mL, 0.15 mmol). The reaction was allowed to stir at ambient temperature for 2 h. The solution was concentrated and purified (ISCO, elution with 0-5% methanol/methylene chloride) to afford 25 mg of the title compound of Example 108 as an off-white solid. 1H NMR (CDCl3): δ 7.74-7.68 (m, 2H), 7.50-7.42 (m, 3H), 7.21-7.13 (m, 2H), 6.80-6.75 (m, 1H), 4.78 and 4.38 (ABq, 2H), 4.31-4.25 (m, 1H), 4.16-4.03 (m, 2H), 3.89-3.80 (m, 1H), 3.71-3.63 (m, 1H), 3.49 (s, 2H), 3.07-2.98 (m, 1H), 2.35 (s, 3H), 2.21 (s, 3H). LRMS (ESI): 321.3 (M+H)+.
Reaction SMILES: S(=O)(=O)(O)O.[N+:6]([O-:9])(O)=[O:7].[C:10]1([CH:16]2[CH2:21][CH2:20][CH2:19][N:18]3[CH:22]=[N:23][CH:24]=[C:17]23)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(=O)([O-])O.[Na+]>>[N+:6]([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[CH:16]1[CH2:21][CH2:20][CH2:19][N:18]2[CH:22]=[N:23][CH:24]=[C:17]12)([O-:9])=[O:7]
Reactant: c1ccc(C2CCCn3cncc32)cc1
Reactant: O=[N+]([O-])O
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: O=[N+]([O-])c1ccccc1C1CCCn2cncc21
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
0.055 ml of sulphuric acid is added slowly dropwise at 0° C. to 0.046 ml of nitric acid. The nitrating acid is subsequently added slowly dropwise at 0° C. to 0.69 mmol of 8-phenyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine. The reaction mixture is subsequently stirred at 0° C. for 5 minutes and then poured into ice-water. The aqueous phase is rendered neutral with saturated aqueous sodium hydrogen carbonate solution and extracted with dichloromethane (3×). The combined organic phases are dried over magnesium sulphate and evaporated. From the residue the title compound is obtained by means of flash chromatography (SiO2 60F) as a brown wax. Rf=0.25 (dichloromethane/ammonia (2M in EtOH) 97:3), Rt=5.10 (Gradient I).
Reaction SMILES: C(O[C:9]1[CH:14]=[CH:13][C:12]([N:15]2[C:19]([C:20]3[N:25]=[C:24]4[N:26]([CH:31]5[CH2:36][CH2:35][O:34][CH2:33][CH2:32]5)[N:27]=[C:28]([CH2:29][CH3:30])[C:23]4=[CH:22][CH:21]=3)=[CH:18][CH:17]=[N:16]2)=[CH:11][CH:10]=1)C1C=CC=CC=1.C([OH:39])C>[Pd]>[CH2:29]([C:28]1[C:23]2[C:24](=[N:25][C:20]([C:19]3[N:15]([C:12]4[CH:13]=[C:14]([OH:39])[CH:9]=[CH:10][CH:11]=4)[N:16]=[CH:17][CH:18]=3)=[CH:21][CH:22]=2)[N:26]([CH:31]2[CH2:36][CH2:35][O:34][CH2:33][CH2:32]2)[N:27]=1)[CH3:30]
Reactant: CCc1nn(C2CCOCC2)c2nc(-c3ccnn3-c3ccc(OCc4ccccc4)cc3)ccc12
Reactant: CCO
Agent: [Pd]
Product: CCc1nn(C2CCOCC2)c2nc(-c3ccnn3-c3cccc(O)c3)ccc12
Reaction time: 4 h

Procedure:
6-{1-[4-(benzyloxy)phenyl]-1H-pyrazol-5-yl}-3-ethyl-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-b]pyridine (290 mg, 0.60 mmol) and ethanol (30 mL) were added to a Parr bottle. 10% Pd/C (150 mg, 0.14 mmol) was added, and the mixture was shaken under an atmosphere of hydrogen (45 psi) for 4 hours. The reaction was degassed under reduced pressure, flushed with argon for 5 minutes, filtered through Celite and concentrated to yield 0.23 g 3-{5-[3-ethyl-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-b]pyridin-6-yl]-1H-pyrazol-1-yl}phenol as an oil. LC/MS (EI) tR 2.87 (Method E), m/z 390.2 (M++1). 1H NMR (CDCl3) δ 1.4 (t, 3H); 1.7 (m, 2H); 2.2 (m, 2H); 3.0 (q, 2H); 3.5 (t, 2H); 4.0 (m, 2H); 4.5 (m, 1H); 6.7-6.9 (m, 3H); 7.0 (s, 1H); 7.2 (m, 1H); 7.3 (d, 2H); 7.7 (s, 1H); 8.0 (m, 1H).
Reaction SMILES: [OH-].[Na+].[C:3]([SH:7])([CH3:6])([CH3:5])[CH3:4].Cl[C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[C:11]([Cl:16])[CH:10]=1>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[Cl:16][C:11]1[CH:10]=[C:9]([CH2:4][C:3]([S:7][C:3]([CH3:6])([CH3:5])[CH2:4][C:9]2[CH:14]=[C:13]([Cl:15])[CH:12]=[C:11]([Cl:16])[CH:10]=2)([CH3:6])[CH3:5])[CH:14]=[C:13]([Cl:15])[CH:12]=1
Reactant: Clc1cc(Cl)cc(Cl)c1
Reactant: CC(C)(C)S
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Product: CC(C)(Cc1cc(Cl)cc(Cl)c1)SC(C)(C)Cc1cc(Cl)cc(Cl)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 19 %

Procedure:
To a solution of 4N sodium hydroxide (0.8 ml) was added tert-butylmercaptan (0.406 ml). The mixture was stirred for 15 minutes at room temperature. Tetra n-butylammonium bromide (322 mg, 1 mmol) and 1,3,5-trichlorobenzene (1) (1.8 g, 10 mmol) were added thereto. The reaction mixture was refluxed at 140° C. for 6.5 hours. The reaction mixture was poured into ice-water, extracted with ethylacetate, washed with water, dried over sodium sulphate, filtrated and concentrated under reduced pressure. The obtained residue was chromatographed twice on silica gel (SiO2 15 g, elution: n-hexane) to yield the objective (4) (138 mg). Yield 19%.
Reaction SMILES: [C:1]([OH:13])(=O)[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[NH2:14][C:15]1[NH:19][N:18]=[N:17][N:16]=1.O>O1CCCC1.CN(C)C=O>[NH:16]1[C:15]([NH:14][C:1](=[O:13])[C:2]2[CH:11]=[CH:10][C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[N:3]=2)=[N:19][N:18]=[N:17]1
Reactant: O=C(O)c1ccc2ccccc2n1
Reactant: Nc1nnn[nH]1
Solvent: O
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: O=C(Nc1nnn[nH]1)c1ccc2ccccc2n1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Quinaldic acid (1.1 g) in tetrahydrofuran (50 ml) containing dimethylformamide (5 ml) was treated with a solution of N,N'-carbonyl diimidazole (1 g) in tetrahydrofuran (40 ml) containing dimethylformamide (5 ml). After 3 hours, 5-aminotetrazole (0.65 g) in dimethylformamide (30 ml) was added and the resulting solution was stirred for 2 days at room temperature. The solvent was distilled off under reduced pressure to give an oil which solidified on trituration with water, m.p. 258° (d).
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[C:3]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[N:5]([CH2:12][C:13]([NH:15][C:16]2[S:20][C:19]3[CH2:21][CH2:22][CH2:23][CH2:24][C:18]=3[C:17]=2[C:25](O)=[O:26])=[O:14])[N:4]=1.N=C=N.[CH2:33]([NH2:35])[CH3:34]>C(Cl)Cl.CN(C=O)C>[CH2:33]([NH:35][C:25]([C:17]1[C:18]2[CH2:24][CH2:23][CH2:22][CH2:21][C:19]=2[S:20][C:16]=1[NH:15][C:13](=[O:14])[CH2:12][N:5]1[C:6]2[CH2:7][CH2:8][CH2:9][CH2:10][C:11]=2[C:3]([C:2]([F:28])([F:1])[F:29])=[N:4]1)=[O:26])[CH3:34]
Reactant: O=C(Cn1nc(C(F)(F)F)c2c1CCCC2)Nc1sc2c(c1C(=O)O)CCCC2
Reactant: CCN
Agent: N=C=N
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCNC(=O)c1c(NC(=O)Cn2nc(C(F)(F)F)c3c2CCCC3)sc2c1CCCC2
Yield: 6.4 %

Procedure:
2-[2-(3-Trifluoromethyl-4,5,6,7-tetrahydroindazol-1-yl)-acetylamino]-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylic acid (20 mg, 0.047 mmol) was dissolved in a solution of DCM (800 μL) and DMF (200 μL). Polymer supported carbodiimide (loading 1.22 mmol/g, 53 mg, 0.064 mmol) was added, followed by ethylamine (2.0 M solution in THF, 94.0 μl, 0.188 mmol). The resultant mixture was heated in a Biotage SmithCreator microwave at 120° C. for 15 min. The resin was filtered off and washed through with MeOH (2×50 mL), EtOAc (2×20 mL) and MeCN (2×20 mL). The combined filtrate was concentrated in vacuo, and the residue obtained purified by preparative reverse phase HPLC to afford the title compound as a white solid (1 mg, 0.003 mmol, 6%).
Reaction SMILES: [CH:1]([C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[O:8])=[CH:5][CH:4]=1)=[CH2:2].[CH2:11](O)[CH2:12][OH:13].C1(C)C=CC=CC=1>C1(C)C=CC(S(O)(=O)=O)=CC=1.O>[CH:1]([C:3]1[CH:10]=[CH:9][C:6]([CH:7]2[O:13][CH2:12][CH2:11][O:8]2)=[CH:5][CH:4]=1)=[CH2:2]
Reactant: OCCO
Reactant: C=Cc1ccc(C=O)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: C=Cc1ccc(C2OCCO2)cc1
Temperature: 45 °C
Yield: 96.3 %

Procedure:
In a 250 ml 3-necked round-bottomed flask, 13.72 g of (103 mmol) of 4-vinylbenzaldehyde, 7.08 g (114 mmol) of ethylene glycol and 0.23 g (1.3 mmol) of p-toluenesulfonic acid are added to 100 ml of toluene. The resulting mixture is refluxed at 45° C. under reduced pressure for 3 hours using a water separator. It is then washed twice with 100 ml of water, and the organic phase is dried over magnesium sulfate and concentrated to yield 17.47 g of crude product in the form of a pale yellow oil. The latter is distilled at 80° C./0.05 mbar. Yield: 12.81 g (72.7 mmol, 70.6% of the theoretical yield). 1H-NMR (CDCl3, 100 mHz): δ7.39/s/4H, 6.68/dd (J1 =11 Hz, J2 =18 Hz)/1H, 5.74/s/1H, 5.72 (J1 =18 Hz, J2 =2 Hz)/1H, 5.22/dd (J1 =11 Hz, J2 =2 Hz)/1H, 3.96/m/4H.
Reaction SMILES: [F:1][C:2]1[C:10]([CH2:11][NH:12][C:13]([C:15]([CH3:18])([CH3:17])[CH3:16])=[O:14])=[CH:9][CH:8]=[C:7]([Cl:19])[C:3]=1[C:4]([OH:6])=O.[NH2:20][C:21]1[CH:22]=[CH:23][C:24]([O:37][CH2:38][CH:39]([F:41])[F:40])=[C:25]([CH:36]=1)[C:26]([NH:28][C:29]1[CH:34]=[CH:33][C:32]([Br:35])=[CH:31][CH:30]=1)=[O:27].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C1COCC1>[F:41][CH:39]([F:40])[CH2:38][O:37][C:24]1[CH:23]=[CH:22][C:21]([NH:20][C:4](=[O:6])[C:3]2[C:7]([Cl:19])=[CH:8][CH:9]=[C:10]([CH2:11][NH:12][C:13]([C:15]([CH3:18])([CH3:17])[CH3:16])=[O:14])[C:2]=2[F:1])=[CH:36][C:25]=1[C:26]([NH:28][C:29]1[CH:34]=[CH:33][C:32]([Br:35])=[CH:31][CH:30]=1)=[O:27]
Reactant: Nc1ccc(OCC(F)F)c(C(=O)Nc2ccc(Br)cc2)c1
Reactant: CC(C)(C)C(=O)NCc1ccc(Cl)c(C(=O)O)c1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Product: CC(C)(C)C(=O)NCc1ccc(Cl)c(C(=O)Nc2ccc(OCC(F)F)c(C(=O)Nc3ccc(Br)cc3)c2)c1F

Procedure:
Prepared analogously to 43b from 2-fluoro-3-(tert-butylcarbonylamino-methyl)-6-chloro benzoic acid (41 mg; 0.13 mmol), 5-amino-N-(4-bromo-phenyl)-2-(2,2-difluoro-ethoxy)benzamide (50 mg; 0.13 mmol), HATU (54 mg; 0.14 mmol), TEA (0.066 mL; 0.47 mmol) in THF (2 mL).
Reaction SMILES: [CH3:1][S:2]([O:5][C:6]1[CH:13]=[CH:12][C:11]([O:14][S:15]([CH3:18])(=[O:17])=[O:16])=[CH:10][C:7]=1[CH:8]=[O:9])(=[O:4])=[O:3].[BH4-].[Na+]>C1COCC1.C(O)C>[CH3:1][S:2]([O:5][C:6]1[CH:13]=[CH:12][C:11]([O:14][S:15]([CH3:18])(=[O:17])=[O:16])=[CH:10][C:7]=1[CH2:8][OH:9])(=[O:3])=[O:4]
Reactant: CS(=O)(=O)Oc1ccc(OS(C)(=O)=O)c(C=O)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Product: CS(=O)(=O)Oc1ccc(OS(C)(=O)=O)c(CO)c1
Reaction time: 0.5 h

Procedure:
To a solution of the product from Step A (17.13 g, 58.2 mmol) in 150 mL of 2:1 THF/ethanol at 0° C. was added sodium borohydride (2.27 g, 60.0 mmol). After 30 minutes, the reaction was carefully quenched by the addition oc saturated NH4Cl solution, then partitioned between EtOAc and saturated NaHCO3 solution. The organic layer was washed with water and brine, dried (Na2SO4), filtered, and concentrated in vacuo. The product was isolated as a yellow oil which was used without further purification.
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]#[N:9])=[C:6](I)[C:5]([O:11][CH3:12])=[C:4]([O:13][CH3:14])[CH:3]=1.B([O-])O[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=1.C(=O)([O-])[O-].[Na+].[Na+].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>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.C(OCC)(=O)C.O1CCOCC1>[F:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)[C:5]([O:11][CH3:12])=[C:4]([O:13][CH3:14])[CH:3]=1
Reactant: [O-]BOc1ccccn1
Reactant: COc1cc(F)c(C#N)c(I)c1OC
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: COc1cc(F)c(C#N)c(-c2ccccn2)c1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 48 %

Procedure:
Stirred dioxane (20 ml) at 80° C. was charged with 6-fluoro-2-iodo-3,4-dimethoxybenzonitrile from Example 1(a) (1.0 g, 3.3 mmol), tetrakis(triphenylphosphine)palladium(0) (0.19 g, 0.16 mmol), the pyridyl boronate from step (a) above (6.1 g, estimated to be 9.9 mmol), copper(I)iodide (0.25 g, 1.3 mmol), sodium carbonate (0.69 g, 6.5 mmol) and triphenylphosphine (0.17 g, 0.65 mmol) and the resulting brown slurry heated to reflux and stirred at this temperature overnight. The resulting suspension was cooled to room temperature, ethyl acetate (20 ml) and water (10 ml) added and the resulting mixture filtered through Arbocel™ filter aid. The phases were separated and the aqueous phase extracted with ethyl acetate (2×20 ml). The organic phases were combined, washed with saturated aqueous NaCl and stripped to an oil. Acetonitrile was added and the mixture warmed then cooled. The resulting suspension was filtered to give a solid that was dried in vacuo overnight at 45° C. to give 0.419 of the product (48%).