Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[F:15])[C:6]2[CH:16]=[CH:17][CH:18]=[CH:19][C:5]=2[NH:4][C:3]1=[O:20].[C:21]1([CH3:31])[CH:26]=[CH:25][C:24]([S:27](Cl)(=[O:29])=[O:28])=[CH:23][CH:22]=1.C(N(CC)CC)C>C(Cl)Cl>[CH3:31][C:21]1[CH:26]=[CH:25][C:24]([S:27]([NH:1][CH:2]2[N:8]=[C:7]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[F:15])[C:6]3[CH:16]=[CH:17][CH:18]=[CH:19][C:5]=3[NH:4][C:3]2=[O:20])(=[O:29])=[O:28])=[CH:23][CH:22]=1
Reactant: NC1N=C(c2ccccc2F)c2ccccc2NC1=O
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)NC2N=C(c3ccccc3F)c3ccccc3NC2=O)cc1
Reaction time: 8 h
Yield: 109.8 %

Procedure:
1,3-Dihydro-3-(RS)-amino-5-(2-fluorophenyl)-2H-1,4-benzodiazepin-2-one (116 mg, 0.43 mmole) and p-toluenesulfonyl chloride (82 mg, 0.43 mmole) were combined at room temperature in 5 ml of methylene chloride. The pH of the reaction mixture was then adjusted to 8.5 with triethylamine and stirring was continued at room temperature overnight. The reaction mixture was partitioned between methylene chloride and 10% citric acid solution. The phases were separated and the organic layer was washed in succession with 10% citric acid solution (1×30 ml), saturated sodium bicarbonate solution (2×30 ml) and brine. The dried (MgSO4) extracts were concentrated to yield 200 mg of crude product. Recrystallization from ethyl acetate afforded the analytical sample as white needles, m.p. 215°-216° C.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]=1[O:15][CH2:16][CH2:17][O:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:4].[OH-].[Na+].CO>C1COCC1>[O:18]([CH2:17][CH2:16][O:15][C:6]1[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH:13]=[CH:14][C:5]=1[C:3]([OH:4])=[O:2])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: COC(=O)c1ccc2ccccc2c1OCCOc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1ccc2ccccc2c1OCCOc1ccccc1
Yield: 83 %

Procedure:
To 9.60 g of 1-(2-phenoxy-ethoxy)-naphthalene-2-carboxylic acid methyl ester in 105 ml of THF were added 30 ml of 2 M aqueous sodium hydroxide and 40 ml of methanol. After 3 h at reflux the organic solvents were removed in vacuo. The residue was treated with 2 M hydrochloric acid, and three times extracted with ethyl acetate. The combined organic layers were dried over magnesium sulphate, and concentrated and dried in vacuo to yield 7.62 g of 1-(2-phenoxy-ethoxy)-naphthalene-2-carboxylic acid.
Reaction SMILES: O=O.[Br:3]/[C:4](=[CH:8]\[CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])/[C:5]([OH:7])=[O:6].C(N(CC)CC)C.Cl>O>[Br:3][C@@H:4]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])[C:5]([OH:7])=[O:6]
Reactant: CCCCC/C=C(\Br)C(=O)O
Agent: Cl
Agent: O=O
Solvent: CCN(CC)CC
Solvent: O
Product: CCCCCC[C@H](Br)C(=O)O
Reaction time: 0.25 h
Yield: 89.2 %

Procedure:
A catalyst solution was prepared by dissolving 59.6 mg (0.045 mmol) of Ru(CF3COO)2 [(S)-MeOBIPHEP-TS-Na] in 20 ml of water in a glove box (O2 content <1 ppm) and was stirred at 20° for 15 min. Then, 1.0 g (4.52 mmol) of (Z)-2-bromo-2-octenoic acid, 30 ml of water and 0.46 g (4.52 mmol) of triethylamine were placed in a 185 ml autoclave and the above-prepared 20 ml of catalyst solution were added. The autoclave was sealed and the hydrogenation was carried out at 20° while stirring and under a constant pressure of 50 bar. After 4 hours the conversion was 100%. The hydrogenation solution was acidified to pH 1 with 1N HCl solution and extracted with diethyl ether. After drying and evaporating the ether extract (40°/20 mbar) the residue was distilled at 115°/0.2 mbar in a bulb tube oven. There was obtained 0.9 g (90%) of (S)-2-bromo-octanoic acid as a colourless oil; chem. purity 98.9 GC area %; 93.0% ee.
Reaction SMILES: [NH2:1][C:2]1[C:15]([I:16])=[CH:14][CH:13]=[CH:12][C:3]=1[C:4]([NH:6][CH2:7][CH2:8][CH2:9][S:10][CH3:11])=[O:5].Cl[C:18](Cl)([O:20]C(=O)OC(Cl)(Cl)Cl)Cl>C(Cl)Cl>[I:16][C:15]1[CH:14]=[CH:13][CH:12]=[C:3]2[C:2]=1[NH:1][C:18](=[O:20])[N:6]([CH2:7][CH2:8][CH2:9][S:10][CH3:11])[C:4]2=[O:5]
Reactant: CSCCCNC(=O)c1cccc(I)c1N
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: ClCCl
Product: CSCCCn1c(=O)[nH]c2c(I)cccc2c1=O
Temperature: 25 °C
Yield: 319 %

Procedure:
To a 100 mL round-bottomed flask was added 2-amino-3-iodo-N-(3-(methylthio)propyl)benzamide (1.25 g, 3.57 mmol) and triphosgene (0.185 mL, 1.25 mmol, Sigma Aldrich) in DCM (20 mL). The reaction was heated to reflux for 15 h, and then cooled to RT. The solvent was removed to give the crude product 1.5 g. MS (ESI, pos. ion) m/z: 376.9 (M+1).
Reaction SMILES: [C:1]([C:4]1[CH:29]=[CH:28][C:7]([O:8][CH2:9][C:10](=[CH2:27])[CH2:11][O:12][C:13]2[CH:18]=[CH:17][C:16]([C:19](=[O:26])[CH2:20][CH2:21][C:22]([O:24]C)=[O:23])=[CH:15][CH:14]=2)=[C:6]([CH2:30][CH2:31][CH3:32])[C:5]=1[OH:33])(=[O:3])[CH3:2].[OH-].[Na+].Cl>C1COCC1.O>[C:1]([C:4]1[CH:29]=[CH:28][C:7]([O:8][CH2:9][C:10](=[CH2:27])[CH2:11][O:12][C:13]2[CH:18]=[CH:17][C:16]([C:19](=[O:26])[CH2:20][CH2:21][C:22]([OH:24])=[O:23])=[CH:15][CH:14]=2)=[C:6]([CH2:30][CH2:31][CH3:32])[C:5]=1[OH:33])(=[O:3])[CH3:2]
Reactant: C=C(COc1ccc(C(=O)CCC(=O)OC)cc1)COc1ccc(C(C)=O)c(O)c1CCC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: C=C(COc1ccc(C(=O)CCC(=O)O)cc1)COc1ccc(C(C)=O)c(O)c1CCC
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a stirred solution of the compound from Step B (550 mg, 1.21 mmole) in THF (15 ml) was added 3 ml of 1N NaOH. The mixture was stirred at room temperature for 1.5 hours. The reaction mixture was diluted with H2O (50 ml) and acidified with concentrated HCl to pH=5. A white solid formed which was extracted with methylene chloride (2×). The combined organic extracts were washed with brine, dried (MgSO4) and concentrated in vacuo to yield the title compound as a white solid, m.p. 136°-137°.
Reaction SMILES: [CH:1]1([NH2:4])[CH2:3][CH2:2]1.C(N(CC)CC)C.[F:12][C:13]([F:26])([F:25])[C:14]1[CH:15]=[C:16]([CH:22]=[CH:23][CH:24]=1)[CH2:17][S:18](Cl)(=[O:20])=[O:19]>C(Cl)Cl>[CH:1]1([NH:4][S:18]([CH2:17][C:16]2[CH:22]=[CH:23][CH:24]=[C:14]([C:13]([F:12])([F:25])[F:26])[CH:15]=2)(=[O:20])=[O:19])[CH2:3][CH2:2]1
Reactant: NC1CC1
Reactant: O=S(=O)(Cl)Cc1cccc(C(F)(F)F)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=S(=O)(Cc1cccc(C(F)(F)F)c1)NC1CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 92.6 %

Procedure:
In this example, 5.3 g of cyclopropylamine is mixed with 9.4 g of triethylamine and then added dropwise to a solution containing 20 g of 3-trifluoromethylbenzylsulfonyl chloride in methylene chloride at 0° C. The resulting reaction mixture is stirred at room temperature (i.e., about 20°-25° C.) for 3 hours. The reaction mixture is washed with saturated aqueous ammonium chloride and then with aqueous 1 wt.% hydrochloric acid until it was neutral. The organic layer is separated, washed twice with 50 ml of aqueous saturated sodium chloride solution, dried over magnesium sulfate and then evaporated to dryness affording 20 g of N-cyclopropyl-3-trifluoromethylbenzylsulfonamide.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[F:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:8][CH:7]=1.[C:18]([CH2:22][CH2:23][C:24](Cl)=[O:25])([O:20][CH3:21])=[O:19]>ClCCl>[F:5][C:6]1[CH:7]=[CH:8][C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:24](=[O:25])[CH2:23][CH2:22][C:18]([O:20][CH3:21])=[O:19])=[CH:14][CH:13]=2)=[CH:10][CH:11]=1
Reactant: COC(=O)CCC(=O)Cl
Reactant: Fc1ccc(-c2ccccc2)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COC(=O)CCC(=O)c1ccc(-c2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 74.6 %

Procedure:
To a stirred suspension of anhydrous aluminum chloride (9.64 g, 0.0723 mol) in dichloromethane (90 mL) at 5° C. was added dropwise a solution of 4-fluorobiphenyl (4.97 g, 0.0289 mol) in dichloromethane (40 mL) followed by the dropwise addition of a solution of 3-carbomethoxypropionyl chloride (3.94 mL, 0.032 mol) in dichloromethane (30 mL), and the mixture stirred. After 2 hours at 5° C., the mixture was allowed to warm to room temperature. After 1 day, the reaction was cooled to 5° C. and quenched by the dropwise addition of water (160 mL). The layers were separated, and the organic layer washed with brine, dried (Na2SO4), and rotary evaporated. The residue was recrystallized from methanol (300 mL) to give 6.17 g of 4-(4′-fluoro-biphenyl-4-yl)-4-oxo-butyric acid, methyl ester as a pale yellow solid; mp 131.5-133.0° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[C:13]([F:14])=[CH:12][C:10]([NH2:11])=[CH:9][C:8]=2[F:15])[CH:2]=1.C(=O)(O)[O-].[Na+].C1COCC1.[CH2:26]([O:33][C:34](Cl)=[O:35])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C(Cl)Cl>[C:34]([NH:11][C:10]1[CH:9]=[C:8]([F:15])[C:7]([C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)=[C:13]([F:14])[CH:12]=1)([O:33][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:35]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: Nc1cc(F)c(-c2cccnc2)c(F)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: O=C(Nc1cc(F)c(-c2cccnc2)c(F)c1)OCc1ccccc1

Procedure:
4-(3-Pyridyl)-3,5-difluoroaniline (PREPARATION 2, 625 mg, 3.03 mmol), sodium bicarbonate (382 mg, 4.55 mmol, 1.5 eq) and dry THF (60 ml) are combined. The resulting mixture is placed under an atmosphere of nitrogen and benzylchloroformate (394 μl, 4.55 mmol, 1.5 eq) is added. The reaction is allowed to stir at 20-25°. After this time, the reaction is added to methylene chloride (150 ml) and washed with saturated sodium bicarbonate then brine, dried (sodium sulfate), filtered and concentrated under reduced pressure to a solid which is puried by silica gel chromatography (200 g of silica gel, eluted with acetonitrile/chloroform (3/97 - 11, 5/95 - 21), the title compound is recovered as a solid, mp 188°-190°; FTIR (neat) cm-1 3030, 1737, 1642, 1478, 1408, 1231, 1029, 723; MS CEI, m/z) 340, 296, 232, 205, 91, 79; NMR (CD3CL3) δ 8.59, 8.53-8.51, 7.95-7.92, 7.56-7.51, 7.44-7.31, 7.28 and 5.21.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16](I)[S:17][C:13]=2[N:12]2[C:19]([CH3:22])=[N:20][N:21]=[C:11]2[CH2:10][N:9]=1.[CH2:23]([N:26]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:29]=[CH:28][C:27]1=[O:36])[C:24]#[CH:25].C(O)C>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([C:25]#[C:24][CH2:23][N:26]3[C:35]4[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=4)[CH:29]=[CH:28][C:27]3=[O:36])[S:17][C:13]=2[N:12]2[C:19]([CH3:22])=[N:20][N:21]=[C:11]2[CH2:10][N:9]=1
Reactant: Cc1nnc2n1-c1sc(I)cc1C(c1ccccc1Cl)=NC2
Reactant: C#CCn1c(=O)ccc2ccccc21
Solvent: CCO
Solvent: ClCCl
Product: Cc1nnc2n1-c1sc(C#CCn3c(=O)ccc4ccccc43)cc1C(c1ccccc1Cl)=NC2

Procedure:
The title compound was prepared by reacting 4-(2-chlorophenyl)-2-iodo-9-methyl-6H thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine with 1-(2-propynyl)-2(1H)quinolinone [ref. A. Lindquist et al., Acta Pharm. Suecica, 9,99 (1972)]as described in EXAMPLE 37. It was isolated by chromatography over 50 g of silica gel using 5% (v/v) of ethanol in methylene chloride and was further purified by rechromatography over 50 g of silica gel using tetrahydrofuran. Crystallization from ethyl acetate/methanol gave off-white crystals of 1-{3-[4-(2-chlorophenyl)-9-methyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-2-yl] 2-propynyl}-2(1H)-quinolinone with m.p. 162-165°. These crystals contained according to analytical data 0.5 molar amounts of water.
Reaction SMILES: [Cl:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].O.[NH2:15][C:16]1[NH:20][N:19]=[N:18][N:17]=1>O1CCCC1.O>[Cl:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:15][C:16]1[NH:20][N:19]=[N:18][N:17]=1)=[O:5]
Reactant: O=C(Cl)c1cccc([N+](=O)[O-])c1Cl
Reactant: Nc1nnn[nH]1
Solvent: C1CCOC1
Solvent: O
Product: O=C(Nc1nnn[nH]1)c1cccc([N+](=O)[O-])c1Cl
Reaction time: 1 h

Procedure:
Similarly, a solution of 109 g of 2-chloro-3-nitrobenzoyl chloride in 100 ml of tetrahydrofuran was reacted with a mixture of 103 g of 5-aminotetrazole monohydrate in 1200 ml of hot tetrahydrofuran and 50 ml of water. A voluminous precipitate appeared and, after 1 hour, the mixture was diluted with 2 liters of water and the resulting white solid was collected and oven-dried to give 2-chloro-3-nitro-N-(1H-tetrazol-5-yl)-benzamide melting at about 279° C. with decomposition. In this case, the indicated acid chloride was obtained by the reaction of 2-chloro-3-nitrobenzoic acid with phosphorus pentachloride in cyclohexane. The acid chloride melts at about 57°-59° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:12])=[C:6]([S:8](Cl)(=[O:10])=[O:9])[CH:7]=1.[NH:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1.C(N(CC)CC)C>C(OCC)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:12])=[C:6]([S:8]([N:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)(=[O:10])=[O:9])[CH:7]=1
Reactant: C1CNCCN1
Reactant: Cc1ccc(F)cc1S(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: Cc1ccc(F)cc1S(=O)(=O)N1CCNCC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 71.1 %

Procedure:
5-Fluoro-2-methylbenzenesulfonyl chloride (35.1 g, 168.5 mmol) in diethyl ether (50 mL) was added drop-wise to a suspension of piperazine (28.8 g, 337.0 mmol) in diethyl ether (500 mL) and triethylamine (47 mL, 337.0 mmol). The white suspension was stirred at room temp for 1.5 h. The mixture was washed with saturated aqueous sodium carbonate. The organic phase was washed with water and brine and dried (Na2SO4). Concentration gave a white solid that was triturated with diethyl ether to give the title compound as a white solid (30.95 g, 36% yield). 1H NMR (300 MHz, CDCl3) δ: 7.57 (1H, dd, J=8.6, 2.7 Hz), 7.25 (1H, dd, J=8.4, 5.1 Hz), 7.12 (1H, td, J=8.1, 2.8 Hz), 3.13-3.10 (4H, m), 2.98-2.85 (4H, m), 2.55 (3H, s), 1.69 (1H, bs). LCMS (M+H) calcd for C11H16FN2O2S: 259.09; found: 259.18.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[CH:11]=[C:10]([S:12]([CH3:14])=O)[N:9]=[C:8]([NH2:15])[N:7]=1.SC[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=1.C1CCN2C(=NCCC2)CC1>COCCOC>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[CH:11]=[C:10]([S:12][CH2:14][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)[N:9]=[C:8]([NH2:15])[N:7]=1
Reactant: SCCc1ccccn1
Reactant: CS(=O)c1cc(-c2ccco2)nc(N)n1
Solvent: COCCOC
Solvent: C1CCC2=NCCCN2CC1
Product: Nc1nc(SCCc2ccccn2)cc(-c2ccco2)n1

Procedure:
From 4-furan-2-yl-6-methanesulfinyl-pyrimidin-2-yl-amine, 2-mercaptoethylpyridine and DBU in DME. ES-MS m/e (%): 299 (M+H+, 100), 194 (98), 106 (70).
Reaction SMILES: [F:1][C:2]1[CH:15]=[CH:14][C:13]2[C:4](=[C:5]([C:17](=[S:25])[O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:6]3[C:11]([N:12]=2)=[CH:10][CH:9]=[C:8]([F:16])[CH:7]=3)[CH:3]=1.[NH4+].[Cl-]>CC(O)C.[Zn]>[F:1][C:2]1[CH:15]=[CH:14][C:13]2[NH:12][C:11]3[C:6](=[CH:7][C:8]([F:16])=[CH:9][CH:10]=3)[CH:5]([C:17](=[S:25])[O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:4]=2[CH:3]=1
Reactant: Fc1ccc2nc3ccc(F)cc3c(C(=S)Oc3ccccc3)c2c1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CC(C)O
Product: Fc1ccc2c(c1)C(C(=S)Oc1ccccc1)c1cc(F)ccc1N2
Reaction time: 1.5 h

Procedure:
Phenyl 2,7-difluoroacridine-9-thiocarboxylate (1.2 g) was suspended in 2-propanol (125 mL) along with NH4Cl (4.57 g). Zinc (5.5 g) was added and the reaction mixture was warmed for 2.5 h followed by a 1.5 h period at room temperature. TLC of the reaction mixture showed complete conversion to a new material. The solution was filtered and the precipitate was washed with CH2Cl2. The filtrate was concentrated and the light orange residue was redissolved in CH2Cl2 and washed with water (2×100 mL). The organic layer was dried over Na2SO4 and concentrated to yield the crude product which was used without further purification. 1H NMR (CDCl3) δ5.12 (s, 1H), 6.19 (br s, 1H), 6.72-7.35 (m, 11H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:11][C:10]([CH3:13])([CH3:12])[CH:9]3[O:14][CH:8]3[C:7]=2[CH:15]=1)#[N:2].[C:16]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])(=[O:19])[NH:17][NH2:18]>C(O)C>[C:21]([O:20][C:16]([NH:17][NH:18][C@@H:8]1[C:7]2[CH:15]=[C:3]([C:1]#[N:2])[CH:4]=[CH:5][C:6]=2[O:11][C:10]([CH3:13])([CH3:12])[C@H:9]1[OH:14])=[O:19])([CH3:24])([CH3:23])[CH3:22]
Reactant: CC(C)(C)OC(=O)NN
Reactant: CC1(C)Oc2ccc(C#N)cc2C2OC21
Solvent: CCO
Product: CC(C)(C)OC(=O)NN[C@@H]1c2cc(C#N)ccc2OC(C)(C)[C@H]1O
Yield: 65.6 %

Procedure:
6-Cyano-3,4-epoxy-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran (8.0 g) and tert-butyl carbazate (6.3 g) were dissolved in 40 ml of ethanol and the solution was heated under reflux for 28 hours. The resulting ethanol was distilled off and the residue was recrystallized from 80 ml of hexane and 8 ml of ethanol to yield 8.7 g of trans-4-(2-tert-butoxycarbonyl- hydrazino)-6-cyano-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-3-ol as white crystals, m.p. 136°-138° C.
Reaction SMILES: O[C:2]1([C:6]2[C:7]([O:28][C@@H:29]([CH3:34])[C:30]([F:33])([F:32])[F:31])=[CH:8][C:9]([C:12]([NH:14][C:15]([C:22]3[N:26]=[C:25]([CH3:27])[O:24][N:23]=3)([CH3:21])[CH2:16][S:17]([CH3:20])(=[O:19])=[O:18])=[O:13])=[N:10][CH:11]=2)[CH2:5][CH2:4][CH2:3]1.CCN(S(F)(F)[F:41])CC>ClCCl>[F:41][C:2]1([C:6]2[C:7]([O:28][C@@H:29]([CH3:34])[C:30]([F:31])([F:32])[F:33])=[CH:8][C:9]([C:12]([NH:14][C:15]([C:22]3[N:26]=[C:25]([CH3:27])[O:24][N:23]=3)([CH3:21])[CH2:16][S:17]([CH3:20])(=[O:18])=[O:19])=[O:13])=[N:10][CH:11]=2)[CH2:3][CH2:4][CH2:5]1
Reactant: Cc1nc(C(C)(CS(C)(=O)=O)NC(=O)c2cc(O[C@@H](C)C(F)(F)F)c(C3(O)CCC3)cn2)no1
Reactant: CCN(CC)S(F)(F)F
Solvent: ClCCl
Product: Cc1nc(C(C)(CS(C)(=O)=O)NC(=O)c2cc(O[C@@H](C)C(F)(F)F)c(C3(F)CCC3)cn2)no1
Temperature: 0 °C
Reaction time: 1 h
Yield: 43.6 %

Procedure:
To a solution of 5-(1-hydroxycyclobutyl)-N-[2-(5-methyl-1,2,4-oxadiazol-3-yl)-1-methylsulfonylpropan-2-yl]-4-[(2S)-1,1,1-trifluoropropan-2-yl]oxypyridine-2-carboxamide (example 126e, 21 mg, 41.5 μmol) in dry dichloromethane (200 μl) under an argon atmosphere cooled down to 0° C. was added DAST (10.0 mg, 8.22 μl, 62.2 μmol). The reaction mixture was stirred at 0° C. for 1 h and quenched by addition of a 2M aqueous solution of sodium carbonate. The bi-phasic mixture was stirred for 15 minutes and the organic phase was collected. The organic phase was evaporated down to dryness and the crude material was purified by preparative HPLC to yield the title compound (9.2 mg, 44%). MS (ESI, m/z): 509.5 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][C:9]([F:12])([F:11])[F:10])[CH:5]=[CH:4][C:3]=1[OH:13].C1N=CN([C:19](N2C=NC=C2)=[O:20])C=1>O1CCOCC1>[F:12][C:9]([F:10])([F:11])[O:8][C:6]1[CH:5]=[CH:4][C:3]2[O:13][C:19](=[O:20])[NH:1][C:2]=2[CH:7]=1
Reactant: Nc1cc(OC(F)(F)F)ccc1O
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: C1COCCO1
Product: O=c1[nH]c2cc(OC(F)(F)F)ccc2o1
Temperature: 70 °C
Reaction time: 7 h
Yield: 72.4 %

Procedure:
To a mixture of 2-amino-4-(trifluoromethoxy)phenol (1.01 g) and 1,4-dioxane (20 mL) was added CDI (1.10 g), followed by heating and stirring at 70° C. for 7 hours. The reaction mixture was cooled to room temperature, and then the solvent was concentrated to a half of the volume under reduced pressure. To the obtained residue was added water (30 mL), followed by adjusting to pH 4 by the addition of concentrated hydrochloric acid under ice-cooling, and stirring at the same temperature for 1 hour. The resulting solid was collected by filtration to obtain 5-(trifluoromethoxy)-1,3-benzoxazol-2(3H)-one (830 mg).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]=O.[NH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C.ClCCl.C(=O)(O)[O-].[Na+]>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: O=Cc1cccs1
Reactant: C1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(Cl)Cl
Product: c1csc(CN2CCCCC2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-Thiophenecarboxaldehyde (1 g, 8.9 mmol) was dissolved in dichloroethane and treated with piperidine and sodium triacetoxyborohydride. The reaction was stirred at room temperature overnight. The reaction was diluted with dichloromethane and aqueous saturated sodium bicarbonate. The organic layer was separated out, washed with water and brine and dried with sodium sulfate. The volatile were removed in vacuo and the residue was purified by column chromatography on silica gel using a gradient of 2 to 8% of methanol in dichloromethane to obtain a brown oil. Yield=1.5 g. MS (M+H)+ 182.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH2:8])[N:5]=[C:4]([N:9]([CH3:19])[C@H:10]([CH3:18])[CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:3]=1.[F:20][C:21]1[CH:28]=[C:27](B2OC(C)(C)C(C)(C)O2)[CH:26]=[CH:25][C:22]=1[C:23]#[N:24].C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.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>[NH2:8][C:6]1[N:7]=[C:2]([C:27]2[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[C:21]([F:20])[CH:28]=2)[CH:3]=[C:4]([N:9]([CH3:19])[C@H:10]([CH3:18])[CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:5]=1
Reactant: CC1(C)OB(c2ccc(C#N)c(F)c2)OC1(C)C
Reactant: C[C@H](Cc1ccccc1)N(C)c1cc(Cl)nc(N)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: C[C@H](Cc1ccccc1)N(C)c1cc(-c2ccc(C#N)c(F)c2)nc(N)n1
Temperature: 140 °C
Reaction time: 0.67 h
Yield: 80.1 %

Procedure:
To a mixture of 6-chloro-N4-methyl-N4-[(1R)-1-methyl-2-phenylethyl]-2,4-pyrimidinediamine (0.4 g, 1.45 mmol), 2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile (0.46 g, 1.88 mmol) and Na2CO3 (0.38 g, 3.63 mmol) in 1,4-dioxane (6 mL) and water (3 mL) was added Pd(PPh3)4 (16 mg, 0.015 mmol), the reaction mixture was heated at 140° C. under microwave conditions with stirring for 40 minutes. The mixture was filtered and concentrated, and the resulting residue was purified by reverse phase chromatography using CH3CN in water from 45% to 55% (0.5% ammonium hydrogen carbonate in water) to afford the title compound (0.42 g) as a yellow solid. LC-MS (ES) m/z=362 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:10][CH3:11])[CH:3]=1.[ClH:12].[H][H]>C(O)C.[Pd]>[ClH:12].[F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[C:4]([O:10][CH3:11])[CH:3]=1
Reactant: [H][H]
Reactant: COc1cc(F)ccc1C#N
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: COc1cc(F)ccc1CN
Reaction time: 40 h
Yield: 88.1 %

Procedure:
To a mixture of 4-fluoro-2-methoxybenzonitrile, (800 mg, 5.3 mmol) and conc.HCl (0.53 mL, 6.36 mmol, 1.2 eq.) in ethanol (20 mL) was added 10% Pd—C (100 mg; Aldrich), and the mixture hydrogenated at 1 atm hydrogen for 15 hrs at room temperature. To this mixture was added an additional amount of conc.HCl (1 mL) and 10% Pd—C (200 mg) and the reaction allowed to continue for another 40 hrs. The mixture was filtered through Celite® and the filtrate concentrated in vacuo to dryness. The residue was triturated with ether to provide the title compound (895 mg, Yield 88%) as a white powder: 1H NMR (CDCl3, 500 MHz) δ ppm: 3.84 (3H, s, OMe), 3.91 (2H, d, J=5.5 Hz, N—CH2), 6.81 (1H, dt, J=2.5 Hz, J=J=8.5 Hz, Ar—H), 6.99 (1H, dd, J=2.5 Hz, J=11.3 Hz, Ar—H), 7.47 (1H, dd, J=7 Hz, J=8.5 Hz, Ar—H); 13C NMR (CDCl3, 125.8 Hz) δ ppm: 36.76, 56.03, 99.30, 99.51 106.28, 106.45, 117.93, 117.95, 131.60, 131.69, 158.56, 158.64, 162.28, 164.22. HRMS (ESI) calcd for C8H11FNO (M+H) 156.0825, found 156.0830.
Reaction SMILES: [I:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6](Cl)=[N:7]2.[NH2:13][C@H:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:16][CH2:15]1>>[C@H:14]1([NH:13][C:6]2[CH:5]=[CH:4][C:3]3[C:8](=[CH:9][CH:10]=[CH:11][C:2]=3[I:1])[N:7]=2)[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:16][CH2:15]1
Reactant: Clc1ccc2c(I)cccc2n1
Reactant: N[C@@H]1CCc2ccccc21
Product: Ic1cccc2nc(N[C@@H]3CCc4ccccc43)ccc12

Procedure:
(R)-Indan-1-yl-(5-iodo-quinolin-2-yl)-amine was prepared from 5-iodo-2-chloroquinoline and (R)-1-aminoindane as described in example 6 step A.