Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[S:10][C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=3)=[N:8][C:7](=[O:17])[C:6]=2[CH:18]=1.Br[CH2:20][CH2:21][CH2:22][CH3:23].C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[CH2:20]([O:1][C:2]1[CH:3]=[CH:4][C:5]2[S:10][C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=3)=[N:8][C:7](=[O:17])[C:6]=2[CH:18]=1)[CH2:21][CH2:22][CH3:23]
Reactant: O=c1nc(-c2ccccn2)sc2ccc(O)cc12
Reactant: CCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCOc1ccc2sc(-c3ccccn3)nc(=O)c2c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 86.2 %

Procedure:
A mixture of 6-hydroxy-2-(2-pyridyl)-4H-1,3-benzothiazine-4-one (0.35 g, 1.3 mmol), 1-bromobutane (0.38 g, 2.7 mmol) and potassium carbonate (0.56 g, 4.0 mmol) and DMF (10 ml) was stirred at room temperature for 15 hrs. The reaction mixture was diluted with water and extracted with ethyl acetate. The extract was washed with water and dried. The solvent was evaporated. The obtained crystals were recrystallized from tetrahydrofuran-hexane to give the titled compound (0.35 g, 83%).
Reaction SMILES: [OH:1][C:2]1[C:7]([C:8]([CH2:11][CH3:12])([CH3:10])[CH3:9])=[CH:6][C:5]([C:13]([CH2:16][CH3:17])([CH3:15])[CH3:14])=[CH:4][C:3]=1[N:18]1[N+:22]([O-])=[C:21]2[CH:24]=[CH:25][CH:26]=[CH:27][C:20]2=[N:19]1.C1(C)C=CC=CC=1.CNC.[H][H]>[C].[Pd].O>[OH:1][C:2]1[C:7]([C:8]([CH2:11][CH3:12])([CH3:10])[CH3:9])=[CH:6][C:5]([C:13]([CH2:16][CH3:17])([CH3:15])[CH3:14])=[CH:4][C:3]=1[N:18]1[N:22]=[C:21]2[CH:24]=[CH:25][CH:26]=[CH:27][C:20]2=[N:19]1
Reactant: CCC(C)(C)c1cc(-n2nc3ccccc3[n+]2[O-])c(O)c(C(C)(C)CC)c1
Reactant: [H][H]
Agent: [Pd]
Agent: CNC
Solvent: O
Solvent: Cc1ccccc1
Product: CCC(C)(C)c1cc(-n2nc3ccccc3n2)c(O)c(C(C)(C)CC)c1
Yield: 90.8 %

Procedure:
36.7 g (0.1 mol) of 2-(2'-hydroxy-3',5'-di-t-amylphenyl)benzotriazole-N-oxide, 0.125 g of 5% palladium carbon, 150 ml of a solvent mixture comprising toluene and water (ratio by volume, 4:1) and 7 g of 50% dimethylamine were charged into a 500-ml four neck flask. After the air in the flask had been replaced by nitrogen, the resultant mixture was agitated at room temperature. Hydrogen was then supplemented to allow for the amount of hydrogen absorbed by the mixture, which was then subjected to reaction until no more hydrogen was absorbed by it. After the reaction had been completed, the catalyst was filtered off, and part of the filtrate was subjected to quantitative analysis using gas chromatography (GC). The results revealed a yield of 90.8% of 2-(2'-hydroxy-3',5'-di-t-amylphenyl)benzotriazole. The solvent was then distilled off from the filtrate, and the residual solid was crystallized using ethanol and then washed with ethanol to obtain 28 g of 2-(2'-hydroxy-3',5'-di-t-amylphenyl)benzotriazole (yield, 80%; melting point, 79° to 82° C.).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[S:9][C:8]([CH3:14])([CH3:13])[CH2:7][C:6]2=[O:15])#[CH:2].I[C:17]1[CH:27]=[CH:26][C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:19][CH:18]=1>CCN(CC)CC.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[CH3:14][C:8]1([CH3:13])[CH2:7][C:6](=[O:15])[C:5]2[C:10](=[CH:11][CH:12]=[C:3]([C:1]#[C:2][C:17]3[CH:27]=[CH:26][C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:19][CH:18]=3)[CH:4]=2)[S:9]1
Reactant: CCOC(=O)c1ccc(I)cc1
Reactant: C#Cc1ccc2c(c1)C(=O)CC(C)(C)S2
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(=O)CC(C)(C)S3)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.2 %

Procedure:
A solution of 6-ethynyl-2,2-dimethylthiochroman-4-one (82.0 mg, 0.38 mmol) and ethyl 4-iodobenzoate (104.9 mg, 0.38 nmuol) in 5.0 mL Et3N was purged with argon for 10 minutes. To this solution were added bis(triphenylphosphine)-palladium(II) chloride (88.0 mg, 0.12 mmol) and copper(I) iodide (22.9 mg, 0.12 mmol). After sparging for an additional 5 minutes with argon, the solution was stirred overnight at room temperature. The reaction mixture was filtered through a pad of Celite using an Et2O wash. Concentration of the filtrate under reduced pressure, followed by column chromatography of the residual solid, afforded 100 mg (72%) of ethyl 4-[(2,2-dimethyl-4-oxo-thiochroman-6-yl)ethynyl]-benzoate as a yellow solid. 1H NMR (300 MHz, CDCl3) δ: 8.25 (1H, d, J=1.8 Hz), 8.00 (2H, d, J=8.4 Hz), 7.55 (2H, d, J=8.4 Hz), 7.53 (1H, dd, J=1.8, 8.2 Hz), 7.21 (1H, d, J=8.2 Hz), 4.37 (2H, q, J=7.1 Hz), 2.88 (2H, s), 1.47 (6H, s), 1.39 (3H, t, J=7.1 Hz).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=2)[N:6]=1.[CH3:15][N:16]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[C:17]1[C:25](O)=[O:26].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C>CN(C)C=O>[CH3:14][O:13][C:10]1[CH:9]=[CH:8][C:7]([C:5]2[N:6]=[C:2]([NH:1][C:25]([C:17]3[N:16]([CH3:15])[C:24]4[C:19]([CH:18]=3)=[CH:20][CH:21]=[CH:22][CH:23]=4)=[O:26])[S:3][CH:4]=2)=[CH:12][CH:11]=1
Reactant: Cn1c(C(=O)O)cc2ccccc21
Reactant: COc1ccc(-c2csc(N)n2)cc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1ccc(-c2csc(NC(=O)c3cc4ccccc4n3C)n2)cc1
Temperature: 0 °C
Reaction time: 12 h

Procedure:
1 g of 2-amino-4-(4-methoxyphenyl)thiazole is dissolved in 20 ml of dimethylformamide and, successively, 0.6 g of 1-methylindole-2-carboxylic acid, then 1.6 g of 1-benzotriazolyl-oxytris(dimethylamino)phosphonium hexafluorophosphate (BOP) and then 0.7 g of triethylamine are added to the reaction mixture at ambient temperature. The reaction mixture is left at ambient temperature for about 12 hours, while stirring well, before pouring into 100 ml of ice-water; the aqueous phase obtained is then extracted with twice 50 ml of ethyl acetate. The organic extracts are dried over anhydrous magnesium sulphate and evaporated to dryness. The residual solid is purified by chromatography on a silica column (eluant: CH2Cl2). Yield
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH:11]=[CH:10][N:9]([C:12]3[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][C:13]=3[CH3:19])[C:4]=2[C:5](=[O:8])[NH:6][N:7]=1.[CH2:20](I)[CH3:21].C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[Cl:1][C:2]1[C:3]2[CH:11]=[CH:10][N:9]([C:12]3[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][C:13]=3[CH3:19])[C:4]=2[C:5](=[O:8])[N:6]([CH2:20][CH3:21])[N:7]=1
Reactant: CCI
Reactant: Cc1ccc(-n2ccc3c(Cl)n[nH]c(=O)c32)c(C)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCn1nc(Cl)c2ccn(-c3ccc(C)cc3C)c2c1=O
Temperature: 25 °C
Reaction time: 7 h
Yield: 92.6 %

Procedure:
A mixture of 4-chloro-1-(2,4-dimethylphenyl)-1,6-dihydro-7H-pyrrolo[2,3-d]pyridazin-7-one (100 mg, 0.365 mmol), ethyl iodide (0.032 ml, 0.40 mmol), potassium carbonate (100 mg, 0.73 mmol) and DMF (1 ml) was stirred at room temperature for 7 hours. The mixture was diluted with water (50 ml) and extracted with ethyl acetate (50 ml). The extract was washed with water, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by silica gel chromatography eluting with hexane/ethyl acetate (5:1) to give 102 mg (93%) of the title compound as crystals.
Reaction SMILES: [Na].[CH2:2]([OH:14])[CH2:3][O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][O:10][CH2:11][CH2:12][OH:13].C1(S(O[CH2:25][CH2:26][O:27][CH2:28][CH2:29][O:30][CH2:31][CH2:32][OH:33])(=O)=O)C=CC=CC=1.C1(S([O-])(=O)=O)C=CC=CC=1.[Na+]>>[CH2:12]([OH:13])[CH2:11][O:10][CH2:9][CH2:8][O:7][CH2:6][CH2:5][O:4][CH2:3][CH2:2][O:14][CH2:25][CH2:26][O:27][CH2:28][CH2:29][O:30][CH2:31][CH2:32][OH:33]
Reactant: OCCOCCOCCOCCO
Reactant: O=S(=O)(OCCOCCOCCO)c1ccccc1
Agent: O=S(=O)([O-])c1ccccc1
Agent: [Na+]
Agent: [Na]
Product: OCCOCCOCCOCCOCCOCCOCCO

Procedure:
Dissolve one equivalent of sodium in at least 5 equivalents of tetraethylene glycol and then add one equivalent of triethylene glycol monobenzenesulfonate. Heat the resulting solution at 100° to 150°C until the elimination of sodium benzene sulfonate is substantially complete. Remove the insoluble sulfonate salt by filtration and fractionally distill the resulting product in vacuo to obtain heptaethylene glycol as the higher boiling fraction.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]#[N:14])=[CH:11][C:10]([C:15]3[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=3)=[N:9]2)=[CH:4][CH:3]=1.[Cl:21][C:22]1[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[C:23]=1[CH:24]=O.C([BH3-])#N.[Na+]>C(O)(=O)C.CO>[Cl:21][C:22]1[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[C:23]=1[CH2:24][NH:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:12]([C:13]#[N:14])=[CH:11][C:10]([C:15]3[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=3)=[N:9]2)=[CH:6][CH:7]=1
Reactant: O=Cc1c(F)cccc1Cl
Reactant: N#Cc1cc(-c2cccnc2)nn1-c1ccc(N)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: N#Cc1cc(-c2cccnc2)nn1-c1ccc(NCc2c(F)cccc2Cl)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 51 %

Procedure:
To a stirred solution of 1-(4-aminophenyl)-3-(3-pyridyl)-5-cyanopyrazole (130 mg, 0.5 mmol) in acetic acid (2 mL) and MeOH (6 mL) at room temperature was added 2-chloro-6-fluorobenzaldehyde (79 mg, 0.5 mmol), followed by sodium cyanoborohydride (79 mg, 1.25 mmol). The reaction mixture was stirred at room temperature for 16 h and then concentrated under a stream of nitrogen. The residue was diluted with water, extracted into ethyl acetate, washed with sodium bicarbonate solution and water, and dried (MgSO4). The residue obtained on concentration was flash chromatographed on silica gel (eluent, gradient of 20-30% EtOAc in CH2Cl2) to provide the title compound (103 mg, 51%). NMR (CDCl3, 400 MHz): 9.1 (s, 1H); 8.7 (br, 1H); 8.3 (d, 1H); 7.6-7.5 (overlapping m, 3H), 7.6-7.5 (overlapping m, 4H), 7.05 (m, 1H); 6.9 (d, 2H), 4.6 (s, 2H).
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.Cl.[CH2:27]1[C:30]2([CH2:35][NH:34][CH2:33][CH2:32][O:31]2)[CH2:29][N:28]1[CH2:36][CH2:37][C:38]1[CH:39]=[C:40]([CH2:44][CH2:45][OH:46])[CH:41]=[CH:42][CH:43]=1.[CH:47]([C:50]1[S:51][CH:52]=[C:53]([C:55](O)=[O:56])[N:54]=1)([CH3:49])[CH3:48].C(N(CC)CC)C>CN(C=O)C>[OH:46][CH2:45][CH2:44][C:40]1[CH:39]=[C:38]([CH:43]=[CH:42][CH:41]=1)[CH2:37][CH2:36][N:28]1[CH2:29][C:30]2([CH2:35][N:34]([C:55]([C:53]3[N:54]=[C:50]([CH:47]([CH3:49])[CH3:48])[S:51][CH:52]=3)=[O:56])[CH2:33][CH2:32][O:31]2)[CH2:27]1
Reactant: CC(C)c1nc(C(=O)O)cs1
Reactant: OCCc1cccc(CCN2CC3(CNCCO3)C2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)c1nc(C(=O)N2CCOC3(CN(CCc4cccc(CCO)c4)C3)C2)cs1
Temperature: 20 °C
Reaction time: 3 h

Procedure:
HATU (0.792 g) was added in one portion to a stirred solution at 0° C. of 2-(3-(2-(5-oxa-2,8-diazaspiro[3.5]nonan-2-yl)ethyl)phenyl)ethanol 2HCl (0.56 g) (example 176 step e), 2-isopropylthiazole-4-carboxylic acid (0.275 g) and triethylamine (1.117 ml) in DMF (7 mL). The mixture was stirred at 20° C. for 3 hours and then partitioned between ethyl acetate and brine, the organic layer was washed with brine (×2), dried, filtered and the solvent evaporated under reduced pressure. The crude product was purified by flash silica chromatography, 5% methanol in ethyl acetate with 1% triethylamine. Pure fractions were evaporated to dryness to afford the subtitled compound. Yield 0.475 g
Reaction SMILES: Cl[C:2]([O:4][CH2:5][Cl:6])=[O:3].Cl.[NH2:8][CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11].C(N(C(C)C)CC)(C)C>ClCCl>[C:13]([O:12][C:10]([CH2:9][NH:8][C:2](=[O:3])[O:4][CH2:5][Cl:6])=[O:11])([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(C)(C)OC(=O)CN
Reactant: O=C(Cl)OCCl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)CNC(=O)OCCl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of chloromethyl chloroformate (1.69 g) in dichloromethane (5 ml) was added dropwise with stirring to an ice-cold solution of tert-butyl glycinate, hydrochloride (2.0 g) and diisopropylethylamine (3.7 g) in dichloromethane (20 ml). After stirring for a further 2 hours at room temperature, the mixture was extracted with ice-cold 0.5 M hydrochloric acid followed by water and aqueous sodium bicarbonate. Drying over magnesium sulfate and evaporation in vacuo gave the title compound as a colourless powder.
Reaction SMILES: S(Cl)([Cl:3])=O.[CH3:5][C:6]1[C:11]([CH3:12])=[C:10]([NH:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]O)[C:9]([N+:20]([O-:22])=[O:21])=[C:8]([O:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[N:7]=1>ClCCl>[Cl:3][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][NH:13][C:10]1[C:9]([N+:20]([O-:22])=[O:21])=[C:8]([O:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[N:7]=[C:6]([CH3:5])[C:11]=1[CH3:12]
Reactant: Cc1nc(Oc2ccccc2)c([N+](=O)[O-])c(NCCCCCO)c1C
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: Cc1nc(Oc2ccccc2)c([N+](=O)[O-])c(NCCCCCCl)c1C
Yield: 86.8 %

Procedure:
Thionyl chloride (10.72 mL, 147 mmol) was added dropwise to a mixture of 5-[(2,3-dimethyl-5-nitro-6-phenoxypyridin-4-yl)amino]pentan-1-ol (34.0 g, 98 mmol) and dichloromethane (250 mL). The reaction mixture was heated at reflux for 2 hours and then it was placed in an ice bath and quenched with water. The reaction mixture was concentrated under reduced pressure. The residue was combined with water (300 mL). Solid sodium bicarbonate was slowly added to pH 10; then the mixture was extracted with ethyl acetate (250 mL). The extract was washed sequentially with saturated sodium bicarbonate (2×100 mL) and brine (1×100 mL), dried over magnesium sulfate and then concentrated under reduced pressure to provide 30.96 g of N-(5-chloropentyl)-2,3-dimethyl-5-nitro-6-phenoxypyridin-4-amine.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH:11]([CH3:13])[CH3:12])[C:3]=1[C:4]#[N:5].O=[C:15]([CH3:22])[CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18]>>[CH2:20]([O:19][C:17]([C:16]1[C:15]([CH3:22])=[N:1][C:2]2[C:3]([C:4]=1[NH2:5])=[C:6]([O:10][CH:11]([CH3:13])[CH3:12])[CH:7]=[CH:8][CH:9]=2)=[O:18])[CH3:21]
Reactant: CCOC(=O)CC(C)=O
Reactant: CC(C)Oc1cccc(N)c1C#N
Product: CCOC(=O)c1c(C)nc2cccc(OC(C)C)c2c1N

Procedure:
Prepared as in Example 2a from 2-amino-6-isopropoxybenzonitrile (Tachdjian, C. et al. PCT Int. Appl. 2008, WO 2008154221) and ethyl 3-oxobutanoate as an off-white solid (32%). 1H NMR (400 MHz, DMSO-d6) δ 1.32 (t, J=7.6 Hz, 3H), 1.38 (d, J=6.0 Hz, 6H), 2.54 (s, 3H), 4.3 (q, J=7.2 Hz, 2H), 4.83-4.89 (m, 1H), 6.93 (d, J=8.0 Hz, 1H), 7.20 (d, J=8.0 Hz, 1H), 7.50 (t, J=8.4 Hz, 1H), 8.14 (s, 2H). MS 289 (MH+).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[C:5]2[S:10][CH:9]=[N:8][C:6]=2[N:7]=1.C([Li])CCC.CCCCCC.CN([CH:31]=[O:32])C>C1COCC1>[Cl:1][C:2]1[N:3]=[C:4]([N:11]2[CH2:12][CH2:13][O:14][CH2:15][CH2:16]2)[C:5]2[S:10][C:9]([CH:31]=[O:32])=[N:8][C:6]=2[N:7]=1
Reactant: Clc1nc(N2CCOCC2)c2scnc2n1
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: O=Cc1nc2nc(Cl)nc(N3CCOCC3)c2s1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of 4-(5-chlorothiazolo[4,5-d]pyrimidin-7-yl)morpholine 16 (1.75 g, 6.85 mmol) in dry THF (40 mL) at −78° C. was added a 2.5M solution of n-butyllithium (nBuLi) in hexane (3.3 mL, 1.2 eq.). After stirring for 1 h, dry DMF (796 μL, 1.5 eq.) was added. The reaction mixture was stirred for 1 h at −78° C. and then warmed slowly to room temperature. After a further 2 h at room temperature the reaction mixture poured onto ice/water yielding a yellow precipitate. This was collected by filtration and air-dried to yield 5-chloro-7-morpholinothiazolo[4,5-d]pyrimidine-2-carbaldehyde 43.
Reaction SMILES: [CH2:1]1[C:6]2=[C:7]([C:10]([OH:12])=O)[CH:8]=[CH:9][N:5]2[CH2:4][CH2:3][O:2]1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.[C:35]1([C@H:41]([NH2:44])[CH2:42][CH3:43])[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>CN(C)C=O.O>[C:35]1([C@H:41]([NH:44][C:10]([C:7]2[CH:8]=[CH:9][N:5]3[CH2:4][CH2:3][O:2][CH2:1][C:6]=23)=[O:12])[CH2:42][CH3:43])[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: CC[C@@H](N)c1ccccc1
Reactant: O=C(O)c1ccn2c1COCC2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: CC[C@@H](NC(=O)c1ccn2c1COCC2)c1ccccc1
Temperature: 50 °C
Reaction time: 1 h
Yield: 59 %

Procedure:
To a solution of 3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazine-8-carboxylic acid (comp. no. 8a) (5 g, 29.9 mmol) in dimethylformamide (50 ml) was added 1-hydroxybenzotriazole (4.45 g, 32.9 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (6.31 g, 32.9 mmol). The mixture was stirred for 1 h at 50° C., then (R)-1-phenyl-propylamine (4.45 g, 32.9 mmol) was added and the mixture was stirred at 25° C. overnight. An excess of water was added, the precipitate was filtered off, washed with a small amount of water and dried in vacuo to give 5.05 g (59%) of 3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazine-8-carboxylic acid ((R)-1-phenyl-propyl)-amide as a white solid. LC/MS (method 2): Rt=1.05 min; m/z=285.23 (M+H+).
Reaction SMILES: O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C[O:14][CH:15](OC)[C:16]1[C:43]([O:44]COC)=[C:42]([C:48]([F:51])([F:50])[F:49])[CH:41]=[CH:40][C:17]=1[CH2:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[CH:31]=[CH:30][C:29]([CH2:32][C:33]([O:35][CH2:36][CH:37]=[CH2:38])=[O:34])=[CH:28][CH:27]=2)=[CH:22][C:21]=1[F:39]>CC(C)=O>[F:39][C:21]1[CH:22]=[C:23]([C:26]2[CH:31]=[CH:30][C:29]([CH2:32][C:33]([O:35][CH2:36][CH:37]=[CH2:38])=[O:34])=[CH:28][CH:27]=2)[CH:24]=[CH:25][C:20]=1[O:19][CH2:18][C:17]1[CH:40]=[CH:41][C:42]([C:48]([F:51])([F:50])[F:49])=[C:43]([OH:44])[C:16]=1[CH:15]=[O:14]
Reactant: C=CCOC(=O)Cc1ccc(-c2ccc(OCc3ccc(C(F)(F)F)c(OCOC)c3C(OC)OC)c(F)c2)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CC(C)=O
Product: C=CCOC(=O)Cc1ccc(-c2ccc(OCc3ccc(C(F)(F)F)c(O)c3C=O)c(F)c2)cc1
Temperature: 50 °C
Reaction time: 1 h
Yield: 91.9 %

Procedure:
p-Toluenesulfonic acid monohydrate (223 mg, 1.18 mmol) was added to a solution of allyl (4′-{[2-(dimethoxymethyl)-3-(methoxymethoxy)-4-(trifluoromethyl)benzyl]oxy}-3′-fluoro-1,1′-biphenyl-4-yl)acetate (618 mg, 1.06 mmol) obtained in Example (12-3) in acetone (10 ml), and the mixture was stirred at 50° C. for 1 hour. The residue obtained by concentrating the reaction mixture was diluted with ethyl acetate. The obtained solution was successively washed with a saturated aqueous sodium hydrogencarbonate solution, water and a saturated aqueous NaCl solution and dried with anhydrous sodium sulfate. The residue obtained by removing the solvent under reduced pressure was purified by silica gel column chromatography (eluting solvent: n-hexane/ethyl acetate=3/1) to give allyl (3′-fluoro-4′-{[2-formyl-3-hydroxy-4-(trifluoromethyl)benzyl]oxy}-1,1′-biphenyl-4-yl)acetate (476 mg, yield: 91%).
Reaction SMILES: [F:1][C:2]([F:28])([F:27])[C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[N:11]=[CH:10][CH:9]=[C:8]2[O:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][CH:23]=1)[C:20]([C:24](O)=[O:25])=[CH:19][CH:18]=[CH:17]2.[C:29]1([NH2:36])[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[NH2:35]>>[NH2:35][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=1[NH:36][C:24]([C:20]1[C:21]2[C:16](=[CH:15][C:14]([O:13][C:8]3[C:7]4[C:12](=[C:3]([C:2]([F:28])([F:1])[F:27])[CH:4]=[CH:5][CH:6]=4)[N:11]=[CH:10][CH:9]=3)=[CH:23][CH:22]=2)[CH:17]=[CH:18][CH:19]=1)=[O:25]
Reactant: Nc1ccccc1N
Reactant: O=C(O)c1cccc2cc(Oc3ccnc4c(C(F)(F)F)cccc34)ccc12
Product: Nc1ccccc1NC(=O)c1cccc2cc(Oc3ccnc4c(C(F)(F)F)cccc34)ccc12
Yield: 80.9 %

Procedure:
The title compound (38.3 mg, 81% yield) was prepared as a brown solid from 6-(8-trifluoromethylquinolin-4-yloxy)-1-naphthoic acid (39.8 mg, 0.1 mmol) and o-phenylenediamine (43.2 mg, 0.4 mmol) by an analogous procedure to that described in example 16. 1H NMR (DMSO-d6) δ 4.98 (s, 2H, benzene-NH2), 6.65 (t, J=7.3 Hz, 1H, Ar—H), 6.83 (d, J=7.6 Hz, 1H, Ar—H), 6.89 (d, J=5.2 Hz, 1H, Ar—H), 7.00 (t, J=7.2 Hz, 1H, Ar—H), 7.38 (d, J=7.5 Hz, 1H, Ar—H), 7.62 (dd, J=2.4 and 9.2 Hz, 1H, Ar—H), 7.68 (t, J=7.7 Hz, 1H, Ar—H), 7.83 (t, J=7.9 Hz, 1H, Ar—H), 7.90 (d, J=7.0 Hz, 1H, Ar—H), 7.97 (d, J=2.3 Hz, 1H, Ar—H), 8.10 (d, J=8.3 Hz, 1H, Ar—H), 8.29 (d, J=7.1 Hz, 1H, Ar—H), 8.47 (d, J=9.2 Hz, 1H, Ar—H), 8.70 (d, J=7.8 Hz, 1H, Ar—H), 8.87 (d, J=5.2 Hz, 1H, Ar—H), 9.86 (s, 1H, benzene-NH). LC-MS (m/z) 474 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[O:10])[NH:8][C:6](=[O:7])[C:5]2=[CH:11][CH:12]=1.O.[NH2:14]N.O>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[O:10])[N:8]([NH2:14])[C:6](=[O:7])[C:5]2=[CH:11][CH:12]=1
Reactant: NN
Reactant: O=C1NC(=O)c2cc(Cl)ccc21
Solvent: O
Solvent: CCO
Product: NN1C(=O)c2ccc(Cl)cc2C1=O
Temperature: 25 °C
Reaction time: 0.03 h
Yield: 20.3 %

Procedure:
To a cooled mixture of 1.81 g (10 mmol) 4-chloro phthalimide in 20 mL ethanol (96%) was added 0.5 mL (10 mmol) hydrazine monohydrate. The reaction mixture was stirred for 2 min. at room temperature and 2 min. at reflux. By adding 50 mL cold water pale yellow crystals formed after 1 h. Resulting crystals was filtered and recrystallized from ethanol to give 0.4 g (20%)4-chloro-N-amino-phthalimide :top 172°-175° C.; 1H NMR (200 MHz, DMSO-d6) d 4.90 (s, 2H, NH2), 7.82-7.92 (m, 3H, C6H3); it solidifies after melting and melts again around 345° C.
Reaction SMILES: Br[C:2]1[C:3]2[N:4]([N:8]=[C:9]([Cl:11])[N:10]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:12][S:13]([C:16]1[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=1[CH2:18][NH2:19])(=[O:15])=[O:14].Cl>>[Cl:11][C:9]1[N:10]=[C:3]2[C:2]([NH:19][CH2:18][C:17]3[CH:20]=[CH:21][CH:22]=[CH:23][C:16]=3[S:13]([CH3:12])(=[O:15])=[O:14])=[CH:7][CH:6]=[CH:5][N:4]2[N:8]=1
Reactant: Clc1nc2c(Br)cccn2n1
Reactant: CS(=O)(=O)c1ccccc1CN
Agent: Cl
Product: CS(=O)(=O)c1ccccc1CNc1cccn2nc(Cl)nc12

Procedure:
(2-Chloro-[1,2,4]triazolo[1,5-a]pyridin-8-yl)-(2-methanesulfonyl-benzyl)-amine was prepared from 8-bromo-2-chloro-[1,2,4]triazolo[1,5-a]pyridine (470.0 mg, 2.022 mmol) and 2-methanesulfonyl-benzylamine; hydrochloride (500.0 mg, 2.255 mmol) in a manner analogous to Example 2d. Product isolated as a yellow solid (0.45 g, 66%). MP=161-163° C. 1H NMR (400 MHz, CDCl3, δ, ppm): 8.11 (d, J=7.6 Hz, 1H), 7.92 (d, J=6.6 Hz, 1H), 7.64-7.60 (m, 2H), 7.56-7.51 (m, 1H), 6.88 (t, J=7.5 Hz, 1H), 6.53 (d, J=7.8 Hz, 1H), 5.43 (t, J=5.9 Hz, 1H), 4.98 (d, J=6.1 Hz, 2H), 3.15 (s, 3H). MS=337, 339 (MH)+. 138b) N(8)-(2-Methanesulfonyl-benzyl)-N(2)-[4-(4-methyl-piperazin-1-yl)-phenyl]-[1,2,4]triazolo[1,5-a]pyridine-2,8-diamine was prepared from (2-chloro-[1,2,4]triazolo[1,5-a]pyridin-8-yl)-(2-methanesulfonyl-benzyl)-amine (75.0 mg, 0.223 mmol) and 4-(4-methyl-piperazin-1-yl)-phenylamine (47.0 mg, 0.246 mmol) with 2,2′-bis-dicyclohexylphosphanyl-biphenyl (25.0 mg, 0.0457 mmol) as the ligand in a manner analogous to Example 2d. Product isolated as a tan foam (0.035 g, 32%). 1H NMR (400 MHz, CDCl3, δ, ppm): 8.11 (d, J=7.9 Hz, 1H), 7.84 (d, J=6.5 Hz, 1H), 7.67-7.59 (m, 2H), 7.55-7.50 (m, 1H), 7.47 (d, J=8.8 Hz, 2H), 6.96 (d, J=8.9 Hz, 2H), 6.68 (t, J=7.3 Hz, 1H), 6.55 (s, 1H), 6.41 (d, J=7.7 Hz, 1H), 5.19 9t, J=6.1 Hz, 1H), 4.96 (d, J=6.1 Hz, 2H), 3.20-3.14 (m, 7H), 2.69-2.58 (m, 4H), 2.39 (s, 3H). MS=492 (MH)+.
Reaction SMILES: [ClH:1].[CH3:2][C@@:3]([C:13]([OH:15])=[O:14])([CH2:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1)[NH2:4].[CH3:16]O>>[ClH:1].[CH3:16][O:14][C:13](=[O:15])[C@:3]([CH3:2])([CH2:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1)[NH2:4]
Reactant: C[C@](N)(Cc1ccc(O)cc1)C(=O)O
Reactant: CO
Agent: Cl
Product: COC(=O)[C@@](C)(N)Cc1ccc(O)cc1
Reaction time: 48 h
Yield: 100 %

Procedure:
Anhydrous hydrogen chloride was bubbled through a solution of α-methyl-L-tyrosine (1 g, 5.13 mmol) in methanol (100 ml) for a few minutes and the solution stirred at room temeprature for 48 h. The solvent was evaporated in vacuo and the residue freeze dried from a mixture of methanol and water to give the title compound as a white powder (1.28 g, 100%); δH (CD3OD) 7.00 (2H, d, J 8.6 Hz, ArH), 6.78 (2H, d, J 8.6 Hz, ArH), 3.82 (3H, s, CO2CH3), 3.19 (1H, d, J 14.3 Hz, CHAHBAr), 3.01 (1H, d, J 14.3 Hz, CHAHBAr) and 1.59 (3H, s, CCH3); m/z (ES, 27V) 210 (M+ +1).