Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([CH3:17])[CH:12]=3)[O:10][C:3]=12.[CH3:18][C:19]1[C:27]([NH2:28])=[CH:26][CH:25]=[C:24]2[C:20]=1[CH:21]=[CH:22][NH:23]2>>[CH3:18][C:19]1[C:27]([NH:28][C:2]2[CH:7]=[CH:6][N:5]=[C:4]3[CH:8]=[C:9]([C:11]4[CH:12]=[C:13]([CH3:17])[CH:14]=[CH:15][CH:16]=4)[O:10][C:3]=23)=[CH:26][CH:25]=[C:24]2[C:20]=1[CH:21]=[CH:22][NH:23]2
Reactant: Cc1c(N)ccc2[nH]ccc12
Reactant: Cc1cccc(-c2cc3nccc(Cl)c3o2)c1
Product: Cc1cccc(-c2cc3nccc(Nc4ccc5[nH]ccc5c4C)c3o2)c1

Procedure:
The title compound was prepared by procedure E using 7-chloro-2-(3-methylphenyl)furo[3,2-b]pyridine (23.00 mg; 0.09 mmol; 1.00 eq.) instead of 7-chloro-2-(3,4,5-trimethoxyphenyl)furo[3,2-b]pyridine, and 4-methyl-1H-indol-5-ylamine (14.49 mg; 0.10 mmol; 1.05 eq.) instead of 6-amino-2,2-difluoro-4H-benzo[1,4]oxazin-3-one, and was obtained as a beige solid (22 mg, 67%). (HPLC (method F): 99%, RT: 4.24 min); 1H NMR (500 MHz, DMSO-d6) δ [ppm] 11.15 (s, 1H), 8.55 (s, 1H), 7.96 (d, J=5.5, 1H), 7.75 (d, J=7.5, 1H), 7.69 (s, 1H), 7.44-7.34 (m, 3H), 7.31 (d, J=8.3, 1H), 7.22 (d, J=7.3, 1H), 7.01 (d, J=8.4, 1H), 6.52 (s, 1H), 6.13 (d, J=5.5, 1H), 2.36 (s, 3H), 2.35 (s, 3H); MS (m/z) 354 [M+H]+, RT: 4.1 min.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:17][CH2:18][C:19]1[C:20]([Cl:33])=[CH:21][C:22]2[CH:23]3[CH2:32][CH2:31][CH2:30][CH:24]3[C:25](=O)[NH:26][C:27]=2[CH:28]=1)[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:43])=CC=1>>[C:1]([O:5][C:6]([N:8]([CH2:17][CH2:18][C:19]1[C:20]([Cl:33])=[CH:21][C:22]2[CH:23]3[CH2:32][CH2:31][CH2:30][CH:24]3[C:25](=[S:43])[NH:26][C:27]=2[CH:28]=1)[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CC(C)(C)OC(=O)N(CCc1cc2c(cc1Cl)C1CCCC1C(=O)N2)Cc1cccc(Cl)c1
Product: CC(C)(C)OC(=O)N(CCc1cc2c(cc1Cl)C1CCCC1C(=S)N2)Cc1cccc(Cl)c1

Procedure:
A solution of 90 mg (0.18 mmol) of 7-(N-tert-butoxycarbonyl-3-chlorobenzyl-amino)ethyl-8-chloro-1,2,3,3a,5,9b-hexahydrocyclopenta[c]quinolin-4-one and 194 mg (0.48 mmol) of Lawesson's reagent are stirred for 1 hour at room temperature and refluxed for 1 hour. After concentration by evaporation in a vacuum, the residue is purified by column chromatography with hexane-ethyl acetate: 80 mg of product.
Reaction SMILES: O[C:2]([CH2:4][CH2:5][CH2:6][CH2:7][C@H:8]1[C@@H:16]2[C@@H:11]([NH:12][C:13]([NH:15]2)=[O:14])[CH2:10][S:9]1)=[O:3].[NH:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1.[N:23]1C=CC=CC=1>S(Cl)(Cl)=O>[N:17]1([C@@:16]23[C@H:8]([CH2:7][CH2:6][CH2:5][CH2:4][C:2]([NH2:23])=[O:3])[S:9][CH2:10][C@@H:11]2[NH:12][C:13](=[O:14])[NH:15]3)[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1
Reactant: C1CNCCN1
Reactant: c1ccncc1
Reactant: O=C(O)CCCC[C@@H]1SC[C@@H]2NC(=O)N[C@@H]21
Solvent: O=S(Cl)Cl
Product: NC(=O)CCCC[C@@H]1SC[C@@H]2NC(=O)N[C@@]21N1CCNCC1
Reaction time: 0.08 h
Yield: 10 %

Procedure:
Biotin (0.34 g, 1.4 mmols) was dissolved in 8 mL of neat thionyl chloride. This reaction was allowed to proceed for 5 min before the reaction was placed under vacuum where excess thionyl chloride was removed. The resulting oil was resuspended in 10 mL of CH2Cl2 and dried down. This process was repeated three times in order to drive off excess thionyl chloride. A solution of piperazine (0.54 g, 6.3 mmols) dissolved in 30 mL of pyridine was added to the resulting oil. This solution was stirred overnight, concentrated and the resulting solid was triturated with 40 mL of MeOH. The MeOH soluble material was collected by filtration, concentrated, and triturated with 40 ml of CH2Cl2. The CH2Cl2 soluble material was collected by filtration, concentrated and chromatographed on a 1 cm silica column with 2:98 NH4OH:ethanol as the running solvent. Elution was monitored by TLC where the product displays an Rf of 0.80 with a 33:67 NH4OH:EtOH developing solution. The appropriate fractions were concentrated to give 42.9 mg of the piperazine biotinamide as a white solid in a 10% yield.
Reaction SMILES: C1C[O:4]CC1.[Cl:6][C:7]1[CH:8]=[CH:9][C:10]2[N:16]([CH3:17])[CH2:15][CH2:14][N:13]=[C:12]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[I:24])[C:11]=2[CH:25]=1.C(=O)(O)[O-].[Na+].BrN1C(=O)CCC1=O>O>[Cl:6][C:7]1[CH:8]=[CH:9][C:10]2[N:16]([CH3:17])[C:15](=[O:4])[CH2:14][N:13]=[C:12]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[I:24])[C:11]=2[CH:25]=1
Reactant: C1CCOC1
Reactant: CN1CCN=C(c2ccccc2I)c2cc(Cl)ccc21
Agent: O=C([O-])O
Agent: O=C1CCC(=O)N1Br
Agent: [Na+]
Solvent: O
Product: CN1C(=O)CN=C(c2ccccc2I)c2cc(Cl)ccc21
Reaction time: 0.5 h

Procedure:
A THF solution of 158 mg 7-chloro-2,3-dihydro-5-(2-iodophenyl)-1-methyl-1H-1,4-benzodiazepine and a sodium bicarbonate aqueous solution were simultaneously added by drops to a THF solution of N-bromosuccinimide at room temperature. After the mixture had been stirred at the same temperature for additional 30 minutes, water was poured thereinto and the resulting mixture was extracted with ethyl acetate. Purifying the crude product by silica gel column chromatography gave 140 mg of 2'-iododiazepam.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:13]=[C:12]([O:14][CH:15]([CH3:17])[CH3:16])[NH:11][N:10]=2)[C:5]([N+:18]([O-:20])=[O:19])=[CH:4][CH:3]=1.[NH2:21][C@H:22]([C:25]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=1)[CH2:23][OH:24].CCN(C(C)C)C(C)C>CCCCO>[F:31][C:28]1[CH:27]=[CH:26][C:25]([C@@H:22]([NH:21][C:2]2[CH:3]=[CH:4][C:5]([N+:18]([O-:20])=[O:19])=[C:6]([NH:8][C:9]3[CH:13]=[C:12]([O:14][CH:15]([CH3:17])[CH3:16])[NH:11][N:10]=3)[N:7]=2)[CH2:23][OH:24])=[CH:30][CH:29]=1
Reactant: CC(C)Oc1cc(Nc2nc(Cl)ccc2[N+](=O)[O-])n[nH]1
Reactant: N[C@@H](CO)c1ccc(F)cc1
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)Oc1cc(Nc2nc(N[C@@H](CO)c3ccc(F)cc3)ccc2[N+](=O)[O-])n[nH]1
Temperature: 165 °C
Yield: 85.8 %

Procedure:
A mixture of 6-chloro-N-(5-isopropoxy-1H-pyrazol-3-yl)-3-nitropyridin-2-amine (Method 28; 0.25 g, 0.84 mmol), (R)-2-amino-2-(4-fluorophenyl)ethanol (0.15 g, 0.97 mmol) and DIEA (0.16 ml, 0.92 mmol) in n-BuOH (3 ml) was heated in a sealed tube at 165° C. for 4 hours. The solvent was removed under reduced pressure and the residue was purified by column chromatography (hexane-EtOAc=1:2) to give the title compound as a yellow solid (0.30 g, 87%). 1H NMR (400 MHz) δ 12.12, 12.10 & 11.61 (s, 1H), 10.94, 10.89 & 10.74 (s, 1H), 9.05, 8.82 & 8.73 (d, J=7.2 Hz, 1H), 8.13 & 8.11 (d, J=9.2 Hz, 1H), 7.45-7.32 (m, 2H), 7.20-7.10 (m, 2H), 6.32 & 6.07 (d, J=9.2 Hz, 1H), 5.90, 5.83 & 5.79 (s, 1H), 5.23, 5.12 & 4.78 (m, 2H), 4.71, 4.64 & 4.37 (m, 1H), 3.69 (m. 2H), 1.34 & 1.29 (d, J=6.0 Hz, 6H). MS: Calcd.: 416. Found: [M+H]+ 417.
Reaction SMILES: C(O)C.Br[C:5]1[CH:6]=[CH:7][C:8]2[NH:14][CH2:13][CH2:12][C:11]([C:15]([O:17][CH3:18])=[O:16])=[CH:10][C:9]=2[CH:19]=1.B([O-])([O-])O[C:22]1[CH:27]=[CH:26][C:25]([O:28][CH2:29][CH2:30][O:31][CH2:32][CH2:33][CH2:34][CH3:35])=[CH:24][CH:23]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)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.O>[CH2:32]([O:31][CH2:30][CH2:29][O:28][C:25]1[CH:24]=[CH:23][C:22]([C:5]2[CH:6]=[CH:7][C:8]3[NH:14][CH2:13][CH2:12][C:11]([C:15]([O:17][CH3:18])=[O:16])=[CH:10][C:9]=3[CH:19]=2)=[CH:27][CH:26]=1)[CH2:33][CH2:34][CH3:35]
Reactant: COC(=O)C1=Cc2cc(Br)ccc2NCC1
Reactant: CCCCOCCOc1ccc(OB([O-])[O-])cc1
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: [K+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OC)CCN3)cc1
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 81.3 %

Procedure:
In toluene (200 ml) and ethanol (35 ml) were suspended methyl 7-bromo-2,3-dihydro-1-benzazepine-4-carboxylate (5.0 g), 4-butoxyethoxyphenyl borate (4.6 g) and 1M potassium carbonate solution (35 ml), and the mixture was stirred for 30 minutes under argon atmosphere. Then, to the mixture was added tetrakistriphenylphosphinepalladium (1 g), and the mixture was heated at 100° C. overnight under argon atmosphere. After allowing to cool, to the mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed a with saturated brine and dried with magnesium sulfate. The solvent was evaporated under reduced pressure, and the resulting residue was purified with silica gel column chromatography (hexane:ethyl acetate=4:1) to give the solid, which was washed with hexane to give methyl 7-(4-butoxyethoxyphenyl)-2,3-dihydro-1-benzazepine-4-carboxylate (5.7 g) as yellow crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([Cl:9])[C:3]=1[NH2:4].C(=O)([O-])O.[Na+].[CH3:15][O:16][C:17](=[O:21])[CH:18](Br)[CH3:19]>O>[CH3:15][O:16][C:17](=[O:21])[CH:18]([NH:4][C:3]1[C:2]([Cl:1])=[CH:8][CH:7]=[CH:6][C:5]=1[Cl:9])[CH3:19]
Reactant: COC(=O)C(C)Br
Reactant: Nc1c(Cl)cccc1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: COC(=O)C(C)Nc1c(Cl)cccc1Cl

Procedure:
40.5 g of 2,6-dichloroaniline, 21 g of sodium hydrogen carbonate and 84 ml of DL-α-bromopropionic acid methyl ester are stirred in a sulphonating flask for 2 days at 140° bath temperature. After cooling, the reaction mixture is poured into water and extracted with ethyl acetate. The combined ethyl acetate fractions are extracted once with saturated sodium chloride solution, dried over sodium sulphate and concentrated in a rotary evaporator. The excess α-bromopropionic acid methyl ester is recovered in a water-jet vacuum. The darkly coloured residue remaining is fractionally distilled in high vacuum. There is obtained 23.6 g of α-(2,6-dichloroanilino)-propionic acid methyl ester; b.p. 85°-87°/0.001 Torr.
Reaction SMILES: [CH3:1][NH:2][C:3]1[N:8]=[C:7]([C:9]2[S:10][C:11]3[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=3[C:13](=[O:15])[N:14]=2)[CH:6]=[CH:5][CH:4]=1.[S:20]1[CH:24]=[CH:23][CH:22]=[C:21]1[C:25](Cl)=[O:26].CN(C)C(=O)C>O>[CH3:1][N:2]([C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([C:9]2[S:10][C:11]3[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=3[C:13](=[O:15])[N:14]=2)[N:8]=1)[C:25]([C:21]1[S:20][CH:24]=[CH:23][CH:22]=1)=[O:26]
Reactant: O=C(Cl)c1cccs1
Reactant: CNc1cccc(-c2nc(=O)c3ccccc3s2)n1
Solvent: CC(=O)N(C)C
Solvent: O
Product: CN(C(=O)c1cccs1)c1cccc(-c2nc(=O)c3ccccc3s2)n1
Temperature: 80 °C
Reaction time: 2 h
Yield: 81.9 %

Procedure:
A mixture of 2-(6-methylamino-2-pyridyl)-4H-1,3-benzothiazine-4-one (0.20 g, 0.74 mmol), 2-thiophenecarbonyl chloride (0.28 g, 1.9 mmol) and N,N-dimethylacetamide (10 ml) was stirred at 80° C. for 2 hrs. After cooling, the reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed successively with saturated aqueous sodium hydrogen carbonate solution and brine and dried. The solvent was evaporated. The residue was recrystallized from tetrahydrofuran-hexane to give the titled compound (0.23 g, 83%).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:23])[CH:10]([N:20]=[N+]=[N-])[CH2:11][O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:24].[H][H]>C(O)C.[Re+5]=S>[ClH:24].[CH2:1]([O:8][C:9](=[O:23])[CH:10]([CH2:11][O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[NH2:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: [H][H]
Reactant: [N-]=[N+]=NC(COCc1ccccc1)C(=O)OCc1ccccc1
Agent: S=[Re+5]
Agent: Cl
Solvent: CCO
Product: NC(COCc1ccccc1)C(=O)OCc1ccccc1
Reaction time: 20 h
Yield: 88 %

Procedure:
1.56 grams (0.005 mole) of 2-azido-3-benzyloxypropionic acid benzyl ester were dissolved in 10 ml of ethanol, 1.50 grams (0.041 mole) of dry hydrogen chloride gas led in and 0.03 grams of rhenium (VII) sulfide added. This reaction mixture was hydrogenated in an autoclave for 20 hours at 25° C. and a hydrogen pressure of 20 bar. After filtering off the catalyst the solvent was vaporized. The oil obtained (1.42 grams=88% of crude O-benzyl-D,L-serine benzyl ester hydrochloride) was dissolved in chloroform and treated with diethyl ether. The precipitated crystals were recrystallized three times from ethanol/diethyl ether. There was obtained 0.78 grams (48% of theory) of O-benzyl-D,L-serine benzyl ester hydrochloride having a melting point of 144.5°-145.5° C. (literature: 147.5°-148.5° C.).
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[P:8](Cl)([Cl:17])(=[O:16])[O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[P:8]([Cl:17])(=[O:16])([O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[O:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Oc1ccccc1
Reactant: O=P(Cl)(Cl)Oc1ccccc1
Product: O=P(Cl)(Oc1ccccc1)Oc1ccccc1

Procedure:
To the reaction mixture of (1), there is added 188 g. phenol and the temperature is raised to 150°C. for 2 hours. The reaction mixture is alllowed to cool and stripped of phenyl phosphorodichloridate. Distillation of the residue affords principally diphenyl phosphorochloridate.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:26])[C:7]=1[CH2:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([O:19][CH3:20])=[CH:16][CH:17]=2)[C:12](=[O:21])[N:11]([CH2:22][C:23]([OH:25])=O)[N:10]=1.N#N.C(N1C=CN=C1)(N1C=CN=C1)=O.Cl.[NH2:42][OH:43]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:26])[C:7]=1[CH2:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([O:19][CH3:20])=[CH:16][CH:17]=2)[C:12](=[O:21])[N:11]([CH2:22][C:23]([NH:42][OH:43])=[O:25])[N:10]=1
Reactant: COc1ccc2c(Cc3c(Cl)cncc3Cl)nn(CC(=O)O)c(=O)c2c1
Reactant: NO
Agent: Cl
Agent: N#N
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: COc1ccc2c(Cc3c(Cl)cncc3Cl)nn(CC(=O)NO)c(=O)c2c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 47.3 %

Procedure:
A solution of [4(3,5-dichloro-pyridin-4-ylmethyl)-7-methoxy-1-oxo-1H-phthalazin-2-yl]-acetic acid (0.61 g, 1.55 mmoles), prepared as described in example 90, in dry DMF (25 ml), pH under N2, was added with 1,1′-carbonyldiimidazole (0.38 g, 2.32 mmoles). The mixture was stirred at room temperature for 4 hours then cooled, added with hydroxylamine hydrochloride (0.18 g, 2.55 mmoles) and stirred overnight. A precipitate formed and the solution was dried under vacuum, then taken up in 10% NaOH. The stirring was kept on for 2 hours, then the solid was filtered, washed with water, then with acetone and ethyl ether. It was taken up in 5% HCl and stirred for 1 hour, then filtered and washed with water, acetone and ethyl ether. The solid was dried under vacuum at 50° C., crystallised from acetic acid (60 ml) and dried under vacuum at 40° C. to give 0.3 g of the title compound (yield: 40%).
Reaction SMILES: [Si:1]([O:8][CH2:9][C@@H:10]([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])[C@H:11]([C:15]1[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=1)/[CH:12]=C/C)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[BH4-].[Na+].C[OH:36].C(Cl)Cl>>[Si:1]([O:8][CH2:9][C@@H:10]([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:29])[CH3:30])[C@H:11]([C:15]1[CH:20]=[CH:19][C:18]([C:21]([F:23])([F:24])[F:22])=[CH:17][CH:16]=1)[CH2:12][OH:36])([C:4]([CH3:6])([CH3:7])[CH3:5])([CH3:3])[CH3:2]
Reactant: CO
Reactant: C/C=C/[C@@H](c1ccc(C(F)(F)F)cc1)[C@@H](CO[Si](C)(C)C(C)(C)C)NC(=O)OC(C)(C)C
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@H](CO[Si](C)(C)C(C)(C)C)[C@@H](CO)c1ccc(C(F)(F)F)cc1
Temperature: -78 °C
Reaction time: 3 h
Yield: 97 %

Procedure:
Tert-butyl (2S,3S,E)-1-(tert-butyldimethylsilyloxy)-3-(4-(trifluoromethyl)phenyl)hex-4-en-2-ylcarbamate (2.0 g, 4.2 mmol) was dissolved in 40 mL of 1:1 MeOH/DCM, and the mixture was chilled to −78° C. Ozone was bubbled through the mixture until a blue color persisted. Nitrogen was then bubbled through the mixture for 15 minutes. NaBH4 (0.80 g, 21 mmol) was added, and the mixture was warmed to room temperature. After 3 hours, the mixture was quenched with aq NH4Cl. The mixture was extracted three times with 50 mL of DCM. The combined organic extracts were dried over MgSO4. Filtration and concentration under reduced pressure afforded tert-butyl (2S,3S)-1-(tert-butyldimethylsilyloxy)-4-hydroxy-3-(4-(trifluoromethyl)phenyl)butan-2-ylcarbamate (1.9 g, 97% yield) as a white solid. 1H NMR (400 MHz, CDCl3) δ ppm 7.56 (d, J=8.03 Hz, 2H) 7.32 (d, J=8.03 Hz, 2H) 4.51 (s, 1H) 4.22-4.16 (m, 1H) 3.90-3.66 (m, 3H) 3.47 (d, J=5.52 Hz, 2H) 3.15-3.20 (m, 1H) 1.45 (s, 9H) 0.84 (s, 9H) 0.01 (s, 3H) −0.01 (s, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH:12]=[CH:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].ClC1C=CC=C(C(OO)=[O:23])C=1.C(OC(=O)C)C>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH:12]2[CH:11]([O:23]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC=CCC1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC2OC2CC1
Temperature: 25 °C
Yield: 81.8 %

Procedure:
To a stirred solution of 16.4 g 2,3,6,7-tetrahydro-azepine-1-carboxylic acid tert-butyl ester in 420 ml dichloromethane was added at −60° C. 35.8 g m-chloroperbenzoic acid (70% purity). The mixture was allowed to slowly warm to room temperature overnight, 1 l ethylacetate was added and the solution was extracted with aqueous sodium bicarbonate, 1N aqueous sodium hydroxide and brine. Evaporation of the solvent and chromatography yielded 14.5 g (82%) 8-oxa-4-aza-bicyclo[5.1.0]octane-4-carboxylic acid tert-butyl ester as colorless liquid; MS (EI): m/e=213 (M+,5%), 158 (22%), 140 (12%), 57 (100%). To a solution of 14.3 g 8-oxa-4-aza-bicyclo[5.1.0]octane-4-carboxylic acid tert-butyl ester in 750 ethanol was added 150 ml water, 35.8 g ammonium chloride and 43.6 g sodium azide. The mixture was stirred at 75° C. over night, the solvents were greatly removed by distillation under vacuum and the residue was suspended in ethanol and filtered. The ethanol was distilled off and the residue was suspended in ethylacetate and filtered. Removal of the solvent and chromatography on silicagel with ethylacetate/hexane 1:1, yielded 13.5 g (79%) 4-azido-5-hydroxy-azepane-1-carboxylic acid tert-butyl ester as a viscous oil; MS (ISP): m/e=257 (M+H+).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH:11][C:12]([CH:14]2[CH2:23][CH2:22][C:21]3[C:16](=[CH:17][C:18]([O:24][C:25]4[CH:30]=[CH:29][N:28]=[C:27]([C:31]#[N:32])[CH:26]=4)=[CH:19][CH:20]=3)[CH2:15]2)=[O:13])[CH:8]=[CH:9][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:33]([CH2:35]N)[OH:34].CCN(C(C)C)C(C)C>CCO>[C:1]([C:5]1[CH:6]=[C:7]([NH:11][C:12]([CH:14]2[CH2:23][CH2:22][C:21]3[C:16](=[CH:17][C:18]([O:24][C:25]4[CH:30]=[CH:29][N:28]=[C:27]([C:31]5[O:34][CH2:33][CH2:35][N:32]=5)[CH:26]=4)=[CH:19][CH:20]=3)[CH2:15]2)=[O:13])[CH:8]=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: NCCO
Reactant: CC(C)(C)c1cccc(NC(=O)C2CCc3ccc(Oc4ccnc(C#N)c4)cc3C2)c1
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)c1cccc(NC(=O)C2CCc3ccc(Oc4ccnc(C5=NCCO5)c4)cc3C2)c1
Temperature: 100 °C
Reaction time: 12 h

Procedure:
To a solution of N-(3-tert-butylphenyl)-7-[(2-cyanopyridin-4-yl)oxy]-1,2,3,4-tetrahydronaphthalene-2-carboxamide (1.184 g, 2.78 mmol) in EtOH (30 mL) was added ethanolamine (1.00 mL, 16.6 mmol) and DIPEA (1.00 mL, 5.74 mmol). The reaction mixture was allowed to stir at 100° C. for 12 h. The mixture was concentrated and the residue was diluted with water and EtOAc. The solution was extracted with EtOAc and the organic solutions were combined, washed with brine, dried over MgSO4, filtered and concentrated. The residue was purified by column chromatography to give N-(3-tert-butylphenyl)-7-{[2-(4,5-dihydro-1,3-oxazol-2-yl)pyridin-4-yl]oxy}-1,2,3,4-tetrahydronaphthalene-2-carboxamide I-305 (1.069 g, 82%) as a white solid. 1H NMR (400 MHz, d6-DMSO, HCl salt) δ: 9.97 (s, 1H), 9.02 (t, 1H), 8.52 (d, 1H), 7.66-7.62 (m, 1H), 7.52-7.47 (m, 1H), 7.40-7.36 (m, 1H), 7.26-7.17 (m, 3H), 7.08-6.94 (m, 3H), 3.72 (t, 2H), 3.59 (q, 2H), 2.97-2.71 (m, 5H), 2.15-2.06 (m, 1H), 1.85-1.74 (m, 1H), and 1.25 (s, 9H). LCMS: (FA) ES+470.4, ES−468.2.
Reaction SMILES: [CH3:1][C:2]([CH3:7])([CH3:6])[C:3]([NH2:5])=[O:4].C(Cl)(=O)[C:9](Cl)=[O:10].[F:14][C:15]([F:37])([F:36])[C:16]1[CH:21]=[C:20]([C:22]2[CH:27]=[C:26]([O:28][C:29]3[CH:30]=[CH:31][C:32]([NH2:35])=[N:33][CH:34]=3)[CH:25]=[CH:24][N:23]=2)[CH:19]=[CH:18][N:17]=1.N1C=CC=CC=1>ClCCCl.O1CCOCC1>[F:37][C:15]([F:14])([F:36])[C:16]1[CH:21]=[C:20]([C:22]2[CH:27]=[C:26]([O:28][C:29]3[CH:30]=[CH:31][C:32]([NH:35][C:9]([NH:5][C:3](=[O:4])[C:2]([CH3:7])([CH3:6])[CH3:1])=[O:10])=[N:33][CH:34]=3)[CH:25]=[CH:24][N:23]=2)[CH:19]=[CH:18][N:17]=1
Reactant: CC(C)(C)C(N)=O
Reactant: O=C(Cl)C(=O)Cl
Reactant: Nc1ccc(Oc2ccnc(-c3ccnc(C(F)(F)F)c3)c2)cn1
Solvent: ClCCCl
Solvent: c1ccncc1
Solvent: C1COCCO1
Product: CC(C)(C)C(=O)NC(=O)Nc1ccc(Oc2ccnc(-c3ccnc(C(F)(F)F)c3)c2)cn1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 58.7 %

Procedure:
A solution of 2,2,2-trimethylacetamide (0.019 g, 0.190 mmol) in DCE (2 mL) was treated with oxalyl chloride (0.017 mL, 0.190 mmol), stirred at RT for 5 min, then heated at 80° C. for 0.5 h. The mixture was cooled to RT, added to a solution of 5-((2′-(trifluoromethyl)-[2,4′-bipyridin]-4-yl)oxy)pyridin-2-amine (0.042 g, 0.126 mmol) and pyridine (0.082 mL, 1.011 mmol) in dioxane (4 mL) and stirred at RT for 3 h. The mixture was treated with satd. NaHCO3, extracted with EtOAc (3×) and the combined organics were dried over Na2SO4 and concentrated to dryness. The material was treated with MeCN and the solid collected via filtration to afford N-((5-((2′-(trifluoromethyl)-[2,4′-bipyridin]-4-yl)oxy)pyridin-2-yl)carbamoyl)pivalamide (34 mg, 59%) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 11.24 (s, 1H), 10.45 (s, 1H), 8.87 (d, J=5.1 Hz, 1H), 8.65 (d, J=5.6 Hz, 1H), 8.51 (s, 1H), 8.37 (d, J=5.2 Hz, 1H), 8.32 (d, J=2.9 Hz, 1H), 8.11 (d, J=9.0 Hz, 1H), 7.97 (d, J=2.4 Hz, 1H), 7.79 (dd, J=9.0, 2.9 Hz, 1H), 7.05 (dd, J=5.6, 2.4 Hz, 1H), 1.21 (s, 9H); MS (ESI) m/z: 460.2 (M+H+).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:14]([C:15]3[CH:22]=[CH:21][C:18]([CH2:19][NH2:20])=[CH:17][CH:16]=3)[N:13]=[C:12]([C:23]([F:26])([F:25])[F:24])[CH:11]=2)=[CH:6][CH:5]=1.C(N(CC)CC)C.[CH3:34][S:35](Cl)(=[O:37])=[O:36]>ClCCl>[CH3:2][O:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[N:14]([C:15]3[CH:22]=[CH:21][C:18]([CH2:19][NH:20][S:35]([CH3:34])(=[O:37])=[O:36])=[CH:17][CH:16]=3)[N:13]=[C:12]([C:23]([F:26])([F:24])[F:25])[CH:11]=2)=[CH:8][CH:9]=1
Reactant: CS(=O)(=O)Cl
Reactant: COc1ccc(-c2cc(C(F)(F)F)nn2-c2ccc(CN)cc2)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(-c2cc(C(F)(F)F)nn2-c2ccc(CNS(C)(=O)=O)cc2)cc1

Procedure:
To a solution of 4-[5-(4-methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzylamine hydrochloride obtained by Example 70 (150 mg) and triethylamine (0.1 ml) in dichloromethane (10 ml) was added dropwise methanesulfonyl chloride (0.06 ml) under ice cooling.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][CH2:7][C:6]([C:12]([OH:14])=[O:13])=[CH:5]2.CCN(CC)CC.[CH3:22][OH:23].CN([CH:27]=[O:28])C>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>[CH3:22][O:23][C:27]([C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][CH2:7][C:6]([C:12]([OH:14])=[O:13])=[CH:5]2)=[O:28]
Reactant: CN(C)C=O
Reactant: CO
Reactant: O=C(O)C1=Cc2cc(Br)ccc2OC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc2c(c1)C=C(C(=O)O)CO2
Temperature: 80 °C
Yield: 66 %

Procedure:
A mixture of XXXI (2 g, 7.84 mmol), Pd (PPh3)4 (1.36 g, 1.18 mmol), Et3N (3.3 mL, 23.52 mmol), MeOH (30 mL) and DMF (10 mL) was heated at 80° C. for 12 h under carbon monoxide atmosphere. After solvent removal, the residue was extracted with EtOAc and the organic phase was washed with brine, dried over Na2SO4, filtered, and evaporated. After silica gel column purification, 1.2 g of 2H-chromene-3,6-dicarboxylic acid 6-methyl ester XXXII was obtained (Yield 66%). MS: calc'd 235 (MH+), exp 235 (MH+).