Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:11])[CH3:10])=[C:4]([F:12])[CH:3]=1.[CH:13](NC(C)C)(C)[CH3:14].[Li]CCCC.ICC.Cl>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:11])[CH3:10])=[C:4]([F:12])[C:3]=1[CH2:13][CH3:14]
Reactant: CC(=O)Nc1ccc(Cl)cc1F
Reactant: CC(C)NC(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: CCI
Solvent: C1CCOC1
Product: CCc1c(Cl)ccc(NC(C)=O)c1F
Temperature: -78 °C
Reaction time: 2 h

Procedure:
To a solution of N-(4-chloro-2-fluorophenyl)acetamide (10.0 g, 53.3 mmol) and diisopropylamine (7.5 mL, 53.3 mmol) in THF (300 mL) at −78° C. is added dropwise n-BuLi (2.5 M in hexanes, 42.6 mL, 106.6 mmol) keeping the reaction temperature below −60° C. After 2 hours, iodoethane (12.4 g, 80 mmol) is added dropwise at −78° C. The reaction mixture is stirred at −78° C. for additional 1.5 hours. A 1N solution of aqueous HCl is added slowly until a pH between 4 and 5 is reached. The mixture is extracted with EtOAc (200 mL×3) and the organic layers are combined washed with water and brine, then dried over MgSO4. The solvent is removed under reduced pressure and the solid residue is stirred in ether and hexane (1:4, 80 mL) for 1 hour. The filtered solid is dried to give N-(4-chloro-3-ethyl-2-fluorophenyl)acetamide.
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[C@H:7]2[C@@H:3]1[C@H:4]([C:9](Cl)([Cl:11])[Cl:10])[O:5][C:6]2=[O:8].CC1(C)[C@H]2[C@@H]1[C@@H](C(Cl)(Cl)Cl)OC2=O.C(=O)([O-])O.[Na+].Cl.C(OC)(C)(C)C>CN(C=O)C>[Cl:10][C:9]([Cl:11])=[CH:4][C@H:3]1[C@@H:7]([C:6]([OH:8])=[O:5])[C:2]1([CH3:1])[CH3:13]
Reactant: CC1(C)[C@H]2[C@H](C(Cl)(Cl)Cl)OC(=O)[C@H]21
Agent: CC1(C)[C@@H]2[C@H]1C(=O)O[C@@H]2C(Cl)(Cl)Cl
Agent: Cl
Agent: O=C([O-])O
Solvent: COC(C)(C)C
Solvent: CN(C)C=O
Product: CC1(C)[C@H](C(=O)O)[C@@H]1C=C(Cl)Cl
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
A mixture of (1R,4R,5S)-6,6-dimethyl-4-(trichloromethyl)-3-oxabicyclo[3.1.0]hexan-2-one (I, R1=X1=X2=Cl) and (1R,4S,5S)-6,6-dimethyl-4-(trichloromethyl)-3-oxabicyclo[3.1.0]hexan-2-one (I, R1=X1=X2=Cl), 0.24 g (0.001 mol), is stirred with sodium hydrogen carbonate, 0.21 g (0.0025 mol), and Pd(C) 5%, 0.01 g, in about 4 ml of DMF at 50° C. under a hydrogen atmosphere of a slight overpressure. After stirring for ½ hour at 50° C. the mixture is stirred at room temperature. Samples taken out for GC analysis are treated with aqueous hydrochloric acid/methyl t-butyl ether and analysed on GC. After 16 hours GC analysis (area-%) shows a content of 39% of II and 32% of unreacted I. The retention time is identical to that of II prepared according to Ref.6, and MS (Mass (intensity in % of base peak): 208 (6) M+, 210 (4) (M+2)+, 175 (25), 173 (78), 165 (27), 163 (39), 111 (22), 109 (28), 91 (100), 77 (46), 39 (64)) is identical to MS of II prepared according to Ref.6.
Reaction SMILES: C([O:8][C:9]([C@@H:11]1[CH2:15][CH2:14][CH2:13][N:12]1[C:16](=[O:29])[C@@H:17]([NH:24][C:25]([O:27][CH3:28])=[O:26])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:10])C1C=CC=CC=1>CO.O1CCCC1.[Pd]>[CH3:28][O:27][C:25]([NH:24][C@@H:17]([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[C:16]([N:12]1[CH2:13][CH2:14][CH2:15][C@H:11]1[C:9]([OH:10])=[O:8])=[O:29])=[O:26]
Reactant: COC(=O)N[C@H](C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1)c1ccccc1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)N[C@H](C(=O)N1CCC[C@H]1C(=O)O)c1ccccc1
Yield: 97.1 %

Procedure:
0.28 g of 1-[(S)-methoxycarbonylamino-phenyl-acetyl]-pyrrolidine-2-(S)-carboxylic acid benzyl ester were dissolved in a mixture of 15 mL of methanol and 15 mL of tetrahydrofuran and hydrogenated for 3 h at room temperature using 0.2 g palladium on charcoal (10%) as catalyst. Filtration followed by concentration in vacuo affords 0.21 g (100%) of the title compound as a white solid. (+)-APCI-MS: 307 (MH+).
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([CH:18]([CH3:20])[CH3:19])[C:13]([C:21]([OH:23])=[O:22])=[CH:12]2)C1C=CC=CC=1>[Pd].C(OCC)(=O)C.C(O)C>[OH:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([CH:18]([CH3:20])[CH3:19])[C:13]([C:21]([OH:23])=[O:22])=[CH:12]2
Reactant: CC(C)n1c(C(=O)O)cc2cc(OCc3ccccc3)ccc21
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CC(C)n1c(C(=O)O)cc2cc(O)ccc21
Temperature: 25 °C

Procedure:
A mixture of 5-benzyloxy-1-isopropyl-1H-indole-2-carboxylic acid (41.6 g, 1.0 eq.) and palladium on activated charcoal (10% m:m, 4.3 g, 0.03 eq.) in ethyl acetate (330 mL) and ethanol (235 mL) was flushed with hydrogen, then vigorously stirred for 2 h30 at room temperature. The resulting back suspension was filtered through a dicalite pad. The pad was washed with a mixture of ethyl acetate and ethanol then the liquor was evaporated in vacuo to yield 26.3 g (quant.) of the desired product as off-white oil. MS (m/e): 218.2 (M−H, 100%).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[C:9]([C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)[C:10]([C:11]3[CH:16]=[CH:15][N:14]=[C:13]([NH:17][CH:18]4[CH2:22][CH2:21][CH2:20][CH2:19]4)[N:12]=3)=[C:4]2[CH:3]=1.[CH:30]([NH2:33])([CH3:32])[CH3:31].C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH:18]1([NH:17][C:13]2[N:12]=[C:11]([C:10]3[C:9]([C:23]4[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=4)=[N:8][N:5]4[CH:6]=[CH:7][C:2]([NH:33][CH:30]([CH3:32])[CH3:31])=[CH:3][C:4]=34)[CH:16]=[CH:15][N:14]=2)[CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: CC(C)N
Reactant: Fc1ccc(-c2nn3ccc(Cl)cc3c2-c2ccnc(NC3CCCC3)n2)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Product: CC(C)Nc1ccn2nc(-c3ccc(F)cc3)c(-c3ccnc(NC4CCCC4)n3)c2c1

Procedure:
4-[5-Chloro-2-(4-fluorophenyl)pyrazolo[1,5-α]pyridin-3-yl]-N-cyclopentyl-2-pyrimidinamine (0.1 g, 0.25 mmol) and isopropylamine were treated with rac-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl, cesium carbonate and palladium (II) acetate as described in Example 2 to give, after purification by flash chromatography (1:1 hexanes-ethyl acetate), 3-[2-(cyclopentylamino)-4-pyrimidinyl]-2-(4-fluorophenyl)-N-isopropylpyrazolo[1,5-α]pyridin-5-amine (70 mg, 66%) as a solid. 1H-NMR (CDCl3): δ 8.17 (d, 1H), 7.9 (d, 1H), 7.58 (q, 2H), 7.4 (m, 1H), 7.15 (t, 2H), 6.24 (dd, 1H), 6.2 (d, 1H), 5.25 (broad s, 1H), 4.4 (m, 1H), 3.95 (d, 1H), 3.75 (m, 1H), 2.1 (m, 2H), 1.5–1.8 (m, 6H), 1.30 (d, 6H); 19F-NMR (CDCl3): δ −113.45; MS m/z 431 (M+1).
Reaction SMILES: [Si:1]([O:8][CH2:9][C@@H:10]([N:24]([CH2:37][CH:38]([CH3:40])[CH3:39])[S:25]([C:28]1[CH:36]=[CH:35][C:31]2[N:32]=[CH:33][S:34][C:30]=2[CH:29]=1)(=[O:27])=[O:26])[C:11]1[S:12][C:13](/[CH:16]=[N:17]\[S:18]([C:20]([CH3:23])([CH3:22])[CH3:21])=[O:19])=[CH:14][CH:15]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[BH4-].[Na+]>CO>[Si:1]([O:8][CH2:9][C@@H:10]([N:24]([CH2:37][CH:38]([CH3:40])[CH3:39])[S:25]([C:28]1[CH:36]=[CH:35][C:31]2[N:32]=[CH:33][S:34][C:30]=2[CH:29]=1)(=[O:27])=[O:26])[C:11]1[S:12][C:13]([CH2:16][NH:17][S:18]([C:20]([CH3:21])([CH3:22])[CH3:23])=[O:19])=[CH:14][CH:15]=1)([C:4]([CH3:6])([CH3:7])[CH3:5])([CH3:2])[CH3:3]
Reactant: CC(C)CN([C@H](CO[Si](C)(C)C(C)(C)C)c1ccc(/C=N\S(=O)C(C)(C)C)s1)S(=O)(=O)c1ccc2ncsc2c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)CN([C@H](CO[Si](C)(C)C(C)(C)C)c1ccc(CNS(=O)C(C)(C)C)s1)S(=O)(=O)c1ccc2ncsc2c1
Reaction time: 4 h

Procedure:
To a solution of N-[(1R)-2-{[tert-butyl(dimethyl)silyl]oxy}-1-(5-{(Z)-[(tert-butylsulfinyl)imino]methyl}thiophen-2-yl)ethyl]-N-(2-methylpropyl)-1,3-benzothiazole-6-sulfonamide (1.78 g, 2.77 mmol) in MeOH (28 mL) at 0° C. was added NaBH4 (0.11 g, 2.77 mmol) and the reaction mixture was stirred for 4 hours before being quenched by the addition of water (50 mL). The slurry was stirred for 20 minutes, then extracted with ethyl acetate (3×100 mL). The organic layers were combined and dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude was purified on silica gel eluting with hexanes and ethyl acetate.
Reaction SMILES: C(N(CC)CC)C.[C:8](N1C=CN=C1)(N1C=CN=C1)=[O:9].[F:20][C:21]([F:34])([F:33])[O:22][C:23]1[CH:32]=[CH:31][C:26]([C:27]([NH:29][NH2:30])=[O:28])=[CH:25][CH:24]=1>C1COCC1>[F:20][C:21]([F:33])([F:34])[O:22][C:23]1[CH:32]=[CH:31][C:26]([C:27]2[O:28][C:8](=[O:9])[NH:30][N:29]=2)=[CH:25][CH:24]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: NNC(=O)c1ccc(OC(F)(F)F)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=c1[nH]nc(-c2ccc(OC(F)(F)F)cc2)o1
Temperature: 25 °C
Reaction time: 2 h
Yield: 94.4 %

Procedure:
Triethylamine (3.52 ml, 25.28 mmol) and 1,1′-carbonyldiimidazole (4.84 g, 29.87 mmol) were added to a solution of 4-trifluoromethoxybenzoic hydrazide (5.06 g, 22.98 mmol) in THF (150 ml) while cooling in an ice-bath and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, to which water was added. The mixture was extracted with ethyl acetate, and the extract was dried over magnesium sulfate and then concentrated under reduced pressure to afford 5-(4-trifluoromethoxyphenyl)-3H-[1,3,4]oxadiazol-2-one (5.34 g, yield 94%) as a colorless crystalline powder.
Reaction SMILES: O.C[Si]([Cl:6])(C)C.[OH:7][C:8]1[CH:9]=[C:10]([C@@:14]2([OH:35])[C@H:19]([CH2:20][N:21]([CH3:30])[CH2:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C@@H:18]3[CH2:31][C@@H:16]([C:17]3([CH3:33])[CH3:32])[C@H:15]2[CH3:34])[CH:11]=[CH:12][CH:13]=1>CC(=O)CC>[ClH:6].[OH:7][C:8]1[CH:9]=[C:10]([C@@:14]2([OH:35])[C@H:19]([CH2:20][N:21]([CH3:30])[CH2:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C@@H:18]3[CH2:31][C@@H:16]([C:17]3([CH3:32])[CH3:33])[C@H:15]2[CH3:34])[CH:11]=[CH:12][CH:13]=1
Reactant: C[Si](C)(C)Cl
Agent: C[C@@H]1[C@H]2C[C@@H]([C@@H](CN(C)CCc3ccccc3)[C@]1(O)c1cccc(O)c1)C2(C)C
Solvent: O
Solvent: CCC(C)=O
Product: Cl
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Add H2O (4 mg, 0.25 mmol) and TMSCl (27 mg, 0.25 mmol) to a solution of (1R,2R,3S,4S,5S)-3-(3-hydroxyphenyl)-2,6,6-trimethyl-4-((methyl(phenethyl)amino)methyl)bicyclo[3.1.1]heptan-3-ol (100 mg, 0.25 mmol) in 2-butanone (5 mL). Stir the reaction mixture at room temperature for 3 hours. After removal solvent by evaporation, wash the residue with EtOAc (1 mL×2) and dry under vacuum to give (1R,2R,3S,4S,5S)-3-(3-hydroxyphenyl)-2,6,6-trimethyl-4-((methyl(phenethyl)amino)methyl)bicyclo[3.1.1]heptan-3-ol hydrochloride (93 mg, Yield: 85.3%) as white solid. 1H NMR (400 MHz, D2O) δ 7.21-7.32 (m, 7H), 7.97-7.99 (d, J=7.2, 1H), 6.71-6.78 (dd, J1=8.0, J2=22.0, 1H), 2.86-3.33 (m, 5H), 2.43-2.68 (m, 7H), 2.11-2.20 (m, 2H), 1.73-1.75 (m, 1H), 1.23-1.25 (d, J=5.6, 3H), 1.04-1.05 (d, J=4.4, 3H), 0.69-0.71 (d, J=5.6, 3H). [α]D20=−8.6 (c=1.4 mg/mL, MeOH).
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[CH:5][NH:4][N:3]=1.C(=NO)C1C(=CC=CC=1)O.C(=O)([O-])[O-].[Cs+].[Cs+].Br[C:24]1[S:25][CH:26]=[CH:27][CH:28]=1>[Cu-]=O.C(#N)C>[CH3:1][C:2]1[CH:6]=[CH:5][N:4]([C:24]2[S:25][CH:26]=[CH:27][CH:28]=2)[N:3]=1
Reactant: Cc1cc[nH]n1
Reactant: Brc1cccs1
Agent: O=[Cu-]
Agent: O=C([O-])[O-]
Agent: ON=Cc1ccccc1O
Solvent: CC#N
Product: Cc1ccn(-c2cccs2)n1
Temperature: 82 °C
Reaction time: 16 h

Procedure:
A mixture of 3-methylpyrazole (500 mg, 6.09 mmol), salicylaldoxime (167 mg, 1.22 mmol), copper (I) oxide (44 mg, 0.30 mmol), and cesium carbonate (3.97 g, 12.2 mmol) was sparged with argon for 3 minutes. To this mixture was added acetonitrile (3 ml) and 2-bromothiophene (0.88 ml, 9.1 mmol). The reaction mixture was sparged with argon for 3 minutes and heated to 82° C. After 16 hours, the reaction mixture was diluted with ethyl acetate, washed with water and brine, then dried over magnesium sulfate, filtered, and concentrated. The residue was purified by column chromatography on silica gel (ethyl acetate/hexanes gradient) to afford 3-methyl-1-(2-thienyl)-1H-pyrazole (faster eluting isomer) and 5-methyl-1-(2-thienyl)-1H-pyrazole (slower eluting isomer).
Reaction SMILES: F[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][O:12]2)=[C:4]([NH2:17])[N:3]=1.[CH3:18][C@H:19]([NH2:23])[CH2:20][CH2:21][CH3:22]>>[CH3:18][C@H:19]([NH:23][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][O:12]2)=[C:4]([NH2:17])[N:3]=1)[CH2:20][CH2:21][CH3:22]
Reactant: Nc1nc(F)nc2c1ncn2C1CCCCO1
Reactant: CCC[C@H](C)N
Product: CCC[C@H](C)Nc1nc(N)c2ncn(C3CCCCO3)c2n1

Procedure:
Prepared similarly to Intermediate 70 from 2-fluoro-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-amine and (2S)-2-pentanamine.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[N:20]=[C:19]([N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)[N:18]=[C:17]([O:27][CH2:28][CH2:29][C:30]([OH:32])=O)[C:16]=2[O:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=2[O:40][CH3:41])(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH:42]([C:45]1[CH:51]=[CH:50][C:48]([NH2:49])=[CH:47][CH:46]=1)([CH3:44])[CH3:43]>>[CH:42]([C:45]1[CH:51]=[CH:50][C:48]([NH:49][C:30](=[O:32])[CH2:29][CH2:28][O:27][C:17]2[C:16]([O:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=3[O:40][CH3:41])=[C:15]([NH:14][S:11]([C:8]3[CH:9]=[CH:10][C:5]([C:1]([CH3:2])([CH3:4])[CH3:3])=[CH:6][CH:7]=3)(=[O:13])=[O:12])[N:20]=[C:19]([N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)[N:18]=2)=[CH:47][CH:46]=1)([CH3:44])[CH3:43]
Reactant: CC(C)c1ccc(N)cc1
Reactant: COc1ccccc1Oc1c(NS(=O)(=O)c2ccc(C(C)(C)C)cc2)nc(N2CCOCC2)nc1OCCC(=O)O
Product: COc1ccccc1Oc1c(NS(=O)(=O)c2ccc(C(C)(C)C)cc2)nc(N2CCOCC2)nc1OCCC(=O)Nc1ccc(C(C)C)cc1

Procedure:
The procedure described in Example 2 was repeated by use of 3-[6-(4-t-butylphenylsulfonylamino)-5-(2-methoxyphenoxy )-2-morpholino-4-pyrimidinyloxy]propionic acid and 4-isopropylaniline, to thereby obtain the title compound as a colorless oil.
Reaction SMILES: Cl[CH2:2][CH2:3][NH:4][C@@H:5]1[CH2:7][C@H:6]1[C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=2)=[CH:10][CH:9]=1.[NH:24]1[CH2:28][CH2:27][C@H:26]([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])[CH2:25]1>CN(C=O)C>[F:21][C:20]([F:23])([F:22])[C:16]1[CH:15]=[C:14]([C:11]2[CH:12]=[CH:13][C:8]([C@@H:6]3[CH2:7][C@H:5]3[NH:4][CH2:3][CH2:2][N:24]3[CH2:28][CH2:27][C@H:26]([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:34])([CH3:33])[CH3:35])[CH2:25]3)=[CH:9][CH:10]=2)[CH:19]=[CH:18][CH:17]=1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCNC1
Reactant: FC(F)(F)c1cccc(-c2ccc([C@@H]3C[C@H]3NCCCl)cc2)c1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@H]1CCN(CCN[C@@H]2C[C@H]2c2ccc(-c3cccc(C(F)(F)F)c3)cc2)C1
Temperature: 25 °C
Reaction time: 48 h
Yield: 37 %

Procedure:
To a solution of (trans)-N-(2-chloroethyl)-2-(3′-(trifluoromethyl)biphenyl-4-yl)cyclopropanamine (750 mg, 2.21 mmol) in dry DMF (7.5 mL), (S)-tert-butyl pyrrolidin-3-ylcarbamate (864 mg g, 4.64 mmol) was added and stirred at RT for 48 h. After completion, the reaction mixture was poured into ice water (25 mL), extracted with EtOAc (2×20 mL). The combined extracts were washed with water (25 mL), brine (20 mL), dried over anhydrous Na2SO4, filtered and evaporated. The crude residue was purified by column chromatography (SiO2) using MeOH: CHCl3(4:96) to get tert-butyl (S)-1-(2-((trans)-2-(3′-(trifluoromethyl)biphenyl-4-yl)cyclopropylamino)ethyl)pyrrolidin-3-ylcarbamate (400 mg, 37%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[N:11][C:10]([OH:13])=[N:9]2)=[CH:4][CH:3]=1.[H-].[Na+].Br[CH:17]([CH3:23])[C:18]([O:20][CH2:21][CH3:22])=[O:19]>CS(C)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH:12]=[N:11][C:10]([O:13][CH:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH3:23])=[N:9]2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(C)Br
Reactant: Oc1ncn(-c2ccc(Cl)cc2)n1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CCOC(=O)C(C)Oc1ncn(-c2ccc(Cl)cc2)n1
Temperature: 0 °C

Procedure:
Six g of 1-(4-chlorophenyl)-3-hydroxy-1,2,4-1H-triazole was added to a suspension of 1.5 g of sodium hydride in 225 ml of dimethylsulfoxide. The mixture was heated on the steam bath for 90 minutes. Then 5.5 g of ethyl 2-bromopropionate was added and the mixture was heated for 90 minutes more. It was then cooled and poured over ice-water, and the solid was collected, dried and recrystallized from toluene to obtain 1.5 g of the desired product, m.p. 62°-64°.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:6]([C:8](=O)[CH3:9])[CH:7]=1.[BH4-].[Na+].[Al+3].[Cl-].[Cl-].[Cl-].O>C1COCC1>[CH2:8]([C:6]1[CH:7]=[C:2]([NH2:1])[CH:3]=[CH:4][C:5]=1[O:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[CH3:9]
Reactant: CC(=O)c1cc(N)ccc1Oc1ccccc1
Agent: [Al+3]
Agent: [BH4-]
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: O
Product: CCc1cc(N)ccc1Oc1ccccc1
Yield: 3.2 %

Procedure:
To a solution of 1-(5-amino-2-phenoxy-phenyl)ethanone (0.5 g, 2.20 mmol ) in THF (15 ml) was added sodium borohydride(0.4 g, 10.5 mmol ) and AlCl3 (anhydrous) (0.803 g, 6.02 mmol ) under nitrogen. The resulting reaction mixture was heated under reflux for 4 hours. Th e mixture was then cooled and iced-water added. The resultant mixture was extracted with EtOAc and dried over Na2SO4. Removal of the solvent afforded a brownish residue which was chromatographed with 4:1 hexane/EtOAc to afford (15 mg, 10%) product 3-ethyl-4-phenoxy-phenylamine.
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@@H:13]([NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)(=O)=O)=CC=1.[N-:28]=[N+:29]=[N-:30].[Na+]>CN(C)C=O.O.C(OCC)(=O)C>[N:28]([CH2:12][C@@H:13]([NH:20][C:21](=[O:22])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[N+:29]=[N-:30]
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H](NC(=O)OC(C)(C)C)c2ccccc2)cc1
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@H](CN=[N+]=[N-])c1ccccc1
Temperature: 65 °C
Reaction time: 8 h
Yield: 90 %

Procedure:
The mixture of (2S)-2-[(tert-butoxycarbonyl)amino]-2-phenylethyl 4-methylbenzenesulfonate (350 mg, 0.9 mmol, 1.0 eq.) and sodium azide (117 mg, 1.8 mmol, 2.0 eq.) in N,N-dimethylformamide (5 ml) was stirred at 65° C. overnight. The mixture was cooled to room temperature and diluted with water and ethyl acetate. The organic layer was separated and washed with brine, dried, and concentrated to afford tert-butyl [(1S)-2-azido-1-phenylethyl]carbamate in 90% yield.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[C:7]([O-:9])=O.[Na+].Cl.N1C=CN=C1.C(=O)=O.Cl.[CH3:21][NH:22][O:23][CH3:24].S(=O)(=O)(O)O>C(#N)C.O.C(Cl)Cl>[CH3:24][O:23][N:22]([CH3:21])[C:7]([C:2]1[N:1]=[CH:6][CH:5]=[CH:4][N:3]=1)=[O:9]
Reactant: O=C([O-])c1ncccn1
Reactant: CNOC
Agent: Cl
Agent: O=C=O
Agent: O=S(=O)(O)O
Solvent: CC#N
Solvent: O
Solvent: ClCCl
Product: CON(C)C(=O)c1ncccn1
Temperature: 52 °C
Reaction time: 1 h
Yield: 91.2 %

Procedure:
Sodium pyrimidine-2-carboxylate (154.05 g), imidazole hydrochloride (119.3 g), and 1,1-carbonyldiimidazole (195 g) was slurried in acetonitrile (700 ml). The mixture was warmed from 15° C. to 52° C. over 0.5 h. Carbon dioxide was vigorously evolved between 30 and 50° C. The mixture was stirred 1 h at 52° C. then cooled to 15° C. and N,O-dimethylhydroxylamine hydrochloride (131.90 g) was added with an exotherm to 34° C. The mixture was cooled to 14° C. and methylene chloride (300 ml) and water (500 ml) was added. The pH was adjusted from 7.6 to 1.6 with aqueous sulfuric acid (6.13 M, 226 ml). The phases were separated and the lower aqueous phase washed with methylene chloride (500 ml). To the combined organics was added water (300 ml) and the pH adjusted to 1.18 with aqueous sulfuric acid (6.13 M, 5.1 ml). The phases were separated and the organics washed with saturated aq. sodium bicarbonate (300 ml). All three aqueous phases were serial back extracted with methylene chloride (500 ml). The bicarbonate wash was back extracted with methylene chloride (500 ml). The combined organics were dried (MgSO4) and concentrated in vacuo to a thin slurry. The residue was slurried in methylene chloride (200 ml) and the solids filtered off. The filtrate was concentrated to afford 160.7 g of the title compound as an oil.
Reaction SMILES: [Cl:1][C:2]1[C:3]([Cl:11])=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[C:12]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C[CH:13]=1.C(O)C.CCOC(/N=N/C(OCC)=O)=O.C([O-])(O)=O.[Na+]>C1COCC1>[CH2:12]([O:8][C:7](=[O:9])[C:6]1[CH:10]=[C:2]([Cl:1])[C:3]([Cl:11])=[N:4][CH:5]=1)[CH3:13]
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: O=C(O)c1cnc(Cl)c(Cl)c1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Product: CCOC(=O)c1cnc(Cl)c(Cl)c1
Temperature: 25 °C
Yield: 103.6 %

Procedure:
To a solution of 5,6-dichloronicotinic acid (10.0 g, 50.0 mmol) in THF (600 mL), triphenylphosphine (19.67 g, 75.0 mmol) and ethanol (5.55 g, 75.0 mmol) is added. The mixture is cooled to 0° C. before DEAD (32.65 g, 75.0 mmol) is added. The mixture is stirred and warmed to rt. Stirring is continued for 16 h before sat. aq. NaHCO3 solution is added. The mixture is repeatedly extracted with EA. The combined org. extracts are dried over MgSO4, filtered and concentrated. The crude product is purified by CC (heptane:EA 7:3) to give 5,6-dichloronicotinic acid ethyl ester (11.4 g) as a white solid; LC-MS: tR=0.96 min, [M+1]+=220.02.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6](=[O:17])[S:7][C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10](Br)[CH:9]=2)=[O:4].[CH:18]1(B(O)O)[CH2:20][CH2:19]1>>[CH3:1][O:2][C:3]([C:5]1[C:6](=[O:17])[S:7][C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([CH:18]1[CH2:20][CH2:19]1)[CH:9]=2)=[O:4]
Reactant: COC(=O)c1c(O)c2ccc(Br)cc2sc1=O
Reactant: OB(O)C1CC1
Product: COC(=O)c1c(O)c2ccc(C3CC3)cc2sc1=O

Procedure:
7-Cyclopropyl-4-hydroxy-2-oxo-2H-thiochromene-3-carboxylic acid methyl ester was prepared from 7-bromo-4-hydroxy-2-oxo-2H-thiochromene-3-carboxylic acid methyl ester under conditions analogous to Example 7(a) using cyclopropylboronic acid. The crude material was used in the next step without purification.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5](=[O:8])[CH2:6][OH:7].[Br:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12](Br)[N:11]=1>CN(C)C=O>[CH3:3][O:4][C:5](=[O:8])[CH2:6][O:7][C:12]1[CH:13]=[CH:14][CH:15]=[C:10]([Br:9])[N:11]=1
Reactant: COC(=O)CO
Reactant: Brc1cccc(Br)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)COc1cccc(Br)n1
Yield: 80.2 %

Procedure:
A suspension of 178 mg of sodium hydride (80% dispersion in mineral oil) in 4 ml of dimethylformamide is mixed under argon atmosphere, stirring and ice cooling with a solution of 361 mg of glycolic acid methyl ester in 2 ml of dimethylformamide and stirred for 3 hours at room temperature. Then, a solution of 948 mg of 2,6-dibromopyridine in 2 ml of dimethylformamide is added under ice cooling and the mixture is stirred for 48 hours at room temperature. The reaction mixture is poured on ice and extracted with ethyl acetate. The organic phase is washed 4 times with saturated common salt solution, dried on sodium sulfate and concentrated by evaporation. 790 mg of 2-(6-bromo-2-pyridyloxy)-acetic acid methyl ester is obtained as oily crude product.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[N:6]([C@H:12]([CH:17]([CH3:19])C)[C:13]([O:15][CH3:16])=[O:14])[CH2:5]2.Br[C:21]1C=CC(C(OC)=O)=C(CBr)[CH:22]=1.Cl.COC(=O)C(C1C=CC=CC=1)N>>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[N:6]([C:12]1([C:13]([O:15][CH3:16])=[O:14])[CH2:17][CH2:19][CH2:22][CH2:21]1)[CH2:5]2
Reactant: COC(=O)[C@@H](C(C)C)N1Cc2cc(Br)ccc2C1=O
Reactant: COC(=O)c1ccc(Br)cc1CBr
Agent: COC(=O)C(N)c1ccccc1
Agent: Cl
Product: COC(=O)C1(N2Cc3cc(Br)ccc3C2=O)CCCC1

Procedure:
The compound of example 368 was prepared analogous to compound of example 359 by reaction of the compound of example 358 and 2-phenyl glycine methyl ester hydrochloride.