Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.[Cl:22][C:23]1[CH:24]=[C:25]([CH:29]=[CH:30][C:31]=1[O:32][CH:33]([CH3:35])[CH3:34])[C:26]([OH:28])=O.[F:36][C:37]1[CH:45]=[CH:44][C:43](/[C:46](/[NH:49]O)=[N:47]/[H])=[C:42]2[C:38]=1[C:39]([CH2:51][CH2:52][C:53]([O:55][CH2:56][CH3:57])=[O:54])=[CH:40][NH:41]2.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[Cl:22][C:23]1[CH:24]=[C:25]([C:26]2[O:28][N:47]=[C:46]([C:43]3[CH:44]=[CH:45][C:37]([F:36])=[C:38]4[C:42]=3[NH:41][CH:40]=[C:39]4[CH2:51][CH2:52][C:53]([O:55][CH2:56][CH3:57])=[O:54])[N:49]=2)[CH:29]=[CH:30][C:31]=1[O:32][CH:33]([CH3:35])[CH3:34]
Reactant: CC(C)Oc1ccc(C(=O)O)cc1Cl
Reactant: [H]/N=C(\NO)c1ccc(F)c2c(CCC(=O)OCC)c[nH]c12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: CCOC(=O)CCc1c[nH]c2c(-c3noc(-c4ccc(OC(C)C)c(Cl)c4)n3)ccc(F)c12
Temperature: 25 °C
Reaction time: 2 h
Yield: 85.4 %

Procedure:
HOBT (166 mg) and EDCI (199 mg) were added to a solution of 3-chloro-4-[(1-methylethyl)oxy]benzoic acid (115 mg) in THF (4 mL). The reaction mixture was stirred at RT for 2 hours. Ethyl 3-{4-fluoro-7-[(Z)-(hydroxyamino)(imino)methyl]-1H-indol-3-yl}propanoate (D45) (205 mg) in THF (4 mL) was added. Then stirring continued overnight. TBAF (760 mg) was then added. The reaction vessel was sealed and heated in Biotage Initiator using initial normal to 120° C. for 3 hours. After cooling, the reaction was quenched with water, and extracted with EtOAc for 3 times. The combined organic solution was washed with brine, and dried over anhydrous sodium sulfate. The dried solution was concentrated. The residue was purified by column chromatography (15% EtOAc in hexane) to afford ethyl 3-[7-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-4-fluoro-1H-indol-3-yl]propanoate (D46) (216 mg) as a pale yellow solid. δH (CDCl3, 400 MHz): 1.25 (3H, t), 1.47 (6H, d), 2.76 (2H, t), 3.24 (2H, t), 4.14 (2H, q), 4.74 (1H, m), 6.91 (1H, dd), 7.09 (1H, d), 7.14 (1H, d), 8.04 (1H, dd), 8.10 (1H, dd), 8.28 (1H, d), 9.71 (1H, br s). MS (ES): C24H23ClFN3O4 requires 471; found 472.2 (M+H+).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:14])OC)=[CH:6][CH:5]=1)([O-:3])=[O:2].[N+:15]([C:18]1[CH:24]=[CH:23][C:21]([NH2:22])=[CH:20][CH:19]=1)([O-:17])=[O:16]>CO>[N+:15]([C:18]1[CH:24]=[CH:23][C:21]([NH:22][C:11]([NH:10][C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=2)=[O:14])=[CH:20][CH:19]=1)([O-:17])=[O:16]
Reactant: Nc1ccc([N+](=O)[O-])cc1
Reactant: COC(=O)Nc1ccc([N+](=O)[O-])cc1
Solvent: CO
Product: O=C(Nc1ccc([N+](=O)[O-])cc1)Nc1ccc([N+](=O)[O-])cc1

Procedure:
One proceeds as described in Example 6 with the difference that a distillating column is attached to the flask, the mixture is maintained in gentle boiling and methanol is removed continuously from the mixture. After 2 hours of reaction the end-product is filtered off, 50 mmoles of methyl N-(4-nitrophenyl)-carbamate and 50 mmoles of 4-nitroaniline are added to the filtrate, and the reaction is repeated. The results of four subsequent cycles are summarized in Table 2.
Reaction SMILES: [CH3:1][C:2]([C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-])=O)=[CH:14][CH:13]=1)([CH3:11])[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1.CC(O)=O>C1COCC1.[Zn]>[CH3:11][C:2]([C:12]1[CH:13]=[CH:14][C:15]([NH2:18])=[CH:16][CH:17]=1)([CH3:1])[CH2:3][CH2:4][N:5]1[CH2:6][CH2:7][O:8][CH2:9][CH2:10]1
Reactant: CC(C)(CCN1CCOCC1)c1ccc([N+](=O)[O-])cc1
Agent: [Zn]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CC(C)(CCN1CCOCC1)c1ccc(N)cc1
Reaction time: 1 h

Procedure:
To a solution of 4-[3-methyl-3-(4-nitro-phenyl)-butyl]-morpholine (0.50g, 1.8 mmol, Step E) in THF (40 mL) was added AcOH (1.97 mmol, 34.5 mmol) followed by zinc (9.1 g, 137 mmol). The mixture was stirred for 1 h and filtered on Celite®. The mixture was diluted with H2O, and aqueous NaHCO3 and the THF was evaporated. The residue was extracted with EtOAc, dried and evaporated to give the title intermediate. Calc'd for C15H24N2O: 248.19.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([NH:11][C:12]([CH:14]2[CH2:18][CH:17]([O:19][C:20]3[C:29]4[C:24](=[C:25]([CH3:32])[C:26]([O:30][CH3:31])=[CH:27][CH:28]=4)[N:23]=[C:22]([C:33]4[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][CH:34]=4)[N:21]=3)[CH2:16][CH:15]2[C:41](=[O:50])[N:42]([CH2:44][CH2:45][CH2:46][CH2:47][CH:48]=[CH2:49])[CH3:43])=[O:13])[CH2:8][CH:7]1C=C)=[O:5])[CH3:2]>CC1C=C(C)C(N2C(=[Ru](Cl)(Cl)=CC3C=CC=CC=3OC(C)C)N(C3C(C)=CC(C)=CC=3C)CC2)=C(C)C=1>[CH2:1]([O:3][C:4]([C:6]12[CH2:8][CH:7]1[CH:49]=[CH:48][CH2:47][CH2:46][CH2:45][CH2:44][N:42]([CH3:43])[C:41](=[O:50])[CH:15]1[CH:14]([CH2:18][CH:17]([O:19][C:20]3[C:29]4[C:24](=[C:25]([CH3:32])[C:26]([O:30][CH3:31])=[CH:27][CH:28]=4)[N:23]=[C:22]([C:33]4[CH:34]=[CH:35][C:36]([O:39][CH3:40])=[CH:37][CH:38]=4)[N:21]=3)[CH2:16]1)[C:12](=[O:13])[NH:11]2)=[O:5])[CH3:2]
Reactant: C=CCCCCN(C)C(=O)C1CC(Oc2nc(-c3ccc(OC)cc3)nc3c(C)c(OC)ccc23)CC1C(=O)NC1(C(=O)OCC)CC1C=C
Agent: Cc1cc(C)c(N2CCN(c3c(C)cc(C)cc3C)C2=[Ru](Cl)(Cl)=Cc2ccccc2OC(C)C)c(C)c1
Product: CCOC(=O)C12CC1C=CCCCCN(C)C(=O)C1CC(Oc3nc(-c4ccc(OC)cc4)nc4c(C)c(OC)ccc34)CC1C(=O)N2
Yield: 74.9 %

Procedure:
The diene 135 (585 mg, 0.854 mmol) and Hoveyda-Grubbs catalyst, IInd generation (50 mg) were dissolved in degassed and dry 1,2-dichloroethane (500 mL). The mixture was heated to reflux temperature over-night under argon atmosphere. Evaporation of the solvent and purification by column chromatography (silica gel; Heptane/EtOAc 70:30) gave the title compound (420 mg, 75%). MS (M+H)+ 658.
Reaction SMILES: [CH3:1][C:2]1[CH2:3][C@H:4]2[C@:17]([CH3:20])([CH2:18][CH:19]=1)[C@@H:16]1[C@H:7]([C@H:8]3[C@@:12]([CH2:14][CH2:15]1)([CH3:13])[C@@H:11]([OH:21])[CH2:10][CH2:9]3)[CH2:6][CH2:5]2.O>CC(C)=O>[CH3:1][C:2]1[CH2:3][C@H:4]2[C@:17]([CH3:20])([CH2:18][CH:19]=1)[C@@H:16]1[C@H:7]([C@H:8]3[C@@:12]([CH2:14][CH2:15]1)([CH3:13])[C:11](=[O:21])[CH2:10][CH2:9]3)[CH2:6][CH2:5]2
Reactant: CC1=CC[C@@]2(C)[C@@H](CC[C@@H]3[C@@H]2CC[C@]2(C)[C@@H](O)CC[C@@H]32)C1
Solvent: O
Solvent: CC(C)=O
Product: CC1=CC[C@@]2(C)[C@@H](CC[C@@H]3[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]32)C1
Yield: 83.6 %

Procedure:
Kiliani's reagent (100 ml) was added slowly to a solution of 3-methyl-5α-androst-2-en-17β-ol (43 g) in acetone (170 ml). When the addition was complete, water was added to give a precipitate, which was filtered off. The product was redissolved in acetone and water was again added. The precipitate was filtered off, washed with water and dried to give 3-methyl-5α-androst-2-en-17-one (35.7 g). A sample was recrystallised from ether-light petroleum (40°-60°) and from ether to give pure material, m.p. 124°-126°; [α]D +141° (c 0.48 in EtOH).
Reaction SMILES: Cl.[O:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[CH2:4][CH:3]1[CH2:11][NH2:12].F[C:14]1[CH:22]=[N:21][CH:20]=[CH:19][C:15]=1[C:16]([OH:18])=[O:17]>>[O:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[CH2:4][CH:3]1[CH2:11][NH:12][C:19]1[CH:20]=[N:21][CH:22]=[CH:14][C:15]=1[C:16]([OH:18])=[O:17]
Reactant: O=C(O)c1ccncc1F
Reactant: NCC1Cc2ccccc2O1
Agent: Cl
Product: O=C(O)c1ccncc1NCC1Cc2ccccc2O1
Yield: 18 %

Procedure:
The title compound was prepared in 18% yield from (2,3-dihydro-1-benzofuran-2-yl)methylamine hydrochloride and 3-fluoroisonicotinic acid according to the procedure for the preparation of Example 5. 1H NMR (400 MHz, DMSO-d6): δ 13.41 (br s, 1H), 8.29 (s, 1H), 7.78 (d, 1H, J=5.0 Hz), 7.75 (br s, 1H), 7.48 (d, 1H, J=5.0 Hz), 7.15 (d, 1H, J=7.2 Hz), 7.01 (t, 1H, J=7.7 Hz), 6.75 (t, 1H, J=7.4 Hz), 6.67 (d, 1H, J=7.9 Hz), 4.95-4.99 (m, 1H), 3.24-3.64 (m, 3H), 2.88-2.95 (m, 1H). [M+H] calc'd for C15H14N2O3, 271; found 271.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([NH:16][C:17](=[O:22])[C:18]([F:21])([F:20])[F:19])[CH:11]=2)[CH:7]=[CH:6][C:5]=1[CH2:23][C:24](O)=[O:25])([O-])=O>C(O)(=O)C.[Fe]>[F:19][C:18]([F:21])([F:20])[C:17]([NH:16][C:12]1[CH:11]=[C:10]([C:8]2[CH:9]=[C:4]3[C:5]([CH2:23][C:24](=[O:25])[NH:1]3)=[CH:6][CH:7]=2)[CH:15]=[CH:14][CH:13]=1)=[O:22]
Reactant: O=C(O)Cc1ccc(-c2cccc(NC(=O)C(F)(F)F)c2)cc1[N+](=O)[O-]
Agent: [Fe]
Solvent: CC(=O)O
Product: O=C1Cc2ccc(-c3cccc(NC(=O)C(F)(F)F)c3)cc2N1
Yield: 11.5 %

Procedure:
2-[2-Nitro-4-(3-trifluoroacetamidophenyl)phenyl]acetic acid (100 mg) and 50 mg of iron powder in 3 mL of acetic acid was heated to 100° C. for 2 hours. The reaction mixture was concentrated and the residue sonicated in 5 mL of ethyl acetate. The insoluble solids were removed by vacuum filtration and the filtrate washed with 1 N hydrochloric acid, water and brine, dried over anhydrous sodium sulfate and concentrated to give 10 mg (14% yield) of the title compound as a rose-colored solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:9])[CH2:7][NH2:8])([CH3:4])([CH3:3])[CH3:2].[Cl:10][C:11]1[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=1)[CH:14]=O>C(Cl)Cl>[C:1]([O:5][C:6](=[O:9])[CH2:7]/[N:8]=[CH:14]/[C:13]1[CH:16]=[CH:17][CH:18]=[C:11]([Cl:10])[CH:12]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)CN
Reactant: O=Cc1cccc(Cl)c1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)C/N=C/c1cccc(Cl)c1
Yield: 94.6 %

Procedure:
In a manner similar to the method described in Example 1a, glycine tert-butyl ester (1.31 g, 10 mmol) was reacted with 3-chlorobenzaldehyde (Aldrich) (1.4 g, 10 mmol) in CH2Cl2 at room temperature for 18 h to give {[1-(3-chloro-phenyl)-meth-(E)-ylidene]-amino}-acetic acid tert-butyl ester as a pale yellow oil (2.4 g, 95%).
Reaction SMILES: [CH2:1]([C:4]1[C:9]([Br:10])=[C:8]([F:11])[CH:7]=[CH:6][C:5]=1[OH:12])[CH:2]=C.S(=O)(=O)(O)O>C1(C)C=CC=CC=1>[Br:10][C:9]1[C:4]2[CH:1]=[CH:2][O:12][C:5]=2[CH:6]=[CH:7][C:8]=1[F:11]
Reactant: C=CCc1c(O)ccc(F)c1Br
Agent: O=S(=O)(O)O
Solvent: Cc1ccccc1
Product: Fc1ccc2occc2c1Br
Yield: 98 %

Procedure:
Beginning with 3 gm (13 mMol) 2-allyl-3-bromo-4-fluorophenol, the title compound was prepared in 98% yield essentially by the procedure described in Preparation XXXI with the exception that the cyclization/dehydration step was performed using sulfuric acid in toluene.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:17](=O)[NH2:18])[CH2:9][N:8]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:7]1)=[O:5])[CH3:2].N1C=CC=CC=1.FC(F)(F)C(OC(=O)C(F)(F)F)=O>C1COCC1>[CH2:1]([O:3][C:4]([C:6]1([C:17]#[N:18])[CH2:9][N:8]([C:10]([O:12][C:13]([CH3:15])([CH3:14])[CH3:16])=[O:11])[CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(C(N)=O)CN(C(=O)OC(C)(C)C)C1
Solvent: C1CCOC1
Solvent: c1ccncc1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: CCOC(=O)C1(C#N)CN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Yield: 94.2 %

Procedure:
3-Carbamoyl-azetidine-1,3-dicarboxylic acid 1-tert-butyl ester 3-ethyl ester (25.4 g; 93.5 mmol) is dissolved in THF (260 ml) and pyridine (19.2 g; 243 mmol) and cooled to 0° C. under stirring. Trifluoroacetic acid anhydride (26.4 ml; 187 mmol) is added dropwise over 10 minutes, the mixture warmed to room temperature and stirred for 30 minutes, poured on water and extracted with TBME three times. The combined organic phases are dried over Na2SO4, filtered, evaporated and purified via chromatography (SiO2; heptane/TBME 6:4) to yield the title compound as light brown oil (22.4 g; 94%).
Reaction SMILES: Cl[C:2]1[C:3]2[C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[CH3:16][NH:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20](B2OC(C)(C)C(C)(C)O2)[CH:19]=1.C(=O)([O-])[O-].[Na+].[Na+].O>O1CCOCC1.[Pd]>[CH3:16][NH:17][C:18]1[CH:19]=[C:20]([C:2]2[C:3]3[C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:9][NH:8][C:4]=3[N:5]=[CH:6][N:7]=2)[CH:21]=[CH:22][CH:23]=1
Reactant: CNc1cccc(B2OC(C)(C)C(C)(C)O2)c1
Reactant: CCOC(=O)c1c[nH]c2ncnc(Cl)c12
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CCOC(=O)c1c[nH]c2ncnc(-c3cccc(NC)c3)c12
Temperature: 150 °C

Procedure:
To a nitrogen purged mixture of ethyl 4-chloro-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylate (300 mg, 1.33 mmol) and N-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (465 mg, 1.99 mmol) in 2 M aqueous sodium carbonate solution (3.32 mL, 6.65 mmol) and dioxane (10 mL) was added SiliaCat® heterogeneous catalysts DPP-Pd (loading=0.28 mmol/g, 950 mg, 0.266 mmol). The reaction mixture was heated by microwave irradiation at 150° C. in a sealed microwave vessel for 30 minutes. Water (5 mL) was added to the reaction mixture and then the biphasic mixture was filtered. The organic layer was separated and the aqueous layer was extracted with ethyl acetate (×3). The combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on silica eluting with 0-100% ethyl acetatehexane to give ethyl 4-(3-(methylamino)phenyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylate. LRMS (ESI) calc'd for C16H17N4O2[M+H]+: 297, found 297.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][OH:5].[ClH:10].[NH2:11][CH2:12][C:13](=[O:19])[CH2:14][CH2:15][C:16](O)=[O:17]>>[ClH:10].[NH2:11][CH2:12][C:13](=[O:19])[CH2:14][CH2:15][C:16]([O:5][CH2:4][C:3]1[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=1[F:1])=[O:17]
Reactant: NCC(=O)CCC(=O)O
Reactant: OCc1ccccc1F
Agent: Cl
Product: NCC(=O)CCC(=O)OCc1ccccc1F
Reaction time: 27 h

Procedure:
From 2-fluorobenzyl alcohol (5.7 g; 45 mmol) and 5-amino-4-oxopentanoic acid hydrochloride (1.0 g; 6.0 mmol). The reaction was complete after 27 h at 100° C. The yield was 0.64 g (44%). Mp 91-94° C. (dec.)
Reaction SMILES: [C:1]1([NH:7][C:8]([C:10]2[CH:11]=[N:12][C:13]3[C:18]([C:19]=2[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:17][CH:16]=[CH:15][C:14]=3[C:26]([F:29])([F:28])[F:27])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[CH3:32]I>CN(C=O)C>[CH3:32][N:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C:8]([C:10]1[CH:11]=[N:12][C:13]2[C:18]([C:19]=1[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)=[CH:17][CH:16]=[CH:15][C:14]=2[C:26]([F:29])([F:27])[F:28])=[O:9]
Reactant: CI
Reactant: O=C(Nc1ccccc1)c1cnc2c(C(F)(F)F)cccc2c1-c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C(=O)c1cnc2c(C(F)(F)F)cccc2c1-c1ccccc1)c1ccccc1
Reaction time: 1 h
Yield: 94.7 %

Procedure:
To a solution of N,4-diphenyl-8-(trifluoromethyl)quinoline-3-carboxamide, (0.150 g, 0.382 mmol), whose preparation is described in Example 368, in DMF (20 mL) is added sodium hydride (0.010 g, 0.421 mmol). After stirring in an ice bath for 1 h, methyl iodide (0.027 mL, 0.421 mmol) is added drop wise and the reaction mixture is removed from the ice bath and stirred 2 h. The reaction mixture is partitioned between ethyl acetate and water and the aqueous layer is extracted with ethyl acetate. The combined extracts are washed with water, brine, and dried with magnesium sulfate. The extracts are concentrated and the residue is chromatographed with 1:4 ethyl acetate:hexanes to afford the title compound as a white solid (0.147 g, 96%). mp 188-190° C.; MS (ESI) m/z 407; HRMS: calcd for C24H17N2F3O+H, 407.13712; found (ESI, [M+H]+), 407.1361.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[C:7]([NH2:19])=[N:8][CH:9]=[C:10]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:11]=1.[C:20](N1C=CN=C1)([N:22]1C=CN=C1)=[S:21].[NH4+].[OH-].O>C1COCC1>[CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[C:7]([NH:19][C:20]([NH2:22])=[S:21])=[N:8][CH:9]=[C:10]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:11]=1
Reactant: S=C(n1ccnc1)n1ccnc1
Reactant: COCCOc1cc(Oc2ccccc2)cnc1N
Agent: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: COCCOc1cc(Oc2ccccc2)cnc1NC(N)=S
Reaction time: 19 h
Yield: 81 %

Procedure:
3-(2-Methoxy-ethoxy)-5-phenoxy-pyridine-2-ylamine (0.3 mmol) is dissolved in THF (4 ml) and 1,1′-thiocarbonyldiimidazole (4 eq.) is added. The reaction solution is stirred 19 hours. 32% NH4OH (21 eq.) is added and stirred 3 hours at room temperature. Water (50 ml) is added and extracted with dichloromethane. The combined organic layers are washed with brine and dried over MgSO4. The solvent is removed in vacuo. [3-(2-Methoxy-ethoxy)-5-phenoxy-pyridine-2-yl]-thiourea is obtained as brown oil in a yield of 81%; HPLC (method C): 1.85 min; LC-MS (method A): 1.68 min, 320.15 (M+H+).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([CH:11]=[O:12])=[CH:8][CH:9]=2)[N:4]=[CH:3][CH:2]=1.[CH3:13][Mg]Br>O1CCCC1>[OH:12][CH:11]([C:7]1[CH:6]=[C:5]2[C:10](=[CH:9][CH:8]=1)[N:1]=[CH:2][CH:3]=[N:4]2)[CH3:13]
Reactant: O=Cc1ccc2nccnc2c1
Reactant: C[Mg]Br
Solvent: C1CCOC1
Product: CC(O)c1ccc2nccnc2c1
Temperature: 25 °C
Yield: 56.5 %

Procedure:
To a mixture of quinoxaline-6-carboxaldehyde (0.10 g, 0.63 mMol) in dry tetrahydrofuran (3 mL) at zero degrees was added methyl magnesium bromide (3M in Et2O, 0.253 mL, 0.76 mMol) drop wise. Upon complete addition the ice bath was removed and the solution allowed to warm to room temperature. The reaction was quenched with methanol and IN hydrochloric acid added until the pH was approximately seven. The neutral solution was partitioned between ethyl acetate and water, the aqueous layer discarded and the organics washed with brine. The organics were dried (MgSO4), filtered, and concentrated to dryness on a rotary evaporator. Purification by flash column chromatography on silica gel using 10-100% methanol in dichloromethane yielded 62 mg (56% yield) of 6-(1-hydroxyethyl)quinoxaline as a clear oil. 1H NMR (DMSO-d6): δ=8.92 (dd, 2H, J=9.1, 1.9 Hz), 8.06 (d, 1H, J=8.6 Hz), 8.02 (d, 1H, J=1.7 Hz), 7.87 (dd, 1H, J=8.7, 1.9 Hz), 5.51 (br s, 1H), 4.99 (q, 1H, J=6.4 Hz), 1.43 (d, 3H, J=6.4 Hz). LC/MS (Method A), rt=0.56 mins., purity=99%, calculated mass=174, [M+H]+=175.
Reaction SMILES: Br[C:2]1[CH:24]=[CH:23][C:5]([CH2:6][N:7]2[C:12]3[C:13]4[CH:19]=[CH:18][CH:17]=[CH:16][C:14]=4[S:15][C:11]=3[C:10](=[O:20])[N:9]([OH:21])[C:8]2=[O:22])=[CH:4][CH:3]=1.[C:25]([C:28]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=1)(=[O:27])[CH3:26]>>[C:25]([C:28]1[CH:33]=[CH:32][C:31]([C:2]2[CH:3]=[CH:4][C:5]([CH2:6][N:7]3[C:12]4[C:13]5[CH:19]=[CH:18][CH:17]=[CH:16][C:14]=5[S:15][C:11]=4[C:10](=[O:20])[N:9]([OH:21])[C:8]3=[O:22])=[CH:23][CH:24]=2)=[CH:30][CH:29]=1)(=[O:27])[CH3:26]
Reactant: O=c1c2sc3ccccc3c2n(Cc2ccc(Br)cc2)c(=O)n1O
Reactant: CC(=O)c1ccc(B(O)O)cc1
Product: CC(=O)c1ccc(-c2ccc(Cn3c(=O)n(O)c(=O)c4sc5ccccc5c43)cc2)cc1

Procedure:
1-(4-Bromo-benzyl)-3-hydroxy-1H-benzo[4,5]thieno[3,2-d]pyrimidine-2,4-dione was treated with 4-acetylphenylboronic acid according to general procedure C. The title compound was obtained as a yellow solid following purification by preparative HPLC. 1H NMR (d6-DMSO, 300 MHz) δ 2.63 (s, 3H); 5.80 (s, 2H); 7.70-8.20 (m, 12H); Ret. time=2.89, m/z=441.0.
Reaction SMILES: [NH2:1][C@@H:2]([CH3:19])[CH2:3][N:4]1[CH:8]=[CH:7][C:6]([C:9]2[CH:16]=[C:15]([Cl:17])[C:12]([C:13]#[N:14])=[C:11]([Cl:18])[CH:10]=2)=[N:5]1.[C:20]([C:23]1[CH:27]=[C:26]([C:28](O)=[O:29])[NH:25][N:24]=1)(=[O:22])[CH3:21].C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C>CN(C=O)C>[C:20]([C:23]1[CH:27]=[C:26]([C:28]([NH:1][C@@H:2]([CH3:19])[CH2:3][N:4]2[CH:8]=[CH:7][C:6]([C:9]3[CH:10]=[C:11]([Cl:18])[C:12]([C:13]#[N:14])=[C:15]([Cl:17])[CH:16]=3)=[N:5]2)=[O:29])[NH:25][N:24]=1)(=[O:22])[CH3:21]
Reactant: CC(=O)c1cc(C(=O)O)[nH]n1
Reactant: C[C@H](N)Cn1ccc(-c2cc(Cl)c(C#N)c(Cl)c2)n1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)c1cc(C(=O)N[C@@H](C)Cn2ccc(-c3cc(Cl)c(C#N)c(Cl)c3)n2)[nH]n1

Procedure:
The title compound was synthesized from (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2,6-dichlorobenzonitrile (0.121 g, 0.41 mmol), 3-acetyl-1H-pyrazole-5-carboxylic acid (0.063 g, 0.41 mmol), HOBt (0.083 g, 0.615 mmol), DIPEA (0.214 mL, 1.23 mmol) and EDCI (0.118 g, 0.615 mmol) using DMF (10 mL) as solvent using the method of Example 34(d). Yield 6.3 mg. 1H NMR (400 MHz; CDCl3): δ 1.29 (d, 3H), 2.55 (s, 3H), 4.36 (m, 2H), 4.57 (m, 1H), 6.64 (d, 1H), 7.40 (s, 1H), 7.58 (d, 1H), 7.83 (s, 2H).
Reaction SMILES: Br[CH:2]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4].[NH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1>C1COCC1.[Cl-].[Na+].O>[C:8]1([CH:2]([N:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[C:3]([O:5][CH2:6][CH3:7])=[O:4])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: C1CCNCC1
Reactant: CCOC(=O)C(Br)c1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)C(c1ccccc1)N1CCCCC1
Reaction time: 3 h
Yield: 34.1 %

Procedure:
To a solution of ethyl 2-bromo-2-phenylacetate 21 (1.50 g, 6.17 mmol) in THF (10 mL) at room temperature was added piperidine (0.641 mL, 6.48 mmol) and TEA (1.72 mL, 12.34 mmol) and the reaction mixture was stirred for 3 h then diluted with brine and extracted with ethyl acetate. The organic layer was dried over Na2SO4, filtered, and concentrated. The crude material was purified by silica gel column chromatography with gradient of ethyl acetate (0-50%) in hexane to afford 22 as a colorless viscous oil (520 mg, 34%). LRMS (ESI): (calc) 247.3 (found) 248.3 (MH)+.
Reaction SMILES: CC1C=CC(S([O:11][CH2:12][CH2:13][O:14][CH:15]2[CH2:20][CH2:19][N:18](C(OCC3C=CC=CC=3)=O)[CH2:17][CH2:16]2)(=O)=O)=CC=1.[O:31]1[CH2:35][CH2:34][C@H:33](O)[CH2:32]1>>[O:31]1[CH2:35][CH2:34][C@H:33]([O:11][CH2:12][CH2:13][O:14][CH:15]2[CH2:16][CH2:17][NH:18][CH2:19][CH2:20]2)[CH2:32]1
Reactant: O[C@H]1CCOC1
Reactant: Cc1ccc(S(=O)(=O)OCCOC2CCN(C(=O)OCc3ccccc3)CC2)cc1
Product: C1CC(OCCO[C@H]2CCOC2)CCN1
Yield: 76.5 %

Procedure:
Using benzyl 4-(2-{[(4-methylphenyl)sulfony]oxy}ethoxy)piperidine-1-carboxylate (4.00 g, 9.23 mmol) produced in Reference Example 1 (1c) and (3S)-tetrahydrofuran-3-ol (1.05 g, 12.0 mmol), the desired title compound (1.52 g, yield 77%) was obtained by the same method as in Reference Examples 1 (1d) and 1 (1e).
Reaction SMILES: [NH2:1][C@:2]12[C@@H:7]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[C@H:6]1[CH2:5][O:4][C:3]2=[O:14].[F:15][C:16]([F:32])([F:31])[C:17]1[O:21][N:20]=[C:19]([C:22]2[S:26][C:25]([S:27](Cl)(=[O:29])=[O:28])=[CH:24][CH:23]=2)[CH:18]=1>N1C=CC=CC=1>[O:14]=[C:3]1[O:4][CH2:5][C@H:6]2[C@:2]1([NH:1][S:27]([C:25]1[S:26][C:22]([C:19]3[CH:18]=[C:17]([C:16]([F:15])([F:31])[F:32])[O:21][N:20]=3)=[CH:23][CH:24]=1)(=[O:28])=[O:29])[C@H:7]2[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: N[C@@]12C(=O)OC[C@@H]1[C@@H]2c1ccccc1
Reactant: O=S(=O)(Cl)c1ccc(-c2cc(C(F)(F)F)on2)s1
Solvent: c1ccncc1
Product: O=C1OC[C@@H]2[C@H](c3ccccc3)[C@]12NS(=O)(=O)c1ccc(-c2cc(C(F)(F)F)on2)s1
Temperature: 0 °C
Reaction time: 8 h
Yield: 74.7 %

Procedure:
(1R*,5R*,6R*)-1-amino-6-phenyl-3-oxa-bicyclo[3.1.0]hexan-2-one (0.14 g, 0.74 mmol) was dissolved in 3 mL of pyridine. After cooling to 0° C., 5-(5-trifluoromethyl-isoxazol-3-yl)-thiophene-2-sulfonyl chloride (0.31 g, 0.96 mmol) was added in one portion. The reaction mixture was warmed to room temperature and stirred overnight. After concentration, the reaction mixture was diluted with EtOAc, washed with 10% citric acid, water (×2), 5% NaHCO3 and brine and dried over Na2SO4. After concentration, the crude product was purified by column chromatography using 2:1 hexanes/EtOAc to afford 0.26 g (75%) of the desired product.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]([OH:11])[CH2:9][OH:10])[CH:5]=[CH:6][CH:7]=1.O.C([O-])([O-])=O.[Na+].[Na+].[CH2:19]([O:26][C:27](Cl)=[O:28])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C(Cl)Cl>[OH:11][CH:8]([C:4]1[CH:3]=[C:2]([NH:1][C:27](=[O:28])[O:26][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:7]=[CH:6][CH:5]=1)[CH2:9][OH:10]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: Nc1cccc(C(O)CO)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: O=C(Nc1cccc(C(O)CO)c1)OCc1ccccc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 42.7 %

Procedure:
1-(3-Aminophenyl)ethane-1,2-diol (10 g) was dissolved in DCM (80 mL). H2O (80 mL) and Na2CO3 (10.98 g) were added and the mixture cooled to 0° C. Benzylchloroformate (22 g) was added drop-wise over 20 minutes and the reaction mixture stirred at room temperature overnight. The organic phase was separated, dried over Na2SO4 and concentrated to give a crude product which was purified by column chromatography to give the title compound (8 g, 45%).