Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH:2]1[NH:6][C:5](=[O:7])[NH:4][C:3]1=[O:8].[C:9]1([OH:15])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>O1CCOCC1>[OH:15][C:9]1[CH:14]=[CH:13][C:12]([CH:2]2[NH:6][C:5](=[O:7])[NH:4][C:3]2=[O:8])=[CH:11][CH:10]=1
Reactant: O=C1NC(=O)C(Cl)N1
Reactant: Oc1ccccc1
Solvent: C1COCCO1
Product: O=C1NC(=O)C(c2ccc(O)cc2)N1
Temperature: 70 °C
Reaction time: 6 h
Yield: 48 %

Procedure:
1.34 g (10 mmol) of 5-chlorohydantoin and 1.88 g (20 mmol) of phenol were dissolved in 10 ml of dioxane. The solution was then heated to a temperature of 70° C. with stirring for 6 hours. The reaction system was then allowed to cool to room temperature. The reaction system was further cooled over an ice bath for 2 hours. The resulting crystal was recovered by filtration, washed thoroughly with water, and then air-dried to obtain 0.93 g (4.8 mmol; yield: 48%) of 5-(p-hydroxyphenyl)hydantoin in the form of white crystal. The crystal thus obtained exhibited a melting point of 262° to 264°0 C. (decomposition). The IR spectrum, NMR spectrum, and Rf value of thin layer chromatography showed a good conformance to that of a specimen which had been separately synthesized.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]([I:11])=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH3:12][O:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][C:23]=1[O:24][CH3:25])[CH2:20][N:19]([CH2:26][CH2:27][CH2:28][CH2:29][NH:30]C(=O)C1C=C(C)C=CC=1O)[CH2:18][CH2:17]2>>[CH3:12][O:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][C:23]=1[O:24][CH3:25])[CH2:20][N:19]([CH2:26][CH2:27][CH2:28][CH2:29][NH:30][C:4](=[O:6])[C:3]1[CH:7]=[C:8]([I:11])[CH:9]=[CH:10][C:2]=1[OH:1])[CH2:18][CH2:17]2
Reactant: O=C(O)c1cc(I)ccc1O
Reactant: COc1cc2c(cc1OC)CN(CCCCNC(=O)c1cc(C)ccc1O)CC2
Product: COc1cc2c(cc1OC)CN(CCCCNC(=O)c1cc(I)ccc1O)CC2

Procedure:
Compound 2e was prepared form 2-hydroxy-5-iodo-benzoic acid and 1b as described above for 2a. The yield of 2c was 27.0%. The 1H-NMR spectrum (300 MHz, CDCl3) of the purified product was: 1.69-1.81 (m, 4H), 2.54-2.65 (m, 2H), 2.75-2.83 (m, 2H), 3.44-3.48 (m, 2H), 3.58 (s, 2H), 3.82 (s, 3H), 3.85 (s, 3H), 6.50 (s, 1H), 6.58 (s, 1H), 6.70-6.74 (d, 1H), 7.54-7.55 (d, 1H), 7.65-7.67 (d, 1H), 8.20 (s, 1H). Anal. (C22H27IN2O4.0.75H2O) C, H, N.
Reaction SMILES: Br[CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]2[C:10]3[C:15]([NH:16][C:17]4[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25]5[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[CH:26]=5)=[C:19]([Cl:32])[CH:18]=4)=[N:14][CH:13]=[N:12][C:11]=3[S:33][C:6]=2[CH:5]=1.[I-].[Na+].C(=O)([O-])[O-].[Na+].[Na+].[NH:42]1[CH:46]=[CH:45][N:44]=[CH:43]1>CN(C=O)C>[Cl:32][C:19]1[CH:18]=[C:17]([NH:16][C:15]2[C:10]3[C:7]4[CH:8]=[CH:9][C:4]([CH2:3][CH2:2][N:42]5[CH:46]=[CH:45][N:44]=[CH:43]5)=[CH:5][C:6]=4[S:33][C:11]=3[N:12]=[CH:13][N:14]=2)[CH:22]=[CH:21][C:20]=1[O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[CH:26]=1
Reactant: Fc1cccc(COc2ccc(Nc3ncnc4sc5cc(CCBr)ccc5c34)cc2Cl)c1
Reactant: c1c[nH]cn1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Fc1cccc(COc2ccc(Nc3ncnc4sc5cc(CCn6ccnc6)ccc5c34)cc2Cl)c1
Temperature: 80 °C
Yield: 42.9 %

Procedure:
To a solution of 7-(2-bromoethyl)-N-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}[1]benzothieno[2,3-d]pyrimidin-4-amine (40 mg, 0.07 mmol, 1 equiv) in DMF were added sodium iodide (11 mg, 0.07 mmol, 1 equiv), sodium carbonate (16 mg, 0.15 mmol, 2 equiv), and imidazole (10 mg, 0.15 mmol, 2 equiv). The resulting mixture was heated at 80° C. for 14 h. The reaction was cooled to rt and then concentrated in vacuo. The resulting crude material was purified by prep-TLC (10% methanol/DCM) and afforded a yellow solid (17.9 mg, 0.03 mmol, 45%). 1H-NMR (CD3OD) δ 8.40 (s, 1H), 8.24 (d, J=8.3 Hz, 1H), 7.71 (m, 2H), 7.45-7.36 (m, 3H), 7.28 (d, J=8.1 Hz, 2H), 7.23 (d, J=9.6 Hz, 1H), 7.10 (d, J=8.1 Hz, 1H), 7.09 (s, 1H), 7.04 (td, 1H), 6.92 (s, 1H), 5.12 (s, 2H), 4.35 (t, 2H), 3.23 (t, 2H); LCMS RT=3.22 min, [M+H]+=530
Reaction SMILES: Br[C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([F:9])[CH:3]=1.[CH:10]([O:13][C:14]1[CH:15]=[C:16](B(O)O)[CH:17]=[CH:18][CH:19]=1)([CH3:12])[CH3:11]>>[CH:10]1([O:13][C:14]2[CH:15]=[C:16]([C:2]3[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([F:9])[CH:3]=3)[CH:17]=[CH:18][CH:19]=2)[CH2:12][CH2:11]1
Reactant: Nc1ccc(Br)cc1F
Reactant: CC(C)Oc1cccc(B(O)O)c1
Product: Nc1ccc(-c2cccc(OC3CC3)c2)cc1F
Yield: 18 %

Procedure:
The title compound (230 mg) was prepared from 4-bromo-2-fluoroaniline (1 g, 5.26 mmol) and 3-isopropoxyphenylboronic acid (1.8 g, 6.84 mmol) as a yellow liquid.
Reaction SMILES: C(O[C:4](=[O:20])[C:5]([CH3:19])([S:14][C:15](=[O:18])[CH2:16][CH3:17])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])C.C[Si]([N-][Si](C)(C)C)(C)C.[Na+]>>[OH:20][C:4]1[C:5]([CH3:19])([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])[S:14][C:15](=[O:18])[C:16]=1[CH3:17]
Reactant: CCCCCCCCC(C)(SC(=O)CC)C(=O)OCC
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Product: CCCCCCCCC1(C)SC(=O)C(C)=C1O
Yield: 99.9 %

Procedure:
From 30 (469 mg, 1.55 mmol) and NaHMDS (3.87 mL, 3.87 mmol, 1.0 M in TH) following general procedure G was obtained 34 (397 mg, 70%). 1H NMR (300 MHz, CDCl3) (enol tautomer) δ 0.86 (t, J=6.8 Hz, 3H), 1.23 (s, 11H), 1.30-1.45 (m, 1H), 1.59 (s, 3H), 1.74 (s, 3H), 1.84-1.88 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 7.48, 14.0, 22.6, 25.2, 25.9, 29.2, 29.4, 29.6, 31.8, 38.5, 58.2, 110.5, 180.9, 198.0. IR (NaCl) 2927, 1601 cm−1
Reaction SMILES: N[C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([CH2:11][C:12]([N:14]([CH3:16])[CH3:15])=[O:13])[CH2:9][CH2:10][C:4]=2[CH:3]=1.[N+:19]([O-:22])(O)=[O:20].[N+](C1C=CC2CCNCCC=2C=1)([O-])=O.C(=O)([O-])[O-].[K+].[K+].ClCC(N(C)C)=O.[I-].[Na+].CN(C=O)C>>[N+:19]([C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([CH2:11][C:12]([N:14]([CH3:16])[CH3:15])=[O:13])[CH2:9][CH2:10][C:4]=2[CH:3]=1)([O-:22])=[O:20]
Reactant: O=[N+]([O-])O
Reactant: CN(C)C(=O)CN1CCc2ccc(N)cc2CC1
Agent: CN(C)C(=O)CCl
Agent: O=C([O-])[O-]
Agent: O=[N+]([O-])c1ccc2c(c1)CCNCC2
Solvent: CN(C)C=O
Product: CN(C)C(=O)CN1CCc2ccc([N+](=O)[O-])cc2CC1
Temperature: 60 °C
Yield: 56 %

Procedure:
2-(7-amino-1,2,4,5-tetrahydro-benzo[d]azepin-3-yl)-N,N-dimethyl-acetamide Into a round bottom flask, 7-Nitro-2,3,4,5-tetrahydro-1H-benzo[d]azepine nitric acid salt (3.80 g, 0.0149 mol), Potassium Carbonate (6.22 g, 0.0450 mol), 2-Chloro-N,N-dimethyl-acetamide (2.30 mL, 0.00224 mol), Sodium Iodide (2.28 g, 0.0152 mol) and DMF (60 mL, 0.8 mol) were added. The mixture was heated at 60° C. overnight. The reaction was partitioned with EtOAc and washed with Water (2×). The organic was separated, washed with Brine, and dried over Sodium Sulfate. The solid was filtered and washed with EtOAc. The solvent was removed under vacuum. The product was isolated via ISCO column chromatography with DCM and Methanol as eluant (0 to 10% Methanol). The collected fractions afforded 2-(7-nitro-1,2,4,5-tetrahydro-benzo[d]azepin-3-yl)-N,N-dimethyl-acetamide as an orange solid (2.31 g, 56%). MP 102-104° C. LCMS (E/I+) 278 (M+H). NMR 1H (CDCl3)-7.95 (m, 2H), 7.24 (d, 1H, J=7.76 Hz), 3.34 st, 2H), 3.12 (s, 3H), 3.03 (m, 4H), 2.97 (s, 3H), 2.76 (m, 4H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([Mg]Br)=[CH:4][CH:3]=1.[CH:10]12[O:16][CH:15]1[CH2:14][CH2:13][CH2:12][CH2:11]2>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:14]2[CH2:13][CH2:12][CH2:11][CH2:10][CH:15]2[OH:16])=[CH:4][CH:3]=1
Reactant: C1CCC2OC2C1
Reactant: Fc1ccc([Mg]Br)cc1
Solvent: C1CCOC1
Product: OC1CCCCC1c1ccc(F)cc1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 72.9 %

Procedure:
To a cooled solution of 4-Fluorophenylmagnesium bromide (1.0M in THF, 4.94 mL, 4.94 mmol) in dry THF (10 mL) at −78° C. is added Copper (I) Bromide Dimethylsulfide complex (51 mg, 0.25 mmol) and the resulting mixture is stirred at −78° C. for 10 min, followed by the slow addition of a solution of 7-Oxa-bicyclo[4.1.0]heptane (500 μL, 4.94 mmol) in THF (2 mL). The reaction is warmed to 0° C. and is stirred for 2 hour. Then the reaction is quenched with saturated NH4Cl solution (20 mL). The resulting mixture is extracted with EtOAc (10 mL×3). The organic layers are combined, washed with brine (10 mL×1), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude is purified by silica flash column chromatography using EtOAc in Heptane (gradient from 0% to 35%) to give 700 mg of desired product.
Reaction SMILES: [C:1]([CH2:3][N:4]([CH:21]([CH3:23])[CH3:22])[C:5]([C:7]1[N:8]=[C:9]([N:12]2[CH2:15][CH:14](OS(C)(=O)=O)[CH2:13]2)[S:10][CH:11]=1)=[O:6])#[N:2].[C:24]([O-:27])(=[S:26])[CH3:25].[K+]>CN(C)C=O>[C:24]([S:26][CH:14]1[CH2:13][N:12]([C:9]2[S:10][CH:11]=[C:7]([C:5](=[O:6])[N:4]([CH2:3][C:1]#[N:2])[CH:21]([CH3:22])[CH3:23])[N:8]=2)[CH2:15]1)(=[O:27])[CH3:25]
Reactant: CC([O-])=S
Reactant: CC(C)N(CC#N)C(=O)c1csc(N2CC(OS(C)(=O)=O)C2)n1
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)SC1CN(c2nc(C(=O)N(CC#N)C(C)C)cs2)C1
Temperature: 90 °C
Reaction time: 3 h
Yield: 57.4 %

Procedure:
To a solution of 1-[4-(N-cyanomethyl-N-isopropyl-carbamoyl)-1,3-thiazol-2-yl]-3-methanesulfonyloxyazetidine (635 mg, 1.77 mmol) (obtained as described in Reference Example 49(5)) in dimethylformamide (19 ml) was added potassium thioacetate (1.21 g, 10.6 mmol) at room temperature, and the reaction mixture was stirred in an oil bath (90° C.) for 3 hours. After checking the completion of the reaction, the reaction mixture was partitioned between ethyl acetate and 10% aqueous sodium chloride solution. The organic layer was washed successively with saturated aqueous sodium hydrogencarbonate solution and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The obtained residue was purified by chromatography on a silica gel column using hexane:ethyl acetate (1:1)→ethyl acetate as the eluant to afford 3-acetylthio-1-[4-(N-cyanomethyl-N-isopropyl-carbamoyl)-1,3-thiazol-2-yl]azetidine (344 mg, yield 57%) as a pale brown solid.
Reaction SMILES: ClC1C=CC(OCC2CCNCC2C2C=CC(Cl)=CC=2)=NC=1.Cl.C([N:31]1[CH2:36][CH2:35][C@H:34]([C@H:37]([O:39][C:40]2[CH:45]=[CH:44][C:43]([Cl:46])=[CH:42][N:41]=2)[CH3:38])[C@@H:33]([C:47]2[CH:52]=[CH:51][C:50]([Cl:53])=[CH:49][CH:48]=2)[CH2:32]1)C1C=CC=CC=1>>[Cl:46][C:43]1[CH:44]=[CH:45][C:40]([O:39][C@@H:37]([C@H:34]2[CH2:35][CH2:36][NH:31][CH2:32][C@@H:33]2[C:47]2[CH:48]=[CH:49][C:50]([Cl:53])=[CH:51][CH:52]=2)[CH3:38])=[N:41][CH:42]=1
Reactant: C[C@@H](Oc1ccc(Cl)cn1)[C@H]1CCN(Cc2ccccc2)C[C@@H]1c1ccc(Cl)cc1
Agent: Cl
Agent: Clc1ccc(C2CNCCC2COc2ccc(Cl)cn2)cc1
Product: C[C@@H](Oc1ccc(Cl)cn1)[C@H]1CCNC[C@@H]1c1ccc(Cl)cc1

Procedure:
In analogy to the procedure described for the synthesis of 5-chloro-2-[(3RS, 4RS)-3-(4-chloro-phenyl)-piperidin-4-ylmethoxy]-pyridine; hydrochloride (example 1, step h) the title compound was prepared from 2-{(R)-1-[(3S,4S)-1-Benzyl-3-(4-chloro-phenyl)-piperidin-4-yl]-ethoxy}-5-chloro-pyridine as yellow oil. MS (m/e): 351.2 [(M+H)+].
Reaction SMILES: O.O.[Sn](Cl)Cl.[F:6][C:7]([F:24])([F:23])[C:8]([NH:10][CH2:11]/[CH:12]=[CH:13]/[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-])=O)[CH:15]=1)=[O:9]>C(O)C>[NH2:20][C:16]1[CH:15]=[C:14](/[CH:13]=[CH:12]/[CH2:11][NH:10][C:8](=[O:9])[C:7]([F:6])([F:23])[F:24])[CH:19]=[CH:18][CH:17]=1
Reactant: O=C(NC/C=C/c1cccc([N+](=O)[O-])c1)C(F)(F)F
Agent: Cl[Sn]Cl
Solvent: CCO
Solvent: O
Product: Nc1cccc(/C=C/CNC(=O)C(F)(F)F)c1

Procedure:
Tin(II) chloride dihydrate (3.28 g, 14.5 mmol) was added to a solution of (E)-2,2,2-trifluoro-N-(3-(3-nitrophenyl)allyl)acetamide (1.0 g, 3.64 mmol) in ethanol. The reaction mixture was stirred under reflux overnight. The mixture was concentrated under reduced pressure to give dark brown viscous liquid. The reaction mixture was partitioned between sat NaHCO3 and EtOAc and then filtered through Celite which was thoroughly washed with ethyl acetate. Organic layer was separated and concentrated under reduced pressure to give (E)-N-(3-(3-aminophenyl)allyl)-2,2,2-trifluoroacetamide as a brown liquid. Yield (0.8 g, 89%); 1H NMR (400 MHz, DMSO-d6) δ 9.70 (bs, 1H), 6.96 (t, J=7.8 Hz, 1H), 6.51-6.60 (m, 2H), 6.45-6.48 (m, 1H), 6.39 (d, J=16.0 Hz, 1H), 6.05-6.10 (m, 1H), 5.07 (bs, 2H), 3.95 (t, J=5.6 Hz, 2H); ESI MS m/z 243.09 [M−H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]([C:22]2[CH:27]=[CH:26][C:25]([C:28]([N:30]([CH2:33][CH3:34])[CH2:31][CH3:32])=[O:29])=[CH:24][CH:23]=2)[N:9]2[CH2:14][CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11][CH2:10]2)[CH:5]=[CH:6][CH:7]=1.[CH:35]1([CH2:41][C:42](O)=[O:43])[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH:35]1([CH2:41][C:42]([NH:1][C:2]2[CH:3]=[C:4]([C@@H:8]([N:9]3[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]3)[C:22]3[CH:27]=[CH:26][C:25]([C:28]([N:30]([CH2:31][CH3:32])[CH2:33][CH3:34])=[O:29])=[CH:24][CH:23]=3)[CH:5]=[CH:6][CH:7]=2)=[O:43])[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1
Reactant: CCN(CC)C(=O)c1ccc(C(c2cccc(N)c2)N2CCN(C(=O)OC(C)(C)C)CC2)cc1
Reactant: O=C(O)CC1CCCCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCN(CC)C(=O)c1ccc([C@@H](c2cccc(NC(=O)CC3CCCCC3)c2)N2CCNCC2)cc1
Reaction time: 22 h
Yield: 91332 %

Procedure:
To a room temperature solution of INTERMEDIATE 5a (250 mg; 0.54 mmol) in DMF (5 mL) was added cyclohexyl acetic acid (92 mg; 0.65 mmol), DIPEA (0.38 mL; 2.16 mmol) and HATU (0.31 g; 0.81 mmol). The reaction mixture was stirred for 22 hours then was concentrated under reduced pressure. The residue was dissolved in dichloromethane, washed with sodium hydroxide (2N) then with HCl (1M). The organic phase was dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure. The residue was dissolved in dichloromethane (10 mL) and TFA (1.5 mL) was added. The reaction mixture was stirred for 4 hours then was washed with saturated sodium bicarbonate. The organic phase was dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure. Column chromatography eluting with 5% methanol in dichloromethane gave COMPOUND 77 (242 g; 92% for two steps). Purity (HPLC-215 nm): >99%; Optical purity (Chiral HPLC-215 nm): >99%. 1H NMR (400 MHz, CD3OD) δ 0.87-0.93 (m, 2H), 0.98 (t, J=7.13 Hz, 3H), 1.08-1.14 (m, 3H), 1.20-1.23 (m, 2H), 1.52-1.71 (br s, 6H), 1.72-1.77 (m, 1H), 2.12 (d, J=7.03 Hz, 2H), 3.09-3.14 (m, 2H), 3.18-3.23 (m, 6H), 3.26-3.33 (br s, 3H), 3.48-3.52 (m, 1H), 5.08 (s, 1H), 7.20 (d, J=4.49 Hz, 2H), 7.24-7.31 (m, 3H), 7.57 (d, J=7.81 Hz, 2H), 7.83 (s, 1H). Found: C, 58.11; H, 8.99; N, 7.46. C30H42N4O2×0.4HCl×6.5H2O has C, 57.90; H, 8.97; N, 9.00%. [α]D17=+4.6 deg [c 0.46, MeOH].
Reaction SMILES: [NH2:1][C:2]1[CH:22]=[CH:21][C:5]([O:6][C:7]2[C:8]3[CH:15]=[C:14]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[NH:13][C:9]=3[N:10]=[CH:11][N:12]=2)=[CH:4][CH:3]=1.[F:23][C:24]1[CH:29]=[CH:28][C:27]([N:30]=[C:31]=[O:32])=[CH:26][CH:25]=1>C1(C)C=CC=CC=1.C(#N)C>[CH2:19]([O:18][C:16]([C:14]1[NH:13][C:9]2[N:10]=[CH:11][N:12]=[C:7]([O:6][C:5]3[CH:21]=[CH:22][C:2]([NH:1][C:31]([NH:30][C:27]4[CH:28]=[CH:29][C:24]([F:23])=[CH:25][CH:26]=4)=[O:32])=[CH:3][CH:4]=3)[C:8]=2[CH:15]=1)=[O:17])[CH3:20]
Reactant: CCOC(=O)c1cc2c(Oc3ccc(N)cc3)ncnc2[nH]1
Reactant: O=C=Nc1ccc(F)cc1
Solvent: CC#N
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cc2c(Oc3ccc(NC(=O)Nc4ccc(F)cc4)cc3)ncnc2[nH]1
Reaction time: 1 h

Procedure:
After dissolving 90 mg of ethyl 4-(4-aminophenoxy)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylate in 3 ml of toluene and 1 ml of acetonitrile at 110° C., 16.6 μl of 4-fluorophenyl isocyanate was added and the mixture was stirred for 1 hour under reflux. After standing at room temperature, the precipitated crystals were filtered out and dried to obtain 110 mg of the title compound.
Reaction SMILES: [N+:1]([C:4]1[C:5]([NH2:15])=[C:6]([NH2:14])[CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:9]=1)([O-:3])=[O:2].[C:16](O)(=[O:20])[C:17](O)=[O:18]>Cl>[N+:1]([C:4]1[CH:9]=[C:8]([C:10]([F:11])([F:12])[F:13])[CH:7]=[C:6]2[C:5]=1[NH:15][C:16](=[O:20])[C:17](=[O:18])[NH:14]2)([O-:3])=[O:2]
Reactant: O=C(O)C(=O)O
Reactant: Nc1cc(C(F)(F)F)cc([N+](=O)[O-])c1N
Agent: Cl
Product: O=c1[nH]c2cc(C(F)(F)F)cc([N+](=O)[O-])c2[nH]c1=O
Temperature: 25 °C

Procedure:
A suspension of 3-nitro-5-trifluoromethyl-1,2-phenylenediamine (0.560 g, 2.53 mmol) and oxalic acid (0.325 g, 2.58 mmol) in 2N HCl (8.5 mL) was refluxed for 6 h. The suspension was then cooled to r.t. and the solid filtered, washed with water (5.0 mL) and dried under vacuum to yield 0.502 (72%) of pure title compound as a yellow brown powder, m.p. 329°-332° C.; 1H NMR (DMSO-d6): 7.640 (s, 1H), 8.111 (s, 1H), 11.414 (s, 1H), 2.432 (1H).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:15]=[CH:14][CH:13]=[CH:12][C:5]=1[C:6](N(OC)C)=[O:7])[CH3:2].Br[C:17]1[C:22]([N:23]([CH2:38][O:39][CH3:40])[S:24]([C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[C:29]([C:34]([F:37])([F:36])[F:35])[CH:28]=2)(=[O:26])=[O:25])=[CH:21][C:20]([Cl:41])=[CH:19][N:18]=1>>[Cl:33][C:30]1[CH:31]=[CH:32][C:27]([S:24]([N:23]([C:22]2[C:17]([C:6](=[O:7])[C:5]3[CH:12]=[CH:13][CH:14]=[CH:15][C:4]=3[O:3][CH2:1][CH3:2])=[N:18][CH:19]=[C:20]([Cl:41])[CH:21]=2)[CH2:38][O:39][CH3:40])(=[O:26])=[O:25])=[CH:28][C:29]=1[C:34]([F:35])([F:37])[F:36]
Reactant: CCOc1ccccc1C(=O)N(C)OC
Reactant: COCN(c1cc(Cl)cnc1Br)S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Product: CCOc1ccccc1C(=O)c1ncc(Cl)cc1N(COC)S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1

Procedure:
4-Chloro-N-[5-chloro-2-(2-ethoxy-benzoyl)-pyridin-3-yl]-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide was prepared from 2-ethoxy-N-methoxy-N-methyl-benzamide and N-(2-bromo-5-chloro-pyridin-3-yl)-4-chloro-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide according to previously described procedure in example 29. The product was purified by flash column chromatography on silica gel using ethyl acetate-hexane. MS m/z: 562.4 (M+H).
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:15]3[CH:20]=[CH:19][C:18]([S:21]([CH3:24])(=[O:23])=[O:22])=[CH:17][CH:16]=3)=[C:11]([NH2:14])[CH:12]=2)[N:7]([C:25]([O:27][CH:28]([CH3:30])[CH3:29])=[O:26])[CH2:6][C@@H:5]1[CH3:31])(=[O:3])[CH3:2].[C:32](NC1C=C2C(=CC=1C1C=NN(C3CC3)C=1)N(C(OC(C)C)=O)C[C@H](C)N2C(=O)C)(=[O:34])[CH3:33]>>[C:32]([NH:14][C:11]1[CH:12]=[C:13]2[C:8](=[CH:9][C:10]=1[C:15]1[CH:16]=[CH:17][C:18]([S:21]([CH3:24])(=[O:23])=[O:22])=[CH:19][CH:20]=1)[N:7]([C:25]([O:27][CH:28]([CH3:30])[CH3:29])=[O:26])[CH2:6][C@H:5]([CH3:31])[N:4]2[C:1](=[O:3])[CH3:2])(=[O:34])[CH3:33]
Reactant: CC(=O)Nc1cc2c(cc1-c1cnn(C3CC3)c1)N(C(=O)OC(C)C)C[C@H](C)N2C(C)=O
Reactant: CC(=O)N1c2cc(N)c(-c3ccc(S(C)(=O)=O)cc3)cc2N(C(=O)OC(C)C)C[C@@H]1C
Product: CC(=O)Nc1cc2c(cc1-c1ccc(S(C)(=O)=O)cc1)N(C(=O)OC(C)C)C[C@H](C)N2C(C)=O

Procedure:
Isopropyl (S)-6-acetamido-4-acetyl-3-methyl-7-(4-(methylsulfonyl)phenyl)-3,4-dihydroquinoxaline-1(2H)-carboxylate was synthesized from isopropyl (S)-4-acetyl-6-amino-3-methyl-7-(4-(methylsulfonyl)phenyl)-3,4-dihydroquinoxaline-1(2H)-carboxylate according to the procedure described above for isopropyl (S)-6-acetamido-4-acetyl-7-(1-cyclopropyl-1H-pyrazol-4-yl)-3-methyl-3,4-dihydroquinoxaline-1(2H)-carboxylate (Example 235). MS (ESI, pos. ion) m/z 510 [M+Na]+.
Reaction SMILES: [OH-].[K+].[NH2:3][C:4]1[N:9]=[CH:8][C:7]([C:10]2[CH:11]=[N:12][N:13]([C@H:15]3[CH2:19][N:18]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C@H:17]([C:27]([O:29]C)=[O:28])[CH2:16]3)[CH:14]=2)=[CH:6][C:5]=1[C:31]1[O:32][C:33]2[CH:39]=[CH:38][CH:37]=[CH:36][C:34]=2[N:35]=1>CO>[NH2:3][C:4]1[N:9]=[CH:8][C:7]([C:10]2[CH:11]=[N:12][N:13]([C@H:15]3[CH2:19][N:18]([C:20]([O:22][C:23]([CH3:25])([CH3:26])[CH3:24])=[O:21])[C@H:17]([C:27]([OH:29])=[O:28])[CH2:16]3)[CH:14]=2)=[CH:6][C:5]=1[C:31]1[O:32][C:33]2[CH:39]=[CH:38][CH:37]=[CH:36][C:34]=2[N:35]=1
Reactant: COC(=O)[C@@H]1C[C@@H](n2cc(-c3cnc(N)c(-c4nc5ccccc5o4)c3)cn2)CN1C(=O)OC(C)(C)C
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)N1C[C@H](n2cc(-c3cnc(N)c(-c4nc5ccccc5o4)c3)cn2)C[C@H]1C(=O)O
Temperature: 50 °C
Reaction time: 2 h
Yield: 47.8 %

Procedure:
(2S,4R)—O1-tert-butyl O2-methyl 4-[4-[6-amino-5-(1,3-benzoxazol-2-yl)-3-pyridyl]pyrazol-1-yl]pyrrolidine-1,2-dicarboxylate was prepared according to the procedure described in Example 26 except that caesium carbonate was used, using (2S,4S)—O1-tert-butyl O2-methyl 4-methylsulphonyloxypyrrolidine-1,2-dicarboxylate (Siddiqui et al., PCT. Int. Appl. US2007/0167426) as alkylating agent to give 442 mg of solid. NMR Spectrum: (CDCl3) 1.45 (s, 5.4H), 1.48 (s, 3.6H), 2.44-2.52 (m, 1H). 2.82-2.96 (m, 1H), 3.79 (s, 1.8H), 3.80 (s, 1.2H), 3.82-3.89 (m, 0.4H), 3.92-3.98 (m, 0.6H), 4.03-4.11 (m, 1H), 4.49-4.55 (m, 0.6H), 4.60-4.65 (m, 0.4H), 4.99-5.10 (m, 1H), 7.05 (bs, 2H), 7.35-7.42 (m, 2H), 7.59-7.63 (m, 1H), 7.68 (s, 1H), 7.74-7.78 (m, 1H), 7.81 (d, 1H), 8.35 (d, 1H), 8.40 (d, 1H) Mass spectrum: M+H+ 505 A solution of potassium hydroxide (1.249 ml, 2N) was added to (2S,4R)—O1-tert-butyl O2-methyl 4-[4-[6-amino-5-(1,3-benzoxazol-2-yl)-3-pyridyl]pyrazol-1-yl]pyrrolidine-1,2-dicarboxylate (420 mg) dissolved in methanol (10 ml) over a period of 10 minutes under argon. The resulting solution was stirred at 50° C. for 2 hours. The methanol was evaporated and the pH was adjusted to 5.5 with HCl 6N. The mixture was evaporated on reduce pressure. The reaction mixture was purified by preparative HPLC using a Waters X-Terra reverse-phase column (C-18, 5 microns silica, 19 mm diameter, 100 mm length, flow rate of 40 ml/minute) and decreasingly polar mixtures of water (containing 0.2% ammonium carbonate) and acetonitrile as eluent. The fractions containing the desired compound were evaporated to dryness to afford (2S,4R)-4-[4-[6-amino-5-(1,3-benzoxazol-2-yl)-3-pyridyl]pyrazol-1-yl]-1-tert-butoxycarbonyl-pyrrolidine-2-carboxylic acid (195 mg) as a solid. NMR Spectrum: (DMSOd6) 1.35 (s, 5.4H), 1.39 (s, 3.6H), 2.32-2.43 (m, 1H), 2.66-2.82 (m, 1H), 3.63-3.71 (m, 1H), 3.80-3.89 (m, 1H), 4.28-4.36 (m, 1H), 4.96-5.06 (m, 1H), 7.40-7.49 (m, 2H), 7.67 (bs, 2H), 7.77-7.81 (m, 1H), 7.82-7.86 (m, 1H), 7.97 (s, 1H), 8.36 (s, 0.6H), 8.39 (s, 0.4H), 8.41-8.46 (m, 1H), 8.50-8.55 (m, 1H); Mass spectrum: M+H+ 491
Reaction SMILES: [C:1]([NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=1)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].C([Li])CCC.CN(C)[CH:21]=[O:22].Cl.C(=O)([O-])[O-].[K+].[K+]>O1CCCC1>[CH:21]([C:13]1[C:8]([NH:7][C:1](=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3])=[N:9][CH:10]=[CH:11][CH:12]=1)=[O:22]
Reactant: CC(C)(C)C(=O)Nc1ccccn1
Reactant: CN(C)C=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)(C)C(=O)Nc1ncccc1C=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 49.8 %

Procedure:
11.4 g (64 mmol) of 2-(pivaloylamino)pyridine was dissolved in 50 mL of tetrahydrofuran, and 100 mL (0.16 mol) of 1.6 M normal-butyllithium was added dropwise thereto at −60° C. The mixture was allowed to react for 3 hours at −10° C. To this reaction mixture, 14 g (0.19 mol) of N,N-dimethylformamide was added dropwise at −60° C., and the reaction liquid was stirred overnight at room temperature. The reaction mixture was poured into ice, and 6 N hydrochloric acid was added thereto to acidify the reaction mixture. Subsequently, potassium carbonate was added to make the reaction mixture alkaline, and the mixture was extracted with ethyl acetate. The organic phase was washed with water, and was dried and concentrated. The residue thus obtained was purified by column chromatography (ethyl acetate:n-hexane=1:4 to 1:0), and thus 6.57 g (yield 50%) of the title compound was obtained as a pale yellow liquid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([N:11]2[CH2:16][CH2:15][O:14][C@@H:13]([CH2:17][NH:18]C(=O)OC(C)(C)C)[CH2:12]2)[CH3:10])[CH:5]=[CH:6][C:7]=1[Cl:8].[ClH:26].CO>O1CCOCC1>[ClH:1].[ClH:26].[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([N:11]2[CH2:16][CH2:15][O:14][C@@H:13]([CH2:17][NH2:18])[CH2:12]2)[CH3:10])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CC(c1ccc(Cl)c(Cl)c1)N1CCO[C@@H](CNC(=O)OC(C)(C)C)C1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: CC(c1ccc(Cl)c(Cl)c1)N1CCO[C@@H](CN)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Intermediate 32 was treated with 4M hydrogen chloride in dioxane (15 ml) and the solution stirred for 2 h at room temperature. The solution was treated with methanol (20 ml) and concentrated in vacuo to give the title compound as an off-white solid (1.53 g).