Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](NCC(O)=O)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C(N1C=CN=C1)([N:15]1[CH:19]=[CH:18]N=C1)=O.C(=O)=O.[F:28][C:29]1[CH:30]=[CH:31][C:32]2[N:38]3[CH:39]=[N:40][C:41]([C:42](=[N:44][OH:45])[NH2:43])=[C:37]3[C@@H:36]3[CH2:46][CH2:47][N:35]3[C:34](=[O:48])[C:33]=2[CH:49]=1>CN(C)C=O>[C:1]([CH:19]([NH2:15])[C:18]1[O:45][N:44]=[C:42]([C:41]2[N:40]=[CH:39][N:38]3[C:32]4[CH:31]=[CH:30][C:29]([F:28])=[CH:49][C:33]=4[C:34](=[O:48])[N:35]4[CH2:47][CH2:46][C@H:36]4[C:37]=23)[N:43]=1)([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: NC(=NO)c1ncn2c1[C@@H]1CCN1C(=O)c1cc(F)ccc1-2
Agent: O=C=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)C(N)c1nc(-c2ncn3c2[C@@H]2CCN2C(=O)c2cc(F)ccc2-3)no1
Reaction time: 8 h
Yield: 61.2 %

Procedure:
8.41 g (48 mmol) of BOC-glycine were dissolved in 30 ml of N,N-dimethylformamide and treated portionwise with 7.8 g (48 mmol) of 1,1'-carbonyldiimidazole. After completion of the CO2 evolution the solution was stirred at 45° for 10'. Then, 12.05 g (40 mmol) of (S)-7-fluoro-12,12a-dihydro-9-oxo-9H,11H-azeto-[2,1-c]imidazo[1,5-a][1,4]benzodiazepine-1-carboxamidoxime were added and the mixture was stirred at 90° overnight. By evaporation of the solution, chromatography of the residue on 550 g of silica gel while eluting with methylene chloride/methanol 19/1 and recrystallization from ethyl acetate there were obtained 10.78 g (61%) of (S)-1-[5-(BOC-aminomethyl)-1,2,4-oxadiazol-3-yl]-7-fluoro-12,12a-dihydro-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepin-9-one of m.p. 147°-150°.
Reaction SMILES: [CH:1]([S:5][P:6]([CH2:9][CH3:10])(S)=[S:7])([CH2:3][CH3:4])[CH3:2]>C(N(CC)CC)C>[CH2:9]([P:6](=[S:7])=[S:5])[CH3:10].[CH:1]([SH:5])([CH2:3][CH3:4])[CH3:2]
Reactant: CCC(C)SP(=S)(S)CC
Solvent: CCN(CC)CC
Product: CCC(C)S
Product: CCP(=S)=S

Procedure:
(a.) Following the procedure as shown in Example 1, step (a), 14.67 g (94%) of the triethylamine salt of S-sec-butyl ethylphosphonotrithioic acid was obtained from 6.0 g (0.0242 mole) of ethylthionophosphine sulfide, 5.80 ml (4.58 g, 0.0508 mole) of sec-butyl mercaptan, and 7.1 ml (5.14 g, 0.0508 mole) of triethylamine.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[Br:12][CH2:13][C:14](Br)=[O:15]>CN(C=O)C.O1CCOCC1>[Br:12][CH2:13][C:14]([NH:1][C:2]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5])=[O:15]
Reactant: O=C(Br)CBr
Reactant: Nc1ccc(O)cc1C(=O)O
Solvent: C1COCCO1
Solvent: CN(C)C=O
Product: O=C(CBr)Nc1ccc(O)cc1C(=O)O
Temperature: 25 °C
Reaction time: 20 h
Yield: 71.8 %

Procedure:
To a solution of 2-amino-5-hydroxybenzoic acid (6.1 g, 0.04 mol) in anhydrous DMF (20 mL) and anhydrous dioxane (20 mL) was added, dropwise, bromoacetyl bromide (8.0 g, 3.5 mL, 100 mol %) while keeping the internal temperature between 0° C. and 5° C. After the addition was completed (~20 min), the ice-bath was removed and the mixture was stirred for 20 h at rt. The reaction mixture was cooled in an ice-bath, water was added (100 mL), and then the mixture was poured into ice-water. The light precipitate which formed was filtered and then dried in a vacuum oven for 20 h at 40°-45° C., giving 7.8 g (72%) of the title compound: mp 213°-215.3° C.; 1H NMR (DMSO-d6) δ13.56 (bs, 1H, OH), 11.19 (s, 1H, NH), 9.68 (s, 1H, OH), 8.19 (d, 1H, J=8.8), 7.36 (d, 1H, J=3.2), 7.01 (dd, 1H, J=3.2, J=9.2), 4.19 (s, 2H); 13C NMR (DMSO-d6) δ168.88, 164.32, 153.08, 131.69, 122.21, 120.79, 119.00, 116.60, 30.66; MS (EI, m/z) 273 (M+), 275 (M+2+). HRMS (EI) calcd for C9H8NO4Br 272.9637, found 272.9634.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[N:7][C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[CH:10][CH:9]=2)(=[O:3])[CH3:2].C(Cl)(Cl)Cl>C(O)(=O)C>[C:1]([NH:4][CH:5]1[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1cnc2ccccc2c1
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: CC(=O)NC1CNc2ccccc2C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 55.7 %

Procedure:
Borane-pyridine complex (320 mg, 3.5 mmol) was added to a solution of 3-acetamidoquinoline (320 mg, 1.7 mmol) in acetic acid (20 ml) and the mixture was stirred at room temperature for 18 h. Chloroform (150 ml) was added and the mixture was washed with 2N sodium hydroxide solution, water and brine. The organic phase was dried and reduced. Chromatography (80% EtOAc/20% 60-80 pet. ether) afforded 3-acetamido-1,2,3,4-tetrahydroquinoline (180 mg, 55%) as a pale yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.[F:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:22]1[C:23]([CH:28]=O)=[CH:24][CH:25]=[CH:26][CH:27]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C1(C2C=CC=CC=2)C=CC=CC=1CN1CCN(C2C=CC=CC=2)CC1>>[F:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[CH2:28][N:12]1[CH2:13][CH2:14][N:9]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[O:2][CH3:1])[CH2:10][CH2:11]1
Reactant: O=Cc1ccccc1-c1ccccc1F
Reactant: COc1ccccc1N1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: c1ccc(-c2ccccc2CN2CCN(c3ccccc3)CC2)cc1
Product: COc1ccccc1N1CCN(Cc2ccccc2-c2ccccc2F)CC1

Procedure:
379 mg of the target compound (1.01 mmol, 32.5%) was obtained using 1-(2-methoxyphenyl)piperazine (1.2 g, 6.20 mmol), 2′-fluorobiphenyl-2-carbaldehyde (620 mg, 3.10 mmol) and NaBH(OAc)3 (2.0 g, 9.30 mmol) according to the synthesis method of Compound 1.
Reaction SMILES: [F:1][C:2]([F:37])([F:36])[C:3]1[CH:4]=[C:5]([CH:13]=[CH:14][C:15](=[O:35])[CH:16]([NH:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:17][C:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[NH:20][CH:19]=2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.C([SnH](CCCC)CCCC)CCC>C1(C)C=CC=CC=1>[F:36][C:2]([F:1])([F:37])[C:3]1[CH:4]=[C:5]([CH2:13][CH2:14][C:15](=[O:35])[CH:16]([NH:27][C:28]([O:30][C:31]([CH3:32])([CH3:33])[CH3:34])=[O:29])[CH2:17][C:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[NH:20][CH:19]=2)[CH:6]=[C:7]([C:9]([F:12])([F:10])[F:11])[CH:8]=1
Reactant: CC(C)(C)OC(=O)NC(Cc1c[nH]c2ccccc12)C(=O)C=Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: CCCC[SnH](CCCC)CCCC
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)NC(Cc1c[nH]c2ccccc12)C(=O)CCc1cc(C(F)(F)F)cc(C(F)(F)F)c1

Procedure:
The product of part (c) was heated under reflux with tri-n-butyltin hydride (51.12 g) in toluene for 20 hours. The reaction was cooled and purified by column chromatography on silica using ethyl acetate/petroleum ether (1:4) to yield the title compound as a white solid (37.1 g), mp=138°-140° C.: found: C, 59.23; H, 4.90; N, 5.28; C26H24F6N2O3 requires C, 59.09, H, 4.96; N, 5.30%.
Reaction SMILES: C1C=C2N=NN([O:10][C:11]([C:13](ON3N=NC4C3=CC=CC=4)=O)=O)C2=CC=1.[F:25][C:26]1[C:27]([NH:45][C:46]2[CH:51]=[CH:50][C:49]([I:52])=[CH:48][C:47]=2[F:53])=[C:28]([CH:36]=[C:37]([CH2:40][NH:41][CH2:42][CH2:43][OH:44])[C:38]=1[F:39])[C:29]([NH:31][O:32][CH2:33][CH2:34][OH:35])=[O:30].[OH2:54].Cl>CN(C)C1C=CN=CC=1.CN(C)C=O.C(Cl)Cl.CO>[O:44]=[C:43]1[O:10][CH2:11][CH2:13][N:41]([CH2:40][C:37]2[C:38]([F:39])=[C:26]([F:25])[C:27]([NH:45][C:46]3[CH:51]=[CH:50][C:49]([I:52])=[CH:48][C:47]=3[F:53])=[C:28]([CH:36]=2)[C:29]([NH:31][O:32][CH2:33][CH2:34][OH:35])=[O:30])[C:42]1=[O:54]
Reactant: O=C(On1nnc2ccccc21)C(=O)On1nnc2ccccc21
Reactant: O=C(NOCCO)c1cc(CNCCO)c(F)c(F)c1Nc1ccc(I)cc1F
Reactant: O
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CO
Solvent: ClCCl
Product: O=C1OCCN(Cc2cc(C(=O)NOCCO)c(Nc3ccc(I)cc3F)c(F)c2F)C1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 6 %

Procedure:
4-Dimethylaminopyridine (12.1 mg) and dibenzotriazol-1-yl oxalate (9.2 mg, 27.4 μmol) were added to a solution of 3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-[(2-hydroxy-ethylamino)-methyl]-benzamide (15.9 mg, 30.2 μmol) obtained in Step B (or Step B′) of Example 72 in anhydrous N,N-dimethylformamide (1.5 ml) at room temperature. The mixture was stirred at room temperature for 2 hours. Water (6 ml) and 1 N hydrochloric acid (0.5 ml) were added, and the reaction mixture was extracted with ethyl acetate (2×10 ml). The combined organic layers were washed with saturated brine (8 ml), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified with a preparative silica gel plate (No. 5744, Merck, CH2Cl2/MeOH (10:1) as a developing solvent) to give 5-(2,3-dioxo-morpholin-4-ylmethyl)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-benzamide (Compound H-7, 1.0 mg, 6% yield).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([OH:17])=O)[CH3:14])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1.[NH2:18][CH:19]1[C:28]2[C:23](=[CH:24][C:25]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[CH:26][CH:27]=2)[CH2:22][NH:21][C:20]1=[O:35]>>[F:8][C:6]1[CH:5]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([NH:18][CH:19]2[C:28]3[C:23](=[CH:24][C:25]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)=[CH:26][CH:27]=3)[CH2:22][NH:21][C:20]2=[O:35])=[O:17])[CH3:14])=[O:11])[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: NC1C(=O)NCc2cc(-c3ccccc3)ccc21
Reactant: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)O
Product: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)NC1C(=O)NCc2cc(-c3ccccc3)ccc21

Procedure:
Following General Procedure D above using N-(3,5-difluorophenylacetyl)-L-alanine (Example B) and 4-amino-7-phenyl-1,2,3,4-tetrahydroisoquinoline-3-one (Example 5-H), the title compound was prepared as a solid having a melting point >240° C. (dec.).
Reaction SMILES: C[O:2][C:3]1(OC)[CH2:9][CH2:8][CH2:7][CH2:6][CH:5]([C:10](=O)[C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:4]1=O.[CH3:20][NH:21][NH2:22]>CCO.CC(O)=O>[CH3:20][N:21]1[C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:3](=[O:2])[C:4]2=[N:22]1
Reactant: CCOC(=O)C(=O)C1CCCCC(OC)(OC)C1=O
Reactant: CNN
Solvent: CCO
Solvent: CC(=O)O
Product: CCOC(=O)c1c2c(nn1C)C(=O)CCCC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 379.8 %

Procedure:
To a solution of ethyl (3,3-dimethoxy-2-oxocycloheptyl)(oxo)acetate 0.090 g (0.33 mmol) in 2 mL of EtOH and 4 mL of AcOH, 0.020 mL (0.039 mmol) of N-methylhydrazine was added. The mixture was stirred overnight at room temperature. The solvent was removed under reduced pressure and the crude solid was purified by flash chromatography on silica gel (eluant: AcOEt/hexane 8/2) to afford 0.035 g (38% yield) of the title compound as colorless oil.
Reaction SMILES: [CH2:1]([C@H:6]1[CH2:11][CH2:10][C@H:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:23]=[CH:22][C:21]([C:24]([OH:26])=O)=[CH:20][CH:19]=3)=[CH:14][CH:13]=2)[CH2:8][CH2:7]1)[CH2:2][CH2:3][CH:4]=[CH2:5].C(N(CC)CC)C.ClC(OCC)=O.[N-:40]=[N+:41]=[N-:42].[Na+]>CC(C)=O.O>[CH2:1]([C@H:6]1[CH2:11][CH2:10][C@H:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:23]=[CH:22][C:21]([C:24]([N:40]=[N+:41]=[N-:42])=[O:26])=[CH:20][CH:19]=3)=[CH:14][CH:13]=2)[CH2:8][CH2:7]1)[CH2:2][CH2:3][CH:4]=[CH2:5]
Reactant: C=CCCC[C@H]1CC[C@H](c2ccc(-c3ccc(C(=O)O)cc3)cc2)CC1
Reactant: [N-]=[N+]=[N-]
Agent: CCOC(=O)Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Solvent: O
Product: C=CCCC[C@H]1CC[C@H](c2ccc(-c3ccc(C(=O)N=[N+]=[N-])cc3)cc2)CC1
Temperature: 2 °C

Procedure:
A mixture of 10.3 g of 4'-[trans-4-(4-pentenyl)cyclohexyl]-4-biphenylcarboxylic acid and 300 ml of acetone was cooled to 2° C. while stirring and gassing with nitrogen, treated dropwise within 10 minutes with a solution of 8.2 ml of triethylamine in 58 ml of acetone and stirred for a further 5 minutes. Thereafter, the mixture was treated dropwise at 0°-2° C. within 10 minutes with a solution of 7.1 ml of ethyl chloroformate in 29 ml of acetone. The mixture was stirred for a further 30 minutes at 0°-2° C. and treated dropwise within 10 minutes with a solution of 5.25 g of sodium azide in 29 ml of water. The reaction mixture was stirred for a further 2.25 hours while cooling with an ice-bath, then poured into 1 l of water and extracted once with 1 l of diethyl ether and once with 500 ml of diethyl ether. The ether phases were washed with water, dried over sodium sulphate, filtered and concentrated. The beige crystalline residue (12.2 g) was separated by chromatography on silica gel with methylene chloride, whereby 9.9 g (89.5%) of 4'-[trans-4-(4-pentenyl)cyclohexyl]-4-biphenylcarboxylic acid azide were obtained as colourless crystals.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([NH:13][C:14]3[CH:15]=[CH:16][C:17]([N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)=[C:18]([CH2:20]O)[CH:19]=3)=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1.S(Cl)(Cl)=O.[CH3:32][N:33]([CH3:38])[CH2:34][CH2:35][NH:36][CH3:37]>CN1C(=O)CCC1.C(Cl)Cl>[Cl:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([NH:13][C:14]3[CH:15]=[CH:16][C:17]([N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)=[C:18]([CH2:20][N:36]([CH2:35][CH2:34][N:33]([CH3:38])[CH3:32])[CH3:37])[CH:19]=3)=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1
Reactant: OCc1cc(Nc2ccnc3cc(Cl)ccc23)ccc1N1CCOCC1
Reactant: CNCCN(C)C
Agent: Cl
Solvent: CN1CCCC1=O
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: CN(C)CCN(C)Cc1cc(Nc2ccnc3cc(Cl)ccc23)ccc1N1CCOCC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 85.5 %

Procedure:
To a suspension of {5-[(7-chloroquinolin-4-yl)amino]-2-(morpholin-4-yl)phenyl}methanol hydrochloride (compound of step C of example 31) (0.100 g, 0.25 mmol) in 4 mL of NMP at 0° C. was added thionyl chloride (90 μL, 1.23 mmol). The reaction mixture was warmed up to room temperature and stirred for 3 h. The reaction mixture was then slowly added to N,N,N′-trimethylethylenediamine (1 mL, 7.50 mmol) in 1 mL of NMP at 0° C. and then stirred at room temperature for 2 h. This solution was diluted in 100 mL of CH2Cl2 and washed with a saturated aqueous solution of NaHCO3. The organic layer was dried over MgSO4, filtered, evaporated and purified by flash chromatography (DCM/MeOH/NH4OH//90/10/1 then 80/20/1) to yield expected compound as a yellow solid (97 mg, 85% yield). LC-MS: m/z (ESI) 454.4 [M+H]+.
Reaction SMILES: [C:1]1([C:7]([SH:20])([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Br[C:24]([CH3:28])([CH3:27])[CH:25]=[O:26]>C1COCC1.C1(C)C=CC=CC=1>[CH3:27][C:24]([S:20][C:7]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)([CH3:28])[CH:25]=[O:26]
Reactant: SC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(C)(Br)C=O
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CC(C)(C=O)SC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 58.7 %

Procedure:
Triphenylmethylmercaptan (362.94 g, 1.31 mol, 100 mol %) dissolved in anhydrous THF (2 L) was cooled in an ice bath under argon. Sodium hydride (60% in oil; 54.39 g, 1.35 mol, 104 mol %) was added in portions over 20 min. 2-bromo-2-methylpropanal (206.06 g, 1.36 mol, 104 mol %; see Stevens & Gillis, 1957, J. Amer. Chem. Soc. 79: 3448-51) was then added slowly over 20 min. The reaction mixture was allowed to warm to room temperature and stirred for 12 hours. The reaction was quenched with water (1 L) and extracted with diethyl ether (3×1 L). The ether extracts were combined, washed with saturated NaCl solution (500 mL), dried over Na2SO4 and filtered. The solvent was removed under reduced pressure to afford a thick orange oil. The crude oil was dissolved in toluene (200 mL) and diluted to 2 L with hot hexanes. The mixture was filtered through a sintered glass funnel and cooled at -5° C. for 12 hours. The white crystalline solid which formed was removed by filtration to afford 266.36 g (59% yield) of the title compound. The melting point of the resulting compound was determined to be 83°-85° C. Nuclear magnetic resonance characterization experiments yielded the following molecular signature:
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][CH:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:4][CH2:3]1.CCN(CC)CC.[C:20]1(=O)[O:25][C:23](=[O:24])[C:22]2=[CH:26][CH:27]=[CH:28][CH:29]=[C:21]12>C1(C)C=CC=CC=1>[O:24]=[C:23]1[C:22]2[C:21](=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:20](=[O:25])[N:1]1[CH:2]1[CH2:3][CH2:4][CH:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:6][CH2:7]1
Reactant: O=C1OC(=O)c2ccccc21
Reactant: CCOC(=O)C1CCC(N)CC1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCOC(=O)C1CCC(N2C(=O)c3ccccc3C2=O)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 34.1 %

Procedure:
A solution of ethyl 4-aminocyclohexanecarboxylate (0.50 g, 2.92 mmol) in toluene (10 mL) was added Et3N (1.02 mL, 7.30 mmol) and phthalic anhydride (0.56 g, 3.80 mmol) and the mixture refluxed for 6-8 h using dean-stark apparatus to remove water. After completion of the reaction (by TLC), the solvent was evaporated under reduced pressure, water (50 mL) added and stirred for 30 min at rt. The solid material thus obtained was collected by filtration under vacuum and dried to obtain the desired product as off-white solid (0.30 g, 34%). 1H NMR (DMSO-d6): δ 7.84 (s, 4H), 4.19 (q, J=7.20 Hz, 2H), 3.71 (m, 1H), 2.71 (m, 1H), 2.06 (m, 2H), 1.90 (m, 2H), 1.69 (m, 2H), 1.60 (m, 2H), and 1.23 (t, J=7.20 Hz, 3H).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:6][OH:7])[C:3]([O-:5])=[O:4].[C:8]([Cl:11])(=O)[CH3:9]>C(O)C>[ClH:11].[NH2:1][C@@H:2]([CH2:6][OH:7])[C:3]([O:5][CH2:8][CH3:9])=[O:4]
Reactant: CC(=O)Cl
Reactant: N[C@@H](CO)C(=O)[O-]
Solvent: CCO
Product: CCOC(=O)[C@@H](N)CO
Product: Cl
Reaction time: 18 h
Yield: 65.2 %

Procedure:
A mixture of (2S)-2-amino-3-hydroxypropanoate (25 g, 238 mmol) and acetyl chloride (34 ml, 476 mmol) in absolute ethanol (250 ml) was stirred at 50° for 18 hr. The volatiles were removed in vacuo until the volume was reduced to ˜100 ml. Upon cooling the resultant precipitate was collected, washed with ether and hexane to give the title compound as a white powder (26.3 g, 65%). δH NMR (DMSO d6) 8.47 (3H, br s), 5.58 (1H, dd), 4.20 (2H, q), 4.08 (1H, t), 3.81 (2H, dd), 1.23 (3H, t).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH2:8])[N:5]=[C:4]([NH:9][C:10]2[CH:15]=[C:14]([F:16])[C:13]([O:17][C:18]3[CH:23]=[CH:22][N:21]=[C:20]4[NH:24][CH:25]=[C:26]([CH3:27])[C:19]=34)=[C:12]([F:28])[CH:11]=2)[CH:3]=1.C(N(CC)CC)C.[H][H]>C(O)C.[Pd]>[F:16][C:14]1[CH:15]=[C:10]([NH:9][C:4]2[CH:3]=[CH:2][N:7]=[C:6]([NH2:8])[N:5]=2)[CH:11]=[C:12]([F:28])[C:13]=1[O:17][C:18]1[CH:23]=[CH:22][N:21]=[C:20]2[NH:24][CH:25]=[C:26]([CH3:27])[C:19]=12
Reactant: Cc1c[nH]c2nccc(Oc3c(F)cc(Nc4cc(Cl)nc(N)n4)cc3F)c12
Reactant: [H][H]
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CCO
Product: Cc1c[nH]c2nccc(Oc3c(F)cc(Nc4ccnc(N)n4)cc3F)c12

Procedure:
50 mg (0.12 mmol) of 6-chloro-N4-{3,5-difluoro-4-[(3-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]phenyl}pyrimidine-2,4-diamine are dissolved in 10 ml of ethanol. 35 μl (0.25 mmol) of triethylamine and 26 mg (0.02 mmol) of 10% palladium-on-carbon are added, and the mixture is hydrogenated under atmospheric pressure in a hydrogen atmosphere overnight. The mixture is then filtered through Celite®, and the celite is washed with methanol. The solvent is removed under reduced pressure and the crude product is purified by preparative HPLC.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=[O:17])[CH3:16])=[C:11]([OH:18])[C:10]=1[CH2:19][CH2:20][CH3:21])[CH3:2].[S:23]([O:27][CH2:28][CH2:29][O:30][CH2:31][CH2:32]OS(=O)(=O)C)(=[O:26])(=[O:25])[CH3:24].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.CN(C)C=O>[CH2:1]([O:3][C:4](=[O:22])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=[O:17])[CH3:16])=[C:11]([O:18][CH2:32][CH2:31][O:30][CH2:29][CH2:28][O:27][S:23]([CH3:24])(=[O:26])=[O:25])[C:10]=1[CH2:19][CH2:20][CH3:21])[CH3:2]
Reactant: CS(=O)(=O)OCCOCCOS(C)(=O)=O
Reactant: CCCc1c(OCCCC(=O)OCC)ccc(C(C)=O)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC(C)=O
Product: CCCc1c(OCCCC(=O)OCC)ccc(C(C)=O)c1OCCOCCOS(C)(=O)=O
Yield: 66.5 %

Procedure:
A mixture of 4 g (0.013 mol) of 4-(4-acetyl-3-hydroxy-2-propylphenoxy)butanoic acid ethyl ester, 17 g (0.065 mol) of diethylene glycol dimesylate and 3.6 g (0.026 mol) of anhydrous potassium carbonate in 80 ml of anhydrous acetone and 40 ml of anhydrous dimethylformamide was stirred at reflux for 20 hours. An additional 1.8 g of potassium carbonate was added and reflux was continued for a total of 44 hours. The reaction mixture was filtered and concentrated in vacuo to an orange oil which was treated with ethyl acetate and sodium chloride solution. The yellow oil obtained on concentration of the ethyl acetate was purified by HPLC, eluting with 15% ethyl acetate/toluene to yield 4.1 g (67% yield) of 4-[4-acetyl-3-[2-[2-[(methylsulfonyl)oxy]ethoxy]-ethoxy]-2-propylphenoxy]butanoic acid ethyl ester as a yellow oil.
Reaction SMILES: C([O:5][C:6](=[O:35])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][N:18]([CH2:27][C:28]2[CH:33]=[CH:32][C:31]([Br:34])=[CH:30][CH:29]=2)[C:19]2[N:24]=[CH:23][C:22]([CH2:25][CH3:26])=[CH:21][N:20]=2)[N:15]=1)([CH3:9])[CH3:8])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[Br:34][C:31]1[CH:32]=[CH:33][C:28]([CH2:27][N:18]([C:19]2[N:20]=[CH:21][C:22]([CH2:25][CH3:26])=[CH:23][N:24]=2)[CH2:17][CH2:16][C:14]2[N:15]=[C:11]([S:10][C:7]([CH3:8])([CH3:9])[C:6]([OH:35])=[O:5])[S:12][CH:13]=2)=[CH:29][CH:30]=1
Reactant: CCc1cnc(N(CCc2csc(SC(C)(C)C(=O)OC(C)(C)C)n2)Cc2ccc(Br)cc2)nc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCc1cnc(N(CCc2csc(SC(C)(C)C(=O)O)n2)Cc2ccc(Br)cc2)nc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 75.9 %

Procedure:
2-[(4-{2-[(4-Bromobenzyl)(5-ethylpyrimidin-2-yl)amino]ethyl}-1,3-thiazol-2-yl)thio]-2-methylpropionic acid tert-butyl ester (350 mg) obtained in Example 402-1 was dissolved in dichloromethane (6 mL), trifluoroacetic acid (2 mL) was added, and the mixture was stirred at room temperature for 20 hr. The reaction mixture was concentrated under reduced pressure, ethyl acetate was added, and the mixture was washed with saturated aqueous sodium hydrogen carbonate solution (at this time point, the object product had been extracted in the ethyl acetate layer). The ethyl acetate layer was washed with aqueous 10% citric acid solution and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent; hexane:ethyl acetate=1:1 to 0:1) to give the title compound (240 mg) as a white solid.
Reaction SMILES: [CH3:1][N:2]([CH2:9][CH2:10][O:11][C:12]1[CH:19]=[CH:18][C:15]([CH:16]=O)=[CH:14][CH:13]=1)[C:3]1[N:8]=[CH:7][CH:6]=[CH:5][N:4]=1.[S:20]1[CH2:24][C:23](=[O:25])[NH:22][C:21]1=[O:26].C([O-])(=O)C.[NH2+]1CCCCC1>C1(C)C=CC=CC=1>[CH3:1][N:2]([CH2:9][CH2:10][O:11][C:12]1[CH:19]=[CH:18][C:15]([CH:16]=[C:24]2[S:20][C:21](=[O:26])[NH:22][C:23]2=[O:25])=[CH:14][CH:13]=1)[C:3]1[N:8]=[CH:7][CH:6]=[CH:5][N:4]=1
Reactant: CN(CCOc1ccc(C=O)cc1)c1ncccn1
Reactant: O=C1CSC(=O)N1
Agent: C1CC[NH2+]CC1
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1
Product: CN(CCOc1ccc(C=C2SC(=O)NC2=O)cc1)c1ncccn1

Procedure:
A solution of 4-[2-(N-methyl-N-(2-pyrimidinyl)amino) ethoxy]benzaldehyde (1.7 g) and 2,4-thiazolidinedione (0.7 g) in toluene (100 ml) containing a catalytic quantity of piperidinium acetate was boiled under reflux in a Dean and Stark apparatus for 2 hours. The mixture was cooled and filtered to give the title compound (mp 189°-90° C.).
Reaction SMILES: [CH3:1][C:2]([N+:15]([O-:17])=[O:16])([CH3:14])[CH2:3][C:4]1[N:8]2[CH:9]=[CH:10][CH:11]=[C:12]([OH:13])[C:7]2=[N:6][CH:5]=1.Cl[CH2:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CC(=O)CC>[C:23]([O:22][C:20](=[O:21])[CH2:19][O:13][C:12]1[C:7]2[N:8]([C:4]([CH2:3][C:2]([CH3:1])([N+:15]([O-:17])=[O:16])[CH3:14])=[CH:5][N:6]=2)[CH:9]=[CH:10][CH:11]=1)([CH3:26])([CH3:25])[CH3:24]
Reactant: CC(C)(C)OC(=O)CCl
Reactant: CC(C)(Cc1cnc2c(O)cccn12)[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CC(C)(C)OC(=O)COc1cccn2c(CC(C)(C)[N+](=O)[O-])cnc12
Yield: 80.8 %

Procedure:
3-(2-Methyl-2-nitropropyl)imidazo[1,2-a]pyridin-8-ol (1.0 g, 4.25 mmol), tert-butyl chloroacetate (964 mg, 6.4 mmol), potassium carbonate (590 mg, 4.27 mmol), and a small amount of potassium iodide in 2-butanone (30 ml) are reacted as described in Amine 9. The crude product residue is chromatographed on silica gel with dichloromethane/ethanol 9:1 to give 1.2 g of tert-butyl[3-(2-methyl-2-nitropropyl)imidazo[1,2-a]pyridin-8-yloxy]-acetate (81%).