Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]([CH3:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:5]=[CH:6][C:7]=1[NH2:8].Br[C:17]1[S:18][CH:19]=[CH:20][N:21]=1>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([CH:9]([CH3:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:5]=[CH:6][C:7]=1[NH:8][C:17]1[S:18][CH:19]=[CH:20][N:21]=1
Reactant: CCOC(=O)C(C)c1ccc(N)c(F)c1
Reactant: Brc1nccs1
Solvent: ClCCl
Product: CCOC(=O)C(C)c1ccc(Nc2nccs2)c(F)c1
Reaction time: 0.25 h
Yield: 63.6 %

Procedure:
A mixture of ethyl 2-(3-fluoro-4-aminophenyl)propionate (15 g) and 2-bromothiazole (11.7 g) is stirred at 150°-155° C for 15 minutes. The reaction mixture is dissolved in methylene chloride and the solution is washed with an aqueous solution of sodium hydrogen carbonate and dried. The solvent is evaporated. The residue is subjected to chromatography using alumina. From benzene eluate, ethyl 2-[3-fluoro-4-(N-thiazol-2-ylamino)phenyl]propionate (13.3 g) is obtained as oily substance boiling at 162°-164° C at 0.2 mmHg.
Reaction SMILES: [C:1]([CH2:4][CH2:5][CH2:6][N:7]([CH3:63])[C@H:8]([C:12]([NH:14][C@H:15]([C:19]([N:21]([C@@H:23]([C@@H:59]([CH3:62])[CH2:60][CH3:61])[C@H:24]([O:57][CH3:58])[CH2:25][C:26]([N:28]1[CH2:32][CH2:31][CH2:30][C@H:29]1[C@H:33]([O:55][CH3:56])[C@@H:34]([CH3:54])[C:35]([NH:37][C@H:38](/[CH:46]=[CH:47]/[C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)[CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)=[O:36])=[O:27])[CH3:22])=[O:20])[CH:16]([CH3:18])[CH3:17])=[O:13])[CH:9]([CH3:11])[CH3:10])(O)=[O:2].Cl.[O:65]=[C:66]1[CH:70]=[CH:69][C:68](=[O:71])[N:67]1[CH2:72][CH2:73][CH2:74][CH2:75][CH2:76][C:77]([NH:79][NH2:80])=[O:78]>>[O:71]=[C:68]1[CH:69]=[CH:70][C:66](=[O:65])[N:67]1[CH2:72][CH2:73][CH2:74][CH2:75][CH2:76][C:77]([NH:79][NH:80][C:1](=[O:2])[CH2:4][CH2:5][CH2:6][N:7]([CH3:63])[C@H:8]([C:12]([NH:14][C@H:15]([C:19]([N:21]([C@@H:23]([C@@H:59]([CH3:62])[CH2:60][CH3:61])[C@H:24]([O:57][CH3:58])[CH2:25][C:26]([N:28]1[CH2:32][CH2:31][CH2:30][C@H:29]1[C@H:33]([O:55][CH3:56])[C@@H:34]([CH3:54])[C:35]([NH:37][C@H:38](/[CH:46]=[CH:47]/[C:48]1[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=1)[CH2:39][C:40]1[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=1)=[O:36])=[O:27])[CH3:22])=[O:20])[CH:16]([CH3:17])[CH3:18])=[O:13])[CH:9]([CH3:11])[CH3:10])=[O:78]
Reactant: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@H](/C=C/c1ccccc1)Cc1ccccc1)OC)N(C)C(=O)[C@@H](NC(=O)[C@H](C(C)C)N(C)CCCC(=O)O)C(C)C
Reactant: NNC(=O)CCCCCN1C(=O)C=CC1=O
Agent: Cl
Product: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@H](/C=C/c1ccccc1)Cc1ccccc1)OC)N(C)C(=O)[C@@H](NC(=O)[C@H](C(C)C)N(C)CCCC(=O)NNC(=O)CCCCCN1C(=O)C=CC1=O)C(C)C

Procedure:
8 mg (9.1 mmol) of N-(3-carboxypropyl)-N-methyl-L-valyl-N-[(3R,4S,5S)-1-{(2S)-2-[(1R,2R)-3-{[(2S,3E)-1,4-diphenylbut-3-en-2-yl]amino}-1-methoxy-2-methyl-3-oxopropyl]pyrrolidin-1-yl}-3-methoxy-5-methyl-1-oxoheptan-4-yl]-N-methyl-L-valinamide and 7.2 mg (27.4 mmol) of 6-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)hexanehydrazide hydrochloride were coupled and worked up in analogy to Intermediate 157. 8.2 mg (82% of theory) of the title compound were obtained as a white solid.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[C:11]([N+:18]([O-])=O)[CH:10]=2)[CH:3]=1.[O:21]1[CH2:26][CH2:25][N:24]([C:27]2[CH:32]=[CH:31][C:30]([NH:33][C:34]([C:36]3[CH:43]=[CH:42][C:39]([CH:40]=O)=[CH:38][CH:37]=3)=[O:35])=[CH:29][CH:28]=2)[CH2:23][CH2:22]1>>[CH3:1][C:2]1[O:6][N:5]=[C:4]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]3[N:15]=[C:40]([C:39]4[CH:38]=[CH:37][C:36]([C:34]([NH:33][C:30]5[CH:29]=[CH:28][C:27]([N:24]6[CH2:23][CH2:22][O:21][CH2:26][CH2:25]6)=[CH:32][CH:31]=5)=[O:35])=[CH:43][CH:42]=4)[NH:18][C:11]=3[CH:10]=2)[CH:3]=1
Reactant: Cc1cc(COc2ccc([N+](=O)[O-])c([N+](=O)[O-])c2)no1
Reactant: O=Cc1ccc(C(=O)Nc2ccc(N3CCOCC3)cc2)cc1
Product: Cc1cc(COc2ccc3nc(-c4ccc(C(=O)Nc5ccc(N6CCOCC6)cc5)cc4)[nH]c3c2)no1

Procedure:
Compound 629 was prepared according to the procedure similar to that described in Scheme III from 1-(5-methylisoxazol-3-yl)methoxy-3,4-dinitrobenzene and 4-(4-(4-morpholinophenyl)aminocarbonylbenzaldehyde. [M+H]+ calcd for C29H27N5O4: 510.21; found: 510.06.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]2[N:13]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[N:14]=[C:15]([CH3:16])[C:3]=12.[CH3:23][O:24][C:25]1[CH:30]=[CH:29][C:28]([S:31]([NH:34][CH2:35][C:36]2[CH:37]=[N:38][CH:39]=[CH:40][CH:41]=2)(=[O:33])=[O:32])=[CH:27][CH:26]=1.[H-].[Na+]>>[CH2:11]([O:10][C:8]([C:7]1[C:2]([N:34]([S:31]([C:28]2[CH:29]=[CH:30][C:25]([O:24][CH3:23])=[CH:26][CH:27]=2)(=[O:33])=[O:32])[CH2:35][C:36]2[CH:37]=[N:38][CH:39]=[CH:40][CH:41]=2)=[C:3]2[C:15]([CH3:16])=[N:14][N:13]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:4]2=[N:5][CH:6]=1)=[O:9])[CH3:12]
Reactant: CCOC(=O)c1cnc2c(c(C)nn2-c2ccccc2)c1Cl
Reactant: COc1ccc(S(=O)(=O)NCc2cccnc2)cc1
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)c1cnc2c(c(C)nn2-c2ccccc2)c1N(Cc1cccnc1)S(=O)(=O)c1ccc(OC)cc1

Procedure:
Following the procedure of Example 53, the product of Example 65 is reacted with (4-methoxybenzenesulfonyl) (3-pyridinylmethyl) amine and sodium hydride to provide ethyl-4-[(4-methoxybenzenesulfonyl)pyridin-3-ylmethylamino]-1-phenyl-3-methyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylate. m.p. 1480-150° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[N:14]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([NH2:25])=[CH:21][CH:20]=3)[N:13]=[C:12]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:11]=2[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:39][S:40](Cl)(=[O:42])=[O:41]>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[N:14]([CH2:18][C:19]3[CH:20]=[CH:21][C:22]([N:25]([S:40]([CH3:39])(=[O:42])=[O:41])[S:40]([CH3:39])(=[O:42])=[O:41])=[CH:23][CH:24]=3)[N:13]=[C:12]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:11]=2[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCc2c(-c3ccccc3)nn(Cc3ccc(N)cc3)c2CC1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCc2c(-c3ccccc3)nn(Cc3ccc(N(S(C)(=O)=O)S(C)(=O)=O)cc3)c2CC1
Reaction time: 0.08 h

Procedure:
1-(4-Amino-benzyl)-3-phenyl-4,5,7,8-tetrahydro-1H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 99, 0.05 mmol) was dissolved in 1 mL of DMF and treated with 1 equivalent of triethylamine. After 5 min, 1.5 equivalents of methanesulfonyl chloride were added and the mixture was stirred overnight. The reaction was quenched with water and extracted with EtOAc (3×). The combined organic layers were dried over Na2SO4 and concentrated. The resulting oil was purified by preparative TLC (50% EtOAc/hexanes) to provide 1-(4-dimethanesulfonylamino-benzyl)-3-phenyl-4,5,7,8-tetrahydro-1H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester. The intermediate was then dissolved in 2 mL of 9:1 CH2Cl2/MeOH and treated with 3 mL of 1 N HCl in Et2O. After 6 h, the volatiles were removed in vacuo. The crude oil was purified by preparative TLC (9:1 CH2Cl2/2 M NH3 in MeOH) to afford 0.006 g of the title compound as an off-white solid. MS (ESI): exact mass calculated for C22H26N4O4S2, 474.14; found, m/z 475.1 [M+H]+. 1H NMR (500 MHz, CD3OD): 7.50-7.47 (m, 2H), 7.44-7.40 (m, 2H), 7.37-7.35 (m, 1H), 7.22-7.20 (m, 2H), 7.13-7.11 (m, 2H), 5.34 (s, 2H), 2.97-2.94 (m, 4H), 2.92 (s, 6H), 2.89-2.87 (m, 2H), 2.82-2.80 (m, 2H).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:38])[C@@H:13]([NH:23][C:24]([C:26]2[CH:30]=[C:29]([OH:31])[N:28]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[N:27]=2)=[O:25])[CH2:14][CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:8][CH2:7]1)=[O:5])[CH3:2].Br[CH2:40][C:41]([O:43][CH2:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)=[O:42].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.C(OCC)(=O)C>[CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:38])[C@@H:13]([NH:23][C:24]([C:26]2[CH:30]=[C:29]([O:31][CH2:40][C:41]([O:43][CH2:44][C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)=[O:42])[N:28]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[N:27]=2)=[O:25])[CH2:14][CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCN(C(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)c2cc(O)n(-c3ccccc3)n2)CC1
Reactant: O=C(CBr)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)N1CCN(C(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)c2cc(OCC(=O)OCc3ccccc3)n(-c3ccccc3)n2)CC1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 14.5 g 4-{(S)-4-tert-butoxycarbonyl-2-[(5-hydroxy-1-phenyl-1H-pyrazole-3-carbonyl)-amino]-butyryl}-piperazine-1-carboxylic acid ethyl ester in 110 ml DMF were added 4.5 ml benzyl bromoacetate and 17.8 g cesium carbonate. After stirring at RT for 12 h the solution was reduced to a volume of 50 ml, diluted with 400 ml ethyl acetate and extracted with aqueous LiCl (4% w/w). The crude product obtained after evaporation of the solvent was purified by flash chromatography on silica eluting with a gradient of n-heptane/ethyl acetate.
Reaction SMILES: C(N(C(C)C)CC)(C)C.[S:10]([C:14]1[CH:15]=[C:16]([NH:20][C:21]2[N:30]=[CH:29][C:28]3[CH:27]=[CH:26][C:25]4[N:31]=[C:32]([C:34]([OH:36])=O)[S:33][C:24]=4[C:23]=3[N:22]=2)[CH:17]=[CH:18][CH:19]=1)(=[O:13])(=[O:12])[NH2:11].[C:37]([O:41][C:42]([NH:44][CH:45]1[CH2:49][CH2:48][NH:47][CH2:46]1)=[O:43])([CH3:40])([CH3:39])[CH3:38].C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>CN(C)C=O>[C:37]([O:41][C:42](=[O:43])[NH:44][CH:45]1[CH2:49][CH2:48][N:47]([C:34]([C:32]2[S:33][C:24]3[C:23]4[N:22]=[C:21]([NH:20][C:16]5[CH:17]=[CH:18][CH:19]=[C:14]([S:10](=[O:12])(=[O:13])[NH2:11])[CH:15]=5)[N:30]=[CH:29][C:28]=4[CH:27]=[CH:26][C:25]=3[N:31]=2)=[O:36])[CH2:46]1)([CH3:40])([CH3:38])[CH3:39]
Reactant: CC(C)(C)OC(=O)NC1CCNC1
Reactant: NS(=O)(=O)c1cccc(Nc2ncc3ccc4nc(C(=O)O)sc4c3n2)c1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NC1CCN(C(=O)c2nc3ccc4cnc(Nc5cccc(S(N)(=O)=O)c5)nc4c3s2)C1
Temperature: 25 °C
Reaction time: 12 h
Yield: 80.4 %

Procedure:
Diisopropylethylamine (68 μl, 0.39 mmol) was added to a mixture of 8-(3-Sulfamoyl-phenylamino)-thiazolo[4,5-h]quinazoline-2-carboxylic acid (78 mg, 0.19 mmol), 3-(tert-butoxycarbonylamino)pyrrolidine (36.2 mg, 0.19 mmol) and PyBrop (91 mg, 0.19 mmol) in dimethylformamide (1 ml). The reaction mixture was stirred at room temperature for 12 h. The reaction was concentrated under reduced pressure, redissolved in isopropanol (˜10 mL) and water was added (˜5 mL). The precipitate formed was isolated by filtration and washed with water (1×5 mL), dilute NaHSO4 (1×5 mL), water (1×5 mL), saturated Na2CO3 (1×5 mL), water (1×5 mL), isopropanol (1×5 mL), diethyl ether (4×5 mL) giving a yellow powder (87 mg, 80% yield). MS (ES+) 570, (ES−) 568.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:15][C:16]([NH2:18])=[S:17])[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]1.Br[CH:20]1[C:25](=O)[CH:24]([C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=2)[CH2:23][CH2:22][CH2:21]1>C(O)C>[Cl:33][C:30]1[CH:31]=[CH:32][C:27]([CH:24]2[C:23]3[N:18]=[C:16]([NH:15][C:5]4[CH:6]=[CH:7][C:8]([N:9]5[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]5)=[C:3]([O:2][CH3:1])[CH:4]=4)[S:17][C:22]=3[CH2:21][CH2:20][CH2:25]2)=[CH:28][CH:29]=1
Reactant: O=C1C(Br)CCCC1c1ccc(Cl)cc1
Reactant: COc1cc(NC(N)=S)ccc1-n1cnc(C)c1
Solvent: CCO
Product: COc1cc(Nc2nc3c(s2)CCCC3c2ccc(Cl)cc2)ccc1-n1cnc(C)c1
Temperature: 25 °C
Yield: 18.7 %

Procedure:
A suspension of [3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-thiourea (50 mg, 0.19 mmol) and of crude 6-bromo-2-(4-chloro-phenyl)-cyclohexanone (74 mg, 0.26 mmol) in ethanol (2 mL) was heated to reflux under an atmosphere of nitrogen for 2 days. After cooling to room temperature the solvent was evaporated under reduced pressure and the residue was purified by column chromatography on silica gel using dichloromethane/methanol (19:1 v/v) as eluent to yield the title compound (16 mg, 19%) as a brown gum. 1H NMR (DMSO-D6, 300 MHz): δ (ppm)=10.37 (s, 1H), 7.79 (s, 1H), 7.68 (d, 1H), 7.66 (s, 2H), 7.50 (d, 1H), 7.26 (d, 1H), 7.17 (d, 1H), 7.03 (s, 1H), 3.80 (m, 1H), 3.80 (s, 3H), 2.87 (m, 2H), 2.18 (m, 2H), 2.14 (s, 3H), 1.90 (m, 2H).
Reaction SMILES: Br[CH:2]1[CH2:16][CH2:15][C:5]2[N:6]=[C:7]([NH:9][C:10]([NH:12][CH2:13][CH3:14])=[O:11])[S:8][C:4]=2[C:3]1=O.[C:18]([NH2:26])(=[S:25])[C:19]1[CH:24]=[CH:23][CH:22]=[N:21][CH:20]=1>C(O)CC>[CH2:13]([NH:12][C:10]([NH:9][C:7]1[S:8][C:4]2[C:3]3[N:26]=[C:18]([C:19]4[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=4)[S:25][C:2]=3[CH2:16][CH2:15][C:5]=2[N:6]=1)=[O:11])[CH3:14]
Reactant: NC(=S)c1cccnc1
Reactant: CCNC(=O)Nc1nc2c(s1)C(=O)C(Br)CC2
Solvent: CCCO
Product: CCNC(=O)Nc1nc2c(s1)-c1nc(-c3cccnc3)sc1CC2
Temperature: 105 °C
Yield: 35.4 %

Procedure:
A suspension of N-(6-bromo-7-oxo-4,5,6,7-tetrahydro-1,3-benzothiazol-2-yl)-N′-ethylurea (25 mg, 0.079 mmol) and thionicotinamide (11 mg, 0.079 mmol) in n-propanol (0.4 mL) was heated to about 105° C. for about 16 hrs. The reaction mixture was concentrated in vacuo and the residual crude material was purified by preparative HPLC. 10 mg (36%) pure product was isolated.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[OH:13])[C:6]([O:8][CH3:9])=[O:7])#[N:2].ClN1C(=O)[CH2:18][CH2:17][C:16]1=O>C(#N)C>[C:1]([C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[O:13][CH:17]([CH3:18])[CH3:16])[C:6]([O:8][CH3:9])=[O:7])#[N:2]
Reactant: COC(=O)c1ccc(O)c(C#N)c1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CC#N
Product: COC(=O)c1ccc(OC(C)C)c(C#N)c1
Temperature: 65 °C
Reaction time: 8 h
Yield: 80.2 %

Procedure:
A portion of residue 3 (4.19 g, ˜7.45 mmol) was dissolved in acetonitrile (50 mL) and treated with N-chlorosuccinimide (1.19 g, 8.94 mmol) at room temperature. The temperature was raised to 65° C. and the mixture stirred overnight. When LC/MS showed complete conversion of starting material, the mixture was cooled to room temperature and partitioned between water (150 mL) and ethyl acetate (150 mL). The organic layer was separated and the organic phase washed twice with 2 N Na2CO3 and brine, dried over Na2SO4 and concentrated under vacuum to give an off white solid. The product was purified by preparative reverse phase HPLC to give pure desired product 4 (1.31 g, 29% from s.m.) as a white foamy solid upon solvent evaporation and high vacuum drying. LRMS (M+H+) m/z 598.0.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([C:18]3[CH2:22][CH2:21][CH2:20][C:19]=3[CH2:23][C:24]3[CH:25]=[C:26]([CH:34]=[CH:35][CH:36]=3)[O:27][CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])[O:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(C2N=C(C3C(CC4C=C(C=CC=4)OCC(OCC)=O)CCC=3)[O:46]C=2C2C=CC=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+].ClC1C=CC=C(C(OO)=O)C=1>C(Cl)Cl>[C:1]1([C:7]2[N:8]=[C:9]([CH:18]3[CH2:22][CH2:21][CH2:20][C:19]3([CH2:23][C:24]3[CH:25]=[C:26]([CH:34]=[CH:35][CH:36]=3)[O:27][CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])[OH:46])[O:10][C:11]=2[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)COc1cccc(CC2CCC=C2c2nc(-c3ccccc3)c(-c3ccccc3)o2)c1
Reactant: CCOC(=O)COc1cccc(CC2=C(c3nc(-c4ccccc4)c(-c4ccccc4)o3)CCC2)c1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CCOC(=O)COc1cccc(CC2(O)CCCC2c2nc(-c3ccccc3)c(-c3ccccc3)o2)c1
Reaction time: 2 h

Procedure:
To a solution of a mixture (300 mg) of ethyl [3-[{2-(4,5-diphenyloxazol-2-yl)-1-cyclopenten-1-yl}methyl]phenoxy]acetate and ethyl [3-[{2-(4,5-diphenyloxazol-2-yl)-2-cyclopenten-1-yl}methyl]phenoxy]acetate in methylene chloride (10 ml) were added sodium carbonate (100 mg) and m-chloroperbenzoic acid (200 mg) at 0° C. After being stirred for 2 hours, the reaction mixture was washed with water and brine and dried over magnesium sulfate. After the solvent was evaporated, the residue containing a mixture of ethyl [3-[{2-(4,5-diphenyloxazol-2-yl)-1,2-epoxycyclopentan-1-yl}methyl]phenoxy]acetate and ethyl [3-[(2-(4,5-diphenyloxazol-2-yl)-2,3-epoxycyclopentan-1-yl]methyl]phenoxy]acetate was dissolved in a mixture of ethyl acetate-ethanol (20 ml-10 ml), and thereto was added 10% palladium on carbon (50 mg). After being stirred for 6 hours under hydrogen atmosphere, the reaction mixture was filtered. The solvent was evaporated in vacuo, the residue was chromatographed on silica gel. The first fraction gave ethyl [3-[{2-(4,5-diphenyloxazol-2-yl)-1-hydroxycyclopentan-1-yl}methyl]phenoxy]acetate (70 mg).
Reaction SMILES: [H-].[Na+].[C:3]([C:5]1[CH:6]=[C:7]2[NH:13][C:12](=[O:14])[N:11]([C@H:15]3[CH2:20][CH2:19][C@H:18]([OH:21])[CH2:17][CH2:16]3)[C:8]2=[N:9][CH:10]=1)#[N:4].[Cl:22][C:23]1[CH:24]=[C:25]([CH:28]=[CH:29][C:30]=1[O:31][CH3:32])[CH2:26]Br>CN(C)C=O>[Cl:22][C:23]1[CH:24]=[C:25]([CH:28]=[CH:29][C:30]=1[O:31][CH3:32])[CH2:26][N:13]1[C:7]2[C:8](=[N:9][CH:10]=[C:5]([C:3]#[N:4])[CH:6]=2)[N:11]([C@H:15]2[CH2:20][CH2:19][C@H:18]([OH:21])[CH2:17][CH2:16]2)[C:12]1=[O:14]
Reactant: COc1ccc(CBr)cc1Cl
Reactant: N#Cc1cnc2c(c1)[nH]c(=O)n2[C@H]1CC[C@H](O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(Cn2c(=O)n([C@H]3CC[C@H](O)CC3)c3ncc(C#N)cc32)cc1Cl
Temperature: 25 °C

Procedure:
Sodium hydride (60% dispersion in mineral oil, 3.58g) was added portionwise to a solution 6-cyano-3-(trans-4-hydroxycyclohexyl)-2,3-dihydro-1H-imidazo[4,5-b]pyridin-2-one (21 g) in N,N-dimethylformamide (210 ml) at 0° C., and the mixture was stirred at ambient temperature for an hour. After adding 3-chloro-4-methoxybenzyl bromide (20.1 g) at ambient temperature, the reaction mixture was stirred at same temperature for 3 hours and partitioned between ethyl acetate and water. The aqueous layer was extracted with ethyl acetate (twice). The combined organic layer was washed with water (twice) and brine, and dried over magnesium sulfate. After evaporation of the solvent, the residue was purified by a silica gel column chromatography eluting with 5% methanol in chloroform and crystallization from ethanol. The crude crystals were suspended in water (400 ml) and stirred at 65° C. for 14 hours to give 1-(3-chloro-4-methoxybenzyl)-6-cyano-3-(trans-4-hydroxycyclohexyl)-2,3-dihydro-1H-imidazo[4,5-b]pyridin-2-one (19.9 g) as a colorless solid.
Reaction SMILES: [NH2:1][C:2]1[C:3]([I:18])=[C:4]([CH2:13][O:14][C:15](=[O:17])[CH3:16])[C:5]([I:12])=[C:6]([C:10]=1[I:11])[C:7](Cl)=[O:8].[NH:19]([CH2:23][CH2:24][OH:25])[CH2:20][CH2:21][OH:22]>>[NH2:1][C:2]1[C:3]([I:18])=[C:4]([CH2:13][O:14][C:15](=[O:17])[CH3:16])[C:5]([I:12])=[C:6]([C:10]=1[I:11])[C:7]([N:19]([CH2:23][CH2:24][OH:25])[CH2:20][CH2:21][OH:22])=[O:8]
Reactant: CC(=O)OCc1c(I)c(N)c(I)c(C(=O)Cl)c1I
Reactant: OCCNCCO
Product: CC(=O)OCc1c(I)c(N)c(I)c(C(=O)N(CCO)CCO)c1I

Procedure:
5-Amino-3-acetoxymethyl-2,4,6-triiodobenzoyl chloride was reacted with diethanolamine according to the general procedure in Example 24 g. Yield of isolated crude product was 98%.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:6]([O:13][CH3:14])(=[O:12])[CH2:7][CH2:8][C:9]([CH3:11])=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl.[Cl-].[Na+].O>[CH3:14][O:13][C:6](=[O:12])[CH2:7][CH2:8][CH:9]([N:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1)[CH3:11]
Reactant: C1CCNC1
Reactant: COC(=O)CCC(C)=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: COC(=O)CCC(C)N1CCCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 36 %

Procedure:
Pyrrolidine (3 mL, 36 mmol, 1.2 eq) was dissolved in DCM (50 mL) and methyl levulinate (4 mL, 30 mmol, 1.0 eq) was added. The solution was stirred at room temperature for 1 hour, then Na(OAc)3BH (7.6 g, 36.0 mmol, 1.2 eq) was added. The mixture was stirred at room temperature for 16 hours, then brine was added, the crude was extracted with DCM and dried. 2.0 g of the title product were obtained (34% yield).
Reaction SMILES: [NH2:1][CH2:2][C:3]([CH3:7])([CH3:6])[CH2:4][OH:5].[CH3:8][O:9][C:10]1[CH:19]=[CH:18][C:13]([CH2:14][N:15]=[C:16]=[O:17])=[CH:12][CH:11]=1>>[OH:5][CH2:4][C:3]([CH3:7])([CH3:6])[CH2:2][NH:1][C:16]([NH:15][CH2:14][C:13]1[CH:18]=[CH:19][C:10]([O:9][CH3:8])=[CH:11][CH:12]=1)=[O:17]
Reactant: COc1ccc(CN=C=O)cc1
Reactant: CC(C)(CN)CO
Product: COc1ccc(CNC(=O)NCC(C)(C)CO)cc1
Yield: 100 %

Procedure:
Prepared as in Example 227d from 3-amino-2,2-dimethylpropan-1-ol and 4-methoxybenzyl isocyanate in 100% yield. MS 267 (MH+).
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:10]=[CH:9][C:7](=[O:8])[NH:6][C:4]1=[O:5].[CH3:11][Si:12]([CH3:19])([CH3:18])[CH2:13][CH2:14][O:15][CH2:16]Cl>CN(C=O)C.O>[CH3:11][Si:12]([CH3:19])([CH3:18])[CH2:13][CH2:14][O:15][CH2:16][N:3]1[CH:10]=[CH:9][C:7](=[O:8])[NH:6][C:4]1=[O:5]
Reactant: C[Si](C)(C)CCOCCl
Reactant: O=c1cc[nH]c(=O)[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C[Si](C)(C)CCOCn1ccc(=O)[nH]c1=O
Temperature: 0 °C
Reaction time: 4 h
Yield: 14.8 %

Procedure:
A solution of 60% sodium hydride (2 g, 50 mmol) in mineral oil was washed with hexanes (2×20 mL) and cooled to 0° C. The solution was diluted with DMF (200 mL) and then uracil (5.6 g, 50 mmol) was added portionwise over 30 minutes. The mixture was treated with 2-(trimethylsilyl)ethoxymethyl chloride (8.8 mL, 50 mmol) and allowed to warm to 25° C. and stand 4 hours. The reaction mixture was diluted with water (500 mL) and extracted with diethyl ether (4×100 mL). The combined extract was washed with brine, dried (Na2SO4), filtered and concentrated. The residue was purified by chromatography on silica gel eluting with hexanes/ethyl acetate (2:1) to give 1-[2-(trimethylsilyl)ethoxymethyl]-2,4(1H,3H)-pyrimidinedione (1.8 g, 7.4 mmol), M.p. 120°-122° C.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[CH3:12][NH2:13]>CCO.O>[F:8][C:5]1[CH:6]=[CH:7][C:2]([NH:13][CH3:12])=[C:3]([N+:9]([O-:11])=[O:10])[CH:4]=1
Reactant: CN
Reactant: O=[N+]([O-])c1cc(F)ccc1F
Solvent: CCO
Solvent: O
Product: CNc1ccc(F)cc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 99 %

Procedure:
1,4-Difluoro-2-nitrobenzene (2.63 g, 16.53 mmol) was dissolved in EtOH (9 mL) and Methylamine 40% in Water (9 mL) was added dropwise at 0° C. and the mixture was warming up to RT overnight. 75 mL of water was added to the reaction mixture and the orange solid was filtered and washed with water (2*10 ml) to afford 2.78 g of 4-fluoro-N-methyl-2-nitrobenzenamine (Yield: 99%) as an orange crystalline solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[CH:6][CH:5]=1.[Br:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[CH:16]=O>C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][C:7](/[N:10]=[CH:16]/[C:15]2[CH:18]=[CH:19][CH:20]=[C:13]([Br:12])[CH:14]=2)=[CH:6][CH:5]=1
Reactant: O=Cc1cccc(Br)c1
Reactant: COC(=O)c1ccc(N)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(/N=C/c2cccc(Br)c2)cc1
Temperature: 25 °C
Yield: 99.5 %

Procedure:
The mixture solution of 4-aminobenzoic acid methyl ester (10.8 g, 71.4 mmol), 3-bromo-benzaldehyde (13.3 g, 72.4 mmol) and p-toluenesulfonic acid (271.8 mg, 1.4 mmol) in toluene (150 mL) was heated to reflux for 12 h. Then the reaction mixture was cooled to room temperature. The solvent was removed in vacuo and the residue was washed with ether to afford 4-{[1-(3-bromo-phenyl)-meth-(E)-ylidene]amino}-benzoic acid methyl ester (22.6 g, quant.) as a light yellow solid: MS (ESI) M+1=318.0.