Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:20][CH2:19][CH2:18][C@H:2]1[C:3]([NH:5][C@H:6]([C:8]([N:10]1[CH2:17][CH2:16][CH2:15][C@H:11]1[C:12]([OH:14])=O)=[O:9])[CH3:7])=[O:4].CN1CC[O:25][CH2:24][CH2:23]1.C(OC(Cl)=O)C(C)C.[NH2:36][C@@H:37]([CH3:44])[CH:38]([OH:43])[C:39]([O:41][CH3:42])=[O:40]>C(#N)C.C(Cl)(Cl)Cl>[C:24]([N:1]1[CH2:20][CH2:19][CH2:18][C@H:2]1[C:3]([NH:5][C@H:6]([C:8]([N:10]1[CH2:17][CH2:16][CH2:15][C@H:11]1[C:12]([NH:36][CH:37]([CH3:44])[CH:38]([OH:43])[C:39]([O:41][CH3:42])=[O:40])=[O:14])=[O:9])[CH3:7])=[O:4])(=[O:25])[CH3:23]
Reactant: C[C@H](NC(=O)[C@@H]1CCCN1)C(=O)N1CCC[C@H]1C(=O)O
Reactant: CN1CCOCC1
Reactant: COC(=O)C(O)[C@H](C)N
Agent: CC(C)COC(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: CC#N
Product: COC(=O)C(O)C(C)NC(=O)[C@@H]1CCCN1C(=O)[C@H](C)NC(=O)[C@@H]1CCCN1C(C)=O
Temperature: -15 °C
Reaction time: 3 h
Yield: 36.3 %

Procedure:
Ac-L-prolyl-L-alanyl-L-proline (0.65 g, 2.00 mmol) was suspended in dry acetonitrile (20 ml) under an argon atmosphere in a flask fitted with an overhead stirrer and internal thermometer. The suspension was cooled to -15° C. and N-methylmorpholine (0.22 ml, 2.00 mmol) was added followed by isobutylchloroformate (0.26 ml, 2.00 mmol) at such a rate as to maintain the internal reaction temperature at -10° to -15° C. After minutes, a solution of methyl (3S)-3-amino-2-hydroxybutanoate (0.53 g, 4.00 mmol) in chloroform (2.5 ml) was added at such a rate as to maintain the internal reaction temperature at -10° to -15° C. The reaction mixture was slowly warmed to room temperature and then stirred for 3 hours. The reaction mixture was evaporated on a rotary evaporator, the residue dissolved in water (20 ml) and treated with a mixed bed resin (J. T. Baker--ANGMI-615, 11.0 g). After 15 minutes the mixture was filtered and the filtrate evaporated on a rotary evaporator. Chromatography using methylene chloride-methanol as the eluent gave the above-named product (0.32 g) in 36% yield.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[CH2:3][NH:4][C:5]([C:7]1([CH2:21][CH2:22][CH2:23]Br)[C:20]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[O:14][C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)=[O:6].[N:27]1([C:33]2[CH:42]=[C:41]3[C:36]([CH:37]=[N:38][N:39]([CH2:44][C:45]4[CH:50]=[CH:49][CH:48]=[CH:47][N:46]=4)[C:40]3=[O:43])=[CH:35][CH:34]=2)[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1>>[N:46]1[CH:47]=[CH:48][CH:49]=[CH:50][C:45]=1[CH2:44][N:39]1[N:38]=[CH:37][C:36]2[C:41](=[CH:42][C:33]([N:27]3[CH2:32][CH2:31][N:30]([CH2:23][CH2:22][CH2:21][C:7]4([C:5](=[O:6])[NH:4][CH2:3][C:2]([F:26])([F:25])[F:1])[C:20]5[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=5[O:14][C:13]5[C:8]4=[CH:9][CH:10]=[CH:11][CH:12]=5)[CH2:29][CH2:28]3)=[CH:34][CH:35]=2)[C:40]1=[O:43]
Reactant: O=c1c2cc(N3CCNCC3)ccc2cnn1Cc1ccccn1
Reactant: O=C(NCC(F)(F)F)C1(CCCBr)c2ccccc2Oc2ccccc21
Product: O=C(NCC(F)(F)F)C1(CCCN2CCN(c3ccc4cnn(Cc5ccccn5)c(=O)c4c3)CC2)c2ccccc2Oc2ccccc21

Procedure:
Step (b) of Example 92 was repeated, except that the compound prepared in step (b) of Example 114 and the compound prepared in step (c) of Example 143 were used as the starting compounds. Thus, the title compound was obtained.
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[NH:4][CH2:5][C:6](=[O:15])[N:7]2[CH2:12][C:13]#[N:14].[C:16](Cl)(Cl)=[O:17].C1(C)C=CC=CC=1.C(N(C(C)C)CC)(C)C.[NH2:36][CH2:37][C:38]1[CH:43]=[CH:42][C:41]([C:44]([N:46]2[CH2:52][CH2:51][CH2:50][CH2:49][C:48]3[CH:53]=[CH:54][CH:55]=[CH:56][C:47]2=3)=[O:45])=[CH:40][C:39]=1[CH3:57]>C1COCC1>[CH3:57][C:39]1[CH:40]=[C:41]([C:44]([N:46]2[CH2:52][CH2:51][CH2:50][CH2:49][C:48]3[CH:53]=[CH:54][CH:55]=[CH:56][C:47]2=3)=[O:45])[CH:42]=[CH:43][C:38]=1[CH2:37][NH:36][C:16]([N:4]1[C:3]2[C:8](=[CH:9][CH:10]=[CH:11][C:2]=2[F:1])[N:7]([CH2:12][C:13]#[N:14])[C:6](=[O:15])[CH2:5]1)=[O:17]
Reactant: O=C(Cl)Cl
Reactant: N#CCN1C(=O)CNc2c(F)cccc21
Reactant: Cc1cc(C(=O)N2CCCCc3ccccc32)ccc1CN
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: Cc1cc(C(=O)N2CCCCc3ccccc32)ccc1CNC(=O)N1CC(=O)N(CC#N)c2cccc(F)c21
Reaction time: 2 h

Procedure:
To a solution of (5-fluoro-2-oxo-3,4-dihydro-2H-quinoxalin-1-yl)acetonitrile from Example 13A (183 mg, 0.89 mmol) in THF (2 ml) were added a solution of phosgene in toluene (20%, 0.61 ml, 1.2 mmol) and diisopropylethylamine (200 μl, 1.2 mmol). The mixture was stirred for 2 h. To the mixture were added a solution of (4-aminomethyl-3-methylphenyl)-(2,3,4,5-tetrahydrobenzo[b]azepin-1-yl)methanone from Example F (260 mg, 0.89 mmol) in THF (2 ml) and diisopropylethylamine (155 μl, 0.89 mmol). The mixture was stirred for 2 h and evaporated in vacuo. The residue was purified by flash column chromatography on silica (eluant EtOAc:pet. ether 80:20 to EtOAc 100%) to give a white solid; yield 268 mg, 57%.
Reaction SMILES: [CH3:1][S:2][C:3]1[S:8][C:7]2[CH:9]=[CH:10][S:11][C:6]=2[C:5](=[O:12])[CH:4]=1.[Br:13]Br.ClCCl.C(OCC)(=O)C>C(O)(=O)C>[Br:13][C:4]1[C:5](=[O:12])[C:6]2[S:11][CH:10]=[CH:9][C:7]=2[S:8][C:3]=1[S:2][CH3:1]
Reactant: BrBr
Reactant: CSc1cc(=O)c2sccc2s1
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: ClCCl
Product: CSc1sc2ccsc2c(=O)c1Br
Temperature: 50 °C
Reaction time: 16 h
Yield: 67 %

Procedure:
5-Methylthio-7-oxo-7H-thieno[3,2-b]thiopyran (2.14 g, 10 mmol) was dissolved in acetic acid (140 ml) and added dropwise with bromine (0.96 ml). The reaction mixture was stirred at 50° C. for 16 hours. The resulting precipitates were collected by filtration, washed with water and dried. The reaction product was purified by column chromatography(Wako Gel™ C-200: dichloromethane-ethyl acetate=15:1) to obtain 1.98 g (yield: 67%) of 6-bromo-5-methylthio-7-oxo-7H-thieno[3,2-b]thiopyran.
Reaction SMILES: [C:1]1([CH2:7][C:8](Cl)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(OCC)C.[Cl:16][C:17]1[CH:18]=[CH:19][C:20]2[N:26]=[C:25]([NH:27][NH2:28])[CH2:24][N:23]=[C:22]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:21]=2[CH:35]=1.C(N(CC)CC)C>C(Cl)(Cl)Cl>[Cl:16][C:17]1[CH:18]=[CH:19][C:20]2[N:26]=[C:25]([NH:27][NH:28][C:8](=[O:9])[CH2:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH2:24][N:23]=[C:22]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:21]=2[CH:35]=1
Reactant: O=C(Cl)Cc1ccccc1
Reactant: NNC1=Nc2ccc(Cl)cc2C(c2ccccc2)=NC1
Solvent: CCOCC
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: O=C(Cc1ccccc1)NNC1=Nc2ccc(Cl)cc2C(c2ccccc2)=NC1
Reaction time: 0.75 h

Procedure:
In a similar manner to Example 31, a solution of 0.85 part of phenylacetyl chloride in 10 parts by volume of diethyl ether is added to a mixture of 1.4 parts of 7-chloro-2-hydrazino-5-phenyl-3H-1,4-benzodiazepine, 1 part by volume of triethylamine and 25 parts by volume of chloroform. The whole mixture is stirred for 45 minutes, whereby 7-chloro-2-(2-phenylacetylhydrazino)-5-phenyl-3H-1,4-benzodiazepine is yielded as crystals. Recrystallization from a mixture of dimethylformamide and water yields colorless fine prisms melting at 220° C to 221° C (effervescence).
Reaction SMILES: [C:1]([C:3]([C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][CH:14]=1)[C:9]([OH:11])=[O:10])([CH3:5])[CH3:4])#N.[H-].C([Al+]CC(C)C)C(C)C.CCCCCC.Cl.C(OCC)(=[O:34])C>C1(C)C=CC=CC=1.O1CCCC1>[CH3:5][C:3]([C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][CH:14]=1)[C:9]([OH:11])=[O:10])([CH3:4])[CH:1]=[O:34]
Reactant: CCOC(C)=O
Reactant: CC(C)(C#N)c1cccc(C(=O)O)c1
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(C)(C=O)c1cccc(C(=O)O)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 73 %

Procedure:
To a solution of 3-(1-cyano-1-methylethyl)benzoic acid (8.60 g, 45.5 mmol) in toluene (60 mL)/tetrahydrofuran (40 mL) was added dropwise a 1.0M solution of diisobutylaluminum hydride in hexane (100 mL, 100 mmol) at −78° C. over 1 hr. After the completion of the dropwise addition, the mixture was stirred at −78° C. for 1 hr and at 0° C. for 1 hr. The reaction mixture was poured into a mixture of ethyl acetate (200 mL) and 3N hydrochloric acid (300 mL), and the organic layer and the aqueous layer were separated and the aqueous layer was extracted with ethyl acetate (2×100 mL). The combined organic layer was washed with saturated brine (50 mL), and dried over anhydrous magnesium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was recrystallized from ethyl acetate and hexane to give the title compound (6.39 g, 73%) as colorless crystals.
Reaction SMILES: [O:1]1[C@H:5]2[O:6][CH2:7][CH2:8][C@H:4]2[C@@H:3]([O:9][C:10](=[O:51])[NH:11][C@@H:12]([CH2:44][C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[C@H:13]([OH:43])[CH2:14][N:15]([S:32]([C:35]2[CH:40]=[CH:39][C:38]([O:41][CH3:42])=[CH:37][CH:36]=2)(=[O:34])=[O:33])CC(C)(C)CCNC(=O)NCC(OCC)=O)[CH2:2]1.O1[C@@H]2OCC[C@@H]2[C@H](OC(=O)N[C@@H](CC2C=CC=CC=2)[C@H](O)CN(S(C2C=CC(OC)=CC=2)(=O)=O)[CH2:67][C:68]([CH3:82])([CH3:81])[CH2:69][CH2:70][NH:71][C:72](=[O:80])[NH:73][CH2:74][C:75](OCC)=[O:76])C1.[NH3:103]>CO>[NH2:103][C:75](=[O:76])[CH2:74][NH:73][C:72]([NH:71][CH2:70][CH2:69][C:68]([CH3:82])([CH3:81])[CH2:67][CH:14]([NH:15][S:32]([C:35]1[CH:36]=[CH:37][C:38]([O:41][CH3:42])=[CH:39][CH:40]=1)(=[O:34])=[O:33])[C@H:13]([OH:43])[C@@H:12]([NH:11][C:10](=[O:51])[O:9][C@H:3]1[C@@H:4]2[C@@H:5]([O:6][CH2:7][CH2:8]2)[O:1][CH2:2]1)[CH2:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)=[O:80]
Reactant: N
Reactant: CCOC(=O)CNC(=O)NCCC(C)(C)CN(C[C@@H](O)[C@H](Cc1ccccc1)NC(=O)O[C@H]1CO[C@H]2OCC[C@H]21)S(=O)(=O)c1ccc(OC)cc1
Reactant: CCOC(=O)CNC(=O)NCCC(C)(C)CN(C[C@@H](O)[C@H](Cc1ccccc1)NC(=O)O[C@@H]1CO[C@@H]2OCC[C@@H]21)S(=O)(=O)c1ccc(OC)cc1
Solvent: CO
Product: COc1ccc(S(=O)(=O)NC(CC(C)(C)CCNC(=O)NCC(N)=O)[C@H](O)[C@H](Cc2ccccc2)NC(=O)O[C@@H]2CO[C@@H]3OCC[C@@H]32)cc1
Temperature: 25 °C
Yield: 52 %

Procedure:
A solution of 22 mg (0.030 mmol) of a 1:1 mixture of ethyl (3S,4R)-1-[(3R,3aS,6aR)hexahydrofuro [2,3-b]furan-3-yloxy]-3-benzyl-4-hydroxy-6-[(4-methoxyphenyl)sulfonyl]-8,8-dimethyl-1,12-dioxo-2,6,11,13-tetraazapentadecan-15-oate and ethyl (3S,4R)-1-[(3S,3aR,6aS)hexahydrofuro[2,3-b]furan-3-yloxy]-3-benzyl-4-hydroxy-6-[(4-methoxyphenyl)sulfonyl]-8,8-dimethyl-1,12-dioxo-2,6,11,13-tetraazapentadecan-15-oate in 3 mL of 2M NH3 in MeOH in a sealed tube was stirred at RT. After 5 days the solution was concentrated in vacuo and the residue subjected to flash chromatography (SiO2, 93:7 CH2Cl2/2M NH3 in MeOH) to afford 11 mg (52%) of the desired product as a white foam.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:9])[CH2:5][C:6]([CH3:8])=[O:7])[CH3:2].N1C[CH2:13][CH2:12][CH2:11]1.O>C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4](=[O:9])[CH2:5][C:6](=[O:7])[CH2:8][CH:12]([CH3:13])[CH3:11])[CH3:2]
Reactant: CCOC(=O)CC(C)=O
Reactant: C1CCNC1
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC(=O)CC(=O)CC(C)C
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 81.7 %

Procedure:
26 g of acetoacetic acid ethyl ester and 15 g of pyrrolidine were boiled in 70 ml of toluene on a water separator until the theoretical quantity of water was separated. The solution was added drop by drop at -40° C. to a suspension of 8.6 g of sodium amide in 300 ml of liquid ammonia. By heating to room temperature, the ammonia was removed. After the reaction solution had been cooled again to 0° C., isopropyl iodide dissolved in 100 ml of toluene was added at the same temperature. The solution was allowed to react for 3 hours at 0° C. The reaction solution was poured into 200 ml of water. The phases were separated and the toluene of the organic phase was removed using a rotary evaporator. Of the residue, 1.2 g of the first runnings was then distilled off at 1.5 torr (2×102Pa) and up to a still temperature of 60° C., which contained above all 2 -isopropyl acetoacetic acid ethyl ester. The brownish oil remaining behind was dissolved in 70 ml of methylene chloride, and 21 g of concentrated hydrochloric acid was added. The material was hydrolyzed for 1.5 hours at ambient temperature. The two phases were separated. The organic phase was dried, the solvent was removed and the residue was distilled. 28.1 g of 5-methyl-3-oxohexanoic acid ethyl ester (82 percent) was obtained.
Reaction SMILES: [H-].[Na+].F[C:4]1[C:9]([F:10])=[CH:8][CH:7]=[CH:6][C:5]=1[C:11]([C:13]1[C:18]([OH:19])=[CH:17][C:16]([N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)=[CH:15][C:14]=1[OH:26])=[O:12].CCOC(C)=O>CN(C=O)C>[F:10][C:9]1[CH:8]=[CH:7][CH:6]=[C:5]2[C:4]=1[O:26][C:14]1[CH:15]=[C:16]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[CH:17]=[C:18]([OH:19])[C:13]=1[C:11]2=[O:12]
Reactant: O=C(c1cccc(F)c1F)c1c(O)cc(N2CCOCC2)cc1O
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=c1c2cccc(F)c2oc2cc(N3CCOCC3)cc(O)c12
Temperature: 75 °C
Yield: 6.3 %

Procedure:
Sodium hydride (24 mg, 1.0 mmol, 60%) was added to a solution of a compound of Example 24 (168 Mg, 0.50 mmol) in DMF (2 mL), then the mixture was heated at 75° C. for 4 h. The reaction was cooled to 22° C., and EtOAc (70 mL) was added to produce a yellow precipitate. The precipitate was filtered and dried to yield 10 mg (7%) of 5-fluoro-1-hydroxy-3-morpholin-4-yl-xanthen-9-one. 1H NMR (CDCl3, 400 MHz) δ: 12.59 (s, 1H), 7.95 (d, 1H), 7.75 (m, 1H), 7.40 (m, 1H), 6.60 (s, 1H), 6.38 (s, 1H), 3.65-3.63 (m, 4H), 3.40-3.38 (m, 4H). LRMS (APCI, positive): 316.3 (m+1).
Reaction SMILES: [Br:1][C:2]1[CH:18]=[CH:17][C:5]([O:6][CH2:7][C:8]2[CH:9]=[C:10]([CH:14]=[CH:15][CH:16]=2)[C:11]([OH:13])=O)=[C:4]([F:19])[CH:3]=1.Cl.[CH2:21]([O:23][C:24](=[O:28])[CH2:25][NH:26][CH3:27])[CH3:22].CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C.C1C=NC2N(O)N=NC=2C=1>C(Cl)Cl>[CH2:21]([O:23][C:24](=[O:28])[CH2:25][N:26]([C:11](=[O:13])[C:10]1[CH:14]=[CH:15][CH:16]=[C:8]([CH2:7][O:6][C:5]2[CH:17]=[CH:18][C:2]([Br:1])=[CH:3][C:4]=2[F:19])[CH:9]=1)[CH3:27])[CH3:22]
Reactant: O=C(O)c1cccc(COc2ccc(Br)cc2F)c1
Reactant: CCOC(=O)CNC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(=O)CN(C)C(=O)c1cccc(COc2ccc(Br)cc2F)c1

Procedure:
A solution of 3-(4-bromo-2-fluoro-phenoxymethyl)-benzoic acid (5.21 g, 16.02 mmol), N-methyl glycine ethyl ester hydrochloride (4.9 g, 32.05 mmol), DIEA (14 mL, 80.01 mmol), EDCI (6.1 g, 32.05 mmol) and HOAT (4.4 g, 32.05 mmol) in methylene chloride (300 mL) was stirred at room temperature for 12 h. The mixture was evaporated and the residue was purified by column (0-50% EtOAc in hexane) to give {{[3-(4-bromo-2-fluoro-phenoxymethyl)-benzoyl]-methyl-amino}-acetic acid ethyl ester, 4.5 g (66%). LC-MS (ES) calculated for C19H19BrFNO4, 423; found m/z 424 [M+H]+.
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[C:8]([Cl:13])[CH:7]=[CH:6]2.[F:14][C:15]1[CH:16]=[C:17]([OH:29])[CH:18]=[C:19]([C:21]2([O:27][CH3:28])[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[CH:20]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CC#N.CCOC(C)=O.O>[Cl:13][C:8]1[CH:7]=[CH:6][C:5]2[C:10](=[CH:11][CH:12]=[C:3]([CH2:2][O:29][C:17]3[CH:18]=[C:19]([C:21]4([O:27][CH3:28])[CH2:22][CH2:23][O:24][CH2:25][CH2:26]4)[CH:20]=[C:15]([F:14])[CH:16]=3)[CH:4]=2)[N:9]=1
Reactant: Clc1ccc2cc(CBr)ccc2n1
Reactant: COC1(c2cc(O)cc(F)c2)CCOCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC#N
Product: COC1(c2cc(F)cc(OCc3ccc4nc(Cl)ccc4c3)c2)CCOCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
6-Bromomethyl-2-chloro-quinoline (2.5 g, 9.7 mmol), 3-fluoro-5-(4-methoxy-tetrahydro-pyran-4-yl)-phenol (9a, 2.2 g, 9.7 mmol), and cesium carbonate (4.7 g, 14.6 mmol) were combined in MeCN (25 mL) and stirred at room temperature for 2 hours. The reaction was diluted with EtOAc and water, and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated to give the desired product, 9b.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4](Cl)=[O:5].[N:7]1[CH:12]=CC=[CH:9][CH:8]=1.C(OCC)(=[O:15])C>>[CH3:1][O:2][CH2:3][C:4]([O:5][CH2:9][CH2:8][NH:7][CH3:12])=[O:15]
Reactant: COCC(=O)Cl
Reactant: c1ccncc1
Reactant: CCOC(C)=O
Product: CNCCOC(=O)COC
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a mixture of tert-butyl 2-hydroxyethyl (methyl)carbamate (1.75 g) obtained in Reference Example 1 and ethyl acetate (10 mL) were added methoxyacetyl chloride (1.20 g) and pyridine (0.97 mL). After stirring at room temperature for 3 hrs., ethyl acetate (70 mL) was added to the reaction mixture. The mixture was washed with water (20 mL), a saturated aqueous sodium hydrogen carbonate solution (20 mL) and water (20 mL), and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was dissolved in ethyl acetate (5 mL), and a 4N hydrogen chloride-ethyl acetate solution (10 mL) was added. After stirring at room temperature for 1 hr., the mixture was concentrated under reduced pressure. Water (60 mL) and diethyl ether (30 mL) were added to the residue. After stirring, the aqueous layer was separated and taken. The aqueous layer was basified with sodium hydrogen carbonate and extracted twice with ethyl acetate (40 mL). The ethyl acetate layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give the title compound (1.00 g) as a colorless oil.
Reaction SMILES: C1(O[C:8](=[O:29])[NH:9][C:10]2[S:14][N:13]=[C:12]([O:15][CH2:16][C:17]3[CH:22]=[C:21]([F:23])[C:20]([CH3:24])=[CH:19][C:18]=3[F:25])[C:11]=2[C:26](=[O:28])[NH2:27])C=CC=CC=1.[NH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][N:37]1[CH2:42][CH2:41][N:40]([CH2:43][CH2:44][OH:45])[CH2:39][CH2:38]1>>[F:25][C:18]1[CH:19]=[C:20]([CH3:24])[C:21]([F:23])=[CH:22][C:17]=1[CH2:16][O:15][C:12]1[C:11]([C:26]([NH2:27])=[O:28])=[C:10]([NH:9][C:8]([NH:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][N:37]2[CH2:42][CH2:41][N:40]([CH2:43][CH2:44][OH:45])[CH2:39][CH2:38]2)=[O:29])[S:14][N:13]=1
Reactant: Cc1cc(F)c(COc2nsc(NC(=O)Oc3ccccc3)c2C(N)=O)cc1F
Reactant: NCCCCCCN1CCN(CCO)CC1
Product: Cc1cc(F)c(COc2nsc(NC(=O)NCCCCCCN3CCN(CCO)CC3)c2C(N)=O)cc1F

Procedure:
The title compound was prepared from [4-carbamoyl-3-(2,5-difluoro-4-methyl-benzyloxy)-isothiazol-5-yl]-carbamic acid phenyl ester and 2-[4-(6-amino-hexyl)-piperazin-1-yl]-ethanol by the procedure analogous to Example 6. HPLC ret. time: 3.0 minutes. 1H NMR (400 MHz, CD3OD) δ7.17 (d, 1H, J=6.4, 9.6 Hz), 7.01 (m, 1H), 5.44 (s, 2H), 3.64 (t, 2H, J=5.6 Hz), 3.18 (t, 2H, J=6.8 Hz), 2.7-2.4 (bm, 8H), 2.50 (t, 2H, J=6.0 Hz), 2.33 (m, 2H), 2.23 (s, 3H), 1.50 (m, 4H), 1.35 (m, 4H) ppm; MS (APCI, m/z): 555 [M+H]+.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH2:7][CH2:8][CH2:9][CH2:10][C:5]=2[N:4]=[C:3]1S(C)(=O)=O.[CH2:15]([N:17]1[C:25]2[C:20](=[N:21][CH:22]=[CH:23][CH:24]=2)[N:19]([C:26]2[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][CH:27]=2)[C:18]1=[O:33])[CH3:16].[H-].[Na+].O>CC(N(C)C)=O>[CH2:15]([N:17]1[C:25]2[C:20](=[N:21][CH:22]=[CH:23][CH:24]=2)[N:19]([C:26]2[CH:27]=[CH:28][C:29]([O:32][C:3]3[N:2]([CH3:1])[C:6]4[CH2:7][CH2:8][CH2:9][CH2:10][C:5]=4[N:4]=3)=[CH:30][CH:31]=2)[C:18]1=[O:33])[CH3:16]
Reactant: Cn1c(S(C)(=O)=O)nc2c1CCCC2
Reactant: CCn1c(=O)n(-c2ccc(O)cc2)c2ncccc21
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: CCn1c(=O)n(-c2ccc(Oc3nc4c(n3C)CCCC4)cc2)c2ncccc21
Yield: 5.8 %

Procedure:
1-Methyl-2-(methylsulfonyl)-4,5,6,7-tetrahydro-1H-benzimidazole (84 mg) was added to a solution of 1-ethyl-3-(4-hydroxyphenyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (100 mg) and NaH (18.8 mg) (60% in mineral oil) in DMA (3 mL) in a microwave vessel. The vessel was sealed and subjected to microwave irradiation (at 120° C. set by IR sensor, fixed hold time: on, Absorption level: High) for 1 h in a Biotage Initiator 60EXP. The mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, eluted with 20%-100% EtOAc in hexane) to give 1-ethyl-3-{4-[(1-methyl-4,5,6,7-tetrahydro-1H-benzimidazol-2-yl)oxy]phenyl}-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (8.90 mg) as white crystals.
Reaction SMILES: ClC1C=C(C=CC=1)C(OO)=[O:6].[C:12]([C:16]([NH:18][C:19]1[CH:31]=[CH:30][C:22]2[S:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[C:21]=2[CH:20]=1)=[O:17])([CH3:15])([CH3:14])[CH3:13].C(Cl)Cl>ClCCCl>[O:6]=[S:23]1[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[C:21]2[CH:20]=[C:19]([NH:18][C:16]([C:12]([CH3:15])([CH3:13])[CH3:14])=[O:17])[CH:31]=[CH:30][C:22]1=2
Reactant: CC(C)(C)C(=O)Nc1ccc2sc3ccccc3c2c1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Solvent: ClCCCl
Product: CC(C)(C)C(=O)Nc1ccc2c(c1)-c1ccccc1S2=O
Yield: 8.9 %

Procedure:
m-Chloroperoxybenzoic acid (50% wt/wt, 770 mg, 2.0 mmol) was added to a solution of 2-(t-butylcarbonylamino)dibenzothiophene (Example 2; 566 mg, 2.0 mmol) in 1,2-dichloroethane and the resultant mixture warmed at 80% for 16 hours then cooled and DCM was added (50 ml). The mixture was washed with 2 M sodium hydroxide, water and brine, dried and evaporated in vacuo to a brown gum. This was purified by chromatography eluting with 0-2% methanol in DCM. The impure product thus obtained was purified by preparative HPLC (Dynamax C-18 60A column eluted with 40-95% acetonitrile in water plus 0.1% trifluoroacetic acid) to obtain the product (53.5 mg) NMR: 9.59 (s, 1H), 8.35 (d, 1H), 8.03 (d, 1H), 7.97 (d, 1H), 7.93 (d, 1H), 7.80 (dd, 1H), 7.70 (t, 1H), 7.56 (t, 1H), 1.16 (s, 9H); m/z 300.
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[C:9]([CH3:12])[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].S(Cl)([Cl:15])=O>C1(C)C=CC=CC=1>[Cl:1][C:2]1[C:10]([Cl:11])=[C:9]([CH3:12])[CH:8]=[CH:7][C:3]=1[C:4]([Cl:15])=[O:5]
Reactant: O=S(Cl)Cl
Reactant: Cc1ccc(C(=O)O)c(Cl)c1Cl
Solvent: Cc1ccccc1
Product: Cc1ccc(C(=O)Cl)c(Cl)c1Cl
Yield: 100 %

Procedure:
2,3-Dichloro-4-methylbenzoic acid (I70) (5.90 g, 26.2 mmol) and thionyl chloride (30 mL, 411 mmol) were heated at 85° C. for 4 hr in toluene (100 mL). The solvents were removed in vacuo and the residue was azeotroped with toluene (3×100 mL). The residue was used in subsequent steps without further purification assuming 100% yield. Compound not characterised at this step.
Reaction SMILES: Br[C:2]([CH3:12])([CH3:11])[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4].[I-].[K+].N1C=[CH:18][N:17]=[N:16]1.C(=O)([O-])[O-].[K+].[K+].[C:26](#[N:28])C>>[N:17]1([C:2]([CH3:12])([CH3:11])[C:3]([C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)=[O:4])[CH:18]=[N:28][CH:26]=[N:16]1
Reactant: CC(C)(Br)C(=O)c1ccccc1
Reactant: c1c[nH]nn1
Reactant: CC#N
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Product: CC(C)(C(=O)c1ccccc1)n1cncn1
Temperature: 75 °C
Reaction time: 8 h
Yield: 28 %

Procedure:
45.4 g (0.2 mol) of α-bromoisobutyrophenone and 1 g of potassium iodide are added to 14 g (0.2 mol) of triazole and 27 g (0.2 mol) of potassium carbonate in 100 ml of acetonitrile at 75° C. When the addition has ended, the mixture is stirred at 75° C. for a further 8 hours, filtered and rinsed with acetonitrile. The filtrate is concentrated, the residue is taken up in chloroform and the mixture is washed twice with water, dried over sodium sulphate and freed from the solvent in vacuo. The residue is recrystallized from ethyl acetate/petroleum ether. 12.1 g (28% of theory) of α-(1,2,4-triazol-1-yl)-isobutyrophenone of melting point 134° C. to 135° C. are obtained.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[O:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[C@H:17]1[CH2:21][CH2:20][CH2:19][N:18]1C(OC(C)(C)C)=O>ClCCl>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[NH:18]1[CH2:19][CH2:20][CH2:21][C@@H:17]1[C:9]1[O:8][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1c1nc2ccccc2o1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: c1ccc2oc([C@H]3CCCN3)nc2c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
In a 16 mL flask, trifluoroacetic acid (4 mL) was added to a mixture of tert-butyl(2R)-2-(1,3-benzoxazol-2-yl)pyrrolidine-1-carboxylate (88 mg, 0.31 mmol; which may be prepared as described in Step 2) dissolved in dichloromethane (4 mL) at 0° C. under nitrogen. The reaction was allowed to warm to room temperature and stirred for 3 h. The reaction mixture was concentrated to dryness and the residue used in the next step without further purification.