Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:4]1[CH2:28][CH2:27][C:7]2([N:11]([CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:10](=[O:19])[C@H:9]([CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[NH:8]2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].O.C[Si]([Cl:34])(C)C>CC(CC)=O>[ClH:34].[C:1]([N:4]1[CH2:5][CH2:6][C:7]2([N:11]([CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:10](=[O:19])[C@H:9]([CH2:20][C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[NH:8]2)[CH2:27][CH2:28]1)(=[O:3])[CH3:2]
Reactant: C[Si](C)(C)Cl
Agent: CC(=O)N1CCC2(CC1)N[C@@H](Cc1ccccc1)C(=O)N2Cc1ccccc1
Solvent: CCC(C)=O
Solvent: O
Product: Cl
Reaction time: 8 h

Procedure:
8-acetyl-1,3-(S)-dibenzyl-1,4,8-triazaspiro[4,5]decan-2-one (1.25 g, 3.3 mmol) was dissolved in ethyl methyl ketone (10 mL), and water (33 μL) and TMSCl (461 μL) were added and the mixture was stirred overnight. The precipitated solid matter was isolated by filtration, washed with diethyl ether, and dried in vacuo. The product 8-acetyl-1,3-(S)-dibenzyl-1,4,8-triazaspiro[4,5]decan-2-one hydrochloride was obtained in a yield of 939 mg (69%).
Reaction SMILES: C(N(CC)CC)C.[OH:8][C:9]1[C:10]([CH3:21])=[C:11]([C:14]([O:19][CH3:20])=[C:15]([CH3:18])[C:16]=1[CH3:17])[CH2:12]Cl.[CH3:22][NH:23][CH2:24][CH2:25][O:26][C:27]1[CH:32]=[C:31]([CH3:33])[CH:30]=[CH:29][C:28]=1[CH:34]([CH3:36])[CH3:35]>CN(C)C=O>[OH:8][C:9]1[C:10]([CH3:21])=[C:11]([C:14]([O:19][CH3:20])=[C:15]([CH3:18])[C:16]=1[CH3:17])[CH2:12][N:23]([CH2:24][CH2:25][O:26][C:27]1[CH:32]=[C:31]([CH3:33])[CH:30]=[CH:29][C:28]=1[CH:34]([CH3:36])[CH3:35])[CH3:22]
Reactant: COc1c(C)c(C)c(O)c(C)c1CCl
Reactant: CNCCOc1cc(C)ccc1C(C)C
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1c(C)c(C)c(O)c(C)c1CN(C)CCOc1cc(C)ccc1C(C)C
Temperature: 25 °C
Yield: 93.6 %

Procedure:
Triethylamine (7.0 ml) was added dropwise to a solution of 3-hydroxy-6-methoxy-2,4,5-trimethylbenzyl chloride (10.73 g) and N-methyl-2-(2-isopropyl-5-methylphenoxy)ethylamine (10.37 g) in N,N-dimethylformamide (60 ml) while stirring the mixture at room temperature. Immediately after the dropwise addition, heat was developed and salt was precipitated. The mixture was stirred at room temperature for 2 hours and triethylamine (2.0 ml) was added. The mixture was stirred for 1 hour. The reaction mixture was poured on ice water and extracted with ethyl acetate to give a crude product. The product was purified by silica gel chromatography (eluent; ethyl acetate/benzene=1/1) to give 18.03 g of the title compound (pale brown solid).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.[C:8]([O:14][CH3:15])(=[O:13])[CH2:9][CH2:10][CH:11]=[CH2:12].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>C(N(CC)CC)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:15][O:14][C:8]([CH2:9][CH2:10][CH:11]=[CH:12][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1)=[O:13]
Reactant: Brc1cccnc1
Reactant: C=CCCC(=O)OC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Product: COC(=O)CCC=Cc1cccnc1

Procedure:
A solution of 3-bromopyridine (7.9 g), methyl 4-pentenoate (7.15 g), palladium acetate (0.11 g) and tri-o-tolylphosphine (0.6 g) in 50 ml of triethylamine is refluxed for 24 hours under argon and the solvent evaporated. The residue is taken up in methylene chloride (50 ml) and washed with water (2×40 ml). The organic phase is dried and evaporated to yield 3-(4-methoxycarbonylbut-1-enyl)pyridine as a colorless liquid; NMR (CDCl3) 3.72 (s, 3H), 6.40 (s, 1H); IR (film) 1725 cm-1.
Reaction SMILES: [NH2:1][C:2]1[CH:31]=[CH:30][C:5]2[NH:6][C:7]([C:12]3[C:13](=[O:29])[C:14]([CH2:24][CH2:25][CH:26]4[CH2:28][CH2:27]4)([CH3:23])[C:15]4[C:20]([C:21]=3[OH:22])=[CH:19][CH:18]=[CH:17][CH:16]=4)=[N:8][S:9](=[O:11])(=[O:10])[C:4]=2[CH:3]=1.N1C=CC=CC=1.[CH3:38][S:39](Cl)(=[O:41])=[O:40]>ClCCl>[CH:26]1([CH2:25][CH2:24][C:14]2([CH3:23])[C:15]3[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:21]([OH:22])=[C:12]([C:7]3[NH:6][C:5]4[CH:30]=[CH:31][C:2]([NH:1][S:39]([CH3:38])(=[O:41])=[O:40])=[CH:3][C:4]=4[S:9](=[O:11])(=[O:10])[N:8]=3)[C:13]2=[O:29])[CH2:28][CH2:27]1
Reactant: CC1(CCC2CC2)C(=O)C(C2=NS(=O)(=O)c3cc(N)ccc3N2)=C(O)c2ccccc21
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC1(CCC2CC2)C(=O)C(C2=NS(=O)(=O)c3cc(NS(C)(=O)=O)ccc3N2)=C(O)c2ccccc21
Reaction time: 12 h
Yield: 77.5 %

Procedure:
To a stirring solution of Example 158 (0.400 g, 0.914 mmol) and pyridine (0.591 mL, 7.312 mmol) in dichloromethane was added methanesulfonyl chloride (0.141 mL, 1.829 mmol) dropwise over 5 minutes and the resulting reaction mixture stirred for 12 hours. The solution was concentrated in. vacuo and purified by flash chromatography on SiO2 eluting with a 0-100% ethyl acetate/hexane gradient yielding the title compound (0.365 g, 77% yield) as a light yellow solid. 1H NMR (300 MHz, DMSO-d6): δ ppm −0.22 (m, 2 H) 0.24 (m, 2 H) 0.85 (m, 2 H) 1.57 (s, 3 H) 2.14 (m, 1 H) 2.32 (m, 1 H) 3.08 (s, 3 H) 7.56 (m, 4 H) 7.73 (m, 4 H) 8.14 (d, J=8.09 Hz, 1 H) 10.23 (m, 1 H) 13.79 (m, 1 H). MS (ESI+) m/z=416 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[C:23](Cl)[CH:22]=[CH:21][C:3]=1[CH2:4][NH:5][C:6]([C:8]1[C:9](=[O:20])[NH:10][N:11]=[C:12]([C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)[CH:13]=1)=[O:7].O=C1C(C(O)=O)=CC(C2C=CN=CC=2)=NN1.C(Cl)(=O)C(Cl)=O.ClC1C=CC=CC=1CN>C(N(CC)CC)C.CN(C)C=O.ClCCl>[Cl:1][C:2]1[CH:24]=[CH:23][CH:22]=[CH:21][C:3]=1[CH2:4][NH:5][C:6]([C:8]1[C:9](=[O:20])[NH:10][N:11]=[C:12]([C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)[CH:13]=1)=[O:7]
Reactant: O=C(NCc1ccc(Cl)cc1Cl)c1cc(-c2ccncc2)n[nH]c1=O
Agent: NCc1ccccc1Cl
Agent: O=C(Cl)C(=O)Cl
Agent: O=C(O)c1cc(-c2ccncc2)n[nH]c1=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(NCc1ccccc1Cl)c1cc(-c2ccncc2)n[nH]c1=O

Procedure:
Working as in example 2 for the preparation of N-(2,4-dichlorobenzyl)-3-oxo-6-pyridin-4-yl-2,3-dihydropyridazine-4-carboxamide, but starting with 0.3 g of 3-oxo-6-pyridin-4-yl-2,3-dihydropyridazine-4-carboxylic acid, 10 cm3 of dichloromethane, 0.02 cm3 of dimethylformamide, 0.12 cm3 of oxalyl chloride, 0.19 cm3 of 2-chlorobenzylamine and 0.19 cm3 of triethylamine, 0.25 g of N-(2-chlorobenzyl)-3-oxo-6-pyridin-4-yl-2,3-dihydropyridazine-4-carboxamide was obtained in the form of a White solid melting above 260° C.
Reaction SMILES: C(O)(=[O:3])C.[Cl:5][C:6]1[CH:24]=[CH:23][C:9]([O:10][C:11]2[CH:16]=[CH:15][C:14]([CH:17]=[C:18]([N+]([O-])=O)[CH3:19])=[CH:13][CH:12]=2)=[CH:8][CH:7]=1.O.CO>[Fe].CCCCCC>[Cl:5][C:6]1[CH:24]=[CH:23][C:9]([O:10][C:11]2[CH:16]=[CH:15][C:14]([CH2:17][C:18](=[O:3])[CH3:19])=[CH:13][CH:12]=2)=[CH:8][CH:7]=1
Reactant: CC(=O)O
Reactant: CC(=Cc1ccc(Oc2ccc(Cl)cc2)cc1)[N+](=O)[O-]
Agent: [Fe]
Solvent: O
Solvent: CCCCCC
Solvent: CO
Product: CC(=O)Cc1ccc(Oc2ccc(Cl)cc2)cc1

Procedure:
A mixture of 4-(4-chlorophenoxy)benzaldehyde (256 g) and butylamine (239 ml) in toluene (1 liter) was heated to reflux and the water formed removed through a Dean & Stark head. After 2 hr the mixture was concentrated in vacuo and the residue dissolved in acetic acid (750 ml) and nitroethane (118.5 ml), heated at 100° for 2 hr, cooled and poured into iced water. The yellow solid was filtered, dried in air and recyrstallised from ethanol (750 ml) to afford 4-(4-chlorophenoxy)phenyl-2-nitropropene (254.7 g), m.p. 69°-71°. Acetic acid (115 ml) was added over 30 min to a well stirred, refluxing mixture of the 4-(4-chlorophenoxy)phenyl-2-nitropropene (28.9 g), iron powder (56 g), water (20 ml) and methanol (150 ml). After 3 hr it was cooled and partitioned between water (500 ml) and dichloromethane (200 ml). The organic phase was filtered, washed with water and satd. aq. sodium bicarbonate, dried over magnesium sulphate and concentrated in vacuo to leave a yellow oil. Trituration with hexane afforded the title compound as fine colourless crystals (14.6 g), m.p. 50°-52°.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].[C:12]([O-])([O-])=O.[K+].[K+].CI.CN([CH:23]=[O:24])C>>[CH3:12][O:1][C:2]1[CH:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:3]=1[C:4]([O:24][CH3:23])=[O:5]
Reactant: CN(C)C=O
Reactant: O=C([O-])[O-]
Reactant: Cc1ccc(C(=O)O)c(O)c1
Agent: [K+]
Solvent: CI
Product: COC(=O)c1ccc(C)cc1OC
Temperature: 60 °C
Reaction time: 1 h

Procedure:
To a solution of 2-hydroxy-4-methylbenzoic acid (10.00 g, 65 mmol) in DMF (10 mL) was added K2CO3 (13.6 g, 98 mmol). The reaction mixture was stirred at 60° C. for 1 h. Methyl iodide (14.0 g, 98 mmol) was added to the reaction mixture and was stirred at 60° C. for 18 h. The reaction mass was quenched in water and concentrated. The reaction mass was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulphate and concentrated to afford 10.00 g of desired product. 1H NMR (300 MHz, DMSO d6): δ 2.34 (s, 3H), 3.74 (s, 3H), 3.79 (s, 3H), 6.81 (d, J=7.2 Hz, 1H), 6.97 (s, 1H), 7.56 (d, J=7.8 Hz, 1H); MS (m/z): 180.95 (M+H)+.
Reaction SMILES: [Cl:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][N:11]=1)[C:6]([OH:8])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:36][O:37][C:38]1[C:43]2[N:44]=[C:45]([NH2:47])[O:46][C:42]=2[C:41]([CH:48]2[CH2:53][CH2:52][O:51][CH2:50][CH2:49]2)=[CH:40][CH:39]=1>C1COCC1.O1CCOCC1.CN(C=O)C>[Cl:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][N:11]=1)[C:6]([NH:47][C:45]1[O:46][C:42]2[C:41]([CH:48]3[CH2:49][CH2:50][O:51][CH2:52][CH2:53]3)=[CH:40][CH:39]=[C:38]([O:37][CH3:36])[C:43]=2[N:44]=1)=[O:8]
Reactant: O=C(O)c1ccnc(CCl)c1
Reactant: COc1ccc(C2CCOCC2)c2oc(N)nc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: C1COCCO1
Product: COc1ccc(C2CCOCC2)c2oc(NC(=O)c3ccnc(CCl)c3)nc12

Procedure:
From 2-chloromethyl-isonicotinic acid, HATU and N-diethylisopropylamine in THF, then treatment with 4-methoxy-7-(tetrahydro-pyran-4-yl)-benzooxazol-2-yl-amine in dioxane and DMF. ES-MS m/e (%): 404 (M{37Cl}+H+, 30), 402 (M{35Cl}+H+, 100).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5](Br)=[CH:4][C:3]=1/[CH:9]=[CH:10]/[C:11]([O:13][CH2:14][CH3:15])=[O:12].O1CCOCC1.CCN(C(C)C)C(C)C.[CH2:31]([SH:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:38][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[CH:4][C:3]=1/[CH:9]=[CH:10]/[C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: CCOC(=O)/C=C/c1cc(Br)ccc1N
Reactant: SCc1ccccc1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: C1COCCO1
Product: CCOC(=O)/C=C/c1cc(SCc2ccccc2)ccc1N
Temperature: 80 °C
Yield: 122.4 %

Procedure:
A screw cap vial was charged with (E)-ethyl 3-(2-amino-5-bromophenyl)acrylate (0.820 g, 2.086 mmol), xantphos (0.092 g, 0.159 mmol), tris(dibenzylideneacetone)dipalladium (0.073 g, 0.080 mmol), 1,4-Dioxane (3.18 ml), and DIPEA (1.108 ml, 6.37 mmol). The vial was purged with Argon, sealed and heated to 80° C. for 10 minutes. The reaction was cooled to RT and benzyl mercaptan (0.395 ml, 3.34 mmol) was added and the reaction was continued heating at 80° C. for an additional 30 minutes. The reaction was cooled to RT, diluted with water and extracted with DCM (3×). The combined organics were washed with water and brine, dried over magnesium sulfate, filtered and concentrated. The resulting material was concentrated, dissolved in minimal DCM and purified via column chromatography (silica gel 40 g, gradient elution 0 to 50% EtOAc:Heptane) to afford 0.80 g of (E)-ethyl 3-(2-amino-5-(benzylthio)phenyl)acrylate. m/z (ESI) 314.1 (M+H)+.
Reaction SMILES: [CH3:1][S:2]([O-:4])=[O:3].[Na+].Cl[C:7]1[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:11][O:10][C:9](=[O:18])[CH:8]=1>CN(C=O)C.C(Cl)Cl>[CH3:1][S:2]([C:7]1[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:11][O:10][C:9](=[O:18])[CH:8]=1)(=[O:4])=[O:3]
Reactant: CCOC(=O)c1coc(=O)cc1Cl
Reactant: CS(=O)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCOC(=O)c1coc(=O)cc1S(C)(=O)=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1.2 g of sodium methylsulfinate are introduced into a solution of 2.02 g of ethyl 4-chloro-2-oxo-2H-pyran-5-carboxylate in DMF, and the mixture is stirred for 2 hours at room temperature. The reaction mixture is diluted with CH2Cl2 and extracted with saturated aqueous NaCl solution. The organic phase is dried with Na2SO4 and evaporated. The distillation residue which has crystallized out is mixed with ether, filtered off with suction and washed with ether. Yield 1.4 g (56.9% of theory); melting point: 95°-97° C.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)[C:5]2[S:10][C:9]([C:11]3[CH:12]=[C:13]([C:17]([OH:19])=[O:18])[CH:14]=[N:15][CH:16]=3)=[CH:8][C:6]=2[N:7]=1.CC1(C)C(C)(C)OB([C:34]2[CH:42]=[CH:41][CH:40]=[C:39]3[C:35]=2[CH:36]=[N:37][NH:38]3)O1>>[NH:38]1[C:39]2[C:35](=[C:34]([C:2]3[N:3]=[C:4]([N:20]4[CH2:25][CH2:24][O:23][CH2:22][CH2:21]4)[C:5]4[S:10][C:9]([C:11]5[CH:12]=[C:13]([C:17]([OH:19])=[O:18])[CH:14]=[N:15][CH:16]=5)=[CH:8][C:6]=4[N:7]=3)[CH:42]=[CH:41][CH:40]=2)[CH:36]=[N:37]1
Reactant: O=C(O)c1cncc(-c2cc3nc(Cl)nc(N4CCOCC4)c3s2)c1
Reactant: CC1(C)OB(c2cccc3[nH]ncc23)OC1(C)C
Product: O=C(O)c1cncc(-c2cc3nc(-c4cccc5[nH]ncc45)nc(N4CCOCC4)c3s2)c1

Procedure:
5-(2-Chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)pyridine-3-carboxylic acid (40 mg) was coupled to 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole 7 via General Procedure A to yield 5 mg of 349. MS (Q1) 459.1 (M)+
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[NH2:7].Cl[CH:9]([C:15](=O)[CH3:16])[C:10]([O:12][CH2:13][CH3:14])=[O:11].Cl>C(O)C.CCOCC>[CH2:13]([O:12][C:10]([C:9]1[N:1]2[CH:6]=[CH:5][N:4]=[CH:3][C:2]2=[N:7][C:15]=1[CH3:16])=[O:11])[CH3:14]
Reactant: Nc1cnccn1
Reactant: CCOC(=O)C(Cl)C(C)=O
Agent: Cl
Solvent: CCOCC
Solvent: CCO
Product: CCOC(=O)c1c(C)nc2cnccn12
Yield: 57.9 %

Procedure:
A solution of pyrazin-2-amine (3.6 g, 37.9 mmol) and ethyl 2-chloro-3-oxobutanoate (5.24 ml, 37.9 mmol) in ethanol (30 ml) was heated at reflux for 9 hours. A 1N solution of HCl in ether was added and the mixture was concentrated under reduced pressure. The residue was triturated with 3×50 ml acetonitrile and filtered to yield crude 2-Methyl-imidazo[1,2-a]pyrazine-3-carboxylic acid ethyl ester (4.5 g, 58%) as an amorphous solid which was used in the next step without further purification.
Reaction SMILES: [Cl:1][CH2:2][C@H:3]1[C:7]2=[C:8]3[C:12](=[C:13]([OH:15])[CH:14]=[C:6]2[N:5]([C:24]([C:26]2[NH:27][C:28]4[C:33]([CH:34]=2)=[CH:32][C:31]([NH:35][C:36]([C:38]2[O:39][C:40]5[C:46]([O:47][CH3:48])=[CH:45][CH:44]=[CH:43][C:41]=5[CH:42]=2)=[O:37])=[CH:30][CH:29]=4)=[O:25])[CH2:4]1)[NH:11][C:10]([C:16]([F:19])([F:18])[F:17])=[C:9]3[C:20]([O:22][CH3:23])=[O:21].Cl[C:50](OC1C=CC([N+]([O-])=O)=CC=1)=[O:51].C(N(CC)CC)C.[NH:69]1[CH2:73][CH2:72][CH2:71][C@H:70]1[CH2:74][OH:75].[Cl-].[Na+]>O1CCCC1.C(OCC)(=O)C>[Cl:1][CH2:2][C@H:3]1[C:7]2=[C:8]3[C:12](=[C:13]([O:15][C:50]([N:69]4[CH2:73][CH2:72][CH2:71][C@H:70]4[CH2:74][OH:75])=[O:51])[CH:14]=[C:6]2[N:5]([C:24]([C:26]2[NH:27][C:28]4[C:33]([CH:34]=2)=[CH:32][C:31]([NH:35][C:36]([C:38]2[O:39][C:40]5[C:46]([O:47][CH3:48])=[CH:45][CH:44]=[CH:43][C:41]=5[CH:42]=2)=[O:37])=[CH:30][CH:29]=4)=[O:25])[CH2:4]1)[NH:11][C:10]([C:16]([F:19])([F:17])[F:18])=[C:9]3[C:20]([O:22][CH3:23])=[O:21]
Reactant: OC[C@@H]1CCCN1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: COC(=O)c1c(C(F)(F)F)[nH]c2c(O)cc3c(c12)[C@H](CCl)CN3C(=O)c1cc2cc(NC(=O)c3cc4cccc(OC)c4o3)ccc2[nH]1
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)c1c(C(F)(F)F)[nH]c2c(OC(=O)N3CCC[C@H]3CO)cc3c(c12)[C@H](CCl)CN3C(=O)c1cc2cc(NC(=O)c3cc4cccc(OC)c4o3)ccc2[nH]1
Reaction time: 1 h
Yield: 70.1 %

Procedure:
Methyl(1S)-chloromethyl-5-hydroxy-3-[5-(7-methoxybenzofuran-2-ylcarbonyl)amino-1H-indol-2-ylcarbonyl]-7-trifluoromethyl-1,2,3,6-tetrahydropyrrolo[3,2-e]indole-8-carboxylate (10.2 mg, 15 μmol) and 4-nitrophenyl chloroformate (7.6 mg, 38 μmol) were dissolved in 1 mL of tetrahydrofuran, and thereto triethylamine (4.2 μL, 30 μmol) was added dropwise with ice cooling. After one hour, (2S)-pyrrolidine-2-methanol (4.4 μL, 45 μmol) was added dropwise. The mixture was stirred for two hours, and stirred further for two hours at room temperature. The reaction mixture was poured into 3 mL of saturated aqueous sodium chloride solution and 3 mL of ethyl acetate for extraction. The extracted matter was dried over anhydrous sodium sulfate, and the solvent was evaporated off. The resulting residue was purified by silica gel column chromatography (hexane:acetone=1:1) to obtain 8.5 mg (70%) of methyl (1S)-chloromethyl-5-{[(2S)-hydroxymethylpyrrolidin-1-ylcarbonyl]oxy}-3-[5-(7-methoxybenzofuran-2-ylcarbonyl)amino-1H-indol-2-ylcarbonyl]-7-trifluoromethyl-1,2,3,6-tetrahydropyrrolo[3,2-e]indole-8-carboxylate.
Reaction SMILES: C([O:5][NH:6][C:7](=[O:26])[CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([CH2:23][C:24]#[N:25])[CH:18]=2)=[CH:13][CH:12]=1)(C)(C)C.FC(F)(F)C(O)=O.ClCCl>>[C:24]([CH2:23][C:19]1[CH:18]=[C:17]([C:14]2[CH:15]=[CH:16][C:11]([O:10][CH2:9][CH2:8][C:7]([NH:6][OH:5])=[O:26])=[CH:12][CH:13]=2)[CH:22]=[CH:21][CH:20]=1)#[N:25]
Reactant: CC(C)(C)ONC(=O)CCOc1ccc(-c2cccc(CC#N)c2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#CCc1cccc(-c2ccc(OCCC(=O)NO)cc2)c1
Yield: 45 %

Procedure:
A solution of O-tert-butyl 3-[4-(3-cyanomethylphenyl)phenoxy]propanohydroxamic acid (0.043 g, 0.12 mmol) in 1:1 trifluoroacetic acid-dichloromethane was stirred overnight at ambient temperature. The reaction mixture was filtered, concentrated in vacuo, and azeotroped with dichloromethane and dichloromethane-ethyl ether. Chromatography on silica gel (40:1, then 20:1 dichloromethane-methanol, both containing 0.25% acetic acid) gave 3-[4-(3-cyanomethylphenyl)phenoxy]propanohydroxamic acid (16 mg, 44%). 1H NMR (DMSO-d6) δ 2.45 (t, 2H, J=6.0 Hz), 4.08 (s, 2H), 4.23 (t, 2H, J=6.0 Hz), 7.02 (d, 2H, J=8.8 Hz), 7.29 (d, 1H, J=7.5 Hz), 7.46 (t, 1H, J=8.0 Hz), 7.57 (d, 1H, J=6 Hz), 7.58 (s, 1H), 7.60 (d, 2H, J=8.8 Hz); 8.84 (br s, 1H), 10.53 (br s, 1H). IR (microscope) 3245 (br), 2924 (m), 2251 (w), 1643 (s), 1608 (s), 1518 (s), i483 (m), 1244 (s), 784 (m) cm-1. MS (DCI/NH3) 314 (M+NH4)+. Anal. Calcd for C17H16N2O3 ·0.70 H2O·0.20 tBuOH: C, 66.04; H, 6.04; N, 8.65. Found: C, 65.93; H, 5.64; N, 8.30.
Reaction SMILES: [CH3:1][CH:2]([CH3:14])[CH2:3][CH2:4][C:5]1[NH:6][C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[CH:9][CH:8]=2.C(N1C=CN=C1)(N1C=CN=C1)=[O:16].CC(C)CCC(O)=O.NC1C(C)=CC=CC=1>ClCCl>[CH3:13][C:12]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[NH:6][C:5](=[O:16])[CH2:4][CH2:3][CH:2]([CH3:14])[CH3:1]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CC(C)CCc1cc2ccccc2[nH]1
Agent: CC(C)CCC(=O)O
Solvent: Cc1ccccc1N
Solvent: ClCCl
Product: Cc1ccccc1NC(=O)CCC(C)C

Procedure:
Preparation of 2-(3-methyl-n-butyl)-indole. Carbonyldiimidazole (65 g) was mixed with 500 ml of dry dichloromethane in a 2-L round bottom flask and stirred magnetically. A solution of 4-methylvaleric acid in 200 ml of dichloromethane was added dropwise over 45 minutes and the mixture was stirred for another 1.25 hours. o-Toluidine (45 g) in 100 ml of dichloromethane was then added over about 20 minutes. After stirring for 2 hours the mixture was washed with water and then the solvent was stripped on a rotary evaporator. The residue was mixed with 150 ml of methanol and 75 ml of water and put in the freezer. Filtration of the precipitate, dilution of the filtrate with water and refiltration of the precipitate gave 75 g (94%) of vacuum dried N-(2-methylphenyl)-4-methylvaleramide which was used without further treatment in the next step.
Reaction SMILES: [I:1]N1C(=O)CCC1=O.[F:9][C:10]1[CH:15]=[CH:14][C:13]([N:16]2[CH2:21][CH2:20][C:19]3=[N:22][C:23]([CH2:25][O:26][C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)=[CH:24][N:18]3[C:17]2=[O:33])=[CH:12][CH:11]=1>C(#N)C.C(O)(=O)C.C(Cl)Cl>[F:9][C:10]1[CH:15]=[CH:14][C:13]([N:16]2[CH2:21][CH2:20][C:19]3=[N:22][C:23]([CH2:25][O:26][C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=4)=[C:24]([I:1])[N:18]3[C:17]2=[O:33])=[CH:12][CH:11]=1
Reactant: O=C1CCC(=O)N1I
Reactant: O=C1N(c2ccc(F)cc2)CCc2nc(COc3ccccc3)cn21
Solvent: CC#N
Solvent: CC(=O)O
Solvent: ClCCl
Product: O=C1N(c2ccc(F)cc2)CCc2nc(COc3ccccc3)c(I)n21
Temperature: 25 °C
Reaction time: 72 h
Yield: 33.1 %

Procedure:
N-iodosuccinimide (73.4 mg, 0.33 mmol) was added to a stirred solution of 6-(4-fluoro-phenyl)-2-phenoxymethyl-7,8-dihydro-6H-imidazo[1,2-c]pyrimidin-5-one (0.1 g, 0.3 mmol) in a mixture of ACN (2 mL) and acetic acid (2 mL). The mixture was stirred at RT for 3 days. The mixture was diluted with DCM and washed with a saturated solution of Na2CO3. The organic layer was separated, dried (Na2SO4), filtered and the solvents evaporated in vacuo. The crude product was triturated with MeOH to yield 6-(4-fluoro-phenyl)-3-iodo-2-phenoxymethyl-7,8-dihydro-6H-imidazo[1,2-c]pyrimidin-5-one (46 mg, 56% yield) as a brown solid, that was used in the next step without further purification.
Reaction SMILES: C1(C)C=CC=CC=1.CS(OC[C@H:14]([C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[CH:23]=1)[O:15][CH:16]1CCCCO1)(=O)=O.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[Cl:28][C:24]1[CH:23]=[C:22]([CH:27]=[CH:26][CH:25]=1)[C@@H:14]1[O:15][CH2:16]1
Reactant: CS(=O)(=O)OC[C@@H](OC1CCCCO1)c1cccc(Cl)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: CO
Solvent: O
Product: Clc1cccc([C@H]2CO2)c1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
Into toluene (10 ml) were added (S)-2-(3-chlorophenyl)-2-(3,4,5,6-tetrahydro-[2H]-pyran-2-yloxy)ethyl methanesulfonate (3.0 g), p-toluenesulfonic acid monohydrate (1.7 g) and methanol (0.5 g), and the resulting mixture was:stirred at 50° C. for 1 hour. The reaction mixture was Washed with a saturated aqueous sodium hydrogen carbonate solution and then with a saturated aqueous sodium chloride solution. To the organic layer was added 20% NaOH (10 ml) and the resulting mixture was stirred vigorously at room temperature for 1 hour. The reaction mixture was subjected to layer separation, and the organic layer was washed with water, then with a saturated aqueous sodium chloride solution and dried with anhydrous magnesium sulfate. The desiccant was filtered off, then the solvent was distilled off, and the resulting oily substance was distilled under reduced pressure to obtain a colorless oily compound mentioned above (1.27 g, 91.7%). The optical purity of the product obtained was 99.9% e.e. as determined by HPLC.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][C:8]([OH:10])=[O:9])[CH:2]=1.[Br:12]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Br:12][CH2:11][C:1]1[CH:2]=[C:3]([CH2:7][C:8]([OH:10])=[O:9])[CH:4]=[CH:5][CH:6]=1
Reactant: Cc1cccc(CC(=O)O)c1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: O=C(O)Cc1cccc(CBr)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 59.8 %

Procedure:
To a solution of m-tolylacetic acid (25.00 g, 166.5 mmol) in anhydrous carbon tetrachloride (200 ml) was added N-bromosuccinimide (30.00 g, 168.6 mmol), and the mixture was gradually heated to the boiling point. After heating the mixture under reflux for 5.5 hr, the reaction mixture was cooled to room temperature, the insoluble material was removed by filtration and washed twice with carbon tetrachloride (100 ml). The filtrate was concentrated, carbon tetrachloride (60 ml) was added and the residue was dissolved by heating at about 70° C. The solution was cooled to about 40° C., and hexane (300 ml) was added dropwise. After stirring at room temperature for 30 min, the precipitated crystals were filtered, washed with hexane and dried under reduced pressure to give (3-bromomethylphenyl)acetic acid (22.80 g, 99.53 mmol, yield 59.8%) as a white solid.