Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]=[C:11](B2OC(C)(C)C(C)(C)O2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[K+].[K+].[CH2:29]([O:36][C:37]1[C:42]([F:43])=[CH:41][CH:40]=[CH:39][C:38]=1Br)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]=[C:11]([C:38]2[CH:39]=[CH:40][CH:41]=[C:42]([F:43])[C:37]=2[O:36][CH2:29][C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Reactant: Fc1cccc(Br)c1OCc1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)N1CC=C(c2cccc(F)c2OCc2ccccc2)CC1
Temperature: 150 °C

Procedure:
To a solution of 1,2,3,6-tetrahydro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-pyridine-1-carboxylic acid ter-butylester (0.75 g, 2.426 mmol) [CAS 375853-82-0] (synthesis described in WO 2004072025 A2 20040826) in 1,4-dioxane (7 ml) and an aqueous saturated solution of K2CO3 (3.5 ml), was added 2-benzyloxy-1-bromo-3-fluoro-benzene (1.023 mg, 3.638 mmol) [1036724-55-6]. The resulting solution was degassed using a stream of nitrogen and to this was added Pd(PPh3)4 (0.14 g, 0.121 mmol). The reaction was then subjected to microwave heating in a sealed tube at 150° C. for 10 min. After cooling to room temperature, the reaction mixture was diluted with water and washed with EtOAc. The organic layer was separated, dried (Na2SO4) and evaporated in vacuo. The residue was purified by column chromatography (silica gel; starting from Heptane/DCM up to 100% as eluent). The desired fractions were collected and evaporated in vacuo to yield intermediate compound D51 (0.727 g, 78%)
Reaction SMILES: [F:1][C:2]1[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:3]=1[O:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][C:13]=1[C:14](ON1C(=O)CCC1=O)=[O:15])[N:10]([CH2:24][CH:25]([CH3:27])[CH3:26])[N:9]=[CH:8]2.[NH2:33][C@H:34]1[CH2:38][CH2:37][NH:36][C:35]1=[O:39]>ClCCl.C(OCC)(=O)C>[F:1][C:2]1[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:3]=1[O:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][C:13]=1[C:14]([NH:33][C@H:34]1[CH2:38][CH2:37][NH:36][C:35]1=[O:39])=[O:15])[N:10]([CH2:24][CH:25]([CH3:26])[CH3:27])[N:9]=[CH:8]2
Reactant: N[C@H]1CCNC1=O
Reactant: CC(C)Cn1ncc2cc(Oc3ccc(F)cc3F)c(C(=O)ON3C(=O)CCC3=O)cc21
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)Cn1ncc2cc(Oc3ccc(F)cc3F)c(C(=O)N[C@H]3CCNC3=O)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.8 %

Procedure:
To a solution of 2,5-dioxopyrrolidin-1-yl 5-(2,4-difluorophenoxy)-1-isobutyl-1H-indazole-6-carboxylate (700 mg, 1.58 mmol) in dichloromethane (5 mL) was added (S)-3-aminopyrrolidin-2-one (prepared according to Example 2, 205 mg, 2.05 mmol) and the reaction was allowed to stir overnight at ambient temperature. The reaction mixture was diluted with ethyl acetate and washed with 1M hydrochloric acid, 1M sodium hydroxide, saturated sodium bicarbonate, and saturated sodium chloride. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography on a silica gel column, eluting with a gradient of 25-100% acetone/hexanes to yield (S)-5-(2,4-difluorophenoxy)-1-isobutyl-N-(2-oxopyrrolidin-3-yl)-1H-indazole-6-carboxamide (Ia) (520 mg, 77%). Mass spec: 429 (M+1). 1H NMR (CDCl3) δ 8.37 (s, 1H), 8.26 (d, 1H), 7.87 (s, 1H), 7.15 (m, 1H), 7.03 (s, 1H), 7.00 (m, 1H), 6.91 (m, 1H), 6.03 (br, 1H), 4.59 (ddd, 1H), 4.22 (d, 2H), 3.46 (m, 2H), 2.87 (m, 1H), 2.36 (m, 1H), 2.10 (m, 1H), 0.92 (d, 6H).
Reaction SMILES: [CH3:1][C:2]1[NH:10][C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]=1[CH3:11].[Br:12][C:13]1[CH:21]=[CH:20][CH:19]=[CH:18][C:14]=1[CH2:15][CH2:16]Br.C(Cl)Cl>CC#N>[CH3:1][C:2]1[N:10]=[C:5]2[N:6]([CH2:16][CH2:15][C:14]3[CH:18]=[CH:19][CH:20]=[CH:21][C:13]=3[Br:12])[CH:7]=[CH:8][CH:9]=[C:4]2[C:3]=1[CH3:11]
Reactant: Cc1[nH]c2ncccc2c1C
Reactant: BrCCc1ccccc1Br
Solvent: CC#N
Solvent: ClCCl
Product: Cc1nc2n(CCc3ccccc3Br)cccc-2c1C

Procedure:
A solution of 2,3-dimethylpyrrolo[2,3-b]pyridine (554 mg, 3.8 mmol) and o-bromophenethyl bromide (1000 mg, 3.8 mmol) in 11 ml CH3CN was refluxed for 16 h. The solvent was evaporated and the residue chromatographed (silica, CH2Cl2 /MeOH; 9/1) to give 546 mg enriched product. Pure 2,3-dimethyl-7-(o-bromophenethyl) pyrrolo[2,3-b]pyridine was obtained by a second chromatography (silica, CH2Cl2 saturated with NH3/petroleum ether; 7/3). A deaerated solution of 2,3-dimethyl-7- (o-bromophenethyl) pyrrolo[2,3-b]pyridine (249 mg, 0.76 mmol) in 25 ml dry THF was cooled to -78° C. and treated with 1.6M n-BuLi in hexane (576 μl, 0.91 mmol). After 3 min a vigurous stream of CO2 (g) was bubbled through the solution. The solution was allowed to warm to room temperature and 1.5 ml H2O was added. The solvent was evaporated and the residue chromatographed (reversed phase silica, MeOH/H2O; 6/4) yielding 51 mg (23%) pure amino acid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][NH:8][C:9](=[O:16])[NH:10][O:11][CH2:12][C:13]([OH:15])=O)=[CH:3][CH:2]=1.[NH2:17][C@@H:18]([CH2:42][C:43]([NH:45][C:46]([C:59]1[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=1)([C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1)[C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)=[O:44])[C:19]([N:21]([C@@H:33]([CH3:41])[CH:34]([O:38][CH2:39][CH3:40])[O:35][CH2:36][CH3:37])[CH2:22][C:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][CH:24]=1)=[O:20]>>[CH2:36]([O:35][CH:34]([O:38][CH2:39][CH3:40])[C@@H:33]([N:21]([CH2:22][C:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][CH:24]=1)[C:19](=[O:20])[C@@H:18]([NH:17][C:13](=[O:15])[CH2:12][O:11][NH:10][C:9]([NH:8][CH2:7][C:4]1[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=1)=[O:16])[CH2:42][C:43](=[O:44])[NH:45][C:46]([C:47]1[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=1)([C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1)[C:59]1[CH:60]=[CH:61][CH:62]=[CH:63][CH:64]=1)[CH3:41])[CH3:37]
Reactant: O=C(O)CONC(=O)NCc1ccncc1
Reactant: CCOC(OCC)[C@H](C)N(Cc1cccc2ccccc12)C(=O)[C@@H](N)CC(=O)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Product: CCOC(OCC)[C@H](C)N(Cc1cccc2ccccc12)C(=O)[C@H](CC(=O)NC(c1ccccc1)(c1ccccc1)c1ccccc1)NC(=O)CONC(=O)NCc1ccncc1

Procedure:
According to the procedure described in the synthesis method of Compound II-15, 2-(3-(pyridin-4-ylmethyl)ureidooxy)acetic acid (Compound VI-10) 52 mg (0.23 mmol) was coupled with (S)-2-amino-N1—((S)-1,1-diethoxypropan-2-yl)-N1-(naphthalen-1-ylmethyl)-N4-tritylsuccinamide (Compound IV-19) 100 mg (0.16 mmol) to obtain the title compound.
Reaction SMILES: [CH:1]1([CH2:4][N:5]([CH2:15][CH2:16][CH3:17])[C:6]2[N:11]=[CH:10][N:9]=[C:8]([C:12]([OH:14])=O)[CH:7]=2)[CH2:3][CH2:2]1.[NH2:18][C:19]1[CH:20]=[C:21]2[C:25](=[CH:26][CH:27]=1)[N:24]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[N:23]=[C:22]2[CH2:35][CH2:36][C:37]([O:39][CH3:40])=[O:38]>C(Cl)Cl>[CH:1]1([CH2:4][N:5]([CH2:15][CH2:16][CH3:17])[C:6]2[N:11]=[CH:10][N:9]=[C:8]([C:12]([NH:18][C:19]3[CH:20]=[C:21]4[C:25](=[CH:26][CH:27]=3)[N:24]([C:28]([O:30][C:31]([CH3:32])([CH3:33])[CH3:34])=[O:29])[N:23]=[C:22]4[CH2:35][CH2:36][C:37]([O:39][CH3:40])=[O:38])=[O:14])[CH:7]=2)[CH2:2][CH2:3]1
Reactant: COC(=O)CCc1nn(C(=O)OC(C)(C)C)c2ccc(N)cc12
Reactant: CCCN(CC1CC1)c1cc(C(=O)O)ncn1
Solvent: ClCCl
Product: CCCN(CC1CC1)c1cc(C(=O)Nc2ccc3c(c2)c(CCC(=O)OC)nn3C(=O)OC(C)(C)C)ncn1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 6-((cyclopropylmethyl)(propyl)amino)pyrimidine-4-carboxylic acid (Intermediate 21, 31 mg; 0.13 mmol) in DCM (5 ml) was treated with tert-butyl 5-amino-3-(3-methoxy-3-oxopropyl)-1H-indazole-1-carboxylate (Intermediate 45, 35 mg; 0.11 mmol) and polymer-supported Mukaiyama reagent (300 mg). After stirring at RT for 3 hours the mixture was filtered and washed with water. The organic phase was passed through a hydrophobic frit and the solvent removed in vacuo. The residue was purified by column chromatography (silica) eluting with petroleum ether containing increasing amounts of EtOAc to give tert-butyl 5-(6-((cyclopropylmethyl)(propyl)amino)pyrimidine-4-carboxamido)-3-(3-methoxy-3-oxopropyl)-1H-indazole-1-carboxylate. The intermediate was redissolved in DCM (2 ml) and treated with TFA (1 ml) and water (1 drop). After stirring at RT for 3 hours the solvent was removed in vacuo. The residue was partitioned between DCM and saturated sodium bicarbonate solution. The separated organic phase was passed through a hydrophobic frit and the solvent removed in vacuo. The residue was purified by column chromatography (silica) eluting with petroleum ether containing increasing amounts of EtOAc to give the title compound as an off-white solid.
Reaction SMILES: C[Al](C)C.[CH3:5]CCCCC.C(C1C=C(C)C=C(C(C)(C)C)C=1O)(C)(C)C.[C:27]([O:30][C@H:31]1[CH2:36][CH2:35][C@H:34]2[C@H:37]3[C@H:47]([CH2:48][CH2:49][C@:32]12[CH3:33])[C@:45]1([CH3:46])[C:40](=[CH:41][C:42](=[O:50])[CH:43]=[CH:44]1)[CH2:39][CH2:38]3)(=[O:29])[CH3:28]>C(OCC)(=O)C.[Ni+2].C/C(/[O-])=C/C(C)=O.O>[C:27]([O:30][C@H:31]1[CH2:36][CH2:35][C@H:34]2[C@H:37]3[C@H:47]([CH2:48][CH2:49][C@:32]12[CH3:33])[C@:45]1([CH3:46])[C:40](=[CH:41][C:42](=[O:50])[CH:43]=[C:44]1[CH3:5])[CH2:39][CH2:38]3)(=[O:29])[CH3:28]
Reactant: CCCCCC
Reactant: CC(=O)O[C@H]1CC[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@H]3CC[C@]12C
Agent: [Ni+2]
Agent: CC(=O)/C=C(/C)[O-]
Agent: C[Al](C)C
Solvent: O
Solvent: CCOC(C)=O
Product: CC(=O)O[C@H]1CC[C@H]2[C@@H]3CCC4=CC(=O)C=C(C)[C@]4(C)[C@H]3CC[C@]12C
Temperature: 60 °C
Yield: 19.9 %

Procedure:
12 ml of trimethylaluminum of a 10% solution in hexane (12 mmol) is introduced at room temperature under nitrogen atmosphere. With stirring, 2.64 g of 2,6-di-tert-butyl-4-methylphenol is added in portions. The solution is stirred for 30 more minutes and 3.27 g (10 mmol) of 17β-acetoxy-androsta-l,4-dien-3-one in 20 ml of ethyl acetate is added at 25° C. The solution is heated to 60° C. and 143 mg of nickel(II)-acetylacetonate is added at 60° C. The solution is stirred for another 2.5 hours at this temperature. After cooling, 1.1 ml water is added for hydrolysis and stirred for 15 minutes. The solid is filtered off, rewashed twice-with 50 ml of ethyl, acetate. After concentration by evaporation of the ethyl acetate phases, a crude product is obtained, which is chromatographed on silica gel with hexane/ethyl acetate as eluent with increasing ethyl acetate portion. 1.55 g of initial material is recovered. 0.68 g of 17β-acetoxy-l-methyl-androsta-1,4-dien-3-one of melting point 144.1° C. is obtained. The yield is 20% of theory or 38% taking into consideration the initial material recovered.
Reaction SMILES: [O:1]=[C:2]1[CH2:9][C:6]([CH3:8])([CH3:7])[CH2:5][C:4]([CH3:10])=[CH:3]1.[C:11]([C:15]1[C:20]([O:21][SiH:22]([CH3:24])[CH3:23])=[C:19]([Br:25])[C:18]([O:26][CH3:27])=[CH:17][C:16]=1[CH2:28]C1C(=O)C=CCC1(C)C)([CH3:14])([CH3:13])[CH3:12]>>[C:11]([C:15]1[C:20]([O:21][SiH:22]([CH3:23])[CH3:24])=[C:19]([Br:25])[C:18]([O:26][CH3:27])=[CH:17][C:16]=1[CH2:28][CH:9]1[C:2](=[O:1])[CH:3]=[C:4]([CH3:10])[CH2:5][C:6]1([CH3:8])[CH3:7])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC1=CC(=O)CC(C)(C)C1
Reactant: COc1cc(CC2C(=O)C=CCC2(C)C)c(C(C)(C)C)c(O[SiH](C)C)c1Br
Product: COc1cc(CC2C(=O)C=C(C)CC2(C)C)c(C(C)(C)C)c(O[SiH](C)C)c1Br
Yield: 60 %

Procedure:
This compound was prepared from isophorone (0.168 g, 1.22 mmol) in the manner previously described for enone 13, affording 0.342 g (60%) of the alkylation product (Rf 0.40, 2:1 hexanes/ethyl acetate) as a colorless, oily solid. 1H NMR (400 MHz, CDCl3) δ0.20 and 0.22 [2s, 2×3H, Si(CH3)2 ], 0.99 [s, 9H, SiC(CH3)3 ], 1.00 and 1.02 (2s, 2×3H, geminal-CH3 's),b 1.91 (s, 3H, 3-CH3), 2.18 and 2.28 (ABq, 2H), 2.42 (dd, 1H), 2.82 (dd, 2H), 3.70 (s, 3H, OCH3), 5.82 (sl d, 1H, 2-H), 6.71 (s, 1H, 6'-H), 6.92 ppm (s, 1H, 3'-H).
Reaction SMILES: [I:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([O:12][CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17]C=2)[CH:3]=1.C(Br)C1C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+].IC1C=CC(C(OC)=O)=C(O)C=1.Cl>CN(C=O)C>[CH2:13]([O:12][C:4]1[CH:3]=[C:2]([I:1])[CH:11]=[CH:10][C:5]=1[C:6]([O:8][CH3:9])=[O:7])[C:14]1[CH:15]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: COC(=O)c1ccc(I)cc1OCCc1ccccc1
Agent: BrCc1ccccc1
Agent: COC(=O)c1ccc(I)cc1O
Agent: Cl
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(I)cc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
The procedure is the same as that followed for methyl 4-iodo-2-phenethyloxybenzoate, using 5.6 ml of benzyl bromide, 14 g of caesium carbonate and 10 g of methyl 4-iodo-2-hydroxybenzoate in 200 ml of DMF. The suspension is stirred for 48 hours at room temperature. The organic phase is acidified at room temperature with a 2N hydrochloric acid solution to pH 5. The desired product is extracted by addition of ethyl ether. The organic phase is washed with water, dried with magnesium sulfate and concentrated using a rotary evaporator. 14 g of the expected compound are recovered in the form of a brown solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[C:14]([C:18]([OH:20])=O)=[CH:13][CH:12]=[CH:11][C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(Cl)CCl.C1C=C2N=NN(O)C2=CC=1.O.[Cl:36][C:37]1[CH:38]=[C:39]([CH:44]=[CH:45][C:46]=1[O:47][CH:48]([CH3:50])[CH3:49])/[C:40](=[N:42]/O)/[NH2:41]>CN(C=O)C>[Cl:36][C:37]1[CH:38]=[C:39]([C:40]2[N:42]=[C:18]([C:14]3[CH:13]=[CH:12][CH:11]=[C:10]4[C:15]=3[CH2:16][CH2:17][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:9]4)[O:20][N:41]=2)[CH:44]=[CH:45][C:46]=1[O:47][CH:48]([CH3:50])[CH3:49]
Reactant: CC(C)Oc1ccc(/C(N)=N/O)cc1Cl
Reactant: CC(C)(C)OC(=O)N1CCc2c(cccc2C(=O)O)C1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)Oc1ccc(-c2noc(-c3cccc4c3CCN(C(=O)OC(C)(C)C)C4)n2)cc1Cl
Temperature: 140 °C
Yield: 68.8 %

Procedure:
To a slurry of 2-(tert-butoxycarbonyl)-1,2,3,4-tetrahydroisoquinoline-5-carboxylic acid (0.380 g, 1.371 mmol) in DMF (1.662 ml) was added EDC (0.263 g, 1.371 mmol) followed by HOBT hydrate. After about 1 h a solution of (Z)-3-chloro-N′-hydroxy-4-isopropoxybenzimidamide (0.285 g, 1.246 mmol) in DMF (0.831 ml) was added and the reaction mixture was heated to 140° C. for about 1 hr. The reaction mixture was concentrated in vacuo and purified by chromatography on silica gel to provide tert-butyl 5-(3-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-5-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (0.403 g, 69%) as a colorless oil. LCMS (Table 1, Method c) Rt=3.43 min, m/z 471 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:12]([CH2:18][CH:19]([CH3:21])[CH3:20])[C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:5]=[C:6]([N+:9]([O-:11])=[O:10])[C:7]=1[OH:8].C([O-])([O-])=O.[Cs+].[Cs+].[CH:28]1([CH2:31]Br)[CH2:30][CH2:29]1.O>CS(C)=O>[Br:1][C:2]1[CH:3]=[C:4]([CH:12]([CH2:18][CH:19]([CH3:20])[CH3:21])[C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:5]=[C:6]([N+:9]([O-:11])=[O:10])[C:7]=1[O:8][CH2:31][CH:28]1[CH2:30][CH2:29]1
Reactant: BrCC1CC1
Reactant: CCOC(=O)C(CC(C)C)c1cc(Br)c(O)c([N+](=O)[O-])c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CS(C)=O
Product: CCOC(=O)C(CC(C)C)c1cc(Br)c(OCC2CC2)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 64.3 %

Procedure:
A solution of ethyl 2-(3-bromo-4-hydroxy-5-nitrophenyl)-4-methylpentanoate (4.1 g, 11.26 mmol) was taken in 50 ml of DMSO and to it added Cs2CO3 (3.02 g, 12.39 mmol). The reaction mixture was stirred at room temperature for 15 minutes and then added cyclopropylmethyl bromide (1.67 g, 12.39 mmol) dropwise. After completion of addition, the reaction mixture was stirred at 70° C. for 4 h. After completion of the reaction, it was poured into water (200 ml) and extracted with ethyl acetate (100 ml×3). The ethyl acetate layer was washed with 1N HCl, water and finally brine solution. The organic layer was then distilled off and the crude residue was purified by column chromatography using Ethyl acetate:hexane (1:3) as eluent provided 3 g of ethyl 2-(3-bromo-4-(cyclopropylmethoxy)-5-nitrophenyl)-4-methylpentanoate. 1H NMR (CDCl3): δ 8.20 (s 1H), 7.20 (s, 1H), 4.15 (q, 2H), 3.60 (t, 1H), 3.45 (d, 2H), 1.95-2.00 (m, 1H), 1.75-1.80 (m, 1H), 1.45-1.50 (m, 1H), 1.20 (t, 3H), 1.00 (m, 6H), 0.35-0.25 (m, 5H). Mass: (414, M+1,100%).
Reaction SMILES: O[CH2:2][C:3]1[CH:4]=[C:5]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:6]=[C:7]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:8]=1.C(Br)(Br)(Br)[Br:20].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl.C(Cl)(Cl)Cl>[CH2:17]([O:16][C:14]([C:5]1[CH:4]=[C:3]([CH2:2][Br:20])[CH:8]=[C:7]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:6]=1)=[O:15])[CH3:18]
Reactant: BrC(Br)(Br)Br
Reactant: CCOC(=O)c1cc(CO)cc(C(=O)OCC)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1cc(CBr)cc(C(=O)OCC)c1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
To a solution of diethyl 5-(hydroxymethyl)benzene-1,3-dioate (3.5 g, 0.014 mol) and carbon tetrabromide (5.0 g, 0.015 mol) in 30 mL CH2Cl2, cooled to 0° C., was added dropwise a solution of triphenylphosphine (3.9 g, 0.015 mol) in 20 mL CH2Cl2. The reaction was stirred at 0° C. for 1.5 h, diluted with CHCl3, and washed with water and brine. Drying, solvent evaporation and flash chromatography (silica gel, 0-30% EtOAc/hexanes) gave diethyl-5-(bromomethyl)benzene-1,3-dioate. 1H NMR (400 MHz, CDCl3) δ 8.61 (s, 1H), 8.25 (app d, J=1.6 Hz, 2H), 4.55 (s, 2H), 4.42 (q, J=7.1 Hz, 4H), 1.42 (t, J=7.1 Hz, 6H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7]([NH:10][C:11](=[O:34])[C@@H:12]([NH:20][C:21](=[O:33])[CH:22]([NH2:32])[C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25]([F:31])[CH:24]=2)[CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[S:8][CH:9]=1)=[O:4].C(N(C(C)C)CC)(C)C.[O:44]=[C:45](Cl)OC(Cl)(Cl)Cl>O1CCCC1.C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7]([NH:10][C:11](=[O:34])[C@@H:12]([N:20]2[C:21](=[O:33])[CH:22]([C:23]3[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25]([F:31])[CH:24]=3)[NH:32][C:45]2=[O:44])[CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[S:8][CH:9]=1)=[O:4]
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Reactant: COC(=O)c1csc(NC(=O)[C@H](Cc2ccccc2)NC(=O)C(N)c2ccc(OC)c(F)c2)n1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: COC(=O)c1csc(NC(=O)[C@H](Cc2ccccc2)N2C(=O)NC(c3ccc(OC)c(F)c3)C2=O)n1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 113.8 %

Procedure:
To a solution of 2-{(S)-2-[2-amino-2-(3-fluoro-4-methoxy-phenyl)-acetylamino]-3-phenyl-propionylamino}-thiazole-4-carboxylic acid methyl ester (0.335 g, 0.688 mmol) and diisopropylethylamine (0.48 mL, 2.75 mmol) in tetrahydrofuran (10 mL) was added to a solution of diphosgene (0.057 mL, 0.48 mmol) in a mixture of toluene (10 mL) and tetrahydrofuran (10 mL) over 10 minute at 0° C. The mixture was stirred at 0° C. for 15 minutes and then diluted with ethyl acetate. The mixture was washed with water, brine and dried over sodium sulfate. Evaporation of the solvents and purification of the residue by chromatography over silica gel eluted with 3:97 methanol/dichloromethane gave 2-{(S)-2-[4-(3-fluoro-4-methoxy-phenyl)-2,5-dioxo-imidazolidin-1-yl]-3-phenyl-propionylamino}-thiazole-4-carboxylic acid methyl ester (0.28 g, 79%).
Reaction SMILES: O1C=[CH:4][CH:3]=[C:2]1P(C1OC=CC=1)C1OC=CC=1.[Cl:17][C:18]1[CH:19]=[CH:20][C:21]2[C:27](=[O:28])[C:26](I)=[C:25]([O:30][CH3:31])[C:24](=[O:32])[NH:23][C:22]=2[CH:33]=1.C([Sn](CCCC)(CCCC)CCCC)C=C>C1(C)C=CC=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]>[CH2:4]([C:26]1[C:27](=[O:28])[C:21]2[CH:20]=[CH:19][C:18]([Cl:17])=[CH:33][C:22]=2[NH:23][C:24](=[O:32])[C:25]=1[O:30][CH3:31])[CH:3]=[CH2:2]
Reactant: c1coc(P(c2ccco2)c2ccco2)c1
Reactant: COc1c(I)c(=O)c2ccc(Cl)cc2[nH]c1=O
Agent: [Pd]
Agent: C=CC[Sn](CCCC)(CCCC)CCCC
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: C=CCc1c(OC)c(=O)[nH]c2cc(Cl)ccc2c1=O
Reaction time: 0.17 h
Yield: 831.6 %

Procedure:
A solution of tri(2-furyl)phosphine (0.019 g) and tris-(dibenzylideneacetone)dipalladium(O) (0.020 g) in toluene (25 mL) was allowed to stir for 10 minutes. To this solution was added 8-chloro-4-iodo-3-methoxy-2,5-dioxo-2,5-dihydro-1H-benz[b]azepine (0.750 g), followed by allyltributyltin (0.83 g). The reaction mixture was heated to reflux for 16 hours, was allowed to cool, and the toluene was evaporated. The residue was dissolved in ethyl acetate, and the resulting solution was filtered through silica gel and stirred over an equal volume of 1 molar aqueous potassium fluoride for 0.5 hour. The organic portion was separated, washed (water, brine), dried, filtered through diatomaceous earth and evaporated. The resulting orange solid was triturated with hexanes and subsequently chromatographed, with ethyl acetate:hexanes (5:1) as the eluent, to afford the title compound (0.189 g); mp 135°-136° C.; NMR: 11.43 (broad s,1), 7.63 (d,1, J=8.5), 7.36 (d,1, J=2.0), 7.29 (dd,1, J=8.6, 1.9), 5.85-5.72 (m,1), 5.00-4.96 (m,1), 4.94 (m,1), 3.80 (s,3), 3.28 (m,2). Analysis for C14H12ClNO3 0.25 H2O.: Calculated: C, 59.58; H, 4.46; N, 4.96; N, 4.96; Found C, 59,74; H, 4.39; N, 4.93.
Reaction SMILES: O[CH2:2][C:3]1[CH:12]=[N:11][C:10]2[N:9]3[CH2:13][CH2:14][CH2:15][C@H:8]3[C:7](=[O:16])[NH:6][C:5]=2[CH:4]=1.Cl.[F:18][C:19]1[CH:20]=[C:21]([CH:28]=[CH:29][C:30]=1[N:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1)[C:22]([NH:24][CH:25]([CH3:27])[CH3:26])=[O:23].[I-].C(C[P+](C)(C)C)#N.C(N(CC)C(C)C)(C)C>C(#N)CC>[F:18][C:19]1[CH:20]=[C:21]([CH:28]=[CH:29][C:30]=1[N:31]1[CH2:32][CH2:33][N:34]([CH2:2][C:3]2[CH:12]=[N:11][C:10]3[N:9]4[CH2:13][CH2:14][CH2:15][C@H:8]4[C:7](=[O:16])[NH:6][C:5]=3[CH:4]=2)[CH2:35][CH2:36]1)[C:22]([NH:24][CH:25]([CH3:27])[CH3:26])=[O:23]
Reactant: O=C1Nc2cc(CO)cnc2N2CCC[C@@H]12
Reactant: CC(C)NC(=O)c1ccc(N2CCNCC2)c(F)c1
Agent: C[P+](C)(C)CC#N
Agent: Cl
Agent: [I-]
Solvent: CCC#N
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)NC(=O)c1ccc(N2CCN(Cc3cnc4c(c3)NC(=O)[C@@H]3CCCN43)CC2)c(F)c1
Temperature: 105 °C
Yield: 33.6 %

Procedure:
(S)-3-(hydroxymethyl)-6a,7,8,9-tetrahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-6(5H)-one (100 mg, 0.456 mmol), 3-fluoro-N-isopropyl-4-(piperazin-1-yl)benzamide hydrochloride (138 mg, 0.456 mmol), (cyanomethyl)trimethylphosphonium iodide (166 mg, 0.684 mmol) and N,N-diisopropylethylamine (0.398 ml, 2.281 mmol) were suspended in propiononitrile (Volume: 1.370 ml) and heated in a closed vial at 90-120° C. for 4 h. The reaction mixture became a dark brown solution. It was cooled to room temperature, concentrated in vacuo, dissolved in DMSO (2 mL) and purified using HPLC (basic, 45-95% ACN in water, basic). The fractions were concentrated in vacuo and the resulting solid was recrystallized from water-MeOH (2:1, 6 mL) and dried in vacuum to afford (S)-3-fluoro-N-isopropyl-4-(4-((6-oxo-5,6,6a,7,8,9-hexahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-3-yl)methyl)piperazin-1-yl)benzamide (71.4 mg, 0.153 mmol, 33.6% yield) as a light yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.14 (d, J=6.57 Hz, 6H) 1.82-2.01 (m, 3H) 2.12-2.24 (m, 1H) 2.46-2.50 (m, 4H) 2.98-3.15 (m, 4H) 3.35-3.44 (m, 3H) 3.54-3.64 (m, 1H) 3.92-4.14 (m, 2H) 6.98 (d, J=1.77 Hz, 1H) 7.03 (t, J=8.84 Hz, 1H) 7.56-7.66 (m, 3H) 8.09 (d, J=7.83 Hz, 1H) 10.45 (s, 1H). [M+H] calc'd for C25H31FN6O2, 467; found, 467.