Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][CH:2]([CH2:6][CH2:7][CH2:8][Br:9])[C:3](Br)=[O:4].[C:10]([O:13][CH2:14][CH:15]([NH:21][C:22]([C:24]1[C:29]([I:30])=[C:28]([NH2:31])[C:27]([I:32])=[C:26]([C:33]([NH:35][CH:36]([CH2:42][O:43][C:44](=[O:46])[CH3:45])[CH2:37][O:38][C:39](=[O:41])[CH3:40])=[O:34])[C:25]=1[I:47])=[O:23])[CH2:16][O:17][C:18](=[O:20])[CH3:19])(=[O:12])[CH3:11]>CC(N(C)C)=O>[C:44]([O:43][CH2:42][CH:36]([NH:35][C:33]([C:26]1[C:27]([I:32])=[C:28]([NH:31][C:3](=[O:4])[CH:2]([Br:1])[CH2:6][CH2:7][CH2:8][Br:9])[C:29]([I:30])=[C:24]([C:22]([NH:21][CH:15]([CH2:16][O:17][C:18](=[O:20])[CH3:19])[CH2:14][O:13][C:10](=[O:12])[CH3:11])=[O:23])[C:25]=1[I:47])=[O:34])[CH2:37][O:38][C:39](=[O:41])[CH3:40])(=[O:46])[CH3:45]
Reactant: O=C(Br)C(Br)CCCBr
Reactant: CC(=O)OCC(COC(C)=O)NC(=O)c1c(I)c(N)c(I)c(C(=O)NC(COC(C)=O)COC(C)=O)c1I
Solvent: CC(=O)N(C)C
Product: CC(=O)OCC(COC(C)=O)NC(=O)c1c(I)c(NC(=O)C(Br)CCCBr)c(I)c(C(=O)NC(COC(C)=O)COC(C)=O)c1I
Temperature: 0 °C
Reaction time: 1 h

Procedure:
2,5-Dibromopentanoyl bromide prepared as described in example 8a (15.9 g, 49.3 mmol) was added dropwise to a stirred solution of N,N'-bis[2-(acetyloxy)-1-[(acetyloxy)methyl]ethyl]-5-amino-2,4,6-triiodo-1,3-benzenedicarboxamide (33 g, 37.8 mmol) in dimethylacetamide (250 ml) at 0°. After the addition, the reaction mixture was stirred at 0° for 1 hour, and then at room temperature for 22 hours. The solution was then added slowly dropwise to a well stirred mixture of ice-water (2 L), when a white solid separated out. This was collected by filtration, washed with ice-water (3×50 ml), and dried in vacuo to obtain the crude product (40.1 g, 91.5% pure). Recrystallization from ethyl acetate furnished analytically pure N,N'-bis[2-(acetyloxy)-1-[(acetyloxy)methyl]ethyl]-5-[(2,5-dibromo-1-oxopentyl)amino]-2,4,6-triiodo-1,3-benzenedicarboxamide as an off-white crystalline compound (35.3 g, 84% yield), m.p. 240°-243°.
Reaction SMILES: [F:1][C:2]1([F:29])[CH2:7][CH2:6][CH:5]([CH2:8][NH:9][C:10]([C:12]2[C:13]3[CH:14]=[CH:15][C:16]([C:23]4[CH2:27][CH2:26][C:25](=[O:28])[CH:24]=4)=[N:17][C:18]=3[CH:19]=[CH:20][C:21]=2[Cl:22])=[O:11])[CH2:4][CH2:3]1.C([SiH](CC)CC)C>[Pd]>[F:29][C:2]1([F:1])[CH2:3][CH2:4][CH:5]([CH2:8][NH:9][C:10]([C:12]2[C:13]3[CH:14]=[CH:15][C:16]([CH:23]4[CH2:27][CH2:26][C:25](=[O:28])[CH2:24]4)=[N:17][C:18]=3[CH:19]=[CH:20][C:21]=2[Cl:22])=[O:11])[CH2:6][CH2:7]1
Reactant: O=C1C=C(c2ccc3c(C(=O)NCC4CCC(F)(F)CC4)c(Cl)ccc3n2)CC1
Agent: [Pd]
Agent: CC[SiH](CC)CC
Product: O=C1CCC(c2ccc3c(C(=O)NCC4CCC(F)(F)CC4)c(Cl)ccc3n2)C1

Procedure:
The title compound was synthesized according to the procedure described in example 126 using 6-chloro-2-(3-oxo-cyclopent-1-enyl)-quinoline-5-carboxylic acid (4,4-difluoro-cyclohexylmethyl)-amide, palladium on carbon and triethylsilane. m/z: 421 [M+H]+
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH:7]([N:10]([C@H:29]2[CH2:34][CH2:33][C@H:32]([CH3:35])[CH2:31][CH2:30]2)[C:11]([NH:13][C:14]2[S:15][C:16]([S:19][CH2:20][C:21](=[O:28])[N:22]3[CH2:27]CC[CH2:24][CH2:23]3)=[CH:17][N:18]=2)=[O:12])[CH2:6][CH2:5]1)(=[O:3])[CH3:2].C([N:39]1[CH2:44][CH2:43][CH:42]([N:45]([C@H]2CC[C@H](C)CC2)[C:46](=O)[NH:47][C:48]2SC(SCC(O)=O)=CN=2)CC1)(=O)C.N1(C2N=CC=CN=2)CCNCC1>>[C:1]([N:4]1[CH2:9][CH2:8][CH:7]([N:10]([C@H:29]2[CH2:34][CH2:33][C@H:32]([CH3:35])[CH2:31][CH2:30]2)[C:11]([NH:13][C:14]2[S:15][C:16]([S:19][CH2:20][C:21](=[O:28])[N:22]3[CH2:27][CH2:48][N:47]([C:46]4[N:45]=[CH:42][CH:43]=[CH:44][N:39]=4)[CH2:24][CH2:23]3)=[CH:17][N:18]=2)=[O:12])[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCC(N(C(=O)Nc2ncc(SCC(=O)N3CCCCC3)s2)[C@H]2CC[C@H](C)CC2)CC1
Reactant: CC(=O)N1CCC(N(C(=O)Nc2ncc(SCC(=O)O)s2)[C@H]2CC[C@H](C)CC2)CC1
Agent: c1cnc(N2CCNCC2)nc1
Product: CC(=O)N1CCC(N(C(=O)Nc2ncc(SCC(=O)N3CCN(c4ncccn4)CC3)s2)[C@H]2CC[C@H](C)CC2)CC1

Procedure:
Prepared in a similar manner to 1-(1-acetyl-piperidin-4-yl)-1-(trans-4-methyl-cyclohexyl)-3-[5-(2-oxo-2-piperidin-1-yl-ethylsulfanyl)-thiazol-2-yl]-urea using {2-[3-(1-acetyl-piperidin-4-yl)-3-(trans-4-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-acetic acid and 2-(piperazinyl)pyrimidine.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[C:4]([NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([OH:16])[CH:11]=2)[N:3]=1.C(OCCO)C.[CH3:23][O:24][C:25]1[CH:26]=[C:27]([CH:29]=[CH:30][CH:31]=1)[NH2:28]>>[CH3:1][C:2]1[N:3]=[C:4]([NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([OH:16])[CH:11]=2)[CH:5]=[C:6]([NH:28][C:27]2[CH:29]=[CH:30][CH:31]=[C:25]([O:24][CH3:23])[CH:26]=2)[N:7]=1
Reactant: COc1cccc(N)c1
Reactant: Cc1nc(Cl)cc(Nc2cccc(O)c2)n1
Solvent: CCOCCO
Product: COc1cccc(Nc2cc(Nc3cccc(O)c3)nc(C)n2)c1
Temperature: 130 °C
Reaction time: 5 h

Procedure:
2-methyl-4-chloro-6-(3-hydroxyphenylamino)pyrimidine (0.71 g, 3.0 mmol) was added to a 2-ethoxyethanol (2.0 mL) solution of 3-methoxyaniline (0.37 g, 3.0 mmol) under a nitrogen atmosphere and the reaction mixture stirred for 5 hours at 130° C.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([C:8]2([C:19]3[CH:24]=[CH:23][N:22]=[C:21]([CH:25]([F:27])[F:26])[CH:20]=3)[C:16]3[C:11](=[C:12]([F:17])[CH:13]=[CH:14][CH:15]=3)[C:10]([NH2:18])=[N:9]2)[CH:5]=[CH:4][N:3]=1.[N:28]1[CH:33]=[C:32](B(O)O)[CH:31]=[N:30][CH:29]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].COCCOC.CCO.O>[F:26][CH:25]([F:27])[C:21]1[CH:20]=[C:19]([C:8]2([C:6]3[CH:5]=[CH:4][N:3]=[C:2]([C:32]4[CH:33]=[N:28][CH:29]=[N:30][CH:31]=4)[CH:7]=3)[C:16]3[C:11](=[C:12]([F:17])[CH:13]=[CH:14][CH:15]=3)[C:10]([NH2:18])=[N:9]2)[CH:24]=[CH:23][N:22]=1
Reactant: OB(O)c1cncnc1
Reactant: NC1=NC(c2ccnc(Br)c2)(c2ccnc(C(F)F)c2)c2cccc(F)c21
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: COCCOC
Solvent: CCO
Product: NC1=NC(c2ccnc(-c3cncnc3)c2)(c2ccnc(C(F)F)c2)c2cccc(F)c21
Temperature: 150 °C
Yield: 39.6 %

Procedure:
1-(2-Bromopyridin-4-yl)-1-(2-(difluoromethyl)pyridin-4-yl)-4-fluoro-1H-isoindol-3-amine (64 mg, 0.15 mmol), 5-pyrimidinylboronic acid (23.80 mg, 0.19 mmol), [1,1′-bis (diphenylphosphino)ferrocene]palladium(II) chloride (6.03 mg, 7.39 μmol), cesium carbonate (0.035 mL, 0.44 mmol) and DME:EtOH:water (6:3:1) (3.00 mL) were put in a microwave vial and heated at 150° C. in a microwave reactor for 20 min. The reaction mixture was filtered through a syringe filter and purified by prep-HPLC. The desired fractions were pooled and freeze dried over night to give the title compound (25.7 mg, 39%).
Reaction SMILES: CN(C)C=O.[NH2:6][CH2:7][CH:8]([C:10]1[CH:15]=[C:14]([Cl:16])[C:13]([NH2:17])=[C:12]([Cl:18])[CH:11]=1)[OH:9].[C:19]1([CH2:29][CH2:30][O:31][C:32](=[O:39])[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37]Br)[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[CH:21][CH:20]=1>C(OCC)(=O)C.CO.C(N(CC)CC)C>[NH2:17][C:13]1[C:12]([Cl:18])=[CH:11][C:10]([CH:8]([OH:9])[CH2:7][NH:6][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][C:32]([O:31][CH2:30][CH2:29][C:19]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH:22]=[CH:21][CH:20]=2)=[O:39])=[CH:15][C:14]=1[Cl:16]
Reactant: O=C(CCCCCBr)OCCc1cccc2ccccc12
Reactant: NCC(O)c1cc(Cl)c(N)c(Cl)c1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CO
Product: Nc1c(Cl)cc(C(O)CNCCCCCC(=O)OCCc2cccc3ccccc23)cc1Cl

Procedure:
According to method I (dimethylformamide, 2 hours at 90° C.) from 2-amino-1-(4-amino-3,5-dichlorophenyl)ethanol and {2-(1-naphthyl)ethyl}6-bromohexanoate. Working up by means of chromatography (ethyl acetate/methanol/triethylamine 16:2:1). Recrystallized as the free base from ethyl acetate. Melting point: 60°-61° C.
Reaction SMILES: [N:1]1[CH2:6][CH2:5][CH2:4][N:3]2[C:7](=[O:10])[S:8][CH2:9][C:2]=12.[F:11][C:12]([F:33])([F:32])[C:13]1[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[CH:24][C:14]=1[CH2:15][N:16]1[CH2:21][CH2:20][CH:19]([CH:22]=O)[CH2:18][CH2:17]1.C([O-])(=O)C.[NH2+]1CCCCC1>CC(O)C>[F:33][C:12]([F:11])([F:32])[C:13]1[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[CH:24][C:14]=1[CH2:15][N:16]1[CH2:21][CH2:20][CH:19](/[CH:22]=[C:9]2\[S:8][C:7](=[O:10])[N:3]3[CH2:4][CH2:5][CH2:6][N:1]=[C:2]\23)[CH2:18][CH2:17]1
Reactant: O=CC1CCN(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)CC1
Reactant: O=C1SCC2=NCCCN12
Agent: C1CC[NH2+]CC1
Agent: CC(=O)[O-]
Solvent: CC(C)O
Product: O=c1s/c(=C\C2CCN(Cc3ccc(C(F)(F)F)cc3C(F)(F)F)CC2)c2n1CCCN=2
Temperature: 60 °C
Reaction time: 8 h
Yield: 75.3 %

Procedure:
To a solution of 2,3,4,8-tetrahydro[1,3]thiazolo[3,4-a]pyrimidin-6-one (0.469 g) and 1-[2,4-bis(trifluoromethyl)benzyl]piperidine-4-carbaldehyde (1.12 g) in 2-propanol (10 mL) was added piperidinium acetate (0.479 g) at room temperature. The reaction mixture was stirred at 60° C. overnight, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane) and recrystallized from heptane to give the title compound (1.08 g).
Reaction SMILES: [CH2:1]([NH:5][C:6](=[O:25])[C:7]([CH3:24])([C:9]1[CH:14]=[CH:13][C:12](B2OC(C)(C)C(C)(C)O2)=[CH:11][CH:10]=1)[CH3:8])[CH:2]([CH3:4])[CH3:3].C([O-])([O-])=O.[K+].[K+].[CH3:32][N:33]1[CH:37]=[CH:36][CH:35]=[C:34]1Br>COCCOC.O.[Cl-].[Na+].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>[CH2:1]([NH:5][C:6](=[O:25])[C:7]([CH3:8])([C:9]1[CH:10]=[CH:11][C:12]([C:34]2[N:33]([CH3:32])[CH:37]=[CH:36][CH:35]=2)=[CH:13][CH:14]=1)[CH3:24])[CH:2]([CH3:3])[CH3:4]
Reactant: Cn1cccc1Br
Reactant: CC(C)CNC(=O)C(C)(C)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1
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: [Cl-]
Solvent: COCCOC
Solvent: O
Product: CC(C)CNC(=O)C(C)(C)c1ccc(-c2cccn2C)cc1
Temperature: 85 °C
Reaction time: 8 h

Procedure:
To a solution of N-isobutyl-2-methyl-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propanamide (example 23a) (19.04 g, 55.14 mmol), K2CO3 (22.86 g, 165.4 mmol), and N-methyl-2-bromopyrrole (7.50 g, 93.74 mmol) in DME/H2O (4/1, 300 mL) was added Pd(PPh3)4 (3.20 g, 2.76 mmol) at RT under argon and the reaction mixture was stirred at 85° C. overnight. After it was cooled down to room temperature, the reaction mixture was diluted with brine, and extracted with EtOAc (3×). The combined organic layers were washed with brine, and dried over Na2SO4. After evaporation of the solvent under reduced pressure, the residue was purified twice by chromatography on silica gel eluting with EtOAc/Hexanes (1/9) to give the title compound as off-white white solid, which was further purified by recrystallization from hexanes, and dried under vacuum overnight. mp: 59-60° C. 1H NMR (400 MHz, DMSO-d6) δ 7.35 (d, J=7.2 Hz, 2H), 7.31 (d, J=7.2 Hz, 2H), 6.79 (m, 1H), 6.09 (m, 1H), 6.01 (m, 1H), 3.60 (s, 3H), 2.82 (t, J=6.4 Hz, 2H), 1.7 (m, 1H), 1.44 (s, 6H), 0.2 (d, J=7.2 Hz, 6H). MS 299 (MH+).
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]([NH:8][CH:9]1[C:18]2[C:13](=[N:14][C:15]([C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][C:27]=3[Cl:33])=[C:16]([C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=3)[CH:17]=2)[O:12][C:11]([CH3:35])([CH3:34])[CH2:10]1)=[O:7])=[O:4].[H-].[Na+]>CS(C)=O.CCOC(C)=O>[Cl:25][C:22]1[CH:21]=[CH:20][C:19]([C:16]2[CH:17]=[C:18]3[CH:9]([N:8]4[CH2:2][C:3](=[O:4])[NH:5][C:6]4=[O:7])[CH2:10][C:11]([CH3:34])([CH3:35])[O:12][C:13]3=[N:14][C:15]=2[C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][C:27]=2[Cl:33])=[CH:24][CH:23]=1
Reactant: CC1(C)CC(NC(=O)NC(=O)CCl)c2cc(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3Cl)nc2O1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CC1(C)CC(N2CC(=O)NC2=O)c2cc(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3Cl)nc2O1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The product obtained in Step A (127 mg, 0.23 mmol) was dissolved in DMSO (2 mL). NaH (20 mg, 0.51 mmol) was added and the reaction was stirred at rt for 1 h. The reaction was diluted with EtOAc and washed with a saturated NaHCO3 solution, 10% NaHSO4, brine, dried (Na2SO4), filtered and concentrated The residue was purified by flash chromatography on silica gel gradient eluted with 0-70% EtOAc in hexane to afford Example 113. Further purification on an AD column, eluting with 12% IPA/heptane provided the two pure enantiomers indicated below:
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([CH:5]=[CH:6]1)[CH:3]([C:8]([OH:10])=[O:9])[CH2:2]2.C([O-])(O)=O.[Na+].[Br:16]Br>O>[Br:16][CH:6]1[CH:5]2[O:9][C:8](=[O:10])[CH:3]3[CH2:2][CH:1]1[CH2:7][CH:4]23
Reactant: BrBr
Reactant: O=C(O)C1CC2C=CC1C2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: O=C1OC2C(Br)C3CC1C2C3
Reaction time: 1 h
Yield: 67.7 %

Procedure:
To a solution of bicyclo[2.2.1]hept-5-ene-3-carboxylic acid (25.0 mL, 204.3 mmol) in NaHCO3 (51.5 g, 612.9 mmol) in water was added bromine (32.7 g, 204.3 mmol) dropwise at 0° C. The solution was stirred for 1 hour and extracted with ether, and the organic phase was washed successively with 1 N Na2S2SO3 solution and brine, and the organic phase was then dried (Na2SO4), filtered and concentrated in vacuo to afford 30 g of crude product that was used without further purification.
Reaction SMILES: C[N:2](/[CH:4]=[C:5]1\[C:6](=O)[C:7]2[S:11][C:10]([CH3:12])=[N:9][C:8]=2[CH2:13][CH2:14]\1)[CH3:3].[CH3:16][O:17][C:18]1[CH:30]=[CH:29][C:21]([CH2:22][N:23]2C(N)=[CH:26][CH:25]=[N:24]2)=[CH:20][CH:19]=1.FC(F)(F)C(O)=O>O>[CH3:16][O:17][C:18]1[CH:30]=[CH:29][C:21]([CH2:22][N:23]2[C:3]3[N:2]=[CH:4][C:5]4[CH2:14][CH2:13][C:8]5[N:9]=[C:10]([CH3:12])[S:11][C:7]=5[C:6]=4[C:26]=3[CH:25]=[N:24]2)=[CH:20][CH:19]=1
Reactant: COc1ccc(Cn2nccc2N)cc1
Reactant: Cc1nc2c(s1)C(=O)/C(=C\N(C)C)CC2
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(Cn2ncc3c4c(cnc32)CCc2nc(C)sc2-4)cc1
Temperature: 100 °C
Yield: 13.1 %

Procedure:
To a mixture of (Z)-6-((dimethylamino)methylene)-2-methyl-5,6-dihydrobenzo[d]thiazol-7(4H)-one (3.5 g, 16.9 mmol) and 1-(4-methoxybenzyl)-1H-pyrazol-5-amine (3.5 g, 17.2 mmol) was added trifluoroacetic acid (2.3 mL, 29.2 mmol). The reaction mixture was heated at 100° C. for 2 hours. The reaction mixture was then poured into ice-cooled water (100 mL) and extracted with dichloromethane (3×75 mL). The combined organic extracts were dried using sodium sulfate and concentrated under reduced pressure to give a dark residue. The crude product was purified by flash column chromatography (SiO2, gradient from 100% chloroform to 2% methanol in chloroform) to a residue, which was further purified by crystallization from methanol and isopropanol to give the pure desired product (0.8 g, 19%) as a solid. 1H NMR (CDCl3, 400 MHz): δ 7.86 (s, 1H), 7.76 (s, 1H), 7.36 (d, J=8.0 Hz, 2H), 6.82 (d, J=8.0 Hz, 2H), 5.59 (s, 2H), 3.75 (s, 3H), 3.17 (t, J=6.8 Hz, 2H), 3.09 (t, J=6.8 Hz, 2H), 2.77 (s, 3H); LCMS [M+H]: 363.
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([CH:19]=[CH:20][CH:21]=1)[O:11][C:12]1[CH:13]=[C:14]([OH:18])[CH:15]=[CH:16][CH:17]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[O-].[Na+].[I-].[K+].Br[CH:28]([C:33]1[CH:38]=[CH:37][C:36]([O:39][C:40]2[CH:45]=[CH:44][C:43]([Cl:46])=[CH:42][CH:41]=2)=[CH:35][CH:34]=1)[C:29]([O:31][CH3:32])=[O:30]>CO.C1C=CC=CC=1.O>[CH3:32][O:31][C:29](=[O:30])[CH:28]([O:18][C:14]1[CH:15]=[CH:16][CH:17]=[C:12]([O:11][C:10]2[CH:19]=[CH:20][CH:21]=[C:8]([O:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH:9]=2)[CH:13]=1)[C:33]1[CH:34]=[CH:35][C:36]([O:39][C:40]2[CH:45]=[CH:44][C:43]([Cl:46])=[CH:42][CH:41]=2)=[CH:37][CH:38]=1
Reactant: COC(=O)C(Br)c1ccc(Oc2ccc(Cl)cc2)cc1
Reactant: Oc1cccc(Oc2cccc(Oc3ccccc3)c2)c1
Agent: C[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CO
Solvent: c1ccccc1
Product: COC(=O)C(Oc1cccc(Oc2cccc(Oc3ccccc3)c2)c1)c1ccc(Oc2ccc(Cl)cc2)cc1

Procedure:
To a solution of 6.96 g of m-(m-phenoxyphenoxy)phenol, 1.19 g of sodium methoxide and 50 mg of potassium iodide in 40 ml of methanol is added 7.11 g of methyl α-bromo-α-(p-(p-chlorophenoxy)phenyl]acetate in 10 ml of benzene. The mixture is refluxed for 20 hours, poured into ice and water and extracted with chloroform. The chloroform extracts are washed with 10% potassium carbonate and with water. The extract is dried over magnesium sulfate and concentrated under vacuum to given an oil. Filtration once through silica gel (chloroform solvent) and again through silica gel with benzene as solvent gives the product as an oil.
Reaction SMILES: [O:1]=[C:2]1[NH:7][CH:6]=[C:5]([CH2:8][C:9]2[C:10](=[O:16])[NH:11][C:12](=[S:15])[NH:13][CH:14]=2)[CH:4]=[CH:3]1.[OH-].[K+].[CH3:19]I>C(O)C>[CH3:19][S:15][C:12]1[NH:13][CH:14]=[C:9]([CH2:8][C:5]2[CH:4]=[CH:3][C:2](=[O:1])[NH:7][CH:6]=2)[C:10](=[O:16])[N:11]=1
Reactant: CI
Reactant: O=c1ccc(Cc2c[nH]c(=S)[nH]c2=O)c[nH]1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CSc1nc(=O)c(Cc2ccc(=O)[nH]c2)c[nH]1
Temperature: 25 °C
Reaction time: 1 h
Yield: 15.9 %

Procedure:
A suspension of 5-(6-oxo-1,6-dihydro-pyridin-3-ylmethyl)-2-thioxo-2,3-dihydro-1H-pyrimidin-4-one (130 mg, 0.55 mmol, 1 eq) and KOH, 85% (1.2 eq, 44 mg) in 5 ml of absolute ethanol was stirred with ultrasound bath at room temperature for 1 hour. In the suspension was then added MeI (1.2 eq, 42 μl) dropwise and the mixture was stirred in a sealed vial at 70° C. (temperature on display of heating device) for 20 hours (overnight). The solvent was then evaporated. In the crude was added 10 ml of water and pH of the solution was adjusted to 7-7.5. The resulting suspension was filtered over filter paper. The filtrate was washed with chloroform (3 times, 30 ml was used in total). pH of the water layer was adjusted to 5-5.5 and using ultrasound bath precipitate was formed. The precipitate was collected, it was dried and obtained was 2-methylsulfanyl-5-(6-oxo-1,6-dihydro-pyridin-3-ylmethyl)-1H-pyrimidin-4-one (22 mg, yield=15.9%, purity=95%) in form of white powder. MS: [M+H]+=250.18 1H NMR (300 MHz; DMSO-d6) δ/ppm 2.46 (s, 3H), 3.31 (s, 2H), 6.25 (d, J=9.37 Hz, 1H), 7.19 (d, J=2.06 Hz, 1H), 7.35 (dd, J=9.37 Hz, J=2.45 Hz, 1H), 7.77 (s, 1H)
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][CH:10]=[C:11]([CH3:13])[CH3:12])=[C:4]([C:14]([CH3:17])([CH3:16])[CH3:15])[CH:3]=1.[BH4-].[Na+].C1C[O:23]CC1.O>C1COCC1.[OH-].[Na+].[Hg](OC(C)=O)OC(C)=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][CH2:10][C:11]([OH:23])([CH3:12])[CH3:13])=[C:4]([C:14]([CH3:17])([CH3:16])[CH3:15])[CH:3]=1
Reactant: CC(C)=CCOc1ccc(Br)cc1C(C)(C)C
Reactant: C1CCOC1
Agent: CC(=O)O[Hg]OC(C)=O
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Product: CC(C)(O)CCOc1ccc(Br)cc1C(C)(C)C
Temperature: 25 °C
Reaction time: 4 h
Yield: 67 %

Procedure:
To a yellow suspension of Hg(OAc)2 (6.36 g, 19.94 mmol, 1.0 equiv) in THF/water (25 mL/ 30 mL) is added 4-bromo-2-tert-butyl-1-(3-methyl-2-butenyloxy)benzene (5.93 g, 19.94 mmol) in THF (5 mL) dropwise and stirred at room temperature for 4 h. To the resulting pale yellow solution is added NaOH (15 mL, 3M) followed by NaBH4 (0.75 g, 19.94 mmol, 1.0 equiv) in NaOH (5 mL, 3M). The resulting ash colored suspension is stirred at room temperature for 30 min, diluted with hexanes, and washed with water, saturated aq. NH4Cl and brine. The aqueous layers are extracted with hexanes; the combined organic layers are dried (MgSO4), filtered and concentrated. The residue is purified by flash column chromatography on silica (hexanes/EtOAc; 101->311) to give the title compound (4.21 g, 67%) as an oil.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7](Br)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[Br:15][C:16]1[C:17]([CH3:27])=[CH:18][C:19]([OH:26])=[C:20]([CH:25]=1)[C:21]([O:23][CH3:24])=[O:22].C(OCC)(=O)C>CN(C)C=O.O>[Br:15][C:16]1[C:17]([CH3:27])=[CH:18][C:19]([O:26][CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[C:20]([CH:25]=1)[C:21]([O:23][CH3:24])=[O:22]
Reactant: COC(=O)c1cc(Br)c(C)cc1O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1cc(Br)c(C)cc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
Potassium carbonate (0.85 g, 6.12 mmol) and benzyl bromide (0.53 ml, 4.49 mmol) were added to a solution of methyl 5-bromo-2-hydroxy-4-methylbenzoate (1 g, 4.08 mmol) in N,N-dimethylformamide (10 ml). The mixture was stirred at room temperature for 72 hours. Ethyl acetate (20 ml) and water (20 ml) were added and the organic layer separated, washed with water (3×10 ml), dried (MgSO4) and the solvent removed in vacuo. Purification by column chromatography (10% ethyl acetate/hexanes) yielded the title compound as an oil. 1.35 g.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[CH:5]([NH:9][C:10](=[O:12])[CH3:11])[CH2:6][C:7]#[CH:8])[CH3:2].[F:14][C:15]1[C:16](I)=[C:17]2[C:21](=[CH:22][CH:23]=1)[NH:20][C:19](=[O:24])/[C:18]/2=[CH:25]\[C:26]1[NH:30][CH:29]=[N:28][C:27]=1[CH3:31]>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.CN(C=O)C.CCN(CC)CC>[CH2:1]([O:3][C:4](=[O:13])[CH:5]([NH:9][C:10](=[O:12])[CH3:11])[CH2:6][C:7]#[C:8][C:16]1[C:15]([F:14])=[CH:23][CH:22]=[C:21]2[C:17]=1/[C:18](=[CH:25]/[C:26]1[NH:30][CH:29]=[N:28][C:27]=1[CH3:31])/[C:19](=[O:24])[NH:20]2)[CH3:2]
Reactant: C#CCC(NC(C)=O)C(=O)OCC
Reactant: Cc1nc[nH]c1/C=C1\C(=O)Nc2ccc(F)c(I)c21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)C(CC#Cc1c(F)ccc2c1/C(=C/c1[nH]cnc1C)C(=O)N2)NC(C)=O

Procedure:
Using Method C above, 2-(acetylamino)-4-pentynoic acid ethyl ester (92.6 mg, 0.51 mmol) (Bachem) was coupled with (Z)-1,3-dihydro-5-fluoro-4-iodo-3-[(4-methyl-1H-imidazol-5-yl)methylene]-2H-indol-2-one (Starting Material 3 supra) (75 mg, 0.203 mmol) using (Ph3P)4Pd (23.5 mg) and Cul (4 mg) as catalyst in DMF (3 mL) and Et3N (3 mL) as solvent at 80° C. for 5 h to give rac-(Z)-2-(acetylamino)-5-[5-fluoro-2,3,dihydro-3-[(4-methyl-1H-imidazol-5-yl)methylene]-2-oxo-1H-indol-4-yl]-4-pentynoic acid ethyl ester. (Yield 70 mg, 81%).
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:26])[N:9]3[CH2:25][CH2:24][CH2:23][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]3[S:17][CH:18]=[C:19]([CH2:21]Cl)[N:20]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH2:27]([NH:30][CH2:31][CH:32]=[CH2:33])[CH:28]=[CH2:29]>O1CCCC1>[Cl:1][C:2]1[C:7]2[C:8](=[O:26])[N:9]3[CH2:25][CH2:24][CH2:23][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]3[S:17][CH:18]=[C:19]([CH2:21][N:30]([CH2:31][CH:32]=[CH2:33])[CH2:27][CH:28]=[CH2:29])[N:20]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: C=CCNCC=C
Reactant: O=C1c2c(Cl)cccc2-n2cnc(-c3nc(CCl)cs3)c2[C@@H]2CCCN12
Solvent: C1CCOC1
Product: C=CCN(CC=C)Cc1csc(-c2ncn3c2[C@@H]2CCCN2C(=O)c2c(Cl)cccc2-3)n1
Reaction time: 8 h
Yield: 55.8 %

Procedure:
A solution of 0.81 g (0.002 mol) of (S)-8-chloro-1-(4-chloromethyl-thiazol-2-yl)-11,12,13,13a-tetrahydro-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepin-9-one in 5 ml of tetrahydrofuran was treated with 3 ml (0.024 mol) of diallylamine and stirred at 50° for 8 hrs. All volatiles were removed in a water-jet vacuum and the residue was chromatographed over silica gel with methylene chloride/methanol 98:2 as the eluent. After recrystallization from diethyl ether there was obtained 0.52 g (55%) of (S)-8-chloro-1-(4-diallylaminomethyl-thiazol-2-yl)-11,12,13,13a-tetrahydro-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepin-9-one in the form of white crystals; m.p. 186-187° and [α]D20 =-67.5° (MeOH, c=1%).
Reaction SMILES: [OH-].[Na+].[CH2:3]([O:5][C:6]1[CH:7]=[C:8]([CH:13]=[CH:14][C:15]=1[C:16]1[CH:17]=[N:18][N:19]([CH3:21])[CH:20]=1)[C:9]([O:11]C)=[O:10])[CH3:4].O.Cl>CCOC(C)=O.CCCCCC>[CH2:3]([O:5][C:6]1[CH:7]=[C:8]([CH:13]=[CH:14][C:15]=1[C:16]1[CH:17]=[N:18][N:19]([CH3:21])[CH:20]=1)[C:9]([OH:11])=[O:10])[CH3:4]
Reactant: CCOc1cc(C(=O)OC)ccc1-c1cnn(C)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: O
Product: CCOc1cc(C(=O)O)ccc1-c1cnn(C)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Aqueous 5 N sodium hydroxide solution (0.6 mL, 3.0 mmol) was added to a methano chloroform (1/1) solution (5 mL) of methyl 3-ethoxy-4-(1-methylpyrazol-4-yl)benzoate (149 mg, 0.57 mmol), and stirred overnight at room temperature. 5 N hydrochloric acid water (0.6 mL, 3.0 mmol) was added to the reaction liquid. The aqueous layer was extracted twice with chloroform, washed with saturated saline water, and dried with magnesium sulfate. The solution was filtered and concentrated under reduced pressure to obtain the title compound as a white solid.