Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[C:12]([O:15][CH2:16][CH:17]1[CH2:20][CH2:19]C1)[CH:11]=[CH:10][CH:9]=2)=[O:5])C.[OH-].[K+].CCO>>[CH:17]1([CH2:16][O:15][C:12]2[CH:11]=[CH:10][CH:9]=[C:8]3[C:13]=2[CH:14]=[C:6]([C:4]([OH:3])=[O:5])[NH:7]3)[CH2:20][CH2:19]1
Reactant: CCOC(=O)c1cc2c(OCC3CCC3)cccc2[nH]1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1cc2c(OCC3CC3)cccc2[nH]1
Reaction time: 24 h

Procedure:
The 4-cyclobutylmethoxy-1H-indole-2-carboxylic acid ethyl ester 78 obtained above is mixed with a 2M-solution of KOH in EtOH (16.9 ml, 33.8 mmol) and stirred for 24 hours. The solvent is then evaporated and the residue is partitioned between water and DCM. The water layer is acidified with HCl and extracted twice with EtOAc. The combined organic layers are washed with brine, dried over anhydrous sodium sulfate, filtered and evaporated to give a white powder.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]([Br:11])=[N:8][C:7]=1[CH3:12])=[O:5])[CH3:2].[Br:13]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]([Br:11])=[N:8][C:7]=1[CH2:12][Br:13])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1sc(Br)nc1C
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)c1sc(Br)nc1CBr
Temperature: 25 °C
Yield: 59.8 %

Procedure:
A mixture of 2-Bromo-4-methyl-thiazole-5-carboxylic acid ethyl ester (5.67 g, 22.68 mmol), N-bromosuccinimide (4.44 g, 24.95 mmol) and benzoyl peroxide (275 mg, 1.13 mmol) in carbon tetrachloride (25 mL) was refluxed for 16 h before it was cooled to room temperature and partitioned between dichloromethane and water, the organic layer was washed with saturated aqueous sodium bicarbonate solution, brine, dried over anhydrous sodium sulfate and concentrated in vacuo to give the title compound as a white solid (4.46 g): MS: (+) m/z 337.80, 329.93, 331.93 (M+1, 79Br/81Br).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][NH:5][C:6]=1[C:7]1[C:12]([F:13])=[CH:11][CH:10]=[C:9]([N+:14]([O-:16])=[O:15])[C:8]=1[F:17].[CH3:18]I>ClCCl.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.[OH-].[Na+]>[Br:1][C:2]1[C:6]([C:7]2[C:12]([F:13])=[CH:11][CH:10]=[C:9]([N+:14]([O-:16])=[O:15])[C:8]=2[F:17])=[N:5][N:4]([CH3:18])[CH:3]=1
Reactant: O=[N+]([O-])c1ccc(F)c(-c2[nH]ncc2Br)c1F
Reactant: CI
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: ClCCl
Product: Cn1cc(Br)c(-c2c(F)ccc([N+](=O)[O-])c2F)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 57.5 %

Procedure:
To a mixture of 4-bromo-5-(2,6-difluoro-3-nitrophenyl)-1H-pyrazole (0.88 g, 2.9 mmol) and methyl iodide (2 mL, 32 mmol) in dichloromethane (20 mL), tetrabutylammonium bromide (0.32 g, 1 mmol) in 7 N sodium hydroxide (20 mL) was added and the mixture was rapidly stirred at room temperature for 3 h. The phases were separated and the organic layer was washed with water, dried over anhydrous sodium sulfate and concentrated. The crude residue was purified by flash chromatography (eluant: dichloromethane/petroleum ether 2:1). The title compound, mixture of the two regioisomers, was obtained as a waxy solid (0.53 g, 57%).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:10]2[C:15]([F:16])=[CH:14][C:13]([C:17]([OH:20])([CH3:19])[CH3:18])=[CH:12][C:11]=2[F:21])=[CH:5][C:6]=1[C:7]([NH2:9])=[O:8].Cl[C:23]1[N:28]=[C:27]2[N:29]=[C:30]([CH:32]([OH:34])[CH3:33])[NH:31][C:26]2=[CH:25][CH:24]=1>>[F:16][C:15]1[CH:14]=[C:13]([C:17]([OH:20])([CH3:18])[CH3:19])[CH:12]=[C:11]([F:21])[C:10]=1[C:4]1[S:3][C:2]([NH:1][C:23]2[N:28]=[C:27]3[N:29]=[C:30]([CH:32]([OH:34])[CH3:33])[NH:31][C:26]3=[CH:25][CH:24]=2)=[C:6]([C:7]([NH2:9])=[O:8])[CH:5]=1
Reactant: CC(C)(O)c1cc(F)c(-c2cc(C(N)=O)c(N)s2)c(F)c1
Reactant: CC(O)c1nc2nc(Cl)ccc2[nH]1
Product: CC(O)c1nc2nc(Nc3sc(-c4c(F)cc(C(C)(C)O)cc4F)cc3C(N)=O)ccc2[nH]1

Procedure:
The title compound was prepared as described in Example 1 Step 5 using 2-amino-5-[2,6-difluoro-4-(1-hydroxy-1-methylethyl)phenyl]thiophene-3-carboxamide (150 mg, 0.48 mmol), and 1-(5-chloro-1H-imidazo[4,5-b]pyridin-2-yl)ethanol (95 mg, 0.48 mmol) as starting materials.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:7]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)[N:6]=[C:5]([CH2:18][OH:19])[CH:4]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[CH3:1][O:2][C:3]1[N:7]([C:8]2[CH:9]=[CH:10][C:11]([C:14]([F:17])([F:15])[F:16])=[CH:12][CH:13]=2)[N:6]=[C:5]([CH:18]=[O:19])[CH:4]=1
Reactant: COc1cc(CO)nn1-c1ccc(C(F)(F)F)cc1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: COc1cc(C=O)nn1-c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A 250 mL round-bottomed flask was charged with (5-methoxy-1-(4-(trifluoromethyl)phenyl)-1H-pyrazol-3-yl)methanol 73 (4.60 g, 16.9 mmol) and 50 mL of CH2Cl2. To this solution was added Dess-Martin periodinane (8.96 g, 21.1 mmol) and the mixture was stirred at room temperature for 1.5 h. The reaction mixture was quenched with saturated aqueous Na2S2O3, extracted with CH2Cl2, dried, and concentrated. Purification by via column chromatography on silica gel (0% to 20% EtOAc in hexanes) to give 5-methoxy-1-(4-(trifluoromethyl)phenyl)-1H-pyrazole-3-carbaldehyde 74.
Reaction SMILES: C(N(C(C)C)C(C)C)C.[NH2:10][C:11]1[CH:12]=[CH:13][C:14]([F:41])=[C:15]([C@:17]23[CH2:25][O:24][C@H:23]([C:26]([F:29])([F:28])[F:27])[C@H:22]2[C:21](=[O:30])[N:20]([CH2:31][CH3:32])[C:19]([NH:33][C:34](=[O:40])[O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[N:18]3)[CH:16]=1.[F:42][CH:43]([F:53])[C:44]1[N:45]=[CH:46][C:47]([C:50](O)=[O:51])=[N:48][CH:49]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2C=CC=CC=2N=N1>C(Cl)Cl>[F:53][CH:43]([F:42])[C:44]1[N:45]=[CH:46][C:47]([C:50]([NH:10][C:11]2[CH:12]=[CH:13][C:14]([F:41])=[C:15]([C@:17]34[CH2:25][O:24][C@H:23]([C:26]([F:29])([F:27])[F:28])[C@H:22]3[C:21](=[O:30])[N:20]([CH2:31][CH3:32])[C:19]([NH:33][C:34](=[O:40])[O:35][C:36]([CH3:37])([CH3:39])[CH3:38])=[N:18]4)[CH:16]=2)=[O:51])=[N:48][CH:49]=1
Reactant: O=C(O)c1cnc(C(F)F)cn1
Reactant: CCN1C(=O)[C@@H]2[C@@H](C(F)(F)F)OC[C@]2(c2cc(N)ccc2F)N=C1NC(=O)OC(C)(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCN1C(=O)[C@@H]2[C@@H](C(F)(F)F)OC[C@]2(c2cc(NC(=O)c3cnc(C(F)F)cn3)ccc2F)N=C1NC(=O)OC(C)(C)C
Reaction time: 16 h
Yield: 91.1 %

Procedure:
N-Ethyl-N-(propan-2-yl)propan-2-amine (190 μL, 1.1 mmol) was added to a stirred mixture of tert-butyl ((4aS,5S,7aS)-7a-(5-amino-2-fluorophenyl)-3-ethyl-4-oxo-5-(trifluoromethyl)-3,4,4a,5,7,7a-hexahydrofuro[3,4-d]pyrimidin-2-yl)carbamate (100 mg, 0.21 mmol), 5-(difluoromethyl)pyrazine-2-carboxylic acid (57 mg, 0.33 mmol) and (1H-benzotriazol-1-yloxy)(tripyrrolidin-1-yl)phosphonium hexafluorophosphate (170 mg, 0.33 mmol) in dry DCM (1 mL) at RT under nitrogen. The reaction was stirred at this temperature for 16 h, and then partitioned between DCM and NaHCO3 (aq.). The aqueous layer was extracted with DCM (×2). The combined extracts were dried by passing through a hydrophobic frit and then evaporated. The residue was purified by column chromatography (normal phase, 10 g, Biotage SNAP cartridge KP-Sil, 12 mL per min, gradient 5% to 30% EtOAc in n-hexane) to give the title compound (118 mg, cream foam). 1H NMR (400 MHz, CDCl3-d) δ ppm 1.14 (t, J=7.07 Hz, 3H) 1.56 (s, 9H) 3.96-4.15 (m, 3H) 4.39 (d, J=9.60 Hz, 1H) 4.50 (dd, J=9.73, 2.91 Hz, 1H) 4.53-4.62 (m, 1H) 6.81 (t, J=54.60 Hz, 1H) 7.22 (dd, J=10.74, 8.97 Hz, 1H) 7.76 (dd, J=6.69, 2.65 Hz, 1H) 7.79-7.84 (m, 1H) 8.93 (s, 1H) 9.52 (s, 1H) 9.65 (s, 1H) 10.64 (s, 1H).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([S:11](Cl)(=[O:13])=[O:12])=[C:7]([F:15])[CH:6]=1)(=[O:3])[CH3:2].[NH2:16][C:17]1[CH:18]=[CH:19][C:20]2[CH2:24][O:23][B:22]([OH:25])[C:21]=2[CH:26]=1.C(N(CC)CC)C.Cl>CN(C)C=O>[F:15][C:7]1[CH:6]=[C:5]([NH:4][C:1](=[O:3])[CH3:2])[CH:10]=[CH:9][C:8]=1[S:11](=[O:13])(=[O:12])[NH:16][C:17]1[CH:18]=[CH:19][C:20]2[CH2:24][O:23][B:22]([OH:25])[C:21]=2[CH:26]=1
Reactant: CC(=O)Nc1ccc(S(=O)(=O)Cl)c(F)c1
Reactant: Nc1ccc2c(c1)B(O)OC2
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(=O)Nc1ccc(S(=O)(=O)Nc2ccc3c(c2)B(O)OC3)c(F)c1
Yield: 73.8 %

Procedure:
A solution of 4-acetamido-2-fluorobenzene-1-sulfonyl chloride (1.47 g, 5.84 mmol) and 6-aminobenzo[c][1,2]oxaborol-1(3H)-ol (0.870 g, 5.84 mmol), triethylamine (8.2 mL, 58.4 mmol), and N,N-dimethylformamide (30 mL) was stirred for one hour at room temperature. The solution was then made to pH 5 using 6 N hydrochloric acid. The solution was then extracted using ethyl acetate and water. The organic layer was washed five times with water, and then washed with brine. The organic layer was dried over sodium sulfate and filtered. The solvent was removed under reduced pressure to give N-(3-fluoro-4-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)sulfamoyl)phenyl)acetamide (1.57 g, 74% yield). 1H NMR (400 MHz, DMSO-d6) δ (ppm) 2.04 (s, 3H), 4.85 (s, 2H), 7.17 (dd, J=2.1 Hz, J=8.2 Hz, 1H), 7.24 (d, J=8.2 Hz, 1H), 7.30 (dd, J=1.8 Hz, J=8.7 Hz, 1H), 7.45 (d, J=1.7 Hz, 1H), 7.65-7.70 (m, 2H), 9.19 (s, 1H), 10.41 (s, 1H), 10.44 (s, 1H)
Reaction SMILES: Br[C:2]1[C:3]([C:19](=[O:21])[NH2:20])=[C:4]2[CH2:9][N:8]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:7][CH2:6][N:5]2[C:17]=1[Cl:18].[C:22]([C:24]1[CH:25]=[C:26](B(O)O)[CH:27]=[CH:28][CH:29]=1)#[N:23].O.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCCC1.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].ClCCl>[C:19]([C:3]1[C:2]([C:28]2[CH:27]=[CH:26][CH:25]=[C:24]([C:22]#[N:23])[CH:29]=2)=[C:17]([Cl:18])[N:5]2[CH2:6][CH2:7][N:8]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:9][C:4]=12)(=[O:21])[NH2:20]
Reactant: N#Cc1cccc(B(O)O)c1
Reactant: CC(C)(C)OC(=O)N1CCn2c(Cl)c(Br)c(C(N)=O)c2C1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCn2c(Cl)c(-c3cccc(C#N)c3)c(C(N)=O)c2C1
Temperature: 100 °C
Reaction time: 6 h
Yield: 53.5 %

Procedure:
To a solution under nitrogen of 6.50 g (17.2 mmol) of tert-butyl 7-bromo-8-carbamoyl-6-chloro-3,4-dihydropyrrolo[1,2-a]pyrazine-2(1H)-carboxylate in 200 ml of tetrahydrofuran are added 2.52 g (17.2 mmol) of 3-cyanophenylboronic acid (CAS 150255-96-2), 10 ml of water, 16.8 g (52.4 mmol) of caesium carbonate and 1.68 g (2.06 mmol) of a complex of 1,1′-bis(diphenylphosphino)ferrocenedichloropalladium (II) and dichloromethane (PdCl2(dppf).CH2Cl2—CAS 95464-05-4). The mixture is stirred for 6 hours at 100° C. and then for 15 hours at 80° C., then cooled to room temperature and filtered through Celite™. The Celite is rinsed with 200 ml of ethyl acetate and 30 ml of water are added to the combined filtrates. The organic phase is separated out by settling, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue obtained is chromatographed on a column of silica gel, eluting with a mixture of 2 to 50% ethyl acetate in dichloromethane, to give 3.69 g of tert-butyl 8-carbamoyl-6-chloro-7-(3-cyanophenyl)-3,4-dihydropyrrolo[1,2-a]pyrazine-2(1H)-carboxylate in the form of a white solid after recrystallization from ethyl acetate and drying at 60° C. under reduced pressure.
Reaction SMILES: [C:1](=[O:6])([O:3][CH2:4][CH3:5])[NH2:2].[H-].[Na+].[C:9](Cl)(=[O:13])[C:10]([CH3:12])=[CH2:11]>CC1C=CC=CC=1C>[C:9]([NH:2][C:1](=[O:6])[O:3][CH2:4][CH3:5])(=[O:13])[C:10]([CH3:12])=[CH2:11]
Reactant: C=C(C)C(=O)Cl
Reactant: CCOC(N)=O
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1C
Product: C=C(C)C(=O)NC(=O)OCC
Temperature: 50 °C
Reaction time: 3 h
Yield: 38.9 %

Procedure:
To the solution of 8.9 g of ethyl carbamate in 50 g of o-xylene, a slurry of 2.2 g of NaH in 20 g of xylene was added dropwise in 30 minutes, followed by stirring for additional 3 hours at 50° C. Then a solution of 10.5 g of methacryloyl chloride in 30 g of xylene was added dropwise to the reaction mixture and the solution was stirred for 1 hour at 60° C. The resultant white precipitate were filtered off and the filtrate was concentrated. The residue was subjected to column chromatography for purification, thereby obtaining 6.1 g of ethyl N-methacryloylcarbamate.
Reaction SMILES: C(OC([NH:11][CH:12]1[CH2:15][CH:14]([C:16]2[CH:21]=[CH:20][C:19]([C:22]3[N:23]=[C:24]([C@@H:27]4[CH2:31][CH2:30][CH2:29][N:28]4[C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[NH:25][CH:26]=3)=[CH:18][CH:17]=2)[CH2:13]1)=O)C1C=CC=CC=1>C(O)(=O)C.Br>[NH2:11][CH:12]1[CH2:13][CH:14]([C:16]2[CH:21]=[CH:20][C:19]([C:22]3[N:23]=[C:24]([C@@H:27]4[CH2:31][CH2:30][CH2:29][N:28]4[C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[NH:25][CH:26]=3)=[CH:18][CH:17]=2)[CH2:15]1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1c1nc(-c2ccc(C3CC(NC(=O)OCc4ccccc4)C3)cc2)c[nH]1
Agent: Br
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCC[C@H]1c1nc(-c2ccc(C3CC(N)C3)cc2)c[nH]1
Yield: 140.4 %

Procedure:
To a suspension of A8 (17.8 g) in acetic acid (250 mL), hydrogen bromide (33% in acetic acid, 25 mL) was added dropwise at rt. After stirring for an additional hour, the reaction was filtered though a pad of CELITE™454, washed with ethyl acetate, concentrated to afford the crude product, which was purified by silica gel flash column chromatography (Hexanes/EtOAc=3/1 (v/v)) to provide A9 (18.5 g).
Reaction SMILES: [OH:1][CH:2]([CH3:20])[CH2:3][N:4]([CH2:16][CH:17]([OH:19])[CH3:18])[CH2:5][CH2:6][N:7]([CH2:12][CH:13]([OH:15])C)[CH2:8][CH:9]([OH:11])[CH3:10].OCCN(CCO)CCN(CCO)CCO>>[OH:15][CH2:13][CH2:12][N:7]([CH2:8][CH:9]([OH:11])[CH3:10])[CH2:6][CH2:5][N:4]([CH2:16][CH:17]([OH:19])[CH3:18])[CH2:3][CH:2]([OH:1])[CH3:20]
Reactant: CC(O)CN(CCN(CC(C)O)CC(C)O)CC(C)O
Agent: OCCN(CCO)CCN(CCO)CCO
Product: CC(O)CN(CCO)CCN(CC(C)O)CC(C)O

Procedure:
Examples of suitable hydroxyalkylated ethylenediamines include, but are not limited to N,N,N′,N′-tetrakis-(2-hydroxypropyl)ethylenediamine and N,N,N′,N′-tetrakis-(hydroxyethyl)ethylenediamine. N-hydroxyethyl,N,N′,N′-tris(2-hydroxypropyl)ethylenediamine, and combinations of two or more thereof will not give solid. Preferably, the hydroxyalkylated ethylenediamine is N,N,N′,N′-tetrakis-(2-hydroxypropyl)ethylenediamine or N,N,N′,N′-tetrakis-(hydroxyethyl)ethylenediamine. The hydroxyalkylated ethylene diamine, N,N,N′,N′-tetrakis-(2-hydroxypropyl)ethylenediamine, is available commercially, for example, from BASF Corporation, Mount Olive, N.J., under the name QUADROL polyol.
Reaction SMILES: C([O:8][C:9]1[CH:51]=[CH:50][C:12]([CH2:13][C:14]([C:40]([O:42]CC2C=CC=CC=2)=[O:41])([CH2:22][CH2:23][C@H:24]([NH:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[CH:11][CH:10]=1)C1C=CC=CC=1>CO.[Pd]>[C:28]([O:27][C:25](=[O:26])[C@@H:24]([NH:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:23][CH2:22][C:14]([C:15]([O:17][C:18]([CH3:19])([CH3:20])[CH3:21])=[O:16])([CH2:13][C:12]1[CH:11]=[CH:10][C:9]([OH:8])=[CH:51][CH:50]=1)[C:40]([OH:42])=[O:41])([CH3:29])([CH3:30])[CH3:31]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCC(Cc1ccc(OCc2ccccc2)cc1)(C(=O)OCc1ccccc1)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@@H](CCC(Cc1ccc(O)cc1)(C(=O)O)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.5 %

Procedure:
To a solution of 1.07 g di-tert-butyl (5S)-2-[4-(benzyloxy)benzyl]-2-(benzyloxycarbonyl)-5-[(tert-butoxycarbonyl)amino]hexanedioate (1.52 mmol) in methanol (20 mL) was added a 10% palladium on carbon hydrogenation catalyst (100 mg) at room temperature. The suspension was stirred overnight at room temperature under an atmosphere of hydrogen. The catalyst was removed by filtration and all volatiles were removed in vacuo. The crude product (800 mg, quantitative yield) was used in the next step without further purification.
Reaction SMILES: [OH-].[Na+].[CH3:3][O:4][C:5]1[CH:10]=[C:9]([S:11]([CH3:13])=O)[C:8]([CH3:14])=[CH:7][C:6]=1[OH:15].[Br:16][CH:17](Br)[CH3:18]>O.[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1>[Br:16][CH2:17][CH2:18][O:15][C:6]1[CH:7]=[C:8]([CH3:14])[C:9]([S:11][CH3:13])=[CH:10][C:5]=1[O:4][CH3:3]
Reactant: COc1cc(S(C)=O)c(C)cc1O
Reactant: CC(Br)Br
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: COc1cc(SC)c(C)cc1OCCBr

Procedure:
A solution of sodium hydroxide (21 g) in water (75 ml) was added to 2-methoxy-5-methyl-4-methylsulphinylphenol (21 g), dibromoethane (160 ml) and benzyltriethylammonium chloride (1.26 g) and the resultant mixture heated at 60° for 18 hours. After cooling, water (50 ml) was added. The organic layer was separated, the aqueous layer extracted with dibromoethane (2×10 ml). The combined organic extracts were washed with 2 N aqueous sodium hydroxide solution (100 ml) and water (100 ml) and the solvent was evaporated under reduced pressure to give an orange oil, which on trituration with 40°-60° petroleum ether afforded a solid, which was filtered off, washed with further petroleum ether and dried in vacuo. The crude mono-ether (29.24 g), m.p. 66°-67° was used without further purification in the next stage. (A sample purified by column chromatography on Florisil eluting with dichloromethane followed by crystallisation from diethyl ether/40°-60° petroleum ether (1:3 v/v) had m.p. 72°-73°).
Reaction SMILES: [Br-].[CH:2]([C:5]1[C:18]2[NH2+:17][C:16]3[C:11](=[CH:12][C:13]([Br:19])=[CH:14][CH:15]=3)[S:10][C:9]=2[CH:8]=[C:7](Br)[CH:6]=1)([CH3:4])[CH3:3].[CH3:21][N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1>C(Cl)(Cl)Cl>[Br-:19].[CH3:21][N:22]1[CH2:27][CH2:26][N:25]([C:7]2[CH:6]=[C:5]([CH:2]([CH3:4])[CH3:3])[C:18]3[C:9]([CH:8]=2)=[S+:10][C:11]2[C:16](=[CH:15][CH:14]=[C:13]([N:25]4[CH2:26][CH2:27][N:22]([CH3:21])[CH2:23][CH2:24]4)[CH:12]=2)[N:17]=3)[CH2:24][CH2:23]1
Reactant: CN1CCNCC1
Reactant: CC(C)c1cc(Br)cc2c1[NH2+]c1ccc(Br)cc1S2
Agent: [Br-]
Solvent: ClC(Cl)Cl
Product: CC(C)c1cc(N2CCN(C)CC2)cc2[s+]c3cc(N4CCN(C)CC4)ccc3nc12
Reaction time: 3 h

Procedure:
To a solution of 1-i-propyl-3,7-dibromophenothiazinium bromide (200 mg, 0.42 mmol) in chloroform (10 mL) kept under argon, 1-methylpiperazine (290 mg, 2.9 mmol) was added (30 min) with vigorous stirring. The mixture was stirred for 3 h and after that extracted once with aqueous HBr (10 mL, 1% v/v) and twice with water. The organic layer was dried (Na2SO4), concentrated and dried under vacuum. Compound was purified by flash chromatography (solvent system: dichloromethane-methanol).
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:32]([O:35][C:36]1[CH:37]=[C:38](O)[CH:39]=[CH:40][CH:41]=1)[CH:33]=[CH2:34].[CH3:43][O:44][C:45]1[CH:46]=[C:47]([CH:52]=[CH:53][C:54]=1[O:55][CH3:56])[CH:48]=[CH:49][CH2:50][OH:51]>C1COCC1.C(OCC)C>[CH2:32]([O:35][C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][C:41]=1[O:51][CH2:50][CH:49]=[CH:48][C:47]1[CH:52]=[CH:53][C:54]([O:55][CH3:56])=[C:45]([O:44][CH3:43])[CH:46]=1)[CH:33]=[CH2:34]
Reactant: COc1ccc(C=CCO)cc1OC
Reactant: C=CCOc1cccc(O)c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOCC
Product: C=CCOc1ccccc1OCC=Cc1ccc(OC)c(OC)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Diethyl azodicarboxylate (26.1 g, 0.15 mol) and triphenyl phosphine (39.3 g, 0.15 mol) were added to a solution of 3-allyloxyphenol (15 g, 0.1 mol) and 3,4-dimethoxycinnamyl alcohol (19.4 g, 0.1 mol) in THF (100 ml). The mixture was stirred at room temperature overnight, and ethyl ether was added. The precipitate was filtered off, and the filtrate was evaporated to a residue, which was purified by HPLC using hexane-ethyl acetate (4:1 v/v) as a liquid phase. 3,4-Dimethoxycinnamyl allyloxyphenyl ether was isolated as a crystalline mass (7.4 g, 23%), m.p. 60°-60.5° C.; NMR (CDCl3): δ3.93, 3.94 (s, s, 2 OCH3), 4.57 (d, t, J=5.5, 1.5, 1.5 Hz, CH2CH=CH2), 4.71 (d, d, J=6.0, 1.5 Hz, CH=CHCH2), 5.28-5.50 (m, CH2CH=CH2), 6.10 (m, CH2CH=CH2 ), 6.26-6.40 (m, CH=CHCH2), 6.56-7.28 (m, ArH).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:31])=[C:4]([C@@H:8]2[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][C@H:9]2[C:28]([OH:30])=O)[CH:5]=[CH:6][CH:7]=1.C(N(CC)C(C)C)(C)C.[NH2:41][C:42]1[CH:47]=[CH:46][C:45]([N:48]2[CH2:53][CH2:52][CH:51]([C:54]([O:56][CH2:57][CH3:58])=[O:55])[CH2:50][CH2:49]2)=[CH:44][CH:43]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>ClCCl>[CH2:57]([O:56][C:54]([CH:51]1[CH2:50][CH2:49][N:48]([C:45]2[CH:46]=[CH:47][C:42]([NH:41][C:28]([C@H:9]3[C@H:8]([C:4]4[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=4[F:31])[C@:12]([C:15]4[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=4[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:25])([CH3:27])[CH3:26])[NH:10]3)=[O:30])=[CH:43][CH:44]=2)[CH2:53][CH2:52]1)=[O:55])[CH3:58]
Reactant: CCOC(=O)C1CCN(c2ccc(N)cc2)CC1
Reactant: CC(C)(C)C[C@@H]1N[C@@H](C(=O)O)[C@H](c2cccc(Cl)c2F)[C@@]1(C#N)c1ccc(Cl)cc1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(=O)C1CCN(c2ccc(NC(=O)[C@@H]3N[C@@H](CC(C)(C)C)[C@](C#N)(c4ccc(Cl)cc4F)[C@H]3c3cccc(Cl)c3F)cc2)CC1
Reaction time: 0.5 h
Yield: 291.1 %

Procedure:
To a stirred solution of (2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxylic acid (20.0 mg) in dichloromethane (5 ml) were added N,N-DIISOPROPYLETHYLAMINE (33 mg) and ethyl 1-(4-aminophenyl)piperidine-4-carboxylate (63.8 mg, 0.257 mmol, Bionet Research Intermediates) followed by N,N,N′,N′-tetramethyl-O-(7-aza-benzotriazol-1-yl)uranium hexafluorophosphate (HATU) (29 mg, Chem-Impex) and the reaction mixture was stirred for 30 min; Another portion of N,N-DIISOPROPYLETHYLAMINE (33 mg), (2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxylic acid (20.0 mg) and HATU (29 mg) was added and stirring was continued for 30 min before the addition of the last portion of N,N-DIISOPROPYLETHYLAMINE (33 mg), (2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxylic acid (20.0 mg) and HATU (29 mg). 1 hr later, the reaction mixture was diluted with CH2Cl2 (80 mL), washed with sat Na2CO3 (2×15 mL), water (2×15 mL) and evaporated. The crude material was purified by flash chromatography (silica gel, 4 g, 4% to 50% EtOAc in hexanes) to give 1-(4-{[(2R,3S,4R,5S)-4-(4-Chloro-2-fluoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-phenyl)-piperidine-4-carboxylic acid ethyl ester as off-white solid (86.9 mg, 97%). MS (ES+) m/z Calcd: [(M+H)+]: 697. found: 697.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]2[S:12][C:11](=[O:13])[N:10]([CH3:14])[C:9]=2[CH:15]=1)=O.[NH2:16][C:17]1[N:22]=[CH:21][CH:20]=[CH:19][N:18]=1>>[N:16]1[C:3]([C:5]2[CH:6]=[CH:7][C:8]3[S:12][C:11](=[O:13])[N:10]([CH3:14])[C:9]=3[CH:15]=2)=[CH:2][N:18]2[CH:19]=[CH:20][CH:21]=[N:22][C:17]=12
Reactant: Nc1ncccn1
Reactant: Cn1c(=O)sc2ccc(C(=O)CBr)cc21
Product: Cn1c(=O)sc2ccc(-c3cn4cccnc4n3)cc21
Yield: 47.8 %

Procedure:
5-(Imidazo[1,2-a]pyrimidin-2-yl)-3-methyl-2-benzothiazolinone (2.7 g) was prepared in substantially the same manner as that of Example 30 from 5-(2-bromoacetyl)-3-methyl-2-benzothiazolinone (5.72 g) and 2-aminopyrimidine (5.7 g).
Reaction SMILES: [NH2:1][C:2]1[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[Br:12]N1C(=O)CCC1=O>ClCCl>[NH2:1][C:2]1[C:10]([F:11])=[CH:9][C:8]([Br:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: O=C1CCC(=O)N1Br
Reactant: Nc1c(F)cccc1C(=O)O
Solvent: ClCCl
Product: Nc1c(F)cc(Br)cc1C(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 77.5 %

Procedure:
A solution of 2-amino-3-fluorobenzoic acid (10.85 g, 70 mmol) in dichloromethane (175 mL) was added N-bromosuccinimide (12.46 g, 70 mmol), and the mixture was stirred at room temperature for 2 hours. The precipitate was filtered and washed with dichloromethane (100 mL*3) to give the title compound (12.7 g, 78%) as a grey solid, which was directly used in the next step without further purification. MS (ES+) C7H5BrFNO2 requires: 233, 235, found: 232, 234 [M+H]+.