Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:7](=[O:8])[C:6]([CH3:9])=[C:5]([CH3:10])[C:4](=[O:11])[C:3]=1[CH2:12][C:13]1[CH:14]=[CH:15][C:16]([O:32]C(=O)C)=[C:17]([CH:31]=1)[C:18]([NH:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=1)=[O:19].C(=O)([O-])O.[Na+]>CO.O>[CH3:1][C:2]1[C:7](=[O:8])[C:6]([CH3:9])=[C:5]([CH3:10])[C:4](=[O:11])[C:3]=1[CH2:12][C:13]1[CH:14]=[CH:15][C:16]([OH:32])=[C:17]([CH:31]=1)[C:18]([NH:20][C:21]1[CH:22]=[CH:23][C:24]([C:27]([F:30])([F:28])[F:29])=[CH:25][CH:26]=1)=[O:19]
Reactant: CC(=O)Oc1ccc(CC2=C(C)C(=O)C(C)=C(C)C2=O)cc1C(=O)Nc1ccc(C(F)(F)F)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CC1=C(C)C(=O)C(Cc2ccc(O)c(C(=O)Nc3ccc(C(F)(F)F)cc3)c2)=C(C)C1=O
Yield: 93.8 %

Procedure:
N-[5-(3,5,6-Trimethyl-1,4-benzoquinon-2-yl)methyl-2-acetoxybenzoyl]-4-trifluoromethylaniline (0.070 g, 0.144 mmol) was dissolved in methanol (4 ml) and after adding thereto an aqueous saturated sodium hydrogencarbonate solution (3 ml), the solution was stirred at room temperature for 3 hours. After the completion of reaction, the reaction solution was diluted with water and then extracted with ethyl acetate. The extract was washed with water and then dried, and the solvent was removed by distillation. The obtained residue was recrystallized from a mixed solvent of ethyl acetate and hexane (1:1) to obtain the titled compound (0.060 g, 0.135 mmol, 94%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][NH:9][C:10]([NH2:12])=[S:11])=[CH:4][CH:3]=1.[CH:13](O)=O>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH:13]=[N:12][C:10](=[S:11])[NH:9]2)=[CH:6][CH:7]=1
Reactant: NC(=S)NNc1ccc(Cl)cc1
Reactant: O=CO
Product: S=c1ncn(-c2ccc(Cl)cc2)[nH]1

Procedure:
Twelve g of 1-(4-chlorophenyl)thiosemicarbazide was suspended in 60 ml of 95% formic acid, and the mixture was stirred under reflux for 24 hours. The mixture was then cooled, and the product precipitated. It was collected and washed with cold denatured ethanol, and was dried to obtain 6.1 g of the desired intermediate, m.p. 222°-224°.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[C:15]2([CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[O:14][CH2:13][C@H:12]1[C:21]1[NH:22][CH:23]=[C:24]([C:26]2[CH:31]=[CH:30][C:29]([C:32]3[CH:37]=[CH:36][C:35]([C:38]4[N:39]=[C:40]([C@@H:43]5[CH2:47][CH2:46][CH2:45][N:44]5C(OC(C)(C)C)=O)[NH:41][CH:42]=4)=[CH:34][CH:33]=3)=[CH:28][CH:27]=2)[N:25]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:1]([O:8][C:9]([N:11]1[C:15]2([CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[O:14][CH2:13][C@H:12]1[C:21]1[NH:22][CH:23]=[C:24]([C:26]2[CH:31]=[CH:30][C:29]([C:32]3[CH:37]=[CH:36][C:35]([C:38]4[N:39]=[C:40]([C@@H:43]5[CH2:47][CH2:46][CH2:45][NH:44]5)[NH:41][CH:42]=4)=[CH:34][CH:33]=3)=[CH:28][CH:27]=2)[N:25]=1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1c1nc(-c2ccc(-c3ccc(-c4c[nH]c([C@@H]5COC6(CCOCC6)N5C(=O)OCc5ccccc5)n4)cc3)cc2)c[nH]1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(OCc1ccccc1)N1[C@H](c2nc(-c3ccc(-c4ccc(-c5c[nH]c([C@@H]6CCCN6)n5)cc4)cc3)c[nH]2)COC12CCOCC2
Reaction time: 2 h
Yield: 47.6 %

Procedure:
(R)-3-(4-{4′-[2-((S)-1-tert-Butoxycarbonyl-pyrrolidin-2-yl)-1H-imidazol-4-yl]-biphenyl-4-yl}-1H-imidazol-2-yl)-1,8-dioxa-4-aza-spiro[4.5]decane-4-carboxylic acid benzyl ester (0.04 gm, 0.05 mmol) was dissolved in DCM (2 mL), TFA (2 mL) was added and the mixture stirred for 2 hours. The solvent was evaporated, the residue redissolved in EtOAc (20 mL) and the organics washed with aqueous NaHCO3, water and brine. Drying the organic layer afforded (R)-3-{4-[4′-((S)-2-pyrrolidin-2-yl-1H-imidazol-4-yl)-biphenyl-4-yl]-1H-imidazol-2-yl}-1,8-dioxa-4-aza-spiro[4.5]decane-4-carboxylic acid benzyl ester (0.015 gm, 44%). LCMS 631.0 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][CH3:14])[C:10](O)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].N1C=CC=CC=1.[F:21]C1N=C(F)N=C(F)N=1>C(Cl)Cl>[F:21][C:10]([C@@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[CH2:13][CH3:14])=[O:11]
Reactant: Fc1nc(F)nc(F)n1
Reactant: CC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC[C@H](NC(=O)OC(C)(C)C)C(=O)F
Temperature: 0 °C
Reaction time: 1 h
Yield: 111.6 %

Procedure:
(S)-2-(Tert-butoxycarbonylamino)butyric acid (0.010 mol) dissolved in DCM (25 ml) was placed in a cooling bath at −10° C. Pyridine (0.010 mol) was added, followed by 2,4,6-trifluoro-1,3,5-triazine (0.0345 mol). The mixture was stirred under nitrogen. After one hour, ice cold water (75 ml) was added. More DCM (45 ml) was added, and the mixture was shaken. The organic phase was separated, washed with ice cold water again (100 ml), then the organic phase dried, filtered, and concentrated to yield 2.29 g of (S)-1,1-dimethylethyl [1-(fluorocarbonyl)propyl]-carbamate (intermediate 25).
Reaction SMILES: [CH2:1]([N:8]1[CH2:15][CH2:14][CH:13]=[CH:12][CH2:11][C@H:10]([NH:16]C(=O)OC(C)(C)C)[C:9]1=[O:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:16][C@H:10]1[CH2:11][CH:12]=[CH:13][CH2:14][CH2:15][N:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:9]1=[O:24]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC=CCCN(Cc2ccccc2)C1=O
Agent: CC(C)(C)OC(=O)N[C@H]1C/C=C\CCN(Cc2ccccc2)C1=O
Agent: N[C@H]1C/C=C\CCN(Cc2ccccc2)C1=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N[C@H]1CC=CCCN(Cc2ccccc2)C1=O
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
To a solution of (S,Z)-tert-butyl 1-benzyl-2-oxo-1,2,3,4,7,8-hexahydroazocin-3-ylcarbamate (10 mg, 0.030 mmol) in DCM (0.2 mL) at rt was added TFA (0.2 mL). The clear solution was stirred at rt for 40 min. The reaction mixture was concentrated and dried in vacuum to give (S,Z)-3-amino-1-benzyl-3,4,7,8-tetrahydroazocin-2(1H)-one (7.0 mg, 0.030 mmol, 100% yield) as an oil. Anal. Calcd. for C14H18N2O m/z 230.3. found: 231.1 (M+H)+.
Reaction SMILES: O[C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=O)=CC=1.[OH:11][C:12]1[CH:24]=[CH:23][C:15]([C:16]([N:18]([CH2:21][CH3:22])[CH2:19][CH3:20])=[O:17])=[CH:14][CH:13]=1>>[C@@H:10]12[CH2:9][C@@H:5]1[CH2:6][N:8]([CH2:6][CH2:5][CH2:9][CH2:10][O:11][C:12]1[CH:24]=[CH:23][C:15]([C:16]([N:18]([CH2:19][CH3:20])[CH2:21][CH3:22])=[O:17])=[CH:14][CH:13]=1)[CH2:2]2
Reactant: CCN(CC)C(=O)c1ccc(O)cc1
Reactant: NC(=O)c1ccc(O)cc1
Product: CCN(CC)C(=O)c1ccc(OCCCCN2C[C@H]3C[C@H]3C2)cc1

Procedure:
The experimental procedure is the same as Steps 1 and 2 of Example 3, but replacing the 4-hydroxybenzamide in Step 1 by 4-hydroxy-N,N-diethylbenzamide.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:15])[NH:13][CH:14]=2)[CH:5]=[CH:4][N:3]=1.Br[CH2:17][CH:18]([F:20])[F:19]>>[F:19][CH:18]([F:20])[CH2:17][N:13]1[CH:14]=[C:10]([C:9]#[C:8][C:6]2[CH:5]=[CH:4][N:3]=[C:2]([CH3:1])[CH:7]=2)[N:11]=[C:12]1[CH3:15]
Reactant: FC(F)CBr
Reactant: Cc1cc(C#Cc2c[nH]c(C)n2)ccn1
Product: Cc1cc(C#Cc2cn(CC(F)F)c(C)n2)ccn1

Procedure:
The title compound, MS: m/e=262.1 (M+H+), was prepared in accordance with the general method of example 1 from 2-methyl-4-(2-methyl-1H-imidazol-4-ylethynyl)-pyridine and 2-bromo-1,1-difluoro ethane.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH:5]([C:7](=[O:17])[C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=1)Cl)[CH3:2].[CH2:19]([O:21][C:22](=[O:26])[CH2:23][C:24]#[N:25])[CH3:20].[Na].N#N>C1COCC1>[CH2:19]([O:21][C:22]([C:23]1[C:5]([C:4]([O:3][CH2:1][CH3:2])=[O:18])=[C:7]([C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=2)[O:17][C:24]=1[NH2:25])=[O:26])[CH3:20]
Reactant: CCOC(=O)CC#N
Reactant: CCOC(=O)C(Cl)C(=O)c1ccc([N+](=O)[O-])cc1
Agent: N#N
Agent: [Na]
Solvent: C1CCOC1
Product: CCOC(=O)c1c(N)oc(-c2ccc([N+](=O)[O-])cc2)c1C(=O)OCC

Procedure:
105 g (0.39 mols, 1 eq) of 4-nitrobenzoyl-chloroacetic acid ethyl ester are dissolved in 600 ml of THF. To this solution are added, on a water bath (T=35° C.), in portions, 49.4 g (0.37 mols) of finely ground sodium cyanoacetic acid ethyl ester (preparation: Chem, Ber. 1962, 95, 307-318.). It is stirred over night (under N2), fully concentrated by evaporation, and extracted with H2O and CH2Cl2. The combined CH2Cl2 phase is washed with H2O, and finally dried over MgSO4 and freed from solvent. Crystallisation from toluene yields the title compound, m.p.: 174-177° C.
Reaction SMILES: C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.[NH2:34][C:35]1[CH:36]=[C:37]2[C:44]3([CH2:49][CH2:48][S:47][C:46]([NH:50][C:51](=[O:57])[O:52][C:53]([CH3:56])([CH3:55])[CH3:54])=[N:45]3)[CH2:43][CH2:42][O:41][C:38]2=[CH:39][CH:40]=1.C(N(CC)C(C)C)(C)C.[C:67]([C:69]1[CH:70]=[CH:71][C:72]([C:75](O)=[O:76])=[N:73][CH:74]=1)#[N:68].C(=O)(O)[O-].[Na+]>ClCCl>[C:67]([C:69]1[CH:70]=[CH:71][C:72]([C:75]([NH:34][C:35]2[CH:36]=[C:37]3[C:44]4([CH2:49][CH2:48][S:47][C:46]([NH:50][C:51](=[O:57])[O:52][C:53]([CH3:54])([CH3:56])[CH3:55])=[N:45]4)[CH2:43][CH2:42][O:41][C:38]3=[CH:39][CH:40]=2)=[O:76])=[N:73][CH:74]=1)#[N:68]
Reactant: N#Cc1ccc(C(=O)O)nc1
Reactant: CC(C)(C)OC(=O)NC1=NC2(CCOc3ccc(N)cc32)CCS1
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC1=NC2(CCOc3ccc(NC(=O)c4ccc(C#N)cn4)cc32)CCS1
Temperature: 25 °C
Reaction time: 1 h
Yield: 102 %

Procedure:
PyBOP (74.5 mg) was added to a solution of the compound 10 obtained in Example 3 (25.0 mg), N,N-diisopropylethylamine (0.0624 ml) and 5-cyanopyridine-2-carboxylic acid (Compound 9-3) (16.9 mg) in dichloromethane (5.0 ml) at room temperature. The mixture was stirred at room temperature for one hour. The reaction solution was poured into aqueous sodium bicarbonate, followed by extraction with ethyl acetate. The extract was washed with brine and dried over anhydrous magnesium sulfate. The drying agent was removed by filtration and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to obtain the title compound (35 mg).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][N:10]=1)[C:5]([OH:7])=[O:6].[CH2:11](N(CC)CC)[CH3:12].ClC(OCC)=O>ClCCl>[F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][N:10]=1)[C:5]([O:7][CH2:11][CH3:12])=[O:6]
Reactant: CCN(CC)CC
Reactant: O=C(O)c1ccnc(F)c1
Agent: CCOC(=O)Cl
Solvent: ClCCl
Product: CCOC(=O)c1ccnc(F)c1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 81.7 %

Procedure:
To a stirred solution of 2-fluoroisonicotinic acid (27) (1.00 g, 7.09 mmol) in anhydrous dichloromethane (30 mL) was added at 0° C., under argon, triethylamine (991 μL, 7.09 mmol). After 5 min, ethyl chloroformate (681 μL, 7.09 mmol) was added and the mixture was stirred at 0° C. for 5 min before addition of N-dimethyl-4-aminopyridine (DMAP, 86 mg, 0.71 mmol). The mixture was stirred at 0° C. for 4 h. After return back to room temperature, the solvent was evaporated under vacuum and the residue was chromatographed (Al2O3, CH2Cl2) to give ester 28 (0.98 g, 5.79 mmol) as a yellow liquid. Yield 82%; Rf (Al2O3, CH2Cl2) 0.90; IR (CCl4) ν 1096, 1210, 1299, 1409, 1572, 1735 cm−1; 1H NMR (200 MHz, CDCl3) δ 1.39 (t, 3H, J=7.1 Hz), 4.40 (q, 2H, J=7.1 Hz), 7.47 (ddd, 1H, 3JH-F=2.4 Hz, J=0.8, 1.3 Hz), 7.72 (ddd, 1H, 5JH-F=1.8 Hz, J=1.3, 5.1 Hz), 8.33 (td, 1H, 4JH-F=0.8 Hz, J=0.8, 5.1 Hz).
Reaction SMILES: C([Li:5])CCC.[CH3:6][Si:7]([CH3:20])([CH3:19])[CH:8]1[C:17]2[N:16]=[CH:15][CH:14]=[C:13]([CH3:18])[C:12]=2[CH2:11][CH2:10][CH2:9]1>CCCCCC.C1COCC1>[Li:5][C:8]1([Si:7]([CH3:19])([CH3:20])[CH3:6])[C:17]2[N:16]=[CH:15][CH:14]=[C:13]([CH3:18])[C:12]=2[CH2:11][CH2:10][CH2:9]1
Reactant: Cc1ccnc2c1CCCC2[Si](C)(C)C
Reactant: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: [Li]C1([Si](C)(C)C)CCCc2c(C)ccnc21

Procedure:
A mixture of a 1.55 molar solution of n-butyl lithium in hexane (14.2 ml, 22mM) and THF (25 ml), maintained below 5° was treated with a solution of 5,6,7,8-tetrahydro-8-trimethylsilyl- 4-methylquinoline (4.4 g, 20 mM) in THF (10 ml) to give 5,6,7,8-tetrahydro-8-lithio-8-trimethylsilyl -4-methylquinoline. After 0.5 hour a solution of t-butyldimethylsilyl isothiocyanate (22 mM) in benzene (15 ml) was added; after a further 0.5 hour the mixture was quenched with 0.5 N hydrochloric acid (60 ml). After 1 hour toluene (50 ml) was added, the aqueous layer was separated, adjusted to pH10 and extracted with dichloromethane. The organic extract was evaporated and chromatographed on silica using ether as eluant. The title thioamide was obtained in 60% yield (identical to authentic material) together with the corresponding nitrile (20%) and 5,6,7,8-tetrahydro-4-methylquinoline (20%).
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[C:13]2[CH:12]=[C:11]([C:14]3[C:19]([Cl:20])=[CH:18][N:17]=[C:16](Cl)[N:15]=3)[S:10][C:9]=2[CH:8]=[CH:7][CH:6]=1)=[O:4].C(OC([N:29]1[CH2:34][CH2:33][N:32]([CH2:35][CH2:36][CH2:37][NH2:38])[C@H:31]([CH3:39])[CH2:30]1)=O)(C)(C)C.C(N(C(C)C)CC)(C)C.C([SiH](CC)CC)C.C(O)(C(F)(F)F)=O.[Li+].[OH-]>O1CCOCC1.ClCCl>[CH3:1][NH:2][C:3]([C:5]1[C:13]2[CH:12]=[C:11]([C:14]3[C:19]([Cl:20])=[CH:18][N:17]=[C:16]([NH:38][CH2:37][CH2:36][CH2:35][N:32]4[CH2:33][CH2:34][NH:29][CH2:30][C@H:31]4[CH3:39])[N:15]=3)[S:10][C:9]=2[CH:8]=[CH:7][CH:6]=1)=[O:4]
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)CCN1CCCN
Reactant: CNC(=O)c1cccc2sc(-c3nc(Cl)ncc3Cl)cc12
Agent: CC[SiH](CC)CC
Agent: [Li+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: C1COCCO1
Product: CNC(=O)c1cccc2sc(-c3nc(NCCCN4CCNC[C@H]4C)ncc3Cl)cc12
Temperature: 90 °C
Reaction time: 7 h
Yield: 46.5 %

Procedure:
A stirred mixture of 2-(2,5-dichloropyrimidin-4-yl)-benzo[b]thiophene-4-carboxylic acid methylamide (0.30 g, 0.89 mmol), (R)-4-(3-aminopropyl)-3-methylpiperazine-1-carboxylic acid tert-butyl ester (0.57 g, 2.2 mmol) and diisopropylethylamine (0.29 g, 2.2 mmol) in 1,4-dioxane (5 mL) is heated at 90° C. under a nitrogen atmosphere for 14 hours. After concentration and subsequent chromatography on silica gel, eluting with 2 M NH3/MeOH in dichloromethane 0-8%, the intermediate is obtained as a solid. The solid is suspended in dichloromethane (3 mL), followed by the successive addition of triethylsilane (0.50 mL) and TFA (3 mL). The resultant yellow solution is stirred for 7 hours. After concentration a wet solid is obtained. The solid is treated with 2 N LiOH, with sonication, until pH reaches 12. The mixture is filtered, the solid is dried before it is subject to chromatography on silica gel, eluting with 2 M NH3/MeOH in dichloromethane 0-20%, to give the title compound as a yellow solid (190 mg, 46% yield). ES+(m/z) 459 (35Cl) and 461 (37Cl) [M+H].
Reaction SMILES: [CH3:1][C:2]([O-])(C)C.[K+].O=[C:8]1[CH2:12][N:11]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C@H:10]([C:20]([O:22][CH3:23])=[O:21])[CH2:9]1>C1COCC1>[CH:1](=[C:8]1[CH2:12][N:11]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C@H:10]([C:20]([O:22][CH3:23])=[O:21])[CH2:9]1)[CH3:2]
Reactant: CC(C)(C)[O-]
Reactant: COC(=O)[C@@H]1CC(=O)CN1C(=O)OC(C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Product: CC=C1C[C@@H](C(=O)OC)N(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Yield: 34.8 %

Procedure:
A solution of Ph3PEtBr (84 g, 227 mmol) and KOtBu (76.7 g, 556 mmol) in THF (1100 mL) was stirred at rt under nitrogen atmosphere for 1 h, and then added (S)-1-tert-butyl 2-methyl 4-oxopyrrolidine-1,2-dicarboxylate (50 g, 206 mmol) in THF (350 mL) dropwise. The mixture was stirred at room temperature for 4 hs. TLC showed the reaction was completed. The mixture was quenched with NH4Cl aqueous and concentrated to remove THF, and then dissolved in EtOAc and water. The combined organic layer was washed with water, brine, dried over Na2SO4, filtered and concentrated. The crude product was purified by column chromatography (PE: EtOAc=30:1 to 5:1) to afford (S)-1-tert-butyl 2-methyl 4-ethylidenepyrrolidine-1,2-dicarboxylate (18.3 g, 35%) as yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][Si:9]([C:22]([CH3:25])([CH3:24])[CH3:23])([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:4][C:3]=1[CH2:26][NH2:27].[C:28]([NH:35][CH2:36][C:37](O)=[O:38])([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C.O.C(OCC)(=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][Si:9]([C:22]([CH3:23])([CH3:24])[CH3:25])([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[CH:4][C:3]=1[CH2:26][NH:27][C:37](=[O:38])[CH2:36][NH:35][C:28]([O:30][C:31]([CH3:33])([CH3:32])[CH3:34])=[O:29]
Reactant: CC(C)(C)[Si](Oc1ccc(Br)c(CN)c1)(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCC(=O)NCc1cc(O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)ccc1Br

Procedure:
A solution of the product from Step B in DMF reacts with N-Boc glycine (1.1 eq), EDC (1.1 eq) and HOBT (1 eq). When the reaction is complete, ethyl acetate and water are added, and the organic phase is washed 5 times with water, once with saturated NaCl, and dried over magnesium sulfate. Filtration and evaporation provides the title compound.
Reaction SMILES: [C:1]([O:6][CH2:7][CH3:8])(=[O:5])[CH:2]=[C:3]=[CH2:4].[Cl:9][C:10]1[CH:11]=[C:12]([C:17](=[N:19][OH:20])C)[CH:13]=[CH:14][C:15]=1[Cl:16]>C(Cl)Cl>[CH2:7]([O:6][C:1](=[O:5])[CH2:2][C:3]1[O:20][N:19]=[C:17]([C:12]2[CH:13]=[CH:14][C:15]([Cl:16])=[C:10]([Cl:9])[CH:11]=2)[CH:4]=1)[CH3:8]
Reactant: C=C=CC(=O)OCC
Reactant: CC(=NO)c1ccc(Cl)c(Cl)c1
Solvent: ClCCl
Product: CCOC(=O)Cc1cc(-c2ccc(Cl)c(Cl)c2)no1
Temperature: 25 °C
Reaction time: 120 h

Procedure:
To a solution of ethyl 2,3-butadienoate (1 eq) and 1-(3,4-dichloro-phenyl)-ethanone oxime (1.03 eq) in DCM (51 vol) was added a 10% aqueous bleach solution (51 vol) and the resultant biphasic system stirred at room temperature for 5 days. The organic layer was separated and the aqueous layer extracted with DCM (3×7 vol). The combined organic layers were washed with water (36 vol), dried over MgSO4, filtered and concentrated. The crude residue was purified by a combination of flash column chromatography (eluent: [0:1 to 1:2] EtOAc:heptane) and prep HPLC to yield [3-(3,4-Dichloro-phenyl)-isoxazol-5-yl]-acetic acid ethyl ester.
Reaction SMILES: Cl.[Br:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH2:6][NH2:7].C(N(CC)CC)C.Cl[C:19]([O:21][CH3:22])=[O:20].[Cl-].[Na+]>C(Cl)(Cl)Cl>[Br:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH2:6][NH:7][C:19](=[O:20])[O:21][CH3:22]
Reactant: NCc1cccc(Br)c1
Reactant: COC(=O)Cl
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: COC(=O)NCc1cccc(Br)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 87 %

Procedure:
To a suspension of 10.0 g of 3-bromobenzylamine hydrochloride in chloroform (100 ml), 9.55 g of triethylamine was added at room temperature. To this solution, 4.67 g of methyl chloroformate was dropwise added under cooling with ice, followed by stirring at room temperature for 2 hours. The reaction solution was poured into a sodium chloride aqueous solution, and the organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to obtain 9.54 g of methyl N-(3-bromobenzyl)carbamate as white crystals.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([NH:11][C:12]([CH:14]2[CH2:18][CH:17]([O:19][C:20]3[C:29]4[C:24](=[CH:25][C:26]([O:30][CH3:31])=[CH:27][CH:28]=4)[N:23]=[C:22]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[CH:21]=3)[CH2:16][CH:15]2[C:38](=[O:46])[NH:39][CH2:40][CH2:41][CH2:42][CH2:43][CH:44]=[CH2:45])=[O:13])[CH2:8][CH:7]1C=C)=[O:5])[CH3:2]>ClCCl.CC1C=C(C)C(N2C(=[Ru](Cl)(Cl)=CC3C=CC=CC=3OC(C)C)N(C3C(C)=CC(C)=CC=3C)CC2)=C(C)C=1>[CH2:1]([O:3][C:4]([C:6]12[CH2:8][CH:7]1[CH:45]=[CH:44][CH2:43][CH2:42][CH2:41][CH2:40][NH:39][C:38](=[O:46])[CH:15]1[CH:14]([CH2:18][CH:17]([O:19][C:20]3[C:29]4[C:24](=[CH:25][C:26]([O:30][CH3:31])=[CH:27][CH:28]=4)[N:23]=[C:22]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[CH:21]=3)[CH2:16]1)[C:12](=[O:13])[NH:11]2)=[O:5])[CH3:2]
Reactant: C=CCCCCNC(=O)C1CC(Oc2cc(-c3ccccc3)nc3cc(OC)ccc23)CC1C(=O)NC1(C(=O)OCC)CC1C=C
Agent: Cc1cc(C)c(N2CCN(c3c(C)cc(C)cc3C)C2=[Ru](Cl)(Cl)=Cc2ccccc2OC(C)C)c(C)c1
Solvent: ClCCl
Product: CCOC(=O)C12CC1C=CCCCCNC(=O)C1CC(Oc3cc(-c4ccccc4)nc4cc(OC)ccc34)CC1C(=O)N2
Yield: 32 %

Procedure:
Compound 91 (363 mg, 0.58 mmol) was dissolved in degassed dichloromethane (100 ml). Hoveyda-Grubbs catalyst 2nd generation (26 mg, 0.041 mmol) was added and the mixture was refluxed under argon atmosphere overnight. The reaction mixture was evaporated on silica and purified by silica gel chromatography (50% EtOAc in hexane→70% EtOAc in hexane) to give the pure title product (111 mg, 32%). MS (M+H+): 597.7
Reaction SMILES: [OH:1][C:2]1[C:3]([N+:16]([O-:18])=[O:17])=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([O:13]CC)=[O:12])=[CH:5]2.[OH-].[K+].[CH2:21](O)C>O>[CH3:21][O:1][C:2]1[C:3]([N+:16]([O-:18])=[O:17])=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([OH:13])=[O:12])=[CH:5]2
Reactant: CCOC(=O)c1cc2c([N+](=O)[O-])c(O)ccc2[nH]1
Reactant: CCO
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: COc1ccc2[nH]c(C(=O)O)cc2c1[N+](=O)[O-]
Temperature: 50 °C
Reaction time: 1 h

Procedure:
Ethyl 5-hydroxy-4-nitroindole-2-carboxylate (1.0 g, 3.8 mmol.) was suspended in a mixture of ethanol (20 ml) and water (5 ml). Potassium hydroxide (840 mg) was added and the mixture stirred at 50° C. under an atmosphere of nitrogen for 1 hour then cooled to ambient temperature. The solvent was evaporated in vacuo and the residue re-dissolved in water (25 ml). The pH was adjusted to pH2 using aqueous hydrochloric acid (2M). The resulting precipitate was filtered off, washed with water and dried in vacuo to give 5-methoxy-4-nitroindole-2-carboxylic acid (790 mg). This was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[N:4]([C:8]([CH:11]3[CH2:14][CH2:13][CH2:12]3)=[N:9][CH:10]=2)[CH:5]=[CH:6][N:7]=1.C1C(=O)N([I:22])C(=O)C1>CN(C=O)C.C(Cl)Cl>[Cl:1][C:2]1[C:3]2[N:4]([C:8]([CH:11]3[CH2:14][CH2:13][CH2:12]3)=[N:9][C:10]=2[I:22])[CH:5]=[CH:6][N:7]=1
Reactant: O=C1CCC(=O)N1I
Reactant: Clc1nccn2c(C3CCC3)ncc12
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Clc1nccn2c(C3CCC3)nc(I)c12

Procedure:
8-Chloro-3-cyclobutylimidazo[1,5-a]pyrazine (1058 mg, 5.1 mmol) and NIS (1146 mg, 5.1 mmol) in anh DMF (10 mL) were stirred at 60° C. under Ar for 6 h. The reaction was diluted with DCM (˜400 mL), washed (H2O, brine), dried (Na2SO4) and concentrated under reduced pressure. Purification of the crude material by flash chromatography on silica gel (50 g cartridge, 10:1-8:1-7:1-6:1 hexanes:EtOAc) afforded the title compound as a pale yellow solid; 1H NMR (400 MHz, CDCl3) δ 7.51 (d, J=4.8 Hz, 1H), 7.26 (d, J=4.8 Hz, 1H), 3.75 (quintetd, J=1.2 Hz, 8.4 Hz, 1H), 2.62-2.42 (m, 4H), 2.32-1.98 (m, 2H); MS (ES+): m/z 334.0 (100) [MH+]; HPLC: tR=3.38 min (OpenLynx, polar—5 min).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[CH:12]([NH2:15])([CH3:14])[CH3:13]>O>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([NH:15][CH:12]([CH3:14])[CH3:13])=[C:3]([N+:9]([O-:11])=[O:10])[CH:4]=1
Reactant: O=[N+]([O-])c1cc(Cl)ccc1Cl
Reactant: CC(C)N
Solvent: O
Product: CC(C)Nc1ccc(Cl)cc1[N+](=O)[O-]
Temperature: 100 °C
Reaction time: 4 h
Yield: 97.2 %

Procedure:
2,5-Dichloronitrobenzene (150 g) was added to isopropylamine (150 g) and the mixture was stirred in a sealed tube at 100° C. for 4 hours. After cooling, water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with water and dried over anhydrous magnesium sulfate and then the solvent was distilled off under reduced pressure to give 4-chloro-N-isopropyl-2-nitroaniline (163 g). A part of the obtained product was recrystallized from methanol, which showed the following physical properties: