Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:28])[CH2:7][NH:8][C:9](=[O:27])[C:10]1[CH:15]=[C:14]([N:16]2[CH2:22][C:21]([CH3:24])([CH3:23])[CH2:20][NH:19][CH:18]([CH3:25])[CH2:17]2)[CH:13]=[CH:12][C:11]=1[NH2:26])([CH3:4])([CH3:3])[CH3:2].[F:29][C:30]1[CH:37]=[CH:36][C:33]([CH:34]=O)=[CH:32][C:31]=1[O:38][CH3:39]>C(O)(=O)C.[C-]#N.[C-]#N.[C-]#N.[C-]#N.[C-]#N.[C-]#N.[K+].[K+].[K+].[Fe+3].C(O)C>[C:1]([O:5][C:6](=[O:28])[CH2:7][N:8]1[C:9](=[O:27])[C:10]2[C:11](=[CH:12][CH:13]=[C:14]([N:16]3[CH2:22][C:21]([CH3:24])([CH3:23])[CH2:20][NH:19][CH:18]([CH3:25])[CH2:17]3)[CH:15]=2)[N:26]=[C:34]1[C:33]1[CH:36]=[CH:37][C:30]([F:29])=[C:31]([O:38][CH3:39])[CH:32]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC1CN(c2ccc(N)c(C(=O)NCC(=O)OC(C)(C)C)c2)CC(C)(C)CN1
Reactant: COc1cc(C=O)ccc1F
Agent: [Fe+3]
Agent: [C-]#N
Agent: [K+]
Solvent: CCO
Solvent: CC(=O)O
Product: COc1cc(-c2nc3ccc(N4CC(C)NCC(C)(C)C4)cc3c(=O)n2CC(=O)OC(C)(C)C)ccc1F
Reaction time: 8 h
Yield: 11.9 %

Procedure:
[2-Amino-5-(3,6,6-trimethylperhydro-1,4-diazepin-1-yl)benzoylamino]acetic acid tert-butyl ester (INTERMEDIATE V.44) (1.00 g, 2.56 mmol), 4-fluoro-3-methoxybenzaldehyde (414 mg, 2.69 mmol), ethanol (20 mL) and acetic acid (3 drops) were stirred overnight at reflux temperature. Solvent was evaporated under reduced pressure. The crude reaction mixture was purified by SCX with product eluted with 2N NH3/MeOH. Solvent was evaporated under reduced pressure and the product dissolved in toluene (10 mL) and water (10 mL). Potassium hexacyanoferrate (III) (8.43 g, 25.6 mmol) was added and the reaction mixture stirred vigorously overnight. The reaction was then quenched by the addition of methanol (300 mL), the mixture filtered through a celite pad and the cake washed with further methanol (200 mL). The filtrate was evaporated to dryness and purified by chromatography on silica gel with a gradient of DCM to DCM:MeOH (3:1, v/v) as eluent to afford [2-(4-fluoro-3-methoxyphenyl)-4-oxo-6-(3,6,6-trimethylperhydro-1,4-diazepin-1-yl)-4H-quinazolin-3-yl]acetic acid tert-butyl ester (INTERMEDIATE VII.12) (160 mg, 0.305 mmol, 12%).
Reaction SMILES: [CH3:1][S@@:2]([CH2:4][CH2:5][CH2:6][O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:3].[S:15](N)([C:18]1[CH:26]=[CH:25][C:21]([N+:22]([O-:24])=[O:23])=[CH:20][CH:19]=1)(=[O:17])=[O:16].CCCCCC>C(Cl)Cl>[S:15]([C:18]1[CH:26]=[CH:25][C:21]([N+:22]([O-:24])=[O:23])=[CH:20][CH:19]=1)([OH:3])(=[O:17])=[O:16].[CH3:1][S@:2]([CH2:4][CH2:5][CH2:6][O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=[NH:22])=[O:3]
Reactant: NS(=O)(=O)c1ccc([N+](=O)[O-])cc1
Reactant: C[S@](=O)CCCOCc1ccccc1
Solvent: ClCCl
Solvent: CCCCCC
Product: C[S@](=N)(=O)CCCOCc1ccccc1
Product: O=[N+]([O-])c1ccc(S(=O)(=O)O)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 27.8 %

Procedure:
To a solution of (S)-((3-(methylsulfinyl)propoxy)methyl)benzene (0.5 g, 2.36 mmol, 1 eq.) was dissolved in DCM (1.5 L) followed by addition of NsNH2 (0.71 g, 3.53 mmol, 1.5 eq.) and PhIO (0.77 g, 03.53 mol, 1.5 eq.). The reaction mixture was stirred at room temperature for 10 min followed by addition of Rh2(OAc)4 (30 mg, 0.07 mmol, 0.03 eq.), stirred for 1.5 hours, and filtered. The filtered cake was slurried with DCM (30 mL). The combined DCM was concentrated to give an oil product that was reslurried with hexane to give the crude title compound (0.26 g) that was recrystallized from MeOH/DCM to furnish the title compound (0.141 g, 15%, 97.78% ee).
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([C:26](=[O:28])[CH3:27])[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:25])[C:15]2[CH:20]=[C:19]([N+:21]([O-:23])=[O:22])[CH:18]=[CH:17][C:16]=2F)[CH2:10][CH2:9]1.[CH3:29][N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1.O>C1COCC1>[CH3:29][N:30]1[CH2:35][CH2:34][N:33]([C:16]2[CH:17]=[CH:18][C:19]([N+:21]([O-:23])=[O:22])=[CH:20][C:15]=2[C:14]([N:11]2[CH2:12][CH2:13][N:8]([C:7]3[CH:6]=[CH:5][C:4]([C:26](=[O:28])[CH3:27])=[CH:3][CH:2]=3)[CH2:9][CH2:10]2)=[O:25])[CH2:32][CH2:31]1
Reactant: CC(=O)c1ccc(N2CCN(C(=O)c3cc([N+](=O)[O-])ccc3F)CC2)c(F)c1
Reactant: CN1CCNCC1
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)c1ccc(N2CCN(C(=O)c3cc([N+](=O)[O-])ccc3N3CCN(C)CC3)CC2)cc1
Temperature: 80 °C

Procedure:
A stirred mixture of 150 mg (0.39 mmol) 1-{3-fluoro-4-[4-(2-fluoro-5-nitro-benzoyl)-piperazin-1-yl]-phenyl}-ethanone, 200 mg (2.0 mmol) 1-methylpiperazine in 4 ml THF was heated to 80° C. for 1 h. Water was added to the reaction mixture, the precipitate isolated, dried and purified by flash-chromatography on silica gel with heptane/AcOEt as eluent. The title compound was obtained as a light yellow powder, MS (m/e): 471.2 (MH+, 100%).
Reaction SMILES: [C:1]([CH:3]1[CH2:7][S:6](=O)[CH2:5][CH2:4]1)#[N:2].C(O)(=O)C.O.[NH2:14][NH2:15]>C(O)C>[NH:14]1[C:4]2[CH2:5][S:6][CH2:7][C:3]=2[C:1]([NH2:2])=[N:15]1
Reactant: N#CC1CCS(=O)C1
Reactant: NN
Solvent: CCO
Solvent: O
Solvent: CC(=O)O
Product: Nc1n[nH]c2c1CSC2
Temperature: 80 °C
Reaction time: 8 h

Procedure:
To a suspension of 1.00 g (7.86 mmol) of 4-cyanotetrahydrothiophenone in 6 mL of ethanol was added 0.275 mL (286 mg, 4.76 mmol) of glacial acetic acid, followed by 0.475 mL (489 mg, 9.77 mmol) of hydrazine hydrate. The resulting clear solution was stirred overnight under nitrogen with heating in an oil bath at 80° C. The cooled reaction mixture was then partitioned between ethyl acetate and saturated sodium bicarbonate aqueous solution. The aqueous phase was re-extracted with an additional portion of ethyl acetate. The combined organic fractions were washed with saturated sodium chloride aqueous solution, then dried over anhydrous sodium sulfate, filtered, and concentrated to a syrup. Trituration of this oil with dichloromethane containing a small amount (less than 3%) of methanol resulted in crystallization. The suspension was heated to gentle reflux for a few minutes and then cooled. The solid was collected on a filter and washed with a small volume of dichloromethane to yield the title compound as almost colorless crystals. LC-MS 142 (M+1).
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[OH:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1.Br[CH2:18][CH:19]([O:23][CH2:24][CH3:25])[O:20][CH2:21][CH3:22].O>CN(C=O)C>[CH3:13][CH2:12][CH2:11][CH:10]([CH3:15])[CH3:9].[CH2:21]([O:20][CH:19]([O:23][CH2:24][CH3:25])[CH2:18][O:16][C:13]1[CH:14]=[CH:15][C:10]([CH2:9][CH2:8][OH:7])=[CH:11][CH:12]=1)[CH3:22]
Reactant: OCCc1ccc(O)cc1
Reactant: CCOC(CBr)OCC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCC(C)C
Product: CCOC(COc1ccc(CCO)cc1)OCC
Temperature: 90 °C

Procedure:
Caesium carbonate (28.3 g) was added to a solution of 4-(2-hydroxyethyl)phenol (10 g) and 2-bromo-1,1-diethoxyethane (11.79 mL) in DMF (150 mL). The resulting suspension was heated at 90° C. for 16 h. The reaction was poured into water (500 mL). The aqueous phase was extracted with ethyl acetate (3×200 mL). The combined organic solutions were washed with water (200 mL) and brine (200 mL), then dried over magnesium sulfate, filtered and evaporated in vacuo. Purification was by silica gel chromatography eluting with isohexane to 1:1 ethyl acetate:isohexane gradient to give the subtitled compound as a yellow oil. Yield 10 g.
Reaction SMILES: [C:1]1([C:7]2[C:11]([C:12]([F:15])([F:14])[F:13])=[C:10]([C:16]3[S:17][C:18]4[C:28]5[C:23](=[CH:24][C:25]([CH:29]=C)=[CH:26][CH:27]=5)[CH2:22][CH2:21][C:19]=4[N:20]=3)[O:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.I([O-])(=O)(=O)=[O:32].[Na+]>C1COCC1.C(O)CCC.O.[Os](=O)(=O)(=O)=O>[C:1]1([C:7]2[C:11]([C:12]([F:15])([F:14])[F:13])=[C:10]([C:16]3[S:17][C:18]4[C:28]5[C:23](=[CH:24][C:25]([CH:29]=[O:32])=[CH:26][CH:27]=5)[CH2:22][CH2:21][C:19]=4[N:20]=3)[O:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: C=Cc1ccc2c(c1)CCc1nc(-c3onc(-c4ccccc4)c3C(F)(F)F)sc1-2
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: O
Solvent: CCCCO
Solvent: C1CCOC1
Product: O=Cc1ccc2c(c1)CCc1nc(-c3onc(-c4ccccc4)c3C(F)(F)F)sc1-2
Reaction time: 1.5 h

Procedure:
To a solution of 3-phenyl-4-(trifluoromethyl)-5-(7-vinyl-4,5-dihydronaphtho[2,1-d]thiazol-2-yl)isoxazole (Preparation 56E, 0.350 g, 0.825 mmol) in THF (7.5 ml) at room temperature, was added a solution of osmium tetroxide, (2.5% in butanol, 1.7 ml, 0.017 mmol) followed by sodium periodate (0.265 g, 1.238 mmol) as a solution in 7.5 ml of water. After stirring for 90 min it was quenched with a saturated solution of sodium bisulfate. The dark colored suspension was filtered through Celite. The filter cake was washed with EtOAc. The combined EtOAc layers were washed with water, dried over anhydrous MgSO4, concentrated, and chromatographed to yield the 2-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-4,5-dihydronaphtho[2,1-d]thiazole-7-carbaldehyde as an orange colored solid. The product had an LC ret. time=3.136 min. (condition: Start % B=50, Final % B=100, Gradient Time=4 min, Flow Rate=4 ml/min, Wavelength=220, Solvent Pair=MeOH−H2O−TFA; Solvent A=10% MeOH−90% H2O−0.1% TFA; Solvent B=90% MeOH−10% H2O−0.1% TFA; Column 1=1: Waters Sunfire C18 4.6×50 mm (4 min. grad)); LC/MS M+1=427.03.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][C:5](=[O:7])[CH3:6].C(N(CC)CC)C.[Br:15][C:16]1[C:17](Cl)=[N:18][C:19]([Cl:22])=[N:20][CH:21]=1>C(#N)C.C(OCC)(=O)C>[Br:15][C:16]1[C:17]([NH:1][CH2:2][CH2:3][NH:4][C:5](=[O:7])[CH3:6])=[N:18][C:19]([Cl:22])=[N:20][CH:21]=1
Reactant: Clc1ncc(Br)c(Cl)n1
Reactant: CC(=O)NCCN
Solvent: CC#N
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC(=O)NCCNc1nc(Cl)ncc1Br
Temperature: 25 °C
Reaction time: 24 h
Yield: 75 %

Procedure:
0.14 ml (1.42 mmol) of N-(2-aminoethyl)acetamide and 0.22 ml (1.60 mmol) of triethylamine are added to a solution of 300 mg (1.32 mmol) of 5-bromo-2,4-dichloro-pyrimidine in 4.2 ml of acetonitrile at room temperature. The mixture is stirred at room temperature for 24 hours and then diluted with ethyl acetate. It is washed with saturated NaCl solution, 10% strength citric acid solution and saturated NaHCO3 solution. The organic phase is dried (Na2SO4), filtered and concentrated. The resulting residue is recrystallized from ethyl acetate. 294 mg (1.00 mmol; yield: 75%) of the product are obtained.
Reaction SMILES: [CH3:1][C:2]1[N:6]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=2)[N:5]=[C:4]([C:15]([OH:17])=O)[CH:3]=1.C(Cl)(=O)C(Cl)=O.[NH3:24]>ClCCl.CN(C=O)C.O1CCOCC1>[CH3:1][C:2]1[N:6]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=2)[N:5]=[C:4]([C:15]([NH2:24])=[O:17])[CH:3]=1
Reactant: Cc1ccc(Cn2nc(C(=O)O)cc2C)cc1
Reactant: N
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: C1COCCO1
Solvent: ClCCl
Product: Cc1ccc(Cn2nc(C(N)=O)cc2C)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mechanically stirred solution of 5-methyl-1-(4-methylbenzyl)-1H-pyrazole-3-carboxylic acid (Intermediate B, 500 mg, 2.17 mmol) in dichloromethane (15 mL) was added dropwise oxalylchloride (950 μL, 10.9 mmol) and one drop DMF. After stirring at rt for 1 h, all volatiles were removed in vacuo. The crude acid chloride thus obtained was re-dissolved in dioxane (10 mL) and added dropwise to aqueous ammonia (33%, 6.4 mL) at 0° C. After the addition was complete, the reaction mixture was stirred at rt for 30 minutes. A white precipitate formed which was collected by filtration and washed with water. The title compound was obtained after drying in vacuo (436 mg, 89%): 1H NMR (400 MHz, DMSO-d6) δ 7.37 (broad s, 1H), 7.14 (d, 2H, and broad s, 1H), 7.02 (d, 2H), 6.43 (s, 1H), 5.28 (s, 2H), 2.27 (s, 3H), 2.19 (s, 3H); ES-MS m/z 230 (MH)+; HPLC RT (Method E) 1.39 min.
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:9][C:10]1[C:19]2[C:18](=[O:20])[NH:17][C@H:16]3[CH2:21][N:22](C(OC(C)(C)C)=O)[CH2:23][C@@H:15]3[C:14]=2[CH:13]=[C:12]([CH2:31][CH3:32])[CH:11]=1>>[ClH:9].[CH2:1]([N:17]1[C@H:16]2[CH2:21][NH:22][CH2:23][C@@H:15]2[C:14]2[CH:13]=[C:12]([CH2:31][CH3:32])[CH:11]=[C:10]([Cl:9])[C:19]=2[C:18]1=[O:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrCc1ccccc1
Reactant: CCc1cc(Cl)c2c(c1)[C@H]1CN(C(=O)OC(C)(C)C)C[C@@H]1NC2=O
Product: CCc1cc(Cl)c2c(c1)[C@H]1CNC[C@@H]1N(Cc1ccccc1)C2=O
Product: Cl

Procedure:
Following the procedures described in Example 24, Parts A and B, except that benzyl bromide was used instead of iodomethane, (3aR,9bS)-tert-butyl 6-chloro-5-oxo-8-ethyl-3,3a,4,5-tetrahydro-1H-pyrrolo[3,4-c]isoquinoline-2(9bH)-carboxylate, the first eluting compound from the OD column separation of N-BOC intermediate enantiomers in Example 29 and 30 (the first eluting compound gave Example 29), was converted to the title compound of Example 43 as an off-white solid. 1H NMR (CD3OD): δ 7.40 (s, 1H), 7.38-7.24 (m, 5H), 7.01 (s, 1H), 5.09 and 4.67 (ABq, 2H, JAB=15.7 Hz), 4.04 (dd, 1H, J=7.4, 11.3 Hz), 3.88-3.81 (m, 1H), 3.65-3.55 (m, 2H), 3.40-3.32 (m, 2H), 2.70 (q, 2H, J=7.5 Hz), 1.25 (t, 3H, J=7.7 Hz). LRMS (ESI): 341.3/343.3 (M+H)+.
Reaction SMILES: [C:1]1([Li])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:8][O:9][C:10]1[CH:28]=[CH:27][C:13]([CH2:14][CH2:15][N:16]2[CH2:21][CH2:20][CH2:19][CH:18]([C:22]([O:24]CC)=O)[CH2:17]2)=[CH:12][CH:11]=1>>[C:1]1([C:22]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)([OH:24])[CH:18]2[CH2:19][CH2:20][CH2:21][N:16]([CH2:15][CH2:14][C:13]3[CH:12]=[CH:11][C:10]([O:9][CH3:8])=[CH:28][CH:27]=3)[CH2:17]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: [Li]c1ccccc1
Reactant: CCOC(=O)C1CCCN(CCc2ccc(OC)cc2)C1
Product: COc1ccc(CCN2CCCC(C(O)(c3ccccc3)c3ccccc3)C2)cc1

Procedure:
The title compound was prepared by the method of Example 11 by reacting phenyllithium with ethyl 1-(4-methoxyphenethyl)piperidine-3-carboxylate. The title compound was obtained as a colourless oil.
Reaction SMILES: NC1N=CN=C2N(CC3OC(=O)C4C(C=3C3C=CC=CC=3)=CC=CC=4)N=C(I)C=12.[F:30][C:31]1[CH:32]=[C:33]([C:39]2[C:47]3[C:42](=[N:43][CH:44]=[N:45][C:46]=3[NH2:48])[NH:41][N:40]=2)[CH:34]=[C:35]([O:37][CH3:38])[CH:36]=1.Br[CH:50]([C:52]1[O:53][C:54](=[O:80])[C:55]2[C:60]([C:61]=1[C:62]1[CH2:68][CH:67]3[N:69]([C:70]([O:72][CH2:73][C:74]4[CH:79]=[CH:78][CH:77]=[CH:76][CH:75]=4)=[O:71])[CH:64]([CH2:65][CH2:66]3)[CH:63]=1)=[CH:59][CH:58]=[CH:57][CH:56]=2)[CH3:51]>>[NH2:48][C:46]1[N:45]=[CH:44][N:43]=[C:42]2[N:41]([CH:50]([C:52]3[O:53][C:54](=[O:80])[C:55]4[C:60]([C:61]=3[C:62]3[CH2:63][CH:64]5[N:69]([C:70]([O:72][CH2:73][C:74]6[CH:75]=[CH:76][CH:77]=[CH:78][CH:79]=6)=[O:71])[CH:67]([CH2:66][CH2:65]5)[CH:68]=3)=[CH:59][CH:58]=[CH:57][CH:56]=4)[CH3:51])[N:40]=[C:39]([C:33]3[CH:34]=[C:35]([O:37][CH3:38])[CH:36]=[C:31]([F:30])[CH:32]=3)[C:47]=12
Reactant: CC(Br)c1oc(=O)c2ccccc2c1C1=CC2CCC(C1)N2C(=O)OCc1ccccc1
Reactant: COc1cc(F)cc(-c2n[nH]c3ncnc(N)c23)c1
Agent: Nc1ncnc2c1c(I)nn2Cc1oc(=O)c2ccccc2c1-c1ccccc1
Product: COc1cc(F)cc(-c2nn(C(C)c3oc(=O)c4ccccc4c3C3=CC4CCC(C3)N4C(=O)OCc3ccccc3)c3ncnc(N)c23)c1
Yield: 92.1 %

Procedure:
Title compound was prepared following the procedure described for the synthesis of Intermediate D1, from 3-(3-fluoro-5-methoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (Intermediate G1, 52.4 mg, 0.202 mmol) and benzyl 3-(3-(1-bromoethyl)-1-oxo-1H-isochromen-4-yl)-8-azabicyclo[3.2.1]oct-2-ene-8-carboxylate (Intermediate C40, 100 mg, 0.202 mmol) to give Benzyl 3-(3-(1-(4-amino-3-(3-fluoro-5-methoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-1-oxo-1H-isochromen-4-yl)-8-azabicyclo[3.2.1]oct-2-ene-8-carboxylate (125 mg, 0.186 mmol, 92% yield) as a yellow solid.
Reaction SMILES: C(ON=O)(C)(C)C.[Cl:8][C:9]([Cl:11])=[CH2:10].[Cl:12][C:13]1[C:14](N)=[C:15]2[C:20](=[CH:21][CH:22]=1)[N:19]=[CH:18][C:17]([CH3:23])=[N:16]2.[NH4+].[Cl-:26]>C(#N)C.[Cu](Cl)Cl.CCOC(C)=O>[Cl:12][C:13]1[C:14]([CH2:10][C:9]([Cl:26])([Cl:11])[Cl:8])=[C:15]2[C:20]([N:19]=[CH:18][C:17]([CH3:23])=[N:16]2)=[CH:21][CH:22]=1
Reactant: [Cl-]
Reactant: Cc1cnc2ccc(Cl)c(N)c2n1
Reactant: C=C(Cl)Cl
Agent: Cl[Cu]Cl
Agent: CC(C)(C)ON=O
Agent: [NH4+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: Cc1cnc2ccc(Cl)c(CC(Cl)(Cl)Cl)c2n1
Reaction time: 4 h
Yield: 56 %

Procedure:
Tert-butylnitrite (2.74 g, 26.60 mmol, 1.5 equiv) was added to a suspension of copper(II) chloride (2.86 g, 21.28 mmol, 1.2 equiv) in anhydrous acetonitrile (25 ml). 1,1-Dichloroethene (25.8 g, 266 mmol, 15 equiv) and a solution of 6-chloro-3-methyl-quinoxalin-5-ylamine (3.43 g, 17.74 mmol) in anhydrous acetonitrile (16 ml) were added. After 4 hours at room temperature, concentrated aqueous NH4Cl solution and EtOAc were added. The mixture was filtered and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified via flash chromatography (gradient of hexane/EtOAc 100:0 to 90:10) to afford the title compound (3.08 g, 56%) as an oil. 1H NMR (400 MHz, CDCl3): δ=8.71 (s, 1H), 8.02 (d, J=8.8 Hz, 1H), 7.74 (d, J=8.8 Hz, 1H), 4.98 (s, 2H), 2.77 (s, 3H). MS (ES+): 310 (M+H)+.
Reaction SMILES: [NH:1]([C:16]([O:18][CH2:19][CH:20]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:26]2[C:21]1=[CH:22][CH:23]=[CH:24][CH:25]=2)=[O:17])[C@H:2]([C:13](O)=[O:14])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.ON1C(=O)CCC1=O.Cl.CN(C)CCCN=C=NCC.C(N(CC)C(C)C)(C)C.[NH2:62][C@H:63]([C:71]([OH:73])=[O:72])[CH2:64][S:65][S:66][C:67]([CH3:70])([CH3:69])[CH3:68].Cl>ClCCl>[NH:6]1[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:4]([CH2:3][C@@H:2]([C:13](=[O:14])[NH:62][C@H:63]([C:71]([OH:73])=[O:72])[CH2:64][S:65][S:66][C:67]([CH3:70])([CH3:68])[CH3:69])[NH:1][C:16](=[O:17])[O:18][CH2:19][CH:20]2[C:32]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[C:26]3[C:21]2=[CH:22][CH:23]=[CH:24][CH:25]=3)=[CH:5]1
Reactant: CC(C)(C)SSC[C@H](N)C(=O)O
Reactant: O=C(N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O)OCC1c2ccccc2-c2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C1CCC(=O)N1O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)SSC[C@H](NC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Temperature: 25 °C
Reaction time: 5.5 h
Yield: 57.3 %

Procedure:
A solution of Fmoc-Trp-OH (5 g, 11.72 mmol) and N-hydroxysuccinimide (1.35 g, 11.72 mmol) in dichloromethane (23 ml) was cooled to 0° C., after which 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC.HCl, 2.25 g, 11.72 mmol) was added and the reaction solution was stirred at room temperature for 5.5 hours. The reaction solution was cooled to 0° C., after which N,N-diisopropylethylamine (2.05 ml, 11.72 mmol) and H-Cys(StBu)-OH (2.45 g, 11.72 mmol) were added and the reaction solution was stirred at room temperature for 14 hours. Dichloromethane and 1 M hydrochloric acid were added to the reaction mixture, followed by extraction with dichloromethane. The organic layer was washed with 25 wt % brine and dried over sodium sulfate. The resulting solution was concentrated under reduced pressure, and the concentration residue was purified by reverse-phase silica gel column chromatography (0.1% aqueous formic acid solution/0.1% formic acid-acetonitrile solution) to afford (5S,8R)-5-((1H-indol-3-yl)methyl)-1-(9H-fluoren-9-yl)-12,12-dimethyl-3,6-dioxo-2-oxa-10,11-dithia-4,7-diazatridecane-8-carboxylic acid (Compound SP602, Fmoc-Trp-Cys(StBu)-OH) (4.15 g, 57%).
Reaction SMILES: [OH-].[Li+:2].[SH:3]([O:6][C:7]([F:10])([F:9])[F:8])(=[O:5])=[O:4]>>[Li:2][S:3]([O:6][C:7]([F:10])([F:9])[F:8])(=[O:5])=[O:4]
Reactant: O=[SH](=O)OC(F)(F)F
Reactant: [Li+]
Agent: [OH-]
Product: [Li]S(=O)(=O)OC(F)(F)F

Procedure:
To a lithium hydroxide (LiOH.2H2O, 4.20 g, 0.10 mol) aqueous solution, HSO3CF3 (15.01 g, 0.10 mol) was added dropwise. Water was evaporated from the resulting solution in a rotavapor, the residue was recrystallized in ethyl cyanide/toluene to yield LiSO3CF3. The LiSO3CF3 obtained was then dried under vaccum at 140° C. for 24 hr.
Reaction SMILES: [H-].[Na+].[C:3]([O:6][CH2:7][C:8]1[CH:9]=[C:10]([CH3:24])[CH:11]=[C:12]2[C:17]=1[N:16]=[CH:15][C:14]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[C:13]2[OH:23])(=[O:5])[CH3:4].Cl[C:26]([O:28][CH2:29][CH:30]([CH3:32])[CH3:31])=[O:27].C(O)(=O)C>CN1CCCC1=O.C(OCC)(=O)C>[C:3]([O:6][CH2:7][C:8]1[CH:9]=[C:10]([CH3:24])[CH:11]=[C:12]2[C:17]=1[N:16]([C:26]([O:28][CH2:29][CH:30]([CH3:32])[CH3:31])=[O:27])[CH:15]=[C:14]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:13]2=[O:23])(=[O:5])[CH3:4]
Reactant: CCOC(=O)c1cnc2c(COC(C)=O)cc(C)cc2c1O
Reactant: CC(C)COC(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: CCOC(=O)c1cn(C(=O)OCC(C)C)c2c(COC(C)=O)cc(C)cc2c1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 49.5 %

Procedure:
Sodium hydride (3.1 g, 60% dispersion) is added at 0° C. to a stirred solution of ethyl 8-((acetyloxy)methyl)-4-hydroxy-6-methyl-3-quinolinecarboxylate (Preparation 25, 29.6 g) in N-methylpyrrolidinone (250 ml). The solution is allowed to warm to room temperature over 10 min and isobutyl chloroformate (25.5 g) is then added. After 30 min, acetic acid (3.6 g) is added. The solvent is evaporated under reduced pressure, and the residual oil is partitioned between ethyl acetate and water. The ethyl acetate layer is concentrated to give an oil. The crude product is dissolved in ethyl acetate (50 ml) and is chromatographed on silica gel with 10% ethyl acetate/hexane as the initial eluant to give 19.5 g of the title compound. A sample is recrystallized from ethyl acetate/hexane for analysis. Physical characteristics: M.p. 101-103° C.; 1H NMR (CDCl3) δ1.05, 1.44, 2.12, 2.18, 2.59, 4.15, 4.45, 5.82, 7.74, 7.88, 9.40. Anal. Found: C, 62.42; H, 6.34; N, 3.45.
Reaction SMILES: [CH2:1]1[CH:5]2[CH2:6][NH:7][CH2:8][CH:4]2[CH2:3][N:2]1[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10].Cl[C:17]1[CH:18]=[CH:19][C:20]2[N:21]([C:23]([C:26]([F:29])([F:28])[F:27])=[N:24][N:25]=2)[N:22]=1.C(N(C(C)C)CC)(C)C>C(O)C>[F:28][C:26]([F:27])([F:29])[C:23]1[N:21]2[N:22]=[C:17]([N:7]3[CH2:6][CH:5]4[CH2:1][N:2]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:3][CH:4]4[CH2:8]3)[CH:18]=[CH:19][C:20]2=[N:25][N:24]=1
Reactant: FC(F)(F)c1nnc2ccc(Cl)nn12
Reactant: CC(C)(C)OC(=O)N1CC2CNCC2C1
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CC2CN(c3ccc4nnc(C(F)(F)F)n4n3)CC2C1
Temperature: 70 °C
Reaction time: 1 h
Yield: 55.9 %

Procedure:
tert-Butyl hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (3.15 g, 14.83 mmol) was added to a mixture of 6-chloro-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine (3 g, 13.48 mmol) and diisopropyethylamine (4.66 mL, 26.96 mmol) and ethanol (50 mL). The mixture was warmed to 70° C. over a period of 10 minutes, stirred at 70° C. for 1 hour, and then allowed to cool to ambient temperature to give a precipitate. The precipitate was collected by filtration, washed with ethanol (50 mL), and dried under vacuum to afford tert-butyl 5-(3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (3.00 g, 55.9%) as a white solid.
Reaction SMILES: [CH2:1]([N:3]([CH2:5][CH3:6])[OH:4])[CH3:2].[CH2:7]=O.[CH2:9]([NH:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH2:10][CH2:11][CH3:12]>>[CH2:1]([N:3]([CH2:5][CH3:6])[O:4][CH2:7][N:13]([CH2:14][CH2:15][CH2:16][CH3:17])[CH2:9][CH2:10][CH2:11][CH3:12])[CH3:2]
Reactant: CCCCNCCCC
Reactant: C=O
Reactant: CCN(O)CC
Product: CCCCN(CCCC)CON(CC)CC

Procedure:
The procedure of Example I is repeated using 26.74 g of diethylhydroxylamine, 29.22 g of aqueous formaldehyde (37%) solution and 38.77 g of di-n-butylamine, to afford the title compound as a colorless liquid.