Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11](/[CH:14]=[C:15]3/[C:16](=[O:22])[N:17]=[C:18](SC)[S:19]/3)[CH:12]=2)[N:7]=[CH:6][C:5]=1[C:23]#[N:24])[CH3:2].[CH:25]1([NH2:28])[CH2:27][CH2:26]1.CCN(C(C)C)C(C)C>>[CH:25]1([NH:28][C:18]2[S:19]/[C:15](=[CH:14]\[C:11]3[CH:12]=[C:13]4[C:8](=[CH:9][CH:10]=3)[N:7]=[CH:6][C:5]([C:23]#[N:24])=[C:4]4[O:3][CH2:1][CH3:2])/[C:16](=[O:22])[N:17]=2)[CH2:27][CH2:26]1
Reactant: NC1CC1
Reactant: CCOc1c(C#N)cnc2ccc(/C=C3\SC(SC)=NC3=O)cc12
Solvent: CCN(C(C)C)C(C)C
Product: CCOc1c(C#N)cnc2ccc(/C=C3\SC(NC4CC4)=NC3=O)cc12

Procedure:
Similar procedure as described in example 14h was used, starting from 4-ethoxy-6-[2-methylsulfanyl-4-oxo-4H-thiazol-(5Z)-ylidenemethyl]-quinoline-3-carbonitrile (example 14g), cyclopropylamine and DIEA to give 6-[2-Cyclopropylamino-4-oxo-4H-thiazol-(5Z)-ylidenemethyl]-4-ethoxy-quinoline-3-carbonitrile. LC-MS m/e 365 (MH+).
Reaction SMILES: C([O:3][C:4](=[O:26])[CH:5]([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:6][NH:7][C:8]1[S:9][CH:10]=[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:12]=1)C.[OH-].[K+].OS([O-])(=O)=O.[K+]>CCO.O>[CH2:19]([CH:5]([CH2:6][NH:7][C:8]1[S:9][CH:10]=[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:12]=1)[C:4]([OH:26])=[O:3])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CCOC(=O)C(CNc1nc(-c2ccccc2)cs1)Cc1ccccc1
Agent: O=S(=O)([O-])O
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)C(CNc1nc(-c2ccccc2)cs1)Cc1ccccc1
Reaction time: 5 h

Procedure:
To a solution of 2-Benzyl-3-(4-phenyl-thiazol-2-ylamino)-propionic ethyl ester (22r) (0.028 mmol, 10 mg) in EtOH (2 mL) and water (200 μL) is added KOH 1N solution (224 μL, 8 eq.). After 5 hours, the solution is neutralized with KHSO4 1N solution and lyophilized before purification.
Reaction SMILES: [F:1][C:2]([F:9])([C:5]([F:8])([F:7])[F:6])[CH2:3][OH:4].[C:10](=O)([O:13]C)[O:11][CH3:12]>C[O-].[Na+].CO>[C:10](=[O:13])([O:4][CH2:3][C:2]([F:9])([F:1])[C:5]([F:8])([F:7])[F:6])[O:11][CH3:12]
Reactant: OCC(F)(F)C(F)(F)F
Reactant: COC(=O)OC
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)OCC(F)(F)C(F)(F)F
Temperature: 120 °C
Yield: 50.9 %

Procedure:
In a flask (500-ml volume) equipped with 10 distillation columns, 2,2,3,3,3-pentafluoropropanol (100 g, 0.67 mol), dimethyl carbonate (180 g, 2.0 mol) and a 28% sodium methoxide/methanol solution (1.3 g) were charged. The flask was heated to 120° C. to allow the starting materials to react for 10 hours while removing the methanol from the distillation columns by evaporation. After allowing the mixture to cool to room temperature, an aqueous solution of ammonium chloride was added to the mixture and the mixture was shaken to remove the sodium methoxide. The organic layer was washed with water, dried and distilled to give methyl 2,2,3,3,3-pentafluoropropyl carbonate as a colorless liquid (71 g, yield 51%). The chemical structure of the produced compound was determined based on the IR and NMR absorbance spectra shown in FIG. 7 and FIG. 8 respectively and the mass spectrometry spectrum (M/e=208).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][O:10][CH3:11])=[CH:4][N:3]=1.C([Li])(C)(C)C.[I:17]I.O>C1COCC1>[F:1][C:2]1[CH:7]=[C:6]([I:17])[C:5]([O:8][CH2:9][O:10][CH3:11])=[CH:4][N:3]=1
Reactant: COCOc1ccc(F)nc1
Reactant: II
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Solvent: O
Product: COCOc1cnc(F)cc1I
Temperature: 25 °C
Yield: 52.8 %

Procedure:
Cool a solution of 2-fluoro-5-methoxymethoxy-pyridine (4.1 g, 26.1 mmol) in THF (60 mL) to −75° C. Add tert-butyllithium (1.7 M in pentane, 30.4 mL, 51.7 mmol) over a period of 30 min. Stir the mixture for an additional half an hour. Add iodine (9.8 g, 38.6 mmol, dissolved in 60 mL of THF). Stir for 1 h after the addition is complete. Allow the temperature to raise to RT over 1 h while stirring. Treat the mixture with water. Extract the solution with ethyl acetate three times. Wash the organic layer with aqueous saturated sodium chloride. Dry the mixture over sodium sulfate. Concentrate the solution in vacuo to a brown solid. Triturate the brown solid with hexane. Filter to afford the title compound (3.9 g, 53%) as a brown solid. 1H NMR (400 MHz, CDCl3) δ 3.53 (s, 3H), 5.23 (s, 2H), 7.39 (d, J=4.0 Hz, 1H), 7.96 (d, J=1.6 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([N:18]3[CH:22]=[CH:21][N:20]=[C:19]3[CH3:23])[O:11][C:12]=2[CH2:13][CH2:14][C:15]([OH:17])=[O:16])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].I[CH2:31][CH3:32].CN(C)C=O>O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[C:10]([N:18]3[CH:22]=[CH:21][N:20]=[C:19]3[CH3:23])[O:11][C:12]=2[CH2:13][CH2:14][C:15]([O:17][CH2:31][CH3:32])=[O:16])=[CH:6][CH:7]=1
Reactant: CCI
Reactant: Cc1nccn1-c1nc(-c2ccc(Cl)cc2)c(CCC(=O)O)o1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CCc1oc(-n2ccnc2C)nc1-c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 91.3 %

Procedure:
A mixture of 4-(4-chlorophenyl)-2-(2-methyl-1-imidazolyl)-5-oxazolepropionic acid(500 mg), potassium carbonate(310 mg), iodoethane(350 mg) and N,N-dimethylformamide(10 ml) was stirred at room temperature for 16 hours. Water was added to the mixture, and the resulting mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with water, and dried(MgSO4). The solvent was evaporated and the crystals thus precipitated were collected by filtration. These were recrystallized from acetone-hexane to give colorless of ethyl 4-(4-chlorophenyl)-2-(2-methyl-1-imidazolyl)-5-oxazolepropionate(495 mg, 91%). mp 70-71° C.
Reaction SMILES: C(OC([C:6]1[CH:7]=[C:8]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[Br:18])[CH:9]=[CH:10][CH:11]=1)=O)C.[CH2:19]([O:21][C:22](C1C=CC=CC=1OB(C1C=CC=CC=1)O)=[O:23])[CH3:20]>>[CH2:19]([O:21][C:22]([C:7]1[C:8]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[Br:18])=[CH:9][CH:10]=[CH:11][CH:6]=1)=[O:23])[CH3:20]
Reactant: CCOC(=O)c1cccc(-c2ccccc2Br)c1
Reactant: CCOC(=O)c1ccccc1OB(O)c1ccccc1
Product: CCOC(=O)c1ccccc1-c1ccccc1Br

Procedure:
Prepared using the same conditions for the synthesis of 2′-bromo-biphenyl-3-carboxylic acid ethyl ester substituting 3-ethoxycarbonylphenyl boronic acid with 2-ethoxycarbonylphenylphenyl boronic acid.
Reaction SMILES: [CH2:1]([C@H:8]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[C@H:9]([OH:18])[CH2:10][NH:11][O:12][CH:13]([CH2:16][CH3:17])[CH2:14][CH3:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:27][O:28][C:29]1[CH:34]=[CH:33][C:32]([S:35](Cl)(=[O:37])=[O:36])=[CH:31][CH:30]=1.C(N(C(C)C)CC)(C)C>O1CCCC1.CN(C)C1C=CN=CC=1>[CH2:1]([C@H:8]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:24])([CH3:23])[CH3:25])[C@H:9]([OH:18])[CH2:10][N:11]([O:12][CH:13]([CH2:14][CH3:15])[CH2:16][CH3:17])[S:35]([C:32]1[CH:31]=[CH:30][C:29]([O:28][CH3:27])=[CH:34][CH:33]=1)(=[O:37])=[O:36])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCC(CC)ONC[C@@H](O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCC(CC)ON(C[C@@H](O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C)S(=O)(=O)c1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 70.3 %

Procedure:
A mixture of tert-butyl (1S,2R)-1-benzyl-3-[(1-ethylpropoxy)amino]-2-hydroxypropylcarbamate (100 mg, 0.273 mmol), 4-methoxyphenylsulphonyl chloride (57 mg, 0.273 mmol), and diisoproylethylamine (0.0476 mL, 0.273 mmol) in anhydrous tetrahydrofuran (2 mL) was stirred under Argon for 16 hours at ambient temperature. A catalytic quantity of 4-dimethylaminopyridine (˜1 mg) was added and the reaction was heated at reflux for approximately two hours. After cooling, the reaction was evaporated in vacuo and the residue was dissolved in ethyl acetate. The solution was washed with aqueous potassium carbonate (5% w/v), aqueous hydrochloric acid (1N) and brine. The organic layer was then dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo. The residue was purified on a preparative TLC plate (20×20 cm, 500 NM) eluting with 95:5 methylene chloride:methanol. The product band was removed, eluted with 4:1 methylene chloride:methanol, filtered, and evaporated in vacuo. The residue was purified again on a preparative TLC plate (20×20 cm, 500 μM) eluting with 95:5 methylene chloride:ethyl acetate. The product band was removed, eluted with 4:1 methylene chloride:methanol, filtered, and evaporated in vacuo to provide tert-butyl (1S,2R)-1-benzyl-3-{(1-ethylpropoxy)[(4-methoxyphenyl)sulfonyl]amino}-2-hydroxypropylcarbamate (103 mg, 70%) as a foam. H1-NMR (chloroform-D3): 0.95 (m, 6H), 1.38 (s, 9H), 1.64 (m, 4H), 3.01 (m, 5H), 3.83 (m, 2H), 3.93 (s, 3H), 4.20 (m, 1H), 4.61 (m, 1H), 7.03 (d, 2H), 7.29 (m, 5H), 7.80 (d, 2H). MS(ESI): 559(M+Na).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH3:23])=[CH:5][C:6]([CH2:12][C:13]2[C:14]([CH3:22])=[N:15][N:16]([CH2:19][C:20]#[N:21])[C:17]=2[CH3:18])=[C:7]2[C:11]=1[CH2:10][CH2:9][CH2:8]2.Cl.[NH2:25][OH:26].C(=O)([O-])[O-].[K+].[K+]>CO.O>[OH:26][NH:25][C:20](=[NH:21])[CH2:19][N:16]1[C:17]([CH3:18])=[C:13]([CH2:12][C:6]2[CH:5]=[C:4]([CH3:23])[C:3]([O:2][CH3:1])=[C:11]3[C:7]=2[CH2:8][CH2:9][CH2:10]3)[C:14]([CH3:22])=[N:15]1
Reactant: NO
Reactant: COc1c(C)cc(Cc2c(C)nn(CC#N)c2C)c2c1CCC2
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: COc1c(C)cc(Cc2c(C)nn(CC(=N)NO)c2C)c2c1CCC2
Temperature: 70 °C
Reaction time: 33 h
Yield: 81.2 %

Procedure:
To a stirred solution of [4-(7-Methoxy-6-methyl-indan-4-ylmethyl)-3,5-dimethyl-pyrazol-1-yl]-acetonitrile (2.0 gm 0.00647 mole) in methanol (50 ml), A suspension of Hydroxylamine hydrochloride (2.29 gm, 0.033 mole) and Potassium carbonate (4.37 gm, 0.0317 mole) in water (20 ml) was added. The reaction mixture was stirred for 30-36 hours at 70° C., cooled and then was filtered. The obtained solid was washed with water (10 ml) and finally with Hexane and dried under vacuum to give 1.8 gm of desired product
Reaction SMILES: [CH2:1]([O:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[C:11]([O:24]C)[N:12]2[CH2:15][CH2:16][CH2:17][CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][NH:19]2)=[C:8]([NH2:26])[N:7]=1)[CH2:2][CH2:3][CH3:4].I[CH2:28][CH2:29][CH2:30][CH3:31]>>[NH2:26][C:8]1[N:7]=[C:6]([O:5][CH2:1][CH2:2][CH2:3][CH3:4])[N:14]=[C:13]2[C:9]=1[NH:10][C:11](=[O:24])[N:12]2[CH2:15][CH2:16][CH2:17][CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][N:19]1[CH2:28][CH2:29][CH2:30][CH3:31]
Reactant: CCCCOc1nc(N)c2nc(OC)n(CCCC3CCCCN3)c2n1
Reactant: CCCCI
Product: CCCCOc1nc(N)c2[nH]c(=O)n(CCCC3CCCCN3CCCC)c2n1

Procedure:
Prepared similarly to Example 14 from 2-(butyloxy)-8-(methyloxy)-9-[3-(2-piperidinyl)propyl]-9H-purin-6-amine and 1-iodobutane.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]3[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=3[CH:9]=2)[C:4](O)=[CH:3][CH:2]=1.CN(C)C1C=CC=CC=1.P(Cl)(Cl)([Cl:27])=O>>[Cl:27][C:4]1[C:5]2[C:10](=[CH:9][C:8]3[CH:11]=[CH:12][CH:13]=[CH:14][C:7]=3[CH:6]=2)[N:1]=[CH:2][CH:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Oc1ccnc2cc3ccccc3cc12
Solvent: CN(C)c1ccccc1
Product: Clc1ccnc2cc3ccccc3cc12

Procedure:
Under a nitrogen atmosphere, benzo[g]quinolin-4-ol (6) (100 mg, 0.51 mmol) was refluxed in 2 ml of phosphorus oxychloride (0.25 M) in the presence of N,N-dimethylaniline (0.25 mL, 3.8 equivalents) until deemed complete by TLC. Removal of the excess phosphorus oxycloride in vacuo and flash chromatography (gradient: 9:1 to 8:2 to 7:3 hexanes:EtOAc) afforded 108 mg of clean 4-chlorobenzo[g]quinoline (7b) in quantitative yield.
Reaction SMILES: Br[CH2:2][C:3]1[O:7][N:6]=[C:5]([C:8]([NH:10][C@@H:11]([CH3:27])[CH2:12][N:13]2[CH:17]=[CH:16][C:15]([C:18]3[CH:23]=[CH:22][C:21]([C:24]#[N:25])=[C:20]([Cl:26])[CH:19]=3)=[N:14]2)=[O:9])[CH:4]=1.[NH:28]1[CH:32]=[CH:31][N:30]=[CH:29]1>C(#N)C>[N:28]1([CH2:2][C:3]2[O:7][N:6]=[C:5]([C:8]([NH:10][C@@H:11]([CH3:27])[CH2:12][N:13]3[CH:17]=[CH:16][C:15]([C:18]4[CH:23]=[CH:22][C:21]([C:24]#[N:25])=[C:20]([Cl:26])[CH:19]=4)=[N:14]3)=[O:9])[CH:4]=2)[CH:32]=[CH:31][N:30]=[CH:29]1
Reactant: C[C@@H](Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1)NC(=O)c1cc(CBr)on1
Reactant: c1c[nH]cn1
Solvent: CC#N
Product: C[C@@H](Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1)NC(=O)c1cc(Cn2ccnc2)on1
Temperature: 25 °C
Reaction time: 8 h
Yield: 13.81 %

Procedure:
(S)-5-(bromomethyl)-N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)-propan-2-yl)isoxazole-3-carboxamide (0.328 g, 0.731 mmol) of Example 197(a) was dissolved in acetonitrile (10 ml) and imidazole (0.31 g, 4.55 mmol) dissolved in acetonitrile (3 ml) was added. The mixture was stirred at RT overnight. The mixture was evaporated, the residue dissolved in ethyl acetate and extracted with water. The organic phase was dried, filtered and evaporated. The product was purified by recrystallization from ethyl acetate. Yield 13.81%. 1H-NMR (400 MHz; DMSO-d6): δ 1.15 (d, 3H), 4.28-4.32 (m, 2H), 4.40-4.48 (m, 1H), 5.50 (s, 2H), 6.63 (s, 1H), 6.93 (d, 1H), 6.93-6.94 (m, 1H), 7.22-7.23 (m, 1H), 7.75-7.77 (m, 1H), 7.80 (d, 1H), 7.90 (dd, 1H), 7.96 (d, 1H), 8.07 (d, 1H), 8.80 (d, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N+:9]([O-])=O)[CH:5]=[CH:6][C:7]=1Cl.[O:12]1[CH2:17][CH2:16][N:15]([CH:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)[CH2:14][CH2:13]1>>[Br:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[N:21]1[CH2:22][CH2:23][CH:18]([N:15]2[CH2:16][CH2:17][O:12][CH2:13][CH2:14]2)[CH2:19][CH2:20]1)[NH2:9]
Reactant: C1CC(N2CCOCC2)CCN1
Reactant: O=[N+]([O-])c1ccc(Cl)c(Br)c1
Product: Nc1ccc(N2CCC(N3CCOCC3)CC2)c(Br)c1

Procedure:
By the reaction and treatment in the same manner as in Starting Material Synthesis Example 40 using 3-bromo-4-chloronitrobenzene and 4-morpholinopiperidine, the title compound was obtained, melting point: 215–217° C.
Reaction SMILES: [F:1][C:2]1[CH:26]=[CH:25][CH:24]=[CH:23][C:3]=1[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([C:14]2[N:19]=[C:18]([NH2:20])[C:17]([O:21]C)=[CH:16][N:15]=2)=[N:6]1.C(=O)([O-])[O-].[K+].[K+].Br[C:34]1[CH:39]=[CH:38][N:37]=[CH:36][C:35]=1[C:40]#[N:41]>CN(C)C=O>[F:1][C:2]1[CH:26]=[CH:25][CH:24]=[CH:23][C:3]=1[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([C:14]2[N:19]=[C:18]([NH:20][C:34]3[CH:39]=[CH:38][N:37]=[CH:36][C:35]=3[C:40]#[N:41])[C:17]([OH:21])=[CH:16][N:15]=2)=[N:6]1
Reactant: N#Cc1cnccc1Br
Reactant: COc1cnc(-c2nn(Cc3ccccc3F)c3ccccc23)nc1N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#Cc1cnccc1Nc1nc(-c2nn(Cc3ccccc3F)c3ccccc23)ncc1O
Temperature: 100 °C
Reaction time: 18 h

Procedure:
50 mg of 4-amino-2-[1-(2-fluorobenzyl)-1H-indazol-3-yl]pyrimidin-5-ol (1-11-1, 0.149 mmol, 1. eq.) were dissolved in 3 ml of N,N-dimethylformamide. 103 mg of potassium carbonate (0.746 mmol, 5 eq.) and 32.8 mg of 4-bromopyridine-3-carbonitrile (0.179 mmol, 1.2 eq.) were added. The reaction mixture was stirred at 100° C. bath temperature for 18 hours. After cooling at room temperature the mixture was filtered off and washed with dichloromethane. The filtrate was concentrated in vacuo. The residue was purified by preparative HPLC and preparative TLC to yield 4.21 mg (0.01 mmol, 6.1%) of the analytically pure target compound.
Reaction SMILES: [CH:1]([CH:4]1[C:9]([O:10][CH3:11])=[N:8][CH2:7][C:6]([O:12][CH3:13])=[N:5]1)([CH3:3])[CH3:2].C([Li])CCC.I[CH2:20][CH2:21][C:22]([F:25])([F:24])[F:23]>C1COCC1.C(OCC)(=O)C>[CH:1]([CH:4]1[C:9]([O:10][CH3:11])=[N:8][CH:7]([CH2:20][CH2:21][C:22]([F:25])([F:24])[F:23])[C:6]([O:12][CH3:13])=[N:5]1)([CH3:3])[CH3:2]
Reactant: FC(F)(F)CCI
Reactant: COC1=NC(C(C)C)C(OC)=NC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC1=NC(C(C)C)C(OC)=NC1CCC(F)(F)F
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 58.5 %

Procedure:
To a stirred solution of 2-isopropyl-3,6-dimethoxy-2,5-dihydro-pyrazine (1 mL, 5.58 mmol) in THF (13.5 mL) under argon at −78° C. was added a solution of n-butyllithium (2.5 M, 2.3 mL, 5.75 mmol). The solution was stirred at −78° C. for 30 minutes. A solution of 1-Iodo-3,3,3-trifluoropropane (925 μL, 5.87 mmol) in THF (11.5 mL) was added slowly. The resulting solution was stirred at −78° C. for 5 hours, warmed to room temperature and diluted with ethyl acetate. The organic layer was washed successively with saturated aqueous NH4Cl solution, water and brine. The organic layer was then dried (MgSO4), concentrated and purified by flash chromatography to yield 2-Isopropyl-3,6-dimethoxy-5-(3,3,3-trifluoro-propyl)-2,5-dihydro-pyrazine (915 mg, 59%). 1H-NMR: 400 MHz, (CDCl3) δ: 4.04-3.99 (m, 1H), 3.98-3.95 (m, 1H), 3.71 (s, 3H), 3.68 (s, 3H), 2.29-2.20 (m, 1H), 2.18-2.04 (m, 3H), 1.94-1.84 (m, 1H), 1.03 (d, J=6.9 Hz, 3H), 0.71 (d, J=6.8 Hz, 3H) ppm.
Reaction SMILES: [CH3:1][C:2]1[NH:6][N:5]=[CH:4][C:3]=1B1OC(C)(C)C(C)(C)O1.Br[C:17]1[N:22]2[CH:23]=[CH:24][N:25]=[C:21]2[C:20]([NH:26][C:27]2[CH:32]=[CH:31][C:30]([N:33]3[CH2:38][CH2:37][N:36]([CH3:39])[CH2:35][CH2:34]3)=[CH:29][CH:28]=2)=[N:19][CH:18]=1>O1CCOCC1.CN(C=O)C.C([O-])([O-])=O.[Na+].[Na+].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>[CH3:39][N:36]1[CH2:37][CH2:38][N:33]([C:30]2[CH:31]=[CH:32][C:27]([NH:26][C:20]3[C:21]4[N:22]([CH:23]=[CH:24][N:25]=4)[C:17]([C:3]4[CH:4]=[N:5][NH:6][C:2]=4[CH3:1])=[CH:18][N:19]=3)=[CH:28][CH:29]=2)[CH2:34][CH2:35]1
Reactant: CN1CCN(c2ccc(Nc3ncc(Br)n4ccnc34)cc2)CC1
Reactant: Cc1[nH]ncc1B1OC(C)(C)C(C)(C)O1
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: [Na+]
Solvent: C1COCCO1
Solvent: CN(C)C=O
Product: Cc1[nH]ncc1-c1cnc(Nc2ccc(N3CCN(C)CC3)cc2)c2nccn12

Procedure:
In the same way as described for Compound 127, step 4, using 5-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (75 mg, 0.36 mmol), (5-bromoimidazo[1,2-a]pyrazin-8-yl)-(4-(4-methylpiperazin-1-yl)phenyl)amine (70 mg, 0.18 mmol) and Pd(PPh3)4 (52 mg, 0.045 mmol) in dioxane (0.6 mL), DMF (1.33 mL) and 1.5M Na2CO3 (0.97 mL). The residue is chromatographed on silica gel, eluting with DCM followed by 95:5 DCM:NH3 (7M in MeOH), and the fractions containing the desired product are combined and evaporated. The title compound is isolated as a solid. HPLC (254 nm): Rt 1.62 min (98.2%); m/z (APCI) 389 (M+H)+.
Reaction SMILES: [CH2:1]([S:5][CH:6]1[CH2:11][O:10][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=2)=[N:8][N:7]1[C:22]([NH:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=1)=[O:23])[CH2:2][CH2:3][CH3:4].C(=O)(O)[O-:36].[Na+].ClC1C=CC=C(C(OO)=O)C=1>ClCCl>[CH2:1]([S:5]([CH:6]1[CH2:11][O:10][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:19])([F:21])[F:20])[CH:13]=2)=[N:8][N:7]1[C:22]([NH:24][C:25]1[CH:26]=[CH:27][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:29][CH:30]=1)=[O:23])=[O:36])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCSC1COC(c2cccc(C(F)(F)F)c2)=NN1C(=O)Nc1ccc(C(F)(F)F)cc1
Reactant: O=C([O-])O
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Solvent: ClCCl
Product: CCCCS(=O)C1COC(c2cccc(C(F)(F)F)c2)=NN1C(=O)Nc1ccc(C(F)(F)F)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To an ice-cooled mixture of 1.1 g 5-(butylthio)-5,6-dihydro-2-[3-(trifluoromethyl)phenyl]-N-[4-(trifluoro-methyl)phenyl]-4H-1,3,4-oxadiazine-4-carboxamide (Compound 14) and 1.8 g sodium bicarbonate in 15 ml dichloromethane was added dropwise a solution of 0.52 g 3-chloroperbenzoic acid in 4 ml dichloromethane. After stirring for 30 min the mixture was filtered. The filtrate was washed with 2M sodium sulfite and saturated sodium bicarbonate and then dried over sodium sulfate and concentrated under vacuum to produce 5-(butylsulfinyl)-5,6-dihydro-2-[3-(trifluoromethyl)phenyl]-N-[4-(trifluoromethyl)phenyl]-4H-1,3,4-oxadiazine-4-carboxamide. The structure was confirmed by 1H NMR.
Reaction SMILES: Cl[C:2]1[N:6]([CH3:7])[N:5]=[C:4]([CH3:8])[C:3]=1[CH:9]=[O:10].[C:11]([O:15][CH2:16][CH3:17])(=[O:14])[CH2:12][SH:13].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH:9]([C:3]1[C:4]([CH3:8])=[N:5][N:6]([CH3:7])[C:2]=1[S:13][CH2:12][C:11]([O:15][CH2:16][CH3:17])=[O:14])=[O:10]
Reactant: Cc1nn(C)c(Cl)c1C=O
Reactant: CCOC(=O)CS
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CSc1c(C=O)c(C)nn1C
Temperature: 80 °C
Yield: 27.8 %

Procedure:
A mixture of 5-chloro-1,3-dimethyl-1H-pyrazole-4-carbaldehyde (5.0 g), ethyl thioglycolate (3.97 g), potassium carbonate (5.53 g), and N,N-dimethylformamide (150 mL) was stirred at 80° C. for over-night. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by flash column chromatography (silica gel, 90:10-50:50 hexane/ethyl acetate) to provide the title compound (2.12 g, 28%) as an oil.
Reaction SMILES: [CH3:1][N:2]1[C:8]2[CH:9]=[CH:10][C:11]([N+:13]([O-])=O)=[CH:12][C:7]=2[CH2:6][N:5]2[CH2:16][CH2:17][CH2:18][CH:4]2[C:3]1=[O:19].[H][H]>[Pd].C(O)C>[NH2:13][C:11]1[CH:10]=[CH:9][C:8]2[N:2]([CH3:1])[C:3](=[O:19])[CH:4]3[CH2:18][CH2:17][CH2:16][N:5]3[CH2:6][C:7]=2[CH:12]=1
Reactant: [H][H]
Reactant: CN1C(=O)C2CCCN2Cc2cc([N+](=O)[O-])ccc21
Agent: [Pd]
Solvent: CCO
Product: CN1C(=O)C2CCCN2Cc2cc(N)ccc21

Procedure:
A mixture of 5.0 g. of 1,2,3,5,10,11a-hexahydro-10- methyl-7-nitro-11H-pyrrolo[2,1-c] [1,4]benzodiazepin-11-one, 200 ml. of ethanol and 1.0 g. of 10% palladium-on-carbon catalyst is shaken in a Parr hydrogenator under about 3 atmospheres of hydrogen pressure until the theoretical amount of hydrogen is absorbed. The catalyst is filtered off and the mother liquor is concentrated to remove the solvent. The residue is purified by partition chromatography on a diatomaceous earth column using a heptane/methyl cellosolve solvent system to yield pure 7 -amino-1,2,3,5,10,11a-hexahydro-10-methyl-11H-pyrrolo[2,1-c]- [1,4]benzodiazepin-11-one.
Reaction SMILES: [CH:1]([P:3](=[O:17])([CH:15]=[CH2:16])[C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[C:6]([O:13][CH3:14])[CH:5]=1)=[CH2:2].[C:18]([O:26][CH2:27][CH3:28])(=[O:25])[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21].C(=O)([O-])[O-].[K+].[K+].Cl>CS(C)=O>[CH3:14][O:13][C:6]1[CH:5]=[C:4]([P:3]2(=[O:17])[CH2:15][CH2:16][C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])([C:18]([O:26][CH2:27][CH3:28])=[O:25])[CH2:2][CH2:1]2)[CH:9]=[CH:8][C:7]=1[N+:10]([O-:12])=[O:11]
Reactant: C=CP(=O)(C=C)c1ccc([N+](=O)[O-])c(OC)c1
Reactant: CCOC(=O)CC(=O)OCC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CCOC(=O)C1(C(=O)OCC)CCP(=O)(c2ccc([N+](=O)[O-])c(OC)c2)CC1
Temperature: 75 °C
Reaction time: 1 h
Yield: 40.8 %

Procedure:
Diethenyl(3-methoxy-4-nitrophenyl)phosphane oxide (INTERMEDIATE 58) (0.45 g, 1.78 mmol) and diethyl malonate (0.285 g, 1.78 mmol) were added to a 15 mL round-bottomed flask. DMSO (10 mL) was added to give a brown solution. Potassium carbonate (0.368 g, 2.67 mmol) was added. The reaction was heated to 75° C. and stirred at that temp for 1 h. The reaction was cooled to RT, and the solution was poured into an HCl solution (1N, 40 mL). The mixture was extracted with EtOAc (3×10 mL), and the combined organic layers were dried (Na2SO4) and concentrated to give the crude product. The crude product was added to a silica gel column (40 g) and eluted with MeOH/DCM (0-5%). The collected fractions were concentrated to give the product (0.3 g, 41%).
Reaction SMILES: Cl.[OH:2][NH2:3].C([O-])(=O)C.[Na+].O=[C:10]1[CH2:15][CH2:14][CH:13]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:12][CH2:11]1>O>[OH:2][N:3]=[C:10]1[CH2:15][CH2:14][CH:13]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:12][CH2:11]1
Reactant: CCOC(=O)C1CCC(=O)CC1
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: CCOC(=O)C1CCC(=NO)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
To a solution of hydroxyamine hydrochloride (15.3 g) and sodium acetate (24.1 g) in water (60 mL) was added ethyl 4-oxocyclohexanecarboxylate (25.0 g) over 20 min. The reaction mixture was stirred at room temperature overnight, and extracted with tert-butyl methyl ether. The extract was washed with saturated brine, and dried over magnesium sulfate to give the title compound (27.2 g).