Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:31])([F:30])[F:29])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:26]=[CH:25][C:21]([C:22](O)=[O:23])=[CH:20][CH:19]=3)=[CH:17][C:9]1=2.[CH3:32][NH:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[O:41][CH3:42]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:31])([F:29])[F:30])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:19]=[CH:20][C:21]([C:22]([N:33]([CH2:34][C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=4[O:41][CH3:42])[CH3:32])=[O:23])=[CH:25][CH:26]=3)=[CH:17][C:9]1=2
Reactant: O=C(O)c1ccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)cc1
Reactant: CNCc1ccccc1OC
Product: COc1ccccc1CN(C)C(=O)c1ccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)cc1

Procedure:
4-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoic acid was reacted with N-methyl-2-methoxybenzylamine as in General Procedure 10 to give the title compound. LCMS: m/z=580.98 (M+H+); retention time=0.96 minutes.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([OH:25])[C@H:9](OS(C2C=CC(C)=CC=2)(=O)=O)[C:10]([O:12][CH3:13])=[O:11])=[CH:4][CH:3]=1.O.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C@H:8]2[O:25][C@H:9]2[C:10]([O:12][CH3:13])=[O:11])=[CH:6][CH:7]=1
Reactant: COC(=O)[C@@H](OS(=O)(=O)c1ccc(C)cc1)[C@H](O)c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)[C@@H]1O[C@@H]1c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 22 h
Yield: 92 %

Procedure:
In dimethylformamide (75 ml) was dissolved methyl (2S,3R)-3-(4-fluorophenyl)-3-hydroxy-2-p-toluenesulfonyloxypropionate (5.48 g, 14.9 mmol), and water (1.4 ml, 74.5 mmol) was added to the solution. The reaction mixture was cooled by an ice bath, potassium carbonate (6.16 g, 44.6 mmol) was added thereto, and the mixture was stirred at room temperature for 22 hours. The reaction mixture was cooled again by an ice bath, water (100 ml) was added thereto, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine and then dried over anhydrous sodium sulfate. After the solvent was removed, the residue obtained was purified by silica gel column chromatography (diethyl ether/hexane=1/3) to obtain methyl (2R,3R)-3-(4-fluorophenyl)-2,3-epoxypropionate (2.69 g, yield: 92%).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:3][CH2:2]1.[CH3:15][NH:16][C:17]([N:19]1[C:27]2[C:22](=[CH:23][C:24]([O:28][C:29]3[CH:34]=[CH:33][N:32]=[C:31]([N:35](C(OC4C=CC=CC=4)=O)[C:36](=O)[O:37]C4C=CC=CC=4)[CH:30]=3)=[CH:25][CH:26]=2)[CH:21]=[CH:20]1)=[O:18]>CN(C)C=O>[CH3:15][NH:16][C:17]([N:19]1[C:27]2[C:22](=[CH:23][C:24]([O:28][C:29]3[CH:34]=[CH:33][N:32]=[C:31]([NH:35][C:36]([N:1]4[CH2:6][CH2:5][CH:4]([CH2:7][CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:3][CH2:2]4)=[O:37])[CH:30]=3)=[CH:25][CH:26]=2)[CH:21]=[CH:20]1)=[O:18]
Reactant: CNC(=O)n1ccc2cc(Oc3ccnc(N(C(=O)Oc4ccccc4)C(=O)Oc4ccccc4)c3)ccc21
Reactant: CCOC(=O)CCCC1CCNCC1
Solvent: CN(C)C=O
Product: CCOC(=O)CCCC1CCN(C(=O)Nc2cc(Oc3ccc4c(ccn4C(=O)NC)c3)ccn2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 80.6 %

Procedure:
Ethyl 4-(piperidin-4-yl)butyrate (650 mg, 2.0 mmol, Production example 43-2) was suspended in N,N-dimethylformamide (3.35 ml); phenyl N-(4-(1-(methylamino)carbonyl-1H-indol-5-yloxy)-pyridin-2-yl)-N-(phenoxycarbonyl)carbamate (350 mg, 0.67 mmol, Production example 5-2) was added; and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was dried over anhydrous magnesium sulfate, concentrated under reduced pressure. The residue was purified by silica gel column chromatography (Fuji Silysia BW-300, hexane-ethyl acetate-methanol system) to yield the title compound (271 mg, 0.54 mmol, 80%) as a pale yellow oil.
Reaction SMILES: [N:1]1([C:7]2[N:14]=[CH:13][CH:12]=[CH:11][C:8]=2[C:9]#[N:10])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[F:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[N:26]=[C:25]([C:27]3[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=3)[N:24]([CH2:34][C:35](Cl)=[O:36])[N:23]=2)=[CH:18][CH:17]=1.C(N(CC)CC)C>ClCCl>[F:15][C:16]1[CH:17]=[CH:18][C:19]([C:22]2[N:26]=[C:25]([C:27]3[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=3)[N:24]([CH2:34][C:35]([N:4]3[CH2:3][CH2:2][N:1]([C:7]4[N:14]=[CH:13][CH:12]=[CH:11][C:8]=4[C:9]#[N:10])[CH2:6][CH2:5]3)=[O:36])[N:23]=2)=[CH:20][CH:21]=1
Reactant: N#Cc1cccnc1N1CCNCC1
Reactant: O=C(Cl)Cn1nc(-c2ccc(F)cc2)nc1-c1ccc(F)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: N#Cc1cccnc1N1CCN(C(=O)Cn2nc(-c3ccc(F)cc3)nc2-c2ccc(F)cc2)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 29.6 %

Procedure:
126 mg 2-piperazin-1-yl-nicotinonitrile was added to 216 mg (3,5-Bis-(4-fluoro-phenyl)-(1,2,4)triazol-1-yl)-acetyl chloride and 150 μL triethylamine in 10 mL dichlormethane. The reaction was stirred 1 day at RT, the solvant was evaporated and the residue was purified by HPLC to give 93 mg of the desired product. (M+H)+: 486
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].F[C:8]1[CH:15]=[CH:14][C:11]([CH:12]=[O:13])=[CH:10][CH:9]=1.[F:16][C:17]([F:23])([CH:20]([F:22])[F:21])[CH2:18][OH:19]>CC(N(C)C)=O>[F:16][C:17]([F:23])([CH:20]([F:22])[F:21])[CH2:18][O:19][C:8]1[CH:15]=[CH:14][C:11]([CH:12]=[O:13])=[CH:10][CH:9]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: OCC(F)(F)C(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: O=Cc1ccc(OCC(F)(F)C(F)F)cc1
Temperature: 20 °C
Yield: 82.2 %

Procedure:
500 ml of dimethylacetamide, 304 g of potassium carbonate, 248 g of 4-fluorobenzaldehyde and 290 g of 2,2,3,3-tetrafluoropropanol are heated for 22.5 hours at 140° C. The reaction mixture is subsequently cooled to 20° C. and filtered. The salt mixture is washed using 300 ml of dimethylacetamide. After the filtrate has been distilled in vacuo at 3 mbar, a bottom temperature of 135° C. and a head temperature of 109° C. to 110° C., 387.95 g of 4-(2,2,3,3-tetrafluoropropoxy) benzaldehyde with a purity (GC) of 98% to 99% are obtained.
Reaction SMILES: [OH:1][C:2]1[C:10]([OH:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].O=O.[OH-].[K+].Br[CH:17](Br)[CH3:18]>O.C(O)C>[CH2:17]1[CH2:18][O:11][C:10]2[C:2](=[C:3]([CH:7]=[CH:8][CH:9]=2)[C:4]([OH:6])=[O:5])[O:1]1
Reactant: CC(Br)Br
Reactant: O=C(O)c1cccc(O)c1O
Agent: O=O
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)c1cccc2c1OCCO2
Yield: 96.7 %

Procedure:
2,3-Dihydroxybenzoic acid (25 g, 0.16 mol) was heated under reflux in an oxygen-free atmosphere with potassium hydroxide (26.42 g, 0.47 mole) and dibromoethane (13.46 g, 0.07 mol) using 95% ethanol (60 ml) and water (142 ml as solvent as described in J. Org. Chem. (1948), 13, 489-95 to give 2,3-ethylenedioxybenzoic acid (12.2 g, 43%), m.pt. 195°-196° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:7]=[CH:8][C:9]=1[OH:10])([O-:3])=[O:2].[CH3:17]OS(OC)(=O)=O>>[N+:1]([C:4]1[CH:5]=[C:6]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:17])([O-:3])=[O:2]
Reactant: COS(=O)(=O)OC
Reactant: O=[N+]([O-])c1cc(-c2ccccc2)ccc1O
Product: COc1ccc(-c2ccccc2)cc1[N+](=O)[O-]

Procedure:
After the 3-nitro-4-hydroxybiphenyl is formed as described above, it is then reacted with dimethylsulfate to form 3-nitro-4-methoxybiphenyl, which is then reduced to form 3-amino-4-methoxybiphenyl. The 3-amino4-methoxybiphenyl is precipitated by the addition of hydrochloric acid solution, forming the desired 3-amino-4-methoxybiphenyl hydrochloride.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](OC)[CH:5]=[C:4]([F:10])[C:3]=1[C:11]1[S:12][CH:13]=[C:14]([C:16]([OH:18])=[O:17])[N:15]=1.FC1C=C([C:36]2([OH:40])[CH2:39][CH2:38][CH2:37]2)C=C(F)C=1B1OC(C)(C)C(C)(C)O1>>[F:10][C:4]1[CH:5]=[C:6]([C:36]2([OH:40])[CH2:39][CH2:38][CH2:37]2)[CH:7]=[C:2]([F:1])[C:3]=1[C:11]1[S:12][CH:13]=[C:14]([C:16]([OH:18])=[O:17])[N:15]=1
Reactant: CC1(C)OB(c2c(F)cc(C3(O)CCC3)cc2F)OC1(C)C
Reactant: COc1cc(F)c(-c2nc(C(=O)O)cs2)c(F)c1
Product: O=C(O)c1csc(-c2c(F)cc(C3(O)CCC3)cc2F)n1

Procedure:
Following the procedure of Intermediate 104, replacing 2,6-difluoro-4-methoxyphenylboronic acid with 1-(3,5-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)cyclobutanol (Intermediate 108) gave the title compound.
Reaction SMILES: [CH3:1][N:2]([CH3:21])[CH2:3][CH2:4][CH:5]1[CH2:11][N:10]([CH3:12])[C:9](=[S:13])[C:8]2[CH:14]=[C:15]([N+:18]([O-])=O)[CH:16]=[CH:17][C:7]=2[O:6]1.[NH4+]=S.C(O)C.Cl>O>[NH2:18][C:15]1[CH:16]=[CH:17][C:7]2[O:6][CH:5]([CH2:4][CH2:3][N:2]([CH3:1])[CH3:21])[CH2:11][N:10]([CH3:12])[C:9](=[S:13])[C:8]=2[CH:14]=1
Reactant: CN(C)CCC1CN(C)C(=S)c2cc([N+](=O)[O-])ccc2O1
Agent: Cl
Solvent: CCO
Solvent: O
Product: CN(C)CCC1CN(C)C(=S)c2cc(N)ccc2O1

Procedure:
To 7.0 g (0.023 mole) of 2-[2-(dimethylamino)ethyl]-2,3-dihydro-4-methyl-7-nitro-1,4-benzoxazepine-5(4H)-thione was added 250 ml of 23% ammonium sulfide in water. Ethyl alcohol was added in amount sufficient to dissolve the starting compound (~50-60 ml). The reaction mixture was heated to reflux for 5 hr. After cooling, the reaction mixture was acidified with concentrated aqueous hydrochloric acid. The ethanol was removed by rotary evaporation at 70° C. The remaining aqueous solution was washed with 3×100 ml of chloroform, filtered, cooled with ice and made slightly basic with sodium hydroxide. The aqueous was then extracted with 3×100 ml of chloroform, dried over sodium sulfate, filtered and concentrated by rotary evaporation. The residue was crystallized from isopropyl alcohol to give 3.5 g (55%) of yellow analytically pure crystals.
Reaction SMILES: [CH2:1]([C:5]1[S:20][C:8]2[N:9]=[CH:10][N:11]=[C:12]([NH:13][CH:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[C:7]=2[CH:6]=1)[CH:2]([CH3:4])[CH3:3].CS(O[CH:26]([C:28]1[CH:33]=[C:32]([F:34])[CH:31]=[C:30]([F:35])[CH:29]=1)[CH3:27])(=O)=O>>[F:34][C:32]1[CH:33]=[C:28]([CH:26]([N:17]2[CH2:18][CH2:19][CH:14]([NH:13][C:12]3[C:7]4[CH:6]=[C:5]([CH2:1][CH:2]([CH3:4])[CH3:3])[S:20][C:8]=4[N:9]=[CH:10][N:11]=3)[CH2:15][CH2:16]2)[CH3:27])[CH:29]=[C:30]([F:35])[CH:31]=1
Reactant: CC(C)Cc1cc2c(NC3CCNCC3)ncnc2s1
Reactant: CC(OS(C)(=O)=O)c1cc(F)cc(F)c1
Product: CC(C)Cc1cc2c(NC3CCN(C(C)c4cc(F)cc(F)c4)CC3)ncnc2s1

Procedure:
The title compound was prepared (127 mg, 69%) from 6-isobutyl-N-(piperidin-4-yl)thieno[2,3-d]pyrimidin-4-amine (125 mg, 0.43 mmol) and 1-(3,5-difluorophenyl)ethyl methanesulfonate (243 mg, 1.03 mmol) by following the general procedure described for Preparation 12. 1H NMR (400 MHz, CDCl3): δ 8.40 (s, 1H), 6.90 (m, 2H), 6.75 (s, 1H), 6.70 (m, 1H), 4.95 (d, 1H), 4.15 (m, 1H), 3.45 (m, 1H), 2.95 (m, 1H), 2.80 (m, 1H), 2.70 (d, 2H), 2.20 (m, 4H), 1.95 (m, 1H), 1.55 (m, 2H), 1.35 (d, 3H), 0.95 (d, 6H). MS (ESI) m/z: Calculated: 430.56; Observed: 431.1 (M++1).
Reaction SMILES: [CH3:1][CH:2]([OH:9])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].C(N(C(C)C)CC)(C)C.[CH3:19][S:20](Cl)(=[O:22])=[O:21]>ClCCl>[S:20]([O:9][CH:2]([CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])[CH3:1])([CH3:19])(=[O:22])=[O:21]
Reactant: CCCCCCC(C)O
Reactant: CS(=O)(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCCCCCC(C)OS(C)(=O)=O
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 100.3 %

Procedure:
To 130 g (0.995 mol) of 2-octanol and 207 ml (1.19 mol, 1.2 equiv) of diisopropylethylamine in 1.5 L dichloromethane at 0° C. under a CaSO4 drying tube was added dropwise 84.4 ml (1.09 mol, 1.1 equiv.) of methanesulfonyl chloride over 1 hour while keeping the internal temperature at less than 5° C. The faintly yellow solution was stirred at 0° C. for an additional 1.5 h. The cold reaction solution was then washed with 2×1 L ice-cold 1M HCl and 1 L of ice-cold H2O and brine and dried over MgSO4. The residue was filtered through Celite and concentrated in vacuo below 35° C. to afford 208 g of a yellow oil. The yellow oil was placed under high-vacuum for 2 h at 25° C. to give 205 g of yellow oil. NMR spectra confirmed the desired title-product having only trace amounts of solvents present.
Reaction SMILES: [C:1]([C:5]1[N:10]=[C:9]([N:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[CH:8]=[C:7]([C:17]2([CH3:20])[CH2:19][CH2:18]2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.C(=O)([O-])[O-].[K+].[K+].Br[CH2:35][CH2:36][CH2:37][Cl:38]>CN(C)C=O>[C:1]([C:5]1[N:10]=[C:9]([N:11]2[CH2:12][CH2:13][N:14]([CH2:35][CH2:36][CH2:37][Cl:38])[CH2:15][CH2:16]2)[CH:8]=[C:7]([C:17]2([CH3:20])[CH2:19][CH2:18]2)[N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: ClCCCBr
Reactant: CC(C)(C)c1nc(N2CCNCC2)cc(C2(C)CC2)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)c1nc(N2CCN(CCCCl)CC2)cc(C2(C)CC2)n1
Temperature: 50 °C
Reaction time: 1.5 h
Yield: 51.4 %

Procedure:
7 g of 2-tert-butyl-4-piperazin-1-yl-6-(1-methylcyclopropyl)-pyrimidine (25.5 mmol; prepared by analogy to steps a.2.1 to a.2.4 starting from 1-methylcyclopropyl carbonic acid chloride) were dissolved in 50 ml of dimethyl formamide. 2.58 of triethylamine (25.5 mmol), and 3.53 g of potassium carbonate were added, followed by dropwise addition of 4.62 g of 1-bromo-3-chloropropane. After stirring for 1.5 h at 50° C. the reaction mixture was stirred overnight at room temperature. The precipitate was filtered off and washed with dimethylformamide. The filtrate was partitioned between 150 ml of ethyl acetate and 50 ml of water. The organic layer was separated and the aqueous layer was extracted with 30 ml of ethyl acetate. The combined organic layers were dried over magnesium sulfate, filtered and evaporated to dryness. The residue was purified by chromatography on silica gel (ethyl acetate) to yield 4.6 g of the title compound.
Reaction SMILES: [CH3:1][N:2]1[CH2:18][CH2:17][C:5]2[N:6]([CH2:14][CH2:15][NH2:16])[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.[CH:19]1([C:25](O)=[O:26])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1.C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C1C=CN=CC=1.ClCCl>[CH3:1][N:2]1[CH2:18][CH2:17][C:5]2[N:6]([CH2:14][CH2:15][NH:16][C:25]([CH:19]3[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)=[O:26])[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1
Reactant: O=C(O)C1CCCCC1
Reactant: Cc1ccc2c(c1)c1c(n2CCN)CCN(C)C1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: Cc1ccc2c(c1)c1c(n2CCNC(=O)C2CCCCC2)CCN(C)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 6.9 %

Procedure:
A mixture of 2-(1,2,3,4-tetrahydro-2,8-dimethylpyrido[4,3-b]indol-5-yl)ethanamine (100 mg, 0.41 mmol), cyclohexane carboxylic acid (52 mg, 0.41 mmol), N,N′-dicyclohexylcarbodiimide (93 mg, 0.45 mmol) and 4-dimethylaminopyridine (55 mg, 0.45 mmol) in dry dichloromethane (2.5 ml) were stirred at room temperature for 3 h. The reaction mixture was filtered through Celite and concentrated using rotary evaporator to afford 10 mg of N-(2-(1,2,3,4-tetrahydro-2,8-dimethylpyrido[4,3-b]indol-5-yl)ethyl)cyclohexanecarboxamide as TFA salt after purification by reversed-phase chromatography (C-18, 500 mm×50 mm, Mobile Phase A=0.05% TFA in water, B=0.05% TFA in acetonitrile, Gradient: 10% B to 80% B in 30 min, injection vol. 5 ml). 1H NMR (DMSO) 9.94 (bs, 1H), 7.86 (t, 1H), 7.38 (d, 1H), 7.11 (s, 1H), 7.0 (d, 1H), 4.56-4.63 (m, 1H), 4.22-4.29 (m, 1H), 4.08-4.13 (m, 3H), 3.72-3.81 (m, 3H), 3.08-3.14 (m, 3H), 2.97 (s, 3H), 2.38 (s, 3H), 1.95-2.0 (m, 1H), 1.50-1.84 (m, 5H), 1.02-1.2 (m, 4H).
Reaction SMILES: Cl[CH2:2][C:3]1[O:7][N:6]=[C:5]([CH2:8][CH3:9])[CH:4]=1.[P:10]([O:17]CC)([O:14][CH2:15][CH3:16])[O:11][CH2:12][CH3:13]>>[CH2:8]([C:5]1[CH:4]=[C:3]([CH2:2][P:10]([O:14][CH2:15][CH3:16])(=[O:17])[O:11][CH2:12][CH3:13])[O:7][N:6]=1)[CH3:9]
Reactant: CCOP(OCC)OCC
Reactant: CCc1cc(CCl)on1
Product: CCOP(=O)(Cc1cc(CC)no1)OCC
Yield: 71.5 %

Procedure:
15 g of 5-chloromethyl-3-ethyl-isoxazole and 18 g of triethyl phosphite are slowly heated to 150° C. and kept at this temperature for 21/2 hours. After cooling, the residue is distilled under reduced pressure. 18.2 g of diethyl (3-ethylisoxazol-5-yl)-methanephosphonate, of boiling point 120°-121° C./0.2 mm Hg are obtained. Yield: 71.2%.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:10][CH3:11])[C:5]([O:8][CH3:9])=[N:6][CH:7]=1.[Cu][C:13]#[N:14]>CN(C)C=O>[CH3:11][O:10][C:4]1[C:5]([O:8][CH3:9])=[N:6][CH:7]=[C:2]([CH:3]=1)[C:13]#[N:14]
Reactant: COc1cc(Br)cnc1OC
Reactant: N#C[Cu]
Solvent: CN(C)C=O
Product: COc1cc(C#N)cnc1OC
Temperature: 18 °C

Procedure:
To a solution of 5-bromo-2,3-dimethoxypyridine (4-2, 0.300 g, 1.38 mmol, 1.0 equiv) in dimethylformamide (3.9 mL) was added copper (I) cyanide (0.15 gL, 1.65 mmol, 1.2 equiv) and the reaction mixture was heated for 40 minutes at 18° C. in a microwave reactor. The reaction mixture was cooled and partitioned between EtOAc (50 mL) and water (50 mL). The organic phase was washed with water (2×30 mL) and brine (1×30 mL), dried over magnesium sulfate and concentrated. The residue was purified via normal phase chromatography (0 to 40% EtOAc in hexanes, silica) to afford the desired product (4-3) as white solid after concentration. ESI+MS[M+H]+C8H8N2O2 calc'd 165.1. found 165.1.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7](Cl)=[C:6]([N+:11]([O-:13])=[O:12])[CH:5]=1.[C:15]([O:19][C:20](=[O:26])[N:21]([CH2:23][CH2:24][NH2:25])[CH3:22])([CH3:18])([CH3:17])[CH3:16].CCN(C(C)C)C(C)C>C1COCC1>[CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([NH:25][CH2:24][CH2:23][N:21]([C:20]([O:19][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:26])[CH3:22])=[C:6]([N+:11]([O-:13])=[O:12])[CH:5]=1
Reactant: CN(CCN)C(=O)OC(C)(C)C
Reactant: COC(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc(NCCN(C)C(=O)OC(C)(C)C)c([N+](=O)[O-])c1
Yield: 103.7 %

Procedure:
4-[2-(tert-Butoxycarbonyl-methyl-amino)-ethylamino]-3-nitro-benzoic acid methyl ester (1.7 g) was prepared by following General Procedure A starting from 4-chloro-3-nitro-benzoic acid methyl ester (1 g), (2-amino-ethyl)-methyl-carbamic acid tert-butyl ester (1.2 g) and DIEA (1.7 mL) in THF (20 mL).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[O:10])[NH:8][C:7]([C:11]3[CH:16]=[CH:15][C:14]([C:17](O)([CH3:19])[CH3:18])=[CH:13][CH:12]=3)=[CH:6][N:5]2[CH:21]=1.C(N(S(F)(F)[F:28])CC)C>ClCCl>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[O:10])[NH:8][C:7]([C:11]3[CH:16]=[CH:15][C:14]([C:17]([F:28])([CH3:19])[CH3:18])=[CH:13][CH:12]=3)=[CH:6][N:5]2[CH:21]=1
Reactant: CC(C)(O)c1ccc(-c2cn3cc(F)cc3c(=O)[nH]2)cc1
Reactant: CCN(CC)S(F)(F)F
Solvent: ClCCl
Product: CC(C)(F)c1ccc(-c2cn3cc(F)cc3c(=O)[nH]2)cc1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
A suspension of 57.3 mg (0.20 mmol) 7-fluoro-3-[4-(1-hydroxy-1-methyl-ethyl)phenyl]-2H-pyrrolo[1,2-a]pyrazin-1-one in 0.5 ml dichloromethane is cooled to −78° C. Then 105 μl (0.80 mmol) diethylaminosulfurtrifluoride are added. The reaction mixture is allowed to reach room temperature over 30 minutes. The reaction mixture is evaporated and the residue is treated with water and saturated sodium hydrogen carbonate solution. The solids are filtered off and chromatographed on a silica gel column with cyclohexane/ethyl acetate as eluent to afford 7-fluoro-3-[4-(1-fluoro-1-methyl-ethyl)-phenyl]-2H-pyrrolo[1,2-a]pyrazin-1-one as white powder; HPLC/MS 2.60 min (B), [M+H] 289; 1H NMR (400 MHz, DMSO-d6) δ [ppm]11.01 (s, 1H), 7.70-7.63 (m, 3H), 7.53-7.44 (m, 3H), 6.76 (d, J=1.9 Hz, 1H), 1.67 (d, J=22.2 Hz, 6H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:12][CH2:11][N:10]([CH2:13][C:14]([C:16]3[CH:27]=[C:26]([C:28]([CH3:31])([CH3:30])[CH3:29])[C:19]([O:20][CH2:21][C:22]([O:24]C)=[O:23])=[C:18]([C:32]([CH3:35])([CH3:34])[CH3:33])[CH:17]=3)=[O:15])[CH2:9][CH2:8]2)=[CH:3][CH:2]=1.Cl>O1CCOCC1.O>[N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:8][CH2:9][N:10]([CH2:13][C:14]([C:16]3[CH:27]=[C:26]([C:28]([CH3:30])([CH3:29])[CH3:31])[C:19]([O:20][CH2:21][C:22]([OH:24])=[O:23])=[C:18]([C:32]([CH3:35])([CH3:34])[CH3:33])[CH:17]=3)=[O:15])[CH2:11][CH2:12]2)=[CH:3][CH:2]=1
Reactant: COC(=O)COc1c(C(C)(C)C)cc(C(=O)CN2CCN(c3ccncc3)CC2)cc1C(C)(C)C
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)c1cc(C(=O)CN2CCN(c3ccncc3)CC2)cc(C(C)(C)C)c1OCC(=O)O
Temperature: 100 °C

Procedure:
A solution of methyl 4-(2-[4-(4-pyridyl)piperazin-1-yl]acetyl)-2,6-di-tert-butylphenoxyacetate (241 mg) in dioxane (2.0 ml) was treated with 1N hydrochloric acid and the mixture heated at 100° C. for 20 hours. The mixture was cooled, diluted with water, filtered and the filtrate freeze-dried. The solid residue was purified by flash chromatography on silica eluting with toluene/ethyl acetate/0.880 ammonia/ethanol (60:20:10:35 v/v/v/v). The fractions containing the desired product were evaporated, the residue treated with dioxane, filtered and the filtrate diluted with water and freeze dried to give a white foam, which on drying at 55° C. gave the title compound, 90 mg: NMR (d6DMSO)δ8.16(2H,d), 7.97(2H,s), 6.84(2H,d), 4.22(2H,s), 3.86(2H,s), 3.37(4H,t), 2.64(4H,t), 1.39(18H,s); m/e 468 (M+H)+ ; calculated for C27H37 N3O4.2H2O: C, 64.4; H, 8.2; N, 8.3. found C, 64.6; H, 7.9; N, 7.9%.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[CH:7]2.[Cu](C#N)[C:12]#[N:13]>O.C(OCC)(=O)C>[C:12]([C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[CH:7]2)#[N:13]
Reactant: N#C[Cu]C#N
Reactant: Brc1cccc2cc[nH]c12
Solvent: CCOC(C)=O
Solvent: O
Product: N#Cc1cccc2cc[nH]c12
Temperature: 200 °C
Reaction time: 2.5 h
Yield: 54.8 %

Procedure:
Combine 7-bromoindole (4.72 g, 24.0 mmol) and copper cyanide (4.30 g, 48.1 mmol) in 1-methyl-2-pyrrolidine (40 mL). Heat to 200° C. After 2.5 hours, cool to room temperature, add water-ethyl acetate (200 mL, 1/1) to give a solid. Filter through the celite, extract the filtrate with ethyl acetate, combine the organic layers, wash with brine, dry over Na2SO4, filter and evaporate in vacuo to give a residue. Chromatograph the residue on silica gel eluting with hexanes: ethyl acetate (10:1) to give (1.87 g) of the title compound as a yellow solid: 1H NMR (300 MHz, DMSO-d6)) 6.64–6.66 (m, 1H), 7.17 (t, 1H, J=7.6 Hz), 7.51–7.53 (m, 1H), 7.60–7.62 (m, 1H), 7.94 (d, 1H, J=8.0 H), 12.03 (br, 1H).
Reaction SMILES: [C:1]1([C:7]2[C:16]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=3)=[N:15][C:14]3[C:9](=[CH:10][CH:11]=[C:12]([C:27]([O:29]C)=[O:28])[CH:13]=3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].Cl>CO>[C:1]1([C:7]2[C:16]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([F:24])([F:25])[F:26])=[CH:19][CH:18]=3)=[N:15][C:14]3[C:9](=[CH:10][CH:11]=[C:12]([C:27]([OH:29])=[O:28])[CH:13]=3)[N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)c1ccc2nc(-c3ccccc3)c(-c3ccc(C(F)(F)F)cc3)nc2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1ccc2nc(-c3ccccc3)c(-c3ccc(C(F)(F)F)cc3)nc2c1
Temperature: 50 °C
Reaction time: 3 h
Yield: 44.4 %

Procedure:
A solution of methyl 2-phenyl-3-(4-(trifluoromethyl)phenyl)quinoxaline-6-carboxylate (80 mg, 0.20 mmol, 1.00 equiv) in MeOH (10 mL) and NaOH (23.5 mg, 3.00 equiv) was placed in a 50-mL round-bottom flask and allowed to react, with stirring, for 3 hrs while the temperature was maintained at 50° C. in an oil bath. The pH value of the solution was adjusted to 3 with HCl (2N). The resulting solids were collected by filtration, yielding 35 mg (45%) of 2-phenyl-3-(4-(trifluoromethyl)phenyl)quinoxaline-6-carboxylic acid as a yellow solid.