Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC1C=CC(N)=CC=1N1C2N(N=C(C3C=NC=CC=3)C=2)C=C1.C(OC(N1CCN(C2C=C(C=C(S(F)(F)(F)(F)F)C=2)C(O)=O)CC1)=O)(C)(C)C.[CH3:51][C:52]1[CH:57]=[CH:56][C:55]([NH:58][C:59]([C:61]2[CH:62]=[C:63]([N:73]3[CH2:78][CH2:77][N:76](C(OC(C)(C)C)=O)[CH2:75][CH2:74]3)[CH:64]=[C:65]([S:67]([F:72])([F:71])([F:70])([F:69])[F:68])[CH:66]=2)=[O:60])=[CH:54][C:53]=1[N:86]1[C:93]2[N:89]([N:90]=[C:91]([C:94]3[CH:95]=[N:96][CH:97]=[CH:98][CH:99]=3)[CH:92]=2)[CH:88]=[CH:87]1.Cl>O1CCOCC1.CO>[CH3:51][C:52]1[CH:57]=[CH:56][C:55]([NH:58][C:59](=[O:60])[C:61]2[CH:62]=[C:63]([N:73]3[CH2:74][CH2:75][NH:76][CH2:77][CH2:78]3)[CH:64]=[C:65]([S:67]([F:71])([F:70])([F:69])([F:72])[F:68])[CH:66]=2)=[CH:54][C:53]=1[N:86]1[C:93]2[N:89]([N:90]=[C:91]([C:94]3[CH:95]=[N:96][CH:97]=[CH:98][CH:99]=3)[CH:92]=2)[CH:88]=[CH:87]1
Reactant: Cc1ccc(NC(=O)c2cc(N3CCN(C(=O)OC(C)(C)C)CC3)cc(S(F)(F)(F)(F)F)c2)cc1-n1ccn2nc(-c3cccnc3)cc12
Agent: CC(C)(C)OC(=O)N1CCN(c2cc(C(=O)O)cc(S(F)(F)(F)(F)F)c2)CC1
Agent: Cc1ccc(N)cc1-n1ccn2nc(-c3cccnc3)cc12
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: Cc1ccc(NC(=O)c2cc(N3CCNCC3)cc(S(F)(F)(F)(F)F)c2)cc1-n1ccn2nc(-c3cccnc3)cc12
Temperature: 80 °C
Reaction time: 1 h

Procedure:
120 mg (0.42 mmol) of the compound of Example 6A and 179 mg (0.42 mmol) of the compound of Example 16A were reacted and worked up analogously to the procedure of Example 16. In this manner, 260 mg (89% of theory) of the Boc-protected intermediate tert-butyl 4-[3-({4-methyl-3-[6-(pyridin-3-yl)-1H-imidazo[1,2-b]pyrazol-1-yl]phenyl}carbamoyl)-5-(pentafluoro-λ6-sulphanyl)-phenyl]piperazine-1-carboxylate were obtained. This compound was dissolved in 3 ml of 1,4-dioxane and 1 ml of methanol, 0.31 ml (1.24 mmol) of a 4 M solution of hydrogen chloride in 1,4-dioxane was added and the mixture was stirred at 80° C. for 1 h. The mixture was then concentrated under reduced pressure and the residue was purified by preparative HPLC (Method 18). The product fractions were concentrated and the residue was dissolved in ethyl acetate and washed successively with saturated potassium carbonate solution and saturated sodium chloride solution. The organic phase was dried over sodium sulphate, filtered and concentrated under reduced pressure. Drying of the residue gave 155 mg (62% of theory) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=3[Cl:20])=[CH:11][C:10]([C:21]([O:23]CC)=[O:22])=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[OH-].[K+]>>[Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=3[Cl:20])=[CH:11][C:10]([C:21]([OH:23])=[O:22])=[N:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1cc(-c2ccc(Cl)cc2Cl)n(-c2cccc(Cl)c2)n1
Agent: [K+]
Agent: [OH-]
Product: O=C(O)c1cc(-c2ccc(Cl)cc2Cl)n(-c2cccc(Cl)c2)n1
Yield: 92 %

Procedure:
Starting from 240 mg (0.61 mmol) of ethyl 1-(3-chlorophenyl)-5-(2,4-dichloro-phenyl)-1H-pyrazole-3-carboxylate from example 18A and 340.3 mg (6.1 mmol) of potassium hydroxide, 204 mg (0.55 mmol, 92% yield of theory) are obtained as crystals according to the method described in example 7A.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3([CH2:22][NH2:23])[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)=[CH:12][CH:11]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[C:31](Cl)(=[O:33])[CH3:32]>ClCCl>[N:1]1([CH2:6][CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3([CH2:22][NH:23][C:31](=[O:33])[CH3:32])[CH2:17][CH2:18][O:19][CH2:20][CH2:21]3)=[CH:12][CH:11]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NCC1(c2ccc(OCCCN3CCCC3)cc2)CCOCC1
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)NCC1(c2ccc(OCCCN3CCCC3)cc2)CCOCC1
Reaction time: 8 h
Yield: 45.1 %

Procedure:
To a stirred solution of {4-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]tetrahydropyran-4-yl}methylamine (200 mg, 0.628 mmol) and triethylamine (106 μL, 0.754 mmol) in anhydrous dichloromethane (8 mL) under nitrogen atmosphere was added dropwise a solution of acetyl chloride (54 μL, 0.754 mmol) in anhydrous dichloromethane (2 mL). After stirring overnight, the reaction mixture was quenched with a saturated aqueous solution of NaHCO3. The organic layer was separated and washed with a saturated aqueous solution of NaHCO3 and water then dried over magnesium sulfate, filtered and concentrated under reduced pressure to give the title compound (102 mg, 45%). 1H NMR (400 MHz, CDCl3) δ7.18 (d, 2H), 6.94 (d, 2H), 4.97 (s, 1H), 4.05 (t, 2H), 3.80 (m, 2H), 3.59 (m, 2H), 3.46 (d, 2H), 2.66 (t, 2H), 2.57 (m, 4H), 2.03 (m, 4H), 1.80 (m, 8H).
Reaction SMILES: [OH:1][C:2]1[C:11]2[CH:10]=[C:9]([O:12][CH3:13])[N:8]=[N:7][C:6]=2[N:5]([CH3:14])[C:4](=[O:15])[C:3]=1[C:16]([NH:18][CH2:19][C:20]([O:22]C(C)(C)C)=[O:21])=[O:17].OC1C2C=C(OC)N=NC=2N(C)C(=O)C=1C(OC)=O.Cl.NCC(OC(C)(C)C)=O>>[OH:1][C:2]1[C:11]2[CH:10]=[C:9]([O:12][CH3:13])[N:8]=[N:7][C:6]=2[N:5]([CH3:14])[C:4](=[O:15])[C:3]=1[C:16]([NH:18][CH2:19][C:20]([OH:22])=[O:21])=[O:17]
Reactant: COc1cc2c(O)c(C(=O)NCC(=O)OC(C)(C)C)c(=O)n(C)c2nn1
Agent: CC(C)(C)OC(=O)CN
Agent: COC(=O)c1c(O)c2cc(OC)nnc2n(C)c1=O
Agent: Cl
Product: COc1cc2c(O)c(C(=O)NCC(=O)O)c(=O)n(C)c2nn1

Procedure:
tert-Butyl 2-(5-hydroxy-3-methoxy-8-methyl-7-oxo-7,8-dihydropyrido[2,3-c]pyridazine-6-carboxamido)acetate. The title compound is prepared from methyl 5-hydroxy-3-methoxy-8-methyl-7-oxo-7,8-dihydropyrido[2,3-c]pyridazine-6-carboxylate and tert-butyl 2-aminoacetate hydrochloride according to Method 3(a).
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[CH:9]=[C:8]([C:10]([OH:12])=O)[CH:7]=[CH:6][C:5]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH3:19].C(N(C(C)C)C(C)C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:53][C:54](=[N:67]O)[C:55]1[CH:56]=[C:57]([CH:62]=[CH:63][C:64]=1[O:65][CH3:66])[C:58]([O:60][CH3:61])=[O:59]>CN(C=O)C>[CH3:66][O:65][C:64]1[CH:63]=[CH:62][C:57]([C:58]([O:60][CH3:61])=[O:59])=[CH:56][C:55]=1[C:54]1[N:53]=[C:10]([C:8]2[CH:7]=[CH:6][C:5]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[CH3:19])=[C:4]([CH2:3][O:2][CH3:1])[CH:9]=2)[O:12][N:67]=1
Reactant: COC(=O)c1ccc(OC)c(C(N)=NO)c1
Reactant: COCc1cc(C(=O)O)ccc1-c1ccccc1C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COCc1cc(-c2nc(-c3cc(C(=O)OC)ccc3OC)no2)ccc1-c1ccccc1C
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of Intermediate 28 (149.42 mg; 0.58 mmol) and n-ethyldiisopropylamine (198.29 μL; 1.17 mmol) in anhydrous DMF (2 mL) and cooled at 0° C., HATU (221.67 mg; 0.58 mmol) was added and the mixture stirred at RT for 10 min. After this time, Intermediate 53 (100 mg; 0.60 mmol) and DIEA (0.10 mL) in anhydrous DMF (1 mL) were added and the mixture was heated at 80° C. for 18 h. The reaction mixture was cooled to RT, partitioned between water and Et2O, dried over MgSO4, filtered and evaporated under vacuum. Product was adsorbed on silica and purified by flash chromatography (cHex/EtOAc from 9:1 to 8:2), which gave the title compound as a colorless oil. LC/MS (Method B): 445.2 (M+H)+. HPLC (Method A) Rt 6.01 min (purity: 96.5%).
Reaction SMILES: [N+](=[CH:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])=[N-].C([O-])(=O)/C=C\C([O-])=O.[S:17]1[CH:21]=[CH:20][CH:19]=[CH:18]1>>[CH:20]12[C@@H:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH:21]1[S:17][CH:18]=[CH:19]2
Reactant: CCOC(=O)C=[N+]=[N-]
Reactant: c1ccsc1
Agent: O=C([O-])/C=C\C(=O)[O-]
Product: CCOC(=O)[C@@H]1C2C=CSC21
Temperature: 46 °C
Reaction time: 0.17 h

Procedure:
A 3-neck, 5 liter flask is fitted with a stirrer, a thermocouple, and a teflon addition tube, and a N2 inlet is charged 2000 ml of thiophene (d=1.05 g/mL, 25.0 mol at beginning and increasing to 45 mol with addition of ethyl diazoacetate solution in thiophene, 17.1 equiv based upon total addition of ethyl diazoacetate and not corrected for potency of EDA, 19.0 equiv based upon potency corrected ethyl diazoacetate). To this is added, under N2, 0.968 g of Rh2(octanoate)4 (1.24 mmoles, 0.0472 mol % based upon g of ethyl diazoacetate not corrected for potency, 0.052 mole % based upon moles of pure ethyl diazoacetate, Johnson Mathey: Lot No. 059255001). The suspension is heated to 46° C. and stirred at 46° C. for 10 minutes to affect dissolution to a green solution. To the solution is added, by a positive displacement pump, a solution of 300 g of ethyl diazoacetate (90% pure, 2.63 moles, 2.37 moles pura, 1.00 equiv, Aldrich: Lot No. 17603PI) dissolved in 1600 mL of thiophene. The rate of addition is such that the total addition time is 8 hours; the slow rate of addition suppresses formation of the maleate and fumarate ethyl esters. When no ethyl diazoacetate remains (approximately thirty minutes), the dark amber reaction (3,985 g) is cooled to 23° C. The reaction mixture is split into portions and the larger portion (3,240 g of 3,985 g total=81.3%) is directly concentrated to an oil. The crude product is passed through the wiped film distillation apparatus at 1.5 torr and 23° C. to degas the product and to remove residual amount of thiophene. The product is then distilled at 120° C. and 1.3 torr. The title compound (faint yellow) is collected in two fractions, 155.0 g and 32.2 g. Analysis by HPLC determines a potency of 78% and 76% for the two lots respectively. Crystallization of the distillate from above is accomplished by dissolution in methanol (2 mL per 1 g of distillate) and cooling to −10° C., at which time the solution is optionally seeded if crystal growth is not observed. Once crystal growth has commenced, the mixture is further cooled to −45° C. and stirred for 2-3 hours, filtered, and washed with cold (−45° C.) methanol (1×1 mL per 1 g of distillate). The material is dried in vacuo at 24° C. to provide the title compound as a white to off-white solid in 80-85% recovery and >98% potency.
Reaction SMILES: [C:1](=[O:29])([O:24][CH2:25][CH:26]([CH3:28])[CH3:27])[O:2][C:3]1[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=[C:5]([C:13]2[N:17]=[CH:16][N:15](/[CH:18]=[CH:19]\[C:20]([NH:22][NH2:23])=[O:21])[N:14]=2)[CH:4]=1.[CH3:30]OC(OC)OC.CS(O)(=O)=O.CO.ClCCl>C1COCC1>[C:1](=[O:29])([O:24][CH2:25][CH:26]([CH3:27])[CH3:28])[O:2][C:3]1[CH:8]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:6]=[C:5]([C:13]2[N:17]=[CH:16][N:15](/[CH:18]=[CH:19]\[C:20]3[O:21][CH:30]=[N:23][N:22]=3)[N:14]=2)[CH:4]=1
Reactant: CC(C)COC(=O)Oc1cc(-c2ncn(/C=C\C(=O)NN)n2)cc(C(F)(F)F)c1
Reactant: COC(OC)OC
Agent: CS(=O)(=O)O
Solvent: C1CCOC1
Solvent: CO
Solvent: ClCCl
Product: CC(C)COC(=O)Oc1cc(-c2ncn(/C=C\c3nnco3)n2)cc(C(F)(F)F)c1
Temperature: 70 °C
Yield: 4.9 %

Procedure:
In a 100-mL, 3-neck round-bottomed flask equipped with nitrogen inlet, and a rubber septum, (Z)-3-(1-(3-hydrazinyl-3-oxoprop-1-enyl)-1H-1,2,4-triazol-3-yl)-5-(trifluoromethyl)phenyl isobutyl carbonate (2 g, 1.0 eq.) was dissolved in THF (20 mL, 10V). Trimethylorthoformate (0.56 g, 1.1 eq.) and methanesulphonic acid (0.23 g, 0.5 eq.) were added and the reaction was refluxed at 70° C. for 2-3 h. The progress of the reaction was followed by TLC analysis on silica gel with 10% MeOH-dichloromethane as mobile phase. SM Rf=0.40 and Product Rf=0.5. Reaction mixture was poured into ice water (100 mL) and extracted with EtOAc (3×50 mL). The combined organic layers were washed with brine solution (3×50 mL), dried over MgSO4, filtered, and concentrated by rotary evaporation (25° C., 20 mmHg) to afford 2.5 g of crude compound. The crude reaction mixture was purified by column chromatography using silica 60/120 using dichloromethane:Methanol as mobile phase. The column was packed in dichloromethane and started eluting in dichloromethane in gradient manner starting with fraction collection (25-mL fractions). Compound started eluting with 0.8% Methanol in dichloromethane. Fractions containing such TLC profile was collected together to obtain pure compound (0.1 g).
Reaction SMILES: C[O:2][C:3]1[CH:19]=[CH:18][C:6]([C:7]([C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[NH:11][CH:10]=2)=[O:8])=[CH:5][CH:4]=1.Cl.N1C=CC=CC=1.Cl>>[OH:2][C:3]1[CH:4]=[CH:5][C:6]([C:7]([C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[NH:11][CH:10]=2)=[O:8])=[CH:18][CH:19]=1
Reactant: COc1ccc(C(=O)c2c[nH]c3ccccc23)cc1
Agent: Cl
Solvent: c1ccncc1
Product: O=C(c1ccc(O)cc1)c1c[nH]c2ccccc12

Procedure:
1 g of compound 1 and 3 g of pyridine hydrochloride were heated at 215° C. for 1 hour in a nitrogen atmosphere. After the mixture was cool,1.5 N hydrochloric acid was added thereto and then the supernatant was removed by centrifugation. The precipitate was dissolved in methanol which contains 10% of aqueous solution of sodium hydroxide, followed by filtering out the resulting precipitate. The obtained solution was acidified to give a crude product. The crude product was recrystallized from ethyl acetate to give 3-(p-hydroxybenzoyl)indole (compound 3). (Yield: 66%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([NH:10][CH2:11][C:12]23[CH2:21][CH:16]4[CH2:17][CH:18]([CH2:20][CH:14]([CH2:15]4)[CH2:13]2)[CH2:19]3)=[O:9])[C:5]([Cl:22])=[CH:4][N:3]=1.C(OC([N:30]1[CH2:35][CH2:34][CH:33]([OH:36])[CH2:32][CH2:31]1)=O)(C)(C)C.[H-].[Na+].Cl>O1CCCC1.CO.O1CCOCC1.C(O)(=O)C>[ClH:1].[Cl:22][C:5]1[C:6]([C:8]([NH:10][CH2:11][C:12]23[CH2:13][CH:14]4[CH2:15][CH:16]([CH2:17][CH:18]([CH2:20]4)[CH2:19]2)[CH2:21]3)=[O:9])=[CH:7][C:2]([O:36][CH:33]2[CH2:34][CH2:35][NH:30][CH2:31][CH2:32]2)=[N:3][CH:4]=1
Reactant: O=C(NCC12CC3CC(CC(C3)C1)C2)c1cc(Cl)ncc1Cl
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CO
Solvent: CC(=O)O
Product: O=C(NCC12CC3CC(CC(C3)C1)C2)c1cc(OC2CCNCC2)ncc1Cl
Yield: 23.1 %

Procedure:
A solution of 2,5-dichloro-N-(tricyclo[3.3.1.13,7]dec-1-ylmethyl)-pyridine-4-carboxamide (0.30 g, Example 1a) and 1-t-butoxycarbonylpiperidine-4-ol (0.344 g) in anhydrous tetrahydrofuran (10 ml) was heated with sodium hydride (50 mg, 60% dispersion) at 70° C. for 24 hours. The solution was cooled, glacial acetic acid (0.1 ml) was added and the mixture partitioned between saturated aqueous sodium bicarbonate solution and dichloromethane. The organic layer was dried over magnesium sulphate, concentrated in vacuo and chromatographed on silica (ethyl acetate: isohexane) to give a colourless solid. This was redissolved in methanol (20 ml) and treated with 4M HCl in dioxan (4 ml). Once deprotection was complete (14 hours) the solution was partially concentrated in vacuo then diluted slowly with diethyl ether with rapid stirring. The resulting white precipitate was filtered, washed with diethyl ether and dried to afford the title compound (0.090 g).
Reaction SMILES: [CH3:1][C:2]1[C:14]([CH3:15])=[C:13]2[C:5]([CH2:6][CH2:7][C:8]3([O:12]2)[CH2:11][CH2:10][CH2:9]3)=[CH:4][C:3]=1[OH:16].C[CH2:18][O:19]C(C)=O>C(C(C#N)=C1C=C(C=CC2C=CC(N(C)C)=CC=2)OC(C)=C1)#N.[Ti](Cl)(Cl)(Cl)Cl>[OH:16][C:3]1[C:2]([CH3:1])=[C:14]([CH3:15])[C:13]2[O:12][C:8]3([CH2:9][CH2:10][CH2:11]3)[CH2:7][CH2:6][C:5]=2[C:4]=1[CH:18]=[O:19]
Reactant: Cc1c(O)cc2c(c1C)OC1(CCC1)CC2
Reactant: CCOC(C)=O
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: CC1=CC(=C(C#N)C#N)C=C(C=Cc2ccc(N(C)C)cc2)O1
Product: Cc1c(C)c2c(c(C=O)c1O)CCC1(CCC1)O2
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
0.3 g of a solution of 7,8-dimethyl-3,4-dihydrospiro[chromene-2,1′-cyclobutan]-6-ol (prepared as described herein) was dissolved in 20 mL of 4-(dicyanomethylene)-2-methyl-6-(4-dimethylaminostyryl)-4H-pyran (DCM). The solution was flushed with Argon then cooled to 0° C. in an ice bath. 0.151 mL (1.4 mmol) of titanium tetrachloride was added followed by 0.149 mL (1.7 mmol, 1.2 eq) of α,α-dichloromethyl-methyl ether. The solution was stirred at 0° C. for 10 min, warmed to room temperature, and stirred overnight. After addition of EtOAc (50 mL), the solution was washed with water, and then dried over Na2SO4. The crude material was purified on a silica column eluting with 1:8 EtOAc/hexane to yield 180 mg of 6-hydroxy-7,8-dimethyl-3,4-dihydrospiro[chromene-2,1′-cyclobutane]-5-carbaldehyde as a yellow solid. 1H-NMR (300 MHz, CDCl3) δ=1.65-1-70 (m, 1H), 1.80-1.97 (m, 2H), 2.06-2.27 (m, 11H), 3.06-3.11 (t, 2H), 10.20 (s, 1H), 12.13 (s, 1H) ppm. MS (m/z)=247 (M+H+).
Reaction SMILES: [Br:1][C:2]1[C:3]([F:17])=[C:4]([NH:9]C(=O)OC(C)(C)C)[CH:5]=[C:6]([Cl:8])[CH:7]=1.Cl>O1CCOCC1>[Br:1][C:2]1[C:3]([F:17])=[C:4]([CH:5]=[C:6]([Cl:8])[CH:7]=1)[NH2:9]
Reactant: CC(C)(C)OC(=O)Nc1cc(Cl)cc(Br)c1F
Agent: Cl
Solvent: C1COCCO1
Product: Nc1cc(Cl)cc(Br)c1F
Temperature: 25 °C

Procedure:
tert-Butyl 3-bromo-5-chloro-2-fluorophenylcarbamate (1.0 g, 3.1 mmol) was treated with 4.0 M HCl in dioxane (10 mL) and the resulting reaction was maintained at room temperature for 4 hours. The reaction mixture was concentrated and partitioned between EtOAc (200 mL) and saturated aqueous NaHCO3 solution (75 mL). The layers were separated and the organic portion was washed with brine (75 mL), dried (Na2SO4), and concentrated to give 3-bromo-5-chloro-2-fluoroaniline as a colorless oil which was carried forward without further purification: LCMS (m/z) 225.9 (MH+), tR=0.96 minute; 1H NMR (400 MHz, CDCl3) δ 6.88 (m, 1H), 6.70 (d, J=7.0 Hz, 1H).
Reaction SMILES: [NH:1]([CH:8]1[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:22]12([C:32](Cl)=[O:33])[CH2:31][CH:26]3[CH2:27][CH:28]([CH2:30][CH:24]([CH2:25]3)[CH2:23]1)[CH2:29]2>>[C:2]1([N:1]([CH:8]2[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][C:15]3[CH:16]=[CH:17][C:18]([F:21])=[CH:19][CH:20]=3)[CH2:9]2)[C:32]([C:22]23[CH2:31][CH:26]4[CH2:25][CH:24]([CH2:30][CH:28]([CH2:27]4)[CH2:29]2)[CH2:23]3)=[O:33])[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Fc1ccc(CCN2CCC(Nc3ccccc3)C2)cc1
Reactant: O=C(Cl)C12CC3CC(CC(C3)C1)C2
Product: O=C(N(c1ccccc1)C1CCN(CCc2ccc(F)cc2)C1)C12CC3CC(CC(C3)C1)C2

Procedure:
3-Anilino-1-(2-(4-fluorophenyl)ethyl)pyrrolidine and 1-adamantanecarbonyl chloride were reacted under the same conditions as in Example 53 to give N-phenyl-N-(1-(2-(4-fluorophenyl)ethyl)pyrrolidin-3-yl)-1-adamantanecarboxamide.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH2:6][NH:5]2.C=O.O.[C:16](O)(=O)C.[BH3-]C#N.[Na+]>CO>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH2:6][N:5]2[CH3:16]
Reactant: O=C1CNc2cc(Br)ccc2N1
Reactant: CC(=O)O
Agent: C=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CN1CC(=O)Nc2ccc(Br)cc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.9 %

Procedure:
To a solution of 6-bromo-3,4-dihydroquinoxalin-2(1H)-one (370 mg, 1.63 mmol) in 10 ml methanol was added a solution of 37% formaldehyde in water (59 mg, 1.95 mmol) and acetic acid (196 mg, 3.26 mmol). The mixture was stirred at room temperature for 2 h, then refluxed for 1 h. After addition of NaBH3CN (307 mg, 4.89 mmol) stirring was continued for 2.5 h at room temperature. Then methanol was removed under vacuum. To the remaining mixture water was added. Then the solution was basified to pH 8-9 with an aqueous solution of sodium hydrogen carbonate and extracted several times with ethyl acetate. The combined organic layers were washed with brine, dried over MgSO4 and evaporated, affording 6-bromo-4-methyl-3,4-dihydroquinoxalin-2(1H)-one (369 mg, 1.53 mmol, 94%) as off-white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:9]2[N:10]=[CH:11][C:12]([NH2:15])=[N:13][CH:14]=2)[CH:5]=[CH:6][C:7]=1[CH3:8].N1C=CC=CC=1.[Cl:22][C:23]1[CH:24]=[CH:25][C:26]([N+:32]([O-:34])=[O:33])=[C:27]([CH:31]=1)[C:28](Cl)=[O:29]>ClCCl>[Cl:22][C:23]1[CH:24]=[CH:25][C:26]([N+:32]([O-:34])=[O:33])=[C:27]([CH:31]=1)[C:28]([NH:15][C:12]1[CH:11]=[N:10][C:9]([C:4]2[CH:5]=[CH:6][C:7]([CH3:8])=[C:2]([CH3:1])[CH:3]=2)=[CH:14][N:13]=1)=[O:29]
Reactant: Cc1ccc(-c2cnc(N)cn2)cc1C
Reactant: O=C(Cl)c1cc(Cl)ccc1[N+](=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1ccc(-c2cnc(NC(=O)c3cc(Cl)ccc3[N+](=O)[O-])cn2)cc1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Into a 250-mL round bottom flask, was placed a solution of 5-(3,4-dimethylphenyl)pyrazin-2-amine (2 g, 10.04 mmol, 1.00 equiv) in dichloromethane (70 mL), pyridine (2.4 g, 30.34 mmol, 3.00 equiv), and a solution of 5-chloro-2-nitrobenzoyl chloride (2.21 g, 10.05 mmol, 1.00 equiv) in dichloromethane (20 mL). The resulting solution was stirred overnight at 25° C. in an oil bath, then diluted with 150 mL of dichloromethane and washed with 2×100 mL of diluted hydrochloric acid, 2×200 mL of brine and 2×100 mL of sodium carbonate (sat.), and then 2×200 mL of brine. The organic layer was dried over sodium sulfate and concentrated under vacuum. The crude product was triturated with 40 mL of ethyl acetate/n-hexane (1:1). This resulted in 3.66 g (95%) of 5-chloro-N-(5-(3,4-dimethylphenyl)pyrazin-2-yl)-2-nitrobenzamide as an off-white solid.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:18])[N:7]3[CH2:15][C:14]([CH3:17])([CH3:16])[CH2:13][CH2:12][C:8]3=[N:9]2)=[CH:4][CH:3]=1.[B-](F)(F)(F)[F:20].[B-](F)(F)(F)F.C1[N+]2(CCl)CC[N+](F)(CC2)C1>CN(C=O)C.O>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:18])[N:7]3[CH2:15][C:14]([CH3:16])([CH3:17])[CH2:13][CH:12]([F:20])[C:8]3=[N:9]2)=[CH:4][CH:3]=1
Reactant: CC1(C)CCc2nc3cc(Br)ccc3c(=O)n2C1
Reactant: F[B-](F)(F)F
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Solvent: O
Solvent: CN(C)C=O
Product: CC1(C)CC(F)c2nc3cc(Br)ccc3c(=O)n2C1
Temperature: 90 °C
Reaction time: 3 h
Yield: 75.2 %

Procedure:
To a solution of 3-bromo-8,8-dimethyl-8,9-dihydro-6H-pyrido[2,1-b]quinazolin-11(7H)-one (0.1 g, 0.327 mmol, 1 equiv) in DMF (5 mL), Selectfluor (0.12 g, 0.327 mmol, 1 eq) was added. The reaction mixture was heated to 90° C. and stirred for 3 hours. After cooling to room temperature, the reaction mixture was diluted with water and extracted with ethyl acetate (3×50 mL), dried over Na2SO4. After filtration and concentration, 80 mg of the desired product was obtained, which was directly used for the next step without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](I)=[C:4]([O:9][C:10]([F:13])([F:12])[F:11])[CH:3]=1.[Li]CCCC.CCCCCC.[CH:25](N1CCOCC1)=[O:26]>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:25]=[O:26])=[C:4]([O:9][C:10]([F:13])([F:12])[F:11])[CH:3]=1
Reactant: FC(F)(F)Oc1cc(Br)ccc1I
Reactant: O=CN1CCOCC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: O=Cc1ccc(Br)cc1OC(F)(F)F
Temperature: -78 °C
Reaction time: 1.5 h
Yield: 76.5 %

Procedure:
A solution of 4-bromo-1-iodo-2-trifluoromethoxy-benzene (1.00 g, 2.72 mmol) in THF (15 mL) was cooled to −78° C., and 2.66 M BuLi in hexane (2.05 mL, 5.44 mmol) was added dropwise. The reaction mixture was stirred at −78° C. for 1.5 h, and N-formylmorpholine (0.57 mL, 5.63 mmol) was added. The reaction mixture was stirred at −78° C. for 15 min and at ambient temperature for 80 min. The reaction was quenched with 0.25 M aqueous citric acid (10 mL), and the resulting mixture was extracted with EtOAc (three times). The combined organic layer was dried over MgSO4, filtered, concentrated, and purified by flash chromatography (silica gel, 2% to 5% EtOAc in hexane) to give 4-bromo-2-trifluoromethoxy-benzaldehyde (560 mg, 77%) as a pale brown solid.
Reaction SMILES: B([C:4]1[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:5]=1[O:6][C@@H:7]([CH3:11])[C:8]([OH:10])=[O:9])(O)O.Br[C:18]1[CH:23]=[CH:22][C:21]([S:24]([N:27]([CH3:29])[CH3:28])(=[O:26])=[O:25])=[CH:20][CH:19]=1>C1COCC1>[Cl:16][C:14]1[CH:13]=[CH:12][C:5]([O:6][C@@H:7]([CH3:11])[C:8]([OH:10])=[O:9])=[C:4]([C:18]2[CH:19]=[CH:20][C:21]([S:24]([N:27]([CH3:29])[CH3:28])(=[O:25])=[O:26])=[CH:22][CH:23]=2)[CH:15]=1
Reactant: CN(C)S(=O)(=O)c1ccc(Br)cc1
Reactant: C[C@H](Oc1ccc(Cl)cc1B(O)O)C(=O)O
Solvent: C1CCOC1
Product: C[C@H](Oc1ccc(Cl)cc1-c1ccc(S(=O)(=O)N(C)C)cc1)C(=O)O

Procedure:
The title compound was prepared by the method of example 144 step (i) using the product from step (iv) and 4-bromo-N,N-dimethylbenzenesulfonamide and THF as solvent. Yield (0.068 g).