Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].C([Li])CCC.[B:24](OC(C)C)([O:29]C(C)C)[O:25]C(C)C>>[CH2:9]([C:3]1[CH:4]=[CH:5][C:6]([B:24]([OH:29])[OH:25])=[C:7]([F:8])[C:2]=1[F:1])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: CCCCCCCCCCc1cccc(F)c1F
Agent: [Li]CCCC
Product: CCCCCCCCCCc1ccc(B(O)O)c(F)c1F

Procedure:
Quantities: compound from Example 27 (26.7 g, 105 mmol), n-butyllithium (11 cm3, 10.0M in hexanes, 0.11 mol) and triisopropyl borate (39.5 g, 0.21 mol). The experimental procedure was as described in Example 28.
Reaction SMILES: C([O:4][C:5]1[CH:13]=[C:12]([CH3:14])[CH:11]=[C:10]2[C:6]=1[CH2:7][CH2:8][CH2:9]2)(=O)C>CCCCCC.C(OCC)(=O)C>[CH3:14][C:12]1[CH:13]=[C:5]([OH:4])[C:6]2[CH2:7][CH2:8][CH2:9][C:10]=2[CH:11]=1
Reactant: CC(=O)Oc1cc(C)cc2c1CCC2
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: Cc1cc(O)c2c(c1)CCC2
Yield: 81 %

Procedure:
Using 6-methyl-2,3-dihydro-1H-inden-4-yl acetate synthesized in Reference Example 174, the title compound was synthesized in the same manner as in Reference Example 175. Yield 81%. Melting point: 82-83° C. (hexane-ethyl acetate).
Reaction SMILES: [Si:1]([O:8][C@H:9]1[CH2:18][C@H:17]([OH:19])[C@H:16]2[C:11]([CH:12]=[CH:13][C@H:14]([CH3:37])[C@@H:15]2[CH2:20][CH2:21][C@H:22]2[O:27][C:26](=[O:28])[CH2:25][C@H:24]([O:29][Si:30]([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31])[CH2:23]2)=[CH:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[C:38](Cl)(=[O:43])[CH2:39][CH:40]([CH3:42])[CH3:41]>>[Si:1]([O:8][C@H:9]1[CH2:18][C@H:17]([O:19][C:38](=[O:43])[CH2:39][CH:40]([CH3:42])[CH3:41])[C@H:16]2[C:11]([CH:12]=[CH:13][C@H:14]([CH3:37])[C@@H:15]2[CH2:20][CH2:21][C@H:22]2[O:27][C:26](=[O:28])[CH2:25][C@H:24]([O:29][Si:30]([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:31])[CH3:32])[CH2:23]2)=[CH:10]1)([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:3])[CH3:2]
Reactant: C[C@H]1C=CC2=C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O)[C@@H]2[C@H]1CC[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CC(=O)O1
Reactant: CC(C)CC(=O)Cl
Product: CC(C)CC(=O)O[C@H]1C[C@H](O[Si](C)(C)C(C)(C)C)C=C2C=C[C@H](C)[C@H](CC[C@@H]3C[C@@H](O[Si](C)(C)C(C)(C)C)CC(=O)O3)[C@H]21
Yield: 89.8 %

Procedure:
A procedure similar to that described in Example 4, above, was followed, but using 1.10 g (2.0 mmol) of (4R,6R)-6-{2-[(1S,2S,6S,8S,8aR)-1,2,6,7,8,8a-hexahydro-6-t-butyldimethylsilyloxy-8-hydroxy-2-methyl-1-naphthyl]ethyl}tetrahydro-4-t-butyldimethylsilyloxy-2H-pyran-2-one [prepared as described in Example 3, above] and 361 mg (3.0 mmol) of isovaleryl chloride, to provide 1.14 g of the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]([C:11]1[CH:12]=[N:13][C:14]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)=[CH:15][CH:16]=1)=[O:10].[C:23]([C:27]1[CH:32]=[CH:31][C:30]([S:33](Cl)(=[O:35])=[O:34])=[CH:29][CH:28]=1)([CH3:26])([CH3:25])[CH3:24]>>[C:23]([C:27]1[CH:32]=[CH:31][C:30]([S:33]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=2[C:9]([C:11]2[CH:12]=[N:13][C:14]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[CH:15][CH:16]=2)=[O:10])(=[O:35])=[O:34])=[CH:29][CH:28]=1)([CH3:26])([CH3:24])[CH3:25]
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Cl)cc1
Reactant: Nc1ccc(Cl)cc1C(=O)c1ccc(N2CCOCC2)nc1
Product: CC(C)(C)c1ccc(S(=O)(=O)Nc2ccc(Cl)cc2C(=O)c2ccc(N3CCOCC3)nc2)cc1

Procedure:
The title compound was prepared according to the general procedure for the synthesis of N-Aryl-benzenesulfonamides previously described using 158 mg of (2-Amino-5-chloro-phenyl)-(6-morpholin-4-yl-pyridin-3-yl)-methanone and 116 mg of 4-tert-butyl-benzenesulfonyl chloride. 1H-NMR (400 MHz, CDCl3): δ 1.22 (s, 3H), 3.76 (t, 4H, J=4.6 Hz), 3.857 (t, 4H, J=4.6H), 8.78 (d, 1H, J=9.2 Hz), 7.30 (m, 2H), 7.34 (m, 1H), 7.46 (m, 1H), 7.54-7.56 (m, 3H), 7.99 (d, 1H, J=9.2 Hz), 8.16 (v, 1H), 9.29 (s, 1H). MS: m/z 515.1 (M++1).
Reaction SMILES: [Br:1][C:2]1[S:3][CH:4]=[CH:5][CH:6]=1.Cl[C:8](=[O:14])[C:9]([O:11][CH2:12][CH3:13])=[O:10].[Cl-].[Cl-].[Cl-].[Al+3]>ClCCl>[Br:1][C:2]1[S:3][C:4]([C:8](=[O:14])[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:5][CH:6]=1
Reactant: CCOC(=O)C(=O)Cl
Reactant: Brc1cccs1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CCOC(=O)C(=O)c1ccc(Br)s1
Reaction time: 0.17 h
Yield: 25.8 %

Procedure:
To a solution of 2-bromothiophene (10 mL, 103.3 mmol, 1.0 eq) in dichloromethane (200 mL) was added ethyl 2-chloro-2-oxoacetate (13.8 mL, 123.9 mmol, 1.2 eq) and aluminum trichloride (16.5 g, 123.9 mmol, 1.2 eq) at 0° C. After stirring for 10 minutes, the reaction mixture was diluted with dichloromethane and poured into ice. The combined organic phase was washed (brine), dried (MgSO4), filtered and concentrated to give a residue, the residue was purified by silica gel column chromatography to yield ethyl 2-(5-bromothiophen-2-yl)-2-oxoacetate (7.0 g, 25.8%). LC-MS (m/z): 262.8 [M+H]+. 1H NMR (400 MHz, DMSO-d6): δ 1.33 (t, J=7.2 Hz, 3H), 4.33-4.39 (m, 2H), 7.48 (d, J=3.6 Hz, 1H), 7.94 (d, J=4.4 Hz, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH:13]=[C:12]([CH:14]=[O:15])[C:11]([CH2:16][N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[N:10]2)=[CH:5][CH:4]=1.[CH:23]1([Mg]Br)[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1>O1CCCC1>[CH:23]1([CH:14]([C:12]2[C:11]([CH2:16][N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[N:10][N:9]([C:6]3[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)[CH:13]=2)[OH:15])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: Br[Mg]C1CCCCC1
Reactant: COc1ccc(-n2cc(C=O)c(CN3CCOCC3)n2)cc1
Solvent: C1CCOC1
Product: COc1ccc(-n2cc(C(O)C3CCCCC3)c(CN3CCOCC3)n2)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 51 %

Procedure:
To a solution (15 mL) of 1-(4-methoxyphenyl)-3-(morpholin-4-ylmethyl)-1H-pyrazole-4-carbaldehyde (2.0 g) synthesized in the above-mentioned (3) in tetrahydrofuran was added dropwise cyclohexylmagnesium bromide (10 mL, 1M tetrahydrofuran solution) under ice-cooling. After the completion of the dropwise addition, the ice bath was removed, and the mixture was stirred at room temperature for 15 min. To the reaction mixture was added aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The extract was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:2, volume ratio) to give the title object compound (1.3 g, 51%) as a pale-yellow oil.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:9]([OH:11])=O)=[N:4][C:5]([Br:8])=[CH:6][N:7]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.CCN(C(C)C)C(C)C.[NH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>CN(C1C=CN=CC=1)C.CS(C)=O.O>[NH2:1][C:2]1[C:3]([C:9]([NH:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[O:11])=[N:4][C:5]([Br:8])=[CH:6][N:7]=1
Reactant: Nc1ccccc1
Reactant: Nc1ncc(Br)nc1C(=O)O
Agent: CN(C)c1ccncc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: Nc1ncc(Br)nc1C(=O)Nc1ccccc1
Reaction time: 0.5 h
Yield: 74.4 %

Procedure:
A mixture of 3-amino-6-bromo-pyrazine-2-carboxylic acid (3.5 g, 16.05 mmol), 1,1′-carbonyldiimidazole (5.205 g, 32.10 mmol), DIPEA (2.282 g, 3.075 mL, 17.66 mmol) and DMAP (98.04 mg, 0.8025 mmol) were combined in DMSO (131 mL) and stirred for 30 min. Aniline (1.495 g, 1.463 mL, 16.05 mmol) was then added and the resulting solution stirred at RT for 18 hours. After this time water was added and the product collected by filtration to give a brown powder (3.5 g, 74% Yield).
Reaction SMILES: [I:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([F:9])[CH:3]=1.[F:10][C:11]1[CH:16]=[C:15]([F:17])[C:14]([N+:18]([O-:20])=[O:19])=[C:13](F)[C:12]=1[F:22]>C1COCC1>[F:9][C:4]1[CH:3]=[C:2]([I:1])[CH:8]=[CH:7][C:5]=1[NH:6][C:13]1[C:14]([N+:18]([O-:20])=[O:19])=[C:15]([F:17])[CH:16]=[C:11]([F:10])[C:12]=1[F:22]
Reactant: O=[N+]([O-])c1c(F)cc(F)c(F)c1F
Reactant: Nc1ccc(I)cc1F
Solvent: C1CCOC1
Product: O=[N+]([O-])c1c(F)cc(F)c(F)c1Nc1ccc(I)cc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 69.5 %

Procedure:
A solution of 4-iodo-2-fluoro aniline (3.64 g, 15.37 mmol) in dry THF (100 mL) was cooled to −78° C. in a dry ice-acetone bath under a nitrogen atmosphere. To this solution was added dropwise via syringe a 1 M solution of LHDMS in THF (15.4 mL). During the addition the solution turns green and the mixture was stirred at that temperature for an additional 1 h. The mixture was cooled and to it was then added dropwise a solution of 1,2,3,5-tetrafluoro-4-nitrobenzene (3 g, 15.37 mmol) in dry THF (10.0 mL) via syringe. During the addition the color of the mixture changes to dark purple. The mixture was then allowed to stir at −78° C. for 1 h and then warmed to room temperature and stirred overnight (12 h). The mixture was then concentrated under vacuo to remove ⅔ of the THF, diluted with ethyl acetate (100 mL), washed with water (2×50 mL), and finally with brine. The organic layer was dried over MgSO4 and evaporated under reduced pressure. The crude material was purified by careful flash column chromatography over silica gel using a 1-5% ethyl acetate/hexanes gradient to afford the desired product as a yellow solid (4.4 g, 70%). 1H NMR (400 MHz, DMSO-d6): 6.85 (t, 1H), 7.35 (d, 1H), 7.60-7.65 (m, 2H), 8.78 (s, 1H).
Reaction SMILES: [H-].[Na+].[NH2:3][C@@H:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C@H:7]([OH:14])[CH2:6][CH2:5]1.F[C:16]1[CH:17]=[CH:18][C:19]2[N:20]([C:22]([C:25]([N:28]([CH3:30])[CH3:29])([CH3:27])[CH3:26])=[N:23][N:24]=2)[CH:21]=1.N>CN(C=O)C.CO.C(Cl)Cl>[CH3:30][N:28]([CH3:29])[C:25]([C:22]1[N:20]2[CH:21]=[C:16]([O:14][C@H:7]3[C:8]4[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=4)[C@@H:4]([NH2:3])[CH2:5][CH2:6]3)[CH:17]=[CH:18][C:19]2=[N:24][N:23]=1)([CH3:27])[CH3:26]
Reactant: CN(C)C(C)(C)c1nnc2ccc(F)cn12
Reactant: N[C@H]1CC[C@@H](O)c2ccccc21
Agent: N
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CO
Product: CN(C)C(C)(C)c1nnc2ccc(O[C@@H]3CC[C@H](N)c4ccccc43)cn12
Temperature: 60 °C
Reaction time: 0.33 h
Yield: 46.9 %

Procedure:
To a suspension of NaH (60% in mineral oil, 112 mg, 2.80 mmol) in DMF (2.50 mL) was added Intermediate A (114 mg, 0.70 mmol) and the reaction stirred for 20 min. Intermediate 76b (153 mg, 0.70 mmol) was added in DMF (2.50 mL) and the reaction heated to 60° C. for 1 h. The reaction was cooled and quenched by dropwise addition of methanol, before being diluted with methanol and loaded onto an SCX-2 cartridge, which was washed with MeOH. The product was eluted with 2M NH3 in MeOH; concentration in vacuo gave a residue. FCC, using 2-10% [2M NH3 in MeOH] in DCM, gave the title compound (120 mg, 47%). LCMS (Method 4): Rt 0.31, m/z 366 [MH+].
Reaction SMILES: [N:1]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[N:4]([C:10]1[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=1)[N:16]=[C:15]([C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[CH:21]=1)[N:14]([CH2:27][C:28](O)=[O:29])[C:13]3=[O:31])[CH2:3][CH2:2]2.Cl.[CH3:33][NH:34][CH3:35].C(N(CC)CC)C.CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O.C(OCC)(=O)C>ClCCl>[N:1]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[N:4]([C:10]1[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=1)[N:16]=[C:15]([C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[CH:21]=1)[N:14]([CH2:27][C:28]([N:34]([CH3:35])[CH3:33])=[O:29])[C:13]3=[O:31])[CH2:3][CH2:2]2
Reactant: O=C(O)Cn1c(-c2cccc(Cl)c2)nc2ccc(N3CCN4CCC3CC4)cc2c1=O
Reactant: CNC
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(C)C(=O)Cn1c(-c2cccc(Cl)c2)nc2ccc(N3CCN4CCC3CC4)cc2c1=O
Reaction time: 2 h
Yield: 10.9 %

Procedure:
2-(6-(1,4-Diazabicyclo[3.2.2]nonan-4-yl)-2-(3-chlorophenyl)-4-oxoquinazolin-3(4H)-yl)acetic acid (Intermediate 11A) (49 mg, 0.11 mmol) and dimethylamine hydrochloride (18.2 mg, 0.22 mmol) were weighed into a round bottomed flask and dichloromethane (1 mL) added to form a suspension. Triethylamine (33.8 mg, 0.33 mmol) was added and the suspension stirred for 5 minutes before dropwise addition of 1-propanephosphonic acid cyclic anhydride as a 50% wt solution in ethyl acetate (107 mg, 0.17 mmol) and the resulting reaction mixture stirred for 2 hours. Reaction mixture was washed with sodium bicarbonate solution and the organics were separated using a hydrophobic frit. The solvent was removed under reduced pressure and then re-dissolved in methanol (1 mL) and purified by preparative-HPLC. To afford the title compound 2-(6-(1,4-diazabicyclo[3.2.2]nonan-4-yl)-2-(3-chlorophenyl)-4-oxoquinazolin-3(4H)-yl)-N,N-dimethylacetamide (5.4 mg, 0.012 mmol).
Reaction SMILES: Br[CH:2]1[CH2:6][CH2:5][N:4]([C:7]2[CH:8]=[N:9][N:10]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)[C:11]=2[CH:12]([CH3:14])[CH3:13])[C:3]1=[O:22].[NH2:23][C:24]1[N:29]=[CH:28][N:27]=[C:26]2[NH:30][N:31]=[C:32]([C:33]#[N:34])[C:25]=12.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[NH2:23][C:24]1[N:29]=[CH:28][N:27]=[C:26]2[N:30]([CH:2]3[CH2:6][CH2:5][N:4]([C:7]4[CH:8]=[N:9][N:10]([C:15]5[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=5)[C:11]=4[CH:12]([CH3:14])[CH3:13])[C:3]3=[O:22])[N:31]=[C:32]([C:33]#[N:34])[C:25]=12
Reactant: CC(C)c1c(N2CCC(Br)C2=O)cnn1-c1ccc(F)cc1
Reactant: N#Cc1n[nH]c2ncnc(N)c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)c1c(N2CCC(n3nc(C#N)c4c(N)ncnc43)C2=O)cnn1-c1ccc(F)cc1
Temperature: 60 °C
Reaction time: 1 h
Yield: 82.3 %

Procedure:
A mixture of 3-bromo-1-[1-(4-fluorophenyl)-5-isopropylpyrazol-4-yl]pyrrolidin-2-one (0.055 g, 0.15 mmol), 4-amino-1H-pyrazolo[3,4-d]pyrimidine-3-carbonitrile (0.050 g, 0.31 mmol) and K2CO3 (0.050 g, 0.36 mmol) in DMF (2.0 mL) was stirred at 60° C. for 1 hr. The mixture was then cooled to room temperature, quenched with water (30 mL), and extracted with IPA:CHCl3 (1:2 v/v, 100 mL). The organic layer was separated, dried over anhydrous sodium sulfate, concentrated in vacuo and purified by flash chromatography (SiO2, 0˜10% MeOH/EtOAc gradient elution) to give 4-amino-1-[1-[1-(4-fluorophenyl)-5-isopropylpyrazol-4-yl]-2-oxo-pyrrolidin-3-yl]pyrazolo[3,4-d]pyrimidine-3-carbonitrile (0.055 g, 82%).
Reaction SMILES: [CH3:1][C:2]1[C:11]2[NH:10][C:9]3=[CH:12][C:13]([C:15](O)=[O:16])=[N:14][N:8]3[C:7](=[O:18])[C:6]=2[CH:5]=[CH:4][CH:3]=1.C(N1C=CN=C1)([N:21]1C=CN=C1)=O.FC(F)(F)C1C2C(=O)N3N=C(C(N)=O)C=C3NC=2C=CC=1>CN(C)C=O.CCOCC.C(Cl)Cl>[CH3:1][C:2]1[C:11]2[NH:10][C:9]3=[CH:12][C:13]([C:15]([NH2:21])=[O:16])=[N:14][N:8]3[C:7](=[O:18])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Cc1cccc2c(=O)n3nc(C(=O)O)cc3[nH]c12
Agent: NC(=O)c1cc2[nH]c3cccc(C(F)(F)F)c3c(=O)n2n1
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCOCC
Product: Cc1cccc2c(=O)n3nc(C(N)=O)cc3[nH]c12
Temperature: 100 °C
Reaction time: 8 h

Procedure:
To a solution of 4,9-dihydro-5-methyl-9-oxo-pyrazolo[5,1-b]quinazoline-2-carboxylic acid (4.86 g; 0.02 mole) in dimethylformamide (50 ml) is added 1,1'-carbonyldiimidazole (4.86 g; 0.03 mole). The reaction mixture is heated at 100° C. for 12 min, then cooled and diluted with ether (75 ml) and methylene chloride (25 ml). The tan solid is filtered off and suspended in cold (0° C.) DMF (50 ml). Annydrous ammonia is bubbled through for 10 min and the resulting solution is allowed to stand at room temperature overnight. The dimethylformamide solution is evapoated to dryness under reduced pressure and the residue is washed with methylene chloride and ether and dried. Yield 3.0 g; mp 340°-345° C. (d). By the same procedure, starting with the corresponding 8-trifluoromethyl compound, the product obtained is 4,9-dihydro-8-trifluoromethyl-9-oxo-pyrazolo[5,1-b]quinazoline-2-carboxamide.
Reaction SMILES: [F:1][C:2]1([CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([S:16]([NH2:19])(=[O:18])=[O:17])=[CH:12][C:11]=2[N+:20]([O-:22])=[O:21])[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[O:23]1[CH2:28][CH2:27][C:26](=O)[CH2:25][CH2:24]1.C([BH3-])#N.[Na+].C(O)(=O)C>O1CCCC1>[F:1][C:2]1([CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([S:16]([NH2:19])(=[O:18])=[O:17])=[CH:12][C:11]=2[N+:20]([O-:22])=[O:21])[CH2:7][CH2:6][N:5]([CH:26]2[CH2:27][CH2:28][O:23][CH2:24][CH2:25]2)[CH2:4][CH2:3]1
Reactant: O=C1CCOCC1
Reactant: NS(=O)(=O)c1ccc(OCC2(F)CCNCC2)c([N+](=O)[O-])c1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: NS(=O)(=O)c1ccc(OCC2(F)CCN(C3CCOCC3)CC2)c([N+](=O)[O-])c1

Procedure:
A mixture of EXAMPLE 173A (0.4 g), dihydro-2H-pyran-4(3H)-one (0.179 g), sodium cyanoborohydride (0.112 g), and acetic acid (0.5 mL) in tetrahydrofuran (3 mL) was stirred overnight. The solvents were removed under reduced pressure. The residue was purified with flash column chromatography on silica gel eluting with 100:5:0.5 ethyl acetate/methanol/NH4OH to give the desired product.
Reaction SMILES: CO[C:3](=[O:20])[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=2)=[N:6][CH:5]=1.Cl.[CH3:22][NH:23][O:24][CH3:25].C([Mg]Cl)(C)C>O1CCCC1>[CH3:25][O:24][N:23]([CH3:22])[C:3](=[O:20])[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[CH:12][C:13]([C:16]([F:17])([F:18])[F:19])=[CH:14][CH:15]=2)=[N:6][CH:5]=1
Reactant: CNOC
Reactant: COC(=O)c1ccc(-c2ccc(C(F)(F)F)cc2)nc1
Agent: CC(C)[Mg]Cl
Agent: Cl
Solvent: C1CCOC1
Product: CON(C)C(=O)c1ccc(-c2ccc(C(F)(F)F)cc2)nc1
Temperature: -30 °C
Yield: 99.7 %

Procedure:
6-(4-Trifluoromethyl-phenyl)-nicotinic acid methyl ester (20 g, 71.2 mmol) is dissolved into anhydrous tetrahydrofuran (TVF) (300 mL) and then cooled to −30° C. while stirring under nitrogen. N,O-dimethylhydroxylamine hydrochloride (10.4 g, 107 mmol) is then added to the solution in one portion. Isopropyl magnesium chloride (107 mL, 2M soln. in THF, 252 mmol) is slowly added to the cooled suspension over 2 h. After complete consumption of starting material, 30% solution of ammonium chloride is added with stirring. The reaction is diluted with diethyl ether, water, and extracted. The organic layer is collected and washed with cold water (2×) and brine. The solution is then dried over anhydrous sodium sulfate, filtered, and concentrated. The N-Methoxy-N-methyl-6-(4-trifluoromethyl-phenyl)-nicotinamide (22 g, 71 mmol) is obtained in purified form after flash column chromatography.
Reaction SMILES: CC(C)=O.C(=O)=O.[CH3:8][C:9]1[N:10]([C:14]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:11]=[CH:12][N:13]=1.CN(C)CCN(C)CCN(C)C.C([Li])CCC.[Cl:50][C:51]1[CH:52]=[C:53]([CH:56]=[CH:57][CH:58]=1)[CH:54]=[O:55]>O1CCCC1.C(OCC)(=O)C>[Cl:50][C:51]1[CH:52]=[C:53]([CH:54]([OH:55])[CH2:8][C:9]2[N:10]([C:14]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH:11]=[CH:12][N:13]=2)[CH:56]=[CH:57][CH:58]=1
Reactant: O=Cc1cccc(Cl)c1
Reactant: Cc1nccn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CN(C)CCN(C)CCN(C)C
Agent: O=C=O
Agent: [Li]CCCC
Solvent: CC(C)=O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: OC(Cc1nccn1C(c1ccccc1)(c1ccccc1)c1ccccc1)c1cccc(Cl)c1
Temperature: -78 °C
Reaction time: 6 h
Yield: 72.6 %

Procedure:
To a stirred, cooled (−78° C., acetone/dry ice bath) solution of 2-methyl-1-tritylimidazole (1 g; CAS 23593-68-2) in tetrahydrofuran (THF) (15 ml) under an argon atmosphere was added pentamethyldiethylene-triamine (0.64 ml). n-butyllithium solution (2.0 ml; 1.6 M in hexanes) was then added dropwise over a period of 10 min. The reaction mixture soon turned to a dark red compact slurry. The mixture was then stirred at a temperature between −40° C. and −50° C. for 6 hours. After cooling again to −78° C., a solution of 3-chlorobenzaldehyde (0.86 g) in THF (5 ml) was added dropwise for 5 minutes. The mixture was stirred overnight, slowly warming up to room temperature. The clear yellow solution was diluted with ethyl acetate (30 ml) and washed with H2O. The aqueous phase was back extracted with ethyl acetate (EtOAc). The combined organics were washed with H2O and brine, dried over MgSO4, filtered and concentrated. The crude product was purified by column chromatography (silica gel; gradient CH2Cl2→CH2Cl2/methanol 92:8) to give 1-(3-chloro-phenyl)-2-(1-trityl-1H-imidazol-2-yl)-ethanol (1.04 g) as light yellow amorphous solid. MS (ISP): 243.3 ([Trt]+)
Reaction SMILES: Br[CH2:2][C:3]1[N:7]2[C:8]3[C:13]([NH:14][C:15](=[O:16])[C:6]2=[N:5][C:4]=1[C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:12][C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][CH:9]=3.[CH3:26][C:27]1[NH:28][CH:29]=[CH:30][N:31]=1>C(#N)C>[CH2:24]([O:23][C:21]([C:4]1[N:5]=[C:6]2[C:15](=[O:16])[NH:14][C:13]3[C:8](=[CH:9][CH:10]=[C:11]([C:17]([F:20])([F:19])[F:18])[CH:12]=3)[N:7]2[C:3]=1[CH2:2][N:28]1[CH:29]=[CH:30][N:31]=[C:27]1[CH3:26])=[O:22])[CH3:25]
Reactant: CCOC(=O)c1nc2c(=O)[nH]c3cc(C(F)(F)F)ccc3n2c1CBr
Reactant: Cc1ncc[nH]1
Solvent: CC#N
Product: CCOC(=O)c1nc2c(=O)[nH]c3cc(C(F)(F)F)ccc3n2c1Cn1ccnc1C
Temperature: 80 °C
Reaction time: 4 h
Yield: 62 %

Procedure:
A suspension of 1-bromomethyl-2-ethoxycarbonyl-7-trifluoromethylimidazo[1,2-a]quinoxalin-4(5H)-one (Example 3) (4.18 g, 10.0 mmol) and 2-methylimidazole (1.8 g, 22.0 mmol) in acetonitrile (200 ml) was stirred at 80° C. for 4 h. The solvent was evaporated in vacuo and the residue submitted to flash chromatography on silica gel 60 eluting with dichloromethane/methanol (19:1). The purified product was washed with water to give 2.6 g (62%) of the title compound. M.p. >250° C.
Reaction SMILES: ClCCl.[OH-].[Na+].Cl.[CH3:7][NH:8][OH:9].[Br:10][CH:11]([CH2:15][CH2:16]Br)[C:12](Cl)=[O:13]>O>[Br:10][CH:11]1[CH2:15][CH2:16][O:9][N:8]([CH3:7])[C:12]1=[O:13]
Reactant: CNO
Reactant: O=C(Cl)C(Br)CCBr
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: CN1OCCC(Br)C1=O
Temperature: 5 °C
Reaction time: 2 h

Procedure:
A mixture of 65 mL of dichloromethane and 2.6 g (33 mmol) of 50% aqueous sodium hydroxide in 8 mL of water was treated with 2.5 g (30 mmol) of N-methylhydroxylamine hydrochloride. After cooling to 5° C., 8.5 g (32 mmol) of 2,4-dibromobutyryl chloride* was added dropwise, with the temperature maintained at 5° to 8° C. An additional 2.6 g of 50% aqueous sodium hydroxide was added, and the mixture was stirred for 2 hours at 5° C. A final 2.6 g of 50% aqueous sodium hydroxide was added, and the mixture was stirred at room temperature for 18 hours. The organic layer was separated, and the aqueous layer was extracted with dichloromethane. The combined organic layers were dried (anhydrous magnesium sulfate) and evaporated.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:13]2[N:21]3[C:16]([CH:17]=[N:18][C:19]([S:22][CH3:23])=[N:20]3)=[CH:15][CH:14]=2)=[C:6]([NH:8][S:9]([CH3:12])(=[O:11])=[O:10])[CH:7]=1.C1C=C(Cl)C=C(C(OO)=[O:32])C=1>CN(C)C=O>[CH3:23][S:22]([C:19]1[N:18]=[CH:17][C:16]2=[CH:15][CH:14]=[C:13]([C:5]3[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][C:6]=3[NH:8][S:9]([CH3:12])(=[O:11])=[O:10])[N:21]2[N:20]=1)=[O:32]
Reactant: CSc1ncc2ccc(-c3ccc(C)cc3NS(C)(=O)=O)n2n1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: CN(C)C=O
Product: Cc1ccc(-c2ccc3cnc(S(C)=O)nn23)c(NS(C)(=O)=O)c1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Into a RB flask, N-[5-Methyl-2-(2-methylsulfanyl-pyrrolo[2,1-f][1,2,4]triazin-7-yl)-phenyl]-methanesulfonamide (580 mg, 1.7 mmol) and N,N-Dimethylformamide (13 mL,) were added. Resulting solution was cooled to 0° C., m-CPBA (70:30, m-Chloroperbenzoic acid:3-Chlorobenzoic acid, 431 mg, 1.75 mmol) was added in portion over 10 minutes. After 2 h, solvent was removed .The residue was partitioned with DCM and sat. NaHCO3 solution. The organic phase was separated, washed with brine, and dried over Magnesium sulfate. N-[2-(2-Methanesulfinyl-pyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-methyl-phenyl]-methanesulfonamide was obtained as a yellow solid (539 mg, 89%) which was taken to the next step without further purifications. LCMS (E/I+) 365 (M+H).