Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.C([Mg]Br)C.[O:12]=[C:13]([CH3:19])[C:14]([O:16][CH2:17][CH3:18])=[O:15].CO.C(Cl)Cl>C1COCC1>[OH:12][C:13]([C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1)([CH3:19])[C:14]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: CCOC(=O)C(C)=O
Reactant: Ic1ccncc1
Agent: CC[Mg]Br
Solvent: CO
Solvent: ClCCl
Solvent: C1CCOC1
Product: CCOC(=O)C(C)(O)c1ccncc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 49.1 %

Procedure:
4-Iodopyridine (15.0 g, 73 mmol) was taken up in dry THF (600 mL) and cooled to 0° C. and then ethylmagnesium bromide (3M solution in THF, 41.8 mL) was gradually added, maintaining the temperature at 0° C. over the period of 30 mins. To the above reaction mixture was then added a solution of ethyl 2-oxopropanoate (12.13 g, 104 mmol) in THF (100 mL). The reaction mixture was stirred at 0° C. for 1 hr. The reaction progress was monitored by TLC using solvent system MeOH:DCM (5:95). After completion of reaction, the reaction mixture was quenched with ice-cold water and extracted with EtOAc (3×1 Lit). The combined organic layers were dried over Na2SO4, and concentrated under vacuum. The crude product residue was combined with a batch of crude product obtained from a second reaction carried out at the same scale, and was purified by column chromatography using silica (100-200 mesh) and solvent system EtOAc:Hexane (4:6) to obtain 7 g (25%) of ethyl 2-hydroxy-2-(pyridin-4-yl)propanoate as a yellow solid. 1H NMR (400 MHz, DMSO-d6): δ 8.52 (d, 2H, J=6 Hz), 7.44 (d, 2H, J=6 Hz), 6.2 (s, 1H), 4.08 (q, 2H, J=7.2 Hz), 1.60 (s, 1H), 1.12 (t, 3H, J=7.2 Hz); LC-MS m/z calculated for [M+H]+ 196.09. found 196.2.
Reaction SMILES: CC1(C)[O:7][C:6](=[O:8])[CH2:5][C:4](=[O:9])O1.[CH:11]([NH:14][C:15]1[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=1[CH:17]=O)([CH3:13])[CH3:12].C(O)(=O)C.C(N)CN>CO>[CH:11]([N:14]1[C:15]2[C:16](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[C:5]([C:6]([OH:7])=[O:8])[C:4]1=[O:9])([CH3:13])[CH3:12]
Reactant: CC(C)Nc1ccccc1C=O
Reactant: CC1(C)OC(=O)CC(=O)O1
Solvent: NCCN
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)n1c(=O)c(C(=O)O)cc2ccccc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 98 %

Procedure:
2,2-Dimethyl-[1,3]dioxane-4,6-dione, commonly Meldrum's acid, (166.9 g, 1.16 mol) was added to a stirred solution of 2-isopropylaminobenzaldehyde (105 g, 0.64 mol), acetic acid (73.6 mL, 1.29 mol) and ethylenediamine (43.0 mL, 0.64 mol) in methanol (1 L) at 0° C. The reaction mixture was stirred for 1 h at 0° C. and then at room temperature overnight. The resulting suspension was filtered and the solid washed with methanol and collected to yield the title intermediate, 1-isopropyl-2-oxo-1,2-dihydroquinoline-3-carboxylic acid (146 g, 98%) as an off-white solid. 1H NMR (CDCl3; 300 MHz): 1.72 (d, 6H, CH(CH3)2), 5.50 (bs, 1H, CH(CH3)2), 7.44 (t, 1H, ArH), 7.75-7.77 (m, 2H, ArH), 7.82 (d, 1H, ArH), 8.89 (s, 1H, CH).
Reaction SMILES: [OH-].[Li+].[Br:3][C:4]1[N:5]([C:15]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:18]([CH:25]3[CH2:27][CH2:26]3)=[CH:17][CH:16]=2)[C:6]([S:9][CH2:10][C:11]([O:13]C)=[O:12])=[N:7][N:8]=1.C1COCC1.Cl>O.C(O)C>[Br:3][C:4]1[N:5]([C:15]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:18]([CH:25]3[CH2:27][CH2:26]3)=[CH:17][CH:16]=2)[C:6]([S:9][CH2:10][C:11]([OH:13])=[O:12])=[N:7][N:8]=1
Reactant: COC(=O)CSc1nnc(Br)n1-c1ccc(C2CC2)c2ccccc12
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: C1CCOC1
Product: O=C(O)CSc1nnc(Br)n1-c1ccc(C2CC2)c2ccccc12
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 93 %

Procedure:
A solution of lithium hydroxide (98 mg, 4.1 mmol) in water (10 mL) was added dropwise over 5 mins to a solution of methyl 2-(5-bromo-4-(1-cyclopropylnaphthalen-4-yl)-4H-1,2,4-triazol-3-ylthio)acetate (prepared as described in example I above; 1.14 g, 2.7 mmol) in ethanol (10 mL) and THF (10 mL) at 0° C. The mixture was stirred at 0° C. for a further 45 mins and then neutralized to pH 7 by the addition of 0.5N HCl solution at 0° C. The resulting mixture was concentrated in vacuo to ⅕th of its original volume, then diluted with water (−20 mL) and acidified to pH 2-3 by the addition of 0.5N HCl to produce a sticky solid. (If the product comes out as an oil during acidification, extraction with DCM is recommended.) The tan solid was collected by vacuum filtration and dried under high vacuum at 50° C. for 16 h in the presence of P2O5 to yield 2-(5-bromo-4-(1-cyclopropylnaphthalen-4-yl)-4H-1,2,4-triazol-3-ylthio)acetic acid (1.02 g, 93%).
Reaction SMILES: C(O)/C=C\CCCCCCC.[CH2:12]([OH:24])[C:13]#[C:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23].N1C2C(=CC=CC=2)C=CC=1>>[CH2:12]([OH:24])/[CH:13]=[CH:14]\[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: CCCCCCCCCC#CCO
Agent: CCCCCCC/C=C\CO
Solvent: c1ccc2ncccc2c1
Product: CCCCCCCCC/C=C\CO

Procedure:
cis-2-Dodecen-1-ol was prepared as described above for cis-2-decen-1-ol except that 35 g of 2-dodecyn-1-ol, 1.0 g of catalyst, and 3.0 ml of quinoline was used. A clear oil, 33.86 g, was obtained after kugelrohr distillation. 1H NMR δ 5.57 (m, 2), 4.19 (d, 2, J=5 Hz), 2.07 (dd, 2, J=6, 12 Hz), 1.5-1.2 (m, 14), 0.88 (t, 3, J=7 Hz).
Reaction SMILES: [C:1]1([NH:7][C:8]([C:10]2([C:13]([OH:15])=O)[CH2:12][CH2:11]2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[N:17](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH2:40]([O:47][C:48]1[CH:57]=[C:56]2[C:51]([C:52]([O:58][C:59]3[CH:60]=[CH:61][C:62](N)=[N:63][CH:64]=3)=[CH:53][CH:54]=[N:55]2)=[CH:50][CH:49]=1)[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1.C1CCN2C(=NCCC2)CC1>C(Cl)Cl>[CH2:40]([O:47][C:48]1[CH:57]=[C:56]2[C:51]([C:52]([O:58][C:59]3[CH:60]=[CH:61][C:62]([N:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[C:8]([C:10]4([C:13]([NH2:17])=[O:15])[CH2:11][CH2:12]4)=[O:9])=[N:63][CH:64]=3)=[CH:53][CH:54]=[N:55]2)=[CH:50][CH:49]=1)[C:41]1[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: Nc1ccc(Oc2ccnc3cc(OCc4ccccc4)ccc23)cn1
Reactant: O=C(O)C1(C(=O)Nc2ccccc2)CC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Product: NC(=O)C1(C(=O)N(c2ccccc2)c2ccc(Oc3ccnc4cc(OCc5ccccc5)ccc34)cn2)CC1

Procedure:
The title compound was prepared according to the procedure described in Example 21 of step 5 by using 1-(phenylcarbamoyl)cyclopropanecarboxylic acid (1.14 g, 5.6 mmol), HATU (2.11 g, 5.6 mmol), 5-(7-(benzyloxy)quinolin-4-yloxy)pyridin-2-amine (960 mg, 2.8 mmol) and DBU (868 mg, 7.0 mmol) in dry DCM (50 mL). The title compound was obtained as a white solid (1.22 g, 82%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[NH2:8].C(N(CC)CC)C.[Br:16][C:17]1[CH:25]=[CH:24][C:20]([C:21](Cl)=O)=[CH:19][CH:18]=1.ClC(Cl)(Cl)C(Cl)(Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl.C(Cl)Cl.CO>[Br:16][C:17]1[CH:25]=[CH:24][C:20]([C:21]2[O:1][C:2]3[CH:7]=[CH:6][N:5]=[CH:4][C:3]=3[N:8]=2)=[CH:19][CH:18]=1
Reactant: O=C(Cl)c1ccc(Br)cc1
Reactant: Nc1cnccc1O
Agent: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CO
Product: Brc1ccc(-c2nc3cnccc3o2)cc1
Reaction time: 16 h

Procedure:
To a cooled (0° C.) suspension of commercially available 4-hydroxy-3-amino-pyridine 14 (4 g, 36 mmol) in DCM (200 ml) were added triethyl amine (6.3 ml, 1.25 eq) and a solution of 4-bromo-benzoyl chloride (15, Rb=H, 8 g, 36 mmol, 1 eq, 0.3M in DCM). The reaction mixture was allowed to reach room temperature and the mixture was stirred for 16 hrs. The mixture was filtered, washed with DCM and ether to furnish crude 16 (Rb=H) as a solid material which was used in the next step without further purification. Hexachloroethane (10.2 g, 43 mmol, 2.5 eq) was dissolved in DCM (150 ml) and triphenyl phosphine (13.56 g, 51.69 mmol, 3 eq) and triethyl amine (19.2 ml, 137.8 mmol, 8 eq) was added. The mixture was stirred for minutes at room temperature and crude compound 16 (Rb=H) was added slowly in 5 equal portions. The mixture was stirred at room temperature for 64 hrs after which time TLC analysis (DCM/MeOH, 97/3, v/v, Rf 0.3) revealed complete reaction. The solution was concentrated and the residue was suspended in DCM. The mixture was filtered and the residue washed with DCM and diethyl ether to give crude 17 (Rb=H) which was used in the next step without further purification.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([CH:7]=[O:8])=[CH:4][CH:3]=1.[Br:9]Br.C(=O)([O-])O.[Na+]>C(O)(=O)C>[Br:9][C:3]1[CH:4]=[C:5]([CH:7]=[O:8])[S:6][C:2]=1[CH3:1]
Reactant: BrBr
Reactant: Cc1ccc(C=O)s1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Product: Cc1sc(C=O)cc1Br
Reaction time: 8 h
Yield: 50 %

Procedure:
To a solution of 5-methylthiophene-2-carbaldehyde (50.0 g) in acetic acid (400 mL) was added dropwise a solution of bromine (25 mL) in acetic acid (200 mL) at room temperature over 6 hr. After the dropwise addition, the reaction mixture was stirred overnight, neutralized with saturated aqueous sodium hydrogen carbonate solution, and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The obtained residue was dissolved in toluene (50 mL), and the mixture was stirred at 110° C. for 2 hr and concentrated. The residue was subjected to silica gel column chromatography, eluted with ethyl acetate-hexane (1:5, volume ratio) and concentrated to give 4-bromo-5-methylthiophene-2-carbaldehyde (40.0 g, yield 50%) as yellow crystals. melting point 60° C.
Reaction SMILES: [OH-].[Na+].P(Br)(Br)[Br:4].[CH3:7][C:8]1([CH3:15])[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1.[C:16]([O-:19])(=O)C.[Na+]>CN(C)C=O.C(Cl)(Cl)Cl>[Br:4][C:11]1[CH2:12][CH2:13][C:8]([CH3:15])([CH3:7])[CH2:9][C:10]=1[CH:16]=[O:19]
Reactant: CC1(C)CCC(=O)CC1
Reactant: BrP(Br)Br
Reactant: CC(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: CC1(C)CCC(Br)=C(C=O)C1
Temperature: 3 °C
Reaction time: 1.5 h
Yield: 58 %

Procedure:
A 3-necked round bottom flask equipped with a nitrogen inlet, a thermometer and an outlet connected to a scrubber containing a solution of 2M NaOH was charged with anhydrous chloroform (15 ml) and anhydrous N,N-dimethylformamide (2.5 ml (32.3 mmol). The solution was cooled to ˜3° C. (internal temperature) under nitrogen before phosphorus tribromide (2.8 ml, 30.0 mmol) was introduced dropwise at a rate so that the reaction was maintained at ˜3° C. After the addition was complete the reaction was allowed to warm slowly to ˜10° C. and then the temperature was raised to 70° C. where it was maintained for 30 min. The reaction was cooled to rt and 4,4-dimethylcyclohexanone (1.4 g, 11.1 mmol) was added slowly over 20 min. After the addition was complete the reaction was warmed to 70° C. and it was stirred for 1.5 h. The mixture was then cooled to rt and poured onto a solution of 4M sodium acetate (15 ml). The pH of the resulting solution was adjusted to ˜7 using a solution of 5M NaOH and the mixture was then extracted with heptanes (×5). The combined organic fractions were dried (Na2SO4), filtered and concentrated under reduced pressure to give 2-bromo-5,5-dimethyl-cyclohex-1-ene carbaldehyde as a yellow oil (1.4 g, 58%). 1H NMR (MeOD) □ 10.05 (1H, s), 2.82 (2H, m), 2.10 (2H, m), 1.59 (2H, t), 0.96 (6H, s).
Reaction SMILES: N[C:2]1[C:10]2[C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[O:7][C:6]=2[C:5]([O:15][CH3:16])=[CH:4][CH:3]=1.N([O-])=O.[Na+].[S:21](=[O:23])=[O:22].[ClH:24]>C(O)(=O)C.O.C(O)(=O)C.C1C=CC=CC=1>[CH3:16][O:15][C:5]1[C:6]2[O:7][C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=3[C:10]=2[C:2]([S:21]([Cl:24])(=[O:23])=[O:22])=[CH:3][CH:4]=1
Reactant: O=S=O
Reactant: Cl
Reactant: COc1ccc(N)c2c1oc1ccccc12
Agent: O=N[O-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: O
Solvent: CC(=O)O
Product: COc1ccc(S(=O)(=O)Cl)c2c1oc1ccccc12
Temperature: 5 °C
Reaction time: 1 h

Procedure:
Intermediate 40 (400 mg, 1.87 mmol) was dissolved in glacial acetic acid (20 ml) and 17% HCl (10 ml). This solution was cooled to 5° C. and a solution of sodium nitrite (260 mg, 3.74 mmol) in water (5 ml) was added slowly during 10 min. The reaction was stirred for 1 h at 5° C. The reaction mixture was then added to a saturated solution of sulfur dioxide (generated from sodium sulfite and conc. HCl) in acetic acid: benzene (3:2) containing cupric chloride dihydrate (100 mg, 0.513 mmol). The reaction was sired at room temperature for 20 h and then poured water (500 ml) and extracted with ethyl acetate (3×100 ml). The extract was washed with water (5×100 ml) and dried over anhydrous sodium sulfate. The solvent was evaporated to give the product as brown solid (350 mg) which was directly used to make the sulfonamide.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][C:4]=1[CH2:5][CH:6]1[C:15]2[C:10](=[C:11]([O:18][CH3:19])[CH:12]=[CH:13][C:14]=2[O:16][CH3:17])[CH2:9][CH2:8][NH:7]1.Br[CH2:27][C:28](Br)=[O:29].[NH2:31][CH:32]1[CH2:40][C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH2:33]1>>[CH3:1][O:2][C:3]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][C:4]=1[CH2:5][CH:6]1[C:15]2[C:10](=[C:11]([O:18][CH3:19])[CH:12]=[CH:13][C:14]=2[O:16][CH3:17])[CH2:9][CH2:8][N:7]1[CH2:27][C:28]([NH:31][CH:32]1[CH2:40][C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH2:33]1)=[O:29]
Reactant: O=C(Br)CBr
Reactant: NC1Cc2ccccc2C1
Reactant: COc1ccc(OC)c(CC2NCCc3c(OC)ccc(OC)c32)c1
Product: COc1ccc(OC)c(CC2c3c(OC)ccc(OC)c3CCN2CC(=O)NC2Cc3ccccc3C2)c1

Procedure:
prepared by reaction of 1-(2,5-Dimethoxy-benzyl)-5,8-dimethoxy-1,2,3,4-tetrahydroisoquinoline and 2-bromoacetyl bromide with 2-amino-indane
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][C:10]([C:12]2[CH:13]=[N:14][C:15]3[C:20]([C:21]=2[OH:22])=[CH:19][C:18](I)=[CH:17][C:16]=3[F:24])=[O:11])=[CH:4][CH:3]=1.[CH3:25][CH:26]([OH:29])[C:27]#[CH:28].CCN(CC)CC>CN(C=O)C.CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][C:10]([C:12]2[CH:13]=[N:14][C:15]3[C:20]([C:21]=2[OH:22])=[CH:19][C:18]([C:28]#[C:27][CH:26]([OH:29])[CH3:25])=[CH:17][C:16]=3[F:24])=[O:11])=[CH:4][CH:3]=1
Reactant: O=C(NCc1ccc(Cl)cc1)c1cnc2c(F)cc(I)cc2c1O
Reactant: C#CC(C)O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CO
Product: CC(O)C#Cc1cc(F)c2ncc(C(=O)NCc3ccc(Cl)cc3)c(O)c2c1
Temperature: 25 °C

Procedure:
A solution of the title compound of Example 5 (540.3 mg), 3-butyn-2-ol (0.13 mL), PdCl2 (PPh3)2 (21.1 mg), and 0.75 mL Et3N in 3 mL DMF is heated at 90° C. for 1 hr. The reaction mixture is cooled to room temperature and partitioned between EtOAc and H2O. The aqueous layer is washed with EtOAc (3×). The combined organic layers are dried over Na2SO4 and condensed to obtain a brown residue. The residue is diluted with MeOH, adsorbed onto silica, and chromatographed eluting with 2.5 % MeOH in CH2Cl2. Fractions homogenous by TLC are combined, condensed and recrystallized from EtOAc/hexanes to yield 0.207 g of the desired product as a creme-colored solid.
Reaction SMILES: [OH-].[K+].C([O:5][C:6](=[O:18])[CH:7]([NH:13][C:14](=[O:17])[CH2:15][Cl:16])[C:8]1[N:9]=[CH:10][S:11][CH:12]=1)C>O.C(O)C>[Cl:16][CH2:15][C:14]([NH:13][CH:7]([C:8]1[N:9]=[CH:10][S:11][CH:12]=1)[C:6]([OH:18])=[O:5])=[O:17]
Reactant: CCOC(=O)C(NC(=O)CCl)c1cscn1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(CCl)NC(C(=O)O)c1cscn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 82.1 %

Procedure:
To a solution of 2.5 g of potassium hydroxide in a mixture of 10 ml of water and 100 ml of ethanol is added 3.0 g of 2-chloroacetamido-4-thiazolyl acetic acid ethyl ester, and the mixture is stirred for one hour at room temperature. The solvent is evaporated under reduced pressure. To the residue is added 10 ml of water. The resulting aqueous solution is washed with ethyl acetate, and then adjusted to pH 2 with 10% hydrochloric acid, whereupon crystals separate out. The crystals are collected by filtration, washed with water, and dried to yield 2.2 g (84% ) of 2-chloroacetamido-4-thiazolyl acetic acid, m.p. 193°-195° C.
Reaction SMILES: [CH:1]([NH:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([N+:10]([O-:12])=[O:11])[CH:5]=1)=[O:2].[H-].[Na+].Cl[CH2:16][C:17](=[O:19])[CH3:18]>CN(C)C=O.C(OCC)(=O)C.O>[N+:10]([C:6]1[CH:5]=[C:4]([N:3]([CH2:16][C:17](=[O:19])[CH3:18])[CH:1]=[O:2])[CH:9]=[CH:8][CH:7]=1)([O-:12])=[O:11]
Reactant: O=CNc1cccc([N+](=O)[O-])c1
Reactant: CC(=O)CCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: CC(=O)CN(C=O)c1cccc([N+](=O)[O-])c1
Reaction time: 0.33 h
Yield: 21 %

Procedure:
To a suspension of N-formyl-3-nitroaniline (1.0 g) in N,N-dimethylformamide (10 ml) was added sodium hydride (60% dispersion in mineral oil, 264 mg), and the mixture was stirred for 20 minutes under nitrogen atmosphere. After a solution of 1-chloropropan-2-one (0.573 ml) in N,N-dimethylformamide (5 ml) was added dropwise to the mixture, the mixture was stirred for 2 hours and diluted with ethyl acetate and water. The separated organic layer was washed with brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified with a silica gel column chromatography eluting with 2% methanol in dichloromethane to give N-(3-nitrophenyl)-N-(2-oxo-propyl)-formamide (280 mg, 21.0%).
Reaction SMILES: Br[Mg][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[NH2:9][C:10]1[C:11]([C:28](N(OC)C)=[O:29])=[N:12][C:13]([C:16]2[CH:21]=[CH:20][C:19]([S:22]([CH:25]([CH3:27])[CH3:26])(=[O:24])=[O:23])=[CH:18][CH:17]=2)=[CH:14][N:15]=1>C1COCC1>[NH2:9][C:10]1[C:11]([C:28]([C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)=[O:29])=[N:12][C:13]([C:16]2[CH:17]=[CH:18][C:19]([S:22]([CH:25]([CH3:27])[CH3:26])(=[O:23])=[O:24])=[CH:20][CH:21]=2)=[CH:14][N:15]=1
Reactant: CON(C)C(=O)c1nc(-c2ccc(S(=O)(=O)C(C)C)cc2)cnc1N
Reactant: Br[Mg]c1ccccc1
Solvent: C1CCOC1
Product: CC(C)S(=O)(=O)c1ccc(-c2cnc(N)c(C(=O)c3ccccc3)n2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 42 %

Procedure:
1M Bromo(phenyl)magnesium in THF (823.2 μL, 0.8232 mmol) was added dropwise to a stirred solution of 3-amino-6-(4-isopropylsulfonylphenyl)-N-methoxy-N-methyl-pyrazine-2-carboxamide (100 mg, 0.2744 mmol) in anhydrous THF (6 mL) at −78° C. under an atmosphere of nitrogen. The reaction was stirred at this temperature for 30 minutes then allowed to warm to ambient temperature over 16 hours. The reaction mixture was concentrated in vacuo and residue was partitioned between DCM and water. The layers were separated and the organic extract was dried (MgSO4) and concentrated in vacuo. The material was purified by reverse phase preparative HPLC [Waters Sunfire C18, 10 μM, 100 Å column, gradient 10%-95% B (solvent A: 0.05% TFA in water; solvent B: CH3CN) over 16 minutes at 25 mL/min]. The fractions were collected, and freeze-dried to give the title compound as a yellow solid (49 mg, 42% Yield). NMR (400.0 MHz, DMSO) δ 1.16 (d, 6H), 3.44 (sept, 1H), 7.55-7.59 (m, 2H), 7.66 (m, 1H), 7.90 (d, 2H), 7.95-7.97 (m, 2H), 8.07 (br s, 2H), 8.18 (d. 2H) and 9.10 (s, 1H) ppm; (ES+) 382.0.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:12]([NH:13][C:14]([C:16]3[CH:24]=C4N=CC=CN4N=3)=[O:15])=[CH:11][NH:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:25][C:26]1([O:29][CH2:28]1)[CH3:27].C(=O)([O-])[O-].[Cs+].[Cs+].C[N:37]([CH3:40])[CH:38]=O>>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:12]([NH:13][C:14]([C:16]3[CH:24]=[N:10][N:9]4[CH:8]=[CH:4][CH:40]=[N:37][C:38]=34)=[O:15])=[CH:11][N:10]([CH2:25][C:26]([OH:29])([CH3:28])[CH3:27])[N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC1(C)CO1
Reactant: CN(C)C=O
Reactant: O=C(Nc1c[nH]nc1-c1cccc(Cl)c1)c1cc2ncccn2n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CC(C)(O)Cn1cc(NC(=O)c2cnn3cccnc23)c(-c2cccc(Cl)c2)n1
Temperature: 50 °C
Reaction time: 7.5 h
Yield: 46 %

Procedure:
N-(3-(3-chlorophenyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-carboxamide (58.9 mg, 0.174 mmol, 1 eq) was dissolved in 5 mL N,N-dimethylformamide. To this solution was added isobutylene oxide (0.5 mL, 6 mmol, 30 eq) and cesium carbonate (56.4 mg, 0.173 mmol, 1.0 eq). The reaction mixture was stirred at 50° C. for 7.5 hours. The reaction mixture was partitioned between ethyl acetate and water, and the organic portion washed with brine, dried over magnesium sulfate and concentrated. The crude product was purified by reverse phase HPLC and lyophilized to give 33.1 mg (46%) of N-(3-(3-chlorophenyl)-1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide. LCMS (ESI) m+H=411.1; 1H NMR (400 MHz, DMSO-d6) δ: 10.02 (s, 1H), 9.36 (d, 1H), 8.83 (d, 1H), 8.69 (s, 1H), 8.35 (s, 1H), 7.84 (s, 1H), 7.76 (d, 1H), 7.58 (t, 1H), 7.49 (d, 1H), 7.33 (d of d, 1H), 4.73 (s, 1H), 4.09 (s, 2H), 1.13 (s, 6H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6](B(O)O)[CH:5]=[CH:4][N:3]=1.Cl[C:12]1[CH:17]=[CH:16][C:15]([CH2:18][NH2:19])=[CH:14][C:13]=1[F:20].[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.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>[F:20][C:13]1[CH:14]=[C:15]([CH2:18][NH2:19])[CH:16]=[CH:17][C:12]=1[C:6]1[CH:5]=[CH:4][N:3]=[C:2]([CH3:1])[CH:7]=1
Reactant: NCc1ccc(Cl)c(F)c1
Reactant: Cc1cc(B(O)O)ccn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: Cc1cc(-c2ccc(CN)cc2F)ccn1
Temperature: 96 °C
Reaction time: 8 h

Procedure:
A mixture of (2-methylpyridin-4-yl)boronic acid 15-1 (822 mg, 6.2 mmol), (4-chloro-3-fluorophenyl)methanamine 15-2 (798 mg, 5.00 mmol), Pd(PPh3)4 (173 mg, 0.15 mmol) and K3PO4 (1.59 g, 7.50 mmol) in dioxane (10 mL) and water (1 mL) was stirred at 96° C. under argon overnight. After cooling to room temperature, the mixture was filtered through celite, washed with ethyl acetate, and dried with Na2SO4. The filtrate was concentrated by rotavap and the residue subjected to silica gel column chromatography with 6% ammonia-saturated methanol in dichloromethane as eluent to give (3-fluoro-4-(2-methylpyridin-4-yl)phenyl)methanamine 15-3 as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:9])=[C:6](N)[CH:7]=1.[ClH:10].N([O-])=O.[Na+].[S:15](=[O:17])=[O:16]>O.C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:9])=[C:6]([S:15]([Cl:10])(=[O:17])=[O:16])[CH:7]=1
Reactant: Cc1ccc(Cl)cc1N
Reactant: Cl
Reactant: O=S=O
Agent: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: Cc1ccc(Cl)cc1S(=O)(=O)Cl
Temperature: 15 °C
Reaction time: 0.5 h

Procedure:
5-Chloro-2-methylbenzeneamine (1002 g) was added over 0.5 hr. to a stirred mixture of 5.5 L of concentrated hydrochloric acid and 1.5 L of acetic acid precooled to 0°-5° C. The resulting suspension was stirred 0.5 hr. A solution of 530 g of sodium nitrite in 0.9 L H2O was added over 1.0 hr. while maintaining the temperature at 0°-5° C. When addition was complete, the mixture was stirred 1.0 hr. at 0°-5° C. The diazonium salt was added to a stirred mixture of 6.0 L of acetic acid, 1000 g of sulfur dioxide and 16.8 g of cuprous chloride while maintaining the temperature about 15° C. When addition of the diazonium salt was complete, the mixture was stirred several hours at about 15° C. then allowed to warm to ambient temperature and stirred overnight. The reaction mixture was poured into ice-water, and the aqueous mixture was extracted with 12 L of methylene chloride. The organic solution was washed twice with 6 L water followed twice with 4 L of saturated sodium bicarbonate solution. The organic solution was dried over magnesium sulfate, filtered and the solvent evaporated in vacuo to give 1279.9 g of the title compound as a black oil.