Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1([CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:16][CH:15]2[NH:17][CH:11]([CH2:12][O:13][CH2:14]2)[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[CH2:25][C:26]1[NH:31][C:30]([C:32]2[S:33][CH:34]=[CH:35][N:36]=2)=[N:29][C@@H:28]([C:37]2[CH:42]=[CH:41][C:40]([F:43])=[CH:39][C:38]=2[Cl:44])[C:27]=1[C:45]([O:47][CH3:48])=[O:46].CCN(C(C)C)C(C)C>C(Cl)Cl>[C:1]([O:5][C:6]([NH:8][C:9]1([CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:10][CH:11]2[N:17]([CH2:25][C:26]3[NH:31][C:30]([C:32]4[S:33][CH:34]=[CH:35][N:36]=4)=[N:29][C@@H:28]([C:37]4[CH:42]=[CH:41][C:40]([F:43])=[CH:39][C:38]=4[Cl:44])[C:27]=3[C:45]([O:47][CH3:48])=[O:46])[CH:15]([CH2:14][O:13][CH2:12]2)[CH2:16]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)CC1(NC(=O)OC(C)(C)C)CC2COCC(C1)N2
Reactant: COC(=O)C1=C(CBr)NC(c2nccs2)=N[C@H]1c1ccc(F)cc1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(=O)CC1(NC(=O)OC(C)(C)C)CC2COCC(C1)N2CC1=C(C(=O)OC)[C@H](c2ccc(F)cc2Cl)N=C(c2nccs2)N1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A mixture of ethyl 2-[7-(tert-butoxycarbonylamino)-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl]acetate 146a (0.1 g, 0.3 mmol) and methyl (4R)-6-(bromomethyl)-4-(2-chloro-4-fluoro-phenyl)-2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylate C (90 mg, 0.2 mmol), DIPEA (77.4 mg, 0.6 mmol) in DCM (5 mL) was stirred for 12 hours at room temperature. The mixture was concentrated to give crude methyl (4R)-6-[[7-(tert-butoxycarbonylamino)-7-(2-ethoxy-2-oxo-ethyl)-3-oxa-9-azabicyclo[3.3.1]nonan-9-yl]methyl]-4-(2-chloro-4-fluoro-phenyl)-2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylate 146b. MS: calc'd (MH+) 692, exp (MH+) 692.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[CH:6][CH:5]=1.Cl[C:12]1[C:13]2[S:20][CH:19]=[CH:18][C:14]=2[N:15]=[CH:16][N:17]=1.CCN(C(C)C)C(C)C>C(O)CCC>[NH2:10][C:7]1[CH:8]=[CH:9][C:4]([CH2:3][CH2:2][NH:1][C:12]2[C:13]3[S:20][CH:19]=[CH:18][C:14]=3[N:15]=[CH:16][N:17]=2)=[CH:5][CH:6]=1
Reactant: Clc1ncnc2ccsc12
Reactant: NCCc1ccc(N)cc1
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: Nc1ccc(CCNc2ncnc3ccsc23)cc1

Procedure:
A solution of 4-(2-amino-ethyl)-phenylamine (compound 12.1; 0.1 mmol.), compound 6.2 (1.0 equivalent) and DIEA (2.5 equivalents) was heated in n-butanol (2 mL) at 135° C. for 2 hours. The reaction mixture was cooled and partitioned between dichloromethane and water. The organic layer was separated, washed with brine, dried and concentrated under reduced pressure to give crude [2-(4-amino-phenyl)-ethyl]-thieno[3,2-d]pyrimidin-4-yl-amine (compound 12.2) which was used without purification for the next step.
Reaction SMILES: [Cl:1][C:2]1[C:7](=[O:8])[N:6]([C:9]2[CH:10]=[C:11]([CH:19]=[CH:20][C:21]=2[CH3:22])[C:12]([NH:14][CH2:15][C:16]([NH2:18])=[O:17])=[O:13])[CH:5]=[N:4][C:3]=1[O:23][CH2:24][C:25]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:26]=1[F:32].Cl.N[CH2:35]C(N)=O>>[NH2:18][C:16]([C@H:15]([NH:14][C:12](=[O:13])[C:11]1[CH:19]=[CH:20][C:21]([CH3:22])=[C:9]([N:6]2[C:7](=[O:8])[C:2]([Cl:1])=[C:3]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:26]=3[F:32])[N:4]=[CH:5]2)[CH:10]=1)[CH3:35])=[O:17]
Reactant: Cc1ccc(C(=O)NCC(N)=O)cc1-n1cnc(OCc2ccc(F)cc2F)c(Cl)c1=O
Reactant: NCC(N)=O
Agent: Cl
Product: Cc1ccc(C(=O)N[C@H](C)C(N)=O)cc1-n1cnc(OCc2ccc(F)cc2F)c(Cl)c1=O

Procedure:
The title compound was prepared using a procedure similar to that used in Step 4 of the synthesis of 3-[5-chloro-4-[(2,4-difluorobenzyl)oxy]-6-oxopyrimidin-1(6H)-yl]-N-[1-(aminocarbonyl)methyl]-4-methylbenzamide by substituting D-alanine amide HCl for glycineamide HCl. 1H NMR (CD3OD/400 MHz) δ 8.32 (s, 1H), 7.96 (m, 1H), 7.82 (m, 1H), 7.61 (q, 1H, J=8.4 Hz), 7.53 (d, 1H, J=8.0 Hz), 7.02 (m, 2H), 5.60 (m, 2H), 4.54 (q, 1H, J=6.0 Hz), 2.20 (s, 3H), 1.45 (d, 3H, J=6.0 Hz). ESHRMS m/1477.1104 (M+H calculated for C22H20ClF2N4O4 requires 477.1136).
Reaction SMILES: [CH2:1]([C:5]1[NH:6][CH:7]=[C:8]([CH:10]=[CH:11][C:12]([O:14][CH3:15])=[O:13])[CH:9]=1)[CH2:2][CH2:3][CH3:4].[H-].[Na+].[C:18]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[C:26]1[CH:31]=[CH:30][C:29]([CH2:32]Br)=[CH:28][CH:27]=1)#[N:19].O>CN(C=O)C>[CH2:1]([C:5]1[N:6]([CH2:32][C:29]2[CH:28]=[CH:27][C:26]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[C:18]#[N:19])=[CH:31][CH:30]=2)[CH:7]=[C:8]([CH:10]=[CH:11][C:12]([O:14][CH3:15])=[O:13])[CH:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1cc(C=CC(=O)OC)c[nH]1
Reactant: N#Cc1ccccc1-c1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCc1cc(C=CC(=O)OC)cn1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 76.9 %

Procedure:
Methyl 3-[2-(n-butyl)pyrrol-4-yl]acrylate (AE) (6.2 g) (prepared, e.g., as described in Preparation 21), in DMF (200 ml) was treated with sodium hydride (1.8 g of 60% mineral oil dispersion) at 0° C., and the resulting mixture was stirred for 30 minutes at 0° C. 2'-(Cyano)biphenyl-4-ylmethyl bromide (9.8 g) was added, and the mixture allowed to come to room temperature. Water was added, and the mixture was extracted with ethyl acetate. The ethyl acetate extract was washed with water, brine, dried over sodium sulfate and evaporated. The residue was chromatographed on silica gel, eluting with 25% ethyl acetate/hexane, affording methyl 3-[2-(n-butyl)-1-(2"-cyanobiphenyl-4'-ylmethyl)pyrrol-4-yl]acrylate (9.17 g), a compound of Formula AF, as an oil.
Reaction SMILES: [CH2:1]([OH:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[C:20](Cl)(=[O:24])[C:21]([CH3:23])=[CH2:22].C(N(CC)CC)C>C(Cl)Cl>[C:20]([O:19][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])(=[O:24])[C:21]([CH3:23])=[CH2:22]
Reactant: C=C(C)C(=O)Cl
Reactant: CCCCCCCC/C=C\CCCCCCCCO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=C(C)C(=O)OCCCCCCCC/C=C\CCCCCCCC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Oleyl alcohol (26.8 grams) is placed in a three-neck flask under a blanket of nitrogen. The entire reaction contents are cooled in an ice bath. Methacryloyl chloride (10.5 grams) dissolved in about 50 mL of methylene chloride is added slowly to the cooled oleyl alcohol with vigorous stirring in about 2 hours. Triethylamine (11.5 g) dissolved in 25 mL of methylene chloride is subsequently added in about an hour. After addition of triethylamine, the solution is allowed to warm to ambient temperature and is stirred for another 4 hours in order to complete the reaction. The precipitated triethylammonium chloride is removed by filtration, and the filtrate is washed with brine solution (saturated NaCl) followed by washings with dil. NaOH and dil. HCl. The organic layer is dried with anhydrous magnesium sulfate and the solvent is removed in vacuo to yield oleyl methacrylate in good yields. Oleyl methacrylate is stabilized from polymerization by addition of approximately 10 ppm hydroquinone. The structure of the product is verified by 1H and 13C NMR spectroscopy.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([OH:11])=O)[CH:5]=[CH:6][CH:7]=1.[C:12](Cl)(=O)[C:13](Cl)=O.[Al+3].[Cl-].[Cl-].[Cl-].C=C>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]2[C:5]([CH2:12][CH2:13][C:9](=[O:11])[CH2:8]2)=[CH:6][CH:7]=1
Reactant: O=C(O)Cc1cccc(Br)c1
Reactant: O=C(Cl)C(=O)Cl
Agent: C=C
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: O=C1CCc2ccc(Br)cc2C1
Temperature: 25 °C

Procedure:
A solution of 3-bromophenylacetic acid (10.4 g, 48.4 mmol) in oxalyl chloride (50 mL, 0.57 mol) was stirred at ambient temperature for 5 min then at reflux for 5 h. The oxalyl chloride was removed in vacuo and the residue was dissolved in anhydrous CH2Cl2 (100 mL). This solution was added dropwise to a rapidly stirred, ice-cooled solution of AlCl3 (23.2 g, 174.2 mmol) in CH2Cl2 (500 mL). A stream of ethylene gas was blown into the vortex of the stirred solution during the addition and the reaction temperature was kept at <5° C. The reaction mixture was allowed to warm to ambient temperature and then poured onto ice and stirred vigorously. The organic portion was removed and the aqueous layer extracted with CH2Cl2 (2×200 mL). The combined CH2Cl2 fractions were passed through a 2″ pad of silica and concentrated to give a thick, red oil. The crude product was purified by silica gel chromatography, eluting with a gradient of hexane:EtOAc—100:0 to 75:25, to provide the title compound as a pale yellow solid. MS: m/z=226 (M+1).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=2)=[C:5]([C:7]([N:9]2[CH2:14][C@H:13]3[C@H:11]([CH2:12]3)[C@H:10]2[CH2:15][NH2:16])=[O:8])[N:6]=1.[O:24]1[CH2:29][CH2:28][O:27][C:26]2=[C:30]([C:33](O)=[O:34])[S:31][CH:32]=[C:25]12>>[NH2:1][C:2]1[S:3][C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=2)=[C:5]([C:7]([N:9]2[CH2:14][C@H:13]3[C@H:11]([CH2:12]3)[C@H:10]2[CH2:15][NH:16][C:33]([C:30]2[S:31][CH:32]=[C:25]3[C:26]=2[O:27][CH2:28][CH2:29][O:24]3)=[O:34])=[O:8])[N:6]=1
Reactant: NC[C@@H]1[C@H]2C[C@H]2CN1C(=O)c1nc(N)sc1-c1cccc(F)c1
Reactant: O=C(O)c1scc2c1OCCO2
Product: Nc1nc(C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CNC(=O)c2scc3c2OCCO3)c(-c2cccc(F)c2)s1

Procedure:
prepared by reaction of [2-Amino-5-(3-fluoro-phenyl)-thiazol-4-yl]-((1S,2S,5R)-2-aminomethyl-3-aza-bicyclo[3.1.0]hex-3-yl)-methanone with 2,3-Dihydro-thieno[3,4-b][1,4]dioxine-5-carboxylic acid. LC-MS (basic): tR=0.75 min; [M+H]+=501.3.
Reaction SMILES: [C:1]([CH2:4][C:5](=[O:7])[CH3:6])(=O)[CH3:2].[O-]S([O-])(=O)=O.[Na+].[Na+].[CH3:15][N:16]([CH3:21])[CH2:17][CH:18]([NH2:20])[CH3:19]>C1COCC1>[CH3:15][N:16]([CH3:21])[CH2:17][CH:18]([N:20]=[C:1]([CH3:2])[CH2:4][C:5](=[O:7])[CH3:6])[CH3:19]
Reactant: CC(=O)CC(C)=O
Reactant: CC(N)CN(C)C
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(=O)CC(C)=NC(C)CN(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 36.7 %

Procedure:
To a solution of 10 g (199.76 mmol) acetylacetone in THF at room temperature loaded with 20 g of Na2SO4 was added 24.49 g (239.71 mmol) 1-dimethylamino-2-propylamine. The slurry was stirred for 16 hours at room temperature and reaction deemed to be complete by GC/MS. All volatiles were evaporated off under vacuum and unreacted acetylacetone and diamine were removed by heating at 60° C. under 100 mTorr vacuum for 2 hours. Yellow residual oil was purified via vacuum transfer heating at 130° C. under 100 mTorr vacuum. 13.5 g of light yellow oil was obtained as pure product with a yield of 74%.
Reaction SMILES: [NH2:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1[NH:13][N:12]=[N:11][N:10]=1.[N:14]([O-])=O.[Na+].Cl.C([O-])(O)=O.[Na+]>>[Cl:8][C:7]1[C:2]2[N:1]=[N:14][N:10]3[N:11]=[N:12][N:13]=[C:9]3[C:3]=2[CH:4]=[CH:5][CH:6]=1
Reactant: O=N[O-]
Reactant: Nc1c(Cl)cccc1-c1nnn[nH]1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Clc1cccc2c1nnn1nnnc21
Yield: 80.5 %

Procedure:
This compound was prepared from 1 g of 5-(2-amino-3-chlorophenyl)tetrazole, 0.45 g of NaNO2, and concentrated HCl by the procedure described in Example 1. The reaction mixture was made basic with aqueous NaHCO3 and extracted with chloroform as before. The combined and dried extracts were concentrated under a stream of nitrogen at room temperature. The residue was washed with hexane and air dried to yield 0.85 g of a cream colored solid identified by thin layer chromatographic analysis and infrared absorption analyses as the essentially pure compound 7-chlorotetrazolo[4,5-C][1,2,3]benzotriazine.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH:10]=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[N+:19]([CH3:22])([O-:21])=[O:20].Cl.O>C1COCC1>[C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)[C@@H:10]([OH:11])[CH2:22][N+:19]([O-:21])=[O:20])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C[N+](=O)[O-]
Reactant: CC(C)(C)OC(=O)N[C@@H](C=O)Cc1ccccc1
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@H](Cc1ccccc1)[C@@H](O)C[N+](=O)[O-]
Yield: 60.6 %

Procedure:
To a stirred solution of 62.3 mg (0.25 mmol) of (R)-2-t-butoxycarbonylamino-3-phenylpropanal [synthesized by the method described in Journal of Medicinal Chemistry, 130, 1162 (1987)] in 1.0 ml of THF was added at 0° C., 0.27 ml (5 mmol) of nitromethane, followed by dropwise addition of 0.5 ml (0.025 mmol) of the lanthanum/(R)-1,1'-bi-2-naphthol complex solution (Reference Example 1, 0.05 mol/l). The resultant mixture was stirred at 0° C. for 2 hours. To this solution were added 0.5 ml of 1N hydrochloric acid and 3 ml of water. The mixture was extracted with diethylether, the extract was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silicagel column chromatography (eluent; n-hexane-ethyl acetate 8:2) to give 47 mg of (2S,3R)-3-t-butoxycarbonylamino-1-nitro-4-phenyl-2-butanol. Yield 60%. (2S,3R)-3-t-Butoxycarbonylamino-1-nitro-4-phenyl-2-butanol:
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[C:23]([Cl:25])[C:22]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=2)=[CH:21][C:3]=1[C:4]([NH:6][C:7]1[N:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:10]=[C:9]([C:18]([OH:20])=O)[CH:8]=1)=[O:5].[CH3:32][C:33]1[C:37]([NH2:38])=[C:36]([CH3:39])[NH:35][N:34]=1.CCN(C(C)C)C(C)C.F[P-](F)(F)(F)(F)F.CN(C(N(C)C)=[N+]1C2C(=NC=CC=2)[N+]([O-])=N1)C>CN(C=O)C>[Cl:1][C:2]1[CH:24]=[C:23]([Cl:25])[C:22]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=2)=[CH:21][C:3]=1[C:4]([NH:6][C:7]1[N:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:10]=[C:9]([C:18]([NH:38][C:37]2[C:33]([CH3:32])=[N:34][NH:35][C:36]=2[CH3:39])=[O:20])[CH:8]=1)=[O:5]
Reactant: O=C(O)c1cc(NC(=O)c2cc(-c3ccccn3)c(Cl)cc2Cl)n(-c2ccccc2)n1
Reactant: Cc1n[nH]c(C)c1N
Agent: CN(C)C(N(C)C)=[N+]1N=[N+]([O-])c2ncccc21
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1n[nH]c(C)c1NC(=O)c1cc(NC(=O)c2cc(-c3ccccn3)c(Cl)cc2Cl)n(-c2ccccc2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 49.6 %

Procedure:
To a solution of 5-(2,4-dichloro-5-(pyridin-2-yl)benzamido)-1-phenyl-1H-pyrazole-3-carboxylic acid (Example 111, 110 mg, 0.24 mmol), 3,5-dimethyl-1H-pyrazol-4-amine (30 mg, 0.27 mmol) and DIPEA (0.17 mL, 0.97 mmol) in DMF (1.5 mL) was added 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (101 mg, 0.26 mmol) and the reaction was stirred for 2 hours at room temperature. The reaction was concentrated in vacuo and the residue purified using Preparative HPLC to afford the title compound (65 mg, 49%).
Reaction SMILES: [Br:1]Br.[Br:3][C:4]1([Br:14])[C:12]2[C:7](=[N:8][CH:9]=[CH:10][CH:11]=2)[NH:6][C:5]1=[O:13].CC(O)(C)C>O>[Br:14][C:4]1([Br:3])[C:12]2[C:7](=[N:8][CH:9]=[C:10]([Br:1])[CH:11]=2)[NH:6][C:5]1=[O:13]
Reactant: BrBr
Reactant: O=C1Nc2ncccc2C1(Br)Br
Solvent: O
Solvent: CC(C)(C)O
Product: O=C1Nc2ncc(Br)cc2C1(Br)Br
Temperature: 15 °C
Yield: 84.1 %

Procedure:
Bromine (13.4 mL, 0.262 mol) was added dropwise over a period of 30 min to a cooled (ice bath) and stirred suspension of 2 (37.86 g, 0.131 mol) in water:t-BuOH=1:1 (1500 mL). Cooling bath was removed and the mixture was stirred at r.t. overnight. Then the solution was cooled to 15° C. and saturated aqueous solution of NaHCO3 (278 mL) was added. A yellow suspension, which was formed, was concentrated in vacuum (bath temperature<32° C.) until about 1000 mL of condensate was collected. The solid was filtered off, washed with water (200 mL), and dried in vacuum to afford 3 (40.85 g, 85%) as tan powder.
Reaction SMILES: ClC1C=CC=C([C:8]([O:10]O)=[O:9])C=1.[C:12]1([S:18]([N:21]2[C:25]3=[N:26][CH:27]=[CH:28][CH:29]=[C:24]3[C:23](C=O)=[CH:22]2)(=[O:20])=[O:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>ClCCl>[CH:8]([O:10][C:23]1[C:24]2[C:25](=[N:26][CH:27]=[CH:28][CH:29]=2)[N:21]([S:18]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)(=[O:20])=[O:19])[CH:22]=1)=[O:9]
Reactant: O=Cc1cn(S(=O)(=O)c2ccccc2)c2ncccc12
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: O=COc1cn(S(=O)(=O)c2ccccc2)c2ncccc12
Temperature: 0 °C

Procedure:
Into a 250 mL 3-necked round bottom flask was placed dichloromethane (30 mL). To the mixture was added mCPBA (m-chloroperbenzoic acid) (2.78 g, 13.69 mmol), while cooling to a temperature of 0° C. This was followed by the addition of a solution of 1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine-3-carbaldehyde (3 g, 10.49 mmol) in dichloromethane (100 mL), which was added dropwise with stirring, while cooling to a temperature of 0° C. The resulting solution was allowed to react, with stirring, 2 hours while the temperature was maintained at 0° C. Then the resulting solution was allowed to react, with stirring, overnight while the temperature was maintained at 30° C. in a bath of oil. The reaction progress was monitored by LC-MS. The residue was purified by eluting through a column with a 1:10 ethyl acetate/petroleum ether solvent system. This resulted in 2 g (63%) of 1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-3-yl formate as a light yellow solid.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][N:6]2[C:11]([C:12]([F:15])([F:14])[F:13])=[CH:10][C:9]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=3)=[N:8][C:7]=12)#[CH:2].Br[C:27]1[C:28]([F:38])=[CH:29][C:30]([F:37])=[C:31]([S:33]([NH2:36])(=[O:35])=[O:34])[CH:32]=1>>[F:37][C:30]1[CH:29]=[C:28]([F:38])[C:27]([C:2]#[C:1][C:3]2[CH:4]=[N:5][N:6]3[C:11]([C:12]([F:14])([F:13])[F:15])=[CH:10][C:9]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=4)=[N:8][C:7]=23)=[CH:32][C:31]=1[S:33]([NH2:36])(=[O:34])=[O:35]
Reactant: NS(=O)(=O)c1cc(Br)c(F)cc1F
Reactant: C#Cc1cnn2c(C(F)(F)F)cc(-c3cccc(C(F)(F)F)c3)nc12
Product: NS(=O)(=O)c1cc(C#Cc2cnn3c(C(F)(F)F)cc(-c4cccc(C(F)(F)F)c4)nc23)c(F)cc1F

Procedure:
The title compound was prepared from 3-ethynyl-7-trifluoromethyl-5-(3-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.10) (178 mg, 0.5 mmol) and commercially available 5-bromo-2,4-difluoro-benzenesulfonamide (136 mg, 0.5 mmol) according to general procedure II. Obtained as a yellow solid (138 mg, 51%). MS (ISN) 545.1 [(M−H)−]; mp 264° C.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([CH:7]([NH2:13])[C:8]2([CH3:12])[CH2:11][O:10][CH2:9]2)=[CH:4][CH:3]=1.C([O:16][C:17]1[C:18](=[O:38])[C:19](=O)[C:20]=1[NH:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([N:30]2[CH2:34][CH2:33][C@@H:32]([OH:35])[CH2:31]2)=[O:29])[C:23]=1[OH:36])C>CO>[OH:36][C:23]1[C:24]([C:28]([N:30]2[CH2:34][CH2:33][C@@H:32]([OH:35])[CH2:31]2)=[O:29])=[CH:25][CH:26]=[CH:27][C:22]=1[NH:21][C:20]1[C:17](=[O:16])[C:18](=[O:38])[C:19]=1[NH:13][CH:7]([C:5]1[O:6][C:2]([CH3:1])=[CH:3][CH:4]=1)[C:8]1([CH3:12])[CH2:9][O:10][CH2:11]1
Reactant: CCOc1c(Nc2cccc(C(=O)N3CC[C@@H](O)C3)c2O)c(=O)c1=O
Reactant: Cc1ccc(C(N)C2(C)COC2)o1
Solvent: CO
Product: Cc1ccc(C(Nc2c(Nc3cccc(C(=O)N4CC[C@@H](O)C4)c3O)c(=O)c2=O)C2(C)COC2)o1
Temperature: 50 °C
Reaction time: 5 h
Yield: 72.1 %

Procedure:
544 mg (3 mmol, 1.5 eq) of C-(5-methylfuran-2-yl)-C-(3-methyloxetan-3-yl)methylamine were added to 693 mg (2 mmol, 1 eq) of 3-ethoxy-4-[2-hydroxy-3-((R)-3-hydroxypyrrolidine-1-carbonyl)phenylamino]cyclobut-3-ene-1,2-dione dissolved under hot conditions in 30 ml of methanol. The reaction medium was heated at 50° C. for 3 days and then at 60° C. for 5 hours. The methanol was evaporated off and the residue was chromatographed on silica gel (column puriFlash IR-50SI/80G, Spot II) then subsequently on silica gel (column puriFlash PF-15SIHP/25G×2, Spot II) eluted with dichloromethane/methanol (gradient). 694 mg of 3-[2-hydroxy-3-((R)-3-hydroxypyrrolidine-1-carbonyl)phenylamino]-4-{[(5-methylfuran-2-yl)-(3-methyloxetan-3-yl)methyl]amino}cyclobut-3-ene-1,2-dione were obtained in the form of an orange amorphous solid. Yield=72%. LC/MS: 99.6% [481].
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11](Br)[C:10]=1[CH3:16].[CH:17](N1CCCCC1)=[O:18]>O1CCCC1.BrCBr>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH:17]=[O:18])[C:10]=1[CH3:16]
Reactant: Cc1c(Br)cccc1COC1CCCCO1
Reactant: O=CN1CCCCC1
Solvent: BrCBr
Solvent: C1CCOC1
Product: Cc1c(C=O)cccc1COC1CCCCO1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
1.2 g of Mg (magnesium shavings) in 15 ml of absolute tetrahydrofuran are initially introduced under a nitrogen atomsphere. A few drops of dibromomethane are added at 65° C. A solution of 14.25 g of 3-bromo-2-methylbenzyl tetrahydro-2-pyranyl ether in 50 ml of tetrahydrofuran is added dropwise while the temperature is kept at 65° C. The refluxed mixture is then stirred for 2 hours. A solution of 5.65 g of N-formylpiperidine in 10 ml of absolute tetrahydrofuran is added dropwise to the reaction mixture after the latter has been cooled to 0° C. Stirring is carried out for 20 hours at room temperature, the mixture is rendered slightly acidic with about 50 ml of 5% strength hydrochloric acid and extraction is carried out several times with ether. The combined ether extracts are washed with water, dried and evaporated down. The crude product (11 g) can be purified by column chromatography over silica gel using 97.5:2.5 toluene/acetone.
Reaction SMILES: B.[N+:2]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][C:13]=1[C:14]([F:17])([F:16])[F:15])[C:8]([NH2:10])=O)([O-:4])=[O:3].CO>C1COCC1>[N+:2]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][C:13]=1[C:14]([F:15])([F:16])[F:17])[CH2:8][NH2:10])([O-:4])=[O:3]
Reactant: NC(=O)c1ccc(C(F)(F)F)c([N+](=O)[O-])c1
Agent: B
Solvent: CO
Solvent: C1CCOC1
Product: NCc1ccc(C(F)(F)F)c([N+](=O)[O-])c1
Reaction time: 72 h

Procedure:
A 1 M solution of Borane in THF (51 ml, 51 mmol) was added at 0° C. to 3-nitro-4-trifluoromethyl-benzoic acid amide (3.00 g, 12.8 mmol) in 50 ml THF and it was stirred for 3 days. Methanol was carefully added and it was stirred for 30 min at r.t and 2 h at reflux. Then it was concentrated i.vac.; NaOH was added (pH 8) and the mixture was extracted with EtOAc. The organic layer was dried with Na2SO4, filtered and concentrated to furnish the crude subtitle compound.
Reaction SMILES: [CH3:1][N:2]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([OH:10])[CH:5]=1)[CH3:3].Cl[CH2:12][C:13]([N:15]([CH3:17])[CH3:16])=[O:14].C([O-])([O-])=O.[K+].[K+]>CS(C)=O.ClCCl>[CH3:1][N:2]([CH3:3])[C:4]1[CH:5]=[C:6]([CH:7]=[CH:8][CH:9]=1)[O:10][CH2:12][C:13]([N:15]([CH3:17])[CH3:16])=[O:14]
Reactant: CN(C)c1cccc(O)c1
Reactant: CN(C)C(=O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CS(C)=O
Product: CN(C)C(=O)COc1cccc(N(C)C)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a mixture of 3-N,N-dimethylamino phenol (69) (3.43 g, 25 mmol) and 2-chloro N,N-dimethylacetamide (3.66 g, 30 mmol) in DMSO (30 mL) was added K2CO3 (6.7 g, 50 mmol) and the resulting suspension was stirred at room temperature for 16 h. The reaction was then diluted with dichloromethane (125 mL), and washed with water (2×100 mL), and brine (100 mL), and dried, and filtered, and the solvent was removed under vacuum. The crude product, Compound 70, was obtained as purple, thick oil that was used in the next step without additional purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[CH:4][N:3]=1.[C:9]1([N:15]=[C:16]=[O:17])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>C1C=CC=CC=1>[F:1][C:2]1[CH:7]=[C:6]([NH:8][C:16]([NH:15][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[O:17])[CH:5]=[CH:4][N:3]=1
Reactant: O=C=Nc1ccccc1
Reactant: Nc1ccnc(F)c1
Solvent: c1ccccc1
Product: O=C(Nc1ccccc1)Nc1ccnc(F)c1
Temperature: 25 °C
Reaction time: 30 h
Yield: 48.9 %

Procedure:
112 mg (1 mmol) of 2-fluoro-4-aminopyridine was added to 9 ml of dry benzene and to the resulting solution was further added 119 mg (1 mmol) of phenyl isocyanate. After stirring at room temperature for 30 hrs., the crystals which deposited were collected by filtration and then subjected to chromatography in a conventional manner using alumina. After developing the column with a benzene-ethyl acetate (3:1 by volume) solvent mixture, eluate containing the objective compound was collected. After distilling solvent off under reduced pressure, the residue was recrystallized from an ethyl acetate-n-hexane solvent mixture to give 113 mg of the objective compound: yield 48.9%; m.p. 179°-180° C.