Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:43]=[CH:42][C:6]([CH2:7][N:8]2[C:12]3=[N:13][CH:14]=[CH:15][C:16]([O:17][C:18]4[CH:23]=[CH:22][C:21]([N:24]([C:33]5[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=5)[C:25]([C:27]5([C:30]([NH2:32])=[O:31])[CH2:29][CH2:28]5)=[O:26])=[CH:20][C:19]=4[F:40])=[C:11]3[C:10](I)=[N:9]2)=[CH:5][CH:4]=1.[CH3:44][N:45]1[CH2:50][CH2:49][N:48]([CH2:51][C:52]#[CH:53])[CH2:47][CH2:46]1.C(N(CC)CC)C>[Cu]I.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.C1COCC1>[CH3:1][O:2][C:3]1[CH:43]=[CH:42][C:6]([CH2:7][N:8]2[C:12]3=[N:13][CH:14]=[CH:15][C:16]([O:17][C:18]4[CH:23]=[CH:22][C:21]([N:24]([C:33]5[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=5)[C:25]([C:27]5([C:30]([NH2:32])=[O:31])[CH2:29][CH2:28]5)=[O:26])=[CH:20][C:19]=4[F:40])=[C:11]3[C:10]([C:53]#[C:52][CH2:51][N:48]3[CH2:49][CH2:50][N:45]([CH3:44])[CH2:46][CH2:47]3)=[N:9]2)=[CH:5][CH:4]=1
Reactant: COc1ccc(Cn2nc(I)c3c(Oc4ccc(N(C(=O)C5(C(N)=O)CC5)c5ccc(F)cc5)cc4F)ccnc32)cc1
Reactant: C#CCN1CCN(C)CC1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1ccc(Cn2nc(C#CCN3CCN(C)CC3)c3c(Oc4ccc(N(C(=O)C5(C(N)=O)CC5)c5ccc(F)cc5)cc4F)ccnc32)cc1
Temperature: 50 °C
Reaction time: 5 h
Yield: 39.4 %

Procedure:
A stirred mixture of N-(4-(1-(4-methoxybenzyl)-3-iodo-1H-pyrazolo[3,4-b]pyridin-4-yloxy)-3-fluorophenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (25 mg, 0.036 mmol), 1-methyl-4-(prop-2-ynyl)piperazine (10 mg, 0.072 mmol; obtained from Example 7, Step D), copper(I)iodide (0.3 mg, 0.002 mmol), triethylamine (0.25 mL, 1.8 mmol), and THF (0.5 mL) was sparged with N2 for 2 minutes, then tetrakis(triphenylphosphine)palladium (2 mg, 0.002 mmol) was added. The sealed reaction was heated to 50° C. for 18 hours. Additional 1-methyl-4-(prop-2-ynyl)piperazine (10 mg, 0.07 mmol), copper(I)iodide (0.3 mg, 0.002 mmol), and tetrakis(triphenylphosphine)palladium (2 mg, 0.002 mmol) were added and heating was continued at 80° C. for 5 hours. After cooling to room temperature, the entire reaction mixture was loaded directly on to a preparative TLC plate, eluting with 10% MeOH (containing 7N NH3) in CHCl3. The product was obtained as a waxy solid (10 mg, 37%). 1H NMR (400 MHz, CDCl3) δ 10.06 (s, 1H), 8.30 (d, J=6 Hz, 1H), 8.25 (s, 1H), 7.77 (m, 1H), 7.45 (m, 2H), 7.34 (d, J=9 Hz, 2H), 7.24 (m, 2H), 7.06 (m, 2H), 6.82 (d, J=9 Hz, 2H), 6.25 (d, J=6 Hz, 1H), 5.60 (s, 2H), 3.76 (s, 3H), 3.55 (s, 2H), 2.68 (m, 4H), 2.39 (m, 4H), 2.23 (s, 3H), 1.81 (m, 2H), 1.62 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH2:10][O:11][CH3:12])[C:6]([O:13][CH3:14])=[CH:5][C:4]=1[O:15][CH2:16][O:17][CH3:18].C([Li])(CC)C.[CH3:24][O:25][C:26]1[C:31]([O:32][CH2:33][O:34][CH3:35])=[CH:30][C:29]([O:36][CH3:37])=[C:28]([O:38][CH2:39][O:40][CH3:41])[C:27]=1[CH2:42][CH:43]=[O:44]>O1CCCC1.CN(C)P(=O)(N(C)C)N(C)C>[CH3:1][O:2][C:3]1[C:4]([O:15][CH2:16][O:17][CH3:18])=[CH:5][C:6]([O:13][CH3:14])=[C:7]([O:9][CH2:10][O:11][CH3:12])[C:8]=1[CH:43]([OH:44])[CH2:42][C:27]1[C:28]([O:38][CH2:39][O:40][CH3:41])=[C:29]([O:36][CH3:37])[CH:30]=[C:31]([O:32][CH2:33][O:34][CH3:35])[C:26]=1[O:25][CH3:24]
Reactant: COCOc1cc(OC)c(OCOC)cc1OC
Reactant: COCOc1cc(OC)c(OCOC)c(CC=O)c1OC
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: COCOc1cc(OC)c(OCOC)c(CC(O)c2c(OC)c(OCOC)cc(OC)c2OCOC)c1OC
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
351 Milligrams (1.36 mM) of 1,4-dimethoxy-2,5-bis(methoxymethoxy)benzene was dissolved in a mixed solvent of 10 ml of tetrahydrofuran with 1 ml of hexamethylphosphoric triamide, and the solution was cooled to -78° C. in a dry ice-acetone bath. Then 1.60 ml (1.05M cyclohexane solution, 1.68 mM) of sec-butyllithium was added to the reaction mixture and stirred for 30 minutes. Next, a tetrahydrofuran solution containing 334 mg (1.11 mM) of 2-[2,5-dimethoxy-3,6-bis(methoxymethoxy)phenyl]acetoaldehyde in 2 ml of tetrahydrofuran was added thereto and stirred for 8 hours. The reaction mixture was concentrated under a reduced pressure, and the residue obtained was purified by a silica gel column chromatography (diameter 2 cm×length 10 cm, eluent: 40% ethyl acetate-n-hexane) to yield 503 mg of 1,2-bis[2,5-dimethoxy-3,6-bis(methoxymethoxy)phenyl]ethanol. Colorless oily substance.
Reaction SMILES: [O:1]=[C:2]1[N:8]2[CH2:9][C@@H:4]([CH2:5][CH2:6][C@H:7]2[C:10]([NH:12][O:13][CH2:14][CH2:15][NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:11])[N:3]1[O:24]S(O)(=O)=O.F[C:30](F)(F)[C:31](O)=O>C(Cl)Cl>[OH:24][N:3]1[C:2](=[O:1])[N:8]2[CH2:9][C@H:4]1[CH2:5][CH2:6][C@H:7]2[C:10]([NH:12][O:13][C@H:14]1[CH2:31][CH2:30][N:16]([C:17]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:23])[CH2:15]1)=[O:11]
Reactant: CC(C)(C)OC(=O)NCCONC(=O)[C@@H]1CC[C@@H]2CN1C(=O)N2OS(=O)(=O)O
Reactant: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC[C@H](ONC(=O)[C@@H]2CC[C@@H]3CN2C(=O)N3O)C1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a mixture of tert-butyl {2-[({[(2S,5R)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]ethyl}carbamate 44 (0.19 g, 0.45 mmol) in DCM (6.0 mL) was added trifluoroacetic acid (0.30 mL) at 0° C. The mixture was stirred at 0° C. for 1 h, concentrated and washed with ether. The white solid was collected by centrifugation. The crude product was purified by preparative HPLC to provide Compound 9 (Table 1) (44 mg) as a white solid.
Reaction SMILES: [F:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([F:12])[C:3]=1[C:13]1[C:22]2[N:21]=[CH:20][CH:19]=[N:18][C:17]=2[C:16]([C:23](O)=[O:24])=[CH:15][CH:14]=1.[NH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=1>>[N:28]1[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=1[NH:26][C:23]([C:16]1[C:17]2[N:18]=[CH:19][CH:20]=[N:21][C:22]=2[C:13]([C:3]2[C:2]([F:1])=[C:7]([O:8][CH3:9])[CH:6]=[C:5]([O:10][CH3:11])[C:4]=2[F:12])=[CH:14][CH:15]=1)=[O:24]
Reactant: Nc1ccccn1
Reactant: COc1cc(OC)c(F)c(-c2ccc(C(=O)O)c3nccnc23)c1F
Product: COc1cc(OC)c(F)c(-c2ccc(C(=O)Nc3ccccn3)c3nccnc23)c1F
Temperature: 25 °C
Reaction time: 72 h

Procedure:
The title compound was prepared in analogy to the procedure described in Step 14.1 but using 8-(2,6-difluoro-3,5-dimethoxy-phenyl)-quinoxaline-5-carboxylic acid (Step 88.1), 2-aminopyridine, and stirring the reaction mixture for 72 h at rt. The crude product was purified by silica gel column chromatography (DCM/MeOH/NH3aq, 96:3:1), followed by trituration in Et2O, a second silica gel column chromatography (Hex/EtOAc, 1:4) and an additional trituration in Et2O. Title compound: ESI-MS: 423.1 [M+H]+; tR=4.21 min (System 1); TLC: Rf=0.19 (Hex/EtOAc, 1:4).
Reaction SMILES: [C:1]1(=[O:9])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.ClC1C=CC=C(C(OO)=[O:18])C=1.C([O-])(O)=O.[Na+]>ClC(Cl)C>[O:18]1[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:1]1=[O:9]
Reactant: O=C1CCCCCCC1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(Cl)Cl
Product: O=C1CCCCCCCO1
Temperature: 80 °C
Reaction time: 18 h
Yield: 73.4 %

Procedure:
43.5 g (345 mmol) of cyclooctanone (compound of formula (VI) with n=6) (ACROS) are placed in solution in 430 ml of dichloroethane. 170 g (985 mmol) of meta-chloroperbenzoic acid are then added. The medium is heated to 80° C. for 48 hours. At room temperature, 400 ml of a Na2S2O5 and NaHCO3 saturated solution (1/1 v/v) are added. The medium is strongly stirred for 18 hours. The organic phase is separated and placed into the presence of KI and H2O for 6 hours. The organic phase is separated and washed with a Na2S2O3 saturated solution, with a NaCl saturated solution, and is then dried on MgSO4, filtered and concentrated in vacuo in order to obtain 36 g of crude product.
Reaction SMILES: C([C@H:3]([S:7]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)(=[N:9][C:10]([C:12]1[CH:13]=[N:14][CH:15]=[C:16]([C:18]#[C:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([NH:26][C:27]([C:29]3[O:30][CH:31]=[CH:32][C:33]=3[CH3:34])=[O:28])[CH:21]=2)[CH:17]=1)=[O:11])=[O:8])[C:4]([O-])=[O:5])C.[NH:41]1[CH2:51][CH2:50][CH2:49][CH:43]([C:44]([O:46][CH2:47][CH3:48])=[O:45])[CH2:42]1>>[CH3:34][C:33]1[CH:32]=[CH:31][O:30][C:29]=1[C:27]([NH:26][C:22]1[CH:21]=[C:20]([C:19]#[C:18][C:16]2[CH:17]=[C:12]([C:10]([N:9]=[S:7]([CH2:3][C:4]([N:41]3[CH2:51][CH2:50][CH2:49][C@H:43]([C:44]([O:46][CH2:47][CH3:48])=[O:45])[CH2:42]3)=[O:5])([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)=[O:8])=[O:11])[CH:13]=[N:14][CH:15]=2)[CH:25]=[CH:24][CH:23]=1)=[O:28]
Reactant: CCOC(=O)C1CCCNC1
Reactant: CC[C@@H](C(=O)[O-])S(=O)(=NC(=O)c1cncc(C#Cc2cccc(NC(=O)c3occc3C)c2)c1)c1ccccc1
Product: CCOC(=O)[C@H]1CCCN(C(=O)CS(=O)(=NC(=O)c2cncc(C#Cc3cccc(NC(=O)c4occc4C)c3)c2)c2ccccc2)C1

Procedure:
In a manner similar to that described in Example 534, (S)-Ethyl(N-{[5-({3-[(3-methyl-2-furoyl)amino]phenyl}ethynyl)pyridin-3-yl]carbonyl}-S-phenylsulfonimidoyl)acetate and ethyl nipecotate were reacted to give the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[C:10]1[C:20]([NH2:21])=[N:19][C:13]2[N:14]=[C:15]([NH2:18])[N:16]=[CH:17][C:12]=2[CH:11]=1.[C:22]([N:26]=[C:27]=[O:28])([CH3:25])([CH3:24])[CH3:23]>>[NH2:18][C:15]1[N:16]=[CH:17][C:12]2[CH:11]=[C:10]([C:3]3[C:4]([CH3:9])=[CH:5][C:6]([CH3:8])=[CH:7][C:2]=3[CH3:1])[C:20]([NH:21][C:27]([NH:26][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:28])=[N:19][C:13]=2[N:14]=1
Reactant: CC(C)(C)N=C=O
Reactant: Cc1cc(C)c(-c2cc3cnc(N)nc3nc2N)c(C)c1
Product: Cc1cc(C)c(-c2cc3cnc(N)nc3nc2NC(=O)NC(C)(C)C)c(C)c1

Procedure:
The title compound was prepared from 0.25 g of 6-(2,4,6-trimethyl-phenyl)-pyrido[2,3-d]pyrimidine-2,7-diamine from Example 96 and 0.109 mL of tert-butyl isocyanate according to Example 2. The product was purified by medium pressure liquid chromatography eluting with 1:1 CHCl3 :EtOAc; mp 281-297° C.; CIMS (1% ammonia in methane): m/z (relative intensity) 379 (MH+ +1, 100), 380 (MH+ +2, 23).
Reaction SMILES: [N+:1]([CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])#[C-:2].[CH:9](OCC)=[S:10].[C-]#N.[Na+]>C(O)C>[CH2:7]([O:6][C:4]([C:3]1[N:1]=[CH:2][S:10][CH:9]=1)=[O:5])[CH3:8]
Reactant: [C-]#[N+]CC(=O)OCC
Reactant: CCOC=S
Agent: [C-]#N
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1cscn1
Temperature: 50 °C
Yield: 92 %

Procedure:
A solution of 4.52 g. (0.04 m) of ethyl isocyanoacetate and 3.60 g. (0.04 m) of ethyl thioformate in 15 ml. of absolute ethanol is added dropwise with vigorous stirring to a suspension of 0.25 g. of sodium cyanide in 10 ml. ethanol at 15° C. An exotherm developes during the addition and is moderated with ice-bath cooling. The reaction mixture is warmed at 50° C. for 30 minutes. The solvent is then removed in vacuo and the resulting residue extracted with several portions of hot hexane to give a 92% yield of 4-ethoxycarbonyl thiazole.
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([CH2:8][C:9]#[N:10])=O)=[CH:4][CH:3]=1.N1C=CC=CC=1.[NH2:19][C:20]([NH2:22])=[S:21].II.[O-]S([O-])(=S)=O.[Na+].[Na+]>CCO>[NH2:22][C:20]1[S:21][C:8]([C:9]#[N:10])=[C:6]([C:5]2[CH:11]=[CH:12][C:2]([F:1])=[CH:3][CH:4]=2)[N:19]=1
Reactant: N#CCC(=O)c1ccc(F)cc1
Reactant: NC(N)=S
Agent: II
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CCO
Product: N#Cc1sc(N)nc1-c1ccc(F)cc1
Temperature: 70 °C
Reaction time: 0.25 h

Procedure:
To a solution of 4-fluorobenzoylacetonitrile (50 g, 306 mmol, 1 eq.) in EtOH (600 mL) was added pyridine (24.7 mL, 306 mmol, 1 eq.). The resulting mixture was stirred at 70° C. for 15 min then cooled to r.t. A previously stirred suspension of thiourea (46.7 g, 613 mmol, 2 eq.) and iodine (77.8 g, 306 mmol, 1 eq.) in EtOH (300 mL) was then slowly added. After 1 h at r.t. a cold 1 M Na2S2O3 solution (360 mL) was added under stirring. The resulting precipitate was filtered, washed with water, and finally dried under vacuo to afford 2-Amino-4-(4-fluoro-phenyl)-thiazole-5-carbonitrile.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[C:8]([OH:10])[CH:7]=[CH:6][N:5]=1.F[C:12]1[CH:17]=[C:16]([F:18])[C:15]([N+:19]([O-:21])=[O:20])=[CH:14][C:13]=1[CH3:22]>CN(C=O)C>[Cl:3][C:4]1[CH:9]=[C:8]([O:10][C:12]2[CH:17]=[C:16]([F:18])[C:15]([N+:19]([O-:21])=[O:20])=[CH:14][C:13]=2[CH3:22])[CH:7]=[CH:6][N:5]=1
Reactant: Cc1cc([N+](=O)[O-])c(F)cc1F
Reactant: Oc1ccnc(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc([N+](=O)[O-])c(F)cc1Oc1ccnc(Cl)c1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 62.9 %

Procedure:
To 60% NaH in mineral oil (0.119 g, 2.97 mmol), under an atmosphere of argon, was added anhydrous DMF (3 mL) and the slurry was cooled in an ice bath. To this suspension was added, in portions, a solution of 2-chloropyridin-4-ol (0.35 g, 2.70 mmol) in DMF (2 mL). The reaction mixture was stirred cold for 5 minutes and then allowed to warm to RT and stirred for 20 minutes. 1,5-difluoro-2-methyl-4-nitrobenzene (0.514 g, 2.97 mmol) was added and the reaction mixture heated at 90° C. for 3 hours, cooled to RT, quenched with water and the mixture was extracted with EtOAc (3×). The combined organic phases were washed with brine, dried (Na2SO4), concentrated in vacuo and purified by silica gel column chromatography (EtOAc/hexanes) to obtain 2-chloro-4-(5-fluoro-2-methyl-4-nitrophenoxy)pyridine (0.48 g, 63% yield) MS (ESI) m/z: 283.0 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[N:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=[CH:6][C:3]=1[CH:4]=O.[F:17][C:18]1[CH:23]=[CH:22][C:21]([NH2:24])=[C:20]([NH2:25])[CH:19]=1>>[F:17][C:18]1[CH:23]=[CH:22][C:21]2[N:24]=[C:4]([C:3]3[C:2]([NH2:1])=[N:9][CH:8]=[C:7]([C:10]4[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=4)[CH:6]=3)[NH:25][C:20]=2[CH:19]=1
Reactant: Nc1ccc(F)cc1N
Reactant: Nc1ncc(-c2ccc(F)cc2)cc1C=O
Product: Nc1ncc(-c2ccc(F)cc2)cc1-c1nc2ccc(F)cc2[nH]1

Procedure:
Using the procedure of step (b) in Example 15, utilizing 2-amino-5-(4-fluorophenyl)nicotinaldehyde and 4-fluoro-o-phenylenediamine gave 3-(6-fluoro-1H-benzimidazol-2-yl)-5-(4-fluorophenyl)-pyridin-2-amine.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10]([F:13])([F:12])[F:11])[C:5]([F:9])=[C:6]([CH:8]=1)[NH2:7].[F:14][C:15]1[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[C:16]=1[C:17]([N:19]=[C:20]=[O:21])=[O:18]>>[Cl:1][C:2]1[CH:3]=[C:4]([C:10]([F:13])([F:11])[F:12])[C:5]([F:9])=[C:6]([NH:7][C:20]([NH:19][C:17](=[O:18])[C:16]2[C:22]([F:26])=[CH:23][CH:24]=[CH:25][C:15]=2[F:14])=[O:21])[CH:8]=1
Reactant: O=C=NC(=O)c1c(F)cccc1F
Reactant: Nc1cc(Cl)cc(C(F)(F)F)c1F
Product: O=C(NC(=O)c1c(F)cccc1F)Nc1cc(Cl)cc(C(F)(F)F)c1F
Yield: 69.2 %

Procedure:
The product was prepared from 5-chloro-2-fluoro-3-trifluoromethylaniline (0.5 g) and 2,6-difluorobenzoylisocyanate (0.4 g) by operating according to the process of Example 1 to obtain the product 0.6 g. (m.p. 187°-189° C.)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[S:9]([N:12]([CH2:14][C:15]1[O:19][CH:18]=[C:17]([C:20](O)=[O:21])[CH:16]=1)[CH3:13])(=[O:11])=[O:10].C1N=CN(C(N2C=NC=C2)=O)C=1.[NH:35]1[CH2:39][CH2:38][N:37]=[C:36]1[C:40]1[CH:45]=[CH:44][C:43]([CH2:46][NH:47][CH3:48])=[CH:42][CH:41]=1.Cl.CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[S:9]([N:12]([CH2:14][C:15]1[O:19][CH:18]=[C:17]([C:20]([N:47]([CH2:46][C:43]2[CH:44]=[CH:45][C:40]([C:36]3[NH:37][CH2:38][CH2:39][N:35]=3)=[CH:41][CH:42]=2)[CH3:48])=[O:21])[CH:16]=1)[CH3:13])(=[O:10])=[O:11]
Reactant: CN(Cc1cc(C(=O)O)co1)S(=O)(=O)c1c(Cl)cccc1Cl
Reactant: CNCc1ccc(C2=NCCN2)cc1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN(Cc1ccc(C2=NCCN2)cc1)C(=O)c1coc(CN(C)S(=O)(=O)c2c(Cl)cccc2Cl)c1

Procedure:
5-({[(2,6-dichlorophenyl)sulfonyl](methyl)amino}methyl)furan-3-carboxylic acid (51 mg, 0.14 mmol) was dissolved in DMF (1 mL) and CDI (34 mg, 0.21 mmol) was added. The mixture was stirred until acid activation was complete. 1-[4-(4,5-dihydro-1H-imidazol-2-yl)phenyl]-N-methylmethanamine.HCl (32 mg, 0.14 mmol) and DIPEA (0.074 mL, 0.42 mmol) were sonicated in DMF (0.5 mL) for 15 min. 0.5 mL of activated acid solution was added to 0.25 mL of amine solution and the reaction was stirred at ambient temperature for 18 h, then microwaved (120° C., 200 W) for 2×20 min. The reaction was concentrated, dissolved in DCM and washed with water (3×1.5 mL) and saturated brine (1 mL)). The organic layer was dried over MgSO4 and solvents were removed in vacuo. A portion of the crude product was purified using prep method A.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[CH:16]=[C:15]([C:17]([F:20])([F:19])[F:18])[N:14]3[N:21]=[C:22]([C:24]4[CH2:29][CH2:28][N:27]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH:26]([CH3:37])[CH:25]=4)[CH:23]=[C:13]3[N:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[H][H].C1(C)C=CC=CC=1>CO.[Pd]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]2[CH2:16][CH:15]([C:17]([F:20])([F:18])[F:19])[N:14]3[N:21]=[C:22]([CH:24]4[CH2:29][CH2:28][N:27]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH:26]([CH3:37])[CH2:25]4)[CH:23]=[C:13]3[NH:12]2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(-c2cc(C(F)(F)F)n3nc(C4=CC(C)N(C(=O)OC(C)(C)C)CC4)cc3n2)cc1OC
Reactant: [H][H]
Agent: [Pd]
Solvent: Cc1ccccc1
Solvent: CO
Product: COc1ccc(C2CC(C(F)(F)F)n3nc(C4CCN(C(=O)OC(C)(C)C)C(C)C4)cc3N2)cc1OC
Yield: 59.5 %

Procedure:
Tert-butyl 4-(5-(3,4-dimethoxyphenyl)-7-(trifluoromethyl)pyrazolo[1,5-a]pyrimidin-2-yl)-2-methyl-5,6-dihydropyridine-1(2H)-carboxylate (Mixture with regioisomer tert-butyl 4-(5-(3,4-dimethoxyphenyl)-7-(trifluoromethyl)pyrazolo[1,5-a]pyrimidin-2-yl)-6-methyl-5,6-dihydropyridine-1(2H)-carboxylate, total is 60 mg, 0.116 mmol) was dissolved in Methanol (2.5 ml). The solution was treated with Hydrogen for 2.5 hrs at room temperature using H-Cube (Full H2, 1 mL/min, small size (30 mm) 10% Palladium on Carbon CatCart). 1 mL Toluene was added. Solvent was concentrated. The crude product was purified on silica-gel (Column Interchim 25 g, 30 μM) eluting with 12-100% EtOAc/Heptane to afford tert-butyl 4-(5-(3,4-dimethoxyphenyl)-7-(trifluoromethyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-2-yl)-2-methylpiperidine-1-carboxylate (36 mg, 0.069 mmol, 59% yield) as a white solid.
Reaction SMILES: CO[CH:3](OC)[N:4]([CH3:6])[CH3:5].[CH2:9]([O:16][N:17]1[C:23](=[O:24])[N:22]2[CH2:25][C@H:18]1[CH2:19][CH2:20][C@H:21]2[C:26]([NH2:28])=[O:27])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>O1CCOCC1>[CH2:9]([O:16][N:17]1[C:23](=[O:24])[N:22]2[CH2:25][C@H:18]1[CH2:19][CH2:20][C@H:21]2[C:26](/[N:28]=[CH:3]\[N:4]([CH3:6])[CH3:5])=[O:27])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: COC(OC)N(C)C
Reactant: NC(=O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Solvent: C1COCCO1
Product: CN(C)/C=N\C(=O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Reaction time: 2 h
Yield: 80.5 %

Procedure:
Dimethoxy-N,N-dimethylmethanamine (0.97 mL, 7 mmol) was added to a solution of (2S,5R)-6-(benzyloxy)-7-oxo-1,6-diaza-bicyclo[3.2.1]octane-2-carboxamide (1.38 g, 5 mmol) in 1,4-dioxane (20 mL) at rt. The mixture was stiffed at 45-50° C. for 2 hrs under vacuum to remove the methanol formed during the reaction. Then, the reaction mixture was concentrated under vacuum, and the residue was washed with Et2O (2×) and dried to give (2S,5R,Z)-6-(benzyloxy)-N-((dimethylamino)methylene)-7-oxo-1,6-diaza-bicyclo[3.2.1]octane-2-carboxamide (1.33 g, 80%) as a white solid. (ESI-MS (EI+, 331, m/z): [M+H]+.
Reaction SMILES: [CH3:1][CH:2]([CH3:7])[CH2:3][N+:4]([O-:6])=[O:5].C(=O)([O-])[O-].[K+].[K+].[CH:14](O)([OH:19])[C:15]([F:18])([F:17])[F:16].O>C(OC)(C)(C)C>[CH3:1][CH:2]([CH3:7])[CH:3]([N+:4]([O-:6])=[O:5])[CH:14]([OH:19])[C:15]([F:18])([F:17])[F:16]
Reactant: OC(O)C(F)(F)F
Reactant: CC(C)C[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COC(C)(C)C
Product: CC(C)C(C(O)C(F)(F)F)[N+](=O)[O-]
Temperature: 15 °C
Reaction time: 0.08 h
Yield: 84 %

Procedure:
3A Molecular sieves (27.04 g) were heated at 120° C. under vacuum for 20 hours and added to a solution of 2-methyl-1-nitropropane (13.0 g) in methyl tert-butyl ether (420 ml). The mixture was stirred for 5 minutes, potassium carbonate (64.5 g) added and the mixture stirred a further 30 minutes. The mixture was cooled to 15° C. and fluoral hydrate (22.0 g) was added over 30 minutes. The reaction mixture was stirred at ambient temperature for 16 hours, then cooled to 15° C. and water (270 ml) added. After stirring for 5 minutes at ambient temperature, the organic phase was separated and washed with 10% aqueous potassium carbonate, 2M hydrochloric acid solution and water. Solvent was then removed by evaporation under reduced pressure at a temperature below 40° C. and the oil azeotroped dry with isopropyl alcohol at a temperature below 50° C. to give 4-methyl-3-nitro-1,1,1-trifluoro-2-pentanol (21.3 g) as an oil which was used without further purification.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([OH:12])[CH:6]=[CH:5]2.[C:13]([O:17][CH3:18])(=[O:16])[CH:14]=[CH2:15].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(N(CC)CC)C>[OH:12][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[CH:3]=[C:2](/[CH:15]=[CH:14]/[C:13]([O:17][CH3:18])=[O:16])[CH:11]=[CH:10]2
Reactant: C=CC(=O)OC
Reactant: Oc1ccc2cc(Br)ccc2c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Product: COC(=O)/C=C/c1ccc2cc(O)ccc2c1
Reaction time: 15 h
Yield: 71.4 %

Procedure:
5 g (22.4 mmol) of 6-bromo-2-naphthol, 6 ml (67.2 mmol) of methyl acrylate, 100 mg (0.45 mmol) of palladium acetate and 25 ml of triethylamine were placed in a flask gassed with nitrogen. After the addition of 545 mg (1.79 mmol) of tri-(o-tolyl)-phosphine the reaction mixture was boiled under reflux overnight. After 15 hours the reaction was interrupted and the mixture was partitioned between ethyl acetate and water. The organic phase was back-washed three times with water and the aqueous phases were each individually back-washed twice with ethyl acetate. The combined organic phases were dried over magnesium sulphate, filtered over Celite and evaporated completely in a vacuum. Chromatography on silica gel with toluene/ethyl acetate (3:2) and subsequent recrystallization from ethyl acetate gave 3.65 g of methyl (E)-3-(6-hydroxy-naphthalen-2-yl)-acrylate. ##STR35##
Reaction SMILES: [CH2:1]=[O:2].[CH2:3]([O:7][P:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[OH:9])[CH:4]([CH3:6])[CH3:5]>O>[CH2:3]([O:7][P:8]([CH2:1][OH:2])([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:9])[CH:4]([CH3:6])[CH3:5]
Reactant: CC(C)COP(O)c1ccccc1
Reactant: C=O
Solvent: O
Product: CC(C)COP(=O)(CO)c1ccccc1
Reaction time: 1 h

Procedure:
15 g of para-formaldehyde are added, at 70°C and with vigorous agitation, to 100 g (0.505 mole) of benzenephosphonous acid isobutyl ester. Agitation is continued for 1 hour at 75°-90°C. The reaction mixture is then cooled, stirred with water, and the organic phase is separated. The aqueous phase is extracted 2 times with chloroform, and the extract is added to the organic phase. After drying with sodium sulfate, distillation is carried out in a water jet vacuum at an interior temperature of up to 80°C. The residue is distilled in a thin layer evaporator at 0.1 torr and a distillation temperature of 190°C. Subsequently, the distillate is again distilled in a normal distillation apparatus. It is pure hydroxymethyl-phenylphosphinic acid isobutyl ester having a boiling point of 155°C at 0.3 torr.