Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[O:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.[Cl:13][C:14]1[C:15](F)=[CH:16][C:17]2[O:22][CH:21]([C:23]([F:26])([F:25])[F:24])[C:20]([C:27]([O:29]CC)=[O:28])=[CH:19][C:18]=2[CH:32]=1>>[Cl:13][C:14]1[C:15]([O:10][C:7]2[CH:6]=[CH:5][C:4]([O:3][C:2]([F:11])([F:12])[F:1])=[CH:9][CH:8]=2)=[CH:16][C:17]2[O:22][CH:21]([C:23]([F:25])([F:24])[F:26])[C:20]([C:27]([OH:29])=[O:28])=[CH:19][C:18]=2[CH:32]=1
Reactant: Oc1ccc(OC(F)(F)F)cc1
Reactant: CCOC(=O)C1=Cc2cc(Cl)c(F)cc2OC1C(F)(F)F
Product: O=C(O)C1=Cc2cc(Cl)c(Oc3ccc(OC(F)(F)F)cc3)cc2OC1C(F)(F)F

Procedure:
The title compound was prepared from 4-(trifluoromethoxy)phenol and ethyl 6-chloro-7-fluoro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylate (Example 183, Step 2) via a procedure similar to that described in Example 183, Steps 3 and 4: mp 198.0-199.2° C. 1H NMR (acetone-d6 /300 MHz) 7.91 (s, 1H), 7.73 (s, 1H), 7.43 (d, 2H, J=9.1 Hz), 7.25 (d, 2H, J=9.1 Hz), 6.70 (s, 1H), 5.82 (q, 1H, J=7.0 Hz). 19F NMR (acetone-d6 /282 MHz) -59.4 (s, 3F), -79.4 (d, 3F, J=7.2 Hz). ESLRMS m/z 453 (M-H). ESHRMS m/z 452.9950 (M-H, Calc'd 452.9964). Anal. Calc'd for C18H9ClF6O5 : C, 47.55; H, 2.00; Cl, 7.80. Found: C, 47.47; H, 1.89; Cl, 8.02.
Reaction SMILES: [O-]CC.[K+:4].[C:5]([O:12][CH2:13][CH3:14])(=[O:11])[C:6]([O:8]CC)=O.[CH2:15]([N:22]([CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:23]1[CH:28]=[C:27]([CH3:29])[C:26]([N+:30]([O-:32])=[O:31])=[CH:25][N:24]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C(OCC)C>[CH2:33]([N:22]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:23]1[CH:28]=[C:27](/[CH:29]=[C:6](\[O-:8])/[C:5]([O:12][CH2:13][CH3:14])=[O:11])[C:26]([N+:30]([O-:32])=[O:31])=[CH:25][N:24]=1)[C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1.[K+:4]
Reactant: CCOC(=O)C(=O)OCC
Reactant: Cc1cc(N(Cc2ccccc2)Cc2ccccc2)ncc1[N+](=O)[O-]
Agent: CC[O-]
Agent: [K+]
Solvent: CCOCC
Product: CCOC(=O)/C([O-])=C/c1cc(N(Cc2ccccc2)Cc2ccccc2)ncc1[N+](=O)[O-]
Reaction time: 0.33 h
Yield: 76.6 %

Procedure:
To a suspension of potassium ethoxide (2.21 g, 26.3 mmol) in diethyl ether (20 mL) was added diethyl oxalate (3.57 mL, 26.3 mmol) under a nitrogen atmosphere. The reaction exhibited a slight exotherm and the reaction mixture was stirred for 20 min. The heterogeneous mixture became a homogeneous orange solution and then became a heterogeneous thick slurry and the stirring was ceased. In a separate container 2-(dibenzylamino)-5-nitro-4-methylpyridine (8.76 g, 26.3 mmol) was diluted with diethyl ether (14.3 mL) to give a suspension. The suspension was added to the slurry obtained above. The mixture was manually stirred using a glass rod, then sonicated for 20 min resulting in a thick black heterogeneous solution. The reaction mixture was allowed to stand under a nitrogen atmosphere overnight. The resulting solid was collected by filtration and rinsed with diethyl ether to give potassium (1Z)-1-[2-(dibenzylamino)-5-nitropyridin-4-yl]-3-ethoxy-3-oxoprop-1-en-2-olate (9.5 g, 76%) as a deep red solid: 1H NMR (300 MHz, CD3OD) δ1.17 (3H, t, J=7.0 Hz), 3.58 (2H, q, J=6.9 Hz), 4.82 (4H, s), 7.22-7.32 (11H, m), 8.74 (1H, s), 8.80 (1H, s).
Reaction SMILES: Br[C:2]1[CH:14]=[C:13]2[C:5]([C:6]3[C:11](=[CH:12]2)[C:10]2([C:26]4[C:18]([C:19]5[C:24]([CH:25]=4)=[CH:23][CH:22]=[CH:21][CH:20]=5)=[CH:17][CH:16]=[CH:15]2)[C:9](Br)=[C:8](Br)[C:7]=3Br)=[C:4](Br)[C:3]=1Br.B(O)(O)[C:33]1[CH:34]=[CH:35][C:36]([C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=2)=[CH:37][CH:38]=1>C1(C)C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+].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>[C:36]1([C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=2)[CH:35]=[CH:34][CH:33]=[CH:38][C:37]=1[C:2]1[CH:14]=[C:13]([C:12]2[CH:25]=[CH:26][CH:18]=[CH:17][C:11]=2[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:5]2[C:6]3[C:15](=[CH:10][C:9]([C:40]4[CH:41]=[CH:42][CH:43]=[CH:44][C:39]=4[C:36]4[CH:37]=[CH:38][CH:33]=[CH:34][CH:35]=4)=[CH:8][CH:7]=3)[C:16]3([C:17]4[CH:18]=[C:26]([C:40]5[CH:41]=[CH:42][CH:43]=[CH:44][C:39]=5[C:36]5[CH:37]=[CH:38][CH:33]=[CH:34][CH:35]=5)[CH:25]=[C:24]([C:23]5[CH:22]=[CH:21][CH:20]=[CH:16][C:15]=5[C:10]5[CH:11]=[CH:6][CH:7]=[CH:8][CH:9]=5)[C:19]=4[C:42]4[C:41]3=[CH:40][C:39]([C:36]3[CH:37]=[CH:38][CH:33]=[CH:34][C:35]=3[C:13]3[CH:14]=[CH:2][CH:3]=[CH:4][CH:5]=3)=[CH:44][CH:43]=4)[C:4]=2[CH:3]=1
Reactant: OB(O)c1ccc(-c2ccccc2)cc1
Reactant: BrC1=C2C(=Cc3cc(Br)c(Br)c(Br)c32)C2(C=CC=C3C2=Cc2ccccc23)C(Br)=C1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: c1ccc(-c2ccccc2-c2ccc3c(c2)C2(c4cc(-c5ccccc5-c5ccccc5)ccc4-c4c(-c5ccccc5-c5ccccc5)cc(-c5ccccc5-c5ccccc5)cc42)c2cc(-c4ccccc4-c4ccccc4)cc(-c4ccccc4-c4ccccc4)c2-3)cc1

Procedure:
In a 250 ml two-necked flask fitted with reflux condenser and precision glass stirrer, 1.6 g of hexabromospirobifluorene and 3 g of biphenylboronic acid are slurried in a mixture of 50 ml of toluene and 50 ml of 1M potassium carbonate solution. The mixture is refluxed under nitrogen and 115 mg of tetrakis(triphenylphosphine)palladium in 5 ml of toluene are added. The mixture is boiled under reflux for 7 hours while stirring. After the reaction is complete, the cooled solution is filtered and the filtrate is extracted twice by shaking with water (to improve the phase separation, chloroform is added). The organic phase is dried over sodium sulfate, filtered through a short column of silica gel and subsequently evaporated on a rotary evaporator. The product is further purified by recrystallization from dichloromethane/pentane. This gives 2 g (80%) of colorless crystals which fluoresce blue under UV illumination.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][N:3]=1.C([Li])CCC.[CH2:17]([N:19]1[CH:23]=[C:22]([S:24]([N:27]2[CH2:36][CH2:35][C:34]3[C@:29]([C:47](OC)=[O:48])([CH2:30][C:31]4[CH:39]=[N:38][N:37]([C:40]5[CH:45]=[CH:44][C:43]([F:46])=[CH:42][CH:41]=5)[C:32]=4[CH:33]=3)[CH2:28]2)(=[O:26])=[O:25])[CH:21]=[N:20]1)[CH3:18].O>O1CCCC1>[CH2:17]([N:19]1[CH:23]=[C:22]([S:24]([N:27]2[CH2:36][CH2:35][C:34]3[C@:29]([C:47]([C:2]4[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][N:3]=4)=[O:48])([CH2:30][C:31]4[CH:39]=[N:38][N:37]([C:40]5[CH:41]=[CH:42][C:43]([F:46])=[CH:44][CH:45]=5)[C:32]=4[CH:33]=3)[CH2:28]2)(=[O:25])=[O:26])[CH:21]=[N:20]1)[CH3:18]
Reactant: FC(F)(F)c1ccnc(Br)c1
Reactant: CCn1cc(S(=O)(=O)N2CCC3=Cc4c(cnn4-c4ccc(F)cc4)C[C@]3(C(=O)OC)C2)cn1
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: CCn1cc(S(=O)(=O)N2CCC3=Cc4c(cnn4-c4ccc(F)cc4)C[C@]3(C(=O)c3cc(C(F)(F)F)ccn3)C2)cn1
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 8.5 %

Procedure:
2-Bromo-4-(trifluoromethyl)pyridine (171 μl, 1.382 mmol) in dry tetrahydrofuran (1 mL) was added to butyllithium (2.5 M in Hexanes) (885 μl, 1.416 mmol) in dry tetrahydrofuran (2 mL) at −78° C. The reaction mixture was stirred at −78° C. for 45 minutes, then a solution of (R)-methyl 6-((1-ethyl-1H-pyrazol-4-yl)sulfonyl)-1-(4-fluorophenyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinoline-4a-carboxylate (220 mg, 0.453 mmol) in dry tetrahydrofuran (2 mL) was added dropwise and the reaction mixture stirred for 1 hour at −78° C. Water (10 mL) was added and the reaction mixture was stirred at room temperature for 10 minutes. The aqueous phase was extracted with ethyl acetate (2×15 mL), and the combined organic layers were washed with brine (20 mL), dried over magnesium sulfate, filtered and concentrated in vacuo to give an orange oil. The crude product was purified by chromatography on silica gel (gradient: 0-80% ethyl acetate in isohexane) and preparative HPLC (Waters, Acidic (0.1% Formic acid), Waters X-Select Prep-C18, 5 μm, 19×50 mm column, 35-70% acetonitrile in water) to afford (R)-(6-((1-ethyl-1H-pyrazol-4-yl)sulfonyl)-1-(4-fluorophenyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methanone (23 mg) as a white solid. LCMS (Method F, ES-API): RT 3.00 min, m+H=601.2; 1H NMR (400 MHz, CDCl3): δ 8.88-8.87 (1H, m), 8.15 (1H, m), 7.71-7.69 (2H, m), 7.67 (1H, d, J=0.6 Hz), 7.47-7.42 (2H, m), 7.30 (1H, s), 7.20-7.14 (2H, m), 6.51 (1H, d, J=2.0 Hz), 5.44 (1H, dd, J=12.0, 2.0 Hz), 4.22-4.16 (3H, m), 3.80-3.76 (1H, m), 2.94 (1H, d, J=16.9 Hz), 2.88-2.79 (1H, m), 2.67 (1H, d, J=12.3 Hz), 2.52-2.40 (2H, m), 1.51 (3H, t, J=7.3 Hz).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][N:8]([CH2:11][CH2:12][CH2:13][NH:14][C:15]2[NH:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[N:16]=2)[CH2:7][CH2:6]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:31][CH2:32][CH2:33][CH2:34]Br>CN(C=O)C>[NH:19]1[C:18]2[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=2[N:16]=[C:15]1[NH:14][CH2:13][CH2:12][CH2:11][N:8]1[CH2:9][CH2:10][N:5]([CH2:4][CH2:3][CH2:2][N:1]2[CH2:34][CH2:33][CH2:32][CH2:31]2)[CH2:6][CH2:7]1
Reactant: BrCCCCBr
Reactant: NCCCN1CCN(CCCNc2nc3ccccc3[nH]2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: c1ccc2[nH]c(NCCCN3CCN(CCCN4CCCC4)CC3)nc2c1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
[3-[4-(3-Amino-propyl)-piperazin-1-yl]-propyl]-(1H-benzimidazol-2-yl)-amine (intermediate) (65 mg, 0.021 mmol) was dissolved in anhydrous DMF (20 mL) in the presence of potassium carbonate (142 mg, 1.0 mmol). 1,4-dibromobutane (0.03 mL, 0.25 mmol) was added. The resulting mixture was stirred for 48 h at room temperature. The
Reaction SMILES: [OH:1][C:2]1[CH:34]=[CH:33][C:5]([C:6]([NH:8][N:9]([C:13](=[O:32])/[CH:14]=[CH:15]/[C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:18]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH:17]=2)[CH:10]([CH3:12])[CH3:11])=[O:7])=[CH:4][CH:3]=1.[C:35]([O-])([O-])=O.[K+].[K+].IC>CC(C)=O>[CH:10]([N:9]([C:13](=[O:32])/[CH:14]=[CH:15]/[C:16]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[N:18]([C:25]([O:27][C:28]([CH3:29])([CH3:31])[CH3:30])=[O:26])[CH:17]=1)[NH:8][C:6](=[O:7])[C:5]1[CH:4]=[CH:3][C:2]([O:1][CH3:35])=[CH:34][CH:33]=1)([CH3:11])[CH3:12]
Reactant: O=C([O-])[O-]
Reactant: CC(C)N(NC(=O)c1ccc(O)cc1)C(=O)/C=C/c1cn(C(=O)OC(C)(C)C)c2ccccc12
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: COc1ccc(C(=O)NN(C(=O)/C=C/c2cn(C(=O)OC(C)(C)C)c3ccccc23)C(C)C)cc1
Temperature: 60 °C

Procedure:
To solution containing (E)-tert-butyl 3-(3-(2-(4-hydroxybenzoyl)-1-isopropylhydrazinyl)-3-oxoprop-1-enyl)-1H-indole-1-carboxylate (100 mg, 0.22 mmol) and K2CO3 (35.8 mg, 0.26 mmol) dissolved in acetone (5.0 ml), iodomethane (0.0673 ml, 1.08 mmol) was added drop-by-drop at 0° C. The reaction mixture was refluxed at 60° C. for 72 hr. After concentration under reduced pressure, the solution was separated through silica gel chromatography (CHCl3:methanol=70:1) so that ivory solid form of (E)-tert-butyl 3-(3-(1-isopropyl-2-(4-methoxybenzoyl)hydrazinyl)-3-oxoprop-1-enyl)-1H-indole-1-carboxylate was obtained (38.4 mg, 37.2%).
Reaction SMILES: [Na].C([O:4][C:5](=O)[CH2:6][C:7]#[N:8])C.[CH3:10][C:11]1[CH:12]=[C:13]([CH:17]=[CH:18][CH:19]=1)[CH2:14][NH:15][NH2:16].N#N>C(O)C.O>[NH2:8][C:7]1[NH:16][N:15]([CH2:14][C:13]2[CH:17]=[CH:18][CH:19]=[C:11]([CH3:10])[CH:12]=2)[C:5](=[O:4])[CH:6]=1
Reactant: CCOC(=O)CC#N
Reactant: Cc1cccc(CNN)c1
Agent: N#N
Agent: [Na]
Solvent: CCO
Solvent: O
Product: Cc1cccc(Cn2[nH]c(N)cc2=O)c1

Procedure:
4.6 g of sodium are dissolved in 100 ml of ethanol. A mixture of 12 g of cyanoacetic acid ethyl ester and 13.6 g of 3-methylbenzylhydrazine is added to this solution. The mixture is heated to the boil for 5 hours while stirring and passing N2 into it. After driving off the solvent, taking up the residue in water, extracting with ether and clarifying with animal charcoal, acidification with acetic acid yields colorless crystals which after again being recrystallised from ethanol melt at 92°. The yield is 10.3 g of the compound identified above, corresponding to 51% of theory.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[C:5]2[CH2:12][N:13]1[C:21]([C:22]2[N:26]([CH3:27])[CH:25]=[C:24]([C:28](O)=[O:29])[CH:23]=2)=[C:20]2[C:15]([N:16]([CH2:34][CH:35]([CH3:37])[CH3:36])[C:17](=[O:33])[N:18]([CH3:32])[C:19]2=[O:31])=[N:14]1.[CH3:38][N:39]([CH3:43])[CH2:40][CH2:41][NH2:42].C(P(=O)(OCC)OCC)#N>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[C:5]2[CH2:12][N:13]1[C:21]([C:22]2[N:26]([CH3:27])[CH:25]=[C:24]([C:28]([NH:42][CH2:41][CH2:40][N:39]([CH3:43])[CH3:38])=[O:29])[CH:23]=2)=[C:20]2[C:15]([N:16]([CH2:34][CH:35]([CH3:37])[CH3:36])[C:17](=[O:33])[N:18]([CH3:32])[C:19]2=[O:31])=[N:14]1
Reactant: CN(C)CCN
Reactant: CC(C)Cn1c(=O)n(C)c(=O)c2c(-c3cc(C(=O)O)cn3C)n(Cc3ccnc4ccc(Cl)cc34)nc21
Agent: CCOP(=O)(C#N)OCC
Product: CC(C)Cn1c(=O)n(C)c(=O)c2c(-c3cc(C(=O)NCCN(C)C)cn3C)n(Cc3ccnc4ccc(Cl)cc34)nc21

Procedure:
This compound was synthesized by the reaction of 5-{2-[(6-chloroquinolin-4-yl)methyl]-7-isobutyl-5-methyl-4,6-dioxo-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-d]pyrimidin-3-yl}-1-methyl-1H-pyrrole-3-carboxylic acid and N,N-dimethylethane-1,2-diamine using diethyl cyanophosphonate as a coupling reagent. Mass: 591.27 (M+H).
Reaction SMILES: Cl.[OH:2][CH2:3][C@@H:4]1[O:8][C:7](=[O:9])[N:6]([C:10]2[CH:15]=[CH:14][C:13]([N:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)=[C:12]([F:22])[CH:11]=2)[CH2:5]1.C(N(CC)CC)C.Cl[C:31]1[CH:36]=[CH:35][C:34]([C:37]#[N:38])=[CH:33][N:32]=1>C(#N)C>[OH:2][CH2:3][C@@H:4]1[O:8][C:7](=[O:9])[N:6]([C:10]2[CH:15]=[CH:14][C:13]([N:16]3[CH2:17][CH2:18][N:19]([C:31]4[CH:36]=[CH:35][C:34]([C:37]#[N:38])=[CH:33][N:32]=4)[CH2:20][CH2:21]3)=[C:12]([F:22])[CH:11]=2)[CH2:5]1
Reactant: N#Cc1ccc(Cl)nc1
Reactant: O=C1O[C@@H](CO)CN1c1ccc(N2CCNCC2)c(F)c1
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: N#Cc1ccc(N2CCN(c3ccc(N4C[C@H](CO)OC4=O)cc3F)CC2)nc1
Reaction time: 0.17 h

Procedure:
5(R)-hydroxymethyl-3-(3-fluoro-4-(piperazin-1-yl)phenyl)oxazolidin-2-one hydrochloride (25 g, 75.4 mmol ) was suspended by stirring in acetonitrile (700 ml) under nitrogen, and triethylamine (16.8 g, 166 mmol ) added, The mixture was stirred for 10 minutes and then 2-chloro-5-cyanopyridine (10.3 g, 75.4 mmol ) added, and the mixture heated under reflux for 18 hours. After cooling, the resultant solid was filtered, washed with water (3×500 ml) and diethyl ether (2×500 ml) to give 5(R)-hydroxymethyl-3-(4-(4-(5-cyanopyrid-2-yl)piperazin-1-yl)-3-fluorophenyl)-oxazolidin-2-one. A further crop was obtained by evaporation of the mother liquors to give a total yield of 23.2 g. MS: ESP+ (M+H)+=398.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[OH:11])[C:5]([OH:7])=[O:6].[F:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17]Br)=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+]>C1COCC1.O>[F:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17][O:6][C:5](=[O:7])[C:4]2[CH:8]=[CH:9][C:10]([O:11][CH2:17][C:16]3[CH:19]=[CH:20][C:13]([F:12])=[CH:14][CH:15]=3)=[C:2]([F:1])[CH:3]=2)=[CH:15][CH:14]=1
Reactant: O=C(O)c1ccc(O)c(F)c1
Reactant: Fc1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: O=C(OCc1ccc(F)cc1)c1ccc(OCc2ccc(F)cc2)c(F)c1
Temperature: 65 °C
Yield: 75.2 %

Procedure:
A mixture of 3-fluoro-4-hydroxybenzoic acid (4.68 g, 30 mmol), 4-fluorobenzyl bromide (17.0 g, 90 mmol) and potassium carbonate (8.3 g, 60 mmol) in THF:water (1:1, 100 mL) was heated at 65° C. for 48 h. After cooling to room temperature the mixture was extracted with ethyl acetate (2×100 mL) and the combined extracts washed with brine (100 mL) and dried over sodium sulfate. Filtration and evaporation gave a residue which was crystallised from ether:heptane to afford the title compound (8.4 g, 75%) as a white solid. MS: m/e=372.0 (M+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[NH:9][C:10]1[NH:14][C:13]2[C:15]([N+:24]([O-])=O)=[C:16]([OH:23])[C:17]([C:19]([O:21][CH3:22])=[O:20])=[CH:18][C:12]=2[N:11]=1.[In].[C:28](O)(=O)[CH3:29].C(OC)(OC)(OC)C>C1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[NH:9][C:10]1[NH:14][C:13]2[C:15]3[N:24]=[C:28]([CH3:29])[O:23][C:16]=3[C:17]([C:19]([O:21][CH3:22])=[O:20])=[CH:18][C:12]=2[N:11]=1
Reactant: COC(=O)c1cc2nc(Nc3c(F)cccc3Cl)[nH]c2c([N+](=O)[O-])c1O
Reactant: CC(=O)O
Agent: COC(C)(OC)OC
Agent: [In]
Solvent: c1ccccc1
Product: COC(=O)c1cc2nc(Nc3c(F)cccc3Cl)[nH]c2c2nc(C)oc12
Yield: 61.9 %

Procedure:
The title compound was prepared following the procedure described for step-4 of Intermediate-55 using methyl 2-[(2-chloro-6-fluorophenyl)amino]-6-hydroxy-7-nitro-1H-benzimidazole-5-carboxylate (0.320 g, 0.840 mmol), benzene (6 mL), indium (0.386 g, 3.363 mmol), acetic acid (0.505 g, 8.40 mmol) and trimethyl orthoacetate (0.812 g, 2.96 mmol) to afford 0.195 g of the desired product. 1HNMR (DMSO-d6): δ 2.63 (s, 3H), 3.88 (s, 3H), 7.439-7.46 (m, 3H), 7.71 (s, 1H), 9.0-10.0 (s, 1H), 11.60 (s, 1H); MS [M+H]+: 375.34.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[O:4][CH2:5][CH2:6][OH:7].[H-].[Na+].[Cl:14][C:15]1[C:24](Cl)=[N:23][C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:16]=1>O1CCOCC1>[Cl:14][C:15]1[C:24]([O:7][CH2:6][CH2:5][O:4][C:3]2[CH:8]=[CH:9][CH:10]=[CH:11][C:2]=2[Cl:1])=[N:23][C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:16]=1
Reactant: OCCOc1ccccc1Cl
Reactant: Clc1nc2ccccc2nc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: Clc1ccccc1OCCOc1nc2ccccc2nc1Cl
Temperature: 25 °C
Reaction time: 3 h

Procedure:
2-(2-Chlorophenoxy)ethanol (0.229 g, 1.33 mmol) was treated with NaH (55% dispersion in mineral oil; 0.058 g, 1.33 mmol) in dioxane (2 mL). After stirring at room temperature for 3 h, the mixture was added dropwise to a slurry of 2.3-dichloroquinoxaline (0.320 g, 1.60 mmol) in dioxane (1 mL). The resulting mixture was stirred at room temperature for 15 h to produce the intermediate 2-chloro-3-[2-(2-chlorophenoxy)ethoxy]quinoxaline which was used directly in the next step.
Reaction SMILES: [Br:1][C:2]1[S:3][C:4]2[C:10](=[O:11])/[C:9](=[CH:12]/[C:13]([O:15][CH2:16][CH3:17])=[O:14])/[CH:8]([CH3:18])[CH2:7][C:5]=2[N:6]=1.[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([Mg]Br)=[CH:22][CH:21]=1>C1COCC1>[Br:1][C:2]1[S:3][C:4]2[C:10]([C:23]3[CH:24]=[CH:25][C:20]([Cl:19])=[CH:21][CH:22]=3)([OH:11])/[C:9](=[CH:12]/[C:13]([O:15][CH2:16][CH3:17])=[O:14])/[CH:8]([CH3:18])[CH2:7][C:5]=2[N:6]=1
Reactant: CCOC(=O)/C=C1/C(=O)c2sc(Br)nc2CC1C
Reactant: Clc1ccc([Mg]Br)cc1
Solvent: C1CCOC1
Product: CCOC(=O)/C=C1\C(C)Cc2nc(Br)sc2C1(O)c1ccc(Cl)cc1
Temperature: -65 °C

Procedure:
A 3-liter flask equipped with a mechanical stirrer, addition funnel, and nitrogen inlet was charged with (E)-ethyl 2-(2-bromo-5-methyl-7-oxo-4,5-dihydrobenzo[d]thiazol-6(7H)-ylidene)acetate (24.1 g, 73 mmol, 1.0 equiv) and then diluted with THF (800 mL). To the resulting solution was added 0.6M LaCl3.2LiCl (243 mL, 146 mmol, 2.0 equiv) and then the reaction mixture was cooled to −65° C. by the aid of a dry-ice acetone bath. The addition funnel was then charged with 1.0M 4-chlorophenylmagnesium bromide (146 mL, 146 mmol, 2.0 equiv) and then slowly added to the reaction mixture over a 25 minute period. Upon completion of the addition, TLC analysis showed full consumption of the starting material (TLC of the starting material in 20% EtOAc/Hex has Rf=0.50; TLC of the product in 20% EtOAc/Hex has Rf=0.38), and the reaction was quenched with saturated NH4Cl (100 mL) and then diluted with EtOAc (1 L) and H2O (1.5 L). The cooling bath was removed and the mixture was allowed to warm to room temperature with stirring. The layers were separated and the aqueous extract was washed with EtOAc (1 L). The combined organics were dried over Na2SO4, filtered through a small plug of silica gel eluting with EtOAc, and then concentrated in vacuo. The resulting crude residue was chromatographed using a 330 g RediSep normal phase silica gel cartridge (EtOAc/Hex, 5%→15%) on a CombiFlash system to afford desired product. TLC (20% EtOAc/Hex) Rf=0.38; 1H NMR (400 MHz, CDCl3) δ 7.31 (d, J=8.6 Hz, 2H), 7.26 (d, J=8.6 Hz, 2H), 5.62 (s, 1H), 4.57-4.40 (m, 1H), 4.22-4.04 (m, 2H), 3.03 (qd, J=16.6, 3.8 Hz, 2H), 2.61 (br s, 1H), 1.38 (d, J=7.2 Hz, 3H), 1.25 (t, J=7.1 Hz, 3H).
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:6]=[C:7]([CH2:13][C:14]([O:16]C)=O)[CH:8]=[CH:9][C:10]=1[O:11][CH3:12].[Br:18][C:19]1[CH:24]=[CH:23][C:22]([C:25](=[O:27])[CH3:26])=[CH:21][CH:20]=1>CCOCC>[Br:18][C:19]1[CH:24]=[CH:23][C:22]([C:25](=[O:27])[CH2:26][C:14](=[O:16])[CH2:13][C:7]2[CH:8]=[CH:9][C:10]([O:11][CH3:12])=[C:5]([O:4][CH3:3])[CH:6]=2)=[CH:21][CH:20]=1
Reactant: CC(=O)c1ccc(Br)cc1
Reactant: COC(=O)Cc1ccc(OC)c(OC)c1
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Product: COc1ccc(CC(=O)CC(=O)c2ccc(Br)cc2)cc1OC
Yield: 50.1 %

Procedure:
Sodium hydride (60% dispersion, 3.80 g, 95.1 mmol) was added portionwise to methyl 2-(3,4-dimethoxyphenyl)acetate (10 g, 47.6 mmol) in Et2O (100 ml) at 0° C. A solution of 4′-bromoacetophenone (9.48 g, 47.6 mmol) in Et2O (50 ml) was added dropwise over 1 h. The mixture was heated at reflux for 16 h, cooled, poured into ice/HCl (2 M), extracted with Et2O (3×100 ml), dried (MgSO4) and the solvent removed under reduced pressure. The residue was crystallized from MeOH to give the title compound (9 g, 50%) as a tan powder.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[Cl:10][C:11]1[CH:36]=[CH:35][CH:34]=[CH:33][C:12]=1[CH2:13][C:14]1[C:21](=[O:22])[N:17]2[CH2:18][CH2:19][CH2:20][N:16]2[C:15]=1[C:23]1[CH:28]=[CH:27][N:26]=[C:25](S(C)(=O)=O)[N:24]=1>C1COCC1.C([O-])(O)=O.[Na+]>[Cl:10][C:11]1[CH:36]=[CH:35][CH:34]=[CH:33][C:12]=1[CH2:13][C:14]1[C:21](=[O:22])[N:17]2[CH2:18][CH2:19][CH2:20][N:16]2[C:15]=1[C:23]1[CH:28]=[CH:27][N:26]=[C:25]([O:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[N:24]=1
Reactant: Oc1ccccc1
Reactant: CS(=O)(=O)c1nccc(-c2c(Cc3ccccc3Cl)c(=O)n3n2CCC3)n1
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=c1c(Cc2ccccc2Cl)c(-c2ccnc(Oc3ccccc3)n2)n2n1CCC2
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of phenol (0.18 g, 1.00 mmol) in THF (4 mL) is added sodium hydride (0.10 g of a 60% dispersion in mineral oil, 1.60 mmol). After stirring 5 min at room temperature a solution of 2-(2-chloro-benzyl)-3-(2-methanesulfonyl-pyrimidin-4-yl)-6,7-dihydro-5H-pyrazolo[1,2-a]pyrazol-1-one, 8, (0.21 g, 0.50 mmol) in THF (5 mL) is added to the reaction mixture. After stirring 1.5 h at room temperature, the mixture is diluted with aqueous saturated NaHCO3. The aqueous phase is extracted three times with CHCl3 and the combined organic phases are washed with aqueous saturated NaHCO3, dried (MgSO4), filtered and concentrated in vacuo. The crude residue is purified over silica (5% MeOH/CHCl3) to afford 100 mg of the desired product as a yellow solid: 1H NMR (300 MHz, CDCl3) δ 8.63 (d, J=5.4 Hz, 1H), 7.47 (t, J=7.8 Hz, 2H), 7.40 (d, J=5.4 Hz, 1H), 7.29-7.10 (m, 7H), 4.16 (t, J=6.9 Hz, 2H), 4.07 (s, 2H), 3.91 (t, J=6.9 Hz, 2H), 2.61 (dddd, J=6.9, 6.9, 6.9, 6.9 Hz, 2H); ESI+ MS: m/z (rel intensity) 418.9 (100, M++H).
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[N:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]2=[N:6][C:5]=1[C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=1.[CH3:20][N:21]1[C:26](=[O:27])[CH:25]=[CH:24][NH:23][C:22]1=[O:28]>>[Cl:19][C:16]1[CH:17]=[CH:18][C:13]([C:5]2[N:6]=[C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][N:8]3[C:4]=2[CH2:3][N:23]2[CH:24]=[CH:25][C:26](=[O:27])[N:21]([CH3:20])[C:22]2=[O:28])=[CH:14][CH:15]=1
Reactant: ClCc1c(-c2ccc(Cl)cc2)nc2ccccn12
Reactant: Cn1c(=O)cc[nH]c1=O
Agent: Cl
Product: Cn1c(=O)ccn(Cc2c(-c3ccc(Cl)cc3)nc3ccccn23)c1=O

Procedure:
The title compound was prepared according to Method B and the experimentals described for compound 92 from 3-(chloromethyl)-2-(4-chlorophenyl)imidazo[1,2-a]pyridine hydrochloride and 3-methylpyrimidine-2,4(1H,3H)-dione. M/e+ 367 for C19H16ClN4O2 (M+H)+; 1H-NMR (400 MHz, CDCl3) δ 8.22 (d, J=5.8 Hz, 1H), 7.66 (d, J=8.4 Hz, 2H), 7.45 (d, J=8.4 Hz, 2H), 7.30 (m, 1H), 6.91 (t, J=6.6 Hz, 1H), 6.63 (d, J=8.0 Hz, 1H), 5.56 (d, J=8.0 Hz, 1H), 5.45 (s, 2H), 5.26 (d, J=0.7 Hz, 1H), 3.34 (s, 3H) ppm.