Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:39])([F:38])[C:3]1[CH:4]=[C:5]([C:13]2[S:14][C:15]([C:24]3[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[C:26]([C:34]([F:37])([F:36])[F:35])[CH:25]=3)=[C:16]([N+:21]([O-])=O)[C:17]=2[N+:18]([O-])=O)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.BrC1SC(Br)=C([N+]([O-])=O)C=1[N+]([O-])=O.FC(F)(F)C1C=C([Sn](CCCC)(CCCC)CCCC)C=C(C(F)(F)F)C=1.O.O.[Sn](Cl)Cl>C(O)C>[F:12][C:9]([F:10])([F:11])[C:7]1[CH:6]=[C:5]([C:13]2[S:14][C:15]([C:24]3[CH:29]=[C:28]([C:30]([F:31])([F:32])[F:33])[CH:27]=[C:26]([C:34]([F:37])([F:36])[F:35])[CH:25]=3)=[C:16]([NH2:21])[C:17]=2[NH2:18])[CH:4]=[C:3]([C:2]([F:39])([F:38])[F:1])[CH:8]=1
Reactant: O=[N+]([O-])c1c(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)sc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1[N+](=O)[O-]
Agent: CCCC[Sn](CCCC)(CCCC)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: Cl[Sn]Cl
Agent: O=[N+]([O-])c1c(Br)sc(Br)c1[N+](=O)[O-]
Solvent: CCO
Solvent: O
Product: Nc1c(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)sc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1N

Procedure:
2,5-Bis-(3,5-bis-trifluoromethyl-phenyl)-3,4-dinitro-thiophene was made by Stille coupling reaction of 2,5-dibromo-3,4-dinitro-thiophene and 3,5-bis-trifluoromethyl-phenyl-tributyl-stannane. It was reduced with tin (II) chloride dihydrate in ethanol to give 2,5-bis-(3,5-bis-trifluoromethyl-phenyl)-thiophene-3,4-diamine. The diamine was reacted with hexaketocyclohexane octahydrate to give compound A. The product is a red-brown solid. It is soluble in common organic solvents such as dichloromethane and THF. It was purified by flash chromatography on silica gel and crystallization in ethanol. The purified product had elemental analysis data consistent with the formula for the desired compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[CH:4][C:3]=1[C@H:17]([NH:19][C:20]([C:22]1([NH:25][C:26](=[O:31])[C:27]([F:30])([F:29])[F:28])[CH2:24][CH2:23]1)=[O:21])[CH3:18].Br[C:33]1[C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH:36]=[CH:35][C:34]=1[O:43][CH3:44].C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.CCOC(C)=O.[Pd].C(P(C(C)(C)C)C(C)(C)C)(C)(C)C.C(P(C(C)(C)C)C(C)(C)C)(C)(C)C>[F:1][C:2]1[CH:7]=[C:6]([C:33]2[C:42]3[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=3)[CH:36]=[CH:35][C:34]=2[O:43][CH3:44])[CH:5]=[CH:4][C:3]=1[C@H:17]([NH:19][C:20]([C:22]1([NH:25][C:26](=[O:31])[C:27]([F:30])([F:28])[F:29])[CH2:23][CH2:24]1)=[O:21])[CH3:18]
Reactant: COc1ccc2ccccc2c1Br
Reactant: C[C@@H](NC(=O)C1(NC(=O)C(F)(F)F)CC1)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1F
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: COc1ccc2ccccc2c1-c1ccc([C@@H](C)NC(=O)C2(NC(=O)C(F)(F)F)CC2)c(F)c1
Temperature: 25 °C

Procedure:
N-{(1R)-1-[2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]ethyl}-1-[(trifluoroacetyl)amino]cyclopropanecarboxamide, (1 g, 2.25 mmol), 1-bromo-2-methoxynaphthalene (534 mg (2.25 mmol), cesium carbonate (1.47 g 4.5 mmol), and bis(tri-t-butylphosphine) palladium (0) (6 mg 0.1 mmol) were stirred in anhydrous dioxane (4 mL) at 90 C overnight in a sealed tube. The reaction was cooled to room temperature and diluted with EtOAc, washed once each with water and brine. The organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 0% to 50% EtOAc/hex. To afford N-{(1R)-1-[2-fluoro-4-(2-methoxy-1-naphthyl)phenyl]ethyl}-1-[(trifluoroacetyl)amino]cyclopropanecarboxamide LC/MS (ES MS, M+H+ found: 475) and proton NMR (400 MHz, CDCl3) δ 1.2 (m, J=2.4 Hz, 2H), 1.58 (d, J=6.8 Hz, 3H), 1.7 (m, J=2.9 Hz, 2H), 3.86 (s, 3H), 5.33 (q, J=7.2 Hz, 1H), 6.64 (d, J=8.8 Hz, 1H), 6.84 (s, 1H), 7.08 to 7.19 (m, 3H), 7.34 (m, 3H), 7.47 (m, J=4.5 Hz, 1H), 7.81 (m, J=5 Hz, 1H), 7.9 (d, J=9 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9](Cl)=[O:10])=[CH:4][CH:3]=1.[CH2:12]([O:14][C:15]([C:17]1[NH:18][CH:19]=[CH:20][C:21]=1[CH3:22])=[O:16])[CH3:13].[Al+3].[Cl-].[Cl-].[Cl-]>ClCCl.ClCCCl>[CH2:12]([O:14][C:15]([C:17]1[NH:18][CH:19]=[C:20]([C:9](=[O:10])[CH2:8][C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[C:21]=1[CH3:22])=[O:16])[CH3:13]
Reactant: CCOC(=O)c1[nH]ccc1C
Reactant: O=C(Cl)Cc1ccc(Cl)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Solvent: ClCCl
Product: CCOC(=O)c1[nH]cc(C(=O)Cc2ccc(Cl)cc2)c1C
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of (4-chlorophenyl)-acetyl chloride (3 mmol) in dichloromethane or 1,2-dichloroethane (4 ml) was added to a solution cooled at −40° C. of 84 (0.229 g, 1.5 mmol) and AlCl3 was added (0.400 g, 3 mmol). The reaction mixture was stirred for 30 minutes at the same temperature. The reaction mixture was poured into ice-water and extracted with ethyl acetate. The organic layer was washed with NaOH (2 M) and brine, dried over Na2SO4, and evaporated to dryness under vacuum to give crude product 85. Crude yield: 96%
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=O.C(O)(=O)[CH2:14][C:15]([OH:17])=[O:16]>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]=[C:6]([OH:11])[CH:5]=[C:14]2[C:15]([OH:17])=[O:16]
Reactant: O=C(O)CC(=O)O
Reactant: O=C1Nc2ccc(Br)cc2C1=O
Solvent: C1CCOC1
Product: O=C(O)c1cc(O)nc2ccc(Br)cc12
Reaction time: 12 h

Procedure:
5-bromoindoline-2,3-dione (0.250 g) was dissolved in THF (3 ml) in a round-bottomed flask and malonic acid (2 eq) was added. The vessel was connected to a reflux condenser and heated to reflux overnight by conventional heating. After 12 hours, solid precipitate was observed. Suspension was concentrated under reduced pressure to remove solvent, water was added, and the suspension was refluxed for 4 hours. The suspension was then filtered to provide 6-bromo-2-hydroxyquinoline-4-carboxylic acid (0.150 g) as a solid.
Reaction SMILES: CS(O)(=O)=O.[CH:6]([O:19][C:20]([C:22]1[N:23]2[CH:26]([S:27][CH2:28][C:29]=1[C:30]1[S:34][C:33]([NH:35][CH2:36][CH2:37][N:38]([CH3:40])[CH3:39])=[N:32][CH:31]=1)[CH:25]([NH:41]C(OC(C)(C)C)=O)[C:24]2=[O:49])=[O:21])([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(=O)(O)[O-].[Na+].C(OCC)(=O)C>C(#N)C>[NH2:41][CH:25]1[C:24](=[O:49])[N:23]2[CH:26]1[S:27][CH2:28][C:29]([C:30]1[S:34][C:33]([NH:35][CH2:36][CH2:37][N:38]([CH3:40])[CH3:39])=[N:32][CH:31]=1)=[C:22]2[C:20]([O:19][CH:6]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1)=[O:21]
Reactant: CN(C)CCNc1ncc(C2=C(C(=O)OC(c3ccccc3)c3ccccc3)N3C(=O)C(NC(=O)OC(C)(C)C)C3SC2)s1
Agent: CS(=O)(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CN(C)CCNc1ncc(C2=C(C(=O)OC(c3ccccc3)c3ccccc3)N3C(=O)C(N)C3SC2)s1
Temperature: 23 °C
Reaction time: 0.08 h
Yield: 98.9 %

Procedure:
Methanesulphonic acid (0.3 cc) is added to a suspension of 2-benzhydryloxycarbonyl-7-t-butoxycarbonylamino-3-[2-(2-dimethylamino-ethylamino)-thiazol-5-yl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene (0.3 g) in acetonitrile (3 cc). The yellow solution obtained is stirred at 23° C. for 5 minutes and is poured onto a mixture of a saturated sodium bicarbonate solution (50 cc) and ethyl acetate (50 cc). The organic phase is dried over anhydrous magnesium sulphate, filtered and concentrated under reduced pressure (20 mm Hg; 2.7 kPa). 7-Amino-2-benzhydryloxycarbonyl-3-[2-(2-dimethylamino-ethylamino)-thiazol-5-yl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene (0.25 g) is thus obtained in the form of a yellow froth.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=2)(O)[CH3:10])[CH:6]=[CH:7][CH:8]=1.II>C(O)(=O)C.O>[CH3:19][O:18][C:14]1[CH:13]=[C:12]([C:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=2)=[CH2:10])[CH:17]=[CH:16][CH:15]=1
Reactant: COc1cccc(C(C)(O)c2cccc(OC)c2)c1
Agent: II
Solvent: O
Solvent: CC(=O)O
Product: C=C(c1cccc(OC)c1)c1cccc(OC)c1
Yield: 96.3 %

Procedure:
5.28 g (20 mmoles) of 1,1-bis(3-methoxyphenyl)ethanol are dissolved in 30 mL of glacial acetic acid. A catalytical amount of iodine is added and the solution refluxed for about 5-15 minutes or until the dehydration is complete. The progress of the reaction is monitored by TLC on silica (5% EtOAc in hexanes). The burgundy red solution is diluted with water (100 mL) and the product extracted with ether (2-3 extractions with 10 mL portions). The combined ethereal extracts are washed consecutively with water (into which a spatula tip of sodium metabisulfite was added) and 10% sodium carbonate, dried over anh. K2CO3 and evaporated to yield 4.63 g (96%) of the title compound. 1H NMR (CDCl3): 6.8-7.3 (m, ArH, 8H), 5.45(s, C═CH2, 2H), 3.75 (s, OCH3, 6H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:11]#[N:12])=[N:4][C:5]([CH2:9]O)=[C:6]([Cl:8])[N:7]=1.N1C=CC=CC=1.S(Cl)([Cl:21])=O.[K+].[Br-]>C(Cl)(Cl)Cl>[NH2:1][C:2]1[C:3]([C:11]#[N:12])=[N:4][C:5]([CH2:9][Cl:21])=[C:6]([Cl:8])[N:7]=1
Reactant: N#Cc1nc(CO)c(Cl)nc1N
Reactant: O=S(Cl)Cl
Agent: [Br-]
Agent: [K+]
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: N#Cc1nc(CCl)c(Cl)nc1N

Procedure:
Compound 2 (3.7 g, 0.02 mole) was suspended in 40 ml of chloroform. To this mixture, 1.8 ml of pyridine and 3.0 ml of thionyl chloride were added slowly while stirring. At the end of this addition, the mixture was stirred for four additional hours at room temperature. The solvent was then removed, and the residue was triturated with 100 ml of cold water. After filtration and washing with cold water, the product (4) was dried in air, yielding 4.0 g (91%) of light yellow solid. The melting point of this solid ranged from 173°-174° C. The IR spectrum (KBr) showed absorptions corresponding to --NH2 at 3201 and 3365.8 cm-1, --C≡N at 2237.6, and --C=N-- at 1648.7 cm-1. The nmr spectrum (DMSO-d6) revealed signals at 7.76 δ (2H, s,NH2) and 4.60 (2H,s,CH2C1).
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[F:5][C:6]1[CH:19]=[CH:18][CH:17]=[CH:16][C:7]=1[CH2:8][C:9]1[CH:10]=[CH:11][C:12](=[O:15])[NH:13][N:14]=1.[Cl:20][C:21]1[CH:29]=[C:28]([Cl:30])[CH:27]=[C:26]([Cl:31])[C:22]=1[C:23](Cl)=[O:24].C(Cl)(=O)C(Cl)=O.C(Cl)Cl>C(Cl)Cl.CN(C=O)C>[Cl:20][C:21]1[CH:29]=[C:28]([Cl:30])[CH:27]=[C:26]([Cl:31])[C:22]=1[C:23]([C:17]1[CH:16]=[C:7]([C:6]([F:5])=[CH:19][CH:18]=1)[CH2:8][C:9]1[CH:10]=[CH:11][C:12](=[O:15])[NH:13][N:14]=1)=[O:24]
Reactant: O=c1ccc(Cc2ccccc2F)n[nH]1
Reactant: O=C(Cl)c1c(Cl)cc(Cl)cc1Cl
Agent: O=C(Cl)C(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(c1ccc(F)c(Cc2ccc(=O)[nH]n2)c1)c1c(Cl)cc(Cl)cc1Cl
Reaction time: 8 h

Procedure:
AlCl3 (1.75 g, 13.1 mmol) was added to a solution of 6-(2-fluorobenzyl)-2H-pyridazin-3-one (0.9 g, 4.4 mmol) [prepared as described above] in methylene chloride (20 ml) at ambient temperature and under a nitrogen atmosphere. 2,4,6-trichlorobenzoyl chloride [(1.98 g, 8.78 mmol) prepared from the corresponding acid by treatment with oxalyl chloride/ methylene chloride with a trace of DMF] was added to the slurry. After stirring overnight, the reaction was quenched with ice. The product was extracted into ethyl acetate, and dried over MgSO4. The solvent was removed in vacuo and the crude product was chromatographed on a silica gel column (ether) to give impure 6-[3-(2,4,6-trichlorobenzoyl)-6-fluorobenzyl)-2H-pyridazin-3-one (0.43 g). Recrystallization from acetone/hexanes mixture gave pure 6-[3-(2,4,6-trichlorobenzoyl)-6-fluorobenzyl)-2H-pyridazin-3-one (0.34 g, 18% yield) as a solid, mp 185.0°-185.3° C.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[N+:8]([C:11]1[CH:12]=[C:13]([C:23]2[CH:24]([CH3:30])[CH2:25][C:26](=[O:29])[NH:27][N:28]=2)[CH:14]=[CH:15][C:16]=1[N:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1)([O-:10])=[O:9]>C(O)(=O)C>[C:1]([N:20]1[CH2:21][CH2:22][N:17]([C:16]2[CH:15]=[CH:14][C:13]([C:23]3[CH:24]([CH3:30])[CH2:25][C:26](=[O:29])[NH:27][N:28]=3)=[CH:12][C:11]=2[N+:8]([O-:10])=[O:9])[CH2:18][CH2:19]1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: CC1CC(=O)NN=C1c1ccc(N2CCNCC2)c([N+](=O)[O-])c1
Solvent: CC(=O)O
Product: CC(=O)N1CCN(c2ccc(C3=NNC(=O)CC3C)cc2[N+](=O)[O-])CC1

Procedure:
0.57 ml (6 mmol) of acetic acid anhydride are added at room temperature to 1.27 g (4 mmol) of 6-[3-nitro-4-(1-piperazinyl)-phenyl]-4,5-dihydro-5-methyl-3(2H)-pyridazinone in 30 ml of acetic acid.
Reaction SMILES: [CH2:1]([N:4]([CH2:14][CH2:15][CH3:16])[C:5]1[N:10]2[CH:11]=[CH:12][N:13]=[C:9]2[CH:8]=[CH:7][CH:6]=1)[CH2:2][CH3:3].[Br:17]NC(=O)CCC(N)=O>CN(C=O)C>[Br:17][C:12]1[N:13]=[C:9]2[CH:8]=[CH:7][CH:6]=[C:5]([N:4]([CH2:1][CH2:2][CH3:3])[CH2:14][CH2:15][CH3:16])[N:10]2[CH:11]=1
Reactant: NC(=O)CCC(=O)NBr
Reactant: CCCN(CCC)c1cccc2nccn12
Solvent: CN(C)C=O
Product: CCCN(CCC)c1cccc2nc(Br)cn12
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 49 %

Procedure:
N,N-Dipropylimidazo[1,2-a]pyridin-5-amine (1.0 g, 4.6 mmol) was diluted in DMF (25 mL). The solution was cooled to 0° C. N-bromosuccinamide (0.83 g, 4.7 mmol) was added. After 5 minutes, the reaction was quenched with water. The solution was extracted with ether, dried, and concentrated. Flash chromatography (40% EtOAc/hexanes) gave the title compound as a yellow oil which solidified upon overnight freezing at −20° C. 0.67 g obtained (49% yield).
Reaction SMILES: [C:1]([CH2:3][C:4]([NH:6][N:7]1[CH:11]=[CH:10][N:9]=[C:8]1[C:12]([O:14]CC)=O)=[O:5])#[N:2].C(N1CCCC(NC2C=C(N(CC3C=CC(OC)=CC=3)C3C=CC=CC=3)C3N(C(C#N)=CN=3)N=2)C1)C1C=CC=CC=1.CC(C)([O-])C.[K+].Cl>C1COCC1.O1CCOCC1>[O:5]=[C:4]1[NH:6][N:7]2[CH:11]=[CH:10][N:9]=[C:8]2[C:12](=[O:14])[CH:3]1[C:1]#[N:2]
Reactant: CCOC(=O)c1nccn1NC(=O)CC#N
Agent: CC(C)(C)[O-]
Agent: COc1ccc(CN(c2ccccc2)c2cc(NC3CCCN(Cc4ccccc4)C3)nn3c(C#N)cnc23)cc1
Agent: Cl
Solvent: C1CCOC1
Solvent: C1COCCO1
Product: N#CC1C(=O)Nn2ccnc2C1=O
Temperature: 0 °C
Reaction time: 16 h

Procedure:
In a 40 ml reaction vial was added ethyl 1-(2-cyanoacetamido)-1H-imidazole-2-carboxylate (3.00 g, 13.50 mmol) prepared as described in (1b) and THF (2 ml). The mixture was cooled to 0° C. and potassium tert-butoxide (40.5 ml, 40.5 mmol) was added dropwise. The mixture was stirred at room temperature for 16 hours. 4.0 M HCl (10.13 ml, 40.5 mmol) in dioxane was added and the mixture was stirred for 30 min. The volatiles were evaporated to provide 6,8-dioxo-5,6,7,8-tetrahydroimidazo[1,2-b]pyridazine-7-carbonitrile which was used without purification in the following step. m/z=(177, M+1).
Reaction SMILES: C([O:4][CH2:5][CH:6]([C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[C:10]([C:15](=[O:17])[CH3:16])[CH:9]=1)[CH3:7])(=O)C.C(=O)(O)[O-].[Na+]>C(O)C.O>[C:15]([C:10]1[CH:9]=[C:8]([CH:6]([CH3:7])[CH2:5][OH:4])[CH:13]=[CH:12][C:11]=1[OH:14])(=[O:17])[CH3:16]
Reactant: CC(=O)OCC(C)c1ccc(O)c(C(C)=O)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CC(=O)c1cc(C(C)CO)ccc1O
Yield: 72 %

Procedure:
2-(3-Acetyl-4-hydroxyphenyl)propyl acetate (20.0g; 0.0847 mol) and sodium bicarbonate (25.4g; 0.31 mol) were dissolved in ethanol (200 ml) and water (150 ml), and the mixture was refluxed for 20 hours. Ethanol was removed in vacuo and the residue was extracted with ether (3 × 150 ml). The combined ether extracts were washed with water, saturated sodium bicarbonate solution, brine, and then dried over magnesium sulphate. The product, after removing solvent, was chromatographed on silica gel using ether as eluent to give a pale brown oil (15.0g; 72% yield).
Reaction SMILES: [CH:1]1[C:14]2[CH:13]([C:15]([O:17][CH3:18])=[O:16])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[O:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH3:19]I>O1CCCC1.O>[CH3:19][C:13]1([C:15]([O:17][CH3:18])=[O:16])[C:14]2[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=2[O:6][C:7]2[C:12]1=[CH:11][CH:10]=[CH:9][CH:8]=2
Reactant: COC(=O)C1c2ccccc2Oc2ccccc21
Reactant: CI
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)C1(C)c2ccccc2Oc2ccccc21
Reaction time: 0.17 h

Procedure:
9.61 g (0.04 mol) of methyl 9-xanthenecarboxylate (obtainable according to step 1.1.a) are dissolved in 150 mL of tetrahydrofuran, combined with a solution of 5.0 g (0.042 mol) potassium lert-butoxide in THF, and stirred for 10 minutes. 5 mL (0.08 mol) of methyl iodide are then added dropwise with gentle cooling; after all has been added, the mixture is stirred for 1 hour at ambient temperature. The reaction mixture is diluted with water to a total volume of 800 mL, extracted with diethyl ether, and the organic phase is extracted with saturated, aqueous Na2CO3 solution, washed with water, dried over magnesium sulfate, and the solvent is distilled off. The product is purified by recrystallization from methanol. Yield: 6.05 g of white crystals (70% of theoretical yield); melting point: 91° C.-92° C.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([N+:8]([O-:10])=[O:9])=[N:6][CH:7]=1.[CH3:11][C@H:12]1[CH2:17][NH:16][CH2:15][CH2:14][N:13]1[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19]>>[CH3:11][C@H:12]1[CH2:17][N:16]([C:2]2[CH:7]=[N:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=2)[CH2:15][CH2:14][N:13]1[C:18]([O:20][C:21]([CH3:22])([CH3:24])[CH3:23])=[O:19]
Reactant: C[C@H]1CNCCN1C(=O)OC(C)(C)C
Reactant: O=[N+]([O-])c1ccc(Br)cn1
Product: C[C@H]1CN(c2ccc([N+](=O)[O-])nc2)CCN1C(=O)OC(C)(C)C
Yield: 63 %

Procedure:
Following the procedures as described for compound 108a, reaction of 5-bromo-2-nitropyridine (1.5 g) and (S)-tert-butyl 2-methylpiperazine-1-carboxylate (2.3 g), gave 107a as a yellow solid (1.5 g, 40%). MS: [M+H]+ 323. See FIG. 7.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:8]([CH2:9][CH3:10])=[N:7][C:6]2[N:11]([CH2:14][CH3:15])[N:12]=[CH:13][C:5]=2[C:4]=1[NH:16][CH:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1.[Cl:23][C:24]1[CH:32]=[C:31]([F:33])[C:30]([S:34](Cl)(=[O:36])=[O:35])=[CH:29][C:25]=1[C:26]([OH:28])=[O:27].CCN(CC)CC>C(Cl)Cl>[Cl:23][C:24]1[CH:32]=[C:31]([F:33])[C:30]([S:34]([NH:1][CH2:2][C:3]2[C:4]([NH:16][CH:17]3[CH2:18][CH2:19][O:20][CH2:21][CH2:22]3)=[C:5]3[CH:13]=[N:12][N:11]([CH2:14][CH3:15])[C:6]3=[N:7][C:8]=2[CH2:9][CH3:10])(=[O:36])=[O:35])=[CH:29][C:25]=1[C:26]([OH:28])=[O:27]
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CN
Reactant: O=C(O)c1cc(S(=O)(=O)Cl)c(F)cc1Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNS(=O)(=O)c1cc(C(=O)O)c(Cl)cc1F

Procedure:
345(a) 5-(Aminomethyl)-1,6-diethyl-N-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-b]pyridin-4-amine (30.0 mg, 0.1 mmol) and 2-chloro-5-(chlorosulfonyl)-4-fluorobenzoic acid (0.1 mmol) was dissolved in DCM (3 mL), followed by the addition of Et3N (10 mg, 0.1 mmol). The resultant solution was stirred overnight. The solution was then purified using a Gilson to give 2-chloro-5-[({[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}amino)sulfonyl]-4-fluorobenzoic acid.
Reaction SMILES: [C:1]1([CH:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:8]=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Br.[CH2:19]([O:21][C:22](=[O:32])[C@@H:23]1[CH2:28][CH2:27][CH2:26][N:25]([CH2:29][CH2:30]Br)[CH2:24]1)[CH3:20]>C1(C)C=CC=CC=1>[CH2:19]([O:21][C:22]([C@@H:23]1[CH2:28][CH2:27][CH2:26][N:25]([CH2:29][CH2:30][O:9][CH:8]=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:24]1)=[O:32])[CH3:20]
Reactant: CCOC(=O)[C@@H]1CCCN(CCBr)C1
Reactant: O=CC(c1ccccc1)c1ccccc1
Agent: Br
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCOC(=O)[C@@H]1CCCN(CCOC=C(c2ccccc2)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 69.6 %

Procedure:
Diphenylacetaldehyde (4.9 g, 0.025 mole) was added dropwise to a mixture of sodium hydride (1.5 g, 0.05 mole, 80% oil dispersion) and dry toluene (25 ml) at 0° C. This mixture was stirred at room temperature for 0.5 h, heated to 50° C. and allowed to cool to room temperature. The above (R)-1-(2-bromoethyl)nipecotic acid ethyl ester hydrobromide (8.6 g, 0.025 mole) was added portionwise whilst the temperature was kept below 30° C. with an ice-water bath. After being stirred for 1 h the reaction mixture was filtered, and the filtrate was evaporated to dryness. Flash chromatography of the residue on silica gel (200 g) using a mixture of heptane and tetrahydrofuran (4/1) as eluent provided the title compound (6.6 g, 69%) as an oil. Tlc: rf 0.24 (SiO2 ; heptane/THF 7/3).
Reaction SMILES: [C:1](Cl)(Cl)=[S:2].[CH3:5][N:6]([CH3:15])[C:7]1[CH:12]=[CH:11][C:10]([NH2:13])=[C:9]([CH3:14])[N:8]=1>O1CCCC1.C(=O)([O-])O.[Na+]>[N:13]([C:10]1[CH:11]=[CH:12][C:7]([N:6]([CH3:5])[CH3:15])=[N:8][C:9]=1[CH3:14])=[C:1]=[S:2]
Reactant: Cc1nc(N(C)C)ccc1N
Reactant: S=C(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1nc(N(C)C)ccc1N=C=S
Temperature: 0 °C
Reaction time: 2 h
Yield: 43.2 %

Procedure:
Thiophosgene (1.3 mL, 16.7 mmol) was added dropwise to a stirred mixture of N2,N2,6-trimethylpyridine-2,5-diamine (2.30 g, 15.2 mmol) in tetrahydrofuran (20 mL) and saturated aqueous sodium hydrogen carbonate (20 mL) at 0° C., and the mixture was stirred at 0° C. for 2 hr. The mixture was diluted with saturated aqueous sodium hydrogen carbonate, and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was washed with diisopropyl ether to give the title compound as a pale yellow powder (1.27 g, 6.57 mmol, 43%).
Reaction SMILES: [CH2:1]([N:8]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH2:9][CH2:10][C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[NH:13][CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].[S:29](Cl)([C:32]1[CH:38]=[CH:37][C:35]([CH3:36])=[CH:34][CH:33]=1)(=[O:31])=[O:30]>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.C1C=CC=CC=1>[S:29]([N:13]1[C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:11]([CH2:10][CH2:9][N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:12]1)([C:32]1[CH:38]=[CH:37][C:35]([CH3:36])=[CH:34][CH:33]=1)(=[O:31])=[O:30]
Reactant: c1ccc(CN(CCc2c[nH]c3ccccc23)Cc2ccccc2)cc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: c1ccccc1
Product: Cc1ccc(S(=O)(=O)n2cc(CCN(Cc3ccccc3)Cc3ccccc3)c3ccccc32)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 74.1 %

Procedure:
N,N-dibenzyl-tryptamine (1.70 g) and tetra-n-butyl ammonium hydrogensulfate (0.17 g) in benzene (5 ml) were added to 50% aqueous NaOH solution (5 ml) and tosyl chloride (1.43 g) and the mixture was stirred at room temperature for 2 hrs. The organic layer was separated, washed with water and then brine and dried over magnesium sulfate. The solvent was evaporated off. Crystallization from acetone/hexane afforded 1.83 g of the title compound.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][CH2:9][C:10]1[O:14][N:13]=[C:12]([C:15]([OH:17])=O)[CH:11]=1.[NH2:18][C@@H:19]([CH3:35])[CH2:20][N:21]1[CH:25]=[CH:24][C:23]([C:26]2[CH:33]=[CH:32][C:29]([C:30]#[N:31])=[C:28]([Cl:34])[CH:27]=2)=[N:22]1>>[Cl:34][C:28]1[CH:27]=[C:26]([C:23]2[CH:24]=[CH:25][N:21]([CH2:20][C@@H:19]([NH:18][C:15]([C:12]3[CH:11]=[C:10]([CH2:9][CH2:8][O:7][CH:2]4[CH2:3][CH2:4][CH2:5][CH2:6][O:1]4)[O:14][N:13]=3)=[O:17])[CH3:35])[N:22]=2)[CH:33]=[CH:32][C:29]=1[C:30]#[N:31]
Reactant: O=C(O)c1cc(CCOC2CCCCO2)on1
Reactant: C[C@H](N)Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1
Product: C[C@@H](Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1)NC(=O)c1cc(CCOC2CCCCO2)on1

Procedure:
The title compound was prepared using the method of Example 34(d) starting from 5-(2-(tetrahydro-2H-pyran-2-yloxy)ethyl)isoxazole-3-carboxylic acid (0.222 g, 0.921 mmol) and (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (0.2 g, 0.767 mmol). The product was purified with reverse phase flash-chromatography. 1H-NMR (400 MHz; DMSO-d6): δ 1.16 (d, 3H), 1.34-1.51 (m, 4H), 1.52-1.69 (m, 2H), 3.06 (t, 2H), 3.37-3.45 (m, 1H), 3.61-3.71 (m, 2H), 3.85-3.93 (m, 1H), 4.28-4.34 (m, 2H), 4.41-4.50 (m, 1H), 4.57-4.61 (m, 1H), 6.51 (d, 1H), 6.93 (d, 1H), 7.81 (d, 1H), 7.92 (dd, 1H), 7.97 (dd, 1H), 8.08 (dd, 1H), 8.74 (d, 1H).