Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:13]=[CH:12][C:5]([C:6]([N:8]([O:10][CH3:11])[CH3:9])=[O:7])=[CH:4][CH:3]=1.[Cl:14][C:15]1[C:20](Cl)=[N:19][CH:18]=[CH:17][N:16]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Cl:14][C:15]1[C:20]([O:1][C:2]2[CH:13]=[CH:12][C:5]([C:6]([N:8]([O:10][CH3:11])[CH3:9])=[O:7])=[CH:4][CH:3]=2)=[N:19][CH:18]=[CH:17][N:16]=1
Reactant: CON(C)C(=O)c1ccc(O)cc1
Reactant: Clc1nccnc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CON(C)C(=O)c1ccc(Oc2nccnc2Cl)cc1

Procedure:
A mixture of 4-hydroxy-N-methoxy-N-methylbenzamide (6.50 g, 35.9 mmol), 2,3-dichloropyrazine (6.95 g, 46.6 mmol), and potassium carbonate (12.40 g, 90 mmol) in acetonitrile (70 mL) was heated at reflux in 18 h. The reaction mixture was cooled, concentrated, taken up in H2O, extracted with EtOAc, dried over MgSO4, concentrated and purified by ISCO (50% EtOAc/Hexanes) to give the titled compound. MS [M+1]: 294.1.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)=[N:4][N:5]([CH3:11])[C:6]=1[O:7][CH:8]([F:10])[F:9].[Cl:19][S:20](O)(=[O:22])=[O:21]>>[Cl:1][C:2]1[C:3]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([S:20]([Cl:19])(=[O:22])=[O:21])[CH:13]=2)=[N:4][N:5]([CH3:11])[C:6]=1[O:7][CH:8]([F:9])[F:10]
Reactant: Cn1nc(-c2ccc(Cl)cc2)c(Cl)c1OC(F)F
Reactant: O=S(=O)(O)Cl
Product: Cn1nc(-c2ccc(Cl)c(S(=O)(=O)Cl)c2)c(Cl)c1OC(F)F
Temperature: 130 °C
Reaction time: 4 h

Procedure:
47.9 g (0.16 mol) of 4-chloro-3-(4-chlorophenyl)-5-difluoromethoxy-1-methyl-1H-pyrazole were added a little at a time at 0° C. to 91 ml of chlorosulfonic acid. The mixture was stirred at 130° C. for 4 hours and then cooled, and the solution was poured carefully into ice-water. Product dissolved in the aqueous phase was extracted twice with dichloromethane. The combined organic phases were subsequently washed with saturated sodium hydrogen carbonate solution and with sodium chloride solution, then dried over magnesium sulfate and finally concentrated. Yield: 47.9 g.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH3:10])[C:5]([NH:8][NH2:9])=[N:6][CH:7]=1.[CH3:11][N:12]1[CH2:16][CH2:15][CH2:14][C@H:13]1[C:17](O)=[O:18].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([CH3:10])[C:5]([NH:8][NH:9][C:17]([C@@H:13]2[CH2:14][CH2:15][CH2:16][N:12]2[CH3:11])=[O:18])=[N:6][CH:7]=1
Reactant: CN1CCC[C@H]1C(=O)O
Reactant: Cc1cc(F)cnc1NN
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: ClCCCl
Product: Cc1cc(F)cnc1NNC(=O)[C@@H]1CCCN1C
Temperature: 25 °C
Reaction time: 18 h
Yield: 56.1 %

Procedure:
A solution of Intermediate 105b (76 mg, 0.537 mmol), (S)-1-methyl-pyrrolidine-2-carboxylic acid (55 mg, 0.72 mmol) and HOBT (8 mg, 0.72 mmol) in anhydrous DCM (5 mL) was treated with EDC (138 mg, 0.717 mmol) and stirred at RT under a nitrogen atmosphere for 18 h. The reaction mixture was diluted with DCM and washed with brine. The organic layer was dried (MgSO4) and concentrated in vacuo. The resultant residue was purified by FCC on silica, using a gradient of 1-10% MeOH in DCM, to afford the title compound (76 mg, 56%). 1H NMR (400 MHz, CDCl3): 1.74-2.05 (3H, m), 2.15-2.33 (4H, m), 2.34-2.46 (1H, m), 2.52 (3H, s), 3.02-3.12 (1H, m), 3.15-3.25 (1H, m), 6.70 (1H, s), 7.08-7.18 (1H, m), 7.90 (1H, d, J=2.8 Hz), 9.52 (1H, br s).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([NH2:10])=[O:9])=[C:6]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][OH:20])=[CH:13][CH:12]=2)[C:5]([C:21]#[N:22])=[C:4]([S:23][CH2:24][C:25]2[N:26]=[C:27]([C:30]3[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=3)[S:28][CH:29]=2)[N:3]=1.O.[C:38]1(C)[CH:43]=CC(S(O)(=O)=O)=C[CH:39]=1>CC(C)=O>[Cl:36][C:33]1[CH:32]=[CH:31][C:30]([C:27]2[S:28][CH:29]=[C:25]([CH2:24][S:23][C:4]3[C:5]([C:21]#[N:22])=[C:6]([C:11]4[CH:12]=[CH:13][C:14]([O:17][CH2:18][CH2:19][OH:20])=[CH:15][CH:16]=4)[C:7]4[C:8](=[O:9])[NH:10][C:38]([CH3:43])([CH3:39])[NH:1][C:2]=4[N:3]=3)[N:26]=2)=[CH:35][CH:34]=1
Reactant: N#Cc1c(SCc2csc(-c3ccc(Cl)cc3)n2)nc(N)c(C(N)=O)c1-c1ccc(OCCO)cc1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CC(C)=O
Product: CC1(C)NC(=O)c2c(nc(SCc3csc(-c4ccc(Cl)cc4)n3)c(C#N)c2-c2ccc(OCCO)cc2)N1

Procedure:
50 mg (0.093 mmol) of the compound from Example 22A were initially charged in 2 ml of acetone, a spatula tip of 4-toluenesulfonic acid monohydrate was added and the mixture was stirred at reflux for 1 h. After cooling, the reaction solution was concentrated and the residue was purified directly by preparative HPLC (Chromasil, water/acetonitrile+0.1% TFA).
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:21])[N:9](C(C)(C3C=CC=CC=3)C)[CH:10](O)[C:6]=2[CH:5]=[C:4]([CH3:22])[N:3]=1.FC(F)(F)C(O)=O.C([SiH](CC)CC)C>[N+](C)([O-])=O>[Cl:1][C:2]1[C:7]2[C:8](=[O:21])[NH:9][CH2:10][C:6]=2[CH:5]=[C:4]([CH3:22])[N:3]=1
Reactant: Cc1cc2c(c(Cl)n1)C(=O)N(C(C)(C)c1ccccc1)C2O
Agent: CC[SiH](CC)CC
Solvent: C[N+](=O)[O-]
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc2c(c(Cl)n1)C(=O)NC2
Yield: 63.5 %

Procedure:
In a similar manner to Step 4 of Example 16, 4-chloro-1-hydroxy-6-methyl-2-(1-methyl-1-phenylethyl)-1,2-dihydropyrrolo[3,4-c]pyridine-3-one (70.0 mg, 0.220 mmol) was dissolved in nitromethane (3.5 mL), and the solution was treated with trifluoroacetic acid (0.509 mL, 6.60 mmol) and triethylsilane (0.141 mL, 0.880 mmol), followed by purification by slurry using isopropylether/hexane to obtain 4-chloro-6-methyl-1,2-dihydropyrrolo[3,4-c]pyridine-3-one (25.5 mg, yield 63%).
Reaction SMILES: Cl.[F:2][C:3]1[CH:31]=[CH:30][C:6]([CH2:7][C@H:8]2[CH2:12][NH:11][C@H:10]([C:13]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([O:22][C:23]4[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=4)=[CH:18][CH:17]=3)=[O:14])[CH2:9]2)=[CH:5][CH:4]=1.[N:32]1[N:33]([CH2:37][C:38](O)=[O:39])[N:34]=[CH:35][CH:36]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[N:32]1[N:33]([CH2:37][C:38]([N:11]2[CH2:12][C@H:8]([CH2:7][C:6]3[CH:5]=[CH:4][C:3]([F:2])=[CH:31][CH:30]=3)[CH2:9][C@H:10]2[C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)=[CH:18][CH:17]=2)=[O:14])=[O:39])[N:34]=[CH:35][CH:36]=1
Reactant: O=C(O)Cn1nccn1
Reactant: O=C(Nc1ccc(Oc2ccc(F)cc2)cc1)[C@@H]1C[C@@H](Cc2ccc(F)cc2)CN1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(Nc1ccc(Oc2ccc(F)cc2)cc1)[C@@H]1C[C@@H](Cc2ccc(F)cc2)CN1C(=O)Cn1nccn1
Temperature: 25 °C
Reaction time: 18 h
Yield: 89.3 %

Procedure:
A round bottom flask was charged with (2S,4R)-4-(4-fluorobenzyl)-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide hydrochloride (150 mg, 0.37 mmole, 1 eq), prepared as in Reference 6, 2H-1,2,3-triazole-2-ylacetic acid (51 mg, 0.40 mmole, 1.1 eq), HATU (152 mg, 0.40 mmole, 1.1 eq) and DMF (1 mL). DIEA (195 μL, 1.11 mmole, 3 eq) was added and the mixture stirred at ambient temperature for 18 hours. The reaction mixture was partitioned between ethyl acetate and deionized water. The aqueous layer was separated and extracted twice with ethyl acetate. The combined organics were washed with 5% lithium chloride (3×5 mL), 1N sodium bicarbonate (2×5 mL) and then deionized water (2×5 mL) and concentrated in vacuo. Product was purified from the residue via flash chromatography (silica, 5% MeOH, 95% EtOAc). Clean fractions were combined and concentrated in vacuo to afford Compound 50, (2S,4R)-1-(2-(2H-1,2,3-triazol-2-yl)acetyl)-4-(4-fluorobenzyl)-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide (171 mg, 89% yield), as a white solid. Major isomer: 1H-NMR (400 MHz, DMSO-D6): σ 9.97 (s, 1H), 7.80 (s, 2H), 7.58-7.51 (m, 2H), 7.34-7.07 (m, 6H), 7.04-6.90 (m, 4H), 5.48 (q, 2H), 4.53-4.46 (m, 1H), 3.85-3.76 (m, 1H), 2.77-2.61 (m, 3H), 2.03-1.86 (m, 2H). MS (EI) for C28H25F2N5O3. found 517.9 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:10]3([CH2:14][CH2:13][NH:12][CH2:11]3)[CH2:9][N:8]([C:15]([NH:17][C:18]3[S:19][C:20]([Cl:23])=[CH:21][N:22]=3)=[O:16])[C:5]2=[CH:6][CH:7]=1.[CH:24](O)=[O:25].Cl.C(N=C=NCCCN(C)C)C>CN(C=O)C.O>[Br:1][C:2]1[CH:3]=[C:4]2[C:10]3([CH2:14][CH2:13][N:12]([CH:24]=[O:25])[CH2:11]3)[CH2:9][N:8]([C:15]([NH:17][C:18]3[S:19][C:20]([Cl:23])=[CH:21][N:22]=3)=[O:16])[C:5]2=[CH:6][CH:7]=1
Reactant: O=C(Nc1ncc(Cl)s1)N1CC2(CCNC2)c2cc(Br)ccc21
Reactant: O=CO
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: O=CN1CCC2(C1)CN(C(=O)Nc1ncc(Cl)s1)c1ccc(Br)cc12
Reaction time: 18 h
Yield: 54.3 %

Procedure:
The 5-bromo-N-(5-chlorothiazol-2-yl)spiro[indoline-3,3′-pyrrolidine]-1-carboxamide (160 mg, 0.387 mmol) obtained in Example 2 was dissolved in N,N′-dimethylformamide (4.0 mL). Thereafter, formic acid (22.0 μL, 0.581 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (148 mg, 0.774 mmol) were added to the above obtained solution, and the thus obtained mixture was then stirred for 18 hours. Thereafter, the reaction solution was diluted with water, and was then extracted with ethyl acetate. The organic layer was washed with brine, and was then dried over anhydrous sodium sulfate, followed by concentration in vacuo. The obtained residue was purified by silica gel column chromatography (chloroform:methanol=20:1) to obtain the captioned compound (92.8 mg, 54%) in the form of a white solid.
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH2:7].[CH3:9][C:10]1[CH:11]=[CH:12][C:13]([C:16](O)=O)=[N:14][CH:15]=1.C(=O)([O-])[O-].[Na+].[Na+]>O>[CH3:9][C:10]1[CH:11]=[CH:12][C:13]([C:16]2[NH:7][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=3[N:8]=2)=[N:14][CH:15]=1
Reactant: Cc1ccc(C(=O)O)nc1
Reactant: Nc1ccccc1N
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: Cc1ccc(-c2nc3ccccc3[nH]2)nc1

Procedure:
6.2 g. of o-phenylenediamine, 7.1 g. of 5-methylpicolinic acid and 40 g. of polyphosphoric acid were stirred under nitrogen gas current at 160° C. to 180° C. for 4 hours. To the reaction mixture were added 400 ml. of water and then a concentrated aqueous solution of sodium carbonate to neutrality. The resulting crystals were filtered off, dried and recrystallized from acetonitrile or ethyl acetate to obtain 9.4 g. of colorless needles of the product (86% of theory), M.P. 229.0°-229.5° C.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[F:7][C:8]1[CH:9]=[C:10]([OH:14])[CH:11]=[CH:12][CH:13]=1.Br[CH2:16][C:17]([NH:19]/[C:20](/[CH3:26])=[CH:21]\[C:22]([O:24][CH3:25])=[O:23])=[O:18]>CC(C)=O>[F:7][C:8]1[CH:9]=[C:10]([CH:11]=[CH:12][CH:13]=1)[O:14][CH2:16][C:17]([NH:19]/[C:20](/[CH3:26])=[CH:21]\[C:22]([O:24][CH3:25])=[O:23])=[O:18]
Reactant: Oc1cccc(F)c1
Reactant: COC(=O)/C=C(/C)NC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)/C=C(/C)NC(=O)COc1cccc(F)c1
Temperature: 25 °C
Yield: 69.8 %

Procedure:
To a suspension of K2CO3 (0.37 g, 2.68 mmol) in acetone (10 mL) were added 3-fluorophenol (0.30 g, 2.68 mmol) and methyl 3-(2-bromoacetamido)crotonate (0.76 g, 3.22 mmol), the mixture was refluxed for 5 h and cooled to rt. The mixture was concentrated in vacuo and the residue was dissolved in CH2Cl2 (40 mL), washed with brine (40 mL×3). The organic phase was dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/EtOAc (V/V)=10:1) to give the title compound as a yellowish solid (0.50 g, 70%).
Reaction SMILES: [CH2:1]([S:8]([NH:11][NH:12][C:13]1[C:14](=[O:24])[N:15]([CH2:20][CH2:21][CH2:22]O)[C:16]([CH3:19])=[CH:17][N:18]=1)(=[O:10])=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Br)(Br)(Br)[Br:26].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl>[CH2:1]([S:8]([NH:11][NH:12][C:13]1[C:14](=[O:24])[N:15]([CH2:20][CH2:21][CH2:22][Br:26])[C:16]([CH3:19])=[CH:17][N:18]=1)(=[O:10])=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrC(Br)(Br)Br
Reactant: Cc1cnc(NNS(=O)(=O)Cc2ccccc2)c(=O)n1CCCO
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Cc1cnc(NNS(=O)(=O)Cc2ccccc2)c(=O)n1CCCBr
Reaction time: 2 h

Procedure:
To a magnetically stirred solution of 3-(2-benzylsulfonylhydrazino)-1-(3-hydroxypropyl)-6-methylpyrazinone, the product of Example 31 (0.429 g, 0.82 mmol) and carbon tetrabromide (0.328 g, 0.99 mmol) in dichloromethane (10 mL), is added triphenylphosphine (0.26 g, 0.99 mmol) portionwise with ice-bath cooling. After the addition is complete, the mixture is stirred for about an additional 2 hours. The solvent is removed in vacuo. The residue is purified by silica gel column chromatography using ethyl acetate/n-hexane as eluent to afford the title compound.
Reaction SMILES: S(Cl)([Cl:3])=O.[CH3:5][CH:6]([N:8]1[C:12]([C:13]([OH:15])=O)=[CH:11][CH:10]=[N:9]1)[CH3:7]>>[CH3:5][CH:6]([N:8]1[C:12]([C:13]([Cl:3])=[O:15])=[CH:11][CH:10]=[N:9]1)[CH3:7]
Reactant: CC(C)n1nccc1C(=O)O
Reactant: O=S(Cl)Cl
Product: CC(C)n1nccc1C(=O)Cl
Temperature: 80 °C

Procedure:
Thionyl chloride (5 ml) was added to 1-(1-methylethyl)-1H-pyrazole-5-carboxylic acid (1 g) and the reaction was heated at 80° C. for 5 h. The reaction was evaporated, then azeotroped with toluene to give title compound, 856 mg.
Reaction SMILES: [OH: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=[CH:12][C:13]1[C:21]2[C:16](=[N:17][CH:18]=[CH:19][CH:20]=2)[NH:15][CH:14]=1.Cl[CH2:23][CH:24]([OH:27])[CH2:25][OH:26].O>C1(C)C=CC=CC=1>[OH:27][CH:24]([CH2:25][OH:26])[CH2:23][O: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=[CH:12][C:13]1[C:21]2[C:16](=[N:17][CH:18]=[CH:19][CH:20]=2)[NH:15][CH:14]=1
Reactant: O=C1Nc2ccc(O)cc2C1=Cc1c[nH]c2ncccc12
Reactant: OCC(O)CCl
Solvent: Cc1ccccc1
Solvent: O
Product: O=C1Nc2ccc(OCC(O)CO)cc2C1=Cc1c[nH]c2ncccc12
Yield: 70 %

Procedure:
To a solution of 5-hydroxy-3-[(7-azaindol-3-yl)methylene]-2-oxindole (2.773 g, 10 mmol) in toluene (100 ml) was added portionwise under nitrogen NaH 80% (0.300 g, 10 mmol). After the salification was complete 3-chloro-1,2-propane-diol (1.547 g, 14 mmol) was added and the mixture heated to reflux for 5 h. After cooling water was added, the organic phase washed and evaporated to dryness. The residue was submitted to flash chromatography using CHCl3 --MeOH mixtures as eluant to give pure title compound in about 70% yield.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=2[F:25])[CH:8]=[C:9]([CH2:11][CH:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)[CH:10]=1)=[O:5])C.[OH-].[K+]>C(O)C.O>[CH:12]1([CH2:11][C:9]2[CH:10]=[C:6]([C:4]([OH:5])=[O:3])[N:7]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=3[F:25])[CH:8]=2)[CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: CCOC(=O)c1cc(CC2CCCC2)cn1Cc1ccc(F)cc1F
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)c1cc(CC2CCCC2)cn1Cc1ccc(F)cc1F

Procedure:
4-Cyclopentylmethyl-1-(2,4-difluorobenzyl)-1H-pyrrole-2-carboxylic acid ethyl ester (A1-III) was taken in ethanol. To it a solution of potassium hydroxide in water was added and the reaction was refluxed for 18 hrs. Ethanol was evaporated; residue was diluted with water and washed with diethyl ether. The aqueous layer was acidified using dilute HCl and extracted with ethyl acetate. Ethyl acetate layer was washed with brine and dried over anhydrous sodium sulfate. Solvent was evaporated to get 4-cyclopentylmethyl-1-(2,4-difluorobenzyl)-1H-pyrrole-2-carboxylic acid (A1-IV).
Reaction SMILES: Cl.[N:2]1([C:8]2[CH:17]=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]=2)[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[CH:18]([O:21][C:22]1[CH:30]=[CH:29][C:28]([S:31]([CH3:34])(=[O:33])=[O:32])=[CH:27][C:23]=1[C:24](O)=[O:25])([CH3:20])[CH3:19]>C(#N)C.C(OCC)C>[CH:18]([O:21][C:22]1[CH:30]=[CH:29][C:28]([S:31]([CH3:34])(=[O:33])=[O:32])=[CH:27][C:23]=1[C:24]([N:5]1[CH2:4][CH2:3][N:2]([C:8]2[CH:17]=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]=2)[CH2:7][CH2:6]1)=[O:25])([CH3:20])[CH3:19]
Reactant: c1ccc2nc(N3CCNCC3)ccc2c1
Reactant: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)O
Agent: Cl
Solvent: CC#N
Solvent: CCOCC
Product: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)N1CCN(c2ccc3ccccc3n2)CC1

Procedure:
Prepared in analogy to example 1.1(b) from 2-piperazin-1-yl-quinoline hydrochloride and 2-isopropoxy-5-methanesulfonyl-benzoic acid (example 2.2) in acetonitrile. Trituration in diethyl ether yields the title compound as a yellowish foam.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:8]([N:9]=[C:10]3[C:15]=1[CH:14]=[C:13](CCC(O)=O)[CH:12]=[CH:11]3)=[CH:7][CH:6]=[CH:5][CH:4]=2.BrC1C=CC([NH2:26])=CC=1.O=P(Cl)(Cl)Cl>>[NH2:26][C:13]1[CH:12]=[CH:11][C:10]2[C:15](=[C:2]([NH2:1])[C:3]3[C:8]([N:9]=2)=[CH:7][CH:6]=[CH:5][CH:4]=3)[CH:14]=1
Reactant: Nc1ccc(Br)cc1
Reactant: Nc1c2ccccc2nc2ccc(CCC(=O)O)cc12
Solvent: O=P(Cl)(Cl)Cl
Product: Nc1ccc2nc3ccccc3c(N)c2c1

Procedure:
Ullmann reaction (Step 1) of 2-chlorobenzoic acid 1 and 4-bromoaniline 2 afforded 4′-bromodiphenylamine-2-carboxylic acid 3. Cyclisation with POCl3 followed by amination gave the expected 3-bromo-9-aminoacridine 5 in good yield and purity.
Reaction SMILES: C[O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][CH:9]([CH2:13][NH:14][CH2:15][CH2:16][CH2:17][O:18][C:19]3[CH:20]=[N:21][C:22]4[C:27]([CH:28]=3)=[CH:26][CH:25]=[CH:24][CH:23]=4)[O:10]2)=[CH:5][CH:4]=1.[OH-].[Na+].CO>Br.C(Cl)Cl>[OH:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][CH:9]([CH2:13][NH:14][CH2:15][CH2:16][CH2:17][O:18][C:19]3[CH:20]=[N:21][C:22]4[C:27]([CH:28]=3)=[CH:26][CH:25]=[CH:24][CH:23]=4)[O:10]2)=[CH:5][CH:4]=1
Reactant: COc1ccc2c(c1)OC(CNCCCOc1cnc3ccccc3c1)CC2
Agent: Br
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CO
Product: Oc1ccc2c(c1)OC(CNCCCOc1cnc3ccccc3c1)CC2
Yield: 64.5 %

Procedure:
A solution of 7-{3-[(7-methoxy-chroman-2-ylmethyl-amino]-propanoxy}-quinoline (2.19 g, 5.7 mmol) in 48% aqueous HBr was heated to reflux for 3 hours. The reaction mixture was then allowed to cool to room temperature and basified with 1N sodium hydroxide until pH 12. The basic reaction mixture was extracted with ethyl acetate (2×100 mL), dried over anhydrous magnesium sulfate, filtered, and the solvent removed under vacuum. Chromatography (7% methanol in methylene chloride containing 1% ammonium hydroxide) afforded 1.34 g of the title compound (63% yield). The corresponding oxalate salt was prepared by adding an excess of oxalic acid in warm ethanol to a solution of the free base in warm ethanol; mp 195.5°-196.5° C.
Reaction SMILES: [O:1]=[O+][O-].[CH2:4]([O:7][C:8]1[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=1[CH2:10][OH:11])[CH:5]=C.[BH4-].[Na+]>CO>[OH:1][CH2:5][CH2:4][O:7][C:8]1[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=1[CH2:10][OH:11]
Reactant: C=CCOc1ccccc1CO
Reactant: O=[O+][O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: OCCOc1ccccc1CO
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 67 %

Procedure:
Ozone was bubbled through a -78° C. dry methanol solution of 2-(allyloxy)benzyl alcohol (LaChapelle et al Tetrahedron, 44(16), 5033-5044 (1988)) (7.0 g, 43 mmol) for 13 minutes, checking the reaction TLC profile every 2 minutes for complete disappearance of the starting olefin (Rf=0.8, 75% EtOAc/hexane). The reaction mixture was purged with nitrogen, NaBH4 (9.7 g, 0.25 mol) was added and the reaction temperature brought to 0° C. After 30 minutes, the reaction was warmed to room temperature, concentrated, diluted with ether, washed with water, brine, dried and concentrated to a residue. The residue was eluted through a pad of silica with EtOAc/hexanes (gradient elution 25%-75% EtOAC). Evaporation of the eluting solvent gave the diol, 2-(2'-hydroxyethoxy)-benzyl alcohol, (4.8 g, 67%) as an oil. MS: MW=168; observed 168, FD, CHCl3).
Reaction SMILES: [C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([C@@H:13]2[CH2:18][CH2:17][CH2:16][CH2:15][NH:14]2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl.C(N(CC)C(C)C)(C)C.[Cl:29][CH2:30][C:31](Cl)=[O:32]>C1COCC1>[C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([C@@H:13]2[CH2:18][CH2:17][CH2:16][CH2:15][N:14]2[C:31](=[O:32])[CH2:30][Cl:29])=[O:12])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(Cl)CCl
Reactant: CC(C)(C)c1cc(NC(=O)[C@@H]2CCCCN2)no1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)c1cc(NC(=O)[C@@H]2CCCCN2C(=O)CCl)no1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of (S)-Piperidine-2-carboxylic acid (5-tert-butyl-isoxazol-3-yl) amide; hydrochloride (611 mg; 2.123 mmol) in THF (15 mL) is added N,N-diisopropylethylamine (0.74 mL; 4.246 mmol), followed by alpha-chloroacetyl chloride (0.17 mL; 2.134 mmol). The reaction mixture is stirred at room temperature for 18 hours.
Reaction SMILES: [CH:1]1([NH:5][S:6]([C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[CH:11][CH:10]=2)(=[O:8])=[O:7])[CH2:4][CH2:3][CH2:2]1.[Cl-].[NH4+]>O.[Fe]>[NH2:15][C:12]1[CH:13]=[CH:14][C:9]([S:6]([NH:5][CH:1]2[CH2:4][CH2:3][CH2:2]2)(=[O:8])=[O:7])=[CH:10][CH:11]=1
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)NC2CCC2)cc1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Product: Nc1ccc(S(=O)(=O)NC2CCC2)cc1
Yield: 92.9 %

Procedure:
To a stirred solution of N-cyclobutyl-4-nitro-benzenesulfonamide (5.8 g, 18.4 mmol) ethanol (400 mL) was added iron powder (5.2 g, 92.0 mmol) and the solution of ammonium chloride (10 g, 184.0 mmol) in water (100 mL). After the reaction mixture was refluxed for 3 h, the iron was filtered off and the filtrate was basified to pH 9 by addition of sodium carbonate. The reaction mixture was extracted with ethyl acetate (300 mL×2). The extract was washed with water (130 mL×2) and brine (130 mL×2), dried over anhydrous sodium sulfate. The solvent was removed in vacuo and the residue was purified by ISCO combi-flash chromatography (gradient elution, 20-60% ethyl acetate in petroleum ether) to afford 4-amino-N-cyclobutyl-benzenesulfonamide (3.87 g, 93%) as a yellow powder: MS (ESI) M+1=227.0.
Reaction SMILES: [C:1]([N:3]=[C:4]([N:7]1[CH2:12][CH2:11][C:10]([CH2:27][C:28]#[N:29])([N:13]2[CH:17]=[C:16]([C:18]3[C:19]4[CH:26]=[CH:25][NH:24][C:20]=4[N:21]=[CH:22][N:23]=3)[CH:15]=[N:14]2)[CH2:9][CH2:8]1)SC)#[N:2].[NH3:30].CO>N.C(O)(C)C>[C:1]([N:3]=[C:4]([N:7]1[CH2:12][CH2:11][C:10]([CH2:27][C:28]#[N:29])([N:13]2[CH:17]=[C:16]([C:18]3[C:19]4[CH:26]=[CH:25][NH:24][C:20]=4[N:21]=[CH:22][N:23]=3)[CH:15]=[N:14]2)[CH2:9][CH2:8]1)[NH2:30])#[N:2]
Reactant: CSC(=NC#N)N1CCC(CC#N)(n2cc(-c3ncnc4[nH]ccc34)cn2)CC1
Reactant: N
Solvent: CC(C)O
Solvent: CO
Product: N#CCC1(n2cc(-c3ncnc4[nH]ccc34)cn2)CCN(C(N)=NC#N)CC1
Temperature: 100 °C
Reaction time: 0.1 h

Procedure:
Methyl N-cyano-4-(cyanomethyl)-4-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]-piperidine-1-carbimidothioate (41.3 mg, 0.102 mmol) (53 mg TFA salt) was dissolved in 2.0 M ammonia in isopropyl alcohol (4.00 mL). The resulting mixture was heated to 100° C. for 1 h in a microwave reactor. Analysis by HPLC and LCMS showed 60% reaction to give the expected M+H 375 (50 area %). To this mixture was added 2 mL of 7 N NH3/MeOH. The resulting mixture was heated at 120° C. for one hour. HPLC and LCMS analyses showed no remaining starting material. The reaction mixture was concentrated on a rotory evaporator. The product was isolated by prep HPLCMS using a 30 mm×100 mm C18 column, eluting with a solvent gradient; 10% ACN—H2O (0.1% TFA), 1.5 min, to 30% at 6 min; 60 mL/min; detector set at m/z 375; retention time, 4.7 min. The eluate was freeze-dried to yield 11.7 mg of the product TFA salt as a white solid. 1H NMR (d6-DMSO) δ 12.69 (s, 1H, NH); 8.92 (s, 1H); 8.81 (s, 1H); 8.51 (s, 1H); 7.75 (m, 1H); 7.22 (m, 1H); 7.18 (s, 2H, NH2); 3.84 (m, 2H); 3.23 (s, 2H); 2.99 (m, 2H); 2.60 (m, 2H); 1.97 (m, 2H). MS (ES) 375 (M+H).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([OH:10])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[F-].[K+].[CH2:13](Cl)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(#N)C>[CH2:13]([O:10][C:8]1[CH:7]=[CH:6][C:3]([CH:4]=[O:5])=[C:2]([OH:1])[CH:9]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=Cc1ccc(O)cc1O
Reactant: ClCc1ccccc1
Agent: [F-]
Agent: [K+]
Solvent: CC#N
Product: O=Cc1ccc(OCc2ccccc2)cc1O
Temperature: 25 °C

Procedure:
A solution of 2,4-dihydroxybenzaldehyde (20 g, 0.144 mol), potassium flouride (16.7 g, 2 equivalents) and benzyl chloride (29 mL, 1.75 equivalents) in acetonitrile (150 mL) is heated at reflux temperature for 16 hr, cooled to room temperature, concentrated, diluted with water and extracted with EtOAc. The combined extracts are dried over MgSO4 and concentrated in vacuo to give an oil residue. The residue is chromatographed (silica gel/10% EtOAc in hexanes to 50% EtOAc in hexanes as gradient eluents) to give the title product as a white solid, 25.9 g, identified by NMR and mass spectral analyses.