Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:10]2[CH:9]=[CH:8][CH:7]=[C:6]([S:11]([N:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)(=[O:13])=[O:12])[C:5]=2[CH:4]=[CH:3][N:2]=1.[OH-].[K+].[CH2:22](Cl)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C(O)C>[CH:1]1[C:10]2[CH:9]=[CH:8][CH:7]=[C:6]([S:11]([N:14]3[CH2:19][CH2:18][N:17]([CH2:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[CH2:16][CH2:15]3)(=[O:12])=[O:13])[C:5]=2[CH:4]=[CH:3][N:2]=1
Reactant: O=S(=O)(c1cccc2cnccc12)N1CCNCC1
Reactant: ClCc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=S(=O)(c1cccc2cnccc12)N1CCN(Cc2ccccc2)CC1
Yield: 79 %

Procedure:
In 150 ml of ethanol were added 2.77 g of 1-(5-isoquinolinesulfonyl)piperazine, i.e., Compound (35), 1.0 g of potassium hydroxide and 1.9 g of benzyl chloride, and the mixture was refluxed under heating for five hours. After the ethanol was removed from the reaction solution, 100 ml of chloroform was added to the resulting solution, and the solution obtained was washed with a buffer solution having a pH of 5.5 and extracted twice with 20 ml of a 2N aqueous hydrochloric acid solution. The aqueous hydrochloric acid layer was rendered alkaline, extracted twice with 50 ml of chloroform, and the chloroform layer extracted was washed with water and dried with anhydrous magnesium sulfate. After the chloroform was distilled therefrom under reduced pressure, 5 ml of a 10N aqueous hydrochloric acid solution was added to the residue and the mixture was condensed to dryness. The crystalline residue thus obtained was recrystallized from ethanol to give 2.9 g of 1-(5-isoquinolinesulfonyl)-4-benzylpiperazine [i.e., Compound (56)] dihydrochloride in a yield of 66%.
Reaction SMILES: [O:1]1[CH:6]=[CH:5][CH2:4][CH2:3][CH2:2]1.C([Li])(C)(C)C.[O:12]1[C:14]([CH2:18][CH3:19])([CH2:15][CH2:16]I)[CH2:13]1>CCCCCC.O1CCCC1.CN(C)P(N(C)C)(N(C)C)=O>[CH2:15]([C:14]1([O:12][CH2:13]1)[CH2:18][CH2:19][C:2]1[O:1][CH2:6][CH2:5][CH2:4][CH:3]=1)[CH3:16]
Reactant: CCC1(CCI)CO1
Reactant: C1=COCCC1
Agent: [Li]C(C)(C)C
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCC1(CCC2=CCCCO2)CO1
Temperature: 25 °C
Reaction time: 2 h
Yield: 86.5 %

Procedure:
To a stirred solution of 3.2 g of dihydropyran and 1.4 g of dry tetrahydrofuran at 0° C. was added dropwise 50 ml 2 M tert-butyl lithium. The reaction was allowed to warm to room temperature, then cooled to -10° to -20° C., and 10 g of 1,2-epoxy-2-(ethyl)-4-iodobutane and 0.7 g of hexamethylphosphoramide was added dropwise over 10 minutes. After stirring for 2 hours at -15° to -20° C., 6-8 ml of dry tetrahydrofuran was added. The reaction mixture was allowed to warm to room temperature, stirred for a total of 2 hours, 40-50 ml of hexane was added, and the mixture was washed with water and then with a saturated sodium chloride and sodium bisulfite mixture, dried and vacuum stripped to give 6 g of the desired material as an oil.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[CH:5][C:6]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8].[CH2:12]([N:14]([CH2:17]C)CC)C.C(Cl)(Cl)=[O:20].C1(C)C=CC=CC=1.CN>O1CCCC1>[CH3:12][NH:14][C:17](=[O:20])[NH:1][C:2]1[S:3][CH:4]=[CH:5][C:6]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: CCOC(=O)c1ccsc1N
Reactant: CCN(CC)CC
Reactant: O=C(Cl)Cl
Agent: CN
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CCOC(=O)c1ccsc1NC(=O)NC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred soIution of ethyl 2-amino-thiophene-3-carboxylate (5,0 g, 29 mmol) and triethylamine (4,1 ml, 29 mmol) in dry tetrahydrofuran (100 ml) was added a 20% solution of phosgene in toluene (16 ml, 32 mmol). The mixture was heated to reflux for 3 h, then cooled to room temperature and exposed to a gaseous stream of methylamine for 10 min. After additional stirring for 30 min., the mixture was filtered and the filtrate was evaporated in vacuo, whereafter the crystalline residue was suspended in water, filtered off, and dried to give the title compound as colourless crystals, m.p. 127° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([NH:15][C@H:16]1[CH2:20][CH2:19][N:18]([C@@H:21]([CH3:25])[C:22]([OH:24])=O)[C:17]1=[O:26])(=[O:14])=[O:13])[CH:6]=[CH:5]2.Cl.CN(C)CCCN=C=NCC.C1C=CC2N(O)N=NC=2C=1.[NH:49]1[CH2:54][CH2:53][O:52][CH2:51][CH2:50]1>C(Cl)Cl.C(N(CC)CC)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([NH:15][C@H:16]1[CH2:20][CH2:19][N:18]([C@@H:21]([CH3:25])[C:22]([N:49]3[CH2:54][CH2:53][O:52][CH2:51][CH2:50]3)=[O:24])[C:17]1=[O:26])(=[O:13])=[O:14])[CH:6]=[CH:5]2
Reactant: C[C@@H](C(=O)O)N1CC[C@H](NS(=O)(=O)c2ccc3cc(Cl)ccc3c2)C1=O
Reactant: C1COCCN1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@@H](C(=O)N1CCOCC1)N1CC[C@H](NS(=O)(=O)c2ccc3cc(Cl)ccc3c2)C1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of (2S)-2-((3S)-3-{[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)propanoic acid [Intermediate 29] (0.105 g) in DCM (10 ml) were added 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (0.152 g), HOBT (0.107 g) and triethylamine (0.222 ml) and the mixture was stirred at room temperature for 30 min. Morpholine (0.07 ml) was added and the resultant mixture stirred at room temperature for 16 h. The mixture was partitioned between DCM and water. The aqueous layer was re-extracted with DCM and the combined, dried (over magnesium sulphate) organic extracts were concentrated under reduced pressure. The residue was purified using SPE (silica, eluting with cyclohexane:ethyl acetate 5:1, and ethyl acetate) to give the title compound (0.1 g) as a white solid.
Reaction SMILES: Cl.[F:2][C:3]12[CH2:11][CH:7]3[CH2:8][CH:9]([CH2:10]1)[C:5]([NH2:12])([CH2:6]3)[CH2:4]2.C([O-])([O-])=O.[K+].[K+].Cl[CH2:20][C:21]([N:23]1[CH2:27][CH2:26][CH2:25][C@H:24]1[C:28]#[N:29])=[O:22]>CS(C)=O.CCOC(C)=O>[F:2][C:3]12[CH2:11][CH:7]3[CH2:6][C:5]([NH:12][CH2:20][C:21]([N:23]4[CH2:27][CH2:26][CH2:25][C@H:24]4[C:28]#[N:29])=[O:22])([CH2:4]1)[CH:9]([CH2:8]3)[CH2:10]2
Reactant: NC12CC3CC1CC(F)(C3)C2
Reactant: N#C[C@@H]1CCCN1C(=O)CCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: N#C[C@@H]1CCCN1C(=O)CNC12CC3CC1CC(F)(C3)C2
Temperature: 25 °C
Reaction time: 3 h
Yield: 38.5 %

Procedure:
To a stirred mixture of the hydrochloride salt obtained from step II (0.19 g, 0.98 mmol) and K2CO3 (0.53 g, 4.0 mmol) in DMSO (4.0 mL) at ice bath temperature under nitrogen atmosphere (S)-1-(2-chloro-acetyl)pyrrolidine-2-carbonitrile (0.17 g, 1.0 mmol) was added. After stirring the reaction mixture at r.t. for 3 h, the reaction mixture was diluted with EtOAc and washed with water and brine, dried over Na2SO4, and the solvent was removed under reduced pressure. The crude product was purified by column chromatography to obtain (2S)-1-[N-(2-fluorohexahydro-2,5-methanopentalen-3a(1H)-yl) glycyl]pyrrolidine-2-carbonitrile as an off-white solid (0.11 g) in 38% yield. m/z (M+1) 292; 1H NMR (CDCl3) 300 MHz δ 4.80-4.73 (m, 1H), 3.77-3.32 (m, 2H), 3.52 (s, 2H), 2.50-2.42 (m, 1H), 2.87-2.08 (m, 6H), 2.0-1.60 (m, 6H), 1.50-1.42 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]([C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=1)(O)[CH3:13])[C:6]1[CH2:22][N:23]([CH3:26])[CH2:24][CH2:25][C:5]2=1>S(=O)(=O)(O)O>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7](/[CH:11]=[C:12](/[C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=1)\[CH3:13])[C:6]1[CH2:22][N:23]([CH3:26])[CH2:24][CH2:25][C:5]2=1
Reactant: CN1CCc2c(n(CC(C)(O)c3ccc(F)cc3)c3ccc(Cl)cc23)C1
Agent: O=S(=O)(O)O
Product: C/C(=C\n1c2c(c3cc(Cl)ccc31)CCN(C)C2)c1ccc(F)cc1
Product: Cl
Temperature: 60 °C
Yield: 55.9 %

Procedure:
1-(6-chloro-2-methyl-3,4-dihydro-1H-pyrido[3,4-b]indol-9(2H)-yl)-2-(4-fluorophenyl) propan-2-ol (30 mg, 0.0806 mmol) was dissolved in 25% sulfuric acid, and the reaction mixture was heated overnight at 60° C. The reaction was monitored by TLC. After completion of the reaction, pH of the reaction mixture was adjusted to 10-12 and extracted with ethyl acetate. The organic layer was dried over Na2SO4, and concentrated under reduced pressure. The crude compound was purified by preparative TLC. The pure compound was stirred in ethanolic HCl to yield HCl salt of (E)-6-chloro-9-(2-(4-fluorophenyl)prop-1-enyl)-2-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (8 mg). 1H NMR (CD3OD):—7.63-7.70 (m, 2H), 7.60 (s, 1H), 7.10-7.20 (m, 3H), 7.0 (s, 1H), 4.65 (d, 1H), 4.43 (d, 1H), 3.78-3.90 (m, 1H), 3.52-3.60 (m, 2H), 3.10-3.25 (m, 5H), 1.96 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9](C#CP(OC)(C[C@@H](O)CC(OC)=O)=O)=[C:10]([CH:17]([CH3:19])[CH3:18])[N:11]3[C:16]=2[CH:15]=[CH:14][CH:13]=[CH:12]3)=[CH:4][CH:3]=1.CO.[CH3:36][CH2:37][O:38][C:39](C)=[O:40]>[Pd]>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:9]([C:39]([O:38][CH2:37][CH3:36])=[O:40])=[C:10]([CH:17]([CH3:19])[CH3:18])[N:11]3[C:16]=2[CH2:15][CH2:14][CH2:13][CH2:12]3)=[CH:6][CH:7]=1
Reactant: CCOC(C)=O
Reactant: COC(=O)C[C@H](O)CP(=O)(C#Cc1c(-c2ccc(F)cc2)c2ccccn2c1C(C)C)OC
Agent: [Pd]
Solvent: CO
Product: CCOC(=O)c1c(-c2ccc(F)cc2)c2n(c1C(C)C)CCCC2
Reaction time: 20 h
Yield: 96 %

Procedure:
To a solution of Example 1, Part C compound 6.50 g, 20.0 mmol) in EtOAc (35 mL)-CH3OH (70 mL) was added 10% Pd-C (1.5 g) and the resulting mixture hydrogenated in a Parr apparatus at 50 psi for 20 hours. The catalyst was removed by filtration through Celite and the filtrate evaporated to a colorless, viscous oil. The crude product was crystallized from hexane to give pure title compound (6.292 g, 96%) as white crystals, mp 85.5°-86.5° C.
Reaction SMILES: [O:1]=[C:2]1[N:8]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C@@H:18]([C:28](O)=[O:29])[CH2:19][C:20]3[CH:25]=[C:24]([Br:26])[CH:23]=[C:22]([Br:27])[CH:21]=3)=[O:16])[CH2:11][CH2:10]2)[CH2:7][CH2:6][C:5]2[CH:31]=[CH:32][CH:33]=[CH:34][C:4]=2[NH:3]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)C(C)C)C.C1C=CC2N(O)N=NC=2C=1.[CH3:76][N:77]([CH3:84])[CH:78]1[CH2:83][CH2:82][NH:81][CH2:80][CH2:79]1>CN(C=O)C.O>[O:1]=[C:2]1[N:8]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C@H:18]([CH2:19][C:20]3[CH:25]=[C:24]([Br:26])[CH:23]=[C:22]([Br:27])[CH:21]=3)[C:28]([N:81]3[CH2:82][CH2:83][CH:78]([N:77]([CH3:84])[CH3:76])[CH2:79][CH2:80]3)=[O:29])=[O:16])[CH2:11][CH2:10]2)[CH2:7][CH2:6][C:5]2[CH:31]=[CH:32][CH:33]=[CH:34][C:4]=2[NH:3]1
Reactant: O=C(O)[C@@H](Cc1cc(Br)cc(Br)c1)OC(=O)N1CCC(N2CCc3ccccc3NC2=O)CC1
Reactant: CN(C)C1CCNCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)C1CCN(C(=O)[C@@H](Cc2cc(Br)cc(Br)c2)OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 150 mg (0.25 mmol) of (R)-1-carboxy-2-(3,5-dibromo-phenyl)-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate, 90 mg (0.28 mmol) TBTU, 95 μL (0.55 mmol) ethyldiisopropylamine and 38 mg (0.28 mmol) HOBt in 6 mL DMF was stirred for 90 min at RT. Then 42 mg (0.33 mmol) 4-dimethylamino-piperidine were added and the reaction mixture was stirred for 16 h at RT. The reaction solution was combined with water, the organic phase was evaporated down and the residue was purified by chromatography (silica gel, DCM/MeOH/NH3 95:5:0.5).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[C@@H:14]([O:15][CH2:16][C:17]3[CH:18]=[CH:19][C:20]4[O:25][CH2:24][CH2:23][N:22]([CH2:26][CH2:27][CH2:28][O:29][CH3:30])[C:21]=4[CH:31]=3)[CH2:13][N:12]([S:32]([C:35]3[CH:40]=[CH:39][C:38]([CH3:41])=[CH:37][CH:36]=3)(=[O:34])=[O:33])[C@H:11]([CH2:42][C:43]([CH3:48])([CH3:47])[C:44](O)=[O:45])[CH2:10]2)=[CH:5][CH:4]=1.[CH3:49][O:50][CH2:51][CH2:52][NH2:53]>>[CH3:49][O:50][CH2:51][CH2:52][NH:53][C:44](=[O:45])[C:43]([CH3:47])([CH3:48])[CH2:42][C@@H:11]1[CH2:10][C@H:9]([C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[C@@H:14]([O:15][CH2:16][C:17]2[CH:18]=[CH:19][C:20]3[O:25][CH2:24][CH2:23][N:22]([CH2:26][CH2:27][CH2:28][O:29][CH3:30])[C:21]=3[CH:31]=2)[CH2:13][N:12]1[S:32]([C:35]1[CH:40]=[CH:39][C:38]([CH3:41])=[CH:37][CH:36]=1)(=[O:33])=[O:34]
Reactant: COCCCN1CCOc2ccc(CO[C@H]3CN(S(=O)(=O)c4ccc(C)cc4)[C@H](CC(C)(C)C(=O)O)C[C@@H]3c3ccc(OC)cc3)cc21
Reactant: COCCN
Product: COCCCN1CCOc2ccc(CO[C@H]3CN(S(=O)(=O)c4ccc(C)cc4)[C@H](CC(C)(C)C(=O)NCCOC)C[C@@H]3c3ccc(OC)cc3)cc21

Procedure:
According to general procedure D, 150 mg of 3-[(2S,4R,5R)-4-(4-methoxy-phenyl)-5-[4-(3-methoxy-propyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-1-(toluene-4-sulfonyl)-piperidin-2-yl]-2,2-dimethyl-propionic acid (from example 65b) and 2-methoxyethylamine are used to afford the title compound as a brown oil. Rf=0.18 (EtOAc-heptane 5:1); Rt=5.05.
Reaction SMILES: [F:1][C:2]1[CH:20]=[CH:19][CH:18]=[CH:17][C:3]=1[C:4]([CH2:6][CH2:7][CH2:8][CH2:9][C:10]([C-:12]1[CH:16]=[CH:15][CH:14]=[CH:13]1)=O)=[O:5].[CH-:21]1[CH:25]=[CH:24][CH:23]=[CH:22]1.[Fe+2:26].S(=O)(=O)(O)O.O>C(O)(=O)C>[C-:12]1([C:10]2[CH2:9][CH2:8][CH2:7][C:6]=2[C:4](=[O:5])[C:3]2[CH:17]=[CH:18][CH:19]=[CH:20][C:2]=2[F:1])[CH:16]=[CH:15][CH:14]=[CH:13]1.[CH-:21]1[CH:25]=[CH:24][CH:23]=[CH:22]1.[Fe+2:26]
Reactant: O=C(CCCCC(=O)[c-]1cccc1)c1ccccc1F
Agent: [Fe+2]
Agent: O=S(=O)(O)O
Agent: c1cc[cH-]c1
Solvent: CC(=O)O
Solvent: O
Product: O=C(C1=C([c-]2cccc2)CCC1)c1ccccc1F

Procedure:
5-(2-Fluorobenzoyl)-pentanoylferrocene (16g, 0.04 mole) and 5% v/v concentrated sulphuric acid in glacial acetic acid (300 ml) were stirred for 15 minutes at room temperature and were then poured into water. The aqueous layer was extracted with chloroform. The combined extracts were washed with water, dried (magnesium sulphate) and evaporated under vacuum. The resulting oil was purified by preparative thin layer chromatography using silica gel, with toluene as eluent, to yield pure b 1-ferrocenyl-2-[2-fluorobenzoyl)cyclopent-1-ene as red crystals; 1.2g (8%) mp 90°-92°.
Reaction SMILES: [NH2:1][C:2]1[C:3]([OH:16])=[C:4]([C:8]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)=[O:9])[CH:5]=[CH:6][CH:7]=1.[CH3:17][O:18][C:19]1[C:20](=O)[C:21](=[O:25])[C:22]=1[O:23]C>CO>[OH:16][C:3]1[C:4]([C:8]([N:10]2[CH2:11][CH2:12][O:13][CH2:14][CH2:15]2)=[O:9])=[CH:5][CH:6]=[CH:7][C:2]=1[NH:1][C:20]1[C:21](=[O:25])[C:22](=[O:23])[C:19]=1[O:18][CH3:17]
Reactant: COc1c(OC)c(=O)c1=O
Reactant: Nc1cccc(C(=O)N2CCOCC2)c1O
Solvent: CO
Product: COc1c(Nc2cccc(C(=O)N3CCOCC3)c2O)c(=O)c1=O
Yield: 54.2 %

Procedure:
A solution of 1.00 g (4.5 mmol) of (3-amino-2-hydroxyphenyl)morpholin-4-ylmethanone and 2.56 g (18.0 mmol) of 3,4-dimethoxycyclobut-3-ene-1,2-dione in 100 ml of methanol was heated at 50° C. for five and a half hours. The reaction medium was concentrated. The residue was taken up in ethyl acetate and was washed twice with a 1 M aqueous sodium dihydrogen phosphate solution. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. The solvent was evaporated off and the residue was chromatographed on silica gel (200 g prepacked column, eluent dichloromethane/methanol from 0 to 5% of methanol). 0.81 g of a yellow solid was obtained (dirty fraction). This solid was taken up in methanol with stirring, filtered and rinsed with methanol. 0.50 g of product was obtained in the form of a pale yellow solid. Yield=33%.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][C:6](Cl)=[O:7].[S:9]1[CH:13]=[CH:12][CH:11]=[C:10]1[C:14]1[CH:15]=[C:16]([NH2:19])[NH:17][N:18]=1.CCN(C(C)C)C(C)C.C(O)C(N)(CO)CO.[C:37]([N:40]1[CH2:46][CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1)(=[O:39])[CH3:38]>CC(N(C)C)=O>[S:9]1[CH:13]=[CH:12][CH:11]=[C:10]1[C:14]1[NH:18][N:17]=[C:16]([NH:19][C:6](=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2][N:43]2[CH2:44][CH2:45][CH2:46][N:40]([C:37](=[O:39])[CH3:38])[CH2:41][CH2:42]2)[CH:15]=1
Reactant: O=C(Cl)CCCCBr
Reactant: Nc1cc(-c2cccs2)n[nH]1
Reactant: CC(=O)N1CCCNCC1
Agent: NC(CO)(CO)CO
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N1CCCN(CCCCC(=O)Nc2cc(-c3cccs3)[nH]n2)CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 16.9 %

Procedure:
Bromovaleryl chloride (1.62 mL, 12.12 mmol) was dissolved in DMA (50 mL). To this, a solution of 5-thiophen-2-yl-2H-pyrazol-3-ylamine (2 g, 12.12 mmol) and DIEA (2.1 mL, 12.12 mmol) was added portionwise at 0° C. The reaction mixture was left stirring 1 hour at 0° C. and then for 2 hours at room temperature. After a total of 3 hours, PS-Trisamine (1 g, ˜4 mmol/g) was added to the mixture and left stirring for 2 hours. Then, N-acetylhomopiperazine (4.3 g, 30.3 mmol) was added and the mixture was left stirring at room temperature for a further 60 hours. After DMA evaporation under reduced pressure, water was added (50 mL) and this was extracted with ethyl acetate (3×30 mL). The aqueous layer was basified with solid NaOH and extracted with ethyl acetate at pH=10 and then again at pH=11. All the organic phases were reunited, dried and evaporated. The residue was purified by silica chromatography eluting with a gradient of ethyl acetate/methanol 9:1 up to ethyl acetate/methanol 8:2, to give the title compound as yellowish oil (800 mg, 17%).
Reaction SMILES: [C:1]([C:4]1[C:5]([C:23](=[O:25])[CH3:24])=[C:6]([OH:22])[C:7](=[CH:20][CH:21]=1)[C:8]([O:10][CH2:11][CH2:12][O:13][CH2:14][CH2:15][O:16][CH2:17][CH2:18][OH:19])=[O:9])(=[O:3])[CH3:2].[Cl-].[C:27](OC1C(=CC=CC=1)C(O)=O)(=[O:29])[CH3:28].C(O)CCCCCO>>[C:1]([C:4]1[C:5]([C:23](=[O:25])[CH3:24])=[C:6]([OH:22])[C:7](=[CH:20][CH:21]=1)[C:8]([O:10][CH2:11][CH2:12][O:13][CH2:14][CH2:15][O:16][CH2:17][CH2:18][O:19][CH2:28][CH2:27][OH:29])=[O:9])(=[O:3])[CH3:2]
Reactant: CC(=O)c1ccc(C(=O)OCCOCCOCCO)c(O)c1C(C)=O
Reactant: CC(=O)Oc1ccccc1C(=O)O
Agent: OCCCCCCO
Agent: [Cl-]
Product: CC(=O)c1ccc(C(=O)OCCOCCOCCOCCO)c(O)c1C(C)=O

Procedure:
The compound was prepared according to the procedure described in Example 1 for the synthesis of (XIX), prepared starting from 6 g of the chloride of acetylsalicylic acid, 4.6 ml of TEA and 1.9 g of 1.6-hexandiol. The product was purified by flash chromatography utilizing an eluent mix constituted by ethylether/hexane 7:3 (v/v). The intermediate fractions were collected, the solvent was evaporated under reduced pressure and a solid residue was obtained which, triturated with isopropyl ether, produced 1 g of 1.6-hexandiol bis-acetylsalicylate (II) with m.p.=96° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:14]([NH2:15])=[CH:13][CH:12]=[CH:11][N:10]=2)=[CH:4][C:3]=1[F:16].[CH:17]1([NH:20][C:21](=[O:25])[C:22](O)=O)[CH2:19][CH2:18]1.CC1C=CC=C(C)N=1.C(P1(=O)OP(=O)(CCC)OP(=O)(CCC)O1)CC>CC1CCCO1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:9]3=[N:10][CH:11]=[CH:12][CH:13]=[C:14]3[N:15]=[C:22]2[C:21]([NH:20][CH:17]2[CH2:19][CH2:18]2)=[O:25])=[CH:4][C:3]=1[F:16]
Reactant: O=C(O)C(=O)NC1CC1
Reactant: Nc1cccnc1Nc1ccc(Cl)c(F)c1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: Cc1cccc(C)n1
Solvent: CC1CCCO1
Product: O=C(NC1CC1)c1nc2cccnc2n1-c1ccc(Cl)c(F)c1
Temperature: -10 °C
Reaction time: 1 h

Procedure:
A mixture of the mono-tosylate salt of N2-(4-chloro-3-fluorophenyl)pyridine-2,3-diamine (C12) [prepared via treatment of C12 with p-toluenesulfonic acid monohydrate (1.5 equivalents) in ethanol at 80° C., followed by cooling to room temperature and isolation via filtration] (1.003 g, 2.447 mmol), (cyclopropylamino)(oxo)acetic acid (P2) (0.304 g, 2.35 mmol), 2,6-dimethylpyridine (0.91 mL, 0.84 g, 7.8 mmol), and 2-methyltetrahydrofuran (10 mL) was cooled to −10° C. and treated with 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxide (50 weight % solution in ethyl acetate, 4.3 mL, 4.6 g, 7.2 mmol). The reaction mixture was warmed to 0° C. and held for 1 hour, heated at reflux for 20 hours, and then cooled to 0° C. and filtered, rinsing with 2-methyltetrahydrofuran. The filtrate was sequentially washed with water (10 mL, 5 mL), with aqueous ammonium hydroxide solution (15%, 3×5 mL), with aqueous hydrochloric acid (0.1 M, 10 mL, 5 mL), and with water (10 mL). The organic layer was distilled to a volume of approximately 4 mL, diluted with 2-nnethyltetrahydrofuran (13 mL), and again distilled to approximately 4 mL, whereupon it was cooled to 50° C. and treated with heptane (3 mL). The resulting slurry was stirred at 50° C. for 2 hours, cooled to 20° C., and stirred for 12 hours. The solid was collected via filtration and washed with a mixture of heptane and 2-methyltetrahydrofuran (2:1, 5 mL). The resulting material (0.488 g) was reslurried in a mixture of 2-propanol and ethyl acetate (9:1, 4.9 mL), warmed to 40° C., cooled to 20° C., and stirred for 16 hours. Filtration and washing with 2-propanol (3 mL) afforded the product as an off-white solid. Yield: 410 mg, 1.24 mmol, 53%. LCMS m/z 330.9, 332.9 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 9.17 (d, J=4.8 Hz, 1H), 8.45 (d, J=4.5 Hz, 1H), 8.27 (d, J=8.0 Hz, 1H), 7.71-7.80 (m, 2H), 7.47 (dd, J=8.0, 4.8 Hz, 1H), 7.40 (br d, J=8.5 Hz, 1H), 2.77-2.86 (m, 1H), 0.65-0.69 (m, 4H).
Reaction SMILES: [CH3:1][C:2]([NH:15]C(=O)OCC1C=CC=CC=1)([C:4]1[CH:9]=[CH:8][C:7]([NH:10][S:11]([CH3:14])(=[O:13])=[O:12])=[CH:6][CH:5]=1)[CH3:3].[H][H].[C:28]([C:32]1[CH:41]=[CH:40][C:35]([CH2:36][N:37]=[C:38]=[S:39])=[CH:34][CH:33]=1)([CH3:31])([CH3:30])[CH3:29]>[Pd].CO>[C:28]([C:32]1[CH:41]=[CH:40][C:35]([CH2:36][NH:37][C:38]([NH:15][C:2]([CH3:3])([C:4]2[CH:5]=[CH:6][C:7]([NH:10][S:11]([CH3:14])(=[O:13])=[O:12])=[CH:8][CH:9]=2)[CH3:1])=[S:39])=[CH:34][CH:33]=1)([CH3:31])([CH3:29])[CH3:30]
Reactant: [H][H]
Reactant: CC(C)(NC(=O)OCc1ccccc1)c1ccc(NS(C)(=O)=O)cc1
Reactant: CC(C)(C)c1ccc(CN=C=S)cc1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)c1ccc(CNC(=S)NC(C)(C)c2ccc(NS(C)(=O)=O)cc2)cc1
Reaction time: 8 h
Yield: 94 %

Procedure:
A suspension of Benzyl N-{1-Methyl-1-[4-(methylsulfonylamino)phenyl]ethyl}carbamate (21-1, 0.5 mmol) and 5% palladium on carbon (100 mg) in MeOH (10 mL) was hydrogenated under a rubber balloon of hydrogen for 1 h. After the solvent was evaporated by rotary evaporator, the residue was dissolved in DMF (5 mL) and treated with 4-t-butylbenzyl isothiocyanate (0.5 mmol). After being stirred overnight, the mixture went to aqueous work-up and the residue was purified by column chromatography on silica gel with EtOAc:hexanes as eluant to afford N-(4-t-Butylbenzyl)-N′-{1-methyl-1-[4-(methylsulfonylamino)phenyl]ethyl}thiourea (21-7, CHK-593)
Reaction SMILES: C(N[CH2:4][CH3:5])C.OS(O)(=O)=O.[CH2:11]=O.[CH3:13][C:14]1(C)C[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]1=[O:23]>>[CH3:11][C:4]1([CH3:5])[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15](=[O:23])[C:14]1=[CH2:13]
Reactant: CC1(C)Cc2ccccc2C1=O
Reactant: C=O
Reactant: CCNCC
Agent: O=S(=O)(O)O
Product: C=C1C(=O)c2ccccc2C1(C)C
Temperature: 110 °C
Yield: 15.9 %

Procedure:
Diethylamine (8.76 g, 0.12 mol) was cooled to 0° C. and 62.5% aq. H2SO4 was added slowly. Aqueous formaldehyde solution (36.5%, 9.86 g, 0.12 mol) was added, followed by dimethylindanone (16.0 g, 0.10 mol). The mixture was heated to 110° C. for 5.5 h. Aqueous workup yielded a ca. 1:1 mixture of starting material and product which was separated by FC on SiO2 to yield the product as a colourless oil (2.73 g, 13%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH2:10][C:11]([OH:13])=[O:12])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[CH2:14]([N:16]([CH2:19][CH3:20])[CH2:17][CH3:18])C>ClCCl>[CH3:14][N:16]1[C:19]2[C:20](=[CH:5][CH:4]=[CH:9][CH:8]=2)[C:18]([C:10]2[C:11](=[O:12])[O:12][C:11](=[O:13])[C:10]=2[C:6]2[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)=[CH:17]1
Reactant: CCN(CC)CC
Reactant: O=C(O)Cc1cccc([N+](=O)[O-])c1
Solvent: ClCCl
Product: Cn1cc(C2=C(c3cccc([N+](=O)[O-])c3)C(=O)OC2=O)c2ccccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 110.1 %

Procedure:
A solution of 1-methylindole-3-glyoxylyl chloride in dichloromethane (350 mL) was added to a solution of 3-nitrophenylacetic acid (8.5 g, 0.093 mL) and triethylamine (13 mL, 93 mmol) in dichloromethane (350 mL) at 0° C. The reaction mixture was then stirred at room temperature overnight and then concentrate under reduced pressure. The crude product was purified on a silica gel column with 6:1 hexane/ethyl acetate to afford 3-(1-methylindol-3-yl)-4-(3-nitrophenyl)furan-2,5-dione (9 g, 55%).