Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:4]#[C:5][C:6]2[CH:16]=[CH:15][C:9]([C:10]([O:12]CC)=[O:11])=[CH:8][C:7]=2[O:17][CH2:18][CH:19]2[CH2:21][CH2:20]2)[CH2:3][CH2:2]1.[Li+].[OH-].CO>O>[CH:1]1([C:4]#[C:5][C:6]2[CH:16]=[CH:15][C:9]([C:10]([OH:12])=[O:11])=[CH:8][C:7]=2[O:17][CH2:18][CH:19]2[CH2:21][CH2:20]2)[CH2:2][CH2:3]1
Reactant: CCOC(=O)c1ccc(C#CC2CC2)c(OCC2CC2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1ccc(C#CC2CC2)c(OCC2CC2)c1
Yield: 104 %

Procedure:
Ethyl 4-(2-cyclopropylethynyl)-3-(cyclopropylmethoxy)benzoate (0.47 g, 1.65 mmol) and LiOH (120 mg, 4.96 mmol) were placed in a 3:1 mixture of methanol:water (50 mL) and heated at 60° C. for 3.5 h. The reaction was cooled and concentrated in vacuo to a volume of 20 mL, then placed in an ice-water bath and acidified to pH 5 with conc. HCl. A white solid precipitated which was filtered and washed thoroughly with water. The solid was dried in the vacuum oven to give the product (0.44 g, 98%). m/z=257.1 (M+1).
Reaction SMILES: [C:1]([CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])#[N:2].C(N(C(C)C)CC)(C)C.Br[CH2:19][C:20]([C:22]1[C:27]([F:28])=[CH:26][CH:25]=[CH:24][C:23]=1[F:29])=[O:21]>O1CCCC1>[C:1]([CH:3]([CH2:19][C:20]([C:22]1[C:23]([F:29])=[CH:24][CH:25]=[CH:26][C:27]=1[F:28])=[O:21])[C:4]([O:6][CH2:7][CH3:8])=[O:5])#[N:2]
Reactant: O=C(CBr)c1c(F)cccc1F
Reactant: CCOC(=O)CC#N
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C(C#N)CC(=O)c1c(F)cccc1F
Temperature: 25 °C
Reaction time: 12 h
Yield: 80.7 %

Procedure:
To a solution of ethyl cyanoacetate (7.24 g) and diisopropylethylamine (19.9 g) in tetrahydrofuran (30 mL) was added dropwise a solution of 2-bromo-1-(2,6-difluorophenyl)ethanone (15.16 g) in tetrahydrofuran (15 mL) at 10-15° C. The mixture was stirred at room temperature for 12 hr. The reaction mixture was filtered, and the obtained filtrate was concentrated under reduced pressure. The residue was dissolved in ethyl acetate, washed successively with water, 1 mol/L hydrochloric acid and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=4:1→3:2) to give the title compound as a pale-green oil (yield 13.8 g, 81%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[NH:7][C@H:8]1[CH2:12][CH2:11][N:10]([CH2:13][C:14]2[CH:19]=C[C:17](C#N)=[C:16](N)[CH:15]=2)[C:9]1=[O:23])([CH3:4])([CH3:3])[CH3:2].[N:25]1[CH:30]=[N:29][CH:28]=[N:27][CH:26]=1.C(O)(=O)C>C(O)C>[C:1]([O:5][C:6](=[O:24])[NH:7][C@H:8]1[CH2:12][CH2:11][N:10]([CH2:13][C:14]2[CH:19]=[C:26]3[C:17]([C:30]([NH2:25])=[N:29][CH:28]=[N:27]3)=[CH:16][CH:15]=2)[C:9]1=[O:23])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCN(Cc2ccc(C#N)c(N)c2)C1=O
Reactant: c1ncncn1
Solvent: CC(=O)O
Solvent: CCO
Product: CC(C)(C)OC(=O)N[C@H]1CCN(Cc2ccc3c(N)ncnc3c2)C1=O
Reaction time: 8 h
Yield: 520.4 %

Procedure:
[1-(3-Amino-4-cyanobenzyl)-2-oxopyrrolidin-3-(S)-yl]carbamic acid tert-butyl ester (890 mg, 2.69 mmol) and 1,3,5-triazine (650 mmol, 8 mmol) are combined in ethanol (40 mL), and acetic acid (480 mg, 8 mmol) added. The reaction mixture is refluxed under nitrogen overnight, cooled and presorbed directly onto silica. The product is purified by column chromatography on silica with 5-20% methanol/dichloromethane (containing 0.5% of 28% aqueous ammonium hydroxide). The product factions are combined and concentrated, and the residue left under high vacuum overnight. The product is isolated as a pale yellow powder (0.50 g, 14 mmol).
Reaction SMILES: [NH2:1][CH:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[O:6][CH2:5][CH2:4][CH2:3]1.[Cl:13][CH2:14][CH2:15][CH2:16][C:17](Cl)=[O:18]>>[Cl:13][CH2:14][CH2:15][CH2:16][C:17]([NH:1][CH:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[O:6][CH2:5][CH2:4][CH2:3]1)=[O:18]
Reactant: NC1CCCOc2ccccc21
Reactant: O=C(Cl)CCCCl
Product: O=C(CCCCl)NC1CCCOc2ccccc21

Procedure:
5-amino-2,3,4,5-tetrahydro-1-benzoxepine and 4-chlorobutyryl choride were used to produce the above compound in the same way as Reference Example 8.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:10]([CH:11]([C:14]3[C:19]([O:20][CH2:21][CH3:22])=[CH:18][CH:17]=[C:16]([F:23])[C:15]=3[Cl:24])OC)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.B(F)(F)F.[CH3:29]COCC.C[Zn]C.C1(C)C=CC=CC=1>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:10]([CH:11]([C:14]3[C:19]([O:20][CH2:21][CH3:22])=[CH:18][CH:17]=[C:16]([F:23])[C:15]=3[Cl:24])[CH3:29])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: CCOc1ccc(F)c(Cl)c1C(OC)c1c[nH]c2ncc(Br)cc12
Reactant: CCOCC
Agent: C[Zn]C
Agent: FB(F)F
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CCOc1ccc(F)c(Cl)c1C(C)c1c[nH]c2ncc(Br)cc12
Reaction time: 1 h

Procedure:
To a cold (−78° C.) solution of 5-Bromo-3-[(2-chloro-6-ethoxy-3-fluorophenyl)-methoxymethyl]-1H-pyrrolo[2,3-b]pyridine (3.0 g, 7.2 mmol) in THF (30 mL) was added BF3.OEt2 (7.1 mL, 56.3 mmol). The reaction mixture was stirred for 1 h, and 2M solution of dimethylzinc in toluene (28 mL, 56 mmol) was added dropwise. The reaction mixture was stirred for 12 h at 50° C. and was quenched with saturate aq. ammonium chloride. The organic layer was separated and aqueous layer was extracted with ethyl acetate (2×30 mL). The combined organic phase was washed with brine, dried (Na2SO4) and concentrated to give a yellowish residue. The residue was adsorbed on silica and purified (100% DCM→5% methanol/DCM) by small pad of silica. The resulting solid was recrystallized with diisopropyl ether to give the title compound. 1H NMR (CDCl3, 400 MHz): δ=1.25 (t, 3H, J=7.0 Hz), 1.79 (d, 3H, J=7.0 Hz), 3.74 (bs, 1H), 3.96 (q, 1H, J=7.0 Hz), 5.05 (q, 1H, J=7.0 Hz), 6.66-6.69 (m, 1H), 6.97 (t, 1H, J=9.0 Hz), 7.69 (s, 1H), 8.25 (s, 1H), 9.24 (s, 1H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]([C:11]2[C:16](Br)=[N:15][CH:14]=[C:13]([CH3:18])[N:12]=2)=[O:10])[CH:5]=[CH:4][N:3]=1.[Cl:19][C:20]1[CH:21]=[C:22]([NH2:26])[CH:23]=[N:24][CH:25]=1>>[CH3:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]([C:11]2[C:16]([NH:26][C:22]3[CH:23]=[N:24][CH:25]=[C:20]([Cl:19])[CH:21]=3)=[N:15][CH:14]=[C:13]([CH3:18])[N:12]=2)=[O:10])[CH:5]=[CH:4][N:3]=1
Reactant: Nc1cncc(Cl)c1
Reactant: Cc1cc(NC(=O)c2nc(C)cnc2Br)ccn1
Product: Cc1cc(NC(=O)c2nc(C)cnc2Nc2cncc(Cl)c2)ccn1

Procedure:
The title compound, MS: m/e=355.1 (M+H+), was prepared in accordance with the general method of example 4, step 2 from 3-bromo-6-methyl-pyrazine-2-carboxylic acid (2-methyl-pyridin-4-yl)-amide and 5-chloropyridine-3-amine.
Reaction SMILES: [Cl:1][C:2]1[C:6]([C:7]#[N:8])=[C:5]([C:9]2[CH:14]=[CH:13][C:12]([NH:15]C(=O)OC(C)(C)C)=[CH:11][CH:10]=2)[S:4][N:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:15][C:12]1[CH:11]=[CH:10][C:9]([C:5]2[S:4][N:3]=[C:2]([Cl:1])[C:6]=2[C:7]#[N:8])=[CH:14][CH:13]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2snc(Cl)c2C#N)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#Cc1c(Cl)nsc1-c1ccc(N)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of tert-Butyl 4-(3-chloro-4-cyanoisothiazol-5-yl)phenylcarbamate (4.76 g, 13.38 mmol) in DCM (100 ml) was treated with 10 mL of TFA. The reaction mixture was stirred at RT overnight. Solvent was removed in vacuo. The residue was diluted with water and DCM (100 ml). Layers were separated and the aqueous layer was extracted with DCM×2. The combined organics was washed with brine and dried with MgSO4, filtered, and concentrated. Product was rinsed with Et2O/hexanes and collected by filtration as a bright yellow solid (3.15 g, 94%).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]2[CH2:8][N:9]([CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:10][CH2:11][CH:5]2[C:4](=O)[N:3]=1.P(Cl)(Cl)(Cl)=O.[NH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1>C(O)C>[CH3:1][C:2]1[N:3]=[C:4]([N:25]2[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)[C:5]2[CH2:11][CH2:10][N:9]([CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:8][C:6]=2[N:7]=1
Reactant: CC1=NC(=O)C2CCN(Cc3ccccc3)CC2=N1
Reactant: C1CCNCC1
Solvent: O=P(Cl)(Cl)Cl
Solvent: CCO
Product: Cc1nc2c(c(N3CCCCC3)n1)CCN(Cc1ccccc1)C2
Reaction time: 72 h

Procedure:
2-methyl-7-(phenylmethyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4(4aH)-one (Preparation 85, 19 g) and phosphorous oxychloride (150 ml) was heated for 1.5 h. The reaction mixture was concentrated and poured onto ice. Sodium carbonate was added to adjust pH to 10, and the product was extracted with chloroform. The organic extracts were concentrated and then purified by passing through a thick pad of florisil (5 cm diameter) the product was eluted with chloroform. Evaporation gave a dark red oil which was dissolved in ethanol (100 ml) and piperidine (25 ml) was added. After 72 h, the reaction mixture was concentrated in vacuo then dissolved in chloroform and basified with sodium hydroxide (2 M solution). The reaction mixture was dried and concentrated before purifying by flash chromatography on florisil eluting the product with petroleum ether (30-40) to give the title compound (12.5 g)
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:17]([O:18][CH3:19])=[CH:16][C:12]([C:13](O)=[O:14])=[CH:11][C:10]=1[Cl:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(C)C=CC=CC=1.S(Cl)([Cl:30])=O>CN(C)C=O>[CH2:1]([O:8][C:9]1[C:17]([O:18][CH3:19])=[CH:16][C:12]([C:13]([Cl:30])=[O:14])=[CH:11][C:10]=1[Cl:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: COc1cc(C(=O)O)cc(Cl)c1OCc1ccccc1
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: COc1cc(C(=O)Cl)cc(Cl)c1OCc1ccccc1
Temperature: 60 °C
Reaction time: 16 h

Procedure:
To 4-benzyloxy-3-chloro-5-methoxybenzoic acid (541 mg), toluene (5.4 mL), N,N-dimethylformamide (1 droplet) and thionyl chloride (0.16 mL) were added, and then the mixture was stirred at 60° C. for 16 hours. The solvent was distilled off under reduced pressure and then azeotroped with toluene to obtain the title compound (578 mg) as a yellow solid.
Reaction SMILES: O[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.C(OCC1C=C(Cl)N=CN=1)C1C=CC=CC=1.C1CCN2C(=NCCC2)CC1>C(#N)C>[NH:7]1[C:8]2[C:4](=[CH:3][CH:2]=[CH:10][CH:9]=2)[CH:5]=[CH:6]1
Reactant: Oc1ccc2[nH]ccc2c1
Agent: Clc1cc(COCc2ccccc2)ncn1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: c1ccc2[nH]ccc2c1

Procedure:
To a solution of 5-hydroxy indole (1.33 g, 10 mmol) and 4-benzyloxymethyl-6-chloro-pyrimidine (2.35 g, 10 mmol) in acetonitrile (20 mL) is added DBU. After 16 h at rt the solution is concentrated under reduced pressure. The residue is purified by FCC (EtOAc/Heptane from 0% to 40%) to give 546-benzyloxymethyl-pyrimidin-4-yloxy)-1H-indole. MS (ESI) m/z 447.0 (M+1).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C@@H:9]2[CH2:14][CH2:13][C@@H:12]([CH3:15])[C@H:11]([OH:16])[CH2:10]2)[C:5]([C:17]([NH2:19])=[O:18])=[CH:4][N:3]=1.[C:20]([NH2:24])([CH3:23])([CH3:22])[CH3:21].CS(C)=O>O>[C:20]([NH:24][C:2]1[N:7]=[C:6]([NH:8][C@@H:9]2[CH2:14][CH2:13][C@@H:12]([CH3:15])[C@H:11]([OH:16])[CH2:10]2)[C:5]([C:17]([NH2:19])=[O:18])=[CH:4][N:3]=1)([CH3:23])([CH3:22])[CH3:21]
Reactant: C[C@@H]1CC[C@@H](Nc2nc(Cl)ncc2C(N)=O)C[C@H]1O
Reactant: CC(C)(C)N
Solvent: O
Solvent: CS(C)=O
Product: C[C@@H]1CC[C@@H](Nc2nc(NC(C)(C)C)ncc2C(N)=O)C[C@H]1O
Temperature: 68 °C
Reaction time: 60 h

Procedure:
A mixture of 2-chloro-4-((1R,3R,4R)-3-hydroxy-4-methylcyclohexylamino)pyrimidine-5-carboxamide (4 g), tert-butylamine (14 mL) and DMSO (20 mL) was heated to 68° C. and held for 60 hours. After cooling to room temperature, water (20× vol, 80 mL) was added over 2 hours. The slurry was agitated for 2 hours and the crude product was collected as the DMSO hemi-solvate of 2-(tert-butylamino)-4-((1R,3R,4R)-3-hydroxy-4-methylcyclohexylamino)-pyrimidine-5-carboxamide (Form H) by suction filtration.
Reaction SMILES: [F-:1].C([N+](CCCC)(CCCC)CCCC)CCC.CC1C=CC(S(O[CH2:30][CH2:31][CH:32]2[CH2:36][C:35](=[O:37])[N:34]([CH2:38][C:39]3[N:46]4[C:42]([S:43][C:44]([CH2:47][O:48][CH3:49])=[N:45]4)=[N:41][C:40]=3[Cl:50])[CH2:33]2)(=O)=O)=CC=1.O>C1COCC1>[Cl:50][C:40]1[N:41]=[C:42]2[N:46]([C:39]=1[CH2:38][N:34]1[CH2:33][CH:32]([CH2:31][CH2:30][F:1])[CH2:36][C:35]1=[O:37])[N:45]=[C:44]([CH2:47][O:48][CH3:49])[S:43]2
Reactant: COCc1nn2c(CN3CC(CCOS(=O)(=O)c4ccc(C)cc4)CC3=O)c(Cl)nc2s1
Reactant: [F-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: C1CCOC1
Solvent: O
Product: COCc1nn2c(CN3CC(CCF)CC3=O)c(Cl)nc2s1
Yield: 22 %

Procedure:
A 1M solution of tetrabutylammonium fluoride in THF solution (4 ml) is added to 2-(1-{[6-chloro-2-(methoxymethyl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl]methyl}-5-oxopyrrolidin-3-yl)ethyl 4-methylbenzenesulfonate a39 (308 mg, 0.617 mmol, 1 eq). The resulting solution is irradiated in a microwave apparatus (Biotage) at 100° C. for 1 h. Water (10 ml) is added to the reaction mixture, and the crude compound is extracted by ethyl acetate (4×10 ml). The cumulated organic layer are washed successively by a saturated NH4Cl aqueous solution (2×10 ml), water (2×10 ml), dried over MgSO4, filtered and condensed under reduced pressure. The residue is purified by flash chromatography over silicagel (eluent: CH2Cl2/MeOH 99:1) to afford 47 mg of pure 1-{[6-chloro-2-(methoxymethyl)-imidazo[2,1-b][1,3,4]thiadiazol-5-yl]methyl}-4-(2-fluoroethyl)pyrrolidin-2-one 28.
Reaction SMILES: [CH2:1]([CH:3]([C:7]1[CH:26]=[C:25]([O:27][CH3:28])[C:24]([O:29][CH3:30])=[CH:23][C:8]=1[C:9]([C:11]1[CH:16]=[C:15]([O:17][CH3:18])[C:14]([O:19][CH3:20])=[C:13]([O:21][CH3:22])[CH:12]=1)=O)[C:4]([CH3:6])=O)[CH3:2].S(=O)(=O)(O)O.O.[NH2:37][NH2:38].C([O-])(O)=O.[Na+].C>C(O)(C)C>[CH3:22][O:21][C:13]1[CH:12]=[C:11]([C:9]2[C:8]3[CH:23]=[C:24]([O:29][CH3:30])[C:25]([O:27][CH3:28])=[CH:26][C:7]=3[CH:3]([CH2:1][CH3:2])[C:4]([CH3:6])=[N:38][N:37]=2)[CH:16]=[C:15]([O:17][CH3:18])[C:14]=1[O:19][CH3:20]
Reactant: CCC(C(C)=O)c1cc(OC)c(OC)cc1C(=O)c1cc(OC)c(OC)c(OC)c1
Reactant: NN
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CC(C)O
Solvent: O
Product: CCC1C(C)=NN=C(c2cc(OC)c(OC)c(OC)c2)c2cc(OC)c(OC)cc21
Temperature: 60 °C
Reaction time: 1 h
Yield: 60.2 %

Procedure:
1.40 g (3.36 mmoles) of 2-(1-ethylacetonyl)-3',4,4',5,5'-pentamethoxybenzophenone are dissolved in 5.4 ml of isopropanol, and 0.175 ml of concentrated sulfuric acid are added dropwise to the solution. The reaction mixture is heated to boiling, stirred at this temperature for one hour, thereafter the mixture is cooled to 60° C. and 0.41 ml (8 mmoles) of 98% hydrazine hydrate are added. The resulting mixture is stirred for a further hour. 0.154 g of sodium hydrocarbonate are added in portions to the mixture, the mixture is heated to boiling, decolorized with charcoal, filtered, the filtrate is evaporated, and the residue is passed onto a filter with a total amount of 25 ml of water. 0.835 g (60.5%) of the title compound are obtained; m.p.: 152°-155° C. When recrystallized from a small amount of isopropanol the product melts at 160°-162° C. C23H28N2O5 =412.5.
Reaction SMILES: [Br:1][C:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([C@@H:11]([OH:13])[CH3:12])[C:5]=2[O:4][C:3]=1[CH3:14].N1C=CN=C1.[CH3:20][C:21]([Si:24](Cl)([CH3:26])[CH3:25])([CH3:23])[CH3:22]>C(Cl)Cl>[Br:1][C:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([C@@H:11]([O:13][Si:24]([C:21]([CH3:23])([CH3:22])[CH3:20])([CH3:26])[CH3:25])[CH3:12])[C:5]=2[O:4][C:3]=1[CH3:14]
Reactant: Cc1oc2c([C@H](C)O)cccc2c1Br
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: Cc1oc2c([C@H](C)O[Si](C)(C)C(C)(C)C)cccc2c1Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.9 %

Procedure:
A solution of (S)-1-(3-bromo-2-methyl-benzofuran-7-yl)-ethanol (1.39 g, 5.47 mmol) in CH2Cl2 (50 mL) is treated with imidazol (0.56 g, 8.21 mmol) and TBSCl (0.91 g, 6.02 mmol). The reaction is stirred at rt overnight. It is diluted with CH2Cl2 (50 mL); washed with 0.1 M HCl (3×30 mL); dried with Na2SO4; filtered and concentrated. The resulting crude material is purified by chromatography gives the title compound (1.92 g, 5.19 mmol, 95%). 1H NMR (CDCl3): δ. −0.02 (s, 3H), 0.07 (s, 3H), 0.91 (s, 3H), 2.48 (s, 3H), 1.52 (d, J=6.2 Hz, 3H), 5.38 (q, J=6.2 Hz, 1H), 7.25 (t, J=8.0 Hz, 1H), 7.30 (dd, J=8.0, 1.7 Hz, 1H), 7.40 (d, J=8.0 Hz, 1H) ppm.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][N:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]([OH:13])=O.O.O[N:16]1[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[N:18]=N1.NCC1C=CC=CN=1>CN(C=O)C>[N:18]1[CH:19]=[CH:24][CH:23]=[CH:22][C:21]=1[CH2:20][NH:16][C:11]([C:2]1[CH:3]=[CH:4][C:5]2[C:10](=[CH:9][CH:8]=[N:7][CH:6]=2)[N:1]=1)=[O:13]
Reactant: On1nnc2ccccc21
Reactant: O=C(O)c1ccc2cnccc2n1
Agent: NCc1ccccn1
Solvent: CN(C)C=O
Solvent: O
Product: O=C(NCc1ccccn1)c1ccc2cnccc2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 103.8 %

Procedure:
To a stirring mixture of 2-[1,6]naphthyridinecarboxylic acid (50 mg, 0.287 mmol) in anhydrous DMF (1.0 mL) at room temperature was added sequentially 1-hydroxybenzotriazole hydrate (42.7 mg, 0.316 mmol), 2-(aminomethyl)pyridine (45.3 μL, 0.431 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarboiimide hydrochloride (61.8 mg, 0.316 mmol). The resulting mixture was allowed to stir at room temperature overnight and it was found to be clear. The solvent was removed under vacuum. Flash column chromatography of the residue (50% hexane/ethyl acetate to 5% methanol/ethyl acetate) afforded the desired product as a light brown solid (78.7 mg, 99%): m.p. 123-125° C.
Reaction SMILES: [CH3:1][N:2]([CH3:19])[CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH:13]=[N:14][CH2:15][CH2:16][CH2:17][CH3:18].[C:20](OC)(=[O:23])[CH2:21][SH:22]>>[CH2:15]([N:14]1[C:20](=[O:23])[CH2:21][S:22][CH:13]1[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=1[O:6][CH2:5][CH2:4][CH2:3][N:2]([CH3:1])[CH3:19])[CH2:16][CH2:17][CH3:18]
Reactant: COC(=O)CS
Reactant: CCCCN=Cc1ccccc1OCCCN(C)C
Product: CCCCN1C(=O)CSC1c1ccccc1OCCCN(C)C

Procedure:
N-[[2-[3-(Dimethylamino)propoxy]phenyl]methylene]-butanamine (5.2 g) is reacted with 4.2 g of methyl thioglycolate following the procedure described in Example 1, part B, to yield 6.5 of 3-butyl-2-[2-[3-(dimethylamino)propoxy]phenyl]-4-thiazolidinone as an oil.
Reaction SMILES: [CH3:1][CH:2]1[CH2:11][C:10]2[N:9]=[C:8]([CH3:12])[C:7]3[NH:13][C:14]4[CH:15]=[CH:16][CH:17]=[CH:18][C:19]=4[C:6]=3[C:5]=2[C:4](=O)[CH2:3]1.N1C=CC=CC=1.Cl.[NH2:28][OH:29]>C(O)C>[CH3:1][CH:2]1[CH2:11][C:10]2[N:9]=[C:8]([CH3:12])[C:7]3[NH:13][C:14]4[CH:15]=[CH:16][CH:17]=[CH:18][C:19]=4[C:6]=3[C:5]=2[C:4](=[N:28][OH:29])[CH2:3]1
Reactant: NO
Reactant: Cc1nc2c(c3c1[nH]c1ccccc13)C(=O)CC(C)C2
Agent: Cl
Solvent: CCO
Solvent: c1ccncc1
Product: Cc1nc2c(c3c1[nH]c1ccccc13)C(=NO)CC(C)C2
Yield: 60.9 %

Procedure:
A mixture of 3,6-dimethyl-2,3,4,7-tetrahydroindolo[2,3-c]quinolin-1-one of Example 12 (0.26 g, 1 mmol), ethanol (4 mL), pyridine (0.15 mL, 1.85 mmol) and hydroxylamine hydrochloride (0.1 g, 1.5 mmol) was refluxed for 3 h. The mixture was cooled, the solid product was filtered off, washed with ethanol, dried, and dissolved in hot water (20 mL). Aqueous ammonium hydroxide was added to pH 9. The precipitate was collected, washed with water, dried and crystallized from ethanol-water, 1:1 to give 0.17 g (61%) of colorless crystals; m.p. 282-283° C.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C:3]1=O.[CH3:9][O:10][CH2:11][CH2:12][NH2:13].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClCCCl>[CH3:9][O:10][CH2:11][CH2:12][NH:13][CH:5]1[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]1
Reactant: CN1CCCCC1=O
Reactant: COCCN
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: COCCNC1CCN(C)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 1-methyl-piperidone (1.00 g) in 1,2-dichloroethane (20 ml) was added 2-methoxyethylamine (0.77 ml), followed by sodium triacetoxyborohydride (2.62 g) and acetic acid (0.53 g). The reaction mixture was stirred at room temperature overnight. Dichloromethane/aqueous sodium hydrogen carbonate extraction and purification on silica gave (2-methoxy-ethyl)-(1-methyl-piperidin-4-yl)-amine (1.52 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:18]=[CH:17][C:6]([CH2:7][NH:8][C@H:9]([CH2:13][CH:14]([CH3:16])[CH3:15])[C:10]([NH2:12])=[O:11])=[CH:5][CH:4]=1.CCN(CC)CC.[Cl:26][C:27]1[CH:32]=[CH:31][C:30]([S:33](Cl)(=[O:35])=[O:34])=[CH:29][CH:28]=1>C(Cl)Cl>[Cl:26][C:27]1[CH:32]=[CH:31][C:30]([S:33]([N:8]([C@H:9]([CH2:13][CH:14]([CH3:16])[CH3:15])[C:10]([NH2:12])=[O:11])[CH2:7][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:18][CH:17]=2)(=[O:35])=[O:34])=[CH:29][CH:28]=1
Reactant: COc1ccc(CN[C@H](CC(C)C)C(N)=O)cc1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(CN([C@H](CC(C)C)C(N)=O)S(=O)(=O)c2ccc(Cl)cc2)cc1
Yield: 39.5 %

Procedure:
(2R)-2-[N-(4-Methoxybenzyl)amino]-4-methylpentanoic acid amide (3.57 g, 14.3 mmol) was dissolved in CH2Cl2 (100 mL) and treated with Et3N (4.2 mL, 29 mmol) and 4-chlorobenzenesulfonyl chloride (3.6 g, 17 mmol) at rt for 18 h. The solvents were removed and the residue was taken into EtOAc (500 mL). The organic solution was washed with H2O, brine, dried over MgSO4, and concentrated. The resulting material was then further purified by flash chromatography (SiO2, 1% MeOH/CH2Cl2) to afford the title compound (2.4 g) as a slightly colored solid in 40% yield. MS (ESI), (M−H)−422.9; 1H NMR (CDCl3) δ 7.63 (d, 2H, J=7.0), 7.42 (d, 2H, J=7.0), 7.25 (d, 2H, J=8.0), 6.79 (d, 2H, J=8.0), 6.25 (br s, 1H), 5.35 (br s, 1H), 4.36 (dd, 2H, J=5.0, 15), 4.26 (t, 1H, J=7.2), 3.78 (s, 3H), 1.83 (m, 1H), 1.18-1.34 (m, 2H), 0.75 (d, 3H, J=7.0), 0.67 (d, 3H, J=7.0); IR (KBr) 3480, 2959, 1693, 1674, 1514, 1333, 1158 cm−1.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([S:14]([CH2:17][CH2:18][CH2:19]Cl)(=[O:16])=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[I-].[K+].C(=O)([O-])[O-].[K+].[K+].[NH:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1>CC#N.C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([S:14]([CH2:17][CH2:18][CH2:19][N:29]2[CH2:34][CH2:33][O:32][CH2:31][CH2:30]2)(=[O:16])=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCN(S(=O)(=O)CCCCl)CC1
Reactant: C1COCCN1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(S(=O)(=O)CCCN2CCOCC2)CC1
Reaction time: 16 h

Procedure:
Amine preparation: A mixture of 1-BOC-piperazine (3.26 g), 3-chloropropanesulfonyl chloride (2.63 g) and triethylamine (2.68 mL) was stirred at room temperature in DCM (25 mL). After 2 h the reaction mixture was diluted with DCM, washed with brine, dried (MgSO4) and the solvent removed in vacuo to yield 4-(3-chloro-propane-1-sulfonyl)-piperazine-1-carboxylic acid tert-butyl ester (4.65 g). A mixture of 4-(3-chloro-propane-1-sulfonyl)-piperazine-1-carboxylic acid tert-butyl ester (4.65 g), potassium iodide (1.1 g),potassium carbonate and morpholine (1.6 mL) was heated to reflux in MeCN (100 ml). After 16 h, the reaction mixture was cooled, diluted with DCM, washed with brine, dried (MgSO4) and the solvent removed in vacuo to yield 4-(3-morpholin-4-yl-propane-1-sulfonyl)-piperazine-1-carboxylic acid tert-butyl ester (4.8 g). Treatment of this compound with HCl in DCM/MeOH yielded the desired compound, which was isolated as the hydrochloride salt.