Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([O:14][CH:15]3[CH2:19][CH2:18][CH2:17][CH2:16]3)[C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[O:5][C:4](=[O:20])[CH:3]=1.[NH2:21][CH2:22][C:23]([OH:25])=[O:24].C(N(CC)CC)C>C(O)C>[CH:15]1([O:14][C:7]2[C:8]([O:12][CH3:13])=[CH:9][CH:10]=[C:11]3[C:6]=2[O:5][C:4](=[O:20])[CH:3]=[C:2]3[NH:21][CH2:22][C:23]([OH:25])=[O:24])[CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: NCC(=O)O
Reactant: COc1ccc2c(Cl)cc(=O)oc2c1OC1CCCC1
Solvent: CCO
Solvent: CCN(CC)CC
Product: COc1ccc2c(NCC(=O)O)cc(=O)oc2c1OC1CCCC1
Temperature: 75 °C
Reaction time: 48 h

Procedure:
A mixture of 4-chloro-8-(cyclopentyloxy)-7-methoxy-2H-chromen-2-one (170 mg, 0.58 mmol), glycine (52 mg, 0.69 mmol), triethylamine (0.2 mL, 1.4 mmol), and ethanol (2 mL) was heated at 75° C. in a sealed vial. After 2 d, more glycine (136 mg, 1.8 mmol) and triethylamine (0.3 mL, 2.2 mmol) were added. The reaction was heated at 75° C. for an additional day, allowed to cool to rt, concentrated, diluted with ethyl acetate (40 mL), and then washed with 1N HCl (50 mL×3). The organic layer was dried, filtered, and concentrated to give 2-(8-(cyclopentyloxy)-7-methoxy-2-oxo-2H-chromen-4-ylamino)acetic acid: 1H NMR (400 MHz, DMSO-d6): δ 7.87 (t, 1H), 7.68 (d, 1H), 7.08 (d, 1H), 4.88 (s, 1H), 4.81 (m, 1H), 4.00 (d, 2H), 3.87 (s, 3H), 1.90-1.44 (m, 8H); MS (ESI): 333.9.
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1([CH3:37])[S:16][CH2:15][CH2:14][N:13]2[C:17]([C:20]3([C:23]4[CH:28]=[CH:27][C:26]([C:29]5[CH:30]=[N:31][CH:32]=[C:33]([CH:36]=5)[C:34]#[N:35])=[CH:25][CH:24]=4)[CH2:22][CH2:21]3)=[N:18][N:19]=[C:12]2[CH2:11]1)(C(C)(C)C)(C)C.Cl>CO>[OH:8][CH2:9][C:10]1([CH3:37])[S:16][CH2:15][CH2:14][N:13]2[C:17]([C:20]3([C:23]4[CH:24]=[CH:25][C:26]([C:29]5[CH:30]=[N:31][CH:32]=[C:33]([CH:36]=5)[C:34]#[N:35])=[CH:27][CH:28]=4)[CH2:22][CH2:21]3)=[N:18][N:19]=[C:12]2[CH2:11]1
Reactant: CC1(CO[Si](C)(C)C(C)(C)C)Cc2nnc(C3(c4ccc(-c5cncc(C#N)c5)cc4)CC3)n2CCS1
Agent: Cl
Solvent: CO
Product: CC1(CO)Cc2nnc(C3(c4ccc(-c5cncc(C#N)c5)cc4)CC3)n2CCS1
Yield: 87.3 %

Procedure:
A solution of the compound (238 mg, 0.45 mmol) obtained in Example 62-1) and 4 M hydrochloric acid (1,4-dioxane solution, 1 mL) in methanol (4 mL) was stirred at room temperature for 15 h. The reaction mixture was concentrated under reduced pressure, saturated aqueous sodium hydrogencarbonate was added to the residue, the mixture was extracted with dichloromethane, and the organic layer was washed with saturated sodium chloride solution and dried with anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (Isco Combiflash, 12 g, methanol:ethyl acetate=0:100 to 40:60, gradient) to obtain the title compound (164 mg, 39%) as a colorless solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[N:12][N:11]3[C:14](=[O:17])[NH:15][N:16]=[C:10]3[C:9]=2[C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)=[CH:4][CH:3]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[O:44]1[CH2:49][CH2:48][N:47]([C:50]2[N:55]=[CH:54][C:53]([CH2:56]O)=[CH:52][CH:51]=2)[CH2:46][CH2:45]1>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[N:12][N:11]3[C:14](=[O:17])[N:15]([CH2:56][C:53]4[CH:54]=[N:55][C:50]([N:47]5[CH2:48][CH2:49][O:44][CH2:45][CH2:46]5)=[CH:51][CH:52]=4)[N:16]=[C:10]3[C:9]=2[C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)=[CH:4][CH:3]=1
Reactant: OCc1ccc(N2CCOCC2)nc1
Reactant: O=c1[nH]nc2c(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3)cnn12
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=c1n(Cc2ccc(N3CCOCC3)nc2)nc2c(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3)cnn12
Yield: 27.5 %

Procedure:
The title compound was prepared using 7,8-bis(4-chlorophenyl)-[1,2,4]triazolo[4,3-b]pyridazin-3(2H)-one, (50 mg, 0.14 mmol), prepared as described in Example 1, Ph3P (110 mg, 0.42 mmol) and (6-morpholinopyridin-3-yl)methanol (29 mg, 0.14 mmol) in THF (1.0 mL) and by following the procedure described in Example 2. The title compound, 7,8-bis(4-chlorophenyl)-2-((6-morpholinopyridin-3-yl)methyl)-[1,2,4]triazolo[4,3-b]pyridazin-3(2H)-one, (20.5 mg, 11%) was obtained as yellow powder. MS M+H=533; 1H NMR (CDCl3) 8.26 δ (1H, d, J=5.0 Hz), 8.15 (1H, s), 7.65 (1H, d, J=5.0 Hz), 7.25-7.36 (6H, m), 7.09 (2H, d, J=10.0 Hz), 6.60 (1H, d, J=10.0 Hz), 5.10 (2H, s), 3.80 (4H, t, J=5.0 Hz), 3.50 (4H, t, J=5.0 Hz).
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[CH2:14][CH2:13][C:12]2[S:11][C:10]3[N:9]=[CH:8][N:7]=[C:6]([O:15][CH:16]4[CH2:21][CH2:20][CH:19]([N:22]([CH3:30])[C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH2:18][CH2:17]4)[C:5]=3[C:4]1=2.[CH3:31][S:32](Cl)(=[O:34])=[O:33].C(N(CC)CC)C>C(Cl)Cl>[CH3:31][S:32]([O:1][CH2:2][C@H:3]1[CH2:14][CH2:13][C:12]2[S:11][C:10]3[N:9]=[CH:8][N:7]=[C:6]([O:15][CH:16]4[CH2:17][CH2:18][CH:19]([N:22]([CH3:30])[C:23](=[O:29])[O:24][C:25]([CH3:26])([CH3:27])[CH3:28])[CH2:20][CH2:21]4)[C:5]=3[C:4]1=2)(=[O:34])=[O:33]
Reactant: CN(C(=O)OC(C)(C)C)C1CCC(Oc2ncnc3sc4c(c23)[C@@H](CO)CC4)CC1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(C(=O)OC(C)(C)C)C1CCC(Oc2ncnc3sc4c(c23)[C@@H](COS(C)(=O)=O)CC4)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 110.6 %

Procedure:
A solution of tert-butyl N-(4-[[(3S)-3-(hydroxymethyl)-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2 (6),9,11-tetraen-12-yl]oxy]cyclohexyl)-N-methylcarbamate (691 mg, 1.59 mmol, 1.00 equiv) in 4 mL of DCM was added MsCl (366 mg, 3.18 mmol, 2.00 equiv) and triethylamine (643 mg, 6.35 mmol, 4.00 equiv) at 0° C. under nitrogen. The resulting solution was stirred for 2 h at room temperature and quenched with water. The resulting solution was extracted with 3×30 mL of DCM. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated under vacuum afford tert-butyl N-(4-[[(3S)-3-[(methanesulfonyloxy)methyl]-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2 (6),9,11-tetraen-12-yl]oxy]cyclohexyl)-N-methylcarbamate (900 mg, crude) as a red oil. MS: m/z 512 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:16]=[C:15]([NH2:17])[CH:14]=[C:6]([C:7]([N:9]([CH3:13])[CH2:10][CH2:11][CH3:12])=[O:8])[CH:5]=1.N1C=CC=CC=1.[CH3:25][S:26](Cl)(=[O:28])=[O:27]>ClCCl>[CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:16]=[C:15]([NH:17][S:26]([CH3:25])(=[O:28])=[O:27])[CH:14]=[C:6]([C:7]([N:9]([CH3:13])[CH2:10][CH2:11][CH3:12])=[O:8])[CH:5]=1
Reactant: CS(=O)(=O)Cl
Reactant: CCCN(C)C(=O)c1cc(N)cc(C(=O)OC)c1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCN(C)C(=O)c1cc(NS(C)(=O)=O)cc(C(=O)OC)c1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
Dissolve 5-amino-N-methyl-N-propyl-isophthalamic acid methyl ester (1.64 g, 6.55 mmol) in dichloromethane (20 mL) and add pyridine (620 mg, 6.88 mmol) and methanesulfonyl chloride (788 mg, 6.88 mmol). Stir at room temperature for 72 h, dilute with dichloromethane, wash with 0.1 N citric acid and saturated aqueous sodium chloride. Dry (magnesium sulfate) and concentrate to give the title compound as an oil.
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:18])[C:7]([C:15]([OH:17])=[O:16])=[C:8]3[S:14][CH2:13][CH2:12][N:9]32)=[CH:4][C:3]=1[F:19].[C:20]([O:24][C:25]([NH:27][CH:28]1[CH2:32][CH2:31][NH:30][CH2:29]1)=[O:26])([CH3:23])([CH3:22])[CH3:21]>N1C=CC=CC=1>[F:19][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:2]=1[N:30]1[CH2:31][CH2:32][CH:28]([NH:27][C:25]([O:24][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:26])[CH2:29]1)[N:9]1[CH2:12][CH2:13][S:14][C:8]1=[C:7]([C:15]([OH:17])=[O:16])[C:6]2=[O:18]
Reactant: O=C(O)c1c2n(c3cc(Cl)c(F)cc3c1=O)CCS2
Reactant: CC(C)(C)OC(=O)NC1CCNC1
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)NC1CCN(c2cc3c(cc2F)c(=O)c(C(=O)O)c2n3CCS2)C1

Procedure:
A mixture of 9.0 g (30 mmol) of 8-chloro-7-fluoro-5-oxo-1,2-dihydro-5H-thiazolo[3,2-a]quinoline-4-carboxylic acid, 8.37 g (45 mmol) of 3-(t-butoxycarbonylamino)pyrrolidine and 100 ml of pyridine is heated at reflux for 18 hours. The solvent is removed in vacuo and the residue triturated with water. The solid which forms is removed by filtration, washed with water and dried in vacuo to give 7-fluoro-8-[3(-t-butoxycarbonylamino)-1-pyrrolidinyl]-5-oxo-1,2-dihydro-5H-thiazolo[3,2-a]quinoline-4-carboxylic acid.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[CH3:9].[C:10]1(=O)[O:15][C:13](=[O:14])[CH:12]=[CH:11]1>C(O)(=O)C>[Br:1][C:2]1[CH:8]=[CH:7][C:5]([N:6]2[C:13](=[O:14])[CH:12]=[CH:11][C:10]2=[O:15])=[CH:4][C:3]=1[CH3:9]
Reactant: O=C1C=CC(=O)O1
Reactant: Cc1cc(N)ccc1Br
Solvent: CC(=O)O
Product: Cc1cc(N2C(=O)C=CC2=O)ccc1Br
Temperature: 115 °C
Reaction time: 0.42 h
Yield: 74.4 %

Procedure:
4-Bromo-3-methylaniline (1.55 g, 8.33 mmol) and maleic anhydride (0.898 g, 9.16 mmol) were dissolved in acetic acid (10 mL) and heated at 115° C. for 12 h. The reaction was then cooled to 25° C. and the acetic acid was removed in vacuo. The resulting residue was suspended in 5% K2CO3 (100 mL), stirred for 25 minutes followed by filtering and rinsing with water. The material was then dried in vacuo to give compound 13B as a light brown solid (1.65 g). HPLC: 100% at 2.96 min (retention time) (YMC S5 ODS column 4.6×50 mm eluting with 10-90% aqueous methanol over 4 minutes containing 0.1% TFA, 4 mL/min, monitoring at 220 nm).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:26]#[N:27])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:20][C:21]3([CH3:24])[CH2:23][CH2:22]3)[C:17](O)=[O:18])[C:10](=[O:25])[CH:9]=2)[CH:7]=1.[NH2:28][C:29]1[CH:41]=[CH:40][C:32]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])=[CH:31][CH:30]=1.CC(C)N=C=NC(C)C>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:26]#[N:27])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:20][C:21]3([CH3:24])[CH2:22][CH2:23]3)[C:17]([NH:28][C:29]3[CH:41]=[CH:40][C:32]([C:33]([O:35][C:36]([CH3:37])([CH3:38])[CH3:39])=[O:34])=[CH:31][CH:30]=3)=[O:18])[C:10](=[O:25])[CH:9]=2)[CH:7]=1
Reactant: CC(C)(C)OC(=O)c1ccc(N)cc1
Reactant: COc1cn(C(CC2(C)CC2)C(=O)O)c(=O)cc1-c1cc(Cl)ccc1C#N
Agent: CC(C)N=C=NC(C)C
Solvent: CN(C)C=O
Product: COc1cn(C(CC2(C)CC2)C(=O)Nc2ccc(C(=O)OC(C)(C)C)cc2)c(=O)cc1-c1cc(Cl)ccc1C#N

Procedure:
95.0 mg (246 μmol) of 2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-(1-methylcyclopropyl)propanoic acid (racemate), 47.5 mg (246 μmol) of tert-butyl 4-aminobenzoate, 34.9 mg (246 μmol) of Oxima and 38.3 μl (246 μmol) of DIC in 2.5 ml of dimethylformamide were reacted according to General Method 5B. Yield: 101 mg (66% of theory)
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([O:7][C:8]2[C:9]3[N:17]=[C:16]([C:18]4[CH:19]=[C:20]([NH:24][S:25]([C:28]5[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=5)(=[O:27])=[O:26])[CH:21]=[N:22][CH:23]=4)[CH:15]=[CH:14][C:10]=3[N:11]=[CH:12][N:13]=2)[CH2:3][CH2:2]1.[C:34](Cl)([CH3:36])=[O:35]>C(Cl)Cl.O>[C:34]([N:1]1[CH2:6][CH2:5][CH:4]([O:7][C:8]2[C:9]3[N:17]=[C:16]([C:18]4[CH:19]=[C:20]([NH:24][S:25]([C:28]5[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=5)(=[O:26])=[O:27])[CH:21]=[N:22][CH:23]=4)[CH:15]=[CH:14][C:10]=3[N:11]=[CH:12][N:13]=2)[CH2:3][CH2:2]1)(=[O:35])[CH3:36]
Reactant: CC(=O)Cl
Reactant: O=S(=O)(Nc1cncc(-c2ccc3ncnc(OC4CCNCC4)c3n2)c1)c1ccccc1
Solvent: ClCCl
Solvent: O
Product: CC(=O)N1CCC(Oc2ncnc3ccc(-c4cncc(NS(=O)(=O)c5ccccc5)c4)nc23)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 7.8 %

Procedure:
To a solution of N-(5-(4-(piperidin-4-yloxy)pyrido[3,2-d]pyrimidin-6-yl)pyridin-3-yl)benzene-sulfonamide (0.082 g, 0.177 mmol) in DCM (0.886 ml) was added TEA (0.062 ml, 0.443 mmol) at room temperature. After stirring for 2 hours at room temperature, AcCl (0.019 ml, 0.266 mmol) was added to the mixture at 0° C. After stirring overnight at room temperature, the reaction mixture was diluted with water and extracted with CH2Cl2. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by prep TLC (DCM:MeOH=20:1) to give N-(5-(4-(1-acetylpiperidin-4-yloxy)-pyrido[3,2-d]pyrimidin-6-yl)pyridin-3-yl)benzenesulfonamide (0.007 g, 7%) as a white solid. 1H-NMR (CDCl3, Varian 400 MHz) δ 2.05-2.18 (2H, m), 2.19 (3H, s), 3.53-3.59 (2H, m), 3.65-3.76 (2H, m), 3.89-3.40 (2H, m), 5.74-8.79 (1H, m), 7.44-7.48 (2H, m), 7.53-7.57 (1H, m), 7.86-7.89 (2H, m), 8.23 (1H, d, J=8.8 Hz), 8.36 (1H, d, J=8.8 Hz), 8.46 (1H, d, J=2.8 Hz), 8.53 (1H, d, J=2.4 Hz), 8.84 (1H, s), 9.12 (1H, d, J=1.6 Hz). m/z=505.1 [M+1]+.
Reaction SMILES: [S:1]([C:5]1[CH:13]=[C:12]([C:14]([OH:16])=[O:15])[CH:11]=[CH:10][C:6]=1[C:7]([OH:9])=[O:8])([OH:4])(=[O:3])=[O:2].C([O:20][C:21](=[O:23])[CH3:22])(=O)C>>[C:21]([C:22]1[CH:11]=[CH:10][C:6]([C:7]([O:8][C:7](=[O:9])[C:6]2[CH:10]=[CH:11][C:12]([C:14]([OH:16])=[O:15])=[CH:13][C:5]=2[S:1]([OH:4])(=[O:3])=[O:2])=[O:8])=[C:5]([S:1]([OH:4])(=[O:3])=[O:2])[CH:13]=1)([OH:20])=[O:23]
Reactant: O=C(O)c1ccc(C(=O)O)c(S(=O)(=O)O)c1
Reactant: CC(=O)OC(C)=O
Product: O=C(O)c1ccc(C(=O)OC(=O)c2ccc(C(=O)O)cc2S(=O)(=O)O)c(S(=O)(=O)O)c1
Temperature: 100 °C
Reaction time: 4 h

Procedure:
A dry 500 ml 3-neck flask was equipped with a condenser, stirrer and thermometer under a nitrogen atmosphere. The vessel was charged with 2-sulfoterephthalic acid (100 g, 447 mmol).and acetic anhydride (127 ml). The solution was stirred at 100° C. for 4 hours and then cooled to room temperature (the reaction mixture became homogeneous at 90° C.). A precipitate which had begun to form at 76° C. was then collected by filtration at room temperature (25° C.) under a N2 atmosphere. It was washed with methylene chloride (5×200 ml) and dried in dessicator under high vacuum for 24 hours. The dry white product melted at 210°-213° C. (Lit 208°-210° C.); 66.8 g (65%).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:16][CH:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1)=[CH:13][CH:12]=[CH:11][C:10]=2[O:22][CH3:23])=O)C.[C:24]([N:28]=[C:29]=[O:30])([CH3:27])([CH3:26])[CH3:25]>>[C:24]([N:28]1[C:4](=[O:3])[C:6]2[CH:7]=[N:8][C:9]3[C:10]([O:22][CH3:23])=[CH:11][CH:12]=[CH:13][C:14]=3[C:15]=2[N:16]([CH:17]2[CH2:18][CH2:19][CH2:20][CH2:21]2)[C:29]1=[O:30])([CH3:27])([CH3:26])[CH3:25]
Reactant: CC(C)(C)N=C=O
Reactant: CCOC(=O)c1cnc2c(OC)cccc2c1NC1CCCC1
Product: COc1cccc2c1ncc1c(=O)n(C(C)(C)C)c(=O)n(C3CCCC3)c12
Yield: 49 %

Procedure:
3-tert-Butyl-1-cyclopentyl-7-methoxy-1H-pyrimido[5,4-c]quinoline-2,4-dione (18 mg) was prepared from 4-cyclopentylamino-8-methoxy-quinoline-3-carboxylic acid ethyl ester (0.10 mmol) and tert-butyl isocyanate (0.4 mmol) following general procedure C. LCMS: m/z 368 [M+1]+.
Reaction SMILES: [CH3:1][C:2]([S:5](/[N:7]=[CH:8]/[C:9]1[N:10]=[C:11]([CH3:14])[NH:12][CH:13]=1)=[O:6])([CH3:4])[CH3:3].[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([Mg]Br)=[CH:19][CH:18]=1.C1COCC1>C(Cl)Cl>[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([CH:8]([C:9]2[N:10]=[C:11]([CH3:14])[NH:12][CH:13]=2)[NH:7][S:5]([C:2]([CH3:1])([CH3:3])[CH3:4])=[O:6])=[CH:19][CH:18]=1
Reactant: Cc1nc(/C=N/S(=O)C(C)(C)C)c[nH]1
Reactant: COc1ccc([Mg]Br)cc1
Solvent: C1CCOC1
Solvent: ClCCl
Product: COc1ccc(C(NS(=O)C(C)(C)C)c2c[nH]c(C)n2)cc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 42 %

Procedure:
To a 100 ml round bottom flask containing −78° C. solution of 2-methyl-N-((1E)-(2-methyl-1H-imidazol-4-yl)methylene]propane-2-sulfinamide (1.170 g, 5.490 mmol) in 25.0 ml of CH2Cl2 was added dropwise 1.0 N 4-methoxyphenylmagnesium bromide in THF (8.230 ml, 8.230 mmol). The resulting solution was stirred at −78° C. for 1 hour. The reaction mixture was quenched with saturated NH4Cl and extracted with CH2Cl2. The combined organic layers were washed with brine, dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated in vacuum. Purification by flash chromatography (SiO2, 0-4% methanol in CH2Cl2, gradient) gave the title compound as a white solid (0.735 g, 42%). 1H NMR (CDCl3, 400 MHz) δ 7.270 (m, 2H), 6.849 (m, 2H), 6.405 (s, 1H), 5.451 (d, J=6.04 Hz, 1H), 4.307 (d, J=6.05 Hz, 1H), 3.791 (s, 3H), 3.433 (s, 1H), 2.282 (s, 3H), 1.251 (s, 9H). ES-MS [M+1]+: 322.3.
Reaction SMILES: C([Li])CCC.[CH3:6][C:7]1[O:8][CH:9]=[CH:10][CH:11]=1.[CH3:12][C:13]1([CH:17]=[O:18])[CH2:16][O:15][CH2:14]1.[Cl-].[NH4+]>CCCCCC.O1CCCC1>[CH3:6][C:7]1[O:8][C:9]([CH:17]([C:13]2([CH3:12])[CH2:16][O:15][CH2:14]2)[OH:18])=[CH:10][CH:11]=1
Reactant: CC1(C=O)COC1
Reactant: Cc1ccco1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Cc1ccc(C(O)C2(C)COC2)o1
Temperature: -70 °C
Reaction time: 3 h
Yield: 92.1 %

Procedure:
12.0 ml (30 mmol, 1.7 eq) of a 2.5 M solution of n-butyllithium in hexane were added dropwise to a solution of 2.46 g (30 mmol, 1.7 eq) of 2-methylfuran in 50 ml of tetrahydrofuran cooled to −70° C. The reaction medium was stirred and allowed to return to ambient temperature for 3 hours. The reaction medium was cooled to −70° C. and then 2.17 g (18 mmol, 1 eq) of 3-methyloxetane-3-carbaldehyde at 83% were added. The reaction medium was stirred at ambient temperature for 3 hours. The reaction medium was treated with a saturated ammonium chloride solution and extracted with ethyl acetate. The organic phases were combined, washed with a saturated sodium chloride solution and evaporated. 3.02 g of (5-methylfuran-2-yl)-(3-methyloxetan-3-yl)methanol were obtained in the form of an orange oil. Yield=92%.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:8][CH2:9][CH2:10][CH2:11][NH:12][C:13]2[NH:14][CH:15]=[CH:16][C:17](=[O:19])[N:18]=2)=[N:4][CH:5]=[CH:6][CH:7]=1.[N:20]1[CH:25]=[CH:24][C:23]([CH:26]=[O:27])=[CH:22][CH:21]=1>Cl>[Cl:1][C:2]1[C:3]([CH2:8][CH2:9][CH2:10][CH2:11][NH:12][C:13]2[NH:14][CH:15]=[C:16]([CH:26]([C:23]3[CH:24]=[CH:25][N:20]=[CH:21][CH:22]=3)[OH:27])[C:17](=[O:19])[N:18]=2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=Cc1ccncc1
Reactant: O=c1cc[nH]c(NCCCCc2ncccc2Cl)n1
Agent: Cl
Product: O=c1nc(NCCCCc2ncccc2Cl)[nH]cc1C(O)c1ccncc1
Yield: 80.1 %

Procedure:
2-[[4-(3-Chloro-2-pyridyl)butyl]amino]-4-(1H)-pyrimidinone (1.37 g) and pyridine 4-aldehyde (0.52 g) were refluxed in concentrated hydrochloric acid (5 ml) for 24 hours. The reaction mixture was evaporated under reduced pressure to afford an oil which was partitioned between chloroform (25 ml) and water (25 ml) with the addition of sodium hydroxide to take the aqueous layer to pH 6.5. The aqueous layer was washed with more chloroform (25 ml) and the combined chloroform extracts were dried (MgSO4) and evaporated under reduced pressure to give a red oil (1.5 g). This oil was stirred under hot diethyl ether which was subsequently decanted (removing some pyridine-4-aldehyde), and the oil was subjected to chromatography on silica gel with gradient elution (100% chloroform→5% methanol in chloroform). The fractions containing the desired product were collected, combined and evaporated under reduced pressure to an oil which solidified on trituration with diethyl ether. Crystallisation from aqueous ethanol afforded a white crystalline solid (0.78 g). This was further purified by dissolution in chloroform, washing with sodium hydroxide solution (pH 13), extraction into dilute hydrochloric acid (pH 4), washing with chloroform, taking to pH 7.5 and extracting back into chloroform. This was evaporated under reduced pressure to afford an oil which was crystallised from aqueous ethanol to afford the title compound (0.53 g), m.p. 90° C.; δ(CDCl3) 1.75 (4H, m), 2.95 (2H, m), 3.40 (2H, m), 5.71 (1H, s), 7.07 (1H, dd), 7.32 (2H, d), 7.40 (3H, br), 7.46 (1H, s), 7.62 (1H, dd), 8.23 (1H, dd), 8.49 (2H, d) ppm.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[F:5][C:6]1[CH:13]=[C:12]([OH:14])[CH:11]=[CH:10][C:7]=1[C:8]#[N:9]>C(O)(=O)C>[F:5][C:6]1[CH:13]=[C:12]([OH:14])[C:11]([N+:1]([O-:4])=[O:2])=[CH:10][C:7]=1[C:8]#[N:9]
Reactant: O=[N+]([O-])O
Reactant: N#Cc1ccc(O)cc1F
Solvent: CC(=O)O
Product: N#Cc1cc([N+](=O)[O-])c(O)cc1F
Temperature: 40 °C
Yield: 30.2 %

Procedure:
Nitric acid (0.326 mL, 7.29 mmol) 70% was added dropwise to a stirred solution of 2-fluoro-4-hydroxybenzonitrile (1 g, 7.29 mmol) in acetic acid (20 mL). The resulting solution was warmed to 40° C. for 24 hr. Solvent removed under reduced pressure to afford a yellow solid. Recrystallisation from EtOH (˜15 mL) afforded 2-fluoro-4-hydroxy-5-nitrobenzonitrile (401 mg, 2.202 mmol, 30.2% yield) as a yellow solid.
Reaction SMILES: [CH:1]([C:4]1[N:13]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]3[N:25]=[C:24]([CH3:26])[O:23][N:22]=3)[CH:16]=2)[C:7]2[C:8](=[O:12])[NH:9][CH:10]=[CH:11][C:6]=2[N:5]=1)([CH3:3])[CH3:2].[C:27]([C:29]1[CH:30]=[C:31](B(O)O)[CH:32]=[CH:33][CH:34]=1)#[N:28]>ClCCl>[CH:1]([C:4]1[N:13]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]3[N:25]=[C:24]([CH3:26])[O:23][N:22]=3)[CH:16]=2)[C:7]2[C:8](=[O:12])[N:9]([C:33]3[CH:32]=[CH:31][CH:30]=[C:29]([C:27]#[N:28])[CH:34]=3)[CH:10]=[CH:11][C:6]=2[N:5]=1)([CH3:3])[CH3:2]
Reactant: N#Cc1cccc(B(O)O)c1
Reactant: Cc1nc(-c2cccc(Cn3c(C(C)C)nc4cc[nH]c(=O)c43)c2)no1
Solvent: ClCCl
Product: Cc1nc(-c2cccc(Cn3c(C(C)C)nc4ccn(-c5cccc(C#N)c5)c(=O)c43)c2)no1

Procedure:
By reaction of 2-isopropyl-3-[3-(5-methyl-[1,2,4]oxadiazol-3-yl)benzyl]-3,5-dihydroimidazo[4,5-c]pyridin-4-one with 3-cyanophenylboronic acid under copper acetate catalysis in dichloromethane, 2-isopropyl-3-[3-(5-methyl-[1,2,4]oxadiazol-3-yl)benzyl]-5-(3-cyanophenyl)-3,5-dihydroimidazo[4,5-c]pyridin-4-one is obtained. By subsequent reaction in ethanol NaHCO3 and then with hydroxylammonium chloride, 2-isopropyl-3-[3-(5-methyl-[1,2,4]oxadiazol-3-yl)benzyl]-5-(3-N-hydroxyamidinophenyl)-3,5-dihydroimidazo[4,5-c]pyridin-4-one is obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][CH:3]=1.[CH:11]([N:14]1[CH2:19][CH2:18][CH:17]([NH:20][S:21]([CH2:24][CH2:25][NH2:26])(=[O:23])=[O:22])[CH2:16][CH2:15]1)([CH3:13])[CH3:12]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([NH:26][CH2:25][CH2:24][S:21](=[O:23])(=[O:22])[NH:20][CH:17]2[CH2:18][CH2:19][N:14]([CH:11]([CH3:12])[CH3:13])[CH2:15][CH2:16]2)=[O:8])=[CH:9][CH:10]=1
Reactant: O=C(O)c1ccc(Cl)cc1
Reactant: CC(C)N1CCC(NS(=O)(=O)CCN)CC1
Product: CC(C)N1CCC(NS(=O)(=O)CCNC(=O)c2ccc(Cl)cc2)CC1

Procedure:
4-Chloro-N-[2-(1-isopropyl-piperidin-4-ylsulfamoyl)-ethyl]-benzamide was prepared by an analogous procedure as described in example 9 starting from 104 mg (1.1 equiv.) 4-chloro-benzoic acid and 150 mg (0.60 mmol) 2-amino-ethanesulfonic acid (1-isopropyl-piperidin-4-yl)-amide. Final purification by preparative RP-HPLC (CH3CN/H2O gradient+0.1% TFA) gave pure 4-chloro-N-[2-(1-isopropyl-piperidin-4-ylsulfamoyl)-ethyl]-benzamide. The title compound was obtained as its trifluoroacetate in form of a colorless amorphous material.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.F[C:8]1[CH:13]=[CH:12][C:11]([C:14](=[O:16])[CH3:15])=[CH:10][CH:9]=1>O>[N:1]1([C:8]2[CH:13]=[CH:12][C:11]([C:14](=[O:16])[CH3:15])=[CH:10][CH:9]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: CC(=O)c1ccc(F)cc1
Reactant: C1COCCN1
Solvent: O
Product: CC(=O)c1ccc(N2CCOCC2)cc1
Temperature: 120 °C
Yield: 93 %

Procedure:
A mixture of morpholine (3.2 g, 37 mmol) and 1-(4-fluorophenyl) ethanone (1.5 g, 11 mmol) is heated at 120° C. The conversion of the 1-(4-fluorophenyl) ethanone is complete after 10 hours. Water (10 ml) is than added into the reaction mixture. The precipitate is filtered off, washed with water and dried under vacuum (30° C.) to give 2.1 g of the title-compound. Yield: 93%; m.p. 95-96° C.; MS 205 (100, M+); H1 NMR (CDCl3): δ 7.99 (d, 2H), 6.86 (d, 2H), 3.86 (t, 4H), 3.30 (t, 4H), 2.53 (s, 3H); C13 NMR (CDCl3): δ 196.76, 154.43, 130.55, 128.36, 113.48, 101.16, 66.7, 47.73, 26.37.