Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:18]=[CH:17][CH:16]=[CH:15][C:5]=1[O:6][CH2:7][CH:8]([OH:14])[CH2:9][NH:10][CH2:11][CH2:12][NH2:13])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH3:25][N:26]1[C:31](=[O:32])[C:30]([Cl:33])=[C:29](Cl)[CH:28]=[N:27]1>C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4]1[CH:18]=[CH:17][CH:16]=[CH:15][C:5]=1[O:6][CH2:7][CH:8]([OH:14])[CH2:9][NH:10][CH2:11][CH2:12][NH:13][C:29]1[CH:28]=[N:27][N:26]([CH3:25])[C:31](=[O:32])[C:30]=1[Cl:33])[CH3:2]
Reactant: CCOc1ccccc1OCC(O)CNCCN
Reactant: Cn1ncc(Cl)c(Cl)c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: CCOc1ccccc1OCC(O)CNCCNc1cnn(C)c(=O)c1Cl
Temperature: 25 °C
Yield: 84 %

Procedure:
5.1 g of N-[3-(o-ethoxyphenoxy)-2-hydroxy-propyl]-ethylenediamine ##STR19## are dissolved in 50 ml of toluene, and 3 g of potassium carbonate are added to the solution. A solution of 3.6 g of 2-methyl-4,5-dichloro-pyridazin-3-one ##STR20## in 50 ml of toluene is then added to the above solution at room temperature, while stirring, and the mixture is then heated under reflux for 17 hours, while stirring. The mixture is then allowed to cool to room temperature and is filtered off under suction from the inorganic residue, and the filtrate is concentrated in vacuo. The residual oil, which solidifies after a short time, is recrystallised from ethyl acetate. The N-[3-(o-ethoxyphenoxy)-2-hydroxy-propyl]-N'-[2-methyl-3-oxo-4-chloro-pyridaz-5-yl]-ethylenediamine ##STR21## is thus obtained.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[N:6]=1.[Br:12][C:13](=[CH2:17])[C:14](O)=[O:15]>O1CCOCC1>[Br:12][C:13](=[CH2:17])[C:14]([NH:1][C:2]1[S:3][CH:4]=[C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[N:6]=1)=[O:15]
Reactant: C=C(Br)C(=O)O
Reactant: CCOC(=O)c1csc(N)n1
Solvent: C1COCCO1
Product: C=C(Br)C(=O)Nc1nc(C(=O)OCC)cs1
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.7 %

Procedure:
To a solution containing 0.688 g of ethyl 2-aminothiazole-4carboxilate (prepared as reported in J.A.C.S. 68,266,1946) and 0.3 g of 2-bromoacrylic acid in 10 ml of dioxane, 0.412 g of N-N'dicyclohexylcarbodiimide were and the mixture was stirred at room temperature overnight. After filtration, the solvent was evaporated in vacuo, the solid residue was dissolved in 50 ml of ethyl acetate, treated with saturated solution of sodium bicarbonate and then with 10% hydrochloric acid. The organic phase was dried over anhydrous sodium sulphate and the solvent evaporated in vacuo. The solid residue was purified by recrystallization from ethanol-water to yield 0.52 g of ethyl 2-(α-bromoacrylamido)thiazole-4-carboxylate.
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][CH2:5][C:6]1[CH2:10][CH:9]([C:11]([O:13][CH3:14])=[O:12])[O:8][N:7]=1>CO.O=[Pt]=O>[CH3:14][O:13][C:11](=[O:12])[CH:9]([OH:8])[CH2:10][CH:6]1[CH2:5][CH2:4][C:3](=[O:2])[NH:7]1
Reactant: COC(=O)CCC1=NOC(C(=O)OC)C1
Agent: O=[Pt]=O
Solvent: CO
Product: COC(=O)C(O)CC1CCC(=O)N1

Procedure:
A suspension of 40 g of 4,5-dihydro-5-methoxycarbonyl-3-isoxazolepropanoic acid methyl ester and 2.0 g of PtO2 in 400 ml of methanol is placed under a hydrogen atmosphere with agitation. After H2 absorption is complete, the solution is filtered and the solvent removed under reduced pressure to give an oil. The oil is triturated with anhydrous diethyl ether to yield 5-oxo-alpha-hydroxy-2-pyrrolidinepropanoic acid methyl ester as a white solid with mp 87°-90° C. NMR (CDCl3) and 6.94 (s, 1H), 4.38 (m, 1H), 3.96 (d, 1H), 3.73 (m, 1H), 3.70 (s, 3H), 2.44-1.81 (m, 6H). Ir(KBr) 3330, 3200, 2980, 1734, 1696, 1436, 1416, 1400, 1382, 1362, 1313, 1297, 1246, 1212.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH3:6])=[O:3].[NH:7]([C:49]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50])[C@H:8]([C:13]([NH:15][C@@H:16]([C:31]([NH:33][C@@H:34]([C:39]([O:41][CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)=[O:40])[CH2:35][CH2:36][CH2:37][CH3:38])=[O:32])[CH2:17][C:18]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[N:20](C(OC)=O)[CH:19]=1)=[O:14])[CH2:9][CH:10]([CH3:12])[CH3:11]>>[NH:7]([C:49]([O:51][C:52]([CH3:55])([CH3:53])[CH3:54])=[O:50])[C@H:8]([C:13]([NH:15][C@@H:16]([C:31]([NH:33][C@@H:34]([C:39]([O:41][CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)=[O:40])[CH2:35][CH2:36][CH2:37][CH3:38])=[O:32])[CH2:17][C:18]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[N:20]([C:2]([O:4][CH2:5][CH3:6])=[O:3])[CH:19]=1)=[O:14])[CH2:9][CH:10]([CH3:12])[CH3:11]
Reactant: CCCC[C@@H](NC(=O)[C@@H](Cc1cn(C(=O)OC)c2ccccc12)NC(=O)[C@H](CC(C)C)NC(=O)OC(C)(C)C)C(=O)OCc1ccccc1
Reactant: CCOC(=O)Cl
Product: CCCC[C@@H](NC(=O)[C@@H](Cc1cn(C(=O)OCC)c2ccccc12)NC(=O)[C@H](CC(C)C)NC(=O)OC(C)(C)C)C(=O)OCc1ccccc1

Procedure:
The title compound was prepared using ethyl chloroformate instead of methyl chloroformate in the same manner described in Example 1-(1) and (2).
Reaction SMILES: Cl.[F:2][C:3]1[C:4]([F:19])=[CH:5][C:6]2[N:15]=[C:14]([NH2:16])[C:13]3[CH:12]=[C:11]([CH3:17])[S:10][C:9]=3[NH:8][C:7]=2[CH:18]=1.C(N(CC)C(C)C)(C)C.[NH:29]1[CH2:34][CH2:33]N[CH2:31][C@@H:30]1[CH2:35][CH2:36][OH:37]>CS(C)=O.C1(C)C=CC=CC=1.O.C(OCC)(=O)C>[F:2][C:3]1[C:4]([F:19])=[CH:5][C:6]2[N:15]=[C:14]([N:16]3[CH2:33][CH2:34][NH:29][C@@H:30]([CH2:35][CH2:36][OH:37])[CH2:31]3)[C:13]3[CH:12]=[C:11]([CH3:17])[S:10][C:9]=3[NH:8][C:7]=2[CH:18]=1
Reactant: OCC[C@H]1CNCCN1
Reactant: Cc1cc2c(s1)Nc1cc(F)c(F)cc1N=C2N
Agent: Cl
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: CS(C)=O
Product: Cc1cc2c(s1)Nc1cc(F)c(F)cc1N=C2N1CCN[C@@H](CCO)C1
Temperature: 120 °C
Yield: 41.3 %

Procedure:
Dissolve 6,7-difluoro-2-methyl-4H-3-thia-4,9-diaza-benzo[f]azulen-10-ylamine hydrochloride (1.51, 4.99 mmol), N,N-diisopropylethylamine (0.91 mL, 5.24 mmol) and (S)-2-piperazin-2-yl-ethanol (1.3 g, 9.99 mmol) in dimethylsulfoxide/toluene (1:2)(18 ml), stir under nitrogen and heat in an oil bath at 120° C. for 72 hours. Dilute the mixture with water (20 mL) and ethyl acetate (40 mL), separate layers and extract the aqueous with ethyl acetate. Combine all ethyl acetate extracts and wash with water and brine. Dry the organic phase (Na2SO4), filter and concentrate under reduced pressure. Purify by silica gel chromatography (eluent: 0-13% 2N ammonia in methanol/dichloromethane) to give 780 mg of impure product. Purify by silica gel chromatography (eluent: 85% dichloromethane/10% acetonitrile/0%2N ammonia in methanol to 80% dichloromethane/10% acetonitrile/10% 2N ammonia in methanol) to give the title compound (516 mg, 27%): Mass Spectrum (ESMS) 379 (M+1); 377 (M−1).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([CH:11]([CH2:14][CH2:15][O:16][CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][O:18]2)[C:12]#[N:13])[CH:7]=[CH:8][C:9]=1[Cl:10].Br[CH2:24][CH2:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28].O>CN(C)C=O>[O:18]1[CH2:19][CH2:20][CH2:21][CH2:22][CH:17]1[O:16][CH2:15][CH2:14][C:11]([C:12]#[N:13])([C:6]1[CH:7]=[CH:8][C:9]([Cl:10])=[C:4]([Cl:3])[CH:5]=1)[CH2:24][CH2:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28]
Reactant: N#CC(CCOC1CCCCO1)c1ccc(Cl)c(Cl)c1
Reactant: CCOC(=O)CCCBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CCCC(C#N)(CCOC1CCCCO1)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 48.9 %

Procedure:
4.6 g of 60% NaH are added in small portions to a solution of 36 g of the above 3,4-dichloro-α-[(2-tetrahydropyranyloxy)ethyl]benzeneacetonitrile (prepared according to PREPARATION II (a)) in 100 ml of dimethylformamide. The reaction mixture is stirred for 3 hours at room temperature and cooled to 0° C. and 22.4 g of ethyl 4-bromobutyrate in 40 ml of dimethylformamide are then added. The reaction mixture is stirred for 3 hours at room temperature, poured into water and extracted with ether and the extract is washed with a saturated solution of NaCl, dried over Na2SO4 and concentrated under vacuum. The residue obtained is purified by chromatography on silica gel using toluene as the eluent to give 24 g of the expected product.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][NH:9][C:10](=[S:13])[NH:11][NH2:12])[CH2:3][CH2:2]1.[C:14]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=1)(=O)[CH3:15].C(O)C>C(O)(=O)C>[O:1]1[CH2:2][CH2:3][N:4]([CH2:7][CH2:8][NH:9][C:10](=[S:13])[NH:11][N:12]=[C:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)[CH3:15])[CH2:5][CH2:6]1
Reactant: NNC(=S)NCCN1CCOCC1
Reactant: CC(=O)c1ccccn1
Solvent: CCO
Solvent: CC(=O)O
Product: CC(=NNC(=S)NCCN1CCOCC1)c1ccccn1
Reaction time: 8 h

Procedure:
A mixture of 6.00 g (0.0294 mole) of 4-(2-morpholinoethyl)thiosemicarbazide, 3.91 g (0.0323 mole) of 2-acetylpyridine, 20 mL of 95% ethanol, and 0.4 mL of glacial acetic acid was heated under reflux for 1.25 hours. The mixture then stood overnight at room temperature. Colourless crystals were collected and recrystallised from 40 mL of 95% ethanol; yield 7.81 g (86%) of pale yellow crystals of 2-acetylpryridine 4-(2-morpholinoethyl)thiosemicarbazone, mp 167.5°-169° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH3:22])[CH2:10][O:11][C:12]1[CH:13]=[CH:14][C:15]([C:18]([O:20]C)=[O:19])=[N:16][CH:17]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1COCC1.[OH-].[Na+].Cl>[Cl-].[Na+].O.CO>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH3:22])[CH2:10][O:11][C:12]1[CH:13]=[CH:14][C:15]([C:18]([OH:20])=[O:19])=[N:16][CH:17]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1ccc(OC[C@H](C)NC(=O)OC(C)(C)C)cn1
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: C[C@@H](COc1ccc(C(=O)O)nc1)NC(=O)OC(C)(C)C

Procedure:
Diisopropyl azodicarboxylate (1.9 M solution in toluene, 9.52 mL) was added to a mixture of methyl 5-hydroxypyridine-2-carboxylate (5.00 g), tert-butyl [(1S)-2-hydroxy-1-methylethyl]carbamate (8.58 g), triphenylphosphine (12.9 g), and THF (50 mL) at 0° C. dropwise. The mixture was stirred at room temperature for 3 days. The mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give methyl 5-({(2S)-2-[(tert-butoxycarbonyl)amino]propyl}oxy)pyridine-2-carboxylate (810 mg) as a mixture with impurities. A mixture of methyl 5-({(2S)-2-[(tert-butoxycarbonyl)amino]propyl}oxy)pyridine-2-carboxylate (810 mg, a mixture with impurities), THF (8 mL), methanol (8 mL), and 1 M sodium hydroxide (8 mL) was stirred at room temperature for 4 hr. The mixture was neutralized with 1 M hydrochloric acid at 0° C., and brine was added. The mixture was extracted with ethyl acetate. The organic layer was separated, washed with water and brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 5-({(2S)-2-[(tert-butoxycarbonyl)amino]propyl}oxy)pyridine-2-carboxylic acid (765 mg) as a mixture with impurities. A mixture of 5-({(2S)-2-[(tert-butoxycarbonyl)amino]propyl}oxy)pyridine-2-carboxylic acid (765 mg, a mixture with impurities), 4-aminobenzene-1,3-diol hydrochloride (417 mg), HATU (982 mg), N,N-diisopropylethylamine (0.902 ml), and DMF (7 mL) was stirred at room temperature overnight. Water was added, and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (442 mg) as a pale yellow oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10][CH2:9]2)=[CH:4][C:3]=1[NH:21][S:22]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)(=[O:24])=[O:23].[CH3:31][C:32]1[CH:37]=[C:36]([O:38][C:39](F)(F)F)[CH:35]=[CH:34][C:33]=1[S:43](Cl)(=[O:45])=[O:44]>>[CH3:39][O:38][C:36]1[CH:35]=[CH:34][C:33]([S:43]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([N:8]3[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]3)=[CH:4][C:3]=2[NH:21][S:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)(=[O:24])=[O:23])(=[O:45])=[O:44])=[C:32]([CH3:31])[CH:37]=1
Reactant: Cc1cc(OC(F)(F)F)ccc1S(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(N)c(NS(=O)(=O)c3ccccc3)c2)CC1
Product: COc1ccc(S(=O)(=O)Nc2ccc(N3CCNCC3)cc2NS(=O)(=O)c2ccccc2)c(C)c1

Procedure:
4-Methoxy-2-methyl-N-[2-[(phenylsulfonyl)amino]-4-(1-piperazinyl)phenyl]benzenesulfonamide was synthesized from N-{2-amino-5-(4-t-butyloxycarbonyl-piperazinyl)-phenyl}benzenesulfonamide and 2-methyl-4-trifluoromethoxybenzenesulfonylchloride (53 mg, 0.455 mmol) according to general method 3 to give before Boc-deprotection 70 mg of a purple solid. MS (posES-FIA) m/z=Found: 571.2. Calcd 571.12. 1H NMR δ 773-7.09 (m, 8H), 6.86 (d, 1H), 6.69 (dd, 1H), 6.48 (d, 1H), 3.29-3.17 (m, 8H), 2.62 (s, 3H).
Reaction SMILES: [C:1]1([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:14]([O-])=[O:15].[Na+].S(=O)(=O)(O)O>ClC=C(Cl)Cl>[N:14]([N:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)=[O:15]
Reactant: O=N[O-]
Reactant: c1ccc(Nc2ccccc2)cc1
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: ClC=C(Cl)Cl
Product: O=NN(c1ccccc1)c1ccccc1

Procedure:
210 g of 20% diphenylamine solution in trichloroethylene, 59 g of 38% sodium nitrite aqueous solution and 150 g of 20% sulfuric acid are simultaneously fed, under stirring, (Re = 8-10×103) at 17°-20° C. for about 7-10 min into a 500 ml reactor equipped with a cooling jacket, a thermometer and an agitator; this is followed by another stirring for about 5-8 min. The stirring is discontinued after said period of time has elapsed; complete layer separation of the organic and aqueous phases takes place during 15-20 min. 217 g of organic phase containing 48.4 g of N-nitrosodiphenylamine and 0.42 g of diphenylamine are obtained. Diphenylamine conversion degree is 99%; N-nitrosodiphenylamine yield, 99.3% in terms of converted diphenylamine.
Reaction SMILES: CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.Cl[C:36]1[C:45]2[C:40](=[CH:41][C:42]([F:46])=[CH:43][CH:44]=2)[N:39]=[C:38]([C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][N:48]=2)[C:37]=1[CH3:53].[NH2:54][C:55]1[CH:56]=[C:57]([NH:67][C:68](=[O:72])[CH:69]([CH3:71])[CH3:70])[CH:58]=[C:59]([N:61]2[CH2:66][CH2:65][O:64][CH2:63][CH2:62]2)[CH:60]=1.C(=O)([O-])[O-].[K+].[K+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(O)(C)(C)C>[F:46][C:42]1[CH:41]=[C:40]2[C:45]([C:36]([NH:54][C:55]3[CH:56]=[C:57]([NH:67][C:68](=[O:72])[CH:69]([CH3:70])[CH3:71])[CH:58]=[C:59]([N:61]4[CH2:66][CH2:65][O:64][CH2:63][CH2:62]4)[CH:60]=3)=[C:37]([CH3:53])[C:38]([C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][N:48]=3)=[N:39]2)=[CH:44][CH:43]=1
Reactant: Cc1c(-c2ccccn2)nc2cc(F)ccc2c1Cl
Reactant: CC(C)C(=O)Nc1cc(N)cc(N2CCOCC2)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: CC(C)(C)O
Product: Cc1c(-c2ccccn2)nc2cc(F)ccc2c1Nc1cc(NC(=O)C(C)C)cc(N2CCOCC2)c1

Procedure:
Prepared according to Procedure X by stirring palladium (II) acetate (2.325 mg, 10.36 μmol), XPhos (0.015 g, 0.031 mmol), 4-chloro-7-fluoro-3-methyl-2-(pyridin-2-yl)quinoline (0.056 g, 0.207 mmol), N-(3-amino-5-morpholinophenyl)-isobutyramide (0.060 g, 0.228 mmol), potassium carbonate (0.072 g, 0.518 mmol), and tert-butanol (1 mL) at 110° C. for 20 minutes. Purification by reverse-phase HPLC (0-70% acetonitrile in water) afforded N-(3-((7-fluoro-3-methyl-2-(2-pyridinyl)-4-quinolinyl)amino)-5-(4-morpholinyl)phenyl)-2-methylpropanamide as a yellow amorphous solid. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.74 (1H, d, J=4.5 Hz), 7.92 (2H, d, J=6.8 Hz), 7.86 (1H, s), 7.78 (1H, d), 7.42 (1H, t), 7.18 (2H, m), 6.35 (1H, br. s.), 6.11 (1H, s), 3.74-3.84 (4H, m), 3.05-3.17 (4H, m), 2.32 (3H, s), 1.20 (3H, s), 1.18 (3H, s). Mass Spectrum (ESI) m/e=499.8 (M+1).
Reaction SMILES: [CH:1]1([NH2:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13](Cl)=[O:14]>ClCCl>[CH:1]1([NH:7][C:13](=[O:14])[CH2:12][CH2:11][CH2:10][CH2:9][Cl:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NC1CCCCC1
Reactant: O=C(Cl)CCCCCl
Solvent: ClCCl
Product: O=C(CCCCCl)NC1CCCCC1
Temperature: 0 °C
Reaction time: 6 h

Procedure:
Dissolve cyclohexylamine (8.86 mL, 77.5 mmol) in dichloromethane (700 mL), cool to 0° C. and add 5-chloropentanoyl chloride (10 mL, 77.5 mmol). After 6 h, wash the mixture with 1N HCl and saturated aqueous sodium bicarbonate and brine, dry the organic layer over sodium sulfate and evaporate to a white solid to obtain 5-chloro-pentanoic acid cyclohexylamide: MS (EI) m/z=217 (M+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[C:15]([C:16]([O:18]C)=[O:17])=[N:14][CH:13]=[CH:12][N:11]3[CH:20]=2)=[CH:4][CH:3]=1.O.O.[OH-].[Li+]>O1CCOCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[C:15]([C:16]([OH:18])=[O:17])=[N:14][CH:13]=[CH:12][N:11]3[CH:20]=2)=[CH:4][CH:3]=1
Reactant: COC(=O)c1nccn2cc(-c3ccc(F)cc3)nc12
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)c1nccn2cc(-c3ccc(F)cc3)nc12
Temperature: 50 °C
Yield: 156 %

Procedure:
The crude methyl 2-(4-fluorophenyl)imidazo[1,2-a]pyrazine-8-carboxylate (35.7 g, 65.8 mmol) was dissolved in 1,4-dioxane (200 mL), then water (20.2 mL) and lithium hydroxide monohydrate (27.6 g, 658 mmol) were added. Heated to about 50° C. overnight. The reaction mixture was cooled to ambient temperature, filtered, and the collected solid was washed with Et2O (4×70 mL). The resulting brown solid was suspended in water (200 mL) and the pH was adjusted to ˜5 with glacial HOAc (100 mL). The solid was collected, washed with water (4×75 mL) and Et2O (2×80 mL) to give the wet crude title compound (26.4 g, 156%) that was carried on without further purification. LC/MS (Table 1, Method b) Rt=1.21 min; MS m/z: 258.2 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[OH:9].CC(C)([O-])C.[K+].C(=O)([O-])[O-].[Cs+].[Cs+].Cl[CH2:25][C:26]1[NH:35][C:34](=[O:36])[C:33]2[C:28](=[CH:29][C:30]([C:37]([O:39][CH3:40])=[O:38])=[CH:31][CH:32]=2)[N:27]=1>C1COCC1.[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C=O)C>[O:36]=[C:34]1[C:33]2[C:28](=[CH:29][C:30]([C:37]([O:39][CH3:40])=[O:38])=[CH:31][CH:32]=2)[N:27]=[C:26]([CH2:25][O:9][C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[C:2]([F:10])([F:11])[F:1])[NH:35]1
Reactant: Oc1ccccc1C(F)(F)F
Reactant: COC(=O)c1ccc2c(=O)[nH]c(CCl)nc2c1
Agent: CC(C)(C)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2c(=O)[nH]c(COc3ccccc3C(F)(F)F)nc2c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 2-(trifluoromethyl)phenol (36 mg, 0.22 mmol) in THF (1 mL) was added potassium tert-butoxide (24 mg, 0.22 mmol) and the reaction was stirred at rt for 3 h. Then tetra-n-butylammonium iodide (9 mg, 0.024 mmol), cesium carbonate (78 mg, 0.24 mmol) and methyl 2-(chloromethyl)-4-oxo-3,4-dihydroquinazoline-7-carboxylate (30 mg, 0.12 mmol) in DMF (1 mL) was added. The reaction mixture was stirred at rt for 2 d. The mixture was then concentrated to afford methyl 4-oxo-2-{[2-(trifluoromethyl)phenoxy]methyl}-3,4-dihydroquinazoline-7-carboxylate. LC-MS: (FA) ES+379.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([OH:15])=[O:14])=[C:11]([S:18]([CH3:21])(=[O:20])=[O:19])[C:10]=1F.O.[OH-].[Li+].O>CN(C)C=O>[Cl:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([OH:15])=[O:14])=[C:11]([S:18]([CH3:21])(=[O:20])=[O:19])[C:10]=1[O:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CS(=O)(=O)c1c(C(=O)O)ccc(Cl)c1F
Reactant: Oc1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: CS(=O)(=O)c1c(C(=O)O)ccc(Cl)c1Oc1ccccc1
Temperature: 100 °C
Yield: 70.4 %

Procedure:
Phenol (2.26 g) was added to a mixture of 4-chloro-3-fluoro-2-methylsulphonylbenzoic acid (4.46 g) and lithium hydroxide monohydrate (1.65 g) in N,N-dimethylformamide and the mixture was stirred and heated at 100° C. overnight. It was cooled, poured into water and acidified to pH 1, extracted with ethyl acetate and the organic phase extracted into aqueous sodium bicarbonate solution. The aqueous layer was acidified to pH 1 and extracted with ethyl acetate, washed with water, dried (magnesium sulphate) and filtered. The filtrate was evaporated to dryness to give 4-chloro-2-methylsulphonyl-3-phenoxybenzoic acid (4.06 g) as an off-white solid m.p. 231°-235° C.
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[CH:6][CH:5]=[N:4]1.F[C:9]1[CH:10]=[C:11]([C:19]([O:21][CH3:22])=[O:20])[C:12](=[CH:17][CH:18]=1)[C:13]([O:15][CH3:16])=[O:14]>CN1CCCC1=O>[N:3]1([C:18]2[CH:17]=[C:12]([C:13]([O:15][CH3:16])=[O:14])[C:11](=[CH:10][CH:9]=2)[C:19]([O:21][CH3:22])=[O:20])[CH:7]=[CH:6][CH:5]=[N:4]1
Reactant: c1cn[nH]c1
Reactant: COC(=O)c1ccc(F)cc1C(=O)OC
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: COC(=O)c1ccc(-n2cccn2)cc1C(=O)OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 50.2 %

Procedure:
26 g of oily sodium hydride was added over 40 min to 200 ml solution of 44 g pyrazole in 1-methyl-2-pyrrolidinone. 125 g of dimethyl 4-fluorophthalate was added thereto over 30 min and stirred at room temperature for 2 hr. The reaction solution was cooled to 0° C. and added to ice water. It was extracted with ethyl acetate, and washed with saturated sodium bicarbonate and brine. It was dried over anhydrous magnesium sulfate and filtered. The filtrate was evaporated, and diethyl ether was added to the resulting crystalline residue which was then collected by filtration to give 77 g of dimethyl 4-(1H-1-pyrazolyl)phthalate.
Reaction SMILES: [C:1]([O:5][C:6](=[O:31])[NH:7][C:8]([C:10]1[CH:15]=[CH:14][C:13]([CH2:16][NH:17][C:18]([C@H:20]2[N:24]3[C:25](=[O:30])[C:26]([NH2:29])=[CH:27][N:28]=[C:23]3[CH2:22][CH2:21]2)=[O:19])=[CH:12][CH:11]=1)=[NH:9])([CH3:4])([CH3:3])[CH3:2].[CH3:32][S:33](Cl)(=[O:35])=[O:34]>N1C=CC=CC=1.CCOC(C)=O>[C:1]([O:5][C:6](=[O:31])[NH:7][C:8](=[NH:9])[C:10]1[CH:15]=[CH:14][C:13]([CH2:16][NH:17][C:18]([C@H:20]2[N:24]3[C:25](=[O:30])[C:26]([NH:29][S:33]([CH3:32])(=[O:35])=[O:34])=[CH:27][N:28]=[C:23]3[CH2:22][CH2:21]2)=[O:19])=[CH:12][CH:11]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC(=N)c1ccc(CNC(=O)[C@@H]2CCc3ncc(N)c(=O)n32)cc1
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NC(=N)c1ccc(CNC(=O)[C@@H]2CCc3ncc(NS(C)(=O)=O)c(=O)n32)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 22 %

Procedure:
To a solution of 1j (50 mg, 0.117 mmol) in 0.5 mL pyridine at 0° C. was added methanesulfonyl chloride (14.8 mg, 0.129 mmol). The solution was stirred at rt for 16 h. The mixture was diluted with 50 mL EtOAc, washed with H2O (2×) and brine, dried (Na2SO4) and concentrated to afford 13 mg (22%) of intermediate 16a. MS (ESI) 505.0 (M+H+).
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([C:8]([C:10]2[CH:19]=[CH:18][C:17]3[C:16]([CH3:21])([CH3:20])[CH2:15][CH2:14][C:13]([CH3:23])([CH3:22])[C:12]=3[CH:11]=2)=[O:9])[CH:5]=C[CH:7]=1.C(N(CCCC)CCCC)CCC.[C]=O.[C:39]([O:42][CH2:43]C)(=[O:41])[CH3:40]>CO.C([O-])(=O)C.C([O-])(=O)C.[Pd+2]>[CH3:20][C:16]1([CH3:21])[CH2:15][CH2:14][C:13]([CH3:22])([CH3:23])[C:12]2[CH:11]=[C:10]([C:8]([C:4]3[CH:5]=[C:40]([CH:7]=[CH:2][CH:3]=3)[C:39]([O:42][CH3:43])=[O:41])=[O:9])[CH:19]=[CH:18][C:17]1=2
Reactant: CCOC(C)=O
Reactant: CC1(C)CCC(C)(C)c2cc(C(=O)c3cccc(I)c3)ccc21
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [C]=O
Solvent: CO
Solvent: CCCCN(CCCC)CCCC
Product: COC(=O)c1cccc(C(=O)c2ccc3c(c2)C(C)(C)CCC3(C)C)c1

Procedure:
A solution of 3-iodophenyl-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)methanone (10.5 g, 25.1 mmol), palladium diacetate (564 mg, 2.5 mmol) and tributylamine (12 ml, 50.5 mmol) in methanol (500 ml) is heated for 3 h at 100° C. under a pressure of carbon monoxide (3 bar). After concentration on an evaporator under vacuum at 40° C., the oil obtained is diluted in ethyl acetate and washed three times with water. The product is purified by flash chromatography on a column of silica.