Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:14])[C@:8]12[CH2:16][C@H:15]1[C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=1)=[O:4].O.[OH-].[Li+]>CO>[F:23][C:20]1[CH:19]=[CH:18][C:17]([C@@H:15]2[C@:8]3([C:7]4[C:11](=[CH:12][CH:13]=[C:5]([C:3]([OH:4])=[O:2])[CH:6]=4)[NH:10][C:9]3=[O:14])[CH2:16]2)=[CH:22][CH:21]=1
Reactant: COC(=O)c1ccc2c(c1)[C@]1(C[C@H]1c1ccc(F)cc1)C(=O)N2
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1ccc2c(c1)[C@@]1(C[C@@H]1c1ccc(F)cc1)C(=O)N2
Temperature: 25 °C
Reaction time: 14 h
Yield: 39.3 %

Procedure:
To a solution of (1S,2R) and (1R,2S)-methyl-2-(4-fluorophenyl)-2′-oxospiro [cyclopropane-1,3′-indoline]-5′-carboxylate (80 mg) in methanol (1 mL); water (0.1 mL) was added lithium hydroxide (10 mg) at room temperature. The mixture was stirred for 14 hours at room temperature. HPLC monitored the reaction finished. The solvent was removed under reduced pressure. The residue was dissolved in 2 mL of DMF. Purification by preparative HPLC gave the title compound as white solid (30 mg). LC/MS m/e calcd. for C17H12FNO3 297, observed (M−H)+: 296. 1HNMR (400 MHz, DMSO-d6) δppm 1.99 (dd, J=9.09, 4.80 Hz, 1 H) 2.35 (dd, J=8.08, 4.80 Hz, 1 H), 3.11 (t, J=8.46 Hz, 1 H) 6.65 (d, J=1.52 Hz, 1 H) 6.94 (d, J=8.08 Hz, 1 H) 7.14 (t, J=8.84 Hz, 2 H) 7.34 (dd, J=8.34, 5.56 Hz, 2 H) 7.72 (dd, J=8.08, 1.52 Hz, 1 H) 10.97 (s, 1 H) 12.36 (br. s., 1 H).
Reaction SMILES: [Li]CCCC.Br[C:7]1[CH:11]=[CH:10][O:9][CH:8]=1.CON(C)[C:15](=[O:25])[CH2:16][NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21].C([O-])(O)=O.[Na+]>CCOCC.C1COCC1>[O:9]1[CH:10]=[CH:11][C:7]([C:15](=[O:25])[CH2:16][NH:17][C:18](=[O:24])[O:19][C:20]([CH3:21])([CH3:22])[CH3:23])=[CH:8]1
Reactant: CON(C)C(=O)CNC(=O)OC(C)(C)C
Reactant: Brc1ccoc1
Agent: O=C([O-])O
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCC(=O)c1ccoc1
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 37.2 %

Procedure:
To a solution of n-BuLi (2.5 M in hexane, 7.68 mL) in anhydrous ether (10 mL) was added dropwise (over a 20-min period) a solution of 3-bromofuran (2.35 g, 16 mmol) in anhydrous THF (15 mL) under nitrogen atmosphere at −78° C. After stirring at −78° C. for 20 min, a solution of the Weinreb amide 45 (1.75 g, 8 mmol) in THF (15 mL) was added slowly to the mixture. The reaction mixture was allowed to warm to room temperature and stirred for 18 h. The mixture was poured into a saturated NaHCO3 solution and extracted with EtOAc. The organic phase was dried over anhydrous MgSO4, filtered and evaporated under vacuum. The residue was further purified by silica column chromatography to provide the titled compound (671 mg, 37%). MNa+248.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([O:11][CH2:12][CH3:13])[N:3]=1.C(=O)([O-])[O-].[K+].[K+].[Cl:20][C:21]1[S:22][C:23]([CH2:26][NH:27][CH2:28][CH3:29])=[CH:24][N:25]=1.O>CN(C)C=O>[CH2:12]([O:11][C:4]1[N:3]=[C:2]([N:27]([CH2:26][C:23]2[S:22][C:21]([Cl:20])=[N:25][CH:24]=2)[CH2:28][CH3:29])[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=1)[CH3:13]
Reactant: CCNCc1cnc(Cl)s1
Reactant: CCOc1ccc([N+](=O)[O-])c(Cl)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOc1ccc([N+](=O)[O-])c(N(CC)Cc2cnc(Cl)s2)n1
Temperature: 25 °C
Yield: 43.9 %

Procedure:
1.36 g of 2-chloro-6-ethoxy-3-nitropyridine, 10 mL of N,N-dimethylformamide (DMF), and 2.00 g of potassium carbonate were added to a 100 mL single neck flask, under stirring at room temperature, 1.20 g of 2-chloro-5-ethylaminomethylthiazole prepared in the example 1 in 5.0 mL of DMF was added dropwise. After that, the reaction solution was heated to 40-80° C. and reacted for 3-6 hr. After cooling down, the resulting mixture was added to water (50 mL), then treated by the method according to the example 1 to obtain 1.01 g of 6-ethoxy-N-((2-chlorothiazole-5-yl)methyl)-N-ethyl-3-nitropyridin-2-amine, a viscous liquid, with 98.6% purity, a yield of 43.2%, and the structure was confirmed by GC-Mass and 1H NMR.
Reaction SMILES: C1C2C(CO[C:16]([NH:18][C@H:19]([C:26]([NH:28][CH2:29][CH2:30][C:31]3[CH:38]=[CH:37][C:35]([OH:36])=[C:33]([OH:34])[CH:32]=3)=[O:27])[CH2:20][O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:17])C3C(=CC=CC=3)C=2C=CC=1.[OH:39][C:40]1[C:49]2[C:44](=[C:45]([OH:50])[CH:46]=[CH:47][CH:48]=2)[N:43]=[C:42](C(O)=O)[CH:41]=1>>[OH:39][C:40]1[C:49]2[C:44](=[C:45]([OH:50])[CH:46]=[CH:47][CH:48]=2)[N:43]=[C:42]([C:16]([NH:18][C@H:19]([C:26]([NH:28][CH2:29][CH2:30][C:31]2[CH:38]=[CH:37][C:35]([OH:36])=[C:33]([OH:34])[CH:32]=2)=[O:27])[CH2:20][O:21][C:22]([CH3:23])([CH3:24])[CH3:25])=[O:17])[CH:41]=1
Reactant: CC(C)(C)OC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)NCCc1ccc(O)c(O)c1
Reactant: O=C(O)c1cc(O)c2cccc(O)c2n1
Product: CC(C)(C)OC[C@H](NC(=O)c1cc(O)c2cccc(O)c2n1)C(=O)NCCc1ccc(O)c(O)c1

Procedure:
The title compound was prepared from N-[Nα-(9-fluorenylmethoxycarbonyl)-O-tert-butyl-L-seryl]dopamine (676 mg, 1.3 mmol, example 42, step A) as described for example 42 (step B) using 4,8-dihydroxyquinoline-2-carboxylic acid (402 mg, 1.96 mmol) instead of caffeic acid. The crude material was purified by flash chromatography using successively 30%, 40% and 70% EtOAc/CH2Cl2/1% AcOH as the eluent. The title compound was obtained as a yellow powder (130 mg, 21%).
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:5]([CH3:15])=[C:6]([C:9]([OH:14])=[C:10]([CH3:13])[C:11]=1[CH3:12])[CH:7]=O)[CH3:2].[CH:16]([C:19]1[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][C:20]=1[O:21][CH2:22][CH2:23][NH2:24])([CH3:18])[CH3:17]>C1C=CC=CC=1>[CH2:1]([O:3][C:4]1[C:5]([CH3:15])=[C:6]([C:9]([OH:14])=[C:10]([CH3:13])[C:11]=1[CH3:12])[CH2:7][NH:24][CH2:23][CH2:22][O:21][C:20]1[CH:25]=[C:26]([CH3:29])[CH:27]=[CH:28][C:19]=1[CH:16]([CH3:18])[CH3:17])[CH3:2]
Reactant: CCOc1c(C)c(C)c(O)c(C=O)c1C
Reactant: Cc1ccc(C(C)C)c(OCCN)c1
Solvent: c1ccccc1
Product: CCOc1c(C)c(C)c(O)c(CNCCOc2cc(C)ccc2C(C)C)c1C
Temperature: 25 °C
Reaction time: 16 h
Yield: 79.5 %

Procedure:
A solution of 3-ethoxy-6-hydroxy-2,4,5-trimethylbenzaldehyde (2.08 g) and 2-(2-isopropyl-5-methylphenoxy)ethylamine (1.93 g) in benzene (50 ml) was refluxed under heating for 6 hours in a Dean-Stark extractor. The solvent was distilled off under reduced pressure and the residue was suspended in ethanol (100 ml). Sodium borohydride (0.40 g) was added with ice-cooling and the mixture was stirred at room temperature for 16 hours. The solvent was distilled off under reduced pressure and water was added. The mixture was extracted with ethyl acetate and the obtained extract was purified by silica gel column chromatography (eluent; ethyl acetate/benzene=1/1) to give 3.06 g of a colorless solid. The solid was recrystallized from a mixed solvent of ethanol-methanol to give 1.99 g of the title compound (colorless needle crystals).
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].Br[CH:8](Br)[C:9]([C:11]([F:14])([F:13])[F:12])=O.[NH2:16][CH:17]([C:21]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=1[F:28])[C:18]([NH2:20])=[O:19].Cl>O>[F:28][C:22]1[CH:23]=[C:24]([F:27])[CH:25]=[CH:26][C:21]=1[C:17]1[C:18](=[O:19])[NH:20][C:9]([C:11]([F:14])([F:13])[F:12])=[CH:8][N:16]=1
Reactant: NC(=O)C(N)c1ccc(F)cc1F
Reactant: O=C(C(Br)Br)C(F)(F)F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: O=c1[nH]c(C(F)(F)F)cnc1-c1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a mixed solution of 121 g of sodium carbonate and 400 ml of water was added dropwise 77.1 g of 1,1-dibromo-3,3,3-trifluoroacetone at such a rate that the temperature of the reaction mixture became not higher than 55° C. After completion of the dropwise addition, the mixture was stirred at room temperature for 30 minutes, followed by adding 500 ml of water and then 40 g of 2-amino-2-(2,4-difluorophenyl)acetamide, and the reaction was allowed to proceed at 60° C. for 2 hours. After completion of the reaction, the reaction mixture was cooled to 10° C. or lower, made acidic by adding 80 ml of concentrated hydrochloric acid at the same temperature, and extracted with ethyl acetate. The organic layer was washed with water and then saturated sodium chloride solution, dried with anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography (eluent, hexane/ethyl acetate=4:1), which afforded 23.3 g (yield, 39%) of the desired compound, 3-(2,4-difluorophenyl)-6-trifluoromethyl-2-oxo-1,2-dihydropyrazine (compound 1-1004; m.p., 178.9° C.). The continued elution with the above solvent system gave 13.2 g of the configurational isomer, 3-(2,4-difluorophenyl)-5-trifluoromethyl-2-oxo-1,2-dihydropyrazine (m.p., 164.6° C.).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH:10]([C:12]1[O:13][CH:14]=[CH:15][CH:16]=1)O)=[O:7])([CH3:4])([CH3:3])[CH3:2].P(Cl)(Cl)(Cl)(Cl)[Cl:18]>>[C:1]([O:5][C:6]([NH:8][CH2:9][CH:10]([Cl:18])[C:12]1[O:13][CH:14]=[CH:15][CH:16]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: CC(C)(C)OC(=O)NCC(O)c1ccco1
Product: CC(C)(C)OC(=O)NCC(Cl)c1ccco1

Procedure:
Following the procedure described in Example 42(b), 14 g of 2-t-butoxycarbonylamino-1-(2-furyl)ethanol [prepared as described in step (a) above] was treated with phosphorus pentachloride to afford 15 g of the title compound as crystals, melting at 75°-77° C. This substance was used for the next step without purification because it was decomposed by silica gel column chromatography.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].S(=O)(=O)(O)O.[CH2:19](O)[CH3:20]>>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH2:19][CH3:20])=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12]
Reactant: CCO
Reactant: O=C(O)c1ccc(Cl)c([N+](=O)[O-])c1
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Yield: 97 %

Procedure:
4-Chloro-3-nitrobenzoic acid (300 g) was dissolved in ethyl alcohol (1500 ml) and concentrated sulfuric acid (100 ml) was added with ice-cooling. The mixture was refluxed under heating for 7 hr. The reaction mixture was poured into ice-cold water and the precipitated crystals were collected by filtration to give the title compound (332 g, yield 97%).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][CH:3]=1.[CH3:10][O:11][CH:12]([O:16][CH3:17])[C:13](=O)[CH3:14]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]/[N:7]=[C:13](/[CH3:14])\[CH:12]([O:16][CH3:17])[O:11][CH3:10])=[CH:4][CH:3]=1
Reactant: COC(OC)C(C)=O
Reactant: NCc1ccc(Cl)cc1
Solvent: Cc1ccccc1
Product: COC(OC)/C(C)=N\Cc1ccc(Cl)cc1
Yield: 100 %

Procedure:
In a three-necked round bottomed flask equipped with a Dean Stark trap and reflux cooler, a solution of 4-chlorobenzylamine (97.3 g, 0.687 mol) and 1,1-dimethoxy-propan-2-one (89.5 g, 0.758 mol) in toluene (300 mL) was heated for 3 h at reflux. The reaction mixture was cooled down and the solvent removed in vacuo to yield the title compound as a pale yellow oil (166 g, 0.687 mol, 100%). MS (ES+): 242 (M(C12H1635ClNO2)+H)+.MS (ES+): 242 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[CH:9]([CH3:24])[C:10]([C:16]1[N:20]([CH3:21])[C:19]([C:22]#[N:23])=[CH:18][CH:17]=1)([OH:15])[C:11]([F:14])([F:13])[F:12].Cl[C:26]1[CH:35]=[CH:34][C:29]([C:30]([O:32]C)=[O:31])=[CH:28][N:27]=1>>[Cl:1][C:2]1[CH:7]=[C:6]([CH:5]=[CH:4][C:3]=1[CH:9]([CH3:24])[C:10]([C:16]1[N:20]([CH3:21])[C:19]([C:22]#[N:23])=[CH:18][CH:17]=1)([OH:15])[C:11]([F:14])([F:13])[F:12])[O:8][C:26]1[CH:35]=[CH:34][C:29]([C:30]([OH:32])=[O:31])=[CH:28][N:27]=1
Reactant: CC(c1ccc(O)cc1Cl)C(O)(c1ccc(C#N)n1C)C(F)(F)F
Reactant: COC(=O)c1ccc(Cl)nc1
Product: CC(c1ccc(Oc2ccc(C(=O)O)cn2)cc1Cl)C(O)(c1ccc(C#N)n1C)C(F)(F)F

Procedure:
The title compound was prepared in analogy to Example 227, step 3, from 5-[2-(2-chloro-4-hydroxy-phenyl)-1-hydroxy-1-trifluoromethyl-propyl]-1-methyl-1H-pyrrole-2-carbonitrile (Example 232 step 2) and methyl 6-chloronicotinate (CAS Reg. No. 73781-91-6). White foam. MS (m/e, ISP neg. ion)=477.9 [M−H+].
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:6][NH:7][C:8]1[CH:15]=[CH:14][C:11]([CH:12]=O)=[CH:10][C:9]=1[N+:16]([O-:18])=[O:17].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C([O-])(O)=O.[Na+]>C1COCC1.C(O)(=O)C>[CH3:6][NH:7][C:8]1[CH:15]=[CH:14][C:11]([CH2:12][N:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)=[CH:10][C:9]=1[N+:16]([O-:18])=[O:17]
Reactant: CNc1ccc(C=O)cc1[N+](=O)[O-]
Reactant: C1CCNC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CNc1ccc(CN2CCCC2)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
5.55 g (78.0 mmol) pyrrolidine are added to a solution of 4.70 g (26.1 mmol) 4-methylamino-3-nitro-benzaldehyde in 100 mL THF and the reaction mixture is acidified with glacial acetic acid. 6.36 g (30.0 mmol) NaBH(OAc)3 are added and the reaction mixture is stirred overnight at RT. The mixture is combined with saturated NaHCO3 solution and the aqueous phase is extracted twice with EtOAc. The combined organic extracts are washed with 200 mL semisaturated NaHCO3 solution and dried over MgSO4. The solvent is eliminated i.vac. and further purification is carried out by column chromatography on silica gel (gradient: DCM to DCM/MeOH 9:1).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]([N:19]4[CH2:24][CH2:23][O:22][CH2:21][CH2:20]4)=[O:18])[CH:15]=3)[C:10]([S:25][CH3:26])=[CH:9]2)=[N:6][CH:7]=1.[OH:27][C:28]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=1>>[OH:27][C:28]1[CH:33]=[CH:32][C:31]([C:2]2[CH:3]=[N:4][C:5]([N:8]3[C:16]4[C:11](=[CH:12][CH:13]=[C:14]([C:17]([N:19]5[CH2:24][CH2:23][O:22][CH2:21][CH2:20]5)=[O:18])[CH:15]=4)[C:10]([S:25][CH3:26])=[CH:9]3)=[N:6][CH:7]=2)=[CH:30][CH:29]=1
Reactant: OB(O)c1ccc(O)cc1
Reactant: CSc1cn(-c2ncc(Br)cn2)c2cc(C(=O)N3CCOCC3)ccc12
Product: CSc1cn(-c2ncc(-c3ccc(O)cc3)cn2)c2cc(C(=O)N3CCOCC3)ccc12

Procedure:
Synthesized from (1-(5-bromopyrimidin-2-yl)-3-(methylthio)-1H-indol-6-yl)(morpholino)methanone (400 mg, 0.923 mmol) and 4-hydroxyphenyl boronic acid (153 mg, 1.108 mmol) in analogy to procedure 1d). Pale brown solid. Yield: 280 mg (68% of theory)
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:11]=3[N:12]=2)=[CH:4][CH:3]=1.[Br:18]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:18][CH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[S:9][C:10]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:11]=3[N:12]=2)=[CH:6][CH:7]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(-c2nc3cc(F)ccc3s2)cc1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: Fc1ccc2sc(-c3ccc(CBr)cc3)nc2c1
Temperature: 25 °C
Yield: 74.1 %

Procedure:
31.6 g of 2-(4-methylphenyl)-5-fluorobenzothiazole was dissolved in 660 ml of carbon tetrachloride, and 23.1 g of N-bromosuccinimide and 700 mg of benzoyl peroxide were added. The mixture was refluxed for 6 hours. The reaction mixture was cooled to room temperature, and the insoluble materials were separated by filtration. The filtrate was concentrated to a volume of 100 ml under reduced pressure. The precipitated crystals were collected by filtration to give 31.0 g of the captioned compound as crude crystals. Recrystallization from carbon tetrachloride gave the captioned compound as colorless platelike crystals.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[C:4]([OH:6])=O.[NH2:12][C:13]1[CH:22]=[CH:21][C:20]2[C:15](=[N:16][C:17]([O:23][CH2:24][CH2:25][CH2:26][N:27]([CH3:29])[CH3:28])=[CH:18][CH:19]=2)[N:14]=1>O>[CH3:29][N:27]([CH3:28])[CH2:26][CH2:25][CH2:24][O:23][C:17]1[N:16]=[C:15]2[C:20]([CH:21]=[CH:22][C:13]([NH:12][C:4](=[O:6])[C:3]3[C:7]([F:11])=[CH:8][CH:9]=[CH:10][C:2]=3[F:1])=[N:14]2)=[CH:19][CH:18]=1
Reactant: CN(C)CCCOc1ccc2ccc(N)nc2n1
Reactant: O=C(O)c1c(F)cccc1F
Solvent: O
Product: CN(C)CCCOc1ccc2ccc(NC(=O)c3c(F)cccc3F)nc2n1
Temperature: 4 °C
Yield: 38.9 %

Procedure:
The procedure is similar to that described in Example 1, but starting with 2,6-difluorobenzoic acid (11.3 g), N,N'-carbonyldiimidazole (12.9 g) and 2-amino-7-(3-dimethylaminopropoxy)-1,8-naphthyridine (11.8 g). The product obtained by precipitation in water followed by drying is dissolved in boiling acetone (450 cc). After 3 hours' cooling at 4° C., the crystallized solid is separated by filtration, washed with acetone (10 cc) and dried at 40° C. under reduced pressure (0.07 kPa). N-[7-(3-Dimethylaminopropoxy)-1,8-naphthyridin-2-yl]-2,6-difluorobenzamide (7.2 g), m.p. 190° C., is obtained.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:22]([CH:24]2[CH2:28][CH2:27][CH2:26][CH2:25]2)[CH3:23])[C:5]([CH3:21])=[C:6]([CH:20]=1)[C:7]([NH:9][CH2:10][C:11]1[C:12](=[O:19])[NH:13][C:14]([CH3:18])=[CH:15][C:16]=1[CH3:17])=[O:8].[CH:29]([C:31]1[N:36]=[CH:35][C:34](B(O)O)=[CH:33][CH:32]=1)=[O:30].C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:24]1([N:22]([CH3:23])[C:4]2[C:5]([CH3:21])=[C:6]([CH:20]=[C:2]([C:34]3[CH:35]=[N:36][C:31]([CH:29]=[O:30])=[CH:32][CH:33]=3)[CH:3]=2)[C:7]([NH:9][CH2:10][C:11]2[C:12](=[O:19])[NH:13][C:14]([CH3:18])=[CH:15][C:16]=2[CH3:17])=[O:8])[CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: Cc1cc(C)c(CNC(=O)c2cc(Br)cc(N(C)C3CCCC3)c2C)c(=O)[nH]1
Reactant: O=Cc1ccc(B(O)O)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: Cc1cc(C)c(CNC(=O)c2cc(-c3ccc(C=O)nc3)cc(N(C)C3CCCC3)c2C)c(=O)[nH]1
Temperature: 100 °C
Yield: 66.1 %

Procedure:
To a stirred solution of 5-bromo-3-(cyclopentyl(methyl)amino)-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-methylbenzamide (0.5 g, 1.12 mmol) and (6-formylpyridin-3-yl)boronic acid (0.39 g, 1.68 mmol) in dioxane/water mixture (15 mL+3 mL), Na2CO3 (0.42 g, 4.09 mmol) was added and solution purged with argon for 15 min. Then Pd(PPh3)4 (0.130 g, 0.112 mmol) was added the mixture was purged again for 10 min. Reaction mass was heated at 100° C. for 4 h. On completion, reaction mixture was diluted with water and extracted with 10% MeOH/DCM. Combined organic layers were dried over Na2SO4 and solvent removed under reduced pressure to afford crude material which was purified by column chromatography over silica gel to afford the title compound (0.35 g, 66% yield).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([OH:17])=[C:6]([C:8](=[O:16])[CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:7]=1.[C:18](OC(=O)C)(=O)[CH3:19].C([O-])(=O)C.[Na+]>>[F:1][C:2]1[CH:7]=[C:6]2[C:5](=[CH:4][CH:3]=1)[O:17][C:18]([CH3:19])=[C:9]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:8]2=[O:16]
Reactant: O=C(Cc1ccccc1)c1cc(F)ccc1O
Reactant: CC(=O)OC(C)=O
Agent: CC(=O)[O-]
Agent: [Na+]
Product: Cc1oc2ccc(F)cc2c(=O)c1-c1ccccc1
Temperature: 25 °C
Yield: 80 %

Procedure:
Intermediate 50 (50 g, 0.217 moles) was taken in a RB flask and to this acetic anhydride (424 ml) and sodium acetate (124 g, 1.51 moles) were added and the mixture was refluxed for 12 h. After cooling to RT, the reaction mixture was quenched by the addition of ice cold water. The solid formed was filtered and washed with water. The product was dried under vacuum to afford the title compound as colourless solid (44 g, 80% yield). 1H-NMR (δ ppm, CDCl3, 400 MHz): δ 7.87(dd, J=8.3,3.0 Hz, 1H), 7.47-7.35(m,5H), 7.29(m, 2H), 2.32(s, 3H).
Reaction SMILES: C(OC([N:8]1[CH:12]([C:13]([N:15]2[CH2:19][CH2:18][CH2:17][CH:16]2[C:20]#[N:21])=[O:14])[CH2:11][CH2:10][CH:9]1[CH2:22][O:23][C:24]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:27]([NH2:34])=[CH:26][CH:25]=1)=O)(C)(C)C.N1C=CC=CC=1.[CH3:41][S:42](Cl)(=[O:44])=[O:43]>C(Cl)Cl>[C:20]([C@@H:16]1[CH2:17][CH2:18][CH2:19][N:15]1[C:13]([C@H:12]1[NH:8][C@@H:9]([CH2:22][O:23][C:24]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[C:27]([NH:34][S:42]([CH3:41])(=[O:44])=[O:43])=[CH:26][CH:25]=2)[CH2:10][CH2:11]1)=[O:14])#[N:21]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1C(COc2ccc(N)c3ccccc23)CCC1C(=O)N1CCCC1C#N
Solvent: ClCCl
Solvent: c1ccncc1
Product: CS(=O)(=O)Nc1ccc(OC[C@H]2CC[C@@H](C(=O)N3CCC[C@H]3C#N)N2)c2ccccc12

Procedure:
The compound of Example 97A (32 mg, 0.07 mmol) was dissolved in CH2Cl2 (1 mL) and pyridine (0.5 mL) in a microwave reaction tube. Methanesulfonyl chloride (6.0 μL, 0.21 mmol) was added. It was reacted under microwave condition at 130° C. for 20 minutes. The mixture was filtered and purified by reverse phase HPLC to give the desired sulfonamide.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:14]([OH:16])=O)[C:5]2[N:10]([CH:11]=1)[CH2:9][CH2:8][S:7](=[O:13])(=[O:12])[N:6]=2.[CH:17]([C:21]1[CH:27]=[CH:26][C:24]([NH2:25])=[CH:23][CH:22]=1)([CH2:19][CH3:20])[CH3:18].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>CN(C=O)C.O>[CH3:1][C:2]1[CH:3]=[C:4]([C:14]([NH:25][C:24]2[CH:26]=[CH:27][C:21]([CH:17]([CH3:18])[CH2:19][CH3:20])=[CH:22][CH:23]=2)=[O:16])[C:5]2[N:10]([CH:11]=1)[CH2:9][CH2:8][S:7](=[O:12])(=[O:13])[N:6]=2
Reactant: CC1=CN2CCS(=O)(=O)N=C2C(C(=O)O)=C1
Reactant: CCC(C)c1ccc(N)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: CCC(C)c1ccc(NC(=O)C2=CC(C)=CN3CCS(=O)(=O)N=C23)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of 7-methyl-3,4-dihydropyrido[2,1-c][1,2,4]thiadiazine-9-carboxylic acid 2,2-dioxide (76 mg) in DMF (3 mL) were added 4-sec-butylaniline (0.069 mL), HOBt (67 mg), and EDCI HCl (84 mg) and the mixture was stirred at room temperature overnight. To the reaction mixture was added water (10 ml), and the resulting precipitate was collected by filtration. The obtained solid was recrystallized from DMSO-ethanol to give the title compound (114 mg) as pale-yellow crystals.
Reaction SMILES: [CH:1]1([C:4]2[CH:28]=[CH:27][CH:26]=[C:25]([N:29]3[C:33](=[O:34])[N:32]([CH3:35])[N:31]=[N:30]3)[C:5]=2[CH2:6][O:7][C:8]2[CH:13]=[CH:12][C:11]([C:14]3[C:15]([CH3:23])=[C:16]([C:20](O)=[O:21])[N:17]([CH3:19])[N:18]=3)=[CH:10][C:9]=2[CH3:24])[CH2:3][CH2:2]1.O1CCCC1.C(Cl)(=O)C([Cl:44])=O>CN(C)C=O>[CH:1]1([C:4]2[CH:28]=[CH:27][CH:26]=[C:25]([N:29]3[C:33](=[O:34])[N:32]([CH3:35])[N:31]=[N:30]3)[C:5]=2[CH2:6][O:7][C:8]2[CH:13]=[CH:12][C:11]([C:14]3[C:15]([CH3:23])=[C:16]([C:20]([Cl:44])=[O:21])[N:17]([CH3:19])[N:18]=3)=[CH:10][C:9]=2[CH3:24])[CH2:3][CH2:2]1
Reactant: O=C(Cl)C(=O)Cl
Reactant: Cc1cc(-c2nn(C)c(C(=O)O)c2C)ccc1OCc1c(C2CC2)cccc1-n1nnn(C)c1=O
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: Cc1cc(-c2nn(C)c(C(=O)Cl)c2C)ccc1OCc1c(C2CC2)cccc1-n1nnn(C)c1=O
Reaction time: 2 h

Procedure:
At room temperature, to the mixture of 5-{4-[2-Cyclopropyl-6-(4-methyl-5-oxo-4,5-dihydro-tetrazol-1-yl)-benzyloxy]-3-methyl-phenyl}-2,4-dimethyl-2H-pyrazole-3-carboxylic acid (described in Reference Preparation example 116) and tetrahydrofuran 50 ml was added oxalyl dichloride 0.5 g and N,N-dimethylformamide 0.1 ml. The mixture was stirred for two hours and concentrated under reduced pressure to give 5-{4-[2-Cyclopropyl-6-(4-methyl-5-oxo-4,5-dihydro-tetrazol-1-yl)-benzyloxy]-3-methyl-phenyl}-2,4-dim ethyl-2H-pyrazole-3-carbonylchloride 1.3 g.