Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[CH2:12]([C:16]1[S:17][C:18]2[CH2:24][CH2:23][CH2:22][CH:21]([CH2:25][OH:26])[C:19]=2[N:20]=1)[CH2:13][CH2:14][CH3:15]>>[CH2:12]([C:16]1[S:17][C:18]2[CH2:24][CH2:23][CH2:22][CH:21]([CH2:25][O:26][S:7]([C:4]3[CH:5]=[CH:6][C:1]([CH3:11])=[CH:2][CH:3]=3)(=[O:9])=[O:8])[C:19]=2[N:20]=1)[CH2:13][CH2:14][CH3:15]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCCCc1nc2c(s1)CCCC2CO
Product: CCCCc1nc2c(s1)CCCC2COS(=O)(=O)c1ccc(C)cc1

Procedure:
The compound is prepared by action of p-toluenesulfonyl chloride on the above derivative (IV), according to the procedure described in Example 1. The product is an undistillable oil which is used crude for the subsequent reactions.
Reaction SMILES: [CH3:1][N:2]([CH2:22][C@@H:23]1[C:26]2[CH:27]=[C:28]([O:33][CH3:34])[C:29]([O:31][CH3:32])=[CH:30][C:25]=2[CH2:24]1)[CH2:3][CH2:4][CH2:5][N:6]1[C:16](=[O:17])[CH2:15][C:14]2[C:9](=[CH:10][C:11]([O:20][CH3:21])=[C:12]([O:18][CH3:19])[CH:13]=2)[CH2:8][CH2:7]1.[C:35]([OH:40])(=[O:39])[C:36]([OH:38])=[O:37]>C(OCC)(=O)C.CC(C)=O>[CH3:1][N:2]([CH2:22][C@@H:23]1[C:26]2[CH:27]=[C:28]([O:33][CH3:34])[C:29]([O:31][CH3:32])=[CH:30][C:25]=2[CH2:24]1)[CH2:3][CH2:4][CH2:5][N:6]1[C:16](=[O:17])[CH2:15][C:14]2[C:9](=[CH:10][C:11]([O:20][CH3:21])=[C:12]([O:18][CH3:19])[CH:13]=2)[CH2:8][CH2:7]1.[C:35]([O-:40])(=[O:39])[C:36]([O-:38])=[O:37]
Reactant: O=C(O)C(=O)O
Agent: COc1cc2c(cc1OC)CC(=O)N(CCCN(C)C[C@H]1Cc3cc(OC)c(OC)cc31)CC2
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: O=C([O-])C(=O)[O-]
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
Ivabradine (44 g) was dissolved in ethyl acetate (700 ml) and to this oxalic acid (22 g) in acetone (50 ml) was added slowly and stirred for 3-4 hours at ambient temperature. The ivabradine oxalate, thus obtained was filtered, washed with ethyl acetate (100 ml) and recrystallized in acetonitrile (350 ml). XRD pattern shows that isolated ivabradine oxalate was crystalline in nature and depicted in FIG. 2.
Reaction SMILES: [CH3:1][N:2]1[C:7]2=[N:8][C:9]([NH:12][C:13]3[CH:18]=[CH:17][C:16]([N:19]4[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]4)=[CH:15][CH:14]=3)=[N:10][CH:11]=[C:6]2[CH2:5][NH:4][C:3]1=[O:26].FC(F)(F)C(O)=O.CC(C)([O-])C.[K+]>O1CCCC1>[CH3:1][N:2]1[C:7]2=[N:8][C:9]([NH:12][C:13]3[CH:14]=[CH:15][C:16]([N:19]4[CH2:20][CH2:21][N:22]([CH3:25])[CH2:23][CH2:24]4)=[CH:17][CH:18]=3)=[N:10][CH:11]=[C:6]2[CH:5]=[N:4][C:3]1=[O:26]
Reactant: CN1CCN(c2ccc(Nc3ncc4c(n3)N(C)C(=O)NC4)cc2)CC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: CN1CCN(c2ccc(Nc3ncc4cnc(=O)n(C)c4n3)cc2)CC1
Reaction time: 48 h
Yield: 62.6 %

Procedure:
Prepared from 250 mg (0.50 mmol) of 1-methyl-7-[4-(4-methylpiperazin-1-yl)phenylamino]-3,4-dihydro-pyrimido[4,5-d]pyrimidin-2(1H)-one, trifluoroacetic acid and 336 mg (2.99 mmol) of potassium tert-butoxide in 12 mL of tetrahydrofuran. The reaction mixture is stirred for 48 hours. After the workup, the semi-solid is triturated in diethyl ether, and the powder is collected and dried to give 110 mg (61%) of the title compound: mp 259-260° C. (dec).
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([O:10][C:11]2[CH:19]=[CH:18][C:17]3[N:16]4[CH2:20][CH2:21][NH:22][C:23](=[O:24])[C:15]4=[CH:14][C:13]=3[CH:12]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2].[H-].[Na+].[CH3:27]I>>[CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([O:10][C:11]2[CH:19]=[CH:18][C:17]3[N:16]4[CH2:20][CH2:21][N:22]([CH3:27])[C:23](=[O:24])[C:15]4=[CH:14][C:13]=3[CH:12]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2]
Reactant: CC(C)N1CCC(Oc2ccc3c(c2)cc2n3CCNC2=O)CC1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Product: CC(C)N1CCC(Oc2ccc3c(c2)cc2n3CCN(C)C2=O)CC1
Yield: 22 %

Procedure:
The title compound was synthesized in analogy to example 17, from 8-(1-isopropyl-piperidin-4-yloxy)-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (example 1), sodium hydride and methyl iodide, to give the desired product as a colorless solid (22%).
Reaction SMILES: CS[C:3]([S:9][CH3:10])=[C:4]([C:7]#[N:8])[C:5]#[N:6].[C:11]([C:15]1[CH:21]=[CH:20][C:18]([NH2:19])=[CH:17][CH:16]=1)([CH3:14])([CH3:13])[CH3:12]>CCO>[C:11]([C:15]1[CH:16]=[CH:17][C:18]([NH:19][C:3](=[C:4]([C:7]#[N:8])[C:5]#[N:6])[S:9][CH3:10])=[CH:20][CH:21]=1)([CH3:14])([CH3:12])[CH3:13]
Reactant: CSC(SC)=C(C#N)C#N
Reactant: CC(C)(C)c1ccc(N)cc1
Solvent: CCO
Product: CSC(Nc1ccc(C(C)(C)C)cc1)=C(C#N)C#N
Temperature: 25 °C
Yield: 53.5 %

Procedure:
A mixture of 2-(di(methylthio)methylene)malononitrile I-7 (300 mg, 1.76 mmol) and 4-tert-butylaniline (263 mg, 1.76 mmol) in EtOH (5 mL) was refluxed for 3 days. After the reaction mixture was allowed to cool to room temperature, the resulting solid was filtered, washed with minimal EtOH, and dried to give compound 5 (255 mg, 53.5% yield, 98.9% purity) as a white powder.
Reaction SMILES: C([O:3][C:4]([C@H:6]1[CH2:11][CH2:10][CH2:9][N:8]([CH2:12][C:13]2[CH:22]=[CH:21][C:20]3[C:15](=[CH:16][CH:17]=[C:18]([O:23][CH:24]4[CH2:29][CH2:28][CH:27]([C:30]([CH3:33])([CH3:32])[CH3:31])[CH2:26][CH2:25]4)[CH:19]=3)[CH:14]=2)[CH2:7]1)=[O:5])C.C(O)C.[OH-].[Na+].O.Cl>>[C:30]([C@H:27]1[CH2:28][CH2:29][C@H:24]([O:23][C:18]2[CH:19]=[C:20]3[C:15](=[CH:16][CH:17]=2)[CH:14]=[C:13]([CH2:12][N:8]2[CH2:9][CH2:10][CH2:11][C@H:6]([C:4]([OH:5])=[O:3])[CH2:7]2)[CH:22]=[CH:21]3)[CH2:25][CH2:26]1)([CH3:33])([CH3:31])[CH3:32]
Reactant: CCOC(=O)[C@H]1CCCN(Cc2ccc3cc(OC4CCC(C(C)(C)C)CC4)ccc3c2)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(C)(C)[C@H]1CC[C@H](Oc2ccc3cc(CN4CCC[C@H](C(=O)O)C4)ccc3c2)CC1
Reaction time: 18 h

Procedure:
(S)-1-[6-(4-tert-Butyl-cyclohexyloxy)-naphthalen-2-ylmethyl]-piperidine-3-carboxylic acid ethyl ester (151.23 mg, 0.33484 mmol) was dissolved in ethanol (5 mL, 80 mmol) then treated with 1 M sodium hydroxide in water (5 mL, 5 mmol). The mixture was stirred vigorously for 18 hours. pH was adjust to 3-4 with 3 N HCl and reaction was then extracted three times with ethyl acetate. Organics were combined then dried over MgSO4, filtered and concentrated to dryness under reduced pressure. Diethyl ether was then added and a white precipitate formed which was removed via filtration to give the title compound as a white solid (21 mg, 13%). EDI-MS: 424.1 (M+H)+. 1H NMR (400 MHz, MeOD) δ=7.82 (s, 1H), 7.74-7.62 (m, 2H), 7.44 (d, J=2.3, 1H), 7.19 (d, J=2.3 Hz, 1H), 7.08 (d, J=2.5, 1H), 4.43-4.34 (m, 1H), 4.33-4.22 (m, 2H), 2.71 (br. s., 1H), 2.16 (d, J=2.0 Hz, 2H), 1.88-167 (m, 4H), 1.40-1.25 (m, 3H), 1.24-1.11 (m, 4H), 1.11-0.94 (m, 5H), 0.80 (s, 9H).
Reaction SMILES: [SH:1][C:2]1[S:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH3:14])[CH:8]=2)[N:3]=1.[O-]Cl.[Na+].[OH-].[NH4+:19]>[OH-].[Na+].O>[CH3:14][O:13][C:9]1[CH:8]=[C:7]([C:4]2[N:3]=[C:2]([S:1][NH2:19])[S:6][N:5]=2)[CH:12]=[CH:11][CH:10]=1
Reactant: [NH4+]
Reactant: COc1cccc(-c2nsc(S)n2)c1
Agent: [Na+]
Agent: [O-]Cl
Agent: [OH-]
Solvent: O
Product: COc1cccc(-c2nsc(SN)n2)c1
Reaction time: 0.25 h

Procedure:
A solution of 2.2 g of 5-mercapto-3-(3-methoxyphenyl)-1,2,4-thiadiazole in 35 ml of 5% sodium hydroxide and a solution prepared by diluting 22 ml of 5.25% NaOCl solution to 35 ml with water were added dropwise simultaneously to 95 ml of ammonium hydroxide solution while maintaining the mixture at 0°. The resulting mixture was stirred for 15 minutes and the precipitated solid was collected, washed with water and dried (P2O5 /high vacuum) to give 1.76 l g of solid, m.p. 157°-160° C.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][CH2:10][OH:11])[CH:5]=[CH:6][CH:7]=1.[CH3:12][S:13](Cl)(=[O:15])=[O:14].CCN(CC)CC>C(Cl)Cl>[C:2]1([CH3:1])[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][CH2:9][CH2:10][O:11][S:13]([CH3:12])(=[O:15])=[O:14])[CH:3]=1
Reactant: CS(=O)(=O)Cl
Reactant: Cc1cccc(CCCO)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cccc(CCCOS(C)(=O)=O)c1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
3-(m-Methylphenyl)-1-propanol (0.45 g, 3.00 mmol), MsCl(278 uL, 3.60 mmol) and Et3N (0.84 mL, 6.00 mmol) were combined in CH2Cl2 (30 mL) and stirred at 0° C. for 4 hrs. The reaction was then diluted with CH2Cl2 (30 mL) and washed with cold brine, dried over Na2SO4 and concentrated to give a light brown oil. This was used without further purification. 1H NMR (300 MHz, CDCl3) δ 2.04-2.09 (m, 2H), 2.33(s, 3H), 2.69-2.74 (t, 2H), 2.99 (s, 3H), 4.20-4.24 (t, 2H), 6.97-7.04 (m, 3H), 7.16-7.19 (m, 1H).
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([CH2:32][C:33]([O:35][CH3:36])=[O:34])[C:9]([C:11]1[CH:31]=[CH:30][C:14]2[N:15]([CH3:29])[C:16]([CH2:18][NH:19][C:20]3[CH:25]=[CH:24][C:23]([C:26](=[NH:28])[NH2:27])=[CH:22][CH:21]=3)=[N:17][C:13]=2[CH:12]=1)=[O:10].Cl[C:38]([O:40][CH:41]1[CH2:46][CH2:45][CH2:44][CH2:43][CH2:42]1)=[O:39]>ClCCl.C(O)C>[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([CH2:32][C:33]([O:35][CH3:36])=[O:34])[C:9]([C:11]1[CH:31]=[CH:30][C:14]2[N:15]([CH3:29])[C:16]([CH2:18][NH:19][C:20]3[CH:25]=[CH:24][C:23]([C:26](=[NH:27])[NH:28][C:38]([O:40][CH:41]4[CH2:46][CH2:45][CH2:44][CH2:43][CH2:42]4)=[O:39])=[CH:22][CH:21]=3)=[N:17][C:13]=2[CH:12]=1)=[O:10]
Reactant: COC(=O)CN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C(=N)N)cc1)n2C)c1ccccn1
Reactant: O=C(Cl)OC1CCCCC1
Agent: Cl
Solvent: CCO
Solvent: ClCCl
Product: COC(=O)CN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C(=N)NC(=O)OC3CCCCC3)cc1)n2C)c1ccccn1
Yield: 40 %

Procedure:
Prepared analogously to Example 90 from 1-methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-methoxycarbonylmethyl-amide-hydrochloride and cyclohexyl chloroformate. Yield: 40% of theory, C32H35N7O5 (597.7) Rf value: 0.26 (silica gel; dichloromethane/ethanol=19:1) ##EQU85##
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[CH:5][NH:4][N:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:20][CH2:21][C@@:22]([CH3:32])([S:28]([CH3:31])(=[O:30])=[O:29])[C:23]([O:25][CH2:26][CH3:27])=[O:24]>C1COCC1>[CH3:32][C@@:22]([S:28]([CH3:31])(=[O:29])=[O:30])([CH2:21][CH2:20][N:4]1[CH:5]=[C:6]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:2]([CH3:1])=[N:3]1)[C:23]([O:25][CH2:26][CH3:27])=[O:24]
Reactant: CCOC(=O)[C@@](C)(CCBr)S(C)(=O)=O
Reactant: Cc1n[nH]cc1-c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Product: CCOC(=O)[C@@](C)(CCn1cc(-c2ccccc2)c(C)n1)S(C)(=O)=O
Temperature: 70 °C
Reaction time: 8 h
Yield: 19.3 %

Procedure:
To a solution of the 3-methyl-4-phenylpyrazole (400 mg, 2.53 mmol, 1 eq) in THF (25 mL) was added cesium carbonate (2.52 g, 7.70 mmol, 3 eq) and (R)-ethyl 4-bromo-2-methyl-2-(methylsulfonyl)butanoate (950 mg, 3.31 mmol, 1.3 eq). The resulting suspension was heated to 70° C. and stirred overnight. The reaction was filtered through celite, and the filter pad was washed with ethyl acetate (2×100 mL). Combined filtrates were concentrated and the crude material was purified on a Analogix SF15-24 g column using an eluant of ethyl acetate in heptane (0-80%) to give ethyl (2R)-2-methyl-4-(3-methyl-4-phenyl-1H-pyrazol-1-yl)-2-(methylsulfonyl)butanoate (178 mg, 19.3%). LC-MS M+H+365.1.
Reaction SMILES: [CH2:1]([C@H:5]1[O:7][C@@H:6]1[C:8]([OH:10])=O)[CH2:2][CH2:3][CH3:4].CCCCC(F)(F)C(O)CC[C@@H]1[C@@H](CCCCCCC(O)=O)C(=O)C[C@H]1O.C1CCC(NC2CCCCC2)CC1.C(Cl)(=O)C(C)(C)C.[NH2:58][C@H:59]1[CH2:64][CH2:63][CH2:62][CH2:61][C@@H:60]1[OH:65]>O1CCCC1>[OH:65][C@H:60]1[CH2:61][CH2:62][CH2:63][CH2:64][C@@H:59]1[NH:58][C:8]([C@@H:6]1[C@@H:5]([CH2:1][CH2:2][CH2:3][CH3:4])[O:7]1)=[O:10]
Reactant: N[C@H]1CCCC[C@@H]1O
Reactant: CCCC[C@H]1O[C@@H]1C(=O)O
Agent: C1CCC(NC2CCCCC2)CC1
Agent: CC(C)(C)C(=O)Cl
Agent: CCCCC(F)(F)C(O)CC[C@H]1[C@H](O)CC(=O)[C@@H]1CCCCCCC(=O)O
Solvent: C1CCOC1
Product: CCCC[C@H]1O[C@@H]1C(=O)N[C@H]1CCCC[C@@H]1O
Reaction time: 0.25 h
Yield: 100 %

Procedure:
Under ice-cooling, to 20 ml of an anhydrous tetrahydrofuran solution containing 2.3 g (7 mmol) of (2S-trans)-3-butyl-oxirane carboxylic acid.dicyclohexylammonium salt was added 2 ml of an anhydrous tetrahydrofuran solution containing 844 mg (7 mmol) of pivaloyl chloride, and the mixture was stirred at the same temperature for 15 minutes. Moreover, the temperature of the reaction mixture was returned to room temperature and the mixture was further stirred for 2 hours. After removing insoluble material in the reaction mixture by filtration, the filtrate was added to 20 ml of an anhydrous tetrahydrofuran solution containing 806 mg (7 mmol) of (1S,2S)-2-aminocyclohexanol under ice-cooling, and the resulting mixture was stirred at room temperature for 2 hours. Under reduced pressure, the reaction mixture was concentrated and ethyl acetate was added to the concentrate, and the resulting mixture was washed successively with a 10% aqueous potassium hydrogen sulfate solution, a saturated aqueous sodium hydrogen carbonate solution, and then, a saturated NaCl solution. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure to obtain 1.69 g (Yield: 100%) of the title compound.
Reaction SMILES: [F:1][C:2]1[C:3](I)=[N:4][CH:5]=[CH:6][CH:7]=1.[CH2:9]([C:13]1[O:14][C:15]2[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=2[N:17]=1)[CH2:10][C:11]#[CH:12]>C(N(CC)CC)C.[Cu](I)I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:1][C:2]1[C:3]([C:12]#[C:11][CH2:10][CH2:9][C:13]2[O:14][C:15]3[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=3[N:17]=2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: Fc1cccnc1I
Reactant: C#CCCc1nc2ccccc2o1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CCN(CC)CC
Product: Fc1cccnc1C#CCCc1nc2ccccc2o1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 15.2 %

Procedure:
In a dry reaction tube containing in suspension copper iodide (28 mg, 0.148 mol) and triethylamine (8.30 mL, 59.20 mmol), were added 3-fluoro-2-iodopyridine (660 mg, 2.96 mmol) and Pd(PPh3)2Cl2 (104 mg, 0.148 mmol) under N2. A yellow suspension was obtained. After a 5 minutes of stirring at room temperature, was added a solution 2-(But-3-ynyl)benzo[d]oxazole (compound 8(A), 510 mg, 3 mmol) in triethylamine (0.2 mL) under N2. Immediately the color of the reaction turns to black. The mixture was stirred at room temperature for 30 min and heated at 50° C. overnight under N2. Triethylamine was removed under reduce pressure and the crude product was purified by flash chromatography (Prepacked column 50 g, Cyclohexane/AcOEt: 60/40 as eluent) following by C18 chromatography (Prepacked column 15 g, H2O/CH3CN: from 80/20 to 40/600 as eluent) to afford 120 mg of 2-(4-(3-fluoropyridin-2-yl)but-3-ynyl)benzo[d]oxazole (Yield: 15%) as white powder (Mp=86-88° C.).
Reaction SMILES: [C:1]1([C:7]2[O:8][C:9]([C:15]([F:18])([F:17])[F:16])=[C:10]([C:12]([OH:14])=O)[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:19][C:20]1[CH:21]=[CH:22][C:23]([N:26]2[CH2:30][CH2:29][CH:28]([OH:31])[CH2:27]2)=[N:24][CH:25]=1>>[OH:31][CH:28]1[CH2:29][CH2:30][N:26]([C:23]2[N:24]=[CH:25][C:20]([NH:19][C:12]([C:10]3[N:11]=[C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[O:8][C:9]=3[C:15]([F:18])([F:17])[F:16])=[O:14])=[CH:21][CH:22]=2)[CH2:27]1
Reactant: O=C(O)c1nc(-c2ccccc2)oc1C(F)(F)F
Reactant: Nc1ccc(N2CCC(O)C2)nc1
Product: O=C(Nc1ccc(N2CCC(O)C2)nc1)c1nc(-c2ccccc2)oc1C(F)(F)F

Procedure:
With a procedure similar to example 43 above, 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid [6-(3-hydroxy-pyrrolidin-1-yl)-pyridin-3-yl]-amide was prepared from 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid and 1-(5-amino-pyridin-2-yl)-pyrrolidin-3-ol. LCMS calcd for C20H17F3N4O3 (m/e) 418, obsd 419 (M+H).
Reaction SMILES: CC(C)([O-])C.[Na+].[CH3:7][C:8]1[NH:9][C:10]2[C:15]([C:16]=1[O:17][C:18]1[CH:23]=[CH:22][C:21]([S:24]([CH3:27])(=[O:26])=[O:25])=[CH:20][CH:19]=1)=[CH:14][C:13]([CH3:28])=[CH:12][CH:11]=2.Br[CH2:30][C:31]([O:33]CC)=[O:32]>C1COCC1.O.[OH-].[Na+]>[CH3:7][C:8]1[N:9]([CH2:30][C:31]([OH:33])=[O:32])[C:10]2[C:15]([C:16]=1[O:17][C:18]1[CH:19]=[CH:20][C:21]([S:24]([CH3:27])(=[O:26])=[O:25])=[CH:22][CH:23]=1)=[CH:14][C:13]([CH3:28])=[CH:12][CH:11]=2
Reactant: Cc1ccc2[nH]c(C)c(Oc3ccc(S(C)(=O)=O)cc3)c2c1
Reactant: CCOC(=O)CBr
Agent: CC(C)(C)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc2c(c1)c(Oc1ccc(S(C)(=O)=O)cc1)c(C)n2CC(=O)O
Reaction time: 0.17 h

Procedure:
Sodium t-butoxide (220 mg) was added to a solution of the product from step (iii) (600 mg) in THF (20 ml) and stirred for 10 min. Ethyl bromoacetate (250 μl) was added and the reaction stirred for a further 1 h. The mixture was then diluted with water (10 ml), 1M aqueous sodium hydroxide (5 ml) added and stirred for 3 h. The mixture was extracted with EtOAc, washed with brine, dried (MgSO4), filtered and evaporated. The residue was purified using reverse phase preparative chromatography (eluent MeCN/NH3(aq)) to give the title compound. Yield 450 mg.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:21]=[CH:20][C:19]([O:22][CH:23]([CH3:25])[CH3:24])=[CH:18][C:11]=3[C:12]=2[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:4][CH:3]=1.[N+:26]([O-])([OH:28])=[O:27]>C(Cl)(Cl)Cl.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:21]=[C:20]([N+:26]([O-:28])=[O:27])[C:19]([O:22][CH:23]([CH3:24])[CH3:25])=[CH:18][C:11]=3[C:12]=2[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1c(-c2ccc(Cl)cc2)oc2ccc(OC(C)C)cc12
Reactant: O=[N+]([O-])O
Solvent: O
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1c(-c2ccc(Cl)cc2)oc2cc([N+](=O)[O-])c(OC(C)C)cc12
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 32 %

Procedure:
Ethyl 2-(4-chlorophenyl)-5-isopropoxybenzofuran-3-carboxylate 4 (30 g, 0.084 mol) was dissolved in chloroform (75 mL) and the resulting solution was cooled in an ice bath. Nitric acid (55 mL) was also dissolved in chloroform (75 mL) and cooled in an ice bath. The acid solution was added dropwise to the solution of ethyl 2-(4-chlorophenyl)-5-isopropoxybenzofuran-3-carboxylate over 1 hour, and the reaction mixture was then stirred at 0° C. for 1.5 hrs. The reaction mixture was then diluted with water (60 mL) and the layers were separated. The organic layer was dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a brown oil which was purified by column chromatography (5/1 PE/EA) to afford ethyl 2-(4-chlorophenyl)-5-isopropoxy-6-nitrobenzofuran-3-carboxylate as a brown solid (11 g, 32%).
Reaction SMILES: O[C:2]1[C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:10][C:9]2[CH2:8][CH2:7][CH2:6][CH2:5][C:4]=2[N:3]=1.P(Cl)(Cl)([Cl:19])=O>>[Cl:19][C:2]1[C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:10][C:9]2[CH2:8][CH2:7][CH2:6][CH2:5][C:4]=2[N:3]=1
Reactant: CCOC(=O)c1cc2c(nc1O)CCCC2
Reactant: O=P(Cl)(Cl)Cl
Product: CCOC(=O)c1cc2c(nc1Cl)CCCC2

Procedure:
Ethyl 2-hydroxy-5,6,7,8-tetrahydroquinoline-3-carboxylate (3.40 g) was dissolved in phosphorus oxychloride (30 ml), and the mixture was stirred with heating to reflux for 10 hr. The reaction mixture was concentrated under reduced pressure, saturated aqueous sodium hydrogen carbonate solution was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane (50:50-100:0) was concentrated under reduced pressure to give the object compound (3.68 g).
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C.[NH2:22][C@@H:23]([CH3:26])[CH2:24][OH:25]>O>[N+:8]([C:7]1[C:2]([NH:22][C@@H:23]([CH3:26])[CH2:24][OH:25])=[N:3][CH:4]=[CH:5][CH:6]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1cccnc1Cl
Reactant: C[C@H](N)CO
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: C[C@@H](CO)Nc1ncccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 114.3 %

Procedure:
A 100-mL round bottomed flask equipped with a magnetic stir bar was charged with 2-chloro-3-nitropyridine (4.0 g, 25.2 mmol), potassium carbonate (4.18 g, 30.3 mmol), and DMF (25 mL). Next, (S)-2-aminopropane-1-ol (1.990 g, 26.5 mmol) was added at rt. The yellow mixture was stirred at rt for 45 min, then was heated to 50° C. for 22 h. Heating was discontinued, and after the mixture had cooled, it was diluted with water (50 mL) and extracted with ethyl acetate. The organic phase was separated and washed with 5% aqueous sodium chloride solution (3×25 mL). The combined aqueous layers were extracted with ethyl acetate. The combined organic phases were concentrated to yield (S)-2-(3-nitropyridin-2-ylamino)propane-1-ol (5.68 g, 28.8 mmol, 114%) as a dark yellow syrup. MS (ESI, pos. ion) m/z 198 [M+1]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[O:9][C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-])=O)=[CH:12][CH:11]=1.O.NN>CO.[Ni]>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[O:9][C:10]1[CH:11]=[CH:12][C:13]([NH2:16])=[CH:14][CH:15]=1
Reactant: O=[N+]([O-])c1ccc(Oc2c(F)cccc2F)cc1
Agent: [Ni]
Agent: NN
Solvent: CO
Solvent: O
Product: Nc1ccc(Oc2c(F)cccc2F)cc1
Reaction time: 0.25 h
Yield: 90.8 %

Procedure:
Into a 500 mL, 3-necked round-bottom flask purged and maintained under an inert atmosphere of nitrogen, was placed a solution of 1,3-difluoro-2-(4-nitrophenoxy)benzene (20 g, 79.62 mmol, 1.00 equiv) in methanol (200 mL), Raney Nickel (2 g). A solution of hydrazine hydrate (12.67 g) in methanol (50 mL) was added dropwise with stirring in 15 min. The resulting solution was stirred for 12 h at 25° C., then filtrated and the filtrate was concentrated under vacuum. The residue was diluted with f ethyl acetate, washed with water and brine, and dried over anhydrous sodium sulfate and concentrated under vacuum to give 16 g (91%) of 4-(2,6-difluorophenoxy)aniline as black oil.
Reaction SMILES: [F:1][CH:2]([F:18])[CH2:3][NH:4][C:5]1[CH:6]=[N:7][CH:8]=[CH:9][C:10]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[F:17].[CH3:19][S:20]([C:23]1[CH:24]=[C:25]([CH:43]=[C:44]([C:46]([F:49])([F:48])[F:47])[CH:45]=1)[C:26](N(C)C1C=NC=CC=1C1C=CC=CC=1C)=[O:27])(=[O:22])=[O:21].F[B-](F)(F)F.BrC1C=CC=C[N+]=1CC.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[F:18][CH:2]([F:1])[CH2:3][N:4]([C:5]1[CH:6]=[N:7][CH:8]=[CH:9][C:10]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[F:17])[C:26](=[O:27])[C:25]1[CH:43]=[C:44]([C:46]([F:49])([F:47])[F:48])[CH:45]=[C:23]([S:20]([CH3:19])(=[O:22])=[O:21])[CH:24]=1
Reactant: Fc1ccccc1-c1ccncc1NCC(F)F
Reactant: Cc1ccccc1-c1ccncc1N(C)C(=O)c1cc(C(F)(F)F)cc(S(C)(=O)=O)c1
Agent: CC[n+]1ccccc1Br
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)c1cc(C(=O)N(CC(F)F)c2cnccc2-c2ccccc2F)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of N-(2,2-difluoroethyl)-4-(2-fluorophenyl)pyridin-3-amine (112 mg, 444 μmol) in CH2Cl2 (3 mL) was added 3-(methylsulfonyl)-5-(trifluoromethyl)benzoic acid (119 mg, 444 μmol, example 114, intermediate) and 2-bromo-1-ethylpyridinium tetrafluoroborate (146 mg, 533 μmol) and N,N-diisopropylethylamine (115 mg, 155 μL, 888 μmol). The reaction mixture was stirred at room temperature for 24 hours and then concentrated under vacuum. The residue was dissolved in 30 mL 1M aqueous HCl and 30 mL EtOAc and the layers were separated. The aqueous layer was extracted a second time with 30 mL EtOAc. The organic layers were washed with 30 mL 1M aqueous HCl and 30 mL 10% aqueous NaHCO3 solution and 30 mL brine, dried over MgSO4, filtered and concentrated under vacuum. Yellow solid (84 mg, 38%). MS (ESI): m/z=503.085 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:17]3[C:12](=[C:13]([CH3:18])[CH:14]=[CH:15][CH:16]=3)[NH:11][N:10]=2)=[CH:5][CH:4]=1.[H-].[Na+].I[CH2:22][CH2:23][CH3:24]>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[N:10]([CH2:22][CH2:23][CH3:24])[N:11]=[C:12]3[C:17]=2[CH:16]=[CH:15][CH:14]=[C:13]3[CH3:18])=[CH:7][CH:8]=1
Reactant: COc1ccc(-c2n[nH]c3c(C)cccc23)cc1
Reactant: CCCI
Agent: [H-]
Agent: [Na+]
Product: CCCn1nc2c(C)cccc2c1-c1ccc(OC)cc1
Yield: 10 %

Procedure:
Prepared according to Method D step B from 3-(4-methoxyphenyl)-7-methyl-1H-indazole (0.115 g, 0.5 mmol), sodium hydride (60% in oil, 0.024 g, 0.6 mmol) and 1-iodopropane (0.098 mL, 1.0 mmol) to give the title compound (0.014 g). Used as is in the next step.