Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[N:11]1[CH2:15][CH:14]2[CH2:16][C:17](=[O:19])[CH2:18][CH:13]2[CH2:12]1.[CH2:20](O)[CH2:21][OH:22].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[N:11]1[CH2:15][CH:14]2[CH2:16][C:17]3([CH2:18][CH:13]2[CH2:12]1)[O:22][CH2:21][CH2:20][O:19]3
Reactant: O=C1CC2CN(c3ccc([N+](=O)[O-])cc3F)CC2C1
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: c1ccccc1
Product: O=[N+]([O-])c1ccc(N2CC3CC4(CC3C2)OCCO4)c(F)c1

Procedure:
19.74 g (74.7 mmol) of 2-(2-fluoro-4-nitrophenyl)-5-oxo-hexahydro-cyclopenta[c]pyrrol prepared in the step 3 and 5.0 ml (89.6 mmol) of ethylene glycol were dissolved in 200 ml of benzene, 1.00 g (5.2 mmol) of p-toluene sulfonic acid hydrate was added, and the mixture was heated to reflux for 1 hour while removing generated water. After the reaction was completed, the mixture was washed with a saturated aqueous solution of sodium carbonate and water, and then, the organic layer was dried over magnesium sulfate, filtered and concentrated under reduced pressure to obtain the title compound, of which NMR data is as follow.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][C:14]2[C:15]([C:27]3[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=3)=[N:16][O:17][C:18]=2/[CH:19]=C/C2C=CC=CC=2)=[CH:8][N:7]=1)=[O:5])[CH3:2].[BH4-].[Na+].C[OH:37]>>[CH2:1]([O:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][C:14]2[C:15]([C:27]3[CH:28]=[CH:29][C:30]([F:33])=[CH:31][CH:32]=3)=[N:16][O:17][C:18]=2[CH2:19][OH:37])=[CH:8][N:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ccc(OCc2c(-c3ccc(F)cc3)noc2/C=C/c2ccccc2)cn1
Reactant: CO
Agent: [BH4-]
Agent: [Na+]
Product: CCOC(=O)c1ccc(OCc2c(-c3ccc(F)cc3)noc2CO)cn1
Reaction time: 1 h
Yield: 59 %

Procedure:
A solution of 5-[3-(4-fluoro-phenyl)-5-((E)-styryl)-isoxazol-4-ylmethoxy]-pyridine-2-carboxylic acid ethyl ester (1.2 g, 3.24 mmol) in methanol (60 mL) was treated at room temperature with sodium borohydride (255.4 mg, 6.48 mmol) and stirred for 1 h. After quenching with aqueous citric acid (100 mL of a 10% solution) and extraction with ethyl acetate the organic phase was dried over sodium sulfate, filtered and concentrated. Purification by chromatography (silica, heptane:ethyl acetete=1:1 to 0:1) afforded the title compound as a white solid (710 mg, 59%). MS: m/e=373.2 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4](S(C)=O)[N:3]=1.[CH2:18]([OH:27])/[CH:19]=[CH:20]/[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4]([O:27][CH2:18][CH:19]=[CH:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[N:3]=1
Reactant: OC/C=C/c1ccccc1
Reactant: CS(=O)c1nc(N)nc(-c2ccco2)c1C#N
Solvent: COCCOC
Solvent: C1CCC2=NCCCN2CC1
Product: N#Cc1c(OCC=Cc2ccccc2)nc(N)nc1-c1ccco1

Procedure:
From 2-amino-4-furan-2-yl-6-methanesulfinyl-pyrimidine-5-carbonitrile, (E)-cinnamyl alcohol and DBU in DME. ES-MS m/e (%): 319 (M+H+, 100).
Reaction SMILES: [C:1]1([CH:7]2[S:12][CH2:11][CH2:10][NH:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:14]1[C:23]2[C:18](=[CH:19][C:20]([O:26][CH3:27])=[C:21]([O:24][CH3:25])[CH:22]=2)[N:17]=[CH:16][N:15]=1.C(=O)([O-])[O-].[K+].[K+].C1(C)C=CC=CC=1>CC(O)C>[CH3:25][O:24][C:21]1[CH:22]=[C:23]2[C:18](=[CH:19][C:20]=1[O:26][CH3:27])[N:17]=[CH:16][N:15]=[C:14]2[N:9]1[CH2:10][CH2:11][S:12][CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:8]1
Reactant: c1ccc(C2CNCCS2)cc1
Reactant: COc1cc2ncnc(Cl)c2cc1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)O
Solvent: Cc1ccccc1
Product: COc1cc2ncnc(N3CCSC(c4ccccc4)C3)c2cc1OC
Temperature: 180 °C

Procedure:
2-Phenyl-thiomorpholine (1 mole equivalent), 4-Chloro-6,7-dimethoxy-quinazoline (1 mole equivalent) and potassium carbonate (1 mole equivalent) were added to a 1:1 mixture of toluene and 2-propanol, corresponding to a final concentration of about 0.5 molar. The reaction mixture was heated in a microwave oven at 180° C. for 15 minutes, and filtrated. The solvent was removed under vacuum and the resultant solid was subjected to preparative LC-MS-purification. Fractions containing the product were collected, pooled and evaporated in vacuo to give the product.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([NH2:9])=[C:4]([NH2:10])[CH:3]=1.[N+]([C:14]1[CH:15]=[C:16]([C:21]([F:24])([F:23])[F:22])[CH:17]=[CH:18][C:19]=1Br)([O-])=O.NC1C(N)=C(NC2C=CC=CC=2)C=CC=1>Cl>[CH3:8][C:7]1[C:2]([CH3:1])=[CH:3][C:4]2[C:5](=[N:9][C:19]3[C:18]([N:10]=2)=[CH:17][C:16]([C:21]([F:24])([F:23])[F:22])=[CH:15][CH:14]=3)[CH:6]=1
Reactant: Cc1cc(N)c(N)cc1C
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1Br
Agent: Cl
Agent: Nc1cccc(Nc2ccccc2)c1N
Product: Cc1cc2nc3ccc(C(F)(F)F)cc3nc2cc1C

Procedure:
The 2,3-dimethyl-7-trifluoromethylphenazine was prepared in a 3-step process, starting with 4,5-dimethyl-1,2-phenylenediamine and 3-nitro-4-bromobenzotrifluoride. The nucleophilic substitution product being the biarylamine was then reduced with stannous chloride in conc. HCl to the diamino diphenylamine.
Reaction SMILES: CS(O[CH2:6][CH2:7][CH:8]1[CH2:11][O:10][CH2:9]1)(=O)=O.O1CC(CCO)C1.CS(Cl)(=O)=O.CCN(C(C)C)C(C)C.[CH:33]1([C:36]2[C:44]([NH:45][S:46]([CH3:49])(=[O:48])=[O:47])=[CH:43][C:42]3[C:38](=[C:39]([C:57]([NH:59][CH3:60])=[O:58])[N:40]([C:50]4[CH:55]=[CH:54][C:53]([CH3:56])=[CH:52][CH:51]=4)[N:41]=3)[CH:37]=2)[CH2:35][CH2:34]1.C(=O)([O-])[O-].[K+].[K+]>C(Cl)Cl.C(#N)C.CCOC(C)=O>[CH:33]1([C:36]2[C:44]([N:45]([S:46]([CH3:49])(=[O:48])=[O:47])[CH2:6][CH2:7][CH:8]3[CH2:9][O:10][CH2:11]3)=[CH:43][C:42]3[C:38](=[C:39]([C:57]([NH:59][CH3:60])=[O:58])[N:40]([C:50]4[CH:55]=[CH:54][C:53]([CH3:56])=[CH:52][CH:51]=4)[N:41]=3)[CH:37]=2)[CH2:34][CH2:35]1
Reactant: CNC(=O)c1c2cc(C3CC3)c(NS(C)(=O)=O)cc2nn1-c1ccc(C)cc1
Reactant: CS(=O)(=O)OCCC1COC1
Agent: CS(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: OCCC1COC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CNC(=O)c1c2cc(C3CC3)c(N(CCC3COC3)S(C)(=O)=O)cc2nn1-c1ccc(C)cc1
Reaction time: 24 h
Yield: 14 %

Procedure:
To a stirred solution of 2-(oxetan-3-yl)ethyl methanesulfonate (11 mg, 0.06 mmol, prepared by treating 2-(oxetan-3-yl)ethanol with methanesulfonyl chloride in DCM in the presence of DIPEA) was added 5-cyclopropyl-6-(methanesulfonamido)-N-methyl-2-(p-tolyl)indazole-3-carboxamide (24 mg, 0.06 mmol) followed by potassium carbonate (68 mg, 0.49 mmol). The resultant suspension was heated at 60° C. for 18 h whereupon another portion of (oxetan-3-yl)ethyl methanesulfonate (81 mg, 0.45 mmol) in ACN (2 mL) was added and heating/stirring continued. After 24 h, the reaction mixture was diluted with EtOAc (15 mL) and the organics washed with water (20 mL). The aqueous layer was back-extracted into EtOAc (15 mL) and the combined organics were then washed with brine (10 mL), dried (MgSO4) and the volatiles removed in vacuo. The residue was purified by preparative HPLC eluting with ACN:0.1% formic acid in water (gradient elution, 5% to 30% to 40% to 100%) to give Compound (3) (4 mg, 14%). ESI-MS m/z calculated for [M+H]+: 483.2 found: 483.1. 1H NMR (400 MHz, CD3CN) δ 7.78 (s, 1H), 7.58 (s, 1H), 7.51 (d, J=8.2 Hz, 2H), 7.40 (d, J=7.94 Hz, 2H), 5.63 (brs, 1H), 4.86-4.78 (m, 2H), 4.40-4.33 (m, 2H), 3.70 (t, J=7.94 Hz, 2H), 3.18-3.05 (m, 4H), 2.98 (d, J=5.0 Hz, 3H), 2.51 (s, 3H), 2.47-2.38 (m, 1H), 2.17-1.97 (m, 2H), 1.19-1.03 (m, 3H), 0.72-0.63 (m, 1H).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]=[O:7].[C:8]([Mg]Cl)#[CH:9]>C1COCC1>[OH:7][CH:6]([C:2]1[NH:1][CH:5]=[CH:4][CH:3]=1)[C:8]#[CH:9]
Reactant: O=Cc1ccc[nH]1
Reactant: C#C[Mg]Cl
Solvent: C1CCOC1
Product: C#CC(O)c1ccc[nH]1

Procedure:
3-Hydroxy-3-(1H-pyrrol-2-yl)-1-propyne was prepared by Method B above using 2-pyrrolecarboxaldehyde (0.389 g, 4 mmol) (Aldrich) in THF (30 mL) and ethynylmagnesium chloride (20 mmol, 40 mL, 0.5M solution in tetrahydrofuran) (Aldrich). (Yield 345 mg, 82%).
Reaction SMILES: [Cl:1][C:2]1[C:10]([F:11])=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:13])[C:5](=[O:12])[NH:6]2.S(=O)(=O)(O)[OH:15].OO>C(O)(=O)C>[Cl:1][C:2]1[C:10]([F:11])=[CH:9][CH:8]=[C:7]2[NH:6][C:5](=[O:15])[O:12][C:4](=[O:13])[C:3]=12
Reactant: O=C1Nc2ccc(F)c(Cl)c2C1=O
Reactant: O=S(=O)(O)O
Agent: OO
Solvent: CC(=O)O
Product: O=c1[nH]c2ccc(F)c(Cl)c2c(=O)o1

Procedure:
7.8 g (0.039 mol) of 4-chloro-5-fluoroisatin are suspended in 50 ml of 100 percent acetic acid, treated with 0.25 ml of concentrated sulphuric acid and then at 30° 4.4 ml (0.043 mol) of 30 percent hydrogen peroxide are added thereto. The mixture is subsequently heated to 70° for 2.5 hours, then cooled to 10° and filtered. The crude product is recrystallized from acetone/hexane, there being obtained 6-chloro-5-fluoroisatoic acid anhydride of melting point 275°-278° (decomposition).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]2[C:19]3=[C:20]4[C:10](=[CH:11][CH:12]=[C:13]([C:21]5[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=5)[C:14]4=[CH:15][CH:16]=[C:17]3[CH:18]=1)[CH:9]=[CH:8]2)([CH3:4])([CH3:3])[CH3:2].CO.[Br-:29].[Br-].[Br-].C([N+](C)(C)C)C1C=CC=CC=1.C([N+](C)(C)C)C1C=CC=CC=1.C([N+](C)(C)C)C1C=CC=CC=1.O>ClCCl>[Br:29][C:11]1[C:10]2[C:20]3=[C:19]4[C:7](=[CH:8][CH:9]=2)[CH:6]=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[CH:18]=[C:17]4[CH:16]=[CH:15][C:14]3=[C:13]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:12]=1
Reactant: CC(C)(C)c1cc2ccc3ccc(-c4ccccc4)c4ccc(c1)c2c34
Reactant: [Br-]
Agent: C[N+](C)(C)Cc1ccccc1
Solvent: O
Solvent: ClCCl
Solvent: CO
Product: CC(C)(C)c1cc2ccc3c(Br)cc(-c4ccccc4)c4ccc(c1)c2c34
Temperature: 25 °C
Reaction time: 2 h
Yield: 186.7 %

Procedure:
Next, a mixed solution of 1.5 g of 7-t-butyl-1-phenylpyrene, 25 ml of dichloromethane and 8 ml of methanol was cooled to 0° C. under a nitrogen gas stream and then 1.7 g of benzyltrimethylammonium tribromide dissolved in 5 ml of dichloromethane was added dropwise. This mixed solution was stirred at room temperature for 2 hours and 20 ml of water was poured into the solution, followed by extraction with 20 ml of dichloromethane. The organic layer was washed twice with 20 ml of water, dried over magnesium sulfate and then evaporated. To the resulting solid, 10 ml of methanol was added, followed by standing overnight. The precipitated solid was filtered and then vacuum-dried to obtain 1.9 g of 1-bromo-7-t-butyl-3-phenylpyrene.
Reaction SMILES: [Cl:1][C:2]1[N:7]2[N:8]=[C:9]3[C:14]([CH:13]=[CH:12][CH:11]=[CH:10]3)=[C:6]2[N:5]=[C:4]([CH3:15])[C:3]=1[CH2:16][C:17]([O:19][CH3:20])=[O:18].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.O1C[CH2:34][CH2:33][CH2:32]1.ICCC>CN(C=O)C>[Cl:1][C:2]1[N:7]2[N:8]=[C:9]3[C:14]([CH:13]=[CH:12][CH:11]=[CH:10]3)=[C:6]2[N:5]=[C:4]([CH3:15])[C:3]=1[CH:16]([CH2:32][CH2:33][CH3:34])[C:17]([O:19][CH3:20])=[O:18]
Reactant: COC(=O)Cc1c(C)nc2c3ccccc3nn2c1Cl
Reactant: C1CCOC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CCCI
Solvent: CN(C)C=O
Product: CCCC(C(=O)OC)c1c(C)nc2c3ccccc3nn2c1Cl
Temperature: 25 °C
Reaction time: 20 h
Yield: 76 %

Procedure:
To a solution of methyl 2-(4-chloro-2-methylpyrimido[1,2-b]indazol-3-yl)acetate (0.289 g; 1 mmol) in dry DMF (4 mL) at −10° C. was slowly added a 1N solution of LHMDS in tetrahydrofuran (1.1 mL; 1.1 mmol). Then, 1-iodopropane (0.146 mL; 1.5 mmol) was added and the reaction mixture was stirred at room temperature for 20 h. The reaction mixture was quenched by addition of a saturated solution of ammonium chloride and the mixture was extracted with ethyl acetate. The organic layer was washed with water, brine, dried over sodium sulfate and concentrated under reduced pressure. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (2-20%) in dichloromethane furnished 0.252 g (76%) of methyl 2-(4-chloro-2-methylpyrimido[1,2-b]indazol-3-yl)pentanoate as an oil. ESI/APCI(+): 332-334 (M+H).
Reaction SMILES: [CH3:1][O:2][N:3]=[CH:4][C:5]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][CH:6]=1.C([BH3-])#N.[Na+]>>[CH3:1][O:2][NH:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][CH:6]=1
Reactant: CON=Cc1ccc(C)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Product: CONCc1ccc(C)cc1
Yield: 76 %

Procedure:
Reduction of 4-methylbenzaldehyde O-methyloxime with sodium cyanoborohydride as described in the preparation of compound 3-B gave the title hydroxylamine as a clear oil (76% yield): bp 70-80° C./3.5 torr (bulb to bulb distillation, air bath temperature). 1HNMR 400 MHz (CDCl3) δ (ppm): 2.36 (3H, s, CH3), 3.54 (3H, s, OCH3), 4.04 (2H, s, NCH2), 5.7 (broad, NH), 7.17 (2H, d, J=8.1 Hz, aromatics), 7.26 (2H, d, J=8.1 Hz, aromatics). The hydrochloride salt was obtained as a white solid: mp 162-164° C. Anal. calcd for C9H13NO—HCl: C, 57.60; H, 7.51; N, 7.46. Found: C, 57.87; H, 7.45; N, 7.25.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][CH3:10])[C:4]=1[NH:11][C:12]([C:14]1[CH:18]=[C:17]([C:19]2[C:24](Br)=[CH:23][N:22]=[C:21]([NH2:26])[N:20]=2)[N:16]([CH3:27])[CH:15]=1)=[O:13])[CH3:2].[CH3:28][Al](C)C>C1COCC1.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>[CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][CH3:10])[C:4]=1[NH:11][C:12]([C:14]1[CH:18]=[C:17]([C:19]2[C:24]([CH3:28])=[CH:23][N:22]=[C:21]([NH2:26])[N:20]=2)[N:16]([CH3:27])[CH:15]=1)=[O:13])[CH3:2]
Reactant: CCc1cccc(CC)c1NC(=O)c1cc(-c2nc(N)ncc2Br)n(C)c1
Reactant: C[Al](C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCc1cccc(CC)c1NC(=O)c1cc(-c2nc(N)ncc2C)n(C)c1
Temperature: 65 °C

Procedure:
To a solution of 5-(2-Amino-5-bromo-pyrimidin-4-yl)-1-methyl-1H-pyrrole-3-carboxylic acid (2,6-diethyl-phenyl)-amide (83.7 mg, 0.1954 mmol) in 4 mL of dry THF, AlMe3 (1M in toluene, 0.488 mL, 0.977 mmol) and Pd(PPh3)4 (22.6 mg, 0.0195 mmol) were added under argon. The mixture was heated at 65° C. for 1 h. After dilution with water and extraction with CH2Cl2 the organic layer was dried over Na2SO4 and concentrated under reduced pressure. The crude was treated with Et2O affording 58.8 mg (83%) of the desired product.
Reaction SMILES: [OH:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:3]1.Br[CH2:23][CH2:24][CH2:25][O:26][C:27]1[CH:35]=[CH:34][C:30]2[O:31][CH2:32][O:33][C:29]=2[CH:28]=1>>[O:31]1[C:30]2[CH:34]=[CH:35][C:27]([O:26][CH2:25][CH2:24][CH2:23][O:14][C:11]3[CH:10]=[CH:9][C:8]([CH:7]4[CH2:6][CH2:5][N:4]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:3][CH:2]4[OH:1])=[CH:13][CH:12]=3)=[CH:28][C:29]=2[O:33][CH2:32]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(O)cc2)C(O)C1
Reactant: BrCCCOc1ccc2c(c1)OCO2
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(OCCCOc3ccc4c(c3)OCO4)cc2)C(O)C1

Procedure:
Analogously to Method I, 0.750 g of tert-butyl 3-hydroxy-4-(4-hydroxyphenyl)piperidine-1-carboxylate and 0.859 g of 5-(3-bromopropoxy)benzo[1,3]dioxole are reacted. The title compound is obtained as a slightly yellowish oil. Rf=0.10 (1:2 EtOAc-heptane); Rt=4.96.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[CH:7]=[C:8]([CH:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)O)[CH:9]=[CH:10][CH:11]=1.C(N(S(F)(F)[F:26])CC)C>ClCCl>[F:26][CH:12]([C:8]1[CH:7]=[C:6]([CH:2]2[O:3][CH2:4][CH2:5][O:1]2)[CH:11]=[CH:10][CH:9]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CCN(CC)S(F)(F)F
Reactant: OC(c1ccccc1)c1cccc(C2OCCO2)c1
Solvent: ClCCl
Product: FC(c1ccccc1)c1cccc(C2OCCO2)c1
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
Combine (3-[1,3]-dioxolan-2-ylphenyl)phenylmethanol (2.3 g, 8.9 mmol) and dichloromethane (50 ml). Cool to about −78° C. Add dropwise a solution of (diethylamino)sulfur trifluoride (1.7 ml, 12.9 mmol). After 10 minutes, quench with water and extract with dichloromethane. Combine the organic layers and wash sequentially with distilled water and brine and then dry (Na2SO4), filter, and concentrate to give a residue. Chromatograph the residue eluting with 7:3 hexane:EtOAc to give the title compound.
Reaction SMILES: [C:1]([C:5]1[CH:21]=[CH:20][C:8]([CH2:9][C:10]2[O:14][N:13]=[C:12]([C:15]([O:17]CC)=O)[N:11]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl.[Cl:23][C:24]1[CH:25]=[C:26]2[C:30](=[CH:31][CH:32]=1)[NH:29][CH:28]=[C:27]2[CH2:33][CH2:34][NH2:35].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CO.CN(C=O)C>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([CH2:9][C:10]2[O:14][N:13]=[C:12]([C:15]([NH:35][CH2:34][CH2:33][C:27]3[C:26]4[C:30](=[CH:31][CH:32]=[C:24]([Cl:23])[CH:25]=4)[NH:29][CH:28]=3)=[O:17])[N:11]=2)=[CH:20][CH:21]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOC(=O)c1noc(Cc2ccc(C(C)(C)C)cc2)n1
Reactant: NCCc1c[nH]c2ccc(Cl)cc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CO
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)c1ccc(Cc2nc(C(=O)NCCc3c[nH]c4ccc(Cl)cc34)no2)cc1
Yield: 22.2 %

Procedure:
This compound was prepared according to method F with ethyl 5-(4-tert-butylbenzyl)-1,2,4-oxadiazole-3-carboxylate (0.125 g; 0.433 mmol) in methanol (2 mL); and 2-(5-chloro-1H-indol-3-yl)ethanamine hydrochloride (0.100 g; 0.433 mmol), HATU (0.164 g; 0.432 mmol), N,N diisopropylethylamine (0.075 mL; 0.432 mmol) in DMF (4 mL). The crude mixture was purified by flash chromatography on silica (eluent 20 to 100% ethyl acetate in heptane) to yield 0.042 g (22%) of 5-(4-tert-butylbenzyl)-N-(2-(5-chloro-1H-indol-3-yl)ethyl)-1,2,4-oxadiazole-3-carboxamide as a white solid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[N:10][C:9]=2[C:19]2[C:20]([F:37])=[C:21]([NH:25][S:26]([C:29]3[C:34]([F:35])=[CH:33][CH:32]=[CH:31][C:30]=3[F:36])(=[O:28])=[O:27])[CH:22]=[CH:23][CH:24]=2)[CH:5]=[CH:4][N:3]=1.[OH-].[NH3:39]>>[NH2:39][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[N:10][C:9]=2[C:19]2[C:20]([F:37])=[C:21]([NH:25][S:26]([C:29]3[C:34]([F:35])=[CH:33][CH:32]=[CH:31][C:30]=3[F:36])(=[O:28])=[O:27])[CH:22]=[CH:23][CH:24]=2)[CH:5]=[CH:4][N:3]=1
Reactant: O=S(=O)(Nc1cccc(-c2nc(C3CCOCC3)sc2-c2ccnc(Cl)n2)c1F)c1c(F)cccc1F
Reactant: N
Agent: [OH-]
Product: Nc1nccc(-c2sc(C3CCOCC3)nc2-c2cccc(NS(=O)(=O)c3c(F)cccc3F)c2F)n1
Temperature: 100 °C
Reaction time: 3 h

Procedure:
A suspension of N-{3-[5-(2-chloro-4-pyrimidinyl)-2-(tetrahydro-2H-pyran-4-yl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide (20.7 g, 36.5 mmol) and ammonia hydroxide (500 mL) was heated in a steel reactor to 100° C. After 3 h, the reaction cooled and checked by HPLC. The reaction mixture was concentrated. The reaction mixture wad diluted with CH2Cl2 (300 mL) and water (300 mL) then acidified with 6N HCl to pH=1. The mixture was extracted with 1% MeOH in CH2Cl2 (4×). The CH2Cl2 layer were dried over Na2SO4 and filtered and concentrated to 400 mL. Ethanol (400 mL) was added to the reaction mixture and concentrated to dryness. Ethanol (400 mL) was added again to the reaction mixture and concentrated to dryness. Ethanol (500 mL) was added to the reaction mixture and refluxed. After 4 h, the reaction mixture was cooled to 0° C., filtered, and wash with EtOH. The product was dried under vacuum at 60° C. for 2 days. Title compound was obtained as an off-white solid (17 g, 85% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.90 (br. s., 1H), 7.98 (d, J=5.3 Hz, 1H), 7.56-7.84 (m, 1H), 6.93-7.54 (m, 5H), 6.77 (br. s., 2H), 5.85 (d, J=4.6 Hz, 1H), 3.92 (d, J=9.9 Hz, 2H), 3.46 (t, J=11.2 Hz, 2H), 3.20-3.32 (m, 1H), 1.90-2.06 (m, 2H), 1.57-1.81 (m, 2H). MS (ESI): 548.10 [M+H]+.
Reaction SMILES: [Na].[N:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]#[N:9])[N:3]=1.[Cl-].[NH4+:11]>CO>[N:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([NH2:11])=[NH:9])[N:3]=1
Reactant: N#Cc1cccnn1
Reactant: [NH4+]
Agent: [Cl-]
Agent: [Na]
Solvent: CO
Product: N=C(N)c1cccnn1
Temperature: 35 °C
Reaction time: 8 h
Yield: 85.6 %

Procedure:
A solution of 1.60 g (0.068 mol) of sodium in 300 ml of anhydrous methanol was treated with a solution of 53.5 g (0.510 mol) of pyridazine-3-carbonitrile in 100 ml of methanol and the mixture was stirred for 8 hours at 35° C. Then, 29 g of ammonium chloride were added and the mixture was refluxed for approximately 14 hours. The hot mixture was filtered and the solid was discarded. 53.3 g of the title compound were obtained from the cold mother liquor by means of filtration.
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]2[CH:9]=[N:10][C:11]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)=[N:12][CH:13]=2)=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:20]O.[C:22]1(=[O:32])[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:24](=[O:31])[NH:23]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[F:1][C:2]1[C:7]([C:8]2[CH:9]=[N:10][C:11]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)=[N:12][CH:13]=2)=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:20][N:23]1[C:24](=[O:31])[C:25]2[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:22]1=[O:32]
Reactant: OCc1cccc(-c2cnc(N3CCOCC3)nc2)c1F
Reactant: O=C1NC(=O)c2ccccc21
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C1c2ccccc2C(=O)N1Cc1cccc(-c2cnc(N3CCOCC3)nc2)c1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.7 %

Procedure:
{2-Fluoro-3-[2-(morpholin-4-yl)pyrimidin-5-yl]phenyl}methanol (337 mg), 1H-isoindole-1,3(2H)-dione (257 mg) and triphenylphosphine (458 mg) were mixed with THF, and diethyl azodicarboxylate (40% toluene solution) (0.68 ml) was added thereto at 0° C., followed by stirring at room temperature overnight. The reaction mixture was stirred at 0° C. for 30 minutes, then filtered, washed with ice-cooled THF, and dried at 50° C. under reduced pressure to obtain 2-{2-fluoro-3-[2-(morpholin-4-yl)pyrimidin-5-yl]benzyl}-1H-isoindole-1,3(2H)-dione (452 mg).
Reaction SMILES: [Mg].CC1CCCO1.[C:8]1([CH:15]([CH3:17])[CH3:16])[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=1.II.C([Mg]Cl)C.BrCCBr.C1(C)CCC(C(C)C)C(Cl)C1.[C:39](=[O:41])=[O:40]>>[CH:11]1([CH3:14])[CH2:12][CH2:13][CH:8]([CH:15]([CH3:17])[CH3:16])[CH:9]([C:39]([OH:41])=[O:40])[CH2:10]1
Reactant: O=C=O
Reactant: Cc1ccc(C(C)C)cc1
Agent: CC1CCC(C(C)C)C(Cl)C1
Agent: CC[Mg]Cl
Agent: II
Solvent: CC1CCCO1
Solvent: BrCCBr
Product: CC1CCC(C(C)C)C(C(=O)O)C1
Temperature: 75 °C
Reaction time: 0.5 h

Procedure:
Magnesium (15.6 g, 50 mesh), 2-methyl-tetrahydrofuran (103 g), para cymene (50 g), iodine (0.1 g), and ethyl magnesium chloride (4 cc) were added under nitrogen to a 1-liter flask equipped with agitation, addition funnel, off-set adaptor for thermometer, gas addition tube, and condenser. The mixture was stirred for 30 min. at 75° C., and then 1,2,-dibromo ethane (4 cc) was slowly added. p-Menth-3-yl chloride (134 g dissolved in para cymene) was then added at a rate of 33 g/hr (0.21 mole/hr). After approximately ½ of the p-menth-3-yl chloride was added, carbon dioxide was concurrently added by bubbling the carbon dioxide into the mixture at a rate of 7.8 g/hr (0.18 mole/hr), and at a temperature of 80° C. After all of the p-menth-3-yl chloride was added, the temperature was raised to 90° C. to complete carbonation. After carbonation was complete, the resultant mixture was hydrolyzed with aqueous hydrochloric acid having a concentration of 15%. VPC analysis showed a yield of 78.3% by weight of p-menthane-3-carboxylic acid.