Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]1[C:15]2[CH:14]=[CH:13][C:12]([CH2:16][N:17]3[CH2:22][CH2:21][CH2:20][CH:19]([C:23]#[N:24])[CH2:18]3)=[CH:11][C:10]=2[C:9]2[C:4]1=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH3:2].C[Al](C)C.[Si]([N:33]=[N+:34]=[N-:35])(C)(C)C>C1(C)C=CC=CC=1>[NH:33]1[C:23]([CH:19]2[CH2:20][CH2:21][CH2:22][N:17]([CH2:16][C:12]3[CH:13]=[CH:14][C:15]4[N:3]([CH2:1][CH3:2])[C:4]5[C:9]([C:10]=4[CH:11]=3)=[CH:8][CH:7]=[CH:6][CH:5]=5)[CH2:18]2)=[N:24][N:35]=[N:34]1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: CCn1c2ccccc2c2cc(CN3CCCC(C#N)C3)ccc21
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Product: CCn1c2ccccc2c2cc(CN3CCCC(c4nnn[nH]4)C3)ccc21
Temperature: 80 °C
Reaction time: 8 h
Yield: 10.9 %

Procedure:
A 100-mL 3-necked round-bottomed flask was charged with a solution of 1-((9-Ethyl-9H-carbazol-3-yl)methyl)piperidine-3-carbonitrile (700 mg, 2.17 mmol, 1.00 equiv, 98%) in toluene (30 mL). To this solution was add AlMe3 (960 mg, 13.07 mmol, 6.02 equiv, 98%) and TMSN3 (1.52 g, 12.95 mmol, 5.97 equiv, 98%). The resulting mixture was stirred at 80° C. overnight. Upon completion, it was cooled down to room temperature and transferred into a reparatory funnel and extracted with ethyl acetate (3×50 mL). Combined organic layers were with brine and aqueous NaHCO3 (10%). The mixture was dried over anhydrous magnesium sulfate, filtered and concentrated to give the crude that was purified by preparative HPLC eluted with 1-10% MeOH in DCM affording 3-((3-(1H-tetrazol-5-yl)piperidin-1-yl)methyl)-9-ethyl-9H-carbazole as white solid (85 mg, 16%). LCMS: [M+H]+: 361. 1H NMR (DMSO-d63, 300 MHz) δ 8.15-8.10 (m, 2H), 7.62-7.57 (m, 2H), 7.47-7.43 (m, 2H), 7.22-7.18 (m, 1H), 4.47-4.40 (m, 2H), 3.92-3.82 (m, 2H), 3.26-3.16 (m, 2H), 2.98-2.94 (m, 1H), 2.37-2.31 (m, 1H), 2.04-2.00 (m, 1H), 1.74-1.57 (m, 3H), 1.32 (t, 3H).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[N+:10]([O-])=O.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(O)C.O>[NH2:10][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:2]=1[OH:1])[C:6]#[N:7]
Reactant: N#Cc1ccc(O)c([N+](=O)[O-])c1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: N#Cc1ccc(O)c(N)c1
Temperature: 80 °C
Reaction time: 1 h
Yield: 45.1 %

Procedure:
To a mixture of 4-hydroxy-3-nitrobenzonitrile (4 g, 0.0244 mol) in ethanol (180 mL) and water (90 mL) was added sodium thiosulfate (17 g, 0.0976 mol) at room temperature. The heterogeneous mixture was stirred at 80° C. under an atmosphere of nitrogen for 1 hour. The reaction mixture was cooled to room temperature, and ethanol was removed under reduced pressure. The yellow solid was filtered, washed with water, and dried under reduced pressure to yield 3-amino-4-hydroxybenzonitrile (1.46 g, 0.011 mol).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[C:11](=[O:12])[O:10][C:8](=O)[C:7]2=[CH:13][CH:14]=1)([OH:3])=[O:2].[NH2:15][C:16]1[CH:24]=[CH:23][C:19]([C:20]([OH:22])=[O:21])=[CH:18][CH:17]=1>>[C:1]([C:4]1[CH:5]=[C:6]2[C:11](=[O:12])[N:15]([C:16]3[CH:24]=[CH:23][C:19]([C:20]([OH:22])=[O:21])=[CH:18][CH:17]=3)[C:8](=[O:10])[C:7]2=[CH:13][CH:14]=1)([OH:3])=[O:2]
Reactant: Nc1ccc(C(=O)O)cc1
Reactant: O=C(O)c1ccc2c(c1)C(=O)OC2=O
Product: O=C(O)c1ccc(N2C(=O)c3ccc(C(=O)O)cc3C2=O)cc1
Yield: 54.4 %

Procedure:
4-carboxyphthalic anhydride (1.0 g, 0.0052 mol) and p-aminobenzoic acid (0.714 g, 0.0052 mol) were refluxed as above overnight. A clean product from the mother liquor fraction was not obtained. Crystallisation of the precipitated product from MeOH/H2O yielded 0.88 g (55%) of 105 as a white solid: mp=377–379° C.; Rf 0.90 (A): Rf 0.76 (B): Rf 0.46 (D): IR (cm−1): 2750–3200 (OH), 3077 (C═CH), 2652 (C—H), 1777 (C═O), 1731 (C═O), 1699 (C═O), 1604 (C═C), 1512 (C═C), 1485 (C═C), 1428 (C═C), 1376 (C—O), 1310 (C—O), 1092 (C—O), 723 (C═CH); MS m/z (rel intensity) 311 (23), 310 (100).
Reaction SMILES: [ClH:1].C(O[C:5](=[NH:14])[C:6]1[CH:11]=[CH:10][C:9]([Br:12])=[CH:8][C:7]=1[F:13])C.[NH3:15]>>[ClH:1].[Br:12][C:9]1[CH:10]=[CH:11][C:6]([C:5]([NH2:14])=[NH:15])=[C:7]([F:13])[CH:8]=1
Reactant: CCOC(=N)c1ccc(Br)cc1F
Reactant: N
Agent: Cl
Product: N=C(N)c1ccc(Br)cc1F
Temperature: 25 °C
Reaction time: 18 h
Yield: 100 %

Procedure:
A mixture of 4-bromo-2-fluoro-benzimidic acid ethyl ester hydrochloride (20.3 g, 72 mmol) in IMS (250 mL) at 0-5° C. was saturated with NH3 (gas), and the flask sealed before allowing to warm to RT and stirring for 18 h. Solvent was removed in vacuo and the residue triturated in diethyl ether to give 4-Bromo-2-fluoro-benzamidine hydrochloride as a white solid (18.1 g, 100%). 1H NMR δ (ppm)(DMSO-d): 9.26 (4 H, s), 7.92-7.87 (1 H, m), 7.71-7.62 (2 H, m).
Reaction SMILES: CC1C=CC(S([O:11][CH2:12][CH2:13][CH:14]2[CH2:20][CH:19]3[N:21]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH:16]([CH2:17][CH2:18]3)[CH2:15]2)(=O)=O)=CC=1.C(=O)([O-])[O-].[K+].[K+].O[C:36]1[CH:41]=[CH:40][C:39]([C:42]2[C:43]3[CH:52]=[CH:51][N:50]([CH3:53])[C:44]=3[N:45]=[C:46]([C:48]#[N:49])[N:47]=2)=[CH:38][C:37]=1[C:54]([F:57])([F:56])[F:55]>CC(N(C)C)=O>[C:48]([C:46]1[N:47]=[C:42]([C:39]2[CH:40]=[CH:41][C:36]([O:11][CH2:12][CH2:13][CH:14]3[CH2:15][CH:16]4[N:21]([C:22]([O:24][C:25]([CH3:26])([CH3:27])[CH3:28])=[O:23])[CH:19]([CH2:18][CH2:17]4)[CH2:20]3)=[C:37]([C:54]([F:57])([F:56])[F:55])[CH:38]=2)[C:43]2[CH:52]=[CH:51][N:50]([CH3:53])[C:44]=2[N:45]=1)#[N:49]
Reactant: Cc1ccc(S(=O)(=O)OCCC2CC3CCC(C2)N3C(=O)OC(C)(C)C)cc1
Reactant: Cn1ccc2c(-c3ccc(O)c(C(F)(F)F)c3)nc(C#N)nc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: Cn1ccc2c(-c3ccc(OCCC4CC5CCC(C4)N5C(=O)OC(C)(C)C)c(C(F)(F)F)c3)nc(C#N)nc21
Temperature: 80 °C
Reaction time: 1 h
Yield: 83.6 %

Procedure:
tert-Butyl 3-(2-{[(4-methylphenyl)sulfonyl]oxy}ethyl)-8-azabicyclo[3.2.1]octane-8-carboxylate (150 mg) and potassium carbonate (100 mg) were added to a solution of 4-[4-hydroxy-3-(trifluoromethyl)phenyl]-7-methyl-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile (100 mg) in DMAc (2 mL) at room temperature, and the mixture was stirred at 80° C. for 1 hour. After the reaction mixture was cooled to room temperature, extraction thereof was performed using EtOAc, and the extract was washed with water and saturated brine. The organic layer was dried over MgSO4 and filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (Hex:EtOAc=80:20 to 50:50), whereby tert-butyl 3-{2-[4-(2-cyano-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-(trifluoromethyl)phenoxy]ethyl}-8-azabicyclo[3.2.1]octane-8-carboxylate (146 mg) was obtained as a white solid.
Reaction SMILES: C[N:2](C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:15]=[C:16]([S:20]([NH:23][CH3:24])(=[O:22])=[O:21])[CH:17]=[CH:18][CH:19]=2)[N:8]=1)=O.[CH:26]1[C:35]2[C:30](=[C:31]([NH:36]N)[CH:32]=[CH:33][CH:34]=2)[CH:29]=[CH:28][N:27]=1>>[CH:26]1[C:35]2[C:30](=[C:31]([N:36]3[C:5]([C:7]4[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]5[CH:15]=[C:16]([S:20]([NH:23][CH3:24])(=[O:22])=[O:21])[CH:17]=[CH:18][CH:19]=5)[N:8]=4)=[CH:4][CH:3]=[N:2]3)[CH:32]=[CH:33][CH:34]=2)[CH:29]=[CH:28][N:27]=1
Reactant: CNS(=O)(=O)c1cccc(-n2ccc(=O)c(C(=O)/C=C/N(C)C)n2)c1
Reactant: NNc1cccc2cnccc12
Product: CNS(=O)(=O)c1cccc(-n2ccc(=O)c(-c3ccnn3-c3cccc4cnccc34)n2)c1

Procedure:
The product was obtained starting from 3-[3-((E)-3-Dimethylamino-acryloyl)-4-oxo-4H-pyridazin-1-yl]-N-methyl-benzenesulfonamide (A-31) and isoquinolin-5-yl-hydrazine according to the method described for example 91. MS: M=459.3 (M+H)+
Reaction SMILES: [NH2:1][C@@H:2]([C:13]1[NH:14][CH:15]=[C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:17]=1)[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.[CH2:24]1[C:29](=[O:30])[N:28]([O:31][C:32](ON2C(=O)CCC2=O)=[O:33])[C:26](=[O:27])[CH2:25]1>C(#N)C>[O:27]=[C:26]1[CH2:25][CH2:24][C:29](=[O:30])[N:28]1[O:31][C:32]([NH:1][C@@H:2]([C:13]1[NH:14][CH:15]=[C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:17]=1)[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1)=[O:33]
Reactant: N[C@H](Cc1c[nH]c2ccccc12)c1nc(-c2ccccc2)c[nH]1
Reactant: O=C(ON1C(=O)CCC1=O)ON1C(=O)CCC1=O
Solvent: CC#N
Product: O=C(N[C@H](Cc1c[nH]c2ccccc12)c1nc(-c2ccccc2)c[nH]1)ON1C(=O)CCC1=O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
302.4 mg (1 mmol) of 2-{(1R)-1-amino-2-[indol-3-yl]ethyl}-4-phenyl-1H-imidazole previously dissolved in 20 mL of anhydrous acetonitrile was added dropwise to a solution of N,N′-disuccinimidylcarbonate (528 mg. 2 mmol, DSC) in 20 mL of anhydrous acetonitrile during 1.5 hour. After a further 4 hours of stirring at room temperature, the solvent was evaporated in vacuo and the residue redissolved in 30 mL of chloroform. Excess DSC was then discarded and the organic layer washed with water (4×30 mL), dried over MgSO4 and concentrated to obtain a brown solid (215 mg-49%). 1H-NMR (CDCl3, 100 MHz) δ: 8.22 (br s, 1H); 8.1-7.08 (m, 12H); 5.9 (br s, 1H); 4.97 (dd, J=3.6 and 3 Hz, 1H); 3.75 (dd, J=3.6 and 14.8 Hz, 1H). 3.06 (dd, J=9.7 and 14.6 Hz, 1H): 2.96 (s, 2H); 2.89 (s, 2H). LC/MS: m/z=329 ((M+H)—SuOH.
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[N:6][CH:5]=[CH:4][N:3]=1.[NH2:9][C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CS(C)=O.O>[Cl:8][C:7]1[C:2]([O:16][C:13]2[CH:14]=[CH:15][C:10]([NH2:9])=[CH:11][CH:12]=2)=[N:3][CH:4]=[CH:5][N:6]=1
Reactant: Clc1nccnc1Cl
Reactant: Nc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: O
Product: Nc1ccc(Oc2nccnc2Cl)cc1
Reaction time: 8 h

Procedure:
To a round-bottomed flask was added 2,3-dichloropyrazine (7.3582 g, 49.4 mmol), 4-aminophenol (5.39 g, 49.4 mmol), and cesium carbonate (48.3 g, 148 mmol) in DMSO (165 mL) at 110° C. to stir overnight. The reaction mixture was diluted with water and extracted with EtOAc. The organic extract was washed with water, sat NaCl, sat sodium bicarbonate, dried with magnesium sulfate, filtered, and concentrated to give the title compound. MS (ESI, pos. ion) m/z: 222.1.
Reaction SMILES: [C:1]1([C:7]2[CH:13]=[CH:12][NH:11][C:10](=[O:14])[CH2:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O1CCC[CH2:16]1.CC(C)([O-])C.[K+].IC>C(OC)(C)(C)C>[CH3:16][N:11]1[CH:12]=[CH:13][C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[CH:8][CH2:9][C:10]1=[O:14]
Reactant: C1CCOC1
Reactant: O=C1CC=C(c2ccccc2)C=CN1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CI
Solvent: COC(C)(C)C
Product: CN1C=CC(c2ccccc2)=CCC1=O
Temperature: -30 °C
Yield: 100 %

Procedure:
The 5-phenyl-1,3-dihydro-azepin-2-one (168.5 g, 911.3 mmol) is combined with tetrahydrofuran (1300 mL) and the solution cooled to about −30° C. Potassium tertiary-butoxide (107.4 g, 956.9 mmol) is added in one portion. Exotherm is observed warming the reaction contents to −12° C. Upon subsiding of the exotherm, the contents are allowed to re-cool to −25° C. and iodomethane (113.5 mL, 1.823 moL) is added providing a slight exotherm. The reaction contents are allowed to warm to room temperature and stirred. After 10 hours the reaction mixture is diluted with methyl tertiary-butyl ether (1300 mL) and extracted with saturated ammonium chloride solution (2×250 mL), water, and saturated aqueous sodium chloride solution. The combined aqueous layers are back extracted with methyl tertiary-butyl ether (200 mL). The methyl tertiary-butyl ether extracts are combined, dried over MgSO4 and filtered. The solution is concentrated via rotary evaporation to provide the title compound (185 g, 100%) as a brown powdery residue. The material is used directly, without purification, in the next step.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([O:9][CH3:10])[CH:5]=[CH:4][C:3]=1[C:11](=[O:15])[CH:12]([CH3:14])[CH3:13].[Br:16]Br.S(=O)(O)[O-].[Na+]>C(O)(=O)C>[Br:16][C:12]([CH3:13])([CH3:14])[C:11]([C:3]1[CH:4]=[CH:5][C:6]([O:9][CH3:10])=[C:7]([Cl:8])[C:2]=1[Cl:1])=[O:15]
Reactant: BrBr
Reactant: COc1ccc(C(=O)C(C)C)c(Cl)c1Cl
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Product: COc1ccc(C(=O)C(C)(C)Br)c(Cl)c1Cl
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
A stirred solution of 2',3'-dichloro-4'methoxyisobutyrophenone (45 g., 0.183 mole) in acetic acid (150 ml.) is treated during 1/2 hour with bromine (30 g., 0.187 mole). The reaction mixture is stirred 10 minutes, then poured into ice water (600 ml.) containing sodium bisulfite (2 g.). The 2-bromo-2'-3'-dichloro-4'-methoxyisobutyrophenone which separates (48 g.) melts at 72°-73° C. after recrystallization from hexane.
Reaction SMILES: [I:1]I.[CH3:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:12]([CH3:21])=[CH:13][C:14]([C:17]([O:19][CH3:20])=[O:18])=[N:15][CH:16]=2)=[CH:7][CH:6]=1>CO.S([O-])([O-])(=O)=O.[Ag+2]>[I:1][C:6]1[CH:7]=[C:8]([C:11]2[C:12]([CH3:21])=[CH:13][C:14]([C:17]([O:19][CH3:20])=[O:18])=[N:15][CH:16]=2)[CH:9]=[CH:10][C:5]=1[O:4][CH3:3]
Reactant: II
Reactant: COC(=O)c1cc(C)c(-c2ccc(OC)cc2)cn1
Agent: [Ag+2]
Agent: O=S(=O)([O-])[O-]
Solvent: CO
Product: COC(=O)c1cc(C)c(-c2ccc(OC)c(I)c2)cn1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 63.8 %

Procedure:
A suspension of iodine (2.45 g, 9.66 mmol), silver sulfate (3.01 g, 9.66 mmol) and methyl 5-(4-methoxyphenyl)-4-methylpyridine-2-carboxylate (2.47 g, 9.59 mmol) in MeOH (20 mL) was stirred at room temperature for 3.5 hours. It was then heated at 36° C. for 4 hours and then at room temperature for another 16 hours. Additional iodine (0.8 g, 3.15 mmol) and silver sulfate (1 g, 3.2 mmol) were added and the reaction was heated to 36° C. for 3 hours. The volatiles were removed and the reaction was diluted with ethyl acetate and aqueous sodium thiosulfate. The organic was washed with brine, dried over sodium sulfate, filtered and then concentrated. The resultant oil was purified by column chromatography to yield methyl 5-(3-iodo-4-methoxyphenyl)-4-methylpyridine-2-carboxylate (2.35 g, 6.12 mmol) as a white solid. MS ESI calc'd. for C15H15INO3 [M+H]+ 384.0, found 384.0.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([CH3:9])=[CH:4][N:3]=1.[NH2:10][CH:11]1[CH2:28][CH2:27][C:14]2([CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]2)[CH2:13][CH2:12]1.CCN(CC)CC>CCO>[Cl:1][C:2]1[N:7]=[C:6]([NH:10][CH:11]2[CH2:12][CH2:13][C:14]3([CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:24])([CH3:25])[CH3:26])=[O:21])[CH2:16][CH2:15]3)[CH2:27][CH2:28]2)[C:5]([CH3:9])=[CH:4][N:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC2(CCC(N)CC2)CC1
Reactant: Cc1cnc(Cl)nc1Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: Cc1cnc(Cl)nc1NC1CCC2(CC1)CCN(C(=O)OC(C)(C)C)CC2
Temperature: 100 °C
Reaction time: 25.5 h
Yield: 23.4 %

Procedure:
To a solution of 2,4-dichloro-5-methyl-pyrimidine (0.58 g, 3.60 mmol) and tert-butyl 9-amino-3-azaspiro[5.5]undecane-3-carboxylate (1.44 g, 5.37 mmol) in EtOH (25 mL) was added Et3N (0.86 g, 8.50 mmol). After addition, the reaction mixture was stirred at 100° C. in a sealed tube for 25.5 h and concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc/PE (v/v)=1/2) to give the title compound as a yellow solid (332.2 mg, 24%).
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:35])([F:34])[C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH2:12][CH2:13][N:14]([C:17]([O:19][CH2:20][C:21]([OH:33])([CH3:32])[CH2:22][N:23]3[CH:27]=[C:26]([N+:28]([O-:30])=[O:29])[N:25]=[C:24]3Cl)=[O:18])[CH2:15][CH:16]=2)=[CH:7][CH:6]=1>CN(C=O)C>[F:3][C:4]([F:35])([F:34])[C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH2:12][CH2:13][N:14]([C:17]([O:19][CH2:20][C:21]3([CH3:32])[O:33][C:24]4=[N:25][C:26]([N+:28]([O-:30])=[O:29])=[CH:27][N:23]4[CH2:22]3)=[O:18])[CH2:15][CH:16]=2)=[CH:7][CH:6]=1
Reactant: CC(O)(COC(=O)N1CC=C(c2ccc(C(F)(F)F)cc2)CC1)Cn1cc([N+](=O)[O-])nc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1(COC(=O)N2CC=C(c3ccc(C(F)(F)F)cc3)CC2)Cn2cc([N+](=O)[O-])nc2O1
Temperature: 0 °C
Reaction time: 1 h
Yield: 38.4 %

Procedure:
Sodium hydride (11 mg, 0.28 mmol) was added to a solution of 3-(2-chloro-4-nitroimidazol-1-yl)-2-hydroxy-2-methylpropyl 4-(4-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine-1-carboxylate prepared in Example 85 (0.11 g, 0.23 mmol) in DMF (1 ml) followed by stirring for 1 hour with cooling on ice-bath. Ice-water was added to the reaction mixture, the resulting mixture was extracted with ethyl acetate. The extract was washed with water, dried over magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methylene chloride/ethyl acetate=4/1) and then washed with diisopropyl ether to afford 2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazol-2-ylmethyl 4-(4-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine-1-carboxylate (0.04 g, yield 39%) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]([O:6][CH3:7])([CH3:5])[CH3:4].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.[I:25][C:26](=[CH2:32])[CH2:27][C@@H](O)CO>ClCCl>[I:25][C:26](=[CH2:27])[CH2:32][C@@H:1]1[CH2:7][O:6][C:3]([CH3:5])([CH3:4])[O:2]1
Reactant: COC(C)(C)OC
Reactant: C=C(I)C[C@@H](O)CO
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: C=C(I)C[C@@H]1COC(C)(C)O1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2,2-Dimethoxypropane and pyridinium p-toluenesulfonate (PPTS) are added to a solution of (R)-4-iodopent-4-ene-1,2-diol in dichloromethane and the mixture stirred at room temperature for 2 hours. Solvents are removed under reduced pressure and the crude product purified by flash chromatography using ethyl acetate/hexane (1:10) eluant.
Reaction SMILES: C[O:2][C:3]([C@H:5]1[CH2:9][O:8][CH:7]([CH2:10][O:11][C:12](=[O:19])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[O:6]1)=[O:4].O1CCCC1.[OH-].[Li+]>O>[C:12]([O:11][CH2:10][C@@H:7]1[O:6][C@@H:5]([C:3]([OH:4])=[O:2])[CH2:9][O:8]1)(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: COC(=O)[C@H]1COC(COC(=O)c2ccccc2)O1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(OC[C@H]1OC[C@H](C(=O)O)O1)c1ccccc1
Reaction time: 1.5 h

Procedure:
To a solution of methyl-2-(R,S)-benzoyloxymethyl-1,3-dioxolane-4-(R)-carboxylate (III), (411 g, 1.54 mmol, 1 eq., 2:1 mixture of cis and trans isomers) in a 1:1 mixture of tetrahydrofuran (THF) and water, lithium hydroxide (LiOH) (64.8 g, 1.54 moles, 1 eq) was added portion wise over a period of 30 min., keeping the reaction flask temperature below 30° C. After 90 min., THF was removed by vacuum and the aqueous solution was acidified to pH=2.5-3.2, by dropwise addition of 30% (w/w) sulphuric acid. The resulting solution was extracted with dichloromethane (4×400 mL). The combined organic phase was washed with brine, dried over sodium sulphate and concentrated to produce 380 g of a dark oil. The isomers were separated by column chromatography on silica gel, using 2% acetic acid in dichloromethane to produce 220 g of the cis isomer (IVa) (56.5%) and 116 g of the trans isomer (IVb) (30%). Each of isomers was independently used for next step.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([F:25])=[C:21]([F:26])[CH:20]=2)=[C:6]([CH:16]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][N:13]=[N:12][CH:11]=1)=[O:8].[CH3:27][N:28]1[CH:32]=[C:31](B2OC(C)(C)C(C)(C)O2)[CH:30]=[N:29]1.C(=O)([O-])[O-].[Na+].[Na+]>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.COCCOC>[F:26][C:21]1[CH:20]=[C:19]([CH2:18][O:17][C:5]2[CH:4]=[CH:3][C:2]([C:31]3[CH:30]=[N:29][N:28]([CH3:27])[CH:32]=3)=[CH:16][C:6]=2[C:7]([NH:9][C:10]2[CH:15]=[CH:14][N:13]=[N:12][CH:11]=2)=[O:8])[CH:24]=[CH:23][C:22]=1[F:25]
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: O=C(Nc1ccnnc1)c1cc(Br)ccc1OCc1ccc(F)c(F)c1
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: COCCOC
Product: Cn1cc(-c2ccc(OCc3ccc(F)c(F)c3)c(C(=O)Nc3ccnnc3)c2)cn1
Temperature: 120 °C

Procedure:
To a microwave vial was added 5-bromo-2-{[(3,4-difluorophenyl)methyl]oxy}-N-4-pyridazinylbenzamide (may be prepared by Example 78; 150 mg, 0.36 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (75 mg, 0.36 mmol), 1,2-dimethoxyethane (2 nil), 1M sodium carbonate (0.71 ml, 0.71 mmol), and tetrakis(triphenylphosphine)palladium(0) (24.75 mg, 0.02 mmol). The vial was sealed and heated to 120° C. for 1 hour under microwave conditions. The mixture was evaporated under reduced pressure and water (5 ml) was added to the residue. The mixture was extracted with ethyl acetate (3×10 ml). The organics were combined and evaporated and the residue was purified using the MDAP to yield the title compound. 80 mg.
Reaction SMILES: [C:1]([CH:3]([C:23]1([CH3:27])[CH2:26][O:25][CH2:24]1)[NH:4][C:5]([C:7]1[CH:12]=[C:11]([O:13][C@@H:14]([CH3:19])[C:15]([F:18])([F:17])[F:16])[C:10]([CH:20]2[CH2:22][CH2:21]2)=[CH:9][N:8]=1)=[O:6])#[N:2].[OH-:28].[Na+].OO>C(O)C>[NH2:2][C:1](=[O:28])[CH:3]([NH:4][C:5]([C:7]1[CH:12]=[C:11]([O:13][C@@H:14]([CH3:19])[C:15]([F:16])([F:18])[F:17])[C:10]([CH:20]2[CH2:21][CH2:22]2)=[CH:9][N:8]=1)=[O:6])[C:23]1([CH3:27])[CH2:26][O:25][CH2:24]1
Reactant: C[C@H](Oc1cc(C(=O)NC(C#N)C2(C)COC2)ncc1C1CC1)C(F)(F)F
Reactant: [OH-]
Agent: OO
Agent: [Na+]
Solvent: CCO
Product: C[C@H](Oc1cc(C(=O)NC(C(N)=O)C2(C)COC2)ncc1C1CC1)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of N-[cyano-(3-methyloxetan-3-yl)methyl]-5-cyclopropyl-4-[(1S)-2,2,2-trifluoro-1-methyl-ethoxy]pyridine-2-carboxamide (example 251c, 0.17 g, 443 μmol) in ethanol (3 ml) was added a 4M aqueous solution of sodium hydroxide (554 μl, 2.22 mmol) and H2O2 35% aqueous solution (215 mg, 190 μl, 2.22 mmol). The reaction mixture was stirred at room temperature overnight. The reaction was then concentrated in vacuo and diluted with ethyl acetate. The organic phase was extracted with a 1M aqueous solution of sodium bicarbonate. The organic phase was collected and the aqueous phase was back-extracted with ethyl acetate. The combined organic phases were dried over sodium sulfate and evaporated down to dryness. The crude material was purified by flash chromatography on silica eluting with a heptane-ethyl acetate gradient to yield the mixture of epimers which was then separated into its individual epimers by preparative chiral HPLC (Chiralpak AD, ethanol/heptane) and the title compound was the second epimer collected and isolated as colorless oil; MS (ESI, m/z): 402.6 (M+H+).
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([CH2:12][CH2:13][NH2:14])[C:9]2[C:4](=[CH:5][C:6]([C:15]([F:18])([F:17])[F:16])=[CH:7][CH:8]=2)[N:3]=1.[F:19][C:20]([F:31])([F:30])[C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.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>[F:19][C:20]([F:31])([F:30])[C:21]1[CH:26]=[CH:25][C:24]([C:2]2[N:11]=[C:10]([CH2:12][CH2:13][NH2:14])[C:9]3[C:4](=[CH:5][C:6]([C:15]([F:18])([F:17])[F:16])=[CH:7][CH:8]=3)[N:3]=2)=[CH:23][CH:22]=1
Reactant: NCCc1nc(Cl)nc2cc(C(F)(F)F)ccc12
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
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: COCCOC
Product: NCCc1nc(-c2ccc(C(F)(F)F)cc2)nc2cc(C(F)(F)F)ccc12

Procedure:
A solution of (2-chloro-7-trifluoromethyl-quinazolin-4-yl)ethylamine (276 mg, 1.00 mmol), p-trifluoromethylphenylboronic acid (285 mg, 1.50 mmol), tetrakis(triphenylphosphine)palladium (116 mg, 0.10 mmol) and sodium carbonate (0.21 g, 2.0 mmol) in dimethoxyethane/water (3 mL, 2:1) was heated at 80° C. for 16 h. The reaction mixture was then concentrated under reduced pressure, diluted with water (50 mL) and extracted with CH2Cl2 (3×25 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated under reduced pressure. Purification by flash chromatography using cyclohexane:ethyl acetate (4:1) as solvent afforded [2-(4-trifluoromethylphenyl)-7-trifluoromethyl-quinazolin-4-yl]ethylamine. Yield=0.20 g, 52%; LC-MS: 3.2 min, 385 (M+); 1H NMR (DMSO-d6): δ 1.34 (t, 3 H, J=7.2 Hz), 3.68-3-78 (m, 2 H), 7.82 (dd, 1 H, J=8.6, 1.7 Hz), 7.88 (d, 2 H, J=8.1 Hz), 8.07 (s, 1 H), 8.50 (d, 1 H, J=8.6 Hz), 8.67 (d, 2 H, J=8.1 Hz), 8.70-8.76 (m, 1 H).