Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][CH2:2][CH2:3][OH:4].Br[CH:6]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(=O)([O-])[O-].[Na+].[Na+]>CCOCC>[C:7]1([CH:6]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[O:4][CH2:3][CH2:2][Br:1])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: BrC(c1ccccc1)c1ccccc1
Reactant: OCCBr
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOCC
Product: BrCCOC(c1ccccc1)c1ccccc1
Temperature: 130 °C
Reaction time: 5 h

Procedure:
37.5 g (0.3 mole) of 2-bromoethanol was added to a mixture of 61.8 g (0.25 mole) of bromodiphenylmethane and 31.8 g (0.3 mole) of sodium carbonate. The reactive medium was slowly heated to 130° C., held at this temperature for 5 hours and then left overnight at room temperature. The mixture was taken up with ether and washed with water. The ethereal extract was dried on sodium sulfate. The evaporation of the ether yielded an oil, which was purified by distillation.
Reaction SMILES: C1(C)C=CC(S(O[CH2:11][CH2:12][CH:13]([C:18]([F:21])([F:20])[F:19])[C:14]([CH3:17])([CH3:16])[CH3:15])(=O)=O)=CC=1.[F:23][C:24]([F:36])([F:35])[CH2:25][CH2:26][S:27]([CH2:30][C:31]([O:33][CH3:34])=[O:32])(=[O:29])=[O:28].C(=O)([O-])[O-].[K+].[K+].Cl>CS(C)=O>[CH3:17][C:14]([CH3:15])([CH3:16])[CH:13]([C:18]([F:19])([F:20])[F:21])[CH2:12][CH2:11][CH:30]([S:27]([CH2:26][CH2:25][C:24]([F:35])([F:36])[F:23])(=[O:29])=[O:28])[C:31]([O:33][CH3:34])=[O:32]
Reactant: Cc1ccc(S(=O)(=O)OCCC(C(C)(C)C)C(F)(F)F)cc1
Reactant: COC(=O)CS(=O)(=O)CCC(F)(F)F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: COC(=O)C(CCC(C(C)(C)C)C(F)(F)F)S(=O)(=O)CCC(F)(F)F
Temperature: 90 °C
Reaction time: 6 h
Yield: 58.5 %

Procedure:
To a solution of 2.9 g of 4,4-dimethyl-3-(trifluoromethyl)pentyl p-toluenesulfonate and 2.0 g of methyl (3,3,3-trifluoropropylsulfonyl)acetate in 30 ml of dimethyl sulfoxide was added 1.2 g of potassium carbonate at room temperature. The reaction mixture was heated to 90° C., stirred at the same temperature for 6 hours, and then allowed to stand to cool to nearly room temperature. To the reaction mixture was added 10% hydrochloric acid, and then extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The obtained residue was subjected to silica gel chromatography to obtain 2.00 g of methyl 6,6-dimethyl-5-trifluoromethyl-2-(3,3,3-trifluoropropylsulfonyl)heptanoate (hereinafter referred to as the present compound (7)).
Reaction SMILES: Cl.[C:2](Cl)(=[O:9])[C:3]1[CH:8]=[CH:7][CH:6]=[N:5][CH:4]=1.[CH2:11]([C:13]1[NH:14][C:15](=[O:18])[NH:16][CH:17]=1)[CH3:12].[Cl-].[Al+3].[Cl-].[Cl-].C(=O)(O)[O-].[Na+]>ClCC(Cl)(Cl)Cl.O>[CH2:11]([C:13]1[NH:14][C:15](=[O:18])[NH:16][C:17]=1[C:2](=[O:9])[C:3]1[CH:8]=[CH:7][CH:6]=[N:5][CH:4]=1)[CH3:12]
Reactant: O=C(Cl)c1cccnc1
Reactant: CCc1c[nH]c(=O)[nH]1
Agent: Cl
Agent: ClCC(Cl)(Cl)Cl
Agent: O=C([O-])O
Solvent: O
Product: CCc1[nH]c(=O)[nH]c1C(=O)c1cccnc1
Temperature: 85 °C

Procedure:
To a well stirred mixture of 8.85 g (50 mmole) nicotinoyl chloride hydrochloride and 5.6 g (50 mmole) 1,3-dihydro-4-ethyl-2H-imidazole-2-one in 100 ml tetrachloroethane is added 22 g (164 mmole) aluminum chloride. The mixture is heated at 85° C. for 2 hours and treated with water. The solution is neutralized with sodium bicarbonate, filtered and taken to dryness. Chromatography over silica gel affords the title compound; m.p. 219°-21°.
Reaction SMILES: [CH:1]1[N:2]=[CH:3][N:4]2[CH:9]=[CH:8][CH:7]=[C:6]([C:10]3[O:19][C:13]4=[C:14]([NH2:18])[N:15]=[CH:16][CH:17]=[C:12]4[CH:11]=3)[C:5]=12.C1C(=O)N([I:27])C(=O)C1>CN(C=O)C>[CH:1]1[N:2]=[CH:3][N:4]2[CH:9]=[CH:8][CH:7]=[C:6]([C:10]3[O:19][C:13]4=[C:14]([NH2:18])[N:15]=[CH:16][C:17]([I:27])=[C:12]4[CH:11]=3)[C:5]=12
Reactant: O=C1CCC(=O)N1I
Reactant: Nc1nccc2cc(-c3cccn4cncc34)oc12
Solvent: CN(C)C=O
Product: Nc1ncc(I)c2cc(-c3cccn4cncc34)oc12
Reaction time: 1 h
Yield: 9.5 %

Procedure:
To a cooled (0° C.) solution of 2-(imidazo[1,5-a]pyridin-8-yl)furo[2,3-c]pyridin-7-amine (82.0 mg, 0.328 mmol) in DMF (4 mL) was added NIS (74.0 mg, 0.329 mmol) in portions. After stirring from 0° C. to RT over 1 h, the mixture was adsorbed onto silica gel. Purification by ISCO chromatography (50 to 100% ethyl acetate:heptane and then 15% methanol:dichloromethane), followed by mass-directed purification afforded 11.7 mg (10%) of the title compound as a yellow solid. 1H NMR (400 MHz, MeOH-d4): δ 9.37 (s, 1H), 8.65 (br s, 1H), 8.62 (d, J=7.07 Hz, 1H), 8.02 (d, J=7.07 Hz, 1H), 7.98 (s, 1H), 7.64 (s, 1H), 7.23 (t, J=7.10 Hz, 1H); MS (ESI): 376.93 [M+H]+; HPLC tR=2.76 min (ZQ3: polar—5 min).
Reaction SMILES: [BH4-].[Na+].[Si:3]([O:10][CH2:11][CH2:12][C:13]1[S:17][C:16]([CH:18]=[O:19])=[CH:15][CH:14]=1)([C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:5])[CH3:4]>C(O)C>[Si:3]([O:10][CH2:11][CH2:12][C:13]1[S:17][C:16]([CH2:18][OH:19])=[CH:15][CH:14]=1)([C:6]([CH3:8])([CH3:9])[CH3:7])([CH3:5])[CH3:4]
Reactant: CC(C)(C)[Si](C)(C)OCCc1ccc(C=O)s1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CC(C)(C)[Si](C)(C)OCCc1ccc(CO)s1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Sodium borohydride (1.74 g) was added to a solution of 5-(2-(tert-butyldimethylsilyloxy)ethyl)thiophene-2-carbaldehyde (12.4 g) (example 4, step b) in ethanol (120 mL) at 0° C. The resulting solution was stirred at 0° C. for 1 h. The reaction mixture was partitioned between brine and ethyl acetate. The organic layer was separated, dried over sodium sulphate, filtered and the solvent evaporated in vacuo to give the subtitled compound. Yield 12.1 g.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([OH:20])([CH2:15][O:16]C(=O)C)[CH2:10][O:11]C(=O)C.P([O-])([O-])([O-])=O>C1CCCCC1>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([OH:20])([CH2:15][OH:16])[CH2:10][OH:11]
Reactant: CC(=O)OCC(O)(COC(C)=O)c1ccc(F)cc1F
Agent: O=P([O-])([O-])[O-]
Solvent: C1CCCCC1
Product: OCC(O)(CO)c1ccc(F)cc1F
Temperature: 30 °C
Reaction time: 24 h
Yield: 93.2 %

Procedure:
A 2 l reaction vessel was charged with 10 g of 2-(2,4-difluorophenyl)-1,3-diacetoxy-2-propanol, 2 g of Lipase AP-6 (made by Amano Pharmaceutical Co., Ltd., derived from Aspergillus niger, Enzyme No. 12), 500 ml of 50 mM phosphate buffer (pH 7.0) and 500 ml of cyclohexane. The resulting mixture was stirred at 30° C. for 24 hours. The reaction liquid was extracted three times with 1000 ml of ethyl acetate and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure and the residue was purified by column chromatography on silica gel (n-hexane/ethyl acetate=1/10) to give 6.6 g of 2-(2,4-difluorophenyl)-1,2,3-propanetriol.
Reaction SMILES: [CH:1]1[C:6]([OH:7])=[CH:5][C:4]2[C:8]([CH2:11][CH2:12][NH2:13])=[CH:9][NH:10][C:3]=2[CH:2]=1.[CH3:14][C:15](ON1C(=O)CCC1=O)=[O:16]>>[CH3:14][C:15]([NH:13][CH2:12][CH2:11][C:8]1[C:4]2[CH:5]=[C:6]([OH:7])[CH:1]=[CH:2][C:3]=2[NH:10][CH:9]=1)=[O:16]
Reactant: CC(=O)ON1C(=O)CCC1=O
Reactant: NCCc1c[nH]c2ccc(O)cc12
Product: CC(=O)NCCc1c[nH]c2ccc(O)cc12

Procedure:
Serotonin (compound 7 in Scheme 3) reacts with N-succinimidyl acetate (8) selectively on the primary alkyl amine, as shown below, to give N-acetylserotonin (9). The electroactive hydroxytryptamine ring system emerges from the reaction unchanged. In practice a biological sample of 1.0 ml volume (for example: cerebrospinal fluid) is degassed by bubbling argon and treated with 0.05 ml of a solution of N-succinimidyl acetate in dioxane (100 mg/ml). The reaction is carried out at a pH of 10-11 in a closed vessel under argon at 70° C. for a period as short as five minutes or as long as two hours. The reaction is then quenched with glycine, giving the non-electroactive sodium N-acetylglycinate (10). ##STR5##
Reaction SMILES: [CH:1]12[O:9][CH:5]([CH2:6][NH:7][CH2:8]1)[CH2:4][N:3]([CH2:10][CH2:11][CH2:12][NH:13][C:14]1[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][CH:15]=1)[CH2:2]2.C([O-])([O-])=O.[K+].[K+].Cl[CH2:29][C:30](=[O:35])[C:31]([CH3:34])([CH3:33])[CH3:32].C(Cl)Cl>CC#N>[CH3:32][C:31]([CH3:34])([CH3:33])[C:30](=[O:35])[CH2:29][N:7]1[CH2:8][CH:1]2[O:9][CH:5]([CH2:4][N:3]([CH2:10][CH2:11][CH2:12][NH:13][C:14]3[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][CH:15]=3)[CH2:2]2)[CH2:6]1
Reactant: N#Cc1ccc(NCCCN2CC3CNCC(C2)O3)cc1
Reactant: CC(C)(C)C(=O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: ClCCl
Product: CC(C)(C)C(=O)CN1CC2CN(CCCNc3ccc(C#N)cc3)CC(C1)O2
Yield: 75.4 %

Procedure:
A mixture of 4-{[3-(9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl)propyl]amino}-benzonitrile (Preparation C, 5.73 g 0.02 mol), K2CO3 (11.05 g, 0.08 mol) in MeCN (300 mL) was treated with 1-chloropinacolone (4.44 g, 0.032 mol). The mixture was stirred at 50° C. overnight before DCM was added and the mixture filtered. The filter cake was then washed with a mixture of DCM and MeCN before the solvent was evaporated from the filtrate. The resulting residue was purified by chromatography on silica, eluting with a gradient of ethyl acetate methanol:ammoniacal methanol (95:5:0 to 95:0:5), to give the title compound (5.8 g, 73.9%).
Reaction SMILES: ClC1C=[CH:9][C:5]([C:6](O)=O)=[C:4]([N+]([O-])=O)C=1.[CH2:14]([O:21][C:22]1[CH:30]=[C:29]([Cl:31])[CH:28]=[CH:27][C:23]=1[C:24]([OH:26])=[O:25])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[CH2:14]([O:21][C:22]1[CH:30]=[C:29]([Cl:31])[CH:28]=[CH:27][C:23]=1[C:24]([O:26][C:5]([CH3:9])([CH3:6])[CH3:4])=[O:25])[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: O=C(O)c1ccc(Cl)cc1OCc1ccccc1
Reactant: O=C(O)c1ccc(Cl)cc1[N+](=O)[O-]
Product: CC(C)(C)OC(=O)c1ccc(Cl)cc1OCc1ccccc1

Procedure:
Instead of the starting material, that is, 4-chloro-2-nitrobenzoic acid, of Reference Example 6, 2-(benzyloxy)-4-chlorobenzoic acid was used for a similar procedure as in Reference Example 6 to obtain tert-butyl 2-(benzyloxy)-4-chlorobenzoate (compound S12a).
Reaction SMILES: [CH2:1]([N:8]1[C:18]2[C:19]3[C:11](=[N:12][NH:13][C:14]=3[N:15]=[C:16]([S:20][CH3:21])[N:17]=2)[CH:10]([C:22](O)=[O:23])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:25]([NH2:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>CN(C=O)C>[CH2:25]([NH:32][C:22]([CH:10]1[CH2:9][N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:18]2[C:19]3[C:11]1=[N:12][NH:13][C:14]=3[N:15]=[C:16]([S:20][CH3:21])[N:17]=2)=[O:23])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: NCc1ccccc1
Reactant: CSc1nc2c3c(n[nH]c3n1)C(C(=O)O)CN2Cc1ccccc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CSc1nc2c3c(n[nH]c3n1)C(C(=O)NCc1ccccc1)CN2Cc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 95.2 %

Procedure:
5-Benzyl-7-(methylthio)-1,3,4,5-tetrahydro-1,2,5,6,8-pentaazaacenaphthylene-3-carboxlic acid (0.71 g, 2.1 mmol) and DMF (20 ml) were placed in a round-bottomed flask. To the stirring mixture was slowly added benzylamine (0.34 mL, 3.2 mmol), HBTU (1.03 g, 3.4 mmol), diisopropylethyl amine (1.1 mL, 6.3 mmol) and the solution was allowed to stir at room temperature for 16 h. The reaction was quenched by addition of EtOAc (200 mL) and washing with water (2×500 mL). The organic layer was combined, dried over MgSO4, and concentrated under reduced pressure to yield a yellow solid (0.84 g, 2.0 mmol). 1H-NMR (DMSO-d6): 8.56 (t, J=2.0 Hz, 1H), 7.40-7.22 (m, 10H), 4.36 (dd, J=8.1 & 21.2 Hz, 3H), 4.38-4.21 (m, 3H), 4.19 (t, J=5.2 Hz, 2H), 3.86-3.76 (m, 3H), 3.17 (d, J=5.2 Hz, 1H). LC: Rt=1.42 min. MS 431.53 [M+H].
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[C:5]([O:11][CH3:12])=[CH:4][C:3]=1[N:13]1[CH2:18][CH2:17][CH:16]([CH2:19][CH2:20][S:21]([CH3:24])(=[O:23])=[O:22])[CH2:15][CH2:14]1>CCOC(C)=O.[Pt]>[CH3:1][C:2]1[C:3]([N:13]2[CH2:18][CH2:17][CH:16]([CH2:19][CH2:20][S:21]([CH3:24])(=[O:22])=[O:23])[CH2:15][CH2:14]2)=[CH:4][C:5]([O:11][CH3:12])=[C:6]([CH:7]=1)[NH2:8]
Reactant: COc1cc(N2CCC(CCS(C)(=O)=O)CC2)c(C)cc1[N+](=O)[O-]
Agent: [Pt]
Solvent: CCOC(C)=O
Product: COc1cc(N2CCC(CCS(C)(=O)=O)CC2)c(C)cc1N
Reaction time: 8 h
Yield: 59.3 %

Procedure:
To 1-[2-methyl-5-(methyloxy)-4-nitrophenyl]-4-[2-(methylsulfonyl)ethyl]piperidine (3.26 g, 9.14 mmol) in EtOAc (100 mL) was added platinum on carbon (sulfided) (1.77 g, 0.460 mmol). The mixture was stirred under H2 (1 atm.) overnight. Filtering the mixture through Celite® and concentrating provided the title compound of Step E (1.77 g, 5.42 mmol, 59%). 1H NMR (400 MHz, DMSO-d6) δ 6.55 (s, 1H), 6.43 (s, 1H), 4.29 (s, 2H), 3.71 (s, 3H), 3.10-3.19 (m, 2H), 2.97 (s, 3H), 2.88 (d, 2H), 2.51-2.58 (m, 2H), 2.06 (s, 3H), 1.61-1.79 (m, 4H), 1.19-1.52 (m, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[C:11]([CH2:13][C:14]#[N:15])[N:12]=2)=[CH:4][CH:3]=1.[N-:22]=[N+:23]=[N-:24].[Na+].[Cl-].[NH4+]>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[S:9][C:10]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)=[C:11]([CH2:13][C:14]3[NH:24][N:23]=[N:22][N:15]=3)[N:12]=2)=[CH:6][CH:7]=1
Reactant: N#CCc1nc(-c2ccc(Cl)cc2)sc1-c1ccccc1
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Clc1ccc(-c2nc(Cc3nnn[nH]3)c(-c3ccccc3)s2)cc1
Temperature: 90 °C
Reaction time: 12 h
Yield: 66 %

Procedure:
To a solution of 2-(4-chlorophenyl)-5-phenylthiazol-4-yl acetonitrile (2.33 g) in N,N-dimethylformamide (30 ml) were added sodium azide (1.40 g) and ammonium chloride (1.3 g), and the mixture was stirred at 90° C. for 12 hours. After removing the solvent under reduced pressure, ethyl acetate and water were added to the residue. The organic layer was collected, dried and the solvent was removed under reduced pressure. The residue was recrystallized from chloroform and methanol to obtain 5-[2-(4-chlorophenyl)-5-phenyl-thiazol-4-ylmethyl]tetrazole (1.75 g).
Reaction SMILES: [NH2:1][C:2]1[N:6]=[CH:5][NH:4][N:3]=1.[OH:7][C:8]([CH3:20])([CH3:19])[CH2:9][O:10][C:11]1([CH3:18])[CH2:16][CH2:15][C:14](=O)[CH2:13][CH2:12]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(O)(=O)C>[CH3:20][C:8]([OH:7])([CH3:19])[CH2:9][O:10][C:11]1([CH3:18])[CH2:16][CH2:15][CH:14]([NH:1][C:2]2[N:6]=[CH:5][NH:4][N:3]=2)[CH2:13][CH2:12]1
Reactant: CC(C)(O)COC1(C)CCC(=O)CC1
Reactant: Nc1nc[nH]n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Product: CC(C)(O)COC1(C)CCC(Nc2nc[nH]n2)CC1
Temperature: 25 °C
Reaction time: 15 h
Yield: 57.6 %

Procedure:
To a solution of 3-amino-1H-1,2,4-triazole (441 mg) and 4-(2-hydroxy-2-methylpropoxy)-4-methylcyclohexanone (1.05 g) in acetic acid (10 mL) was added sodium triacetoxyborohydride (1.67 g), and the mixture was stirred at room temperature for 15 hr. The solvent was evaporated under reduced pressure, the residue was diluted with saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate-isopropyl alcohol (3:1). The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography [eluent: methanol/ethyl acetate=0/100→10/90 (volume ratio)] to give colorless amorphous 2-methyl-1-{[1-methyl-4-(1H-1,2,4-triazol-3-ylamino)cyclohexyl]oxy}propan-2-ol (810 mg, 54%) as a diastereomixture.
Reaction SMILES: [CH3:1][O:2]/[N:3]=[C:4](/[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)\[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][OH:14])=[CH:9][CH:8]=1.[CH:21]1([CH2:24][O:25][C:26]2[CH:31]=[C:30](O)[CH:29]=[CH:28][C:27]=2[CH2:33][CH2:34][C:35]([O:37]C)=[O:36])[CH2:23][CH2:22]1>>[CH:21]1([CH2:24][O:25][C:26]2[CH:31]=[C:30]([O:14][CH2:13][C:10]3[CH:11]=[CH:12][C:7]([O:6][CH2:5]/[C:4](=[N:3]\[O:2][CH3:1])/[C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)=[CH:8][CH:9]=3)[CH:29]=[CH:28][C:27]=2[CH2:33][CH2:34][C:35]([OH:37])=[O:36])[CH2:22][CH2:23]1
Reactant: COC(=O)CCc1ccc(O)cc1OCC1CC1
Reactant: CO/N=C(\COc1ccc(CO)cc1)c1ccccc1
Product: CO/N=C(\COc1ccc(COc2ccc(CCC(=O)O)c(OCC3CC3)c2)cc1)c1ccccc1
Yield: 4.2 %

Procedure:
Compound 58 was synthesized from (1Z)-2-[4-(hydroxymethyl)phenoxy]-1-phenylethanone O-methyloxime (0.656 g, 2.4 mmol) and methyl 3-[2-(cyclopropylmethoxy)-4-hydroxyphenyl]propanoate (0.6 g, 2.4 mmol) by following the procedure described in scheme 18 (0.04 g, yield: 4.20%); Purity: 98.15%.
Reaction SMILES: C(OC([NH:8][CH2:9][C:10]([NH:12][C@@:13]1([C:28]([OH:30])=[O:29])[CH2:18][C@H:17]([S:19][C:20]2[NH:24][CH:23]=[N:22][N:21]=2)[C@@H:16]2[C@H:14]1[C@H:15]2[C:25]([OH:27])=[O:26])=[O:11])=O)(C)(C)C.[ClH:31]>C(OCC)(=O)C>[ClH:31].[NH2:8][CH2:9][C:10]([NH:12][C@@:13]1([C:28]([OH:30])=[O:29])[CH2:18][C@H:17]([S:19][C:20]2[NH:24][CH:23]=[N:22][N:21]=2)[C@@H:16]2[C@H:14]1[C@H:15]2[C:25]([OH:27])=[O:26])=[O:11]
Reactant: CC(C)(C)OC(=O)NCC(=O)N[C@@]1(C(=O)O)C[C@H](Sc2nnc[nH]2)[C@H]2[C@H](C(=O)O)[C@H]21
Agent: Cl
Solvent: CCOC(C)=O
Product: NCC(=O)N[C@@]1(C(=O)O)C[C@H](Sc2nnc[nH]2)[C@H]2[C@H](C(=O)O)[C@H]21
Temperature: 25 °C
Reaction time: 2 h
Yield: 98 %

Procedure:
Dissolve (1R,2S,4S,5R,6R)-2-[[-2-(tert-butoxycarbonylamino)acetyl]amino]-4-(4H-1,2,4-triazol-3-ylsulfanyl)bicyclo[3.1.0]hexane-2,6-dicarboxylic acid (220 mg, 0.49 mmol) in a saturated solution of hydrogen chloride gas in ethyl acetate (7 mL) and stir at room temperature for 2 hours. Remove the solvent to provide the title compound as a white solid (180 mg, 98%). MS (m/z): 342 (M+1).
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[C:14]2[N:22]3[C:17]([CH:18]=[N:19][C:20](O)=[N:21]3)=[CH:16][CH:15]=2)[CH2:6]1)(=[O:4])=[O:3].C1C=CC(N(S(C(F)(F)F)(=O)=O)S(C(F)(F)F)(=O)=O)=CC=1.C(N(CC)C(C)C)(C)C.CN(C)C=O.[NH2:59][C:60]1[CH:65]=[CH:64][C:63]([CH:66]2[CH2:69][N:68]([CH2:70][C:71]([NH2:73])=[O:72])[CH2:67]2)=[CH:62][CH:61]=1>>[CH3:1][S:2]([N:5]1[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[C:14]2[N:22]3[C:17]([CH:18]=[N:19][C:20]([NH:59][C:60]4[CH:65]=[CH:64][C:63]([CH:66]5[CH2:67][N:68]([CH2:70][C:71]([NH2:73])=[O:72])[CH2:69]5)=[CH:62][CH:61]=4)=[N:21]3)=[CH:16][CH:15]=2)[CH2:6]1)(=[O:3])=[O:4]
Reactant: NC(=O)CN1CC(c2ccc(N)cc2)C1
Reactant: CS(=O)(=O)N1Cc2cccc(-c3ccc4cnc(O)nn34)c2C1
Agent: O=S(=O)(N(c1ccccc1)S(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CS(=O)(=O)N1Cc2cccc(-c3ccc4cnc(Nc5ccc(C6CN(CC(N)=O)C6)cc5)nn34)c2C1
Yield: 7.7 %

Procedure:
7-(2-Methanesulfonyl-2,3-dihydro-1H-isoindol-4-yl)-pyrrolo[2,1-f][1,2,4]triazin-2-ol (80 mg, 0.2 mmol), N-Phenylbis(trifluoromethanesulphonimide) (95.1 mg, 0.266 mmol), N,N-Diisopropylethylamine (0.126 mL, 0.726 mmol), and N,N-Dimethylformamide (2 mL, 30 mmol) and stir at room temperature for half an hour. Add 2-[3-(4-Amino-phenyl)-azetidin-1-yl]-acetamide (71 mg, 0.34 mmol) and stir at 60° C. overnight. The reaction was concentrated, DMSO added, filtered and placed onto the Gilson for purification. The most pure fractions were collected, basified with sat sodium bicarbonate extracted with EtOAc, dried, filtered and concentrated to give a yellow solid (8 mg, 6%). MP 216-218° C. LCMS (E/I+) 518 (M+H). NMR 1H (DMSO-d6)-9.48 (s, 1H), 9.02 (s, 1H), 7.97 (d, 1H, J=7.81 Hz), 7.64 (d, 2H, J=8.55 Hz), 7.56 (t, 1H, J=7.80 Hz), 7.44 (d, 1H, J=7.74 Hz), 7.21 (d, 2H, J=8.34 Hz), 7.12 (bs, 1H), 7.05-7.08 (m, 2H), 6.99 (d, 1H, J=4.69 Hz), 4.74 (s, 4H), 3.69 (t, 2H, J=7.40 Hz), 3.53-3.61 (m, 1H), 3.15 (t, 2H, J=6.86 Hz), 3.02 (s, 2H), 2.92 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([I:9])[CH:3]=1.Br[CH2:11][C:12](=[O:17])[CH2:13][CH2:14][CH2:15][Cl:16].C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:11][C:12](=[O:17])[CH2:13][CH2:14][CH2:15][Cl:16])=[C:4]([I:9])[CH:3]=1
Reactant: O=C(CBr)CCCCl
Reactant: Oc1ccc(Br)cc1I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=C(CCCCl)COc1ccc(Br)cc1I
Temperature: 25 °C
Reaction time: 48 h
Yield: 46 %

Procedure:
The mixture of 4-bromo-2-iodophenol (3.30 g, 11.04 mmol), 1-bromo-5-chloropentan-2-one (75% purity, 3.9 g, 14.66 mmol), and K2CO3 (2.3 g, 16.64 mmol) in acetone (66 mL) was stirred for 48 hours at ambient temperature. The insoluble material was removed by filtration and washed with EtOAc. The filtrate was evaporated in vacuo. The residue was purified by silicagel column chromatography (EtOAc-hexane, a linear gradient of EtOAc from 0 to 25%) afforded 1-(4-bromo-2-iodophenoxy)-5-chloropentan-2-one (2.12 g).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[OH:11].O[CH:19]1[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[Na]>C1(C)C=CC=CC=1.O>[CH3:25][N:22]1[CH2:23][CH2:24][CH:19]([O:11][CH:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:2]2[S:1][C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[N:3]=2)[CH2:20][CH2:21]1
Reactant: CN1CCC(O)CC1
Reactant: OC(c1ccccc1)c1nc2ccccc2s1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na]
Solvent: Cc1ccccc1
Solvent: O
Product: CN1CCC(OC(c2ccccc2)c2nc3ccccc3s2)CC1
Temperature: 25 °C

Procedure:
A mixture of benzothiazol-2-ylphenylmethanol (0.36 g), 4-hydroxy-1-methylpiperidine (0.17 g) and para-toluenesulfonic acid (0.57 g) in toluene (22 mL) is heated overnight in a Dean-Stark apparatus. The mixture is cooled back to room temperature and poored into water, alcalinised with 1N sodium hydroxyde and extracted twice with ethyl acetate. Pooled organic extracts are washed with brine, dried over magnesium sulfate and concentrated. The residue is purified by column chromatography over silica gel (gradient dichloromethane/methanol from 98/2 to 90/10) to give 2-[(1-methylpiperidin-4-yloxy)phenylmethyl]benzothiazole melting at 115° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:17]=[C:18]([CH:20]=[CH:21][CH:22]=1)[NH2:19].[C:23]([C:27]1[CH:31]=[C:30]([NH:32][C:33](=O)[O-:34])[N:29]([C:36]2[CH:41]=[CH:40][N:39]=[C:38]([CH3:42])[CH:37]=2)[N:28]=1)([CH3:26])([CH3:25])[CH3:24]>C1COCC1.CN(C1C=CN=CC=1)C>[C:23]([C:27]1[CH:31]=[C:30]([NH:32][C:33]([NH:19][C:18]2[CH:20]=[CH:21][CH:22]=[C:16]([O:15][C:6]3[C:5]4[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=4)[N:9]=[CH:8][N:7]=3)[CH:17]=2)=[O:34])[N:29]([C:36]2[CH:41]=[CH:40][N:39]=[C:38]([CH3:42])[CH:37]=2)[N:28]=1)([CH3:26])([CH3:25])[CH3:24]
Reactant: COc1cc2ncnc(Oc3cccc(N)c3)c2cc1OC
Reactant: Cc1cc(-n2nc(C(C)(C)C)cc2NC(=O)[O-])ccn1
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Product: COc1cc2ncnc(Oc3cccc(NC(=O)Nc4cc(C(C)(C)C)nn4-c4ccnc(C)c4)c3)c2cc1OC
Yield: 39.2 %

Procedure:
Using the procedure described in Example 306B, to a solution of 3-(6,7-dimethoxyquinazolin-4-yloxy)aniline (88 mg, 0.29 mmol), prepared as described in Example 113A, in THF (2 ml) was added DMAP (20 mg, 0.16 mmol) and 3-tert-butyl-1-(2-methylpyridin-4-yl)-1H-pyrazol-5-ylcarbamate (130 mg, 0.37 mmol) described in the previous step. The crude was purified by silica gel chromatography (DCM/MeOH 0-10%) to afford 1-(3-tert-butyl-1-(2-methylpyridin-4-yl)-1H-pyrazol-5-yl)-3-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)urea (63 mg, 39%) as a solid. 1H NMR (300 MHz, DMSO-d6) δ 1.27 (s, 9H), 2.49 (s, 3H), 3.98 (s, 6H), 6.40 (s, 1H), 6.95 (d, J=7.8 Hz, 1H), 7.22 (d, J=7.8 Hz, 1H), 7.39-7.44 (m, 3H), 7.45-7.55 (m, 3H), 8.49 (d, J=6 Hz, 1H), 8.52 (s, 1H), 8.66 (s, 1H), 9.27 (s, 1H); LC-MS (ESI) m/z 554 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[N:10]=[N:11][C:12]([C:23]#[C:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:13][C:14]=1[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OC1N=NC(Cl)=CC=1OCC1C=CC=CC=1)C1C=CC=CC=1.C(C1C=CC=C([F:62])C=1)#C>>[CH2:1]([O:8][C:9]1[N:10]=[N:11][C:12]([C:23]#[C:24][C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([F:62])[CH:26]=2)=[CH:13][C:14]=1[O:15][CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C#Cc1cccc(F)c1
Reactant: C(#Cc1cc(OCc2ccccc2)c(OCc2ccccc2)nn1)c1ccccc1
Agent: Clc1cc(OCc2ccccc2)c(OCc2ccccc2)nn1
Product: Fc1cccc(C#Cc2cc(OCc3ccccc3)c(OCc3ccccc3)nn2)c1

Procedure:
Prepared as described for 3,4-bis(benzyloxy)-6-(phenylethynyl)pyridazine (Intermediate 2) from 3,4-bis(benzyloxy)-6-chloropyridazine (Intermediate 1) and 1-ethynyl-3-fluorobenzene.