Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Na+].[I:3]I.[C:5]1([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:10]=[CH:9][C:8]([C:11]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[CH:16]=2)([OH:14])[C:12]#[CH:13])=[CH:7][CH:6]=1>CO>[C:5]1([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:10]=[CH:9][C:8]([C:11]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[CH:16]=2)([OH:14])[C:12]#[C:13][I:3])=[CH:7][CH:6]=1
Reactant: II
Reactant: C#CC(O)(c1ccc(-c2ccccc2)cc1)c1cccc(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: OC(C#CI)(c1ccc(-c2ccccc2)cc1)c1cccc(Cl)c1
Yield: 56.9 %

Procedure:
40 ml of concentrated sodium hydroxide solution and 25.4 g (0.1 mol) of iodine were simultaneously introduced into a solution of 31.9 g (0.1 mol) of 3-(4-biphenylyl)-3-(3-chlorophenyl)-1-propyn-3-ol in 350 ml of methanol at 20° C., with slight external cooling and while stirring. The mixture was stirred for three hours and filtered to remove a slight turbidity and the filtrate was stirred into 1,000 ml of water. The reaction product thereby separated out as a semi-solid mass. The supernatant liquid was decanted, the residue was taken up in ethyl acetate and the solution was washed several times with 100 ml of water each time and dried over sodium sulphate. Thereafter, it was concentrated by distilling off the solvent in vacuo, and the oily residue was dissolved in a little ether. After adding petroleum ether, crystallization occurred. 25.3 g (56.9% of theory) of 3-(4-biphenylyl)-3-(3-chlorophenyl)-1-iodo-1-propyn-3-ol were obtained as colorless crystals of melting point 99°-100° C.
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:16]=[CH:15][C:14]([N:17]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[N:20](C(O)=O)[CH2:19][CH2:18]3)=[CH:13][CH:12]=2)[CH2:7][CH2:6]1)(=[O:4])=[O:3].Cl>ClCCl.O1CCOCC1>[CH3:1][S:2]([N:5]1[CH2:6][CH2:7][N:8]([C:11]2[CH:12]=[CH:13][C:14]([N:17]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[NH:20][CH2:19][CH2:18]3)=[CH:15][CH:16]=2)[CH2:9][CH2:10]1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)N1CCN(c2ccc(N3CCN(C(=O)O)c4ccccc43)cc2)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: CS(=O)(=O)N1CCN(c2ccc(N3CCNc4ccccc43)cc2)CC1
Reaction time: 16 h

Procedure:
31.5 g of the tert-butyl ester of 4-[4-(4-(methanesulphonyl)piperazin-1-yl)phenyl]-3,4-dihydro-2H-quinoxaline-1-carboxylic acid are placed in 400 ml of dichloromethane and then 333 ml of 4N hydrochloric acid in dioxane are added. After stirring for 16 h under an inert atmosphere, the solvents are evaporated under reduced pressure. Water, a saturated aqueous sodium hydrogencarbonate solution and dichloromethane are added. The aqueous sodium phase is extracted twice with dichloromethane. The organic phases are combined, washed with water and dried over magnesium sulphate and then the solvent is evaporated under reduced pressure. 23.2 g of 1-[4-(4-(methanesulphonyl)piperazin-1-yl)phenyl]-1,2,3,4-tetrahydroquinoxaline are obtained. The product is subsequently used as is without other purification.
Reaction SMILES: [K+].[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([NH:12][C:13]2[CH:14]=[C:15]([C:19]([C:21]3[C:29]4[CH:28]=[N:27][CH:26]=[N:25][C:24]=4[N:23]([CH2:30][C:31]([O-])=[O:32])[CH:22]=3)=[O:20])[CH:16]=[N:17][CH:18]=2)=[O:11])=[CH:5][CH:4]=1.Cl.CN.[CH3:37][N:38](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>N1C=CC=CC=1.C(Cl)Cl>[Cl:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][C:10]([NH:12][C:13]2[CH:18]=[N:17][CH:16]=[C:15]([C:19]([C:21]3[C:29]4[CH:28]=[N:27][CH:26]=[N:25][C:24]=4[N:23]([CH2:30][C:31]([NH:38][CH3:37])=[O:32])[CH:22]=3)=[O:20])[CH:14]=2)=[O:11])=[CH:7][CH:8]=1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: O=C([O-])Cn1cc(C(=O)c2cncc(NC(=O)Cc3ccc(Cl)cc3)c2)c2cncnc21
Agent: CN
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: c1ccncc1
Product: CNC(=O)Cn1cc(C(=O)c2cncc(NC(=O)Cc3ccc(Cl)cc3)c2)c2cncnc21
Temperature: 25 °C

Procedure:
{5-[(5-{[(4-chlorophenyl)acetyl]amino}pyridin-3-yl)carbonyl]-7H-pyrrolo[2,3-d]pyrimidin-7-yl}acetic acid potassium salt (Example 307, 50 mg, 0.102 mmol) was added to a stirred solution of methyl amine hydrochloride (10.3 mg, 0.153 mmol) and HATU (58.2 mg, 0.153 mmol) in pyridine (2 mL). The resultant solution was stirred at 50° C. (reactivial) for 14 hours. The reaction was cooled to 25° C., diluted with DCM (5 mL) then quenched with saturated NaHCO3 (aq) (5 mL) and extracted with further DCM (3×5 mL).
Reaction SMILES: [CH:1]1([C:4]([NH:6][C:7]2[N:8]=[C:9]3[CH:14]=[CH:13][C:12]([S:15][C:16]4[CH:25]=[CH:24][CH:23]=[CH:22][C:17]=4[C:18]([O:20]C)=[O:19])=[N:11][N:10]3[CH:26]=2)=[O:5])[CH2:3][CH2:2]1.[OH-].[Na+]>>[CH:1]1([C:4]([NH:6][C:7]2[N:8]=[C:9]3[CH:14]=[CH:13][C:12]([S:15][C:16]4[CH:25]=[CH:24][CH:23]=[CH:22][C:17]=4[C:18]([OH:20])=[O:19])=[N:11][N:10]3[CH:26]=2)=[O:5])[CH2:3][CH2:2]1
Reactant: COC(=O)c1ccccc1Sc1ccc2nc(NC(=O)C3CC3)cn2n1
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)c1ccccc1Sc1ccc2nc(NC(=O)C3CC3)cn2n1
Yield: 87.2 %

Procedure:
In the same manner as in Example 276 and using methyl 2-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}thio)benzoate (390 mg, 1.1 mmol) and 4N aqueous sodium hydroxide solution (2 mL) as starting materials, the title compound (340 mg, 92%) was obtained as a pale-yellow solid.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[N+:8]([C:11]1[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=1)[CH2:14]Br)([O-:10])=[O:9].C(N(CC)CC)C>CN(C)C=O>[N+:8]([C:11]1[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=1)[CH2:14][N:5]1[CH2:6][CH2:7][CH:2]([OH:1])[CH2:3][CH2:4]1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1cccc(CBr)c1
Reactant: OC1CCNCC1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cccc(CN2CCC(O)CC2)c1
Reaction time: 16 h
Yield: 57.9 %

Procedure:
1.41 g (0.01389 mol) of 4-hydroxypiperidine were dissolved in 60 ml of dimethylformamide and cooled to 0°. 3.0 g (0.01389 mol) of 3-nitrobenzyl bromide and 4.3 ml (0.03056 mol) of triethylamine were added under argon and the mixture was left to come to room temperature. It was stirred for 16 hrs., the solvent was distilled off and the residue was taken up in dichloromethane. The organic phase was washed with water and saturated sodium chloride solution, dried over magnesium sulfate and concentrated and the residue was chromatographed on silica gel with dichloromethane/methanol (19:1) as the eluent. 1.9 g (58%) of 1-(3-nitro-benzyl)-piperidin-4-ol were obtained as a yellow oil. MS: me/e=237 (C12H17N2O3+)
Reaction SMILES: [CH:1]1([CH2:7][S:8][C:9]2[CH:22]=[CH:21][C:12]3[NH:13][C:14]([NH:16][C:17](=[O:20])[O:18][CH3:19])=[N:15][C:11]=3[CH:10]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:23][N:24]([CH3:29])[CH2:25][CH2:26]CO.O>C1(C)C=CC=CC=1>[CH:5]1[CH2:4][CH2:3][CH2:2][CH:1]([CH2:7][S:8][C:9]2[CH:22]=[CH:21][C:12]3[NH:13][C:14]([NH:16][C:17](=[O:20])[O:18][CH2:19][CH2:26][CH2:25][N:24]([CH3:29])[CH3:23])=[N:15][C:11]=3[CH:10]=2)[CH:6]=1
Reactant: COC(=O)Nc1nc2cc(SCC3CCCCC3)ccc2[nH]1
Reactant: CN(C)CCCO
Solvent: O
Solvent: Cc1ccccc1
Product: CN(C)CCCOC(=O)Nc1nc2cc(SCC3C=CCCC3)ccc2[nH]1

Procedure:
A mixture of 0.01 mole of the methyl ester of Example 4 and 0.02 mole of 3-dimethylamino-1-propanol is refluxed in 20 ml of toluene until all the H2O present has been azeotroped off. The heating mantle is removed and 0.25 g of aluminum isopropoxide is added. The mixture is then refluxed overnight. After cooling the solid present is filtered off, washed with water and crystallized.
Reaction SMILES: CO[C:3]([C:5]1[N:6]=[CH:7][C:8]2[C:9](=[O:23])[N:10]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:11]=[CH:12][C:13]=2[C:14]=1[OH:15])=[O:4].[NH2:24][CH2:25][CH2:26][CH2:27][C:28]([OH:30])=[O:29].C[O-].[Na+]>>[CH2:16]([N:10]1[C:9](=[O:23])[C:8]2[CH:7]=[N:6][C:5]([C:3]([NH:24][CH2:25][CH2:26][CH2:27][C:28]([OH:30])=[O:29])=[O:4])=[C:14]([OH:15])[C:13]=2[CH:12]=[CH:11]1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: NCCCC(=O)O
Reactant: COC(=O)c1ncc2c(=O)n(Cc3ccccc3)ccc2c1O
Agent: C[O-]
Agent: [Na+]
Product: O=C(O)CCCNC(=O)c1ncc2c(=O)n(Cc3ccccc3)ccc2c1O
Yield: 50.8 %

Procedure:
A mixture of 7-benzyl-4-hydroxy-8-oxo-7,8-dihydro-[2,7]naphthyridine-3-carboxylic acid methyl ester (50 mg, 0.16 mmol), 4-aminobutyric acid (832 mg, 8.06 mmol) and NaOMe solution (12 mL, 6.05 mmol, 0.5 M in MeOH) was refluxed for 48 h. Solvent was evaporated in vacuo, and the residue was partitioned between water and EtOAc. 1 M HCl was added with vigorous stirring until pH was about 2. The organic layer was dried over MgSO4 and concentrated. The crude product was purified by silica gel chromatography (5-60% EtOAc/hexanes+2% AcOH) to give 31 mg of the title compound as a light yellow solid. MS: (+) m/z 382.01 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([C:15]1[CH:23]=[CH:22][C:18]([C:19](O)=[O:20])=[CH:17][CH:16]=1)[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:24][C:25]1[CH:30]=[C:29]([C:31]2[S:32][CH:33]=[CH:34][CH:35]=2)[CH:28]=[CH:27][C:26]=1[NH:36][C:37](=[O:43])[O:38][C:39]([CH3:42])([CH3:41])[CH3:40].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C.C([O-])(O)=O.[Na+]>CN(C=O)C>[C:1]([O:5][C:6]([NH:8][CH:9]([C:15]1[CH:16]=[CH:17][C:18]([C:19]([NH:24][C:25]2[CH:30]=[C:29]([C:31]3[S:32][CH:33]=[CH:34][CH:35]=3)[CH:28]=[CH:27][C:26]=2[NH:36][C:37]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:43])=[O:20])=[CH:22][CH:23]=1)[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2cccs2)cc1N
Reactant: CCOC(=O)C(NC(=O)OC(C)(C)C)c1ccc(C(=O)O)cc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)C(NC(=O)OC(C)(C)C)c1ccc(C(=O)Nc2cc(-c3cccs3)ccc2NC(=O)OC(C)(C)C)cc1

Procedure:
4-{1-[(tert-butoxycarbonyl)amino]-2-ethoxy-2-oxoethyl}benzoic acid (1.2 g, 3.71 mmol), tert-butyl [2-amino-4-(2-thienyl)phenyl]carbamate (1.293 g, 4.45 mmol), BOP (2.462 g, 5.57 mmol) and DIPEA (0.972 mL, 5.57 mmol) were stirred in DMF (10 ml) at room temperature for 3 days. Saturated NaHCO3 was added and the products extracted into EtOAc. The combined organic extracts were washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by prep-HPLC to give the desired product as a pale yellow powder. 1H NMR (DMSO-d6, 600 MHz) δ 9.89 (s, 1H), 8.71 (br s, 1H), 7.93 (d, J=8.4 Hz, 2H), 7.87 (d, J=8.4 Hz, 1H), 7.83 (d, J=1.8 Hz, 1H), 7.60 (d, J=8.4 Hz, 1H), 7.54 (d, J=8.4 Hz, 2H), 7.50 (m, 2H), 7.42 (d, J=3.6 Hz, 1H), 7.10 (dd, J=5.4 and 3.6 Hz, 1H), 5.27 (d, J=8.4 Hz, 1H), 4.08 (m, 2H), 1.43 (s, 9H), 1.38 (s, 9H), 1.11 (t, J=7.2 Hz, 3H). MS: cal'd 596 (MH+), exp 440, 484, 496 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]([OH:19])([C@H:16]([SH:18])[CH3:17])[CH2:10][N:11]1[CH:15]=[N:14][CH:13]=[N:12]1.C(N(CC)CC)C.[C:27](Cl)(=[O:29])[CH3:28]>ClCCl>[C:27]([S:18][C@H:16]([CH3:17])[C@:9]([C:3]1[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=1[F:1])([OH:19])[CH2:10][N:11]1[CH:15]=[N:14][CH:13]=[N:12]1)(=[O:29])[CH3:28]
Reactant: CC(=O)Cl
Reactant: C[C@@H](S)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)S[C@H](C)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
In dichloromethane (1.5 ml) was dissolved (2R,3R)-2-(2,4-difluorophenyl)-3-mercapto-1-(1H-1,2,4-triazol-1-yl)-2-butanol (60 mg), followed by addition of triethylamine (33 ml) and acetyl chloride (13 ml) under ice-cooling. The mixture was then stirred at room temperature for 30 minutes, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (eluent: hexane-ethyl acetate=1:2) and the desired fraction was concentrated to give (2R,3R)-3-acetylthio-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2-butanol (compound 45:59 mg) as a colorless solid.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]2[CH:9]=[C:10]([S:14]([NH2:17])(=[O:16])=[O:15])[CH:11]=[CH:12][CH:13]=2)=[C:6]([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)[N:5]=[C:4]([C:25]([F:28])([F:27])[F:26])[N:3]=1.[OH:29][C:30]1[CH:40]=[CH:39][C:33]([C:34]([NH:36][O:37][CH3:38])=[O:35])=[CH:32][C:31]=1[O:41][CH3:42].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH3:42][O:41][C:31]1[CH:32]=[C:33]([CH:39]=[CH:40][C:30]=1[O:29][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([S:14]([NH2:17])(=[O:16])=[O:15])[CH:9]=2)=[C:6]([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)[N:5]=[C:4]([C:25]([F:28])([F:27])[F:26])[N:3]=1)[C:34]([NH:36][O:37][CH3:38])=[O:35]
Reactant: NS(=O)(=O)c1cccc(-c2c(Cl)nc(C(F)(F)F)nc2-c2ccc(F)cc2)c1
Reactant: CONC(=O)c1ccc(O)c(OC)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CONC(=O)c1ccc(Oc2nc(C(F)(F)F)nc(-c3ccc(F)cc3)c2-c2cccc(S(N)(=O)=O)c2)c(OC)c1
Temperature: 65 °C

Procedure:
A suspension of 3-[4-chloro-6-(4-fluorophenyl)-2-(trifluoromethyl)pyrimidin-5-yl]benzenesulfonamide (0.15 g, 0.35 mmol), 4-hydroxy-N,3-dimethoxybenzamide (0.102 g, 0.52 mmol) and potassium carbonate (0.52 mmol) in acetonitrile (3 ml) were heated to reflux (65° C.) for 2 hours. Subsequently the reaction mixture was poured onto ice-cold water, extracted with dichloromethane (50 ml) and washed with brine. Evaporation of the organic layer furnished a crude material, which was purified by column chromatography; elution with 2% MeOH in dichloromethane furnished the required compound. 1H-NMR (DMSO-d6) δ: 3.73 (s, 3H), 3.79 (s, 3H), 7.16-7.20 (m, 2H), 7.37 (d, 1H), 7.41-7.45 (m, 5H), 7.53 (s, 1H), 7.62-7.63 (d, 2H), 7.85 (d, 1H), 7.89 (s, 1H). 11.9 (s, 1H); MS m/z: 593 (M++1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:16][C:17]2[N:22]=[C:21]([C:23](OCC)=[O:24])[CH:20]=[C:19]([CH2:28][O:29][CH2:30][C:31]([F:34])([F:33])[F:32])[N:18]=2)[CH:6]=[CH:7][C:8]=1[C:9]1[CH:14]=[C:13]([CH3:15])[N:12]=[N:11][CH:10]=1.[H-].C([Al+]CC(C)C)C(C)C.CO.O>ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:16][C:17]2[N:22]=[C:21]([CH:23]=[O:24])[CH:20]=[C:19]([CH2:28][O:29][CH2:30][C:31]([F:34])([F:33])[F:32])[N:18]=2)[CH:6]=[CH:7][C:8]=1[C:9]1[CH:14]=[C:13]([CH3:15])[N:12]=[N:11][CH:10]=1
Reactant: CCOC(=O)c1cc(COCC(F)(F)F)nc(Nc2ccc(-c3cnnc(C)c3)c(OC)c2)n1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: O
Solvent: CO
Solvent: ClCCl
Product: COc1cc(Nc2nc(C=O)cc(COCC(F)(F)F)n2)ccc1-c1cnnc(C)c1
Temperature: -78 °C
Reaction time: 2 h

Procedure:
Ethyl 2-(3-methoxy-4-(6-methylpyridazin-4-yl)phenylamino)-6-((2,2,2-trifluoroethoxy)methyl)-pyrimidine-4-carboxylate (595 mg, 1.25 mmol) was dissolved in dichloromethane (25 mL) under nitrogen atmosphere and cooled at −78° C. Diisobutyl aluminum hydride (1 M in hexane, 4.36 mL, 4.36 mmol) was added over 10 min. After 1 h diisobutyl aluminum hydride (1 M in hexane, 1.4 mL) was added and the mixture was stirred for 2 h. MeOH (3 mL) was added and the mixture was let to rt. Water (5 mL) was added. The slurry was stirred for 20 min and filtrated through a plug of diatomeous earth. The filter plug was washed with 10% MeOH in DCM. The phases were separated and the aqueous phase was extracted with DCM. The combined organic layer was dried over sodium sulfate, filtered and concentrated onto silica. The residue was purified by column chromatography on silica eluting with a gradient of methanol in dichloromethane to give the title compound as a solid, 270 mg (50%).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([OH:16])[CH:8]=2)[N:3]=1.[C:17]([C@@H:21]1[CH2:26][CH2:25][C@H:24](O)[CH2:23][CH2:22]1)([CH3:20])([CH3:19])[CH3:18].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1(C)C=CC=CC=1.C1COCC1>[C:17]([C@H:21]1[CH2:26][CH2:25][C@H:24]([O:16][C:7]2[CH:8]=[C:9]3[C:4](=[CH:5][CH:6]=2)[N:3]=[C:2]([CH3:1])[CH:11]=[C:10]3[C:12]([F:13])([F:15])[F:14])[CH2:23][CH2:22]1)([CH3:20])([CH3:19])[CH3:18]
Reactant: CC(C)(C)[C@H]1CC[C@@H](O)CC1
Reactant: Cc1cc(C(F)(F)F)c2cc(O)ccc2n1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: Cc1cc(C(F)(F)F)c2cc(O[C@H]3CC[C@H](C(C)(C)C)CC3)ccc2n1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
2-Methyl-4-trifluoromethyl-quinolin-6-ol (0.771 g, 0.00339 mol, cis-4-tert-Butyl-cyclohexanol (0.8570 g, 0.005484 mol) and Triphenylphosphine (1.423 g, 0.005425 mol) were placed in a flask, and dissolved in Toluene (25 mL). For the Mitsunobu reaction of certain analogs, THF was substituted for toluene as solvent. Diisopropyl azodicarboxylate (1.137 mL, 0.005430 mol) was then added dropwise. After 3 d stirring at RT, the reaction was evaporated to dryness. The residue was purified by silica gel chromatography using 0-30% ethyl acetate in hexanes as eluent (Rf=0.38 in 3:1 hexanes/ethyl acetate). Isolated was 0.739 g of product (60%). ESI-MS(M+H+): 366.20.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[F:10])[C:5]#[N:6].[ClH:11].C([OH:14])C>>[ClH:11].[F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[F:10])[C:5](=[NH:6])[OH:14]
Reactant: CCO
Reactant: N#Cc1ccc(F)c(F)c1
Agent: Cl
Product: N=C(O)c1ccc(F)c(F)c1

Procedure:
In anhydrous ethanol, compound [L'], commercially available 3,4-difluorobenzonitrile is reacted with gaseous hydrogen chloride to yield compound [M'], 3,4-difluorobenzimidate hydrogen chloride. In ethanol, compound [M'] is reacted with gaseous ammonia to yield compound [N'], 3,4-difluorobenzamidine hydrogen chloride.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[N:12]=[C:11]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[N:10]=[C:9]([C:19]3[CH:24]=[CH:23][C:22]([NH:25][C:26](=[O:37])[NH:27][C:28]4[CH:36]=[CH:35][C:31]([C:32]([OH:34])=O)=[CH:30][CH:29]=4)=[CH:21][CH:20]=3)[N:8]=2)[CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:71][N:72]([CH3:77])[CH2:73][CH2:74][NH:75][CH3:76]>CN1C(=O)CCC1>[CH3:71][N:72]([CH3:77])[CH2:73][CH2:74][N:75]([CH3:76])[C:32](=[O:34])[C:31]1[CH:35]=[CH:36][C:28]([NH:27][C:26]([NH:25][C:22]2[CH:21]=[CH:20][C:19]([C:9]3[N:10]=[C:11]([N:13]4[CH2:14][CH2:15][O:16][CH2:17][CH2:18]4)[N:12]=[C:7]([N:4]4[CH2:5][CH2:6][O:1][CH2:2][CH2:3]4)[N:8]=3)=[CH:24][CH:23]=2)=[O:37])=[CH:29][CH:30]=1
Reactant: CNCCN(C)C
Reactant: O=C(Nc1ccc(C(=O)O)cc1)Nc1ccc(-c2nc(N3CCOCC3)nc(N3CCOCC3)n2)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: CN(C)CCN(C)C(=O)c1ccc(NC(=O)Nc2ccc(-c3nc(N4CCOCC4)nc(N4CCOCC4)n3)cc2)cc1
Yield: 50.2 %

Procedure:
To the stirred solution of 4-(3-(4-(4,6-dimorpholino-1,3,5-triazin-2-yl)phenyl)ureido)benzoic acid (150 mg; 0.297 mmol), Hunig's base (303 μL, 1.782 mmol), HBTU (563 mg, 1.485 mmol) in 2 mL of NMP was reacted according to example 68 with N1,N1,N2-trimethylethane-1,2-diamine (154 μL, 1.188 mmol) to give N-(2-(dimethylamino)ethyl)-4-(3-(4-(4,6-dimorpholino-1,3,5-triazin-2-yl)phenyl)ureido)-N-methylbenzamide as a white solid (88 mg, 50% yield); MS (ESI) m/z=590.2.
Reaction SMILES: [O:1]=[C:2]([CH2:8][CH3:9])[CH2:3][C:4]([O:6][CH3:7])=[O:5].[CH:10]([O-])([O-])OC>>[CH3:10][O:1]/[C:2](/[CH2:8][CH3:9])=[CH:3]/[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC([O-])[O-]
Reactant: CCC(=O)CC(=O)OC
Product: CC/C(=C\C(=O)OC)OC

Procedure:
reacting methyl 3-oxovalerate with methyl orthoformate (commercially available) to give methyl (E)-3-methoxy-2-pentenoate,
Reaction SMILES: [CH:1]([S:4][S:5][CH2:6][C:7]([OH:9])=O)([CH3:3])[CH3:2].ClC(OCC(C)C)=O.CN1CCOCC1.[Br:25][C:26]1[CH:27]=[C:28]([NH:32][C:33]2[C:42]3[C:37](=[CH:38][CH:39]=[C:40]([NH2:43])[CH:41]=3)[N:36]=[CH:35][N:34]=2)[CH:29]=[CH:30][CH:31]=1>O1CCCC1.C(Cl)Cl.CO>[Br:25][C:26]1[CH:27]=[C:28]([NH:32][C:33]2[C:42]3[C:37](=[CH:38][CH:39]=[C:40]([NH:43][C:7](=[O:9])[CH2:6][S:5][S:4][CH:1]([CH3:2])[CH3:3])[CH:41]=3)[N:36]=[CH:35][N:34]=2)[CH:29]=[CH:30][CH:31]=1
Reactant: Nc1ccc2ncnc(Nc3cccc(Br)c3)c2c1
Reactant: CC(C)SSCC(=O)O
Agent: CC(C)COC(=O)Cl
Solvent: CN1CCOCC1
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)SSCC(=O)Nc1ccc2ncnc(Nc3cccc(Br)c3)c2c1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 1 %

Procedure:
A solution of 1.4 grams of disulfide acid from Example 78 in 30 mL of tetrahydrofuran was cooled in an ice bath. A 1.1 mL portion of isobutyl chloroformate followed by a 0.9 mL portion of N-methylmorpholine were added. After stirring for 5 minutes at 0° C., 0.66 grams of N-(3-bromophenyl)-4,6-quinazolindiamine was added. The mixture was stirred for 3 hours at 0° C. and then allowed to warm to room temperature. The reaction was quenched with water and the tetrahydrofuran was evaporated under vacuum. Addition of methylene chloride followed by washing the methylene chloride layer with water and evaporation of the solvent gave a crude product. Silica gel chromatography with methanol in methylene chloride gave 0.01 grams of product.
Reaction SMILES: Cl.[N:2]1[N:3]([C:7]2[CH:8]=[C:9]([CH:17]=[CH:18][CH:19]=2)[CH2:10][C@@H:11]2[CH2:16][CH2:15][CH2:14][CH2:13][NH:12]2)[N:4]=[CH:5][CH:6]=1.[N:20]1[N:21]([C:25]2[CH:33]=[CH:32][CH:31]=[CH:30][C:26]=2[C:27](O)=[O:28])[N:22]=[CH:23][CH:24]=1>>[N:2]1[N:3]([C:7]2[CH:8]=[C:9]([CH:17]=[CH:18][CH:19]=2)[CH2:10][C@@H:11]2[CH2:16][CH2:15][CH2:14][CH2:13][N:12]2[C:27]([C:26]2[CH:30]=[CH:31][CH:32]=[CH:33][C:25]=2[N:21]2[N:22]=[CH:23][CH:24]=[N:20]2)=[O:28])[N:4]=[CH:5][CH:6]=1
Reactant: O=C(O)c1ccccc1-n1nccn1
Reactant: c1cc(C[C@@H]2CCCCN2)cc(-n2nccn2)c1
Agent: Cl
Product: O=C(c1ccccc1-n1nccn1)N1CCCC[C@H]1Cc1cccc(-n2nccn2)c1

Procedure:
The title compound was prepared from (S)-2-(3-[1,2,3]triazol-2-yl-benzyl)-piperidine hydrochloride and 2-(2H-1,2,3-triazol-2-yl)benzoic acid E-2 following the procedure described for B-28. LC-MS D: tR=0.91 min; [M+H]+=414.05.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6].[F:13][C:14]([F:25])([F:24])[C:15]1[CH:16]=[C:17](B(O)O)[CH:18]=[CH:19][CH:20]=1.N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[F:13][C:14]([F:25])([F:24])[C:15]1[CH:20]=[C:19]([NH:1][C:2]2[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=2)[C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH:18]=[CH:17][CH:16]=1
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Reactant: CCOC(=O)c1cccc(N)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)c1cccc(Nc2cccc(C(F)(F)F)c2)c1
Yield: 59.3 %

Procedure:
A solution of ethyl 3-aminobenzoate (0.300 g; 1.82 mmol), 3-(trifluoromethyl)phenylboronic acid (0.690 g; 3.63 mmol), copper acetate (0.660 g, 3.63 mmol) and pyridine (0.293 mL, 3.63 mmol) in dichloromethane (3 mL) was stirred at room temperature for 18 hours and filtered through celite and concentrated under reduced pressure. The residue was dissolved in water and extracted with ethyl acetate (2×200 mL). The organic layers were washed with brine, dried and concentrated under reduced pressure. The crude material was purified by flash chromatography on silica gel (eluent 5 to 40% ethyl acetate in heptane) to afford 0.334 g (60%) of ethyl 3-(3-(trifluoromethyl)phenylamino)benzoate.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[C:21]([C:22]([O:24][CH3:25])=[O:23])=[C:20]3[C:15]([C:16]4[CH:28]=[CH:27][O:26][C:17]=4[CH2:18][O:19]3)=[CH:14][CH:13]=2)(=[O:10])=[O:9])=[C:4](/[CH:29]=[CH:30]\[CH2:31][N:32]2[CH2:36][CH2:35][C@@H:34]([O:37][C:38](=[O:40])[CH3:39])[CH2:33]2)[CH:3]=1.BrC1C=C(F)C=CC=1S(NC1C(C(OC)=O)=C2C(C3C=COC=3CO2)=CC=1)(=O)=O.C([Sn](CCCC)(CCCC)/C=C\CN1CC[C@H](OC(=O)C)C1)CCC>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[C:21]([C:22]([O:24][CH3:25])=[O:23])=[C:20]3[C:15]([C:16]4[CH:28]=[CH:27][O:26][C:17]=4[CH2:18][O:19]3)=[CH:14][CH:13]=2)(=[O:9])=[O:10])=[C:4](/[CH:29]=[CH:30]\[CH2:31][N:32]2[CH2:36][CH2:35][C@H:34]([O:37][C:38](=[O:40])[CH3:39])[CH2:33]2)[CH:3]=1
Reactant: COC(=O)c1c(NS(=O)(=O)c2ccc(F)cc2/C=C\CN2CC[C@@H](OC(C)=O)C2)ccc2c1OCc1occc1-2
Agent: CCCC[Sn](/C=C\CN1CC[C@H](OC(C)=O)C1)(CCCC)CCCC
Agent: COC(=O)c1c(NS(=O)(=O)c2ccc(F)cc2Br)ccc2c1OCc1occc1-2
Product: COC(=O)c1c(NS(=O)(=O)c2ccc(F)cc2/C=C\CN2CC[C@H](OC(C)=O)C2)ccc2c1OCc1occc1-2

Procedure:
Prepared by proceeding in a similar manner to Intermediate 82, starting from methyl 7-(2-bromo-4-fluorobenzenesulfonylamino)-4H-furo[2,3-c]chromene-6-carboxylate (Intermediate 7) and acetic acid (S)-1-((Z)-3-tributylstannanylallyl)-pyrrolidin-3-yl ester (Intermediate 85).