Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[CH:29]=[CH:28][C:6]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([CH:15]3[CH2:18][N:17](C(OC(C)(C)C)=O)[CH2:16]3)=[CH:11][C:10]=2[O:26][CH3:27])=[CH:5][CH:4]=1)[CH3:2].[CH3:30][S:31]([OH:34])(=[O:33])=[O:32].C(OCC)(=O)C>C(O)C>[CH3:30][S:31]([OH:34])(=[O:33])=[O:32].[CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([CH:15]3[CH2:18][NH:17][CH2:16]3)=[CH:11][C:10]=2[O:26][CH3:27])=[CH:28][CH:29]=1)[CH3:2]
Reactant: CCc1ccc(COc2ccc(C3CN(C(=O)OC(C)(C)C)C3)cc2OC)cc1
Agent: CS(=O)(=O)O
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCc1ccc(COc2ccc(C3CNC3)cc2OC)cc1
Temperature: 80 °C
Reaction time: 3 h
Yield: 77 %

Procedure:
To a solution of tert-butyl 3-[4-(4-ethylbenzyloxy)-3-methoxyphenyl]azetidine-1-carboxylate (32.4 g) prepared in (2) in ethanol (160 mL) was added methanesulfonic acid (6.3 mL). The reaction mixture was stirred at 80° C. for 3 hr. Ethyl acetate (320 mL) was added to the reaction mixture. The precipitated solid was collected on a filter and dried to give the title compound (24.3 g, 77%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:18])[CH2:9][C:10]([OH:17])([C:13]([F:16])([F:15])[F:14])[CH:11]=O)=[C:4]([O:19][CH3:20])[C:3]=1[F:21].[NH2:22][C:23]1[CH:32]=[CH:31][CH:30]=[C:29]2[C:24]=1[CH:25]=[CH:26][C:27](=[O:33])[NH:28]2>[O-]CC.[O-]CC.[O-]CC.[O-]CC.[Ti+4]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:18])[CH2:9][C:10]([OH:17])([C:13]([F:14])([F:15])[F:16])[CH:11]=[N:22][C:23]2[CH:32]=[CH:31][CH:30]=[C:29]3[C:24]=2[CH:25]=[CH:26][C:27](=[O:33])[NH:28]3)=[C:4]([O:19][CH3:20])[C:3]=1[F:21]
Reactant: COc1c(C(C)CC(O)(C=O)C(F)(F)F)ccc(Cl)c1F
Reactant: Nc1cccc2[nH]c(=O)ccc12
Agent: [Ti+4]
Agent: CC[O-]
Product: COc1c(C(C)CC(O)(C=Nc2cccc3[nH]c(=O)ccc23)C(F)(F)F)ccc(Cl)c1F

Procedure:
In the same way as in Example 14, 100 mg (0.3 mmol) of 4-(4-chloro-3-fluoro-2-methoxyphenyl)-2-hydroxy-2-(trifluoromethyl)pentanal, 48 mg (0.3 mmol) of 5-aminoquinolone and 0.1 ml of titanium tetraethoxide are reacted to give 5-{[4-(4-chloro-3-fluoro-2-methoxyphenyl)-2-hydroxy-2-(trifluoromethyl)pentylidene]-amino}quinolin-2(1H)-one. 130 mg of crude imine are cyclized in the same way as in Example 14 at −30° C. with 2.5 ml (2.5 mmol) of 1 M boron tribromide solution to give the desired product. Column chromatography on silica gel (hexane/ethyl acetate 50%) and subsequent preparative thin-layer chromatography on amine phase (Merck) with ethyl acetate/methanol/triethylamine 25:3:1 and preparative HPLC yield 11 mg of product.
Reaction SMILES: [C:1]([O:11][CH2:12][CH3:13])(=[O:10])[CH:2]=[CH:3][CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[Cl:14][C:15]1[CH:16]=[C:17](I)[CH:18]=[CH:19][CH:20]=1.C([O-])(=O)C.[Na+].O>CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:14][C:15]1[CH:20]=[C:19](/[C:3](/[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6])=[CH:2]/[C:1]([O:11][CH2:12][CH3:13])=[O:10])[CH:18]=[CH:17][CH:16]=1
Reactant: CCOC(=O)C=CCC(=O)OCC
Reactant: Clc1cccc(I)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)/C=C(\CC(=O)OCC)c1cccc(Cl)c1
Temperature: 100 °C
Reaction time: 21 h
Yield: 20.1 %

Procedure:
A mixture of diethyl glutaconate (10.0 g. 53.7 mmol), 3-chloroiodobenzene (11.5 g, 48.2 mmol), sodium acetate (4.40 g, 53.7 mmol) and palladium acetate (1.1 g, 4.9 mmol) in DMF (30 mL) was heated to 100° C., stirred for 21 hours, cooled to room temperature, poured into water, filtered, and extracted with ethyl acetate. The combined extracts were washed with water and brine, dried (MgSO4), filtered, and concentrated. The concentrate was purified by flash column chromatography on silica gel 8:1 hexanes/ethyl acetate to provide 2.88 g (20%) of the desired product. MS (DCI/NH3) m/z 297 (M+H)+; 1H NMR (CDCl3) δ 7.43 (m, 2H), 7.32 (m, 3H), 6.26 (s, 2H), 4.19 (m, 4H), 1.21 (t, 3H), 1.31 (t, 3H).
Reaction SMILES: Cl[CH2:2][CH2:3][C@H:4]([O:11][C:12]1[CH:13]=[C:14]([C:18](=[O:20])[CH3:19])[CH:15]=[CH:16][CH:17]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[CH3:21][CH:22]([CH3:39])[C:23]([NH:25][C:26]1[CH:31]=[C:30]([CH:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)[CH:29]=[CH:28][C:27]=1[CH3:38])=[O:24]>>[C:18]([C:14]1[CH:13]=[C:12]([CH:17]=[CH:16][CH:15]=1)[O:11][C@H:4]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH2:3][CH2:2][N:35]1[CH2:36][CH2:37][CH:32]([C:30]2[CH:29]=[CH:28][C:27]([CH3:38])=[C:26]([NH:25][C:23](=[O:24])[CH:22]([CH3:21])[CH3:39])[CH:31]=2)[CH2:33][CH2:34]1)(=[O:20])[CH3:19]
Reactant: CC(=O)c1cccc(O[C@@H](CCCl)c2ccccc2)c1
Reactant: Cc1ccc(C2CCNCC2)cc1NC(=O)C(C)C
Product: CC(=O)c1cccc(O[C@@H](CCN2CCC(c3ccc(C)c(NC(=O)C(C)C)c3)CC2)c2ccccc2)c1

Procedure:
Prepared by Procedure G and Scheme AI using 1-(3-{[(1S)-3-chloro-1-phenylpropyl]oxy}phenyl)ethanone and 2-methyl-N-[2-methyl-5-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 512.9 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:14]=[CH:15][CH:16]=1)[CH:6]([OH:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C([Li])CCC.[C:22](=O)=[O:23]>CCOCC.CCCCCC>[CH3:1][O:2][C:3]1[CH:16]=[CH:15][CH:14]=[C:5]2[C:4]=1[C:22](=[O:23])[O:13][CH:6]2[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: COc1cccc(C(O)c2ccccc2)c1
Reactant: O=C=O
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCCCCC
Product: COc1cccc2c1C(=O)OC2c1ccccc1

Procedure:
To 3-methoxybenzhydrol (42.8 g.) in dry ether (800 ml.) is added 2.3 M. n-butyl lithium in hexane (250 ml.), dropwise with stirring under nitrogen. The deep red solution is stirred and heated under reflux for 2 hours and then poured into a stirred slurry of a large excess of solid carbon dioxide in ether and stirred until no carbon dioxide remains. The resulting suspension is extracted with water, the extract is acidified with concentrated hydrochloric acid, the precipitate is filtered off, washed with water, dried, and recrystallised from isopropanol to give 7-methoxy-3-phenylphthalide, m.p. 135°-138°C.
Reaction SMILES: CC1(C)CO[CH:5]([CH2:8][CH2:9][C:10]([C:12]2[CH:17]=[CH:16][C:15]([S:18]([CH3:21])(=[O:20])=[O:19])=[CH:14][CH:13]=2)=O)OC1.[F:23][C:24]1[CH:30]=[CH:29][C:27]([NH2:28])=[CH:26][CH:25]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[F:23][C:24]1[CH:30]=[CH:29][C:27]([N:28]2[CH:5]=[CH:8][CH:9]=[C:10]2[C:12]2[CH:13]=[CH:14][C:15]([S:18]([CH3:21])(=[O:19])=[O:20])=[CH:16][CH:17]=2)=[CH:26][CH:25]=1
Reactant: CC1(C)COC(CCC(=O)c2ccc(S(C)(=O)=O)cc2)OC1
Reactant: Nc1ccc(F)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CS(=O)(=O)c1ccc(-c2cccn2-c2ccc(F)cc2)cc1
Yield: 45 %

Procedure:
A mixture of 3-(5,5-dimethyl-1,3-dioxan-2-yl)-1-[4-(methylsulfonyl)phenyl]propan-1-one (Step 5), (1.6 g, 4.9 mmol), 4-fluoroaniline (510 μl, 5.4 mmol) and p-toluenesulfonic acid (120 mg) in toluene (200 ml) was heated to reflux for 72 hours. The reaction mixture was cooled, filtered and concentrated. The crude solid (2.48 g) was purified by chromatography (silica gel, hexane/ethyl acetate, 6/4) to give 1-[4-fluorophenyl)-2-[4-(methylsulfonyl)phenyl]-1H-pyrrole (695 mg, 45%) as a white solid: mp (DSC) 163° C. Anal Calc'd. for C17H14NSFO2 : C, 64.75; H, 4.47; N, 4.44. Found: C, 64.71; H, 4.53; N, 4.43.
Reaction SMILES: [CH2:1]([N:3]([CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]2[NH:20][CH2:19][CH2:18][NH:17][C:16]2=[O:21])=[CH:11][CH:10]=1)[CH2:4][CH3:5])[CH3:2].[CH:22](OCC)=[O:23]>>[CH2:1]([N:3]([CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]2[N:20]([CH:22]=[O:23])[CH2:19][CH2:18][NH:17][C:16]2=[O:21])=[CH:11][CH:10]=1)[CH2:4][CH3:5])[CH3:2]
Reactant: CCOC=O
Reactant: CCN(CC)CCOc1ccc(C2NCCNC2=O)cc1
Product: CCN(CC)CCOc1ccc(C2C(=O)NCCN2C=O)cc1

Procedure:
29.2 g (0.1 mol) of 3-(4-diethylaminoethoxyphenyl)-piperazin-2-one are acylated by boiling with ethyl formate and the mixture is worked up, as described in Example 5. After being worked up, the product is precipitated as the salt of naphthalene-1,4-disulphonic acid by adding this acid.
Reaction SMILES: [OH-:1].[Na+].[C:3]([O:7][C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:16]1[CH:21]=[CH:20][C:19]([CH2:22][N:23]2[C:27]([C:28]#[N:29])=[C:26]([CH:30]([OH:34])[CH2:31][CH2:32][CH3:33])[N:25]=[C:24]2[CH2:35][CH2:36][CH2:37][CH3:38])=[CH:18][CH:17]=1)=[O:9])([CH3:6])([CH3:5])[CH3:4]>C(O)C>[C:3]([O:7][C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:16]1[CH:21]=[CH:20][C:19]([CH2:22][N:23]2[C:27]([C:28]([NH2:29])=[O:1])=[C:26]([CH:30]([OH:34])[CH2:31][CH2:32][CH3:33])[N:25]=[C:24]2[CH2:35][CH2:36][CH2:37][CH3:38])=[CH:18][CH:17]=1)=[O:9])([CH3:6])([CH3:5])[CH3:4]
Reactant: CCCCc1nc(C(O)CCC)c(C#N)n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Reactant: [OH-]
Agent: [Na+]
Solvent: CCO
Product: CCCCc1nc(C(O)CCC)c(C(N)=O)n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1

Procedure:
14 ml of a 1N aqueous solution of sodium hydroxide were added to a solution of 0.86 g of 1-[(2'-t-butoxycarbonylbiphenyl-4-yl)methyl]-2-butyl-4-(1-hydroxybutyl)imidazole-5-carbonitrile [prepared as described in step (b) above] in 14 ml of ethanol, and the resulting mixture was heated under reflux for 10 hours. At the end of this time, the reaction mixture was worked up in a similar manner to that described in Example 45(c) to afford 0.58 g of the title compound as an amorphous solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([OH:11])[C:5](=[CH:9][CH:10]=1)[C:6]([OH:8])=[O:7].C(=O)([O-])O.[Na+].[CH2:17]([O:25][C:26](Cl)=[O:27])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24].Cl>O>[CH2:17]([O:25][C:26]([NH:1][C:2]1[CH:3]=[C:4]([OH:11])[C:5](=[CH:9][CH:10]=1)[C:6]([OH:8])=[O:7])=[O:27])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: CCCCCCCCOC(=O)Cl
Reactant: Nc1ccc(C(=O)O)c(O)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: CCCCCCCCOC(=O)Nc1ccc(C(=O)O)c(O)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 47.9 %

Procedure:
To an aqueous solution dissolved 153 g of 4-aminosalicylic acid and 170 g of sodium hydrogen carbonate in 2200 ml of water, 193 g of n-octylchloroformate was dropwise added over 2 hours at room temperature. After finishing dropwise addition, the mixture was further stirred for 5 hours at room temperature. An aqueous solution containing 30 g of concentrated hydrochloric acid and 1200 ml of water was added to the reaction mixture. Precipitated crystals were filtered and dried to obtain 148 g of desired 4-(n-octyloxycarbonylamino)salicylic acid as colorless crystals. Yield was 48%.
Reaction SMILES: Cl[C:2]1[N:6]([CH3:7])[N:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].Cl.[F:12][C:13]1([F:19])[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1>>[F:12][C:13]1([F:19])[CH2:18][CH2:17][N:16]([C:2]2[N:6]([CH3:7])[N:5]=[CH:4][C:3]=2[N+:8]([O-:10])=[O:9])[CH2:15][CH2:14]1
Reactant: FC1(F)CCNCC1
Reactant: Cn1ncc([N+](=O)[O-])c1Cl
Agent: Cl
Product: Cn1ncc([N+](=O)[O-])c1N1CCC(F)(F)CC1
Yield: 97 %

Procedure:
Reaction of 5-chloro-1-methyl-4-nitro-1H-pyrazole and 4,4 di-fluoropiperidine hydrochloride gave 4,4-difluoro-1-(1-methyl-4-nitro-1H-pyrazol-5-yl)piperidine as a white solid (289 mg, 97%). 1H NMR (400 MHz, CDCl3) δ 8.03 (s, 1H), 3.79 (s, 3H), 3.36-3.31 (m, 4H), 2.22-2.09 (m, 4H)
Reaction SMILES: FC(F)(F)C(O)=O.C(OC(=O)[NH:14][C@H:15]([C:17]1[N:25]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=2)[C:20]2=[N:21][CH:22]=[CH:23][CH:24]=[C:19]2[N:18]=1)[CH3:16])(C)(C)C>C(Cl)Cl>[N:27]1[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=1[N:25]1[C:20]2=[N:21][CH:22]=[CH:23][CH:24]=[C:19]2[N:18]=[C:17]1[C@@H:15]([NH2:14])[CH3:16]
Reactant: C[C@H](NC(=O)OC(C)(C)C)c1nc2cccnc2n1-c1ccccn1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@H](N)c1nc2cccnc2n1-c1ccccn1
Reaction time: 0.5 h
Yield: 18.7 %

Procedure:
Trifluoroacetic acid (20 mL) was added to a solution of [(S)-1-(3-pyridin-2-yl-3H-imidazo[4,5-b]pyridin-2-yl)ethyl]carbamic acid tert-butyl ester (1.10 g, 3.24 mmol) in DCM (10 mL) and stirred for 30 min. The reaction mixture was concentrated in vacuo and the residue purified by chromatography (SiO2 0-10% (2M ammonia in methanol) in DCM) to give the title compound (0.145 g, 19%). LCMS (method H): Rt 0.26 min, [M+H]+ 240.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[N:8][N:7]2[CH:10]=[C:11]([C:13]3[CH:14]=[CH:15][C:16]([C:19]([OH:21])=O)=[N:17][CH:18]=3)[CH:12]=[C:6]2[C:5]=1[NH:22][C@H:23]1[C@@H:27]([CH3:28])[CH2:26][N:25]([C:29]([C:31]2([C:34]#[N:35])[CH2:33][CH2:32]2)=[O:30])[CH2:24]1)(=[O:3])[NH2:2].C[CH2:37][N:38](C(C)C)[CH:39](C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CNC.C1COCC1>CN(C=O)C>[C:34]([C:31]1([C:29]([N:25]2[CH2:26][C@H:27]([CH3:28])[C@H:23]([NH:22][C:5]3[C:6]4[N:7]([CH:10]=[C:11]([C:13]5[CH:18]=[N:17][C:16]([C:19](=[O:21])[N:38]([CH3:39])[CH3:37])=[CH:15][CH:14]=5)[CH:12]=4)[N:8]=[CH:9][C:4]=3[C:1]([NH2:2])=[O:3])[CH2:24]2)=[O:30])[CH2:32][CH2:33]1)#[N:35]
Reactant: C[C@H]1CN(C(=O)C2(C#N)CC2)C[C@H]1Nc1c(C(N)=O)cnn2cc(-c3ccc(C(=O)O)nc3)cc12
Reactant: CCN(C(C)C)C(C)C
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: CNC
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: C[C@H]1CN(C(=O)C2(C#N)CC2)C[C@H]1Nc1c(C(N)=O)cnn2cc(-c3ccc(C(=O)N(C)C)nc3)cc12
Reaction time: 1 h
Yield: 55.3 %

Procedure:
To solution of 5-(3-carbamoyl-4-((3S,4S)-1-(1-cyanocyclopropanecarbonyl)-4-methylpyrrolidin-3-ylamino)pyrrolo[1,2-b]pyridazin-6-yl)picolinic acid (15 mg, 0.026 mmol), DIPEA (0.018 mL, 0.102 mmol) and BOP (16.94 mg, 0.038 mmol) in DMF (0.3 mL) was added a 2 M solution of dimethylamine in THF (0.026 mL, 0.051 mmol) and the resulting mixture was stirred for 1 h. The mixture was concentrated to remove the THF and was purified by preparative LC/MS with the following conditions: column: Waters XBridge C18, 19×200 mm, 5-μm particles; Guard Column: Waters XBridge C18, 19×10 mm, 5-μm particles; Mobile Phase A: 5:95 acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10-mM ammonium acetate; Gradient: 10-100% B over 15 minutes, then a 7-minute hold at 100% B; Flow: 25 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation to afford 7.2 mg of the title compound. LCMS (method H) retention time=1.78 min. (MH+501.2). 1H NMR (500 MHz, METHANOL-d4, appeared as rotomers) δ 9.06 (dd, J=7.9, 1.5 Hz, 1H), 8.40-8.29 (m, 2H), 8.22 (dd, J=11.1, 1.7 Hz, 1H), 7.80 (d, J=7.9 Hz, 1H), 7.47-7.34 (m, 1H), 5.28-5.04 (m, 1H), 4.58-4.42 (m, 2H), 4.13-3.87 (m, 2H), 3.64-3.52 (m, 1H), 3.34-3.26 (m, 6H), 3.09-2.89 (m, 1H), 2.01-1.83 (m, 1H), 1.80-1.59 (m, 3H), 1.51-1.35 (m, 3H).
Reaction SMILES: C(OC(=O)[N:7]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][C:22]([N:25]3[CH2:29][C@H:28]([CH2:30][NH:31][C:32](=[O:34])[CH3:33])[O:27][C:26]3=[O:35])=[CH:21][C:20]=2[F:36])=[CH:15][CH:14]=1)[CH2:8][CH2:9][CH2:10][F:11])(C)(C)C.[ClH:38].O1CCOCC1>C(Cl)Cl>[ClH:38].[F:36][C:20]1[CH:21]=[C:22]([N:25]2[CH2:29][C@H:28]([CH2:30][NH:31][C:32](=[O:34])[CH3:33])[O:27][C:26]2=[O:35])[CH:23]=[CH:24][C:19]=1[C:16]1[CH:17]=[CH:18][C:13]([CH2:12][NH:7][CH2:8][CH2:9][CH2:10][F:11])=[CH:14][CH:15]=1
Reactant: CC(=O)NC[C@H]1CN(c2ccc(-c3ccc(CN(CCCF)C(=O)OC(C)(C)C)cc3)c(F)c2)C(=O)O1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: CC(=O)NC[C@H]1CN(c2ccc(-c3ccc(CNCCCF)cc3)c(F)c2)C(=O)O1
Reaction time: 12 h
Yield: 95.3 %

Procedure:
A solution of BOC-amine 121 (15.65 g, 30.3 mmol) in CH2Cl2 (30 mL) was treated with a solution of 4 N hydrogen chloride in 1,4-dioxane (37.5 mL, 150.0 mmol, 5.0 equiv) at room temperature and stirred for 12 h. When TLC and HPLC/MS showed that the reaction was complete, the solvents were removed in vacuo. The residue was suspended in a mixture of acetonitrile (CH3CN, 200 mL) and methanol (MeOH, 50 mL), and the resulting slurry was stirred at room temperature for 1 h. The solids were collected by filtration, washed with 20% MeOH/CH3CN (2×50 mL), and dried in vacuo to afford the desired (5S)—N-(3-{2-fluoro-4′-[(3-fluoro-propylamino)-methyl]-biphenyl-4-yl}-2-oxo-oxazolidin-5-ylmethyl)-acetamide mono hydrochloride salt 11 (13.0 g, 95.3% yield) as white crystals. 1H NMR (300 MHz, DMSO-d6) δ 1.90 (s, 3H, COCH3), 2.11-2.20 (m, 2H), 3.10 (m, 2H), 3.50 (t, 2H, J=5.4 Hz), 3.87 (dd, 1H, J=6.4, 9.2 Hz), 4.24 (t, 1H, J=9.1 Hz), 4.27 (s, 2H, ArCH2), 4.54 (t, 1H, J=5.8 Hz), 4.70 (t, 1H, J=5.8 Hz), 4.83 (m, 1H), 7.50 (dd, 1H, J=2.2, 8.6 Hz), 7.65-7.74 (m, 6H, aromatic-H), 8.37 (t, 1H, J=5.8 Hz, NHCOCH3), 9.43 (br. s, 2H, RArN+H2). C22H25F2N3O3HCl, LCMS (EI) m/e 418 (M++H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([CH2:15]Cl)=[N:13][N:14]=[C:10]3[CH2:9][N:8]=[C:7]([C:17]3[C:22]([F:23])=[CH:21][CH:20]=[CH:19][C:18]=3[F:24])[C:6]=2[CH:25]=1.[I-].[K+].[CH3:28][CH:29]=[CH:30][CH2:31][NH2:32]>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([CH2:15][NH:32][CH2:31][CH2:30][CH:29]=[CH2:28])=[N:13][N:14]=[C:10]3[CH2:9][N:8]=[C:7]([C:17]3[C:22]([F:23])=[CH:21][CH:20]=[CH:19][C:18]=3[F:24])[C:6]=2[CH:25]=1
Reactant: CC=CCN
Reactant: Fc1cccc(F)c1C1=NCc2nnc(CCl)n2-c2ccc(Cl)cc21
Agent: [I-]
Agent: [K+]
Solvent: C1CCOC1
Product: C=CCCNCc1nnc2n1-c1ccc(Cl)cc1C(c1c(F)cccc1F)=NC2

Procedure:
In the manner given in Example 32, 8-chloro-1-(chloromethyl)-6-(2,6-difluorophenyl)-4H-s-triazolo[4,3-a][1,4]-benzodiazepine, potassium iodide, and methylallylamine in tetrahydrofuran are reacted to give 8-chloro-1-[(allylmethylamino)methyl]-6-(2,6-difluorophenyl)-4H-s-triazolo-[4,3-a][1,4]benzodiazepine.
Reaction SMILES: C=O.[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([O:35][CH:36]([F:38])[F:37])=[C:8]([C:10]2[C:14]([NH:15][C:16]([C:18]3[CH:19]=[N:20][N:21]4[CH:26]=[CH:25][CH:24]=[N:23][C:22]=34)=[O:17])=[CH:13][N:12]([CH2:27][CH:28]=[C:29]3[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]3)[N:11]=2)[CH:9]=1.[BH3-][C:40]#N.[Na+].C(#N)C>CO>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([O:35][CH:36]([F:37])[F:38])=[C:8]([C:10]2[C:14]([NH:15][C:16]([C:18]3[CH:19]=[N:20][N:21]4[CH:26]=[CH:25][CH:24]=[N:23][C:22]=34)=[O:17])=[CH:13][N:12]([CH2:27][CH:28]=[C:29]3[CH2:34][CH2:33][N:32]([CH3:40])[CH2:31][CH2:30]3)[N:11]=2)[CH:9]=1
Reactant: [BH3-]C#N
Reactant: O=C(Nc1cn(CC=C2CCNCC2)nc1-c1cc(Cl)ccc1OC(F)F)c1cnn2cccnc12
Agent: C=O
Agent: [Na+]
Solvent: CO
Solvent: CC#N
Product: CN1CCC(=CCn2cc(NC(=O)c3cnn4cccnc34)c(-c3cc(Cl)ccc3OC(F)F)n2)CC1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 1.2 %

Procedure:
An aqueous solution of 40% formaldehyde (210 mg) was added to solution of N-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-[2-(piperidin-4-ylidene)ethyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide (360.00 mg, 0.700 mmol) in methanol (30 mL). The resulting solution was stirred at ambient temperature for 2.5 h and NaBH3CN (44.02 mg, 0.700 mmol) was added. The resulting solution was stirred at this temperature for 3 h and concentrated under vacuum. The residue was applied onto a short pad of silica gel eluting with dichloromethane/MeOH (10/1). The crude product (60 mg) was purified by Flash-Prep-HPLC with the following conditions (IntelFlash-1): Column, silica gel; mobile phase, ACN/10 mmol NH4HCO3=40% increasing to ACN/10 mmol NH4HCO3=75% within 6 min; Detector, UV 254 nm to obtain 4.3 mg (1%) of N-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-[2-(1-methylpiperidin-4-ylidene)ethyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide as a light yellow solid. LCMS (Method 32): [M+H]+=528.1, RT=2.21 min. 1H NMR (400 MHz, DMSO-d6) δ: (ppm) 9.73 (s, 1H), 9.34 (dd, 1H, J=1.6, 6.8 Hz), 8.68-8.66 (m, 2H), 8.32 (s, 1H), 7.67-7.61 (m, 2H), 7.45 (d, 1H, J=8.4 Hz), 7.28 (dd, 1H, J=4.0, 6.8 Hz), 7.06 (t, 1H, J=73.2 Hz), 5.44 (t, 1H, J=6.8 Hz), 4.27 (d, 2H, J=6.8 Hz), 2.81-2.68 (m, 2H), 2.52-2.50 (m, 2H), 2.50-2.42 (m, 2H), 2.19 (s, 3H), 2.12-2.04 (m, 2H).
Reaction SMILES: C(OC([NH:8][C:9]([NH:25]C(OC(C)(C)C)=O)=[N:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([C:17]2[C:22]([C:23]#[N:24])=[CH:21][CH:20]=[CH:19][N:18]=2)[CH:12]=1)=O)(C)(C)C.[ClH:33]>ClCCl.O1CCOCC1>[ClH:33].[ClH:33].[C:23]([C:22]1[C:17]([C:13]2[CH:12]=[C:11]([NH:10][C:9]([NH2:25])=[NH:8])[CH:16]=[CH:15][CH:14]=2)=[N:18][CH:19]=[CH:20][CH:21]=1)#[N:24]
Reactant: CC(C)(C)OC(=O)NC(=Nc1cccc(-c2ncccc2C#N)c1)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: N#Cc1cccnc1-c1cccc(NC(=N)N)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of N,N′-bis(tert-butoxycarbonyl)-N″-(3-(3-cyanopyridin-2-yl)phenyl)guanidine (200 mg) in dichloromethane (2 ml) was added a solution of hydrogen chloride in 1,4-dioxane (4N, 4 ml), and the mixture was stirred at room temperature for 18 hours. The solvent was evaporated under reduced pressure. To the residue was added 5% ethanol in ethyl acetate (20 ml), and the precipitate was collected by filtration and dried under reduced pressure to give 3-(3-cyanopyridin-2-yl)phenylguanidine dihydrochloride (90 mg).
Reaction SMILES: [Br-:1].[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.C([O-])([O-])=O.[Ca+2].[Cl:42][C:43]1[C:44]([CH3:64])=[C:45]([CH:49]=[C:50]([Cl:63])[C:51]=1[O:52][C:53]1[CH:58]=[CH:57][C:56]([OH:59])=[C:55]([CH:60]([CH3:62])[CH3:61])[CH:54]=1)[C:46]([OH:48])=[O:47]>CO.C(Cl)Cl>[Cl:42][C:43]1[C:44]([CH3:64])=[C:45]([CH:49]=[C:50]([Cl:63])[C:51]=1[O:52][C:53]1[CH:54]=[C:55]([CH:60]([CH3:61])[CH3:62])[C:56]([OH:59])=[C:57]([Br:1])[CH:58]=1)[C:46]([OH:48])=[O:47]
Reactant: Cc1c(C(=O)O)cc(Cl)c(Oc2ccc(O)c(C(C)C)c2)c1Cl
Reactant: [Br-]
Agent: C[N+](C)(C)Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: ClCCl
Solvent: CO
Product: Cc1c(C(=O)O)cc(Cl)c(Oc2cc(Br)c(O)c(C(C)C)c2)c1Cl
Yield: 32.7 %

Procedure:
A suspension of benzyltrimethylamonium tribromide (2.2 g, 5.63 mmol) and CaCO3 (0.28 g, 2.82 mmol) was stirred for 2 hr at 20° C. in a 1:1 MeOH/CH2Cl2 solution (10 mL) containing 3,5-dichloro-2-methyl-4-(4-hydroxy-3-isopropylphenoxy)-benzoic acid (1.0 g, 2.82 mmol). Once HPLC analysis indicated that conversion to the desired monobrominated phenol was optimal, the reaction was quenched by addition of 15 mL of 1N HCl. After removal of the organic solvents under vacuum using a rotary evaporator, the aqueous suspension was extracted twice with EtOAc. After drying the combined EtOAc layers over MgSO4, the salts were filtered prior to removal of the EtOAc under vacuum. The resulting residue after purification by gradient elution from a reverse phase C18 column employing MeOH/H2O containing 0.1% TFA yielded 3,5-dichloro-2-methyl-4-(3-bromo-4-hydroxy-5-isopropylphenoxy)benzoic acid (400 mg).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][O:31]C(=O)C)=[CH:14][CH:13]=2)=[CH:8][CH:7]=1)=[O:5])C.[OH-].[Na+]>C(O)C.O>[OH:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][O:18][C:15]1[CH:14]=[CH:13][C:12]([C:9]2[CH:10]=[CH:11][C:6]([C:4]([OH:5])=[O:3])=[CH:7][CH:8]=2)=[CH:17][CH:16]=1
Reactant: CCOC(=O)c1ccc(-c2ccc(OCCCCCCCCCCCCOC(C)=O)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)c1ccc(-c2ccc(OCCCCCCCCCCCCO)cc2)cc1
Yield: 97.6 %

Procedure:
30 m moles(14.1 g) of the above 4'-(12-acetyloxydodecyloxy)biphenyl-4-carboxylic acid ethyl ester and 10 g of sodium hydroxide were stirred for 10 min. at 70° C. in 40 ml of ethanol and 80 ml of water. After the reaction, the reaction solution was concentrated to obtain 11.7 g of 4'-(12-hydroxydodecyloxy)biphenyl-4-carboxylic acid. (yield: 98%)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH3:9].[Br-:10].[Na+].O>C(O)(=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][Br:10]
Reactant: [Br-]
Reactant: Cc1ccc(Cl)cc1Cl
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: Clc1ccc(CBr)c(Cl)c1
Temperature: 80 °C

Procedure:
To a 500 mL round bottom flask fitted with a Teflon magnetic stirrer was added 2,4-dichlorotoluene (Aldrich) (14.4 g, 90 mmol) in 300 mL glacial acetic acid. To this was added sodium bromide (9.4 g, 92 mmol) and anhydrous ceric ammonium nitrate (100 g, 182 mmol) and the reaction mixture was heated at 80° C. for 2.5 h. The reaction mixture was then poured into 1000 g of ice and water. The slurry was extracted with ether (3×200 mL) and the combined ether layers were washed with saturated aqueous sodium bicarbonate. The organic layer was dried over MgSO4, filtered, and the solvent removed under reduced pressure. The crude product was chromatographed by flash column chromatography on silica gel (eluted with 100% hexanes) and the desired product obtained. 1H-NMR 500 MHz (CDCl3): δ 4.58 (s, 2H), 7.28 (m, 1H), 7.43 (m, 2H),