Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]([CH2:5][CH2:6][OH:7])[CH2:2][CH2:3][OH:4].C(N(CC)CC)C.[CH3:15][O:16][C:17]1[C:25]([Cl:26])=[CH:24][CH:23]=[C:22]([Cl:27])[C:18]=1[C:19](Cl)=[O:20]>C1(C)C=CC=CC=1>[OH:4][CH2:3][CH2:2][N:1]([CH2:5][CH2:6][OH:7])[C:19](=[O:20])[C:18]1[C:22]([Cl:27])=[CH:23][CH:24]=[C:25]([Cl:26])[C:17]=1[O:16][CH3:15]
Reactant: COc1c(Cl)ccc(Cl)c1C(=O)Cl
Reactant: OCCNCCO
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: COc1c(Cl)ccc(Cl)c1C(=O)N(CCO)CCO
Reaction time: 2 h
Yield: 76 %

Procedure:
Diethanolamine (11 grams; 0.105 mol), triethylamine (12 grams) and toluene (100 ml) were placed in a 250 ml, 3-necked glass reaction flask equipped with stirrer, thermometer and reflux condenser. 2-methoxy-3,6-dichlorobenzoic acid chloride (23.9 grams; 0.1 mol) in toluene (25 ml) were added to the reaction mixture by means of an addition funnel. The reaction mixture was stirred for two hours and then filtered. The recovered solid material was heated in ethyl acetate and filtered. Toluene was added to the oily residue, heated to dissolve the oil and cooled. The desired product first formed as an oil and then crystalized. The product weighed 23.6 grams representing a yield of 76%.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11]([S:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][C:27]#[C:28][CH3:29])=[CH:21][CH:20]=2)([C:14](=[O:17])[NH:15][OH:16])[CH2:10][CH2:9]1)=O)(C)(C)C.Cl>O1CCOCC1>[OH:16][NH:15][C:14]([C:11]1([S:18][C:19]2[CH:20]=[CH:21][C:22]([O:25][CH2:26][C:27]#[C:28][CH3:29])=[CH:23][CH:24]=2)[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1)=[O:17]
Reactant: CC#CCOc1ccc(SC2(C(=O)NO)CCN(C(=O)OC(C)(C)C)CC2)cc1
Agent: Cl
Solvent: C1COCCO1
Product: CC#CCOc1ccc(SC2(C(=O)NO)CCNCC2)cc1

Procedure:
4-(4-But-2-ynyloxy-phenylsulfanyl)-4-hydroxycarbamoyl-piperidine-1-carboxylic acid tert-butyl ester, prepared by the method outlined in Example 14 (Step 3) (0.175 g, 0.4 mmol), was treated with 4N hydrochloric acid in dioxane (5 mL) at 25° C. for 1 h 15 min. The reaction mixture was concentrated in vacuo, diethyl ether was added and the resulting precipitate isolated by filtration to give 4-(4-but-2-ynyloxy-phenylsulfanyl)-piperidine-4-carboxylic acid hydroxyamide as a white solid (0.12 g). Electrospray Mass Spectroscopy: ((M+H)+=321)
Reaction SMILES: [CH2:1]([C:5]1[C:9]([CH2:10][O:11][C:12]2[CH:20]=[CH:19][C:15]([C:16]([OH:18])=O)=[CH:14][N:13]=2)=[CH:8][O:7][N:6]=1)[CH2:2][CH2:3][CH3:4].C(C1C(COC2C=CC(C(O)=O)=CN=2)=C(C)ON=1)CCC.[NH2:42][C@@H:43]([CH3:46])[CH2:44][OH:45]>>[CH2:1]([C:5]1[C:9]([CH2:10][O:11][C:12]2[CH:20]=[CH:19][C:15]([C:16]([NH:42][C@@H:43]([CH3:46])[CH2:44][OH:45])=[O:18])=[CH:14][N:13]=2)=[CH:8][O:7][N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: C[C@H](N)CO
Reactant: CCCCc1nocc1COc1ccc(C(=O)O)cn1
Agent: CCCCc1noc(C)c1COc1ccc(C(=O)O)cn1
Product: CCCCc1nocc1COc1ccc(C(=O)N[C@@H](C)CO)cn1
Yield: 79 %

Procedure:
As described for example 19b, 6-(3-butyl-isoxazol-4-ylmethoxy)-nicotinic acid (200 mg, 0.72 mmol) was converted, instead of 6-(3-butyl-5-methyl-isoxazol-4-ylmethoxy)-nicotinic acid, using (S)-(+)-2-amino-1-propanol instead of rac-2,2,2-trifluoro-1-(methyl)ethylamine, to the title compound (190 mg, 79%) which was obtained as a white solid after purification by chromatography (silica, heptane:ethyl acetate 7:3 to 0:1). MS: m/e=332.1 [M−H]−.
Reaction SMILES: [I-:1].[I-].[I-].[C:4]([N:11]1[CH2:16][CH2:15][N:14]([C:17]2[CH:18]=[C:19]([CH3:32])[C:20]3[C:29]([CH:30]=2)=[S+:28][C:27]2[C:22](=[C:23]([CH3:31])[CH:24]=[CH:25][CH:26]=2)[N:21]=3)[CH2:13][CH2:12]1)([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5].C(N1CC[N:43]([C:46]2C=C(C)[C:49]3[C:58]([CH:59]=2)=[S+]C2C(=C(C)C=CC=2)N=3)[CH2:42]C1)(OC(C)(C)C)=O.C(N1CCN(C2C=C(C)C3C(C=2)=[S+]C2C(=C(C)C=CC=2)N=3)CC1)(OC(C)(C)C)=O.CO>>[I-:1].[C:4]([N:11]1[CH2:12][CH2:13][N:14]([C:17]2[CH:18]=[C:19]([CH3:32])[C:20]3[C:29]([CH:30]=2)=[S+:28][C:27]2[C:22](=[C:23]([CH3:31])[CH:24]=[C:25]([N:43]([CH3:42])[CH2:46][CH2:59][CH2:58][CH3:49])[CH:26]=2)[N:21]=3)[CH2:15][CH2:16]1)([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5]
Reactant: Cc1cccc2[s+]c3cc(N4CCN(C(=O)OC(C)(C)C)CC4)cc(C)c3nc12
Agent: [I-]
Solvent: CO
Product: CCCCN(C)c1cc(C)c2nc3c(C)cc(N4CCN(C(=O)OC(C)(C)C)CC4)cc3[s+]c2c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 3-(4-Boc-piperazin-1-yl)-1,9-dimethylphenothiazin-5-ium triiodide (158 mg, 0.2 mmol) in methanol (5 mL) methyl(n-butyl)amine (0.065 mL, 25.2 mg, 0.6 mmol) was added. Reaction mixture was stirred for 24 h at room temperature. The resulting mixture was concentrated to dryness and purified by flash chromatography using the methanol-chloroform gradient to provide the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:15]=[CH:14][C:7]([CH:8]=[CH:9][C:10](=[N:12][OH:13])[NH2:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].C(=O)([O-])[O-].[Na+].[Na+].[C:22](OC(=O)C)(=O)[CH3:23]>>[CH3:22][C:23]1[O:13][N:12]=[C:10](/[CH:9]=[CH:8]/[C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:15][CH:14]=2)[N:11]=1
Reactant: NC(C=Cc1ccc([N+](=O)[O-])cc1)=NO
Reactant: CC(=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: Cc1nc(/C=C/c2ccc([N+](=O)[O-])cc2)no1

Procedure:
A suspension of p-nitrocinnamamidoxime (20.7 g.) in acetic anhydride (70 ml.) was heated on a steam-bath for one hour when solution occurred. The cooled solution was neutralized with saturated sodium carbonate solution and the precipitated solid filtered off, washed with water, and dried. Recrystallization of the solid from ethanol (1,200 ml) gave title compound as yellow needles, 13.5g (58.5%), m.p. 190°-191°, λmax. (EtOH) 226, 310 nm., (ε 11,500, 21,000), νmax. (Nujol) 1338 and 1502 (NO2), 972 cm.-1 (trans CH=CH), τ (CF3CO2H) values include 2.15, 2.68 (AB quartet, J 17; trans CH=CH), 7.15 (CH3).
Reaction SMILES: [CH3:1][N:2]([CH3:20])[CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][C:8]=1[C:14]1[N:15]([CH3:19])[N:16]=[CH:17][CH:18]=1.[F:21][C:22]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:23]=1[N:29]=[C:30]=[O:31]>C(Cl)Cl>[F:21][C:22]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:23]=1[NH:29][C:30]([NH:13][C:10]1[CH:11]=[CH:12][C:7]([O:6][CH2:5][CH2:4][CH2:3][N:2]([CH3:1])[CH3:20])=[C:8]([C:14]2[N:15]([CH3:19])[N:16]=[CH:17][CH:18]=2)[CH:9]=1)=[O:31]
Reactant: CN(C)CCCOc1ccc(N)cc1-c1ccnn1C
Reactant: O=C=Nc1ccc(F)cc1F
Solvent: ClCCl
Product: CN(C)CCCOc1ccc(NC(=O)Nc2ccc(F)cc2F)cc1-c1ccnn1C
Reaction time: 2 h
Yield: 90.2 %

Procedure:
To a solution of 4-(3-dimethylamino-propoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenylamine (21.4 mg, 0.078 mmol) in CH2Cl2 (2 mL) was added 2,4-difluorophenyl isocyanate (0.10 μL, 0.084 mmol) and stirred for two hours. The resulting material was purified by solid phase extraction (SCX, 1 gram cartridge), eluting with methanol (30 mL) followed by 2M NH3 in methanol (30 mL). The NH3 containing fractions were dried in vacuo to afford Compound 124 as a colorless solid (30.2 mg, 73%). LCMS m/z (%)=430 (MH+) (100), 1H NMR (400 MHz, DMSO-d6) δ: 8.94 (bs, 1H), 8.46 (bs, 1H), 8.09-8.00 (m, 1H), 7.45 (d, J=1.80 Hz, 1H), 7.42 (dd, J=8.89, 2.72 Hz, 1H), 7.34-7.26 (m, 1H), 7.09 (d, J=8.94 Hz, 1H), 7.06-6.99 (m, 1H), 6.24 (d, J=1.83 Hz, 1), 3.97 (t, J=6.32 Hz, 2H), 3.65 (s, 3H), 2.23 (t, J=7.07 Hz, 2H), 2.10 (s, 6H), 1.78-1.69 (m, 2H).
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[NH2:8].[CH:9]([CH:11]=O)=O>O>[CH2:4]1[CH:3]2[CH:2]([NH:1][CH:3]3[NH:8][CH:9]4[CH:11]([CH2:4][CH2:5][CH2:6][CH2:7]4)[NH:1][CH:2]3[NH:8]2)[CH2:7][CH2:6][CH2:5]1
Reactant: NC1CCCCC1N
Reactant: O=CC=O
Solvent: O
Product: C1CCC2NC3NC4CCCCC4NC3NC2C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 8.4 %

Procedure:
To an ice-cold solution of 11.4 grams (0.1 mole) of 1,2-diaminocyclohexane and 5 ml of water was added dropwise 8.3 grams of 40% aqueous glyoxal (2.9 grams, 0.05 mole). Within 5-10 minutes a precipitate formed, which was allowed to stand at room temperature for one hour, then heated at 65°-70° C. for 1.5 hours. The solid was recrystallized from acetonitrile to give 1.05 grams of tan crystals, m.p. 148°-155° C.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[Cl-].[Al+3].[Cl-].[Cl-].[CH:9]1[C:22]2[CH2:21][C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[O:14][C:13]=2[CH:12]=[CH:11][CH:10]=1.Cl>ClCCCl>[CH:9]1[C:22]2[CH2:21][C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[O:14][C:13]=2[CH:12]=[CH:11][C:10]=1[C:1]([CH3:2])=[O:3]
Reactant: CC(=O)Cl
Reactant: c1ccc2c(c1)Cc1ccccc1O2
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: CC(=O)c1ccc2c(c1)Cc1ccccc1O2
Temperature: 16 °C
Reaction time: 0.5 h

Procedure:
A 21.4 ml portion of acetyl chloride in 30 ml of 1,2-dichloroethane was added dropwise to 40 g of aluminum chloride in 105 ml of 1,2-dichloroethane. This mixture was stirred 1/2 hour and then added portionwise to an ice-cooled solution of 54.66 g of xanthene in 225 ml of 1,2-dichloroethane. The reaction was then allowed to warm to 16° C. and poured onto ice. A 180 ml portion of concentrated hydrochloric acid was added, the mixture was allowed to stand overnight and the layers separated. The aqueous layer was extracted with two 100 ml portions of chloroform then the organic layers was combined, dried, filtered through hydrous magnesium silicate and evaporated, giving the desired intermediate as a white crystalline solid, mp 103°-104° C.
Reaction SMILES: [CH3:1][N:2]([CH3:10])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH3:9].C([Li])CCC.C(O[K:21])(C)(C)C>C(OCC)C>[CH3:1][N:2]([CH3:10])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][K:21]
Reactant: Cc1ccccc1N(C)C
Reactant: CC(C)(C)O[K]
Agent: [Li]CCCC
Solvent: CCOCC
Product: CN(C)c1ccccc1C[K]
Temperature: 25 °C
Reaction time: 3 h
Yield: 80 %

Procedure:
13.4 g of ortho-dimethylaminotoluene (or N,N-dimethyl-o-toluidine) (M=135 g.mol−1; 99 mmol) are diluted in a mixture of 40 ml of hexanes and 20 ml of diethyl ether. At ambient temperature, under nitrogen and with stirring, 40 ml of a solution of butyllithium (2.5M in hexane) are added. After 3 h, 1 equivalent of tBuOK is added in fractions, under argon. The solution is heated and a yellow precipitate appears. The stirring is maintained overnight. The solution is filtered and the yellow precipitate is washed three times with a mixture of hexanes (3×40 ml). After drying under vacuum, the solid is milled and dried again under vacuum overnight. 14.9 g of yellow powder of ortho-dimethylaminobenzyl potassium are obtained (yield=80%). 1H NMR (THF-d8, 22° C.): δ=2.03 and 2.57 (2×1H, s, KCH2—), 2.67 (s, 6H, —NMe2), 5.11 (t, 1H, JH-H=7 Hz, aromatic CH), 6.04 (d, 1H, JH-H=7 Hz, aromatic CH), 6.16 (t, 1H, JH-H=7 Hz, aromatic CH), 6.26 (t, 1H, JH-H=7 Hz, aromatic CH).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([N:17]2[C:21]([CH:22]([CH3:24])[CH3:23])=[C:20](C(O)=O)[N:19]=[N:18]2)[CH:7]=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)[CH:9]=1)([OH:3])=[O:2].C(=O)=O>>[CH:22]([C:21]1[N:17]([C:6]2[CH:5]=[C:4]([C:1]([OH:3])=[O:2])[CH:9]=[C:8]([C:10]3[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=3)[CH:7]=2)[N:18]=[N:19][CH:20]=1)([CH3:24])[CH3:23]
Reactant: Cc1ccc(-c2cc(C(=O)O)cc(-n3nnc(C(=O)O)c3C(C)C)c2)cc1
Agent: O=C=O
Product: Cc1ccc(-c2cc(C(=O)O)cc(-n3nncc3C(C)C)c2)cc1
Temperature: 25 °C

Procedure:
The 1-(5-carboxy-4′-methyl-biphenyl-3-yl)-5-isopropyl-1H-[1,2,3]triazole-4-carboxylic acid from step 2 was heated to 170° C. until no further carbon dioxide was released. The reaction mixture was cooled to room temperature, and the resulting crude 5-(5-Isopropyl-[1,2,3]triazol-1-yl)-4′-methyl-biphenyl-3-carboxylic acid was used directly in the next step without further purification.
Reaction SMILES: [Br:1][C:2]1[C:10]2[N:9]=[CH:8][NH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH3:13][Si:14]([CH2:17][CH2:18][O:19][CH2:20]Cl)([CH3:16])[CH3:15]>C1COCC1>[Br:1][C:2]1[C:10]2[N:9]=[CH:8][N:7]([CH2:20][O:19][CH2:18][CH2:17][Si:14]([CH3:16])([CH3:15])[CH3:13])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: Brc1cccc2[nH]cnc12
Reactant: C[Si](C)(C)CCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOCn1cnc2c(Br)cccc21
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 90 %

Procedure:
To a solution of 4-bromo-1H-benzo[d]imidazole (1.1 g, 5.6 mmol) in THF was added NaH (448 mg, 11.2 mmol) at 0° C. After stirring at for 30 minutes at room temperature 0° C., SEM-Cl (1.4 g, 8.4 mmol) was added to the mixture at 0° C. The mixture was then stirred at room temperature for 16 h, at which time TLC showed the completion of the reaction. The reaction was quenched by addition of aq. NH4Cl and the mixture extracted with ethyl acetate with the combined organic layers were dried over anhydrous Na2SO4 and concentrated in vacuum to give the desired product and used in the next step without further purification (1.65 g, Yield 90%). LCMS (m/z): 229.0 (M+1)
Reaction SMILES: [Br-:1].[K+].Br.N([O-])=O.[Na+].[C:8]([O:12][CH2:13][C@@H:14]([C:16]([OH:18])=[O:17])N)([CH3:11])([CH3:10])[CH3:9]>>[Br:1][CH:14]([CH2:13][O:12][C:8]([CH3:11])([CH3:10])[CH3:9])[C:16]([OH:18])=[O:17]
Reactant: [Br-]
Reactant: CC(C)(C)OC[C@H](N)C(=O)O
Agent: Br
Agent: O=N[O-]
Agent: [K+]
Product: CC(C)(C)OCC(Br)C(=O)O
Temperature: -7 °C
Reaction time: 3 h
Yield: 99.7 %

Procedure:
A mixture of potassium bromide (6.830 g, 57.39 mmol) and 0.75 M HBr solution (91 mL, 68.24 mmol) was cooled down to −7° C. Sodium nitrite (2.093 g, 29.47 mmol) and L-serine tert-butyl ether (2.50 g, 15.51 mmol) were added successively and the mixture was stirred 3 h at room temperature. The mixture was cooled down to 0° C., and was extracted with ethyl acetate (3×100 mL). Combined organic phases were washed with brine (2×180 mL), dried over MgSO4, filtrated and evaporated. The expected product, e.g. 2-bromo-3-tert-butoxypropanoic acid (3.481 g, quantitative yield), was isolated as a light yellow oil. This intermediate was used in the next step without further purification.
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[NH:9][C:8]3[CH:16]=[N:17][C:18]([NH:20][C:21]4[CH:29]=[CH:28][C:24]([C:25](O)=[O:26])=[CH:23][C:22]=4[O:30][CH3:31])=[N:19][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.F[P-](F)(F)(F)(F)F.C[N:40](C(N(C)C)=[N+]1C2C(=NC=CC=2)[N+]([O-])=N1)C.C(N(C(C)C)CC)(C)C.[Cl-].[NH4+]>C(OCC)(=O)C.O.CN(C)C=O>[CH:1]1([N:6]2[CH2:12][C:11]([F:13])([F:14])[C:10](=[O:15])[NH:9][C:8]3[CH:16]=[N:17][C:18]([NH:20][C:21]4[CH:29]=[CH:28][C:24]([C:25]([NH2:40])=[O:26])=[CH:23][C:22]=4[O:30][CH3:31])=[N:19][C:7]2=3)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CN(C)C(N(C)C)=[N+]1N=[N+]([O-])c2ncccc21
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(C(N)=O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 17.3 %

Procedure:
To a mixture of 0.07 g (0.16 mmole) of 4-(9-cyclopentyl-7,7-difluoro-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-benzoic acid (I-151), 0.07 g (0.19 mmole) of 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxide hexafluorophosphate and 2 mL of dimethylformamide was added 0.04 mL (0.24 mmole) of diisopropylethylamine. After stirring at room temperature for 30 minutes, 0.013 g (0.24 mmole) of ammonium chloride was added. The mixture was stirred at room temperature for 18 hours. The mixture was diluted with ethyl acetate and water. The aqueous phase was extracted twice with ethyl acetate and the combined organic layers washed with water, then brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was triturated with hot methanol to give 0.012 g of 4-(9-cyclopentyl-7,7-difluoro-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-benzamide (I-152).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[NH:15][C:16]([C:18]1[CH:23]=[CH:22][C:21]([CH:24]=[CH:25][C:26]([OH:28])=O)=[CH:20][CH:19]=1)=[O:17])=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN(CC)CC.CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F.[NH2:63][CH2:64][CH2:65][C:66]1[CH:67]=[N:68][CH:69]=[CH:70][CH:71]=1.[NH4+].[Cl-]>CN(C=O)C.CCOC(C)=O>[N:68]1[CH:69]=[CH:70][CH:71]=[C:66]([CH2:65][CH2:64][NH:63][C:26]([CH:25]=[CH:24][C:21]2[CH:20]=[CH:19][C:18]([C:16]([NH:15][C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:4])[CH3:3])=[O:17])=[CH:23][CH:22]=2)=[O:28])[CH:67]=1
Reactant: NCCc1cccnc1
Reactant: CC(C)(C)OC(=O)Nc1ccccc1NC(=O)c1ccc(C=CC(=O)O)cc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Nc1ccccc1NC(=O)c1ccc(C=CC(=O)NCCc2cccnc2)cc1
Reaction time: 0.5 h

Procedure:
To a stirred solution at room temperature of compound XIII (80 mg, 0.21 mmol) in anhydrous DMF (3 ml) under nitrogen were added Et3N (35 μl, 0.25 mmol) and BOP reagent (102 mg, 0.23 mmol), respectively. After 30 min, a solution of 3-(2-aminoethyl)pyridine (51 mg, 0.42 mmol) or RXH (1.5–2.0 equiv.), Et3N (87 μl, 0.63 mmol) in anhydrous DMF (1 ml) was added dropwise. After 3–5 h, the reaction mixture was poured into a saturated aqueous solution of NH4Cl, and diluted with AcOEt. After separation, the organic layer was successively washed with sat NH4Cl, H2O and brine, dried over MgSO4, filtered, and concentrated to afford the title compound XIVf. It was used in the next step without further purification.
Reaction SMILES: [C:1]1([N:7]2[C:12](=[O:13])[C:11]3[S:14][CH:15]=[C:16]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[C:10]=3[N:9]=[CH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N[C:24]1C(C2C=CC=CC=2)=CS[C:25]=1C(OC)=O.C(OCC)(OCC)OCC.C(C1CCC(N)CC1)C>C(O)(=O)C>[CH2:24]([CH:4]1[CH2:5][CH2:6][CH:1]([N:7]2[C:12](=[O:13])[C:11]3[S:14][CH:15]=[C:16]([C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=4)[C:10]=3[N:9]=[CH:8]2)[CH2:2][CH2:3]1)[CH3:25]
Reactant: O=c1c2scc(-c3ccccc3)c2ncn1-c1ccccc1
Reactant: COC(=O)c1scc(-c2ccccc2)c1N
Agent: CCC1CCC(N)CC1
Solvent: CCOC(OCC)OCC
Solvent: CC(=O)O
Product: CCC1CCC(n2cnc3c(-c4ccccc4)csc3c2=O)CC1
Yield: 4.7 %

Procedure:
In the same manner as the synthesis of Compound 1, methyl 3-amino-4-phenylthiophene-2-carboxylate (100 mg, 0.43 mmol), triethyl orthoformate (1.0 ml), 4-ethylcyclohexanamine (0.133 ml, 0.90 mmol), and acetic acid (0.1 ml) were used to give 6.8 mg (0.02 mmol, 4.7% yield) of the title compound.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][C:5]([N:7]([C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=1)[C:8]1[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=1)=O.B.S(C)C.CO>O1CCCC1>[Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][N:7]([C:8]1[CH:9]=[CH:10][C:11]([F:14])=[CH:12][CH:13]=1)[C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=1
Reactant: O=C(CCCCl)N(c1ccc(F)cc1)c1ccc(F)cc1
Agent: B
Solvent: CSC
Solvent: CO
Solvent: C1CCOC1
Product: Fc1ccc(N(CCCCCl)c2ccc(F)cc2)cc1
Yield: 91.5 %

Procedure:
To a stirred and cooled (0° C.) solution of 48 parts of 4-chloro-N,N-bis(4-fluorophenyl)butanamide in 108 parts of tetrahydrofuran were added 240 parts of a solution of borane, compound with thiobismethane, in tetrahydrofuran. After stirring overnight at room temperature, the reaction mixture was decomposed with 160 parts of methanol. After evaporation, the residue was purified by column chromatography over silica gel using a mixture of triohloromethane and petroleum ether (20:80 by volume) as eluent. The pure fractions were collected and the eluent was evaporated, yielding 32.5 parts (91.5%) of N-(4-chlorobutyl)-4-fluoro-N-(4-fluorophenyl)benzenamine as a residue (int. 70).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[N+:7]([C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][C:18]=1[CH2:19][CH3:20])[C:13]([OH:15])=O)([O-:9])=[O:8].CN(C=O)C.[NH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[N+:7]([C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][C:18]=1[CH2:19][CH3:20])[C:13]([NH:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:15])([O-:9])=[O:8]
Reactant: CCc1ccc(C(=O)O)cc1[N+](=O)[O-]
Reactant: Nc1ccccc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Product: CCc1ccc(C(=O)Nc2ccccc2)cc1[N+](=O)[O-]
Yield: 74 %

Procedure:
Prepared according to the procedure described for Example 1 using oxalyl chloride (2.0 mL, 22.93 mmol), 3-nitro-4-ethylbenzoic acid (4.00 g, 20.51 mmol), DMF (1.0 mL, 12.92 mmol), and aniline (3.8 mL, 41.70 mmol) to afford the 5 product (4.1 g); m.p. 111-113° C. after trituration in hexane.
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1.Cl.I[C:13]1[CH:14]=[C:15]([C:19]2([O:29][CH3:30])[CH2:23][CH2:22][N:21]([CH2:24][C:25]([F:28])([F:27])[F:26])[CH2:20]2)[CH:16]=[CH:17][CH:18]=1>>[C:8]([C:5]1[CH:6]=[CH:7][C:2]([S:1][C:13]2[CH:14]=[C:15]([C:19]3([O:29][CH3:30])[CH2:23][CH2:22][N:21]([CH2:24][C:25]([F:28])([F:27])[F:26])[CH2:20]3)[CH:16]=[CH:17][CH:18]=2)=[CH:3][CH:4]=1)(=[O:10])[CH3:9]
Reactant: CC(=O)c1ccc(S)cc1
Reactant: COC1(c2cccc(I)c2)CCN(CC(F)(F)F)C1
Agent: Cl
Product: COC1(c2cccc(Sc3ccc(C(C)=O)cc3)c2)CCN(CC(F)(F)F)C1
Yield: 75 %

Procedure:
Using an analogous procedure to that described in Example 10, 4'-mercaptoacetophenone was reacted with 3-(3-iodophenyl)-3-methoxy-1-(2,2,2-trifluoroethyl)pyrrolidine hydrochloride to give 3-[3-(4-acetylphenylthio)phenyl]-3-methoxy-1-(2,2,2-trifluoroethyl)pyrrolidine as a gum in 75% yield.
Reaction SMILES: C1COCC1.[NH2:6][C:7]1[C:12]2=[CH:13][C:14]([C:16](OCC)=[O:17])=[CH:15][N:11]2[N:10]=[CH:9][N:8]=1.CC(C[AlH]CC(C)C)C.[C@H](O)(C([O-])=O)[C@@H](O)C([O-])=O.[Na+].[K+]>CCOC(C)=O>[NH2:6][C:7]1[C:12]2=[CH:13][C:14]([CH2:16][OH:17])=[CH:15][N:11]2[N:10]=[CH:9][N:8]=1
Reactant: CCOC(=O)c1cc2c(N)ncnn2c1
Agent: CC(C)C[AlH]CC(C)C
Agent: O=C([O-])[C@H](O)[C@@H](O)C(=O)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Nc1ncnn2cc(CO)cc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 72 %

Procedure:
To a solution of THF (150 mL) was added ethyl 4-aminopyrrolo[2,1-f][1,2,4]triazine-6-carboxylate (2.29 g, 4.65 mmol) followed by 1 M DIBAL in THF (28.8 mL, 28.8 mmol). The solution was stirred at rt for 1 h. The rxn mixture was treated with EtOAc followed by aq Rochelle's salt. This heterogeneous mixture was then heated at 60° C. for 30 min. The solution was transferred to a separatory funnel, separated and washed with water. The aq layer was back extracted with EtOAc. The organic layer was dried (MgSO4), filtered, and concentrated to yield 550 mg (93%) of the desired product. MS [M+H]+=165; LCMS RT=1.03.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([CH3:12])=[CH:9][CH:10]=2)[N:5]=[C:4]([C:13]([OH:15])=O)[CH:3]=1.[CH2:16]([O:18][C:19]([N:21]1[CH2:26][CH2:25][N:24]([C:27](=[O:38])[C@@H:28]([NH2:37])[CH2:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:23][CH2:22]1)=[O:20])[CH3:17].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C=O)C.O>[CH2:16]([O:18][C:19]([N:21]1[CH2:22][CH2:23][N:24]([C:27](=[O:38])[C@@H:28]([NH:37][C:13]([C:4]2[CH:3]=[C:2]([OH:1])[C:11]3[C:6](=[CH:7][C:8]([CH3:12])=[CH:9][CH:10]=3)[N:5]=2)=[O:15])[CH2:29][C:30]([O:32][C:33]([CH3:35])([CH3:34])[CH3:36])=[O:31])[CH2:25][CH2:26]1)=[O:20])[CH3:17]
Reactant: Cc1ccc2c(O)cc(C(=O)O)nc2c1
Reactant: CCOC(=O)N1CCN(C(=O)[C@@H](N)CC(=O)OC(C)(C)C)CC1
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CCOC(=O)N1CCN(C(=O)[C@H](CC(=O)OC(C)(C)C)NC(=O)c2cc(O)c3ccc(C)cc3n2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 4 g of 4-Hydroxy-7-methyl-quinoline-2-carboxylic acid and 6.4 g of 4-((S)-2-Amino-3-tert-butoxycarbonyl-propionyl)-piperazine-1-carboxylic acid ethyl ester in 37 ml of DMF, 3.0 g of HOBT and 3.7 g of EDC was added and the reaction mixture was stirred for 2 h at RT. Then, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic phase was dried over MgSO4 and the solvents were removed under reduced pressure. The crude product was purified by crystallization from ethyl acetate/heptane. Yield: 5.4 g.