Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br.[NH2:2][CH2:3][C:4]([NH:6][C@H:7]1[CH2:12][CH2:11][CH2:10][CH2:9][C@H:8]1[NH:13][C:14](=[O:25])[C:15]1[CH:20]=[CH:19][C:18]([S:21]([NH2:24])(=[O:23])=[O:22])=[CH:17][CH:16]=1)=[O:5].[Cl:26][C:27]1[CH:28]=[C:29]([S:33](Cl)(=[O:35])=[O:34])[CH:30]=[CH:31][CH:32]=1.CCOC(C)=O>CN(C=O)C>[NH2:24][S:21]([C:18]1[CH:17]=[CH:16][C:15]([C:14]([NH:13][C@@H:8]2[CH2:9][CH2:10][CH2:11][CH2:12][C@@H:7]2[NH:6][C:4](=[O:5])[CH2:3][NH:2][S:33]([C:29]2[CH:30]=[CH:31][CH:32]=[C:27]([Cl:26])[CH:28]=2)(=[O:35])=[O:34])=[O:25])=[CH:20][CH:19]=1)(=[O:23])=[O:22]
Reactant: NCC(=O)N[C@H]1CCCC[C@H]1NC(=O)c1ccc(S(N)(=O)=O)cc1
Reactant: O=S(=O)(Cl)c1cccc(Cl)c1
Agent: Br
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: NS(=O)(=O)c1ccc(C(=O)N[C@@H]2CCCC[C@@H]2NC(=O)CNS(=O)(=O)c2cccc(Cl)c2)cc1
Reaction time: 8 h
Yield: 29.4 %

Procedure:
N-(cis)-{2-[(aminoacetyl)amino]cyclohexyl}-4-(aminosulfonyl)benzamide hydrogen bromide, (61b), (70 mg) was dissolved in DMF (2.5 mL) prior to the addition of 3-chlorobenzenesulfonyl chloride (51 mg). After stirring overnight, EtOAc was added and the solution was washed with 1N HCl. The EtOAc was dried, filtered, and concentrated. Reverse phase HPLC purification (gradient elution, water/acetonitrile/TFA) of the resulting residue provided the title benzamide (25 mg). MS found: (M+H)+=530.1.
Reaction SMILES: [CH2:1]([N:8]1[C:20]2[C:19]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[N:13]=[C:12](Cl)[C:11]=2[N:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH3:22]>>[CH2:1]([N:8]1[C:20]2[C:19]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[N:13]=[C:12]([NH2:22])[C:11]=2[N:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Clc1nc2ccccc2c2c1ncn2Cc1ccccc1
Reactant: N
Product: Nc1nc2ccccc2c2c1ncn2Cc1ccccc1

Procedure:
Using the method of Example 100, 1-benzyl-4-chloro-1H-imidazo[4,5-c]quinoline (from Example 80) was reacted with ammonia to provide white solid 1-benzyl-1H-imidazo[4,5-c]quinolin-4-amine after recrystallization from N,N-dimethylformamide, m.p. 257°-259° C. Analysis: Calculated for C17H14N4: % C, 74.4; % H, 5.1; % N, 20.4; Found: % C, 74.3; % H, 5.4; % N, 20.5.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9](=[O:12])[CH2:10][CH3:11].[Br:13]Br>C(OCC)C>[Br:13][CH:10]([CH3:11])[C:9]([C:3]1[CH:4]=[C:5]([F:8])[CH:6]=[CH:7][C:2]=1[F:1])=[O:12]
Reactant: CCC(=O)c1cc(F)ccc1F
Reactant: BrBr
Solvent: CCOCC
Product: CC(Br)C(=O)c1cc(F)ccc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2′,5′-difluoropropiophenone (2.12 g) in diethyl ether (20 ml) under ice-cooling was added bromine dropwise, and the mixture was stirred at room temperature overnight. To this reaction mixture was added ice and the diethyl ether layer was separated, followed by washing with water and saturated aqueous solution of sodium hydrogen carbonate in that order and dried over anhydrous magnesium sulfate (MgSO4). The ether layer was concentrated under reduced pressure to provide the title compound.
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]2[CH:19]=[CH:18][C:12]3[C:13](=[O:17])[CH:14]=[CH:15][O:16][C:11]=3[C:10]=2[CH2:20][CH:21]=[CH2:22])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.I[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C([O-])(=O)C.[Na+].CN(C)C=O>[Cl-].C([N+](CC)(CC)CC)C.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CCOCC>[C:1]1([CH2:7][O:8][C:9]2[CH:19]=[CH:18][C:12]3[C:13](=[O:17])[CH:14]=[CH:15][O:16][C:11]=3[C:10]=2[CH2:20]/[CH:21]=[CH:22]/[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Ic1ccccc1
Reactant: C=CCc1c(OCc2ccccc2)ccc2c(=O)ccoc12
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC[N+](CC)(CC)CC
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOCC
Product: O=c1ccoc2c(C/C=C/c3ccccc3)c(OCc3ccccc3)ccc12
Temperature: 25 °C
Reaction time: 24 h
Yield: 55.5 %

Procedure:
A mixture of 8.76 g (30 mmol) of 7-(phenylmethoxy)-8-(2-propenyl)-4H-1-benzopyran-4-one (preceding example), 6.70 g (32.84 mmol) of iodobenzene, 5.11 g (30.84 mmol) of tetraethylammonium chloride, 8.94 g (91.22 mmol) of anhydrous sodium acetate, and 64 mL of dry N,N-dimethylformamide was stirred at room temperature while being purged with a stream of argon. Palladium(II) acetate (0.38 g; 1.7 mmol) was added and stirring was continued at room temperature, for 24 hr. The dark mixture was diluted with water and worked-up with ether in the usual manner (the ether extracts were additionally washed with 12% aqueous sodium bisulfite solution). Recrystallization of the crude product from acetonitrile afforded 6.13 g (55.5%) of the title compound as a brown solid. The analytical specimen was obtained from a separate experiment as yellow crystals, mp 131°-133° C.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH2:16]=O>C(O)=O>[CH3:16][N:13]1[CH2:12][CH2:11][CH:10]([C:7]2[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)[CH2:15][CH2:14]1
Reactant: O=[N+]([O-])c1ccc(C2CCNCC2)cc1
Reactant: C=O
Solvent: O=CO
Product: CN1CCC(c2ccc([N+](=O)[O-])cc2)CC1
Temperature: 110 °C

Procedure:
4-(4-Nitrophenyl)piperidine (515 mg) was added to 4 mL 90% formic acid and 1.5 mL formalin added. The solution was stirred and heated at 110° C. for 17 h, evaporated and the solids dissolved in 20 mL water. After basification to pH 14 with 5M sodium hydroxide solution the precipitated solid was extracted into t-butyl methyl ether (3×30 mL). Drying (sodium sulphate) and evaporating gave pure product as pale cream solid. NMR δ 8.15(d,2H), 7.39(d, 2H), 3.00(m,2H), 2.60(m,1H), 2.31(s, 3H), 2.08 (m, 2H), 1.86 (m, 4H).
Reaction SMILES: [NH2:1][CH:2]([CH2:5][OH:6])[CH2:3][OH:4].[F:7][C:8]([F:15])([F:14])[C:9](OCC)=[O:10]>O1CCCC1>[F:7][C:8]([F:15])([F:14])[C:9]([NH:1][CH:2]([CH2:5][OH:6])[CH2:3][OH:4])=[O:10]
Reactant: NC(CO)CO
Reactant: CCOC(=O)C(F)(F)F
Solvent: C1CCOC1
Product: O=C(NC(CO)CO)C(F)(F)F
Temperature: 0 °C
Reaction time: 2 h

Procedure:
4 g of 2-aminopropan-1,3-diol (43.9 mmol) were supplemented with 20 ml of tetrahydrofuran. The reaction mixture was then cooled to 0° C. on an ice bath and 5.8 ml of ethyl trifluoroacetate (48.3 mmol) were gradually added. This solution was stirred for 2 hours at room temperature.
Reaction SMILES: CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.O.Cl.[NH2:37][CH:38]1[C:44]2([CH2:49][CH2:48][O:47][CH2:46][CH2:45]2)[O:43][C:42]2[CH:50]=[CH:51][CH:52]=[CH:53][C:41]=2[NH:40][C:39]1=[O:54].[N:55]([C:62]([O:64][C:65]([CH3:68])([CH3:67])[CH3:66])=[O:63])([CH3:61])[C@H:56]([C:58](O)=[O:59])[CH3:57]>CN(C=O)C.[Cl-].[Na+].O>[CH3:61][N:55]([C@@H:56]([CH3:57])[C:58](=[O:59])[NH:37][C@H:38]1[C:44]2([CH2:45][CH2:46][O:47][CH2:48][CH2:49]2)[O:43][C:42]2[CH:50]=[CH:51][CH:52]=[CH:53][C:41]=2[NH:40][C:39]1=[O:54])[C:62](=[O:63])[O:64][C:65]([CH3:68])([CH3:66])[CH3:67]
Reactant: C[C@@H](C(=O)O)N(C)C(=O)OC(C)(C)C
Reactant: NC1C(=O)Nc2ccccc2OC12CCOCC2
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Product: C[C@@H](C(=O)N[C@@H]1C(=O)Nc2ccccc2OC12CCOCC2)N(C)C(=O)OC(C)(C)C
Yield: 37.2 %

Procedure:
A solution of HBTU (43.2 g, 114 mmol, Eq: 1.2) and HOBT.H2O (17.4 g, 114 mmol, Eq: 1.2) in DMF (300 mL) was added to a mixture of 3-amino-2′,3′,5′,6′-tetrahydro-3H-spiro[benzo[b][1,4]oxazepine-2,4′-pyran]-4(5H)-one hydrochloride (27 g, 94.8 mmol, Eq: 1.00), BOC-N-Me-Ala-OH (23.1 g, 114 mmol, Eq: 1.2) and TEA (38.4 g, 52.9 mL, 379 mmol, Eq: 4) in DMF (300 mL). After 18 h the mixture was poured into brine (750 mL) and the mixture extracted with EtOAc. The combined extracts were washed with 1:1 sat NaHCO3/brine, brine, dried over Na2SO4, and concentrated. The residue was purified by flash chromatography to afford a mixture of diastereomers (36.2 g) as a light yellow solid. The diastereomers were separated by supercritical fluid chromatography (SFC) using a Daicel AD column (5×25 cm) eluted with 15% MeOH/CO2 at 200 mL/min and 220 nM detection at 100 bar backpressure and 35° C. oven. The first diastereomer eluted from the column afforded the title compound (15.29 g, 37%) as an off-white foam. MS m/z 434.1 (MH+).
Reaction SMILES: C([O:3][C:4](=[O:42])[C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]([N:14]2[CH2:18][C@H:17]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[C:20]=3[F:26])[C@:16]([C:29]3[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][C:30]=3[F:36])([C:27]#[N:28])[C@@H:15]2[CH2:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:13])=[CH:7][CH:6]=1)C.[OH-].[Na+].Cl>CO>[Cl:25][C:21]1[C:20]([F:26])=[C:19]([C@H:17]2[CH2:18][N:14]([C:12]([NH:11][C:8]3[CH:7]=[CH:6][C:5]([C:4]([OH:42])=[O:3])=[CH:10][CH:9]=3)=[O:13])[C@@H:15]([CH2:37][C:38]([CH3:41])([CH3:40])[CH3:39])[C@@:16]2([C:29]2[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][C:30]=2[F:36])[C:27]#[N:28])[CH:24]=[CH:23][CH:22]=1
Reactant: CCOC(=O)c1ccc(NC(=O)N2C[C@H](c3cccc(Cl)c3F)[C@@](C#N)(c3ccc(Cl)cc3F)[C@@H]2CC(C)(C)C)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)C[C@@H]1N(C(=O)Nc2ccc(C(=O)O)cc2)C[C@H](c2cccc(Cl)c2F)[C@@]1(C#N)c1ccc(Cl)cc1F
Temperature: 25 °C
Reaction time: 20 h
Yield: 53.3 %

Procedure:
A mixture of rac-4-{[(2S,3R,4S)-4-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-2-(2,2-dimethyl-propyl)-pyrrolidine-1-carbonyl]-amino}-benzoic acid ethyl ester (0.2 g, 0.32 mmol) in methanol (5 mL) was added an aqueous solution (1 N) of NaOH (5 mL, 5 mmol). The reaction mixture was stirred at room temperature for 20 h. The “pH” of the mixture was adjusted to 5-6 by diluted aqueous HCl solution. The mixture was partitioned between EtOAc and water. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The organic layers were combined, washed with water, brine, dried over MgSO4, and concentrated. The residue was purified by chromatography (75% EtOAc in hexanes) to give rac-4-{[(2S,3R,4S)-4-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-2-(2,2-dimethyl-propyl)-pyrrolidine-1-carbonyl]amino}-benzoic acid as a white solid (0.1 g, 50%). HRMS (ES+) m/z Calcd for C30H27Cl2F2N3O3+H [(M+H): 586.1471; Found: 586.1473.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([C:11](O)=[O:12])=[CH:10][C:5]=2[N:4]=[C:3]1[NH:14][C:15]1[S:16][C:17]2[CH:23]=[C:22]([O:24][C:25]([F:28])([F:27])[F:26])[CH:21]=[CH:20][C:18]=2[N:19]=1.[CH2:29]([O:31][CH2:32][CH2:33][NH2:34])[CH3:30].C1C=CC(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)=CC=1.CCN(C(C)C)C(C)C>>[CH2:29]([O:31][CH2:32][CH2:33][NH:34][C:11]([C:9]1[CH:8]=[CH:7][C:6]2[N:2]([CH3:1])[C:3]([NH:14][C:15]3[S:16][C:17]4[CH:23]=[C:22]([O:24][C:25]([F:28])([F:27])[F:26])[CH:21]=[CH:20][C:18]=4[N:19]=3)=[N:4][C:5]=2[CH:10]=1)=[O:12])[CH3:30]
Reactant: Cn1c(Nc2nc3ccc(OC(F)(F)F)cc3s2)nc2cc(C(=O)O)ccc21
Reactant: CCOCCN
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: CCOCCNC(=O)c1ccc2c(c1)nc(Nc1nc3ccc(OC(F)(F)F)cc3s1)n2C
Yield: 25.6 %

Procedure:
1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid (2-ethoxy-ethyl)-amide (27 mg) was prepared by following General Procedure N starting from 1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid (90 mg), 2-ethoxyethylamine (20 mg), DPPA (61 mg), and DIEA (28 mg). LC/MS: m/z 481.0. 1H NMR (DMSO-d6, 400 MHz): δ 12.37 (bs, 1H), 8.47 (s, 1H), 8.07 (s, 1H), 7.90 (s, 1H), 7.76 (d, 1H), 7.71 (d, 1H), 7.47 (d, 1H), 7.35 (s, 1H), 3.62 (bs, 3H), 3.54-3.37 (m, 6H), 1.11 (t, 3H).
Reaction SMILES: [Cl:1][C:2]1[N:10](CC=C)[C:9]2[C:8](=[O:14])[NH:7][C:6](=[O:15])[N:5]([CH2:16][CH2:17][CH2:18][CH2:19][F:20])[C:4]=2[N:3]=1.C(O)(=O)C.C1([SiH3])C=CC=CC=1>C(Cl)Cl.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:1][C:2]1[NH:10][C:9]2[C:8](=[O:14])[NH:7][C:6](=[O:15])[N:5]([CH2:16][CH2:17][CH2:18][CH2:19][F:20])[C:4]=2[N:3]=1
Reactant: C=CCn1c(Cl)nc2c1c(=O)[nH]c(=O)n2CCCCF
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [SiH3]c1ccccc1
Solvent: ClCCl
Solvent: CC(=O)O
Product: O=c1[nH]c(=O)n(CCCCF)c2nc(Cl)[nH]c12
Temperature: 25 °C
Reaction time: 16 h
Yield: 40.7 %

Procedure:
To a suspension of 8-chloro-3-(4-fluorobutyl)-7-(2-propen-1-yl)-3,7-dihydro-1H-purine-2,6-dione (100 mg, 0.33 mmol, 1eq) in anhydrous DCM (2 ml) was added palladium tetrakis (38 mg, 0.033 mmol, 10% bw), followed by acetic acid (115 ul, 121 mg, 2.01 mmol, 6eq) and phenyl silane (410 ul, 360 mg, 3.33 mmol, 10eq). The resulting light yellow solution was stirred at ambient temperature for 16 h to give a dark purple solution. The solvent was removed under a stream of nitrogen and the residue dissolved in a DMSO/methanol solution (3 ml, 2:1) with heating. The gelatinous mixture was allowed to cool to ambient temperature, filtered then purified by mass directed autopreparative HPLC to give the title compound as a white solid (35 mg, 43%). m/z 261.2[MH+] NMR (400 MHz, MeOD), δH 4.45 (2H, dt, J=47 and 6 Hz), 4.03 (2H, t, J=7 Hz), 1.90-1.65 (4H, m).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:11]2[CH:12]=[C:13]([N:17]3[CH:22]=[C:21]([O:23][CH2:24][C:25]4[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=4)[C:20](=[O:33])[CH:19]=[C:18]3[CH2:34][OH:35])[CH:14]=[CH:15][CH:16]=2)=[C:4]2[CH:10]=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.I(C1C=CC=CC=1C(O)=O)(=O)=O>CS(C)=O.S([O-])([O-])(=O)=S.[Na+].[Na+].C([O-])(O)=O.[Na+].O>[Cl:1][C:2]1[C:3]([C:11]2[CH:12]=[C:13]([N:17]3[CH:22]=[C:21]([O:23][CH2:24][C:25]4[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=4)[C:20](=[O:33])[CH:19]=[C:18]3[CH:34]=[O:35])[CH:14]=[CH:15][CH:16]=2)=[C:4]2[CH:10]=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: COc1ccc(COc2cn(-c3cccc(-c4c(Cl)cnc5[nH]ccc45)c3)c(CO)cc2=O)cc1
Agent: O=C(O)c1ccccc1I(=O)=O
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Solvent: O
Solvent: CS(C)=O
Product: COc1ccc(COc2cn(-c3cccc(-c4c(Cl)cnc5[nH]ccc45)c3)c(C=O)cc2=O)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 1.44 g (2.95 mmol) 1-[3-(5-chloro-1H-pyrrolo[2,3-b]pyridin-4-yl)-phenyl]-2-hydroxymethyl-5-(4-methoxy-benzyloxy)-1H-pyridin-4-one in 14.5 mL DMSO was added 1.67 g (5.90 mmol) o-iodoxybenzoic acid (99%). The mixture was stirred for 4 h at room temperature, then slowly diluted with 30 mL of a 1:1:1 mixture of sat. aq. sodium thiosulfate, sat. aq. NaHCO3, and water. The crude product precipitated and was collected by filtration and dried in vacuo. Purification by automated flash chromatography (40 g silica gel cartridge 0-10% MeOH/EtOAc over 30 min afforded 1-[3-(5-chloro-1H-pyrrolo[2,3-b]pyridin-4-yl)-phenyl]-5-(4-methoxy-benzyloxy)-4-oxo-1,4-dihydro-pyridine-2-carbaldehyde. 1H NMR (300 MHz, DMSO-d□): δ 9.56 (s, 1 H); 8.36 (s, 1 H); 7.81-7.59 (m, 6 H); 7.35 (d, J=8.35 Hz, 2 H); 6.93 (d, J=8.32 Hz, 2 H); 6.87 (s, 1 H); 6.32 (d, J=3.42 Hz, 1 H); 5.00 (s, 2 H); 3.74 (s, 3 H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([S:10]([N:13]([CH2:15][C:16]2[O:17][CH:18]=[C:19]([C:21]([OH:23])=O)[N:20]=2)[CH3:14])(=[O:12])=[O:11])=[C:5]([CH3:24])[CH:4]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.Cl.Cl.[CH3:48][O:49][CH:50]1[CH2:55][CH2:54][CH2:53][N:52]([CH2:56][C:57]2[CH:62]=[CH:61][C:60]([CH2:63][NH:64][CH3:65])=[CH:59][CH:58]=2)[CH2:51]1>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH3:24])[C:6]([S:10]([N:13]([CH2:15][C:16]2[O:17][CH:18]=[C:19]([C:21]([N:64]([CH2:63][C:60]3[CH:59]=[CH:58][C:57]([CH2:56][N:52]4[CH2:53][CH2:54][CH2:55][CH:50]([O:49][CH3:48])[CH2:51]4)=[CH:62][CH:61]=3)[CH3:65])=[O:23])[N:20]=2)[CH3:14])(=[O:12])=[O:11])=[C:7]([CH3:9])[CH:8]=1
Reactant: CNCc1ccc(CN2CCCC(OC)C2)cc1
Reactant: COc1cc(C)c(S(=O)(=O)N(C)Cc2nc(C(=O)O)co2)c(C)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: COc1cc(C)c(S(=O)(=O)N(C)Cc2nc(C(=O)N(C)Cc3ccc(CN4CCCC(OC)C4)cc3)co2)c(C)c1

Procedure:
The title compound was prepared according to general procedure BH using 2-({[(4-methoxy-2,6-dimethylphenyl)sulfonyl](methyl)amino}methyl)-1,3-oxazole-4-carboxylic acid (40 mg, 0.11 mmol), EDCI (29 mg, 0.15 mmol), HOBt (22 mg, 0.16 mmol) DIPEA (0.04 mL, 0.21 mmol), 1-{4-[(3-methoxypiperidin-1-yl)methyl]phenyl}-N-methylmethanamine dihydrochloride (38 mg, 0.13 mmol) and DCM (5 mL).
Reaction SMILES: [F-:1].[K+].[CH3:3][N:4]1[C:8](Cl)=[C:7]([CH:10]=[O:11])[C:6]([C:12]([F:15])([F:14])[F:13])=[N:5]1>CN(C=O)C>[F:1][C:8]1[N:4]([CH3:3])[N:5]=[C:6]([C:12]([F:15])([F:14])[F:13])[C:7]=1[CH:10]=[O:11]
Reactant: [F-]
Reactant: Cn1nc(C(F)(F)F)c(C=O)c1Cl
Agent: [K+]
Solvent: CN(C)C=O
Product: Cn1nc(C(F)(F)F)c(C=O)c1F
Temperature: 150 °C
Yield: 102.3 %

Procedure:
A suspension of anhydrous KF (4 g) in anhydrous DMF (20 mL) was stirred under N2 and 1-methyl-3-trifluoromethyl-5-chloropyrazole-4-carboxaldehyde (10.6 g) added. The mixture was heated at 150 ° C. for 6 h. The mixture was poured onto ice (250 g) and was mixed thoroughly. The mixture was extracted with ether (5×50 mL). The ether solution was dried (MgSO4) and concentrated in vacuo leaving an amber liquid (10 g). The liquid was distilled under reduced pressure to give one fraction, 8.0 g yellow liquid b.p. 68-74 ° C. @ 0.4 Torr.
Reaction SMILES: Br[C:2]1[N:6]2[C:7]3[CH:21]=[CH:20][CH:19]=[CH:18][C:8]=3[C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=3)=[N:10][CH2:11][C:5]2=[N:4][N:3]=1.[CH3:22][N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1>>[CH3:22][N:23]1[CH2:28][CH2:27][N:26]([C:2]2[N:6]3[C:7]4[CH:21]=[CH:20][CH:19]=[CH:18][C:8]=4[C:9]([C:12]4[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=4)=[N:10][CH2:11][C:5]3=[N:4][N:3]=2)[CH2:25][CH2:24]1
Reactant: CN1CCNCC1
Reactant: Brc1nnc2n1-c1ccccc1C(c1ccccn1)=NC2
Product: CN1CCN(c2nnc3n2-c2ccccc2C(c2ccccn2)=NC3)CC1

Procedure:
In the manner given in Example 1, 1-bromo-6-(2-pyridyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine is heated with excess 1-methylpiperazine to give 1-(4-methyl-piperazino)-6-(2-pyridyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine.
Reaction SMILES: [CH2:1]([O:8][C:9]([CH:11]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:12][S:13]([C:16]([CH3:21])([CH3:20])[C:17](Cl)=[O:18])(=[O:15])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:29][CH:30]1[O:35][CH:34]([CH3:36])[CH2:33][NH:32][CH2:31]1>N1C=CC=CC=1>[CH3:36][C@H:34]1[CH2:33][N:32]([C:17]([C:16]([S:13]([CH2:12][CH:11]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:10])(=[O:15])=[O:14])([CH3:21])[CH3:20])=[O:18])[CH2:31][C@@H:30]([CH3:29])[O:35]1
Reactant: CC(C)(C(=O)Cl)S(=O)(=O)CC(Cc1ccccc1)C(=O)OCc1ccccc1
Reactant: CC1CNCC(C)O1
Solvent: c1ccncc1
Product: C[C@@H]1CN(C(=O)C(C)(C)S(=O)(=O)CC(Cc2ccccc2)C(=O)OCc2ccccc2)C[C@H](C)O1

Procedure:
In an analogous manner to that described in Example 2, paragraphs (c) and (d), by the reaction of (RS)-2-[[2-[(benzyloxy)carbonyl]-3-phenylpropyl]sulfonyl]-2-methylpropionyl chloride with 2,6-dimethylmorpholine in pyridine followed by chromatographic separation of the resulting diastereomers there was obtained benzyl (RS)-α-[[[1-[(cis-2,6-dimethylmorpholino)carbonyl]-1-methylethyl]sulfonyl]methyl]hydrocinnamate, MS: 501 (M)+, as a colourless oil.
Reaction SMILES: [C:1]1([N:7]2[CH:11]=[C:10]([CH2:12]O)[CH:9]=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(Cl)([Cl:16])=O.C(=O)([O-])O.[Na+]>ClCCl>[Cl:16][CH2:12][C:10]1[CH:9]=[N:8][N:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:11]=1
Reactant: O=S(Cl)Cl
Reactant: OCc1cnn(-c2ccccc2)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: ClCc1cnn(-c2ccccc2)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 106.2 %

Procedure:
(1-Phenyl-1H-pyrazol-4-yl)methanol (6.3 g) synthesized in Reference Example 17 was dissolved in dichloromethane (100 mL) and, after ice-cooling, thionyl chloride (5.59 g) was added thereto, and the mixture was stirred at 0° C. for 2 hr. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with dichloromethane. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent; hexane:ethyl acetate=4:1) to give the title compound (7.4 g) as a white solid.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1.Cl[C:12]1[N:20]=[CH:19][CH:18]=[CH:17][C:13]=1[C:14]([OH:16])=[O:15]>O1CCOCC1>[OH:1][CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][N:8]([C:12]2[N:20]=[CH:19][CH:18]=[CH:17][C:13]=2[C:14]([OH:16])=[O:15])[CH2:7][CH2:6]1
Reactant: O=C(O)c1cccnc1Cl
Reactant: OCCCN1CCNCC1
Solvent: C1COCCO1
Product: O=C(O)c1cccnc1N1CCN(CCCO)CC1

Procedure:
Grams 8.65 of 1-(3-hydroxypropyl)piperazine and 4.7 g of 2-chloronicotinic acid in 100 ml dioxane were refluxed for 6 hours. The reaction mixture was cooled and settled. The residual oil, crystallized from 95° ethanol, gave 2.3 g of 2-[4-(3-hydroxypropyl)piperazin-1-yl]nicotinic acid, melting at 222°-225° C. (with decomposition).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4]([C:9]([F:12])([F:11])[F:10])[CH:3]=1.[CH3:13][N:14](C=O)C>[C-]#N.[C-]#N.[Zn+2].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:8][C:5]1[CH:6]=[CH:7][C:2]([C:13]#[N:14])=[CH:3][C:4]=1[C:9]([F:12])([F:11])[F:10]
Reactant: CN(C)C=O
Reactant: Nc1ccc(I)cc1C(F)(F)F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: N#Cc1ccc(N)c(C(F)(F)F)c1
Reaction time: 12 h
Yield: 99.28 %

Procedure:
4-Iodo-2-trifluoromethylphenylamine (50 mg, 0.17 mmol), Zn(CN)2 (0.88 eq, 0.15 mmol, 18.00 mg), and Pd(PPh3)4 (0.1 eq, 0.02 mmol, 19.64 mg) were added in DMF. Zn(CN)2 (0.88 eq, 0.15 mmol, 18.00 mg) and Pd(PPh3)4 (0.1 eq, 0.02 mmol, 19.64 mg) were added into the reaction mixture. The reaction mixture was stirred for 12 hr. The reaction mixture was purified according to step 1 of Example 8 to give a title product as a yellow solid (31.4 mg, 99.28%).
Reaction SMILES: C[O:2][C:3]1[CH:4]=[N:5][CH:6]=[C:7]([CH:10]=1)[C:8]#[N:9].Cl.N1C=CC=CC=1.O.C(=O)(O)[O-].[Na+]>C(OCC)C>[OH:2][C:3]1[CH:4]=[N:5][CH:6]=[C:7]([CH:10]=1)[C:8]#[N:9]
Reactant: COc1cncc(C#N)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CCOCC
Solvent: O
Product: N#Cc1cncc(O)c1
Temperature: 200 °C
Yield: 94.9 %

Procedure:
A mixture of 1 g of 5-methoxynicotinonitrile (7.46 mmol) and 8.62 g of pyridine hydrochloride is heated at 200° C. for 2 hours. The crude reaction product is diluted in a water fraction several times with diethyl ether. The aqueous phase is basified by adding sodium bicarbonate and then extracted again with diethyl ether. The organic phase is dried and then concentrated to yield 850 mg of 5-hydroxynicotinonitrile (95%) in the form of a beige solid.
Reaction SMILES: C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[NH2:15][CH2:16][C:17]1[C:18]([F:34])=[C:19]([O:24][C:25]2[CH:26]=[C:27]([CH:30]=[C:31]([Cl:33])[CH:32]=2)[C:28]#[N:29])[C:20]([Br:23])=[CH:21][CH:22]=1.[Br:35][C:36]1[N:37]=[CH:38][NH:39][C:40]=1[C:41](O)=[O:42]>CN(C=O)C>[Br:35][C:36]1[N:37]=[CH:38][NH:39][C:40]=1[C:41]([NH:15][CH2:16][C:17]1[CH:22]=[CH:21][C:20]([Br:23])=[C:19]([O:24][C:25]2[CH:26]=[C:27]([C:28]#[N:29])[CH:30]=[C:31]([Cl:33])[CH:32]=2)[C:18]=1[F:34])=[O:42]
Reactant: N#Cc1cc(Cl)cc(Oc2c(Br)ccc(CN)c2F)c1
Reactant: O=C(O)c1[nH]cnc1Br
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: N#Cc1cc(Cl)cc(Oc2c(Br)ccc(CNC(=O)c3[nH]cnc3Br)c2F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 45.8 %

Procedure:
EDC (0.059 g, 0.309 mmol) and HOBT (0.042 g, 0.309 mmol) were added to a solution of 3-{[3-(aminomethyl)-6-bromo-2-fluorophenyl]oxy}-5-chlorobenzonitrile (0.100 g, 0.281 mmol) and 4-bromo-1H-imidazole-5-carboxylic acid (0.054 g, 0.281 mmol) in DMF (2 ml). The mixture was stirred at RT overnight. The reaction mixture was extracted with ethyl acetate and saturated aqueous sodium bicarbonate and the organic layer was dried over sodium sulfate and concentrated. Purification by reverse phase HPLC (acetonitrile:water with 0.1% formic acid) gave 0.068 g (45%) of the title compound as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.34 (br. s., 1H), 7.77 (s, 2H), 7.58 (d, 1H), 7.45 (s, 1H), 7.40 (t, 1H), 7.27 (t, 1H), 4.45 (d, 2H). ES MS: m/z 527 (M+1).