Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:3]2[N:11]([C:12]3[C:17]([F:18])=[CH:16][CH:15]=[CH:14][C:13]=3[F:19])[N:10]=[C:9]([C:20]3[CH:25]=[CH:24][C:23]([CH2:26][C:27]#[N:28])=[CH:22][CH:21]=3)[C:4]=2[C:5](=[O:8])[NH:6][CH:7]=1.C(=O)([O-])[O-:30].[K+].[K+].OO.O>CS(C)=O>[Br:1][C:2]1[C:3]2[N:11]([C:12]3[C:17]([F:18])=[CH:16][CH:15]=[CH:14][C:13]=3[F:19])[N:10]=[C:9]([C:20]3[CH:25]=[CH:24][C:23]([CH2:26][C:27]([NH2:28])=[O:30])=[CH:22][CH:21]=3)[C:4]=2[C:5](=[O:8])[NH:6][CH:7]=1
Reactant: N#CCc1ccc(-c2nn(-c3c(F)cccc3F)c3c(Br)c[nH]c(=O)c23)cc1
Reactant: O=C([O-])[O-]
Agent: OO
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: NC(=O)Cc1ccc(-c2nn(-c3c(F)cccc3F)c3c(Br)c[nH]c(=O)c23)cc1
Reaction time: 8 h
Yield: 70 %

Procedure:
To a solution of (4-(7-bromo-1-(2,6-difluorophenyl)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-3-yl)phenyl)acetonitrile (126.2 mg) obtained in Example 104 and potassium carbonate (47.4 mg) in DMSO (2 mL) was added 30% aqueous hydrogen peroxide (131 μL) at room temperature, and the mixture was stirred overnight. The reaction mixture was poured into water, and the precipitated crystals were collected by filtration, and washed with water. The obtained crystals were purified by HPLC (C18, mobile phase: water/acetonitrile (containing 0.1% TFA)) to give the title compound (92 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:16]=[CH:17][C:18]=1[O:19][CH3:20])[CH:6]=[CH:7][C:8]([N:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1)=[O:9].Br[C:22]1[CH:27]=[CH:26][C:25]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[CH:24][CH:23]=1>>[C:25]1([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:26]=[CH:27][C:22](/[C:6](/[C:5]2[CH:16]=[CH:17][C:18]([O:19][CH3:20])=[C:3]([O:2][CH3:1])[CH:4]=2)=[CH:7]/[C:8]([N:10]2[CH2:11][CH2:12][O:13][CH2:14][CH2:15]2)=[O:9])=[CH:23][CH:24]=1
Reactant: COc1ccc(C=CC(=O)N2CCOCC2)cc1OC
Reactant: Brc1ccc(-c2ccccc2)cc1
Product: COc1ccc(/C(=C\C(=O)N2CCOCC2)c2ccc(-c3ccccc3)cc2)cc1OC

Procedure:
Analogous to Example 21, the title compound was prepared starting from 3,4-dimethoxycinnamic acid morpholide and 4-bromo-biphenyl.
Reaction SMILES: S(Cl)([Cl:3])=O.O[CH2:6][C:7]1[S:22][C:10]2[N:11]([CH2:18][CH:19]([CH3:21])[CH3:20])[C:12](=[O:17])[N:13]([CH3:16])[C:14](=[O:15])[C:9]=2[C:8]=1[C:23]([N:25]1[CH2:29][CH2:28][CH2:27][CH2:26]1)=[O:24]>ClCCl>[Cl:3][CH2:6][C:7]1[S:22][C:10]2[N:11]([CH2:18][CH:19]([CH3:21])[CH3:20])[C:12](=[O:17])[N:13]([CH3:16])[C:14](=[O:15])[C:9]=2[C:8]=1[C:23]([N:25]1[CH2:29][CH2:28][CH2:27][CH2:26]1)=[O:24]
Reactant: O=S(Cl)Cl
Reactant: CC(C)Cn1c(=O)n(C)c(=O)c2c(C(=O)N3CCCC3)c(CO)sc21
Solvent: ClCCl
Product: CC(C)Cn1c(=O)n(C)c(=O)c2c(C(=O)N3CCCC3)c(CCl)sc21
Reaction time: 1 h

Procedure:
Thionyl chloride (0.046 ml) was added to a solution of 1-{[1,2,3,4-tetrahydro-6-(hydroxymethyl)-3-methyl-1-(2-methylpropyl)-2,4-dioxothieno[2,3-d]pyrimidin-5-yl]carbonyl }pyrrolidine (0.1 15 g) in anhydrous dichloromethane (5 ml) under nitrogen. After 1 hour, the mixture was evaporated. The residue was redissolved in ethyl acetate (25 ml), washed with saturated aqueous sodium bicarbonate solution, dried over anhydrous magnesium sulfate, filtered and evaporated to give the subtitle compound (0.11 g) as an oil.
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][CH:7]=[CH:8][C:9]=1[C:10]([NH2:12])=[O:11])(=[O:3])[CH3:2].C1C(=O)N([Cl:20])C(=O)C1>CC(O)=O>[C:1]([NH:4][C:5]1[S:6][C:7]([Cl:20])=[CH:8][C:9]=1[C:10]([NH2:12])=[O:11])(=[O:3])[CH3:2]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CC(=O)Nc1sccc1C(N)=O
Solvent: CC(=O)O
Product: CC(=O)Nc1sc(Cl)cc1C(N)=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
2-acetylamino-thiophene-3-carboxylic acid amide (2.38 g, 12.9 mmol) is dissolved in AcOH (25 mL). NCS (1.9 g, 14.3 mmol) is added and the resulting suspension is stirred at room temperature. After overnight stirring, another 150 mg (1.13 mmol) of NCS is added to the mixture and stirring is continued at 35° C. for 3 h. The mixture is evaporated, and the resulting residue is suspended in water, sonicated, and filtered to give the desired product.
Reaction SMILES: [CH2:1]([C@H:3]1[CH2:7][NH:6][CH2:5][C@H:4]1[NH:8][C:9]1[C:10]2[N:11]([CH:18]=[C:19]([C:21]3[CH:22]=[N:23][C:24]([CH2:27][NH:28][C:29](=[O:33])[CH2:30][O:31][CH3:32])=[CH:25][CH:26]=3)[CH:20]=2)[N:12]=[CH:13][C:14]=1[C:15]([NH2:17])=[O:16])[CH3:2].Cl[C:35]1[S:36][C:37]([C:40]#[N:41])=[CH:38][N:39]=1.C(N(C(C)C)CC)(C)C>CC(N(C)C)=O>[C:40]([C:37]1[S:36][C:35]([N:6]2[CH2:7][C@H:3]([CH2:1][CH3:2])[C@H:4]([NH:8][C:9]3[C:10]4[N:11]([CH:18]=[C:19]([C:21]5[CH:22]=[N:23][C:24]([CH2:27][NH:28][C:29](=[O:33])[CH2:30][O:31][CH3:32])=[CH:25][CH:26]=5)[CH:20]=4)[N:12]=[CH:13][C:14]=3[C:15]([NH2:17])=[O:16])[CH2:5]2)=[N:39][CH:38]=1)#[N:41]
Reactant: N#Cc1cnc(Cl)s1
Reactant: CC[C@H]1CNC[C@H]1Nc1c(C(N)=O)cnn2cc(-c3ccc(CNC(=O)COC)nc3)cc12
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: CC[C@H]1CN(c2ncc(C#N)s2)C[C@H]1Nc1c(C(N)=O)cnn2cc(-c3ccc(CNC(=O)COC)nc3)cc12
Temperature: 100 °C
Reaction time: 0.25 h
Yield: 22 %

Procedure:
A mixture of 4-(((3S,4S)-4-ethylpyrrolidin-3-yl)amino)-6-(6-((2-methoxyacetamido)methyl)pyridin-3-yl)pyrrolo[1,2-b]pyridazine-3-carboxamide, 2hydroiodide from Step 5 of Example 266 (30 mg, 0.042 mmol), 2-chlorothiazole-5-carbonitrile (7.36 mg, 0.051 mmol) and diisopropylethylamine (0.052 mL, 0.297 mmol) in DMA (0.25 mL) was heated to 100° C. for 2 hr. The reaction mixture was purified via preparative LC/MS with the following conditions: Column: Waters XBridge C18, 19×150 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: 5-100% B over 15 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation to afford the title compound (5.3 mg, 0.024 mmol, 22% yield). 1H NMR (500 MHz, METHANOL-d4) δ 8.80 (d, J=2.0 Hz, 1H), 8.14 (s, 1H), 8.02 (dd, J=8.2, 2.2 Hz, 1H), 7.98 (d, J=1.5 Hz, 1H), 7.69 (s, 1H), 7.39 (d, J=7.9 Hz, 1H), 7.14 (d, J=1.5 Hz, 1H), 5.07 (t, J=4.5 Hz, 1H), 4.58 (s, 2H), 4.01 (dd, J=10.9, 4.0 Hz, 1H), 3.97 (s, 2H), 3.83 (d, J=7.9 Hz, 2H), 3.46 (s, 4H), 2.79-2.66 (m, 1H), 1.77 (tq, J=14.6, 7.1 Hz, 2H), 1.04 (t, J=7.4 Hz, 3H). MS (ES+) m/z: 560.1 (M+H); LC retention time: 1.31 min (analytical LCMS Method H).
Reaction SMILES: [C:1]([C:3]1[C:8](=[NH:9])[N:7]2[CH:10]=[CH:11][CH:12]=[C:13]([CH3:14])[C:6]2=[N:5][CH:4]=1)#[N:2].[N-:15]=[N+:16]=[N-:17].[Na+].Cl>CN(P(N(C)C)(N(C)C)=O)C>[CH3:14][C:13]1[C:6]([NH:5][CH:4]=[C:3]([C:8]2[NH:9][N:17]=[N:16][N:15]=2)[C:1]#[N:2])=[N:7][CH:10]=[CH:11][CH:12]=1
Reactant: Cc1cccn2c(=N)c(C#N)cnc12
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: [Na+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: Cc1cccnc1NC=C(C#N)c1nnn[nH]1
Temperature: 70 °C
Reaction time: 3 h
Yield: 79 %

Procedure:
To 100 ml of HMPA were added 10.0 g (54.3 mmoles) of 3-cyano-4-imino-9-methyl-4H-pyrido[1,2-a]-pyrimidine and 3.53 g (54.3 mmoles) of sodium azide, and the reaction was carried out with stirring at 70° C. for 3 hours. After cooling, the reaction mixture was neutralized with diluted hydrochloric acid, and the crystals precipitated were collected by filtration to obtain 9.8 9 of light-brown power of 3-(3-methyl-2-pyridyl)amino-2-(1H-tetrazol-5-yl)-2-propenonitrile. Yield: 79%.
Reaction SMILES: [CH2:1]([N:3]([CH2:7][CH3:8])[CH2:4][CH2:5][NH2:6])[CH3:2].Cl[C:10]1[N:11]=[N+:12]([O-:23])[C:13]2[CH:22]=[C:21]3[C:17]([CH2:18][CH2:19][CH2:20]3)=[CH:16][C:14]=2[N:15]=1>COCCOC>[O-:23][N+:12]1[C:13]2[CH:22]=[C:21]3[C:17](=[CH:16][C:14]=2[N:15]=[C:10]([NH:6][CH2:5][CH2:4][N:3]([CH2:7][CH3:8])[CH2:1][CH3:2])[N:11]=1)[CH2:18][CH2:19][CH2:20]3
Reactant: CCN(CC)CCN
Reactant: [O-][n+]1nc(Cl)nc2cc3c(cc21)CCC3
Solvent: COCCOC
Product: CCN(CC)CCNc1nc2cc3c(cc2[n+]([O-])n1)CCC3
Yield: 96.2 %

Procedure:
N1,N1-Diethyl-1,2-ethanediamine (0.50 mL, 3.5 mmol) was added to a stirred solution of chloride 21 (314 mg, 1.4 mmol) in DME (50 mL) and the solution stirred at reflux temperature for 2 h. The solvent was evaporated and the residue partitioned between DCM (100 mL) and dilute aqueous NH3 solution (50 mL). The organic fraction was dried and the solvent evaporated. The residue was purified by chromatography, eluting with a gradient (0-10%) of MeOH/DCM, to give 1-oxide 26 (406 mg, 95%) as a yellow solid: mp (MeOH/EtOAc) 109-112° C.; 1H NMR δ 7.93 (s, 1H, H-9), 7.31 (s, 1H, H-5), 7.14 (br s, 1H, NH), 3.97-4.03 (m, 2H, CH2N), 3.42-3.46 (m, 2H, CH2N), 3.25-3.33 (m, 4H, 2×CH2N), 2.19-2.29 (m, 4H, H-6, H-8), 2.08-2.14 (m, 2H, H-7), 1.45 (t, J=7.3 Hz, 6H, 2×CH3); 13C NMR δ 158.2, 154.6, 148.4, 143.7, 129.8, 120.7, 114.4, 50.8, 47.7 (2), 36.3, 33.1, 32.3, 25.7, 8.8 (2). Anal. calcd for C16H23N5O: C, 63.8; H, 7.7; N, 23.2. Found: C, 63.9; H, 7.7; N, 23.3%.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[C:7]3[C:8](=[O:30])[C:9]4[CH:21]=[CH:20][C:19](OS(C(F)(F)F)(=O)=O)=[CH:18][C:10]=4[C:11]([CH3:17])([CH3:16])[C:12]=3[NH:13][C:14]=2[N:15]=1)#[N:2].[N:31]1([CH:37]2[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]2)[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1>>[CH3:17][C:11]1([CH3:16])[C:12]2[NH:13][C:14]3[N:15]=[C:3]([C:1]#[N:2])[CH:4]=[CH:5][C:6]=3[C:7]=2[C:8](=[O:30])[C:9]2[CH:21]=[CH:20][C:19]([N:40]3[CH2:41][CH2:42][CH:37]([N:31]4[CH2:36][CH2:35][O:34][CH2:33][CH2:32]4)[CH2:38][CH2:39]3)=[CH:18][C:10]1=2
Reactant: CC1(C)c2cc(OS(=O)(=O)C(F)(F)F)ccc2C(=O)c2c1[nH]c1nc(C#N)ccc21
Reactant: C1CC(N2CCOCC2)CCN1
Product: CC1(C)c2cc(N3CCC(N4CCOCC4)CC3)ccc2C(=O)c2c1[nH]c1nc(C#N)ccc21

Procedure:
According to the method used for synthesizing Compound B2-1, trifluoromethanesulfonic acid 2-cyano-10,10-dimethyl-5-oxo-10,11-dihydro-5H-1,11-diaza-benzo[b]fluoren-8-yl ester was introduced with 4-morpholin-4-yl piperidine to obtain the title compound.
Reaction SMILES: C([O:3][CH:4](OCC)[CH2:5][CH2:6][NH:7][C:8]([C:10]1[S:18][C:17]2[C:12](=[N:13][CH:14]=[CH:15][C:16]=2[O:19][C:20]2[CH:25]=[CH:24][C:23]([NH:26][C:27]([NH:29][C:30]3[CH:35]=[C:34]([CH3:36])[CH:33]=[CH:32][C:31]=3[F:37])=[O:28])=[C:22]([F:38])[CH:21]=2)[CH:11]=1)=[O:9])C.Cl.O.[OH-].[Na+]>O1CCCC1>[F:38][C:22]1[CH:21]=[C:20]([CH:25]=[CH:24][C:23]=1[NH:26][C:27]([NH:29][C:30]1[CH:35]=[C:34]([CH3:36])[CH:33]=[CH:32][C:31]=1[F:37])=[O:28])[O:19][C:16]1[CH:15]=[CH:14][N:13]=[C:12]2[CH:11]=[C:10]([C:8]([NH:7][CH2:6][CH2:5][CH:4]=[O:3])=[O:9])[S:18][C:17]=12
Reactant: CCOC(CCNC(=O)c1cc2nccc(Oc3ccc(NC(=O)Nc4cc(C)ccc4F)c(F)c3)c2s1)OCC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(F)c(NC(=O)Nc2ccc(Oc3ccnc4cc(C(=O)NCCC=O)sc34)cc2F)c1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a stirred solution of N-(3,3-diethoxypropyl)-7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridine-2-carboxamide (1.23 g, 2.11 mmol) in 20 ml of tetrahydrofuran was added 2 ml of 2M HCl (4.0 mmol). The mixture was stirred at room temperature for 5 hours and poured into 100 ml of water. 1M NaOH solution was added slowly until pH=7˜8. The precipitates were filtered, washed with water and dried in vacuo to give 7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]-N-(3-oxopropyl)thieno[3,2-b]pyridine-2-carboxamide as brown solid. Yield: 1.07 g, 100%.
Reaction SMILES: Cl.[NH2:2][OH:3].N1C=CC=CC=1.[Cl:10][C:11]1[CH:27]=[CH:26][C:14]2[CH2:15][CH2:16][N:17]([C:20](=[O:25])[C:21]([F:24])([F:23])[F:22])[CH2:18][CH2:19][C:13]=2[C:12]=1[NH:28][CH2:29][C:30]1[CH:35]=[CH:34][C:33]([C:36](=O)[CH2:37][CH:38]([CH3:40])[CH3:39])=[CH:32][CH:31]=1>C(O)C>[Cl:10][C:11]1[CH:27]=[CH:26][C:14]2[CH2:15][CH2:16][N:17]([C:20](=[O:25])[C:21]([F:23])([F:24])[F:22])[CH2:18][CH2:19][C:13]=2[C:12]=1[NH:28][CH2:29][C:30]1[CH:35]=[CH:34][C:33]([C:36](=[N:2][OH:3])[CH2:37][CH:38]([CH3:40])[CH3:39])=[CH:32][CH:31]=1
Reactant: NO
Reactant: CC(C)CC(=O)c1ccc(CNc2c(Cl)ccc3c2CCN(C(=O)C(F)(F)F)CC3)cc1
Agent: Cl
Solvent: CCO
Solvent: c1ccncc1
Product: CC(C)CC(=NO)c1ccc(CNc2c(Cl)ccc3c2CCN(C(=O)C(F)(F)F)CC3)cc1
Yield: 43.6 %

Procedure:
Add hydroxylamine hydrochloride (6.3 mg, 0.091 mmol) and pyridine (15 uL, 0.182 mmol) to a solution of 7-chloro-6-[4-(3-methyl-butyryl)-benzylamino]-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (42 mg, 0.091 mmol) in ethanol (1 mL). Heat the mixture to reflux for 18 h. Remove the solvent in vacuo and partition the residue between DCM and 0.1N aqueous HCl. Dry the organic phase over Na2SO4, filter and concentrate in vacuo. Purify by chromatography on silica gel eluting with hexane/EtOAc (95:5 to 1:1 gradient over 30 min). Concentrate in vacuo to obtain 7-chloro-6-[4-(1-hydroxyimino-3-methyl-butyl)-benzylamino]-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine as an off-white solid (19.1 mg, 44%). MS (ES+) m/z: 482 (M+H)+.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][C@H:12]([O:14][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16])[CH2:11][C@@H:10]([OH:22])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:23](O)(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.N(C(OCC)=O)=NC(OCC)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1.COC(C)(C)C>[CH2:1]([N:8]1[CH2:13][C@H:12]([O:14][Si:15]([C:18]([CH3:19])([CH3:21])[CH3:20])([CH3:16])[CH3:17])[CH2:11][C@H:10]([O:22][C:23](=[O:30])[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1ccccc1
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1C[C@@H](O)CN(Cc2ccccc2)C1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: COC(C)(C)C
Product: CC(C)(C)[Si](C)(C)O[C@@H]1C[C@H](OC(=O)c2ccccc2)CN(Cc2ccccc2)C1
Yield: 33.6 %

Procedure:
To a solution of 1.8 g (5.6 mmol) (3R,5R)-1-benzyl-5-(tert-butyl-dimethyl-silanyloxy)-piperidin-3-ol in 50 ml THF were consecutively added 0.75 g (6.2 mmol) benzoic acid, 1.1 g (6.2 mmol) diethyl azodicarboxylate and 1.6 g (6.2 mmol) triphenylphosphine at 0° C. After 6 h the reaction mixture was diluted with tert-butyl methyl ether washed with a 2N aqueous solution of sodium carbonate. The aqueous layer was extracted with 3 portions of tert-butyl methyl ether. The combined organic extracts were washed with a 2N aqueous solution of sodium carbonate and brine and dried over sodium sulfate. Flash chromatography gave 0.80 g (3S,5R)-benzoic acid 1-benzyl-5-(tert-butyl-dimethyl-silanyloxy)-piperidin-3-yl ester as a light brown oil. The ester was dissolved in a mixture of 50 ml dioxane and 18 ml 1N aqueous sodium hydroxide solution. The reaction mixture was heated at 70° C. for 5 h. After cooling to room temperature the mixture was extracted with tert-butyl methyl ether. The organic extract was washed with a 2N aqueous solution of sodium carbonate. The combined aqueous layers were extracted with two portions of tert-butyl methyl ether. The combined organic extracts were washed with brine and dried over sodium sulfate. Flash chromatography gave 0.10 g (17%) of the title compound as a light brown oil.
Reaction SMILES: Cl.[S:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=[C:3]1[C:11]1[CH2:12][CH2:13][NH:14][CH2:15][CH:16]=1.[Cl:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22]Br)=[CH:20][CH:19]=1>>[S:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=[C:3]1[C:11]1[CH2:12][CH2:13][N:14]([CH2:22][C:21]2[CH:24]=[CH:25][C:18]([Cl:17])=[CH:19][CH:20]=2)[CH2:15][CH:16]=1
Reactant: Clc1ccc(CBr)cc1
Reactant: C1=C(c2nc3ccccc3s2)CCNC1
Agent: Cl
Product: Clc1ccc(CN2CC=C(c3nc4ccccc4s3)CC2)cc1
Yield: 60.1 %

Procedure:
4-(Benzothiazol-2-yl)-1,2,3,6-tetrahydropyridine hydrochloride (520 mg, 2 mmol) was reacted with 4-chlorobenzyl bromide (507 mg, 2.4 mmol) as exemplified in Example 1. The crude product was recrystallised from dichloromethane and methanol to afford the title compound as a yellow solid (410 mg, 60%); (Found: C, 66.70; H, 4.87; N, 8.16. C19H17ClN2S requires C, 66.95; H, 5.03; N, 8.22%). δH (CDCl3), 2.74 (2H, m, NCH2CH2), 2.83 (2H, m, NCH2 CH2), 3.22 (2H, m, NCH2CH2), 3.63 (2H, s, NCH2Ar), 6.67 (1H, m, NCH2CH), 7.31 (4H, s, ArH), 7.34 (1H, d of t, J 8.1Hz, J 1.2Hz, ArH), 7.44 (1H, d of t, J 7.4Hz, J 1.2Hz, ArH), 7.82 (1H, d, J 7.8Hz, ArH), 7.97 (1H, d, J 8.1Hz, ArH). m/z (ES+) 341 (M+1)+.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:21]=[CH:20][C:6]([CH2:7][O:8][N:9]2C(=O)C3C(=CC=CC=3)C2=O)=[CH:5][CH:4]=1.O.NN>C(O)C>[F:1][C:2]([F:22])([F:23])[C:3]1[CH:21]=[CH:20][C:6]([CH2:7][O:8][NH2:9])=[CH:5][CH:4]=1
Reactant: O=C1c2ccccc2C(=O)N1OCc1ccc(C(F)(F)F)cc1
Agent: NN
Solvent: O
Solvent: CCO
Product: NOCc1ccc(C(F)(F)F)cc1
Reaction time: 16 h
Yield: 68 %

Procedure:
To a stirring solution of 2-((4-(trifluoromethyl)benzyl)oxy)isoindoline-1,3-dione (9 g, 28.0 mmol) in ethanol (90 mL) was added hydrazine hydrate (1.543 g, 30.8 mmol) at RT. Reaction mixture was stirred for 16 h. Reaction mixture was filtered and filtrate was diluted with water and extracted with EtOAC. The organic layer was separated and distilled out to get the titled compound in 68% yield.
Reaction SMILES: [CH2:1](C1C=CC=CC=1O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].[OH:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2([C:52]3[CH:57]=[CH:56][C:55]([OH:58])=[CH:54][CH:53]=3)[C:37]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[C:31]([C:45]3[CH:50]=[CH:49][C:48]([OH:51])=[CH:47][CH:46]=3)([C:38]3[CH:43]=[CH:42][C:41]([OH:44])=[CH:40][CH:39]=3)[C:30]3[C:25]2=[CH:26][CH:27]=[CH:28][CH:29]=3)=[CH:20][CH:19]=1>>[CH2:1]([C:22]1[CH:23]=[C:18]([OH:17])[CH:19]=[CH:20][C:21]=1[C:24]1([C:52]2[CH:53]=[CH:54][C:55]([OH:58])=[CH:56][C:57]=2[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH3:1])[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:30]=2[C:31]([C:38]2[CH:43]=[CH:42][C:41]([OH:44])=[CH:40][C:39]=2[CH2:22][CH2:23][CH2:18][CH2:19][CH2:20][CH2:21][CH2:24][CH2:25][CH3:26])([C:45]2[CH:50]=[CH:49][C:48]([OH:51])=[CH:47][C:46]=2[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:37][CH2:36][CH3:35])[C:32]2[C:37]1=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: Oc1ccc(C2(c3ccc(O)cc3)c3ccccc3C(c3ccc(O)cc3)(c3ccc(O)cc3)c3ccccc32)cc1
Reactant: CCCCCCCCCc1ccccc1O
Product: CCCCCCCCCc1cc(O)ccc1C1(c2ccc(O)cc2CCCCCCCCC)c2ccccc2C(c2ccc(O)cc2CCCCCCCCC)(c2ccc(O)cc2CCCCCCCCC)c2ccccc21

Procedure:
The reaction product from Example 13 and 2-nonylphenol should be substituted for the phenol of Example 15 in this Example and the procedures of Example 12 should be followed in this Example to obtain the product herein.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:12])=[CH:4][C:5]([F:11])=[C:6]([CH:10]=1)[C:7](O)=[O:8].Cl.C(N=C=NCCCN(C)C)C.[CH3:25][N:26]([CH3:31])[S:27]([NH2:30])(=[O:29])=[O:28]>ClCCl.CN(C)C1C=CN=CC=1>[Cl:1][C:2]1[C:3]([F:12])=[CH:4][C:5]([F:11])=[C:6]([CH:10]=1)[C:7]([NH:30][S:27](=[O:29])(=[O:28])[N:26]([CH3:31])[CH3:25])=[O:8]
Reactant: CN(C)S(N)(=O)=O
Reactant: O=C(O)c1cc(Cl)c(F)cc1F
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CN(C)S(=O)(=O)NC(=O)c1cc(Cl)c(F)cc1F
Temperature: 25 °C
Reaction time: 24 h
Yield: 22.2 %

Procedure:
To a mixture of 5-chloro-2,4-difluorobenzoic acid (3.48 g, 18.1 mmol) in anhydrous dichloromethane (100 mL) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (5.20 g, 27.1 mmol), N,N-dimethylpyridin-4-amine (5.04 g, 41.3 mmol), and N,N-dimethylsulfamide (3.37 g, 27.1 mmol) at room temperature. The resulting mixture was stirred at room temperature for 24 h. The mixture was then cooled to 0° C. and quenched with hydrochloride acid (1N, 100 mL) followed by extraction with dichloromethane (2×200 mL). The organic layer was washed with ammonium chloride solution (3×30 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated in vacuo and the crude product was crystallized from ethyl acetate and hexanes to afford the title compound as a white solid (1.20 g, 22%): 1H NMR (300 MHz, DMSO-d6) δ 12.05 (s, 1H), 7.98-7.93 (m, 1H), 7.74-7.68 (m, 1H), 2.89 (s, 6H); MS (ES−) m/z 297.1, 299.1 (M−1).
Reaction SMILES: [N:1]1[N:2]=[C:3]([C:10]2[CH:19]=[CH:18][C:17]3[C:12](=[C:13]([O:20][CH:21]4[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]4)[CH:14]=[CH:15][CH:16]=3)[N:11]=2)[N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12.CCN(C(C)C)C(C)C.[Si]([N:40]=[C:41]=[O:42])(C)(C)C>C(Cl)Cl.CN(C1C=CN=CC=1)C>[N:1]1[N:2]=[C:3]([C:10]2[CH:19]=[CH:18][C:17]3[C:12](=[C:13]([O:20][CH:21]4[CH2:26][CH2:25][N:24]([C:41]([NH2:40])=[O:42])[CH2:23][CH2:22]4)[CH:14]=[CH:15][CH:16]=3)[N:11]=2)[N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12
Reactant: c1cc(OC2CCNCC2)c2nc(-c3nnc4ccccn34)ccc2c1
Reactant: C[Si](C)(C)N=C=O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: NC(=O)N1CCC(Oc2cccc3ccc(-c4nnc5ccccn45)nc23)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 63.9 %

Procedure:
To a solution of 2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)-8-(piperidin-4-yloxy)quinoline (prepared as described in Example 9, 46 mg, 0.133 mmol) in CH2Cl2 (5 mL) were added DIEA (116 μL, 0.67 mmol), DMAP (2 mg, 0.01 mmol), and TMS-isocyanate (104 μL, 0.67 mmol). The reaction mixture was stirred at ambient temperature for 16 hours then partitioned between saturated NaHCO3 and CH2Cl2. The aqueous layer was extracted with CH2Cl2 and the combined organic phases were washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by flash column chromatography with gradient elution (CH2Cl2 to 1% MeOH/CH2Cl2 to 3% MeOH/CH2Cl2) to afford desired product (33 mg, 64%) as a colorless glass. MS ESI (+) m/z 411.2 (M+Na+) detected.
Reaction SMILES: B#B.[O:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[CH:5]=[C:4]1[C:12](O)=[O:13]>O1CCCC1>[O:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[CH:5]=[C:4]1[CH2:12][OH:13]
Reactant: O=C(O)c1cc2ccccc2o1
Agent: B#B
Solvent: C1CCOC1
Product: OCc1cc2ccccc2o1
Reaction time: 0.5 h
Yield: 78.5 %

Procedure:
1 Molar diborane in tetrahydrofuran (61.6 mL, 61.6 mmol) was added dropwise over 10 minutes to a stirred solution of benzofuran-2-carboxylic acid (5.00 g, 30.8 mmol) in tetrahydrofuran (50 mL) at 0° C. Stirring was continued at 0° C. for 30 minutes, then at room temperature for 18 hours. The reaction mixture was quenched carefully by slow addition of 1:1 tetrahydrofuran/water, and extracted with ether. The organic extracts were dried (MgSO4) and concentrated to afford 3.58 g (78%) of product as a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[NH:6][N:7]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:9]=1)=[O:4].Br[CH2:17][CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH3:1][O:2][C:3]([C:5]1[N:6]([CH2:17][CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[N:7]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:9]=1)=[O:4]
Reactant: COC(=O)c1cc(-c2ccccc2)n[nH]1
Reactant: CCOC(=O)CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)CCCn1nc(-c2ccccc2)cc1C(=O)OC
Temperature: 60 °C

Procedure:
5-Phenyl-2H-pyrazole-3-carboxylic acid methyl ester (9.10 g, 45.0 mmol) is taken up in 100 mL acetonitrile and heated to 60° C. Ethyl 4-bromobutanoate (8.78 g, 45.0 mmol) and potassium carbonate (8.09 g, 58.5 mmol) are added and the reaction mixture is heated to 85° C. and stirred under reflux for 5 h. The reaction mixture is filtered and the filtrate is concentrated under reduced pressure. The residue is taken up in water and extracted with ethyl acetate. The combined organic phases are dried over Na2SO4 and concentrated under reduced pressure. The residue is purified by flash column chromatography (silica gel, 8-40% ethyl acetate in heptane). Yield: 10.3 g. Rf (silica gel, 2% methanol in DCM)=0.41.