Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:4]2[NH:5][CH:6]=[C:7]([I:9])[N:8]=2)[CH2:3][CH2:2]1.[F:10][C:11]1[CH:16]=[CH:15][C:14](B(O)O)=[CH:13][CH:12]=1>C1COCC1>[CH:1]1([C:4]2[N:5]([C:14]3[CH:15]=[CH:16][C:11]([F:10])=[CH:12][CH:13]=3)[CH:6]=[C:7]([I:9])[N:8]=2)[CH2:3][CH2:2]1
Reactant: Ic1c[nH]c(C2CC2)n1
Reactant: OB(O)c1ccc(F)cc1
Solvent: C1CCOC1
Product: Fc1ccc(-n2cc(I)nc2C2CC2)cc1
Reaction time: 8 h
Yield: 45.6 %

Procedure:
2-Cyclopropyl-4-iodo-1H-imidazole (500 mg, 2.14 mmol) was dissolved in 20 ml THF. 4-Fluorobenzene boronic acid (613 mg, 4.38 mmol) and [Cu(OH)TMEDA]2Cl2 (347 mg, 0.75 mmol) were added. Oxygen was bubbled through the reaction mixture for 60 min and stirring was continued under an oxygen atmosphere at RT overnight. The reaction mixture was filtered through a dicalite speed plus pad and washed with 30 mL ethyl acetate. After drying the crude product was purified by flash chromatography on silica gel (heptane/ethyl acetate 90:10→50:50 gradient) to get the desired compound as a white solid (320 mg, 46%), MS: m/e=329.1 (M+H+). Preparation of the Compounds of Formula I
Reaction SMILES: [C:1]([CH2:3][CH2:4][C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][CH:12]=1)[CH:8]=O)#[N:2].[C:13]([C:16]1[C:17](=[O:25])[N:18]([CH3:24])[C:19]([CH3:23])=[CH:20][C:21]=1[OH:22])(=[O:15])[CH3:14]>C(O)C>[OH:22][C:21]1[CH:20]=[C:19]([CH3:23])[N:18]([CH3:24])[C:17](=[O:25])[C:16]=1[C:13](=[O:15])[CH:14]=[CH:8][C:7]1[CH:10]=[CH:11][CH:12]=[C:5]([CH2:4][CH2:3][C:1]#[N:2])[CH:6]=1
Reactant: N#CCCc1cccc(C=O)c1
Reactant: CC(=O)c1c(O)cc(C)n(C)c1=O
Solvent: CCO
Product: Cc1cc(O)c(C(=O)C=Cc2cccc(CCC#N)c2)c(=O)n1C
Yield: 46.7 %

Procedure:
According to the same manner as that of Example a-1 except that 0.74 g of 3-(2-cyanoethyl)benzaldehyde was used in place of 3-[(methoxycarbonyl)methoxy]benzaldehyde, 0.93 g of 3-acetyl-4-hydroxy-1,6-dimethyl-2(1H)-pyridinone was used in place of 3-acetyl-4-hydroxy-6-methyl-2(1H)-pyridinone, and 8 ml of ethanol was used in place of pyridine, 0.70 g of 4-hydroxy-3-[3-[3-(2-cyanoethyl)phenyl]-1-oxo-2-propenyl]-1,6-dimethyl-2(1H)-pyridinone [Compound No. (106a)] was obtained as a yellow crystal.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[CH:9][S:10][C:3]=12.C([Li])CCC.[C:16]([O:20][C:21](=[O:35])[N:22]([CH2:27][C:28]1[CH:29]=[N:30][C:31](Br)=[CH:32][CH:33]=1)[CH2:23][CH2:24][O:25][CH3:26])([CH3:19])([CH3:18])[CH3:17]>C1COCC1.[Cl-].[Zn+2].[Cl-]>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:31]3[N:30]=[CH:29][C:28]([CH2:27][N:22]([CH2:23][CH2:24][O:25][CH3:26])[C:21](=[O:35])[O:20][C:16]([CH3:17])([CH3:18])[CH3:19])=[CH:33][CH:32]=3)[S:10][C:3]=12
Reactant: COCCN(Cc1ccc(Br)nc1)C(=O)OC(C)(C)C
Reactant: Clc1ccnc2ccsc12
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [Zn+2]
Solvent: C1CCOC1
Product: COCCN(Cc1ccc(-c2cc3nccc(Cl)c3s2)nc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 71.7 %

Procedure:
To a solution of 7-chlorothieno[3,2-b]pyridine (1) (8.84 g, 52.1 mmol) in THF (100 mL) at −78° C. was added n-butyllithium (20.86 mL, 52.1 mmol). After 30 min, zinc chloride (52.1 mL, 52.1 mmol) (1M in ether) was added at −78° C. and the reaction mixture was warmed to r.t. After 1 h, palladium tetrakistriphenylphosphine (1.004 g, 0.869 mmol) and 144 (6 g, 17.38 mmol) in THF (25 mL) were added and the mixture was heated to reflux for 1 h. It was then partitioned between saturated aqueous NaHCO3 solution and EtOAc. The organic layer was collected and the aqueous layer was extracted with EtOAc (3×100 mL). The combined organic layers were washed with brine and evaporated under reduce pressure. The residue was purified by flash column chromatography, eluents Hexane/EtOAc:5/5, 3/7, 0/10, to afford compound 145 (5.41 g, 72% yield). 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.65 (d, J=5.1 Hz, 1H), 8.52 (d, J=1.6 Hz, 1H), 8.39 (s, 1H), 8.27 (d, J=8.0 Hz, 1H), 7.80 (dd, J=8.1, 2.1 Hz, 1H), 7.58 (d, J=5.1 Hz, 1H), 4.48 (s, 2H), 3.43-3.35 (m, 4H), 3.22 (s, 3H), 1.43-1.33 (m, 9H). MS (m/z): 434.2 (M+H).
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH:10]1[CH2:21][NH:20][CH2:19][CH:18]([CH2:22][O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[NH:17][C:16](=O)[CH2:15][S:14][CH2:13][C:12](=O)[NH:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl>C1COCC1>[CH2:24]([O:23][CH2:22][CH:18]1[CH2:19][NH:20][CH2:21][CH:10]([CH2:9][O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[NH:11][CH2:12][CH2:13][S:14][CH2:15][CH2:16][NH:17]1)[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: O=C1CSCC(=O)NC(COCc2ccccc2)CNCC(COCc2ccccc2)N1
Agent: Cl
Solvent: C1CCOC1
Product: c1ccc(COCC2CNCC(COCc3ccccc3)NCCSCCN2)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
5,9-Bis(benzyloxymethyl)-1-thia-4,7,10-triazacyclododecane-3,11-dione (0.352 g, 0.769 mmol) was dissolved in dry THF (10 ml) and cooled to 0° C. A 1M solution of borohydride -THF complex in THF (5 ml) was added under nitrogen and the mixture was stirred for 1 hour at ambient temperature and refluxed for 0.5 hours. To the cooled solution was added 2M hydrochloric acid (3 ml) and the resulting mixture was evaporated to dryness. Water (1 ml) and 25% ammonia solution (1 ml) was added and the mixture was extracted 3 times with 4 ml chloroform. The combined extracts were concentrated in vacuo and gave a yellow oil which showed absence of carbonyl bands in IR. Yield: 0.29 g (88%), FAB MS: 430(M+1).
Reaction SMILES: [OH:1][C:2]1[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][C:3]=1[C:4]([C:6]1[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[CH:8][CH:7]=1)=[O:5].[OH-].[K+].[CH3:24][N:25]([CH3:29])[C:26](Cl)=[S:27]>>[CH3:24][N:25]([CH3:29])[C:26](=[S:27])[O:1][C:2]1[CH:17]=[CH:16][C:15]([C:18]([F:19])([F:20])[F:21])=[CH:14][C:3]=1[C:4](=[O:5])[C:6]1[CH:7]=[CH:8][C:9]([C:10]#[N:11])=[CH:12][CH:13]=1
Reactant: CN(C)C(=S)Cl
Reactant: N#Cc1ccc(C(=O)c2cc(C(F)(F)F)ccc2O)cc1
Agent: [K+]
Agent: [OH-]
Product: CN(C)C(=S)Oc1ccc(C(F)(F)F)cc1C(=O)c1ccc(C#N)cc1
Yield: 78.1 %

Procedure:
Following the procedure described in Preparation IVc and starting from 8 g (0.0274 mol) of 4-(2-hydroxy-5-trifluoromethylbenzoyl)benzonitrile, 1.97 g (0.035 mol) of potassium hydroxide and 4.1 g (0.033 mol) of dimethylthiocarbamoyl chloride, an amount of 8.1 g of the expected product (yield: 77.9%) is obtained after purification by flash chromatography using a hexane/ethyl acetate mixture (5/1 v/v) as the eluent.
Reaction SMILES: [Cl:1][C:2]1[C:7](=[O:8])[N:6]([CH3:9])[CH:5]=[C:4]([NH:10][CH:11]([C:29]2[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=2)[C:12]2[C:13]([C:26]([OH:28])=O)=[N:14][N:15]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=3)[CH:16]=2)[CH:3]=1>C(Cl)Cl.CO>[Cl:1][C:2]1[C:7](=[O:8])[N:6]([CH3:9])[CH:5]=[C:4]([N:10]2[CH:11]([C:29]3[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=3)[C:12]3[C:13](=[N:14][N:15]([CH2:17][C:18]4[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=4)[CH:16]=3)[C:26]2=[O:28])[CH:3]=1
Reactant: COc1ccc(Cn2cc(C(Nc3cc(Cl)c(=O)n(C)c3)c3ccc(Cl)cc3)c(C(=O)O)n2)cc1
Solvent: ClCCl
Solvent: CO
Product: COc1ccc(Cn2cc3c(n2)C(=O)N(c2cc(Cl)c(=O)n(C)c2)C3c2ccc(Cl)cc2)cc1

Procedure:
The title compound was prepared in analogy to the procedure described in Example 1 using 4-((5-chloro-1-methyl-6-oxo-1,6-dihydropyridin-3-ylamino)(4-chlorophenyl)methyl)-1-(4-methoxy-benzyl)-1H-pyrazole-3-carboxylic acid (Step 9.5). tR: 4.58 min (HPLC 1); tR: 1.01 min (LC-MS 2); ESI-MS: 495/497 [M+H]+ (LC-MS 2); Rf=0.55 (CH2Cl2/MeOH 9:1).
Reaction SMILES: [CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13](Br)=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18].[CH2:19]([C:23]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][CH:24]=1)[CH2:20][CH2:21][CH3:22].C(=O)([O-])[O-].[Na+].[Na+].C1COCC1>C(Cl)(Cl)Cl>[CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13]([C:26]4[CH:27]=[CH:28][C:23]([CH2:19][CH2:20][CH2:21][CH3:22])=[CH:24][CH:25]=4)=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18]
Reactant: CCCCc1ccc(B(O)O)cc1
Reactant: CN1C(=O)CC[C@]2(C)c3ccc(Br)cc3CC[C@@H]12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Product: CCCCc1ccc(-c2ccc3c(c2)CC[C@H]2N(C)C(=O)CC[C@]32C)cc1
Yield: 76.6 %

Procedure:
A 15 mL round bottom flask was charged with (+)-(4aR)-(10bR)-4-methyl-8-bromo-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one (200 mg, 0.65 mmol), tetrakis (triphenylphosphine)palladium(0) (23 mg, 0.02 mmol), 4-n-butylphenylboronic acid (139 mg, 0.78 mmol), 0.65 mL of 2M sodium carbonate solution and 2 mL of THF, fitted with a reflux condenser, and the stirred mixture was heated at 80°, under nitrogen, for 24 h. The mixture was cooled, diluted with chloroform (75 mL) and washed with brine (2×25 mL). The combined organic extracts were dried over sodium sulfate, concentrated, and purified by silica gel chromatography (ethyl acetate eluent), to give 180 mg (77%) of the title compound as a white solid. mp 102°-108°. FDMS: m/e=361. α[D]589 =+68.70 (c=1.05, chloroform).
Reaction SMILES: [K].C([O:9][C:10]1[CH:15]=[C:14]([CH2:16][C:17]([CH3:27])([CH3:26])[C:18](=[O:25])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:13]=[CH:12][C:11]=1[N:28]1[S:32](=[O:34])(=[O:33])[NH:31][C:30](=[O:35])[CH2:29]1)C1C=CC=CC=1>CCO.O.[Pd]>[CH3:26][C:17]([CH3:27])([C:18](=[O:25])[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)[CH2:16][C:14]1[CH:13]=[CH:12][C:11]([N:28]2[S:32](=[O:34])(=[O:33])[NH:31][C:30](=[O:35])[CH2:29]2)=[C:10]([OH:9])[CH:15]=1
Reactant: CC(C)(Cc1ccc(N2CC(=O)NS2(=O)=O)c(OCc2ccccc2)c1)C(=O)c1ccccc1
Agent: [Pd]
Agent: [K]
Solvent: CCO
Solvent: O
Product: CC(C)(Cc1ccc(N2CC(=O)NS2(=O)=O)c(O)c1)C(=O)c1ccccc1

Procedure:
A solution of 5-[2-benzyloxy-4-(2,2-dimethyl-3-oxo-3-phenylpropyl)-phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one potassium salt (60 mg) in 4 mL of EtOH/water (1:1) is hydrogenated over Degussa 5% Pd/C (15 mg) at 1 atm for 30 min. The catalyst is filtered and the solvent is removed under reduced pressure and the residue triturated with ether to give the title compound as a solid: (M−1)−=387. HPLC retention time=1.42 min (Method A).
Reaction SMILES: Cl[C:2]1[O:3][C:4]2[C:5](=[C:7]([C:19]#[N:20])[C:8]([CH3:18])=[C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:10]=2[F:11])[N:6]=1.[CH:21]([N:24]([CH:27]([CH3:29])C)CC)([CH3:23])C.N1CCCC1>ClCCl>[F:11][C:10]1[C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:8]([CH3:18])[C:7]([C:19]#[N:20])=[C:5]2[C:4]=1[O:3][C:2]([N:24]1[CH2:21][CH2:23][CH2:29][CH2:27]1)=[N:6]2
Reactant: CCN(C(C)C)C(C)C
Reactant: Cc1c(-c2ccccc2)c(F)c2oc(Cl)nc2c1C#N
Solvent: ClCCl
Solvent: C1CCNC1
Product: Cc1c(-c2ccccc2)c(F)c2oc(N3CCCC3)nc2c1C#N
Yield: 96.8 %

Procedure:
2-Chloro-7-fluoro-5-methyl-6-phenyl-1,3-benzoxazole-4-cabonitrile (I-130) (0.13 g, 0.45 mmol) was dissolved in dichloromethane (10 ml), and diisopropylethylamine (92.0 μl, 0.54 mmol) and pyrrolidine (41.0 μl, 0.50 mmol) were added. This was heated under reflux for 4 hours, and diluted with dichloromethane. After washing with water and drying over anhydrous sodium sulfate, the solvent was evaporated away under reduced pressure, and the resulting residue was purified by silica gel column chromatography (dichloromethane to dichloromethane:methanol=100:1) to obtain a pale yellow oil (0.14 g, 98%).
Reaction SMILES: C[O:2][C:3]([CH:5]1[CH2:10][CH2:9][N:8]([C:11]([N:13]2[C@@:17]([C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=3)([CH3:18])[C@@:16]([C:27]3[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=3)([CH3:26])[N:15]=[C:14]2[C:34]2[CH:35]=[N:36][C:37]([C:43]([CH3:46])([CH3:45])[CH3:44])=[CH:38][C:39]=2[O:40][CH2:41][CH3:42])=[O:12])[CH2:7][CH2:6]1)=[O:4].O.[OH-].[Li+].Cl>O.O1CCCC1>[C:43]([C:37]1[N:36]=[CH:35][C:34]([C:14]2[N:13]([C:11]([N:8]3[CH2:7][CH2:6][CH:5]([C:3]([OH:4])=[O:2])[CH2:10][CH2:9]3)=[O:12])[C@@:17]([C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=3)([CH3:18])[C@@:16]([C:27]3[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=3)([CH3:26])[N:15]=2)=[C:39]([O:40][CH2:41][CH3:42])[CH:38]=1)([CH3:44])([CH3:45])[CH3:46]
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(C(=O)OC)CC1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(C(=O)O)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 98.1 %

Procedure:
A mixture of 1-[(4S,5R)-2-(6-tert-Butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl]-piperidine-4-carboxylic acid methyl ester (575 mg, 0.864 mmole, example 210) and lithium hydroxide hydrate (217 mg, 5.179 mmole) in water (20 mL) and tetrahydrofuran (20 mL) was stirred at room temperature for 4 h before neutralized with 1N hydrochloric acid and extracted with ethyl acetate. The organic extracts were washed with brine and dried over sodium sulfate and concentrated to give the title compound (552.5 mg, 98%). HR-MS (ES, m/z) calculated for C35H41Cl2N4O4 [(M+H)+] 651.2500, observed 651.2498.
Reaction SMILES: [C:1]([CH2:3][CH2:4][C:5]([P:12]([O:17]CC)([O:14]CC)=[O:13])([OH:11])[C:6]([O:8]CC)=[O:7])#[N:2].C[Si](Br)(C)C.O>C(Cl)(Cl)Cl>[C:1]([CH2:3][CH2:4][C:5]([OH:11])([P:12]([OH:14])([OH:17])=[O:13])[C:6]([OH:8])=[O:7])#[N:2]
Reactant: CCOC(=O)C(O)(CCC#N)P(=O)(OCC)OCC
Agent: C[Si](C)(C)Br
Solvent: O
Solvent: ClC(Cl)Cl
Product: N#CCCC(O)(C(=O)O)P(=O)(O)O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of 2.77 g (0.01 mole) of ethyl 4-cyano-2-diethoxyphosphinyl-2-hydroxybutanoate in 30 ml of CHCl3 is treated with 10.7 g (0.07 mole) of trimethylsilyl bromide. The solution is stirred at 50° for about one day. It's cooled to room temperature, and water is added. The mixture is stirred for about 30 minutes. The layers are separated, and the water layer is washed several times with CHCl3. The water layer is evaporated to dryness under vacuum, and the residue is triturated with acetone to convert it to a solid (filter to collect it), which is 4-cyano-2-hydroxy-2-phosphonobutanoic acid.
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8](=[O:38])[NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][C:18]2[N:19]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[O:32][C:33]([F:36])([F:35])[F:34])[N:20]=[CH:21][C:22]=2[CH:23]2[CH2:25][CH2:24]2)=[CH:12][C:11]=1[CH3:37])([CH3:6])([CH3:5])[CH3:4].I[CH3:40]>CN(C=O)C>[C:3]([O:7][C:8](=[O:38])[N:9]([C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][C:18]2[N:19]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[O:32][C:33]([F:36])([F:34])[F:35])[N:20]=[CH:21][C:22]=2[CH:23]2[CH2:25][CH2:24]2)=[CH:12][C:11]=1[CH3:37])[CH3:40])([CH3:6])([CH3:5])[CH3:4]
Reactant: Cc1cc(OCc2c(C3CC3)cnn2-c2ccccc2OC(F)(F)F)ccc1NC(=O)OC(C)(C)C
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc(OCc2c(C3CC3)cnn2-c2ccccc2OC(F)(F)F)ccc1N(C)C(=O)OC(C)(C)C
Reaction time: 0.5 h
Yield: 98.4 %

Procedure:
Sodium hydride (60% in mineral oil, 183 mg, 4.58 mmol) is added to a solution of {4-[4-cyclopropyl-2-(2-trifluoromethoxy-phenyl)-2H-pyrazol-3-ylmethoxy]-2-methyl-phenyl}-carbamic acid tert-butyl ester (1.92 g, 3.81 mmol) and DMF (15 mL) in an ice bath. The mixture is stirred for 30 minutes and iodomethane (0.36 mL, 5.7 mmol) is added. The bath is removed and the mixture is stirred for 1 h and quenched with a mixture if ice and ammonium chloride. The mixture is diluted with ethyl acetate and water. The organic layer is washed with brine and dried over MgSO4 to provide 1.94 g (98%) of the title compound as an oil. LC-ES/MS m/e 518.2 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][OH:9])=[C:4]([CH3:10])[CH:3]=1.[S:11](Cl)([CH3:14])(=[O:13])=[O:12].[NH4+].[Cl-]>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][O:9][S:11]([CH3:14])(=[O:13])=[O:12])=[C:4]([CH3:10])[CH:3]=1
Reactant: CS(=O)(=O)Cl
Reactant: Cc1cc(Br)ccc1CO
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Product: Cc1cc(Br)ccc1COS(C)(=O)=O
Temperature: -15 °C
Reaction time: 1.5 h

Procedure:
To a solution of (4-bromo-2-methyl-phenyl)-methanol (46.65 g, 0.2320 mol) in DCM (500 mL) at −15° C. was added mesyl chloride (20.65 mL, 0.2668 mol) followed by TEA (37.04 mL, 0.2668 mol). The reaction was stirred at −15° C. for 1.5 hour. A saturated solution of NH4Cl was then added at −15° C. and the resulting mixture was extracted with DCM. The organic phase was dried over MgSO4, filtered, and concentrated under reduced pressure to afford methanesulfonic acid 4-bromo-2-methyl-benzyl ester as a white solid in quantitative yield (65 g), which was used directly in step 3 without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:18]=[CH:17][C:5]([CH:6]=[C:7]2[C:12](=[O:13])[O:11][C:10]([CH3:15])([CH3:14])[O:9][C:8]2=[O:16])=[CH:4][CH:3]=1.[H-].[Na+].[I-].[CH3:22][S+](C)(C)=O.C(OCC)(=O)C>CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:6]2[C:7]3([C:8](=[O:16])[O:9][C:10]([CH3:15])([CH3:14])[O:11][C:12]3=[O:13])[CH2:22]2)=[CH:17][CH:18]=1
Reactant: C[S+](C)(C)=O
Reactant: CC1(C)OC(=O)C(=Cc2ccc(Br)cc2)C(=O)O1
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC1(C)OC(=O)C2(CC2c2ccc(Br)cc2)C(=O)O1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 43.3 %

Procedure:
To a cooled solution of 5-(4-bromobenzylidene)-2,2-dimethyl-1,3-dioxane-4,6-dione (1.48 g) in DMF (20 mL) at 0-5° C. was added by dropwise addition a prepared solution of the dimethylsufoxonium-methylide from sodium hydride (60% in oil) (0.209 g), trimethylsulfoxonium iodide (1.152 g) in DMF (20 mL) at room temperature. Upon completion of addition the mixture was stirred at this temperature for a further 20 min. The mixture was then carefully poured onto a stirred mixture of ice/water and ethyl acetate. The crude product was extracted into ethyl acetate, washed well with saturated brine and dried over sodium sulfate. Filtration and evaporation gave the crude product. This sample was then recrystallised from a mixture of ethyl acetate:isohexane (3:1) to give the subtitle compound (0.670 g) as a colourless solid.
Reaction SMILES: [CH:1]1([NH:4][CH:5]2[CH2:10][CH2:9][N:8]([C:11]3[C:16]([F:17])=[CH:15][C:14]([C:18]([F:21])([F:20])[F:19])=[CH:13][N:12]=3)[CH2:7][CH2:6]2)[CH2:3][CH2:2]1.[CH3:22][C:23]1[N:27]([C:28]2[CH:36]=[CH:35][C:31]([C:32](O)=[O:33])=[CH:30][CH:29]=2)[N:26]=[CH:25][N:24]=1>>[CH:1]1([N:4]([CH:5]2[CH2:10][CH2:9][N:8]([C:11]3[C:16]([F:17])=[CH:15][C:14]([C:18]([F:20])([F:19])[F:21])=[CH:13][N:12]=3)[CH2:7][CH2:6]2)[C:32](=[O:33])[C:31]2[CH:30]=[CH:29][C:28]([N:27]3[C:23]([CH3:22])=[N:24][CH:25]=[N:26]3)=[CH:36][CH:35]=2)[CH2:2][CH2:3]1
Reactant: Cc1ncnn1-c1ccc(C(=O)O)cc1
Reactant: Fc1cc(C(F)(F)F)cnc1N1CCC(NC2CC2)CC1
Product: Cc1ncnn1-c1ccc(C(=O)N(C2CC2)C2CCN(c3ncc(C(F)(F)F)cc3F)CC2)cc1

Procedure:
The title compound is prepared from cyclopropyl-(3′-fluoro-5′-trifluoromethyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-amine and 4-(5-methyl-[1,2,4]triazol-1-yl)-benzoic acid following a procedure analogous to that described in Example 90. LC (method 19): tR=4.54 min; Mass spectrum (ESI+): m/z=489 [M+H]+.
Reaction SMILES: C(Cl)(=O)C.[NH:5]1[CH2:10][CH2:9][CH:8]([O:11][CH2:12][CH2:13][CH2:14][NH:15][C:16]([N:18]2[CH2:26][C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH2:19]2)=[O:17])[CH2:7][CH2:6]1.NC1C=C2C(=CC=1)CN(C(N[C:40]1[CH:45]=[CH:44][C:43]([C:46](=[O:51])NCCC)=[CH:42][CH:41]=1)=O)C2>>[C:46]([N:5]1[CH2:6][CH2:7][CH:8]([O:11][CH2:12][CH2:13][CH2:14][NH:15][C:16]([N:18]2[CH2:26][C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH2:19]2)=[O:17])[CH2:9][CH2:10]1)(=[O:51])[C:43]1[CH:44]=[CH:45][CH:40]=[CH:41][CH:42]=1
Reactant: O=C(NCCCOC1CCNCC1)N1Cc2ccccc2C1
Reactant: CCCNC(=O)c1ccc(NC(=O)N2Cc3ccc(N)cc3C2)cc1
Solvent: CC(=O)Cl
Product: O=C(NCCCOC1CCN(C(=O)c2ccccc2)CC1)N1Cc2ccccc2C1

Procedure:
The title compound was prepared as described in Example 278, substituting benzoyl chloride for acetyl chloride and N-(3-(piperidin-4-yloxy)propyl)isoindoline-2-carboxamide for 5-amino-N-(4-(propylcarbamoyl)phenyl)isoindoline-2-carboxamide. 1H NMR (300 MHz, DMSO-d6) δ ppm 7.21-7.50 (m, 9H) 6.27 (t, J=5.43 Hz, 1H) 4.57 (s, 4H) 3.40-3.58 (m, 6H) 3.07-3.21 (m, 2H) 1.74-1.93 (br m, 2H) 1.62-1.75 (m, 2H) 1.44 (br m, 2H); MS (ESI(+)) m/e 408 (M+H)+.
Reaction SMILES: [OH:1][N:2]=[C:3]([C:5]1[C:9]([NH:10][CH2:11][CH2:12][NH:13][S:14]([CH3:17])(=[O:16])=[O:15])=[N:8][O:7][N:6]=1)[NH2:4].[F:18][C:19]([F:28])([F:27])[C:20]1[CH:21]=[C:22]([CH:24]=[CH:25][CH:26]=1)N>>[OH:1][N:2]=[C:3]([C:5]1[C:9]([NH:10][CH2:11][CH2:12][NH:13][S:14]([CH3:17])(=[O:16])=[O:15])=[N:8][O:7][N:6]=1)[NH:4][C:25]1[CH:24]=[CH:22][CH:21]=[C:20]([C:19]([F:28])([F:27])[F:18])[CH:26]=1
Reactant: Nc1cccc(C(F)(F)F)c1
Reactant: CS(=O)(=O)NCCNc1nonc1C(N)=NO
Product: CS(=O)(=O)NCCNc1nonc1C(=NO)Nc1cccc(C(F)(F)F)c1

Procedure:
The title compound was prepared according to the procedure of Example 17, step E, using N′-hydroxy-4-({2-[(methylsulfonyl)amino]ethyl}amino)-1,2,5-oxadiazole-3-carboximidamide and 3-trifluoromethylaniline [Aldrich, product # A41801] as the starting materials. LCMS for C13H16F3N6O4S (M+H)+: m/z=409.1. 1H NMR (500 MHz, DMSO-d6): δ 11.63 (s, 1H), 9.08 (s, 1H), 7.39 (t, J=7.6 Hz, 1H), 7.21 (m, 2H), 7.10 (s, 1H), 6.99 (d, J=8.1 Hz, 1H), 6.28 (t, J=5.4 Hz, 1H), 3.36 (q, J=5.8 Hz, 2H), 3.17 (q, J=5.8 Hz, 2H), 2.91 (s, 3H).
Reaction SMILES: [CH2:1]([NH:8][CH:9]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:10]([O:12]C)=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C1COCC1.[OH-].[Na+]>[CH2:1]([NH:8][CH:9]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:10]([OH:12])=[O:11])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)C(NCc1ccccc1)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)C(NCc1ccccc1)c1ccccc1
Yield: 99.9 %

Procedure:
A solution of methyl 2-(benzylamino)-2-phenylacetate (1.00 g, 3.90 mmol) in THF (90 ml) and 1N NaOH (10 ml) was stirred at room temperature overnight (LC-MS monitoring: complete conversion). The solvent was removed under reduced pressure, and the crude product was partitioned between EtOAc and water. The aqueous phase was acidified with conc. HCl (pH about 3) and then extracted with EtOAc (three times). The organic phase was dried over Na2SO4, filtered and evaporated to dryness to give the title compound as a white solid (940 mg, quantitative yield), which is used in the next step without any further purification.
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[C:11](=[C:12](OS(C(F)(F)F)(=O)=O)[N:13]([CH2:18][CH3:19])[N:14]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[CH3:28][N:29]([CH3:39])[C:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1>>[CH2:18]([N:13]1[C:12]([C:33]2[CH:34]=[CH:35][C:30]([N:29]([CH3:39])[CH3:28])=[CH:31][CH:32]=2)=[C:11]2[C:15]([CH2:16][CH2:17][NH:8][CH2:9][CH2:10]2)=[N:14]1)[CH3:19]
Reactant: CN(C)c1ccc(B(O)O)cc1
Reactant: CCn1nc2c(c1OS(=O)(=O)C(F)(F)F)CCN(C(=O)OC(C)(C)C)CC2
Product: CCn1nc2c(c1-c1ccc(N(C)C)cc1)CCNCC2
Yield: 40.4 %

Procedure:
The title compound (57 mg) was prepared according to Example 263 using 205 mg of 2-ethyl-3-trifluoromethanesulfonyloxy-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 193, Step A) and 115 mg of 4-dimethylaminophenylboronic acid. MS (ESI): exact mass calculated for C17H24N4, 284.20; found, m/z 285.5 [M+H]+. 1H NMR (500 MHz, CD3OD): 7.87-7.85 (m, 2H), 7.65-7.63 (m, 2H), 4.67 (br s, 2H), 4.06 (q, J=9.0 Hz, 2H), 4.00-3.62 (m, 2H), 3.36 (s, 6H), 3.32-3.29 (m, 2H), 3.18-2.81 (m, 2H), 1.31 (t, J=9.0 Hz, 3H).