Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Na].[CH3:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[SH:9].[CH2:10]([O:12][CH:13]([O:16][CH2:17][CH3:18])[CH2:14]Br)[CH3:11]>C(O)C>[CH2:10]([O:12][CH:13]([O:16][CH2:17][CH3:18])[CH2:14][S:9][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[CH3:2])[CH3:11]
Reactant: Cc1ccccc1S
Reactant: CCOC(CBr)OCC
Agent: [Na]
Solvent: CCO
Product: CCOC(CSc1ccccc1C)OCC
Yield: 89 %

Procedure:
In ethanol (50 mL) was dissolved sodium metal (1.6 g, 66 mmol) at 23° C. 2-Methylbenzenethiol (8.1 mL, 68 mmol) was slowly added to this solution, followed by bromoacetaldehyde diethylacetal (9.50 mL, 63 mmol). The reaction mixture was stirred at reflux for 18 h. The solvent was then evaporated in vacuo and the residue was washed with H2O (100 mL) and extracted with ether (100 mL). The organic solution was dried (MgSO4), concentrated in vacuo and purified by distillation to afford the title compound (13.48 g, 82% yield): 1H NMR (400 MHz, CDCl3) δ ppm: 7.33 (1H, d, J=7.9 Hz), 7.16–7.08 (3H, m), 4.65 (1H, t, J=5.6 Hz), 3.66 (2H, q, J=7.0 Hz), 3.55 (2H, q, J=7.0 Hz), 3.09 (2H, d, J=5.6 Hz), 2.38 (3H, s), 1.20 (6H, t, J=7.0 Hz). LCMS (M+H)+ m/z 241 (t=2.65 min.).
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3[N:17]=[CH:18][N:19]=[C:20]([C:21]4[CH:26]=[C:25]([CH3:27])[CH:24]=[CH:23][C:22]=4[O:28][CH2:29][CH:30]4[CH2:32][CH2:31]4)[C:15]=3[NH:14][C:13]=2[CH3:33])=[O:11])[CH2:5][CH2:4]1.[CH3:34][O:35][CH2:36][C:37](Cl)=[O:38]>>[CH:30]1([CH2:29][O:28][C:22]2[CH:23]=[CH:24][C:25]([CH3:27])=[CH:26][C:21]=2[C:20]2[C:15]3[NH:14][C:13]([CH3:33])=[C:12]([C:10]([NH:9][C@H:6]4[CH2:7][CH2:8][C@@H:3]([NH:2][C:37](=[O:38])[CH2:36][O:35][CH3:34])[CH2:4][CH2:5]4)=[O:11])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:31][CH2:32]1
Reactant: COCC(=O)Cl
Reactant: Cc1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)N[C@H]4CC[C@@H](N)CC4)c(C)[nH]c23)c1
Agent: Cl
Product: COCC(=O)N[C@H]1CC[C@@H](NC(=O)c2c(C)[nH]c3c(-c4cc(C)ccc4OCC4CC4)ncnc23)CC1

Procedure:
Starting from N-(cis-4-aminocyclohexyl)-4-[2-(cyclopropylmethoxy)-5-methylphenyl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f30) and commercially available methoxy-acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10](Cl)(=[O:12])=[O:11])([O-:3])=[O:2].C(N(CC)CC)C.[CH:21]1([NH2:26])[CH2:25][CH2:24][CH2:23][CH2:22]1>ClCCl>[CH:21]1([NH:26][S:10]([C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N+:1]([O-:3])=[O:2])(=[O:12])=[O:11])[CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: NC1CCCC1
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1ccccc1S(=O)(=O)NC1CCCC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 80.3 %

Procedure:
To a solution of 2-nitrobenzene-1-sulfonyl chloride (22.1 g, 100 mol) in dichloromethane (500 mL) at 0° C. was added triethylamine (14 g, 138.6 mol) and cyclopentanamine (9 g, 105.9 mmol) in several portions over 10-15 minutes. The reaction mixture was stirred at room temperature for 4 hours, concentrated and purified by silica gel chromatography to afford the product N-cyclopentyl-2-nitrobenzenesulfonamide (23 g, yield 85.2%). 1H NMR (400 MHz, CDCl3) δ ppm 8.16-8.18 (m, 1H), 7.84-7.87 (m, 1H), 7.40-7.78 (m, 2H), 5.25-5.27 (d, 1H, J=7.6 Hz), 3.76-3.81 (m, 1H), 1.79-1.87 (m, 2H), 1.62-1.70 (m, 2H), 1.39-1.58 (m, 4H).
Reaction SMILES: CCN(C(C)C)C(C)C.[CH3:10][O:11][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:21]=1[O:20][C:19](=[O:22])[C:18]([C:23]([OH:25])=O)=[CH:17]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:50][N:51]([CH3:65])[C:52]1[N:57]=[CH:56][C:55]([C:58]2[CH:59]=[C:60]([NH2:64])[CH:61]=[CH:62][CH:63]=2)=[CH:54][CH:53]=1>CN(C=O)C>[CH3:50][N:51]([CH3:65])[C:52]1[N:57]=[CH:56][C:55]([C:58]2[CH:59]=[C:60]([NH:64][C:23]([C:18]3[C:19](=[O:22])[O:20][C:21]4[C:16]([CH:17]=3)=[CH:15][CH:14]=[CH:13][C:12]=4[O:11][CH3:10])=[O:25])[CH:61]=[CH:62][CH:63]=2)=[CH:54][CH:53]=1
Reactant: COc1cccc2cc(C(=O)O)c(=O)oc12
Reactant: CN(C)c1ccc(-c2cccc(N)c2)cn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cccc2cc(C(=O)Nc3cccc(-c4ccc(N(C)C)nc4)c3)c(=O)oc12
Temperature: 25 °C
Yield: 66.7 %

Procedure:
DIEA (0.012 mL, 0.071 mmol) was added to 8-methoxy-3-carboxy-coumarin (0.014 g, 0.065 mmol) and HATU (0.027 g, 0.071 mmol) in 0.5 mL of DMF with constant stirring at room temperature until a clear solution resulted. Subsequently, 3-(6-dimethylamino-pyridin-3-yl)-phenylamine (0.014 g, 0.065 mmol) was added and allowed to react overnight when a solid precipitated out of solution. The resulting precipitate was filtered, dried under suction, and finally dried overnight in vacuo to give 0.018 g of product in 66% yield: LCMS (ESI) m/z 416 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][NH:11][C:10](=[O:14])[CH:9]=2)=[C:4]([O:15][CH3:16])[CH:3]=1.Br[C:18]1[CH:19]=[CH:20][C:21]2[C:22]3[CH2:31][N:30]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:29][CH2:28][C:23]=3[N:24]([CH3:27])[C:25]=2[CH:26]=1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N:11]([C:18]3[CH:19]=[CH:20][C:21]4[C:22]5[CH2:31][N:30]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:29][CH2:28][C:23]=5[N:24]([CH3:27])[C:25]=4[CH:26]=3)[C:10](=[O:14])[CH:9]=2)=[C:4]([O:15][CH3:16])[CH:3]=1
Reactant: Cn1c2c(c3ccc(Br)cc31)CN(C(=O)OC(C)(C)C)CC2
Reactant: COc1cc(F)ccc1-c1cc[nH]c(=O)c1
Product: COc1cc(F)ccc1-c1ccn(-c2ccc3c4c(n(C)c3c2)CCN(C(=O)OC(C)(C)C)C4)c(=O)c1
Yield: 46.8 %

Procedure:
4-(4-Fluoro-2-methoxyphenyl)pyridin-2(1H)-one (100 mg, 0.45 mmol) and tert-butyl 7-bromo-5-methyl-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate (166 mg, 0.454 mmol) were reacted following the procedure of Example 30 (step g) to provide the title compound (106 mg, 46%) as a yellow oil: 1H NMR (300 MHz, CDCl3) δ 7.53 (d, J=8.2 Hz, 1H), 7.41 (d, J=7.1 Hz, 1H), 7.39-7.32 (m, 2H), 7.08 (d, J=8.0 Hz, 1H), 6.80-6.70 (m, 3H), 6.46 (dd, J=7.1, 1.9 Hz, 1H), 4.66 (br s, 2H), 3.87 (s, 3H), 3.86-3.78 (m, 2H), 3.64 (s, 3H), 2.83 (t, J=6.1 Hz, 2H), 1.50 (s, 9H).
Reaction SMILES: [Cl-].[CH3:2][O:3][CH2:4][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CC(C)([O-])C.[K+].[F:30][C:31]1[CH:32]=[C:33]([CH:37]2[CH2:42][CH2:41][C:40](=O)[CH2:39][CH2:38]2)[CH:34]=[CH:35][CH:36]=1.O>C1COCC1.C1(C)C=CC=CC=1>[F:30][C:31]1[CH:32]=[C:33]([CH:37]2[CH2:42][CH2:41][C:40](=[CH:2][O:3][CH3:4])[CH2:39][CH2:38]2)[CH:34]=[CH:35][CH:36]=1
Reactant: O=C1CCC(c2cccc(F)c2)CC1
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Solvent: Cc1ccccc1
Product: COC=C1CCC(c2cccc(F)c2)CC1
Temperature: -30 °C
Reaction time: 0.5 h
Yield: 93.7 %

Procedure:
Well-dried methoxymethyltriphenylphosphonium chloride (112.1 g) and THF (1000 ml) were mixed under a nitrogen atmosphere, and cooled to −30° C. Then, potassium t-butoxide (t-BuOK; 36.7 g) was put in thereto in twice in the temperature range of −30° C. to 20° C. After the mixture had been stirred at −20° C. for 30 minutes, the compound (35) (41.9 g) dissolved in THF (200 ml) was added dropwise thereto in the temperature range of −30° C. to −20° C. After the reaction had been stirred at −10° C. for 30 minutes, it was poured into a mixture of water (500 ml) and toluene (500 ml), and mixed. The mixture was then allowed to stand until it had separated into two phases of organic and aqueous phases, and an extractive operation was carried out. The organic phase obtained was fractionated, washed with water, and then dried over anhydrous magnesium sulfate. The solution obtained was concentrated under reduced pressure, and the residue obtained was purified with a fractional operation by means of column chromatography using toluene as the eluent and silica gel as the stationary phase powder. The eluent obtained was concentrated under reduced pressure, giving 45.0 g of 1-(3-fluorophenyl)-4-methoxymethylenecyclohexane (36). The yield based on the compound (35) was 93.7%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)[C:5]([CH2:7][C:8]#[N:9])=[O:6].[C:13]1([N:19](C2C=CC=CC=2)[CH:20]=N)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)[C:5]([C:7](=[CH:20][NH:19][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:8]#[N:9])=[O:6]
Reactant: N=CN(c1ccccc1)c1ccccc1
Reactant: N#CCC(=O)c1cccc(Cl)c1
Solvent: Cc1ccccc1
Product: N#CC(=CNc1ccccc1)C(=O)c1cccc(Cl)c1
Temperature: 100 °C
Yield: 75.3 %

Procedure:
A solution of 3-chlorobenzoylacetonitrile (476 mg, 2.66 mmol, 1.0 eq) and diphenylformamidine (522 mg, 2.66 mmol, 1.0 eq) in 25 mL of toluene was stirred at room temperature for 2 h then heated to 100° C. overnight. The solution was cooled and diluted with hexanes. The resulting solid was filtered and dried to provide the desired product (566 mg, 75%). HPLC (4 minute 10-95 gradient) tR 2.97 min; MS m/z 283.2 [M+H]+; 1H NMR (CDCl3), δ 8.06 (d, J=13.2 Hz, 1H), 7.85 (m, 2H), 7.46 (m, 4H), 7.27 (m, 4H) ppm.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([O:8][CH2:9][C:10]2[C:11]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)=[N:12][O:13][C:14]=2[CH3:15])=[N:6][CH:7]=1.C([Li])CCC.[O:28]1[CH2:31][C:30](=[O:32])[CH2:29]1.CO>C1COCC1>[F:22][C:19]1[CH:20]=[CH:21][C:16]([C:11]2[C:10]([CH2:9][O:8][C:5]3[N:6]=[CH:7][C:2]([C:30]4([OH:32])[CH2:31][O:28][CH2:29]4)=[CH:3][CH:4]=3)=[C:14]([CH3:15])[O:13][N:12]=2)=[CH:17][CH:18]=1
Reactant: Cc1onc(-c2ccc(F)cc2)c1COc1ccc(Br)cn1
Reactant: O=C1COC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CO
Product: Cc1onc(-c2ccc(F)cc2)c1COc1ccc(C2(O)COC2)cn1
Temperature: 25 °C
Yield: 29.9 %

Procedure:
A solution of 5-bromo-2-[3-(4-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-pyridine (110 mg, 0.3 mmol) in THF (3 mL) was treated at −78° C. with n-butyllithium (1.6 M solution in hexanes, 189 μL, 0.3 mmol) and then with 3-oxetanone (23.0 mg, 0.3 mmol). After 20 minutes methanol was added and the mixture was warmed to room temperature. Concentration and purification by chromatography (silicagel, heptane:ethyl acetate=85:15 to 8:3) to afforded the title product (32 mg, 30%) which was obtained as a colourless oil. MS: m/e=357.1 [M+H]+.
Reaction SMILES: [N:1]([C@@H:4]([CH3:21])[CH2:5][N:6]1[C:20]2[C:13]3[N:14]=[C:15]([C:17]([NH2:19])=[O:18])[O:16][C:12]=3[CH:11]=[CH:10][C:9]=2[CH:8]=[N:7]1)=[N+]=[N-]>CO.[Pd]>[NH2:1][C@@H:4]([CH3:21])[CH2:5][N:6]1[C:20]2[C:13]3[N:14]=[C:15]([C:17]([NH2:19])=[O:18])[O:16][C:12]=3[CH:11]=[CH:10][C:9]=2[CH:8]=[N:7]1
Reactant: C[C@@H](Cn1ncc2ccc3oc(C(N)=O)nc3c21)N=[N+]=[N-]
Agent: [Pd]
Solvent: CO
Product: C[C@H](N)Cn1ncc2ccc3oc(C(N)=O)nc3c21
Temperature: 25 °C

Procedure:
To a solution of the product from Step E (0.18 g, 0.631 mmol) in methanol (10 mL) was added 10% palladium-on-carbon (20 mg). This mixture was maintained under an atmosphere of hydrogen at room temperature for three days. The reaction mixture was filtered and evaporated to a tan solid (0.16 g): mp 60–65° C.; LC/MS m/z 260. Analysis. Calculated for C12H13N5O2.0.5 CH3OH: C, 54.54; H, 5.49; N, 25.44. Found: C, 54.79; H, 5.35; N, 25.29.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]=[C:11]([OH:13])[N:10]([CH3:14])[N:9]=2)=[C:4]([F:15])[CH:3]=1.[OH-].[Na+].Cl[CH:19]([F:21])[F:20]>O1CCOCC1.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]=[C:11]([O:13][CH:19]([F:21])[F:20])[N:10]([CH3:14])[N:9]=2)=[C:4]([F:15])[CH:3]=1
Reactant: FC(F)Cl
Reactant: Cn1nc(-c2ccc(Cl)cc2F)cc1O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: Cn1nc(-c2ccc(Cl)cc2F)cc1OC(F)F
Yield: 82.6 %

Procedure:
57.1 g of 3-(4-chloro-2-fluorophenyl)-5-hydroxy-1-methyl-1H-pyrazole from Example 2.1 were initially charged in 500 ml of dioxane. A solution of 18.8 g of NaOH in 50 ml of H2O was added, the mixture was heated at reflux and 85 g (0.98 mol=3.9 eq.) of gaseous chlorodifluoromethane were introduced. The mixture was poured into 1.5 l of water and extracted twice with 500 ml of MTBE, and the combined organic phases were extracted once with 500 ml of water and once with 500 ml of saturated sodium chloride solution. Drying and concentration of the organic phase gave 57.6 g of 53% pure 3-(4-chloro-2-fluorophenyl)-5-difluoromethoxy-1-methyl-1H-pyrazole as an oil which was purified further by vacuum distillation. This gave the title compound in a purity of 94% in a yield of 43.8%.
Reaction SMILES: Br[CH2:2][C:3]1[NH:8][C:7]([C:9]2[S:10][CH:11]=[CH:12][N:13]=2)=[N:6][CH:5]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=2[C:21]2[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=2)[C:4]=1[C:31]([O:33][CH2:34][CH3:35])=[O:32].[NH:36]1[CH2:41][CH2:40][O:39][CH2:38][C@H:37]1[C:42]([OH:44])=[O:43]>>[CH2:34]([O:33][C:31]([C:4]1[CH:5]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=2[C:21]2[CH:22]=[CH:23][C:24]([C:27]([F:28])([F:29])[F:30])=[CH:25][CH:26]=2)[N:6]=[C:7]([C:9]2[S:10][CH:11]=[CH:12][N:13]=2)[NH:8][C:3]=1[CH2:2][N:36]1[CH2:41][CH2:40][O:39][CH2:38][C@H:37]1[C:42]([OH:44])=[O:43])=[O:32])[CH3:35]
Reactant: CCOC(=O)C1=C(CBr)NC(c2nccs2)=NC1c1ccc(F)cc1-c1ccc(C(F)(F)F)cc1
Reactant: O=C(O)[C@@H]1COCCN1
Product: CCOC(=O)C1=C(CN2CCOC[C@H]2C(=O)O)NC(c2nccs2)=NC1c1ccc(F)cc1-c1ccc(C(F)(F)F)cc1
Yield: 50 %

Procedure:
Ethyl 6-(bromomethyl)-4-(5-fluoro-4′-(trifluoromethyl)-[1,1′-biphenyl]-2-yl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate (3 g, 5.3 mmol) was reacted with (S)-morpholine-3-carboxylic acid (0.69 g, 5.3 mmol) according to the procedure as described in Example 1, Step C to give the title compound as a yellow solid (1.64 g, 50%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [C:1]([C:9]1[C:10]([O:20]C(=O)C)=[C:11]([CH:15]([CH3:19])[C:16]([OH:18])=[O:17])[CH:12]=[CH:13][CH:14]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.OS(O)(=O)=O.[CH3:29]O>>[CH3:29][O:18][C:16](=[O:17])[CH:15]([C:11]1[CH:12]=[CH:13][CH:14]=[C:9]([C:1](=[O:8])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:10]=1[OH:20])[CH3:19]
Reactant: CO
Reactant: CC(=O)Oc1c(C(=O)c2ccccc2)cccc1C(C)C(=O)O
Agent: O=S(=O)(O)O
Product: COC(=O)C(C)c1cccc(C(=O)c2ccccc2)c1O
Reaction time: 8 h
Yield: 70 %

Procedure:
A solution of 2-(3′-benzoyl-2′-acetoxyphenyl)propionic acid (1) (6.2 g) in methanol (35 ml) was added wish concentrated H2SO4 (0.3 ml). The mixture was stirred at room temperature for 15 hours until disappearance (1) and of the reaction intermediates. The solvent was evaporated off under vacuum and the residue was dissolved in ethyl acetate (30 ml) and washed with water. The organic layer was treated with a NaOH solution (100 ml), and the basic phase was acidified with 4N HCl and extracted with ethyl acetate (2×25 ml). The collected organic layers were washed with brine, dried over Na2SO4 and evaporated under vacuum. The crude product (4.3 g) was dissolved in isopropyl ether (5 ml) and the slightly yellow precipitate was filtered. n-Hexane (25 ml) was added to the residue and the mixture was stirred overnight. After filtration, 3.2 g of (2) were obtained (0.11 mol; 70% yield starting from 4) as a whitish solid (melting point 108-111° C.).
Reaction SMILES: C[Si](C)(C)[N-][Si](C)(C)C.[Li+].[CH2:11]([NH:18][C:19]([C:21]1[S:25][CH:24]=[N:23][C:22]=1[CH3:26])=[O:20])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[I:27]I>O1CCCC1>[CH2:11]([NH:18][C:19]([C:21]1[S:25][C:24]([I:27])=[N:23][C:22]=1[CH3:26])=[O:20])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: Cc1ncsc1C(=O)NCc1ccccc1
Reactant: II
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1nc(I)sc1C(=O)NCc1ccccc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 47.1 %

Procedure:
A solution of lithium hexamethyldisilazide (4.63 g, 27.65 mmol) in anhydrous tetrahydrofuran (25 mL) was added dropwise to a solution of N-benzyl-4-methylthiazole-5-carboxamide (2.79 g, 12.02 mmol) in anhydrous tetrahydrofuran (25 mL) at −78° C. under nitrogen atmosphere. The reaction mixture was stirred at −78° C. for 1 hour, then iodine (1.68 g, 13.22 mmol) was added in portions. The mixture was stirred at ambient temperature for 90 minutes, quenched with methanol (2 mL) and water (2 mL). The solvent was removed in vacuo and the residue was diluted with water (30 mL) and extracted with dichloromethane (3×40 mL). The organic layers were combined, dried over anhydrous sodium sulphate, filtered and concentrated in vacuo. The residue was purified by column chromatography (20-35% ethyl acetate in hexanes) to afford the title compound as a white solid (2.03 g, 47%): 1H NMR (300 MHz, CDCl3) δ 7.39-7.30 (m, 5H), 6.02 (br s, 1H), 4.57 (d, J=6.0 Hz, 2H), 2.68 (s, 3H); MS (ES+) m/z 359.1 (M+1).
Reaction SMILES: [C:1](=[O:4])([O-:3])[O-:2].[Cs+].[Cs+].BrC1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[CH:14]=[C:13](O)[CH:12]=[CH:11]2.[CH3:19][N:20](C)C=O>>[N:20]1[CH:17]=[CH:16][CH:15]=[C:14]([CH2:13][CH2:12][C@H:11]2[CH:10]=[CH:9][O:2][C:1](=[O:3])[O:4]2)[CH:19]=1
Reactant: O=C([O-])[O-]
Reactant: CN(C)C=O
Reactant: Oc1ccc2cc(Br)ccc2c1
Agent: [Cs+]
Product: O=C1OC=C[C@H](CCc2cccnc2)O1

Procedure:
Prepared according to the method described in Example 1e) from cesium carbonate (13.7 g), 6bromo-2-naphthol (9.27 g) and a solution of (4S)-4-[2-(3-pyridyl)ethyl]-1,3-dioxin-2-one (7.3 g, Example 18d)) in dry N,N-dimethylformamide (100 ml) to give the title compound as beige crystals after recrystallisation from aqueous ethanol (9.14 g).
Reaction SMILES: [CH2:1]([NH:8][C:9]([C:28]1([C:31](O)=[O:32])[CH2:30][CH2:29]1)([C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][CH2:23][C:24]([F:27])([F:26])[F:25])=[CH:16][CH:15]=1)[C:10]([F:13])([F:12])[F:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)(=O)C(Cl)=O>C(Cl)Cl.CN(C=O)C>[CH2:1]([N:8]1[C:9]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][CH2:23][C:24]([F:26])([F:27])[F:25])=[CH:16][CH:15]=2)([C:10]([F:12])([F:11])[F:13])[C:28]2([CH2:30][CH2:29]2)[C:31]1=[O:32])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)C1(C(NCc2ccccc2)(c2ccc(OCCCC(F)(F)F)cc2)C(F)(F)F)CC1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C1N(Cc2ccccc2)C(c2ccc(OCCCC(F)(F)F)cc2)(C(F)(F)F)C12CC2
Temperature: 25 °C
Reaction time: 16 h
Yield: 77.3 %

Procedure:
To a solution of Intermediate 14E (506 mg, 1.1 mmol) in CH2Cl2 (11 mL) was added oxalyl chloride (0.12 mL, 2.2 mmol) followed by several drops of DMF. The reaction was stirred at rt for 16 h. The solvent was removed in vacuo and the residue was purified by silica gel chromatography (24 g silica gel, eluted with EtOAc in hexanes) to provide Intermediate 14F (389 mg, 72%) as a yellow oil. LCMS Anal. Calc'd for C23H21F6NO2 457.41, found [M+H] 458.2.
Reaction SMILES: O1CCCC1.[CH3:6][S:7]([O:10][C:11]1[CH:16]=[CH:15][C:14]([C:17](=[O:20])[CH2:18][CH3:19])=[CH:13][CH:12]=1)(=[O:9])=[O:8].[Br:21]Br.C(=O)([O-])O.[Na+]>C(OCC)(=O)C.CCCCCC>[CH3:6][S:7]([O:10][C:11]1[CH:16]=[CH:15][C:14]([C:17](=[O:20])[CH:18]([Br:21])[CH3:19])=[CH:13][CH:12]=1)(=[O:9])=[O:8]
Reactant: CCC(=O)c1ccc(OS(C)(=O)=O)cc1
Reactant: BrBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(Br)C(=O)c1ccc(OS(C)(=O)=O)cc1
Reaction time: 1 h

Procedure:
A tetrahydrofuran solution (50 mL) of 15.0 g (100 mmol) of p-hydroxypropiophenone and 12.143 g (1.2 equivalents) of triethylamine was cooled to 5° C. To this solution, 12.60 g (1.1 equivalents) of methanesulfonyl chloride was added dropwise over 30 minutes, followed by 1 hour of stirring. To the resulting solution, 40 mL of water and 70 mL of ethyl acetate were added to conduct extraction. The organic layer was washed with 50 mL of saturated brine, dried over anhydrous magnesium sulfate, and subjected to distillation under a reduced pressure to remove the solvents. A white solid was obtained as a result. This white solid was crystallized from 40 mL of ethyl acetate and 120 mL of hexane to thereby obtain white crystals of p-(methanesulfonyloxy)propiophenone (21.17 g, isolation yield: 93%). To a tetrahydrofuran solution (20 mL) of 4.560 g (20 mmol) of p-(methanesulfonyloxy)propiophenone, a hexane solution (5 mL) of 3.516 g (1.1 equivalent) of bromine was added at 15° C., followed by 1 hour of stirring. To the resulting solution, 30 mL of saturated sodium hydrogen carbonate and 30 mL of ethyl acetate were added to conduct extraction. The organic layer was washed with 20 mL of a saturated sodium hydrogen carbonate solution, dried over anhydrous magnesium sulfate, and subjected to distillation under a reduced pressure to remove the solvent. 1-[4-(Methanesulfonyloxy)phenyl]-2-bromo-1-propanone was obtained as an yellow, oily substance (10.12 g, crude yield: 97%).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH2:11][CH2:12][N:13]([CH3:17])[C:14]([CH3:16])([CH3:15])[C:5]=3[C:4]=2[CH:3]=1.[F:18][C:19]([F:29])([F:28])[C:20]1[CH:25]=[CH:24][C:23]([CH:26]=[CH2:27])=[CH:22][N:21]=1.[OH-].[K+]>CN1C(=O)CCC1>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:27][CH2:26][C:23]3[CH:22]=[N:21][C:20]([C:19]([F:29])([F:18])[F:28])=[CH:25][CH:24]=3)[C:6]3[CH2:11][CH2:12][N:13]([CH3:17])[C:14]([CH3:15])([CH3:16])[C:5]=3[C:4]=2[CH:3]=1
Reactant: CN1CCc2[nH]c3ccc(Cl)cc3c2C1(C)C
Reactant: C=Cc1ccc(C(F)(F)F)nc1
Agent: [K+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Product: CN1CCc2c(c3cc(Cl)ccc3n2CCc2ccc(C(F)(F)F)nc2)C1(C)C

Procedure:
The title compound is prepared from a mixture of 8-chloro-2,3,4,5-tetrahydro-1,1,2-trimethyl-1H-pyrido[4,3-b]indole, 2-(trifluoromethyl)-5-vinylpyridine and KOH (5-7 equiv) in NMP at a temperature ranging between 25 deg C. to 100 deg C. The product obtained is isolated by preparative HPLC.
Reaction SMILES: [OH:1][C:2]1C(OCCC)=CC(C=O)=C[C:3]=1[N+]([O-])=O.[OH:17][C:18]1[CH:19]=[C:20]([CH:23]=[CH:24][C:25]=1[O:26][CH3:27])[CH:21]=[O:22].BrCCO>>[OH:1][CH2:2][CH2:3][O:17][C:18]1[CH:19]=[C:20]([CH:23]=[CH:24][C:25]=1[O:26][CH3:27])[CH:21]=[O:22]
Reactant: COc1ccc(C=O)cc1O
Reactant: CCCOc1cc(C=O)cc([N+](=O)[O-])c1O
Agent: OCCBr
Product: COc1ccc(C=O)cc1OCCO

Procedure:
Followed procedure described in Intermediate 65, step 2 starting from 3-hydroxy-4-methoxybenzaldehyde and 2-bromoethanol, using crude material for next step.
Reaction SMILES: [CH:1]([NH:14][CH:15]([C:18]1[O:22][N:21]=[C:20]([CH3:23])[C:19]=1[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1C(=O)C1C=CC(Cl)=CC=1)[C:16]#[N:17])([C:8]1[CH:13]=[CH:12]C=C[CH:9]=1)C1C=CC=CC=1.C(O)(C(F)(F)F)=O.Cl[CH2:47][CH2:48][Cl:49]>>[Cl:49][C:48]1[CH:12]=[CH:13][C:8]([C:1]2[C:29]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[C:19]3[C:20]([CH3:23])=[N:21][O:22][C:18]=3[CH:15]([C:16]#[N:17])[N:14]=2)=[CH:9][CH:47]=1
Reactant: ClCCCl
Reactant: Cc1noc(C(C#N)NC(c2ccccc2)c2ccccc2)c1-c1ccccc1C(=O)c1ccc(Cl)cc1
Solvent: O=C(O)C(F)(F)F
Product: Cc1noc2c1-c1ccccc1C(c1ccc(Cl)cc1)=NC2C#N
Temperature: 80 °C

Procedure:
To a re-sealable vial was added 2-(benzhydrylamino)-2-(4-(2-(4-chlorobenzoyl)phenyl)-3-methylisoxazol-5-yl)acetonitrile (16 mg, 0.031 mmol), DCE (0.5 mL), and TFA (0.5 mL, 6.49 mmol). The vial was sealed and heated to 80° C. for 3.5 h before cooling to room temperature and concentrating. The crude residue was purified via Biotage (EtOAc/hex) to afford the titled compound (9 mg, 0.027 mmol).