Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][C:12]2[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=2[NH2:19])(=[O:10])=[O:9])=[CH:4][CH:3]=1>N([O-])=O.[Na+].O.Cl>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][C:12]2[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=2[N:19]2[C:17]([CH3:16])=[CH:12][C:13]([CH3:14])=[N:19]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)Oc2cc(C)ccc2N)cc1
Agent: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: Cc1ccc(S(=O)(=O)Oc2cc(C)ccc2-n2nc(C)cc2C)cc1
Reaction time: 0.5 h
Yield: 68.6 %

Procedure:
To 453 mg of 2-amino-5-methylphenyl 4-methylbenzene sulfonate was added 1.6 ml of 5N-hydrochloric acid, and a solution in which 146 mg of sodium nitrite was dissolved in 1 ml of water was added dropwise at 0° C., and stirred for 30 minutes. Then, a solution in which 736 mg of stannous chloride was dissolved in 0.8 ml of 5N-hydrochloric acid was added dropwise at 0° C. and stirred for 1 hour. The solvent was distilled off under reduced pressure, 3.2 ml of ethanol and 167 μl of acetyl acetone were added and heated at reflux for 2 hours. To the reaction mixture was added 50 ml of water, neutralized with a saturated sodium bicarbonate solution, and extracted with 80 ml of ethyl acetate. After the organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and purified using silica gel column chromatography (hexane:ethyl acetate=2:1) to yield 199.6 mg of the title compound.
Reaction SMILES: [Br:1][C:2]1[S:6][CH:5]=[C:4]([C:7]([OH:9])=O)[CH:3]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=N[C:29]2[CH:30]=[CH:31][CH:32]=[N:33][C:28]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.N1CCCCC1>CN(C=O)C>[Br:1][C:2]1[S:6][CH:5]=[C:4]([C:7]([N:33]2[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32]2)=[O:9])[CH:3]=1
Reactant: O=C(O)c1csc(Br)c1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCNCC1
Solvent: CN(C)C=O
Product: O=C(c1csc(Br)c1)N1CCCCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 43.6 %

Procedure:
5-Bromo-thiophene-3-carboxylic acid (150 mg, 0.72 mmol) was dissolved in DMF (3 mL). DIPEA (2.16 mmol), HATU (0.72 mmol) and piperidine (0.72 mmol) were added and the reaction mixture stirred at room temperature for 1 hour. The mixture was partitioned between ethyl acetate and water and the organic solution separated, washed with 1 N hydrochloric acid, dried over magnesium sulfate, filtered and the solvent evaporated. The residue was purified by flash chromatography on silica, eluting with 0%-50% ethyl acetate in cyclohexane. The fractions containing the desired product were concentrated under vacuum to give the title compound (86 mg). LCMS m/z 273.97 [M+H]+ R.T.=3.19 min (Analytical Method 5).
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[C:4]([NH2:18])=[N:5][CH:6]=[C:7]([C:9]2[S:13][C:12]3=[N:14][CH:15]=[C:16](I)[N:11]3[N:10]=2)[CH:8]=1.[CH3:21][S:22]([C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1)(=[O:24])=[O:23].C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:21][S:22]([C:25]1[CH:30]=[CH:29][C:28]([C:16]2[N:11]3[C:12]([S:13][C:9]([C:7]4[CH:8]=[C:3]([C:2]([F:20])([F:19])[F:1])[C:4]([NH2:18])=[N:5][CH:6]=4)=[N:10]3)=[N:14][CH:15]=2)=[CH:27][CH:26]=1)(=[O:24])=[O:23]
Reactant: Nc1ncc(-c2nn3c(I)cnc3s2)cc1C(F)(F)F
Reactant: CS(=O)(=O)c1ccc(B(O)O)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CS(=O)(=O)c1ccc(-c2cnc3sc(-c4cnc(N)c(C(F)(F)F)c4)nn23)cc1
Temperature: 25 °C
Yield: 57.1 %

Procedure:
3-(trifluoromethyl)-5-(5-iodoimidazo[2,1-b][1,3,4]thiadiazol-2-yl)pyridin-2-amine (0.100 g, 0.243 mmol, 1 eq) was dissolved in dioxane (1.5 mL), then 4-(methylsulfonyl)phenylboronic acid (0.078 g, 0.389 mmol, 1.6 eq) was added followed by 2M aq. Na2CO3 (0.5 mL, 4 eq). The suspension was degassed (N2, 15 min) and equipped with an argon balloon. Pd(Ph3P)2Cl2 (0.043 g, 0.061 mmol, 0.25 eq) was quickly added, and the reaction flask was placed in a pre-heated bath (115° C.). After stirring at reflux temperature for 3 h the mixture was cooled to RT and concentrated. The residue was taken up in water, and the solid obtained was filtered off, washed with Et2O and dried. The crude product was suspended in CH3CN at 50° C., filtered off and dried in vacuo to afford the desired product (0.061 g, 57%). HPLC-MS (10-95% B in 4 min at 0.5 mL+2 min 100% B, flow 0.8 mL/min, 50° C.): tR=4.04 min, [M+H]+ m/z 440.0; 1H-NMR (DMSO-d6+TFA): δ=8.88 (1H, s), 8.36 (2H, d, J=8.4 Hz), 8.28 (1H, s), 8.17 (1H, s), 8.06 (2H, d, J=8.4 Hz), 3.24 (3H, s) ppm.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][CH:5]=[C:6]2[CH:10]=[C:9]([C:11](OCC)=[O:12])[NH:8][C:7]=12.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[Cl:1][C:2]1[N:3]=[CH:4][CH:5]=[C:6]2[CH:10]=[C:9]([CH2:11][OH:12])[NH:8][C:7]=12
Reactant: CCOC(=O)c1cc2ccnc(Cl)c2[nH]1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCc1cc2ccnc(Cl)c2[nH]1
Temperature: 0 °C
Yield: 84.3 %

Procedure:
To a solution of ethyl 7-chloro-1H-pyrrolo[2,3-c]pyridine-2-carboxylate (preparation described in Reference Example 1) (230 mg, 1.02 mmol) in tetrahydrofuran (4 mL) at 0° C. under an atmosphere of nitrogen was added portionwise lithium aluminum hydride (94 mg, 2.0 mmol). The reaction mixture was maintained at 0° C. for 4 h then quenched by adding water (100 μL), 15% aqueous sodium hydroxide (100 μL), and water (250 μL) successively. The mixture was filtered through a pad of diatomaceous earth, washing well with ethyl acetate. Solvent evaporation provided 184 mg of crude yellow solid. Purification by column chromatography (silica gel, 60:40 hexanes/ethyl acetate) afforded (7-chloro-1H-pyrrolo[2,3-c]pyridin-2-yl)methanol (157 mg, 0.860 mmol, 84%) as an off-white powder: Rf 0.30 (silica gel, 70:30 hexanes/ethyl acetate); mp 185-187° C.; 1H NMR (300 MHz, CD3OD) δ4.94 (2H, s), 6.56 (1H, s), 7.49 (1H, d, J=5.5 Hz), 7.84 (1H, d, J=5.5 Hz); ESI MS m/z 183 [C8H7ClN2O+H]+; HPLC (H2O/CH3CN 100:0 to 0:100 over 20 min, hold for 10 min, 0.05% TFA added to solvents) 95.4% (AUC), tR=11.1 min.
Reaction SMILES: [ClH:1].[NH2:2][CH2:3][CH:4]1[CH2:13][CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[O:5]1.C[O-].[Na+].[F:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH:25]=[C:26]([CH:30]=O)[CH:27]=[N:28][CH:29]=2)=[CH:20][CH:19]=1.[BH4-].[Na+].Cl>CO.O>[ClH:1].[F:17][C:18]1[CH:19]=[CH:20][C:21]([C:24]2[CH:25]=[C:26]([CH2:30][NH:2][CH2:3][CH:4]3[CH2:13][CH2:12][C:11]4[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=4)[O:5]3)[CH:27]=[N:28][CH:29]=2)=[CH:22][CH:23]=1
Reactant: NCC1CCc2ccccc2O1
Reactant: O=Cc1cncc(-c2ccc(F)cc2)c1
Agent: C[O-]
Agent: Cl
Agent: [BH4-]
Solvent: CO
Solvent: O
Product: Fc1ccc(-c2cncc(CNCC3CCc4ccccc4O3)c2)cc1
Temperature: 0 °C
Reaction time: 15 h
Yield: 72.2 %

Procedure:
20.27 g of 2-aminomethylchroman hydrochloride are introduced into 130 g of methanol, and 20.4 g of a 30% sodium methoxide solution in methanol are subsequently added. 20.43 g of 5-(4-fluorophenyl)pyridine-3-carbaldehyde are added to the white suspension at 35° C., and the mixture is stirred for 1.5 hours before 4.20 g of sodium borohydride are added in portions. After 15 hours, 56.4 ml of water are added, and the pH of the mixture is adjusted to pH 2 using 37% hydrochloric acid. After the suspension has been cooled to 0° C., the crystals are filtered off, washed with methanol and dried under reduced pressure, giving 28.2 g of 2-[5-(4-fluorophenyl)-3-pyridylmethylaminomethyl]chroman hydrochloride (64% yield).
Reaction SMILES: [Br:1][C:2]1[S:10][C:9]2[C:8](=[O:11])[N:7]([CH:12]3[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]3)[C:6](=[O:25])[NH:5][C:4]=2[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:33][C:34]1[O:38][N:37]=[C:36]([CH2:39][CH3:40])[N:35]=1>CN(C=O)C>[Br:1][C:2]1[S:10][C:9]2[C:8](=[O:11])[N:7]([CH:12]3[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:22])([CH3:24])[CH3:23])=[O:19])[CH2:14][CH2:13]3)[C:6](=[O:25])[N:5]([CH2:33][C:34]3[O:38][N:37]=[C:36]([CH2:39][CH3:40])[N:35]=3)[C:4]=2[CH:3]=1
Reactant: CCc1noc(CCl)n1
Reactant: CC(C)(C)OC(=O)N1CCC(n2c(=O)[nH]c3cc(Br)sc3c2=O)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCc1noc(Cn2c(=O)n(C3CCN(C(=O)OC(C)(C)C)CC3)c(=O)c3sc(Br)cc32)n1
Temperature: 100 °C
Reaction time: 2 h

Procedure:
Tert-butyl 4-(6-bromo-2,4-dioxo-1,4-dihydrothieno[3,2-d]pyrimidin-3(2H)-yl)piperidine-1-carboxylate (5.00 g, compound B53) and potassium carbonate (1.60 g) are suspended in dry DMF (50 ml) and 5-(chloromethyl)-3-ethyl-1,2,4-oxadiazole (1.70 g, compound D7) is added. The reaction mixture is stirred at 100° C. for 2 h and then poured into ice-cold water (250 ml). The resulting precipitate is filtered off and dried in vacuo to afford the title compound as a solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]([OH:18])=[O:17])=[CH:11][C:10]=1[O:19][CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:21]([Li])CCC.CI>C1COCC1>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]([CH3:21])[C:16]([OH:18])=[O:17])=[CH:11][C:10]=1[O:19][CH3:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1cc(CC(=O)O)ccc1OCc1ccccc1
Reactant: [Li]CCCC
Solvent: C1CCOC1
Solvent: CI
Product: COc1cc(C(C)C(=O)O)ccc1OCc1ccccc1
Temperature: -10 °C
Reaction time: 1 h
Yield: 89 %

Procedure:
Specifically, a solution of 2-(4-benzyloxy-3-methoxyphenyl) acetic acid 15.0 g, 55.1 mmoles) in dry THF (350 mL) was cooled to -78° C. under argon and treated dropwise with n-butyllithium (42 mL, 2.6M in hexanes). The yellow suspension was then allowed to warm to -10° C. and stirred for 60 minutes. A solution of methyl iodide (3.9 mL, 62.6 mmoles) in THF (15 mL total solution) was then added dropwise via syringe over 30 min resulting in a now homogeneous and clear solution. After 2 hours the THF was rotary evaporated and the residue was dissolved in ethyl acetate (500 mL), extracted with 10% phosphoric acid (3×100 mL), extracted with brine (1×100 mL) and dried over magnesium sulfate. Rotary evaporation afforded a yellow oil which solidified on standing. The solid was triturated with n-pentane and filtered to give 2-(4-benzyloxy-3-methoxyphenyl)propionic acid (14.0 g, 89%) as a yellow powder.
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[C:11]([CH3:13])[N:10]=[C:9]1[CH:14]1[C:23](=O)[C:22]2[C:21]([C:25]([O:27]C)=O)=[CH:20][CH:19]=[CH:18][C:17]=2[NH:16][CH:15]1[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[NH2:36][NH2:37]>>[CH2:1]([N:8]1[CH:12]=[C:11]([CH3:13])[N:10]=[C:9]1[CH:14]1[C:23]2=[N:36][NH:37][C:25](=[O:27])[C:21]3[CH:20]=[CH:19][CH:18]=[C:17]([C:22]=32)[NH:16][CH:15]1[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NN
Reactant: COC(=O)c1cccc2c1C(=O)C(c1nc(C)cn1Cc1ccccc1)C(c1ccccc1)N2
Solvent: O
Product: Cc1cn(Cc2ccccc2)c(C2c3n[nH]c(=O)c4cccc(c34)NC2c2ccccc2)n1
Temperature: 25 °C
Reaction time: 5 h
Yield: 16 %

Procedure:
A mixture of methyl 3-(1-benzyl-4-methyl-1H-imidazol-2-yl)-4-oxo-2-phenyl-1,2,3,4-tetrahydroquinoline-5-carboxylate (250 mg, 0.57 mmol) and hydrazine monohydrate (3 mL) was stirred room temperature for 5 h. The resulting mixture was evaporated under reduced pressure to 15 ml and then filtered; the filtrate was concentrated to give 9-(1-benzyl-4-methyl-1H-imidazol-2-yl)-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one as a white solid (40 mg, yield 16%). LC-MS (ESI) m/z: 434 (M+1)+.
Reaction SMILES: Cl[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:7][CH:6]=1)=O.[NH2:17][C:18]1[S:19][CH:20]=[CH:21][N:22]=1>C(O)C>[S:19]1[CH:20]=[CH:21][N:22]2[CH:2]=[C:3]([C:5]3[CH:10]=[CH:9][C:8]([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:7][CH:6]=3)[N:17]=[C:18]12
Reactant: CCOC(=O)Cc1ccc(C(=O)CCl)cc1
Reactant: Nc1nccs1
Solvent: CCO
Product: CCOC(=O)Cc1ccc(-c2cn3ccsc3n2)cc1
Yield: 31 %

Procedure:
A mixture of 38 g of ethyl 4-(chloroacetyl)phenylacetate, 60 ml of ethanol and 32 g of 2-aminothiazole is heated under reflux for 2 hours. The ethanol is distilled off under reduced pressure, and water is added to the residue. The mixture is extracted with benzene, and the extract is washed with water, dried and concentrated. To the residual reddish brown oil are added benzene and isopropyl ether, and the crystalline precipitate is filtered off and recrystallized from ethanol to give 14 g of ethyl 4-(imidazo[2,1-b]-thiazol-6-yl)phenylacetate as colorless crystals melting at 117°-119°C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([NH:17][C@H:18]([C:20]([OH:22])=O)[CH3:19])=[O:16])[CH3:14])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1.[NH:23]1[CH2:27][CH2:26][CH2:25][CH2:24]1>C(Cl)(Cl)Cl.CO>[F:8][C:6]1[CH:5]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([NH:17][C@H:18]([C:20]([N:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)=[O:22])[CH3:19])=[O:16])[CH3:14])=[O:11])[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: C[C@H](NC(=O)[C@H](C)NC(=O)Cc1cc(F)cc(F)c1)C(=O)O
Reactant: C1CCNC1
Solvent: ClC(Cl)Cl
Solvent: CO
Product: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)N[C@@H](C)C(=O)N1CCCC1

Procedure:
Following General Procedure C and using N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alanine (from Example D7 above) and pyrrolidine (Aldrich), the title compound was prepared as a solid. The reaction was monitored by tlc (Rf=0.15 in 95:5 CHCl3/MeOH) and the product was purified by silica gel chromatography using CHCl3/MeOH as the eluent.
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][CH:5]([C:10]1[S:11][C:12]([C:15]2[CH:20]=[CH:19][N:18]=[C:17]([S:21][CH3:22])[N:16]=2)=[CH:13][CH:14]=1)[CH2:6][N+:7]([O-])=O>C(O)C.[Ni]>[CH3:22][S:21][C:17]1[N:16]=[C:15]([C:12]2[S:11][C:10]([CH:5]3[CH2:6][NH:7][C:3](=[O:2])[CH2:4]3)=[CH:14][CH:13]=2)[CH:20]=[CH:19][N:18]=1
Reactant: COC(=O)CC(C[N+](=O)[O-])c1ccc(-c2ccnc(SC)n2)s1
Agent: [Ni]
Solvent: CCO
Product: CSc1nccc(-c2ccc(C3CNC(=O)C3)s2)n1

Procedure:
The nitro derivative from Step B (100 mg, 0.283 mmol) was dissolved in 10 ml of ethanol and hydrogenated with Raney-nickel for 18 hours. The catalyst was then filtered off and the solution was heated to reflux for 3 hours. After evaporation, the crude product was purified by preparative HPLC. Yield: 19 mg (23%).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15](=[O:47])[C:16]2[CH:21]=[CH:20][C:19]([NH:22][C:23]3[N:24]=[CH:25][C:26]4[N:32]([CH3:33])[C:31](=[O:34])[C:30]([F:36])([F:35])[CH2:29][N:28]([CH:37]5[CH2:41][CH2:40][CH2:39][CH2:38]5)[C:27]=4[N:42]=3)=[C:18]([C:43]([F:46])([F:45])[F:44])[CH:17]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH:37]1([N:28]2[CH2:29][C:30]([F:36])([F:35])[C:31](=[O:34])[N:32]([CH3:33])[C:26]3[CH:25]=[N:24][C:23]([NH:22][C:19]4[CH:20]=[CH:21][C:16]([C:15]([NH:14][CH:11]5[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]5)=[O:47])=[CH:17][C:18]=4[C:43]([F:44])([F:45])[F:46])=[N:42][C:27]2=3)[CH2:41][CH2:40][CH2:39][CH2:38]1
Reactant: CN1C(=O)C(F)(F)CN(C2CCCC2)c2nc(Nc3ccc(C(=O)NC4CCN(C(=O)OC(C)(C)C)CC4)cc3C(F)(F)F)ncc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN1C(=O)C(F)(F)CN(C2CCCC2)c2nc(Nc3ccc(C(=O)NC4CCNCC4)cc3C(F)(F)F)ncc21
Yield: 82.6 %

Procedure:
A solution of 0.0298 g (0.0446 mmole) 4-[4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-trifluoromethyl-benzoylamino]-piperidine-1-carboxylic acid tert-butyl ester (I-211) in 4 mL of dichloromethane was stirred with 2 mL of trifluoroacetic acid for 2 hours and then concentrated under reduced pressure. The residue was dissolved in 80 mL of dichloromethane, washed with 15 mL of sodium carbonate solution, twice with 15 mL of brine and concentrated under reduced pressure. The residue was purified by reverse phase silica gel chromatography, eluting with water-acetonitrile (gradient, 90:10-0:100) to give 0.0209 g of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-N-piperidin-4-yl-3-trifluoromethyl-benzamide (I-212) as a white solid.
Reaction SMILES: Cl.[OH:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([OH:12])=[O:11])=[CH:5][CH:4]=1.[CH3:13]O>>[CH3:13][O:11][C:10](=[O:12])[CH2:9][C:6]1[CH:5]=[CH:4][C:3]([OH:2])=[CH:8][CH:7]=1
Reactant: O=C(O)Cc1ccc(O)cc1
Reactant: CO
Agent: Cl
Product: COC(=O)Cc1ccc(O)cc1
Temperature: 25 °C

Procedure:
Hydrogen chloride was bubbled through a solution of (4-hydroxyphenyl) acetic acid (25 g, 0.16 mole) in methanol (100 ml) at room temperature. An exotherm resulted in the solution refluxing for about 10 minutes. The mixture was allowed to cool to room temperature and the solvent was evaporated in vacuo to afford methyl(4-hydroxyphenyl)acetate as a yellow oil (27.5 g) which crystallised on seeding, m.p. 46-52° C.
Reaction SMILES: [H-].[Na+:2].ClC1C=C(C=CC=1)N.[CH3:11][C:12]1[CH2:16][C:15]([CH3:17])=[C:14]([CH3:18])[C:13]=1[CH3:19]>O1CCCC1>[CH3:11][C:12]1[CH:16]([Na:2])[C:15]([CH3:17])=[C:14]([CH3:18])[C:13]=1[CH3:19]
Reactant: CC1=C(C)C(C)=C(C)C1
Reactant: [Na+]
Agent: [H-]
Solvent: Nc1cccc(Cl)c1
Solvent: C1CCOC1
Product: CC1=C(C)C([Na])C(C)=C1C
Temperature: 50 °C
Reaction time: 1 h

Procedure:
Sodium hydride (containing mineral oil; the content of sodium hydride: 60%) (0.80 g) and m-chloroaniline (0.064 g) were added to the solution of tetramethylcyclopentadiene (1.34 g; purity: 91.3%; pure compound: 1.22 g) dissolved in tetrahydrofuran (6.73 g), and stirred at 50° C. for one hour. Thus, tetramethylcyclopentadienylsodium was obtained in the form of a solution in tetrahydrofuran.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[OH:18].[CH3:19][C:20](C)([O-:22])[CH3:21].[K+].C(C1OC1)Br>CC(N(C)C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[O:18][CH2:19][CH:20]1[CH2:21][O:22]1
Reactant: Oc1ccccc1CCCCc1ccccc1Cl
Reactant: CC(C)(C)[O-]
Agent: BrCC1CO1
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: Clc1ccccc1CCCCc1ccccc1OCC1CO1
Yield: 88.5 %

Procedure:
Following a procedure similar to that described in Example 1(a), 800 mg of 2-[4-(2-chlorophenyl)butyl]phenol (prepared as described in Preparation 18), 344 mg of potassium t-butoxide and 835 mg of epibromohydrin were reacted in 20 ml of dimethylacetamide. The crude product, extracted as described in Example 1(a), was purified as described in Example 1(a), to give 860 mg (yield 88%) of the title compound as a colorless oil.
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[C:3]1[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[CH:25][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([CH:15]=[C:16]3[S:20][C:19](SCC)=[N:18][C:17]3=[O:24])=[CH:12][CH:13]=2)[CH:8]=[N:7]1.[CH3:35][O:36][CH2:37][CH:38]1[N:42]([CH3:43])[CH2:41][CH:40]([NH:44][CH3:45])[CH2:39]1>>[F:1][C:2]([F:34])([F:33])[C:3]1[CH:28]=[C:27]([C:29]([F:31])([F:32])[F:30])[CH:26]=[CH:25][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([CH:15]=[C:16]3[S:20][C:19]([N:44]([CH:40]4[CH2:39][CH:38]([CH2:37][O:36][CH3:35])[N:42]([CH3:43])[CH2:41]4)[CH3:45])=[N:18][C:17]3=[O:24])=[CH:12][CH:13]=2)[CH:8]=[N:7]1
Reactant: CCSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(C(F)(F)F)cc3C(F)(F)F)c2)S1
Reactant: CNC1CC(COC)N(C)C1
Product: COCC1CC(N(C)C2=NC(=O)C(=Cc3ccc4c(cnn4Cc4ccc(C(F)(F)F)cc4C(F)(F)F)c3)S2)CN1C

Procedure:
5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-[(5-methoxymethyl-1-methyl-pyrrolidin-3-yl)-methyl-amino]-thiazol-4-one was prepared from 5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-ethylsulfanyl-thiazol-4-one and (5-Methoxymethyl-1-methyl-pyrrolidin-3-yl)-methyl-amine following General Procedure C.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:7][CH2:6][CH2:5][N:4]1[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9].[CH3:15][S:16](Cl)(=[O:18])=[O:17].O>C(Cl)Cl>[CH3:15][S:16]([O:1][CH2:2][CH:3]1[CH2:7][CH2:6][CH2:5][N:4]1[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])(=[O:18])=[O:17]
Reactant: CC(C)(C)OC(=O)N1CCCC1CO
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OC(=O)N1CCCC1COS(C)(=O)=O
Temperature: -20 °C
Reaction time: 0.5 h

Procedure:
To a solution of tert-butyl 2-(hydroxymethyl)pyrrolidine-1-carboxylate (1.0 g, 5.0 mmol) and TEA (1.0 g, 9.9 mmol) in CH2Cl2 (40 mL) was slowly added MsCl (0.63 g, 5.5 mmol). The reaction mixture was stirred for 30 min at −20° C. and then water (60 mL) was added. The aqueous phase was separated and extracted with CH2Cl2. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to afford the crude tert-butyl 2-((methylsulfonyloxy)methyl)pyrrolidine-1-carboxylate that was used directly without further purification.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].FC(F)(F)C(O)=O.[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:54]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:53])[CH2:46][CH:47]1[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1.[CH2:55]([S:57](Cl)(=[O:59])=[O:58])[CH3:56]>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:54]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:53])[CH2:46][CH:47]1[CH2:52][CH2:51][N:50]([S:57]([CH2:55][CH3:56])(=[O:59])=[O:58])[CH2:49][CH2:48]1
Reactant: O=C(CC1CCNCC1)Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Reactant: CCS(=O)(=O)Cl
Solvent: O=C(O)C(F)(F)F
Product: CCS(=O)(=O)N1CCC(CC(=O)Nc2ccc3cc2CCc2cncc(c2)Nc2ncc(Cl)c(n2)N3)CC1
Yield: 45 %

Procedure:
The desired compound was prepared according to the procedure of Example A42, using N-[6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-piperidin-4-ylacetamide tris(trifluoroacetate) and ethanesulfonyl chloride as starting materials in 45% yield. 1H NMR (300 MHz, DMSO-d6): δ 10.00 (s, 1H), 9.40 (m, 2H), 8.98 (s, 1H), 8.28 (m, 2H), 8.21 (s, 1H), 7.65 (m, 1H), 7.30 (m, 1H), 7.07 (m, 1H), 3.60 (m, 2H), 2.99 (m, 6H), 2.81 (m, 2H), 2.32 (m, 2H), 1.91 (m, 1H), 1.80 (m, 2H), 1.25 (m, 2H), 1.20 (t, 3H). LCMS for C26H31ClN7O3S (M+H)+: m/z=556.2.