Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[CH:4]=1)#[CH:2].[CH2:10]([O:12][C:13]([C:15]1[N:16]([CH3:22])[C:17](Br)=[N:18][C:19]=1[CH3:20])=[O:14])[CH3:11]>>[CH2:10]([O:12][C:13]([C:15]1[N:16]([CH3:22])[C:17]([C:2]#[C:1][C:3]2[CH:4]=[C:5]([CH3:9])[CH:6]=[CH:7][CH:8]=2)=[N:18][C:19]=1[CH3:20])=[O:14])[CH3:11]
Reactant: C#Cc1cccc(C)c1
Reactant: CCOC(=O)c1c(C)nc(Br)n1C
Product: CCOC(=O)c1c(C)nc(C#Cc2cccc(C)c2)n1C

Procedure:
The title compound, MS: m/e=283.6 (M+H+), was prepared in accordance with the general method of example 1b from 1-ethynyl-3-methyl-benzene and 2-bromo-3,5-dimethyl-3H-imidazole-4-carboxylic acid ethyl ester.
Reaction SMILES: [Br:1][C:2]1[CH:15]=[CH:14][C:13]2[O:12][C:11]3[C:6](=[CH:7][C:8]([OH:16])=[CH:9][CH:10]=3)[C:5]3([CH2:21][O:20][CH2:19][C:18](=[O:22])[NH:17]3)[C:4]=2[CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].I[CH2:30][C:31]([CH3:34])([CH3:33])[CH3:32]>CN(C=O)C>[Br:1][C:2]1[CH:15]=[CH:14][C:13]2[O:12][C:11]3[C:6](=[CH:7][C:8]([O:16][CH2:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[CH:9][CH:10]=3)[C@:5]3([CH2:21][O:20][CH2:19][C:18](=[O:22])[NH:17]3)[C:4]=2[CH:3]=1
Reactant: O=C1COCC2(N1)c1cc(O)ccc1Oc1ccc(Br)cc12
Reactant: CC(C)(C)CI
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)(C)COc1ccc2c(c1)[C@]1(COCC(=O)N1)c1cc(Br)ccc1O2
Temperature: 115 °C

Procedure:
In a 25-ml flask, 2′-bromo-7′-hydroxyspiro[morpholine-3,9′-xanthen]-5-one (0.020 g, 0.055 mmol) was dissolved in DMF (1 mL). Cesium carbonate (0.043 g, 0.133 mmol) was added, followed by 1-iodo-2,2-dimethylpropane (0.022 g, 0.110 mmol). The reaction was heated in a 115° C. oil bath for 10 h. The reaction was cooled to ambient temperature and concentrated. The residue was taken up in 0.3 M aqueous HCl (15 mL) and the aqueous layer was extracted with EtOAc (3×20 mL). The organic layers were combined, washed with saturated brine (5 mL), dried over sodium sulfate, and concentrated. The residue was purified by chromatography (25% EtOAc/hexane) to afford (R)-2′-bromo-7′-(neopentyloxy)spiro[morpholine-3,9′-xanthen]-5-one.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:20]=[C:13]([C:14]([O:16][CH2:17][CH2:18][CH3:19])=[O:15])[C:12]([OH:21])=[CH:11][CH:10]=1.Cl[C:23]1[C:32]2[C:27](=[CH:28][C:29]([O:35][CH3:36])=[C:30]([O:33][CH3:34])[CH:31]=2)[N:26]=[CH:25][CH:24]=1>CN(C)C1C=CN=CC=1.ClC1C=CC=CC=1Cl>[CH3:34][O:33][C:30]1[CH:31]=[C:32]2[C:27](=[CH:28][C:29]=1[O:35][CH3:36])[N:26]=[CH:25][CH:24]=[C:23]2[O:21][C:12]1[CH:11]=[CH:10][C:9]([C:3]2[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=2[F:1])=[CH:20][C:13]=1[C:14]([O:16][CH2:17][CH2:18][CH3:19])=[O:15]
Reactant: COc1cc2nccc(Cl)c2cc1OC
Reactant: CCCOC(=O)c1cc(-c2ccc(F)cc2F)ccc1O
Agent: CN(C)c1ccncc1
Solvent: Clc1ccccc1Cl
Product: CCCOC(=O)c1cc(-c2ccc(F)cc2F)ccc1Oc1ccnc2cc(OC)c(OC)cc12
Temperature: 120 °C
Reaction time: 8 h
Yield: 20 %

Procedure:
Propyl 5-(2,4-difluorophenyl)salicylate (179 mg), 4-chloro-6,7-dimethoxyquinoline (70 mg), and 4-dimethylaminopyridine (110 mg) were suspended in o-dichlorobenzene (1 ml), and the suspension was stirred at 120° C. overnight. The reaction solution was cooled to room temperature, and the solvent was removed by distillation under the reduced pressure. Water was then added to the residue, and the mixture was extracted with chloroform. The chloroform layer was washed with water and was dried over anhydrous sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by column chromatography using acetone-hexane to give the title compound (30 mg, yield 10%).
Reaction SMILES: C([O:8][NH:9][C:10]([C:12]1[CH:17]=[CH:16][C:15]([NH:18][C:19]([C:21]2[CH:29]=[C:28]3[C:24]([C:25]([CH2:35][CH3:36])=[N:26][N:27]3[CH:30]3[CH2:34][CH2:33][CH2:32][CH2:31]3)=[CH:23][CH:22]=2)=[O:20])=[CH:14][CH:13]=1)=[O:11])C1C=CC=CC=1>C(OCC)(=O)C.CO.[Pd]>[OH:8][NH:9][C:10]([C:12]1[CH:17]=[CH:16][C:15]([NH:18][C:19]([C:21]2[CH:29]=[C:28]3[C:24]([C:25]([CH2:35][CH3:36])=[N:26][N:27]3[CH:30]3[CH2:34][CH2:33][CH2:32][CH2:31]3)=[CH:23][CH:22]=2)=[O:20])=[CH:14][CH:13]=1)=[O:11]
Reactant: CCc1nn(C2CCCC2)c2cc(C(=O)Nc3ccc(C(=O)NOCc4ccccc4)cc3)ccc12
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: CCc1nn(C2CCCC2)c2cc(C(=O)Nc3ccc(C(=O)NO)cc3)ccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 48.7 %

Procedure:
A mixture of 187 mg (0.387 mmol, 1.0 equiv) 1-cyclopentyl-3-ethyl-1H-indazole-6-carboxylic acid (4-benzyloxycarbamoyl-phenyl)-amide and 200 mg 10% Pd/C in 10 mL ethyl acetate and 10 mL methanol was placed on a Parr® hydrogenation appartus and shaken under 30 psi H2 at room temperature for 1 hour. The reaction mixture was filtered through Celite®, and the filtrate concentrated and dried to give a tan solid. Purification on a silica gel column (CH3OH/CH2Cl2 gradient 4%, 10%, 20%, flash) gave 74 mg (49%) of a tan solid: mp 175° C. (dec); HRMS calcd for C22H24N4O3+H: 393.1928. Found: 393.1949.
Reaction SMILES: [CH:1]1([NH2:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:8]1(=O)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1>C1C=CC=CC=1>[CH:1]1([N:7]=[C:8]2[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NC1CCCCC1
Reactant: O=C1CCCCC1
Solvent: c1ccccc1
Product: C1CCC(=NC2CCCCC2)CC1
Temperature: 80 °C

Procedure:
Cyclohexylamine Compound 20a (4.64 g, 46.50 mmol) was added to a solution of cyclohexanone Compound 2a (4.0 g, 46.50 mmol) in benzene (100 mL) at ambient temperature under a N2 atmosphere. The mixture was refluxed at 80° C. for 5 hours, using a Dean Stark apparatus for the removal of water, and concentrated to dryness. The crude product was purified by distillation at aspirator pressure to afford cyclohexyl-cyclohexylidene-amine Compound 20b (7.33 g, 88%) as a clear oil.
Reaction SMILES: [C:1]([C:4]1[S:8][C:7]([NH2:9])=[N:6][C:5]=1[CH3:10])(=[O:3])[CH3:2].[Cl:11][C:12]1[CH:17]=[C:16]([Cl:18])[CH:15]=[C:14]([CH3:19])[C:13]=1[S:20](Cl)(=[O:22])=[O:21]>>[C:1]([C:4]1[S:8][C:7]([NH:9][S:20]([C:13]2[C:14]([CH3:19])=[CH:15][C:16]([Cl:18])=[CH:17][C:12]=2[Cl:11])(=[O:22])=[O:21])=[N:6][C:5]=1[CH3:10])(=[O:3])[CH3:2]
Reactant: Cc1cc(Cl)cc(Cl)c1S(=O)(=O)Cl
Reactant: CC(=O)c1sc(N)nc1C
Product: CC(=O)c1sc(NS(=O)(=O)c2c(C)cc(Cl)cc2Cl)nc1C

Procedure:
The title compound was prepared from 5-acetyl-2-amino-4-methylthiazole and 2,4-dichloro-6-methylbenzenesulfonyl chloride as described in the synthetic METHOD B to give a white-yellow solid (28.4 mg) with purity >90%. MS (pos) m/z 379.1, 381.1.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([N:8]2[CH2:12][C:11]3([CH2:18][CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)[O:10][C:9]2=[O:19])=[CH:4][CH:3]=1.[CH3:20][N:21]([CH3:39])[C:22]([C:24]1[N:33]([CH:34]2[CH2:38][CH2:37][CH2:36][CH2:35]2)[C:27]2[N:28]=[C:29](Cl)[N:30]=[CH:31][C:26]=2[CH:25]=1)=[O:23]>>[CH:34]1([N:33]2[C:27]3[N:28]=[C:29]([NH:1][C:2]4[CH:3]=[CH:4][C:5]([N:8]5[CH2:12][C:11]6([CH2:18][CH2:17][CH2:16][NH:15][CH2:14][CH2:13]6)[O:10][C:9]5=[O:19])=[CH:6][N:7]=4)[N:30]=[CH:31][C:26]=3[CH:25]=[C:24]2[C:22]([N:21]([CH3:39])[CH3:20])=[O:23])[CH2:35][CH2:36][CH2:37][CH2:38]1
Reactant: Nc1ccc(N2CC3(CCCNCC3)OC2=O)cn1
Reactant: CN(C)C(=O)c1cc2cnc(Cl)nc2n1C1CCCC1
Product: CN(C)C(=O)c1cc2cnc(Nc3ccc(N4CC5(CCCNCC5)OC4=O)cn3)nc2n1C1CCCC1
Yield: 50.4 %

Procedure:
Following general N—C coupling procedure 1, 3-(6-Amino-pyridin-3-yl)-1-oxa-3,8-diaza-spiro[4.6]undecan-2-one (0.100 g, 0.276 mmol) was combined with 2-Chloro-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (0.081 g, 0.276 mmol, 1.0 eq) which gave 7-cyclopentyl-N,N-dimethyl-2-(5-(2-oxo-1-oxa-3,8-diazaspiro[4.6]undecan-3-yl)pyridin-2-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide as white solid (0.075 g, 0.139 mmol) in 50% yield. 1H NMR (400 MHz, CDCl3) 6 ppm 1.58-1.82 (m, 4H) 1.97-2.27 (m, 14H) 2.47-2.65 (m, 2H) 2.86-3.11 (m, 4H) 3.16 (s, 7H) 3.80-3.88 (m, 2H) 4.80 (qd, J=8.95, 8.78 Hz, 1H) 6.46 (s, 1H) 8.06 (s, 1H) 8.13 (dd, J=9.03, 3.01 Hz, 1H) 8.21-8.32 (m, 1H) 8.50 (d, J=9.03 Hz, 1H) 8.72 (s, 1H); HRMS calc for m/z=531.2832 and found m/z=531.2858 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([S:11](Cl)(=[O:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][NH2:24])=[CH:18][CH:17]=1>C(Cl)Cl>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([S:11]([NH:24][CH2:23][CH2:22][C:19]2[CH:20]=[CH:21][C:16]([Cl:15])=[CH:17][CH:18]=2)(=[O:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: O=C(O)c1cc(S(=O)(=O)Cl)ccc1Cl
Reactant: NCCc1ccc(Cl)cc1
Solvent: ClCCl
Product: O=C(O)c1cc(S(=O)(=O)NCCc2ccc(Cl)cc2)ccc1Cl
Reaction time: 8 h

Procedure:
2-Chloro-5-chlorosulfonyl benzoic acid, 3.5 g. (0.014 mole), is added to a solution of 2-(p-chlorophenyl)ethylamine, 6.5 g. (0.042 mole) in 25 ml. methylene chloride. The resulting slurry is stirred overnight and filteredto recover 9.7 g. of residue. This is recrystallized three times from aqueous isopropanol, then dissolved in 1N aqueous sodium hydroxide, washedthree times with ether, and then acidified with conc. hydrochloric acid. The resulting precipitate is recrystallized twice from aqueous isopropanolto yield the desired product, m.p. 176°- 178° C.
Reaction SMILES: [CH:1]1([N:6]2[CH2:11][CH2:10][N:9]([C:12]([C:14]3[CH:15]=[C:16]4[C:20](=[CH:21][CH:22]=3)[NH:19][C:18]([C:23]([OH:25])=O)=[CH:17]4)=[O:13])[CH2:8][CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[CH3:49][CH:50]1[CH2:55][CH2:54][NH:53][CH2:52][CH2:51]1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH:1]1([N:6]2[CH2:7][CH2:8][N:9]([C:12]([C:14]3[CH:15]=[C:16]4[C:20](=[CH:21][CH:22]=3)[NH:19][C:18]([C:23]([N:53]3[CH2:54][CH2:55][CH:50]([CH3:49])[CH2:51][CH2:52]3)=[O:25])=[CH:17]4)=[O:13])[CH2:10][CH2:11]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)c1cc2cc(C(=O)N3CCN(C4CCCC4)CC3)ccc2[nH]1
Reactant: CC1CCNCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC1CCN(C(=O)c2cc3cc(C(=O)N4CCN(C5CCCC5)CC4)ccc3[nH]2)CC1

Procedure:
The title compound was synthesized in analogy to example 1, from 5-(4-cyclopentyl-piperazine-1-carbonyl)-1H-indole-2-carboxylic acid 1:1 hydrochloride, O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (commercially available), 4-methyl piperidine (commercially available) and N,N-diisopropylethylamine in N,N-dimethyl-formamide to give the desired product after purification by preparative HPLC on reversed phase eluting with a gradient formed from acetonitrile/water/formic acid.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([S:8][CH3:9])[N:3]=1.C(NC(C)C)(C)C.[C:17]([C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([N+:25]([O-:27])=[O:26])[CH:20]=1)#[CH:18]>C1COCC1.[Cu]I.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>[CH3:9][S:8][C:4]1[N:3]=[C:2]([C:18]#[C:17][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([N+:25]([O-:27])=[O:26])[CH:20]=2)[CH:7]=[CH:6][N:5]=1
Reactant: C#Cc1cccc([N+](=O)[O-])c1
Reactant: CSc1nccc(I)n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CSc1nccc(C#Cc2cccc([N+](=O)[O-])c2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.6 %

Procedure:
4-Iodo-2-(methylthio)pyrimidine (39.7 g, 0.157 mol) and diisopropylamine (44.2 mL, 0.315 mol) were dissolved in dry THF (720 mL) and argon gas was bubbled through the solution for 20 min. Copper(I) iodide (2.99 g, 14.3 mmol) and bis(triphenylphosphine)palladium dichloride (5.51 g, 7.85 mmol) were added and then 1-ethynyl-3-nitrobenzene (25.4 g, 0.173 mol) in dry THF (100 mL) was added dropwise over about 30 min with the temperature being maintained at about 25° C. Following complete addition, the mixture was stirred at rt overnight. The mixture is filtered and washed with THF. The filtrate is concentrated under reduced pressure. The residue was washed with EtOAc/MeOH to give pale-yellow solid (42 g).
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]3[C:12]([C:18](=[O:23])[C:19]([O:21][CH3:22])=[O:20])=[C:13]([CH3:17])[S:14][C:15]=3[CH3:16])=[CH:10][C:5]=2[CH2:4][CH2:3][CH2:2]1.[CH3:24][Mg]Br>C(OCC)C>[O:1]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]3[C:12]([C:18]([OH:23])([CH3:24])[C:19]([O:21][CH3:22])=[O:20])=[C:13]([CH3:17])[S:14][C:15]=3[CH3:16])=[CH:10][C:5]=2[CH2:4][CH2:3][CH2:2]1
Reactant: C[Mg]Br
Reactant: COC(=O)C(=O)c1c(C)sc(C)c1-c1ccc2c(c1)CCCO2
Solvent: CCOCC
Product: COC(=O)C(C)(O)c1c(C)sc(C)c1-c1ccc2c(c1)CCCO2
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 55 %

Procedure:
Under a nitrogen atmosphere, a solution of methyl 2-[4-(3,4-dihydro-2H-1-benzopyran-6-yl)-2,5-dimethylthiophen-3-yl]-2-oxoacetate (360 mg, 1.09 mmol) in anhydrous diethyl ether (5 mL) was cooled to 0° C. Methyl magnesium bromide 3.0 M in diethyl ether (0.73 mL, 2.18 mmol) was added dropwise and the reaction mixture was stirred at 0° C. for 15 minutes, before being quenched with a minimum of water. Ethyl acetate (8 mL) was added and the mixture was dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (cyclohexane/ethyl acetate 100/0 to 80/20) to provide the desired alcohol (42b) (206 mg, 0.59 mmol, 55%) as a colorless oil.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[C:11]([Cl:18])=[CH:10][C:9]=1[NH2:19])([CH3:4])([CH3:3])[CH3:2].C([O:25][C:26](=O)[CH2:27][C:28]([C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C:36]2[CH:41]=[CH:40][N:39]=[C:38]([CH3:42])[CH:37]=2)[CH:31]=1)=[O:29])(C)(C)C>>[C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[C:11]([Cl:18])=[CH:10][C:9]=1[NH:19][C:26](=[O:25])[CH2:27][C:28]([C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C:36]2[CH:41]=[CH:40][N:39]=[C:38]([CH3:42])[CH:37]=2)[CH:31]=1)=[O:29])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1cc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)ccn1
Reactant: CC(C)(C)OC(=O)Nc1cc(C(F)(F)F)c(Cl)cc1N
Product: Cc1cc(-c2cccc(C(=O)CC(=O)Nc3cc(Cl)c(C(F)(F)F)cc3NC(=O)OC(C)(C)C)c2)ccn1

Procedure:
The title compound was prepared from (2-amino-4-chloro-5-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example J24) (466 mg, 1.5 mmol) and 3-[3-(2-methyl-pyridin-4-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K12) (467 mg, 1.5 mmol) according to the general procedure M. Obtained as an orange oil (360 mg, 44%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([N:12]1[CH2:17][CH2:16][N:15]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([CH3:24])[CH:19]=3)[CH2:14][CH2:13]1)[N:8]([C:25]1[CH:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:28]=[CH:27][C:26]=1[O:35][CH3:36])[CH:7]2[CH2:37][C:38]([O:40]C)=[O:39].[OH-].[Na+]>O1CCOCC1>[F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([N:12]1[CH2:17][CH2:16][N:15]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([CH3:24])[CH:19]=3)[CH2:14][CH2:13]1)[N:8]([C:25]1[CH:30]=[C:29]([C:31]([F:33])([F:32])[F:34])[CH:28]=[CH:27][C:26]=1[O:35][CH3:36])[CH:7]2[CH2:37][C:38]([OH:40])=[O:39]
Reactant: COC(=O)CC1c2cccc(F)c2N=C(N2CCN(c3cccc(C)c3)CC2)N1c1cc(C(F)(F)F)ccc1OC
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: COc1ccc(C(F)(F)F)cc1N1C(N2CCN(c3cccc(C)c3)CC2)=Nc2c(F)cccc2C1CC(=O)O

Procedure:
In 40 ml of dioxane, 892 mg (1.56 mmol) of methyl {8-fluoro-2-[4-(3-methylphenyl)-1-piperazinyl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-3,4-dihydro-4-quinazolinyl}acetate (Example 33A) and 187.6 mg (4.69 mmol) of sodium hydroxide are stirred at 50° C. for 2 hours. Following removal of the solvent, the residue is taken up in water and adjusted to pH 4–5 using 1N hydrochloric acid. The product is filtered off and then washed with water and dried under reduced pressure.
Reaction SMILES: [C:1]1([CH2:7][C:8]([OH:10])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(Cl)(=O)C(Cl)=O.[CH3:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([O:25]C)=[CH:21][CH:20]=1.[Al+3].[Cl-].[Cl-].[Cl-]>ClCCl.CN(C=O)C>[OH:25][C:22]1[CH:23]=[CH:24][C:19]([O:18][CH3:17])=[CH:20][C:21]=1[C:8](=[O:10])[CH2:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COc1ccc(OC)cc1
Reactant: O=C(O)Cc1ccccc1
Agent: O=C(Cl)C(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1ccc(O)c(C(=O)Cc2ccccc2)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 49 %

Procedure:
Phenylacetic acid (7.39 g, 54.28 mmoles) was dissolved in 50 ml dichloromethane. To this mixture, oxalylchloride (4.74 ml, 54.28 mmoles) and DMF (3 drops) were added at 0° C. and stirred for 30 min. The solvent was evaporated and dissolved in 30 ml dichloromethane. To this mixture, 4-methoxyanisole (10 g, 53.47 mmoles) was added and cooled to 0° C. At 0° C. AlCl3 (9.63 g, 72.37 mmoles) was added and the reaction mixture was warmed to RT and stirred for 12 h. The reaction mixture was quenched by the addition of 2N HCl and extracted with ethyl acetate, dried over sodium sulphate and concentrated. The crude product was purified by column chromatography with ethyl acetate: petroleum ether to afford the title compound as yellow liquid (4.3 g, 49% yield. 1H-NMR (δ ppm, DMSO-d6, 400 MHz): δ 11.30(s,1H), 7.42(d, J=3.0 Hz, 1H), 7.33-7.21(m, 5H), 7.17(dd, J=9.0,3.1 Hz, 1H), 6.92(d, J=9.0 Hz, 1H), 4.43(s, 2H), 3.74(s, 3H).
Reaction SMILES: [CH3:1][S:2]([NH:5][NH2:6])(=[O:4])=[O:3].CCN(C(C)C)C(C)C.C[O:17][C:18](=O)[C:19]1[CH:24]=[C:23]([C:25]2[CH:26]=[N:27][N:28]([CH3:30])[CH:29]=2)[C:22]([C:31]([F:34])([F:33])[F:32])=[CH:21][C:20]=1[NH:35][C:36](OC1C=CC(Cl)=CC=1)=[O:37]>O1CCOCC1>[CH3:30][N:28]1[CH:29]=[C:25]([C:23]2[CH:24]=[C:19]3[C:20](=[CH:21][C:22]=2[C:31]([F:32])([F:33])[F:34])[NH:35][C:36](=[O:37])[N:6]([NH:5][S:2]([CH3:1])(=[O:4])=[O:3])[C:18]3=[O:17])[CH:26]=[N:27]1
Reactant: CS(=O)(=O)NN
Reactant: COC(=O)c1cc(-c2cnn(C)c2)c(C(F)(F)F)cc1NC(=O)Oc1ccc(Cl)cc1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: Cn1cc(-c2cc3c(=O)n(NS(C)(=O)=O)c(=O)[nH]c3cc2C(F)(F)F)cn1
Temperature: 90 °C
Reaction time: 19 h
Yield: 42 %

Procedure:
CH3SO2NHNH2 (130 mg, 2.4 equiv) and i-Pr2NEt (169 μL, 2 equiv) were added to a solution of 2-(4-chloro-phenoxycarbonylamino)-5-(1-methyl-1H-pyrazol-4-yl)-4-trifluoromethyl-benzoic acid methyl ester (224 mg, 0.49 mmol) in dioxane (11 mL). The mixture was stirred for 19 h (TLC control) at 90° C. The mixture was evaporated to dryness. The crude product was triturated with hexanes and DCM. The formed precipitate was filtered and washed with hexanes to give N-[6-(1-methyl-1H-pyrazol-4-yl)-2,4-dioxo-7-trifluoromethyl-1,4-dihydro-2H-quinazolin-3-yl]-methanesulfonamide (83 mg, 42%) as a white solid. ESI-MS: m/z 404 [M+H]+, 1H-NMR (DMSO-d6, 400 MHz) 7.91 (s, 2H), 7.57 (s, 1H), 7.54 (s, 1H), 3.88 (s, 3H), 3.14 (s, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][C:11]([C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=1)([CH3:16])[C:12]([O:14]C)=[O:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].O[Li].O>C1COCC1.O>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][C:11]([C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=1)([CH3:16])[C:12]([OH:14])=[O:13])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: COC(=O)C(C)(CCNC(=O)OC(C)(C)C)c1ccc(Cl)cc1
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)NCCC(C)(C(=O)O)c1ccc(Cl)cc1
Reaction time: 8 h
Yield: 98.9 %

Procedure:
Methyl 4-(tert-butoxycarbonylamino)-2-(4-chlorophenyl)-2-methylbutanoate (720 mg, 2.11 mmol) was dissolved in THF (4.2 mL) and water (1.8 mL). The mixture was treated with LiOH—H2O (265 mg, 6.32 mmol) and allowed to stir overnight to completion by LCMS analysis. The mixture was diluted with water and washed twice with diethyl ether (discarded). The aqueous was treated with 3M HCl solution until a pH of about 2 to about 3 (white ppt) and extracted with ethyl acetate several times. The combined organic portions were washed with water, then brine, separated, dried over MgSO4, filtered, and concentrated in vacuo to afford 4-(tert-butoxycarbonylamino)-2-(4-chlorophenyl)-2-methylbutanoic acid as a colorless oil (684 mg, 99%). LCMS (APCI+) [M+H]+326.0; Rt: 2.26 min.
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=1)=[O:3].[OH:14][CH2:15][C:16]1[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=1>C(Cl)Cl.CN(C)C1C=CN=CC=1>[C:2](=[O:3])([O:4][C:5]1[CH:6]=[CH:7][C:8]([N+:11]([O-:13])=[O:12])=[CH:9][CH:10]=1)[O:14][CH2:15][C:16]1[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=1
Reactant: OCc1ccncc1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: O=C(OCc1ccncc1)Oc1ccc([N+](=O)[O-])cc1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
20.3 g of p-nitrophenyl chloroformate were dissolved in 150 ml of CH2Cl2 (absolute) and the solution was cooled to 0° C. under N2. 520 mg of 4-dimethylaminopyridine (DMAP) were added and 10 g of 4-hydroxymethylpyridine in 50 ml of CH2Cl2 (absolute) were then added dropwise to this solution. The mixture was stirred overnight at R.T. and the crystals which had precipitated were filtered off. The crystals were recrystallized using fresh CH2Cl2 under the influence of heat and, after cooling, were filtered off again.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[CH2:3][N:4]1[C:9](=[O:10])[CH2:8][NH:7][C:6]([C:11]2[CH:16]=[C:15]([Cl:17])[CH:14]=[C:13]([Cl:18])[CH:12]=2)=[N:5]1.C(N(CC)CC)C.[CH3:28][O:29][C:30]([S:32]Cl)=[O:31]>O1CCCC1>[F:20][C:2]([F:1])([F:19])[CH2:3][N:4]1[C:9](=[O:10])[CH2:8][N:7]([S:32][C:30]([O:29][CH3:28])=[O:31])[C:6]([C:11]2[CH:12]=[C:13]([Cl:18])[CH:14]=[C:15]([Cl:17])[CH:16]=2)=[N:5]1
Reactant: COC(=O)SCl
Reactant: O=C1CNC(c2cc(Cl)cc(Cl)c2)=NN1CC(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)SN1CC(=O)N(CC(F)(F)F)N=C1c1cc(Cl)cc(Cl)c1
Reaction time: 0.5 h
Yield: 42.4 %

Procedure:
To a solution of 1-(2,2,2-trifluoroethyl)-3-(3,5-dichlorophenyl)-4,5-dihydro-1,2,4-triazin-6-one (110 mg, 0.34 mmol) dissolved in 5 mL tetrahydrofuran was added triethylamine (0.06 mL, 0.40 mmol) and methoxy-carbonylsulfenyl chloride (0.04 mL, 0.40 mmol). After 30 min, the reaction was quenched with water and diluted with ethyl acetate. The aqueous layer was extracted with ethyl acetate (2×5 mL), and the combined organic extracts were dried over magnesium sulfate, filtered, and concentrated in vacuo. The crude material was subjected to flash column chromatography (10% ethyl acetate/hexanes) to afford 1-(2,2,2-trifluoroethyl)-3-(3,5-dichlorophenyl)-4-(methoxycarbonylthio)-4,5-dihydro-1,2,4-triazin-6-one (60 mg, 43%) in 80% purity by LC.
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH2:7][CH2:8][CH3:9])=[CH:5][C:4]([C:10]2[S:11][CH:12]=[CH:13][CH:14]=2)=[N:3]1.[I:15]N1C(=O)CCC1=O.S([O-])([O-])(=O)=S.[Na+].[Na+].C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O>[I:15][C:5]1[C:4]([C:10]2[S:11][CH:12]=[CH:13][CH:14]=2)=[N:3][N:2]([CH3:1])[C:6]=1[CH2:7][CH2:8][CH3:9]
Reactant: O=C1CCC(=O)N1I
Reactant: CCCc1cc(-c2cccs2)nn1C
Agent: O=C([O-])[O-]
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCc1c(I)c(-c2cccs2)nn1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.7 %

Procedure:
To a solution of 1-methyl-5-propyl-3-(2-thienyl)-1H-pyrazole (2.5 mmol) in 7 mL dry N,N-dimethylformamide under argon atmosphere was added N-iodosuccinimide (2.6 mmol) in small portions at 0° C. The reaction mixture was allowed to warm to room temperature and stirred overnight. 5% aqueous sodium thiosulfate solution and saturated aqueous sodium carbonate solution were added and the mixture was stirred at room temperature for 1 h, then extracted with MTBE. The combined organic extracts were successively washed with water and brine, dried over MgSO4, filtered and concentrated to afford 720 mg of 4-iodo-1-methyl-5-propyl-3-(2-thienyl)-1H-pyrazole (88% yield) that was used in the next step without further purification.