Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS(O)(=O)=O.[Br:6][C:7]1[CH:8]=[C:9]([CH:23]=[CH:24][CH:25]=1)[CH2:10][N:11]([CH3:22])[CH2:12][CH:13]([C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=1)O.[OH-].[NH4+]>ClCCCl>[Br:6][C:7]1[CH:8]=[C:9]2[C:23]([CH:13]([C:15]3[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=3)[CH2:12][N:11]([CH3:22])[CH2:10]2)=[CH:24][CH:25]=1
Reactant: Cc1ccc(C(O)CN(C)Cc2cccc(Br)c2)cc1
Agent: CS(=O)(=O)O
Agent: [NH4+]
Agent: [OH-]
Solvent: ClCCCl
Product: Cc1ccc(C2CN(C)Cc3cc(Br)ccc32)cc1
Temperature: 40 °C
Yield: 38.7 %

Procedure:
Methane sulfonic acid (30 mL, 480 mmol) was added dropwise via addition funnel to a mixture of the product from Step B (4.58 g, 8.57 mmol) in 1,2-dichloroethane (80 mL) at 40° C. After the addition was completed, the reaction mixture was heated at 40° C. for an additional hour. The cooled reaction mixture was poured over ice and made basic to pH 9 with concentrated ammonium hydroxide. The reaction mixture was extracted with ethyl acetate (4×). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated in vacuo. Purification by column chromatography (120 g silica; 90:10 hexane/ethyl acetate) provided 7-bromo-2-methyl-4-p-tolyl-1,2,3,4-tetrahydroisoquinoline (1.05 g, 40%). This product was resolved by chrial HPLC (Chiralpak AD, 95:5 heptane/isopropanol with 0.1% diethylamine). The (+)enantiomer (430 mg, 41%) was obtained as a clear oil: [α]25d+11.9° (0.2, methanol); 1H NMR (500 MHz, CDCl3) δ 7.22 (s, 1H), 7.16 (d, J=8.3 Hz, 1H), 7.09 (d, J=7.9 Hz, 2H), 7.04 (d, J=8.1 Hz, 2H), 6.74 (d, J=8.5 Hz, 1H), 4.03-3.98 (m, 1H), 3.70 (d, J=15.0 Hz, 1H), 3.56 (d, J=15.0 Hz, 1H), 3.01-2.98 (m, 1H), 2.53-2.49 (m, 1H), 2.40 (s, 3H), 2.32 (s, 3H).
Reaction SMILES: Br[C:2]1[S:3][C:4]([CH3:8])=[C:5]([CH3:7])[N:6]=1.[CH2:9]([N:13]1[N:17]=[C:16]2[CH:18]=[CH:19][CH:20]=[CH:21][C:15]2=[N:14]1)[CH2:10][C:11]#[CH:12]>>[CH3:7][C:5]1[N:6]=[C:2]([C:12]#[C:11][CH2:10][CH2:9][N:13]2[N:14]=[C:15]3[CH:21]=[CH:20][CH:19]=[CH:18][C:16]3=[N:17]2)[S:3][C:4]=1[CH3:8]
Reactant: C#CCCn1nc2ccccc2n1
Reactant: Cc1nc(Br)sc1C
Product: Cc1nc(C#CCCn2nc3ccccc3n2)sc1C
Yield: 17115.4 %

Procedure:
The title compound was prepared in accordance with the general method of Example 1, from 2-bromo-4,5-dimethylthiazole (100 mg, 0.52 mmol) and 2-(but-3-ynyl)-2H-benzo[d][1,2,3]triazole (89 mg, 0.52 mmol, Example 109(D)). The crude residue was purified by flash chromatography (cyclohexane/AcOEt 4:1) to yield 25 mg (89 mmol, 17%) of 2-(4-(4,5-dimethylthiazol-2-yl)but-3-ynyl)-2H-benzo[d][1,2,3]triazole as a yellow solid (M.P.=96-98° C.).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[NH:13][C:12](=[O:14])[N:11]([C:15]2[CH:24]=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[C:17]([O:25][CH3:26])[CH:16]=2)[N:10]=1.[H-].[Na+].[CH2:29](Br)[CH3:30]>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[N:13]([CH2:29][CH3:30])[C:12](=[O:14])[N:11]([C:15]2[CH:24]=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[C:17]([O:25][CH3:26])[CH:16]=2)[N:10]=1
Reactant: CCBr
Reactant: COC(=O)c1ccc(-n2nc(-c3c(Cl)cccc3Cl)[nH]c2=O)cc1OC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCn1c(-c2c(Cl)cccc2Cl)nn(-c2ccc(C(=O)OC)c(OC)c2)c1=O
Reaction time: 0.42 h
Yield: 37.9 %

Procedure:
To a solution of methyl 4-(3-(2,6-dichlorophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-2-methoxybenzoate (Intermediate-21, 0.100 g, 0.25 mmol) in dry DMF (3 mL) was added NaH (0.012 g, 0.30 mmol) at 0° C. and the reaction mixture was stirred for 20-30 minutes. Ethyl bromide (0.028 g, 0.25 mmol) was added and the reaction mixture was further stirred at 60° C. for 5-6 h. The reaction mass was quenched with water and extracted in ethyl acetate. The organic layer was dried and concentrated to afford 0.040 g of the crude product which was further purified by column chromatography in basic alumina eluting with 0.5-1.0% methanol:DCM to afford 0.040 g of pure product. 1H NMR (300 MHz, DMSO d6): δ 1.13 (t, 3H), 3.54-3.56 (m, 2H), 3.78 (s, 3H), 3.86 (s, 3H), 7.65 (d, J=8.4 Hz, 1H), 7.77 (m, 4H), 7.84 (d, J=8.4 Hz, 1H); MS (m/z): 421.95 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]2[N:17]=[C:16]([NH:18]C(=O)C3C=CC=CC=3)[S:15][C:5]=2[C:6]([CH:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)=[N:7][CH:8]=1.[OH-].[Na+]>CO>[CH3:1][O:2][C:3]1[C:4]2[N:17]=[C:16]([NH2:18])[S:15][C:5]=2[C:6]([CH:9]2[CH2:10][CH2:11][O:12][CH2:13][CH2:14]2)=[N:7][CH:8]=1
Reactant: COc1cnc(C2CCOCC2)c2sc(NC(=O)c3ccccc3)nc12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1cnc(C2CCOCC2)c2sc(N)nc12
Temperature: 130 °C
Yield: 77.2 %

Procedure:
To a stirred suspension of 314 mg (0.85 mmol) N-[7-methoxy-4-(tetrahydro-pyran-4-yl)-thiazolo[5,4-c]pyridin-2-yl]-benzamide in 2.5 ml methanol was added 0.85 ml 5 N aq. sodium hydroxide solution and the resulting solution was then heated at 130° C. for 12 min in a microwave oven. The reaction mixture was then cooled to room temperature and partitioned between tetrahydrofuran and 1 N aq. sodium hydroxide solution. The phases were separated and the organic phase was dried over sodium sulfate and concentrated in vacuo. Flash chromatography (methanol/dichloromethane) afforded 174 mg (77%) 7-methoxy-4-(tetrahydro-pyran-4-yl)-thiazolo[5,4-c]pyridin-2-ylamine as a light yellow crystalline solid. ES-MS m/e (%): 266 (M+H+, 100).
Reaction SMILES: [CH3:1][C:2]1[C:7]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.ClC1C=C(C=CC=1)C(OO)=[O:20]>C(Cl)Cl>[CH3:1][C:2]1[C:7]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:6][CH:5]=[CH:4][N+:3]=1[O-:20]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1ncccc1Oc1ccccc1
Solvent: ClCCl
Product: Cc1c(Oc2ccccc2)ccc[n+]1[O-]
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 2-methyl-3-phenoxy-pyridine (0.501 g, 2.70 mmol) (Butler, D E et al. J. Med. Chem 1981, 24, 346-350) in CH2Cl2 (2.7 mL) was added 3-chloroperoxybenzoic acid (0.698 g, 4.05 mmol) and the solution stirred at room temperature for 24 h. Reaction mixture was diluted with CH2Cl2 (30 mL) and the organic layer was washed with saturated aqueous NaHCO3 (2×30 mL), dried (MgSO4), and concentrated to give 2-methyl-3-phenoxy-pyridine 1-oxide as a brown oil, which was used without further purification. 1H NMR (CDCl3) δ 2.54 (s, 3H), 6.77 (d, 1H), 6.97-7.06 (m, 3H), 7.16-7.21 (m, 1H), 7.34-7.41 (m, 2H), 8.11 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][C:8]([C:14]([F:17])([F:16])[F:15])=[CH:7][C:3]=1[C:4](O)=[O:5].O=S(Cl)[Cl:20]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][C:8]([C:14]([F:17])([F:16])[F:15])=[CH:7][C:3]=1[C:4]([Cl:20])=[O:5]
Reactant: O=C(O)c1cc(C(F)(F)F)cc([N+](=O)[O-])c1Cl
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: O=C(Cl)c1cc(C(F)(F)F)cc([N+](=O)[O-])c1Cl

Procedure:
To a solution of 2-chloro-3-nitro-5-trifluoromethylbenzoic acid (1.35 g) in toluene (15 ml) are added 1.2 ml of SOCl2. After refluxing for 2 hours, the end of the reaction is confirmed by monitoring by infrared (new band at 1788 cm−1). The reaction medium is evaporated to dryness and the resulting yellow oil, 2-chloro-3-nitro-5-trifluoromethylbenzoyl chloride, is used without further purification in the following step.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:13]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[CH:15]=3)[N:12]=[C:11]([C:21]([O:23]CC)=[O:22])[CH:10]=2)[CH:5]=[CH:6][C:7]=1[F:8].ClC1C=C(N2C(C3C=C(F)C=C(Cl)C=3)=CC(C(O)=O)=N2)C=CC=1F>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:13]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[CH:15]=3)[N:12]=[C:11]([C:21]([OH:23])=[O:22])[CH:10]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CCOC(=O)c1cc(-c2ccc(F)c(Cl)c2)n(-c2cccc(Cl)c2)n1
Agent: O=C(O)c1cc(-c2cc(F)cc(Cl)c2)n(-c2ccc(F)c(Cl)c2)n1
Product: O=C(O)c1cc(-c2ccc(F)c(Cl)c2)n(-c2cccc(Cl)c2)n1

Procedure:
The preparation of the title compound takes place starting from the compound of Example 29A in analogy to the synthesis of the compound of Example 71A. 5.30 g (100% of theory) of the title compound are obtained.
Reaction SMILES: C([O-])(=O)C.[Na+].Br[C:7]1[CH:20]=[C:19](Br)[CH:18]=[CH:17][C:8]=1[O:9][C:10]1[C:11]([NH2:16])=[N:12][CH:13]=[CH:14][CH:15]=1.[H][H]>CCO.[OH-].[OH-].[Pd+2]>[O:9]([C:10]1[C:11]([NH2:16])=[N:12][CH:13]=[CH:14][CH:15]=1)[C:8]1[CH:7]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: [H][H]
Reactant: Nc1ncccc1Oc1ccc(Br)cc1Br
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCO
Product: Nc1ncccc1Oc1ccccc1
Reaction time: 0.5 h
Yield: 71.6 %

Procedure:
A 2 L Parr bottle was charged with sodium acetate (28.6 g, 349 mmol), 10% Pd(OH)2/C (5.0 g, 7.12 mmol) and 3-(2,4-dibromophenoxy)pyridin-2-amine (60 g, 174 mmol) in 1 L EtOH and placed under 35 psi hydrogen for 18 hours. The reaction was filtered through a plug of celite and then concentrated. The residue was redissolved in CH2Cl2 and washed with aqueous sodium bicarbonate. The organic layer was dried over sodium sulfate, filtered and concentrated. The dark residue was dissolved in EtOAc and charcoal added. The mixture was stirred for 30 minutes then filtered though a plug of celite. The crude material was triturated with 4:1 (EtOAc and hexanes) to afford 3-phenoxypyridin-2-amine (23.2 g, 71.4% yield).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:11]([CH3:20])(O)[O:10][N:9]=2)=[CH:4][CH:3]=1.BrC1C=CC(C2C(C3C=CC(SC)=C(F)C=3)C(C)(O)ON=2)=CC=1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[C:11]([CH3:20])[O:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: CC1(O)ON=C(c2ccc(Br)cc2)C1c1ccccc1
Agent: CSc1ccc(C2C(c3ccc(Br)cc3)=NOC2(C)O)cc1F
Product: Cc1onc(-c2ccc(Br)cc2)c1-c1ccccc1

Procedure:
The title compound was prepared according to the procedure of step 2 in the Example 168 using 3-(4-bromophenyl)-5-methyl-4-phenyl-4,5-dihydro-5-isoxazolol, instead of 3-(4-bromophenyl)-4-(3-fluoro-4-methylthiophenyl)-5-methyl-4,5-dihydro-5-isoxazolol.
Reaction SMILES: Br[C:2]1[C:3]([CH3:15])=[C:4]([O:13][CH3:14])[C:5]2[O:9][CH:8]([CH3:10])[CH2:7][C:6]=2[C:11]=1[CH3:12].[CH3:16][C:17]1[CH:22]=[CH:21][C:20]([N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)=[CH:19][CH:18]=1>>[CH3:14][O:13][C:4]1[C:5]2[O:9][CH:8]([CH3:10])[CH2:7][C:6]=2[C:11]([CH3:12])=[C:2]([N:26]2[CH2:27][CH2:28][N:23]([C:20]3[CH:21]=[CH:22][C:17]([CH3:16])=[CH:18][CH:19]=3)[CH2:24][CH2:25]2)[C:3]=1[CH3:15]
Reactant: Cc1ccc(N2CCNCC2)cc1
Reactant: COc1c(C)c(Br)c(C)c2c1OC(C)C2
Product: COc1c(C)c(N2CCN(c3ccc(C)cc3)CC2)c(C)c2c1OC(C)C2
Yield: 41.7 %

Procedure:
By using 5-bromo-7-methoxy-2,4,6-trimethyl-2,3-dihydro-1-benzofuran (542 mg, 2.0 mmol) synthesized in Reference example 83 and 1-(4-methylphenyl)piperazine (704 mg, 4.0 mmol), the reaction was carried out in the same manner as Example 21 to synthesize the title compound 306 mg (yield 42%).
Reaction SMILES: [C:1]1([CH:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:8]2[CH2:11][CH:10]([CH:12]=[O:13])[CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C-:20]#[N:21].[K+]>O.O1CCCC1>[OH:13][CH:12]([CH:10]1[CH2:11][N:8]([CH:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:9]1)[C:20]#[N:21]
Reactant: O=CC1CN(C(c2ccccc2)c2ccccc2)C1
Reactant: [C-]#N
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: N#CC(O)C1CN(C(c2ccccc2)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 83.7 %

Procedure:
To a solution of 1.13 g (4.49 mmoles) of crude 1-diphenylmethyl-3-formylazetidine in a mixture of 2 ml of water and 2 ml of tetrahydrofuran is added 878 mg (3 equivalents) of potassium cyanide, and the mixture is stirred at room temperature for 2 hours, mixed with water and extracted with methylene chloride. The extract is washed with water, dried, and evaporated to yield 1.046 g of crude 2-hydroxy-2-(1-diphenylmethylazetidin-3-yl)acetonitrile as hemi-solid product in 83% yield.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([OH:7])=[O:6].[I:12]C1CC(=O)NC1=O.S([O-])([O-])(=O)=S.[Na+].[Na+]>FC(F)(F)S(O)(=O)=O>[F:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([I:12])[C:10]=1[CH3:11])[C:5]([OH:7])=[O:6]
Reactant: Cc1ccc(C(=O)O)cc1F
Reactant: O=C1CC(I)C(=O)N1
Agent: O=S(=O)(O)C(F)(F)F
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Product: Cc1c(F)cc(C(=O)O)cc1I
Temperature: -20 °C
Reaction time: 24 h
Yield: 52.9 %

Procedure:
A solution of 3-fluoro-4-methylbenzoic acid (149.7 g) in trifluoromethanesulphonic acid (1050 ml) at −22° C. under nitrogen was treated portionwise over 1.25 h with iodosuccinimide (203.5 g). The mixture was stirred at −20° C. for and further portions of iodosuccinimide were added after 2.5 h (46.5 g) and 20.5 h (30 g). The mixture was stirred at −20° C. for a further 24 h then added slowly to a mixture of aqueous sodium thiosulphate (10%, 1.5 L) and ice (3 kg). The resultant precipitate was collected by filtration and stirred with ethyl acetate (5 L) and aqueous sodium thiosulphate (10%, 1.5 L). The organic phase was dried (MgSO4) and concentrated to ˜1.5 L then left overnight. The precipitate was collected by filtration and further material was obtained through concentration of the filtrate to give the title compound as a white solid (133.9 g).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:27]3[CH2:32][CH2:31][N:30]([C:33]([O:35][CH2:36][C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)=[O:34])[CH2:29][CH2:28]3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([NH:17]C(OC(C)(C)C)=O)=[C:13]([O:25][CH3:26])[CH:12]=3)[C:3]=12.FC(F)(F)C(O)=O>ClCCl>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:27]3[CH2:32][CH2:31][N:30]([C:33]([O:35][CH2:36][C:37]4[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=4)=[O:34])[CH2:29][CH2:28]3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([NH2:17])=[C:13]([O:25][CH3:26])[CH:12]=3)[C:3]=12
Reactant: COc1cc(-c2nn(C3CCN(C(=O)OCc4ccccc4)CC3)c3ncnc(N)c23)ccc1NC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(-c2nn(C3CCN(C(=O)OCc4ccccc4)CC3)c3ncnc(N)c23)ccc1N
Temperature: 25 °C
Reaction time: 18 h
Yield: 94.8 %

Procedure:
To a mixture of benzyl 4-(4-amino-3-{4-[(tert-butoxycarbonyl)amino]-3-methoxyphenyl}-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-1-piperidinecarboxylate (7.68 g, 0.0134 mol) in dichloromethane (10 mL) was added a 25% solution of trifluoroacetic acid in dichloromethane at 0° C. The mixture was stirred under an atmosphere of nitrogen at room temperature for 18 hours. The solvents were removed under reduced pressure. The residue was cooled to 0° C. and basified with an aqueous 5 N solution of sodium hydroxide. The aqueous layer was extracted with dichloromethane (3×150 mL). The combined organic layer was washed with water and brine, and dried over magnesium sulfate. The solvents were removed under reduced pressure to give benzyl 4-[4-amino-3-(4-amino-3-methoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]-1-piperidinecarboxylate (6.02 g, 0.0127 mol).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[O:14]C2N=NC=CC=2C=1O)=[O:5])[CH3:2].C(O[C:19](=[O:31])[C:20]1[C:25]([O:26][CH2:27][CH3:28])=[CH:24][C:23]([CH3:29])=[N:22][C:21]=1Cl)C>>[CH2:1]([O:3][C:4]([C:6]1[O:14][C:21]2=[N:22][C:23]([CH3:29])=[CH:24][C:25]([O:26][CH2:27][CH3:28])=[C:20]2[C:19]=1[OH:31])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1oc2nnccc2c1O
Reactant: CCOC(=O)c1c(OCC)cc(C)nc1Cl
Product: CCOC(=O)c1oc2nc(C)cc(OCC)c2c1O

Procedure:
This compound was prepared using a method analogous to that of 5-hydroxyfuro[2,3-c]pyridazine-6-carboxylic acid ethyl ester (A.2.3.1), 2-chloro-4-ethoxy-6-methylnicotinic acid ethyl ester replacing 3-chloropyridazine-4-carboxylic acid ethyl ester;
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH:13]3[CH2:15][CH2:14]3)[C:11](=[O:16])[N:10]([CH2:17][C:18](O)=[O:19])[N:9]=2)=[CH:4][CH:3]=1.[NH2:21][CH2:22][CH:23]([NH:34][C:35](=[O:41])[O:36][C:37]([CH3:40])([CH3:39])[CH3:38])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[C:30]([F:33])([F:32])[F:31]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH:13]3[CH2:14][CH2:15]3)[C:11](=[O:16])[N:10]([CH2:17][C:18]([NH:21][CH2:22][CH:23]([NH:34][C:35](=[O:41])[O:36][C:37]([CH3:38])([CH3:40])[CH3:39])[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[C:30]([F:33])([F:32])[F:31])=[O:19])[N:9]=2)=[CH:4][CH:3]=1
Reactant: O=C(O)Cn1nc(-c2ccc(Cl)cc2)n(C2CC2)c1=O
Reactant: CC(C)(C)OC(=O)NC(CN)c1ccccc1C(F)(F)F
Product: CC(C)(C)OC(=O)NC(CNC(=O)Cn1nc(-c2ccc(Cl)cc2)n(C2CC2)c1=O)c1ccccc1C(F)(F)F

Procedure:
Analogously to the procedure of Example 63, 43 mg (146 μmol) of [3-(4-chlorophenyl)-4-cyclopropyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]acetic acid [for the preparation see Example 88A in WO 2007/134862] were reacted with 49 mg (161 μmol) of tert-butyl {2-amino-1-[2-(trifluoromethyl)phenyl]ethyl}carbamate. This gave 59 mg (69% of theory) of the title compound.
Reaction SMILES: [CH3:1][C:2]1([CH2:14][OH:15])[CH2:6][N:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[NH:4][C:3]1=[O:13].[CH:16]1[CH:21]=[C:20]2[C:22]([O:24][S:25](=[O:27])(=[O:26])[C:19]2=[CH:18][CH:17]=1)=[O:23]>C(#N)C>[S:25]([C:19]1[CH:18]=[CH:17][CH:16]=[CH:21][C:20]=1[C:22]([O:15][CH2:14][C:2]1([CH3:1])[CH2:6][N:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[NH:4][C:3]1=[O:13])=[O:23])([OH:27])(=[O:26])=[O:24]
Reactant: CC1(CO)CN(c2ccccc2)NC1=O
Reactant: O=C1OS(=O)(=O)c2ccccc21
Solvent: CC#N
Product: CC1(COC(=O)c2ccccc2S(=O)(=O)O)CN(c2ccccc2)NC1=O
Reaction time: 24 h

Procedure:
To a suspension of 4-methyl-4-hydroxymethyl-1-phenyl-3-pyrazolidinone (dimezone-S) (10 g, 48.5 mmol) in dry acetonitrile (200 ml), was added 2-sulfobenzoic acid cyclic anhydride (8.9 g, 48.5 mmol) in a single portion at room temperature with stirring. The reaction mixture was heated to reflux under nitrogen until complete dissolution was observed. The reflux was continued for 24 hours and the mixture was cooled in an ice/water bath for 2 hours. A solid precipitate was obtained which was recovered by filtration and washed with ice cooled acetonitrile. After drying under vacuum, 17.9 g (95%) of 4-methyl-3-oxo-1-phenyl-pyrazolidin-4-yl)methyl 2-sulfobenzoate (Compound II) were isolated as an off-white solid.
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]1[C:8]([NH:9][C:10](=O)[CH3:11])=[CH:7][C:6]([CH3:13])=[N:5]1.ClC1C=[C:19]([I:21])[C:18]([C:22]([F:25])([F:24])[F:23])=[CH:17][N:16]=1.O.[OH-].[Li+]>C1COCC1.CCOC(C)=O.O.CN(C=O)C>[CH3:3][N:4]1[C:8]([NH:9][C:10]2[CH:11]=[C:19]([I:21])[C:18]([C:22]([F:25])([F:24])[F:23])=[CH:17][N:16]=2)=[CH:7][C:6]([CH3:13])=[N:5]1
Reactant: FC(F)(F)c1cnc(Cl)cc1I
Reactant: CC(=O)Nc1cc(C)nn1C
Agent: [H-]
Agent: [Li+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1cc(Nc2cc(I)c(C(F)(F)F)cn2)n(C)n1
Temperature: 35 °C
Reaction time: 0.5 h
Yield: 54.1 %

Procedure:
A suspension of 2,5-dimethylpyrazol-3-amine (1 g, 9.00 mmol), potassium acetate (0.971 g, 9.90 mmol) and acetic anhydride (1.002 mL, 9.00 mmol) in EtOAc (25 mL) was stirred at 25° C. overnight. Silica gel was added and the mixture was concentrated. The crude product was purified by flash chromatography on silica gel eluting with 0 to 5% MeOH in DCM. The solvent was evaporated to dryness to afford N-(2,5-dimethylpyrazol-3-yl)acetamide (1.400 g, 102%) as a pale yellow oil. Mass spectrum: MH+ 154 Sodium hydride (0.385 g, 9.14 mmol) was added to N-(2,5-dimethylpyrazol-3-yl)acetamide (1.4 g, 9.14 mmol) dissolved in THF (20 mL) under nitrogen. The resulting light suspension was stirred at 35° C. for 30 minutes then 2-chloro-4-iodo-5-(trifluoromethyl)pyridine (1.338 g, 4.35 mmol) was added. DMF (2 mL) was added and the mixture was stirred at 80° C. for 18 hours. The reaction mixture was cooled to room temperature, quenched with water (20 mL). Lithium hydroxide hydrate (0.548 g, 13.06 mmol) was added and the mixture was stirred at room temperature for 1.5 hours. The mixture was diluted with EtOAc and water, the phases were separated and the organic phase washed with brine, dried over magnesium sulfate and concentrated. The residue was purified by flash chromatography on silica gel (40 g) eluting with 0 to 50% EtOAc in DCM. After collection of the fractions and evaporation of the solvents, the resulting solid was triturated in petroleum ether, collected by filtration, washed with petroleum ether and dried to a constant weight to afford N-(2,5-dimethylpyrazol-3-yl)-4-iodo-5-(trifluoromethyl)pyridin-2-amine (900 mg, 54.1%) as an off-white solid.
Reaction SMILES: [CH:1](I)([CH3:3])[CH3:2].[F:5][C:6]([F:18])([F:17])[C:7]1[C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:10][NH:9][N:8]=1.CCN(C(C)C)C(C)C>CN(C=O)C.C(OCC)(=O)C.CN(C)C1C=CN=CC=1>[CH:1]([N:9]1[CH:10]=[C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:7]([C:6]([F:5])([F:17])[F:18])=[N:8]1)([CH3:3])[CH3:2]
Reactant: CCOC(=O)c1c[nH]nc1C(F)(F)F
Reactant: CC(C)I
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cn(C(C)C)nc1C(F)(F)F
Temperature: 60 °C
Reaction time: 3 h
Yield: 44.3 %

Procedure:
Isopropyl iodide (1.225 g, 7.21 mmol) was added to a solution of ethyl 3-(trifluoromethyl)-1H-pyrazole-4-carboxylate (500 mg, 2.402 mmol) and DIEA (652 mg, 5.04 mmol) in DMF (5 mL) and the reaction stirred at RT for 3 h and 60° C. for 3 h. The reaction was diluted with ethyl acetate (30 mL), washed with 5% citric acid (30 mL), saturated sodium bicarbonate (30 mL) and brine (30 mL), dried (Na2SO4) and concentrated in vacuo to give an oil. LC and LCMS showed starting material still present (˜40%). The oil was dissolved in DMF (4 mL), treated with DIEA (652 mg, 5.04 mmol), isopropyliodide (1.22 g, 7.21 mmol) and catalytic 4-dimethylaminopyridine (˜5 mg) and stirred at RT overnight. The reaction was diluted with ethyl acetate (30 mL), washed with 5% citric acid (30 mL) saturated sodium bicarbonate (30 mL) and brine (30 mL), dried Na2SO4), concentrated in vacuo and purified by column chromatography (ethyl acetate/hexane) to afford ethyl 1-isopropyl-3-(trifluoromethyl)-1H-pyrazole-4-carboxylate (266 mg, 44% yield). 1H NMR (300 MHz, DMSO-d6): δ 1.26 (s, 9 H), 1.43 (d, 6 H), 4.23 (q, 2 H), 4.64 (hp, 1 H), 8.62 (s, 1 H); MS (ESI) m/z: 251.0 (M+H+).
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[CH2:12][C@H:11]([N:13]2[C:17]3[CH:18]=[C:19]([F:22])[CH:20]=[CH:21][C:16]=3[N:15]=[C:14]2[C@@H:23]([NH2:25])[CH3:24])[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:27]1[N:35]=[CH:34][N:33]=[C:32]2[C:28]=1[N:29]=[CH:30][N:31]2C1CCCCO1.CCN(C(C)C)C(C)C>CC(O)C>[CH2:1]([O:8][C@@H:9]1[CH2:12][C@H:11]([N:13]2[C:17]3[CH:18]=[C:19]([F:22])[CH:20]=[CH:21][C:16]=3[N:15]=[C:14]2[C@@H:23]([NH:25][C:27]2[N:35]=[CH:34][N:33]=[C:32]3[C:28]=2[N:29]=[CH:30][NH:31]3)[CH3:24])[CH2:10]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[C@H](N)c1nc2ccc(F)cc2n1[C@H]1C[C@@H](OCc2ccccc2)C1
Reactant: Clc1ncnc2c1ncn2C1CCCCO1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: C[C@H](Nc1ncnc2[nH]cnc12)c1nc2ccc(F)cc2n1[C@H]1C[C@@H](OCc2ccccc2)C1
Temperature: 90 °C
Yield: 76.9 %

Procedure:
A mixture of (S)-1-[1-(cis-3-benzyloxycyclobutyl)-6-fluoro-1H-benzoimidazol-2-yl]ethylamine (310 mg, 0.91 mmol), 6-chloro-9-(tetrahydropyran-2-yl)-9H-purine (219 mg, 0.91 mmol) and DIPEA (0.81 mL, 4.57 mmol) in IPA (5 mL) was heated at 90° C. in a sealed vial for 16 h. After cooling to RT, the reaction mixture was concentrated in vacuo, dissolved in DCM and loaded onto an Isolute® SCX-2 cartridge which was washed with DCM, MeOH followed by 2M NH3/MeOH. The product containing fractions were combined and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, gradient 0-10% 2M NH3/MeOH in DCM) to afford the title compound as a glassy white solid (320 mg, 76%). LCMS (Method B): RT 2.76 min [M+H]+ 458. 1H NMR (CDCl3, 400 MHz): δ 8.48 (1H, s), 7.95 (1H, s), 7.71-7.58 (2H, m), 7.42-7.35 (5H, m), 7.07-6.90 (2H, m), 5.95 (1H, s, br), 4.97-4.80 (m, 1H), 4.52 (2H, s), 4.05-3.92 (1H, m), 3.01-2.86 (2H, m), 2.81-2.64 (1H, m), 1.75 (3H, d, J=6.85 Hz).