Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:5]1[CH2:19]Br)(=[O:3])[CH3:2].[C:21](=[S:24])([O-:23])[CH3:22].[K+]>CC(C)=O.CCOC(C)=O>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:5]1[CH2:19][S:24][C:21](=[O:23])[CH3:22])(=[O:3])[CH3:2]
Reactant: CCOC(=O)Cc1c(CBr)n(C(C)=O)c2ccccc12
Reactant: CC([O-])=S
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: CCOC(=O)Cc1c(CSC(C)=O)n(C(C)=O)c2ccccc12
Yield: 84.2 %

Procedure:
To a solution of ethyl 2-(1-acetyl-2-(bromomethyl)-1H-indol-3-yl)acetate (I-4A, 640 mg, 1.9 mmol) in acetone (10 ml) was added potassium ethanethioate (1.3 g, 11.2 mmol). The solution was heated at reflux for 1 hour. The solution was cooled and then diluted with EtOAc (50 ml) and washed with NaHCO3 (aq) (2×25 ml). The organic layer was dried with Na2SO4, filtered and concentrated. The crude product was introduced to a silica gel loading column and purified by column chromatography (10-30 EtOAc/hexanes) to get 533 mg (1.6 mmol, 84%) product. MS (m/z) 334 [M+H]+.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]([C:11]1[CH:19]=[CH:18][C:14]([C:15](O)=[O:16])=[CH:13][CH:12]=1)[CH:8]([CH3:10])[CH3:9]>C1COCC1>[CH2:7]([C:11]1[CH:12]=[CH:13][C:14]([CH2:15][OH:16])=[CH:18][CH:19]=1)[CH:8]([CH3:10])[CH3:9]
Reactant: CC(C)Cc1ccc(C(=O)O)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)Cc1ccc(CO)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of lithium aluminum hydride (30 mL, 1M in THF, 30 mmol) was added dropwise to a solution of 4-isobutylbenzoic acid (5.34 g, 30 mmol) in THF (50 mL) at 0° C. The ice bath was removed and the reaction was stirred at room temperature for 1 h. The reaction was carefully poured onto a mixture of ice and aqueous HCl (10 mL, 6N). The product was extracted into EtOAc and the organic solution was dried (MgSO4), filtered, and concentrated to obtain (4-isobutyl-phenyl)-methanol which was used in the next step without further purification. 1H NMR (400 MHz, CDCl3) δ 7.26 (d, 2H), 7.13 (d, 2H), 4.65 (s, 2H), 2.46 (d, 2H), 1.85 (m, 1H), 0.89 (d, 6H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:19]=[CH:18][C:17](Br)=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:21][C:22]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][CH:23]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:19]=[CH:18][C:17]([C:25]3[CH:26]=[CH:27][C:22]([F:21])=[CH:23][CH:24]=3)=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ncc(Br)cn2)CC1
Reactant: OB(O)c1ccc(F)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: CC(C)(C)OC(=O)N1CCN(c2ncc(-c3ccc(F)cc3)cn2)CC1
Yield: 95.8 %

Procedure:
4-(5-Bromopyrirnidin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (1.01 g), 4-fluorophenylboronic acid (0.45 g), tetrakis(triphenylphosphine)palladium(0) (0.12 g) and potassium phosphate (1.25 g) were dissolved in a mixture of 1,2-dimethoxyethane (40 ml) and water (10 ml), degassed and heated to reflux under nitrogen. After 16 h. the reaction was cooled, reduced in vacuo, dissolved in diethyl ether (100 ml) and washed with water (3×20 ml), saturated brine (20 ml), dried (Na2SO4) and evaporated. The black residue was then chromatographed on silica, with 2% methanol/dichloromethane to provide the title compound as a pale yellow solid (1.01 g, 96%).
Reaction SMILES: CC(C)([O-])C.[K+].[F:7][C:8]([F:17])([F:16])[C:9]1[CH:10]=[C:11]([OH:15])[CH:12]=[CH:13][CH:14]=1.[CH2:18]([O:20][C:21](=[O:26])[CH:22]=[C:23](Cl)[CH3:24])[CH3:19]>O1CCCC1>[CH2:18]([O:20][C:21](=[O:26])/[CH:22]=[C:23](/[O:15][C:11]1[CH:12]=[CH:13][CH:14]=[C:9]([C:8]([F:16])([F:17])[F:7])[CH:10]=1)\[CH3:24])[CH3:19]
Reactant: CCOC(=O)C=C(C)Cl
Reactant: Oc1cccc(C(F)(F)F)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCOC(=O)/C=C(\C)Oc1cccc(C(F)(F)F)c1
Temperature: 23 °C
Yield: 62.7 %

Procedure:
Potassium t-butoxide (6.90 g, 0.061 mol) was added to a stirred solution of 3-trifluoromethyl-phenol (5.00 g, 0.031 mol) in tetrahydrofuran (35 mL) at 23° C. under nitrogen and the reaction mixture was heated to reflux for 0.75 h. The reaction mixture was cooled to 23° C. and a solution of 3-chloro-but-2-enoic acid ethyl ester (prepared as in Example 191, 4.56 g, 0.031 mol) in tetrahydrofuran (40 mL) was added to the reaction mixture. The reaction mixture was refluxed for an additional 3 h. After this time, the mixture was concentrated in vacuo and the residue was diluted with water and extracted with diethyl ether. The organic layer was then washed with 5% aqueous sodium hydroxide solution followed by a saturated aqueous sodium chloride solution, dried over sodium sulfate and concentrated in vacuo to afford (E)-3-(3-trifluoromethyl-phenoxy)-but-2-enoic acid ethyl ester (5.33 g, 63%) as a yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([NH2:18])=[CH:5][C:6]2[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][O:15][CH3:16])[CH2:9][CH2:8][C:7]=2[CH:17]=1.Cl[C:20]1[N:25]=[C:24]([NH:26][C:27]2[CH:32]=[CH:31][C:30]([N:33]3[CH2:38][CH2:37][O:36][CH2:35][CH2:34]3)=[CH:29][C:28]=2[O:39][CH3:40])[C:23]([Cl:41])=[CH:22][N:21]=1.Cl.C(O)(C)C>O1CCOCC1>[Cl:41][C:23]1[C:24]([NH:26][C:27]2[CH:32]=[CH:31][C:30]([N:33]3[CH2:34][CH2:35][O:36][CH2:37][CH2:38]3)=[CH:29][C:28]=2[O:39][CH3:40])=[N:25][C:20]([NH:18][C:4]2[C:3]([O:2][CH3:1])=[CH:17][C:7]3[CH2:8][CH2:9][N:10]([CH2:13][CH2:14][O:15][CH3:16])[CH2:11][CH2:12][C:6]=3[CH:5]=2)=[N:21][CH:22]=1
Reactant: COc1cc(N2CCOCC2)ccc1Nc1nc(Cl)ncc1Cl
Reactant: COCCN1CCc2cc(N)c(OC)cc2CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CC(C)O
Product: COCCN1CCc2cc(Nc3ncc(Cl)c(Nc4ccc(N5CCOCC5)cc4OC)n3)c(OC)cc2CC1
Temperature: 130 °C
Reaction time: 0.5 h

Procedure:
Combined 8-Methoxy-3-(2-methoxy-ethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamine (55 mg, 0.00022 mol), (2,5-Dichloro-pyrimidin-4-yl)-(2-methoxy-4-morpholin-4-yl-phenyl)-amine (86 mg, 0.00024 mol), 4 M of Hydrogen chloride in 1,4-Dioxane (70 uL) and Isopropyl alcohol (2.2 mL, 0.029 mol) in microwave vessel. Heat at 130° C. for 10 minutes. Heat for another 10 minutes. Cool to room temp. Solid precipitated out of solution. Filtered off solid. The filtrate was treated with MP-carbonate 250 mgs and stirred for 30 min. The mixture was concentrated and purified by ISCO chromatography (40 g SiO2 column, gradient 100% DCM to 10% MeOH/DCM. Isolated 5-Chloro-N*2*-[8-methoxy-3-(2-methoxy-ethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yl]-N*4*-(2-methoxy-4-morpholin-4-yl-phenyl)-pyrimidine-2,4-diamine as an off-white solid (49 mgs, 39%) Melting point: 138-140° C. δ 8.30 (d, J=8.8 Hz, 1H), 8.12 (s, 1H), 8.03 (d, J=1.8 Hz, 1H), 7.57 (s, 1H), 7.45 (s, 1H), 6.65 (s, 1H), 6.57-6.52 (m, 2H), 3.94-3.88 (m, 10H), 3.36 (br s, 2H), 3.39 (d, J=1.7 Hz, 3H), 3.18-3.17 (m, 4H), 2.90-2.74 (m, 10H); LC/MS: 568.87 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH2:23][CH2:24][OH:25])[CH2:10][C:11]([N:13]([CH3:22])[C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)=[O:12])[CH:5]=[CH:6][C:7]=1[Cl:8].CCN(CC)CC.[CH3:33][S:34](Cl)(=[O:36])=[O:35]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH2:23][CH2:24][O:25][S:34]([CH3:33])(=[O:36])=[O:35])[CH2:10][C:11]([N:13]([CH3:22])[C:14]2[CH:15]=[CH:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=2)=[O:12])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: COc1ccc(N(C)C(=O)CC(CCO)c2ccc(Cl)c(Cl)c2)cc1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(N(C)C(=O)CC(CCOS(C)(=O)=O)c2ccc(Cl)c(Cl)c2)cc1

Procedure:
3,4-Dichloro-beta-(2-hydroxyethyl)-N-methyl-N-(4-methoxyphenyl)-benzene propanamide (2.0 g) in CH2Cl2 (50 mL) was cooled to -5° to -10° C. and treated sequentially with Et3N (0.911 mL), and methanesulfonyl chloride (0.64 mL). After two hours the reaction mixture was washed with water (100 mL), brine (100 mL) and the organic layer separated, dried over MgSO4, filtered and concentrated under reduced pressure to give the title compound (2.56 g).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11]([C:22]2[CH:37]=[CH:36][C:25]([C:26]([NH:28][NH:29][C:30]([CH:32]3[CH2:35][CH2:34][CH2:33]3)=O)=[O:27])=[CH:24][CH:23]=2)([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.S(OS(C(F)(F)F)(=O)=O)(C(F)(F)F)(=O)=O>C(Cl)Cl>[CH2:1]([N:8]1[CH2:13][CH2:12][C:11]([C:22]2[CH:23]=[CH:24][C:25]([C:26]3[O:27][C:30]([CH:32]4[CH2:33][CH2:34][CH2:35]4)=[N:29][N:28]=3)=[CH:36][CH:37]=2)([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=2)[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1cccc(C2(c3ccc(C(=O)NNC(=O)C4CCC4)cc3)CCN(Cc3ccccc3)CC2)c1
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1cccc(C2(c3ccc(-c4nnc(C5CCC5)o4)cc3)CCN(Cc3ccccc3)CC2)c1
Temperature: -78 °C
Reaction time: 2 h
Yield: 99 %

Procedure:
To a solution of cyclobutanecarboxylic acid N′-{4-[1-benzyl-4-(3-methoxy-phenyl)-piperidin-4-yl]-benzoyl}-hydrazide (0.2 g, 0.40 mmol) in CH2Cl2 (3 mL) was added pyridine (0.08 mL, 1.0 mmol). The reaction mixture was cooled to −78° C. Triflic anhydride (0.14 mL, 0.84 mmol) was added dropwise. The mixture was stirred at −78° C. for 1 hour and at room temperature for 2 hours. The reaction was quenched with saturated aqueous sodium bicarbonate (3 mL). The aqueous layer was washed with CH2Cl2 (3×5 mL) and the combined extracts were dried (MgSO4) and concentrated. Purification by flash chromatograpy with EtOAc afforded 0.19 g (quantitative yield) of 1-Benzyl-4-[4-(5-cyclobutyl-[1,3,4]oxadiazol-2-yl)-phenyl]-4-(3-methoxy-phenyl)-piperidine. 1HNMR (400 MHz, CDCl3) δ 7.92 (d, 2H), 7.37 (d, 2H), 7.36-7.16 (comp, 6H), 6.83 (d, 1H), 6.80 (s, 1H), 6.60 (d, 1H), 3.81-3.78 (m, 1H), 3.77 (s, 3H), 3.45 (s, 2H), 2.82-2.38 (comp, 10H), 2.21-2.19 (comp, 2H); MS (M+1) 480.2.
Reaction SMILES: [OH:1][C:2]([C:5]1[CH:31]=[CH:30][C:8]([C:9]([NH:11][C:12]2[CH:17]=[C:16]([N:18]3[CH2:23][CH2:22][CH:21]([C:24]([OH:26])=O)[CH2:20][CH2:19]3)[N:15]3[N:27]=[CH:28][CH:29]=[C:14]3[N:13]=2)=[O:10])=[CH:7][CH:6]=1)([CH3:4])[CH3:3].CN.C[CH2:35][N:36]=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C>[OH:1][C:2]([C:5]1[CH:6]=[CH:7][C:8]([C:9]([NH:11][C:12]2[CH:17]=[C:16]([N:18]3[CH2:19][CH2:20][CH:21]([C:24]([NH:36][CH3:35])=[O:26])[CH2:22][CH2:23]3)[N:15]3[N:27]=[CH:28][CH:29]=[C:14]3[N:13]=2)=[O:10])=[CH:30][CH:31]=1)([CH3:3])[CH3:4]
Reactant: CC(C)(O)c1ccc(C(=O)Nc2cc(N3CCC(C(=O)O)CC3)n3nccc3n2)cc1
Reactant: CCN=C=NCCCN(C)C
Agent: CN
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CNC(=O)C1CCN(c2cc(NC(=O)c3ccc(C(C)(C)O)cc3)nc3ccnn23)CC1
Yield: 54.5 %

Procedure:
A solution of 1-(5-(4-(2-hydroxypropan-2-yl)benzamido)pyrazolo[1,5-a]pyrimidin-7-yl)piperidine-4-carboxylic acid (Compound 244, 80 mg, 0.189 mmol), methylamine (33 μL, 0.378 mmol), EDCI (72 mg, 0.378 mmol), and HOBT (13 mg, 0.094 mmol) in DMF (4 mL) were stirred for 12 hours at room temperature. The reaction was complete as determined by LCMS analysis. The reaction mixture was then partitioned between ethyl acetate and water and the separated organic layer was dried over Mg2SO4, filtered, and concentrated under reduced pressure. Purification by preparatory HPLC, 30-50% (MeCN/H2O gradient+0.01% TFA) provided the titled compound as a yellow oil (45 mg, 55%). 1H NMR (DMSO-d6) δ: 10.90 (s, 1H), 8.09 (d, J=2.3 Hz, 1H), 8.00 (d, J=8.8 Hz, 2H), 7.80-7.87 (m, 1H), 7.60 (d, 2H), 7.41 (s, 1H), 6.35 (d, J=2.3 Hz, 1H), 4.46 (d, J=12.1 Hz, 2H), 3.10 (td, J=12.3, 2.8 Hz, 2H), 2.59 (d, J=4.5 Hz, 3H), 1.71-1.90 (m, 4H), 1.44 (s, 6H). ESI-MS: m/z 437.0 (M+H)+.
Reaction SMILES: I[CH2:2][C:3]1([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1.[CH2:21]([O:25][C:26]1[CH:31]=[CH:30][C:29]([SH:32])=[CH:28][CH:27]=1)[C:22]#[C:23][CH3:24].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CCOC(C)=O>[CH2:21]([O:25][C:26]1[CH:27]=[CH:28][C:29]([S:32][CH2:2][C:3]2([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]2)=[CH:30][CH:31]=1)[C:22]#[C:23][CH3:24]
Reactant: CC#CCOc1ccc(S)cc1
Reactant: CCOC(=O)C1(CI)CCN(C(=O)OC(C)(C)C)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC#CCOc1ccc(SCC2(C(=O)OCC)CCN(C(=O)OC(C)(C)C)CC2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 99 %

Procedure:
A mixture of 0.294 g (0.74 mmol) of 1-(tert-Butyl) 4-ethyl 4-(iodomethyl)piperidine-1,4-dicarboxylate, 0.145 (0.814 mmol) of 4-but-2-ynyloxy-benzenethiol and 0.204 g (1.48 mmol) of K2CO3 in 2.0 mL of DMF was stirred at room temperature for 18 h. The resulting mixture was diluted with EtOAc, washed with H2O, brine, dried over MgSO4 and concentrated in vacuo. The residue was chromatographed on silica gel eluting with EtOAc:Hexanes (1:19) to provide 0.328 g (99%) of the desired product as a colorless oil. Electrospray Mass Spec: 448.3 (M+H)+
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=O.[CH3:17][CH:18]([CH3:26])[CH2:19][C:20](=O)[CH2:21][C:22](=[O:24])[CH3:23]>>[Br:8][C:5]1[CH:4]=[C:3]2[C:2](=[CH:7][CH:6]=1)[N:1]=[C:20]([CH2:19][CH:18]([CH3:26])[CH3:17])[C:21]([C:22](=[O:24])[CH3:23])=[C:9]2[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Nc1ccc(Br)cc1C(=O)c1ccccc1
Reactant: CC(=O)CC(=O)CC(C)C
Product: CC(=O)c1c(CC(C)C)nc2ccc(Br)cc2c1-c1ccccc1
Yield: 9 %

Procedure:
The title compound was prepared from (2-Amino-5-bromo-phenyl)-phenyl-methanone [example A16] and 6-methyl-2,4-heptanedione according to the procedure of example 1. Yield: 9%. MS: m/z=381 (M).
Reaction SMILES: [OH:1][C:2]1[C:3]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][C:4]=2[S:5][C:6]=1[C:7]([O:9][CH3:10])=[O:8].S(OC)(O[CH3:23])(=O)=O.C(=O)(O)[O-].[Na+]>CC(C)=O>[CH3:23][O:1][C:2]1[C:3]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:16])[F:17])=[CH:11][C:4]=2[S:5][C:6]=1[C:7]([O:9][CH3:10])=[O:8]
Reactant: COS(=O)(=O)OC
Reactant: COC(=O)c1sc2cc(C(F)(F)F)ccc2c1O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Product: COC(=O)c1sc2cc(C(F)(F)F)ccc2c1OC

Procedure:
A mixture of compound 68b (0.543 mmol, 150 mg), dimethyl sulfate (0.608 mmol, 0.058 mL), and sodium bicarbonate (0.57 mmol, 48 mg) in acetone was heated at reflux overnight. The reaction mixture was cooled and filtered. The filtrate was concentrated and the residue was partitioned between EtOAc and water. The organic solution was concentrated and purified by flash column chromatography (silica gel, 10% EtOAc/hexanes) to give compound 68c.
Reaction SMILES: [F:1][CH:2]([F:34])[C:3]1[N:8]=[CH:7][C:6]([CH2:9][NH:10][C:11](=[O:17])[C:12]([CH3:16])([CH3:15])[CH2:13]O)=[CH:5][C:4]=1[C:18]1[NH:22][C:21](=[O:23])[N:20]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=2)[N:19]=1.CCN(S(F)(F)[F:41])CC>C(Cl)Cl>[F:41][CH2:13][C:12]([CH3:16])([CH3:15])[C:11]([NH:10][CH2:9][C:6]1[CH:7]=[N:8][C:3]([CH:2]([F:1])[F:34])=[C:4]([C:18]2[NH:22][C:21](=[O:23])[N:20]([C:24]3[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=3)[N:19]=2)[CH:5]=1)=[O:17]
Reactant: CC(C)(CO)C(=O)NCc1cnc(C(F)F)c(-c2nn(-c3ccc(C(F)(F)F)cc3)c(=O)[nH]2)c1
Reactant: CCN(CC)S(F)(F)F
Solvent: ClCCl
Product: CC(C)(CF)C(=O)NCc1cnc(C(F)F)c(-c2nn(-c3ccc(C(F)(F)F)cc3)c(=O)[nH]2)c1
Yield: 8.5 %

Procedure:
The title compound was prepared by following the procedure as described in step-2 of Example-134 by using N-((6-(difluoromethyl)-5-(1-(4-(trifluoromethyl)phenyl)-4,5-dihydro-5-oxo-1H-1,2,4-triazol-3-yl)pyridin-3-yl)methyl)-3-hydroxy-2,2-dimethylpropanamide (0.060 g, 0.12 mmol), DAST (0.060 g, 0.37 mmol), DCM (10 mL) to afford 0.005 g the desired product. 1H NMR (300 MHz, DMSO d6): δ 0.80 (br s, 6H), 4.22 (br s, 1H), 4.38-4.42 (m, 3H), 7.41-7.66 (m, 3H), 7.95 (br s, 1H), 8.08-8.11 (m, 2H), 8.61 (s, 1H); MS (m/z): 488.23 (M+H)+.
Reaction SMILES: [C:1]([CH:3]([CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]2[O:14][CH2:15][O:16][C:9]=12)C(O)=O)#[N:2].CN(C)C=O>O>[C:1]([CH2:3][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]2[O:14][CH2:15][O:16][C:9]=12)#[N:2]
Reactant: N#CC(Cc1cccc2c1OCO2)C(=O)O
Solvent: O
Solvent: CN(C)C=O
Product: N#CCCc1cccc2c1OCO2
Temperature: 150 °C

Procedure:
0.046 mole of the acid obtained in stage B is mixed with 19 ml of dimethylformamide and the mixture is then heated to 150° C. for 2 hours. The mixture is taken up with water and the product is extracted with ethyl ether. The organic phases are washed with sodium bicarbonate solution and then with water; they are dried and the solvent is evaporated off to obtain an oily residue.
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:8]([CH3:32])([CH3:31])[NH:9][C:10](=[O:30])[C:11]=1[C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19]C2C=CC3C(=CC=CC=3)N=2)=[CH:14][CH:13]=1)(=O)=O.[N:35]1[CH:40]=[CH:39][C:38](B(O)O)=[CH:37][CH:36]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:32][C:8]1([CH3:31])[NH:9][C:10](=[O:30])[C:11]([C:12]2[CH:13]=[CH:14][C:15]([O:18][CH2:19][C:36]3[CH:37]=[CH:38][C:39]4[C:40](=[CH:8][CH:7]=[CH:11][CH:10]=4)[N:35]=3)=[CH:16][CH:17]=2)=[C:7]1[C:38]1[CH:39]=[CH:40][N:35]=[CH:36][CH:37]=1
Reactant: OB(O)c1ccncc1
Reactant: CC1(C)NC(=O)C(c2ccc(OCc3ccc4ccccc4n3)cc2)=C1OS(=O)(=O)C(F)(F)F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CC1(C)NC(=O)C(c2ccc(OCc3ccc4ccccc4n3)cc2)=C1c1ccncc1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 29.7 %

Procedure:
To a solution of 2,2-dimethyl-5-oxo-4-(4-(quinolin-2-ylmethoxy)phenyl)-2,5-dihydro-1H-pyrrol-3-yl trifluoromethanesulfonate (2.0 g, 0.004 mol) in 1,4-dioxane (50 mL) were added pyridin-4-yl boronic acid (598 mg, 4.8 mol), Na2CO3 (1.0 g, 0.012 mol) and water (20 mL) at RT under an inert atmosphere. The mixture was stirred for 30 min and then Pd(PPh3)4 (468 mg, 0.4 mol) was added. The mixture was then heated at 80° C. for 16 h, diluted with water, and extracted with EtOAc (2×200 mL). The combined organic layers were washed with water and brine, and then dried over Na2SO4 and concentrated in vacuo to afford 5,5-dimethyl-4-(pyridin-4-yl)-3-(4-(quinolin-2-ylmethoxy)phenyl)-1H-pyrrol-2(5H)-one (250 mg, 15%) as a white solid. 1H NMR (500 MHz, d6-DMSO): δ 8.74-8.68 (m, 1H), 8.66-8.56 (m, 2H), 8.06-7.94 (m, 2H), 7.78 (t, J=7.2 Hz, 1H), 7.66-7.56 (m, 3H), 7.30-7.18 (m, 4H), 6.98-6.88 (m, 3H), 5.36 (s, 2H), 1.36 (s, 6H). MS: M+H: m/z=422.1; M+Na: m/z=444.1. HPLC: 89%, (Condition-I).
Reaction SMILES: [ClH:1].[Br:2][C:3]1[CH:8]=[C:7](C)[CH:6]=[CH:5][C:4]=1[NH:10][NH2:11].Br[C:13]1C(C)=CC=CC=1N>>[ClH:1].[Br:2][C:3]1[C:8]([CH3:13])=[CH:7][CH:6]=[CH:5][C:4]=1[NH:10][NH2:11]
Reactant: Cc1ccc(NN)c(Br)c1
Reactant: Cc1cccc(N)c1Br
Agent: Cl
Product: Cc1cccc(NN)c1Br

Procedure:
2-Bromo-3-methylphenylhydrazine hydrochloride (23 g) was prepared as described for 2-bromo-4-methylphenylhydrazine hydrochloride in Example 4, except using 2-bromo-3-methylaniline as starting material.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[CH:7][C:8]([Cl:42])=[C:9]([N:11]2[C:15](=[O:16])[N:14]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]4[CH:29]=[C:28]([CH2:30][CH2:31][CH3:32])[CH:27]=[CH:26][C:25]=4[S:33](=[O:36])(=[O:35])[NH2:34])=[CH:20][C:19]=3[F:37])[C:13]([CH2:38][CH2:39][CH2:40][CH3:41])=[N:12]2)[CH:10]=1)(=[O:3])[CH3:2].[Cl:43][C:44]1[CH:52]=[CH:51][CH:50]=[CH:49][C:45]=1[C:46](O)=[O:47].C1N=CN(C(N2C=NC=C2)=O)C=1.C1CCN2C(=NCCC2)CC1>>[C:1]([NH:4][C:5]1[CH:6]=[CH:7][C:8]([Cl:42])=[C:9]([N:11]2[C:15](=[O:16])[N:14]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]4[CH:29]=[C:28]([CH2:30][CH2:31][CH3:32])[CH:27]=[CH:26][C:25]=4[S:33](=[O:36])(=[O:35])[NH:34][C:46](=[O:47])[C:45]4[CH:49]=[CH:50][CH:51]=[CH:52][C:44]=4[Cl:43])=[CH:20][C:19]=3[F:37])[C:13]([CH2:38][CH2:39][CH2:40][CH3:41])=[N:12]2)[CH:10]=1)(=[O:3])[CH3:2]
Reactant: CCCCc1nn(-c2cc(NC(C)=O)ccc2Cl)c(=O)n1Cc1ccc(-c2cc(CCC)ccc2S(N)(=O)=O)cc1F
Reactant: O=C(O)c1ccccc1Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCC2=NCCCN2CC1
Product: CCCCc1nn(-c2cc(NC(C)=O)ccc2Cl)c(=O)n1Cc1ccc(-c2cc(CCC)ccc2S(=O)(=O)NC(=O)c2ccccc2Cl)cc1F
Yield: 56 %

Procedure:
Reaction of 2-[5-(acetylamino)-2-chlorophenyl]-5-n-butyl-2,4-dihydro-4-[(3-fluoro-5'-n-propyl-2'-sulfamoylbiphenyl-4-yl)methyl]-3H-1,2,4-triazol-3-one (from Step E) with 2-chlorobenzoic acid (2 equivalents), CDI (2 equiv), and DBU (2 equiv) according to the procedure of Example 69 gave a 56% yield of the title compound as a white, glassy solid, mp 144°-146° C.; homogeneous by TLC (95:5 CH2Cl2 --MeOH); mass spectrum (FAB) m/e 752 (M+1)+.
Reaction SMILES: [OH:1][C:2]1[CH2:7][N:6]([CH3:8])[S:5](=[O:10])(=[O:9])[N:4]([CH3:11])[C:3]=1[C:12]([O:14]C)=O.[NH2:16][C:17]1[CH:21]=[C:20]([CH3:22])[O:19][N:18]=1>>[OH:1][C:2]1[CH2:7][N:6]([CH3:8])[S:5](=[O:9])(=[O:10])[N:4]([CH3:11])[C:3]=1[C:12]([NH:16][C:17]1[CH:21]=[C:20]([CH3:22])[O:19][N:18]=1)=[O:14]
Reactant: Cc1cc(N)no1
Reactant: COC(=O)C1=C(O)CN(C)S(=O)(=O)N1C
Product: Cc1cc(NC(=O)C2=C(O)CN(C)S(=O)(=O)N2C)no1
Yield: 49 %

Procedure:
The synthesis was effected analogously to Example 1 using in each case 1.0 equivalent of methyl 5,6-dihydro-4-hydroxy-2,6-dimethyl-1,1-dioxo-2H-1,2,6-thiadiazine-3-carboxylate and 3-amino-5-methylisoxazole. Recrystallisation from a diisopropyl ether/tetrahydrofuran mixture gives the title compound in a yield of 49%.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([C:14]#[C:15][C:16]2[N:20]3[N:21]=[CH:22][CH:23]=[CH:24][C:19]3=[N:18][CH:17]=2)[CH2:9]1)(OC(C)(C)C)=O.C(O)(C(F)(F)F)=O>C(Cl)Cl>[N:18]1[CH:17]=[C:16]([C:15]#[C:14][CH:10]2[CH2:11][CH2:12][CH2:13][NH:8][CH2:9]2)[N:20]2[C:19]=1[CH:24]=[CH:23][CH:22]=[N:21]2
Reactant: CC(C)(C)OC(=O)N1CCCC(C#Cc2cnc3cccnn23)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C(#CC1CCCNC1)c1cnc2cccnn12
Temperature: 25 °C
Reaction time: 8 h
Yield: 121.5 %

Procedure:
To a solution of 1-BOC-3-(2-(imidazo[1,2-b]pyridazin-3-yl)ethynyl)piperidine (0.39 g, 1.2 mmol) in CH2Cl2 (10 mL) was added TFA (1.23 g, 10.8 mmol), the mixture was stirred at rt overnight and evaporated in vacuo. To the residue was added 10 mL 10% K2CO3 solution, extracted with EtOAc (20 mL×3), dried with Na2SO4, after filtration, and the filtrate was evaporated under reduced pressure to give 0.33 g product as yellow oil (107.0%). 1H NMR (300 MHz, CDCl3) δ: 8.43 (1H, d, J=4.5 Hz), 7.93-7.97 (1H, dd, J=1.8 and 9.0 Hz), 7.91 (1H, s), 7.05-7.09 (1H, dd, J=4.5 and 9.0 Hz), 2.82-2.98 (4H, m), 2.08-2.11 (1H, m), 1.75-1.84 (2H, m), 1.53-1.58 (2H, m).