Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Na+].[Br:3][C:4]1[CH:9]=[C:8]([F:10])[C:7]([F:11])=[CH:6][C:5]=1[OH:12].Br[CH2:14][CH2:15][C:16]([OH:18])=[O:17].Cl>O>[Br:3][C:4]1[CH:9]=[C:8]([F:10])[C:7]([F:11])=[CH:6][C:5]=1[O:12][CH2:14][CH2:15][C:16]([OH:18])=[O:17]
Reactant: Oc1cc(F)c(F)cc1Br
Reactant: O=C(O)CCBr
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)CCOc1cc(F)c(F)cc1Br
Temperature: 100 °C
Yield: 65.8 %

Procedure:
A solution of 1.68 g of NaOH (42 mmol) in 5 mL of water was added slowly to the suspension of 2.29 mL (20 mmol) 2-bromo-4,5-difluorophenol and 3.07 g (20 mmol) 3-bromopropionic acid. The mixture was heated at 100° C. in an oil bath for 5 hours, and then allowed to cool to room temperature. Water was added to completely dissolve any solid material and the reaction mixture was made acidic with concentrated HCl. The product was extracted into ether (3 times), and the combined organic layers was dried over Na2SO4 and evaporated to give 3.7 g (66%) of the title compound as a light brown solid. 1H NMR (300 MHz, CDCl3): δ 7.4 (t, 1H), 6.8 (q, 1H), 4.3 (t, 2H), 2.9 (t, 2H).
Reaction SMILES: [NH2:1][C@H:2]([CH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1)[CH2:3][OH:4].[H-].[Na+].[H][H].Cl[CH2:16][C:17](OCC)=[O:18]>C1COCC1>[CH:5]1([C@H:2]2[NH:1][C:17](=[O:18])[CH2:16][O:4][CH2:3]2)[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1
Reactant: [H][H]
Reactant: CCOC(=O)CCl
Reactant: N[C@@H](CO)C1CCCCC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C1COC[C@@H](C2CCCCC2)N1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 57.7 %

Procedure:
To a solution containing 3.8 g (26.5 mmol, 1.0 equiv) of (R)-2-amino-2-cyclohexyl-ethanol in 100 mL of THF was added sodium hydride (1.4 g, 58.4 mmol, 60% in mineral oil, 2.2 equiv). The reaction mixture was stirred at 25° C. for 30 minutes, at which time hydrogen evolution had ceased. The mixture was cooled at 0° C. and was added ethyl chloroacetate (3.3 g, 26.5 mmol, 1.0 equiv), dropwise, over 5 minutes. The reaction mixture was stirred for 1 hour at 25° C. and then 2 hours at reflux. The solvent was removed under vacuum and to the residue was added 1.0 N HCl aq. solution until pH=6. The mixture was extracted with ethyl acetate. The resulting organic extracts were washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was recrystallized from EtOAc/heptane to give product 2.8 g. The mother liquid was concentrated and the residue was purified by silica gel column chromatography (acetone/heptane 50%) to give product 1.3 g. Combined yield 4.1 g (84%)
Reaction SMILES: C([O:3][C:4](=[O:33])[CH2:5][O:6][C:7]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=1[CH2:14][O:15][C:16]1[CH:21]=[C:20]([CH3:22])[N:19]([C:23]2[C:28]([F:29])=[CH:27][CH:26]=[CH:25][C:24]=2[F:30])[C:18](=[O:31])[C:17]=1[Br:32])C.[OH-].[Na+].CO.O>C1COCC1>[Br:32][C:17]1[C:18](=[O:31])[N:19]([C:23]2[C:28]([F:29])=[CH:27][CH:26]=[CH:25][C:24]=2[F:30])[C:20]([CH3:22])=[CH:21][C:16]=1[O:15][CH2:14][C:8]1[CH:9]=[CH:10][C:11]([F:13])=[CH:12][C:7]=1[O:6][CH2:5][C:4]([OH:33])=[O:3]
Reactant: CCOC(=O)COc1cc(F)ccc1COc1cc(C)n(-c2c(F)cccc2F)c(=O)c1Br
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cc(OCc2ccc(F)cc2OCC(=O)O)c(Br)c(=O)n1-c1c(F)cccc1F
Yield: 59.5 %

Procedure:
A solution of ethyl[2-({[3-bromo-1-(2,6-difluorophenyl)-6-methyl-2-oxo-1,2-dihydropyridin-4-yl]oxy}methyl)-5-fluorophenoxy]acetate (from Step 3) (0.62 g, 1.18 mmol), 1.5 N NaOH solution in 1:1 MeOH:water (1.2 mL, 1.77 mmol), and THF (1.2 mL) were refluxed at 60° C. for 1 h. The solution was concentrated on a rotary evaporator, cooled, and 5% citric acid added. The solid precipitate was filtered and dried in vacuo. Product obtained as a pale yellow solid (0.35 g, 60%). 1H NMR (CD3OD/400 MHz) δ7.59 (m, 1H), 7.49 (m, 1H), 7.22 (m, 2H), 6.75 (m, 2H), 6.72 (s, 1H), 5.43 (s, 2H), 4.66 (s, 2H), 2.07 (s, 3H). ESHRMS m/z 498.0143 and 500.0186 (M+H calculated for C21H16BrF3NO5 requires 498.0158 and 500.0141).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]2[N:33]=[C:11]3[CH:12]=[C:13]([NH:16][C:17]([C:19]4[N:20]([CH3:32])[N:21]=[CH:22][C:23]=4[C:24]([N:26]4[CH2:31][CH2:30][O:29][CH2:28][CH2:27]4)=[O:25])=[O:18])[CH:14]=[CH:15][N:10]3[N:9]=2)[CH:5]=[CH:6][CH:7]=1.Br[CH2:35][CH2:36][F:37].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CCOC(C)=O>[F:37][CH2:36][CH2:35][O:1][C:2]1[CH:3]=[C:4]([C:8]2[N:33]=[C:11]3[CH:12]=[C:13]([NH:16][C:17]([C:19]4[N:20]([CH3:32])[N:21]=[CH:22][C:23]=4[C:24]([N:26]4[CH2:27][CH2:28][O:29][CH2:30][CH2:31]4)=[O:25])=[O:18])[CH:14]=[CH:15][N:10]3[N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Cn1ncc(C(=O)N2CCOCC2)c1C(=O)Nc1ccn2nc(-c3cccc(O)c3)nc2c1
Reactant: FCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cn1ncc(C(=O)N2CCOCC2)c1C(=O)Nc1ccn2nc(-c3cccc(OCCF)c3)nc2c1
Temperature: 60 °C
Reaction time: 16 h
Yield: 23.3 %

Procedure:
To a solution of 2-methyl-4-(morpholine-4-carbonyl)-2H-pyrazole-3-carboxylic acid [2-(3-hydroxy-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-7-yl]-amide (Example 80) (350 mg, 0.782 mmol) in DMF (5 ml) was added 1-bromo-2-fluoroethane (250 mg, 1.96 mmol) and K2CO3 (108 mg, 0.782 mmol). The reaction mixture was stirred at 60° C. for 16 h. The reaction mixture was diluted with EtOAc (30 ml) and washed with water (2×10 ml) and brine (15 ml). The organic layer was dried over anhydrous Na2SO4, filtered, and evaporated off in vacuum. The crude material thus obtained was purified by column chromatography over silica gel (5% MeOH/DCM) to afford 2-methyl-4-(morpholine-4-carbonyl)-2H-pyrazole-3-carboxylic acid {2-[3-(2-fluoro-ethoxy)-phenyl]-[1,2,4]triazolo[1,5-a]pyridin-7-yl}-amide as off-white solid (90 mg, 23%). LC-MS: m/z=494.2 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[N:14][C:15]=3[NH2:17])[N:10]([C@H:18]3[CH2:23][CH2:22][C@@H:21]([N:24]4[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]4)[CH2:20][CH2:19]3)[N:9]=2)=[CH:4][CH:3]=1.Br[CH2:32][C:33]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:34].C(N(CC)C(C)C)(C)C.CN(C)C=[O:53]>>[C:33]([OH:53])(=[O:34])[CH3:35].[C:33]([OH:53])(=[O:34])[CH3:35].[NH2:17][C:15]1[N:14]=[CH:13][N:12]=[C:11]2[N:10]([C@H:18]3[CH2:23][CH2:22][C@@H:21]([N:24]4[CH2:25][CH2:26][N:27]([CH3:30])[CH2:28][CH2:29]4)[CH2:20][CH2:19]3)[N:9]=[C:8]([C:5]3[CH:4]=[CH:3][C:2]([NH:1][CH2:32][C:33]([C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)=[O:34])=[CH:7][CH:6]=3)[C:16]=12
Reactant: CN1CCN([C@H]2CC[C@@H](n3nc(-c4ccc(N)cc4)c4c(N)ncnc43)CC2)CC1
Reactant: CN(C)C=O
Reactant: O=C(CBr)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)O
Product: CN1CCN([C@H]2CC[C@@H](n3nc(-c4ccc(NCC(=O)c5ccccc5)cc4)c4c(N)ncnc43)CC2)CC1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
Cis-3-(4-aminophenyl)-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.6 g, 0.00148 mol) and bromoacetophenone (0.295 g, 0.00148 mol) were dissolved in anhydrous N,N-dimethylformamide (30 mL) and the resulting mixture was stirred at ambient temperature under an atmosphere of nitrogen for 5 min. N,N-diisopropylethylamine (0.095 g, 0.00074 mol) was added dropwise and stirring under an atmosphere of nitrogen was continued for sixteen hours. The reaction mixture was concentrated under reduced pressure and the residue was purified by preparative HPLC (Hypersil C18, 8 μm, 25 cm; 10-60% acetonitrile-0.1 M ammonium acetate over 25 min, 21 mL/min) to yield cis-2-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}anilino)-1-phenyl-1-ethanone diacetate (0.410 g, 0.00064 mol) as a white solid.
Reaction SMILES: Cl.[C:2]1([C@@H:8]2[CH2:10][C@H:9]2[NH2:11])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:12][C:13]1[CH:20]=[CH:19][C:16]([CH:17]=O)=[CH:15][CH:14]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl.O>[F:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17][NH:11][C@@H:9]2[CH2:10][C@H:8]2[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:15][CH:14]=1
Reactant: N[C@@H]1C[C@H]1c1ccccc1
Reactant: O=Cc1ccc(F)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: Fc1ccc(CN[C@@H]2C[C@H]2c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 49.7 %

Procedure:
A mixture of (trans)-2-phenylcyclopropanamine hydrochloride (0.25 g, 1.50 mmol) and 4-fluorobenzaldehyde (0.18 mL, 1.65 mmol) in CH2Cl2 (8 mL) and water (0.5 mL) was vigorously stirred at room temperature for 10 min. Then, NaBH(OAc)3 (0.41 g, 1.95 mmol) was slowly added and stirring continued for 1.5 h. The reaction mixture was washed with an aqueous saturated solution of NaHCO3 (10 mL), the organic layer was dried over anhydrous Na2SO4, filtered and, after removal of the solvent, the residual oil was purified by column chromatography on silica gel (3% MeOH/CH2Cl2) affording 0.18 g of N-(4-fluorobenzyl)-N-[(trans)-2-phenylcyclopropyl]amine [Rf=0.5 (5% MeOH/CH2Cl2), colorless oil, 49% yield].
Reaction SMILES: [C:1]([NH:7][C:8]1[N:9]=[C:10]([OH:29])[C:11]2[CH:17]=[C:16]([CH2:18][CH2:19][C:20]3[CH:28]=[CH:27][C:23]([C:24](O)=[O:25])=[CH:22][CH:21]=3)[CH:15]=[N:14][C:12]=2[N:13]=1)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].C1(NP(Cl)(=O)OC2C=CC=CC=2)C=CC=CC=1.CN1CCOCC1.Cl.[NH2:55][C@H:56]([C:64]([O:66][CH2:67][CH3:68])=[O:65])[CH2:57][CH2:58][C:59]([O:61][CH2:62][CH3:63])=[O:60]>CN1CCCC1=O>[C:1]([NH:7][C:8]1[N:9]=[C:10]([OH:29])[C:11]2[CH:17]=[C:16]([CH2:18][CH2:19][C:20]3[CH:28]=[CH:27][C:23]([C:24]([NH:55][C@H:56]([C:64]([O:66][CH2:67][CH3:68])=[O:65])[CH2:57][CH2:58][C:59]([O:61][CH2:62][CH3:63])=[O:60])=[O:25])=[CH:22][CH:21]=3)[CH:15]=[N:14][C:12]=2[N:13]=1)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3]
Reactant: CC(C)(C)C(=O)Nc1nc(O)c2cc(CCc3ccc(C(=O)O)cc3)cnc2n1
Reactant: CCOC(=O)CC[C@H](N)C(=O)OCC
Agent: Cl
Agent: O=P(Cl)(Nc1ccccc1)Oc1ccccc1
Solvent: CN1CCCC1=O
Solvent: CN1CCOCC1
Product: CCOC(=O)CC[C@H](NC(=O)c1ccc(CCc2cnc3nc(NC(=O)C(C)(C)C)nc(O)c3c2)cc1)C(=O)OCC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 0.19 g (1.0 eq) of 4-[2-(2-pivaloylamino-4-hydroxypyrido[2,3-d]pyrimidin-6-yl)ethyl]benzoic acid 0.19 g (1.5 eq) of phenyl N-phenylphosphoramidochloridate, 0.24 g (5.0 eq) of N-methylmorpholine, and 20 mL of N-methylpyrrolidone is stirred under nitrogen and at room temperature for one hour and 0.23 g (2.0 eq) of diethyl L-glutamate hydrochloride is added. The mixture is stirred for an additional 24 hours under nitrogen and the solvents then removed by evaporation. Chloroform is added and this mixture is then washed with water, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue is chromatographed, eluting with 2% methanol/chloroform to yield diethyl N-(4-[2-(2-pivaloylamino-4-hydroxypyrido[2,3-d]pyrimidin-6-yl)ethyl]benzoyl)-L-glutamate. m.p. >250° C.; 1H NMR (CDCl3) delta 8.63 (s, 1H), 8.33 (s, 1H), 7.74 (d, J=8.11 Hz, 2H, Ar), 7.21 (d, J=8.11 Hz, 2H, Ar), 7.19 (d, J=6.9 Hz, 1H, NH), 4.77-4.84 (m, 1H-CH--), 4.24 (q, J=7.4 Hz, 2H, CO2CH2), 4.12 (q, J=7.4 Hz, 2H, COOCH), 3.05 (s, 4H, 2° aliphatic), 1.97-2.61 (m, 4H, 2° aliphatic), 1.34 (s, 9H, t-butyl), 1.29 (t, J=8.4 Hz, 3H, --CH3), 1.22 (t, J=8.4 Hz, 3H, --CH3).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([N:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH:2]=1.Br[CH2:14][C:15]#[N:16]>>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([N:7]2[CH2:8][CH2:9][N:10]([CH2:14][C:15]#[N:16])[CH2:11][CH2:12]2)[CH:2]=1
Reactant: N#CCBr
Reactant: c1cncc(N2CCNCC2)c1
Product: N#CCN1CCN(c2cccnc2)CC1

Procedure:
The title compound is synthesized by coupling of 1-Pyridin-3-yl-piperazine and bromoacetonitrile analogously to the preparation of Intermediate 149.2 as a white solid; ES-MS: M+=203.2: AtRet=1.10.
Reaction SMILES: [CH2:1]([C:3]1[CH:17]=[CH:16][C:6]2=[C:7]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[O:8][N:9]=[C:5]2[CH:4]=1)[CH3:2].[Br:18]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:18][CH:1]([C:3]1[CH:17]=[CH:16][C:6]2=[C:7]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[O:8][N:9]=[C:5]2[CH:4]=1)[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCc1ccc2c(-c3ccccc3)onc2c1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CC(Br)c1ccc2c(-c3ccccc3)onc2c1

Procedure:
A mixture of 1.9 g (0.0085 mole) of 6-ethyl-3-phenyl-2,1-benzisoxazole, 1.5 g (0.0087 mole) of N-bromosuccinimide and a few crystals of dibenzoyl peroxide in 100 ml of carbon tetrachloride was heated at reflux for 2 hr under floodlight illumination and under an argon atmosphere. The cooled reaction mixture was filtered, and the filtrate was washed twice with 100 ml portions of 10% sodium bicarbonate solution, once with water (100 ml) and dried over sodium sulfate. The sodium sulfate was removed by filtration and the filtrate was concentrated to a dark brown oil which solidified upon standing. The solid was purified by chromatography (3.5×60 cm glass column; 180 g of silica gel; benzene). Fractions containing the title compound were combined and the solvent was evaporated under reduced pressure to give a viscous oil which solidified upon standing. The solid was recrystallized from diethyl ether-petroleum ether (30°-60° C.) to give 1.7 g (65%) of mustard yellow crystals, m.p. 99°-102° C.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:7][N:8]([CH3:22])[C:9]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:14][CH2:13][C:12](=O)[CH2:11][CH2:10]1.C(O)(=O)C>ClCCCl>[CH3:7][N:8]([CH3:22])[C:9]1([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:10][CH2:11][CH:12]([N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[CH2:13][CH2:14]1
Reactant: C1CCNCC1
Reactant: CN(C)C1(c2ccccc2)CCC(=O)CC1
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CN(C)C1(c2ccccc2)CCC(N2CCCCC2)CC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Piperidine (400 μl, 4 mmole) and 4-dimethylamino-4-phenylcyclohexanone (434 mg, 2 mmole) were dissolved in dry 1,2-dichloroethane (10 ml). Glacial acetic acid (2 mmole) and sodium triacetoxy boron hydride (600 mg, 2.8 mmole) were added to this mixture and the whole was stirred for 24 hours at RT. The reaction mixture was worked up by distilling off the 1,2-dichloroethane and the mixture was adjusted to pH 11 with 5M NaOH. The alkaline phase was diluted with water (10 ml) and extracted with EE (3×20 ml). The organic phase was dried with Na2SO4 and concentrated by evaporation. Dimethyl-(1-phenyl-4-piperidine-1-ylcyclohexyl)-amine was purified by chromatography with ethanol. The non-polar diastereoisomer (15 mg) still contained impurities, which also could not be removed by further purification attempts. The polar diastereoisomer was obtained as a colourless oil in a yield of 92 mg (16%).
Reaction SMILES: [CH3:1][N:2]([CH2:4][CH2:5][CH:6]([OH:12])[C:7]1[S:8][CH:9]=[CH:10][CH:11]=1)[CH3:3].[OH-].[K+].F[C:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18][CH:17]=1.[C:26]([C@H:29]([C@@H:31]([C:33]([OH:35])=[O:34])[OH:32])[OH:30])([O-:28])=[O:27].[K+]>CS(C)=O.O>[CH3:1][N:2]([CH2:4][CH2:5][CH:6]([O:12][C:24]1[C:25]2[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:21]=[CH:22][CH:23]=1)[C:7]1[S:8][CH:9]=[CH:10][CH:11]=1)[CH3:3].[C:26]([C@H:29]([C@@H:31]([C:33]([O-:35])=[O:34])[OH:32])[OH:30])([O-:28])=[O:27]
Reactant: O=C([O-])[C@@H](O)[C@H](O)C(=O)O
Reactant: Fc1cccc2ccccc12
Reactant: CN(C)CCC(O)c1cccs1
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: CN(C)CCC(Oc1cccc2ccccc12)c1cccs1
Product: O=C([O-])[C@@H](O)[C@H](O)C(=O)[O-]
Temperature: 110 °C
Reaction time: 2 h

Procedure:
A mixture of N,N-dimethyl-3-hydroxy-3-(2-thienyl)propylamine (185 g, 1 mole), potassium hydroxide (112 g, 2 moles) and 1-fluoronaphthalene (146 g, 1 mole) in dimethylsulfoxide (1000 ml) is stirred at 110° C. for 2 hours. After cooling down to 20° C., the mixture is filtered, diluted with water (3 l), monopotassium D-tartrate (188 g, 1 mole) is added, and the mixture is stirred at 80° C. for 0.5 hour. After cooling down, the precipitated product is sucked off, washed with water and dried. Yield: 328 g (85%).
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:4]=[C:5]([C:13]2[N:17]=[CH:16][N:15](/[CH:18]=[CH:19]\[C:20]([OH:22])=O)[N:14]=2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[CH3:25][C:26]1[NH:30][N:29]=[CH:28][C:27]=1[C:31]([NH:33][NH2:34])=[O:32].C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC.CCN(C(C)C)C(C)C>CCOC(C)=O.CCO>[F:23][C:2]([F:24])([F:1])[C:3]1[CH:4]=[C:5]([C:13]2[N:17]=[CH:16][N:15](/[CH:18]=[CH:19]\[C:20]([NH:34][NH:33][C:31]([C:27]3[CH:28]=[N:29][NH:30][C:26]=3[CH3:25])=[O:32])=[O:22])[N:14]=2)[CH:6]=[C:7]([C:9]([F:12])([F:10])[F:11])[CH:8]=1
Reactant: Cc1[nH]ncc1C(=O)NN
Reactant: O=C(O)/C=C\n1cnc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)n1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: Cc1[nH]ncc1C(=O)NNC(=O)/C=C\n1cnc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)n1
Temperature: -60 °C
Reaction time: 1 h
Yield: 29.7 %

Procedure:
In a 50 mL, 3-neck round-bottom flask, (Z)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)acrylic acid (Example 1, Step 4; 0.5 g, 1.0 eq.) was dissolved in EtOAc:EtOH (15 mL, 2:1) and cooled to −60° C. where 5-methyl-1H-pyrazole-4-carbohydrazide (0.24 g, 1.0 eq.) was introduced dropwise. T3P (50% in EtOAc) (1.69 mL, 1.5 eq.) was added dropwise followed by DIPEA (2 mL, 8 eq.) and the reaction mixture was stirred for 1 h at −60° C. The reaction mixture was concentrated under reduced pressure (25° C., 20 mm Hg) to afford the crude product that was purified by column chromatography (60/120 silica gel) using methanol/dichloromethane gradient (the column was packed in dichloromethane and the desired compound started eluting from 3% methanol/dichloromethane). Fractions containing the desired compounds were combined to afford (Z)—N′-(3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)acryloyl)-5-methyl-1H-pyrazole-4-carbohydrazide (0.2 g, yield: 42%).
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[C:19]([O:21]C)[CH:18]=[CH:17][C:3]=1[C:4]([NH:6][C:7]1[C:12]([OH:13])=[CH:11][C:10]([O:14]C)=[CH:9][C:8]=1[Cl:16])=O.CCOC(/N=N/C(OCC)=O)=O>C1COCC1.C(OCC)(=O)C>[Cl:16][C:8]1[C:7]2[N:6]=[C:4]([C:3]3[CH:17]=[CH:18][C:19]([OH:21])=[CH:20][C:2]=3[Cl:1])[O:13][C:12]=2[CH:11]=[C:10]([OH:14])[CH:9]=1
Reactant: COc1ccc(C(=O)Nc2c(O)cc(OC)cc2Cl)c(Cl)c1
Agent: CCOC(=O)/N=N/C(=O)OCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Oc1ccc(-c2nc3c(Cl)cc(O)cc3o2)c(Cl)c1
Yield: 92.4 %

Procedure:
2-Chloro-N-(2-chloro-6-hydroxy-4-methoxy-phenyl)-4-methoxy-benzamide (40 mg) was completely dissolved in THF (5 mL) and PPH3 (46 mg) was added and the mixture was stirred until all PPH3 dissolved. To this mixture was added drop wise DEAD (0.03 mL) diluted in THF (0.5 mL). The mixture was stirred at room temperature for 2 h and the reaction mixture was diluted with ethyl acetate and washed with water, brine, dried over MgSO4 and concentrated. Flash chromatography on silica gel eluting with 10% to 30% ethyl acetate-hexane afforded 32 mg (85%) of the title compound as a solid. MS: 324 (MH+), HPLC tR: 3.18 min.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH:10](CCO)[CH2:9]1)=[O:7])([CH3:4])(C)C.ClC(Cl)(OC(=O)OC(Cl)(Cl)Cl)Cl>ClCCl.CCN(C(C)C)C(C)C>[CH2:10]1[CH:9]2[N:8]([C:6](=[O:7])[O:5][CH2:1][CH2:4]2)[CH2:13][CH2:12][NH:11]1
Reactant: CC(C)(C)OC(=O)N1CCNC(CCO)C1
Agent: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C1OCCC2CNCCN12
Reaction time: 0.5 h

Procedure:
3-(2-Hydroxy-ethyl)-piperazine-1-carboxylic acid tert-butyl ester (58 mg, 0.25 mmol) was dissolved in 4 mL of dichloromethane and 1 mL of DIPEA, and then triphosgene (27 mg, 0.09 mmol) was added at room temperature. The reaction mixture was stirred for 30 minutes, and the solvent was removed in vacuo. The residue was dissolved in 3 mL of dichloromethane and 1 mL of TFA. After the reaction mixture was stirred for 1 hour, the solvent was removed in vacuo to give hexahydro-pyrazino[1,2-c][1,3]oxazin-6-one trifluoro acetitic acid salt (Compound D) as a crude product which was used directly without further purification. LC/MS: calc'd 157 (MH+), exp 157 (MH+).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[C:7]([C:9]([CH3:12])([CH3:11])[CH3:10])[CH:6]=[C:5]([C:13]([CH3:16])([CH3:15])[CH3:14])[C:4]=1[OH:17].N[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[SH:25].C([N:28](CC)CC)C>C1COCC1>[NH2:28][S:25][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[CH2:2][C:3]1[CH:8]=[C:7]([C:9]([CH3:12])([CH3:11])[CH3:10])[CH:6]=[C:5]([C:13]([CH3:16])([CH3:15])[CH3:14])[C:4]=1[OH:17]
Reactant: CCN(CC)CC
Reactant: Nc1ccccc1S
Reactant: CC(C)(C)c1cc(CBr)c(O)c(C(C)(C)C)c1
Solvent: C1CCOC1
Product: CC(C)(C)c1cc(Cc2ccccc2SN)c(O)c(C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A solution of 2-(bromomethyl)-4,6-di-tert-butylphenol (1.03 g, 3.4 mmol) in THF (20 mL) was added dropwise to a solution of 2-Aminothiophenol (0.43 g, 3.4 mmol) and triethylamine (0.50 mL) in THF (20 mL) and stirred at room temperature for 12 hours. A solid had formed and was filtered out followed by removal of the solvent in vacuum. The crude product was dissolved in dichloromethane, washed with saturated NaCl solution and dried over MgSO4. The product was obtained as a yellow oil in a quantitative yield.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]([O:10]C)=[S:9])[S:5][C:6]=1[CH3:7].[OH-].[Na+]>CO.O>[Br:1][C:2]1[CH:3]=[C:4]([C:8]([OH:10])=[S:9])[S:5][C:6]=1[CH3:7]
Reactant: COC(=S)c1cc(Br)c(C)s1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1sc(C(O)=S)cc1Br
Temperature: 25 °C
Reaction time: 5 h
Yield: 94.9 %

Procedure:
To 1.0 g (3.7 mmol) of methyl 4-bromo-5-methylthiothiophene-2-carboxylate (as prepared in Example 241, step (a) dissolved in 25 ml of MeOH was added 450 mg of NaOH dissolved in 10 ml of H2O. The reaction was stirred for 5 hours at room temperature, and then the solvents were removed under vacuum. The residue of the reaction was extracted with ethyl acetate (2×50 mL) and 1N HCl. The organic layer was collected, dried (Na2SO4), filtered and concentrated under vacuum to yield 833 mg (89%) of 4-bromo-5-methylthiothiophene-2-carboxylic acid as a white solid.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:13]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)=O)[CH:7]=[CH:8][C:9]=1[N+:10]([O-:12])=[O:11])([O-:3])=[O:2].O1CCCC1.B(F)(F)F.CCOCC.[BH4-].[Na+]>CCOCC.CO>[N+:1]([C:4]1[CH:5]=[C:6]([CH:7]=[CH:8][C:9]=1[N+:10]([O-:12])=[O:11])[CH2:13][N:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1)([O-:3])=[O:2]
Reactant: O=C(c1ccc([N+](=O)[O-])c([N+](=O)[O-])c1)N1CCOCC1
Agent: FB(F)F
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Solvent: CCOCC
Product: O=[N+]([O-])c1ccc(CN2CCOCC2)cc1[N+](=O)[O-]
Temperature: 2.5 °C
Reaction time: 0.38 h
Yield: 98.4 %

Procedure:
(3,4-Dinitrophenyl)-morpholin-4-yl-methanone (0.750 Kg, 2.67 mol, 1.O wt) and tetrahydrofuran (7.50 L, 1O.O vol) were charged to a flask under nitrogen and cooled to 0 to 5° C. Borontrifluoride etherate (0.713 L, 5.63 mol, 0.95 vol) was added at 0 to 5° C. and the suspension was stirred at this temperature for 15 to 30 minutes. Sodium borohydride (0.212 Kg, 5.60 mol, 0.282 wt) was added in 6 equal portions over 90 to 120 minutes. (A delayed exotherm was noted 10 to 15 minutes after addition of the first portion. Once this had started and the reaction mixture had been re-cooled, further portions were added at 10 to 15 minute intervals, allowing the reaction to cool between additions). The reaction mixture was stirred at 0 to 5° C. for 30 minutes. Reaction completion was determined by 1H NMR analysis (d6-DMSO). Methanol (6.30 L, 8.4 vol) was added dropwise at 0 to 10° C. to quench the reaction mixture (rapid gas evolution, some foaming). The quenched reaction mixture was stirred at 0 to 10° C. for 25 to 35 minutes then warmed to and stirred at 20 to 3O° C. (exotherm, gas/ether evolution on dissolution of solid) until gas evolution had slowed. The mixture was heated to and stirred at 65 to 7O° C. for 1 hour. The mixture was cooled to 30 to 4O° C. and concentrated under vacuum at 40 to 45° C. to give crude 4-(3,4-dinitro-benzyl)-morpholine (0.702 Kg, 98.4%) as a yellow/orange solid.