Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Sn](Cl)Cl.Cl.[F:5][C:6]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:7]=1[O:8][CH2:9][C:10]1[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-])=O)[C:11]=1[C:12]#[N:13].[OH-].[K+]>>[NH2:18][C:14]1[CH:15]=[CH:16][CH:17]=[C:10]([CH2:9][O:8][C:7]2[CH:21]=[CH:22][C:23]([F:25])=[CH:24][C:6]=2[F:5])[C:11]=1[C:12]#[N:13]
Reactant: N#Cc1c(COc2ccc(F)cc2F)cccc1[N+](=O)[O-]
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [K+]
Product: N#Cc1c(N)cccc1COc1ccc(F)cc1F
Temperature: 15 °C
Reaction time: 3 h
Yield: 91.5 %

Procedure:
To a cooled (15° C.) and stirred solution of tin (II) chloride (0.37 g, 1.65 mmol) and con. hydrochloric acid (2.0 mL) was added a solution of 2-(2,4-difluorophenoxymethyl)-6-nitrobenzonitrile (160.0 mg, 0.55 mmol). The reaction mixture was slowly warmed to room temperature and stirred for 3 hours. The reaction mixture was poured on to crushed-ice and potassium hydroxide solution, stirred, extracted with dichloromethane, filtered and dried to yield 131 mg of 2-amino-6-(2,4-difluorophenoxymethyl)benzonitrile.
Reaction SMILES: C(Cl)(=O)C([Cl:4])=O.[Cl:7][CH2:8][CH2:9][CH2:10][C:11]([CH3:16])([CH3:15])[C:12](O)=[O:13]>CN(C=O)C.C(Cl)(Cl)Cl>[Cl:7][CH2:8][CH2:9][CH2:10][C:11]([CH3:16])([CH3:15])[C:12]([Cl:4])=[O:13]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CC(C)(CCCCl)C(=O)O
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: CC(C)(CCCCl)C(=O)Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Oxalyl chloride (888 mg, 7 mmols) was added to a chloroform (10 ml) solution of the resulting carboxylic acid (0.9 g, 5 mmols) and DMF (catalytic amount, 1 drop), and stirred at room temperature for 1 hour. The reaction mixture was concentrated to obtain 5-chloro-2,2-dimethylpentanoic acid chloride,
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[CH:11]=O)=[CH:8][CH:7]=[CH:6][CH:5]=2.[CH3:13][NH2:14].[BH4-].[Na+]>CO>[CH3:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[CH2:11][NH:14][CH3:13])=[CH:8][CH:7]=[CH:6][CH:5]=2
Reactant: Cc1[nH]c2ccccc2c1C=O
Reactant: CN
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CNCc1c(C)[nH]c2ccccc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 63 %

Procedure:
To a solution of 2-methylindole-3-carboxaldehyde (10.00 g, 62.84 mmole) in MeOH (100 mL) was added 2 M CH3NH2 in MeOH (200 mL). After stirring for 3 hours at RT, the reaction solution was concentrated to a yellow oil which solidified under vacuum. This solid was dissolved in ethanol (350 mL) and NaBH4 (2.38 g, 62.8 mmole) was added. The reaction was stirred at RT for 6 hours, then was concentrated under vacuum. The remaining residue was diluted with saturated aqueous Na2CO3 (50 mL) and extracted with EtOAc (2×200 mL). The organic phase was separated, washed with brine, and dried over Na2SO4. Flash chromatography on silica gel (9:1 CHCl3/MeOH containing 5% NH4OH) and drying under high vacuum gave the title compound (6.88 g, 63%) as a faintly yellow viscous solid: MS (ES) m/e 175 (M+H)+.
Reaction SMILES: [C:1]([N:9]1[CH2:22][CH2:21][C:20]2[C:19]3[C:18](Br)=[CH:17][CH:16]=[CH:15][C:14]=3[NH:13][C:12]=2[CH2:11][CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[C:30]1(B(O)O)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.CCOC(C)=O.CCCCCCC>O1CCCC1.CN(C)C(=O)C.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]([N:9]1[CH2:22][CH2:21][C:20]2[C:19]3[C:18]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)=[CH:17][CH:16]=[CH:15][C:14]=3[NH:13][C:12]=2[CH2:11][CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OB(O)c1ccccc1
Reactant: O=C(c1ccccc1)N1CCc2[nH]c3cccc(Br)c3c2CC1
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: [K+]
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Solvent: C1CCOC1
Product: O=C(c1ccccc1)N1CCc2[nH]c3cccc(-c4ccccc4)c3c2CC1
Yield: 95.5 %

Procedure:
A mixture of 3-benzoyl-10-bromo-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (0.517 g, 1.40 mmol), potassium carbonate (0.77 g, 5.60 mmol), phenylboronic acid (0.194 g, 1.54 mmole), tetrakis(triphenylphosphine)palladium (0.16 g, 0.14 mmol) in tetrahydrofuran (7.0 mL) and N,N-dimethylacetamide (7.0 mL) reacted in a manner similar to Preparation 1. Column chromatography (silica gel, 10-50% EtOAc/heptane) afforded 0.49 g (95%) of the title compound as a solid: mp 223-226° C.; 1H NMR (400 MHz, CDCl3) δ 8.25, 7.57-7.23, 7.18-7.12, 6.98-6.89, 4.02-3.93, 3.76-3.67, 3.65-3.56, 3.43-3.35, 3.18-3.12, 2.90-2.83, 2.66-2.58, 2.43-2.34; IR (drift) 3231, 3203, 1602, 1501, 1468, 1433, 1352, 1336, 1249, 786, 758, 746, 740, 706, 700 cm−1; MS (EI) m/z 366 (M+); Anal. Calcd for C25H22N2O: C, 81.94; H, 6.05; N, 7.64. Found: C, 81.75; H, 6.07; N, 7.61.
Reaction SMILES: [CH3:1][C:2]1[N:7]2[C:8](=[O:31])[C:9]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=3)=[C:10]([CH:12]([N:14]3C(=O)C4C(=CC=CC=4)C3=O)[CH3:13])[N:11]=[C:6]2[CH:5]=[CH:4][CH:3]=1.O.NN>CCO>[NH2:14][CH:12]([C:10]1[N:11]=[C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([CH3:1])[N:7]2[C:8](=[O:31])[C:9]=1[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=1)[CH3:13]
Reactant: Cc1cccc2nc(C(C)N3C(=O)c4ccccc4C3=O)c(-c3ccccn3)c(=O)n12
Agent: NN
Solvent: CCO
Solvent: O
Product: Cc1cccc2nc(C(C)N)c(-c3ccccn3)c(=O)n12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of 2-(1-(6-methyl-4-oxo-3-(pyridin-2-yl)-4H-pyrido[1,2-a]pyrimidin-2-yl)ethyl)isoindoline-1,3-dione (0.934 g, 2.276 mmol) in EtOH (45.5 mL) was added hydrazine, monohydrate (1.104 mL, 22.76 mmol), and the mixture was stirred under reflux. After 1 h, the mixture was cooled to rt and the precipitate was filtered and washed with EtOAc (50 mL×2). The filtrate was concd under reduced pressure, redissolved in EtOAc (50 mL) and water (50 mL). The aq layer was extracted with EtOAc (50 mL×1). The combined organic layers were treated with 2M aq HCl (50 mL). The separated aq layer was washed with EtOAc (50 mL×2) to remove organic impurities and then basified to ˜pH 13 with 10 N NaOH (20 mL), and extracted with EtOAc (50 mL×3). The combined organic layers were washed with water (100 mL×1), brine (100 mL×1), and dried over MgSO4, filtered, and concd under reduced pressure to give the desired product as a yellow syrupy solid. The combined aq layers still contained the desired product. The combined aq layers were satd with NaCl and extracted with DCM (100 mL×2). The organic layers were combined with the above yellow syrupy solid, dried over MgSO4, filtered, and concd under reduced pressure to give 2-(1-amino-ethyl)-6-methyl-3-(pyridin-2-yl)-4H-pyrido[1,2-a]pyrimidin-4-one as a yellow foamy solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 8.64 (1 H, ddd, J=4.9, 2.0, 1.0 Hz), 7.85 (1 H, td, J=7.7, 1.9 Hz), 7.67 (1 H, dd, J=9.0, 6.8 Hz), 7.54 (1 H, dt, J=7.8, 1.1 Hz), 7.44 (1 H, ddd, J=8.9, 1.4, 0.7 Hz), 7.35 (1 H, ddd, J=7.6, 4.9, 1.2 Hz), 6.89-6.95 (1 H, m), 3.70 (1 H, q, J=6.7 Hz), 2.91 (3 H, s), 1.88 (2 H, br. s.), 1.19 (3 H, d, J=6.7 Hz); Mass Spectrum (ESI) m/e=281.0 (M+1).
Reaction SMILES: [CH:1]([C:3]1[C:7]([C:8]([F:11])([F:10])[F:9])=[C:6]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[N:5]([CH3:17])[N:4]=1)=[O:2].[CH:18]1([Mg]Br)[CH2:20][CH2:19]1.[Cl-].[NH4+]>O1CCCC1>[CH:18]1([CH:1]([OH:2])[C:3]2[C:7]([C:8]([F:11])([F:10])[F:9])=[C:6]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[N:5]([CH3:17])[N:4]=2)[CH2:20][CH2:19]1
Reactant: CCOC(=O)c1c(C(F)(F)F)c(C=O)nn1C
Reactant: Br[Mg]C1CC1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCOC(=O)c1c(C(F)(F)F)c(C(O)C2CC2)nn1C
Reaction time: 0.5 h
Yield: 31.5 %

Procedure:
A solution of 1.82 g (7.28 mmol) of ethyl 3-formyl-1-methyl-4-(trifluoromethyl)-1H-pyrazole-5-carboxylate in 80 ml of tetrahydrofuran is admixed under argon at −78° C. with 17.5 ml (8.73 mmol) of 0.5M cyclopropylmagnesium bromide solution in tetrahydrofuran, and stirred for 30 minutes at this temperature and then overnight at room temperature. The reaction solution is admixed with saturated ammonium chloride solution and extracted with ethyl acetate, and the organic phase is dried over sodium sulphate and concentrated by evaporation on a rotary evaporator. Chromatographic purification on silica gel gives 0.67 g of ethyl 3-[cyclopropyl(hydroxy)methyl]-1-methyl-4-(trifluoromethyl)-1H-pyrazole-5-carboxylate (31%).
Reaction SMILES: [CH3:1][N:2]([CH3:9])[CH:3]1[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1.[NH2:10][C:11]1[N:12]=[CH:13][C:14]([C:26]2[CH:34]=[CH:33][C:29]([C:30](O)=[O:31])=[CH:28][CH:27]=2)=[N:15][C:16]=1[C:17](=[O:25])[NH:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.CCN(C(C)C)C(C)C>CN(C1C=CN=CC=1)C.CS(C)=O>[NH2:10][C:11]1[C:16]([C:17]([NH:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[O:25])=[N:15][C:14]([C:26]2[CH:27]=[CH:28][C:29]([C:30]([N:6]3[CH2:7][CH2:8][CH:3]([N:2]([CH3:9])[CH3:1])[CH2:4][CH2:5]3)=[O:31])=[CH:33][CH:34]=2)=[CH:13][N:12]=1
Reactant: CN(C)C1CCNCC1
Reactant: Nc1ncc(-c2ccc(C(=O)O)cc2)nc1C(=O)Nc1ccccc1
Agent: CN(C)c1ccncc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CN(C)C1CCN(C(=O)c2ccc(-c3cnc(N)c(C(=O)Nc4ccccc4)n3)cc2)CC1
Temperature: 38 °C
Reaction time: 6 h
Yield: 80 %

Procedure:
N,N-dimethylpiperidin-4-amine (57.54 mg, 0.449 mmol) was weighed into a greenhouse tube and treated with a solution of 4-(5-amino-6-(phenylcarbamoyl)pyrazin-2-yl)benzoic acid (50 mg, 0.150 mmol), CDI (48.51 mg, 0.299 mmol) and DMAP (1.82 mg, 0.015 mmol) in DMSO (1 mL of a stock solution). DIPEA (78.2 uL, 0.449 mmol) was then added and the mixture stirred at 38° C. for 6 hours. The reaction mixture was filtered and the resultant residue was purified by reverse phase preparative HPLC [Waters Sunfire C18, 10 uM, 100 A column, gradient 10%-95% B (solvent A: 0.05% TFA in water, solvent B: CH3CN) over 16 minutes at 25 mL/min]. The fractions were freeze-dried to give the title compound as a solid (54.65, 80% Yield). (ES+) 445
Reaction SMILES: [CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([CH:10]3[C:22]4[NH:21][C:20]5[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=5)[C:14]=4[CH2:13][CH2:12][N:11]3[C:23]3[N:28]=[CH:27][C:26](Br)=[CH:25][N:24]=3)=[CH:4][C:3]=2[O:2]1.[N:30]1[CH:35]=[CH:34][CH:33]=[C:32](B(O)O)[CH:31]=1.C(N(CC)CC)C>CN(C=O)C.C(OCC)(=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([CH:10]3[C:22]4[NH:21][C:20]5[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=5)[C:14]=4[CH2:13][CH2:12][N:11]3[C:23]3[N:28]=[CH:27][C:26]([C:32]4[CH:31]=[N:30][CH:35]=[CH:34][CH:33]=4)=[CH:25][N:24]=3)=[CH:4][C:3]=2[O:2]1
Reactant: Brc1cnc(N2CCc3c([nH]c4ccccc34)C2c2ccc3c(c2)OCO3)nc1
Reactant: OB(O)c1cccnc1
Agent: [Fe+2]
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: c1cncc(-c2cnc(N3CCc4c([nH]c5ccccc45)C3c3ccc4c(c3)OCO4)nc2)c1
Temperature: 50 °C

Procedure:
A stirred mixture of palladium(II) acetate (27 mg, 0.12 mmol) and 1,1′-bis(diphenylphosphino)ferrocene (dppf) (83 mg, 0.15 mmol) in dry DMF (20 ml) was warmed to 50° C. for 15 min and then cooled. 1-(3,4-methylenedioxyphenyl)-2-(5-bromopyrimidin-2-yl)-2,3,4,9-tetrahydro-1H-β-carboline (674 mg, 1.5 mmol) (prepared as in Example 52), pyridine-3-boronic acid (203 mg, 1.7 mmol) and triethylamine (0.3 ml, 2.1 mmol) were added to the solution and the mixture heated to 90° C. for 16 h. The solution was diluted with ethyl acetate and filtered through filter paper. The organic phase was washed with brine and water, then dried over Na2SO4. A small amount of silica gel was added into the solution and the solution was dried in vacuo. Purification by flash column (silica gel, hexane:ethyl acetate=1:1, v/v, followed by hexane:ethyl acetate=1:2, v/v) yielded the product as a white solid.
Reaction SMILES: Br[C:2]1[CH:14]=[CH:13][C:5]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])=[C:4]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)[CH:3]=1.[Cl:23][C:24]1[CH:25]=[C:26](B(O)O)[CH:27]=[CH:28][CH:29]=1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C(=O)C>[Cl:23][C:24]1[CH:29]=[C:28]([C:2]2[CH:14]=[CH:13][C:5]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])=[C:4]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[CH:3]=2)[CH:27]=[CH:26][CH:25]=1
Reactant: CC(C)(C)OC(=O)c1ccc(Br)cc1Nc1ccc(F)cc1
Reactant: OB(O)c1cccc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: CC(C)(C)OC(=O)c1ccc(-c2cccc(Cl)c2)cc1Nc1ccc(F)cc1
Temperature: 110 °C
Reaction time: 19 h

Procedure:
To N,N-dimethylacetamide 2.5 mL solution of tert-butyl 4-bromo-2-(4-fluoroanilino)benzoate 80 mg were added 3-chlorophenylboronic acid 51 mg, sodium carbonate 58 mg and polymer-carried di(acetato)dicyclohexylphenylphosphine palladium(II) 7 mg, and it was stirred at 110° C. for 19 hours. After the reaction mixture was cooled to room temperature, polymer-carried di(acetato)dicyclohexylphenylphosphine palladium(II) 7 mg was added to it, and it was stirred at 110° C. for 30 hours. After the reaction mixture was cooled to room temperature, insoluble matter was filtrated, and ethyl acetate and 10% citric acid aqueous solution were added to it. The organic layer was separated and collected,dried over anhydrous magnesium sulfate after sequential washing with 10% citric acid aqueous solution and saturated sodium chloride aqueous solution, the solvent was removed under reduced pressure. The obtained residue was refined by silica gel column chromatography [Trikonex company, Flash Tube 2008, eluent; hexane:ethyl acetate=4:1] to give tert-butyl 4-(3-chlorophenyl)-2-(4-fluoroanilino)benzoate.
Reaction SMILES: [C:1]([Si:5]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[O:6][CH:7]([CH2:12][N:13](CC1C=CC=CC=1)CC1C=CC=CC=1)[C:8]([CH3:11])([OH:10])[CH3:9])([CH3:4])([CH3:3])[CH3:2]>CCO.[OH-].[OH-].[Pd+2]>[NH2:13][CH2:12][CH:7]([O:6][Si:5]([C:1]([CH3:4])([CH3:3])[CH3:2])([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)[C:8]([CH3:11])([OH:10])[CH3:9]
Reactant: CC(C)(O)C(CN(Cc1ccccc1)Cc1ccccc1)O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: CC(C)(O)C(CN)O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Yield: 92 %

Procedure:
(RS)-3-(tert-Butyl-diphenyl-silanyloxy)-4-dibenzylamino-2-methyl-butan-2-ol (Example 95, step 2) was hydrogenated in EtOH with Pd(OH)2 for 16 hours at 60° C. The desired (RS)-4-amino-3-(tert-butyl-diphenyl-silanyloxy)-2-methyl-butan-2-ol (4.2 g, 92% yield) was obtained as a colorless oil, MS: m/e=358.2 (M+H+) and used in the next step without further purification.
Reaction SMILES: [NH2:1][CH:2]([C:10]1[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[CH:12][C:11]=1[O:18][CH3:19])[CH2:3][CH2:4][CH2:5][C:6]([O:8]C)=O.[C:20]1([C:26]2[CH:27]=[C:28]([CH:31]=[CH:32][N:33]=2)[CH:29]=O)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[CH3:19][O:18][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]([O:16][CH3:17])[C:10]=1[CH:2]1[N:1]([CH2:29][C:28]2[CH:31]=[CH:32][N:33]=[C:26]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH:27]=2)[C:6](=[O:8])[CH2:5][CH2:4][CH2:3]1
Reactant: COC(=O)CCCC(N)c1c(OC)cccc1OC
Reactant: O=Cc1ccnc(-c2ccccc2)c1
Product: COc1cccc(OC)c1C1CCCC(=O)N1Cc1ccnc(-c2ccccc2)c1

Procedure:
Prepared according to the described general procedure 1 (GP1) by reaction of methyl 5-amino-5-(2,6-dimethoxyphenyl)pentanoate with 2-phenylisonicotinaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.63 min.; [M+H]+: 403.13 g/mol.
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([CH3:7])[C:3]=1[C:8]#[N:9].CN(C)[CH:12]=[CH:13][C:14]([C:16]1[CH:17]=[CH:18][C:19]([F:27])=[C:20]([N:22]([CH3:26])[C:23](=[O:25])[CH3:24])[CH:21]=1)=O.C(OCC)(=O)C>C(O)(=O)C>[F:27][C:19]1[CH:18]=[CH:17][C:16]([C:14]2[N:6]3[N:5]=[C:4]([CH3:7])[C:3]([C:8]#[N:9])=[C:2]3[N:1]=[CH:12][CH:13]=2)=[CH:21][C:20]=1[N:22]([CH3:26])[C:23](=[O:25])[CH3:24]
Reactant: CC(=O)N(C)c1cc(C(=O)C=CN(C)C)ccc1F
Reactant: Cc1n[nH]c(N)c1C#N
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CC(=O)N(C)c1cc(-c2ccnc3c(C#N)c(C)nn23)ccc1F
Yield: 74.9 %

Procedure:
A mixture of 0.046 g (0.38 mmol) of 5-amino-3-methyl-1H-pyrazole-4-carbonitrile and 0.1 g (0.38 mmol) of N-[5-(3-dimethylamino-acryloyl)-2-fluoro-phenyl]-N-methyl-acetamide in 10 mL of glacial acetic acid was refluxed for 2.5 hours and then the solvent was removed by reduced pressure distillation. To the resulting residue were added 15 mL of dichloromethane and 10 mL of saturated sodium bicarbonate solution. The two layers were separated, and the aqueous layer was washed with 10 mL of dichloromethane. The organic layers were washed with 10 mL of water and dried over magnesium sulfate. The dichloromethane layer was evaporated to dryness to yield an oil which, in the presence of ethyl acetate, gave 92 mg of N-{2-fluoro-5-[3-cyano-2-methyl-pyrazolo[1,5-a]pyrimidin-7-yl]-phenyl}-N-methyl-acetamide as a solid (yield 75%).
Reaction SMILES: [CH:1]1([C:4]2[N:8]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[N:7]=[C:6]([NH:16][C:17]3[C:22](I)=[CH:21][N:20]=[C:19]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[N:18]=3)[CH:5]=2)[CH2:3][CH2:2]1.N(C(C)C)C(C)C.[Si:37]([C:41]#[CH:42])([CH3:40])([CH3:39])[CH3:38]>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.[Cu]I.C1COCC1>[CH:1]1([C:4]2[N:8]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[N:7]=[C:6]([NH:16][C:17]3[C:22]([C:42]#[C:41][Si:37]([CH3:40])([CH3:39])[CH3:38])=[CH:21][N:20]=[C:19]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[N:18]=3)[CH:5]=2)[CH2:3][CH2:2]1
Reactant: C#C[Si](C)(C)C
Reactant: CC(C)(C)OC(=O)n1nc(Nc2nc(-c3ccccc3)ncc2I)cc1C1CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CC(C)(C)OC(=O)n1nc(Nc2nc(-c3ccccc3)ncc2C#C[Si](C)(C)C)cc1C1CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 118.9 %

Procedure:
Under nitrogen, to the mixture of tert-butyl 5-cyclopropyl-3-(5-iodo-2-phenylpyrimidin-4-ylamino)-1H-pyrazole-1-carboxylate (245 mg, 0.49 mmol, 1.0 equiv), PdCl2(PPh3)2 (40 mg, 0.057 mmol, 0.12 equiv.), CuI (22 mg, 0.115 mmol, 0.23 equiv.), i-Pr2NH (1.7 mL, 11.78 mmol, 24 equiv.) and THF (10 mL), TMS-acetylene (3.5 mL, 25 mmol, 51 equiv.) were added. After stirring at r.t. for 2 h, silica gel was added to the reaction mixture and the solvents were removed. The residue was purified by silica gel chromatography (hexane/EtOAc=3:1 as eluant) afford tert-butyl 5-cyclopropyl-3-(2-phenyl-5-((trimethylsilyl)ethynyl) pyrimidin-4-ylamino)-1H-pyrazole-1-carboxylate (276 mg, 98%). LC-MS (m/z): 474.2 [M+H]+. To the solution of tert-butyl 5-cyclopropyl-3-(2-phenyl-5-((trimethylsilyl)ethynyl)pyrimidin-4-ylamino)-1H-pyrazole-1-carboxylate (276 mg, 0.58 mmol, 1 equiv.) in CH2Cl2 (2 mL) was added TFA (2 mL). After 10 min at rt, the reaction mixture was concentrated to generate crude N-(5-cyclopropyl-1H-pyrazol-3-yl)-2-phenyl-5-((trimethylsilyl)ethynyl)pyrimidin-4-amine, which was used in next step without further purification. LC-MS (m/z): 374.2 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([C:8](Cl)=[O:9])[CH:3]=1.[NH2:11][C:12]1[C:13]([CH3:18])=[CH:14][CH:15]=[CH:16][CH:17]=1.CCN(C(C)C)C(C)C>C(Cl)Cl>[Cl:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([C:8]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH3:18])=[O:9])[CH:3]=1
Reactant: O=C(Cl)c1cc(Cl)ncn1
Reactant: Cc1ccccc1N
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1ccccc1NC(=O)c1cc(Cl)ncn1

Procedure:
A cooled (0° C.) solution of 6-chloropyrimidine-4-carbonyl chloride (26.76 g; 151 mmol), obtained as described above for Intermediate 7 step 1, in anhydrous DCM (270 ml) was treated dropwise over 25 minutes with a solution of o-toluidine (13.6 ml; 126.0 mmol) and DIEA (43.4 ml; 252 mmol) in anhydrous DCM (100 mL). At the end of addition, the reaction mixture was washed with water then brine, dried over MgSO4, filtered and dried under vacuum to afford the title compound used without further purification as a brown solid. 1H NMR (300 MHz, DMSO-d6) δ 10.47 (1H, br s), 9.32 (1H, d, J=1.0 Hz), 8.25 (1H, d, J=1.0 Hz), 7.65-7.63 (1H, m), 7.34-7.19 (3H, m), 2.31 (3H, s). MS (ESI+): 248.0; MS (ESI−): 246.1. HPLC (Condition A): Rt 4.19 min (HPLC purity 96.0%).
Reaction SMILES: Cl.[CH2:2]([NH:4][C:5](=[O:20])[CH:6]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)=[CH:10][CH:9]=1)[CH3:7])[CH3:3]>C(O)C.[Pt](=O)=O>[CH2:2]([NH:4][C:5](=[O:20])[CH:6]([C:8]1[CH:13]=[CH:12][C:11]([CH:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)=[CH:10][CH:9]=1)[CH3:7])[CH3:3]
Reactant: CCNC(=O)C(C)c1ccc(-c2ccncc2)cc1
Agent: O=[Pt]=O
Agent: Cl
Solvent: CCO
Product: CCNC(=O)C(C)c1ccc(C2CCNCC2)cc1

Procedure:
4.4 mL 1N HCl are added to 1.12 g (4.40 mmol) N-ethyl-2-(4-pyridin-4-yl-phenyl)-propionamide (V.1) in 15 mL ethanol. The mixture is hydrogenated (5 bar) for 6 h at rt using 110 mg platinum(IV) oxide. After that time, the catalyst is filtered off and the solvent is evaporated. The residue is taken up in water, alkalized with 1N NaOH and extracted with DCM (2×). The organic layer is dried over magnesium sulphate and the solvent is evaporated. The residue is purified by HPLC (column: Gemini; eluent A: water+0.1% NH4OH, eluent B: MeOH) to yield the desired product.
Reaction SMILES: C[CH:2]1[CH2:6][S:5][CH:4]([C:7]([O:9][CH:10]([CH3:12])[CH3:11])=[O:8])[C:3]1=[N:13][OH:14].[ClH:15]>C(OC)(C)(C)C>[Cl:15][CH:2]1[CH2:6][S:5][CH:4]([C:7]([O:9][CH:10]([CH3:12])[CH3:11])=[O:8])[C:3]1=[N:13][OH:14]
Reactant: CC(C)OC(=O)C1SCC(C)C1=NO
Reactant: Cl
Solvent: COC(C)(C)C
Product: CC(C)OC(=O)C1SCC(Cl)C1=NO
Temperature: 0 °C
Reaction time: 2 h

Procedure:
334 g (1.54 mol) of i-propyl 4-methyl-3-hydroximino-tetrahydrothiophene-2-carboxylate are dissolved in 5 litres of methyl tert-butyl ether and cooled using an ice bath. Hydrogen chloride is then—after the ice bath had been removed—introduced with stirring for two hours. The mixture is subsequently concentrated using water pump vacuum and the amorphous residue is crystallized from acetone.
Reaction SMILES: C(OC([NH:11][C@@H:12]([CH2:17][N:18]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]([O:15][CH3:16])=[O:14])=O)C1C=CC=CC=1.[H][H]>CO>[NH2:11][C@@H:12]([CH2:17][N:18]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)[C:13]([O:15][CH3:16])=[O:14]
Reactant: [H][H]
Reactant: COC(=O)[C@H](CN(c1ccccc1)c1ccccc1)NC(=O)OCc1ccccc1
Solvent: CO
Product: COC(=O)[C@@H](N)CN(c1ccccc1)c1ccccc1
Yield: 91 %

Procedure:
In order to eliminate the Z protecting group, 2.7 g (6.68 mmol) of the Z-protected derivative (4) were dissolved in 500 ml of methanol, and 100 mg of catalyst (10% Pd(OH)2—C) were supplied under a protective atmosphere of nitrogen. The inert gas was subsequently displaced with a large excess of hydrogen and the mixture was shaken for 2 h in the hydrogen atmosphere. In order to terminate the reaction, the catalyst was filtered off and the filtrate was concentrated. 1.65 g (yield: 91%) of methyl 2-amino-3-diphenylaminopropionate (5) were obtained.