Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([CH:18]([C:25]4[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=4)[C:19]4[N:23]([CH3:24])[CH:22]=[N:21][N:20]=4)[CH:16]=3)[N:11]([CH3:32])[C:10](=[O:33])[CH:9]=2)[CH:5]=[CH:6][CH:7]=1.CC([OH:38])(C)C.[K].O>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([C:18]([C:25]4[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=4)([OH:38])[C:19]4[N:23]([CH3:24])[CH:22]=[N:21][N:20]=4)[CH:16]=3)[N:11]([CH3:32])[C:10](=[O:33])[CH:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)O
Reactant: Cn1cnnc1C(c1ccc(Cl)cc1)c1ccc2c(c1)c(-c1cccc(Cl)c1)cc(=O)n2C
Agent: [K]
Solvent: CN(C)C=O
Solvent: O
Product: Cn1cnnc1C(O)(c1ccc(Cl)cc1)c1ccc2c(c1)c(-c1cccc(Cl)c1)cc(=O)n2C
Temperature: 25 °C
Reaction time: 1 h
Yield: 77 %

Procedure:
Air was bubbled in a mixture of 4-(3-chlorophenyl)-6-[(4-chlorophenyl)(4-methyl-4H-1,2,4-triazol-3-yl)methyl]-1-methyl-2(1H)-quinolinone (see Example B7) (0.0018 mol) in N,N-dimethylformamide (8 ml) at 5° C. for 30 minutes. 2-methyl-2-propanol, potassium salt (0.0036 mol) was added portionwise. The mixture was stirred at room temperature for 1 hour, poured out into water, filtered and washed several times with water. The precipitate was taken up in CH2Cl2. The organic layer was separated dried (MgSO4), filtered and the solvent was evaporated till dryness. The residue (1.1 g) was purified by column chromatography over silica gel (eluent: CH2Cl2/CH3OH/NH4OH 92/8/0.1; 15–40 μm). The pure fractions were collected and the solvent was evaporated. The residue (0.75 g, 85%) was crystallized from 2 propanone/DIPE. The precipitate was filtered off and dried, yielding 0.68 g (77%) of 4-(3-chlorophenyl)-6-[(4-chlorophenyl)hydroxy(4-methyl-4H-1,2,4-triazol-3-yl)methyl]-1-methyl-2(1H)-quinolinone, mp. 182° C.
Reaction SMILES: [CH3:1][C:2]([CH3:15])([CH2:13]O)[CH2:3][N:4]1[C:8](=[O:9])[C:7]([CH3:10])=[C:6]([CH3:11])[C:5]1=[O:12].[Cl:16][CH2:17][C:18]([OH:20])=[O:19].S(=O)(=O)(O)O.C1(C)C=CC=CC=1>O>[Cl:16][CH2:17][C:18]([O:20][CH:3]([N:4]1[C:8](=[O:9])[C:7]([CH3:10])=[C:6]([CH3:11])[C:5]1=[O:12])[C:2]([CH3:15])([CH3:13])[CH3:1])=[O:19]
Reactant: O=C(O)CCl
Reactant: CC1=C(C)C(=O)N(CC(C)(C)CO)C1=O
Agent: O=S(=O)(O)O
Solvent: Cc1ccccc1
Solvent: O
Product: CC1=C(C)C(=O)N(C(OC(=O)CCl)C(C)(C)C)C1=O
Yield: 84.1 %

Procedure:
A mixture of 105.6 g (0.5 mole) of N-(2,2-dimethyl-3-hydroxypropyl)dimethylmaleimide, 56.7 g (0.6 mole) of chloroacetic acid, 5.9 g of concentrated sulfuric acid and 400 ml of toluene are heated as described in Example 1 until the formation of water (9 ml) has ceased. The reaction solution is worked up as in Example 1, affording 121 g of a colourless liquid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[CH2:12][CH2:11][C:10]3[CH:13]=[C:14]([Cl:17])[CH:15]=[CH:16][C:9]=3[CH:8]([N:18]3[CH2:23][CH2:22][N:21]([C:24](=[O:32])[CH2:25][CH:26]4[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]4)[CH2:20][CH2:19]3)[C:5]2=[N:6][CH:7]=1.[CH:33]1[CH:38]=[CH:37][C:36]([O:39][C:40](OC2C=CC=CC=2)=[N:41][C:42]#[N:43])=[CH:35][CH:34]=1>CC(O)C>[Br:1][C:2]1[CH:3]=[C:4]2[CH2:12][CH2:11][C:10]3[CH:13]=[C:14]([Cl:17])[CH:15]=[CH:16][C:9]=3[CH:8]([N:18]3[CH2:19][CH2:20][N:21]([C:24](=[O:32])[CH2:25][CH:26]4[CH2:31][CH2:30][N:29]([C:40](=[N:41][C:42]#[N:43])[O:39][C:36]5[CH:37]=[CH:38][CH:33]=[CH:34][CH:35]=5)[CH2:28][CH2:27]4)[CH2:22][CH2:23]3)[C:5]2=[N:6][CH:7]=1
Reactant: N#CN=C(Oc1ccccc1)Oc1ccccc1
Reactant: O=C(CC1CCNCC1)N1CCN(C2c3ccc(Cl)cc3CCc3cc(Br)cnc32)CC1
Solvent: CC(C)O
Product: N#CN=C(Oc1ccccc1)N1CCC(CC(=O)N2CCN(C3c4ccc(Cl)cc4CCc4cc(Br)cnc43)CC2)CC1
Temperature: 80 °C
Yield: 87.4 %

Procedure:
1-(3-Bromo-8-chloro-6,11-dihydro-5 H-benzo[5,6]-cyclohepta[1,2-b] pyridin-11-yl)-4-[(4-piperidinyl)acetyl]-piperazine (Formula 47.0) (prepared as described in Preparative Example 11) (2.5 g) (1 equivalent) and diphenylcyanocarbon-imidate (1.38 g) (1.2 equivalents) were dissolved in 2-propanol (65 ml) and the solution was heated at 80° C. under reflux and under nitrogen for 24 h. The mixture was evaporated to dryness and the product was chromatographed on a silica gel column (60×2.5 cm) using neat ethyl acetate as the eluant to give the title compound (Formula 2.0) (2.7921 g; 87%), FABMS: m/z 661 (MH+).
Reaction SMILES: [CH2:1]([N:13]([CH3:20])[CH2:14][CH2:15][C:16]([CH3:19])([NH2:18])[CH3:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[C:21](ON1C(=O)CCC1=O)([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22]>C1COCC1>[CH2:1]([N:13]([CH3:20])[CH2:14][CH2:15][C:16]([NH:18][C:21](=[O:22])[O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)([CH3:19])[CH3:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCCCN(C)CCC(C)(C)N
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Solvent: C1CCOC1
Product: CCCCCCCCCCCCN(C)CCC(C)(C)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 69.2 %

Procedure:
Crude N1-dodecyl-N1,3-dimethylbutane-1,3-diamine (5.61 g, 19.7 mmol) was dissolved into THF (100 mL) and cooled in an ice bath. Solid CbzOSu (4.91 g, 1 equiv, 19.7 mmol) was added to the reaction in one portion. The reaction was left to stir at room temperature for 16 h. The solvent was removed and the residue was taken up in a mixture of ethyl acetate (150 mL) and water (50 mL). The layers were separated and the organic layer washed with 1 M sodium carbonate (2×50 mL) and brine (50 mL). The organic layer was dried over anhydrous MgSO4, filtered and concentrated to a pale yellow oil (8.08 g). The crude oil was purified on an ISCO purification system with gradient elution from 25-100% ethyl acetate in hexanes. The desired fractions were collected and concentrated to give a pale yellow oil (5.71 g, yield: 69.2%). 1H NMR (CDCl3, 400 MHz): δ 0.89-0.92 (t, J=6, 3H), 1.21-1.36 (m, 17H), 1.39 (s, 6H), 1.56-1.66 (m, 4H), 2.21 (s, 3H), 2.30-2.34 (t, J=8, 2H), 2.46-2.49 (t, J=6, 2H), 5.06 (s, 2H), 7.28-7.41 (m, 5H). LRMS (ESI+) for C26H46N2O2 (418.4); Found: 419 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([O:13][C:14]1[CH:20]=[CH:19][C:17]([NH2:18])=[CH:16][CH:15]=1)[CH:7]=[CH:6]2.C[N:22]([CH:24]=O)C.Br[CH2:27][C:28]([C:30]1[CH:35]=[CH:34][C:33]([O:36][CH2:37][CH2:38][CH2:39][N:40]([CH2:43][CH3:44])[CH2:41][CH3:42])=[CH:32][CH:31]=1)=O>O.CCOC(C)=O>[CH2:4]([C:24]1[N:18]([C:17]2[CH:19]=[CH:20][C:14]([O:13][C:8]3[CH:7]=[CH:6][C:5]4[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[CH:4]=4)[CH:9]=3)=[CH:15][CH:16]=2)[CH:27]=[C:28]([C:30]2[CH:35]=[CH:34][C:33]([O:36][CH2:37][CH2:38][CH2:39][N:40]([CH2:43][CH3:44])[CH2:41][CH3:42])=[CH:32][CH:31]=2)[N:22]=1)[CH2:3][CH2:12][CH3:11]
Reactant: CN(C)C=O
Reactant: COc1ccc2cc(Oc3ccc(N)cc3)ccc2c1
Reactant: CCN(CC)CCCOc1ccc(C(=O)CBr)cc1
Solvent: CCOC(C)=O
Solvent: O
Product: CCCCc1nc(-c2ccc(OCCCN(CC)CC)cc2)cn1-c1ccc(Oc2ccc3cc(OC)ccc3c2)cc1
Temperature: 25 °C

Procedure:
To a stirred solution of an 4-(6-methoxy-naphthalen-2-yloxy)aniline (5 mmol) in anhydrous DMF (20 mL) DIEA (15 mmol) was added, followed by slow addition of the 2-bromo-1-{4-[3-(diethylamino)propoxy]phenyl}ethanone described above (4.6 mmol), according to General Procedure R2. The reaction mixture was stirred under nitrogen at rt until completion, as indicated by TLC or HPLC. The reaction mixture was then diluted with cold H2O and the product was isolated in EtOAc. The combined organic layers were washed with brine and dried over sodium sulfate. Evaporation of solvent in vacuuo afforded the desired product. The crude alkylated aniline was used for further transformation without additional purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11](=[O:12])[C:10](I)=[C:9]([O:14]C)[C:8](=[O:16])[NH:7][C:6]=2[CH:17]=1.C([Sn](CCCC)(CCCC)[C:23]1[O:24][CH:25]=[CH:26][CH:27]=1)CCC>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1C=CC=C1P(C1OC=CC=1)C1OC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11](=[O:12])[C:10]([C:23]3[O:24][CH:25]=[CH:26][CH:27]=3)=[C:9]([OH:14])[C:8](=[O:16])[NH:7][C:6]=2[CH:17]=1
Reactant: COc1c(I)c(=O)c2ccc(Cl)cc2[nH]c1=O
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccco1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: c1coc(P(c2ccco2)c2ccco2)c1
Solvent: Cc1ccccc1
Product: O=c1[nH]c2cc(Cl)ccc2c(=O)c(-c2ccco2)c1O
Reaction time: 0.17 h
Yield: 55.2 %

Procedure:
A solution of tri(2-furyl)phosphine (0.026 g) and tris(dibenzylideneacetone)dipalladium (O) (0.026 g) in toluene (50 mL) was allowed to stir for 10 minutes. To this solution was added 8-chloro-4-iodo-3-methoxy-2,5-dioxo-2,5-dihydro-1H-benz-[b]azepine (1.0 g), followed by 2-tributylstannylfuran (1.2 g). The reaction was heated to reflux for 0.5 hour, was allowed to cool, and the toluene was evaporated. The residue was triturated with hot hexanes (75 mL). The isolated solid was recrystallized from ethyl acetate/hexanes (1:1) to afford the title compound (0.44 g); mp 233-234 C.; NMR: 11.47 (bs, 1), 7.79 (s, 1), 7.58 (d, 1, J=8.9), 7.34-7.31 (m, 2), 6.91 (d, 1, J=3.4), 6.61 (m, 1), 3.82 (s, 3). Analysis for C15H10ClNO4 0.5 H2O.: Calculated: C, 57.61; H, 3.54; N, 4.47; Found C, 57.77; H, 3.13; N, 4.46.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:32])[CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]([OH:31])([C:27]([F:30])([F:29])[F:28])[C:23]([F:26])([F:25])[F:24])=[CH:18][CH:17]=3)[CH2:11][CH2:10]2)=[CH:4][C:3]=1[F:33].Cl[C:35](OC1C=CC([N+]([O-])=O)=CC=1)=[O:36].Cl.[O:48]1[CH2:52][CH2:51][C@H:50]([NH2:53])[CH2:49]1.C(N(CC)CC)C>O1CCCC1>[F:33][C:3]1[CH:4]=[C:5]([CH:8]([CH:9]2[CH2:10][CH2:11][N:12]([CH2:15][C:16]3[CH:17]=[CH:18][C:19]([C:22]([OH:31])([C:27]([F:30])([F:28])[F:29])[C:23]([F:24])([F:25])[F:26])=[CH:20][CH:21]=3)[CH2:13][CH2:14]2)[OH:32])[CH:6]=[CH:7][C:2]=1[NH:1][C:35]([NH:53][C@H:50]1[CH2:51][CH2:52][O:48][CH2:49]1)=[O:36]
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: Nc1ccc(C(O)C2CCN(Cc3ccc(C(O)(C(F)(F)F)C(F)(F)F)cc3)CC2)cc1F
Reactant: N[C@H]1CCOC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(Nc1ccc(C(O)C2CCN(Cc3ccc(C(O)(C(F)(F)F)C(F)(F)F)cc3)CC2)cc1F)N[C@H]1CCOC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 17.5 %

Procedure:
2-(4-((4-((4-Amino-3-fluorophenyl)(hydroxy)methyl)piperidin-1-yl)methyl)phenyl)-1,1,1,3,3,3-hexafluoropropan-2-ol (0.125 mmol, 60 mg) and 4-nitrophenyl chloroformate (0.125 mmol, 25.2 mg) were combined in tetrahydrofuran (2 mL) and the reaction stirred at room temperature for 1 hour. (S)-Tetrahydrofuran-3-amine hydrochloride (0.125 mmol, 15.43 mg) and triethylamine (0.500 mmol, 50.6 mg) were added and the mixture stirred at room temperature overnight. The mixture was concentrated under reduced pressure and the resulting residue purified by silica gel column chromatography (eluting with dichloromethane to 10% methanol/dichloromethane) to afford the title compound (13 mg). MS (ESI) m/z 594.7 [M+H]+
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][C:11](=[N:13][O:14][CH3:15])[CH2:10][C@H:9]1[C:16]([OH:18])=[O:17])=[O:7])(C)(C)C.[CH3:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[C:26]1[CH:31]=[CH:30][C:29](C(O)=O)=[C:28]([CH3:35])[CH:27]=1.[CH3:36]O>>[CH3:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[C:26]1[CH:31]=[CH:30][C:29]([C:6]([N:8]2[CH2:12][C:11](=[N:13][O:14][CH3:15])[CH2:10][C@H:9]2[C:16]([O:18][CH3:36])=[O:17])=[O:7])=[C:28]([CH3:35])[CH:27]=1
Reactant: Cc1cc(-c2ccccc2C)ccc1C(=O)O
Reactant: CO
Reactant: CON=C1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Product: CON=C1C[C@@H](C(=O)OC)N(C(=O)c2ccc(-c3ccccc3C)cc2C)C1

Procedure:
Following the general method as outlined in Example 11, starting from (2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylic acid, 2′,3-dimethyl[1,1′-biphenyl]-4-carboxylic acid, and methanol, the title compound was isolated as a mixture of two isomers in 81.4% purity by HPLC.
Reaction SMILES: [C-:1]#[N:2].[K+].[C-]#N.[Na+].[C:7]([O:11][C:12]([NH:14][C@@H:15]1[CH2:19][CH2:18][C@H:17]([CH2:20]OS(C)(=O)=O)[CH2:16]1)=[O:13])([CH3:10])([CH3:9])[CH3:8]>CN(C=O)C>[C:7]([O:11][C:12](=[O:13])[NH:14][C@H:15]1[CH2:19][CH2:18][C@@H:17]([CH2:20][C:1]#[N:2])[CH2:16]1)([CH3:10])([CH3:9])[CH3:8]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CC[C@H](COS(C)(=O)=O)C1
Reactant: [C-]#N
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](CC#N)C1
Temperature: 80 °C
Reaction time: 8 h
Yield: 31.9 %

Procedure:
In a round-bottomed flask, methanesulfonic acid (cis)-3-tert-butoxycarbonylamino-cyclopentylmethyl ester (crude from Step 4, 779 mg) was dissolved in DMF (5 ml). Potassium cyanide (277 mg, 4.25 mmol) was added and the reaction mixture was stirred at 80° C. overnight. Sodium cyanide (104 mg, 2.12 mmol) was added and the reaction mixture was stirred at 80° C. for 48 h. The reaction was cooled to room temperature, quenched with water and extracted with diethyl ether (2×). The combined organic layers were washed twice with water and once with brine then dried over sodium sulfate, filtered and concentrated. The residue was chromatographed over silica gel with EtOAc/hexanes (gradient 0-30% EtOAc) to afford 190 mg (38%, 2 steps) of (cis-3-cyanomethyl-cyclopentyl)-carbamic acid tert-butyl ester as a light yellow oil.
Reaction SMILES: [CH2:1]([O:3][P:4]([C:9]([F:19])([F:18])[C:10]1[CH:15]=[CH:14][C:13]([CH:16]=[O:17])=[CH:12][CH:11]=1)(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2].CC(C)=[O:22].OS(O)(=O)=O.O=[Cr](=O)=O>CC(C)=O>[CH2:1]([O:3][P:4]([C:9]([F:19])([F:18])[C:10]1[CH:15]=[CH:14][C:13]([C:16]([OH:22])=[O:17])=[CH:12][CH:11]=1)([O:5][CH2:6][CH3:7])=[O:8])[CH3:2]
Reactant: CC(C)=O
Reactant: CCOP(=O)(OCC)C(F)(F)c1ccc(C=O)cc1
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Product: CCOP(=O)(OCC)C(F)(F)c1ccc(C(=O)O)cc1
Yield: 98 %

Procedure:
To a solution of [Difluoro-(4-formyl-phenyl)-methyl]-phosphonic acid diethyl ester (260 mg, 0.9 mmol) in acetone (25 mL) at room temperature was added Jones reagent (5 mL). The reaction was quenched by addition of ethanol (5 mL). The reaction was then concentrated under reduced pressure to 5 mL. The residue was diluted with ethyl acetate and washed with water (2×20 mL), saturated sodium chloride (20 mL), dried over magnesium sulfate, filtered, and concentrated under reduced pressure to yield a white crystalline solid (268 mg, 98%). 1H NMR (400 MHz, DMSO): δ 8.09 (d, 2H), 7.70 (d, 2H), 4.15 (m, 4H), 1.22 (t, 6H); Mass Spectrum (Chemical Ionization, 1% NH in CH4) m/z 309 (M+H).
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1)=[O:6].Br[CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CN(C=O)C>[Cl:14][C:11]1[CH:12]=[CH:13][C:8]([CH2:7][C:5]([O:4][CH3:3])=[O:6])=[C:9]([CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:10]=1
Reactant: COC(=O)Cc1ccc(Cl)cc1
Reactant: BrCCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)Cc1ccc(Cl)cc1CCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 40.4 %

Procedure:
To a solution of 4.35 g of 60% sodium hydride in 50 ml of DMF was added dropwise 20.0 g of methyl 4-chlorophenyl acetate in 25 ml of DMF. Once the evolution had ceased a mixture of 20.0 g of 2-bromoethyl benzene in 25 m of DMF was added and the reaction was stirred at room temPerature overnight. The reaction was then partitioned between 400 ml of ether and 200 ml of H2O. The ether extracts were washed with H2O, dried over magnesium sulfate, filtered and concentrated to 32.9 g of a yellow oil. Chromatography on silica gel with 5% ethyl acetate in hexane afforded 12.6 g of the title compound as a clear, colorless oil.
Reaction SMILES: [NH2:1][CH:2](N1C(=O)C2=CC=CC=C2C1=O)[CH2:3][CH2:4][O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.O.[NH2:25]N.[ClH:27]>CO>[ClH:27].[ClH:27].[NH2:25][CH:3]([CH2:4][O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH2:2][NH2:1]
Reactant: NC(CCOCc1ccccc1)N1C(=O)c2ccccc2C1=O
Reactant: NN
Agent: Cl
Solvent: CO
Solvent: O
Product: NCC(N)COCc1ccccc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
1-Amino-2-benzyloxymethyl-1-phthalimido-ethane (3.0 g, 9.7 mmol) is dissolved in 50 ml dry methanol and hydrazine hydrate (968 mg, 19.3 mmol) is added. After being refluxed for 4 hours, the reaction mixture is stirred for 24 hours at ambient temperature and 50 ml 2N hydrochloric acid was added. The phthalhydrazide is removed by filtration and the 1,2-diamino-1-benzyloxymethyl-ethane-dihydrochloride is purified by recrystallisation from dry ethanol.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:4]=1[CH:5]=O.[NH2:13][C:14]1[S:15][CH:16]=[CH:17][N:18]=1.[BH4-].[Na+].CO>ClC(Cl)C.N1CCCCC1>[CH3:1][O:2][C:3]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:4]=1[CH2:5][NH:13][C:14]1[S:15][CH:16]=[CH:17][N:18]=1
Reactant: Nc1nccs1
Reactant: COc1ccc(C=O)c(OC)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CO
Solvent: C1CCNCC1
Product: COc1ccc(CNc2nccs2)c(OC)c1
Yield: 64 %

Procedure:
2,4-Dimethoxybenzaldehyde (25 g, 150 mmol), 2-aminothiazole (15.1 g, 150 mmol) and piperidine (150 mg, 1.76 mmol) were combined in dichloroethane (500 ml) and the mixture was heated to reflux over 4 Å molecular sieves for 18 hours. The sieves were removed by filtration and the reaction mixture diluted with methanol (300 ml). Sodium borohydride (25 g, 662 mmol) was added in portions and the reaction mixture heated to reflux for 2 hours. The cooled reaction mixture was quenched with water (50 mL) and the organic solvents evaporated in vacuo. The aqueous residue was extracted with ethyl acetate (2×100 mL) and the combined organic solutions extracted with 2M HCl (2×50 mL). The acidic solution was basified with solid potassium carbonate and re-extracted with ethyl acetate (2×50 mL). The organic layer was dried over Na2SO4, filtered and evaporated in vacuo. The residue was purified by column chromatography eluting with 9:1 dichloromethane:methanol to yield the title compound (24 g, 96 mmol, 64%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][N:5]([CH2:7][C:8]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[C:12]=2[F:18])=[O:9])[CH:6]=1.[CH2:19]([O:26][C:27]1[CH:36]=[C:35]2[C:30]([C:31](Cl)=[N:32][CH:33]=[N:34]2)=[CH:29][CH:28]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.Cl.O1CCOCC1>CC(N(C)C)=O.ClCCl>[CH2:19]([O:26][C:27]1[CH:36]=[C:35]2[C:30]([C:31]([NH:1][C:2]3[CH:3]=[N:4][N:5]([CH2:7][C:8]([NH:10][C:11]4[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[C:12]=4[F:18])=[O:9])[CH:6]=3)=[N:32][CH:33]=[N:34]2)=[CH:29][CH:28]=1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: Clc1ncnc2cc(OCc3ccccc3)ccc12
Reactant: Nc1cnn(CC(=O)Nc2cccc(F)c2F)c1
Agent: Cl
Solvent: CC(=O)N(C)C
Solvent: C1COCCO1
Solvent: ClCCl
Product: O=C(Cn1cc(Nc2ncnc3cc(OCc4ccccc4)ccc23)cn1)Nc1cccc(F)c1F
Temperature: 90 °C
Yield: 87.4 %

Procedure:
2-(4-amino-1H-pyrazol-1-yl)-N-(2,3-difluorophenyl)acetamide (504 mg, 2 mmol) was added to a solution of 7-(benzyloxy)-4-chloroquinazoline (541 mg, 2 mmol) in dimethylacetamide (10 ml) under argon. A solution of 4.0 N hydrochloric acid in dioxane (500 μl, 2 mmol) was added and the mixture was heated at 90° C. for 1.5 hours. The mixture was cooled, diluted with dichloromethane and the resultant precipitate recovered by filtration. The solid was washed with dichloromethane and diethyl ether and dried in vacuo to yield 2-(4-{[7-(benzyloxy)quinazolin-4-yl]amino}-1H-pyrazol-1-yl)-N-(2,3-difluorophenyl)acetamide (850 mg, 81% yield):
Reaction SMILES: O.[NH2:2][NH2:3].CC(N(C)C)=O.[CH3:10][C:11]1[CH:12]=[C:13]([S:19](Cl)(=[O:21])=[O:20])[CH:14]=[C:15]([CH3:18])[C:16]=1[OH:17]>O1CCOCC1>[CH3:10][C:11]1[CH:12]=[C:13]([S:19]([NH:2][NH2:3])(=[O:21])=[O:20])[CH:14]=[C:15]([CH3:18])[C:16]=1[OH:17]
Reactant: NN
Reactant: Cc1cc(S(=O)(=O)Cl)cc(C)c1O
Solvent: CC(=O)N(C)C
Solvent: O
Solvent: C1COCCO1
Product: Cc1cc(S(=O)(=O)NN)cc(C)c1O

Procedure:
15.0 g (0.3 mol) of hydrazine hydrate are first introduced into 60 ml of dimethylacetamide. 22 g (0.1 mol) of 3,5-dimethyl-4-hydroxybenzenesulfonic acid chloride dissolved in 60 ml of dioxane are added dropwise to this solution over the course of 15 minutes. This causes the temperature to rise to 90° C., at which level it is maintained by slight cooling. The mixture is allowed to react for a further 90 minutes and is then completely concentrated under reduced pressure. The residue is recrystallised first from a little water and then from isopropanol. This gives 3,5-dimethyl-4-hydroxybenzenesulphonic acid hydrazide, which melts at 186° C. (with decomposition).
Reaction SMILES: Br[CH2:2][C:3]1[C:4]([C:42](OC)=[O:43])=[CH:5][C:6]2[C:11]([CH:12]=1)=[CH:10][C:9]([C:13]([OH:41])([C:17]1[N:18]=[CH:19][N:20](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[CH:21]=1)[CH:14]([CH3:16])[CH3:15])=[CH:8][CH:7]=2.O.[NH2:47][NH2:48]>>[OH:41][C:13]([C:9]1[CH:8]=[CH:7][C:6]2=[CH:5][C:4]3[C:42](=[O:43])[NH:47][NH:48][CH2:2][C:3]=3[CH:12]=[C:11]2[CH:10]=1)([C:17]1[N:18]=[CH:19][NH:20][CH:21]=1)[CH:14]([CH3:15])[CH3:16]
Reactant: COC(=O)c1cc2ccc(C(O)(c3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)cn3)C(C)C)cc2cc1CBr
Reactant: NN
Solvent: O
Product: CC(C)C(O)(c1ccc2cc3c(cc2c1)CNNC3=O)c1c[nH]cn1

Procedure:
By a ring closure reaction, a detritylation reaction and purification in the same manner as in Example 1 using methyl 3-bromomethyl-6-[1-hydroxy-2-methyl-1-(1-trityl-1H-imidazol-4-yl)propyl]-2-naphthoate (0.95 g) and hydrazine monohydrate (0.50 ml), 7-[1-hydroxy-1-(1H-imidazol-4-yl)-2-methylpropyl]-3,4-dihydrobenzo[g]phthalazin-1(2H)-one (0.05 g) was obtained as a colorless amorphous solid and 7-[1-hydroxy-1-(1H-imidazol-4-yl)-2-methylpropyl]benzo[g]phthalazin-1(2H)-one (5 mg) was obtained as a colorless amorphous solid.
Reaction SMILES: [H-].[Na+].C(OP([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])(OCC)=O)C.[H][H].[F:19][C:20]([F:30])([F:29])[C:21]1[CH:28]=[CH:27][C:24]([CH:25]=O)=[CH:23][CH:22]=1>C(COC)OC.O>[CH2:15]([O:14][C:12](=[O:13])[CH2:11][CH2:25][C:24]1[CH:23]=[CH:22][C:21]([C:20]([F:19])([F:29])[F:30])=[CH:28][CH:27]=1)[CH3:16]
Reactant: O=Cc1ccc(C(F)(F)F)cc1
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Reactant: [H][H]
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: CCOC(=O)CCc1ccc(C(F)(F)F)cc1
Temperature: 10 °C
Reaction time: 0.5 h
Yield: 57.3 %

Procedure:
Dimethoxyethane 700 ml was added to 60% sodium hydride 24.8 g (620 mmol), the mixture was stirred at room temperature while a solution of ethyl diethylphosphonoacetate 139 g (620 mmol) in dimethoxyethane (100 ml) was added dropwise. After the generation of hydrogen gas was stopped, the solution was cooled to 10° C., and a solution of 4-trifluoromethylbenzaldehyde 100 g (574 mmol) in dimethoxyethane (100 ml) was added dropwise keeping the liquid temperature below 25° C. After addition, the mixture was stirred for 30 minutes, the reactant was added to water one liter, and the product was extracted with diethylether. The extract was washed with a sodium chloride aqueous solution, and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluent: heptane/ethyl acetate=3/1). Such obtained purified material was hydrogenated in the presence of 5% palladium carbon as a catalyst in ethanol 300 ml. The catalyst was filtered off, the solvent was distilled off at reduced pressure to obtain 3-(4-trifluoromethylphenyl)propionic acid ethylester 81.0 g (329 mmol). The yield was 57.3% from 4-trifluoro methylbenzaldehyde.