Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.[O:9]1[CH2:14][CH2:13][CH:12]([CH:15]([N:19]2[CH:23]=[C:22](B3OC(C)(C)C(C)(C)O3)[CH:21]=[N:20]2)[CH2:16][C:17]#[N:18])[CH2:11][CH2:10]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].O1CCOCC1.O>CCOC(C)=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>[Cl:1][C:2]1[N:7]=[C:6]([C:22]2[CH:21]=[N:20][N:19]([CH:15]([CH:12]3[CH2:13][CH2:14][O:9][CH2:10][CH2:11]3)[CH2:16][C:17]#[N:18])[CH:23]=2)[CH:5]=[CH:4][N:3]=1
Reactant: CC1(C)OB(c2cnn(C(CC#N)C3CCOCC3)c2)OC1(C)C
Reactant: Clc1ccnc(Cl)n1
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: CCOC(C)=O
Solvent: O
Solvent: C1COCCO1
Product: N#CCC(C1CCOCC1)n1cc(-c2ccnc(Cl)n2)cn1
Temperature: 100 °C
Yield: 71.4 %

Procedure:
A mixture of 2,4-dichloropyrimidine (0.589 g, 0.00395 mol), 3-(tetrahydro-2H-pyran-4-yl)-3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]propanenitrile (1.30 g, 0.00392 mol), tetrakis(triphenylphosphine)palladium(0) (0.3 g, 0.0002 mol), and potassium phosphate (2.5 g, 0.012 mol) in 1,4-dioxane (10 mL, 0.1 mol) and water (1 mL, 0.06 mol) was heated at 100° C. overnight. After cooling to room temperature, the mixture was diluted with EtOAc, washed with water, brine, dried over MgSO4, filtered and concentrated. The residue was purified on silica gel, eluting with 0 to 100% EtOAc in hexanes, to provide the desired product (890 mg, 71.36%). LCMS (M+H) 318.3
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:5](=[N:6][C:7](S(C)(=O)=O)=[N:8][CH:9]=2)[N:4]([CH3:15])[N:3]=1.[NH2:16][CH2:17][CH2:18][N:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1>>[Br:1][C:2]1[C:10]2[C:5](=[N:6][C:7]([NH:16][CH2:17][CH2:18][N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)=[N:8][CH:9]=2)[N:4]([CH3:15])[N:3]=1
Reactant: NCCN1CCOCC1
Reactant: Cn1nc(Br)c2cnc(S(C)(=O)=O)nc21
Product: Cn1nc(Br)c2cnc(NCCN3CCOCC3)nc21

Procedure:
Prepared as described above in Example 8 starting from 3-bromo-6-methanesulfonyl-1-methyl-1H-pyrazolo[3,4-d]pyrimidine and N-aminoethylmorpholine to give the title compound (3-bromo-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)-(2-morpholin-4-yl-ethyl)-amine; 1H-NMR (DMSO): δ 2.43 (m, 4H), 2.50 (m, 2H), 3.47 (m, 2H), 3.55 (m, 2H), 3.77 (s, 3H), 7.61 (br s, 1H), 8.63 (s, 1H); LC/MS (m/e)=340.21 (MH+), Rt=1.13 min.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][C:13]=1[O:14][CH3:15])[NH:10][N:9]=[C:8]2[CH2:16][N:17]1[CH2:22][CH2:21][N:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[O:29][CH3:30])[CH2:19][CH2:18]1.[CH3:31][O:32][C:33]1[CH:34]=[C:35]([CH2:41]Cl)[CH:36]=[CH:37][C:38]=1[O:39][CH3:40].O>CN(C)C=O>[CH3:3][O:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][C:13]=1[O:14][CH3:15])[N:10]([CH2:41][C:35]1[CH:36]=[CH:37][C:38]([O:39][CH3:40])=[C:33]([O:32][CH3:31])[CH:34]=1)[N:9]=[C:8]2[CH2:16][N:17]1[CH2:18][CH2:19][N:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[O:29][CH3:30])[CH2:21][CH2:22]1
Reactant: COc1ccc(CCl)cc1OC
Reactant: COc1cc2[nH]nc(CN3CCN(c4ccccc4OC)CC3)c2cc1OC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(Cn2nc(CN3CCN(c4ccccc4OC)CC3)c3cc(OC)c(OC)cc32)cc1OC
Reaction time: 0.5 h
Yield: 79.6 %

Procedure:
In dimethylformamide was suspended 61.6 mg of sodium hydride at 0° C., and 590 mg of 5,6-dimethoxy-3-[[4-(2-methoxyphenyl)-1-piperazinyl]methyl]indazole was added thereto, followed by stirring for 30 minutes. To the mixture was added 290 mg of 3,4-dimethoxyphenylmethyl chloride. After 1.5 hours, 2.0 ml of water was added to the reaction mixture, followed by evaporation of the solvent. The residue was purified by silica gel column chromatography (chloroform:ethanol=20:1) and recrystallized from ethanol to yield 654 mg of the title compound.
Reaction SMILES: Br[CH2:2][CH2:3][N:4]1[C:8]2[N:9]=[C:10]([NH2:14])[N:11]=[C:12]([Cl:13])[C:7]=2[CH:6]=[CH:5]1.[F:15][C:16]1[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=1[N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Cl:13][C:12]1[C:7]2[CH:6]=[CH:5][N:4]([CH2:3][CH2:2][N:26]3[CH2:25][CH2:24][N:23]([C:17]4[CH:18]=[CH:19][C:20]([F:22])=[CH:21][C:16]=4[F:15])[CH2:28][CH2:27]3)[C:8]=2[N:9]=[C:10]([NH2:14])[N:11]=1
Reactant: Nc1nc(Cl)c2ccn(CCBr)c2n1
Reactant: Fc1ccc(N2CCNCC2)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Nc1nc(Cl)c2ccn(CCN3CCN(c4ccc(F)cc4F)CC3)c2n1
Temperature: 50 °C

Procedure:
To a solution of the title A compound in Example 29, 7-(2-bromoethyl)-4-chloro-7H-pyrrolo[2,3-d]pyrimidin-2-amine (225 mg, 0.817 mmol) and 1-(2,4-difluorophenyl)piperazine (193 mg, 0.976 mmol) in 1 mL of dry acetone is added potassium carbonate (322 mg, 2.44 mmol). The mixture is heated at 50° C. for 24 h, cooled to RT, concentrated in vacuo, and the residue taken up in water. The aqueous mixture is repeatedly extracted with EtOAc, and the combined organic extracts are dried (Na2SO4), filtered and evaporated to dryness. The residue is purified by column chromatography on silica gel, eluting with 2% MeOH in DCM to afford 4-chloro-7-(2-(4-(2,4-difluorophenyl)piperazin-1-yl)ethyl)-7H-pyrrolo[2,3-d]pyrimidin-2-amine as a yellow solid: 1H NMR (CDCl3) δ 2.68 (m, 4H), 2.77 (t, 2H, J=8.0 Hz), 3.01 (m, 4H), 4.19 (t, 2H, J=8.0 Hz), 4.88 (brs, 2H), 6.36 (d, 1H, J=4.0 Hz), 6.77-6.87 (m, 3H), 6.96 (d, 1H, J=4.0 Hz).
Reaction SMILES: [ClH:1].C(OC([N:9]1[CH2:14][CH2:13][CH:12]([CH2:15][N:16]2[CH2:21][CH2:20][N:19]([C:22]3[CH:27]=[CH:26][N:25]=[C:24]([CH3:28])[N:23]=3)[CH2:18][CH2:17]2)[CH2:11][CH2:10]1)=O)(C)(C)C>C(OCC)(=O)C>[ClH:1].[ClH:1].[ClH:1].[CH3:28][C:24]1[N:23]=[C:22]([N:19]2[CH2:20][CH2:21][N:16]([CH2:15][CH:12]3[CH2:13][CH2:14][NH:9][CH2:10][CH2:11]3)[CH2:17][CH2:18]2)[CH:27]=[CH:26][N:25]=1
Reactant: Cc1nccc(N2CCN(CC3CCN(C(=O)OC(C)(C)C)CC3)CC2)n1
Agent: Cl
Solvent: CCOC(C)=O
Product: Cc1nccc(N2CCN(CC3CCNCC3)CC2)n1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Ethyl acetate saturated with gaseous HCl (50 ml) was added to a solution of 1-tert-butoxycarbonyl-4-[1-(2-methylpyrimidin-4-yl)piperazin-4-ylmethyl]piperidine (3.02 g) in ethyl acetate (15 ml) and the resulting suspension stirred at ambient temperature for 3 hours. Solvent was evaporated to give 4-[1-(2-methylpyrimidin-4-yl)piperazin-4-ylmethyl]piperidine trihydrochloride (2.78 g) as a colourless foam.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[CH:29]=[CH:28][C:9]3[C:10]4[N:11]=[C:12]([C:18]5[N:19]([CH2:23][C:24]([F:27])([F:26])[F:25])[N:20]=[CH:21][N:22]=5)[S:13][C:14]=4[CH2:15][CH2:16][O:17][C:8]=3[CH:7]=2)[CH:3]=[N:2]1.C(Cl)Cl.C(Cl)(Cl)Cl.C(N(CC)CC)C.[CH3:44][S:45](Cl)(=[O:47])=[O:46]>>[CH3:44][S:45]([N:2]1[CH:3]=[C:4]([C:6]2[CH:29]=[CH:28][C:9]3[C:10]4[N:11]=[C:12]([C:18]5[N:19]([CH2:23][C:24]([F:26])([F:25])[F:27])[N:20]=[CH:21][N:22]=5)[S:13][C:14]=4[CH2:15][CH2:16][O:17][C:8]=3[CH:7]=2)[CH:5]=[N:1]1)(=[O:47])=[O:46]
Reactant: CS(=O)(=O)Cl
Reactant: FC(F)(F)Cn1ncnc1-c1nc2c(s1)CCOc1cc(-c3cn[nH]c3)ccc1-2
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)n1cc(-c2ccc3c(c2)OCCc2sc(-c4ncnn4CC(F)(F)F)nc2-3)cn1
Temperature: 40 °C
Reaction time: 6 h
Yield: 7 %

Procedure:
To a round bottom flask containing 8-(1H-Pyrazol-4-yl)-2-[2-(2,2,2-trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene (0.200 g, 0.000478 mol) in methylene chloride (3 mL, 0.05 mol) and chloroform (2 mL, 0.02 mol) was added triethylamine (0.080 mL, 0.00057 mol) and methanesulfonyl chloride (0.088 mL, 0.00114 mol). The reaction was stirred at 40° C. for 6 h. The mixture was washed with water followed by brine, dried with MgSO4 and concentrated. The crude was loaded as a solid onto silica gel and purified by flash chromatography (1-10% MeOH in DCM) followed by reverse-phase HPLC to give 238 (16.5 mg) as a colorless solid. MS(ESI+) 497.0. 1H NMR (400 MHz, DMSO) δ 8.88 (s, 1H), 8.56 (s, 1H), 8.33 (d, J=8.3, 1H), 8.30 (s, 1H), 7.65 (dd, J=8.3, 1.6, 1H), 7.55 (d, J=1.5, 1H), 5.86 (q, J=8.7, 2H), 4.42 (t, J=4.9, 2H), 3.58 (s, 3H), 3.49 (t, J=4.9, 2H)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][NH:5][C:6]=1[C:7]1[CH:8]=[C:9]([CH:13]=[CH:14][C:15]=1[CH3:16])[C:10]([OH:12])=O.CC1NC(C2C=C(C=CC=2C)C(O)=O)=C(C)N=1.Cl.[NH:35]1[CH2:40][CH2:39][CH:38]([C:41]2[CH:48]=[CH:47][C:44]([C:45]#[N:46])=[CH:43][CH:42]=2)[CH2:37][CH2:36]1.Cl.N1CC(C2C=CC(C#N)=CC=2)C1>>[Cl:1][C:2]1[CH:3]=[N:4][NH:5][C:6]=1[C:7]1[CH:8]=[C:9]([CH:13]=[CH:14][C:15]=1[CH3:16])[C:10]([N:35]1[CH2:40][CH2:39][CH:38]([C:41]2[CH:48]=[CH:47][C:44]([C:45]#[N:46])=[CH:43][CH:42]=2)[CH2:37][CH2:36]1)=[O:12]
Reactant: N#Cc1ccc(C2CCNCC2)cc1
Reactant: Cc1ccc(C(=O)O)cc1-c1[nH]ncc1Cl
Agent: Cc1nc(C)c(-c2cc(C(=O)O)ccc2C)[nH]1
Agent: Cl
Agent: N#Cc1ccc(C2CNC2)cc1
Product: Cc1ccc(C(=O)N2CCC(c3ccc(C#N)cc3)CC2)cc1-c1[nH]ncc1Cl

Procedure:
The title compound was prepared using standard chemical manipulations and procedures similar to those used for preparation of compound 5, except 3-(4-chloro-1H-pyrazol-5-yl)-4-methylbenzoic acid (compound 51.3) was used in place of 3-(2,4-dimethyl-1H-imidazol-5-yl)-4-methylbenzoic acid (compound 5.7) and 4-(piperidin-4-yl)benzonitrile hydrochloride (compound 1.2) was used in place of 4-(azetidin-3-yl)benzonitrile hydrochloride (compound 5.2). m/z (ES+) 405 (M+H)+.
Reaction SMILES: CC(C)([O-])C.[K+].[N:7]1([S:12]([C:15]2[CH:16]=[C:17]3[C:21](=[CH:22][CH:23]=2)[NH:20][C:19](=[O:24])[C:18]23[O:29][CH2:28][CH2:27][CH2:26][O:25]2)(=[O:14])=[O:13])[CH2:11][CH2:10][CH2:9][CH2:8]1.Cl[CH2:31][C:32]([CH3:36])([CH3:35])[C:33]#[N:34].O>CS(C)=O>[CH3:31][C:32]([CH3:36])([CH2:35][N:20]1[C:21]2[C:17](=[CH:16][C:15]([S:12]([N:7]3[CH2:11][CH2:10][CH2:9][CH2:8]3)(=[O:13])=[O:14])=[CH:23][CH:22]=2)[C:18]2([O:29][CH2:28][CH2:27][CH2:26][O:25]2)[C:19]1=[O:24])[C:33]#[N:34]
Reactant: CC(C)(C#N)CCl
Reactant: O=C1Nc2ccc(S(=O)(=O)N3CCCC3)cc2C12OCCCO2
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CC(C)(C#N)CN1C(=O)C2(OCCCO2)c2cc(S(=O)(=O)N3CCCC3)ccc21
Temperature: 130 °C
Reaction time: 0.33 h
Yield: 77 %

Procedure:
At room temperature, to a stirred solution of potassium t-butoxide (0.287 g, 2.56 mmol, 1.2 eq) in anhydrous DMSO (4 mL) was added 5′-(pyrrolidin-1-ylsulfonyl)spiro[1,3-dioxane-2,3′-indol]-2′(1′H)-one (0.72 g, 2.13 mmol). After stirring 20 minutes, 3-chloro-2,2-dimethylpropionitrile (3 eq) was added drop-wise and the reaction was heated at 130° C. for 20 hr. The reaction mixture was heated at 126° C. for 16 h. After cooling to room temperature, the reaction was poured into H2O (100 mL) and extracted with Et2O (3×). The combined organic extracts were dried over Na2SO4, filtered and concentrated. The crude product was purified on Biotage KP silica gel eluting with CH2Cl2/CH3OH H4OH (97/2/1) followed by a second chromatography eluting with 50/50 Pet. ether/EtOAc to give the title compound as a white solid (0.69 g, 77% yield). NMR: consistent.
Reaction SMILES: [CH3:1][N:2]1[CH2:15][CH2:14][C:5]2[NH:6][C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.[H-].[Na+].Br[CH2:19][C:20]1([C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)[O:24][CH2:23][CH2:22][O:21]1.O>CN1C(=O)CCC1>[F:31][C:28]1[CH:27]=[CH:26][C:25]([C:20]2([CH2:19][N:6]3[C:7]4[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=4[C:4]4[CH2:3][N:2]([CH3:1])[CH2:15][CH2:14][C:5]3=4)[O:21][CH2:22][CH2:23][O:24]2)=[CH:30][CH:29]=1
Reactant: Cc1ccc2[nH]c3c(c2c1)CN(C)CC3
Reactant: Fc1ccc(C2(CBr)OCCO2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN1CCCC1=O
Product: Cc1ccc2c(c1)c1c(n2CC2(c3ccc(F)cc3)OCCO2)CCN(C)C1
Temperature: 100 °C

Procedure:
2,8-Dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (4.6 g, 23 mmol) was dissolved in 35 mL of NMP. Sodium hydride (1.93 g, 48.3 mmol) was added at RT under nitrogen atmosphere. 2-Bromomethyl-2-(4-fluorophenyl)-1,3-dioxolane (6 g, 23 mmol) was added and the reaction mixture was heated at 100° C. overnight. Water was added and the product was extracted with EtOAc. The organic layer was washed with water, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 0-5% MeOH:DCM.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([C@@H:12]2[C:17]([C:18]#[N:19])=[C:16]([CH3:20])[N:15]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=3)[C:14](=[O:31])[N:13]2[CH3:32])=[C:7]([S:9]([O-:11])=[O:10])[CH:8]=1)#[N:2].[Na+].Br[CH2:35][CH:36]1[CH2:38][CH2:37]1.[I-].[K+]>CN(C=O)C>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([C@@H:12]2[C:17]([C:18]#[N:19])=[C:16]([CH3:20])[N:15]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:29])([F:30])[F:28])[CH:22]=3)[C:14](=[O:31])[N:13]2[CH3:32])=[C:7]([S:9]([CH2:35][CH:36]2[CH2:38][CH2:37]2)(=[O:11])=[O:10])[CH:8]=1)#[N:2]
Reactant: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2S(=O)[O-])N(C)C(=O)N1c1cccc(C(F)(F)F)c1
Reactant: BrCC1CC1
Agent: [I-]
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2S(=O)(=O)CC2CC2)N(C)C(=O)N1c1cccc(C(F)(F)F)c1
Temperature: 130 °C

Procedure:
The reaction was carried out under argon. Sodium 5-cyano-2-{(4S)-5-cyano-3,6-dimethyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidin-4-yl}benzenesulfinate (100 mg, 67 μmol; purity 32%) was suspended in DMF (2000 μl). 1-(Bromomethyl)cyclopropane (278 mg, 2.06 mmol) was then added, and the mixture was heated in a closed tube at 130° C. overnight. Molecular sieve (4 Å), potassium iodide (110 mg, 0.66 mmol) and more 1-(bromomethyl)cyclopropane (89 mg, 0.66 mmol) were then added, and the reaction mixture was once more heated in a closed tube at 100° C. for 6 h. The mixture was then filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Gromsil C-18 10 μm; mobile phase: acetonitrile/water+0.1% TFA 10:90→90:10). The title compound was obtained as a solid (16.2 mg, 44% of theory).
Reaction SMILES: [C:1]([CH:5]([C:33]1[CH:38]=[CH:37][C:36]2[O:39][CH2:40][O:41][C:35]=2[CH:34]=1)[O:6][C:7]1[C:12]([CH2:13][CH2:14][CH3:15])=[CH:11][C:10]([CH2:16][N:17]2[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[N:19](C(OCC)=O)[C:18]2=[O:31])=[CH:9][C:8]=1[Cl:32])([O:3]C)=[O:2].[OH-].[Na+].Cl>CO>[C:1]([CH:5]([C:33]1[CH:38]=[CH:37][C:36]2[O:39][CH2:40][O:41][C:35]=2[CH:34]=1)[O:6][C:7]1[C:12]([CH2:13][CH2:14][CH3:15])=[CH:11][C:10]([CH2:16][N:17]2[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[NH:19][C:18]2=[O:31])=[CH:9][C:8]=1[Cl:32])([OH:3])=[O:2]
Reactant: CCCc1cc(Cn2c(=O)n(C(=O)OCC)c3ccccc32)cc(Cl)c1OC(C(=O)OC)c1ccc2c(c1)OCO2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCc1cc(Cn2c(=O)[nH]c3ccccc32)cc(Cl)c1OC(C(=O)O)c1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 2 h
Yield: 51.2 %

Procedure:
To a solution of 0.088 g (0.15 mmol) of the product of step F in 4 mL of methanol was added 250 μL of a 5.0 N solution of sodium hydroxide and the reaction was stirred at room temperature for 2 hours. The reaction mixture was then adjusted to pH=6 with dropwise addition of 2 N hydrochloric acid, and then concentrated in vacuo. The residue was redissolved in methanol, filtered, and evaporated. The mixture was then purified on a silica gel flash chromatography column eluted with CHCl3 -MeOH-NH4OH (80:15:1). Evaporation of the purified fractions and drying in vacuo afforded 0.038 g (51%) of the title compound.
Reaction SMILES: C[N:2](C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]([F:24])([F:23])[F:22])[CH:15]=2)[N:8]=1)=O.[F:26][C:27]1[CH:32]=[CH:31][C:30]([NH:33]N)=[CH:29][CH:28]=1>>[F:26][C:27]1[CH:32]=[CH:31][C:30]([N:33]2[C:5]([C:7]3[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]4[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]([F:24])([F:23])[F:22])[CH:15]=4)[N:8]=3)=[CH:4][CH:3]=[N:2]2)=[CH:29][CH:28]=1
Reactant: NNc1ccc(F)cc1
Reactant: CN(C)/C=C/C(=O)c1nn(-c2cccc(OC(F)(F)F)c2)ccc1=O
Product: O=c1ccn(-c2cccc(OC(F)(F)F)c2)nc1-c1ccnn1-c1ccc(F)cc1

Procedure:
Reaction of 3-((E)-3-dimethylamino-acryloyl)-1-(3-trifluoromethoxy-phenyl)-1H-pyridazin-4-one (A-6) and (4-fluoro-phenyl)-hydrazine according to example 43 gave the desired product. MS: M=416.9 (M+H)+
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[N:12]([S:13]([C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=3)(=[O:15])=[O:14])[C@@H:11]([CH2:23][CH2:24][C:25]([NH:27][NH2:28])=[O:26])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[CH:29](Cl)(Cl)Cl>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[N:12]([S:13]([C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=3)(=[O:14])=[O:15])[C@@H:11]([CH2:23][CH2:24][C:25]3[O:26][CH:29]=[N:28][N:27]=3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: ClC(Cl)Cl
Reactant: Cc1ccc(S(=O)(=O)N2[C@@H](CCC(=O)NN)CC[C@H]2c2ccc(F)cc2)cc1
Product: Cc1ccc(S(=O)(=O)N2[C@@H](CCc3nnco3)CC[C@H]2c2ccc(F)cc2)cc1

Procedure:
The title compound, light yellow oil, MS: m/e=416.1 (M+H′) and [α]D2=−80.1° (c=0.2211 in chloroform), was prepared in accordance with the general method of example 127 from (2R,5S)-3-[5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-propionic acid hydrazide and triethyl orthoformiate.
Reaction SMILES: [ClH:1].[N+:2]1([O-])[C:3]([CH3:9])=[CH:4][CH:5]=[CH:6][C:7]=1[CH3:8].[OH-].[NH4+]>P(Cl)(Cl)(Cl)=O>[Cl:1][C:5]1[CH:4]=[C:3]([CH3:9])[N:2]=[C:7]([CH3:8])[CH:6]=1
Reactant: Cl
Reactant: Cc1cccc(C)[n+]1[O-]
Agent: [NH4+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1cc(Cl)cc(C)n1
Temperature: 0 °C
Reaction time: 3 h
Yield: 58.7 %

Procedure:
A mixture of 2,6-lutidine-N-oxide hydrochloride (48 g) and phosphorus oxychloride (110 ml) is heated 6.5 hours at reflux. After cooling the reaction mixture is carefully poured into crushed ice (1 kg). While the temperature is maintained below 15° C., concentrated ammonium hydroxide is added up to reach pH 8. The product that separates is extracted with ethyl ether (2×500 ml) which is dried and distilled off. The residue is dissolved in ethanol (400 ml) and boiled 3 hours with triethylamine (20 ml). After cooling, the solution is evaporated to dryness, treated with water (200 ml) and extracted with ethyl ether (4×150 ml). The combined extracts are dried and the solvent evaporated. The residue after distillation gives 4-chloro-2,6-dimethylpyridine (25 g), b.p. (15 mm)=67°-69° C. To a mixture of sodium (10 g, 30% dispersion in toluene) in anhydrous dimethyoxyethane (40 ml) cooled in an ice-bath and kept under argon, trimethyltin chloride (12.1 g) in dimethoxymethane (6 ml) is added over a one hour period while keeping the temperature at 0° C. The mixture is stirred 2.5 hours at 0° C.; then 4-chloro-2,6-dimethylpyridine (7 g) in dimethoxyethane is slowly dropped into. Stirring is continued for an additional hour then the reaction mixture is allowed to stand overnight at room temperature. The reaction mixture is diluted with ethyl ether (100 ml) and filtered. The solvent is evaporated, the residue dissolved in ethyl ether (100 ml) and filtered again. After evaporation of the solvent the residue is distilled giving 2,6-dimethyl-4-(trimethyl-stannyl)pyridine (8.8 g), b.p. (15 m)=130°-140° C.
Reaction SMILES: S(Cl)([Cl:3])=O.Cl.[NH2:6][CH2:7][C:8](=[O:14])[CH2:9][CH2:10][C:11]([OH:13])=[O:12]>CN(C)C=O>[ClH:3].[NH2:6][CH2:7][C:8](=[O:14])[CH2:9][CH2:10][C:11]([O:13][CH2:7]/[CH:8]=[CH:9]\[CH2:10][CH3:11])=[O:12]
Reactant: O=S(Cl)Cl
Reactant: NCC(=O)CCC(=O)O
Agent: Cl
Solvent: CN(C)C=O
Product: CC/C=C\COC(=O)CCC(=O)CN
Yield: 68 %

Procedure:
To 1 ml of thionyl chloride (SOCl2) were added 3 drops of N,N-dimethylformamide (DMF) with stirring. Following the addition of 5-aminolevulinic acid hydrochloride (ALA.HCl, 200 mg, 1.19 mol), the solution was stirred for 12 hours at room temperature. Concentration in a vacuum was conducted before the addition of cis-2-pentenol. Then, the reaction mixture was stirred for 1.5 hours at room temperature, followed by purification by silica gel chromatography to afford cis-2-pentenyl 5-aminolevulinate hydrochloride at a yield of 68%.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[OH:12].[Cl:13][C:14]1[CH:15]=[C:16]([CH:20](O)[CH2:21][CH2:22][CH2:23][CH2:24][N:25]2[CH2:30][CH2:29][CH:28]([C:31]3[CH:32]=[C:33]([NH:37][C:38](=[O:42])[CH:39]([CH3:41])[CH3:40])[CH:34]=[CH:35][CH:36]=3)[CH2:27][CH2:26]2)[CH:17]=[CH:18][CH:19]=1.Cl>>[Cl:13][C:14]1[CH:15]=[C:16]([CH:20]([O:12][C:3]2[CH:4]=[C:5]([C:8]([F:10])([F:11])[F:9])[CH:6]=[CH:7][C:2]=2[F:1])[CH2:21][CH2:22][CH2:23][CH2:24][N:25]2[CH2:26][CH2:27][CH:28]([C:31]3[CH:32]=[C:33]([NH:37][C:38](=[O:42])[CH:39]([CH3:40])[CH3:41])[CH:34]=[CH:35][CH:36]=3)[CH2:29][CH2:30]2)[CH:17]=[CH:18][CH:19]=1
Reactant: Oc1cc(C(F)(F)F)ccc1F
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCC(O)c3cccc(Cl)c3)CC2)c1
Agent: Cl
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCCC(Oc3cc(C(F)(F)F)ccc3F)c3cccc(Cl)c3)CC2)c1

Procedure:
Prepared by Procedure A and Scheme AN using 2-fluoro-5-(trifluoromethyl)phenol and N-(3-{1-[5-(3-chlorophenyl)-5-hydroxypentyl]-4-piperidinyl}phenyl)-2-methylpropanamide: 1H NMR (400 MHz, CDCl3), HCl salt δ 8.17 (s, br, 1H), 7.75-6.88 (m, 11H), 5.26-5.14 (m, 1H), 3.68-3.56 (m, br, 2H), 3.05-2.90 (br, 2H), 2.90-2.60 (m, br, 4H), 2.56-2.36 (m, br, 2H), 2.18-1.84 (m, br, 6H), 1.70-1.44 (m, br, 2H), 1.25 (d, 6H, J=7.2 Hz). Anal. Calc. for C33H38Cl2F4N2O2.0.9EtOAc: C, 60.98; H, 6.32; N, 3.89; Found: C, 60.99; H, 6.17; N, 3.81. ESMS m/e: 605.2 (M+H)+.
Reaction SMILES: C[O:2][C:3]1[N:8]=[C:7]([C:9]([O:11]C)=[O:10])[CH:6]=[CH:5][C:4]=1[N:13]1[CH:17]=[C:16]([CH3:18])[N:15]=[CH:14]1.[ClH:19]>>[ClH:19].[CH3:18][C:16]1[N:15]=[CH:14][N:13]([C:4]2[C:3](=[O:2])[NH:8][C:7]([C:9]([OH:11])=[O:10])=[CH:6][CH:5]=2)[CH:17]=1
Reactant: COC(=O)c1ccc(-n2cnc(C)c2)c(OC)n1
Agent: Cl
Product: Cc1cn(-c2ccc(C(=O)O)[nH]c2=O)cn1
Temperature: 25 °C

Procedure:
A mixture of C2 (12.8 g, 51.8 mmol) and 37% hydrochloric acid (25 mL) was heated at reflux for 18 hours. After the reaction mixture had cooled to room temperature, the solid was collected via filtration; it was stirred with 1,4-dioxane (2×20 mL) and filtered again, to afford the product as a yellow solid. Yield: 13 g, 51 mmol, 98%. 1H NMR (400 MHz, CD3OD) δ 9.52 (br s, 1H), 8.07 (d, J=7.5 Hz, 1H), 7.78 (br s, 1H), 7.21 (d, J=7.5 Hz, 1H), 2.44 (s, 3H).
Reaction SMILES: [CH3:1][CH:2]([O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=O)=[CH:7][C:6]=1[C:14]([F:17])([F:16])[F:15])[CH3:3].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.O[NH:40][C:41](=[NH:58])[C:42]1[CH:43]=[C:44]2[C:48](=[CH:49][CH:50]=1)[N:47]([CH2:51][CH2:52][C:53]([O:55][CH2:56][CH3:57])=[O:54])[N:46]=[CH:45]2.C(=O)(O)[O-].[Na+]>CN(C=O)C.C(OCC)(=O)C>[CH3:3][CH:2]([O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]2[O:11][N:40]=[C:41]([C:42]3[CH:43]=[C:44]4[C:48](=[CH:49][CH:50]=3)[N:47]([CH2:51][CH2:52][C:53]([O:55][CH2:56][CH3:57])=[O:54])[N:46]=[CH:45]4)[N:58]=2)=[CH:7][C:6]=1[C:14]([F:17])([F:16])[F:15])[CH3:1]
Reactant: CCOC(=O)CCn1ncc2cc(C(=N)NO)ccc21
Reactant: CC(C)Oc1ccc(C(=O)O)cc1C(F)(F)F
Agent: CCN=C=NCCCN(C)C
Agent: O=C([O-])O
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)CCn1ncc2cc(-c3noc(-c4ccc(OC(C)C)c(C(F)(F)F)c4)n3)ccc21
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 42 %

Procedure:
4-[(1-Methylethyl)oxy]-3-(trifluoromethyl)benzoic acid (D36) (100 mg, 0.4 mmol) was dissolved in DMF (5 ml) and then EDAC (115 mg, 0.6 mmol) and HOBt (81 mg, 0.6 mmol) were added. The mixture was stirred for 30 minutes and then Ethyl 3-{5-[(hydroxyamino)(imino)methyl]-1H-indazol-1-yl}propanoate (D52) (111 mg, 0.40 mmol) was added and the reaction was heated overnight at 80° C. Further EDAC (50 mg) was added and the reaction was heated for another 4 hours. Further EDAC (20 mg) was added and the reaction was heated overnight. The reaction mixture was added to a mixture of ethyl acetate and sodium bicarbonate, the organics were separated and the aqueous extracted with further ethyl acetate. The combined organics were washed with water and then brine, dried and evaporated to give the crude product. This material was purified by flash chromatography (SiO2) to afford the title compound (82 mg). MS (ES): C24H23F3N4O4 requires 488; found (MH+) 489.