Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]12([CH2:11][OH:12])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[OH:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][C:21](O)=[O:22])=[CH:16][CH:15]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1C=CC=CC=1>[OH:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][C:21]([O:12][CH2:11][C:1]23[CH2:8][CH:7]4[CH2:6][CH:5]([CH2:4][CH:3]([CH2:9]4)[CH2:2]2)[CH2:10]3)=[O:22])=[CH:16][CH:15]=1
Reactant: O=C(O)Cc1ccc(O)cc1
Reactant: OCC12CC3CC(CC(C3)C1)C2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: O
Product: O=C(Cc1ccc(O)cc1)OCC12CC3CC(CC(C3)C1)C2
Reaction time: 8 h

Procedure:
1-Adamantanemethanol (8.31 g, 0.05 mol), 4-hydroxyphenylacetic acid (7.6 g, 0.05 mol) and p-toluenesulfonic acid (1 g, 0.006 mol) were refluxed in benzene (100 mL) with continuous water separation for 8 hours. The reaction mixture was allowed to cool with stirring overnight, then was washed, first with water (100 mL), then with aqueous 5% NaHCO3 solution (100 mL), then twice more with water (100 mL). Drying over anhydrous MgSO4, filtering and concentrating in vacuo afforded (adamant-1-yl)methyl 4-hydroxyphenylacetate, which was then combined with epichlorohydrin (50 mL) and refluxed for 2 hours in the presence of DBU (1 mL, 0.007 mol). Excess epichlorohydrin was removed in vacuo. The oily residue was dissolved in acetonitrile (100 mL) and combined with isopropylamine (20 mL, 0.23 mol). The resultant reaction mixture was refluxed for 4 hours. The oily brown residue was partitioned between ethyl ether (100 mL) and 1M aqueous KOH solution (100 mL ). The ether layer was separated and to it was added 1N HCl (30 mL). The resultant acid layer was separated and to it were added ethyl ether (100 mL) and 1M aqueous KOH solution (30 mL). The resultant ether layer was separated, dried over anhydrous MgSO4, filtered and evaporated in vacuo to give the free amine base as a crude product. The crude product (5.16 g, 72.5% yield) was dissolved in acetone (25 mL), and oxalic acid (1.8 g) in acetone (25 mL) was added dropwise, with stirring. The mixture was allowed to stir for 24 hours with additional acetone. The acetone solution was evaporated and the oily residue was partitioned between ether (100 mL) and 1M aqueous KOH solution (100 mL). The ether solution was dried over anhydrous MgSO4, filtered and concentrated. The oily residue was dissolved in acetone and an equivalent amount of oxalic acid in acetone was added dropwise. The oxalate salt of (adamant-1-yl)methyl 4-(2-hydroxy-3-isopropylamino)propoxyphenylacetate which separated was removed and dried. It melted at 55°-57° C. NMR and elemental analysis were consistent with structure. The free base has the formula: ##STR298##
Reaction SMILES: C(O)C.[CH2:4]([CH:7]1[CH2:11][CH2:10][CH:9]([CH:12]2[CH2:17][CH2:16][CH:15]([CH:18]=[O:19])[CH2:14][CH2:13]2)[CH2:8]1)[CH2:5][CH3:6].[BH4-].[Na+]>O>[CH2:4]([CH:7]1[CH2:11][CH2:10][CH:9]([CH:12]2[CH2:17][CH2:16][CH:15]([CH2:18][OH:19])[CH2:14][CH2:13]2)[CH2:8]1)[CH2:5][CH3:6]
Reactant: CCCC1CCC(C2CCC(C=O)CC2)C1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCCC1CCC(C2CCC(CO)CC2)C1
Temperature: 0 °C
Reaction time: 20 h
Yield: 90.5 %

Procedure:
Ethanol (30 ml) was added to 4-(3-propylcyclopentyl)cyclohexanecarboaldehyde (2.3 g) obtained in the second step in Example 3, in a reaction vessel under an atmosphere of nitrogen, and the mixture was cooled to 0° C., and sodium borohydride (0.22 g) was added slowly. After the mixture had been returned to room temperature and stirred for another 20 hours and water (30 ml) was added. The mixture was separated, and the water layer was extracted with diethyl ether three times, and then the combined organic layer was washed with brine. The solution was dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (eluent: ethyl acetate/n-heptane=1/2 by volume) to give (4-(3-propylcyclopentyl)cyclohexyl)methanol (2.1 g).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:34])=[C:4]([CH:31]=[CH:32][CH:33]=1)[CH2:5][NH:6][C:7]([C@@H:9]1[CH2:14][C@@H:13]2[C@@H:11]([CH2:12]2)[N:10]1[C:15](=[O:30])[CH2:16][N:17]1[C:25]2[C:20](=[CH:21][CH:22]=[C:23]([OH:26])[CH:24]=2)[C:19]([C:27](=[O:29])[CH3:28])=[CH:18]1)=[O:8].C(=O)([O-])[O-].[Cs+].[Cs+].Cl[CH2:42][C:43]1[NH:47][N:46]=[N:45][N:44]=1.Cl>CS(C)=O.O>[Cl:1][C:2]1[C:3]([F:34])=[C:4]([CH:31]=[CH:32][CH:33]=1)[CH2:5][NH:6][C:7]([C@@H:9]1[CH2:14][C@@H:13]2[C@@H:11]([CH2:12]2)[N:10]1[C:15](=[O:30])[CH2:16][N:17]1[C:25]2[C:20](=[CH:21][CH:22]=[C:23]([O:26][CH2:42][C:43]3[NH:47][N:46]=[N:45][N:44]=3)[CH:24]=2)[C:19]([C:27](=[O:29])[CH3:28])=[CH:18]1)=[O:8]
Reactant: CC(=O)c1cn(CC(=O)N2[C@@H]3C[C@@H]3C[C@H]2C(=O)NCc2cccc(Cl)c2F)c2cc(O)ccc12
Reactant: ClCc1nnn[nH]1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: O
Product: CC(=O)c1cn(CC(=O)N2[C@@H]3C[C@@H]3C[C@H]2C(=O)NCc2cccc(Cl)c2F)c2cc(OCc3nnn[nH]3)ccc12
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A solution of (1R,3S,5R)-2-[2-(3-Acetyl-6-hydroxy-indol-1-yl)-acetyl]-2-aza-bicyclo[3.1.0]-hexane-3-carboxylic acid 3-chloro-2-fluoro-benzylamide Example 584 (80.0 mg, 0.165 mmol) in DMSO (2 mL) was treated with cesium carbonate (162 mg, 0.496 mmol). After stirring at RT for 5 min, 5-(chloromethyl)-1H-tetrazole (21.0 mg, 0.174 mmol) was added and stirring was continued at RT for 36 h. The mixture was neutralised by addition of 1N HCl, diluted with water extracted with EtOAc (2×). The combined organic layers were washed with water (2×) and brine. The resulting suspension was filtered over phase separator and concentrated. The filtered solid was triturated with methanol, decanted and dried in vacuo to give the title compound. The filtrate was purified by preparative HPLC (Macherey-Nagel Nucleosil 100-10 C18, 5 μm, 40×250 mm, flow: 40 mL/min, eluent: 20-100% CH3CN/H2O/20 min, 100% CH3CN/2 min, CH3CN and H2O containing 0.1% TFA) to afford after lyophilization of the purified fractions a second batch of the title compound as a white solid. MS (LC/MS): 566 [M+H]+; tR (HPLC conditions k): 3.22 min.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=3[Cl:20])[N:11]=[C:10]([C:21]([N:23]3[CH2:28][CH2:27][C:26]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)([C:29](O)=[O:30])[CH2:25][CH2:24]3)=[O:22])[C:9]=2[CH3:38])=[CH:4][CH:3]=1.[Cl-].[NH4+].F[P-](F)(F)(F)(F)F.[N:48]1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=3[Cl:20])[N:11]=[C:10]([C:21]([N:23]3[CH2:28][CH2:27][C:26]([C:32]4[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=4)([C:29]([NH2:48])=[O:30])[CH2:25][CH2:24]3)=[O:22])[C:9]=2[CH3:38])=[CH:6][CH:7]=1
Reactant: Cc1c(C(=O)N2CCC(C(=O)O)(c3ccccc3)CC2)nn(-c2ccc(Cl)cc2Cl)c1-c1ccc(Cl)cc1
Reactant: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1c(C(=O)N2CCC(C(N)=O)(c3ccccc3)CC2)nn(-c2ccc(Cl)cc2Cl)c1-c1ccc(Cl)cc1
Yield: 44 %

Procedure:
1-{[5-(4-Chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazol-3-yl]carbonyl}-4-phenylpiperidine-4-carboxylic acid (1 eq., 12.7 mg, 0.024 mmol), ammonium chloride (10 eq., 12.7 mg, 0.24 mmol), benzotriazole-1-yl-oxytris(dimethylamino)phosphonium hexafluorophosphate (BOP) (1 eq, 10.5 mg, 0.024 mmol), and triethylamine (10.1 eq., 0.03 mL, 0.024 mmol) was stirred in tetrahydrofuran (5 mL) for 3 d. The reaction was concentrated in vacuo. The crude reaction material was then purified by silica gel column chromatography using 0-100% ethyl acetate/hexane to yield pure 1-{[5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazol-3-yl]carbonyl}-4-phenylpiperidine-4-carboxamide (6 mg, 44%). 1H NMR (300 MHz, CHLOROFORM-d) d ppm 1.92-2.31 (m, 5H) 2.46 (d, J=13.94 Hz, 2H) 3.65 (t, J=10.36 Hz, 1H) 3.75-3.90 (m, 1H) 4.02 (d, J=13.38 Hz, 1H) 4.23 (d, J=13.00 Hz, 1H) 5.24 (br. s., 2H) 7.07 (d, J=8.38 Hz, 2H) 7.12-7.20 (m, 1H) 7.20-7.49 (m, 9H).
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[CH:14][C:5]2[NH:6][C:7](=[O:13])[CH2:8][CH2:9][C:10]([CH3:12])([CH3:11])[C:4]=2[CH:3]=1.Cl[C:17]1[N:22]=[C:21]([NH:23][C:24]2[C:34]([F:35])=[CH:33][CH:32]=[CH:31][C:25]=2[C:26]([NH:28][CH2:29][CH3:30])=[O:27])[C:20]([Cl:36])=[CH:19][N:18]=1>>[Cl:36][C:20]1[C:21]([NH:23][C:24]2[C:34]([F:35])=[CH:33][CH:32]=[CH:31][C:25]=2[C:26]([NH:28][CH2:29][CH3:30])=[O:27])=[N:22][C:17]([NH:1][C:2]2[CH:15]=[CH:14][C:5]3[NH:6][C:7](=[O:13])[CH2:8][CH2:9][C:10]([CH3:12])([CH3:11])[C:4]=3[CH:3]=2)=[N:18][CH:19]=1
Reactant: CCNC(=O)c1cccc(F)c1Nc1nc(Cl)ncc1Cl
Reactant: CC1(C)CCC(=O)Nc2ccc(N)cc21
Product: CCNC(=O)c1cccc(F)c1Nc1nc(Nc2ccc3c(c2)C(C)(C)CCC(=O)N3)ncc1Cl

Procedure:
2-[5-Chloro-2-(5,5-dimethyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-7-ylamino)-pyrimidin-4-ylamino]-N-ethyl-3-fluoro-benzamide was prepared from 7-amino-5,5-dimethyl-1,3,4,5-tetrahydro-benzo[b]azepin-2-one and 2-(2,5-dichloro-pyrimidin-4-ylamino)-N-ethyl-3-fluoro-benzamide in an analogous manner to Example 308c. Product isolated as a yellow foam (213 mg, 51%). LCMS (m/e) 497 (M+H); 1H-NMR (CDCl3, 400 MHz) δ 8.73 (s, 1H), 8.10 (s, 1H), 7.56 (d, 1H, J=8.5 Hz), 7.40-7.35 (m, 1H), 7.34-7.25 (m, 2H), 7.21 (s, 1H), 7.10 (s, 1H), 6.96 (s, 1H), 6.72 (d, 1H, J=8.5 Hz), 6.15-6.06 (m, 1H), 3.48-3.38 (m, 2H), 2.36 (t, 2H, J=6.8 Hz), 2.08 (t, 2H, J=6.8 Hz), 1.35 (s, 6H), 1.17 (t, 3H, J=7.3 Hz).
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][C@H:9]1[CH2:14][OH:15])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C([O-])(O)=O.[Na+].Cl[C:22]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:23]>C(Cl)Cl.O>[C:4]([O:3][C:1]([N:8]1[CH2:13][CH2:12][N:11]([C:22]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:23])[CH2:10][C@H:9]1[CH2:14][OH:15])=[O:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCNC[C@H]1CO
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(C(=O)OCc2ccccc2)C[C@H]1CO
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To solution of (S)-1-Boc-2-hydroxymethyl-piperazine (500 mg) in DCM (15 mL) were added NaHCO3 (369 mg), water (3 mL) and benzyl chloroformate (0.464 mL) at RT. The resulting emulsion was vigorously stirred at RT overnight. The mixture was diluted with water and extracted with DCM. The combined org. layers were dried (MgSO4), filtered off and evaporated in vacuo. The residue was purified by CC (Biotage, SNAP 25 g cartridge, solvent A: Hept; solvent B: EA; gradient in % B: 50 for 6CV, 50 to 70 over 3CV, 70 for 2CV) to afford 714 mg of colourless oil. LC-MS (B): tR=0.82 min; [M+H]+: 350.94.
Reaction SMILES: [N:1]1([C:8]2[CH:9]=[CH:10][C:11]3[N:12]([C:14]([C:17]([F:20])([F:19])[F:18])=[N:15][N:16]=3)[N:13]=2)[CH2:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[F:21][C:22]1[CH:29]=[CH:28][CH:27]=[CH:26][C:23]=1[CH:24]=O>>[F:21][C:22]1[CH:29]=[CH:28][CH:27]=[CH:26][C:23]=1[CH2:24][N:4]1[CH2:5][CH2:6][CH2:7][N:1]([C:8]2[CH:9]=[CH:10][C:11]3[N:12]([C:14]([C:17]([F:18])([F:19])[F:20])=[N:15][N:16]=3)[N:13]=2)[CH2:2][CH2:3]1
Reactant: FC(F)(F)c1nnc2ccc(N3CCCNCC3)nn12
Reactant: O=Cc1ccccc1F
Product: Fc1ccccc1CN1CCCN(c2ccc3nnc(C(F)(F)F)n3n2)CC1

Procedure:
Reductive amination of 6-(1,4-diazepan-1-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine with 2-fluorobenzaldehyde was carried out according to General Synthetic Method 8. The crude product was purified by hplc using a Waters XBridge Prep C18 OBD column (5μ silica, 19 mm diameter, 100 mm length) eluted with decreasingly polar mixtures of water (containing 0.05% aqueous ammonia) and acetonitrile as eluents to give 6-[4-[(2-fluorophenyl)methyl]-1,4-diazepan-1-yl]-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]=O.[CH3:9][CH:10]([CH3:19])[CH:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[NH2:12].O>C(Cl)Cl>[CH3:9][CH:10]([CH3:19])[CH:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)/[N:12]=[CH:7]/[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1
Reactant: O=Cc1ccccn1
Reactant: CC(C)C(N)c1ccccc1
Solvent: O
Solvent: ClCCl
Product: CC(C)C(/N=C/c1ccccn1)c1ccccc1

Procedure:
In air, 2-pyridinecarboxaldehyde (0.185 g, 0.164 mL, 1.72 mmol, 1.00 equiv) was added to a solution of 2-methyl-1-phenylpropan-1-amine (0.257 g, 1.72 mmol, 1.00 equiv) in CH2Cl2 (8 mL). After heating at reflux for 2 h with azeotropic removal of water using a Dean-Stark trap, the reaction mixture was concentrated under reduced pressure and dried under high vacuum to give ligand (L-1), (E)-2-Methyl-1-phenyl-N-(pyridin-2-ylmethylene)propan-1-amine, as a yellow oil (0.379 g, 92% yield).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=2)=[N:6][CH:5]=[CH:4][N:3]=1.[NH:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1>O1CCCC1>[CH3:15][O:14][C:11]1[CH:12]=[CH:13][C:8]([C:7]2[C:2]([N:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)=[N:3][CH:4]=[CH:5][N:6]=2)=[CH:9][CH:10]=1
Reactant: C1CNCCN1
Reactant: COc1ccc(-c2nccnc2Cl)cc1
Solvent: C1CCOC1
Product: COc1ccc(-c2nccnc2N2CCNCC2)cc1

Procedure:
Couple 2-chloro-3-(4-methoxyphenyl)-pyrazine (0.236 g, 1.07 mmol) and piperazine (3.10 g, 36.0 mmol) in tetrahydrofuran (5 mL) and heat at 120° C. for 2 hr. Purify using silica gel chromatography, eluting with 0:100 to 20:80 methanol:DCM, to give the title preparation (0.220 g, 76%). MS (ES): m/z=271 [M+H]+.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][C:6]#[CH:7].[F:8][C:9]([F:19])([F:18])[CH2:10][CH2:11][S:12]([CH2:15][C:16]#[N:17])(=[O:14])=[O:13].C(=O)([O-])[O-].[K+].[K+].Cl>CS(C)=O>[F:19][C:9]([F:8])([F:18])[CH2:10][CH2:11][S:12]([CH:15]([CH2:7][CH2:6][CH2:5][CH2:4][C:3]#[CH:2])[C:16]#[N:17])(=[O:13])=[O:14]
Reactant: N#CCS(=O)(=O)CCC(F)(F)F
Reactant: C#CCCCCCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: C#CCCCCC(C#N)S(=O)(=O)CCC(F)(F)F
Temperature: 60 °C
Reaction time: 4 h
Yield: 29.4 %

Procedure:
To a solution of 1.0 g of 6-chloro-1-hexyne and 1.7 g of (3,3,3-trifluoropropylsulfonyl)acetonitrile in 20 ml of dimethyl sulfoxide, 1.2 g of potassium carbonate was added at room temperature. The mixture was stirred at 60° C. for 4 hours and then at 90° C. for 2 hours, and then allowed to stand near room temperature. To the reaction mixture, 10% hydrochloric acid was added, followed by extraction with ethyl acetate. The organic layer was washed with a saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The obtained residue was subjected to silica gel chromatography to obtain 0.70 g of 2-(3,3,3-trifluoropropylsulfonyl)-7-octynenitrile (hereinafter referred to as the present compound (23)).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[C:11](=[O:15])[N:10]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[C:17]=1[CH2:23][OH:24])[N:9]([CH3:25])[CH2:8]2)([CH3:4])([CH3:3])[CH3:2].[C:26](OC(=O)C)(=[O:28])[CH3:27].N1C=CC=CC=1>ClCCl>[C:26]([O:24][CH2:23][C:17]1[C:18]([Cl:22])=[CH:19][CH:20]=[CH:21][C:16]=1[N:10]1[N:9]([CH3:25])[CH2:8][C:7]2[C:12](=[CH:13][CH:14]=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[CH:6]=2)[C:11]1=[O:15])(=[O:28])[CH3:27]
Reactant: CN1Cc2cc(C(C)(C)C)ccc2C(=O)N1c1cccc(Cl)c1CO
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)OCc1c(Cl)cccc1N1C(=O)c2ccc(C(C)(C)C)cc2CN1C
Temperature: 45 °C
Reaction time: 8 h
Yield: 87.8 %

Procedure:
In a 100 mL round-bottomed flask, 6-tert-butyl-2-(3-chloro-2-(hydroxymethyl)phenyl)-3-methyl-3,4-dihydrophthalazin-1(2H)-one (500 mg, 1.39 mmol, Eq: 1.00), acetic anhydride (711 mg, 657 μl, 6.97 mmol, Eq: 5) and pyridine (331 mg, 338 μl, 4.18 mmol, Eq: 3) were combined with dichloromethane (10.0 ml) to give a colorless solution. The reaction mixture was heated to 45° C. and stirred for 8 h. Cooled to room temperature and stirred for 48 h. The crude reaction mixture was concentrated in vacuo to a tan oil. The crude material was purified by flash chromatography (silica gel, 20%-30% ethyl acetate/hexanes gradient) to give 2-(6-tert-butyl-3-methyl-1-oxo-3,4-dihydrophthalazin-2(1H)-yl)-6-chlorobenzyl acetate (489 mg, 88%): 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.37 (s, 9H) 2.03 (s, 3H) 2.62 (s, 3H) 4.45 (s, 2H) 5.33 (s, 2H) 7.23 (d, J=1.51 Hz, 1H) 7.35-7.39 (m, 2H) 7.43-7.52 (m, 2H) 8.03 (d, J=8.31 Hz, 1H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:9]2[C:14](=[O:15])[C:13]([O:16][CH3:17])=[C:12](Br)[CH:11]=[N:10]2)[CH:5]=[CH:6][C:7]=1[F:8].[CH3:19][C:20]1[CH:21]=[C:22](B(O)O)[CH:23]=[CH:24][C:25]=1[S:26][CH3:27]>>[F:1][C:2]1[CH:3]=[C:4]([N:9]2[C:14](=[O:15])[C:13]([O:16][CH3:17])=[C:12]([C:22]3[CH:23]=[CH:24][C:25]([S:26][CH3:27])=[C:20]([CH3:19])[CH:21]=3)[CH:11]=[N:10]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: COc1c(Br)cnn(-c2ccc(F)c(F)c2)c1=O
Reactant: CSc1ccc(B(O)O)cc1C
Product: COc1c(-c2ccc(SC)c(C)c2)cnn(-c2ccc(F)c(F)c2)c1=O

Procedure:
The title compound was prepared according to the method of Example 6 starting with 2-(3,4-difluorophenyl)-4-methoxy-5-bromo-3(2H)-pyridazinone in place of 2-benzyl-4-bromo-5-methoxy-3(2H)-pyridazinone and substituting 3-methyl-4-(methylthio)benzeneboronic acid in place of 4-fluorobenzeneboronic acid (yield: 2.0 g, 85%). 1H NMR (300 MHz, CDCl3) δ 2.39 (s, 3H), 2.53 (s, 3H), 4.11 (s, 3H), 7.22-7.32 (m, 2H), 7.34 (s, 1H), 7.42-7.50 (m, 2H), 7.55-7.64 (m, 1H), 7.92 (s, 1H). MS (APCI+) m/z 375 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:10]2[C:5](=[N:6][C:7]([NH:11][CH2:12][CH2:13][O:14][CH3:15])=[N:8][CH:9]=2)[N:4]([CH3:16])[N:3]=1.CC1(C)C(C)(C)OB([C:25]2[CH:31]=[CH:30][C:28]([NH2:29])=[CH:27][CH:26]=2)O1>>[NH2:29][C:28]1[CH:30]=[CH:31][C:25]([C:2]2[C:10]3[C:5](=[N:6][C:7]([NH:11][CH2:12][CH2:13][O:14][CH3:15])=[N:8][CH:9]=3)[N:4]([CH3:16])[N:3]=2)=[CH:26][CH:27]=1
Reactant: CC1(C)OB(c2ccc(N)cc2)OC1(C)C
Reactant: COCCNc1ncc2c(Cl)nn(C)c2n1
Product: COCCNc1ncc2c(-c3ccc(N)cc3)nn(C)c2n1

Procedure:
Prepared as described above in Example 15 starting from (3-chloro-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)-(2-methoxy-ethyl)-amine and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline to give the title compound [3-(4-amino-phenyl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl]-(2-methoxy-ethyl)-amine; LC/MS (m/e)=299.0 (MH+), Rt=1.42 min.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:6][CH2:5][N:4]([C:7]2[C:26](/[CH:27]=[CH:28]/[C:29](=O)[CH3:30])=[CH:25][C:10]([C:11]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:16][CH:15]=3)=[O:12])=[CH:9][N:8]=2)[CH2:3]1.C1(C)C=CC(S([NH:41][NH2:42])(=O)=O)=CC=1.CCO.C[O-].[Na+]>C(O)=O>[OH:1][C@@H:2]1[CH2:6][CH2:5][N:4]([C:7]2[C:26]([C:27]3[NH:42][N:41]=[C:29]([CH3:30])[CH:28]=3)=[CH:25][C:10]([C:11]([NH:13][C:14]3[CH:15]=[CH:16][C:17]([O:20][C:21]([F:22])([F:24])[F:23])=[CH:18][CH:19]=3)=[O:12])=[CH:9][N:8]=2)[CH2:3]1
Reactant: CC(=O)/C=C/c1cc(C(=O)Nc2ccc(OC(F)(F)F)cc2)cnc1N1CC[C@@H](O)C1
Reactant: Cc1ccc(S(=O)(=O)NN)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O=CO
Product: Cc1cc(-c2cc(C(=O)Nc3ccc(OC(F)(F)F)cc3)cnc2N2CC[C@@H](O)C2)[nH]n1
Temperature: 80 °C
Reaction time: 1.5 h

Procedure:
(R,E)-6-(3-Hydroxypyrrolidin-1-yl)-5-(3-oxobut-1-en-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 3.1, 50 mg, 0.091 mmol) and toluene-4-sulfonic acid hydrazide (34.5 mg, 0.181 mmol) and EtOH (302 μL) were added to a MW vial, which was sealed and stirred at 80° C. for 1.5 h. The mixture was cooled to RT, NaOMe (17.15 mg, 0.318 mmol) was added and the RM was stirred at 80° C. for 48 h. Aq. The RM was acidified with aq. formic acid, filtered through a 0.2 μM PTFE membrane filter and purified by preparative HPLC (Condition 9, from 20% to 50% in 18 min) to yield the title compound as a white solid. UPLC-MS (Condition 1) tR=2.08 min, m/z=448.0 [M+H]+, m/z=446.0 [M−H]−; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.68-1.79 (m, 1H) 1.78-1.90 (m, 1H) 2.29 (br. s, 3H) 2.98 (d, J=11.74 Hz, 1H) 3.25-3.37 (m, 2H) 3.40-3.53 (m, 1H) 4.21 (br. s, 1H) 4.83 (br. s, 1H) 6.13 (s, 1H) 7.33 (d, J=8.31 Hz, 2H) 7.86 (d, 2H) 8.01 (br. s, 1H) 8.71 (br. s, 1H) 10.15 (s, 1H) 12.57 (br. s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[C:4]([O:11][C@@H:12]2[CH2:17][CH2:16][CH2:15][CH2:14][C@H:13]2[O:18][CH3:19])[CH:3]=1.[H][H]>CO.[Pd]>[F:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4]([O:11][C@@H:12]2[CH2:17][CH2:16][CH2:15][CH2:14][C@H:13]2[O:18][CH3:19])[CH:3]=1
Reactant: [H][H]
Reactant: CO[C@@H]1CCCC[C@H]1Oc1cc(F)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Product: CO[C@@H]1CCCC[C@H]1Oc1cc(F)ccc1N

Procedure:
(R,R)-4-fluoro-2-(2-methoxycyclohexyloxy)-nitrobenzene (0.18 g) in methanol (20.0 ml) was hydrogenated under 50 psi hydrogen for 20 h at rt using palladium on charcoal (5%) (40 mg) as catalyst. The catalyst was filtered off; the resulting solution was evaporated to dryness to yield an oil.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][C:13]=1[O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:9](=[O:10])[O:8][CH2:7]2)([O-])=O>CO.O1CCCC1.[Ni]>[NH2:1][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][C:13]=1[O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:9](=[O:10])[O:8][CH2:7]2
Reactant: O=C1OCc2cc([N+](=O)[O-])c(Oc3ccccc3)cc21
Agent: [Ni]
Solvent: C1CCOC1
Solvent: CO
Product: Nc1cc2c(cc1Oc1ccccc1)C(=O)OC2
Yield: 67.5 %

Procedure:
950 mg of 5-nitro-6-phenoxyphthalide in 120 ml of methanol and 30 ml of tetrahydrofuran is hydrogenated in the presence of 2 g of Raney nickel within 3 hours at 20 bar, filtered, and concentrated. From methanol, 570 mg of 5-amino-6-phenoxyphthalide is obtained, mp 205°-206.5° C.
Reaction SMILES: [CH2:1]([NH:5][S:6]([C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][C:17]=1[Cl:18])[C:12](O)=[O:13])(=[O:8])=[O:7])[CH2:2][CH2:3][CH3:4].[ClH:19]>S(Cl)(Cl)=O>[CH2:1]([NH:5][S:6]([C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][C:17]=1[Cl:18])[C:12]([Cl:19])=[O:13])(=[O:8])=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: Cl
Reactant: CCCCNS(=O)(=O)c1cc(C(=O)O)ccc1Cl
Solvent: O=S(Cl)Cl
Product: CCCCNS(=O)(=O)c1cc(C(=O)Cl)ccc1Cl

Procedure:
29.4 g of 3-n-butylsulfamoyl-4-chlorobenzoic acid were boiled under reflux in 140 ml of thionyl chloride until complete dissolution and until HCl had finished to develop (about 2 hours), the thionyl chloride was distilled off under reduced pressure and the residue was crystallized under diisopropyl ether. Colorless crystals, melting point: 110° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.[OH-].[Na+].Br[CH2:12][C:13]1[O:17][N:16]=[CH:15][CH:14]=1>CO.O>[O:17]1[C:13]([CH2:12][S:8][C:5]2[CH:6]=[CH:7][C:2]([NH2:1])=[CH:3][CH:4]=2)=[CH:14][CH:15]=[N:16]1
Reactant: Nc1ccc(S)cc1
Reactant: BrCc1ccno1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Nc1ccc(SCc2ccno2)cc1
Yield: 99.9 %

Procedure:
To a mixed solution of 4-aminothiophenol (600 mg) and sodium hydroxide (276 mg) in methanol (10 ml) and water (6 ml), a solution of 5-bromomethyl isoxazole (932 mg) in methanol (5 ml) was added at 0° C. Water was added to the mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure, to give 4-[(isoxazol-5-ylmethyl)sulfanyl]aniline (988 mg) as oil.