Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH:2]([CH:6]1[CH2:11][C@H:10]([N:12]([C:17]([C:19]2[N:23]([CH2:24][CH2:25][CH2:26][CH2:27][O:28][CH3:29])[C:22]3[CH:30]=[CH:31][CH:32]=[CH:33][C:21]=3[N:20]=2)=[O:18])[CH2:13][CH:14]([CH3:16])[CH3:15])[CH2:9][N:8](C(OC(C)(C)C)=O)[CH2:7]1)[CH2:3][O:4][CH3:5].CO.[ClH:43]>>[ClH:43].[ClH:43].[OH:1][CH:2]([C@H:6]1[CH2:7][NH:8][CH2:9][C@@H:10]([N:12]([CH2:13][CH:14]([CH3:16])[CH3:15])[C:17]([C:19]2[N:23]([CH2:24][CH2:25][CH2:26][CH2:27][O:28][CH3:29])[C:22]3[CH:30]=[CH:31][CH:32]=[CH:33][C:21]=3[N:20]=2)=[O:18])[CH2:11]1)[CH2:3][O:4][CH3:5]
Reactant: COCCCCn1c(C(=O)N(CC(C)C)[C@H]2CC(C(O)COC)CN(C(=O)OC(C)(C)C)C2)nc2ccccc21
Agent: Cl
Solvent: CO
Product: COCCCCn1c(C(=O)N(CC(C)C)[C@@H]2CNC[C@H](C(O)COC)C2)nc2ccccc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
tert-Butyl (5S)-3-(1-hydroxy-2-methoxyethyl)-5-[{[1-(4-methoxybutyl)-1H-benzimidazol-2-yl]carbonyl}(2-methylpropyl)amino]piperidine-1-carboxylate (150 mg) was dissolved in 10-20%-hydrogen chloride methanol solution (10 ml), and the mixture was stirred at room temperature for 3 hr. The solvent was evaporated under reduced pressure to give the object product (140 mg).
Reaction SMILES: Cl.[CH3:2][C@@H:3]1[CH2:8][N:7]([CH2:9][C:10]([OH:12])=O)[CH2:6][C@H:5]([CH3:13])[O:4]1.[NH2:14][C@@H:15]([CH2:33][O:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[C:16]([NH:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)=[CH:21][CH:20]=1)=[O:17]>>[CH2:35]([O:34][CH2:33][C@H:15]([NH:14][C:10](=[O:12])[CH2:9][N:7]1[CH2:6][C@H:5]([CH3:13])[O:4][C@H:3]([CH3:2])[CH2:8]1)[C:16]([NH:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)=[CH:21][CH:20]=1)=[O:17])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: N[C@@H](COCc1ccccc1)C(=O)Nc1ccc(Oc2ccc(F)cc2)cc1
Reactant: C[C@@H]1CN(CC(=O)O)C[C@H](C)O1
Agent: Cl
Product: C[C@@H]1CN(CC(=O)N[C@@H](COCc2ccccc2)C(=O)Nc2ccc(Oc3ccc(F)cc3)cc2)C[C@H](C)O1
Yield: 34.5 %

Procedure:
Proceeding as in Example 1, but substituting 2-((2R,6S)-2,6-dimethylmorpholino)acetic acid hydrochloride and (S)-2-amino-3-(benzyloxy)-N-(4-(4-fluorophenoxy)phenyl)propanamide, gave Compound 234, (S)-3-(benzyloxy)-2-(2-((2R,6S)-2,6-dimethylmorpholino)acetamido)-N-(4-(4-fluorophenoxy)phenyl)propanamide (14.8 mg, 34.5%). Major isomer: 1H-NMR (400 MHz, DMSO-D6): σ 10.21 (s, 1H), 7.99 (d, 1H), 7.60 (d, 2H), 7.30 (m, 5H), 7.21 (t, 2H), 7.04-6.98 (m, 4H), 4.70 (m, 1H), 4.52 (s, 2H), 3.73 (m, 2H), 3.55 (m, 2H), 2.98 (d, 2H), 2.77 (d, 1H), 2.71 (d, 1H), 1.76 (dd, 2H), 1.02 (d, 3H), 0.98 (d, 3H). MS (EI) for C30H34FN3O5. found 536.6 (MH+).
Reaction SMILES: O.[NH2:2][NH2:3].[Cl:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]([C:18]([C:20]2[CH:25]=[CH:24][C:23]([S:26][CH3:27])=[CH:22][CH:21]=2)=O)[CH2:12][C:13](OCC)=[O:14])=[CH:7][CH:6]=1.[OH-].[Na+]>C(O)C>[Cl:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[C:18]([C:20]3[CH:25]=[CH:24][C:23]([S:26][CH3:27])=[CH:22][CH:21]=3)=[N:3][NH:2][C:13](=[O:14])[CH2:12]2)=[CH:7][CH:6]=1
Reactant: NN
Reactant: CCOC(=O)CC(C(=O)c1ccc(SC)cc1)c1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CSc1ccc(C2=NNC(=O)CC2c2ccc(Cl)cc2)cc1
Temperature: 100 °C

Procedure:
Hydrazine hydrate (10.56 g, 210.9 mmol) was added to a solution of ethyl 3-(4-chlorophenyl)-4-[4-(methylthio)phenyl]-4-oxobutanoate (42.54 g, 117.2 mmol) in ethanol (85 ml), followed by heating under reflux for 15 hours at a bath temperature of 100° C. A 4 N aqueous solution of sodium hydroxide (40 ml) was added to the reaction mixture. After the mixture was ice-cooled, precipitated crystals were collected by filtration, washed with water (3×100 ml), dried in air, and then dried under reduced pressure (100° C., 2 hours), whereby the title compound (31.49 g, 81.2%) was obtained as pale yellow crystalline powder.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([O:13][C:14]1[CH:19]=[CH:18][C:17](/[CH:20]=[CH:21]/[C:22]([OH:24])=[O:23])=[CH:16][CH:15]=1)=[C:8]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:7]([CH2:31][CH2:32][CH3:33])=[CH:6]2.B(Br)(Br)Br>C(Cl)Cl>[OH:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([O:13][C:14]1[CH:15]=[CH:16][C:17](/[CH:20]=[CH:21]/[C:22]([OH:24])=[O:23])=[CH:18][CH:19]=1)=[C:8]([C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[C:7]([CH2:31][CH2:32][CH3:33])=[CH:6]2
Reactant: CCCc1cc2cc(OC)ccc2c(Oc2ccc(/C=C/C(=O)O)cc2)c1-c1ccccc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CCCc1cc2cc(O)ccc2c(Oc2ccc(/C=C/C(=O)O)cc2)c1-c1ccccc1
Yield: 66.5 %

Procedure:
Methyl ether (100) (0.15 g, 0.34 mmol) was treated with BBr3 in CH2Cl2 to give the crude product as a yellow viscous oil, which was purified by reverse phase preparation HPLC on Agilent 1100 to afford 96 mg (66%) of the title compound (101) as pale yellow solid. mp 120-122° C. 1H NMR (400 MHz, CH3OH-d4): δ 0.77 (t, J=7.4 Hz, 3H), 1.45-1.55 (m, 2H), 2.52 (t, J=7.8 Hz, 2H), 6.25 (d, J=15.9 Hz, 1H), 6.55 (d, J=8.7 Hz, 2H), 6.96 (dd, J1=9.0 Hz, J2=2.4 Hz, 1H), 7.10-7.16 (m, 3H), 7.18-7.27 (m, 3H), 7.34 (d, J=8.8 Hz, 2H), 7.48-7.56 (m, 2H), 7.69 (d, J=9.0 Hz, 1H). LCMS (ESI): m/z 425 (M+H)+, m/z 423 (M−H)−. Anal. Calc for C28H24O4.0.33H2O: C, 78.12; H, 5.78. Found: C, 77.97; H, 5.58.
Reaction SMILES: [NH2:1][C:2]1[C:6]2[C:7](=[O:19])[N:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[Cl:18])[CH:9]=[C:10](Br)[C:5]=2[NH:4][N:3]=1.CC1(C)C(C)(C)OB(B2OC(C)(C)C(C)(C)O2)O1.C([O-])(=O)C.[K+].Br[C:44]1[N:49]=[CH:48][C:47]([N:50]2[CH2:55][CH2:54][O:53][CH2:52][CH2:51]2)=[CH:46][CH:45]=1.C(=O)([O-])[O-].[Na+].[Na+]>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.O.CN(C)C=O>[NH2:1][C:2]1[C:6]2[C:7](=[O:19])[N:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[Cl:18])[CH:9]=[C:10]([C:44]3[CH:45]=[CH:46][C:47]([N:50]4[CH2:51][CH2:52][O:53][CH2:54][CH2:55]4)=[CH:48][N:49]=3)[C:5]=2[NH:4][N:3]=1
Reactant: Brc1ccc(N2CCOCC2)cn1
Reactant: Nc1n[nH]c2c(Br)cn(-c3ccccc3Cl)c(=O)c12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(=O)[O-]
Agent: CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C
Solvent: CN(C)C=O
Solvent: O
Product: Nc1n[nH]c2c(-c3ccc(N4CCOCC4)cn3)cn(-c3ccccc3Cl)c(=O)c12
Temperature: 110 °C
Reaction time: 8 h
Yield: 4.8 %

Procedure:
A mixture of 3-amino-7-bromo-5-(2-chlorophenyl)-1,5-dihydro-4H-pyrazolo[4,3-c]pyridin-4-one obtained in Step B of Example 18 (300 mg), 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi-1,3,2-dioxaborolane (269 mg), (1,1′-bis(diphenylphosphino)ferrocene)dichloropalladium(II) (21.5 mg), potassium acetate (173 mg) and N,N-dimethylformamide (4.0 mL) was stirred overnight at 110° C. under argon atmosphere. The reaction mixture was cooled to room temperature, 4-(6-bromopyridin-3-yl)morpholine (430 mg), aqueous sodium carbonate solution (2 M, 0.883 mL) and tetrakis(triphenylphosphine)palladium(0) (102 mg) were added thereto, and the reaction mixture was stirred at 120° C. for 5 hr under argon atmosphere. The reaction mixture was cooled to room temperature, water was added thereto, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (basic silica gel, methanol/ethyl acetate). The obtained rough-purified product was crystallized from methanol/ethyl acetate/hexane to give the title compound (18.0 mg).
Reaction SMILES: C(OP([CH:9]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:10][CH3:11])(=O)OCC)C.[CH2:18]([O:20][C:21]([C@H:23]1[C@H:25]([CH:26]=O)[C:24]1([CH3:29])[CH3:28])=[O:22])[CH3:19].O>O1CCCC1>[CH2:18]([O:20][C:21]([CH:23]1[CH:25]([CH:26]=[C:9]([CH2:10][CH3:11])[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:24]1([CH3:28])[CH3:29])=[O:22])[CH3:19]
Reactant: CCOC(=O)[C@H]1[C@H](C=O)C1(C)C
Reactant: CCOP(=O)(OCC)C(CC)c1ccccc1
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)C1C(C=C(CC)c2ccccc2)C1(C)C
Reaction time: 6 h
Yield: 52 %

Procedure:
51.2 g (0.2 mol) of 1-phenylpropyl-phosphonic acid diethyl ester, dissolved in 30 ml of anhydrous tetrahydrofuran, were added dropwise to a mixture of 24 g (0.214 mol) of potassium tert.-butylate and 300 ml of anhydrous tetrahydrofuran at 20°-25° C., while stirring. After the mixture had been subsequently stirred at 20°-25° C. for a further 2 hours, 34 g (0.2 mol) of cis/trans-2,2-dimethyl-3-formyl-cyclopropanecarboxylic acid ethyl ester, dissolved in 50 ml of anhydrous tetrahydrofuran, were added dropwise at 25° C., while stirring. Stirring was then continued at 60° C. for a further 6 hours. 500 ml of water were then added and the reaction mixture was extracted twice with 300 ml of methylene chloride each time. The organic phases were separated off and dried over magnesium sulphate, the solvent was distilled off under a waterpump vacuum and the residue was distilled in vacuo. 28.3 g (52% of theory) of 2,2-dimethyl-3-(2-ethyl-2-phenyl-vinyl)cyclopropanecarboxylic acid ethyl ester (isomer mixture) were obtained as a yellow oil with a boiling point of 142°-150° C./2 mbar.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11](=[O:18])[C:10]([C:19]([O-:21])=[O:20])=[CH:9]2)=[CH:4][CH:3]=1.[OH-].[Na+]>C(O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11](=[O:18])[C:10]([C:19]([OH:21])=[O:20])=[CH:9]2)=[CH:4][CH:3]=1
Reactant: O=C([O-])c1cn(-c2ccc(F)cc2)c2ccccc2c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1cn(-c2ccc(F)cc2)c2ccccc2c1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 76 %

Procedure:
To a solution of intermediate j (5 g, 0.013 mol) dissolved in ethylalcohol (50 ml, 10 v/w) was added 1N NaOH aq (100 ml). The mixture was stirred at room temperature for 3 h. After completion of the reaction, the solvent was evaporated in vacuo, and the residue was poured into water (50 ml) and extracted with CH2Cl2 (150 mL*4). Then the aqueous layer was separated and acidified to pH 6 with 6N aqueous hydrochloric acid, then stirred at room temperature for 0.5 h, and the precipitate was filtered to give white solid 2.8 g. Yield: 60%.
Reaction SMILES: [C:1]1([C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:10]=[C:9]([C:17](O)=[O:18])[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.ClC(OCC)=O.Cl.[CH2:34]([C@@H:36]1[CH2:41][CH2:40][CH2:39][CH2:38][NH:37]1)[CH3:35]>C1(C)C=CC=CC=1>[CH2:34]([C@@H:36]1[CH2:41][CH2:40][CH2:39][CH2:38][N:37]1[C:17]([C:9]1[N:8]=[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:16]2[C:11]([CH:10]=1)=[CH:12][CH:13]=[CH:14][CH:15]=2)=[O:18])[CH3:35]
Reactant: O=C(O)c1cc2ccccc2c(-c2ccccc2)n1
Reactant: CC[C@@H]1CCCCN1
Agent: CCOC(=O)Cl
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CC[C@@H]1CCCCN1C(=O)c1cc2ccccc2c(-c2ccccc2)n1
Yield: 57.9 %

Procedure:
Operations are carried out as for Example 7, starting from 2.5 g of 1-phenyl isoquinoline 3-carboxylic acid, 2.86 g of triethylamine, 1.24 g of ethyl chloroformate and 1.93 g of 2(R)-ethyl piperidine hydrochloride in 100 ml of toluene. After chromatography, 2 g of 2(R)-ethyl 1-[(1-phenyl 3-isoquinolyl) carbonyl]piperidine in the form of oil are obtained. αD26 =+1.4° (2% in ethanol).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[CH2:11][O:10][CH2:9][CH:8]([C:12]3[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=3)[C:6]=2[N:7]=1.[CH3:23][NH2:24]>>[Cl:1][C:2]1[N:3]=[C:4]([NH:24][CH3:23])[C:5]2[CH2:11][O:10][CH2:9][CH:8]([C:12]3[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=3)[C:6]=2[N:7]=1
Reactant: FC(F)(F)c1ccc(C2COCc3c(Cl)nc(Cl)nc32)cc1
Reactant: CN
Product: CNc1nc(Cl)nc2c1COCC2c1ccc(C(F)(F)F)cc1

Procedure:
2,4-dichloro-8-(4-(trifluoromethyl)phenyl)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidine (Preparation Z) was reacted as described in Preparation Xa with methanamine to give 2-chloro-N-methyl-8-(4-(trifluoromethyl)phenyl)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-4-amine (Preparation Zb). LC-MS (M+H)+=344.1.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]([NH:10][C:11]2[CH:21]=[CH:20][C:14]([C:15]([O:17]CC)=[O:16])=[CH:13][CH:12]=2)=[O:9])[CH2:4][CH2:3]1.O[Li].O.C1COCC1.Cl>O>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]([NH:10][C:11]2[CH:21]=[CH:20][C:14]([C:15]([OH:17])=[O:16])=[CH:13][CH:12]=2)=[O:9])[CH2:4][CH2:3]1
Reactant: CCOC(=O)c1ccc(NC(=O)N2CCN(C)CC2)cc1
Agent: Cl
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Product: CN1CCN(C(=O)Nc2ccc(C(=O)O)cc2)CC1
Yield: 78 %

Procedure:
A solution of 162 (1.39 g, 4.77 mmol) and LiOH.H2O (300 mg, 7.16 mmol) in 1:1 THF:water (8 ml) was stirred at room temperature for 24 h. 1 M HCl was added to reach pH=5 and the solvent was evaporated. The title compound was purified by preparative HPLC (Aquasil C18, reverse phase, eluent: MeOH/water) to give 979 mg (78%) of the title compound 163 as a white powder. 1H NMR: (400 MHz, DMSO) δ (ppm): 8.81 (s, 1H), 7.78 (dt, J=8.6, 1.8 Hz, 2H), 7.53 (dt, J=8.8, 2.0 Hz, 2H), 3.44 (t, J=4.9 Hz, 4H), 2.31 (t, J=5.0 Hz, 4H), 2.19 (s, 3H).
Reaction SMILES: [CH3:1][NH:2][CH3:3].Br[CH2:5][C:6](=[O:21])[CH:7]([C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>C(O)C.CCOCC>[CH3:1][N:2]([CH3:3])[CH2:5][C:6](=[O:21])[CH:7]([C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=C(CBr)C(c1ccccc1)c1ccc(F)cc1
Reactant: CNC
Solvent: CCOCC
Solvent: CCO
Product: CN(C)CC(=O)C(c1ccccc1)c1ccc(F)cc1
Reaction time: 0.75 h

Procedure:
Dimethylamine in ethanol (30 ml s of 33% solution) was added to a solution of 3-bromo-1-p-fluorophenyl-1-phenyl-propan-2-one (13g) in dry ether. After 45 minutes, the reaction mixture was extracted with dilute hydrochloric acid and ether. Basification of the acid extract and subsequent isolation through ether in the usual manner gave 3-dimethylamino-1-p-fluorophenyl-1-phenyl-propan-2-one isolated as the hydrochloride (5 8g., 53%), m.p. 219° - 220°.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]3[CH:13]=[C:14]4[C@:19]([C:21]([C:23]5[S:24][CH:25]=[CH:26][N:27]=5)=[O:22])([CH2:20][C:11]=3[CH:10]=[N:9]2)[CH2:18][N:17]([S:28]([C:31]2[CH:32]=[N:33][CH:34]=[C:35](F)[CH:36]=2)(=[O:30])=[O:29])[CH2:16][CH2:15]4)=[CH:4][CH:3]=1.[NH:38]1[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]1>CN1CCCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]3[CH:13]=[C:14]4[C@:19]([C:21]([C:23]5[S:24][CH:25]=[CH:26][N:27]=5)=[O:22])([CH2:20][C:11]=3[CH:10]=[N:9]2)[CH2:18][N:17]([S:28]([C:31]2[CH:32]=[N:33][CH:34]=[C:35]([N:38]3[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]3)[CH:36]=2)(=[O:30])=[O:29])[CH2:16][CH2:15]4)=[CH:4][CH:3]=1
Reactant: C1CCNCC1
Reactant: O=C(c1nccs1)[C@]12Cc3cnn(-c4ccc(F)cc4)c3C=C1CCN(S(=O)(=O)c1cncc(F)c1)C2
Agent: CN1CCCC1
Product: O=C(c1nccs1)[C@]12Cc3cnn(-c4ccc(F)cc4)c3C=C1CCN(S(=O)(=O)c1cncc(N3CCCCC3)c1)C2
Temperature: 100 °C
Yield: 31.3 %

Procedure:
A mixture of (R)-(1-(4-fluorophenyl)-6-((5-fluoropyridin-3-yl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(thiazol-2-yl)methanone (100 mg, 0.185 mmol) and piperidine (47 mg, 0.56 mmol) in N-methylpyrrolidine (1 mL) was heated at 100° C. for 6 hours. The mixture was cooled and the reaction mixture was purified by preparative HPLC (Gilson, Acidic (0.1% Formic acid), Waters X-Select Prep-C18, 5 μm, 19×50 mm column, 5-95% acetonitrile in water) to give (R)-(1-(4-fluorophenyl)-6-((5-(piperidin-1-yl)pyridin-3-yl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(thiazol-2-yl)methanone as a white solid (35 mg). LCMS (Method F, ES-API): RT 2.64 min, m+H=605; 1H NMR (400 MHz, CDCl3): δ 8.39 (d, 1H, J=3.0 Hz), 8.27 (d, 1H, J=2.0 Hz), 8.05 (d, 1H, J=3.0 Hz), 7.65 (d, 1H, J=3.0 Hz), 7.54-7.41 (m, 2H), 7.31-7.30 (m, 2H). 7.19-7.14 (m, 2H), 6.53 (d, 1H, J=2.0 Hz), 5.51 (dd, 1H, J=12.0, 2.0 Hz), 4.21 (d, 1H, J=17.0 Hz), 3.90-3.86 (m, 1H), 3.27-3.25 (m, 4H), 2.91-2.81 (m, 3H), 2.61-2.52 (m, 2H), 1.75-1.56 (m, 6H).
Reaction SMILES: [CH2:1]([CH:3]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([C:18](=[O:31])[NH:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=2)[CH:11]=1)[C:4]([O:6]CC)=[O:5])[CH3:2].[OH-].[Na+]>C(O)C>[CH2:1]([CH:3]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([C:18](=[O:31])[NH:19][CH2:20][C:21]2[CH:22]=[CH:23][C:24]([C:27]([F:29])([F:28])[F:30])=[CH:25][CH:26]=2)[CH:11]=1)[C:4]([OH:6])=[O:5])[CH3:2]
Reactant: CCOC(=O)C(CC)Cc1ccc(OC)c(C(=O)NCc2ccc(C(F)(F)F)cc2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCC(Cc1ccc(OC)c(C(=O)NCc2ccc(C(F)(F)F)cc2)c1)C(=O)O
Temperature: 50 °C
Reaction time: 4 h
Yield: 106.9 %

Procedure:
Ethyl 2-ethyl-3-[4-methoxy-3-[N-[[4-(trifluoromethyl)phenyl]methyl]carbamoyl]phenyl]propanoate (1.26 g, 2.88 mmol; Example 7), 15 ml of ethanol and 15 ml of 1 mol/l aqueous solution of sodium hydroxide were mixed and, after stirring for 4 hours at 50° C., the reaction mixture was concentrated under reduced pressure. The residue was dissolved in water, which was made acidic with dilute hydrochloric acid. The precipitates produced were filtered, dried and then recrystallized from ethyl acetate to obtain 1.26 g (95%) of the title compound as colorless prisms. Melting point 144.5-146.5° C.; Mass analysis m/z 409(M+); Elemental analysis C21H22F3NO4(409.40):
Reaction SMILES: [H-].[Na+].[N+:3]([C:6]1[CH:14]=[C:13]2[C:9]([C:10]([CH:15]=O)=[N:11][NH:12]2)=[CH:8][CH:7]=1)([O-:5])=[O:4].[CH3:17][Si:18]([CH2:21][CH2:22][O:23][CH2:24]Cl)([CH3:20])[CH3:19].[NH4+].[Cl-]>O.C1COCC1>[CH3:15][C:10]1[C:9]2[C:13](=[CH:14][C:6]([N+:3]([O-:5])=[O:4])=[CH:7][CH:8]=2)[N:12]([CH2:24][O:23][CH2:22][CH2:21][Si:18]([CH3:20])([CH3:19])[CH3:17])[N:11]=1
Reactant: C[Si](C)(C)CCOCCl
Reactant: O=Cc1n[nH]c2cc([N+](=O)[O-])ccc12
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1nn(COCC[Si](C)(C)C)c2cc([N+](=O)[O-])ccc12
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 52.8 %

Procedure:
To a flask was added NaH (60% in mineral oil, 0.473 g, 11.8 mmol) and THF (59.1 mL). The mixture was cooled to about 0° C. 6-Nitro-1H-indazole-3-carbaldehyde (2.26 g, 11.8 mmol, ChemPacific) was added in several smaller portions and the mixture was stirred at about 0° C. for about 20 min. SEMCl (2.30 mL, 13.0 mmol) was added dropwise and the mixture was stirred at about 0° C. for about 10 min and then stirred at rt for about 72 h. To the mixture was added saturated aqueous NH4Cl (25 mL) and water (10 mL). The aqueous layer was separated and extracted with DCM (2×50 mL). The combined organic layers were washed with brine (20 mL), dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (80 g silica gel) eluting with 10 to 25% EtOAc/heptane to give 3-methyl-6-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole (1.915 g, 50%): 1H NMR (400 MHz, DMSO) δ 10.24 (s, 1H), 8.94 (d, J=1.5 Hz, 1H), 8.36 (dd, J=6.5, 2.3 Hz, 1H), 8.31-8.13 (m, 1H), 6.08 (s, 2H), 3.58 (s, 2H), 0.83 (s, 2H), −0.12 (s, 9H).
Reaction SMILES: [CH3:1][CH2:2][CH2:3][C:4](Cl)=[O:5].[C:7]1([C:13]2[CH:14]=[C:15]3[C:21]([NH2:22])=[N:20][NH:19][C:16]3=[N:17][N:18]=2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.Cl>N1C=CC=CC=1>[C:7]1([C:13]2[CH:14]=[C:15]3[C:21]([NH:22][C:4](=[O:5])[CH2:3][CH2:2][CH3:1])=[N:20][NH:19][C:16]3=[N:17][N:18]=2)[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: Nc1n[nH]c2nnc(-c3ccccc3)cc12
Reactant: CCCC(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Product: CCCC(=O)Nc1n[nH]c2nnc(-c3ccccc3)cc12

Procedure:
n-Butyryl chloride (120 μl, 0.73 mmol) was added to a solution of 5-phenyl-1H-pyrazolo[3,4-c]pyridazin-3-ylamine (Description 8; 100 mg, 0.47 mmol) in pyridine (0.5 mL). The reaction mixture was stirred at reflux for 16 hours, then allowed to cool. The solution was acidified to pH 1 with 5N HCl, and the resulting solids were filtered and dried. Purification by column chromatography (5% MeOH/CHCl3) afforded the title compound as a solid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6](Cl)[C:5]([F:9])=[CH:4][N:3]=1.[Cl:10][C:11]1[CH:12]=[C:13]([CH:15]=[CH:16][CH:17]=1)[NH2:14]>>[Cl:10][C:11]1[CH:12]=[C:13]([NH:14][C:2]2[N:7]=[C:6]([NH:14][C:13]3[CH:15]=[CH:16][CH:17]=[C:11]([Cl:10])[CH:12]=3)[C:5]([F:9])=[CH:4][N:3]=2)[CH:15]=[CH:16][CH:17]=1
Reactant: Fc1cnc(Cl)nc1Cl
Reactant: Nc1cccc(Cl)c1
Product: Fc1cnc(Nc2cccc(Cl)c2)nc1Nc1cccc(Cl)c1

Procedure:
In like manner to the preparation of N2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine, 2,4-dichloro-5-fluoropyrimidine and 3-chloroaniline were reacted to yield N2,N4-bis(3-chlorophenyl)-5-fluoro-2,4-pyrimidinediamine. 1H NMR (CD3OD): δ 8.08 (d, 1H, J=5.4 Hz), 7.70 (t, 1H, J=1.8 Hz), 7.57 (t, 1H, J=1.2 Hz), 7.54 (m, 1H), 7.35 (m, 4H), 7.28 (t, 1H, J=1.8 Hz), 7.24 (m, 1H), 7.22 (t, 1H, J=1.8 Hz); 19F NMR (CD3OD): −43631; LCMS: ret. time: 28.99 min.; purity: 99%; MS (m/e): 349 (M+).
Reaction SMILES: [Br:1][C:2]1[C:7]([CH:8]=[O:9])=[CH:6][CH:5]=[C:4]([Br:10])[N:3]=1.P([O-])(O)(O)=[O:12].[Na+].CC(=CC)C.Cl([O-])=O.[Na+].Cl>C(O)(C)(C)C.O>[Br:1][C:2]1[N:3]=[C:4]([Br:10])[CH:5]=[CH:6][C:7]=1[C:8]([OH:12])=[O:9]
Reactant: O=P([O-])(O)O
Reactant: O=Cc1ccc(Br)nc1Br
Agent: CC=C(C)C
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CC(C)(C)O
Product: O=C(O)c1ccc(Br)nc1Br
Yield: 88 %

Procedure:
To a solution of 2,6-dibromo-3-formylpyridine (0.3 g) in tert-butanol (12 mL)-water (1 mL) were added sodium dihydrogen phosphate (0.14 g), 2-methyl-2-butene (0.32 g) and a solution of sodium chlorite (0.36 g) in water (2 mL) successively at room temperature, and the mixture was stirred for 2 hours. The reaction mixture was poured into water. The mixture was acidified by adding 1 mol/L hydrochloric acid, and the resulting mixture was extracted with ethyl acetate. The extract was washed with water, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure to give the title compound (0.28 g).
Reaction SMILES: C1(C)C=CC=CC=1.[CH3:8][CH:9]([CH3:17])[C:10](=[O:16])[CH2:11][C:12]([O:14]C)=O.C(N)CN.[NH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>O>[CH3:17][CH:9]([CH3:8])[C:10](=[O:16])[CH2:11][C:12]([NH:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:14]
Reactant: COC(=O)CC(=O)C(C)C
Reactant: Nc1ccccc1
Solvent: Cc1ccccc1
Solvent: NCCN
Solvent: O
Product: CC(C)C(=O)CC(=O)Nc1ccccc1
Temperature: 80 °C
Reaction time: 16 h
Yield: 0.2 %

Procedure:
A three-necked, 12-L round-bottom flask equipped with a mechanical stirrer, a thermometer and set up for distillation is charged with 2.6 L of toluene, 1.73 kg (12 mol) of methyl 4-methyl-3-oxopentanoate and 72 g (1.18 mol) of ethylene diamine. The mixture is heated to 80° C. and charged with 0.49 kg of aniline. The mixture is brought to reflux and distillation started. After 40 minutes a further 0.245 kg of aniline is charged and at 40 minute intervals a further two portions of aniline (0.245 and 0.25 kg) are charged. Distillation is continued for a further one to five hours until a total of 985 mL of solvent is removed. The solution is stirred at room temperature for 16 hours an a further 550 mL of solvent is removed by vacuum distillation (using approximately 85 mm Hg). The mixture is cooled and 2 L of water is charged to provide an oil. The mixture is warmed to 40° C. and a further 1.0 L of water is charged. Seven hundred milliliters of toluene-water mixture is removed by vacuum distillation (approximately 20 mm Hg). Two liters of water is charged and the mixture is allowed to stand for 10 days. The product is isolated by filtration and washed with three portions of hexane. Drying in vacuo gives 1.7 g of 4-methyl-3-oxo-N-phenylpentanamide as a hydrate; mp 46.5°-58.8° C.