Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:3]=1[CH:4]=O.[CH3:12][NH:13][CH3:14].C([BH3-])#N.[Na+].C(O)(=O)C>CO>[F:1][C:2]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:3]=1[CH2:4][N:13]([CH3:14])[CH3:12]
Reactant: COc1ccc(F)c(C=O)c1
Reactant: CNC
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: COc1ccc(F)c(CN(C)C)c1
Yield: 97 %

Procedure:
2-Fluoro-5-methoxybenzaldehyde (2.62 g, 17.0 mmol), dimethylamine (2M in methanol, 17 mL, 34 mmol) and sodium cyanoborohydride (1.1.7 g, 18.7 mmol) were stirred at ambient temperature in a solution of glacial acetic acid (2 mL) in methanol (100 mL) for 66 h. The solvent was removed in vacuo. The residue was treated with 10% sodium carbonate solution and extracted with ethyl acetate. The ethyl acetate layer was washed with water (2×), brine (1×), and dried over MgSO4. After filtration, the solvent was removed in vacuo to give (2-fluoro-5-methoxybenzyl)dimethylamine (3.02 g, 97%) as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7](=[O:19])[CH2:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]([NH:15][CH:16]([CH3:18])[CH3:17])[N:10]=2)=[CH:4][CH:3]=1.CO[CH:22](OC)[N:23]([CH3:25])[CH3:24]>CN(C)C=O>[CH3:22][N:23]([CH3:25])[CH:24]=[C:8]([C:9]1[CH:14]=[CH:13][N:12]=[C:11]([NH:15][CH:16]([CH3:17])[CH3:18])[N:10]=1)[C:7]([C:5]1[S:6][C:2]([Cl:1])=[CH:3][CH:4]=1)=[O:19]
Reactant: COC(OC)N(C)C
Reactant: CC(C)Nc1nccc(CC(=O)c2ccc(Cl)s2)n1
Solvent: CN(C)C=O
Product: CC(C)Nc1nccc(C(=CN(C)C)C(=O)c2ccc(Cl)s2)n1
Temperature: 100 °C
Reaction time: 2 h
Yield: 95 %

Procedure:
To a suspension of 1-(5-chloro-2-thienyl)-2-[2-(isopropylamino)pyrimidin-4-yl]ethanon (1 eq, 13.5 mmol) in 6 mL N,N-dimethylformamide, was added of N,N-dimethylformamide dimethyl acetal (3.4 eq, 46 mmol). The mixture was stirred at 100° C. for 2 h and then allowed to cool to room temperature. The solvent was evaporated to afford 4.5 g (95% yield) of 3-(dimethylamino)-1-(5-chloro-2-thienyl)-2-[2-(isopropylamino)pyrimidin-4-yl]prop-2-en-1-one which was used in the next step without further purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][CH:3]=1.Br[C:12]1[CH:13]=[CH:14][C:15]([F:18])=[N:16][CH:17]=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>[F:18][C:15]1[CH:14]=[CH:13][C:12]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)=[CH:17][N:16]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: Fc1ccc(Br)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: Fc1ccc(-c2ccc(F)nc2)cc1
Yield: 84.2 %

Procedure:
The procedure described in Example 4, step 4.2 is followed. Starting from 2.0 g (14.29 mmol) of 4-fluorobenzeneboronic acid, 5.21 g (14.29 mmol) of 5-bromo-2-fluoropyridine, 0.82 g (0.71 mmol) of Pd(PPh3)4 and 50 ml of a 1M aqueous solution of sodium carbonate, 2.30 g of product is obtained in the form of a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8](O)[CH2:9][NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:4][CH:3]=1.[C:19]1(=[O:29])[NH:23][C:22](=[O:24])[C:21]2=[CH:25][CH:26]=[CH:27][CH:28]=[C:20]12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([N:23]2[C:19](=[O:29])[C:20]3[C:21](=[CH:25][CH:26]=[CH:27][CH:28]=3)[C:22]2=[O:24])[CH2:9][NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)NCC(O)c1ccc(Cl)cc1
Reactant: O=C1NC(=O)c2ccccc21
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCC(c1ccc(Cl)cc1)N1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
At RT, 2.61 g of rac-tert-butyl [2-(4-chlorophenyl)-2-hydroxyethyl]carbamate (Example 45A, 9.62 mmol), 1.42 g of phthalimide (9.62 mmol) and 3.78 g of triphenylphosphine (14.43 mmol) were initially charged in abs. THF. 4.03 g (14.43 mmol) of diisopropyl azodicarboxylate were then added dropwise, and the mixture was stirred at RT for 30 min. The reaction mixture was concentrated and purified by silica gel chromatography (mobile phase: cyclohexane:ethyl acetate 10:1). This gave 2.92 g of the title compound (55% of theory, purity about 73%).
Reaction SMILES: O[C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[CH:9][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:4]2[N:3]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C.Cl.Cl.[F:54][C:55]1[CH:56]=[C:57]([C@H:62]2[CH2:66][CH2:65][CH2:64][NH:63]2)[C:58]([CH3:61])=[N:59][CH:60]=1>CN(C=O)C>[F:54][C:55]1[CH:56]=[C:57]([C@H:62]2[CH2:66][CH2:65][CH2:64][N:63]2[C:2]2[CH:7]=[CH:6][N:5]3[N:8]=[CH:9][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:4]3[N:3]=2)[C:58]([CH3:61])=[N:59][CH:60]=1
Reactant: CCOC(=O)c1cnn2ccc(O)nc12
Reactant: Cc1ncc(F)cc1[C@H]1CCCN1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)c1cnn2ccc(N3CCC[C@@H]3c3cc(F)cnc3C)nc12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 72.2 %

Procedure:
To a solution of ethyl 5-hydroxypyrazolo[1,5-a]pyrimidine-3-carboxylate (Preparation B, Step A, 372 mg, 1.8 mmol) in DMF (10 mL) was added (benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (874 mg, 1.98 mmol). The mixture was stirred at ambient temperature for 10 minutes then treated with DIEA (1.57 mL, 8.99 mmol) and (R)-5-fluoro-2-methyl-3-(pyrrolidin-2-yl)pyridine dihydrochloride (455 mg, 1.80 mmol). After stirring at ambient temperature for 4 hours the mixture was partitioned between 10% citric acid (50 mL) and EtOAc (50 mL). The layers were separated and the aqueous layer was extracted with EtOAc (2×30 mL). The combined organic phases were washed successively with water (30 mL), saturated NaHCO3 (30 mL), water (30 mL) and brine (2×30 mL), then dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel column chromatography eluting with 1% MeOH/DCM to afford the product as white foam (480 mg, 72% yield). MS (apci) m/z=370.0 (M+H).
Reaction SMILES: [OH:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6](O)[CH:5]=[CH:4][N:3]=1.P(Cl)(Cl)([Cl:14])=O.C(N(CC)C(C)C)(C)C>C1(C)C=CC=CC=1>[Cl:14][C:6]1[CH:5]=[CH:4][NH:3][C:2](=[O:1])[C:7]=1[N+:8]([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1c(O)ccnc1O
Reactant: O=P(Cl)(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Product: O=c1[nH]ccc(Cl)c1[N+](=O)[O-]
Temperature: 47 °C

Procedure:
A 150 mL flask is charged with 2,4-dihydroxy-3-nitropyridine (Compound XII) (10.0 g, 0.064 mole), and toluene (30 mL). The mixture is stirred at moderate speed and warmed to 47° C. Phosphorus oxychloride (POCl3) (4.4 g, 0.0289 moles) is added over 10 minutes, via a syringe pump, giving an exotherm to 49° C. N,N-diisopropylethylamine (DIPEA) (2.22 g, 0.017 moles) is added over 10 minutes, giving an exotherm to 51° C. Another portion of POCl3 (4.4 g, 0.0289 moles) is added over 10 minutes, followed by another portion of DIPEA (2.22 g, 0.017 moles) over 10 minutes. A third portion of POCl3 (4.4 g, 0.0289 moles) is added over 10 minutes, followed by a third portion of DIPEA (2.22 g, 0.017 moles) over 10 minutes, followed by a final portion of POCl3 (4.4 g, 0.0289 moles) over 10 minutes (total POCl3 added is 17.7 g), then by a final portion of DIPEA (2.22 g, 0.017 moles) over 10 min. (total DIPEA added is 8.9 g). The reaction is then stirred at 50° C. for 5 hr until IPC indicates complete consumption of Compound XII. The reaction is allowed to cool to 20° C. over 30 minutes and 50 mL of water is added over 1.5 hr allowing the temperature to rise to 47° C. This mixture is stirred for four hours while cooling to 25° C. The batch is filtered washing twice with 15 mL of water, then twice with 15 mL of toluene. The product is dried to give Compound II.
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:24]=[CH:25][C:26]=2[O:27][CH3:28])[CH2:10][N:11]2[C:19]3[N:18]=[C:17]([CH:20]([CH3:22])[CH3:21])[NH:16][C:15]=3[C:14](=O)[N:13]=[CH:12]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.P(Cl)(Cl)(Cl)=O.ClC1N=C2C(NC=N2)=C[N:36]=1.N>C1COCC1>[NH2:36][C:14]1[N:13]=[CH:12][N:11]([CH2:10][C:9]2[CH:24]=[CH:25][C:26]([O:27][CH3:28])=[C:7]([O:6][CH:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)[CH:8]=2)[C:19]2[C:15]=1[N:16]=[C:17]([CH:20]([CH3:22])[CH3:21])[N:18]=2
Reactant: COc1ccc(Cn2cnc(=O)c3[nH]c(C(C)C)nc32)cc1OC1CCCC1
Reactant: Clc1ncc2[nH]cnc2n1
Agent: N
Solvent: C1CCOC1
Solvent: O=P(Cl)(Cl)Cl
Product: COc1ccc(Cn2cnc(N)c3nc(C(C)C)nc2-3)cc1OC1CCCC1

Procedure:
3-(3-Cyclopentyloxy-4-methoxy-benzyl)-8-isopropyl-hypoxanthine (5.74 g, 15 mmole) and phosphorus oxychloride (60 ml) were heated to 65° C. for 30 minutes. The reaction mixture was evaporated to dryness in vacuo and the residue evaporated twice with toluene. The crude chloropurine (15 mmole) was dissolved in THF (80ml ) and 32% aqueous ammonia solution (36.2 ml) and heated together with liquid ammonia (50 g) in a 450 ml pressure reactor to 60° C. (340 psi) for 4 hours. The solvents were evaporated in vacuo and the residue suspended in a mixture of diethyl ether and 1 M NaOH solution. The solid was collected and crystallized from ethyl acetate to give the title compound, 3.92 g (68.5 %) mp 190-193° C.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH2:8][CH:9]2[C:12]([OH:14])=O)=[CH:4][CH:3]=1.[CH3:15][N:16]([CH3:34])[C:17]1[CH:22]=[CH:21][C:20]([CH2:23][NH:24][C:25]2[CH:30]=[CH:29][C:28]([CH:31]([CH3:33])[CH3:32])=[CH:27][CH:26]=2)=[CH:19][CH:18]=1>>[CH3:15][N:16]([CH3:34])[C:17]1[CH:18]=[CH:19][C:20]([CH2:23][N:24]([C:25]2[CH:30]=[CH:29][C:28]([CH:31]([CH3:32])[CH3:33])=[CH:27][CH:26]=2)[C:12]([CH:9]2[C:10]3[C:5](=[CH:4][CH:3]=[C:2]([F:1])[CH:11]=3)[CH2:6][CH2:7][CH2:8]2)=[O:14])=[CH:21][CH:22]=1
Reactant: CC(C)c1ccc(NCc2ccc(N(C)C)cc2)cc1
Reactant: O=C(O)C1CCCc2ccc(F)cc21
Product: CC(C)c1ccc(N(Cc2ccc(N(C)C)cc2)C(=O)C2CCCc3ccc(F)cc32)cc1
Yield: 90.6 %

Procedure:
By the reaction and treatment in the same manner as in Example 12 using 7-fluoro-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (0.41 g) and [(4-dimethylaminophenyl)methyl](4-isopropylphenyl)amine (0.57 g) as starting materials, N-[(4-dimethylaminophenyl)methyl]-7-fluoro-N-(4-isopropylphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.85 g) was obtained. This compound was dissolved in ethyl acetate, and 4 mol/L-HCl/dioxane was added. The precipitated solid was collected by filtration to give N-[(4-dimethylaminophenyl)methyl]-7-fluoro-N-(4-isopropylphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide hydrochloride (0.85 g). melting point: 165.6° C.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]([NH2:26])=[N:8][N:9]([C:11]2[N:16]=[C:15]([C:17]3[CH:22]=[CH:21][C:20]([N:23]([CH3:25])[CH3:24])=[CH:19][CH:18]=3)[CH:14]=[CH:13][N:12]=2)[CH:10]=1)=[O:5])C>[OH-].[K+].CO>[NH2:26][C:7]1[C:6]([C:4]([OH:5])=[O:3])=[CH:10][N:9]([C:11]2[N:16]=[C:15]([C:17]3[CH:22]=[CH:21][C:20]([N:23]([CH3:25])[CH3:24])=[CH:19][CH:18]=3)[CH:14]=[CH:13][N:12]=2)[N:8]=1
Reactant: CCOC(=O)c1cn(-c2nccc(-c3ccc(N(C)C)cc3)n2)nc1N
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CN(C)c1ccc(-c2ccnc(-n3cc(C(=O)O)c(N)n3)n2)cc1
Temperature: 95 °C
Yield: 73.9 %

Procedure:
A suspension of 3-Amino-1-[4-(4-dimethylamino-phenyl)-pyrimidin-2-yl]-1H-pyrazole-4-carboxylic acid ethyl ester (250 mg, 0.71 mM) in 1 N KOH (3 ml) and MeOH (4 ml) was heated at 95° C. for 1 hr allowing some methanol to distil off. The reaction was cooled to room temperature and neutralized with 1 N HCl. The resulting precipitate was collected via filtration, washed with water (1×3 ml) and then dried in vacuo overnight to afford 3-Amino-1-[4-(4-dimethylamino-phenyl)-pyrimidin-2-yl]-1H-pyrazole-4-carboxylic acid (170 mg, 73% yield) as a yellow solid. ES-MS MH+325.4 1H NMR (300 MHz, ppm, DMSO-d6): 8.72 (s, 1H), 8.60 (d, 1H), 8.15 (d, 2H), 7.70 (d, 1H), 6.82 (d, 2H), 5.77 (br, 2H), 3.03 (s, 6H)
Reaction SMILES: [C:1]([CH:3]([Na])[C:4](=[O:6])[CH3:5])#[N:2].Br[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[C:11]=1[Cl:17]>CN(C=O)C.[Cl-].[NH4+]>[Cl:17][C:11]1[C:12]([Cl:16])=[CH:13][CH:14]=[CH:15][C:10]=1[CH2:9][CH:3]([C:4](=[O:6])[CH3:5])[C:1]#[N:2]
Reactant: Clc1cccc(CBr)c1Cl
Reactant: CC(=O)C([Na])C#N
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: CC(=O)C(C#N)Cc1cccc(Cl)c1Cl
Temperature: 0 °C
Reaction time: 2 h
Yield: 106.3 %

Procedure:
To a solution of (1-cyano-2-oxopropyl)sodium (1.28 g, 12.16 mmol) in DMF (80 mL) was added 1-(bromomethyl)-2,3-dichlorobenzene (2.043 g, 8.51 mmol) dropwise over a period of 30 min at 0° C. The mixture was stirred at 0° C. for 1 h and at room temperature for 2 h. Then this solution was diluted with saturated aq. ammonium chloride solution. The resulting solution was extracted with ethyl acetate (80 mL×3). The combined organic layers were washed with water and brine, dried over sodium sulphate, concentrated under reduced pressure to give the crude product (2.19 g, 100%), which was used for the next step without further purification. LC/MS: MS (ES+) m/e 242 (MH+).
Reaction SMILES: [CH2:1]([C:3]([C:17]1[CH:30]=[CH:29][C:20]([O:21][CH2:22][C:23](=[O:28])[C:24]([CH3:27])([CH3:26])[CH3:25])=[C:19]([CH3:31])[CH:18]=1)([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[NH:16][N:15]=[N:14][N:13]=2)=[CH:8][CH:7]=1)[CH2:4][CH3:5])[CH3:2].[BH4-].[Na+]>CCO>[CH2:1]([C:3]([C:17]1[CH:30]=[CH:29][C:20]([O:21][CH2:22][CH:23]([OH:28])[C:24]([CH3:25])([CH3:27])[CH3:26])=[C:19]([CH3:31])[CH:18]=1)([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[NH:16][N:15]=[N:14][N:13]=2)=[CH:8][CH:7]=1)[CH2:4][CH3:5])[CH3:2]
Reactant: CCC(CC)(c1ccc(-c2nnn[nH]2)cc1)c1ccc(OCC(=O)C(C)(C)C)c(C)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CCC(CC)(c1ccc(-c2nnn[nH]2)cc1)c1ccc(OCC(O)C(C)(C)C)c(C)c1
Reaction time: 1 h
Yield: 86.4 %

Procedure:
To a mixture of 1-(4-{1-Ethyl-1-[4-(1H-tetrazol-5-yl)-phenyl]-propyl}-2-methyl-phenoxy)-3,3-dimethyl-butan-2-one (0.37 g, 0.88 mmol) and EtOH (5 mL) was added NaBH4 (0.037 g, 0.97 mmol) and the solution stirred for 1 hour. The solids were removed by filtration and the solution concentrated. The residue was purified by ISCO (10-30 [89% EtOAc: 10% MeOH: 1% AcOH] gradient) to furnish the title compound (0.32 g, 0.76 mmol, 86%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:8]2[C:9]([C:14]([OH:16])=O)=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:5]=[CH:6][CH:7]=1.O=S(Cl)Cl.Cl[Sn](Cl)(Cl)Cl.C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH3:1][C:2]1[C:3]2[C:14](=[O:16])[C:9]3[C:8](=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:4]=2[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cccc(-c2ccccc2C(=O)O)c1
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: Cc1cccc2c1C(=O)c1ccccc1-2
Temperature: 25 °C
Yield: 14 %

Procedure:
A mixture of 1.32 g (6.2 mmol) of 3'-methyl-2-biphenylcarboxylic acid, 40 mL of CH2Cl2 and 0.70 mL (9.6 mmol) of SOCl2 was warmed to reflux for 2 h. The solution was cooled to room temperature and 1.10 mL (9.4 mmol) of SnCl4 was added dropwise with stirring. The dark brown homogenous mixture was stirred for 18 h, poured into 50 mL of cold saturated aqueous NaHCO3, and extracted with 2×50 mL of ether. The ether extracts were combined and washed with 30 mL of saturated NaHCO3 solution, 30 mL of H2 0 and 30 mL of brine, dried (MgSO4) and concentrated in vacuo. Chromatography over SiO2 (Biotage 40 S) using 1% EtOAc in hexanes provided 168 mg (16% yield) of 1-methyl-9-fluorenone (Ladd, D. L. et al., Synthesis and dopaminergic binding of 2-aryldopamine analogues: Phenethylamines, 3-benzazepines, and 9-(aminomethyl)fluorenes. J. Med. Chem. 1986, 29, 1904-1912).
Reaction SMILES: [CH3:1][C:2]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([CH:20]([N:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)[CH2:21][NH2:22])=[CH:16][CH:15]=1>>[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([CH:20]([N:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)[CH2:21][NH:22][C:4](=[O:6])[C:3]2[CH:7]=[CH:8][CH:9]=[C:10]([CH3:11])[C:2]=2[CH3:1])=[CH:16][CH:15]=1
Reactant: COc1ccc(C(CN)N2CCCCC2)cc1
Reactant: Cc1cccc(C(=O)O)c1C
Product: COc1ccc(C(CNC(=O)c2cccc(C)c2C)N2CCCCC2)cc1

Procedure:
From 2,3-dimethylbenzoic acid and 2-(4-methoxy-phenyl)-2-piperidin-1-yl-ethylamine.
Reaction SMILES: [CH2:1]([C:7]1[CH:12]=[CH:11][C:10]([C:13]2[C:14]([C:33]#[N:34])=[N:15][N:16]([C:22]([CH3:32])([CH3:31])[CH2:23][C:24]3[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][CH:25]=3)[C:17]=2[O:18]COC)=[CH:9][CH:8]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].Cl.O1CCOCC1>O1CCCC1.CO>[CH2:1]([C:7]1[CH:8]=[CH:9][C:10]([C:13]2[C:14]([C:33]#[N:34])=[N:15][N:16]([C:22]([CH3:32])([CH3:31])[CH2:23][C:24]3[CH:25]=[CH:26][C:27]([CH3:30])=[CH:28][CH:29]=3)[C:17]=2[OH:18])=[CH:11][CH:12]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCc1ccc(-c2c(C#N)nn(C(C)(C)Cc3ccc(C)cc3)c2OCOC)cc1
Agent: Cl
Solvent: C1COCCO1
Solvent: C1CCOC1
Solvent: CO
Product: CCCCCCc1ccc(-c2c(C#N)nn(C(C)(C)Cc3ccc(C)cc3)c2O)cc1
Temperature: 25 °C
Reaction time: 14 h
Yield: 36.6 %

Procedure:
266 mg of 4-(4-hexylphenyl)-5-(methoxymethoxy)-1-(2-methyl-1-(p-tolyl)propan-2-yl)-1H-pyrazole-3-carbonitrile was dissolved in 4 mL of tetrahydrofuran and 0.8 mL of methanol, mixed with 4 M hydrochloric acid in dioxane (0.70 mL, 2.8 mmol) and stirred at room temperature for 14 hours. After completion of the reaction, the solvent was partly distilled off under reduced pressure, and the crystals precipitated in the reaction mixture were separated by filtration and washed with isopropyl ether. The filtrate was combined with the isopropyl ether washing and concentrated under reduced pressure, and the resulting residue was purified by intermediate pressure silica gel column chromatography (silica gel 10 g, ethyl acetate:hexane=0:100 to 20:80) to give 88.1 mg of the desired product as a white solid.
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]2[CH2:8][CH2:9][N:10]([C:12](=[O:21])[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[S:19][CH3:20])[CH2:11][C:4]=2[CH:3]=1.O.[NH2:23][NH2:24]>>[NH:23]([C:2]1[N:7]=[N:6][C:5]2[CH2:8][CH2:9][N:10]([C:12](=[O:21])[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[S:19][CH3:20])[CH2:11][C:4]=2[CH:3]=1)[NH2:24]
Reactant: NN
Reactant: CSc1ccccc1C(=O)N1CCc2nnc(Cl)cc2C1
Solvent: O
Product: CSc1ccccc1C(=O)N1CCc2nnc(NN)cc2C1

Procedure:
23.1 g of 3-chloro-5,6,7,8-tetrahydro-6-(o-methylmercaptobenzoyl)pyrido[4,3-c]pyridazine are stirred in 100 cc of hydrazine hydrate at a bath temperature of 100° for 2 hours, and the reaction mixture is worked up as described in Example 17. The gentisinato of the title compound has a M.P. of 172°-175°.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=3)([C:13]#[N:14])[CH:11]([CH2:22][C:23]([CH3:26])([CH3:25])[CH3:24])[NH:10][CH:9]2[C:27](O)=[O:28])[CH:5]=[CH:6][CH:7]=1.[F:30][C:31]([F:41])([F:40])[C:32]1[CH:39]=[CH:38][CH:37]=[CH:36][C:33]=1[CH2:34][NH2:35].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[F:30][C:31]([F:40])([F:41])[C:32]1[CH:39]=[CH:38][CH:37]=[CH:36][C:33]=1[CH2:34][NH:35][C:27]([CH:9]1[CH:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[C:12]([C:15]2[CH:16]=[CH:17][C:18]([Cl:21])=[CH:19][CH:20]=2)([C:13]#[N:14])[CH:11]([CH2:22][C:23]([CH3:26])([CH3:24])[CH3:25])[NH:10]1)=[O:28]
Reactant: NCc1ccccc1C(F)(F)F
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2)C1(C#N)c1ccc(Cl)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)CC1NC(C(=O)NCc2ccccc2C(F)(F)F)C(c2cccc(Cl)c2)C1(C#N)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 32.3 %

Procedure:
A mixture of rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (86.2 mg, 0.20 mmol), 2-trifluoromethyl-benzyl amine (52.55 mg, 0.3 mmol), 2-(7-azabenzotriazol-1-yl)-n,n,n′,n′-tetramethyluronium hexafluorophosphate (HATU, 76 mg, 0.2 mmol) and iPr2NEt (0.1 mL, 0.55 mmol) in CH2Cl2 (2 mL) was stirred at rt overnight. The mixture was then diluted with CH2Cl2 and washed with water, brine. The organic phase was separated, filtered and dried over Na2SO4. The mixture was then concentrated and purified by reverse phase chromatography (20-95% of ACN/water) to give rac rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid 2-trifluoromethyl-benzylamide (38 mg, 32.3%) as an off-white powder. HRMS (ES+) m/z Calcd for C31H30Cl2F3N3O+H [(M+H)+]: 588.1791. found: 588.1795.
Reaction SMILES: [ClH:1].Br[C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1.[C:9]1([CH:15]=[CH:16][CH:17]([OH:20])[C:18]#[CH:19])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu](I)I>[ClH:1].[C:9]1(/[CH:15]=[CH:16]/[C:17](=[O:20])/[CH:18]=[CH:19]/[C:3]2[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: Brc1ccncc1
Reactant: C#CC(O)C=Cc1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Agent: Cl
Solvent: CCN(CC)CC
Product: O=C(/C=C/c1ccccc1)/C=C/c1ccncc1
Temperature: 120 °C

Procedure:
4-bromopyridine hydrochloride (194 mg, 1 mmol), phenylpent-1-en-4-yn-3-ol (190 mg, 1.2 mmol), bis(triphenylphosphine)palladium(II) dichloride (14 mg, 0.02 mmol), copper iodide (3 mg, 0.03 mmol) and triphenylphosphine (52 mg, 0.2 mmol) were introduced in a 10 mL microwave vial flushed with argon. This was diluted with anhydrous triethylamine (900 μL, 4 mmol) in anhydrous degased 1,4-dioxane (1.1 mL). The solution was heated under microwave irradiation at 120° C. for 45 min. The reaction mixture was diluted with chloroform (15 mL) and extracted with a 1M aqueous solution of hydrochloric acid (3×20 mL). The aqueous was next basified with an aqueous solution of sodium hydroxide (5M, 20 mL). Product was extracted with ethyl acetate (3×40 mL). The combined organic layers were dried over magnesium sulfate, filtered, and evaporated to dryness to give crude product which was purified by flash chromatography (SiO2, 70% ethyl acetate in hexanes) to give the desired product as a free base. This was dissolved in 1,4-dioxane (15 mL) and hydrogen chloride 1.25M in ethanol (2 mL) was added. The suspension was filtered to recover the hydrochloric salt of the final compound TG011A96 (115 mg, 42%) as a fine yellow powder.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][CH:12]([C:15]([OH:17])=O)[CH2:11][CH2:10]2)=[CH:5][CH:4]=1)#[N:2].[CH3:18][C@H:19]1[CH2:24][NH:23][C@H:22]([CH3:25])[CH2:21][NH:20]1>>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([N:9]2[CH2:10][CH2:11][CH:12]([C:15]([N:20]3[CH2:21][C@@H:22]([CH3:25])[NH:23][CH2:24][C@@H:19]3[CH3:18])=[O:17])[CH2:13][CH2:14]2)=[CH:7][CH:8]=1)#[N:2]
Reactant: N#Cc1ccc(N2CCC(C(=O)O)CC2)cc1
Reactant: C[C@@H]1CN[C@@H](C)CN1
Product: C[C@@H]1CN(C(=O)C2CCN(c3ccc(C#N)cc3)CC2)[C@@H](C)CN1

Procedure:
The title compound (D17) was prepared from 1-(4-cyanophenyl)-piperidine4-carboxylic acid (D3) and (2S, 5R)-2,5-dimethylpiperazine using the procedure of Description D15.