Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[N:5]2[CH:6]=[CH:7][C:8]([C:10](=O)[CH3:11])=[CH:9][C:4]2=[CH:3][CH:2]=1.Cl.S1C2C=C[N:19]=CC=2C=C1CN>>[N:1]1[N:5]2[CH:6]=[CH:7][C:8]([CH:10]([NH2:19])[CH3:11])=[CH:9][C:4]2=[CH:3][CH:2]=1
Reactant: NCc1cc2cnccc2s1
Reactant: CC(=O)c1ccn2nccc2c1
Agent: Cl
Product: CC(N)c1ccn2nccc2c1

Procedure:
Intermediate 3 was prepared from 1-(pyrazolo[1,5-a]pyridin-5-yl)ethanone (3-3) following the procedures similar to the procedures of intermediate D′ from D′-3. MS (m/z): 162 (M+1)+.
Reaction SMILES: [Na].[Cl:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](Cl)=[N:5][N:4]=1.[CH3:14][OH:15]>>[CH3:14][O:15][C:6]1[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]([Cl:2])=[N:4][N:5]=1
Reactant: Clc1nnc(Cl)c2ccccc12
Reactant: CO
Agent: [Na]
Product: COc1nnc(Cl)c2ccccc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
0.23 g(0.01 mol) of metallic sodium was dissolved in 50 ml of absolute methanol and then 1.99 g(0.01 mol) of 1,4-dichlorophthalazine was added thereto and completely dissolved. The reaction solution was stirred for one hour at room temperature and then treated according to the same manner as Preparation 5 to obtain the title compound as an amorphous white crystal.
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:39][CH2:38][N:37]([CH2:40][C:41](O)=[O:42])[CH2:36][CH2:35]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:44][CH2:45][CH3:46])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:47]([O:49][CH2:50][CH2:51][NH:52][CH2:53][CH2:54][O:55][CH2:56][CH3:57])[CH3:48]>>[C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:39][CH2:38][N:37]([CH2:40][C:41]([N:52]([CH2:53][CH2:54][O:55][CH2:56][CH3:57])[CH2:51][CH2:50][O:49][CH2:47][CH3:48])=[O:42])[CH2:36][CH2:35]3)=[O:33])[C@@:13]([C:25]3[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=3)([CH3:24])[C@@:14]([C:17]3[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=3)([CH3:16])[N:15]=2)=[C:7]([O:44][CH2:45][CH3:46])[CH:6]=1)([CH3:2])([CH3:4])[CH3:3]
Reactant: CCOCCNCCOCC
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(CC(=O)O)CC1
Product: CCOCCN(CCOCC)C(=O)CN1CCN(C(=O)N2C(c3cnc(C(C)(C)C)cc3OCC)=N[C@@](C)(c3ccc(Cl)cc3)[C@@]2(C)c2ccc(Cl)cc2)CC1

Procedure:
In a manner analogous to the method described in example 99, {4-[(4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl]-piperazin-1-yl}-acetic acid was coupled with bis-(2-ethoxy-ethyl)-amine (TCI-US) to give the title compound. HR-MS (ES, m/z) calculated for C43H59Cl2N6O5 [(M+H)+] 809.3919, observed 809.3118.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][N:8]=[C:9]2Cl)=[CH:4][CH:3]=1.BrC1C=C2C(=CC=1)C([O:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=NC=C2>>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][N:8]=[C:9]2[O:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:4][CH:3]=1
Reactant: Clc1nccc2ccc(Br)cc12
Reactant: Brc1ccc2c(Oc3ccccc3)nccc2c1
Product: Brc1ccc2ccnc(Oc3ccccc3)c2c1

Procedure:
Compound 37c was prepared from 37b using the procedure described for 1c. 1H-NMR 200 MHz (CDCl3) δ: 6.76-6.97 (2H, m), 7.18-8.09 (7H, m), 8.60-8.64 (1H, m).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:15](Br)[C:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:17].O>CC(C)=O>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:15][C:16](=[O:17])[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:4][CH:3]=1
Reactant: Cc1ccc(O)cc1
Reactant: O=C(CBr)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: Cc1ccc(OCC(=O)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
4-Methylphenol (5.4g; 0.05 m) and potassium carbonate (6.9g; excess) were mixed in dry acetone (40 ml.) phenacyl bromide (9.95 g.; 0.05 m) was added and the mixture was boiled under reflux with vigorous stirring for 4 hours. The mixture was cooled to room temperature, poured into iced water extracted with ether, washed with dilute sodium hydroxide solution water, dried and evaporated. The crude product was recrystallised from ethanol to give the title compound, m.p. 65° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH3:8])=[C:6]([C:9]([OH:11])=[O:10])[CH:5]=[CH:4][N:3]=1.[C:12](=O)([O-])[O-].[K+].[K+].CI>CN(C=O)C>[Cl:1][C:2]1[C:7]([CH3:8])=[C:6]([C:9]([O:11][CH3:12])=[O:10])[CH:5]=[CH:4][N:3]=1
Reactant: Cc1c(C(=O)O)ccnc1Cl
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)c1ccnc(Cl)c1C
Temperature: 25 °C
Reaction time: 18.5 h
Yield: 70.8 %

Procedure:
To a stirred solution of 2-chloro-3-methylpyridine-4-carboxylic acid (780 mg, 4.5 mmol) in anhydrous DMF (5.0 ml), was added potassium carbonate (1.25 g, 9.1 mmol), followed by methyl iodide (0.42 ml, 6.8 mmol) dropwise. A further 4 ml of DMF was added and the reaction mixture was stirred at room temperature under nitrogen for 18.5 hours. The solvent was removed in-vacuo and the residue was then partitioned between CH2Cl2 (20 ml) and water (20 ml). The layers were separated and the aqueous layer was extracted with CH2Cl2 (3×15 ml). The combined organic layers were washed with water (2×30 ml), brine (40 ml), dried (MgSO4), filtered and concentrated in-vacuo. The residue was purified by column chromatography (10 g SNAP cartridge, Isolera, 0-6% ethyl acetate:heptanes) to give the title compound (591 mg, 59%) as a colourless oil. LC-MS 84%, m/z=185.9, 187.9; 1H NMR (500 MHz, Chloroform-d) δ ppm 8.33 (d, J=5.04 Hz, 1H) 7.54 (d, J=5.04 Hz, 1H) 3.95 (s, 3H) 2.60 (s, 3H).
Reaction SMILES: CS(O[CH2:6][CH2:7][C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([C:23]#[N:24])[CH:18]=3)=[CH:13][C:11]=2[CH:12]=1)(=O)=O.[CH3:25][C@@H:26]1[CH2:30][CH2:29][CH2:28][NH:27]1.C([O-])([O-])=O.[Cs+].[Cs+].CC#N>C(Cl)Cl>[CH3:25][C@@H:26]1[CH2:30][CH2:29][CH2:28][N:27]1[CH2:6][CH2:7][C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]3[CH:18]=[C:19]([CH:20]=[CH:21][CH:22]=3)[C:23]#[N:24])=[CH:13][C:11]=2[CH:12]=1
Reactant: CS(=O)(=O)OCCc1cc2cc(-c3cccc(C#N)c3)ccc2o1
Reactant: C[C@@H]1CCCN1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: ClCCl
Product: C[C@@H]1CCCN1CCc1cc2cc(-c3cccc(C#N)c3)ccc2o1
Temperature: 40 °C
Reaction time: 96 h
Yield: 28 %

Procedure:
The crude product from Example 112D, the mono-(L)-tartaric acid salt of (2R)-2-methylpyrrolidine (306 mg, 1.3 mmol), and Cs2CO3 (652 mg, 2.0 mmol) were stirred in an approximately 0.2 M MeCN solution of (2R)-2-methylpyrrolidine (1.6 mL, 0.3 mmol). The mixture was heated at 40° C. overnight. More Cs2CO3 (326 mg, 1.0 mmol) and acetonitrile (0.5 mL) were added and the reaction was stirred at 40° C. for four days. The mixture was cooled to room temperature, diluted with CH2Cl2, filtered, and concentrated. The residue was chromatographed twice through a short column of silica with a 0 to 5% gradient of MeOH/CH2Cl2 to provide the title compound as an orange-tan gum (28% yield). 1HNMR (300 MHz, CD3OD) δ 1.18 (d, 3H), 1.39-1.54 (m, 1H), 1.75-1.87 (m, 2H), 1.96-2.09 (m, 1H), 2.27-2.39 (m, 1H), 2.46-2.63 (m, 2H), 2.95-3.15 (m, 2H), 3.20-3.35 (m, 2H), 6.63 (s, 1H), 7.49-7.52 (m, 2H), 7.62 (dd, 1H), 7.67 (ddd, 1H), 7.78 (dd, 1H), 7.90 (ddd, 1H), 7.98 (dd, 1H).
Reaction SMILES: C[O:2][C:3](=O)[CH:4]=[CH:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[N:12]=[CH:11][N:10]=[C:9]2[O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.CC(C[AlH]CC(C)C)C>C1(C)C=CC=CC=1>[O:16]([C:9]1[C:8]2[C:13](=[CH:14][CH:15]=[C:6]([CH:5]=[CH:4][CH2:3][OH:2])[CH:7]=2)[N:12]=[CH:11][N:10]=1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: COC(=O)C=Cc1ccc2ncnc(Oc3ccccc3)c2c1
Agent: CC(C)C[AlH]CC(C)C
Solvent: Cc1ccccc1
Product: OCC=Cc1ccc2ncnc(Oc3ccccc3)c2c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 73.3 %

Procedure:
To a solution of ester 24 (1.35 g, 4.41 mmol) in toluene (60 mL) under N2 at −78° C. was added DIBAL-H (8.8 mL of a 1M solution in toluene, 8.8 mmol) dropwise. The reaction was then warmed to 0° C. and stirred for 30 minutes, then quenched with 30 mL of saturated Rochelle's salt and the mixture stirred overnight. The bilayer was transferred to a separatory funnel and the organic layer washed with H2O and brine and dried (MgSO4). After filtration the organic layer was concentrated under reduced pressure to provide a yellow oil which was purified by silica gel chromatography eluting with 1:1 hexanes:EtOAc, then EtOAc. The allylic alcohol 25 (900 mg, 73%) was isolated as a pale yellow oil. 1H NMR (CDCl3; 400 MHz): δ: 8.72 (s, 1 H), 8.27 (s, 1H), 7.66 (m, 2H), 7.62 (m, 1H), 7.47 (m, 3H), 7.34 (m, 1H), 7.24 (m, 2H), 6.82 (dd, 1h), 6.56 (m, 1H), 4.41 (dd, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]12[CH2:16][CH2:15][C:12]([C:17]([OH:19])=O)([CH2:13][CH2:14]1)[CH2:11][CH2:10]2)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:20][C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=1[C:28]([F:31])([F:30])[F:29]>>[C:1]([O:5][C:6]([NH:8][C:9]12[CH2:10][CH2:11][C:12]([C:17]([NH:20][C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=3[C:28]([F:31])([F:29])[F:30])=[O:19])([CH2:15][CH2:16]1)[CH2:13][CH2:14]2)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: Nc1ccc(Cl)cc1C(F)(F)F
Reactant: CC(C)(C)OC(=O)NC12CCC(C(=O)O)(CC1)CC2
Product: CC(C)(C)OC(=O)NC12CCC(C(=O)Nc3ccc(Cl)cc3C(F)(F)F)(CC1)CC2

Procedure:
In a similar manner to Example 133, 4-tert-butoxycarbonylaminobicyclo[2.2.2]octane-1-carboxylic acid (150 mg) and 2-amino-5-chlorobenzotrifluoride (173 μL) were used to obtain 4-tert-butoxycarbonylamino-N-(4-chloro-2-trifluoromethylphenyl)bicyclo[2.2.2]octane-1-carboxamide (79.7 mg).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][N:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]([OH:13])=O.O.ON1C2C=CC=CC=2N=N1.[CH2:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH2:28][CH2:27][NH:26]1>CN(C=O)C>[CH2:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH2:28][CH2:27][N:26]1[C:11]([C:2]1[CH:3]=[CH:4][C:5]2[C:10](=[CH:9][CH:8]=[N:7][CH:6]=2)[N:1]=1)=[O:13]
Reactant: c1ccc2c(c1)CCNC2
Reactant: O=C(O)c1ccc2cnccc2n1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: O=C(c1ccc2cnccc2n1)N1CCc2ccccc2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.3 %

Procedure:
To a stirring mixture of 2-[1,6]naphthyridinecarboxylic acid (50 mg, 0.287 mmol) in anhydrous DMF (1.0 mL) at room temperature was added sequentially 1-hydroxybenzotriazole hydrate (42.7 mg, 0.316 mmol), 1,2,3,4-tetrahydroisoquinoline (55.6 μL, 0.431 mmol) and 1-(3dimethylaminopropyl)-3-ethylcarboiimide hydrochloride (61.8 mg, 0.316 mmol). The resulting mixture was allowed to stir at room temperature overnight and it was found to be clear. The solvent was removed under vacuum. Flash column chromatography of the residue (100% ethyl acetate) afforded the desired product as a white solid (79.1 mg, 95%): m.p. 98-100° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH:14]([OH:28])[CH2:15][O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=2)=[CH:4][CH:3]=1.[CH2:29]([O:31][C:32](=[O:52])[CH2:33][C:34]1([C:37]2[CH:42]=[CH:41][C:40](B3OC(C)(C)C(C)(C)O3)=[CH:39][CH:38]=2)[CH2:36][CH2:35]1)[CH3:30]>>[CH2:29]([O:31][C:32](=[O:52])[CH2:33][C:34]1([C:37]2[CH:42]=[CH:41][C:40]([C:2]3[CH:7]=[CH:6][C:5]([C:8]4[O:12][N:11]=[C:10]([CH3:13])[C:9]=4[CH:14]([OH:28])[CH2:15][O:16][CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=4)=[CH:4][CH:3]=3)=[CH:39][CH:38]=2)[CH2:36][CH2:35]1)[CH3:30]
Reactant: CCOC(=O)CC1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1C(O)COCc1cccc(C(F)(F)F)c1
Product: CCOC(=O)CC1(c2ccc(-c3ccc(-c4onc(C)c4C(O)COCc4cccc(C(F)(F)F)c4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 1, Step 7, using 1-[5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-2-(3-trifluoromethyl-benzyloxy)-ethanol and {1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropyl}-acetic acid ethyl ester.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=2)=[CH:5][CH:4]=1.[C:20](Cl)(=[O:22])[CH3:21]>C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([N:9]([CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=2)[C:20](=[O:22])[CH3:21])=[CH:7][CH:8]=1
Reactant: COc1ccc(NCCc2cccc(OC)c2)cc1
Reactant: CC(=O)Cl
Solvent: CCOC(C)=O
Product: COc1ccc(N(CCc2cccc(OC)c2)C(C)=O)cc1
Temperature: 0 °C
Reaction time: 18 h
Yield: 51.8 %

Procedure:
(4-Methoxy-phenyl)-[2-(3-methoxy-phenyl)-ethyl]-amine (3.87 mmol) and acetyl chloride (4.26 mmol) were reacted ethyl acetate (50 mL). After 18 hours, the reaction was poured into ice (150 mL) and the organic extract was dried over sodium sulfate, filtered through celite and concentrated. The title compound (0.60 g) was obtained after silica gel chromatography (eluant: gradient from 10% to 40% ethyl acetate-hexane); MS: 300.4 (MH+); HPLC tR: 2.65 min; TLC Rf: 0.19 (ethyl acetate-hexane 2:3).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]#[N:11])=[CH:5][CH:4]=1.C([Li])CCC.CCCCCC.[C:23]1(=[O:29])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1.[Cl-].[NH4+]>O1CCCC1>[C:10]([CH:9]([C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)[C:23]1([OH:29])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1)#[N:11]
Reactant: O=C1CCCCC1
Reactant: COc1ccc(CC#N)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COc1ccc(C(C#N)C2(O)CCCCC2)cc1
Temperature: -70 °C
Reaction time: 0.75 h

Procedure:
p-Methoxyphenylacetonitrile (50 gm, 0.3 mole) was added to dry tetrahydrofuran (250 ml) and the solution cooled to -70° C. under nitrogen. n-Butyl lithium in hexane (210 ml, 0.3 mole) was added dropwise, with stirring. The temperature was maintained below -50° C. and a yellow precipitate appeared. After the addition was complete, the reaction mixture was maintained below -50° C. for 30 minutes and cyclohexanone (35 ml, 0.3 mole) was added. After a further 45 minutes below -50° C. the temperature was allowed to rise to 0° C. and a saturated ammonium chloride solution was added. The layers were separated and the aqueous layer extracted with diethyl ether. The combined organic solution was washed with brine, dried over magnesium sulphate and evaporated. The product crystallized (25.2 gm, m.p. 125°-127° C.).
Reaction SMILES: Cl.Cl.[NH:3]1[CH2:8][CH2:7][NH:6][CH2:5][CH:4]1[C:9]([OH:11])=[O:10].[OH-].[Na+].[CH3:14][C:15]([O:18][C:19](ON=C(C1C=CC=CC=1)C#N)=[O:20])([CH3:17])[CH3:16]>O.O1CCOCC1.O1CCOCC1>[C:15]([O:18][C:19]([N:6]1[CH2:7][CH2:8][NH:3][CH:4]([C:9]([OH:11])=[O:10])[CH2:5]1)=[O:20])([CH3:17])([CH3:16])[CH3:14]
Reactant: CC(C)(C)OC(=O)ON=C(C#N)c1ccccc1
Reactant: O=C(O)C1CNCCN1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCNC(C(=O)O)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-piperazine-carboxylic acid dihydrochloride (1.0 g, 4.92 mmol) in 20 mL of water/dioxane 1:1, NaOH 6N was added to adjust the pH to 11. A solution of BOC-ON® (1.34 g, 5.41 mmol) in dioxane (5 mL) was then added dropwise, while maintaining the pH=11 during the addition and the resulting solution was stirred overnight at room temperature. Another 0.134 g of BOC-ON® were added and the reaction mixture was stirred for 2 h. The solvent was evaporated under reduced pressure and the residue was diluted with diethyl ether/water (60 mL). The phases were separated and the pH of the aqueous layer was adjusted to 7 by slow addition of HCl 1N. Evaporation of water under reduced pressure afforded the title compound as a white solid which was dried in a vacuum oven at 50° C. and used without further purification for the next step.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Cl[C:8]1[CH:9]=[CH:10][C:11]([N+:15]([O-:17])=[O:16])=[C:12]([CH:14]=1)[NH2:13]>CN(C=O)C>[N:1]1([C:8]2[CH:9]=[CH:10][C:11]([N+:15]([O-:17])=[O:16])=[C:12]([NH2:13])[CH:14]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: Nc1cc(Cl)ccc1[N+](=O)[O-]
Reactant: C1COCCN1
Solvent: CN(C)C=O
Product: Nc1cc(N2CCOCC2)ccc1[N+](=O)[O-]
Temperature: 120 °C
Reaction time: 8 h

Procedure:
To a solution of morpholine (0.88 mL) and 5-chloro-2-nitroaniline (1.76 g) in DMF (50 mL) was added TEA (2.78 mL). The mixture was stirred at 120° C. overnight, cooled down and the solvent was removed in vacuo. The residue was purified by CC (Biotage, SNAP 50 g cartridge, solvent A: Hept; solvent B: EA; gradient in % B: 10 for 3CV, 10 to 30 over 6CV, 30 for 2CV, 30 to 50 over 4CV, 50 for 6CV) to afford 380 mg of yellow powder. LC-MS (B): tR=0.69 min; [M+H]+: 224.15.
Reaction SMILES: [CH2:1]([C:5]1[N:10]2[N:11]=[CH:12][CH:13]=[C:9]2[N:8]([CH:14]2[CH2:23][CH2:22][C:17]3(OCC[O:18]3)[CH2:16][CH2:15]2)[C:7](=[O:24])[C:6]=1[CH2:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]2[C:33]([C:38]#[N:39])=[CH:34][CH:35]=[CH:36][CH:37]=2)=[CH:28][CH:27]=1)[CH2:2][CH2:3][CH3:4].Cl.[OH-].[Na+]>O1CCCC1.C(OCC)(=O)C>[CH2:1]([C:5]1[N:10]2[N:11]=[CH:12][CH:13]=[C:9]2[N:8]([C@H:14]2[CH2:23][CH2:22][C@H:17]([OH:18])[CH2:16][CH2:15]2)[C:7](=[O:24])[C:6]=1[CH2:25][C:26]1[CH:27]=[CH:28][C:29]([C:32]2[C:33]([C:38]#[N:39])=[CH:34][CH:35]=[CH:36][CH:37]=2)=[CH:30][CH:31]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(C2CCC3(CC2)OCCO3)c2ccnn12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](O)CC2)c2ccnn12
Temperature: 70 °C
Reaction time: 2 h

Procedure:
To a solution of 4′-{[7-butyl-4-(1,4-dioxaspiro[4.5]dec-8-yl)-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile (3.6 g) in tetrahydrofuran (40 mL) was added 3M hydrochloric acid (40 mL), and the mixture was stirred at 70° C. for 2 hr. The mixture was allowed to cool, and diluted with ethyl acetate, and the mixture was neutralized with 8M aqueous sodium hydroxide solution. The mixture was extracted with ethyl acetate, and the organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The residue was dissolved in ethanol (20 mL)-tetrahydrofuran (20 mL). Thereto was added sodium borohydride (0.26 g) at 0° C. After stirring for 1 hr, ethyl acetate and saturated aqueous ammonium chloride solution were added. The mixture was extracted with ethyl acetate, and the organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography to give the title compound as a pale-yellow amorphous solid (2.9 g, 87%).
Reaction SMILES: [C:1]1([P:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)(=[O:9])[OH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.[OH-].[Li+:18].O>CC(O)C>[C:1]1([P:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)(=[O:8])[O-:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1.[Li+:18]
Reactant: O=P(O)(c1ccccc1)c1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: O
Product: O=P([O-])(c1ccccc1)c1ccccc1

Procedure:
To a flask were added 1.0 g diphenylphosphinic acid, 182 mg lithium hydroxide monohydrate, 10 ml of water and 30 ml 2-propanol. The mixture was heated to 70 C under nitrogen until a clear solution was obtained. The mixture was cooled and the solvent was removed under reduced pressure and the product was slurried in a small amount of 2-propanol, filtered and washed with 2-propanol. After drying, a white solid was obtained.
Reaction SMILES: Cl[C:2]1[C:7]([CH3:8])=[CH:6][C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1.[CH3:12][NH2:13]>CCO>[CH3:12][NH:13][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1
Reactant: Cc1cc([N+](=O)[O-])cnc1Cl
Reactant: CN
Solvent: CCO
Product: CNc1ncc([N+](=O)[O-])cc1C
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
2-Chloro-3-methyl-5-nitropyridine (5.00 g, 29.0 mmol) was added portion wise to a cooled (0° C.) 35% solution of methylamine in EtOH (20 mL) and the reaction was allowed to warm to rt. After approximately 5 min an exotherm and gas evolution was observed and the reaction mixture solidified. EtOH (10 mL) was added and the reaction mixture was stirred at rt for 20 min, then diluted with ice/water (30 mL) and cooled to 0° C. The mixture was stirred vigorously for 15 min and then allowed to stand for 17 h. A solid was isolated by filtration, washed with H2O and dried in vacuo to yield N,3-dimethyl-5-nitropyridin-2-amine (4.44 g) which was used without further purification. A mixture of N,3-dimethyl-5-nitropyridin-2-amine (4.44 g, 26.6 mmol), Boc2O (11.6 g, 53.1 mmol) and 4-(dimethylamino)pyridine (649 mg, 5.31 mmol) in MeCN (230 mL) was stirred at 75° C. for 21 h. Further Boc2O (2.32 g, 10.6 mmol) was added and heating at 75° C. was continued for 24 h, before cooling to rt. Imidazole (5.06 g, 74.4 mmol) was added and the mixture concentrated in vacuo. Purification by gradient flash chromatography eluting with 5-20% EtOAc in heptane yielded the title compound (6.20 g, 23.2 mmol) as a yellow oil which solidified upon standing.
Reaction SMILES: CS[C:3]1[N:4]=[C:5]([CH2:12][C:13]2[CH:17]=[CH:16][S:15][CH:14]=2)[NH:6][C:7](=[O:11])[C:8]=1[C:9]#[N:10].[CH3:18][C:19]1([CH3:25])[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1>>[CH3:18][C:19]1([CH3:25])[CH2:24][CH2:23][N:22]([C:3]2[N:4]=[C:5]([CH2:12][C:13]3[CH:17]=[CH:16][S:15][CH:14]=3)[NH:6][C:7](=[O:11])[C:8]=2[C:9]#[N:10])[CH2:21][CH2:20]1
Reactant: CSc1nc(Cc2ccsc2)[nH]c(=O)c1C#N
Reactant: CC1(C)CCNCC1
Product: CC1(C)CCN(c2nc(Cc3ccsc3)[nH]c(=O)c2C#N)CC1

Procedure:
In analogy to the preparation of Example 1, 100 mg (0.38 mmol) of 4-(methylsulphanyl)-6-oxo-2-(3-thienylmethyl)-1,6-dihydropyrimidine-5-carbonitrile are reacted with 430 mg (3.80 mmol) of 4,4-dimethylpiperidine to give 42 mg (34% of theory) of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:47])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][C:6]=1[C:15]#[C:16][C:17]1[C:22]([C:23]([F:26])([F:25])[F:24])=[CH:21][N:20]=[C:19]([NH:27][C:28]2[CH:33]=[CH:32][C:31]([CH:34]3[CH2:39][CH2:38][N:37]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:36][CH2:35]3)=[CH:30][CH:29]=2)[N:18]=1>CN(C=O)C.CCN(CC)CC.[Pd]>[CH3:1][O:2][C:3](=[O:47])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]([F:12])([F:13])[F:14])=[CH:7][C:6]=1[CH2:15][CH2:16][C:17]1[C:22]([C:23]([F:25])([F:26])[F:24])=[CH:21][N:20]=[C:19]([NH:27][C:28]2[CH:29]=[CH:30][C:31]([CH:34]3[CH2:39][CH2:38][N:37]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:36][CH2:35]3)=[CH:32][CH:33]=2)[N:18]=1
Reactant: COC(=O)Cc1ccc(C(F)(F)F)cc1C#Cc1nc(Nc2ccc(C3CCN(C(=O)OC(C)(C)C)CC3)cc2)ncc1C(F)(F)F
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)Cc1ccc(C(F)(F)F)cc1CCc1nc(Nc2ccc(C3CCN(C(=O)OC(C)(C)C)CC3)cc2)ncc1C(F)(F)F
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A suspension of 10% Pd/C (0.050 g) and tert-butyl 4-(4-((4-((2-(2-methoxy-2-oxoethyl)-5-(trifluoromethyl)phenyl)ethynyl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)piperidine-1-carboxylate (A60) (0.200 g, 0.302 mmol) in DMF (10 mL) and Et3N (1 mL) was stirred at room temperature for 16 hours under an atmosphere of hydrogen. The resulting mixture was filtered through Celite, washing with MeOH. The volatiles were removed under reduced pressure then the residue was adsorbed onto silica gel and purified by column chromatography (Biotage Isolera, SiO2 cartridge, 0-100% EtOAc in petroleum benzine 40-60° C.; repeated twice) to give the title compound A61 (170 mg, 84%); 1H NMR (400 MHz, CDCl3) δ 8.54 (s, 1H), 7.55 (d, J=8.6 Hz, 2H), 7.49 (s, 1H), 7.47-7.45 (m, 1H), 7.41 (s, 1H), 7.37 (d, J=8.0 Hz, 1H), 7.20 (d, J=8.5 Hz, 2H), 4.37-4.17 (m, 2H), 3.79 (s, 2H), 3.69 (s, 3H), 3.24-3.14 (m, 2H), 3.21-3.06 (m, 2H), 2.92-2.72 (m, 2H), 2.71-2.52 (m, 1H), 1.90-1.74 (m, 2H), 1.68-1.60 (m, 2H), 1.48 (s, 9H). LCMS-A: rt 7.149 min; m/z 667 [M+H]+.