Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][C:3]=1[CH:4]=O.[CH2:14]([NH2:16])[CH3:15].C([BH3-])#N.[Na+].C(O)(=O)C>CO>[Br:1][C:2]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][C:3]=1[CH2:4][NH:16][CH2:14][CH3:15]
Reactant: O=Cc1cc(C(F)(F)F)ccc1Br
Reactant: CCN
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CCNCc1cc(C(F)(F)F)ccc1Br
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-Bromo-5-(trifluoromethyl)benzaldehyde (20 g, 79.1 mmol), ethylamine (2M in MeOH; 59.3 mL, 118.6 mmol), and sodium cyanoborohydride (7.45 g, 118.6 mmol) were combined in MeOH (200 mL). Acetic acid (6.79 mL, 118.6 mmol) was added, and the reaction was stirred at room temperature overnight. The mixture was concentrated and partitioned between CH2Cl2 and H2O. The aqueous layer was separated and extracted twice with CH2Cl2, and the combined organic layers were dried over Na2SO4 and concentrated to give (2-bromo-5-trifluoromethyl-benzyl)-ethyl-amine.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([F:12])[CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.[CH:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][C:14]=1[CH2:23][CH2:24][NH2:25].[OH-].[NH4+]>O>[F:12][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:6]=1[N:5]=[CH:4][CH:3]=[C:2]2[NH:25][CH2:24][CH2:23][C:14]1[CH:15]=[CH:16][C:17]2[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:13]=1
Reactant: Fc1cccc2c(Cl)ccnc12
Reactant: NCCc1ccc2ccccc2c1
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Product: Fc1cccc2c(NCCc3ccc4ccccc4c3)ccnc12
Yield: 40.2 %

Procedure:
A mixture of 2.0 g of 4-chloro-8-fluoroquinoline and 3.8 g of 2-(2-naphthyl)ethyl amine was heated under nitrogen to 160°-165° C. for one hour. Then 200 mL of a 50:50 mixture of ammonium hydroxide in water was added. The product was extracted from the mixture into CH2Cl2, which was then concentrated to dryness. The residue was recrystallized from pentane/ethyl acetate to give 1.4 g of the title product. Yield 41.2%. M.P. 173°-174° C.
Reaction SMILES: [CH3:1][C:2]1[C:3]2[S:10][C:9]([C:11]3[N:15]4[N:16]=[C:17]([NH:20][C@H:21]5[CH2:26][CH2:25][C@H:24]([OH:27])[CH2:23][CH2:22]5)[CH:18]=[CH:19][C:14]4=[N:13][CH:12]=3)=[CH:8][C:4]=2[CH:5]=[N:6][CH:7]=1.[H-].[Na+].[CH3:30]I>CN(C=O)C>[CH3:30][N:20]([C@H:21]1[CH2:26][CH2:25][C@H:24]([OH:27])[CH2:23][CH2:22]1)[C:17]1[CH:18]=[CH:19][C:14]2[N:15]([C:11]([C:9]3[S:10][C:3]4[C:2]([CH3:1])=[CH:7][N:6]=[CH:5][C:4]=4[CH:8]=3)=[CH:12][N:13]=2)[N:16]=1
Reactant: CI
Reactant: Cc1cncc2cc(-c3cnc4ccc(N[C@H]5CC[C@H](O)CC5)nn34)sc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cncc2cc(-c3cnc4ccc(N(C)[C@H]5CC[C@H](O)CC5)nn34)sc12
Reaction time: 2 h

Procedure:
To a solution of trans-4-(3-(7-methylthieno[3,2-c]pyridin-2-yl)imidazo[1,2-b]pyridazin-6-ylamino)cyclohexanol (37 mg, 0.0975 mmol, 1.0 equiv) in DMF (2.00 mL) was added sodium hydride (20 mg, 0.488 mmol, 5.0 equiv) and methyl iodide (68 mg, 0.488 mmol, 5.0 equiv). After 2 h, the reaction mixture was quenched with water and extracted with ethyl acetate. Purification by column chromatography gave 20 mg (50%) of N-((1r,4r)-4-methoxycyclohexyl)-N-methyl-3-(7-methylthieno[3,2-c]pyridin-2-yl)imidazo[1,2-b]pyridazin-6-amine as the less polar product and 10 mg (25%) of trans-4-(N-methyl-N-(3-(7-methylthieno[3,2-c]pyridin-2-yl)imidazo[1,2-b]pyridazin-6-yl)amino)cyclohexanol as the more polar product.
Reaction SMILES: [C:1]([N:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[C:18]([C:20]3[C:31](=[O:32])[N:30]([CH3:33])[C:23]4[N:24]=[C:25](NC)[N:26]=[CH:27][C:22]=4[CH:21]=3)[C:17]([CH3:34])=[CH:16][C:15]=2[F:35])=[O:12])[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[NH2:36][C@H:37]([CH3:40])[CH2:38][OH:39]>C1COCC1>[C:1]([N:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[C:18]([C:20]3[C:31](=[O:32])[N:30]([CH3:33])[C:23]4[N:24]=[C:25]([NH:36][C@H:37]([CH3:40])[CH2:38][OH:39])[N:26]=[CH:27][C:22]=4[CH:21]=3)[C:17]([CH3:34])=[CH:16][C:15]=2[F:35])=[O:12])[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: C[C@@H](N)CO
Reactant: CNc1ncc2cc(-c3cc(NC(=O)Nc4cnn(C(C)(C)C)c4)c(F)cc3C)c(=O)n(C)c2n1
Solvent: C1CCOC1
Product: Cc1cc(F)c(NC(=O)Nc2cnn(C(C)(C)C)c2)cc1-c1cc2cnc(N[C@H](C)CO)nc2n(C)c1=O
Yield: 61.9 %

Procedure:
Using general method E, 1-(1-tert-butyl-1H-pyrazol-4-yl)-3-(2-fluoro-4-methyl-5-(8-methyl-2-(methylsulfinyl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl)urea from Example 109 (0.085 g, 0.17 mmol) and (R)-2-aminopropan-1-ol (0.037 g, 0.50 mmol) were combined in THF (1 mL) to provide (R)-1-(1-tert-butyl-1H-pyrazol-4-yl)-3-(2-fluoro-5-(2-(1-hydroxypropan-2-ylamino)-8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)-4-methylphenyl)urea as a white solid (0.055 g, 63% yield). 1H NMR (400 MHz, DMSO-d6): δ 8.64 (s, 1H), 8.60 (s, 1H), 8.40 (d, J=2.0 Hz, 1H), 7.94 (d, J=8.8 Hz, 1H), 7.77 (s, 1H), 7.64 (s, 1H), 7.59 (d, J=8.0 Hz, 1H) 7.36 (s, 1H), 7.10 (d, J=12.4 Hz, 1H), 4.72 (t, J=5.6 Hz, 1H), 4.10-4.06 (m, 1H), 3.56-3.53 (m, 3H), 2.05 (s, 3H), 1.45 (s, 9H), 1.17 (d, J=6.4 Hz, 3H); (ESI) m/z: 523.2 (M+H+).
Reaction SMILES: [C:1](Cl)(=[O:4])[CH:2]=[CH2:3].Cl.[CH2:7]([O:14][NH2:15])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C(N(CC)C(C)C)(C)C>ClCCl>[CH2:7]([O:14][NH:15][C:1](=[O:4])[CH:2]=[CH2:3])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: C=CC(=O)Cl
Reactant: NOCc1ccccc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C=CC(=O)NOCc1ccccc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 48.4 %

Procedure:
A solution of acryloyl chloride (3 mL; 3.342 g; 36.9 mmole) dissolved in dry dichloromethane (25 mL) was cooled at 0° C. with an ice bath. A mixture of O-benzyl hydroxylamine hydrochloride (6.4902 g; 40.66 mmole) and N,N-diisopropylethylamine (15.6 mL; 11.575 g; 89.56 mmole) in dry dichloromethane (110 mL) was slowly added over a period of 1 hour to the cooled solution. Next, the ice bath was removed, and the reaction mixture was left stirring overnight while its temperature warmed up gradually to room temperature. Water (250 mL) was added to the reaction and the layers were separated. The organic solution was washed with diluted hydrochloric acid (0.2N; 3×300 mL), a saturated sodium bicarbonate solution (1×200 mL), water (3×250 mL), and finally brine (1×250 mL). The organic layer was then dried over magnesium sulfate, filtered, and the solvent removed under reduced pressure. The residue was purified by flash chromatography using a mixture of hexane and ethyl acetate (70:30) to elute the product. The purification gave 3.165 g (48.4%) of N-benzyloxyacrylamide (30) as a viscous colorless oil.
Reaction SMILES: Cl.[CH3:2][CH:3]1[CH2:8][CH2:7][CH2:6][NH:5][CH:4]1[C:9]([OH:11])=[O:10].Cl[C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14].C1(C)C=CC=CC=1>[OH-].[Na+].C1COCC1>[CH2:16]([O:15][C:13]([N:5]1[CH2:6][CH2:7][CH2:8][CH:3]([CH3:2])[CH:4]1[C:9]([OH:11])=[O:10])=[O:14])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CC1CCCNC1C(=O)O
Reactant: O=C(Cl)OCc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CC1CCCN(C(=O)OCc2ccccc2)C1C(=O)O
Temperature: 0 °C
Reaction time: 8 h

Procedure:
3-Methylpiperidine-2-carboxylic acid hydrochloride (28.5 g, 31.6 mmol) was dissolved in (1:1) 2 M NaOH/THF (600 mL) and cooled to 0° C. Benzyl chloroformate (31.57 ml, 222 mmol) was then added dropwise and the reaction was stirred overnight. Toluene was then added and organic layer discarded to remove unreacted chloroformate. The aqueous layer was made acidic (pH=2) with conc. HCl and the product was extracted with EtOAc, dried (MgSO4), and concentrated in vacuo to give a crude residue which was used without further purification (41.6 g, 94.5%). 1H NMR (CDCl3, 400 MHz) δ 7.40-7.37 (m, 5H), 5.19 (m, 2H), 4.95-4.72 (m, 1H), 4.14-4.03 (m, 1H), 3.36-3.25 (m, 1H), 1.93-1.53 (m, 5H), 1.20-1.05 (m, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[O:10])[NH:8][CH2:7][CH:6]([CH2:11][C:12](OCC)=[O:13])[N:5]2[CH:17]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[O:10])[NH:8][CH2:7][CH:6]([CH2:11][CH2:12][OH:13])[N:5]2[CH:17]=1
Reactant: CCOC(=O)CC1CNC(=O)c2cc(Br)cn21
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C1NCC(CCO)n2cc(Br)cc21
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 92.9 %

Procedure:
Ethyl 2-(7-bromo-1-oxo-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazin-4-yl)acetate (1.23 g, 4.1 mmol) was treated with THF (30 mL), cooled to 0° C. and treated with LiAlH4, 1.0 M solution in THF (4.1 mL, 4.1 mmol) and stirred at 0° C. for 30 min. The reaction was quenched by slow dropwise addition of an aq. solution of sodium potassium tartrate and stirred at RT for 30 min. The resulting mixture was extracted with EtOAc (3×25 mL), washed with brine and dried over MgSO4, filtered and concentrated in vacuo to afford crude 7-bromo-4-(2-hydroxyethyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-1(2H)-one (987 mg, 3.81 mmol, 93% yield) as a white crystalline solid: 1H NMR (400 MHz, MeOH-d4) δ ppm 7.10 (1H, s), 6.83 (1H, s), 4.47 (1H, tt, J=7.1, 3.7 Hz), 3.85 (1H, dd, J=13.2, 4.2 Hz), 3.68 (1H, dt, J=11.2, 5.6 Hz), 3.46-3.56 (2H, m), 1.91-2.07 (2H, m). m/z (ESI, +ve ion) 259.0/261.0 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:34])[CH2:4][C:5]1[CH:6]=[C:7]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][C:13]=2[CH2:22][NH:23][C@H:24]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH2:26][C@H:25]2[OH:33])[C:8]([F:11])=[CH:9][CH:10]=1.[C:35](Cl)(Cl)=[O:36]>>[CH3:1][O:2][C:3](=[O:34])[CH2:4][C:5]1[CH:6]=[C:7]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:20])([F:21])[F:19])=[CH:14][C:13]=2[CH2:22][N:23]2[C@H:24]3[C:32]4[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=4[CH2:26][C@H:25]3[O:33][C:35]2=[O:36])[C:8]([F:11])=[CH:9][CH:10]=1
Reactant: COC(=O)Cc1ccc(F)c(-c2ccc(C(F)(F)F)cc2CN[C@H]2c3ccccc3C[C@H]2O)c1
Reactant: O=C(Cl)Cl
Product: COC(=O)Cc1ccc(F)c(-c2ccc(C(F)(F)F)cc2CN2C(=O)O[C@@H]3Cc4ccccc4[C@@H]32)c1

Procedure:
Prepared according to the procedure described in Example 25, Step 5, using the following starting materials: {6-fluoro-2′-[((1S,2R)-2-hydroxy-indan-1-ylamino)-methyl]-4′-trifluoromethyl-biphenyl-3-yl}-acetic acid methyl ester and phosgene (1.9M in toluene).
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-])=O)=[C:6]([N:11]2[CH2:16][CH2:15][N:14]([CH2:17][C:18]([N:20]([CH3:26])[C:21]3[S:22][CH:23]=[CH:24][N:25]=3)=[O:19])[CH2:13][CH2:12]2)[C:5]([Br:27])=[CH:4][N:3]=1.[CH3:28][N:29]([CH3:38])[C:30]1[CH:37]=[CH:36][C:33]([CH:34]=O)=[CH:32][CH:31]=1.[O-]S(S([O-])=O)=O.[Na+].[Na+]>C(O)C>[Br:27][C:5]1[C:6]([N:11]2[CH2:16][CH2:15][N:14]([CH2:17][C:18]([N:20]([CH3:26])[C:21]3[S:22][CH:23]=[CH:24][N:25]=3)=[O:19])[CH2:13][CH2:12]2)=[C:7]2[N:8]=[C:34]([C:33]3[CH:36]=[CH:37][C:30]([N:29]([CH3:38])[CH3:28])=[CH:31][CH:32]=3)[NH:1][C:2]2=[N:3][CH:4]=1
Reactant: CN(C(=O)CN1CCN(c2c(Br)cnc(N)c2[N+](=O)[O-])CC1)c1nccs1
Reactant: CN(C)c1ccc(C=O)cc1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCO
Product: CN(C)c1ccc(-c2nc3c(N4CCN(CC(=O)N(C)c5nccs5)CC4)c(Br)cnc3[nH]2)cc1
Temperature: 70 °C

Procedure:
To a mixture of 2-(4-(2-amino-5-bromo-3-nitropyridin-4-yl)piperazin-1-yl)-N-methyl-N-(thiazol-2-yl)acetamide (0.035 g, 0.08 mmol), ethanol (3.5 ml), and 4-dimethylaminobenzaldehyde (0.016 g, 0.11 mmol) was added a freshly prepared aqueous solution of Na2S2O4 (1M; 0.32 ml, 0.32 mmol). The reaction mixture was heated at 70° C. for 3 h, then allowed to cool to room temperature and the solvents were removed in vacuo. The residue was absorbed on silica gel and the free running powder was placed on a 10 g isolute silica column which was eluted with 30% to 60% ethyl acetate in dichloromethane. The title compound was obtained as a pale yellow solid after trituration with diethyl ether (0.006 g, 14%); 1H-NMR (500 MHz, DMSO-d6) 2.76 (br s, 4H, piperazine N(CH2)2), 2.99 (s, 6H, N(CH3)2), 3.66 (br s, 6H, piperazine N(CH2)2 and NCH2CO), 3.75 (s, 3H, N—CH3), 6.81 (d, J=9.2 Hz, 2H) and 8.01 (d, J=9.7 Hz, 2H) (3,5-C6H4NMe2 and 2,6-C6H4—NMe2), 7.31 (d, J=3.5 Hz, 1H, thiazole 5-H), 7.55 (d, J=3.9 Hz, 1H, thiazole-H), 8.15 (s, 1H, imidazo[4,5-b]pyridine 5-H), 13.19 (s, 1H, imidazo[4,5-b]pyridine N—H);
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:4]=[C:5](B(O)O)[CH:6]=[CH:7][CH:8]=1.COC1C=CC=C(OC)C=1C1C=CC=CC=1P(C1CCCCC1)C1CCCCC1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].Cl[C:52]1[CH:57]=[CH:56][C:55]([N:58]2[C:67]3[C:62](=[CH:63][C:64]([S:68]([NH:71][C:72]4[CH:76]=[CH:75][O:74][N:73]=4)(=[O:70])=[O:69])=[CH:65][CH:66]=3)[CH:61]=[CH:60][C:59]2=[O:77])=[CH:54][CH:53]=1>O1CCOCC1.O>[O:74]1[CH:75]=[CH:76][C:72]([NH:71][S:68]([C:64]2[CH:63]=[C:62]3[C:67](=[CH:66][CH:65]=2)[N:58]([C:55]2[CH:54]=[CH:53][C:52]([C:5]4[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:13])([F:12])[F:1])[CH:4]=4)=[CH:57][CH:56]=2)[C:59](=[O:77])[CH:60]=[CH:61]3)(=[O:70])=[O:69])=[N:73]1
Reactant: O=c1ccc2cc(S(=O)(=O)Nc3ccon3)ccc2n1-c1ccc(Cl)cc1
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: O=c1ccc2cc(S(=O)(=O)Nc3ccon3)ccc2n1-c1ccc(-c2cccc(C(F)(F)F)c2)cc1
Temperature: 120 °C
Yield: 19.4 %

Procedure:
A vial was charged with (3-(trifluoromethyl)phenyl)boronic acid (188 mg, 0.991 mmol), S-Phos Precatalyst (25.1 mg, 0.033 mmol), and potassium phosphate (281 mg, 1.322 mmol). The vial was flushed with Ar (g), then a solution of 1-(4-chlorophenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (166 mg, 0.330 mmol) in 1,4-dioxane (1322 μl) was added. Water (330 μl) was then added, and the vial was sealed and heated to 120° C. for 30 min in a Biotage Initiator microwave reactor. The mixture was extracted with EtOAc (3×). The combined organic extracts were concentrated. The residue was taken up in MeOH and filtered through a 0.2 micron filter. The resulting solution was purified by reverse-phase HPLC (25-70% CH3CN/H2O with 0.1% TFA). Fractions containing product were combined and lyophilized to give N-3-isoxazolyl-2-oxo-1-(3′-(trifluoromethyl)-4-biphenylyl)-1,2-dihydro-6-quinolinesulfonamide (32.5 mg, 0.064 mmol, 19.23% yield) as an off-white powder. NMR (400 MHz, DMSO-d6) δ=11.62 (s, 1H), 8.69 (d, J=1.9 Hz, 1H), 8.35 (d, J=2.3 Hz, 1H), 8.21 (d, J=9.5 Hz, 1H), 8.10-8.01 (m, 2H), 7.99-7.94 (m, 2H), 7.83-7.70 (m, 3H), 7.52-7.41 (m, 2H), 6.78 (t, J=9.0 Hz, 2H), 6.40 (d, J=1.9 Hz, 1H). m/z (ESI) 511.9 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1([CH3:37])[C:24]2[CH2:25][CH2:26][N:27]([CH2:29][CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH2:28][C:23]=2[C:5]2[C:6]([OH:22])=[CH:7][C:8]([C:10]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=3)([CH3:14])[CH2:11][CH2:12][CH3:13])=[CH:9][C:4]=2[O:3]1.Cl.[N:39]1([CH2:44][CH2:45][CH2:46][C:47](O)=[O:48])[CH2:43][CH2:42][CH2:41][CH2:40]1.C1(N=C=NC2CCCCC2)CCCCC1>>[ClH:21].[CH3:37][C:2]1([CH3:1])[C:24]2[CH2:25][CH2:26][N:27]([CH2:29][CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH2:28][C:23]=2[C:5]2[C:6]([O:22][C:47](=[O:48])[CH2:46][CH2:45][CH2:44][N:39]3[CH2:43][CH2:42][CH2:41][CH2:40]3)=[CH:7][C:8]([C:10]([C:15]3[CH:16]=[CH:17][C:18]([Cl:21])=[CH:19][CH:20]=3)([CH3:14])[CH2:11][CH2:12][CH3:13])=[CH:9][C:4]=2[O:3]1
Reactant: O=C(O)CCCN1CCCC1
Reactant: CCCC(C)(c1ccc(Cl)cc1)c1cc(O)c2c(c1)OC(C)(C)C1=C2CN(CCc2ccccc2)CC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Product: CCCC(C)(c1ccc(Cl)cc1)c1cc(OC(=O)CCCN2CCCC2)c2c(c1)OC(C)(C)C1=C2CN(CCc2ccccc2)CC1

Procedure:
5,5-Dimethyl-10-hydroxy-2-phenethyl-8-(4-chlorophenyl-1-methylbutyl)-1,2,3,4-tetrahydro-5H[1]benzopyrano [3,4-d]pyridine, γ-pyrrolidino-butyric acid hydrochloride and dicyclohexylcarbodiimide are reacted in equimolar amounts according to Example 7 to produce the desired product.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([CH:9]=[CH:10]OCC)=[CH:4][N:3]=1.Cl>C(O)(C)C>[Cl:1][C:2]1[N:3]=[CH:4][C:5]2[CH:9]=[CH:10][NH:8][C:6]=2[N:7]=1
Reactant: CCOC=Cc1cnc(Cl)nc1N
Agent: Cl
Solvent: CC(C)O
Product: Clc1ncc2cc[nH]c2n1
Temperature: 90 °C
Reaction time: 2 h
Yield: 100.9 %

Procedure:
A 500 mL round bottomed flask was charged with 2-Chloro-5-(2-ethoxyvinyl)-pyrimidin-4-ylamine 2 (4.4 g, 20 mmol). Isopropanol (200 mL) is added followed by 25 mL of concentrated hydrochloric acid. The solution is heated to 90° C. and stirred for two hours. After cooling to room temperature, the solution is concentrated under reduced pressure then basified to pH 9 with saturated aqueous NaHCO3. The aqueous layer is extracted with ethyl acetate, and the organic extracts are combined and washed with saturated aqueous NaHCO3 and brine. The organic extracts are dried over Na2SO4, filtered, and concentrated under reduced pressure. Purification by short-filtration (SiO2, Hexanes:Ethyl acetate/1:1) gives 3 (3.1 g, 92%) as a white solid.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:10]2[CH:11]=[CH:12][C:13]([OH:15])=[CH:14][C:9]=2[O:8][CH:7]=1)=O)C.CC(C[AlH]CC(C)C)C>C1COCC1>[OH:3][CH2:4][C:6]1[C:10]2[CH:11]=[CH:12][C:13]([OH:15])=[CH:14][C:9]=2[O:8][CH:7]=1
Reactant: CCOC(=O)c1coc2cc(O)ccc12
Agent: CC(C)C[AlH]CC(C)C
Solvent: C1CCOC1
Product: OCc1coc2cc(O)ccc12
Temperature: 25 °C
Yield: 101.2 %

Procedure:
To a cooled (0° C.) solution of 6-hydroxy-benzofuran-3-carboxylic acid ethyl ester (5.85 g, 28.4 mmol) in THF (250 mL) was added DIBALH as a solution in THF (100 mL, 100 mmol) and the reaction mixture was allowed to warm (rt, 1 h). The reaction was cooled (−78° C.) and treated dropwise with Rochelles salt (120 mL). The resulting mixture was stirred (rt, o/n). The layers were separated and the aqueous layer was extracted with DCM (2×200 mL) and EtOAc (2×200 mL). The organic layers were combined, dried, filtered and concentrated in vacuo to provide the title compound as a white solid (4.72 g, 100%). 1H NMR (500 MHz, CD3OD): 7.53 (s, 1H), 7.45 (d, J=8.4, 1H), 6.85 (d, J=2.1, 1H), 6.76 (dd, J=8.4, 2.1, 1H), 4.70 (s, 2H).
Reaction SMILES: [I:1][C:2]1[CH:3]=[N:4][NH:5][CH:6]=1.[H-].[Na+].CS(O[CH:14]1[CH2:17][N:16]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:15]1)(=O)=O>CN(C=O)C>[I:1][C:2]1[CH:3]=[N:4][N:5]([CH:14]2[CH2:15][N:16]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:17]2)[CH:6]=1
Reactant: Ic1cn[nH]c1
Reactant: CC(C)(C)OC(=O)N1CC(OS(C)(=O)=O)C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CC(n2cc(I)cn2)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 61.1 %

Procedure:
At 0° C., a solution of 4-iodopyrazole (3.0 g, 15.46 mmol) in DMF (40 mL) was treated with NaH (60% mineral oil dispersion, 1.11 g, 46.39 mmol) in portions. The mixture stirred for 30 minutes, followed by the slow addition of 1-(tert-butoxycarbonyl)azetidin-3-yl methanesulfonate (5.0 g, 20.1 mmol). The reaction mixture was warmed to RT and then heated at 100° C. for 5 hours. The reaction mixture was poured into ice cold water, stirred for 30 minutes, and resulting precipitate collected by filtration and dried. The resulting residue washed with pentane and dried to obtain tert-butyl 3-(4-iodo-1H-pyrazol-1-yl)azetidine-1-carboxylate (3.3 g, 62% yield); 1H-NMR (400 MHz, CDCl3): 7.58 (s, 1H), 7.57 (s, 1H), 5.07-5.0 (m, 1H), 4.39-4.34 (m, 2H), 4.29-4.25 (dd, 2H), 1.45 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([C:14](=[O:19])[C:15]([CH3:18])([CH3:17])[CH3:16])=[CH:12][N:11]=[CH:10][N:9]=2)=[CH:4][CH:3]=1>C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:13]([CH:14]([OH:19])[C:15]([CH3:17])([CH3:16])[CH3:18])=[CH:12][N:11]=[CH:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: CC(C)(C)C(=O)c1cncnc1-c1ccc(Cl)cc1
Solvent: CCO
Product: CC(C)(C)C(O)c1cncnc1-c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 66.2 %

Procedure:
1.2 g of 4-(4-chlorophenyl)-5-pivaloylpyrimidine was dissolved in 20 ml of ethanol, then 1.2 g of a borane ammonia complex was added, and the mixture was stirred at room temperature for 30 minutes. After the solvent was distilled off under reduced pressure, water was added, and extraction with chloroform was carried out. The extract layer was washed with water and dried over anhydrous sodium sulfate. The solvent was distilled off to obtain 0.8 g of the desired product as a viscous liquid. nD20.2 1.5575
Reaction SMILES: [CH3:1][N:2]1[CH2:8][CH:7]([CH3:9])[C:6]2[CH:10]=[C:11](Br)[CH:12]=[CH:13][C:5]=2[CH2:4][CH2:3]1.CN1CC(C)C2C=C(I)C=CC=2CC1.CN1CC(C)C2C=C(C(F)(F)F)C=CC=2CC1.CN1CC(CC)C2C=C(C(F)(F)F)C=CC=2CC1.CN1CC(CC)C2C=C([Cl:78])C=CC=2CC1.CN1CC(CC)C2C=C(Br)C=CC=2CC1.CN1CC(CC)C2C=C(I)C=CC=2CC1.CN1CC(C)C2C=C(Cl)C(Cl)=CC=2CC1.CN1CC(CC)C2C=C(Cl)C(Cl)=CC=2CC1.CN1CC(C)C2C=C(Cl)C(F)=CC=2CC1.CN1CC(CC)C2C=C(Cl)C(F)=CC=2CC1>>[CH3:1][N:2]1[CH2:8][CH:7]([CH3:9])[C:6]2[CH:10]=[C:11]([Cl:78])[CH:12]=[CH:13][C:5]=2[CH2:4][CH2:3]1
Reactant: CCC1CN(C)CCc2ccc(Cl)cc21
Reactant: CC1CN(C)CCc2ccc(Br)cc21
Agent: CC1CN(C)CCc2cc(Cl)c(Cl)cc21
Agent: CC1CN(C)CCc2cc(F)c(Cl)cc21
Agent: CC1CN(C)CCc2ccc(C(F)(F)F)cc21
Product: CC1CN(C)CCc2ccc(Cl)cc21

Procedure:
N-methyl-8-Bromo-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine; N-methyl-8-Iodo-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine; N-methyl-8-Trifluoromethyl-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine; N-methyl-8-Trifluoromethyl-1-ethyl-2,3,4,5-tetrahydro-1H-3-benzazepine; N-methyl-8-Chloro-1-ethyl-2,3,4,5-tetrahydro-1H-3-benzazepine; N-methyl-8-Bromo-1-ethyl-2,3,4,5-tetrahydro-1H-3-benzazepine; N-methyl-8-Iodo-1-ethyl-2,3,4,5-tetrahydro-1H-3-benzazepine; N-methyl-7,8-Dichloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine; N-methyl-7,8-Dichloro-1-ethyl-2,3,4,5-tetrahydro-1H-3-benzazepine; N-methyl-8-Chloro-7-fluoro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine; and N-methyl-8-Chloro-7-fluoro-1-ethyl-2,3,4,5-tetrahydro-1H-3-benzazepine; or a pharmaceutically acceptable salt, solvate or hydrate thereof.
Reaction SMILES: Cl.[NH2:2][C:3]1[S:4][CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([CH:14]3[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]3)=[CH:10][CH:9]=2)[N:7]=1.[CH:20](OCC)(OCC)[O:21][CH2:22][CH3:23]>>[CH:14]1([C:11]2[CH:12]=[CH:13][C:8]([C:6]3[N:7]=[C:3]([N:2]=[CH:20][O:21][CH2:22][CH3:23])[S:4][CH:5]=3)=[CH:9][CH:10]=2)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: Nc1nc(-c2ccc(C3CCCCC3)cc2)cs1
Reactant: CCOC(OCC)OCC
Agent: Cl
Product: CCOC=Nc1nc(-c2ccc(C3CCCCC3)cc2)cs1
Temperature: 130 °C
Reaction time: 1 h
Yield: 95.6 %

Procedure:
A mixture of 2-amino-4-(4-cyclohexylphenyl)thiazole hydrochloride (1.0 g) and triethyl orthoformate (5 ml) was stirred at 130° C. for 1 hour. The reaction mixture was concentrated under reduced pressure, and to the remaining crystals was added hexane, followed by filtration. The filtrate was concentrated to give crystals of 4-(4-cyclohexylphenyl)-2-ethoxymethyleneaminothiazole (1.02 g, yield of 95.6 %). Recrystallization from diethyl etherhexane produced yellowish prisms, mp of 84° to 85° C.
Reaction SMILES: [Br-].[Br:2][CH2:3][CH2:4][CH2:5][P+:6]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[N-:25]=[N+:26]=[N-:27].[Na+]>C(O)C.O>[Br-:2].[N:25]([CH2:3][CH2:4][CH2:5][P+:6]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[N+:26]=[N-:27]
Reactant: BrCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: [N-]=[N+]=[N-]
Agent: [Br-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: [N-]=[N+]=NCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1

Procedure:
(3-Bromo-propyl)-triphenyl-phosphonium bromide was dissolved in ethanol/water (1/1). To it sodium azide was added. The reaction mixture was heated up to reflux overnight. Solvents were removed by evaporation. The residue was extracted by dry ethanol. Filtered and evaporated to give crude (3-azido-propyl)-triphenyl-phosphonium bromide and was used directly for the next step reaction without further purification.