Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[N:2]1CCOCC1.[C:8]1([C:14]2[NH:18][N:17]=[C:16]([C:19]([NH:21][CH2:22][C:23]([N:25]3[CH2:30][CH2:29][CH:28]([O:31][C:32]4[CH:40]=[CH:39][CH:38]=[CH:37][C:33]=4[C:34]([OH:36])=O)[CH2:27][CH2:26]3)=[O:24])=[O:20])[CH:15]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.ClC(OCC(C)C)=O>C1COCC1>[C:34]([C:33]1[CH:37]=[CH:38][CH:39]=[CH:40][C:32]=1[O:31][CH:28]1[CH2:27][CH2:26][N:25]([C:23](=[O:24])[CH2:22][NH:21][C:19]([C:16]2[CH:15]=[C:14]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[NH:18][N:17]=2)=[O:20])[CH2:30][CH2:29]1)(=[O:36])[NH2:2]
Reactant: O=C(NCC(=O)N1CCC(Oc2ccccc2C(=O)O)CC1)c1cc(-c2ccccc2)[nH]n1
Reactant: CN1CCOCC1
Agent: CC(C)COC(=O)Cl
Solvent: C1CCOC1
Product: NC(=O)c1ccccc1OC1CCN(C(=O)CNC(=O)c2cc(-c3ccccc3)[nH]n2)CC1
Yield: 60.3 %

Procedure:
N-Methyl morpholine (28 mg, 0.28 mmol) was added to a cold (−70° C.) solution of 2-(1-{2-[(5-phenyl-1H-pyrazole-3-carbonyl)-amino]-acetyl}-piperidin-4-yloxy)-benzoic acid (100 mg, 0.2 mmol) in THF (2 mL) followed by isobutyl chloroformate (41 mg, 0.3 mmol) and stirring was continued at the at −70° C. for 1 hr. After complete formation of anhydride, ammonia gas was bubbled through the reaction mixture at −70° C. for 10 minutes. The resulting mixture was then stirred at room temperature for 1 hr. Water (10 mL) was added, the precipitated was filtered and dried to afford 54 mg (60.6% yield) of 5-phenyl-1H-pyrazole-3-carboxylic acid {2-[4-(2-carbamoyl-phenoxy)-piperidin-1-yl]-2-oxo-ethyl}-amide. LC/MS [M+H]+: 448.18, 93.4%. 1H NMR (300 MHz, DMSO-d6): δ 7.9 (m, 1H), 7.8 (m, 2H), 7.5 (m, 3H), 7.4 (m, 1H), 7.3 (m, 1H), 7.1 (m, 2H), 4.3 (s, 2H), 4.0 (m, 1H), 3.8 (m, 1H), 3.5 (m, 2H), 2.1 (m, 3H), 1.9 (m, 3H), 1.1 (m, 1H).
Reaction SMILES: [Cl:1][CH2:2][C:3]([NH:5][NH:6][C:7]([C:9]1[C:17]2[C:12](=[C:13]([O:18][CH3:19])[CH:14]=[CH:15][CH:16]=2)[N:11]([CH2:20][CH:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)[CH:10]=1)=O)=O.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:28]>O1CCCC1.ClCCl>[Cl:1][CH2:2][C:3]1[S:28][C:7]([C:9]2[C:17]3[C:12](=[C:13]([O:18][CH3:19])[CH:14]=[CH:15][CH:16]=3)[N:11]([CH2:20][CH:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)[CH:10]=2)=[N:6][N:5]=1
Reactant: COc1cccc2c(C(=O)NNC(=O)CCl)cn(CC3CCCCC3)c12
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Solvent: C1CCOC1
Solvent: ClCCl
Product: COc1cccc2c(-c3nnc(CCl)s3)cn(CC3CCCCC3)c12
Yield: 352.5 %

Procedure:
To a solution of 1-cyclohexylmethyl-7-methoxy-1H-indole-3-carboxylic acid N′-(2-chloroacetyl)hydrazide (prepared as described in Example 37; 50 mg, 0.139 mmol) in tetrahydrofuran (0.5 ml) was added phosphorus pentasulfide (62 mg, 0.139 mmol) and the reaction mixture subjected to microwave irradiation at 150° C. for 5 minutes. The reaction was repeated twice on a 0.7 mmol scale. The combined reaction mixture was poured into a separating funnel and diluted with dichloromethane (60 ml). The organics were washed with 5% aqueous sodium carbonate (2×30 ml), brine (30 ml), dried over sodium sulfate and the solvent removed in vacuo. The resulting residue was purified by flash column chromatography to afford 3-(5-chloromethyl-[1,3,4]thiadiazol-2-yl)-1-cyclohexylmethyl-7-methoxy-1H-indole (186 mg, 0.49 mmol).
Reaction SMILES: [C:1]([O:10]N1C(=O)CCC1=O)([O:3][CH2:4][CH2:5][Si:6]([CH3:9])([CH3:8])[CH3:7])=O.[Si:18]([O:25][CH:26]1[CH2:31][CH2:30][CH:29]([CH2:32][C@H:33]([NH:37][C:38](=[O:44])[O:39][C:40]([CH3:43])([CH3:42])[CH3:41])[CH2:34][NH:35][CH3:36])[CH2:28][CH2:27]1)([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19].C([O-])([O-])=O.[K+].[K+]>O.C(Cl)Cl>[Si:18]([O:25][CH:26]1[CH2:27][CH2:28][CH:29]([CH2:32][C@H:33]([NH:37][C:38](=[O:44])[O:39][C:40]([CH3:43])([CH3:42])[CH3:41])[CH2:34][N:35]([CH3:36])[C:1]([O:3][CH2:4][CH2:5][Si:6]([CH3:7])([CH3:8])[CH3:9])=[O:10])[CH2:30][CH2:31]1)([C:21]([CH3:23])([CH3:24])[CH3:22])([CH3:20])[CH3:19]
Reactant: CNC[C@H](CC1CCC(O[Si](C)(C)C(C)(C)C)CC1)NC(=O)OC(C)(C)C
Reactant: C[Si](C)(C)CCOC(=O)ON1C(=O)CCC1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Product: CN(C[C@H](CC1CCC(O[Si](C)(C)C(C)(C)C)CC1)NC(=O)OC(C)(C)C)C(=O)OCC[Si](C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 69.8 %

Procedure:
Solid Teoc-OSu (1.35 g, 5.25 mmol) was added to a two-phase solution of (S)-tert-butyl 1-(4-(tert-butyldimethylsilyloxy)cyclohexyl)-3-(methylamino)propan-2-ylcarbamate (2.0 g, 5.0 mmol), K2CO3 (0.75 g, 9.0 mmol) in H2O (6 ml) and CH2Cl2 (12 mL). The mixture was vigorously stirred for 2 h at rt. The product was extracted with CH2Cl2. The combined organic layers were washed with sat'd aq NaHCO3 and brine, dried over Na2SO4 and evaporated. The residue was purified by column chromatography to provide (S)-tert-butyl 1-(4-(tert-butyldimethylsilyloxy)cyclohexyl)-3-(N-methyl-N-(2-(trimethylsilyl)ethoxycarbonyl)amino)propan-2-ylcarbamate (1.9 g, 3.49 mmol, 70% yield). 1H NMR (400 MHz, CD3OD): 0.05 (s, 15H), 0.87 (s, 9H), 1.40 (s, 9H), 1.69 (s, 3H), 2.96 (m, 3H), 3.40-3.52 (m, 1H), 3.81-3.92 (m, 1H), 4.12-4.29 (m, 2H). MS (E/Z): 545 (M+H+)
Reaction SMILES: [C:1]1([C:7]2[C:8]([C:23]([O:25][CH3:26])=[O:24])=[N:9][C:10]([C:13]3[CH:22]=[C:21]4[C:16]([CH2:17][CH2:18][CH2:19][NH:20]4)=[CH:15][CH:14]=3)=[CH:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[S:27]1[C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=2[N:29]=[C:28]1[NH:36][C:37](=O)[O:38]C1C=CC([N+]([O-])=O)=CC=1>CC#N>[S:27]1[C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=2[N:29]=[C:28]1[NH:36][C:37]([N:20]1[C:21]2[C:16](=[CH:15][CH:14]=[C:13]([C:10]3[N:9]=[C:8]([C:23]([O:25][CH3:26])=[O:24])[C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)=[CH:12][CH:11]=3)[CH:22]=2)[CH2:17][CH2:18][CH2:19]1)=[O:38]
Reactant: COC(=O)c1nc(-c2ccc3c(c2)NCCC3)ccc1-c1ccccc1
Reactant: O=C(Nc1nc2ccccc2s1)Oc1ccc([N+](=O)[O-])cc1
Solvent: CC#N
Product: COC(=O)c1nc(-c2ccc3c(c2)N(C(=O)Nc2nc4ccccc4s2)CCC3)ccc1-c1ccccc1
Temperature: 25 °C

Procedure:
A mixture of methyl 3-phenyl-6-(1,2,3,4-tetrahydroquinolin-7-yl)picolinate (29H) (17 mg, 0.049 mmol) and 4-nitrophenyl benzo[d]thiazol-2-ylcarbamate (19) (15.5 mg, 0.049 mmol) in anhydrous CH3CN (0.8 mL) was heated to reflux for 6 hours, cooled to rt, concentrated under reduced pressure, and the crude material was purified by column chromatography on silica gel eluting with a gradient of PE:EtOAc 72:28-55:45, to provide the desired product methyl 6-(1-(benzo[d]thiazol-2-ylcarbamoyl)-1,2,3,4-tetrahydroquinolin-7-yl)-3-phenylpicolinate (29I): 1H NMR (300 MHz, CDCl3) δ 8.23 (1H, d), 8.13 (1H, d), 7.85-7.76 (3H, m), 7.66 (1H, d), 7.48-7.35 (4H, m), 7.34-7.28 (2H, m), 6.89 (1H, d), 3.98 (2H, t), 3.71 (3H, s), 2.85 (2H, t), 2.09 (2H, m).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[CH2:3][C:4]1[CH:10]=[C:9]([Br:11])[CH:8]=[CH:7][C:5]=1[NH2:6].[N:14]([O-])=O.[Na+].O>C(O)(=O)C>[F:13][C:2]([F:1])([F:12])[C:3]1[C:4]2[C:5](=[CH:7][CH:8]=[C:9]([Br:11])[CH:10]=2)[NH:6][N:14]=1
Reactant: O=N[O-]
Reactant: Nc1ccc(Br)cc1CC(F)(F)F
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: FC(F)(F)c1n[nH]c2ccc(Br)cc12
Temperature: 15 °C

Procedure:
18 parts of 2-(2,2,2-trifluoro-ethyl)-4-bromo-aniline are dissolved in 490 parts by volume of glacial acetic acid. To this solution, well stirred at 15° C., is added all at once a solution of 4.9 parts of sodium nitrite in 11.9 parts of water. At the end of 3 days, the acetic acid is evaporated and the residue is taken up in 40 parts of water, the solid filtered off, washed and dried. 18 parts of 3-trifluoromethyl-5-bromo-indazole are thus obtained.
Reaction SMILES: [C:1]([O:7][CH3:8])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].CO[CH:11](OC)[N:12]([CH3:14])[CH3:13]>>[CH3:8][O:7][C:1](=[O:6])[C:2](=[CH:11][N:12]([CH3:14])[CH3:13])[C:3](=[O:4])[CH3:5]
Reactant: COC(=O)CC(C)=O
Reactant: COC(OC)N(C)C
Product: COC(=O)C(=CN(C)C)C(C)=O
Temperature: 25 °C
Yield: 93.7 %

Procedure:
A solution of methyl acetoacetate (5.0 mL, 46.33 mmol) and N,N-dimethylformamide dimethylacetal (6.8 mL, 47.95 mmol) was heated to 80° C. for 2.3 h. At this time, the reaction was cooled to 25° C. and was then concentrated in vacuo to afford 2-dimethylaminomethylene-3-oxo-butyric acid methyl ester (7.43 g, 94%) as a red/black solid. This material was used without further purification.
Reaction SMILES: [Na].[C:2]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]1[C:12](=[O:16])[CH2:13][CH2:14][CH:15]=1)(O)=[O:3].C(Cl)(=O)C([Cl:20])=O>O1CCCC1.CCOCC>[Cl:20][C:2]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]1[C:12](=[O:16])[CH2:13][CH2:14][CH:15]=1)=[O:3]
Reactant: O=C(O)CCCCCCC1=CCCC1=O
Reactant: O=C(Cl)C(=O)Cl
Agent: [Na]
Solvent: CCOCC
Solvent: C1CCOC1
Product: O=C(Cl)CCCCCCC1=CCCC1=O
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a suspension of 1.94 g (0.08 mol) of sodium hydri in 100 ml of tetrahydrofuran is added with stirring under argo dropwise a solution of 17 g (0.08 mol) of 2-(6-carboxyhexyl)-cyclopent-2-en-1-one in 160 ml of tetrahydrofuran. After the addition is complete, the mixture is stirred for 1 hour 15 minutes. The mixture is cooled to 0° C. and 13 ml of oxalyl chloride is added. The mixture is stirred at 0° C. for 30 minutes and at room temperature for 30 minutes. The solution is diluted with 500 ml of ether and filtered through Celite. The solvent is removed from the filtrate and the residue is extracted with hot hexane twice. The hexane is removed to give 16.0 g of the title compound.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[N:9]=[C:8](/[CH:11]=[CH:12]/[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[NH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.F[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=1.N1C=CC=CC=1N1C2C=CC=CC=2N=C1/C=C/C1C=CC=CC=1.[ClH:49]>CO>[ClH:49].[CH3:1][C:2]1[C:10]2[N:9]=[C:8](/[CH:11]=[CH:12]/[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:7]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cccc2[nH]c(/C=C/c3ccccc3)nc12
Reactant: Fc1ccccn1
Agent: C(=C/c1nc2ccccc2n1-c1ccccn1)\c1ccccc1
Agent: Cl
Solvent: CO
Product: Cc1cccc2c1nc(/C=C/c1ccccc1)n2-c1ccccn1

Procedure:
Free base of the titled compound was prepared from (E)-4-methyl-2-styryl-1H-benzimidazole and 2-fluoropyridine according to the preparation of (E)-1-(2-pyridyl)-2-styryl-1H-benzimidazole (Example 1, method B). The free base was treated with a 10% methanol solution of hydrogen chloride and concentrated to dryness. The residue was recrystallized from 2-propanol/isopropyl ether to give the titled compound. MW: 347.85; mp: 218.0-225.0° C.; 1H-NMR (DMSO) δ: 8.85-8.80 (1H, m), 8.45 (1H, d, J=16.1 Hz), 8.27 (1H, ddd, J=7.7,7.7, 1.5 Hz), 7.86 (1H, d, J=7.7 Hz), 7.77 (1H, dd, J=7.7, 4.5 Hz), 7.70-7.65 (2H, m), 7.48-7.42 (3H, m), 7.41-7.33 (3H, m), 7.17 (1H, d, J=16.1 Hz), 2.76 (3H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:10](B3OC(C)(C)C(C)(C)O3)=[CH:9][N:8]([S:20]([C:23]3[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=3)(=[O:22])=[O:21])[C:5]2=[N:6][CH:7]=1.Cl[C:31]1[N:36]=[C:35]([NH:37][C@H:38]2[CH2:49][CH2:48][CH2:47][C@:40]3([O:44][C:43](=[O:45])[N:42]([CH3:46])[CH2:41]3)[CH2:39]2)[C:34]([F:50])=[CH:33][N:32]=1.C([O-])([O-])=O.[Na+].[Na+]>C(#N)C.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>[Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:31]3[N:36]=[C:35]([NH:37][C@H:38]4[CH2:49][CH2:48][CH2:47][C@:40]5([O:44][C:43](=[O:45])[N:42]([CH3:46])[CH2:41]5)[CH2:39]4)[C:34]([F:50])=[CH:33][N:32]=3)=[CH:9][N:8]([S:20]([C:23]3[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=3)(=[O:21])=[O:22])[C:5]2=[N:6][CH:7]=1
Reactant: CN1C[C@@]2(CCC[C@H](Nc3nc(Cl)ncc3F)C2)OC1=O
Reactant: Cc1ccc(S(=O)(=O)n2cc(B3OC(C)(C)C(C)(C)O3)c3cc(Cl)cnc32)cc1
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+]
Solvent: CC#N
Product: Cc1ccc(S(=O)(=O)n2cc(-c3ncc(F)c(N[C@H]4CCC[C@]5(C4)CN(C)C(=O)O5)n3)c3cc(Cl)cnc32)cc1
Temperature: 120 °C

Procedure:
To a solution of 5-chloro-1-(p-tolylsulfonyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[2,3-b]pyridine (0.031 g, 0.0724 mmol) in acetonitrile (0.570 mL) was added (5S,7S)-7-(2-chloro-5-fluoropyrimidin-4-ylamino)-3-methyl-1-oxa-3-azaspiro[4.5]decan-2-one, 63c, (0.019 g, 0.060 mmol) and degassed under N2. Na2CO3 (0.091 ml, of 2 M, 0.1810 mmol) was added followed by Pd(PPh3)4 (0.010 g, 0.009 mmol). The reaction was sealed and heated in a microwave at 120° C. for 30 min. The mixture was then concentrated in vacuo. The material was diluted in CH2Cl2 and silica gel chromatography (Hexanes:EtOAc then 20% MeOH in CH2Cl2) gave product 63d. LCMS+: 585.25 at 4.17 min (10-90% MeOH, 3/5 grad/run, Formic Acid).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:15](=[CH:16][CH:17]=1)[O:14][C:7]1=[N:8][CH:9]=[C:10]([O:12][CH3:13])[CH:11]=[C:6]1[C:5]2=[O:18].[CH2:19]1COCC1.C[Mg]Cl>>[Br:1][C:2]1[CH:3]=[C:4]2[C:15](=[CH:16][CH:17]=1)[O:14][C:7]1=[N:8][CH:9]=[C:10]([O:12][CH3:13])[CH:11]=[C:6]1[C:5]2([CH3:19])[OH:18]
Reactant: C1CCOC1
Reactant: COc1cnc2oc3ccc(Br)cc3c(=O)c2c1
Agent: C[Mg]Cl
Product: COc1cnc2c(c1)C(C)(O)c1cc(Br)ccc1O2
Temperature: -30 °C

Procedure:
To a slurry of 7-bromo-3-methoxy-5H-chromeno[2,3-b]pyridin-5-one (23 g, 75 mmol) in THF (751 mL, 75 mmol) at −40° C. was added methylmagnesium chloride, 3.0 M solution in THF (88 mL, 263 mmol) over 2 minutes such that the temperature did not rise above −35° C. The resulting red slurry was maintained at −30° C. After 1 hour the reaction, which was now homogeneous, was quenched with 50 mL of ethyl acetate. The solution was then carefully quenched with 800 mL of 50% ammonium chloride. The mixture was poured into a separatory funnel containing ethyl acetate (100 mL). The layers were separated and the organics were washed with brined, dried over sodium sulfate, filtered and concentrated. The aqueous layer was extracted with ethyl acetate (3×500 mL). The combined organic layers were washed with water and then brine, dried over sodium sulfate, filtered, and combined with the above derived oil. This organic solution was washed with brined, dried over sodium sulfate, fitlered and concentrated to provide 7-bromo-3-methoxy-5-methyl-5H-chromeno[2,3-b]pyridin-5-ol as a yellow solid.
Reaction SMILES: F[B-](F)(F)F.[CH3:6][O:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH2:14][C:15](=[NH:19])OCC.C(N(CC)CC)C.[C:27]1([C:33]2([C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)[C@H:41]3[C@H:37]([CH2:38][NH:39][CH2:40]3)[C@@H:36]([OH:42])[CH2:35][CH2:34]2)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C(=O)([O-])[O-].[K+].[K+]>ClCCl>[C:43]1([C:33]2([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C@H:41]3[C@H:37]([CH2:38][N:39]([C:15](=[NH:19])[CH2:14][C:9]4[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=4[O:7][CH3:6])[CH2:40]3)[C@@H:36]([OH:42])[CH2:35][CH2:34]2)[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=1
Reactant: O[C@H]1CCC(c2ccccc2)(c2ccccc2)[C@@H]2CNC[C@@H]21
Reactant: CCOC(=N)Cc1ccccc1OC
Agent: F[B-](F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccccc1CC(=N)N1C[C@H]2[C@@H](C1)C(c1ccccc1)(c1ccccc1)CC[C@@H]2O
Yield: 57 %

Procedure:
A solution of 1.56 g of ethyl (2-methoxyphenyl)-acetimidate tetrafluoroborate and 0.96 cm3 of triethylamine in 20 cm3 of dry dichloromethane is added to a solution of 2 g of (3aR,4S,7aR)-7,7-diphenyl-4-perhydroisoindolol in 30 cm3 of dry dichloromethane, and the reaction mixture is then refluxed for 2 hours. 10 cm3 of a 10% aqueous solution of potassium carbonate are then added, the mixture is decanted and then the organic phase is washed with 20 cm3 of water, dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (2.7 kPa). The residue is chromatographed on an alumina column (diameter 3.6 cm, height 31 cm), eluting under a nitrogen pressure of 0.1 bar with a dichloromethane and methanol mixture (95/5 by volume) and collecting fractions of 50 cm3. Fractions 5 to 30 are pooled and concentrated to dryness under reduced pressure (2.7 kPa). The solid obtained is washed with isopropyl oxide, drained and dried. 1.4 g of (3aR,4S,7aR)-7,7-diphenyl-2-[1-imino-2-(2-methoxyphenyl)ethyl]-4-perhydroisoindolol are obtained in the form of white crystals; melting point 105° C., with decomposition.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Cl:7][C:8]1[C:9]([F:16])=[N:10][C:11]([F:15])=[N:12][C:13]=1F.C(N(CC)C(C)C)(C)C>O1CCOCC1>[Cl:7][C:8]1[C:13]([N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)=[N:12][C:11]([F:15])=[N:10][C:9]=1[F:16]
Reactant: C1COCCN1
Reactant: Fc1nc(F)c(Cl)c(F)n1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: Fc1nc(F)c(Cl)c(N2CCOCC2)n1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Morpholine (0.774 mg) was added to a solution of 5-chloro-2,4,6-trifluoropyrimidine (1.5 g), N,N-diisopropylethylamine (1.15 g) in 1,4-dioxane (30 ml) and stirred at room temperature for 16 h. The mixture was partitioned between ethyl acetate and water, the organic layer dried (MgSO4) and evaporated under reduced pressure. The residue was purified by chromatography on silica eluting with 8% ethyl acetate in isohexane. Yield 0.88 g
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C@H:5]1[CH2:9][CH2:8][N:7]([CH2:10][C@H:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)O)[CH2:6]1.COCO[C@H]1CCN([C@H](C2C=CC=CC=2)CO)C1.[CH3:37][O:38][C:39]1[CH:48]=[C:47]([NH:49][CH3:50])[CH:46]=[CH:45][C:40]=1[C:41]([O:43][CH3:44])=[O:42]>>[CH3:37][O:38][C:39]1[CH:48]=[C:47]([N:49]([C@@H:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:10][N:7]2[CH2:8][CH2:9][C@H:5]([O:4][CH2:3][O:2][CH3:1])[CH2:6]2)[CH3:50])[CH:46]=[CH:45][C:40]=1[C:41]([O:43][CH3:44])=[O:42]
Reactant: COCO[C@H]1CCN(C[C@@H](O)c2ccccc2)C1
Reactant: CNc1ccc(C(=O)OC)c(OC)c1
Agent: COCO[C@H]1CCN([C@@H](CO)c2ccccc2)C1
Product: COCO[C@H]1CCN(C[C@H](c2ccccc2)N(C)c2ccc(C(=O)OC)c(OC)c2)C1
Yield: 41 %

Procedure:
This was prepared from 2-(3-(S)-methoxymethoxypyrrolidin-1-yl)-1-(S)-phenylethanol and 2-(3-(S)-methoxymethoxypyrrolidin-1-yl)-2-(R)-phenylethanol and methyl 2-methoxy-4-methylaminobenzoate in 41% yield according to a procedure similar to that described in Example 1 (i).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]([NH:17][C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH2:25][CH3:26])[CH:19]=3)=[C:15]3[C:10]([CH:11]=[CH:12][CH:13]=[CH:14]3)=[N:9]2)=[CH:4][CH:3]=1.[CH:27]1([N:33]=[C:34]=[O:35])[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1.CCN(CC)CC>ClCCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]([N:17]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH2:25][CH3:26])[CH:19]=3)[C:34]([NH:33][CH:27]3[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]3)=[O:35])=[C:15]3[C:10]([CH:11]=[CH:12][CH:13]=[CH:14]3)=[N:9]2)=[CH:6][CH:7]=1
Reactant: CCOc1cccc(Nc2c3ccccc3nn2-c2ccc(Cl)cc2)c1
Reactant: O=C=NC1CCCCC1
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: CCOc1cccc(N(C(=O)NC2CCCCC2)c2c3ccccc3nn2-c2ccc(Cl)cc2)c1

Procedure:
In analogy to the procedure described in example 1.2, [2-(4-chloro-phenyl)-2H-indazol-3-yl]-(3-ethoxy-phenyl)-amine was reacted with cyclohexylisocyanate ([3173-53-3]) in 1,2-dichloroethane in the presence of Et3N (3 eq.) for 3 d under reflux conditions to give the title compound as yellow solid. MS; m/e=489.1 [M+H+].
Reaction SMILES: [NH2:1][C:2]1[C:7](Br)=[CH:6][C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1.[CH3:12][Si:13]([C:16]#[CH:17])([CH3:15])[CH3:14].C(N(CC)CC)C>O1CCCC1.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>[N+:9]([C:5]1[CH:6]=[C:7]([C:17]#[C:16][Si:13]([CH3:15])([CH3:14])[CH3:12])[C:2]([NH2:1])=[N:3][CH:4]=1)([O-:11])=[O:10]
Reactant: Nc1ncc([N+](=O)[O-])cc1Br
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C[Si](C)(C)C#Cc1cc([N+](=O)[O-])cnc1N
Temperature: 25 °C
Reaction time: 16 h

Procedure:
12.0 g 2-Amino-3-bromo-5-nitropyridine, 1.93 g dichlorobis(triphenyl-phosphine)palladium(II) and 0.524 g copper(I) iodide were dispersed under nitrogen in 60 ml dry tetrahydrofuran (THF). 7.03 g trimethylsilylacetylene and 16.71 g triethylamine were added and the mixture was stirred 16 hours (hrs) at room temperature (RT). The mixture was filtered, the filtrate was evaporated and the residue purified by chromatography on silica in ethyl acetate/heptane mixtures.
Reaction SMILES: [CH3:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2C2CCCCO2)=[C:4]([C:17]2[C:18]([NH:23][C:24]3[CH:29]=[CH:28][C:27]([NH:30][C:31]([CH:33]4[CH2:35][CH2:34]4)=[O:32])=[CH:26][CH:25]=3)=[N:19][CH:20]=[CH:21][CH:22]=2)[N:3]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][NH:8]2)=[C:4]([C:17]2[C:18]([NH:23][C:24]3[CH:29]=[CH:28][C:27]([NH:30][C:31]([CH:33]4[CH2:35][CH2:34]4)=[O:32])=[CH:26][CH:25]=3)=[N:19][CH:20]=[CH:21][CH:22]=2)[N:3]=1
Reactant: Cc1nc(-c2cccnc2Nc2ccc(NC(=O)C3CC3)cc2)c2ncn(C3CCCCO3)c2n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1nc(-c2cccnc2Nc2ccc(NC(=O)C3CC3)cc2)c2nc[nH]c2n1
Temperature: 0 °C
Reaction time: 1 h
Yield: 30.6 %

Procedure:
A suspension of N-(4-(3-(2-methyl-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)pyridin-2-ylamino)phenyl)cyclopropanecarboxamide (80 mg, 0.170 mmol) in DCM (3 mL) was cooled to 0° C. and treated with trifluoroacetic acid (3 mL, 40.4 mmol). The yellow solution was stirred at 0° C. for 1 h. The mixture was concentrated in vacuo, the residue was neutralized with 2 M NH3 in MeOH and then concentrated in vacuo. The crude product was purified by chromatography through a Redi-Sep pre-packed silica gel column (40 g) eluting with a gradient of 2% to 10% 2 M NH3-MeOH in DCM to give N-(4-(3-(2-methyl-9H-purin-6-yl)pyridin-2-ylamino)phenyl)cyclopropanecarboxamide (20 mg, 0.052 mmol, 30.5% yield) as a yellow solid. 1H NMR (400 MHz, d6-DMSO) δ 13.47-13.72 (m, 1H); 12.82 (s, 1H); 10.10 (s, 1H); 9.78 (s, 1H); 8.59 (s, 1H); 8.33 (d, J=3.20 Hz, 1H); 7.75 (d, J=76.46 Hz, 2H); 7.58 (d, J=8.53 Hz, 2H); 6.94-7.03 (m, 1H); 2.87 (s, 3H); 1.72-1.82 (m, 1H); 0.72-0.84 (m, 4H). m/z (ESI, +ve ion) 386 (M+H)+.
Reaction SMILES: N[C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[C:4]([NH:13][C@H:14]2[CH2:19][CH2:18][CH2:17][CH2:16][C@@H:15]2[N:20]2[CH2:24][CH2:23][CH2:22][CH2:21]2)[CH:3]=1.N([O-])=O.[Na+].[F:29]B(F)F.F>O>[F:29][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[C:4]([NH:13][C@H:14]2[CH2:19][CH2:18][CH2:17][CH2:16][C@@H:15]2[N:20]2[CH2:24][CH2:23][CH2:22][CH2:21]2)[CH:3]=1
Reactant: FB(F)F
Reactant: CCOC(=O)c1ccc(N)cc1N[C@H]1CCCC[C@@H]1N1CCCC1
Agent: F
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: CCOC(=O)c1ccc(F)cc1N[C@H]1CCCC[C@@H]1N1CCCC1

Procedure:
Ethyl 4-amino-2-{[(1S,2S)-2-pyrrolidin-1-ylcyclohexyl]amino}benzoate was allowed to react with sodium nitrite (NaNO2) and trifluoroborane-hydrogen fluoride complex (BF3.HF) in water at 10° C. for 10 minutes. By post-treating the reaction liquid, ethyl 4-fluoro-2-{[(1S,2S)-2-pyrrolidin-1-ylcyclohexyl]amino}benzoate was obtained.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[CH:4][CH:3]=1.[H-].[Na+].Br[C:12]1[C:13]2[N:14]([C:19]([C:22]([NH:24][C:25]3[CH:30]=[CH:29][N:28]=[CH:27][C:26]=3[F:31])=[O:23])=[CH:20][N:21]=2)[N:15]=[C:16]([Cl:18])[CH:17]=1>C1COCC1.CN(C=O)C>[Br:1][C:2]1[N:7]=[C:6]([NH:8][C:12]2[C:13]3[N:14]([C:19]([C:22]([NH:24][C:25]4[CH:30]=[CH:29][N:28]=[CH:27][C:26]=4[F:31])=[O:23])=[CH:20][N:21]=3)[N:15]=[C:16]([Cl:18])[CH:17]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: Nc1cccc(Br)n1
Reactant: O=C(Nc1ccncc1F)c1cnc2c(Br)cc(Cl)nn12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: O=C(Nc1ccncc1F)c1cnc2c(Nc3cccc(Br)n3)cc(Cl)nn12
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 99.1 %

Procedure:
To a solution of 6-bromopyridin-2-amine (1.24 g, 7.17 mmol) in THF (10.00 mL) was added 60% NaH (294 mg, 7.35 mmol). The mixture was stirred for 30 min until cessation H2 evolution. The resulting dark green solution was added by syringe to a suspension of 8A (800 mg, 2.453 mmol) in DMF (10 mL). The reaction mixture was stirred at room temperature overnight, and then added to ice water. The brown solid was collected by filtration and dried under vacuum to give 17A (1.125 g, 89%) MS (m+1)=462. HPLC Peak Rt=3.696 minutes (Chromolith column 4.6×50 mm eluting with 10-90% aqueous methanol over 4 minutes containing 0.1% TFA, 4 mL/min, monitoring at 220 nm).