Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]12([C:11]3[CH:30]=[CH:29][C:14]([O:15][CH2:16][C:17]([NH:19][C:20]4[CH:21]=[N:22][CH:23]=[C:24]([CH:28]=4)[C:25](O)=[O:26])=[O:18])=[CH:13][CH:12]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[N:31]1[CH:36]=[CH:35][C:34]([CH2:37][CH2:38][NH2:39])=[CH:33][CH:32]=1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CO>CN(C1C=CN=CC=1)C.CN(C=O)C>[C:1]12([C:11]3[CH:30]=[CH:29][C:14]([O:15][CH2:16][C:17]([NH:19][C:20]4[CH:21]=[N:22][CH:23]=[C:24]([CH:28]=4)[C:25]([NH:39][CH2:38][CH2:37][C:34]4[CH:35]=[CH:36][N:31]=[CH:32][CH:33]=4)=[O:26])=[O:18])=[CH:13][CH:12]=3)[CH2:10][CH:5]3[CH2:4][CH:3]([CH2:9][CH:7]([CH2:6]3)[CH2:8]1)[CH2:2]2
Reactant: NCCc1ccncc1
Reactant: O=C(COc1ccc(C23CC4CC(CC(C4)C2)C3)cc1)Nc1cncc(C(=O)O)c1
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Solvent: CO
Product: O=C(COc1ccc(C23CC4CC(CC(C4)C2)C3)cc1)Nc1cncc(C(=O)NCCc2ccncc2)c1
Yield: 60 %

Procedure:
To solution of 5-[2-(4-adamantan-1-yl-phenoxy)-acetylamino]-nicotinic acid (40 mg, 0.098 mmol), 2-pyridine-4-yl-ethylamine (24.06 mg, 0.196 mmol) and DMAP (24.06 mg, 0.196 mmol) in DMF was added PyBOP (102.7 mg, 0.196 mmol) at room temperature, and stirred. Reaction mixture was poured onto ice cold water; diluted by methanol/MC mixture (10%). The organic phase was separated, sequentially washed with aqueous sodium bicarbonate, brine and water, dried over anhydrous MgSO4, and concentrated. The resultant crude product was purified by PLC (MeOH:MC=1:9) to afford 5-[2-(4-adamantan-1-yl-phenoxy)acetylamino]-N-(2-pyridine-4-yl-ethyl)nicotinamide as a colorless solid (30 mg, 60% yield).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[CH2:27]Br)=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[CH:29]([Si:32]([CH:37]([CH3:39])[CH3:38])([CH:34]([CH3:36])[CH3:35])[SH:33])([CH3:31])[CH3:30]>CN(C=O)C>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[CH2:27][S:33][Si:32]([CH:34]([CH3:36])[CH3:35])([CH:37]([CH3:39])[CH3:38])[CH:29]([CH3:30])[CH3:31])=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4CBr)cc3)cc2)CC1
Reactant: CC(C)[Si](S)(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4CS[Si](C(C)C)(C(C)C)C(C)C)cc3)cc2)CC1
Reaction time: 8 h

Procedure:
1-[4′-(4-Bromomethyl-3-methyl-isoxazol-5-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester (1.0 g, 2.27 mmol) and triisopropylsilanethiol (0.488 mL, 2.27 mmol) were dissolved in DMF (25 mL) and the solution was degassed with N2 for 10 minutes. Cesium carbonate was added and the reaction stirred overnight under N2 atmosphere. Standard aqueous workup afforded a mixture of the desired product plus de-protected free thiol which was taken directly to the next step.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][N:10]=[C:11]=[O:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=1>C1COCC1.C1C=CC=CC=1>[C:1]1([CH2:7][CH2:8][CH2:9][NH:10][C:11]([NH:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)=[O:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NCc1ccccn1
Reactant: O=C=NCCCc1ccccc1
Solvent: c1ccccc1
Solvent: C1CCOC1
Product: O=C(NCCCc1ccccc1)NCc1ccccn1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 92 %

Procedure:
To a solution of 3-phenylpropyl isocyanate (1.8 mmol) in anhydrous THF (10 mL) at 0° C. under an argon atmosphere was added 2-aminomethyl-pyridine (1.8 mmol). The reaction mixture was stirred at 0° C. for 10 min, the solvent was evaporated under reduced pressure, and the resultant solid was recrystallized from CH2Cl2/Et2O to give pure 59.1 in 92% yield. White solid. m p 89-90° C. When anhydrous benzene was used as solvent the product was directly crystallized out and isolated by filtration (93% yield).
Reaction SMILES: Cl.[NH2:2][C:3]1[C:4]([OH:9])=[N:5][CH:6]=[N:7][CH:8]=1.C(N(CC)CC)C.[CH3:17][O:18][C:19]1[C:20](=O)[C:21](=[O:25])[C:22]=1[O:23]C>CO>[OH:9][C:4]1[C:3]([NH:2][C:20]2[C:21](=[O:25])[C:22](=[O:23])[C:19]=2[O:18][CH3:17])=[CH:8][N:7]=[CH:6][N:5]=1
Reactant: COc1c(OC)c(=O)c1=O
Reactant: Nc1cncnc1O
Agent: Cl
Solvent: CO
Solvent: CCN(CC)CC
Product: COc1c(Nc2cncnc2O)c(=O)c1=O
Temperature: 50 °C
Yield: 79.4 %

Procedure:
1.00 g (6.78 mmol, 1 eq) of 5-aminopyrimidin 4-ol hydrochloride and 0.95 ml (6.78 mmol, 1 eq) of triethylamine were added to a suspension of 3.86 g (27.16 mmol, 4 eq) of 3,4-dimethoxycyclobut-3-ene-1,2-dione in 20 ml of methanol. The reaction medium was heated at 50° C. for 18 hours. The reaction medium was left at ambient temperature. The precipitate was filtered off and washed with methanol. 1.19 g of product were obtained in the form of a yellow solid. Yield=79%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](I)[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[C:22]([F:23])=[C:21]([F:24])[CH:20]=[CH:19][C:11]=1[C:12]([NH:14][O:15][CH2:16][CH2:17][OH:18])=[O:13].[CH3:25][Si:26]([C:29]#[CH:30])([CH3:28])[CH3:27]>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>[Cl:1][C:2]1[CH:7]=[C:6]([C:30]#[C:29][Si:26]([CH3:28])([CH3:27])[CH3:25])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[C:22]([F:23])=[C:21]([F:24])[CH:20]=[CH:19][C:11]=1[C:12]([NH:14][O:15][CH2:16][CH2:17][OH:18])=[O:13]
Reactant: C#C[Si](C)(C)C
Reactant: O=C(NOCCO)c1ccc(F)c(F)c1Nc1ccc(I)cc1Cl
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Product: C[Si](C)(C)C#Cc1ccc(Nc2c(C(=O)NOCCO)ccc(F)c2F)c(Cl)c1
Reaction time: 0.33 h
Yield: 76 %

Procedure:
The product of Example 6, Step C, 2-(2-chloro-4-iodo-phenylamino)-3,4-difluoro-N-(2-hydroxy-ethoxy)-benzamide (3.25 g, 6.93 mmol) and (trimethylsilyl)acetylene (1.10 mL, 7.78 mmol) were combined in triethylamine (17 mL). Dichlorobis(triphenylphosphine)-palladium(II) (0.120 g, 0.017 mol) and cuprous iodide (0.033 g, 0.17 mmol) were added and the resultant solution was stirred at ambient temperature for 22 h. The reaction mixture was adsorbed onto Celite® for 20 min and was filtered, washing with ethyl acetate. The filtrate was concentrated to a thick oil, further diluted with ethyl acetate (100 mL) and washed with aqueous citric acid (2 M, 2×25 mL), water, and brine. The organic layer was then dried over magnesium sulfate and concentrated in vacuo to afford a tan-colored solid. Recrystallization form heptane-ethyl acetate afforded 2-(2-chloro-4-trimethylsilanylethynyl-phenylamino)-3,4-difluoro-N-(2-hydroxy-ethoxy)-benzamide (2.34 g, 76% yield) as a grey-colored solid: 1H NMR (400 MHz, DMSO-d6) δ 11.96 (s, 1 H), 8.95 (s, 1 H), 7.53 (d, J=1.7 Hz, 1 H), 7.47 (m, 1 H), 7.32 (m, 1 H), 7.27 (dd, J=8.4, 1.8 Hz, 1 H), 6.72 (dd, J=8.0, 6.6 Hz, 1 H), 4.73 (t, J=5.5 Hz, 1 H), 3.87 (apparent t, J=4.7 Hz, 2 H), 3.57 (m, 2 H), 0.21 (s, 9 H); MS (APCI+)=439.1; MS (APCI−)=437.1.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@H:12]([CH2:13][F:14])[C@@H:11]([C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:22]=[N:23][C:24]([C:27]#N)=[CH:25][CH:26]=3)=[CH:17][CH:16]=2)[O:10][C:9]1([CH3:30])[CH3:29])=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-:31].[K+].C[OH:34]>>[C:1]([O:5][C:6]([N:8]1[C@H:12]([CH2:13][F:14])[C@@H:11]([C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][C:24]([C:27]([OH:34])=[O:31])=[N:23][CH:22]=3)=[CH:17][CH:16]=2)[O:10][C:9]1([CH3:30])[CH3:29])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CO
Reactant: [OH-]
Reactant: CC(C)(C)OC(=O)N1[C@H](CF)[C@@H](c2ccc(-c3ccc(C#N)nc3)cc2)OC1(C)C
Agent: [K+]
Product: CC(C)(C)OC(=O)N1[C@H](CF)[C@@H](c2ccc(-c3ccc(C(=O)O)nc3)cc2)OC1(C)C
Temperature: 65 °C

Procedure:
To the solution of (4S,5R)-5-[4-(6-Cyano-pyridin-3-yl)-phenyl]-4-fluoromethyl-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester (0.3 g, 0.729 mmol) in methanol (3 mL) is added KOH (0.409 g, 7.29 mmol) at room temperature. Resulting reaction mixture heated at 65° C. for 48 hours. Solvent is evaporated in vacuo, water (10 mL) is added and aqueous layer is washed with CH2Cl2. Aqueous layer is acidified with saturated citric acid solution and extracted with CH2Cl2. Organic layer dried over sodium sulphate, solvent is evaporated in vacuo to afford title compound (0.22 g): 1H-NMR (400 MHz, DMSO-d6): δ: 1.43 (s, 9H), 1.51 (s, 3H), 1.64 (s, 3H), 3.84-3.90 (m, 2H), 4.45-4.59 (m, 2H), 4.77-5.0 (m, 2H), 5.14 (d, 1H, J=7.2 Hz), 7.61 (d, 2H, J=8.08 Hz), 7.83 (d, 2H, J=8.12 Hz), 8.08 (d, 1H, J=8.32 Hz), 8.23 (d, 1H, J=8.68 Hz), 9.0 (s, 1H). LC-MS (m/z): [M+H]=431.2.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[O:9][C:8](=[O:13])[CH:7]=[C:6]2[NH:14][CH:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1.[NH:21]1[C:29]2[C:24](=[CH:25][C:26]([CH:30]=O)=[CH:27][CH:28]=2)[CH:23]=[CH:22]1.[H-].[Na+].[CH3:34]I>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[O:9][C:8](=[O:13])[CH:7]=[C:6]2[N:14]([CH:15]1[CH2:20][CH2:19][N:18]([CH2:30][C:26]2[CH:25]=[C:24]3[C:29](=[CH:28][CH:27]=2)[NH:21][CH:22]=[CH:23]3)[CH2:17][CH2:16]1)[CH3:34]
Reactant: CI
Reactant: COc1ccc2oc(=O)cc(NC3CCNCC3)c2c1
Reactant: O=Cc1ccc2[nH]ccc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc2oc(=O)cc(N(C)C3CCN(Cc4ccc5[nH]ccc5c4)CC3)c2c1
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
6-Methoxy-4-(piperidin-4-ylamino)-chromen-2-one and indole-5-carboxaldehyde were allowed to react under reductive alkylation conditions to give a crude beige product. After trituration of the crude product with hot ethyl acetate, filtration and concentration, the resulting partially-purified white powder was carried on to the subsequent alkylation step. A solution of this material (202 mg, 0.5 mmol) in 2 mL DMF under nitrogen at 0° C., was treated with NaH (60% dispersion in mineral oil, 50 mg, 12.5 mmol). After 45 minutes, methyl iodide (33 uL, 0.525 mmol) was added via syringe. The reaction was stirred at 0° C. for two hours, and then allowed to warm to room temperature and stirred overnight. After 17 hours, the reaction was quenched by slow addition of distilled water, diluted with CH2Cl2/MeOH (95:5), washed with distilled water, dried (Na2SO4) and concentrated to give a yellow oil. Purification by flash silica gel chromatography (0 to 5% MeOH in CH2Cl2) gave the titled compound as a yellow foam (80 mg). 1H NMR (300 MHz, ppm, DMSO-d6) δ 1.57-1.71 (m, 2H), 1.86-1.96 (m, 2H), 2.04-2.15 (m, 2H), 2.73 (m, 2H), 3.46-3.58 (m, 3H), 3.77 (s, 3H), 3.83 (s, 3H), 5.21 (s, 1H), 6.38 (d, J=3.1 Hz, 1H), 7.10-7.23 (m, 3H), 7.29 (d, J=3.1 Hz, 1H), 7.37 (d, J=8.4 Hz, 1H), 7.45 (s, 1H), 7.63 (d, J=2.8 Hz, 1H) MS(ESI) 418 (M+H), 416 (M−H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][C:7]=1[CH3:8].S(=O)(=O)(O)O.[CH3:14][CH:15]([NH2:23])[CH2:16][CH2:17][CH2:18][C:19](O)([CH3:21])[CH3:20].Cl>CO>[NH2:23][CH:15]([CH2:16][CH2:17][CH2:18][C:19]([C:4]1[CH:5]=[CH:6][C:7]([CH3:8])=[C:2]([CH3:1])[CH:3]=1)([CH3:21])[CH3:20])[CH3:14]
Reactant: CC(N)CCCC(C)(C)O
Reactant: Cc1ccccc1C
Agent: Cl
Agent: O=S(=O)(O)O
Solvent: CO
Product: Cc1ccc(C(C)(C)CCCC(C)N)cc1C

Procedure:
21.2 Parts of o-xylene, 128 parts of 98% w/w sulphuric acid, 24 parts of methanol, and 36.3 parts of heptaminol hydrochloride were stirred at room temperature for 3 days. The work up was carried out as described in Example 2 and gave on distillation 36.2 parts of 2-amino-6-(3,4-dimethylphenyl)-6-methylheptane b16 164°-8° with the following percentage composition by weight.
Reaction SMILES: BrC1C=C(OC)C(Cl)=C(CC2C=CC(OCC)=CC=2)C=1.[CH2:21]([O:24][C:25]1[C:26]([Cl:42])=[C:27]([C:32]([C:34]2[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=2)=O)[CH:28]=[C:29]([Br:31])[CH:30]=1)[CH:22]=[CH2:23]>>[CH2:21]([O:24][C:25]1[CH:30]=[C:29]([Br:31])[CH:28]=[C:27]([CH2:32][C:34]2[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=2)[C:26]=1[Cl:42])[CH:22]=[CH2:23]
Reactant: C=CCOc1cc(Br)cc(C(=O)c2ccc(OC)cc2)c1Cl
Agent: CCOc1ccc(Cc2cc(Br)cc(OC)c2Cl)cc1
Product: C=CCOc1cc(Br)cc(Cc2ccc(OC)cc2)c1Cl

Procedure:
Similar procedure with preparation of 74 proceeded except for using compound 183 to obtain the compound 184.
Reaction SMILES: OC(C(F)(F)F)=O.[NH:8]1[CH2:11][CH:10]([NH:12][C:13](=[O:30])[CH2:14][NH:15][C:16]2[C:20]3[CH:21]=[C:22]([O:25][C:26]([F:29])([F:28])[F:27])[CH:23]=[CH:24][C:19]=3[O:18][N:17]=2)[CH2:9]1.[O:31]1[C:35]2[CH:36]=[CH:37][C:38]([CH:40]3[CH2:45][CH2:44][C:43](=O)[CH2:42][CH2:41]3)=[CH:39][C:34]=2[O:33][CH2:32]1>>[O:31]1[C:35]2[CH:36]=[CH:37][C:38]([CH:40]3[CH2:45][CH2:44][CH:43]([N:8]4[CH2:9][CH:10]([NH:12][C:13](=[O:30])[CH2:14][NH:15][C:16]5[C:20]6[CH:21]=[C:22]([O:25][C:26]([F:28])([F:27])[F:29])[CH:23]=[CH:24][C:19]=6[O:18][N:17]=5)[CH2:11]4)[CH2:42][CH2:41]3)=[CH:39][C:34]=2[O:33][CH2:32]1
Reactant: O=C1CCC(c2ccc3c(c2)OCO3)CC1
Reactant: O=C(CNc1noc2ccc(OC(F)(F)F)cc12)NC1CNC1
Solvent: O=C(O)C(F)(F)F
Product: O=C(CNc1noc2ccc(OC(F)(F)F)cc12)NC1CN(C2CCC(c3ccc4c(c3)OCO4)CC2)C1

Procedure:
The title compound was prepared as a white solid from reaction of N-azetidin-3-yl-2-(5-trifluoromethoxy-benzo[d]isoxazol-3-ylamino)-acetamide TFA salt (as prepared in Example 1, Step D) and 4-benzo[1,3]dioxol-5-yl-cyclohexanone using the procedure described in Step E of Example 1.
Reaction SMILES: Cl.[OH:2][CH2:3][C:4]([NH2:12])([CH2:8][CH2:9][CH2:10][NH2:11])[C:5](O)=[O:6].Cl.C[O-].[Na+]>CO>[OH:2][CH2:3][C:4]1([NH2:12])[CH2:8][CH2:9][CH2:10][NH:11][C:5]1=[O:6]
Reactant: NCCCC(N)(CO)C(=O)O
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: NC1(CO)CCCNC1=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 80.5 %

Procedure:
2-Hydroxymethyl-2,5-diaminopentanoic acid hydrochloride (5 g or 2.5×10-2 mole) is suspended in 75 ml of absolute methanol and the solution is saturated with dry hydrogen chloride. The homogenous solution is then heated under reflux for 48 hours. The reaction mixture is regularly saturated with dry hydrogen chloride. The solvent is evaporated under reduced pressure and the hygroscopic residue is dried under high vacuo (6.2 g) and identified as dihydrochloride of 2-hydroxymethyl-2,5-diaminopentanoic acid methyl ester by NMR. The ester (6.2 g) is dissolved in 100 ml of absolute methanol and 175 ml of a methanolic solution of sodium methylate (1.15 g of Na or 5×10-2 mole) is added. The reaction mixture is stirred at room temperature under nitrogen for 24 hours. The solvent is evaporated under reduced pressure and the residue is extracted many times with hot chloroform to yield analytically pure 3-hydroxymethyl-3-amino-2-piperidone (2.9 g) (yield 81%), m.p. 145° C.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][CH:7]=1)[CH:2]1[O:4][CH2:3]1.[CH3:13][C:14]([NH2:25])([CH3:24])[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1>>[ClH:12].[OH:4][CH:2]([CH2:1][O:5][C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][CH:7]=1)[CH2:3][NH:25][C:14]([CH3:24])([CH3:13])[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1
Reactant: Clc1ccc(OCC2CO2)cc1
Reactant: COc1ccc(CC(C)(C)N)cc1
Product: COc1ccc(CC(C)(C)NCC(O)COc2ccc(Cl)cc2)cc1
Product: Cl
Yield: 135.9 %

Procedure:
Using the method of Example 6, supra, 4-chlorophenyl glycidyl ether (185 mg, 1 mmol) and 1,1-dimethyl-2-(4-methoxyphenyl)ethylamine (269 mg, 1.5 mmol) were used to prepare 272 mg of the title compound as a white solid: GC/EI-MS, m/z (rel. int.) 348 (M−15, 1), 244 (35), 243 (15), 242 (100), 163 (9), 121 (24), 114 (7), 71 (24), 70 (26), 58 (15), 42 (7).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([NH2:21])=[CH:5][C:6]2[CH2:12][CH2:11][N:10]([CH:13]([CH2:17][O:18][CH3:19])[CH2:14][O:15][CH3:16])[CH2:9][CH2:8][C:7]=2[CH:20]=1.Cl[C:23]1[N:28]=[C:27]([NH:29][C@@H:30]2[CH2:35][CH2:34][CH2:33][CH2:32][C@H:31]2[NH:36][S:37]([CH3:40])(=[O:39])=[O:38])[C:26]([Cl:41])=[CH:25][N:24]=1>>[Cl:41][C:26]1[C:27]([NH:29][C@@H:30]2[CH2:35][CH2:34][CH2:33][CH2:32][C@H:31]2[NH:36][S:37]([CH3:40])(=[O:39])=[O:38])=[N:28][C:23]([NH:21][C:4]2[C:3]([O:2][CH3:1])=[CH:20][C:7]3[CH2:8][CH2:9][N:10]([CH:13]([CH2:14][O:15][CH3:16])[CH2:17][O:18][CH3:19])[CH2:11][CH2:12][C:6]=3[CH:5]=2)=[N:24][CH:25]=1
Reactant: COCC(COC)N1CCc2cc(N)c(OC)cc2CC1
Reactant: CS(=O)(=O)N[C@@H]1CCCC[C@H]1Nc1nc(Cl)ncc1Cl
Product: COCC(COC)N1CCc2cc(Nc3ncc(Cl)c(N[C@@H]4CCCC[C@H]4NS(C)(=O)=O)n3)c(OC)cc2CC1

Procedure:
The title compound was prepared from 8-Methoxy-3-(2-methoxy-1-methoxymethyl-ethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamine and N-[(1R,2R)-2-(2,5-Dichloro-pyrimidin-4-ylamino)-cyclohexyl]-methanesulfonamide in an analogous manner to Example 61e. Product isolated as an off-white solid (0.044 g, 45%). MP: 167-172° C. 1H NMR (400 MHz, CDCl3, δ, ppm): 7.96-7.92 (m, 2H), 7.30 (s, 1H), 6.65 (s, 1H), 5.37-5.30 (m, 2H), 3.98-3.87 (m, 1H), 3.86 (s, 3H), 3.57-3.51 (m, 2H), 3.47-3.41 (m, 2H), 3.32 (s, 6H), 3.30-3.19 (m, 1H), 3.06-2.98 (m, 1H), 2.90-2.75 (m, 11H), 2.25-2.15 (m, 2H), 1.86-1.75 (m, 2H), 1.42-1.30 (m, 4H). MS: 597.44 (MH)+.
Reaction SMILES: [OH-].[Na+].[CH2:3]1[CH:8]2[C:9]3[CH:21]=[CH:20][CH:19]=[CH:18][C:10]=3[CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[N:7]2[CH2:6][CH2:5][N:4]1[CH2:22][C:23]([O:25]CC)=[O:24]>CO>[CH2:3]1[CH:8]2[C:9]3[CH:21]=[CH:20][CH:19]=[CH:18][C:10]=3[CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[N:7]2[CH2:6][CH2:5][N:4]1[CH2:22][C:23]([OH:25])=[O:24]
Reactant: CCOC(=O)CN1CCN2c3ccccc3Cc3ccccc3C2C1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)CN1CCN2c3ccccc3Cc3ccccc3C2C1
Yield: 86.4 %

Procedure:
2N Aqueous sodium hydroxide solution (5 ml) was added to a solution of 1.68 g of ethyl 2-(1,2,3,4,10,14b-hexahydrodibenzo[c,f]pyrazino[1,2-a]azepin-2-yl)acetate in 17 ml of methanol. The solution was refluxed for 30 min and then concentrated. The residue was dissolved in hot water and the solution was neutralized with 0.5N hydrochloric acid. The precipitates were collected by filtration to give 1.33 g of colorless crystals, which were recrystallized from aqueous ethanol to give colorless needles, mp 162°-163° C.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH:6]([C:9]1[CH:17]=[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][N:11]2[N:10]=1)([CH3:8])[CH3:7].[OH-].[Na+].CN([CH:23]=[O:24])C>>[CH:6]([C:9]1[C:17]([CH:23]=[O:24])=[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][N:11]2[N:10]=1)([CH3:8])[CH3:7]
Reactant: CC(C)c1cc2ccccn2n1
Reactant: CN(C)C=O
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Product: CC(C)c1nn2ccccc2c1C=O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 82 %

Procedure:
Upon stirring 3 mL of DMF at room temperature, neat phosphorous oxychloride (0.8 mL 1.3 equivalents) was added dropwise. The resulting mixture was stirred at room temperature for 10 minutes, followed by dropwise addition of neat 2-isopropylpyrazolo[1,5-a]pyridine (1 g, 1 equivalent). The solution was stirred at room temperature for 19 hours and poured into 100 mL of ice water. The pH of the aqueous solution was adjusted to 8 using solid NaOH. The precipitate formed was collected by filtration and dried under reduced pressure to furnish 2-isopropylpyrazolo[1,5-a]pyridine-3-carbaldehyde (0.97 g, 82% yield) as a white solid. Compound 1073.
Reaction SMILES: [CH:1]1([N:4]([CH:33]2[CH2:35][CH2:34]2)[C:5]([C:7]2[N:30]([CH2:31][CH3:32])[C:10]3=[N:11][C:12]([NH:19][C:20]4[S:21][C:22]([C:25]([O:27]CC)=[O:26])=[CH:23][N:24]=4)=[C:13]4[N:17]=[CH:16][N:15]([CH3:18])[C:14]4=[C:9]3[CH:8]=2)=[O:6])[CH2:3][CH2:2]1.[OH-].[Na+]>CCO>[CH:33]1([N:4]([CH:1]2[CH2:2][CH2:3]2)[C:5]([C:7]2[N:30]([CH2:31][CH3:32])[C:10]3=[N:11][C:12]([NH:19][C:20]4[S:21][C:22]([C:25]([OH:27])=[O:26])=[CH:23][N:24]=4)=[C:13]4[N:17]=[CH:16][N:15]([CH3:18])[C:14]4=[C:9]3[CH:8]=2)=[O:6])[CH2:34][CH2:35]1
Reactant: CCOC(=O)c1cnc(Nc2nc3c(cc(C(=O)N(C4CC4)C4CC4)n3CC)c3c2ncn3C)s1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCn1c(C(=O)N(C2CC2)C2CC2)cc2c3c(ncn3C)c(Nc3ncc(C(=O)O)s3)nc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of ethyl 2-(7-(dicyclopropylcarbamoyl)-6-ethyl-1-methyl-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-4-ylamino)thiazole-5-carboxylate (example 19, 14.6 mg, 0.030 mmol) in EtOH (296 μL) was added 1 N NaOH aqueous solution (296 μL). The reaction mixture was stirred at rt 3 h and stirred at 50° C. 18 h. After cooling to room temperature, ethanol was removed by concentration in vacuo. The residue was acidified with 1 N HCl and the solid product was collected by filtration. 2-(7-(Dicyclopropylcarbamoyl)-6-ethyl-1-methyl-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-4-ylamino)thiazole-5-carboxylic acid was isolated as a pale yellow solid which was used crude in the next reaction.
Reaction SMILES: N[C:2]1[S:3][C:4]2[C:9]([NH:10][C@H:11]([CH2:14][CH2:15][CH3:16])[CH2:12][OH:13])=[N:8][C:7]([SH:17])=[N:6][C:5]=2[N:18]=1.[ClH:19].N([O-])=O.[Na+]>C(#N)C.O>[Cl:19][C:2]1[S:3][C:4]2[C:9]([NH:10][C@H:11]([CH2:14][CH2:15][CH3:16])[CH2:12][OH:13])=[N:8][C:7]([S:17][S:17][C:7]3[N:8]=[C:9]([NH:10][C@@H:11]([CH2:12][OH:13])[CH2:14][CH2:15][CH3:16])[C:4]4[S:3][C:2]([Cl:19])=[N:18][C:5]=4[N:6]=3)=[N:6][C:5]=2[N:18]=1
Reactant: CCC[C@H](CO)Nc1nc(S)nc2nc(N)sc12
Reactant: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: CCC[C@H](CO)Nc1nc(SSc2nc(N[C@@H](CO)CCC)c3sc(Cl)nc3n2)nc2nc(Cl)sc12
Reaction time: 48 h
Yield: 78 %

Procedure:
(2R)-2-[(2-Amino-5-mercapto[1,3]thiazolo[4,5-d]pyrimidin-7-yl)amino]pentan-1-ol (4.0 g, 14 mmol) was dissolved in acetonitrile (100 ml) and concentrated hydrochloric acid (150 mL). Sodium nitrite (1.93 g, 28 mmol) was dissolved in water (10 mL) and added at 0° C. The reaction mixture was left at 0° C. for 2 days until the reaction was complete by LCMS. The reaction mixture was poured onto ice and the precipitated product was collected by filtration. The solid was dried in vacuo to give 3.3 g (78% yield) of the title compound.
Reaction SMILES: [C:1]1([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC([CH2:17][C:18]([OH:20])=[O:19])=O.[C:21]([O:24]C(=O)C)(=[O:23])[CH3:22]>N1C=CC=CC=1>[CH2:7]([C:8]1[C@@H:9]([O:20][C:18](=[O:19])[CH3:17])[C@@H:10]([O:24][C:21](=[O:23])[CH3:22])[CH:11]=[CH:12][CH:13]=1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(=O)OC(C)=O
Reactant: CC(=O)CC(=O)O
Reactant: c1ccc(Cc2ccccc2)cc1
Solvent: c1ccncc1
Product: CC(=O)O[C@H]1C=CC=C(Cc2ccccc2)[C@H]1OC(C)=O

Procedure:
The title compound is prepared by the microbial oxidation of diphenylmethane by Pseudomonas putida 39D using the method of T. Hudlicky et al. J. Am. Chem. Soc. 110, 4735-41 (1988) and D. Gibson et al. Biochemistry, 9, 1626-30 (1970) followed by protection as the diacetate using acetic anhydride in pyridine.
Reaction SMILES: O=[C:2]1[CH2:6][CH2:5][N:4]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:3]1.[CH3:12][C:13]1[CH:14]=[C:15]([NH2:19])[CH:16]=[CH:17][CH:18]=1.S1C=CC=C1.[H][H]>CO.[Pd]>[CH3:12][C:13]1[CH:14]=[C:15]([NH:19][CH:2]2[CH2:6][CH2:5][N:4]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:3]2)[CH:16]=[CH:17][CH:18]=1
Reactant: Cc1cccc(N)c1
Reactant: [H][H]
Reactant: CCOC(=O)N1CCC(=O)C1
Agent: [Pd]
Solvent: c1ccsc1
Solvent: CO
Product: CCOC(=O)N1CCC(Nc2cccc(C)c2)C1
Yield: 100 %

Procedure:
A mixture of 7.9 parts of ethyl 3-oxo-1-pyrrolidinecarboxylate, 5.35 parts of 3-methylbenzenamine, 1 part of a solution of thiophene in methanol 4% and 200 parts of methanol was hydrogenated at normal pressure and at 50° C. with 2 parts of palladium-on-charcoal catalyst 10%. After the calculated amount of hydrogen was taken up, the catalyst was filtered off and the filtrate was evaporated, yielding 12.4 parts (100%) of ethyl 3-[(3-methylphenyl)amino]-1-pyrrolidinecarboxylate as a residue (intermediate 19).