Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([C@@H:12]2[O:17][CH2:16][CH2:15][N:14]([C@@H:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH3:19])[CH2:13]2)=[CH:8][CH:7]=1)=[O:4].C(=O)([O-])[O-].[K+].[K+].Cl.[CH3:33][NH:34][CH3:35]>O1CCCC1.C(#N)C>[CH3:33][N:34]([CH3:35])[CH2:2][C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([C@@H:12]2[O:17][CH2:16][CH2:15][N:14]([C@@H:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH3:19])[CH2:13]2)=[CH:8][CH:7]=1)=[O:4]
Reactant: C[C@H](c1ccccc1)N1CCO[C@@H](c2ccc(NC(=O)CCl)cc2)C1
Reactant: CNC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: C1CCOC1
Product: C[C@H](c1ccccc1)N1CCO[C@@H](c2ccc(NC(=O)CN(C)C)cc2)C1
Yield: 125.2 %

Procedure:
A solution of 2-chloro-N-((2S)-4-(((1R)-1-phenylethyl)morpholin-2-yl)phenyl)acetamide (0.9 g, 2.5 mmol), potassium carbonate (1.72 g, 12.5 mmol), and dimethylamine hydrochloride (1.00 g, 12.5 mmol) in tetrahydrofuran (40 ml) and acetonitrile (80 ml) was stirred at 95° C. for 10 hours. After filtration, the solvent was removed in vacuo and the residue was partitioned between water and dichloromethane. The organic layer was dried over anhydrous sodium sulfate and the solvent was evaporated under reduced pressure give N2,N2-dimethyl-N1-(4-((2S)-4-((1R)-1-phenylethyl)morpholin-2-yl)phenyl)glycinamide (1.15 g, quant.) as an yellow oil.
Reaction SMILES: [CH3:1][C:2]([NH:10][C:11]([C:13]1[CH:18]=[CH:17][C:16](Br)=[C:15]([O:20][CH2:21][CH:22]2[CH2:24][CH2:23]2)[N:14]=1)=[O:12])([C:4]1[N:8]=[C:7]([CH3:9])[O:6][N:5]=1)[CH3:3].CC([Si](C)(C)[O:30][C@H:31]1[CH2:35][CH2:34][NH:33][CH2:32]1)(C)C>>[CH3:1][C:2]([NH:10][C:11]([C:13]1[CH:18]=[CH:17][C:16]([N:33]2[CH2:34][CH2:35][C@H:31]([OH:30])[CH2:32]2)=[C:15]([O:20][CH2:21][CH:22]2[CH2:24][CH2:23]2)[N:14]=1)=[O:12])([C:4]1[N:8]=[C:7]([CH3:9])[O:6][N:5]=1)[CH3:3]
Reactant: Cc1nc(C(C)(C)NC(=O)c2ccc(Br)c(OCC3CC3)n2)no1
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1CCNC1
Product: Cc1nc(C(C)(C)NC(=O)c2ccc(N3CC[C@H](O)C3)c(OCC3CC3)n2)no1

Procedure:
The title compound was synthesized in analogy to Example 322b, using 5-bromo-6-cyclopropylmethoxy-pyridine-2-carboxylic acid [1-methyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethyl]-amide (Example 322a) and (35)-3-[[(1,1-dimethylethyl)dimethylsilyl]oxy]-pyrrolidine (CAN 207113-36-8) as starting materials. The protecting group was removed with tetrabutylammonium fluoride in THF; LC-MS (UV peak area/ESI) 100%, 402.2134 (M+H)+.
Reaction SMILES: C([O:3][C:4](=[O:20])[C@@H:5]([O:18][CH3:19])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][CH2:16]Br)=[CH:9][CH:8]=1)C.[F:21][C:22]1[CH:23]=[C:24]([CH:35]=[CH:36][CH:37]=1)[C:25]([NH:27][C:28]1[CH:33]=[CH:32][C:31]([OH:34])=[CH:30][CH:29]=1)=[O:26].[OH-].[Na+]>>[F:21][C:22]1[CH:23]=[C:24]([CH:35]=[CH:36][CH:37]=1)[C:25]([NH:27][C:28]1[CH:33]=[CH:32][C:31]([O:34][CH2:16][CH2:15][CH2:14][O:13][C:10]2[CH:9]=[CH:8][C:7]([CH2:6][C@H:5]([O:18][CH3:19])[C:4]([OH:3])=[O:20])=[CH:12][CH:11]=2)=[CH:30][CH:29]=1)=[O:26]
Reactant: CCOC(=O)[C@H](Cc1ccc(OCCCBr)cc1)OC
Reactant: O=C(Nc1ccc(O)cc1)c1cccc(F)c1
Agent: [Na+]
Agent: [OH-]
Product: CO[C@@H](Cc1ccc(OCCCOc2ccc(NC(=O)c3cccc(F)c3)cc2)cc1)C(=O)O

Procedure:
(2S)-3-[4-(3-Bromo-propoxy)-phenyl]-2-methoxy-propionic acid ethyl ester from Example 173, Step A was treated with 3-Fluoro-N-(4-hydroxy-phenyl)-benzamide from Step A under the Standard Procedure J. The compound thus obtained was allowed to react under Standard hydrolysis procedure C (NaOH) to give the title compound. MS(ES) for C26H26FNO6 [M+H]+: 468.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].CN(C=O)C.[CH2:28](I)[CH3:29]>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:15]=[CH:16][C:17]([O:20][CH2:28][CH3:29])=[CH:18][CH:19]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCI
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(O)cc2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CCOc1ccc(N2CCN(C(=O)OC(C)(C)C)CC2)cc1
Temperature: 0 °C
Reaction time: 5 h

Procedure:
A mixture of 1-(tert-butyloxycarbonyl)-4-(4-hydroxyphenyl)piperazine (XXII, 0.602 g, 2.2 mmol) in dry THF (4 ml) is added to an ice-cooled slurry of sodium hydride (0.1013 g, 2.5 mmol--60% in oil) in THF (1 ml). DMF (15.3 ml) is added to solubilize the solids that had precipitated, after which ethyl iodide (0.34 ml, 4.3 mmol) is added. The ice/water bath is removed and the mixture stirred for five hr. Another portion of ethyl iodide (0.35 ml, 4.4 mmol) is added and the mixture is allowed ti stir over the weekend at 20-25°, at which time it is concentrated and the resulting solids are partitioned between ethyl acetate and aqueous saturated sodium bicarbonate. The combined organic phases are dried over magnesium sulfate, concentrated, and the residue chromatographed on silica gel eluting with methanol/dichloromethane (1/99) containing ammonium hydroxide (0.5%), followed by methanol/dichloromethane (2/98) containing ammonium hydroxide (0.5%). The appropriate fractions are pooled and concentrated to give 1-(tert-butyloxycarbonyl)-4-(4-ethoxyphenyl)piperazine (XXIII). 1-(Tert-butyloxycarbonyl)-4-(4-ethoxyphenyl)-piperazine (XXIII, 0.43 g) is dissolved in methanol and methanol saturated with hydrochloric acid gas is added. After stirring at 20-25° for 5 hours the slurry is concentrated and ether is added. The solids are collected, washed with ether, and dried to give 1-(4-ethoxyphenyl)piperazine dihydrochloride (XXIV), MS (m/z) 206; IR (mineral oil) 1253, 1511, 2542, 2432, 1475 and 2622 cm-1.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1.[Cl:13][C:14]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=1[S:21](Cl)(=[O:23])=[O:22]>>[Cl:13][C:14]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=1[S:21]([NH:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1)(=[O:23])=[O:22]
Reactant: O=S(=O)(Cl)c1ccc(F)cc1Cl
Reactant: CCOC(=O)Cc1csc(N)n1
Product: CCOC(=O)Cc1csc(NS(=O)(=O)c2ccc(F)cc2Cl)n1

Procedure:
The title compound was prepared from ethyl 2-amino-4-thiazolylacetate and 2-chloro-4-fluorobenzenesulfonyl chloride as described in the synthetic METHOD B to give a white solid (13.9 mg) with purity >90%. MS (pos) m/z 379.2, 381.2.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][N:16]([CH2:19][CH2:20][CH2:21][CH2:22][N:23]([CH2:27][CH2:28][CH3:29])[CH2:24][CH2:25][CH3:26])[CH2:17][CH3:18])=[CH:11][CH:10]=1)(C)(C)C.Cl.O1CCOCC1>CO>[NH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][N:16]([CH2:17][CH3:18])[CH2:19][CH2:20][CH2:21][CH2:22][N:23]([CH2:27][CH2:28][CH3:29])[CH2:24][CH2:25][CH3:26])=[CH:11][CH:10]=1
Reactant: CCCN(CCC)CCCCN(CC)Cc1ccc(CNC(=O)OC(C)(C)C)cc1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: CCCN(CCC)CCCCN(CC)Cc1ccc(CN)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.5 %

Procedure:
The compound (311 mg) obtained in Example 23-5 was dissolved in anhydrous methanol (1.0 ml) and added with a 4 mol/l hydrogen chloride/dioxane solution (3.0 ml) and the whole was stirred at room temperature for 1 hour. After completion of the reaction, the solvent was distilled off. The resultant was added with a 1 mol/l sodium hydroxide aqueous solution, subjected to extraction with chloroform, and washed with a saturated saline solution. The organic layer was dried with anhydrous sodium sulfate. The solvent was distilled off, thereby obtaining the subject compound (219 mg) as a pale-yellow oily substance.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([CH2:6][CH2:7][CH2:8][C:9]([OH:11])=O)[N:3]=[N:2]1.[CH3:12][NH:13][CH:14]1[CH2:19][CH2:18][N:17]([C:20]([O:22][CH2:23][C:24]2[CH:29]=[C:28]([Cl:30])[CH:27]=[C:26]([Cl:31])[CH:25]=2)=[O:21])[CH2:16][CH2:15]1.CCN(C(C)C)C(C)C.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC>CN(C=O)C>[CH3:12][N:13]([CH:14]1[CH2:19][CH2:18][N:17]([C:20]([O:22][CH2:23][C:24]2[CH:25]=[C:26]([Cl:31])[CH:27]=[C:28]([Cl:30])[CH:29]=2)=[O:21])[CH2:16][CH2:15]1)[C:9](=[O:11])[CH2:8][CH2:7][CH2:6][C:4]1[N:3]=[N:2][NH:1][CH:5]=1
Reactant: CNC1CCN(C(=O)OCc2cc(Cl)cc(Cl)c2)CC1
Reactant: O=C(O)CCCc1c[nH]nn1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(C(=O)CCCc1c[nH]nn1)C1CCN(C(=O)OCc2cc(Cl)cc(Cl)c2)CC1
Temperature: 25 °C
Reaction time: 216 h

Procedure:
4-(1H-1,2,3-Triazol-4-yl)butanoic acid (Example 17, step 4) (200 mg, 1.289 mmol) and 3,5-dichlorobenzyl 4-(methylamino)piperidine-1-carboxylate (Step 2) (456 mg, 1.289 mmol) were dissolved in DMF (6 ml) and treated with DIPEA (1.126 ml, 6.45 mmol) followed by 50% T3P® in DMF (1.505 ml, 2.58 mmol). After stirring at RT for 9 days, the mixture was evaporated under reduced pressure. The crude product was solubilised in DCM and washed with 10% citric acid. The organic portion was passed through a phase separating cartridge and the filtrate was evaporated under reduced pressure. The crude residue was purified by chromatography on silica eluting with 0-10% MeOH in EtOAc to afford the title compound;
Reaction SMILES: Cl[C:2]1[NH:3][C:4](=[O:12])[C:5]2[CH:10]=[CH:9][N:8]([CH3:11])[C:6]=2[N:7]=1.Cl.[F:14][C:15]1[CH:20]=[CH:19][C:18]([CH:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)=[CH:17][CH:16]=1.C(N(CC)C(C)C)(C)C>C(O)C>[F:14][C:15]1[CH:20]=[CH:19][C:18]([CH:21]2[CH2:22][CH2:23][N:24]([C:2]3[NH:3][C:4](=[O:12])[C:5]4[CH:10]=[CH:9][N:8]([CH3:11])[C:6]=4[N:7]=3)[CH2:25][CH2:26]2)=[CH:17][CH:16]=1
Reactant: Cn1ccc2c(=O)[nH]c(Cl)nc21
Reactant: Fc1ccc(C2CCNCC2)cc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: Cn1ccc2c(=O)[nH]c(N3CCC(c4ccc(F)cc4)CC3)nc21
Temperature: 140 °C
Yield: 104.6 %

Procedure:
A microwave reaction vial was charged with 2-chloro-7-methyl-3,7-dihydro-pyrrolo[2,3-d]pyrimidin-4-one (Intermediate A) (25 mg, 0.13 mmol), 4-(4-fluorophenyl)piperidine hydrochloride (35.2 mg, 0.16 mmol), and N,N-diisopropylethylamine (52.8 mg, 0.41 mmol) in ethanol (1.5 mL). The vial was sealed and then heated in the microwave at 140° C. for 15 min. At this time, the resulting mixture was concentrated in vacuo. Flash chromatography (20/1 methylene chloride/methanol) afforded 2-[4-(4-fluoro-phenyl)-piperidin-1-yl]-7-methyl-3,7-dihydro-pyrrolo[2,3-d]pyrimidin-4-one (44.4 mg, 36%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.5-1.7 (m, 2H) 1.8 (d, J=11.55 Hz, 2H) 2.8 (br. s., 1H) 2.9 (t, J=12.05 Hz, 2H) 3.5 (s, 3H) 4.5 (d, J=13.05 Hz, 2H) 6.2 (d, J=3.51 Hz, 1H) 6.7 (d, J=3.26 Hz, 1H) 7.1 (t, J=8.78 Hz, 2H) 7.3 (dd, J=8.53, 5.52 Hz, 2H) 10.7 (s, 1H). LC-MS calcd. for C18H20FN4O [(M+H)+] 327, obsd. 327.0.
Reaction SMILES: C(N(CC)CC)C.ClC(Cl)(O[C:12](=[O:18])[O:13][C:14](Cl)(Cl)Cl)Cl.[NH2:20][C:21]1[CH:26]=[C:25]([C:27]([CH3:29])=[O:28])[CH:24]=[CH:23]C=1O.Cl>C1COCC1>[CH3:29][C:27]([C:25]1[CH:24]=[CH:23][C:14]2[O:13][C:12](=[O:18])[NH:20][C:21]=2[CH:26]=1)=[O:28]
Reactant: CC(=O)c1ccc(O)c(N)c1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)c1ccc2oc(=O)[nH]c2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
7.8 ml of triethylamine and 2.75 g (0.0093 mol) of triphosgene are added to a mixture of 4.2 g (0.0277 mol) of 2-amino-4-methylcarbonylphenol in 100 ml of THF, at 0° C. The mixture is stirred at room temperature for 1 hour, poured into 100 ml of a 0.5N HCl solution and extracted with ethyl acetate, the organic phase is dried and the solvent is evaporated off. The compound of the title is obtained.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[N:5][C:6]([NH:9][CH2:10][CH2:11][C:12]2[CH:17]=[C:16]([CH3:18])[C:15]([O:19]C)=[CH:14][C:13]=2[CH3:21])=[N:7][CH:8]=1)[CH3:2].[F:22][C:23]([F:34])([F:33])[O:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29]Br)=[CH:27][CH:26]=1>>[CH2:1]([C:3]1[CH:4]=[N:5][C:6]([N:9]([CH2:29][C:28]2[CH:31]=[CH:32][C:25]([O:24][C:23]([F:22])([F:33])[F:34])=[CH:26][CH:27]=2)[CH2:10][CH2:11][C:12]2[C:13]([CH3:21])=[CH:14][C:15]([OH:19])=[C:16]([CH3:18])[CH:17]=2)=[N:7][CH:8]=1)[CH3:2]
Reactant: CCc1cnc(NCCc2cc(C)c(OC)cc2C)nc1
Reactant: FC(F)(F)Oc1ccc(CBr)cc1
Product: CCc1cnc(N(CCc2cc(C)c(O)cc2C)Cc2ccc(OC(F)(F)F)cc2)nc1

Procedure:
Similarly prepared from 5-ethyl-N-[2-(4-methoxy-2,5-dimethylphenyl)ethyl]pyrimidin-2-amine and 4-trifluoromethoxy benzyl bromide.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[C:8](F)[C:5]([C:6]#[N:7])=[CH:4][N:3]=1.[CH3:11][N:12]1[CH2:16][CH2:15][C@@H:14]([OH:17])[CH2:13]1>>[NH2:1][C:2]1[CH:9]=[C:8]([O:17][C@@H:14]2[CH2:15][CH2:16][N:12]([CH3:11])[CH2:13]2)[C:5]([C:6]#[N:7])=[CH:4][N:3]=1
Reactant: N#Cc1cnc(N)cc1F
Reactant: CN1CC[C@@H](O)C1
Product: CN1CC[C@@H](Oc2cc(N)ncc2C#N)C1

Procedure:
From intermediate 21 and (R)-1-methylpyrrolidin-3-ol, reacted in an analogous manner to the preparation of intermediate 47. (UPLC-MS 3) tR 0.28 min; ESI-MS 219.2 [M+H]+.
Reaction SMILES: [BH4-].[Na+].[Br:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[CH:10]=[N:9][CH:8]=[CH:7]2.[C:14](O)(=[O:16])[CH3:15]>C(OC(=O)C)(=O)C>[Br:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[CH2:10][N:9]([C:14](=[O:16])[CH3:15])[CH:8]=[CH:7]2
Reactant: Brc1ccc2cnccc2c1
Reactant: CC(=O)O
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Product: CC(=O)N1C=Cc2cc(Br)ccc2C1
Temperature: 60 °C

Procedure:
Sodium borohydride (1.12 g, 29.6 mmol) is added portionwise to a cooled (0° C.) solution of 6-bromoisoquinoline [J Chem Soc Perkin Trans 2, 1998, 437] (1.544 g, 7.42 mmol) in acetic acid (10 ml) and acetic anhydride (3 ml). After heating at 60° C. for 4 hours, the mixture is cooled, evaporated and diluted with water. After adjustment to pH10 with potassium carbonate and extraction with ethyl acetate, the combined organic phases are washed twice with 0.5N HCl and brine, then dried over sodium sulphate. Evaporation affords 1-(6-bromo-1H-isoquinolin-2-yl)-ethanone, MH+ 253. Glyoxylic acid (0.812 g, 8.80 mmol) is added to mixture of 1-(6-bromo-1H-isoquinolin-2-yl)-ethanone (1.50 g, 5.90 mmol) in 6N HCl (20 ml). The reaction is heated at 100° C. for 2 hours, cooled to RT and washed with ethyl acetate. After evaporation, the residue is taken into methanol (20 ml), concentrated sulphuric acid (10 drops) is added and the mixture heated at reflux for 14 hours. After partial evaporation of the solvent, the resultant solid is collected by filtration, washed with methanol and dried to afford (6-bromo-isoquinolin-4-yl)-acetic acid methyl ester cooled (0° C.) solution of (6-bromo-isoquinolin-4-yl)-acetic acid methyl ester (50 mg, 0.18 mmol) in 3:1 THF-water (3 ml). After 1 hour the solvent is evaporated to afford (6-bromo-isoquinolin-4-yl)-acetic acid lithium salt, MH+ 266.
Reaction SMILES: [N:1]1([CH2:6][C:7]2[CH:21]=[CH:20][C:10]([CH2:11][N:12]3[CH:16]=[C:15]([C:17]([OH:19])=O)[N:14]=[CH:13]3)=[CH:9][CH:8]=2)[CH:5]=[CH:4][CH:3]=[N:2]1.[C:22]([O:26][C:27](=[O:39])[NH:28][C:29]1[CH:34]=[C:33]([CH3:35])[C:32]([CH2:36][NH2:37])=[C:31]([CH3:38])[N:30]=1)([CH3:25])([CH3:24])[CH3:23].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[C:22]([O:26][C:27](=[O:39])[NH:28][C:29]1[CH:34]=[C:33]([CH3:35])[C:32]([CH2:36][NH:37][C:17]([C:15]2[N:14]=[CH:13][N:12]([CH2:11][C:10]3[CH:9]=[CH:8][C:7]([CH2:6][N:1]4[CH:5]=[CH:4][CH:3]=[N:2]4)=[CH:21][CH:20]=3)[CH:16]=2)=[O:19])=[C:31]([CH3:38])[N:30]=1)([CH3:25])([CH3:24])[CH3:23]
Reactant: Cc1cc(NC(=O)OC(C)(C)C)nc(C)c1CN
Reactant: O=C(O)c1cn(Cc2ccc(Cn3cccn3)cc2)cn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cc(NC(=O)OC(C)(C)C)nc(C)c1CNC(=O)c1cn(Cc2ccc(Cn3cccn3)cc2)cn1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 1-(4-Pyrazol-1-ylmethyl-benzyl)-1H-imidazole-4-carboxylic acid (0.67 g, 2.4 mmol), (5-Aminomethyl-4,6-dimethyl-pyridin-2-yl)-carbamic acid tert-butyl ester (0.61 g, 2.4 mmol), HATU (1.8 g, 4.8 mmol) and DIPEA (1.3 mL, 7.2 mmol) in 10 mL DMF was stirred at room temperature for 16 h. The mixture was evaporated and the residue was partitioned between ethyl acetate and 1 N aq. HCl. The organic layer was dried over MgSO4 and evaporated in vacuo. The crude product was purified by preparative HPLC (Waters Sunfire Prep C18 PBD 5 um, 30×100 mm, 5 to 100% ACN and 0.1% TFA, flow 40 ml/min). LCMS (method A) RtA=1.418 min; [M+H]+=516.1.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:8])=[N:6][CH:7]=1.CCN(C(C)C)C(C)C.Cl[C:19]([O:21][C:22]1[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=1)=[O:20]>C(Cl)Cl>[Cl:8][C:5]1[N:6]=[CH:7][C:2]([NH:1][C:19](=[O:20])[O:21][C:22]2[CH:23]=[CH:24][C:25]([N+:28]([O-:30])=[O:29])=[CH:26][CH:27]=2)=[CH:3][CH:4]=1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: Nc1ccc(Cl)nc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(Nc1ccc(Cl)nc1)Oc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 5-amino-2-chloropyridine (162 mg, 1262 μmol) and DIEA (275 μL, 1578 mmol) in DCM (6.0 mL) was added 4-nitrophenyl chloroformate (212 mg, 1052 μmol). The resulting mixture was then stirred at RT for overnight. A yellow precipitation was observed. The yellow solid was collected by filtration to give the title compound as a light yellow solid, which was used in the next step without purification requirement.
Reaction SMILES: [NH2:1][CH:2]1[CH:8]=[CH:7][C:6]2[CH:9]=[CH:10][CH:11]=[CH:12][C:5]=2[N:4]([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:3]1=[O:19].[C:20]([S:23][C@@H:24]([C@@H:28]([CH3:31])[CH2:29][CH3:30])[C:25](O)=[O:26])(=[O:22])[CH3:21]>>[C:20]([S:23][C@@H:24]([C@@H:28]([CH3:31])[CH2:29][CH3:30])[C:25]([NH:1][CH:2]1[CH:8]=[CH:7][C:6]2[CH:9]=[CH:10][CH:11]=[CH:12][C:5]=2[N:4]([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:3]1=[O:19])=[O:26])(=[O:22])[CH3:21]
Reactant: CCOC(=O)CN1C(=O)C(N)C=Cc2ccccc21
Reactant: CC[C@H](C)[C@H](SC(C)=O)C(=O)O
Product: CCOC(=O)CN1C(=O)C(NC(=O)[C@@H](SC(C)=O)[C@@H](C)CC)C=Cc2ccccc21
Yield: 48.6 %

Procedure:
0.525 g (2 mmol) of 3-amino-1-ethoxycarbonylmethyl-1H-[1]benzazepin-2-one and 0.418 g (2.2 mmol) of (2S,3S)-2-acetylthio-3-methylvaleric acid were reacted in the same manner as that of Example A-2. Thus, 0.42 g of the title compound was obtained as a colorless amorphous product. Yield 48%.
Reaction SMILES: [CH:1]12[CH2:9][CH:5]([C:6]1([CH3:8])[CH3:7])C[CH2:3][CH:2]2C.[C:11]([OH:14])(=[O:13])[CH3:12].[O:15](O)O>C(Cl)(Cl)Cl>[C:11]([OH:14])(=[O:13])[CH3:12].[C:5]12([OH:15])[CH2:9][CH:1]([C:6]1([CH3:8])[CH3:7])[CH2:2][CH2:3][C:11]2([OH:14])[CH3:12]
Reactant: OOO
Reactant: CC1CCC2CC1C2(C)C
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: CC1(O)CCC2CC1(O)C2(C)C

Procedure:
The mixture was extracted with 50% EtOAc/hexanes two times. The combined organic extract was washed with 10% NaHSO3 solution and water, dried over anhydrous Na2SO4 and concentrated to afford the crude product as a tan oil (2.85 g). The pinanediol acetate 3 was purified by silica gel chromatography, eluting with 5˜50% EtOAc/hex, to yield a nearly colorless oil (2.03 g, 84%) containing a small amount of a less polar pinane-keto-alcohol acetate byproduct. IR (CHCl3): 3450, 3000, 2927, 2870, 1730, 1475, 1455, 1388, 1370, 1230, 1128, 1042, and 605 cm−1. 1HNMR (400 MHz, CDCl3): δ 4.26-4.38 (m, 2H), 4.03-4.09 (m, 1H), 3.15 (s, 1H, OH), 2.89 (d, J=6.2 Hz, 1H, OH), 2.46-2.54 (m, 1H), 2.18-2.26 (m, 1H), 2.10 (t, J=5.8 Hz, 1H), 2.06(s, 3H), 1.92-2.05 (m, 2H), 1.79-1.87 (m, 1H), 1.63-1.70 (m, 1H), 1.38 (d, J=10.4 Hz, 1H), 1.27 (s, 3H), 0.94 (s, 3H).
Reaction SMILES: O.[C:2]([O-:9])(=[O:8])[CH2:3][CH2:4][C:5]([O-:7])=[O:6].[NH4+].[NH4+].[C:12]1([CH3:22])[CH:17]=[CH:16]C(S(O)(=O)=O)=CC=1>C(O)CCC>[C:2]([O:9][CH2:22][CH2:12][CH2:17][CH3:16])(=[O:8])[CH2:3][CH2:4][C:5]([O:7][CH2:2][CH2:3][CH2:4][CH3:5])=[O:6]
Reactant: O=C([O-])CCC(=O)[O-]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: [NH4+]
Solvent: O
Solvent: CCCCO
Product: CCCCOC(=O)CCC(=O)OCCCC

Procedure:
For the esterification reaction, a three-neck flask (500 ml) with a water separator is used, in which n-butanol, 52 g of diammonium succinate and 0.45 g of para-toluenesulfonic acid are initially charged. The mixture is brought to boiling with stirring. During the reaction, the dibutyl succinate formed is enriched in the flask (together with butanol). The water/n-butanol azeotrope and NH3 are distilled off via the top and condensed in the water separator. The condensate is separated into a butanol phase and a water phase. The butanol phase is recycled into the flask. The reaction ran for a total of 240 hours.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([OH:10])=[C:6]([CH:9]=1)[CH2:7][OH:8].Cl[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=2)=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH2:12][C:13]2[CH:14]=[CH:15][C:16]([C:19]3[CH:24]=[CH:23][C:22]([C:25]([F:26])([F:27])[F:28])=[CH:21][CH:20]=3)=[CH:17][CH:18]=2)=[C:6]([CH2:7][OH:8])[CH:9]=1
Reactant: OCc1cc(F)ccc1O
Reactant: FC(F)(F)c1ccc(-c2ccc(CCl)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: OCc1cc(F)ccc1OCc1ccc(-c2ccc(C(F)(F)F)cc2)cc1

Procedure:
A solution of 4.59 g (36.9 mmol) of 5-fluoro-2-hydroxybenzyl alcohol [CAS 2357-33-7] in 200 ml of dry acetonitrile is mixed with 10.0 g (36.9 mmol) of 4-chloromethyl-4′-trifluoromethylbiphenyl and 6.13 g (44.3 mmol) of anhydrous potassium carbonate and heated under reflux for 12 hours. The mixture is then concentrated to dryness. The residue is taken up in ethyl acetate, washed with water and saturated sodium chloride solution and dried over sodium sulfate. After concentration, the resulting crude product is purified by flash chromatography on silica gel 60 (mobile phase: cyclohexane/ethyl acetate 5:1). 11.8 g (32.9 mmol, 89% of theory) of the title compound are obtained.
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[C:11]([O:13][CH3:14])[C:10]([F:15])=[CH:9][C:8]=2[C:16]2[C:17]3[NH:24][C:23]([CH3:25])=[C:22]([C:26]([NH:28][C@@H:29]4[CH2:34][CH2:33][NH:32][CH2:31][C@H:30]4[OH:35])=[O:27])[C:18]=3[N:19]=[CH:20][N:21]=2)[CH2:4][CH2:3]1.[CH3:36][O:37][CH2:38][C:39](Cl)=[O:40]>>[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[C:11]([O:13][CH3:14])[C:10]([F:15])=[CH:9][C:8]=2[C:16]2[C:17]3[NH:24][C:23]([CH3:25])=[C:22]([C:26]([NH:28][C@@H:29]4[CH2:34][CH2:33][N:32]([C:39](=[O:40])[CH2:38][O:37][CH3:36])[CH2:31][C@H:30]4[OH:35])=[O:27])[C:18]=3[N:19]=[CH:20][N:21]=2)[CH2:4][CH2:3]1
Reactant: COCC(=O)Cl
Reactant: COc1cc(OCC2CC2)c(-c2ncnc3c(C(=O)N[C@@H]4CCNC[C@H]4O)c(C)[nH]c23)cc1F
Agent: Cl
Product: COCC(=O)N1CC[C@@H](NC(=O)c2c(C)[nH]c3c(-c4cc(F)c(OC)cc4OCC4CC4)ncnc23)[C@H](O)C1

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-5-fluoro-4-methoxyphenyl]-N-[(3R*,4R*)-3-hydroxypiperidin-4-yl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f47) and commercially available methoxy-acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[C:5]1[CH:10]=[C:9]([OH:11])[CH:8]=[C:7]([OH:12])[CH:6]=1)[CH3:2].[CH2:14](Br)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31].[Na]>C(O)C>[CH2:1]([O:3][C:4](=[O:13])[C:5]1[CH:10]=[C:9]([O:11][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[CH:8]=[C:7]([O:12][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH3:14])[CH:6]=1)[CH3:2]
Reactant: CCCCCCCCCCCCCCCCCCBr
Reactant: CCOC(=O)c1cc(O)cc(O)c1
Agent: [Na]
Solvent: CCO
Product: CCCCCCCCCCCCCCCCCCOc1cc(OCCCCCCCCCCCCCCCCCC)cc(C(=O)OCC)c1

Procedure:
50 m mol of 3,5-dihydroxybenzoic acid ethyl ester, 120 m mol of stearyl bromide, and 110 m mol of sodium were made to react in ethanol, thereby forming 35 m mol of 3,5-dioctadecyloxybenzoic acid ethyl ester. This ester, 25 m mol, was first hydrolyzed into the corresponding acid, which in turn was converted into its acid chloride. The acid chloride was reacted in the same way as in Example 1, whereby 10 m mol of N-(3,5-dioctadecyloxybenzoyl)-N'methylsulfonyl-p-quinonediimine was obtained which is represented by the following formula: ##STR30##