Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:29]2[CH2:34][CH2:33][CH2:32][CH2:31][CH:30]=2)=[CH:4][C:5]([O:27][CH3:28])=[C:6]([CH:26]=1)[C:7]([N:9]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[CH2:13][N:12]2[C:20]([C:23](O)=[O:24])=[CH:21][CH:22]=[C:11]2[CH2:10]1)=[O:8].[CH3:35][NH:36][CH2:37][CH:38]([OH:41])[CH2:39][OH:40].ON1C2C=CC=CC=2N=N1.Cl.C(N=C=N)C.C(N(CC)C(C)C)(C)C>C(OCC)(=O)C>[Cl:1][C:2]1[C:3]([C:29]2[CH2:34][CH2:33][CH2:32][CH2:31][CH:30]=2)=[CH:4][C:5]([O:27][CH3:28])=[C:6]([CH:26]=1)[C:7]([N:9]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[CH2:13][N:12]2[C:20]([C:23]([N:36]([CH2:37][CH:38]([OH:41])[CH2:39][OH:40])[CH3:35])=[O:24])=[CH:21][CH:22]=[C:11]2[CH2:10]1)=[O:8]
Reactant: CNCC(O)CO
Reactant: COc1cc(C2=CCCCC2)c(Cl)cc1C(=O)N1Cc2ccc(C(=O)O)n2Cc2ccccc21
Agent: CCN=C=N
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(C2=CCCCC2)c(Cl)cc1C(=O)N1Cc2ccc(C(=O)N(C)CC(O)CO)n2Cc2ccccc21
Temperature: 25 °C
Reaction time: 12 h
Yield: 91.4 %

Procedure:
10-(5-Chloro-4-cyclohex-1-en-1-yl-2-methoxybenzoyl)-10,11-dihydro-5H-pyrrolo [2,1-c][1,4]benzodiazepine-3-carboxylic acid of Example 1, Step G (0.370 g, 0.776 mmol), 3-methylamino-1,2-propanediol (0.098 g, 0.931 mmol), 1-hydroxy benzotriazole (0.115 g, 0.854 mmol) and 1-[3-dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (0.164 g, 0.854 mmol) were combined in amine-free N,N-dimethylformamide (3.9 mL), followed by addition of N,N-diisopropylethylamine (0.202 mL, 1.16 mmol). The reaction was stirred at room temperature for 12 hours, then diluted with ethyl acetate and washed with 1 N hydrochloric acid, 1 N sodium hydeoxide and brine. The combined aqueous washings were saturated with sodium chloride and extracted with ethyl acetate. The combined organic phases were dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by flash column chromatography on silica gel eluting with a solvent gradient from 0 to 5% of methanol in chloroform, to afford 0.400 g of the title compound as a white, crystalline solid, m.p.155-157° C.
Reaction SMILES: C(OC(=O)[N:7]([CH:25]([CH3:27])[CH3:26])[C:8]1[C:9]2[N:10]([C:14]([C:17]3[CH:22]=[CH:21][N:20]=[C:19](SC)[N:18]=3)=[CH:15][N:16]=2)[CH:11]=[CH:12][N:13]=1)(C)(C)C.[CH:29]([NH2:32])([CH3:31])[CH3:30]>>[CH:25]([NH:7][C:8]1[C:9]2[N:10]([C:14]([C:17]3[CH:22]=[CH:21][N:20]=[C:19]([NH:32][CH:29]([CH3:31])[CH3:30])[N:18]=3)=[CH:15][N:16]=2)[CH:11]=[CH:12][N:13]=1)([CH3:26])[CH3:27]
Reactant: CC(C)N
Reactant: CSc1nccc(-c2cnc3c(N(C(=O)OC(C)(C)C)C(C)C)nccn23)n1
Product: CC(C)Nc1nccc(-c2cnc3c(NC(C)C)nccn23)n1

Procedure:
Isopropyl-[3-(2-isopropylamino-pyrimidin-4-yl)-imidazo[1,2-a]pyrazin-8-yl]-amine was prepared by a process analogous to that described in Example 12 starting from isopropyl-[3-(2-methylsulfanyl-pyrimidin-4-yl)-imidazo[1,2-a]pyrazin-8-yl]-carbamic acid tert-butyl ester (from Example 11 supra), and isopropylamine. LC-MS: [M+H]+ 312.3.
Reaction SMILES: CC([O-])(C)C.[K+].[CH3:7][CH2:8][SH:9].[C:10]([O:14][C:15]([N:17]1[CH2:21][CH2:20][CH2:19][C@H:18]1[CH:22]=[C:23]([C:25]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26])[CH3:24])=[O:16])([CH3:13])([CH3:12])[CH3:11]>C1COCC1>[C:10]([O:14][C:15]([N:17]1[CH2:21][CH2:20][CH2:19][C@H:18]1[C@H:22]([S:9][CH2:8][CH3:7])[C@H:23]([C:25]([O:27][CH2:28][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)=[O:26])[CH3:24])=[O:16])([CH3:11])([CH3:12])[CH3:13]
Reactant: CCS
Reactant: CC(=C[C@@H]1CCCN1C(=O)OC(C)(C)C)C(=O)OCc1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCS[C@H]([C@@H](C)C(=O)OCc1ccccc1)[C@@H]1CCCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 83.1 %

Procedure:
To a stirred suspension of t-BuOK (609 mg, 5.43 mmol) in THF (90 ml) was added EtSH (8.04 ml, 0.11 mol). After stirring for 30 min at room temperature, a solution of (2S)-2-(2-benzyloxycarbonyl-propenyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (3.75 g, 10.8 mmol) in THF (75 ml) was added to the mixture. After 2.5 h, the mixture was quenched with saturated NH4Cl aqueous solution, and then concentrated in vacuo. The residue was diluted with EtOAc (400 ml), and washed with saturated NH4Cl aqueous solution (150 ml), saturated NaHCO3 aqueous solution (150 ml) and H2O (150 ml). The organic layer was dried over anhydrous Na2SO4, and then concentrated in vacuo. The residue was purified by column chromatography on silica gel (hexane/EtOAc=12/1 to 8/1) to give (2S)-2-[(1R,2S)-2-benzyloxycarbonyl-1-ethylsulfanyl-propyl]-pyrrolidine-1-carboxylic acid tert-butyl ester (3.66 g, 83%).
Reaction SMILES: [ClH:1].[C:2]([C@@:4]1([CH:28]2[CH2:30][CH2:29]2)[CH2:8][CH2:7][N:6]([C:9]2[CH:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]3[CH:17]=[N:18][N:19]([C:21]([CH3:26])([CH3:25])[C:22]([OH:24])=O)[CH:20]=3)[N:10]=2)[C:5]1=[O:27])#[N:3].C(N=C=NCCCN(C)C)C.O.ON1C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.[NH:62]1[CH2:67][CH2:66][O:65][CH2:64][CH2:63]1>CN(C)C=O>[ClH:1].[CH:28]1([C@:4]2([C:2]#[N:3])[CH2:8][CH2:7][N:6]([C:9]3[CH:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]4[CH:17]=[N:18][N:19]([C:21]([CH3:25])([CH3:26])[C:22]([N:62]5[CH2:67][CH2:66][O:65][CH2:64][CH2:63]5)=[O:24])[CH:20]=4)[N:10]=3)[C:5]2=[O:27])[CH2:30][CH2:29]1
Reactant: CC(C)(C(=O)O)n1cc(Nc2nccc(N3CC[C@@](C#N)(C4CC4)C3=O)n2)cn1
Reactant: C1COCCN1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C(=O)N1CCOCC1)n1cc(Nc2nccc(N3CC[C@@](C#N)(C4CC4)C3=O)n2)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 37.7 %

Procedure:
To a solution of 2-(4-((4-((3S)-3-cyano-3-cyclopropyl-2-oxopyrrolidin-1-yl)pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)-2-methylpropanoic acid hydrochloride (80 mg) obtained in Example 108 in N,N-dimethylformamide (2.0 mL) were added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (58 mg), 1-hydroxybenzotriazole monohydrate (57 mg), N,N-diisopropylethylamine (97 μL) and morpholine (19 mg), and the mixture was stirred overnight at room temperature. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (NH, hexane/ethyl acetate). To a solution of the residue (87 mg) in ethanol (3.0 mL) was added dropwise 1 M hydrochloric acid (0.19 mL), the mixture was stirred for 5 min, and the solvent was evaporated under reduced pressure. The residue was recrystallized (ethanol/diisopropyl ether) to give the title compound (35 mg).
Reaction SMILES: [CH2:1]([S:6][CH2:7][CH2:8][CH2:9]Cl)[CH2:2][CH2:3][CH2:4][CH3:5].[NH2:11][C:12]1[N:16]=[C:15]([SH:17])[NH:14][N:13]=1.N1C=CC=CC=1.NC1N=C(SCCSCCSCCCCCC)NN=1>C(#N)C.O>[NH2:11][C:12]1[N:16]=[C:15]([S:17][CH2:9][CH2:8][CH2:7][S:6][CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])[NH:14][N:13]=1
Reactant: Nc1n[nH]c(S)n1
Reactant: CCCCCSCCCCl
Agent: CCCCCCSCCSCCSc1nc(N)n[nH]1
Solvent: c1ccncc1
Solvent: O
Solvent: CC#N
Product: CCCCCSCCCSc1nc(N)n[nH]1

Procedure:
Compound 9 was prepared from a mixture of 3-chloropropyl pentyl sulfide, 3-amino-5-mercapto-1,2,4-triazole and pyridine in acetonitrile, as described previously for Compound 12. The reaction mixture was poured into water and extracted with CH2Cl2. The extracts were washed with water and brine, dried over MgSO4, and concentrated under vacuum to provide Compound 9 in 71% yield.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]([OH:17])([C:13]([F:16])([F:15])[F:14])[C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=1.[Cl:18][C:19]1[N:24]=[CH:23][C:22]([S:25]([N:28]2[CH2:33][CH2:32][NH:31][CH:30]([C:34]#[C:35][CH3:36])[CH2:29]2)(=[O:27])=[O:26])=[CH:21][CH:20]=1.CCN(C(C)C)C(C)C>O1CCOCC1>[Cl:18][C:19]1[N:24]=[CH:23][C:22]([S:25]([N:28]2[CH2:33][CH2:32][N:31]([C:2]3[N:3]=[CH:4][C:5]([C:8]([OH:17])([C:13]([F:16])([F:15])[F:14])[C:9]([F:10])([F:11])[F:12])=[CH:6][N:7]=3)[CH:30]([C:34]#[C:35][CH3:36])[CH2:29]2)(=[O:27])=[O:26])=[CH:21][CH:20]=1
Reactant: OC(c1cnc(Cl)nc1)(C(F)(F)F)C(F)(F)F
Reactant: CC#CC1CN(S(=O)(=O)c2ccc(Cl)nc2)CCN1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CC#CC1CN(S(=O)(=O)c2ccc(Cl)nc2)CCN1c1ncc(C(O)(C(F)(F)F)C(F)(F)F)cn1
Temperature: 120 °C
Reaction time: 24 h
Yield: 113 %

Procedure:
A mixture of 2-(2-chloropyrimidin-5-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol (490 mg, 1.747 mmol, Intermediate D), 1-((6-chloropyridin-3-yl)sulfonyl)-3-(prop-1-yn-1-yl)piperazine (325 mg, 1.08 mmol), Hünig's base (1.0 mL, 5.73 mmol) and dioxane (5.0 mL) was heated at 120° C. for 15 h. The temperature was increased to 130° C. and stirring was continued for 24 h. The dark mixture was allowed to cool to room temperature and was then purified by silica gel chromatography (80 g silica gel, 10-50% EtOAc in hexane) to give 2-(2-(4-((6-chloro-3-pyridinyl)sulfonyl)-2-(1-propyn-1-yl)-1-piperazinyl)-5-pyrimidinyl)-1,1,1,3,3,3-hexafluoro-2-propanol as a white foam (0.664 g).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]([NH2:10])=[O:9])[CH:3]=1.[NH2:11][C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1>>[C:8]([C:4]1[CH:3]=[C:2]([O:18][C:15]2[CH:16]=[CH:17][C:12]([NH2:11])=[CH:13][CH:14]=2)[CH:7]=[CH:6][N:5]=1)(=[O:9])[NH2:10]
Reactant: NC(=O)c1cc(Cl)ccn1
Reactant: Nc1ccc(O)cc1
Product: NC(=O)c1cc(Oc2ccc(N)cc2)ccn1

Procedure:
Entry 43: 4-Chloropyridine-2-carbonyl chloride HCl salt was reacted with ammonia according to Method A1, Step 3b to form 4-chloro-2-pyridinecarboxamide. 4-Chloro-2-pyridinecarboxamide was reacted with 4-aminophenol according to Method A2, Step 4 to form 4-(2-carbamoyl-4-pyridyloxy)aniline. According to Method C1a, 4-chloro-3-(trifluoromethyl)phenyl isocyanate was reacted with 4-(2-carbamoyl-4-pyridyloxy)aniline to afford the urea.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH:8]=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].[N:12]1([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1>>[N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8][N:15]2[CH2:14][CH2:13][N:12]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:17][CH2:16]2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Product: CC(C)(C)OC(=O)N1CCN(Cc2ccc([N+](=O)[O-])cc2)CC1

Procedure:
The title compound was prepared from 4-nitrobenzaldehyde and 1,1-dimethylethyl 1-piperazinecarboxylate using a method similar to that described for D21 in Description 21A although the product was purified by column chromatography followed by passing through an SCX column eluting with MeOH then 2M NH3 in MeOH. MS (ES): 266.1, 222.2, no molecular ion (MH+) observed.
Reaction SMILES: [OH-].[K+:2].[F:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[CH:6][CH:5]=1.[N+:12]([CH2:14][C:15]([O:17]C)=[O:16])#[C-:13]>CO>[F:3][C:4]1[CH:11]=[CH:10][C:7]([C@@H:8]2[O:9][CH:13]=[N:12][C@H:14]2[C:15]([O-:17])=[O:16])=[CH:6][CH:5]=1.[K+:2]
Reactant: [C-]#[N+]CC(=O)OC
Reactant: O=Cc1ccc(F)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: O=C([O-])[C@@H]1N=CO[C@H]1c1ccc(F)cc1
Yield: 106.4 %

Procedure:
To a stirred and cooled (4° C.) solution of KOH (3.04 g, 46.02 mmol) in MeOH (50 mL) were slowly added 4-fluorobenzaldehyde (4.13 mL, 38.35 mmol) and methyl 2-isocyanoacetate (4.00 g, 38.35 mmol). This mixture was stirred at RT under N2 atmosphere for 7 h. The solvent was evaporated and the residue was dried overnight under vacuum to give potassium (±)-threo-5-(4-fluorophenyl)-4,5-dihydrooxazole-4-carboxylate ANP 20162 (10.09 g, quantitative yield), as a beige powder. This material was used in the next reaction without further purification.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[N:18]=[C:17]([NH:19][C:20]3[CH:25]=[C:24]([O:26][C:27]4[C:28]([CH3:39])=[N:29][CH:30]=[C:31]([C:37]=4[CH3:38])[C:32]([O:34]CC)=[O:33])[C:23]([Br:40])=[CH:22][N:21]=3)[S:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>CCO>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[N:18]=[C:17]([NH:19][C:20]3[CH:25]=[C:24]([O:26][C:27]4[C:28]([CH3:39])=[N:29][CH:30]=[C:31]([C:37]=4[CH3:38])[C:32]([OH:34])=[O:33])[C:23]([Br:40])=[CH:22][N:21]=3)[S:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)c1cnc(C)c(Oc2cc(Nc3nc(C4CCN(C(=O)OC(C)(C)C)CC4)ns3)ncc2Br)c1C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1ncc(C(=O)O)c(C)c1Oc1cc(Nc2nc(C3CCN(C(=O)OC(C)(C)C)CC3)ns2)ncc1Br
Temperature: 60 °C
Reaction time: 1 h
Yield: 24.8 %

Procedure:
Ethyl 5-(2-(3-(1-(tert-butoxycarbonyl)piperidin-4-yl)-1,2,4-thiadiazol-5-ylamino)-5-bromopyridin-4-yloxy)-4,6-dimethylnicotinate (0.050 g, 0.08 mmol) was dissolved in EtOH (2 mL). NaOH (1N in H2O, 0.28 ml, 0.28 mmol) was added. The reaction stirred at 60° C. for 1 hour. The solution was cooled and concentrated. The material was acidified with saturated NH4Cl solution and extracted with dichloromethane. The organic layer was washed with water, dried and concentrated to give 5-(2-(3-(1-(tert-butoxycarbonyl)piperidin-4-yl)-1,2,4-thiadiazol-5-ylamino)-5-bromopyridin-4-yloxy)-4,6-dimethylnicotinic acid (0.012 g, 25% yield) as an off white solid. 1H NMR (400 MHz, DMSO-d6) δ 1.39 (s, 9H), 1.52-1.55 (m, 2H), 1.89-1.93 (m, 2H), 2.34 (s, 6H), 2.84-2.93 (m, 3H), 3.90-3.94 (m, 2H), 6.20 (s, 1H), 8.62 (s, 1H), 8.89 (s, 1H), 11.69 (s, 1H), 13.09 (s, 1H).
Reaction SMILES: Cl[CH2:2][C:3]1[C:4]([CH3:9])=[N:5][CH:6]=[CH:7][CH:8]=1.[C-:10]#[N:11].[Na+].O.C(OCC)(=O)C>CS(C)=O>[C:10]([CH2:2][C:3]1[C:4]([CH3:9])=[N:5][CH:6]=[CH:7][CH:8]=1)#[N:11]
Reactant: Cc1ncccc1CCl
Reactant: [C-]#N
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1ncccc1CC#N
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 88.5 %

Procedure:
The mixture of 3-chloromethyl-2-methylpyridine (9.2 g) and sodium cyanide (9.55 g) in dimethyl sulfoxide (80 ml) was stirred for 30 minutes at 80° C. The reaction mixture was poured into a mixture of water (200 ml) and ethyl acetate (1 l). Organic layer was separated, washed with brine and dried over magnesium sulfate. Concentration of the solvent gave a residue, which was chromatographed on silica gel (300 ml) eluting with a mixture of hexane and ethyl acetate (1:4, V/V) to give 3-cyanomethyl-2-methylpyridine (7.6 g).
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][O:5][CH2:4][CH:3]1[C:8]([O:10][CH3:11])=[O:9].O[C:13]1CCOCC=1C(OC)=O.[H-].[Na+].IC>CN(C=O)C.C(OCC)(=O)C>[CH3:13][C:3]1([C:8]([O:10][CH3:11])=[O:9])[C:2](=[O:1])[CH2:7][CH2:6][O:5][CH2:4]1
Reactant: COC(=O)C1COCCC1=O
Reactant: COC(=O)C1=C(O)CCOC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CI
Solvent: CCOC(C)=O
Product: COC(=O)C1(C)COCCC1=O
Reaction time: 0.17 h
Yield: 61 %

Procedure:
Methyl 4-oxo-tetrahydro-2H-pyran-3-carboxylate and methyl 4-hydroxy-5,6-dihydro-2H-pyran-3-carboxylate (13.5 g, 85.5 mmol) were dissolved in DMF (70 mL). Sodium hydride (60%, 3.6 g, 1.05 eq) was added at 0° C. After 10 min, iodomethane (6.7 mL, 1.25 eq) was added. The reaction was stirred overnight, diluted with ethyl acetate (200 mL), and washed with water (5×100 mL). The aqueous layer was re-extracted with ethyl acetate. The combined organic layers were washed with brine, dried over MgSO4, and concentrated. The residue was purified by chromatography on silica gel eluting with 20% ethyl acetate/hexane to yield 8.2 g (61%) of methyl 3-methyl-4-oxo-tetrahydro-2H-pyran-3-carboxylate.
Reaction SMILES: [CH:1]1([C:4]2[N:9]=[C:8]([C:10]([NH:12][C:13]3[CH:21]=[N:20][CH:19]=[CH:18][C:14]=3[C:15](O)=[O:16])=[O:11])[C:7]([NH:22][C:23]3[CH:24]=[N:25][CH:26]=[N:27][CH:28]=3)=[N:6][CH:5]=2)[CH2:3][CH2:2]1.Cl.[O:30]1[CH2:33][CH:32]([NH2:34])[CH2:31]1>>[O:30]1[CH2:33][CH:32]([NH:34][C:15]([C:14]2[CH:18]=[CH:19][N:20]=[CH:21][C:13]=2[NH:12][C:10]([C:8]2[C:7]([NH:22][C:23]3[CH:24]=[N:25][CH:26]=[N:27][CH:28]=3)=[N:6][CH:5]=[C:4]([CH:1]3[CH2:3][CH2:2]3)[N:9]=2)=[O:11])=[O:16])[CH2:31]1
Reactant: O=C(O)c1ccncc1NC(=O)c1nc(C2CC2)cnc1Nc1cncnc1
Reactant: NC1COC1
Agent: Cl
Product: O=C(NC1COC1)c1ccncc1NC(=O)c1nc(C2CC2)cnc1Nc1cncnc1
Yield: 58 %

Procedure:
According to the procedure described in step 3 of example 99, 3-{[6-cyclopropyl-3-(pyrimidin-5-ylamino)-pyrazine-2-carbonyl]-amino}-isonicotinic acid (example 99, step 2) was reacted with oxetan-3-amine hydrochloride, providing the title compound as yellow solid (58%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[C:8]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=1)[CH:7]=[C:6]2Cl.C1(O)C=CC=CC=1.[NH3:29]>>[NH2:29][C:6]1[C:5]2[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[CH:4]=2)[N:9]=[C:8]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=2)[CH:7]=1
Reactant: N
Reactant: COc1cccc(-c2cc(Cl)c3cc(OC)ccc3n2)c1
Solvent: Oc1ccccc1
Product: COc1cccc(-c2cc(N)c3cc(OC)ccc3n2)c1
Temperature: 180 °C

Procedure:
A mixture of 6-methoxy-2-(3-methoxyphenyl)-4-chloroquinoline (5.90 g, 19.68 mmol) and phenol (20 g) was heated with stirring at 180° C. and ammonia was passed through the reaction mixture during 11 h. Phenol was then removed by steam distillation. The mixture was filtered and the filtrate was basified to pH 8 by adding 8% Na2CO3 aqueous solution. The solid formed was collected by filtration and dried to give the desired 4-amino-6-methoxy-2-(3-methoxyphenyl)quinoline, 5.313 g (96.3%); mp 148-149° C.; 1H NMR (DMSO-d6) δ 3.85, 3.90 (each: 3H, s, OCH3), 6.67 (2H, s, exchangeable, NH2), 7.00 (1H, dd, J=2.9 and 8.1 Hz, ArH), 7.10 (1H, s, ArH), 7.28 (1H, dd, J=2.9 and 8.8 Hz, ArH), 7.40 (1H, t, J=8.1 Hz, ArH), 7.53 (1H, d, J=2.9 Hz, ArH), 7.61 (1H, 1H, d, J=8.1 Hz, ArH), 7.64 (1H, t, J=2.2 Hz, ArH), 7.77 (1H, d, J=8.8 Hz, ArH). Anal. Calcd. for (C17H16N2O2): C, 72.84; H, 5.75; N, 9.99. Found: C, 72.82; H, 5.51; N, 10.12.
Reaction SMILES: [SH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.Br[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30]([O:32][CH3:33])=[O:31].Cl.[Na+].[Cl-]>C1COCC1.CO.CCOC(C)=O>[CH3:33][O:32][C:30]([CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][S:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1)=[O:31]
Reactant: COC(=O)CCCCCCCCCBr
Reactant: O=C(O)c1ccc(S)cc1
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)CCCCCCCCCSc1ccc(C(=O)O)cc1
Reaction time: 72 h
Yield: 100 %

Procedure:
4-Mercaptobenzoic acid (2.0 g, 13 mmol) was placed in THF (25 ml). DIEA (3.7 g, 28.5 mmol) was added followed by a solution of methyl 10-bromodecanoate (3.44 g, 13 mmol) in THF (10 ml). After 1 h the solvent was removed under vacuum to yield a slurry, which was stored at rt for 3 days. AcOEt (100 ml) and 1 N HCl (50 ml) were added, but the precipitate did not dissolve very well. Sat. NaCl was added and then methanol in order to aid phase separation. The aqueous phase was removed, and DCM was added to the organic phase, but the precipitates still did not dissolve. The organic phase was concentrated under vacuum and dried with toluene by adding and evaporating twice. Drying under vacuum yielded a white solid (4.4 g, quantitative yield).
Reaction SMILES: [CH2:1]([NH2:8])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].C[O:10][C:11](=[O:28])[C:12]([O:26][CH3:27])([CH3:25])[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22](O)=[O:23])=[CH:16][CH:15]=1.C(O[C@@H](CC1C=CC(O[C@@H](C(=O)NCCC2C=CC(OC3C=CC=CC=3)=CC=2)C)=CC=1)C(O)=O)C>>[CH2:1]([NH:8][C:22]([CH2:21][O:20][C:17]1[CH:16]=[CH:15][C:14]([CH2:13][C:12]([O:26][CH3:27])([CH3:25])[C:11]([OH:28])=[O:10])=[CH:19][CH:18]=1)=[O:23])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: COC(=O)C(C)(Cc1ccc(OCC(=O)O)cc1)OC
Reactant: CCCCCCCN
Agent: CCO[C@@H](Cc1ccc(O[C@H](C)C(=O)NCCc2ccc(Oc3ccccc3)cc2)cc1)C(=O)O
Product: CCCCCCCNC(=O)COc1ccc(CC(C)(OC)C(=O)O)cc1

Procedure:
The title compound was prepared from 3-(4-carboxymethoxy-phenyl)-2-methoxy-2-methyl-propionic acid methyl ester heptyl amine via the same procedure used for the preparation of (2S,1R)-2-ethoxy-3-(4-{1-[2-(4-phenoxy-phenyl)-ethylcarbamoyl]-ethoxy}-phenyl)-propionic acid (Example 1, step 3) to produce a colorless oil.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([O:7][CH2:8][C:9]([OH:11])=O)[CH:2]=1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.[OH:26][C:27]([C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[CH:28]1[CH2:33][CH2:32][N:31]([CH2:34][CH2:35][CH2:36][CH2:37][NH2:38])[CH2:30][CH2:29]1>ClCCl>[OH:26][C:27]([C:45]1[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=1)([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[CH:28]1[CH2:29][CH2:30][N:31]([CH2:34][CH2:35][CH2:36][CH2:37][NH:38][C:9](=[O:11])[CH2:8][O:7][C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)[CH2:32][CH2:33]1
Reactant: NCCCCN1CCC(C(O)(c2ccccc2)c2ccccc2)CC1
Reactant: O=C(O)COc1cccnc1
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: ClCCCl
Product: O=C(COc1cccnc1)NCCCCN1CCC(C(O)(c2ccccc2)c2ccccc2)CC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
1.8 g (11.6 mmol) (pyridin-3-yloxy)-acetic acid and 1.7 ml (12.2 mmol) TEA are suspended in 80 ml absolute dichlormethane and cooled to ca. 0° C. under moisture exclusion. 2.1 g (13.7 mmol) 88% HOBT and 2.7 g (14.1 mmol) EDC are added and the mixture is stirred for 30 min under ice-cooling. 4,. g (13.0 mmol) 4-[4-(hydroxy-diphenylmehyl)-piperidin-1-yl]-butylamine are added and the mixture is stirred overnight without cooling. Subsequently, the batch is washed with 50 ml 1M sodium hydroxide solution and twice each with 30 ml water. The organic phase is dried over sodium sulfate and the solvent is removed under vacuum. The residue is chromatographically purified over silica gel with CHCl3/CH3OH/NH4OH (90/10/0 to 90/10/1): Yield 2.0 g (34%) of a colorless resin.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[C:6]([CH3:8])[CH:7]=1.[C:10]([O-])([O-])=O.[K+].[K+].CI>CC(C)=O>[Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([O:9][CH3:10])[CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: Cc1cc(O)cc(Br)c1
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: COc1cc(C)cc(Br)c1
Temperature: 40 °C
Reaction time: 16 h

Procedure:
To a mixture of 3-bromo-5-methyl-phenol (185 g; 0.940 mol) and K2CO3 (437 g, 3.17 mol) in acetone (2 L) is added MeI (424 g, 2.99 mol). The mixture is stirred at 40° C. for 16 h. The mixture is cooled to ambient temperature, filtered, and concentrated under reduced pressure. After filtration, the mixture is purified by flash silica gel chromatography to afford 1-Bromo-3-methoxy-5-methyl-benzene, D-4-1 (189 g, quant. yield) as a light yellow oil.
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[C:3]1[CH:4]=[C:5]([C:13]([N:15]2[CH2:20][CH2:19][C@H:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C@H:17]([C:27]3[CH:32]=[CH:31][C:30](Cl)=[CH:29][CH:28]=3)[CH2:16]2)=[O:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[NH:36]1[CH2:41][CH2:40][O:39][CH2:38][CH2:37]1.C1(C2C=CC=CC=2)C=CC=CC=1P(C1CCCCC1)C1CCCCC1>>[F:1][C:2]([F:35])([F:34])[C:3]1[CH:4]=[C:5]([C:13]([N:15]2[CH2:20][CH2:19][C@H:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C@H:17]([C:27]3[CH:32]=[CH:31][C:30]([N:36]4[CH2:41][CH2:40][O:39][CH2:38][CH2:37]4)=[CH:29][CH:28]=3)[CH2:16]2)=[O:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: C1COCCN1
Reactant: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CC[C@H](c2ccccc2)[C@H](c2ccc(Cl)cc2)C1
Agent: c1ccc(-c2ccccc2P(C2CCCCC2)C2CCCCC2)cc1
Product: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CC[C@H](c2ccccc2)[C@H](c2ccc(N3CCOCC3)cc2)C1

Procedure:
The title compound, MS: m/e=563.3 (M+), was prepared in accordance with the general method of example 10 from rac-cis-(3,5-bis-trifluoromethyl-phenyl)-[3-(4-chloro-phenyl)-4-phenyl-piperidin-1-yl]-methanone, morpholine and biphenyl-2-yl-dicyclohexyl-phosphane as ligand.