Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].COC(=O)C(NC(=O)[C@H](C)N)C1CC1.[CH3:16][O:17][C:18](=[O:37])[CH:19]([NH:23][C:24](=[O:36])[CH:25]([NH:28]C(OC(C)(C)C)=O)[CH2:26][CH3:27])[CH:20]1[CH2:22][CH2:21]1>>[ClH:1].[CH3:16][O:17][C:18](=[O:37])[CH:19]([NH:23][C:24](=[O:36])[CH:25]([NH2:28])[CH2:26][CH3:27])[CH:20]1[CH2:21][CH2:22]1
Reactant: CCC(NC(=O)OC(C)(C)C)C(=O)NC(C(=O)OC)C1CC1
Agent: COC(=O)C(NC(=O)[C@H](C)N)C1CC1
Agent: Cl
Product: CCC(N)C(=O)NC(C(=O)OC)C1CC1

Procedure:
Following the procedure for the preparation of methyl(L-alanylamino)(cyclopropyl)acetate hydrochloride but substituting methyl({2-[(tert-butoxycarbonyl)amino]butanoyl}amino)(cyclopropyl)acetate and making non-critical variations provided the title compound as a solid: 1H NMR (DMSO-d6) δ 0.29–0.40, 0.88–0.94, 1.12, 1.37, 1.75–1.82, 3.57, 3.62–3.79, 8.29.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[C:7](B2OC(C)(C)C(C)(C)O2)[CH:6]=[C:5]([CH3:18])[C:3]=1[NH2:4].Cl[C:20]1[N:25]=[CH:24][N:23]([CH3:26])[C:22](=[O:27])[CH:21]=1.C([O-])([O-])=O.[Na+].[Na+]>CN(C)C=O>[NH2:4][C:3]1[C:5]([CH3:18])=[CH:6][C:7]([C:20]2[N:25]=[CH:24][N:23]([CH3:26])[C:22](=[O:27])[CH:21]=2)=[CH:8][C:2]=1[CH3:1]
Reactant: Cn1cnc(Cl)cc1=O
Reactant: Cc1cc(B2OC(C)(C)C(C)(C)O2)cc(C)c1N
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc(-c2cc(=O)n(C)cn2)cc(C)c1N
Temperature: 65 °C
Reaction time: 12 h

Procedure:
In a microwave vial 2,6-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (5.6 g) and 6-chloro-3-methylpyrimidin-4(3H)-one (3 g) are suspended in N,N-dimethylformamide (30 mL) and Na2CO3 (26 mL of a 2M aqueous solution). The mixture is purged for 5 minutes with argon. [1,1′-Bis(diphenylphosphino)-ferrocene]-dichloropalladium dichloromethane complex (508 mg) is added, the vial is sealed and the mixture is stirred at 65° C. for 12 hours. After cooling to room temperature the mixture is Partitioned between water and ethyl acetate. The aqueous phase is extracted twice with ethyl acetate and the combined organic phases are washed with brine and dried (MgSO4). The solvents are evaporated to give the title compound. Yield: 2.6 g; LC (method 11): tR=0.71 min; Mass spectrum (ESI+): m/z=230 [M+H]+.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[C:10](=[O:11])[C:9]2[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=2[O:7][C:6]2[CH:16]=[CH:17][CH:18]=[CH:19][C:5]1=2.O[C:21]1[CH:22]=[C:23]([CH:28]=[CH:29][CH:30]=1)[C:24]([O:26][CH3:27])=[O:25].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[O:11]=[C:10]1[C:9]2[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=2[O:7][C:6]2[CH:16]=[CH:17][CH:18]=[CH:19][C:5]=2[N:4]1[CH2:3][CH2:2][O:1][C:21]1[CH:22]=[C:23]([CH:28]=[CH:29][CH:30]=1)[C:24]([O:26][CH3:27])=[O:25]
Reactant: O=C1c2ccccc2Oc2ccccc2N1CCO
Reactant: COC(=O)c1cccc(O)c1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1cccc(OCCN2C(=O)c3ccccc3Oc3ccccc32)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Title compound 462 (0.300 g, 1.18 mmol), methyl 3-hydroxybenzoate (0.179 g, 1.18 mmol) and triphenylphosphine (0.401 g, 1.53 mmol) were dissolved in THF (5 mL) then diethylazodicarboxylate (0.222 mL, 1.41 mmol) was added. The reaction mixture was stirred at room temperature for 3 hours. The solvent was evaporated to provide title compound 463.
Reaction SMILES: [OH:1][CH2:2][CH:3]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])[CH:4]([CH3:6])[CH3:5].C(N(CC)CC)C>CS(C)=O>[CH3:5][CH:4]([CH3:6])[CH:3]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])[CH:2]=[O:1]
Reactant: CC(C)C(CO)NC(=O)OC(C)(C)C
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CC(C)C(C=O)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 72.1 %

Procedure:
To a solution of 1.75 g of tert-butyl 1-hydroxy-3-methylbutan-2-ylcarbamate (Formula 20) in 25 mL of DMSO was added 3.6 mL of triethylamine. The solution was cooled to 0° C. and 4.1 grams of sulfur trioxide pyridine complex in 25 mL of DMSO was added. The reaction mixture was stirred at room temperature for 1 hour. Then, the mixture was poured onto ice-water and extracted with ethyl acetate. The organic layers were washed with 10% acetic acid, water, 5% sodium bicarbonate, and brine, dried over sodium sulfate and concentrated. Column chromatography (30% ethyl acetate/hexane) gave 1.25 g of tert-butyl 3-methyl-1-oxobutan-2-ylcarbamate (Formula 21) as a clear oil. 1H NMR (300 MHz, CDCl3) δ 0.95 (d, J=7.32 Hz, 3H), 1.03 (d, J=6.83 Hz, 3H), 1.45 (s, 9H), 2.27-2.29 (m, 1H), 4.24-4.26 (m, 1H), 9.65 (s, 1H).
Reaction SMILES: [NH2:1][CH2:2][C:3]([NH:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[C:11]([CH:50]=[CH:51][CH:52]=1)[C:12]([NH:14][C:15]1[C:16]([CH3:49])=[C:17]([C:24]([C:26]2[CH:27]=[CH:28][C:29]([NH:42][C:43](=[O:48])[C:44]([F:47])([F:46])[F:45])=[C:30]([CH:41]=2)[C:31]([O:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)=[O:32])=[O:25])[N:18]2[C:23]=1[CH:22]=[CH:21][CH:20]=[CH:19]2)=[O:13])=[O:4].[CH2:53]([O:60][C:61]([C:63]1[CH:64]=[C:65]([CH:92]=[CH:93][C:94]=1[NH:95][C:96](=[O:101])[C:97]([F:100])([F:99])[F:98])[C:66]([C:68]1[N:76]2[C:71]([CH:72]=[CH:73][CH:74]=[CH:75]2)=[C:70]([NH:77][C:78]([C:80]2[CH:81]=[C:82]([CH:88]=[CH:89][CH:90]=2)[O:83][CH2:84][C:85](O)=[O:86])=[O:79])[C:69]=1[CH3:91])=[O:67])=[O:62])[C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1>>[CH2:53]([O:60][C:61]([C:63]1[CH:64]=[C:65]([CH:92]=[CH:93][C:94]=1[NH:95][C:96](=[O:101])[C:97]([F:100])([F:99])[F:98])[C:66]([C:68]1[N:76]2[C:71]([CH:72]=[CH:73][CH:74]=[CH:75]2)=[C:70]([NH:77][C:78]([C:80]2[CH:81]=[C:82]([CH:88]=[CH:89][CH:90]=2)[O:83][CH2:84][C:85]([NH:1][CH2:2][C:3]([NH:5][CH2:6][CH2:7][O:8][C:9]2[CH:10]=[C:11]([CH:50]=[CH:51][CH:52]=2)[C:12]([NH:14][C:15]2[C:16]([CH3:49])=[C:17]([C:24]([C:26]3[CH:27]=[CH:28][C:29]([NH:42][C:43](=[O:48])[C:44]([F:45])([F:46])[F:47])=[C:30]([CH:41]=3)[C:31]([O:33][CH2:34][C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=3)=[O:32])=[O:25])[N:18]3[C:23]=2[CH:22]=[CH:21][CH:20]=[CH:19]3)=[O:13])=[O:4])=[O:86])=[O:79])[C:69]=1[CH3:91])=[O:67])=[O:62])[C:54]1[CH:55]=[CH:56][CH:57]=[CH:58][CH:59]=1
Reactant: Cc1c(NC(=O)c2cccc(OCCNC(=O)CN)c2)c2ccccn2c1C(=O)c1ccc(NC(=O)C(F)(F)F)c(C(=O)OCc2ccccc2)c1
Reactant: Cc1c(NC(=O)c2cccc(OCC(=O)O)c2)c2ccccn2c1C(=O)c1ccc(NC(=O)C(F)(F)F)c(C(=O)OCc2ccccc2)c1
Product: Cc1c(NC(=O)c2cccc(OCCNC(=O)CNC(=O)COc3cccc(C(=O)Nc4c(C)c(C(=O)c5ccc(NC(=O)C(F)(F)F)c(C(=O)OCc6ccccc6)c5)n5ccccc45)c3)c2)c2ccccn2c1C(=O)c1ccc(NC(=O)C(F)(F)F)c(C(=O)OCc2ccccc2)c1

Procedure:
By following the process described in stage G of Example 42, the coupling of the amine obtained in stage A above with (3-{[(3-{3-[(benzyloxy)carbonyl]-4-[(trifluoroacetyl)amino]benzoyl}-2-methylindolizin-1-yl)amino]carbonyl}phenoxy)acetic acid (described in stage D of Example 44) is carried out.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15]([NH:17][C@H:18]4[CH2:23][CH2:22][CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19]4)[C:14]([F:31])=[CH:13][N:12]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.Cl.CC(O)C>C(O)(C)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15]([NH:17][C@H:18]4[CH2:23][CH2:22][CH2:21][NH:20][CH2:19]4)[C:14]([F:31])=[CH:13][N:12]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](Nc2nc(-c3c[nH]c4ncc(Cl)cc34)ncc2F)C1
Agent: Cl
Solvent: CC(C)O
Product: Fc1cnc(-c2c[nH]c3ncc(Cl)cc23)nc1N[C@H]1CCCNC1
Temperature: 80 °C
Reaction time: 3 h

Procedure:
To a suspension of tert-butyl (3S)-3-[[2-(5-chloro-1H-pyrrolo[5,4-b]pyridin-3-yl)-5-fluoro-pyrimidin-4-yl]amino]piperidine-1-carboxylate, 2b, (0.45 g, 1.01 mmol) in isopropanol (3 mL) was added propan-2-ol hydrochloride (1.5 mL of 5M solution, 7.500 mmol). The reaction mixture was warmed to 80° C. and stirred for 3 hours. The mixture was cooled to room temperature and all volatiles were removed at reduced pressure. The resulting crude product, 5b, was used without further purification.
Reaction SMILES: FC(F)(F)C([N:5]([C@@H:13]1[CH2:15][C@H:14]1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:6][CH:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1)=O.[CH3:24][C:25]([CH3:32])([CH:30]=O)[C:26]([O:28]C)=[O:27].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>ClCCCl.IC1C=CC=CC=1>[CH3:24][C:25]([CH3:32])([CH2:30][N:10]1[CH2:9][CH2:8][CH:7]([CH2:6][NH:5][C@@H:13]2[CH2:15][C@H:14]2[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:12][CH2:11]1)[C:26]([OH:28])=[O:27]
Reactant: COC(=O)C(C)(C)C=O
Reactant: O=C(N(CC1CCNCC1)[C@@H]1C[C@H]1c1ccccc1)C(F)(F)F
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: Ic1ccccc1
Solvent: ClCCCl
Product: CC(C)(CN1CCC(CN[C@@H]2C[C@H]2c2ccccc2)CC1)C(=O)O
Reaction time: 18 h

Procedure:
To a solution of 2,2,2-trifluoro-N-(trans-2-phenylcyclopropyl)-N-(piperidin-4-ylmethyl)acetamide (130 mg, 0.398 mmol) in 1,2-dichloroethane (DCE) (2 mL) were added methyl 2,2-dimethyl-3-oxopropanoate in iodobenzene (160 mg, 0.478 mmol) and sodium triacetoxyborohydride (118 mg, 0.558 mmol), and the reaction mixture was stirred for 18 h. Additional methyl 2,2-dimethyl-3-oxopropanoate in iodobenzene (320 mg) and sodium triacetoxyborohydride (236 mg) were added and the mixture was stirred at rt for 2 h. The mixture was quenched with water (2 mL) and extracted with DCM (3×). The extract was dried (Na2SO4) and concentrated. The residue was dissolved in methanol (2.000 mL) and sodium hydroxide (3M, 0.664 mL, 1.992 mmol) was added. The mixture was stirred at rt for 18 h and concentrated. The residue was treated with methanol and filtered. The filtrate was purified using reverse-phase HPLC under the acidic conditions. The resulting TFA salt was treated with ACN (1 mL) and 1N HCl aqueous solution and concentrated to give 64 mg of product as off-white solid (HCl salt). MS: (M+H)+=311.4. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.19-1.34 (m, 7H), 1.59-1.83 (m, 3H), 1.98 (br. s., 3H), 2.58-2.74 (m, 1H), 2.85-3.24 (m, 7H), 3.42 (br. s., 2H), 7.08-7.43 (m, 5H).
Reaction SMILES: Cl.[C:2]([NH2:5])(=[NH:4])[CH3:3].C[O-].[Na+].[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17]1[CH:22]=[CH:21][C:20]([CH2:23][CH:24]([C:30](=O)[CH2:31][CH2:32][CH3:33])[C:25](OCC)=[O:26])=[C:19]([F:35])[CH:18]=1)#[N:10].[Cl-].[NH4+]>CO.C(OCC)(=O)C>[F:35][C:19]1[CH:18]=[C:17]([C:12]2[C:11]([C:9]#[N:10])=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:22]=[CH:21][C:20]=1[CH2:23][C:24]1[C:25](=[O:26])[NH:5][C:2]([CH3:3])=[N:4][C:30]=1[CH2:31][CH2:32][CH3:33]
Reactant: CC(=N)N
Reactant: CCCC(=O)C(Cc1ccc(-c2ccccc2C#N)cc1F)C(=O)OCC
Agent: C[O-]
Agent: Cl
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: CO
Product: CCCc1nc(C)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1F
Temperature: 25 °C
Reaction time: 15 h
Yield: 77.9 %

Procedure:
To a suspension of acetamidine hydrochloride (2.67 g) in methanol (50 ml) was added sodium methoxide (28% in methanol, 8.2 mL) dropwise, followed by addition of a solution of ethyl 2-[(2′-cyano-3-fluorobiphenyl-4-yl)methyl]-3-oxohexanoate (5.18 g) in methanol (20 ml) at room temperature. After being stirred at room temperature for 15 hr, ethyl acetate and saturated aqueous ammonium chloride solution were added. The layers were separated and the aqueous layer was extracted with ethyl acetate. The combined organic layer was successively washed with water and saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting solid was collected and washed with diisopropyl ether to give the title compound as a white solid (3.97 g, 78%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@@H:13]([CH2:14][OH:15])[CH2:12][O:11][C@@H:10]([O:16][CH2:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)C(C)C)(C)C>CS(C)=O.ClCCl>[C:1]([O:5][C:6]([N:8]1[C@@H:13]([CH:14]=[O:15])[CH2:12][O:11][C@@H:10]([O:16][CH2:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)CO[C@H]1CN(C(=O)OC(C)(C)C)[C@@H](CO)CO1
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)CO[C@H]1CN(C(=O)OC(C)(C)C)[C@@H](C=O)CO1
Reaction time: 0.33 h

Procedure:
Add pyridine sulfur trioxide complex (4.82 g, 30.26 mmol) to (2R,5S)-2-(2,2-dimethylpropoxy)-5-hydroxymethylmorpholine-4-carboxylic acid tert-butyl ester (5.10 g, 16.81 mmol) and N,N-diisopropylethylamine (7.61 g, 58.83 mmol) in dimethylsulfoxide (42 mL) and dichloromethane (8 mL) at −4° C. Stir 20 minutes, pour into ice cold saturated aqueous sodium chloride. Extract with 10% ethyl acetate/hexanes. Wash with 0.1 N aqueous citric-acid and saturated aqueous sodium chloride. Dry (magnesium sulfate), filter and concentrate to give the desired compound of a colorless oil, which is used directly in the next step without further purification (5.02 g).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]([CH2:22][C:23](O)=[O:24])[C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:26][NH:27][CH2:28][C:29]1[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=1>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]([C:15]2[CH:16]=[CH:17][C:18]([CH3:21])=[CH:19][CH:20]=2)[CH2:22][C:23]([N:27]([CH3:26])[CH2:28][C:29]2[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=2)=[O:24])(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CNCc1cccnc1
Reactant: Cc1ccc(N(CC(=O)O)S(=O)(=O)c2ccc(C(C)(C)C)cc2)cc1
Product: Cc1ccc(N(CC(=O)N(C)Cc2cccnc2)S(=O)(=O)c2ccc(C(C)(C)C)cc2)cc1

Procedure:
prepared by reaction of [(4-tert-butyl-benzenesulfonyl)-p-tolyl-amino]-acetic acid with methyl-pyridin-3-ylmethyl-amine
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([Br:13])=[CH:9][C:8]=1[CH:14]=O)[CH3:2].Cl.[CH2:18]([O:20][C:21](=[O:24])[CH2:22][NH2:23])[CH3:19].CCN(CC)CC.O>ClCCl>[CH2:1]([O:3][C:4](=[O:16])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([Br:13])=[CH:9][C:8]=1/[CH:14]=[N:23]/[CH2:22][C:21]([O:20][CH2:18][CH3:19])=[O:24])[CH3:2]
Reactant: CCOC(=O)COc1ccc(Br)cc1C=O
Reactant: CCOC(=O)CN
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)C/N=C/c1cc(Br)ccc1OCC(=O)OCC
Temperature: 25 °C
Reaction time: 4 h

Procedure:
4-Bromo-2-formylphenoxyacetic acid ethyl ester (1.44 g, 5 mmol) was dissolved in dichloromethane (50 mL) and glycine ethyl ester hydrochloride (1.39 g, 10 mmol) as well as Et3N (1.4 mL, 10 mmol) was added. The mixture was stirred at room temperature for 4 h. Water and dichloromethane was added and the organic phase was passed through a phase separation filter and then evaporated to give {4-bromo-2-[(E)-ethoxycarbonylmethyliminomethyl]phenoxy}acetic acid ethyl ester, which was redissolved in dichloromethane (50 mL) and treated with NaBH(OAc)3 (2.11 g, 10 mmol) and AcOH (1 mL), and then stirred at room temperature for 5 h. Saturated Na2CO3, water and dichloromethane was added, and the organic phase was passed through a phase separation filter and evaporated to give the title compound (1.56 g, 84% overall yield).
Reaction SMILES: [Cl:1][C:2]1[C:19]([Cl:20])=[CH:18][C:5]([CH2:6][N:7]2C(=O)C3C(=CC=CC=3)C2=O)=[C:4]([O:21][CH3:22])[CH:3]=1.O.NN>CCO>[Cl:1][C:2]1[C:19]([Cl:20])=[CH:18][C:5]([CH2:6][NH2:7])=[C:4]([O:21][CH3:22])[CH:3]=1
Reactant: COc1cc(Cl)c(Cl)cc1CN1C(=O)c2ccccc2C1=O
Agent: NN
Solvent: CCO
Solvent: O
Product: COc1cc(Cl)c(Cl)cc1CN
Yield: 77.6 %

Procedure:
To a solution of 2-(4,5-dichloro-2-methoxybenzyl)isoindoline-1,3-dione (1.8 g, 5 mmol) in EtOH (5 mL), hydrazine hydrate (1.34 g, 27 mmol) was added and the resulting mixture was stirred at reflux for 1 h. The mixture was concentrated in vacuo and the residue was purified by flash column chromatography on silica gel (dichloromethane/methanol=20:1) to afford the desired product (0.8 g, 78% yield).
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].[Cl:5][CH:6]1[CH2:11][CH2:10][CH:9]([C:12]2[S:16][C:15]([NH2:17])=[N:14][N:13]=2)[CH2:8][CH2:7]1>C(OCC)(=O)C>[Cl:5][CH:6]1[CH2:7][CH2:8][CH:9]([C:12]2[S:16][C:15]([N:17]=[C:1]=[O:2])=[N:14][N:13]=2)[CH2:10][CH2:11]1
Reactant: O=C(Cl)Cl
Reactant: Nc1nnc(C2CCC(Cl)CC2)s1
Solvent: CCOC(C)=O
Product: O=C=Nc1nnc(C2CCC(Cl)CC2)s1

Procedure:
A saturated solution of phosgene in ethyl acetate (500 ml) is charged into a glass reaction vessel equipped with a mechanical stirrer. 5-(4-Chlorocyclohexyl)-2-amino-1,3,4-thiadiazole (6 grams) is added to the reaction vessel and the resulting mixture is stirred and heated at reflux for a period of about 4 hours, resulting in the formation of a precipitate. The reaction mixture is then purged with nitrogen gas to remove unreacted phosgene. The purged mixture is then filtered to recover the precipitate. The precipitate is then recrystallized to yield the desired product 5-(4-chlorocyclohexyl)-1,3,4-thiadiazol-2-yl isocyanate dimer.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[H][H]>O1CCCC1.[Ru].C>[C:4]([CH:3]1[CH2:7][CH:8]([CH3:11])[CH2:9][CH2:10][CH:2]1[NH2:1])([OH:6])=[O:5]
Reactant: Cc1ccc(N)c(C(=O)O)c1
Reactant: [H][H]
Agent: [Ru]
Solvent: C1CCOC1
Product: CC1CCC(N)C(C(=O)O)C1
Reaction time: 14 h

Procedure:
50 g (0.33 mol) of 2-amino-5-methyl-benzoic acid, dissolved in 100 ml of tetrahydrofuran, are hydrogenated for 14 hours at 200° C. and 200 bar hydrogen in the presence of 5 g of ruthenium/charcoal. After cooling and evaporation, 30 g o f 2-carboxy-4-methyl-cyclohexan-1-yl -amine are obtained as a pale oil.
Reaction SMILES: [C:1]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:6]=[CH:5][C:4]([CH2:7][C@H:8]2[N:12](C(=O)C(C)(C)C)[C:11](=[O:19])[C@H:10]([CH3:20])[CH2:9]2)=[CH:3][CH:2]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:38]([OH:40])[CH3:39]>>[CH2:38]([O:40][C:11](=[O:19])[C@H:10]([CH3:20])[CH2:9][C@H:8]([NH2:12])[CH2:7][C:4]1[CH:5]=[CH:6][C:1]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:2][CH:3]=1)[CH3:39]
Reactant: C[C@@H]1C[C@@H](Cc2ccc(-c3ccccc3)cc2)N(C(=O)C(C)(C)C)C1=O
Reactant: CCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: CCOC(=O)[C@H](C)C[C@H](N)Cc1ccc(-c2ccccc2)cc1

Procedure:
0.5 g (3R,5S)-5-biphenyl-4-ylmethyl-1-(2,2-dimethylpropionyl)-3-methylpyrrolidin-2-one, 5 ml ethanol and 1.1 g para-toluenesulphonic acid were heated at about 80-120° C. for about 24 hours. The mixture was evaporated to dryness to obtain (2R,4S)-4-amino-5-biphenyl-4-yl-2-methylpentanoic acid ethyl ester (p-toluenesulphonate salt). 1H NMR (CDCl3): 1.08 (3H), 1.16 (3H), 1.87 (1H), 1.95 (1H), 2.38 (3H), 2.77 (1H), 2.92 (1H), 3.15 (1H), 3.69 (1H), 4.07 (2H), 7.16-7.77 (13H), 9.89 (3H).
Reaction SMILES: N[C:2]1[N:3]=[CH:4][C:5]2[NH:6][C:7]3[C:12]([C:13]=2[CH:14]=1)=[CH:11][CH:10]=[CH:9][CH:8]=3.N([O-])=O.[Na+].[BrH:19]>>[Br:19][C:2]1[N:3]=[CH:4][C:5]2[NH:6][C:7]3[C:12]([C:13]=2[CH:14]=1)=[CH:11][CH:10]=[CH:9][CH:8]=3
Reactant: Nc1cc2c(cn1)[nH]c1ccccc12
Reactant: Br
Agent: O=N[O-]
Agent: [Na+]
Product: Brc1cc2c(cn1)[nH]c1ccccc12

Procedure:
2 g of 3-amino-β-carboline, suspended in 25 ml of 48% hydrobromic acid, are mixed with 6 ml of a 2-molar sodium nitrite solution at 0°-5° C. The mixture is added at 0°-5° C. to a solution of 2.1 g of copper-I-bromide in 20 ml of 24% hydrobromic acid. The reaction mixture is heated briefly in a steam bath and then repeatedly extracted with a mixture consisting of 9 parts of ethyl acetate and one part of ethane. The combined extracts are evaporated, the residue chromatographed (silica gel, methylene chloride/methanol=19:1). The main fraction crystallizes on treatment with ethyl acetate. Yield: 0.5 g of 3-bromo-β-carboline; melting point: 300° C.
Reaction SMILES: [Br:1][CH2:2][C:3]1[C:4]([C:25]([F:28])([F:27])[F:26])=[C:5]([CH:8]=[CH:9][C:10]=1[N:11]=C(C1C=CC=CC=1)C1C=CC=CC=1)[C:6]#[N:7].Cl>C1COCC1>[NH2:11][C:10]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([C:25]([F:27])([F:28])[F:26])[C:3]=1[CH2:2][Br:1]
Reactant: N#Cc1ccc(N=C(c2ccccc2)c2ccccc2)c(CBr)c1C(F)(F)F
Agent: Cl
Solvent: C1CCOC1
Product: N#Cc1ccc(N)c(CBr)c1C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h
Yield: 46.7 %

Procedure:
To a stirred solution of the diphenylmethylidene from step E (0.250 g, 0.56 mmol) in THF (4 mL) was added 2N HCl (0.4 mL). After stirring at rt for 2 h, the reaction was partitioned in EtOAc/hexanes (20 mL; 1:2). The layers were separated and the organic portion was dried (MgSO4) and concentrated. Purification by SiO2 chromatography (10-50% EtOAc in hexane2) afforded 4-amino-3-(bromomethyl)-2-(trifluoromethyl)benzonitrile (0.073 g, 50%) as a yellow solid: 1H NMR (400 MHz, DMSO-d6) δ 7.61 (d, J=8.6 Hz, 1H), 6.98 (d, J=8.6 Hz, 1H), 6.82 (bs, 2H), 4.71 (s, 2H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[N:5]=[C:4]([N:9]([CH3:16])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:3]=1.C(=O)([O-])[O-].[K+].[K+].[NH:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1>CN(C=O)C>[Cl:8][C:6]1[N:5]=[C:4]([N:9]([CH3:16])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:3]=[C:2]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[N:7]=1
Reactant: C1COCCN1
Reactant: CN(c1ccccc1)c1nc(Cl)nc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CN(c1ccccc1)c1nc(Cl)nc(N2CCOCC2)n1
Temperature: 25 °C
Reaction time: 24 h
Yield: 83.6 %

Procedure:
The obtained 2,4-dichloro-6-(N-methyl-N-phenylamino)-1,3,5-triazine (956 mg, 3.75mmol) was dissolved in DMF (10 ml), added with anhydrous potassium carbonate (518 mg, 3.77 mmol), cooled to -5° C.-0° C. and gradually added dropwise with morpholine (359 mg, 4.13 mmol) dissolved in DMF (5 ml). The reaction mixture was stirred at room temperature for 24 hours and evaporated under reduced pressure. The residue was added with ethyl acetate and shaken for mixing. The organic layer was separated from the mixture, washed with water and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure and the obtained residue was purified by silica gel column chromatography, using dichloromethane and ethyl acetate (20:1) as eluant, to obtain 958 mg (yield: 83.5%) of 2-chloro-4-(N-methyl-N-phenylamino)-6-morpholino-1,3,5-triazine as colorless crystals having melting point of 93.5° C.-95.5° C.
Reaction SMILES: CO[C:3](=[O:18])[CH:4]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[CH:12]=1)[CH2:5][CH:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1.[NH2:19][C:20]1[S:21][CH:22]=[CH:23][N:24]=1.C[O-].[Mg+2].C[O-].CO>>[Cl:17][C:13]1[CH:12]=[C:11]([CH:4]([CH2:5][CH:6]2[CH2:7][CH2:8][CH2:9][CH2:10]2)[C:3]([NH:19][C:20]2[S:21][CH:22]=[CH:23][N:24]=2)=[O:18])[CH:16]=[CH:15][CH:14]=1
Reactant: Nc1nccs1
Reactant: COC(=O)C(CC1CCCC1)c1cccc(Cl)c1
Agent: C[O-]
Agent: [Mg+2]
Solvent: CO
Product: O=C(Nc1nccs1)C(CC1CCCC1)c1cccc(Cl)c1
Temperature: 100 °C
Yield: 61.9 %

Procedure:
A mixture of 2-(3-chloro-phenyl)-3-cyclopentyl-propionic acid methyl ester (113 mg, 0.42 mmol) and 2-aminothiazole (84 mg, 0.84 mmol) in a solution of magnesium methoxide in methanol (7.4 wt %, 2.4 mL, 1.69 mmol) was refluxed at 100° C. for 20 h. The reaction mixture was then concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 80/20 hexanes/ethyl acetate) afforded 2-(3-chloro-phenyl)-3-cyclopentyl-N-thiazol-2-yl-propionamide (87 mg, 53%) as a white solid: mp 138.8-141.2° C.; EI-HRMS m/e calcd for C17H19ClN2OS (M+) 334.0906, found 334.0907.
Reaction SMILES: S(S([O-])=O)([O-])=O.[Na+].[Na+].[CH3:9][C:10]1[CH:15]=[CH:14][C:13]([N:16]2[CH:20]=[CH:19][CH:18]=[CH:17]2)=[C:12]([N+:21]([O-])=O)[CH:11]=1.O1CCCC1>O.C(O)C>[NH2:21][C:12]1[CH:11]=[C:10]([CH3:9])[CH:15]=[CH:14][C:13]=1[N:16]1[CH:20]=[CH:19][CH:18]=[CH:17]1
Reactant: Cc1ccc(-n2cccc2)c([N+](=O)[O-])c1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(-n2cccc2)c(N)c1

Procedure:
20 g of sodium hydrosulfite are added portionwise to a solution of 18.18 g (0.09 mole) of 1-(4-methyl-2-nitrophenyl)pyrrole in 400 ml. of tetrahydrofuran and 200 ml. of water. The resulting solution is heated on a steam bath for 5 minutes and an additional 20 g. of sodium hydrosulfite are added and the solution is heated for 5 minutes on a steam bath. Then 38.3 g. of sodium hydrosulfite and a solution of 400 ml. of ethanol and 500 ml. of water are added, and again the solution is heated on a steam bath for 5 minutes. The solvent is removed to give a tan solid which is recrystallized from hexane to give white crystals, m.p. 89°-90° C. of 1-(2-amino-4-methylphenyl)pyrrole.