Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([N:8]2[CH2:19][CH2:18][C:17]3[C:16]4[CH2:15][C:14]([CH3:21])([CH3:20])[CH2:13][C:12]=4[S:11][C:10]=3[C:9]2=[O:22])[C:3]=1[CH:23]=[O:24].[CH3:25][O:26][CH2:27][CH2:28][N:29]1[CH2:34][CH2:33][N:32]2[N:35]=[C:36]([NH:38][C:39]3[C:40](=[O:55])[N:41]([CH3:54])[CH:42]=[C:43](B4OC(C)(C)C(C)(C)O4)[CH:44]=3)[CH:37]=[C:31]2[CH2:30]1>>[CH3:20][C:14]1([CH3:21])[CH2:13][C:12]2[S:11][C:10]3[C:9](=[O:22])[N:8]([C:4]4[C:3]([CH:23]=[O:24])=[C:2]([C:43]5[CH:44]=[C:39]([NH:38][C:36]6[CH:37]=[C:31]7[CH2:30][N:29]([CH2:28][CH2:27][O:26][CH3:25])[CH2:34][CH2:33][N:32]7[N:35]=6)[C:40](=[O:55])[N:41]([CH3:54])[CH:42]=5)[CH:7]=[CH:6][N:5]=4)[CH2:19][CH2:18][C:17]=3[C:16]=2[CH2:15]1
Reactant: COCCN1CCn2nc(Nc3cc(B4OC(C)(C)C(C)(C)O4)cn(C)c3=O)cc2C1
Reactant: CC1(C)Cc2sc3c(c2C1)CCN(c1nccc(Cl)c1C=O)C3=O
Product: COCCN1CCn2nc(Nc3cc(-c4ccnc(N5CCc6c(sc7c6CC(C)(C)C7)C5=O)c4C=O)cn(C)c3=O)cc2C1

Procedure:
Following the procedure in Example 304, and starting with 4-chloro-2-{4,4-dimethyl-9-oxo-7-thia-10-azatricyclo[6.4.0.02,6]dodeca-1(8),2(6)-dien-10-yl}pyridine-3-carbaldehyde 109a (250 mg, 0.693 mmol) and 3-(5-(2-methoxyethyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-ylamino)-1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one 304d (595 mg, 0.1.386 mmol), 308a was obtained as a yellow solid (250 mg, 57%). MS-ESI: [M+H]+ 628.3
Reaction SMILES: CCN(C(C)C)C(C)C.[Br:10][C:11]1[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=1)[CH2:14]Br.[CH3:19][NH:20][CH2:21][CH2:22][C:23]#[N:24]>CN(C=O)C>[Br:10][C:11]1[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=1)[CH2:14][N:20]([CH3:19])[CH2:21][CH2:22][C:23]#[N:24]
Reactant: CNCCC#N
Reactant: BrCc1cccc(Br)c1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(CCC#N)Cc1cccc(Br)c1
Reaction time: 16 h
Yield: 116.9 %

Procedure:
Hunig's base (26.5 mL, 0.15 mol) was added to 3-bromobenzyl bromide (38 g, 0.15 mol) and N-methyl-β-alanine nitrile (14.2 mL, 0.15 mol) in dry DMF (400 mL). The solution was stirred 16 h, concentrated in vacuo to near dryness, triturated with ether/EtOAc, and filtered. [A second reaction was repeated on 12 g]. The combined filtrates were concentrated by rotory evaporation and the residue was charged (CH2Cl2) to a 65 (M) Biotage® silica gel column; Segment 1: Gradient elution from 5-15% B over 1.3 L; Segment 2: 15%-100% B (A=Hexanes; B=EtOAc) over 6.75 L to give Example 4, 3-((3-bromobenzyl)(methyl)amino)-propanenitrile 44.4 g (88%). 1H NMR (500 MHz, DMSO-d6) δ 7.54 (s, 1H), 7.46 (d, J=7.6 Hz, 1H), 7.34 (d, J=7.6 Hz, 1H), 7.30 (t, J=7.6 Hz, 1H), 3.54 (s, 2H), 2.71 (t, J=6.4 Hz, 2H), 2.63 (t, J=6.4 Hz, 2H), 2.17 (s, 3H). RT=1.1 minutes (condition 2); LRMS: Anal. Calcd. for C11H13BrN2: 253.03. found: 253.05 (M+H).
Reaction SMILES: [CH2:1]([C:8]1[C:17](=[O:18])[C:16]2[C:11](=[CH:12][C:13]([Cl:19])=[CH:14][CH:15]=2)[N:10]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([N:26]3C(C)=CC=C3C)[N:21]=2)[C:9]=1[C:33]1[O:34][CH:35]=[CH:36][N:37]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.NO>CCO.O>[NH2:26][C:22]1[N:21]=[C:20]([N:10]2[C:11]3[C:16](=[CH:15][CH:14]=[C:13]([Cl:19])[CH:12]=3)[C:17](=[O:18])[C:8]([CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[C:9]2[C:33]2[O:34][CH:35]=[CH:36][N:37]=2)[CH:25]=[CH:24][CH:23]=1
Reactant: Cc1ccc(C)n1-c1cccc(-n2c(-c3ncco3)c(Cc3ccccc3)c(=O)c3ccc(Cl)cc32)n1
Agent: Cl
Agent: NO
Solvent: CCO
Solvent: O
Product: Nc1cccc(-n2c(-c3ncco3)c(Cc3ccccc3)c(=O)c3ccc(Cl)cc32)n1

Procedure:
A solution of 3-benzyl-7-chloro-1-[6-(2,5-dimethyl-pyrrol-1-yl)-pyridin-2-yl]-2-oxazol-2-yl-1H-quinolin-4-one (640 mg) in EtOH (3.5 mL) and water (1.3 mL) and hydroxylamine hydrochloride (450 mg) was stirred for 48 h at 60° C. After evaporation of volatiles, the dark brown residue was partitioned into EtOAc and H2O, and the organic phase adsorbed on silica to provide 1-(6-amino-pyridin-2-yl)-3-benzyl-7-chloro-2-oxazol-2-yl-1H-quinolin-4-one (Compound 141). M+H=428; mp=279.3-282.8° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:22])[C:10]2[CH:15]=[CH:14][C:13]([N:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)=[N:12][CH:11]=2)=[CH:4][C:3]=1[NH:23][C:24](=[O:32])[C:25]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=1.[C:33](Cl)(=[O:38])[CH2:34][CH:35]([CH3:37])[CH3:36]>>[CH3:36][CH:35]([CH3:37])[CH2:34][C:33]([N:19]1[CH2:18][CH2:17][N:16]([C:13]2[N:12]=[CH:11][C:10]([C:9]([NH:8][C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([NH:23][C:24](=[O:32])[C:25]4[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=4)[CH:4]=3)=[O:22])=[CH:15][CH:14]=2)[CH2:21][CH2:20]1)=[O:38]
Reactant: O=C(Nc1ccc(Cl)c(NC(=O)c2ccc(F)cc2)c1)c1ccc(N2CCNCC2)nc1
Reactant: CC(C)CC(=O)Cl
Product: CC(C)CC(=O)N1CCN(c2ccc(C(=O)Nc3ccc(Cl)c(NC(=O)c4ccc(F)cc4)c3)cn2)CC1

Procedure:
N-(4-chloro-3-(4-fluorobenzamido)phenyl)-6-(piperazin-1-yl)nicotinamide (0.182 mmol) was used in general procedure 1 with isovaleryl chloride (0.20 mmol). The product was purified by RP-HPLC to give 6-(4-(3-methylbutanoyl)piperazin-1-yl)-N-(3-(4-fluorobenzamido)-4-chlorophenyl)-pyridine-3-carboxamide. MS (Q1) 538.5 (M)+
Reaction SMILES: C([O:3][C:4](=[O:22])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([NH:12][C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17](Br)[N:16]=2)=[O:14])[CH:7]=1)C.[Cl:23][C:24]1[CH:25]=[C:26](B(O)O)[CH:27]=[C:28]([Cl:30])[CH:29]=1>>[Cl:23][C:24]1[CH:25]=[C:26]([C:17]2[N:16]=[C:15]([C:13]([NH:12][C:8]3[CH:7]=[C:6]([CH2:5][C:4]([OH:3])=[O:22])[CH:11]=[CH:10][CH:9]=3)=[O:14])[CH:20]=[CH:19][CH:18]=2)[CH:27]=[C:28]([Cl:30])[CH:29]=1
Reactant: CCOC(=O)Cc1cccc(NC(=O)c2cccc(Br)n2)c1
Reactant: OB(O)c1cc(Cl)cc(Cl)c1
Product: O=C(O)Cc1cccc(NC(=O)c2cccc(-c3cc(Cl)cc(Cl)c3)n2)c1

Procedure:
The pyridyl bromide (77)(44 mg, 0.12 mmol) was coupled to 3,5-dichloro-phenylboronic acid (20 mg, 0.10 mmol) using Method E. During this reaction, hydrolysis occurred. The residue was extracted using Work-up E1 to give the acid. The solid was further purified by preparative HPLC to give the title compound.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[N:4]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[C:10]([CH2:15][O:16][C:17]3[CH:18]=[CH:19][CH:20]=[C:21]4[C:26]=3[N:25]=[C:24]([CH3:27])[CH:23]=[CH:22]4)[C:9]=2[Cl:28])[CH:5]=[CH:6][CH:7]=1.[CH3:29][N:30]([CH3:44])[C:31]([C:33]1[CH:43]=[CH:42][C:36]([CH:37]=[CH:38][C:39](O)=[O:40])=[CH:35][CH:34]=1)=[O:32].Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1>CN(C)C=O.O>[Cl:28][C:9]1[C:10]([CH2:15][O:16][C:17]2[CH:18]=[CH:19][CH:20]=[C:21]3[C:26]=2[N:25]=[C:24]([CH3:27])[CH:23]=[CH:22]3)=[C:11]([Cl:14])[CH:12]=[CH:13][C:8]=1[N:4]1[CH:5]=[CH:6][CH:7]=[C:3]1[CH2:2][NH:1][C:39](=[O:40])[CH:38]=[CH:37][C:36]1[CH:42]=[CH:43][C:33]([C:31](=[O:32])[N:30]([CH3:44])[CH3:29])=[CH:34][CH:35]=1
Reactant: CN(C)C(=O)c1ccc(C=CC(=O)O)cc1
Reactant: Cc1ccc2cccc(OCc3c(Cl)ccc(-n4cccc4CN)c3Cl)c2n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc2cccc(OCc3c(Cl)ccc(-n4cccc4CNC(=O)C=Cc4ccc(C(=O)N(C)C)cc4)c3Cl)c2n1
Reaction time: 18 h
Yield: 82 %

Procedure:
To a solution of 2-aminomethyl-1-[2,4-dichloro-3-(2-methylquinolin-8-yloxymethyl)phenyl]pyrrole (100 mg) and 4-(dimethylcarbamoyl)cinnamic acid (58.5 mg) in N,N-dimethylformamide (2 ml) were added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (55.8 mg) and 1-hydroxybenzotriazole (49.2 mg) at ambient temperature, and the mixture was allowed to stand for 18 hours. The reaction mixture was poured into water and extracted with chloroform. The separated organic layer was washed with water, saturated sodium bicarbonate solution and brine, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by preparative thin layer chromatography (chloroform:methanol=20:1, V/V) to give 1-[2,4-dichloro-3-(2-methylquinolin-8-yloxymethyl)phenyl]-2-[4-(dimethylcarbamoyl)cinnamoylaminomethyl]pyrrole (122 mg) as an amorphous powder.
Reaction SMILES: BrC[CH2:3][C:4]([C:6]1[C:11]([CH3:12])=[CH:10][C:9]([CH3:13])=[CH:8][C:7]=1[CH3:14])=O.[NH2:15][C:16]([NH2:18])=[S:17]>CO>[NH2:18][C:16]1[S:17][CH:3]=[C:4]([C:6]2[C:11]([CH3:12])=[CH:10][C:9]([CH3:13])=[CH:8][C:7]=2[CH3:14])[N:15]=1
Reactant: Cc1cc(C)c(C(=O)CCBr)c(C)c1
Reactant: NC(N)=S
Solvent: CO
Product: Cc1cc(C)c(-c2csc(N)n2)c(C)c1
Yield: 70 %

Procedure:
A solution of 80 g of 2,4,6-trimethylphenyl bromoethyl ketone and 35 g of thiourea in 250 ml of methanol is refluxed for 3 hours. After cooling the reaction mixture, the precipitate is filtered off and washed abundantly with diethyl ether. After concentration of the filtrate to a third of the initial volume, a second bath of crystals is recovered. Yield: 70%. m.p.=138° C. The hydrobromide prepared by the action of HBr in ethanol melts at 295° C.
Reaction SMILES: [SH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13].[C:15]1([CH:21]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)O)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>FC(F)(F)C(O)=O>[C:15]1([CH:21]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[S:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C(O)CCCCCCCCCCS
Reactant: OC(c1ccccc1)c1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)CCCCCCCCCCSC(c1ccccc1)c1ccccc1
Yield: 44 %

Procedure:
A solution of 11-mercaptoundecanoic acid (300 mg, 1.3 mmol) and diphenylmethanol (255 mg, 1.3 mmol) in trifluoroacetic acid was stirred at RT, under nitrogen for 30 min. Trifluoroacetic acid was evaporated under high vacuum, the residue dissolved in ether (20 ml), washed with water (3×20 ml), dried and evaporated. The residue was purified by chromatography (light pet—ethyl acetate, 80:20-50:50) on silica to give the desired product (220 mg, 42%), m.p. (Found C, 74.55; H, 8.77. C24H34O2S requires C, 74.96; H, 8.39) ms (EI) 384.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH2:11][CH2:12][CH2:13][NH:14][CH2:15][CH:16]=2)=[CH:6][CH:5]=1.[H][H]>[Pd].CO>[CH3:2][O:3][C:4]1[CH:5]=[CH:6][C:7]([CH:10]2[CH2:11][CH2:12][CH2:13][NH:14][CH2:15][CH2:16]2)=[CH:8][CH:9]=1
Reactant: [H][H]
Reactant: COc1ccc(C2=CCNCCC2)cc1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: COc1ccc(C2CCCNCC2)cc1
Yield: 80 %

Procedure:
A mixture of 5-(4-methoxyphenyl)-2,3,4,7-tetrahydro-1H-azepine hydrochloride (0.35 g, 1.5 mmol) and 10% palladium on carbon (0.2 g) in methanol (10 mL) was stirred overnight under balloon pressure of hydrogen. The reaction mixture was filtered through Celite and concentrated to yield 4-(4-methoxyphenyl)azepane (0.26 g, 1.2 mmol, 79%). LCMS: R.T. 0.60 min. LCMS (ES-API), m/z 206.0 (M+H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]([NH:12][CH2:13][CH2:14][C:15]([O:17]CC)=[O:16])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>CO>[C:1]([O:5][C:6]([NH:8][CH2:9][C:10]([NH:12][CH2:13][CH2:14][C:15]([OH:17])=[O:16])=[O:11])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)CCNC(=O)CNC(=O)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)NCC(=O)NCCC(=O)O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 16 %

Procedure:
A solution of (6) at 0° C. (3.43 g; 0.012 mmol) in methanol (40 ml) was treated with 2N sodium hydroxide (6.9 ml; 0.013 mmol). The mixture was stirred at ambient temperature for 90 minutes. After evaporation of the methanol and removal of the insoluble material by filtration, the solution was adjusted to pH5 with 6N hydrochloric acid. The mixture was extracted with dichloromethane and the organic layer evaporated to dryness to give 3-[(2-tertbutoxycarbonylaminoacetyl)amino]propanoic acid (7).
Reaction SMILES: [C:1]([O:5][C:6](=[O:27])[N:7]([CH2:24]C=C)[CH2:8][C@@H:9]([N:21]=[N+:22]=[N-:23])[C@H:10]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH:11]=[CH2:12])([CH3:4])([CH3:3])[CH3:2]>C(Cl)Cl.[Cl-].[Cl-].[Zn+2]>[C:1]([O:5][C:6]([N:7]1[CH2:24][CH:12]=[CH:11][C@@H:10]([O:13][CH2:14][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[C@H:9]([N:21]=[N+:22]=[N-:23])[CH2:8]1)=[O:27])([CH3:4])([CH3:2])[CH3:3]
Reactant: C=CCN(C[C@@H](N=[N+]=[N-])[C@@H](C=C)OCc1ccccc1)C(=O)OC(C)(C)C
Agent: [Cl-]
Agent: [Zn+2]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC=C[C@@H](OCc2ccccc2)[C@H](N=[N+]=[N-])C1

Procedure:
A solution of Mo(CHCMe2Ph)(NAr)(OCMe(CF3)2)2(phen) (8 mg, 9 μmol, 5 mol %) and ZnCl2 (1.2 mg, 9 μmol) in CH2Cl2 (18 mL) was heated for 30 min to 100° C. Subsequently, (2R,3R)-allyl-(2-azido-3-benzyloxy-pent-4-enyl)-carbamic acid tert-butylester (66 mg, 0.177 mmol) was added and the mixture was heated for 30 min under reflux. After removal of the solvent, the residue is purified by means of column chromatography at silica gel (hexane/ethylacetate, 20:1). 1H NMR (300 MHz, CD2Cl2): δ=7.40-7.29 (m, 5H), 5.76 (br s, 2H), 4.67 (d, J=11.5 Hz, 1H), 4.55 (d, J=11.5 Hz, 1H), 427-3.97 (m, 2H), 3.85-3.54 (m, 4H), 1.45 (s, 9H); 13C NMR (75 MHz, CD2Cl2): δ=155.1, 138.3, 131.1, 129.8, 128.7, 128.3, 128.1, 80.5, 79.1, 72.3, 64.0, 48.8, 47.5, 28.4; [α]20D=6−26.3 (2.65, CH2Cl2); IR (film, cm−1): 3065, 3031, 2976, 2927, 2857, 2108, 1699, 1657, 1496, 1456, 1393, 1366, 1248, 1168, 1135, 1095, 737, 698 cm−1; MS (EI) m/z: 344 ([M+], <1), 260 (1), 225 (2), 186 (1), 180 (3), 169 (14), 160 (6), 125 (11), 91 (100), 57 (57); HRMS (ESI) (C18H24N4O3+H) calculated: 345.1927. found: 345.1921; C18H24N4O3 (344.41) calculated: C, 62.77; H, 7.02; N, 16.27. found: C, 62.72; H, 6.94; N, 16.19. The obtained data correspond to those of literature (A. Fürstner, O. R Thiel, J. Org. Chem. 2000, 65, 1738).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](/[C:12](=[N:16]\[O:17][CH2:18][CH:19]([CH3:21])[CH3:20])/[C:13]([OH:15])=O)[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].[NH2:22][C:23]1[S:24][C:25]2[CH:31]=[CH:30][CH:29]=[CH:28][C:26]=2[N:27]=1.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[S:24]1[C:25]2[CH:31]=[CH:30][CH:29]=[CH:28][C:26]=2[N:27]=[C:23]1[NH:22][C:13](=[O:15])/[C:12](/[C:4]1[CH:5]=[CH:6][C:7]([S:8]([CH3:11])(=[O:9])=[O:10])=[C:2]([Cl:1])[CH:3]=1)=[N:16]/[O:17][CH2:18][CH:19]([CH3:21])[CH3:20]
Reactant: Nc1nc2ccccc2s1
Reactant: CC(C)CO/N=C(/C(=O)O)c1ccc(S(C)(=O)=O)c(Cl)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)CO/N=C(/C(=O)Nc1nc2ccccc2s1)c1ccc(S(C)(=O)=O)c(Cl)c1
Reaction time: 2 h
Yield: 59.5 %

Procedure:
(E)-(3-chloro-4-methanesulfonyl-phenyl)-isobutoxyimino-acetic acid (prepared as in Example 24, 104 mg, 0.31 mmol), 2-aminobenzothiazole (47 mg, 0.31 mmol) and N,N-diisopropylethylamine (163 μL, 0.94 mmol) were combined in methylene chloride (1.5 mL) and cooled in an ice bath. O-(7-Azabenzotriazole-1-yl)-N,N,N′N′-tetramethyluronium hexafluoro-phosphate (119 mg, 0.31 mmol) was added and the ice bath was removed. After stirring 2 h, the reaction mixture was evaporated in vacuo. The residue was treated with saturated aqueous sodium bicarbonate solution (1 mL) and extracted with chloroform (2×3 mL). The combined organic phases were dried over sodium sulfate and evaporated in vacuo. The residue was purified by flash column chromatography (Merck silica gel 60, 40-63 μm; 30% ethyl acetate/hexanes) to afford (E)-N-benzothiazol-2-yl-2-(3-chloro-4-methanesulfonyl-phenyl)-2-isobutoxyimino-acetamide (86 mg, 60%) as a white solid after lyophilization from aqueous acetonitrile: LC-MS (ESI) m/e calcd for C20H20ClN3O4S2 [M+] 465.06, found 466 [M+H+]; H1-NMR (400 MHz, CDCl3) δ ppm 0.97 (d, J=6.6 Hz, 6 H, 2×CH3), 2.09 (m, 1 H, CH), 3.32 (s, 3 H, SO2CH3), 4.12 (d, J=6.8 Hz, 2 H, OCH2), 7.35 (brt, J=7.8 Hz, 1H, Ar), 7.48 (brt, J=7.8 Hz, 1H, Ar), 7.63 (dd, Jo=8.2, Jm=1.6 Hz, 1 H, Ar), 7.74 (d, Jm=1.6 Hz, 1 H, Ar), 7.83 (m, 2H, Ar), 8.24 (d, Jo=8.2 Hz, 1 H, Ar), 10.25 (brs, 1 H, NH).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[S:15])[NH:10][CH2:11][C:12](N)=[O:13])=[CH:4][CH:3]=1.[CH2:16](I)[CH3:17]>C(O)C>[CH2:16]([S:15][C:9]1[N:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[C:12](=[O:13])[CH2:11][N:10]=1)[CH3:17]
Reactant: NC(=O)CNC(=S)Nc1ccc(F)cc1
Reactant: CCI
Solvent: CCO
Product: CCSC1=NCC(=O)N1c1ccc(F)cc1
Yield: 29.9 %

Procedure:
A mixture of 2-[3-(4-fluorophenyl)-thioureido]-acetamide (9.1 g) and ethyl iodide (12.5 g) was heated at reflux in ethanol (200 mL) for 4 hours. The solvent was evaporated. The residue was dissolved in ethyl acetate (500 mL) then washed with water. The organic phase was extracted with 2N HCl (2×400 mL). The acid extract was made basic with 5% sodium bicarbonate solution. The precipitate was collected by filtration and dried. Crystallization from diethyl ether afforded the title compound (2.85 g) as an off-white solid, m.p. 114°-115° C. Anal. Calcd. for. C11H11F N2O S: C, 55.45; H, 4.65; N, 11.76. Found: C, 55.17; H, 4.54; N, 11.81. Mass spectrum (EI, M.+) m/z 238. 1H-NMR (DMSO-d6 ; 400 MHz) δ7.32-7.39 (m, 4H), 4.30 (s, 2H), 3.07 (q, 2H), and 1.28 ppm (t, 3H).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][N:6]=[C:5]([N:9]2[C:16]3[C@@H:15]4[CH2:17][C@@H:14]4[CH2:13][C:12]=3[C:11]([C:18]([OH:20])=O)=[N:10]2)[CH:4]=1)#[N:2].[NH2:21][C@@H:22]([CH:25]([CH3:27])[CH3:26])[CH2:23][OH:24].C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[OH:24][CH2:23][C@@H:22]([NH:21][C:18]([C:11]1[C:12]2[CH2:13][C@H:14]3[CH2:17][C@H:15]3[C:16]=2[N:9]([C:5]2[CH:4]=[C:3]([C:1]#[N:2])[CH:8]=[CH:7][N:6]=2)[N:10]=1)=[O:20])[CH:25]([CH3:27])[CH3:26]
Reactant: CC(C)[C@H](N)CO
Reactant: N#Cc1ccnc(-n2nc(C(=O)O)c3c2[C@@H]2C[C@@H]2C3)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)[C@@H](CO)NC(=O)c1nn(-c2cc(C#N)ccn2)c2c1C[C@H]1C[C@@H]21
Temperature: 23 °C
Reaction time: 0.5 h
Yield: 80.2 %

Procedure:
To a solution of (1aR,5aR)-2-(4-cyano-pyridin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic acid (50 mg, 0.188 mmol), (S)-2-amino-3-methylbutan-1-ol (19.37 mg, 0.188 mmol), and triethylamine (0.052 mL, 0.376 mmol) in DMF (2 mL) was added HATU (71.4 mg, 0.188 mmol). The mixture was stirred at 23° C. for 30 min and purified by HPLC to give the title compound (53 mg) as a white solid. LCMS m/z=352.3 [M+H]+; 1H NMR (400 MHz, CDCl3) δ 0.46 (td, J=4.7, 3.3 Hz, 1H), 1.04 (d, J=6.8 Hz, 3H), 1.05 (d, J=6.7 Hz, 3H), 1.26 (td, J=8.0, 4.9 Hz, 1H), 2.05 (oct, J=6.8 Hz, 1H), 2.26-2.32 (m, 1H), 2.52 (t, J=5.6 Hz, 1H), 2.78-2.82 (m, 1H), 2.93 (d, J=16.8 Hz, 1H), 3.02 (dd, J=16.7, 6.4 Hz, 1H), 3.75-3.92 (m, 3H), 7.00 (d, J=7.8 Hz, 1H), 7.41 (dd, J=5.1, 1.4 Hz, 1H), 8.17 (s, 1H), 8.62 (d, J=5.1 Hz, 1H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]([OH:6])=[O:5].[C:7]1(=[O:17])[O:12][C:10](=[O:11])[C:9]2=[CH:13][CH:14]=[CH:15][CH:16]=[C:8]12>>[CH:15]1[CH:16]=[C:8]([C:7]([NH:1][CH2:2][CH2:3][C:4]([OH:6])=[O:5])=[O:17])[C:9]([C:10]([OH:12])=[O:11])=[CH:13][CH:14]=1
Reactant: O=C1OC(=O)c2ccccc21
Reactant: NCCC(=O)O
Product: O=C(O)CCNC(=O)c1ccccc1C(=O)O
Reaction time: 3 h
Yield: 90 %

Procedure:
25 grams (0.28 mole) of β-alanine and 41.6 grams (0.28 mole) of phthalic anhydride were heated at 150° C. while stirring for three hours and then cooled. On recrystallizing with ethyl acetate, N-phthalyl-β-alanine was obtained in 90% yield (55 grams).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH2:11][C:12]([CH3:15])([CH3:14])[CH3:13])[C:3]=1[C:4]#[N:5].[C:16]([N:24]=[C:25]=[O:26])(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[C:4]([C:3]1[C:6]([O:10][CH2:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:7][CH:8]=[CH:9][C:2]=1[NH:1][C:25]([NH:24][C:16](=[O:23])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)=[O:26])#[N:5]
Reactant: CC(C)(C)COc1cccc(N)c1C#N
Reactant: O=C=NC(=O)c1ccccc1
Product: CC(C)(C)COc1cccc(NC(=O)NC(=O)c2ccccc2)c1C#N
Yield: 96 %

Procedure:
Prepared as in Example 146a from 2-amino-6-(neopentyloxy)-benzonitrile (Example 217b) and benzoyl isocyanate in 96% yield as a white solid. MS 352 (MH+).
Reaction SMILES: [C:1]([O:5][C:6](=[O:9])[CH2:7][NH2:8])([CH3:4])([CH3:3])[CH3:2].[CH:10]1([CH2:15][CH:16]=O)[CH2:14][CH2:13][CH2:12][CH2:11]1>C(Cl)Cl>[C:1]([O:5][C:6](=[O:9])[CH2:7]/[N:8]=[CH:16]/[CH2:15][CH:10]1[CH2:14][CH2:13][CH2:12][CH2:11]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)CN
Reactant: O=CCC1CCCC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)C/N=C/CC1CCCC1
Yield: 88.8 %

Procedure:
In a manner similar to the method described in Example 1a, glycine tert-butyl ester (0.7 g, 5 mmol) was reacted with 2-cyclopentylacetaldehyde (Betapharma) (0.9 g, 8 mmol) in CH2Cl2 at room temperature for 20 h to give [2-cyclopentyl-eth-(E)-ylideneamino]-acetic acid tert-butyl ester as a colorless oil (1 g, 90%).
Reaction SMILES: [C:1]1([NH:7][C:8]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:16]1([CH2:22][CH2:23][CH:24]=O)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[C:1]1([NH:7][C:8]([N:10]2[CH2:15][CH2:14][N:13]([CH2:24][CH2:23][CH2:22][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:12][CH2:11]2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=CCCc1ccccc1
Reactant: O=C(Nc1ccccc1)N1CCNCC1
Product: O=C(Nc1ccccc1)N1CCN(CCCc2ccccc2)CC1

Procedure:
The title compound was prepared from piperazine-1-carboxylic acid phenylamide and 3-phenylpropionaldehyde. 1H NMR (400 MHz, CDCl3): 7.36-7.16 (m, 9H), 7.05-7.00 (m, 1H), 6.40 (br s, 1H), 3.52-3.47 (m, 4H), 2.65 (t, J=7.6 Hz, 2H), 2.47-2.38 (m, 4H), 2.39 (t, J=7.4 Hz, 2H), 1.88-1.79 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]([N:5]1[C@@H:13]2[C@@H:8]([C@@:9]([OH:23])([C:14]#[C:15][C:16]3[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=3)[CH2:10][CH2:11][CH2:12]2)[CH2:7][CH2:6]1)=[O:4].[CH3:24][NH:25][C:26](=[O:32])[CH2:27][CH2:28][C:29](O)=[O:30]>>[CH3:24][NH:25][C:26](=[O:32])[CH2:27][CH2:28][C:29]([O:23][C@@:9]1([C:14]#[C:15][C:16]2[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=2)[CH2:10][CH2:11][CH2:12][C@@H:13]2[C@H:8]1[CH2:7][CH2:6][N:5]2[C:3]([O:2][CH3:1])=[O:4])=[O:30]
Reactant: COC(=O)N1CC[C@H]2[C@@H]1CCC[C@]2(O)C#Cc1cccc(C)c1
Reactant: CNC(=O)CCC(=O)O
Product: CNC(=O)CCC(=O)O[C@@]1(C#Cc2cccc(C)c2)CCC[C@@H]2[C@H]1CCN2C(=O)OC

Procedure:
Synthesis in analogy to the General Method 1 starting from (3aS,4R,7aS)-4-hydroxy-4-m-tolylethynyl-octahydro-indole-1-carboxylic acid methyl ester and N-methylsuccinamic acid to yield (3aR,4S,7aR)-methyl 4-(4-(methylamino)-4-oxobutanoyloxy)-4-(m-tolylethynyl)octahydro-1H-indole-1-carboxylate. MS [M+H]=427; RT=1.06 min; UPLC Method I
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)(=[O:4])[CH2:2][CH3:3].CO[CH:13](OC)[N:14]([CH3:16])[CH3:15]>>[CH3:16][N:14]([CH3:15])[CH:13]=[C:2]([CH3:3])[C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4]
Reactant: CCC(=O)c1ccccc1
Reactant: COC(OC)N(C)C
Product: CC(=CN(C)C)C(=O)c1ccccc1

Procedure:
A mixture of 57.0 g of propiophenone in 150 ml of N,N-dimethylformamide dimethyl acetal was stirred and heated at reflux for 24 hours. Then the solvent was removed in vacuo to give a yellow oil. The oil was subjected to Kugelrohr distillation to give 69.8 g of 3-dimethylamino-2-methylacrylophenone as a yellow oil, B.P. 100° C. (0.050 mm Hg).
Reaction SMILES: C[O:2][C:3](=[O:29])[C:4]([N+:26]([O-:28])=[O:27])([O:6][C:7]1[CH:12]=[C:11]([O:13][C:14]2[C:19]([Cl:20])=[CH:18][C:17]([C:21]([F:24])([F:23])[F:22])=[CH:16][C:15]=2[Cl:25])[CH:10]=[CH:9][CH:8]=1)[CH3:5].[OH-].[Na+].O>C(#N)C>[Cl:20][C:19]1[CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=[C:15]([Cl:25])[C:14]=1[O:13][C:11]1[CH:10]=[CH:9][CH:8]=[C:7]([CH:12]=1)[O:6][C:4]([N+:26]([O-:28])=[O:27])([CH3:5])[C:3]([OH:29])=[O:2]
Reactant: COC(=O)C(C)(Oc1cccc(Oc2c(Cl)cc(C(F)(F)F)cc2Cl)c1)[N+](=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Solvent: O
Product: CC(Oc1cccc(Oc2c(Cl)cc(C(F)(F)F)cc2Cl)c1)(C(=O)O)[N+](=O)[O-]
Yield: 70.4 %

Procedure:
135 g (0.3 mol) of 5-(2,6-dichloro-4-trifluoromethylphenoxy)-2-nitro-α-phenoxy-propionic acid methyl ester and 30 ml of concentrated aqueous sodium hydroxide solution were stirred in 400 ml of acetonitrile and 150 ml of water at 20° C. for 24 hours. The solution was concentrated, the residue was taken up in 500 ml of water and the aqueous mixture was acidified with 50 ml of concentrated hydrochloric acid. 93 g (71% of theory) of 5-(2,6-dichloro-4-trifluoromethyl-phenoxy)-2-nitro-α-phenoxy-propionic acid were obtained in the form of pale yellow crystals of melting point 146° C. (after recrystallization from toluene/cyclohexane).