Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH:2]1[CH2:5][CH:4]([NH:6][C:7]2[C:12](=[O:13])[NH:11][CH:10]=[C:9]([C:14]3[CH:19]=[CH:18][N:17]=[C:16]([C:20]([NH:22][C:23]4[CH:28]=[CH:27][C:26]([CH:29]([CH3:31])[CH3:30])=[C:25]([CH3:32])[CH:24]=4)=[O:21])[CH:15]=3)[CH:8]=2)[CH2:3]1.[C:33]([Cl:37])(=[O:36])[CH:34]=[CH2:35]>C(Cl)Cl>[ClH:37].[C:33]([N:2]1[CH2:5][CH:4]([NH:6][C:7]2[C:12](=[O:13])[NH:11][CH:10]=[C:9]([C:14]3[CH:19]=[CH:18][N:17]=[C:16]([C:20]([NH:22][C:23]4[CH:28]=[CH:27][C:26]([CH:29]([CH3:30])[CH3:31])=[C:25]([CH3:32])[CH:24]=4)=[O:21])[CH:15]=3)[CH:8]=2)[CH2:3]1)(=[O:36])[CH:34]=[CH2:35]
Reactant: C=CC(=O)Cl
Reactant: Cc1cc(NC(=O)c2cc(-c3c[nH]c(=O)c(NC4CNC4)c3)ccn2)ccc1C(C)C
Agent: Cl
Solvent: ClCCl
Product: C=CC(=O)N1CC(Nc2cc(-c3ccnc(C(=O)Nc4ccc(C(C)C)c(C)c4)c3)c[nH]c2=O)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 22.5 %

Procedure:
To a solution of 5-(azetidin-3-ylamino)-N-(4-isopropyl-3-methylphenyl)-6-oxo-1,6-dihydro-[3,4′-bipyridine]-2′-carboxamide hydrochloride (60 mg, 0.14 mmol) in DCM (20 mL) was added acryloyl chloride (0.14 mL, 0.17 mmol) and TEA (0.1 mL, 0.7 mmol)). The mixture was stirred overnight at RT. The reaction was quenched by addition of MeOH (2 mL) and 4M HCl in 1,4-dioxane (2 mL). Water was added, the mixture extracted several times with ethyl acetate, the organic layers dried (MgSO4), filtered and concentrated. The residue was purified by Prep. HPLC (pH<7) and converted to the HCl salt to afford 5-((1-acryloylazetidin-3-yl)amino)-N-(4-isopropyl-3-methylphenyl)-6-oxo-1,6-dihydro-[3,4′-bipyridine]-2′-carboxamide hydrochloride (16 mg, 24% yield) as a yellow solid: 1H NMR (400 MHz, MeOD) δ 8.70 (d, J=4.8 Hz, 1H), 8.37 (d, J=1.2 Hz, 1H), 7.81 (dd, J=1.6, 5.2 Hz, 1H), 7.52 (s, 1H), 7.47 (s, 1H), 7.41 (d, J=1.6 Hz, 1H), 6.92 (s, 1H), 6.74 (d, J=2.4 Hz, 1H), 6.41 (dd, J=10.0, 16.8 Hz, 1H), 6.28 (dd, J=2.0, 16.8 Hz, 1H), 5.78 (dd, J=2.0, 10 Hz, 1H), 4.78-4.81 (m, 1H), 4.52-4.59 (m, 2H), 4.23-4.27 (m, 1H), 4.02-4.04 (m, 1H), 2.90-2.94 (m, 1H), 2.38 (s, 3H), 1.29 (d, J=6.8 Hz, 6H); MS (ES) m/z 472 (M+H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([NH:7][CH2:8][CH:9]2[CH2:14][CH2:13][N:12](C(OCC3C=CC=CC=3)=O)[CH2:11][CH2:10]2)=[CH:3][CH:2]=1.[H][H]>[Pd].C(O)C>[NH:12]1[CH2:13][CH2:14][CH:9]([CH2:8][NH:7][C:4]2[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=2)[CH2:10][CH2:11]1
Reactant: [H][H]
Reactant: O=C(OCc1ccccc1)N1CCC(CNc2ccncc2)CC1
Agent: [Pd]
Solvent: CCO
Product: c1cc(NCC2CCNCC2)ccn1

Procedure:
Benzyl 4-[(4-pyridinylamino)methyl]-1-piperidinecarboxylate (EXAMPLE 1) (7 g, 21 mmol) was dissolved in abs. Ethanol (150 mL) with 10% palladium on carbon (700 mg) and stirred under 1 atm of hydrogen for 2 h. The catalyst was filtered off and the filtrate was concentrated under reduced pressure to afford the N-(4-piperidinylmethyl)-4-pyridinamine as a clear oil which was used without further purification.
Reaction SMILES: [C:1]([OH:6])(=[O:5])[C:2]([OH:4])=[O:3].[C:7]([OH:16])(=[O:15])[CH:8]([CH:10]([C:12]([OH:14])=[O:13])[OH:11])[OH:9]>>[C:1]([O-:6])(=[O:5])[C:2]([O-:4])=[O:3].[C:7]([O-:16])(=[O:15])[CH:8]([CH:10]([C:12]([O-:14])=[O:13])[OH:11])[OH:9]
Reactant: O=C(O)C(O)C(O)C(=O)O
Reactant: O=C(O)C(=O)O
Product: O=C([O-])C(=O)[O-]
Product: O=C([O-])C(O)C(O)C(=O)[O-]

Procedure:
When the alcoholic solution saturated with oxalic acid or tartaric acid was added to the ethereal solution of the above-mentioned syrupy residue with cooling, there was obtained oxalate(mp. 222° C.) or tartarate (mp. 246° C.), respectively.
Reaction SMILES: [CH3:1][NH:2][C:3]1[N:8]=[C:7]([N:9]2[CH2:14][CH2:13][N:12]([CH3:15])[CH2:11][CH2:10]2)[N:6]=[C:5]([N:16]2[CH2:21][CH2:20][CH2:19][CH:18]([C:22](O)=[O:23])[CH2:17]2)[N:4]=1.[F:25][C:26]([F:36])([F:35])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[CH2:33][NH2:34].CN(C1C=CC=CN=1)C.CCN=C=NCCCN(C)C>C(Cl)Cl.CN(C=O)C.CO>[F:25][C:26]([F:35])([F:36])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[CH2:33][NH:34][C:22]([CH:18]1[CH2:19][CH2:20][CH2:21][N:16]([C:5]2[N:4]=[C:3]([NH:2][CH3:1])[N:8]=[C:7]([N:9]3[CH2:10][CH2:11][N:12]([CH3:15])[CH2:13][CH2:14]3)[N:6]=2)[CH2:17]1)=[O:23]
Reactant: CNc1nc(N2CCN(C)CC2)nc(N2CCCC(C(=O)O)C2)n1
Reactant: NCc1ccccc1C(F)(F)F
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Solvent: CO
Solvent: CN(C)C=O
Product: CNc1nc(N2CCN(C)CC2)nc(N2CCCC(C(=O)NCc3ccccc3C(F)(F)F)C2)n1
Temperature: 0 °C
Reaction time: 2 h
Yield: 26.9 %

Procedure:
A solution of 1-[4-(methylamino)-6-(4-methyl-1-piperazinyl)-1,3,5-triazin-2-yl]-3-piperidinecarboxylic acid (0.18 g, 0.55 mmol, 1.0 equiv), [(2-trifluoromethyl-phenyl)methyl]amine (0.12 g, 0.68 mmol, 1.25 equiv), and dimethylaminopyridine (DMAP, 14 mg, 0.11 mmol, 0.2 equiv) in CH2Cl2 and DMF was cooled to ˜0° C. using an ice bath. Next EDCI (0.16 g, 0.82 mmol, 1.5 equiv) was added. The reaction mixture was stirred at 0° C. for 30 min and at room temperature for an additional 2 hours. The reaction was monitored by HPLC. The solution was then diluted with CH2Cl2 and washed with saturated aqueous NaCl. The organic layer was dried over Na2SO4, and concentrated to provide the crude product. The crude product was dissolved in methanol and purified by HPLC to afford 73 mg of the title compound. MS (ES+): m/e 493.3 [M+H]+.
Reaction SMILES: [CH3:1][C:2]([N:11]1[CH:15]=[C:14]([NH:16][C:17](=[O:23])[CH:18]([NH2:22])[CH2:19][CH2:20][CH3:21])[N:13]=[CH:12]1)([CH3:10])[CH2:3][N:4]1[CH2:9][CH2:8][O:7][CH2:6][CH2:5]1.[OH:24][C@@H:25]([CH:29]([CH3:31])[CH3:30])[C:26](O)=[O:27]>>[CH3:1][C:2]([N:11]1[CH:15]=[C:14]([NH:16][C:17](=[O:23])[CH:18]([NH:22][C:26](=[O:27])[CH:25]([OH:24])[CH:29]([CH3:31])[CH3:30])[CH2:19][CH2:20][CH3:21])[N:13]=[CH:12]1)([CH3:10])[CH2:3][N:4]1[CH2:5][CH2:6][O:7][CH2:8][CH2:9]1
Reactant: CC(C)[C@H](O)C(=O)O
Reactant: CCCC(N)C(=O)Nc1cn(C(C)(C)CN2CCOCC2)cn1
Product: CCCC(NC(=O)C(O)C(C)C)C(=O)Nc1cn(C(C)(C)CN2CCOCC2)cn1

Procedure:
2-Amino-pentanoic acid [1-(1,1-dimethyl-2-morpholin-4-yl-ethyl)-1H-imidazol-4-yl]-amide was coupled with (S)-2-hydroxy-3-methyl-butyric acid to afford the title compound: 13C NMR (100 MHz, CDCl3) 13.9, 16.1, 19.1, 19.4, 25.9, 32.3, 35.4, 52.8, 55.5, 59.2, 67.4, 68.8, 105.3, 131.3, 137.2, 169.4, 174.1; MS m/z 424.4 (M+1).
Reaction SMILES: [CH2:1]([OH:3])[CH3:2].[H-].[Na+].[C:6]([N:10]=[N:11][C:12]1([N:18]=[C:19]=[O:20])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)([CH3:9])([CH3:8])[CH3:7].[N-]=C=O>O>[C:6]([N:10]=[N:11][C:12]1([NH:18][C:19]([O:3][CH2:1][CH3:2])=[O:20])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)([CH3:9])([CH3:7])[CH3:8]
Reactant: CCO
Reactant: CC(C)(C)N=NC1(N=C=O)CCCCC1
Agent: [H-]
Agent: [N-]=C=O
Agent: [Na+]
Solvent: O
Product: CCOC(=O)NC1(N=NC(C)(C)C)CCCCC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To 50 ml of ethanol in a 125 ml erlenmeyer flask stirred with a magnetic stirrer, was slowly added 2.1 grams (0.05 moles) of 57% sodium hydride. After the temperature came back to 25° C., 10.5 grams (0.05 moles) of 1-t-butylazo-1-isocyanatocyclohexane was added dropwise over 5 minutes. After the addition was complete, the reaction was stirred an additional 30 minutes at room temperature. Gas chromatography indicated that the 1-t-butylazo-1-isocyanatocyclohexane had reacted almost immediately. The reaction mixture was poured into 300 ml water and the product extracted with 100 ml pentane. The pentane extract was separated, washed with water, 10% NaHCO3 solution, dried over anhydrous Na2SO4, filtered and the pentane evaporated under reduced pressure to leave 10.3 grams (80.5% crude yield) of a yellow liquid. The product had a strong carbonyl band at 1730 cm-1 and a sharp NH band at 3400 cm-1 in its infrared spectrum and the isocyanate band at 2225 cm-1 was absent.
Reaction SMILES: NC1CCC(NC2N=C(NC3CCC(N)CC3)N=C(Cl)N=2)CC1.C(OC(=O)[NH:30][C@@H:31]1[CH2:35][CH2:34][N:33]([C:36](=[O:52])[NH:37][CH:38]2[CH2:43][CH2:42][CH:41]([NH:44]C(OC(C)(C)C)=O)[CH2:40][CH2:39]2)[CH2:32]1)(C)(C)C>>[NH2:44][CH:41]1[CH2:42][CH2:43][CH:38]([NH:37][C:36]([N:33]2[CH2:34][CH2:35][C@@H:31]([NH2:30])[CH2:32]2)=[O:52])[CH2:39][CH2:40]1
Reactant: CC(C)(C)OC(=O)NC1CCC(NC(=O)N2CC[C@@H](NC(=O)OC(C)(C)C)C2)CC1
Agent: NC1CCC(Nc2nc(Cl)nc(NC3CCC(N)CC3)n2)CC1
Product: NC1CCC(NC(=O)N2CC[C@@H](N)C2)CC1

Procedure:
(R)-3-Amino-pyrrolidine-1-carboxylic acid (4-amino-cyclohexyl)-amide is prepared analogously to N,N′-bis-(4-amino-cyclohexyl)-6-chloro-[1,3,5]triazine-2,4-diamine (Intermediate IA) by replacing Intermediate IA1 with [(R)-1-(4-tert-butoxycarbonylamino-cyclohexylcarbamoyl)-pyrrolidin-3-yl]-carbamic acid tert-butyl ester (IF2)
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([NH:10][C:11]1[CH:12]=[C:13]([CH:31]=[CH:32][CH:33]=1)[C:14]([C:16]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[N:18]([CH2:25][CH2:26][CH2:27][C:28]([OH:30])=[O:29])[CH:17]=1)=[O:15])=[O:9])([CH3:6])([CH3:5])[CH3:4].[CH2:34](Br)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.Cl>CN(C)C=O>[CH2:34]([N:10]([C:11]1[CH:12]=[C:13]([CH:31]=[CH:32][CH:33]=1)[C:14]([C:16]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[N:18]([CH2:25][CH2:26][CH2:27][C:28]([O:30][CH2:14][C:13]2[CH:31]=[CH:32][CH:33]=[CH:11][CH:12]=2)=[O:29])[CH:17]=1)=[O:15])[C:8]([O:7][C:3]([CH3:6])([CH3:4])[CH3:5])=[O:9])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: CC(C)(C)OC(=O)Nc1cccc(C(=O)c2cn(CCCC(=O)O)c3ccccc23)c1
Reactant: BrCc1ccccc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N(Cc1ccccc1)c1cccc(C(=O)c2cn(CCCC(=O)OCc3ccccc3)c3ccccc23)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 96.9 %

Procedure:
60% Sodium hydride in mineral oil (0.13 g) was added to a solution of 4-[3-(3-tert-butoxycarbonylaminobenzoyl)indol-1-yl]butyric acid (0.47 g) in N,N-dimethylformamide (7 ml). The mixture was stirred at 0° C. for 1 hour. Benzyl bromide (0.95 g) was added to the mixture and the ixture was stirred at room temperature for 20 hours. The mixture was poured into ice water and 0.5N-hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water, dried over magnesium sulfate and evaporated. The residue was chromatographed on silica gel (30 g) eluting with a mixture of n-hexane and ethyl acetate (5:1) to give benzyl 4-[3-[3-(N-benzyl-N-tert-butoxycarbonylamino)benzoyl]indol-1-yl]butyrate (325 mg) as an oil.
Reaction SMILES: C1CO[C:8]23OCCO[C:3]2([C@:4]2([CH2:27][CH2:26][C@H:25]4[C@@H:15]([CH2:16][C@H:17]([CH2:28][OH:29])[CH:18]5[C@:23]4([CH3:24])[CH2:22][CH2:21][CH2:20][CH2:19]5)[C@@H:6]2[CH2:7]3)[CH3:5])[O:2]1.C([C@@H]1C2[C@](C)(CCC(=[O:50])C2)[C@@H]2[C@H]([C@H]3[C@@](CC2)(C)C(=O)CC3)C1)#N>>[OH:29][CH2:28][C@@H:17]1[CH:18]2[C@:23]([CH3:24])([CH2:22][CH2:21][C:20](=[O:50])[CH2:19]2)[C@@H:25]2[C@H:15]([C@H:6]3[C@@:4]([CH2:27][CH2:26]2)([CH3:5])[C:3](=[O:2])[CH2:8][CH2:7]3)[CH2:16]1
Reactant: C[C@]12CCC(=O)CC1[C@@H](C#N)C[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Reactant: C[C@]12CCCCC1[C@@H](CO)C[C@@H]1[C@@H]2CC[C@@]2(C)[C@H]1CC13OCCOC12OCCO3
Product: C[C@]12CCC(=O)CC1[C@@H](CO)C[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Yield: 85 %

Procedure:
The title compound II-an was prepared in 85% yield from 3,3:17,17-bis(ethylendioxy)-6α-hydroxymethylandrostane by the procedure described above for the preparation of 6α-cyanoandrostane-3,17-dione (II-ac, Prepn. 3). The combined organic extracts were washed with H2O, dried over Na2SO4 and evaporated to dryness. 1H-NMR (300 MHz, acetone-d6, ppm from TMS): δ 3.50 (m, 3H), 2.52-0.74 (m, 21H), 1.11 (s, 3H), 0.88 (s, 3H).
Reaction SMILES: [CH:1]([C:4]1([C:10]([OH:12])=O)[CH2:8][CH2:7][C:6](=[O:9])[CH2:5]1)([CH3:3])[CH3:2].S(Cl)([Cl:15])=O>C1C=CC=CC=1>[CH:1]([C:4]1([C:10]([Cl:15])=[O:12])[CH2:8][CH2:7][C:6](=[O:9])[CH2:5]1)([CH3:3])[CH3:2]
Reactant: O=S(Cl)Cl
Reactant: CC(C)C1(C(=O)O)CCC(=O)C1
Solvent: c1ccccc1
Product: CC(C)C1(C(=O)Cl)CCC(=O)C1
Temperature: 45 °C
Reaction time: 3 h
Yield: 30 %

Procedure:
A solution of 1-isopropyl-3-oxocyclopentylcarboxylic acid (20.1 g, 118.9 mmol) in benzene (150 mL) was slowly treated with thionyl chloride (23.5 mL, 322.1 mmol) and the resulting solution was stirred at 45° C. for 3 hours. The solvent and the volatile components were evaporated under reduced pressure (100 torr) and the residue was distilled to obtain 6.727 g (30%) of the desired product, B.P.: 110-114° C. at 5 torr. 1H NMR (500 MHz, CDCl3): 2.82 (dd, J=18.36, 1.76 Hz, 1H), 2.50 (m, 1H), 2.35 (m, 2H), 2.20 to 190 (bm, 3H), 1.03 (bd, J=8.2 Hz, 6H).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]C(=O)N(C)C)=[C:6]([CH2:16][CH2:17][CH3:18])[C:5]=1[OH:19])(=[O:3])[CH3:2].[OH-].[K+].C(O)C.Cl>O>[OH:19][C:5]1[C:6]([CH2:16][CH2:17][CH3:18])=[C:7]([SH:10])[CH:8]=[CH:9][C:4]=1[C:1](=[O:3])[CH3:2]
Reactant: CCCc1c(SC(=O)N(C)C)ccc(C(C)=O)c1O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCCc1c(S)ccc(C(C)=O)c1O
Yield: 94.1 %

Procedure:
Reflux a stirred mixture of dimethyl-thiocarbamic acid S-(4-acetyl-3-hydroxy-2-propyl-phenyl)ester (1.08 g, 3.84 mmol), potassium hydroxide (1.1 g, 19.2 mmol), ethanol (25 mL), and water (10 mL) for 2 hours. Cool the reaction in an ice/water bath and adjust the pH to 2 with aqueous 5N hydrochloric acid. Extract the mixture with ethyl acetate (3×50 mL). Combine the extracts and wash with water (50 mL) and brine (50 mL) and dry over magnesium sulfate, filter, and concentrate to afford the title compound (0.76 g, 94%) as a brown oil which solidifies on standing. LCMS (m/z) 211 m−1.
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[C:11]([CH3:13])[C:10]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][NH:21][C:22]3[CH:32]=[CH:31][C:25]([O:26][CH2:27][C:28]([OH:30])=O)=[CH:24][CH:23]=3)[CH:15]=2)=[C:9]([CH3:33])[CH:8]=1)[CH3:2].Cl.[CH3:35][NH:36][O:37][CH3:38].C(N(CC)CC)C.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>CN(C)C=O.C(OCC)(=O)C>[CH2:1]([O:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[C:9]([CH3:33])[C:10]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][NH:21][C:22]3[CH:23]=[CH:24][C:25]([O:26][CH2:27][C:28]([N:36]([O:37][CH3:38])[CH3:35])=[O:30])=[CH:31][CH:32]=3)[CH:15]=2)=[C:11]([CH3:13])[CH:12]=1)[CH3:2]
Reactant: CNOC
Reactant: CCOCCOc1cc(C)c(-c2cccc(CNc3ccc(OCC(=O)O)cc3)c2)c(C)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOCCOc1cc(C)c(-c2cccc(CNc3ccc(OCC(=O)N(C)OC)cc3)c2)c(C)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 66.3 %

Procedure:
To a solution of [4-({[4′-(2-ethoxyethoxy)-2′,6′-dimethylbiphenyl-3-yl]methyl}amino)phenoxy]acetic acid (0.22 g, 0.49 mmol), N,O-dimethylhydroxylamine hydrochloride (72 mg, 0.74 mmol), triethylamine (0.12 mL, 0.86 mmol) and 1-hydroxybenzotriazole (98 mg, 0.64 mmol) in N,N-dimethylformamide (15 mL) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (122 mg, 0.64 mmol) under ice-cooling, and the mixture was stirred at room temperature for 18 hr. The reaction solution was diluted with ethyl acetate, washed successively with aqueous citric acid solution, water and aqueous sodium chloride solution, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:5-2:1) to give the title compound (160 mg, yield 66%) as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[C:6]([CH2:7][Cl:8])=[CH:5][S:4][C:3]=1[C:9](Cl)=[O:10].[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([NH:19][C:20](=[O:29])[C:21]2[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:22]=2[NH2:28])=[CH:15][CH:14]=1.N1C=CC=CC=1>C(Cl)Cl>[Cl:12][C:13]1[CH:14]=[CH:15][C:16]([NH:19][C:20](=[O:29])[C:21]2[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:22]=2[NH:28][C:9]([C:3]2[S:4][CH:5]=[C:6]([CH2:7][Cl:8])[C:2]=2[Cl:1])=[O:10])=[CH:17][CH:18]=1
Reactant: O=C(Cl)c1scc(CCl)c1Cl
Reactant: Nc1ccc(Cl)cc1C(=O)Nc1ccc(Cl)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(Nc1ccc(Cl)cc1)c1cc(Cl)ccc1NC(=O)c1scc(CCl)c1Cl
Temperature: 25 °C
Reaction time: 17 h
Yield: 79.7 %

Procedure:
To a solution of 3-chloro-4-chloromethyl-2-(chlorocarbonyl)thiophene (3.1 g, 13.5 mmol) in methylene chloride (40 mL) at 0° C. was added N-(4-chlorophenyl)-2-amino-5-chlorobenzamide (3.8 g, 13.5 mmol), followed after 5 minutes by pyridine (1.6 mL, 16 mmol). The mixture was warmed to ambient temperature. After 17 hours, the mixture was concentrated of all volatiles in vacuo. The resulting solid was triturated with water and a small amount of acetonitrile and dried in vacuo to afford 5.1 g (80% yield) of N-(4-chlorophenyl)-2-[((4-(chloromethyl)-3-chlorothiophen-2-yl)carbonyl)amino]-5-chlorobenzamide as a tan powder: NMR (DMSO-d6) 11.1 (s, 1), 10.8 (s, 1), 8.3 (d, 1), 8.2 (s, 1), 7.9 (s, 1), 7.7 (d, 2), 7.6 (dd, 1), 7.4 (d, 2), 4.8 (s, 2) ppm.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[S:6][C:7]=1[CH3:8].[OH:15][C:16]1[CH:23]=[CH:22][C:19]([CH:20]=[O:21])=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH3:8][C:7]1[S:6][C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:4][C:3]=1[CH2:2][O:15][C:16]1[CH:23]=[CH:22][C:19]([CH:20]=[O:21])=[CH:18][CH:17]=1
Reactant: Cc1sc(-c2ccccc2)nc1CCl
Reactant: O=Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1sc(-c2ccccc2)nc1COc1ccc(C=O)cc1
Temperature: 80 °C
Reaction time: 3 h
Yield: 92.9 %

Procedure:
A mixture of 4-chloromethyl-5-methyl-2-phenylthiazole (5.40 g), 4-hydroxybenzaldehyde (2.91 g), anhydrous potassium carbonate (4.95 g) and N,N-dimethylformamide (50 mL) was stirred at 80° C. for 3 hrs. The reaction mixture was poured into water, and the precipitated solid was collected by filtration, and dried with air to give crystals (6.85 g, 93%) of 4-[(5-methyl-2-phenyl-4-thiazolyl)methoxy]benzaldehyde. Recrystallization from ethyl aceetate-hexane gave colorless prism crystals. melting point: 18-119° C.
Reaction SMILES: [Li].[Cl:2][C:3]1[CH:4]=[C:5]([C:9]([O-])=[CH:10][C:11](=O)[C:12]([O:14]CC)=[O:13])[CH:6]=[N:7][CH:8]=1.ClC1C=C(C2N(C3C=CC=CN=3)N=C(C(O)=O)C=2)C=C(F)C=1.Cl.[Cl:42][C:43]1[CH:44]=[C:45]([NH:50][NH2:51])[CH:46]=[CH:47][C:48]=1[F:49]>>[Cl:42][C:43]1[CH:44]=[C:45]([N:50]2[C:9]([C:5]3[CH:6]=[N:7][CH:8]=[C:3]([Cl:2])[CH:4]=3)=[CH:10][C:11]([C:12]([OH:14])=[O:13])=[N:51]2)[CH:46]=[CH:47][C:48]=1[F:49]
Reactant: CCOC(=O)C(=O)C=C([O-])c1cncc(Cl)c1
Reactant: NNc1ccc(F)c(Cl)c1
Agent: Cl
Agent: O=C(O)c1cc(-c2cc(F)cc(Cl)c2)n(-c2ccccn2)n1
Agent: [Li]
Product: O=C(O)c1cc(-c2cncc(Cl)c2)n(-c2ccc(F)c(Cl)c2)n1

Procedure:
1.70 g (4.24 mmol) of the compound of Example 14A is reacted analogously to the synthesis of the compound of Example 20A with 1.25 g (6.36 mmol) of 3-chloro-4-fluorophenylhydrazine hydrochloride. After hydrolysis, 896 mg (60% of theory) of the title compound is obtained.
Reaction SMILES: [P:1]([O:9]CC)([O:6][CH2:7][CH3:8])([O:3][CH2:4][CH3:5])=[S:2].[OH-].[K+:13]>C(O)C>[K+:13].[P:1]([O-:9])([O:6][CH2:7][CH3:8])([O:3][CH2:4][CH3:5])=[S:2]
Reactant: CCOP(=S)(OCC)OCC
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CCOP([O-])(=S)OCC
Yield: 74.1 %

Procedure:
To 86 g (434 mmole) of O,O,O-triethyl thiophosphate in 300 ml of absolute ethanol was added 28 g (440 mmole) of 88% KOH. The resulting mixture was refluxed for 20 hours, filtered while warm, concentrated in vacuo, and triturated with 20% diethyl ether/80% hexanes to yield 67 g of the title compound, a white solid mp 192°-197° C.
Reaction SMILES: [CH:1]1[CH2:12][CH2:11][CH:10]=[CH:9][CH2:8][CH2:7][CH:6]=[CH:5][CH2:4][CH2:3][CH:2]=1.N#[N+][O-:15]>>[C:1]1(=[O:15])[CH2:12][CH2:11][CH2:10][CH:9]=[CH:8][CH2:7][CH2:6][CH:5]=[CH:4][CH2:3][CH2:2]1
Reactant: N#[N+][O-]
Reactant: C1=CCCC=CCCC=CCC1
Product: O=C1CCC=CCCC=CCCC1

Procedure:
The homogenizing plate serves to back up the reaction mixture before entry into the tube bundle, in order, for example, to achieve a defined pressure drop of 100-200 mbar, for example in the reaction of 1,5,9-cyclododecatriene with dinitrogen monoxide to give cyclododeca-4,8-dienone. This example relates to a specific embodiment; in principle, it is possible to provide pressure drops of 0.01 bar to 10 bar, provided that, in principle, the pressure drop is defined essentially by the homogenizing plate and, by virtue of the pressure drop, homogeneous through-flow (with regard to the throughput) over the cross section of the tube bundle (especially at the feed end) results from the operating parameters and the flow properties of the homogenizing plate. The pressure drop is determined to a crucial degree by the operating parameter range (pressure, temperature, flow rate), which in turn depends significantly on the conversion reaction to be performed. The invention shall not be restricted to the reaction of 1,5,9-cyclododecatriene with dinitrogen monoxide; instead, the invention is suitable for performing a multitude of various conversions and reactions. Preferably, each of the holes of the homogenizing plate is arranged opposite exactly one inlet of a corresponding tube of the tube bundle. Instead of or in combination with the homogenizing plate, homogenization, which is provided by controlled backup of the reaction mixture in the feed hood before entry into the tube bundle, can also be accomplished by providing internals at the feed end of the tube bundle, or else restrictors which narrow the tube inlet in a controlled manner. Such restrictor elements can be secured, for example, by means of screw connections on or in the particular tube inlet; the restrictors provided here may, for example, be screw heads. In this case, each screw head partly covers exactly one tube inlet of a tube. The screw head can be provided with holes, for example when the screw head completely covers the tube inlet. In addition, differences in the form of the screw head or of the restrictor compared to the form of the internal cross section of the tube can reduce the tube inlet at the feed end in a defined manner.
Reaction SMILES: FC1C=C(CC(N[C@H](C(O)=O)C(C)C)=O)C=C(F)C=1.[F:20][C:21]1[CH:22]=[C:23]([CH2:28][C:29]([NH:31][C@H:32]([C:37]([O:39]C)=[O:38])[CH2:33][CH:34]([CH3:36])[CH3:35])=[O:30])[CH:24]=[C:25]([F:27])[CH:26]=1>>[F:20][C:21]1[CH:22]=[C:23]([CH2:28][C:29]([NH:31][C@H:32]([C:37]([OH:39])=[O:38])[CH2:33][CH:34]([CH3:36])[CH3:35])=[O:30])[CH:24]=[C:25]([F:27])[CH:26]=1
Reactant: COC(=O)[C@H](CC(C)C)NC(=O)Cc1cc(F)cc(F)c1
Agent: CC(C)[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)O
Product: CC(C)C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)O
Yield: 80.9 %

Procedure:
A method similar to that used for the preparation of (107b) was used except that methyl N-[(3,5-difluorophenyl)acetyl]-L-leucinate (108a) (280 mg) was used instead of methyl N-[(3,5-difluorophenyl)acetyl]-L-valinate to afford the desired product (216 mg ). 1H NMR (300 MHz, CDCl3) δ 0.83 (d, 3, J=6 Hz), 0.89 (d, 3H, J=6 Hz), 1.51(m, 3H),3.52 (s, 2H), 4.22 (m, 1H), 7.07 (m, 3H), 8.41 (d, 1H, J=8 Hz), 12.54 (s, 1H).
Reaction SMILES: [N:1]([C@H:4]1[CH2:10][CH2:9][C@@H:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:7][NH:6][C:5]1=[O:17])=[N+:2]=[N-:3].Br[CH2:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21].[H-].[Na+]>>[N:1]([C@H:4]1[CH2:10][CH2:9][C@@H:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:7][N:6]([CH2:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C:5]1=[O:17])=[N+:2]=[N-:3]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: [N-]=[N+]=N[C@H]1CC[C@@H](c2ccccc2)CNC1=O
Agent: [H-]
Agent: [Na+]
Product: CC(C)(C)OC(=O)CN1C[C@H](c2ccccc2)CC[C@H](N=[N+]=[N-])C1=O

Procedure:
Using a similar procedure to that described in Example 1(h), 1.21 g of 3(S*)-azido-6(S*)-phenylperhydroazepin-2-one (Isomer B) [prepared as described in Example 1(g)], 1 ml of t-butyl bromoacetate and 252 mg of sodium hydride (as a 55% w/w dispersion in mineral oil) afforded 1.9 g of the title compound as a syrup.