Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH:2]([C:11]1[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[CH:13][C:12]=1[O:19][CH3:20])[CH2:3][CH:4]([CH3:10])[C:5]([O:7]CC)=O.[C:21]1([C:27]2[CH:28]=[C:29]([CH:32]=[CH:33][N:34]=2)[CH:30]=O)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[CH3:18][O:17][C:16]1[CH:15]=[CH:14][CH:13]=[C:12]([O:19][CH3:20])[C:11]=1[CH:2]1[N:1]([CH2:30][C:29]2[CH:32]=[CH:33][N:34]=[C:27]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH:28]=2)[C:5](=[O:7])[CH:4]([CH3:10])[CH2:3]1
Reactant: CCOC(=O)C(C)CC(N)c1c(OC)cccc1OC
Reactant: O=Cc1ccnc(-c2ccccc2)c1
Product: COc1cccc(OC)c1C1CC(C)C(=O)N1Cc1ccnc(-c2ccccc2)c1

Procedure:
Prepared according to the described general procedure 2 (GP2) by reaction of ethyl 4-amino-4-(2,6-dimethoxyphenyl)-2-methylbutanoate with 2-phenylisonicotinaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.65 min.; [M+H]+: 402.99 g/mol.
Reaction SMILES: [C:1]([O-:4])(=[O:3])[CH3:2].[K+].[I-].[K+].C(O)(=O)C.Br[CH2:13][C:14](=[O:36])[C@@H:15]1[C@:32]2([CH3:33])[C@H:18]([C@H:19]3[C@H:29]([C:30](=[O:34])[CH2:31]2)[C@:27]2([CH3:28])[C@H:22]([CH2:23][C@@H:24]([OH:35])[CH2:25][CH2:26]2)[CH2:21][CH2:20]3)[CH2:17][CH2:16]1>CC(C)=O.O>[C:1]([O:4][CH2:13][C:14](=[O:36])[C@@H:15]1[C@:32]2([CH3:33])[C@H:18]([C@H:19]3[C@H:29]([C:30](=[O:34])[CH2:31]2)[C@:27]2([CH3:28])[C@H:22]([CH2:23][C@@H:24]([OH:35])[CH2:25][CH2:26]2)[CH2:21][CH2:20]3)[CH2:17][CH2:16]1)(=[O:3])[CH3:2]
Reactant: CC(=O)[O-]
Reactant: C[C@]12CC[C@H](O)C[C@@H]1CC[C@H]1[C@@H]3CC[C@H](C(=O)CBr)[C@@]3(C)CC(=O)[C@@H]12
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)O
Solvent: CC(C)=O
Product: CC(=O)OCC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@@H](O)CC[C@]4(C)[C@H]3C(=O)C[C@]12C
Yield: 22.8 %

Procedure:
Acetyl chloride (9.71 ml) was added to a stirred solution of (3β,5α)-3-hydroxypregnane-11,20-dione (97.1 g) [prepared as described by Cameron et al., J. Chem. Soc., 1955, 2807] in methanol (2.4 l) and a solution of bromine (18.5 ml) in methanol (1 l) was then added over 30 min at room temperature. The reaction mixture was poured into water (30 l) and the precipitated solid was filtered off, washed with water and dissolved in dichloromethane. After drying the solution over sodium sulfate, the solvent was removed under reduced pressure to give crude (3β,5α)-21-bromo-3-hydroxypregnane-11,20-dione (120 g). δ (CDCl3) 0.61 (s,3H), 1.02 (s,3H), 3.00-3.20 (m,1H), 3.49-3.62 (m,2H) and 3.85 (s,2H). Potassium acetate (240 g), potassium iodide (6 g) and glacial acetic acid (250 ml) were added to a solution of (3β,5α)-21-bromo-3-hydroxypregnane-11,20-dione (120 g) in acetone (4.8 l) and the mixture was heated under reflux for 3 h. The reaction mixture was poured into water (50 l) and the precipitated solid was filtered off, washed with water and dissolved in dichloromethane. After drying the solution over sodium sulfate, the solvent was removed under reduced pressure. The residue was chromatographed over silica gel and the purified product was crystallised from diethyl ether to give (3β,5α)-21-(acetyloxy)-3-hydroxypregnane-11,20-dione (26 g) m.p. 163°-165° C.; [α]D +103.3° (c 0.97). 4-Toluenesulfonyl chloride (52 g) was added to a solution of (3β,5α)-21-(acetyloxy)-3-hydroxypregnane-11,20-dione (26 g) in pyridine (260 ml) and the solution was stirred for 4 h at room temperature. The reaction mixture was poured into water (2.6 l) and the precipitated solid was filtered off, washed with water and dissolved in dichloromethane. After drying the solution over sodium sulfate, the solvent was removed under reduced pressure. Crystallisation of the residue from methanol gave (3β,5α)-21-(acetyloxy)-3-{[(4-methylphenyl)sulfonyl]oxy}pregnane-11,20-dione (35 g). m.p. 155°-156° C.; [α]D +62.4° (c 1.11).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:29])[NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][N:13]2[C:18](=[O:19])[CH:17]=[CH:16][C:15]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([N+:26]([O-])=O)[CH:21]=3)=[N:14]2)[CH:7]=1)[CH3:2]>C1COCC1.[Ni]>[CH2:1]([O:3][C:4](=[O:29])[NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][N:13]2[C:18](=[O:19])[CH:17]=[CH:16][C:15]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([NH2:26])[CH:21]=3)=[N:14]2)[CH:7]=1)[CH3:2]
Reactant: CCOC(=O)Nc1cccc(Cn2nc(-c3cccc([N+](=O)[O-])c3)ccc2=O)c1
Agent: [Ni]
Solvent: C1CCOC1
Product: CCOC(=O)Nc1cccc(Cn2nc(-c3cccc(N)c3)ccc2=O)c1
Reaction time: 6 h

Procedure:
1 g (2.5 mmol) of ethyl{3-[3-(3-nitrophenyl)-6-oxo-6H-pyridazin-1-yl-methyl]phenyl}carbamate are dissolved in 10 ml of THF, 1 g of Raney nickel is added, and the mixture is hydrogenated at room temperature for 6 h under a hydrogen atmosphere. The reaction mixture is filtered, the filter residue is rinsed with THF, and the filtrate is evaporated to dryness.
Reaction SMILES: [CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([CH:10]3[C:14]4[NH:15][C:16]5[CH:17]=[CH:18][CH:19]=[CH:20][C:21]=5[C:22](=[O:23])[C:13]=4[CH2:12][N:11]3[C:24]([C:26]3[O:27][C:28]([C:31]4[CH:36]=[CH:35][C:34]([N+:37]([O-])=O)=[CH:33][CH:32]=4)=[CH:29][CH:30]=3)=[O:25])=[CH:4][C:3]=2[O:2]1>[Pd]>[CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([CH:10]3[C:14]4[NH:15][C:16]5[CH:17]=[CH:18][CH:19]=[CH:20][C:21]=5[C:22](=[O:23])[C:13]=4[CH2:12][N:11]3[C:24]([C:26]3[O:27][C:28]([C:31]4[CH:32]=[CH:33][C:34]([NH2:37])=[CH:35][CH:36]=4)=[CH:29][CH:30]=3)=[O:25])=[CH:4][C:3]=2[O:2]1
Reactant: O=C(c1ccc(-c2ccc([N+](=O)[O-])cc2)o1)N1Cc2c([nH]c3ccccc3c2=O)C1c1ccc2c(c1)OCO2
Agent: [Pd]
Product: Nc1ccc(-c2ccc(C(=O)N3Cc4c([nH]c5ccccc5c4=O)C3c3ccc4c(c3)OCO4)o2)cc1

Procedure:
1,2,3,4-Tetrahydro-3-(3,4-methylenedioxyphenyl)-2-[(5-(4-nitrophenyl))-furoyl]-9H-pyrrolo[3,4-b]quinolin-9-one (25 mg, 0.0479 mmol) (prepared as in Example 33) was stirred with 10% Pd on Carbon (5.1 mg, 0.00479 mmol) under 1 atm H2 at room temperature for 14 h. The solvent was evaporated and product isolated by preparative TLC as a yellow powder.
Reaction SMILES: IC1C=CC(C2NC([C@@H](N3C(=O)[C@@H](CCC(O)=O)NC3=O)C(C)C)=NC=2)=CC=1.C1(C[C@H]2NC(=O)N([C@H](C3NC(C4C=CC(I)=CC=4F)=C(C)N=3)[C@H](C3C=CC=CC=3)C)C2=O)CC1.N[C@H](C1C=CC(OC[C@@H](O)CO)=CC=1)C(N[C@H](C1NC(C2C=CC(I)=CC=2F)=C(Cl)N=1)[C@H](C1C=CC=CC=1)C)=O.[C:103]([O:107][C:108]([NH:110][C@H:111]([C:115]1[CH:120]=[CH:119][C:118]([O:121][CH2:122][C@H:123]2[CH2:127][O:126][C:125]([CH3:129])([CH3:128])[O:124]2)=[CH:117][CH:116]=1)[C:112]([OH:114])=[O:113])=[O:109])([CH3:106])([CH3:105])[CH3:104].CC1(C)O[C@H](CO)CO1>>[C:103]([O:107][C:108]([NH:110][C@H:111]([C:115]1[CH:120]=[CH:119][C:118]([O:121][CH2:122][C@@H:123]2[CH2:127][O:126][C:125]([CH3:129])([CH3:128])[O:124]2)=[CH:117][CH:116]=1)[C:112]([OH:114])=[O:113])=[O:109])([CH3:106])([CH3:104])[CH3:105]
Reactant: CC(C)(C)OC(=O)N[C@@H](C(=O)O)c1ccc(OC[C@H]2COC(C)(C)O2)cc1
Agent: CC(C)[C@@H](c1ncc(-c2ccc(I)cc2)[nH]1)N1C(=O)N[C@H](CCC(=O)O)C1=O
Agent: CC1(C)OC[C@@H](CO)O1
Agent: C[C@@H](c1ccccc1)[C@H](NC(=O)[C@H](N)c1ccc(OC[C@@H](O)CO)cc1)c1nc(Cl)c(-c2ccc(I)cc2F)[nH]1
Product: CC(C)(C)OC(=O)N[C@@H](C(=O)O)c1ccc(OC[C@@H]2COC(C)(C)O2)cc1

Procedure:
Prepared by the same method as described in example 1 except that (i) (R)-tert-butoxycarbonylamino-[4-((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-phenyl]-acetic acid was used in place of (R)-tert-butoxycarbonylamino-[4-(2-tert-butoxy-ethoxy)-phenyl]-acetic acid in step 74-G and (ii) cyclization of (R)-2-amino-N-{(1S,2S)-1-[4-chloro-5-(2-fluoro-4-iodo-phenyl)-1H-imidazol-2-yl]-2-phenyl-propyl}-2-[4-((S)-2,3-dihydroxy-propoxy)-phenyl]-acetamide in step 74-H was performed as described in step 34-H. (R)-tert-Butoxycarbonylamino-[4-((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-phenyl]-acetic acid was prepared as described in steps 33-T and 33-U except that in step 70-T (R)-2,2-dimethyl-1,3-dioxolane-4-methanol was used in place of (S)-2,2-dimethyl-1,3-dioxolane-4-methanol. HR-MS: calcd for C30H27ClFlN4O5 [M+H+] 705.0772. Found 705.0771.
Reaction SMILES: [F:1][C:2]1([F:29])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[NH:11][C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([O:19][CH:20]2[CH2:25][CH2:24][N:23]([CH:26]([CH3:28])[CH3:27])[CH2:22][CH2:21]2)=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1.[CH3:30][C:31]1[CH:36]=[CH:35][C:34](B(O)O)=[CH:33][CH:32]=1>>[F:29][C:2]1([F:1])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[N:11]([C:34]3[CH:35]=[CH:36][C:31]([CH3:30])=[CH:32][CH:33]=3)[C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([O:19][CH:20]2[CH2:25][CH2:24][N:23]([CH:26]([CH3:27])[CH3:28])[CH2:22][CH2:21]2)=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1
Reactant: Cc1ccc(B(O)O)cc1
Reactant: CC(C)N1CCC(Oc2ccc3[nH]c(C(=O)N4CCC(F)(F)CC4)cc3c2)CC1
Product: Cc1ccc(-n2c(C(=O)N3CCC(F)(F)CC3)cc3cc(OC4CCN(C(C)C)CC4)ccc32)cc1

Procedure:
In analogy to the procedure described for the synthesis of example 6, the title compound was synthesized from (4,4-difluoro-piperidin-1-yl)-[5-(1-isopropyl-piperidin-4-yloxy)-1H-indol-2-yl]-methanone (intermediate 1) and 4-methylphenylboronic acid. The title compound was obtained in 59% yield as light yellow foam. MS (m/e): 496.1 (MH+, 100%).
Reaction SMILES: O[C:2]1([C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)[CH2:7][CH:6]2[CH2:8][CH2:9][CH:3]1[CH2:4][C:5]2=[O:10].CCN(CC)CC.S(Cl)(C)(=O)=O>C(Cl)Cl.CN(C1C=CN=CC=1)C>[N:13]1[CH:14]=[CH:15][CH:16]=[C:11]([C:2]2[CH:3]3[CH2:9][CH2:8][CH:6]([CH:7]=2)[C:5](=[O:10])[CH2:4]3)[CH:12]=1
Reactant: O=C1CC2CCC1CC2(O)c1cccnc1
Agent: CN(C)c1ccncc1
Agent: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C1CC2CCC1C=C2c1cccnc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 58.9 %

Procedure:
To a solution of 0.5 g of crude 5-hydroxy-5-pyridin-3-yl-bicyclo[2.2.2]octan-2-one (intermediate K3A.2) in 20 mL DCM were added 84 mg DMAP and 1.6 mL NEt3. The mixture was cooled to 0° C. before 0.53 mL of mesylchloride was added dropwise. The resulting suspension was stirred at 0° C. for 1 h and then overnight at rt. The reaction was quenched by the addition of sat. aq. NaHCO3 solution. The water phase was extracted with EtOAc. The combined organic phases were washed with brine, dried over MgSO4 and concentrated in vacuo. Purification by CC (EtOAc) yielded 0.27 g of rac-(1R*,4R*)-5-pyridin-3-yl-bicyclo[2.2.2]oct-5-en-2-one as yellow oil.
Reaction SMILES: [C:1]1([CH2:9][CH:10](C(O)=O)[C:11]([OH:13])=[O:12])[C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[CH:2]=1.O>CN(C)C(=O)C>[C:1]1([CH2:9][CH2:10][C:11]([OH:13])=[O:12])[C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[CH:2]=1
Reactant: O=C(O)C(CC1=Cc2ccccc21)C(=O)O
Solvent: O
Solvent: CC(=O)N(C)C
Product: O=C(O)CCC1=Cc2ccccc21
Temperature: 125 °C

Procedure:
0.027 mole of the diacid obtained in stage B is mixed in 20 ml of N,N-dimethylacetamide and the mixture is heated to 125° C. for 5 hours. It is taken up with water and extracted with ethyl ether. The ether phase is washed repeatedly several times with water and concentrated.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1([C:16]2[S:17][CH:18]=[CH:19][N:20]=2)[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5]1.Br[CH2:22][C:23]([OH:25])=[O:24]>CN(C)C=O>[C:12]([O:11][C:9]([N:6]1[CH2:7][CH2:8][C:4]([C:16]2[S:17][CH:18]=[CH:19][N:20]=2)([O:3][CH2:22][C:23]([OH:25])=[O:24])[CH2:5]1)=[O:10])([CH3:15])([CH3:14])[CH3:13]
Reactant: O=C(O)CBr
Reactant: CC(C)(C)OC(=O)N1CCC(O)(c2nccs2)C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(OCC(=O)O)(c2nccs2)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To an ambient suspension of NaH (5.40 g, 135 mmol) in N,N-dimethylformamide (50 mL) was added dropwise a solution of tert-butyl 3-hydroxy-3-(thiazol-2-yl)pyrrolidine-1-carboxylate (7.30 g, 27 mmol) in N,N-dimethylformamide (20 mL). After 30 minutes, bromoacetic acid (7.50 g, 54.0 mmol) in N,N-dimethylformamide (20 mL) was added dropwise. The solution was stirred at room temperature for 16 hours and then heated to 50° C. for 3 hours. The reaction was cooled to room temperature and was quenched by the addition of water. The solution was basicified to pH 10 by the addition of 2.5 M NaOH solution. The aqueous layer was extracted with ether, and the organics discarded. The aqueous layer was acidified to pH 1 with 6 M HCl solution, and then extracted with ethyl acetate (2×). The combined organics were washed with water, brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure to give the product. MS ESI(+) m/z 329.3 [M+H]+.
Reaction SMILES: [CH3:1]C1C=CC(C2C=NN(C)C=2)=C(C=1)C(OC)=O.Br[C:19]1[CH:20]=[C:21]2[C:26](=[CH:27][CH:28]=1)[N:25]=[C:24]([NH:29][CH2:30][C@@H:31]1[C@H:36]([CH3:37])[CH2:35][CH2:34][CH2:33][N:32]1[C:38]([C:40]1[CH:45]=[C:44]([CH3:46])[CH:43]=[CH:42][C:41]=1[N:47]1[N:51]=[CH:50][CH:49]=[N:48]1)=[O:39])[N:23]=[CH:22]2.CB1OB(C)OB(C)O1>>[CH3:37][C@@H:36]1[CH2:35][CH2:34][CH2:33][N:32]([C:38]([C:40]2[CH:45]=[C:44]([CH3:46])[CH:43]=[CH:42][C:41]=2[N:47]2[N:51]=[CH:50][CH:49]=[N:48]2)=[O:39])[C@@H:31]1[CH2:30][NH:29][C:24]1[N:23]=[CH:22][C:21]2[C:26](=[CH:27][CH:28]=[C:19]([CH3:1])[CH:20]=2)[N:25]=1
Reactant: Cc1ccc(-n2nccn2)c(C(=O)N2CCC[C@@H](C)[C@H]2CNc2ncc3cc(Br)ccc3n2)c1
Reactant: COC(=O)c1cc(C)ccc1-c1cnn(C)c1
Agent: CB1OB(C)OB(C)O1
Product: Cc1ccc(-n2nccn2)c(C(=O)N2CCC[C@@H](C)[C@H]2CNc2ncc3cc(C)ccc3n2)c1

Procedure:
The title compound was prepared following the same general protocol as described for methyl 5-methyl-2-(1-methyl-1H-pyrazol-4-yl)benzoate in Example A1, using ((2S,3R)-2-(((6-bromoquinazolin-2-yl)amino)methyl)-3-methylpiperidin-1-yl)(5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl)methanone (synthesized in Example A122) and 2,4,6-trimethyl-1,3,5,2,4,6-trioxatriborinane. ESI-MS (m/z): 456 [M+1]+.
Reaction SMILES: Cl.O[CH:3]1[O:11][C@H:10]([CH2:12][OH:13])[C@@H:8]([OH:9])[C@H:6]([OH:7])[C@H:4]1[NH2:5].[S-:14][C:15]#[N:16].[NH4+]>O>[SH:14][C:15]1[NH:16][CH:3]=[C:4]([C@@H:6]([OH:7])[C@H:8]([OH:9])[C@H:10]([OH:11])[CH2:12][OH:13])[N:5]=1
Reactant: N[C@H]1C(O)O[C@H](CO)[C@@H](O)[C@@H]1O
Reactant: N#C[S-]
Agent: Cl
Agent: [NH4+]
Solvent: O
Product: OC[C@@H](O)[C@@H](O)[C@H](O)c1c[nH]c(S)n1
Temperature: 84.5 °C
Reaction time: 8 h
Yield: 49.6 %

Procedure:
To glucosamine hydrochloride (200 g, 0.928 mol) were added water (300 mL) and ammonium thiocyanate (212 g, 2.78 mol, 3.0 equivalents) at 25° C., and the mixture was stirred at 80 to 89° C. for 8 hr. The reaction mixture was allowed to cool to 60° C., water (300 mL) and seed crystals were added thereto, and the mixture was stirred at 25 to 40° C. for 15 hr. The crystals were collected by filtration, washed twice with water (100 mL), and vacuum-dried (50° C.) to a constant amount to give (1R,2S,3R)-1-(2-sulfanyl-1H-imidazol-4-yl)butane-1,2,3,4-tetraol (101.4 g). yield 50%.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[N:11]1[C:15]([OH:16])=[C:14]([C:17](=O)[CH3:18])[C:13]([CH3:20])=[N:12]1.[CH3:21][O:22][C:23]([C:25]1[CH:34]=[CH:33][C:28]([C:29]([NH:31][NH2:32])=[O:30])=[CH:27][CH:26]=1)=[O:24].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(O)(C)C>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[N:11]1[C:15](=[O:16])[C:14](=[C:17]([NH:32][NH:31][C:29](=[O:30])[C:28]2[CH:27]=[CH:26][C:25]([C:23]([O:22][CH3:21])=[O:24])=[CH:34][CH:33]=2)[CH3:18])[C:13]([CH3:20])=[N:12]1
Reactant: COC(=O)c1ccc(C(=O)NN)cc1
Reactant: CC(=O)c1c(C)nn(-c2ccc3ccccc3n2)c1O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CC(C)O
Product: COC(=O)c1ccc(C(=O)NNC(C)=C2C(=O)N(c3ccc4ccccc4n3)N=C2C)cc1
Yield: 30.5 %

Procedure:
2.0 mL of an isopropyl alcohol solution of 28.7 mg (0.11 mmol) of 1-(1-(quinolin-2-yl)-5-hydroxy-3-methyl-1H-pyrazol-4-yl)-ethanone, 20.8 mg (0.11 mmol) of 4-methoxycarbonylbenzhydrazide and 6.1 mg (0.03 mmol) of p-toluenesulfonic acid monohydrate was refluxed with heating for 48 hours. After cooling, the precipitate was collected by filtration and washed with methanol and acetonitrile to obtain 14.9 mg of the desired product as a purple solid (yield 31%).
Reaction SMILES: C([NH:5][S:6]([C:9]1[CH:14]=[C:13]([CH2:15][NH:16][C:17](=[O:19])[CH3:18])[CH:12]=[CH:11][C:10]=1[C:20]([O:22][CH3:23])=[O:21])(=[O:8])=[O:7])(C)(C)C>FC(F)(F)C(O)=O>[C:17]([NH:16][CH2:15][C:13]1[CH:12]=[CH:11][C:10]([C:20]([O:22][CH3:23])=[O:21])=[C:9]([S:6]([NH2:5])(=[O:7])=[O:8])[CH:14]=1)(=[O:19])[CH3:18]
Reactant: COC(=O)c1ccc(CNC(C)=O)cc1S(=O)(=O)NC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1ccc(CNC(C)=O)cc1S(N)(=O)=O
Yield: 76.2 %

Procedure:
A solution of 2.09 g (6.1 mmol) of N-tert-butyl-5-acetamidomethyl-2-methoxycarbonylbenzenesulfonamide in 25 ml of trifluoroacetic acid is stirred at room temperature for 14 h and then evaporated to dryness. Crystallization of the residue from ethyl acetate yields 1.33 g (76%) of 5-acetamidomethyl-2-methoxycarbonylbenzenesulfonamide of mp. 173°-175° C.
Reaction SMILES: [O:1]=[C:2]1[NH:8][C:7]2[CH:9]=[C:10]([CH3:13])[CH:11]=[CH:12][C:6]=2[NH:5][CH2:4][CH:3]1[NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16].[O:22]1[CH:26]=[CH:25][CH:24]=[C:23]1[C:27](Cl)=[O:28].N1C=CC=CC=1.O>ClCCCl>[O:1]=[C:2]1[NH:8][C:7]2[CH:9]=[C:10]([CH3:13])[CH:11]=[CH:12][C:6]=2[N:5]([C:27]([C:23]2[O:22][CH:26]=[CH:25][CH:24]=2)=[O:28])[CH2:4][CH:3]1[NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16]
Reactant: O=C(Cl)c1ccco1
Reactant: Cc1ccc2c(c1)NC(=O)C(NC(=O)OC(C)(C)C)CN2
Solvent: ClCCCl
Solvent: c1ccncc1
Solvent: O
Product: Cc1ccc2c(c1)NC(=O)C(NC(=O)OC(C)(C)C)CN2C(=O)c1ccco1
Yield: 81.3 %

Procedure:
2-Oxo-3-tert-butoxycarbonylamino-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine (2.00 g) obtained from Referential Example 7 was suspended in 1,2-dichloroethane (40 ml), 2-furancarbonyl chloride (1.05 g) and pyridine (626 mg) were added thereto, the mixture was refluxed for 2 hours. Water (100 ml) was added to the reaction mixture, extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium bicarbonate, dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and diisopropyl ether was added to the residue for trituration, collected by filtration, to thereby obtain 2.15 g of the titled compound (Yield: 77,4%).
Reaction SMILES: C[C:2]1([CH3:10])[CH2:7][CH2:6][CH2:5][C:4]([CH3:9])(C)N1.C(=O)=O.[Li]CCCC.[Cl:19][C:20]1[C:21]([Cl:29])=[N:22][CH:23]=[C:24]([CH:28]=1)[C:25]([OH:27])=[O:26].C(=O)C1C=CC=CC=1>C1COCC1>[Cl:29][C:21]1[N:22]=[CH:23][C:24]2[C:25](=[O:27])[O:26][CH:9]([C:4]3[CH:5]=[CH:6][CH:7]=[CH:2][CH:10]=3)[C:28]=2[C:20]=1[Cl:19]
Reactant: CC1(C)CCCC(C)(C)N1
Reactant: O=C(O)c1cnc(Cl)c(Cl)c1
Agent: O=C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O=Cc1ccccc1
Product: O=C1OC(c2ccccc2)c2c1cnc(Cl)c2Cl
Temperature: -50 °C
Reaction time: 0.5 h
Yield: 88.8 %

Procedure:
A solution of 2,2,6,6-tetramethyl-piperidine (7.5 ml, 44 mmol) in a 250 ml round bottomed flask equipped with a magnetic stirrer, is put under argon atmosphere and 30 ml of dry THF is added. The reaction mixture is cooled to −50° C. by adding a controlled amount of dry ice to an acetone bath. The cooled reaction mixture is treated dropwise with nBuLi solution (16.3 mL of a 2.5 M solution in hexanes, 40 mmol) and the reaction is let stir at that −50° C. for 0.5 h. A solution of 5,6-dichloro-nicotinic acid, (3.7 g, 18.5 mmol) in THF (15 mL) is added dropwise to the reaction at −50° C. The reaction is stirred at −50° C. for 0.5 h. The reaction mixture is treated with benzaldehyde (2.5 ml, 24 mmol) dropwise at −50° C. The reaction is stirred at −50° C. for 2 h and warmed to room temperature overnight. The reaction mixture is concentrated to remove solvent and water and ether are added. The aqueous layer is extracted with ether (6×50 ml). The aqueous phase is treated with 1N HCl, until the pH of aqueous layer is ˜6 and is then extracted with ether (3×40 mL.) The aqueous solution is treated with 1N HCl solution until the pH ˜2 and solution is heated at 100° C. overnight. On cooling a white precipitate appeared. The precipitate is filtered off and washed with bicarbonate and air-dried to give the title compound (4.6 g, 89%) as a white solid.
Reaction SMILES: [N+:1]([C:4]1[CH:22]=[CH:21][C:7]([C:8](=[O:20])[CH2:9][CH:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:12](=O)[O:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].S(Cl)([Cl:25])=O.Cl>C1C=CC=CC=1>[N+:1]([C:4]1[CH:22]=[CH:21][C:7]([C:8]([CH:9]=[CH:10][C:19]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:12]([Cl:25])=[O:11])=[O:20])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=C(CC1OC(=O)c2ccccc21)c1ccc([N+](=O)[O-])cc1
Reactant: O=S(Cl)Cl
Agent: Cl
Solvent: c1ccccc1
Product: O=C(C=Cc1ccccc1C(=O)Cl)c1ccc([N+](=O)[O-])cc1
Reaction time: 1 h

Procedure:
A 500 ml flask fitted with a reflux condenser was charged with 29.7 grams (0.1 mol) of 3-(4-nitrophenacyl)phthalide, 0.12 mol of freshly distilled thionyl chloride and 100 ml of benzene. The mixture was heated to reflux temperature on a steambath, and a clear solution formed on initiation of refluxing, with evolution of HCl. The evolution ceased after 1 hour, after which benzene and excess unreacted thionyl chloride were distilled off under reduced pressure. The residual solid in the flask was triturated with ligroin, filtered and dried to yield o-(4'-nitrobenzoylvinyl)benzoyl chloride, m.p. 133°-134° C. Analysis shows 59.4% carbon, 3.36% hydrogen, 4.56% nitrogen and 11.72% chlorine as against calculated values of 60.87%, 3.19%, 4.44% and 11.23% for C16H10ClNO4.
Reaction SMILES: BrBr.Cl[CH2:4][CH2:5][CH2:6][C:7](=[O:9])[CH3:8].[C:10]1([SH:16])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[OH-].[K+]>C(Cl)Cl.CO>[C:10]1([S:16][C:6]2([C:7]([CH3:8])=[O:9])[CH2:4][CH2:5]2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: Sc1ccccc1
Reactant: CC(=O)CCCCl
Agent: BrBr
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: ClCCl
Product: CC(=O)C1(Sc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 48.1 %

Procedure:
A solution of 134 g (0.83 mol) of bromine in 130 ml of methylene chloride is added dropwise with stirring at 10° C. to a solution of 100 g (0.83 mol) of 5-chloropentan-2-one in 400 ml of methylene chloride. The reaction mixture is stirred for 1 hour at room temperature, then washed with water and dilute, aqueous sodium carbonate solution and dried over sodium sulphate. The mixture is concentrated by removing the solvent under reduced pressure, and the residue is taken up in 200 ml of methanol and 91.5 g (0.83 mol) of thiophenol are added at 5° C. with stirring. A mixture of 93 g of potassium hydroxide powder in 500 ml of methanol is then added dropwise. The reaction mixture is first stirred at room temperature for 2 hours and then at 40° C. for 4 hours. The mixture is subsequently concentrated by removing the solvent under reduced pressure and the residue which remains is taken up in methylene chloride. The organic solution is washed successively with water, dilute aqueous sodium carbonate solution and again with water, then concentrated under reduced pressure and then subjected to a vacuum distillation. In this manner, 76.8 g (48% of theory) of methyl 1-phenylmercaptocyclopropyl ketone of boiling point 155° C./20 mbar are obtained.
Reaction SMILES: [CH3:1][O:2][N:3]([CH3:8])[C:4](=[O:7])[CH:5]=[CH2:6].[C:9]([NH2:13])([CH3:12])([CH3:11])[CH3:10]>>[C:9]([NH:13][CH2:6][CH2:5][C:4]([N:3]([O:2][CH3:1])[CH3:8])=[O:7])([CH3:12])([CH3:11])[CH3:10]
Reactant: C=CC(=O)N(C)OC
Reactant: CC(C)(C)N
Product: CON(C)C(=O)CCNC(C)(C)C
Temperature: 25 °C
Reaction time: 48 h
Yield: 69.8 %

Procedure:
N-Methoxy-N-methyl-acrylamide (5 g, 43.4 mmol, 1.0 equiv) was dissolved in t-butylamine (3.36 g, 46 mmol, 1.06 equiv). The resulting solution was stirred at room temperature for 48 h. The excess primary amine was removed in vacuo and the crude product was purified by flash chromatography on silica using 100% CH2Cl2 to 2% MeOH in CH2Cl2 to give the desired product as a light yellow oil (5.7 g, 70%); MS, m/z 189=M+1.