Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([CH2:8][C:9]([C:11]2[CH:16]=[CH:15][C:14]([NH:17][S:18]([CH3:21])(=[O:20])=[O:19])=[CH:13][CH:12]=2)=[O:10])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[BH4-].[Na+]>CCO>[N:1]1([CH2:8][CH:9]([C:11]2[CH:12]=[CH:13][C:14]([NH:17][S:18]([CH3:21])(=[O:20])=[O:19])=[CH:15][CH:16]=2)[OH:10])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CS(=O)(=O)Nc1ccc(C(=O)CN2CCCCCC2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CS(=O)(=O)Nc1ccc(C(O)CN2CCCCCC2)cc1
Reaction time: 2.5 h

Procedure:
To a nitrogen covered mixture of 1.39 g (4.01 mmol) of the ketone, N-[4-[2-(Hexahydro-1H-azepin-1-yl)-1-oxoethyl]phenyl]methanesulfonamide from Preparation 7 in 25 ml of absolute EtOH, cooled in a cold bath is added 0.332 g (8.78 mmol) of sodium borohydride in portions over 10 min. Stirring is continued in the cold for 15 min and at ambient temperature for 2.5 hrs and an additional 0.193 g (5.10 mmol) of sodium borohydride is added. After stirring for an additional 1.5 hrs at ambient temperature, there is added an additional 0.202 g (5.34 mmol) of sodium borohydride. At the end of a total of 6 hrs, a suspended solid is collected on a filter, washed with EtOH and the combined filtrates are concentrated in vacuo. A solution of the residue in 25 ml of H2O is cooled in an ice bath, acidified to pH 3 with 2.5N HCl, washed twice with EtOAc, and then made basic with solid NaHCO3. The mixture is then saturated with NaCl and extracted four times with CH2Cl2. The combined extracts are washed with dilute brine, dried over MgSO4 and concentrated in vacuo. The residue is chromatographed on a 150 ml silica gel column (elution with 5% MeOH:CH2Cl2 containing 0.5% NH4OH) and 4.8 ml fractions are collected. Fractions at approximately 138-290 are combined and recrystallized from EtOAc to yield the title compound in two crops. M.p. 123°-124° C. and m.p. 120°-122.5° C.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([CH3:12])(=[O:11])=[O:10])=[CH:5][CH:4]=1.CS(C)=O.[OH:17][N:18]1[C:22](=[O:23])[C:21]2=[CH:24][CH:25]=[CH:26][CH:27]=[C:20]2[C:19]1=[O:28].C(=O)([O-])[O-].[K+].[K+]>O>[CH3:12][S:9]([C:6]1[CH:7]=[CH:8][C:3]([CH2:2][O:17][N:18]2[C:22](=[O:23])[C:21]3[C:20](=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:19]2=[O:28])=[CH:4][CH:5]=1)(=[O:11])=[O:10]
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: CS(=O)(=O)c1ccc(CCl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CS(=O)(=O)c1ccc(CON2C(=O)c3ccccc3C2=O)cc1
Temperature: 50 °C
Reaction time: 2 h
Yield: 64.2 %

Procedure:
To a mixture of 659 mg of 1-(chloromethyl)-4-(methylsulfonyl)benzene and 10 ml of DMSO were added 525 mg of N-hydroxyphthalimide and 445 mg of potassium carbonate, followed by stirring at 50° C. for 2 hours. The reaction solution was cooled, water was then added thereto, and the precipitated crystal was collected by filtration to obtain 685 mg of 2-{[4-(methylsulfonyl)benzyl]oxy}-1H-isoindole-1,3(2H)-dione as a white solid.
Reaction SMILES: C(O[C:6](=O)[NH:7][CH2:8][CH2:9][NH:10][CH:11]([C:14]1[N:23]([CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:22](=[O:31])[C:21]2[C:16](=[CH:17][C:18]([Cl:32])=[CH:19][CH:20]=2)[N:15]=1)[CH2:12][CH3:13])(C)(C)C.C(N1[C:50](=[O:51])[C:49]2C(=CC(Cl)=CC=2)N=C1C(Br)CC)C1C=CC=CC=1.C(OC(=O)NCCN)(C)(C)C.C(=O)(O)[O-].[Na+]>CCO>[CH2:24]([N:23]1[C:22](=[O:31])[C:21]2[C:16](=[CH:17][C:18]([Cl:32])=[CH:19][CH:20]=2)[N:15]=[C:14]1[CH:11]([N:10]1[C:50](=[O:51])[CH2:49][CH2:6][NH:7][CH2:8][CH2:9]1)[CH2:12][CH3:13])[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: CCC(NCCNC(=O)OC(C)(C)C)c1nc2cc(Cl)ccc2c(=O)n1Cc1ccccc1
Reactant: CCC(Br)c1nc2cc(Cl)ccc2c(=O)n1Cc1ccccc1
Agent: CC(C)(C)OC(=O)NCCN
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CCC(c1nc2cc(Cl)ccc2c(=O)n1Cc1ccccc1)N1CCNCCC1=O

Procedure:
Preparation of {2-[1-(3-benzyl-7-chloro-4-oxo-3,4-dihydro-quinazolin-2-yl)-propylamino]-ethyl}-carbamic acid tert-butyl ester: A mixture of 3-benzyl-2-(1-bromo-propyl)-7-chloro-3H-quinazolin-4-one (3.9 g, 10 mmol) (WO 0130768), (2-amino-ethyl)-carbamic acid tert-butyl ester (2.40 g, 15 mmol) and sodium bicarbonate (1.26 g, 15 mmol) in EtOH (50 mL) was refluxed overnight. The salts were removed by filtration and the filtrate was concentrated to dryness. The residue which remained was purified by flash chromatography on silica gel (10–15% EtOH in hexane) to give the title compound (2.90 g) as a white solid: MS (ES) m/e 471.2 (M+H)+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH2:12][CH2:11][N:10](C(OC(C)(C)C)=O)[CH2:9][CH:8]=1.FC(F)(F)C(O)=O>ClCCl>[NH:10]1[CH2:9][CH:8]=[C:7]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)[CH2:12][CH2:11]1
Reactant: CC(C)(C)OC(=O)N1CC=C(c2ccccn2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C1=C(c2ccccn2)CCNC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of tert-butyl 4-(pyridin-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate (1.1 g, 4.23 mmol) in dichloromethane (50 ml) was added trifluoroacetic acid (4 ml), and the reaction mixture was allowed to react with stirring overnight at room temperature. The reaction mixture was concentrated in vacuo to afford 2-(1,2,3,6-tetrahydropyridin-4-yl)pyridine as a crude yellow oil (600 mg).
Reaction SMILES: [CH2:1]([C@H:4]1[CH2:9][CH2:8][C@H:7]([CH:10]2[CH2:13][C:12](=[CH2:14])[CH2:11]2)[CH2:6][CH2:5]1)[CH2:2][CH3:3].[Cl:15][C:16]([Cl:21])(Cl)[C:17](Cl)=[O:18]>>[CH2:1]([C@H:4]1[CH2:9][CH2:8][C@H:7]([CH:10]2[CH2:13][C:12]3([CH2:14][C:17](=[O:18])[C:16]3([Cl:21])[Cl:15])[CH2:11]2)[CH2:6][CH2:5]1)[CH2:2][CH3:3]
Reactant: C=C1CC([C@H]2CC[C@H](CCC)CC2)C1
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Product: CCC[C@H]1CC[C@H](C2CC3(CC(=O)C3(Cl)Cl)C2)CC1

Procedure:
35 mmol of 4C are reacted with trichloroacetyl chloride in analogy to Example 1B.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][N:8]([CH:11]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:7][CH2:6]1.[C:24](OC(=O)C)(=[O:26])[CH3:25].Cl>>[C:24]([NH:1][CH2:2][CH2:3][CH2:4][N:5]1[CH2:6][CH2:7][N:8]([CH:11]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:9][CH2:10]1)(=[O:26])[CH3:25]
Reactant: NCCCN1CCN(C(c2ccccc2)c2ccccc2)CC1
Reactant: CC(=O)OC(C)=O
Agent: Cl
Product: CC(=O)NCCCN1CCN(C(c2ccccc2)c2ccccc2)CC1
Temperature: 100 °C
Reaction time: 1.5 h

Procedure:
A mixture of 1-(3-aminopropyl)-4-benzhydrylpiperazine (1.55 g) and acetic anhydride (16 ml) was stirred at 100° C. for 1.5 hours. The reaction mixture was concentrated and the residue was extracted with ethyl acetate. The extract was washed successively with aqueous sodium bicarbonate and water, dried and evaporated in vacuo. The residue was purified by column chromatography on silica gel eluting with ethyl acetate. The fractions containing the desired compound were combined and evaporated in vacuo to give a residue. According to a conventional manner, the residue was converted to hydrochloric acid salt, which was recrystallized from a mixture of methanol and diethyl ether to afford 1-(3-acetylaminopropyl)-4-benzhydrylpiperazine (0.8 g) as white crystals. mp: 240°-255° C. (dec.)
Reaction SMILES: [CH2:1]([C:5]1[N:10]=[C:9]([C:11]([OH:13])=O)[C:8]([NH:14][C:15]2[CH:16]=[N:17][CH:18]=[N:19][CH:20]=2)=[CH:7][N:6]=1)[CH:2]([CH3:4])[CH3:3].[CH3:21][NH:22][C:23]([C:25]1[N:26]([CH3:31])[N:27]=[CH:28][C:29]=1[NH2:30])=[O:24]>>[CH3:31][N:26]1[C:25]([C:23](=[O:24])[NH:22][CH3:21])=[C:29]([NH:30][C:11]([C:9]2[C:8]([NH:14][C:15]3[CH:16]=[N:17][CH:18]=[N:19][CH:20]=3)=[CH:7][N:6]=[C:5]([CH2:1][CH:2]([CH3:3])[CH3:4])[N:10]=2)=[O:13])[CH:28]=[N:27]1
Reactant: CC(C)Cc1ncc(Nc2cncnc2)c(C(=O)O)n1
Reactant: CNC(=O)c1c(N)cnn1C
Product: CNC(=O)c1c(NC(=O)c2nc(CC(C)C)ncc2Nc2cncnc2)cnn1C

Procedure:
The product was obtained starting from 2-isobutyl-5-(pyrimidin-5-ylamino)-pyrimidine-4-carboxylic acid (60 mg, 0.22 mmol; example 331, step 1) and 4-amino-2-methyl-2H-pyrazole-3-carboxylic acid methylamide (44 mg, 0.28 mmol) according to the method described in example 64, step 6 after purification by preparative HPLC using an acetonitrile/water gradient as yellow solid (42 mg, 47%).
Reaction SMILES: [Cl:1]([O-:3])=[O:2].[Na+].C(O)(=O)C(C)O.[C:11]([OH:23])(=[O:22])[CH2:12][C:13]([CH2:18][C:19]([OH:21])=[O:20])([C:15]([OH:17])=[O:16])[OH:14]>>[C:11]([OH:23])(=[O:22])[CH2:12][C:13]([CH2:18][C:19]([OH:21])=[O:20])([C:15]([OH:17])=[O:16])[OH:14].[Cl:1]([OH:3])=[O:2]
Reactant: [O-][Cl+][O-]
Agent: CC(O)C(=O)O
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Product: [O-][Cl+]O

Procedure:
In practice, the reactants and reactions are produced by mixing bulk quantities of sodium chlorite and lactic acid. In practice, three parts of sodium chlorite at a concentration of 26% by volume are mixed with one part of lactic acid at a concentration of 88% by volume which is a food grade of lactic acid. The 26% by volume of sodium chlorite and 88% by volume of lactic acid are commonly commercially available bulk quantities of these compounds and are generally provided to industry commercially in either drum lots or bulk quantities for example tank cars or tank trucks. Furthermore, note in the above reaction Number 1. that citric acid, HOC(CH2COOH)2COOH, may be substituted for the lactic acid to produce a salt of citric acid and chlorous acid in an aqueous solution along with the other acids previously mentioned.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH:6]=[CH:7][C:8](=[O:12])[C:9]=1[O:10][CH3:11])=[O:5].[Cl:13][C:14](=[CH2:19])[CH:15]=[CH:16]OC>C1C=CC=CC=1>[CH3:11][O:10][C:9]1[C:8](=[O:12])[C:7]2[C:6]([C:4](=[O:5])[C:3]=1[O:2][CH3:1])=[CH:19][C:14]([Cl:13])=[CH:15][CH:16]=2
Reactant: C=C(Cl)C=COC
Reactant: COC1=C(OC)C(=O)C=CC1=O
Solvent: c1ccccc1
Product: COC1=C(OC)C(=O)c2cc(Cl)ccc2C1=O

Procedure:
A benzene (8 ml) solution of 2,3-dimethoxybenzo-1,4-quinone (1.0 g, 5.9 mmol) and 3-chloro-1-methoxy-1,3-butadiene (1.4 g, 12.0 mmol) is stirred for 35 hours under an inert atmosphere. After this time, oxygen or air is briefly bubbled through the solution (20 minutes) and the contents are passed through a silica gel plug to afford 1.07 g (72%) of analytically pure 2,3-dimethoxy-6-chloro-1,4-naphthoquinone, mp 127°-130° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([CH:9]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:10]([OH:12])=[O:11])=[CH:5][CH:4]=1.[N:20]12[CH2:27][CH2:26][CH:23]([CH2:24][CH2:25]1)[C@@H:22](O)[CH2:21]2.C1C=CC2N(O)N=NC=2C=1.C1CCC(N=C=NC2CCCCC2)CC1>C1COCC1>[CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([CH:9]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:10]([O:12][C@@H:22]2[CH:23]3[CH2:26][CH2:27][N:20]([CH2:25][CH2:24]3)[CH2:21]2)=[O:11])=[CH:5][CH:4]=1
Reactant: O[C@H]1CN2CCC1CC2
Reactant: COc1ccc(C(Nc2ccccc2)C(=O)O)cn1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: COc1ccc(C(Nc2ccccc2)C(=O)O[C@H]2CN3CCC2CC3)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 23 %

Procedure:
A mixture of 2-(6-methoxypyridin-3-yl)-2-(phenylamino)acetic acid (I1) (100 mg, 0.39 mmol), (R)-quinuclidin-3-ol (59.1 mg, 0.46 mmol), HOBT (71.2 mg, 0.46 mmol) and DCC (96 mg, 0.46 mmol) was dissolved in dry THF (10 ml). The resulting reaction was stirred at room temperature overnight. Then solvent was removed under reduced pressure, and the residue was taken up with EtOAc and washed twice with 2M K2CO3. The organic phase was dried over Na2SO4, filtered and evaporated to dryness. The crude was purified by flash chromatography (DCM/MeOH=98/2) to obtain (R)-quinuclidin-3-yl 2-(6-methoxypyridin-3-yl)-2-(phenylamino)acetate (33 mg, 23% yield).
Reaction SMILES: [CH3:1][NH:2][C:3]1[S:4][C:5](=[CH:9][C:10]2[CH:15]=[CH:14][C:13]([N:16]3[CH2:21][CH2:20][C:19](=O)[CH2:18][CH2:17]3)=[CH:12][CH:11]=2)[C:6](=[O:8])[N:7]=1.[OH:23][C@@H:24]([CH2:37][NH2:38])[CH2:25][O:26][C:27]1[C:35]2[NH:34][C:33](=[O:36])[NH:32][C:31]=2[CH:30]=[CH:29][CH:28]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>CN(C)C=O.C(O)(=O)C>[OH:23][C@@H:24]([CH2:37][NH:38][CH:19]1[CH2:20][CH2:21][N:16]([C:13]2[CH:14]=[CH:15][C:10]([CH:9]=[C:5]3[S:4][C:3]([NH:2][CH3:1])=[N:7][C:6]3=[O:8])=[CH:11][CH:12]=2)[CH2:17][CH2:18]1)[CH2:25][O:26][C:27]1[C:35]2[NH:34][C:33](=[O:36])[NH:32][C:31]=2[CH:30]=[CH:29][CH:28]=1
Reactant: CNC1=NC(=O)C(=Cc2ccc(N3CCC(=O)CC3)cc2)S1
Reactant: NC[C@H](O)COc1cccc2[nH]c(=O)[nH]c12
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: CNC1=NC(=O)C(=Cc2ccc(N3CCC(NC[C@H](O)COc4cccc5[nH]c(=O)[nH]c45)CC3)cc2)S1
Temperature: 25 °C
Reaction time: 24 h
Yield: 65.1 %

Procedure:
1-[4-(2-Methylamino-4-oxo-4H-thiazol-5-ylidenemethyl)-phenyl]-piperidin-4-one (which was obtained in Intermediate 18)(0.15 g, 0.47 mmol) and (S)-4-[2-hydroxy-3-aminopropoxy]-1,3-dihydro-2 H-benzimidazol-2-one (Jesudason, C. D., et al., EP 0 764 640) (0.11 g, 0.47 mmol) were mixed in dimethylformamide (15 mL) and then treated with sodium triacetoxyborohydride (0.16 g, 0.75 mmol) and acetic acid (0.15 mL). After stirring at room temperature under a nitrogen atmosphere for one day the mixture was poured into a saturated aqueous sodium bicarbonate solution. The precipitate was collected and purified by column chromatography (eluent: methanol/methylene chloride) to give the title compound as a pale yellowish solid(0.16 g, 65%); mp>160° C. (dec.); 1H NMR (300 MHz, DMSO-d6) δ 1.20-1.45 (m, 2 H), 1.75-2.00 (m, 2 H), 2.60-3.00 (m, 5H), 3.05 (s, 3 H), 3.75-4.15 (m, 5H), 6.57 (d, J=7.8 Hz, 1 H), 6.62 (d, J=8.1 Hz, 1 H), 6.87 (t, J=8.1 Hz, 1 H), 7.02 (d, J=8.7 Hz, 2 H), 7.38 (d, J=8.7 Hz, 2 H), 7.47 (s, 1H), 10.56 (s, 1 H), 10.70 (brs, 1 H); MS (ES) m/z: 262.1 ((M+2 H)2+, 100%); 522.9 (MH+, 75%); HRMS Calcd. for C26H31N6O4S (MH+): 523.2128. Found: 523.2142.
Reaction SMILES: [CH3:1][C@H:2]([NH:11][CH3:12])[C@H:3]([OH:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.CN>>[CH3:1][C@H:2]([NH:11][CH3:12])[C@@H:3]([OH:10])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CN[C@@H](C)[C@H](O)c1ccccc1
Agent: CN
Product: CN[C@@H](C)[C@@H](O)c1ccccc1

Procedure:
The combination of yeast transformation of benzaldehyde to produce PAC and chemical conversion of the PAC to make l-ephedrine is described in U.S. Pat. No. 1,956,950. The PAC can be converted by a chemical reductive amination with methylamine to optically pure L-ephedrine as follows: ##STR2## The l-ephedrine can then converted in high yield to d-pseudoephedrine as follows: ##STR3## It is apparent from this reaction scheme that microbial transformation of benzaldehyde by yeast to form L-(-)phenyl acetyl carbinol in high yield and purity is of prime importance for successful commercial operation of the synthetic route.
Reaction SMILES: [CH3:1][N:2]([CH3:6])[CH2:3][CH2:4][OH:5].[H-].[Na+].[NH2:9][C:10]1[C:19]2[C:14](=[C:15](F)[C:16]([N:20]3[C:28]4[CH2:27][C:26]([CH3:30])([CH3:29])[CH2:25][C:24](=[O:31])[C:23]=4[C:22]([CH3:32])=[CH:21]3)=[CH:17][CH:18]=2)[N:13]=[CH:12][N:11]=1>CN(C=O)C>[NH2:9][C:10]1[C:19]2[C:14](=[C:15]([O:5][CH2:4][CH2:3][N:2]([CH3:6])[CH3:1])[C:16]([N:20]3[C:28]4[CH2:27][C:26]([CH3:30])([CH3:29])[CH2:25][C:24](=[O:31])[C:23]=4[C:22]([CH3:32])=[CH:21]3)=[CH:17][CH:18]=2)[N:13]=[CH:12][N:11]=1
Reactant: Cc1cn(-c2ccc3c(N)ncnc3c2F)c2c1C(=O)CC(C)(C)C2
Reactant: CN(C)CCO
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cn(-c2ccc3c(N)ncnc3c2OCCN(C)C)c2c1C(=O)CC(C)(C)C2
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 73.9 %

Procedure:
In a microwave vial with a stir bar, N,N-dimethylethanolamine (101 mg, 1.13 mmol) is dissolved in DMF (5 mL). To this solution is added sodium hydride (60% suspension in mineral oil, 45 mg, 1.136 mmol) and the mixture stirred at room temperature for 5 minutes and 1-(4-Amino-8-fluoro-quinazolin-7-yl)-3,6,6-trimethyl-1,5,6,7-tetrahydro-indol-4-one (192 mg, 0.568 mmol) is added. The reaction is sealed and placed in the microwave reactor where it is heated to 150° C. for 30 minutes. The reaction is cooled, quenched by adding 25 mL sat. NH4Cl (aq) and extracted with CH2Cl2 (3×5 mL). The combined organics are dried with Na2SO4, concentrated and purified by silica gel chromatography by two gradient runs on the same column, the first 0% to 100% ethyl acetate in hexanes and the second 0% to 50% methanol in ethyl acetate. This gives 1-[4-Amino-8-(2-dimethylamino-ethoxy)-quinazolin-7-yl]-3,6,6-trimethyl-1,5,6,7-tetrahydro-indol-4-one as a yellow powder (171 mg, 74% yield) (LC/MS m/z=408 [M+H]+).
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]2[CH2:7][CH2:8][CH2:9][C:4]=2[C:3]=1[C:10]#[N:11].[CH:12]1([C:15](=[O:21])[CH:16]=[C:17](OC)[CH3:18])[CH2:14][CH2:13]1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[Sn](Cl)(Cl)(Cl)Cl>C1(C)C=CC=CC=1>[NH2:11][C:10]1[C:3]2[C:4]3[CH2:9][CH2:8][CH2:7][C:5]=3[S:6][C:2]=2[N:1]=[C:17]([CH3:18])[C:16]=1[C:15]([CH:12]1[CH2:14][CH2:13]1)=[O:21]
Reactant: N#Cc1c(N)sc2c1CCC2
Reactant: COC(C)=CC(=O)C1CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: Cc1nc2sc3c(c2c(N)c1C(=O)C1CC1)CCC3
Yield: 5 %

Procedure:
To a stirred solution of 0.30 g (1.83 mmol) of 2-amino-5,6-dihydro-4H-cyclopenta[b]thiophene-3-carbonitrile in 6 ml toluene was added 0.30 g (2.14 mmol) 1-cyclopropyl-3-methoxy-but-2-en-1-one and 3 mg of p-toluenesulfonic acid. The mixture was heated at reflux for 2 hours, concentrated in vacuo, partitioned between ethyl acetate and water. The combined organic phases were dried over sodium sulfate and evaporated to dryness. The residue was taken up in n-butyl acetate 6 ml and 1.018 g (3.91 mmol) tin (IV) chloride was heated under reflux for 30 minute and allowed to cool. The mixture was partitioned between aqueous sodium hydroxide and ethyl acetate. Flash chromatography (heptane/ethyl acetate 3:1) afforded 25 mg (5%) (4-amino-6-methyl-2,3-dihydro-1H-8-thia-7-aza-cyclopenta[a]inden-5-yl)-cyclopropyl-methanone as a white solid. ES-MS m/e (%): 273 (M+H+, 100).
Reaction SMILES: [S-:1][C:2]#[N:3].[K+].[NH2:5][C:6]1[CH:7]=[CH:8][C:9]([O:12][C:13]2[CH:14]=[C:15]([CH:20]=[CH:21][C:22]=2[O:23][CH3:24])[C:16]([O:18][CH3:19])=[O:17])=[N:10][CH:11]=1.BrBr>C(O)(=O)C>[NH2:3][C:2]1[S:1][C:11]2[C:6]([N:5]=1)=[CH:7][CH:8]=[C:9]([O:12][C:13]1[CH:14]=[C:15]([CH:20]=[CH:21][C:22]=1[O:23][CH3:24])[C:16]([O:18][CH3:19])=[O:17])[N:10]=2
Reactant: COC(=O)c1ccc(OC)c(Oc2ccc(N)cn2)c1
Reactant: N#C[S-]
Agent: BrBr
Agent: [K+]
Solvent: CC(=O)O
Product: COC(=O)c1ccc(OC)c(Oc2ccc3nc(N)sc3n2)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 67.8 %

Procedure:
To a suspension of potassium thiocyanate (12.1 g, 125 mmol) in acetic acid (100 mL) was added a solution of methyl 3-[(5-aminopyridin-2-yl)oxy]-4-methoxybenzoate (26.7 mmol) in acetic acid (100 mL), and the mixture was stirred at room temperature for 15 min. The obtained solution was cooled to 0° C., a solution of bromine (6.55 g, 41.0 mmol) in acetic acid (80 mL) was added dropwise for 1 hr or more. After the completion of the dropwise addition, the mixture was stirred for 16 hr, during which the reaction temperature was allowed to gradually warm to room temperature. The yielded yellow solid was filtered off, and washed with water. The filtrate and the washing solution were combined, and concentrated under reduced pressure, and the residue was treated with saturated aqueous sodium hydrogen carbonate solution (200 mL). The obtained solution was extracted with ethyl acetate (100 mL×6), and the combined organic layer was dried over anhydrous magnesium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure to give the title compound (6.0 g, total of 3 steps 67%) as a pale-brown solid.
Reaction SMILES: [C:1]1([C:7]2[C:8]3[CH:17]=[CH:16][S:15][C:9]=3[NH:10][C:11](=S)[CH2:12][N:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:18]([NH:21][NH2:22])(=[O:20])[CH3:19].O>C(O)C>[C:18]([NH:21][NH:22][C:11]1[CH2:12][N:13]=[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:8]2[CH:17]=[CH:16][S:15][C:9]=2[N:10]=1)(=[O:20])[CH3:19]
Reactant: CC(=O)NN
Reactant: S=C1CN=C(c2ccccc2)c2ccsc2N1
Solvent: CCO
Solvent: O
Product: CC(=O)NNC1=Nc2sccc2C(c2ccccc2)=NC1

Procedure:
1.5 g (0.00582 mol) of 1,3-dihydro-5-phenyl-2H-thieno[2,3-e]-1,4-diazepine-2-thione are heated to reflux for 4 hours under a nitrogen atmosphere with 1.3 g (0.0175 mol) of acetyl hydrazine in 120 ml of absolute ethanol. The solvent is evaporated and the crystals obtained are shaken with water in a separating funnel. After filtration under a vacuum, the product is recrystallized from ethyl acetate containing active carbon to give colorless crystals of 2-(2-acetylhydrazino)-5-phenyl-3H-thieno[2,3-e]-1,4-diazepine, melting point 194°-196° C. (transition).
Reaction SMILES: [Cl:1][C:2]1[C:20]([CH3:21])=[CH:19][CH:18]=[C:4]2[C:5]([N:7]([C:10]3([C:16]#[N:17])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]3)[C:8](=[O:9])[C:3]=12)=[O:6].S(=O)(=O)(O)[OH:23].O>C(Cl)Cl>[Cl:1][C:2]1[C:20]([CH3:21])=[CH:19][CH:18]=[C:4]2[C:5]([N:7]([C:10]3([C:16]([NH2:17])=[O:23])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]3)[C:8](=[O:9])[C:3]=12)=[O:6]
Reactant: Cc1ccc2c(c1Cl)C(=O)N(C1(C#N)CCCCC1)C2=O
Reactant: O=S(=O)(O)O
Solvent: O
Solvent: ClCCl
Product: Cc1ccc2c(c1Cl)C(=O)N(C1(C(N)=O)CCCCC1)C2=O
Reaction time: 4 h
Yield: 62 %

Procedure:
A solution of about 4.35 g (14.4 mmol) of 3-chloro-N-(1-cyanocyclohexyl)-4-methylphthalimide in about 50 ml methylene chloride is added to concentrated sulfuric acid and water at less than 10° C. with rapid stirring. The reaction mixture is stirred very vigorously at ambient temperatures for 4 hours (reaction complete by thin layer chromatography), poured over crushed ice and extracted with about 450 ml methylene chloride. The organic extracts are combined and concentrated in vacuo to give a white fluffy precipitate. The precipitate is filtered and air dried to give the title product, 2.86 g (62% yield), mp 192°-208° C., identified by infrared and NMR analysis.
Reaction SMILES: [N+:1]([CH2:4][CH3:5])([O-])=O.C(O[C:9](=[O:19])[CH:10]=[CH:11][C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=1)C.[OH-].C[N+](C)(C)CC1C=CC=CC=1.C1(C)C=CC=CC=1>CO>[Cl:18][C:15]1[CH:14]=[CH:13][C:12]([CH:11]2[CH:4]([CH3:5])[NH:1][C:9](=[O:19])[CH2:10]2)=[CH:17][CH:16]=1
Reactant: CCOC(=O)C=Cc1ccc(Cl)cc1
Reactant: CC[N+](=O)[O-]
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: CO
Product: CC1NC(=O)CC1c1ccc(Cl)cc1

Procedure:
A mixture of 150 g. (2 mole) of nitroethane, 105 g. (0.5 mole) of ethyl-p-chlorocinnamate and 6.6 g. of Triton B (a 35% solution of trimethyl-benzyl-ammonium hydroxide in methanol) is heated for 20 hours at 80°C. After the reaction has finished, toluene is added, washing is carried out with a saturated solution of sodium chloride and the organic solution is dried and evaporated to dryness and the residue is distilled. Yield: 80%; B.P.: 150°-155°C./0.3 mm.Hg.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:13]([N:15]3[CH2:19][CH:18]=[CH:17][CH2:16]3)=[O:14])=[C:9]([Cl:12])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[Cl:20][C:21]1[CH:41]=[CH:40][C:24]2[NH:25][C:26]([C@@H:28]([NH2:39])[CH2:29][CH2:30][CH2:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])=[N:27][C:23]=2[CH:22]=1.C(N(CC)CC)C>CN(C)C=O>[Cl:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[C:13]([N:15]1[CH2:19][CH:18]=[CH:17][CH2:16]1)=[O:14])[N:5]=[CH:4][N:3]=[C:2]2[NH:39][C@H:28]([C:26]1[NH:25][C:24]2[CH:40]=[CH:41][C:21]([Cl:20])=[CH:22][C:23]=2[N:27]=1)[CH2:29][CH2:30][CH2:31][C:32]([O:34][C:35]([CH3:37])([CH3:36])[CH3:38])=[O:33]
Reactant: O=C(c1cc2ncnc(Cl)c2cc1Cl)N1CC=CC1
Reactant: CC(C)(C)OC(=O)CCC[C@H](N)c1nc2cc(Cl)ccc2[nH]1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)CCC[C@H](Nc1ncnc2cc(C(=O)N3CC=CC3)c(Cl)cc12)c1nc2cc(Cl)ccc2[nH]1

Procedure:
Prepared analogously to Example 2d from 4,6-dichloro-7-(2,5-dihydropyrrol-1-yl-carbonyl)-quinazoline, (S)-1-(5-chloro-1H-benzimidazol-2-yl)-4-(tert.-butyloxycarbonyl)-butylamine and triethylamine in N,N-dimethylformamide.