Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[N:11](COC(=O)C(C)(C)C)[C:10](=[O:20])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH2:21][N:22]([C:29]3[CH:37]=[CH:36][C:32]([C:33](O)=[O:34])=[CH:31][CH:30]=3)[CH2:23][CH2:24][O:25]C(=O)C)[CH:8]=2)[N:3]=1.[C:38]([C:40]1[CH:41]=[C:42]([CH:45]=[CH:46][CH:47]=1)[CH2:43][NH2:44])#[N:39]>>[C:38]([C:40]1[CH:41]=[C:42]([CH:45]=[CH:46][CH:47]=1)[CH2:43][NH:44][C:33](=[O:34])[C:32]1[CH:31]=[CH:30][C:29]([N:22]([CH2:21][C:7]2[CH:8]=[C:9]3[C:4](=[CH:5][CH:6]=2)[N:3]=[C:2]([CH3:1])[NH:11][C:10]3=[O:20])[CH2:23][CH2:24][OH:25])=[CH:37][CH:36]=1)#[N:39]
Reactant: N#Cc1cccc(CN)c1
Reactant: CC(=O)OCCN(Cc1ccc2nc(C)n(COC(=O)C(C)(C)C)c(=O)c2c1)c1ccc(C(=O)O)cc1
Product: Cc1nc2ccc(CN(CCO)c3ccc(C(=O)NCc4cccc(C#N)c4)cc3)cc2c(=O)[nH]1

Procedure:
Using the procedure described in Example 10, p-[N-(3,4-dihydro-2-methyl-4-oxo-3-pivaloyloxymethylquinazolin-6-ylmethyl)-N-(2-acetoxyethyl)amino]benzoic acid was reacted with 3-cyanobenzylamine to give N-(3-cyanobenzyl)-p-[N-(3,4-dihydro-2-methyl-4-oxoquinazolin-6-ylmethyl)-N-(2-hydroxyethyl)amino]benzamide, m.p. 110°-112° C., as a foam.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[S:9][C:10]1[CH:19]=[CH:18][C:13]([C:14]([NH:16][CH3:17])=[O:15])=[CH:12][CH:11]=1.Cl[C:21]1[CH:30]=[CH:29][N:28]=[C:27]2[C:22]=1[CH:23]=[CH:24][C:25]([CH2:31][CH2:32][CH3:33])=[N:26]2.C(O)C>>[CH3:17][NH:16][C:14](=[O:15])[C:13]1[CH:18]=[CH:19][C:10]([S:9][C:3]2[CH:4]=[CH:5][C:6]([CH3:8])=[CH:7][C:2]=2[NH:1][C:21]2[C:22]3[C:27](=[N:26][C:25]([CH2:31][CH2:32][CH3:33])=[CH:24][CH:23]=3)[N:28]=[CH:29][CH:30]=2)=[CH:11][CH:12]=1
Reactant: CNC(=O)c1ccc(Sc2ccc(C)cc2N)cc1
Reactant: CCCc1ccc2c(Cl)ccnc2n1
Solvent: CCO
Product: CCCc1ccc2c(Nc3cc(C)ccc3Sc3ccc(C(=O)NC)cc3)ccnc2n1

Procedure:
The product from Example 85b (0.155 g, 0.57 mmol) was reacted with the product from Example 2g as a 3.15M solution in ethanol (0.18 mL, 0.57 mmol) for 24 h following the procedure from Example 1g giving the crude title compound which was purified by HPLC with TFA providing the product as a trifluoroacetic acid salt (0.180 g, 56%). 1H NMR (300 MHz, DMSO-d6) δ ppm: 0.97 (t, J=7.35 Hz, 3 H) 1.72-1.91 (m, 2 H) 2.41 (s, 3 H) 2.75 (d, J=4.41 Hz, 3 H) 2.97 (t, J=7.35 Hz, 2 H) 6.36 (d, J=6.99 Hz, 1 H) 7.20 (d, J=8.46 Hz, 2 H) 7.33-7.47 (m, 2 H) 7.50 (d, 1 H) 7.63 (d, J=8.46 Hz, 2 H) 7.77 (d, J=8.82 Hz, 1 H) 8.30-8.44 (m, J=6.62, 6.62 Hz, 2 H) 8.91 (d, J=8.82 Hz, 1 H) 10.86-11.09 (s, 1 H); MS (ESI+) m/z 443.2 (M+H)+; (ESI−) m/z 441.2 (M−H)−.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[CH2:13](I)[CH3:14].C([O-])([O-])=O.[K+].[K+]>CC#N.CCOC(C)=O.O>[CH2:13]([O:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8])[CH3:14]
Reactant: COC(=O)c1cc(O)ccc1C
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CCOc1ccc(C)c(C(=O)OC)c1
Temperature: 100 °C
Yield: 99.3 %

Procedure:
To a mixture of methyl 5-hydroxy-2-methylbenzoate (134a, 0.600 g, 3.63 mmol) and ethyl iodide (1.13 g, 7.26 mmol) in CH3CN (10 mL) was added K2CO3 (1.00 g, 7.26 mmol) at room temperature. The resulting mixture was heated at 100° C. for 12 hours. The reaction mixture was diluted with EtOAc (25 mL) and H2O (10 mL). The organic layer was separated and washed with NaOH (2 N, 5 mL), H2O (5 mL) and brine (5 mL), dried over Na2SO4 and concentrated under vacuum to give methyl 5-ethoxy-2-methylbenzoate (134b, 0.7 g, 99%) as yellow liquid.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH2:8]O)=[CH:6][CH:5]=[CH:4][N:3]=1.P(Br)(Br)[Br:11]>C(Cl)Cl>[Br:11][CH2:8][C:7]1[C:2]([Cl:1])=[N:3][CH:4]=[CH:5][CH:6]=1
Reactant: OCc1cccnc1Cl
Reactant: BrP(Br)Br
Solvent: ClCCl
Product: Clc1ncccc1CBr
Temperature: 25 °C
Yield: 64 %

Procedure:
To a stirred solution of the title compound of Step A (5.50 g, 38.3 mmol) in CH2Cl2 (60 mL) at 0° C. under N2 was added phosphorus tribromide (3.60 mL, 38.3 mmol). The solution was allowed to warm to room temperature overnight. The solution was poured into ice water and the aqueous layer was extracted with CHCl3. The combined organic extracts were washed with water, 5% NaHCO3, and saturated aqueous NACl, dried over MgSO4 and concentrated in vacuo to a yellow oil. Purification by flash chromatography during with 20% ethyl acetate/hexanes afforded the title compound of Step B as a white solid (5.06 g). 1H NMR (CDCl3, 300 MHz) δ8.34 (dd, 1H), 7.80 (dd,1H), 7.26 (dd, 1H), 4.56 (s,2H).
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C:3](=[O:9])[CH2:2]2.CC(C)([O-])C.[K+].[H][H]>CC(O)C>[N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C@@H:3]([OH:9])[CH2:2]2
Reactant: O=C1CN2CCC1CC2
Reactant: [H][H]
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)O
Product: O[C@H]1CN2CCC1CC2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
1.63 g (13 mmol) of the 3-quinuclidinone (I), 1.1 mg (1.3 μmol) of {[(S)-(6,6′-dimethyl-1,1′-biphenyl-2,2′-diyl)-bis(di-p-tolylphosphine)]ruthenium (II) dichloride (DMF)n} complex, 12.7 ml of 2-propanol and 31 μl (1.55 μmol) of a 0.05 M 2-propanol solution of (2R,3R,4R,5R)-3,4-O-isopropylidenehexane-2,5-diamine were added to an autoclave in which the inside had been replaced with argon followed by carrying out a degassing procedure and stirring for 30 minutes at room temperature. 0.26 mL (0.26 mmol) of a 2-propanol solution of potassium tert-butoxide (1.0 M) were added thereto followed by stirring for 16 hours at 20 to 25° C. at a hydrogen pressure of 2.0 MPa to obtain (R)-3-quinuclidinol (3-R). S/C, conversion rate and enantiomeric excess are indicated below.
Reaction SMILES: C=O.[CH3:3][O:4][C:5]1[CH:10]=[C:9]([CH:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[CH:8]=[CH:7][C:6]=1[NH:17][C:18]1[N:23]=[C:22]([CH2:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[CH2:32][C:33]([NH2:35])=[O:34])[C:21]([C:36]([F:39])([F:38])[F:37])=[CH:20][N:19]=1.[C:40](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].CO.C(Cl)Cl>CO.C(OCC)(=O)C>[CH3:3][O:4][C:5]1[CH:10]=[C:9]([CH:11]2[CH2:16][CH2:15][N:14]([CH3:40])[CH2:13][CH2:12]2)[CH:8]=[CH:7][C:6]=1[NH:17][C:18]1[N:23]=[C:22]([CH2:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[CH2:32][C:33]([NH2:35])=[O:34])[C:21]([C:36]([F:37])([F:38])[F:39])=[CH:20][N:19]=1
Reactant: COc1cc(C2CCNCC2)ccc1Nc1ncc(C(F)(F)F)c(CCc2ccccc2CC(N)=O)n1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CO
Product: COc1cc(C2CCN(C)CC2)ccc1Nc1ncc(C(F)(F)F)c(CCc2ccccc2CC(N)=O)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 60.8 %

Procedure:
Formaldehyde solution (37% aq.; 32 μL, 0.39 mmol) was added to a stirred solution of 2-(2-(2-(2-((2-methoxy-4-(piperidin-4-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)ethyl)phenyl)acetamide (2) (40 mg, 78 μmol) in dry MeOH (2 mL). Sodium triacetoxyborohydride (83 mg, 0.39 mmol) was added under nitrogen and the resulting mixture was stirred at room temperature for 2 hours. The crude mixture was diluted with ethyl acetate and adsorbed onto silica gel. Chromatography (SiO2, 0-20% MeOH/DCM) gave the title compound (3) (25 mg, 61%) as a solid; 1H NMR (400 MHz, CD2Cl2) δ 8.53 (s, 1H), 8.34 (d, J=8.3 Hz, 1H), 7.94 (s, 1H), 7.29-7.15 (m, 4H), 6.92 (dd, J=8.3, 1.4 Hz, 1H), 6.82 (d, J=1.7 Hz, 1H), 6.12 (bs, 1H), 5.84 (bs, 1H), 3.91 (s, 3H), 3.68 (s, 2H), 3.60 (d, J=10.6 Hz, 2H), 3.24-3.03 (m, 4H), 2.80 (s, 3H), 2.79 (m, 2H), 2.71 (m, 1H), 2.42-2.20 (m, 2H), 2.01 (m, 2H). LCMS Method C: rt 4.92 min; m/z 528.1 [M+1]+, 526.1 [M−1]−.
Reaction SMILES: [C:1]([N:6]1[C:14]2[C:9](=[CH:10][C:11]([O:15][CH2:16][CH3:17])=[CH:12][CH:13]=2)[CH:8]([CH2:18][CH2:19][N:20]2[CH2:25][CH:24]=[C:23]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH2:22][CH2:21]2)[CH:7]1[CH2:32][CH3:33])(=[O:5])[CH:2]([CH3:4])[CH3:3].[C:34]([N:39]1[C:47]2[C:42](=[CH:43][C:44]([O:48][CH2:49][CH3:50])=[CH:45][CH:46]=2)[CH:41]([CH2:51][CH2:52][N:53]2[CH2:58][CH:57]=[C:56]([C:59]3[CH:64]=[CH:63][C:62]([Cl:65])=[CH:61][CH:60]=3)[CH2:55][CH2:54]2)[CH:40]1[CH2:66][CH3:67])(=[O:38])[CH:35]([CH3:37])[CH3:36]>>[C:1]([N:6]1[C:14]2[C:9](=[CH:10][C:11]([O:15][CH2:16][CH3:17])=[CH:12][CH:13]=2)[CH:8]([CH2:18][CH2:19][N:20]2[CH2:25][CH2:24][CH:23]([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH2:22][CH2:21]2)[CH:7]1[CH2:32][CH3:33])(=[O:5])[CH:2]([CH3:3])[CH3:4].[C:34]([N:39]1[C:47]2[C:42](=[CH:43][C:44]([O:48][CH2:49][CH3:50])=[CH:45][CH:46]=2)[CH:41]([CH2:51][CH2:52][N:53]2[CH2:58][CH2:57][CH:56]([C:59]3[CH:64]=[CH:63][C:62]([Cl:65])=[CH:61][CH:60]=3)[CH2:55][CH2:54]2)[CH:40]1[CH2:66][CH3:67])(=[O:38])[CH:35]([CH3:36])[CH3:37]
Reactant: CCOc1ccc2c(c1)C(CCN1CC=C(c3ccccc3)CC1)C(CC)N2C(=O)C(C)C
Reactant: CCOc1ccc2c(c1)C(CCN1CC=C(c3ccc(Cl)cc3)CC1)C(CC)N2C(=O)C(C)C
Product: CCOc1ccc2c(c1)C(CCN1CCC(c3ccc(Cl)cc3)CC1)C(CC)N2C(=O)C(C)C
Product: CCOc1ccc2c(c1)C(CCN1CCC(c3ccccc3)CC1)C(CC)N2C(=O)C(C)C

Procedure:
In the manner described in Example 14, reduction of 1-isobutyryl-2-ethyl-5-ethoxy-3-[2-(4-phenyl-3,6-dihydro-1(2H)-pyridyl)ethyl]indoline and 1-isobutyryl-2-ethyl-5-ethoxy-3-{2-[4-(p-chlorophenyl)-3,6-dihydro-1(2H)-pyridyl]-ethyl} indoline provides the corresponding 1-isobutyryl-2-ethyl-5-ethoxy-3-[2-(4-phenylpiperidino)ethyl]indoline and 1-isobutyryl-2-ethyl-5-ethoxy-3-{2-[4-(p-chlorophenyl)piperidino]ethyl} indoline.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([CH3:10])[CH:9]=1)[CH2:5]Br.[Br:11][C:12]1[CH:18]=[CH:17][C:15]([NH2:16])=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[Br:11][C:12]1[CH:18]=[CH:17][C:15]([NH:16][CH2:5][C:4]2[CH:3]=[C:2]([CH3:1])[CH:9]=[C:8]([CH3:10])[CH:7]=2)=[CH:14][CH:13]=1
Reactant: Nc1ccc(Br)cc1
Reactant: Cc1cc(C)cc(CBr)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(C)cc(CNc2ccc(Br)cc2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.9 %

Procedure:
A mixture of 3,5-dimethylbenzyl bromide (1.59 g, 7.986 mmol), 4-bromoaniline (1.374 g, 7.986 mmol), potassium carbonate (5.519 g, 39.93 mmol) and N,N-dimethylformamide (6.5 ml) was stirred at 80° for 2 hours under argon atmosphere. The reaction mixture was cooled to room temperature, diluted with water, and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The residue obtained by evaporation of the solvent under reduced pressure was purified by column chromatography on silica gel (n-hexane:ethyl acetate=15:1) to give the title compound (2.106 g, 57.2%) as a pale yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][C@@H:6]2[OH:11].[CH3:12][C:13]([Si:16](Cl)([CH3:18])[CH3:17])([CH3:15])[CH3:14].N1C=CN=C1>CN(C=O)C.C([O-])(O)=O.[Na+]>[Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][C@@H:6]2[O:11][Si:16]([C:13]([CH3:15])([CH3:14])[CH3:12])([CH3:18])[CH3:17]
Reactant: O[C@H]1CCc2c(Br)cccc21
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: O=C([O-])O
Agent: [Na+]
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)O[C@H]1CCc2c(Br)cccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 88 %

Procedure:
To a solution of (S)-4-bromo-2,3-dihydro-1H-inden-1-ol IND INT-1 (1.56 g, 7.3 mm) in DMF (5 mL) was added TBDMSCl (1.3 g, 8.7 mmol) and imidazole (1.24 g, 18.3 mmol) and the reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with saturated NaHCO3 solution (30 mL) and extracted with EA (2×50 mL). The organic layers were washed with water and brine, and dried over MgSO4. The crude product was purified by chromatography (EA/hexane) to afford 2.1 g (88%) of (S)-((4-bromo-2,3-dihydro-1H-inden-1-yl)oxy)(tert-butyl)dimethylsilane IND INT-3 as white solid. LCMS-ESI (m/z) calculated for C15H23BrOSi: 327.3; no M+ observed, tR=5.73 min (Method 2). 1H NMR (400 MHz, CDCl3) δ 7.35 (d, J=7.8 Hz, 1H), 7.22 (d, J=7.4 Hz, 1H), 7.07 (t, J=7.7 Hz, 1H), 5.28 (t, J=7.1 Hz, 1H), 3.00 (ddd, J=16.4, 9.1, 2.9 Hz, 1H), 2.73 (dt, J=16.5, 8.3 Hz, 1H), 2.42 (dddd, J=12.8, 8.0, 7.1, 3.0 Hz, 1H), 1.91 (dtd, J=12.8, 8.9, 7.1 Hz, 1H), 0.98-0.88 (m, 9H), 0.14 (d, J=7.4 Hz, 6H).
Reaction SMILES: [Na+].[CH2:2]([S:6]([NH-:9])(=[O:8])=[O:7])[CH2:3][CH2:4][CH3:5].CC(C)=O.[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([N:21]=[C:22]=[O:23])=[CH:17][CH:16]=1>O>[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22]([NH:9][S:6]([CH2:2][CH2:3][CH2:4][CH3:5])(=[O:8])=[O:7])=[O:23])=[CH:17][CH:16]=1
Reactant: O=C=Nc1ccc(Cl)cc1
Reactant: CCCCS([NH-])(=O)=O
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: CCCCS(=O)(=O)NC(=O)Nc1ccc(Cl)cc1
Reaction time: 1 h
Yield: 65.7 %

Procedure:
1-butanesulfonamide sodium salt (9.1 g, 57 mmole) was dissolved in water (40 ml) and acetone (40 ml) was added. To the resulting mixture was added dropwise 40 ml of acetone containing 4-chlorophenyl isocyanate (8.6 g). After two hours solid was removed from the reaction mixture by filtration. The solid was washed with water and the combined filtrate was treated with 1N HCl (57 ml). After about one hour, precipitate was collected from the filtrate and washed with water. After drying at 65° C. under vacuum, 10.7 g of product were obtained.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:18][C@H:17]([OH:19])[CH2:16][C@H:12]1[C:13](O)=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:20]([N:22](CC)CC)C.ClC(OCC)=O.CN>ClCCl.CO>[CH2:1]([O:8][C:9]([N:11]1[CH2:18][C@H:17]([OH:19])[CH2:16][C@H:12]1[C:13]([NH:22][CH3:20])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)[C@@H]1C[C@@H](O)CN1C(=O)OCc1ccccc1
Reactant: CCN(CC)CC
Agent: CCOC(=O)Cl
Agent: CN
Solvent: CO
Solvent: ClCCl
Product: CNC(=O)[C@@H]1C[C@@H](O)CN1C(=O)OCc1ccccc1
Reaction time: 0.33 h

Procedure:
trans-1-Benzyloxycarbonyl-4-hydroxy-L-proline (3.06 g) was dissolved in dry dichloromethane (48 ml), and triethylamine (1.75 ml) was added thereto, followed by addition of ethyl chloroformate (1.88 g) at -50° C. under nitrogen stream. The resultant mixture was stirred at -30° to -50° C. for 30 minutes, and a solution of methylamine (1.44 g) in dichloromethane (5 ml) and methanol (3.7 ml) was added thereto at -50° C. Stirring was continued at -30° to -50° C. for 20 minutes. The reaction mixture was successively washed with dilute hydrochloric acid, aqueous sodium chloride solution, dilute sodium hydroxide solution and sodium chloride solution and dried over magnesium sulfate. After removal of the solvent, the residue was crystallized from ether to give (2S,4R)-1-benzyloxycarbonyl-2-methylaminocarbonyl-4-hydroxypyrrolidine.
Reaction SMILES: [N+:1]([C:4]1[CH:15]=[CH:14][C:7]2[CH2:8][CH2:9][CH2:10][CH2:11][CH:12](O)[C:6]=2[CH:5]=1)([O-:3])=[O:2].S([O-])(O)(=O)=O.[K+].O>C(OCC)(=O)C>[N+:1]([C:4]1[CH:15]=[CH:14][C:7]2[CH2:8][CH2:9][CH2:10][CH:11]=[CH:12][C:6]=2[CH:5]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc2c(c1)C(O)CCCC2
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Product: O=[N+]([O-])c1ccc2c(c1)C=CCCC2
Temperature: 160 °C
Yield: 74.5 %

Procedure:
A mixture of 3-nitro-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-ol (70.67 g) and potassium hydrogensulfate (53.00 g) was heated at 160° C. for 1 hour. After cooling, to the mixture was added a mixture of water (400 ml) and ethyl acetate (400 ml). The organic layer was separated and the aqueous layer was extracted with ethyl acetate (200 ml). The combined organic layer was washed with brine (150 ml), dried over anhydrous sodium sulfate, and evaporated in vacuo. The residue was purified by column chromatography on silica gel with a mixture of n-hexane and chloroform (1:1) as an eluent to give 2-nitro-6,7-dihydro-5H-benzocycloheptene (48.1 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[NH:9][C:10]([NH:12][C:13](=[O:15])[NH2:14])=[S:11].[I:16][CH3:17]>CO>[I-:16].[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[NH+:9]=[C:10]([N:12]([C:13](=[O:15])[NH2:14])[CH3:17])[SH:11]
Reactant: NC(=O)NC(=S)Nc1c(Cl)cccc1Cl
Reactant: CI
Solvent: CO
Product: CN(C(N)=O)C(S)=[NH+]c1c(Cl)cccc1Cl
Product: [I-]

Procedure:
26.4 g (0.1 mole) of 1-(2,6-dichlorophenyl)-3-carbamylthiourea is combined with 200 ml of methanol and 14.1 g (0.1 mole) of iodomethane and refluxed for 4 hours. This is then evaporated to dryness and 100 ml of hexane is added. The mixture is filtered to obtain 1-(2,6-dichlorophenyl)-3-carbamyl-3-methylthiouronium iodide.
Reaction SMILES: [OH-].[Na+].[Na].[CH3:4][SH:5].CS.[Na].[C:9]1([NH:15][C:16](=[O:24])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2Cl)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>O>[C:9]1([NH:15][C:16](=[O:24])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[S:5][CH3:4])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=C(Nc1ccccc1)c1ccccc1Cl
Reactant: CS
Agent: [Na+]
Agent: [Na]
Agent: [OH-]
Solvent: O
Product: CSc1ccccc1C(=O)Nc1ccccc1
Temperature: 25 °C

Procedure:
To a 500 ml four-necked flask equipped with a stirrer, a thermometer, and acondenser, 46.3 g (0.2 mol) of N-phenyl-2-chlorobenzamide obtained in Production Example 1, 100 g of toluene, and 9.3 g of an aqueous solution of 50% by weight tetra-n-butylammonium bromide are placed. Separately, 12.0 g (0.30 mol) of sodium hydroxide and 113.7 g of water are placed intoanother container under a nitrogen gas atmosphere, and 14.5 g (0.30 mol) ofmethanethiol are added to the above mixture at room temperature over about 1 hour to prepare 140.2 g of sodium salt solution of methanethiol. 140.2 g(0.3 mol) of the aqueous solution of sodium methyl mercaptan thus prepared is added to the mixture containing N-phenyl-2-chlorobenzamide described above at 80° C. while stirring, to be allowed to react with each other under reflux for 1 hour. After completion of the reaction, the reaction mixture is cooled to room temperature to precipitate white crystals, which are washed with water and then with toluene and dried, to give 46.2 g of N-phenyl-2-(methylthio)benzamide (melting point 148°to 149° C.). The yield of the product against N-phenyl-2-chlorobenzamide is 95%.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]([CH2:15][CH3:16])[CH2:5][CH2:6][O:7][C:8]1[C:9]([F:14])=[N:10][CH:11]=[CH:12][CH:13]=1.[I:17][C:18]1[CH:19]=[C:20]2[C:25](=[CH:26][CH:27]=1)[N:24]=[C:23]([C:28](OCC)=[O:29])[CH:22]=[CH:21]2.C(N(CCNC(C1C=NC2C(=CC=C(I)C=2)N=1)=O)CCOC1C(F)=NC=CC=1)C>>[CH2:15]([N:4]([CH2:3][CH2:2][NH:1][C:28]([C:23]1[CH:22]=[CH:21][C:20]2[C:25](=[CH:26][CH:27]=[C:18]([I:17])[CH:19]=2)[N:24]=1)=[O:29])[CH2:5][CH2:6][O:7][C:8]1[C:9]([F:14])=[N:10][CH:11]=[CH:12][CH:13]=1)[CH3:16]
Reactant: CCOC(=O)c1ccc2cc(I)ccc2n1
Reactant: CCN(CCN)CCOc1cccnc1F
Agent: CCN(CCNC(=O)c1cnc2cc(I)ccc2n1)CCOc1cccnc1F
Product: CCN(CCNC(=O)c1ccc2cc(I)ccc2n1)CCOc1cccnc1F
Yield: 95.2 %

Procedure:
This compound was prepared, starting from compound 5 (200 mg, 0.88 mmol) and ethyl 6-iodoquinoline-2-carboxylate (66) (203 mg, 0.62 mmol), according to the procedure developed for compound 10. Reaction time under reflux: 12 h; the purification was performed using column chromatography (Al2O3, CH2Cl2/EtOH, 98/2, v/v) to give compound 67 (302 mg, 0.59 mmol) as a brown oil. Yield 96%; Rf (Al2O3, CH2Cl2/EtOH, 98/2, v/v) 0.68; IR (CCl4) ν 1190, 1466, 1522, 1683, 2960 cm−1; 1H NMR (200 MHz, CDCl3) δ 1.13 (t, 3H, J=7.1 Hz), 2.76 (q, 2H, J=7.1 Hz), 2.87 (t, 2H, J=6.0 Hz), 3.02 (t, 2H, J=5.8 Hz), 3.62 (q, 2H, J=6.0 Hz), 4.14 (t, 2H, J=5.8 Hz), 6.95 (ddd, 1H, 5JH-F=0.7 Hz, J=4.8, 7.8 Hz), 7.21 (ddd, 1H, 4JH-F=10.0 Hz, J=1.5, 7.8 Hz), 7.65 (m, 1H), 7.66 (d, 1H, J=8.9 Hz), 7.94 (dd, 1H, J=1.9, 8.9 Hz), 8.16 (d, 1H, J=8.6 Hz), 8.26 (s, 1H), 8.29 (d, 1H, J=8.6 Hz), 8.57 (m, 1H): ESI-MS m/z 508.9 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[OH:12].Br[CH2:14][CH:15]1[CH2:17][CH2:16]1>>[Br:1][C:2]1[CH:7]=[C:6]([C:8]([F:10])([F:11])[F:9])[CH:5]=[CH:4][C:3]=1[O:12][CH2:14][CH:15]1[CH2:17][CH2:16]1
Reactant: BrCC1CC1
Reactant: Oc1ccc(C(F)(F)F)cc1Br
Product: FC(F)(F)c1ccc(OCC2CC2)c(Br)c1

Procedure:
Starting from commercially available 2-bromo-4-trifluoromethyl-phenol and bromomethyl-cyclopropane the title compound is obtained as colorless oil after distillation at 5×10−3 mbar.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[N:8]=[CH:7][C:6]([NH:9][C:10]2[C:11]3[CH2:19][NH:18][CH2:17][CH2:16][C:12]=3[N:13]=[CH:14][N:15]=2)=[CH:5][CH:4]=1.Cl[C:23]1[C:28]([S:29]([CH3:32])(=[O:31])=[O:30])=[CH:27][CH:26]=[CH:25][N:24]=1.C(N(CC)C(C)C)(C)C>>[F:21][C:2]([F:20])([F:1])[C:3]1[N:8]=[CH:7][C:6]([NH:9][C:10]2[C:11]3[CH2:19][N:18]([C:23]4[C:28]([S:29]([CH3:32])(=[O:31])=[O:30])=[CH:27][CH:26]=[CH:25][N:24]=4)[CH2:17][CH2:16][C:12]=3[N:13]=[CH:14][N:15]=2)=[CH:5][CH:4]=1
Reactant: CS(=O)(=O)c1cccnc1Cl
Reactant: FC(F)(F)c1ccc(Nc2ncnc3c2CNCC3)cn1
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)c1cccnc1N1CCc2ncnc(Nc3ccc(C(F)(F)F)nc3)c2C1

Procedure:
The title compound was prepared according to the procedure described for Compound 4 and reacting N-(6-(trifluoromethyl)pyridin-3-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-amine (140 mg, 0.47 mmol) with 2-chloro-3-(methylsulfonyl)pyridine (Ponticello, JOC, 44(17), 1979) (0.115 g, 0.06 mmol) in the presence of N,N-diisopropylethylamine (0.17 mL, 0.98 mmol) to give the desired Compound 5 as an off-white powder (55 mg, 26%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([OH:11])[C:9]=1[OH:10])[CH:5]=[O:6].C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:19][CH2:20]Br>CN(C=O)C.ClCCl>[F:1][C:2]1[C:9]2[O:10][CH2:19][CH2:20][O:11][C:8]=2[CH:7]=[C:4]([CH:5]=[O:6])[CH:3]=1
Reactant: BrCCBr
Reactant: O=Cc1cc(O)c(O)c(F)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=Cc1cc(F)c2c(c1)OCCO2
Temperature: 80 °C
Reaction time: 2.5 h
Yield: 86.7 %

Procedure:
3-fluoro-4,5-dihydroxybenzaldehyde (0.9 g; 5.7 mmol) and cesium carbonate (4.6 g; 14.2 mmol) were stirred in DMF (15 ml) at room temperature for 15 min. 1,2 Dibromoethane (638 μl; 7.4 mmol) was added and reaction mixture was stirred at 80° C. for 2.5 h and then diluted with dichloromethane (100 ml). The mixture was washed with water (2×50 ml), 10% aqueous citric acid (50 ml), brine (50 ml), dried over sodium sulfate and evaporated to dryness to yield 8-fluoro-2,3-dihydro-1,4-benzodioxine-6-carbaldehyde (0.9 g; 87% yield). 1H NMR (400 MHz, CD3OD) δ 9.74 (d, 1H), 7.25 (m, 2H), 4.37 (m, 4H).
Reaction SMILES: [O:1]=[C:2]1[CH:11]=[C:10]([CH:12]([CH3:16])[C:13]([OH:15])=[O:14])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[NH:3]1.[N+:17]([O-])([OH:19])=[O:18]>O>[N+:17]([C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[NH:3][C:2](=[O:1])[CH:11]=[C:10]2[CH:12]([CH3:16])[C:13]([OH:15])=[O:14])([O-:19])=[O:18]
Reactant: O=[N+]([O-])O
Reactant: CC(C(=O)O)c1cc(=O)[nH]c2ccccc12
Solvent: O
Product: CC(C(=O)O)c1cc(=O)[nH]c2ccc([N+](=O)[O-])cc12
Temperature: 5 °C
Reaction time: 0.67 h
Yield: 90 %

Procedure:
α-(1,2-Dihydro-2-oxo-quinol-4-yl)propionic acid (15g.) was added in portions to stirred fuming nitric acid cooled to 5° C. The rate of addition was such that the reaction temperature remained between 5° and 10° C. After the addition was complete, the mixture was stirred at ambient temperature for 40 minutes and was then poured into water (1.2 l.). The resultant solid was separated by filtration, washed with water and dried in vacuo to give α-(6-nitro-1,2-dihydro-2-oxo-quinol-4-yl)propionic acid as a white solid (90% yield), with m.p. 276°-278° C. (decomposition).
Reaction SMILES: [CH2:1]([C@@H:3]1[CH2:7][CH2:6][NH:5][C@H:4]1[C:8]([OH:10])=S)[CH3:2].C[C@@H]1CCN[C@H]1C([OH:19])=S.C(S)C.C(CCC(Cl)=S)(=O)C>>[CH2:1]([C@@H:3]1[CH2:7][CH2:6][NH:5][C@H:4]1[C:8]([OH:10])=[O:19])[CH3:2]
Reactant: CC[C@@H]1CCN[C@H]1C(O)=S
Reactant: C[C@@H]1CCN[C@H]1C(O)=S
Agent: CC(=O)CCC(=S)Cl
Solvent: CCS
Product: CC[C@@H]1CCN[C@H]1C(=O)O

Procedure:
Following the general procedure of Example 79 (a) to (d) but substituting an equivalent amount of ethyl mercaptan for the methanethiol one obtains (trans)-3-ethyl-D,L-proline.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[CH3:5][O:6][P:7]([O:10]C)[O:8][CH3:9]>>[C:1]([P:7](=[O:10])([O:8][CH3:9])[O:6][CH3:5])(=[O:3])[CH3:2]
Reactant: COP(OC)OC
Reactant: CC(=O)Cl
Product: COP(=O)(OC)C(C)=O
Temperature: 80 °C

Procedure:
Acetyl chloride (7.85 ml, 110 mmol) was cooled to 0° C. and stirred. Trimethylphosphite (11.8 ml, 100 mmol) was added drop-wise over one hour while the cooling was maintained. The mixture was then heated to 80° C. for 5 minute to remove un-reacted acetyl chloride (the flow of argon accelerates the process). The crude product was used in the next step without additional purification (theoretical yield is 15.2 g).