Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:8]2[C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][C:10]([CH2:17][OH:18])=[N:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.[CH3:26][S:27](Cl)(=[O:29])=[O:28]>ClCCl>[Cl:1][C:2]1[C:3]([N:8]2[C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][C:10]([CH2:17][O:18][S:27]([CH3:26])(=[O:29])=[O:28])=[N:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)c1cc(CO)nn1-c1ncccc1Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1cc(COS(C)(=O)=O)nn1-c1ncccc1Cl
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Under argon 2.10 g (7.85 mmol) of methyl 2-(3-chloropyridin-2-yl)-5-hydroxymethyl-2H-pyrazole-3-carboxylate are introduced in 13 ml of dichloromethane and this initial charge is cooled to 0° C. and admixed dropwise in succession with 1.64 ml (11.8 mmol) of triethylamine and 0.67 ml (8.63 mmol) of methanesulphonyl chloride. It is stirred at this temperature for 30 minutes, diluted with 50 ml of dichloromethane and washed successively with 50 ml each of saturated aqueous sodium hydrogen sulphate solution, 10 percent strength aqueous hydrochloric acid and saturated aqueous sodium chloride solution. The organic phase is dried over magnesium sulphate and then the solvent is removed on a rotary evaporator.
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:8]=[CH:7][C:6]([CH3:9])=[CH:5][C:4]=1[N:10]1[CH2:15][CH2:14][N:13]([C:16]([C@@H:18]2[C@H:23]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:22][CH2:21][NH:20][CH2:19]2)=[O:17])[CH2:12][CH2:11]1.[Cl:30][C:31]1[CH:32]=[C:33]([S:37](Cl)(=[O:39])=[O:38])[CH:34]=[CH:35][CH:36]=1.C=O>>[Cl:30][C:31]1[CH:32]=[C:33]([S:37]([N:20]2[CH2:21][CH2:22][C@@H:23]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C@@H:18]([C:16]([N:13]3[CH2:12][CH2:11][N:10]([C:4]4[CH:5]=[C:6]([CH3:9])[CH:7]=[CH:8][C:3]=4[CH3:2])[CH2:15][CH2:14]3)=[O:17])[CH2:19]2)(=[O:39])=[O:38])[CH:34]=[CH:35][CH:36]=1
Reactant: Cc1ccc(C)c(N2CCN(C(=O)[C@H]3CNCC[C@H]3c3ccccc3)CC2)c1
Reactant: O=S(=O)(Cl)c1cccc(Cl)c1
Agent: C=O
Agent: Cl
Product: Cc1ccc(C)c(N2CCN(C(=O)[C@H]3CN(S(=O)(=O)c4cccc(Cl)c4)CC[C@H]3c3ccccc3)CC2)c1

Procedure:
In analogy to example 1, step 3, from [4-(2,5-dimethyl-phenyl)-piperazin-1-yl]-((3R,4R)-4-phenyl-piperidin-3-yl)-methanone hydrochloride and 3-chlorobenzene-sulfonyl chloride was prepared [(3R,4R)-1-(3-chloro-benzenesulfonyl)-4-phenyl-piperidin-3-yl]-[4-dimethyl-phenyl)-piperazin-1-yl]-methanone as a white foam, MS: 552.2 ([M+H, 1Cl])+.
Reaction SMILES: [Cl-:1].[Al+3].[Cl-].[Cl-].S(Cl)(Cl)(=O)=O.[CH:10]1[C:23]2[NH:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[S:15][C:14]=2[CH:13]=[CH:12][C:11]=1[C:24]#[N:25]>ClCCCl>[Cl:1][C:18]1[CH:17]=[C:16]2[C:21](=[CH:20][CH:19]=1)[NH:22][C:23]1[CH:10]=[C:11]([C:24]#[N:25])[CH:12]=[CH:13][C:14]=1[S:15]2
Reactant: [Cl-]
Reactant: N#Cc1ccc2c(c1)Nc1ccccc1S2
Agent: [Al+3]
Solvent: ClCCCl
Solvent: O=S(=O)(Cl)Cl
Product: N#Cc1ccc2c(c1)Nc1ccc(Cl)cc1S2
Temperature: 25 °C
Reaction time: 48 h
Yield: 7143.1 %

Procedure:
Aluminium chloride (0.5 g) and sulphuryl chloride (39.7 cc) are added in the course of 4 hours to a solution, heated to 50° C., of 2-phenothiazinecarbonitrile (100 g) in 1,2-dichloroethane (3000 cc). The reaction mixture is brought to reflux for 2 hours, and then stirred for 48 hours at 25° C. The precipitate formed is filtered off, washed with 1,2-dichloroethane (2×200 cc) and then with ethyl ether (200 cc) and dried at 40° C. under reduced pressure (30 mm Hg; 4 kPa) to give 7-chloro-2-phenothiazinecarbonitrile (69.3 g) in the form of a yellow-green solid, m.p. 235° C.
Reaction SMILES: [CH2:1]([Li])[CH2:2][CH2:3][CH3:4].[Cu]C#N.[CH3:9][C@:10]12[CH2:26][CH2:25][C:24]3[C@@H:15]([CH2:16][CH2:17][C:18]4[C:23]=3[CH2:22][CH2:21][C:20](=[O:27])[CH:19]=4)[C@@H:14]1[CH:13]=[CH:12][C:11]2=[O:28]>CCCCCC.O1CCCC1.N>[CH2:1]([C@H:13]1[C@H:14]2[C@H:15]3[C:24]([CH2:25][CH2:26][C@:10]2([CH3:9])[C:11](=[O:28])[CH2:12]1)=[C:23]1[C:18](=[CH:19][C:20](=[O:27])[CH2:21][CH2:22]1)[CH2:17][CH2:16]3)[CH2:2][CH2:3][CH3:4]
Reactant: C[C@]12CCC3=C4CCC(=O)C=C4CC[C@H]3[C@@H]1C=CC2=O
Reactant: [Li]CCCC
Agent: N#C[Cu]
Agent: N
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCCC[C@@H]1CC(=O)[C@@]2(C)CCC3=C4CCC(=O)C=C4CC[C@H]3[C@H]12
Reaction time: 1.5 h

Procedure:
6.25 ml of a 15% solution of n-butyllithium in hexane are added to a suspension of 500 mg of copper(I) cyanide in 10 ml of absolute tetrahydrofuran drop by drop at -78° C. After addition, it is stirred for 15 minutes more at -78° C., before a solution of 1.2 g of 4,9,15-estratriene-3,17-dione in 20 ml of absolute tetrahydrofuran is added drop by drop. Then it is stirred for 90 minutes, during which the temperature of the reaction solution is allowed gradually to rise to -20° C. For finishing, it is poured in concentrated aqueous ammonia solution and extracted with ethyl acetate. After recrystallization of the crude product from ethyl acetate/diisopropyl ether, 940 mg of 15β-n-butyl-4,9-estradiene-3,17-dione with a melting point of 159° to 161° C. are obtained.
Reaction SMILES: [CH:1]1([C:4]2[O:5][C:6]3[C:12]([C:13]4[CH:18]=[C:17]([CH3:19])[C:16](=[O:20])[N:15]([CH3:21])[CH:14]=4)=[CH:11][C:10]([NH:22][S:23]([CH2:26][CH3:27])(=[O:25])=[O:24])=[CH:9][C:7]=3[CH:8]=2)[CH2:3][CH2:2]1.C(O)(C(F)(F)F)=O>[SiH](CC)(CC)CC.C(Cl)Cl>[CH:1]1([CH:4]2[CH2:8][C:7]3[CH:9]=[C:10]([NH:22][S:23]([CH2:26][CH3:27])(=[O:25])=[O:24])[CH:11]=[C:12]([C:13]4[CH:18]=[C:17]([CH3:19])[C:16](=[O:20])[N:15]([CH3:21])[CH:14]=4)[C:6]=3[O:5]2)[CH2:3][CH2:2]1
Reactant: CCS(=O)(=O)Nc1cc(-c2cc(C)c(=O)n(C)c2)c2oc(C3CC3)cc2c1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCS(=O)(=O)Nc1cc2c(c(-c3cc(C)c(=O)n(C)c3)c1)OC(C1CC1)C2
Temperature: 25 °C
Reaction time: 8 h
Yield: 9.7 %

Procedure:
To a mixture of the title compound from Example 495, Step 4, (30 mg, 0.08 mmol) in Et3SiH (1 mL) in a sealed tube was added TFA (0.2 mL) at 0° C. It was allowed to warm up to room temperature and stirred overnight. The resulting mixture was diluted with DCM (30 mL) and washed with 1 N NaOH, water and brine. The organic phase was dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was recrystallized from EtOAc to give the title compound (3 mg, 10% yield) as a white solid. 1H NMR (CDCl3, 300 MHz): δ 7.77 (s, 1H), 7.57 (s, 1H), 7.04 (d, J=3.0 Hz, 2H), 6.44 (s, 1H), 4.37-4.29 (m, 1H), 3.63 (s, 3H), 3.37-3.29 (m, 1H), 3.13-3.03 (m, 3H), 2.22 (s, 3H), 1.40 (t, J=7.5 Hz, 3H), 1.26-1.14 (m, 1H), 0.71-0.33 (m, 4H). LCMS: 389 (M+1)+.
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][CH:4]=1.C(O[C:13]([CH:15]1[CH2:20][CH2:19][N:18]([S:21]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)(=[O:23])=[O:22])[CH2:17][CH2:16]1)=[O:14])C.[Cl-].[NH4+]>O1CCCC1>[F:9][C:6]1[CH:7]=[CH:8][C:3]([C:13]([C:3]2[CH:8]=[CH:7][C:6]([F:9])=[CH:5][CH:4]=2)([CH:15]2[CH2:16][CH2:17][N:18]([S:21]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)(=[O:22])=[O:23])[CH2:19][CH2:20]2)[OH:14])=[CH:4][CH:5]=1
Reactant: CCOC(=O)C1CCN(S(=O)(=O)c2ccccc2)CC1
Reactant: Fc1ccc(Br)cc1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: C1CCOC1
Product: O=S(=O)(c1ccccc1)N1CCC(C(O)(c2ccc(F)cc2)c2ccc(F)cc2)CC1
Reaction time: 2 h

Procedure:
To a suspension of 33.78 g (1.39 mole) of magnesium trimmings in 1 liter of tetrahydrofuran (dried over molecular sieves 5A) under an atmosphere of nitrogen and cooled in an ice bath was added dropwise a solution of 243.25 g (1.39 mole) of p-bromoflurobenzene in 150 of tetrahydrofuran. The mixture was stirred for 2 hr after the addition was completed. To this mixture was added 103 g (0.346 mole) of 1-(phenylsulfonyl)-4-piperidinecarboxylic acid ethyl ester as a solid, and the solution was stirred at ambient temperature for 5 hr. The reaction mixture was poured into an icy aqueous solution of ammonium chloride. The phases was separated, and the solvent was removed in vacuo from the organic phase. The residue was partitioned between methylene chloride and dilute sodium hydroxide. The methylene chloride solution was dried over magnesium sulfate and was reduced in vacuo to ≃1 liter volume. The title compound was obtained by adding hexane and cooling, recrystallizing and the precipitate from ethyl acetate and hexane and drying the solid under high vacuum at 130° C. for 45 min at which time the product had partially melted, m.p. 142.5°-144° C.
Reaction SMILES: C(OC([N:8]([CH3:18])[C@@H:9]([CH2:13][C:14]([CH3:17])([CH3:16])C)[C:10]([OH:12])=O)=O)(C)(C)C.[F:19][C:20]([F:37])([F:36])[C:21]1[CH:22]=[C:23]([N:27]2[CH2:31][C@@H:30]3[C@@H:32]([NH2:35])[CH2:33][CH2:34][C@@H:29]3[CH2:28]2)[CH:24]=[CH:25][CH:26]=1.FC(F)(F)C1N=C(N2C[C@@H]3[C@@H](N)CC[C@@H]3C2)C=CC=1>>[CH3:18][NH:8][C@H:9]([C:10]([NH:35][C@@H:32]1[C@@H:30]2[C@@H:29]([CH2:28][N:27]([C:23]3[CH:24]=[CH:25][CH:26]=[C:21]([C:20]([F:37])([F:19])[F:36])[CH:22]=3)[CH2:31]2)[CH2:34][CH2:33]1)=[O:12])[CH2:13][CH:14]([CH3:16])[CH3:17]
Reactant: CN(C(=O)OC(C)(C)C)[C@@H](CC(C)(C)C)C(=O)O
Reactant: N[C@H]1CC[C@@H]2CN(c3cccc(C(F)(F)F)c3)C[C@@H]21
Agent: N[C@H]1CC[C@@H]2CN(c3cccc(C(F)(F)F)n3)C[C@@H]21
Product: CN[C@@H](CC(C)C)C(=O)N[C@H]1CC[C@@H]2CN(c3cccc(C(F)(F)F)c3)C[C@@H]21

Procedure:
The title compound was prepared by substituting N-(tert-butoxycarbonyl)-N-methyl-L-leucine for (S)-2-(tert-butoxycarbonyl(methyl)amino)-4,4-dimethylpentanoic acid and (3aR,4S,6aS)-2-[3-(trifluoromethyl)phenyl]octahydrocyclopenta[c]pyrrol-4-amine from Example 605 Step B for (3aR,4S,6aS)-2-(6-(trifluoromethyl)pyridin-2-yl)octahydrocyclopenta[c]pyrrol-4-amine in the procedure described in Example 587: 1H NMR (500 MHz, pyridine-d5) δ ppm 8.34 (d, J=7.4, 1H), 7.34 (t, J=7.9, 1H), 7.06 (d, J=7.6, 1H), 6.94 (s, 1H), 6.78 (dd, J=8.3, 2.2, 1H), 4.46-4.38 (m, 1H), 3.55 (dd, J=9.9, 2.8, 1H), 3.37-3.32 (m, 1H), 3.27 (dd, J=8.3, 5.8, 1H), 3.17 (dd, J=9.5, 7.9, 1H), 3.01 (dd, J=9.7, 3.3, 1H), 2.79-2.70 (m, 2H), 2.46 (s, 3H), 0.2-1.86 (br s, 1H), 2.13 (dt, J=12.5, 6.7, 1H), 2.01-1.87 (m, 2H), 1.79-1.65 (m, 2H), 1.65-1.57 (m, 1H), 1.46-1.38 (m, 1H), 0.94 (d, J=6.6, 3H), 0.88 (d, J=6.6, 3H); MS (ESI+) m/z 398 (M+H)+.
Reaction SMILES: [CH2:1]([N:3]([CH2:21][CH3:22])[C:4]([N:6]1[CH2:12][CH2:11][C:10]2[CH:13]=[CH:14][C:15]([S:17]([NH2:20])(=[O:19])=[O:18])=[CH:16][C:9]=2[CH2:8][CH2:7]1)=[O:5])[CH3:2].[CH:23]1([N:29]=[C:30]=[O:31])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1>>[CH:23]1([NH:29][C:30]([NH:20][S:17]([C:15]2[CH:14]=[CH:13][C:10]3[CH2:11][CH2:12][N:6]([C:4](=[O:5])[N:3]([CH2:1][CH3:2])[CH2:21][CH3:22])[CH2:7][CH2:8][C:9]=3[CH:16]=2)(=[O:18])=[O:19])=[O:31])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: O=C=NC1CCCCC1
Reactant: CCN(CC)C(=O)N1CCc2ccc(S(N)(=O)=O)cc2CC1
Product: CCN(CC)C(=O)N1CCc2ccc(S(=O)(=O)NC(=O)NC3CCCCC3)cc2CC1

Procedure:
In a manner analogous to that described in Example 1, from 3-diethylcarbamoyl-2,3,4,5-tetrahydro-1H-3-benzazepine-7-sulfonamide and cyclohexylisocyanate, there is obtained 1-cyclohexyl-3-[(3-diethylcarbamoyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)sulfonyl]urea, m.p. 168°-169° C. The starting material can be prepared by the reaction of 2,3,4,5-tetrahydro-1H-3-benzazepine-7-sulfonamide hydrochloride with diethylcarbamoyl chloride in a manner analogous to that described in Example 1.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[C:8]1[C:9]2[N:10]([CH:14]=[CH:15][N:16]=2)[N:11]=[CH:12][CH:13]=1.[I:17]N1C(=O)CCC1=O.C(O)(C(F)(F)F)=O>C(Cl)(Cl)Cl>[I:17][C:14]1[N:10]2[N:11]=[CH:12][CH:13]=[C:8]([C:3]3[CH:4]=[N:5][CH:6]=[CH:7][C:2]=3[CH3:1])[C:9]2=[N:16][CH:15]=1
Reactant: O=C1CCC(=O)N1I
Reactant: Cc1ccncc1-c1ccnn2ccnc12
Solvent: ClC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccncc1-c1ccnn2c(I)cnc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 8-(4-methylpyridin-3-yl)imidazo[1,2-b]pyridazine, (480 mg, 1.48 mmol) in CHCl3 (15 mL) were added N-iodo succinimide (400 mg, 1.776 mmol) and TFA (0.34 g, 2.96 mmol). The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was quenched with saturated NaHCO3 and extracted with CH2Cl2. The combined organic layer was washed with water and brine, and dried over Na2SO4. The crude product was purified by BIOTAGE® (20-40% EtOAc/CH2Cl2; 1.2 L). 1H NMR (400 MHz, CDCl3) δ ppm 8.50-8.70 (3H, m), 7.90 (1H, s), 7.22-7.39 (4H, m), 7.06 (1H, d, J=4.53 Hz), 2.32 (3H, s); LC/MS: Rt=1.13 min. LC/MS (Condition A): 336.97.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:15]([CH3:19])([CH3:18])[CH:16]=O)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br-].[CH2:21]([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]>>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([CH3:19])([CH3:18])[CH:16]=[CH:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C=O)c1cccc(OCc2ccccc2)c1
Reactant: CCCCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Product: CCCCCC=CC(C)(C)c1cccc(OCc2ccccc2)c1
Yield: 67.5 %

Procedure:
Similarly, 1-benzyloxy-3-(1,1-dimethyloct-2-enyl)benzene (13.5 g., 70%) was prepared from 15.75 g. (0.062 mol.) of 2-(3-benzyloxyphenyl)-2-methyl-propionaldehyde and 37.5 g. (0.0899 mol.) of hexyltriphenylphosphonium bromide. The product was an oil.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1/[C:11](=[CH:19]/[C:20]1[NH:21][C:22]([CH3:28])=[CH:23][C:24]=1[C:25](O)=[O:26])/[C:12](=[O:18])[NH:13]2.[CH3:29][NH:30][CH2:31][CH:32]([OH:39])[CH2:33][N:34]1[CH2:38][CH2:37][CH2:36][CH2:35]1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C>[OH:39][CH:32]([CH2:33][N:34]1[CH2:35][CH2:36][CH2:37][CH2:38]1)[CH2:31][N:30]([CH3:29])[C:25]([C:24]1[CH:23]=[C:22]([CH3:28])[NH:21][C:20]=1/[CH:19]=[C:11]1\[C:12](=[O:18])[NH:13][C:14]2[C:10]\1=[C:9]([C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([F:8])[C:2]=1[F:1])[CH:17]=[CH:16][CH:15]=2)=[O:26]
Reactant: Cc1cc(C(=O)O)c(/C=C2\C(=O)Nc3cccc(-c4cccc(F)c4F)c32)[nH]1
Reactant: CNCC(O)CN1CCCC1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: Cc1cc(C(=O)N(C)CC(O)CN2CCCC2)c(/C=C2\C(=O)Nc3cccc(-c4cccc(F)c4F)c32)[nH]1

Procedure:
2-[4-(2,3-Difluoro-phenyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-5-methyl-1H-pyrrole-3-carboxylic acid (115 mg, 0.3 mmol) was coupled with 1-methylamino-3-pyrrolidin-1-yl-propan-2-ol (3 eq.), EDC (2 eq.), HOBt (1 eq.) in DMF (1.5 mL) to give 108 mg of the titled compound as a yellow solid. MS 521.2 [M++1].
Reaction SMILES: C(N(CC)CC)C.[CH3:8][C:9]1[CH:10]=[C:11]2[N:16]([CH:17]=1)[CH:15]=[CH:14][CH:13]=[CH:12]2.[N+:18]([C:21]1[CH:29]=[CH:28][C:24]([C:25](Cl)=[O:26])=[CH:23][CH:22]=1)([O-:20])=[O:19].C(=O)([O-])O.[Na+]>ClC(Cl)C>[CH3:8][C:9]1[CH:10]=[C:11]2[N:16]([C:17]=1[C:25]([C:24]1[CH:23]=[CH:22][C:21]([N+:18]([O-:20])=[O:19])=[CH:29][CH:28]=1)=[O:26])[CH:15]=[CH:14][CH:13]=[CH:12]2
Reactant: Cc1cc2ccccn2c1
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CC(Cl)Cl
Product: Cc1cc2ccccn2c1C(=O)c1ccc([N+](=O)[O-])cc1
Yield: 74.8 %

Procedure:
4.54 ml (32.52 mmol) of triethylamine are added, at ambient temperature under an inert atmosphere, to 3.56 g (27.14 mmoles) of 2-methylindolizine in 15 ml of dichloroethane, followed, dropwise, by 5.53 g (29.85 mmol) of 4-nitrobenzoic acid chloride. The reaction medium is stirred for 18 h at ambient temperature, hydrolysed with a saturated aqueous solution of sodium hydrogen carbonate and then extracted with dichloromethane. The organic phase is washed with a saturated aqueous solution of sodium chloride, dried over sodium sulphate, and then concentrated under reduced pressure. The residue obtained is washed with diethyl ether. 5.69 g of a yellow solid are obtained.
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:11])([F:10])[C:5]([O:7]CC)=O.[C:12]1(/[CH:18]=[CH:19]/[C:20](=[O:22])[CH3:21])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[F:11][C:4]([F:3])([F:10])[C:5](=[O:7])[CH2:21][C:20](=[O:22])[CH:19]=[CH:18][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CCOC(=O)C(F)(F)F
Reactant: CC(=O)/C=C/c1ccccc1
Agent: [H-]
Agent: [Na+]
Product: O=C(C=Cc1ccccc1)CC(=O)C(F)(F)F
Temperature: 40 °C
Reaction time: 3 h

Procedure:
Sodium hydride (547 mg, 60% dispersion in mineral oil, 13.68 mmol) was added to ethyl trifluoroacetate (1.63 mL, 13.68 mmol). (Note: Carefulness is required. The reaction caught fire upon adding sodium hydride to ethyl trifluoroacetate.) Trans-4-Phenyl-3-buten-2-one (1 g, 6.84 mmol) was added, and the reaction was stirred for 3 hours at 40° C. The reaction was cooled to room temperature and quenched with water, then diluted with 1 N HCl. The mixture was extracted with ethyl acetate, dried over MgSO4, and concentrated. The reaction was assumed to be quantitative. LC-MS (C12H9F3O2 calculated 242) m/z 243 (M+H).
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]([C:13]([F:16])([F:15])[F:14])=[CH:4][C@H:5]1[C@H:7]([C:8](O)=[O:9])[C:6]1([CH3:12])[CH3:11].S(Cl)([Cl:21])=O>>[Cl:21][C:8]([C@H:7]1[C@H:5]([CH:4]=[C:3]([C:13]([F:16])([F:15])[F:14])[C:2]([F:18])([F:17])[F:1])[C:6]1([CH3:12])[CH3:11])=[O:9]
Reactant: CC1(C)[C@@H](C=C(C(F)(F)F)C(F)(F)F)[C@@H]1C(=O)O
Reactant: O=S(Cl)Cl
Product: CC1(C)[C@@H](C=C(C(F)(F)F)C(F)(F)F)[C@@H]1C(=O)Cl

Procedure:
A mixture of (+)-cis/trans-3-(3,3,3-trifluoro-2-trifluoromethyl-prop-1-en-1-yl)-2,2-dimethylcyclopropane carboxylic acid (0.4 g) and thionyl chloride (5.0 ml) was heated at the reflux temperature for a period of 2 hours, after which the excess thionyl chloride was removed by distillation under reduced pressure, leaving (+)-cis/trans-1-chlorocarbonyl-3-(3,3,3-trifluoro-2-trifluoromethyl-prop-1-en-1-yl)-2,2-dimethylcyclopropane.
Reaction SMILES: [ClH:1].O=[C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]1[C:9]([O:11]C)=O.[C:13]1([SH:19])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)(O)[O-].[Na+]>O>[ClH:1].[CH2:5]1[C:4]2[C:9](=[O:11])[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[S:19][C:3]=2[CH2:8][CH2:7][NH:6]1
Reactant: Sc1ccccc1
Reactant: COC(=O)C1C=NC=CC1=O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: O=c1c2c(sc3ccccc13)CCNC2
Temperature: 100 °C
Reaction time: 4 h
Yield: 54 %

Procedure:
2.33 g of methyl 4-oxo-3-pyridinecarboxylate hydrochloride and 1.1 ml of thiophenol were slowly added at 100° C. with stirring to 35 g of polyphosphoric acid and the mixture was stirred at 100° C. for 4 hours and was then poured into 500 ml of water. The pH of the mixture was adjusted to 8 by addition of sodium bicarbonate and the mixture was extracted with chloroform three times. The organic phase was washed with water, dried over magnesium sulfate and filtered and the filtrate was evaporated to dryness under reduced pressure. The residue was dissolved in a small amount of chloroform and the solution was acidified with a solution of hydrogen chloride in ether. Additional ether was added and the mixture was filtered. The product was crystallized from aqueous methanol and dried over P2O5 to obtain 1.365 g (54% yield) of 1,2,3,4-tetrahydro-10H-(1)-benzothiopyrano[3,2-c]pyridin-10-one hydrochloride melting at 270°-272° C. (decomp.)
Reaction SMILES: [CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@H:10]([O:12][S:13]([CH3:16])(=[O:15])=[O:14])[CH2:9][C@H:8]1[CH2:17][CH2:18]OS(C)(=O)=O)=[O:6])[CH:2]=[CH2:3].[C:24]([C:27]1[NH:28][CH:29]=[CH:30][N:31]=1)(=[O:26])[NH2:25]>>[CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@H:10]([O:12][S:13]([CH3:16])(=[O:14])=[O:15])[CH2:9][C@H:8]1[CH2:17][CH2:18][N:28]1[CH:29]=[CH:30][N:31]=[C:27]1[C:24](=[O:26])[NH2:25])=[O:6])[CH:2]=[CH2:3]
Reactant: NC(=O)c1ncc[nH]1
Reactant: C=CCOC(=O)N1C[C@H](OS(C)(=O)=O)C[C@H]1CCOS(C)(=O)=O
Product: C=CCOC(=O)N1C[C@H](OS(C)(=O)=O)C[C@H]1CCn1ccnc1C(N)=O
Yield: 68 %

Procedure:
(2R,4R)-1-Allyloxycarbonyl-4-methylsulfonyloxy-2-(2-methylsulfonyloxyethyl) pyrrolidine (21.5 g) and 2-carbamoylimidazole (7.07 g) were reacted in substantially the same manner as that of Preparation 10-3) to give (2R,4R)-1-allyloxycarbonyl-2-{2-(2-carbamoylimidazol-1-yl) ethyl}-4-methylsulfonyloxypyrrolidine (15.2 g) as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH2:4][CH2:5][N:6]=1.[C:7]1([CH:13]=[C:14]2[C:19](=[O:20])[C:18](=[CH:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:17][O:16][CH2:15]2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(Cl)(Cl)Cl>CC(C)=O>[S:3]1[CH2:4][CH2:5][N:6]=[C:2]1[NH:1][C:19]1([OH:20])[C:18](=[CH:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:17][O:16][CH2:15][C:14]1=[CH:13][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: NC1=NCCS1
Reactant: O=C1C(=Cc2ccccc2)COCC1=Cc1ccccc1
Solvent: ClC(Cl)Cl
Solvent: CC(C)=O
Product: OC1(NC2=NCCS2)C(=Cc2ccccc2)COCC1=Cc1ccccc1
Reaction time: 8 h
Yield: 45.5 %

Procedure:
A solution of 2-amino-2-thiazoline (2.2 g, 22 mmole) in 100 ml of acetone is added to a suspension of tetrahydro-3,5-bis(phenylmethylene)-4H-pyran-4-one (5.0 g, 18 mmole) in 50 ml of acetone and heated at reflux temperature for 5 hours and then kept at room temperature overnight. Chloroform (75 ml) is added to the stirred mixture and, after 10 minutes, the product is collected and washed with acetone to give 3.1 g of crude product. When the filtrate, concentrated and resuspended in acetone, is stirred with additional 2-amino-2-thiazoline (2.2 g) at room temperature overnight, another 2.5 g is isolated for a combined yield of 5.6 g (82%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:20][C@@H:19]([CH3:21])[N:18]2[C@H:10]([CH2:11][C:12]3[C:17]2=[N:16][C:15]([CH2:22][O:23][CH2:24][CH3:25])=[CH:14][CH:13]=3)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Br:26]N1C(=O)CCC1=O>>[C:1]([O:5][C:6]([N:8]1[CH2:20][C@@H:19]([CH3:21])[N:18]2[C@H:10]([CH2:11][C:12]3[C:17]2=[N:16][C:15]([CH2:22][O:23][CH2:24][CH3:25])=[C:14]([Br:26])[CH:13]=3)[CH2:9]1)=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOCc1ccc2c(n1)N1[C@H](C2)CN(C(=O)OC(C)(C)C)C[C@H]1C
Product: CCOCc1nc2c(cc1Br)C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@@H](C)N21

Procedure:
This compound was prepared in analogy to example 6, intermediate from (4R,9aR)-6-ethoxymethyl-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylic acid tert-butyl ester and N-bromosuccinimide.
Reaction SMILES: [C:1]1([C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]=[C:9]([OH:17])[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.Cl[C:26]([N:28]1[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1)=[O:27]>CN(C)C=O>[N:28]1([C:26]([O:17][C:9]2[CH:8]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]=2)=[O:27])[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1
Reactant: Oc1cc(-c2ccccc2)c2ccccc2n1
Reactant: O=C(Cl)N1CCCCC1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(Oc1cc(-c2ccccc2)c2ccccc2n1)N1CCCCC1
Yield: 13.7 %

Procedure:
The procedure is as in Example 33, but starting with 4-phenyl-2-quinolinol (2.47 g), triethylamine (2.33 cc) and 1-(chlorocarbonyl)piperidine (2.47 g) in dimethylformamide (30 cc). The residue obtained is purified by chromatography on silica gel using a cyclohexane/ethyl acetate (80:20 by volume) eluant. 4-Phenyl-2-quinolyl 1-piperidinecarboxylate (0.51 g), m.p. 85° C., is thereby isolated.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][C:10]([CH3:13])=[CH:11][CH:12]=2)[C:5]([C:14]#[N:15])=[C:4](SC)[N:3]=1.[CH:18]1([OH:24])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1.C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1[N:3]=[C:4]([O:24][CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)[C:5]([C:14]#[N:15])=[C:6]([C:8]2[O:9][C:10]([CH3:13])=[CH:11][CH:12]=2)[N:7]=1
Reactant: CSc1nc(N)nc(-c2ccc(C)o2)c1C#N
Reactant: OC1CCCCC1
Solvent: COCCOC
Solvent: C1CCC2=NCCCN2CC1
Product: Cc1ccc(-c2nc(N)nc(OC3CCCCC3)c2C#N)o1

Procedure:
From 2-amino-4-(5-methyl-furan-2-yl)-6-methylsulfanyl-pyrimidine-5-carbonitrile, cyclohexanol and DBU in DME. ES-MS m/e (%): 299 (M+H+, 50), 217 (M+H—C6H10+, 100).