Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7](=[O:23])[NH:8][C:9]2[CH:14]=[CH:13][N:12]3[N:15]=[C:16]([N:18]4[CH2:22][CH2:21][CH2:20][CH2:19]4)[N:17]=[C:11]3[CH:10]=2)=[C:5]([C:24](O)=[O:25])[CH:4]=[N:3]1.[NH:27]1[CH2:30][CH2:29][CH2:28]1.CCCP(=O)=O.C(N(CC)C(C)C)(C)C>O1CCCC1>[N:18]1([C:16]2[N:17]=[C:11]3[CH:10]=[C:9]([NH:8][C:7]([C:6]4[N:2]([CH3:1])[N:3]=[CH:4][C:5]=4[C:24]([N:27]4[CH2:30][CH2:29][CH2:28]4)=[O:25])=[O:23])[CH:14]=[CH:13][N:12]3[N:15]=2)[CH2:19][CH2:20][CH2:21][CH2:22]1
Reactant: Cn1ncc(C(=O)O)c1C(=O)Nc1ccn2nc(N3CCCC3)nc2c1
Reactant: C1CNC1
Agent: CCCP(=O)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: Cn1ncc(C(=O)N2CCC2)c1C(=O)Nc1ccn2nc(N3CCCC3)nc2c1
Reaction time: 18 h
Yield: 81.7 %

Procedure:
A mixture of 1-methyl-5-(2-(pyrrolidin-1-yl)-[1,2,4]triazolo[1,5-a]pyridin-7-ylcarbamoyl)-1H-pyrazole-4-carboxylic acid (150 mg, 422 μmol), azetidine (85.4 μl, 1.27 mmol), propylphosphonic anhydride (50% in ethyl acetate, 622 μl, 1.06 mmol) and N,N-diisopropylethylamine (287 μl, 1.69 mmol) in tetrahydrofuran (6 ml) was stirred for 18 hours at 70°. The solvent was evaporated, the residue was triturated with sodium hydrogencarbonate solution. The precipitated solid was filtered off, washed with water and dried affording 4-(azetidine-1-carbonyl)-2-methyl-2H-pyrazole-3-carboxylic acid (2-pyrrolidin-1-yl-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-amide (136 mg, 81.7%) as a light brown solid. mp: >250° C., MS: m/z=395.4 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH2:11][C:12]2[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=2[F:19])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[C:20]1([CH2:26][CH2:27]O)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(C=P(CCCC)(CCCC)CCCC)#N>C1(C)C=CC=CC=1.CCCCCC>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH:11]([C:12]2[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=2[F:19])[CH2:27][CH2:26][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=S(=O)(Cc1cc(F)ccc1F)c1ccc(Cl)cc1
Reactant: OCCc1ccccc1
Agent: CCCCP(=CC#N)(CCCC)CCCC
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: O=S(=O)(c1ccc(Cl)cc1)C(CCc1ccccc1)c1cc(F)ccc1F
Yield: 74.5 %

Procedure:
Under an argon atmosphere, the 2-[(4-chlorophenyl)sulfonylmethyl]-1,4-difluorobenzene (100 mg, 0.330 mmol) obtained in Example 5, and 2-phenylethyl alcohol (79.2 μl, 0.661 mmol) were dissolved in toluene (3 ml), followed by the addition of cyanomethylenetri-n-butylphosphorane (159 μl, 0.661 mmol). The resulting mixture was heated under reflux for 13 hours under an argon atmosphere. The reaction mixture was then concentrated. The residue thus obtained was subjected to flash chromatography on a silica gel column and the fraction obtained from the hexane:ethyl acetate=93:7 eluate was concentrated. The solid thus obtained was washed with hexane, whereby the title compound (100 mg, 0.246 mmol, 74%) was obtained as a white powder.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH2:12][CH2:13][CH3:14])[C:10](=[O:15])[C:9]([F:17])([F:16])[CH2:8][N:7]([CH:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)[C:6]=2[N:23]=1.[NH2:24][C:25]1[CH:33]=[CH:32][C:28]([C:29]([OH:31])=[O:30])=[CH:27][CH:26]=1.Cl>C(O)C>[CH:18]1([N:7]2[CH2:8][C:9]([F:17])([F:16])[C:10](=[O:15])[N:11]([CH2:12][CH2:13][CH3:14])[C:5]3[CH:4]=[N:3][C:2]([NH:24][C:25]4[CH:33]=[CH:32][C:28]([C:29]([OH:31])=[O:30])=[CH:27][CH:26]=4)=[N:23][C:6]2=3)[CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: Nc1ccc(C(=O)O)cc1
Reactant: CCCN1C(=O)C(F)(F)CN(C2CCCC2)c2nc(Cl)ncc21
Agent: Cl
Solvent: CCO
Product: CCCN1C(=O)C(F)(F)CN(C2CCCC2)c2nc(Nc3ccc(C(=O)O)cc3)ncc21
Yield: 81.3 %

Procedure:
A mixture of 0.20 g (0.58 mmole) of 2-chloro-9-cyclopentyl-7,7-difluoro-5-propyl-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VII-144) and 0.12 g (0.87 mmole) of 4-aminobenzoic acid in a 1:4 mixture of 10 mL of ethanol and 1M hydrochloric acid was heated at 100 degrees for 18 hours. After cooling, the precipitate was collected by filtration, washed with water and dried to give 0.21 g of 4-(9-cyclopentyl-7,7-difluoro-6-oxo-5-propyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-benzoic acid (I-144).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8](=[O:10])[CH3:9])[CH:5]=[CH:6][CH:7]=1.F[C:12]1[CH:17]=[CH:16][C:15]([C:18](=[O:20])[CH3:19])=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[C:18]([C:15]1[CH:16]=[CH:17][C:12]([O:1][C:2]2[CH:3]=[C:4]([C:8](=[O:10])[CH3:9])[CH:5]=[CH:6][CH:7]=2)=[CH:13][CH:14]=1)(=[O:20])[CH3:19]
Reactant: CC(=O)c1ccc(F)cc1
Reactant: CC(=O)c1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CC(=O)c1ccc(Oc2cccc(C(C)=O)c2)cc1
Temperature: 140 °C
Reaction time: 16 h

Procedure:
A mixture of 1-(3-hydroxyphenyl)ethanone (8 g, 58.7 mmol), 1-(4-fluorophenyl)ethanone (8.1 g, 58.7 mmol) and anhydrous potassium carbonate (16.2 g, 117.5 mmol) in DMSO (150 mL) was stirred for 16 hours at 140° C. The mixture was partitioned between ethyl acetate and water. The aqueous layer was acidified with 1M HCl until pH=6-7 and extracted with ethyl acetate. The combined organics were washed with brine, dried (MgSO4), filtered, and concentrated under reduced pressure. The crude product was chromatographed on silica gel (ethyl actetate/heptane: 1/1) resulting in 1-(3-(4-acetylphenoxy)phenyl)ethanone (11 g, 74%) as a white solid.
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][C:11]1[CH:12]=[CH:13][C:14]2[CH:25]=[CH:24][C:18]3=[N:19][CH:20]=[C:21](Cl)[CH:22]=[C:17]3[C:16](=[O:26])[C:15]=2[CH:27]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH3:28][N:29]1[CH:33]=[C:32](B2OC(C)(C)C(C)(C)O2)[CH:31]=[N:30]1.C(=O)([O-])[O-].[Na+].[Na+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Si:1]([O:8][CH2:9][CH2:10][C:11]1[CH:12]=[CH:13][C:14]2[CH:25]=[CH:24][C:18]3=[N:19][CH:20]=[C:21]([C:32]4[CH:31]=[N:30][N:29]([CH3:28])[CH:33]=4)[CH:22]=[C:17]3[C:16](=[O:26])[C:15]=2[CH:27]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: CC(C)(C)[Si](C)(C)OCCc1ccc2ccc3ncc(Cl)cc3c(=O)c2c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: Cn1cc(-c2cnc3ccc4ccc(CCO[Si](C)(C)C(C)(C)C)cc4c(=O)c3c2)cn1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
A test tube fitted with a teflon septum was charged with 7-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-3-chloro-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one (9 mg, 0.023 mmol), PdCl2(PPh3)2 (2 mg, 0.002 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (14 mg, 0.068 mmol), and sodium carbonate (7 mg, 0.068 mmol). The tube was evacuated and backfilled with argon three times. Fully degassed dioxane (0.5 mL) was added and the mixture was stirred at 100° C. overnight. The solution was diluted with ethyl acetate, washed with water and brine, dried over magnesium sulfate, concentrated in vacuo, and purified via flash chromatography (silica, 20-100% ethyl acetate/hexanes) to afford the title compound. LRMS (APCI) calc'd for (C26H32N3O2Si) [M+H]+, 446.2; found 446.2.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](/[C:8](/[CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])=[CH:9]/[CH:10]=O)[CH:5]=[CH:6][CH:7]=1.[C:17]([CH:21]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:19][CH3:20])=[O:18]>ClCCl>[CH3:20][O:19][C:17](=[O:18])/[CH:21]=[CH:10]/[CH:9]=[C:8](/[C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=1)\[CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCCCC/C(=C\C=O)c1cccc(F)c1
Solvent: ClCCl
Product: CCCCC/C(=C\C=C\C(=O)OC)c1cccc(F)c1

Procedure:
As described in Example 99, (E)-3-(3-fluorophenyl)-2-octenal (5.43 g was treated with (carbomethoxymethylene)triphenylphosphorane (9 g) in dichloromethane (50 mL) for 4 days at room temperature. The ester was isolated in the usual manner and purified by HPLC (ether-hexane; 1:9) to provide 6.04 g of (E,E)-5-(3-fluorophenyl)-2,4-decadienoic acid methyl ester as an oil.
Reaction SMILES: [CH3:1][N:2]1[CH:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:9]2[C:4](=[C:5]([NH:18][C:19](=[O:23])[CH:20]=NO)[CH:6]=[CH:7][CH:8]=2)[CH2:3]1.[OH:24]S(O)(=O)=O.[OH-].[Na+]>>[CH3:1][N:2]1[CH2:11][CH:10]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:9]2=[CH:8][CH:7]=[C:6]3[C:5]([NH:18][C:19](=[O:23])[C:20]3=[O:24])=[C:4]2[CH2:3]1
Reactant: CN1C=C(c2ccccc2)c2cccc(NC(=O)C=NO)c2C1
Reactant: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: CN1Cc2c(ccc3c2NC(=O)C3=O)C(c2ccccc2)C1
Temperature: 45 °C

Procedure:
17.5 g (0.0566 mol) of N-methyl-4-phenyl-8-(hydroxyiminoacetylamino)isoquinoline were added in small portions to 43.75 ml of concentrated H2SO4 at 45° C. and the mixture was warmed at 45° C. for 75 minutes. It was cooled to room temperature and poured onto 450 g of ice. A pH of 6.8 was then established with 2N NaOH. The precipitate which had separated out was filtered off with suction and washed with water. After drying, 15.3 g (92.5% of theory) of orange-colored crude product are obtained. (Melting point of the pure product=about 188° C., decomposition).
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[C:6]([Cl:9])[N:5]=[C:4]([C:10]([O:12][CH3:13])=[O:11])[CH:3]=1.[Br:14]N1C(C)(C)C(=O)N(Br)C1=O.OS([O-])=O.[Na+].CCOC(C)=O>ClCCCl>[NH2:1][C:2]1[C:7]([F:8])=[C:6]([Cl:9])[N:5]=[C:4]([C:10]([O:12][CH3:13])=[O:11])[C:3]=1[Br:14]
Reactant: CC1(C)C(=O)N(Br)C(=O)N1Br
Reactant: COC(=O)c1cc(N)c(F)c(Cl)n1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCCl
Product: COC(=O)c1nc(Cl)c(F)c(N)c1Br
Temperature: 83 °C
Yield: 60.5 %

Procedure:
Methyl 4-amino-6-chloro-5-fluoropicolinate (1.0 g, 4.9 mmol) was combined with 1,3-dibromo-5,5-dimethylhydantoin (1.7 g, 5.9 mmol) in 1,2-dichloroethane (15 mL) and heated at reflux (83° C.) for 4 h. The cooled mixture was stirred with 10% NaHSO3 solution and EtOAc (30 mL). The organic phase was separated, washed with water (2×20 mL), brine (10 mL), dried (Na2SO4) and concentrated. The residue was purified by silica gel chromatography (5-50% EtOAc-hexane) to give an orange solid (840 mg, 61%): mp 138-139° C.; EIMS m/z 282, 284; 1H NMR (400 MHz, CDCl3) δ 5.09 (s, 2H, NH2), 3.97 (s, 3H, Me); 19F NMR (376 MHz, CDCl3) δ −135.55 (s).
Reaction SMILES: [Cl:1][C:2]1[O:6][N:5]=[C:4]([C:7]([OH:9])=O)[CH:3]=1.O=S(Cl)[Cl:12]>C(Cl)(Cl)Cl>[Cl:1][C:2]1[O:6][N:5]=[C:4]([C:7]([Cl:12])=[O:9])[CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1cc(Cl)on1
Solvent: ClC(Cl)Cl
Product: O=C(Cl)c1cc(Cl)on1

Procedure:
To solution of 5-chloroisoxazole-3-carboxylic acid (Example 22, 0.253 g, 1.71 mmol, 2.0 equiv) in CHCl3 (21 mL) was added SOCl2 (9 mL). The reaction mixture was heated to reflux for 26 h. The volatiles were removed under reduced pressure to give crude 5-chloroisoxazole-3-carbonyl chloride.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([CH3:11])[CH:3]=1.[S:12](=[O:16])(=[O:15])([OH:14])N>>[NH2:1][C:2]1[C:7]([S:12]([OH:16])(=[O:15])=[O:14])=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([CH3:11])[CH:3]=1
Reactant: Cc1cc(N)ccc1[N+](=O)[O-]
Reactant: NS(=O)(=O)O
Product: Cc1cc(N)c(S(=O)(=O)O)cc1[N+](=O)[O-]

Procedure:
1 mol of 1-amino-3-methyl-4-nitrobenzene, 1,000 ml of one of the solvents indicated below, 198 g of sulphamic acid and the % by volume of catalyst indicated below are reacted analogously to Example 2. The yields of 1-amino-3-methyl-4-nitrobenzene-6-sulphonic acid obtained, and the reaction temperatures are indicated in the table which follows:
Reaction SMILES: [C:1]1(/[C:7](/[C:17]2[CH:22]=[CH:21][C:20]([CH:23]=[CH:24][C:25](O)=[O:26])=[CH:19][CH:18]=2)=[C:8](/[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)\[CH2:9][CH3:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:28]1([CH3:38])[CH:33]=[CH:32][CH:31]=[C:30]([S:34]([NH2:37])(=[O:36])=[O:35])[CH:29]=1>>[C:1]1([C:7]([C:17]2[CH:22]=[CH:21][C:20]([CH:23]=[CH:24][C:25]([NH:37][S:34]([C:30]3[CH:31]=[CH:32][CH:33]=[C:28]([CH3:38])[CH:29]=3)(=[O:35])=[O:36])=[O:26])=[CH:19][CH:18]=2)=[C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:9][CH3:10])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC/C(=C(\c1ccccc1)c1ccc(C=CC(=O)O)cc1)c1ccccc1
Reactant: Cc1cccc(S(N)(=O)=O)c1
Product: CCC(=C(c1ccccc1)c1ccc(C=CC(=O)NS(=O)(=O)c2cccc(C)c2)cc1)c1ccccc1

Procedure:
Prepared by coupling 1a and m-toluenesulfonamide (Synlett, 1997, 375) in accordance with Procedure 1, Method B described hereinabove. Yield (24%); 1H NMR (CDCl3) δ 7.86 (m, 2H), 7.50 (d, J=15.7 Hz, 1H), 7.42-7.07 (m, 14H), 6.86 (d, J=8.4 Hz, 2H), 6.27 (d, J=15.7 Hz, 1H), 2.47 (q, J=7.3 Hz, 2H), 2.41 (s, 3H), 0.93 (t, J=7.3 Hz, 3H); APcI m/z: 508 (M+H+).
Reaction SMILES: [NH:1]([C@H:3]1[C@@H:7]([CH3:8])[CH2:6][N:5]([O:9]CC2C=CC=CC=2)[C:4]1=[O:17])N.C(O)(=O)C>C(O)C.[Pd]>[NH2:1][C@H:3]1[C@@H:7]([CH3:8])[CH2:6][N:5]([OH:9])[C:4]1=[O:17]
Reactant: C[C@H]1CN(OCc2ccccc2)C(=O)[C@H]1NN
Agent: [Pd]
Solvent: CCO
Solvent: CC(=O)O
Product: C[C@H]1CN(O)C(=O)[C@H]1N
Yield: 24.6 %

Procedure:
The hydrazine from step C (69 mg) was dissolved in ethanol (20 ml) and glacial acetic acid (5 ml) and the solution was hydrogenated at 50 psi for 2 h in the presence of palladium black (50 mg). The solution was filtered and further hydrogenated in the presence of platinum oxide (50 mg) at 50 psi for 1.5 h. The solution was filtered and the solvent evaporated to dryness. The residue was dissolved in water (10 ml) and applied to a column containing Dowex 50W-X8 (100-200 mesh, 2×2cm, H+ form). After washing the resin with water (3×15 ml) the product was eluted with dilute aqueous ammonia solution. The fractions containing the product were freeze dried to give cis-3-amino-1-hydroxy-4-methylpyrrolidin-2-one (9.4 mg). 1H NMR (250 MHz, D2O) δ3.91 (1H; d, J=8.09 Hz; CO--CH--N), 3.78 (1 H; dd, Jgem =10.0 Hz, J=7.OO Hz; CHHD AHBN), 3.23 (1H; dd, Jgem =10.1 Hz, J=3.0 Hz; CHAHBN ), 2.79-2.69 (1H; m; CHCH3), 1.10 (3H; d, J=7.22 Hz, CH3). Irradiation of the signal at 2.79ppm gave an NOE to the signals at 3.91 and 3.78, confirming the cis geometry. (m/e: theory, 130.0742; found, 130.0749).
Reaction SMILES: Br[C:2]1[N:6]2[CH2:7][C:8]3([C:15]4[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=4)[NH:14][CH2:13][CH2:12][N:9]3[C:10](=[O:11])[C:5]2=[CH:4][CH:3]=1.[CH3:23][N:24](C=O)C>[C-]#N.[Zn+2].[C-]#N>[CH3:22][O:21][C:18]1[CH:19]=[CH:20][C:15]([C:8]23[NH:14][CH2:13][CH2:12][N:9]2[C:10](=[O:11])[C:5]2[N:6]([C:2]([C:23]#[N:24])=[CH:3][CH:4]=2)[CH2:7]3)=[CH:16][CH:17]=1
Reactant: CN(C)C=O
Reactant: COc1ccc(C23Cn4c(Br)ccc4C(=O)N2CCN3)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: COc1ccc(C23Cn4c(C#N)ccc4C(=O)N2CCN3)cc1
Temperature: 160 °C
Yield: 71 %

Procedure:
8-bromo-10a-(4-methoxyphenyl)-2,3,10,10a-tetrahydro-1H,5H-imidazo[1,2-a]pyrrolo[1,2-d]pyrazin-5-one (50 mg, 0.14 mmol), zinc cyanide (24 mg, 0.20 mmol) and palladium(0) tetrakistriphenylphosphine (32 mg, 0.03 mmol) were suspended in dry DMF (2.5 mL) in a microwave vial flushed with argon. The mixture was heated in the microwave at 160° C. for 20 minutes. Water was added and the mixture extracted with CH2Cl2. The organic layers were dried (MgSO4), filtrated and concentrated in vacuo. The resulting residue was purified by flash chromatography (Biotage SP4 12 g cartridge, gradient 0-10% MeOH in CH2Cl2) to give 10a-(4-methoxyphenyl)-5-oxo-2,3,10,10a-tetrahydro-1H,5H-imidazo[1,2-a]pyrrolo[1,2-d]pyrazine-8-carbonitrile as a brown solid (45 mg, yield 71%) ESI-MI m/z [M+H]+ 309.1.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[CH:4](Cl)Cl.[OH2:11]>[Cl-].[Zn+2].[Cl-]>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[CH:4]=[O:11]
Reactant: Clc1ccccc1C(Cl)Cl
Reactant: O
Agent: [Cl-]
Agent: [Zn+2]
Product: O=Cc1ccccc1Cl
Temperature: 120 °C
Reaction time: 0.5 h
Yield: 96.8 %

Procedure:
195.3 g (1.0 mol) of 2-chlorobenza1 chloride are initially charged at 120° C. At this temperature 20 ml (21.8 g, 1.09 mol of water) of a 10% strength aqueous zinc chloride solution are metered in over a period of 5 hours. The mixture is stirred for a further 30 minutes at 120° C. After cooling to room temperature the reaction mixture is extracted with 1×10 ml and 2×5 ml of water. The organic phase is subsequently free of chloride and is worked up by distillation. 136.0 g (97% of theoretical) of 2-chlorobenzaldehyde (b.p.: 90° C./16 torr) with a purity of >99.9% are obtained. The combined aqueous phases (20 ml, 22.0 g) are used in Example 2 as catalyst solution.
Reaction SMILES: C([O:9][C@H:10]1[C@@H:14]([O:15]C(=O)C2C=CC=CC=2)[C@H:13]([CH2:24][O:25]C(=O)C2C=CC=CC=2)[O:12][C@@H:11]1[N:34]1[CH:42]=[N:41][C:40]2[C:35]1=[N:36][CH:37]=[N:38][C:39]=2Cl)(=O)C1C=CC=CC=1.SC([OH:47])C.C[O-].[Na+].C(O)(=O)C>CO>[C@H:11]1([N:34]2[CH:42]=[N:41][C:40]3[C:39](=[O:47])[NH:38][CH:37]=[N:36][C:35]2=3)[O:12][C@@H:13]([CH2:24][OH:25])[C@H:14]([OH:15])[C@@H:10]1[OH:9]
Reactant: CC(O)S
Reactant: O=C(OC[C@@H]1O[C@H](n2cnc3c(Cl)ncnc32)[C@@H](OC(=O)c2ccccc2)[C@H]1OC(=O)c1ccccc1)c1ccccc1
Agent: C[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: O=c1[nH]cnc2c1ncn2[C@H]1O[C@@H](CO)[C@H](O)[C@@H]1O
Yield: 1359.3 %

Procedure:
A mixture of 9 (1.05 g, 1.70 mmol), mercaptoethanol (0.48 ml, 6.9 mmol), and NaOMe in MeOH (100 ml) was refluxed for four hours. The reaction mixture was cooled, neutralized with glacial acetic acid and evaporated to dryness. The solid obtained was washed with CHCl3 and the residue was crystallized from EtOH to give pure 11 (6.198 g, 47%) as white crystals: m.p. 212°-213° C. (dec).
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[NH:7][C:6]1=[O:14].C(N(CC)CC)C.[CH3:22][S:23](Cl)(=[O:25])=[O:24]>C1COCC1>[O:14]=[C:6]1[N:5]([CH2:4][CH2:3][NH:2][S:23]([CH3:22])(=[O:25])=[O:24])[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[NH:7]1
Reactant: CS(=O)(=O)Cl
Reactant: NCCn1c(=O)[nH]c2ccccc21
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CS(=O)(=O)NCCn1c(=O)[nH]c2ccccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 15.1 %

Procedure:
To a solution of 1-(2-aminoethyl)-1,3-dihydro-2H-benzimidazol-2-one hydrochloride (2.8 g, 13 mmoles) in THF (30 ml) and triethyl amine (5.5 ml, 39 mmoles) was added methanesulfonyl chloride (1.12 ml, 14 mmoles) and the reaction mixture was stirred for 2 hours at room temperature. The organic solvent was evaporated and the residue was partitioned into water and ethyl acetate. The organic layer was washed with saturated aqueous Na2CO3 solution and taken to dryness. The crude residue was purified by flash chromatography (CH2Cl2-methanol 96-4) to give 0.5 g of the title compound as a white solid. M.p. 162-170° C.
Reaction SMILES: F[C:2](F)(F)C(O)=O.C([Zn]CC)C.ICI.[I:16][C:17](=[CH2:37])[CH2:18][C@@H:19]([CH2:28][O:29][Si:30]([CH3:36])([CH3:35])[C:31]([CH3:34])([CH3:33])[CH3:32])[O:20][Si:21]([CH3:27])([CH3:26])[C:22]([CH3:25])([CH3:24])[CH3:23]>ClCCCl>[I:16][C:17]1([CH2:18][C@@H:19]([CH2:28][O:29][Si:30]([CH3:36])([CH3:35])[C:31]([CH3:34])([CH3:33])[CH3:32])[O:20][Si:21]([CH3:27])([CH3:26])[C:22]([CH3:25])([CH3:24])[CH3:23])[CH2:2][CH2:37]1
Reactant: C=C(I)C[C@@H](CO[Si](C)(C)C(C)(C)C)O[Si](C)(C)C(C)(C)C
Reactant: O=C(O)C(F)(F)F
Agent: CC[Zn]CC
Solvent: ICI
Solvent: ClCCCl
Product: CC(C)(C)[Si](C)(C)OC[C@H](CC1(I)CC1)O[Si](C)(C)C(C)(C)C
Reaction time: 0.58 h

Procedure:
Trifluoroacetic acid (8 eq) is added to a solution of diethyl zinc (16 eq) in DCE at 0° C. and stirred for 35 mins. Diiodomethane (8 eq) is added at 0° C., and the mixture stirred for an additional 20 min. A solution of (S)-5-(2-iodoallyl)-2,2,3,3,8,8,9,9-octamethyl-4,7-dioxa-3,8-disiladecane (1 eq) in DCE is added and the reaction stirred at room temperature overnight. The reaction is quenched by addition of a mixture of methanol and brine. After stirring for an additional hour, the mixture is concentrated under reduced pressure. The crude material is extracted with aqueous NH4Cl/CHCl3 and the organic layer washed with brine, dried (MgSO4) and concentrated under reduced pressure. The crude material is triturated in hexane and the solution filtered and evaporated to afford (S)-5-((1-iodocyclopropyl)methyl)-2,2,3,3,8,8,9,9-octamethyl-4,7-dioxa-3,8-disiladecane.
Reaction SMILES: [CH2:1]([C@:3]1([OH:9])[CH2:7][CH2:6][NH:5][C@H:4]1[CH3:8])[CH3:2].F[C:11]1[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[C:13]([O:19][CH3:20])[CH:12]=1.C(=O)([O-])[O-].[Li+].[Li+]>>[CH2:1]([C@:3]1([OH:9])[CH2:7][CH2:6][N:5]([C:11]2[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[C:13]([O:19][CH3:20])[CH:12]=2)[C@H:4]1[CH3:8])[CH3:2]
Reactant: COc1cc(F)ccc1C#N
Reactant: CC[C@]1(O)CCN[C@H]1C
Agent: O=C([O-])[O-]
Agent: [Li+]
Product: CC[C@]1(O)CCN(c2ccc(C#N)c(OC)c2)[C@H]1C

Procedure:
By an operation in the same manner as in Example 1 and using (2S,3S)-3-ethyl-2-methylpyrrolidin-3-ol 0.5 oxalate (257 mg), 4-fluoro-2-methoxybenzonitrile (447 mg) and lithium carbonate (218 mg), the title compound was obtained as colorless oil (yield: 305 mg, yield: 79%).
Reaction SMILES: COC(Cl)=O.[C:6]1([CH2:12][CH:13]([NH:20][C:21]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:22])[CH2:14][O:15][CH2:16][C:17](O)=[O:18])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C([N:33](CC)CC)C.N>ClCCl>[C:25]1([CH2:24][O:23][C:21](=[O:22])[NH:20][CH:13]([CH2:14][O:15][CH2:16][C:17]([NH2:33])=[O:18])[CH2:12][C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: O=C(O)COCC(Cc1ccccc1)NC(=O)OCc1ccccc1
Reactant: CCN(CC)CC
Agent: COC(=O)Cl
Agent: N
Solvent: ClCCl
Product: NC(=O)COCC(Cc1ccccc1)NC(=O)OCc1ccccc1
Temperature: -5 °C
Reaction time: 0.5 h

Procedure:
Methylchloroformate, 0.89 g (0.0094 mol) is added dropwise with stirring to a solution of 2.75 g (0.008 mol) of (±)-[3-phenyl-2-[[(phenylmethoxy)carbonyl]amino]propoxy]acetic acid and 0.96 g (0.0095 mol) of triethylamine in 100 ml of dichloromethane at -5°-10° C. The mixture is stirred for 30 minutes at -5° C., allowed to reach 0° C. and saturated with ammonia for 5 minutes. The mixture is allowed to reach room temperature and stirred for one hour, the solvent is evaporated in vacuo, the residue dissolved in 200 ml of dichloromethane, washed with a saturated aqueous solution of sodium chloride, 2×200 ml, the dichloromethane layer separated, dried over sodium sulfate, and evaporated in vacuo. The residue is purified by chromatography using silica gel and eluting with dichloromethane-methanol (95:5) to give (±)-phenylmethyl-[1-[(2-amino-2-oxoethoxy)methyl]-2-phenylethyl]carbamate, 2.5 g; mp 135°-137°.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.[Si:10](Cl)([CH3:13])([CH3:12])[CH3:11].[Li]CCCC.O>C1COCC1>[CH3:9][O:8][C:5]1[CH:6]=[CH:7][C:2]([Si:10]([CH3:13])([CH3:12])[CH3:11])=[CH:3][CH:4]=1
Reactant: C[Si](C)(C)Cl
Reactant: COc1ccc(Br)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc([Si](C)(C)C)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.8 %

Procedure:
4-Bromoanisole (9.35 g, 50.0 mmol, 1.0 eq) was dissolved in anhydrous THF (200 mL). Me3SiCl (12.7 mL, 100.0 mmol, 2.0 eq) was added at 0° C. followed by n-BuLi (2.5 M in hexanes, 40 mL, 100.0 mmol, 2.0 eq). The reaction mixture was stirred at room temperature for 1 h. Water (150 mL) was then added, the organic layer was separated and the aqueous layer was extracted with Et2O (150 mL×2). The combined organic extracts were dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give (4-methoxyphenyl)trimethylsilane as a light yellow oil (8.1 g, 90% yield). 1H NMR (300 MHz, CDCl3) δ: 7.48 (d, J=11.2 Hz, 2H), 6.95 (d, J=11.2 Hz, 2H), 3.84 (s, 3H), 0.27 (s, 9H).
Reaction SMILES: CS([Cl:5])(=O)=O.C(N1CCNCC1)=O.C([N:16]1[CH2:21][CH2:20][N:19]([S:22]([CH3:25])(=[O:24])=[O:23])[CH2:18][CH2:17]1)=O.Cl>C(N(CC)CC)C.C(Cl)Cl>[ClH:5].[CH3:25][S:22]([N:19]1[CH2:20][CH2:21][NH:16][CH2:17][CH2:18]1)(=[O:24])=[O:23]
Reactant: CS(=O)(=O)N1CCN(C=O)CC1
Reactant: CS(=O)(=O)Cl
Agent: Cl
Agent: O=CN1CCNCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)N1CCNCC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Methanesulfonyl chloride (3.65 ml) was added to a methylene chloride (50 ml) solution containing N-formylpiperazine (5.08 g) and triethylamine (6.85 ml) under ice-cooling, and the mixture was stirred at room temperature for 18 hours to undergo reaction, thereby obtaining 1-formyl-4-methanesulfonylpiperazine. This compound was acid-treated with hydrochloric acid to obtain 1-methanesulfonylpiperazine.hydrochloride. Also, 1-(phenylsulfonyl)piperazine.hydrochloride was obtained in the same manner as mentioned above by using the corresponding starting material.