Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:30])([F:29])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[C:25]([Br:26])=[CH:24][CH:23]=[C:22](Cl)[N:21]=3)[C@H:14]2[CH3:28])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.Cl.[F:32][CH:33]1[CH2:36][NH:35][CH2:34]1.C(=O)(O)[O-].[Na+]>CS(C)=O>[F:1][C:2]([F:30])([F:29])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[C:25]([Br:26])=[CH:24][CH:23]=[C:22]([N:35]4[CH2:36][CH:33]([F:32])[CH2:34]4)[N:21]=3)[C@H:14]2[CH3:28])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: C[C@H]1[C@@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)OC(=O)N1Cc1nc(Cl)ccc1Br
Reactant: FC1CNC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CS(C)=O
Product: C[C@H]1[C@@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)OC(=O)N1Cc1nc(N2CC(F)C2)ccc1Br
Temperature: 150 °C
Reaction time: 8 h

Procedure:
To a solution of (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[(3-bromo-6-chloropyridin-2-yl)methyl]-4-methyl-1,3-oxazolidin-2-one (INTERMEDIATE 24, 2.0 g, 3.86 mmol) in DMSO (25 mL), under nitrogen, were added 3-fluoroazetidine hydrochloride (2.16 g, 19.3 mmol) and sodium bicarbonate (1.95 g, 23.2 mmol). The resulting mixture was stirred at 150° C. overnight. The reaction mixture was quenched with water, then extracted 3 times with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate in hexanes to afford the titled compound. 1H NMR (500 MHz, CDCl3): δ 7.92 (s, 1H); 7.81 (s, 2H); 7.60 (d, J=8.5 Hz, 1H); 6.20 (d, J=8.6 Hz, 1H); 5.79 (d, J=8.6 Hz, 1H); 5.52 (m, 0.5H); 5.40 (m, 0.5H); 4.90 (d, J=16.9 Hz, 1H); 4.40-4.24 (m, 4H); 4.20-4.09 (m, 2H); 0.82 (d, J=6.6 Hz, 3H).
Reaction SMILES: C([O:3][C:4]([C@@H:6]1[C@@H:10]([C:11](=[O:20])[NH:12][C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)[CH2:9][N:8]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:7]1)=[O:5])C.Cl>C1COCC1.O.C(OCC)(=O)C>[C:24]([O:23][C:21]([N:8]1[CH2:9][C@H:10]([C:11](=[O:20])[NH:12][C:13]2[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=2)[C@@H:6]([C:4]([OH:5])=[O:3])[CH2:7]1)=[O:22])([CH3:27])([CH3:25])[CH3:26]
Reactant: CCOC(=O)[C@H]1CN(C(=O)OC(C)(C)C)C[C@@H]1C(=O)Nc1ccc(Cl)cc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)N1C[C@H](C(=O)O)[C@@H](C(=O)Nc2ccc(Cl)cc2)C1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
The ester obtained from step 2a (4.07 g; 10.3 mmol) is dissolved in a mixture of THF/water (1:1; 40 ml). LiOH monohydrate (0.947 g; 22.6 mmol) is added to the mixture and complete saponification is obtained after stirring for 18 h at 25° C. The mixture is acidified with 1N aq. HCl and diluted with ethyl acetate (100 ml). The organic phase is washed with brine (100 ml) and dried over Na2SO4. The organic phase is filtered and the filtrate is evaporated to dryness. Yield: 3.28 g (86.7%), ESI-MS: m/z=367 [M−H]−, Cl-pattern
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10](Cl)[CH:9]=[C:8]2[C:3]=1[C:4]([OH:18])([C:14]([F:17])([F:16])[F:15])[CH2:5][C:6](=[O:13])[NH:7]2.CC([O-])=O.[K+]>C(O)C.[Pd]>[NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4]([OH:18])([C:14]([F:17])([F:15])[F:16])[CH2:5][C:6](=[O:13])[NH:7]2
Reactant: Nc1cc(Cl)cc2c1C(O)(C(F)(F)F)CC(=O)N2
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CCO
Product: Nc1cccc2c1C(O)(C(F)(F)F)CC(=O)N2
Reaction time: 2 h
Yield: 101.5 %

Procedure:
A mixture of 5-amino-7-chloro-3,4-dihydro-4-hydroxy-4-(trifluoromethyl)-1H-quinolin-2-one (8.0 g, 28 mmol), KOAc (5.6 g, 57 mmol) and 10% Pd—C (4.0 g) in 200 mL ethanol was stirred under an atmosphere of hydrogen for 2 h. The mixture was filtered through Celite and concentrated under reduced pressure. The resultant solid was dissolved in EtOAc (250 mL) and washed sequentially with saturated NaHCO3 (200 mL) and brine (200 mL), dried over MgSO4, filtered and concentrated to afford 7.0 g (100%) of 5-amino-3,4-dihydro-4-hydroxy-4-(trifluoromethyl)-1H-quinolin-2-one, a foamy tan solid. 1H NMR (400 MHz, acetone-d6) δ 9.16 (broad s, 1H), 6.99 (t, 1H, J=8.0), 6.44 (broad s, 1H), 6.39 (d, 1H, J=7.9), 6.26 (d, 1H, J=7.9), 5.44 (broad s, 2H), 3.09 (d, AB, J=17.0), 2.93 (d, AB, J=17.0).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:9]=[CH:8][N:7]([C@@H:10]2[O:32][C@H:31]([CH2:33][O:34]C(=O)C3C=CC=CC=3)[C@@H:21]([O:22]C(=O)C3C=CC=CC=3)[C@H:11]2[O:12]C(=O)C2C=CC=CC=2)[N:6]=1)=[O:4].C[O-].[Na+]>CO>[CH3:1][O:2][C:3]([C:5]1[N:9]=[CH:8][N:7]([C@@H:10]2[O:32][C@H:31]([CH2:33][OH:34])[C@@H:21]([OH:22])[C@H:11]2[OH:12])[N:6]=1)=[O:4]
Reactant: COC(=O)c1ncn([C@@H]2O[C@H](COC(=O)c3ccccc3)[C@@H](OC(=O)c3ccccc3)[C@H]2OC(=O)c2ccccc2)n1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1ncn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)n1

Procedure:
A solution of 1-(2,3,5-tri-O-benzoyl-β-D-ribofuranosyl)-1,2,4-triazole-3-carboxylic acid methyl ester (25.0 g., 43.8 mmol) and sodium methoxide (400 mg.) in methanol (200 ml.) was refluxed for 45 min. The solution was neutralized with Bio-Rad AG50-X2 (H), filtered and the filtrate was concentrated to a syrup. Crystallization of the syrup from methanolethyl acetate provided 8.0 g. (70.5%) of product with M.P. 117-199°.
Reaction SMILES: [O:1]=[S:2]1(=[O:21])[CH:7]([CH3:8])[CH2:6][C:5]2[CH:9]=[CH:10][CH:11]=[C:12]([S:13]([NH:16][C:17](NC)=[O:18])(=[O:15])=[O:14])[C:4]=2[O:3]1.C(Cl)(Cl)=O>ClC1C=CC=CC=1>[O:21]=[S:2]1(=[O:1])[CH:7]([CH3:8])[CH2:6][C:5]2[CH:9]=[CH:10][CH:11]=[C:12]([S:13]([N:16]=[C:17]=[O:18])(=[O:15])=[O:14])[C:4]=2[O:3]1
Reactant: CNC(=O)NS(=O)(=O)c1cccc2c1OS(=O)(=O)C(C)C2
Agent: O=C(Cl)Cl
Solvent: Clc1ccccc1
Product: CC1Cc2cccc(S(=O)(=O)N=C=O)c2OS1(=O)=O

Procedure:
10 g of N-(3,4-dihydro-2,2-dioxo-3-methyl-1,2-benzoxathiin-8-ylsulfonyl)-N'-methylurea are dispersed in 400 ml of absolute chlorobenzene and the dispersion is saturated with phosgene at about 130° C., whereupon a clear solution forms. The solvent is then distilled off in vacuo, with the exclusion of moisture, to give 3,4-dihydro-2,2-dioxo-3-methyl-1,2-benzoxathiin-8-ylsulfonylisocyanate in the form of an oil, which can be used without further purification for obtaining the fused N-phenylsulfonyl-N'-pyrimidinylureas and N-phenylsulfonyl-N'-triazinylureas of the formula I.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:9][C:10]([C:12]2[CH:17]=[CH:16][C:15]([CH2:18][CH3:19])=[CH:14][CH:13]=2)=[O:11])=[CH:4][CH:3]=1.[C:20]([O:27][CH3:28])(=[O:26])[CH2:21][C:22]([O:24][CH3:25])=[O:23]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([CH:21]([C:20]([O:27][CH3:28])=[O:26])[C:22]([O:24][CH3:25])=[O:23])[CH2:9][C:10]([C:12]2[CH:13]=[CH:14][C:15]([CH2:18][CH3:19])=[CH:16][CH:17]=2)=[O:11])=[CH:6][CH:7]=1
Reactant: COC(=O)CC(=O)OC
Reactant: CCc1ccc(C(=O)C=Cc2ccc(Cl)cc2)cc1
Product: CCc1ccc(C(=O)CC(c2ccc(Cl)cc2)C(C(=O)OC)C(=O)OC)cc1

Procedure:
By a procedure similar to that of example 1.59.2, starting from 3-(4-chlorophenyl)-1-(4-ethylphenyl)prop-2-en-1-one and dimethyl malonate, dimethyl 2-(1-(4-chlorophenyl)-3-(4-ethylphenyl)-3-oxopropyl)malonate was obtained as pale yellowish solid.
Reaction SMILES: C([N:3]([CH2:6]C)[CH2:4][CH3:5])C.NC1C=[C:13]([N+:15]([O-:17])=[O:16])[CH:12]=[CH:11][C:10]=1[OH:18].CI>CO>[CH3:6][NH:3][C:4]1[CH:5]=[C:13]([N+:15]([O-:17])=[O:16])[CH:12]=[CH:11][C:10]=1[OH:18]
Reactant: Nc1cc([N+](=O)[O-])ccc1O
Reactant: CCN(CC)CC
Solvent: CO
Solvent: CI
Product: CNc1cc([N+](=O)[O-])ccc1O
Temperature: 40 °C
Reaction time: 1 h

Procedure:
Triethylamine (2 ml, 14.4 mmol) was added to a solution of 2-amino-4-nitrophenol (1) (1.54 g, 10 mmol) and methyl iodide (1 ml, 16 mmol) in methanol (10 ml). After 1 hour at 40° C., further methyl iodide (1 ml) and triethylamine (1 ml) were added and the mixture was stirred at 40° C. for a further 2 hours. The reaction mixture was concentrated to dryness in vacuo, the residue was added to aqueous 2N sodium acetate solution and the mixture was extracted with ethyl acetate. The organic phase was dried with sodium sulfate and chromatographed on silica gel (eluent dichloromethane/methanol 95/5). Yield 880 mg (52%).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([CH2:12][CH2:13][CH2:14][CH2:15][C:16]([N:18]([C@H:20]([C:25]2[CH:26]=[N:27][C:28]([O:31][CH3:32])=[CH:29][CH:30]=2)[CH2:21][C:22]([OH:24])=[O:23])[CH3:19])=[O:17])[C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2>CCO.C(O)(=O)C.O=[Pt]=O>[NH2:1][C:2]1[N:3]=[C:4]([CH2:12][CH2:13][CH2:14][CH2:15][C:16]([N:18]([C@H:20]([C:25]2[CH:26]=[N:27][C:28]([O:31][CH3:32])=[CH:29][CH:30]=2)[CH2:21][C:22]([OH:24])=[O:23])[CH3:19])=[O:17])[C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:10]=2[CH:11]=1
Reactant: COc1ccc([C@H](CC(=O)O)N(C)C(=O)CCCCc2nc(N)cc3ccccc23)cn1
Agent: O=[Pt]=O
Solvent: CC(=O)O
Solvent: CCO
Product: COc1ccc([C@H](CC(=O)O)N(C)C(=O)CCCCc2nc(N)cc3c2CCCC3)cn1
Reaction time: 16 h

Procedure:
A solution of the acid 3-5 (150 mg, 0.34 mmol) in EtOH (30 mL) and acetic acid (4 mL) was degassed with argon. PtO2 (25 mg) was added and the mixture placed under an atmosphere of hydrogen gas (balloon) for 16 hours. The mixture was filtered through celite, the solvent removed and the residue purified by reverse phase HPLC (preppak C-18 column; water/acetonitrile/0.1% TFA gradient). After lyophilization, the title compound 3-6 was obtained as a light yellow powder. Mass spectrum: exact mass calculated for C24H33N4O4 (M+H) is 441.2496; found 441.2493.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[NH2:11])[NH:7][C:6](=[O:12])[C:5]2([CH3:14])[CH3:13].[N:15]1([C:20]2[CH:27]=[CH:26][C:23]([CH:24]=O)=[CH:22][CH:21]=2)[CH:19]=[CH:18][N:17]=[CH:16]1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(O)C>[CH3:13][C:5]1([CH3:14])[C:4]2[C:8](=[CH:9][C:10]3[NH:11][C:24]([C:23]4[CH:22]=[CH:21][C:20]([N:15]5[CH:19]=[CH:18][N:17]=[CH:16]5)=[CH:27][CH:26]=4)=[N:1][C:2]=3[CH:3]=2)[NH:7][C:6]1=[O:12]
Reactant: O=Cc1ccc(-n2ccnc2)cc1
Reactant: CC1(C)C(=O)Nc2cc(N)c(N)cc21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Product: CC1(C)C(=O)Nc2cc3[nH]c(-c4ccc(-n5ccnc5)cc4)nc3cc21
Reaction time: 3 h

Procedure:
2.0 g. (10.4 mmol) 5,6-diamino-3,3-dimethyl-indolin-2-one, 1.8 g. (10.4 mmol) 4-(1H-imidazol-1-yl)-benzaldehyde, 0.2 g. (1 mmol) p-toluenesulphonic acid and 120 ml. ethanol were mixed together, heated to the boiling point and air passed therethrough for 3 hours. After concentration and acidification with ethanolic hydrochloric acid, the crystallisate obtained was filtered off with suction, suspended in water and neutralised with an aqueous solution of ammonia. The residue obtained was recrystallised from methanol. There was obtained 1.0 g. (28% of theory) of the title compound; m.p. 300° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:17][N:18]2[C:22]3[CH:23]=[CH:24][C:25]([CH2:27][N:28]([CH3:30])[CH3:29])=[CH:26][C:21]=3[N:20]=[N:19]2)=[C:4]2[C:9](=[CH:10][C:11]=1[Cl:12])[N:8]=[C:7]([O:13]C)[C:6]([O:15]C)=[N:5]2.Cl>O1CCOCC1>[Cl:1][C:2]1[C:3]([CH2:17][N:18]2[C:22]3[CH:23]=[CH:24][C:25]([CH2:27][N:28]([CH3:30])[CH3:29])=[CH:26][C:21]=3[N:20]=[N:19]2)=[C:4]2[C:9](=[CH:10][C:11]=1[Cl:12])[NH:8][C:7](=[O:13])[C:6](=[O:15])[NH:5]2
Reactant: COc1nc2cc(Cl)c(Cl)c(Cn3nnc4cc(CN(C)C)ccc43)c2nc1OC
Agent: Cl
Solvent: C1COCCO1
Product: CN(C)Cc1ccc2c(c1)nnn2Cc1c(Cl)c(Cl)cc2[nH]c(=O)c(=O)[nH]c12
Yield: 92.5 %

Procedure:
A mixture of 6,7-dichloro-2,3-dimethoxy-5-[5-(N,N-dimethylaminomethyl)-1,2,3-benzotriazol-1-ylmethyl]quinoxaline (Preparation 24, 110 mg, 0.25 mmol), 2M hydrochloric acid (10 mL) and dioxane (10 mL) was heated at reflux for 5.5 hours. The mixture was concentrated under reduced pressure, diluted with acetone (10 mL) and filtered. The solid was dried under vacuum to give the title compound as an off-white solid (97 mg, 94%), mp 282° C. Found: C, 45.57; H, 4.00; N, 17.67. C18H16Cl2N6 O2. HCl.H2O requires C, 45.64; H, 4.04; N, 17.74%.
Reaction SMILES: B(Br)(Br)Br.[Br:5][C:6]1[C:15]([O:16]C)=[CH:14][CH:13]=[C:12]2[C:7]=1[CH:8]=[CH:9][N:10]=[C:11]2[Cl:18].N>ClCCl>[Br:5][C:6]1[C:15]([OH:16])=[CH:14][CH:13]=[C:12]2[C:7]=1[CH:8]=[CH:9][N:10]=[C:11]2[Cl:18]
Reactant: COc1ccc2c(Cl)nccc2c1Br
Agent: BrB(Br)Br
Agent: N
Solvent: ClCCl
Product: Oc1ccc2c(Cl)nccc2c1Br
Temperature: 25 °C
Reaction time: 48 h
Yield: 92 %

Procedure:
A solution of 1M BBr3 in dichloromethane (25.5 ml) was added dropwise to a stirred solution of 5-bromo-1-chloro-6-methoxyisoquinoline (1.26 g) in dichloromethane at 10° C. The mixture was stirred at ambient temperature for 48 h then poured into ice-water and the pH adjusted to 8 by adding concentrated aqueous ammonia. The mixture was extracted with ethyl acetate (x 2) and the aqueous phase then acidified to pH ˜4 using dilute hydrochloric acid. The aqueous phase was extracted with ethyl acetate (x 2), the combined organics were dried (Na2SO4) and concentrated in vacuo to give 5-bromo-1-chloro-6-hydroxyisoquinoline (1.1 g), El-MS: m/z=257.9, 260.0 and 261.6 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([OH:14])=O)[N:8]=[CH:7][N:6]=[C:5]2[NH:15][CH:16]([C:18]1[NH:22][C:21]2[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:20]=2[N:19]=1)[CH3:17].FC1C(OC(N(C)C)=[N+](C)C)=C(F)C(F)=C(F)C=1F.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.[NH:63]1[CH2:68][CH2:67][CH2:66][CH2:65][CH:64]1[CH2:69][CH2:70][C:71]([O:73][CH2:74][CH3:75])=[O:72]>CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([N:63]1[CH2:68][CH2:67][CH2:66][CH2:65][CH:64]1[CH2:69][CH2:70][C:71]([O:73][CH2:74][CH3:75])=[O:72])=[O:14])[N:8]=[CH:7][N:6]=[C:5]2[NH:15][CH:16]([C:18]1[NH:22][C:21]2[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:20]=2[N:19]=1)[CH3:17]
Reactant: CC(Nc1ncnc2cc(C(=O)O)c(Cl)cc12)c1nc2cc(Cl)ccc2[nH]1
Reactant: CCOC(=O)CCC1CCCCN1
Agent: CN(C)C(Oc1c(F)c(F)c(F)c(F)c1F)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)CCC1CCCCN1C(=O)c1cc2ncnc(NC(C)c3nc4cc(Cl)ccc4[nH]3)c2cc1Cl

Procedure:
Prepared analogously to Example 37a from 6-chloro-4-[1-(5-chloro-1H-benzimidazol-2-yl)-ethylamino]-7-hydroxycarbonyl-quinazoline, pentafluorophenyl-tetramethyluronium-hexafluorophosphate (PFTU), diisopropylethylamine and ethyl 3-piperidin-2-yl-propionate in DMSO at ambient temperature.
Reaction SMILES: [CH2:1]([NH:4][C:5]1[CH:6]=[C:7]([CH2:11][C:12]([OH:14])=[O:13])[CH:8]=[CH:9][CH:10]=1)[CH:2]=[CH2:3].[C:15]([OH:20])(=[O:19])[CH:16]([CH3:18])O.C1(C)C(S(O)(=O)=O)=CC=CC=1>C1(C)C=CC=CC=1>[CH2:1]([NH:4][C:5]1[CH:6]=[C:7]([CH2:11][C:12]([O:14][CH:16]([C:15]([OH:20])=[O:19])[CH3:18])=[O:13])[CH:8]=[CH:9][CH:10]=1)[CH:2]=[CH2:3]
Reactant: C=CCNc1cccc(CC(=O)O)c1
Reactant: CC(O)C(=O)O
Agent: Cc1ccccc1S(=O)(=O)O
Solvent: Cc1ccccc1
Product: C=CCNc1cccc(CC(=O)OC(C)C(=O)O)c1

Procedure:
A flask containing 10.0 g. 3-(allylamino)phenylacetic acid, 3.3 g. lactic acid, 500 mg. toluenesulfonic acid and 500 ml. toluene equipped with a Soxhlet extractor charged with activated 4 Å Linde molecular sieves. The solution is refluxed for 24 hours during which time the Soxhlet extractor is charged twice more with fresh sieves. The hot solution is filtered and left to cool, whereupon 1-carboxyethyl 3-(allylamino)phenylacetate separates as off-white crystals.
Reaction SMILES: C[C@@:2]([OH:14])([C@@H:6]([NH2:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:3](N)=[O:4].[CH2:15]([OH:19])[CH:16]([CH3:18])[CH3:17]>>[NH2:13][C@@H:6]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C@@H:2]([OH:14])[C:3]([O:19][CH2:15][CH:16]([CH3:18])[CH3:17])=[O:4]
Reactant: CC(C)CO
Reactant: C[C@](O)(C(N)=O)[C@@H](N)c1ccccc1
Product: CC(C)COC(=O)[C@H](O)[C@@H](N)c1ccccc1

Procedure:
To a mixture of crude (2R, 3S)-2-hydroxy-3-amine-3-phenylpropionamide (CVII, EXAMPLE 6, 180 mg, 1 mmol) in isobutyl alcohol (2.5 ml) is bubbled anhydrous hydrogen chloride gas until saturated allowing the temperature to rise. The reaction mixture is then heated to 100° overnight. The resulting solution is evaporated to dryness under house vacuum at 50°. The residue is dissolved in water (5 ml), and the aqueous is neutralized with saturated potassium carbonate solution to pH>9. The basic aqueous is extracted with ethyl acetate (15 ml×3). The combined organic phase is dried over magnesium sulfate, filtered and the solvent removed under reduced pressure. The residue is purified by flash chromatography (methanol/dichloromethane, 1/5) to give the title compound, NMR (300 MHz, CDCl3) 7.44-7.28, 4.34, 4.30, 4.00, 1.95 and 0.95 δ; CMR (300 MHz, CDCl3) 173.5, 142.3, 128.5, 127.5, 126.7, 75.0, 71.8, 58.0, 27.6 and 18.9 δ; MS (m/z) 238 (M++1), 165, 136, 118, 107, 106, 104, 91, 79, 77 and 57; HRMS (m/z) calculated for C13H19N1O3+H1=238.1443, observed=238.1441.
Reaction SMILES: Cl.[NH2:2][C:3]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([Br:15])[CH:10]=1)([CH:6]([F:8])[F:7])[CH2:4][OH:5].C([O-])([O-])=O.[Na+].[Na+].[Cl:22][CH2:23][C:24](Cl)=[O:25].CO>ClCCl.O.CC(OC)(C)C>[Br:15][C:11]1[CH:10]=[C:9]([C:3]([NH:2][C:24](=[O:25])[CH2:23][Cl:22])([CH2:4][OH:5])[CH:6]([F:7])[F:8])[CH:14]=[CH:13][CH:12]=1
Reactant: NC(CO)(c1cccc(Br)c1)C(F)F
Reactant: O=C(Cl)CCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: COC(C)(C)C
Solvent: O
Product: O=C(CCl)NC(CO)(c1cccc(Br)c1)C(F)F
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
2-Amino-2-(3-bromo-phenyl)-3,3-difluoro-propan-1-ol hydrochloride (6.5 g, 24.43 mmol) was put between 60 ml aqueous 2 M Na2CO3 solution and 60 ml dichloromethane and cooled to 0° C. under strong stirring. Then chloroacetylchloride (2.94 ml, 36.6 mmol), diluted in 8 ml dichloromethane, was added dropwise to the biphasic solution. After the complete addition, the reaction was stirred for 30 minutes at r.t. After completion 10 ml MeOH were added and stirring was continued for 10 minutes. Then TBME and water were added. The phases were separated, and the aqueous phase was extracted with TBME. The organic phases were washed with water and brine, dried over Na2SO4 and concentrated under reduced pressure to yield the title compound as off-white solid. 1H-NMR (360 MHz, DMSO-d6): 8.72 (s, 1H), 7.53 (m, 2H), 7.35 (m, 2H), 6.48 (t, 1H, CHF2), 5.39 (t, 1H), 4.18 (m, 2H), 3.10 (s, 2H); MS: 342 [(M+H)+].
Reaction SMILES: [F:1][CH2:2][CH2:3][OH:4].[H-].[Na+].Cl[C:8]1[N:13]=[CH:12][C:11]([C:14](=[O:16])[CH3:15])=[CH:10][CH:9]=1>CN(C=O)C>[F:1][CH2:2][CH2:3][O:4][C:8]1[N:13]=[CH:12][C:11]([C:14](=[O:16])[CH3:15])=[CH:10][CH:9]=1
Reactant: CC(=O)c1ccc(Cl)nc1
Reactant: OCCF
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)c1ccc(OCCF)nc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
530 μl (8.68 mmol) of 2-fluoroethanol are added to a suspension of 347.05 mg (8.68 mmol) of sodium hydride in 10 mL of DMF. The reaction mixture is placed under magnetic stirring at room temperature for 15 minutes. A solution of 500 mg (2.89 mmol) of 1-(6-chloropyrid-3-yl)ethanone in 3 mL of DMF is added dropwise to the reaction medium. The reaction is stirred at room temperature overnight. The reaction medium is evaporated to dryness. The crude product is taken up in water and extracted with ethyl acetate. The organic phase is dried over magnesium sulfate and evaporated to dryness. After purification by chromatography on silica gel (eluent A/B: heptane/EtOAc, gradient A/B: t 0 min 0% B, t 5 min 10% B, t 30 min 30% B), 362 mg of 1-[6-(2-fluoroethoxy)pyrid-3-yl]ethanone were obtained, corresponding to the following characteristics:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2([CH2:17][NH:18][CH3:19])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].C(=O)([O-])[O-].[K+].[K+].Br[CH2:27][CH2:28][CH2:29][Cl:30]>CN(C)C=O>[Cl:30][CH2:29][CH2:28][CH2:27][N:18]([CH3:19])[CH2:17][C:11]1([C:5]2[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=2)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]1
Reactant: CNCC1(c2ccc(OC)c(OC)c2)CCCCC1
Reactant: ClCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(C2(CN(C)CCCCl)CCCCC2)cc1OC
Reaction time: 16 h

Procedure:
A solution of 3.40 g (0.0129 mol) of 1-(3,4-dimethoxyphenyl)-N-methyl-1-cyclohexanemethanamine in 50 ml of abs. dimethylformamide was treated with 3.57 g (0.0258 mol) of anhydrous potassium carbonate. The mixture was stirred at 5° and treated with 1.4 ml (0.0129 mol) of 1-bromo-3-chloropropane and subsequently stirred initially at 30° for 4 hours and thereafter at room temperature for 16 hours. The solvent was then evaporated at room temperature under reduced pressure and the residue was treated with water. The mixture was extracted three times with ether and the organic extracts were dried over magnesium sulphate, filtered and evaporated under reduced pressure. The oily residue was distilled under a pressure of 300 Pa at 195°, whereby there was obtained N-(3-chloropropyl)-1-(3,4-dimethoxyphenyl)-N-methylcyclohexanemethanamine as a colourless viscous oil which was used directly in the next step.
Reaction SMILES: Br[CH:2]1[CH2:6][CH2:5][CH2:4][C:3]1=O.[CH2:8]([SH:12])[CH:9]([SH:11])[CH3:10]>>[CH3:10][CH:9]1[S:11][C:3]2[CH2:4][CH2:5][CH2:6][C:2]=2[S:12][CH2:8]1
Reactant: O=C1CCCC1Br
Reactant: CC(S)CS
Product: CC1CSC2=C(CCC2)S1
Yield: 69 %

Procedure:
The procedure of Example 1(a) is followed using 2-bromocyclopentanone and 1,2-propanedithiol to give 2,3,6,7-tetrahydro-2-methyl-5H-cyclopenta-1,4-dithiin as a greenish oil, bp 92.5°-93°/1 mm, Yield 69%. NMR, 1.42 (3d), 1.6-2.2 (2m), 2.2-2.65 (4m), 2.5-3.7 (3m) (CDCl3). IR 2920, 1605, 1420, 1310, 1260, 1125, 870, 720.
Reaction SMILES: [CH3:1][SiH:2]([Cl:4])[Cl:3].[Si:5]([CH3:9])([CH3:8])([Cl:7])Cl>>[Si:5]([Cl:7])([CH3:9])([CH3:1])[CH3:8].[CH3:1][SiH:2]([Cl:4])[Cl:3]
Reactant: C[Si](C)(Cl)Cl
Agent: C[SiH](Cl)Cl
Product: C[Si](C)(C)Cl

Procedure:
The procedure of Example 2 was followed using a 2 l flask, 106.39 g (2.72 mols) of K metal, 807.1 g of THF, 69.7 g (0.638 mol) of Me3SiCl, 25.9 g (0.225 mol) of MeSiHCl2, and 105.9 g (0.751 mol) of CH2 =CHSiMeCl2. Workup yielded 81.3 g of nonvolatile polymer, b.p. greater than 65°/0.5 mm. Pyrolysis of this polymer to 1200° yielded 51.7% of SiC composition. This examples shows the effectiveness of MeSiHCl2 in increasing SiC yield when compared to the use of Me2SiCl2 in Example D.
Reaction SMILES: [NH2:1][N+:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[C:4]([Br:10])[C:3]=1[NH2:11].CC1C=C(C)C=C(C)C=1S([O-])(=O)=O.[CH2:25]([O:27][C:28]([C:30]1([CH:33]=O)[CH2:32][CH2:31]1)=[O:29])[CH3:26].[OH-].[K+]>O1CCOCC1.CO>[CH2:25]([O:27][C:28]([C:30]1([C:33]2[N:11]=[C:3]3[C:4]([Br:10])=[CH:5][CH:6]=[C:7]([O:8][CH3:9])[N:2]3[N:1]=2)[CH2:32][CH2:31]1)=[O:29])[CH3:26]
Reactant: COc1ccc(Br)c(N)[n+]1N
Reactant: CCOC(=O)C1(C=O)CC1
Agent: Cc1cc(C)c(S(=O)(=O)[O-])c(C)c1
Agent: [K+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CO
Product: CCOC(=O)C1(c2nc3c(Br)ccc(OC)n3n2)CC1
Temperature: 90 °C
Reaction time: 6 h

Procedure:
1.0 g (2.6 mmol) of crude 2,4,6-Trimethyl-benzenesulfonate 1,2-diamino-3-bromo-6-methoxy-pyridinium (see preparation of compound 311) was dissolved in dioxane (8.5 mL), under argon, and treated with 1-formyl-cyclopropanecarboxylic acid ethyl ester (0.56 g, 3.9 mmol) and heated to 90° C. for 22 hours. The brown solution was cooled to rt and treated with 1N KOH in MeOH (2.6 mL) and left at rt for 6 hours. The solvent was evaporated in vacuo and a NaCl solution was added to the product as well as aq. NaHCO3. The product was extracted with DCM (×3) and the combined organic phases was dried over Na2SO4, filtered and concentrated in vacuo. The product was purified by flash chromatography on silica using DCM:EtOAc 96:4->85:15 as eluent. The title compound was obtained as a colourless solid (0.22 g).