Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[CH:4]([S:11]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)(=[O:13])=[O:12])[CH:5]1[CH2:9][CH2:8][C:7](=[O:10])[CH2:6]1.[H-].[Na+].C1C=CC(S(N(S(C2C=CC=CC=2)(=O)=O)[F:33])(=O)=O)=CC=1.O>CN(C=O)C>[CH3:1][O:2][C:3](=[O:20])[C:4]([S:11]([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)(=[O:12])=[O:13])([F:33])[CH:5]1[CH2:9][CH2:8][C:7](=[O:10])[CH2:6]1
Reactant: COC(=O)C(C1CCC(=O)C1)S(=O)(=O)c1ccccc1
Reactant: O=S(=O)(c1ccccc1)N(F)S(=O)(=O)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)C(F)(C1CCC(=O)C1)S(=O)(=O)c1ccccc1
Reaction time: 1 h
Yield: 28.3 %

Procedure:
To a stirred solution of 1.34 g (4.5 mmol) of benzenesulfonyl-(3-oxo-cyclopentyl)-acetic acid methyl ester in 15 mL of DMF at 0° C., 199 mg (5.0 mmol, 1.1 eq) of NaH (60%) were added. The reaction mixture was stirred at this temperature for one hour, and 2.14 g (6.75 mmol, 1.5 eq) of N-fluorobenzenesulfonimide were added. After 2 hours at RT, the reaction mixture was poured into water and extracted with EtOAc. The combined organic phases were dried over Na2SO4, filtered and evaporated. The resulting two diastereomers were separated by column chromatography on silica gel with heptane/EtOAc (from 2:1 to 2:1) yielding 0.40 g (28%) of (RS,SR)-benzenesulfonyl-fluoro-(3-oxo-cyclopentyl)-acetic acid methyl ester as a white solid, MS: 332 (MNH4+) and 0.52 g (37%) of (RR,SS)-benzenesulfonyl-fluoro-(3-oxo-cyclopentyl)-acetic acid methyl ester as a white solid, MS: 332 (MNH4+).
Reaction SMILES: CN1CCN(C2C=CC(N[CH:15]=[C:16]3[C:24]4[C:19](=[CH:20][C:21]([C:25]([C:27]5[CH:28]=[C:29]([NH:33][C:34]([C:36]6[C:40]([Cl:41])=[CH:39][N:38]([CH2:42][CH3:43])[N:37]=6)=[O:35])[CH:30]=[CH:31][CH:32]=5)=[O:26])=[CH:22][CH:23]=4)[NH:18][C:17]3=[O:44])=CC=2)CC1.C1COCC1.[N:50]1([CH2:55][C:56]2[CH:61]=[CH:60][C:59]([NH2:62])=[CH:58][CH:57]=2)[CH2:54][CH2:53][CH2:52][CH2:51]1>CCOC(C)=O.CCCCCC>[O:44]=[C:17]1[C:16](=[CH:15][NH:62][C:59]2[CH:58]=[CH:57][C:56]([CH2:55][N:50]3[CH2:54][CH2:53][CH2:52][CH2:51]3)=[CH:61][CH:60]=2)[C:24]2[C:19](=[CH:20][C:21]([C:25]([C:27]3[CH:28]=[C:29]([NH:33][C:34]([C:36]4[C:40]([Cl:41])=[CH:39][N:38]([CH2:42][CH3:43])[N:37]=4)=[O:35])[CH:30]=[CH:31][CH:32]=3)=[O:26])=[CH:22][CH:23]=2)[NH:18]1
Reactant: Nc1ccc(CN2CCCC2)cc1
Reactant: CCn1cc(Cl)c(C(=O)Nc2cccc(C(=O)c3ccc4c(c3)NC(=O)C4=CNc3ccc(N4CCN(C)CC4)cc3)c2)n1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CCn1cc(Cl)c(C(=O)Nc2cccc(C(=O)c3ccc4c(c3)NC(=O)C4=CNc3ccc(CN4CCCC4)cc3)c2)n1
Temperature: 65 °C
Reaction time: 24 h
Yield: 31 %

Procedure:
A small screw cap test tube was charged with 4-Chloro-1-ethyl-1H-pyrazole-3-carboxylic acid [3-(3-{[4-(4-methyl-piperazin-1-yl)-phenylamino]-methylene}-2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide (as prepared in Example 342, 100 mg, 0.229 mmol) and THF (2.5 mL). To the resulting solution was added 4-Pyrrolidin-1-ylmethyl-phenylamine (40.3 mg, 0.229 mmol), and the mixture was stirred for 24 h at 65° C. Subsequently, the reaction mixture was cooled to room temperature and diluted with EtOAc (5 mL) and Hexane (˜40 mL). The solid that precipitated was collected by filtration and washed with 0° C. acetone (˜10 mL) affording the title compound in 31% yield (0.043 g, 0.072 mmol).
Reaction SMILES: [C:1]1([C:7]2[CH:14]=[CH:13][C:10]([CH:11]=[O:12])=[CH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:15]1([Mg]Br)[CH2:17][CH2:16]1>>[CH:15]1([CH:11]([C:10]2[CH:9]=[N:8][C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[CH:14][CH:13]=2)[OH:12])[CH2:17][CH2:16]1
Reactant: Br[Mg]C1CC1
Reactant: O=Cc1ccc(-c2ccccc2)nc1
Product: OC(c1ccc(-c2ccccc2)nc1)C1CC1

Procedure:
Synthesized using compound 43b (227 mg, 1.24 mmol) and cyclopropylmagnesium bromide (4.96 mL, 2.48 mmol, 0.5 M in THF) according to Method D. Crude product was purified by flash chromatography on silica-gel using a mixture of hexane/ethyl acetate (3:1) as eluent. Light yellow solid. Yield: 234 mg, 84%. 1H NMR (CDCl3, 500 MHz): δH (ppm)=0.35-0.44 (m, 1H), 0.49 (dq, J=9.4, 4.7 Hz, 1H), 0.55-0.68 (m, 2H), 1.21 (qt, J=8.1, 5.0 Hz, 1H), 3.00 (br, s, 1H), 4.05 (d, J=8.2 Hz, 1H), 7.38-7.44 (m, 1H), 7.44-7.50 (m, 2H), 7.66-7.70 (m, 1H), 7.80-7.85 (m, 1H), 7.94-8.00 (m, 2H), 8.64-8.69 (m, 1H); 13C NMR (CDCl3, 125 MHz): δC (ppm)=2.8, 3.6, 19.0, 75.9, 120.3, 126.8, 128.7, 128.8, 134.5, 137.7, 139.1, 147.6, 156.5; MS (ESI): m/z=226.28 [M+H]+.
Reaction SMILES: [NH2:1][CH2:2][C:3]([NH:5][C:6]1[S:7][CH:8]=[C:9]([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[N:10]=1)=[O:4].C(N(CC)C(C)C)(C)C.Cl[C:27]1[N:32]=[C:31]([N:33]2[CH:38]=[C:37]([CH:39]3[C:45]4[CH:46]=[CH:47][C:48]([CH3:50])=[CH:49][C:44]=4[CH:43]=[CH:42][C:41]4[CH:51]=[C:52]([CH3:55])[CH:53]=[CH:54][C:40]3=4)[C:36](=[O:56])[NH:35][C:34]2=[O:57])[CH:30]=[CH:29][N:28]=1>CN1CCCC1=O>[CH3:50][C:48]1[CH:47]=[CH:46][C:45]2[CH:39]([C:37]3[C:36](=[O:56])[NH:35][C:34](=[O:57])[N:33]([C:31]4[CH:30]=[CH:29][N:28]=[C:27]([NH:1][CH2:2][C:3]([NH:5][C:6]5[S:7][CH:8]=[C:9]([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[N:10]=5)=[O:4])[N:32]=4)[CH:38]=3)[C:40]3[CH:54]=[CH:53][C:52]([CH3:55])=[CH:51][C:41]=3[CH:42]=[CH:43][C:44]=2[CH:49]=1
Reactant: Cc1ccc2c(c1)C=Cc1cc(C)ccc1C2c1cn(-c2ccnc(Cl)n2)c(=O)[nH]c1=O
Reactant: CCOC(=O)Cc1csc(NC(=O)CN)n1
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)Cc1csc(NC(=O)CNc2nccc(-n3cc(C4c5ccc(C)cc5C=Cc5cc(C)ccc54)c(=O)[nH]c3=O)n2)n1

Procedure:
A mixture of the product from step (i) (0.194 g), N,N-diisopropylethylamine (0.35 ml) and the product from example 8 step (ii) (0.25 g) in 1-methyl-2-pyrrolidinone (5 ml) was heated at 90° C. for 10 hours. The mixture was partitioned between ethyl acetate and water. The organic phase was washed with water, dried (MgSO4) and evaporated. Purification was by chromatography eluting with 70% ethyl acetate in isohexane. Yield 0.175 g.
Reaction SMILES: [N:1]([O-:3])=O.[Na+].[CH3:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][CH2:14][C:15]([OH:17])=[O:16])=[CH:9][CH:8]=1.Cl>O>[CH3:5][O:6][C:7]1[CH:8]=[CH:9][C:10]([N:13]([N:1]=[O:3])[CH2:14][C:15]([OH:17])=[O:16])=[CH:11][CH:12]=1
Reactant: O=N[O-]
Reactant: COc1ccc(NCC(=O)O)cc1
Agent: Cl
Agent: [Na+]
Solvent: O
Product: COc1ccc(N(CC(=O)O)N=O)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 100 %

Procedure:
Sodium nitrite (3.97 g, 57.5 mmol) in 10 mL of water was added to a suspension of N-(4-methoxyphenyl)glycine (9.92 g, 54.7 mmol) in 50 mL of water under N2. This was allowed to stir at room temperature until solution clarified, about 6 hours. The solution was acidified with concentrated hydrochloric acid to pH 3 and a precipitate formed. The solid was collected and washed with 50 mL water, then dried in vacuo to give 11.50 g (100%) of the desired compound as a white solid. 1H NMR (CDCl3): δ 7.17 (d, J=8.8, 2H); 6.70 (d, J=8.8, 2H); 4.30 (s, 2H), 3.56 (s, 3H), 2.29 (br s, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[OH:10])[C:5]#[N:6].O.C(=O)(O)[O-].[Na+].Cl[CH2:18][C:19](Cl)=[O:20]>CC(C)=O>[O:20]=[C:19]1[NH:1][C:2]2[CH:3]=[C:4]([C:5]#[N:6])[CH:7]=[CH:8][C:9]=2[O:10][CH2:18]1
Reactant: O=C(Cl)CCl
Reactant: N#Cc1ccc(O)c(N)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: N#Cc1ccc2c(c1)NC(=O)CO2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3-amino-4-hydroxybenzonitrile (g, 10 mmol was dissolved in acetone (20 mL) and water (20 mL) containing sodium bicarbonate (4 g). 2-chloroacetyl chloride was added slowly and the mixture heated to reflux for 4 h and then allowed to stir overnight at 25 ° C. The layers were separated, and the water layer was extracted with ethyl acetate. The organic layers were combined and evaporated to give 3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-carbonitrile as an oil (1.3 g): 1H NMR (400 M ; DMSO-D6): 7.4 (d, 1H); 7.2 (s, 1H); 7.1 (d, 1H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]([C:28]2[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=2)[CH:10]=[C:11]([C:13]([N:15]2[CH2:20][CH2:19][C:18]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)(O)[CH2:17][CH2:16]2)=[O:14])[N:12]=1.Cl>ClCCl.CCOCC>[Cl:34][C:31]1[CH:32]=[CH:33][C:28]([N:9]2[CH:10]=[C:11]([C:13]([N:15]3[CH2:16][CH:17]=[C:18]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[CH2:19][CH2:20]3)=[O:14])[N:12]=[C:8]2[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[CH3:1])=[CH:29][CH:30]=1
Reactant: Cc1ccccc1-c1nc(C(=O)N2CCC(O)(c3ccccc3)CC2)cn1-c1ccc(Cl)cc1
Agent: Cl
Solvent: CCOCC
Solvent: ClCCl
Product: Cc1ccccc1-c1nc(C(=O)N2CC=C(c3ccccc3)CC2)cn1-c1ccc(Cl)cc1

Procedure:
A 30-mg sample of 1-{[2-(2-methylphenyl)-1-(4-chlorophenyl)-1H-imidazol-4-yl]carbonyl}-4-phenyl-4-piperidinol (Table entry 414), was dissolved in 20 mL dichloromethane, and then 5 mL 2M HCl in ether was added to the solution. Evaporation of the solvent at high temperature (ca. 70° C., 16 hr) in a multiple sample evaporator (GeneVac) gave 1-{[1-(4-chlorophenyl)-2-(2-methylphenyl)-1H-imidazol-4-yl]carbonyl}-4-phenyl-1,2,3,6-tetrahydropyridine (yellow solid). 1H NMR (400 MHz, CD3COCD3) δ 8.31 (s, 1H), 7.05-7.35 (m, 13 H), 6.05 (s, 1 H), 4.2 (m, 2 H), 3.85 (m, 2H), 2.5 (m, 2H), 2.0 (s, 3H); LC-MS m/z 454 (MH+), retention time 2.92 min (method 2).
Reaction SMILES: [Br-].O=[C:3]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:4][CH:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8][CH2:7][C:6]1=[N+](C)C.Br.C(C1C2C(=CC=CC=2)CCC=1N(C)C)C(C1C=CC=CC=1)=O.[NH2:47][C:48]1[CH:56]=[C:52]([C:53]([OH:55])=[O:54])[C:51]([OH:57])=[CH:50][CH:49]=1>C(O)(=O)C>[C:53]([C:52]1[CH:56]=[C:48]([N:47]2[C:6]3[CH2:7][CH2:8][C:9]4[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=4[C:5]=3[CH:4]=[C:3]2[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:49]=[CH:50][C:51]=1[OH:57])([OH:55])=[O:54]
Reactant: C[N+](C)=C1CCc2ccccc2C1CC(=O)c1ccccc1
Reactant: Nc1ccc(O)c(C(=O)O)c1
Agent: Br
Agent: CN(C)C1=C(CC(=O)c2ccccc2)c2ccccc2CC1
Agent: [Br-]
Solvent: CC(=O)O
Product: O=C(O)c1cc(-n2c(-c3ccccc3)cc3c2CCc2ccccc2-3)ccc1O
Temperature: 75 °C
Reaction time: 4.5 h

Procedure:
A mixture of 10.0 g of tautomeric N-[3,4-dihydro-1-(2-oxo-2-phenylethyl)-2(1H)-naphthalenylidene]-N-methylmethanaminium bromide in equilibrium with 1-phenacyl-2-dimethylamino-3,4-dihydronaphthalene hydrobromide and 4.1 g of 5-aminosalicylic acid in 50 ml of acetic acid is vigorously stirred at 75° C. for 4.5 hours. The reaction mixture is then cooled to 20° C., filtered and the precipitate collected, washed successively with one 20 ml portion of acetic acid and five 20 ml portions of hexane and then dried for 20 hours under vacuum to give 3-(3-carboxy-4-hydroxyphenyl)-4,5-dihydro-2-phenylbenz[e]indole.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]([N:13]([C:24]2[CH:29]=[CH:28][C:27]([C:30](OC)=[O:31])=[CH:26][CH:25]=2)[C:14]2[CH:19]=[CH:18][C:17]([C:20](OC)=[O:21])=[CH:16][CH:15]=2)[CH:10]=[CH:9][C:4]=1[C:5](OC)=[O:6].[H-].[Al+3].[Li+].[H-].[H-].[H-].O>O1CCCC1.ClCCl>[OH:21][CH2:20][C:17]1[CH:16]=[CH:15][C:14]([N:13]([C:24]2[CH:25]=[CH:26][C:27]([CH2:30][OH:31])=[CH:28][CH:29]=2)[C:11]2[CH:10]=[CH:9][C:4]([CH2:5][OH:6])=[C:3]([O:2][CH3:1])[CH:12]=2)=[CH:19][CH:18]=1
Reactant: COC(=O)c1ccc(N(c2ccc(C(=O)OC)cc2)c2ccc(C(=O)OC)c(OC)c2)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: O
Product: COc1cc(N(c2ccc(CO)cc2)c2ccc(CO)cc2)ccc1CO
Temperature: -78 °C
Reaction time: 1 h
Yield: 96 %

Procedure:
A solution of compound 7 (1.35 g, 3 mmol) in 20 mL of THF is added dropwise to a suspension of lithium aluminium hydride (LiAlH4, 1.7 g, 45 mmol, 15 eq.) in dry tetrahydrofuran (THF) (30 mL) at −78° C. The temperature of the medium is allowed to return to room temperature and then the reaction is heated under reflux with stirring. After 1 hour, the solution is cooled to −78° C. and diluted with dichloromethane, and then water (10 mL) is slowly poured in. The solid obtained is filtered and washed with dichloromethane. The mother liquors are washed with water and with brine and then dried and concentrated to give 1.05 g (2.88 mmol) of a pasty compound (yield: 97%).
Reaction SMILES: Cl/[C:2](/[N+]([O-])=O)=[CH:3]\[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][CH:5]=1.[OH:15][C:16]1[CH:21]=[C:20]([OH:22])[N:19]=[CH:18][N:17]=1.N12CCCN=C1CCCCC2>C(O)C>[CH3:11][O:10][C:7]1[CH:8]=[CH:9][C:4]([C:3]2[C:21]3[C:20](=[O:22])[NH:19][CH:18]=[N:17][C:16]=3[O:15][CH:2]=2)=[CH:5][CH:6]=1
Reactant: COc1ccc(/C=C(\Cl)[N+](=O)[O-])cc1
Reactant: Oc1cc(O)ncn1
Solvent: CCO
Solvent: C1CCC2=NCCCN2CC1
Product: COc1ccc(-c2coc3nc[nH]c(=O)c23)cc1

Procedure:
As in the procedure described in the literature [D. Dauzonne, Tetrahedron, 1992, 3069-3080], stir a suspension of 10.1 g (47.4 mmol) 1-[(Z)-2-chloro-2-nitrovinyl]-4-methoxybenzene and 5.8 g (52.2 mmol) 4,6-dihydroxypyrimidine in 200 ml ethanol for ten minutes at 85° C. Next, slowly add 15.6 ml (15.9 g, 104.3 mmol) 1,8-diazabicyclo[5.4.0]undec-7-ene. Stir for 15 h at this temperature and then concentrate by vacuum evaporation. Take up the residue in dichloromethane and chromatograph on silica gel (solvent: dichloromethane/methanol 95:5). Mix the solid obtained with acetonitrile and then filter. 2.3 g (20% of theor.) of the target product is obtained.
Reaction SMILES: [CH3:1][CH:2]([O:4][C:5]1[CH:6]=[C:7]([O:19][C:20]2[CH:25]=[CH:24][C:23]([S:26]([CH3:29])(=[O:28])=[O:27])=[CH:22][N:21]=2)[CH:8]=[C:9]2[C:13]=1[NH:12][C:11]([C:14]([O:16]CC)=[O:15])=[CH:10]2)[CH3:3].[OH-].[Na+].C(O)C.Cl>O.O1CCCC1>[CH3:3][CH:2]([O:4][C:5]1[CH:6]=[C:7]([O:19][C:20]2[CH:25]=[CH:24][C:23]([S:26]([CH3:29])(=[O:28])=[O:27])=[CH:22][N:21]=2)[CH:8]=[C:9]2[C:13]=1[NH:12][C:11]([C:14]([OH:16])=[O:15])=[CH:10]2)[CH3:1]
Reactant: CCOC(=O)c1cc2cc(Oc3ccc(S(C)(=O)=O)cn3)cc(OC(C)C)c2[nH]1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: C1CCOC1
Product: CC(C)Oc1cc(Oc2ccc(S(C)(=O)=O)cn2)cc2cc(C(=O)O)[nH]c12
Temperature: 50 °C
Reaction time: 2 h
Yield: 63.6 %

Procedure:
A mixture of ethyl 7-(1-methylethoxy)-5-{[5-(methylsulfonyl)pyridin-2-yl]oxy}-1H-indole-2-carboxylate (10.7 g), 1M aqueous sodium hydroxide solution (50 mL), ethanol (50 mL) and tetrahydrofuran (50 mL) was stirred at 50° C. for 2 h. 1M Hydrochloric acid (50 mL) was added to the mixture and the mixture was adjusted to pH=6 by 1M aqueous sodium hydroxide solution and water. The whole was extracted with ethyl acetate. The organic layer was washed with brine, dried (MgSO4), filtered, and concentrated in vacuo to give the title compound (6.35 g, 64%) as a brown amorphous solid. MS 391 (MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([C:13]([F:16])([F:15])[F:14])[C:9]([F:12])([F:11])[F:10])=[N:6][CH:7]=1.[Cl:17]N1C(=O)CCC1=O>C(#N)C>[NH2:1][C:2]1[C:7]([Cl:17])=[N:6][C:5]([CH:8]([C:9]([F:10])([F:11])[F:12])[C:13]([F:16])([F:14])[F:15])=[CH:4][CH:3]=1
Reactant: Nc1ccc(C(C(F)(F)F)C(F)(F)F)nc1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CC#N
Product: Nc1ccc(C(C(F)(F)F)C(F)(F)F)nc1Cl
Yield: 85.8 %

Procedure:
In 10 ml of acetonitrile was dissolved 0.56 g (2.3 mmol) of 5-amino-2-[2,2,2-trifluoro-1-(trifluoromethyl)ethyl]pyridine, to which was added 0.31 g (2.3 mmol) of N-chlorosuccinimide (NCS). The mixture thus obtained was heated under reflux for one hour to make progress a reaction. The solvent was distilled off under reduced pressure, and the residue was separated and purified by silica gel column chromatography (hexane/ethyl acetate=2:1) to obtain 0.55 g of 3-amino-2-chloro-6-[2,2,2-trifluoro-1-(trifluoromethyl)ethyl]pyridine (Compound No. 4-2) (yield: 86%).
Reaction SMILES: [CH3:1][CH:2]([CH2:4][CH2:5][CH2:6][C@H:7]([C@@H:9]1[C@:26]2([CH3:27])[C@H:12]([C@H:13]3[C@H:23]([CH2:24][CH2:25]2)[C@:21]2([CH3:22])[C:16]([CH2:17][C@@H:18]([OH:28])[CH2:19][CH2:20]2)=[CH:15][CH2:14]3)[CH2:11][CH2:10]1)[CH3:8])[CH3:3].S=[C:30]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:31]1[C:32]([O-:34])=[O:33].C(=O)([O-])[O-].[K+].[K+]>C(Cl)(Cl)Cl>[CH3:3][CH:2]([CH2:4][CH2:5][CH2:6][C@H:7]([C@@H:9]1[C@:26]2([CH3:27])[C@H:12]([C@H:13]3[C@H:23]([CH2:24][CH2:25]2)[C@:21]2([CH3:22])[C:16]([CH2:17][C@@H:18]([OH:28])[CH2:19][CH2:20]2)=[CH:15][CH2:14]3)[CH2:11][CH2:10]1)[CH3:8])[CH3:1].[C:32]([O-:34])(=[O:33])[C:31]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:30]=1
Reactant: O=C([O-])C1C=CC=CC1=S
Agent: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Product: O=C([O-])c1ccccc1

Procedure:
5-Cholesten-3β-ol-thionobenzoate (100 mg, 0.198 mmol), symdibromo-tetrachloroethane (323 mg, 0.991 mmol, and 4-methoxy-4'-dimethylaminodiphenyltelluride (0.7 mg, 0.00198 mmol) were stirred in a two phase system of chloroform (2 ml) and aqueous potassium carbonate (2.5 ml, 20%) at room temperature for 47 h. The reaction was worked up in exactly the same way as described above to afford 5-cholesten-3β-ol-benzoate (75 mg, 77%) m.p. 144°-145° (lit., 150°-151°). The i.r. spectrum was identical to that of an authentic sample.
Reaction SMILES: [CH3:1][CH:2]1[C:7](=[O:8])[NH:6][C:5]2[CH:9]=[C:10](Cl)[CH:11]=[CH:12][C:4]=2[O:3]1.N[C:15]1C=C(Cl)C=CC=1O>>[CH3:1][CH:2]1[C:7](=[O:8])[NH:6][C:5]2[CH:9]=[CH:10][CH:11]=[C:12]([CH3:15])[C:4]=2[O:3]1
Reactant: Nc1cc(Cl)ccc1O
Reactant: CC1Oc2ccc(Cl)cc2NC1=O
Product: Cc1cccc2c1OC(C)C(=O)N2

Procedure:
2-Methyl-6-chloro-1,4-benzoxazin-3-one from 2-amino-4-chlorophenol
Reaction SMILES: S(=O)(=O)(O)O.N[C:7]1[CH:16]=[C:15]2[C:10]([C:11]([Br:21])=[N:12][N:13]([CH:18]([CH3:20])[CH3:19])[C:14]2=[O:17])=[CH:9][CH:8]=1.N([O-])=[O:23].[Na+].NC(N)=O>C(O)(=O)C.O>[OH:23][C:7]1[CH:16]=[C:15]2[C:10]([C:11]([Br:21])=[N:12][N:13]([CH:18]([CH3:20])[CH3:19])[C:14]2=[O:17])=[CH:9][CH:8]=1
Reactant: CC(C)n1nc(Br)c2ccc(N)cc2c1=O
Reactant: O=N[O-]
Agent: NC(N)=O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CC(C)n1nc(Br)c2ccc(O)cc2c1=O
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 93.2 %

Procedure:
Concentrated sulfuric acid (17 ml) was added slowly to a solution of 7-Amino-2-Isopropyl-4-bromo-2H-phthalazin-1-one (4.6 g, 0.016 mol) in acetic acid (50 ml). The reaction mixture was cooled to 0° C. and a solution of NaNO2 (1.52 g, 0.022 mol) in water (10 ml) was added dropwise. The reaction mixture was stirred for a further 20 minutes at 0° C. prior to the addition of urea (0.55 g, 0.009 mol) and cold water (50 ml). The reaction mixture was then added carefully to a refluxing mixture of sulfuric acid (28 ml) in water (115 ml) and the reaction was stirred for a further 10 minutes at reflux before being allowed to cool to room temperature. Upon standing, an orange precipitate was observed, which was collected by filtration and washed with water to give the title compound (4.22 g, 93% yield) as an orange powder.
Reaction SMILES: C([O:3][C:4](=[O:17])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([SH:13])=[CH:9][C:8]=1[CH2:14][CH2:15][CH3:16])C.Cl[CH2:19][C:20]1[N:21]=[C:22]([C:26]2[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][CH:27]=2)[O:23][C:24]=1[CH3:25].C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C>[CH3:25][C:24]1[O:23][C:22]([C:26]2[CH:27]=[CH:28][C:29]([C:32]([F:35])([F:33])[F:34])=[CH:30][CH:31]=2)=[N:21][C:20]=1[CH2:19][S:13][C:10]1[CH:11]=[CH:12][C:7]([O:6][CH2:5][C:4]([OH:3])=[O:17])=[C:8]([CH2:14][CH2:15][CH3:16])[CH:9]=1
Reactant: Cc1oc(-c2ccc(C(F)(F)F)cc2)nc1CCl
Reactant: CCCc1cc(S)ccc1OCC(=O)OCC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CCCc1cc(SCc2nc(-c3ccc(C(F)(F)F)cc3)oc2C)ccc1OCC(=O)O
Reaction time: 4 h
Yield: 55.9 %

Procedure:
To a mixture of (4-mercapto-2-propyl-phenoxy)-acetic acid ethyl ester (127 mg, 0.5 mmol) and 4-Chloromethyl-5-methyl-2-(4-trifluoromethyl-phenyl)-oxazole (131 mg, 0.48 mmol) in acetonitrile (2 mL) was added cesium carbonate (326 mg, 1 mmol). After 4 h at room temperature, the reaction was quenched by water, extracted with ethyl acetate. Combined organic layers were washed with brine, dried (sodium sulfate) and concentrated. The residue was taken into THF (2 mL) and treated with lithium hydroxide (1N, 0.5 mL) at room temperature for 2 h. THF was evaporated, the residue was treated with water (0.5 mL) and extracted with ether. The aqueous was acidified with 5 N HCl, extracted with ether, dried over sodium sulfate and concentrated. The crude product was purified by reversed phase HPLC to give the title compound (125 mg, 53.7%)
Reaction SMILES: O1[C:5]2([CH2:10][CH2:9][CH:8]([NH:11][S:12]([C:15]3[CH:19]=[C:18]([Cl:20])[S:17][C:16]=3[Cl:21])(=[O:14])=[O:13])[CH2:7][CH2:6]2)[O:4]CC1.[OH-].[Na+].[Na+].[Cl-].C(Cl)Cl>CC(C)=O.O>[O:4]=[C:5]1[CH2:6][CH2:7][CH:8]([NH:11][S:12]([C:15]2[CH:19]=[C:18]([Cl:20])[S:17][C:16]=2[Cl:21])(=[O:14])=[O:13])[CH2:9][CH2:10]1
Reactant: O=S(=O)(NC1CCC2(CC1)OCCO2)c1cc(Cl)sc1Cl
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)=O
Solvent: ClCCl
Product: O=C1CCC(NS(=O)(=O)c2cc(Cl)sc2Cl)CC1
Reaction time: 6 h
Yield: 80.5 %

Procedure:
p-TosOH×H2O 4 g (21.0 mmol) was added to a solution of 2,5-dichloro-thiophene-3-sulfonic acid-(1,4-dioxa-spiro[4.5]dec-8-yl)-amide 894 mg (2.40 mmol) in acetone (10 ml) and water (1 ml) and stirring was performed for 6 h at RT. After addition of aqueous 1M NaOH (100 ml) and aqueous saturated NaCl solution (100 ml), extraction was performed with CH2Cl2 (3×200 ml). After separation of the organic phases, drying over Na2SO4 and filtration, the solvent was removed by distillation. After purification by means of column chromatography, the product 2,5-dichloro-thiophene-3-sulfonic acid (4-oxo-cyclohexyl)-amide 634 mg (80% of theoretical) was obtained.
Reaction SMILES: [F:1][C:2]([F:43])([F:42])[C:3]1[CH:4]=[C:5]([CH:35]=[C:36]([C:38]([F:41])([F:40])[F:39])[CH:37]=1)[CH2:6][N:7]([C:30]1[NH:34][N:33]=[N:32][N:31]=1)[CH:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]([O:17][CH:18]([CH3:20])[CH3:19])=[O:16])[C:10]2[C:21]([CH3:29])=[C:22]([C:25]([F:28])([F:27])[F:26])[CH:23]=[CH:24][C:9]1=2.CO.[C:46]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>ClCCl>[F:39][C:38]([F:41])([F:40])[C:36]1[CH:35]=[C:5]([CH:4]=[C:3]([C:2]([F:42])([F:1])[F:43])[CH:37]=1)[CH2:6][N:7]([C:30]1[N:31]=[N:32][N:33]([CH3:46])[N:34]=1)[CH:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]([O:17][CH:18]([CH3:19])[CH3:20])=[O:16])[C:10]2[C:21]([CH3:29])=[C:22]([C:25]([F:26])([F:27])[F:28])[CH:23]=[CH:24][C:9]1=2
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: Cc1c(C(F)(F)F)ccc2c1N(C(=O)OC(C)C)CCCC2N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1nnn[nH]1
Agent: CCOC(=O)N=NC(=O)OCC
Solvent: ClCCl
Solvent: CO
Product: Cc1c(C(F)(F)F)ccc2c1N(C(=O)OC(C)C)CCCC2N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1nnn(C)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 53 %

Procedure:
To a solution of (+/−)-isopropyl 5-[(3,5-bistrifluoromethyl-benzyl)-(1H-tetrazol-5-yl)-amino]-9-methyl-8-trifluormethyl-2,3,4,5-tetrahydrobenzo[b]azepine-1-carboxylate (87 mg, 0.139 mmol), methanol (0.564 mL, 13.9 mmol), triphenyl phosphine (73 mg, 0.278 mmol) in dry dichloromethane (3.4 mL) at 0° C., under nitrogen, add diethyl azodicarboxylate (0.128 mL, 0.278 mmol). Stir the reaction mixture at room temperature for 3 h. Remove the solvents under reduced pressure and purify the residue by flash chromatography, eluting with hexanes/ethyl acetate to afford the title compound (47 mg, 53%). MS (ES+): 639 (M+H).