Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH:2]([CH3:37])[CH2:3][CH2:4][N:5]1[C:13](=[O:14])[C:12]2[N:11](COCC[Si](C)(C)C)[C:10]([O:23][C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([O:30][C:31]([F:34])([F:33])[F:32])[CH:25]=3)=[N:9][C:8]=2[N:7]([CH3:35])[C:6]1=[O:36].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1.C(OCC)(=O)C>[OH:1][CH:2]([CH3:37])[CH2:3][CH2:4][N:5]1[C:13](=[O:14])[C:12]2[NH:11][C:10]([O:23][C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([O:30][C:31]([F:33])([F:34])[F:32])[CH:25]=3)=[N:9][C:8]=2[N:7]([CH3:35])[C:6]1=[O:36]
Reactant: CC(O)CCn1c(=O)c2c(nc(Oc3cccc(OC(F)(F)F)c3)n2COCC[Si](C)(C)C)n(C)c1=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(O)CCn1c(=O)c2[nH]c(Oc3cccc(OC(F)(F)F)c3)nc2n(C)c1=O
Yield: 83.8 %

Procedure:
To a solution of 1-(3-hydroxybutyl)-3-methyl-8-(3-(trifluoromethoxy)phenoxy)-7-((2-(trimethylsilyl)ethoxy)methyl)-1H-purine-2,6(3H,7H)-dione (1.1 g, 2.02 mmol) in THF (5 mL) was added TBAF (5 mL, 1 mmol/L in THF) and the mixture was heated at reflux for 16 h. The mixture was cooled and diluted with ethyl acetate. The organic phase was washed with brine and saturated aqueous ammonium chloride; then it was dried and concentrated to give a crude product which was purified by silica gel chromatography eluting with DCM/methanol (45:1) to give (701 mg, 83.8% yield) as white solid. LCMS retention time 1.372 min; LCMS MH+ 415.
Reaction SMILES: [N:1]1([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Br[C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=1[C:22]([F:25])([F:24])[F:23].C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(C)([O-])C.[Na+]>C(OC(=O)C)C.C1(C)C=CC=CC=1>[C:10]([O:9][C:7]([N:1]1[CH2:6][CH2:5][N:4]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=2[C:22]([F:23])([F:25])[F:24])[CH2:3][CH2:2]1)=[O:8])([CH3:13])([CH3:12])[CH3:11]
Reactant: Fc1ccc(Br)c(C(F)(F)F)c1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(F)cc2C(F)(F)F)CC1

Procedure:
A mixture of tert-butyl piperazine-1-carboxylate 1.04 g, (5.6 mmol), 2-bromo-5-fluoro benzotrifluoride (1.21 g, 5.0 mmol), tris(dibenzylidineacetone)dipalladium (0) (45.8 mg, 0.05 mmol), rac-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (93.4 mg, 0.15 mmol) and sodium tert-butoxide (600 mg, 6.25 mmol) were charged to a microwave vial. Toluene (10.0 mL) was introduced under nitrogen atmosphere and the reaction mixture was irradiated at 110° C. for 30 minutes. Reaction was complete as determined by TLC. The reaction was repeated four times. Reaction mixtures were combined, diluted with ethylacetate, washed with water, saturated brine then dried over MgSO4 and concentrated. The crude product was purified via flash column chromatography to yield tert-butyl-4-(4-fluoro-2-(trifluoromethyl)phenyl)piperazine-1-carboxylate in quantitative yield (6.8 g) as yellow oil.
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]2[C:12]([C:17]([OH:19])=[O:18])=[N:13][CH:14]=[CH:15][CH:16]=2)[N:7]([C:20]2[C:25]([CH3:26])=[CH:24][CH:23]=[CH:22][C:21]=2[CH3:27])[N:6]=1)([CH3:4])([CH3:3])[CH3:2].C(O)(=O)C.[Cl:32]CCl.ClN1C(=O)CCC1=O.[OH-].[K+]>O>[C:1]([C:5]1[C:9]([Cl:32])=[C:8]([NH:10][C:11]2[C:12]([C:17]([OH:19])=[O:18])=[N:13][CH:14]=[CH:15][CH:16]=2)[N:7]([C:20]2[C:25]([CH3:26])=[CH:24][CH:23]=[CH:22][C:21]=2[CH3:27])[N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: ClCCl
Reactant: Cc1cccc(C)c1-n1nc(C(C)(C)C)cc1Nc1cccnc1C(=O)O
Agent: O=C1CCC(=O)N1Cl
Agent: [K+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: Cc1cccc(C)c1-n1nc(C(C)(C)C)c(Cl)c1Nc1cccnc1C(=O)O
Temperature: 25 °C
Reaction time: 12 h
Yield: 76 %

Procedure:
To a solution of 3-{[3-tert-butyl-1-(2,6-dimethylphenyl)-1H-pyrazol-5-yl]amino}pyridine-2-carboxylic acid (Example 10, 50 mg, 0.14 mmol) in an acetic acid/dichloromethane mixture (1 mL of each) was added N-chlorosuccinimide (18 mg, 0.14 mmol). The solution was stirred at rt for 12 h, and then water (10 mL) was added. The reaction mixture was basified to pH 9 using KOH (1.0 M ice cold solution). The water layer was extracted with dichloromethane (50 mL), and the organic phase was subsequently washed with saturated sodium sulfite, brine, and concentrated to dryness. The crude material was subjected to HPLC purification to give the desired product (42 mg, 76%). 1H NMR (300 MHz, CD2Cl2) δ 10.45 (s, 1H), 9.30 (s, 1H), 8.04 (d, 1H), 7.50 (m, 1H), 7.25 (m, 2H), 7.15 (m, 2H), 2.02 (s, 6H), 1.43 (s, 9H). ES-MS m/z 399.0 (MH+); HPLC RT (min) 3.33.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:13])=[C:4]([I:12])[C:5]([OH:11])=[C:6]([C:8](=[O:10])[CH3:9])[CH:7]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH:21]([CH3:27])[C:22]([O:24][CH2:25][CH3:26])=[O:23]>CN(C)C=O.O.C(OCC)(=O)C>[C:8]([C:6]1[C:5]([O:11][CH:21]([CH3:27])[C:22]([O:24][CH2:25][CH3:26])=[O:23])=[C:4]([I:12])[C:3]([F:13])=[C:2]([Cl:1])[CH:7]=1)(=[O:10])[CH3:9]
Reactant: CC(=O)c1cc(Cl)c(F)c(I)c1O
Reactant: CCOC(=O)C(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: CCOC(=O)C(C)Oc1c(C(C)=O)cc(Cl)c(F)c1I
Temperature: 60 °C
Reaction time: 3 h
Yield: 55.5 %

Procedure:
A solution of 1-(5-chloro-4-fluoro-2-hydroxy-3-iodophenyl)ethanone (5.00 g, 15.9 mmol) in N,N-dimethylformamide (80.0 mL) was treated with potassium carbonate (4.39 g, 31.8 mmol), followed by ethyl 2-bromopropanoate (2.48 mL, 19.1 mmol), and then stirred at 60° C. for 3 h. The reaction was stirred overnight at 60° C., and then worked up per the procedure below. The reaction was then re-submitted to the reaction conditions and stirred at 90° C. for 4 h. The reaction mixture was diluted with water and ethyl acetate. The organic layer was separated and washed with brine, dried over magnesium sulfate, filtered, and concentrated to give a crude residue. Purification by flash column chromatography (100% hexanes to 10% EtOAc/hexanes) gave the desired product (3.66 g, 56%) as a mixture of enantiomers. LCMS calculated for C13H14ClFIO4 (M+H)+: m/z=415.0; found: 414.9.
Reaction SMILES: C1(O[C:8](=[O:24])[NH:9][C:10]2[CH:15]=[C:14]([O:16][C@H:17]([CH3:21])[CH2:18][O:19][CH3:20])[C:13]([C:22]#[N:23])=[CH:12][N:11]=2)C=CC=CC=1.C(C1C=CC(NC([N:36]2C[CH2:41][CH2:40][CH2:39][C:38]3[CH:43]=[CH:44][C:45]([CH:47]([O:50]C)OC)=[N:46][C:37]2=3)=O)=NC=1)#N.[CH3:52][N:53]([CH:55]=[O:56])[CH3:54]>>[C:22]([C:13]1[C:14]([O:16][C@H:17]([CH3:21])[CH2:18][O:19][CH3:20])=[CH:15][C:10]([NH:9][C:8]([N:36]2[C:37]3[C:38](=[CH:43][C:44]([CH2:52][N:53]4[CH2:54][CH2:54][N:53]([CH3:55])[CH2:52][C:55]4=[O:56])=[C:45]([CH:47]=[O:50])[N:46]=3)[CH2:39][CH2:40][CH2:41]2)=[O:24])=[N:11][CH:12]=1)#[N:23]
Reactant: COC[C@@H](C)Oc1cc(NC(=O)Oc2ccccc2)ncc1C#N
Reactant: CN(C)C=O
Reactant: COC(OC)c1ccc2c(n1)N(C(=O)Nc1ccc(C#N)cn1)CCCC2
Product: COC[C@@H](C)Oc1cc(NC(=O)N2CCCc3cc(CN4CCN(C)CC4=O)c(C=O)nc32)ncc1C#N

Procedure:
From intermediates 145 and 81, coupled in an analogous manner to intermediate 236, but using DMF instead of THF, and deprotected in an analagous manner to Example 201. The title compound was obtained as an off-white solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:44])[CH2:7][CH2:6][CH2:5][N:4]([C:8]([CH:10]2[CH2:14][CH:13]([C:15]([O:17]C)=[O:16])[CH:12]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[F:25])[N:11]2[C:26](=[O:43])[CH2:27][NH:28][C:29]([NH:31][C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([CH2:38][C:39]([O:41]C)=[O:40])[CH:33]=2)=[O:30])=[O:9])[CH2:3]1.[OH-].[K+]>O.CO>[C:39]([CH2:38][C:34]1[CH:33]=[C:32]([NH:31][C:29](=[O:30])[NH:28][CH2:27][C:26]([N:11]2[CH:12]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[F:25])[CH:13]([C:15]([OH:17])=[O:16])[CH2:14][CH:10]2[C:8]([N:4]2[CH2:5][CH2:6][CH2:7][C:2]([CH3:1])([CH3:44])[CH2:3]2)=[O:9])=[O:43])[CH:37]=[CH:36][CH:35]=1)([OH:41])=[O:40]
Reactant: COC(=O)Cc1cccc(NC(=O)NCC(=O)N2C(C(=O)N3CCCC(C)(C)C3)CC(C(=O)OC)C2c2ccccc2F)c1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC1(C)CCCN(C(=O)C2CC(C(=O)O)C(c3ccccc3F)N2C(=O)CNC(=O)Nc2cccc(CC(=O)O)c2)C1
Yield: 36 %

Procedure:
A The reaction is carried out in a way analogous to that described in Example 3, but from 1.6 g of methyl (2RS,4RS,5SR)-2-(3,3-dimethylpiperidinocarbonyl)-5-(2-fluorophenyl)-1-{2-[3-(3-(methoxycarbonylmethyl)phenyl)ureido]acetyl}pyrrolidine-4-carboxylate and 0.3 g of potassium hydroxide in a mixture of 20 cm3 of distilled water and 40 cm3 of methanol. After treatment, there is obtained 0.55 g of (2RS,4SR,5SR)-1-{2-[3-(3-(carboxymethyl)phenyl)ureido]acetyl}-2-(3,3-dimethylpiperidinocarbonyl)-5-(2-fluorophenyl)pyrrolidine-4-carboxylic acid, melting at 173° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12](=[O:17])[CH2:13][C:14](=[O:16])[CH3:15])[CH:5]=[CH:6][C:7]=1[O:8]C.B(OB=O)=O.[CH2:23]([N:25]([CH2:38][CH3:39])[C:26]1[CH:33]=[CH:32][C:29]([CH:30]=O)=[C:28]([O:34][CH2:35][O:36][CH3:37])[CH:27]=1)[CH3:24].B(OCCCC)(OCCCC)O[CH2:42]CCC.C(N)CCC>C(OCC)(=O)C.[Cl-].[Na+].O>[CH2:23]([N:25]([CH2:38][CH3:39])[C:26]1[CH:33]=[CH:32][C:29](/[CH:30]=[CH:15]/[C:14](=[O:16])[CH2:13][C:12](=[O:17])/[CH:11]=[CH:10]/[C:4]2[CH:5]=[CH:6][C:7]([OH:8])=[C:2]([O:1][CH3:42])[CH:3]=2)=[C:28]([O:34][CH2:35][O:36][CH3:37])[CH:27]=1)[CH3:24]
Reactant: COc1ccc(C=CC(=O)CC(C)=O)cc1O
Reactant: CCCCOB(OCCCC)OCCCC
Reactant: CCN(CC)c1ccc(C=O)c(OCOC)c1
Agent: O=BOB=O
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCCCN
Solvent: O
Product: CCN(CC)c1ccc(/C=C/C(=O)CC(=O)/C=C/c2ccc(O)c(OC)c2)c(OCOC)c1
Reaction time: 1 h
Yield: 149.9 %

Procedure:
6-(3-Hydroxy-4-methoxyphenyl)hex-5-ene-2,4-dione (20 mg, 0.085 mmol) and boron trioxide (11 mg, 0.16 mmol) were placed in a 20 mL reaction vessel, and dissolved in 0.4 mL of ethyl acetate. To the stirring solution at 80° C. was added a solution of 4-diethylamino-2-(methoxymethoxy)benzaldehyde (26 mg, 0.11 mmol) and tri-n-butyl borate (25 μL, 93 μmol) in 0.7 mL of ethyl acetate. After the reaction mixture was stirred for 2 h at the same temperature, n-butylamine (10 μL, 0.10 mmol) was added with additional stirring for 1 h. The resulting mixture was diluted with 25 mL of brine, and the solution was extracted with 50 mL of ethyl acetate. The organic layer was dried over MgSO4, filtered, and concentrated in vacuo to give a crude solid of (1E,6E)-1-[4-diethylamino-2-(methoxymethoxy)phenyl]-7-(4-hydroxy-3-methoxyphenyl)hepta-1,6-diene-3,5-dione (57.8 mg).
Reaction SMILES: [F:1][C:2]1([F:32])[CH2:5][CH:4]([C:6]2[O:10][N:9]=[C:8]([C:11]3[CH:12]=[CH:13][C:14]([CH3:31])=[C:15]([NH:17][C:18]([C:20]4[N:24]5[CH:25]=[C:26]([CH2:29][OH:30])[CH:27]=[CH:28][C:23]5=[N:22][CH:21]=4)=[O:19])[CH:16]=3)[N:7]=2)[CH2:3]1.CCN(C(C)C)C(C)C.CS(Cl)(=O)=O.C([O-])([O-])=O.[K+].[K+].[F:53][CH2:54][CH2:55]O>C(Cl)Cl>[F:32][C:2]1([F:1])[CH2:5][CH:4]([C:6]2[O:10][N:9]=[C:8]([C:11]3[CH:12]=[CH:13][C:14]([CH3:31])=[C:15]([NH:17][C:18]([C:20]4[N:24]5[CH:25]=[C:26]([CH2:29][O:30][CH2:55][CH2:54][F:53])[CH:27]=[CH:28][C:23]5=[N:22][CH:21]=4)=[O:19])[CH:16]=3)[N:7]=2)[CH2:3]1
Reactant: OCCF
Reactant: Cc1ccc(-c2noc(C3CC(F)(F)C3)n2)cc1NC(=O)c1cnc2ccc(CO)cn12
Agent: CS(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(-c2noc(C3CC(F)(F)C3)n2)cc1NC(=O)c1cnc2ccc(COCCF)cn12
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
N-(5-(5-(3,3-difluorocyclobutyl)-1,2,4-oxadiazol-3-yl)-2-methylphenyl)-6-(hydroxymethyl)imidazo[1,2-a]pyridine-3-carboxamide (F159) (95 mg, 0.216 mmol) was dissolved in DCM (1 mL) and DIEA (0.65 mmol). MsCl (0.65 mmol) was added dropwise and the resulting mixture was stirred for 15 minutes at room temperature. The reaction mixture was subjected to aqueous workup, extracted with DCM (2 mL), dried over Na2SO4 and concentrated to give a crude which was dissolved in 0.8 mL of 2-fluoroethanol followed by addition of K2CO3(90 mg, 0.65 mmol). The resulting mixture was heated at 120° C. for 20 minutes. The reaction mixture was subjected to standard aqueous workup and purified by silica chromatography to yield N-(5-(5-(3,3-difluorocyclobutyl)-1,2,4-oxadiazol-3-yl)-2-methylphenyl)-6-((2-fluoroethoxy)methyl)imidazo[1,2-a]pyridine-3-carboxamide (F176). 1H NMR (400 MHz, CDCl3) δ 9.56 (s, 1H), 8.60 (d, J=1.6, 1H), 8.21 (s, 1H), 7.89 (dd, J=1.7, 7.9, 1H), 7.77 (d, J=9.2, 1H), 7.62 (s, 1H), 7.53 (dd, J=1.7, 9.2, 1H), 7.42 (d, J=8.1, 1H), 4.72-4.64 (m, 3H), 4.59-4.52 (m, 1H), 3.86-3.79 (m, 1H), 3.79-3.73 (m, 1H), 3.68 (m, 1H), 3.16 (m, 4H), 2.47 (s, 3H). MS m/z 486.1 (M+1)+.
Reaction SMILES: C([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:23]3[C:18](=[CH:19][C:20]([O:26][CH2:27][CH2:28][CH2:29][N:30]4[CH2:35][CH2:34][N:33]([CH3:36])[CH2:32][CH2:31]4)=[C:21]([O:24][CH3:25])[CH:22]=3)[N:17]=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.Cl.[N+](C1C=CC(OC(=O)[NH:49][C:50]2[CH:55]=[CH:54][C:53]([N:56]3[CH2:60][CH2:59][CH2:58][CH2:57]3)=[CH:52][CH:51]=2)=CC=1)([O-])=O>>[N:56]1([C:53]2[CH:54]=[CH:55][C:50]([NH:49][C:6]([N:8]3[CH2:13][CH2:12][CH:11]([C:14]4[C:23]5[C:18](=[CH:19][C:20]([O:26][CH2:27][CH2:28][CH2:29][N:30]6[CH2:31][CH2:32][N:33]([CH3:36])[CH2:34][CH2:35]6)=[C:21]([O:24][CH3:25])[CH:22]=5)[N:17]=[CH:16][N:15]=4)[CH2:10][CH2:9]3)=[O:5])=[CH:51][CH:52]=2)[CH2:57][CH2:58][CH2:59][CH2:60]1
Reactant: O=C(Nc1ccc(N2CCCC2)cc1)Oc1ccc([N+](=O)[O-])cc1
Reactant: COc1cc2c(C3CCN(C(=O)OC(C)(C)C)CC3)ncnc2cc1OCCCN1CCN(C)CC1
Agent: Cl
Product: COc1cc2c(C3CCN(C(=O)Nc4ccc(N5CCCC5)cc4)CC3)ncnc2cc1OCCCN1CCN(C)CC1

Procedure:
The title compound was prepared from 4-{6-Methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]-quinazolin-4-yl}-piperidine-1-carboxylic acid tert-butyl ester, prepared as described in Example 207a, and (4-pyrrolidin-1-yl-phenyl)-carbamic acid 4-nitro-phenyl ester hydrochloride, prepared as described in Example 74a, using essentially the protocol given for Example 170c. 1H-NMR (400 MHz, CDCl3) δ 9.07 (s, 1H), 7.34 (s, 1H), 7.25 (s, 1H), 7.19 (m, 2H), 6.52 (m, 2H), 6.24 (s, 1H), 4.27 (m, 4H), 4.04 (s, 3H), 3.57 (tt, 1H), 3.26 (m, 4H), 3.14 (td, 2H), 2.58 (m, 2H), 2.64-2.35 (br, 8H), 2.30 (s, 3H), 2.20-2.08 (m, 4H), 2.04-1.93 (m, 6H). LC/MS (ESI): calcd mass 587.4, found 588.4 (MH)+.
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].[Cl:5][C:6]1[C:7]([CH2:13][O:14][C:15]2[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][CH:16]=2)=[N:8][C:9]([Cl:12])=[CH:10][CH:11]=1>C1(C)C=CC=CC=1>[Cl:5][C:6]1[C:7]([CH2:13][O:14][C:15]2[CH:20]=[CH:19][C:18]([N:21]=[C:1]=[O:2])=[CH:17][CH:16]=2)=[N:8][C:9]([Cl:12])=[CH:10][CH:11]=1
Reactant: Nc1ccc(OCc2nc(Cl)ccc2Cl)cc1
Reactant: O=C(Cl)Cl
Solvent: Cc1ccccc1
Product: O=C=Nc1ccc(OCc2nc(Cl)ccc2Cl)cc1
Reaction time: 0.33 h

Procedure:
Dry toluene (225 ml) was cooled to a temperature of from about 0° to 5° C. and a stream of phosgene gas passed therethrough until 17.4 grams had been absorbed. A solution of 4-((3,6-dichloro-2-pyridinyl)methoxy)benzenamine (15.8 grams; 0.058 mole) in 125 ml. of toluene was added portionwise thereto over a period of about 8 minutes while maintaining the reaction temperature at about 2° to 5° C. The cloudy reaction mixture was then stirred for about 20 minutes with the temperature thereof slowly increasing as excess phosgene was purged from the reaction mixture with nitrogen. At a temperature of about 85° C., the reaction mixture became clear. The toluene solvent was then removed from the reaction mixture under reduced pressure and the residue obtained extracted with hexane. The yellow crystalline product recovered from the hexane extract upon cooling was identified as the desired 3,6-dichloro-2-((4-isocyanatophenoxy)methyl)pyridine compound and was found to have a melting point of 61.5° - 62.5° C.
Reaction SMILES: [S:1]([C:4]1[CH:5]=[CH:6][C:7]([O:13][C:14]([F:17])([F:16])[F:15])=[C:8]([CH:12]=1)[C:9]([OH:11])=[O:10])([OH:3])=[O:2].[C:18](=O)([O-])[O-].[K+].[K+].CI>CN(C=O)C>[CH3:18][S:1]([C:4]1[CH:5]=[CH:6][C:7]([O:13][C:14]([F:15])([F:16])[F:17])=[C:8]([CH:12]=1)[C:9]([OH:11])=[O:10])(=[O:3])=[O:2]
Reactant: O=C([O-])[O-]
Reactant: O=C(O)c1cc(S(=O)O)ccc1OC(F)(F)F
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1ccc(OC(F)(F)F)c(C(=O)O)c1
Temperature: 25 °C
Reaction time: 60 h

Procedure:
To 5-Sulfino-2-trifluoromethoxy-benzoic acid (0.82 g) in DMF (5 mL) was added 1.3 g of potassium carbonate, and the reaction mixture was stirred for 5 minutes before methyl iodide (0.66 mL) was added. The reaction mixture was then stirred at room temperature for 60 hours. After such time the reaction mixture was concentrated in vacuo, and the residue was treated with 1N NaOH (10 mL) and THF (4 mL). The reaction mixture was stirred for a further 2 hours at room temperature. After such time the solution was acidified with concentrated HCl solution. THF was then removed in vacuo, and the precipitate was isolated by filtration and washed several times with water to yield the title compound. MS (m/e): 283.0 (M−H, 100%).
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[C@H:29]1[CH2:34][C@H:33]2[C@H:35]3[C@H:44]([CH2:45][CH2:46][C@:31]2([CH3:32])[CH2:30]1)[C:43]1[CH:42]=[CH:41][C:40]([O:47][CH3:48])=[CH:39][C:38]=1[CH2:37][CH2:36]3>ClCCl>[Br:1][C@@H:29]1[CH2:34][C@H:33]2[C@H:35]3[C@H:44]([CH2:45][CH2:46][C@:31]2([CH3:32])[CH2:30]1)[C:43]1[CH:42]=[CH:41][C:40]([O:47][CH3:48])=[CH:39][C:38]=1[CH2:37][CH2:36]3
Reactant: COc1ccc2c(c1)CC[C@@H]1[C@@H]2CC[C@]2(C)C[C@@H](O)C[C@@H]12
Reactant: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1ccc2c(c1)CC[C@@H]1[C@@H]2CC[C@]2(C)C[C@H](Br)C[C@@H]12
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a stirred suspension of 2.67 g (15.0 mmol) N-bromosuccinimide in 18 ml dry dichloromethane, a solution of 3.93 g (15.0 mmol) triphenylphosphine in 18 ml dry dichloromethane is added dropwise at 10° C. After 5 min, 1.72 g (6.0 mmol) 16β-hydroxy-3-methoxy-estra-1,3,5(10)-triene are added and the mixture is stirred at room temperature for 2 h. After column chromatography of the reaction product on silica gel (60 g) using 300 ml of dichloromethane, the target compound is obtained in the form of colorless crystals.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4]([CH2:9][S:10][CH3:11])[CH:3]=1.[F:12][C:13]1[CH:26]=[CH:25][C:16]2[S:17][C:18]([S:21](Cl)(=[O:23])=[O:22])=[C:19]([CH3:20])[C:15]=2[CH:14]=1>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][S:21]([C:18]2[S:17][C:16]3[CH:25]=[CH:26][C:13]([F:12])=[CH:14][C:15]=3[C:19]=2[CH3:20])(=[O:23])=[O:22])=[C:4]([CH2:9][S:10][CH3:11])[CH:3]=1
Reactant: CSCc1cc(Br)ccc1N
Reactant: Cc1c(S(=O)(=O)Cl)sc2ccc(F)cc12
Product: CSCc1cc(Br)ccc1NS(=O)(=O)c1sc2ccc(F)cc2c1C
Yield: 70.5 %

Procedure:
This compound was prepared in analogy to Example 1 starting from 4-bromo-2-methylsulfanylmethyl-phenylamine (Allen, David George; Eldred, Colin David; Judkins, Brian David; Mitchell, William Leonard, WO 9749699, 4.6 g) and 5-fluoro-3-methylbenzo[b]thiophene-2-sulphonyl chloride (1.06 g) to obtain the desired compound (1.3 g) as a brownish solid. MS (ISN): 458.1, 460.0 (M−H)−
Reaction SMILES: [CH:1](=[N+:19]([O-:38])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[P:39]([O:50]CCCC)([O:45][CH2:46][CH2:47][CH2:48][CH3:49])[O:40][CH2:41][CH2:42][CH2:43][CH3:44].[CH2:55](I)[CH2:56][CH2:57][CH3:58]>>[CH2:1]([N:19]([CH:20]([P:39](=[O:50])([O:45][CH2:46][CH2:47][CH2:48][CH3:49])[O:40][CH2:41][CH2:42][CH2:43][CH3:44])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[O:38][CH2:55][CH2:56][CH2:57][CH3:58])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCI
Reactant: CCCCOP(OCCCC)OCCCC
Reactant: CCCCCCCCCCCCCCCCCC=[N+]([O-])CCCCCCCCCCCCCCCCCC
Product: CCCCCCCCCCCCCCCCCCN(OCCCC)C(CCCCCCCCCCCCCCCCC)P(=O)(OCCCC)OCCCC
Temperature: 70 °C
Yield: 34.6 %

Procedure:
Following the procedure of Example 7, the title compound is prepared from 10.0 g (18 mmol) of N-(1-octadecylidene)octadecylamine N-oxide, 7.0 g (28 mmol) of tri-n-butyl phosphite and 5.15 g (28 mmol) of n-butyl iodide by heating at 70° C. for 16 hours. The residue is purified by flash chromatography (10:1 hexane:ethyl acetate eluent) followed by HPLC to give 4.9 g (35% yield) of the title compound as a white solid melting at 38°-40° C.
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[CH2:13]([C:17]1[N:22]2[N:23]=[C:24]([CH3:26])[N:25]=[C:21]2[N:20]([CH:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)[C:19](=[O:33])[C:18]=1[CH2:34][C:35]1[CH:40]=[CH:39][C:38]([C:41]2[C:42]([C:47]#[N:48])=[CH:43][CH:44]=[CH:45][CH:46]=2)=[CH:37][CH:36]=1)[CH2:14][CH2:15][CH3:16]>C(OCC)(=O)C>[CH2:13]([C:17]1[N:22]2[N:23]=[C:24]([CH3:26])[N:25]=[C:21]2[N:20]([CH:27]2[CH2:28][CH2:29][O:30][CH2:31][CH2:32]2)[C:19](=[O:33])[C:18]=1[CH2:34][C:35]1[CH:36]=[CH:37][C:38]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=2[C:47]2[NH:3][C:4](=[O:7])[O:5][N:48]=2)=[CH:39][CH:40]=1)[CH2:14][CH2:15][CH3:16]
Reactant: [NH3+]O
Reactant: CCCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(C2CCOCC2)c2nc(C)nn12
Reactant: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2)c(=O)n(C2CCOCC2)c2nc(C)nn12
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 53.1 %

Procedure:
A mixture of hydroxylammonium chloride (1.1 g), sodium hydrogen carbonate (1.8 g) and dimethyl sulfoxide (15 mL) was stirred at 40° C. for 30 min, 4′-{[7-butyl-2-methyl-5-oxo-4-(tetrahydro-2H-pyran-4-yl)-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile (0.52 g) was added, and the mixture was stirred at 90° C. for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was dissolved in tetrahydrofuran (15 mL). N,N′-Carbonyldiimidazole (0.21 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.18 mL) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous potassium hydrogensulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as colorless crystals (0.31 g, 52%).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12](=[O:17])[CH:11]=[CH:10]2.[Br:18][C:19]1[CH:24]=[CH:23][C:22]([Br:25])=[CH:21][C:20]=1[SH:26]>>[Br:18][C:19]1[CH:24]=[CH:23][C:22]([Br:25])=[CH:21][C:20]=1[S:26][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12](=[O:17])[CH:11]=[CH:10]2
Reactant: O=c1ccc2cc(OCCCCBr)ccc2[nH]1
Reactant: Sc1cc(Br)ccc1Br
Product: O=c1ccc2cc(OCCCCSc3cc(Br)ccc3Br)ccc2[nH]1

Procedure:
Prepared analogous to Example 122 from 6-(4-bromobutoxy)-carbostyril (m.p.: 198°-199° C.) and 2,5-dibromothiophenol.