Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[I-].[CH3:4][S+](C)(C)=O.[C:9]1([CH:15]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[O:16][C:17]([C:19]([C:21]2[C:30]([F:31])=[C:29]([F:32])[C:24]([C:25]([O:27][CH3:28])=[O:26])=[C:23]([F:33])[C:22]=2[F:34])=[CH2:20])=[O:18])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.Cl>CN(C)C=O.O.C(OCC)(=O)C>[C:35]1([CH:15]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[O:16][C:17]([C:19]2([C:21]3[C:22]([F:34])=[C:23]([F:33])[C:24]([C:25]([O:27][CH3:28])=[O:26])=[C:29]([F:32])[C:30]=3[F:31])[CH2:4][CH2:20]2)=[O:18])[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1
Reactant: C=C(C(=O)OC(c1ccccc1)c1ccccc1)c1c(F)c(F)c(C(=O)OC)c(F)c1F
Reactant: C[S+](C)(C)=O
Agent: Cl
Agent: [H-]
Agent: [I-]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)c1c(F)c(F)c(C2(C(=O)OC(c3ccccc3)c3ccccc3)CC2)c(F)c1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 66.1 %

Procedure:
In 330 ml of N,N-dimethylformamide was suspended 3.7 g of 60% sodium hydride. To the resulting suspension was added 20.2 g of trimethylsulfoxonium iodide with ice-cooling. The resulting mixture was stirred at room temperature for 1 hour. Thereto was added 33.0 g of methyl 4-(1-diphenylmethoxycarbonylvinyl)-2,3,5,6-tetrafluorobenzoate. The resulting mixture was stirred at the same temperature for 2 hours. To the reaction mixture were added 300 ml of ethyl acetate and 900 ml of water in this order. The resulting mixture was adjusted to pH 1 with 2N hydrochloric acid. The organic layer was separated, washed with water and a saturated aqueous sodium chloride solution in this order, and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The residue obtained was purified by a column chromatography (eluant: toluene) to obtain 22.5 g (yield: 66.1%) of methyl 4-(1-diphenylmethoxycarbonylcyclopropyl)-2,3,5,6-tetrafluorobenzoate.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)=[CH:3][CH:2]=1.[H-].[Na+].[C:15]([C:17]1[CH:24]=[CH:23][C:20]([CH2:21]Br)=[CH:19][CH:18]=1)#[N:16].O>CN(C)C=O>[N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:8][CH2:9][N:10]([CH2:21][C:20]3[CH:23]=[CH:24][C:17]([C:15]#[N:16])=[CH:18][CH:19]=3)[CH2:11][CH2:12]2)=[CH:3][CH:2]=1
Reactant: N#Cc1ccc(CBr)cc1
Reactant: c1cc(N2CCNCC2)ccn1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1ccc(CN2CCN(c3ccncc3)CC2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 14.2 %

Procedure:
A solution of N-(4-pyridyl)piperazine (0.33 g) in dry dimethylformamide (15 ml) was treated with sodium hydride (0.14 g) (45-55% dispersion in oil). The reaction mixture was then stirred for 30 minutes at ambient temperature under argon. 4-Cyanobenzyl bromide (0.41 g) was added and the mixture heated slowly to 80° C. and then maintained at this temperature for 2 hours. The resulting mixture was then poured into water, basified with aq.NaHCO3 solution and then extracted with diethyl ether. The organic extracts were then washed with aq.NaHCO3, water. brine, dried (MgSO4) and evaporated. The residue was recrystallised from toluene/hexane to give 1-(4-pyridyl)-4-(4-cyanobenzyl)piperazine (0.08 g) as a solid. m.p. 137-138° C.; microanalysis, found: C, 73.3; H, 6.5; N, 19.8%; C17H18N4 requires: C, 73.4; H, 6.5; N, 20.1%; NMR: (CDCl3) 2.56(t,4H); 3.35(t,4H); 3.61(s,2H); 6.67(dd,2H); 7.49(d,2H); 7.63(d,2H); 8.28(dd,2H); MS: m/z 279(MH)+.
Reaction SMILES: [NH2:1][C@:2]1([CH2:15][OH:16])[CH2:6][CH2:5][C@@H:4]([C:7]2[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=2)[CH2:3]1.[C:17]([O-])([O-])=[O:18].[K+].[K+]>C(=O)(OCC)OCC>[CH3:14][O:13][C:10]1[CH:11]=[CH:12][C:7]([C@@H:4]2[CH2:5][CH2:6][C@@:2]3([NH:1][C:17](=[O:18])[O:16][CH2:15]3)[CH2:3]2)=[CH:8][CH:9]=1
Reactant: COc1ccc([C@@H]2CC[C@](N)(CO)C2)cc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(=O)OCC
Product: COc1ccc([C@@H]2CC[C@]3(COC(=O)N3)C2)cc1
Yield: 79.9 %

Procedure:
To a suspension of [(1R,3R)-1-amino-3-(4-methoxy-phenyl)-cyclopentyl]-methanol (6.70 g, 30.3 mmol) in diethyl carbonate was added K2CO3 (4.83 g, 35.0 mmol) and the mixture was heated at reflux for about 20 hours. The reaction was concentrated, taken up in EtOAc (150 mL), washed with water (75 mL), dried over Na2SO4, filtered and concentrated. The crude product was further purified via flash chromatography with a gradient of from 40% to 80% EtOAc in heptane. Pure fractions were combined and concentrated to yield 5.99 g (80%) of (5R,7R)-7-(4-methoxy-phenyl)-3-oxa-1-aza-spiro[4.4]nonan-2-one as a white solid.
Reaction SMILES: CN(C)[CH:3]=[CH:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][C:8]=1[OH:15])=[O:6].[I:17]N1C(=O)CCC1=O.CO>C(Cl)(Cl)Cl>[I:17][C:4]1[C:5](=[O:6])[C:7]2[C:8](=[CH:9][C:10]([O:13][CH3:14])=[CH:11][CH:12]=2)[O:15][CH:3]=1
Reactant: COc1ccc(C(=O)C=CN(C)C)c(O)c1
Reactant: O=C1CCC(=O)N1I
Solvent: CO
Solvent: ClC(Cl)Cl
Product: COc1ccc2c(=O)c(I)coc2c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 3-(dimethylamino)-1-(2-hydroxy-4-methoxyphenyl)prop-2-en-1-one (20.0 g, 90.37 mmol) in anhydrous chloroform (100 ml) at 0° C. was added N-iodosuccinimide (23.5 g, 99.22 mmol) and silica gel (40 g). The reaction mixture was stirred at 0° C. for 60 minutes, then the insoluble material filtered off. The filtrate was washed with aqueous sodium thiosulfate (0.5M, 2×50 ml), followed by brine (100 ml), then dried over sodium sulfate. The solvent was removed under reduced pressure, providing an orange solid. To this solid was added methanol (30 ml), and the mixture was sonicated, filtered, the solid washed with methanol (2×5 ml), and the solid dried under reduced pressure, to give 3-iodo-7-methoxychromen-4-one as a pale yellow solid.
Reaction SMILES: C1C2C(=CC=CC=2)C=CC=1.[Cl-].[Al+3].[Cl-].[Cl-].[C:15]([C:18]1[CH:27]=[CH:26][C:25]2[C:20](=[CH:21][CH:22]=[C:23]([O:29][CH3:30])[C:24]=2Br)[CH:19]=1)(=[O:17])[CH3:16].BrC1C2C(=CC=CC=2)C=CC=1OC>>[C:15]([C:18]1[CH:27]=[CH:26][C:25]2[C:20](=[CH:21][CH:22]=[C:23]([O:29][CH3:30])[CH:24]=2)[CH:19]=1)(=[O:17])[CH3:16]
Reactant: COc1ccc2cc(C(C)=O)ccc2c1Br
Agent: COc1ccc2ccccc2c1Br
Agent: [Al+3]
Agent: [Cl-]
Solvent: c1ccc2ccccc2c1
Product: COc1ccc2cc(C(C)=O)ccc2c1
Temperature: 0 °C
Reaction time: 20 h

Procedure:
48 Grams of naphthalene and 16.7 g of anhydrous aluminum chloride are added to the solution of 2-acetyl-5-bromo-6-methoxynaphthalene obtained as in example 1a), while keeping the temperature at -10° C. The reaction mixture is kept under stirring for 2 hours at 0° C. and for 20 hours at room temperature and then it is worked as in example 1 obtaining 38.8 g of product with a yield equal to 79.2% calculated on the basis of the starting material 1-bromo-2-methoxynaphthalene.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH:10]=[C:11]2[CH2:16][CH2:15][N:14]([CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:13][CH2:12]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.B.O.S(=O)(=O)(O)[OH:27]>CCOCC.C(OCC)(=O)C>[CH2:17]([N:14]1[CH2:13][CH2:12][CH:11]([C:10](=[O:27])[CH2:9][CH2:8][CH2:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:16][CH2:15]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: C(CCCc1ccccc1)=C1CCN(Cc2ccccc2)CC1
Reactant: O=S(=O)(O)O
Agent: B
Solvent: CCOCC
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(CCCc1ccccc1)C1CCN(Cc2ccccc2)CC1
Reaction time: 0.5 h

Procedure:
To a solution of 4-(4-phenylbutylidene)-1-benzylpiperidine (from the Step C) (4.37 g) in anhydrous ether (150 mL) under nitrogen with stirring was add 1M borane solution in TEF (45 mL). The reaction was stirred for 3 h when water (2 mL) was added dropwise. The mixture was stirred a further 30 min and was then cooled in an ice bath. A solution of chromic anhydride (2.5 g), concentrated sulfuric acid (5.44 mL) and water (125 mL) was added dropwise with vigorous magnetic stirring over 5 min. After another 5 min, the ice bath was removed. After 1.5 h at rt, 0.5N sodium hydroxide and ether (400 mL each) were added and the mixture was stirred until the residue dissolved. The layers were separated and the aqueous layer was extracted twice with ether. The combined ether layers were washed with an aqueous EDTA solution, water and brine (100 mL each), dried over sodium sulfate and concentrated under reduced pressure to give a colorless gel. Flash chromatography on silica gel with 30-50% ethyl acetate in hexanes with 3% (v/v) TEA gave the title compound (1 g) as a colorless gel. Rf: 0.43 (30% ethyl acetate in hexanes with 3% (v/v) TEA). 1H NMR (500 MHz, CDCl3): δ7.25-7.33 (m, 7 H), 7.16-7.22 (m, 3 H), 3.51 (s, 2 H), 2.89-2.93 (m, 2 H), 2.63 (t, J=7.6 Hz, 2 H), 2.46 (t, J=7.2 Hz, 2 H), 2.38 (tt, J=11.5 and 3.9 Hz, 1 H), 1.99-2.03 (m, 2 H), 1.92 (tt, J=7.2 and 7.6 Hz, 2 H), 1.76-1.81 (m, 2 H), 1.65-1.72 (m, 2 H).
Reaction SMILES: [OH:1][C@@H:2]([C:5]1[N:10]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([O:17][C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)=[CH:13][CH:12]=2)[N:8]=[C:7]([C:25]([NH:27][C@@H:28]([CH3:33])[C:29]([O:31]C)=O)=[O:26])[CH:6]=1)[CH2:3][OH:4].[NH3:34]>CO>[NH2:34][C:29](=[O:31])[C@@H:28]([NH:27][C:25]([C:7]1[CH:6]=[C:5]([C@H:2]([OH:1])[CH2:3][OH:4])[N:10]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([O:17][C:18]3[CH:19]=[CH:20][C:21]([F:24])=[CH:22][CH:23]=3)=[CH:13][CH:12]=2)[N:8]=1)=[O:26])[CH3:33]
Reactant: N
Reactant: COC(=O)[C@H](C)NC(=O)c1cc([C@H](O)CO)nc(-c2ccc(Oc3ccc(F)cc3)cc2)n1
Solvent: CO
Product: C[C@H](NC(=O)c1cc([C@H](O)CO)nc(-c2ccc(Oc3ccc(F)cc3)cc2)n1)C(N)=O
Reaction time: 8 h
Yield: 87 %

Procedure:
To (S)-methyl 2-(6-((S)-1,2-dihydroxyethyl)-2-(4-(4-fluorophenoxy)phenyl) pyrimidine-4-carboxamido)propanoate (0.120 g, 0.263 mmol) was added MeOH (2.5 mL) and 7M NH3 in MeOH (2.5 mL, 17.5 mmol). The reaction was sealed, stirred overnight then evaporated in vacuo. MeOH was added and the reaction mixture evaporated again in vacuo. The resulting solid was triturated with 4 mL 20% EtOAc/hexanes, filtered, and rinsed once with 2 mL 20% EtOAc/hexanes. The material was dried under vacuum to give N-((S)-1-amino-1-oxopropan-2-yl)-6-((S)-1,2-dihydroxyethyl)-2-(4-(4-fluorophenoxy)phenyl)pyrimidine-4-carboxamide (Compound Example No. 16) as a pale peach-colored powder (0.099 g, 0.23 mmol. 87% yield). 1H NMR (400 MHz, DMSO-d6): 8.99 (1 H, d, J=7.7 Hz), 8.55 (2 H, d, J=9.0 Hz), 8.01 (1 H, s), 7.60 (1 H, s), 7.33-7.25 (2 H, m), 7.24-7.17 (3 H, m), 7.14 (2 H, d, J=8.8 Hz), 5.83 (1 H, d, J=5.3 Hz), 4.83 (1 H, t, J=5.9 Hz), 4.70 (1 H, q, J=3.9 Hz), 4.50 (1 H, p, J=7.2 Hz), 3.84-3.77 (1 H, m), 3.71-3.63 (1 H, m), 1.41 (3 H, d, J=7.0 Hz); LC/MS: m/z=441.2 [M+H]+.
Reaction SMILES: O[C:2]1([C:22]2[S:23][CH:24]=[CH:25][N:26]=2)[CH2:8][CH:7]2[N:9]([C:10]([C:12]3[CH:16]=[C:15]([C:17]4[CH:18]=[N:19][NH:20][CH:21]=4)[S:14][CH:13]=3)=[O:11])[CH:4]([CH2:5][CH2:6]2)[CH2:3]1.CCN(S(F)(F)[F:33])CC.C(=O)([O-])O.[Na+]>C(Cl)Cl>[F:33][C:2]1([C:22]2[S:23][CH:24]=[CH:25][N:26]=2)[CH2:8][CH:7]2[N:9]([C:10]([C:12]3[CH:16]=[C:15]([C:17]4[CH:18]=[N:19][NH:20][CH:21]=4)[S:14][CH:13]=3)=[O:11])[CH:4]([CH2:5][CH2:6]2)[CH2:3]1
Reactant: O=C(c1csc(-c2cn[nH]c2)c1)N1C2CCC1CC(O)(c1nccs1)C2
Reactant: CCN(CC)S(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: O=C(c1csc(-c2cn[nH]c2)c1)N1C2CCC1CC(F)(c1nccs1)C2
Reaction time: 1 h
Yield: 13.4 %

Procedure:
(3-Hydroxy-3-thiazol-2-yl-8-aza-bicyclo[3.2.1]oct-8-yl)-[5-(1H-pyrazol-4-yl)-thiophen-3-yl]-methanone (0.09 g, 0.23 mmol) in DCM (30 mL) was cooled to −78° C., under nitrogen. DAST (0.04 mL, 0.3 mmol) was added and the reaction mixture stirred for 1 hour. Saturated aqueous sodium hydrogen carbonate and DCM were added, the organics separated, washed with brine, dried over magnesium sulphate, filtered and the solvent removed by evaporation under vacuum. The residues were purified by flash chromatography, eluting with ethyl acetate. The fraction containing the desired product was concentrated under vacuum to give the title compound as a white solid (0.012 g). LCMS m/z 389.1 [M+H]+. R.T.=8.05 min (Analytical Method 2).
Reaction SMILES: O[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[N+:15]([O-:17])=[O:16])[N:5]=[C:4]([CH3:18])[CH:3]=1.CN(C)C=O.P(Cl)(Cl)([Cl:26])=O.O>C(Cl)(Cl)Cl>[Cl:26][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[N+:15]([O-:17])=[O:16])[N:5]=[C:4]([CH3:18])[CH:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1cc(O)nc(Nc2ccccc2[N+](=O)[O-])n1
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(Cl)nc(Nc2ccccc2[N+](=O)[O-])n1

Procedure:
A mixture of 160 g (0.65 mol) of N-(6-hydroxy-4-methylpyrimidin-2-yl)-o-nitroaniline, 2 ml of N,N-dimethylformamide and 120 ml of phosphorus oxychloride are heated at reflux for 3 hours. After having been cooled, and black slurry is dissolved in chloroform and this solution is added dropwise to 1 l of water. The temperature is maintained at 35° by the addition of ice. After 1 hour the organic phase is separated off and the aqueous phase is washed with chloroform. The two chloroform solutions are together dried and concentrated by evaporation. The black residue is dissolved in hot toluene, filtered and crystallised by the addition of hexane. 104.9 g (61%) of the title compound of formula ##STR16## (compound No. 2.007) are obtained in the form of crystals having a melting point of 175° C.
Reaction SMILES: [CH3:1][C:2]1[C:3]2[N:4]([CH:22]=[N:23][N:24]=2)[N:5]=[C:6]([N:8]2[CH2:13][CH2:12][CH:11]([OH:14])[CH:10]([Se]C3C=CC=CC=3)[CH2:9]2)[CH:7]=1.ClN1C(=O)CCC1=O.N12CCCN=C1CCCCC2>ClCCl>[CH3:1][C:2]1[C:3]2[N:4]([CH:22]=[N:23][N:24]=2)[N:5]=[C:6]([N:8]2[CH2:13][CH2:12][CH:11]([OH:14])[CH:10]=[CH:9]2)[CH:7]=1
Reactant: Cc1cc(N2CCC(O)C([Se]c3ccccc3)C2)nn2cnnc12
Agent: O=C1CCC(=O)N1Cl
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Product: Cc1cc(N2C=CC(O)CC2)nn2cnnc12
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of 387 mg of 1-(8-methyl-1,2,4-triazolo-[4,3-b]pyridazin-6-yl)-3-(phenylselenyl)-4-piperidinol in dichloromethane at room temperature was treated with a solution of 147 mg of N-chlorosuccinimide in 3 ml of dichloromethane and stirred at room temperature. A white precipitate formed. After 15 minutes, 305 mg of 1,8-diazabicyclo [5,4,0]undec-7-ene was added and stirring continued at room temperature for 20 hours. This resulted in a very dark-colored solution. The reaction volume was reduced at the rotary evaporator and the solution put directly on a silica gel (20 g) flash chromatography column. After rinsing the material on the column with dichloromethane, it was eluted with 95% dichloromethane/5% ethanol (10% concentrated ammonium hydroxide). The clean fractions were combined to give, on evaporation of the solvent, a tan viscous oil which slowly crystallized to give 1-(8-methyl-1,2,4-triazolo[4,3-b]pyridazin-6-yl)-1,4,5,6-tetrahydro-4-pyridinol melting at about 171°-173° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH:9]=[CH2:10])=[CH:4][C:3]=1[O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([SiH:26]([CH3:28])[CH3:27])=[CH:22][CH:21]=1>O1CCCC1.C(OCC)(=O)C>[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([Si:26]([CH2:10][CH2:9][CH2:8][C:5]2[CH:6]=[CH:7][C:2]([F:1])=[C:3]([O:11][C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:4]=2)([CH3:27])[CH3:28])=[CH:22][CH:21]=1
Reactant: C=CCc1ccc(F)c(Oc2ccccc2)c1
Reactant: COc1ccc([SiH](C)C)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1ccc([Si](C)(C)CCCc2ccc(F)c(Oc3ccccc3)c2)cc1
Temperature: 150 °C

Procedure:
To a mixture of 1.14 g (0.005 mole) of 3-(4-fluoro-3-phenoxyphenyl)-1-propene and 0.004 g (0.00001 mole) of hydrogen hexachloroplatinate hydrate in 1 mL of tetrahydrofuran under nitrogen was added slowly 0.83 g (0.005 mole) of (4-methoxyphenyl)dimethylsilane. After completion of addition the reaction mixture was diluted with a mixture of petroleum ether and ethyl acetate. This solution was treated with activated carbon and then was filtered through a short column of silica gel. The solvent was evaporated under reduced pressure, leaving a residue. This residue was heated at 150° C. at 0.1 mm of Hg to remove impurities. The pot residue was a light brown liquid weighing 1.25 g. The ir and proton nmr spectra confirmed that this residue was (4-methoxyphenyl)[3-(4-fluoro-3-phenoxyphenyl)propyl]dimethylsilane, compound 37 of Table 1.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[CH2:14][C:13](=[O:15])[NH:12][C:11]3[CH:16]=[C:17]([C:21]([F:24])([F:23])[F:22])[C:18]([CH3:20])=[CH:19][C:10]=3[N:9]=2)[CH:5]=[CH:6][CH:7]=1.CC1(C)C(C)(C)OB([C:33]2[CH:38]=[CH:37][C:36]([S:39]([NH2:42])(=[O:41])=[O:40])=[CH:35][CH:34]=2)O1>>[CH3:20][C:18]1[C:17]([C:21]([F:24])([F:23])[F:22])=[CH:16][C:11]2[NH:12][C:13](=[O:15])[CH2:14][C:8]([C:4]3[CH:3]=[C:2]([C:33]4[CH:38]=[CH:37][C:36]([S:39]([NH2:42])(=[O:41])=[O:40])=[CH:35][CH:34]=4)[CH:7]=[CH:6][CH:5]=3)=[N:9][C:10]=2[CH:19]=1
Reactant: CC1(C)OB(c2ccc(S(N)(=O)=O)cc2)OC1(C)C
Reactant: Cc1cc2c(cc1C(F)(F)F)NC(=O)CC(c1cccc(Br)c1)=N2
Product: Cc1cc2c(cc1C(F)(F)F)NC(=O)CC(c1cccc(-c3ccc(S(N)(=O)=O)cc3)c1)=N2

Procedure:
The title compound was prepared from 4-(3-bromo-phenyl)-7-methyl-8-trifluoromethyl-1,3-dihydro-benzo[b][1,4]diazepin-2-one (Example B.1) (200 mg, 0.50 mmol) and commercially available 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-benzenesulfonamide [CAS-no. 214360-51-7] (170 mg, 0.60 mmol) according to the general procedure II. Obtained as a white solid (165 mg, 69%). MS (ISP) 473.9 [(M+H)+]; mp>260° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[N:11]=[C:10]([C:18]3[CH:23]=[CH:22][N:21]=[C:20](Cl)[CH:19]=3)[N:9]=2)=[CH:4][C:3]=1[CH3:25].[C:26]([NH:30][S:31]([C:34]1[S:35][C:36](B2OC(C)(C)C(C)(C)O2)=[CH:37][CH:38]=1)(=[O:33])=[O:32])([CH3:29])([CH3:28])[CH3:27]>>[C:26]([NH:30][S:31]([C:34]1[S:35][C:36]([C:20]2[CH:19]=[C:18]([C:10]3[N:9]=[C:8]([C:5]4[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([CH3:25])[CH:4]=4)[CH:13]=[C:12]([C:14]([F:16])([F:17])[F:15])[N:11]=3)[CH:23]=[CH:22][N:21]=2)=[CH:37][CH:38]=1)(=[O:32])=[O:33])([CH3:29])([CH3:27])[CH3:28]
Reactant: CC(C)(C)NS(=O)(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)s1
Reactant: Cc1cc(-c2cc(C(F)(F)F)nc(-c3ccnc(Cl)c3)n2)ccc1Cl
Product: Cc1cc(-c2cc(C(F)(F)F)nc(-c3ccnc(-c4ccc(S(=O)(=O)NC(C)(C)C)s4)c3)n2)ccc1Cl

Procedure:
5-{4-[4-(4-Chloro-3-methyl-phenyl)-6-trifluoromethyl-pyrimidin-2-yl]-pyridin-2-yl}-thiophene-2-sulfonic acid tert-butyl amide was prepared from 4-(4-chloro-3-methyl-phenyl)-2-(2-chloro-pyridin-4-yl)-6-trifluoromethyl-pyrimidine (example E.43) (0.14 g, 0.36 mmol) and N-tert-butyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-thiophene-2-sulfonamide (example F.1) (0.15 g, 0.43 mmol) according to the general procedure VI. Obtained as a light brown solid (0.14 g), which was subsequently deprotected.
Reaction SMILES: C(BC(C(C)C)C)(C(C)C)C.[CH3:12][C:13]([CH3:28])([CH2:24][CH2:25][CH2:26][CH3:27])[CH:14]([O:17]C1CCCCO1)[C:15]#[CH:16].C([N+]([O-])(CC)CC)C.[OH-].[Na+].[I:39]I.S([O-])([O-])(=O)=S.[Na+].[Na+]>COCCOCCOC.O.O1CCCC1>[CH3:12][C:13]([CH3:28])([CH2:24][CH2:25][CH2:26][CH3:27])[CH:14]([OH:17])/[CH:15]=[CH:16]/[I:39]
Reactant: C#CC(OC1CCCCO1)C(C)(C)CCCC
Reactant: II
Agent: CC(C)C(C)BC(C)C(C)C
Agent: CC[N+]([O-])(CC)CC
Agent: O=S([O-])([O-])=S
Solvent: COCCOCCOC
Solvent: O
Solvent: C1CCOC1
Product: CCCCC(C)(C)C(O)/C=C/I
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To 233 ml. of a 0.43 M solution of disiamylborane in diglyme cooled to 0° C. under an inert atmosphere is added 23.8 g. (0.100 mole) 4,4-dimethyl-3-tetrahydropyranyloxy-1-octyne (Example 995). The mixture is allowed to come to room temperature and is stirred at ambient temperature for 3 hours. The solution is cooled to 0° C. and 22.5 g. (0.30 mole) of triethylamine oxide is added portionwise such that the temperature is maintained at 0°-5° C. The mixture is stirred at 0° C. for 1 hour and is then poured into 150 ml. of 1 N sodium hydroxide followed immediately by a solution of 25.4 g. (0.100 mole) of iodine in 60 ml. of tetrahydrofuran. The mixture is stirred at ambient temperatures for 0.5 hour and poured into 500 ml. of water. The mixture is decolorized by addition of sodium thiosulfate solution and is extracted into ether. The organic phase is washed with water and the solvent is removed in vacuo. The residue is stirred at room temperature for 20 hours with 900 ml. 3:1:1 tetrahydrofuran-acetic acid-water. The solution is evaporated in vacuo and the residue is chromatographed on silica gel in benzene using 10-20% ethylacetate in benzene.
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[C:7]([CH3:12])[CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[N:3]=1.O=P(Cl)(Cl)[Cl:20]>CN(C=O)C>[Cl:20][C:2]1[C:11]2[C:6](=[C:7]([CH3:12])[CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[N:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOC(=O)c1nc(O)c2cccc(C)c2n1
Solvent: CN(C)C=O
Product: CCOC(=O)c1nc(Cl)c2cccc(C)c2n1
Temperature: 80 °C
Reaction time: 48 h
Yield: 90 %

Procedure:
A mixture of ethyl 4-hydroxy-8-methylquinazoline-2-carboxylate (330 mg, 1.39 mmol), POCl3 (20 mL), and DMF (3 drops) was stirred at 80° C. for 48 h. The mixture was concentrated under reduced pressure and the solid residue was partitioned between DCM (100 mL) and cold H2O (100 mL). The separated aqueous phase was extracted with DCM (2×100 mL) and the combined organic layers were dried over MgSO4, filtered, and concentrated. The residue was purified by silica gel chromatography eluting with EtOAc/hexanes to afford ethyl 4-chloro-8-methylquinazoline-2-carboxylate as a solid (320 mg, 90%). 1H NMR (300 MHz, DMSO-d6) δ1.39 (t, J=7.1 Hz, 3H), 2.76 (s, 3H), 4.45 (q, J=7.1 Hz, 2H), 7.90 (m, 1H), 8.1 (m, 1H), 8.2 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1B(O)O.Cl[C:12]1[C:17]([CH2:18][OH:19])=[CH:16][CH:15]=[CH:14][N:13]=1.C(=O)(O)[O-].[Na+].O1CCOCC1>O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:12]1[C:17]([CH2:18][OH:19])=[CH:16][CH:15]=[CH:14][N:13]=1
Reactant: OCc1cccnc1Cl
Reactant: OB(O)c1ccccc1Cl
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])O
Solvent: C1COCCO1
Solvent: O
Product: OCc1cccnc1-c1ccccc1Cl
Temperature: 70 °C
Reaction time: 3 h
Yield: 65.3 %

Procedure:
Into a 50-mL round-bottom flask, was placed a solution of (2-chlorophenyl)boronic acid (1.6 g, 10.23 mmol, 1.20 equiv), (2-chloropyridin-3-yl)methanol (1 g, 6.97 mmol, 1.00 equiv), Pd(dppf)Cl2 (570 mg, 0.78 mmol, 0.10 equiv), and sodium bicarbonate (1.7 g, 20.24 mmol, 3.00 equiv) in a solvent mixture of dioxane (10 mL) and water (10 mL). The resulting solution was stirred for 3 h at 70° C., and then it was diluted with 20 mL of H2O. The resulting solution was extracted with 2×20 mL of dichloromethane, and the combined organic layers were concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:100-1:5) as eluent to furnish 1 g (65%) of [2-(2-chlorophenyl)pyridin-3-yl]methanol as a white solid.