Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([S:8]([CH3:10])=O)[C:5]([C:11]#[N:12])=[C:4]([C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)[N:3]=1.[N:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[CH2:25]CS.C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1[N:3]=[C:4]([C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)[C:5]([C:11]#[N:12])=[C:6]([S:8][CH2:10][CH2:25][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][N:19]=2)[N:7]=1
Reactant: CS(=O)c1nc(N)nc(-c2cccnc2)c1C#N
Reactant: SCCc1ccccn1
Solvent: C1CCC2=NCCCN2CC1
Solvent: COCCOC
Product: N#Cc1c(SCCc2ccccn2)nc(N)nc1-c1cccnc1

Procedure:
From 2-amino-4-methanesulfinyl-6-pyridin-3-yl-pyrimidine-5-carbonitrile, 2-pyridylethylmercaptan and DBU in DME. EI-MS m/e (%): 334 (M+, 35), 333 ([M—H]+, 100), 138 (52), 106 (33).
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]2[C:10](Br)=[CH:9][CH:8]=[CH:7][C:5]=2[CH:6]=1.[CH2:12]([N:19]1[CH2:24][CH2:23][C:22](=[O:25])[CH:21]([CH3:26])[CH2:20]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[CH2:12]([N:19]1[CH2:24][CH2:23][C:22]([OH:25])([C:10]2[C:4]3[O:3][C:2]([CH3:1])=[CH:6][C:5]=3[CH:7]=[CH:8][CH:9]=2)[CH:21]([CH3:26])[CH2:20]1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: Cc1cc2cccc(Br)c2o1
Reactant: CC1CN(Cc2ccccc2)CCC1=O
Product: Cc1cc2cccc(C3(O)CCN(Cc4ccccc4)CC3C)c2o1
Yield: 66.7 %

Procedure:
Beginning with 1.0 gm (4.74 mMol) 2-methyl-7-bromobenzofuran and 1.01 gm (4.98 mMol) 1-benzyl-3-methyl-4-oxopiperidine, 1.06 gm of the desired compound was prepared as an orange oil essentially as described in EXAMPLE 19.
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:6]([C:31]1[CH:36]=[CH:35][N:34]=[CH:33][N:32]=1)[S:7]([C:10]1[CH:15]=[C:14]([F:16])[C:13]([O:17][C@H:18]2[CH2:22][CH2:21][CH2:20][C@@H:19]2[C:23]2[N:27]([CH2:28][CH3:29])[N:26]=[CH:25][CH:24]=2)=[CH:12][C:11]=1[F:30])(=[O:9])=[O:8].C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCl>[CH2:28]([N:27]1[C:23]([C@H:19]2[CH2:20][CH2:21][CH2:22][C@@H:18]2[O:17][C:13]2[C:14]([F:16])=[CH:15][C:10]([S:7]([NH:6][C:31]3[CH:36]=[CH:35][N:34]=[CH:33][N:32]=3)(=[O:9])=[O:8])=[C:11]([F:30])[CH:12]=2)=[CH:24][CH:25]=[N:26]1)[CH3:29]
Reactant: CCn1nccc1[C@H]1CCC[C@@H]1Oc1cc(F)c(S(=O)(=O)N(Cc2ccc(OC)cc2OC)c2ccncn2)cc1F
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCn1nccc1[C@H]1CCC[C@@H]1Oc1cc(F)c(S(=O)(=O)Nc2ccncn2)cc1F
Yield: 71.8 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 1b by using the N-(2,4-dimethoxybenzyl)-4-{[(1S*,2R*)-2-(1-ethyl-1H-pyrazol-5-yl)cyclopentyl]oxy}-2,5-difluoro-N-(pyrimidin-4-yl)benzenesulfonamide (210 mg, 0.350 mmol) prepared in Example 37b, triethylsilane (0.20 mL), trifluoroacetic acid (2.0 mL) and dichloromethane (2.0 mL), to yield the title compound (113 mg, 72%) as a colorless solid.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:10]=[CH:11][C:12]([NH:15][C:16]([NH:18][C:19](=[O:25])[C:20]([O:23][CH3:24])([CH3:22])[CH3:21])=[O:17])=[N:13][CH:14]=2)[CH:5]=[CH:4][N:3]=1.[CH2:26]([N:29]1[CH:33]=[C:32](B2OC(C)(C)C(C)(C)O2)[CH:31]=[N:30]1)[CH:27]=[CH2:28].C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:26]([N:29]1[CH:33]=[C:32]([C:2]2[CH:7]=[C:6]([O:8][C:9]3[CH:10]=[CH:11][C:12]([NH:15][C:16]([NH:18][C:19](=[O:25])[C:20]([O:23][CH3:24])([CH3:22])[CH3:21])=[O:17])=[N:13][CH:14]=3)[CH:5]=[CH:4][N:3]=2)[CH:31]=[N:30]1)[CH:27]=[CH2:28]
Reactant: C=CCn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: COC(C)(C)C(=O)NC(=O)Nc1ccc(Oc2ccnc(Cl)c2)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: C=CCn1cc(-c2cc(Oc3ccc(NC(=O)NC(=O)C(C)(C)OC)nc3)ccn2)cn1
Temperature: 90 °C
Yield: 15.3 %

Procedure:
A mixture of Example C5 (0.12 g, 0.33 mmol), 1-allyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.085 g, 0.36 mmol) and K2CO3 (0.14 g, 0.99 mmol) in dioxane (4 mL) and H2O (1 mL) was sparged with Ar, treated with Pd(PPh3)4 (0.040 g, 0.034 mmol), sparged again with Ar and heated at 90° C. overnight. The mixture was cooled to RT, treated with satd. NaHCO3, extracted with EtOAc (3×) and the combined organics were dried over Na2SO4, concentrated to dryness and purified via reverse phase silica gel chromatography (MeCN/H2O (0.1% TFA)) to obtain N-((5-((2-(1-allyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)carbamoyl)-2-methoxy-2-methylpropanamide (22 mg, 14.6%). 1H NMR (400 MHz, DMSO-d6): δ 10.83 (s, 1H), 10.21 (br s, 1H), 8.41 (d, J=5.8 Hz, 1H), 8.33 (s, 1H), 8.28 (d, J=2.9 Hz, 1H), 8.05 (s, 1H), 8.03 (br s, 1H), 7.76 (dd, J=9.0, 2.9 Hz, 1H), 7.31 (d, J=2.4 Hz, 1H), 6.77 (d, J=5.7 Hz, 1H), 6.02 (m, 1H), 5.21 (m, 1H), 5.13 (m, 1H), 4.77 (d, J=5.8 Hz, 2H), 3.21 (s, 3H), 1.36 (s, 6H); MS (ESI) m/z: 437.2 (M+H+).
Reaction SMILES: [BH4-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]([C:28]2[CH:33]=[CH:32][C:31]([CH:34]=[O:35])=[CH:30][CH:29]=2)[N:11]2[CH2:14][C:13](=[C:15]([C:20]3[CH:25]=[C:24]([F:26])[CH:23]=[C:22]([F:27])[CH:21]=3)[S:16]([CH3:19])(=[O:18])=[O:17])[CH2:12]2)=[CH:6][CH:5]=1.O>CO>[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]([C:28]2[CH:29]=[CH:30][C:31]([CH2:34][OH:35])=[CH:32][CH:33]=2)[N:11]2[CH2:12][C:13](=[C:15]([C:20]3[CH:21]=[C:22]([F:27])[CH:23]=[C:24]([F:26])[CH:25]=3)[S:16]([CH3:19])(=[O:18])=[O:17])[CH2:14]2)=[CH:6][CH:5]=1
Reactant: CS(=O)(=O)C(=C1CN(C(c2ccc(Cl)cc2)c2ccc(C=O)cc2)C1)c1cc(F)cc(F)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CS(=O)(=O)C(=C1CN(C(c2ccc(Cl)cc2)c2ccc(CO)cc2)C1)c1cc(F)cc(F)c1
Reaction time: 1 h
Yield: 57.8 %

Procedure:
0.020 g of sodium borohydride is added to a solution of 0.50 g of (RS)-1-{(4-chlorophenyl)(4-formylphenyl)methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine in 15 cm3 of methanol at 0° C. After 1 hour at 0° C. , 40 cm3 of water are added and the product extracted with 100 cm3 of dichloromethane. The organic phase is washed twice with 40 cm3 of water and then 40 cm3 of a saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2.7 kPa). The residue obtained is chromatographed on a silica gel column (particle size 0.04-0.06 mm, diameter 3.2 cm, height 14 cm), at an argon pressure of 0.5 bar with a mixture of ethyl acetate and cyclohexane (30/70 by volume) and collecting 20 cm3 fractions. Fractions 20 to 25 are combined and then concentrated to dryness under reduced pressure (2.7 kPa). 0.29 g of (RS)-1-{(4-chlorophenyl)[4-(hydroxymethyl)phenyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine is obtained in the form of a white foam [NMR spectrum in DMSO-d6, T=300K, δ in ppm (250 MHz): 3.02 (3H, s, SCH3), 3.90 (2H, s, NCH2), 4.20 (2H, s, NCH2), 4.42 (2H, d, J=5 Hz, OCH2), 4.75 (1H, s, NCH), 5.10 (1H, t, J=5 Hz, OH), between 7.10 and 7.50 (11H, m, 11CH arom.)].
Reaction SMILES: [H-].[Na+].[C:3]([O:10][CH3:11])(=[O:9])[CH2:4][C:5](OC)=[O:6].[CH3:12][N:13]1[CH:18]=[CH:17][C:16](=O)[O:15]C1=O>CN(C)C=O>[OH:15][C:16]1[CH:17]=[CH:18][N:13]([CH3:12])[C:5](=[O:6])[C:4]=1[C:3]([O:10][CH3:11])=[O:9]
Reactant: COC(=O)CC(=O)OC
Reactant: Cn1ccc(=O)oc1=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1c(O)ccn(C)c1=O
Temperature: 80 °C
Reaction time: 0.33 h
Yield: 39.9 %

Procedure:
Under ice cooling, 568 mg of sodium hydride (60%) was added to a mixture of 181 mg of dimethyl malonate and 70 ml of N,N-dimethylformamide, and the mixture was stirred for 20 minutes. After the mixture was heated to 80° C., 1.50 g of 3-methyl-2H-1,3-oxazine-2,6(3H)-dione was added to the mixture, followed by further stirring at 120° C. for 7 hours. The reaction mixture was concentrated under reduced pressure, 2 mol/L hydrochloric acid was added to the residue, and the mixture was stirred at 60° C. for 15 minutes. The mixture was extracted with ethyl acetate. The organic layer was washed with an aqueous saturated sodium chloride solution, dried with sodium sulfate, filtered, and concentrated. The residue was subjected to silica gel column chromatography (eluent: ethyl acetate) to obtain 100 mg of methyl 4-hydroxy-1-methyl-2-oxo-1,2-dihydropyridine-3-carboxylate represented by the formula:
Reaction SMILES: [C:1](=[C:4]([C:7]#[N:8])[C:5]#[N:6])([CH3:3])[CH3:2].Br[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12]>[Zn].C1COCC1>[C:5]([CH:4]([C:7]#[N:8])[C:1]([CH3:3])([CH3:2])[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])#[N:6]
Reactant: CCOC(=O)CBr
Reactant: CC(C)=C(C#N)C#N
Agent: [Zn]
Solvent: C1CCOC1
Product: CCOC(=O)CC(C)(C)C(C#N)C#N
Reaction time: 1 h

Procedure:
Zinc powder (1.23 g, 18.85 mmol) was added to a THF (20 mL) solution of isopropylidenemalononitrile (1.0 g, 9.42 mmol), ethyl bromoacetate (3.15 g, 18.85 mmol) and titanium bis(cyclopentadienyl)dichloride (235 mg, 0.94 mmol). After stirring for 1 hour the solution was partitioned between ethyl acetate and aqueous 1N HCl. The organic phase was washed with water, brine, dried over MgSO4 and filtered. The solution was concentrated and the crude residue purified by silica gel chromatography using a hexanes/EtOAc gradient to give the indicated product. 1H NMR (400 MHz, CD3CN): δ 4.55 (s, 1H); 4.10 (q, J=7.2 Hz, 2H); 2.48 (s, 2H); 1.24 (s, 6H); 1.21 (t, J=7.2 Hz, 3H).
Reaction SMILES: ClC1C=C(C=CC=1)C(OO)=[O:6].[F:12][C:13]([F:27])([F:26])[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][C:22]([F:25])([F:24])[F:23])[N:16]=1>C(Cl)(Cl)Cl>[F:27][C:13]([F:12])([F:26])[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][C:22]([F:25])([F:24])[F:23])[N+:16]=1[O-:6]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: FC(F)(F)Cc1cccc(CC(F)(F)F)n1
Solvent: ClC(Cl)Cl
Product: [O-][n+]1c(CC(F)(F)F)cccc1CC(F)(F)F
Temperature: 25 °C
Reaction time: 4 h
Yield: 58.4 %

Procedure:
3-Chloroperoxybenzoic acid (4.52 g, 26.2 mmol) was added to a solution of 2,6-bis-(2,2,2-trifluoro-ethyl)-pyridine (4.25 g, 17.5 mmol) in CHCl3 (70 mL). The reaction was stirred at room temperature for 4 hours and then quenched with satd Na2SO3. The layers were separated and the aqueous layer was extracted with CH2Cl2. The organic layers were washed with 1 N NaOH, brine, dried over Na2SO4 and concentrated to a yellow oil. Purification by flash column chromatography (0% to 50% EtOAc in hexanes) gave the product as a yellow solid (2.65 g, 58%). 1H NMR (400 MHz, CDCl3): δ 3.96 (q, J=10.4 Hz, 4H), 7.27 (t, J=8.1 Hz, 1H), 7.47 (d, J=8.1 Hz, 2H).
Reaction SMILES: [C:1]([O:5]CC)(=O)[NH:2][NH2:3].Cl[C:9]1[N:10]=[N:11][C:12]([C:16]2[CH:21]=[CH:20][C:19]([C:22]#[N:23])=[CH:18][CH:17]=2)=[C:13]([CH3:15])[CH:14]=1>C(O)CCC>[CH3:15][C:13]1[C:12]([C:16]2[CH:21]=[CH:20][C:19]([C:22]#[N:23])=[CH:18][CH:17]=2)=[N:11][N:10]2[C:1](=[O:5])[NH:2][N:3]=[C:9]2[CH:14]=1
Reactant: CCOC(=O)NN
Reactant: Cc1cc(Cl)nnc1-c1ccc(C#N)cc1
Solvent: CCCCO
Product: Cc1cc2n[nH]c(=O)n2nc1-c1ccc(C#N)cc1

Procedure:
A 12.6 g. portion of ethyl carbazate is dissolved in 300 ml. of butanol. A 13.77 g. portion of 3-chloro-5-methyl-6-(p-cyanophenyl)pyridazine is added and the mixture is stirred at reflux for 18 hours. The mixture is cooled in ice and the solid is recovered by filtration and air dried, giving 6.3 g. of the desired product as a cream colored solid, m.p.>300° C.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[C:5]2[S:10][C:9]([NH:11][C:12](=[O:18])[CH2:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[CH:8][C:6]=2[N:7]=1.CC1(C)C(C)(C)OB([C:33]2[CH:41]=[CH:40][CH:39]=[C:38]3[C:34]=2[CH:35]=[N:36][NH:37]3)O1>>[NH:37]1[C:38]2[C:34](=[C:33]([C:2]3[N:3]=[C:4]([N:19]4[CH2:24][CH2:23][O:22][CH2:21][CH2:20]4)[C:5]4[S:10][C:9]([NH:11][C:12](=[O:18])[CH2:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[CH:8][C:6]=4[N:7]=3)[CH:41]=[CH:40][CH:39]=2)[CH:35]=[N:36]1
Reactant: CC(C)(C)CC(=O)Nc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Reactant: CC1(C)OB(c2cccc3[nH]ncc23)OC1(C)C
Product: CC(C)(C)CC(=O)Nc1cc2nc(-c3cccc4[nH]ncc34)nc(N3CCOCC3)c2s1

Procedure:
Crude N-(2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)-3,3-dimethylbutanamide (55 mg) was coupled to 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole 7 via General Procedure A. The product was purified by reverse phase HPLC to yield 16.9 mg of 173. MS (Q1) 451 (M)+
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[N:21]=[C:22]([S:33][C:34]3[N:39]=[CH:38][CH:37]=[CH:36][N:35]=3)[NH:23][C:24]=2[C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=2)=[CH:16][CH:15]=1>ClCCl>[CH3:32][O:31][C:28]1[CH:27]=[CH:26][C:25]([C:24]2[N:23]=[C:22]([S:33]([C:34]3[N:39]=[CH:38][CH:37]=[CH:36][N:35]=3)=[O:9])[NH:21][C:20]=2[C:17]2[CH:18]=[CH:19][C:14]([O:13][CH3:12])=[CH:15][CH:16]=2)=[CH:30][CH:29]=1
Reactant: COc1ccc(-c2nc(Sc3ncccn3)[nH]c2-c2ccc(OC)cc2)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: COc1ccc(-c2nc(S(=O)c3ncccn3)[nH]c2-c2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 86.5 %

Procedure:
A solution of 2.164 g of 3-chloroperbenzoic acid (80%) in 150 ml of dichloromethane is added dropwise to a solution of 3.91 g of 4,5-bis(4-methoxyphenyl)-2-(2-pyrimidinylthio)imidazole in 100 ml of dichloromethane. The mixture is stirred for 3 hours at room temperature, the solution is washed with sodium bicarbonate solution, dried over sodium sulfate, and concentrated to dryness under vacuum. The residue is chromatographed on 150 g of silica gel with acetone/hexane, thus producing 3.52 g of 4,5-bis(4-methoxyphenyl)-2-(2-pyrimidinylsulfinyl)imidazole as an amorphous foam.
Reaction SMILES: [CH2:1]1[CH2:13][O:12][C:11]2[CH:10]=[CH:9][C:5]([CH2:6][CH2:7][NH2:8])=[CH:4][C:3]=2[O:2]1.Cl[C:15]1[C:16]2[C:29]([CH3:30])=[C:28]([CH3:31])[S:27][C:17]=2[N:18]=[C:19]([C:21]2[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=2)[N:20]=1>>[N:23]1[CH:24]=[CH:25][CH:26]=[C:21]([C:19]2[N:20]=[C:15]([NH:8][CH2:7][CH2:6][C:5]3[CH:9]=[CH:10][C:11]4[O:12][CH2:13][CH2:1][O:2][C:3]=4[CH:4]=3)[C:16]3[C:29]([CH3:30])=[C:28]([CH3:31])[S:27][C:17]=3[N:18]=2)[CH:22]=1
Reactant: NCCc1ccc2c(c1)OCCO2
Reactant: Cc1sc2nc(-c3cccnc3)nc(Cl)c2c1C
Product: Cc1sc2nc(-c3cccnc3)nc(NCCc3ccc4c(c3)OCCO4)c2c1C

Procedure:
With the procedure of Example 1, the reaction of 3,4-ethylenedioxyphenethylamine with 4-chloro-2-(pyridin-3-yl)-5,6-dimethyl-thieno-[2,3-d]-pyrimidine yields 2-(pyridin-3-yl)-4-(3,4-ethylenedioxyphenethylamino)-5,6-dimethyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [CH:1]1([N:7]2[C:12](=[O:13])[C:11]([C:14]([NH:16][CH2:17][C:18]([O:20]CC)=[O:19])=[O:15])=[C:10]([OH:23])[N:9]([CH:24]3[CH2:29][CH2:28][CH2:27][N:26](C(OCC4C=CC=CC=4)=O)[CH2:25]3)[C:8]2=[O:40])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1>C(O)(=O)C.Br.O>[CH:1]1([N:7]2[C:12](=[O:13])[C:11]([C:14]([NH:16][CH2:17][C:18]([OH:20])=[O:19])=[O:15])=[C:10]([OH:23])[N:9]([CH:24]3[CH2:29][CH2:28][CH2:27][NH:26][CH2:25]3)[C:8]2=[O:40])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)CNC(=O)c1c(O)n(C2CCCN(C(=O)OCc3ccccc3)C2)c(=O)n(C2CCCCC2)c1=O
Agent: Br
Solvent: O
Solvent: CC(=O)O
Product: O=C(O)CNC(=O)c1c(O)n(C2CCCNC2)c(=O)n(C2CCCCC2)c1=O
Temperature: 60 °C
Yield: 18.9 %

Procedure:
N-{[3-Cyclohexyl-6-hydroxy-2,4-dioxo-1-(3-piperidinyl)-1,2,3,4-tetrahydro-5-pyrimidinl]carbonyl}glycine hydrobromide. Phenylmethyl 3-[3-cyclohexyl-5-({[2-(ethyloxy)-2-oxoethyl]amino}carbonyl)-6-hydroxy-2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl]-1-piperidinecarboxylate (1.2 g, 2.15 mmoles) was stirred in a mixture of acetic acid (30 mL) and 48% hydrobromic acid (5.0 mL) for 40 hours—reaction incomplete. The mixture was then heated at 60° C. for 2 hours, diluted with water and extracted with ethyl acetate (×5). The combined extracts were dried and evaporated, and recrystallized from diethyl ether-hexane to give the title compound (160 mg, 20%). 1H NMR (400 MHz, DMSO-d6) δ ppm 12.84 (br. s., 1 H), 10.11 (s, 1H), 8.86 (s, 1 H), 5.12 (s, 1 H), 4.63 (t, J=12.00 Hz, 1 H), 4.09 (s, 2 H), 3.66 (t, J=11.37 Hz, 1 H), 3.28 (d, J=10.61 Hz, 2 H), 2.77 (t, J=11.12 Hz, 1 H), 2.36 (dd, J=12.38, 3.54 Hz, 1 H), 2.22-2.32 (m, 2 H), 1.89 (d, J=12.63 Hz, 1 H), 1.69-1.81 (m, 4 H), 1.55-1.67 (m, 4 H), 1.27 (q, J=12.88 Hz, 2 H), 1.11 (q, J=12.97 Hz, 1 H)
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[N:5]=[CH:6][N:7]([CH2:10][CH3:11])[C:8]=1[CH3:9].[CH3:12][C:13]1[N:18]=[C:17]([SH:19])[N:16]=[C:15]([OH:20])[CH:14]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:10]([N:7]1[C:8]([CH3:9])=[C:4]([CH2:3][S:19][C:17]2[N:16]=[C:15]([OH:20])[CH:14]=[C:13]([CH3:12])[N:18]=2)[N:5]=[CH:6]1)[CH3:11]
Reactant: Cc1cc(O)nc(S)n1
Reactant: CCn1cnc(CCl)c1C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCn1cnc(CSc2nc(C)cc(O)n2)c1C
Temperature: 25 °C
Reaction time: 72 h
Yield: 32.3 %

Procedure:
A mixture of 4-(chloromethyl)-1-ethyl-5-methyl-1H-imidazole hydrochloride (450 mg, 2.3 mmol), 6-methyl-2-sulfanylpyrimidin-4-ol (215 mg, 1.5 mmol), and potassium carbonate (720 mg, 5.2 mmol) in acetone (15 mL) was stirred at room temperature for 3 days. The solid material was removed by filtration. The filtrate was recovered and evaporated. The crude product was purified by flash chromatography (0-6% MeOH/DCM), affording 2-{[(1-ethyl-5-methyl-1H-imidazol-4-yl)methyl]sulfanyl}-6-methylpyrimidin-4-ol (128 mg, 32% yield); 1H NMR (400 MHz, DMSO-d6): δ 1.26 (t, 3H, J=6.7 Hz), 2.18 (m, 6H), 3.86 (m, 2H), 4.26 (s, 2H), 5.95 (s, 1H), 7.55 (s, 1H); M+266. The product was used without further purification.
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[S:9]([N:15]=[C:16]=[O:17])([N:12]=[C:13]=[O:14])(=[O:11])=[O:10]>C1C=CC=CC=1>[CH2:1]([O:8][C:13]([NH:12][S:9]([NH:15][C:16]([O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:17])(=[O:11])=[O:10])=[O:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCc1ccccc1
Reactant: O=C=NS(=O)(=O)N=C=O
Solvent: c1ccccc1
Product: O=C(NS(=O)(=O)NC(=O)OCc1ccccc1)OCc1ccccc1
Reaction time: 1 h
Yield: 107.2 %

Procedure:
10 g of anhydrous benzyl alcohol are placed in 150 ml of absolute benzene and 7.4 g of sulfuryl diisocyanate are added dropwise accompanied by stirring. The exothermic reaction which takes place leads to a rise in the temperature to 45° C. and shortly after the start a precipitate is formed. Following the temperature drop, stirring is continued for 1 hour at ambient temperature. The resulting precipitate is suction filtered and dried at 60° C. giving a yield of 18.06 g of colorless crystals (99.2% of theory), m.p. 139°-141° C., which can be recrystallized from ethanol.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[O:9][CH2:10][C:11]([F:14])([F:13])[F:12].C([Li])CCC.CN(C)[CH:22]=[O:23]>O>[Cl:1][C:2]1[C:3]([O:9][CH2:10][C:11]([F:12])([F:13])[F:14])=[CH:4][CH:5]=[C:6]([F:8])[C:7]=1[CH:22]=[O:23]
Reactant: Fc1ccc(OCC(F)(F)F)c(Cl)c1
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: O
Product: O=Cc1c(F)ccc(OCC(F)(F)F)c1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 19.1 %

Procedure:
To 2-chloro-4-fluoro-1-(2,2,2-trifluoro-ethoxy)-benzene (124, 2.10 g, 9.19 mmol), under an atmosphere of nitrogen at −78° C., n-butyllithium (2.50 M in hexane, 3.86 mL) was added slowly. After 60 minutes, N,N-dimethylformamide (0.782 mL, 0.0101 mol) was added to the reaction. After 30 minutes, the reaction was allowed to warm to room temperature for 10 minutes. The reaction was poured into water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 20% ethyl acetate in hexane to give the desired compound (125, 450 mg, 19.0%).
Reaction SMILES: [CH2:1]([C:5]1[NH:6][C:7](=[O:23])[N:8]([C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][C:11]=2[C:19]([F:22])([F:21])[F:20])[N:9]=1)[CH2:2][CH2:3][CH3:4].[C:24]([NH:28][S:29]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[C:38]1[CH:43]=[CH:42][C:41]([CH2:44]Br)=[CH:40][CH:39]=1)(=[O:31])=[O:30])([CH3:27])([CH3:26])[CH3:25]>>[CH2:1]([C:5]1[N:6]([CH2:44][C:41]2[CH:42]=[CH:43][C:38]([C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=3[S:29](=[O:31])(=[O:30])[NH:28][C:24]([CH3:25])([CH3:27])[CH3:26])=[CH:39][CH:40]=2)[C:7](=[O:23])[N:8]([C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][C:11]=2[C:19]([F:21])([F:22])[F:20])[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nn(-c2ccc([N+](=O)[O-])cc2C(F)(F)F)c(=O)[nH]1
Reactant: CC(C)(C)NS(=O)(=O)c1ccccc1-c1ccc(CBr)cc1
Product: CCCCc1nn(-c2ccc([N+](=O)[O-])cc2C(F)(F)F)c(=O)n1Cc1ccc(-c2ccccc2S(=O)(=O)NC(C)(C)C)cc1
Yield: 88 %

Procedure:
By the procedure of Example 13, Step A, 5-n-butyl-2,4-dihydro-2-[4-nitro-2-(trifluoromethyl)phenyl]-3H-1,2,4-triazol-3-one (from Step A) was alkylated with [2'-(N-t-butylsulfamoyl)biphenyl-4-yl]-methyl bromide (from Example 12, Step D). Flash chromatography of the crude product on silica gel (gradient elution with 0.5-5.0% MeOH in CH2Cl2) gave an 88% yield of the title compound as an orange solid, mp >78° C. (gradual), homogeneous by TLC (98:2 CH2Cl2 --MeOH), mass spectrum (FAB) m/e 632 (M+1)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:14]=[CH:13][C:6]([NH:7][CH2:8][CH2:9][C:10]([OH:12])=[O:11])=[CH:5][CH:4]=1.[C:15](Cl)([Cl:17])=[O:16]>C(Cl)Cl>[Cl:17][C:15]([N:7]([CH2:8][CH2:9][C:10]([OH:12])=[O:11])[C:6]1[CH:13]=[CH:14][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)=[O:16]
Reactant: COc1ccc(NCCC(=O)O)cc1
Reactant: O=C(Cl)Cl
Solvent: ClCCl
Product: COc1ccc(N(CCC(=O)O)C(=O)Cl)cc1
Yield: 99.5 %

Procedure:
By working in a manner similar to that described in Example 6, but starting from 3-(4-methoxyanilino)propionic acid (2.88 g; 14.7 mmol), methylene chloride (20 cc) and phosgene (4.3 g; 43.5 mmol), almost pure N-chloroformyl-3-(4-methoxyanilino)propionic acid (3.77 g) is obtained in the form of a white powder which melts at 90° C. After recrystallisation in a hexane/ethyl acetate mixture (50:50 by volume), the product melts at 93° C. The structure of the product obtained is confirmed by the infrared spectrum, mass spectrum and proton nuclear magnetic resonance spectrum.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH:3]([CH2:7][NH:8][C:9]([C:11]2[S:15][C:14]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)=[N:13][C:12]=2[CH3:23])=[O:10])[CH2:2]1.F[C:25]1[CH:34]=[CH:33][CH:32]=[CH:31][C:26]=1[C:27]([O:29][CH3:30])=[O:28].CS(C)=O.C(=O)([O-])[O-].[K+].[K+]>O>[Cl:22][C:19]1[CH:18]=[CH:17][C:16]([C:14]2[S:15][C:11]([C:9]([NH:8][CH2:7][CH:3]3[CH2:4][CH2:5][CH2:6][N:1]([C:25]4[CH:34]=[CH:33][CH:32]=[CH:31][C:26]=4[C:27]([O:29][CH3:30])=[O:28])[CH2:2]3)=[O:10])=[C:12]([CH3:23])[N:13]=2)=[CH:21][CH:20]=1
Reactant: Cc1nc(-c2ccc(Cl)cc2)sc1C(=O)NCC1CCCNC1
Reactant: COC(=O)c1ccccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: COC(=O)c1ccccc1N1CCCC(CNC(=O)c2sc(-c3ccc(Cl)cc3)nc2C)C1
Temperature: 130 °C
Reaction time: 6 h
Yield: 20.3 %

Procedure:
N-(Piperidin-3-yl methyl)-2-(4-chlorophenyl)-4-methylthiazole-5-carboxamide (105 mg, 0.300 mmol) and methyl 2-fluorobenzoate (0.0382 mL, 0.300 mmol) were added to dimethylsulfoxide (5 mL). To this mixture, potassium carbonate (82.9 mg, 0.600 mmol) was added and the mixture was stirred for 6 hours at 130° C. Subsequently, water was added and the mixture was extracted with ethyl acetate. The extract was washed with brine, followed by drying over magnesium sulfate and evaporation of the solvent. Purification of the residue by silica gel column chromatography (hexane:ethyl acetate=10:1->2:1) gave 29.5 mg (20%) of the desired compound as a colorless oil.
Reaction SMILES: C(N(S(F)(F)[F:7])CC)C.[Br:10][C:11]1[CH:12]=[C:13]([CH:17](O)[CH2:18][CH2:19][NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH:14]=[CH:15][CH:16]=1>>[Br:10][C:11]1[CH:12]=[C:13]([CH:17]([F:7])[CH2:18][CH2:19][NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH:14]=[CH:15][CH:16]=1
Reactant: CC(C)(C)OC(=O)NCCC(O)c1cccc(Br)c1
Reactant: CCN(CC)S(F)(F)F
Product: CC(C)(C)OC(=O)NCCC(F)c1cccc(Br)c1
Temperature: -78 °C

Procedure:
Diethylaminosulphur trifluoride (DAST) is added under an inert atmosphere to a cold (−78° C.) solution of alcohol 39. The reaction mixture is stirred at −78° C. until no starting material is seen by TLC. The reaction mixture is partitioned between water and EtOAc, and aqueous layer is extracted with EtOAc. The combined organic layers are washed with brine and dried over anhydrous MgSO4. Purification by flash chromatography gives tert-butyl 3-(3-bromophenyl)-3-fluoropropylcarbamate.