Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[N:2](/[CH:4]=[N:5]/[C:6]([C:8]1[N:12]2[CH2:13][CH2:14][N:15]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:16][C:11]2=[N:10][N:9]=1)=[S:7])C.N1C=CC=CC=1>C(O)C.CO>[S:7]1[C:6]([C:8]2[N:12]3[CH2:13][CH2:14][N:15]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:16][C:11]3=[N:10][N:9]=2)=[N:5][CH:4]=[N:2]1
Reactant: CN(C)/C=N/C(=S)c1nnc2n1CCN(C(=O)OC(C)(C)C)C2
Solvent: c1ccncc1
Solvent: CCO
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCn2c(nnc2-c2ncns2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 53.9 %

Procedure:
A mixture of 1,1-dimethylethyl 3-({[(1E)-(dimethylamino)methylidene]amino}carbonothioyl)-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazine-7(8H)-carboxylate (I113)(0.118 g, 0.349 mmol) and pyridine (0.056 ml, 0.698 mmol) in ethanol (2 ml) was stirred at 25° C. and hydroxylamine O-sulfonic acid (0.043 g, 0.384 mmol) in methanol (1.2 ml) was added in one batch. The mixture was stirred at RT and after a few minutes the solution became clear. After 1 h, the mixture had changed from orange to pale yellow in colour. The solvents were evaporated and the concentrated mixture was diluted with DCM (50 ml) and washed with water (5 ml), 0.2M NaOH (5 ml) and water (5 ml) and the organic layer was dried and concentrated. Chromatography (SP4, 0-100% ethyl acetate in isohexane) gave a white foam (58 mg). NMR showed some high field impurities therefore the foam was triturated with isohexane to give a white solid in 51.2 mg of desired product.
Reaction SMILES: P(Br)(Br)Br.Br[CH2:6][C:7]1[N:11]([CH3:12])[N:10]=[CH:9][CH:8]=1.[CH3:13][C:14]1[N:19]=[C:18]([SH:20])[N:17]=[C:16]([OH:21])[CH:15]=1>>[CH3:13][C:14]1[N:19]=[C:18]([S:20][CH2:6][C:7]2[N:11]([CH3:12])[N:10]=[CH:9][CH:8]=2)[N:17]=[C:16]([OH:21])[CH:15]=1
Reactant: Cn1nccc1CBr
Reactant: Cc1cc(O)nc(S)n1
Agent: BrP(Br)Br
Product: Cc1cc(O)nc(SCc2ccnn2C)n1
Yield: 55 %

Procedure:
The title compound was prepared by following the procedure described for Example 55 from 1-methyl-1H-pyrazole-5-carbaldehyde to provide (1-methyl-1H-pyrazol-5-yl)methanol, which gave 5-(bromomethyl)-1-methyl-1H-pyrazole upon reaction with phosphorous tribromide. The reaction of 5-(bromomethyl)-1-methyl-1H-pyrazole and 6-methyl-2-sulfanylpyrimidin-4-ol provided 6-methyl-2-{[(1-methyl-1H-pyrazol-5-yl)methyl]sulfanyl}pyrimidin-4-ol as a white solid (0.742 g, 55% yield); 1H NMR (400 MHz, DMSO-d6): δ 2.21 (s, 3H), 3.82 (s, 3H), 4.47 (s, 2H), 6.04 (bs, 1H), 6.23 (d, J=1.7 Hz, 1H), 7.29 (d, J=1.7 Hz, 1H), 8.19 (s, 1H); M+236.3.
Reaction SMILES: [C:1]1([CH2:7][O:8][N:9]2[C:15](=[O:16])[N:14]3[CH2:17][C@H:10]2[CH2:11][CH2:12][C@H:13]3[C:18]([OH:20])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[I-].ClC1C=CC=C[N+]=1C.[NH2:37][C:38]1[CH:43]=[CH:42][C:41]([Br:44])=[CH:40][N:39]=1>ClCCl>[CH2:7]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([NH:37][C:38]1[CH:43]=[CH:42][C:41]([Br:44])=[CH:40][N:39]=1)=[O:20])[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Reactant: Nc1ccc(Br)cn1
Agent: C[n+]1ccccc1Cl
Agent: [I-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc(Br)cn1)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
To a solution of (2S,5R)-6-(phenylmethoxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxylic acid (0.400 g, 1.448 mmol) in dry dichloromethane (17.66 mL) was added triethylamine (0.504 ml, 3.62 mmol), 2-chloro-1-methylpyridinium iodide (0.433 g, 1.694 mmol), and 2-amino-5-bromopyridine (0.311 g, 1.795 mmol) sequentially at room temperature under nitrogen. The reaction mixture was heated to 50° C. for 1 hour then purified on the mass directed HPLC (30×100 mm Waters Sunfire column; 5 micron; 50 ml/min; acetonitrile/water with 0.1% TFA over 15 min). Fractions containing the title compound were concentrated under vacuum then lyophilized overnight to afford the title compound as a yellow solid.
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH:23]4[CH2:25][CH2:24]4)=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1.[C:26]([N:29]1[CH2:33][CH2:32][NH:31][C:30]1=[O:34])(=[O:28])[CH3:27]>>[C:26]([N:29]1[CH2:33][CH2:32][N:31]([C:2]2[CH:3]=[CH:4][C:5]([C:8]([N:10]3[CH2:15][CH2:14][N:13]([C:16]4[C:21]([CH3:22])=[CH:20][C:19]([CH:23]5[CH2:25][CH2:24]5)=[CH:18][N:17]=4)[CH2:12][CH2:11]3)=[O:9])=[CH:6][N:7]=2)[C:30]1=[O:34])(=[O:28])[CH3:27]
Reactant: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(Br)nc2)CC1
Reactant: CC(=O)N1CCNC1=O
Product: CC(=O)N1CCN(c2ccc(C(=O)N3CCN(c4ncc(C5CC5)cc4C)CC3)cn2)C1=O
Yield: 56.1 %

Procedure:
Using (6-bromopyridin-3-yl)[4-(5-cyclopropyl-3-methylpyridin-2-yl)piperazin-1-yl]methanone (241 mg) described in Preparation Example 144 and 1-acetylimidazolidin-2-one (115 mg) and by the reaction and treatment in the same manner as in Example 1, the title compound (151 mg) was obtained.
Reaction SMILES: [Br:1][C:2]1[C:3]([C:12]#[N:13])=[C:4]([C:9]([OH:11])=[O:10])[NH:5][C:6]=1[CH2:7]C.COC(C1NC(C)=CC=1C#N)=O>>[Br:1][C:2]1[C:3]([C:12]#[N:13])=[C:4]([C:9]([OH:11])=[O:10])[NH:5][C:6]=1[CH3:7]
Reactant: CCc1[nH]c(C(=O)O)c(C#N)c1Br
Agent: COC(=O)c1[nH]c(C)cc1C#N
Product: Cc1[nH]c(C(=O)O)c(C#N)c1Br

Procedure:
The title compound was prepared by a procedure analogous to Intermediate 33 starting from 3-cyano-5-methyl-1H-pyrrole-2-carboxylic acid methyl ester (Intermediate 28).
Reaction SMILES: Br[CH2:2][CH:3]=[C:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[CH2:8][S:7][C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]1=2.[C:19](=[O:22])([O-:21])[O-].[K+].[K+].[CH2:25]([O:27][C:28]([CH:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1)=[O:29])[CH3:26]>CS(C)=O.C1C=CC=CC=1.[I-].[Na+]>[C:28]([OH:29])(=[O:27])[C:19]([OH:21])=[O:22].[CH2:25]([O:27][C:28]([CH:30]1[CH2:35][CH2:34][N:33]([CH2:2][CH:3]=[C:4]2[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[CH2:8][S:7][C:6]3[CH:15]=[CH:16][CH:17]=[CH:18][C:5]2=3)[CH2:32][CH2:31]1)=[O:29])[CH3:26]
Reactant: CCOC(=O)C1CCNCC1
Reactant: BrCC=C1c2ccccc2CSc2ccccc21
Reactant: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: c1ccccc1
Product: CCOC(=O)C1CCN(CC=C2c3ccccc3CSc3ccccc32)CC1
Product: O=C(O)C(=O)O
Temperature: 100 °C
Reaction time: 4 h
Yield: 72 %

Procedure:
To a solution of 11-(2-bromoethylidene)-6,11-dihydrodibenzo[b,e]thiepine (4.76 g, 0.015 mol, prepared similarly as described in Coll. Czech. Chem. Comm. 52, 1566, 1987) in dimethylsulfoxide (90 ml), potassium carbonate (3.1 g, 0.0225 mol), 4-piperidinecarboxylic acid ethyl ester (2.36 g, 0.015 mol) and sodium iodide (50 mg) were added and the mixture was stirred at 100° C. for 4 h. The reaction mixture was diluted with benzene (100 ml), the solid was filtered off and the filtrate was washed with water (4×60 ml). The benzene solution was dried (MgSO4) and the solvent removed in vacuo. The oily residue (6.34 g) was dissolved in acetone and treated with an ethanolic solution of oxalic acid. The resulting precipitate was filtered off and washed with a hot mixture of ethanol and acetone, affording 5.2 g (72%) of 1-(2-(6,11-dihydrodibenzo[b,e]thiepin-11-ylidene)-1-ethyl)-4-piperidinecarboxylic acid ethyl ester hydrogen oxalate.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[CH:9]1[O:13][N:12]=[C:11]([C:14]2[N:15]=[C:16]([CH:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)[S:17][CH:18]=2)[CH2:10]1.C(N(CC)C(C)C)(C)C.[Cl:34][CH2:35][C:36](Cl)=[O:37].O>C(Cl)Cl>[Cl:34][CH2:35][C:36]([N:22]1[CH2:23][CH2:24][CH:19]([C:16]2[S:17][CH:18]=[C:14]([C:11]3[CH2:10][CH:9]([C:3]4[C:4]([F:8])=[CH:5][CH:6]=[CH:7][C:2]=4[F:1])[O:13][N:12]=3)[N:15]=2)[CH2:20][CH2:21]1)=[O:37]
Reactant: Fc1cccc(F)c1C1CC(c2csc(C3CCNCC3)n2)=NO1
Reactant: O=C(Cl)CCl
Solvent: ClCCl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(CCl)N1CCC(c2nc(C3=NOC(c4c(F)cccc4F)C3)cs2)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a mixture of 4-[4-[5-(2,6-difluorophenyl)-4,5-dihydro-3-isoxazolyl]-2-thiazolyl]piperidine (i.e. the product of Example 1, Step D) (4.2 g, 12.0 mmol) and N,N-diisopropylethylamine (1.63 g, 12.6 mmol) in methylene chloride (25 mL) at 0° C. was added a solution of 2-chloroacetyl chloride (1.43 g, 1.26 mmol) in dichloromethane (3 mL), after which time the reaction mixture was allowed to warm to room temperature. After 4 h, the reaction mixture was poured into water and the layers were separated. The organic layer was washed with aqueous hydrochloric acid solution (1 N), saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by medium pressure liquid chromatography on silica gel (0 to 100% gradient of ethyl acetate in hexanes as eluant) to provide the title compound as a tan solid (2.8 g).
Reaction SMILES: [NH2:1][C:2]1[C:6]([Br:7])=[C:5]([C:8]([CH3:11])([CH3:10])[CH3:9])[O:4][N:3]=1.[C:12]1([S:18](Cl)(=[O:20])=[O:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>N1C=CC=CC=1.CN(C)C1C=CN=CC=1.ClCCl>[Br:7][C:6]1[C:2]([NH:1][S:18]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)(=[O:20])=[O:19])=[N:3][O:4][C:5]=1[C:8]([CH3:11])([CH3:10])[CH3:9]
Reactant: CC(C)(C)c1onc(N)c1Br
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(C)c1onc(NS(=O)(=O)c2ccccc2)c1Br
Temperature: 50 °C
Reaction time: 6 h

Procedure:
3-Amino-4-bromo-5-tert-butylisoxazole (219 mg, 1.0 mmol)was dissolved in dry pyridine (1 ml). Benzenesulfonyl chloride (0.14 ml, 1.1 mmol) and 4-dimethylamino-pyridine (5 mg) were added and the solution was stirred at 50 ° C. for 6 h. The reaction mixture was diluted with dichloromethane (75 ml), washed with 1N HCl (50 ml) and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure to yield a crude product, which was purified by column chromatography (9:1 hexanes/ethyl acetate). A crystalline solid was obtained after recrystallization from ethyl acetate/hexanes, m.p. 139°-141° C.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[C:9]([C@H:10]3[CH2:12][C@H:11]3NC)[C:4]=2[CH2:3][CH2:2]1.[CH2:15]([N:17](CC)CC)C.[C:22](Cl)(=[O:25])[CH2:23][CH3:24]>C(Cl)Cl>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[C:9]([C@H:10]3[CH2:12][C@H:11]3[CH2:15][NH:17][C:22](=[O:25])[CH2:23][CH3:24])[C:4]=2[CH2:3][CH2:2]1
Reactant: CCN(CC)CC
Reactant: CCC(=O)Cl
Reactant: CN[C@@H]1C[C@@H]1c1cccc2c1CCO2
Solvent: ClCCl
Product: CCC(=O)NC[C@@H]1C[C@@H]1c1cccc2c1CCO2
Yield: 21.8 %

Procedure:
A solution of (cis)-2-(2,3-dihydrobenzofuran-4-yl)cycloprop-1-yl methyl amine (0.43 mmol), triethylamine (1.30 mmol) and propionyl chloride (0.65 mmol) in 10 mL of methylene chloride was stirred at room temperature overnight. The reaction mixture was washed with brine (2×20 mL). The organic phase was separated, dried over magnesium sulfate, filtered and concentrated in vacuo. Purification by silica gel column chromatography (Hex:EtOAc, 4:1) provided 23 mg of the desired product (22%) as a yellow oil. HPLC purity >95%.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[N:11]=[C:10]([CH3:13])[CH:9]=[C:8]2[C:14]([F:17])([F:16])[F:15].B(Br)(Br)Br.CO.C(=O)(O)[O-].[Na+]>ClCCl>[OH:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[N:11]=[C:10]([CH3:13])[CH:9]=[C:8]2[C:14]([F:17])([F:15])[F:16]
Reactant: COc1cccc2c(C(F)(F)F)cc(C)nc12
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: Cc1cc(C(F)(F)F)c2cccc(O)c2n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 79.6 %

Procedure:
A solution of 11 g (45.6.10-3 mol) of 8-methoxy-2-methyl-4-trifluoromethylquinoline in 360 ml of dichloromethane is cooled to -60° C. and 228 ml of a 1 M solution of boron tribromide in dichloromethane are added dropwise. The reaction medium is subsequently stirred for 1 hour at room temperature, 250 ml of methanol are then added slowly and stirring is continued for 2 hours. 250 ml of dichloromethane are added and sodium bicarbonate solution is added to render the medium alkaline. The organic phase is separated off, washed with water, dried over sodium sulfate and concentrated under reduced pressure to give 8.25 g of the expected product in the form of brown crystals (yield=79.5%).
Reaction SMILES: [C:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5][CH:4]=1)#[N:2].[C:12](OC)(=[O:20])[C:13]1[C:14](=[CH:16][CH:17]=[CH:18][CH:19]=1)[SH:15].C(N(CC)CC)C>C1(C)C=CC=CC=1>[NH:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:3]([C:1]2[S:15][C:14]3[CH:16]=[CH:17][CH:18]=[CH:19][C:13]=3[C:12](=[O:20])[N:2]=2)=[CH:4]1
Reactant: N#Cc1c[nH]c2ccccc12
Reactant: COC(=O)c1ccccc1S
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: O=c1nc(-c2c[nH]c3ccccc23)sc2ccccc12
Yield: 19.5 %

Procedure:
3-Cyanoindole (1.00 g, 7.0 mmol) and methyl thiosalicylate (1.20 g, 7.0 mmol) were dissolved in toluene (10 ml), and triethylamine (1.5 ml, 10.4 mmol) was added thereto. The reaction mixture was refluxed for 24 hrs. The solvent was evaporated. The residue was recrystallized from ethanol to give the titled compound (0.38 g, 20%) as pale yellow crystals.
Reaction SMILES: [C:1]1([Se:7][CH2:8][CH2:9][OH:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C=O.[CH2:13](Cl)[Cl:14]>>[C:1]1([Se:7][CH2:8][CH2:9][O:10][CH2:13][Cl:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: ClCCl
Reactant: OCC[Se]c1ccccc1
Agent: C=O
Product: ClCOCC[Se]c1ccccc1

Procedure:
To a solution of 2-(phenylselenyl)ethanol (4.0 g, 20 mmol) [prepared according to the literature procedure: P. Rollin, V. V. Bencomo, P. Sinay, Synthesis, 13 (1984)] in CH2Cl2 (15 mL) was added paraformaldehyde (620 mg, 20 mmol). HCl gas was then bubbled into the solution at 5° C. for 2 hr. The solution was dried (MgSO4), and the solvent was removed under reduced pressure to give the title compound as a colorless oil in a quantitative yield.
Reaction SMILES: ClN([C:10]1[C:19]2[C:14](=[CH:15][C:16](O)=[C:17](OC)[CH:18]=2)[N:13]=[CH:12][N:11]=1)C1C=CC=CC=1F.BrCCCOC1CCCCO1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[N:13]1[C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:10]=[N:11][CH:12]=1
Reactant: COc1cc2c(N(Cl)c3ccccc3F)ncnc2cc1O
Agent: BrCCCOC1CCCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: c1ccc2ncncc2c1
Temperature: 90 °C
Yield: 172.9 %

Procedure:
A mixture of 4-(chloro-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline (3.28 g, 10 mmol), (prepared as described for the starting material in Example 2), 1-bromo-3-tetrahydropyranyloxypropane (2.5 g, 11 mmol) and potassium carbonate (5.0 g, 36 mmol) in DMF (50 ml) was stirred and heated at 90° C. for 3 hours. The reaction mixture was allowed to cool, was diluted with water (500 ml) and extracted with ethyl acetate (3×100 ml). The extracts were combined, washed with water (×3), and then brine, and dried (MgSO4). The solvent was removed by evaporation and the residue was purified by column chromatography eluting with ethyl acetate. The purified product was recrystallized from ethyl acetatethexane to give 4-(chloro-2-fluoroanilino)-6-methoxy-7-tetrshydropyran-2-yloxypropoxy)quinazoline (2.25 g, 49%).
Reaction SMILES: [CH2:1]([Mg]Br)[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH2:11](Br)[CH:12]=[CH2:13]>O1CCCC1>[C:3]1([CH2:2][CH2:1][CH2:13][CH:12]=[CH2:11])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: Br[Mg]CCc1ccccc1
Reactant: C=CCBr
Solvent: C1CCOC1
Product: C=CCCCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of phenethyl magnesium bromide (prepared from 25 g, 0.135 mol of phenethyl bromide and excess magnesium turnings) in anhydrous tetrahydrofuran (50 ml) was added to a stirred solution of allyl bromide (16.34 g, 0.135 mol) in anhydrous tetrahydrofuran (150 ml) at room temperature and under an atmosphere of dry nitrogen. The mixture was stirred at room temperature for 3 hours and the solvent was then evaporated off under reduced pressure and the residue was dissolved in ethyl acetate. The solution was washed with a saturated aqueous solution of ammonium chloride and the solvent was evaporated off under reduced pressure to give an oil which was distilled to give 5-phenylpent-1-ene as a colourless oil (b.p. 40° C., 0.5 mm, Hg).
Reaction SMILES: C[O:2][C:3](=[O:16])[CH:4]([O:12]C(=O)C)[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([Br:11])[N:6]=1.[OH-].[K+:18]>C1COCC1.CO>[Br:11][C:7]1[N:6]=[C:5]([CH:4]([OH:12])[C:3]([O-:16])=[O:2])[CH:10]=[CH:9][CH:8]=1.[K+:18]
Reactant: COC(=O)C(OC(C)=O)c1cccc(Br)n1
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C([O-])C(O)c1cccc(Br)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of methyl(acetyloxy)(6-bromopyridin-2-yl)acetate (1.36 g, 4.70 mmol) in THF (20 mL) and MeOH (10 mL) was added aqueous KOH (1.0 M, 9.88 mL, 9.88 mmol). The solution was stirred at room temperature for 2 hours and then the solvent was evaporated to give the title compound as a colorless solid which was carried on without purification.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([NH2:8])=[N:6][CH:7]=1.[F:9][C:10]1[CH:11]=[C:12](B(O)O)[CH:13]=[CH:14][C:15]=1[OH:16].C(=O)([O-])[O-].[Na+].[Na+]>C(O)C.O.C1(C)C=CC=CC=1.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>[NH2:8][C:5]1[N:4]=[CH:3][C:2]([C:12]2[CH:13]=[CH:14][C:15]([OH:16])=[C:10]([F:9])[CH:11]=2)=[CH:7][N:6]=1
Reactant: Nc1ncc(Br)cn1
Reactant: OB(O)c1ccc(O)c(F)c1
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: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCO
Product: Nc1ncc(-c2ccc(O)c(F)c2)cn1
Temperature: 120 °C

Procedure:
A mixture of 5-bromopyrimidin-2-amine (3.3 g, 19 mmol), (3-fluoro-4-hydroxyphenyl)boronic acid (2.7 g, 17 mmol), tetrakis(triphenylphosphine)palladium (0.6 g, 0.5 mmol), sodium carbonate (18.3 g, 172 mmol) in ethanol (15 mL), water (5 mL) and toluene (15 mL) was heated at 120° C. for 3 h. The volatiles were removed under reduced pressure. The residue was diluted with EtOAc, washed with water and brine, dried over MgSO4, filtered, and concentrated to obtain the desired product which was directly used in the next step.
Reaction SMILES: [CH2:1]([SH:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[CH2:8](S)[CH2:9][CH2:10]C.CC(S)CC.C(S)CC.CC(S)C.BrC1OC=C([C:32]([OH:34])=[O:33])C=1>>[CH2:5]([C:4]1[S:7][CH:1]=[C:2]([C:32]([OH:34])=[O:33])[CH:3]=1)[CH2:6][CH2:8][CH2:9][CH3:10]
Reactant: O=C(O)c1coc(Br)c1
Reactant: CCCCS
Reactant: CCCCCCS
Agent: CC(C)S
Agent: CCC(C)S
Agent: CCCS
Product: CCCCCc1cc(C(=O)O)cs1

Procedure:
By the same procedure, an equivalent amount of 1-hexanethiol, 1-butanethiol, 2-butanethiol, 1-propanethiol or 2-propanethiol is reacted with 5-bromofuran-3-carboxylic acid to produce, respectively:
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1([CH3:16])[C:8]([CH3:10])([CH3:9])[O:7][B:6]([C:11]2[CH:12]=[N:13][NH:14][CH:15]=2)[O:5]1.Cl.Cl[CH2:19][CH2:20][N:21]1[CH2:25][CH2:24][CH2:23][CH2:22]1.O>CN(C)C=O.C(OCC)(=O)C>[N:21]1([CH2:20][CH2:19][N:14]2[CH:15]=[C:11]([B:6]3[O:7][C:8]([CH3:9])([CH3:10])[C:4]([CH3:16])([CH3:3])[O:5]3)[CH:12]=[N:13]2)[CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: ClCCN1CCCC1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: CC1(C)OB(c2cnn(CCN3CCCC3)c2)OC1(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of sodium hydride (0.272 g, 11.34 mmol) in N,N-dimethylformamide (13 mL) was added 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1.0 g, 5.15 mmol) and 2-chloroethylpyrrolidine HCl salt (0.964 g, 5.67 mmol) as solutions in N,N-dimethylformamide (2 mL each). The reaction was stirred at room temperature for 0.5 hours and then heated to 65° C. for 3 hours. The reaction was cooled to room temperature and diluted with ethyl acetate (50 mL). Water (50 mL) was added, and the layers were separated. The aqueous layer was extracted with additional ethyl acetate (2×30 mL). The combined organics were washed with water, dried with anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the title compound, which was used without further purification. MS ESI(+) m/z 292.2 [M+H]+;
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:18])[CH2:15][CH2:16][CH3:17])[C:11]([C:19]([F:22])([F:21])[F:20])=[CH:10][C:9]=1[NH:23][C:24](=[O:40])[CH2:25][C:26](=O)[C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([C:33]2[CH:34]=[N:35][CH:36]=[N:37][CH:38]=2)[CH:28]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:18][N:14]([CH2:15][CH2:16][CH3:17])[C:12]1[C:11]([C:19]([F:22])([F:20])[F:21])=[CH:10][C:9]2[NH:23][C:24](=[O:40])[CH2:25][C:26]([C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([C:33]4[CH:38]=[N:37][CH:36]=[N:35][CH:34]=4)[CH:28]=3)=[N:7][C:8]=2[CH:13]=1
Reactant: CCCN(C)c1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3cncnc3)c2)cc1C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCN(C)c1cc2c(cc1C(F)(F)F)NC(=O)CC(c1cccc(-c3cncnc3)c1)=N2

Procedure:
The title compound was prepared from {5-(methyl-propyl-amino)-2-[3-oxo-3-(3-pyrimidin-5-yl-phenyl)-propionylamino]-4-trifluoromethyl-phenyl}-carbamic acid tert-butyl ester (Example M90) (0.40 g, 0.70 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a light orange solid (210 mg, 66%).
Reaction SMILES: [CH:1]([NH:3][NH:4][CH:5]=O)=O.C[Si](Cl)(C)C.CCN(CC)CC.[NH2:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][C:27]([OH:29])=[O:28])=[CH:22][CH:21]=1>N1C=CC=CC=1>[N:4]1[N:3]=[CH:1][N:19]([C:20]2[CH:21]=[CH:22][C:23]([CH2:26][C:27]([OH:29])=[O:28])=[CH:24][CH:25]=2)[CH:5]=1
Reactant: Nc1ccc(CC(=O)O)cc1
Reactant: O=CNNC=O
Agent: C[Si](C)(C)Cl
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: O=C(O)Cc1ccc(-n2cnnc2)cc1
Temperature: 100 °C
Yield: 92.9 %

Procedure:
Adapting a protocol by Catarzi et al (J. Med Chem., 2001, 44, 3157–3165), diformylhydrazine (352 mg, 4.0 mmol) and then dropwise trimethylsilyl chloride (2.53 mL, 20 mmol) and Et3N(1.30 mL, 9.3 mmol) were added to a suspension of 4-aminophenylacetic acid (201 mg, 1.33 mmol) in anhydrous pyridine. The mixture was heated at 100° C. overnight, volatiles were removed at reduced pressure and the resulting solid was treated with water (6 mL), collected, washed with H2O and dried in vacuo to provide 251 mg (93%) of 141JP01 as a light brown solid. LCMS m/z 204[M+H]+. 1H-NMR (DMSO-d6) δ 9.05 (s, 2H), 7.62 (d, 1H, J=8.6), 7.40 (d, 1H, J=8.2), 3.61 (s, 2H).
Reaction SMILES: [CH:1]([C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][CH:4]=1)=O.[NH:11]1[CH2:14][CH:13]([C:15]([OH:17])=[O:16])[CH2:12]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl.CO>[C:7]([C:6]1[CH:9]=[CH:10][C:3]([CH2:1][N:11]2[CH2:14][CH:13]([C:15]([OH:17])=[O:16])[CH2:12]2)=[CH:4][CH:5]=1)#[N:8]
Reactant: N#Cc1ccc(C=O)cc1
Reactant: O=C(O)C1CNC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Solvent: CC(=O)O
Product: N#Cc1ccc(CN2CC(C(=O)O)C2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 75 %

Procedure:
A mixture of 4-formylbenzonitrile (2.88 g, 22 0 mmol), azetidine-3-carboxylic acid (2.02 g, 20 mmol), and acetic acid (1.15 mL, 20.0 mmol) in dichloromethane (20 mL) and methanol (80 mL) was stirred at room temperature for 1 h. Sodium triacetoxyborohydride (6.78 g, 32.0 mmol) was added and stirring was continued at room temperature for 18 hr. The volatiles were removed under reduced pressure, and the residue was partitioned between water (50 mL) and diethyl ether (50 mL). The aqueous layer was collected, washed with diethyl ether (50 mL), and concentrated. The residue was dissolved in water (20 mL) and loaded onto a 2.5×20 cm HP-20 column [Preparation of HP-20 Gel: ˜400 ml of dry, unused MCI CHP-20 Gel (75-150 micron) was swelled in methanol for 24 hrs. The gel was filtered and rinsed with 1 liter of methanol. It was then transferred to a bottle for storage under methanol. Immediately before use, the desired amount of gel was rinsed thoroughly with 20 volumes of water]. The column was eluted with 240 mL of water and 400 mL of methanol. The product containing fractions were concentrated and co-evaporated from ethanol and ethyl acetate/heptane to afford 1-(4-cyanobenzyl)azetidine-3-carboxylic acid (3.25 g, 15.0 mmol, 75% yield) as a white solid. MS:(M+H)=217.18. 1H NMR (400 MHz, MeOD) δ ppm 3.39 (m, 1H), 4.08 (m, 4H), 4.32 (s, 2H), 7.63 (d, J=8.3 Hz, 2H), and 7.82 (d, J=8.3 Hz, 2H).