Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]([C:8]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:9]=1[CH:10]=[CH:11][N:12]=[CH:13]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H]>CO.[Pt]=O>[O:1]([C:8]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:9]=1[CH2:10][CH2:11][NH:12][CH2:13]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: [H][H]
Reactant: c1ccc(Oc2cccc3cnccc23)cc1
Agent: O=[Pt]
Solvent: CO
Product: c1ccc(Oc2cccc3c2CCNC3)cc1
Yield: 59.2 %

Procedure:
A solution of 5-phenoxyisoquinoline (1 g, 4.5 mmol) in methanol (50 ml) was shaken on a Parr hydrogenator at 55 psi hydrogen in the presence of platinum oxide (0.2 g) for 3 h. The catalyst was then removed by filtration and the solvent evaporated. The residue was triturated with hexane to give the title compound as a colourless solid (0.6 g, 60%); δH (CDCl3) 2.65-2.75 (2H, m, ArCH2CH2N), 3.1-3.2 (2H, m, ArCH2CH2N), 4.05 (2H, br s, ArCH2N), 6.75 (1H, d, J 8 Hz, ArH), 6.83 (1H, d, J 8 Hz, ArH), and 6.9-7.35 (6H, m, ArH); m/z (CI+, NH3) 226 (M+1)+.
Reaction SMILES: [Cl:1][C:2]1[C:3](Cl)=[N:4][CH:5]=[C:6]([CH:12]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8].[F:14][C:15]([F:19])([F:18])[CH2:16][OH:17].C[Si]([N-][Si](C)(C)C)(C)C.[Na+]>C1COCC1>[Cl:1][C:2]1[C:3]([O:17][CH2:16][C:15]([F:19])([F:18])[F:14])=[N:4][CH:5]=[C:6]([CH:12]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: CCOC(=O)c1cnc(Cl)c(Cl)c1
Reactant: OCC(F)(F)F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)c1cnc(OCC(F)(F)F)c(Cl)c1
Temperature: -73 °C
Reaction time: 0.5 h
Yield: 92.9 %

Procedure:
To a solution of ethyl 5,6-dichloronicotinate (6.28 g, 28.5 mmol) and 2,2,2-trifluoroethanol (2.71 ml, 37.1 mmol) in THF (90 ml) at −73° C. was added NaHMDS (37.1 ml, 37.1 mmol). The reaction was stirred at −73° C. for 30 minutes, then at 0° C. for 5 hours. The reaction was quenched with 30 mL saturated NH4Cl solution. The reaction mixture was then poured into 50 mL brine and phases were separated. The aqueous layer was extracted with DCM (2×100 mL). The combined organics were dried (Na2SO4) and concentrated. Silica gel chromatography with 100% heptane to 30% EtOAc in heptane provided final product (7.51 g). LCMS m/z 284.1 (M+H)+, Rt 1.07 min.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([C:18]([C:26]4[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=4)([C:20]4[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=4)[OH:19])[CH:16]=3)[N:11]=[C:10]([O:32]C)[CH:9]=2)[CH:5]=[CH:6][CH:7]=1.Cl.[CH2:35]1COCC1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([C:18]([OH:19])([C:26]4[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=4)[C:20]4[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=4)[CH:16]=3)[N:11]([CH3:35])[C:10](=[O:32])[CH:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: C1CCOC1
Reactant: COc1cc(-c2cccc(Cl)c2)c2cc(C(O)(c3cccnc3)c3cccnc3)ccc2n1
Agent: Cl
Product: Cn1c(=O)cc(-c2cccc(Cl)c2)c2cc(C(O)(c3cccnc3)c3cccnc3)ccc21
Yield: 100 %

Procedure:
Following the same procedure as described in example 1F, [4-(3-chloro-phenyl)-2-methoxy-quinolin-6-yl]-di-pyridin-3-yl-methanol (300 mg, 0.66 mmol) was treated with HCl in aqueous THF to yield the title compound (290 mg, 100% yield).
Reaction SMILES: [C:1]([NH:3][C:4](=[N:7][CH2:8][CH2:9][S:10][CH2:11][C:12]1[C:17]([O:18][CH3:19])=[CH:16][CH:15]=[CH:14][N:13]=1)SC)#[N:2].[CH3:20][NH2:21]>C(O)C>[C:1]([NH:3][C:4]([NH:21][CH3:20])=[N:7][CH2:8][CH2:9][S:10][CH2:11][C:12]1[C:17]([O:18][CH3:19])=[CH:16][CH:15]=[CH:14][N:13]=1)#[N:2]
Reactant: COc1cccnc1CSCCN=C(NC#N)SC
Reactant: CN
Solvent: CCO
Product: CNC(=NCCSCc1ncccc1OC)NC#N
Reaction time: 8 h

Procedure:
N-cyano-N'-[2-((3-methoxy-2-pyridyl)methylthio)ethyl]S-methylisothiourea (1.9 g) in ethanol (10 ml) was treated with ethanolic methylamine (20 ml 33% solution) and the resultant clear solution was allowed to stand overnight. Excess of methylamine was removed by bubbling nitrogen through the solution and the crystalline precipitate was recrystallised from ethanol to yield the title product (1.2 g), m.p. 122°-123°.
Reaction SMILES: C(C(CC)(P(O)(O)=O)C(O)=O)C.[H-].[Na+].[CH3:15][O:16][C:17]1[CH:18]=[C:19]([CH:23]2[CH2:27][CH2:26][CH2:25][C:24]2=O)[CH:20]=[CH:21][CH:22]=1.[C:29]([O:32][CH2:33][CH3:34])(=[O:31])[CH3:30]>COCCOC.O>[CH3:15][O:16][C:17]1[CH:18]=[C:19]([CH:23]2[CH2:27][CH2:26][CH2:25][C:24]2=[CH:30][C:29]([O:32][CH2:33][CH3:34])=[O:31])[CH:20]=[CH:21][CH:22]=1
Reactant: CCOC(C)=O
Reactant: COc1cccc(C2CCCC2=O)c1
Agent: CCC(CC)(C(=O)O)P(=O)(O)O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: CCOC(=O)C=C1CCCC1c1cccc(OC)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of diethyl phosphono acetic acid (8.0 ml) in 1,2-dimethoxyethane (80 ml) was added sodium hydride (60% in oil, 1.4 g) at 0° C. under N2. After being stirred for 1 hour at ambient temperature, to the solution was added a solution of 2-(3-methoxyphenyl)cyclopentanone (4.5 g) in 1,2-dimethoxyethane (20 ml). After being stirred for 12 hours, the reaction mixture was poured into a mixture of ethyl acetate and water. The organic layer was washed with saturated sodium bicarbonate aqueous solution and brine. The dried solvent was concentrated and the obtained residue was purified by column chromatography on silica gel to give ethyl [2-(3-methoxyphenyl)cyclopentylidene]acetate (5.0 g).
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[O:13][CH3:14])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.S(=O)(=O)(O)O.[N+:20]([O-])([O-:22])=[O:21].[K+].C(=O)([O-])[O-].[Na+].[Na+]>>[N:1]1([C:7]2[CH:12]=[C:11]([N+:20]([O-:22])=[O:21])[CH:10]=[CH:9][C:8]=2[O:13][CH3:14])[CH2:2][CH2:3][NH:4][CH2:5][CH2:6]1
Reactant: O=[N+]([O-])[O-]
Reactant: COc1ccccc1N1CCNCC1
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: COc1ccc([N+](=O)[O-])cc1N1CCNCC1

Procedure:
2-(Piperazin-1-yl)anisole (5.1 g; 26 mmol) is acidified slowly with 6 ml of sulfuric acid (5N) and then dehydrated by evaporation under reduced pressure. Concentrated sulfuric acid is then added (22 ml) very slowly (25 min) and the reaction medium is stirred until a homogeneous mixture is obtained. Potassium nitrate (3.1 g; 31 mmol) is added portionwise over 35 minutes. The reaction is stirred for 4 hours. The solution is then poured onto ice and neutralized by addition of sodium carbonate (to pH≈7-8). The nitro derivative is extracted from the aqueous phase with ethyl acetate (4×80 ml), dried over magnesium sulfate and purified by flash chromatography with an eluent gradient (2 to 5% methanol in dichloromethane in the presence of 0.5% aqueous ammonia).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]([S:14]([NH2:17])(=[O:16])=[O:15])([C:10]([OH:13])([CH3:12])[CH3:11])[CH3:9])[CH:5]=[CH:6][CH:7]=1.C(O)(=O)C.[CH2:22]([O:24][C:25](OCC)(OCC)OCC)[CH3:23]>>[Br:1][C:2]1[CH:3]=[C:4]([C:8]2([CH3:9])[C:10]([CH3:12])([CH3:11])[O:13][C:25]([O:24][CH2:22][CH3:23])=[N:17][S:14]2(=[O:15])=[O:16])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(O)C(C)(c1cccc(Br)c1)S(N)(=O)=O
Reactant: CCOC(OCC)(OCC)OCC
Solvent: CC(=O)O
Product: CCOC1=NS(=O)(=O)C(C)(c2cccc(Br)c2)C(C)(C)O1
Temperature: 100 °C
Reaction time: 6 h

Procedure:
A suspension of 14.40 g of 2-(3-bromophenyl)-3-hydroxy-3-methylbutane-2-sulfonamide (50%, contaminated with 1-(3-bromophenyl)ethanesulfonamide)) in 100 ml of tetraethoxymethane was admixed with 12 ml of acetic acid and stirred at 100° C. under a strong argon stream for 6 hours. After the removal of the solvent under reduced pressure (bath temperature 70° C.), the viscous residue was dried at 50° C. in a vacuum drying cabinet for 16 hours. The conversion was checked by LCMS and found to be incomplete. Therefore, the oily residue was left to react on the rotary evaporator under reduced pressure (bath temperature 80° C.) for 4 hours. After the addition of 10 ml of acetic acid, the bath temperature was increased to 85° C. and the pressure was adjusted to 150 mbar. Subsequently, the volatile constituents were removed, again under reduced pressure, and the crude product was purified by means of normal phase chromatography using a Flashmaster with an n-heptane/ethyl acetate gradient. The product-containing fractions were combined and concentrated by rotary evaporation. This gave the product (5.97 g) with a molecular weight of 376.3 g/mol (C14H18BrNO4S).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]([NH:17][CH2:18][C:19]([NH:21][C@H:22]([C:30]([NH:32][CH3:33])=[O:31])[CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:20])=[O:16])[C:10](=[O:34])[CH:9]1[CH2:35][C:36]1[CH:41]=[CH:40][C:39]([OH:42])=[CH:38][CH:37]=1)=O)(C)(C)C.FC(F)(F)C(O)=O>>[OH:42][C:39]1[CH:38]=[CH:37][C:36]([CH2:35][CH:9]2[NH:8][CH2:13][CH2:12][N:11]([CH2:14][C:15]([NH:17][CH2:18][C:19]([NH:21][C@H:22]([C:30]([NH:32][CH3:33])=[O:31])[CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[O:20])=[O:16])[C:10]2=[O:34])=[CH:41][CH:40]=1
Reactant: CNC(=O)[C@H](Cc1ccccc1)NC(=O)CNC(=O)CN1CCN(C(=O)OC(C)(C)C)C(Cc2ccc(O)cc2)C1=O
Solvent: O=C(O)C(F)(F)F
Product: CNC(=O)[C@H](Cc1ccccc1)NC(=O)CNC(=O)CN1CCNC(Cc2ccc(O)cc2)C1=O

Procedure:
Piperazinone acetyl-gly-phe-NHCH3 11a (0.58 g, 1.0×10-3 mole) and trifluoroacetic acid are stirred at room temperature for 1/2 hour. The solvent is then evaporated and the residue dissolved in CH2Cl2. The CH2Cl2 solution is washed in turn with saturated aqueous NaHCO3 and saturated aqueous NaCl before being dried over Na2SO4. Filtration of the drying agent and evaporation of the filtrate give 12a which is purified by chromatography and the structure corroborated by NMR. NMR (Acetone - d6)δ (d, 3, methyl amide), 3.0-4.3 (m, 14, methylenes and phenolic-OH), 4.53 (m, 1, phenylalanine methine), 6.88 (8, 4, aromatic), 7.25 (s, 5, aromatic), 7.6-8.0 (m, 3, amide NH's).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:5]=1[O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[N+:19]([O-])=O>CO.[Pd].C(O)C>[CH3:1][O:2][C:3](=[O:22])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:5]=1[O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[NH2:19]
Reactant: COC(=O)c1ccc(OC)cc1Oc1ccccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Solvent: CCO
Product: COC(=O)c1ccc(OC)cc1Oc1ccccc1N
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 1-1 (7.360 g, 21.87 mmol) in methanol (200 mL) was added to a suspension of 10% palladium on carbon in ethanol (100 mL). The mixture was stirred under hydrogen gas pressure at room temperature for 3 hours. The reaction mixture was filtered through celite and the filtrate evaporated in vacuo to afford the title compound 1-2 as an oil.
Reaction SMILES: [NH2:1][C:2]1[CH:13]=[CH:12][C:5]2[O:6][C:7]3([C:10](=[O:11])[C:4]=2[CH:3]=1)[CH2:9][CH2:8]3.[CH3:14][N:15]=[C:16]=[O:17]>O1CCCC1>[CH3:14][NH:15][C:16](=[O:17])[NH:1][C:2]1[CH:13]=[CH:12][C:5]2[O:6][C:7]3([C:10](=[O:11])[C:4]=2[CH:3]=1)[CH2:9][CH2:8]3
Reactant: Nc1ccc2c(c1)C(=O)C1(CC1)O2
Reactant: CN=C=O
Solvent: C1CCOC1
Product: CNC(=O)Nc1ccc2c(c1)C(=O)C1(CC1)O2

Procedure:
5-Aminospiro[benzo[b]furan-2(3H),1'-cyclopropane]-3-one (1.75 g.) and methyl isocyanate (1 ml.) were stirred in tetrahydrofuran for 2 hours at room temperature. The solvent was evaporated off under reduced pressure, and the residue was recrystallized from ethanol to give yellow prisms of 5-methylureidospiro[benzo[b]furan-2(3H),1'-cyclopropane]-3-one (1.06 g.).
Reaction SMILES: C1(S([N:10]2C3C(=CC(SC)=CC=3)C=C2)(=O)=O)C=CC=CC=1.C(=O)=O.Cl.[C:25]1([S:31]([N:34]2[C:42]3[C:37](=[CH:38][C:39]([CH3:43])=[CH:40][CH:41]=3)[CH:36]=[C:35]2[C:44](O)=[S:45])(=[O:33])=[O:32])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(Cl)(=O)OCC.N>O1CCCC1.C([Li])CCC.C(OCC)(=O)C.C(N(CC)CC)C.CN(C)P(=O)(N(C)C)N(C)C>[C:25]1([S:31]([N:34]2[C:42]3[C:37](=[CH:38][C:39]([CH3:43])=[CH:40][CH:41]=3)[CH:36]=[C:35]2[C:44]([NH2:10])=[S:45])(=[O:33])=[O:32])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: Cc1ccc2c(c1)cc(C(O)=S)n2S(=O)(=O)c1ccccc1
Reactant: CSc1ccc2c(ccn2S(=O)(=O)c2ccccc2)c1
Agent: CCOC(=O)Cl
Agent: Cl
Agent: N
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: Cc1ccc2c(c1)cc(C(N)=S)n2S(=O)(=O)c1ccccc1
Reaction time: 0.5 h
Yield: 49.6 %

Procedure:
To a solution of 1-benzenesulfonyl-5-methylthioindole (2 g) in tetrahydrofuran (70 ml), n-butyl lithium (5 ml, 1.59M) was added dropwise at −78° C. under nitrogen atmosphere, the mixture was stirred at the same temperature for 30 minutes, followed by drwopise addition of hexamethylphosphoric triamide (2.3 ml), and the mixture was stirred at the same temperature for 10 minutes. The stirred reaction mixture was heated to 15 to 30° C. over 30 minutes while carbon dioxide gas was blown therein at −78° C. To the reaction mixture was added 1N hydrochloric acid and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with water and dried. The solvent was distilled off under reduced pressure. The resulting residue was separated using silica gel column chromatography (dichloromethane methanol:acetic acid=100:5:1) to obtain a crude product (4 g). To absolution of the resulting crude 1-benzenesulfonyl-5-methylthioindole-2-carboxylic acid (4 g) in tetrahydrofuran (70 ml) was added triethylamine (1.84 ml) and ethyl chlorocarbonate (1 ml) under ice-cooling, the mixture was stirred at the same temperature for 30 minutes, followed by addition of aqueous ammonia (2 ml) at the same temperature. The mixture was stirred for 15 minutes. The reaction mixture was diluted with ethyl acetate, washed with water and dried. The solvent was distilled off under reduced pressure. The resulting residue was recrystallized (hexane/ethyl acetate) to obtain 1.08 g of the desired product as a white powder.
Reaction SMILES: C(O[CH:4]=[C:5]([C:8]#[N:9])[C:6]#[N:7])C.[Cl:10][C:11]1[CH:17]=[CH:16][C:14]([NH2:15])=[CH:13][CH:12]=1>>[Cl:10][C:11]1[CH:17]=[CH:16][C:14]([NH:15][CH:4]=[C:5]([C:8]#[N:9])[C:6]#[N:7])=[CH:13][CH:12]=1
Reactant: Nc1ccc(Cl)cc1
Reactant: CCOC=C(C#N)C#N
Product: N#CC(C#N)=CNc1ccc(Cl)cc1

Procedure:
{[(4-Chlorophenyl)amino]methylene}methane-1,1-dicarbonitrile was synthesized in the same manner using (ethoxymethylene)methane-1,1-dicarbonitrile and 4-chloroaniline. The NMR data for this compound are shown below.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[C@@H:11]1[O:21][C@H:20]2[C@@H:13]([O:14][Si:15]([CH:31]([CH3:33])[CH3:32])([CH:28]([CH3:30])[CH3:29])[O:16][Si:17]([CH:25]([CH3:27])[CH3:26])([CH:22]([CH3:24])[CH3:23])[O:18][CH2:19]2)[C@@H:12]1[OH:34].[C:35]([O-])([O-])=O.[Cs+].[Cs+].CI>CN(C=O)C.C(Cl)Cl>[Cl:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[C@@H:11]1[O:21][C@H:20]2[C@@H:13]([O:14][Si:15]([CH:28]([CH3:30])[CH3:29])([CH:31]([CH3:33])[CH3:32])[O:16][Si:17]([CH:25]([CH3:26])[CH3:27])([CH:22]([CH3:23])[CH3:24])[O:18][CH2:19]2)[C@@H:12]1[O:34][CH3:35]
Reactant: O=C([O-])[O-]
Reactant: CC(C)[Si]1(C(C)C)OC[C@H]2O[C@@H](n3cnc4c(Cl)ncnc43)[C@@H](O)[C@@H]2O[Si](C(C)C)(C(C)C)O1
Agent: [Cs+]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CI
Product: CO[C@H]1[C@@H]2O[Si](C(C)C)(C(C)C)O[Si](C(C)C)(C(C)C)OC[C@H]2O[C@H]1n1cnc2c(Cl)ncnc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 48 %

Procedure:
To a suspension of (6aR,8R,9S,9aS)-8-(6-chloro-9H-purin-9-yl)-2,2,4,4-tetraisopropyltetrahydro-6H-furo[3,2-f][1,3,5,2,4]trioxadisilocin-9-ol (3.06 g, 5.79 mmol) and Cs2CO3 (18.86 g, 57.9 mmol) in DMF (58 mL) at 0° C. was added methyl iodide (3.60 mL, 57.9 mmol) dropwise and reaction was stirred for 3 h while warming to r.t. The solution was diluted with CH2Cl2 (150 mL) and washed with saturated aq NH4Cl. The aq layer was extracted with CH2Cl2 (2×100 mL) and the combined organics were dried (Na2SO4), filtered, and concentrated. The crude material was purified by flash chromatography (5 to 30% EtOAc/hexanes) to afford the title compound (1.51 g, 48%).
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([N:6]=[C:7]([C:13]([F:16])([F:15])[F:14])[C:8](O)=[N:9]2)=[CH:4][CH:3]=1.O=P(Cl)(Cl)[Cl:19].O.C(#N)C.O>C(#N)C>[Cl:19][C:8]1[C:7]([C:13]([F:16])([F:15])[F:14])=[N:6][C:5]2[C:10]([N:9]=1)=[CH:11][C:2]([F:1])=[CH:3][CH:4]=2
Reactant: O=P(Cl)(Cl)Cl
Reactant: Oc1nc2cc(F)ccc2nc1C(F)(F)F
Solvent: O
Solvent: CC#N
Product: Fc1ccc2nc(C(F)(F)F)c(Cl)nc2c1
Temperature: 100 °C
Yield: 95 %

Procedure:
7-Fluoro-3-(trifluoromethyl)quinoxalin-2-ol (24.1 g) and POCl3 (158.1 g) were combined and warmed to 100° C. for 12 h. The reaction mixture was cooled to room temperature and diluted with acetonitrile (104 mL). To a separate vessel was charged water (320 g) and acetonitrile (124 g), then cooled to 10° C. The reaction mixture was added to the acetonitrile/water mixture over 1 hour. The slurry was cooled to 10° C. for 30 min, then it was filtered and the cake was washed with 2:1 (v/v) water:acetonitrile (3×65 mL). The solid was dried under vacuum at 50° C. for 14 h (24.7 g, 95% yield).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][OH:10])=[CH:4][CH:3]=1.[CH3:11][C:12]1[C:17]([CH3:18])=[CH:16][C:15]([CH3:19])=[CH:14][C:13]=1O.C(P(CCCC)CCCC)CCC>C1(C)C=CC=CC=1>[CH3:11][C:12]1[C:17]([CH3:18])=[CH:16][C:15]([CH3:19])=[CH:14][C:13]=1[O:10][CH2:9][CH2:8][C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=1
Reactant: OCCc1ccc(Br)cc1
Reactant: Cc1cc(C)c(C)c(O)c1
Agent: CCCCP(CCCC)CCCC
Solvent: Cc1ccccc1
Product: Cc1cc(C)c(C)c(OCCc2ccc(Br)cc2)c1
Temperature: 25 °C
Yield: 72.5 %

Procedure:
A mixture of 2-(4-bromophenyl)ethanol (20.0 mL, 143 mmol), 2,3,5-trimethylphenol (31.1 g, 229 mmol), azodicarboxylic dipiperidide (72.1 g, 286 mmol) and tributylphosphine (88 mL; 357 mmol) in toluene (2.00 L) was heated to reflux for 2 h. The mixture was allowed to cool to rt. The mixture was filtered, washed with toluene and the solvents were partially removed under reduced pressure. The residue was diluted with Et2O and washed with aq. 1M NaOH (2×). The org. extracts were dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the residue by FC (petroleum ether→Et2O/petroleum ether 1:3) yielded the title compound (33.1 g, 73%). LC-MS: Rt=6.95.
Reaction SMILES: Cl[C:2]1[C:3]([CH2:10][N:11]2[CH:15]=[CH:14][N:13]=[C:12]2[C:16]2[N:21]=[CH:20][CH:19]=[CH:18][N:17]=2)=[N:4][CH:5]=[C:6]([O:8][CH3:9])[N:7]=1.[NH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1>>[CH3:9][O:8][C:6]1[N:7]=[C:2]([N:22]2[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)[C:3]([CH2:10][N:11]2[CH:15]=[CH:14][N:13]=[C:12]2[C:16]2[N:21]=[CH:20][CH:19]=[CH:18][N:17]=2)=[N:4][CH:5]=1
Reactant: C1CCNCC1
Reactant: COc1cnc(Cn2ccnc2-c2ncccn2)c(Cl)n1
Product: COc1cnc(Cn2ccnc2-c2ncccn2)c(N2CCCCC2)n1
Temperature: 110 °C

Procedure:
A mixture of 2-[1-(3-chloro-5-methoxy-pyrazin-2-ylmethyl)-1H-imidazol-2-yl]-pyrimidine (30 mg, 0.099 mmol), and piperidine (1 mL) is heated at 110° C. in a sealed tube for 1 hour. On cooling, the volatile materials are removed in vacuo and the residue is purified by PTLC (silica gel; 10% MeOH in DCM) to give 35 mg of 2-[1-(5-Methoxy-3-piperidin-1-yl-pyrazin-2-ylmethyl)-1H-imidazol-2-yl]-pyrimidine. 1H NMR (CDCl3) 8.74 (d, 2H), 7.62 (s, 1H), 7.21 s, 1H), 7.08–7.15 (m, 2H), 5.86 (s, 2H), 3.87 (s, 3H), 3.06–3.15 (m, 4H), 1.52–1.66 (m, 6H).
Reaction SMILES: [C:1]1([S:7]([C:10]2([CH2:19][NH2:20])[CH2:18][C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH2:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:21]([C:24]1[C:29]([CH:30]([CH3:32])[CH3:31])=[CH:28][CH:27]=[CH:26][C:25]=1[CH:33]([CH3:35])[CH3:34])=[C:22]=[O:23]>>[C:1]1([S:7]([C:10]2([CH2:19][NH:20][C:22]([NH:21][C:24]3[C:25]([CH:33]([CH3:34])[CH3:35])=[CH:26][CH:27]=[CH:28][C:29]=3[CH:30]([CH3:32])[CH3:31])=[O:23])[CH2:11][C:12]3[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH2:18]2)(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: NCC1(S(=O)(=O)c2ccccc2)Cc2ccccc2C1
Reactant: CC(C)c1cccc(C(C)C)c1N=C=O
Product: CC(C)c1cccc(C(C)C)c1NC(=O)NCC1(S(=O)(=O)c2ccccc2)Cc2ccccc2C1
Yield: 36 %

Procedure:
Similarly to Example 1(c), by reaction of 168 mg (0.6 mmol) of C-(2-benzenesulfonyl-indan-2-yl)-methylamine with 131 mg (0.64 mmol) of 2-isocyanato-1,3-diisopropyl-benzene. 106 mg of 1-(2-benzenesulfonyl-indan-2-ylmethyl)-3-(2,6-diisopropyl-phenyl)-urea is obtained in the form of a white solid. (Yield=36%).
Reaction SMILES: Cl.[CH2:2]([C:4]1[CH:8]=[C:7]([CH2:9][CH3:10])[N:6]([CH2:11][C@H:12]2[CH2:17][CH2:16][C@H:15]([NH2:18])[CH2:14][CH2:13]2)[N:5]=1)[CH3:3].C(N(CC)CC)C.[Cl:26][C:27]1[CH:28]=[N:29][C:30]([CH3:36])=[C:31]([CH:35]=1)[C:32](Cl)=[O:33]>C(Cl)Cl>[Cl:26][C:27]1[CH:28]=[N:29][C:30]([CH3:36])=[C:31]([CH:35]=1)[C:32]([NH:18][C@H:15]1[CH2:14][CH2:13][C@H:12]([CH2:11][N:6]2[C:7]([CH2:9][CH3:10])=[CH:8][C:4]([CH2:2][CH3:3])=[N:5]2)[CH2:17][CH2:16]1)=[O:33]
Reactant: CCc1cc(CC)n(C[C@H]2CC[C@H](N)CC2)n1
Reactant: Cc1ncc(Cl)cc1C(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCc1cc(CC)n(C[C@H]2CC[C@H](NC(=O)c3cc(Cl)cnc3C)CC2)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Trans-4-(3,5-diethyl-pyrazol-1-ylmethyl)-cyclohexylamine hydrochloride (Intermediate B) (65 mg, 0.238 mmol) was placed in a flask with DCM (5 ml) and triethylamine (72 mg, 0.714 mmol). 5-Chloro-2-methylnicotinoyl chloride (Intermediate C) (54 mg, 0.238 mmol) was added portionwise. After addition of the acid chloride, the reaction mixture was stirred at RT for 1 hour and partitioned between DCM and sat. NaHCO3. The organic phase was passed through a phase separator and the solvent was removed in vacuo. The crude product was triturated in EtOAc:iso-hexane—1:1, filtered and dried to afford the title compound; 1H NMR (d6-DMSO, 400 MHz) δ 8.52 (1H, d), 8.39 (1H, d), 7.79 (1H, d), 5.82 (1H, s), 3.76 (2H, d), 3.67 (1H, m), 2.57 (2H, q), 2.47 (5H, m), 1.89 (2H, m), 1.72 (1H, m), 1.57 (2H, m), 1.23 (10H, m); LC-MS Rt 2.35 mins, [M+H]+ 389; Method LowpH_v002.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([C:13]2[CH:18]=[N:17][CH:16]=[CH:15][N:14]=2)=[C:6]([CH:12]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8].[CH3:19][C:20]1[CH:21]=[C:22](B(O)O)[CH:23]=[N:24][CH:25]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.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]>[CH3:19][C:20]1[CH:21]=[C:22]([C:2]2[CH:3]=[CH:4][C:5]([C:13]3[CH:18]=[N:17][CH:16]=[CH:15][N:14]=3)=[C:6]([CH:12]=2)[C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH:23]=[N:24][CH:25]=1
Reactant: Cc1cncc(B(O)O)c1
Reactant: CCOC(=O)c1cc(Cl)ccc1-c1cnccn1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc(-c2cncc(C)c2)ccc1-c1cnccn1
Temperature: 100 °C

Procedure:
A mixture of ethyl 5-chloro-2-pyrazin-2-ylbenzoate (3-2, 0.120 g, 0.457 mmol, 1.0 equiv), 5-methylpyridine-3-boronic acid (0.094 g, 0.685 mmol, 1.5 equiv), PdCl2(dppf) (0.050 g, 0.069 mmol, 0.1 equiv) and 4M Cs2CO3 (0.400 mL, 1.599 mmol, 3.5 equiv) in DMF (2.3 mL) was combined and heated to 100° C. in a microwave reactor for 2 hours and fifty minutes. The reaction mixture was filtered and put on a reverse phase preparative HPLC system running acetonitrile/water with a TFA buffer (5 to 60% CH3CN in water). The cleanest fractions were pooled, concentrated and freebased to afford the product (3-3) as a white solid. ESI+ MS [M+H]+ C19H17N3O2: 320.1 found, 320.37 required.