Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[CH2:4][NH:5][CH:6]1[CH2:11][C:10]([CH3:13])([CH3:12])[N:9]([C:14](=[O:16])[CH3:15])[C:8]([CH3:18])([CH3:17])[CH2:7]1.[C:20]([N:23]1[C:28]([CH3:30])([CH3:29])[CH2:27]C(O)[CH2:25][C:24]1([CH3:33])[CH3:32])(=[O:22])[CH3:21].[NH2-].[Li+].CO>CCCCCCC.O>[C:20]([N:23]1[C:24]([CH3:33])([CH3:32])[CH2:25][CH:1]([O:2][C:3](=[O:19])[CH2:4][NH:5][CH:6]2[CH2:11][C:10]([CH3:13])([CH3:12])[N:9]([C:14](=[O:16])[CH3:15])[C:8]([CH3:18])([CH3:17])[CH2:7]2)[CH2:27][C:28]1([CH3:30])[CH3:29])(=[O:22])[CH3:21]
Reactant: CC(=O)N1C(C)(C)CC(O)CC1(C)C
Reactant: COC(=O)CNC1CC(C)(C)N(C(C)=O)C(C)(C)C1
Agent: [Li+]
Agent: [NH2-]
Solvent: O
Solvent: CO
Solvent: CCCCCCC
Product: CC(=O)N1C(C)(C)CC(NCC(=O)OC2CC(C)(C)N(C(C)=O)C(C)(C)C2)CC1(C)C
Yield: 73.1 %

Procedure:
To a four-necked flask equipped with a thermometer, a stirrer and a Deanstark trap were added 27 g (0.1 mole) of N-(1-acetyl-2,2,6,6-tetramethyl-4-piperidinyl)glycine methyl ester, 21.9 g (0.11 mole) of 1-acetyl-2,2,6,6-tetramethyl-4-piperidinol, 0.23 g of lithium amide and 100 g of heptane. The temperature was raised with stirring, and reaction was carried out at 98° to 105° C. for 6 hours, during which methanol was removed from the reaction system by means of the Deanstark trap. After completion of the reaction, the reaction solution was cooled, and water was added thereto to dissolve the product in the heptane layer. The heptane layer was separated and concentrated by removing heptane by distillation. The residue was purified by column chromatographic separation to obtain 32 g of N-(1-acetyl-2,2,6,6-tetramethyl-4-piperidinyl)glycine(1-acetyl-2,2,6,6-tetramethyl-4-piperidinyl)ester as a pale yellow liquid. Yield, 73% based on N-(1-acetyl-2,2,6,6-tetramethyl-4-piperidinyl)-glycine methyl ester.
Reaction SMILES: [CH2:1]([C:5]1[NH:6][C:7]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[C:8]([S:10][CH3:11])[N:9]=1)[CH2:2][CH2:3][CH3:4].CS.Br[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[C:28]([C:33]([O:35][CH3:36])=[O:34])=[CH:29][CH:30]=[CH:31][CH:32]=2)=[CH:23][CH:22]=1>>[CH2:1]([C:5]1[N:6]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[C:33]([O:35][CH3:36])=[O:34])=[CH:23][CH:22]=2)[C:7]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[C:8]([S:10][CH3:11])[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: COC(=O)c1ccccc1-c1ccc(CBr)cc1
Reactant: CCCCc1nc(SC)c(C(=O)OCC)[nH]1
Agent: CS
Product: CCCCc1nc(SC)c(C(=O)OCC)n1Cc1ccc(-c2ccccc2C(=O)OC)cc1
Yield: 69.3 %

Procedure:
The operation is carried out as in Example 5, starting with 0.6 g of ethyl 2-butyl-4-(methylthio)-1H-imidazole-5-carboxylate (prepared as indicated in Stages C and D of Preparation 1, replacing the ethanethiol with methanethiol), using 907 mg of methyl 4'-(bromomethyl)-(1,1'-biphenyl)-2-carboxylate. After chromatography on silica (eluant: methylene chloride - ethyl acetate (97-3)), 0.8 g of the desired product is obtained.
Reaction SMILES: [CH3:1][C:2]([CH3:22])=[CH:3][CH2:4][CH2:5]/[C:6](/[CH3:21])=[CH:7]/[CH2:8][CH2:9]/[C:10](/[CH3:20])=[CH:11]/[CH2:12][S:13][CH2:14][C@H:15]([NH2:19])[C:16]([OH:18])=[O:17].[CH2:23]1[C@H:30]([N:31]2[C:40](=[O:41])[C:39]3[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=3)[C:32]2=[O:33])[C:28](=[O:29])[O:27][C:25](=[O:26])[CH2:24]1.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[C:16]([C@@H:15]([NH:19][C:25](=[O:26])[CH2:24][CH2:23][C@H:30]([N:31]1[C:40](=[O:41])[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[C:32]1=[O:33])[C:28]([OH:29])=[O:27])[CH2:14][S:13][CH2:12]/[CH:11]=[C:10](\[CH3:20])/[CH2:9][CH2:8]/[CH:7]=[C:6](\[CH3:21])/[CH2:5][CH2:4][CH:3]=[C:2]([CH3:22])[CH3:1])([OH:18])=[O:17]
Reactant: O=C1CC[C@H](N2C(=O)c3ccccc3C2=O)C(=O)O1
Reactant: CC(C)=CCC/C(C)=C/CC/C(C)=C/CSC[C@H](N)C(=O)O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)=CCC/C(C)=C/CC/C(C)=C/CSC[C@H](NC(=O)CC[C@@H](C(=O)O)N1C(=O)c2ccccc2C1=O)C(=O)O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of S-trans, trans-farnesyl-L-cysteine (325 mg, 1 mmol) and N-phthaloyl-L-glutamic anhydride (259 mg, 1 mmol) in CH2Cl2 (10 mL) was added N,N-diisopropyl-ethyl-amine (0.87 mL, 5 mmol). The solution was stirred at room temperature for 2 h. The reaction was quenched with 1N HCl (10 mL) and the pH was adjusted to 2.0-3.0. The mixtures were extracted with ethyl acetate (15 mL×3). The organic layer was dried over Na2SO4 and concentrated in vacuo and the residue was purified by preparative HPLC (350 mg, 60%) to yield Compound C-2, which is identical to the S—R stereoisomer of the Compound C racemate in Examples 5 and 5a. 1H-NMR (500 MHz, CDCl3): δ 1.50 (s, 3H), 1.52 (s, 3H), 1.55 (s, 3H), 1.60 (s, 3H), 1.86-1.98 (m, 8H), 2.33-2.43 (m, 2H), 2.54-2.57 (m, 2H), 2.78 (dd, J=5.0, 15.0 Hz, 1H), 2.91 (dd, J=5.0, 15.0 Hz, 1H), 3.06 (dd, J=5.0, 10.0 Hz, 1H), 3.14 (dd, J=5.0, 10.0 Hz, 1H), 4.65 (dd, J=5.0, 10.0 Hz, 1H), 4.96 (t, J=5.0 Hz, 1H), 5.00 (m, 2H), 5.11 (t, J=5.0 Hz, 1H), 6.79 (d, J=10.0 Hz, 1H), 7.63-7.65 (m, 2H), 7.74-7.76 (m, 2H), 8.00 (broad, 2H). 13C-NMR (125 MHz, CDCl3): δ 16.06, 16.18, 17.76, 25.19, 25.78, 26.47, 26.73, 29.77, 32.59, 32.79, 39.65, 39.72, 51.10, 51.85, 119.37, 123.76, 123.80, 124.36, 131.39, 131.62, 134.40, 135.36, 140.24, 167.75, 172.78, 173.05, 174.51; ES-MS: mass calcd for Chemical Formula: C31H40N2O7S 584.72. Found (M+) m/z 585.3, (M+Na) m/z 607.3.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][C:10]2[CH:11]=[N:12][CH:13]=[C:14]([CH:19]=2)[C:15]([O:17][CH3:18])=[O:16])[CH:5]=[CH:6][CH:7]=1.[CH3:20][C:21]1[CH:22]=[C:23]([CH:27]=[CH:28][CH:29]=1)[C:24](O)=[O:25]>>[CH3:20][C:21]1[CH:22]=[C:23]([CH:27]=[CH:28][CH:29]=1)[C:24]([NH:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][C:10]2[CH:11]=[N:12][CH:13]=[C:14]([CH:19]=2)[C:15]([O:17][CH3:18])=[O:16])[CH:5]=[CH:6][CH:7]=1)=[O:25]
Reactant: Cc1cccc(C(=O)O)c1
Reactant: COC(=O)c1cncc(C#Cc2cccc(N)c2)c1
Product: COC(=O)c1cncc(C#Cc2cccc(NC(=O)c3cccc(C)c3)c2)c1

Procedure:
In a manner similar to that described in Example 1, methyl 5-((3-aminophenyl)ethynyl)nicotinate and 3-methylbenzoic acid are converted to the title compound.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][C:4](=O)[CH2:3][CH2:2]1.[CH3:8][CH:9]([CH3:12])[CH2:10][NH2:11].[S-:13][C:14]#[N:15].[K+].II>>[CH2:10]([N:11]1[C:4]2[CH2:3][CH2:2][O:1][CH2:6][C:5]=2[S:13][C:14]1=[NH:15])[CH:9]([CH3:12])[CH3:8]
Reactant: O=C1CCOCC1
Reactant: CC(C)CN
Reactant: N#C[S-]
Agent: II
Agent: [K+]
Product: CC(C)Cn1c2c(sc1=N)COCC2

Procedure:
Commercially available dihydro-2H-pyran-4(3H)-one (Aldrich), 2-methylpropan-1-amine (Aldrich), potassium thiocyanate (Aldrich) and iodine (EMD chemicals) were processed using the method described in Example 91A to afford the title compound. MS (ESI+) m/z 213 (M+H)+.
Reaction SMILES: [CH:1]1([C:4]2[C:5]([O:19][C:20]3[CH:25]=[CH:24][C:23]([N+:26]([O-])=O)=[CH:22][C:21]=3[F:29])=[CH:6][C:7]3[C:11]([CH:12]=2)=[N:10][N:9]([CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][O:14]2)[CH:8]=3)[CH2:3][CH2:2]1.CO.CN(C)N>CCOC(C)=O.C(Cl)Cl>[CH:1]1([C:4]2[C:5]([O:19][C:20]3[CH:25]=[CH:24][C:23]([NH2:26])=[CH:22][C:21]=3[F:29])=[CH:6][C:7]3[C:11]([CH:12]=2)=[N:10][N:9]([CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][O:14]2)[CH:8]=3)[CH2:3][CH2:2]1
Reactant: O=[N+]([O-])c1ccc(Oc2cc3cn(C4CCCCO4)nc3cc2C2CC2)c(F)c1
Agent: CN(C)N
Solvent: CCOC(C)=O
Solvent: CO
Solvent: ClCCl
Product: Nc1ccc(Oc2cc3cn(C4CCCCO4)nc3cc2C2CC2)c(F)c1
Temperature: 60 °C
Reaction time: 2 h
Yield: 98 %

Procedure:
To a 25 mL glass vial is added 6-cyclopropyl-5-(2-fluoro-4-nitrophenoxy)-2-(tetrahydro-2H-pyran-2-yl)-2H-indazole (395 mg, 994 μmol) and MeOH (20 mL, 494 mmol). To the suspension is added N,N-dimethylhydrazine (756 μL, 9.94 mmol) and FeCl3 (163 mg, 994 μmol). The vial is capped, and heated to 60° C. and stirred for 2 hours and then stirred at 50° C. overnight. The mixture is filtered over a Buchner funnel and the solid washed with MeOH (100 mL). The filtrate is collected and concentrated to give a brown/orange solid. The residue is purified on a silica gel column eluting with DCM (A) and a 10% MeOH in a DCM solution (B), gradient from 100% (A) to 85%(A): 15%(B) over 50 min to give a yellow solid as the title compound (358 mg, 98% yield). MS (m/z): 368 (M+H).
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH3:5])[CH3:2].[F:6][C:7]([F:25])([F:24])[C:8]1[C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:12](Cl)[CH:11]=[C:10]([C:20]([F:23])([F:22])[F:21])[N:9]=1.O>CN(C=O)C>[CH2:1]([N:3]([CH2:4][CH3:5])[C:12]1[CH:11]=[C:10]([C:20]([F:23])([F:22])[F:21])[N:9]=[C:8]([C:7]([F:25])([F:24])[F:6])[C:13]=1[C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH3:2]
Reactant: CCNCC
Reactant: CCOC(=O)c1c(Cl)cc(C(F)(F)F)nc1C(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1c(N(CC)CC)cc(C(F)(F)F)nc1C(F)(F)F
Reaction time: 8 h
Yield: 63.9 %

Procedure:
Diethylamine (2.1 ml, 0.020 mol) was slowly added to a solution of 3.0 g (0.009 mol) of product of Example 19 in 15 ml of DMF and stirred overnight. Reaction mixture was poured into water, extracted with ether, washed with water, dried (MgSO4) and concentrated. The residue was kugelrohr distilled twice at 28 Pa, pot temperature 76° C., to afford 2.06 g (63.2%) of product as a yellow oil, nD25 1.4593.
Reaction SMILES: [CH2:1]([N:8]1CCN(C2SC(C(O)=O)=C(C)N=2)C1=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:23][C:24]1[N:25]=[C:26]([N:32]2[CH2:36][CH2:35][N:34]([CH2:37][CH2:38][C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[C:33]2=[O:45])[S:27][C:28]=1[C:29]([OH:31])=O.C(N)C1C=CC=CC=1>>[CH2:1]([NH:8][C:29]([C:28]1[S:27][C:26]([N:32]2[CH2:36][CH2:35][N:34]([CH2:37][CH2:38][C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[C:33]2=[O:45])=[N:25][C:24]=1[CH3:23])=[O:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1nc(N2CCN(CCc3ccccc3)C2=O)sc1C(=O)O
Reactant: Cc1nc(N2CCN(Cc3ccccc3)C2=O)sc1C(=O)O
Solvent: NCc1ccccc1
Product: Cc1nc(N2CCN(CCc3ccccc3)C2=O)sc1C(=O)NCc1ccccc1
Yield: 26 %

Procedure:
Following the procedure as describe in Example 9, making variations as required to replace 2-(3-benzyl-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid with 4-methyl-2-(2-oxo-3-phenethylimidazolidin-1-yl)thiazole-5-carboxylic acid to react with benzylamine, the title compound was obtained as a white powder in 26% yield: mp 156-157° C.; 1H NMR (300 MHz, CDCl3) δ 7.36-7.18 (m, 10H), 5.93 (s, 1H), 4.54 (d, J=5.7 Hz, 2H), 3.99 (t, J=7.8 Hz, 2H), 3.54 (t, J=7.2 Hz, 2H), 3.41 (t, J=7.8 Hz, 2H), 2.87 (t, J=7.2 Hz, 2H), 2.59 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 162.4, 157.3, 155.3, 153.0, 151.7, 138.2, 137.9, 128.7, 128.6, 127.8, 127.6, 126.7, 117.1, 45.3, 44.0, 42.7, 42.0, 34.0, 17.2; MS (ES+) m/z 421.2 (M+1).
Reaction SMILES: [BrH:1].Br.[CH3:3][NH:4][CH2:5][CH:6]=[CH:7][CH2:8][NH:9][CH3:10]>CO.CC(O)C.O.[Pd]>[BrH:1].[BrH:1].[CH3:3][NH:4][CH2:5][CH2:6][CH2:7][CH2:8][NH:9][CH3:10]
Reactant: CNCC=CCNC
Agent: [Pd]
Agent: Br
Solvent: CO
Solvent: CC(C)O
Solvent: O
Product: CNCCCCNC
Yield: 181.5 %

Procedure:
N,N′-dimethyl-2-butene-1,4-diamine dihydrobromide 73 (35 g) dissolved in a mixture of MeOH (600 ml), i-PrOH (50 ml) and water (100 ml) was hydrogenated in the presence of 10% Pd/C (4 g) at 30 psi for 18 h. The reaction mixture was filtered and the filtrate was concentrated to give N,N′-dimethylputrescine dihydrobromide 74 (32 g) as a white solid.
Reaction SMILES: OO.C(O[C:10]([C:12](F)(F)F)=[O:11])(C(F)(F)F)=O.C(C1N=[N+:20]([O-:39])[C:21]2[CH:30]=[C:29]3[C:25]([CH2:26][CH:27](CCN4CCOCC4)[CH2:28]3)=[CH:24][C:22]=2[N:23]=1)C.C(O)(C(F)(F)F)=[O:41]>C(Cl)Cl.C(Cl)(Cl)Cl.N>[N+:20]([C:21]1[CH:30]=[C:29]2[C:25]([CH2:26][CH2:27][CH2:28]2)=[CH:24][C:22]=1[NH:23][C:10](=[O:11])[CH3:12])([O-:39])=[O:41]
Reactant: O=C(O)C(F)(F)F
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Reactant: CCc1nc2cc3c(cc2[n+]([O-])n1)CC(CCN1CCOCC1)C3
Agent: N
Agent: OO
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: CC(=O)Nc1cc2c(cc1[N+](=O)[O-])CCC2
Temperature: 20 °C
Reaction time: 0.17 h

Procedure:
H2O2 (70%, 0.39 mL, ca. 8.1 mmol) was added dropwise to a stirred solution of TFAA (1.12 mL, 8.1 mmol) in DCM (15 mL) at 0° C. The solution was stirred at 20° C. for 10 min, then cooled to 0° C., added to a solution of 1-oxide 163 (265 mg, 0.81 mmol) and TFA (0.13 mL, 1.7 mmol) in CHCl3 (15 mL) at 0° C. The solution was stirred at 20° C. for 4.5 h, diluted with dilute aqueous NH3 solution until basic and extracted with CHCl3 (3×30 mL). The combined organic fraction was dried and the solvent evaporated. The residue was purified by chromatography, eluting with a gradient (1-10%) of MeOH/DCM, to give (i) starting material 163 (62 mg, 23%) and (ii) 1,4-dioxide 164 (83 mg, 30%) as a yellow solid which was converted to the hydrochloride salt: mp 131-133° C.; 1H NMR δ 13.40 (br s, 1H, HCl), 8.30 (s, 1H, H-9), 8.25 (s, 1H, H-5), 4.32 (t, J=12.0 Hz, 2H, CH2), 4.00 (dd, J=12.0, 3.0 Hz, 2H, H-6, H-8), 3.48 (d, J=12.0 Hz, 2H, H-6, H-8), 3.32-3.39 (m, 2H, CH2), 3.20 (q, J=7.5 Hz, 2H, CH2), 3.06-3.09 (m, 2H, CH2), 2.88-2.94 (m, 4H, 2×CH2), 2.67-2.73 (m, 1H, H-7), 2.25-2.28 (m, 2H, CH2), 1.43 (t, J=7.5 Hz, 3H, CH3); 13C NMR δ 156.0, 152.6, 148.2, 139.3, 133.9, 116.3, 114.3, 63.6 (2), 56.5, 52.0 (2), 39.1, 38.6, 37.8, 28.5, 23.9, 9.3; HRMS (FAB+) calcd for C18H25N4O3 (MH+) m/z 344.1848, found 344.1846.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:9](O)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:7]=1[OH:8].C(O)(C(F)(F)F)=O.[SiH](CC)(CC)CC>C(Cl)Cl>[CH2:9]([C:6]1[CH:5]=[N:4][CH:3]=[C:2]([Br:1])[C:7]=1[OH:8])[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: Oc1c(Br)cncc1C(O)c1ccccc1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Oc1c(Br)cncc1Cc1ccccc1
Temperature: 25 °C
Reaction time: 10 h
Yield: 1.1 %

Procedure:
A mixture of 3-bromo-5-(hydroxy(phenyl)methyl)pyridin-4-ol (2.55 g, 91 mmol), TFA (16 mL) and Et3SiH in CH2Cl2 (30 mL) was stirred at rt for 10 h. The reaction mixture was concentrated in vacuo and the residue was purified by flash column chromatography on silica gel eluting with hexane/EtOAc/MeOH//600:300:50 followed by hexane/EtOAc/MeOH 11400:400:50:10 to afford an impure product which was triturated with a small amount of MeOH and Et2O to obtain the desired product (255 mg, 10%) as a white solid. 1H NMR (DMSO-d6) δ 11.75 (br s, 1H), 8.13 (s, 1H), 7.54 (s, 1H), 7.26-7.14 (m, 5H), 2.49 (s, 2H).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[C:18]([N:20]([S:22]([C:25]3[C:33]4[O:32][C:31]([F:35])([F:34])[O:30][C:29]=4[CH:28]=[CH:27][CH:26]=3)(=[O:24])=[O:23])C)[CH:17]=[CH:16][C:15]=2[O:36][CH3:37])[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:38]>CCOCC.ClCCl>[ClH:38].[CH3:37][O:36][C:15]1[CH:16]=[CH:17][C:18]([NH:20][S:22]([C:25]2[C:33]3[O:32][C:31]([F:35])([F:34])[O:30][C:29]=3[CH:28]=[CH:27][CH:26]=2)(=[O:24])=[O:23])=[CH:19][C:14]=1[N:11]1[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1
Reactant: COc1ccc(N(C)S(=O)(=O)c2cccc3c2OC(F)(F)O3)cc1N1CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: ClCCl
Solvent: CCOCC
Product: COc1ccc(NS(=O)(=O)c2cccc3c2OC(F)(F)O3)cc1N1CCNCC1

Procedure:
The title compound was prepared by treatment of 4-{5-[(2,2-Difluoro-benzo[1,3]dioxole-4-sulfonyl)-methyl-amino]-2-methoxy-phenyl}-piperazine-1-carboxylic acid tert-butyl ester with HCl in ether and dichloromethane as solvent.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[CH:5]([S:7]([C:10]1[S:11][CH:12]=[CH:13][CH:14]=1)(=[O:9])=[O:8])[CH3:6])[CH3:2].[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[CH2:1]([O:3][C:4](=[O:15])[C:5]([CH3:6])([S:7]([C:10]1[S:11][CH:12]=[CH:13][CH:14]=1)(=[O:8])=[O:9])[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH3:2]
Reactant: CCOC(=O)C(C)S(=O)(=O)c1cccs1
Reactant: BrCc1ccccc1
Product: CCOC(=O)C(C)(Cc1ccccc1)S(=O)(=O)c1cccs1

Procedure:
2-Methyl-3-phenyl-2-(thiophene-2-sulfonyl)-propionic acid ethyl ester was prepared according to the general method as outlined in example 9. Starting from 2-(thiophen-2-sulfonyl)-propionic acid ethyl ester (3.0 g, 12 mmol) and benzyl bromide (2.48 g, 15 mmol). Yield 5.2 g (%); tan oil; MS 339.1 (M+H).
Reaction SMILES: [CH2:1]([C:4]1[N:5]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[C:25]3[N:29](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:28]=[N:27][N:26]=3)=[CH:15][CH:14]=2)[CH:6]=[C:7]([CH2:9][CH2:10][NH2:11])[N:8]=1)[CH2:2][CH3:3].O.[C:50]([O:54][CH2:55][CH3:56])(=[O:53])[CH:51]=[O:52].C([OH:59])C.Cl>O1CCCC1>[C:50]([OH:54])(=[O:53])[C:51]([OH:59])=[O:52].[CH2:1]([C:4]1[N:5]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[C:25]3[NH:29][N:28]=[N:27][N:26]=3)=[CH:15][CH:14]=2)[C:6]2[CH:51]([C:50]([O:54][CH2:55][CH3:56])=[O:53])[NH:11][CH2:10][CH2:9][C:7]=2[N:8]=1)[CH2:2][CH3:3]
Reactant: CCO
Reactant: CCCc1nc(CCN)cn1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: CCOC(=O)C=O
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: CCCc1nc2c(n1Cc1ccc(-c3ccccc3-c3nnn[nH]3)cc1)C(C(=O)OCC)NCC2
Product: O=C(O)C(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 2-n-propyl-4-(2-aminoethyl)-1-[2'-(1-trityl-1H-tetrazol-5-yl)biphenyl-4-yl)methylimidazole (21.95 g) and tetrahydrofuran (200 ml) is added a solution of ethyl glyoxylate hydrate (4.25 g) in tetrahydrofuran (20 ml) at 5° C. The mixture is stirred overnight at room temperature and refluxed for 30 minutes. To a mixture is added a 8% hydrogen chloride ethanol solution (100 ml) at room temperature. The reaction mixture is stirred for 30 minutes, then evaporated. The residue is dissolved in chloroform and washed successively with a saturated sodium hydrogen carbonate solution and brine. The organic layer is dried and evaporated. The oxalate is recrystallized from ethanol to give ethyl 2-n-propyl-3-[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl-4,5,6,7-tetrahydroimidazo[4,5-c]pyridine-4-carboxylate oxalate (10.84 g).
Reaction SMILES: [C:1]([O:6][CH2:7][CH:8]1[CH2:13][CH2:12][CH:11]=[CH:10][CH2:9]1)(=[O:5])[C:2]([CH3:4])=[CH2:3].ClC1C=CC=C(C(OO)=[O:22])C=1.S([O-])([O-])=O.[Na+].[Na+].C1C(C(O[O-])=O)=CC=CC=1>C(Cl)Cl>[C:1]([O:6][CH2:7][CH:8]1[CH2:13][CH2:12][CH:11]2[O:22][CH:10]2[CH2:9]1)(=[O:5])[C:2]([CH3:4])=[CH2:3]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C=C(C)C(=O)OCC1CC=CCC1
Agent: O=C(O[O-])c1ccccc1
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: C=C(C)C(=O)OCC1CCC2OC2C1
Reaction time: 3 h
Yield: 94.6 %

Procedure:
A 8 liter, 4 necked flask equipped with a thermometer, cooling jacket, stirring means and drip funnel was charged with 200 g of cyclohexen-4-ylmethyl methacrylate produced in Step A and 1200 ml of methylene chloride. The reactants were cooled to a temperature below 10° C. A solution of 268.6 g of m-chloroperbenzoic acid (80% purity, Kishida Chemicals) in 2800 ml of methylene chloride was added thereto dropwise over 3 hours and then allowed to react for additional 3 hours with stirring. After the reaction, an amount of 10% aqueous solution of sodium sulfite was added to the reaction mixture and allowed to react at room temperature for 1 hour to decompose unreacted perbenzoate. After having confirmed the absence of perbenzoate using starch-iodine indicator paper, the reaction mixture was washed with 1000 ml of an aqueous solution containing 81 g of sodium carbonate and then with an amount of saline successively. Thereafter the mixture was dried over magnesium sulfate and evaporated under reduced pressure with addition of 40 mg of p-methoxyquinone as a polymerization inhibitor to remove the solvent. 206 g of crude product of the titled compound was obtained. Yield: 95% of theory.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[O:9][CH3:10].C(O[CH:14]=[C:15]([C:21](=[O:32])[C:22]1[CH:27]=[C:26]([F:28])[C:25]([F:29])=[C:24]([CH3:30])[C:23]=1F)[C:16]([O:18][CH2:19][CH3:20])=[O:17])C.F[C:34]1C(C)=C(F)C(F)=CC=1C(CC(OCC)=O)=O>C(Cl)(Cl)Cl>[F:28][C:26]1[CH:27]=[C:22]2[C:23](=[C:24]([CH3:30])[C:25]=1[F:29])[N:6]([C:5]1[CH:7]=[CH:8][C:2]([F:1])=[C:3]([O:9][CH2:10][CH3:34])[CH:4]=1)[CH:14]=[C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:21]2=[O:32]
Reactant: COc1cc(N)ccc1F
Reactant: CCOC=C(C(=O)OCC)C(=O)c1cc(F)c(F)c(C)c1F
Reactant: CCOC(=O)CC(=O)c1cc(F)c(F)c(C)c1F
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1cn(-c2ccc(F)c(OCC)c2)c2c(C)c(F)c(F)cc2c1=O
Temperature: 90 °C
Reaction time: 0.25 h

Procedure:
4-Fluoro-3-methoxyaniline (1.4 g) was added to a chloroform solution (10 ml) of ethyl 3-ethoxy-2-(2,4,5-trifluoro-3-methylbenzoyl)acrylate synthesized from ethyl 2,4,5-trifluoro-3-methylbenzoylacetate (2.6 g) in accordance with a method known per se in the art. The mixture was concentrated under reduced pressure, and anhydrous potassium carbonate (3.0 g) and N,N-dimethylformamide (7 ml) were added to the residue, followed by stirring at 90° C. for 15 minutes. The reaction mixture was allowed to cool, and chloroform (100 ml) and distilled water (250 ml) were added to the mixture, thereby conducting liquid separation. A chloroform layer was then washed twice with distilled water (250 ml), dried over anhydrous magnesium sulfate and concentrated under reduced pressure. Deposits were dispersed in ethanol, collected by filtration and washed with ethanol and diisopropyl ether in that order to obtain the title compound (2.59 g) as a colorless powder.
Reaction SMILES: [NH2:1][C:2]1[C:6]([C:7]#[N:8])=[CH:5][NH:4][N:3]=1.O/[C:10](/[C:16]([O-:18])=[O:17])=[C:11](/[OH:15])\[C:12]([O-:14])=O.[C:19](OCC)(=O)C>C(O)(=O)C>[CH3:19][O:18][C:16]([C:10]1[N:1]=[C:2]2[C:6]([C:7]#[N:8])=[CH:5][NH:4][N:3]2[C:12](=[O:14])[C:11]=1[OH:15])=[O:17]
Reactant: N#Cc1c[nH]nc1N
Reactant: O=C([O-])/C(O)=C(\O)C(=O)[O-]
Reactant: CCOC(C)=O
Solvent: CC(=O)O
Product: COC(=O)c1nc2c(C#N)c[nH]n2c(=O)c1O
Temperature: 100 °C
Reaction time: 48 h
Yield: 62 %

Procedure:
3-amino-4-pyrazole carbonitrile (400 mg, 3.7 mmol) and dihydroxyfumarate (978 mg, 5.5 mmol) were dissolved in glacial acetic acid (5 mL) and the mixture was heated to 100° C. After 2 d, the reaction was complete by HPLC analysis and was cooled to room temperature. Ethyl acetate (10 mL) was added to initiate precipitation of product and the resulting precipitate was collected by filtration. The product was isolated in 62% yield (534 mg).
Reaction SMILES: [N:1]1[CH:6]=[C:5]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]O)[CH:4]=[N:3][CH:2]=1.S(Cl)([Cl:16])=O>ClCCl>[N:1]1[CH:6]=[C:5]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][Cl:16])[CH:4]=[N:3][CH:2]=1
Reactant: O=S(Cl)Cl
Reactant: OCCCCCCc1cncnc1
Solvent: ClCCl
Product: ClCCCCCCc1cncnc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 20.6 g of 5-pyrimidinehexanol in 80 ml of dichloromethane was cooled in an ice bath as a solution of 12.3 ml of thionyl chloride in 40 ml of dichloromethane was added dropwise. The mixture was stirred at room temperature for 1 hour and at reflux temperature for 1 hour, was concentrated, azeotroped with toluene, diluted with dichloromethane and washed with water, saturated sodium bicarbonate, and brine. Evaporation gave 22.3 g of 6-(5-pyrimidinyl)hexylchloride.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[O:11][CH:10]=[N:9][C:8]=2[C:12]([O:14]C)=[O:13])=[N:3][CH:2]=1.[Li+].[OH-]>C1COCC1.O.CCOC(C)=O.Cl>[N:1]1[CH:6]=[CH:5][C:4]([C:7]2[O:11][CH:10]=[N:9][C:8]=2[C:12]([OH:14])=[O:13])=[N:3][CH:2]=1
Reactant: COC(=O)c1ncoc1-c1ccncn1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1ncoc1-c1ccncn1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A solution of methyl 5-(pyrimidin-4-yl)oxazole-4-carboxylate (179 mg, 0.80 mmol) in THF/H2O (1:1, 6 mL) was treated with LiOH (60 mg, 1.43 mmol) at 0° C. The reaction mixture was stirred at 0° C. for 15 min, then diluted with EtOAc and 1N aq. HCl-solution was added (to reach pH=1). The layers were separated and the aq. layer extracted with EtOAc (2×), EtOAc/MeOH 4:1 then DCM/MeOH 4:1. The combined organic extracts were dried (Na2SO4), filtered and concentrated in vacuo to obtain the title compound as a solid which was used without further purification. LC-MS conditions A: tR=0.56 min, [M+H]+=192.47.