Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:13]2[CH:18]=[CH:17][N:16]=[C:15]([NH:19][C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26](OC)=O)[CH:21]=3)[N:14]=2)=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:6]=1.C[Mg]Cl.[Cl-].[NH4+].[O:35]1CC[CH2:37][CH2:36]1>>[NH2:1][C:2]1[S:3][C:4]([C:13]2[CH:18]=[CH:17][N:16]=[C:15]([NH:19][C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([CH2:26][CH:36]([OH:35])[CH3:37])[CH:21]=3)[N:14]=2)=[C:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:6]=1
Reactant: COC(=O)c1cccc(Nc2nccc(-c3sc(N)nc3-c3ccccc3)n2)c1
Reactant: C1CCOC1
Agent: C[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Product: CC(O)Cc1cccc(Nc2nccc(-c3sc(N)nc3-c3ccccc3)n2)c1

Procedure:
To a suspension of N-[4-(2-amino-4-phenyl-thiazol-5-yl)-pyrimidin-2-yl]-N-(3-methoxycarbonyl-phenyl)-amine (800 mg, 2.0 mmol) in tetrahydrofuran (30 ml) is added a solution of methyl magnesium chloride (6 ml of a 20% THF solution) without cooling. The temperature of the reaction mixture rises to about +45° C. and the starting material dissolves immediately yielding a yellow clear solution. After an additional hour the solution is poured onto crushed ice and ammonium chloride. The colorless precipitate is filtered and washed with ethyl acetate and tetrahydrofuran. The organic phases are pooled, dried and concentrated under reduced pressure. Chromatography of the resulting solid gives the N-[4-(2-amino-4-phenyl-thiazol-5-yl)-pyrimidin-2-yl]-N-[3-(2-hydroxy-2-methyl-ethyl)-phenyl]-amine, m.p. 219–220° C.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][O:3][CH:2]1[CH2:7][CH2:8][Mg]Br.[Br:11][C:12]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:13]=1[CH:14]=[O:15]>C1COCC1>[Br:11][C:12]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:13]=1[CH:14]([OH:15])[CH2:8][CH2:7][CH:2]1[O:3][CH2:4][CH2:5][CH2:6][O:1]1
Reactant: O=Cc1ccc(F)cc1Br
Reactant: Br[Mg]CCC1OCCCO1
Solvent: C1CCOC1
Product: OC(CCC1OCCCO1)c1ccc(F)cc1Br
Temperature: 25 °C
Reaction time: 48 h
Yield: 511.7 %

Procedure:
Add (1,3-dioxan-2-ylethyl)magnesium bromide (0.5 M in THF, 40 mL, 20 mmol) to a solution of 2-bromo-4-fluoro-benzaldehyde (3 g, 15 mmol) in THF (20 mL) at 0° C. under N2. Continue to stir the mixture for 48 h at RT. Quench the reaction mixture with 1 N HCl, followed by the basification with diluted ammonium hydroxide to ˜pH 9. Extract the product with chloroform/IPA (3/1). Dry the organic layer over sodium sulfate. Concentrate the solution in vacuo. Purify by column chromatography (10% methanol in DCM) to give the title compound as a yellow oil (24.5 g, 95%). MS (ES) m/z 319/321 [M+1]+.
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[N:6][CH:5]=[CH:4][N:3]=1.[F:9][C:10]1[CH:15]=[CH:14][C:13](B(O)O)=[CH:12][CH:11]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C1(P(C2CCCCC2)C2CCCCC2)CCCCC1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[Cl:8][C:7]1[C:2]([C:13]2[CH:14]=[CH:15][C:10]([F:9])=[CH:11][CH:12]=2)=[N:3][CH:4]=[CH:5][N:6]=1
Reactant: Clc1nccnc1Cl
Reactant: OB(O)c1ccc(F)cc1
Agent: [Pd]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: Fc1ccc(-c2nccnc2Cl)cc1
Temperature: 25 °C
Yield: 55 %

Procedure:
First, 5.06 g of 2,3-dichloropyrazine, 5.23 g of 4-fluorophenyl boronic acid, 22.16 g of cesium carbonate, and 200 mL of dioxane were put in a three-neck flask equipped with a reflux pipe, and 0.467 g of tris(dibenzylideneacetone)dipalladium(0) (abbreviation: Pd2(dba)3) and 2.5 mL of tricyclohexylphosphine (abbreviation: Cy3P) were added thereto while the mixture was stirred under a nitrogen atmosphere, and they were reacted at 85° C. for 11 hours. After the reaction, the reaction solution was cooled down to room temperature and filtrated. A solvent of the obtained filtrate was distilled off, and the obtained residue was refined with a column chromatography using dichloromethane as a development solvent, so that 2-chloro-3-(4-fluorophenyl)pyrazine was obtained (light yellow powder, yield: 55%). A synthesis scheme of Step 1 is shown by the following (a1-1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]3[CH:15]=[N:16][N:17]([CH:19](Br)[CH2:20][CH3:21])[N:18]=3)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[NH:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]3[CH:15]=[N:16][N:17]([CH2:19][CH2:20][CH2:21][CH:25]4[CH2:26][CH2:27][CH2:28][NH:23][CH2:24]4)[N:18]=3)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: CCC(Br)n1ncc(-c2ccc(-c3ccc(Cl)cc3)cc2)n1
Reactant: C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: Clc1ccc(-c2ccc(-c3cnn(CCCC4CCCNC4)n3)cc2)cc1
Yield: 131.3 %

Procedure:
41-[3-[4-(p-chlorophenyl)-5-phenyl-(-[1,2,3]triazol-2-yl)]-3-bromopropane (26 mg, 0.07 mmol) and piperidine (9 mg, 0.10 mmol) were refluxed in ethanol for 1 h in presence of dry sodium carbonate (11 mg, 0.10 mmol). The reaction mixture was then filtrated. The solid was washed with CH2Cl2. The combined filtrates was evaporated in vacuo. The resulting oil was then purified by chromatography on silica gel eluting with EtOAc to afford 1-[3-[4-(p-chlorophenyl)-5-phenyl-(-[1,2,3]triazol-2-yl)propyl]-piperidine (35 mg, 75% yield); 1H NMR (200 MHz, CDCl3, 25° C.) δ=7.53-7.46 (4H, m), 7.39-7.31 (5H, m), 4.52 (2H, t, 3J=7.1 Hz), 2.46-2.39 (6H, m), 2.23 (2H, qt, 3J=7.2 Hz), 1.58 (4H, qt, 3J=5.5 Hz), 1.42 (2H, qt, 3J=5.5 Hz) ppm. ES-MS: m/z=382 (5), 381 (4), 380 (14) [M+●]; 98 (100) [M-283]; 84 (30) [M-297].
Reaction SMILES: Cl.[NH:2]([C:6]1[CH:14]=[CH:13][C:9]([C:10](Cl)=[O:11])=[CH:8][CH:7]=1)[C:3]([NH2:5])=[NH:4].[C:15]([O:19][C:20](=[O:42])[CH2:21][C:22]1([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[O:26][N:25]=[C:24]([C:27]2[CH:32]=[C:31]([CH3:33])[CH:30]=[C:29]([OH:34])[CH:28]=2)[CH2:23]1)([CH3:18])([CH3:17])[CH3:16].N1C=CC=CC=1.C(=O)(O)[O-].[Na+]>O.C(#N)C.CN1C(=O)CCC1>[C:15]([O:19][C:20](=[O:42])[CH2:21][C:22]1([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[O:26][N:25]=[C:24]([C:27]2[CH:32]=[C:31]([CH3:33])[CH:30]=[C:29]([O:34][C:10](=[O:11])[C:9]3[CH:8]=[CH:7][C:6]([NH:2][C:3]([NH2:5])=[NH:4])=[CH:14][CH:13]=3)[CH:28]=2)[CH2:23]1)([CH3:17])([CH3:18])[CH3:16]
Reactant: N=C(N)Nc1ccc(C(=O)Cl)cc1
Reactant: Cc1cc(O)cc(C2=NOC(CC(=O)OC(C)(C)C)(C(=O)OC(C)(C)C)C2)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CN1CCCC1=O
Solvent: CC#N
Product: Cc1cc(OC(=O)c2ccc(NC(=N)N)cc2)cc(C2=NOC(CC(=O)OC(C)(C)C)(C(=O)OC(C)(C)C)C2)c1
Reaction time: 0.5 h
Yield: 57.7 %

Procedure:
4-Carbamimidamidobenzoyl chloride hydrochloride (299 mg) was added to a mixture of tert-butyl 5-(2-tert-butoxy-2-oxoethyl)-3-(3-hydroxy-5-methylphenyl)-4,5-dihydro-1,2-oxazole-5-carboxylate (500 mg), pyridine (0.6 mL), and NMP (0.6 mL) at 50 C, and the obtained mixture was stirred at 50 C for 30 minutes. Further, 4-carbamimidamidobenzoyl chloride hydrochloride (299 mg) was added thereto, and the obtained mixture was stirred at 50 C for 3 hours. The reaction mixture was fractionated by HPLC (C18, mobile phase: water/acetonitrile (system containing 0.1% TFA)). To the obtained fraction, a saturated aqueous solution of sodium bicarbonate was added, followed by extraction with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain the title compound (407 mg).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][C:9](=O)[CH2:8][CH2:7]1.Cl.[NH2:14][OH:15]>>[OH:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][C:9](=[N:14][OH:15])[CH2:8][CH2:7]1
Reactant: O=C1CCN(CCCCO)CC1
Reactant: NO
Agent: Cl
Product: OCCCCN1CCC(=NO)CC1

Procedure:
1-(4-Hydroxybutyl)-4-piperidone oxime is prepared from 1-(4-hydroxybutyl)-4-piperidone and hydroxylamine hydrochloride essentially as described above in Example 38, Scheme C, step b.
Reaction SMILES: C[Si](Br)(C)C.C([NH:8][CH:9](/[CH:20]=[C:21](\[CH3:33])/[CH2:22][P:23]([O:29]C(C)C)([O:25]C(C)C)=[O:24])[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11])=O.C(O)C1C=CC=CC=1>ClCCl>[NH2:8]/[C:9](=[CH:20]/[CH:21]([CH3:33])[CH2:22][P:23]([OH:29])([OH:25])=[O:24])/[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11]
Reactant: C/C(=C\C(NC=O)C(=O)OCc1ccccc1)CP(=O)(OC(C)C)OC(C)C
Agent: C[Si](C)(C)Br
Solvent: ClCCl
Solvent: OCc1ccccc1
Product: CC(/C=C(/N)C(=O)OCc1ccccc1)CP(=O)(O)O
Reaction time: 20 h

Procedure:
23 ml (178 mmols) of trimethylsilyl bromide are added dropwise at room temperature to a solution of 18.3 g (44.5 mmols) of benzyl E-2-formylamino-4-methyl-5-diisopropylphosphono-3-pentenoate in 73 ml of dichloromethane. After 20 hours at room temperature 46 ml of benzyl alcohol are added dropwise, and the reaction mixture is allowed to stand for additional 20 hours at room temperature. The dichloromethane is distilled off, first 40 ml of ethanol and then dropwise 40 ml of propylene oxide in 40 ml of ethanol are added. The crystalline precipitate formed is filtered off, triturated with 200 ml of water and filtrated off again. Benzyl E-2-amino-4-methyl-5-phosphono-pentenoate of m.p. 196°-197° (decomp.) is thus obtained.
Reaction SMILES: I[C:2]1[CH:7]=[N:6][N:5](C2CCCCO2)[C:4](=[O:14])[CH:3]=1.[Cl:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[OH:22]>>[Cl:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[O:22][C:2]1[CH:7]=[N:6][NH:5][C:4](=[O:14])[CH:3]=1
Reactant: Oc1ccccc1Cl
Reactant: O=c1cc(I)cnn1C1CCCCO1
Product: O=c1cc(Oc2ccccc2Cl)cn[nH]1

Procedure:
In an analogous manner to the stepwise sequence outlined in Intermediate 18, starting from 5-iodo-2-(tetrahydro-pyran-2-yl)-2H-pyridazin-3-one (Intermediate 18, step 2) and 2-chloro-phenol afforded 5-(2-chloro-phenoxy)-2H-pyridazin-3-one which was then reacted in an analogous manner to that outlined in the synthesis of Intermediate 19 (steps 4 and 5) alkylating with 2-bromo-3-(tetrahydro-pyran-4-yl)-propionic acid methyl ester (Intermediate 14) to afforded 2-[4-(2-chloro-phenoxy)-6-oxo-6H-pyridazin-1-yl]-3-(tetrahydro-pyran-4-yl)-propionic acid. This material was used crude without further purification in Example 135. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.08-1.38 (m, 3H), 1.45 (d, J=12.4 Hz, 1H), 1.60 (d, J=12.1 Hz, 1H), 1.88-2.00 (m, 1H), 2.04-2.17 (m, 1H), 3.09-3.25 (m, 2H), 3.74-3.85 (m, 2H), 5.42 (dd, J=10.8, 4.4 Hz, 1H), 5.73 (d, J=2.9 Hz, 1H), 7.36-7.47 (m, 1H), 7.47-7.55 (m, 2H), 7.71 (d, J=7.7 Hz, 1H), 8.21 (d, J=2.9 Hz, 1H), 13.10 (br. s., 1H).
Reaction SMILES: [Li].[N+:2]([CH:5]([CH3:7])[CH3:6])([O-:4])=[O:3].[N+]([C:11]1([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:14][CH2:13][CH2:12]1)([O-])=O>CN(C)P(N(C)C)(N(C)C)=O>[N+:2]([C:5]([C:11]1([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:14][CH2:13][CH2:12]1)([CH3:7])[CH3:6])([O-:4])=[O:3]
Reactant: CC(C)[N+](=O)[O-]
Reactant: CCOC(=O)C1([N+](=O)[O-])CCC1
Agent: [Li]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCOC(=O)C1(C(C)(C)[N+](=O)[O-])CCC1
Reaction time: 3 h
Yield: 70 %

Procedure:
The lithium salt of 2-nitropropane (9.9 g.) was dissolved in 200 ml. of hexamethylphosphoramide under nitrogen and ethyl 1-nitrocyclobutanecarboxylate was added. The mixture was stirred for three hours under fluorescent lighting. The mixture was then diluted with 400 ml. of water and extracted three times with 200 ml. portions of ether. The combined ether extracts were washed three times with water, dried over magnesium sulfate, and the ethyl 1-(α-nitroisopropyl)cyclobutanecarboxylate (70 percent yield) was recovered by distillation: b.p. (0.1 mm.), 62° C.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11](=[O:13])[CH3:12])=[CH:6][CH:5]=1)([O-:3])=[O:2].[H-].[Na+].Cl[CH2:17][C:18]1[O:22][C:21]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:20][CH:19]=1.[I-].[K+]>CN(C)C=O.C(OCC)C.O.C(O)(=O)C>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH:10]([C:11](=[O:13])[CH3:12])[CH2:17][C:18]2[O:22][C:21]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:20][CH:19]=2)=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: CC(=O)Cc1ccc([N+](=O)[O-])cc1
Reactant: CCOC(=O)c1ccc(CCl)o1
Agent: [H-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOCC
Solvent: CC(=O)O
Product: CCOC(=O)c1ccc(CC(C(C)=O)c2ccc([N+](=O)[O-])cc2)o1
Yield: 98.8 %

Procedure:
3.00 g of p-nitrophenylacetone was dissolved in 50 ml of dimethylformamide, and 0.70 g of 60% oily sodium hydride was added under cooling with ice with stirring, followed by stirring at the same temperature for 10 minutes. 5 ml of a dimethylformamide solution containing 3.40 g of ethyl 5-chloromethyl-2-furancarboxylate, and 3.05 g of potassium iodide were added thereto, followed by stirring at room temperature for 2.5 hours. Then, the reaction solution was acidified by an addition of acetic acid. Water and ethyl ether were added, and the mixture was extracted. Then, the organic layer was washed with a saturated sodium chloride aqueous solution and dried over anhydrous magnesium sulfate. The drying agent was filtered off, and then, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=5/1→2/1) to obtain 5.48 g of the above-identified compound.
Reaction SMILES: [CH2:1]([N:8]1[CH2:26][CH2:25][C:11]2[N:12]=[C:13]([C:17]3[CH:22]=[C:21]([Cl:23])[CH:20]=[C:19]([Cl:24])[CH:18]=3)[N:14]=[C:15]([OH:16])[C:10]=2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:27][C:28]1[CH:35]=[CH:34][C:31]([CH2:32]Br)=[CH:30][CH:29]=1>>[CH2:1]([N:8]1[CH2:26][CH2:25][C:11]2[N:12]=[C:13]([C:17]3[CH:18]=[C:19]([Cl:24])[CH:20]=[C:21]([Cl:23])[CH:22]=3)[N:14]=[C:15]([O:16][CH2:32][C:31]3[CH:34]=[CH:35][C:28]([F:27])=[CH:29][CH:30]=3)[C:10]=2[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Fc1ccc(CBr)cc1
Reactant: Oc1nc(-c2cc(Cl)cc(Cl)c2)nc2c1CN(Cc1ccccc1)CC2
Product: Fc1ccc(COc2nc(-c3cc(Cl)cc(Cl)c3)nc3c2CN(Cc2ccccc2)CC3)cc1

Procedure:
The title compound was prepared from 6-benzyl-2-(3,5-dichloro-phenyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-ol (which was obtained in Intermediate 7) and 4-fluorobenzyl bromide according to Method A; 1H NMR (DMSO-d6, 300 MHz) δ 3.67 (br s, 4H), 4.24 (br s, 2H), 4.43 (br s, 2H), 5.64 (s, 2H), 7.25 (t, J=8.9 Hz, 2H), 7.60 (m, 3H), 7.83 (s, 1H), 7.95 (s, 1H); LC retention time 3.21 min; MS: m/z (ESI) 494 (M+H).
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]([CH2:17][C:18]([F:21])([F:20])[F:19])[C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[C:7]([C:13]([F:16])([F:15])[F:14])[CH:6]=1.O[C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][CH:31]=1)[NH:28][CH:27]=[CH:26]2>>[NH:28]1[C:29]2[C:25](=[CH:24][C:23]([O:1][CH2:2][CH2:3][N:4]([CH2:17][C:18]([F:19])([F:20])[F:21])[C:5]3[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[C:7]([C:13]([F:15])([F:16])[F:14])[CH:6]=3)=[CH:31][CH:30]=2)[CH:26]=[CH:27]1
Reactant: Oc1ccc2[nH]ccc2c1
Reactant: N#Cc1ccc(N(CCO)CC(F)(F)F)cc1C(F)(F)F
Product: N#Cc1ccc(N(CCOc2ccc3[nH]ccc3c2)CC(F)(F)F)cc1C(F)(F)F

Procedure:
Synthesized as described in Example 1C using 4-[(2-hydroxyethyl)(2,2,2-trifluoroethyl)amino]-2-(trifluoromethyl)benzonitrile and 5-hydroxyindole: MS (APCI) m/z 426 (M−1).
Reaction SMILES: [NH:1]([C:32]([O:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)=[O:33])[CH2:2][C:3]([NH:5][C@H:6]([C:14]([NH:16][CH2:17][C:18]([N:20]1[CH2:31][CH2:30][CH2:29][C@H:21]1[C:22]([O:24]C(C)(C)C)=[O:23])=[O:19])=[O:15])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:4]>FC(F)(F)C(O)=O>[NH:1]([C:32]([O:34][CH2:35][C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1)=[O:33])[CH2:2][C:3]([NH:5][C@H:6]([C:14]([NH:16][CH2:17][C:18]([N:20]1[CH2:31][CH2:30][CH2:29][C@H:21]1[C:22]([OH:24])=[O:23])=[O:19])=[O:15])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:4]
Reactant: CC(C)(C)OC(=O)[C@@H]1CCCN1C(=O)CNC(=O)[C@H](Cc1ccccc1)NC(=O)CNC(=O)OCc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: O=C(CNC(=O)OCc1ccccc1)N[C@@H](Cc1ccccc1)C(=O)NCC(=O)N1CCC[C@H]1C(=O)O
Reaction time: 0.33 h

Procedure:
25.6 g of Z-Gly-Phe-Gly-Pro-OtBu are dissolved in 260 ml of 90 % strength trifluoracetic acid and the solution is allowed to stand for 20 minutes at 22°C. Thereafter it is concentrated in a rotational evaporator at 25°C bath temperature until it has an oily consistency; 250 ml of water are then added and the viscous mass is thoroughly kneaded at 0°C. The aqueous phase is decanted off, and the residue is washed twice more in the same manner with 100 ml of water at a time. The residue is then dried in a high vacuum at 30°C bath temperature. The residue hereupon obtained is mixed with 600 ml of ether-petroleum ether (1:1), triturated, filtered off and dried. The product is directly processed further.
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.O1CCCC1.[CH3:16][O:17][C:18]1[C:19]([N+:32]([O-:34])=[O:33])=[C:20]([CH:25]=[C:26]([O:30][CH3:31])[C:27]=1[O:28][CH3:29])[C:21](OC)=[O:22].CO>C1(C)C=CC=CC=1.O>[CH3:16][O:17][C:18]1[C:19]([N+:32]([O-:34])=[O:33])=[C:20]([CH:25]=[C:26]([O:30][CH3:31])[C:27]=1[O:28][CH3:29])[CH2:21][OH:22]
Reactant: COC(=O)c1cc(OC)c(OC)c(OC)c1[N+](=O)[O-]
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: CO
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: COc1cc(CO)c([N+](=O)[O-])c(OC)c1OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 22.4 %

Procedure:
A 1.0 M solution of diisobutylaluminum hydride in tetrahydrofuran (19.7 ml, 19.7 mmol) was added to a solution of methyl 3,4,5-trimethoxy-2-nitrobenzoate (5.0 g, 18.5 mmol) in toluene (100 ml) at -50° C. under an argon atmosphere, and the mixture was stirred for 30 min. Methanol (10 ml) was added thereto, and the temperature of the mixture was raised to room temperature. Water was added to the mixture, followed by extraction twice with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate=2:1) to give 3,4,5-trimethoxy-2-nitrobenzyl alcohol (1.01 g, 23%) as light yellow powder.
Reaction SMILES: [CH3:1][S:2][C:3]1[S:4][C:5]([C:13]2[CH:17]=[CH:16][N:15]([CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])[N:14]=2)=[C:6]2[CH2:11][CH2:10][NH:9][C:8](=[O:12])[C:7]=12.[H-].[Na+].I[CH:29]([CH3:31])[CH3:30]>CN(C=O)C>[CH3:1][S:2][C:3]1[S:4][C:5]([C:13]2[CH:17]=[CH:16][N:15]([CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:24])([CH3:23])[CH3:25])[N:14]=2)=[C:6]2[CH2:11][CH2:10][N:9]([CH:29]([CH3:31])[CH3:30])[C:8](=[O:12])[C:7]=12
Reactant: CSc1sc(-c2ccn(COCC[Si](C)(C)C)n2)c2c1C(=O)NCC2
Reactant: CC(C)I
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CSc1sc(-c2ccn(COCC[Si](C)(C)C)n2)c2c1C(=O)N(C(C)C)CC2
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 3-(methylsulfanyl)-1-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazol-3-yl)-6,7-dihydrothieno[3,4-c]pyridin-4(5H)-one (30 mg, 0.076 mmol) in DMF (0.7 mL) at 0° C. was added NaH (1.8 mg, 0.076 mmol). After 10 min, 2-iodopropane (13 mg, 0.076 mmol) was added and the reaction mixture was stirred at rt overnight, The resulting mixture was concentrated and purified directly by silica gel chromatography (gradient elution, 0-40% EtOAc/hexanes) to afford the title compound. LRMS (ESI) m/z 438.0 [(M+H)+; calcd for C20H31N3O2S2Si: 438].
Reaction SMILES: [I:1][C:2]1[N:3]=[C:4]([C@@H:8]2[CH2:12][C@H:11]([CH3:13])[CH2:10][N:9]2[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[NH:5][C:6]=1I.S([O-])([O-])=O.[Na+].[Na+]>C(O)C.O>[I:1][C:2]1[NH:3][C:4]([C@@H:8]2[CH2:12][C@H:11]([CH3:13])[CH2:10][N:9]2[C:14]([O:16][C:17]([CH3:18])([CH3:20])[CH3:19])=[O:15])=[N:5][CH:6]=1
Reactant: C[C@H]1C[C@@H](c2nc(I)c(I)[nH]2)N(C(=O)OC(C)(C)C)C1
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: C[C@H]1C[C@@H](c2ncc(I)[nH]2)N(C(=O)OC(C)(C)C)C1
Temperature: 90 °C
Yield: 46.2 %

Procedure:
A solution of (2S,4S)-tert-butyl 2-(4,5-diiodo-1H-imidazol-2-yl)-4-methylpyrrolidine-1-carboxylate (2.25 g, 4.4 mmol) in 18 mL ethanol and 18 mL water was treated with sodium sulfite (5.59 g, 44.4 mmol) and heated at 90° C. overnight. The mixture was partitioned between ethyl acetate and water. The aqueous phase was extracted with more ethyl acetate and the combined organic phase was washed with brine, dried over sodium sulphate, filtered, concentrated, and purified by silica gel chromatography to give 766 mg (2S,4S)-tert-butyl 2-(5-iodo-1H-imidazol-2-yl)-4-methylpyrrolidine-1-carboxylate.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([C:5]([OH:7])=[O:6])[CH2:2]1.C(O)(=O)C.[Cl:12][C:13]1[CH:14]=[C:15]([C:23]2[N:27]=[C:26]([C:28]3[CH:35]=[CH:34][C:31]([CH:32]=O)=[CH:30][CH:29]=3)[O:25][N:24]=2)[CH:16]=[CH:17][C:18]=1[O:19][CH:20]([CH3:22])[CH3:21].C([BH3-])#N.[Na+]>CO>[Cl:12][C:13]1[CH:14]=[C:15]([C:23]2[N:27]=[C:26]([C:28]3[CH:29]=[CH:30][C:31]([CH2:32][N:1]4[CH2:4][CH:3]([C:5]([OH:7])=[O:6])[CH2:2]4)=[CH:34][CH:35]=3)[O:25][N:24]=2)[CH:16]=[CH:17][C:18]=1[O:19][CH:20]([CH3:21])[CH3:22]
Reactant: O=C(O)C1CNC1
Reactant: CC(C)Oc1ccc(-c2noc(-c3ccc(C=O)cc3)n2)cc1Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)Oc1ccc(-c2noc(-c3ccc(CN4CC(C(=O)O)C4)cc3)n2)cc1Cl
Reaction time: 18 h
Yield: 55.4 %

Procedure:
Azetidine-3-carboxylic acid (3.72 g, 36.8 mmol) (Synchem) was dissolved in acetic acid (16.03 ml, 280 mmol) and methanol (2 ml). This was added to a stirred suspension of 4-(3-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-5-yl)benzaldehyde (12 g, 35.0 mmol) in MeOH (600 ml). The reaction was stirred for about 18 h. Sodium cyanoborohydride (5.50 g, 88 mmol) was added and the reaction stirred for about 4 h. The reaction was cooled with an ice bath and the precipitate was collected by vacuum filtration and washed with ice cold methanol and then ether. TLC showed impurities still present. The solid was dissolved in 1:1 EtOAc /(6:3:1 CHCl3/MeOH/NH4OH) with a little extra added NH4OH. Chromatography over silica gel in a mixture of 1:1 EtOAc/(6:3:1 CHCl3/MeOH/NH4OH) increasing to all 6:3:1 CHCl3/MeOH/NH4OH eluted the product. The fractions were evaporated to dryness to afford a colorless film/oil. Methanol was added and the mixture swirled but this gave low recovery on filtration. The mixture was dissolved in methanol. and the filtrate evaporated to dryness. The residue was resuspended in the minimum amount of methanol, water was added and the mixture filtered, washed with water and then ether. The residue was dried under vacuum at ambient temperature and then under vacuum at about 60° C. to remove trace methanol to afford 1-(4-(3-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-5-yl)benzyl)azetidine-3-carboxylic acid (8.3 g, 19.40 mmol, 55.4% yield) as a white solid: LCMS (Table 1, Method a) Rt=2.94 min.; MS m/z: 428.31, 430.27 (M+H)+; mp 194.8-195.9° C.; 1H NMR (400 MHz, DMSO) δ ppm 8.12 (d, J=8.34 Hz, 2H), 8.06 (d, J=2.13 Hz, 1H), 8.00 (dd, J=8.67, 2.15 Hz, 1H), 7.54 (d, J=8.36 Hz, 2H), 7.39 (d, J=9.06 Hz, 1H), 4.88-4.77 (m, 1H), 3.67 (s, 2H), 3.48-3.38 (m, 2H), 3.29-3.19 (m, 3H), 1.35 (d, J=6.02 Hz, 6H).
Reaction SMILES: Br[CH2:2][C:3]1[NH:8][C:7]([C:9]2[C:14]([F:15])=[CH:13][CH:12]=[CH:11][N:10]=2)=[N:6][CH:5]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=2[Cl:23])[C:4]=1[C:24]([O:26][CH2:27][CH3:28])=[O:25].[NH:29]1[CH2:34][CH2:33][O:32][CH:31]([C:35]([OH:37])=[O:36])[CH2:30]1>>[Cl:23][C:17]1[CH:18]=[C:19]([Cl:22])[CH:20]=[CH:21][C:16]=1[CH:5]1[N:6]=[C:7]([C:9]2[C:14]([F:15])=[CH:13][CH:12]=[CH:11][N:10]=2)[NH:8][C:3]([CH2:2][N:29]2[CH2:34][CH2:33][O:32][CH:31]([C:35]([OH:37])=[O:36])[CH2:30]2)=[C:4]1[C:24]([O:26][CH2:27][CH3:28])=[O:25]
Reactant: CCOC(=O)C1=C(CBr)NC(c2ncccc2F)=NC1c1ccc(Cl)cc1Cl
Reactant: O=C(O)C1CNCCO1
Product: CCOC(=O)C1=C(CN2CCOC(C(=O)O)C2)NC(c2ncccc2F)=NC1c1ccc(Cl)cc1Cl
Yield: 42.6 %

Procedure:
Ethyl 6-(bromomethyl)-4-(2,4-dichlorophenyl)-2-(3-fluoropyridin-2-yl)-1,4-dihydropyrimidine-5-carboxylate (0.75 g, 1.53 mmol) was reacted with morpholine-2-carboxylic acid (0.26 g, 1.53 mmol) according to the procedure as described in Example 1, Step C to give the title compound as a yellow solid (0.35 g, 43%). The compound was characterized by the following spectroscopic data: