Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Li+].[CH2:2]([C:4]1[N:12]=[CH:11][CH:10]=[CH:9][C:5]=1[C:6]([O-])=[O:7])[CH3:3].[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[CH2:2]([C:4]1[C:5]([CH2:6][OH:7])=[CH:9][CH:10]=[CH:11][N:12]=1)[CH3:3]
Reactant: CCc1ncccc1C(=O)[O-]
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCc1ncccc1CO
Temperature: 25 °C
Reaction time: 3 h

Procedure:
The 2-ethyl nicotinic acid lithium salt (5 g, 3.18 mmol) in distilled THF (400 mL) under nitrogen was cooled to 0° C. and lithium aluminum hydride (1M in THF) (25 mL) was added dropwise. The reaction was stirred for 3 hours at room temperature then cooled to 0° C. and quenched with EtOAc (949 μL), then H2O (949 μL), then 15% NaOH (949 μL), followed by H2O (2.8 mL). The solution was filtered and the solvent removed under reduced pressure. Toluene was added and the solvent was removed under reduced pressure to give the desired 2-ethyl-3 -hydroxymethylpyridine.
Reaction SMILES: [CH2:1]1[O:12][C:11]2[CH:10]=[C:9]3[C:5]([CH:6]=[CH:7][CH2:8]3)=[CH:4][C:3]=2[O:2]1.[OH2:13].[OH-].[Na+].OO>O1CCCC1.C(OCC)(=O)C>[CH2:1]1[O:2][C:3]2[CH:4]=[C:5]3[C:9]([CH2:8][CH:7]([OH:13])[CH2:6]3)=[CH:10][C:11]=2[O:12]1
Reactant: O
Reactant: C1=Cc2cc3c(cc2C1)OCO3
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: OC1Cc2cc3c(cc2C1)OCO3
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of 9.0 g of 5,6-methylenedioxyindene in 23 ml of tetrahydrofuran was cooled to 0° C. in a nitrogen atmosphere. A solution of 2.2 ml of 10.0 M borane/methyl sulfide complex in 5 ml of tetrahydrofuran was added dropwise thereto. The temperature of the mixture was elevated from 0° C. to room temperature over 4 h and then 1.8 ml of water was added dropwise thereto. 7.4 ml of a 3 M aqueous sodium hydroxide solution and then 5.5 ml of a 35% aqueous hydrogen peroxide solution were added thereto under cooling with ice and the mixture was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate, washed with an aqueous common salt solution and dried over magnesium sulfate. The solvent was distilled off and the residue was crystallized from ethyl acetate to obtain 6.4 g of the intended compound in the form of white crystals.
Reaction SMILES: COP([CH2:7][C:8](=[O:22])[CH2:9][CH2:10][CH2:11][CH2:12][C:13]1[N:18]=[C:17]2[NH:19][CH2:20][CH2:21][C:16]2=[CH:15][CH:14]=1)(=O)OC.[CH3:23][C:24]1[N:29]=[CH:28][C:27]([CH:30]=O)=[CH:26][N:25]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[NH:19]1[C:17]2=[N:18][C:13]([CH2:12][CH2:11][CH2:10][CH2:9][C:8](=[O:22])[CH:7]=[CH:30][C:27]3[CH:26]=[N:25][C:24]([CH3:23])=[N:29][CH:28]=3)=[CH:14][CH:15]=[C:16]2[CH2:21][CH2:20]1
Reactant: Cc1ncc(C=O)cn1
Reactant: COP(=O)(CC(=O)CCCCc1ccc2c(n1)NCC2)OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ncc(C=CC(=O)CCCCc2ccc3c(n2)NCC3)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 82.7 %

Procedure:
To a solution of 23-7 (0.49 g, 1.5 mmol) and 2-methyl-pyrimidine-5-carbaldehyde (0.183 g, 1.5 mmol) in 15 mL DMF was added K2CO3 (0.310 g, 2.25 mmol). The mixture was stirred at ambient temperature for 2 hr and concentrated to a paste. The residue was purified by PCTLC (0–10% MeOH/CH2Cl2) which provided 0.400 g (83% yield) of 23-8.
Reaction SMILES: [CH2:1]([O:3][C:4]([C@@H:6]1[O:8][C@H:7]1[C:9]([O-:11])=O)=[O:5])[CH3:2].[K+].S(Cl)(Cl)=O.[CH3:17][CH:18]([CH3:28])[CH2:19][CH:20]([NH2:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(N(CC)CC)C>>[CH3:17][CH:18]([CH3:28])[CH2:19][CH:20]([NH:27][C:9]([C@@H:7]1[O:8][C@H:6]1[C:4]([O:3][CH2:1][CH3:2])=[O:5])=[O:11])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CC(C)CC(N)c1ccccc1
Reactant: CCOC(=O)[C@@H]1O[C@H]1C(=O)[O-]
Agent: [K+]
Solvent: O=S(Cl)Cl
Solvent: CCN(CC)CC
Product: CCOC(=O)[C@@H]1O[C@H]1C(=O)NC(CC(C)C)c1ccccc1
Yield: 95.9 %

Procedure:
The reactions and treatments of Example 5 were repeated using potassium (2R,3R)-3-ethoxycarbonyloxirane-2-carboxylate (3.97 g, 20.0 mmol.), thionyl chloride (2.86 g, 24.0 mmol), 3-methyl-1-phenylbutylamine (4.25 g, 26.0 mmol), and triethylamine (2.63 g, 26.0 mmol.), to give the desired compound as a colorless viscous oil (5.86 g, yield: 96%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([OH:8])[CH:7]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:19]/[CH:20]=[CH:21]/[C:22]([O:24][CH2:25][CH3:26])=[O:23]>CN1C(=O)CCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH:7]=1)[O:8][CH2:19]/[CH:20]=[CH:21]/[C:22]([O:24][CH2:25][CH3:26])=[O:23]
Reactant: O=[N+]([O-])c1ccc(Br)cc1O
Reactant: CCOC(=O)/C=C/CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: CCOC(=O)/C=C/COc1cc(Br)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 20 h
Yield: 99 %

Procedure:
5-Bromo-2-nitrophenol (10 g, 45.9 mmol) and K2CO3 (8.24 g, 59.6 mmol) were suspended in NMP (81 mL) (a bright red suspension) and ethyl 4-bromocrotonate (10.26 mL, 59.63 mmol) was added dropwise at room temperature. The reaction was stirred at room temperature over night (20 h). The mixture was poured into ice/water (500 mL) and stirred for 30 min. The precipitate was collected by filtration and washed with water (2×200 mL), air dried for 10 min and then washed with heptane (200 mL). Heptane (200 mL) was added to the solid and stirred for 1 h. The solid was filtered off, washed with heptane (2×50 mL) and dried in vacuo to afford a beige solid. The title compound (15.0 g, 99%) was obtained and was used without further purification.
Reaction SMILES: C[Si](N[Si](C)(C)C)(C)C.[Li]CCCC.[C:15]([CH:18]([CH2:24][CH:25]([CH3:27])[CH3:26])[C:19]([O:21][CH2:22][CH3:23])=[O:20])(=O)C.C=O>C1COCC1>[CH2:24]([C:18](=[CH2:15])[C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:25]([CH3:27])[CH3:26]
Reactant: CCOC(=O)C(CC(C)C)C(C)=O
Agent: C=O
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C=C(CC(C)C)C(=O)OCC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Bis(trimethylsilyl)amine (9.50 g, 59.0 mmol) in 250 ml of THF was metallated by 23.5 ml (59.0 mmol) of 2.5 M nBuLi in hexanes at −78° C. This mixture was additionally stirred for 0.5 h at room temperature, then cooled again to −78° C., and 10.0 g (53.7 mmol) of ethyl 2-acetyl-4-methylpentanoate was added. The resulting mixture was stirred for 1 h at room temperature, cooled to −78° C., and 8.0 g (09.27 mmol) of paraformaldehyde was added. This mixture was stirred overnight at room temperature, then filtered through glass frit (G3), and evaporated to dryness. Fractional rectification of the residue gave the title product, 50-55° C./4 mm Hg. Yield 6.50 g (78%).
Reaction SMILES: [C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24](/[C:26](=[N:71]/[O:72][C:73]([C:86]2[CH:91]=[CH:90][CH:89]=[CH:88][CH:87]=2)([C:80]2[CH:85]=[CH:84][CH:83]=[CH:82][CH:81]=2)[C:74]2[CH:79]=[CH:78][CH:77]=[CH:76][CH:75]=2)/[C:27]([NH:29][CH:30]2[C:69](=[O:70])[N:32]3[C:33]([C:57]([O:59][CH2:60][C:61]4[CH:66]=[CH:65][C:64]([O:67][CH3:68])=[CH:63][CH:62]=4)=[O:58])=[C:34]([CH:37]=P(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[CH2:35][S:36][C@H:31]23)=[O:28])[N:25]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Si:92]([O:99][CH2:100][CH:101]=O)([C:95]([CH3:98])([CH3:97])[CH3:96])([CH3:94])[CH3:93]>ClCCl>[C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24](/[C:26](=[N:71]/[O:72][C:73]([C:80]2[CH:81]=[CH:82][CH:83]=[CH:84][CH:85]=2)([C:74]2[CH:75]=[CH:76][CH:77]=[CH:78][CH:79]=2)[C:86]2[CH:87]=[CH:88][CH:89]=[CH:90][CH:91]=2)/[C:27]([NH:29][CH:30]2[C:69](=[O:70])[N:32]3[C:33]([C:57]([O:59][CH2:60][C:61]4[CH:62]=[CH:63][C:64]([O:67][CH3:68])=[CH:65][CH:66]=4)=[O:58])=[C:34](/[CH:37]=[CH:101]\[CH2:100][O:99][Si:92]([C:95]([CH3:96])([CH3:97])[CH3:98])([CH3:93])[CH3:94])[CH2:35][S:36][C@H:31]23)=[O:28])[N:25]=1)([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: COc1ccc(COC(=O)C2=C(C=P(c3ccccc3)(c3ccccc3)c3ccccc3)CS[C@@H]3C(NC(=O)/C(=N\OC(c4ccccc4)(c4ccccc4)c4ccccc4)c4csc(NC(c5ccccc5)(c5ccccc5)c5ccccc5)n4)C(=O)N23)cc1
Reactant: CC(C)(C)[Si](C)(C)OCC=O
Solvent: ClCCl
Product: COc1ccc(COC(=O)C2=C(/C=C\CO[Si](C)(C)C(C)(C)C)CS[C@@H]3C(NC(=O)/C(=N\OC(c4ccccc4)(c4ccccc4)c4ccccc4)c4csc(NC(c5ccccc5)(c5ccccc5)c5ccccc5)n4)C(=O)N23)cc1

Procedure:
A solution of 4-methoxyphenylmethyl 7-[(Z)-2-(2-tritylaminothiazol-4-yl)-2-trityloxyiminoacetamido]-3-(triphenylphosphoranylidene)methyl-3-cephem-4-carboxylate (9.07 g; 7.27 mmol) and t-butyldimethylsilyloxyacetaldehyde (1.8 g; 10.34 mmol) in dichloromethane (100 ml) was stirred at room temperature for 16 hours. After the solvent was distilled off under reduced pressure, the residue was purified by chromatography on a silica gel column (n-hexane:ethyl acetate=2.5:1) whereby the title compound (4.99 g; 4.36 mmol; 60% was obtained.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:15]=[CH:14][C:10]([C:11](=[S:13])[NH2:12])=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.Br[CH2:17][CH:18](OC)OC.C1(C)C=CC(S(O)(=O)=O)=CC=1>CCO>[S:13]1[CH:18]=[CH:17][N:12]=[C:11]1[C:10]1[CH:9]=[CH:8][C:7]([N:4]2[CH2:3][CH2:2][O:1][CH2:6][CH2:5]2)=[CH:15][CH:14]=1
Reactant: NC(=S)c1ccc(N2CCOCC2)cc1
Reactant: COC(CBr)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Product: c1csc(-c2ccc(N3CCOCC3)cc2)n1
Temperature: 95 °C
Yield: 81.2 %

Procedure:
To a solution of 4-morpholinobenzothioamide (2.22 g, 10 mmol) in EtOH (50 mL) were added 2-bromo-1,1-dimethoxyethane (1.69 g, 10 mmol) and p-toluenesulfonic acid (1.90 g, 10 mmol). The reaction mixture was heated at 95° C. overnight, then cooled to rt and filtered. The filter cake was dried to give the title compound as a yellow solid (2.00 g, 81%).
Reaction SMILES: [NH:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[C:12]([O:14][CH3:15])=[O:13])[C:4](=[O:5])[C:2]1=[O:3].Cl.[CH:17]([N:20]([CH:24]([CH3:26])[CH3:25])[CH2:21][CH2:22]Cl)([CH3:19])[CH3:18]>>[CH:17]([N:20]([CH:24]([CH3:26])[CH3:25])[CH2:21][CH2:22][N:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[C:12]([O:14][CH3:15])=[O:13])[C:4](=[O:5])[C:2]1=[O:3])([CH3:19])[CH3:18]
Reactant: COC(=O)c1cccc2c1NC(=O)C2=O
Reactant: CC(C)N(CCCl)C(C)C
Agent: Cl
Product: COC(=O)c1cccc2c1N(CCN(C(C)C)C(C)C)C(=O)C2=O

Procedure:
By using methyl 7-isatincarboxylate and 2-diisopropylaminoethyl chloride hydrochloride, a method analogous to that described in Reference Example 7 was carried out to obtain methyl 1-(2-diisopropylaminoethyl)-7-isatincarboxylate in an oil (yield: 94.6%).
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([C:17]3[C:25]4[C:20](=[CH:21][CH:22]=[C:23]([O:26][CH:27]([F:29])[F:28])[CH:24]=4)[N:19]([CH:30]4[CH2:35][CH2:34][N:33]([CH3:36])[CH2:32][CH2:31]4)[N:18]=3)[N:15]=2)[N:10](COCC[Si](C)(C)C)[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].FC(F)(F)C(O)=O.C(N)CN.O>ClCCl.C(OCC)(=O)C>[C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([C:17]3[C:25]4[C:20](=[CH:21][CH:22]=[C:23]([O:26][CH:27]([F:29])[F:28])[CH:24]=4)[N:19]([CH:30]4[CH2:35][CH2:34][N:33]([CH3:36])[CH2:32][CH2:31]4)[N:18]=3)[N:15]=2)[NH:10][CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN1CCC(n2nc(-c3cnc4c(n3)c(C(=O)NC(C)(C)C)cn4COCC[Si](C)(C)C)c3cc(OC(F)F)ccc32)CC1
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: NCCN
Product: CN1CCC(n2nc(-c3cnc4[nH]cc(C(=O)NC(C)(C)C)c4n3)c3cc(OC(F)F)ccc32)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 87.5 %

Procedure:
In a 10 ml round-bottomed flask, 2-[5-difluoromethoxy-1-(1-methyl-piperidin-4-yl)-1H-indazol-3-yl]-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid tert-butylamide (crude from Step 2, 103 mg, 0.131 mmol) was dissolved in dichloromethane (0.7 ml) and trifluoroacetic acid (0.40 ml, 5.2 mmol) was added. The reaction mixture was stirred at room temperature for 2 h then concentrated. The residue was suspended in dichloromethane (0.7 ml) and ethylenediamine (0.53 ml, 7.85 mmol) was added. The light yellow suspension was stirred at room temperature for 1 h then water and ethyl acetate were added. The suspension was filtered and washed with hot water and ethyl acetate. The product collected was dried under high vacuum to provide 57 mg (83%) of 2-[5-difluoromethoxy-1-(1-methyl-piperidin-4-yl)-1H-indazol-3-yl]-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid tert-butylamide as a light yellow powder. MS: (M+H)+=498; 1H NMR (DMSO-d6, 300 MHz): δ (ppm) 9.08 (s, 1H), 8.38 (s, 1H), 8.20 (s, 1H), 7.86-8.00 (m, 2H), 7.39 (d, J=8.3 Hz, 1H), 7.19 (t, J=74.4 Hz, 1H), 4.67-4.83 (m, 1H), 2.95 (d, J=7.9 Hz, 2H), 2.27 (s, 3H), 2.12-2.32 (m, 4H), 2.00 (d, J=10.2 Hz, 2H), 1.50 (s, 9H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:30])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]([F:16])=[C:12]2[C:7]=1[C:8](=[O:29])[C:9]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([C:26](=[O:28])[CH3:27])=[CH:22][CH:21]=1)=[C:10]([CH2:17][CH3:18])[NH:11]2.Cl[C:32](OC(=O)C)([F:34])[F:33]>>[CH3:1][O:2][C:3](=[O:30])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]([F:16])=[C:12]2[C:7]=1[C:8]([O:29][CH:32]([F:34])[F:33])=[C:9]([CH2:19][C:20]1[CH:21]=[CH:22][C:23]([C:26](=[O:28])[CH3:27])=[CH:24][CH:25]=1)[C:10]([CH2:17][CH3:18])=[N:11]2
Reactant: CCc1[nH]c2c(F)ccc(OCC(=O)OC)c2c(=O)c1Cc1ccc(C(C)=O)cc1
Reactant: CC(=O)OC(F)(F)Cl
Product: CCc1nc2c(F)ccc(OCC(=O)OC)c2c(OC(F)F)c1Cc1ccc(C(C)=O)cc1

Procedure:
The title compound was prepared by the method of Preparation 1d using [3-(4-acetylbenzyl)-2-ethyl-8-fluoro-4-oxo-1,4-dihydroquinolin-5-yloxy]acetic acid methyl ester and acetic acid chlorodifluoromethyl ester.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](/[C:8](/[C:25]2[CH:30]=[CH:29][C:28]([C:31]#[C:32][CH2:33][N:34]3[CH2:39][CH2:38][N:37]([CH3:40])[CH2:36][CH2:35]3)=[CH:27][CH:26]=2)=[CH:9]/[CH2:10][O:11][C:12]2[CH:23]=[CH:22][C:15]([O:16][CH2:17][C:18]([O:20]C)=[O:19])=[C:14]([CH3:24])[CH:13]=2)=[CH:4][CH:3]=1.O.[OH-].[Li+]>C(O)C.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5](/[C:8](/[C:25]2[CH:30]=[CH:29][C:28]([C:31]#[C:32][CH2:33][N:34]3[CH2:35][CH2:36][N:37]([CH3:40])[CH2:38][CH2:39]3)=[CH:27][CH:26]=2)=[CH:9]/[CH2:10][O:11][C:12]2[CH:23]=[CH:22][C:15]([O:16][CH2:17][C:18]([OH:20])=[O:19])=[C:14]([CH3:24])[CH:13]=2)=[CH:4][CH:3]=1
Reactant: COC(=O)COc1ccc(OC/C=C(/c2ccc(Cl)cc2)c2ccc(C#CCN3CCN(C)CC3)cc2)cc1C
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1cc(OC/C=C(/c2ccc(Cl)cc2)c2ccc(C#CCN3CCN(C)CC3)cc2)ccc1OCC(=O)O
Reaction time: 72 h

Procedure:
The above ester (0.36 g, 0.658 mmol) was dissolved in ethanol (30 mL), a solution of lithium hydroxide monohydrate (0.10 g, 2.38 mmol) in water (4 mL) was added and the mixture was left to stand for 72 h. The solvents were evaporated in vacuo; the residue was diluted with water (25 mL), acidified with acetic acid (0.25 mL) and extracted with chloroform (2×50 mL). The organic solution was dried with anhydrous potassium carbonate and subsequently evaporated in vacuo. The residue was triturated with hexanes (2×20 mL) yielding the title compound as amorphous solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@H:8]([O:22][CH2:23][CH2:24][NH:25][C:26](=[N:29][C:30]#[N:31])SC)[C@@H:9]2[CH2:14][CH2:13][CH2:12][N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10]2)[CH:5]=[CH:6][CH:7]=1.[CH3:32][NH2:33].CCO>>[Cl:1][C:2]1[CH:3]=[C:4]([C@H:8]([O:22][CH2:23][CH2:24][NH:25][C:26]([NH:33][CH3:32])=[N:29][C:30]#[N:31])[C@@H:9]2[CH2:14][CH2:13][CH2:12][N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CSC(=NC#N)NCCO[C@@H](c1cccc(Cl)c1)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Reactant: CN
Solvent: CCO
Product: CNC(=NC#N)NCCO[C@@H](c1cccc(Cl)c1)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Reaction time: 8 h

Procedure:
A 100 mL flask was charged with (R)-tert-butyl 3-((R)-(3-chlorophenyl)(2-((cyanoimino)(methylthio)methylamino)ethoxy)methyl)piperidine-1-carboxylate (2.2 g, 4.72 mmol) dissolved in 50 mL MeNH2/EtOH solution and stirred overnight. The mixture was concentrated in vacuo and used without any further purification.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[NH:14][C:15]([NH:17][CH2:18][C:19]2[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:20]=2[F:26])=[O:16])=[CH:4][CH:3]=1.[CH2:27]([O:29][C:30]([C:32]1([C:35]2[CH:40]=[CH:39][C:38](B3OC(C)(C)C(C)(C)O3)=[CH:37][CH:36]=2)[CH2:34][CH2:33]1)=[O:31])[CH3:28]>>[CH2:27]([O:29][C:30]([C:32]1([C:35]2[CH:40]=[CH:39][C:38]([C:2]3[CH:7]=[CH:6][C:5]([C:8]4[O:12][N:11]=[C:10]([CH3:13])[C:9]=4[NH:14][C:15]([NH:17][CH2:18][C:19]4[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:20]=4[F:26])=[O:16])=[CH:4][CH:3]=3)=[CH:37][CH:36]=2)[CH2:33][CH2:34]1)=[O:31])[CH3:28]
Reactant: Cc1noc(-c2ccc(Br)cc2)c1NC(=O)NCc1c(F)cccc1F
Reactant: CCOC(=O)C1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4NC(=O)NCc4c(F)cccc4F)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 3, Step 5, using 1-[5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-3-(2,6-difluoro-benzyl)-urea and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:19]([C:20]3[CH:25]=[CH:24][C:23]([CH2:26][O:27][CH3:28])=[CH:22][CH:21]=3)=[N:18][CH:17]=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:29]>O1CCOCC1>[ClH:29].[ClH:29].[CH3:28][O:27][CH2:26][C:23]1[CH:24]=[CH:25][C:20]([C:19]2[C:14]([N:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]3)=[N:15][CH:16]=[CH:17][N:18]=2)=[CH:21][CH:22]=1
Reactant: COCc1ccc(-c2nccnc2N2CCN(C(=O)OC(C)(C)C)CC2)cc1
Agent: Cl
Solvent: C1COCCO1
Product: COCc1ccc(-c2nccnc2N2CCNCC2)cc1
Yield: 80 %

Procedure:
Suspend 3′-(4-methoxymethyl-phenyl)-2,3,5,6-tetrahydro-[1,2′]bipyrazinyl-4-carboxylic acid tert-butyl ester (1.3 g, 3.26 mmol) in 1,4-dioxane (10 mL). Add HCl in dioxane (4 M, 10 mL), stir for 2 hr. then filter off the yellow solid. Wash with dioxane then diethyl ether to give 3′-(4-methoxymethyl-phenyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl dihydrochloride as yellow solid (935 mg, 80%). MS (ES): m/z=285 [M+H]+.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:14]([CH2:15][CH2:16][O:17][CH3:18])[C:13]3[C:19]([O:26][CH3:27])=[CH:20][C:21]([C:23](=[O:25])[CH3:24])=[CH:22][C:12]=3[N:11]=2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[C:28]1([Mg]Br)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>C1COCC1>[CH:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:14]([CH2:15][CH2:16][O:17][CH3:18])[C:13]3[C:19]([O:26][CH3:27])=[CH:20][C:21]([C:23]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)([OH:25])[CH3:24])=[CH:22][C:12]=3[N:11]=2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2]
Reactant: COCCn1c(-c2ccc(C(C)C)cc2)nc2cc(C(C)=O)cc(OC)c21
Reactant: Br[Mg]c1ccccc1
Solvent: C1CCOC1
Product: COCCn1c(-c2ccc(C(C)C)cc2)nc2cc(C(C)(O)c3ccccc3)cc(OC)c21
Temperature: 25 °C
Reaction time: 1 h
Yield: 171 %

Procedure:
A solution of 163 mg (0.445 mmol) 1-[2-(4-isopropyl-phenyl)-7-methoxy-1-(2-methoxy-ethyl)-1H-benzoimidazol-5-yl]-ethanone in 2 ml THF is treated with excess phenylmagnesiumbromide (prepared from 112 μl bromobenzene and 26 mg magnesium in 5 ml diethyl ether). The resulting mixture is stirred at room temperature for 1 h. The reaction mixture is poured on water and extracted (3×) with ethyl acetate. The combined organic layers are washed with water (2×) and brine, dried over MgSO4, filtered and concentrated in vacuo. The residue is purified by flash-chromatography on silica gel (hexane:EtOAc=2:1) to afford 109 mg of the title compound as an oil.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]1[CH2:21][CH2:20][C:19]2[C:14](=[CH:15][C:16]([CH:22]=[CH:23][C:24]([O:26]CC)=[O:25])=[CH:17][CH:18]=2)[CH2:13]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>CO.C1COCC1>[CH2:1]([O:8][C:9]([NH:11][C@H:12]1[CH2:21][CH2:20][C:19]2[C:14](=[CH:15][C:16]([CH:22]=[CH:23][C:24]([OH:26])=[O:25])=[CH:17][CH:18]=2)[CH2:13]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)C=Cc1ccc2c(c1)C[C@@H](NC(=O)OCc1ccccc1)CC2
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)C=Cc1ccc2c(c1)C[C@@H](NC(=O)OCc1ccccc1)CC2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2 g (5.3 mmole) of (2S)-2-benzyloxycarbonylamino-7-(3-ethoxy-3-oxo-1-propenyl)-tetralin were dissolved in 20 ml of methanol and 30 ml of THF, and 5.3 ml of 1N NaOH were added. The solution was stirred overnight at ambient temperature. The solvent was evaporated off, the residue was taken up in water and washed with ethyl ether; the aqueous phase was acidified with 5% citric acid and then extracted with ethyl acetate. It was dried over sodium sulfate and the solvent was evaporated off. The product of the heading was obtained.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:10]([NH:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([Cl:21])[CH:14]=2)=[N:9][C:8](Cl)=[CH:7][N:6]=1)=[O:4].[OH:23][CH2:24][CH:25]1[CH2:29][CH2:28][CH2:27][NH:26]1.C(N(CC)CC)C.O>O1CCCC1>[CH3:1][O:2][C:3]([C:5]1[C:10]([NH:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([Cl:21])[CH:14]=2)=[N:9][C:8]([N:26]2[CH2:27][CH2:28][CH2:29][C@H:25]2[CH2:24][OH:23])=[CH:7][N:6]=1)=[O:4]
Reactant: COC(=O)c1ncc(Cl)nc1NCc1ccc(OC)c(Cl)c1
Reactant: OCC1CCCN1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1ncc(N2CCC[C@H]2CO)nc1NCc1ccc(OC)c(Cl)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 69 %

Procedure:
A mixture of 2-methoxycarbonyl-3-(3-chloro-4-methoxybenzylamino)-5-chloropyrazine (150 mg), 2-hydroxymethylpyrrolidine (88.6 mg), and triethylamine (0.12 ml) in tetrahydrofuran (5 ml) is stirred at room temperature for 4 hours, and the mixture is heated at 50° C. for 2 hours. To the mixture is added 2-hydroxymethylpyrrolidine (44.3 mg), and the mixture is stirred at 50° C. for one hour. After cooling, water is added to the reaction mixture, and the mixture is extracted with ethyl acetate. The extract is washed with water and brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting yellow oil is purified by silica gel column chromatography (solvent; chloroform:hexane=1:1) to give (S)-2-methoxycarbonyl-3-(3-chloro-4-methoxybenzylamino)-5-(2-hydroxymethyl-1-pyrrolidinyl)-pyrazine (123 mg) as pale yellow powder, MS (m/z): 407 (MH+).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:4]=1[C:12]([F:18])([F:17])[C:13]([F:16])([F:15])[F:14].[C:19]([N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1)([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20].C([O-])(O)=O.[Na+]>C(Cl)Cl>[C:19]([N:26]1[CH2:27][CH2:28][N:29]([CH2:2][C:3]2[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:4]=2[C:12]([F:18])([F:17])[C:13]([F:16])([F:15])[F:14])[CH2:30][CH2:31]1)([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20]
Reactant: O=[N+]([O-])c1ccc(C(F)(F)C(F)(F)F)c(CBr)c1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(Cc2cc([N+](=O)[O-])ccc2C(F)(F)C(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-Bromomethyl-4-nitro-1-pentafluoroethyl-benzene (2.5 g) was dissolved in CH2Cl2 and added to N-Boc-piperazine (2.5 g) and NaHCO3 (1 g) and stirred at RT overnight. The mixture was diluted with CH2Cl2 (100 ml), washed with sat'd NH4Cl, dried over MgSO4, filtered and concentrated. The residue was purified by silica gel chromatography (hexane, CH2Cl2:hexane 2:8) to give the compound as an yellow solid.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[I:11][C:12]1[CH:13]=[C:14]([CH:16]=[CH:17][CH:18]=1)[NH2:15].C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1>[I:11][C:12]1[CH:13]=[C:14]([NH:15][C:2]2[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=2)[CH:16]=[CH:17][CH:18]=1
Reactant: Nc1cccc(I)c1
Reactant: O=[N+]([O-])c1cccnc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: O=[N+]([O-])c1cccnc1Nc1cccc(I)c1
Yield: 21.2 %

Procedure:
A mixture of 2-chloro-3-nitropyridine (8.5 g), 3-iodoaniline (12.5 g) and potassium carbonate (9.0 g) in 1,4-dioxane (100 ml) was stirred under reflux for 20 hours. After cooling, insoluble materials were removed by filtration and the filtrate was concentrated. The resultant solid was collected and washed with isopropyl ether to give 2-(3-iodophenylamino)-3-nitropyridine (3.88 g) as an orange solid.