Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Na].Cl[C:3]1[NH:8][C:7](=[O:9])[C:6]([F:10])=[CH:5][N:4]=1.[CH:11]([OH:15])([CH2:13][CH3:14])[CH3:12]>>[CH:11]([O:15][C:3]1[NH:8][C:7](=[O:9])[C:6]([F:10])=[CH:5][N:4]=1)([CH2:13][CH3:14])[CH3:12]
Reactant: O=c1[nH]c(Cl)ncc1F
Reactant: CCC(C)O
Agent: [Na]
Product: CCC(C)Oc1ncc(F)c(=O)[nH]1
Yield: 91.4 %

Procedure:
A 300 ml quantity of absolute sec-butanol, 5.8 g of metal sodium and 14.9 g of 2-chloro-5-fluoropyrimidin-4-one are treated in the same manner as in Example 6 to obtain crystals, which are then recrystallized from a water-ethanol mixture to give 17.0 g of white crystalline 2-sec-butoxy-5-fluoropyrimidin-4-one in a yield of 91.4%, m.p. 104°-105° C.
Reaction SMILES: [CH3:1][N:2]([CH3:21])[CH2:3][CH2:4][NH:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17](F)=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7].[C:22](N1C=CN=C1)([N:24]1C=CN=C1)=[O:23].CN(CCN)C.N1(C2C=CC(C(N)=O)=CC=2)CCNCC1>O1CCCC1>[NH2:24][C:22]([C:17]1[CH:18]=[CH:19][C:14]([N:11]2[CH2:12][CH2:13][N:8]([C:6]([NH:5][CH2:4][CH2:3][N:2]([CH3:21])[CH3:1])=[O:7])[CH2:9][CH2:10]2)=[CH:15][CH:16]=1)=[O:23]
Reactant: CN(C)CCNC(=O)N1CCN(c2ccc(F)cc2)CC1
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: CN(C)CCN
Agent: NC(=O)c1ccc(N2CCNCC2)cc1
Solvent: C1CCOC1
Product: CN(C)CCNC(=O)N1CCN(c2ccc(C(N)=O)cc2)CC1
Yield: 20 %

Procedure:
This compound was prepared according to the procedure used to synthesize the compound of Example 11. A mixture of 3.1 g (0.019 mole) of 1,1'-carbonyldiimidazole, 1.7 g (0.019 mole) of unsym-dimethylethylenediamine and 3.9 g (0.019 mole) of 4-(1-piperazinyl)benzamide in a total volume of 150 ml of tetrahydrofuran gave a suspended white solid. The collected solid was recrystallized from ethanol-benzene to give 1.2 g (20%) of the title compound as a white solid, m.p. 193°-195° C.
Reaction SMILES: [CH:1]([NH:4][C:5]1[C:14]2[C:9](=[CH:10][C:11]([C:15]3[CH:16]=[C:17]([CH:21]=[CH:22][C:23]=3[CH3:24])[C:18]([OH:20])=O)=[CH:12][CH:13]=2)[CH:8]=[N:7][N:6]=1)([CH3:3])[CH3:2].CN.[CH3:27][N:28](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.C(Cl)Cl>[CH:1]([NH:4][C:5]1[C:14]2[C:9](=[CH:10][C:11]([C:15]3[CH:16]=[C:17]([CH:21]=[CH:22][C:23]=3[CH3:24])[C:18]([NH:28][CH3:27])=[O:20])=[CH:12][CH:13]=2)[CH:8]=[N:7][N:6]=1)([CH3:3])[CH3:2]
Reactant: Cc1ccc(C(=O)O)cc1-c1ccc2c(NC(C)C)nncc2c1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CN
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CNC(=O)c1ccc(C)c(-c2ccc3c(NC(C)C)nncc3c2)c1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
A solution of 3-(1-(isopropylamino)phthalazin-6-yl)-4-methylbenzoic acid (0.22 g, 0.7 mmol) in DMF (2 mL) at RT was treated with a 2 M solution of methylamine (2 mL, 3 mmol), and HATU (0.4 g, 1 mmol). The mixture was stirred at RT for 15 h. The mixture was diluted with 100 mL DCM, washed with 20 mL sat. NaHCO3, dried over anhydrous Na2SO4, concentrated in vacuo and purified by column eluting with 2-3% 2M ammonia MeOH/DCM to give the title compound. MS (ES+): 335 (M+H)+.
Reaction SMILES: [NH2:1][CH:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=2[N:4]([CH3:19])[C:3]1=[O:20].[CH3:21][CH:22]([C:26]([NH:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C:36]([F:39])([F:38])[F:37])[CH:31]=1)=[O:27])[C:23](O)=[O:24]>>[CH3:21][CH:22]([C:26]([NH:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C:36]([F:37])([F:38])[F:39])[CH:31]=1)=[O:27])[C:23]([NH:1][CH:2]1[C:3](=[O:20])[N:4]([CH3:19])[C:5]2[CH:18]=[CH:17][CH:16]=[CH:15][C:6]=2[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:8]1)=[O:24]
Reactant: CN1C(=O)C(N)N=C(c2ccccc2)c2ccccc21
Reactant: CC(C(=O)O)C(=O)NCc1cccc(C(F)(F)F)c1
Product: CC(C(=O)NCc1cccc(C(F)(F)F)c1)C(=O)NC1N=C(c2ccccc2)c2ccccc2N(C)C1=O

Procedure:
The title compound, MS: m/e=523.4 (M+H+), was prepared in analogy to example 16 from 3-amino-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one and 2-methyl-N-(3-trifluoromethyl-benzyl)-malonamic acid.
Reaction SMILES: [Cl:1][C:2]1[N:6]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[NH:4][C:3]=1[CH:13]=[O:14].CI.[C:17](=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[Cl:1][C:2]1[N:6]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:4]([CH3:17])[C:3]=1[CH:13]=[O:14]
Reactant: O=Cc1[nH]c(-c2ccccc2)nc1Cl
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CI
Product: Cn1c(-c2ccccc2)nc(Cl)c1C=O
Reaction time: 1 h

Procedure:
1 g (4.8 mmol) of 5-chloro-2-phenyl-3H-imidazole-4-carbaldehyde, 0.824 g (5.8 mmol) of methyl iodide and 1.338 g (9.7 mmol) of potassium carbonate in 50 ml of DMF were stirred at room temperature for 4 h. The reaction mixture was poured onto 200 ml of water, the resulting mixture stirred for 1 h, and the product was filtered off with suction and dried. Yield: 820 mg.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:22](O)=[O:23])[C:7]([C:10]2[C:11]([C:19](O)=[O:20])=[CH:12][C:13]([N+:16]([O-:18])=[O:17])=[CH:14][CH:15]=2)=[CH:8][CH:9]=1)([O-:3])=[O:2].O.Cl>O1CCCC1>[N+:1]([C:4]1[CH:5]=[C:6]([CH2:22][OH:23])[C:7]([C:10]2[C:11]([CH2:19][OH:20])=[CH:12][C:13]([N+:16]([O-:18])=[O:17])=[CH:14][CH:15]=2)=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=C(O)c1cc([N+](=O)[O-])ccc1-c1ccc([N+](=O)[O-])cc1C(=O)O
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: O=[N+]([O-])c1ccc(-c2ccc([N+](=O)[O-])cc2CO)c(CO)c1
Reaction time: 19 h

Procedure:
3.6 g (10.83 mmol) 4,4′-Dinitro-1,1′-biphenyl-2,2′-dicarboxylic acid is dissolved in 25 ml tetrahydrofuran and added drop wise in a the course of 1 hours to 65 ml (65.02 mmol) of a borane-tetrahydrofuran complex 1.0 M solution in tetrahydrofuran. After 19 hours at 25° C., 50 ml water is carefully added. After 1 h the solution is acidified to pH=1-2 with 10 ml 1N HCl solution and allowed to stirred for 30 min. The reaction mixture is then partitioned between ethyl acetate and water; the organic phase is washed repeatedly with water, dried over sodium sulfate, filtered and concentrated by rotary evaporation. The residue, 4.2 g of 4,4′-Dinitro-1,1′-biphenyl-2,2′-dimethanol as white powder is used without further purification.
Reaction SMILES: [NH2:1][C:2]1[C:3]([Cl:14])=[N:4][C:5]([O:11][CH2:12][CH3:13])=[C:6]([CH:10]=1)[C:7]([OH:9])=O.[C:15]1([C:21]2[CH:25]=[C:24]([CH2:26][N:27]3[CH2:32][CH2:31][CH:30]([CH2:33][NH2:34])[CH2:29][CH2:28]3)[O:23][N:22]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[NH2:1][C:2]1[C:3]([Cl:14])=[N:4][C:5]([O:11][CH2:12][CH3:13])=[C:6]([CH:10]=1)[C:7]([NH:34][CH2:33][CH:30]1[CH2:29][CH2:28][N:27]([CH2:26][C:24]2[O:23][N:22]=[C:21]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:25]=2)[CH2:32][CH2:31]1)=[O:9]
Reactant: NCC1CCN(Cc2cc(-c3ccccc3)no2)CC1
Reactant: CCOc1nc(Cl)c(N)cc1C(=O)O
Product: CCOc1nc(Cl)c(N)cc1C(=O)NCC1CCN(Cc2cc(-c3ccccc3)no2)CC1

Procedure:
According to the same procedure described in example 225, using the compound prepared in Example 292 instead of 4-amino-5-cyano-6-ethoxypicolinic acid, and using the compound prepared in Example 9 instead of tert-butyl 4-(aminomethyl)piperidine-1-carboxylate, the title compound having the following physical data was obtained.
Reaction SMILES: [O:1]=[C:2]1[NH:25][C:24]2[CH:26]=[CH:27][CH:28]=[CH:29][C:23]=2[C:4]2([CH2:9][CH2:8][N:7]([CH:10]3[CH2:15][CH2:14][N:13](C(OC(C)(C)C)=O)[CH2:12][CH2:11]3)[CH2:6][CH2:5]2)[O:3]1>Cl>[NH:13]1[CH2:14][CH2:15][CH:10]([N:7]2[CH2:8][CH2:9][C:4]3([O:3][C:2](=[O:1])[NH:25][C:24]4[CH:26]=[CH:27][CH:28]=[CH:29][C:23]3=4)[CH2:5][CH2:6]2)[CH2:11][CH2:12]1
Reactant: CC(C)(C)OC(=O)N1CCC(N2CCC3(CC2)OC(=O)Nc2ccccc23)CC1
Agent: Cl
Product: O=C1Nc2ccccc2C2(CCN(C3CCNCC3)CC2)O1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
tert-Butyl 4-(2-oxo-1,2-dihydrospiro[benzo[d][1,3]oxazine-4,4′-piperidine]-1′-yl)piperidine-1-carboxylate (vib) (432 mg, 1.08 mmol) was dissolved in 3.0 N methanolic HCl (10 mL) and stirred at room temperature for 18 hours. Additional 3.0 N methanolic HCl was added (10 mL) and the reaction heated at 60° C. for 2 hours. The reaction mixture was concentrated under reduced pressure, treated with acetonitrile (approx. 25 mL) and re-concentrated to afford 1′-(piperidin-4-yl)spiro[benzo[d][1,3]oxazine-4,4′-piperidin]-2(1H)-one (compound no. 49) bis-hydrochloride as a crystalline white solid. LC/MS m/z 302.0 [M+H]+, retention time 0.34 min (RP-C18, 10-99% CH3CN/0.05% TFA).
Reaction SMILES: Cl.CN.[CH2:4]([N:6](CC)CC)C.[C:11](Cl)(=[O:19])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]>ClCCl>[CH3:4][NH:6][C:11](=[O:19])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCC(=O)Cl
Reactant: CCN(CC)CC
Agent: CN
Agent: Cl
Solvent: ClCCl
Product: CCCCCCCC(=O)NC
Temperature: 25 °C
Reaction time: 3 h

Procedure:
25 g (0.37 mol) of methylamine hydrochloride are dissolved in 125 mL of dichloromethane, and 115 mL of triethylamine are then added. At 0° C., 70 mL (0.41 mol) of octanoyl chloride are added slowly. The reaction mixture is stirred for 3 hours at room temperature. The mixture is filtered and 100 ml of water are then added to the filtrate. The organic phase is separated out by settling, dried over sodium sulfate and evaporated. 61 g of N-methyloctanamide are obtained in quantitative yield.
Reaction SMILES: C(OC([NH:8][C@@H:9]([C:14](O)=O)[C@H:10]([CH3:13])[O:11][CH3:12])=O)(C)(C)C.[C:17]([C:21]1[CH:26]=[CH:25][C:24]([NH2:27])=[C:23]([NH2:28])[CH:22]=1)([CH3:20])([CH3:19])[CH3:18]>>[C:17]([C:21]1[CH:26]=[CH:25][C:24]2[NH:27][C:14]([C@H:9]([NH2:8])[C@@H:10]([O:11][CH3:12])[CH3:13])=[N:28][C:23]=2[CH:22]=1)([CH3:20])([CH3:18])[CH3:19]
Reactant: CC(C)(C)c1ccc(N)c(N)c1
Reactant: CO[C@@H](C)[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Product: CO[C@@H](C)[C@@H](N)c1nc2cc(C(C)(C)C)ccc2[nH]1

Procedure:
The title compound was prepared according to Method 1 using N-(tert-butoxycarbonyl)-O-methyl-D-threonine and 4-tert-butyl-1,2-diaminobenzene. The residue was purified by elution through an SCX cartridge with MeOH followed by 2M NH3 in MeOH followed by silica gel column chromatography eluting with 90:10:1 DCM:MeOH:NH3.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([N:11]2[CH:15]=[N:14][C:13]([C:16]([F:19])([F:18])[F:17])=[N:12]2)=[C:6]([CH:10]=1)[C:7]([OH:9])=O.[CH3:20][C@@H:21]1[CH2:26][CH2:25][CH2:24][NH:23][C@@H:22]1[CH2:27][NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[CH3:20][C@@H:21]1[CH2:26][CH2:25][CH2:24][N:23]([C:7](=[O:9])[C:6]2[CH:10]=[C:2]([CH3:1])[CH:3]=[CH:4][C:5]=2[N:11]2[CH:15]=[N:14][C:13]([C:16]([F:19])([F:18])[F:17])=[N:12]2)[C@@H:22]1[CH2:27][NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32]
Reactant: C[C@@H]1CCCN[C@@H]1CNC(=O)OC(C)(C)C
Reactant: Cc1ccc(-n2cnc(C(F)(F)F)n2)c(C(=O)O)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(-n2cnc(C(F)(F)F)n2)c(C(=O)N2CCC[C@@H](C)[C@H]2CNC(=O)OC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of 5-methyl-2-(3-(trifluoromethyl)-1H-1,2,4-triazol-1-yl)benzoic acid (0.24 g, 0.869 mmol), tert-butyl (((2S,3R)-3-methylpiperidin-2-yl)methyl)carbamate (0.22 g, 0.96 mmol) and DIPEA (0.3 mL, 1.738 mmol) in DCM (20 mL) was added HATU (0.33 g, 0.869 mmol). The mixture was stirred at rt for 1 h. The mixture was diluted with DCM and was washed with satd. NaHCO3 and brine and dried over Na2SO4. The solvent was removed in vacuo to obtain the title compound with no further purification for next step. ESI-MS (m/z): 482 [M+1]+.
Reaction SMILES: [CH3:1][C:2]1[N:6]2[CH:7]=[CH:8][CH:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([N:17]4[CH:21]=[CH:20][N:19]=[C:18]4[CH3:22])=[CH:13][CH:12]=3)[C:5]2=[CH:4][N:3]=1.[Br:23]N1C(=O)CCC1=O>C(Cl)Cl>[Br:23][C:4]1[N:3]=[C:2]([CH3:1])[N:6]2[CH:7]=[CH:8][CH:9]=[C:10]([C:11]3[CH:12]=[CH:13][C:14]([N:17]4[CH:21]=[CH:20][N:19]=[C:18]4[CH3:22])=[CH:15][CH:16]=3)[C:5]=12
Reactant: Cc1nccn1-c1ccc(-c2cccn3c(C)ncc23)cc1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Product: Cc1nccn1-c1ccc(-c2cccn3c(C)nc(Br)c23)cc1

Procedure:
Combine 2.2 g (7.6 mmol) of the product of Example XIV with 1.4 g (7.9 mmol) of N-bromosuccinimide in 50 ml of methylene chloride and stir at room temperature for 1 hr. Wash the reaction with 100 ml of 10% potassium carbonate solution, dry over magnesium sulfate, treat with charcoal, and remove the solvent in vacuo. Crystallize the residue from ether to provide the title compound.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([NH:9][CH:10]2[CH2:15][CH2:14][CH2:13][N:12]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:11]2)[C:5](=[O:8])[NH:6][N:7]=1.[C:23]([C:27]1[N:28]=[CH:29][C:30]([C:33]([NH:35][C:36]2[CH:41]=[C:40](B3OC(C)(C)C(C)(C)O3)[CH:39]=[CH:38][C:37]=2[F:51])=[O:34])=[N:31][CH:32]=1)([CH3:26])([CH3:25])[CH3:24].C(=O)([O-])[O-].[Na+].[Na+].CN(C=O)C>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O.O1CCOCC1>[C:23]([C:27]1[N:28]=[CH:29][C:30]([C:33]([NH:35][C:36]2[CH:41]=[C:40]([C:2]3[CH:3]=[C:4]([NH:9][CH:10]4[CH2:15][CH2:14][CH2:13][N:12]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:11]4)[C:5](=[O:8])[NH:6][N:7]=3)[CH:39]=[CH:38][C:37]=2[F:51])=[O:34])=[N:31][CH:32]=1)([CH3:26])([CH3:24])[CH3:25]
Reactant: CC(C)(C)c1cnc(C(=O)Nc2cc(B3OC(C)(C)C(C)(C)O3)ccc2F)cn1
Reactant: CC(C)(C)OC(=O)N1CCCC(Nc2cc(Cl)n[nH]c2=O)C1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCCC(Nc2cc(-c3ccc(F)c(NC(=O)c4cnc(C(C)(C)C)cn4)c3)n[nH]c2=O)C1
Temperature: 125 °C
Yield: 36.5 %

Procedure:
In a 100-mL single-neck round-bottomed flask equipped with a magnetic stirrer and reflux condenser, 10b (500 mg, 1.52 mmol), 5-tert-Butyl-N-(2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrazine-2-carboxamide (600 mg, 1.50 mmol) and sodium carbonate (320 mg, 3.01 mmol) were mixed with DMF (8 mL), dioxane (5 mL) and water (2 mL). This mixture was degassed with nitrogen for 30 min. Tetrakis(triphenylphosphine)palladium (175 mg, 0.151 mmol) was added and the mixture was refluxed at 125° C. (bath temperature) for 14 h. The reaction mixture was then cooled to room temperature, and water (100 mL) was added. The resulting precipitate was filtered, and the filter cake was washed with water (250 mL). The filter cake was purified using a silica gel column eluting the desired product with 4-6% methanol in methylene chloride to afford a 36% yield (310 mg) of 10d as a off-white solid: mp 120-121° C.; 1H NMR (500 MHz, CDCl3) δ 10.13 (s, 1H), 10.02 (s, 1H), 9.39 (s, 1H), 8.99 (d, 1H, J=7.5 Hz), 8.68 (s, 1H), 7.56 (br s, 1H), 7.22 (m, 1H), 6.88 (s, 1H), 5.15 (s, 1H), 3.85 (s, 1H), 3.64 (m, 1H), 3.50 (m, 3H), 1.92-1.82 (m, 3H, 1.71 (m, 1H), 1.42 (br s, 1811); MS (APCI+) m/z 566.9 (M+H).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH3:11][C:12]1([CH3:34])[CH2:21][C:20]([CH3:23])([CH3:22])[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([C:24]#[C:25][C:26]3[CH:31]=[CH:30][C:29]([CH2:32][OH:33])=[CH:28][N:27]=3)[CH:18]=2)[O:13]1.C(N(CC)CC)C>C(Cl)Cl>[CH3:11][C:12]1([CH3:34])[CH2:21][C:20]([CH3:22])([CH3:23])[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([C:24]#[C:25][C:26]3[CH:31]=[CH:30][C:29]([CH:32]=[O:33])=[CH:28][N:27]=3)[CH:18]=2)[O:13]1
Reactant: CC1(C)CC(C)(C)c2cc(C#Cc3ccc(CO)cn3)ccc2O1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: ClCCl
Product: CC1(C)CC(C)(C)c2cc(C#Cc3ccc(C=O)cn3)ccc2O1
Temperature: -60 °C
Reaction time: 0.17 h

Procedure:
A solution of 1.396 g (11 mmol) of freshly distilled oxalyl chloride in 25 ml of methylene chloride is placed in a 4-necked flask equipped with a stirrer, a thermometer and two pressure-equalizing addition funnels fitted with drying tubes. The solution is cooled to -60 degrees C. and then treated dropwise with a solution of 1.875 g (24 mmol) of dimethyl sulfoxide (distilled from calcium hydride) in 5/ml of methylene chloride over a five minute period. The reaction mixture is then stirred at -60 degrees C. for an additional 10 minutes. A solution of 3.10 g (10 mmol) of 2,2,4,4-tetramethyl-6-[(5-hydroxymethylpyrid-2-yl)ethynyl]-chroman (Compound 50) in 10 ml of methylene chloride is then added to the reaction mixture over a period of 5 minutes. The mixture is stirred for a further 15 minutes and is then treated with 5.06 g (50 mmol) of triethylamine. The cooling bath is then removed and the mixture is allowed to warm to room temperature. Thirty ml of water is then added to the mixture and stirring is continued for a further 10 minutes. The organic layer is then separated and the aqueous layer is extracted with 20 ml of methylene chloride. The organic layers are then combined and washed successively with dilute HCl, water and dilute Na2CO3 solution and then dried (MgSO4). The solution is then filtered and concentrated in vacuo and the residue is purified by chromatography followed by recrystallization to give the title compound.
Reaction SMILES: [CH3:1][CH:2]([CH3:28])[CH:3]([NH:15][C:16]([CH:18]1[CH2:22][CH:21]([CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH2:20][NH:19]1)=[O:17])[CH:4]1[CH:9]([OH:10])[CH:8]([OH:11])[CH:7]([OH:12])[CH:6]([S:13][CH3:14])[O:5]1.[CH:29](=[NH:33])OCC.[OH-].[Na+]>O1CCOCC1>[CH3:1][CH:2]([CH3:28])[CH:3]([NH:15][C:16]([CH:18]1[CH2:22][CH:21]([CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH2:20][N:19]1[CH:29]=[NH:33])=[O:17])[CH:4]1[CH:9]([OH:10])[CH:8]([OH:11])[CH:7]([OH:12])[CH:6]([S:13][CH3:14])[O:5]1
Reactant: CCCCCC1CNC(C(=O)NC(C(C)C)C2OC(SC)C(O)C(O)C2O)C1
Reactant: CCOC=N
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CCCCCC1CC(C(=O)NC(C(C)C)C2OC(SC)C(O)C(O)C2O)N(C=N)C1
Reaction time: 0.5 h
Yield: 5.3 %

Procedure:
A stirred suspension of 4-pentyl-pyrrolidine-2-carboxylic acid [2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide (153 mg, 0.34 mmol, 1 equiv) and ethyl formimidate (Aldrich) (44 mg, 0.40 mmol, 1.2 equiv.) in dioxane (1 mL) was treated with 1M aqueous NaOH (0.74 mL, 0.74 mmol, 2.2 equiv). After 1 h additional ethyl formimidate (44 mg, 0.40 mmol, 1.2 equiv) was added to the reaction mixture, and stirring was continued for 30 min. The reaction mixture was frozen and lyophilized. The lyophilized powder was purified by column chromatography to furnish the title compound (8 mg): TLC Rf=0.48 CHCl3/ MeOH/32% aqueous AcOH (5:3:1); MS (ESPOS): 447.7 [M+H]+, 469.7 [M+Na]+; MS (ESNEG): 481.6 [M−H+HCl]−.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:30]=[CH:29][C:12]([O:13][CH2:14][CH2:15][CH:16]3[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]3)=[C:11](I)[CH:10]=2)[C:5]([Cl:32])=[CH:4][N:3]=1.[CH:33]([C:35]1[CH:36]=[C:37]([NH2:41])[CH:38]=[N:39][CH:40]=1)=[CH2:34]>>[NH2:41][C:37]1[CH:36]=[C:35](/[CH:33]=[CH:34]/[C:11]2[CH:10]=[C:9]([NH:8][C:6]3[C:5]([Cl:32])=[CH:4][N:3]=[C:2]([Cl:1])[N:7]=3)[CH:30]=[CH:29][C:12]=2[O:13][CH2:14][CH2:15][CH:16]2[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]2)[CH:40]=[N:39][CH:38]=1
Reactant: CC(C)(C)OC(=O)N1CCC(CCOc2ccc(Nc3nc(Cl)ncc3Cl)cc2I)CC1
Reactant: C=Cc1cncc(N)c1
Product: CC(C)(C)OC(=O)N1CCC(CCOc2ccc(Nc3nc(Cl)ncc3Cl)cc2/C=C/c2cncc(N)c2)CC1
Yield: 99 %

Procedure:
The desired compound was prepared according to the procedure of Example B334, step G, using tert-butyl 4-(2-{4-[(2,5-dichloropyrimidin-4-yl)amino]-2-iodophenoxy}ethyl)piperidine-1-carboxylate and 5-vinylpyridine-3-amine as the starting materials in 99% yield. LCMS for C29H35Cl2N6O3 (M+H)+: m/z=585.3, 587.2.
Reaction SMILES: C([NH:4][C:5]1[CH:10]=[CH:9][C:8]([S:11][CH2:12][O:13][CH3:14])=[CH:7][C:6]=1[N+:15]([O-:17])=[O:16])(=O)C.[OH-].[Na+]>CO>[NH2:4][C:5]1[CH:10]=[CH:9][C:8]([S:11][CH2:12][O:13][CH3:14])=[CH:7][C:6]=1[N+:15]([O-:17])=[O:16]
Reactant: COCSc1ccc(NC(C)=O)c([N+](=O)[O-])c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COCSc1ccc(N)c([N+](=O)[O-])c1

Procedure:
1.4 G. of 1-acetamido-2-nitro-4-methoxymethylthiobenzene is treated on a steam bath for 15 minutes with 3 ml. 5N sodium hydroxide and 6 ml. methanol. The mixture is concentrated, extracted with chloroform and the chloroform extracts dried and stripped yielding 1-amino-2-nitro-4-methoxymethylthiobenzene as a red solid.
Reaction SMILES: [CH3:1][N:2]([CH3:29])[C:3]1([C:8]2[N:12]3[CH:13]=[C:14]([O:17][C@H:18]4[C:27]5[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=5)[C@@H:21]([NH2:28])[CH2:20][CH2:19]4)[CH:15]=[CH:16][C:11]3=[N:10][N:9]=2)[CH2:7][CH2:6][CH2:5][CH2:4]1.ClC(Cl)(Cl)C[O:33][C:34](=O)[NH:35][C:36]1[N:37]([C:45]2[CH:50]=[CH:49][C:48]([CH3:51])=[CH:47][CH:46]=2)[N:38]=[C:39]([C:41]([CH3:44])([CH3:43])[CH3:42])[CH:40]=1.CCN(C(C)C)C(C)C.O>O1CCOCC1.CCOC(C)=O>[C:41]([C:39]1[CH:40]=[C:36]([NH:35][C:34]([NH:28][C@@H:21]2[C:22]3[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=3)[C@H:18]([O:17][C:14]3[CH:15]=[CH:16][C:11]4[N:12]([C:8]([C:3]5([N:2]([CH3:29])[CH3:1])[CH2:7][CH2:6][CH2:5][CH2:4]5)=[N:9][N:10]=4)[CH:13]=3)[CH2:19][CH2:20]2)=[O:33])[N:37]([C:45]2[CH:50]=[CH:49][C:48]([CH3:51])=[CH:47][CH:46]=2)[N:38]=1)([CH3:44])([CH3:42])[CH3:43]
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)OCC(Cl)(Cl)Cl)cc1
Reactant: CN(C)C1(c2nnc3ccc(O[C@@H]4CC[C@H](N)c5ccccc54)cn23)CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)N[C@H]2CC[C@@H](Oc3ccc4nnc(C5(N(C)C)CCCC5)n4c3)c3ccccc32)cc1
Reaction time: 4 h
Yield: 13 %

Procedure:
A mixture of Intermediate 99d (108 mg, 0.27 mmol), (5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl)-carbamic acid 2,2,2-trichloro-ethyl ester (for reference procedure see Synthetic Communications, 2009, 39, 3999-4009, which is incorporated herein by reference in its entirety; 105 mg, 0.27 mmol) and DIPEA (93 μL, 0.54 mmol) in dioxane (3 mL) was stirred at 60° C. for 18 h and then at 80° C. for 4 h. The reaction mixture was diluted with EtOAc and then poured into water. The aqueous phase was extracted with EtOAc (×3) and the combined organic layers were washed with brine, dried (MgSO4) and concentrated in vacuo. The resultant residue was purified by MDAP (Method 7) to afford the title compound (23 mg, 13%). LCMS (Method 5): Rt 3.90 min, m/z 647 [MH+]. 1H NMR (400 MHz, CD3OD): 1.34 (9H, s), 1.59-1.85 (4H, m), 1.91-2.15 (3H, m), 2.18 (6H, s), 2.21-2.36 (5H, m), 2.42 (3H, s), 4.91-4.96 (1H, m), 5.34 (1H, t, J=4.1 Hz), 6.37 (1H, s), 7.22-7.40 (9H, m), 7.65 (1H, d, J=9.9 Hz), 8.46 (1H, d, J=2.2 Hz).
Reaction SMILES: [CH3:1][CH:2]([C:4]1[N:5]=[CH:6][NH:7][C:8]=1[C:9]1[CH:14]=[CH:13][C:12]([S:15][CH3:16])=[CH:11][CH:10]=1)[CH3:3].ClC(Cl)C(O)=O.[CH:23]([O:25][CH2:26][CH3:27])=[CH2:24].[OH-].[Na+]>C1(C)C=CC=CC=1>[CH3:3][CH:2]([C:4]1[N:5]=[CH:6][N:7]([CH:23]([O:25][CH2:26][CH3:27])[CH3:24])[C:8]=1[C:9]1[CH:14]=[CH:13][C:12]([S:15][CH3:16])=[CH:11][CH:10]=1)[CH3:1]
Reactant: C=COCC
Reactant: CSc1ccc(-c2[nH]cnc2C(C)C)cc1
Agent: O=C(O)C(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: CCOC(C)n1cnc(C(C)C)c1-c1ccc(SC)cc1
Temperature: 25 °C
Yield: 100 %

Procedure:
A mixture of 7.48 g (32.2 mmoles) of 4-(1-methylethyl)-5-(4-methythiophenyl)-1H-imidazole, 4.56 g (35.3 mmoles) of dichloroacetic acid and 17.57 g (0.24 mole) of ethyl vinyl ether in 350 ml of toluene were heated at reflux for 3.5 hours. The reaction mixture was cooled to room temperature and was then stirred overnight with 100 ml of 25% aqueous sodium hydroxide. The organic layer was separated and the aqueous was extracted with ether (2×). The organic fractions were combined, washed with brine, and dried over anhydrous potassium carbonate. Removal of the solvent in vacuo afforded 9.8 g of an orange oil which was used in the subsequent reaction without purification.