Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH:8]([CH3:10])[CH3:9])[CH:5]=[CH:4][C:3]=1[N:11]([CH2:20][CH3:21])[C:12]1[N:17]=[C:16](Cl)[N:15]=[C:14]([CH3:19])[N:13]=1.[Cl:22][C:23]1[CH:28]=[C:27]([Cl:29])[CH:26]=[CH:25][C:24]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+].C(O)C>C(OCC)(=O)C.C1C=CC=CC=1>[Br:1][C:2]1[CH:7]=[C:6]([CH:8]([CH3:10])[CH3:9])[CH:5]=[CH:4][C:3]=1[N:11]([CH2:20][CH3:21])[C:12]1[N:17]=[C:16]([C:26]2[CH:25]=[CH:24][C:23]([Cl:22])=[CH:28][C:27]=2[Cl:29])[N:15]=[C:14]([CH3:19])[N:13]=1
Reactant: OB(O)c1ccc(Cl)cc1Cl
Reactant: CCN(c1nc(C)nc(Cl)n1)c1ccc(C(C)C)cc1Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: c1ccccc1
Product: CCN(c1nc(C)nc(-c2ccc(Cl)cc2Cl)n1)c1ccc(C(C)C)cc1Br

Procedure:
Part C: A mixture of N-(2-bromo-4-isopropylphenyl)-N-ethyl-4-chloro-6-methyl-1,3,5-triazine-2-amine (370 mg), 2,4-dichlorophenylboronic acid (210 mg) tetrakis(triphenylphoshine)palladium(0) (50 mg), 1M aqueous sodium carbonate (2 mL), ethanol (0.75 mL) and benzene (6 mL) was refluxed for 10 hr.The cooled mixture was diluted with ethyl acetate and the aqueous layer was removed. The organic layer was washed with water and brine, dried, and concentrated in vacuo The crude reaction product was chromatographed on silica gel using ethyl acetate/hexanes (1:9) as eluent. The title compound was obtained as a pure colorless viscous oil (210 mg) that crystallized on standing and trituration with petroleum ether to colorless crystals (82 mg). Elemental Analysis: Calcd. for C21H21N4Cl2Br: C, 52.52: H, 4.417; N, 11.67. Found: C, 52.79; H, 4.34; N, 11.40.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:20])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([OH:16])=O)=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[CH3:45][N:46]([CH3:60])[CH2:47][CH2:48][CH2:49][O:50][C:51]1[CH:57]=[CH:56][C:54]([NH2:55])=[CH:53][C:52]=1[O:58][CH3:59]>>[Cl:20][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([Cl:1])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([NH:55][C:54]2[CH:56]=[CH:57][C:51]([O:50][CH2:49][CH2:48][CH2:47][N:46]([CH3:60])[CH3:45])=[C:52]([O:58][CH3:59])[CH:53]=2)=[O:16])=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18]
Reactant: COc1cc(N)ccc1OCCCN(C)C
Reactant: O=C(O)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: COc1cc(NC(=O)c2cc([N+](=O)[O-])c(Sc3c(Cl)cncc3Cl)s2)ccc1OCCCN(C)C

Procedure:
Prepared according to the procedure described for example 70 from 5-[(3,5-dichloro-4-pyridyl)sulfanyl]-4-nitro-thiophene-2-carboxylic acid (250 mg, 0.71 mmol), 2-(7-Aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU) (126 mg, 0.33 mmol) and 4-(3-dimethylaminopropoxy)-3-methoxy-aniline as in step B of 207 (298 mg, 0.78 mmol). The title compound was obtained as a yellow solid (50.0 mg, 13% yield). 1H NMR (400 MHz, d6-DMSO) δ: 10.45 (1H, s), 9.32 (1H, br), 9.01 (2H, m), 8.67 (1H, s), 7.33 (1H, m), 7.20 (1H, m), 4.02 (2H, m), 3.74 (3H, s), 3.21 (2H, m), 2.83 (6H, s), 2.07 (2H, m). MS m/z: 557.30, 559.29 [M+H]+.
Reaction SMILES: [C:1](#[N:4])[CH:2]=[CH2:3].Br[C:6]1[C:7]([CH3:20])=[N:8][N:9]([C:11]2[CH:16]=[CH:15][N:14]=[C:13]3[NH:17][CH:18]=[CH:19][C:12]=23)[CH:10]=1.C(N(CC)CC)C.CN(C=O)C>C(OCC)(=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:20][C:7]1[C:6](/[CH:3]=[CH:2]/[C:1]#[N:4])=[CH:10][N:9]([C:11]2[CH:16]=[CH:15][N:14]=[C:13]3[NH:17][CH:18]=[CH:19][C:12]=23)[N:8]=1
Reactant: Cc1nn(-c2ccnc3[nH]ccc23)cc1Br
Reactant: C=CC#N
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: Cc1nn(-c2ccnc3[nH]ccc23)cc1/C=C/C#N
Yield: 191.3 %

Procedure:
A solution of 2-propenenitrile (0.043 mL, 0.00065 mol), bis(triphenylphosphine)palladium(II) chloride (0.0091 g, 0.000013 mol), 4-(4-bromo-3-methyl-1H-pyrazol-1-yl)-1H-pyrrolo[2,3-b]pyridine (0.036 g, 0.00013 mol), and triethylamine (TEA) (0.15 mL, 0.0011 mol) in DMF (0.15 mL, 0.0019 mol) was microwaved at 120° C. for 2 h. The solution was then diluted with ethyl acetate and washed with water (×2) and brine successively. The organic phase was dried and concentrated in vacuo to give 62 mg of the product as an orange solid. The orange solid was purified by prep-LCMS to give 12 mg of an off-white solid as a trifluoroacetic acid (TFA) salt which was triturated with MTBE (1 mL) to provide the purified product as a pale green solid. (dried at 60° C. for 4 h, 9 mg, 28% yield).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][NH:5][C:6]1[CH:7]=[C:8]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)[CH:9]=[CH:10][CH:11]=1.Br[CH2:23][C:24]1[CH:36]=[CH:35][C:27]([O:28][CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])=[C:26]([CH3:37])[CH:25]=1.C(N(CC)C(C)C)(C)C>C(#N)C>[CH3:1][O:2][CH2:3][CH2:4][N:5]([CH2:23][C:24]1[CH:36]=[CH:35][C:27]([O:28][CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])=[C:26]([CH3:37])[CH:25]=1)[C:6]1[CH:7]=[C:8]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:19])([F:20])[F:21])=[CH:14][CH:13]=2)[CH:9]=[CH:10][CH:11]=1
Reactant: CCOC(=O)COc1ccc(CBr)cc1C
Reactant: COCCNc1cccc(-c2ccc(C(F)(F)F)cc2)c1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)COc1ccc(CN(CCOC)c2cccc(-c3ccc(C(F)(F)F)cc3)c2)cc1C
Reaction time: 3 h
Yield: 52.8 %

Procedure:
To a solution of N-(2-methoxyethyl)-N-[4′-(trifluoromethyl)-1,1′-biphenyl-3-yl]amine (0.1 g, 0.34 mmol) in anhydrous acetonitrile (10 mL) was added ethyl [4-(bromomethyl)-2-methylphenoxy]acetate (0.097 g, 0.34 mmol) and N,N-diisopropylethylamine (0.059 mL, 0.34 mmol). The resulting mixture was heated to reflux and stirred under nitrogen for 3 h. The reaction mixture was concentrated in vacuo and the residue partitioned between water (20 mL) and CH2Cl2 (40 mL), the organic extract was separated by hydrophobic frit and the solvents removed in vacuo. Purification by Biotage™ chromatography (Silica, 12 g) eluting 9:1 cyclohexane:EtOAc afforded the title compound as a colourless oil (90 mg).
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[NH:13][C@H:12]([CH3:17])[CH2:11]3)[C:4]([CH3:7])=[CH:5][CH:6]=1.C(=O)(O)[O-].[Na+].Cl[C:24]([O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:25]>C1COCC1.O>[CH3:1][C:2]1[N:3]([C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[N:13]([C:24]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[O:25])[C@H:12]([CH3:17])[CH2:11]3)[C:4]([CH3:7])=[CH:5][CH:6]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: Cc1ccc(C)n1-c1ccc2c(c1)C[C@@H](C)N2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(C)n1-c1ccc2c(c1)C[C@@H](C)N2C(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a stirred solution of (2R)-5-(2,5-dimethyl-1H-pyrrol-1-yl)-2,3-dihydro-2-methyl-1H-indole (Step 2, 0.100 g, 0.442 mmol) in THF/H2O (8:1, 4.5 mL) is added sodium bicarbonate (0.072 g, 0.884 mmol) followed by benzyl chloroformate (80 μL, 0.53 mmol) at 0° C. The reaction mixture is stirred at 0° C. for 30 mins and at ambient temperature for 2 h and is then concentrated under reduced pressure. The residue is taken up in CH2Cl2 (40 mL), washed with H2O (2×10 mL) and saline (2×10 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue is purified by chromatography on a Biotage Flash 40S 40 g silica gel cartridge (1% EtOAc/Hexanes) to give the title compound, MS (ESI+) for C23H24N2O2 m/z 361 (M+H)+.
Reaction SMILES: [C:1]([N:5]1[CH2:10][CH2:9][C@@H:8]([O:11][C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][C:21]=2[O:22][CH3:23])[N:18]=[CH:17][N:16]=[C:15]3[NH:24][C:25]2[CH:30]=[CH:29][C:28]([F:31])=[C:27]([Cl:32])[C:26]=2[F:33])[CH2:7][C@@H:6]1[C:34]([O:36]C)=[O:35])(=[O:4])[CH:2]=[CH2:3].O.[OH-].[Li+]>O1CCCC1.CO>[C:1]([N:5]1[CH2:10][CH2:9][C@@H:8]([O:11][C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][C:21]=2[O:22][CH3:23])[N:18]=[CH:17][N:16]=[C:15]3[NH:24][C:25]2[CH:30]=[CH:29][C:28]([F:31])=[C:27]([Cl:32])[C:26]=2[F:33])[CH2:7][C@@H:6]1[C:34]([OH:36])=[O:35])(=[O:4])[CH:2]=[CH2:3]
Reactant: C=CC(=O)N1CC[C@@H](Oc2cc3c(Nc4ccc(F)c(Cl)c4F)ncnc3cc2OC)C[C@@H]1C(=O)OC
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: C=CC(=O)N1CC[C@@H](Oc2cc3c(Nc4ccc(F)c(Cl)c4F)ncnc3cc2OC)C[C@@H]1C(=O)O
Reaction time: 1 h
Yield: 68.5 %

Procedure:
15 mg of the compound obtained in Example 133 was dissolved in 0.2 ml of a mixed solvent of tetrahydrofuran and methanol (1:1), and 1.4 mg of lithium hydroxide monohydrate was added thereto at 0° C. The resulting mixture was incubated at room temperature for one hour. After the reaction terminated, the resulting solution was acidified to pH 4 with a 3N HCl and extracted twice with methylene chloride. The organic layer was dried over anhydrous magnesium sulfate, filtered and distilled under a reduced pressure. The resulting residue was purified by column chromatography (methylene chloride:ethyl acetate:methanol=1:1:1) to obtain the title compound (10 mg, 69%).
Reaction SMILES: C(N(CC)C(C)C)(C)C.[Si](Cl)(C)(C)C.[NH2:15][CH2:16][CH:17]([SH:20])[CH2:18][CH3:19].Cl[C:22]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][C:29]([N+:32]([O-:34])=[O:33])=[CH:28][CH:27]=1)=[O:23]>CC#N>[N+:32]([C:29]1[CH:28]=[CH:27][C:26]([CH2:25][O:24][C:22]([NH:15][CH2:16][CH:17]([SH:20])[CH2:18][CH3:19])=[O:23])=[CH:31][CH:30]=1)([O-:34])=[O:33]
Reactant: O=C(Cl)OCc1ccc([N+](=O)[O-])cc1
Reactant: CCC(S)CN
Agent: C[Si](C)(C)Cl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CCC(S)CNC(=O)OCc1ccc([N+](=O)[O-])cc1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
N,N-Diisopropylethylamine (8.50 ml, 0.0488 mol) and Me3SiCl (3.50 ml, 0.0239 mol) were added to an ice-cold, stirring solution of 1-amino-2-butanethiol (3.00 g, 0.0212 mol) in MeCN (16.0 ml). The solution was stirred 10 minutes at 0°, then treated with more N,N-diisopropylethylamine (3.70 ml, 0.0212 mol) and with a solution of p-nitrobenzyl chloroformate (4.57 g, 0.0212 mol) in MeCN (5.0 ml). The resulting mixture was stirred for 30 minutes at 0° and 90 minutes at room temperature. The mixture was poured into ice-water (50 ml) and extracted with EtOAc (75 ml). The organic phase was separated, washed with 1.25N HCl, 5% NaHCO3, and brine, dried with MgSO4, filtered and evaporated under vacuum to an oil (5.79 g).
Reaction SMILES: [CH3:1][C:2]1[CH:28]=[CH:27][C:5]([C:6]([C:8]2[N:9]([CH2:13]/[CH:14]=[CH:15]/[C:16]3[CH:17]=[C:18]([CH:24]=[CH:25][CH:26]=3)[C:19]([O:21]CC)=[O:20])[CH:10]=[CH:11][CH:12]=2)=[O:7])=[CH:4][CH:3]=1>[OH-].[Li+].C1COCC1.CO>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([C:8]2[N:9]([CH2:13]/[CH:14]=[CH:15]/[C:16]3[CH:17]=[C:18]([CH:24]=[CH:25][CH:26]=3)[C:19]([OH:21])=[O:20])[CH:10]=[CH:11][CH:12]=2)=[O:7])=[CH:27][CH:28]=1
Reactant: CCOC(=O)c1cccc(/C=C/Cn2cccc2C(=O)c2ccc(C)cc2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1ccc(C(=O)c2cccn2C/C=C/c2cccc(C(=O)O)c2)cc1
Yield: 92.5 %

Procedure:
A solution of ethyl 3-{(1E)-3-[2-(4-methylbenzoyl)-1H-pyrrol-1-yl]prop-1-enyl}benzoate (1.94 g) in 1N aqueous lithium hydroxide solution (10 ml), THF (10 ml) and methanol (10 ml) were stirred at 50° C. for 3 hours. Methanol and THF in the reaction solution were evaporated under reduced pressure, and the residue was diluted with water, and washed with diethyl ether. The aqueous layer was acidified with diluted hydrochloric acid solution, and extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over magnesium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (1.66 g, yield for 2 steps: 93%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[C:15](=O)([O-])[O-].[K+].[K+].IC>CN(C)C=O.O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: Oc1ccc(-c2ccc(Br)cc2)cc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(-c2ccc(Br)cc2)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 623.3 %

Procedure:
Part A: To a solution of 12.4 grams (5.0 mmol) of 4-(4′-bromophenyl)phenol in 50 mL of dimethylformamide was added 10.1 grams of potassium carbonate followed by 10.51 grams of iodomethane and this stirred at room temperature for 48 hours. The solution was diluted with 400 mL of water and extracted with ethyl acetate. The organics were dried over magnesium sulfate filtered and concentrated to yield 14.1 grams of crude product. Purification by recrystallization from ethyl acetate hexane gave 8.2 grams of 4-(4′-bromophenyl)anisole as a white crystalline solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13](Cl)=[C:14]([N+:19]([O-:21])=[O:20])[CH:15]=[N:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[NH2:30][CH2:31][CH2:32][CH2:33][NH:34][C:35](=[O:41])[O:36][C:37]([CH3:40])([CH3:39])[CH3:38]>>[CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([NH:30][CH2:31][CH2:32][CH2:33][NH:34][C:35](=[O:41])[O:36][C:37]([CH3:39])([CH3:38])[CH3:40])=[C:14]([N+:19]([O-:21])=[O:20])[CH:15]=[N:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1cnc2cc(OCc3ccccc3)ccc2c1Cl
Reactant: CC(C)(C)OC(=O)NCCCN
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NCCCNc1c([N+](=O)[O-])cnc2cc(OCc3ccccc3)ccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.8 %

Procedure:
A modification of the method described in Part E of Example 367 was used to treat 7-benzyloxy-4-chloro-3-nitroquinoline (87.81 g, 279 mmol, Parts A through D of Example 367) with triethylamine (58.3 mL, 419 mmol) and tert-butyl N-(3-aminopropyl)carbamate (58.0 g, 334 mmol). The reaction was stirred overnight at ambient temperature. After filtration, the solid was washed with water and 1:1 cold 2-propanol:water. After the drying step 120.98 g of tert-butyl 3-[(7-benzyloxy-3-nitroquinolin-4-yl)amino]propylcarbamate were obtained.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[O:3][C:4]1[CH:5]=[CH:6][C:7]2[O:12][CH:11]([C:13]([OH:15])=O)[CH2:10][NH:9][C:8]=2[CH:16]=1.[C:19](=[O:36])([O:34][CH3:35])[O:20][C:21]1[CH:26]=[C:25]([NH2:27])[C:24]([Br:28])=[CH:23][C:22]=1[CH:29]1[CH2:33][CH2:32][CH2:31][CH2:30]1.N1C=CC=CC=1.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC>CC1CCCO1>[C:19](=[O:36])([O:34][CH3:35])[O:20][C:21]1[CH:26]=[C:25]([NH:27][C:13]([CH:11]2[O:12][C:7]3[CH:6]=[CH:5][C:4]([O:3][C:2]([F:1])([F:18])[F:17])=[CH:16][C:8]=3[NH:9][CH2:10]2)=[O:15])[C:24]([Br:28])=[CH:23][C:22]=1[CH:29]1[CH2:33][CH2:32][CH2:31][CH2:30]1
Reactant: COC(=O)Oc1cc(N)c(Br)cc1C1CCCC1
Reactant: O=C(O)C1CNc2cc(OC(F)(F)F)ccc2O1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: c1ccncc1
Solvent: CC1CCCO1
Product: COC(=O)Oc1cc(NC(=O)C2CNc3cc(OC(F)(F)F)ccc3O2)c(Br)cc1C1CCCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 77.1 %

Procedure:
6-(Trifluoromethoxy)-3,4-dihydro-2H-1,4-benzoxazine-2-carboxylic acid (490 mg, 1.86 mmol) and (5-amino-4-bromo-2-cyclopentyl-phenyl) methyl carbonate (585 mg, 1.86 mmol) were dissolved in 2-methyltetrahydrofuran (13 mL). Pyridine (376 μL, 4.65 mmol) and T3P (2960 mg, 2.8 mL of 50% w/w solution, 4.66 mmol) were added and the reaction was stirred for 1 h at room temperature. Purification by silica gel chromatography (10-75% ethyl acetate/hexanes) yielded 4-bromo-2-cyclopentyl-5-(6-(trifluoromethoxy)-3,4-dihydro-2H-benzo[b][1,4]oxazine-2-carboxamido)phenyl methyl carbonate (802 mg, 77% yield). LC/MS m/z 560.2 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([S:9][CH2:10][C:11]#[N:12])[S:5][C:6]=1[C:7]#[N:8].CO[CH:15](OC)[N:16]([CH3:18])[CH3:17]>>[C:7]([C:6]1[S:5][C:4]([S:9][CH2:10][C:11]#[N:12])=[N:3][C:2]=1[N:1]=[CH:15][N:16]([CH3:18])[CH3:17])#[N:8]
Reactant: N#CCSc1nc(N)c(C#N)s1
Reactant: COC(OC)N(C)C
Product: CN(C)C=Nc1nc(SCC#N)sc1C#N

Procedure:
The title compound was prepared from the reaction of 4-Amino-2-cyanomethylsulfanyl-thiazole-5-carbonitrile with N,N-dimethylformamide dimethyl acetal using the procedure from Example 156B to provide the title compound.
Reaction SMILES: [C:1]1([P:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(OC(=O)C(C)(C)CCCCC[Br:30])C>C1(C)C=CC=CC=1>[Br-:30].[C:14]1([PH+:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CCOC(=O)C(C)(C)CCCCCBr
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: [Br-]
Product: c1ccc([PH+](c2ccccc2)c2ccccc2)cc1
Temperature: 122 °C
Yield: 125.9 %

Procedure:
Triphenylphosphine (14.8 g, 56.6 mmoL) was added to a solution of 7-bromo-2,2-dimethylheptanoic acid ethyl ester (15.0 g, 56.6 mmoL) in toluene (110 mL). The solution was heated to reflux (oil bath 122° C.) for 24 h. The toluene was evaporated and the residue was washed with heptane (2×60 mL), diethyl ether (2×60 mL), and dried in high vacuum to a constant weight to provide 6-ethoxycarbonyl-6-methylheptyl)triphenylphosphonium bromide (24.39 g, 81.8% yield) as a off-white powder (m.p. 165-170° C.). 1H NMR (Field: 300 MHz, Solvent: CDCl3/TMS) δ (ppm): 7.88-7.82 (m, 9H), 7.75-7.72 (m, 6H), 4.06 (q, 2H, J=6.9 Hz), 3.76 (m, 2H), 1.64 (m, 4H), 1.46-1.41 (m, 2H), 1.20 (t, 5H, J=6.9 Hz), 1.10 (s, 6H). 13C NMR (Field: 75 MHz, Solvent: CDCl3/TMS) δ (ppm): 177.82, 134.99, 133.69 (d, J=10 Hz), 130.57 (d, J=12 Hz), 117.69 (d, J=85 Hz), 60.29, 42.12, 40.09, 30.94 (d, J=16 Hz), 25.26 (d, J=41 Hz), 23.18 (d, J=41 Hz), 14.40. HRMS (FIA-ESI-TOFM)): Calculated for C29H36BrO2P (M+H)+ 447.2447, found 447.2446.
Reaction SMILES: [NH2:1][C@H:2]([C:7]([OH:9])=O)[CH2:3][CH:4]([CH3:6])[CH3:5].[NH2:10][C@H:11]([C:13]([OH:15])=O)[CH3:12].[NH2:16][C@H:17]([C:21]([OH:23])=[O:22])[CH:18]([CH3:20])[CH3:19]>>[NH2:1][C@H:2]([C:7]([NH:10][C@H:11]([C:13]([NH:1][CH2:2][C:7]([NH:16][C@H:17]([C:21]([OH:23])=[O:22])[CH:18]([CH3:20])[CH3:19])=[O:9])=[O:15])[CH3:12])=[O:9])[CH2:3][CH:4]([CH3:5])[CH3:6]
Reactant: C[C@H](N)C(=O)O
Reactant: CC(C)C[C@H](N)C(=O)O
Reactant: CC(C)[C@H](N)C(=O)O
Product: CC(C)C[C@H](N)C(=O)N[C@@H](C)C(=O)NCC(=O)N[C@H](C(=O)O)C(C)C

Procedure:
The completed Boc-tetrapeptide resin was subjected to steps (1) and (2) to cleave the Boc group and worked up as described for (A) to yield 707 mg of peptide resin. Amino acid analysis: Gly 1.05, Ala 1.00, Val 1.12, Leu 1.05.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([N:9]=[CH:10]N(C)C)=[C:4]([Cl:14])[N:3]=1.P(=O)(O)(O)[OH:16]>P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[NH2:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([NH:9][CH:10]=[O:16])=[C:4]([Cl:14])[N:3]=1
Reactant: O=P(O)(O)O
Reactant: CN(C)C=Nc1c(Cl)nc(N)nc1Cl
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Product: Nc1nc(Cl)c(NC=O)c(Cl)n1
Yield: 72 %

Procedure:
In another experiment, a slurry of 2-amino-4,6-dichloro-5-{[(dimethylamino)methylene]amino}-pyrimidine (Example 2, 25.0 g, 0.107 mol) in 1.5M aqueous potassium phosphate buffer (300 mL, prepared as above ) was gently refluxed for 4 hours. pH was maintained at 3.2 by addition of 85% phosphoric acid, as required, throughout this period. The precipitate was filtered, washed with water (3×10 mL), methanol (2×10 mL), and dried (50° C.,) 25 mm Hg) to give the title compound as an off-white powder (16.0 g, 72% ) with purity identical to that of the characterics sample described above (elemental analysis and 1H-NMR).
Reaction SMILES: [Na+].[Na+].P(O[CH2:8][C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C=O)([O-])([O-])=O.C1N=C(N)C2N=CN([C@@H]3O[C@H](COP(OP(OC[C@H]4[O:48][C@@H:47]([N:49]5[CH:54]=[C:53]([C:55]([NH2:57])=[O:56])[CH2:52][CH:51]=[CH:50]5)[C@H:46](O)[C@@H]4O)(O)=O)(O)=O)[C@@H](O)[C@H]3O)C=2N=1.CCOCCOCCO>C(O)C(N)(CO)CO.Cl>[C:47]([NH:49][C:50]1[CH:51]=[CH:52][C:53]([C:55]([NH2:57])=[O:56])=[CH:54][CH:8]=1)(=[O:48])[CH3:46]
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)COP(=O)([O-])[O-]
Reactant: NC(=O)C1=CN([C@@H]2O[C@H](COP(=O)(O)OP(=O)(O)OC[C@H]3O[C@@H](n4cnc5c(N)ncnc54)[C@H](O)[C@@H]3O)[C@@H](O)[C@H]2O)C=CC1
Agent: Cl
Agent: NC(CO)(CO)CO
Agent: [Na+]
Solvent: CCOCCOCCO
Product: CC(=O)Nc1ccc(C(N)=O)cc1

Procedure:
The following components were combined at a temperature between 0°-4°: G6PDH, 10.0 ml of ca. 2 mg/ml solution suspended in 0.055 M Tris-HCl buffer; Glucose-6-phosphate disodium salt, 100 mg; NADH, 200 mg; Carbitol, 3.0 ml.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[C:17]([NH2:19])[CH:16]=[CH:15][C:14]=2[O:20][CH3:21])=[CH:9][CH:8]=1)=[O:6])[CH3:3].CN1CCOCC1.[CH:29]1([C:32](Cl)=[O:33])[CH2:31][CH2:30]1>C1COCC1>[CH2:2]([O:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[C:17]([NH:19][C:32]([CH:29]3[CH2:31][CH2:30]3)=[O:33])[CH:16]=[CH:15][C:14]=2[O:20][CH3:21])=[CH:9][CH:8]=1)=[O:6])[CH3:3]
Reactant: CCOC(=O)c1ccc(-c2cc(N)ccc2OC)cc1
Reactant: O=C(Cl)C1CC1
Agent: Cl
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: CCOC(=O)c1ccc(-c2cc(NC(=O)C3CC3)ccc2OC)cc1
Reaction time: 18 h
Yield: 93.5 %

Procedure:
A mixture of 5′-amino-2′methoxy-biphenyl-4-carboxylic acid ethyl ester hydrochloride (100 mg), N-methylmorpholine (0.1 ml) and cyclopropanecarbonyl chloride (29 mg) in dry THF (3 ml) was stirred at 20 C for 18 h. The mixture was then evaporated and the residue partitioned between sodium bicarbonate solution and ethyl acetate. The dried extracts were then evaporated giving the title compound as a dark oil (88 mg)
Reaction SMILES: [C:1]([C@H:5]1[CH2:10][CH2:9][C@H:8]([C:11]([OH:13])=O)[CH2:7][CH2:6]1)([O:3][CH3:4])=[O:2].S(Cl)(Cl)=O.[I-].[F:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[Zn+]>O1CCCC1>[CH3:4][O:3][C:1]([CH:5]1[CH2:6][CH2:7][CH:8]([C:11](=[O:13])[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[F:19])[CH2:9][CH2:10]1)=[O:2]
Reactant: COC(=O)[C@H]1CC[C@H](C(=O)O)CC1
Reactant: Fc1ccccc1[Zn+]
Agent: [I-]
Solvent: C1CCOC1
Solvent: O=S(Cl)Cl
Product: COC(=O)C1CCC(C(=O)c2ccccc2F)CC1
Temperature: 25 °C
Yield: 67.3 %

Procedure:
In an oven dried 1 neck round bottom flask with reflux condenser and stirbar, trans-4-carbomethoxycyclohexane-1-carboxylic acid (840 mg; 4.5 mmol) was heated to reflux in the presence of 15 mL thionyl chloride. After 3 hours reflux, mixture cooled to 40° C. under nitrogen flow, and excess thionyl chloride was removed at reduced pressure. Residue was taken up in 5 mL of dry tetrahydrofuran and added to a 0° C. mixture of 2-fluorophenylzinc iodide (9.0 mL; 4.5 mmol), tetrakis(triphenylphospine)palladium (0) (272 mg; 0.2 mmol) in 10 mL anhydrous tetrahydrofuran. Mixture was allowed to warm to room temperature over 16 hours. Reaction was quenched with 6 mL 1N HCl and ethyl acetate was taken in. Organics separated and aqueous re-extracted with 20 mL ethyl acetate. Combined organics were washed with sat. NaHCO3, water, brine and dried over MgSO4. Material was purified via flash silica plug (10:1) using 15% ethyl acetate in hexanes isocratic to give 800 mg of title compound. (67% yield)
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:11])[CH2:9][CH3:10])=[CH:4][CH:3]=1.Cl.[CH3:13][NH:14][CH3:15].[CH2:16]=O>>[CH3:13][N:14]([CH3:15])[CH2:10][CH:9]([CH3:16])[C:8]([C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=1)=[O:11]
Reactant: CCC(=O)c1ccc(F)cc1
Reactant: C=O
Reactant: CNC
Agent: Cl
Product: CC(CN(C)C)C(=O)c1ccc(F)cc1

Procedure:
A mixture of 15.2 g. (0.10 mole) of 4'-fluoropropiophenone, 8.2 g. (0.10 mole) of dimethylamine hydrochloride, 3.6 g. (0.12 mole) of paraformaldehyde in 20 ml. of absolute alcohol was stirred at 95°-100°C for three hours. The mixture is cooled and the precipitated product is filtered. The product is dissolved in water, made alkaline with sodium hydroxide. The free base is extracted into ether. The ether layer is dried over anhydrous sodium sulfate and concentrated in vacuo to give 3-dimethylamino-4'-fluoro-2methylpropiophenone
Reaction SMILES: [CH3:1][NH:2][C:3](=[S:6])[NH:4][NH2:5].[Cl:7][CH2:8][C:9](=O)[C:10]([CH3:13])([CH3:12])[CH3:11]>>[ClH:7].[C:10]([C:9]1[N:2]([CH3:1])[C:3](=[N:4][NH2:5])[S:6][CH:8]=1)([CH3:13])([CH3:12])[CH3:11]
Reactant: CNC(=S)NN
Reactant: CC(C)(C)C(=O)CCl
Product: Cl
Product: Cn1c(C(C)(C)C)csc1=NN

Procedure:
From 4-methyl-3-thiosemicarbazide and 1-chloro-3,3-dimethyl-2-butanone.