Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:6]2=[N:7][CH:8]=[CH:9][CH:10]=[C:5]2[N:4]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[N:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.[Cl:58][C:59]1[CH:60]=[C:61]([CH:63]=[CH:64][CH:65]=1)[NH2:62]>O1CCOCC1.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].CCOC(C)=O.O>[Cl:58][C:59]1[CH:60]=[C:61]([NH:62][C:2]2[C:6]3=[N:7][CH:8]=[CH:9][CH:10]=[C:5]3[N:4]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[N:3]=2)[CH:63]=[CH:64][CH:65]=1
Reactant: CC(C)(C)OC(=O)n1nc(Br)c2ncccc21
Reactant: Nc1cccc(Cl)c1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)n1nc(Nc2cccc(Cl)c2)c2ncccc21
Temperature: 100 °C
Reaction time: 12 h

Procedure:
A mixture of 3 (505 mg, 1.7 mmol), Cs2CO3 (1.1 g, 3.4 mmol), Pd2(dba)3 (119 mg, 0.13 mmol) and 2-Dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (XPhos) in a 50 mL round-bottomed flask were subjected to evacuation and purging (3× with Argon). A solution of 3-chloroaniline (0.20 mL, 1.87 mmol) in 1,4-dioxane (0.1 M) was added. The r×n mixture was heated to 100° C. After 12 h, the r×n was added to EtOAc:H2O (1:1; 250 mL) and the organic layer was separated. The aqueous layer was reextracted with EtOAc (2×50 mL). The collected organic layers were washed with brine (50 mL), dried (MgSO4), filtered and concentrated to afford a crude solid. The material was taken through to the next step.
Reaction SMILES: [Br:1][C:2]1[S:3][C:4]([C:7]([OH:9])=O)=[CH:5][N:6]=1.[N:10]1([CH2:15][CH2:16][CH2:17][NH2:18])[CH:14]=[CH:13][N:12]=[CH:11]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C>ClCCl>[N:10]1([CH2:15][CH2:16][CH2:17][NH:18][C:7]([C:4]2[S:3][C:2]([Br:1])=[N:6][CH:5]=2)=[O:9])[CH:14]=[CH:13][N:12]=[CH:11]1
Reactant: O=C(O)c1cnc(Br)s1
Reactant: NCCCn1ccnc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(NCCCn1ccnc1)c1cnc(Br)s1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2-Bromothiazole-5-carboxylic acid (0.4 g, 1.923 mmol), 3-(1H-imidazole-1-yl)propan-1-amine (0.265 g, 2.115 mmol), and benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (BOP) (0.935 g, 2.115 mmol) were mixed in dichloromethane (7 ml), treated with Hunig's base (0.705 ml, 4.04 mmol) and stirred at 25° C. for 2 hours. The reaction mixture was diluted with dichloromethane and washed with water and brine. The organic layer was dried (MgSO4), filtered and concentrated. Purification by flash chromatography (silica gel, 2-20% methanol/dichloromethane) afforded the title compound.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:10]=2)[CH:7]=1.[C:15]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH3:24])[CH:18]=1)#[CH:16]>>[C:11]([C:9]1[CH:10]=[C:5]2[N:4]=[CH:3][C:2]([C:16]#[C:15][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH3:24])[CH:18]=3)=[CH:7][N:6]2[N:8]=1)([CH3:14])([CH3:13])[CH3:12]
Reactant: C#Cc1cccc(OC)c1
Reactant: CC(C)(C)c1cc2ncc(Br)cn2n1
Product: COc1cccc(C#Cc2cnc3cc(C(C)(C)C)nn3c2)c1

Procedure:
The title compound, yellow solid, MS: m/e=306.2 (M+H+), can be prepared in accordance with the general method of example 1 from 6-bromo-2-tert-butyl-pyrazolo[1,5-a]pyrimidine (example 9, step 1) and 1-ethynyl-3-methoxybenzene.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][NH:5][C:4](=[O:8])[CH2:3]1.N1C=CN=C1.[Si:14](Cl)([C:27]([CH3:30])([CH3:29])[CH3:28])([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CN(C=O)C.CN(C1C=CN=CC=1)C.C1COCC1>[O:1]([CH:2]1[CH2:7][CH2:6][NH:5][C:4](=[O:8])[CH2:3]1)[Si:14]([C:27]([CH3:30])([CH3:29])[CH3:28])([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: O=C1CC(O)CCN1
Agent: CN(C)c1ccncc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CC(C)(C)[Si](OC1CCNC(=O)C1)(c1ccccc1)c1ccccc1
Yield: 26.5 %

Procedure:
(±) 4-hydroxypiperidin-2-one (0.80 g, 6.94 mmol) was dissolved in DMF. DMAP (0.085 g, 0.694 mmol) and imidazole (0.92 g, 13.88 mmol) were added. After the resulting mixture was stirred evenly, the solution of TBDPS-Cl (2.3 g, 8.33 mmol) in THF was added and stirred at room temperature overnight. After the reaction completed, the reaction mixture was dried by spinning. Column chromatography afforded colorless oily liquid 0.65 g, yield 60%.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:6]([CH2:13][CH3:14])[N:5]=[CH:4][CH:3]=1.[Br:15]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl>[Cl:1][C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:6]([CH:13]([Br:15])[CH3:14])[N:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1c(Cl)ccnc1CC
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)c1c(Cl)ccnc1C(C)Br

Procedure:
A mixture of the above ethylnicotinate (5.45 g), N-bromosuccinimide (NBS) (5.50 g) and 2,2'-azobis(2-methylpropionitrile) (AIBN) (0.40 g) in carbon tetrachloride (50 ml) is heated under reflux for 2 hours, then cooled, filtered and concentrated in vacuo to give ethyl 4-chloro-2-(1-bromoethyl)-nicotinate.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]=[C:8]2[C:17](=[O:18])[NH:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:19]([F:22])([F:21])[F:20])[CH:14]=3)[N:9]2[C:23]=1[CH2:24][C:25]1[NH:26][CH:27]=[CH:28][N:29]=1)=[O:5])C>Br>[C:4]([C:6]1[N:7]=[C:8]2[C:17](=[O:18])[NH:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:19]([F:21])([F:20])[F:22])[CH:14]=3)[N:9]2[C:23]=1[CH2:24][C:25]1[NH:29][CH:28]=[CH:27][N:26]=1)([OH:5])=[O:3]
Reactant: CCOC(=O)c1nc2c(=O)[nH]c3cc(C(F)(F)F)ccc3n2c1Cc1ncc[nH]1
Agent: Br
Product: O=C(O)c1nc2c(=O)[nH]c3cc(C(F)(F)F)ccc3n2c1Cc1ncc[nH]1
Temperature: 80 °C
Reaction time: 16 h
Yield: 110.2 %

Procedure:
A suspension of 2-ethoxycarbonyl-1-(1-imidazolylmethyl)-7-trifluoromethylimidazo[1,2-a]quinoxalin-4(5H)-one (Example 5) (1.9 g, 4.69 mmol) in hydrobromic acid (48% in water) (100 ml) was stirred at 80° C. for 16 h. The mixture was concentrated in vacuo, and the residue stirred with methanol to give 1.95 g (88%) of the title compound as a HBr salt, which was isolated by filtration.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][NH2:11])=[CH:6][CH:5]=1.C(N(CC)CC)C.[OH:19][C:20]1([C:30]#[C:31][C:32]([C:34]2[CH:35]=[N:36][C:37]([CH3:40])=[CH:38][CH:39]=2)=O)[CH2:29][CH2:28][C:23]2([O:27][CH2:26][CH2:25][O:24]2)[CH2:22][CH2:21]1>C(O)C>[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:32]([C:34]3[CH:35]=[N:36][C:37]([CH3:40])=[CH:38][CH:39]=3)=[CH:31][C:30]([C:20]3([OH:19])[CH2:21][CH2:22][C:23]4([O:27][CH2:26][CH2:25][O:24]4)[CH2:28][CH2:29]3)=[N:11]2)=[CH:6][CH:5]=1
Reactant: COc1ccc(NN)cc1
Reactant: Cc1ccc(C(=O)C#CC2(O)CCC3(CC2)OCCO3)cn1
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: COc1ccc(-n2nc(C3(O)CCC4(CC3)OCCO4)cc2-c2ccc(C)nc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 22.5 %

Procedure:
To a solution of 4-methoxyphenylhydrazine hydrochloride (359 mg, 2.06 mmol) in ethanol (4 mL), triethylamine (286 μL, 2.06 mmol) was added dropwise, and the obtained solution was stirred at room temperature for 30 minutes. To the reaction solution, a solution of 3-(8-hydroxy-1,4-dioxaspiro[4.5]decan-8-yl)-1-(6-methylpyridin-3-yl)-2-propyn-1-one (Reference Example 16) (563.7 mg, 1.87 mmol) in ethanol (5.4 mL) was added dropwise, and the obtained solution was stirred at room temperature for 22 hours. Thereafter, the reaction solution was concentrated under reduced pressure. Water was added to the residue and the resultant was extracted with ethyl acetate. The organic layer was washed with distilled water and brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, n-hexane/ethyl acetate) to obtain the captioned compound (177 mg, 0.42 mmol, 22%) as an amorphous product.
Reaction SMILES: [CH3:1][C@@H:2]1[O:6][C:5](=[O:7])[C@H:4]([O:8][CH2:9][C:10]([CH3:12])=[CH2:11])[C@H:3]1[O:13][CH2:14][C:15]([CH3:17])=[CH2:16].[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[CH3:12][C:10](=[CH2:11])[CH2:9][O:8][C@H:4]([C@@H:3]([O:13][CH2:14][C:15]([CH3:17])=[CH2:16])[C@@H:2]([OH:6])[CH3:1])[CH2:5][OH:7]
Reactant: C=C(C)CO[C@H]1[C@H](C)OC(=O)[C@@H]1OCC(=C)C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: C=C(C)CO[C@@H]([C@H](C)O)[C@H](CO)OCC(=C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.5 %

Procedure:
To a solution of (3R,4S,5S)-5-methyl-3,4-bis(2-methylallyloxy)dihydrofuran-2(3H)-one (1 g, 4.16 mmol) in THF (10 mL) at 0° C. was added 1.0 M LAH (9.57 mL, 9.57 mmol) in THF over 15 min. The mixture was warmed to room temperature and stirred for 2 h, then carefully added dropwise to an ice cold saturated aqueous ammonium chloride (NH4Cl) solution (100 mL). The phases were separated and the aqueous layer was extracted with DCM. The combined organic layers were dried over sodium sulfate (Na2SO4), filtered, and the filtrate was concentrated. Purification by flash chromatography (SiO2) afforded the title compound as a colorless oil (920 mg, 90%): 1H NMR (400 MHz, CDCl3) δ 4.99 (d, J=7.8 Hz, 2H), 4.91 (d, J=8.9 Hz, 2H), 4.09-3.92 (m, 5H), 3.93-3.83 (m, 1H), 3.82-3.73 (m, 1H), 3.70 (q, J=4.7 Hz, 1H), 3.39 (dd, J=6.0, 5.0 Hz, 1H), 3.14 (s, 1H), 2.46 (s, 1H), 1.77 (s, 3H), 1.76 (s, 3H), 1.26 (d, J=6.3 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 141.95, 141.75, 112.99, 112.79, 81.57, 79.41, 75.52, 74.57, 67.60, 61.33, 19.67, 19.63, 19.61.
Reaction SMILES: C([O:3][C:4](=[O:20])[CH2:5][CH2:6][NH:7][C:8](=[S:19])[NH:9][C:10]1[CH:18]=[C:17]2[C:13]([CH:14]=[N:15][NH:16]2)=[CH:12][CH:11]=1)C.[OH-].[Na+]>CO.O>[NH:16]1[C:17]2[C:13](=[CH:12][CH:11]=[C:10]([NH:9][C:8]([NH:7][CH2:6][CH2:5][C:4]([OH:20])=[O:3])=[S:19])[CH:18]=2)[CH:14]=[N:15]1
Reactant: CCOC(=O)CCNC(=S)Nc1ccc2cn[nH]c2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)CCNC(=S)Nc1ccc2cn[nH]c2c1
Yield: 54.1 %

Procedure:
A solution of 0.6 g (2.05 mmol) of the ester thus obtained and 0.09 g (2.36 mmol) of sodium hydroxide in 15 ml of methanol and 0.1 ml of water is left at room temperature and under agitation for 20 hr. After concentration to dryness, 10 ml of water is added to the residue is obtained. After purification by extraction with ethyl acetate (3 × 20 ml), the aqueous phase is cooled and then acidified with a 3 N hydrochloric acid solution until a pH close to 3 is obtained 0.293 g (yield 56%) of (lH-indazol-6-yl)thiocarbamoyl-beta-alanine is obtained in the form of a solid having a melting point of 175° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]2[C:17]3[CH:18]=[C:19]([NH:22][S:23]([CH3:26])(=[O:25])=[O:24])[CH:20]=[CH:21][C:16]=3[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][C:14]=3[O:27][CH:28]([F:30])[F:29])[O:9]2)[CH:5]=[CH:6][CH:7]=1.[Br-].[CH2:32]([O:34][C:35](=[O:39])[CH2:36][CH2:37][Zn+])[CH3:33].O>C1COCC1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Pd]>[F:29][CH:28]([F:30])[O:27][C:14]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:15]=1[C:16]1[CH:21]=[CH:20][C:19]([NH:22][S:23]([CH3:26])(=[O:24])=[O:25])=[CH:18][C:17]=1[CH:8]([C:4]1[CH:3]=[C:2]([CH2:37][CH2:36][C:35]([O:34][CH2:32][CH3:33])=[O:39])[CH:7]=[CH:6][CH:5]=1)[O:9]2
Reactant: CCOC(=O)CC[Zn+]
Reactant: CS(=O)(=O)Nc1ccc2c(c1)C(c1cccc(Br)c1)Oc1cccc(OC(F)F)c1-2
Agent: [Pd]
Agent: [Br-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)CCc1cccc(C2Oc3cccc(OC(F)F)c3-c3ccc(NS(C)(=O)=O)cc32)c1

Procedure:
A solution of Example 103 (0.05 g, 0.10 mmol), tetrakis(triphenylphosphine) palladium(O) (0.01, 0.01 mmol), and 3-ethoxy-3-oxopropylzincbromide (0.6 ml of 0.5M solution in THF) in THF (2 mL) was shaken in a sealed tube at 80° C. for 15 hours, treated with water (2 mL), and extracted with ethyl acetate. The extract was the concentrated and the residue was purified by high throughput HPLC with aqueous 0.1% TFA and CH3CN to provide the titled compound. 1H NMR (300 MHz, DMSO-d6) δ 9.98 (s, 1H), 8.17 (d, J=9 Hz, 1H), 6.52-7.74 (m, 10H), 6.31 (s, 1H), 4.18 (q, J=7 Hz, 2H), 3.02 (s, 3H), 1.25 (t, J=7 Hz, 3H); MS (ESI(−)Q1MS m/z 516 (M−H).
Reaction SMILES: [C:1]([C:3]1[N:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[C:21]3[NH:25][N:24]=[N:23][N:22]=3)=[CH:11][CH:10]=2)[C:6]([CH2:26][CH2:27][CH3:28])=[N:5][C:4]=1[N:29]1[CH:33]=[CH:32][CH:31]=[C:30]1[C:34](=[O:39])[C:35]([F:38])([F:37])[F:36])#[N:2].[BH4-].[Na+].CC(C)=O>C(O)C>[C:1]([C:3]1[N:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[C:21]3[NH:22][N:23]=[N:24][N:25]=3)=[CH:11][CH:10]=2)[C:6]([CH2:26][CH2:27][CH3:28])=[N:5][C:4]=1[N:29]1[CH:33]=[CH:32][CH:31]=[C:30]1[CH:34]([OH:39])[C:35]([F:38])([F:36])[F:37])#[N:2]
Reactant: CCCc1nc(-n2cccc2C(=O)C(F)(F)F)c(C#N)n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: CC(C)=O
Product: CCCc1nc(-n2cccc2C(O)C(F)(F)F)c(C#N)n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Reaction time: 1 h

Procedure:
A solution of 5-cyano-4-[2-(1-oxo-2,2,2-trifluoroethyl)-1H-pyrrol-1-yl]-2 propyl-1-[(2'-(1H-tetrazol-5-yl)biphen-4-yl)methyl]-1H-imidazole (Example 27, 300 mg) in ethanol (5 mL) was chilled to 10° C. and treated with NaBH4 (30 mg). There was a period of rapid gas evolution then the reaction was stirred for 1 hour. Acetone (0.1 mL) was added and the reaction was stirred 10 minutes longer before partitioning between ethyl acetate and 10% citric acid (aq). The organic layer was washed with saturated aqueous NaCl, dried over MgSO4 and evaporated. Flash chromatography on silica gel, eluting with CHCl3CH3OH--CH3CN (90:5:5) gives the title compound as a foam upon evaporation of solvents. The foam was triturated with hexane diisopropyl ether (3:1) to give a colorless powder. MS (FAB, thioglycerol) 533 (m+1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9](Br)[CH:10]=1)[C:5]([OH:7])=[O:6].[CH3:12][S:13]C.[Na].CS(C)=O>O>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([S:13][CH3:12])[CH:10]=1)[C:5]([OH:7])=[O:6]
Reactant: CSC
Reactant: O=C(O)c1cc(Br)cc(Br)c1
Agent: [Na]
Solvent: O
Solvent: CS(C)=O
Product: CSc1cc(Br)cc(C(=O)O)c1
Temperature: 100 °C

Procedure:
A mixture of 3,5-dibromobenzoic acid (2.5 g, 8.9 mmol), sodium methyl sulfide (1.4 g, 20 mmol), and dimethyl sulfoxide (10 mL) was sealed in a microwave tube and heated with an oil bath at 100° C. for 4 h. TLC indicated completion of the reaction. The reaction mixture was poured into water and extracted with EtOAc (3×50 mL). The combined organic layers were washed with brine, dried (Na2SO4), and concentrated. The residue was used for the next step reaction without purification. 1H NMR (400 MHz, CDCl3): δ 7.97 (t, 1H, J=1.6 Hz), 7.87 (t, 1H, J=1.6 Hz), 7.57 (t, 1H, J=1.6 Hz), 2.53 (s, 3H).
Reaction SMILES: Cl[C:2]1[C:7]([CH:8]=[O:9])=[C:6]([Cl:10])[N:5]=[C:4]([S:11][CH3:12])[N:3]=1.[CH3:13][CH2:14][CH:15]([NH2:18])[CH2:16][CH3:17]>>[Cl:10][C:6]1[C:7]([CH:8]=[O:9])=[C:2]([NH:18][CH:15]([CH2:16][CH3:17])[CH2:14][CH3:13])[N:3]=[C:4]([S:11][CH3:12])[N:5]=1
Reactant: CSc1nc(Cl)c(C=O)c(Cl)n1
Reactant: CCC(N)CC
Product: CCC(CC)Nc1nc(SC)nc(Cl)c1C=O

Procedure:
Prepared as described above in Example 2 starting from 4,6-dichloro-2-methylsulfanyl-pyrimidine-5-carbaldehyde and 3-pentylamine to give the title compound 4-chloro-6-(1-ethyl-propylamino)-2-methylsulfanyl-pyrimidine-5-carbaldehyde. 1H-NMR: δ 0.92 (t, 6H, J=7.3 Hz), 1.50-1.74 (m, 4H), 2.52 (s, 3H), 4.22 (m, 1H), 9.21 (br s, 1H), 10.33 (s, 1H). LC MS (m/e)=274 (MH+).
Reaction SMILES: [CH3:1][C@:2]12[C:8]([CH3:10])([CH3:9])[C@H:5]([CH2:6][CH2:7]1)[CH:4]([C:11](Cl)=[O:12])[C:3]2=O.C(N(CC)CC)C.C(O[C:27]([N:29](C)[NH:30][C:31]1[CH:36]=[C:35]([C:37]([F:40])([F:39])[F:38])[CH:34]=[CH:33][C:32]=1[C:41]([F:44])([F:43])[F:42])=O)(C)(C)C.Cl.O1CCOCC1.O.[Cl-].[Na+].O>ClCCCl.ClCCl>[F:42][C:41]([F:43])([F:44])[C:32]1[CH:33]=[CH:34][C:35]([C:37]([F:40])([F:39])[F:38])=[CH:36][C:31]=1[N:30]1[C:11](=[O:12])[C:4]2[C@@H:5]3[C:8]([CH3:10])([CH3:9])[C@@:2]([CH3:1])([CH2:7][CH2:6]3)[C:3]=2[N:29]1[CH3:27]
Reactant: CC1(C)[C@@H]2CC[C@@]1(C)C(=O)C2C(=O)Cl
Reactant: CN(Nc1cc(C(F)(F)F)ccc1C(F)(F)F)C(=O)OC(C)(C)C
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCCl
Solvent: C1COCCO1
Solvent: ClCCl
Product: Cn1c2c(c(=O)n1-c1cc(C(F)(F)F)ccc1C(F)(F)F)[C@H]1CC[C@]2(C)C1(C)C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 45.7 %

Procedure:
A solution of (1R,4R)-4,7,7-trimethyl-3-oxo-bicyclo[2.2.1]heptane-2-carbonyl chloride (Intermediate 20; 415 mg, 1.93 mmol) in 1,2-dichloroethane (12 mL) was added to a cooled (0° C.) solution of triethylamine (380 μL, 2.73 mmol) and N′-(2,5-bis-trifluoromethyl-phenyl)-N-methyl-hydrazinecarboxylic acid tert-butyl ester (480 mg, 1.34 mmol) in 1,2-dichloroethane (8 mL) over a period of 1 min. The reaction mixture was stirred for 10 min at room temperature and then in an oil bath at 50° C. for 45 min. A solution of HCl in dioxane (4 M; 10 mL, 40 mmol) was added and the mixture was heated at reflux for 1.5 h and then allowed to cool to room temperature. Dichloromethane (75 mL) and 1:1 water/brine (20 mL) were added. The mixture was shaken and the layers separated. The aqueous layer was back-extracted with dichloromethane (30 mL). The combined organic layers were dried (magnesium sulfate), filtered, evaporated, and purified using an ISCO40 g column, eluting with 40-100% ethyl acetate/hexanes. Fractions homogeneous for the product were evaporated, co-evaporated successively with methanol and ether, and then dried under high vacuum at 95° C. to give (4S,7R)-2-(2,5-bis-trifluoromethyl-phenyl)-1,7,8,8-tetramethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (256 mg, 46%) as an off-white solid. ES(+)-MS (M+H) 419.
Reaction SMILES: [CH2:1]([C:13]1[CH:17]=[C:16]([CH:18]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:19]([OH:21])=O)[O:15][N:14]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].C(C1ON=C(C(C2C=CC=CC=2)C(O)=O)C=1)CCCCCCCCCCC.C(N1C=CN=C1)(N1C=CN=C1)=O.Cl.[CH3:68][O:69][C:70]1[CH:76]=[C:75]([O:77][CH3:78])[CH:74]=[C:73]([O:79][CH3:80])[C:71]=1[NH2:72].C(N(CC)CC)C>O1CCCC1>[CH2:1]([C:13]1[CH:17]=[C:16]([CH:18]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:19]([NH:72][C:71]2[C:73]([O:79][CH3:80])=[CH:74][C:75]([O:77][CH3:78])=[CH:76][C:70]=2[O:69][CH3:68])=[O:21])[O:15][N:14]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: COc1cc(OC)c(N)c(OC)c1
Reactant: CCCCCCCCCCCCc1cc(C(C(=O)O)c2ccccc2)on1
Agent: CCCCCCCCCCCCc1cc(C(C(=O)O)c2ccccc2)no1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCc1cc(C(C(=O)Nc2c(OC)cc(OC)cc2OC)c2ccccc2)on1
Reaction time: 1.9 h

Procedure:
To a room temperature, stirred solution of 3-dodecyl-α-phenyl-5-isoxazole acetic acid and 5-dodecyl-α-phenyl-3-isoxazole acetic acid (48.42 g, 0.1303 mol) in dry tetrahydrofuran (1.4 L) was added in one portion 1,1'-carbonyldiimidazole (22.5 g, 0.139 mol), and the solution was stirred for 1.9 hours under nitrogen. To the mixture was added 2,4,6-trimethoxyaniline hydrochloride (28.5 g, 0.130 mol) and triethylamine (19 mL, 0.14 mol), and the mixture was stirred for 1.8 days under nitrogen. The mixture was rotoevaporated and partitioned between ethyl acetate and 1M HCl. The organic layer was washed (1M HCl; saturated NaCl), dried (MgSO4), and rotoevaporated to a tar. The tar was dissolved (THF) and repeatedly chromatographed on silica gel (230-400 mesh) using Heptane-ether-triethylamine-methanol (20:40:6:1) as eluent. Fractions containing pure compound were combined, rotoevaporated, dissolved in toluene, and reevaporated. The residue was crystallized from diisopropyl ether to give pure title compound; yield 17.6 g (25%); mp 107°-108° C.
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)[CH2:4]1.CCN(CC)CC.[C:23]([O:27][C:28]([NH:30][CH2:31][C:32](O)=[O:33])=[O:29])([CH3:26])([CH3:25])[CH3:24].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>ClCCl>[C:23]([O:27][C:28]([NH:30][CH2:31][C:32]([NH:1][CH2:2][CH:3]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:10]=[CH:11][C:12]([Cl:15])=[CH:13][CH:14]=2)[CH2:4]1)=[O:33])=[O:29])([CH3:26])([CH3:25])[CH3:24]
Reactant: NCC1CCN(Cc2ccc(Cl)cc2)C1
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCC(=O)NCC1CCN(Cc2ccc(Cl)cc2)C1
Temperature: 25 °C
Reaction time: 15 h
Yield: 90.3 %

Procedure:
A mixture of 3-(aminomethyl)-1-(4-chlorobenzyl)pyrrolidine (860 mg, 3.8 mmol), Et3N (5.7 mmol), N-tert-butoxycarbonylglycine (704 mg), EDCI (594 mg), HOBt (673 mg), and dichloromethane (20 mL) was stirred at room temperature for 15 h. Dichloromethane (50 mL) was added and the solution was washed with 2 N NaOH solution (50 mL×2), dried over anhydrous sodium sulfate, filtered, and concentrated to afford 3-[{N-(tert-butoxycarbonyl)glycyl)aminomethyl]-1-(4-chlorobenzyl)pyrrolidine (1.31 g, 90%).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:5][C:6]=1[C:7]([O:9][CH3:10])=[O:8].F[C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=1[N+:25]([O-:27])=[O:26]>C(Cl)Cl>[F:24][C:21]1[CH:22]=[CH:23][C:18]([NH:1][C:2]2[S:3][C:4]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[CH:5][C:6]=2[C:7]([O:9][CH3:10])=[O:8])=[C:19]([N+:25]([O-:27])=[O:26])[CH:20]=1
Reactant: COC(=O)c1cc(-c2ccccc2)sc1N
Reactant: O=[N+]([O-])c1cc(F)ccc1F
Solvent: ClCCl
Product: COC(=O)c1cc(-c2ccccc2)sc1Nc1ccc(F)cc1[N+](=O)[O-]

Procedure:
Methyl 2-amino-5-phenyl-thiophene-3-carboxylate and 2,5-difluoronitrobenzene, m.p. 150° C. (CH2Cl2).
Reaction SMILES: C1O[C:4]2([CH2:13][CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[C:9]([C:14]([NH2:16])=[O:15])[CH:10]=3)[CH2:5]2)[O:3]C1.C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(C)=O>[CH2:5]1[C:6]2[C:11](=[CH:10][C:9]([C:14]([NH2:16])=[O:15])=[CH:8][CH:7]=2)[CH2:12][CH2:13][C:4]1=[O:3]
Reactant: NC(=O)c1ccc2c(c1)CCC1(C2)OCCO1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)=O
Product: NC(=O)c1ccc2c(c1)CCC(=O)C2
Yield: 38.3 %

Procedure:
2-Tetralone-6-carboxamide ethylene ketal (250 mg, 1.07 mmol) and catalytic p-toluenesulfonic acid were stirred in acetone (50 mL) at ambient temperature for 48 hours. The volatiles were removed in vacuo and the residue triturated in ethyl acetate. The solids were filtered, washed and dried to yield 77.5 mg (38%) of 2-Tetralone-6-carboxamide as a white powder, pure by NMR, TLC. MS.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1I.[CH2:10]([O:12][P:13]([O:17]CC)[O:14][CH2:15][CH3:16])[CH3:11]>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[P:13](=[O:17])([O:14][CH2:15][CH3:16])[O:12][CH2:10][CH3:11]
Reactant: Fc1cccc(F)c1I
Reactant: CCOP(OCC)OCC
Product: CCOP(=O)(OCC)c1c(F)cccc1F
Reaction time: 20 h
Yield: 74 %

Procedure:
2,6-difluoroiodobenzene (3.0 g, 12.5 mmol) was combined with triethylphosphite (10.7 mL, 62.5 mmol) in a pressure vessel which had been flushed with nitrogen. The vessel was sealed and rotated in the photoreactor (16 bulbs —350 nm) for 20 hours. The reaction mixture was put under hi-vacuum (0.08 Torr) at 50° C. for 5 hours. A column was run in hexanes and ethyl acetate (increasing polarity as run). The top spot, which was UV active, was separated. After removing solvent, a yellow-tinted liquid was left (2.30 g, 74% yield). 1H NMR (400.14 MHz, DMSO) δ 7.72 (m), 7.21 (m, 2H), 4.10 (m, 4H), 1.25 (t, J=7.04 Hz). 31P {1H} NMR (161.97 MHz, DMSO): δ 8.23. The phosphonate can be hydrolyzed as described above to provide the corresponding phosphonic acid.