Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[C:4]([N+:10]([O-:12])=[O:11])[CH:3]=1.C([Sn](CCCC)(CCCC)[C:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH:19]=1)CCC.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.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>[C:18]1([C:2]2[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[C:4]([N+:10]([O-:12])=[O:11])[CH:3]=2)[CH2:23][CH2:22][CH2:21][CH2:20][CH:19]=1
Reactant: COc1ccc(Br)cc1[N+](=O)[O-]
Reactant: CCCC[Sn](CCCC)(CCCC)C1=CCCCC1
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
Product: COc1ccc(C2=CCCCC2)cc1[N+](=O)[O-]
Yield: 74 %

Procedure:
To a stirred solution of 2.1 g (0.0091 Mol) 4-bromo-2-nitroanisole in 50 ml dioxane were added 1.05 g (0.00091 Mol) tetrakis(triphenylphosphine)palladium, 4.03 g (0.011 Mol) tri-n-butyl-(1-cyclohex-1-enyl)-stannane and 18.3 ml 2 M aqueous Na2CO3 solution. The mixture was heated for 16 h at reflux and then poured onto water. After extraction with dichloro methane, drying of the combined organic phases over sodium sulfate and evaporation of the solvent the crude material was subjected to column chromatography (ethyl acetate/hexane 1:10) to yield 1.57 g of 4-cyclohex-1-enyl-1-methoxy-2-nitro-benzene as a yellow liquid. EI-MS m/e (%): 233 ([M]+, 100).
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]1[CH:4]=[C:5]([CH:24]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:26]=1)[C:6]([N:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH:9]1[CH2:15][C:16]1[CH:21]=[C:20]([F:22])[CH:19]=[C:18]([F:23])[CH:17]=1)=[O:7].[CH3:33][C:34]1[CH:39]=[CH:38][CH:37]=[C:36]([CH3:40])[C:35]=1[NH:41][C:42](=[O:50])[CH2:43][N:44]1[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]1.[BH4-].[Na+].C(O)C>CC(O)C.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-].C(Cl)Cl.O>[F:31][C:2]([F:1])([F:32])[C:3]1[CH:4]=[C:5]([CH:24]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:26]=1)[C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([N:47]2[CH2:48][CH2:49][N:44]([CH2:43][C:42]([NH:41][C:35]3[C:36]([CH3:40])=[CH:37][CH:38]=[CH:39][C:34]=3[CH3:33])=[O:50])[CH2:45][CH2:46]2)[CH2:10][C@@H:9]1[CH2:15][C:16]1[CH:17]=[C:18]([F:23])[CH:19]=[C:20]([F:22])[CH:21]=1)=[O:7]
Reactant: O=C1CCN(C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)C(Cc2cc(F)cc(F)c2)C1
Reactant: Cc1cccc(C)c1NC(=O)CN1CCNCC1
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: [BH4-]
Solvent: O
Solvent: CC(C)O
Solvent: ClCCl
Product: Cc1cccc(C)c1NC(=O)CN1CCN([C@H]2CCN(C(=O)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@@H](Cc3cc(F)cc(F)c3)C2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 8.2 %

Procedure:
A mixture of (±)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-[(3,5-difluorophenyl)methyl]-4-piperidinone (0.0058 mol), N-(2,6-dimethylphenyl)-1-piperazineacetamide (0.0058 mol) and titanium(IV)isopropoxide (0.0064 mol) in 2-propanol (5 ml) was stirred at RT overnight. NaBH4 (0.0116 mol) and ethanol (15 ml) were added. The mixture was stirred for 2 day. Water (5 ml) was added and the mixture was stirred for 10 minutes. CH2Cl2 (200 ml) was added. The organic layer was separated, dried, filtered and the solvent was evaporated. This fraction was purified by HPLC over silica gel (eluent: CH2Cl2/CH3OH 98/2 to 90/10 over a 30-minute period). Two pure fractions (F1 and F2) were collected and their solvents were evaporated. F1 was purified by column chromatography over RP18 (eluent: NH4OAc (0.5% in H2O)/CH3CN 40/60). The pure fractions were collected and the solvent was evaporated. The residue was dried, yielding 0.33 g (8%) of (±)-cis-4-[1-[3,5-bis(trifluoromethyl)benzoyl]-2-[(3,5-difluorophenyl)methyl]-4-piperidinyl]-N-(2,6-dimethylphenyl)-1-piperazineacetamide (compound 132). F2 was purified by column chromatography over silica gel (eluent: CH2Cl2/CH3OH 100/0 to 98/2 over a 30-minute period). The pure fractions were collected and the solvent was evaporated. The residue was dissolved in CH2Cl2, filtered and the solvent was evaporated. The residue was dried, yielding 0.24 g (6%) of (±)-trans-4-[1-[3,5-bis(trifluoromethyl)benzoyl]-2-[(3,5-difluorophenyl)methyl]-4-piperidinyl]-N-(2,6-dimethylphenyl)-1-piperazineacetamide (compound 133).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH2:15][O:14][C:13](=[O:16])[C:12]=2[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].CC(C[AlH]CC(C)C)C.[OH-].[Na+]>ClCCl>[CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8](/[C:11](=[C:12](\[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)/[CH2:13][OH:16])/[CH2:15][OH:14])=[CH:9][CH:10]=1)(=[O:3])=[O:4]
Reactant: CS(=O)(=O)c1ccc(C2=C(c3ccccc3)C(=O)OC2)cc1
Agent: CC(C)C[AlH]CC(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc(/C(CO)=C(/CO)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.7 %

Procedure:
To a solution of 110 g of 4-(4-methanesulfonyl-phenyl)-3-phenyl-5H-furan-2-one in 1.5 L of dichloromethane stirred at −78° C., 150 mL of DIBAL was added dropwise. The resulting mixture was warmed to room temperature and stirred overnight. The reaction mixture was then cooled to −78° C., and 1.2 L of 1 M aqueous NaOH was added dropwise. After the addition, the resulting mixture was warmed to room temperature and the organic phase was separated. The aqueous phase was extracted with dichloromethane. The organic phases were combined and dried over Na2SO4. 110 g of the titled compound was obtained after evaporation. 1H NMR (acetone-d6, 500 M Hz): δ 7.69 (d, 2H), 7.36 (d, 2H), 7.16–7.05 (m, 5H), 4.66 (d, 2H), 4.63 (d, 2H), 4.19 (t, 1H, OH), 4.17 (t, 1 H. OH), 3.04 (s, 3H).
Reaction SMILES: [CH:1]([C:4]1[CH:28]=[CH:27][C:7]([CH2:8][C:9]2[C:10]([CH3:26])=[C:11]([NH:18][C:19](=[O:25])[CH2:20][C:21]([CH3:24])([CH3:23])[CH3:22])[C:12]([CH3:17])=[CH:13][C:14]=2[O:15]C)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].B(Br)(Br)Br.C(=O)([O-])O.[Na+]>ClCCl>[CH:1]([C:4]1[CH:28]=[CH:27][C:7]([CH2:8][C:9]2[C:10]([CH3:26])=[C:11]([NH:18][C:19](=[O:25])[CH2:20][C:21]([CH3:22])([CH3:24])[CH3:23])[C:12]([CH3:17])=[CH:13][C:14]=2[OH:15])=[CH:6][CH:5]=1)([CH3:3])[CH3:2]
Reactant: COc1cc(C)c(NC(=O)CC(C)(C)C)c(C)c1Cc1ccc(C(C)C)cc1
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1cc(O)c(Cc2ccc(C(C)C)cc2)c(C)c1NC(=O)CC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 97 %

Procedure:
To a solution of N-(3-(4-isopropylbenzyl)-4-methoxy-2,6-dimethylphenyl)-3,3-dimethylbutanamide obtained in Reference Example 333 (1.99 g, 5.21 mmol) in dichloromethane (25 mL) was added dropwise boron tribromide (a 1.0 M dichloromethane solution, 10.4 mL, 10.4 mmol) under argon atmosphere at −78° C., and the mixture was stirred for 30 minutes. The reaction solution was warmed to room temperature and was stirred for 14 hours. The reaction solution was added to a saturated sodium hydrogen carbonate solution to separate the organic layer, and then the aqueous layer was extracted with ethyl acetate. The entire organic layer was washed with a saturated brine, dried over anhydrous sodium sulfate, filtered and then concentrated under reduced pressure to obtain 1.83 g (yield 97%) of the oily title compound. Melting point: 202-203° C. (ethyl acetate).
Reaction SMILES: O.NN.[CH3:4][C:5]1[N:10]=[C:9]([CH2:11][CH2:12][N:13]2C(=O)C3=CC=CC=C3C2=O)[CH:8]=[CH:7][CH:6]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[CH3:4][C:5]1[N:10]=[C:9]([CH2:11][CH2:12][NH2:13])[CH:8]=[CH:7][CH:6]=1
Reactant: Cc1cccc(CCN2C(=O)c3ccccc3C2=O)n1
Agent: NN
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Cc1cccc(CCN)n1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 62.9 %

Procedure:
28.5 ml (29.4 g, 586 mmol) of hydrazine monohydrate was added to a solution of 39.0 g (147 mmol) of N-[2-(6-methyl-2-pyridyl)ethyl]phthalimide obtained in the above step (1) in 300 ml of ethanol and the mixture was stirred at room temperature for 1.5 h. The mixture was poured into 300 ml of a saturated aqueous sodium carbonate solution. After extraction with chloroform, the organic layer was concentrated and the oily residue thus obtained was purified by distillation (75° to 80° C./0.01 mmHg). 12.6 g (yield: 63%) of the intended compound was obtained as a colorless oil.
Reaction SMILES: [CH:1]1([NH:4][C:5]([C:7]2[N:8]=[N:9][N:10]([C:12]3[CH:17]=[CH:16][C:15]([C:18]([NH:20][CH2:21][CH3:22])=[O:19])=[CH:14][C:13]=3[OH:23])[CH:11]=2)=[O:6])[CH2:3][CH2:2]1.Br[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][F:30].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH:1]1([NH:4][C:5]([C:7]2[N:8]=[N:9][N:10]([C:12]3[CH:17]=[CH:16][C:15]([C:18]([NH:20][CH2:21][CH3:22])=[O:19])=[CH:14][C:13]=3[O:23][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][F:30])[CH:11]=2)=[O:6])[CH2:3][CH2:2]1
Reactant: CCNC(=O)c1ccc(-n2cc(C(=O)NC3CC3)nn2)c(O)c1
Reactant: FCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCNC(=O)c1ccc(-n2cc(C(=O)NC3CC3)nn2)c(OCCCCCF)c1
Temperature: 50 °C
Reaction time: 8 h
Yield: 58.6 %

Procedure:
To a solution of N-cyclopropyl-1-{4-[(ethylamino)carbonyl]-2-hydroxyphenyl}-1H-1,2,3-triazole-4-carboxamide (0.16 g) obtained in Example 139 in DMF (5 ml) were added 1-bromo-5-fluoropentane (0.11 g) and potassium carbonate (0.07 g), and the mixture was stirred at 50° C. overnight. The reaction mixture was allowed to cool to room temperature, and water was added to the reaction mixture. The deposited precipitate was collected by filtration, washed with water, and recrystallized from ethanol-water to give the title compound as a pale-brown powder (0.12 g, 60%).
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([C:14]#[C:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:10][N:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].I[CH3:25]>CN(C=O)C>[C:1]([N:5]([CH3:25])[C:6]([C:8]1[CH:13]=[CH:12][C:11]([C:14]#[C:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[CH:10][N:9]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CI
Reactant: CC(C)(C)NC(=O)c1ccc(C#Cc2ccccc2)cn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C(=O)c1ccc(C#Cc2ccccc2)cn1)C(C)(C)C
Temperature: 2.5 °C
Reaction time: 0.5 h
Yield: 61.7 %

Procedure:
(74 mg, 266 μmol) 5-Phenylethynyl-pyridine-2-carboxylic acid tert-butylamide (Example 1, step 2) was dissolved in DMF (1 ml) and cooled to 0-5° C. NaH (55%) (14 mg, 319 μmol, 1.2 equiv.) was added and the mixture was stirred for 30 min at 0-5° C. Iodomethane (22 μl, 346 μmol, 1.3 equiv.) was added, and the mixture was then stirred for 1 hour at room temperature. The reaction mixture was evaporated and treated with sat. NaHCO3 solution and extracted twice with a small volume of CH2Cl2. The organic layers were loaded directly to silica gel column and the crude material was purified by flash chromatography on silica gel (20 g, ethyl acetate/heptane gradient, 0:100 to 100:0). The desired 5-phenylethynyl-pyridine-2-carboxylic acid tert-butyl-methyl-amide (48 mg, 62% yield) was obtained as a light yellow solid, MS: m/e=293.0 (M+H+).
Reaction SMILES: CN1CCN(CC2CCCN(C3C=CC([N+]([O-])=O)=CC=3)C2)CC1.[CH3:24][O:25][C:26]1[CH:27]=[C:28]([N:35]2[CH2:40][CH2:39][CH2:38][C@H:37]([C:41]([N:43]3[CH2:48][CH2:47][N:46]([CH3:49])[CH2:45][CH2:44]3)=O)[CH2:36]2)[CH:29]=[CH:30][C:31]=1[N+:32]([O-:34])=[O:33]>>[CH3:24][O:25][C:26]1[CH:27]=[C:28]([N:35]2[CH2:40][CH2:39][CH2:38][C@H:37]([CH2:41][N:43]3[CH2:44][CH2:45][N:46]([CH3:49])[CH2:47][CH2:48]3)[CH2:36]2)[CH:29]=[CH:30][C:31]=1[N+:32]([O-:34])=[O:33]
Reactant: COc1cc(N2CCC[C@H](C(=O)N3CCN(C)CC3)C2)ccc1[N+](=O)[O-]
Agent: CN1CCN(CC2CCCN(c3ccc([N+](=O)[O-])cc3)C2)CC1
Product: COc1cc(N2CCC[C@H](CN3CCN(C)CC3)C2)ccc1[N+](=O)[O-]

Procedure:
1-[(R)-1-(3-Methoxy-4-nitro-phenyl)-piperidin-3-ylmethyl]-4-methyl-piperazine was prepared in an analogous fashion to 1-Methyl-4-[1-(4-nitro-phenyl)-piperidin-3-ylmethyl]-piperazine of Example 455a replacing (4-Methyl-piperazin-1-yl)-[1-(4-nitro-phenyl)-piperidin-3-yl]-methanone with [(S)-1-(3-Methoxy-4-nitro-phenyl)-piperidin-3-yl]-(4-methyl-piperazin-1-yl)-methanone. 1-[(R)-1-(3-Methoxy-4-nitro-phenyl)-piperidin-3-ylmethyl]-4-methyl-piperazine was isolated as an orange oil (170 mg, 77%). LC/MS (E/I+) 349.20 (M+H).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[CH:9][C:8]([Br:11])=[CH:7][C:3]=1[C:4]([OH:6])=O.C(N(CC)C(C)C)(C)C.[CH3:21][S@:22]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)(=[NH:24])=[O:23].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C=O)C.CCOC(C)=O>[NH2:1][C:2]1[N:10]=[CH:9][C:8]([Br:11])=[CH:7][C:3]=1[C:4]([N:24]=[S@@:22]([CH3:21])(=[O:23])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:6]
Reactant: C[S@](=N)(=O)c1ccccc1
Reactant: Nc1ncc(Br)cc1C(=O)O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: C[S@@](=O)(=NC(=O)c1cc(Br)cnc1N)c1ccccc1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 84.4 %

Procedure:
To a solution of 2-amino-5-bromonicotinic acid (189 mg, 0.87 mmol), N,N-diisopropylethylamine (0.30 mL, 1.7 mmol), and (S)-(+)-S-methyl-S-phenylsulfoximine (162 mg, 1.0 mmol) in 4.0 mL DMF at room temperature was added BOP (423 mg, 0.96 mmol). The solution was stirred 30 minutes, then heated at 60° C. for 30 minutes, and then cooled back to room temperature. After 19 hours, the mixture was dissolved in EtOAc, washed with Na2CO3 solution, H2O, brine, dried with anhydrous Na2SO4 and rotary evaporated. The yellow foam was purified by chromatography (silica gel, CHCl3/EtOAc) to give the title compound as a light yellow solid (260 mg, 84%).
Reaction SMILES: [Si:1]([O:8][CH2:9][C@@H:10]([N:13]([CH2:21][C:22](=[O:28])[C:23]([CH:25]1[CH2:27][CH2:26]1)=C)[C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH:11]=C)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Si](OC[C@@H]1C=C(C)C(=O)CN1C(OC(C)(C)C)=O)(C(C)(C)C)(C)C>>[Si:1]([O:8][CH2:9][C@@H:10]1[CH:11]=[C:23]([CH:25]2[CH2:26][CH2:27]2)[C:22](=[O:28])[CH2:21][N:13]1[C:14]([O:15][C:16]([CH3:19])([CH3:17])[CH3:18])=[O:20])([C:4]([CH3:5])([CH3:7])[CH3:6])([CH3:3])[CH3:2]
Reactant: C=C[C@@H](CO[Si](C)(C)C(C)(C)C)N(CC(=O)C(=C)C1CC1)C(=O)OC(C)(C)C
Agent: CC1=C[C@@H](CO[Si](C)(C)C(C)(C)C)N(C(=O)OC(C)(C)C)CC1=O
Product: CC(C)(C)OC(=O)N1CC(=O)C(C2CC2)=C[C@H]1CO[Si](C)(C)C(C)(C)C

Procedure:
The title compound was prepared from (S)-tert-butyl 1-(tert-butyldimethylsilyloxy)but-3-en-2-yl(3-cyclopropyl-2-oxobut-3-enyl)carbamate (Intermediate 262, 5.16 g, 12.60 mmol) following the procedure described for Intermediate 7, except the reaction mixture was heated at 85° C. overnight The desired product was obtained as a light yellow oil (3.82 g, 79%).
Reaction SMILES: [CH3:1][S:2]([CH2:5][C:6]1[CH:11]=[CH:10][C:9]([N+]([O-])=O)=[CH:8][CH:7]=1)(=[O:4])=[O:3].C([O-])=O.[NH4+:18]>CCO.O.CCOC(C)=O.[Fe]>[CH3:1][S:2]([CH2:5][C:6]1[CH:11]=[C:10]([CH:9]=[CH:8][CH:7]=1)[NH2:18])(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cc1ccc([N+](=O)[O-])cc1
Reactant: [NH4+]
Agent: [Fe]
Agent: O=C[O-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCO
Product: CS(=O)(=O)Cc1cccc(N)c1
Temperature: 90 °C
Yield: 71.3 %

Procedure:
To a mixture of 1-(methylsulfonylmethyl)-4-nitrobenzene (0.77 g, 3.56 mmol) in EtOH (10 mL) and H2O (5 mL) was added iron (1.0 g, 17.82 mmol) and ammonium formate (2.25 g, 35.6 mmol). After heating at 90° C. for 2 h, it was diluted with EtOAc, washed with saturated NaHCO3, brine, dried and concentrated to give 3-(methylsulfonylmethyl)aniline (0.47 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([C:28](O)=[O:29])=[CH:5][C:6]2[N:10]=[C:9]([NH:11][C:12]3[S:13][C:14]4[CH:20]=[C:19]([O:21][C:22]([F:25])([F:24])[F:23])[CH:18]=[CH:17][C:15]=4[N:16]=3)[N:8]([CH3:26])[C:7]=2[CH:27]=1.[CH2:31]([NH2:33])[CH3:32].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>>[CH2:31]([NH:33][C:28]([C:4]1[C:3]([O:2][CH3:1])=[CH:27][C:7]2[N:8]([CH3:26])[C:9]([NH:11][C:12]3[S:13][C:14]4[CH:20]=[C:19]([O:21][C:22]([F:23])([F:25])[F:24])[CH:18]=[CH:17][C:15]=4[N:16]=3)=[N:10][C:6]=2[CH:5]=1)=[O:29])[CH3:32]
Reactant: COc1cc2c(cc1C(=O)O)nc(Nc1nc3ccc(OC(F)(F)F)cc3s1)n2C
Reactant: CCN
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CCNC(=O)c1cc2nc(Nc3nc4ccc(OC(F)(F)F)cc4s3)n(C)c2cc1OC

Procedure:
6-Methoxy-1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid ethylamide (37 mg) was prepared by following General Procedure F starting from 6-methoxy-1-methyl-2-(6-trifluoromethoxy-benzo-thiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid (75 mg), ethylamine (2 M in THF, 171 uL), HBTU (78 mg), and DIEA (45 uL). LC/MS: m/z 466.7. 1H NMR (DMSO-d6, 400 MHz): δ 12.25 (s, 1H), 8.22 (t, 1H), 8.10 (s, 1H), 7.90 (s, 1H), 7.71 (d, 1H), 7.34 (d, 1H), 7.24 (s, 1H), 3.98 (s, 3H), 3.64 (s, 3H), 3.39-3.30 (m, 2H), 1.14 (t, 3H).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[C:9]([NH:10][C:11]3[C:20]4[C:15](=[C:16]([CH3:27])[CH:17]=[C:18]([S:21]([CH2:24][CH2:25][OH:26])(=[O:23])=[O:22])[CH:19]=4)[N:14]=[CH:13][C:12]=3[C:28]([NH2:30])=[O:29])[C:4]=2[CH2:3][CH2:2]1.[H-].[Na+].[CH3:33]I>CN(C)C=O>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[C:9]([NH:10][C:11]3[C:20]4[C:15](=[C:16]([CH3:27])[CH:17]=[C:18]([S:21]([CH2:24][CH2:25][O:26][CH3:33])(=[O:22])=[O:23])[CH:19]=4)[N:14]=[CH:13][C:12]=3[C:28]([NH2:30])=[O:29])[C:4]=2[CH2:3][CH2:2]1
Reactant: CI
Reactant: Cc1cc(S(=O)(=O)CCO)cc2c(Nc3cccc4c3CCO4)c(C(N)=O)cnc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCCS(=O)(=O)c1cc(C)c2ncc(C(N)=O)c(Nc3cccc4c3CCO4)c2c1
Reaction time: 18 h

Procedure:
To a solution of Example 523 (0.018 g) in dry N,N-dimethylformamide (1 ml) under nitrogen was added sodium hydride (60% dispersion in mineral oil, 0.0017 g). The mixture was stirred at room temperature for 10 min when methyl iodide (0.0026 ml) was added, stirring was continued for 18 h at room temperature and the solvent evaporated in vacuo. The residue was partitioned between ethyl acetate and water and the organic layer dried (MgSO4) and evaporated. The crude product was purified using mass directed preparative HPLC (Method A) to give the title compound as a yellow solid (0.0024 g).
Reaction SMILES: [Cl:1][C:2]1[N:6]([CH3:7])[N:5]=[C:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[C:3]=1[C:14]([C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=1[CH3:25])=[CH:15][O:16]C.Cl.C([O-])(O)=O.[Na+]>O1CCOCC1>[Cl:1][C:2]1[N:6]([CH3:7])[N:5]=[C:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[C:3]=1[CH:14]([C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=1[CH3:25])[CH:15]=[O:16]
Reactant: COC=C(c1ccc(Cl)cc1C)c1c(-c2ccccn2)nn(C)c1Cl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: Cc1cc(Cl)ccc1C(C=O)c1c(-c2ccccn2)nn(C)c1Cl
Temperature: 70 °C
Yield: 99.9 %

Procedure:
To a solution of 2-(5-chloro-4-(1-(4-chloro-2-methylphenyl)-2-methoxyvinyl)-1-methyl-1H-pyrazol-3-yl)pyridine (16.6 g, 44.4 mmol) in dioxane (80 mL) was added 6 N HCl (340 mL, 2040 mmol). The mixture was heated at about 70° C. for about 10 h then allowed to cool to rt. The mixture was neutralized with a saturated aqueous NaHCO3 solution then extracted with EtOAc (2×500 mL). The combined organic layers were washed with brine (500 mL), dried with Na2SO4, filtered and concentrated in vacuo to give 2-(5-chloro-1-methyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(4-chloro-2-methylphenyl)acetaldehyde (15.98 g, 100%): LC-MS (Table 1, Method g) Rt=2.48 min, m/z 360/362 (M+H)+; 1H-NMR (CDCl3, Bruker 400 MHz) δ 9.83 (s, 1H), 8.41-8.37 (m, 1H), 8.02-7.98 (m, 1H), 7.74-7.68 (m, 1H), 7.23-7.13 (m, 2H), 7.05-6.97 (m, 1H), 6.93 (d, J=8.4 Hz, 1H), 5.75 (s, 1H), 3.94 (s, 3H), 2.37 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:8]C(=O)OC(C)(C)C)[C:3]=1[CH:16]=[O:17].FC(F)(F)C(O)=O>C(Cl)Cl>[NH2:8][C:4]1[N:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[CH:16]=[O:17]
Reactant: CC(C)(C)OC(=O)Nc1nccc(Cl)c1C=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1nccc(Cl)c1C=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Dissolve tert-butyl 4-chloro-3-formylpyridin-2-ylcarbamate (1.6 g, 6.2 mmol) in anhydrous CH2Cl2 (50 mL) under N2 atmosphere. Add dropwise trifluoroacetic acid (2.4 mL, 31.0 mmol) to the reaction mixture and stir at room temperature overnight. Add saturated aq. sodium carbonate (50 mL) to the reaction mixture, separate the organic layer, extract the aq. layer with CH2Cl2 (2×20 mL) and dry with MgSO4. Filter and concentrate under reduced pressure to afford the title product as a yellow solid.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([P:19]([CH3:22])([CH3:21])=[O:20])=[CH:15][CH:14]=2)[N:3]=1.Cl.[CH3:24][C:25]1[CH:26]=[C:27]([CH:29]=[C:30]([CH3:32])[CH:31]=1)[NH2:28]>C(O)C.CO>[CH3:24][C:25]1[CH:26]=[C:27]([NH:28][C:2]2[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]3[CH:18]=[CH:17][C:16]([P:19]([CH3:22])([CH3:21])=[O:20])=[CH:15][CH:14]=3)[N:3]=2)[CH:29]=[C:30]([CH3:32])[CH:31]=1
Reactant: CP(C)(=O)c1ccc(Nc2ncc(C(F)(F)F)c(Cl)n2)cc1
Reactant: Cc1cc(C)cc(N)c1
Agent: Cl
Solvent: CCO
Solvent: CO
Product: Cc1cc(C)cc(Nc2nc(Nc3ccc(P(C)(C)=O)cc3)ncc2C(F)(F)F)c1
Yield: 65 %

Procedure:
To a solution of 4-chloro-N-[4-(dimethylphosphoryl)phenyl]-5-(trifluoromethyl)pyrimidin-2-amine (prepared as in Example 1: 40 mg, 0.12 mmol) in 2 mL of ethanol was added 10 μL of Hydrochloric acid in Methanol (2M) and 3,5-Dimethyl aniline (14 mg, 0.12 mmol). The mixture was microwave at 120 degrees for 20 minutes. The reaction mixture was filtered through a syringe filter and purified by prep-HPLC (Waters Sunfire C18 column with ACN/water mobile phases) to yield a white solid as product (32 mg, 65% yield.) MS/ES+: m/z=435
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1C=CN=C1.[I:25]I.O[CH2:28][CH2:29][CH2:30][N:31]([CH:41]([CH3:43])[CH3:42])[S:32]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)(=[O:34])=[O:33]>C(Cl)Cl>[I:25][CH2:28][CH2:29][CH2:30][N:31]([CH:41]([CH3:43])[CH3:42])[S:32]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)(=[O:34])=[O:33]
Reactant: II
Reactant: CC(C)N(CCCO)S(=O)(=O)c1ccccc1
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)N(CCCI)S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of triphenylphosphine (4.4 g, 16.6 mmol) and imidazole (1.2 g, 16.7 mmol) in CH2Cl2 (40 mL) at RT, is added iodine (4.3 g, 17 mmol) portionwise. To this solution is added N-(3-hydroxypropyl)-N-isopropylbenzenesulfonamide (4.2 g, 16.5 mmol) in CH2Cl2 (8 mL) dropwise and the mixture allowed to stir at RT for 18 h. The mixture is then filtered and the filtrate concentrated to an oil, which is partitioned between ether and saturated sodium thiosulfate. The aqueous phase is extracted with ether. The combined organic layers are reduced to 10 mL and then filtered through a plug of silica, eluting with hexane. Evaporation of solvent affords the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4](F)[CH:3]=1.[C:12]([O:16][C:17]([N:19]1[CH2:28][CH2:27][CH:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]2[OH:29])[CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[C:12]([O:16][C:17]([N:19]1[CH2:28][CH2:27][C:26]2[C:21](=[CH:22][CH:23]=[CH:24][C:25]=2[O:29][C:4]2[CH:3]=[C:2]([Cl:1])[CH:7]=[CH:6][C:5]=2[N+:8]([O-:10])=[O:9])[CH2:20]1)=[O:18])([CH3:15])([CH3:13])[CH3:14]
Reactant: CC(C)(C)OC(=O)N1CCC2C(=CC=CC2O)C1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCc2c(cccc2Oc2cc(Cl)ccc2[N+](=O)[O-])C1
Temperature: 60 °C
Reaction time: 24 h
Yield: 97.7 %

Procedure:
A mixture of 4-chloro-2-fluoronitrobenzene (1.93 g, 11 mmols), 2-tert-butoxycarbonyl-5-hydroxy-tetrahydroisoquinoline (2.74 g, 11 mmols), potassium carbonate (1.53 g, 11 mmols) and N,N-dimethylformamide (20 ml) was stirred at 60° C. for 24 hours. The reaction mixture was cooled, then poured into water, and extracted with ethyl acetate. The extract was washed with water, and then dried with anhydrous magnesium sulfate, and the solvent was evaporated away. The residue was purified through silica gel column chromatography to give an oil of 2-tert-butoxycarbonyl-5-(5-chloro-2-nitrophenoxy)-1,2,3,4-tetrahydroisoquinoline (4.35 g, 97.7%).