Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][CH2:2]1.NC1C=CC=CC=1S.C=O.[CH3:20][O:21][C:22]1[C:30]([C:31]([F:34])([F:33])[F:32])=[CH:29][C:25]([C:26](Cl)=[O:27])=[CH:24][C:23]=1[C:35]([N:37]1[CH2:41][CH2:40][CH2:39][CH2:38]1)=[O:36]>C(Cl)(Cl)Cl.C(N(CC)CC)C>[CH3:20][O:21][C:22]1[C:30]([C:31]([F:34])([F:33])[F:32])=[CH:29][C:25]([C:26]([N:3]2[C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[S:1][CH2:2]2)=[O:27])=[CH:24][C:23]=1[C:35]([N:37]1[CH2:41][CH2:40][CH2:39][CH2:38]1)=[O:36]
Reactant: COc1c(C(=O)N2CCCC2)cc(C(=O)Cl)cc1C(F)(F)F
Reactant: c1ccc2c(c1)NCS2
Agent: C=O
Agent: Nc1ccccc1S
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: COc1c(C(=O)N2CCCC2)cc(C(=O)N2CSc3ccccc32)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2,3-dihydro-1,3-benzothiazole synthesized from 2-aminobenzenethiol (464 mg) and 37% formalin (0.31 mL) in the same manner as in Example 1 was dissolved in chloroform (10 mL), and triethylamine (1.03 mL) and 4-methoxy-3-(pyrrolidine-1-carbonyl)-5-trifluoromethylbenzoyl chloride were added to the solution, and then the mixture was stirred at room temperature for 2 hours. The solvent was distilled off under reduced pressure and water was added, and then the mixture was extracted with ethyl acetate. The organic layer was washed with 1N hydrochloric acid, 1N sodium hydroxide and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the obtained residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=1:2) to obtain the title compound (778 mg) as a pale yellow amorphous product.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:18])[N:9]([CH3:17])[CH2:10][C:11]3[N:12]([CH:13]=[N:14][C:15]=3I)[C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH3:19][CH:20]([OH:23])[C:21]#[CH:22]>C(NCC)C.C(Cl)CCl.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.[Cu]I>[Cl:1][C:2]1[C:7]2[C:8](=[O:18])[N:9]([CH3:17])[CH2:10][C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:22]#[C:21][CH:20]([OH:23])[CH3:19])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: C#CC(C)O
Reactant: CN1Cc2c(I)ncn2-c2cccc(Cl)c2C1=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: ClCCCl
Solvent: CCNCC
Product: CC(O)C#Cc1ncn2c1CN(C)C(=O)c1c(Cl)cccc1-2

Procedure:
7.47 g (20 mmol) of 7-chloro-4,5-dihydro-3-iodo-5-methyl-6H-imidazo[1,5-a][1,4]benzodiazepine-6-one were heated to boiling under reflux for 4 hours with 1.75 g (25 mmol) of 3-butyn-2-ol, 70 mg of bis-(triphenyl -phosphine)-palladium(II) dichloride and 10 mg of copper(I) iodide in 50 ml of diethylamine and 20 ml of ethylene chloride. After evaporation of the solvent the residue was taken up in methylene chloride and the resulting suspension was suction filtered. The material obtained was washed with methylene chloride and, after recrystallization from ethyl acetate, there was obtained 7-chloro -4,5-dihydro-3-(3-hydroxy-1-butynyl)-5-methyl-6H-imidazo -[1,5-a][1,4]benzodiazepin-6-one of melting point 251-252° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12](=[O:13])[CH:11]=[C:10]([CH3:14])[N:9]1[CH3:15].[N+:16]([O-])([OH:18])=[O:17].O.CC(OC)(C)C>C(O)(C(F)(F)F)=O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12](=[O:13])[C:11]([N+:16]([O-:18])=[O:17])=[C:10]([CH3:14])[N:9]1[CH3:15]
Reactant: O=[N+]([O-])O
Reactant: Cc1cc(=O)n(-c2ccccc2F)n1C
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: COC(C)(C)C
Product: Cc1c([N+](=O)[O-])c(=O)n(-c2ccccc2F)n1C
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
2-(2-Fluorophenyl)-1,5-dimethyl-1H-pyrazol-3(2H)-one (260 g, 1261 mmol) in TFA (1040 ml) was cooled to −10° C. and stirred for 30 mins. To the mixture was added fuming nitric acid (84 ml) dropwise and this was stirred for 15 mins under cooling then at RT for 1 hr. The resulting mixture was poured onto a mixture of ice (1500 ml), water (1000 ml) and TBME (2500 ml) and stirred until the ice melted, then at RT for 1 hr. The mixture was filtered, washed with water (200 ml) and TBME (1000 ml). The collected crystals were dried to give the title compound as red-brown crystals.
Reaction SMILES: [NH2:1][N:2]1[CH2:7][CH2:6][O:5][CH2:4][CH2:3]1.[CH3:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:16]=[C:17]([C:28](O)=[O:29])[N:18]([CH3:27])[C:19]=2[C:20]2[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=2)=[CH:11][CH:10]=1>>[N:2]1([NH:1][C:28]([C:17]2[N:18]([CH3:27])[C:19]([C:20]3[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=3)=[C:15]([C:12]3[CH:11]=[CH:10][C:9]([CH3:8])=[CH:14][CH:13]=3)[N:16]=2)=[O:29])[CH2:7][CH2:6][O:5][CH2:4][CH2:3]1
Reactant: NN1CCOCC1
Reactant: Cc1ccc(-c2nc(C(=O)O)n(C)c2-c2ccc(C)cc2)cc1
Product: Cc1ccc(-c2nc(C(=O)NN3CCOCC3)n(C)c2-c2ccc(C)cc2)cc1

Procedure:
Using essentially the same procedure as Example 9, Step B, but using 4-aminomorpholine (0.025 mL), 4,5-di-(4-methylphenyl)-1-methylimidazole-2-carboxylic acid (25 mg, 0.08 mmol) from Example 9, Step A was converted to the title compound.
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]1[CH:4]=[C:5]([CH:25]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:27]=1)[C:6]([N:8]1[CH2:24][CH2:23][C:11]2([N:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:14][NH:13][C:12]2=[O:22])[CH2:10][CH2:9]1)=[O:7].Cl.Cl[CH2:36][CH2:37][N:38]1[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]1>>[F:33][C:2]([F:1])([F:32])[C:3]1[CH:4]=[C:5]([CH:25]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:27]=1)[C:6]([N:8]1[CH2:9][CH2:10][C:11]2([N:15]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH2:14][N:13]([CH2:36][CH2:37][N:38]3[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]3)[C:12]2=[O:22])[CH2:23][CH2:24]1)=[O:7]
Reactant: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCC2(CC1)C(=O)NCN2c1ccccc1
Reactant: ClCCN1CCCCC1
Agent: Cl
Product: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCC2(CC1)C(=O)N(CCN1CCCCC1)CN2c1ccccc1

Procedure:
The title compound, MS: m/e=583.2 (M+H+), was prepared in accordance with the general method of example 4 from 8-(3,5-bis-trifluoromethyl-benzoyl)-1-phenyl-1,3,8-triaza-spiro[4.5]decan-4-one and 1-(2-chloroethyl)piperidine hydrochloride.
Reaction SMILES: [I:1][C:2]1[C:10]([NH2:11])=[C:9]([I:12])[CH:8]=[C:7]([I:13])[C:3]=1[C:4]([OH:6])=[O:5].C1(=O)[N:18]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24](Cl)=[O:25])C(=O)C2=CC=CC=C12>>[I:1][C:2]1[C:10]([NH:11][C:24](=[O:25])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][NH2:18])=[C:9]([I:12])[CH:8]=[C:7]([I:13])[C:3]=1[C:4]([OH:6])=[O:5]
Reactant: Nc1c(I)cc(I)c(C(=O)O)c1I
Reactant: O=C(Cl)CCCCCN1C(=O)c2ccccc2C1=O
Product: NCCCCCC(=O)Nc1c(I)cc(I)c(C(=O)O)c1I

Procedure:
The same procedure is used as for Compound I, using 2,4,6-triiodo-3-amino-benzoic acid as iodo starting material and ε-phthalimidocaproic acid chloride.
Reaction SMILES: [OH:1][C:2]1[CH:14]=[CH:13][C:5]([CH:6]=[CH:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:4][CH:3]=1.[O:15]1[CH:20]=[CH:19][CH2:18][CH2:17][CH2:16]1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[Na]>C(OCC)C>[O:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH:16]1[O:1][C:2]1[CH:3]=[CH:4][C:5]([CH:6]=[CH:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:13][CH:14]=1
Reactant: C1=COCCC1
Reactant: CCOC(=O)C=Cc1ccc(O)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na]
Solvent: CCOCC
Product: CCOC(=O)C=Cc1ccc(OC2CCCCO2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 30 ml of anhydrous diethyl ether solution containing 5 g of ethyl 4-hydroxycinnamate was added 7.1 ml of dihydropyran and 50 mg of p-toluenesulfonic acid were added, the mixture was stirred at room temperature for 2 hours. Then the reaction mixture was neutralized with 1%-sodium hydroxude solution, washed with water, and dried with anhydrous sodium sulfate. The solvent was removed by evaporation to yield 6.8 g of ethyl 4-(2-tetrahydropyranyloxy)cinnamate. Colorless indefinite form crystatls. Melting point: 52°-53° C.
Reaction SMILES: Cl[C:2]1[N:6]([CH2:7][CH3:8])[N:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].ClC(Cl)(Cl)C(Cl)(Cl)Cl>C1COCC1.[Cl-].[Na+].O>[CH2:7]([N:6]1[CH:2]=[C:3]([N+:9]([O-:11])=[O:10])[CH:4]=[N:5]1)[CH3:8]
Reactant: CCn1ncc([N+](=O)[O-])c1Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: O
Product: CCn1cc([N+](=O)[O-])cn1
Temperature: -78 °C
Reaction time: 2.5 h
Yield: 88.2 %

Procedure:
To a solution of 5-chloro-1-ethyl-4-nitro-1H pyrazole (1 equiv) in THF (0.6 M) was added dropwise a 1.0 M solution of lithium bis(trimethylsilyl)amide (2.6 equiv) at −78° C. The reaction mixture was stirred at −78° C. for 30 min before the addition of hexachloroethane (1.5 equiv) in THF (1.2 M). The mixture was stirred at −78° C. for 2.5 h then warmed to room temperature. The reaction was diluted with brine (1.8 M) and extracted with ethyl acetate. The combined extracts were washed with brine, dried over sodium sulfate, filtered and concentrated. The crude product was purified by silica gel chromatography (10-15% ethyl acetate in petroleum ether) to afford the desired product as a white solid (88.2% yield). MS (ESI) m/z 176.0 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:4][C:3]=1[OH:16].[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([N:24]=[C:25]=[O:26])=[CH:20][C:19]=1[C:27]([F:30])([F:29])[F:28]>C1COCC1.O>[CH2:9]([O:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:25]([NH:24][C:21]2[CH:22]=[CH:23][C:18]([Cl:17])=[C:19]([C:27]([F:29])([F:28])[F:30])[CH:20]=2)=[O:26])=[C:3]([OH:16])[CH:4]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=C=Nc1ccc(Cl)c(C(F)(F)F)c1
Reactant: Nc1ccc(OCc2ccccc2)cc1O
Solvent: O
Solvent: C1CCOC1
Product: O=C(Nc1ccc(Cl)c(C(F)(F)F)c1)Nc1ccc(OCc2ccccc2)cc1O
Reaction time: 1.25 h

Procedure:
To a solution of 1.00 g (4.6 mMol) 2-amino-5-benzyloxy-phenol [preparation see: WO 03/045925; page 146] in 15 ml THF, a solution of 1.1 g (5.0 mMol) 4-chloro-3-trifluoromethyl-phenylisocyanate in 15 ml THF is added dropwise. After 75 min at rt, the reaction mixture is diluted in water and EtOAc, the aq. phase separated off and extracted twice with EtOAc. The organic layers are washed with water and brine, dried (Na2SO4) and concentrated. Trituration from hexane gives the crystalline title compound: m.p.: 182-184° C.; HPLC: tRet=17.5.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[N:9][C:8]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[C:7]2[C:18]1[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=1.[CH3:25][O:26][C:27](=[O:39])[C:28]([C:31]1[CH:36]=[CH:35][C:34]([CH:37]=O)=[CH:33][CH:32]=1)([CH3:30])[CH3:29]>>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[N:9][C:8]([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)=[C:7]2[C:18]1[CH:19]=[C:20]([NH:24][CH2:37][C:34]2[CH:33]=[CH:32][C:31]([C:28]([CH3:30])([CH3:29])[C:27]([O:26][CH3:25])=[O:39])=[CH:36][CH:35]=2)[CH:21]=[CH:22][CH:23]=1
Reactant: COC(=O)C(C)(C)c1ccc(C=O)cc1
Reactant: Nc1cccc(-c2c(-c3ccccc3)nnc3c(Cl)cccc23)c1
Product: COC(=O)C(C)(C)c1ccc(CNc2cccc(-c3c(-c4ccccc4)nnc4c(Cl)cccc34)c2)cc1

Procedure:
The title compound was prepared from 3-(8-chloro-3-phenyl-cinnolin-4-yl)-phenylamine and 2-(4-formyl-phenyl)-2-methyl-propionic acid methyl ester according to the procedure of Step 5 Example 6. MS (ES) m/z 522.2.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:5]=[C:4]([C:13]([CH3:17])([CH3:16])[C:14]#[N:15])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl[C:25]([O:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:26]>C(Cl)Cl>[C:14]([C:13]([C:4]1[CH:3]=[C:2]([NH:1][C:25](=[O:26])[O:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:5]=1)([CH3:17])[CH3:16])#[N:15]
Reactant: CC(C)(C#N)c1cc(N)n(-c2ccccc2)n1
Reactant: O=C(Cl)Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: CC(C)(C#N)c1cc(NC(=O)Oc2ccccc2)n(-c2ccccc2)n1
Yield: 76.1 %

Procedure:
Using the procedure described in Example 306A, to a solution of 2-(5-amino-1-phenyl-1H-pyrazol-3-yl)-2-methylpropanenitrile (451 mg, 2 mmol) and potassium carbonate (359 mg, 2.6 mmol) in anhydrous DCM (4 ml) was added dropwise phenyl chloroformate (0.28 ml, 2.2 mmol) as a solution in DCM (2 ml) to afford phenyl 3-(2-cyanopropan-2-yl)-1-phenyl-1H-pyrazol-5-ylcarbamate (527 mg, 76%). 1H NMR (300 MHz, CDCl3) δ 1.74 (s, 6H), 6.66 (s, 1H), 7.05-7.60 (m, 11H); LC-MS (ESI) m/z 347 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[OH:11].C1(=O)O[CH2:15][CH2:14][O:13]1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1>[CH3:10][O:9][C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[C:4]=1[O:11][CH:14]([OH:13])[CH3:15]
Reactant: COc1cccc(OC)c1O
Reactant: O=C1OCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: COc1cccc(OC)c1OC(C)O
Yield: 100.7 %

Procedure:
A mixture of 6.0 g of 2,6-dimethoxyphenol, 6.8 g of ethylene carbonate and 5.4 g of potassium carbonate in 40 ml of toluene was refluxed for 17 hours. After cooling, toluene solution was separated, dried (Na2SO4) and solvent was evaporated. 7.77 g of desired compound was obtained.
Reaction SMILES: [OH-].[Na+].[C:3]([CH2:6][C:7](=[O:9])[CH3:8])(=[O:5])[CH3:4].[CH2:10](Br)[CH:11]=[CH2:12]>CO>[CH2:12]([CH:6]([C:7](=[O:9])[CH3:8])[C:3](=[O:5])[CH3:4])[CH:11]=[CH2:10]
Reactant: C=CCBr
Reactant: CC(=O)CC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: C=CCC(C(C)=O)C(C)=O
Temperature: 0 °C
Yield: 48 %

Procedure:
NaOH (4.51 g, 113 mmol) was dissolved in anhydrous MeOH. After cooling the mixture to 0° C. using an ice-bath, acetylacetone (10.0 g, 99.8 mmol) was added while stirring over a period of several minutes. Allyl bromide (10.4 mL, 123 mmol) was then added without cooling over a period of 10 min. After addition was complete, the reaction mixture was refluxed for an additional 2 h. The mixture was cooled and filtered to remove excess NaBr. MeOH and the excess allyl bromide were removed by distillation. The product, 5, was isolated as a yellow oil, 6.72 g (48% yield), between 81-87° C.
Reaction SMILES: Cl.[C:2]([O:6][C:7](=[O:14])[C@H:8]([CH2:10][CH:11]([CH3:13])[CH3:12])[NH2:9])([CH3:5])([CH3:4])[CH3:3].C(N(C(C)C)CC)(C)C.[CH2:24]([C:28]1[CH:33]=[C:32](Cl)[N:31]=[C:30]([N:35]2[CH:39]=[C:38]([C:40]3[CH:45]=[CH:44][C:43]([O:46][C:47]([F:50])([F:49])[F:48])=[CH:42][CH:41]=3)[N:37]=[CH:36]2)[N:29]=1)[CH2:25][CH2:26][CH3:27]>CS(C)=O>[C:2]([O:6][C:7](=[O:14])[CH:8]([NH:9][C:32]1[CH:33]=[C:28]([CH2:24][CH2:25][CH2:26][CH3:27])[N:29]=[C:30]([N:35]2[CH:39]=[C:38]([C:40]3[CH:45]=[CH:44][C:43]([O:46][C:47]([F:48])([F:49])[F:50])=[CH:42][CH:41]=3)[N:37]=[CH:36]2)[N:31]=1)[CH2:10][CH:11]([CH3:12])[CH3:13])([CH3:5])([CH3:4])[CH3:3]
Reactant: CC(C)C[C@H](N)C(=O)OC(C)(C)C
Reactant: CCCCc1cc(Cl)nc(-n2cnc(-c3ccc(OC(F)(F)F)cc3)c2)n1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CCCCc1cc(NC(CC(C)C)C(=O)OC(C)(C)C)nc(-n2cnc(-c3ccc(OC(F)(F)F)cc3)c2)n1
Temperature: 80 °C
Yield: 84.9 %

Procedure:
L-Leucine tert-butyl ester hydrochloride (291 mg) was dissolved in DMSO (5 mL) under an argon atmosphere and treated with diisopropylethylamine (450 μL, 2.6 mmol, 4 eq.) followed by 4-Butyl-6-chloro-2-[4-(4-trifluoromethoxy-phenyl)-imidazol-1-yl]-pyrimidine (274 mg). The mixture was heated to 80° C. for 48 h. DMSO and the volatiles were removed in vacuo to give a crude residue from which 2-{6-butyl-2-[4-(4-trifluoromethoxyphenyl) imidazol-1-yl] pyrimidin-4-ylamino}-4-methyl-pentanoic acid tert-butyl ester (321 mg) was isolated by flash chromatography (n-hexanes/ethyl acetate 4/1).
Reaction SMILES: [F:1][C:2]1[CH:38]=[CH:37][C:5]([CH2:6][C@@H:7]2[CH2:12][CH2:11][CH2:10][N:9]([C:13]([C@H:15]3[C@H:20]([NH:21][C:22]([NH:24][C:25]4[CH:30]=[CH:29][CH:28]=[C:27]([C:31]5[N:35]([CH3:36])[N:34]=[N:33][N:32]=5)[CH:26]=4)=[O:23])[CH2:19][CH2:18][NH:17][CH2:16]3)=[O:14])[CH2:8]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:46][S:47](Cl)(=[O:49])=[O:48]>ClCCl>[F:1][C:2]1[CH:38]=[CH:37][C:5]([CH2:6][C@@H:7]2[CH2:12][CH2:11][CH2:10][N:9]([C:13]([C@H:15]3[C@H:20]([NH:21][C:22]([NH:24][C:25]4[CH:30]=[CH:29][CH:28]=[C:27]([C:31]5[N:35]([CH3:36])[N:34]=[N:33][N:32]=5)[CH:26]=4)=[O:23])[CH2:19][CH2:18][N:17]([S:47]([CH3:46])(=[O:49])=[O:48])[CH2:16]3)=[O:14])[CH2:8]2)=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)Cl
Reactant: Cn1nnnc1-c1cccc(NC(=O)N[C@@H]2CCNC[C@H]2C(=O)N2CCC[C@@H](Cc3ccc(F)cc3)C2)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cn1nnnc1-c1cccc(NC(=O)N[C@@H]2CCN(S(C)(=O)=O)C[C@H]2C(=O)N2CCC[C@@H](Cc3ccc(F)cc3)C2)c1
Reaction time: 0.42 h
Yield: 57.7 %

Procedure:
In a dry flask 1-{(3R,4R)-3-[(S)-3-(4-fluoro-benzyl)-piperidine-1-carbonyl]-piperidin-4-yl}-3-[3-(1-methyl-1H-tetrazol-5-yl)-phenyl]-urea (67 mg, 0.11 mmol) was dissolved in dichloromethane (2 mL), and then triethylamine (65 ·L, 0.47 mmol) and methanesulfonyl chloride (9 μL, 0.11 mmol) were added. The reaction mixture was stirred for 25 minutes. The reaction mixture was concentrated in vacuo then was purified by preparative reverse-phase HPLC (10-80% acetonitrile in water with 0.05% trifluoroacetic acid) to give a white amorphous solid (38 mg, 60%). 1H NMR NMR (400 MHz, DMSO-d6, 140° C.), δ: 8.37 (s, 1H), 7.89 (t, 1H, J=2), 7.54 (d, 1H, J=6), 7.44(t, 1H, J=8), 7.35 (m, 1H), 7.14 (m, 2H), 6.99 (t, 2H, J=9), 6.05 (d, 1H, J=8), 4.12 (s, 3H), 4.05 (d, 2H, J=14), 3.85 (m, 1H), 3.63 (m, 2H), 3.16 (td, 1H, J=10, J′=4), 2.90 (m, 3H), 2.88 (s, 3H), 2.66 (m, 1H), 2.56 (dd, 1H, J=14, J′=6), 2.44 (dd, 1H, J=14, J′=8), 2.01 (m, 1H), 1.79 (qd, 1H, J=13, J′=4), 1.65 (bs, 3H), 1.40 (m, 1H), 1.20 (m, 1H). HRMS (ESI), C28H36FN8O4S m+/z: calc. 599.2564, found=599.2586.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[N:11]([S:12]([C:15]3[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[CH:10]=[CH:9][C:5]2=[N+:6]([O-])[CH:7]=1.[CH3:22][N:23](C)C(Cl)=O.C[Si](C#N)(C)C>ClCCCl>[Cl:1][C:2]1[CH:3]=[C:4]2[N:11]([S:12]([C:15]3[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[CH:10]=[CH:9][C:5]2=[N:6][C:7]=1[C:22]#[N:23]
Reactant: CN(C)C(=O)Cl
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c2cc(Cl)c[n+]3[O-])cc1
Agent: C[Si](C)(C)C#N
Solvent: ClCCCl
Product: Cc1ccc(S(=O)(=O)n2ccc3nc(C#N)c(Cl)cc32)cc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 53.3 %

Procedure:
To a solution of 6-chloro-1-tosyl-1H-pyrrolo[3,2-b]pyridine-4-oxide (8.75 g, 27.12 mmol) in 1,2-dichloroethane (250 mL) was added dimethylcarbamic chloride (4.37 g, 40.66 mmol) and trimethylsilyl cyanide (4.03 g, 40.66 mmol) successively. The mixture was stirred under nitrogen at 80° C. overnight. The reaction mixture was quenched by adding sat'd. aq. NaHCO3 solution. The organic layer was washed with water (50 mL×3), dried (Na2SO4), filtered, and concentrated in vacuo. The crude product was purified by SiO2 chromatography eluting with petroleum ether EtOAc (8:1) to afford 4.8 g (53%) of 6-chloro-1-tosyl-1H-pyrrolo[3,2-b]pyridine-5-carbonitrile as a white solid. MS (ESI): m/z=332.0 [M+1]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:25]([F:28])([F:27])[F:26])=[C:6]([CH:24]=1)[C:7]([N:9]1[CH2:14][CH2:13][N:12]([C:15]2[CH:23]=[CH:22][C:18]([C:19](O)=O)=[CH:17][N:16]=2)[CH2:11][CH2:10]1)=[O:8].[NH2:29][CH2:30][CH:31]([NH2:35])[CH2:32][CH2:33][CH3:34]>O=P(Cl)(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:25]([F:28])([F:27])[F:26])=[C:6]([C:7]([N:9]2[CH2:14][CH2:13][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19]4[NH:35][CH:31]([CH2:32][CH2:33][CH3:34])[CH2:30][N:29]=4)=[CH:17][N:16]=3)[CH2:11][CH2:10]2)=[O:8])[CH:24]=1
Reactant: O=C(O)c1ccc(N2CCN(C(=O)c3cc(F)ccc3C(F)(F)F)CC2)nc1
Reactant: CCCC(N)CN
Solvent: O=P(Cl)(Cl)Cl
Product: CCCC1CN=C(c2ccc(N3CCN(C(=O)c4cc(F)ccc4C(F)(F)F)CC3)nc2)N1
Temperature: 25 °C
Yield: 9 %

Procedure:
To a stirred solution of 6-[4-(5-fluoro-2-trifluoromethylbenzoyl)piperazin-1-yl]nicotinic acid (0.509 g, 1.281 mmol) in POCl3(10 mL) was added dropwise 1,2-diaminopentane (3.50 g, 34.0 mmol). The resulting mixture was stirred at reflux for 16 h and then allowed to cool to ambient temperature and concentrated. The residue was taken up in saturated NaHCO3 and extracted with dichloromethane. The combined organic layers were dried over Na2SO4 and concentrated. The crude product was purified by chromatography to afford the title compound in 9% yield (0.052 g). 1H NMR (300 MHz, CDCl3) δ 9.09 (d, J=2.2 Hz, 1H), 8.56 (dd, J=2.2, 9.2 Hz, 1H), 7.74 (dd, J=5.1, 8.8 Hz, 1H), 7.22 (d, J=7.8 Hz, 1H), 7.10 (dd, J=2.4, 8.0 Hz, 1H), 6.65 (d, J=9.2 Hz, 1H), 4.32-3.49 (m, 9H), 1.92-0.75 (m, 9H). MS (ES+) m/z 464 (M+1).
Reaction SMILES: [CH3:1][CH:2](/[CH:4]=[CH:5]/[CH2:6][CH2:7][CH2:8][CH2:9][C:10]([NH:12][CH2:13][C:14]1[CH:15]=[CH:16][C:17]([OH:22])=[C:18]([O:20][CH3:21])[CH:19]=1)=[O:11])[CH3:3].C([O-])([O-])=O.[K+].[K+].[I-].[Na+].P(O)([O-])([O-])=O.[Na+].[Na+].Cl[CH2:39][C:40]([O:42][CH3:43])=[O:41]>CC(C)=O>[CH3:43][O:42][C:40](=[O:41])[CH2:39][O:22][C:17]1[CH:16]=[CH:15][C:14]([CH2:13][NH:12][C:10](=[O:11])[CH2:9][CH2:8][CH2:7][CH2:6][CH:5]=[CH:4][CH:2]([CH3:1])[CH3:3])=[CH:19][C:18]=1[O:20][CH3:21]
Reactant: COc1cc(CNC(=O)CCCC/C=C/C(C)C)ccc1O
Reactant: COC(=O)CCl
Agent: O=C([O-])[O-]
Agent: O=P([O-])([O-])O
Agent: [I-]
Solvent: CC(C)=O
Product: COC(=O)COc1ccc(CNC(=O)CCCCC=CC(C)C)cc1OC
Yield: 71.3 %

Procedure:
To a mixture of Capsaicin (17 g, 55.7 mmol), anhydrous K2CO3 (26 g, 188 mmol), sodium iodide (4.5 g, 30 mmol) and disodium phosphate (4.5 g, 32 mmol) in anhydrous acetone (425 ml) was added methyl chloroacetate (9 g, 83 mmol) and refluxed for 6 hours. Acetone was distilled off and water (150 ml) was added. Crude 10 was filtered, dried and recrystallised from toluene to give pure 10 (15 g, 71.4%) as a white power. The melting point was found to be 99.5-103.5° C. It was analyzed by HPLC and found to be 99.3% pure.
Reaction SMILES: [CH2:1]([N:3]([CH2:48]C)[C:4]([C:6]1[CH:11]=[C:10]([C:12]2[CH:13]=[N:14][N:15]([CH2:17][CH2:18][CH2:19][OH:20])[CH:16]=2)[CH:9]=[CH:8][C:7]=1[NH:21][C:22]1[C:27]([C:28]([F:31])([F:30])[F:29])=[CH:26][N:25]=[C:24]([NH:32][C:33]2[CH:45]=[CH:44][C:36]([CH2:37][P:38](=[O:43])([OH:42])[O:39][CH2:40][CH3:41])=[CH:35][C:34]=2[O:46][CH3:47])[N:23]=1)=[O:5])C.CN(C)C(C1C=C(C2C=NN(CCCO)C=2)C=CC=1NC1C(C(F)(F)F)=CN=C(NC2C=CC(CP(=O)(OCC)OCC)=CC=2OC)N=1)=O>>[CH3:48][N:3]([CH3:1])[C:4]([C:6]1[CH:11]=[C:10]([C:12]2[CH:13]=[N:14][N:15]([CH2:17][CH2:18][CH2:19][OH:20])[CH:16]=2)[CH:9]=[CH:8][C:7]=1[NH:21][C:22]1[C:27]([C:28]([F:29])([F:30])[F:31])=[CH:26][N:25]=[C:24]([NH:32][C:33]2[CH:45]=[CH:44][C:36]([CH2:37][P:38](=[O:42])([OH:43])[O:39][CH2:40][CH3:41])=[CH:35][C:34]=2[O:46][CH3:47])[N:23]=1)=[O:5]
Reactant: CCOP(=O)(O)Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(-c4cnn(CCCO)c4)cc3C(=O)N(CC)CC)n2)c(OC)c1
Agent: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(-c4cnn(CCCO)c4)cc3C(=O)N(C)C)n2)c(OC)c1)OCC
Product: CCOP(=O)(O)Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(-c4cnn(CCCO)c4)cc3C(=O)N(C)C)n2)c(OC)c1
Yield: 56 %

Procedure:
Prepared analogously to Compound 3A using diethyl (4-{[4-({2-(dimethylcarbamoyl)-4-[1-(3-hydroxypropyl)-1H-pyrazol-4-yl]phenyl}amino)-5-(trifluoromethyl)pyrimidin-2-yl]amino}-3-methoxybenzyl)phosphonate (Compound 12B, 72 mg, 102 μmol) to afford 39 mg of the title compound (56%). 1H NMR (400 MHz, CD3OD) δ 8.26 (s, 1H), 8.18 (s, 1H), 7.93 (s, 1H), 7.79-7.86 (m, 1H), 7.70-7.79 (m, 2H), 7.59 (d, J=2.0 Hz, 1H), 7.01 (s, 1H), 6.61 (br. s., 1H), 4.32 (t, J=6.8 Hz, 2H), 3.88 (s, 3H), 3.76 (quin, J=6.9 Hz, 2H), 3.59 (t, J=6.1 Hz, 2H), 3.04 (s, 3H), 2.90 (d, J=3.8 Hz, 4H), 2.85 (s, 1H), 2.04-2.17 (m, 2H), 1.11 (t, J=7.1 Hz, 3H). MS (ESI): m/z 678.70 [M+H]+. UPLC: tR=0.95 min (UPLC-SQD: analytical—2 min).