Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I-].C[S+](C)(C)=O.[CH3:7]C([O-])(C)C.[K+].[CH3:13][O:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[C:16]=1[C:23](=[CH2:29])[C:24]([O:26][CH2:27][CH3:28])=[O:25].O>CS(C)=O>[CH3:22][O:21][C:17]1[CH:18]=[CH:19][CH:20]=[C:15]([O:14][CH3:13])[C:16]=1[C:23]1([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:7][CH2:29]1
Reactant: CC(C)(C)[O-]
Reactant: C=C(C(=O)OCC)c1c(OC)cccc1OC
Agent: C[S+](C)(C)=O
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CCOC(=O)C1(c2c(OC)cccc2OC)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 69.7 %

Procedure:
To trimethylsulfoxonium iodide (32 g, 1.2 equiv) in DMSO (250 ml) was added ground KOt-Bu (17.62 g, 1.3 equiv) and this mixture was stirred at r.t. for 30 min. A solution of the styrene 17 (28.53 g, 121 mmol) in DMSO (55 ml) was then added and this mixture was stirred at r.t. for 3 h. The reaction was poured into water (1.0 L) mixed with sat. NHCl (350 ml). The product was extracted into hexane (2×300 ml) and this solution was washed with water and brine, dried over Na2SO4 and filtered through silica (400 ml). The product was then eluted with EtOAc/hexane 15 and 20% to yield 18 (21.1 g, 70%) as a colorless oil.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:11]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:13]=1)[C:7](OC)=[O:8])([O-:3])=[O:2].O.[NH2:19][NH2:20]>CO>[N+:1]([C:4]1[CH:5]=[C:6]([CH:11]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:13]=1)[C:7]([NH:19][NH2:20])=[O:8])([O-:3])=[O:2]
Reactant: COC(=O)c1cc([N+](=O)[O-])cc(C(F)(F)F)c1
Reactant: NN
Solvent: CO
Solvent: O
Product: NNC(=O)c1cc([N+](=O)[O-])cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 90.3 %

Procedure:
A mixture of methyl 3-nitro-5-(trifluoromethyl)benzoate (20 g, 80 mmol) and hydrazine hydrate (5.56 mL, 96 mmol) in MeOH (100 mL) was stirred for 16 h at 25° C. Then the solvent was concentrated to yield an off white solid of 3-nitro-5-(trifluoromethyl)benzohydrazide (20 g, 72.2 mmol, 90% yield): 1H NMR (400 MHz, CD3OD) δ 8.89 (s, 1H), 8.65 (s, 1H), 8.50 (s, 1H); ES-LCMS m/z 250 (M+H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])=[CH:4][CH:3]=1.[CH2:14]([N:26]([CH2:28][CH2:29][CH2:30]O)[CH3:27])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]>>[CH2:14]([N:26]([CH2:28][CH2:29][CH2:30][O:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])=[CH:6][CH:7]=1)[CH3:27])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: COC(=O)CCc1ccc(O)cc1
Reactant: CCCCCCCCCCCCN(C)CCCO
Product: CCCCCCCCCCCCN(C)CCCOc1ccc(CCC(=O)OC)cc1
Yield: 68 %

Procedure:
Methyl 3-(4-hydroxyphenyl)propanoate (1.0 g, 5.5 mmol) and 3-(N-dodecyl-N-methylamino)propanol (1.43 g, 5.5 mmol) were reacted as described in example 1 to give 1.57 g (43%) of title material as an oil.
Reaction SMILES: [OH:1][CH2:2][C:3]1[S:4][CH:5]=[C:6]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:7]=1.N1C=CC=CC=1.Cl[C:20]([O:22][CH2:23][C:24]([Cl:27])([Cl:26])[Cl:25])=[O:21]>C(Cl)Cl>[Cl:25][C:24]([Cl:27])([Cl:26])[CH2:23][O:22][C:20]([O:1][CH2:2][C:3]1[S:4][CH:5]=[C:6]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:7]=1)=[O:21]
Reactant: CCOC(=O)c1csc(CO)n1
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)c1csc(COC(=O)OCC(Cl)(Cl)Cl)n1
Reaction time: 0.5 h
Yield: 47.1 %

Procedure:
To a solution of ethyl 2-(hydroxymethyl)-thiazole-4-carboxylate 33 (38.4 g) and pyridine (41 mL) in 100 mL of CH2Cl2 is slowly added 2,2,2-trichloroethyl chloroformate (32 mL, 0.23 mol) at 0° C. After the resulting mixture is stirred for 30 minutes, the reaction is quenched by the addition of 10% aq NaHCO3. The organic layer is separated, and the aqueous layer is extracted with CH2Cl2. The combined organic extracts are washed with 2 N HCl, 10% aq NaHCO3, and brine, dried (Na2SO4), and concentrated. The residue is then recrystallized in ethanol (50 mL) to yield a light yellow solid (35 g). The mother liquor is concentrated and chromatographed to afford an additional amount (35 g) of product.
Reaction SMILES: C(O[N:6]1[CH2:11][CH2:10][CH:9]([O:12][C:13]2[CH:30]=[C:29]([N:31]([CH3:33])[CH3:32])[CH:28]=[CH:27][C:14]=2[C:15]([NH:17][C:18]2[C:19]([C:23]([O:25][CH3:26])=[O:24])=[CH:20][S:21][CH:22]=2)=[O:16])[CH2:8][C:7]1=C=O)(C)(C)C.[C:36]([O:40][C:41](N1CCC(OC2C=C(N(C)C)C=CC=2C(O)=O)CC1)=[O:42])([CH3:39])([CH3:38])[CH3:37].NC1C(C(OC)=O)=CSC=1>>[C:36]([O:40][C:41]([N:6]1[CH2:7][CH2:8][CH:9]([O:12][C:13]2[CH:30]=[C:29]([N:31]([CH3:33])[CH3:32])[CH:28]=[CH:27][C:14]=2[C:15]([NH:17][C:18]2[C:19]([C:23]([O:25][CH3:26])=[O:24])=[CH:20][S:21][CH:22]=2)=[O:16])[CH2:10][CH2:11]1)=[O:42])([CH3:39])([CH3:38])[CH3:37]
Reactant: COC(=O)c1cscc1NC(=O)c1ccc(N(C)C)cc1OC1CCN(OC(C)(C)C)C(=C=O)C1
Reactant: CN(C)c1ccc(C(=O)O)c(OC2CCN(C(=O)OC(C)(C)C)CC2)c1
Agent: COC(=O)c1cscc1N
Product: COC(=O)c1cscc1NC(=O)c1ccc(N(C)C)cc1OC1CCN(C(=O)OC(C)(C)C)CC1
Yield: 51 %

Procedure:
Using methods substantially equivalent to those described in Example 12-C, methyl 4-[2-(1-tert-butoxy-carbonylpiperidin-4-yloxy)-4-(dimethylamino)benzoylamino]-thiophene-3-carboxylate was prepared in a 51% yield from 2-(1-tert-butoxycarbonylpiperidin-4-yloxy)-4-(dimethyl-amino)benzoic acid and methyl 4-aminothiophene-3-carboxylate.
Reaction SMILES: [Cl:1][C:2]1[C:9]([C:10]#[C:11][Si](C)(C)C)=[C:8](F)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[NH2:17][CH:18]([CH2:23][CH3:24])[C:19]([CH3:22])([OH:21])[CH3:20].C([O-])([O-])=O.[K+].[K+].CN1C(=O)CCC1>O>[Cl:1][C:2]1[C:3]([C:4]#[N:5])=[CH:6][CH:7]=[C:8]2[C:9]=1[CH:10]=[CH:11][N:17]2[CH:18]([CH2:23][CH3:24])[C:19]([OH:21])([CH3:22])[CH3:20]
Reactant: C[Si](C)(C)C#Cc1c(F)ccc(C#N)c1Cl
Reactant: CCC(N)C(C)(C)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN1CCCC1=O
Product: CCC(n1ccc2c(Cl)c(C#N)ccc21)C(C)(C)O
Temperature: 60 °C
Reaction time: 18 h
Yield: 42.5 %

Procedure:
A mixture of 2-chloro-4-fluoro-3-((trimethylsilyl)ethynyl)benzonitrile (Example 32B) (0.163 g, 0.647 mmol), 3-amino-2-methylpentan-2-ol (0.091 g, 0.776 mmol), and K2CO3 (0.179 g, 1.294 mmol) in anhyd NMP (3 mL) was stirred in a heating block at 60° C. under N2. After 18 h, the mixture was subjected to microwave heating (140° C.) for 15 min. Upon cooling the mixture was poured into water and extracted with EtOAc (×3). Combined organics were washed (water, brine), dried over Na2SO4 and concentrated in vacuo. The residue was purified by low pressure liquid chromatography (silica gel, EtOAc/hexanes, gradient elution) affording 4-chloro-1-(2-hydroxy-2-methylpentan-3-yl)-1H-indole-5-carbonitrile (0.0761 g, 43% yield) as a yellow gum: 1H NMR (400 MHz, CDCl3) δ 7.48 (d, J=2.2 Hz, 1H), 7.42 (d, J=8.6 Hz, 1H), 7.35 (d, J=8.7 Hz, 1H), 6.77 (d, J=3.3 Hz, 1H), 4.07 (dd, J=11.6, 3.6 Hz, 1H), 2.09 (m, J=3.6 Hz, 2H), 1.44 (s, 1H), 1.35 (s, 3H), 1.08 (s, 3H), 0.65 (t, J=7.3 Hz, 3H); MS (LCMS ES+) m/z 277 ([M+H]+, 70%), 318 ({[M+H]+MeCN}+, 100%).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH:7]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][O:9]2)=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].CS(O[CH2:30][CH2:31][C:32]1[N:33]=[C:34]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[O:35][C:36]=1[CH3:37])(=O)=O>CC#N.C(OCC)C>[C:15]([O:14][C:12]([CH:7]1[CH2:6][C:5]2[C:10](=[CH:11][C:2]([O:1][CH2:30][CH2:31][C:32]3[N:33]=[C:34]([C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=4)[O:35][C:36]=3[CH3:37])=[CH:3][CH:4]=2)[O:9][CH2:8]1)=[O:13])([CH3:18])([CH3:17])[CH3:16]
Reactant: Cc1oc(-c2ccccc2)nc1CCOS(C)(=O)=O
Reactant: CC(C)(C)OC(=O)C1COc2cc(O)ccc2C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CC#N
Product: Cc1oc(-c2ccccc2)nc1CCOc1ccc2c(c1)OCC(C(=O)OC(C)(C)C)C2
Temperature: 25 °C

Procedure:
To a stirred solution of tert-butyl 7-hydroxychromane-3-carboxylate (2.5 g, 10 mmol) in CH3CN (20 ml), K2CO3 (4.1 g) and 2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethyl methanesulfonate (3.7 g) were added and the reaction mixture was heated under reflux for overnight. The reaction mixture was cooled to room temperature and diluted with 100 ml of diethyl ether. The diluted solution was passed through a pad of silica and the silica was washed with more ether. The ether solution was evaporated to dryness and purified using silica chromatography. The product was isolated as a white sold (2.8 g, 64.3%).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[CH:12]=[N:13][N:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][N:18]=3)[C:15]=2[CH3:16])=[O:10])=[CH:4][C:3]=1[C:27]#[N:28].CC1(C)C(C)(C)OB([C:37]2[CH2:42][CH2:41][CH:40]([N:43]3[CH2:48][CH2:47][O:46][CH2:45][CH2:44]3)[CH2:39][CH:38]=2)O1>O1CCCC1.C(=O)([O-])[O-].[Na+].[Na+].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:27]([C:3]1[CH:4]=[C:5]([NH:8][C:9]([C:11]2[CH:12]=[N:13][N:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:24])[F:25])=[CH:19][N:18]=3)[C:15]=2[CH3:16])=[O:10])[CH:6]=[N:7][C:2]=1[C:37]1[CH2:42][CH2:41][CH:40]([N:43]2[CH2:44][CH2:45][O:46][CH2:47][CH2:48]2)[CH2:39][CH:38]=1)#[N:28]
Reactant: CC1(C)OB(C2=CCC(N3CCOCC3)CC2)OC1(C)C
Reactant: Cc1c(C(=O)Nc2cnc(Cl)c(C#N)c2)cnn1-c1ccc(C(F)(F)F)cn1
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: C1CCOC1
Product: Cc1c(C(=O)Nc2cnc(C3=CCC(N4CCOCC4)CC3)c(C#N)c2)cnn1-c1ccc(C(F)(F)F)cn1
Temperature: 90 °C
Yield: 54.1 %

Procedure:
N-(6-Chloro-5-cyanopyridin-3-yl)-5-methyl-1-[5-(trifluoromethyl)pyridin-2-yl]-1H-pyrazole-4-carboxamide (200 mg), 4-[4-(4,4,5,5-tetramethyl-[1,3,2] dioxaborolan-2-yl)cyclohex-3-en-1-yl]morpholine (159 mg) described in Reference Example 166 and tetrakis(triphenylphosphine)palladium (57 mg) were dissolved in a mixture of tetrahydrofuran (1 ml) and 1M aqueous solution of sodium carbonate (0.54 ml), and stirred at 90° C. After completion of the reaction, the reaction solution was left stand, filtered through Celite, washed with chloroform and the filtrate was concentrated. Water was added to the resulting residue and the precipitate was filtered. The obtained solid was refluxed in ethanol, the resulting solution was left stand, the precipitated solid was collected by filtration and dried in vacuo to give the titled compound (143 mg) as a pale yellow solid.
Reaction SMILES: [NH:1]([C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10])[C@H:2]([C:6]([OH:8])=O)[CH:3]([CH3:5])[CH3:4].[NH2:19][C@H:20]([C:24]([N:26]([CH3:42])[C@H:27]([C:31]([N:33]1[CH2:41][CH2:40][CH2:39][C@H:34]1[C:35]([O:37][CH3:38])=[O:36])=[O:32])[CH:28]([CH3:30])[CH3:29])=[O:25])[CH:21]([CH3:23])[CH3:22].CN1CCOCC1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>ClCCl>[NH:1]([C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10])[C@H:2]([C:6]([NH:19][C@H:20]([C:24]([N:26]([CH3:42])[C@H:27]([C:31]([N:33]1[CH2:41][CH2:40][CH2:39][C@H:34]1[C:35]([O:37][CH3:38])=[O:36])=[O:32])[CH:28]([CH3:30])[CH3:29])=[O:25])[CH:21]([CH3:22])[CH3:23])=[O:8])[CH:3]([CH3:4])[CH3:5]
Reactant: COC(=O)[C@@H]1CCCN1C(=O)[C@H](C(C)C)N(C)C(=O)[C@@H](N)C(C)C
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: COC(=O)[C@@H]1CCCN1C(=O)[C@H](C(C)C)N(C)C(=O)[C@@H](NC(=O)[C@@H](NC(=O)OCc1ccccc1)C(C)C)C(C)C
Temperature: 0 °C
Reaction time: 8 h
Yield: 91.2 %

Procedure:
15.29 g (61 mmol) of Z-Val-OH and 21.96 g (61 mmol) of H-Val-MeVal-Pro-OMe were dissolved in 610 ml of dichloromethane and cooled to 0° C. After addition of 8.16 mol(73.2 mmol) of N-methylmorpholine, 2.77 g (20.3 mmol) of HOBt and 11.74 g (61 mmol) of EDCI, the reaction mixture was stirred overnight at room temperature, diluted with dichloromethane and thoroughly washed with saturated aqueous NaHCO3 solution (3×), water (1×), 5% citric acid (3×) and saturated NaCl solution. The organic phase was dried over sodium sulfate, filtered and evaporated to dryness to yield 31.96 g of the product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=O)[CH:8]([CH2:14][C:15]([O:17][CH3:18])=[O:16])[CH2:7][CH2:6]2.P(Cl)(Cl)(Cl)(Cl)[Cl:20]>C1C=CC=CC=1>[Cl:20][C:9]1[C:10]2[C:5](=[CH:4][C:3]([O:2][CH3:1])=[CH:12][CH:11]=2)[CH:6]=[CH:7][C:8]=1[CH2:14][C:15]([O:17][CH3:18])=[O:16]
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: COC(=O)CC1CCc2cc(OC)ccc2C1=O
Solvent: c1ccccc1
Product: COC(=O)Cc1ccc2cc(OC)ccc2c1Cl
Reaction time: 5 h

Procedure:
To a mixture of 25 g. of 6-methoxy-2-(methoxycarbonylmethyl)-1-tetralone and 150 ml. of benzene, 21 g. of phosphorus pentachloride are slowly added. After the addition, the chlorination mixture is allowed to stand for an additional five hours; then it is added to 500 g. of ice and extracted with xylene. The extracts, containing methyl 1-chloro-6-methoxy-3,4-dihydro-2-naphthylacetate, are combined, washed with water to neutrality and dried over sodium sulfate; then 23 g. of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone are added and the resulting mixture is refluxed for five hours. The dehydrogenation mixture is cooled, filtered, and evaporated. The residue is taken up in acetone and chromatographed on alumina and evaporated to yield methyl 1-chloro-6-methoxy-2-naphthylacetate.
Reaction SMILES: [CH3:1][CH:2]1[CH:6]([CH3:7])[O:5][C:4]2([CH2:12][C:11]([CH3:14])([CH3:13])[C:10](/[CH:16]=[CH:17]/[Sn](CCCC)(CCCC)CCCC)([OH:15])[C:9]([CH3:31])=[CH:8]2)[O:3]1.[F:32][C:33]([F:43])([F:42])/[C:34](/I)=[CH:35]/[C:36]([O:38][CH2:39][CH3:40])=[O:37].[F-].[K+]>CC#N.CC#N.Cl[Pd]Cl.CN(C)C=O>[OH:15][C:10]1(/[CH:16]=[CH:17]/[C:34](/[C:33]([F:32])([F:42])[F:43])=[CH:35]\[C:36]([O:38][CH2:39][CH3:40])=[O:37])[C:11]([CH3:14])([CH3:13])[CH2:12][C:4]2([O:5][CH:6]([CH3:7])[CH:2]([CH3:1])[O:3]2)[CH:8]=[C:9]1[CH3:31]
Reactant: CCOC(=O)/C=C(\I)C(F)(F)F
Reactant: CCCC[Sn](/C=C/C1(O)C(C)=CC2(CC1(C)C)OC(C)C(C)O2)(CCCC)CCCC
Agent: Cl[Pd]Cl
Agent: [F-]
Agent: [K+]
Solvent: CC#N
Solvent: CN(C)C=O
Product: CCOC(=O)/C=C(\C=C\C1(O)C(C)=CC2(CC1(C)C)OC(C)C(C)O2)C(F)(F)F
Temperature: 25 °C
Reaction time: 3 h
Yield: 65.2 %

Procedure:
Under argon, 2,3,7,9,9-pentamethyl-8-[(E)-2-(tributylstannyl)vinyl]-1,4-dioxaspiro[4.5]dec-6-en-8-ol (300 mg, 0.55 mmol) and ethyl (2Z)-4,4,4-trifluoro-3-iodobut-2-enoate (163 mg, 0.55 mmol) in a round-bottom flask that had been dried by heating were dissolved in abs. N,N-dimethylformamide (4 ml), dichlorobis(acetonitrile)palladium(II) (7 mg, 0.03 mmol) was added and the mixture was stirred at room temperature for 3 h. After the addition of potassium fluoride solution, the reaction mixture was stirred further at room temperature overnight. The aqueous phase was then repeatedly extracted thoroughly with diethyl ether, and the combined organic phases were then dried over magnesium sulfate, filtered and concentrated under reduced pressure. By final column chromatography purification of the resulting crude product (ethyl acetate/heptane gradient), ethyl (2E,4E)-5-(8-hydroxy-2,3,7,9,9-pentamethyl-1,4-dioxaspiro[4.5]dec-6-en-8-yl)-3-(trifluoromethyl)penta-2,4-dienoate (150 mg, 61% of theory) was obtained in the form of a colorless oil. 1H-NMR (400 MHz, CDCl3 δ, ppm) 7.47 (d, 1H), 6.29 (d, 1H), 6.25 (s, 1H), 5.48 (s, 1H), 4.26 (q, 2H), 3.68 (m, 1H), 3.59 (m, 1H), 1.93 (d, 1H), 1.83 (br. m, 1H, OH), 1.77 (d, 1H), 1.69 (s, 3H), 1.32 (t, 3H), 1.25 (m, 3H), 1.18 (m, 3H), 1.10 (s, 3H), 0.91 (s, 3H).
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][C:5]1[C:10]([CH2:11][CH3:12])=[N:9][C:8]2[N:13]([CH2:16][CH3:17])[N:14]=[CH:15][C:7]=2[C:6]=1[NH:18][CH:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1.C(N(CC)C(C)C)(C)C.[CH2:34]([O:36][C:37]1[C:38](=O)[C:39](=[O:44])[C:40]=1[O:41]CC)[CH3:35]>C(O)C>[CH2:16]([N:13]1[C:8]2=[N:9][C:10]([CH2:11][CH3:12])=[C:5]([CH2:4][NH:3][C:38]3[C:39](=[O:44])[C:40](=[O:41])[C:37]=3[O:36][CH2:34][CH3:35])[C:6]([NH:18][CH:19]3[CH2:20][CH2:21][O:22][CH2:23][CH2:24]3)=[C:7]2[CH:15]=[N:14]1)[CH3:17]
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CN
Reactant: CCOc1c(OCC)c(=O)c1=O
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: CCOc1c(NCc2c(CC)nc3c(cnn3CC)c2NC2CCOCC2)c(=O)c1=O
Reaction time: 8 h

Procedure:
A suspension of 5-(aminomethyl)-1,6-diethyl-N-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-b]pyridin-4-amine dihydrochloride (0.60 g, 1.6 mmol) in ethanol (8 mL) was treated with N,N-diisopropylethylamine (DIEA, 0.57 mL, 3.3 mmol), giving a clear, homogeneous mixture, which was then cooled in an ice-water bath. 3,4-Diethoxycyclobut-3-ene-1,2-dione (TCI America, 0.41 g, 0.36 mmol) was then added dropwise via syringe. Following completion of the addition, the mixture was allowed to regain room temperature and stir overnight. The precipitated solid was collected by Büchner filtration, washed with ethanol, and dried under house vacuum to provide the title compound as a white solid. ES/MS calcd. for C22H30N5O4+ 428.2. found m/z=428.3 (M+H)+.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[NH:12][CH:13]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=3)[CH:14]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)[N:15]=2)=[C:7]([O:30][CH2:31][CH3:32])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:40](Cl)([Cl:42])=[O:41]>C(Cl)Cl>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:15]([C:40]([Cl:42])=[O:41])[CH:14]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)[CH:13]([C:23]3[CH:24]=[CH:25][C:26]([Cl:29])=[CH:27][CH:28]=3)[N:12]=2)=[C:7]([O:30][CH2:31][CH3:32])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOc1cc(C(C)(C)C)ccc1C1=NC(c2ccc(Cl)cc2)C(c2ccc(Cl)cc2)N1
Reactant: O=C(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOc1cc(C(C)(C)C)ccc1C1=NC(c2ccc(Cl)cc2)C(c2ccc(Cl)cc2)N1C(=O)Cl
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 56.6 %

Procedure:
To a solution of 2-(4-tert-butyl-2-ethoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-1H-imidazole (19.7 g, 42.144 mmol) and triethylamine (17.6 mL, 126.432 mmol) in methylene chloride (200 mL) cooled to 0° C. was added phosgene (44.6 mL, 84.288 mmol, 20% solution in toluene, Fluka). The reaction mixture was stirred at 0° C. for 30 min then concentrated to dryness. The orange residue was taken in methylene chloride (100 mL), and the solution was filtered through a plug of silica gel (50 g). It was washed with methylene chloride (˜600 mL). The filtrate was concentrated, and the residue was purified by flash chromatography (silica gel, eluting with 10% ethyl acetate in hexane) to give racemic-2-(4-tert-butyl-2-ethoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazole-1-carbonyl chloride as white solids (12.650 g). The enantiomers of 2-(4-tert-butyl-2-ethoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazole-1-carbonyl chloride were separated by chiral chromatography using a Waters Delta Prep 4000 and Modcol spring column (50 mm×70 cm) packed with R,R-Whelk-O1 spherical Kromasil silica gel (purchased from Regis Technologies). Eluent: 30% methylene chloride in hexane. Flowrate: 85 mL/min. Loading scale: 2.4-3.0 g. The first peak coming off the column is the desired (4S,5R)-2-(4-tert-butyl-2-ethoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazole-1-carbonyl chloride.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]([CH3:17])([CH3:16])[CH2:10]/[CH:11]=[CH:12]/[C:13]([OH:15])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].ON1C2N=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.[C:40]([N:43]([CH3:73])[NH:44][C:45](=[O:72])[C@H:46]([N:54]([CH3:71])[C:55](=[O:70])[C@H:56]([NH:68][CH3:69])[CH2:57][C:58]1[CH:67]=[CH:66][C:65]2[C:60](=[CH:61][CH:62]=[CH:63][CH:64]=2)[CH:59]=1)[CH2:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)(=[O:42])[CH3:41].C(N(C(C)C)CC)(C)C>C(Cl)Cl>[C:1]([O:5][C:6](=[O:7])[NH:8][C:9]([CH3:17])([CH3:16])[CH2:10]/[CH:11]=[CH:12]/[C:13](=[O:15])[N:68]([C@@H:56]([C:55](=[O:70])[N:54]([C@H:46]([CH2:47][C:48]1[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=1)[C:45]([NH:44][N:43]([C:40](=[O:42])[CH3:41])[CH3:73])=[O:72])[CH3:71])[CH2:57][C:58]1[CH:67]=[CH:66][C:65]2[C:60](=[CH:61][CH:62]=[CH:63][CH:64]=2)[CH:59]=1)[CH3:69])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C/C=C/C(=O)O)NC(=O)OC(C)(C)C
Reactant: CN[C@H](Cc1ccc2ccccc2c1)C(=O)N(C)[C@H](Cc1ccccc1)C(=O)NN(C)C(C)=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N(C)NC(=O)[C@@H](Cc1ccccc1)N(C)C(=O)[C@@H](Cc1ccc2ccccc2c1)N(C)C(=O)/C=C/CC(C)(C)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 8 h
Yield: 62.5 %

Procedure:
To a solution of (2E)-5-(tert-butyloxycarbonylamino)-5-methylhex-2-enoic acid (0.1 g, 0.42 mmol) in methylene chloride (5 ml) was added 1-hydroxy-7-azabenzotriazole (0.06 g, 0.42 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.08 g, 0.42 mmol) and the mixture was cooled to 0° C. Then (2R)-N-[(1R)-2-(N'-acetyl-N'-methylhydrazino)-1-benzyl-2-oxoethyl]-N-methyl-2-(methylamino)-3-(2-naphthyl)propionamide (0.13 g, 0.28 mmol) and diisopropylethylamine (0.062 ml, 0.36 mmol) were added and the mixture was stirred at room temperature overnight. Then methylene chloride (50 ml) was added and the mixture was washed with water (10 ml), saturated sodium bicarbonate (10 ml), brine (10 ml), dried (MgSO4), filtered and concentrated in vacuo. The product was chromatographed on silica (40 g) with heptane:ethyl acetate (1:1) to give 0.12 g (63%) of ((3E)-4-[N-((1R)-1-(N-[(1R)-2-(N'-acetyl-N'-methylhydrazino)-1-benzyl-2-oxoethyl]-N-methylcarbamoyl)-2-(2-naphthyl)ethyl)-N-methylcarbamoyl]-1,1-dimethylbut-3-enyl)carbamic acid tert-butyl ester as a colourless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]([CH:12]([CH3:14])[CH3:13])=[CH:10][C:9]([S:15](=[O:18])(=[O:17])[NH2:16])=[C:8]([CH3:19])[C:4]=1[C:5](O)=[O:6].S(Cl)([Cl:22])=O>CN(C)C=O.C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[C:11]([CH:12]([CH3:14])[CH3:13])=[CH:10][C:9]([S:15](=[O:18])(=[O:17])[NH2:16])=[C:8]([CH3:19])[C:4]=1[C:5]([Cl:22])=[O:6]
Reactant: COc1c(C(C)C)cc(S(N)(=O)=O)c(C)c1C(=O)O
Reactant: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: COc1c(C(C)C)cc(S(N)(=O)=O)c(C)c1C(=O)Cl
Reaction time: 1.5 h

Procedure:
72 g of 2-methoxy-3-isopropyl-5-sulphamoyl-6-methylbenzoic acid (0.25 mole), 250 ml of chloroform, 23 ml of thionyl chloride and 3 drops of dimethylformamide are placed in a 1 liter flask fitted with an agitator and a condenser. The mixture is heated to reflux for 1.5 hours, then 18 ml of thionyl chloride is added and the reflux is continued for 1.5 hours. The solids dissolve completely.
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[Br:13][C:14]1[CH:19]=[CH:18][C:17]([F:20])=[C:16]([F:21])[C:15]=1[F:22].[C:23](=[O:25])=[O:24]>C1COCC1>[Br:13][C:14]1[C:15]([F:22])=[C:16]([F:21])[C:17]([F:20])=[C:18]([CH:19]=1)[C:23]([OH:25])=[O:24]
Reactant: Fc1ccc(Br)c(F)c1F
Reactant: O=C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: O=C(O)c1cc(Br)c(F)c(F)c1F
Temperature: -78 °C
Reaction time: 1 h
Yield: 94.5 %

Procedure:
To a solution of diisopropylamine (10.14 g, 100.20 mmol) in THF (100 mL) was added n-BuLi (40.08 mL, 2.5 M in hexane, 100.20 mmol) at −78° C. under nitrogen atmosphere. The stirring was maintained at this temperature for 1 h. Then a solution of 1-bromo-2,3,4-trifluorobenzene (17.62 g, 83.50 mmol) in THF (120 mL) was added. After stirring for 1 h at −78° C., the mixture was transferred to a bottle with dry ice. The mixture was stirred overnight at room temperature. The reaction was quenched with 10% aqueous HCl and pH was adjusted to 1-2. The mixture was extracted with ethyl acetate (100 mL×3). The combined organic extracts were washed with water (100 mL) and brine (100 mL) sequentially, dried over Na2SO4, filtered and concentrated under reduced pressure to afford the desired product (20.12 g, 94.5% yield). 1H NMR (400 MHz, DMSO-d6): δ 13.95 (s, 1H), 7.97 (m, 1H).