Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([O:11][C:12]3[CH:13]=[CH:14][C:15]([CH3:32])=[C:16]([NH:18][C:19](=[O:31])[C:20]4[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([C:29]#[N:30])([CH3:28])[CH3:27])[CH:21]=4)[CH:17]=3)[CH:8]=[CH:7][C:5]=2[N:6]=1.N1C=CC=CC=1.[C:39](Cl)(=[O:41])[CH3:40]>O1CCCC1.C(OCC)(=O)C>[C:39]([NH:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([O:11][C:12]3[CH:13]=[CH:14][C:15]([CH3:32])=[C:16]([NH:18][C:19](=[O:31])[C:20]4[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([C:29]#[N:30])([CH3:27])[CH3:28])[CH:21]=4)[CH:17]=3)[CH:8]=[CH:7][C:5]=2[N:6]=1)(=[O:41])[CH3:40]
Reactant: CC(=O)Cl
Reactant: Cc1ccc(Oc2ccc3nc(N)sc3c2)cc1NC(=O)c1cccc(C(C)(C)C#N)c1
Solvent: c1ccncc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(=O)Nc1nc2ccc(Oc3ccc(C)c(NC(=O)c4cccc(C(C)(C)C#N)c4)c3)cc2s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 63 %

Procedure:
To a solution of N-{5-[(2-amino-1,3-benzothiazol-6-yl)oxy]-2-methylphenyl}-3-(1-cyano-1-methylethyl)benzamide (200 mg, 0.452 mmol) produced in Example A7(vii) in tetrahydrofuran (2.0 mL) were added pyridine (180 μL, 2.25 mmol) and acetyl chloride (51 μL, 0.723 mmol), and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate (20 mL), washed with 5% aqueous sodium hydrogencarbonate solution (10 mL) and saturated brine (10 mL), successively, and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (hexane/ethyl acetate=50/50→0/100), and the obtained solution was concentrated under reduced pressure. The residue was recrystallized from 2-butanone/hexane to give the title compound (138 mg, 63%) as colorless crystals.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[NH:11]([CH2:15][CH2:16][OH:17])[CH2:12][CH2:13][OH:14]>CO.ClCCl>[OH:14][CH2:13][CH2:12][N:11]([C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1)[CH2:15][CH2:16][OH:17]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: OCCNCCO
Solvent: ClCCl
Solvent: CO
Product: O=[N+]([O-])c1ccc(N(CCO)CCO)cc1
Temperature: 130 °C
Yield: 84.6 %

Procedure:
A mixture of 4-fluoronitrobenzene (5 g, 35 mmol) and diethanolamine (7.5 g, 71 mmol) was heated to 130° C. without solvent for 4 hours. The crude reaction mixture after chromatography on silica gel (gravity, methanol:dichloromethane 1:19 then 1:9) gave the title compound (6.7 g, 85% yield). 1H NMR (300 MHz, DMSO-d6) δ 7.98 (d, 2H), 6.78 (d, 2H), 4.83 (t, 2H), 3.50-3.65 (m, 8H). 13C NMR (75 MHz, DMSO-d6) δ 154.36, 136.16, 126.77, 111.66, 58.89, 54.17. Mass spectrum m/z 227 (MH+). Anal. calcd. for C10H14N2O4C, 53.09; H, 6.24; N, 12.38. Found C, 53.09, H, 6.32, N, 12.34.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4]([C:9]#[C:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[Cl:17])[CH:3]=1.[CH2:18]([O:20][C:21](=[O:28])[CH2:22][C:23](=O)[CH:24]([CH3:26])[CH3:25])[CH3:19]>CCO.C(OCC)(=O)C>[CH2:18]([O:20][C:21]([C:22]1[C:23]([CH:24]([CH3:26])[CH3:25])=[N:8][C:5]2[C:4]([C:9]=1[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[Cl:17])=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)=[O:28])[CH3:19]
Reactant: Nc1ccc(Cl)cc1C#Cc1ccccc1Cl
Reactant: CCOC(=O)CC(=O)C(C)C
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCOC(=O)c1c(C(C)C)nc2ccc(Cl)cc2c1Cc1ccccc1Cl
Yield: 22.9 %

Procedure:
To a solution of 4-chloro-2-(2-chloro-phenylethynyl)-phenylamine (prepared as described in example 10 step A, 100 mg, 0.38 mmol) and 4-methyl-3-oxo-pentanoic acid ethyl ester (0.092 ml, 0.57 mmol) in anhydrous EtOH (10 ml), was added p-TsOH—H2O (72.56 mg, 0.38 mmol) and the mixture was refluxed for 72 h. After cooling, the reaction mixture was diluted with ethyl acetate and the organic layer was washed with saturated sodium bicarbonate solution and brine, dried over sodium sulfate, concentrated in vacuo. The crude residue was purified by flash column chromatography (elution with 3% EtOAc in hexane) to give 6-chloro-4-(2-chloro-benzyl)-2-isopropyl-quinoline-3-carboxylic acid ethyl ester (35 mg, 23% yield) as a yellow sticky solid. LC-MS: 402 (M+H)+.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[C:7]([C:10]([O:12][CH3:13])=[O:11])[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.[H-].[Na+].CI.[CH3:18]N1C2C=C(C(OC)=O)C=CC=2N=C1>C1COCC1>[CH3:18][N:3]1[C:4]2[CH:9]=[CH:8][C:7]([C:10]([O:12][CH3:13])=[O:11])=[CH:6][C:5]=2[N:1]=[CH:2]1
Reactant: COC(=O)c1ccc2nc[nH]c2c1
Reactant: COC(=O)c1ccc2ncn(C)c2c1
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: C1CCOC1
Product: COC(=O)c1ccc2c(c1)ncn2C
Reaction time: 0.5 h
Yield: 78 %

Procedure:
A solution of methyl 1H-benzo[d]imidazole-6-carboxylate (9.5 g, 53.9 mmol) in THF (100 mL) had NaH (2.59 g, 64.7 mmol) added at 0° C. After stirring for 30 min, CH3I (13.23 g, 93.2 mmol) was added and the mixture was stirred at room temperature for 1 h. The reaction was then quenched by addition of water and extracted with DCM (3×100 mL). The combined organic layers were dried over Na2SO4 and concentrated to give a mixture of two isomeric products methyl 1-methyl-1H-benzo[d]imidazole-6-carboxylate and methyl 1-methyl-1H-benzo[d]imidazole-5-carboxylate (8.0 g, Yield 78%). LCMS (m/z): 191.06 (M+1). This crude mixture was used directly in the next step.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][N:8]2[C:16]3[C:11](=[CH:12][C:13]([OH:17])=[CH:14][CH:15]=3)[C:10]([CH3:19])([CH3:18])[CH2:9]2)[CH:2]=1.[CH2:20]([N:27]=[C:28]=[O:29])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[CH2:20]([NH:27][C:28](=[O:29])[O:17][C:13]1[CH:12]=[C:11]2[C:16](=[CH:15][CH:14]=1)[N:8]([CH2:7][C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1)[CH2:9][C:10]2([CH3:19])[CH3:18])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CC1(C)CN(Cc2cccnc2)c2ccc(O)cc21
Reactant: O=C=NCc1ccccc1
Product: CC1(C)CN(Cc2cccnc2)c2ccc(OC(=O)NCc3ccccc3)cc21

Procedure:
The title compound was synthesized from 1-(3-pyridylmethyl)-3,3-dimethylindolin-5-ol (20.0 mg, 0.09 mmol) using the same procedure employed for Example 2 (2), but with benzylisocyanate instead of 4-isopropylphenylisocyanate. The product was obtained as a white solid (12.8 mg, 40%) having the following characteristics.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[CH:8]([OH:18])[CH2:9][CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[CH2:19]([O:21][C:22]([C:24]1([C:27]2[CH:32]=[CH:31][C:30]([C:33]3[CH:38]=[CH:37][C:36](B4OC(C)(C)C(C)(C)O4)=[CH:35][CH:34]=3)=[CH:29][CH:28]=2)[CH2:26][CH2:25]1)=[O:23])[CH3:20]>>[CH2:19]([O:21][C:22]([C:24]1([C:27]2[CH:28]=[CH:29][C:30]([C:33]3[CH:34]=[CH:35][C:36]([C:2]4[CH:3]=[N:4][CH:5]=[CH:6][C:7]=4[CH:8]([OH:18])[CH2:9][CH2:10][CH2:11][C:12]4[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=4)=[CH:37][CH:38]=3)=[CH:31][CH:32]=2)[CH2:26][CH2:25]1)=[O:23])[CH3:20]
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(B4OC(C)(C)C(C)(C)O4)cc3)cc2)CC1
Reactant: OC(CCCc1ccccc1)c1ccncc1Br
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4cnccc4C(O)CCCc4ccccc4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 1, Step 2, using the following starting materials: 1-(3-bromo-pyridin-4-yl)-4-phenyl-butan-1-ol and 1-[4′-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=2)[CH:5]=[C:6]2[C:11]=1[NH:10][C:9](=[O:12])[CH:8]=[CH:7]2.[CH2:20]([N:23]=[C:24]=[O:25])[CH2:21][CH3:22].CO>C1COCC1>[CH3:1][C:2]1[CH:3]=[C:4]([C:13]2[CH:18]=[CH:17][C:16]([O:19][C:24](=[O:25])[NH:23][CH2:20][CH2:21][CH3:22])=[CH:15][CH:14]=2)[CH:5]=[C:6]2[C:11]=1[NH:10][C:9](=[O:12])[CH:8]=[CH:7]2
Reactant: CCCN=C=O
Reactant: Cc1cc(-c2ccc(O)cc2)cc2ccc(=O)[nH]c12
Solvent: CO
Solvent: C1CCOC1
Product: CCCNC(=O)Oc1ccc(-c2cc(C)c3[nH]c(=O)ccc3c2)cc1

Procedure:
A solution of 8-methyl-6-[4-hydroxyphenyl]-2-(1H)-quinolone (0.30 g) and n-propylisocyanate (0.5 cm3) was heated under reflux in THF (10 cm3) under nitrogen for 50 hours. Methanol (10 cm3) was then added to dissolve solid material, followed by silica (Merck "MK 60.9385" [Trade Mark]) (10 g), and the volatile material was removed in vacuo. The residue was placed on top of a silica column (Merck "MK 60.9385") and eluted with chloroform:methanol, 19:1. Combination and evaporation of appropriate fractions in vacuo gave a solid which was recrystallised from propan-2-ol to afford the title compound, m.p. 224°-228°, (0.28 g).
Reaction SMILES: FC(F)(F)C(O)=O.ClCCl.[NH2:11][C:12]1[N:17]=[CH:16][N:15]=[C:14]2[N:18]([CH:33]3[CH2:38][CH2:37][CH:36]([N:39]4[CH2:44][CH2:43][N:42]([CH3:45])[CH2:41][CH2:40]4)[CH2:35][CH2:34]3)[N:19]=[C:20]([C:21]3[CH:26]=[CH:25][C:24]([NH:27]C(=O)[O-])=[C:23]([O:31][CH3:32])[CH:22]=3)[C:13]=12>ClCCl>[NH2:27][C:24]1[CH:25]=[CH:26][C:21]([C:20]2[C:13]3[C:14](=[N:15][CH:16]=[N:17][C:12]=3[NH2:11])[N:18]([C@H:33]3[CH2:38][CH2:37][C@H:36]([N:39]4[CH2:40][CH2:41][N:42]([CH3:45])[CH2:43][CH2:44]4)[CH2:35][CH2:34]3)[N:19]=2)=[CH:22][C:23]=1[O:31][CH3:32]
Reactant: COc1cc(-c2nn(C3CCC(N4CCN(C)CC4)CC3)c3ncnc(N)c23)ccc1NC(=O)[O-]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(-c2nn([C@H]3CC[C@H](N4CCN(C)CC4)CC3)c3ncnc(N)c23)ccc1N

Procedure:
A mixture of trifluoroacetic acid/dichloromethane (20:80, 150 mL) was added to a solution of N-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-2-methoxyphenyl)carbamate(4.75 g, 8.85 mmol) in dichloromethane (100 mL) at 0° C. 2 hours later, the ice-bath was removed and the solvents were evaporated and the residue was dissolved in dichloromethane. Sodium hydroxide (1.0N) was added to adjust the pH to about 10. The solid formed upon removal of organic solvent was collect by filtration to give trans-3-(4-amino-3-methoxyphenyl)-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (3.85 g, 100%). 1H NMR (DMSO-d6) δ 1.44 (m, 2H), 1.96 (m, 6H), 2.21 (s, 3H), 2.33 (m, 5H), 2.53 (m, 4H), 3.83 (s, 3H), 4.60 (m, 1H), 5.03 (bs, 2H), 6.76 (d, J=7.91 Hz, 1H), 6.98 (d, J=7.89 Hz, 1H), 7.03 (m, 2H), 8.19 (s, 1H).
Reaction SMILES: [NH2:1][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.[CH3:15][Si:16]([CH3:44])([CH3:43])[C:17]1[CH:18]=[C:19]([CH:36]=[C:37]([Si:39]([CH3:42])([CH3:41])[CH3:40])[CH:38]=1)[C:20](NC1N=CC(/C=C/C(OCC)=O)=CC=1)=[O:21]>>[CH3:40][Si:39]([CH3:42])([CH3:41])[C:37]1[CH:36]=[C:19]([CH:18]=[C:17]([Si:16]([CH3:44])([CH3:43])[CH3:15])[CH:38]=1)[C:20]([NH: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)=[O:21]
Reactant: CCOC(=O)C=Cc1ccc(N)cc1
Reactant: CCOC(=O)/C=C/c1ccc(NC(=O)c2cc([Si](C)(C)C)cc([Si](C)(C)C)c2)nc1
Product: CCOC(=O)C=Cc1ccc(NC(=O)c2cc([Si](C)(C)C)cc([Si](C)(C)C)c2)cc1
Yield: 62 %

Procedure:
Using BTMB (10.0 g) and ethyl 4-aminocinnamate (8.62 g), Compound 3a (10.3 g, 62%) was obtained as a yellow solid in the same manner as Compound 1b was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8](Cl)(=[O:10])=[O:9].N1C=CC=CC=1.[NH:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1.S(Cl)(Cl)(=O)=O>C(Cl)Cl>[N:18]1([S:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])(=[O:10])=[O:9])[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1
Reactant: O=S(=O)(Cl)c1ccccc1Cl
Reactant: C1COCCN1
Solvent: O=S(=O)(Cl)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=S(=O)(c1ccccc1Cl)N1CCOCC1
Reaction time: 0.25 h

Procedure:
To a solution of a 2-chlorobenzene sulfonyl chloride (10 g, 47.4 mmol) in DCM (100 ml) cooled to 0° C. was added pyridine (5.7 ml, 71.1 mmol) and morpholine (6.2 ml, 71.1 mmol) dropwise. Stirring was continued for 15 minutes after which time no sulfonyl chloride was evident by LC-MS. The reaction was quenched by the addition of 2N HCl, washed with further portions of 2N HCl, dried over sodium sulfate, filtered and concentrated in vacuo to yield the title compound without need for additional purification. (11.2 g, 100%). δH (400 MHz, DMSO-d6) 7.97 (1H, dd, 7.8, 1.5 Hz), 7.66-7.77 (2H, m), 7.58 (1H, ddd, 8.1, 6.7, 1.8 Hz), 3.57-3.64 (4H, m), 3.11-3.18 (4H, m); TR=1.25 min.
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([CH3:7])[C:3]=1[C:8]1[S:9][C:10]2[CH:16]=[C:15]([S:17](Cl)(=[O:19])=[O:18])[C:14]([F:21])=[CH:13][C:11]=2[N:12]=1.FC1C=CC2SC(C3C(C)=NNC=3N)=NC=2C=1.[N:39]1[CH:44]=[CH:43][C:42]([CH2:45][NH2:46])=[CH:41][CH:40]=1.C(N(CC)CC)C>C(Cl)(Cl)Cl>[N:39]1[CH:44]=[CH:43][C:42]([CH2:45][NH:46][S:17]([C:15]2[C:14]([F:21])=[CH:13][C:11]3[N:12]=[C:8]([C:3]4[C:4]([CH3:7])=[N:5][NH:6][C:2]=4[NH2:1])[S:9][C:10]=3[CH:16]=2)(=[O:19])=[O:18])=[CH:41][CH:40]=1
Reactant: Cc1n[nH]c(N)c1-c1nc2cc(F)c(S(=O)(=O)Cl)cc2s1
Reactant: NCc1ccncc1
Agent: Cc1n[nH]c(N)c1-c1nc2cc(F)ccc2s1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: Cc1n[nH]c(N)c1-c1nc2cc(F)c(S(=O)(=O)NCc3ccncc3)cc2s1
Yield: 24 %

Procedure:
The title compound (15 mg) was prepared from crude 2-(5-amino-3-methyl-1H-pyrazol-4-yl)-5-fluorobenzothiazole-6-sulfonyl chloride, which had been derived from the chlorosulfonation of 90 mg of 4-(5-fluorobenzothiazol-2-yl)-5-methyl-2H-pyrazol-3-ylamine, 32 mg (0.30 mmol) of C-pyridin-4-ylmethylamine, and triethylamine (0.50 mL) in chloroform. MS (m/z, ES+): 419.1 (M+1, 100%), 210.0 (100%). Yield=24%.
Reaction SMILES: [CH2:1]([N:3]1[C:8]([CH3:9])=[C:7]([CH3:10])[CH:6]=[C:5]([C:11]([OH:13])=O)[C:4]1=[O:14])[CH3:2].[CH2:15]([NH2:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2C=CC=CC=2N=N1>CN(C=O)C.C(OCC)(=O)C>[CH2:15]([NH:22][C:11]([C:5]1[C:4](=[O:14])[N:3]([CH2:1][CH3:2])[C:8]([CH3:9])=[C:7]([CH3:10])[CH:6]=1)=[O:13])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CCn1c(C)c(C)cc(C(=O)O)c1=O
Reactant: NCc1ccccc1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CCn1c(C)c(C)cc(C(=O)NCc2ccccc2)c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.1 %

Procedure:
1-Ethyl-3-carboxy-5,6-dimethyl-2-pyridone (3-003-04) (195 mg) was dissolved in DMF (3 mL), and to the reaction mixture were added benzylamine (0.17 mL), diisopropylethylamine (0.35 mL), and benzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate (PyBOP, 624 mg), and the reaction mixture was stirred at room temperature for 1 h. The reaction mixture was diluted with ethyl acetate, washed twice with hydrochloric acid and aqueous sodium bicarbonate solution, respectively, and water, dried over magnesium sulfate, and evaporated under reduced pressure. The residue (0.40 g) was subjected to silica gel (30 g) column chromatography (chloroform) to give 1-ethyl-2-oxo-5,6-dimethyl-1,2-dihydropyridine-3-carboxylic acid benzylamide (3-003) (259 mg, 91.1%) as a crystal, followed by recrystallization from methylene/n-hexane to give colorless needle crystal (207 mg, 72.9%, m.p. 117° C.)
Reaction SMILES: [CH:1]1([C:5]2[NH:9][N:8]=[C:7]([NH2:10])[CH:6]=2)[CH2:4][CH2:3][CH2:2]1.[Cl:11][C:12]1[CH:19]=[CH:18][C:15]([CH:16]=O)=[CH:14][CH:13]=1.[CH3:20][C:21]1(C)OC(=O)CC(=O)[O:22]1>CCO>[Cl:11][C:12]1[CH:19]=[CH:18][C:15]([CH:16]2[CH2:20][C:21](=[O:22])[NH:10][C:7]3=[N:8][NH:9][C:5]([CH:1]4[CH2:4][CH2:3][CH2:2]4)=[C:6]23)=[CH:14][CH:13]=1
Reactant: O=Cc1ccc(Cl)cc1
Reactant: CC1(C)OC(=O)CC(=O)O1
Reactant: Nc1cc(C2CCC2)[nH]n1
Solvent: CCO
Product: O=C1CC(c2ccc(Cl)cc2)c2c(n[nH]c2C2CCC2)N1
Temperature: 75 °C
Reaction time: 0.5 h
Yield: 59 %

Procedure:
To 5-cyclobutyl-1H-pyrazol-3-ylamine (1.0 g, 7.3 mmol) in EtOH (20 mL) was added 4-chlorobenzaldehyde (1.1 g, 8.0 mmol) followed by Meldrum's Acid (1.1 g, 8.0 mmol). The reaction mixture was then heated to 75° C. (oil bath). After 30 min, the reaction was cooled to room temperature, the solid was filtered off, and then washed with MeOH (5 mL) and hexanes (10 mL). The solid was collected and dried under reduced pressure to give the title compound (1.3 g, 59% yield) as a colorless solid. 500 MHz 1H NMR (DMSO-d6) d 12.0 (s, 1H), 10.3 (s, 1H), 7.34 (d, J=8.7 Hz, 2H), 7.11 (d, J=8.3 Hz, 2H), 4.20 (dd, J=7.1, 4.2 Hz, 1H), 3.17 (dddd, J=8.7, 8.7, 8.7, 8.7 Hz, 1H), 2.84 (dd, 15.8, 7.1 Hz, 1H), 2.44 (dd, J=16.2, 4.6 Hz, 1H), 2.09-1.87 (m, 4H), 1.83-1.69 (m, 1H), 1.68-1.61 (m, 1H). 13C NMR (125 Mz, DMSO-d6) d 169.8, 149.5, 144.1, 142.8, 131.7, 129.4, 129.2, 101.1, 41.3, 33.9, 31.0, 28.8, 28.4, 18.7. LRMS m/z (APCI+) 303 (M+1).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C@@H:6]1[C@H:10]([O:11][Si](C(C)(C)C)(C)C)[C@@H:9]([C@@H:19]([CH3:21])[OH:20])[O:8][C@H:7]1[N:22]1[CH:29]=[C:28]([CH3:30])[C:26](=[O:27])[NH:25][C:23]1=[O:24].[CH3:31][O:32][C:33]1[CH:54]=[CH:53][C:36]([C:37](Cl)([C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)[C:38]2[CH:43]=[CH:42][C:41]([O:44][CH3:45])=[CH:40][CH:39]=2)=[CH:35][CH:34]=1.F.F.F.C(N(CC)CC)C.C(N(CC)CC)C>C1COCC1.CCOC(C)=O>[CH3:45][O:44][C:41]1[CH:40]=[CH:39][C:38]([C:37]([O:20][C@H:19]([CH3:21])[C@H:9]2[O:8][C@@H:7]([N:22]3[CH:29]=[C:28]([CH3:30])[C:26](=[O:27])[NH:25][C:23]3=[O:24])[C@H:6]([O:5][CH2:4][CH2:3][O:2][CH3:1])[C@@H:10]2[OH:11])([C:46]2[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=2)[C:36]2[CH:53]=[CH:54][C:33]([O:32][CH3:31])=[CH:34][CH:35]=2)=[CH:43][CH:42]=1
Reactant: COc1ccc(C(Cl)(c2ccccc2)c2ccc(OC)cc2)cc1
Reactant: COCCO[C@@H]1[C@H](O[Si](C)(C)C(C)(C)C)[C@@H]([C@@H](C)O)O[C@H]1n1cc(C)c(=O)[nH]c1=O
Agent: F
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COCCO[C@@H]1[C@H](O)[C@@H]([C@@H](C)OC(c2ccccc2)(c2ccc(OC)cc2)c2ccc(OC)cc2)O[C@H]1n1cc(C)c(=O)[nH]c1=O
Temperature: 45 °C
Reaction time: 18 h
Yield: 72.4 %

Procedure:
Compound 11 (0.42 g, 0.96 mmol) was mixed with 4,4′-dimethoxytrityl chloride (0.82 g, 2.41 mmol) and dried over P2O5 under reduced pressure. The mixture was dissolved in anhydrous pyridine (3 mL) and stirred at 45° C. for 18 h under an atmosphere of argon. The reaction mixture was cooled to room temperature and diluted with EtOAc (40 mL) and washed with saturated aqueous NaHCO3 (60 mL) and brine (40 mL), dried over Na2SO4, filtered and concentrated. The residue obtained was purified by silica gel column chromatography and eluted first with 50% EtOAc in hexanes and then with 5% methanol in CH2Cl2. The product obtained was dissolved in a mixture of triethylamine trihydrofluoride (1.38 mL, 8.44 mmol) and triethylamine (0.58 mL, 4.22 mmol) in THF (8.4 mL). After 72 h the mixture was diluted with EtOAc (60 mL), washed with water (40 mL), saturated aqueous NaHCO3 (40 mL) and brine (40 mL) then dried over Na2SO4, filtered and evaporated. The residue obtained was purified by silica gel column chromatography and eluted with 70% EtOAc in hexanes to yield Compound 12 (0.44 g, 73%). ES MS m/z 631.2 [M+H]+.
Reaction SMILES: [C-]#N.[Na+].[C:4](CCCCCCNCCCS(O)(=O)=O)#[N:5].[Cl:20][C:21]([Cl:31])=[CH:22][C@@H:23]1[C@H:25]([C:26](Cl)=[O:27])[C:24]1([CH3:30])[CH3:29].[O:32]([C:39]1[CH:40]=[C:41]([CH:44]=[CH:45][CH:46]=1)[CH:42]=[O:43])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>O.CCCCCCC>[Cl:20][C:21]([Cl:31])=[CH:22][C@@H:23]1[C@H:25]([C:26]([O:43][CH:42]([C:4]#[N:5])[C:41]2[CH:44]=[CH:45][CH:46]=[C:39]([O:32][C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=3)[CH:40]=2)=[O:27])[C:24]1([CH3:30])[CH3:29]
Reactant: CC1(C)[C@H](C=C(Cl)Cl)[C@@H]1C(=O)Cl
Reactant: O=Cc1cccc(Oc2ccccc2)c1
Reactant: N#CCCCCCCNCCCS(=O)(=O)O
Agent: [C-]#N
Agent: [Na+]
Solvent: CCCCCCC
Solvent: O
Product: CC1(C)[C@H](C=C(Cl)Cl)[C@@H]1C(=O)OC(C#N)c1cccc(Oc2ccccc2)c1
Reaction time: 1 h

Procedure:
A stirred mixture of sodium cyanide (18.0 g, 0.36 mole) and 3-(cyanohexylamino)propanesulfonic acid (1.34 g, 0.006 mole) in 300 ml of water was warmed to 40°. During a one hour period, maintaining a reaction temperature of about 40°, a solution of cis-3-(2,2-dichloroethenyl)-2,2-dimethylcyclopropanecarbonyl chloride (71.7 g, 0.315 mole) and 3-phenoxybenzaldehyde (61.9 g, 0.3 mole) in 262.2 g of n-heptane was added. The mixture was then stirred at 40° for one additional hour, after which it was washed with an aqueous solution containing 20% sodium carbonate and then with water. The organic phase was separated from the mixture and the solvent removed by distillation under reduced pressure to give α-cyano-3-phenoxybenzyl cis-3-(2,2-dichloroethenyl)-2,2-dimethylcyclopropanecarboxylate.
Reaction SMILES: [C:1]([OH:5])(=[O:4])[CH2:2][OH:3].C(=O)([O-])[O-].[K+].[K+].[I-].[K+].Cl[CH2:15][C:16]([O:18][C:19]1([CH3:29])[CH:26]2[CH2:27][CH:22]3[CH2:23][CH:24]([CH2:28][CH:20]1[CH2:21]3)[CH2:25]2)=[O:17]>C(OCC)C.CC(C)=O.CN(C=O)C>[CH3:29][C:19]1([O:18][C:16](=[O:17])[CH2:15][O:5][C:1](=[O:4])[CH2:2][OH:3])[CH:26]2[CH2:27][CH:22]3[CH2:23][CH:24]([CH2:28][CH:20]1[CH2:21]3)[CH2:25]2
Reactant: CC1(OC(=O)CCl)C2CC3CC(C2)CC1C3
Reactant: O=C(O)CO
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOCC
Solvent: CC(C)=O
Product: CC1(OC(=O)COC(=O)CO)C2CC3CC(C2)CC1C3
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 67.1 %

Procedure:
37.6 g (494 mmol) of glycolic acid, 700 mL of DMF, 86.5 g (626 mmol) of potassium carbonate, and 28.3 g (170 mmol) of potassium iodide were added to a 2 L three-neck flask equipped with a thermometer, a cooling pipe, and a stirring apparatus, and then stirred for 30 minutes at room temperature. Subsequently, a solution of 300 mL of dimethylformaldehyde with 100 g (412 mmol) of 2-methyl-2-adamantyl chloroacetate was gradually added thereto. Then, the resultant was heated at 40° C., and stirred for 4 hours. After the reaction, 2,000 mL of diethylether was added thereto and filtrated, thereby obtaining the solution (filtrate). The solution thus obtained was washed three times using 500 mL of distilled water. Thereafter, crystallization was conducted using a mixture solvent of 300 mL of toluene and 200 mL of heptane, thereby obtaining 78 g of the intended compound in the form of a colorless solid (yield: 67%, GC purity: 99%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][NH2:11])=[O:7])(C)(C)[CH3:2].C(N(C(C)C)CC)(C)C.[CH3:21][Si:22](CCOC([Cl:30])=O)([CH3:24])[CH3:23]>C1COCC1.ClCCl>[ClH:30].[CH3:21][Si:22]([CH2:2][CH2:1][O:5][C:6]([NH:8][CH2:9][CH2:10][NH2:11])=[O:7])([CH3:24])[CH3:23]
Reactant: C[Si](C)(C)CCOC(=O)Cl
Reactant: CC(C)(C)OC(=O)NCCN
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C[Si](C)(C)CCOC(=O)NCCN
Product: Cl
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
N-(t-Butyloxycarbonyl)-1,2-diaminoethane (8.0 g, 50 mmol) is dissolved in THF (200 mL), diisopropylethylamine (6.5 g, 50 mmol) is added and the solution cooled to 0° C. To this cold solution is added dropwise trimethylsilylethoxycarbonylchloride (9.0 g, 50 mmol) over 10 minutes. After stirring an additional 30 minutes the reaction is filtered and the filtrate is evaporated to an oil. This oil is dissolved in 100 mL of diethyl ether and washed with dilute HCl solution (3×25 mL), dried, filtered and evaporated to give an oil. The oil is dissolved in 100 mL of dichloromethane and dry HCl gas is bubbled through the solution for 30 minutes and the reaction stirred for 1 hour. The reaction is diluted with 200 mL of cold diethyl ether and allowed to stand at −5° C. for 12 hours. The colorless solid formed is collected and stored protected from moisture.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=O.[C:11]1([NH:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[NH2:24])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(N=C=NC(C)C)(C)C.C(N(CC)CC)C>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([NH:24][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[NH:17][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)=[O:9]
Reactant: O=C(O)c1cncc(Br)c1
Reactant: Nc1ccccc1Nc1ccccc1
Agent: CC(C)N=C=NC(C)C
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Nc1ccccc1Nc1ccccc1)c1cncc(Br)c1
Temperature: 50 °C
Yield: 83.2 %

Procedure:
A mixture of 5-bromonicotinic acid (20.0 g, 99 mmol), N-phenyl-o-phenylenediamine (19.32 g, 105 mmol), diisopropylcarbodiimide (DIC) (26.5 g, 210 mmol), and triethylamine (Et3N)(2.65 g, 27 mmol) in DCM (anhydrous, 350 mL) was heated to about 50° C. and degassed overnight under argon. After cooling to RT, the solids were then filtered off. The filtrate was washed with water (2×200 mL), dried over sodium sulfate and loaded onto silica gel. A flash column (gradient of 3% to 10% ethyl acetate in DCM) gave 30.32 g of 1E; 83% yield, pure by HNMR.