Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([NH:6][C:7](=[O:23])[NH:8][C@H:9]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:10]([O:12]C(C)(C)C)=[O:11])[CH2:5][CH2:4][CH2:3][CH2:2]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH:1]1([NH:6][C:7](=[O:23])[NH:8][C@H:9]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:10]([OH:12])=[O:11])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)[C@H](NC(=O)NC1CCCC1)c1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(NC1CCCC1)N[C@@H](C(=O)O)c1ccccc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 64.2 %

Procedure:
To a stirred solution of (R)-tert-butyl 2-(3-cyclopentylureido)-2-phenylacetate (1.31 g, 4.10 mmol) in CH2Cl2 (25 mL) was added TFA (4 mL) and trietheylsilane (1.64 mL; 10.3 mmol) dropwise, and the resulting solution was stirred at room temperature for 6 hours. The volatile components were removed under reduced pressure and the crude product was recrystallized in ethyl acetate/pentanes to yield (R)-2-(3-cyclopentylureido)-2-phenylacetic acid as a white solid (0.69 g, 64%). 1H NMR (500 MHz, DMSO-d6) δ ppm 1.17-1.35 (m, 2H) 1.42-1.52 (m, 2H) 1.53-1.64 (m, 2H) 1.67-1.80 (m, 2H) 3.75-3.89 (m, 1H) 5.17 (d, J=7.93 Hz, 1H) 6.12 (d, J=7.32 Hz, 1H) 6.48 (d, J=7.93 Hz, 1H) 7.24-7.40 (m, 5H) 12.73 (s, 1H). LC-MS: Anal. Calcd. for C14H18N2O3: 262.31. found: 263.15 (M+H)+. HPLC XTERRA® C-18 3.0×50 mm, 0 to 100% B over 2 minutes, 1 minute hold time, A=90% water, 10% methanol, 0.2% H3PO4, B=10% water, 90% methanol, 0.2% H3PO4, RT=1.24 min, 100% homogeneity index.
Reaction SMILES: [CH2:1]([CH:4]1[CH2:6][C:5]1([C:11]([O-:13])=O)[C:7]([O:9][CH3:10])=[O:8])[CH2:2][CH3:3].ClC(OCC)=O.[Br:20][C:21]1[CH:27]=[CH:26][C:24]([NH2:25])=[C:23]([CH3:28])[CH:22]=1.C(N(CC)CC)C>>[Br:20][C:21]1[CH:27]=[CH:26][C:24]([NH:25][C:11]([C:5]2([C:7]([O:9][CH3:10])=[O:8])[CH2:6][CH:4]2[CH2:1][CH2:2][CH3:3])=[O:13])=[C:23]([CH3:28])[CH:22]=1
Reactant: CCCC1CC1(C(=O)[O-])C(=O)OC
Reactant: Cc1cc(Br)ccc1N
Agent: CCOC(=O)Cl
Solvent: CCN(CC)CC
Product: CCCC1CC1(C(=O)Nc1ccc(Br)cc1C)C(=O)OC
Yield: 53.8 %

Procedure:
Mono-methyl 2-(n-propyl)cyclopropane-1,1-dicarboxylate (2.47 grams, 0.013 mole) from Part B, above, ethyl chloroformate (1.44 grams, 0.013 mole) and 4-bromo-2-methylaniline (2.48 grams, 0.013 mole) were reacted sequentially in the presence of triethylamine (1.35 grams, 0.013 mole) in a manner similar to that described in Example XXXIII to give 2.43 grams (0.007 mole) of methyl 1-(4-bromo-2-methyl-phenylaminocarbonyl)-2-n-propylcyclopropanecarb oxylate having a melting point of 60° C.-≢66° C.
Reaction SMILES: Br[C:2]1[S:6][C:5]([NH:7][C:8]2[C:9]([O:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[C:21]([CH3:24])([CH3:23])[CH3:22])=[N:10][CH:11]=[CH:12][CH:13]=2)=[N:4][C:3]=1[C:25]([F:28])([F:27])[F:26].[CH:29]([C:31]1[CH:32]=[C:33](B(O)O)[CH:34]=[CH:35][CH:36]=1)=[O:30]>>[C:21]([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[O:14][C:9]1[C:8]([NH:7][C:5]2[S:6][C:2]([C:35]3[CH:36]=[C:31]([CH:32]=[CH:33][CH:34]=3)[CH:29]=[O:30])=[C:3]([C:25]([F:28])([F:27])[F:26])[N:4]=2)=[CH:13][CH:12]=[CH:11][N:10]=1)([CH3:24])([CH3:23])[CH3:22]
Reactant: CC(C)(C)c1ccccc1Oc1ncccc1Nc1nc(C(F)(F)F)c(Br)s1
Reactant: O=Cc1cccc(B(O)O)c1
Product: CC(C)(C)c1ccccc1Oc1ncccc1Nc1nc(C(F)(F)F)c(-c2cccc(C=O)c2)s1

Procedure:
Example 374a was synthesized from N-(5-bromo-4-(trifluoromethyl)thiazol-2-yl)-2-(2-tert-butylphenoxy)pyridin-3-amine (Example 323a) and 3-formylphenyl boronic acid according to a similar procedure described for Example 107. Example 374a was obtained as a white foam. (M+H)+=498.3.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:7]=[CH:6][S:5][C:4]=1[C:8]([OH:10])=O.F[P-](F)(F)(F)(F)F.Br[P+](N1CCCC1)(N1CCCC1)[N:20]1[CH2:24]CC[CH2:21]1.CNC.C(N(C(C)C)CC)(C)C>C(#N)C>[CH3:21][N:20]([CH3:24])[C:8]([C:4]1[S:5][CH:6]=[CH:7][C:3]=1[O:2][CH3:1])=[O:10]
Reactant: COc1ccsc1C(=O)O
Reactant: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: CNC
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccsc1C(=O)N(C)C
Reaction time: 36 h
Yield: 193.6 %

Procedure:
To a suspension of 3-methoxythiophene carboxylic acid (1.84 g, 11.61 mmol), from step A, in 60 mL of acetonitrile at room temperature was added bromotripyrroli-dinophosphonium hexafluorophosphate (PyBrop, 5.40 g, 11.60 mmol), dimethyl amine (2.0 M in THF, 14.5 ml, 29.0 mmol) and diisopropylethyl amine (5.0 mL, 28.63 mmol) successively. After stirred for 1.5 day, the mixture was concentrated under reduced pressure to a yellow oil, which was purified by preparative TLC (CH2Cl2—MeOH=40:1). The silica was extracted with CH2Cl2 and methanol, the extracts were filtered and concentrated to an oil, which was further dried on high vacuum, yielding 4.16 g of N,N-dimethyl 3-methoxythiophene amide (contaminated by PyBrop impurity) (MH+=186.0).
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:13]2[S:14][CH:15]=[CH:16][C:12]=2[O:11][N:10]=1.B(Br)(Br)Br>ClCCl>[OH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:13]2[S:14][CH:15]=[CH:16][C:12]=2[O:11][N:10]=1
Reactant: COc1ccccc1-c1noc2ccsc12
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Oc1ccccc1-c1noc2ccsc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 69.4 %

Procedure:
To a solution of 23 g of 3-(2-methoxyphenyl)thieno[2,3-d]isoxazole in 450 ml of dichloromethane was added a boron tribromide solution in dichloromethane (150 ml, 1 M solution) over one hour. The reaction mixture was stirred for an additional one hour at room temperature and then poured over 600 ml of ice water. A precipitate was filtered off and washed with 50% ether/ethyl acetate. The aqueous phase was also extracted with 50% ether/ethyl acetate and the combined solvent solution was washed with water and dried over anhydrous magnesium sulfate. Evaporation of the solvent solution left 17 g of a solid which was passed through a silica gel column packed in hexane and eluted with 50% ether/hexane. The resultant solid was recrystallized from ether/hexane to give 15 g of a solid, m.p. 121°-123 C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH2:11][CH3:12])=[C:6]([N+:13]([O-])=O)[CH:5]=1>CO.CCOC(C)=O.[Pd]>[CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH2:11][CH3:12])=[C:6]([NH2:13])[CH:5]=1
Reactant: CCNc1ccc(C(=O)OC)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: CCNc1ccc(C(=O)OC)cc1N
Yield: 89 %

Procedure:
3-Amino-4-ethylamino-benzoic acid methyl ester (6.4 g) was prepared by following General Procedure B starting from 4-ethylamino-3-nitro-benzoic acid methyl ester (8.3 g) and Pd/C (20% by weight, 170 mg) in MeOH:EtOAc (1:1, 50.0 mL). The crude product was used in the next step without further purification.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:16]#[N:17])=[N:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14][OH:15])[CH:9]=2)=[CH:6][N:7]=1.[NH2:18][C:19]1[CH:20]=[C:21]([CH:26]=[CH:27][N:28]=1)[C:22]([NH:24][NH2:25])=O>CN(C=O)C>[NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([CH2:14][OH:15])[CH:11]=[CH:12][CH:13]=2)=[N:4][C:3]=1[C:16]1[NH:25][N:24]=[C:22]([C:21]2[CH:26]=[CH:27][N:28]=[C:19]([NH2:18])[CH:20]=2)[N:17]=1
Reactant: NNC(=O)c1ccnc(N)c1
Reactant: N#Cc1nc(-c2cccc(CO)c2)cnc1N
Solvent: CN(C)C=O
Product: Nc1cc(-c2n[nH]c(-c3nc(-c4cccc(CO)c4)cnc3N)n2)ccn1
Temperature: 180 °C
Yield: 5.8 %

Procedure:
To a solution of of 3-amino-6-[3-(hydroxymethyl)phenyl]pyrazine-2-carbonitrile (250 mg, 1.11 mmol) was added 2-aminoisonicotinic acid hydrazide (311 mg, 2.04 mmol). After being heated at 180° C. for 90 min, the reaction mixture was dissolved in DMF and washed with water, ethyl acetate (10 mL×3). The aqueous phase was extracted once with additional ethyl acetate. The combined organic layers were washed with saturated aqueous sodium chloride then dried over anhydrous magnesium sulfate. Filtration and concentration in vacuo gave a crude oil, which was purified by preparative HPLC to yield (3-{5-amino-6-[3-(2-aminopyridin-4-yl)-1H-1,2,4-triazol-5-yl]pyrazin-2-yl}phenyl)methanol (23.2 mg, 5.7% yield): 1H NMR (400 MHz, DMSO-d6): δ 8.80 (s, 1H), 8.15 (s, 1H), 8.10 (m, 1H), 7.70 (m, 2H), 7.43 (m, 2H), 7.20 (m, 1H), 6.10 (s, 2H), 5.25 (m, 1H) 4.60 (m, 1H); MS (EI) for C18H16N8O: 361.11 (MH+).
Reaction SMILES: S(Cl)([Cl:4])(=O)=O.[CH2:6]([O:10][CH:11]=[CH:12][C:13](=[O:18])[C:14]([F:17])([F:16])[F:15])[CH2:7][CH2:8][CH3:9]>ClCCl>[CH2:6]([O:10][CH:11]=[C:12]([Cl:4])[C:13](=[O:18])[C:14]([F:16])([F:17])[F:15])[CH2:7][CH2:8][CH3:9]
Reactant: CCCCOC=CC(=O)C(F)(F)F
Reactant: O=S(=O)(Cl)Cl
Solvent: ClCCl
Product: CCCCOC=C(Cl)C(=O)C(F)(F)F
Temperature: 0 °C
Reaction time: 4 h
Yield: 92.1 %

Procedure:
28.0 g (0.22 mole) of sulphuryl chloride in 60 ml of dichloromethane are added dropwise with stirring to 39.0 g (0.2 mole) of 4-n-butoxy-1,1,1-trifluoro-but-3-en-2-one in 200 ml of dichloromethane at 0° C. After stirring for 4 hours at 0° C., the solvent and unreacted sulphuryl chloride are distilled off and the residue is distilled slowly under reduced pressure. 42.5 g of pale yellow 4-n-butoxy-3-chloro-1,1,1-trifluorobut-3-en-2-one of boiling point 105°-106° C./12 mbar, nD20 =1.4484 are obtained.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:9]([OH:11])=O)=[CH:4][C:5]([F:8])=[N:6][CH:7]=1.[CH:12]([NH2:14])=O>>[F:8][C:5]1[N:6]=[CH:7][C:2]2[N:1]=[CH:12][NH:14][C:9](=[O:11])[C:3]=2[CH:4]=1
Reactant: NC=O
Reactant: Nc1cnc(F)cc1C(=O)O
Product: O=c1[nH]cnc2cnc(F)cc12
Yield: 20 %

Procedure:
Reaction of 5-amino-2-fluoropyridine-4-carboxylic acid with formamide at 140° C. as above gave 6-fluoro-3H-pyrido[3,4-d]pyrimidin-4-one (-20%). 1H NMR (DMSO) 6 12.48 (1H, m), 8.74 (1H, s), 8.16 (1H, s), 7.63 (1H, d, J=3 Hz).
Reaction SMILES: ClC(Cl)(Cl)[C:3]([C:5]1[N:14]2[C:8]([CH2:9][N:10]([C:19]([C:21]3[CH:26]=[CH:25][C:24]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[CH3:33])=[C:23]([CH3:34])[CH:22]=3)=[O:20])[C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[CH2:13]2)=[CH:7][CH:6]=1)=[O:4].[Cl:37][C:38]1[CH:45]=[CH:44][C:41]([CH2:42][NH2:43])=[CH:40][CH:39]=1>>[Cl:37][C:38]1[CH:45]=[CH:44][C:41]([CH2:42][NH:43][C:3]([C:5]2[N:14]3[C:8]([CH2:9][N:10]([C:19]([C:21]4[CH:26]=[CH:25][C:24]([C:27]5[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=5[CH3:33])=[C:23]([CH3:34])[CH:22]=4)=[O:20])[C:11]4[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=4[CH2:13]3)=[CH:7][CH:6]=2)=[O:4])=[CH:40][CH:39]=1
Reactant: NCc1ccc(Cl)cc1
Reactant: Cc1ccccc1-c1ccc(C(=O)N2Cc3ccc(C(=O)C(Cl)(Cl)Cl)n3Cc3ccccc32)cc1C
Product: Cc1ccccc1-c1ccc(C(=O)N2Cc3ccc(C(=O)NCc4ccc(Cl)cc4)n3Cc3ccccc32)cc1C

Procedure:
The title compound was synthesized in the manner of Example 13 from 2,2,2-trichloro-1-{10-[(2,2′-dimethyl-1,1′-biphenyl-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}ethanone of Example 6 and 4-chlorobenzylamine, m.p. 196-197° C. MS [(+)ESI, m/z]: 558 [M+H]+
Reaction SMILES: [C:1]([C:5]1[N:10]=[C:9]([CH3:11])[C:8](/[CH:12]=[CH:13]/[C:14]([OH:16])=O)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH2:17][C:18]1[CH:19]=[C:20]2[C:24](=[CH:25][CH:26]=1)[NH:23][C:22]([CH2:27][OH:28])=[CH:21]2>>[C:1]([C:5]1[N:10]=[C:9]([CH3:11])[C:8](/[CH:12]=[CH:13]/[C:14]([NH:17][C:18]2[CH:19]=[C:20]3[C:24](=[CH:25][CH:26]=2)[NH:23][C:22]([CH2:27][OH:28])=[CH:21]3)=[O:16])=[CH:7][CH:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: Nc1ccc2[nH]c(CO)cc2c1
Reactant: Cc1nc(C(C)(C)C)ccc1/C=C/C(=O)O
Product: Cc1nc(C(C)(C)C)ccc1/C=C/C(=O)Nc1ccc2[nH]c(CO)cc2c1

Procedure:
Analogous to the procedure used to prepare Example 1, (2E)-3-[6-(tert-butyl)-2-methyl(3-pyridyl)]prop-2-enoic acid, Example 75(c), (110 mg, 0.50 mmol) and (5-aminoindol-2-yl)methan-1-ol, Example 74(b), (81, 0.50 mmol) provided, after purification by silica gel chromatography (25:75 hexane:EtOAc), the title compound as a pale yellow solid. MP 213° C. MS (ESI, pos. ion) m/z: 364 (M+1).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([C@H:7]2[CH2:11][CH2:10][CH2:9][N:8]2[C:12]([C:14]2[CH:15]=[C:16]([CH:21]=[CH:22][CH:23]=2)[C:17]([O:19]C)=[O:18])=[O:13])[S:5][CH:6]=1.[Li+].[OH-].Cl>C1COCC1.O>[CH3:1][C:2]1[N:3]=[C:4]([C@H:7]2[CH2:11][CH2:10][CH2:9][N:8]2[C:12]([C:14]2[CH:15]=[C:16]([CH:21]=[CH:22][CH:23]=2)[C:17]([OH:19])=[O:18])=[O:13])[S:5][CH:6]=1
Reactant: COC(=O)c1cccc(C(=O)N2CCC[C@@H]2c2nc(C)cs2)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1csc([C@H]2CCCN2C(=O)c2cccc(C(=O)O)c2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.1 %

Procedure:
To the solution of (R)-methyl 3-(2-(4-methylthiazol-2-yl)pyrrolidine-1-carbonyl)benzoate (155 mg, 0.49 mmol) in THF (5 mL) was added 1N LiOH (2 mL) and the reaction mixture was stirred at rt for 1 h. Then the volatiles were removed on a rotavap under reduced pressure. Then reaction mixture was diluted with water, acidified with 1N HCl to pH ˜3 and extracted with ethyl acetate. Organic layer was dried and evaporated to yield 132 mg of the acid (R)-3-(2-(4-methylthiazol-2-yl)pyrrolidine-1-carbonyl)benzoic acid. \
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=2)=[O:9])[CH2:4][CH2:3]1.[CH3:21][S:22](Cl)(=[O:24])=[O:23].C(N(CC)CC)C>C(Cl)Cl>[CH3:21][S:22]([O:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=2)=[O:9])[CH2:4][CH2:3]1)(=[O:24])=[O:23]
Reactant: O=C(OCc1ccc([N+](=O)[O-])cc1)N1CCC(O)CC1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OC1CCN(C(=O)OCc2ccc([N+](=O)[O-])cc2)CC1
Reaction time: 0.17 h
Yield: 62.4 %

Procedure:
To a solution of 4-hydroxy-1-(p-nitrobenzyloxycarbonyl)piperidine (2.96 g, 14.8 mmol) (obtained as described in Reference Example 51(1)) in methylene chloride (90 ml) were added methanesulfonyl chloride (1.15 ml, 14.8 mmol) and triethylamine (2.07 ml, 14.8 mmol) in an ice bath. The reaction mixture was brought to room temperature in 10 minutes, and then stirred for 6 hours. After checking the completion of the reaction, the reaction mixture was partitioned between ethyl acetate and saturated aqueous sodium hydrogencarbonate solution. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The obtained residue was recrystallized from a solution of n-hexane:ethyl acetate (1:1) to afford 4-methanesulfonyloxy-1-(p-nitrobenzyloxycarbonyl)piperidine (3.31 g, yield 87%) as pale yellow crystals.
Reaction SMILES: [C:1]([C:3]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:4][CH2:5][N:6]([CH2:8][CH2:9][C:10]1[CH:11]=[CH:12][C:13]2[O:17][CH2:16][CH2:15][C:14]=2[CH:18]=1)[CH3:7])#[N:2].[OH-].[K+].C([OH:35])C>O>[O:17]1[C:13]2[CH:12]=[CH:11][C:10]([CH2:9][CH2:8][N:6]([CH2:5][CH2:4][C:3]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:1]([NH2:2])=[O:35])[CH3:7])=[CH:18][C:14]=2[CH2:15][CH2:16]1
Reactant: CCO
Reactant: CN(CCc1ccc2c(c1)CCO2)CCC(C#N)(c1ccccc1)c1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: CN(CCc1ccc2c(c1)CCO2)CCC(C(N)=O)(c1ccccc1)c1ccccc1
Temperature: 140 °C

Procedure:
A mixture containing 1-cyano-1,1-diphenyl-3-[N-{2-(2,3-dihydrobenzofur-5-yl)ethyl}-N-methylamino]propane (0.087 g), potassium hydroxide (0.074 g), ethanol (6 ml) and water (6 ml) was heated at 140° C. in a stainless steel pressure vessel for 48 hours. On cooling to room temperature the mixture was concentrated in vacuo. Water (20 ml) was added to the residue and the mixture was extracted with dichloromethane (3×20 ml). The combined dichloromethane extracts were dried (Na2SO4) and concentrated in vacuo to give a gum which was purified by column chromatography on silica eluting with dichloromethane containing methanol (0% up to 10%). The product-containing fractions were combined and concentrated in vacuo to give the title compound as a glass, yield 0.056 g.
Reaction SMILES: C[C:2]1[CH:3]=[C:4]([C:9]([C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[C:14](C)[CH:13]=2)(C)C)[CH:5]=[CH:6][C:7]=1[OH:8].[CH2:20]([Cl:22])[Cl:21].C(Cl)(Cl)=O>[OH-].[K+]>[CH:5]1[C:4]([C:9]([C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=2)=[C:20]([Cl:22])[Cl:21])=[CH:3][CH:2]=[C:7]([OH:8])[CH:6]=1
Reactant: Cc1cc(C(C)(C)c2ccc(O)c(C)c2)ccc1O
Reactant: ClCCl
Agent: O=C(Cl)Cl
Agent: [K+]
Agent: [OH-]
Product: Oc1ccc(C(=C(Cl)Cl)c2ccc(O)cc2)cc1

Procedure:
A solution prepared by dissolving 0.2 kg of 2.2-bis(3-methyl-4-hydroxyphenyl) propane in 1.2 kg of aqueous potassium hydroxide having a concentration of 16 mass % was mixed with 1.0 kg of methylene chloride. Then, while the solution was being stirred, phosgene gas was blown into the solution while cooling at 1 L/min until pH becomes 9 or less. Subsequently, the reaction solution was separated in a stand still manner, and a methylene chloride solution of an oligomer which has 2 to 6 polymerization degree and a chloroformate group at its molecular terminal was obtained as an organic layer (a solid content concentration of 0.30 kg/L). This oligomer is referred to as “PCO-C” hereinafter.
Reaction SMILES: [C:1]1([O:7][CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(=O)(=O)(O)O.[N:14]1[CH:19]=[CH:18][C:17]([CH:20]=O)=[CH:16][CH:15]=1>>[CH3:8][O:7][C:1]1[CH:6]=[CH:5][C:4]([CH:20]([C:4]2[CH:5]=[CH:6][C:1]([O:7][CH3:8])=[CH:2][CH:3]=2)[C:17]2[CH:16]=[CH:15][N:14]=[CH:19][CH:18]=2)=[CH:3][CH:2]=1
Reactant: COc1ccccc1
Reactant: O=Cc1ccncc1
Agent: O=S(=O)(O)O
Product: COc1ccc(C(c2ccncc2)c2ccc(OC)cc2)cc1
Temperature: 70 °C

Procedure:
Anisole, 108.13 g (1.0 mole) was cooled in an ice bath. Concentrated sulfuric acid, 115.3 ml (2.0 mole) was added while stirring the mixture in an ice bath. The temperature rose to 55° C. The reaction was then cooled in the ice bath. To this solution was added 4-pyridine carboxaldehyde, 53.5 g (0.5 mole). The temperature rose to 95° C. and further cooling and stirring brought the temperature down to 20° C. The reaction mixture was heated to 70° C. for 31/2 hr. The red gel was made alkaline with 50% sodium hydroxide-ice mix. The alkaline phase was extracted with toluene and the toluene extracted with a saturated sodium chloride solution. The product crystallized from the toluene solution while standing at room temperature. The white solid can be recrystallized from hot hexane-isopropyl alcohol.
Reaction SMILES: Br[CH:2]([CH2:8][CH2:9][CH2:10]Br)[C:3]([O:5][CH2:6][CH3:7])=[O:4].C(=O)([O-])[O-].[K+].[K+].[CH2:18]([NH2:30])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29].CO>C(O)C>[CH2:6]([O:5][C:3](=[O:4])[C@@H:2]1[CH2:8][CH2:9][CH2:10][N:30]1[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH3:7]
Reactant: CCCCCCCCCCCCN
Reactant: CCOC(=O)C(Br)CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CCO
Product: CCCCCCCCCCCCN1CCC[C@H]1C(=O)OCC

Procedure:
In 150 ml of ethanol was dissolved 22.8 g of ethyl 2,5-dibromovalerate, and 15 g of potassium carbonate was suspended in the solution. To the suspension was added dropwise a methanolic solution of 18.5 g of laurylamine under ice-cooling. After the addition, the reaction mixture was allowed by react at a refluxing temperature of methanol for 5 hours to obtain N-dodecylproline ethyl ester.
Reaction SMILES: [CH2:1]1[O:6][CH:2]1[CH2:3][CH2:4][CH3:5].[CH2:7]([NH2:19])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][NH2:18]>>[CH2:17]([NH:18][CH2:1][CH:2]([OH:6])[CH2:3][CH2:4][CH3:5])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][NH:19][CH2:1][CH:2]([OH:6])[CH2:3][CH2:4][CH3:5]
Reactant: CCCC1CO1
Reactant: NCCCCCCCCCCCN
Product: CCCC(O)CNCCCCCCCCCCCNCC(O)CCC

Procedure:
Condensation of 1-pentene oxide and 1,11-undecanediamine affords N,N'-(1,11-undecylene)-bis[2-hydroxypentylamine] (I: R = CH3 (CH2)2, R' = H, X = (CH2)11, Z = H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](Cl)[N:5]2[N:9]=[CH:10][CH:11]=[C:4]2[N:3]=1.[CH:12]([S:15]([C:18]1[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=1[NH2:20])(=[O:17])=[O:16])([CH3:14])[CH3:13].[H-].[Na+]>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([NH:20][C:19]2[CH:21]=[CH:22][CH:23]=[CH:24][C:18]=2[S:15]([CH:12]([CH3:14])[CH3:13])(=[O:17])=[O:16])[N:5]2[N:9]=[CH:10][CH:11]=[C:4]2[N:3]=1
Reactant: CC(C)S(=O)(=O)c1ccccc1N
Reactant: Clc1cc(Cl)n2nccc2n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)S(=O)(=O)c1ccccc1Nc1cc(Cl)nc2ccnn12
Temperature: 50 °C
Reaction time: 2 h

Procedure:
To a solution of 5,7-dichloro-pyrazolo[1,5-a]pyrimidine (1.0 mmol) and 2-(isopropylsulfonyl)aniline(1.0 mmol) in 5 mL of DMF, was added carefully NaH (24 mg). The resulting suspension was stirred at 50° C. for 2 hours. After cooling at RT and careful quenching (ice), water was added and the mixture was extracted with EtOAc. The organic layers were collected, dried (Na2SO4), filtrated and concentrated. The residue was purified over SiO2 column chromatography (eluent: 9:1 Hexane:EtOAc), to give the desired 5-chloro-N-(2-(isopropylsulfonyl)phenyl)pyrazolo[1,5-a]pyrimidin-7-amine. MS (ES+): 351.06 (M+1)+.
Reaction SMILES: [CH2:1]([O:3][C:4]1[NH:8][N:7]=[C:6]([NH:9][C:10]2[C:15]([N+:16]([O-])=O)=[CH:14][CH:13]=[C:12]([NH:19][C@H:20]([C:22]3[N:27]=[CH:26][C:25]([F:28])=[CH:24][N:23]=3)[CH3:21])[N:11]=2)[CH:5]=1)[CH3:2].[CH2:29](O)C.C(OCC)(=O)C>[Cl-].[Na+].O.[Pd]>[CH2:1]([O:3][C:4]1[NH:8][N:7]=[C:6]([N:9]2[C:10]3=[N:11][C:12]([NH:19][C@H:20]([C:22]4[N:27]=[CH:26][C:25]([F:28])=[CH:24][N:23]=4)[CH3:21])=[CH:13][CH:14]=[C:15]3[N:16]=[CH:29]2)[CH:5]=1)[CH3:2]
Reactant: CCOc1cc(Nc2nc(N[C@@H](C)c3ncc(F)cn3)ccc2[N+](=O)[O-])n[nH]1
Reactant: CCO
Agent: [Pd]
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: CCOc1cc(-n2cnc3ccc(N[C@@H](C)c4ncc(F)cn4)nc32)n[nH]1
Temperature: 25 °C

Procedure:
N2-(5-Ethoxy-1H-pyrazol-3-yl)-N6-[(1S)-1-(5-fluoropyrimidin-2-yl)ethyl]-3-nitropyridine-2,6-diamine (Intermediate 28, 0.3 g) was dissolved into ethanol (20 mL) with Pd—C (90 mg) and a hydrogen inlet. The mixture was stirred at room temperature until no starting material was detected with TLC or LCMS. Formylamidine acetate (0.5 g) was added to the filtrate after the filtration of resulting mixture. The mixture was stirred at 85° C. for 4 hours. Ethyl acetate (40 mL) was added into the resulting mixture, and brine (10 mL×3) was used to wash the organic layer. The organic layer was dried and concentrated. The resulting residue was separated by silica gel column (Ethyl acetate/MeOH) to afford 0.034 g of the title compound. MS (electrospray): 369 (M+1) for C17H17FN8O. 1H NMR (300 MHz, CD3OD) δ ppm 8.70 (s, 2H) 8.30 (s, 1H) 7.80 (d, 1H) 6.80 (d, 1H) 6.30 (s, 1H) 5.40 (m, 1H) 4.30 (q, 2H) 1.70 (d, 3H) 1.55 (t, 3H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4](=O)[CH:5](Cl)[C:6]1[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([F:13])[CH:7]=1.[C:17]([NH2:20])(=[S:19])[CH3:18]>>[CH3:1][O:2][C:3]([C:4]1[N:20]=[C:17]([CH3:18])[S:19][C:5]=1[C:6]1[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([F:13])[CH:7]=1)=[O:16]
Reactant: COC(=O)C(=O)C(Cl)c1ccc(C)c(F)c1
Reactant: CC(N)=S
Product: COC(=O)c1nc(C)sc1-c1ccc(C)c(F)c1

Procedure:
prepared by reaction of 3-chloro-3-(3-fluoro-4-methyl-phenyl)-2-oxo-propionic acid methyl ester with thioacetamide. LC-MS: tR=1.00 min; [M+H]+=266.0.
Reaction SMILES: [Br:1][C:2]1[O:6][C:5]([C:7]([OH:9])=O)=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([NH2:25])=[CH:21][C:20]=1[N:26]1[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]1>S(Cl)(Cl)=O>[Br:1][C:2]1[O:6][C:5]([C:7]([NH:25][C:22]2[CH:23]=[CH:24][C:19]([O:18][CH3:17])=[C:20]([N:26]3[CH2:27][CH2:28][N:29]([CH3:32])[CH2:30][CH2:31]3)[CH:21]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: COc1ccc(N)cc1N1CCN(C)CC1
Reactant: O=C(O)c1ccc(Br)o1
Solvent: CCN(CC)CC
Solvent: O=S(Cl)Cl
Product: COc1ccc(NC(=O)c2ccc(Br)o2)cc1N1CCN(C)CC1
Reaction time: 18 h
Yield: 86.4 %

Procedure:
5-Bromofuroic acid (0.432;2.26 mmol) was heated at reflux in thionyl chloride (10 ml) for 30 minutes, cooled, evaporated in vacuo and the residue azeotroped with toluene. The residue was redissolved in CH2 Cl2 (10 ml) and treated with dry triethylamine (0.32 ml;2.26 mmol) and 4-methoxy-3-(4-methyl-1-piperazinyl)benzenamine (0.5 g;2.26 mmol). The solution was stirred under Ar (18 hours), evaporated in vacuo and partitioned satd. K2CO3 (aq)/EtOAc. The organic phases were combined, dried over Na2SO4, filtered and the filtrate evaporated in vacuo to a brown gum. The gum was purified by flash silica-gel chromatography and eluted with 2%MeOH/CHCl3 to yield the title compound as a pale yellow foam (0.77 g;86%), which was converted to the oxalate salt, mp=125°-127° C.