Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH:2]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:3]1([N:8]([CH3:10])[CH3:9])[CH2:7][CH2:6][CH2:5][CH2:4]1.ClC1C(C(F)(F)F)=CC=CC=1C(NC(C1(N(C)C)CCCC1)C1C=CC=CC=1)=O.[CH3:46][O:47][C:48]1[CH:56]=[CH:55][CH:54]=[C:53]([CH3:57])[C:49]=1[C:50](O)=[O:51].O.ON1C2C=CC=CC=2N=N1.C1CCC(N=C=NC2CCCCC2)CC1>C(Cl)Cl>[CH3:9][N:8]([CH3:10])[C:3]1([CH:2]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[NH:1][C:50](=[O:51])[C:49]2[C:48]([O:47][CH3:46])=[CH:56][CH:55]=[CH:54][C:53]=2[CH3:57])[CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: CN(C)C1(C(N)c2ccccc2)CCCC1
Reactant: COc1cccc(C)c1C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)C1(C(NC(=O)c2cccc(C(F)(F)F)c2Cl)c2ccccc2)CCCC1
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O
Product: COc1cccc(C)c1C(=O)NC(c1ccccc1)C1(N(C)C)CCCC1
Reaction time: 8 h

Procedure:
A mixture of {1-[amino(phenyl)methyl]cyclopentyl}dimethylamine D3 enantiomer 2 (0.220 g, 1 mmol), 2-methoxy-6-methylbenzoic acid (0.200 g, 1.2 mmol), 1-hydroxybenzotriazole hydrate (0.183 g, 1.2 mmol) and PS-DCC (1 g of 1.3 mmol/g loading, 1.3 mmol) in DCM (10 ml) was stirred vigorously overnight. The mixture was washed with saturated aqueous sodium hydrogen carbonate, the layers separated through a phase separation cartridge and the organic layer applied to an SCX cartridge. The cartridge was eluted with DCM (×2), and then methanol (×2) followed by 1M ammonia in methanol. Evaporation of the solvent afforded the title compound which was characterised. 1H NMR (CDCl3) δ: 1.00-1.10 (1H, m), 1.25-1.40 (1H, m), 1.40-1.60 (2H, m), 1.60-1.80 (2H, m), 1.80-2.00 (2H, m), 2.24 (6H, s), 2.28 (3H, s), 3.80 (3H, s), 5.17 (1H, d, J=6 Hz), 6.75 (1H, d, J=8 Hz), 6.79 (1H, d, J=8 Hz), 7.10 (1H, br s), 7.15-7.30 (4H, m), 7.44 (2H, m). Mass Spectrum (Electrospray LC/MS): Found 367 (MH+). C23H30N2O2 requires 366. Ret. time 1.92 min. The title product was converted to the corresponding hydrochloride salt (0.34 g, 85%).
Reaction SMILES: [F:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][O:7][C:8]2[CH:9]=[CH:10][C:11](I)=[C:12]([CH2:14][C:15]([NH:17][C@H:18]([CH3:22])[C:19]([NH2:21])=[O:20])=[O:16])[CH:13]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:33](OCC)(=[O:35])C>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[F:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][O:7][C:8]2[CH:13]=[C:12]3[C:11](=[CH:10][CH:9]=2)[C:33](=[O:35])[N:17]([C@H:18]([CH3:22])[C:19]([NH2:21])=[O:20])[C:15](=[O:16])[CH2:14]3)=[CH:4][CH:3]=1
Reactant: C[C@@H](NC(=O)Cc1cc(OCc2ccc(F)cc2)ccc1I)C(N)=O
Reactant: CCOC(C)=O
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: C[C@H](C(N)=O)N1C(=O)Cc2cc(OCc3ccc(F)cc3)ccc2C1=O
Yield: 25 %

Procedure:
As described for example 20f, the title compound (10 mg, 25%) was prepared from a mixture of 2-(R)-{2-[5-(4-Fluoro-benzyloxy)-2-iodo-phenyl]-acetylamino}-propionamide (50 mg, 0.109 mmol), triethylamine (0.030 mL, 0.218 mmol), bis (triphenylphosphine) palladium II chloride (1.5 mg, 0.0022 mmol) in 1 mL ethyl acetate. MS: m/e=357.2 (M+H+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:19])=[C:6]([C:8]2[N:17]=[C:16](Cl)[C:15]3[C:10](=[N:11][CH:12]=[CH:13][N:14]=3)[N:9]=2)[CH:7]=1.[CH3:20][O:21][C:22](=[O:30])[C:23]1[C:28]([NH2:29])=[CH:27][CH:26]=[N:25][CH:24]=1.C(N(CC)CC)C>ClC(Cl)C>[CH3:20][O:21][C:22](=[O:30])[C:23]1[C:28]([NH:29][C:16]2[C:15]3[C:10](=[N:11][CH:12]=[CH:13][N:14]=3)[N:9]=[C:8]([C:6]3[CH:7]=[C:2]([Br:1])[CH:3]=[CH:4][C:5]=3[F:19])[N:17]=2)=[CH:27][CH:26]=[N:25][CH:24]=1
Reactant: COC(=O)c1cnccc1N
Reactant: Fc1ccc(Br)cc1-c1nc(Cl)c2nccnc2n1
Solvent: CCN(CC)CC
Solvent: CC(Cl)Cl
Product: COC(=O)c1cnccc1Nc1nc(-c2cc(Br)ccc2F)nc2nccnc12
Temperature: 70 °C
Yield: 74.6 %

Procedure:
To a solution of 2-(5-bromo-2-fluorophenyl)-4-chloropteridine 106 (200 mg, 0.589 mmol), 4-aminonicotinic acid methyl ester (224 mg, 1.47 mmol) in dichloroethane (5 mL), was added dropwise triethylamine (300 μL, 2.07 mmol). The resulting mixture was heated at 70° C. for 15 min, then quenched with silica and purified by column chromatography (AcOEt/CH2Cl2/triethylamine, 70/19/1). Crystallization from AcOEt/Et2O afforded 200 mg of the title product 107 as yellow prisms (LCMS analysis).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5](I)=[CH:4][N:3]=1.[O:10]1[CH2:14][CH2:13][CH2:12][CH:11]1[CH2:15][OH:16].CC1(C)C(C)(C)OB([C:25]2[S:26][CH:27]=[CH:28][CH:29]=2)O1>>[Cl:1][C:2]1[N:7]=[C:6]([O:16][CH2:15][CH:11]2[CH2:12][CH2:13][CH2:14][O:10]2)[C:5]([C:25]2[S:26][CH:27]=[CH:28][CH:29]=2)=[CH:4][N:3]=1
Reactant: Clc1ncc(I)c(Cl)n1
Reactant: OCC1CCCO1
Reactant: CC1(C)OB(c2cccs2)OC1(C)C
Product: Clc1ncc(-c2cccs2)c(OCC2CCCO2)n1

Procedure:
Preparation according to procedures 4b and 3 with the use of 2,4-dichloro-5-iodopyrimidine, 2-tetrahydrofuranyl-methanol and 4,4,5,5-tetramethyl-2-(2-thienyl)-1,3,2-dioxaborolane.
Reaction SMILES: [OH:1][C:2]1[C:3]([C:12](Cl)=[O:13])=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.[CH2:15]1[CH:24]2[CH:19]([CH2:20][CH2:21][CH2:22][CH2:23]2)[CH2:18][CH2:17][NH:16]1.CCN(C(C)C)C(C)C>C1COCC1>[OH:1][C:2]1[C:3]([C:12]([N:16]2[CH2:17][CH2:18][CH:19]3[CH:24]([CH2:23][CH2:22][CH2:21][CH2:20]3)[CH2:15]2)=[O:13])=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2
Reactant: C1CCC2CNCCC2C1
Reactant: O=C(Cl)c1ccc2cccnc2c1O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: O=C(c1ccc2cccnc2c1O)N1CCC2CCCCC2C1
Temperature: 50 °C

Procedure:
A solution of 8-hydroxyquinoline-7-carbonyl chloride of Preparation 2 (70 mg, 0.35 mmol) and decahydroisoquinoline (62.6 mg, 0.45 mmol) in THF (8 mL) and DIPEA (259 mg, 2.0 mmol) was stirred and heated at 50° C. overnight. The reaction mixture was concentrated under reduced pressure and the residue was partitioned between DCM and H2O. The separated organics were dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, DCM:MeOH 98:2) and then by preparative HPLC. Product-containing fractions were combined, made basic with a saturated aqueous solution of sodium hydrogen carbonate and CH3CN was removed under reduced pressure. The aqueous phase was extracted with DCM and the separated organics dried over Na2SO4, filtered and concentrated to dryness, affording the title compound (49 mg, 0.16 mmol) as a off-white solid.
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:13][C@@H:14]2[CH2:18][C@H:17]([O:19][CH2:20][CH2:21][OH:22])[C@@H:16]([OH:23])[C@H:15]2[OH:24])=[N:4][C:5]([S:9][CH2:10][CH2:11][CH3:12])=[N:6][C:7]=1[Cl:8].[N:25]([O-])=O.[Na+]>C(O)(=O)C.C(OCC)(=O)C>[Cl:8][C:7]1[C:2]2[N:1]=[N:25][N:13]([C@@H:14]3[CH2:18][C@H:17]([O:19][CH2:20][CH2:21][OH:22])[C@@H:16]([OH:23])[C@H:15]3[OH:24])[C:3]=2[N:4]=[C:5]([S:9][CH2:10][CH2:11][CH3:12])[N:6]=1
Reactant: O=N[O-]
Reactant: CCCSc1nc(Cl)c(N)c(N[C@@H]2C[C@H](OCCO)[C@@H](O)[C@H]2O)n1
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CCCSc1nc(Cl)c2nnn([C@@H]3C[C@H](OCCO)[C@@H](O)[C@H]3O)c2n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 85.5 %

Procedure:
To a stirring solution of (1S,2S,3R,5S)-3-((5-amino-6-chloro-2-(propylthio)pyrimidin-4-yl)amino)-5-(2-hydroxyethoxy)cyclopentane-1,2-diol (OLACINA; 1.14 g, 3 mmol) in acetic acid (5 mL) was added sodium nitrite (0.23 g, 3.3 mmol) while maintaining the reaction temperature at 20-30° C. The reaction mixture was stirred for 30 minutes. It was then diluted with ethyl acetate (50 mL), washed with water (2×35 mL) and evaporated under reduced pressure. The crude product was triturated in hexane (20 mL) and filtered to give CLTOL as an off-white powder (1.00 g, 86% yield): 98 area % by HPLC; mp 98-107° C.; 13C NMR (CDCl3, 125 MHz) δ13.4, 22.0, 33.5, 33.7, 61.75, 61.77, 71.1, 74.9, 75.4, 82.0, 131.8, 150.7, 152.9, 171.8.
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]1[CH:8]=[CH:7][C:6]([CH3:9])=[N:5]1.S(C1C=CC(C)=CC=1)(OC[C@@H:15]1[CH2:29][C@H:28]2[C@@H:18]([CH2:19][C:20]3[C:30]4[C:23](=[CH:24][CH:25]=[CH:26][C:27]2=4)[NH:22][CH:21]=3)[N:17]([CH3:31])[CH2:16]1)(=O)=O.[CH3:39]N(C)C=O>>[CH3:9][C:6]1[CH:7]=[C:8]([CH3:39])[N:4]([CH2:3][C@@H:15]2[CH2:29][C@H:28]3[C@@H:18]([CH2:19][C:20]4[C:30]5[C:23](=[CH:24][CH:25]=[CH:26][C:27]3=5)[NH:22][CH:21]=4)[N:17]([CH3:31])[CH2:16]2)[N:5]=1
Reactant: CN(C)C=O
Reactant: Cc1ccn(C)n1
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H]2C[C@@H]3c4cccc5[nH]cc(c45)C[C@H]3N(C)C2)cc1
Agent: [H-]
Agent: [Na+]
Product: Cc1cc(C)n(C[C@@H]2C[C@@H]3c4cccc5[nH]cc(c45)C[C@H]3N(C)C2)n1
Reaction time: 0.5 h

Procedure:
0.7 g of 50% sodium hydride in an oil was added in small portions to a mixture of 1.9 g of 2,5-dimethylpyrazole and 50 ml of dimethylformamide, and the resulting mixture was stirred for 30 minutes. 2.0 g of 6-methylergolin-8β-ylmethyl tosylate was added to the mixture which was then heated on a water bath for 3 hours. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (eluted with ethyl acetate:ethanol=10:1 by volume). The product was recrystallized from isopropyl alcohol to obtain 0.8 g of the titled compound as colorless prisms having a melting point of 187°-190° C.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]23[O:16][CH2:15][C:12]([CH2:17][CH2:18][CH3:19])([CH2:13][O:14]2)[CH2:11][O:10]3)=[CH:5][CH:4]=1)#[CH:2].[CH3:20][N:21]=[C:22]=[S:23]>>[CH3:20][NH:21][C:22](=[S:23])[C:2]#[C:1][C:3]1[CH:4]=[CH:5][C:6]([C:9]23[O:10][CH2:11][C:12]([CH2:17][CH2:18][CH3:19])([CH2:13][O:14]2)[CH2:15][O:16]3)=[CH:7][CH:8]=1
Reactant: CN=C=S
Reactant: C#Cc1ccc(C23OCC(CCC)(CO2)CO3)cc1
Product: CCCC12COC(c3ccc(C#CC(=S)NC)cc3)(OC1)OC2

Procedure:
N-Methyl-3-[4-(4-n-propyl-2,6,7-trioxabicyclo[2,2,2]oct-1-yl)phenyl]-prop-2-yn-thioamide was prepared from 1-(4-ethynylphenyl)-4-n-propyl-2-yn-thioamide was prepared from 1-(4-ethynylphenyl)-4-n-propyl-2,6,7-trioxabicyclo[2,2,2]octane and methylisothiocyanate in a manner analogous to the synthesis of N-Methyl-3-[4-(4-n-propyl-2,6,7-trioxabicyclo[2,2,]oct-1-yl)phenyl]-prop-2-ynamide.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10].Cl.Cl[C:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[N:19]=[CH:18][C:17]=1[N+:26]([O-:28])=[O:27]>>[N+:26]([C:17]1[CH:18]=[N:19][C:20]2[C:25]([C:16]=1[NH:1][CH2:2][CH2:3][CH2:4][CH2:5][NH:6][C:7](=[O:13])[O:8][C:9]([CH3:10])([CH3:12])[CH3:11])=[CH:24][CH:23]=[CH:22][CH:21]=2)([O-:28])=[O:27]
Reactant: CC(C)(C)OC(=O)NCCCCN
Reactant: O=[N+]([O-])c1cnc2ccccc2c1Cl
Agent: Cl
Product: CC(C)(C)OC(=O)NCCCCNc1c([N+](=O)[O-])cnc2ccccc12
Yield: 99886.9 %

Procedure:
Using the general method of Example 1 Part A, tert-butyl N-(4-aminobutyl)carbamate (254 g, 1.35 mol) was reacted with 4-chloro-3-nitroquinoline hydrochloride (331 g, 1.35 mmol) to provide 486 g of tert-butyl N-(4-[(3-nitroquinolin-4-yl)amino]butyl)carbamate as yellow solid. Analysis: Calculated for C18H24N4O4: % C, 59.99; % H, 6.71; % N, 15.55. Found: % C, 59.68; % H, 6.59; % N, 15.74.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([C:14](=O)[CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:5]([CH:9]=[C:10]([O:12][CH3:13])[CH:11]=1)[C:6](O)=[O:7].O.[NH2:24][NH2:25]>>[CH2:15]([C:14]1[C:4]2[C:5](=[CH:9][C:10]([O:12][CH3:13])=[CH:11][C:3]=2[O:2][CH3:1])[C:6](=[O:7])[NH:25][N:24]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: NN
Reactant: COc1cc(OC)c(C(=O)Cc2ccccc2)c(C(=O)O)c1
Solvent: O
Product: COc1cc(OC)c2c(Cc3ccccc3)n[nH]c(=O)c2c1

Procedure:
This compound is obtained according to the procedure described in 1.2. by reacting unpurified 3,5-dimethoxy-2-(phenylacetyl)benzoic acid with hydrazine hydrate.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.[CH3:10][C:11]1[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][C:12]=1[NH2:13]>C(O)C>[OH:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[N:13][C:12]1[CH:14]=[CH:15][CH:16]=[C:17]([Cl:18])[C:11]=1[CH3:10]
Reactant: O=Cc1ccccc1O
Reactant: Cc1c(N)cccc1Cl
Solvent: CCO
Product: Cc1c(Cl)cccc1N=Cc1ccccc1O
Reaction time: 0.25 h

Procedure:
o-Hydroxybenzaldehyde (0.20 mole) was treated with 2-methyl-3-chloroaniline (0.20 mole) with vigorous stirring in a 1 liter Erlenmeyer flask. After 15 mins. 33 cc of 95% ethanol was added and the reaction mixture was stirred vigorously for an additional 45 mins. The reaction mixture was left standing at room temperature for 10 min., then it was placed in an ice-bath for 0.5 hour. The crystals which formed were collected, washed with 95% ethanol, and air dried. Recrystallization from 85% ethanol gave N-(o-hydroxybenzylidene)-2-methyl-3-chloroaniline. m.p. 95°-97° C.
Reaction SMILES: CCN(C(C)C)C(C)C.[F:10][C:11]([F:28])([F:27])[O:12][C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[O:21][C:20](=[O:23])[C:19]([C:24]([OH:26])=O)=[CH:18]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[O:53]1[C:57]2[CH:58]=[CH:59][C:60]([C:62]3[CH:63]=[C:64]([NH2:68])[CH:65]=[CH:66][CH:67]=3)=[CH:61][C:56]=2[O:55][CH2:54]1>CN(C=O)C>[O:53]1[C:57]2[CH:58]=[CH:59][C:60]([C:62]3[CH:63]=[C:64]([NH:68][C:24]([C:19]4[C:20](=[O:23])[O:21][C:22]5[C:17]([CH:18]=4)=[CH:16][CH:15]=[CH:14][C:13]=5[O:12][C:11]([F:10])([F:28])[F:27])=[O:26])[CH:65]=[CH:66][CH:67]=3)=[CH:61][C:56]=2[O:55][CH2:54]1
Reactant: O=C(O)c1cc2cccc(OC(F)(F)F)c2oc1=O
Reactant: Nc1cccc(-c2ccc3c(c2)OCO3)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1cccc(-c2ccc3c(c2)OCO3)c1)c1cc2cccc(OC(F)(F)F)c2oc1=O
Temperature: 25 °C
Yield: 70 %

Procedure:
DIEA (0.014 mL, 0.077 mmol) was added to 8-trifluoromethoxy-3-carboxy-coumarin (0.019 g, 0.070 mmol) and HATU (0.029 g, 0.077 mmol) in 0.36 mL of DMF with constant stirring at room temperature until a clear solution resulted. Subsequently, 3-Benzo[1,3]dioxol-5-yl-phenylamine (0.015 g, 0.070 mmol) was added and allowed to react overnight when a solid precipitated out of solution. The resulting precipitate was filtered, dried under suction, and finally dried overnight in vacuo to give 0.023 g of product in 70% yield: LCMS (ESI) m/z 470 (MH+).
Reaction SMILES: [O:1]=[C:2]1[C:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH2:5][CH2:4][N:3]1[CH2:19][C:20]([OH:22])=O.FC1C=CC(C2(C3C=CC(F)=CC=3)CCN(CC(O)=O)C2=O)=CC=1.[F:47][C:48]1[CH:49]=[C:50]([CH:56]=[C:57]([F:59])[CH:58]=1)/[C:51](=[N:54]/[H])/[NH:52]O.ON/C(=N\[H])/C1C=CC(C(F)(F)F)=CC=1>>[F:47][C:48]1[CH:49]=[C:50]([C:51]2[N:54]=[C:20]([CH2:19][N:3]3[CH2:4][CH2:5][C:6]([C:7]4[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=4)([C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=4)[C:2]3=[O:1])[O:22][N:52]=2)[CH:56]=[C:57]([F:59])[CH:58]=1
Reactant: O=C(O)CN1CCC(c2ccccc2)(c2ccccc2)C1=O
Reactant: [H]/N=C(\NO)c1cc(F)cc(F)c1
Agent: O=C(O)CN1CCC(c2ccc(F)cc2)(c2ccc(F)cc2)C1=O
Agent: [H]/N=C(\NO)c1ccc(C(F)(F)F)cc1
Product: O=C1N(Cc2nc(-c3cc(F)cc(F)c3)no2)CCC1(c1ccccc1)c1ccccc1

Procedure:
The title compound was prepared using the procedure described in Example 190 substituting 2-(2-oxo-3,3-diphenylpyrrolidin-1-yl)acetic acid from Example 1C for 2-(3,3-bis(4-fluorophenyl)-2-oxopyrrolidin-1-yl)acetic acid and (Z)-3,5-difluoro-N-hydroxybenzimidamide for (Z)—N-hydroxy-4-(trifluoromethyl)benzimidamide. 1H NMR (300 MHz, CDCl3) δ ppm 7.56-7.49 (m, 2H), 7.42-7.24 (m, 10H), 7.01-6.91 (m, 1H), 4.89 (s, 2H), 3.57 (t, 2H), 2.90 (t, J=6.5, 2H); MS (DCI) m/z 432.1 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[O:3][C:4]1[CH:9]=[CH:8][C:7](OS(C2C=CC(C)=CC=2)(=O)=O)=[CH:6][CH:5]=1.[C:23]([C:25]1[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[C:27]([O:33][CH3:34])[CH:26]=1)#[CH:24]>CCCCCCC>[CH3:32][O:31][C:28]1[CH:29]=[CH:30][C:25]([C:23]#[C:24][C:7]2[CH:6]=[CH:5][C:4]([O:3][C:2]([F:1])([F:21])[F:22])=[CH:9][CH:8]=2)=[CH:26][C:27]=1[O:33][CH3:34]
Reactant: Cc1ccc(S(=O)(=O)Oc2ccc(OC(F)(F)F)cc2)cc1
Reactant: C#Cc1ccc(OC)c(OC)c1
Solvent: CCCCCCC
Product: COc1ccc(C#Cc2ccc(OC(F)(F)F)cc2)cc1OC

Procedure:
This product was prepared from toluene-4-sulfonic acid 4-trifluoromethoxy-phenyl ester and 4-ethynyl-1,2-dimethoxy-benzene following the general procedure for the Sonogashira cross-coupling process described above. Chromatography eluent: heptane; yield (140 mg, 87%); 1H NMR δ (CDCl3): 7.52 (d, J=8.40 Hz, 2H), 7.21-7.16 (m, 3H), 6.83 (d, J=8.41 Hz, 2H), 3.85 (s, 6H); LCMS m/z: 322.
Reaction SMILES: C1(N(C(=O)C2C=CC([N+]([O-])=O)=CC=2)N)C=CC=CC=1.P(Cl)(Cl)(Cl)(Cl)Cl.Cl.C1(O)C=CC=CC=1.ClP([N:38]([C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1)[N:39]=[C:40]([Cl:50])[C:41]1[CH:46]=[CH:45][C:44]([N+:47]([O-:49])=[O:48])=[CH:43][CH:42]=1)(Cl)=O>C(Cl)(Cl)(Cl)Cl>[C:51]1([NH:38][N:39]=[C:40]([Cl:50])[C:41]2[CH:46]=[CH:45][C:44]([N+:47]([O-:49])=[O:48])=[CH:43][CH:42]=2)[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=1
Reactant: O=[N+]([O-])c1ccc(C(Cl)=NN(c2ccccc2)P(=O)(Cl)Cl)cc1
Agent: Cl
Agent: ClP(Cl)(Cl)(Cl)Cl
Agent: NN(C(=O)c1ccc([N+](=O)[O-])cc1)c1ccccc1
Solvent: Oc1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: O=[N+]([O-])c1ccc(C(Cl)=NNc2ccccc2)cc1
Temperature: 25 °C

Procedure:
A quantity (12.86 g., 0.05 mole) of p-nitrobenzoic acid phenylhydrazide, prepared according to the method described by J. Hausknecht, Chem. Ber. 22, p. 324 (1889), was added to a suspension of 10.41 g. (0.05 mole) phosphorus pentachloride in 75 ml. carbon tetrachloride, and the resulting suspension was heated to the reflux temperature. Heating at the reflux temperature was continued until evolution of hydrogen chloride gas ceased. After cooling the reaction mixture to about 25° C., it was poured into an ice-cold suspension of 15.5 g. (0.17 mole) of phenol in 50 ml. carbon tetrachloride. When the reaction between the phenol and the p-nitrobenzoyl chloride (dichlorophosphinyl)phenylhydrazone intermediate was completed, the carbon tetrachloride solvent and other volatile components were removed by evaporation under reduced pressure at 30° C. The resulting suspension of p-nitrobenzoyl chloride phenylhydrazone in triphenyl phosphate was filtered and the filter cake comprising the p-nitrobenzoyl chloride phenylhydrazone was washed with 100 ml. carbon tetrachloride, 50 ml. methanol, and 50 ml. ether. The solid on the filter was recrystallized from a solvent mixture consisting of 100 ml. benzene and 300 ml. naphtha (boiling range 203° to 212° F.). There was thus obtained 4.10 g. of p-nitrobenzoyl chloride phenylhydrazone having a melting point of 156° to 157.5° C. A second recrystallization from a mixture of benzene and Skellysolve C gave the compound melting at 157° to 158.5° C.
Reaction SMILES: [Cl-].[CH3:2][C:3]1[N:8]2[N:9]=[C:10]([CH2:12][P+](C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[N:11]=[C:7]2[C:6]([CH3:32])=[CH:5][N:4]=1.[CH3:33][N:34]1[C:38]([CH:39]=O)=[N:37][C:36]([N:41]2[CH2:45][CH2:44][CH2:43][CH:42]2[CH3:46])=[N:35]1>>[CH3:2][C:3]1[N:8]2[N:9]=[C:10](/[CH:12]=[CH:39]/[C:38]3[N:34]([CH3:33])[N:35]=[C:36]([N:41]4[CH2:45][CH2:44][CH2:43][CH:42]4[CH3:46])[N:37]=3)[N:11]=[C:7]2[C:6]([CH3:32])=[CH:5][N:4]=1
Reactant: Cc1cnc(C)n2nc(C[P+](c3ccccc3)(c3ccccc3)c3ccccc3)nc12
Reactant: CC1CCCN1c1nc(C=O)n(C)n1
Agent: [Cl-]
Product: Cc1cnc(C)n2nc(/C=C/c3nc(N4CCCC4C)nn3C)nc12
Yield: 73.6 %

Procedure:
Was prepared in the same manner as described in Example 49e) using ((5,8-dimethyl-[1,2,4]triazolo[1,5-c]pyrimidin-2-yl)methyl)triphenylphosphonium chloride (350 mg, 763 μmol, Eq: 1.00) and 1-methyl-3-(2-methylpyrrolidin-1-yl)-1H-1,2,4-triazole-5-carbaldehyde (148 mg, 763 μmol, Eq: 1.00) affording 5,8-dimethyl-2-{(E)-2-[2-methyl-5-(2-methyl-pyrrolidin-1-yl)-2H-[1,2,4]triazol-3-yl]-vinyl}-[1,2,4]triazolo[1,5-c]pyrimidine (190 mg, 73.6%) as a bright yellow solid. MS: m/z=339.5 (M+H+)
Reaction SMILES: I.[CH3:2][C:3]1([CH3:29])[CH2:7][NH:6][CH2:5][C@H:4]1[NH:8][C:9]1[C:10]2[N:11]([CH:18]=[C:19]([C:21]3[CH:26]=[CH:25][N:24]=[C:23]([O:27][CH3:28])[CH:22]=3)[CH:20]=2)[N:12]=[CH:13][C:14]=1[C:15]([NH2:17])=[O:16].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)[C:41]2[CH:42]=CC=C[C:40]=2[N:39]=N1.C(N(CC)C(C)C)(C)C.CN(C)C=[O:69]>>[C:40]([CH2:41][C:42]([N:6]1[CH2:7][C:3]([CH3:29])([CH3:2])[C@H:4]([NH:8][C:9]2[C:10]3[N:11]([CH:18]=[C:19]([C:21]4[CH:26]=[CH:25][N:24]=[C:23]([O:27][CH3:28])[CH:22]=4)[CH:20]=3)[N:12]=[CH:13][C:14]=2[C:15]([NH2:17])=[O:16])[CH2:5]1)=[O:69])#[N:39]
Reactant: CN(C)C=O
Reactant: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Reactant: COc1cc(-c2cc3c(N[C@@H]4CNCC4(C)C)c(C(N)=O)cnn3c2)ccn1
Agent: F[P-](F)(F)(F)(F)F
Agent: I
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(-c2cc3c(N[C@@H]4CN(C(=O)CC#N)CC4(C)C)c(C(N)=O)cnn3c2)ccn1
Reaction time: 2 h
Yield: 52 %

Procedure:
A solution of (S)-4-((4,4-dimethylpyrrolidin-3-yl)amino)-6-(2-methoxypyridin-4-yl)pyrrolo[1,2-b]pyridazine-3-carboxamide hydroiodide (12 mg, 0.024 mmol) in N,N-dimethylformamide (1 mL), was added BOP (10.2 mg, 0.024 mmol) and N,N-diisopropylethylamine (0.012 mL, 0.07 mmol). The mixture was stirred for 2 h. The crude material was purified via preparative LC/MS with the following conditions: Column: Waters XBridge C18, 19×250 mm, 5-μm particles; Guard Column: Waters XBridge C18, 19×10 mm, 5-μm particles; Mobile Phase A: 5:95 acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10-mM ammonium acetate; Gradient: 25-100% B over 25 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation to give the title compound (7 mg, 52% yield). 1H NMR (400 MHz, METHANOL-d4, Rotamer) δ 8.36 (s, 1H), 8.27 (d, J=3.7 Hz, 1H), 8.20 (d, J=5.9 Hz, 1H), 7.67-7.62 (m, 1H), 7.57 (dd, J=16.5, 1.8 Hz, 1H), 7.53 (d, J=3.1 Hz, 1H), 4.73 (t, J=5.9 Hz, 1H), 4.28-4.17 (m, 1H), 4.15 (d, J=6.4 Hz, 3H), 3.89 (d, J=3.5 Hz, 1H), 3.86-3.83 (m, 1H), 3.65-3.46 (m, 4H), 1.36-1.25 (m, 6H). MS (ES+) m/z: 448.2, 448.2 (M+H); LC retention time: 2.86 min (analytical HPLC Method I).
Reaction SMILES: [C:1]([O:4][C:5]1[C:13]2[O:12][CH:11]=[C:10]([CH2:14][NH:15][C:16](=[O:18])[CH3:17])[C:9]=2[CH:8]=[CH:7][CH:6]=1)(=O)[CH3:2].[C:19](=O)([O-])[O-:20].[K+].[K+].C[OH:26]>>[C:16]([NH:15][CH2:14][C:10]1[C:9]2[CH:8]=[CH:7][CH:6]=[C:5]([O:4][CH2:1][C:2]([O:20][CH3:19])=[O:26])[C:13]=2[O:12][CH:11]=1)(=[O:18])[CH3:17]
Reactant: O=C([O-])[O-]
Reactant: CC(=O)NCc1coc2c(OC(C)=O)cccc12
Reactant: CO
Agent: [K+]
Product: COC(=O)COc1cccc2c(CNC(C)=O)coc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 78 %

Procedure:
7-acetoxy-3-((acetylamino)methyl)benzofuran (258 mg) and potassium carbonate (82 mg) were added to methanol (5 ml) and the obtained mixture was stirred at room temperature for 1 hour. After removing methanol under reduced pressure, DMF (5 ml) and methyl bromoacetate (0.15 ml) were added to the residue, followed by stirring the resultant for 18 hours. The reaction solution was poured into water layer (30 ml) and the resultant was extracted twice with ethyl acetate (20 ml). The organic layers were combined and washed with saturated brine, followed by drying over anhydrous sodium sulfate. After removing the sodium sulfate by filtration, the solvent was removed under reduced pressure and the residue was purified by column chromatography (solvent: chloroform/methanol=95/5) using silica gel to obtain the desired compound (227 mg, yield: 78%).