Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([F:12])[CH:11]=1)[NH:8][C:7](=S)[CH2:6][CH2:5]2.[C:14]([NH:17][NH2:18])(=O)[CH3:15]>C(O)CCC>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([F:12])[CH:11]=1)[N:8]1[C:14]([CH3:15])=[N:17][N:18]=[C:7]1[CH2:6][CH2:5]2
Reactant: CC(=O)NN
Reactant: Fc1cc(Br)cc2c1NC(=S)CC2
Solvent: CCCCO
Product: Cc1nnc2n1-c1c(F)cc(Br)cc1CC2
Temperature: 120 °C

Procedure:
To a stirred solution of 6-bromo-8-fluoro-3,4-dihydroquinoline-2(1H)-thione (109-4; 3.0 g, 0.011 mol) in n-butanol (25 mL) was added acetic hydrazide (4.81 g, 0.065 mol) and then followed by the addition of molecular sieves. Reaction mass was heated to 120° C. for 16 h. The reaction mixture was concentrated and directly purified by silica gel column chromatography to obtain title compound. MS (M+1): 284.2.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]3[CH:19]=[C:18]([CH2:20][C:21]4[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=4)[C:17](=[O:27])[C:8]4[CH:9]=[C:10]([OH:16])[CH:11]=[C:12]([S:13][C:14]=2[CH:15]=1)[C:7]3=4.Cl.Cl[CH2:30][C:31]1[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]3[CH:19]=[C:18]([CH2:20][C:21]4[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=4)[C:17](=[O:27])[C:8]4[CH:9]=[C:10]([O:16][CH2:30][C:31]5[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=5)[CH:11]=[C:12]([S:13][C:14]=2[CH:15]=1)[C:7]3=4
Reactant: O=c1c(Cc2cccnc2)cn2c3c(cc(O)cc13)Sc1cc(Br)ccc1-2
Reactant: ClCc1cccnc1
Agent: Cl
Product: O=c1c(Cc2cccnc2)cn2c3c(cc(OCc4cccnc4)cc13)Sc1cc(Br)ccc1-2
Yield: 95.2 %

Procedure:
According to Example 34, the compound (120 mg) produced in Example 54 was reacted with 3-chloromethylpyridine hydrochloride (68 mg) to obtain the title compound (138 mg; 95%).
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][C:5]1[N:13]2[C:8]([CH2:9][CH2:10][CH2:11][CH2:12]2)=[CH:7][C:6]=1[C:14]([O:16]C)=O.[O-]CC.[Na+]>C(O)C>[C:14]1(=[O:16])[C:6]2[CH:7]=[C:8]3[N:13]([C:5]=2[CH2:4][CH2:3][NH:2]1)[CH2:12][CH2:11][CH2:10][CH2:9]3
Reactant: COC(=O)c1cc2n(c1CCN)CCCC2
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: O=C1NCCc2c1cc1n2CCCC1
Temperature: 55 °C
Reaction time: 5 h
Yield: 66.5 %

Procedure:
A 100-mL single-neck round-bottomed flask equipped with a magnetic stirrer and nitrogen inlet was purged with nitrogen and charged with methyl 3-(2-aminoethyl)-5,6,7,8-tetrahydroindolizine-2-carboxylate hydrogen chloride salt 118c (estimated 1.74 mmol, presuming quantitative yield), sodium ethoxide (354 mg, 5.22 mmol) and ethanol (20 mL). The mixture was stirred at 55° C. for 5 h. After that time, the reaction mixture was concentrated under reduced pressure and the residue was partitioned between ethyl acetate (200 mL) and water (100 mL). The organic layer was separated, and the aqueous layer was extracted with ethyl acetate (2×100 mL). The combined organic layers were washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography to afford a 67% yield (220 mg) of 118d as a white solid: mp 195-197° C.; 1H NMR (500 MHz, DMSO-d6) d 6.76 (s, 1H), 5.89 (s, 1H), 3.78 (t, 2H, J=6.5 Hz), 3.35 (m, 2H), 2.66 (m, 4H), 1.87 (m, 2H), 1.72 (m, 2H); (APCI+) m/z 191.3 (M+H)
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH:3]=[N:2]1.[F:7][C:8]1[C:21]([N:22]=[C:23]=[S:24])=[CH:20][C:11]2[CH:12]([CH2:17][C:18]#[CH:19])[C:13](=[O:16])[NH:14][O:15][C:10]=2[CH:9]=1>C1C=CC=CC=1>[F:7][C:8]1[C:21]([NH:22][C:23]([N:2]2[CH2:3][CH2:4][CH2:5][CH:6]=[N:1]2)=[S:24])=[CH:20][C:11]2[CH:12]([CH2:17][C:18]#[CH:19])[C:13](=[O:16])[NH:14][O:15][C:10]=2[CH:9]=1
Reactant: C1=NNCCC1
Reactant: C#CCC1C(=O)NOc2cc(F)c(N=C=S)cc21
Solvent: c1ccccc1
Product: C#CCC1C(=O)NOc2cc(F)c(NC(=S)N3CCCC=N3)cc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 28.8 %

Procedure:
0.32 g of 1,4,5,6-tetrahydropyridazine was dissolved in 20 ml of benzene, and 1.00 g of 7-fluoro-4-propargyl-2H-benzoxazin-3(4H)-one-6-ylisothiocyanate was added thereto. The mixture was stirred at room temperature for 3 hours. After the reaction, benzene was distilled off to obtain a crude product. This crude product was purified by silica gel column chromatography (developing solvent: chloroform) to obtain 0.38 g of the above-identified compound as yellow crystals.
Reaction SMILES: C([NH:4][C:5]1[C:6](I)=[C:7]([C:11](I)=[C:12]([NH:15][C:16](=[O:22])[CH2:17][C:18]([OH:21])([OH:20])[OH:19])[C:13]=1I)[C:8]([OH:10])=[O:9])(=O)C.[N+](C1C(NC(=O)C(CO)(CO)CO)=C(C=CC=1)C(O)=O)([O-])=O>>[NH2:4][C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([NH:15][C:16](=[O:22])[CH2:17][C:18]([OH:21])([OH:20])[OH:19])[CH:13]=1)[C:8]([OH:10])=[O:9]
Reactant: CC(=O)Nc1c(I)c(NC(=O)CC(O)(O)O)c(I)c(C(=O)O)c1I
Agent: O=C(O)c1cccc([N+](=O)[O-])c1NC(=O)C(CO)(CO)CO
Product: Nc1cc(NC(=O)CC(O)(O)O)cc(C(=O)O)c1

Procedure:
In the preparation of the 3-acetamido-2,4,6-triiodo-5-trishydroxymethylacetamido-benzoic acid of the invention, 3-nitro-trishydroxymethylacetamido-benzoic acid is reduced to form 3-amino-5-trishydroxymethylacetamido-benzoic acid. The latter is then iodinated to form 3-amino-2,4,6-triiodo-5-trishydroxymethylacetamido-benzoic acid, after which the 3-amino compound is acylated to form the desired 3-acetamido-2,4,6-triiodo-5-trishydroxymethylacetamido-benzoic acid.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.CN(C)[CH:8]=[O:9].[CH3:11][C:12]1[CH:16]=[C:15]([C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=2)[O:14][CH:13]=1.[OH-].[Na+]>ClC(Cl)C>[CH:8]([C:13]1[O:14][C:15]([C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=2)=[CH:16][C:12]=1[CH3:11])=[O:9]
Reactant: CN(C)C=O
Reactant: Cc1ccc(-c2cc(C)co2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Solvent: CC(Cl)Cl
Product: Cc1ccc(-c2cc(C)c(C=O)o2)cc1
Temperature: 0 °C

Procedure:
Phosphorus oxychloride (12 ml) was added slowly to dimethylformamide (9.85 ml) with stirring at 0° C., and the mixture stirred at 0° C. for 30 minutes. A solution of 3-methyl-5-(4-methylphenyl)furan (22 g) in 50 ml of dichloroethane was added dropwise over a period of 15 minutes, maintaining the temperature at 0° C. The mixture was then stirred at room temperature for 11/2 hours. Ice water was then added, and the pH of the aqueous layer adjusted to about 8 with dilute sodium hydroxide. The organic layer was separated, the aqueous layer extracted with dichloromethane, the organic portions combined and solvent removed under reduced pressure. The solvent was removed from the filtrate under reduced pressure, and the residue flash chromatographed on silica gel, eluting with 10% ethyl acetate in heptane, to yield 19.2 g of 2-formyl-3-methyl-5-(4-methylphenyl)furan.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[O:9][CH:8]=[CH:7][C:6]=2[C:5]([CH2:11][CH2:12][CH2:13][N:14]2C(=O)C3[C:16](=CC=CC=3)[C:15]2=[O:24])=[CH:4][CH:3]=1>CN>[Cl:1][C:2]1[C:10]2[O:9][CH:8]=[CH:7][C:6]=2[C:5]([CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:24])[CH3:16])=[CH:4][CH:3]=1
Reactant: O=C1c2ccccc2C(=O)N1CCCc1ccc(Cl)c2occc12
Agent: CN
Product: CC(=O)NCCCc1ccc(Cl)c2occc12
Temperature: 0 °C
Reaction time: 18 h
Yield: 62.1 %

Procedure:
A solution of 2-[3-(7-chloro-benzofuran-4-yl)-propyl]-isoindole-1,3-dione (0.5 g) in ethanolic methylamine (10 ml) was stirred at room temperature for 4 h. The solvent was evaporated and the residue suspended in dry THF (15 ml) and cooled to 0° C. Pyridine (0.27 ml) and acetic anhydride (0.2 ml) were added and the mixture allowed to warm to room temperature and stirred for 18 h. The solvent was evaporated and the residue purified by column chromatography, eluting with dichloromethane/methanol 100:1 gave the title compound as a colourless solid (230 mg) mp 61-62°
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]=[C:11]([CH3:13])[O:10][N:9]=2)=[CH:4][C:3]=1[CH2:14][CH3:15].B([C:19]1[CH:27]=[CH:26][C:22]([C:23]([OH:25])=[O:24])=[CH:21][CH:20]=1)(O)O>>[CH3:13][C:11]1[O:10][N:9]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([C:19]3[CH:27]=[CH:26][C:22]([C:23]([OH:25])=[O:24])=[CH:21][CH:20]=3)=[C:3]([CH2:14][CH3:15])[CH:4]=2)[N:12]=1
Reactant: CCc1cc(-c2noc(C)n2)ccc1Br
Reactant: O=C(O)c1ccc(B(O)O)cc1
Product: CCc1cc(-c2noc(C)n2)ccc1-c1ccc(C(=O)O)cc1

Procedure:
The title compound was prepared as in Description 15 from 3-(4-bromo-3-ethylphenyl)-5-methyl-1,2,4-oxadiazole (D81, 0.8 g) and 4-boronobenzoic acid (0.49 g) as a cream solid (0.66 g, 71%).
Reaction SMILES: ClCl.[Cl:3][C:4]1[S:5][C:6]2[C:12]([N:13]3[C:18](=[O:19])[CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[N:15]([CH3:24])[C:14]3=[O:25])=[C:11]([F:26])[CH:10]=[CH:9][C:7]=2[N:8]=1.[Cl:27]N1C(=O)CCC1=O>>[Cl:3][C:4]1[S:5][C:6]2[C:12]([N:13]3[C:18](=[O:19])[C:17]([Cl:27])=[C:16]([C:20]([F:22])([F:23])[F:21])[N:15]([CH3:24])[C:14]3=[O:25])=[C:11]([F:26])[CH:10]=[CH:9][C:7]=2[N:8]=1
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2c(F)ccc3nc(Cl)sc23)c1=O
Reactant: O=C1CCC(=O)N1Cl
Agent: ClCl
Product: Cn1c(C(F)(F)F)c(Cl)c(=O)n(-c2c(F)ccc3nc(Cl)sc23)c1=O

Procedure:
Once the pyrimidinedione ring (VIII) is formed, additional substituents may be optionally added. For example, a chlorine moiety is added to the 3-(2-chloro-6-fluorobenzothiazol-7-yl)-1-methyl-6-trifluoromethyl-2,4-(1H,3H)-pyrimidinedione molecule by treating it with N-chlorosuccinimide under acidic conditions, affording 3-(2-chloro-6-fluorobenzothiazol-7-yl)-1-methyl-5-chloro-6-trifluoromethyl-2,4-(1H,3H)-pyrimidinedione (IX). Example 8 provides the detailed procedure for this method. ##STR3##
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][CH:17]=1)[O:5][C:6]1[N:14]=[CH:13][CH:12]=[CH:11][C:7]=1[C:8]([OH:10])=O.CN1CCOCC1.ClC(OCC(C)C)=O.[Cl:33][C:34]1[CH:41]=[CH:40][CH:39]=[CH:38][C:35]=1[CH2:36][NH2:37]>C(Cl)Cl.O>[Cl:33][C:34]1[CH:41]=[CH:40][CH:39]=[CH:38][C:35]=1[CH2:36][NH:37][C:8](=[O:10])[C:7]1[CH:11]=[CH:12][CH:13]=[N:14][C:6]=1[O:5][C:4]1[CH:15]=[CH:16][CH:17]=[C:2]([F:1])[CH:3]=1
Reactant: O=C(O)c1cccnc1Oc1cccc(F)c1
Reactant: NCc1ccccc1Cl
Agent: CC(C)COC(=O)Cl
Solvent: O
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: O=C(NCc1ccccc1Cl)c1cccnc1Oc1cccc(F)c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 71.3 %

Procedure:
To a stirred solution of 2-(3-Fluoro-phenoxy)-nicotinic acid (0.300 grams, 1.29 mmole) and NMM (0.144 grams, 1.41 mmole) in dry methylene chloride (15 ml) at −10° C. was added isobutyl chloroformate (0.193 grams, 1.41 mmole). After 20 minutes at −10° C. 2-chlorobenzylamine (0.219 grams, 1.55 mmole) was added and the mixture was allowed to warm to room temperature over night. The mixture was poured into water and extracted with ethyl acetate. The combined organics were washed with 1 N NaOH, water and brine, dried over MgSO4, filtered and concentrated to give a solid that was purified by chromatography on silica gel eluting with 30% ethyl acetate/hexane to give a white solid. Recrystalization from ethyl acetate/hexane gave a solid (0.328 g). M.P. 115-117° C.; Anal. calcd. for C19H14N2O2ClF: C, 63.96; H, 3.95; N, 7.85. Found: C, 64.04; H, 3.92; N, 7.85.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:4]=[C:5]([C:9]2[C:17]3[S:16][C:15]([C:18]([NH:20][C@@H:21]4[CH:26]5[CH2:27][CH2:28][N:23]([CH2:24][CH2:25]5)[CH2:22]4)=[O:19])=[CH:14][C:13]=3[CH:12]=[CH:11][CH:10]=2)[CH:6]=[CH:7][CH:8]=1.[O:29]1[C:33]([C:34]([Cl:36])=[O:35])=[CH:32][CH:31]=[N:30]1>>[ClH:36].[N:23]12[CH2:24][CH2:25][CH:26]([CH2:27][CH2:28]1)[C@@H:21]([NH:20][C:18]([C:15]1[S:16][C:17]3[C:9]([C:5]4[CH:4]=[C:3]([NH:2][C:34]([C:33]5[O:29][N:30]=[CH:31][CH:32]=5)=[O:35])[CH:8]=[CH:7][CH:6]=4)=[CH:10][CH:11]=[CH:12][C:13]=3[CH:14]=1)=[O:19])[CH2:22]2
Reactant: Nc1cccc(-c2cccc3cc(C(=O)N[C@H]4CN5CCC4CC5)sc23)c1
Reactant: O=C(Cl)c1ccno1
Agent: Cl
Product: O=C(Nc1cccc(-c2cccc3cc(C(=O)N[C@H]4CN5CCC4CC5)sc23)c1)c1ccno1

Procedure:
50 mg (0.12 mmol) of 7-(3-aminophenyl)-N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-1-benzothiophene-2-carboxamide hydrochloride (Example 21) and 31.8 mg (0.24 mmol) of isoxazole-5-carbonyl chloride are reacted together by general method F. 44.4 mg (72.6% of theory) of the title compound are obtained.
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([CH2:21]C)[C:5]([NH:10][C@@H:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:13][C@@H:12]2[OH:20])=[N:6][C:7]=1[CH2:8][CH3:9].[CH:23]1(C2N=C(N[C@@H]3C4C(=CC=CC=4)C[C@@H]3O)C(C)=NC=2)CC1>>[Br:1][C:2]1[N:3]=[C:4]([CH3:21])[C:5]([NH:10][C@@H:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:13][C@@H:12]2[OH:20])=[N:6][C:7]=1[CH:8]1[CH2:23][CH2:9]1
Reactant: CCc1nc(N[C@@H]2c3ccccc3C[C@@H]2O)c(CC)nc1Br
Reactant: Cc1ncc(C2CC2)nc1N[C@@H]1c2ccccc2C[C@@H]1O
Product: Cc1nc(Br)c(C2CC2)nc1N[C@@H]1c2ccccc2C[C@@H]1O

Procedure:
Following the procedure for the preparation of (1R,2S)-1-[(5-bromo-3,6-diethylpyrazin-2-yl)amino]-2,3-dihydro-1H-inden-2-ol but substituting (1R,2S)-1-[(6-cyclopropyl-3-methylpyrazin-2-yl)amino]-2,3-dihydro-1H-inden-2-ol and making non-critical variations provided the title compound as a solid: 1H NMR (CDCl3) δ 0.99, 2.08, 2.38, 3.04, 3.25, 4.72, 4.97, 5.45, 7.24-7.31; MS (ESI+) for C17H18BrN3O m/z 362 (M+H)+.
Reaction SMILES: [CH2:1]([N:3]1[CH:7]([CH2:8][CH2:9][O:10][C:11]2[CH:17]=[CH:16][C:14]([NH2:15])=[CH:13][CH:12]=2)[CH:6]=[N:5][NH:4]1)[CH3:2].[C:18]1([C:24]2[O:28][N:27]=[CH:26][C:25]=2[CH2:29][CH2:30][CH2:31][C:32](O)=[O:33])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>O.CN(C)C=O>[CH2:1]([N:3]1[CH:7]([CH2:8][CH2:9][O:10][C:11]2[CH:12]=[CH:13][C:14]([NH:15][C:32](=[O:33])[CH2:31][CH2:30][CH2:29][C:25]3[CH:26]=[N:27][O:28][C:24]=3[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)=[CH:16][CH:17]=2)[CH:6]=[N:5][NH:4]1)[CH3:2]
Reactant: CCN1NN=CC1CCOc1ccc(N)cc1
Reactant: O=C(O)CCCc1cnoc1-c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: CCN1NN=CC1CCOc1ccc(NC(=O)CCCc2cnoc2-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.2 %

Procedure:
A mixture of 4-[2-(3-ethyl-4H-triazol-4-yl)ethoxy]aniline (0.51 g), 4-(5-phenyl-4-isoxazolyl)butanoic acid (0.51 g), 1-hydroxy-1H-1,2,3-benzotriazole hydrate (0.40 g), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.50 g) and N,N-dimethylformamide (20 ml) was stirred at room temperature overnight. The reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with dilute hydrochloric acid, saturated aqueous sodium hydrogencarbonate and then saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and N-[4-[2-(3-ethyl-4H-triazol-4-yl)ethoxy]phenyl]-4-(5-phenyl-4-isoxazolyl)butaneamide (0.83 g, yield 84%) was obtained as colorless crystals from a fraction eluted with ethyl acetate-hexane (1:1, volume ratio). The crystals were recrystallized from acetone-hexane. melting point: 125–126° C.
Reaction SMILES: [CH2:1]([C@@H:3]1[CH2:7][CH2:6][CH2:5][NH:4]1)[CH3:2].[Cl:8][C:9]1[CH:14]=[C:13](Cl)[N:12]=[C:11]([NH:16][CH3:17])[N:10]=1>O1CCOCC1.C([O-])(O)=O.[Na+]>[Cl:8][C:9]1[CH:14]=[C:13]([N:4]2[CH2:5][CH2:6][CH2:7][C@H:3]2[CH2:1][CH3:2])[N:12]=[C:11]([NH:16][CH3:17])[N:10]=1
Reactant: CNc1nc(Cl)cc(Cl)n1
Reactant: CC[C@@H]1CCCN1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: CC[C@@H]1CCCN1c1cc(Cl)nc(NC)n1
Temperature: 100 °C
Reaction time: 8 h
Yield: 88.3 %

Procedure:
A mixture of (2R)-2-ethylpyrrolidine (0.8 g, 5.90 mmol) and 4,6-dichloro-N-methyl-2-pyrimidinamine (0.997 g, 5.60 mmol) in 1,4-dioxane (40 mL) and saturated aqueous NaHCO3 (20 mL) was stirred overnight at 100° C. into a sealed tube. The reaction mixture was poured onto water (˜400 mL). A white precipitate was formed. The aqueous mixture was filtered, and the white solid was washed with water (˜100 mL). The wet solid was dried overnight on vacuum at 40° C. to afford the title compound (1.19 g). LC-MS (ES) m/z=241 [M+H]+.
Reaction SMILES: B.[CH3:2][N:3]1[CH2:8][CH2:7][C:6](=[N:9][NH:10]C(OC(C)(C)C)=O)[CH2:5][CH2:4]1.Cl>C1COCC1>[CH3:2][N:3]1[CH2:8][CH2:7][CH:6]([NH:9][NH2:10])[CH2:5][CH2:4]1
Reactant: CN1CCC(=NNC(=O)OC(C)(C)C)CC1
Agent: B
Agent: Cl
Solvent: C1CCOC1
Product: CN1CCC(NN)CC1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 81.8 %

Procedure:
A solution of 1 M borane in THF (30 mL) was added to solid 2.80 g (12.3 mmol) of tert-butyl N′-(1-Methyl-piperidin-4-ylidene)-hydrazinecarboxylate. The mixture was stirred under N2 for 16 h when 40 mL of 6M HCl was carefully added. The mixture was heated to 60° C. for 30 min. The mixture was concentrated in vacuo at ambient temperature for 2 days. Petroleum ether (200 mL) and powdered NaOH (5 g) were added, and the mixture was stirred manually for 30 min. The mixture was dried with MgSO4, filtered, and carefully concentrated to give 1.3 g of (1-methyl-piperidin-4-yl)-hydrazine.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH3:13])[N:11]=[CH:10][C:9]=2[C:14]([NH2:16])=O)=[CH:4][CH:3]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:26])=CC=1>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH3:13])[N:11]=[CH:10][C:9]=2[C:14](=[S:26])[NH2:16])=[CH:4][CH:3]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: Cn1ncc(C(N)=O)c1-c1ccc(F)cc1
Solvent: C1CCOC1
Product: Cn1ncc(C(N)=S)c1-c1ccc(F)cc1
Yield: 83.2 %

Procedure:
A solution of the compound (446 mg, 2.04 mmol) obtained in step 3 and Lawesson's reagent (658 mg, 1.63 mmol) in THF (8.5 mL) was heated at 60° C. for 1 hr. The reaction mixture was concentrated under reduced pressure, and the residue was purified by NH-silica gel column chromatography (solvent gradient; 20→50% ethyl acetate/hexane) to give a mixture (3:2 (mol/mol), 319 mg, 67%) of 5-(4-fluorophenyl)-1-methyl-1H-pyrazole-4-carbothioamide and 3-(4-fluorophenyl)-1-methyl-1H-pyrazole-4-carbothioamide as a yellow powder.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[C:4]1[CH:9]=[C:8]([C:10]#[C:11][Si](C)(C)C)[C:7]([C:16]([F:19])([F:18])[F:17])=[CH:6][C:5]=1[NH2:20].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[CH3:1][O:2][C:3](=[O:21])[C:4]1[CH:9]=[C:8]([C:10]#[CH:11])[C:7]([C:16]([F:18])([F:17])[F:19])=[CH:6][C:5]=1[NH2:20]
Reactant: COC(=O)c1cc(C#C[Si](C)(C)C)c(C(F)(F)F)cc1N
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: C#Cc1cc(C(=O)OC)c(N)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 59 %

Procedure:
To a solution of 2-amino-4-trifluoromethyl-5-trimethylsilanylethynyl-benzoic acid methyl ester (1.65 g, 5.23 mmol) in THF (20 mL) was added a solution of TBAF in THF (1M, 10.5 mL, 2 equiv) and the resulting solution was stirred at r.t. for 10 min. The solvent was removed in vacuo and the crude oil was dissolved in AcOEt. The organic phase was washed with saturated NH4Cl and water, dried (Na2SO4) and concentrated in vacuo to afford a dark red oil. The crude product was purified by flash chromatography (EtOAc/hexanes (1:3)) to furnish 2-amino-5-ethynyl-4-trifluoromethyl-benzoic acid methyl ester (750 mg, 55%) as an orange oil. (ESI-MS: m/z 285.3 [M+CH3CN+H]+, rt 5.60 min).
Reaction SMILES: Br[C:2]1[C:3]([NH:9][CH:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.[CH2:15]([OH:18])[C:16]#[CH:17].O.O.O.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1(C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)[Pd][P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCCC1>[Cl:8][C:5]1[N:4]=[C:3]([NH:9][CH:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)[C:2]([C:17]#[C:16][CH2:15][OH:18])=[CH:7][N:6]=1
Reactant: C#CCO
Reactant: Clc1ncc(Br)c(NC2CCCC2)n1
Agent: c1ccc([P]([Pd][P](c2ccccc2)(c2ccccc2)c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: OCC#Cc1cnc(Cl)nc1NC1CCCC1
Temperature: 67 °C

Procedure:
A nitrogen-flushed, suitably equipped 5 L 4-neck round bottom flask is charged with 200 g (0.723 mol, 1.0 eq.) of 5-bromo-2-chloro-N-cyclopentylpyrimidin-4-amine (A1f) and 2303 g, (2600 mL) of tetrahydrofuran. The mixture is stirred, heated to reflux (67° C.) and 200 mL of distillate is collected. The sample is cooled to 25° C. and 52.7 g (0.940 mol, 55.6 mL, 1.3 eq.) of propargyl alcohol (A1e), 570.3 g (1.808 mol, 2.5 eq.) of tetrabutylammonium fluoride trihydrate and 25.4 g (0.036 mol, 0.05 eq.) of bis(triphenylphosphine)palladium (II) dichloride are added. The sample is stirred, heated to reflux (67° C.) and maintained at this temperature for 2 h or until 5-7% of the starting material A1f remains as determined by HPLC analysis. The sample is cooled to 25° C. and concentrated under reduced pressure (100 mbar, 30° C. maximum internal temperature) to a volume of 1150 mL to remove tetrahydrofuran. 541 g, (600 mL) of ethyl acetate is charged. The sample is again concentrated under reduced pressure (100 mbar, 30° C. maximum internal temperature) to a volume of 1150 mL to remove residual tetrahydrofuran. 2706 g (3000 mL) of ethyl acetate and a solution of 63 g of sodium bicarbonate dissolved in 1500 g (1500 mL) of water are added. The sample is stirred at 25° C. for 10 min and the phases are separated. The organic (top) phase is washed once with 1500 g (1500 mL) of water. The sample is stirred for 10 min and the phases are separated. The organic (top) phase is concentrated under reduced pressure (100 mbar, 30° C. maximum internal temperature) to a volume of 625 mL to remove ethyl acetate. 1582 g (2000 mL) of acetone is added to the concentrate. The sample is stirred, heated to reflux (58° C.) and maintained at this temperature for 30 min. It is then cooled to 40° C. and clarified by filtering through a pad of filter cel. The flask and filter cake are washed twice with 158 g (200 mL, 2×100 mL per wash) of acetone. The sample is concentrated under reduced pressure (100 mbar, 30° C. maximum internal temperature) to a volume of 460 mL. It is then cooled to 4° C. and is hold at this temperature for 1 h. The solids are filtered and the filter cake is washed twice with 158 g (2×100 mL) of cold (4° C.) acetone. The solids are dried at 50° C. for 16 h, to afford 85.6 g (47.4%, corrected) of Compound A1d as a tan, crystalline solid, mp=162-163° C.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]([O:9]C)=[O:8])=[C:5]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH3:17])[CH:12]=2)[O:4][N:3]=1>O1CCCC1>[CH3:1][C:2]1[C:6]([C:7]([OH:9])=[O:8])=[C:5]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH3:17])[CH:12]=2)[O:4][N:3]=1
Reactant: COC(=O)c1c(C)noc1-c1cccc(C)c1
Solvent: C1CCOC1
Product: Cc1cccc(-c2onc(C)c2C(=O)O)c1
Reaction time: 20 h
Yield: 98.3 %

Procedure:
Methyl 3-methyl-5-(3-methylphenyl)-4-isoxazole carboxylate (183 mg) was dissolved in tetrahydrofuran/distilled water=4/1 (2 ml). Lithium hydroxide (66.5 mg) was added at room temperature, and the mixture was stirred at that temperature for 20 hours. After the completion of the reaction, 5%-aqueous hydrochloric acid was added to acidify the system, and the reaction product was extracted by liquid separation using chloroform and washed with saturated aqueous solution of sodium chloride. The product was dried over sodium sulfate to concentrate and the residue was dried using a vacuum pump. Thus, a useful intermidiate, i.e., 3-methyl-5-(3-methylphenyl)-4-isoxazole carboxylic acid (169 mg, yield 98%) was obtained.
Reaction SMILES: [CH3:1][N:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[C:4]([C:11]2[S:15][CH:14]=[N:13][CH:12]=2)[C:3]1=[O:16].Cl[Sn]Cl.C([O-])(O)=O.[Na+]>C(O)C>[NH2:8][C:6]1[CH:5]=[C:4]([C:11]2[S:15][CH:14]=[N:13][CH:12]=2)[C:3](=[O:16])[N:2]([CH3:1])[CH:7]=1
Reactant: Cn1cc([N+](=O)[O-])cc(-c2cncs2)c1=O
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: Cn1cc(N)cc(-c2cncs2)c1=O
Temperature: 90 °C
Reaction time: 15 h

Procedure:
To a solution of 1-methyl-5-nitro-3-thiazol-5-yl-1H-pyridin-2-one (290 mg, 1.22 mmol) in ethanol (10 mL) was added SnCl2 (2.342 g, 12.22 mmol). The mixture was stirred at 90° C. for 15 h. After cooled to rt, sat. NaHCO3 (aq) was added dropwise to the reaction to adjust the pH to 9-10. The resulting solution was filtered through a Celite pad. The filtrate was concentrated to dryness in vacuo to afford the crude product, which was used directly in the next step without purification. MS (ES+): m/z 208.21 [MH+]. HPLC: tR=1.47 min (ZQ2000, polar—5 min).