Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:19](Cl)=[N:18][CH:17]=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[F:27][C:28]([F:39])([F:38])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1B(O)O.O>CN(C)C(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:19]([C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=3[C:28]([F:39])([F:38])[F:27])=[N:18][CH:17]=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: OB(O)c1ccccc1C(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CCN(c2nccnc2Cl)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(c2nccnc2-c2ccccc2C(F)(F)F)CC1
Temperature: 115 °C
Yield: 29.8 %

Procedure:
Dissolve 3′-chloro-2,3,5,6-tetrahydro-[1,2′]bipyrazinyl-4-carboxylic acid t-butyl ester (1.00 g, 3.35 mmol) in N,N-dimethylacetamide (purged with nitrogen) (12 mL). Add potassium carbonate (1.11 g, 8.04 mmol) and 2-trifluoromethylbenzeneboronic acid (764 mg, 4.02 mmol) then purge with nitrogen for 15 min. Add deoxygenated water (6 mL) and tetrakis(triphenylphosphine)palladium(0) (0.039 g, 0.034 mmol) and purge with nitrogen for 15 min. Heat at 115° C. for 21 hr. under nitrogen. Cool to room temperature, add water (20 mL) and extract with DCM (4×20 mL). Concentrate the DCM extracts and purify (silica gel chromatography, eluting with 10:90 to 20:80 ethyl acetate:isohexane), to give 3′-(2-trifluoromethylphenyl)-2,3,5,6-tetrahydro-[1,2′]bipyrazinyl-4-carboxylic acid t-butyl ester (408 mg, 29%). MS (ES): m/z=409 [M+H]+.
Reaction SMILES: [CH:1]([CH:3]([CH:13]([CH3:15])[CH3:14])[CH2:4][C:5]1[CH:9]([C:10]([CH3:12])=[CH2:11])[CH2:8][CH2:7][CH:6]=1)=[O:2].[Sn](Cl)(Cl)(Cl)Cl.[C:21](=O)([O-])[O-].[Na+].[Na+]>[N+](C)([O-])=O>[O:2]1[CH:1]2[CH2:11][CH:10]([CH3:12])[C:9]31[C:5]([CH2:4][CH:3]2[CH:13]([CH3:15])[CH3:14])=[C:6]([CH3:21])[CH2:7][CH2:8]3
Reactant: C=C(C)C1CCC=C1CC(C=O)C(C)C
Reactant: O=C([O-])[O-]
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: [Na+]
Solvent: C[N+](=O)[O-]
Product: CC1=C2CC(C(C)C)C3CC(C)C2(CC1)O3

Procedure:
To a solution, cooled to -40°, of 3.3 g of 2-(2-formyl-3-methylbutyl)-3-isopropenyl-1-cyclopentene in 225 ml of nitromethane were added 45 ml of a 0.5-M solution of tin tetrachloride in nitromethane. The reaction mixture became intensely yellow in colour and an initially resulting precipitate dissolved again. The mixture was treated immediately with excess 2-N sodium carbonate solution and extracted with ether. After washing, the ethereal phase was dried in a conventional manner and the solvent was removed. Distillation under a high vacuum yielded 2.6 g of crude 3a,6-epoxy-7-isopropyl-1,4-dimethyl-2,3,3a,4,5,6,7,8-octahydroazulene in the form of a colourless oil which could be separated by chromatography on 40 times the amount of Florisil (magnesium silicate gel) with hexane/ether (19:1) into two pairs of epimers (A and B). Epimer A: b.p.0.01 ca 75°; IR(film):νmax = 1465/40, 1380, 1345, 1245, 1162, 1125, 1108, 1080, 1050, 995, 965, 945, 910, 880 cm-1. The odour is camphorous, woody. Epimer B: b.p.0.01 ca 80°IR(film):νmax = 1465/35, 1380, 1340, 1295, 1245, 1200/1195, 1170, 1145, 1110, 1060, 1030, 1000, 990, 950, 925, 910, 878 cm-1. The odour is camphorous, dull.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH2:11])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[NH2:12][NH2:13]>O>[NH:12]([C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH2:11])(=[O:10])=[O:9])=[CH:4][CH:3]=1)[NH2:13]
Reactant: NS(=O)(=O)c1ccc(Cl)cc1
Reactant: NN
Solvent: O
Product: NNc1ccc(S(N)(=O)=O)cc1
Temperature: 25 °C
Yield: 94.8 %

Procedure:
A stirred solution of 4-chlorobenzenesulfonamide (38.33 g, 200 mmol) and anhydrous hydrazine (31.4 mL, 1.0 mol) was heated at reflux for 30 hours. After cooling to room temperature, the mixture was poured into water (500 mL) with swirling. The resulting precipitate was collected by filtration, washed thoroughly with water several times, air-dried, and dried under vacuum to give the title compound (35.5 g, 95% yield) as a white solid. Mp 169–171° C. 1H NMR (300 MHz, THF-d8) δ 7.59 (d, J=8.8 Hz, 2H), 6.77 (d, J=8.8 Hz, 2H), 6.62 (br, 1H), 5.99 (br, 2H), 3.87 (br, 2H). Mass spectrum (API-TIS) m/z 188 (MH+).
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:6]([C:31]1[CH:36]=[CH:35][N:34]=[CH:33][N:32]=1)[S:7]([C:10]1[CH:15]=[CH:14][C:13]([O:16][C@H:17]2[CH2:22][CH2:21][CH2:20][CH2:19][C@@H:18]2[C:23]2[N:27]([CH3:28])[N:26]=[CH:25][CH:24]=2)=[C:12]([CH3:29])[C:11]=1[F:30])(=[O:9])=[O:8].C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCl>[F:30][C:11]1[C:12]([CH3:29])=[C:13]([O:16][C@H:17]2[CH2:22][CH2:21][CH2:20][CH2:19][C@@H:18]2[C:23]2[N:27]([CH3:28])[N:26]=[CH:25][CH:24]=2)[CH:14]=[CH:15][C:10]=1[S:7]([NH:6][C:31]1[CH:36]=[CH:35][N:34]=[CH:33][N:32]=1)(=[O:8])=[O:9]
Reactant: COc1ccc(CN(c2ccncn2)S(=O)(=O)c2ccc(O[C@H]3CCCC[C@@H]3c3ccnn3C)c(C)c2F)c(OC)c1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1c(O[C@H]2CCCC[C@@H]2c2ccnn2C)ccc(S(=O)(=O)Nc2ccncn2)c1F
Yield: 94.4 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 1b by using the N-(2,4-dimethoxybenzyl)-2-fluoro-3-methyl-4-{[(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cyclohexyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide (175.6 mg, 0.29 mmol) prepared in Example 66a, triethylsilane (0.10 mL), trifluoroacetic acid (0.5 mL) and dichloromethane (2.0 mL), to yield the title compound (122 mg, 93%) as a colorless solid.
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.[C:13]([O:17][C:18]([NH:20][CH2:21][CH2:22][C:23]([OH:25])=O)=[O:19])([CH3:16])([CH3:15])[CH3:14].[CH2:26]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH2:28][CH:27]1[NH:35][C:36]1[N:37]=[CH:38][C:39]2[CH2:45][NH:44][CH2:43][CH2:42][C:40]=2[N:41]=1>CN(C)C1C=CN=CC=1.ClCCl>[CH2:26]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH2:28][CH:27]1[NH:35][C:36]1[N:37]=[CH:38][C:39]2[CH2:45][N:44]([C:23](=[O:25])[CH2:22][CH2:21][NH:20][C:18](=[O:19])[O:17][C:13]([CH3:14])([CH3:15])[CH3:16])[CH2:43][CH2:42][C:40]=2[N:41]=1
Reactant: c1ccc2c(c1)CC(Nc1ncc3c(n1)CCNC3)C2
Reactant: CC(C)(C)OC(=O)NCCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCC(=O)N1CCc2nc(NC3Cc4ccccc4C3)ncc2C1
Reaction time: 2 h
Yield: 83.4 %

Procedure:
Add 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (2.69 g; 1.5 equiv; 14.06 mmoles) to a flask containing 3-(tert-butoxycarbonylamino)propanoic acid (1.8 g; 1.0 equiv; 9.37 mmoles), N-indan-2-yl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-amine (2.50 g; 1.0 equiv; 9.37 mmoles) and N,N-dimethyl-4-pyridinamine, (0.229 g; 0.2 equiv; 1.87 mmoles) in dichloromethane (30 mL). Stir the mixture for 2 hours, then load the solution directly onto a silica gel column and purify by column chromatography (30 to 100% ethyl acetate in dichloromethane) to give tert-butyl {3-[2-(2,3-dihydro-1H-inden-2-ylamino)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl]-3-oxopropyl}carbamate (3.42 g; 83%) as a colorless foam: MS (m/z): 438(M+1).
Reaction SMILES: [N+:1]([CH2:4][C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=O)([O-:3])=[O:2].[CH2:13]([O:15][CH:16]([O:19][CH2:20][CH3:21])[CH2:17][NH2:18])[CH3:14]>C1(C)C=CC=CC=1>[CH2:13]([O:15][CH:16]([O:19][CH2:20][CH3:21])[CH2:17][NH:18][C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[CH:4][N+:1]([O-:3])=[O:2])[CH3:14]
Reactant: O=C(C[N+](=O)[O-])c1ccccc1
Reactant: CCOC(CN)OCC
Solvent: Cc1ccccc1
Product: CCOC(CNC(=C[N+](=O)[O-])c1ccccc1)OCC
Yield: 86.4 %

Procedure:
Alpha-nitro acetophenone (5.7 g, 0.0345 mol) is taken up in 100 mL toluene and 4.6 g (0.0345 mol) of amino acetaldehyde diethyl acetal is added. The reactants are put into a 250 mL RB flask fitted with a Dean-Stark trap. The trap is filled with 4A molecular sieves and the mixture is heated at reflux for 18 hours. The toluene is removed in vacuo to give 8.36 g of α-(2,2-diethoxyethylamino)-β-nitrostyrene as a brown oil. To this oil is added 50 mL of concentrated HCl. As the flask is swirled the oil turns to a yellow suspension. After 10 minutes the solid is filtered to give 2.48 g of a yellow solid. Recrystallization from ether/ethylacetate/hexane gives the product as two fractions, 2.08 g of mp 190°-192° C.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[CH:9][C:10]=2[C:11]2[CH:12]=[C:13]([C:16]([NH:18][CH:19]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=3)[C:20]([F:23])([F:22])[F:21])=[O:17])[S:14][CH:15]=2)[CH:7]=1.[N:30]1[C:39]2[C:34](=[CH:35][C:36](B(O)O)=[CH:37][CH:38]=2)[CH:33]=[CH:32][CH:31]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[N:30]1[C:39]2[C:34](=[CH:35][C:36]([N:4]3[CH:3]=[CH:2][C:7]4=[C:10]([C:11]5[CH:12]=[C:13]([C:16]([NH:18][CH:19]([C:24]6[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=6)[C:20]([F:23])([F:21])[F:22])=[O:17])[S:14][CH:15]=5)[CH:9]=[N:8][N:6]4[CH2:5]3)=[CH:37][CH:38]=2)[CH:33]=[CH:32][CH:31]=1
Reactant: OB(O)c1ccc2ncccc2c1
Reactant: O=C(NC(c1ccccn1)C(F)(F)F)c1cc(-c2cnn3cc(Br)cnc23)cs1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: O=C(NC(c1ccccn1)C(F)(F)F)c1cc(-c2cnn3c2C=CN(c2ccc4ncccc4c2)C3)cs1

Procedure:
4-(6-bromopyrazolo[1,5-a]pyrimidin-3-yl)-N-(2,2,2-trifluoro-1-pyridin-2-ylethyl)thiophene-2-carboxamide (1 eq) was mixed with quinolin-6-ylboronic acid (1.3 eq). Dioxane (10 mL) and 1M Na2CO3 (2 eq) were added. The mixture was evacuated and flushed with nitrogen under stirring, then a solution Pd(Ph3P)4 (0.05 eq) in dioxane was added under inert gas. The temperature was brought to 100° C. The reaction mixture was stirred at this temperature overnight. The reaction mixtures were filtered through Celite, and the latter was washed with methanol. Purification by reverse phase LC gave 4-(6-quinolin-6-ylpyrazolo[1,5-c]pyrimidin-3-yl)-N-(2,2,2-trifluoro-1-pyridin-2-ylethyl)thiophene-2-carboxamide. 1H NMR (400 MHz, DMSO-d6): 6.11-6.22 (1H, m), 7.47-7.52 (1H, m), 7.67 (1H, dd, J=8.3 Hz, J=4.4 Hz), 7.81 (1H, d, J=7.8 Hz), 7.93-7.98 (1H, m), 8.19 (1H, d, J=8.8 Hz), 8.32 (1H, d, J=1.2 Hz), 8.34 (1H, dd, J=8.8 Hz, J=1.95 Hz), 8.48-8.53 (1H, m), 8.59 (1H, d, J=1.95 Hz), 8.67-8.70 (1H, m), 8.72 (1H, s), 8.76 (1H, d, J=1.2 Hz), 9.00 (1H, dd, J=4.4 Hz, J=1.7 Hz), 9.26 (1H, d, J=2.2 Hz), 9.54 (1H, d, J=9.3 Hz), 9.71 (1H, d, J=2.2 Hz). LC-MS APCI: m/z 531.0 [M+H]+.
Reaction SMILES: CN(C)C=O.[NH2:6][C:7]1[N:12]=[C:11]([N:13]2[C:22]3[C:17](=[CH:18][C:19]([F:25])=[C:20](F)[C:21]=3[F:23])[C:16](=[O:26])[C:15]([C:27]([OH:29])=[O:28])=[CH:14]2)[C:10]([F:30])=[CH:9][C:8]=1[F:31].Cl.Cl.[NH2:34][CH:35]1[CH2:38][NH:37][CH2:36]1.CN1CCCC1>C(O)C>[NH2:34][CH:35]1[CH2:38][N:37]([C:20]2[C:21]([F:23])=[C:22]3[C:17]([C:16](=[O:26])[C:15]([C:27]([OH:29])=[O:28])=[CH:14][N:13]3[C:11]3[C:10]([F:30])=[CH:9][C:8]([F:31])=[C:7]([NH2:6])[N:12]=3)=[CH:18][C:19]=2[F:25])[CH2:36]1
Reactant: NC1CNC1
Reactant: Nc1nc(-n2cc(C(=O)O)c(=O)c3cc(F)c(F)c(F)c32)c(F)cc1F
Agent: CN1CCCC1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCO
Product: Nc1nc(-n2cc(C(=O)O)c(=O)c3cc(F)c(N4CC(N)C4)c(F)c32)c(F)cc1F
Temperature: 90 °C
Reaction time: 1 h
Yield: 68.2 %

Procedure:
To 270 mg of N,N-dimethylformamide were added 90 mg of 1-(6-amino-3,5-difluoropyridine-2-yl)-6,7,8-trifluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid, 50 mg of 3-aminoazetidine dihydrochloride, and 110 mg of N-methylpyrrolidine, and the mixture was stirred at 90° C. for 1 hour. After adding 0.3 ml of ethanol, the mixture was allowed to cool, and the precipitate was collected by-filtration and washed with ethanol and diisopropylether successively to obtain 70 mg of the title compound as a colorless powder.
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:3]=1[CH2:4][N:5]1[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1.[O:16]=[C:17]1[C:22]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:21][CH2:20][CH2:19][N:18]1[CH2:35][C:36](O)=[O:37].Cl.C(N=C=NCCCN(C)C)C>ClC(Cl)C>[Cl:1][C:2]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:3]=1[CH2:4][N:5]1[CH2:6][CH2:7][N:8]([C:36](=[O:37])[CH2:35][N:18]2[CH2:19][CH2:20][CH2:21][C:22]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:17]2=[O:16])[CH2:9][CH2:10]1
Reactant: Clc1ccc(CN2CCNCC2)c(Cl)c1
Reactant: O=C(O)CN1CCCC(c2ccccc2)(c2ccccc2)C1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CC(Cl)Cl
Product: O=C(CN1CCCC(c2ccccc2)(c2ccccc2)C1=O)N1CCN(Cc2ccc(Cl)cc2Cl)CC1
Temperature: 85 °C
Reaction time: 8 h

Procedure:
A solution of 1-(2,4-dichlorobenzyl)piperazine (0.415 g, 1.693 mmol), 2-(2-oxo-3,3-diphenylpiperidin-1-yl)acetic acid (0.498 g, 1.608 mmol; Example 68E) and N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (0.389 g, 2.031 mmol) were stirred together in dichloroethane (0.5 mL) at room temperature for 2 hours. The reaction was then heated to 85° C. and stirred overnight. The reaction was cooled, loaded onto a SF25-40 column (Analogix®) and the product eluted using a gradient of 5% ethyl acetate/hexanes to 100% ethyl acetate over 30 minutes, then holding at 100% ethyl acetate for 15 minutes (Flow=45 mL/minute) to yield the title compound. 1H NMR (300 MHz, CDCl3) δ 7.42-7.36 (m, 2H), 7.32 (s, 11H), 4.23 (s, 2H), 3.65 (s, 2H), 3.57 (s, 2H), 3.49 (dd, J=6.5, 13.6, 4H), 2.72-2.56 (m, 2H), 2.48 (s, 4H), 1.94-1.74 (m, 2H); MS (ESI+) m/z 536.1 (M+H)+.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6](O)=[O:7])#[CH:2].Cl.[CH3:13][O:14][NH2:15]>>[C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([NH:15][O:14][CH3:13])=[O:7])#[CH:2]
Reactant: C#Cc1cccc(C(=O)O)c1
Reactant: CON
Agent: Cl
Product: C#Cc1cccc(C(=O)NOC)c1
Yield: 106.7 %

Procedure:
In a manner similar to that described for Example 478 (step 1), 3-ethynylbenzoic acid (0.1 g, 0.685 mmol) and O-methylhydroxylamine hydrogen chloride (0.057 g, 0.685 mmol) were reacted to give the title compound (0.128 g, 61%).
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[N:13]=[C:14]([CH3:24])[S:15][C:16]=1[C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=1)=[O:11].Cl[C:26]1[N:31]=[CH:30][C:29]([Cl:32])=[CH:28][N:27]=1.CCN(C(C)C)C(C)C>C(O)(C)C>[Cl:32][C:29]1[CH:28]=[N:27][C:26]([NH:1][CH2:2][C@@H:3]2[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]2[C:10]([C:12]2[N:13]=[C:14]([CH3:24])[S:15][C:16]=2[C:17]2[CH:18]=[CH:19][C:20]([F:23])=[CH:21][CH:22]=2)=[O:11])=[N:31][CH:30]=1
Reactant: Cc1nc(C(=O)N2CCC[C@@H](C)[C@H]2CN)c(-c2ccc(F)cc2)s1
Reactant: Clc1cnc(Cl)nc1
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc(C(=O)N2CCC[C@@H](C)[C@H]2CNc2ncc(Cl)cn2)c(-c2ccc(F)cc2)s1
Temperature: 120 °C
Reaction time: 1 h

Procedure:
A mixture of ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(5-(4-fluorophenyl)-2-methylthiazol-4-yl)methanone (50 mg, 145 μmol), 2,5-dichloropyrimidine (43 mg, 287 μmol), and DIPEA (75 mg, 431 mol) in isopropanol was stirred at 120° C. for 1 h in a microwave reactor. The crude reaction mixture was purified by reverse-phase preparative HPLC to afford the title compound. MS (ESI) 460 (M+H). 1H NMR (500 MHz, CDCl3) δ 8.25-6.85 (m, 7H), 5.55-2.65 (m, 8H), 1.95-0.85 (m, 8H).
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1([CH3:16])[C:8]([CH3:10])([CH3:9])[O:7][B:6]([C:11]2[CH:12]=[N:13][NH:14][CH:15]=2)[O:5]1.[F:17][CH:18]([F:21])[CH2:19]I>CN(C=O)C.[Cl-].[Na+].O>[F:17][CH:18]([F:21])[CH2:19][N:14]1[CH:15]=[C:11]([B:6]2[O:7][C:8]([CH3:9])([CH3:10])[C:4]([CH3:16])([CH3:3])[O:5]2)[CH:12]=[N:13]1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Reactant: FC(F)CI
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC1(C)OB(c2cnn(CC(F)F)c2)OC1(C)C
Reaction time: 0.25 h

Procedure:
NaH (60%, 128 mg) was added to a solution of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (313 mg, 1.61 mmol) in DMF (4 mL). After stirring for 15 minutes, 1,1-difluoro-2-iodoethane (372 mg, 1.94 mmol) in DMF (1 mL) was added. The resulting solution was stirred at 80° C. under microwave irradiation for 60 minutes. The reaction mixture was diluted with brine and extracted with EtOAc. The combined organic layers were washed with water, dried with Na2SO4, and concentrated in vacuo to afford the title compound as a yellow oil that was used directly in the next step (210 mg, 50%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([NH2:12])[CH:6]=[CH:5]2.CO[CH:15]([N:18](C)C)OC.NOS(O)(=O)=O>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]1[N:18]=[CH:15][N:12]=[C:7]1[CH:6]=[CH:5]2
Reactant: COC(OC)N(C)C
Reactant: Nc1ccc2cc(Br)ccc2n1
Agent: NOS(=O)(=O)O
Solvent: CN(C)C=O
Product: Brc1ccc2c(ccc3ncnn32)c1
Temperature: 130 °C
Reaction time: 72 h

Procedure:
8a (497 mg, 2.46 mmol) and dimethoxymethyldimethylamine (1 mL) were combined in DMF (5 mL) and heated to 130° C. for 1 hour. The reaction was concentrated and redissolved in MeOH (5 mL) and pyridine (400 mg). Hydroxylamine-O-sulfonic acid (282 mg, 2.49 mmol) was added, and the mixture was stirred at room temperature for 3 days. The solution was concentrated and poured into water, and the resulting solid was filtered and dried to give the desired product, 8b.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]([CH:7]2[N:14]=[C:13]3[N:9]([CH2:10][CH2:11][S:12]3)[CH2:8]2)=[CH:5][CH:6]=1.O>CC(=O)C>[CH:1]1[CH:6]=[CH:5][C:4]([C@@H:7]2[N:14]=[C:13]3[N:9]([CH2:10][CH2:11][S:12]3)[CH2:8]2)=[CH:3][CH:2]=1
Reactant: c1ccc(C2CN3CCSC3=N2)cc1
Solvent: CC(C)=O
Solvent: O
Product: c1ccc([C@H]2CN3CCSC3=N2)cc1
Temperature: 15 °C
Yield: 116.9 %

Procedure:
To a refluxing solution of 20.43 g of tetramisole (0.1 mol) in 190 ml of 2-propanone and 10 ml. of water was added 15.9 g of L-N-[(4-methoxyphenyl)sulfonyl]glutamic acid (0.05 mol). The mixture was refluxed for another 5 minutes and cooled to 15° C. After 12 hours the precipitate was filtered off, washed with 2-propanone and dried under vacuo at 70° C., yielding 23.88 g of levamisole.L-N-[(4-methoxyphenyl)sulfonyl]glutamic acid (salt) (yield=91.6%) αD20 =-63.5° (c5, 1N HCl); mp. 127.6°-129.3° C.
Reaction SMILES: CN(C)CC[C:5]1[CH:21]=[CH:20][CH:19]=[CH:18][C:6]=1[C:7]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([OH:11])[C:8]([OH:10])=[O:9].[CH3:23][N:24]([CH3:45])[CH2:25][CH2:26]C1C=CC=CC=1C(C1C=CC=CC=1)(O)C(OC)=O>>[CH3:23][N:24]([CH3:45])[CH2:25][CH2:26][O:10][C:8](=[O:9])[C:7]([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)([C:6]1[CH:5]=[CH:21][CH:20]=[CH:19][CH:18]=1)[OH:11]
Reactant: COC(=O)C(O)(c1ccccc1)c1ccccc1CCN(C)C
Reactant: CN(C)CCc1ccccc1C(O)(C(=O)O)c1ccccc1
Product: CN(C)CCOC(=O)C(O)(c1ccccc1)c1ccccc1

Procedure:
0.24 g (0.802 mmol) of o-(2-dimethylaminoethyl)benzilic acid shown below was obtained as a faint yellow solid from 0.31 g (1.0 mmol) of methyl o-(2-dimethylaminoethyl)benzilate in the same manner as in Production Example 2 (4). ##STR24## Its spectroscopic data are as follows: 1H-NMR (CDCl3) δ (ppm) : 2.87 (6H, s), 3.09 (2H, t, J=4.8 Hz), 3.51 (2H, t, J=4.8 Hz), 7.21~7.30 (6H, m), 7.50~7.54 (4H, m).
Reaction SMILES: [F:1][C:2]1[C:3]([I:12])=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.O>N1CCCCC1.CC(O)C>[F:1][C:2]1[C:3]([I:12])=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])/[C:5]/2=[CH:9]\[C:8]1[NH:7][CH:6]=[CH:5][CH:4]=1
Reactant: O=C1Cc2c(ccc(F)c2I)N1
Solvent: CC(C)O
Solvent: C1CCNCC1
Solvent: O
Product: O=C1Nc2ccc(F)c(I)c2/C1=C/c1ccc[nH]1
Temperature: 85 °C

Procedure:
A mixture of 1,3-dihydro-5-fluoro-4-iodo-2H-indol-2-one (1.40 g, 5.05 mmol) (see Starting Material 10), and excess 2-pyrrolecarboxyaldehyde (0.60 g, 6.3 mmol) (Aldrich) in 1% piperidine in 2-propanol (20 mL) was heated at 85° C. for 2.25 h. Hot water (20 mL) was added. On cooling, the crystallized product was filtered off, washed with aqueous 2-propanol and dried. (Yield 1.50 g, 84%).
Reaction SMILES: [N:1]1([C:4]([C:6]2[CH:11]=[CH:10][C:9]([N+:12]([O-])=O)=[C:8]([O:15][CH3:16])[CH:7]=2)=[O:5])[CH2:3][CH2:2]1.OCC1(OC[C@@H](O)[C@@H](O)[C@H]1O)O>CO.[Pd]>[NH2:12][C:9]1[CH:10]=[CH:11][C:6]([C:4]([N:1]2[CH2:3][CH2:2]2)=[O:5])=[CH:7][C:8]=1[O:15][CH3:16]
Reactant: COc1cc(C(=O)N2CC2)ccc1[N+](=O)[O-]
Agent: [Pd]
Agent: OCC1(O)OC[C@@H](O)[C@@H](O)[C@H]1O
Solvent: CO
Product: COc1cc(C(=O)N2CC2)ccc1N
Yield: 33 %

Procedure:
To a solution of aziridin-1-yl(3-methoxy-4-nitrophenyl)methanone (1 equiv) in MeOH (0.24 M) was added 10% palladium on carbon (25% by weight). The reaction mixture was stirred at 50° C. under hydrogen atmosphere (50 Psi) overnight then filtered through celite. The filtrate was concentrated and the residue was purified by silica gel chromatography (50% ethyl acetate in petroleum ether) to afford the title compound (33% yield) as a yellow solid. MS (ESI) m/z 193.1 [M+1]+.
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]1[CH2:9][CH2:8][N:7]([CH2:10][CH2:11][OH:12])[CH2:6][CH2:5]1.Cl[C:14]1[CH:19]=[CH:18][N:17]=[C:16]([NH2:20])[CH:15]=1.[Cl-].[Na+]>COCCOCCOC.O.C1COCC1>[CH3:3][N:4]1[CH2:9][CH2:8][N:7]([CH2:10][CH2:11][O:12][C:14]2[CH:19]=[CH:18][N:17]=[C:16]([NH2:20])[CH:15]=2)[CH2:6][CH2:5]1
Reactant: Nc1cc(Cl)ccn1
Reactant: CN1CCN(CCO)CC1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: COCCOCCOC
Product: CN1CCN(CCOc2ccnc(N)c2)CC1
Temperature: 40 °C
Reaction time: 1 h
Yield: 78 %

Procedure:
Sodium hydride (60% in mineral oil; 43.56 g; 1089 mmol) was added to a 3 L reaction flask under nitrogen. A mechanical stirrer and thermocouple was attached. Dry diglyme (400 mL) was added. A solution of 2-(4-methylpiperazin-1-yl)ethanol (157 g; 1089 mmol) in diglyme (450 mL) was added slowly with stirring. The mixture was stirred with warming to 40° C. for 1 hour. 4-Chloropyridin-2-amine (70.0 g; 544.5 mmol) was added as a solid. The mixture was heated to 80° C. with stirring until effervescence had ceased. The temperature was increased to 157° C. for 16 hours. The mixture was allowed to cool and diluted with water (500 mL). THF (1000 mL) was added followed by sodium chloride (sufficient to saturate the aqueous phase). The phases were separated and the aqueous phase was further extracted with THF (3×800 mL). Additional water was added as required to aid in phase separation. The combined organic phases were dried with sodium sulfate (1000 g) for 16 hours and filtered. The solvent was removed under vacuum to remove the majority of the THF. The solution was filtered through Celite to remove fine particulates rinsing with diglyme. The diglyme was removed under vacuum (10 mm Hg vacuum, with the bath temperature increased to 60° C.). The residue was placed under high vacuum for 1 hour and then triturated with ether (400 mL). The resulting solids were collected by filtration, washed with ether and dried under vacuum to give the product (100.4 g) as an off white solid.
Reaction SMILES: [C:1]([O:10]C)(=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[SH:4].[C:12]([C:14]1[CH:15]=[C:16]([CH:22]=[CH:23][N:24]=1)[C:17]([O:19][CH2:20][CH3:21])=[O:18])#[N:13].C(N(CC)CC)C>C1(C)C=CC=CC=1>[O:10]=[C:1]1[C:2]2[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=2[S:4][C:12]([C:14]2[CH:15]=[C:16]([CH:22]=[CH:23][N:24]=2)[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[N:13]1
Reactant: CCOC(=O)c1ccnc(C#N)c1
Reactant: COC(=O)c1ccccc1S
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccnc(-c2nc(=O)c3ccccc3s2)c1
Yield: 71.9 %

Procedure:
A mixture of methyl thiosalicylate (3.0 g, 17.8 mmol), ethyl 2-cyanoisonicotinate (3.1 g, 17.8 mmol), triethylamine (5.0 ml, 35.8 mmol) and toluene (10 ml) was refluxed for 8 hrs as described in Example 1. The precipitated crystals were collected by filtration and recrystallized from diisopropylether-chlorobenzene to give the titled compound (4.0 g, 71%).