Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O=C1CCC(=O)N1[C:8]1[C:16]2[C:11](=[CH:12][C:13]([C:26]([O-])=[O:27])=[C:14]([O:17][C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=3[F:25])[CH:15]=2)[N:10]([CH2:29][C:30]([F:33])([CH3:32])[CH3:31])[N:9]=1.[NH2:34][C@H:35]1[CH2:40][CH2:39][CH2:38][NH:37][C:36]1=[O:41]>ClCCl.C(OCC)(=O)C>[F:25][C:19]1[CH:20]=[C:21]([F:24])[CH:22]=[CH:23][C:18]=1[O:17][C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][C:13]=1[C:26]([NH:34][C@H:35]1[CH2:40][CH2:39][CH2:38][NH:37][C:36]1=[O:41])=[O:27])[N:10]([CH2:29][C:30]([F:33])([CH3:31])[CH3:32])[N:9]=[CH:8]2
Reactant: CC(C)(F)Cn1nc(N2C(=O)CCC2=O)c2cc(Oc3ccc(F)cc3F)c(C(=O)[O-])cc21
Reactant: N[C@H]1CCCNC1=O
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)(F)Cn1ncc2cc(Oc3ccc(F)cc3F)c(C(=O)N[C@H]3CCCNC3=O)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 1000.8 %

Procedure:
To a solution of 2,5-dioxopyrrolidin-1-yl-5-(2,4-difluorophenoxy)-1-(2-fluoro-2-methylpropyl)-1H-indazole-6-carboxylate (100 mg, 0.217 mmol; prepared according to Example 26) in dichloromethane (1 mL) was added (S)-3-aminopiperidin-2-one (prepared according to Example 3; 521 mg, 4.56 mmol), and the reaction mixture was allowed to stir overnight at ambient temperature. The reaction mixture was diluted with ethyl acetate and washed with 1M hydrochloric acid, 1M sodium hydroxide, saturated sodium bicarbonate, and saturated sodium chloride. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography on silica gel, eluting with 50% acetone/hexanes to yield (S)-5-(2,4-difluorophenoxy)-1-(2-fluoro-2-methylpropyl)-N-(2-oxopiperidin-3-yl)-1H-indazole-6-carboxamide (Ik) (1.00 g, 99%). Mass spec: 461 (M+1). 1H NMR (CDCl3) δ 8.53 (s, 1H), 8.40 (s, 1H), 7.90 (s, 1H), 7.15 (m, 1H), 7.03 (s, 1H), 6.99 (m, 1H), 6.90 (m, 1H), 6.09 (br, 1H), 4.56 (d, 1H), 4.53 (m, 1H), 3.36 (m, 2H), 2.70 (m, 1H), 1.97 (m, 1H), 1.66 (m, 1H), 1.39 (d, 3H), 1.38 (d, 3H).
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[CH:9]=[C:8]([NH2:10])[N:7]=[CH:6][N:5]=1.[N:11]([O-])=[O:12].[Na+].C([O-])(O)=O.[Na+]>O>[NH2:3][C:4]1[C:9]([N:11]=[O:12])=[C:8]([NH2:10])[N:7]=[CH:6][N:5]=1
Reactant: Nc1cc(N)ncn1
Reactant: O=N[O-]
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: Nc1ncnc(N)c1N=O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To 250 mL of 2N HCl was added 8.0 g (55 mmoles) of 4,6-diaminopyrimidine hydrochloride (34). The 4,6-diamino-pyrimidine hydrochloride was allowed to dissolve. The solution was then cooled to 0° C. and a solution of 4.2 g (61 mmoles) of NaNO2 dissolved in 15 mL of H2O was added dropwise within 20 minutes while stirring. Stirring was continued for another 30 minutes at 0° and then 2 hours at room temperature. The violet solution was neutralized by NaHCO3, the precipitate collected, washed with H2O and ethanol and dried to give 35 as 6.3 g (82 % yield) of a blue-violet crystal powder (m.p. >350° C.).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH3:13])=[C:11]([C:14]([OH:16])=O)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[NH2:17][C:18]1[CH:19]=[CH:20][C:21]([N:26]2[CH2:31][CH2:30][N:29]([CH:32]3[CH2:37][CH2:36][O:35][CH2:34][CH2:33]3)[CH2:28][CH2:27]2)=[C:22]([CH:25]=1)[C:23]#[N:24]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:12]([CH3:13])=[C:11]([C:14]([NH:17][C:18]3[CH:19]=[CH:20][C:21]([N:26]4[CH2:31][CH2:30][N:29]([CH:32]5[CH2:33][CH2:34][O:35][CH2:36][CH2:37]5)[CH2:28][CH2:27]4)=[C:22]([C:23]#[N:24])[CH:25]=3)=[O:16])[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: Cc1c(C(=O)O)cnn1-c1ccc(Cl)cc1
Reactant: N#Cc1cc(N)ccc1N1CCN(C2CCOCC2)CC1
Product: Cc1c(C(=O)Nc2ccc(N3CCN(C4CCOCC4)CC3)c(C#N)c2)cnn1-c1ccc(Cl)cc1
Yield: 46.4 %

Procedure:
By the reaction and treatment in the same manner as in Example 64 using 1-(4-chlorophenyl)-5-methylpyrazole-4-carboxylic acid (1 g) and 5-amino-2-[4-(3,4,5,6-tetrahydro-2H-pyran-4-yl)piperazin-1-yl]benzonitrile (1.1 g), the title compound (0.9 g) was obtained, melting point: 276° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[C:7](Cl)=[O:8])([O-:3])=[O:2].[CH2:13]([N:20]1[CH2:25][CH2:24][CH:23]([OH:26])[CH2:22][CH2:21]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[C:7]([O:26][CH:23]1[CH2:24][CH2:25][N:20]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:21][CH2:22]1)=[O:8])([O-:3])=[O:2]
Reactant: O=C(Cl)c1cccc([N+](=O)[O-])c1
Reactant: OC1CCN(Cc2ccccc2)CC1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: O=C(OC1CCN(Cc2ccccc2)CC1)c1cccc([N+](=O)[O-])c1
Yield: 90.9 %

Procedure:
0.388 g (0.0021 mol) of 3-nitro-benzoyl chloride were dissolved in 20 ml of toluene under argon and treated while stirring with 0.5 g (0.0026 mol) of 1-benzyl-4-hydroxy-piperidine and 0.643 ml (0.0046 mol) of triethylamine. After boiling at reflux for 2 hrs. the suspension was filtered and the filtrate was completely freed from solvent. The residue was chromatographed over silica gel with ethyl acetate/hexane 1:2 as the eluent. 0.65 g (92%) of 1-benzyl-piperidin-4-yl 3-nitro-benzoate was obtained as a yellow oil. MS: mele (% basic peak)=340 (C19H20 N2O4+, 27), 263 (25), 173 (36.5), 150 (14.5), 91 (100), 82 (100).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[Li+].CCC[CH2-].[Cl-].[CH:17]([SiH:20]([CH:24]([CH3:26])[CH3:25])[CH:21]([CH3:23])[CH3:22])([CH3:19])[CH3:18].O>O1CCCC1>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][N:8]2[Si:20]([CH:24]([CH3:26])[CH3:25])([CH:21]([CH3:23])[CH3:22])[CH:17]([CH3:19])[CH3:18])=[CH:4][CH:3]=1
Reactant: Fc1ccc2cc[nH]c2c1
Reactant: CC(C)[SiH](C(C)C)C(C)C
Agent: [CH2-]CCC
Agent: [Cl-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)[Si](C(C)C)(C(C)C)n1ccc2ccc(F)cc21
Temperature: -78 °C
Reaction time: 0.08 h
Yield: 88.1 %

Procedure:
To a solution of 400 mg (2.96 mmol) of 6-fluoroindole dissolved in 6 ml of anhydrous tetrahydrofuran are added dropwise at −78° C. under argon 1.18 ml of a N-butyllithium solution (2.5M in hexane, 2.96 mmol). The reaction mixture is stirred for 5 min at −78° C., then 634 μL (2.96 mmol) of triisopropylsilane chloride are added dropwise at −78° C. to the reaction mixture. This mixture is stirred for 20 min at room temperature then water is added. The product is extracted several times with ethyl acetate. The organic phases are combined, dried over magnesium sulfate and concentrated. The residue is purified by chromatography on silica (cyclohexane/ethyl acetate eluent: 99:1) to yield 760 mg (89%) of 6-fluoro-1-triisopropylsilylindole as a colourless oil.
Reaction SMILES: [C:1]([CH:6]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:3][CH2:4][CH3:5])=[O:2].[CH3:26][C:27]1[N:32]=[CH:31][C:30]([CH2:33][OH:34])=[C:29]([CH:35]=O)[C:28]=1[OH:37].C(N(CC)CC)C>C1COCC1>[CH2:4]([O:3][C:1](=[O:2])[CH:6]=[CH:35][C:29]1[C:30]([CH2:33][OH:34])=[CH:31][N:32]=[C:27]([CH3:26])[C:28]=1[OH:37])[CH3:5]
Reactant: Cc1ncc(CO)c(C=O)c1O
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)C=Cc1c(CO)cnc(C)c1O
Reaction time: 1 h
Yield: 100.1 %

Procedure:
A clear solution of (carbethoxymethylene)triphenylphosphorane (22.3 g, 64.02 mmol) in THF was added to pyridoxal (13.01 g, 64.0 mmol) in THF at room temperature. The mixture was stirred for one hour, then triethylamine (10 mL) was added and the mixture was stirred until the solution turned to a yellow suspension. The solvent was evaporated, and the crude product purified by column chromatography on silica gel using a mixture of dichloromethane:methyl alcohol (20:1) as eluant to give 3-(3-hydroxy-5-hydroxymethyl-2-methyl-pyridin-4-yl)-acrylic acid ethyl ester (34) (15.2 g, quantitative yield) as a yellow solid.
Reaction SMILES: [CH:1]1([O:7][CH2:8][CH:9]2[CH2:14][CH:13]([C:15]([O:17][CH3:18])=[O:16])[CH2:12][CH2:11][NH:10]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.[C:28](Cl)(=[O:31])[O:29][CH3:30].[NH4+].[Cl-]>ClCCl>[CH:1]1([O:7][CH2:8][CH:9]2[CH2:14][CH:13]([C:15]([O:17][CH3:18])=[O:16])[CH2:12][CH2:11][N:10]2[C:28]([O:29][CH3:30])=[O:31])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)C1CCNC(COC2CCCCC2)C1
Reactant: COC(=O)Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)C1CCN(C(=O)OC)C(COC2CCCCC2)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 97.2 %

Procedure:
Methyl 2-(cyclohexyloxymethyl)piperidine-4-carboxylate (2.13 g, 8.34 mmol) was dissolved in dichloromethane (50 mL). DIPEA (2.034 mL, 11.68 mmol) and methyl carbonochloridate (0.788 mL, 10.01 mmol) were added and the mixture was stirred at room temperature for 3 h. 0.1 M NH4Cl was added and the aqueous layer was extracted with DCM. The combined organic layers were filtered through a phase separator and evaporated. Dimethyl 2-(cyclohexyloxymethyl)piperidine-1,4-dicarboxylate (2.54 g, 97%) was isolated. MS m/z 314 (M+H)+
Reaction SMILES: [NH2:1][C@H:2]([CH2:13][O:14][CH3:15])[C:3]([NH:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:4].[C:16](OC(=O)C)(=[O:18])[CH3:17]>[Pd].N1C=CC=CC=1>[CH3:17][C:16]([NH:1][C@@H:2]([C:3]([NH:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:4])[CH2:13][O:14][CH3:15])=[O:18]
Reactant: COC[C@@H](N)C(=O)NCc1ccccc1
Reactant: CC(=O)OC(C)=O
Agent: [Pd]
Solvent: c1ccncc1
Product: COC[C@@H](NC(C)=O)C(=O)NCc1ccccc1

Procedure:
The second method describes the process, wherein D-serine is protected with benzyloxycarbonyl chloride to give N-Benzyloxycarbonyl-D-serine of Formula-IV. The compound of Formula-IV on alkylation with methyl iodide in the presence of silver oxide and solvent acetonitrile yields the compound (2R)-methyl 2-(benzyloxycarbonylamino)-3-methoxypropanoate of Formula-V, and which is purified by flash column chromatography using silica gel and methanol-chloroform eluent before the next stage. The compound of Formula-V is hydrolyzed to give (2R)-2-(benzyloxycarbonylamino)-3-methoxypropanoic acid of Formula-VI. The compound of Formula-VI is cooled to −78° C. in tetrahydrofuran and reacted with isobutyl chloroformate in presence of N-methylmorpholine followed by reaction with benzylamine to yield the compound (2R)-benzyl 1-(benzylamino)-3-methoxy-1-oxopropan-2-ylcarbamate of Formula-VII. The compound of Formula-VII on hydrogenation using palladium on carbon gives deprotected compound (2R)-2-amino-N-benzyl-3-methoxy-propanamide of Formula-VIII. The compound of Formula-VIII is acetylated using acetic anhydride in the presence of solvent pyridine to give crude Lacosamide of the Formula-I. The crude compound is purified by flash column chromatography to give pure Lacosamide.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7](O)[CH3:8].S(Cl)([Cl:12])=O>ClCCl>[Cl:12][CH:7]([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1)[CH3:8]
Reactant: CC(O)c1ccccn1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: CC(Cl)c1ccccn1
Temperature: 20 °C
Reaction time: 2 h
Yield: 97 %

Procedure:
To an ice-cooled solution of 1-(pyridin-2-yl)ethanol (4.5 g, 36 mmol) in dry dichloromethane (100 mL) was slowly added thionyl dichloride (20 mL). The mixture was then warmed to 20° C. After 2 h, the reaction was concentrated in vacuo, and the resulting residue was diluted with water (40 mL) and dichloromethane (60 mL). The solution was neutralized with saturated aqueous sodium carbonate solution. The organic layer was washed with saturated aqueous sodium chloride solution (3×30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to afford crude 2-(1-chloroethyl)pyridine (5.0 g, 97% yield). The product was used without further purification.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)[C:7](=[O:18])[NH:6][CH2:5]2.[CH:19]1([NH:22][C:23](=[O:40])[C:24]2[CH:29]=[CH:28][C:27]([CH3:30])=[C:26](B3OC(C)(C)C(C)(C)O3)[CH:25]=2)[CH2:21][CH2:20]1>>[CH:19]1([NH:22][C:23](=[O:40])[C:24]2[CH:29]=[CH:28][C:27]([CH3:30])=[C:26]([C:2]3[CH:3]=[C:4]4[C:9](=[CH:10][CH:11]=3)[N:8]([CH:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)[C:7](=[O:18])[NH:6][CH2:5]4)[CH:25]=2)[CH2:20][CH2:21]1
Reactant: O=C1NCc2cc(Br)ccc2N1C1CCOCC1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1B1OC(C)(C)C(C)(C)O1
Product: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc2c(c1)CNC(=O)N2C1CCOCC1

Procedure:
The title compound was prepared as pale yellow solid, using 6-Bromo-1-(tetrahydro-2H-pyran-4-yl)-3,4-dihydroquinazolin-2(1H)one and N-cyclopropyl-4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide, by a method analogous to that described in Example 3 above. MS m/e 406 (M+H)+.
Reaction SMILES: C[O:2][C:3](=[O:25])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]2[N:11]=[C:12](Cl)[C:13]3[N:14]([C:16](=[O:23])[N:17]([C:19]([CH3:22])([CH3:21])[CH3:20])[N:18]=3)[CH:15]=2)[CH:5]=1.[CH:26]([NH2:29])([CH3:28])[CH3:27]>C1COCC1.CCOC(C)=O>[C:19]([N:17]1[C:16](=[O:23])[N:14]2[CH:15]=[C:10]([C:6]3[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=3)[C:3]([OH:2])=[O:25])[N:11]=[C:12]([NH:29][CH:26]([CH3:28])[CH3:27])[C:13]2=[N:18]1)([CH3:21])([CH3:20])[CH3:22]
Reactant: CC(C)N
Reactant: COC(=O)c1cccc(-c2cn3c(=O)n(C(C)(C)C)nc3c(Cl)n2)c1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)Nc1nc(-c2cccc(C(=O)O)c2)cn2c(=O)n(C(C)(C)C)nc12
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A solution of 580 mg of 3-(2-tert-butyl-8-chloro-3-oxo-2,3-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-6-yl)-benzoic acid methyl ester and 944 mg of isopropylamine in THF (8.0 mL) was stirred at ambient temperature. After 72 h, the reaction was diluted with EtOAc and washed with water followed by sat. sodium chloride solution. The organic layer was dried over sodium sulfate, filtered, and concentrated to an orange semi-solid. This material was dissolved in 1,4-dioxane (6.0 mL) and 2N KOH (1.0 mL) was added. This mixture was heated at reflux for 16 h, cooled to ambient temperature and the solvent removed. The residue was dissolved in water and the pH adjusted to 3 with 2N HCl prior to extraction with 9:1 chloroform/MeOH (3×). The organic extracts were washed with sat. sodium chloride solution, dried over sodium sulfate, filtered, and concentrated to leave 3-(2-tert-butyl-8-isopropylamino-3-oxo-2,3-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-6-yl)-benzoic acid as a yellow solid. MS (M+H+)=370.4.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([OH:11])[CH:8]=[CH:9][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:12][O:13]C(Cl)Cl>ClCCl.[Ti](Cl)(Cl)(Cl)Cl>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH:12]=[O:13])=[C:7]([OH:11])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(Cl)Cl
Reactant: CC(C)(C)c1cccc(O)c1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: CC(C)(C)c1ccc(C=O)c(O)c1
Temperature: 25 °C
Yield: 76.9 %

Procedure:
A stirred, cooled (ice bath) solution of 3-tert-butyl phenol (1.5 g, 10 mmol) in anhydrous dichloromethane was treated with titanium tetrachloride (1.86 mL, 17 mmol) followed by α,α-dichloromethyl ether (0.9 mL, 20 mmol). The reaction was allowed to warm to ambient temperature over 1 h, quenched cautiously with ice and water and extracted with dichloromethane. The organic extract was washed with water and brine, dried over sodium sulfate, filtered and evaporated in vacuo to a residue that was subjected to flash column chromatography using 2–2.5% ethyl acetate in hexane as the eluent to afford the title compound (1.37 g, 77%). 1H NMR (300 MHz, CDCl3): δ 11.02 (s, 1H), 9.81 (s, 1H), 7.45 (d, J=8.2 Hz, 1H), 7.03 (dd, J=8.2, 1.7 Hz, 1H), 6.99 (d, J=1.7 Hz, 1H), 1.31 (s, 9H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[C:4]([I:12])[CH:3]=1.S(=O)(=O)(O)O.[CH3:18]O>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH3:18])=[O:10])=[C:4]([I:12])[CH:3]=1
Reactant: O=C(O)Cc1ccc(F)cc1I
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)Cc1ccc(F)cc1I
Yield: 95 %

Procedure:
A solution of the acid 324 (3.95 g, 14.1 mmol) and sulfuric acid (0.5 mL) in methanol (50 mL) was heated under reflux for 18 h, then cooled and concentrated under reduced pressure. The residue was partitioned between ethyl acetate and water; the organic phase was collected, dried (anhydrous MgSO4), filtered and concentrated to afford pure 325 (3.93 g, 95% yield). 1H NMR (400 MHz, CDCl3) δ (ppm): 7.57 (dd, J=8.2, 2.7 Hz, 1H); 7.25 (dd, J=8.6, 5.9 Hz, 1H); 7.05 (dt, J=8.2, 2.7 Hz, 1H); 3.78 (s, 2H); 3.72 (s, 3H). LCMS: (M+H) 295.0.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]#[C:9][CH2:10][CH2:11][CH2:12][CH3:13].[I-:14].[K+].[N:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[CH3:22]>CC(=O)CC>[I-:14].[CH2:2]([N+:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[CH3:22])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]#[C:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: CCCCC#CCCCCCCCl
Reactant: Cc1ccccn1
Agent: [I-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCCCC#CCCCCCC[n+]1ccccc1C
Yield: 85 %

Procedure:
12-Chloro-dodec-5-yne (1 mmol) was mixed with potassium iodide (3 mmol) and 2-picoline (3 mmol) in butanone. room temperature. The butanone was removed in a vacuum, and the resulting residue was partitioned between water and ethyl ether. The aqueous layer was washed extensively with ether until no 2-picoline was left in the aqueous layer. The resulting aqueous solution of the product was extracted with chloroform. The chloroform was removed to afford the product (85%). 1HNMR (300 MHz, CDCl3, ppm) 9.62 (d, 1H), 8.39 (dd, 1H), 7.99 (m, 1H), 7.91 (d, 1H), 4.88 (t, 2H), 2.97 (s, 3H), 2.12-2.20 m, 4H), 1.90-2.00 (m, 2H), 1.32-1.58 (m, 8H), 0.88 (t, 3H).
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.[NH:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1>CN1C(=O)CCC1.O>[N+:8]([C:4]1[CH:3]=[C:2]([N:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[CH:7]=[CH:6][CH:5]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1cccc(F)c1
Reactant: C1CNCCN1
Solvent: O
Solvent: CN1CCCC1=O
Product: O=[N+]([O-])c1cccc(N2CCNCC2)c1
Temperature: 70 °C
Yield: 70.5 %

Procedure:
A suspension of 3-fluoronitrobenzene (23 ml; 0.21 mol) and piperazine (55.5 g; 0.64 mol) in anhydrous NMP (30 ml) was heated to 70° C. for five days. The cooled mixture was diluted with water (250 ml) and extracted with dichloromethane. The combined extracts were dried over magnesium sulphate and concentrated under reduced pressure. The residue was purified by column-chromatography on silica gel eluting subsequently with mixtures of ethyl acetate and methanol (4:1 v/v) and (1:1 v/v) to leave the desired product as oily crystals (30.7 g; 71%).
Reaction SMILES: C(N(CC)CC)C.Cl.[CH2:9]([N:11]([CH2:19][CH3:20])[C:12]1[CH:17]=[CH:16][C:15]([NH2:18])=[CH:14][CH:13]=1)[CH3:10].[C:21](Cl)(=[O:23])[CH3:22]>ClCCl>[C:21]([NH:18][C:15]1[CH:16]=[CH:17][C:12]([N:11]([CH2:9][CH3:10])[CH2:19][CH3:20])=[CH:13][CH:14]=1)(=[O:23])[CH3:22]
Reactant: CC(=O)Cl
Reactant: CCN(CC)c1ccc(N)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCN(CC)c1ccc(NC(C)=O)cc1
Temperature: 0 °C
Yield: 80 %

Procedure:
Triethylamine (22.3 g, 30.6 mL, 0.22 mol) was added to a suspension of N,N-diethyl-p-phenylenediamine hydrochloride (20 g, 0.1 mol) in dichloromethane (150 mL) at room temperature. The mixture was cooled to 0° C. and acetyl chloride (7.85 g, 0.1 mol) was added dropwise, with stirring. The mixture was allowed to warm to room temperature, and the precipitate which had formed was removed by filtration. The solid residue was washed with dichloromethane, and the combined dichloromethane solutions were concentrated. The dark oil produced was triturated with hexanes (100 mL) to afford a light brown crystalline solid, which was purified by recrystallization from 50% aqueous ethanol to afford the N-acetyl-4-diethylaminoaniline (16.5 g, 80% yield) as a gray solid. The structure of this compound was confirmed by mass spectroscopy and by 1H NMR spectroscopy.
Reaction SMILES: COP([CH:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9](=[O:16])[O:8]1)(=O)OC.[F:17][C:18]1[CH:25]=[CH:24][C:23]([CH:26]=O)=[CH:22][C:19]=1[C:20]#[N:21].C(N(CC)CC)C>O1CCCC1>[F:17][C:18]1[CH:25]=[CH:24][C:23]([CH:26]=[C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9](=[O:16])[O:8]2)=[CH:22][C:19]=1[C:20]#[N:21]
Reactant: COP(=O)(OC)C1OC(=O)c2ccccc21
Reactant: N#Cc1cc(C=O)ccc1F
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: N#Cc1cc(C=C2OC(=O)c3ccccc32)ccc1F
Temperature: 20 °C
Reaction time: 0.5 h

Procedure:
To a mixture of (3-oxo-1,3-dihydro-isobenzofuran-1-yl)phosphonic acid dimethyl ester (35.0 g, 0.14 mol) in tetrahydrofuran (200 ml) and 2-fluoro-5-formylbenzonitrile (20.9 g, 0.14 mol) in tetrahydrofuran (130 ml) was added triethylamine (14 ml, 0.14 mol) drop-wise over 25 min, with the temperature kept below 15° C. The reaction mixture was warmed slowly to 20° C. over 1 hour and concentrated in vacuo. The white residue was slurried in water (250 ml) for 30 minutes, filtered, washed with water, hexane and ether, and dried to yield 2-fluoro-5-(3-oxo-3H-isobenzofuran-1-ylidenemethyl)benzonitrile as a 50:50 mixture of E and Z isomers (37.2 g, 96%); m/z [M+1]+ 266 (98% purity)
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][CH:7]=[CH:8][C:9]=1[N:10]([C:17]([C@H:19]1[CH2:24][CH2:23][C@H:22]([CH3:25])[CH2:21][CH2:20]1)=[O:18])[CH:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1)=[O:4].[CH2:26]=O>ClCCCl>[CH3:1][O:2][C:3]([C:5]1[S:6][CH:7]=[CH:8][C:9]=1[N:10]([C:17]([C@H:19]1[CH2:20][CH2:21][C@H:22]([CH3:25])[CH2:23][CH2:24]1)=[O:18])[CH:11]1[CH2:12][CH2:13][N:14]([CH3:26])[CH2:15][CH2:16]1)=[O:4]
Reactant: COC(=O)c1sccc1N(C(=O)[C@H]1CC[C@H](C)CC1)C1CCNCC1
Reactant: C=O
Solvent: ClCCCl
Product: COC(=O)c1sccc1N(C(=O)[C@H]1CC[C@H](C)CC1)C1CCN(C)CC1

Procedure:
To a stirred solution of 3-[(trans-4-methyl-cyclohexanecarbonyl)-piperidin-4-yl-amino]-thiophene-2-carboxylic acid methyl ester (1.0 g, 2.7 mmol), from step 3, in 1,2-dichloroethane (10 mL) was sequentially added aq. 37% HCHO solution (0.45 mL, 5.4 mmol) and NaBH(OAC)3 (2.86 g, 13.5 mmol) in one portion, stirred for over night, reaction was then quenched with aq. 10% NaOH solution, extracted with DCM. The combined organic extract was washed with brine, dried, and concentrated to obtain 3-[(trans-4-methyl-cyclohexanecarbonyl)-(1-methyl-piperidin-4-yl)-amino]-thiophene-2-carboxylic acid methyl ester (0.876 g, 85.5%) as a white solid. NMR 1H (CDCl3, 400 MHz): 7.54 (d, 1H), 6.86 (d, 1H), 4.7-4.6 (m, 1H), 3.85 (s, 3H), 2.9-2.7 (m, 2H), 2.22 (s, 3H), 2.15-1.1 (m, 14H), 0.8 (d, 3H), 0.75-0.5 (m, 2H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[C:10]([F:13])([F:12])[F:11])[CH2:5][NH2:6].[CH:14]1[C:23]2[C:18](=[C:19]([CH:24]([CH3:28])[C:25](O)=[O:26])[CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][N:15]=1.C1C2C(=C(CC(O)=O)C=CC=2)C=CN=1>>[F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[C:10]([F:11])([F:12])[F:13])[CH2:5][NH:6][C:25](=[O:26])[CH:24]([C:19]1[CH:20]=[CH:21][CH:22]=[C:23]2[C:18]=1[CH:17]=[CH:16][N:15]=[CH:14]2)[CH3:28]
Reactant: NCc1ccc(C(F)(F)F)c(F)c1
Reactant: CC(C(=O)O)c1cccc2cnccc12
Agent: O=C(O)Cc1cccc2cnccc12
Product: CC(C(=O)NCc1ccc(C(F)(F)F)c(F)c1)c1cccc2cnccc12

Procedure:
The title compound was prepared using the procedure described in Example 222B using 3-fluoro-4-(trifluoromethyl)benzylamine and 2-(5-isoquinolinyl)propanoic acid instead of 4-(trifluoromethoxy)benzylamine and 5-isoquinolinylacetic acid. MS (ESI+) m/z 377 (M+H)+; MS (ESI−) m/z 375 (M−H)−; 1H NMR (DMSO, 300 MHz) δ 1.53 (d, J 7.1, 3H), 4.35 (d, J 6.1, 2H), 4.47 (q, J 7.1, 1H), 7.18 (m, 2H), 7.70 (m, 3H), 8.05 (m, 2H), 8.53 (d, J 6.1, 1H), 8.68 (t, J 6.8, 1H), 9.32 (s, 1H); Anal. Calcd for C20H16F4N2O+1.25HCl: C, 56.93; H, 4.12; N, 6.64. Found: C, 56.72; H, 4.45; N, 7.03.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[C:11]1[N:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[Cl:22])[N:14]=[CH:13][CH:12]=1.[Cl:23][S:24](O)(=[O:26])=[O:25]>>[Cl:23][S:24]([C:6]1[C:7]([O:9][CH3:10])=[CH:8][C:3]([O:2][CH3:1])=[C:4]([C:11]2[N:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[Cl:22])[N:14]=[CH:13][CH:12]=2)[CH:5]=1)(=[O:26])=[O:25]
Reactant: COc1ccc(-c2ccnn2-c2ccccc2Cl)c(OC)c1
Reactant: O=S(=O)(O)Cl
Product: COc1cc(OC)c(S(=O)(=O)Cl)cc1-c1ccnn1-c1ccccc1Cl
Temperature: 25 °C
Reaction time: 3 h

Procedure:
2.1 18.0 g of 5-(2,4-dimethoxyphenyl)-1-(2-chlorophenyl)-1H-pyrazole are added at −5° to 30 ml of chlorosulfonic acid, and the mixture is stirred at room temperature for a further 3 hours. The mixture is poured onto ice, and the deposited crystals are separated off and washed with water, giving 23.6 g of 5-(5-chlorosulfonyl-2,4-dimethoxyphenyl)-1-(2-chlorophenyl)-1H-pyrazole (“2a”).