Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[CH:6][C:3]=1[C:4]#[N:5].I[CH2:17][CH2:18][CH3:19]>>[F:1][C:2]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:11][CH2:12][N:13]([CH2:17][CH2:18][CH3:19])[CH2:14][CH2:15]2)=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: CCCI
Reactant: N#Cc1cc(N2CCNCC2)ccc1F
Product: CCCN1CCN(c2ccc(F)c(C#N)c2)CC1

Procedure:
Beginning with 2-fluoro-5-piperazin-1-yl-benzo-nitrile and 1-iodopropane, the title compound was recovered by the procedure described in Example 2. MS m/z (rel. intensity, 70 eV) 247 (M+, 25), 218 (bp), 175 (28), 147 (33), 70 (65).
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:12]3=[N:14][C:15]([CH3:18])=[C:16](Br)[N:11]3[CH:10]=[CH:9][C:8]=2[C@@H:7]([O:19][CH2:20][CH2:21][O:22][CH3:23])[C@H:6]([O:24][C:25](=[O:30])[C:26]([CH3:29])([CH3:28])[CH3:27])[C@H:5]1[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)(=[O:3])[CH3:2].[C:37]1(B(O)O)[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.[F-].[K+].P(C(C)(C)C)(C(C)(C)C)C(C)(C)C>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1COCC1>[C:1]([N:4]1[C:13]2[C:12]3=[N:14][C:15]([CH3:18])=[C:16]([C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)[N:11]3[CH:10]=[CH:9][C:8]=2[C@@H:7]([O:19][CH2:20][CH2:21][O:22][CH3:23])[C@H:6]([O:24][C:25](=[O:30])[C:26]([CH3:29])([CH3:28])[CH3:27])[C@H:5]1[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)(=[O:3])[CH3:2]
Reactant: OB(O)c1ccccc1
Reactant: COCCO[C@@H]1c2ccn3c(Br)c(C)nc3c2N(C(C)=O)[C@H](c2ccccc2)[C@H]1OC(=O)C(C)(C)C
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1CCOC1
Product: COCCO[C@@H]1c2ccn3c(-c4ccccc4)c(C)nc3c2N(C(C)=O)[C@H](c2ccccc2)[C@H]1OC(=O)C(C)(C)C
Temperature: 25 °C
Reaction time: 48 h

Procedure:
2.61 g (4.67 mmol) (7R,8R,9R)-10-acetyl-3-bromo-7-(2-methoxyethoxy)-2-methyl-9-phenyl-8-pivaloyloxy-7.8.9.10-tetrahydroimidazo[1.2-h][1.7]naphthyridine, 0.63 g (5.14 mmol) phenylboronic acid, 0.89 g (15.4 mmol) KF (spray-dried), 0.14 g (0.15 mmol) Pd2(dba)3, 0.07g (0.36 mmol/10wt % solution in hexane)P(t-Bu)3 and THF (30 ml) are added to a Schlenk tube under argon. Afterwards the Schlenk tube is evacuated and refilled with argon in a freeze-pump-thaw cycles technique three times. The reaction mixture is stirred under argon for 2 d at 25° C. Subsequently the reaction is diluted by adding of ethyl acetate and then filtrated through silica gel. The concentrated crude product is purified by column chromatography (diethyl ether/petrol ether: 6/4) to give 1.80 g (3.24 mmol/70%) of the title compound as an amorphous colourless solid. 1H-NMR (200 MHz, [D6] DMSO): δ=1.20 (s, 9H), 2.20(s, 3H), 2.43(s, 3H), 3.30 (s, 3H), 3.40–3.57(m, 2H), 3.88 (t, 2H), 4.64 (d, 1H), 5.35 (t, 1H), 5.83(d, 1H), 7.00(d, 1H), 7.10–7.30(m, 5H), 7.41–7.68 (m, 5H), 8.24(d, 1H).
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][S:9]([C:12]1[CH:33]=[CH:32][C:15]([O:16][C:17]2[N:22]=[CH:21][N:20]=[C:19]3[N:23]([CH:26]4[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]4)[N:24]=[CH:25][C:18]=23)=[CH:14][CH:13]=1)(=[O:11])=[O:10].[S:34]1[CH:38]=[CH:37][N:36]=[C:35]1[CH:39]=O.C(N(CC)CC)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH3:8][S:9]([C:12]1[CH:13]=[CH:14][C:15]([O:16][C:17]2[N:22]=[CH:21][N:20]=[C:19]3[N:23]([CH:26]4[CH2:27][CH2:28][N:29]([CH2:39][C:35]5[S:34][CH:38]=[CH:37][N:36]=5)[CH2:30][CH2:31]4)[N:24]=[CH:25][C:18]=23)=[CH:32][CH:33]=1)(=[O:11])=[O:10]
Reactant: CS(=O)(=O)c1ccc(Oc2ncnc3c2cnn3C2CCNCC2)cc1
Reactant: O=Cc1nccs1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)c1ccc(Oc2ncnc3c2cnn3C2CCN(Cc3nccs3)CC2)cc1

Procedure:
4-(4-Methanesulfonyl-phenoxy)-1-(1-thiazol-2-ylmethyl-piperidin-4-yl)-1H-pyrazolo[3,4-d]pyrimidine was prepared according to General Procedure H by the reaction of 4-(4-methanesulfonyl-phenoxy)-1-piperidin-4-yl-1H-pyrazolo[3,4-d]pyrimidine trifluoroacetate salt (Intermediate 25) with 2-thiazolecarboxaldehyde (available from Aldrich Chemical Company, Inc., Milwaukee, Wis., USA), triethylamine, and sodium triacetoxyborohydride in 1,2-dichloroethane. 1H NMR (400 MHz, DMSO-d6) δ 1.95-2.00 (m, 2H), 2.21-2.33 (m, 2H), 2.39-2.45 (m, 3H), 3.04-3.08 (m, 2H), 3.30 (methyl sulfonyl and water peak), 3.92 (s, 2H), 4.79-4.85 (m, 1H), 7.63-7.74 (m, 4H), 8.05-8.07 (m, 2H), 8.39 (s, 1H), 8.56 (s, 1H). Mass spectrum MH+=471.
Reaction SMILES: [CH3:1][C:2]1([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([N+:25]([O-:27])=[O:26])[CH:20]=2)[N:7]2[CH:3]1[C:4](=O)[CH:5]([CH2:9][CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]2=O.[BH4-].[Na+].B(F)(F)F.N1CCNCC1>O1CCCC1>[N+:25]([C:21]1[CH:20]=[C:19]([C:2]2([CH3:1])[N:7]3[CH:3]2[CH2:4][CH:5]([CH2:9][CH2:10][CH2:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:6]3)[CH:24]=[CH:23][CH:22]=1)([O-:27])=[O:26]
Reactant: CC1(c2cccc([N+](=O)[O-])c2)C2C(=O)C(CCCc3ccccc3)C(=O)N21
Agent: C1CNCCN1
Agent: FB(F)F
Agent: [BH4-]
Solvent: C1CCOC1
Product: CC1(c2cccc([N+](=O)[O-])c2)C2CC(CCCc3ccccc3)CN21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Or Method B: (i) To a stirred solution of 6-methyl-6-(3-nitrophenyl)-3-(3-phenylpropyl)azabicyclo[3.1.0]hexane-2,4-dione (Preparation 136, 15.0 g, 41.2 mmol) in tetrahydrofuran (60 ml) under nitrogen was added sodium borohydride (3.27 g, 86.4 mmol) and the reaction mixture was stirred at room temperature for 1 h. The reaction mixture was cooled to between 0° C. and 5° C. and borontrifluoride diethyletherate (16.36 g, 115 mmol) was added. The reaction mixture was allowed to warm to room temperature over 2 h before being heated under reflux for a further 2 h. The reaction mixture was cooled to between 0° C. and 5° C. and an aqueous solution of piperazine (20.92 g in 120 ml) was added. The reaction mixture was then heated under reflux for 18 h. The tetrahydrofuran was removed by distillation and the reaction mixture was allowed to cool to 50° C. Ethyl acetate (90 ml) was added and the resulting biphasic mixture was allowed to cool to room temperature. The phases were separated and the organic extract was washed water (3×60 ml) to afford a solution of 6-(3-nitrophenyl)-6-methyl-3-(3-phenylpropyl)azabicyclo[3.1.0]hexane in ethyl acetate. (ii) To the reaction mixture was added 5% palladium on charcoal (Johnsson Matthey type 87, 1.5 g) and the reaction mixture was placed under an atmosphere of hydrogen (60 psi) at 25° C. for 16 h. The catalyst was removed by filtration through Celite™ and the filtrate was concentrated in vacuo to afford the title compound as a yellow oil which crystallised on standing (11.09 g, 88%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][C:5]1[S:9][C:8]([C:10]([NH2:12])=[O:11])=[CH:7][CH:6]=1.[C:13]1([C@H:19]2[O:21][CH2:20]2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CS(C)=O.O>[OH:21][C@H:19]([C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)[CH2:20][N:1]([CH2:20][C@H:19]([OH:21])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:2][CH2:3][CH2:4][C:5]1[S:9][C:8]([C:10]([NH2:12])=[O:11])=[CH:7][CH:6]=1
Reactant: c1ccc([C@@H]2CO2)cc1
Reactant: NCCCc1ccc(C(N)=O)s1
Solvent: CS(C)=O
Solvent: O
Product: NC(=O)c1ccc(CCCN(C[C@H](O)c2ccccc2)C[C@H](O)c2ccccc2)s1

Procedure:
30 g of 5-(3-aminopropyl)-2-thiophenecarboxamide and 20.2 ml of (R)-phenylethylene oxide were stirred at 95° for 24 hours in 400 ml of dimethyl sulphoxide. After cooling, the mixture was diluted with 1.3 l of water and extracted three times with about 600 ml of methylene chloride. The methylene chloride solutions were washed twice with water, dried over sodium sulphate and evaporated in vacuo. Chromatography of the residue on silica gel with ether/methanol gave 21 g of 5-[3-[bis[(R)-β-hydroxyphenethyl]amino]propyl]-2-thiophenecarboxamide; UV: ε276 =9900; [α]D =-69° (c=0.1% in dioxan).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([Cl:10])=[C:7]([NH2:9])[CH:8]=1.[C:11](Cl)(=[O:16])[C:12]([CH3:15])([CH3:14])[CH3:13]>C1COCC1>[NH2:9][C:7]1[CH:8]=[C:3]([CH:4]=[CH:5][C:6]=1[Cl:10])[CH2:2][NH:1][C:11](=[O:16])[C:12]([CH3:15])([CH3:14])[CH3:13]
Reactant: CC(C)(C)C(=O)Cl
Reactant: NCc1ccc(Cl)c(N)c1
Solvent: C1CCOC1
Product: CC(C)(C)C(=O)NCc1ccc(Cl)c(N)c1

Procedure:
The title compound was prepared according to the procedure described in step-2 of Intermediate-83 by using 5-(aminomethyl)-2-chlorobenzenamine (2.0 g), pivaloyl chloride (0.2 mL), TEA (2 mL) and THF (10 mL) to afford 2.0 g of the desired product.
Reaction SMILES: CO[C:3]([C:5]1[N:6]=[CH:7][C:8]2[C:9](=[O:23])[N:10]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:11]=[CH:12][C:13]=2[C:14]=1[OH:15])=[O:4].[NH2:24][CH2:25][C:26]([OH:28])=[O:27].C[O-].[Na+]>>[CH2:16]([N:10]1[C:9](=[O:23])[C:8]2[CH:7]=[N:6][C:5]([C:3]([NH:24][CH2:25][C:26]([OH:28])=[O:27])=[O:4])=[C:14]([OH:15])[C:13]=2[CH:12]=[CH:11]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: NCC(=O)O
Reactant: COC(=O)c1ncc2c(=O)n(Cc3ccccc3)ccc2c1O
Agent: C[O-]
Agent: [Na+]
Product: O=C(O)CNC(=O)c1ncc2c(=O)n(Cc3ccccc3)ccc2c1O
Yield: 73 %

Procedure:
A mixture of 7-benzyl-4-hydroxy-8-oxo-7,8-dihydro-[2,7]naphthyridine-3-carboxylic acid methyl ester (60 mg, 0.19 mmol), glycine (726 mg, 9.68 mmol) and NaOMe solution (14.5 mL, 7.26 mmol, 0.5 M in MeOH) was refluxed for 16 h. Solvent was evaporated in vacuo, and the residue was partitioned between water (50 mL) and EtOAc (50 mL). 1 M HCl was added with vigorous stirring until pH was about 2. The organic layer was dried over MgSO4 and concentrated. The crude product was purified by silica gel chromatography (20-100% EtOAc/hexanes) to give 49 mg of the title compound as a light yellow solid. MS: (+) m/z 354.07 (M+1).
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:8]=[CH:7][C:6]([C@H:9]2[CH2:14][C@@H:13]([C:15]([O:17][CH3:18])=[O:16])[CH2:12][CH2:11][NH:10]2)=[CH:5][CH:4]=1.[F:21][C:22]([F:36])([F:35])[C:23]1[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][C:24]=1[CH2:25]Br.[Na+].[I-].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CCOC(C)=O.O>[F:21][C:22]([F:35])([F:36])[C:23]1[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:32])[F:33])=[CH:27][C:24]=1[CH2:25][N:10]1[CH2:11][CH2:12][C@H:13]([C:15]([O:17][CH3:18])=[O:16])[CH2:14][C@@H:9]1[C:6]1[CH:5]=[CH:4][C:3]([C:2]([F:19])([F:1])[F:20])=[CH:8][CH:7]=1
Reactant: FC(F)(F)c1ccc(C(F)(F)F)c(CBr)c1
Reactant: COC(=O)[C@H]1CCN[C@@H](c2ccc(C(F)(F)F)cc2)C1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)[C@H]1CCN(Cc2cc(C(F)(F)F)ccc2C(F)(F)F)[C@@H](c2ccc(C(F)(F)F)cc2)C1
Temperature: 150 °C
Yield: 62 %

Procedure:
(±)-Methyl(cis)-2-[4-(trifluoromethyl)phenyl]piperidine-4-carboxylate (Example (18b) (88 mg), 2,5-bis(trifluoromethyl)benzyl bromide (110 mg), NaI (25 mg) and K2CO3 (100 mg) in DMF (3 ml) were placed in a microwave tube and the contents were heated in the microwave oven for 20 min at 150° C. The cooled mixture was dispersed between water and EtOAc and the organic extracts were washed with sodium thiosulfate, brine, dried (MgSO4) and evaporated. The crude oil was purified by chromatography on silica using 5-8% EtOAc in hexane to yield a colourless oil (98 mg, 62%) which crystallized on standing. 1H NMR (400 MHz, CDCl3) δ: 1.81-1.89 (2H, m), 1.97 (1H, d, J 13.2), 2.09-2.17 (2H, m), 2.49-2.56 (1H, m), 2.94-2.96 (1H, m), 3.34 (1H, d, J 15.6), 3.40 (1H, dd, J 2.6, 11.3), 3.66 (4H, d, J 15.6), 7.53-7.59 (5H, m), 7.68 (1H, d, J 8.2), 8.19 (1H, s); M/Z (ES+) 514 (MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][N:15]([CH2:17][CH:18]=[CH2:19])[CH3:16])[CH:5]=[CH:4][C:3]=1[C:20]([C:22]1[CH:27]=[CH:26][C:25]([Br:28])=[CH:24][CH:23]=1)=O.[CH:29]([NH2:31])=O>C(O)=O>[CH2:17]([N:15]([CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][O:8][C:6]1[CH:7]=[C:2]2[C:3]([C:20]([C:22]3[CH:27]=[CH:26][C:25]([Br:28])=[CH:24][CH:23]=3)=[N:31][CH:29]=[N:1]2)=[CH:4][CH:5]=1)[CH3:16])[CH:18]=[CH2:19]
Reactant: C=CCN(C)CCCCCCOc1ccc(C(=O)c2ccc(Br)cc2)c(N)c1
Reactant: NC=O
Solvent: O=CO
Product: C=CCN(C)CCCCCCOc1ccc2c(-c3ccc(Br)cc3)ncnc2c1

Procedure:
A solution of 230 mg of [2-amino-4-[6-(allyl-methyl-amino)-hexyloxy]-phenyl]-(4-bromo-phenyl)-methanone in 0.5 ml of formic acid and 2 ml of formamide is boiled at 165° C. for 25 min., then concentrated and converted into the free amine (title compound) with methylene chloride/saturated sodium bicarbonate solution. After purification (silica gel, methylene chloride/methanol 2.5% to 10%) the residue is dissolved in methylene chloride/ether and treated with 23.7 mg of fumaric acid. After stirring and filtration there are obtained 30 mg of allyl-[6-[4-(4-bromo-phenyl)-quinazolin-7-yloxy]-hexyl]-methyl-amine.fumarate (1:1), m.p 90°-95° C., MS: m/e 454 (M+H+, 1 Br).
Reaction SMILES: [F:1][C:2]1[CH:21]=[C:20](I)[CH:19]=[CH:18][C:3]=1[NH:4][C:5]1[C:6]([C:12]([NH:14][CH2:15][CH2:16][OH:17])=[O:13])=[CH:7][NH:8][C:9](=[O:11])[CH:10]=1.[Si:23]([C:27]#[CH:28])([CH3:26])([CH3:25])[CH3:24]>C1COCC1.CN(C=O)C.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:1][C:2]1[CH:21]=[C:20]([C:28]#[C:27][Si:23]([CH3:26])([CH3:25])[CH3:24])[CH:19]=[CH:18][C:3]=1[NH:4][C:5]1[C:6]([C:12]([NH:14][CH2:15][CH2:16][OH:17])=[O:13])=[CH:7][NH:8][C:9](=[O:11])[CH:10]=1
Reactant: C#C[Si](C)(C)C
Reactant: O=C(NCCO)c1c[nH]c(=O)cc1Nc1ccc(I)cc1F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: C[Si](C)(C)C#Cc1ccc(Nc2cc(=O)[nH]cc2C(=O)NCCO)c(F)c1
Yield: 72 %

Procedure:
4-(2-Fluoro-4-iodoanilino)-N-(2-hydroxyethyl)-6-oxo-1,6-dihydro-3-pyridinecarboxamide was reacted with TMS-acetylene in the presence of CuI, (Ph3P)2PdCl2 and TEA in THF/DMF (1:1) as for example 2. The residue resulting from removal of the reaction solvents under reduced pressure was purified by column chromatography on silica gel (10% MeOH/CH2Cl2 as eluant) to give 4-{2-fluoro-4-[(trimethylsilyl)ethynyl]anilino}-N-(2-hydroxyethyl)-6-oxo-1,6-dihydro-3-pyridinecarboxamide as an off-white solid (72%), used directly in the next step. 1H NMR [(CD3)2SO, 400 MHz] δ 11.45 (br s, 1H), 10.45 (s, 1H), 8.50 (t, J=5.4 Hz, 1H), 7.96 (s, 1H), 7.48 (t, J=8.4 Hz, 1H), 7.42 (dd, J=11.5, 1.8 Hz, 1H), 7.30 (dd, J=8.3, 1.4 Hz, 1H), 5.65 (s, 1H), 4.71 (t, J=5.7 Hz, 1H), 3.49 (q, J=5.9 Hz, 2H), 3.29-3.24 (m, 2H), 0.24 (s, 9H). HRMS (FAB+) calcd C19H23FN3O3Si (MH+) 388.1493, found 388.1488.
Reaction SMILES: [O:1]=[S:2]1(=[O:17])[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][C:8]1[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][CH:9]=1.[CH3:18][C:19]1[CH:24]=[C:23]([CH3:25])[CH:22]=[CH:21][C:20]=1[N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>CN(C)C=O.O>[CH3:18][C:19]1[CH:24]=[C:23]([CH3:25])[CH:22]=[CH:21][C:20]=1[N:26]1[CH2:27][CH2:28][N:29]([C:12]([C:11]2[CH:10]=[CH:9][C:8]([CH2:7][N:3]3[CH2:4][CH2:5][CH2:6][S:2]3(=[O:1])=[O:17])=[CH:16][CH:15]=2)=[O:14])[CH2:30][CH2:31]1
Reactant: O=C(O)c1ccc(CN2CCCS2(=O)=O)cc1
Reactant: Cc1ccc(N2CCNCC2)c(C)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(N2CCN(C(=O)c3ccc(CN4CCCS4(=O)=O)cc3)CC2)c(C)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 57.3 %

Procedure:
4-(1,1-Dioxo-1λ6-isothiazolidin-2-ylmethyl)benzoic acid (268 mg) described in Preparation Example 18, 1-(2,4-dimethylphenyl)piperazine (199 mg), 1-hydroxybenzotriazole 1 hydrate (142 mg) were dissolved in N,N-dimethylformamide (5 mL), 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride (202 mg) was added, and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and the solvent was evaporated. The obtained residue was purified by column chromatography (chloroform:methanol) to give the title compound (256 mg).
Reaction SMILES: [C:1]1([CH:8]=[CH:7][C:5]([OH:6])=[CH:4][CH:3]=1)[OH:2].[OH-].[Na+].[Na].F[C:13]1[C:18]([F:19])=[CH:17][C:16]([C:20]([F:23])([F:22])[F:21])=[CH:15][N:14]=1>CS(C)=O.O>[F:19][C:18]1[C:13]([O:2][C:1]2[CH:8]=[CH:7][C:5]([OH:6])=[CH:4][CH:3]=2)=[N:14][CH:15]=[C:16]([C:20]([F:22])([F:21])[F:23])[CH:17]=1
Reactant: Fc1cc(C(F)(F)F)cnc1F
Reactant: Oc1ccc(O)cc1
Agent: [Na+]
Agent: [Na]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: Oc1ccc(Oc2ncc(C(F)(F)F)cc2F)cc1
Temperature: 60 °C
Reaction time: 0.17 h

Procedure:
Hydroquinone (4.4 g, 0.04 mole) was dissolved in 65 ml of dimethylsulfoxide and powdered sodium hydroxide (1.4 g, 0.035 mole) was added in one portion and the mixture stirred under nitrogen atmosphere for 10 minutes to convert to the sodium salt. 2,3-Difluoro-5-(trifluoromethyl)pyridine (6.0 g, 0.033 mole) was then added and the mixture was stirred at 50° C. for 1.5 hours then warmed to 60° C. for a moment, let cool for 15 minutes and then poured into 500 ml of cold water. Additional sodium hydroxide (~3 g in water) was added to convert the desired product to its sodium salt. The insoluble bis-derivative was then removed by extraction with hexane. The clear aqueous phase was separated, cooled and acidified with concentrated hydrochloric acid. The solid which separated was collected on a filter, washed, dried on a vacuum funnel and taken up in hot hexane. After treating with decolorizing carbon, filtering, concentrating and cooling the white crystalline product separated. Yield: 2.6 g. M.P. 97.5-98.5.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[N:9]=[CH:8][N:7]([CH3:11])[C:6]=2[CH:5]=[CH:4][CH:3]=1.[N:12]([C:15]1[CH:16]=[N:17][CH:18]=[CH:19][C:20]=1[O:21][CH3:22])=[C:13]=[S:14]>CN(C=O)C>[CH3:22][O:21][C:20]1[CH:19]=[CH:18][N:17]=[CH:16][C:15]=1[NH:12][C:13]([NH:1][C:2]1[C:10]2[N:9]=[CH:8][N:7]([CH3:11])[C:6]=2[CH:5]=[CH:4][CH:3]=1)=[S:14]
Reactant: Cn1cnc2c(N)cccc21
Reactant: COc1ccncc1N=C=S
Solvent: CN(C)C=O
Product: COc1ccncc1NC(=S)Nc1cccc2c1ncn2C
Temperature: 25 °C
Reaction time: 64 h

Procedure:
A mixture of 4-amino-1-methylbenzimidazole (0.100 g, 0.679 mmol) and 3-isothiocyanato-4-methoxy-pyridine (0.113 mg, 0.680 mmol, example 4, step a) in DMF was stirred at room temperature for 64 hours. After removal of DMF in vacuo, the residue was treated with water. The precipitated solid was filtered, washed with water, and dried to give a portion of the title compound. The filtrate was concentrated and the oily brown residue was dried under vacuum to provide a second potion of the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([NH:11][CH2:12][CH2:13][N:14]([CH3:16])[CH3:15])=[O:10])=[CH:4][CH:3]=1.CCN=C=NCCCN(C)C.ON1C2C=CC=CC=2N=N1.CN(C1C=CC=CN=1)C.[CH2:47]([O:54][C:55]([N:57]1[CH2:62][CH2:61][CH:60]([C:63](O)=[O:64])[CH2:59][CH2:58]1)=[O:56])[C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1>C(OCC)(=O)C.O.O1CCCC1.C(N(CC)CC)C>[CH3:16][N:14]([CH3:15])[CH2:13][CH2:12][NH:11][C:9](=[O:10])[CH2:8][C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:63]([CH:60]2[CH2:61][CH2:62][N:57]([C:55]([O:54][CH2:47][C:48]3[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=3)=[O:56])[CH2:58][CH2:59]2)=[O:64])=[CH:7][CH:6]=1
Reactant: CN(C)CCNC(=O)Cc1ccc(N)cc1
Reactant: O=C(O)C1CCN(C(=O)OCc2ccccc2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccccn1
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: CN(C)CCNC(=O)Cc1ccc(NC(=O)C2CCN(C(=O)OCc3ccccc3)CC2)cc1
Reaction time: 20 h
Yield: 49.4 %

Procedure:
2-(4-Aminophenyl)-N-[2-(dimethylamino)ethyl]acetamide (221 mg), WSC (249 mg), 1-hydroxybenzotriazole (199 mg), triethylamine (0.4 ml), and dimethylaminopyridine (244 mg) were added to a tetrahydrofuran (10 ml) solution of 1-[(benzyloxy)carbonyl]-4-piperidinecarboxylic acid (290 mg), which was stirred for 20 hours. The reaction mixture was poured into water, and extraction was conducted using ethyl acetate. The organic layer was washed with water, saturated aqueous sodium bicarbonate solution, and saturated aqueous sodium chloride solution, dried over sodium sulfate, and then concentrated. The residue was recrystallized from methanol-diisopropyl ether, to give the titled compound (230 mg).
Reaction SMILES: [C:1]([CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])#[N:2].[Cl:9][C:10]([Cl:18])=[CH:11][CH:12](Cl)[C:13](Cl)([CH3:15])[CH3:14].ClC(Cl)=CC=C(C)C>C(#N)C>[C:1]([C:3]1([C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH:12]([CH:11]=[C:10]([Cl:18])[Cl:9])[C:13]1([CH3:15])[CH3:14])#[N:2]
Reactant: CCOC(=O)CC#N
Reactant: CC(C)(Cl)C(Cl)C=C(Cl)Cl
Agent: CC(C)=CC=C(Cl)Cl
Solvent: CC#N
Product: CCOC(=O)C1(C#N)C(C=C(Cl)Cl)C1(C)C
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A mixture of ethyl cyanoacetate (12.44 parts), 1,1,3,4-tetrachloro-4-methylpent-1-ene (11.1 parts), 1,1-dichloro-4-methylpenta-1,3-diene (7.55 parts), cupric acetate H2O (2.0 parts) and in two cases lithium halide, in acetonitrile (100 parts by volume) is heated to reflux and held at 75°-80° C. for 6 hours. After cooling to room temperature the suspension is filtered and the residue is washed twice with acetonitrile (20 parts by volume). The combined filtrate and washes are distilled under reduced pressure to remove acetonitrile and the residue is extracted with a mixture of toluene (100 parts by volume), water (150 parts by volume) and concentrated hydrochloric acid (100 parts by volume). After filtering from extraneous matter the filtrates are separated and the toluene layer is washed twice with hydrochloric acid (50 parts by volume) diluted with water (50 parts) and finally four times with water (50 parts). The toluene is removed by distillation under reduced pressure to yield crude ethyl 1-cyano-3-(2',2'-dichlorovinyl)-2,2-dimethylcyclopropane-1-carboxylate. Details are given in the following table:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([NH2:8])[N:5]=[C:4]([SH:9])[N:3]=1.CC(C)([O-])C.[K+].[F:16][C:17]1[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:18]=1[CH2:19]Br>CS(C)=O>[F:16][C:17]1[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:18]=1[CH2:19][S:9][C:4]1[N:5]=[C:6]([NH2:8])[CH:7]=[C:2]([NH2:1])[N:3]=1
Reactant: Nc1cc(N)nc(S)n1
Reactant: Fc1cccc(CBr)c1F
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: Nc1cc(N)nc(SCc2cccc(F)c2F)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 94.1 %

Procedure:
4,6-diamino-2-pyrimidinethiol (7.3 g) was dissolved in DMSO (100 ml) at room temperature under an atmosphere of nitrogen. Potassium tert-butoxide (1M in THF, 48.3 ml) was added followed by 2,3-difluorobenzyl-bromide (10.0 g). The mixture was stirred for 2 hours at room temperature. The reaction mixture was then partitioned between ethyl acetate and ammonium chloride. The organic phase was washed with ammonium chloride (3×) and brine, then dried over magnesium sulphate and evaporated to give the subtitled product as a white solid (12.2 g).
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:14]([C:15]3[CH:20]=[CH:19][C:18]([S:21]([CH3:24])(=[O:23])=[O:22])=[CH:17][CH:16]=3)=[CH:13][C:12]([C:25]([F:28])([F:27])[F:26])=[N:11]2)=[CH:6][CH:5]=1.[CH3:29][O:30][CH2:31]Cl.Cl>CN(C)C=O>[CH3:29][O:30][CH2:31][O:3][C:4]1[CH:5]=[CH:6][C:7]([N:10]2[C:14]([C:15]3[CH:16]=[CH:17][C:18]([S:21]([CH3:24])(=[O:23])=[O:22])=[CH:19][CH:20]=3)=[CH:13][C:12]([C:25]([F:26])([F:27])[F:28])=[N:11]2)=[CH:8][CH:9]=1
Reactant: CS(=O)(=O)c1ccc(-c2cc(C(F)(F)F)nn2-c2ccc(O)cc2)cc1
Reactant: COCCl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCOc1ccc(-n2nc(C(F)(F)F)cc2-c2ccc(S(C)(=O)=O)cc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 77.7 %

Procedure:
Sodium hydride (0.17 g) was added to a solution of 1-(4-hydroxyphenyl)-5-[4-(methylsulfonyl)phenyl]-3-(trifluoromethyl)pyrazole (1.5 g) in N,N-dimethylformamide (15 ml) at 5° C. The mixture was stirred at ambient temperature for 30 minutes. To the mixture was added chloromethyl methyl ether (0.4 g) in N,N-dimethylformamide (2 ml) at 5° C. The obtained mixture was stirred at 5° C. for 2 hours and at ambient temperature for 1 hour, poured into a mixture of ice and dilute hydrochloric acid, and extracted with ethyl acetate. The extract was washed with water, dried, and evaporated. The residue (1.3 g) was recrystallized from isopropanol to give crystals of 1-[4-(methoxymethoxy)phenyl]-5-[4-(methylsulfonyl)phenyl]-3-(trifluoromethyl)pyrazole (1.3 g).