Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]=O)[CH:5]=[N:6][CH:7]=1.Br[C:11]1[CH:12]=[C:13](CO)[CH:14]=[N:15][CH:16]=1>C(Cl)(Cl)Cl.O=[Mn]=O>[N:15]1([CH2:4][CH2:3][C:2]#[C:7][C:2]2[CH:7]=[N:6][CH:5]=[C:4]([CH2:8][N:15]3[CH2:16][CH2:11][CH2:12][CH2:13][CH2:14]3)[CH:3]=2)[CH2:16][CH2:11][CH2:12][CH2:13][CH2:14]1
Reactant: OCc1cncc(Br)c1
Reactant: O=Cc1cncc(Br)c1
Agent: O=[Mn]=O
Solvent: ClC(Cl)Cl
Product: C(#Cc1cncc(CN2CCCCC2)c1)CCN1CCCCC1
Yield: 51 %

Procedure:
5-Bromo-pyridine-3-carbaldehyde. (5-Bromo-pyridin-3-yl)-methanol (1.13 g, 6.00 mmol) was dissolved in CHCl3 (40 mL) and treated with MnO2 (3.60 g). The reaction mixture was heated at reflux temperature for 3 h. The hot reaction mixture was filtered through a pad of diatomaceous earth and the filtrate was concentrated to yield the title compound (0.570 g, 51%).
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[O:6][C@@H:5]2[CH2:7][CH2:8][CH2:9][C@@H:10]([NH2:11])[C@@H:4]2[O:3]1.[CH3:13][C:14]1([CH3:39])[CH2:23][CH2:22][C:21]([CH3:25])([CH3:24])[C:20]2[CH:19]=[C:18]([C:26]3[N:31]=[C:30]([N:32]4[CH2:37][CH2:36][C:35](=O)[CH2:34][CH2:33]4)[CH:29]=[CH:28][CH:27]=3)[CH:17]=[CH:16][C:15]1=2>C1COCC1>[CH3:1][C:2]1([CH3:12])[O:6][C@@H:5]2[CH2:7][CH2:8][CH2:9][C@@H:10]([NH:11][CH:35]3[CH2:34][CH2:33][N:32]([C:30]4[CH:29]=[CH:28][CH:27]=[C:26]([C:18]5[CH:17]=[CH:16][C:15]6[C:14]([CH3:39])([CH3:13])[CH2:23][CH2:22][C:21]([CH3:25])([CH3:24])[C:20]=6[CH:19]=5)[N:31]=4)[CH2:37][CH2:36]3)[C@@H:4]2[O:3]1
Reactant: CC1(C)O[C@H]2[C@H](N)CCC[C@H]2O1
Reactant: CC1(C)CCC(C)(C)c2cc(-c3cccc(N4CCC(=O)CC4)n3)ccc21
Solvent: C1CCOC1
Product: CC1(C)O[C@H]2[C@H](NC3CCN(c4cccc(-c5ccc6c(c5)C(C)(C)CCC6(C)C)n4)CC3)CCC[C@H]2O1

Procedure:
The preparation is carried out analogously to FS1008 in THF starting from 34 mg (0.199 mmol) of (3aS,4R,7aR)-2,2-dimethylhexahydrobenzo-1,3-dioxol-4-yl-amine and 80 mg (0.199 mmol) of 6′-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-2,3,5,6-tetrahydro-1,2′-bipyridinyl-4-one. The purification is carried out by means of flash chromatography on silica gel.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:20]2[O:24][C:23]([C:25]([O:27]CC)=[O:26])=[N:22][N:21]=2)=[N:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([S:14]([CH:17]([CH3:19])[CH3:18])(=[O:16])=[O:15])=[CH:10][CH:9]=2)=[CH:6][N:7]=1.[OH-].[Na+]>O>[NH2:1][C:2]1[C:3]([C:20]2[O:24][C:23]([C:25]([OH:27])=[O:26])=[N:22][N:21]=2)=[N:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([S:14]([CH:17]([CH3:19])[CH3:18])(=[O:16])=[O:15])=[CH:10][CH:9]=2)=[CH:6][N:7]=1
Reactant: CCOC(=O)c1nnc(-c2nc(-c3ccc(S(=O)(=O)C(C)C)cc3)cnc2N)o1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(C)S(=O)(=O)c1ccc(-c2cnc(N)c(-c3nnc(C(=O)O)o3)n2)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 66.3 %

Procedure:
A solution of ethyl 5-[3-amino-6-(4-isopropylsulfonylphenyl)pyrazin-2-yl]-1,3,4-oxadiazole-2-carboxylate (50 mg, 0.1198 mmol) in NaOH (59.90 μL of 1 M, 0.05990 mmol) was stirred at room temperature for 1 h. Water (0.5 mL) was added and the reaction mixture stirred at room temperature for 5 min and then filtered. The yellow solid obtained was dried under vacuum to give the product (30.93 mg, 62%); 1H NMR (400 MHz, DMSO) d 1.19 (d, 6H), 3.40-3.49 (m, 1H), 7.90 (br s, 2H), 7.96 (d, 2H), 8.32 (d, 2H) and 9.00 (s, 1H) ppm; MS (ES+) 390.13
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[C@H:4]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[C:16]([N+:21]([O-])=O)[CH:15]=1)[NH:5][C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7]>CO.[Pd]>[CH3:1][O:2][C:3](=[O:24])[C@H:4]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[C:16]([NH2:21])[CH:15]=1)[NH:5][C:6]([O:8][C:9]([CH3:12])([CH3:10])[CH3:11])=[O:7]
Reactant: COC(=O)[C@H](Cc1ccc(O)c([N+](=O)[O-])c1)NC(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CO
Product: COC(=O)[C@H](Cc1ccc(O)c(N)c1)NC(=O)OC(C)(C)C
Yield: 82.2 %

Procedure:
A mixture of N-(tert-butoxycarbonyl)-3-nitro-L-tyrosine methyl ester (2.0 g) and 10% Pd—C (1.0 g) in MeOH (10 ml) was subjected to catalytic hydrogenolysis at atmospheric pressure. The catalyst was filtered off and the filtrate was evaporated in vacuo. The residue was triturated with ether to give 3-amino-N-(tert-butoxycarbonyl)-L-tyrosine methyl ester (1.5 g) as a solid. To a solution of the obtained compound (1.0 g) in CH2Cl2 (10 ml) was added 2,6-dichlorobenzoyl chloride (0.74 g) and DIEA (1.1 g) and the mixture was stirred at room temperature overnight. The solvent was removed in vacuo and the residue was purified by column chromatography on silica gel (eluent; 2:1, Hexane/AcOEt) to give N-(tert-butoxycarbonyl)-3-(2,6-dichlorobenzamido)-L-tyrosine methyl ester (1.2 g). The obtained compound was treated in a similar manner as described in R. Example 4 to give 3-[(2,6-Dichlorobenzoyl)amino]-L-tyrosine methyl ester, hydrochloride salt.
Reaction SMILES: C([O:8][CH2:9][CH:10]1[O:24][C:14]2=[C:15]3[C:20](=[CH:21][CH:22]=[C:13]2[O:12][CH2:11]1)[N:19]=[C:18]([CH3:23])[CH:17]=[CH:16]3)C1C=CC=CC=1.C1CCCCC=1>CCO.[Pd]>[CH3:23][C:18]1[CH:17]=[CH:16][C:15]2[C:20](=[CH:21][CH:22]=[C:13]3[O:12][CH2:11][C@@H:10]([CH2:9][OH:8])[O:24][C:14]3=2)[N:19]=1
Reactant: Cc1ccc2c3c(ccc2n1)OCC(COCc1ccccc1)O3
Agent: [Pd]
Solvent: CCO
Solvent: C1=CCCCC1
Product: Cc1ccc2c3c(ccc2n1)OC[C@@H](CO)O3
Yield: 97.7 %

Procedure:
To a solution of (2S)-2[(benzyloxy)methyl-8-methyl-2,3-dihydro[1,4]dioxino [2,3-f]quinoline (0.16 g, 0.5 mmol) in EtOH (1 mL) was added cyclohexene (0.5 mL) then 10% Pd/C (0.016 g, 10 mol %). The mixture was heated to reflux under N2 for 18 h then cooled and filtered. The catalyst was rinsed with methanol and the filtrate was concentrated in vacuo to afford 0.113 g (98%) of the title alcohol as an off-white solid.
Reaction SMILES: N#N.[CH3:3][C:4]1([C:9]2[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=2)[CH:12]=[O:13])[O:8][CH2:7][CH2:6][O:5]1.[BH4-].[Na+].O>CO>[CH3:3][C:4]1([C:9]2[CH:10]=[C:11]([CH2:12][OH:13])[CH:14]=[CH:15][CH:16]=2)[O:5][CH2:6][CH2:7][O:8]1
Reactant: CC1(c2cccc(C=O)c2)OCCO1
Agent: N#N
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CC1(c2cccc(CO)c2)OCCO1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), to a ice-cold solution of 3-(2-methyl-[1,3]dioxolan-2-yl)-benzaldehyde (896 mg, 4.66 mmol) in MeOH (10.0 mL) was added NaBH4 (228 mg, 5.79 mmol in four equal portion). The reaction mixture was then stirred for 1 h at rt. Water was added and the mixture was extracted twice with EA. The combined org. extracts were washed with brine, dried over Na2SO4, filtered, and the solvent was removed under reduced pressure to give the title compound as a colorless oil: TLC:rf (50:50 hept-EA)=0.28. LC-MS-conditions 02: tR=0.74 min; [M+H]+=195.71.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([CH3:20])[C:5]2[CH:11]=[CH:10][C:9](=[O:12])[N:8]([C@H:13]3[CH2:18][CH2:17][C@H:16]([OH:19])[CH2:15][CH2:14]3)[C:6]=2[N:7]=1.[Br:21]N1C(=O)CCC1=O>CN(C)C=O>[NH2:1][C:2]1[N:3]=[C:4]([CH3:20])[C:5]2[CH:11]=[C:10]([Br:21])[C:9](=[O:12])[N:8]([C@H:13]3[CH2:14][CH2:15][C@H:16]([OH:19])[CH2:17][CH2:18]3)[C:6]=2[N:7]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1nc(N)nc2c1ccc(=O)n2[C@H]1CC[C@H](O)CC1
Solvent: CN(C)C=O
Product: Cc1nc(N)nc2c1cc(Br)c(=O)n2[C@H]1CC[C@H](O)CC1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of 2-amino-8-(trans-4-hydroxycyclohexyl)-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one (115 mg, 0.419 mmol) in dimethylformamide (2.0 mL) was added N-bromosuccinimide (75 mg, 0.42 mmol). After stirring for 1.5 hr at room temperature the solution was concentrated. The residue was slurried in methanol, filtered solids, and the filtrated was concentrated and purified by flash chromatography eluting with chloroform/7 N ammonia in methanol (0.5-3%). Combined solids to afford the title compound (120 mg, 81%).
Reaction SMILES: [CH:1](=O)[C:2]1[CH:12]=[C:9]([O:10][CH3:11])[C:7]([OH:8])=[C:4]([O:5][CH3:6])[CH:3]=1.[NH2:14][CH2:15][CH2:16][SH:17].Cl.C([O-])(=O)C.[Na+]>O.C(O)C>[CH3:11][O:10][C:9]1[CH:12]=[C:2]([CH:1]2[NH:14][CH2:15][CH2:16][S:17]2)[CH:3]=[C:4]([O:5][CH3:6])[C:7]=1[OH:8]
Reactant: COc1cc(C=O)cc(OC)c1O
Reactant: NCCS
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: COc1cc(C2NCCS2)cc(OC)c1O
Yield: 44.4 %

Procedure:
In a solvent including an ethyl alcohol (2 mL) and water (2 mL), a mixture including syringaldehyde (100 mg, 0.55 mmol), cysteamine.HCl (93.2 mg, 0.82 mmol), and sodium acetate (72 mg, 0.88 mmol) was stirred at room temperature for 4 hours. The produced precipitate was filtered and washed with water and methylene chloride to obtain a solid target product Compound 80.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Br:8])[CH:7]=1.[F:9][C:10]1[CH:11]=[C:12](B(O)O)[CH:13]=[CH:14][CH:15]=1>>[Br:8][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([C:14]2[CH:13]=[CH:12][CH:11]=[C:10]([F:9])[CH:15]=2)[CH:7]=1
Reactant: OB(O)c1cccc(F)c1
Reactant: Brc1cncc(Br)c1
Product: Fc1cccc(-c2cncc(Br)c2)c1

Procedure:
Prepared according to the procedure described in Example 1, Step 10, using 3,5-dibromo-pyridine and 3-fluorophenylboronic acid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8]/[N:9]=[C:10](\[C:17]#[C:18][Si](C)(C)C)/[CH2:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH:18]=[CH:17][C:10]([CH2:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15])=[N:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N/N=C(\C#C[Si](C)(C)C)CCCC(=O)O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)n1ccc(CCCC(=O)O)n1
Temperature: 25 °C
Reaction time: 48 h
Yield: 100 %

Procedure:
To a stirred solution of 77.0 g, (236 mmol) of (5Z)-5-[(tert-butoxycarbonyl)hydrazono]-7-(trimethylsilyl)hept-6-ynoic acid from step B above in 500 mL of THF was added 350 mL (350 mmol) of a 1.0 M solution of tetrabutylammonium fluoride in THF over 30 min. The resulting mixture was stirred at ambient temperature for 48 h and then evaporated to dryness in vacuo. The residue was diluted with 1 L of a 5% aqueous acetic acid solution and the aqueous phase extracted with ethyl acetate (3×350 mL). The combined organic layers were washed with water (2×100 mL), and brine (150 mL), dried over magnesium sulfate, filtered and evaporated to dryness in vacuo. The crude residue was purified by silica gel chromatography eluting with 3% acetic acid and 35% ethyl acetate in hexanes mixture to afford the title compound as yellow oil (60 g, quantitative yield). LC-MS: m/z (ES) 255 (MH)−.
Reaction SMILES: C([NH:3][C@@H:4]1[C:17](=[O:18])[N:6]2[C:7]([C:14]([OH:16])=[O:15])=[C:8]([CH2:11][S:12][CH3:13])[CH2:9][S:10][C@H:5]12)=O.Cl>CO.O>[NH2:3][C@@H:4]1[C:17](=[O:18])[N:6]2[C:7]([C:14]([OH:16])=[O:15])=[C:8]([CH2:11][S:12][CH3:13])[CH2:9][S:10][C@H:5]12
Reactant: CSCC1=C(C(=O)O)N2C(=O)[C@@H](NC=O)[C@H]2SC1
Agent: Cl
Solvent: CO
Solvent: O
Product: CSCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Reaction time: 1.5 h

Procedure:
(i) 7β-Formamido-3-methylthiomethylceph-3-em-4-carboxylic acid (2.88g) was dissolved in methanol (25 ml.) and the stirred solution was treated with concentrated hydrochloric acid (4.0 ml.). After 1.5 hr. at room temperature the solution was diluted with water (80 ml.) and washed with ethyl acetate (2 × 30 ml.) and ether (2 × 20 ml.), rotary evaporated to remove residual ether, and the pH adjusted to 3.5 with 0.880-ammonia. The precipitate was collected after overnight refrigeration, washed with water (2 × 10 ml), methanol (2 × 10 ml.) and ether (3 × 20 ml.), then dried giving 7β-amino-3-methylthiomethylceph-3-em-4-carboxylic acid as a colourless powder (1.41 g.), m.p. 222°-225° (decomp.), Rf 0.60 (System 2), TLC Rf 0.15, moves 2.0 cm. towards the cathode on electrophoresis at pH 1.9 (3-acetoxymethyl-7β-aminoceph-3-em-4-carboxylic acid moves 1.85 cm. under identical conditions), λmax (pH6 buffer) 266 nm. (ε 9,590), νmax. (Nujol) 1804 (β-lactam), 1536 cm.-1 (carboxylate), τ(D2O with NaHCO3) 4.53 (~0.5-proton doublet, J 4.5 Hz.; C-7 H), 4.88 (1-proton doublet, J 4.5 Hz.; C-6 H), 5.21 (~0.5-proton doublet, J 4.5 Hz.; C-7 H), 6.14, 6.63 [two 1-proton doublets (branches of a quartet), J 18 Hz.; C-2 H2 ], 6.21, 6.68 [two 1-proton doublets (branches of a quartet), J 14 Hz.; C-3 CH2 ], 7.95 (3-proton singlet; SCH3) [Found: C, 41.2; H, 4.6; N, 10.2; S, 23.6. C9H12N2O3S (260) requires C, 41.5; H, 4.6; N, 10.8; S, 24.6%].
Reaction SMILES: [C:1]([C:3]1[CH:33]=[CH:32][C:6]([O:7][C:8]2[CH:9]=[C:10]([CH:20]=[C:21]([O:23][C:24]3[CH:29]=[CH:28][C:27]([C:30]#[N:31])=[CH:26][CH:25]=3)[N:22]=2)[C:11]([NH:13][CH:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)=[O:12])=[CH:5][CH:4]=1)#[N:2].[C:34]([O:38][C:39](=[O:45])[NH:40][CH2:41][CH2:42][CH2:43]Br)([CH3:37])([CH3:36])[CH3:35].C(=O)([O-])[O-].[K+].[K+]>>[C:34]([O:38][C:39](=[O:45])[NH:40][CH2:41][CH2:42][CH2:43][N:17]1[CH2:16][CH2:15][CH:14]([NH:13][C:11]([C:10]2[CH:20]=[C:21]([O:23][C:24]3[CH:25]=[CH:26][C:27]([C:30]#[N:31])=[CH:28][CH:29]=3)[N:22]=[C:8]([O:7][C:6]3[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:33][CH:32]=3)[CH:9]=2)=[O:12])[CH2:19][CH2:18]1)([CH3:37])([CH3:36])[CH3:35]
Reactant: CC(C)(C)OC(=O)NCCCBr
Reactant: N#Cc1ccc(Oc2cc(C(=O)NC3CCNCC3)cc(Oc3ccc(C#N)cc3)n2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC(C)(C)OC(=O)NCCCN1CCC(NC(=O)c2cc(Oc3ccc(C#N)cc3)nc(Oc3ccc(C#N)cc3)c2)CC1
Yield: 80.6 %

Procedure:
2,6-Bis(4-cyano phenoxy)-N-piperidin-4-yl-isonicotinamide 0.16 g (0.364 mmol), (3-bromo-propyl)-carbamic acid tert-butyl ester 0.12 g (0.50 mmol) and potassium carbonate 0.175 g (1.26 mmol) were used and the procedure of Example 11(e) was followed to afford 0.175 g of the required product. Percentage purity (LCMS): 80.4%, (M+1)=596.2+1. NMR (DMSO-d6): δ 1.40 (9H, s), 1.88 (9H, m), 2.95 (4H, m), 3.85 (2H, m), 6.86 (2H, brs), 7.26 (2H, s), 7.34 (4H, d), 7.85 (4H, d), 8.15 (2H, brs), 9.02 (1H, brs).
Reaction SMILES: C([C@H:3]([S:7]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)(=[N:9][C:10]([C:12]1[CH:13]=[N:14][CH:15]=[C:16]([C:18]#[C:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([OH:26])[CH:21]=2)[CH:17]=1)=[O:11])=[O:8])[C:4]([O-:6])=O)C.[CH3:33][NH:34][CH2:35][CH2:36][OH:37]>>[OH:37][CH2:36][CH2:35][N:34]([CH3:33])[C:4](=[O:6])[CH2:3][S@:7](=[O:8])([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[N:9][C:10](=[O:11])[C:12]1[CH:17]=[C:16]([C:18]#[C:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([OH:26])[CH:21]=2)[CH:15]=[N:14][CH:13]=1
Reactant: CNCCO
Reactant: CC[C@@H](C(=O)[O-])S(=O)(=NC(=O)c1cncc(C#Cc2cccc(O)c2)c1)c1ccccc1
Product: CN(CCO)C(=O)C[S@@](=O)(=NC(=O)c1cncc(C#Cc2cccc(O)c2)c1)c1ccccc1
Yield: 62.8 %

Procedure:
In a manner similar to that described for Example 471, (S)-Ethyl[N-({5-[(3-hydroxyphenyl)ethynyl]pyridin-3-yl}carbonyl)-S-phenylsulfonimidoyl]acetate (65 mg, 0.14 mmol) and 2-(methylamino)ethanol (0.1 mL, 1.2 mmol) were reacted to give the title as clear oil (42 mg, 61%).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.C1CCN(C(N=NC(N2CCCCC2)=O)=O)CC1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:47]([C:49]1[CH:57]=[CH:56][C:52]([CH2:53][CH2:54]O)=[CH:51][CH:50]=1)#[N:48]>ClCCl.CCCCCCC>[CH:6]([C:5]1[CH:8]=[CH:9][C:2]([O:1][CH2:54][CH2:53][C:52]2[CH:56]=[CH:57][C:49]([C:47]#[N:48])=[CH:50][CH:51]=2)=[CH:3][CH:4]=1)=[O:7]
Reactant: N#Cc1ccc(CCO)cc1
Reactant: O=Cc1ccc(O)cc1
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CCCCCCC
Product: N#Cc1ccc(CCOc2ccc(C=O)cc2)cc1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 35.1 %

Procedure:
p-Hydroxybenzaldehyde (24.9 g; 203.8 mmole) was dissolved in dichloromethane (dry). ADDP (47.2 g; 187 mmole) was added followed by addition of triphenylphosphine (49 g; 187 mmole). The reaction mixture was stirred at room temperature for 45 minutes and then p-cyanophenethyl alcohol (25 g; 110 mmole) dissolved in a small amount of dichloromethane (dry) was added in portions during one hour. The reaction mixture was stirred at room temperature over night, filtered and evaporated. Chromatography of the residue on silica gel using ethyl acetate:heptane as eluant gave 9.7 g (22.7% yield) of 4-[2-(4-formylphenoxy)ethyl]benzonitrile.
Reaction SMILES: Cl[CH2:2][Si:3]([C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][C:7]=1[Cl:13])([CH3:5])[CH3:4].[Na].[NH:15]1[CH:19]=[N:18][CH:17]=[N:16]1>CN(C)C=O.O>[Cl:13][C:7]1[CH:8]=[C:9]([Cl:12])[CH:10]=[CH:11][C:6]=1[Si:3]([CH3:5])([CH3:4])[CH2:2][N:15]1[CH:19]=[N:18][CH:17]=[N:16]1
Reactant: C[Si](C)(CCl)c1ccc(Cl)cc1Cl
Reactant: c1nc[nH]n1
Agent: [Na]
Solvent: O
Solvent: CN(C)C=O
Product: C[Si](C)(Cn1cncn1)c1ccc(Cl)cc1Cl
Reaction time: 2 h
Yield: 80.4 %

Procedure:
A mixture of 5.1 g (0.020 mol) of chloromethyl(2,4-dichlorophenyl)dimethysilane and 2.0 g (0.022 mol) of 1,2,4-triazole sodium salt in 10 ml of dry dimethylformamide was stirred at 80°-90° for 2 hours. The resulting slurry was cooled, diluted with water, and washed with ether. The ether extracts were washed with several portions of water and once with brine, dried over magnesium sulfate, and evaporated to leave 4.6 g (81%) of the title compound as a pale yellow liquid: nD23 1.5580; ir (neat) 1550, 1485, 1440, 1345, 1260, 1240, 1130, 1085, 1025, 1005, 835 cm-1 ; nmr (CDCl3) 0.5 (6H, s), 4.1 (2H, s), 7.2-7.5 (3H, m), 7.8 (1H, s), 7.9 (1H, s).
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][O:5][N:6]1[C:14](=[O:15])[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]1=[O:16].[C:17]([O:21][C:22](=[O:28])[NH:23][S:24](Cl)(=[O:26])=[O:25])([CH3:20])([CH3:19])[CH3:18].C(N(CC)CC)C>C(Cl)Cl>[C:17]([O:21][C:22](=[O:28])[NH:23][S:24](=[O:26])(=[O:25])[NH:2][CH2:3][CH2:4][O:5][N:6]1[C:7](=[O:16])[C:8]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:14]1=[O:15])([CH3:20])([CH3:18])[CH3:19]
Reactant: CC(C)(C)OC(=O)NS(=O)(=O)Cl
Reactant: NCCON1C(=O)c2ccccc2C1=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NS(=O)(=O)NCCON1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 7 h
Yield: 74.6 %

Procedure:
To a mixture of 2-(2-aminoethoxy)-1H-isoindole-1,3(2H)-dione hydrochloride 75 (0.53 g, 2.19 mmol, EP 16744522 A1, 2006), tert-butyl(chlorosulfonyl)carbamate 76 (0.71 g, 3.28 mmol, WO 2006/84281 A1) in DCM (10 mL) was added triethylamine (0.92 mL, 6.57 mmol) slowly at 0° C. The resulting mixture was stirred at room temperature for 7 h and concentrated to provide a residue which was subjected to chromatography to give 77 (0.63 g, 74%) as a white foam.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([O:11][CH:12]([C:17]([O:30][CH3:31])([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:13]([O:15]C)=[O:14])[N:4]=1.[OH-].[K+]>O1CCOCC1.O>[CH3:10][O:9][C:7]1[CH:8]=[C:3]([O:2][CH3:1])[N:4]=[C:5]([O:11][CH:12]([C:17]([O:30][CH3:31])([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:13]([OH:15])=[O:14])[N:6]=1
Reactant: COC(=O)C(Oc1nc(OC)cc(OC)n1)C(OC)(c1ccccc1)c1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: COc1cc(OC)nc(OC(C(=O)O)C(OC)(c2ccccc2)c2ccccc2)n1
Temperature: 100 °C
Reaction time: 3 h

Procedure:
2.12 g (5 mmol) of methyl 2-(4,6-dimethoxy-pyrimidin-2-yl-oxy)-3-methoxy-3,3-diphenylpropionate were dissolved in 50 ml of dioxane, 10 ml of 1 N KOH solution were added, and the mixture was stirred at 100° C. for 3 h. The solution was diluted with 300 ml of water and extracted with ethyl acetate to remove unreacted ester. The aqueous phase was then adjusted to pH 1–2 with dilute hydrochloric acid and extracted with ethyl acetate. After drying over magnesium sulfate and removal of the solvent by distillation, the residue was mixed with an ether/hexane mixture, and the precipitate which formed was filtered off with suction. After drying, 1.85 g (90%) of a white powder remained.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[C:16]3[CH:17]=[CH:18][C:19]([CH:27]([OH:30])[C:28]#[CH:29])=[CH:20][C:21]=3[C:22]([CH3:26])([CH3:25])[CH2:23][CH:24]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.I[C:32]1[CH:40]=[CH:39][C:35]([C:36]([OH:38])=[O:37])=[CH:34][CH:33]=1>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.[Cu](I)I>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[C:16]3[CH:17]=[CH:18][C:19]([CH:27]([OH:30])[C:28]#[C:29][C:32]4[CH:40]=[CH:39][C:35]([C:36]([OH:38])=[O:37])=[CH:34][CH:33]=4)=[CH:20][C:21]=3[C:22]([CH3:26])([CH3:25])[CH2:23][CH:24]=2)=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C#CC(O)c1ccc2c(c1)C(C)(C)CC=C2c1ccc(OCc2ccccc2)cc1
Reactant: O=C(O)c1ccc(I)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Product: CC1(C)CC=C(c2ccc(OCc3ccccc3)cc2)c2ccc(C(O)C#Cc3ccc(C(=O)O)cc3)cc21

Procedure:
In a manner similar to that of Example 16b, by reacting 0.28 g (0.71 mmol) of 1-[5-(4-benzyloxyphenyl)-8,8-dimethyl-7,8-dihydro-2-naphthyl]prop-2-yn-1-ol with 0.146 g (0.6 mmol) of 4-iodobenzoic acid, 0.010 g (0.015 mmol) of trans-dichlorobis(triphenylphosphine)palladium and 0.006 g (0.003 mmol) of copper iodide, a yellow solid is obtained (0.03 g; yield=10%; m.p.=171° C.).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[CH:5]([NH:8][C:9]([CH2:11][CH2:12][CH2:13][CH3:14])=[O:10])[C:6]#[N:7])[CH3:2].[CH3:16][O:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22][SH:23])=[CH:20][CH:19]=1.C(N(CC)CC)C>C(O)C>[NH2:7][C:6]([S:23][CH2:22][C:21]1[CH:24]=[CH:25][C:18]([O:17][CH3:16])=[CH:19][CH:20]=1)=[C:5]([NH:8][C:9]([CH2:11][CH2:12][CH2:13][CH3:14])=[O:10])[C:4]([O:3][CH2:1][CH3:2])=[O:15]
Reactant: COc1ccc(CS)cc1
Reactant: CCCCC(=O)NC(C#N)C(=O)OCC
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCCCC(=O)NC(C(=O)OCC)=C(N)SCc1ccc(OC)cc1

Procedure:
3 g of the product obtained in Stage 1 above, 4 ml of paramethoxybenzylmercaptan, 0.2 ml of triethylamine and 5 ml of ethanol are mixed together.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][N:8]2[CH3:11])=[CH:4][C:3]=1[CH2:12][C:13]1[N:17]2[N:18]=[C:19]([CH:22]=[O:23])[CH:20]=[CH:21][C:16]2=[N:15][CH:14]=1.[CH2:24]([Mg]Br)[CH3:25]>C1COCC1>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][N:8]2[CH3:11])=[CH:4][C:3]=1[CH2:12][C:13]1[N:17]2[N:18]=[C:19]([CH:22]([OH:23])[CH2:24][CH3:25])[CH:20]=[CH:21][C:16]2=[N:15][CH:14]=1
Reactant: CC[Mg]Br
Reactant: Cn1ncc2cc(Cc3cnc4ccc(C=O)nn34)c(F)cc21
Solvent: C1CCOC1
Product: CCC(O)c1ccc2ncc(Cc3cc4cnn(C)c4cc3F)n2n1
Reaction time: 16 h
Yield: 10 %

Procedure:
To a solution of 3-((6-fluoro-1-methyl-1H-indazol-5-yl)methyl)imidazo[1,2-b]pyridazine-6-carbaldehyde (52 mg, 0.168 mmol) in THF (4 mL) at 0° C., was added a solution of ethylmagnesium bromide in THF (1M, 0.336 mL) dropwise. After stirring for 16 h, the reaction mixture was quenched with NH4Cl(aq), extracted with EtOAc, dried over Na2SO4. Filtered through Celite and concentrated in vacuo to give a crude product (14 mg, 10%). LCMS (method B): [MH]+=340, tR=2.04 min.
Reaction SMILES: [CH2:1]([C:3]1[S:4][CH:5]=[C:6]([CH2:8]P(=O)(OCC)OCC)[N:7]=1)[CH3:2].[H-].[Na+].[CH3:19][O:20][CH2:21][O:22][C:23]1[C:27]([CH:28]=O)=[CH:26][N:25]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[N:24]=1.O>O1CCCC1>[CH2:1]([C:3]1[S:4][CH:5]=[C:6](/[CH:8]=[CH:28]/[C:27]2[C:23]([O:22][CH2:21][O:20][CH3:19])=[N:24][N:25]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH:26]=2)[N:7]=1)[CH3:2]
Reactant: CCOP(=O)(Cc1csc(CC)n1)OCC
Reactant: COCOc1nn(-c2ccccc2)cc1C=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCc1nc(/C=C/c2cn(-c3ccccc3)nc2OCOC)cs1
Reaction time: 0.5 h
Yield: 74.6 %

Procedure:
To a solution of diethyl [(2-ethyl-1,3-thiazol-4-yl)methyl]phosphonate (4.64 g) in tetrahydrofuran (75 mL) was added sodium hydride (60% in oil, 0.96 g) at room temperature, and the mixture was stirred for 30 min. 3-(Methoxymethoxy)-1-phenyl-1H-pyrazole-4-carbaldehyde (6.32 g) was added to the reaction mixture, and the mixture was heated under reflux for 15 hrs. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography and eluted with ethyl acetate-hexane (1:9-1:1, v/v) to give 2-ethyl-4-{(E)-2-[3-(methoxymethoxy)-1-phenyl-1H-pyrazol-4-yl]ethenyl}-1,3-thiazole as a pale-yellow oil (4.49 g, yield 66%).