Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][CH:2]([F:31])[C:3]1[CH:7]=[C:6]([CH:8]([F:10])[F:9])[N:5]([CH2:11][C:12]([N:14]2[CH2:19][CH2:18][CH:17]([C:20]3[N:25]=[C:24]([C:26]([O:28]CC)=[O:27])[CH:23]=[CH:22][CH:21]=3)[CH2:16][CH2:15]2)=[O:13])[N:4]=1.O.[OH-].[Li+]>O1CCCC1.O>[F:31][CH:2]([F:1])[C:3]1[CH:7]=[C:6]([CH:8]([F:9])[F:10])[N:5]([CH2:11][C:12]([N:14]2[CH2:19][CH2:18][CH:17]([C:20]3[N:25]=[C:24]([C:26]([OH:28])=[O:27])[CH:23]=[CH:22][CH:21]=3)[CH2:16][CH2:15]2)=[O:13])[N:4]=1
Reactant: CCOC(=O)c1cccc(C2CCN(C(=O)Cn3nc(C(F)F)cc3C(F)F)CC2)n1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1cccc(C2CCN(C(=O)Cn3nc(C(F)F)cc3C(F)F)CC2)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of ethyl 6-(1-{[3,5-bis(difluoromethyl)-1H-pyrazol-1-yl]acetyl}piperidin-4-yl)pyridine-2-carboxylate (15.5 g) in tetrahydrofuran (160 ml) and water (40 ml) is added, at room temperature, lithium hydroxide monohydrate (1.99 g). The mixture is stirred at room temperature for 1 hour, and then ice-cold 1N HCl solution is added. The aqueous phase is extracted with ethyl acetate. The combined organic phases are dried over sodium sulphate and concentrated under reduced pressure. This gives 6-(1-{[3,5-bis(difluoromethyl)-1H-pyrazol-1-yl]acetyl}piperidin-4-yl)pyridine-2-carboxylic acid (11.5 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][O:8][C:9]2=[O:12])=[CH:5][CH:4]=1.[Br:13]N1C(=O)CCC1=O.C(OOCC1C=CC=CC=1)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:13][CH:7]1[C:6]2[C:10](=[CH:11][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[C:9](=[O:12])[O:8]1
Reactant: COc1ccc2c(c1)C(=O)OC2
Reactant: O=C1CCC(=O)N1Br
Agent: c1ccc(COOCc2ccccc2)cc1
Solvent: ClC(Cl)(Cl)Cl
Product: COc1ccc2c(c1)C(=O)OC2Br
Reaction time: 2.5 h
Yield: 78.5 %

Procedure:
6-Methoxy-3H-isobenzofuran-1-one (35.28 g, 0.215 mole), prepared as described in example 34, suspended in CCl4 (350 ml) under N2 was added with N-bromosuccinimide (40 g, 0.225 mole) and benzyl peroxide in catalytic amount, then slowly brought to reflux. After 2.5 hours the heating was stopped and the mixture was left to stand overnight at room temperature. Further catalyst was added and the mixture was heated for further 3.5 hours. The mixture was cooled in ice, filtered over celite washing well with CCl4 and dried to give 41 g of the title compound (yield: 78%).
Reaction SMILES: CN([CH2:4][C:5]1[CH:10]=[C:9]([CH3:11])[C:8]([OH:12])=[C:7]([CH3:13])[CH:6]=1)C.CI.[CH2:16]=[CH:17][CH:18]=[CH2:19]>C(OCC)(=O)C>[CH3:13][C:7]1[C:8](=[O:12])[C:9]([CH3:11])=[CH:10][C:5]2([CH2:19][CH2:18][CH:17]=[CH:16][CH2:4]2)[CH:6]=1
Reactant: Cc1cc(CN(C)C)cc(C)c1O
Reactant: C=CC=C
Solvent: CI
Solvent: CCOC(C)=O
Product: CC1=CC2(C=C(C)C1=O)CC=CCC2
Temperature: 120 °C
Yield: 87.6 %

Procedure:
To a 250 mL glass reaction vessel containing an ethyl acetate (120 mLs) solution of N,N-dimethyl,2,6-dimethyl-4-aminomethylphenol (3.58 g; 20 mmols), there was added methyl iodide (20 mmols) to give a colorless slurry. The reaction vessel was sealed and 1,3-butadiene (100 mmols) was introduced into the system. The reaction mixture was heated to 120° C. and the pressure was increased from atmospheric up to 70 psig. The reaction mixture was maintained at these conditions for approximately 16 hours. The reaction vessel was then cooled to room temperature. After cooling, the reaction mixture was filtered to remove ammonium iodide salt by-product. The filtrate was concentrated to afford a viscous oil which was crystallized from ethanol to give 3.3 g of 2,4-dimethylspiro[5.5]undeca-1,4,8-trien-3-one (84% yield by vapor phase chromatography).
Reaction SMILES: [CH:1](NC(C)C)([CH3:3])[CH3:2].C([Li])CCC.CCCCCC.[CH:19]1([C:25]([O:27][CH3:28])=[O:26])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1.C(Br)C#C>O1CCCC1.CN(C)P(N(C)C)(N(C)C)=O>[CH2:3]([C:19]1([C:25]([O:27][CH3:28])=[O:26])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1)[C:1]#[CH:2]
Reactant: COC(=O)C1CCCCC1
Reactant: CC(C)NC(C)C
Agent: C#CCBr
Agent: [Li]CCCC
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: C1CCOC1
Solvent: CCCCCC
Product: C#CCC1(C(=O)OC)CCCCC1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 88.4 %

Procedure:
To a solution of diisopropylamine (879 μL, 6.22 mmol) in anhydrous tetrahydrofuran (12 mL) at −40° C. under nitrogen was added 1.6 M n-butyl lithium in hexane (3.9 mL, 6.22 mmol), followed by hexamethylphosphoramide (4 mL). The mixture was cooled down to −78° C. and added a solution of methyl cyclohexanecarboxylate (80 7 μL, 5.65 mmol) in tetrahydrofuran (4 mL) with the temperature maintained below −70° C. throughout the addition. After 15 min, propargyl bromide (80% w/w in xylene, 2.5 mL, 22.6 mmol) was added, and the reaction mixture was allowed to warm to room temperature. After 30 min, it was quenched with saturated ammonium chloride, and extracted with ethyl acetate. The organic phase was washed with water (×4), dried over MgSO4, filtered and concentrated to get 900 mg the title intermediate as a pale brown oil.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH2:14]([S:21](Cl)(=[O:23])=[O:22])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C([O-])([O-])=O.[Na+].[Na+]>CC#N.CCOC(C)=O>[C:1]([N:8]1[CH2:9][CH2:10][N:11]([S:21]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)(=[O:23])=[O:22])[CH2:12][CH2:13]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: O=S(=O)(Cl)Cc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCN(S(=O)(=O)Cc2ccccc2)CC1
Yield: 97.1 %

Procedure:
Acylation of N-Boc-piperazine (1.86 g, 10 mmoL) with benzylsulfonyl chloride (1.9 g, 10 mmol) in CH3CN (20 mL) in the presence of Na2CO3 (1.01 g, 12 mmol) was carried out at rt for 16 hours. The mixture was diluted with EtOAc (150 mL), washed with water (50 mL), dried over MgSO4, and concentrated to give 1N-Boc-4N-benzylsulfonyl-piperazine (3.3 g, 98%). 1H NMR (CDCl3) δ 7.39 (bs, 5H), 4.23 (s, 2H), 3.38-3.35 (m, 4H), 3.07-3.05 (m, 4H), 1.44 (s, 9H). The Boc-intermediate was deprotected with 4M HCl in dioxane (20 mL) at rt for 1 hour. The mixture was diluted with EtOAc, washed with 1N NaOH and water, dried over MgSO4, and concentrated to give the product (1.9 g, 81%). 1H NMR (CDCl3) δ 7.46-7.43 (bs, 5H), 4.22 (s, 2H), 3.11-3.08 (m, 4H), 2.83-2.79 (m, 4H).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][C:12]([N:14]([CH3:16])[CH3:15])=[O:13].[H-].[Na+].[H][H].[CH2:21](Cl)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CN(C=O)C>[CH2:21]([N:7]1[C:8]2[C:4](=[CH:3][C:2]([I:1])=[CH:10][CH:9]=2)[C:5]([CH2:11][C:12]([N:14]([CH3:15])[CH3:16])=[O:13])=[CH:6]1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: ClCc1ccccc1
Reactant: CN(C)C(=O)Cc1c[nH]c2ccc(I)cc12
Reactant: [H][H]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C)C(=O)Cc1cn(Cc2ccccc2)c2ccc(I)cc12
Reaction time: 1 h
Yield: 85 %

Procedure:
To a solution of 2-(5-Iodo-1H-indol-3-yl)-N,N-dimethyl-acetamide (24.7 g, 75.4 mmol) in DMF (90 mL), under an inert atmosphere sodium hydride (1.91 g 95%, 75.4 mmol) is added which leads to the formation of a pale yellow solution. When the evolution of hydrogen has ceased, benzyl chloride (9.54 g, 75.4 mmol) is added in three portions over a period of 10 minutes. The mixture warms to 60° C., and after stirring for one hour a suspension forms. On the rotavapor, a part of the DMF (about 80 mL) is removed, which leads to crystallization of the product. Water (300 mL) is added, and the crystallized product is triturated at 80° C. for one hour on the rotavapor. The product is filtered off, washed twice with water (200 mL each washing), and dried to give 26.8 g (85%) of the title compound as pale yellow crystals, mp=167-168° C. From the mother liquor, another crop (2.6 g, 8%) is obtained which is also pure. 1H-NMR (DMSO-D6, 300 MHz) δ 3.33, 3.72 (2 s, 3H each, N(CH3)2); 3.72 (s, 2H, CH2CO); 5.34 (CH2Ph); 7.08-7.15, 7.15-7.30 (2 m, 5H, Ph); 7.24 (d, 3J=8.7 Hz, H-7); 7.26 (s, 1H, H-2); 7.32 (dd, 4J=1.3 Hz, H-6); 7.94 (d, 1H, H-4). 13C-NMR (DMSO-D6, 75 MHz) δ 30.90 (CH2CO); 35.72, 37.89 (N(CH3)2); 49.70 (CH2Ph); 83.31 (C-5); 108.61 (C-3); 113.26 (C-2); 127.65 (2 Ph-C); 128.06 (C-6 or Ph C-4); 128.53 (C-4); 129.19 (Ph C-4 or C-6); 129.22 (2 Ph-C); 129.83 (C-7); 131.38 (Ph ipso-C); 135.79 (C-9); 138.67 (C-8); 170.82 (CONMe2).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([N+:14]([O-:16])=[O:15])[CH:9]=2)=[CH:4][C:3]=1[CH:17]([OH:19])[CH3:18].[CH3:20][C:21]([CH3:23])=O>>[N+:14]([C:10]1[CH:9]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]3[NH:1][C:21]([CH3:23])([CH3:20])[O:19][CH:17]([CH3:18])[C:3]=3[CH:4]=2)[CH:13]=[CH:12][CH:11]=1)([O-:16])=[O:15]
Reactant: CC(C)=O
Reactant: CC(O)c1cc(-c2cccc([N+](=O)[O-])c2)ccc1N
Product: CC1OC(C)(C)Nc2ccc(-c3cccc([N+](=O)[O-])c3)cc21

Procedure:
Prepared from 1-(4-amino-3′-nitro-biphenyl-3-yl)-ethanol and acetone in the same fashion as that of Example 4. Yellow solid: mp 188-189° C.; Anal. Calc. For C17H18N2O3.0.35H2O: C, 67.02; H, 6.19; N, 9.20. Found: C, 66.7; H, 5.89; N, 9.03.
Reaction SMILES: [CH:1]1[C:14]2[NH:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[O:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[C:17]1([CH:23](Cl)[CH3:24])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.O>CN(C)C=O>[C:17]1([CH:23]([N:13]2[C:14]3[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=3[O:6][C:7]3[C:12]2=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH3:24])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: c1ccc2c(c1)Nc1ccccc1O2
Reactant: CC(Cl)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(c1ccccc1)N1c2ccccc2Oc2ccccc21
Reaction time: 0.5 h

Procedure:
A solution of phenoxazine 76 g, 0.417 mol (Aldrich Chemical Co., Milwaukee, WI, Cat. No. P1,585-8) in dry dimethylformamide (120 ml) was added to a stirred suspension of sodium hydride (22 g, 0.458 mol, 50% suspension in mineral oil) in dry dimethylformamide (500 ml). After 1 hour at room temperature α-phenylethyl chloride (59 g, 0.43 mol) was added dropwise and when the addition was completed, stirring was continued for another 30 min. The solution was poured into water, the product extracted with ethyl acetate, the extract washed with water, and dried over sodium sulfate. The solvent was removed under reduced pressure. N-α-Phenylethylphenoxazine was crystallized from ether-hexane, mp 100° C.
Reaction SMILES: [CH2:1]([C@H:8]([NH:30][C:31](=[O:38])[O:32][CH:33]1[CH2:37][CH2:36][O:35][CH2:34]1)[C@@H:9]([OH:29])[CH:10]([NH:17][S:18]([C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=1)(=[O:20])=[O:19])[O:11][CH:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N[C@@H](CC1C=CC=CC=1)[C@H](O)CN(OC1CCCC1)S(C1C=CC(OC)=CC=1)(=O)=O.FC(F)(F)C(O)=O.C(N(CC)C(C)C)(C)C>>[CH2:1]([C@H:8]([NH:30][C:31](=[O:38])[O:32][C@H:33]1[CH2:37][CH2:36][O:35][CH2:34]1)[C@@H:9]([OH:29])[CH:10]([NH:17][S:18]([C:21]1[CH:22]=[CH:23][C:24]([O:27][CH3:28])=[CH:25][CH:26]=1)(=[O:20])=[O:19])[O:11][CH:12]1[CH2:13][CH2:14][CH2:15][CH2:16]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(S(=O)(=O)NC(OC2CCCC2)[C@H](O)[C@H](Cc2ccccc2)NC(=O)OC2CCOC2)cc1
Agent: COc1ccc(S(=O)(=O)N(C[C@@H](O)[C@@H](N)Cc2ccccc2)OC2CCCC2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(S(=O)(=O)NC(OC2CCCC2)[C@H](O)[C@H](Cc2ccccc2)NC(=O)O[C@H]2CCOC2)cc1
Reaction time: 18 h
Yield: 87 %

Procedure:
tetrahydro-3-furanyl N-((1S,2R)-1-benzyl-3-(cyclopentyloxy)[(4-methoxyphenyl)sulfonyl]amino-2-hydroxypropyl)carbamate. A mixture of 2,5-dioxo-1-pyrrolidinyl[(3S)tetrahydro-3-furanyl]carbonate (13.8 mg, 0.0602 mmol, WO94/05639), N1-[(2R,3S)-3-amino-2-hydroxy-4-phenylbutyl]-N1-(cyclopentyloxy)-4-methoxy-1-benzenesulfonamide×trifluoracetic acid (Step 1, Example 48), (30 mg, 0.0547 mmol), and N,N-diisopropylethylamine (23.8 μL, 0.137 mmol) were combined at ambient temperature under an Argon atmosphere. After stirring for 18 hours, the reaction mixture was evaporated in vacuo to a residue and purified on a preparative silica gel TLC plate (20×20 cm, 500 μM) eluting with 96:4 chloroform:methanol. The product band was removed, eluted with 3:1 methylene chloride:methanol, filtered, evaporated in vacuo and dried under high vacuum to provide (3S)tetrahydro-3-furanyl N-((1S,2R)-1-benzyl-3-(cyclopentyloxy)[(4-methoxyphenyl)sulfonyl]amino-2-hydroxypropyl)carbamate (26 mg, 87%) as a foam. H1-NMR (chloroform-D3): 1.73 (m, 9H), 2.14 (m, 1H), 2.92 (m, 5H), 3.77 (m, 6H), 3.87 (s, 3H), 4.79 (bm, 2H), 5.10 (bs, 1H), 6.97 (d, 2H), 7.23 (m, 5H), 7.70 (d, 2H). MS(ESI): 571 (M+Na).
Reaction SMILES: CN1CCOCC1.[F:8][C:9]([F:18])([F:17])[C:10]1[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=1[NH2:12].[O:19]=[C:20]1[CH2:37][CH2:36][C@@:35]2([CH3:38])[C:22]([CH2:23][CH2:24][C@@H:25]3[C@@H:34]2[CH2:33][CH2:32][C@@:30]2([CH3:31])[C@H:26]3[CH2:27][CH2:28][C@@H:29]2[C:39](Cl)=[O:40])=[CH:21]1>C(Cl)Cl>[O:19]=[C:20]1[CH2:37][CH2:36][C@@:35]2([CH3:38])[C:22]([CH2:23][CH2:24][C@@H:25]3[C@@H:34]2[CH2:33][CH2:32][C@@:30]2([CH3:31])[C@H:26]3[CH2:27][CH2:28][C@@H:29]2[C:39]([NH:12][C:11]2[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=2[C:9]([F:17])([F:18])[F:8])=[O:40])=[CH:21]1
Reactant: Nc1ccccc1C(F)(F)F
Reactant: C[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@]43C)[C@@H]1CC[C@@H]2C(=O)Cl
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: C[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@]43C)[C@@H]1CC[C@@H]2C(=O)Nc1ccccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of N-methylmorpholine (0.28 g, 2.8 mmol) and 2-(trifluoromethyl)aniline (0.5 g, 3.1 mmol) in anhydrous CH2Cl2 (3.0 mL) at 0° C. under a nitrogen atmosphere was added a solution of 3-oxoandrost-4-ene-17β-carbonyl chloride from Step A (2.56 mmol) in anhydrous CH2Cl2 (8.1 mL) dropwise. The ice bath was removed and the mixture stirred at room temperature overnight. The reaction was then concentrated and the residue was purified by flash chromatography on silica gel eluting with 0 to 50% EtOAc-hexanes to afford the desired product as a white solid.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].C(#N)C.[Si](Cl)(Cl)(Cl)Cl.C(Cl)Cl.[C:16]([C:18]1[C:19]([C:32]2[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][C:33]=2[Cl:39])=[C:20]([C:29]([NH2:31])=O)[S:21][C:22]=1[N:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1)#[N:17]>>[Cl:39][C:33]1[CH:34]=[C:35]([Cl:38])[CH:36]=[CH:37][C:32]=1[C:19]1[C:18]([C:16]#[N:17])=[C:22]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[S:21][C:20]=1[C:29]1[NH:31][N:3]=[N:2][N:1]=1
Reactant: N#Cc1c(N2CCOCC2)sc(C(N)=O)c1-c1ccc(Cl)cc1Cl
Reactant: [N-]=[N+]=[N-]
Agent: Cl[Si](Cl)(Cl)Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: CC#N
Product: N#Cc1c(N2CCOCC2)sc(-c2nnn[nH]2)c1-c1ccc(Cl)cc1Cl
Reaction time: 0.5 h
Yield: 54.5 %

Procedure:
To a mixture of sodium azide (34.01 mg, 0.0005232 mol) in ACN (0.3 mL, 0.005 mol) was added silicon(IV) chloride (0.105 mmol, 0.000105 mol) in DCM (0.1 mL, 0.002 mol) and the mixture was stirred for 30 min. 4-cyano-3-(2,4-dichlorophenyl)-5-morpholinothiophene-2-carboxamide (20.0 mg, 0.0000523 mol) was added to the above mixture, followed by sodium azide (0.0340 g, 0.000523 mol) and silicon(IV) chloride (0.16 mmol, 0.00016 mol) in DCM (0.16 mL, 0.0025 mol) and the mixture was irradiated in microwave at 160° C. for 30 min. The reaction was evaporated and purified by column chromatography to afford 4-(2,4-dichlorophenyl)-2-morpholino-5-(1H-tetrazol-5-yl)thiophene-3-carbonitrile (11.6 mg, 54.4%). LCMS: (FA) ES+ 407.09, ES− 405.20; 1H NMR (300 MHz, d1-chloroform) δ: 7.60 (d, 1H), 7.42 (dd, 1H), 7.30 (d, 1H), 3.90-3.85 (m, 4H), 3.72-3.63 (m, 4H).
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([NH:17][C:18]3[N:23]=[C:22](Cl)[N:21]=[CH:20][N:19]=3)=[CH:14][CH:15]=2)[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:25]CN(C(C)C)C(C)C.[NH2:34][C:35]1[CH:36]=[CH:37][C:38]([O:46][CH3:47])=[C:39]([NH:41][C:42](=[O:45])[CH:43]=[CH2:44])[CH:40]=1>>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([N:17]([CH3:25])[C:18]3[N:19]=[CH:20][N:21]=[C:22]([NH:34][C:35]4[CH:36]=[CH:37][C:38]([O:46][CH3:47])=[C:39]([NH:41][C:42](=[O:45])[CH:43]=[CH2:44])[CH:40]=4)[N:23]=3)=[CH:14][CH:15]=2)[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Clc1ncnc(Nc2ccc3c(cnn3Cc3ccccc3)c2)n1
Reactant: C=CC(=O)Nc1cc(N)ccc1OC
Reactant: CCN(C(C)C)C(C)C
Product: C=CC(=O)Nc1cc(Nc2ncnc(N(C)c3ccc4c(cnn4Cc4ccccc4)c3)n2)ccc1OC
Temperature: 100 °C

Procedure:
To a slurry of (1-benzyl-1H-indazol-5-yl)-(4-chloro-[1,3,5]triazin-2-yl)-amine (Example 3, Step 3) (90 mg, 0.256 mmol) in IpOH (3 ml) was added DIEA (0.067 mL, 0.385 mmol) and N-(5-amino-2-methoxy-phenyl)acrylamide (Example 12, Step 2) (54. mg, 0.282 mmol). The mixture was heated at 100° C. for 18 h. The solution was then cooled to RT. A precipitate fell out of solution, was filtered off and dried under reduced pressure to give N-(5-{4-[(1-benzyl-1H-indazol-5-yl)-methyl-amino]-[1,3,5]triazin-2-ylamino}-2-methoxyphenyl)acrylamide: MS m/z=507 [M+H]+. Calc'd for C28H26N802: 506.22.
Reaction SMILES: [CH3:1][C:2]([CH2:6][CH2:7][CH:8]=[C:9]([CH3:21])[CH2:10][CH2:11][CH:12]=[C:13]([CH3:20])[CH2:14][CH2:15][CH:16]=[C:17]([CH3:19])[CH3:18])=[CH:3][CH2:4]Br.[CH3:22][O:23][CH:24]([CH2:27][OH:28])[CH2:25][OH:26].[OH-].[K+].O>CS(C)=O.O1CCCC1>[CH3:1][C:2]([CH2:6][CH2:7][CH:8]=[C:9]([CH3:21])[CH2:10][CH2:11][CH:12]=[C:13]([CH3:20])[CH2:14][CH2:15][CH:16]=[C:17]([CH3:19])[CH3:18])=[CH:3][CH2:4][O:26][CH2:25][CH:24]([O:23][CH3:22])[CH2:27][OH:28]
Reactant: COC(CO)CO
Reactant: CC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CCBr
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CS(C)=O
Product: COC(CO)COCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)C
Reaction time: 2 h

Procedure:
In a mixture of 20 ml of dimethyl sulfoxide and 12 ml of tetrahydrofuran were dissolved 2.2 g of 3-(3,7, 11,15-tetramethyl-2,6,10,14-hexadecatetraenyl bromide and 2.3 g of 2-O-methylglycerin, and 2.0 g of powdered potassium hydroxide was added. The mixture was stirred for 2 hours, poured into cold water and extracted with ethyl acetate. The extract was washed with water, dried and concentrated. The residue was purified by chromatography on a silica gel column to give 1.15 g of the above-identified compound as light-yellow liquid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]=O)[CH:2]=1.[C:9]([NH:12][CH2:13][C:14]([OH:16])=[O:15])(=O)[CH3:10].C([O-])(=O)C.[Na+].C(OC(=O)C)(=O)C>C(OC)(C)(C)C.CC(C)=O>[CH3:10][C:9]1[O:16][C:14](=[O:15])/[C:13](=[CH:7]/[C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)/[N:12]=1
Reactant: CC(=O)NCC(=O)O
Reactant: O=Cc1cccnc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Solvent: CC(C)=O
Solvent: COC(C)(C)C
Product: CC1=N/C(=C\c2cccnc2)C(=O)O1
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
Under nitrogen, acetone (40.0 l), followed by pyridine-3-carbaldehyde (20.0 kg, 186.9 mol), was added to N-acetylglycine (32.7 kg, 280.0 mol) and sodium acetate (15.3 kg, 186.9 mol). With stirring, acetic anhydride (40.0 l, 429.0 mol) was added. Within 30 min, the reaction mixture was heated to reflux temperature and then stirred under reflux for 1.5 h. This gave a thin reddish suspension. The suspension was cooled to 50° C., and methyl tert-butyl ether (80.0 l) was then added. Ice-water (<2° C., 200.0 l) was added as quickly as possible (<5 min), with stirring and cooling, and the mixture was then stirred at 5–10° C. for 1 h. The beige suspension was introduced into a centrifuge which had been inertized with nitrogen. The precipitate was centrifuged, washed with deionized water (80.0 l) and dried under reduced pressure at 40° C. Yield: 24.8 kg (131.9 mol, 70.6% of theory). M.p.: 173° C.; MS (DCl): m/z (%)=189 ([M+H+], 100); 1H-NMR (200 MHz, DMSO-d6): δ=2.40 (s, 3H), 7.28 (s, 1H), 7.53 (dd, 1H), 8.61 (d, 2H), 9.18 (brs, 1H); IR (KBr): ν=1799.9, 1777.4, 898.0 cm−1.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[CH2:5](Br)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]>CS(C)=O>[N:1]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])=[N+:2]=[N-:3]
Reactant: CCCCCCCCBr
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CCCCCCCCN=[N+]=[N-]
Temperature: 25 °C
Reaction time: 5 h

Procedure:
In a 100 mL round bottomed flask, sodium azide (2.60 g, 37.6 mmol) was dissolved in 80 mL DMSO, 1-Octyl bromide (5.5 g, 28.4 mmol) was added and stirred at room temperature for 5 h. The reaction was quenched by addition of water (200 mL) and was stirred for 1 h. The mixture was extracted with diethyl ether (50×3). The combined organic layers were washed with brine solution. The ether solution was dried over anhydrous MgSO4 and the solvent was removed by rotary evaporation. The product was further purified by filtration through a short silica gel column using hexane as eluent. Yield: 2.5 g (78%) IR (neat) 2957, 2857, 2093, 1466, 1377, 1279 cm−1; 1H NMR (400 MHz, CDCl3) δ 3.21 (d, J=6.2 Hz, 2H), 1.55-1.57 (m, 2H), 1.25-1.32 (m, 10H), 0.84 (m, 3H); 13C NMR (CDCl3) δ 51.51, 31.80, 29.19, 29.16, 28.89, 26.77, 22.66, 14.06,
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[CH2:14][I:15])=[CH:4][CH:3]=1.[C:16]1([P: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)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C1(C)C=CC=CC=1>[I-:15].[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[CH2:14][P+:22]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[CH:4][CH:3]=1
Reactant: Clc1ccc(-c2ccccc2CI)cc1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: Clc1ccc(-c2ccccc2C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: [I-]
Temperature: 25 °C
Yield: 93 %

Procedure:
To a solution of 4′-chloro-2-(iodomethyl)biphenyl in toluene (11 mL), triphenylphosphine (1.20 g, 4.57 mmol) was added. The result mixture was refluxed overnight, allowed to cool to room temperature and filtered. The solid was washed with ether and dried under vacuum to afford ((4′-Chlorobiphenyl-2-yl)methyl)triphenylphosphonium iodide (2.50 g, 93%): 1H NMR (400 MHz, chloroform-d) δ ppm 6.35-8.06 (m, 23 H), 5.12-5.63 (m, 2 H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH3:7][C:8]1([CH3:11])[CH2:10][S:9]1.O>C1C=CC=CC=1>[CH3:7][C:8]([SH:9])([CH3:11])[CH2:10][N:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1
Reactant: C1CNCCN1
Reactant: CC1(C)CS1
Solvent: c1ccccc1
Solvent: O
Product: CC(C)(S)CN1CCNCC1
Temperature: 80 °C
Reaction time: 1 h
Yield: 62.3 %

Procedure:
Piperazine (7.72 g, 89.8 mmol) was dissolved in benzene (10 mL) and 2,2-dimethylthiirane (3.16 g, 35.9 mmol) was added. The reaction mixture was stirred at 80° C. for 1 hour, poured into the water and extracted with ethyl acetate (3×100 mL). The combined organic extracts were washed with brine and dried over anhydrous sodium sulfate. Volatiles were evaporated and the residue was dried on vacuum pump overnight to afford 3.9 g of the title compound. 1H NMR (CDCl3, 300 MHz): δ1.29 (s, 6H), 2.34 (s, 2H), 2.58 (t, 4H), 2.63 (s, 1H), 2.85 (t, 4H).
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[S:9][C:8]([CH:10]=O)=[CH:7][CH:6]=1)[CH3:3].N1CCCCC1.C(O)(=O)[CH2:19][C:20]([OH:22])=[O:21]>N1C=CC=CC=1>[CH3:3][N:2]([CH2:4][C:5]1[S:9][C:8]([CH:10]=[CH:19][C:20]([OH:22])=[O:21])=[CH:7][CH:6]=1)[CH3:1]
Reactant: O=C(O)CC(=O)O
Reactant: CN(C)Cc1ccc(C=O)s1
Solvent: C1CCNCC1
Solvent: c1ccncc1
Product: CN(C)Cc1ccc(C=CC(=O)O)s1
Yield: 54.8 %

Procedure:
5-(Dimethylaminomethyl)thiophene-2-carboxaldehyde (40.09 g) and piperidine (3 ml) were added to a solution of malonic acid (24.65 g) in pyridine (150 ml). The mixture was stirred under reflux for 7 hours. During the reaction a solid precipitated and slowly re-dissolved. The solution was allowed to cool and was then poured on to 2 M hydrochloric acid (150 ml). The volume of the solution was reduced to about 120 ml by evaporation at reduced pressure and extracted with diethyl ether. The ether extracts were washed with water. The aqueous phase was cooled and the solid, which precipitated out, was filtered off and washed with water-isopropanol. More solid was obtained by evaporating the filtrate to about 100 ml and adding isopropanol and cooling the mixture in ice for about 15 minutes. This solid was filtered off, and washed with isopropanol. The solids were combined and recrystallised from isopropanol-water to give 3-(5-dimethylaminomethyl-2-thienyl)acrylic acid (27.45 g) m.p. 223.5°-225° C.