Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[C:2]1[C:7]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[N:6][C:5]([NH2:14])=[CH:4][N:3]=1.P(Cl)(Cl)([Cl:17])=O>>[Cl:17][C:2]1[C:7]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[N:6][C:5]([NH2:14])=[CH:4][N:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Nc1cnc(O)c(N2CCOCC2)n1
Product: Nc1cnc(Cl)c(N2CCOCC2)n1

Procedure:
Treatment of the 2-hydroxy-3-morpholino-5-aminopyrazine with phosphorus oxychloride by the method described in Preparation 13, Step B, gives the desired 2-chloro-3-morpholino-5-aminopyrazine.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8]([C:10]2[CH2:11][CH2:12][O:13][C:14]3[CH:20]=[CH:19][C:18]([C:21]4[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=4)=[CH:17][C:15]=3[CH:16]=2)=[O:9])[CH2:3][CH2:2]1.[CH:28]1([CH2:34][CH:35]=O)[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH:28]1([CH2:34][CH2:35][N:1]2[CH2:2][CH2:3][CH:4]([NH:7][C:8]([C:10]3[CH2:11][CH2:12][O:13][C:14]4[CH:20]=[CH:19][C:18]([C:21]5[CH:22]=[CH:23][C:24]([CH3:27])=[CH:25][CH:26]=5)=[CH:17][C:15]=4[CH:16]=3)=[O:9])[CH2:5][CH2:6]2)[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1
Reactant: O=CCC1CCCCC1
Reactant: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)NC2CCNCC2)CCO3)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)NC2CCN(CCC4CCCCC4)CC2)CCO3)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.8 %

Procedure:
To N-(4-piperidinyl)-7-(4-methylphenyl)-2,3-dihydro-1-benzooxepine-4-carboxamide (0.15 g) and cyclohexylactaldehyde (0.07 g) dissolved in 1,2-dichloroethane (10 ml) was added under ice cooling sodium triacetoxyborohydride (0.12 g), and the resulting mixture was stirred at room temperature overnight under a nitrogen atmosphere. The reaction mixture was evaporated to remove the solvent, was mixed with a 1 N aqueous solution of sodium hydroxide and was extracted with ethyl acetate. The organic layer was washed with water and an aqueous saturated solution of sodium chloride, and was then dried with anhydrous magnesium sulfate. The resulting organic layer was evaporated under reduced pressure to remove the solvent to obtain crude crystals. The crude crystals were recrystallized from ethyl acetate/hexane to obtain N-(1-(2-cyclohexylethyl)piperidin-4-yl)-7-(4-methylphenyl)-2,3-dihydro-1-benzooxepine-4-carboxamide (compound 60) (0.16 g) as colorless prisms.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.Br[C:11]1[CH:12]=[C:13]([CH:24]=[CH:25][C:26]=1[Cl:27])[CH2:14][NH:15][C@@H:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH3:17].C(=O)([O-])[O-].[K+].[K+]>[Cu]I.CN1C(=O)CCC1>[N:1]1([C:11]2[CH:12]=[C:13]([CH:24]=[CH:25][C:26]=2[Cl:27])[CH2:14][NH:15][C@@H:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH3:17])[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: C[C@@H](NCc1ccc(Cl)c(Br)c1)c1ccccc1
Reactant: c1ccc2[nH]cnc2c1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: C[C@@H](NCc1ccc(Cl)c(-n2cnc3ccccc32)c1)c1ccccc1
Temperature: 150 °C
Yield: 19.3 %

Procedure:
To a mixture of 1H-benzo[d]imidazole (0.106 g, 0.90 mmol) and (R)—N-(3-bromo-4-chlorobenzyl)-1-phenylethanamine 75 (0.247 g, 0.76 mmol) was added potassium carbonate (0.141 g, 1.0 mmol), copper(I) iodide (0.023 g, 0.12 mmol), and NMP (0.8 mL). The reaction mixture was degassed and heated to 150° C. for 3 d, diluted with EtOAc, filtered, and concentrated in vacuo. Purification by flash column chromatography on silica gel (eluted with 40% to 100% EtOAc in hexanes) gave (1R)—N-(3-(1H-benzo[d]imidazol-1-yl)-4-chlorobenzyl)-1-phenylethanamine 76 (0.053 g, 19% yield) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 1.38 (d, J=6.7 Hz, 3H), 3.69 (s, 2H), 3.82 (q, J=6.7 Hz, 1H), 7.20-7.43 (m, 11H), 7.55 (d, J=8.2 Hz, 1H), 7.79 (d, J=7.2 Hz, 1H), 8.04 (s, 1H). Mass spectrum: calculated for C22H20ClN3 361.1. found 362.2 (M++1).
Reaction SMILES: [F:1][C:2]1[C:11]([F:12])=[C:10]([OH:13])[CH:9]=[CH:8][C:3]=1[C:4]([O:6]C)=[O:5].[F:14][C@@H:15]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH2:16]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[F:1][C:2]1[C:11]([F:12])=[C:10]([O:13][CH2:16][CH:15]([F:14])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH:9]=[CH:8][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: COC(=O)c1ccc(O)c(F)c1F
Reactant: CCCCCC[C@H](F)CO
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCCCCCC(F)COc1ccc(C(=O)O)c(F)c1F
Temperature: 25 °C

Procedure:
0.05 mol of methyl 2,3-difluoro-4-hydroxybenzoate, 0.05 mol of (S)-2-fluorooctan-1-ol and 0.06 mol of triphenylphosphine are dissolved in 125 ml of tetrahydrofuran, and 0.06 mol of diethyl azodicarboxylate is added dropwise with stirring and ice cooling. The mixture is allowed to warm to room temperature and is stirred for a further 8 hours. The solvent is then removed by distillation, and the methyl 2,3-difluoro-4-(2-fluorooctyloxy)benzoate is purified by column chromatography. 2,3-Difluoro-4-(2-fluorooctyloxy)benzoic acid is obtained therefrom by hydrolysis using aqueous/alcoholic potassium hydroxide solution.
Reaction SMILES: [NH2:1][C:2]1[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=2)=[C:5]([S:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)[CH:16]=2)[NH:4][N:3]=1.[Cl:29][C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([Cl:36])[C:31]=1[S:37](Cl)(=[O:39])=[O:38].O>N1C=CC=CC=1>[Cl:29][C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([Cl:36])[C:31]=1[S:37]([NH:1][C:2]1[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=2)=[C:5]([S:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][C:22]3[CH:23]=[CH:24][C:25]([F:28])=[CH:26][CH:27]=3)[CH:16]=2)[NH:4][N:3]=1)(=[O:39])=[O:38]
Reactant: O=S(=O)(Cl)c1c(Cl)cccc1Cl
Reactant: Nc1n[nH]c(SCc2cccc(Oc3ccc(F)cc3)c2)c1-c1ccccn1
Solvent: O
Solvent: c1ccncc1
Product: O=S(=O)(Nc1n[nH]c(SCc2cccc(Oc3ccc(F)cc3)c2)c1-c1ccccn1)c1c(Cl)cccc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 53.7 %

Procedure:
3-Amino-4-(2-pyridyl)-5-(3-(4-fluorophenoxy)benzylthio)-(1H)-pyrazole (0.39 g, 0.99 mmol) was dissolved in 5 ml of pyridine. Commercial 2,6-dichlorobenzenesulfonyl chloride (0.26 g, 1.04 mmol) was added and the red solution was stirred overnight at room temperature. The reaction mixture was poured into 50 ml of water and was extracted twice with 100 ml portions of ethyl acetate. The organic layers were washed with water and brine, combined, dried over MgSO4 and concentrated. The crude product was slurried in cold ethyl acetate and the solid was filtered off and washed with small portions of cold ethyl acetate and cold diethyl ether and dried under vacuum to afford 0.32 g (53% yield) of the final compound.
Reaction SMILES: [OH:1][C:2]1[N:9]=[C:8]([CH3:10])[CH:7]=[C:6]([NH:11][CH3:12])[C:3]=1[C:4]#[N:5].O.NN>C(O)C.[Ni]>[NH2:5][CH2:4][C:3]1[C:2]([OH:1])=[N:9][C:8]([CH3:10])=[CH:7][C:6]=1[NH:11][CH3:12]
Reactant: CNc1cc(C)nc(O)c1C#N
Agent: [Ni]
Agent: NN
Solvent: O
Solvent: CCO
Product: CNc1cc(C)nc(O)c1CN
Temperature: 55 °C
Reaction time: 2 h
Yield: 35.9 %

Procedure:
2-hydroxy-6-methyl-4-(methylamino)nicotinonitrile (163 mg, 1.0 mmol) was dissolved in ethanol (10 mL) and was warmed to 55° C. before it was treated with Raney nickel (0.5 mL slurry in water) followed by addition of hydrazine monohydrate (2 mL). The resulting mixture was allowed to stir at 55° C. for 2 hours. The cooled reaction mixture was filtered through celite, rinsed with methanol. The filtrate was concentrated in vacuo to provide crude product which was purified by silica gel column chromatography with dichloromethane/methanol=10:1 to afford 3-(aminomethyl)-6-methyl-4-(methylamino)pyridin-2-ol (60 mg, 36% yield) as a brown solid.
Reaction SMILES: [CH:1]([SH:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:12]([O:16][C:17]([N:19]1[CH2:23][CH2:22][CH2:21][C@H:20]1[CH:24]1[O:26][CH2:25]1)=[O:18])([CH3:15])([CH3:14])[CH3:13]>CO>[C:12]([O:16][C:17]([N:19]1[CH2:23][CH2:22][CH2:21][C@H:20]1[CH:24]([OH:26])[CH2:25][S:4][CH:1]([CH3:3])[CH3:2])=[O:18])([CH3:15])([CH3:14])[CH3:13]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C1CO1
Reactant: CC(C)S
Solvent: CCN(CC)CC
Solvent: CO
Product: CC(C)SCC(O)[C@@H]1CCCN1C(=O)OC(C)(C)C
Reaction time: 2 h

Procedure:
Isopropylmercaptan (0.93 ml) and triethylamine (1.39 ml) were added to (2S)-1-(t-butoxycarbonyl)-2-(1,2-epoxyethyl)-pyrrolidine (2.11 g) as obtained in Example 1-A) in methanol (100 ml), and the mixture was stirred for 2 hours under reflux. The reaction mixture was concentrated and the residue was purified by silica gel column chromatography (eluate: hexane-ethyl acetate) to give 1.66 g of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[C:11]([F:14])([F:13])[F:12].Cl.CN(C)CCCN=C=NCC.[Cl:27][C:28]1[CH:29]=[C:30]([CH:35]2[CH:39]([NH:40][CH3:41])[CH2:38][N:37]([C:42]([CH:44]3[CH2:49][CH2:48][N:47]([C:50]([C:52]4([CH3:55])[CH2:54][CH2:53]4)=[O:51])[CH2:46][CH2:45]3)=[O:43])[CH2:36]2)[CH:31]=[CH:32][C:33]=1[Cl:34]>ClCCl>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:40]([CH:39]2[CH:35]([C:30]3[CH:31]=[CH:32][C:33]([Cl:34])=[C:28]([Cl:27])[CH:29]=3)[CH2:36][N:37]([C:42]([CH:44]3[CH2:45][CH2:46][N:47]([C:50]([C:52]4([CH3:55])[CH2:54][CH2:53]4)=[O:51])[CH2:48][CH2:49]3)=[O:43])[CH2:38]2)[CH3:41])=[O:8])=[CH:4][C:3]=1[C:11]([F:14])([F:13])[F:12]
Reactant: CNC1CN(C(=O)C2CCN(C(=O)C3(C)CC3)CC2)CC1c1ccc(Cl)c(Cl)c1
Reactant: O=C(O)c1ccc(Cl)c(C(F)(F)F)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: CN(C(=O)c1ccc(Cl)c(C(F)(F)F)c1)C1CN(C(=O)C2CCN(C(=O)C3(C)CC3)CC2)CC1c1ccc(Cl)c(Cl)c1
Reaction time: 72 h
Yield: 88.8 %

Procedure:
To a mixture of 4-chloro-3-(trifluoromethyl)benzoic acid (31 mg, 0.14 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (27 mg, 0.14 mmol) was added at 0° C. under an atmosphere of nitrogen a solution {4-[(3SR,4RS)-3-(3,4-dichloro-phenyl)-4-methylamino-pyrrolidine-1-carbonyl]-piperidin-1-yl}-(1-methyl-cyclopropyl)-methanone (50 mg, 0.11 mmol) in dichloromethane (1 mL). The solution was stirred for 3 d in a thawing ice bath. The resulting solution was diluted with dichloromethane and was washed twice with water (10 mL). The aqueous layers were extracted with dichloromethane (10 mL) and the combined organic layers were dried over sodium sulfate. Purification by chromatography (SiO2, heptane:ethyl acetate:methanol=50:50:0 to 0:90:10) afforded the title compound (63 mg, 86%) as a light brown foam. MS m/e: 646.3 [M+H]+.
Reaction SMILES: Cl.Cl.[NH2:3][CH:4]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:5]([O:7][C@@H:8]1[CH:13]2[CH2:14][CH2:15][N:10]([CH2:11][CH2:12]2)[CH2:9]1)=[O:6].C(N(CC)CC)C.[C:29](Cl)(=[O:32])[O:30][CH3:31]>C(Cl)Cl>[CH3:31][O:30][C:29]([NH:3][CH:4]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:5]([O:7][C@@H:8]1[CH:13]2[CH2:12][CH2:11][N:10]([CH2:15][CH2:14]2)[CH2:9]1)=[O:6])=[O:32]
Reactant: NC(C(=O)O[C@H]1CN2CCC1CC2)c1ccccc1
Reactant: COC(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)NC(C(=O)O[C@H]1CN2CCC1CC2)c1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 40.5 %

Procedure:
To a suspension of (R)-quinuclidin-3-yl 2-amino-2-phenylacetate dihydrochloride (I25) (150 mg, 0.45 mmol) in DCM (5 ml), were added triethylamine (188 μl, 1.35 mmol) and methyl carbonochloridate (41.7 μl, 0.54 mmol). The reaction was stirred at RT for 4 hours, and then the solvent was evaporated. The residue was taken up with EtOAc and washed with water and brine. The organic phase was dried over Na2SO4 and evaporated to obtain (R)-quinuclidin-3-yl 2-(methoxycarbonylamino)-2-phenylacetate (58.0 mg; 40% yield). The compound was used in the next step without any further purification.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([S:11][C:12]2[C:20]3[C:15](=[CH:16][C:17]([Cl:21])=[CH:18][CH:19]=3)[NH:14][C:13]=2[CH3:22])[CH:6]=1)[CH3:2].Br[C:25]1[CH:26]=[N:27][N:28]([CH2:30][CH2:31][CH2:32][CH3:33])[CH:29]=1>>[CH2:1]([O:3][C:4](=[O:23])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([S:11][C:12]2[C:20]3[C:15](=[CH:16][C:17]([Cl:21])=[CH:18][CH:19]=3)[N:14]([C:25]3[CH:26]=[N:27][N:28]([CH2:30][CH2:31][CH2:32][CH3:33])[CH:29]=3)[C:13]=2[CH3:22])[CH:6]=1)[CH3:2]
Reactant: CCCCn1cc(Br)cn1
Reactant: CCOC(=O)c1cccc(Sc2c(C)[nH]c3cc(Cl)ccc23)c1
Product: CCCCn1cc(-n2c(C)c(Sc3cccc(C(=O)OCC)c3)c3ccc(Cl)cc32)cn1

Procedure:
Prepared according to the procedure described in Example 55, Step 2 using the following starting materials: 3-(6-chloro-2-methyl-1H-indol-3-ylsulfanyl)-benzoic acid ethyl ester and 4-Bromo-1-butyl-1H-pyrazole
Reaction SMILES: [C:1]([O:5][CH3:6])(=[O:4])[CH:2]=[O:3].[CH3:7][PH:8](=[O:10])[CH3:9].C[O-].[Na+]>O1CCOCC1.C(OCC)(=O)C>[CH3:7][P:8]([CH3:9])([CH:2]([OH:3])[C:1]([O:5][CH3:6])=[O:4])=[O:10]
Reactant: C[PH](C)=O
Reactant: COC(=O)C=O
Agent: C[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: COC(=O)C(O)P(C)(C)=O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of 17.6 g (0.2 mol) of methyl glyoxylate in 30 ml of dioxane is added dropwise to a solution of 15.6 g (0.2 mol) of dimethylphosphine oxide in 50 ml of dioxane. A spatula-tip of sodium methylate is added, the mixture is stirred at 25° C. for 24 hours and the evaporated residue is freed from adhering dioxane under a high vacuum and taken up in ethyl acetate to give, after trituration, 16.4 g (49.4%) of colorless product of melting point 84°-86°.
Reaction SMILES: [F:1][C:2]([C:5]1[N:6]=[C:7]([CH2:10][N:11]2[CH:15]=[CH:14][C:13]([NH2:16])=[N:12]2)[S:8][CH:9]=1)([F:4])[CH3:3].[C:17]1([C:23]2[O:27][CH:26]=[N:25][C:24]=2[C:28](O)=[O:29])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[F:1][C:2]([C:5]1[N:6]=[C:7]([CH2:10][N:11]2[CH:15]=[CH:14][C:13]([NH:16][C:28]([C:24]3[N:25]=[CH:26][O:27][C:23]=3[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)=[O:29])=[N:12]2)[S:8][CH:9]=1)([F:4])[CH3:3]
Reactant: CC(F)(F)c1csc(Cn2ccc(N)n2)n1
Reactant: O=C(O)c1ncoc1-c1ccccc1
Product: CC(F)(F)c1csc(Cn2ccc(NC(=O)c3ncoc3-c3ccccc3)n2)n1

Procedure:
Following general procedure B, 1-[4-(1,1-difluoro-ethyl)-thiazol-2-ylmethyl]-1H-pyrazol-3-ylamine and 5-phenyl-oxazole-4-carboxylic acid. LC-MS-conditions 02: tR=1.04 min; [M+H]+=415.86.
Reaction SMILES: [C:1]([O:5][C:6](=[O:39])[CH2:7][CH:8]([NH:15][S:16]([C:19]1[CH:24]=[CH:23][C:22]([NH2:25])=[CH:21][C:20]=1[O:26][CH2:27][CH2:28][C:29]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:32]=[CH:31][CH:30]=1)(=[O:18])=[O:17])[C:9]([N:11]([O:13][CH3:14])[CH3:12])=[O:10])([CH3:4])([CH3:3])[CH3:2].[C:40](Cl)(=[O:42])[CH3:41].C(N(CC)CC)C>C(Cl)Cl>[C:1]([O:5][C:6](=[O:39])[CH2:7][CH:8]([NH:15][S:16]([C:19]1[CH:24]=[CH:23][C:22]([NH:25][C:40](=[O:42])[CH3:41])=[CH:21][C:20]=1[O:26][CH2:27][CH2:28][C:29]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:32]=[CH:31][CH:30]=1)(=[O:18])=[O:17])[C:9]([N:11]([O:13][CH3:14])[CH3:12])=[O:10])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(=O)Cl
Reactant: CON(C)C(=O)C(CC(=O)OC(C)(C)C)NS(=O)(=O)c1ccc(N)cc1OCCc1cccc2ccccc12
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CON(C)C(=O)C(CC(=O)OC(C)(C)C)NS(=O)(=O)c1ccc(NC(C)=O)cc1OCCc1cccc2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.6 %

Procedure:
To a solution of 3-[4-amino-2-(2-naphthalen-1-yl-ethoxy)-benzenesulfonylamino]-N-methoxy-N-methyl-succinamic acid tert-butyl ester (300 mg, 0.54 mmol) and acetyl chloride (45 mg, 0.57 mg) in methylene chloride (10 mL) was added triethylamine (58 mg, 0.57 mmol) and the reaction mixture was stirred at room temperature overnight. The solvent was evaporated and the residue was taken up in ethyl acetate (50 mL). The resulting solution was extracted with 0.1N HCl (50 mL) and brine (50 mL), dried (MgSO4), and evaporated to give 3-(4-acetylamino-2-(2-naphthalen-1-yl-ethoxy)-benzenesulfonylamino)-N-methoxy-N-methyl-succinamic acid tert-butyl ester (300 mg) as an amorphous solid.
Reaction SMILES: [C:1]1(=[O:18])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][C:9](=[O:17])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:19](O)[CH2:20][OH:21].C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[O:18]1[C:1]2([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9](=[O:17])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]2)[O:21][CH2:20][CH2:19]1
Reactant: O=C1CCCCCCCC(=O)CCCCCCC1
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: O=C1CCCCCCCC2(CCCCCCC1)OCCO2

Procedure:
To a solution of 44.0 g (175 mmol) of 1,9-cyclohexadecanedione in 125 ml of toluene is added 13.1 g (210 mmol) of ethylene glycol and 500 mg (2.5 mmol) of p-toluenesulphonic acid. The mixture is then heated with a water separator until visible amounts of water are no longer eliminated. Washing with sat. NaHCO3 solution is then carried out, the phases are separated, the organic phase is dried over Na2SO4, filtration is carried out, and the solvent is removed on a rotary evaporator. This gives 57.7 g of a solid comprising 3 components having the following GC content: 1,9-cyclohexadecanedione (33.7%); 1,4-dioxaspiro-[4.15]-eicosan-13-one (52.5%); 1,4,14,17-tetraoxadispiro-[4.7.4.7]-tetracosane (13.2%).
Reaction SMILES: Cl[CH2:2][C:3]1[C:4]([NH2:10])=[N:5][C:6]([CH3:9])=[N:7][CH:8]=1.C(N(CC)CC)C.[CH2:18]([O:25][C:26]1[CH:35]=[C:34]2[C:29]([CH2:30][CH2:31][NH:32][CH2:33]2)=[CH:28][CH:27]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CN(C)C=O>[CH2:18]([O:25][C:26]1[CH:35]=[C:34]2[C:29]([CH2:30][CH2:31][N:32]([CH2:2][C:3]3[C:4]([NH2:10])=[N:5][C:6]([CH3:9])=[N:7][CH:8]=3)[CH2:33]2)=[CH:28][CH:27]=1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: Cc1ncc(CCl)c(N)n1
Reactant: c1ccc(COc2ccc3c(c2)CNCC3)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1ncc(CN2CCc3ccc(OCc4ccccc4)cc3C2)c(N)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 50.9 %

Procedure:
A suspension of 0.23 g (0.0012 mol) of 5-chloromethyl-2-methyl-pyrimidin-4-ylamine in 10 ml of dimethylformamide was treated with 0.42 ml (0.0030 mol) of triethylamine and 0.29 g (0.0012 mol) of 7-benzyloxy-1,2,3,4-tetrahydro-isoquinoline and the mixture was stirred at room temperature under argon for 18 hours. The solvent was distilled off in a high vacuum. The residue was partitioned between dichloromethane/water, extracted and dried over MgSO4. After removing the solvent the residue was chromatographed on silica gel with ethyl acetate as the eluent. 0.22 g (51%) of 5-(7-benzyloxy-3,4-dihydro-1H-isoquinolin-2-ylmethyl)-2-methyl-pyrimidin-4-ylamine was obtained as a colourless solid; m.p. 151°-153°.
Reaction SMILES: [F:1][C:2]([F:12])([C:5]([F:11])([F:10])[C:6]([F:9])([F:8])[F:7])[CH2:3][OH:4].F[C:14]1[CH:21]=[CH:20][C:17]([CH:18]=[O:19])=[CH:16][CH:15]=1.[H-].[Na+]>CN(C)C=O>[F:1][C:2]([F:12])([C:5]([F:10])([F:11])[C:6]([F:7])([F:8])[F:9])[CH2:3][O:4][C:14]1[CH:21]=[CH:20][C:17]([CH:18]=[O:19])=[CH:16][CH:15]=1
Reactant: OCC(F)(F)C(F)(F)C(F)(F)F
Reactant: O=Cc1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=Cc1ccc(OCC(F)(F)C(F)(F)C(F)(F)F)cc1
Yield: 9.6 %

Procedure:
Following the above procedure, a solution of 2,2,3,3,4,4,4-heptafluoro-1-butanol (750 μL, 6 mmol) in N,N-dimethylformamide (8 mL) and 4-fluorobenzaldehyde (429 μL, 4 mmol) were reacted together with sodium hydride (288 mg as 55-60% mineral oil dispersion, 6 mmol) in N,N-dimethylformamide (2 mL). Flash chromatography gave 117 mg of 4-(2,2,3,3,4,4,4-heptafluorobutoxy)benzaldehyde; 1H NMR (300 MHz, CDCl3) δ 9.93 (s, 1H), 7.89 (d, 2H), 7.08 (d, 2H), 4.54 (tt, 2H) ppm.
Reaction SMILES: [C:1]([O:5][C:6](=[O:9])[NH:7][NH2:8])([CH3:4])([CH3:3])[CH3:2].Cl.Cl[CH2:12][C:13]1[N:14]=[C:15]([CH:18]([CH3:20])[CH3:19])[S:16][CH:17]=1>C(O)(C)C>[CH:18]([C:15]1[S:16][CH:17]=[C:13]([CH2:12][NH:8][NH:7][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:9])[N:14]=1)([CH3:20])[CH3:19]
Reactant: CC(C)(C)OC(=O)NN
Reactant: CC(C)c1nc(CCl)cs1
Agent: Cl
Solvent: CC(C)O
Product: CC(C)c1nc(CNNC(=O)OC(C)(C)C)cs1

Procedure:
A solution of 7.5 g (57 mmol) to t-butylcarbazate in 200 ml of isopropyl alcohol was treated with a solution of 1.0 g (57 mmol) of 4-(chloromethyl)-2-isopropylthiazole hydrochloride in 10 ml of isopropyl alcohol. The resulting solution was heated at reflux for 16 h, allowed to cool, and concentrated in vacuo. The residue was diluted with 1N HCl, washed with three portions of ethyl acetate, basified to pH 12 with aqueous NaOH, and extracted with three portion of ethyl acetate. The combined organic layers were dried over MgSO4 and concentrated in vacuo. Purification of the residue by silica gel chromatography using 20% ethyl acetate in hexane provided 0.32 g (21%) of the desired compound (Rf 0.4, 5% methanol in chloroform). 1H NMR (CDCl3) δ 1.40 (d, J=7 Hz, 6H), 1.47 (s, 9H), 2.53 (br, 1H), 3.33 (heptet, J=7 Hz, 1H), 4.11 (s, 2H), 6.22 (br, 1H), 7.01 (s, 1H). Mass spectrum: (M+H)+=272.
Reaction SMILES: [CH2:1]=[CH:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[Br:9][CH2:10][S:11](Br)(=[O:13])=[O:12].C(=O)([O-])[O-].[K+].[K+]>C(Cl)Cl>[Br:9][CH2:10][S:11]([CH:1]=[CH:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])(=[O:13])=[O:12]
Reactant: O=S(=O)(Br)CBr
Reactant: C=CCCCCCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: CCCCCCC=CS(=O)(=O)CBr
Reaction time: 0.25 h
Yield: 87.2 %

Procedure:
A mixture of 1-octene (2.82 g) and bromomethanesulfonyl bromide (6.0 g) in methylene chloride (4 mL) was irradiated at -20° C. with an ultraviolet lamp for 0.5 hours. A small amount of solid potassium carbonate was added and then removed by filtration. The reaction mixture was diluted with methylene chloride (50 mL), cooled in ice and treated with a solution of triethylamine (4.45 g) in 10 mL of methylene chloride. The reaction mixture was stirred for 0.25 hours and was washed with dilute HCl and water. The methylene chloride layer was separated, dried over anhydrous magnesium sulfate and the methylene chloride removed in vacuo to give 5.9 g (97% yield) of oily 1-octenyl bromomethyl sulfone which was characterized by IR and NMR spectroscopy.
Reaction SMILES: C(P(=O)(OCC)OCC)#N.[F:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[N:17]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[CH:23]=1)[C:16]([C:29](O)=[O:30])=[CH:15]2.[NH2:32][C:33]1[CH:34]=[N:35][C:36]([NH:39][CH3:40])=[CH:37][CH:38]=1.C(N(CC)CC)C>CN(C)C=O>[CH3:40][NH:39][C:36]1[N:35]=[CH:34][C:33]([NH:32][C:29]([C:16]2[N:17]([CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[CH:23]=3)[C:18]3[C:14]([CH:15]=2)=[CH:13][C:12]([F:11])=[CH:20][CH:19]=3)=[O:30])=[CH:38][CH:37]=1
Reactant: O=C(O)c1cc2cc(F)ccc2n1Cc1cccc(F)c1
Reactant: CNc1ccc(N)cn1
Agent: CCOP(=O)(C#N)OCC
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CNc1ccc(NC(=O)c2cc3cc(F)ccc3n2Cc2cccc(F)c2)cn1
Reaction time: 0.17 h
Yield: 86.4 %

Procedure:
0.27 ml (1.67 mmol) of diethyl cyanophosphonate is added dropwise at 20° C. under argon to a solution of 0.4 g (1.39 mmol) of 5-fluoro-1-(3-fluorobenzyl)-1H-indole-2-carboxylic acid (obtained in step 1.1) and 0.216 g (1.67 mmol) of 3-amino-6-(methylamino)pyridine (WO2005/028452) in 10 ml of dry dimethylformamide. The mixture is stirred for 10 minutes and then 0.43 ml (3.08 mmol) of triethylamine is added dropwise. The mixture is stirred at ambient temperature for 18 hours and concentrated under reduced pressure, and then the residue is taken up in 50 ml of ethyl acetate. This solution is then successively washed with three times 20 ml of a saturated sodium hydrogencarbonate solution, 50 ml of water and 20 ml of a saturated sodium chloride solution and then dried over sodium sulfate, filtered and concentrated under reduced pressure. The solid obtained is triturated from hot isopropyl ether. 0.471 g of a solid is obtained, which solid is dried under reduced pressure.