Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)S(O[CH2:7][C@H:8]1[O:12][CH2:11][C@@H:10]([S:13][C:14](=[O:16])[CH3:15])[CH2:9]1)(=O)=O.[N-:19]=[N+:20]=[N-:21].C([N+](CCCC)(CCCC)CCCC)CCC>C(Cl)Cl>[N:19]([CH2:7][C@H:8]1[O:12][CH2:11][C@@H:10]([S:13][C:14](=[O:16])[CH3:15])[CH2:9]1)=[N+:20]=[N-:21]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(=O)S[C@@H]1CO[C@H](COS(=O)(=O)C(F)(F)F)C1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: ClCCl
Product: CC(=O)S[C@@H]1CO[C@H](CN=[N+]=[N-])C1
Yield: 87.8 %

Procedure:
The title compound is prepared by the procedure of Example 43 using 0.560 g of product from Example 60 in 2 ml of methylene chloride, 0.569 g of tetrabutylammonium azide in 2 ml of methylene chloride to give 0.321 g of the desired product.
Reaction SMILES: [C:1]([C:3]1[N:7]([CH3:8])[C:6]([C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[NH:14][C:13](=NC#N)[C:12]23[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)=[CH:5][CH:4]=1)#[N:2].C(NCC)C>C1COCC1>[C:1]([C:3]1[N:7]([CH3:8])[C:6]([C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[N:14]=[CH:13][C:12]23[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)=[CH:5][CH:4]=1)#[N:2]
Reactant: Cn1c(C#N)ccc1-c1ccc2c(c1)C1(CCCCC1)C(=NC#N)N2
Solvent: C1CCOC1
Solvent: CCNCC
Product: Cn1c(C#N)ccc1-c1ccc2c(c1)C1(C=N2)CCCCC1
Temperature: 25 °C
Yield: 69.5 %

Procedure:
Crude 5′-(5-cyano-1-methyl-1H-pyrrol-2-yl)spiro[cyclohexane-1,3′-[3H]indol]-2′-ylidenecyanamide (95.0 g; purity 78% HPLC area) in THF (250 mL) was treated with diethylamine (105 g) and refluxed with a concomitant addition of THF (3.35 L) until dissolved. The solvent was distilled off (2.5 L) during which a precipitate was formed. The flask was cooled to ambient temperature and the white precipitate was filtered, washed with ether and dried to give 58.0 g (61% yield) of purified 5′-(5-cyano-1-methyl-1H-pyrrol-2-yl)spiro[cyclohexane-1,3′-[3H]indol])-2′-ylidenecyanamide (purity>99% HPLC area).
Reaction SMILES: P([O-])([O-])(O[CH:4]1[O:11][C@H:10]([CH2:12][OH:13])[C@@H:8]([OH:9])[C@H:6]([OH:7])[CH2:5]1)=O.[C:16]([NH:19][C@@H:20]1[C@@H:26]([OH:27])[C@H:25]([OH:28])[C@@H:24]([CH2:29][OH:30])[O:23][CH:21]1[OH:22])(=[O:18])[CH3:17].C1C(=O)NC(=O)N([C@@H]2O[C@H](COP(OP(O)(O)=O)(O)=O)[C@@H](O)[C@H]2O)C=1.C(OP(O)(O)=O)[C@H]1O[C@H](OP(O)(O)=O)[C@H](O)[C@@H](O)[C@@H]1O>>[C:16]([NH:19][C@@H:20]1[C@@H:26]([OH:27])[C@H:25]([O:28][C@@H:4]2[O:11][C@H:10]([CH2:12][OH:13])[C@H:8]([OH:9])[C@H:6]([OH:7])[CH2:5]2)[C@@H:24]([CH2:29][OH:30])[O:23][CH:21]1[OH:22])(=[O:18])[CH3:17]
Reactant: O=P([O-])([O-])OC1C[C@@H](O)[C@H](O)[C@@H](CO)O1
Reactant: CC(=O)N[C@H]1C(O)O[C@H](CO)[C@@H](O)[C@@H]1O
Agent: O=P(O)(O)OC[C@H]1O[C@H](OP(=O)(O)O)[C@H](O)[C@@H](O)[C@@H]1O
Agent: O=c1ccn([C@@H]2O[C@H](COP(=O)(O)OP(=O)(O)O)[C@@H](O)[C@H]2O)c(=O)[nH]1
Product: CC(=O)N[C@H]1C(O)O[C@H](CO)[C@@H](O[C@H]2C[C@@H](O)[C@@H](O)[C@@H](CO)O2)[C@@H]1O

Procedure:
2-Deoxyglucose 6-phosphate (2, 60 mg, 190 μmol), N-acetylglucosamine (6, 71 mg, 321 μmol), UDP (2 mg, 5 μmol), PEP (44 mg, 210 μmol), glucose 1, 6-diphosphate (0.1 mg) and bovine serum albumin (BSA, 5 mg) are dissolved in 10 ml of deoxygenated buffer. The enzymes are subsequently added:
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([OH:28])[CH:6]=[CH:7][C:8]=1[C:9]1[N:13]([CH3:14])[C:12]([C:15]([CH3:27])([O:17][C:18]2[C:23]([F:24])=[CH:22][C:21]([F:25])=[CH:20][C:19]=2[F:26])[CH3:16])=[N:11][N:10]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:36][C:37]([NH2:39])=[O:38].O>CN(C=O)C>[ClH:2].[Cl:2][C:3]1[CH:4]=[C:5]([CH:6]=[CH:7][C:8]=1[C:9]1[N:13]([CH3:14])[C:12]([C:15]([CH3:16])([O:17][C:18]2[C:23]([F:24])=[CH:22][C:21]([F:25])=[CH:20][C:19]=2[F:26])[CH3:27])=[N:11][N:10]=1)[O:28][CH2:36][C:37]([NH2:39])=[O:38]
Reactant: NC(=O)CBr
Reactant: Cn1c(-c2ccc(O)cc2Cl)nnc1C(C)(C)Oc1c(F)cc(F)cc1F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cn1c(-c2ccc(OCC(N)=O)cc2Cl)nnc1C(C)(C)Oc1c(F)cc(F)cc1F
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 75.1 %

Procedure:
3-chloro-4-{4-methyl-5-[1-methyl-1-(2,4,6-trifluorophenoxy)ethyl]-4H-1,2,4-triazol-3-yl}phenol monohydrochloride (40 mg) was suspended in DMF (2 ml), potassium carbonate (64 mg) and 2-bromoacetamide (26 mg) were added thereto, followed by stirring at 60° C. for 30 minutes. The reaction solution was cooled to room temperature, water was added thereto, followed by extraction with ethyl acetate. The organic layer was washed with water and saturated brine in this order and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol=100:1 to 100:5). The resulting residue was dissolved in ethyl acetate, 4M hydrogen chloride-ethyl acetate (1 ml) was added thereto and the solvent was evaporated under reduced pressure. The residue was washed with ethyl acetate to obtain 2-(3-chloro-4-{4-methyl-5-[1-methyl-1-(2,4,6-trifluorophenoxy)ethyl]-4H-1,2,4-triazol-3-yl}phenoxy}acetamide monohydrochloride (17 mg), as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:17]([OH:19])=O)[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN1CCOCC1.ClC(OCC(C)C)=O.[NH2:35][CH:36]1[CH:43]2[CH2:44][CH:39]3[CH2:40][CH:41]([CH2:45][CH:37]1[CH2:38]3)[CH2:42]2>ClCCl>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:17]([NH:35][CH:36]1[CH:37]2[CH2:45][CH:41]3[CH2:40][CH:39]([CH2:44][CH:43]1[CH2:42]3)[CH2:38]2)=[O:19])[CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Reactant: NC1C2CC3CC(C2)CC1C3
Agent: CC(C)COC(=O)Cl
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)NC1C2CC3CC(C2)CC1C3
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a cold (ca. -78°) solution of 106 g (0.4 mole) of t-butoxycarbonyl-L-phenylalanine (Boc-Phe) and 88 ml (ca. 0.8 mole) of N-methylmorpholine in 300 ml of dichloromethane, stirred over 30 g of 4 A molecular sieves, was added dropwise 52.4 ml (ca. 0.4 mole) of isobutyl chloroformate. The mixture was allowed to warm slowly to 5° and then recooled to about -78°. After adding 75 g (0.4 mole) of 2-aminoadamantane, the mixture was allowed to warm to room temperature and to stir overnight. The mixture was clarified by filtration and washed with several portions of 0.5M sodium bisulfate. The organic layer was heated at reflux over activated charcoal, filtered, dried over sodium sulfate, and concentrate in vacuo to dryness. The resultant title compound was used without further purification in subsequent reactions.
Reaction SMILES: [N:1]1[CH:6]=[C:5]([C:7]([NH:9][C:10]2([C:13]([OH:15])=O)[CH2:12][CH2:11]2)=[O:8])[CH:4]=[N:3][CH:2]=1.[Cl:16][C:17]1[CH:32]=[CH:31][C:20]([O:21][C:22]2[CH:27]=[CH:26][C:25]([CH:28]([NH2:30])[CH3:29])=[CH:24][CH:23]=2)=[C:19]([F:33])[CH:18]=1>>[Cl:16][C:17]1[CH:32]=[CH:31][C:20]([O:21][C:22]2[CH:23]=[CH:24][C:25]([CH:28]([NH:30][C:13]([C:10]3([NH:9][C:7]([C:5]4[CH:4]=[N:3][CH:2]=[N:1][CH:6]=4)=[O:8])[CH2:11][CH2:12]3)=[O:15])[CH3:29])=[CH:26][CH:27]=2)=[C:19]([F:33])[CH:18]=1
Reactant: CC(N)c1ccc(Oc2ccc(Cl)cc2F)cc1
Reactant: O=C(NC1(C(=O)O)CC1)c1cncnc1
Product: CC(NC(=O)C1(NC(=O)c2cncnc2)CC1)c1ccc(Oc2ccc(Cl)cc2F)cc1
Yield: 29 %

Procedure:
Analogously to Example (1e) the title compound was prepared from 1-[(pyrimidine-5-carbonyl)-amino]-cyclopropanecarboxylic acid and 1-[4-(4-chloro-2-fluoro-phenoxy)-phenyl]-ethylamine.
Reaction SMILES: [O-]CC.[Na+].[Na].[C:6]([OH:9])(=O)C.[Cl:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17]1[CH:18]=[C:19]([NH:22][C:23](=[NH:25])[CH3:24])[NH:20][N:21]=1.C(OC(=O)OCC)C>C(O)C>[Cl:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17]1[CH:18]=[C:19]2[N:22]=[C:23]([CH3:24])[NH:25][C:6](=[O:9])[N:20]2[N:21]=1
Reactant: CC(=O)O
Reactant: CC(=N)Nc1cc(-c2ccccc2Cl)n[nH]1
Agent: CC[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CCO
Solvent: CCOC(=O)OCC
Product: Cc1nc2cc(-c3ccccc3Cl)nn2c(=O)[nH]1
Temperature: 25 °C
Yield: 84.3 %

Procedure:
To an ethanolic solution of sodium ethoxide, generated by portionwise addition of sodium metal (10.5 g, 455 mmol) to stirred ethanol (450 ml), was added N-[5-(2-chlorophenyl)-2H-pyrazol-3-yl]-acetamidine, acetate salt (I-1A-1b; 13.4 g, 45.5 mmol) in one portion. Diethylcarbonate (44.1 ml, 364 mmol) was added, dropwise, and the mixture was heated to reflux, overnight. After cooling to room temperature, the reaction was concentrated, in vacuo, and then extracted with ethyl acetate from water, adjusted to pH 6 with 3 M aqueous HCL. The combined organic layers were washed with brine, dried (MgSO4), filtered, and then concentrated, in vacuo, to afford the crude product as an off-white solid (11.0 g). The solids were triturated from ethyl acetate (100 ml), the supernate was decanted away, the solids were washed with additional ethyl acetate (100 ml) and then dried, in vacuo, to afford I-1A-1c as a colorless solid (10.0 g, 84%): +APcI MS (M+1) 261.2; 1H NMR (400 MHz, CD3OD) δ 7.84-7.81 (m, 1H), 7.54-7.51 (m, 1H), 7.44-7.38 (m, 2H), 6.77 (s, 1H), 2.42 (s, 3H).
Reaction SMILES: [CH3:1][S:2][C:3]1[NH:4][CH2:5][CH2:6][N:7]=1.I.[CH2:9]([N:11](CC)CC)[CH3:10].C([O:18][C:19](Cl)=[O:20])C>C(Cl)Cl>[CH3:1][S:2][C:3]1[NH:7][CH2:6][CH2:5][N:4]=1.[CH2:9]([NH:11][C:19](=[O:20])[O-:18])[CH3:10]
Reactant: CCOC(=O)Cl
Reactant: CCN(CC)CC
Agent: CSC1=NCCN1
Agent: I
Solvent: ClCCl
Product: CCNC(=O)[O-]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 2-methylthio-2-imidazoline.HI (Aldrich) (10 g, 0.041 mole) and triethylamine (8.3 g, 0.0082 mole) in CH2Cl2 (50 mL) was added ethylchloroformate (Aldrich) (4.5 g, 0.041 mole) dropwise at ice bath temperature. The reaction was stirred overnight at room temperature. The precipitate was filtered and washed with CH2Cl2. The CH2Cl2 from the filtrate was washed with H2O (3×), dried over MgSO4 and removed under vacuum to yield 2-methylthio-2-imidazoline-N-ethylcarbamate (7.1 g) as a clear yellow oil.
Reaction SMILES: [NH2:1]/[C:2](/[CH3:11])=[C:3](/[CH2:9][CH3:10])\[C:4]([O:6][CH2:7][CH3:8])=[O:5].C(N(C(C)C)CC)(C)C.Cl[C:22](=[O:29])[CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25].C(=O)(O)[O-].[Na+]>C1COCC1>[CH2:27]([O:26][C:24](=[O:25])[CH2:23][C:22]([NH:1]/[C:2](/[CH3:11])=[C:3](/[CH2:9][CH3:10])\[C:4]([O:6][CH2:7][CH3:8])=[O:5])=[O:29])[CH3:28]
Reactant: CCOC(=O)CC(=O)Cl
Reactant: CCOC(=O)/C(CC)=C(/C)N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)CC(=O)N/C(C)=C(/CC)C(=O)OCC
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.6 %

Procedure:
A 100-mL round bottom flask was charged with ethyl (Z)-3-amino-2-ethyl-but-2-enoate (880 mg, 5.6 mmol, 1 eq.), diisopropylethylamine (750 mg, 5.8 mmol, 1.04 eq.) and THF (10 ml). To the mixture was added ethyl 3-chloro-3-oxo-propanoate (840 mg, 5.6 mmol, 1 eq.) dropwise by a syringe at 0° C. After the addition was complete, the resulting mixture was stirred at room temperature overnight and then added to aqueous sodium bicarbonate solution. The mixture was extracted with ethyl acetate (3×15 ml). The combined organic layer was dried over anhydrous Na2SO4. Removal of solvent gave the crude product ethyl (Z)-3-[(3-ethoxy-3-oxo-propanoyl)amino]-2-ethyl-but-2-enoate as yellow oil (1.3 g, 86% yield).
Reaction SMILES: [C:1]1(=[O:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:8][C@H:9]1[O:14][C@@H:13]([O:15][C@@H:16]2[CH2:32][C@:31]3([OH:33])[C@@:19]([CH:42]=[O:43])([C@@H:20]4[C@@H:28]([CH2:29][CH2:30]3)[C@:27]3([OH:34])[C@@:23]([CH3:41])([C@@H:24]([C:35]5[CH2:40][O:39][C:37](=[O:38])[CH:36]=5)[CH2:25][CH2:26]3)[CH2:22][CH2:21]4)[CH2:18][CH2:17]2)[CH2:12][C@H:11]([OH:44])[C@@H:10]1[OH:45].[BH4-].[Na+].S(=O)(=O)(O)O>O1CCOCC1>[C:1]1(=[O:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:8][CH:9]1[O:14][CH:13]([O:15][CH:16]2[CH2:32][C:31]3([OH:33])[C:19]([CH2:42][OH:43])([CH:20]4[CH:28]([CH2:29][CH2:30]3)[C:27]3([OH:34])[C:23]([CH3:41])([CH:24]([C:35]5[CH2:40][O:39][C:37](=[O:38])[CH:36]=5)[CH2:25][CH2:26]3)[CH2:22][CH2:21]4)[CH2:18][CH2:17]2)[CH2:12][CH:11]([OH:44])[CH:10]1[OH:45]
Reactant: C[C@H]1O[C@@H](O[C@H]2CC[C@]3(C=O)[C@H]4CC[C@]5(C)[C@@H](C6=CC(=O)OC6)CC[C@]5(O)[C@@H]4CC[C@]3(O)C2)C[C@H](O)[C@@H]1O
Agent: O=S(=O)(O)O
Agent: [BH4-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O=C1CCCCC1
Product: CC1OC(OC2CCC3(CO)C4CCC5(C)C(C6=CC(=O)OC6)CCC5(O)C4CCC3(O)C2)CC(O)C1O
Reaction time: 1 h

Procedure:
1.5 g. cyclohexanone-helveticoside are dissolved in 20 ml. of 80% aqueous dioxane and treated dropwise over a period of 1 hour with a solution of 0.35 g. sodium borohydride in 20 ml. of 75% dioxane. The reaction mixture is stirred for 1 hour, after which no more cyclohexanone-helveticoside can be detected. The solution is adjusted to pH 7 with dilute sulfuric acid, and the dioxane is evaporated under reduced pressure in a rotating evaporator. The aqueous phase is extracted repeatedly with chloroform. The combined chloroform extracts are dried over anhydrous sodium sulfate and evaporated. The residue is purified chromatographically over silica gel, using chloroform as solvent. Yield: 750 mg. cyclohexanone-helveticosol. Melting point: 155°-164°C;[α D20 ] (C = 1, chloroform) : +23°.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:16]([CH3:17])=[CH:15][C:12]([CH:13]=[O:14])=[CH:11][C:10]=1[CH2:18][CH3:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O-:20][Mn](=O)(=O)=O.[K+]>CC(C)=O>[CH2:1]([O:8][C:9]1[C:16]([CH3:17])=[CH:15][C:12]([C:13]([OH:20])=[O:14])=[CH:11][C:10]=1[CH2:18][CH3:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCc1cc(C=O)cc(C)c1OCc1ccccc1
Reactant: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCc1cc(C(=O)O)cc(C)c1OCc1ccccc1
Temperature: 45 °C
Reaction time: 16 h
Yield: 72.3 %

Procedure:
To a solution of 4-benzyloxy-3-ethyl-5-methyl-benzaldehyde (25.0 g, 98.3 mmol) in acetone (500 mL), KMnO4 (20.2 g, 127.8 mmol) is added. The mixture becomes warm (45° C.). The mixture is stirred at rt for 16 h before it is filtered over glass filters. The clear, colourless filtrate is concentrated, diluted with water and acidified with 2N aq. HCl, then extracted twice with EA. The combined org. extracts are dried over MgSO4, filtered, concentrated and dried to give 4-benzyloxy-3-ethyl-5-methyl-benzoic acid as a pale yellow solid (19.2 g). LC-MS: tR=1.00 min; 1H NMR (D6-DMSO): δ 1.13-1.22 (m, 3H), 2.32 (s, 3H), 2.64-2.72 (m, 2H), 4.87 (s, 2H), 7.34-7.56 (m, 5H), 7.69 (m, 2H), 12.66 (br s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2N(C)C(=O)[CH2:9][N:8]=[C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:6]=2[CH:20]=1.[CH3:21][O:22][C:23](=[O:26])OC>>[CH3:21][O:22][C:23]([C:9]1[NH:8][C:7]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[C:6]2[C:5]=1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:20]2)=[O:26]
Reactant: COC(=O)OC
Reactant: CN1C(=O)CN=C(c2ccccc2)c2cc(Cl)ccc21
Product: COC(=O)c1[nH]c(-c2ccccc2)c2cc(Cl)ccc12

Procedure:
The starting material can be prepared from 7-chloro-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one and dimethylcarbonate in a manner analogous to that described in Example 1. After recrystallization from acetone, there is obtained 5-chloro-3-phenylisoindole-1-carboxylic acid methyl ester; melting point 208°-210° C. (decomposition).
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]1([CH2:22][O:21][C:20]3[CH:23]=[C:24]4[C:28](=[CH:29][C:19]1=3)[CH2:27][CH2:26][O:25]4)[C:5](=[O:18])[N:6]2[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1.BrC1C=CC=C2C=1[C:33]1([C:49]3=CC4OCOC=4C=[C:48]3[O:47][CH2:46]1)C(=O)N2CCCCC.O1C=CC(B(O)O)=C1.CN(C)C1N=CC(B(O)O)=CC=1>>[O:47]1[CH:48]=[CH:49][C:33]([C:2]2[CH:10]=[CH:9][CH:8]=[C:7]3[C:3]=2[C:4]2([CH2:22][O:21][C:20]4[CH:23]=[C:24]5[C:28](=[CH:29][C:19]2=4)[CH2:27][CH2:26][O:25]5)[C:5](=[O:18])[N:6]3[CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)=[CH:46]1
Reactant: CCCCCN1C(=O)C2(COc3cc4c(cc32)OCO4)c2c(Br)cccc21
Reactant: O=C1N(Cc2ccccn2)c2cccc(Br)c2C12COc1cc3c(cc12)CCO3
Agent: CN(C)c1ccc(B(O)O)cn1
Agent: OB(O)c1ccoc1
Product: O=C1N(Cc2ccccn2)c2cccc(-c3ccoc3)c2C12COc1cc3c(cc12)CCO3

Procedure:
Following the procedure as described in EXAMPLE 4, and making non-critical variations using 4′-bromo-1′-(pyridin-2-ylmethyl)-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one to replace 4′-bromo-1′-pentylspiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one, and 3-furanboronic acid to replace [6-(dimethylamino)pyridin-3-yl]boronic acid, the title compound was obtained (75%) as a colorless solid: mp 195-197° C.; 1H NMR (300 MHz, CDCl3) δ 8.58 (d, 1H), 7.68 (t, 1H), 7.32-7.21 (m, 4H), 6.97 (d, 1H), 6.92 (d, 1H), 6.77 (s, 1H), 6.60 (s, 1H), 6.35 (s, 1H), 5.99 (s, 1H), 5.12 (ABq, 2H), 4.71 (ABq, 2H), 4.57 (t, 2H), 3.03 (t, 2H); MS (ES+) m/z 437.4 (M+1).
Reaction SMILES: [P:1]([O-:6])([O-:5])([O:3][CH3:4])=[O:2].P([O-])([O-])([O-])=O.[Na].[F:13][C:14]1[C:19]([F:20])=[C:18]([C:21]([F:24])([F:23])[F:22])[CH:17]=[CH:16][C:15]=1[C:25]1[N:26]=[C:27]([NH:30][C:31](=[O:46])[CH2:32][C:33]2[C:41]3[C:40](=[O:42])[N:39]([CH3:43])[C:38](=[O:44])[N:37]([CH3:45])[C:36]=3[S:35][N:34]=2)[S:28][CH:29]=1.P(OCI)(OC(C)(C)C)(OC(C)(C)C)=O>CN(C=O)C>[P:1]([OH:6])([OH:5])([O:3][CH2:4][N:26]1[C:25]([C:15]2[CH:16]=[CH:17][C:18]([C:21]([F:23])([F:24])[F:22])=[C:19]([F:20])[C:14]=2[F:13])=[CH:29][S:28][C:27]1=[N:30][C:31](=[O:46])[CH2:32][C:33]1[C:41]2[C:40](=[O:42])[N:39]([CH3:43])[C:38](=[O:44])[N:37]([CH3:45])[C:36]=2[S:35][N:34]=1)=[O:2]
Reactant: Cn1c(=O)c2c(CC(=O)Nc3nc(-c4ccc(C(F)(F)F)c(F)c4F)cs3)nsc2n(C)c1=O
Reactant: COP(=O)([O-])[O-]
Agent: CC(C)(C)OP(=O)(OCI)OC(C)(C)C
Agent: O=P([O-])([O-])[O-]
Agent: [Na]
Solvent: CN(C)C=O
Product: Cn1c(=O)c2c(CC(=O)N=c3scc(-c4ccc(C(F)(F)F)c(F)c4F)n3COP(=O)(O)O)nsc2n(C)c1=O

Procedure:
Di-tert-butyl 4-[2,3-difluoro-4-(trifluoromethyl)phenyl]-2-{[(5,7-dimethyl-4,6-dioxo-4,5,6,7-tetrahydro[1,2]thiazolo[5,4-d]pyrimidin-3-yl)acetyl]imino}-1,3-thiazol-3(2H)-yl]methyl phosphate: The title compound was prepared according to the general procedure as described in step 2 of method B for the preparation of phosphate derivatives by the reaction of sodium salt of N-{4-[2,3-difluoro-4-(trifluoromethyl)phenyl]-1,3-thiazol-2-yl}-2-(5,7-dimethyl-4,6-dioxo-4,5,6,7-tetrahydro[1,2]thiazolo[5,4-d]pyrimidin-3-yl)acetamide (2.0 g, 3.71 mmol) with freshly prepared di-tert-butyl iodomethyl phosphate (Intermediate 2) (1.948 g, 5.56 mol) in dry DMF (20 ml) to yield 1.035 g of product as a white solid. Alternatively the title compound was also prepared according to the general procedure as described in method A for the preparation of phosphate derivatives by coupling N-{4-[2,3-difluoro-4-(trifluoromethyl)phenyl]-1,3-thiazol-2-yl}-2-(5,7-dimethyl-4,6-dioxo-4,5,6,7-tetrahydro[1,2]thiazolo[5,4-d]pyrimidin-3-yl)acetamide (500 mg, 0.967 mmol) with freshly prepared di-tert-butyl iodomethyl phosphate (Intermediate 2) (1.18 g, 3.38 mmol) in presence of sodium hydride (60% dispersion in mineral oil, 58 mg, 1.45 mmol) in dry DMF (5 ml) to yield 135 mg of product as an off-white solid. 1H NMR (300 MHz, CDCl3): δ 1.46 (s, 18H), 3.36 (s, 3H), 3.57 (s, 3H), 4.66 (s, 2H), 6.38 (s, 2H), 7.40 (t, J=7.8 Hz, 1H), 7.64 (s, 1H), 8.15 (t, J=7.5 Hz, 1H); ESI-MS (m/z) 739.06 (M−H)−.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][CH2:11][NH:12][CH:13]2[CH2:18][CH2:17][C:16]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=3)([N:19]([CH3:21])[CH3:20])[CH2:15][CH2:14]2)=[CH:2]1.[C:28](OC(=O)C)(=[O:30])[CH3:29]>N1C=CC=CC=1>[CH3:21][N:19]([CH3:20])[C:16]1([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=2)[CH2:17][CH2:18][CH:13]([N:12]([CH2:11][CH2:10][C:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[NH:1][CH:2]=2)[C:28](=[O:30])[CH3:29])[CH2:14][CH2:15]1
Reactant: CC(=O)OC(C)=O
Reactant: CN(C)C1(c2ccccn2)CCC(NCCc2c[nH]c3ccccc23)CC1
Solvent: c1ccncc1
Product: CC(=O)N(CCc1c[nH]c2ccccc12)C1CCC(c2ccccn2)(N(C)C)CC1
Temperature: 25 °C
Reaction time: 22 h

Procedure:
N′-[2-(1H-indol-3-yl)ethyl]-N,N-dimethyl-1-pyridin-2-yl cyclohexane-1,4-diamine (250 mg) was dissolved in dry pyridine (5 ml), acetic anhydride (0.64 ml) was added and the mixture was stirred for 22 hours at room temperature. Some ice was added to the reaction mixture and it was then concentrated to low volume. The residue was taken up in 1M sodium hydroxide solution (20 ml) and ethyl acetate (20 ml) and stirred. A white solid was left behind, which could be suction filtered (86 mg). The aqueous phase of the filtrate was extracted with ethyl acetate (2×20 ml). The combined organic extracts were concentrated to low volume after drying. The residue obtained in this way was identical to the solid obtained earlier. Both substances were combined. 219 mg N-(4-dimethylamino-4-pyridin-2-yl cyclohexyl)-N-[2-(1H-indol-3-yl)ethyl] acetamide were obtained (mp 209–210° C.), of which 195 mg were dissolved in 2-butanone (25 ml) with gentle heating to 40° C. and converted into the corresponding dihydrochloride with chlorotrimethyl silane (0.303 ml) (white solid; 219 mg; mp 244–247° C.).
Reaction SMILES: [C:1]1([NH:7][C:8]2[CH:13]=[CH:12][C:11]([C:14]3[CH:26]=[CH:25][C:17]([NH:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[CH:16][CH:15]=3)=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.F[C:28]1[CH:33]=[CH:32][C:31]([N+:34]([O-:36])=[O:35])=[CH:30][CH:29]=1.[F-].[Cs+].O>CS(C)=O>[C:19]1([N:18]([C:28]2[CH:33]=[CH:32][C:31]([N+:34]([O-:36])=[O:35])=[CH:30][CH:29]=2)[C:17]2[CH:25]=[CH:26][C:14]([C:11]3[CH:12]=[CH:13][C:8]([NH:7][C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)=[CH:9][CH:10]=3)=[CH:15][CH:16]=2)[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: c1ccc(Nc2ccc(-c3ccc(Nc4ccccc4)cc3)cc2)cc1
Agent: [Cs+]
Agent: [F-]
Solvent: CS(C)=O
Solvent: O
Product: O=[N+]([O-])c1ccc(N(c2ccccc2)c2ccc(-c3ccc(Nc4ccccc4)cc3)cc2)cc1
Temperature: 100 °C
Reaction time: 24 h

Procedure:
One hundred and twenty (120) ml of DMSO as a solvent was added to 10.0 g of N,N′-diphenylbenzidine (29.7 mmol), 8.38 g of p-fluoronitrobenzene (59.4 mmol), and 4.5 g of cesium fluoride (29.7 mmol), and the mixture was stirred in a nitrogen atmosphere at 100° C. for 24 hours. Following reaction, the mixture was poured with stirring into 2500 ml of cold water to obtain crude crystals of N,N′-diphenyl-N-(4-nitrophenyl)-1,1′-biphenyl-4,4′-diamine (NTPD). Subsequently, the mixture was dried for 12 hours in a vacuum at 60° C.
Reaction SMILES: II.Br[CH2:4][CH2:5][CH:6]([O:9][CH3:10])[O:7][CH3:8].[Cl:11][C:12]1[CH:17]=[C:16]([CH:18]=[O:19])[C:15]([F:20])=[CH:14][N:13]=1.[NH4+].[Cl-]>C1COCC1.O>[Cl:11][C:12]1[CH:17]=[C:16]([CH:18]([OH:19])[CH2:4][CH2:5][CH:6]([O:9][CH3:10])[O:7][CH3:8])[C:15]([F:20])=[CH:14][N:13]=1
Reactant: COC(CCBr)OC
Reactant: O=Cc1cc(Cl)ncc1F
Agent: II
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Product: COC(CCC(O)c1cc(Cl)ncc1F)OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 24.5 %

Procedure:
To a solution of Mg (0.71 g, 30 mmol) in THF (10 mL) are added cat iodine and a solution of 3-bromo-1,1-dimethoxy-propane (3.99 g, 21.57 mmol) in THF (10 mL). The mixture is stirred at room temperature for 2 hours. At −30° C., to a solution of 2-chloro-5-fluoro-pyridine-4-carbaldehyde (2.0 g, 12.54 mmol) in THF (5 mL) is added to the above prepared Grignard reagent. The mixture is stirred at this temperature for 2 hours. Then the reaction mixture is cooled in an ice bath, saturated NH4Cl and water are added and the mixture is extracted with EtOAc. The combined organic layers are washed with brine, dried over Na2SO4, filtered and concentrated down. The crude product is purified by chromatography (EtOAc/hexane: 10%˜40%) to give 1-(2-chloro-5-fluoro-pyridin-4-yl)-4,4-dimethoxy-butan-1-ol (0.81 g, 25%). M/Z=264.13[M+1]