Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4](=[O:30])[CH2:5][N:6]([CH2:20][CH2:21][NH:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[C:7](=[O:19])[CH2:8][CH2:9][N:10]1[CH:18]=[C:16]([CH3:17])[C:14](=[O:15])[NH:13][C:11]1=[O:12])C.[OH-].[Na+]>CO>[C:23]([NH:22][CH2:21][CH2:20][N:6]([C:7](=[O:19])[CH2:8][CH2:9][N:10]1[CH:18]=[C:16]([CH3:17])[C:14](=[O:15])[NH:13][C:11]1=[O:12])[CH2:5][C:4]([OH:30])=[O:3])([O:25][C:26]([CH3:28])([CH3:29])[CH3:27])=[O:24]
Reactant: CCOC(=O)CN(CCNC(=O)OC(C)(C)C)C(=O)CCn1cc(C)c(=O)[nH]c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1cn(CCC(=O)N(CCNC(=O)OC(C)(C)C)CC(=O)O)c(=O)[nH]c1=O
Reaction time: 1 h

Procedure:
N-(N'-BOC-aminoethyl)-N-[(1-thyminyl)propanoyl]glycine ethyl ester (0.83 g, 0.00195 mol) was dissolved in methanol (25 mL). Sodium hydroxide (2M, 25 mL) was added. The solution was stirred for 1 h. The methanol was removed by evaporation in vacuo, and the pH adjusted to 2 with 4M hydrochloric acid at 0° C. The product was isolated by filtration, washed with ether (3×15 mL), and dried over sicapent, in vacuo. Yield: 0.769 g, 99%). M.p. 213° C. (decomp.).
Reaction SMILES: Cl.[NH:2]([C:4]1[CH:9]=[C:8]([C:10]#[N:11])[CH:7]=[CH:6][N:5]=1)[NH2:3].CN(C)/[CH:14]=[CH:15]/[C:16]([C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH3:24])[CH:19]=1)=O>>[CH3:24][C:20]1[CH:19]=[C:18]([C:16]2[N:2]([C:4]3[CH:9]=[C:8]([C:10]#[N:11])[CH:7]=[CH:6][N:5]=3)[N:3]=[CH:14][CH:15]=2)[CH:23]=[CH:22][CH:21]=1
Reactant: N#Cc1ccnc(NN)c1
Reactant: Cc1cccc(C(=O)/C=C/N(C)C)c1
Agent: Cl
Product: Cc1cccc(-c2ccnn2-c2cc(C#N)ccn2)c1

Procedure:
The title compound was prepared in quantitative yield from 2-hydrazinylpyridine-4-carbonitrile hydrochloride salt (PREPARATION 3) and (2E)-3-(dimethylamino)-1-(3-methylphenyl)prop-2-en-1-one according to the procedure for the preparation of Example 12, part B. 1H NMR (400 MHz, CDCl3): δ 2.35 (3H, s), 6.51 (1H, d, J=1.6 Hz), 7.00 (1H, d, J=3.2 Hz), 7.22 (3H, m), 7.38 (1H, dd, J=5.2, 1.2 Hz), 7.77 (1H, d, J=1.6 Hz), 7.92 (1H, s), 8.42 (1H, d, J=4.8 Hz).
Reaction SMILES: [C:1]([NH2:5])([CH3:4])([CH3:3])[CH3:2].[C:6]1([C:12]2[S:16][N:15]=[C:14]3[C:17]([O:19][C:20](=[O:21])[C:13]=23)=[O:18])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>ClCCl>[C:1]([NH:5][C:17]([C:14]1[C:13]([C:20]([OH:21])=[O:19])=[C:12]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[S:16][N:15]=1)=[O:18])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C1OC(=O)c2c1nsc2-c1ccccc1
Reactant: CC(C)(C)N
Solvent: ClCCl
Product: CC(C)(C)NC(=O)c1nsc(-c2ccccc2)c1C(=O)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 49 %

Procedure:
With ice cooling, 0.64 g (8.8 mmol) of tert-butylamine was dripped into 2.0 g (8.7 mmol) of 5-phenyl-isothiazole-3,4-dicarboxylic anhydride in 10 ml of dichloromethane, and the whole was stirred for 3 hours at room temperature. The solution was when evaporated down, 25 ml of water was added, and the solution was acidified to a pH of 2 with 6N HCl and extracted three times, each time with 30 ml of ethyl acetate. The organic phase was washed with 20 ml of saturated sodium chloride solution, dried over magnesium sulfate and evaporated down. The residue was chromatographed on silica gel (developer: ethanol/toluene 2:3). Yield: 49%.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.[S:15]([O-:18])([O-:17])=[O:16].[Na+:19].[Na+].O>CO>[Na+:19].[C:6]1([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:7]=[CH:8][C:3]([CH2:2][S:15]([O-:18])(=[O:17])=[O:16])=[CH:4][CH:5]=1
Reactant: O=S([O-])[O-]
Reactant: BrCc1ccc(-c2ccccc2)cc1
Agent: [Na+]
Solvent: CO
Solvent: O
Product: O=S(=O)([O-])Cc1ccc(-c2ccccc2)cc1
Temperature: 60 °C
Reaction time: 12 h
Yield: 50.4 %

Procedure:
A mixture of 28.69 g of 4-bromomethylbiphenyl and 29.27 g of sodium sulfite in 200 ml of a mixture of water and methanol (1:1) was stirred at 60° C. for 12 hours. After cooling to room temperature, the solvent was removed under reduced pressure and the aqueous residue was extracted twice with 100 ml of ethyl acetate. The aqueous phase was concentrated by rotary evaporation and the solid residue was stirred with 200 ml of isopropanol for 1 hour. After filtration to remove the solid constituents, the filtrate was concentrated by rotary evaporation. This gave the product (15.80 g) with a molecular weight of 270.3 g/mol (C13H11O3S.Na).
Reaction SMILES: [CH3:1][C:2]1[CH2:3][C:4]2[CH:5]=[C:6]3[C:10](=[CH:11][C:12]=2[C:13]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH:9]([Li])[CH2:8][CH2:7]3.[Si:21]([CH3:25])([CH3:24])(Cl)[Cl:22]>C1COCC1>[Cl:22][Si:21]([CH3:25])([CH3:24])[CH:3]1[C:4]2[C:12](=[CH:11][C:10]3[CH2:9][CH2:8][CH2:7][C:6]=3[CH:5]=2)[C:13]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[C:2]1[CH3:1]
Reactant: [Li]C1CCc2cc3c(cc21)C(c1ccccc1)=C(C)C3
Reactant: C[Si](C)(Cl)Cl
Solvent: C1CCOC1
Product: CC1=C(c2ccccc2)c2cc3c(cc2C1[Si](C)(C)Cl)CCC3
Temperature: 22.5 °C
Yield: 96.1 %

Procedure:
(6-Methyl-7-phenyl-1,2,3,5-tetrahydro-s-indacenyl) lithium (17.8305 g, 0.07068 moles) 25 in THF (50 mL) was added dropwise to a solution of Me2SiCl2 (21.3694 g, 0.1656 moles) in THF (100 mL) at 0° C. This mixture was then allowed to stir at 20-25° C. 16 hours. After the reaction period the volatiles were removed and the residue extracted and filtered using hexane. The removal of the hexane resulted in the isolation of the desired product as a viscous yellow oil (23.0231 g, 96.1 percent).
Reaction SMILES: C(OC([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([S:15]([C:18]2[CH:19]=[C:20]3[C:25](=[CH:26][CH:27]=2)[CH:24]=[N:23][CH:22]=[CH:21]3)(=[O:17])=[O:16])[C@@H:10]([CH3:28])[CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O.C(=O)(O)[O-].[Na+]>ClCCl>[CH3:28][C@H:10]1[CH2:9][NH:8][CH2:14][CH2:13][CH2:12][N:11]1[S:15]([C:18]1[CH:19]=[C:20]2[C:25](=[CH:26][CH:27]=1)[CH:24]=[N:23][CH:22]=[CH:21]2)(=[O:17])=[O:16]
Reactant: C[C@H]1CN(C(=O)OC(C)(C)C)CCCN1S(=O)(=O)c1ccc2cnccc2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@H]1CNCCCN1S(=O)(=O)c1ccc2cnccc2c1
Yield: 48.3 %

Procedure:
1.1 g of (S)-6-(4-tert-butoxycarbonyl-2-methyl-1,4-diazepan-1-ylsulfonyl)isoquinoline was dissolved in 50 mL of dichloromethane, and 1.8 mL of trifluoroacetic acid was added dropwise thereto at room temperature and then reacted for 6 hours. The reaction solution was neutralized with a saturated aqueous solution of sodium bicarbonate, followed by extraction with dichloromethane (50 mL×2). The extract was dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated, and the obtained crude product was purified by silica gel column chromatography (dichloromethane:methanol:28% ammonia water=10:1:0.05) to obtain 0.4 g of the compound of interest as a white crystal (48%).
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH:4]([NH:8]C(=O)OC(C)(C)C)[CH2:3]1.[C:16](O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:8][CH:4]1[CH2:5][CH2:6][CH2:7][C:2]([CH3:16])([OH:1])[CH2:3]1
Reactant: O=C(O)C(F)(F)F
Reactant: CC(C)(C)OC(=O)NC1CCCC(O)C1
Solvent: ClCCl
Product: CC1(O)CCCC(N)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of crude tert-butyl (3-hydroxycyclohexyl)carbamate (4.0 g, crude) in DCM (40 mL) was added TFA (20 mL) under cooling in an ice bath. The resulting reaction mixture was stirred at room temperature for 2 h. The mixture was concentrated to give a crude product (3.0 g, crude), which was used in the next step without further purification. MS (ESI) m/z 130.1 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[C:7](C)=[CH:6][CH:5]=[CH:4][C:3]=1[C@H:9]1CCNC[C@H]1O.CC1C(C)=CC=CC=1[C@@H:24]1[CH2:29][CH2:28][NH:27][CH2:26][C@@H:25]1[OH:30].CC1C(C)=CC=CC=1[C@H]1CCNC[C@@H]1[OH:45].CC1C(C)=CC=CC=1[C@@H]1CCNC[C@H]1O>>[CH3:1][C:2]1[C:3]([CH3:9])=[CH:4][CH:5]=[CH:6][C:7]=1[O:45][CH:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH:25]1[OH:30]
Reactant: Cc1cccc([C@@H]2CCNC[C@@H]2O)c1C
Reactant: Cc1cccc([C@H]2CCNC[C@@H]2O)c1C
Reactant: Cc1cccc([C@H]2CCNC[C@H]2O)c1C
Agent: Cc1cccc([C@@H]2CCNC[C@H]2O)c1C
Product: Cc1cccc(OC2CCNCC2O)c1C

Procedure:
Retention times were as follows: (3S,4R)-4-(2,3-dimethylphenyl)-3-hydroxypiperidine, 14.5 minutes; (3R,4S)-4-(2,3-dimethylphenyl)-3-hydroxypiperidine, 16.5 minutes; (3R,4R)-4-(2,3-dimethylphenyl)-3-hydroxypiperidine, 15 minutes; and nM (3S,4S)-4-(2,3-dimethylphenyl)-3-hydroxypiperidine, 17 minutes. The identification of each compound was made by optical rotation.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:18]([NH:20][C:21]2[CH:22]=[C:23]3[C:28](=[CH:29][CH:30]=2)[CH:27]=[N:26][CH:25]=[CH:24]3)=[O:19])[CH2:9][NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:4][CH:3]=1.C(Cl)CCl.[CH3:35][C:36]1([C:39](O)=[O:40])[CH2:38][CH2:37]1>N1C=CC=CC=1.CN(C1C=CN=CC=1)C>[CH3:35][C:36]1([C:39]([O:1][C:2]2[CH:7]=[CH:6][C:5]([CH:8]([CH2:9][NH:10][C:11]([O:12][C:13]([CH3:14])([CH3:16])[CH3:15])=[O:17])[C:18]([NH:20][C:21]3[CH:22]=[C:23]4[C:28](=[CH:29][CH:30]=3)[CH:27]=[N:26][CH:25]=[CH:24]4)=[O:19])=[CH:4][CH:3]=2)=[O:40])[CH2:38][CH2:37]1
Reactant: CC(C)(C)OC(=O)NCC(C(=O)Nc1ccc2cnccc2c1)c1ccc(O)cc1
Reactant: CC1(C(=O)O)CC1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)NCC(C(=O)Nc1ccc2cnccc2c1)c1ccc(OC(=O)C2(C)CC2)cc1
Reaction time: 8 h

Procedure:
To tert-butyl 2-(4-hydroxyphenyl)-3-(isoquinolin-6-ylamino)-3-oxopropylcarbamate (E8) in pyridine was added EDC, DMAP, and 1-methylcyclopropanecarboxylic acid, and the solution was flushed with N2, capped, and stirred overnight. The mixture was poured into EtOAc/NaHCO3(sat) and the aqueous layer was further extracted with EtOAc. The organics were dried (Na2SO4), filtered, and evaporated. Column chromatography 5% MeOH/CH2Cl2 gave pure 4-(3-(tert-butoxycarbonylamino)-1-(isoquinolin-6-ylamino)-1-oxopropan-2-yl)phenyl 1-methylcyclopropanecarboxylate (E11).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[C:13]([OH:15])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].ClC(OCC(C)C)=O.C(N(CC)CC)C.[C:31]([C:33]1[CH:34]=[C:35]([CH:40]=[CH:41][CH:42]=1)[C:36]([NH:38]O)=[NH:37])#[N:32]>C1COCC1.CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[C:13]1[O:15][N:38]=[C:36]([C:35]2[CH:40]=[CH:41][CH:42]=[C:33]([C:31]#[N:32])[CH:34]=2)[N:37]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Reactant: N#Cc1cccc(C(=N)NO)c1
Agent: CC(C)COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC[C@H]1c1nc(-c2cccc(C#N)c2)no1
Temperature: 120 °C
Yield: 44 %

Procedure:
(S)-2-[3-(3-Cyano-phenyl)-[1,2,4]oxadiazol-5-yl]-pyrrolidine-1-carboxylic acid tert-butyl ester (698 mg, 44%) was prepared according to the procedure in Example 25 from (S)-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester (1.00 g, 4.66 mmol) with isobutyl chloroformate (0.64 mL, 4.9 mmol) and triethylamine (1.6 mL, 11.5 mmol) in THF (14 mL). Then 3-cyano-N-hydroxy-benzamidine (753 mg, 4.67 mmol) and DMF (15 mL) were added and the mixture was heated at 120° C. for 18 h.
Reaction SMILES: CI.C(=O)([O-])[O-].[K+].[K+].[CH3:9][C:10]1[C:15]([SH:16])=[CH:14][CH:13]=[CH:12][CH:11]=1.[CH3:17]CCCCC>CN(C=O)C.O>[CH3:9][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=1[S:16][CH3:17]
Reactant: Cc1ccccc1S
Reactant: CCCCCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CI
Solvent: CN(C)C=O
Product: CSc1ccccc1C
Temperature: 50 °C
Reaction time: 4 h

Procedure:
Methyl iodide (0.5 mL, 8.1 mmol) and potassium carbonate (1.1 g, 8.1 mmol) were added to a solution of o-thiocresol (1.0 g, 8.1 mmol) in 10 mL of DMF. The reaction was stirred at 50° C. for 4 hours and poured into hexane and water. The organic layer was separated, dried over magnesium sulfate and concentrated to afford 1.1 g of desired material.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([CH:9]=O)=[CH:7][CH:6]=[CH:5][N:4]=1.[CH3:11][C:12]1[N:13]=[C:14]([CH2:17][C:18]([CH3:20])=O)[S:15][CH:16]=1.[NH2:21]/[C:22](/[CH3:26])=[CH:23]\[C:24]#[N:25]>C(O)(C)C>[CH3:1][O:2][C:3]1[C:8]([CH:9]2[C:17]([C:14]3[S:15][CH:16]=[C:12]([CH3:11])[N:13]=3)=[C:18]([CH3:20])[NH:21][C:22]([CH3:26])=[C:23]2[C:24]#[N:25])=[CH:7][CH:6]=[CH:5][N:4]=1
Reactant: C/C(N)=C/C#N
Reactant: COc1ncccc1C=O
Reactant: CC(=O)Cc1nc(C)cs1
Solvent: CC(C)O
Product: COc1ncccc1C1C(C#N)=C(C)NC(C)=C1c1nc(C)cs1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
150 mg (1.09 mmol) of 2-methoxy-3-pyridinecarboxaldehyde, 170 mg (1.09 mmol) of the compound from example 4A and 90 mg (1.09 mmol) of 3-aminocrotononitrile are dissolved in 4 ml of isopropanol and stirred at the reflux temperature overnight. After cooling to room temperature, the volatile components are removed in a rotary evaporator, and the crude product is taken up in 3 ml of ethyl acetate. The crystallizing solid is removed by filtration. The precipitate obtained in this way is washed with a little diethyl ether. 216 mg (58% of theory) of the title compound are obtained.
Reaction SMILES: F[C:2]1[C:7]([C:8]2[N:16]=[C:15]([CH3:17])[N:14]=[C:13]3[C:9]=2[N:10]=[CH:11][N:12]3C2CCCCO2)=[CH:6][C:5]([CH2:24][O:25][CH2:26][C:27]2[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=2)=[CH:4][N:3]=1.[NH2:35][C:36]1[CH:44]=[CH:43][CH:42]=[C:41]2[C:37]=1[CH:38]=[CH:39][NH:40]2.Cl>CCO.CO.N>[CH3:34][O:33][C:30]1[CH:29]=[CH:28][C:27]([CH2:26][O:25][CH2:24][C:5]2[CH:6]=[C:7]([C:8]3[N:16]=[C:15]([CH3:17])[N:14]=[C:13]4[C:9]=3[N:10]=[CH:11][NH:12]4)[C:2]([NH:35][C:36]3[C:37]4[CH:38]=[CH:39][NH:40][C:41]=4[CH:42]=[CH:43][CH:44]=3)=[N:3][CH:4]=2)=[CH:32][CH:31]=1
Reactant: Nc1cccc2[nH]ccc12
Reactant: COc1ccc(COCc2cnc(F)c(-c3nc(C)nc4c3ncn4C3CCCCO3)c2)cc1
Agent: Cl
Agent: N
Solvent: CCO
Solvent: CO
Product: COc1ccc(COCc2cnc(Nc3cccc4[nH]ccc34)c(-c3nc(C)nc4[nH]cnc34)c2)cc1
Temperature: 100 °C
Reaction time: 1.75 h
Yield: 7.2 %

Procedure:
6-(2-Fluoro-5-((4-methoxybenzyloxy)methyl)pyridin-3-yl)-2-methyl-9-(tetrahydro-2H-pyran-2-yl)-9H-purine (171.2 mg, 0.3694 mmol) and 4-aminoindole (Aldrich, St. Louis, Mo., 69.2 mg, 0.524 mmol) were suspended in EtOH (2.0 mL) and hydrochloric acid (J.T. Baker, Phillipsburg, N.J., 5 N, 0.090 mL, 0.45 mmol) was added. The flask was fitted with a reflux condenser and placed in a preheated oil bath (100° C.) and stirred for about 105 minutes. Then, the reaction was cooled to room temperature and diluted with MeOH and 2 N ammonia in MeOH. The reaction was concentrated and treated with DMF and DCM and filtered. The filtrate was filtered again, and the solid was again washed with DCM. This filtrate was concentrated and purified by HPLC (10% to 100% MeCN/water with 0.1% TFA over 30 minutes with a total flow rate of 100 ml/min). The fractions with product were collected, concentrated, and filtered through a silica gel filter (about 1 inch, 10:1 DCM/2 N ammonia in MeOH) to give N-(5-((4-methoxybenzyloxy)methyl)-3-(2-methyl-9H-purin-6-yl)pyridin-2-yl)-1H-indol-4-amine (13.1 mg, 7% yield). MS (ESI pos. ion) m/z 492 (M+H)+. 1H NMR (d6-DMSO, 400 MHz) δ 12.49 (s, 1H), 11.17 (s, 1H), 9.84 (s, 1H), 8.64 (s, 1H), 8.33 (s, 1H), 8.04 (d, J=6.85 Hz, 1H), 7.38-7.32 (m, 3H), 7.12-7.04 (m, 2H), 6.93 (d, J=8.80 Hz, 2H), 6.72 (s, 1H), 4.53 (s, 2H), 4.51 (s, 2H), 3.75 (s, 3H), 2.92 (s, 3H).
Reaction SMILES: [F:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][N:7]([CH2:10][C:11]2[CH:19]=[CH:18][C:14]([C:15](O)=[O:16])=[CH:13][C:12]=2[C:20]([F:23])([F:22])[F:21])[CH2:6][CH2:5]1.[I-].ClC1C=CC=C[N+]=1C.[CH3:33][C:34]1[CH:40]=[CH:39][C:37]([NH2:38])=[CH:36][C:35]=1[NH:41][C:42]1[N:47]=[C:46]([C:48]2[CH:49]=[N:50][CH:51]=[N:52][CH:53]=2)[CH:45]=[CH:44][N:43]=1.C(N(C(C)C)CC)(C)C>CN(C)C=O.O>[F:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][N:7]([CH2:10][C:11]2[CH:19]=[CH:18][C:14]([C:15]([NH:38][C:37]3[CH:39]=[CH:40][C:34]([CH3:33])=[C:35]([NH:41][C:42]4[N:47]=[C:46]([C:48]5[CH:53]=[N:52][CH:51]=[N:50][CH:49]=5)[CH:45]=[CH:44][N:43]=4)[CH:36]=3)=[O:16])=[CH:13][C:12]=2[C:20]([F:23])([F:21])[F:22])[CH2:6][CH2:5]1
Reactant: Cc1ccc(N)cc1Nc1nccc(-c2cncnc2)n1
Reactant: O=C(O)c1ccc(CN2CCN(CCF)CC2)c(C(F)(F)F)c1
Agent: C[n+]1ccccc1Cl
Agent: [I-]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(NC(=O)c2ccc(CN3CCN(CCF)CC3)c(C(F)(F)F)c2)cc1Nc1nccc(-c2cncnc2)n1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 55.2 %

Procedure:
Under an argon atmosphere, 1.71 g of 4-[4-(2-fluoroethyl)piperazin-1-ylmethyl]-3-trifluoromethylbenzoic acid (Reference Example 14) was dissolved in 14 ml of anhydrous N,N-dimethylformamide and 1.56 g of 2-chloro-1-methylpyridinium iodide was added, followed by stirring at room temperature for 10 minutes. 1.50 g of 4-methyl-3-[4-(5-pyrimidinyl)pyrimidin-2-ylamino]aniline (Reference Example 18) and 1.13 ml of N,N-diisopropyl-N-ethylamine were added in turn, followed by stirring at room temperature for 1 hour. 300 ml of water was added to the reaction solution, followed by extraction with ethyl acetate. Two hundred ml of saturated sodium hydrogen carbonate was added to the aqueous layer and the mixture was further extracted with ethyl acetate. The organic layers were combined and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by column chromatography and the crude crystals were washed with diethyl ether-ethyl acetate to obtain 1.68 g of the objective compound as pale yellow crystals.
Reaction SMILES: Br[C:2]1[C:10]([F:11])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][C:6]2=[O:12].[Cu][C:14]#[N:15]>CN(C=O)C>[F:11][C:10]1[CH:9]=[CH:8][C:7]2[C:6](=[O:12])[CH2:5][CH2:4][C:3]=2[C:2]=1[C:14]#[N:15]
Reactant: O=C1CCc2c1ccc(F)c2Br
Reactant: N#C[Cu]
Solvent: CN(C)C=O
Product: N#Cc1c(F)ccc2c1CCC2=O
Temperature: 150 °C

Procedure:
To a flask charged with 4-Bromo-5-fluoro-2,3-dihydro-1H-inden-1-one [made following the procedure described in Intermediate 35, Step B of PCT publication WO 2010/129379) (1.0 g, 4.4 mmol) and a stir bar was added copper(I) cyanide (0.47 g, 5.2 mmol) and DMF (20 ml). The reaction was sealed with a condenser, purged three times with nitrogen, and heated to 150° C. for 16 hours. TLC at that point showed two new spots. The spot right below SM was the title product. LC-MS (IE, m/z): 176 [M+1].
Reaction SMILES: [Cl:1][C:2]([O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[N+:12]([O-])=O)=[CH:3][Cl:4].[H][H].[O-][Si]([O-])=O.[Mg+2]>C(OCC)(=O)C.C(OCC)(=O)C.CCCCCC.[Pd]>[NH2:12][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=1[O:5][C:2]([Cl:1])=[CH:3][Cl:4]
Reactant: [H][H]
Reactant: O=[N+]([O-])c1ccccc1OC(Cl)=CCl
Agent: [Pd]
Agent: O=[Si]([O-])[O-]
Agent: [Mg+2]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: Nc1ccccc1OC(Cl)=CCl
Yield: 89.2 %

Procedure:
Two hundred and eighteen grams of 1,2-dichloro-1-(2-nitrophenoxy)ethene in ethyl acetate with 2.2 g of 10% palladium-on-charcoal was treated with 60 pounds per square inch gauge of hydrogen at 60° until there was no further uptake of hydrogen. The reaction mixture was filtered through Celite® and concentrated in vacuo to yield a brown oil. This oil was taken up in 20% ethyl acetate/hexane and passed through a column of Florisil® two times to yield 169.5 g of oil after evaporation of the solvent.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([CH:8]2[CH2:10][CH2:9]2)[O:6][CH:7]=1.[K].[C:12]1(=[O:22])[NH:16][C:15](=[O:17])[C:14]2=[CH:18][CH:19]=[CH:20][CH:21]=[C:13]12.O>CN(C=O)C>[CH:8]1([C:5]2[O:6][CH:7]=[C:3]([CH2:2][N:16]3[C:12](=[O:22])[C:13]4[C:14](=[CH:18][CH:19]=[CH:20][CH:21]=4)[C:15]3=[O:17])[N:4]=2)[CH2:10][CH2:9]1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: ClCc1coc(C2CC2)n1
Agent: [K]
Solvent: CN(C)C=O
Solvent: O
Product: O=C1c2ccccc2C(=O)N1Cc1coc(C2CC2)n1
Temperature: 25 °C
Reaction time: 24 h
Yield: 51.4 %

Procedure:
To the stirred solution of 4-chloromethyl-2-cyclopropyl-oxazole (4.0 g, 25.38 mmol) in dry DMF (30 mL), was added potassium salt of phthalimide (4.7 g, 25.38 mmol) at rt. The resulting mixture was stirred for 24 h at rt and monitored through TLC. After completion of the reaction, water (200 mL) was added and the crude was extracted with ethyl acetate (3×50 mL). The combined organic layer was washed with brine, dried over anhydrous sodium sulphate and concentrated under reduced pressure to obtained crude residue which was purified via column chromatography (100-200 silica gel, elution with 20% EtOAc in hexane). 3.5 g of 2-(2-cyclopropyl-oxazol-4-ylmethyl)-isoindole-1,3-dione was obtained as a white solid, 269.2 (M+H)+, which contained phthalimide. This compound was used for the next step as such.
Reaction SMILES: [NH2:1][C:2]([CH2:25][OH:26])([CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[CH:13][CH:12]=1)[CH2:3][O:4][P:5](=[O:8])([OH:7])[OH:6].C(N([CH2:43][C:44]([OH:46])=O)CC(O)=O)CN(CC(O)=O)CC(O)=O.B(O)(O)O.Cl>C(O)C>[OH:26][CH2:25][C:2]([N:1]1[CH2:12][C:11]2[C:43](=[CH:3][CH:2]=[CH:9][CH:10]=2)[C:44]1=[O:46])([CH2:9][CH2:10][C:11]1[CH:12]=[CH:13][C:14]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[CH:15][CH:16]=1)[CH2:3][O:4][P:5](=[O:6])([OH:7])[OH:8]
Reactant: CCCCCCCCc1ccc(CCC(N)(CO)COP(=O)(O)O)cc1
Reactant: O=C(O)CN(CCN(CC(=O)O)CC(=O)O)CC(=O)O
Agent: Cl
Agent: OB(O)O
Solvent: CCO
Product: CCCCCCCCc1ccc(CCC(CO)(COP(=O)(O)O)N2Cc3ccccc3C2=O)cc1
Reaction time: 1 h

Procedure:
The endproduct of step d) ((R/S)-FTY720-phosphate) (50 mg; 0.125 mmol) is suspended in a solution of EDTA (0.5 ml; 10 mM in water) and aqueous boric acid (0.5 ml; 3% in water; adjusted to pH 10.5 with aqueous KOH10%). After addition of OPA (33 mg, 0.25 mmol), dissolved in ethanol (0.5 ml), the reaction is kept at RT for 1 hour (ultrasound). After that the pH is adjusted to 3.5 (aqueous HCl; 1N) and extracted with ethylacetate (three times). The organic layer is dried over Na2SO4 and the compound is purified on silica gel using methylenechloride/methanol (95/5→0/100) as mobile phase.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5]([Cl:8])=[CH:6][CH:7]=1.OS(O)(=O)=O.[CH:14]1(C(O)=O)[CH2:18][CH2:17][CH2:16][CH2:15]1>O>[Cl:1][C:2]1[N:3]=[N:4][C:5]([Cl:8])=[CH:6][C:7]=1[CH:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: Clc1ccc(Cl)nn1
Reactant: O=C(O)C1CCCC1
Agent: O=S(=O)(O)O
Solvent: O
Product: Clc1cc(C2CCCC2)c(Cl)nn1
Temperature: 70 °C
Reaction time: 1 h
Yield: 92 %

Procedure:
3,6-Dichloropyridazine (10 g) was suspe n ded in water (200 ml), conc. H2SO4 (19.7 g) and cyclopentane carboxylic acid (32.7 g) was added and the reaction degassed under N2 at 70° C. Silver nitrate (2.28 g) was added followed by dropwise a ddition of ammonium persulfate (45.9 g) in water (120 ml). After ail additional one hour heating at 70° C., the reaction was poured onto ice, basfied to pH 8-9 with aqueous ammonium hydroxide and extracted into ethyl acetate (3×500 ml), dried (MgSO4) and evaporated to dryness. Purified with hexane-ethyl acetate mixtures to obtain pure product (13.4 g). 1H NMR (360 MHz, CDCl3) δ1.57 (2 H, m), 1.82 (4 H, m), 2.20 (1 H, m), 3.30 (1 H, m), 7.38 (1 H, s); MS (ES+) m/e 217 [MH]+.
Reaction SMILES: COC1C=C(OC)C=CC=1C[O:6][N:7]1[C:12](=[O:13])[C:11]2[O:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[C:10]=2[NH:9][C:8]1=[O:21].[Br:28][C:29]1[CH:36]=[CH:35][C:32]([CH2:33]Br)=[CH:31][CH:30]=1>>[Br:28][C:29]1[CH:36]=[CH:35][C:32]([CH2:33][N:9]2[C:10]3[C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=4[O:14][C:11]=3[C:12](=[O:13])[N:7]([OH:6])[C:8]2=[O:21])=[CH:31][CH:30]=1
Reactant: COc1ccc(COn2c(=O)[nH]c3c(oc4ccccc43)c2=O)c(OC)c1
Reactant: BrCc1ccc(Br)cc1
Product: O=c1c2oc3ccccc3c2n(Cc2ccc(Br)cc2)c(=O)n1O

Procedure:
Following general procedure B2 and D1, 3-(2,4-dimethoxy-benzyloxy)-1H-benzo[4,5]furo[3,2-d]pyrimidine-2,4-dione was alkylated with 4-bromobenzyl bromide and subsequently deprotected to provide the title compound as a white solid. 1H NMR (d6-DMSO, 300 MHz) δ 5.52 (s, 2H); 7.29-7.40 (m, 3H); 7.52 (d, J=8 Hz, 2H); 7.60 (dd, J=8 Hz, 1H); 7.75-7.81 (m, 2H); Ret. time=2.70 min., m/z=387.0.