Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([N:11]2[CH2:16][CH2:15][C:14](=[O:17])[N:13]3[CH2:18][CH:19]=[C:20]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[N:21]=[C:12]23)[CH:8]=[CH:7][N:6]=1)(=O)=O.[C:28]([O:32][C:33](=[O:46])[NH:34][CH:35]([C:37]1[CH:42]=[CH:41][C:40]([CH2:43][CH2:44][NH2:45])=[CH:39][CH:38]=1)[CH3:36])([CH3:31])([CH3:30])[CH3:29].O1CCOCC1>CN1CCCC1=O>[C:28]([O:32][C:33](=[O:46])[NH:34][CH:35]([C:37]1[CH:42]=[CH:41][C:40]([CH2:43][CH2:44][NH:45][C:5]2[N:10]=[C:9]([N:11]3[CH2:16][CH2:15][C:14](=[O:17])[N:13]4[CH2:18][CH:19]=[C:20]([C:22]5[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=5)[N:21]=[C:12]34)[CH:8]=[CH:7][N:6]=2)=[CH:39][CH:38]=1)[CH3:36])([CH3:30])([CH3:29])[CH3:31]
Reactant: CS(=O)(=O)c1nccc(N2CCC(=O)N3CC=C(c4ccccc4)N=C32)n1
Reactant: CC(NC(=O)OC(C)(C)C)c1ccc(CCN)cc1
Solvent: CN1CCCC1=O
Solvent: C1COCCO1
Product: CC(NC(=O)OC(C)(C)C)c1ccc(CCNc2nccc(N3CCC(=O)N4CC=C(c5ccccc5)N=C43)n2)cc1

Procedure:
The mixture of 1-(2-methanesulfonyl-pyrimidin-4-yl)-8-phenyl-1,2,3,6-tetrahydro -pyrimido[1,2-a]pyrimidin-4-one (0.20 g, 053 mmol) and {1-[4-(2-amino -ethyl)-phenyl]-ethyl}-carbamic acid tert-butyl ester (0.304 g, 0.79 mmol) in 1:1 dioxane: 1-methyl -2-pyrrolidinone (6 mL) was heated to 100° C. for 17 h. The mixture was partitioned between water (10 mL) and ethyl acetate (20 mL). The organic phase was separated, washed with water, saturated sodium bicarbonate, brine, dried over magnesium sulfate and chromatographed on silica gel using 0-4% MeOH/CH2Cl2to afford a white solid. M+1=568.
Reaction SMILES: [S:1]1[CH2:7][C:5](=[O:6])[NH:4][C:2]1=[S:3].[Cl:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][C:16]=1[Cl:17])[CH:12]=O.C([O-])(=O)C.[Na+]>CO>[Cl:8][C:9]1[CH:10]=[C:11]([CH:12]=[C:7]2[S:1][C:2](=[S:3])[NH:4][C:5]2=[O:6])[CH:14]=[CH:15][C:16]=1[Cl:17]
Reactant: O=Cc1ccc(Cl)c(Cl)c1
Reactant: O=C1CSC(=S)N1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CO
Product: O=C1NC(=S)SC1=Cc1ccc(Cl)c(Cl)c1
Temperature: 65 °C
Reaction time: 1.75 h

Procedure:
A 50 mL flask was charged with 899 mg rhodanine (6.75 mmol, 1.0 equiv), 1.77 g 3,4-dichlorobenzaldehyde (10.1 mmol, 1.5 equiv), 1.66 g sodium acetate (20.25 mmol, 3.0 equiv) and 20 mL methanol. The mixture was heated to 65° C. with stirring for 1.75 h. The yellow solid was then filtered and washed (4×MeOH) to give the product 5-(3,4-dichlorophenylmethylene)-4-oxo-2-thionothiazolidine as a yellow solid (1.059 g 3.67 mmol, 54%).
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.[F:8][C:9]1[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[CH:12]=[C:11]([F:18])[C:10]=1F>>[F:8][C:9]1[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[CH:12]=[C:11]([F:18])[C:10]=1[S:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1cc(F)c(F)c(F)c1
Reactant: Sc1ccncc1
Product: O=[N+]([O-])c1cc(F)c(Sc2ccncc2)c(F)c1

Procedure:
is synthesized analogously to C2 from 4-mercaptopyridine and 1,2,3-trifluoro-5-nitrobenzene.
Reaction SMILES: S1C=CC=C1.[F:6][C:7]1[CH:18]=[CH:17][C:10]2[S:11][CH:12]=[C:13]([CH2:14][C:15]#[N:16])[C:9]=2[CH:8]=1.CO>N.C(Cl)(Cl)Cl.[Ni]>[F:6][C:7]1[CH:18]=[CH:17][C:10]2[S:11][CH:12]=[C:13]([CH2:14][CH2:15][NH2:16])[C:9]=2[CH:8]=1
Reactant: N#CCc1csc2ccc(F)cc12
Agent: [Ni]
Agent: N
Solvent: c1ccsc1
Solvent: ClC(Cl)Cl
Solvent: CO
Product: NCCc1csc2ccc(F)cc12
Temperature: 10 °C
Reaction time: 8 h
Yield: 70 %

Procedure:
Methanolic ammonia solution (15 mL) and thiophene solution (1 mL) were added to Raney Ni (5 g) taken in a reaction flask. This was followed by the addition of (5-Fluoro-benzo[b]thiophen-3-yl)-acetonitrile (I-45b: 700 mg, 3.66 mmol) in methanolic ammonia solution (15 mL) at 0° C. The resulting reaction mass was stirred at 10° C. overnight under hydrogen atmosphere. The reaction was monitored by TLC (5% methanol in chloroform). The reaction mass was filtered, washed with methanol and the filtrate was concentrated under reduced pressure to afford 500 mg of the crude product which was used for the next step without further purification. LCMS: 92.76%, m/z=196.1 (M+1)
Reaction SMILES: [OH:1][B:2]1[C:6]2[CH:7]=[C:8]([OH:12])[CH:9]=[C:10]([CH3:11])[C:5]=2[CH:4]([CH2:13][C:14]([O:16]CC)=[O:15])[O:3]1.[Li+].[OH-].Cl>CO.O>[OH:1][B:2]1[C:6]2[CH:7]=[C:8]([OH:12])[CH:9]=[C:10]([CH3:11])[C:5]=2[CH:4]([CH2:13][C:14]([OH:16])=[O:15])[O:3]1
Reactant: CCOC(=O)CC1OB(O)c2cc(O)cc(C)c21
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1cc(O)cc2c1C(CC(=O)O)OB2O
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of ethyl 2-(1,6-dihydroxy-4-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-3-yl)acetate (300 mg, 1.2 mmol) in MeOH (2 mL) was added LiOH (144 mg, 6 mmol) in 5 ml H2O at 0° C. The reaction mixture was stirred at room temperature for 1.5 h and acidified by 1N HCl to pH=5.0. The resulting mixture was extracted with EtOAc (3×20 mL) and the combined organic layers were dried over anhydrous Na2SO4 and concentrated in vacuo to give a crude product, which was used directly in next step without further purification.
Reaction SMILES: C(OC([NH:11][CH2:12][C:13]([NH:15][C:16]([C:24]([N:26]1[CH2:33][CH2:32][CH2:31][C@H:27]1[C:28]([NH2:30])=[O:29])=[O:25])=[CH:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:14])=O)C1C=CC=CC=1.[BrH:34]>C(O)(=O)C>[BrH:34].[NH2:11][CH2:12][C:13]([NH:15][C:16]([C:24]([N:26]1[CH2:33][CH2:32][CH2:31][C@H:27]1[C:28]([NH2:30])=[O:29])=[O:25])=[CH:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:14]
Reactant: NC(=O)[C@@H]1CCCN1C(=O)C(=Cc1ccccc1)NC(=O)CNC(=O)OCc1ccccc1
Agent: Br
Solvent: CC(=O)O
Product: NCC(=O)NC(=Cc1ccccc1)C(=O)N1CCC[C@H]1C(N)=O

Procedure:
1.3 g of benzyloxycarbonyl-glycyl-dehydrophenylalanyl-prolinamide are dissolved in 6 ml of 30% HBr in glacial acetic acid. After a reaction time of 20 minutes, at room temperature, the product is precipitated with ether, centrifuged and washed several times with ether.
Reaction SMILES: [O:1]=[C:2]1[N:6]=[C:5]([P:7](=[O:14])([O:11][CH2:12][CH3:13])[O:8][CH2:9][CH3:10])[C:4](=[O:15])[NH:3]1.C([O-])([O-])=O.[K+].[K+].I[CH2:23][CH2:24][CH2:25][CH3:26]>CN(C=O)C.C(OCC)(=O)C>[CH2:23]([N:3]1[C:4](=[O:15])[C:5]([P:7](=[O:14])([O:11][CH2:12][CH3:13])[O:8][CH2:9][CH3:10])=[N:6][C:2]1=[O:1])[CH2:24][CH2:25][CH3:26]
Reactant: CCOP(=O)(OCC)C1=NC(=O)NC1=O
Reactant: CCCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCCN1C(=O)N=C(P(=O)(OCC)OCC)C1=O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of diethyl 2,5-dioxo-4-imidazolylphosphonate (6.00 g, 0.025 moles) in DMF (15 mL), under N2, is added K2CO3 (17.5 g, 0.127 moles) and 1-iodobutane (2.9 mL, 0.025 moles). This mixture is stirred at room temperature for 16 hours and then the mixture is filtered and the solid washed with ethyl acetate. The filtrate is concentrated in vacuo, to afford a yellow oil which is redissolved in ethyl acetate and washed with water and brine and then dried over MgSO4. Evaporation of solvents under high vacuum affords the required product as a viscous yellow oil which solidifies on standing.
Reaction SMILES: C(NCC)C.[C:6]([OH:12])(=[O:11])[CH2:7][CH2:8][C:9]#[CH:10].[I:13][C:14]1[S:15][CH:16]=[C:17](I)[CH:18]=1>>[I:13][C:14]1[S:15][C:16]([C:10]#[C:9][CH2:8][CH2:7][C:6]([OH:12])=[O:11])=[CH:17][CH:18]=1
Reactant: C#CCCC(=O)O
Reactant: Ic1csc(I)c1
Solvent: CCNCC
Product: O=C(O)CCC#Cc1ccc(I)s1
Reaction time: 8 h
Yield: 29.8 %

Procedure:
To 75 ml of diethylamine was added with stirring 3.76 g of 4-pentynoic acid, 22 g of 2,4-diiodothiophene, and 300 mg of tetrakis-(triphenylphosphine)palladium(o). The slurry was degassed with argon and 960 mg of CuI was added. The slurry was maintained under argon and allowed to stir overnight, producing a dark brown solution. Thereafter, the solvent was removed under reduced pressure and 100 ml of 10% HCl was added to the residue. The residue was filtered and then extracted 3 x with ethyl acetate. The combined extracts were washed 1 x with water, dried over anhydrous MgSO4, filtered, and stripped. The resulting residue was flash chromatographed on a column of silica gel. Elution with a mixture of 30/70/2 parts ethyl acetate/hexane/acetic acid produced 3.5 g of the titled product as a yellow solid.
Reaction SMILES: [CH3:1][C@@H:2]1[NH:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[NH:5][C:4](=[O:13])[C@H:3]1[NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18].N1C=CC=CC=1.[O:28]1[CH2:33][CH2:32][CH:31]([C:34](Cl)=[O:35])[CH2:30][CH2:29]1>C(Cl)Cl>[CH3:1][C@@H:2]1[N:8]([C:34]([CH:31]2[CH2:32][CH2:33][O:28][CH2:29][CH2:30]2)=[O:35])[C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[NH:5][C:4](=[O:13])[C@H:3]1[NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18]
Reactant: C[C@@H]1Nc2ccccc2NC(=O)[C@H]1NC(=O)OC(C)(C)C
Reactant: O=C(Cl)C1CCOCC1
Solvent: c1ccncc1
Solvent: ClCCl
Product: C[C@H]1[C@H](NC(=O)OC(C)(C)C)C(=O)Nc2ccccc2N1C(=O)C1CCOCC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 46.1 %

Procedure:
To a 0° C. solution of tert-butyl(2S,3S)-2-methyl-4-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-ylcarbamate (prepared as in Example 1, 330 mg, 1.13 mmol) in methylene chloride (10 ml) was added pyridine (277 μl, 3.4 mmol) and tetrahydro-2H-pyran-4-carbonyl chloride (185 mg, 1.25 mmol). It was stirred at 0° C. for one hour and then warmed to room temperature and stirred overnight. After this time another portion of tetrahydro-2H-pyran-4-carbonyl chloride (252 mg, 1.70 mmol) was added and the reaction mixture was stirred at room temperature another 3 h. After this time the reaction mixture was diluted with methylene chloride (30 mL), washed with a saturated aqueous sodium bicarbonate solution (30 mL), and saturate aqueous sodium chloride solution (30 mL), the organic layer was then dried over sodium sulfate, filtered to remove the drying agent, and concentrated in vacuo. The crude material was then purified on an Intelliflash 280 system (12 g silica gel column, 20-65% ethyl acetatehexanes) to afford tert-butyl(2S,3S)-2-methyl-4-oxo-1-(tetrahydro-2H-pyran-4-carbonyl)-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-ylcarbamate (210 mg, 46%) as a white foam: LC-MS m/z 426 [M+Na]+.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.[NH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1.CC([O-])(C)C.[Na+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:9][O:8][C:5]1[CH:6]=[CH:7][C:2]([N:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)=[CH:3][CH:4]=1
Reactant: C1CCNCC1
Reactant: COc1ccc(Cl)cc1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: COc1ccc(N2CCCCC2)cc1
Reaction time: 12 h
Yield: 66.9 %

Procedure:
The general procedure from Example 1 was followed using 4-chloroanisole (171 mg, 1.2 mmol) and piperidine (100 μl, 1.0 mmol) with Pd2(dba)3 (20 mg, 0.0218 mmol) and (Me3C)2PH(O) (14.5 mg, 0.0878 mmol) and NaOtBu (144 mg, 1.5 mmol) in 4.0 mL of toluene. After 12 h, the reaction mixture was chromatographed with 5% ethyl acetate/hexane to give 128 mg (67% yield) of N-(4-methoxyphenyl)piperidine. It was >95% pure by 1H NMR and GC/MS. 1H NMR (500 MHz, CDCl3): δ 6.81 (d, J=9.11 Hz, 2H), 6.72 (d, J=9.11 Hz, 2H), 3.65 (s, 3H), 2.92 (t, J=5.46 Hz, 4H), 1.60 (m, 4H), 1.46 (m, 2H) ppm. 13C NMR (125 MHz, CDCl3): δ 153.5, 146.8, 118.6, 114.3, 55.4, 52.2, 26.1, 24.1 ppm.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11](=[O:14])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:15][Li]>>[CH2:1]([N:8]1[CH2:13][CH2:12][C:11]([CH3:15])([OH:14])[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: [Li]C
Reactant: O=C1CCN(Cc2ccccc2)CC1
Product: CC1(O)CCN(Cc2ccccc2)CC1

Procedure:
1-Benzyl-piperidin-4-one was reacted with methyllithium according to Method AI and the 1-benzyl-4-methyl-piperidin-4-ol obtained was hydrogenated in debenzylating conditions according to Method AH. In this way the product was obtained with molecular weight 115.1 (C6H13NO); MS (ESI): 116 (M+H+).
Reaction SMILES: [CH2:1]([N:8]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[OH:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:17]([N:35]1[C:39](=[O:40])[CH:38]=[CH:37][C:36]1=[O:41])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34]>>[CH2:17]([N:35]1[C:36](=[O:41])[CH2:37][CH:38]([O:9][N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:39]1=[O:40])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34]
Reactant: ON(Cc1ccccc1)Cc1ccccc1
Reactant: CCCCCCCCCCCCCCCCCCN1C(=O)C=CC1=O
Product: CCCCCCCCCCCCCCCCCCN1C(=O)CC(ON(Cc2ccccc2)Cc2ccccc2)C1=O

Procedure:
The procedure of Example 1 is repeated using 6.10 g (29 mmole) of N,N-dibenzylhydroxylamine and 10.0 g (29 mmole) of N-n-octadecylmaleimide. The residue is purified by preparative HPLC (Silica gel: 9:1 heptane:ethyl acetate eluent) to give 8.0 g (49%) of a waxy solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[S:10]C(=O)[C:12](=[O:14])[N:13]=1.[Cl:16][C:17]1[CH:18]=[C:19]([CH:21]=[CH:22][C:23]=1[Cl:24])[NH2:20]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]([NH:13][C:12]([NH:20][C:19]1[CH:21]=[CH:22][C:23]([Cl:24])=[C:17]([Cl:16])[CH:18]=1)=[O:14])=[S:10]
Reactant: Nc1ccc(Cl)c(Cl)c1
Reactant: O=C1N=C(c2c(Cl)cccc2Cl)SC1=O
Solvent: Cc1ccccc1
Product: O=C(NC(=S)c1c(Cl)cccc1Cl)Nc1ccc(Cl)c(Cl)c1
Temperature: 90 °C

Procedure:
26.0 g of 2-(2,6-dichlorophenyl)-thiazoline-4,5-dione are suspended in 250 ml of dry toluene and heated to 90° C. while stirring. Gas is evolved and a violet solution is obtained, to which is added 16.2 g of 3,4-dichloroaniline dissolved in 30 ml of toluene. After stirring for 15 minutes the solution is cooled and the precipitate obtained is drawn off. Yield 20.1 g. Melting point 168° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]1[O:10][CH2:11][C:12](=[O:19])[C:13]=1[C:14]([O:16][CH2:17][CH3:18])=[O:15].[NH:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][N:27]=2)[C:22]([CH:29]=O)=[CH:21]1.N1CCCCC1>C(O)C>[NH:20]1[C:28]2=[N:27][CH:26]=[CH:25][CH:24]=[C:23]2[C:22]([CH:29]=[C:11]2[O:10][C:9]([NH:8][C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[OH:1])=[C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:12]2=[O:19])=[CH:21]1
Reactant: CCOC(=O)C1=C(Nc2ccccc2O)OCC1=O
Reactant: O=Cc1c[nH]c2ncccc12
Solvent: C1CCNCC1
Solvent: CCO
Product: CCOC(=O)C1=C(Nc2ccccc2O)OC(=Cc2c[nH]c3ncccc23)C1=O
Yield: 12.8 %

Procedure:
To a solution of ethyl 2-[(2-hydroxyphenyl)amino]-4-oxo-4,5-dihydrofuran-3-carboxylate (0.050 g, 0.19 mmol) which similarly prepared according to the procedure described in the Example 4 and 7-azaindole-3-carboxaldehyde (0.023 g, 0.16 mmol) in ethanol (1.0 mL), piperidine (0.0010 mL, 0.010 mmol) was added at ambient temperature. The mixture was refluxed for 2 days. The precipitate was collected by filtration, washed with hot ethanol. The solid was washed hexane then dried to afford the titled compound (0.008 g, y. 11%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19]([OH:25])[CH:20]=[CH:21][C:22]=4[F:24])[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1.Cl[C:28]1[N:33]=[CH:32][C:31]([F:34])=[CH:30][N:29]=1>>[CH3:1][O:2][C:3](=[O:26])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19]([O:25][C:28]5[N:33]=[CH:32][C:31]([F:34])=[CH:30][N:29]=5)[CH:20]=[CH:21][C:22]=4[F:24])[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(O)ccc(F)c43)ccc21
Reactant: Fc1cnc(Cl)nc1
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(Oc5ncc(F)cn5)ccc(F)c43)ccc21

Procedure:
The title compound is prepared from {(S)-6-[(R)-7-fluoro-4-hydroxy-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester and 2-chloro-5-fluoro-pyrimidine following a procedure analogous to that described for Intermediate 12. LC (method 2): tR=1.03 min; Mass spectrum (ESI+): m/z=455 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)[N:9]2[CH2:14][CH2:13][NH:12][CH:11]([CH3:15])[CH2:10]2)=[CH:4][CH:3]=1.[CH3:23][C:24]1[CH:29]=[C:28]([CH3:30])[CH:27]=[C:26]([CH3:31])[C:25]=1[NH:32][C:33](=[O:36])[CH2:34]Cl.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>O1CCCC1.CN(C)C=O>[F:22][C:19]1[CH:18]=[CH:17][C:16]([CH:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[N:9]2[CH2:14][CH2:13][N:12]([CH2:34][C:33](=[O:36])[NH:32][C:25]3[C:24]([CH3:23])=[CH:29][C:28]([CH3:30])=[CH:27][C:26]=3[CH3:31])[CH:11]([CH3:15])[CH2:10]2)=[CH:21][CH:20]=1
Reactant: Cc1cc(C)c(NC(=O)CCl)c(C)c1
Reactant: CC1CN(C(c2ccc(F)cc2)c2ccc(F)cc2)CCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1cc(C)c(NC(=O)CN2CCN(C(c3ccc(F)cc3)c3ccc(F)cc3)CC2C)c(C)c1
Temperature: 70 °C
Reaction time: 3 h

Procedure:
A mixture of 300 mg of 1-[bis(4-fluorophenyl)methyl]-3-methylpiperazine and 252 mg of N-(2,4,6-trimethylphenyl) chloroacetamide was dissolved in 20 ml of a 1:1 by volume mixture of tetrahydrofuran and N,N-dimethylformamide. 100 mg of anhydrous potassium carbonate were then added to the solution, and the reaction mixture was stirred at 70° C. for 3 hours, after which ethyl acetate was added to it and the organic layer was separated. The organic layer was washed three times with water, and then dried over anhydrous magnesium sulfate. The solvent was then removed by evaporation under reduced pressure, and the residue was subjected to silica gel thin layer chromatography using a 1:1 by volume mixture of cyclohexane and ethyl acetate as the developing solvent, to afford a purified 1-[bis(4-fluorophenyl)methyl]-4-[(2,4,6-trimethylphenyl)carbamoylmethyl]-3-methylpiperazine.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[C:4](=[O:18])[NH:5][C:6](=[O:17])[N:7]([CH:16]=1)[C@@H:8]1[O:15][C@H:12]([CH2:13][OH:14])[C@@H:10]([OH:11])[CH2:9]1.C(N(CC)CC)C.[C:28](Cl)(=[O:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>CC(N(C)C)=O>[C:28]([N:5]1[C:4](=[O:18])[C:3]([C:2]([F:1])([F:19])[F:20])=[CH:16][N:7]([C@@H:8]2[O:15][C@H:12]([CH2:13][OH:14])[C@@H:10]([OH:11])[CH2:9]2)[C:6]1=[O:17])(=[O:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: O=c1[nH]c(=O)n([C@H]2C[C@H](O)[C@@H](CO)O2)cc1C(F)(F)F
Solvent: CC(=O)N(C)C
Solvent: CCN(CC)CC
Product: O=C(c1ccccc1)n1c(=O)c(C(F)(F)F)cn([C@H]2C[C@H](O)[C@@H](CO)O2)c1=O
Temperature: 0 °C
Reaction time: 8 h

Procedure:
12 grams of 2'-deoxy-5-trifluoromethyluridine was dissolved in 30 ml of dimethylacetamide. Thereto was added 8 ml of triethylamine, and further to the mixture being cooled with ice-water was added 5.6 g of benzoyl chloride. The whole mixture was stirred overnight. The reaction mixture was subjected to filtration, the resulting filtrate was subjected to evaporation and the residue was dissolved in ether. To the ether solution being stirred was slowly added water. The resulting precipitate was collected by filtration. The precipitate collected was recrystallized from ether-petroleum ether. The yield was 8.0 g. M.p. 144.5° to 146° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:28])[CH2:7][O:8][CH2:9][CH2:10][C:11]12[CH2:18][CH2:17][C:14]([C:19]3[CH:20]=[C:21](B(O)O)[CH:22]=[CH:23][CH:24]=3)([CH2:15][CH2:16]1)[O:13][CH2:12]2)([CH3:4])([CH3:3])[CH3:2].[CH2:29](Br)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C([O-])([O-])=O.[Na+].[Na+].O>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:29]([C:21]1[CH:20]=[C:19]([C:14]23[CH2:17][CH2:18][C:11]([CH2:10][CH2:9][O:8][CH2:7][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:28])([CH2:16][CH2:15]2)[CH2:12][O:13]3)[CH:24]=[CH:23][CH:22]=1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: CC(C)(C)OC(=O)COCCC12CCC(c3cccc(B(O)O)c3)(CC1)OC2
Reactant: BrCc1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)COCCC12CCC(c3cccc(Cc4ccccc4)c3)(CC1)OC2
Temperature: 100 °C
Reaction time: 18 h

Procedure:
A mixture of (3-(4-(2-(2-(tert-butoxy)-2-oxoethoxy)ethyl)-2-oxabicyclo[2.2.2]octan-1-yl)phenyl)boronic acid (49A; 20 mg, 0.051 mmol), benzyl bromide (0.012 mL, 0.102 mmol), and Na2CO3 (16 mg, 0.15 mmol) in 1,4-dioxane (1 mL)/water (0.2 mL) was degassed under Ar for 3 min using an ultrasonicator and then (Ph3P)4Pd (59 mg, 0.051 mmol) was added. The reaction was stirred at 100° C. under Ar for 18 h, then was cooled to rt and partitioned between EtOAc (5 mL) and water, dried (MgSO4), and concentrated in vacuo to give the crude product as a yellow oil, which was used in the next reaction without further purification.
Reaction SMILES: Cl.[CH3:2][NH:3][CH3:4].[C:5]([C:7]1[CH:12]=[CH:11][N:10]=[C:9]([CH2:13]Br)[CH:8]=1)#[N:6].C(N(CC)CC)C>CC(C)=O>[C:5]([C:7]1[CH:12]=[CH:11][N:10]=[C:9]([CH2:13][N:3]([CH3:4])[CH3:2])[CH:8]=1)#[N:6]
Reactant: N#Cc1ccnc(CBr)c1
Reactant: CNC
Agent: Cl
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: CN(C)Cc1cc(C#N)ccn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 66.8 %

Procedure:
Dimethylamine hydrochloride (4.78 g, 58.6 mmol) was added to a solution of 4-cyano-2-bromomethylpyridine (3.95 g, 19.5 mmol) and triethylamine (13.58 mL, 97.7 mmol) in acetone (40 mL). The reaction mixture was stirred overnight at room temperature in a sealed tube. The reaction mixture was concentrated under reduced pressure and partitioned between methylene chloride and saturated sodium bicarbonate. The organic layer was separated and washed with water, saturated sodium chloride, dried (sodium sulfate), filtered, and concentrated under reduced pressure. Purification by flash column chromatography (silica, 99:1 methylene chloride/methanol) gave the desired 4-cyano-2-(dimethylamino)methylpyridine (2.10 g): 1H NMR (300 MHz, CDCl3) δ 8.73 (d, J=5.0 Hz, 1H), 7.71 (s, 1H), 7.41 (dd, J=5.0, 1.2 Hz, 1H), 3.65 (s, 2H), 2.31 (s, 6H); ESI MS m/z 162 [M+H]+.
Reaction SMILES: [Li][CH2:2]CCC.[CH2:6]([O:18][C:19]1[CH:26]=[CH:25][C:22]([CH:23]=O)=[CH:21][CH:20]=1)[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17].[Na+].[Cl-]>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[CH2:6]([O:18][C:19]1[CH:26]=[CH:25][C:22]([CH:23]=[CH2:2])=[CH:21][CH:20]=1)[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: [Li]CCCC
Reactant: CCCCCCCCCCCCOc1ccc(C=O)cc1
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [Cl-]
Solvent: C1CCOC1
Product: C=Cc1ccc(OCCCCCCCCCCCC)cc1
Temperature: 0 °C
Reaction time: 2.5 h

Procedure:
To Methyltriphenylphosphonium bromide (8.13 g, 2.28×10−2 mol) in 60 ml of dry THF was added n-BuLi (1.6 M solution in hexane, 15.8 ml, 2.53×10−2 mol) dropwise at −78° C. After 2.5 h, the reaction mixture was gradually warmed up to 0° C., and again cooled to −78° C. 4-Dodecyloxybenzaldehyde (6.00 g, 2.07×10−2 mol) in 20 ml of dry THF was slowly added to the reaction mixture. The reaction mixture was stirred overnight and meanwhile gradually warmed up to 10° C. Aqueous NaCl was added to the reaction mixture and the organic layer was extracted with petroleum ether. The organic layer was dried over Na2SO4. After the solvent was evaporated, the residue was chromatographed on silica gel with 1:1 hexane:CH2Cl2. Yield=5.358 g (90% based on 6.00 g of 4-dodecyloxybenzaldehyde). 1H NMR (250 MHz, CDCl3): δ 7.33 (d, 2H, J=8.7 Hz, Ph), 6.85 (d, 2H, J=8.7 Hz, Ph), 6.66 (dd, 1H, J=10.8, 17.6 Hz, vinyl-H), 5.60 (d, 1H, J=17.5 Hz, vinyl-H), 5.11 (d, 1H, J=10.6 Hz, vinyl-H), 3.95 (t, 2H, J=6.6 Hz, OCH2), 1.78 (quint, 2H, J=7.0 Hz, OCH2CH2), 1.38-1.52 (m, 2H, —CH2—), 1.16-1.38 (m, 16H, —CH2—), 0.88 (t, 3H, J=6.6 Hz, —CH3). CI MS m/z: 288.245 (M+) (calcd 288.245).