Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH:2]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]#[N:14])[C:3]([O:5][CH3:6])=[O:4].[CH2:15]([O:17][CH:18]([O:21][CH2:22][CH3:23])[CH2:19][SH:20])[CH3:16].C(Cl)Cl>C(N(CC)CC)C>[CH2:15]([O:17][CH:18]([O:21][CH2:22][CH3:23])[CH2:19][S:20][CH:2]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]#[N:14])[C:3]([O:5][CH3:6])=[O:4])[CH3:16]
Reactant: COC(=O)C(Br)CCCCCCC#N
Reactant: CCOC(CS)OCC
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(CSC(CCCCCCC#N)C(=O)OC)OCC

Procedure:
The starting material is prepared as follows: To the mixture of 13.6 g of methyl 2-bromo-8-cyano-octanoate, 11.6 g of 2,2-diethoxy-ethylmercaptan and 150 ml of methylene chloride, 5.56 g of triethylamine are added dropwise while stirring. After overnight-stirring at room temperature the mixture is evaporated, the residue triturated with diethyl ether, washed with water, dried and evaporated, to yield the methyl 2-(2,2-diethoxyethylmercapto)-8-cyano-octanoate showing NMR bands aft 4.58, 3.71 and 2.75 ppm.
Reaction SMILES: [Cl-].[Li+].C(OP([CH:11]([CH2:17][CH2:18][CH2:19][O:20][CH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][O:22]1)[C:12]([O:14][CH2:15][CH3:16])=[O:13])(OCC)=O)C.C1CCN2C(=NCCC2)CC1.[C:38]1([CH:48]=O)[C:47]2[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=2)[CH:41]=[CH:40][CH:39]=1.Cl>C1COCC1>[C:38]1([CH:48]=[C:11]([CH2:17][CH2:18][CH2:19][O:20][CH:21]2[CH2:26][CH2:25][CH2:24][CH2:23][O:22]2)[C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:47]2[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=2)[CH:41]=[CH:40][CH:39]=1
Reactant: CCOC(=O)C(CCCOC1CCCCO1)P(=O)(OCC)OCC
Reactant: O=Cc1cccc2ccccc12
Agent: Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: CCOC(=O)C(=Cc1cccc2ccccc12)CCCOC1CCCCO1
Yield: 84 %

Procedure:
579 mg of lithium chloride was suspended in 20 ml of dry THF under an argon stream, and 5.0 g of ethyl 2-diethylphosphono-5-(2-tetrahydropyranyloxy)pentanoate was added under stirring. After stirring the mixture for 5 minutes at room temperature, 2.6 g of DBU was added, and the mixture was stirred at room temperature for 10 minutes. Then, 1.7 g of α-naphthoaldehyde was added, and the mixture was stirred at room temperature overnight. Then, the reaction solution was neutralized with 1N hydrochloric acid under cooling with ice and extracted with ethyl acetate. The ethyl acetate layer thereby obtained was washed with water and with a saturated sodium chloride aqueous solution and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane/ethyl acetate=10/1) to obtain 3.37 g of ethyl 3-(1-naphthyl)-2-[3-(2-tetrahydropyranyloxy)propyl]-2-propenoate as slightly yellow oily substance.
Reaction SMILES: [CH2:1]([C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([N:18]2[CH2:23][CH2:22][N:21]([C:24]3[N:29]=[CH:28][C:27]([CH2:30][OH:31])=[CH:26][CH:25]=3)[CH2:20][CH2:19]2)=[N:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:39][O:40][CH2:41][C:42](Cl)=[O:43]>C(Cl)Cl>[CH2:1]([C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([N:18]2[CH2:23][CH2:22][N:21]([C:24]3[N:29]=[CH:28][C:27]([CH2:30][O:31][C:42](=[O:43])[CH2:41][O:40][CH3:39])=[CH:26][CH:25]=3)[CH2:20][CH2:19]2)=[N:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COCC(=O)Cl
Reactant: OCc1ccc(N2CCN(c3nnc(Cc4ccccc4)c4ccccc34)CC2)nc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COCC(=O)OCc1ccc(N2CCN(c3nnc(Cc4ccccc4)c4ccccc34)CC2)nc1
Reaction time: 1 h
Yield: 40.5 %

Procedure:
{6-[4-(4-Benzyl-phthalazin-1-yl)-piperazin-1-yl]-pyridin-3-yl}-methanol (80 mg, 0.194 mmol), CH2Cl2 (1 mL), and triethylamine (40 μL, 2.916 mmol) are added to a flask. Add methoxyacetyl chloride (23.2 mg, 0.214 mmol) dropwise at room temperature. Stir 1 h. The crude mixture is purified by flash chromatography on silica gel (MeOH/CH2Cl2) to afford the title compound (38 mg, 40%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:21]2[CH2:25][C@H:24]([CH2:26][N:27]3[CH:31]=[CH:30][N:29]=[N:28]3)[O:23][C:22]2=[O:32])[CH:5]=[CH:6][C:7]=1[C:8]1[CH:9]=[N:10][C:11]([C:14]2[CH2:18][C@@H:17]([CH2:19][OH:20])[O:16][N:15]=2)=[CH:12][CH:13]=1.Cl.[C:34](Cl)(=[O:41])[C:35]1[CH:40]=[CH:39][CH:38]=[N:37][CH:36]=1.CN(C)C=O>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[C:34]([O:20][CH2:19][C@H:17]1[O:16][N:15]=[C:14]([C:11]2[CH:12]=[CH:13][C:8]([C:7]3[CH:6]=[CH:5][C:4]([N:21]4[CH2:25][C@H:24]([CH2:26][N:27]5[CH:31]=[CH:30][N:29]=[N:28]5)[O:23][C:22]4=[O:32])=[CH:3][C:2]=3[F:1])=[CH:9][N:10]=2)[CH2:18]1)(=[O:41])[C:35]1[CH:40]=[CH:39][CH:38]=[N:37][CH:36]=1
Reactant: O=C(Cl)c1cccnc1
Reactant: O=C1O[C@@H](Cn2ccnn2)CN1c1ccc(-c2ccc(C3=NO[C@H](CO)C3)nc2)c(F)c1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: O=C(OC[C@@H]1CC(c2ccc(-c3ccc(N4C[C@H](Cn5ccnn5)OC4=O)cc3F)cn2)=NO1)c1cccnc1
Reaction time: 16 h
Yield: 48.4 %

Procedure:
(5R)-3-(3-Fluoro {6-[(5S)-5-(hydroxymethyl)-4,5,-dihydroisoxazol-3-yl]pyridin-3-yl}phenyl)-4-(1H-1,2,3-triazol-1-ylmethyl)-1,3-oxazolidin-2-one (Example 1, 200 mg, 0.46 mM), nicotinoylchloride hydrochloride (175 mg, 0.98 mM), 4-(dimethylamino)pyridine (DMAP, 20 mg, 0.17 mM) were placed in a flask. Anhydrous dimethylformamide (2 mL) and anhydrous pyridine (2 mL) were added and the suspension was stirred for 16 hours during which it became a clear solution. 500 mg silicagel was added and the solvents were evaporated. The residue was chromatographed on silicagel eluting with a gradient of methanol in dichloromethane (1–20%) to give title compound (120 mg, 48%).
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[C:7]2[OH:12].C(N(C(C)C)C(C)C)C.Cl[CH2:23][O:24][CH3:25].C(=O)([O-])[O-].[Na+].[Na+]>ClCCl>[F:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[C:7]2[O:12][CH2:23][O:24][CH3:25]
Reactant: Oc1cccc2c(F)cccc12
Reactant: COCCl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COCOc1cccc2c(F)cccc12
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 79.6 %

Procedure:
A solution of 0.257 g of 5-fluoro-1-hydroxynaphthalene in 6 ml of dry dichloromethane was cooled in an ice/salt bath after which was added 0.36 ml (2.07 mmol) of ethyl diisopropylamine followed by 0.15 ml (0.16 g, 1.96 mmol) of chloromethylmethyl ether. The mixture was stirred at 0° C. for 0.5 h after which it was allowed to warm to RT and stirred at RT for 11 h. The mixture was poured into saturated sodium carbonate solution, extracted twice with dichloromethane, dried, filtered and concentrated to an oil. The material was dissolved in a minimum volume of dichloromethane and flash chromatographed on silica gel, eluting with ethyl acetate/heptane to provide 0.260 g (79%) of 5-fluoro-1-methoxymethyloxynaphthalene.
Reaction SMILES: COC1C=C(C=CC=1OC)C(C1C=CC=C(N)C=1)=O.[CH3:20][O:21][C:22]1[CH:23]=[C:24]([CH:36]=[CH:37][C:38]=1[O:39][CH3:40])[C:25]([C:27]1[CH:32]=[CH:31][C:30]([N+:33]([O-])=O)=[CH:29][CH:28]=1)=[O:26]>[Pd].C(OCC)(=O)C>[CH3:20][O:21][C:22]1[CH:23]=[C:24]([CH:36]=[CH:37][C:38]=1[O:39][CH3:40])[C:25]([C:27]1[CH:28]=[CH:29][C:30]([NH2:33])=[CH:31][CH:32]=1)=[O:26]
Reactant: COc1ccc(C(=O)c2ccc([N+](=O)[O-])cc2)cc1OC
Agent: [Pd]
Agent: COc1ccc(C(=O)c2cccc(N)c2)cc1OC
Solvent: CCOC(C)=O
Product: COc1ccc(C(=O)c2ccc(N)cc2)cc1OC

Procedure:
3,4-Dimethoxy-4′-aminobenzophenone was prepared analogously to 3,4-dimethoxy-3′-aminobenzophenone using 3,4-dimethoxy-4′-nitrobenzophenone (1 g, 3.5 mmol) and 0.1 g of 10% palladium on carbon catalyst in 110 mL of ethyl acetate. The crude product was purified by flash column chromatography (silica gel, 12% ethyl acetate/methylene chloride) to afford 0.32 g (36%) of the product as a yellow solid: mp 189-191° C.; 1H NMR (CDCl3) δ7.80-7.62 (m, 2 H); 7.45-7.29 (m, 2 H), 6.96-6.80 (m, 1 H), 6.75-6.61 (m, 2 H), 4.14 (s, 2 H), 3.95 (s, 3 H), 3.93 (s, 3 H); 13C NMR (CDCl3) δ194.2, 152.2, 150.5, 148.8, 132.6, 131.3, 128.0, 124.3, 113.6, 112.3, 109.7, 56.0; Anal. Calcd for C15H15NO3. Theoretical: C, 70.02; H, 5.88; N, 5.44. Found: C, 69.95;H, 6.18; N, 5.13.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH:4]1[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[O:6][CH2:5]1.C(N(CC)CC)C.[C:21](#[N:24])[CH:22]=[CH2:23]>CO>[O:6]1[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH2:13][CH:4]([CH2:3][CH2:2][NH:1][CH2:23][CH2:22][C:21]#[N:24])[CH2:5]1
Reactant: C=CC#N
Reactant: NCCC1COc2ccccc2C1
Solvent: CCN(CC)CC
Solvent: CO
Product: N#CCCNCCC1COc2ccccc2C1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
17.7 g (0.1 mol) of 3-(2-aminoethyl)chroman are dissolved in 100 ml of methanol, and then 10.5 g (0.1 mol) of triethylamine and 5.84 g (0.11 mol) of acrylonitrile are added to the solution. The reaction mixture is stirred for 15 hours at room temperature and then concentrated under a water-jet vacuum. The residue is taken up in diethyl ether and washed neutral with ice-water. The ethereal phase is dried over potassium carbonate and concentrated by evaporation. N-[2-(chroman-3-yl)ethyl]-N-(2-cyanoethyl)-amine is thus obtained in the form of a pale yellow oil.
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:20][C:21]2[CH:25]=[C:24]([CH:26]3[CH2:28][CH2:27]3)[NH:23][N:22]=2)=[CH:4][C:5]([NH:10][C@H:11]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[CH3:12])=[C:6]([CH:9]=1)[C:7]#[N:8].[C:29](O)(=O)C.C(N)=N.C(=O)(O)[O-].[Na+].CCOC(C)=O>CCO>[CH:26]1([C:24]2[NH:23][N:22]=[C:21]([N:20]3[C:3]4[CH:4]=[C:5]([NH:10][C@H:11]([C:13]5[CH:14]=[CH:15][C:16]([F:19])=[CH:17][CH:18]=5)[CH3:12])[C:6]([C:7]#[N:8])=[CH:9][C:2]=4[N:1]=[CH:29]3)[CH:25]=2)[CH2:28][CH2:27]1
Reactant: CC(=O)O
Reactant: C[C@H](Nc1cc(Nc2cc(C3CC3)[nH]n2)c(N)cc1C#N)c1ccc(F)cc1
Agent: N=CN
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(C)=O
Product: C[C@H](Nc1cc2c(cc1C#N)ncn2-c1cc(C2CC2)[nH]n1)c1ccc(F)cc1
Yield: 81.9 %

Procedure:
A mixture of (s)-5-amino-4-(5-cyclopropyl-1H-pyrazol-3-ylamino)-2-[1-(4-fluorophenyl)ethylamino]benzonitrile (Method 69; 3.85 g, 10.2 mmol) and formamidine acetate (2.13 g, 20.5 mmol) in EtOH (50 ml) was heated at reflux for 2 hrs. After cooling, the reaction mixture was treated with saturated sodium bicarbonate solution (10 ml) and EtOAc (30 ml). The organic layer was separated, washed with brine (10 ml), and dried over Na2SO4. The solvent was removed under reduced pressure and the residue was purified by column chromatography (EtOAc:MeOH=30:1) to give the title compound as an off-white solid (3.23 g, 82%). NMR (400 MHz) 12.79 (s, 1H), 8.44 (s, 1H), 7.95 (s, 1H), 7.53 (m, 2H), 7.14 (m, 2H), 7.01 (s, 1H), 6.10 (s, 1H), 6.09 (d, J=7.6 Hz, 1H), 4.63 (m, 1H), 1.97 (m, 1H), 1.55 (d, J=6.8 Hz, 3H), 1.03 (m, 2H), 0.76 (m, 2H). MS: Calcd.: 386; Found: [M+H]+ 387.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[C:6]([I:11])[CH:5]=1.[C:13](Cl)(=[O:15])[CH3:14]>N1C=CC=CC=1>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:13](=[O:15])[CH3:14])=[C:6]([I:11])[CH:5]=1
Reactant: COC(=O)c1ccc(N)c(I)c1
Reactant: CC(=O)Cl
Solvent: c1ccncc1
Product: COC(=O)c1ccc(NC(C)=O)c(I)c1
Reaction time: 0.5 h

Procedure:
To a stirred solution of 4-amino-3-iodo-benzoic acid methyl ester (11.1 g, 40.0 mmol) in pyridine (80 mL) was added acetyl chloride (3.30 g, 42.0 mmol) at 0° C. under nitrogen. Stirring continued at 0° C. for 30 minutes. The ice-bath was removed, and stirring continued at room temperature for 16 hours. Pyridine was evaporated under reduced pressure. The residue was taken in ethyl acetate (300 mL). The organic phase was washed with 2 N aqueous HCl (200 mL), water (200 mL), brine (200 mL), and then dried over anhydrous Na2SO4. Removal of solvent gave 4-acetylamino-3-iodo-benzoic acid methyl ester as a white solid. Yield: 12.71 g (99%).
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7]([Cl:9])[C:6]([C:10]([O:12][CH3:13])=[O:11])=[CH:5][C:3]=1[NH2:4].[O:14]=[C:15](Cl)OC(Cl)(Cl)Cl>C1COCC1.C1(C)C=CC=CC=1>[F:1][C:2]1[CH:8]=[C:7]([Cl:9])[C:6]([C:10]([O:12][CH3:13])=[O:11])=[CH:5][C:3]=1[N:4]=[C:15]=[O:14]
Reactant: COC(=O)c1cc(N)c(F)cc1Cl
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: COC(=O)c1cc(N=C=O)c(F)cc1Cl
Temperature: 25 °C
Yield: 95.8 %

Procedure:
A solution of 2-fluoro-4-chloro-5-methoxycarbonylaniline (1.0 g, 5 mmol) in THF (10 mL) was added dropwist to a solution of diphosgene (2.0 g, 10 mmol) in toluene (20 mL) with stirring at room temperature. The reaction mixture was stirred at room temperature for one hour and then heated to reflux for 4 hours. The mixture was then cooled to room temperature and the solvents were evaporated under reduced pressure to give 1.1 g of 2-fluoro-4-chloro-5-methoxycarbonylphenyl isocyanate as a solid. This was used for the next step without further purification.
Reaction SMILES: [CH2:1]([CH:3]([O:6][C:7]1[CH:12]=[C:11]([CH3:13])[N:10]=[C:9]([O:14][C:15]2[C:20]([CH3:21])=[CH:19][C:18]([OH:22])=[CH:17][C:16]=2[CH3:23])[C:8]=1[CH3:24])[CH2:4][CH3:5])[CH3:2].[H-].[Na+].[CH3:27]I>C1COCC1>[CH2:1]([CH:3]([O:6][C:7]1[CH:12]=[C:11]([CH3:13])[N:10]=[C:9]([O:14][C:15]2[C:20]([CH3:21])=[CH:19][C:18]([O:22][CH3:27])=[CH:17][C:16]=2[CH3:23])[C:8]=1[CH3:24])[CH2:4][CH3:5])[CH3:2]
Reactant: CI
Reactant: CCC(CC)Oc1cc(C)nc(Oc2c(C)cc(O)cc2C)c1C
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCC(CC)Oc1cc(C)nc(Oc2c(C)cc(OC)cc2C)c1C
Reaction time: 0.08 h

Procedure:
To a solution of 4-[4-(1-ethyl-propoxy)-3,6-dimethyl-pyridin-2-yloxy]-3,5-dimethyl-phenol (40 mg, 0.12 mmol) in 3 ml of dry THF was added 10 mg of 60% sodium hydride in oil at room temperature. After stirring for 5 min, 0.3 ml of methyl iodide was added and the resulting mixture was stirred at room temperature overnight. The mixture was quenched with water and extracted with ethyl acetate. The organic layer was dried and concentrated to give a yellow solid. The solid was purified through silica gel column chromatography using hexane to 1:1 chloroform:hexane as eluent to yield 20 mg of the title compound as yellow solid. 1H NMR (CDCl3) δ 6.66 (s, 2H), 6.28 (s, 1H), 4.20 (m, 1H), 3.79 (s, 3H), 2.20 (s, 3H), 2.19 (s, 3H0, 2.08 (s, 6H), 1.71 (m, 4H), 0.97 (t, 6H) ppm.
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]([S:17]([C:20]2[CH:24]=[CH:23][N:22]([CH3:25])[N:21]=2)(=[O:19])=[O:18])[C:8]2[CH:9]=[C:10]([CH:14]=[CH:15][CH:16]=2)[C:11](O)=[O:12])=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:61][CH2:62][CH2:63][OH:64]>C(#N)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]([S:17]([C:20]2[CH:24]=[CH:23][N:22]([CH3:25])[N:21]=2)(=[O:18])=[O:19])[C:8]2[CH:9]=[C:10]([CH:14]=[CH:15][CH:16]=2)[C:11]([NH:61][CH2:62][CH2:63][OH:64])=[O:12])=[CH:26][CH:27]=1
Reactant: NCCO
Reactant: Cn1ccc(S(=O)(=O)N(Cc2ccc(Cl)cc2)c2cccc(C(=O)O)c2)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: Cn1ccc(S(=O)(=O)N(Cc2ccc(Cl)cc2)c2cccc(C(=O)NCCO)c2)n1

Procedure:
A solution of 3-[(4-chloro-benzyl)-(1-methyl-1H-pyrazole-3-sulfonyl)-amino]-benzoic acid (30 mg, 0.07 mmol), diisopropylethylamine (0.26 ml, 0.14 mmol). HATU (56 mg, 0.15 mmol) and 2-aminoethanol (9 μL, 0.14 mmol) were stirred in dry acetonitrile (3 ml) for 18 hrs. The reaction mixture was concentrated in vacuo and the residue partitioned between dichloromethane (3 ml) and water (3 ml). The organic layer was separated and dried by passage through a hydrophobic frit, then concentrated in vacuo. The crude residue was purified by preparative HPLC to afford the title compound as an off white solid (11.9 mg). HPLC retention time 5.03 min. Mass spectrum (ES+) m/z 449 (M+H).
Reaction SMILES: [OH:1][CH:2]([C:7]1[CH:12]=[CH:11][C:10]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[CH:9][CH:8]=1)[C:3](=[O:6])[CH2:4][CH3:5].[CH3:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26]Br)=[CH:22][CH:21]=1.[OH-].[Na+]>CS(C)=O.O>[OH:1][C:2]([C:7]1[CH:8]=[CH:9][C:10]([N:13]2[CH2:14][CH2:15][O:16][CH2:17][CH2:18]2)=[CH:11][CH:12]=1)([C:3](=[O:6])[CH2:4][CH3:5])[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=1
Reactant: Cc1ccc(CBr)cc1
Reactant: CCC(=O)C(O)c1ccc(N2CCOCC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: CCC(=O)C(O)(Cc1ccc(C)cc1)c1ccc(N2CCOCC2)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
1-Hydroxy-1-(4-morpholinophenyl)-butan-2-one, one equivalent of 4-methylphenylmethyl bromide and 1.2 equivalent of sodium hydroxide are suspended in dimethyl sulfoxide and the resulting mixture is stirred at room temperature for 24 hours. The reaction mixture is diluted with the same amount of water and extracted several times with dichloromethane. The combined organic extracts are dried over sodium sulfate and evaporated to give crude 2-hydroxy-2-(4-morpholinophenyl)-1-(4-methylphenyl)-pentan-3-one as a viscous oil. The compound is purified by chromatography on silica gel (eluant: hexane/ethyl acetate 9:1). Pure 2-hydroxy-2-(4-morpholinophenyl)-1-(4-methylphenyl)-pentan-3-one is thus obtained as colorless crystals with a melting point of 160° C.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[C:7]([C:9]1[N:17]2[C:12]([CH2:13][O:14][CH2:15][CH2:16]2)=[C:11]([C:18]([OH:20])=O)[CH:10]=1)=[O:8].ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.Cl.[Cl:44][C:45]1[CH:46]=[C:47]([C@H:55]([NH2:58])[CH2:56][CH3:57])[CH:48]=[CH:49][C:50]=1[C:51]([F:54])([F:53])[F:52].C(N(CC)CC)C>CN(C)C=O>[Cl:44][C:45]1[CH:46]=[C:47]([C@H:55]([NH:58][C:18]([C:11]2[CH:10]=[C:9]([C:7]([N:3]3[CH2:4][CH2:5][CH2:6][C@@H:2]3[CH3:1])=[O:8])[N:17]3[CH2:16][CH2:15][O:14][CH2:13][C:12]=23)=[O:20])[CH2:56][CH3:57])[CH:48]=[CH:49][C:50]=1[C:51]([F:53])([F:54])[F:52]
Reactant: CC[C@@H](N)c1ccc(C(F)(F)F)c(Cl)c1
Reactant: C[C@H]1CCCN1C(=O)c1cc(C(=O)O)c2n1CCOC2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC[C@@H](NC(=O)c1cc(C(=O)N2CCC[C@@H]2C)n2c1COCC2)c1ccc(C(F)(F)F)c(Cl)c1
Temperature: 50 °C
Reaction time: 2 h
Yield: 73 %

Procedure:
To a solution of 6-((S)-2-methyl-pyrrolidine-1-carbonyl)-3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazine-8-carboxylic acid (Comp. No. 7c) (75 mg, 0.270 mmol) in dimethylformamide (2 ml) was added 1-hydroxybenzotriazole (41 mg, 0.30 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (58 mg, 0.30 mmol). The mixture was stirred for 2 h at 50° C., then (R)-1-(3-chloro-4-trifluoromethyl-phenyl)-propylamine hydrochloride (81 mg, 0.3 mmol) and triethylamine (82 mg, 0.81 mmol) were added and the mixture was stirred at 25° C. overnight. The mixture was filtered through a small filter cartridge and the solution was purified by reverse phase HPLC (acetonitrile/water gradient with 0.1% trifluoroacetic acid) to give 98 mg (73%) of 6-((S)-2-methyl-pyrrolidine-1-carbonyl)-3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazine-8-carboxylic acid [(R)-1-(3-chloro-4-trifluoromethyl-phenyl)-propyl]-amide as white solid. LC/MS (method 3): Rt=2.03 min; m/z=498.22 (M+H+). 1H-NMR: δ (ppm)=8.20 (1H, d), 7.83 (1H, d), 7.67 (1H, s), 7.50 (1H, d), 7.25 (1H, s), 4.96 (1H, d), 4.83-4.91 (m, 2H), 4.18-4.30 (2H, m), 3.92-4.01 (2H, m), 3.79-3.85 (1H, m), 3.69 (2H, bs), 2.07 (1H, m), 1.96 (1H, m), 1.76-1.85 (3H, m), 1.54-1.60 (1H, m), 1.19 (3H, d), 0.90 (3H, t).
Reaction SMILES: [H-].[Na+].[CH2:3]([C:5]1([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH2:10][CH2:9][CH:8]([OH:11])[CH2:7][CH2:6]1)[CH3:4].[Si:20]([O:27][CH2:28][CH2:29][C@H:30]1[CH2:41][CH2:40][C:39]2[S:38][C:37]3[N:36]=[CH:35][N:34]=[C:33](Cl)[C:32]=3[C:31]1=2)([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21]>C1COCC1>[Si:20]([O:27][CH2:28][CH2:29][C@H:30]1[CH2:41][CH2:40][C:39]2[S:38][C:37]3[N:36]=[CH:35][N:34]=[C:33]([O:11][CH:8]4[CH2:9][CH2:10][C:5]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])([CH2:3][CH3:4])[CH2:6][CH2:7]4)[C:32]=3[C:31]1=2)([C:23]([CH3:26])([CH3:24])[CH3:25])([CH3:22])[CH3:21]
Reactant: CCC1(NC(=O)OC(C)(C)C)CCC(O)CC1
Reactant: CC(C)(C)[Si](C)(C)OCC[C@H]1CCc2sc3ncnc(Cl)c3c21
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCC1(NC(=O)OC(C)(C)C)CCC(Oc2ncnc3sc4c(c23)[C@@H](CCO[Si](C)(C)C(C)(C)C)CC4)CC1
Temperature: 18 °C
Reaction time: 14 h
Yield: 47.1 %

Procedure:
Sodium hydride (605 dispersion in mineral oil, 283 mg, 7.08 mmol, 3.65 equiv) was treated with tert-butyl N-(1-ethyl-4-hydroxycyclohexyl)carbamate (430 mg, 1.77 mmol, 0.91 equiv) in 50 mL of distilled THF at room temperature for 30 mins. Then a solution of (3R)-3-[2-[(tert-butyldimethylsilyl)oxy]ethyl]-12-chloro-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraene (25.1, 716 mg, 1.94 mmol, 1.00 equiv) in THF (5 mL) was added dropwise and the resulting solution was stirred for 14 hr at 18° C. The reaction was then quenched with saturated aqueous NH4Cl and extracted with 3×50 mL of ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:5) to afford the corresponding tert-butyl N-(4-[[(3R)-3-[2-[(tert-butyldimethylsilyl)oxy]ethyl]-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-12-yl]oxy]-1-ethylcyclohexyl)carbamate (480 mg, 43%) as a colorless oil. MS: 576 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH2:8]O)=[CH:6][CH:5]=[C:4]([C:10]([F:13])([F:12])[F:11])[N:3]=1.[BrH:14]>>[Br:14][CH2:8][C:7]1[C:2]([CH3:1])=[N:3][C:4]([C:10]([F:13])([F:12])[F:11])=[CH:5][CH:6]=1
Reactant: Cc1nc(C(F)(F)F)ccc1CO
Reactant: Br
Product: Cc1nc(C(F)(F)F)ccc1CBr
Temperature: 135 °C
Yield: 71 %

Procedure:
A mixture of (2-methyl-6-(trifluoromethyl)pyridin-3-yl)methanol (1.677 g, 8.77 mmol, 76% pure) in 48% aq. HBr (10 mL) was heated to reflux (oil bath temperature, 135° C.) for 24 h. The volatile components of the resulting biphasic mixture were distilled under vacuum to remove most of the hydrogen bromide (sodium hydroxide trap). The residue was partitioned between 2:1 EtOAc/THF and water (at pH 3) and the organic phase was dried (MgSO4), filtered and evaporated. The solid residue was re-evaporated after addition of dichloromethane/hexanes to obtain the title compound as a tan solid, 1.19 g, 71% yield (based on the purity of the starting material). HPLC/MS: retention time=2.15 min, [M+H]+=254.
Reaction SMILES: [BH4-].[Na+].[C:3]1([C@@H:9]2[CH2:11][C@H:10]2[NH:12][CH:13]=O)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.II.CO>O1CCCC1>[CH3:13][NH:12][C@@H:10]1[CH2:11][C@H:9]1[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: O=CN[C@@H]1C[C@H]1c1ccccc1
Agent: II
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CN[C@@H]1C[C@H]1c1ccccc1
Yield: 57.1 %

Procedure:
To a suspension of sodium borohydride (0.66 g, 17.57 mmol) in tetrahydrofuran (55 ml) was added dropwise at room temperature a solution of the compound (2.36 g, 14.64 mmol) obtained in step A in tetrahydrofuran (32 ml). Then, a solution of iodine (1.86 g, 7.33 mmol) in tetrahydrofuran (63 ml) was added dropwise, and the mixture was heated under reflux overnight. The reaction mixture was ice-cooled, methanol (125 ml) was added, and the mixture was concentrated under reduced pressure. To the residue was added 10% aqueous potassium carbonate solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The insoluble material was filtered off, and the solution was concentrated under reduced pressure. The obtained oil was purified by silica gel column chromatography (chloroform-methanol) to give the title compound (1.23 g, yield 57%) as a pale-yellow oil.