Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH2:9])[C:5]([CH3:8])=[N:6][CH:7]=1.CC1(C)C(C)(C)OB([C:18]2[CH:30]=[CH:29][C:21]3[N:22]=[C:23]([NH:25][C:26](=[O:28])[CH3:27])[S:24][C:20]=3[CH:19]=2)O1.C(=O)([O-])[O-].[K+].[K+]>COCCOC.O>[NH2:9][C:4]1[CH:3]=[C:2]([C:18]2[CH:30]=[CH:29][C:21]3[N:22]=[C:23]([NH:25][C:26](=[O:28])[CH3:27])[S:24][C:20]=3[CH:19]=2)[CH:7]=[N:6][C:5]=1[CH3:8]
Reactant: Cc1ncc(Br)cc1N
Reactant: CC(=O)Nc1nc2ccc(B3OC(C)(C)C(C)(C)O3)cc2s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: CC(=O)Nc1nc2ccc(-c3cnc(C)c(N)c3)cc2s1
Temperature: 100 °C
Reaction time: 1.33 h
Yield: 50.1 %

Procedure:
5-bromo-2-methylpyridin-3-amine (224.9 mg, 1.202 mmol), N-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]thiazol-2-yl)acetamide (413.7 mg, 1.300 mmol), potassium carbonate (549.4 mg, 3.975 mmol), and Pd(dppf)Cl2*DCM complex (108.7 mg, 0.133 mmol) were suspended in DME (5.0 ml) and water (1.25 ml), and the flask was fit with a reflux condensor and argon was bubbled through for about 15 seconds. Then, the flask was placed in a preheated oil bath (100° C.) and stirred under argon for 80 minutes. The reaction was cooled to room temperature, and the aqueous phase was removed via pipette. The reaction was then concentrated, treated with MeOH, and filtered. Solid washed with MeOH, water, MeOH, and Et2O. Solid then collected and dried under high vacuum to afford N-(6-(5-amino-6-methylpyridin-3-yl)benzo[d]thiazol-2-yl)acetamide (179.7 mg, 50% yield). MS (ESI pos. ion) m/z: 299. Calculated exact mass for C15H14N4OS: 298.
Reaction SMILES: [C@:1]12([CH3:13])[C:7]([CH3:9])([CH3:8])[CH:4]([CH2:5][CH2:6]1)[CH2:3][CH:2]2[C:10](Cl)=[O:11].[I:14][C:15]1[CH:20]=[CH:19][C:18]([CH:21]([OH:26])[C:22]([CH3:25])([CH3:24])[CH3:23])=[C:17]([N+:27]([O-:29])=[O:28])[CH:16]=1>CN(C1C=CN=CC=1)C.ClCCl>[C@:1]12([CH3:13])[C:7]([CH3:9])([CH3:8])[CH:4]([CH2:5][CH2:6]1)[CH2:3][CH:2]2[C:10]([O:26][CH:21]([C:18]1[CH:19]=[CH:20][C:15]([I:14])=[CH:16][C:17]=1[N+:27]([O-:29])=[O:28])[C:22]([CH3:24])([CH3:25])[CH3:23])=[O:11]
Reactant: CC(C)(C)C(O)c1ccc(I)cc1[N+](=O)[O-]
Reactant: CC1(C)C2CC[C@@]1(C)C(C(=O)Cl)C2
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)C(OC(=O)C1CC2CC[C@]1(C)C2(C)C)c1ccc(I)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 91 %

Procedure:
Under a nitrogen atmosphere, (1S)-camphanic acid chloride (1.68 g, 7.77 mmol) was added to a solution of (RS)-1-(4-iodo-2-nitrophenyl)-2,2-dimethyl-1-propanol (2.17 g, 6.47 mmol) and DMAP (1.18 g, 9.7 mmol) in anhydrous dichloromethane (50 mL). The mixture was stirred overnight at room temperature and then washed with saturated NaHCO3 solution (60 mL) and water (60 mL). The organic phase was dried over Na2SO4, concentrated in vacuo and purified by silica gel column chromatography to yield (RS)-1-(4-iodo-2-nitrophenyl)-2,2-dimethyl-1-propyl (1S)-camphanate (2.94 g, 88%, 1:1 mixture of diastereomers) as a white solid. 1H NMR (400 MHz, CDCl3) for diastereomers: δ 8.23 (m, 1 H, Ph-H), 7.90 (m, 1 H, Ph-H), 7.31 (m, 1 H, Ph-H), 6.56 and 6.51 (2 s, 1 H, Ph-CH), 2.38 (m, 1 H), 2.07-1.9 (m, 2 H), 1.69 (m, 1 H), 1.13, 1.11, 1.07, 1.04, 1.02, 0.87 (6 s, 9 H, CH3×3), 0.96 (s, 9 H, (CH3)3C).
Reaction SMILES: [Si:1](Cl)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].N1C=CN=C1.[OH:14][CH:15]([CH3:26])[CH2:16][O:17][C:18]1[CH:25]=[CH:24][C:21]([CH:22]=[O:23])=[CH:20][CH:19]=1.C(=O)(O)[O-].[Na+]>CN(C)C=O>[Si:1]([O:14][CH:15]([CH3:26])[CH2:16][O:17][C:18]1[CH:25]=[CH:24][C:21]([CH:22]=[O:23])=[CH:20][CH:19]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(O)COc1ccc(C=O)cc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: O=C([O-])O
Agent: [Na+]
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(COc1ccc(C=O)cc1)O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 20 h

Procedure:
5.39 g (35.7 mmol) of tert-butyldimethylsilyl chloride and 3.30 g (48.5 mmol) of imidazole are added successively to a solution of 4.60 g (25.5 mmol) of the compound from Example 40A in 120 ml of dry dimethylformamide, and the mixture is stirred at RT for 20 h. 100 ml of saturated sodium bicarbonate solution are then added, and the reaction mixture is extracted with diethyl ether (three times, 100 ml each). The combined organic phases are dried over magnesium sulphate. After removal of the solvent on a rotary evaporator, the crude product is purified chromatographically on silica gel 60 (mobile phase gradient cyclohexane/ethyl acetate 50:1→10:1).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:15]=[C:16]([O:18][C@H:19]2[CH2:23][CH2:22][N:21]([CH3:24])[C:20]2=[O:25])[CH:17]=1)[C:5]([NH:7][C:8]1[CH:13]=[N:12][C:11]([CH3:14])=[CH:10][N:9]=1)=[O:6].F[C:27]1[CH:32]=[CH:31][C:30]([S:33]([CH3:36])(=[O:35])=[O:34])=[CH:29][CH:28]=1.C(=O)([O-])[O-].[K+].[K+]>CC(N(C)C)=O>[CH3:24][N:21]1[CH2:22][CH2:23][C@H:19]([O:18][C:16]2[CH:15]=[C:4]([CH:3]=[C:2]([O:1][C:27]3[CH:32]=[CH:31][C:30]([S:33]([CH3:36])(=[O:35])=[O:34])=[CH:29][CH:28]=3)[CH:17]=2)[C:5]([NH:7][C:8]2[CH:13]=[N:12][C:11]([CH3:14])=[CH:10][N:9]=2)=[O:6])[C:20]1=[O:25]
Reactant: CS(=O)(=O)c1ccc(F)cc1
Reactant: Cc1cnc(NC(=O)c2cc(O)cc(O[C@H]3CCN(C)C3=O)c2)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: Cc1cnc(NC(=O)c2cc(Oc3ccc(S(C)(=O)=O)cc3)cc(O[C@H]3CCN(C)C3=O)c2)cn1
Temperature: 120 °C
Reaction time: 2 h
Yield: 68 %

Procedure:
A mixture of 3-hydroxy-5-[(3S)-1-methyl-2-oxo-pyrrolidin-3-yl]oxy-N-(5-methylpyrazin-2-yl)benzamide (Intermediate 18) (136 mg, 0.4 mmol), 1-fluoro-4-methylsulfonyl-benzene (105 mg, 0.6 mmol) and potassium carbonate (111 mg, 0.8 mmol) in DMA (5 mL) was stirred at 120° C. for 2 hours. The solution was evaporated under reduced pressure, the residue dissolved in ethyl acetate (40 mL), washed with water (2×20 mL), brine (20 mL), dried (MgSO4), filtered and the solvent removed under reduced pressure. The residue was purified by flash chromatography on silica, eluting with a gradient of 0-4% methanol in DCM to afford product (135 mg, 68%). 1H NMR δ (300 MHz, CDCl3) 2.15-2.30 (m, 1H), 2.53-2.69 (m, 4H), 2.94 (s, 3H), 3.08 (s, 3H), 3.36-3.58 (m, 2H), 4.96 (t, 1H), 7.02 (s, 1H), 7.15 (d, 2H), 7.25 (s, 1H), 7.50 (s, 1H), 7.93 (d, 2H), 8.15 (s, 1H), 8.55 (s, 1H), 9.53 (s, 1H); m/z 497 (M+H)+.
Reaction SMILES: [NH2:1][CH:2]([CH3:18])[C:3]([N:5]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:4].[CH3:19][C:20]1[CH:21]=[C:22]([N:26]=[C:27]=[O:28])[CH:23]=[CH:24][CH:25]=1>>[CH3:19][C:20]1[CH:21]=[C:22]([NH:26][C:27](=[O:28])[NH:1][CH:2]([CH3:18])[C:3]([N:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)=[O:4])[CH:23]=[CH:24][CH:25]=1
Reactant: CC(N)C(=O)N(c1ccccc1)c1ccccc1
Reactant: Cc1cccc(N=C=O)c1
Product: Cc1cccc(NC(=O)NC(C)C(=O)N(c2ccccc2)c2ccccc2)c1
Yield: 43.2 %

Procedure:
Working in a manner similar to that described in Example 1, but starting with (RS)-2-amino-N,N-diphenylpropionamide (1.2 g) and 3-methylphenyl isocyanate (0.66 g), and after recrystallization in methanol, (RS)-2-[3-(3-methylphenyl)ureido]-N,N-diphenylpropionamide (0.8 g), m.p. 197° C., is obtained.
Reaction SMILES: CS(O[CH2:6][CH2:7][C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]#[N:24])=[CH:19][CH:18]=3)=[CH:13][C:11]=2[CH:12]=1)(=O)=O.[F:25][CH2:26][C@@H:27]1[CH2:31][CH2:30][CH2:29][NH:28]1>>[F:25][CH2:26][C@@H:27]1[CH2:31][CH2:30][CH2:29][N:28]1[CH2:6][CH2:7][C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]#[N:24])=[CH:19][CH:18]=3)=[CH:13][C:11]=2[CH:12]=1
Reactant: FC[C@@H]1CCCN1
Reactant: CS(=O)(=O)OCCc1cc2cc(-c3ccc(C#N)cc3)ccc2o1
Product: N#Cc1ccc(-c2ccc3oc(CCN4CCC[C@H]4CF)cc3c2)cc1

Procedure:
The product from Example 1C and the product from Example 164C were processed as described in Example 1D to provide the titled compound, except that potassium carbonate was substituted for sodium carbonate, and the reaction was run at 60° C. for 3 days, then worked up by pouring into toluene. The organic phase was extracted with 7:2:1 of water/N-methylpyrrolidinone/10% aqueous methanesulfonic acid, and the aqueous phase then covered with isopropyl acetate and adjusted to pH 11 with 50% aqueous NaOH. After shaking and separation of the layers, the isopropanol extract was saved, then combined with a second isopropanol extract of the aqueous layer. The combined isopropanol extract was washed three times with 5% aqueous NaHCO3, water, dried over magnesium sulfate, filtered, and concentrated in vacuo to a brown oil. The free base was converted to the mono-L-tartrate salt by addition of 1 equivalent of L-tartaric acid to the free base in ethanol. Two hours after removal of some of the ethanol under vacuum, the mixture deposited an off-white solid. The solid was collected by filtrate and dried in vacuo overnight to give the title product as the tartrate salt of 4-{2-[2-(2(R)-fluoromethyl-pyrrolidin-1-yl)-ethyl]-benzofuran-5-yl}-benzonitrile, mp 156.3° C., MS m/z (M+H)+ 349; 13C NMR (DMSO) δ 158.6, 154.2, 145.2, 133.2, 132.7, 129.4, 127.7, 122.8, 119.2, 118.9, 111.2, 109.4, 103.0, 85.6 and 84.3, 72.1, 62.8, 53.5, 52.3, 27.2, 26.4, 22.7.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.[C:12]([C:14]1[CH:15]=[N:16][CH:17]=[C:18]([CH:21]=1)[C:19]#[N:20])#[CH:13]>>[F:8][C:5]1[CH:6]=[CH:7][C:2]([C:13]#[C:12][C:14]2[CH:15]=[N:16][CH:17]=[C:18]([CH:21]=2)[C:19]#[N:20])=[CH:3][C:4]=1[N+:9]([O-:11])=[O:10]
Reactant: O=[N+]([O-])c1cc(Br)ccc1F
Reactant: C#Cc1cncc(C#N)c1
Product: N#Cc1cncc(C#Cc2ccc(F)c([N+](=O)[O-])c2)c1
Yield: 9.1 %

Procedure:
Prepare essentially as described in EXAMPLE 142 using 4-bromo-1-fluoro -2-nitrobenzene (1.0 g, 4.5 mmol) and 5-ethynylnicotinonitrile, (prepared as described in PREPARATION 4), (0.7 g, 5.5 mmol) to give the title compound as a yellow solid (0.11 g, 9%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([C@H:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]([C:22](=[O:30])[C:23]3[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=3)[C@@H:14]([CH3:31])[CH2:13]2)[C:9](=[O:11])[CH3:10])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[CH2:38]([O:40][C:41](=[O:47])[C:42]([CH3:46])([CH3:45])[CH2:43]Cl)[CH3:39]>CN(C=O)C>[CH2:38]([O:40][C:41](=[O:47])[C:42]([CH3:46])([CH3:45])[CH2:43][O:29][C:26]1[CH:25]=[CH:24][C:23]([C:22]([N:15]2[C:16]3[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=3)[C@H:12]([N:8]([C:9](=[O:11])[CH3:10])[C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)[CH2:13][C@@H:14]2[CH3:31])=[O:30])=[CH:28][CH:27]=1)[CH3:39]
Reactant: CC(=O)N(c1ccc(Cl)cc1)[C@@H]1C[C@H](C)N(C(=O)c2ccc(O)cc2)c2ccccc21
Reactant: CCOC(=O)C(C)(C)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(C)COc1ccc(C(=O)N2c3ccccc3[C@H](N(C(C)=O)c3ccc(Cl)cc3)C[C@@H]2C)cc1
Temperature: 90 °C
Yield: 31.2 %

Procedure:
(2S,4R)-N-(4-Chloro-phenyl)-N-[1-(4-hydroxy-benzoyl)-2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl]-acetamide (0.32 g, 0.74 mmol) was dissolved in 10 ml DMF at room temperature and K2CO3 (0.51 g, 3.7 mmol) was added. 3-Chloro-2,2-dimethyl-propionic acid ethyl ester (0.25 g, 1.52 mmol) was added and the reaction was allowed to heat to 90° C. for 6 days. The reaction mixture was concentrated in vacuo. The residue was partitioned between ethyl acetate and water, then extracted three times with ethyl acetate, dried over MgSO4, filtered and concentrated down. The crude residue was purified by silica gel chromatography (60% EtOAc/40% Hexane) to afford the (2S,4R)-3-(4-{4-[acetyl(4-chloro-phenyl)-amino]-2-methyl-3,4-dihydro-2H-quinoline-1-carbonyl}-phenoxy)-2,2-dimethyl-propionic acid ethyl ester (0.13 g, 32%).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]2([C:21]3[C:12](=[CH:13][C:14]4[O:19][CH2:18][CH2:17][O:16][C:15]=4[CH:20]=3)[O:11][CH2:10]2)[C:2]1=[O:22].Br[CH2:24][CH2:25][CH:26]([CH3:28])[CH3:27].BrCC1CCCCO1>>[CH3:27][CH:26]([CH3:28])[CH2:25][CH2:24][N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]2([C:21]3[C:12](=[CH:13][C:14]4[O:19][CH2:18][CH2:17][O:16][C:15]=4[CH:20]=3)[O:11][CH2:10]2)[C:2]1=[O:22]
Reactant: CC(C)CCBr
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)OCCO3
Agent: BrCC1CCCCO1
Product: CC(C)CCN1C(=O)C2(COc3cc4c(cc32)OCCO4)c2ccccc21

Procedure:
Following the procedure as described in EXAMPLE 4 and making non-critical variations using 2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one to replace 5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2″(1′H)-one, and 1-bromo-3-methylbutane to replace 2-(bromomethyl)tetrahydro-2H-pyran, 1′-(3-methylbutyl)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one was obtained (64%) as a colorless solid: mp 134-137° C. (hexanes); 1H NMR (300 MHz, CDCl3) δ7.30 (ddd, J=7.7, 7.7, 1.3 Hz, 1H), 7.15 (dd, J=7.2, 0.9 Hz, 1H), 7.03 (ddd, J=7.4, 7.4, 0.7 Hz, 1H), 6.89 (d, J=7.8 Hz, 1H), 6.49 (s, 1H), 6.20 (s, 1H), 4.88 (d, J=9.0 Hz, 1H), 4.62 (d, J=9.0 Hz, 1H), 4.21-4.16 (m, 2H), 4.14-4.09 (m, 2H), 3.89-3.80 (m, 1H), 3.73-3.63 (m, 1H), 1.75-1.59 (m, 3H), 1.00 (d, J=6.3 Hz, 6H); 13C NMR (75 MHz, CDCl3) δ177.3, 155.4, 144.6, 142.5, 138.3, 132.8, 128.9, 124.0, 123.2, 121.3, 111.6, 108.6, 99.4, 80.2, 64.6, 64.0, 58.1, 38.9, 36.3, 26.2, 22.7, 22.6; MS (ES+) m/z 366.3 (M+1); Anal. Calcd for C22H23NO4: C, 72.31; H, 6.34; N, 3.83. Found: C, 72.21; H, 6.31; N, 3.55.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[C:4]([Br:11])[CH:3]=1.O.O.Cl[Sn]Cl.[OH-].[Na+]>C(O)C>[Br:1][C:2]1[CH:7]=[C:6]([CH:5]=[C:4]([Br:11])[CH:3]=1)[NH2:8]
Reactant: O=[N+]([O-])c1cc(Br)cc(Br)c1
Agent: Cl[Sn]Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Nc1cc(Br)cc(Br)c1
Temperature: 80 °C
Yield: 86.3 %

Procedure:
To a solution of 1,3-dibromo-5-nitro-benzene (85.0 g, 0.30 mol) in 1 L of ethanol was added SnCl2.2H2O (341.0 g, 1.50 mol) portion wise at room temperature. The reaction mixture was heated under reflux at 80° C. for 1.5 h. After cooling to room temperature, the solvent was evaporated under reduced pressure and the crude white solid thus obtained was basified with 4N NaOH solution to pH 12. The mixture was extracted with ethyl acetate (×3) and the combined organic layer was washed with brine solution and dried over Na2SO4. The solvent was removed under reduced pressure, to give the desired compound as a brown solid (65.0 g, 86%).
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:9])[C@H:5]([CH2:7][OH:8])[NH2:6].[C:10]([O-])([O-])=[O:11].[K+].[K+].ClC(Cl)(OC(=O)OC(Cl)(Cl)Cl)Cl>O.C1(C)C=CC=CC=1>[C:4]([C@@H:5]1[CH2:7][O:8][C:10](=[O:11])[NH:6]1)([O:3][CH3:2])=[O:9]
Reactant: COC(=O)[C@@H](N)CO
Reactant: O=C([O-])[O-]
Agent: Cl
Agent: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: COC(=O)[C@@H]1COC(=O)N1
Reaction time: 2 h
Yield: 88.4 %

Procedure:
To (S)-serine methyl ester hydrochloride (20 g, 128.64 mmol) in water (230 ml) was added KHCO3 (14.16 g, 141.52 mmol) and K2CO3 (19.56 g, 141.52 mmol) at room temperature. It was then cooled by an ice bath and triphosgene (19.04 gm, 64.32 mmol) was added in toluene (192 ml) via an addition funnel over 25 minutes. The reaction mixture turned cloudy. After 2 h, reaction phases were separated and the aqueous layer was lyophilized to yield (S)-4-carbomethoxy-2-oxazolidinone as a white solid (16.5 g) in 88% yield.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][OH:18].C(N(CC)CC)C.[CH3:26][S:27](Cl)(=[O:29])=[O:28]>ClCCl>[CH3:26][S:27]([O:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][O:11][C:2]1[CH:3]=[CH:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:1]=1)(=[O:29])=[O:28]
Reactant: OCCCCCCOc1ccc2ccccc2c1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCCCCCCOc1ccc2ccccc2c1
Reaction time: 1 h

Procedure:
To a mixture of 10.4 g. of 6-(2-naphthyloxy)-1-hexanol and 8.1 g. of triethylamine in 250 ml. of dichloromethane chilled to -8° C. under nitrogen is added dropwise 5.1 g. of methanesulfonyl chloride. After one hour at 0° to -6° C., the mixture is washed with cold water, 10% hydrochloric acid solution, saturated sodium bicarbonate solution, saturated sodium chloride solution, and dried (magnesium sulfate). The solvent is removed under vacuum to give the product as a white solid.
Reaction SMILES: [N:1]1[CH:6]=[C:5]([CH2:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:4]=[N:3][CH:2]=1.[CH:14](OCC)=[O:15].[H-].[Na+]>C(COC)OC.C(OCC)(=O)C>[CH:14]([CH:8]([CH2:7][C:5]1[CH:6]=[N:1][CH:2]=[N:3][CH:4]=1)[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[O:15]
Reactant: CCOC(=O)CCc1cncnc1
Reactant: CCOC=O
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: CCOC(=O)C(C=O)Cc1cncnc1
Reaction time: 24 h

Procedure:
A mixture of ethyl 3-(5-pyrimidyl)propionate (2.28 g) and ethyl formate (1.41 ml) dissolved in dry dimethoxyethane (5 ml) was added dropwise over 30 min to a suspension of sodium hydride (60%, 4.0 g) in DME (5 ml) under nitrogen, keeping the temperature below 0° C. Stirring was continued for a further 24 h, then the mixture was poured onto ice and washed with ether. The aqueous layer was adjusted to pH 7, then evaporated and the residue extracted with acetone. Filtration and evaporation gave crude product, which was taken up in ethyl acetate, charcoaled, dried and evaporated to give ethyl 2-formyl-3-(5-pyrimidyl)propionate. Like other compounds of this type, this proved difficult to characterise and was used without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]([C:22]2[CH:27]=[CH:26][C:25]([C:28]([N:30]([CH2:33][CH3:34])[CH2:31][CH3:32])=[O:29])=[CH:24][CH:23]=2)[N:9]2[CH2:14][CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11][CH2:10]2)[CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.[CH:42]1([C:48](Cl)=[O:49])[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]1>ClCCl.CN(C1C=CN=CC=1)C>[CH:42]1([C:48]([NH:1][C:2]2[CH:3]=[C:4]([C@@H:8]([N:9]3[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]3)[C:22]3[CH:27]=[CH:26][C:25]([C:28]([N:30]([CH2:33][CH3:34])[CH2:31][CH3:32])=[O:29])=[CH:24][CH:23]=3)[CH:5]=[CH:6][CH:7]=2)=[O:49])[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]1
Reactant: CCN(CC)C(=O)c1ccc(C(c2cccc(N)c2)N2CCN(C(=O)OC(C)(C)C)CC2)cc1
Reactant: O=C(Cl)C1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCN(CC)C(=O)c1ccc([C@@H](c2cccc(NC(=O)C3CCCCC3)c2)N2CCNCC2)cc1
Reaction time: 5 h

Procedure:
To a room temperature solution of INTERMEDIATE 5a (250 mg; 0.54 mmol) in dichloromethane (5 mL) were added triethylamine (0.15 mL; 1.08 mmol), DMAP (cat.) and cyclohexane carbonyl chloride (86 μL; 0.64 mmol). The reaction mixture was stirred for 5 hours then more triethylamine (0.08 mL; 0.58 mmol) and DMAP (cat.) were added. The reaction mixture was stirred overnight then more cyclohexane carbonyl chloride (28 μL; 0.21 mmol) was added. The reaction mixture stirred for 5 hours then was washed with two portions of saturated sodium bicarbonate. The organic phase was dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure. Column chromatography eluting with 2% methanol in dichloromethane gave the desired product.
Reaction SMILES: O1CCOCC1.[NH2:7][C:8]1[CH:9]=[CH:10][C:11]([CH3:15])=[CH:12][C:13]=1[OH:14].C(=O)([O-])[O-].[Ca+2].[Cl:21][CH2:22][C:23](Cl)=[O:24]>O>[OH:14][C:13]1[CH:12]=[C:11]([CH3:15])[CH:10]=[CH:9][C:8]=1[NH:7][C:23](=[O:24])[CH2:22][Cl:21]
Reactant: O=C(Cl)CCl
Reactant: Cc1ccc(N)c(O)c1
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: O
Solvent: C1COCCO1
Product: Cc1ccc(NC(=O)CCl)c(O)c1
Temperature: 60 °C
Reaction time: 2 h
Yield: 72.4 %

Procedure:
To 130 ml of dioxane, were added 20.0 g (163 mmol) of 6-amino-m-cresol and 9.2 g (92 mmol) of calcium carbonate, followed by heating to 60° C. To the obtained solution, there was added 22.1 g (196 mmol) of chloroacetyl chloride over 40 minutes and the mixture was further stirred at 60° C. for 2 hours. After cooling, the mixture was poured into 500 ml of water, extracted with 700 ml of ethyl acetate and dried over anhydrous Glauber's salt. After distilling off the solvent under reduced pressure, the obtained greenish brown solid was recrystallized from acetonitrile. Thus 23.5 g (118 mmol) of N-(2-hydroxy-4-methylphenyl)chloroacetamide was obtained as pale green crystals. The yield was 72%.
Reaction SMILES: [CH:1]1([C:4](Cl)=[O:5])[CH2:3][CH2:2]1.[N+:7](=[CH:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[N-:8]>CCOCC>[CH:1]1([C:4](=[O:5])[C:9](=[N+:7]=[N-:8])[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:3][CH2:2]1
Reactant: O=C(Cl)C1CC1
Reactant: CCOC(=O)C=[N+]=[N-]
Solvent: CCOCC
Product: CCOC(=O)C(=[N+]=[N-])C(=O)C1CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 44.2 %

Procedure:
Cyclopropanecarbonyl chloride (36 g, 0.34 mol) was added dropwise to a stirred solution of ethyl diazoacetate (86.2 g, 0.76 mol) in dry ether (500 ml) at 0° C. under a nitrogen atmosphere. The mixture was allowed to warm to room temperature then was stirred for 1 day, heated to gentle reflux for 2 days, then left to stand at room temperature for 5 days. Evaporation of the mixture followed by distillation afforded ethyl 3-cyclopropyl-2-diazo-3-oxo-propanoate (27.4 g, 44%) bp 85°-90° at 1 mm Hg).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:14]2[CH2:13][CH2:12][CH2:11][CH2:10][C:9]=2[CH:8]=[CH:7][C:6]=1[NH2:15])=[O:4].[C:16]1([S:22](Cl)(=[O:24])=[O:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>N1C=CC=CC=1>[CH3:1][O:2][C:3]([C:5]1[C:14]2[CH2:13][CH2:12][CH2:11][CH2:10][C:9]=2[CH:8]=[CH:7][C:6]=1[NH:15][S:22]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)(=[O:24])=[O:23])=[O:4]
Reactant: COC(=O)c1c(N)ccc2c1CCCC2
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: c1ccncc1
Product: COC(=O)c1c(NS(=O)(=O)c2ccccc2)ccc2c1CCCC2
Reaction time: 1 h

Procedure:
To a solution of 2-amino-5,6,7,8-tetrahydronaphthalene-1-carboxylic acid methyl ester (Intermediate 5, 1.5 g) in pyridine (20 mL) was added benzenesulfonyl chloride (0.95 mL). The mixture was stirred for 1 hour then concentrated under vacuum. The residue was dissolved in ethyl acetate and washed with 1N hydrochloric acid, dried with magnesium sulfate and filtered. The filtrate was evaporated under vacuum to give the title compound as an off-white crystalline solid (2.4 g).
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:8])[CH2:6][NH2:7])[CH3:3].C(N(CC)CC)C.[N+:16]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[S:25](Cl)(=[O:27])=[O:26])([O-:18])=[O:17].Cl>C(Cl)Cl>[N+:16]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[S:25]([NH:7][CH2:6][C:5]([O:4][CH2:2][CH3:3])=[O:8])(=[O:27])=[O:26])([O-:18])=[O:17]
Reactant: CCOC(=O)CN
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)CNS(=O)(=O)c1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 48 h
Yield: 83 %

Procedure:
To a suspension of glycine ethyl ester hydrochloride (9.45 g) in methylene chloride (100 ml) were added triethylamine (18.9 ml) and 2-nitrobenzenesulfonyl chloride (10.0 g) in succession under cooling with ice and the mixture was stirred at room temperature for 2 days. To the reaction mixture was added 1N hydrochloric acid under cooling with ice, followed by extraction with methylene chloride. The organic layer was washed with saturated aqueous solution of sodium hydrogencarbonate, then saturated sodium chloride solution, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the precipitated crystals were washed with a mixed solvent of n-hexane and diethyl ether, collected by filtration and air-dried to obtain the title compound (10.8 g).