Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([CH3:27])([CH3:26])[C:3]([O:5][CH2:6][N:7]1[C:15]2[N:14]=[CH:13][NH:12][C:11]=2[C:10](=[O:16])[N:9]([CH2:17][O:18][C:19](=[O:24])[C:20]([CH3:23])([CH3:22])[CH3:21])[C:8]1=[O:25])=[O:4].[Cl:28]N1C(=O)CCC1=O>CN(C)C=O.C(OCC)(=O)C>[Cl:28][C:13]1[NH:12][C:11]2[C:10](=[O:16])[N:9]([CH2:17][O:18][C:19](=[O:24])[C:20]([CH3:21])([CH3:23])[CH3:22])[C:8](=[O:25])[N:7]([CH2:6][O:5][C:3](=[O:4])[C:2]([CH3:27])([CH3:26])[CH3:1])[C:15]=2[N:14]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: CC(C)(C)C(=O)OCn1c(=O)c2[nH]cnc2n(COC(=O)C(C)(C)C)c1=O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)C(=O)OCn1c(=O)c2[nH]c(Cl)nc2n(COC(=O)C(C)(C)C)c1=O
Reaction time: 0.17 h
Yield: 63.9 %

Procedure:
2,2-Dimethylpropionic acid [3-(2,2-dimethylpropionyloxymethyl)-2,6-dioxo-2,3,6,7-tetrahydropurin-1-yl]methyl ester (2.31 g) was dissolved in N,N-dimethylformamide (18 ml), and N-chlorosuccinimide (973 mg) was added to the solution while cooling on ice. Then, the mixture was stirred for 10 minutes on ice, and then at room temperature for 20 hours. The obtained reaction mixture was diluted with ethyl acetate, washed with water, and dried over anhydrous magnesium sulfate. After removing the solvent by distillation from the organic layer, the residue was purified by silica gel column chromatography to give 1.61 g of the title compound from the elution fraction of hexane-ethyl acetate (1:1).
Reaction SMILES: [Cl:1][C:2]1[C:6]([CH2:7][OH:8])=[C:5]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)[S:4][N:3]=1.[F:16][C:17]1[C:22]([F:23])=[C:21](O)[CH:20]=[CH:19][C:18]=1/[CH:25]=[CH:26]/[C:27]([O:29]CC)=[O:28]>>[Cl:1][C:2]1[C:6]([CH2:7][O:8][C:21]2[CH:20]=[CH:19][C:18](/[CH:25]=[CH:26]/[C:27]([OH:29])=[O:28])=[C:17]([F:16])[C:22]=2[F:23])=[C:5]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)[S:4][N:3]=1
Reactant: OCc1c(Cl)nsc1-c1ccc(Cl)cc1
Reactant: CCOC(=O)/C=C/c1ccc(O)c(F)c1F
Product: O=C(O)/C=C/c1ccc(OCc2c(Cl)nsc2-c2ccc(Cl)cc2)c(F)c1F

Procedure:
The title compound was prepared according to the procedure described in Example 135 following Step 8 and 9 by coupling of (3-chloro-5-(4-chlorophenyl)isothiazol-4-yl)methanol and (E)-ethyl 3-(2,3-difluoro-4-hydroxyphenyl)acrylate then hydrolysis to afford the desired product as an off-white solid. 1H NMR (400 MHz, CDCl3) δ 7.81 (d, J=12.5 Hz, 1H), 7.48 (s, 2H), 7.28 (s, 2H), 6.52 (d, J=11.5 Hz, 1H), 5.04 (s, 2H).
Reaction SMILES: [C:1]([CH2:3][CH2:4][N:5]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][C:7]([OH:9])=O)#[N:2].C(N1C=CN=C1)(N1C=CN=C1)=O.Cl.[CH2:30]([NH2:41])[CH2:31][C:32]1[CH:40]=[CH:39][C:38]2[O:37][CH2:36][O:35][C:34]=2[CH:33]=1.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[C:1]([CH2:3][CH2:4][N:5]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][C:7]([NH:41][CH2:30][CH2:31][C:32]1[CH:40]=[CH:39][C:38]2[O:37][CH2:36][O:35][C:34]=2[CH:33]=1)=[O:9])#[N:2]
Reactant: NCCc1ccc2c(c1)OCO2
Reactant: CC(C)(C)OC(=O)N(CCC#N)CC(=O)O
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N(CCC#N)CC(=O)NCCc1ccc2c(c1)OCO2
Reaction time: 0.5 h
Yield: 88.8 %

Procedure:
In a manner similar to the preparation of compounds of formula (Yc3) above, to 2-[(2-cyanoethyl)(dimethylethoxycarbonyl)amino]acetic acid (8.3 g, 39 mmol) dissolved in CH2Cl2 (100 mL) was added carbonyldiimidazole (6.2 g, 38 mmol). After stirring for 30 minutes, homopiperonylamine, hydrochloride (8.0 g, 41 mmol) and diisopropylethylamine (7.5 mL, 43 mmol) were added. After stirring for 18 hours, most of the solvent was removed in vacuo and the residue was partitioned with ethyl acetate and 1N HCl. The organic layer was separated, washed with aqueous bicarbonate and brine, dried (Na2SO4), and the solvent was removed in vacuo to give 13 g of 2-[(2-cyanoethyl)(dimethylethoxycarbonyl)amino]-N-[2-(1,3-benzodioxol-5-yl)ethyl]acetamide.
Reaction SMILES: [O:1]=[C:2]1[C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:10][C:9]([C:18]([O:20]C)=[O:19])=[C:8]2[N:3]1[CH:4]=[CH:5][C:6]1[CH:24]=[CH:23][S:22][C:7]=12.[OH-].[K+].Cl>O.CO>[O:1]=[C:2]1[C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:10][C:9]([C:18]([OH:20])=[O:19])=[C:8]2[N:3]1[CH:4]=[CH:5][C:6]1[CH:24]=[CH:23][S:22][C:7]=12
Reactant: COC(=O)c1cc(-c2ccccc2)c(=O)n2ccc3ccsc3c12
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1cc(-c2ccccc2)c(=O)n2ccc3ccsc3c12

Procedure:
aa) 1.34 g of methyl 7-oxo-8-phenyl-7H-thieno[2,3-a]quinolizine-10-carboxylate were heated under reflux and under argon with 0.45 g of potassium hydroxide in 25 ml of water/methanol. After the reaction was completed, the mixture was acidified with 2N hydrochloric acid and the yellow crystals were removed by filtration. After washing with water, the acid was dried in vacuo for several hours. There was obtained 7-oxo-8-phenyl-7H-thieno[2,3-a]quinolizine-10-carboxylic acid of m.p 185°-186° (dec.).
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])[NH:7][C:8]1[S:9][C:10](Br)=[CH:11][N:12]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:15][Si:16]([C:19]#[CH:20])([CH3:18])[CH3:17].O>C(N(CC)CC)C.[Cu]I>[C:1]([O:5][C:6](=[O:14])[NH:7][C:8]1[S:9][C:10]([C:20]#[C:19][Si:16]([CH3:18])([CH3:17])[CH3:15])=[CH:11][N:12]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: C#C[Si](C)(C)C
Reactant: CC(C)(C)OC(=O)Nc1ncc(Br)s1
Agent: [Cu]I
Solvent: O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)Nc1ncc(C#C[Si](C)(C)C)s1
Temperature: 80 °C
Yield: 79.1 %

Procedure:
(5-Bromo-thiazol-2-yl)-carbamic acid tert-butyl ester (2.0 g, 7.164 mmol) was taken in triethylamine (20 ml). To this solution was added CuI (0.041 g, 0.215 mmol), PdCl2 (PPh3)2 (0.050 g, 0.071 mmol) followed by the addition of trimethylsilylacetylene (1.055 g, 10.741 mmol). The reaction was heated at 80° C. overnight. Reaction mixture was cooled to room temperature and poured into water (50 ml), extracted with ethyl acetate (30 ml×3). The combined organic layer was washed with 1N HCl followed by brine and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure. The crude product was purified by column chromatography over silica gel using 6% ethyl acetate hexane as eluent to provide pure (5-trimethylsilanylethynyl-thiazol-2-yl)-carbamic acid tert-butyl ester (1.679 g).
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][CH:10]=[C:9]([Si:13]([CH3:16])([CH3:15])[CH3:14])[C:3]=1[C:4]([N:6]=[C:7]=[O:8])=[O:5].[CH:17]([NH2:20])([CH3:19])[CH3:18]>C1(C)C=CC=CC=1.CCCCCC.C(=O)=O>[Cl:1][C:2]1[CH:12]=[CH:11][CH:10]=[C:9]([Si:13]([CH3:16])([CH3:15])[CH3:14])[C:3]=1[C:4]([NH:6][C:7]([NH:20][CH:17]([CH3:19])[CH3:18])=[O:8])=[O:5]
Reactant: CC(C)N
Reactant: C[Si](C)(C)c1cccc(Cl)c1C(=O)N=C=O
Agent: O=C=O
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: CC(C)NC(=O)NC(=O)c1c(Cl)cccc1[Si](C)(C)C
Reaction time: 0.5 h

Procedure:
2-Chloro-6-trimethylsilylbenzoyl isocyanate (1.3 g, 5 mmol) was dissolved in 40 mL toluene and isopropyl amine (1 g) added over a period of 30 seconds. After stirring 30 min, the solvent was removed to yield an oil. The oil was dissolved in hexane and cooled in dry ice to yield 1.2 g of crystals of the title compound. m.p. 113°-116° C.
Reaction SMILES: O.[NH2:2][CH:3]1[CH2:8][CH2:7][N:6]([CH2:9][CH2:10][C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[NH:13][CH:12]=2)[CH2:5][CH2:4]1.[C:20]1([N:26]=[C:27]=[S:28])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C1C=CC=CC=1>[C:20]1([NH:26][C:27]([NH:2][CH:3]2[CH2:8][CH2:7][N:6]([CH2:9][CH2:10][C:11]3[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[NH:13][CH:12]=3)[CH2:5][CH2:4]2)=[S:28])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: S=C=Nc1ccccc1
Reactant: NC1CCN(CCc2c[nH]c3ccccc23)CC1
Solvent: O
Solvent: c1ccccc1
Product: S=C(Nc1ccccc1)NC1CCN(CCc2c[nH]c3ccccc23)CC1
Reaction time: 24 h

Procedure:
4-Amino-1-[2-(3-indolyl)ethyl]piperidine hydrate (1.31 g, 0.005 mole) was dissolved in benzene (125 ml) and phenyl isothiocyanate (0.74g, 0.0055 mole) added dropwise with stirring. After 24 hr., the mixture was filtered to give the title compound (free base) as a white amorphous solid (1.76g). This was dissolved in a minimum of hot ethanol, saturated ethanol-HCl added until acid, and then the solution allowed to crystallise. Filtration afforded the title compound hydrochloride as colourless prisms (1.75g), m.p. 224.8°.
Reaction SMILES: [N:1]([CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[N:12]=[N:13][S:14][CH:15]=1)=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>O1CCCC1>[S:14]1[CH:15]=[C:11]([C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[CH2:4][NH2:1])[N:12]=[N:13]1
Reactant: [N-]=[N+]=NCc1ccccc1-c1csnn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: NCc1ccccc1-c1csnn1

Procedure:
A solution of 4-(2-azidomethyl-phenyl)-[1,2,3]thiadiazole (1.0 g, 4.6 mmol), triphenylphosphine (1.4 g, 5.5 mmol) and water (0.12 ml, 6.9 mmol) in tetrahydrofuran (20 ml) was stirred at room temperature overnight. Solvent evaporation and flash chromatography (silica gel, chloroform-2-propanol, 95:5–92:8) gave 2-[1,2,3]thiadiazole-4-yl-benzylamine; 1H NMR (CDCl3, 300 MHz) δ 8.87 (s, 1H), 7.67 (d, 1H, J=8 Hz), 7.45 (m, 3H), 3.88 (s, 2H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:19])=[CH:4][C:5]([N:14]2[CH:18]=[N:17][N:16]=[N:15]2)=[C:6](/[CH:8]=[CH:9]/[C:10]([O:12]C)=[O:11])[CH:7]=1.[OH-].[Na+]>CO.C1COCC1>[Cl:1][C:2]1[C:3]([F:19])=[CH:4][C:5]([N:14]2[CH:18]=[N:17][N:16]=[N:15]2)=[C:6](/[CH:8]=[CH:9]/[C:10]([OH:12])=[O:11])[CH:7]=1
Reactant: COC(=O)/C=C/c1cc(Cl)c(F)cc1-n1cnnn1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)/C=C/c1cc(Cl)c(F)cc1-n1cnnn1
Yield: 42.1 %

Procedure:
To Intermediate 5C (5 g, 17.7 mmol) in MeOH (50 mL) and THF (25 mL) was added 10% NaOH solution (25 mL). After 2H, the reaction was concentrated and the residue was diluted with H2O. The pH was adjusted to 2 to 3 with 1.5N HCl and the resultant solid was filtered and washed with petroleum ether to afford 2 g of Intermediate 5. MS (ESI) m/z: 269.0 (M+H)+.
Reaction SMILES: C(O)(C(F)(F)F)=O.C(OC([N:15]1[CH2:20][C@@H:19]2[CH2:21][C@H:16]1[CH2:17][N:18]2[CH2:22][C:23]1[N:24]([CH3:49])[C:25]2[C:30]([N:31]=1)=[C:29]([N:32]1[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1)[N:28]=[C:27]([N:38]1[C:42]3[CH:43]=[CH:44][CH:45]=[CH:46][C:41]=3[N:40]=[C:39]1[CH2:47][CH3:48])[N:26]=2)=O)(C)(C)C>C(Cl)Cl>[C@H:19]12[CH2:21][C@H:16]([NH:15][CH2:20]1)[CH2:17][N:18]2[CH2:22][C:23]1[N:24]([CH3:49])[C:25]2[C:30]([N:31]=1)=[C:29]([N:32]1[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1)[N:28]=[C:27]([N:38]1[C:42]3[CH:43]=[CH:44][CH:45]=[CH:46][C:41]=3[N:40]=[C:39]1[CH2:47][CH3:48])[N:26]=2
Reactant: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3C[C@@H]4C[C@H]3CN4C(=O)OC(C)(C)C)n(C)c2n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3C[C@@H]4C[C@H]3CN4)n(C)c2n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 63 %

Procedure:
A mixture of 2-(2-ethylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purine-8-carbaldehyde (200 mg, 0.51 mmol), (1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (122 mg, 0.62 mmol) and molecular sieves (4 Å, powdered, 520 mg) in DCE (10 mL) was stirred at ambient temperature for 3 h. Sodium triacetoxyborohydride (162 mg, 0.76 mmol) was added and the mixture stirred for 17 h, then loaded onto an Isolute® SCX-2 cartridge (25 g). The cartridge was then washed with methanol and the desired product was subsequently eluted using 2 M NH3 in MeOH. The product was collected and concentrated in vacuo. The resultant residue was purified by flash chromatography (Si—PPC, EtOAc:MeOH; gradient from 100:0 to 85:15) to give (1S,4S)-5-[2-(2-ethylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purin-8-ylmethyl]-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester as a white solid. TFA (3 mL) was added to a solution of (1S,4S)-5-[2-(2-ethylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purin-8-ylmethyl]-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester in DCM (10 mL) and the mixture stirred at ambient temperature for 30 min, then loaded onto an Isolute® SCX-2 cartridge (25 g). The cartridge was then washed with methanol and the desired product was subsequently eluted using 2 M NH3 in MeOH. The product was collected and concentrated in vacuo. The resultant residue was purified by flash chromatography (Si—PPC, DCM: MeOH; gradient from 100:0 to 85:15) to afford 395 as a white solid (153 mg, 63%). LCMS (Method G): RT=5.78 min, M+H+=474. 1H NMR (CDCl3, 400 MHz) δ 8.01 (m, 1 H); 7.75 (m, 1 H); 7.26 (m, 2 H); 4.34 (m, 4 H); 4.00 (d, J=13.6 Hz, 1 H); 3.92-3.83 (m, 8 H); 3.70 (s, 1 H); 3.45 (s, 1 H); 3.35 (q, J=7.5 Hz, 2 H); 3.25 (d, J=10.2 Hz, 1 H); 2.97-2.91 (m, 2 H); 2.70 (d, J=10.2 Hz, 1 H); 1.85 (d, J=10.1 Hz, 1 H); 1.70 (d, J=10.1 Hz, 1 H) and 1.45 (t, J=7.5 Hz, 3 H)
Reaction SMILES: [O:1]=[C:2]1[N:10]([CH2:11][CH2:12][CH3:13])[C:9]2[N:8]=[C:7]([C:14]34[CH2:21][CH2:20][C:17]([CH2:22][CH2:23][C:24](O)=[O:25])([CH2:18][CH2:19]3)[CH2:16][CH2:15]4)[NH:6][C:5]=2[C:4](=[O:27])[N:3]1[CH2:28][CH2:29][CH3:30]>C1COCC1.CO>[OH:25][CH2:24][CH2:23][CH2:22][C:17]12[CH2:16][CH2:15][C:14]([C:7]3[NH:6][C:5]4[C:4](=[O:27])[N:3]([CH2:28][CH2:29][CH3:30])[C:2](=[O:1])[N:10]([CH2:11][CH2:12][CH3:13])[C:9]=4[N:8]=3)([CH2:21][CH2:20]1)[CH2:19][CH2:18]2
Reactant: CCCn1c(=O)c2[nH]c(C34CCC(CCC(=O)O)(CC3)CC4)nc2n(CCC)c1=O
Solvent: CO
Solvent: C1CCOC1
Product: CCCn1c(=O)c2[nH]c(C34CCC(CCCO)(CC3)CC4)nc2n(CCC)c1=O
Reaction time: 60 h
Yield: 85.7 %

Procedure:
To a solution of 3-[4-(2,6-dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-bicyclo-[2.2.2]oct-1-yl]-propionic acid (41.7 mg, 1.0 mmol) in THF (25 ml), cooled to 0° C. with the aid of an ice bath, was added BH3 (1.0 M in THF, 3.0 mmol). The resulting mixture was allowed to reach ambient temperature and stirred for a period of 60 h. Following the addition of MeOH (10 ml), the mixture was concentrated in vacuo to afford a white solid that was dissolved in MeOH. (20 ml), stirred at rt for 2 h and evaporated to dryness in vacuo. The resulting white solid was recrystallized from EtOAc to afford 345 mg (86%) of a white powder MS: 403 (MH−).
Reaction SMILES: [C:1]12([CH2:10][NH2:11])[C:7]([CH3:9])([CH3:8])[CH:4]([CH2:5][CH2:6]1)[CH2:3][CH2:2]2.[CH:12](=O)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.O>C1(C)C=CC=CC=1>[CH:12](=[C:10]([NH2:11])[C:1]12[C:7]([CH3:8])([CH3:9])[CH:4]([CH2:5][CH2:6]1)[CH2:3][CH2:2]2)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CC1(C)C2CCC1(CN)CC2
Reactant: O=Cc1ccccc1
Solvent: O
Solvent: Cc1ccccc1
Product: CC1(C)C2CCC1(C(N)=Cc1ccccc1)CC2

Procedure:
10-Bornanamine (824mg) in toluene (20ml) was treated with benzaldehyde (0.55ml) and the solution refluxed under nitrogen under a Dean and Stark water trap for four days. Evaporation of the solvent in vacuo afforded impure 10-benzylidene-10-bornanamine which was dissolved in dimethoxyethane (10ml) containing lithium aluminium hydride (112mg.). The resulting mixture was refluxed for 2.25 hours, cooled, and the excess hydride decomposed by the addition of water. The precipitated inorganic material was removed by filtration and the solvent was evaporated in vacuo. The residual gum was triturated with 2N-hydrochloric acid to afford an insoluble hydrochloride which was collected by filtration and then partitioned between ether and 2N-sodium hydroxide. The dried ethereal layer was evaporated in vacuo to give a yellow oil which was dissolved in ether and treated with ethanolic hydrogen chloride. The precipitated solid was collected and recrystallized from water to give title compound m.p. 310° (Found: C, 72.65; H, 9.65; Cl, 13.3; N, 4.95. C17H26ClN requires C, 72.95; H, 9.35; Cl, 12.65; N, 5.0%).
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]Cl.[Mg].[Cl:9][C:10]1[CH:11]=[C:12]([CH:15]=[CH:16][CH:17]=1)[CH:13]=[O:14].O>O1CCCC1>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH:13]([C:12]1[CH:15]=[CH:16][CH:17]=[C:10]([Cl:9])[CH:11]=1)[OH:14]
Reactant: O=Cc1cccc(Cl)c1
Reactant: ClCCCCCBr
Agent: [Mg]
Solvent: O
Solvent: C1CCOC1
Product: OC(CCCCCBr)c1cccc(Cl)c1

Procedure:
A solution (30 ml) of 1-bromo-5-chloropentane (7.0 g) in tetrahydrofuran was gently added dropwise under refluxing to a suspension (30 ml) of magnesium (0.92 g) in tetrahydrofuran. After confirmation of disappearance of magnesium, a solution (30 ml) of 3-chlorobenzaldehyde (5.3 g) in tetrahydrofuran was dropwise added. After cooling, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give 6-bromo-1-(3-chlorophenyl)-1-hexanol, which was dissolved in chloroform (50 ml). Thereto was added 15 equivalents of manganese dioxide, and the mixture was stirred at room temperature for 48 hr. The reaction mixture was filtered, and the residue was purified by silica gel column chromatography to give 6-bromo-1-(3-chlorophenyl)-1-hexanone.
Reaction SMILES: [C:1]([S:4][CH2:5][C@H:6]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][C@H:9]([C:16]([OH:18])=[O:17])[NH:8][C:7]1=[O:19])(=[O:3])[CH3:2].[CH2:20](Br)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O.O>[C:1]([S:4][CH2:5][C@H:6]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][C@H:9]([C:16]([O:18][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:17])[NH:8][C:7]1=[O:19])(=[O:3])[CH3:2]
Reactant: CC(=O)SC[C@H]1CCCCCC[C@H](C(=O)O)NC1=O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)SC[C@H]1CCCCCC[C@H](C(=O)OCc2ccccc2)NC1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Trans 3-(acetylthiomethyl)-2-oxo-1-azacyclodecane-10-carboxylic acid (0.15 g, 0.52 mmol) is dissolved in dimethylformamide (2.5 mL). Benzyl bromide (0.062 mL, 0.52 mmol) and cesium carbonate (0.085 g, 0.26 mmol) are added, and the reaction is stirred at room temperature overnight. The reaction is diluted with water, and the aqueous layer is extracted several times with methylene chloride. The combined organic layers are dried (MgSO4), and the solvent is evaporated. The product is purified by silica gel chromatography (10% ethyl acetate/hexane) to give trans benzyl 3-(acetylthiomethyl)-2-oxo-1-azacyclodecane-10-carboxylate m.p. 117°-118° C.
Reaction SMILES: CC(OC(/N=N/C(OC(C)C)=O)=O)C.C1(C)C=CC=CC=1.[F:22][C:23]([F:42])([F:41])[O:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]2[CH:32]=[CH:33][C:34]3[O:38][N:37]=[C:36]([OH:39])[C:35]=3[CH:40]=2)=[CH:27][CH:26]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:62][N:63]1[CH:67]=[C:66]([CH2:68]O)[N:65]=[CH:64]1>C1COCC1>[CH3:62][N:63]1[CH:67]=[C:66]([CH2:68][O:39][C:36]2[C:35]3[CH:40]=[C:31]([C:28]4[CH:29]=[CH:30][C:25]([O:24][C:23]([F:22])([F:41])[F:42])=[CH:26][CH:27]=4)[CH:32]=[CH:33][C:34]=3[O:38][N:37]=2)[N:65]=[CH:64]1
Reactant: Cn1cnc(CO)c1
Reactant: Oc1noc2ccc(-c3ccc(OC(F)(F)F)cc3)cc12
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: Cn1cnc(COc2noc3ccc(-c4ccc(OC(F)(F)F)cc4)cc23)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 30.3 %

Procedure:
Diisopropylazodicarboxylate 40% solution in toluene (0.27 mL, 0.51 mmol) was added under stirring to a solution of 5-(4-(trifluoromethoxy)phenyl)benzo[d]isoxazol-3-ol (100 mg, 0.34 mmol), triphenylphosphine on resin (3 mmol/g) (330 mg, 1 mmol), and 1-methylimidazol-4-yl methanol (60 mg, 0.51 mmol) in THF. The reaction mixture was stirred at ambient temperature overnight. Volatiles were evaporated under vacuum and the residue was purified on 12 g silica gel with 0-20% methanol in dichloromethane and gave the title compound (40 mg, 0.103 mmol) as yellowish oil.
Reaction SMILES: [C:1]1(C)C=CC(S(O)(=O)=O)=CC=1.[OH:12][C:13]1[CH:14]=[C:15]([CH:19]=[CH:20][C:21]=1[I:22])[C:16]([OH:18])=[O:17].O>CO>[OH:12][C:13]1[CH:14]=[C:15]([CH:19]=[CH:20][C:21]=1[I:22])[C:16]([O:18][CH3:1])=[O:17]
Reactant: O=C(O)c1ccc(I)c(O)c1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CO
Product: COC(=O)c1ccc(I)c(O)c1
Temperature: 70 °C
Yield: 377.8 %

Procedure:
6.1 g (35.6 mmol) of paratoluene sulfonic acid is added to a solution of 47 g (150 mmol) of 3-hydroxy-4-iodobenzoic acid in 300 ml of methanol. The reaction mixture is heated at 70° C. for 48 hours. After adding 1000 ml of water, the precipitate is filtered, and rinsed with water to neutral pH. 37.4 g (76%) of methyl 3-hydroxy-4-iodobenzoate is obtained in the form of a beige powder.
Reaction SMILES: [CH3:1][N:2]([CH3:30])[C:3]1[CH:29]=[CH:28][C:6]([C:7]([N:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C@H:12]([NH:19][C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)[CH2:11][C@@H:10]2[CH3:27])=[O:8])=[CH:5][CH:4]=1.C(N(C(C)C)CC)(C)C.[C:40](Cl)(=[O:42])[CH3:41]>C(Cl)Cl>[Cl:26][C:23]1[CH:22]=[CH:21][C:20]([N:19]([C@H:12]2[C:13]3[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:9]([C:7](=[O:8])[C:6]3[CH:5]=[CH:4][C:3]([N:2]([CH3:1])[CH3:30])=[CH:29][CH:28]=3)[C@@H:10]([CH3:27])[CH2:11]2)[C:40](=[O:42])[CH3:41])=[CH:25][CH:24]=1
Reactant: CC(=O)Cl
Reactant: C[C@H]1C[C@@H](Nc2ccc(Cl)cc2)c2ccccc2N1C(=O)c1ccc(N(C)C)cc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N(c1ccc(Cl)cc1)[C@@H]1C[C@H](C)N(C(=O)c2ccc(N(C)C)cc2)c2ccccc21
Temperature: 25 °C
Reaction time: 4 h
Yield: 34 %

Procedure:
To a solution of (±)-cis-1-(4-dimethylamino-benzoyl)-2-methyl-1,2,3,4-tetrahydro-4-(N-4-chlorophenyl)aminoquinoline (120 mg, 0.29 mmol) in methylene chloride (2 mL) was added diisopropylethylamine (37 mg, 0.051 mL, 0.29 mmol) followed by acetyl chloride (2 mL). The mixture was stirred at rt 4 h. The mixture was concentrated under reduced pressure, dissolved in ethyl acetate, washed with sat. aqueous sodium bicarbonate, brine and dried over sodium sulfate. The drying agent was removed by filtration under reduced pressure, concentrated and purified by silica gel chromatography (100% hexanes-25/75 hexanes/ethyl acetate gradient) to afford pure (±)-cis-N-(4-chloro-phenyl)-N-[1-(4-dimethylamino-benzoyl)-2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl]-acetamide (45 mg, 34%).
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:32])=[C:4]([N:8]2[C:13](=[O:14])[CH:12]([Se]C3C=CC=CC=3)[CH2:11][N:10]([CH2:22][C:23]3[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=3)[C:9]2=[O:31])[CH:5]=[CH:6][CH:7]=1.OO.O>C1COCC1>[Br:1][C:2]1[C:3]([CH3:32])=[C:4]([N:8]2[C:13](=[O:14])[CH:12]=[CH:11][N:10]([CH2:22][C:23]3[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=3)[C:9]2=[O:31])[CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(CN2CC([Se]c3ccccc3)C(=O)N(c3cccc(Br)c3C)C2=O)cc1
Agent: OO
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(Cn2ccc(=O)n(-c3cccc(Br)c3C)c2=O)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 53.8 %

Procedure:
A solution of 3-(3-bromo-2-methylphenyl)-1-(4-methoxybenzyl)-5-(phenylselanyl)dihydropyrimidine-2,4(1H,3H)-dione (5.43 g, 9.73 mmol) in THF (97 mL) was treated with 30% aqueous hydrogen peroxide (5.0 mL, 48.6 mmol) and the mixture was stirred at room temperature for 30 min. Water was added and the mixture was extracted with EtOAc. The organic phase was washed with brine, dried and concentrated. The residue was purified by column chromatography on silica gel (220 g), eluting with EtOAc-hexanes (gradient from 25-70%), to provide 3-(3-bromo-2-methylphenyl)-1-(4-methoxybenzyl)pyrimidine-2,4(1H,3H)-dione as a white solid (2.10 g, 54% yield). Mass spectrum m/z 401, 403 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ 7.95 (d, J=7.9 Hz, 1H), 7.70-7.65 (m, 1H), 7.32-7.28 (m, 2H), 7.25-7.22 (m, 2H), 6.96-6.91 (m, 2H), 5.86 (d, J=7.9 Hz, 1H), 4.89 (d, J=2.4 Hz, 2H), 3.74 (s, 3H), 2.02 (s, 3H).