Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:16](=[O:17])[C:15]3[CH:18]=[CH:19][CH:20]=[CH:21][C:14]=3[NH:13][C:12](=[O:22])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.[H-].[Na+].[CH3:25][N:26]([CH2:28][CH2:29]Cl)[CH3:27]>C1(C)C=CC=CC=1>[CH3:25][N:26]([CH3:27])[CH2:28][CH2:29][N:13]1[C:14]2[CH:21]=[CH:20][CH:19]=[CH:18][C:15]=2[C:16](=[O:17])[CH:9]([C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)[CH2:10][CH2:11][C:12]1=[O:22]
Reactant: COc1ccc(C2CCC(=O)Nc3ccccc3C2=O)cc1
Reactant: CN(C)CCCl
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COc1ccc(C2CCC(=O)N(CCN(C)C)c3ccccc3C2=O)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To azeotropically dried 4,5-Dihydro-5-(4-methoxyphenyl)-1-benzazocine-2,6(1H,3H)-dione (1.80 g) in toluene (40 ml) was added 60% sodium hydride in mineral oil (0.27 g) and the mixture stirred under nitrogen at room temperature overnight. The slurry was stirred and heated to 70° for 15 minutes, and the freshly prepared N,N-dimethylaminoethyl chloride (1.25 g) was slowly added. After a half an hour at 70°, a further 1.25 g of N,N-dimethylaminoethyl chloride was added. The temperature was then raised to 90° and maintained for 3 hours. The cooled reaction mixture was filtered through sintered glass and the filtered solid discarded. The filtrate was evaporated and the residue was triturated with ether. The resulting white solid was collected on a filter; wt. 1.58 g (72%), mp=115-116. Recrystallization from ether gave pure titled product; wt. 1.25 g, mp=116°-117°.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]([CH2:20]Br)[NH:12][C:11]([C:22]2[S:23][CH:24]=[CH:25][N:26]=2)=[N:10]1.Cl.[N:28]1[CH:32]([CH:33]2[CH2:38][O:37][CH2:36][CH2:35][NH:34]2)[N:31]=[N:30][N:29]=1>>[N:31]1[CH:32]([CH:33]2[N:34]([CH2:20][C:13]3[NH:12][C:11]([C:22]4[S:23][CH:24]=[CH:25][N:26]=4)=[N:10][CH:9]([C:3]4[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=4[Br:1])[C:14]=3[C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:35][CH2:36][O:37][CH2:38]2)[N:28]=[N:29][N:30]=1
Reactant: CCOC(=O)C1=C(CBr)NC(c2nccs2)=NC1c1ccc(F)cc1Br
Reactant: C1COCC(C2N=NN=N2)N1
Agent: Cl
Product: CCOC(=O)C1=C(CN2CCOCC2C2N=NN=N2)NC(c2nccs2)=NC1c1ccc(F)cc1Br
Yield: 41.6 %

Procedure:
Ethyl 4-(2-bromo-4-fluorophenyl)-6-(bromomethyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate (0.5 g, 1 mmol) was reacted with 3-(5H-tetrazol-5-yl)morpholine hydrochloride (0.19 g, 1 mmol) according to the procedure as described in Example 28 to give the title compound as a yellow solid (0.24 g, 42%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [ClH:1].[NH:2]1[CH2:7][CH2:6][C:5]2([C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:9]=[CH:8]2)[CH2:4][CH2:3]1>C(O)C.[Pd]>[ClH:1].[NH:2]1[CH2:7][CH2:6][C:5]2([C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH2:9][CH2:8]2)[CH2:4][CH2:3]1
Reactant: C1=CC2(CCNCC2)c2ccccc21
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: c1ccc2c(c1)CCC21CCNCC1
Reaction time: 1 h
Yield: 42.3 %

Procedure:
A solution of spiro[indene-1,4'-piperidine]hydrochloride (1.9 g, 8.6 mmol) in ethanol (50 ml) was hydrogenated at 50 p.s.i. for 1 hour, in the present of 10% palladium on carbon (0.3 g, 16% (w/w)). The catalyst was filtered off, and the ethanol removed in vacuo. The remaining solid was recrystallised from 4:1 ethyl acetate:ethanol to give spiro[indane-1,4'-piperidine] hydrochloride (814 mg, 43%) as a white crystalline solid. N.M.R. (D2O)δ 1.79 (2H, d, J=14 Hz), 2.06 (2H, t of d, J=14 and 4 Hz), 2.14 (2H, t, J=7 Hz), 2.98 (2H, t, j=7 Hz), 3.25 (2H, t of d, J=14 and 2 Hz), 3.48 (2H, m), 7.33 (4H, m)
Reaction SMILES: [Cl:1][C:2]1(NS(N(C)C)(=O)=O)[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][CH:17]=2)[N:14]=[CH:13][C:12](=[O:18])[N:11]3[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:4][NH:3]1.ClC1C([NH:39][S:40]([N:43]([CH3:45])[CH3:44])(=[O:42])=[O:41])=CC(B2OC(C)(C)C(C)(C)O2)=CN=1.BrC1C=C2C(N=CC(=O)N2C2C=CC=CC=2)=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].O1CCOCC1>[Cl:1][C:2]1[C:7]([NH:39][S:40]([N:43]([CH3:45])[CH3:44])(=[O:42])=[O:41])=[CH:6][C:5]([C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][CH:17]=2)[N:14]=[CH:13][C:12](=[O:18])[N:11]3[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[CH:4][N:3]=1
Reactant: CN(C)S(=O)(=O)Nc1cc(B2OC(C)(C)C(C)(C)O2)cnc1Cl
Reactant: CN(C)S(=O)(=O)NC1(Cl)C=CC(c2ccc3ncc(=O)n(-c4ccccc4)c3c2)=CN1
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Agent: O=c1cnc2ccc(Br)cc2n1-c1ccccc1
Solvent: C1COCCO1
Product: CN(C)S(=O)(=O)Nc1cc(-c2ccc3ncc(=O)n(-c4ccccc4)c3c2)cnc1Cl
Temperature: 110 °C

Procedure:
N-(2-chloro-5-(3-oxo-4-phenyl-3,4-dihydroquinoxalin-6-yl)pyridin-2-yl)dimethylaminosulfonamide. To a 5 mL microwave tube was added N-(2-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)dimethylaminosulfonamide (0.079 g, 0.219 mmol), 7-bromo-1-phenylquinoxalin-2(1H)-one (0.060 g, 0.199 mmol), 1,1′-bis(diphenylphosphino)ferrocene]dichloride palladium(II) (0.015 g, 0.020 mmol), sodium carbonate (0.249 mL, 0.498 mmol), and dioxane (3 mL). The resulting mixture was sealed and subject to microwave heating at 110° C. for 20 min. The reaction mixture was partitioned between pH 7 buffer (1M Tris-HCl) and DCM. The aqueous layer was extracted with DCM (2×10 mL). The combined organic layers were dried over MgSO4 and concentrated. The crude product was purified by column chromatography (12 g, 3% MeOH and 32% EtOAc in DCM) to afford the desired product as a light yellow solid (65.0 mg). MS (ESI pos. ion) m/z: calcd for C21H18ClN5O3S: 455.1; found: 455.8 [M+1]. 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 2.80 (s, 6 H) 6.76-6.86 (m, 2 H) 7.35 (d, J=7.16 Hz, 2 H) 7.53 (d, J=8.33 Hz, 1 H) 7.58-7.72 (m, 3 H) 7.94 (s, 1 H) 8.04 (d, J=8.18 Hz, 1 H) 8.20 (s, 1 H) 8.45 (s, 1 H).
Reaction SMILES: [CH3:1][C:2]([CH3:5])([O-])[CH3:3].[K+].[CH:7]([CH:9]1[CH:14]([CH3:15])[CH2:13][CH2:12][CH:11]2[C:16]([CH3:18])([CH3:17])[CH:10]12)=[O:8].C(Cl)C(=C)C>CN(C=O)C.[Cl-].[Na+].O>[CH3:1][C:2](=[CH2:5])[CH2:3][C:9]1([CH:7]=[O:8])[CH:14]([CH3:15])[CH2:13][CH2:12][CH:11]2[CH:10]1[C:16]2([CH3:17])[CH3:18]
Reactant: CC(C)(C)[O-]
Reactant: CC1CCC2C(C1C=O)C2(C)C
Agent: C=C(C)CCl
Agent: [Cl-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: C=C(C)CC1(C=O)C(C)CCC2C1C2(C)C
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 66.7 %

Procedure:
A 4 neck 2 liter round bottomed flask was charged with 500 ml of DMF and 78.0 g of potassium t-butoxide (0.66 mole). The flask was cooled to 0° C. and 100.0 g of 2-formylcarane at a purity of 75% (0.45 mole) in 75 ml of DMF were added dropwise over 30 minutes at 0°-5° C. The mixture was stirred for 20 minutes at 0°-5° C. Then 60.0 g of methallyl chloride (0.66 mole) in 50 ml of DMF were added dropwise over about 25 minutes between 5°-12° C. The batch was poured with stirring into 2 liters of cold brine and extracted with 3×250 ml of hexane. The hexane extracts were washed with 3×500 ml of water and 500 ml of brine. The hexane was dried with sodium sulfate, filtered, and concentrated in vacuo. In this way 127.8 g of crude product were obtained. The crude product was charged into a 250 ml 3 neck flask and heated under nitrogen at 165°-180° C. for 4.5 hours. The crude aldehyde was distilled to afford 88.4 g of purified product (80% yield). BP 79° C./0.1 mmHg; 1H-NMR (300 MHz), δ 0.6-1.0 (3H, m), 1.04 (3H, s), 1.06 (3H, s), 1.0-1.12 (2H, m), 1.2-1.4 (3H, m), 1.6-1.8 (2H, m), 1.82 (3H, s), 2.44 (2H, m), 4.83 (2H, m), 9.63 (1H, s); 13C-NMR (75 MHz), δ 16.44, 17.68, 20.06, 20.31, 24.66, 27.04, 28.76, 31.24, 33.36, 40.74, 45.73, 49.66, 115.93, 141.89, 204.41; IR (Neat), 2970, 2730, 1725, 1645, 1460, 1380, 895 cm-1 ; MS (m/e), 220 (M+), 205, 191, 177, 165, 147, 135, 121, 107, 93, 81, 69, 55, 41 (Base);
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[C:19]([F:22])([F:21])[F:20])[NH:8][C:9]2=[O:12])=[CH:4][CH:3]=1.[O:23]=[CH:24][C@@H:25]([C@@H:27]([CH2:29]O)[OH:28])[OH:26].C(O)(=O)C>CO>[F:21][C:19]([F:22])([F:20])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[C:7]1[NH:8][C:9](=[O:12])[C:10]2[C:5]([CH:6]=1)=[CH:4][CH:3]=[C:2]([NH:1][CH2:29][C@H:27]([OH:28])[C@H:25]([OH:26])[CH2:24][OH:23])[CH:11]=2
Reactant: O=C[C@H](O)[C@H](O)CO
Reactant: Nc1ccc2cc(-c3ccccc3C(F)(F)F)[nH]c(=O)c2c1
Solvent: CC(=O)O
Solvent: CO
Product: O=c1[nH]c(-c2ccccc2C(F)(F)F)cc2ccc(NC[C@H](O)[C@H](O)CO)cc12
Temperature: 25 °C
Reaction time: 4 h
Yield: 285.6 %

Procedure:
The 7-amino-3-(2-trifluoromethylphenyl)-2H-isoquinolin-1-one (2.04 g, 0.986 mmol) obtained in step C of Example 1-1 and D-(−)-erythrose (807 mg, 6.72 mmol) were dissolved in methanol (40 ml). Thereafter, acetic acid (2.31 ml, 40.3 mmol) and a 1 M sodium cyanoborohydride THF solution (20.2 ml, 20.2 mmol) were added at 0° C. to the obtained solution, and the obtained mixture was then stirred at a room temperature for 4 hours. Thereafter, the reaction mixture was concentrated under reduced pressure, and water was then added to the concentrate, followed by extraction with methylene chloride. The extract was washed with a saturated saline solution, and was then dried over sodium sulfate, followed by concentration under reduced pressure. The obtained residue was purified by silica gel chromatography (methylene chloride:methanol=15:1 to 10:1), so as to obtain 3-(2-trifluoromethylphenyl)-7-((2S,3R)-2,3,4-trihydroxybutylamino)-2H-isoquinolin-1-one (1.15 g, 42%).
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[K+].[C:11]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)(=[O:13])[CH3:12].[C:20](OCC)(=[O:26])[C:21]([O:23][CH2:24][CH3:25])=[O:22]>C1COCC1>[OH:26][C:20](=[CH:12][C:11](=[O:13])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:21]([O:23][CH2:24][CH3:25])=[O:22]
Reactant: CCOC(=O)C(=O)OCC
Reactant: CC(=O)c1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Product: CCOC(=O)C(O)=CC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 114.6 %

Procedure:
To a solution of potassium bis(trimethylsilyl)amide (8.88 g, 44.5 mmol) in 400 mL of THF was added dropwise acetophenone (4.85 mL, 41.6 mmol) at 78° C. After 1 hour, diethyl oxalate (6.2 mL, 45.8 mmol) was added dropwise at the same temperature. The reaction mixture was allowed to warm up to room temperature and stirred overnight. The solvent was removed in vacuo. The resulting yellowish solid was filtered and washed with Et2O to give the title compound 2 (10.5 g, 98%) as a sodium salt of Ethyl 2-hydroxy-4-oxo-4-phenyl-2-butenoate (2). To a solution of sodium salt of 2 in EtOH (300 mL) was added 4-amidosulfonylphenylhydrazine 1b (10 g, 44.7 mmol) at room temperature. The reaction mixture was stirred for 1 hour and then 2.4 mL of AcOH was added. The reaction mixture was refluxed for 2 hours. After cooling, the solvent was removed in vacuo. The resulting solid was purified by recrystallization with MeOH to afford the titled compound (13.5 g, 89% yield) as a white solid. mp 191.5-194.6° C. 1H NMR (300 MHz, DMSO-d6): δ 7.87 (d, J=8 Hz, 2H), 7.58-7.48 (m, 4H), 7.44-7.38 (m, 3H), 7.34-7.27 (m, 2H), 7.16 (s, 1H), 4.35 (q, J=7 Hz, 2H), 1.32 (t, J=7 Hz, 3H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([N+:25]([O-:27])=[O:26])=[C:11]([CH:22]=[CH:23][CH:24]=1)[C:12]([O:14]CC1C=CC=CC=1)=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>C(O)C>[CH2:1]([O:8][C:9]1[C:10]([N+:25]([O-:27])=[O:26])=[C:11]([CH:22]=[CH:23][CH:24]=1)[C:12]([OH:14])=[O:13])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(OCc1ccccc1)c1cccc(OCc2ccccc2)c1[N+](=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1cccc(OCc2ccccc2)c1[N+](=O)[O-]
Temperature: 60 °C
Reaction time: 1 h
Yield: 91.2 %

Procedure:
To a suspension of benzyl 3-benzyloxy-2-nitrobenzoate (640 mg) in ethanol (5 ml) was added 1N sodium hydroxide solution (1.94 ml) at ambient temperature, and the mixture was stirred at 60° C. for 1 hour. The reaction mixture was adjusted to pH 4, and the resulting precipitates were collected by filtration and dried to give 3-benzyloxy-2-nitrobenzoic acid (439 mg).
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2[CH2:11][CH2:12][C:13]3=[O:18])=[CH:5][CH:4]=1.[BrH:21].BrBr.S(=O)(O)[O-].[Na+]>C(O)(=O)C.ClCCl.O>[Br:21][CH:12]1[CH2:11][C:10]2[C:14](=[CH:15][CH:16]=[CH:17][C:9]=2[C:6]2[CH:5]=[CH:4][C:3]([C:2]([F:19])([F:20])[F:1])=[CH:8][CH:7]=2)[C:13]1=[O:18]
Reactant: O=C1CCc2c1cccc2-c1ccc(C(F)(F)F)cc1
Reactant: Br
Agent: BrBr
Agent: O=S([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: CC(=O)O
Product: O=C1c2cccc(-c3ccc(C(F)(F)F)cc3)c2CC1Br
Temperature: 0 °C
Reaction time: 3 h

Procedure:
2.76 g (10 mmol) of 4-(4-trifluoromethylphenyl)-1-indanone are dissolved in 20 ml of glacial acetic acid and, after addition of 10 μl of a 48% strength solution of HBr in glacial acetic acid, while stirring a solution of 0.516 ml (10.05 mmol) of bromine in glacial acetic acid is added. After 3 h at room temperature, the reaction mixture is poured into a mixture of 100 ml of water with 100 g of ice and 100 mg of sodium bisulfite, and the resulting suspension is shaken with dichloromethane. The organic phase is washed 3× with water, dried over sodium sulfate, filtered and concentrated in vacuo. The residue is chromatographed on silica gel with dichloromethane/n-heptane 3/1. 2-Bromo-4-(4-trifluoromethylphenyl)-1-indanone is obtained with a melting point of 102-105° C., in addition to a little 2,2-dibromo compound.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH:11]([CH2:15][CH2:16][CH2:17][CH2:18][NH:19][C:20]2[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=2)[C:12]([OH:14])=[O:13])=[CH:6][CH:5]=1)([O-:3])=[O:2].S(=O)(=O)(O)O.[CH2:34](O)[CH3:35]>>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH:11]([CH2:15][CH2:16][CH2:17][CH2:18][NH:19][C:20]2[CH:21]=[CH:22][C:23]([N+:26]([O-:28])=[O:27])=[CH:24][CH:25]=2)[C:12]([O:14][CH2:34][CH3:35])=[O:13])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=C(O)C(CCCCNc1ccc([N+](=O)[O-])cc1)Nc1ccc([N+](=O)[O-])cc1
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)C(CCCCNc1ccc([N+](=O)[O-])cc1)Nc1ccc([N+](=O)[O-])cc1

Procedure:
5 g of 2,6-bis[(4-nitrophenyl)amino]hexanoic acid dissolved in 50 ml of ethanol and 1.5 ml of sulphuric acid are introduced into a 100 ml three-necked flask equipped with a condenser and a thermometer, and the mixture is then refluxed overnight.
Reaction SMILES: [O-]CC.[Na+].[Na].[OH:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[C:12](=[O:16])[CH2:11][CH2:10]2.C1(C)C=CC(S(O[CH2:27][CH2:28][Cl:29])(=O)=O)=CC=1>C(O)C>[Cl:29][CH2:28][CH2:27][O:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[C:12](=[O:16])[CH2:11][CH2:10]2
Reactant: Cc1ccc(S(=O)(=O)OCCCl)cc1
Reactant: O=C1CCc2cc(O)ccc21
Agent: CC[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CCO
Product: O=C1CCc2cc(OCCCl)ccc21
Reaction time: 25 h

Procedure:
To a solution of sodium ethoxide in ethanol prepared from 5.68 g of sodium and 500 ml of absolute ethanol, 36.75 g of 5-hydroxy-1-indanone in 500 ml of slightly-heated ethanol are added in the course of 30 minutes. Then, 74.5 g of β-chloroethyl p-toluenesulphonate in 100 ml of ethanol are dropwise added, and the mixture is refluxed under stirring for 25 hours. Then the mixture is cooled, the insolubilized sodium p-toluenesulphonate 40 g, dry) is filtered off, and the ethanol is evaporated till dryness under vacuum. The residue (71.6 g) is treated with water (250 ml) and methylene chloride (250 ml); the aqueous phase is extracted two further times with methylene chloride, and the organic extracts are washed twice with 100 ml of 10% sodium hydroxide and with water till neutralization. The solvent is evaporated and the residue (54 g) is purified over silica-gel column; by eluting with methylene chloride:hexane (9:1) the excess β-chloro-ethyl p-toluenesulphonate is separated, and the desired product is isolated with methylene chloride; 26.6 g (51%) of a yellow solid are obtained. M.P. 79°-82° C. and analysis correct.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:8]=[CH:7][C:6]([CH2:9][OH:10])=[CH:5][CH:4]=1.Cl[C:14]1[CH:24]=[C:18]2[N:19]([CH3:23])[CH2:20][CH2:21][CH2:22][N:17]2[C:16](=[O:25])[N:15]=1>>[CH3:23][N:19]1[CH2:20][CH2:21][CH2:22][N:17]2[C:16](=[O:25])[N:15]=[C:14]([O:10][CH2:9][C:6]3[CH:5]=[CH:4][C:3]([C:2]([F:11])([F:12])[F:1])=[CH:8][CH:7]=3)[CH:24]=[C:18]12
Reactant: CN1CCCn2c1cc(Cl)nc2=O
Reactant: OCc1ccc(C(F)(F)F)cc1
Product: CN1CCCn2c1cc(OCc1ccc(C(F)(F)F)cc1)nc2=O

Procedure:
The title compound or its salt was prepared by a procedure similar to that described for E2 starting from (4-(trifluoromethyl)phenyl)methanol and 8-chloro-1-methyl-3,4-dihydro-1H-pyrimido[1,6-a]pyrimidin-6(2H)-one.
Reaction SMILES: [H-].COCCO[Al+]OCCOC.[Na+].[H-].[CH3:15][NH:16][C:17](=O)[CH2:18][C:19]1([NH:33][CH3:34])[CH2:28][CH:27]2[N:22]([CH2:23][CH2:24][C:25]3[CH:32]=[CH:31][CH:30]=[CH:29][C:26]=32)[CH2:21][CH2:20]1>C1(C)C=CC=CC=1.C1COCC1>[CH3:34][NH:33][C:19]1([CH2:18][CH2:17][NH:16][CH3:15])[CH2:28][CH:27]2[N:22]([CH2:23][CH2:24][C:25]3[CH:32]=[CH:31][CH:30]=[CH:29][C:26]=32)[CH2:21][CH2:20]1
Reactant: CNC(=O)CC1(NC)CCN2CCc3ccccc3C2C1
Agent: COCCO[Al+]OCCOC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CNCCC1(NC)CCN2CCc3ccccc3C2C1

Procedure:
To a 500 ml round bottomed flask with stirring bar, reflux condenser, dropping funnel and argon inlet was added a solution of sodium bis (2-methoxyethoxy)aluminum hydride (20.63 ml of a 3.4 M solution in toluene) and 100 ml of dry THF. This solution was heated at reflux and a solution of the acetamide (5.04 g, 17.54 mmol) from Step B in 100 ml of dry THF was added dropwise over 45 minutes. When the addition was complete the mixture was heated at reflux for 2 hours. The reaction mixture was chilled in an ice bath and quenched with 100 ml of saturated aqueous potassium sodium tartrate solution. The resulting mixture was diluted with ethyl acetate (300 ml) and the layers were separated. The organic phase was washed with an additional 200 ml of tartrate solution and 200 ml of brine. Drying (K2CO3), filtration and removal of the solvent in vacuo left 4.90 g of (2RS, 11bSR)-2-methylamino-2-(2 -methylaminoethyl)-1,3,4,6,7,11b-hexahydrobenzo[a]quinolizine as an oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][CH:3]=1.[C:9]([Si:11]([CH3:14])([CH3:13])[CH3:12])#[CH:10]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:10]#[C:9][Si:11]([CH3:14])([CH3:13])[CH3:12])=[CH:4][CH:3]=1
Reactant: Brc1ccc(I)cc1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Product: C[Si](C)(C)C#Cc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 92.9 %

Procedure:
Into a 100-mL three neck round-bottom flask, which was maintained with an inert atmosphere of nitrogen, was placed a solution of 1-bromo-4-iodobenzene (1.00 g, 3.53 mmol) in tetrahydrofuran/TEA (9:1) (30 mL). PdCl2(PPh3)2 (50 mg, 0.07 mmol), CuI (13.4 mg, 0.07 mmol), and ethynyltrimethylsilane (748 μL, 5.29 mmol) were added and the mixture was stirred for 18 h at room temperature, then concentrated under reduced pressure. The residue was diluted with water (50 mL) and extracted with ethyl acetate (3×20 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with petroleum ether as the eluent to yield the title compound as a light yellow solid (0.83 g, 93%).
Reaction SMILES: [Li]CCCC.[CH3:6][O:7][C:8](=[O:20])[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:12][CH:11]=1.[CH:21]1([CH2:26]I)[CH2:25][CH2:24][CH2:23][CH2:22]1>C1COCC1.COC1SC(=O)N(CSP(OC)(OC)=S)N=1>[CH3:6][O:7][C:8](=[O:20])[CH:9]([C:10]1[CH:11]=[CH:12][C:13]([S:16]([CH3:19])(=[O:17])=[O:18])=[CH:14][CH:15]=1)[CH2:26][CH:21]1[CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: ICC1CCCC1
Reactant: COC(=O)Cc1ccc(S(C)(=O)=O)cc1
Agent: COc1nn(CSP(=S)(OC)OC)c(=O)s1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COC(=O)C(CC1CCCC1)c1ccc(S(C)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of diispropylamine (25 mmol, 3.6 mL) in 24 mL of THF and 7.5 mL of methidathion (DMTP) at −78° C. is added n-BuLi (25 mmol, 10 mL, 2.5 M in hexanes) and the mixture stirred for 15 min. 4-Methylsulfonylphenylacetic acid methyl ester (24 mmol, 5.47 g) in 24 mL of THF and 7.5 mL of DMTP is then added dropwise over 30 min and the reaction is stirred for 90 min further. Cyclopentylmethyliodide (28.9 mmol, 6.08 g) in 10 mL of THF is then added dropwise and the reaction is stirred for 1 h at −78° C. before allowing to warm to RT. After 12 h, the reaction is quenched with water, evaporated and then partitioned between ethyl acetate (EtOAc) and brine, and the organic solution is dried and evaporated to afford an oil. The crude material is chromatographed on silica (eluent: 5%→25% EtOAc in hexanes) to afford 3-cyclopentyl-2-(4-methanesulfonyl-phenyl)-propionic acid methyl ester.
Reaction SMILES: O[CH2:2][C:3]1[S:4][CH:5]=[CH:6][C:7]=1[CH3:8].[Br-:9].[C:10]1([PH+:16]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C(#N)C>[Br-:9].[CH3:8][C:7]1[CH:6]=[CH:5][S:4][C:3]=1[CH2:2][P+:16]([C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: c1ccc([PH+](c2ccccc2)c2ccccc2)cc1
Reactant: Cc1ccsc1CO
Agent: [Br-]
Solvent: CC#N
Product: Cc1ccsc1C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 70 °C

Procedure:
2-Hydroxymethyl-3-methyl-thiophene (4.5 g.) was dissolved in 90 ml. of acetonitrile and 12.3 g. of triphenylphosphonium bromide were added. The reaction mixture was heated to 70° C. for 3 hours. After cooling the resulting precipitate was filtered off, washed with benzene and dried at 80° C. under high vacuum. The resulting (3-methyl-2-thenyl)triphenylphosphonium bromide has a m.p. 266°-269° C.
Reaction SMILES: [C:1]([N:5]1[C:10](=[O:11])[C:9]([Cl:12])=[C:8]([S:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][CH2:23][CH2:24][O:25][Si](C(C)(C)C)(C)C)=[CH:17][CH:16]=2)[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].Cl>>[C:1]([N:5]1[C:10](=[O:11])[C:9]([Cl:12])=[C:8]([S:13][CH2:14][C:15]2[CH:16]=[CH:17][C:18]([CH2:21][CH2:22][CH2:23][CH2:24][OH:25])=[CH:19][CH:20]=2)[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)n1ncc(SCc2ccc(CCCCO[Si](C)(C)C(C)(C)C)cc2)c(Cl)c1=O
Agent: Cl
Product: CC(C)(C)n1ncc(SCc2ccc(CCCCO)cc2)c(Cl)c1=O

Procedure:
To 0.2 g 2-tert-butyl-4-chloro-5-(4-(4-tert-butyldimethylsilyloxy butyl)benzyl)thio-3(2H)-pyridazinone (0.404 mmol) is added 5 ml of 1% concd. HCl
Reaction SMILES: [OH-].[Na+].[O:3]=[C:4]1[CH2:9][N:8](C(=O)C(F)(F)F)[CH2:7][CH2:6][N:5]1[C:16]1[CH:21]=[CH:20][C:19]([S:22]([NH:25][C:26]2[CH:31]=[CH:30][N:29]=[CH:28][N:27]=2)(=[O:24])=[O:23])=[CH:18][CH:17]=1.Cl>>[O:3]=[C:4]1[CH2:9][NH:8][CH2:7][CH2:6][N:5]1[C:16]1[CH:17]=[CH:18][C:19]([S:22]([NH:25][C:26]2[CH:31]=[CH:30][N:29]=[CH:28][N:27]=2)(=[O:24])=[O:23])=[CH:20][CH:21]=1
Reactant: O=C1CN(C(=O)C(F)(F)F)CCN1c1ccc(S(=O)(=O)Nc2ccncn2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: O=C1CNCCN1c1ccc(S(=O)(=O)Nc2ccncn2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 341.6 %

Procedure:
Prepared using general procedure 13. To a stirring solution of sodium hydroxide (1.0M in H2O, 10 mL, 10 mmol), at 0° C., was added 4-(2-oxo-4-(2,2,2-trifluoroacetyl)piperazin-1-yl)-N-(pyrimidin-4-yl)benzenesulfonamide (0.45 g, 1.01 mmol) portionwise over 10 minutes. The mixture was stirred at ambient temperature for 30 minutes. The solution was cooled to 0° C. followed by the addition of 1.0 N HCl aqueous solution (10 mL, 10 mmol). The light yellow solution was azeotroped with MeOH (4×100 mL) at <30° C. The obtained solid was suspended in 50% MeOH in CH2Cl2 (200 mL) and stirred for 5 minutes. The mixture was filtered and the filtrate was evaporated to give the desired amine as light yellow solid (1.15 g, quantitative yield). LC/MS (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)), m/z: M+1 obs=334.1; tR=0.44 min.