Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH2:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]=[C:10]2[CH2:16][CH2:17][NH2:18])([O:3][CH2:4][CH3:5])=[O:2].[CH:19](=O)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[BH4-].[Na+]>CCO>[CH2:19]([NH:18][CH2:17][CH2:16][C:10]1[C:9]2[C:13](=[CH:14][CH:15]=[C:7]([CH2:6][C:1]([O:3][CH2:4][CH3:5])=[O:2])[CH:8]=2)[NH:12][CH:11]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=Cc1ccccc1
Reactant: CCOC(=O)Cc1ccc2[nH]cc(CCN)c2c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)Cc1ccc2[nH]cc(CCNCc3ccccc3)c2c1
Temperature: 25 °C
Reaction time: 22 h
Yield: 72.7 %

Procedure:
To a solution of 2-[5-carboethoxymethyl-1H-indol-3-yl]ethylamine (2.8 g, 11.37 mmol) in EtOH (45 ml) was added freshly distilled benzaldehyde (1.21 g, 11.37 mmol) and the resulting solution was stirred at room temperature for 22 h. NaBH4 (0.434 g, 11.48 mmol) was added portionwise over 10 min at room temperature and the resulting mixture was stirred for a further 0.5 h before the solvent was removed under vacuum. The resulting residue was taken up into water (20 ml) and acidified with 1N HCl (30 ml). The mixture was then basified with 2N NaOH and extracted with EtOAc (4×70 ml). The combined organic phases were washed with brine (50 ml), dried and concentrated. Chromatography of the residue on silica-gel eluting with CH2Cl2 /EtOH (90:10) gave the title-product (2.78 g, 73%); δ(360 MHz, CDCl3) 1.25 (3H, t, J=7.1 Hz, CH3); 2.98 (4H, s, 2 of CH2); 3.68 (2H, s, CH2); 3.81 (2H, s, CH2); 4.14 (2H, q, J=7.1 Hz, CH2); 6.98 (1H, d, J=2.2 Hz, Ar-H); 7.11 (1H, dd, J=1.6 and 8.3 Hz, Ar-H); 7.20-7.32 (6H, m, Ar-H); 7.49 (1H, d, J=0.7 Hz, Ar-H); 7.99 (1H, br s, indole N-H).
Reaction SMILES: CN(C)[CH:3]=[CH:4][C:5](=O)[C:6]([CH3:14])([C:8]1[O:12][N:11]=[C:10]([CH3:13])[N:9]=1)[CH3:7].[N+]([O-])(O)=O.[N+]([O-])(O)=O.[CH3:25][O:26][C:27]1[CH:28]=[C:29]([NH:39][C:40]([NH2:42])=[NH:41])[CH:30]=[CH:31][C:32]=1[N:33]1[CH:37]=[C:36]([CH3:38])[N:35]=[CH:34]1>>[CH3:25][O:26][C:27]1[CH:28]=[C:29]([NH:39][C:40]2[N:42]=[C:5]([C:6]([CH3:14])([C:8]3[O:12][N:11]=[C:10]([CH3:13])[N:9]=3)[CH3:7])[CH:4]=[CH:3][N:41]=2)[CH:30]=[CH:31][C:32]=1[N:33]1[CH:37]=[C:36]([CH3:38])[N:35]=[CH:34]1
Reactant: COc1cc(NC(=N)N)ccc1-n1cnc(C)c1
Reactant: Cc1noc(C(C)(C)C(=O)C=CN(C)C)n1
Solvent: O=[N+]([O-])O
Product: COc1cc(Nc2nccc(C(C)(C)c3nc(C)no3)n2)ccc1-n1cnc(C)c1

Procedure:
The title compound was prepared from crude 1-dimethylamino-4-methyl-4-(3-methyl-[1,2,4]oxadiazol-5-yl)-pent-1-en-3-one (140 mg, 0.6 mmol) and N-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-guanidine dinitrate (186 mg, 0.5 mmol) using in analogous manner the procedure described in example 39b). Obtained as a pale-yellow solid (31 mg, 13%).
Reaction SMILES: [CH2:1]([NH:7][C:8]([NH:10][C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([Cl:18])[CH:12]=1)=[S:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[C:19]([C:24](O)=[O:25])#[C:20][C:21]([OH:23])=[O:22]>>[Cl:18][C:13]1[CH:12]=[C:11]([N:10]=[C:8]2[N:7]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])[C:24](=[O:25])[C:19](=[CH:20][C:21]([OH:23])=[O:22])[S:9]2)[CH:16]=[CH:15][C:14]=1[Cl:17]
Reactant: O=C(O)C#CC(=O)O
Reactant: CCCCCCNC(=S)Nc1ccc(Cl)c(Cl)c1
Product: CCCCCCN1C(=O)C(=CC(=O)O)SC1=Nc1ccc(Cl)c(Cl)c1
Yield: 14.7 %

Procedure:
Prepared by the method described in Example 1 from N-hexyl-N'-(3,4-dichlorophenyl)thiourea (5.4 g, 18 mmoles) and acetylenedicarboxylic acid (2.1 g, 17 mmoles). Recrystallization from acetonitrile then methanol gave the product (1 g), mp 156°-157° C.
Reaction SMILES: Cl[C:2]1[C:11]([N:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[N:18]1[CH:23]=[C:22]([O:24][CH2:25][CH2:26][OH:27])[CH:21]=[N:20][CH:19]=1>>[N:18]1[CH:23]=[C:22]([O:24][CH2:25][CH2:26][O:27][C:2]2[C:11]([N:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)=[N:10][C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[N:3]=2)[CH:21]=[N:20][CH:19]=1
Reactant: OCCOc1cncnc1
Reactant: Clc1nc2ccccc2nc1N1CCNCC1
Product: c1ccc2nc(N3CCNCC3)c(OCCOc3cncnc3)nc2c1

Procedure:
The title compound was prepared according to the procedure described in Example 162, Step 2, starting from 2-chloro-3-(1-piperazinyl)quinoxaline (0.66 g, 2.65 mmol; from is Example 162, Step 1) and 2-(5-pyrimidinyloxy)ethanol (0.45 g, 3.20 mmol). Yield 0.55 g (59%); mp 115-117° C.; HRMS m/z calcd for C18H20N6O2 (M)+352.1648, found 352.1654. Anal. (C18H20N6O2) C, H, N.
Reaction SMILES: [C:1]1(=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:8]([NH2:11])[CH2:9][NH2:10].C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[CH:1]1([NH:10][CH2:9][CH2:8][NH2:11])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C1CCCCC1
Reactant: NCCN
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: NCCNC1CCCCC1
Reaction time: 48 h
Yield: 45.2 %

Procedure:
To a solution of cyclohexanone (6.260 g, 63.8 mmol), ethylenediamine (42.640 mL, 637.8 mmol), acetic acid (36.515 mL, 637.8 mmol), and 4 {acute over (Å)} molecular sieves (25 g) in anhydrous methanol (250 mL) was added sodium cyanoborohydride (8.017 g, 127.6 mmol). The mixture was stirred for 48 hrs, filtered to remove the solids, and concentrated in vacuo. The residue was dissolved in 3 N aqueous sodium hydroxide (150 mL) and extracted with methylene chloride (3×300 mL). The combined organic layers were washed with basic saturated aqueous sodium chloride, dried (anhydrous sodium sulfate), filtered, and concentrated to give the crude product. The material was vacuum distilled to give the desired product as a clear liquid (4.1 g, 45%). 1H NMR (300 MHz, CDCl3) δ 2.80-2.76 (td, 2H, J=0.9, 6.0 Hz), 2.68-2.64 (td, 2H, J=0.9, 6.0 Hz), 2.43-2.34 (m, 1H), 1.89-1.83 (m, 2H), 1.74-1.70 (m, 2H), 1.62-1.57 (m, 1H), 1.32-0.98 (m, 8H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:18]=[CH:17][C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:19]#[C:20][CH3:21])[CH:15]=3)[CH:10]=2)[CH:5]=[CH:6][C:7]=1[F:8].[H][H]>C(OCC)(=O)C.[C].[Pd]>[F:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:18]=[CH:17][C:16]3[C:11](=[CH:12][CH:13]=[C:14]([CH2:19][CH2:20][CH3:21])[CH:15]=3)[CH:10]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CC#Cc1ccc2cc(-c3ccc(F)c(F)c3)ccc2c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCCc1ccc2cc(-c3ccc(F)c(F)c3)ccc2c1
Reaction time: 6 h
Yield: 95.9 %

Procedure:
7.4 g of 2-(3,4-difluorophenyl)-6-(1-propynyl)naphthalene was dissolved in 80 ml of ethyl acetate. To the solution was then added 1.5 g of 5% palladium carbon. Hydrogen was then introduced into the reaction mixture at ordinary temperature and pressure. The reaction mixture was then stirred for 6 hours. The catalyst was then removed by filtration. The solvent was then distilled off to obtain 7.2 g of 2-(3,4-difluorophenyl)-6-propylnaphthalene. The product was then recrystallized from methanol to obtain 4.2 g of a purified product. (Cr 62.5 I)
Reaction SMILES: [H-].[Na+].[N:3]1([C:14](=[O:15])[C:13]2[NH:12][CH:11]=[N:10][C:9]=2[N:7]([CH3:8])[C:5]1=[O:6])[CH3:4].Br[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH:26]=[CH2:27].O>CS(C)=O>[CH2:27]([N:12]1[C:13]2[C:14](=[O:15])[N:3]([CH3:4])[C:5](=[O:6])[N:7]([CH3:8])[C:9]=2[N:10]=[CH:11]1)[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH:18]=[CH2:17]
Reactant: C=CCCCCCCCCCBr
Reactant: Cn1c(=O)c2[nH]cnc2n(C)c1=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: C=CCCCCCCCCCn1cnc2c1c(=O)n(C)c(=O)n2C
Reaction time: 0.33 h
Yield: 94.2 %

Procedure:
This example illustrates a synthesis of 7-(11,10-Oxidondecyl)-1,3-dimethylxanthine (inventive compound no. 1423). Sodium hydride (95%) (0.575 g, 24 mmol) was added to a solution of theophylline (3.6 g, 20 mmol) in dimethylsulfoxide (100 mL). After 20 minutes of stirring, 1-bromoundec-10-ene (4.66 g, 20 mmol) was added and stirred for 12 hours at room temperature. The reaction mixture was then poured into a separatory funnel containing water (300 mL) and extracted with dichloromethane (5×100 mL). The organic extracts were combined, washed with water (100 mL) and brine (100 mL), dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The crude product obtained was further purified by flash chromatography over silica gel using 50% hexane/ethyl acetate eluant, yielding 6.26 g (94% yield) of 7-(10-undecenyl)-1,3-dimethylxanthine (inventive compound no. 1420).
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([CH2:12][CH:13]2[CH2:16][NH:15][CH2:14]2)(=[O:11])=[O:10])=[CH:5][CH:4]=1.Br[CH2:18][C:19]([C:21]1[CH:25]=[CH:24][S:23][CH:22]=1)=[O:20]>>[F:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([CH2:12][CH:13]2[CH2:16][N:15]([CH2:18][C:19]([C:21]3[CH:25]=[CH:24][S:23][CH:22]=3)=[O:20])[CH2:14]2)(=[O:11])=[O:10])=[CH:5][CH:4]=1
Reactant: O=C(CBr)c1ccsc1
Reactant: O=S(=O)(CC1CNC1)c1ccc(F)cc1
Agent: Cl
Product: O=C(CN1CC(CS(=O)(=O)c2ccc(F)cc2)C1)c1ccsc1

Procedure:
Prepared according to the method of Example 2 using 3-{[(4-fluorophenyl)sulfonyl]methyl}azetidine hydrochloride (Example 1 Step 4) and 2-bromo-1-(3-thienyl)ethanone. 1H NMR (500 MHz, d6-DMSO) δ 10.51 (1H, s), 8.52 (1H, s), 7.96 (2H, dd, J=5.1, 8.7 Hz), 7.72 (1H, dd, J=2.8, 5.0 Hz), 7.55 (2H, t, J=8.8 Hz), 7.49 (1H, d, J=4.3 Hz), 4.91 (2H, s), 4.19 (2H, s), 4.00 (2H, s), 3.82 (2H, d, J=6.7 Hz), 3.10–3.03 (1H, m); m/z (ES+) 354 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[CH2:5][NH:6][C:7](=[O:11])[CH:8]([CH3:10])[CH3:9])[CH3:2].C[Si](C)(C)[N-][Si](C)(C)C.[Li+].[CH3:23][CH2:24][CH2:25]CCC.C(Br)C=C>C1COCC1>[CH2:1]([O:3][C:4](=[O:12])[CH:5]([NH:6][C:7](=[O:11])[CH:8]([CH3:9])[CH3:10])[CH2:25][CH:24]=[CH2:23])[CH3:2]
Reactant: CCOC(=O)CNC(=O)C(C)C
Reactant: CCCCCC
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: C=CCBr
Product: C=CCC(NC(=O)C(C)C)C(=O)OCC

Procedure:
11.74 g of the above prepared isobutyrylamino-acetic acid ethyl ester (67.78 mmol) was dissolved in 250 ml of abs. THF and cooled down to −78°. 139 ml of 1M lithium hexamethyldisilazide in hexane (2.05 eq.) were added within 30 Min. via dropping funnel. After keeping the yellow suspension for additional 30 Min. at −78°, 6.021 ml of allyl bromide (1.05 eq.) was added and stirring continued for 15 Min. at the same temperature and for 30 Min. at 0°. Pouring of the homogeneous reaction mixture onto crashed ice/HCl, twofold extraction with AcOEt, twofold washing with water and brine, drying over magnesium sulfate, and evaporation of the solvents, followed by flash chromatography (SiO2, hexane/AcOEt=7/3) afforded. 11.70 g of the title compound as pale-yellow oil.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([NH2:9])[C:3]=1[NH2:10].[C:11]([O-])(O)=O.[Na+]>C(O)=O.O>[CH3:1][C:2]1[C:3]2[N:10]=[CH:11][NH:9][C:4]=2[CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: O=C([O-])O
Reactant: Cc1cc(C)c(N)c(N)c1
Agent: [Na+]
Solvent: O=CO
Solvent: O
Product: Cc1cc(C)c2nc[nH]c2c1

Procedure:
Intermediate 179.1 (275 mg) in 3 mL formic acid was irradiated in a microwave reactor at 150° C. for 5 min. The mixture was diluted with water, neutralized with sat. NaHCO3, then extracted with EtOAc (3×). The organic phase was washed with water and brine, dried (Na2SO4) and concentrated to afford 245 mg of Intermediate 179.2 as an orange solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([N:9]2[C:13]([CH3:14])=[CH:12][CH:11]=[C:10]2[CH3:15])[CH:3]=1.Br[CH2:17][C@H:18]([N:20]1[C:24]([CH3:25])=[CH:23][CH:22]=[C:21]1[CH3:26])[CH3:19]>>[CH3:1][C:2]1[CH:7]=[C:6]([CH2:8][CH2:17][C@H:18]([N:20]2[C:24]([CH3:25])=[CH:23][CH:22]=[C:21]2[CH3:26])[CH3:19])[N:5]=[C:4]([N:9]2[C:13]([CH3:14])=[CH:12][CH:11]=[C:10]2[CH3:15])[CH:3]=1
Reactant: Cc1ccc(C)n1[C@H](C)CBr
Reactant: Cc1cc(C)nc(-n2c(C)ccc2C)c1
Product: Cc1cc(CC[C@@H](C)n2c(C)ccc2C)nc(-n2c(C)ccc2C)c1

Procedure:
By analogy to Example 76, Step A, the anion of 4,6-dimethyl-2-(2,5-dimethylpyrrol-1-yl)pyridine was alkylated with (R)-1-(2-bromo-1-methylethyl)-2,5-dimethylpyrrole to give (R)-4-methyl-2-(2,5-dimethylpyrrol-1-yl)-6-(3-(2,5-dimethylpyrrol-1-yl)-3-methylpropyl)pyridine.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][CH:5]=[C:6]([N:9]2[CH2:14][CH2:13][N:12]([CH3:15])[CH2:11][CH2:10]2)[C:7]=1[Cl:8].O.[NH2:17][NH2:18]>CCOCC>[Cl:8][C:7]1[C:6]([N:9]2[CH2:14][CH2:13][N:12]([CH3:15])[CH2:11][CH2:10]2)=[CH:5][N:4]=[N:3][C:2]=1[NH:17][NH2:18]
Reactant: NN
Reactant: CN1CCN(c2cnnc(Cl)c2Cl)CC1
Solvent: O
Solvent: CCOCC
Product: CN1CCN(c2cnnc(NN)c2Cl)CC1
Temperature: 100 °C
Reaction time: 0.17 h

Procedure:
3,4-Dichloro-5-(4-methylpiperazin-1-yl)pyridazine (500 mg, 2.023 mmol) was placed in a microwave tube and hydrazine monohydrate (1.772 g, 1.717 mL, 35.40 mmol) was added. The resulting suspension was stirred at 100° C. for ˜10 mins. The brown reaction mixture was allowed to cool to RT, whereupon solid started to precipitate. The suspension was sonicated and the suspended solid was collected by filtration. This material was dissolved in water, basified with saturated NaHCO3 and partitioned with 10% MeOH in DCM. The aqueous layer was extracted with further 10% MeOH in DCM (6×10 mL) and the combined organics were dried over Na2SO4, filtered and concentrated under reduced pressure to give a yellow solid. This material was sonicated in ether and the suspended solid was collected by filtration to give [4-chloro-5-(4-methylpiperazin-1-yl)pyridazin-3-yl]hydrazine as an ochre powder (155.9 mg, 32% Yield).
Reaction SMILES: Br[C:2]1[C:10]2[C:9]([NH:11][C@H:12]([C:14]3[N:19]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[C:18](=[O:26])[C:17]4=[C:27]([CH3:30])[CH:28]=[CH:29][N:16]4[N:15]=3)[CH3:13])=[N:8][CH:7]=[N:6][C:5]=2[N:4]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[CH:3]=1.[CH3:39][C:40]1[CH:41]=[C:42]([NH:55][S:56]([CH3:59])(=[O:58])=[O:57])[CH:43]=[C:44](B2OC(C)(C)C(C)(C)O2)[CH:45]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:39][C:40]1[CH:41]=[C:42]([NH:55][S:56]([CH3:59])(=[O:58])=[O:57])[CH:43]=[C:44]([C:2]2[C:10]3[C:9]([NH:11][C@H:12]([C:14]4[N:19]([C:20]5[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=5)[C:18](=[O:26])[C:17]5=[C:27]([CH3:30])[CH:28]=[CH:29][N:16]5[N:15]=4)[CH3:13])=[N:8][CH:7]=[N:6][C:5]=3[N:4]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[CH:3]=2)[CH:45]=1
Reactant: Cc1cc(NS(C)(=O)=O)cc(B2OC(C)(C)C(C)(C)O2)c1
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc4c3c(Br)cn4COCC[Si](C)(C)C)n(-c3ccccc3)c(=O)c12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: Cc1cc(NS(C)(=O)=O)cc(-c2cn(COCC[Si](C)(C)C)c3ncnc(N[C@@H](C)c4nn5ccc(C)c5c(=O)n4-c4ccccc4)c23)c1
Temperature: 100 °C
Reaction time: 8 h
Yield: 46.3 %

Procedure:
(S)-2-(1-((5-Bromo-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (200 mg, 0.34 mmol) was treated N-(3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methane sulfonamide (160 mg, 0.51 mmol), tetrakis(triphenylphosphine)palladium(0) (20 mg, 0.02 mmol), aqueous solution 2M of sodium carbonate (260 μl, 0.5 mmol) and 4 ml N,N-dimethylformide according to the method described in Preparation 186 but stirring at 100° C. overnight. The crude was purified using SP1® Purification System (hexane-ethyl acetate) to give 110 mg (38% yield) of the title compound. Purity 80%.
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][N+:7]([CH3:10])([CH3:9])[CH3:8])(=O)[OH:2].C(O)(=O)[C:12]1[C:13](=[CH:15][CH:16]=[CH:17][CH:18]=1)[OH:14].[S:21]([O-:24])([O-:23])=[O:22].[Na+:25].[Na+]>>[S:21]([O-:24])([O-:23])=[O:22].[Na+:25].[C:1]([O:4][CH2:5][CH2:6][N+:7]([CH3:10])([CH3:9])[CH3:8])(=[O:2])[C:12]1[C:13](=[CH:15][CH:16]=[CH:17][CH:18]=1)[OH:14]
Reactant: C[N+](C)(C)CCOC(=O)O
Reactant: O=C(O)c1ccccc1O
Agent: O=S([O-])[O-]
Agent: [Na+]
Product: C[N+](C)(C)CCOC(=O)c1ccccc1O

Procedure:
To an aqueous solution containing 28.5 grams of choline carbonate is added 13.8 grams of salicylic acid and 12.6 grams of sodium sulfite. The mixture is stirred until complete solution is achieved and the ebullition of gases cease. The solution of choline salicylate sodium sulfite thus formed is sufficiently pure to be used for further pharmaceutical manufacture. The compound choline salicylate sodium sulfite may be obtained by removing the solvent under high vacuum with the aid of gentle warming. The compound is a colorless crystal, that is highly hygroscopic, rapidly absorbing water on exposure to the atmosphere. An 0.1 molar solution of choline salicylate sodium sulfite has a specific electrical conductivity of 8.16× 10-3.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:18]3[CH:19]=[CH:20][CH:21]=[C:22]([C:23]([F:26])([F:25])[F:24])[C:17]=3[O:16][N:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.Cl.CCOCC>CO>[NH:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:18]3[CH:19]=[CH:20][CH:21]=[C:22]([C:23]([F:26])([F:25])[F:24])[C:17]=3[O:16][N:15]=2)[CH2:10][CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2noc3c(C(F)(F)F)cccc23)CC1
Agent: Cl
Solvent: CO
Solvent: CCOCC
Product: FC(F)(F)c1cccc2c(C3CCNCC3)noc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
A mixture of 4-(7-trifluoromethyl-benzo[d]isoxazol-3-yl)-piperidine-1-carboxylic acid tert-butyl ester (8.00 g, 21.6 mmol), HCl (100 mL of a 1 M ether solution, 100 mmol), and methanol (50 mL) was stirred at room temperature under nitrogen overnight. The reaction was concentrated and the solid triturated with methanoVether to afford 5.84 g (88%) of the desired product as a white powder, mp: 242-243° C.
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C:3]1[CH:4]=[C:5]([CH:9]2[S:14][C:13]3[CH:15]=[CH:16][C:17]4[C:22]([C:12]=3[NH:11][C:10]2=[O:23])=[CH:21][CH:20]=[CH:19][CH:18]=4)[CH:6]=[CH:7][CH:8]=1.C(=O)([O-])[O-].[K+].[K+].Cl.[CH3:33][N:34]([CH3:39])[CH2:35][CH2:36][CH2:37]Cl.CC(C)=O>O>[CH3:33][N:34]([CH3:39])[CH2:35][CH2:36][CH2:37][N:11]1[C:10](=[O:23])[CH:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:1])([F:24])[F:25])[CH:4]=2)[S:14][C:13]2[CH:15]=[CH:16][C:17]3[C:22]([C:12]1=2)=[CH:21][CH:20]=[CH:19][CH:18]=3
Reactant: CN(C)CCCCl
Reactant: O=C1Nc2c(ccc3ccccc23)SC1c1cccc(C(F)(F)F)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: CN(C)CCCN1C(=O)C(c2cccc(C(F)(F)F)c2)Sc2ccc3ccccc3c21

Procedure:
A mixture of 3-(3-trifluoromethylphenyl)-1H-naphtho[2,1-b][1,4]thiazin-2(3H)-one (18.0 g), potassium carbonate (24.2 g), 3-(dimethylamino)propyl chloride hydrochloride (9.5 g), acetone (400 ml) and water (4 ml) is refluxed for 48 hours. The insoluble materials are filtered off and acetone is distilled off, and to the residue are added ethanol (200 ml) and 10% hydrochloric acid (100 ml), and the mixture is refluxed for one hour. After ethanol is distilled off and the insoluble materials are filtered off, the resulting mixture is made alkaline with sodium hydrogen carbonate and extracted with ethyl acetate. The extract is distilled to remove the solvent to give 1-[3-(dimethylamino)propyl]-3-(3-trifluoromethylphenyl)-1H-naphtho[2,1-b][1,4]-thiazin-2(3H)-one as oil.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[C:10]([CH:21]=[CH:22][CH:23]=2)[CH2:11][NH:12][CH2:13][CH2:14][CH2:15][N:16]([CH2:19][CH3:20])[CH2:17][CH3:18])[CH:5]=[CH:4][N:3]=1.[NH2:24][CH2:25][CH2:26][C:27]1[CH:32]=[CH:31][C:30]([OH:33])=[CH:29][CH:28]=1>>[CH2:17]([N:16]([CH2:19][CH3:20])[CH2:15][CH2:14][CH2:13][NH:12][CH2:11][C:10]1[CH:9]=[C:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:24][CH2:25][CH2:26][C:27]3[CH:32]=[CH:31][C:30]([OH:33])=[CH:29][CH:28]=3)[N:7]=2)[CH:23]=[CH:22][CH:21]=1)[CH3:18]
Reactant: CCN(CC)CCCNCc1cccc(-c2ccnc(Cl)n2)c1
Reactant: NCCc1ccc(O)cc1
Product: CCN(CC)CCCNCc1cccc(-c2ccnc(NCCc3ccc(O)cc3)n2)c1

Procedure:
Intermediate 64 was coupled with tyramine following procedure F. LC-MS showed the product had the expected M+H+ of 434. 1H NMR (Varian 300 MHz, CDCl3, shifts relative to the solvent peak at 7.24 ppm) δ 8.4 (d, 1H), 8.2 (m, 2H), 8.1 (m, 1H), 8.0 (m, 1H), 7.5 (m, 3H), 7.2 (m, 1H), 7.1 (m, 4H), 6.6 (m, 2H), 4.2 (m, 1H), 3.5 (m, 2H), 2.7 (m, 3H), 2.6 (m, 6H), 1.7 (m, 2H), 1.0 (m, 6H).
Reaction SMILES: [H-].[Na+].Cl[C:4]1[C:5]([O:10][CH2:11][CH2:12][O:13][C:14]2[C:15]([N:20]3[CH2:25][CH2:24][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:22][CH2:21]3)=[N:16][CH:17]=[CH:18][N:19]=2)=[N:6][CH:7]=[CH:8][N:9]=1.O.[O:34]1CCOC[CH2:35]1>CO>[CH3:35][O:34][C:4]1[C:5]([O:10][CH2:11][CH2:12][O:13][C:14]2[C:15]([N:20]3[CH2:25][CH2:24][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:22][CH2:21]3)=[N:16][CH:17]=[CH:18][N:19]=2)=[N:6][CH:7]=[CH:8][N:9]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2nccnc2OCCOc2nccnc2Cl)CC1
Reactant: C1COCCO1
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COc1nccnc1OCCOc1nccnc1N1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 100 °C
Reaction time: 0.25 h
Yield: 47 %

Procedure:
NaH (50% in mineral oil; 0.010 g, 2.1 mmol) was added to a stirred solution of the product from Step 1 (0.38 g, 0.87 mmol) in dioxane (8 mL) and MeOH (2 mL) in a reaction tube. As the gas evolution had ceased, the tube was sealed and the mixture was stirred at 100° C. for 15 min. The reaction was poured into water and extracted with toluene, dried (MgSO4) and concentrated. The residue was purified by column chromatography on silica using toluene/EtOAc (7:3) as eluent to give 0.178 g (47%) of the title product. Pos-EI-MS shows M+ and 11 ions supporting the stated structure. HRMS m/z calcd for C20H28N6O5 (M)+ 432.2121, found 432.2126.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][C@@H:13]2[O:18][C:17]3[C:19]([CH:26]=[CH:27][CH3:28])=[C:20]([N+:23]([O-])=O)[CH:21]=[CH:22][C:16]=3[O:15][CH2:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][CH:13]2[O:18][C:17]3[C:19]([CH:26]=[CH:27][CH3:28])=[C:20]([NH2:23])[CH:21]=[CH:22][C:16]=3[O:15][CH2:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: CC=Cc1c([N+](=O)[O-])ccc2c1O[C@@H](COS(=O)(=O)c1ccc(C)cc1)CO2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CC=Cc1c(N)ccc2c1OC(COS(=O)(=O)c1ccc(C)cc1)CO2
Temperature: 25 °C

Procedure:
10.0 g (24.0 mmole) of {(2R)-7-nitro-8-[1-propenyl]-2,3-dihydro-1,4-benzodioxin-2-yl}methyl 4-methylbenzenesulfonate and 28.0 g (123 mmole) of stannous chloride dihydrate were combined and heated to 70° C. in ethyl acetate (250 mL) for 6 hours under nitrogen. After cooling to room temperature, the reaction mixture was poured into ice and was made basic with sodium bicarbonate. It was then extracted with ethyl acetate, washed with brine, dried over magnesium sulfate, filtered and evaporated to a brown oil. The crude oil was then chromatographed on silica gel with 50% hexane/methylene chloride to remove impurities and the desired product was eluted with 0.5% methanol/CH2Cl2 to give 8.16 g (91%) of the (R)-enantiomer of the title compound as a yellow oil. For analytical purposes, 50 mg of the yellow oil was crystallized from ethanol with the addition of fumaric acid to give the fumarate of the title compound. MS (ESI) m/z 375 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]#[C:10][CH2:11][N:12]1[CH2:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]1=[O:21].[H][H]>CCO.[Pd]>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][CH2:11][N:12]1[CH2:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]1=[O:21]
Reactant: O=C1c2ccccc2CN1CC#Cc1ccc(F)cc1F
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: O=C1c2ccccc2CN1CCCc1ccc(F)cc1F

Procedure:
2-[3-(2,4-Difluoro-phenyl)-prop-2-ynyl]-2,3-dihydro-isoindol-1-one was dissolved in EtOH (5 mL) and a small amount of 10% Pd/C was added. A hydrogen balloon was attached to the flask and the system was evacuated and flushed three times. The reaction was allowed to stir for twenty-two hours. The reaction mixture was filtered and concentrated to provide the title compound as a colourless oil (13.0 mg).