Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][S:8](=O)[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.C(OC(=O)C)(=[O:14])C.N1C(C)=CC=CC=1C>C(OCC)(=O)C>[O:1]1[C:5]2([CH2:10][CH2:9][S:8][CH:7]([OH:14])[CH2:6]2)[O:4][CH2:3][CH2:2]1
Reactant: O=S1CCC2(CC1)OCCO2
Reactant: CC(=O)OC(C)=O
Solvent: CCOC(C)=O
Solvent: Cc1cccc(C)n1
Product: OC1CC2(CCS1)OCCO2
Temperature: 150 °C

Procedure:
A mixture of 0.88 g of product from Example 393, 5.0 ml of acetic anhydride and 2.0 ml of lutidine is heated at 110°-115° C. for 2.5 hours, followed by increasing the temperature to 150° C. and then heated for 3 hours. The reaction mixture is diluted with ethyl acetate, washed 2× with 1N hydrochloric acid, water, saturated sodium chloride, dried and concentrated in vacuo. The residue is dissolved in methylene chloride, filtered through a pad of hydrous magnesium silicate and reconcentrated in vacuo to give 0.569 g of the desired product.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][C:7]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[CH:6][C:5]2=[O:18].C([O:26][C:27]1[C:28](=[O:43])[O:29][CH:30]([CH2:40][CH2:41]O)[C:31]=1[O:32]CC1C=CC=CC=1)C1C=CC=CC=1>>[OH:26][C:27]1[C:28](=[O:43])[O:29][CH:30]([CH2:40][CH2:41][O:1][C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[O:8][C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:6][C:5]3=[O:18])[C:31]=1[OH:32]
Reactant: O=c1cc(-c2ccccc2)oc2ccc(O)cc12
Reactant: O=C1OC(CCO)C(OCc2ccccc2)=C1OCc1ccccc1
Product: O=C1OC(CCOc2ccc3oc(-c4ccccc4)cc(=O)c3c2)C(O)=C1O

Procedure:
Mitsunoble coupling of 0.33 g (1.4 mmol) of 6-hydroxyflavone with 0.40 g (1.17 mmol) of 3,4-dibenzyloxy-5-(2-hydroxyethyl)-2(5H)-furanone and subsequent benzyl group deprotection by hydrogenation were performed in a similar manner as described in the synthesis of 3,4-dihydroxy-5-[2-(4-phenoxy)phenoxyethyl]-2(5H)-furanone to provide 3,4-dihydroxy-5-[2-(flavone-6-oxy)ethyl]-2(5H)-furanone as a tan solid: mp 200-220° C. dec. (acetone/hexanes), 1H NMR (DMSO-d6) δ 8.13-7.36 (m, 8H), 7.01 (s, 1H), 4.92 (dd, 1H), 4.17 (t, 2H), 2.47-2.27 (m, 1H), 1.98-1.85 (m, 1H). 13C NMR (DMSO-d6) δ 177.23, 170.22, 162.71, 156.02, 155.36, 150.80, 132.06, 131.51, 129.42, 126.59, 124.31, 123.85, 120.49, 117.44, 106.43, 105.85, 72.24, 64.20, 31.71. Anal Calcd for C21H16O7 +0.25 H2O: C, 65.55; H, 4.44. Found: C, 65.59; H, 4.49.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:25]=[CH:24][CH:23]=[CH:22][C:4]=1[CH2:5][NH:6][C:7]1[C:8]2[C:13]([N:14]=[C:15]3[C:20]=1[C:19](=[O:21])[CH2:18][CH2:17][CH2:16]3)=[CH:12][CH:11]=[CH:10][CH:9]=2.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[CH3:1][O:2][C:3]1[CH:25]=[CH:24][CH:23]=[CH:22][C:4]=1[CH2:5][NH:6][C:7]1[C:8]2[C:13]([N:14]=[C:15]3[C:20]=1[CH:19]([OH:21])[CH2:18][CH2:17][CH2:16]3)=[CH:12][CH:11]=[CH:10][CH:9]=2
Reactant: COc1ccccc1CNc1c2c(nc3ccccc13)CCCC2=O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccccc1CNc1c2c(nc3ccccc13)CCCC2O
Temperature: 0 °C
Yield: 73.3 %

Procedure:
3,4-Dihydro-9-(2-methoxybenzylamino)acridin-1(2H)-one (4.0 g) was dissolved in 100 ml of dry THF and chilled in ice-water. 1M lithium aluminum hydride in THF (6.5 ml) was added through a syringe. The reaction mixture was stirred 30 minutes in the cold and then an additional 2.0 ml of 1M lithium aluminum hydride solution was added. The reaction mixture was quenched by the sequential addition of 0.5 ml of water, 0.5 ml of 15% sodium hydroxide and 1.5 ml of water. The inorganic salts were filtered from the reaction and the organic phase was evaporated to a gum. Trituration with ether gave a solid (2.95 g). Analytically pure material was obtained by recrystallization from ethyl acetate-pentate, mp 115°-117° C.
Reaction SMILES: [ClH:1].[NH2:2][N:3]=[CH:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH2:15][C:14]3([CH2:20][CH2:19][N:18]([CH2:21]C(OCC)=O)[CH2:17][CH2:16]3)[O:13][N:12]=2)=[CH:7][CH:6]=1.C(=O)([O-])[O-].[K+].[K+].BrC[CH2:35][CH2:36][CH2:37][C:38]([O:40][CH2:41][CH3:42])=[O:39].[I-].[K+]>C(O)C.O>[ClH:1].[NH2:2][N:3]=[CH:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH2:15][C:14]3([CH2:16][CH2:17][N:18]([CH2:21][CH2:35][CH2:36][CH2:37][C:38]([O:40][CH2:41][CH3:42])=[O:39])[CH2:19][CH2:20]3)[O:13][N:12]=2)=[CH:7][CH:6]=1
Reactant: CCOC(=O)CN1CCC2(CC1)CC(c1ccc(C=NN)cc1)=NO2
Reactant: CCOC(=O)CCCCBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CCO
Solvent: O
Product: CCOC(=O)CCCCN1CCC2(CC1)CC(c1ccc(C=NN)cc1)=NO2
Temperature: 25 °C

Procedure:
To a suspension of 1.1 g (4.56 mmol) of the intermediate from Example 5. Step B in 20 ml dry ethanol were added 1.26 g (9.12 mmol) potassium carbonate. After 15 min stirring at room temperature 1.03 g (4.93 mmol) ethyl 5-bromopentanoate and a catalytic amount of potassium iodide were added. It was stirred over night at room temperature, and the reaction was brought to completion by addition of another 0.52 g (2.49 mmol) ethyl 5-bromopentanoate and heating with reflux for 3 h. The mixture was poured into water and extracted three times with ethyl acetate. The combined organic layers were washed with water, dried over sodium sulfate, and concentrated under reduced pressure. The title compound was obtained by chromatography on silica gel with dichloromethane/ethanol 95:5 followed by 92:8.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:10])[CH3:9].[C:11]1(=[O:18])[O:17][C:15](=[O:16])[CH2:14][CH2:13][CH2:12]1>C1C=CC=CC=1>[C:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH:1][C:11]([CH2:12][CH2:13][CH2:14][C:15]([OH:17])=[O:16])=[O:18])(=[O:10])[CH3:9]
Reactant: O=C1CCCC(=O)O1
Reactant: CC(=O)c1ccccc1N
Solvent: c1ccccc1
Product: CC(=O)c1ccccc1NC(=O)CCCC(=O)O
Yield: 66.8 %

Procedure:
1-(2-aminophenyl)ethane-1-one (4.00 g) and glutaric anhydride (4.10 g) were dissolved in benzene (30 ml) and the solution was heated to reflux for 3.5 hours, followed by concentration of the mixture. The residue was recrystallized from ethyl acetate to obtain 4.93 g of 4-(N-(2-acetylphenyl)carbamoyl)butanoic acid as colorless plate-like crystals. Yield: 66%.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:9]=[N:10][C:11]2[C:16]([CH:17]=1)=[CH:15][C:14]([F:18])=[CH:13][CH:12]=2)(C)(C)C.FC(F)(F)C(O)=O.O>ClCCCl>[F:18][C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][CH:13]=1)[N:10]=[CH:9][C:8]([NH2:7])=[CH:17]2
Reactant: CC(C)(C)OC(=O)Nc1cnc2ccc(F)cc2c1
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCCl
Product: Nc1cnc2ccc(F)cc2c1

Procedure:
A solution of (6-fluoro-quinolin-3-yl)-carbamic acid tert-butyl ester (1.3 g, 4.95 mmol) in 1,2-dichloroethane (15 mL) was treated with trifluoroacetic acid (15 mL) and water (1 mL). The resultant solution was stirred at room temperature for 6 hours. The solvents were evaporated in vacuo, and the residue was triturated in diethyl ether. The solid was purified by flash chromatography using a gradient of 2 N ammonia in methanol (0% to 3%) in dichloromethane as the eluant, to give the product as a colorless solid, 0.47 g (59%). MS: m/z 162.9 (MH+).
Reaction SMILES: [CH:1]12[O:9][CH:5]([CH2:6][NH:7][CH2:8]1)[CH2:4][N:3]([CH2:10][CH2:11][CH2:12][O:13][C:14]1[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][CH:15]=1)[CH2:2]2.[CH3:22][S:23]([N:26]([CH2:34][CH2:35][O:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[CH2:27][CH2:28]OS(C)(=O)=O)(=[O:25])=[O:24].C([O-])([O-])=O.[K+].[K+]>C(#N)C>[C:18]([C:17]1[CH:20]=[CH:21][C:14]([O:13][CH2:12][CH2:11][CH2:10][N:3]2[CH2:2][CH:1]3[O:9][CH:5]([CH2:6][N:7]([CH2:28][CH2:27][N:26]([CH2:34][CH2:35][O:36][C:37]4[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=4)[S:23]([CH3:22])(=[O:25])=[O:24])[CH2:8]3)[CH2:4]2)=[CH:15][CH:16]=1)#[N:19]
Reactant: CS(=O)(=O)OCCN(CCOc1ccccc1)S(C)(=O)=O
Reactant: N#Cc1ccc(OCCCN2CC3CNCC(C2)O3)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CS(=O)(=O)N(CCOc1ccccc1)CCN1CC2CN(CCCOc3ccc(C#N)cc3)CC(C1)O2
Temperature: 60 °C
Reaction time: 8 h
Yield: 58.8 %

Procedure:
A suspension of 4-[3-(9-oxa-3,7-diaza-bicyclo[3.3.1]non-3-yl)-propoxy]-benzonitrile (1.5 g, 5.5 mmol, see WO 01/28992), methanesulfonic acid 2-[methanesulfonyl-(2-phenoxy-ethyl)-amino]-ethyl ester (1.51 g, 4.5 mmol, preparation P above) and dry K2CO3 (1.69 g, 12.3 mmol) in dry acetonitrile (100 ml) was stirred at 60° C. overnight under nitrogen atmosphere. The reaction mixture was filtered and solvent concentrated under reduced pressure. The residue was purified by column chromatography over silica gel using 3% methanol in dichloromethane as eluent to give the title compound (1.4 g) as a liquid.
Reaction SMILES: [N+]([C:4]1[CH:5]=[C:6]([CH:9]=[C:10]([N+:12]([O-:14])=[O:13])[CH:11]=1)[C:7]#[N:8])([O-])=O.[CH3:15][C:16]1[N:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[CH3:15][C:16]1[N:21]=[CH:20][C:19]([O:22][C:4]2[CH:5]=[C:6]([CH:9]=[C:10]([N+:12]([O-:14])=[O:13])[CH:11]=2)[C:7]#[N:8])=[CH:18][CH:17]=1
Reactant: N#Cc1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Reactant: Cc1ccc(O)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(Oc2cc(C#N)cc([N+](=O)[O-])c2)cn1
Temperature: 110 °C
Yield: 73.5 %

Procedure:
3,5-dinitro-benzonitrile (3 g, 16 mmol), 6-methylpyridin-3-ol (1.7 g, 16 mmol), and K2CO3 (4.3 g, 31 mmol) were dissolved in DMF and heated to 110° C. overnight. The reaction mixture was poured into water and the mixture was extracted with EtOAc. The combined organics were washed with brine, dried (Na2SO4), concentrated in vacuo and purified by silica gel chromatography to provide 3-(6-methylpyridin-3-yloxy)-5-nitrobenzonitrile (3 g, 76% yield). 1H NMR (400 MHz, DMSO) δ 8.50 (s, 1H), 8.38 (s, 1H), 8.08 (s, 1H), 8.01 (s, 1H), 7.59-7.56 (d, J=10 Hz, 1H), 7.38-7.36 (d, J=8.4 Hz, 1H), 1.98 (s, 3H); MS (ESI) m/z: 256.3 [M+H]+.
Reaction SMILES: COC1C=CC=CC=1C(CC1CCCCO1)C#N.[H-].[Na+].ClCN1C=NC=N1.[C:28]([C:30]([C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][C:45]=1[O:50][CH3:51])([CH2:37][CH:38]1[CH2:43][CH2:42]C[CH2:40][O:39]1)[CH2:31][N:32]1[CH:36]=[N:35][CH:34]=[N:33]1)#[N:29]>CCCCCC.CN(C=O)C.CS(C)=O>[C:28]([C:30]([C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][C:45]=1[O:50][CH3:51])([CH2:37][CH:38]1[CH2:43][CH2:42][CH2:40][O:39]1)[CH2:31][N:32]1[CH:36]=[N:35][CH:34]=[N:33]1)#[N:29]
Reactant: COc1ccccc1C(C#N)(CC1CCCCO1)Cn1cncn1
Agent: COc1ccccc1C(C#N)CC1CCCCO1
Agent: ClCn1cncn1
Agent: [H-]
Solvent: CS(C)=O
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: COc1ccccc1C(C#N)(CC1CCCO1)Cn1cncn1
Yield: 56 %

Procedure:
This compound was prepared using the procedure described in Example 2b except using 27.0 g. (0.110 mole) of 2-(2-methoxyphenyl)-3-(tetrahydropyran-2-yl)propionitrile, 6.6 g. (0.165 mole) of 60% sodium hydride which had been washed with hexane to remove the mineral oil originally present, 19 g. (0.165 mole) of 1-(chloromethyl)-1,2,4-triazole, and 400 ml. of a 1 to 1 mixture of DMSO and DMF. The 1-[2-cyano-2-(2-methoxyphenyl)-3-(tetrahydropyran-2-yl)propyl]-1,2,4-triazole, 20.0 g. (56% yield), was obtained as a solid, melting point 120°-121° C.
Reaction SMILES: [Cl:1][CH:2]([C:8]([CH3:10])=O)[C:3](OCC)=[O:4].COC1C=CC([C:17]([NH2:19])=[NH:18])=CC=1>C(Cl)(Cl)Cl>[Cl:1][C:2]1[C:8]([CH3:10])=[N:18][CH:17]=[N:19][C:3]=1[OH:4]
Reactant: COc1ccc(C(=N)N)cc1
Reactant: CCOC(=O)C(Cl)C(C)=O
Solvent: ClC(Cl)Cl
Product: Cc1ncnc(O)c1Cl
Reaction time: 8 h
Yield: 37.2 %

Procedure:
Under N2, a solution of ethyl 2-chloroacetoacetate (1.8 ml, d=1.15, 0.013 mol) in CHCl3 (50 ml) was added dropwise to a solution 4-methoxybenzamidine (3.9 g, 0.026 mol) in CHCl3 (100 ml). After stirring overnight, the reaction mixture was filtered and the filtrate was washed with dilute NaOH solution. The aqueous layer was extracted with CH2Cl2 (3×) and the organic layer was dried, filtered and concentrated to dryness. The residue was chromatographed on silica gel and the product was eluted with 2% CH3OH-CHCl3 (v/v) to yield 0.7 g (22%) of product m.p. 250°-251° C.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([CH:7]=[O:8])[C:4]([CH:9]([F:11])[F:10])=[N:3]1.S(Cl)([Cl:15])(=O)=O>ClC1C=CC=CC=1>[CH3:1][N:2]1[CH:6]=[C:5]([C:7]([Cl:15])=[O:8])[C:4]([CH:9]([F:10])[F:11])=[N:3]1
Reactant: Cn1cc(C=O)c(C(F)F)n1
Reactant: O=S(=O)(Cl)Cl
Solvent: Clc1ccccc1
Product: Cn1cc(C(=O)Cl)c(C(F)F)n1
Yield: 96.6 %

Procedure:
The solution of 16 g (100 mol) of 1-methyl-3-difluoromethyl-1H-pyrazole-4-carbaldehyde, 13.5 g (100 mmol) of sulphuryl chloride and 0.2 g of 2,2-azoisobutyronitrile in 50 ml of chlorobenzene was stirred at 70-80° C. for 6 h. The reaction solution was concentrated. 18.8 g of the product (95% yield) was obtained as an oil with a purity (GC) of 98%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:18]=[C:19]([Cl:21])[CH:20]=1)[C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11](F)=[C:10]([N+:15]([O-:17])=[O:16])[CH:9]=1)=[O:6].[OH-].[K+].[C:24]([NH:31][C:32]1[CH:37]=[CH:36][C:35]([OH:38])=[CH:34][CH:33]=1)([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25].O>CS(C)=O>[C:27]([O:26][C:24](=[O:25])[NH:31][C:32]1[CH:33]=[CH:34][C:35]([O:38][C:11]2[CH:12]=[CH:13][C:8]([NH:7][C:5](=[O:6])[C:4]3[CH:3]=[C:2]([Cl:1])[CH:20]=[C:19]([Cl:21])[CH:18]=3)=[CH:9][C:10]=2[N+:15]([O-:17])=[O:16])=[CH:36][CH:37]=1)([CH3:30])([CH3:28])[CH3:29]
Reactant: O=C(Nc1ccc(F)c([N+](=O)[O-])c1)c1cc(Cl)cc(Cl)c1
Reactant: CC(C)(C)OC(=O)Nc1ccc(O)cc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)Nc1ccc(Oc2ccc(NC(=O)c3cc(Cl)cc(Cl)c3)cc2[N+](=O)[O-])cc1
Temperature: 80 °C

Procedure:
To a solution of Example 254a (2.0 g, 6.1 mmol) in DMSO (50 mL) was added KOH (1.4 g, 24.3 mmol) and N-Boc-4-aminophenol (1.3 g, 6.1 mmol). The mixture was heated at 80° C. for 4 h. The reaction was cooled and poured into water. The aqueous phase was extracted with ethyl acetate (2×). The combined organic phases were washed with water, brine, and dried over sodium sulfate, filtered and concentrated under vacuum giving the title compound. The residue was purified by silica gel chromatography eluting with hexanes/ethyl acetate/methanol (80:10:10) to give the desired product (1.6 g, 51%).
Reaction SMILES: CS(Cl)(=O)=O.[CH3:6][O:7][C:8]1[CH:23]=[C:22]2[C:11]([C:12]([CH2:26][CH3:27])([CH2:24][CH3:25])[C:13]3[CH:17]=[CH:16][N:15]([CH2:18][C@H:19](O)[CH3:20])[C:14]=32)=[CH:10][CH:9]=1.C(N(CC)CC)C.[N-:35]=[N+:36]=[N-:37].[Na+]>ClCCl.CN(C)C=O.O>[N:35]([C@@H:19]([CH3:20])[CH2:18][N:15]1[CH:16]=[CH:17][C:13]2[C:12]([CH2:26][CH3:27])([CH2:24][CH3:25])[C:11]3[C:22]([C:14]1=2)=[CH:23][C:8]([O:7][CH3:6])=[CH:9][CH:10]=3)=[N+:36]=[N-:37]
Reactant: CCC1(CC)c2ccc(OC)cc2-c2c1ccn2C[C@@H](C)O
Reactant: [N-]=[N+]=[N-]
Agent: CS(=O)(=O)Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: O
Product: CCC1(CC)c2ccc(OC)cc2-c2c1ccn2C[C@H](C)N=[N+]=[N-]
Yield: 78.8 %

Procedure:
1.42 ml of methanesulfonyl chloride were added dropwise while stirring to a solution, cooled to 0°, of 2.73 g of (R)-1-(7-methoxy-4,4-diethyl-1,4-dihydro-indeno[1,2-b]pyrrol-1-yl)-propan-2-ol and 5.08 ml of triethylamine in 70 ml of dichloromethane and the mixture was stirred at this temperature for an additional 1.5 hours. The reaction mixture was subsequently diluted with 100 ml of dichloromethane, washed twice with 70 ml of saturated sodium hydrogen carbonate solution each time and the combined aqueous phases were extracted once with 70 ml of dichloromethane. The combined organic phases were washed with 70 ml of saturated sodium chloride solution, dried over magnesium sulfate and evaporated in a vacuum. The brown oil obtained was dissolved in 50 ml of anhydrous dimethylformamide, treated with 1.18 g of sodium azide and the reaction mixture was heated to 60° for 15 hours while stirring. After cooling, the solution was poured into 70 ml of water and extracted three times with 80 ml of ethyl acetate each time. The combined organic phases were washed once with 70 ml of water and once with 80 ml of saturated sodium chloride solution, dried over magnesium sulfate and the solution was concentrated in a vacuum. The brown oil obtained was purified by column chromatography on silica gel (hexane/ethyl acetate 4:1). 2.33 g (79%) of (S)-1-(2-azido-propyl)-7-methoxy-4,4-diethyl-1,4-dihydro-indeno[1,2-b]pyrrole were obtained as a yellow oil.
Reaction SMILES: C1C=CC=CC=1.[NH2:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][CH3:16])[CH:11]=[CH:10][C:9]=1[CH3:17].[CH:18](=O)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C([BH3-])#N.[Na+]>O>[CH2:18]([NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][CH3:16])[CH:11]=[CH:10][C:9]=1[CH3:17])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=Cc1ccccc1
Reactant: CCOc1ccc(C)c(N)c1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O
Solvent: c1ccccc1
Product: CCOc1ccc(C)c(NCc2ccccc2)c1

Procedure:
100 ml of benzene was added to 20.8 g (138 mmol) of 2-amino-4-ethoxytoluene and 17.8 g (168 mmol) of benzaldehyde, and the mixture was heated with refluxing for 5 hours in a reaction vessel equipped with a water separator. After cooling, the reaction solution was concentrated under reduced pressure. 640 ml of methanol was added to the residue, followed by the addition of acetic acid to adjust pH to 5. To this was added 13.1 g (208 mmol) of sodium cyanoborohydride while stirring under cooling with ice, and the mixture was stirred overnight at room temperature. The reaction mixture was concentrated, purified by column chromatography (silica gel, chloroform), and recrystallized (chloroform-n-hexane) to obtain 19.7 g (yield, 59.2%) of colorless prisms of the title compound.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([C:25](=[O:30])[C:26]([F:29])([F:28])[F:27])[CH2:23][CH2:22][C:21]([C:31]([OH:33])=O)=[CH:20][C:19]=3[CH:34]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].[NH2:35][C:36]1[CH:41]=[CH:40][C:39]([CH:42]([C:44]2[CH:49]=[C:48]([CH3:50])[CH:47]=[CH:46][N:45]=2)[OH:43])=[C:38]([C:51]([F:54])([F:53])[F:52])[CH:37]=1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>CN(C)C=O.CN(C)C1C=CN=CC=1.O.C(N(CC)CC)C>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([C:25](=[O:30])[C:26]([F:29])([F:28])[F:27])[CH2:23][CH2:22][C:21]([C:31]([NH:35][C:36]4[CH:41]=[CH:40][C:39]([CH:42]([OH:43])[C:44]5[CH:49]=[C:48]([CH3:50])[CH:47]=[CH:46][N:45]=5)=[C:38]([C:51]([F:54])([F:52])[F:53])[CH:37]=4)=[O:33])=[CH:20][C:19]=3[CH:34]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCN3C(=O)C(F)(F)F)cc1
Reactant: Cc1ccnc(C(O)c2ccc(N)cc2C(F)(F)F)c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(C(O)c4cc(C)ccn4)c(C(F)(F)F)c2)CCN3C(=O)C(F)(F)F)cc1
Reaction time: 8 h
Yield: 38.6 %

Procedure:
7-[4-(2-butoxyethoxy)phenyl]-1-trifluoroacetyl-2,3-dihydro-1H-1-benzazepine-4-carboxylic acid (2 g), (4-amino-2-trifluoromethylphenyl)(4-methylpyridin-2-yl)methanol (1.2 g) and 1-hydroxybenzotriazole (0.96 g) were dissolved in N,N-dimethylformamide (25 ml), and to the solution were added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (2.4 g), triethylamine (3 ml) and 4-dimethylaminopyridine (catalytic amount) at room temperature under ice-cooling, and the mixture was stirred overnight. The mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and then, the solvent was distilled off. The residue was purified by basic silica gel column chromatography (elution solvent: ethyl acetate/hexane), to give 7-[4-(2-butoxyethoxy)phenyl]-N-[4-[hydroxy(4-methylpyridin-2-yl)methyl]-3-trifluoromethylphenyl]-1-trifluoroacetyl-2,3-dihydro-1H-1-benzazepine-4-carboxamide (1.2 g) as pale yellow amorphous.
Reaction SMILES: [OH-].[K+].C(O)CO.NC1[S:9][C:10]2[CH:16]=[C:15]([CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:14]=[CH:13][C:11]=2[N:12]=1>O.C1(C)C=CC=CC=1.C(O)(=O)C>[NH2:12][C:11]1[CH:13]=[CH:14][C:15]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:16][C:10]=1[SH:9]
Reactant: Nc1nc2ccc(Cc3ccccc3)cc2s1
Agent: [K+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Solvent: OCCO
Product: Nc1ccc(Cc2ccccc2)cc1S
Reaction time: 7 h
Yield: 93.8 %

Procedure:
A solution of 103 g of potassium hydroxide in 125 ml of water was mixed with 62.5 ml of ethylene glycol and 25 g of 2-amino-6-benzylbenzothiazole was added to the mixture under an atmosphere of nitrogen. The mixture was stirred whilst heating it on an oil bath kept at 135° C. for 7 hours. After it had been allowed to cool, the mixture was diluted with 250 ml of toluene and 105 ml of acetic acid were added dropwise to it. The toluene layer was separated off, and the aqueous solution remaining was again extracted with toluene. The combined toluene extracts were washed with an aqueous solution of sodium bicarbonate, with water and with an aqueous solution of sodium chloride, after which the resulting solution was dried over anhydrous magnesium sulfate. Distillation of the solvent afforded 21.0 g of the title compound as a syrup. This product crystallized on standing and was used in the following reaction without further purification.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]2[S:9][N:8]=[C:7]([N:10]3[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][C:18]4[CH:19]=[C:20]5[CH2:28][C:26](=[O:27])[NH:25][C:21]5=[CH:22][C:23]=4[Cl:24])[CH2:12][CH2:11]3)[C:5]=2[CH:6]=1.C1COCC1.[CH2:34]([S:36]([OH:39])(=[O:38])=[O:37])[CH3:35]>O>[CH:1]1[CH:2]=[CH:3][C:4]2[S:9][N:8]=[C:7]([N:10]3[CH2:11][CH2:12][N:13]([CH2:16][CH2:17][C:18]4[CH:19]=[C:20]5[CH2:28][C:26](=[O:27])[NH:25][C:21]5=[CH:22][C:23]=4[Cl:24])[CH2:14][CH2:15]3)[C:5]=2[CH:6]=1.[S:36]([CH2:34][CH3:35])([O-:39])(=[O:38])=[O:37]
Reactant: CCS(=O)(=O)O
Agent: O=C1Cc2cc(CCN3CCN(c4nsc5ccccc45)CC3)c(Cl)cc2N1
Solvent: O
Solvent: C1CCOC1
Product: CCS(=O)(=O)[O-]
Temperature: 60 °C

Procedure:
1 g of ziprasidone free base was added to 45 mL of THF and 1 mL of water, and the mixture was heated to 60° C. while stirring. The mixture was maintained at 60° C. for two hours, at which time all of the free base had dissolved. 156 mg of ethanesulfonic acid was added and stirring was maintained at 60° C. for two more hours. The mixture turned from light orange to hazy during this time, at which point heating was stopped and the salt started to precipitate. The mixture was allowed to cool to room temperature overnight while stirring continued. The salt was then harvested by filtration as in Example 5.
Reaction SMILES: [CH2:1](O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH:10]([CH3:12])[CH3:11].FC(F)(F)S(O)(=O)=O.C=CCCCCCCCC(C)C.C(OCCCCCCCCCCCC)CCCCCCCCCCC>>[CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH:10]([CH3:11])[CH3:12]
Reactant: CC(C)CCCCCCCCCO
Agent: C=CCCCCCCCC(C)C
Agent: CCCCCCCCCCCCOCCCCCCCCCCCC
Agent: O=S(=O)(O)C(F)(F)F
Product: CCCCCCCCCC(C)C

Procedure:
300.0 g Lial® 123 (isododecanol from Sasol) and 18.0 g trifluoromethanesulfonic acid (50% by weight in water) were introduced into a distillation apparatus and heated for 1.5 h to 240° C. The organic phase of the distillate obtained (171.9 g) was dried over sodium sulfate and the product was isolated by filtration). The product then contained 91.5% isododecene, 7.5% Lial® 123 and 1.0% didodecyl ether (GC analysis).