Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][CH2:21][CH:22]([OH:25])[CH2:23][OH:24])=[O:19].N1C=CC=CC=1.[C:32](Cl)(=[O:54])[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH3:53]>C(Cl)(Cl)Cl>[C:32]([CH:21]([CH:22]([CH2:23][OH:24])[OH:25])[O:20][C:18](=[O:19])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH3:1])(=[O:54])[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH3:53]
Reactant: CCCCCCCCCCCCCCCCCC(=O)OCC(O)CO
Reactant: CCCCCCCCCCCCCCCCCCCCCC(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: CCCCCCCCCCCCCCCCCCCCCC(=O)C(OC(=O)CCCCCCCCCCCCCCCCC)C(O)CO
Temperature: 25 °C
Reaction time: 8 h

Procedure:
100 g (279.3 mmol) of 1-monostearin is dissolved in 750 ml of warm chloroform (Note: the chloroform is washed three times with distilled water, dried over MgSO4, and filtered before use). 24.8 ml (307.2 mmol) of pyridine is then added to the solution. (Note: the pyridine is dried over 3A molecular sieves, manufactured by Linde, before use). 110 g (307.2 mmol) of behenoyl chloride is dissolved in 250 ml of washed chloroform and added dropwise to the well stirred solution. The reaction is gently warmed with a heating mantel and is stirred overnight (16 hrs.) Upon completion of the reaction, the solvent is removed under reduced pressure. The remaining solid/oil is transferred to a 2 liter beaker and 1 liter of acetone/ethanol 50:50 is added. The mixture is heated to boiling and the remaining solids filtered. The filtrate is then placed in a 50° C. incubator overnight and filtered. The filtrate is cooled to room temperature and any solid diacylglyceride is removed by suction filtration.
Reaction SMILES: [CH3:1][Si:2]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)([O:5][CH3:6])[O:3][CH3:4].[H][H]>CCCCCC.[Pd]>[CH:7]1([Si:2]([CH:1]2[CH2:11][CH2:12][CH2:7][CH2:8][CH2:9]2)([O:3][CH3:4])[O:5][CH3:6])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: [H][H]
Reactant: CO[Si](C)(OC)c1ccccc1
Agent: [Pd]
Solvent: CCCCCC
Product: CO[Si](OC)(C1CCCCC1)C1CCCCC1

Procedure:
An amount, as set forth in Table 1, of a catalyst constituted by palladium supported on active carbon, sold by DUTRAL Company under the trade name MPT/5, containing 5% by weight of palladium, was loaded, in the form of a suspension in n-hexane at 30% by weight, into an autoclave having a volume of 500 cm3. Then methyl-phenyl-dimethoxy-silane and the solvent were added in the amount, as set forth in the Table, till the volume reached 200 cm3. The mixture was then heated gradually over one hour, under strong stirring, at the temperature and the hydrogen pressure, as set forth in Table 1. After the reaction times indicated hereinbefore, the hydrogenation was practically over. The final mass was cooled, the catalyst was separated by decantation and filtration then the solvent was evaporated. Di-cyclohexyl-dimethoxy-silane was obtained, having a purity of 99.6% and in the amount and with yields as set forth in Table 1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][N:15]=[CH:16][CH:17]=3)[C:12]3[CH:19]=[CH:20][C:21]([C:23]([NH:25][NH2:26])=[O:24])=[CH:22][C:11]=3[N:10]=2)[CH:5]=[CH:6][CH:7]=1.[CH:27](OCC)(OCC)OCC>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][N:15]=[CH:16][CH:17]=3)[C:12]3[CH:19]=[CH:20][C:21]([C:23]4[O:24][CH:27]=[N:26][N:25]=4)=[CH:22][C:11]=3[N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(OCC)OCC
Reactant: NNC(=O)c1ccc2c(c1)nc(Nc1cccc(Cl)c1)c1ccncc12
Product: Clc1cccc(Nc2nc3cc(-c4nnco4)ccc3c3cnccc23)c1
Yield: 56 %

Procedure:
5-(3-chlorophenylamino)benzo[c][2,6]naphthyridine-8-carbohydrazide (1.0 eq, 21 mg, 0.057 mmol) was suspended in triethyl orthoformate (0.5 ml) and the mixture reacted in a microwave reactor at 120° C. for 80 minutes. The precipitate that formed upon cooling was filtered and dried to afford N-(3-chlorophenyl)-8-(1,3,4-oxadiazol-2-yl)benzo[c][2,6]naphthyridin-5-amine as a solid (12 mg, 56% yield). LCMS (ES): 95% pure, m/z 374 [M+1]+.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][C@H:5]([O:11]C1C=CC=C2C=CC=CC=12)[C:6]1[S:10][CH:9]=[CH:8][CH:7]=1.[CH2:22]1N(P(OC2C=CC(OP(N3CC3)(NCCC(C3C=CC=NC=3)=O)=O)=CC=2)(NCCC(C2C=CC=NC=2)=O)=O)C1.C(C1SC=CC=1)(=O)C.CNC.C=O>>[CH3:22][N:2]([CH3:1])[CH2:3][CH2:4][C:5]([C:6]1[S:10][CH:9]=[CH:8][CH:7]=1)=[O:11]
Reactant: O=C(CCNP(=O)(Oc1ccc(OP(=O)(NCCC(=O)c2cccnc2)N2CC2)cc1)N1CC1)c1cccnc1
Reactant: CNCC[C@H](Oc1cccc2ccccc12)c1cccs1
Agent: C=O
Agent: CC(=O)c1cccs1
Agent: CNC
Product: CN(C)CCC(=O)c1cccs1

Procedure:
Synthesis of duloxetine is described in detail in EP-A-273 658, EP-A-457 559 and EP-A-650965, starting from 2-acetylthiophene, an aminomethylation with dimethylamine and formaldehyde (Mannich reaction) is carried out in step-A. The 3-dimethylamino-1-(2-thienyl)-1-propanone formed is reduced to the corresponding alcohol 1-hydroxy-1-(2-thenyl)-3-dimethylaminopropane by means of complex hydrides in step B. The alcohol is then converted in step C with an alkali metal hydride and 1-fluoro-naphthalene, optionally in the presence of a potassium compound (cf. EP-A-650 965), to the naphthyl derivative, N,N-dimethyl-3-(1-naphthyloxy)-3-(2-thienyl) propylamine. In the final step D, the amino group is then demethylated by reaction with a chloroformic acid ester, preferably phenyl chloroformate or trichloroethyl chloroformate, optionally in the presence of a mixture of zinc and formic acid (EP-A-457 559), followed by alkaline hydrolysis of the carbamate to give N-methyl-3-(1-naphthyloxy)-3-(2-thienyl) propylamine.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[C:22]2[CH2:21][CH2:20][CH2:19][CH2:18][C:17]=2[C:16]2[C:11]1=[CH:12][CH:13]=[C:14]([C:23]1[CH:28]=[CH:27][C:26]([N:29]([CH3:31])[CH3:30])=[CH:25][CH:24]=1)[CH:15]=2)C.C1C2N(CC3C=CC(C([NH:53][OH:54])=O)=CC=3)C3C(=CC=CC=3)C=2C=CC=1>>[OH:54][NH:53][C:4](=[O:3])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[C:22]2[CH2:21][CH2:20][CH2:19][CH2:18][C:17]=2[C:16]2[C:11]1=[CH:12][CH:13]=[C:14]([C:23]1[CH:28]=[CH:27][C:26]([N:29]([CH3:31])[CH3:30])=[CH:25][CH:24]=1)[CH:15]=2
Reactant: O=C(NO)c1ccc(Cn2c3ccccc3c3ccccc32)cc1
Reactant: CCOC(=O)CCCCCn1c2c(c3cc(-c4ccc(N(C)C)cc4)ccc31)CCCC2
Product: CN(C)c1ccc(-c2ccc3c(c2)c2c(n3CCCCCC(=O)NO)CCCC2)cc1

Procedure:
Compound 33 was prepared from 6-(6-bromo-1,2,3,4-tetrahydro-carbazol-9-yl)-hexanoic acid ethyl ester (compound 32) using the procedure described above for compound 29 as a white solid (85%). 1H NMR (400 MHz, MeOD): δ 7.86 (d, 2H), 7.65 (m, 3H), 7.33 (s, 2H), 4.09 (t, 2H), 2.76 (m, 4H), 2.16 (s, 1H), 2.08 (t, 2H), 1.98 (m, 2H), 1.90 (m, 2H), 1.77 (m, 2H), 1.66 (m, 2H), 1.38 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][CH2:9][C:10]2=[O:13])=[CH:5][CH:4]=1.[Br:14]Br>CCOCC>[Br:14][CH:9]1[CH2:8][CH2:7][C:6]2[C:11](=[CH:12][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[C:10]1=[O:13]
Reactant: COc1ccc2c(c1)C(=O)CCC2
Reactant: BrBr
Solvent: CCOCC
Product: COc1ccc2c(c1)C(=O)C(Br)CC2
Yield: 87.2 %

Procedure:
To a 10° C. solution of 25 g (0.142 mol) of 7-methoxy-3,4-dihydro-1(2 H)-naphthalenone in 1 liter ether was added dropwise (maintaining reaction temperature at about 10° C.) 37.9 g (0.237 mol) of bromine. The reaction solution was concentrated on a rotating evaporator and the residue crystallized from ether to give 31.6 g (81%) of present title compound, m.p. 79-80° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:10])[NH2:9])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:11][C:12]1[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][C:13]=1B(O)O.C(N(CC)CC)C>ClCCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[C:1]([O:5][C:6]([N:8]([CH3:10])[NH:9][C:16]1[CH:15]=[CH:14][CH:13]=[C:12]([Cl:11])[C:17]=1[Cl:18])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(N)C(=O)OC(C)(C)C
Reactant: OB(O)c1cccc(Cl)c1Cl
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: CN(Nc1cccc(Cl)c1Cl)C(=O)OC(C)(C)C
Temperature: 50 °C
Yield: 39.1 %

Procedure:
A mixture of N-methyl-hydrazinecarboxylic acid tert-butyl ester (Intermediate 1; 1.00 g, 6.8 mmol), 2,3-dichlorophenylboronic acid (Lancaster; 1.29 g, 6.8 mmol), copper(II) acetate (1.24 g, 6.8 mmol) and triethylamine (960 μL, 6.8 mmol) in 1,2-dichloroethane (15 mL) was heated in an oil bath at 50° C. for 3 h. The mixture was allowed to cool, and it was then adsorbed onto silica gel and purified by chromatography using an ISCO 40 g column, eluting with 10% ethyl acetate/hexanes, to give N′-(2,3-dichloro-phenyl)-N-methyl-hydrazinecarboxylic acid tert-butyl ester (775 mg, 39%) as a solid.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][OH:11])=[CH:4][CH:3]=1.N1C=CN=C1.[C:17]([Si:21](Cl)([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)([CH3:20])([CH3:19])[CH3:18]>CN(C)C=O>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][CH2:10][O:11][Si:21]([C:17]([CH3:20])([CH3:19])[CH3:18])([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:6][CH:7]=1
Reactant: OCCCc1ccc(O)cc1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](OCCCc1ccc(O)cc1)(c1ccccc1)c1ccccc1
Temperature: 2.5 °C
Reaction time: 2 h
Yield: 96.2 %

Procedure:
A solution of 3-(4-hydroxyphenyl)-1-propanol (10.0 g, 66.0 mmol) and imidazole (6.7 g, 98.4 mmol) in N,N-dimethylformamide (50 ml) was cooled to 0-5° C. and treated dropwise with tert-butylchlorodiphenylsilane (21.5 g, 78.2 mmol). The resulting mixture was stirred at 0-5° C. for 2 hours and then quenched by addition of water (400 ml) and toluene (500 ml). The organic phase was washed with water, brine and dried over anhydrous magnesium sulfate. Evaporation of the solvent and chromatography of the residue on silica gel (elution toluene-ethyl acetate, 95:5) gave 24.8 g (96%) of the title material as a clear oil.
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH3:5])[CH3:2].[C:6]([O:10][CH2:11][CH3:12])(=[O:9])[CH:7]=[CH2:8].C1C2NC3C(=CC=CC=3)SC=2C=CC=1.COC1C=CC(O)=CC=1>>[CH2:1]([N:3]([CH2:8][CH2:7][C:6]([O:10][CH2:11][CH3:12])=[O:9])[CH2:4][CH3:5])[CH3:2]
Reactant: C=CC(=O)OCC
Reactant: CCNCC
Agent: COc1ccc(O)cc1
Agent: c1ccc2c(c1)Nc1ccccc1S2
Product: CCOC(=O)CCN(CC)CC
Yield: 96 %

Procedure:
The following materials were charged to the reaction vessel: anhydrous diethylamine (292 grams); ethyl acrylate (200 grams); phenothiazine (1.0 gram); and p-methoxyphenol (1.0 gram). This mixture was heated at reflux (about 56°-60°C.) for 24 hours. At the end of this period, unreacted amine was removed by distillation. The product was recovered at 80°-81°C. and 10 mm. mercury pressure in a yield of 96 percent. The product is designated herein as Amine Catalyst IX and has the formula, (C2H5)2N-CH2CH2 -C(O)OC2H5, as verified analytically by infrared spectroscopy.
Reaction SMILES: [F:1][C:2]([F:19])([CH3:18])[CH2:3][N:4]1[CH2:10][CH2:9][C:8]2[CH:11]=[C:12]([NH2:17])[C:13]([O:15][CH3:16])=[CH:14][C:7]=2[CH2:6][CH2:5]1.Cl[C:21]1[N:26]=[C:25]([NH:27][C:28]2[CH:33]=[CH:32][C:31]([N:34]3[CH2:39][CH2:38][O:37][CH2:36][CH2:35]3)=[CH:30][C:29]=2[O:40][CH3:41])[C:24]([Cl:42])=[CH:23][N:22]=1>>[Cl:42][C:24]1[C:25]([NH:27][C:28]2[CH:33]=[CH:32][C:31]([N:34]3[CH2:35][CH2:36][O:37][CH2:38][CH2:39]3)=[CH:30][C:29]=2[O:40][CH3:41])=[N:26][C:21]([NH:17][C:12]2[C:13]([O:15][CH3:16])=[CH:14][C:7]3[CH2:6][CH2:5][N:4]([CH2:3][C:2]([F:1])([F:19])[CH3:18])[CH2:10][CH2:9][C:8]=3[CH:11]=2)=[N:22][CH:23]=1
Reactant: COc1cc2c(cc1N)CCN(CC(C)(F)F)CC2
Reactant: COc1cc(N2CCOCC2)ccc1Nc1nc(Cl)ncc1Cl
Product: COc1cc2c(cc1Nc1ncc(Cl)c(Nc3ccc(N4CCOCC4)cc3OC)n1)CCN(CC(C)(F)F)CC2

Procedure:
The title compound was prepared from 3-(2,2-Difluoro-propyl)-8-methoxy-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamine and (2,5-Dichloro-pyrimidin-4-yl)-(2-methoxy-4-morpholin-4-yl-phenyl)-amine in an analogous manner to Example 61e. Product isolated as an off-white solid (0.047 g, 57%). MP: 215-220° C. 1HNMR (400 MHz, CDCl3, δ, ppm): 8.23 (d, 1H, J=8.8 Hz), 8.10 (s, 1H), 8.01 (s, 1H), 7.51 (s, 1H), 7.44 (s, 1H), 6.62 (s, 1H), 6.54 (d, 1H, J+2.3 Hz), 6.50 (dd, 1H, J=8.8 Hz and 2.0 Hz), 3.91 (s, 3H), 3.90-3.87 (m, 4H), 3.86 (s, 3H), 3.18-3.12 (m, 4H), 2.90-2.76 (m, 10H), 1.68 (t, 3H, J=18.7 Hz). MS: 589 (MH)+.
Reaction SMILES: [CH2:1]1[C:10](=[O:11])[CH2:9][C:8]2[C:3](=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:2]1.C(N(CC)CC)C.[Si:19](Cl)([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20]>CN(C)C1C=CN=CC=1.C(Cl)Cl>[Si:19]([O:11][C:10]1[CH2:1][CH2:2][C:3]2[C:8](=[CH:7][CH:6]=[CH:5][CH:4]=2)[CH:9]=1)([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O=C1CCc2ccccc2C1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](C)(C)OC1=Cc2ccccc2CC1
Reaction time: 72 h

Procedure:
Charge an oven dried, nitrogen flushed 125-mL round bottomed flask equipped with a stirring bar with β-tetralone (4.977 grams, 0.0340 moles), triethylamine (6.970 grams, 0.0689 moles), 4-dimethylamino pyridine (0.217 grams, 0.0018 moles), t-butyldimethylsilyl chloride (10.701 grams, 0.0709 moles) and 40 mL methylene chloride. Stir for 72 hours, filter, wash the filtrate with 1×5 mL saturated sodium bicarbonate solution, 1×5 mL water, dry over magnesium sulfate, concentrate using a Buchi rotavapor and distill (142°-145° C., 1 Torr) to obtain the named compound
Reaction SMILES: Br[C:2]1[CH2:3][NH:4][C:5]2[C:9]([CH:10]=1)=[CH:8][C:7]([P:19]([O:24][CH2:25][CH3:26])(=[O:23])[O:20][CH2:21][CH3:22])([P:11]([O:16][CH2:17][CH3:18])(=[O:15])[O:12][CH2:13][CH3:14])[CH:6]=2.C([Li])CCC>C1COCC1.CCCCCC>[N:4]1[C:5]2[C:9](=[CH:8][C:7]([P:19]([O:24][CH2:25][CH3:26])(=[O:23])[O:20][CH2:21][CH3:22])([P:11]([O:12][CH2:13][CH3:14])(=[O:15])[O:16][CH2:17][CH3:18])[CH:6]=2)[CH:10]=[CH:2][CH:3]=1
Reactant: CCOP(=O)(OCC)C1(P(=O)(OCC)OCC)C=C2C=C(Br)CNC2=C1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCOP(=O)(OCC)C1(P(=O)(OCC)OCC)C=c2cccnc2=C1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of dihydro-3-bromo-1-pyrindine-6,6-bisphosphonic acid, tetraethyl ester (10 mmol) [prepared as described in Example E (part I) hereinbefore] in THF (10 ml) cooled to -78° C. is added a solution of n-butyllithium (2.1 equivalent) in hexane over 30 minutes. The reaction is kept at -78° C. for an additional 30 minutes. To this solution is added 4-iodobutanol trimethylsilyl (TMS) ether (2.5 equivalent) and the reaction is allowed to warm to room temperature over 30 minutes. After standard aqueous work-up, dihydro-3-(4-butanol, TMS ether)-1-pyrindine-6,6-bisphosphonic acid, tetraethyl ester is isolated and used in the next reaction without purification.
Reaction SMILES: [F:1][C:2]1[C:7](B(O)O)=[CH:6][CH:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[Na+].[Na+].C(OC([N:24]([C:33]1[S:42][CH2:41][C@H:40]2[C@:35]([C:43]3[S:44][CH:45]=[C:46](Br)[CH:47]=3)([CH2:36][CH2:37][O:38][CH2:39]2)[N:34]=1)C(=O)C1C=CC=CC=1)=O)(C)(C)C.C(OCC)(=O)C>CN(C=O)C.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>[F:1][C:2]1[C:7]([C:46]2[CH:47]=[C:43]([C@@:35]34[N:34]=[C:33]([NH2:24])[S:42][CH2:41][C@@H:40]3[CH2:39][O:38][CH2:37][CH2:36]4)[S:44][CH:45]=2)=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: OB(O)c1cccnc1F
Reactant: CC(C)(C)OC(=O)N(C(=O)c1ccccc1)C1=N[C@@]2(c3cc(Br)cs3)CCOC[C@H]2CS1
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+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: NC1=N[C@@]2(c3cc(-c4cccnc4F)cs3)CCOC[C@H]2CS1
Temperature: 90 °C
Reaction time: 7 h
Yield: 36.1 %

Procedure:
2-Fluoropyridine-3-boronic acid (15.7 mg), tetrakis(triphenylphosphine)palladium (4.3 mg) and a 1 N sodium carbonate solution (112 μL) were added to a solution of (±)-N-tert-butoxycarbonyl-N-[(4aS*,8aS*)-8a-(4-bromo-thiophen-2-yl)-4a,7,8,8a-tetrahydro-4H,5H-6-oxa-3-thia-1-azanaphthalen-2-yl]benzamide (20.0 mg) in DMF (1 mL). After replacement with nitrogen, the mixture was stirred at 90° C. for seven hours. After cooling to room temperature, ethyl acetate was added to the reaction mixture. The organic layer was washed with water and brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by NH-silica gel column chromatography to obtain the title compound (4.7 mg).
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[C:16]([O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:15][C:9]2[C:10](=[O:14])[CH:11]=[CH:12][O:13][C:8]=2[CH:7]=1)(=[O:4])=[O:3].[CH3:24]I.[H-].[Na+]>>[CH3:24][N:5]([C:6]1[C:16]([O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:15][C:9]2[C:10](=[O:14])[CH:11]=[CH:12][O:13][C:8]=2[CH:7]=1)[S:2]([CH3:1])(=[O:3])=[O:4]
Reactant: CS(=O)(=O)Nc1cc2occc(=O)c2cc1Oc1ccccc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Product: CN(c1cc2occc(=O)c2cc1Oc1ccccc1)S(C)(=O)=O

Procedure:
7-Methylsulfonylamino-6-phenoxy-4H-1-benzopyran-4-one was reacted with methyl iodide in the presence of sodium hydride to obtain 7-(N-methyl-N-methylsulfonylamino)-6-phenoxy-4H-1-benzopyran-4-one.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]2[CH2:13][O:12][CH:11]([CH2:14][NH:15][CH2:16][CH3:17])[O:10][C:9]=2[CH:18]=1)(=[O:4])=[O:3].[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(=O)([O-])[O-].[K+].[K+].C(#N)C>CCOC(C)=O>[CH2:19]([N:15]([CH2:14][CH:11]1[O:10][C:9]2[CH:18]=[C:5]([S:2]([CH3:1])(=[O:4])=[O:3])[CH:6]=[CH:7][C:8]=2[CH2:13][O:12]1)[CH2:16][CH3:17])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CCNCC1OCc2ccc(S(C)(=O)=O)cc2O1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CCN(Cc1ccccc1)CC1OCc2ccc(S(C)(=O)=O)cc2O1
Yield: 89.5 %

Procedure:
N-{[7-(methylsulfonyl)-4H-1,3-benzodioxin-2-yl]methyl}ethanamine (0.93 g, 3.4 mmol), benzylbromide (0.43 ml, 3.6 mmol), potassium carbonate (0.61 g, 4.4 mmol) and ACN (20 ml) were heated at 70° C. for 2 h. EtOAc (50 ml) was added before the reaction mixture was filtered and concentrated. Purification by flash chromatography (isooctane/EtOAc 1:1) afforded the title compound (1.1 g). 1H-NMR (400 MHz, MeOH): δ 7.47 (1H, dd, J1 8 Hz, J2 1.6 Hz), δ 7.31 (7H, m), δ 5.18 (1H, t, J 5.2 Hz), δ 4.97 (2H, dd, J1 41 Hz, J2 15 Hz), δ 3.09 (3H, s), δ 2.90 (2H, m), δ 2.70 (2H, m), δ 1.12 (3H, t, J 7.2 Hz).
Reaction SMILES: FC(F)(F)C([N:5]([CH2:15][CH:16]1[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][OH:24])[CH2:18][CH2:17]1)[C@@H:6]1[CH2:8][C@H:7]1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=O.[OH-].[Na+].C(OCC)(=O)C>C(O)C>[C:9]1([C@@H:7]2[CH2:8][C@H:6]2[NH:5][CH2:15][CH:16]2[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][OH:24])[CH2:18][CH2:17]2)[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: O=C(N(CC1CCN(CCO)CC1)[C@@H]1C[C@H]1c1ccccc1)C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCO
Product: OCCN1CCC(CN[C@@H]2C[C@H]2c2ccccc2)CC1
Temperature: 80 °C
Yield: 32.4 %

Procedure:
To the solution of 2,2,2-trifluoro-N-((1-(2-hydroxyethyl)piperidin-4-yl)methyl)-N-(trans-2-phenylcyclopropyl)acetamide (40 mg, 0.108 mmol) in ethanol (2 mL) was added 1 M NaOH (1 mL, 1.000 mmol). The reaction was heated to 80° C. for 1 hr. Then 10 ml of ethyl acetate was added. Layers were separated, organic layer was washed with brine, dried over MgSO4, filtered and evaporated. The oil was purified on preparative HPLC (5 to 70% AcCN: H2O gradient with 0.1% formic acid modifier). The fractions were collected. The combined fractions were neutralized with aq. NH4OH, concentrated and extracted with ethyl acetate. Organic layer was washed with brine, dried over MgSO4 and evaporated. 2-(4-(((trans-2-phenylcyclopropyl)amino)methyl)piperidin-1-yl)ethanol (10 mg, 0.035 mmol, 32.1% yield) was isolated as colorless oil. 1H NMR (400 MHz, METHANOL-d4) δ 7.19-7.28 (m, 2H), 7.10-7.16 (m, 1H), 7.03-7.09 (m, 2H), 3.70 (t, J=6.32 Hz, 2H), 2.95-3.08 (m, 2H), 2.61 (d, J=6.82 Hz, 2H), 2.54 (t, J=6.19 Hz, 2H), 2.25-2.37 (m, 1H), 2.02-2.16 (m, 2H), 1.92 (ddd, J=3.28, 5.87, 9.28 Hz, 1H), 1.69-1.85 (m, 2H), 1.49-1.64 (m, J=3.54, 7.48, 7.48, 14.84 Hz, 1H), 1.20-1.36 (m, 2H), 1.08 (dt, J=4.77, 9.41 Hz, 1H), 1.01 (dt, J=5.59, 7.26 Hz, 1H); LC-MS Rt=0.48 min; MS (ESI): 275.2 [M+H]+.
Reaction SMILES: Cl[C:2]1[N:6]=[CH:5][N:4]([C:7]2[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[C:9]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=3)[N:8]=2)[N:3]=1.[NH2:27][C:28]1[CH:33]=[CH:32][C:31](B2OC(C)(C)C(C)(C)O2)=[CH:30][N:29]=1>>[F:14][C:13]([F:16])([F:15])[C:11]1[CH:10]=[C:9]([C:17]2[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=2)[N:8]=[C:7]([N:4]2[CH:5]=[N:6][C:2]([C:31]3[CH:32]=[CH:33][C:28]([NH2:27])=[N:29][CH:30]=3)=[N:3]2)[CH:12]=1
Reactant: FC(F)(F)c1ccc(-c2cc(C(F)(F)F)cc(-n3cnc(Cl)n3)n2)cc1
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Product: Nc1ccc(-c2ncn(-c3cc(C(F)(F)F)cc(-c4ccc(C(F)(F)F)cc4)n3)n2)cn1

Procedure:
The title compound was prepared from 2-(3-chloro-[1,2,4]triazol-1-yl)-4-trifluoromethyl-6-(4-trifluoromethyl-phenyl)-pyridine (example E.92) (0.314 g, 0.8 mmol) and commercially available 2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.176 g, 0.8 mmol) according to the general procedure VI. Obtained as a white solid (0.027 g, 8%). MS (ISP) 451.2 [(M+H)+].
Reaction SMILES: N12CCCN=C1CCCCC2.[Cl:12][C:13]1[CH:26]=[CH:25][C:16]2[N:17]([CH3:24])[C:18](=[O:23])[CH2:19][S:20](=[O:22])(=[O:21])[C:15]=2[CH:14]=1.[F:27][C:28]1[CH:33]=[CH:32][C:31]([N:34]=[C:35]=[O:36])=[CH:30][CH:29]=1.Cl>CN(C)C=O>[Cl:12][C:13]1[CH:26]=[CH:25][C:16]2[N:17]([CH3:24])[C:18](=[O:23])[CH:19]([C:35](=[O:36])[NH:34][C:31]3[CH:32]=[CH:33][C:28]([F:27])=[CH:29][CH:30]=3)[S:20](=[O:22])(=[O:21])[C:15]=2[CH:14]=1
Reactant: CN1C(=O)CS(=O)(=O)c2cc(Cl)ccc21
Reactant: O=C=Nc1ccc(F)cc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: CN1C(=O)C(C(=O)Nc2ccc(F)cc2)S(=O)(=O)c2cc(Cl)ccc21
Reaction time: 1 h
Yield: 68.4 %

Procedure:
To a solution of 1,8-diazabicyclo-[5,4,0]undec-7-ene (14.12 g) in dimethylformamide (111 ml) was added, dropwise in 10 minutes, a solution of 7-chloro-4-methyl-2H-1,4-benzothiazin-3(4H)one 1,1-dioxide (22.8 g) and 4-fluorophenylisocyanate (12.82 g) in dimethylformamide (111.4 ml) at room temperature. After being stirred for one hour, the mixture was poured into 1% hydrochloric acid (1 l). The separated solids were collected by filtration and washed with water. The wet solids were dissolved in ethyl acetate. The mixture was washed with 1% hydrochloric acid, with water, dried over magnesium sulfate, and evaporated under reduced pressure. The residue was crystallized from diethyl ether to yield 24.3 g of 7-chloro-2-(4-fluorophenylcarbamoyl)-4-methyl-2H-1,4-benzothiazin-3(4H)one 1,1-dioxide.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]=[CH:16][CH2:17][N:18]2[CH:22]=[CH:21][CH:20]=[N:19]2)=[CH:11][CH:10]=1)C1C=CC=CC=1.[CH2:23]([SH:25])[CH3:24]>B(F)(F)F.CCOCC>[CH2:23]([S:25][CH:15]([C:12]1[CH:11]=[CH:10][C:9]([OH:8])=[CH:14][CH:13]=1)[CH2:16][CH2:17][N:18]1[CH:22]=[CH:21][CH:20]=[N:19]1)[CH3:24]
Reactant: CCS
Reactant: C(=Cc1ccc(OCc2ccccc2)cc1)Cn1cccn1
Agent: FB(F)F
Solvent: CCOCC
Product: CCSC(CCn1cccn1)c1ccc(O)cc1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 86 %

Procedure:
4.51 g of 1-benzyloxy-4-[3-(1-pyrazolyl)prop-1-enyl]benzene were dissolved in a mixture of 25 ml of ethanethiol and 25 ml of boron trifluoride diethyl etherate, and the resulting mixture was stirred at 25° C. for 0.75 hours. The excess thiol was removed by evaporation, and the residue was partitioned between ethyl acetate and water. The organic phase was separated, dried over sodium sulfate, and filtered. The filtrate was evaporated, and the residue was chromatographed on silica gel using chloroform for the elution. The eluate was evaporated, whereby 3.5 g (86%) of 4-[1-ethylthio-3-(1-pyrazolyl)propyl]phenol in the form of an oil was obtained.