Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br.Br[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=1.CCN(C(C)C)C(C)C.[C:19]1([S:25]([O-:27])=[O:26])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[Na+]>CC#N>[C:19]1([S:25]([CH2:3][C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=2)(=[O:27])=[O:26])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: BrCc1ccccn1
Reactant: O=S([O-])c1ccccc1
Agent: Br
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: O=S(=O)(Cc1ccccn1)c1ccccc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 79.7 %

Procedure:
To a stirred suspension of 2.5 g (0.010 mol) of 2-bromomethyl-pyridine hydrobromide in 10 mL of CH3CN at RT, was added 1.78 mL (0.0105 mol, 1.05 eq.) of Hunig's base. After complete dissolution of the salt, 1.62 g (0.010 mol, 1 eq.) of sodium benzene sulfinat and 0.52 g (0.002 mol, 0.2 eq.) were added. The mixture was stirred at RT for 48 hours, and then the reaction was quenched by addition of water, and the product extracted with EtOAc. The combined organic phases were dried over Na2SO4, filtered and dried under vacuum to afford 1.86 g (80%) of 2-benzenesulfonylmethyl-pyridine.
Reaction SMILES: [OH:1][CH:2]([C:4]1[O:5][CH:6]=[CH:7][C:8]=1Br)[CH3:3].BrBr.Cl.[OH2:13]>CO>[CH3:8][C:4]1[O:5][CH:6]=[CH:7][C:3](=[O:13])[C:2]=1[OH:1]
Reactant: O
Reactant: CC(O)c1occc1Br
Agent: BrBr
Agent: Cl
Solvent: CO
Product: Cc1occc(=O)c1O
Temperature: 96 °C

Procedure:
To a sample of 2-(1-hydroxyethyl)-3-bromo-furan (0.54 g, 2.8 mmoles) in 15 ml water and 15 ml methanol at 0° C. was added 0.24 g (3.0 mmoles) of bromine. After allowing the reaction to come to room temperature, the reaction was treated with 3 ml of conc. HCl and heated to 96° C. for 2 hours, removing much of the methanol. After cooling, maltol was isolated by the method of Example 1.
Reaction SMILES: [N+]([O-])([O-])=O.[Na+].N[C:7]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:8]=1[C:9](=[O:22])[C:10]([O:20][CH3:21])=[C:11]([O:18][CH3:19])[C:12]2=[O:17].C(O)(=O)C.N([O-])=O.[Na+].[ClH:31]>O>[Cl:31][C:7]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:8]=1[C:9](=[O:22])[C:10]([O:20][CH3:21])=[C:11]([O:18][CH3:19])[C:12]2=[O:17]
Reactant: Cl
Reactant: COC1=C(OC)C(=O)c2c(N)cccc2C1=O
Agent: O=N[O-]
Agent: O=[N+]([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: COC1=C(OC)C(=O)c2c(Cl)cccc2C1=O
Temperature: -5 °C

Procedure:
A solution of sodium nitrate (0.69 g, 10 mmol) in water (5 ml) was added at 0°-5° C. to a solution of 5-amino-2,3-dimethoxy-1,4-naphthoquinone (1.17 g, 5 mmol) in 5:1 acetic acid:water (25 ml) containing concentrated hydrochloric acid (1.7 ml). A further quantity of sodium nitrite (0.69 g) was then added to the reaction mixture after cooling to -5° C., followed by a solution of cuprous chloride (0.6 g) in concentrated hydrochloric acid (5 ml). The mixture was allowed to warm to 22° C. and solid cuprous chloride was added portionwise until the mixture assumed a green color. Water was then added to the reaction mixture and the precipitated yellow solid filtered off, washed with water and recrystallized from methanol:water (2:1) giving 1.01 g of 5-chloro-2,3-dimethoxy-1,4-naphthoquinone, mp 120°-121° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:25]=[CH:24][C:6]2[N:7]=[C:8]([C:10]3[CH:11]=[CH:12][C:13]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[N:14][CH:15]=3)[O:9][C:5]=2[CH:4]=1.[H-].[Na+].Br[CH2:29][CH2:30][F:31]>CN(C=O)C>[F:31][CH2:30][CH2:29][N:16]([C:13]1[CH:12]=[CH:11][C:10]([C:8]2[O:9][C:5]3[CH:4]=[C:3]([O:2][CH3:1])[CH:25]=[CH:24][C:6]=3[N:7]=2)=[CH:15][N:14]=1)[C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:20])[CH3:21]
Reactant: COc1ccc2nc(-c3ccc(NC(=O)OC(C)(C)C)nc3)oc2c1
Reactant: FCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc2nc(-c3ccc(N(CCF)C(=O)OC(C)(C)C)nc3)oc2c1
Temperature: 25 °C

Procedure:
tert-Butyl [5-(6-methoxy-1,3-benzoxazol-2-yl)pyridin-2-yl]carbamate (0.65 mmol) and sodium hydride (0.78 mmol) were dissolved in dry DMF (20 mL) at 0° C. After 5 min 1-bromo-2-fluoroethane (0.72 mmol) was added and the reaction was allowed to warm to r.t. After 2 h additional sodium hydride and 1-bromo-2-fluoroethane was added and the reaction mixture was stirred over night. The solvent was removed under reduced pressure and redissolved in EtOAc. Water was added and the layers separated. The aqueous layer was extracted with EtOAc (2×), dried (Na2SO4) and evaporated to give 253 mg as brown oil. The crude product was taken to the next step without further purification. MS m/z 388 (M+H).
Reaction SMILES: [C:1]([C:3]1C=CC(C(C2C(=O)CC(C(F)(F)F)CC=2OCC)NC(NC2C=CC=C(C(F)(F)F)C=2)=O)=CC=1)#N.[C:38]([C:40]1[CH:45]=[CH:44][C:43]([CH:46]([C:61]2[C:66](=[O:67])[CH2:65][CH:64]([C:68]3[S:69][CH:70]=[CH:71][CH:72]=3)[CH2:63][C:62]=2[OH:73])[NH:47][C:48]([NH:50][C:51]2[CH:56]=[CH:55][CH:54]=[C:53]([C:57]([F:60])([F:59])[F:58])[CH:52]=2)=[O:49])=[CH:42][CH:41]=1)#[N:39]>>[C:38]([C:40]1[CH:45]=[CH:44][C:43]([CH:46]([C:61]2[C:62](=[O:73])[CH2:63][CH:64]([C:68]3[S:69][CH:70]=[CH:71][CH:72]=3)[CH2:65][C:66]=2[O:67][CH2:1][CH3:3])[NH:47][C:48]([NH:50][C:51]2[CH:56]=[CH:55][CH:54]=[C:53]([C:57]([F:60])([F:59])[F:58])[CH:52]=2)=[O:49])=[CH:42][CH:41]=1)#[N:39]
Reactant: N#Cc1ccc(C(NC(=O)Nc2cccc(C(F)(F)F)c2)C2=C(O)CC(c3cccs3)CC2=O)cc1
Reactant: CCOC1=C(C(NC(=O)Nc2cccc(C(F)(F)F)c2)c2ccc(C#N)cc2)C(=O)CC(C(F)(F)F)C1
Product: CCOC1=C(C(NC(=O)Nc2cccc(C(F)(F)F)c2)c2ccc(C#N)cc2)C(=O)CC(c2cccs2)C1

Procedure:
The title compound is prepared in analogy to 1-((4-cyanophenyl)(2-ethoxy-6-oxo-4-(tri-fluoromethyl)cyclohex-1-enyl)methyl)-3-(3-(trifluoromethyl)phenyl)urea (intermediate 13), using 1-((4-cyanophenyl)(2-hydroxy-6-oxo-4-(thiophen-2-yl)cyclohex-1-enyl)methyl)-3-(3-(trifluoromethyl)phenyl)urea (intermediate 20, 444 mg, 0.87 mmol) as starting material. Yield: 507 mg; ESI mass spectrum [N+H]+=540, Retention time HPLC: 1.29 min (V011_S01).
Reaction SMILES: Br.Cl.[NH:3]([C:7]1[S:8][CH:9]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([NH2:18])[CH:13]=2)[N:11]=1)[C:4]([NH2:6])=[NH:5].[C:19]([NH:27][C:28]#[N:29])(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[OH-].[Na+]>CN(C)C=O.O>[NH:3]([C:7]1[S:8][CH:9]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([NH:18][C:28]([NH2:29])=[N:27][C:19](=[O:26])[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH:13]=2)[N:11]=1)[C:4]([NH2:6])=[NH:5]
Reactant: N#CNC(=O)c1ccccc1
Reactant: N=C(N)Nc1nc(-c2cccc(N)c2)cs1
Agent: Br
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: N=C(N)Nc1nc(-c2cccc(NC(N)=NC(=O)c3ccccc3)c2)cs1
Temperature: 90 °C

Procedure:
A mixture of 2-guanidino-4-(3-aminophenyl)-thiazole hydrochloride hydrobromide (1.2 g.) and benzoylcyanamide (0.7 g.) in dimethylformamide (15 ml.) and water (10 ml.) was heated at 90° C. for 2 hours. The mixture was diluted with water (30 ml.) and made strongly basic with dilute sodium hydroxide solution. The mixture was extracted with ethyl acetate (2×50 ml.) and the extract evaporated to dryness to give 2-guanidino-4-[3-(2-benzoylguanidino)phenyl]-thiazole as a dark gum (0.9 g.)
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([CH3:17])([C:14]([OH:16])=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].N1C=CC=CC=1.C(Cl)(=O)C(Cl)=O.[C:30]([C:34]1[CH:35]=[C:36]([CH:38]=[CH:39][CH:40]=1)[NH2:37])([CH3:33])([CH3:32])[CH3:31]>CN(C=O)C.ClC(Cl)C.ClCCl>[C:30]([C:34]1[CH:35]=[C:36]([NH:37][C:14]([C:11]2([CH3:17])[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:13][CH2:12]2)=[O:16])[CH:38]=[CH:39][CH:40]=1)([CH3:33])([CH3:31])[CH3:32]
Reactant: CC(C)(C)OC(=O)N1CCC(C)(C(=O)O)CC1
Reactant: CC(C)(C)c1cccc(N)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: CC(Cl)Cl
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(C)(C(=O)Nc2cccc(C(C)(C)C)c2)CC1
Reaction time: 0.67 h
Yield: 61 %

Procedure:
To a solution of 1-(tert-butoxycarbonyl)-4-methylpiperidine-4-carboxylic acid (0.30 g, 1.2 mmol), DMF (20 drops), and pyridine (0.38 g, 4.8 mmol) in dichloroethane (10 mL) was added oxalyl chloride (0.15 g, 1.2 mmol). The mixture was stirred for 40 minutes, and 3-tert-butylaniline was added. The mixture was stirred for 1 hour, diluted with dichloromethane, washed twice each with sat. aq. NaHCO3 and 1.0 N aq. HCl, dried over MgSO4, and concentrated. Silica gel chromatography (0-2% MeOH:CH2Cl2) gave the title compound in 61% yield. MS (ES+) [M+H]+=375.
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][N:19]2[C:27]3[CH:26]=[CH:25][N:24]=[CH:23][C:22]=3[CH:21]=[CH:20]2)[C:13](=[O:28])[CH2:12]1)=O)C1C=CC=CC=1.C(O)=O.CO.[Cl:34][C:35]1[S:39][C:38]([CH:40]=[CH:41][S:42](Cl)(=[O:44])=[O:43])=[CH:37][CH:36]=1>[Pd].C(#N)C>[Cl:34][C:35]1[S:39][C:38]([CH:40]=[CH:41][S:42]([N:11]2[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][N:19]3[C:27]4[CH:26]=[CH:25][N:24]=[CH:23][C:22]=4[CH:21]=[CH:20]3)[C:13](=[O:28])[CH2:12]2)(=[O:44])=[O:43])=[CH:37][CH:36]=1
Reactant: O=S(=O)(Cl)C=Cc1ccc(Cl)s1
Reactant: O=C1CN(C(=O)OCc2ccccc2)CCN1CCn1ccc2cnccc21
Agent: [Pd]
Solvent: O=CO
Solvent: CC#N
Solvent: CO
Product: O=C1CN(S(=O)(=O)C=Cc2ccc(Cl)s2)CCN1CCn1ccc2cnccc21

Procedure:
4-(Benzyloxycarbonyl)-1-(2-pyrrolo[3,2-c]pyridin-1-ylethyl)-piperazin-2-one (0.028 g, 0.074 mmol), EXAMPLE 98, is treated with 4% HCO2H/MeOH (5 mL) and a catalytic amount of Pd black for 5 minutes. The reaction mixture is filtered washed with methanol and the filtrate is concentrated to a residue. The residue is treated with acetonitrile (3 mL) excess N-methylmorpholine (0.04 mL) and 2-(5-chlorothiophen-2-yl)ethene-sulfonyl chloride (0.018 g, 0.074 mmol), EXAMPLE 3, and processed as usual (EXAMPLE 719). Further chromatographic purification (NH4OH/MeOH/CH2Cl2: 1/4/95) yields the title compound: MS m/z 451, 453 (M+H); 1H NMR (CDCl3, 300 MHz) δ8.93 (bs, 1H), 8.24 (bs, 1H), 7.41 (d, 1H), 7.23 (d, 1H), 7.14 (m, 2H), 6.94 (d, 1H), 6.68 (d. 1H), 6.18 (d, 1H), 4.43 (t, 2H), 3.67 (t, 2H), 2.88 (t, 2H), 2.66 (t, 2H).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[C:15]([NH:22][CH:23]1[CH2:28][CH2:27][CH2:26][NH:25][CH2:24]1)([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16]>>[N+:12]([C:3]1[CH:4]=[C:5]([C:8]([F:11])([F:10])[F:9])[CH:6]=[CH:7][C:2]=1[N:25]1[CH2:26][CH2:27][CH2:28][CH:23]([NH:22][C:15](=[O:16])[O:17][C:18]([CH3:20])([CH3:19])[CH3:21])[CH2:24]1)([O-:14])=[O:13]
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1F
Reactant: CC(C)(C)OC(=O)NC1CCCNC1
Product: CC(C)(C)OC(=O)NC1CCCN(c2ccc(C(F)(F)F)cc2[N+](=O)[O-])C1
Yield: 99 %

Procedure:
Method 1 was followed using 1-fluoro-2-nitro-4-(trifluoromethyl)benzene (1.0 eq), 3-(N-Boc-amino) piperidine (1.2 eq), and TEA (1.5 eq) at 55° C. for 1 hour yielding tert-butyl 1-(2-nitro-4-(trifluoromethyl)phenyl)piperidin-3-ylcarbamate (99%). LCMS (m/z): 390.1 (MH+); LC Rt=3.58 min.
Reaction SMILES: C([O:4][CH2:5][CH2:6][CH:7]([CH3:20])[CH:8]([O:14][CH:15]([O:17][CH2:18][CH3:19])[CH3:16])[CH2:9][CH:10]=[C:11]([CH3:13])[CH3:12])(=O)C.C(=O)([O-])[O-].[K+].[K+].O>CO>[CH3:20][CH:7]([CH:8]([O:14][CH:15]([O:17][CH2:18][CH3:19])[CH3:16])[CH2:9][CH:10]=[C:11]([CH3:13])[CH3:12])[CH2:6][CH2:5][OH:4]
Reactant: CCOC(C)OC(CC=C(C)C)C(C)CCOC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: CCOC(C)OC(CC=C(C)C)C(C)CCO
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 8-acetoxy-2,6-dimethyl-5-[(1-ethoxyethoxy)]-2-octene (0.5 mmole), saturated potassium carbonate solution (9 ml), water (6 ml) and methanol (100 ml) is stirred for 3 hours at room temperature. Most of the methanol is removed in vacuo and the residue is treated with ethyl acetate (500 ml) and water (200 ml). The organic phase is dried (Na2SO4) and evaporated in vacuo to give the crude product. This material is further purified by column chromatography on silica gel (25 g, 15% ethyl acetate in hexane) to give 3,7-dimethyl-4-[(1-ethoxyethoxy)]-6-octen-1-ol as a colorless oil.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([S:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[Br:16])[CH:3]=1.NC1C=CC(C#N)=CC=1OC1C=CC=CC=1Br.[CH3:34][N:35]1[CH2:40][CH2:39][C:38](=O)[CH2:37][CH2:36]1.C(OC(N1CCC(=O)CC1)=O)(C)(C)C>>[Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][CH:38]2[CH2:39][CH2:40][N:35]([CH3:34])[CH2:36][CH2:37]2)=[C:4]([S:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[Br:16])[CH:3]=1
Reactant: Nc1ccc(Br)cc1Sc1ccccc1Br
Reactant: CN1CCC(=O)CC1
Agent: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: N#Cc1ccc(N)c(Oc2ccccc2Br)c1
Product: CN1CCC(Nc2ccc(Br)cc2Sc2ccccc2Br)CC1

Procedure:
Using an adaptation of the method described in Procedure 3, substituting 4-bromo-2-(2-bromophenylsulfanyl)-aniline, 2e for 4-amino-3-(2-bromophenoxy)-benzonitrile, 2a, and 1-methylpiperidin-4-one for 4-oxo-piperidine-1-carboxylic acid tert-butyl ester, the title compound [4-bromo-2-(2-bromophenylsulfanyl)-phenyl]-(1-methyl-piperidin-4-yl)-amine, 3e was obtained.
Reaction SMILES: [OH:1][CH:2]([CH2:14][CH2:15][CH2:16][C:17]1[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=1)[CH2:3][CH2:4][CH2:5][CH2:6][O:7]C1CCCCO1.CC(C)([O-])C.[K+].Br[CH2:30][C:31]([O-:33])=[O:32].[Na+]>CN(C)C=O.O1CCCC1.CCOCC.O>[OH:7][CH2:6][CH2:5][CH2:4][CH2:3][CH:2]([CH2:14][CH2:15][CH2:16][C:17]1[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=1)[O:1][CH2:30][C:31]([OH:33])=[O:32]
Reactant: O=C([O-])CBr
Reactant: OC(CCCCOC1CCCCO1)CCCc1cccnc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: CCOCC
Product: O=C(O)COC(CCCCO)CCCc1cccnc1
Temperature: 10 °C
Reaction time: 0.5 h

Procedure:
To a solution of 4.17 g (13.8 mmol) of 5-hydroxy-8-(3-pyridyl)-1-(2-tetrahydropyranyloxy)-octane in 30 mL dry dimethylformamide is added 17 mL (27.6 mmol) of a 1.61 M solution of potassium t-butoxide in tetrahydrofuran and the resulting red solution is stirred for 0.5 hour. Then the mixture is cooled to 10° C. and 4.9 g (30.4 mmol) of sodium bromoacetate is added followed by 40 mL dry dimethylformamide, and the reaction mixture stirred at room temperature for 18 hours. The reaction mixture is diluted with ether and water. The ether layer is separated and the aqueous phase is adjusted to pH=6.5 using 1N aqueous hydrochloric acid. The resulting solution is extracted thrice with ethyl acetate. The aqueous phase is again adjusted to pH=6.5 and extracted again. The combined organic phase is washed with brine, dried, filtered, and concentrated to give 8-hydroxy-4-[3-(3-pyridyl)propyl]-3-oxa-octanoic acid.
Reaction SMILES: [CH3:1][N:2]([CH3:21])[S:3]([C:6]1[CH:19]=[CH:18][C:17]2[S:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([F:20])[CH:14]=3)[NH:9][C:8]=2[CH:7]=1)(=[O:5])=[O:4].[H-].[Na+].Cl[CH2:25][CH2:26][CH2:27][N:28]1[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]1>CN(C)C=O>[CH3:1][N:2]([CH3:21])[S:3]([C:6]1[CH:19]=[CH:18][C:17]2[S:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([F:20])[CH:14]=3)[N:9]([CH2:25][CH2:26][CH2:27][N:28]3[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]3)[C:8]=2[CH:7]=1)(=[O:4])=[O:5]
Reactant: CN1CCN(CCCCl)CC1
Reactant: CN(C)S(=O)(=O)c1ccc2c(c1)Nc1ccc(F)cc1S2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1CCN(CCCN2c3ccc(F)cc3Sc3ccc(S(=O)(=O)N(C)C)cc32)CC1
Reaction time: 1 h
Yield: 75.6 %

Procedure:
12 grams of N,N-dimethyl-7-fluoro-phenothiazine-2-sulphonamide were dissolved in 50 milliliters of dry dimethylformamide, 1.9 grams of 50% sodium hydride in oil added and the mixture stirred for 1 hour. 7.2 grams of 1-(3-chloropropyl)-4-methylpiperazine were then added and the mixture heated for two hours on a steam bath. Then the mixture was poured onto crushed ice, the resulting mixture extracted with ether, the ether phase washed, dried over anhydrous magnesium sulphate and the ether evaporated. 13 grams of 2-dimethylsulphamoyl-7-fluoro-10-(3-(4-methylpiperazin-1-yl)propyl)phenothiazine was thus obtained as a yellow oil. The dimaleate was made from an ethanol solution of the base and melted at 166°-169° Centigrade.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH:7]([N:10]1[CH2:15][CH2:14][CH:13]([C:16](OCC)=[O:17])[CH2:12][CH2:11]1)([CH3:9])[CH3:8].[OH-].[Na+].C(=O)([O-])[O-].[K+].[K+]>O1CCCC1.O>[CH:7]([N:10]1[CH2:15][CH2:14][CH:13]([CH2:16][OH:17])[CH2:12][CH2:11]1)([CH3:9])[CH3:8]
Reactant: CCOC(=O)C1CCN(C(C)C)CC1
Agent: O=C([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)N1CCC(CO)CC1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 108.7 %

Procedure:
Lithium aluminum hydride (1.10 g) is suspended in tetrahydrofuran (80 ml), and thereto is added a solution of ethyl 1-isopropylpiperidine-4-carboxylate (5.00 g) obtained in Reference Example 127 in tetrahydrofuran (30 ml) dropwise under ice-cooling. The reaction solution is stirred for 2 hours under the ice-cooling, and water (1.1 ml), 15% aqueous sodium hydroxide solution (1.1 ml) and water (3.3 ml) are added dropwise successively and stirred for additional 10 minutes. To the resulting reaction solution is added potassium carbonate, and the mixture is stirred for 20 minutes, and then the insoluble materials are removed by filtration. The filtrate is concentrated under reduced pressure, and then the resulting residue is purified by NH-silica gel column chromatography (eluent: chloroform/ethyl acetate=1/1) to give (1-isopropylpiperidin-4-yl)methanol (4.29 g).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[C:20]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[O:28][CH3:29])=[C:19]([O:30][CH2:31][CH2:32][NH2:33])[N:18]=[CH:17][N:16]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:34][S:35](Cl)(=[O:37])=[O:36]>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[C:20]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[O:28][CH3:29])=[C:19]([O:30][CH2:31][CH2:32][NH:33][S:35]([CH3:34])(=[O:37])=[O:36])[N:18]=[CH:17][N:16]=2)(=[O:12])=[O:13])=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1ccccc1Oc1c(NS(=O)(=O)c2ccc(C(C)(C)C)cc2)ncnc1OCCN
Reactant: CS(=O)(=O)Cl
Product: COc1ccccc1Oc1c(NS(=O)(=O)c2ccc(C(C)(C)C)cc2)ncnc1OCCNS(C)(=O)=O
Yield: 20.6 %

Procedure:
According to Example 4a) 100 mg 4-tert.-butyl-N-[6-(2-aminoethoxy)-5-(o-methoxy-phenoxy)-4-pyrimidinyl]-benzene sulfonamide was reacted with 74 mg methanesulfonylchloride to give 24 mg 4-tert.-butyl-N-{6-[2-(methanesulfonyl-amino)-ethoxy]-5-(o-methoxy-phenoxy)-pyrimidin-4-yl}-benzenesulfonamide. LC-MS: tR=5.11 min, [M−1]−=549.45.
Reaction SMILES: [N:1]([C:4]1[C:9]([F:10])=[CH:8][N:7]=[CH:6][C:5]=1[CH:11]=O)=[N+:2]=[N-:3].[Cl:13][C:14]1[CH:19]=[C:18]([F:20])[CH:17]=[C:16]([Cl:21])[C:15]=1[NH2:22].C(N(CC)CC)C>C(Cl)Cl.[Ti](Cl)(Cl)(Cl)Cl>[N:1]([C:4]1[C:9]([F:10])=[CH:8][N:7]=[CH:6][C:5]=1/[CH:11]=[N:22]/[C:15]1[C:14]([Cl:13])=[CH:19][C:18]([F:20])=[CH:17][C:16]=1[Cl:21])=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=Nc1c(F)cncc1C=O
Reactant: Nc1c(Cl)cc(F)cc1Cl
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: [N-]=[N+]=Nc1c(F)cncc1/C=N/c1c(Cl)cc(F)cc1Cl
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a cooled (0° C.) solution of 4-azido-5-fluoro-pyridine-3-carbaldehyde (2.44 g, 14.7 mmol), 2,6-dichloro-4-fluorophenylamine (2.65 g, 14.7 mmol) and triethylamine (6.1 mL, 44 mmol) in DCM (50 mL) was added titanium tetrachloride (1M in DCM, 8.8 mL, 8.8 mmol) dropwise. The reaction mixture was stirred at 0° C. for 1 hour, warmed to room temperature, and stirred for a further 4 hours. The mixture was concentrated under reduced pressure. The residue was dissolved in toluene and filtered through Celite®. The filtrate was concentrated under to dryness under reduced pressure to afford the title compound that was used without further purification.
Reaction SMILES: [F:1][C:2]1[C:3]([O:53]C)=[CH:4][C:5]([C:34]([N:36]2[C@H:45]([CH2:46][N:47]3[CH2:52][CH2:51][O:50][CH2:49][CH2:48]3)[CH2:44][C:43]3[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=3)[CH2:37]2)=[O:35])=[C:6]([C:8]2[N:12]([CH3:13])[C:11]([CH3:14])=[C:10]([C:15]([N:17]([C:24]3[CH:25]=[C:26]4[CH:32]=[CH:31][N:30]([CH3:33])[C:27]4=[N:28][CH:29]=3)[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[O:16])[CH:9]=2)[CH:7]=1.B(Br)(Br)Br.C(O)C.C(=O)(O)[O-].[Na+]>ClCCl>[F:1][C:2]1[C:3]([OH:53])=[CH:4][C:5]([C:34]([N:36]2[C@H:45]([CH2:46][N:47]3[CH2:48][CH2:49][O:50][CH2:51][CH2:52]3)[CH2:44][C:43]3[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=3)[CH2:37]2)=[O:35])=[C:6]([C:8]2[N:12]([CH3:13])[C:11]([CH3:14])=[C:10]([C:15]([N:17]([C:24]3[CH:25]=[C:26]4[CH:32]=[CH:31][N:30]([CH3:33])[C:27]4=[N:28][CH:29]=3)[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)=[O:16])[CH:9]=2)[CH:7]=1
Reactant: COc1cc(C(=O)N2Cc3ccccc3C[C@H]2CN2CCOCC2)c(-c2cc(C(=O)N(c3ccccc3)c3cnc4c(ccn4C)c3)c(C)n2C)cc1F
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCO
Product: Cc1c(C(=O)N(c2ccccc2)c2cnc3c(ccn3C)c2)cc(-c2cc(F)c(O)cc2C(=O)N2Cc3ccccc3C[C@H]2CN2CCOCC2)n1C
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a solution of the compound of Step A (1 g; 1.37 mmol) in anhydrous dichloromethane (10 mL) there is added, dropwise at 0° C., a 1M solution of boron tribromide in dichloromethane (1.8 mL; 1.8 mmol). After stirring for 15 hours at ambient temperature, the reaction mixture is poured dropwise into a solution of ethanol (15 mL) at −10° C. After stirring for one hour, saturated aqueous sodium bicarbonate solution is added, and the reaction mixture is extracted with dichloromethane. After drying over MgSO4, the residue is purified on a silica gel column using a mixture of dichloromethane and methanol as eluant to yield the expected product.
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([OH:9])=[CH:4][C:3]=1[CH3:10].N1C=CN=C1.[CH:16]([Si:19](Cl)([CH:23]([CH3:25])[CH3:24])[CH:20]([CH3:22])[CH3:21])([CH3:18])[CH3:17]>C(Cl)Cl>[CH3:10][C:3]1[CH:4]=[C:5]([O:9][Si:19]([CH:23]([CH3:25])[CH3:24])([CH:20]([CH3:22])[CH3:21])[CH:16]([CH3:18])[CH3:17])[CH:6]=[C:7]([CH3:8])[C:2]=1[NH2:1]
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Reactant: Cc1cc(O)cc(C)c1N
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: Cc1cc(O[Si](C(C)C)(C(C)C)C(C)C)cc(C)c1N
Yield: 79.1 %

Procedure:
A solution of 4-amino-3,5-dimethylphenol (5.0 g, 36.46 mmol, Fieser, L. F. Organic Syntheses, Collect Vol II, 1943, 39), imidazole (6.21 g, 77.37 mmol) and triisopropylsilyl chloride (7.70 g, 40.1 mmol) in CH2Cl2 (80 mL) was stirred at room temperature for 1 h. The reaction mixture was diluted with CH2Cl2 (100.0 mL) and washed with water and brine. The organic layer was dried over MgSO4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel, eluting with ethyl acetate-hexanes (1:19) to afford 2,6-dimethyl-4-triisopropylsilanyloxyphenylamine (8.46 g, 79%): 1H NMR (300 MHz, CDCl3): δ 6.57 (s, 2H), 2.19 (s, 6H), 1.23 (m, 3H), 1.12 (m, 18H). TLC conditions: Uniplate silica gel, 250 microns; Mobile phase=ethyl acetate-hexanes (1:9); Rf=0.51.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([CH:11]([OH:13])[CH3:12])[C:8]2[C:4](=[CH:5][N:6]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])[N:7]=2)[CH:3]=1.N12CCCN=C1CCCCC2.[Cl:33][C:34]([Cl:38])([Cl:37])[C:35]#[N:36]>C(OCC)C>[Cl:33][C:34]([Cl:38])([Cl:37])[C:35](=[NH:36])[O:13][CH:11]([C:9]1[C:8]2[C:4](=[CH:5][N:6]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:20])([CH3:19])[CH3:21])[N:7]=2)[CH:3]=[C:2]([Cl:1])[CH:10]=1)[CH3:12]
Reactant: CC(O)c1cc(Cl)cc2cn(COCC[Si](C)(C)C)nc12
Reactant: N#CC(Cl)(Cl)Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCOCC
Product: CC(OC(=N)C(Cl)(Cl)Cl)c1cc(Cl)cc2cn(COCC[Si](C)(C)C)nc12
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
(±)-1-(5-Chloro-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazol-7-yl)ethanol (0.54 g, 1.65 mmol) was dissolved in diethyl ether (5 mL), cooled to 0° C. and treated with 1,8-diazabicyclo(5.4.0)undec-7-ene (50 μL, 0.33 mmol). The reaction was stirred for 10 min and treated with trichloroacetonitrile (250 μL, 2.48 mmol) dropwise over 10 min. The reaction was allowed to warm to room temperature overnight and concentrated. Flash chromatography on silica gel (5% ethyl acetate/hexanes) gave 600 mg (77%) as an oil. 1H-NMR (CDCl3, 300 MHz) δ 8.34 (s, 1H), 8.02 (s, 1H), 7.56 (d, J =1.5 Hz, 1H), 7.33 (m, 1H), 6.62 (q, J=6.2 Hz, 1H), 5.68 (s, 2H), 3.59-3.65 (m, 2H), 1.79 (m, 3H), 0.88-0.94 (m, 2H), 0.05 (s, 9H).