Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:21])[CH2:3][CH2:4][CH2:5][NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=O.[NH2:22][C:23]1[C:24]([Cl:29])=[N:25][CH:26]=[CH:27][CH:28]=1.C(N(CC)CC)C.N1C=CC=CC=1>C(Cl)Cl.[Ti](Cl)(Cl)(Cl)Cl>[Cl:29][C:24]1[C:23]([N:22]=[C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[NH:6][CH2:5][CH2:4][CH2:3][N:2]([CH3:21])[CH3:1])=[CH:28][CH:27]=[CH:26][N:25]=1
Reactant: CN(C)CCCNc1ccccc1C(=O)c1ccccc1
Reactant: Nc1cccnc1Cl
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: CN(C)CCCNc1ccccc1C(=Nc1cccnc1Cl)c1ccccc1

Procedure:
To a mixture of 2.82 g (0.01 mole) of [2-[[3-(dimethylamino)propyl]amino]phenyl]phenylmethanone and 1.29 g (0.01 mole) of 3-amino-2-chloropyridine, 6.2 ml (0.048 mole) of triethylamine and 20 ml of methylene chloride stirred in an ice bath under nitrogen atmosphere was added 2.28 g (0.012 mole) of titanium tetrachloride in 10 ml of methylene chloride during a 5 minute period. The mixture was then stirred at room temperature for 2 days during which time mass spec-CI showed little change in relative intensity of M.W. 129 (starting pyridine) and M.W. 393 (title product). Water was added to the reaction mixture and stirring was continued for 1.5 hr. The mixture was filtered to remove solid and the filter cake was rinsed with methylene chloride. Saturated sodium chloride solution was added to facilitate separation of layers. The methylene chloride layer was washed once with more sodium chloride solution. The aqueous layer having a pH of about 6 was basified to about pH 8-9 with potassium carbonate and then extracted twice with methylene chloride. The latter methylene chloride layers were washed with sodium chloride solution. All the methylene chloride extracts were combined, dried and evaporated to give 4.8 g of semi-solid product. TLC of the product showed it contained very little starting 3-amino-2-chloropyridine. Mass Spec. analysis showed the presence of compounds with molecular weight corresponding to title product (393), 3-amino-2-chloropyridine (129) and triethylamine (102) but no [2-[[3-(dimethylamino)propyl]amino]phenyl]phenylmethanone. 1HNMR spectrum in CDCl3 containing 1% TMS indicated the product was mostly title compound and some triethylamine. No 3-amino-2-chloropyridine was seen. The chemical shifts, multiplicities and assignments are given below.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][S:13][CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-])=O.O.C(N(CC)CC)C>C(OCC)(=O)C>[N:10]1([C:7]2[CH:6]=[CH:5][C:4]([NH2:1])=[CH:9][CH:8]=2)[CH2:11][CH2:12][S:13][CH2:14][CH2:15]1
Reactant: O=[N+]([O-])c1ccc(N2CCSCC2)cc1
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCN(CC)CC
Product: Nc1ccc(N2CCSCC2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 69.4 %

Procedure:
Stannous chloride dihydrate (10 g, 44.4 mmol) was added to a solution of 4-(4-nitro-phenyl)-thiomorpholine (2 g, 8.9 mmol) in ethyl acetate and stirred at room temperature for 4 hr. Water was added and the reaction mixture was neutralized with triethyl amine. The organic layer was dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure to yield 4-thiomorpholin-4-yl-phenylamine (1.2 g, 60%) as a solid.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][NH:8][C:7](=[O:11])[N:6]=1)(=[O:3])[CH3:2].S(=O)(=O)(O)O.[F:17][C:18](I)([F:20])[F:19].OO>S([O-])([O-])(=O)=O.[Fe+2].CS(C)=O>[C:1]([NH:4][C:5]1[C:10]([C:18]([F:20])([F:19])[F:17])=[CH:9][NH:8][C:7](=[O:11])[N:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1cc[nH]c(=O)n1
Reactant: FC(F)(F)I
Agent: [Fe+2]
Agent: O=S(=O)(O)O
Agent: O=S(=O)([O-])[O-]
Solvent: CS(C)=O
Product: CC(=O)Nc1nc(=O)[nH]cc1C(F)(F)F
Temperature: 45 °C
Reaction time: 0.33 h
Yield: 35 %

Procedure:
0.15 g (1.0 mmol) of N4-acetylcytosine was weighed and placed in a 50 ml two-neck flask equipped with a magnetic rotor and the atmosphere in the flask was replaced with argon. The following materials were added thereinto: 17 ml of dimethyl sulfoxide, 2.0 ml of a 1N dimethyl sulfoxide solution of sulfuric acid, 1.0 ml of a 3.0 mol/l dimethyl sulfoxide solution of trifluoromethyl iodide, 0.2 ml of a 30% hydrogen peroxide aqueous solution and 0.3 ml of a 1.0 mol/l aqueous solution of iron (II) sulfate. The mixture was stirred at 40 to 50° C. for 20 minutes and then the resulting solution was cooled to room temperature. Formation of N4-acetyl-5-trifluoromethylcytosine (19F-NMR yield: 35%) was confirmed by 19F-NMR with 2,2,2-trifluoroethanol as an internal standard. N4-acetyl-5-trifluoromethylcytosine was obtained as a white solid (0.067 g, yield: 30%) by column chromatography.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10](O)=[O:11])=[CH:5][CH:4]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].Cl>C1COCC1>[F:1][C:2]([F:13])([F:14])[C:3]1[CH:4]=[CH:5][C:6]([CH2:9][CH2:10][OH:11])=[CH:7][CH:8]=1
Reactant: O=C(O)Cc1ccc(C(F)(F)F)cc1
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: OCCc1ccc(C(F)(F)F)cc1
Temperature: 25 °C

Procedure:
3.0 g (14.7 mmol) of 4-trifluoromethylphenylacetic acid are introduced into 30 ml of abs. THF at 0° C., then a 1 M solution of 557 mg (14.7 mmol) of lithium aluminum hydride in 14.7 ml of THF is added dropwise, and the solution is stirred at room temperature until reaction is complete. The mixture is added to ice, acidified with hydrochloric acid and extracted with ethyl acetate. The organic phase is concentrated, and the crude product is purified by chromatography on silica gel. 2 g (92% of theory) of the title compound are obtained.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2([C:17]3[CH:22]=[CH:21][C:20]([C:23]#[N:24])=[CH:19][CH:18]=3)[CH2:16][CH2:15]2)=[CH:10][CH:9]=1>O1CCCC1>[Cl:7][C:8]1[CH:9]=[CH:10][C:11]([C:14]2([C:17]3[CH:18]=[CH:19][C:20]([CH2:23][NH2:24])=[CH:21][CH:22]=3)[CH2:15][CH2:16]2)=[CH:12][CH:13]=1
Reactant: N#Cc1ccc(C2(c3ccc(Cl)cc3)CC2)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: NCc1ccc(C2(c3ccc(Cl)cc3)CC2)cc1

Procedure:
230 mg of Lithiumaluminiumhydride are suspended in 10 ml of tetrahydrofuran, 234 mg of 1-(4-chlorophenyl)-1-(4-cyanophenyl)cyclopropane in 5 ml tetrahydrofuran added dropwise and the mixture refluxed for 18 hours. The mixture is then hydrolysed with 1N HCl and extracted with dichloromethane. The oily title compound is directly reacted further.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5]([N:8]2[C:12]([OH:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[N:9]2)=[CH:6][CH:7]=1.[F-].[K+].Br[CH2:21][N:22]1[C:26](=[O:27])[C:25]2[C:28]([CH:34]([CH3:36])[CH3:35])=[CH:29][C:30]([O:32][CH3:33])=[CH:31][C:24]=2[S:23]1(=[O:38])=[O:37].[Cl-].[NH4+]>CN(C=O)C.C(OCC)(=O)C>[CH:34]([C:28]1[C:25]2[C:26](=[O:27])[N:22]([CH2:21][O:13][C:12]3[N:8]([C:5]4[N:4]=[N:3][C:2]([Cl:1])=[CH:7][CH:6]=4)[N:9]=[C:10]([C:14]([F:17])([F:15])[F:16])[CH:11]=3)[S:23](=[O:38])(=[O:37])[C:24]=2[CH:31]=[C:30]([O:32][CH3:33])[CH:29]=1)([CH3:36])[CH3:35]
Reactant: Oc1cc(C(F)(F)F)nn1-c1ccc(Cl)nn1
Reactant: COc1cc(C(C)C)c2c(c1)S(=O)(=O)N(CBr)C2=O
Agent: [Cl-]
Agent: [F-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1cc(C(C)C)c2c(c1)S(=O)(=O)N(COc1cc(C(F)(F)F)nn1-c1ccc(Cl)nn1)C2=O
Temperature: 20 °C
Reaction time: 0.17 h
Yield: 76.3 %

Procedure:
To a mixture of 1-(3-chloropyridazin-6-yl)-3-trifluoromethyl-5-hydroxypyrazole (264 mg; 1 mmol) in DMF under nitrogen was added 96 mg (1.66 mmol) of KF and the mixture was stirred at 20° C. for 10 minutes. To the resulting mixture was added 2-bromomethyl-4-isopropyl-6-methoxy-1,2-benzisothiazol-3(2H)-one 1,1-dioxide (289 mg, 0.83 mmol) and the resulting mixture was stirred at room temperature (20° C.) for 1 hour and poured into saturated ammonium chloride solution/ethyl acetate. The aqueous layer was extracted with ethyl acetate (3×), the combined organic layer was dried over magnesium sulfate and concentrated in vacuo. The residue was purified by flash chromatography (silica gel; 20% ethyl acetate in hexane) and recrystallized from ether/hexane to afford 337 mg (77%) of 4-isopropyl-6-methoxy-2-[1-(3-chloropyridazin-6-yl)-3-trifluoromethylpyrazol-5-yl-oxymethyl]-1,2-benzisothiazol-3(2H)-one 1,1-dioxide (Formula I: R1 =3-Cl-6-pyridazinyl; R2 =CF3 ; R3 =H; R4 =CH(CH3)2 ; R5 =6-OCH3) as a white solid, m.p. 110°-1110° C.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]23[CH2:16][C:14]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)([CH2:15]2)[C:13](=[O:23])[N:12]([CH2:24][CH2:25][CH3:26])[C:11]3=[O:27])=[CH:6][CH:5]=1)([O-])=O.CCCCCC.CCOCC>C(OCC)(=O)C.[Pd]>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([C:10]23[CH2:15][C:14]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)([CH2:16]2)[C:13](=[O:23])[N:12]([CH2:24][CH2:25][CH3:26])[C:11]3=[O:27])=[CH:6][CH:5]=1
Reactant: CCCN1C(=O)C2(c3ccccc3)CC(c3ccc([N+](=O)[O-])cc3)(C2)C1=O
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCOCC
Solvent: CCCCCC
Product: CCCN1C(=O)C2(c3ccccc3)CC(c3ccc(N)cc3)(C2)C1=O

Procedure:
In a manner analogous to that described in Example 12a, 1.8 g of 1-(4-nitrophenyl)-5-phenyl-3-n-propyl-3-azabicyclo[3.1.1]heptane-2,4-dione are dissolved in 40 ml of ethyl acetate, hydrogenated in the presence of 0.2 g of 5% palladium-on-carbon and worked up. Melting point 144°-145° (from n-hexane/ether).
Reaction SMILES: C([O:3][C:4](=[O:27])[CH2:5][P:6]([C:11]1([NH:16][C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:18])[CH2:13][CH:12]1[CH:14]=[CH2:15])([O:8][CH2:9][CH3:10])=[O:7])C.[OH-].[Na+]>C1COCC1>[CH2:20]([O:19][C:17]([NH:16][C:11]1([P:6]([CH2:5][C:4]([OH:27])=[O:3])([O:8][CH2:9][CH3:10])=[O:7])[CH2:13][CH:12]1[CH:14]=[CH2:15])=[O:18])[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: C=CC1CC1(NC(=O)OCc1ccccc1)P(=O)(CC(=O)OCC)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: C=CC1CC1(NC(=O)OCc1ccccc1)P(=O)(CC(=O)O)OCC
Temperature: 25 °C
Reaction time: 8 h
Yield: 68.5 %

Procedure:
A solution of [(1-benzyloxycarbonylamino-2-vinyl-cyclopropyl)-ethoxy-phosphinoyl]-acetic acid ethyl ester (352 mg, 0.89 mmol) in THF (3 mL) was stirred at 0° C. as 1 N NaOH (980 μL, 0.98 mmol) was added. The solution was stirred overnight at r.t. and then concentrated, diluted with H2O (10 mL) and washed with ethyl acetate. The aqueous layer was acidified with 1 N HCl (5 mL) and extracted with ethyl acetate (×2). The organic extracts were washed with H2O, dried (MgSO4) and concentrated to yield [(1-Benzyloxycarbonylamino-2-vinyl-cyclopropyl)-ethoxy-phosphinoyl]-acetic acid (224 mg, 69%). 1H NMR (300 MHz, CDCl3): δ 7.34 (s, 5H), 5.91 (m, 2H), 5.20 (m, 2H), 4.21 (m, 2H), 3.11 (m, 2H), 2.30 (m, 1H), 2.03 (m, 1H), 1.85 (m, 2H), 1.70 (m, 2H), 1.58 (m, 2H), 1.38 (m, 2H), 1.25 (m, 3H). 31P (121.4 MHz, CDCl3): 45.109, 41.119, 40.965, 39.514
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:10][O:9]2)=[CH:4][C:3]=1[Cl:11].[NH2:12][CH2:13][CH2:14][OH:15].CCOC(C)=O.C1COCC1>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:9])[CH2:10][NH:12][CH2:13][CH2:14][OH:15])=[CH:4][C:3]=1[Cl:11]
Reactant: Clc1cc(C2CO2)ccc1Br
Reactant: NCCO
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: OCCNCC(O)c1ccc(Br)c(Cl)c1
Temperature: 25 °C
Reaction time: 7 h

Procedure:
To a stirred solution of (RS)-2-(4-bromo-3-chloro-phenyl)-oxirane (15.2 g) in THF (40 ml) was added 2-aminoethanol (35.1 ml) and the mixture was stirred at room temperature for 7 hours. The reaction mixture was then poured into EtOAc/THF (1:1) and washed with saturated brine. The organic layer was separated and was then dried over Na2SO4 and concentrated in vacuo to afford (RS)-1-(4-bromo-3-chlorophenyl)-2-(2-hydroxyethylamino)ethanol (19.0 g) as a yellow oil which was used in the next step without further purification. MS (ISP): 298.1 ([{81Br37Cl}M+H]+), 296.0 ([{81Br35Cl or 79Br37Cl}M+H]+), 293.9 ([{79Br35Cl}M+H]).
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH:11](O)=[O:12]>>[N+:1]([C:4]1[CH:10]=[CH:9][C:7]([NH:8][CH:11]=[O:12])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=CO
Reactant: Nc1ccc([N+](=O)[O-])cc1
Product: O=CNc1ccc([N+](=O)[O-])cc1

Procedure:
Was prepared according to Example 2 from 4-nitroaniline and formic acid.
Reaction SMILES: C([O-])([O-])=O.[Cs+].[Cs+].[CH3:7][C:8]1[N:9]=[CH:10][NH:11][CH:12]=1.Br[C:14]1[CH:15]=[CH:16][C:17]([NH2:20])=[N:18][CH:19]=1>[Cu]I.CN(C=O)C>[CH3:7][C:8]1[N:9]=[CH:10][N:11]([C:14]2[CH:15]=[CH:16][C:17]([NH2:20])=[N:18][CH:19]=2)[CH:12]=1
Reactant: Nc1ccc(Br)cn1
Reactant: Cc1c[nH]cn1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Cc1cn(-c2ccc(N)nc2)cn1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a microwave tube with a magnetic stirring bar was charged CuI (382 mg, 2.0 mmol), Cs2CO3 (6.5 g, 20.0 mmol), 4-methyl-1H-imidazole (1.15 g, 14.0 mmol), 5-bromopyridin-2-amine (1.75 g, 10.0 mmol), and DMF (10 mL) under N2. The system was sealed and then evacuated twice and back filled with N2. The reaction mixture was stirred for 30 min at room temperature, and then heated at 120° C. for 48 h. The reaction mixture was then cooled to ambient temperature, diluted with 30 mL of ethyl acetate, washed with water. The combined organic layers were concentrated, and the resulting residue was purified by column chromatography on silica gel to provide 5-(4-methyl-1H-imidazol-1-yl)pyridin-2-amine (134). 1H NMR (400 MHz, d6-DMSO) δ 8.09 (m, 1H), 7.85 (d, J=1.6 Hz, 1H), 7.56 (dd, J=2.8, 8.8 Hz, 1H), 7.22 (t, J=1.2 Hz, 1H), 6.51 (dd, J=0.8, 8.8 Hz, 1H), 6.15 (s, 2H), 2.14 (d, J=1.2 Hz, 3H). MS m/z 175.1 (M+1)+.
Reaction SMILES: Br[CH2:2]/[CH:3]=[CH:4]/[CH2:5][O:6][CH2:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([CH2:14][N:15]([CH3:29])[S:16]([C:19]2[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=2)(=[O:18])=[O:17])[CH2:10][CH2:9]1.[OH:30][CH2:31][CH2:32][NH:33][CH2:34][CH2:35][OH:36]>CN(C)C(=O)C>[OH:30][CH2:31][CH2:32][N:33]([CH2:34][CH2:35][OH:36])[CH2:2]/[CH:3]=[CH:4]/[CH2:5][O:6][CH2:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([CH2:14][N:15]([CH3:29])[S:16]([C:19]2[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=2)(=[O:18])=[O:17])[CH2:10][CH2:9]1
Reactant: OCCNCCO
Reactant: CN(C[C@H]1CC[C@H](COC/C=C/CBr)CC1)S(=O)(=O)c1ccc(C(F)(F)F)cc1
Solvent: CC(=O)N(C)C
Product: CN(C[C@H]1CC[C@H](COC/C=C/CN(CCO)CCO)CC1)S(=O)(=O)c1ccc(C(F)(F)F)cc1

Procedure:
In analogy to the method described in example 12.1, trans-N-[4-(4-bromo-(E)-but-2-enyloxymethyl)-cyclohexylmethyl]-N-methyl-4-trifluoromethyl-benzenesulfonamide was reacted with bis-(2-hydroxy-ethyl)-amine in N,N-dimethylacetamide at room temperature to yield trans-N-(4-{4-[bis-(2-hydroxy-ethyl)-amino]-(E)-but-2-enyloxymethyl}-cyclohexylmethyl)-N-methyl-4-trifluoromethyl-benzenesulfonamide as light yellow solid, MS: 523 (MH+).
Reaction SMILES: C(OC(N1CC2C([CH2:11][N:12]([CH2:16][C:17]3[S:25][C:24]4[C:23]([N:26]5[CH2:31][CH2:30][O:29][CH2:28][CH2:27]5)=[N:22][C:21]([Cl:32])=[N:20][C:19]=4[CH:18]=3)[CH2:13]2)C1)=O)(C)(C)C.[C:33]([O:37][C:38]([N:40]1[CH:45]2[CH2:46][CH2:47][CH:41]1CNC2)=[O:39])([CH3:36])([CH3:35])[CH3:34]>>[C:33]([O:37][C:38]([N:40]1[CH:45]2[CH2:46][CH2:47][CH:41]1[CH2:11][N:12]([CH2:16][C:17]1[S:25][C:24]3[C:23]([N:26]4[CH2:27][CH2:28][O:29][CH2:30][CH2:31]4)=[N:22][C:21]([Cl:32])=[N:20][C:19]=3[CH:18]=1)[CH2:13]2)=[O:39])([CH3:36])([CH3:34])[CH3:35]
Reactant: CC(C)(C)OC(=O)N1CC2CN(Cc3cc4nc(Cl)nc(N5CCOCC5)c4s3)CC2C1
Reactant: CC(C)(C)OC(=O)N1C2CCC1CNC2
Product: CC(C)(C)OC(=O)N1C2CCC1CN(Cc1cc3nc(Cl)nc(N4CCOCC4)c3s1)C2

Procedure:
Prepared according to the method used in the preparation of 5-(2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid tert-butyl ester using 3,8-diaza-bicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester in place of hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid tert-butyl ester. The title compound was obtained as a tan solid (103 mg, 74%).
Reaction SMILES: Cl[CH:2]1[C:8]2[CH:9]=[C:10]([F:13])[CH:11]=[CH:12][C:7]=2[S:6][C:5]2[CH:14]=[CH:15][C:16]([CH3:18])=[CH:17][C:4]=2[CH2:3]1.[N:19]1([CH2:25][CH2:26][N:27]2[CH2:31][CH2:30][O:29][C:28]2=[O:32])[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1>C(Cl)(Cl)Cl>[F:13][C:10]1[CH:11]=[CH:12][C:7]2[S:6][C:5]3[CH:14]=[CH:15][C:16]([CH3:18])=[CH:17][C:4]=3[CH2:3][CH:2]([N:22]3[CH2:23][CH2:24][N:19]([CH2:25][CH2:26][N:27]4[CH2:31][CH2:30][O:29][C:28]4=[O:32])[CH2:20][CH2:21]3)[C:8]=2[CH:9]=1
Reactant: Cc1ccc2c(c1)CC(Cl)c1cc(F)ccc1S2
Reactant: O=C1OCCN1CCN1CCNCC1
Solvent: ClC(Cl)Cl
Product: Cc1ccc2c(c1)CC(N1CCN(CCN3CCOC3=O)CC1)c1cc(F)ccc1S2

Procedure:
17.6 g of 10-chloro-8-fluoro-10,11-dihydro-2-methyl-dibenzo[b,f]thiepin are heated for 20 hours under reflux conditions together with 27.3 g of 3-[2-(1-piperazinyl)-ethyl]-2-oxazolidinone in 100 ml of chloroform. After evaporation of the chloroform, the residue is mixed with ice, benzene and aqueous sodium hydroxide solution and again mixed well. The benzene phase is acidified with 6 N aqueous hydrochloric acid and maintained in an ice bath for 30 minutes. The precripitate, which is formed, is filtered, made alkaline with aqueous sodium hydroxide solution and taken up in benzene. The benzene phase is dried over sodium sulphate and evaporated, whereby 3-{2-[4-(8-fluoro-10,11-dihydro-2-methyl-dibenzo [b,f]thiepin-10-yl)-1-piperazinyl]-ethyl}-2-oxazolidinone is obtained, which is converted into the corresponding dihydrochloride by reaction with ethanolic hydrochloric acid. The dihydrochloric melts at 210° (dec;).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:27])[C:5]([N:7]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([NH2:26])=[CH:22][CH:21]=1)[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=1)=[O:6])[CH3:2].[C:28](Cl)(=[O:42])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35]/[CH:36]=[CH:37]\[CH2:38][CH2:39][CH2:40][CH3:41].Cl>N1C=CC=CC=1>[O:6]=[C:5]([N:7]([CH2:19][C:20]1[CH:21]=[CH:22][C:23]([NH:26][C:28](=[O:42])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35]/[CH:36]=[CH:37]\[CH2:38][CH2:39][CH2:40][CH3:41])=[CH:24][CH:25]=1)[CH2:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]([F:16])([F:17])[F:18])=[CH:13][CH:14]=1)[C:4]([O:3][CH2:1][CH3:2])=[O:27]
Reactant: CCOC(=O)C(=O)N(Cc1ccc(N)cc1)Cc1ccc(C(F)(F)F)cc1
Reactant: CCCC/C=C\CCCCCCCC(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Product: CCCC/C=C\CCCCCCCC(=O)Nc1ccc(CN(Cc2ccc(C(F)(F)F)cc2)C(=O)C(=O)OCC)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 87.7 %

Procedure:
To a cold (0° C.) solution of ethyl{(4-aminobenzyl)[4-(trifluoromethyl)benzyl]amino}-(oxo)acetate (140 mg, 0.37 mmol) in anhydrous pyridine (2 mL) was added (9Z)-tetradec-9-enoyl chloride (100 mg, 0.40 mmol) under inert atmosphere. The resulting reaction mixture was stirred for 1 h at 0° C. A 5 N aqueous solution of HCl (10 mL) was added and the mixture was extracted with Et2O (3×10 mL). The combined organic layers were dried over MgSO4, filtered and concentrated to give a yellow oil. This crude product was purified by SPE (NH2 Isolute column) to give the title compound as a pale yellow oil (191 mg, 88%). 1H NMR (CDCl3, 300 MHz) δ 7.62 (m, 2H), 7.52 (m, 2H), 7.39 (d, 1H, J=8.0 Hz), 7.33 (d, 1H, J=7.9 Hz), 7.20 (m, 3H), 5.36 (m, 2H), 4.52 (s, 1H), 4.46 (s, 1H), 4.42-4.30 (m, 4H), 2.37 (t, 2H, J=7.5 Hz), 2.03 (m, 4H), 1.74 (m, 2H), 1.39-1.29 (m, 15H), 0.90 (t, 3H, 3=6.9 Hz). M−(LC/MS(ESI)): 587; M+(LC/MS(ESI)): 589. HPLC (Condition A), Rt: 7.24 min (HPLC purity: 97.3%).
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:3]=1[NH2:4].[N:12]([O-])=O.[Na+].[Sn](Cl)Cl>Cl.O>[Br:1][C:2]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:3]=1[NH:4][NH2:12]
Reactant: Nc1cc([N+](=O)[O-])ccc1Br
Reactant: O=N[O-]
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [Na+]
Solvent: O
Product: NNc1cc([N+](=O)[O-])ccc1Br
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To 2-bromo-5-nitro-aniline (5 g) in conc hydrochloric acid (50 ml) at 0° C. was added a solution of sodium nitrite (1.45 g) in water (20 ml). After 1 h, a solution of tin dichloride (8.73 g) in conc hydrochloric acid (15 ml) was added. The reaction was stirred for 30 min at 0° C. and 1 h at room temperature. The resulting solid was filtered off and recrystalised from hot ethanol. Yield 2.9 g.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[C:8]([C:15]2[C:24]3[C:19](=[CH:20][C:21]([O:25][CH2:26][CH2:27][O:28]C4CCCCO4)=[CH:22][CH:23]=3)[N:18]=[CH:17][CH:16]=2)=[C:9]2[CH2:14][CH2:13][CH2:12][N:10]2[N:11]=1>C(O)(=O)C.O1CCCC1.O>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[C:8]([C:15]2[C:24]3[C:19](=[CH:20][C:21]([O:25][CH2:26][CH2:27][OH:28])=[CH:22][CH:23]=3)[N:18]=[CH:17][CH:16]=2)=[C:9]2[CH2:14][CH2:13][CH2:12][N:10]2[N:11]=1
Reactant: c1ccc(-c2nn3c(c2-c2ccnc4cc(OCCOC5CCCCO5)ccc24)CCC3)nc1
Solvent: C1CCOC1
Solvent: O
Solvent: CC(=O)O
Product: OCCOc1ccc2c(-c3c(-c4ccccn4)nn4c3CCC4)ccnc2c1

Procedure:
Heat a solution of 4-(2-pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-7-[2-(tetrahydropyran-2-yloxy)ethoxy]quinoline (421 mg, 0.92 mmol) in acetic acid:tetrahydrofuran:water (4:2:1) (20 mL). Remove the solvent in vacuo and recover the residue with chloroform:isopropyl (3:1). Wash the organic layer with saturated sodium bicarbonate and dry over sodium sulfate. Concentrate in vacuo. The residue will be pure enough for the next step in the scheme (425 mg, 100%). MS ES+ m/e 373.1 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:13]=[CH:12][C:5]([O:6][C:7]([CH3:11])([CH3:10])[CH:8]=[O:9])=[CH:4][CH:3]=1.[CH3:14][Mg]Br.[Cl-].[NH4+]>O1CCCC1>[Br:1][C:2]1[CH:13]=[CH:12][C:5]([O:6][C:7]([CH3:10])([CH3:11])[CH:8]([OH:9])[CH3:14])=[CH:4][CH:3]=1
Reactant: C[Mg]Br
Reactant: CC(C)(C=O)Oc1ccc(Br)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(O)C(C)(C)Oc1ccc(Br)cc1
Reaction time: 1 h
Yield: 70 %

Procedure:
To a solution of 2-(4-bromophenoxy)-2-methylpropanal (5.3 g) in tetrahydrofuran (100 mL) was added methylmagnesium bromide (9.5 mL, 3 M diethyl ether solution) at −20° C., and the mixture was stirred for 1 hr. A saturated ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with 1 M hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound as a colorless solid (4.0 g, 70%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH:7]=[CH:8][N:9]2[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[CH:5][CH:4]=1.[Cl:19][C:20]1[S:21][C:22]2[CH:28]=[C:27](I)[CH:26]=[CH:25][C:23]=2[N:24]=1.[F-].[Cs+]>C(COC)OC.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:19][C:20]1[S:21][C:22]2[CH:28]=[C:27]([C:8]3[N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[C:10]4[C:6]([CH:7]=3)=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[CH:11]=4)[CH:26]=[CH:25][C:23]=2[N:24]=1
Reactant: COc1ccc2ccn(C(=O)OC(C)(C)C)c2c1
Reactant: Clc1nc2ccc(I)cc2s1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cs+]
Agent: [F-]
Solvent: COCCOC
Solvent: O
Product: COc1ccc2cc(-c3ccc4nc(Cl)sc4c3)n(C(=O)OC(C)(C)C)c2c1
Temperature: 25 °C
Yield: 83 %

Procedure:
tert-butyl 6-methoxy-1H-indole-1-carboxylate, from example 1BO, (2.50 g, 8.6 mmol) is dissolved in anhydrous dimethoxyethane (21.5 mL). To the solution is added 2-chloro-6-iodobenzothiazole (2.42 g, 8.2 mmol), cesium fluoride (2.53 g, 16.7 mmol) and PdCl2(PPh3)2 (0.23 g, 0.33 mmol). The reaction mixture is heated at reflux. After 17 h the reaction mixture is cooled to room temperature, diluted with water (100 mL) and extracted with ethyl acetate (4×20 mL). The extract is washed with saturated aqueous NaHCO3 (20 mL), dried over MgSO4 and concentrated under vacuum to give tert-butyl 2-(2-chlorobenzothiazol-6-yl)-6-methoxy-indole-1-carboxylate (2.95 g, 83%) as a hard foam.