Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:4]=1[CH2:5]O.N1C=CC=CC=1.P(Br)(Br)[Br:20]>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:4]=1[CH2:5][Br:20]
Reactant: COc1ccc(CO)c(OC)c1
Reactant: BrP(Br)Br
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: COc1ccc(CBr)c(OC)c1
Temperature: 4 °C
Reaction time: 0.75 h

Procedure:
2 g (11.77 mmol) of 2,4-dimethoxybenzyl alcohol (Aldrich, Steinheim, FRG) are dissolved in 30 ml of abs. toluene, and this solution is treated with 0.3 ml of pyridine. The clear solution is cooled down to approximately 4° C. and 1.12 ml (0.992 equivalents) of PBr3 in 6 ml of abs. toluene are added dropwise to it over the space of 30 min. After a further 45 min, the reaction solution is poured onto ice-water and the whole is extracted with ether. The organic phase is washed, in succession, with water, sat. sodium bicarbonate solution and saline (all being cold). The combined aqueous phases are reextracted with ether. The combined organic phases are dried over Na2SO4 and the ether is removed on a RE at about 30° C. The toluene solution which remains, and which contains the title compound, is immediately subjected to further use. TLC (hexane:ethyl acetate, 1:1): decomposition.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8]3=[C:9]([CH2:11][CH2:12][N:7]3[C@H:6]3[CH2:13][CH2:14][N:15](C(OC(C)(C)C)=O)[CH2:16][C@@H:5]23)[CH:10]=1.[Cl:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([Cl:31])[C:26]=1B(O)O>>[Cl:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([Cl:31])[C:26]=1[C:2]1[CH:3]=[C:4]2[C:8]3=[C:9]([CH2:11][CH2:12][N:7]3[C@H:6]3[CH2:13][CH2:14][NH:15][CH2:16][C@@H:5]23)[CH:10]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@H]2[C@@H](C1)c1cc(Br)cc3c1N2CC3
Reactant: OB(O)c1c(Cl)cccc1Cl
Product: Clc1cccc(Cl)c1-c1cc2c3c(c1)[C@@H]1CNCC[C@@H]1N3CC2

Procedure:
The title compound was prepared by Example 305, Step A, from tert-butyl(6aS,10aR)-2-bromo-4,5,7,8,10,10a-hexahydropyrido[4,3-b]pyrrolo[3,2,1-hi]indole-9(6aH)-carboxylate and the corresponding 2,6-dichlorobenzeneboronic acid followed by hydrolysis of the resultant BOC protected amine adduct by the procedure of Example 305, Step B. 1H NMR (CDCl3, 300 MHz) δ7.38 (dd, 2H), 7.15 (t, 1H), 6.80 (d, 1H), 6.73 (d, 1H), 3.69 (td, 1H), 3.57-3.30(m, 3H), 3.28-3.00 (m, 3H), 3.00-2.83 (m, 3H), 2.20 (bs, 2H), 2.00-1.81 (m, 2H). MS (CI): 346 (M+H+).
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[C:8]2[CH:9]=[C:10]([C:13]3[NH:17][C:16]([C:18]#[N:19])=[CH:15][CH:14]=3)[CH:11]=[CH:12][C:7]=2[NH:6][C:5](=[O:20])[CH2:4][O:3]1.I[CH3:23]>>[CH3:1][C:2]1([CH3:21])[C:8]2[CH:9]=[C:10]([C:13]3[N:17]([CH3:23])[C:16]([C:18]#[N:19])=[CH:15][CH:14]=3)[CH:11]=[CH:12][C:7]=2[NH:6][C:5](=[O:20])[CH2:4][O:3]1
Reactant: CI
Reactant: CC1(C)OCC(=O)Nc2ccc(-c3ccc(C#N)[nH]3)cc21
Product: Cn1c(C#N)ccc1-c1ccc2c(c1)C(C)(C)OCC(=O)N2

Procedure:
Prepared from 5-(5,5-dimethyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-7-yl)-1H-pyrrole-2-carbonitrile and iodomethane generally according to the procedure of example 3. 1H-NMR (DMSO-d6) δ 10.06 (s, 1H), 7.40 (d, J=1.87 Hz, 1H), 7.34 (dd, J=1.87, 8.32 Hz, 1H), 7.20 (d, J=8.38 Hz, 1H), 7.03 (d, J=3.99 Hz, 1H), 6.35 (d, J=4.00, 1H), 4.27 (s, 2H), 3.71 (s, 3H), 1.58 (s, 6H); MS (FI) m/z 294 ([M−H]−, 100%)
Reaction SMILES: F[C:2]1[C:7]([S:8]([CH3:11])(=[O:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:12]1[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][CH3:20])[CH2:14][CH2:13]1.[NH3:21]>CO>[CH3:11][S:8]([C:7]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][CH3:20])[CH2:14][CH2:13]2)[C:2]=1[NH2:21])(=[O:10])=[O:9]
Reactant: N
Reactant: CCCN1CCC(c2cccc(S(C)(=O)=O)c2F)CC1
Solvent: CO
Product: CCCN1CCC(c2cccc(S(C)(=O)=O)c2N)CC1
Temperature: 160 °C

Procedure:
4-[2-fluoro-3-(methylsulfonyl)phenyl]-1-propylpiperidine (0.45 g, 1.52 mmol) was dissolved in a solution of ammonia in methanol (7 M, 15 ml). The mixture was heated to 160° C. in a sealed tube under microwave radiation for 20 h. The solvent was evaporated and the crude product was purified on a preparative HPLC-system. Yield: 0.125 g (30%). The amine was converted to the hydrochloric acid salt and recrystallized from ethanol/diethyl ether: M.p. 232-233° C. MS m/z (relative intensity, 70 eV) 296 (M+, 22), 267 (bp), 224 (31), 130 (23) 117 (20).
Reaction SMILES: F[P-](F)(F)(F)(F)F.C[N+:9](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.[C:25]([O:29][C:30]([NH:32][C:33]1([C:66]([OH:68])=O)[CH2:38][CH2:37][N:36]([C:39]2[CH:44]=[CH:43][CH:42]=[C:41]([C:45]3[C:53]4[C:48](=[CH:49][N:50]=[C:51]([C:54]5[CH:55]=[N:56][CH:57]=[CH:58][CH:59]=5)[CH:52]=4)[N:47]([CH:60]4[CH2:65][CH2:64][CH2:63][CH2:62][O:61]4)[N:46]=3)[N:40]=2)[CH2:35][CH2:34]1)=[O:31])([CH3:28])([CH3:27])[CH3:26].[Cl-].[NH4+].C(N(CC)C(C)C)(C)C>CN(C)C=O>[C:66]([C:33]1([NH:32][C:30](=[O:31])[O:29][C:25]([CH3:26])([CH3:27])[CH3:28])[CH2:34][CH2:35][N:36]([C:39]2[CH:44]=[CH:43][CH:42]=[C:41]([C:45]3[C:53]4[C:48](=[CH:49][N:50]=[C:51]([C:54]5[CH:55]=[N:56][CH:57]=[CH:58][CH:59]=5)[CH:52]=4)[N:47]([CH:60]4[CH2:65][CH2:64][CH2:63][CH2:62][O:61]4)[N:46]=3)[N:40]=2)[CH2:37][CH2:38]1)(=[O:68])[NH2:9]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: CC(C)(C)OC(=O)NC1(C(=O)O)CCN(c2cccc(-c3nn(C4CCCCO4)c4cnc(-c5cccnc5)cc34)n2)CC1
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC1(C(N)=O)CCN(c2cccc(-c3nn(C4CCCCO4)c4cnc(-c5cccnc5)cc34)n2)CC1
Reaction time: 18 h

Procedure:
N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate 45.6 mg, 0.120 mmol) was added to a mixture of 4-(tert-butoxycarbonylamino)-1-(6-(5-(pyridin-3-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridin-3-yl)pyridin-2-yl)piperidine-4-carboxylic acid (60.0 mg, 0.100 mmol), ammonium chloride 21 mg (0.40 mmol) and N,N-Diisopropylethylamine (0.087 ml, 0.50 mmol) in 2 ml of N,N-dimethylformamide. The mixture was stirred for 18 hours and concentrated. The residue was partitioned between ethyl acetate and 1% of aqueous citric acid. The organic extracts were washed with water, 5% aqueous solution of NaHCO3, brine, dried over MgSO4 and concentrated to give tert-Butyl 4-carbamoyl-1-(6-(5-(pyridin-3-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridin-3-yl)pyridin-2-yl)piperidin-4-ylcarbamate. Yield 47 mg (78%). ESI MS m/z 599.2 (M+1).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH2:12][C:11]3([O:16][CH2:15][CH2:14][O:13]3)[CH2:10]2)=[CH:5][CH:4]=1)#N.C([Mg]Cl)(C)C.[CH2:30]([Mg]Cl)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.[Cl-].[NH4+].C1C[O:44]CC1>>[C:31]1([CH2:30][C:1]([C:3]2[CH:8]=[CH:7][C:6]([C:9]3([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH2:12][C:11]4([O:16][CH2:15][CH2:14][O:13]4)[CH2:10]3)=[CH:5][CH:4]=2)=[O:44])[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(C#N)cc2)CC2(C1)OCCO2
Reactant: C1CCOC1
Reactant: Cl[Mg]Cc1ccccc1
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Product: CC(C)(C)OC(=O)NC1(c2ccc(C(=O)Cc3ccccc3)cc2)CC2(C1)OCCO2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of tert-butyl [2-(4-cyanophenyl)-5,8-dioxaspiro[3.4]oct-2-yl]carbamate (1-6) (15.0 g, 45.4 mmol) in THF (150 mL) at −78° C. was added isopropylmagnesium chloride (22.7 mL, 45.4 mmol, 2M in THF). After 1 hour, benzylmagnesium chloride (68 mL, 135 mmol, 2M in THF) was added and the reaction was allowed to slowly warm to rt over 5 hours. The reaction mixture was poured into saturated ammonium chloride, extracted with EtOAc, dried over sodium sulfate, filtered and concentrated. The crude residue was purified by column chromatography eluting with 1-60% EtOAc/Hexane. The appropriate fractions were combined and the solvent removed in vacuo to give tert-butyl {2-[4-(phenylacetyl)phenyl]-5,8-dioxaspiro[3.4]oct-2-yl}carbamate (1-7). MS (M+H)+: 424.
Reaction SMILES: [CH:1]([N:4]([CH:26]([CH3:28])[CH3:27])[C:5]([C@H:7]1[CH2:12][CH2:11][C@H:10]2[C@H:13]3[C@H:22]([CH2:23][CH2:24][C@:8]12[CH3:9])[C:21]1[CH:20]=[CH:19][C:18]([OH:25])=[CH:17][C:16]=1[CH2:15][CH2:14]3)=[O:6])([CH3:3])[CH3:2].C(O)(=O)C.[N+:33]([O-])([OH:35])=[O:34].[N:37]([O-:39])=[O:38].[Na+]>O>[CH:26]([N:4]([CH:1]([CH3:2])[CH3:3])[C:5]([C@H:7]1[CH2:12][CH2:11][C@H:10]2[C@H:13]3[C@H:22]([CH2:23][CH2:24][C@:8]12[CH3:9])[C:21]1[CH:20]=[C:19]([N+:33]([O-:35])=[O:34])[C:18]([OH:25])=[CH:17][C:16]=1[CH2:15][CH2:14]3)=[O:6])([CH3:28])[CH3:27].[CH:26]([N:4]([CH:1]([CH3:2])[CH3:3])[C:5]([C@H:7]1[CH2:12][CH2:11][C@H:10]2[C@H:13]3[C@H:22]([CH2:23][CH2:24][C@:8]12[CH3:9])[C:21]1[CH:20]=[CH:19][C:18]([OH:25])=[C:17]([N+:37]([O-:39])=[O:38])[C:16]=1[CH2:15][CH2:14]3)=[O:6])([CH3:28])[CH3:27]
Reactant: O=N[O-]
Reactant: CC(C)N(C(=O)[C@H]1CC[C@H]2[C@@H]3CCc4cc(O)ccc4[C@H]3CC[C@]12C)C(C)C
Reactant: O=[N+]([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CC(C)N(C(=O)[C@H]1CC[C@H]2[C@@H]3CCc4c(ccc(O)c4[N+](=O)[O-])[C@H]3CC[C@]12C)C(C)C
Product: CC(C)N(C(=O)[C@H]1CC[C@H]2[C@@H]3CCc4cc(O)c([N+](=O)[O-])cc4[C@H]3CC[C@]12C)C(C)C
Temperature: 75 °C
Yield: 35 %
Yield: 20 %

Procedure:
A solution of N,N-diisopropyl-estr-1,3,5(10)-triene-3-ol-17β-carboxamide (141 mg, 0.368 mmol) in boiling acetic acid (7 mL) was slowly cooled to 75° C. and treated with a solution of concentrated nitric acid (24.8 μL) in water (1.4 mL) containing a catalytic unit of sodium nitrite. The reaction mixture was allowed to slowly cool to room temperature, then was diluted with water and extracted with ethyl acetate. The extract was washed thoroughly with water, dried, concentrated and purified by chromatography (silica gel, dichloromethane containing 5 to 10% ether) affording 55.2 mg (35%, mp 143.5°-144.5° C.) of N,N-diisopropyl-2-nitro-estr-1,3,5(10)-triene-3-ol-17β-carboxamide and 32.2 mg (20%, mp 239°-241° C.) of N,N-diisopropyl-4-nitro-estr-1,3,5(10)-triene-3-ol-17β-carboxamide.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.C([Li])CCC.[O:14]1[CH2:19][CH2:18][C:17](=O)[CH2:16][CH2:15]1.Cl>O1CCCC1.CCCCCC>[O:14]1[CH2:15][CH:16]=[C:17]([C:2]2[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=2)[CH2:18][CH2:19]1
Reactant: O=C1CCOCC1
Reactant: Oc1ccc(Br)cc1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: Oc1ccc(C2=CCOCC2)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
[lacuna] is added at −40° C. to 12.7 g of 4-bromophenol in 150 ml of tetrahydrofuran. At this same temperature, 100 ml of 1.6 M butyllithium in hexane are added to the reaction mixture, followed by addition of 8.1 g of 4-tetrahydropyranone. The reaction mixture is left stirring for 18 hours at room temperature and then hydrolysed with 1 N hydrochloric acid. The resulting mixture is extracted several times with diethyl ether, the organic phase is dried over magnesium sulphate and the solvents are evaporated off under reduced pressure. The solid obtained is purified by chromatography on a column of silica gel, eluting with a cyclohexane/ethyl acetate mixture varying from 90/10 to 80/20 (v/v).
Reaction SMILES: [C:1]1(C)[CH:6]=C[C:4]([NH:7][C:8]2C=CC=C[C:9]=2C=O)=[CH:3][CH:2]=1.[O:17]1[CH:21]=[CH:20][CH:19]=[C:18]1[C:22]([CH2:24][C:25](=O)[CH3:26])=[O:23].N1CCCCC1>C(O)C>[O:17]1[CH:21]=[CH:20][CH:19]=[C:18]1[C:22]([C:24]1[C:8]([CH3:9])=[N:7][C:4]2[C:26]([CH:25]=1)=[CH:6][CH:1]=[CH:2][CH:3]=2)=[O:23]
Reactant: Cc1ccc(Nc2ccccc2C=O)cc1
Reactant: CC(=O)CC(=O)c1ccco1
Solvent: C1CCNCC1
Solvent: CCO
Product: Cc1nc2ccccc2cc1C(=O)c1ccco1
Yield: 77 %

Procedure:
A solution of 410 mg (1.95 mmol) N-(p-tolyl)-o-aminobenzaldehyde 326 mg (2.15 mmol), (2-furoyl)acetone and 50 mg piperidine in 4 ml 95% ethanol was heated overnight under reflux. Removal of he volatile materials left a black, gummy oil which was taken up in dichloromethane and, after being washed with 3M NaOH, brine, and dried (MgSO4), purified by flash chromatography [eluent, 3:2 pentane-diethyl ether (3:2)] yielding 355 mg (1.50 mmol, 77%) product.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:16])[CH3:15])[C:11]([Cl:17])=[CH:10][C:9]=1[NH2:18])([CH3:4])([CH3:3])[CH3:2].C([O:24][C:25](=O)[CH2:26][C:27]([C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([C:35]2[N:36]([CH3:40])[N:37]=[CH:38][CH:39]=2)[CH:30]=1)=[O:28])(C)(C)C>>[C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:16])[CH3:15])[C:11]([Cl:17])=[CH:10][C:9]=1[NH:18][C:25](=[O:24])[CH2:26][C:27]([C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([C:35]2[N:36]([CH3:40])[N:37]=[CH:38][CH:39]=2)[CH:30]=1)=[O:28])([CH3:4])([CH3:2])[CH3:3]
Reactant: CN(C)c1cc(NC(=O)OC(C)(C)C)c(N)cc1Cl
Reactant: Cn1nccc1-c1cccc(C(=O)CC(=O)OC(C)(C)C)c1
Product: CN(C)c1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3ccnn3C)c2)cc1Cl

Procedure:
The title compound was prepared from (2-amino-4-chloro-5-dimethylamino-phenyl)-carbamic acid tert.-butyl ester (Example J1) (143 mg, 0.5 mmol) and 3-[3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-3-oxo-propionic acid tert.-butyl ester (Example K7) (180 mg, 0.6 mmol) according to the general procedure M. Obtained as an amorphous yellow substance (160 mg).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]2[N:13]=[CH:12][C:11]([CH2:14][CH2:15][CH3:16])=[CH:10][N:9]=2)=[CH:4][C:3]=1[F:17].CC1(C)C(C)(C)OB([C:26]2[CH:31]=[CH:30][C:29]([O:32][C:33]([F:36])([F:35])[F:34])=[CH:28][CH:27]=2)O1.[F-].[Cs+].O>O1CCOCC1.CCOCC>[F:17][C:3]1[CH:4]=[C:5]([C:8]2[N:13]=[CH:12][C:11]([CH2:14][CH2:15][CH3:16])=[CH:10][N:9]=2)[CH:6]=[N:7][C:2]=1[C:26]1[CH:27]=[CH:28][C:29]([O:32][C:33]([F:34])([F:35])[F:36])=[CH:30][CH:31]=1
Reactant: CC1(C)OB(c2ccc(OC(F)(F)F)cc2)OC1(C)C
Reactant: CCCc1cnc(-c2cnc(Cl)c(F)c2)nc1
Agent: [Cs+]
Agent: [F-]
Solvent: CCOCC
Solvent: O
Solvent: C1COCCO1
Product: CCCc1cnc(-c2cnc(-c3ccc(OC(F)(F)F)cc3)c(F)c2)nc1
Temperature: 100 °C

Procedure:
10.2 mmol of 2-(6-chloro-5-fluoropyridin-3-yl)-5-propylpyrimidine and 10.2 mmol of 4,4,5,5-tetramethyl-2-(4-trifluoromethoxyphenyl)-1,3,2-dioxaborolane are dissolved in 30 ml of dioxane, and 20.4 mmol of caesium fluoride and 0.5 mmol of bis(tricyclohexylphosphine)palladium dichloride catalyst are added. The mixture is heated at 100° C. for 18 hours with stirring. Water and MTB ether are added to the batch, and the organic phase is washed with water, dried using sodium sulfate and evaporated. The residue is purified by chromatography on silica gel with heptane/MTB ether 2/1 and recrystallised from isopropanol, giving 2-[5-fluoro-6-(4-trifluoromethoxyphenyl)pyridin-3-yl]-5-propylpyrimidine.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:10]([Cl:11])=[CH:9][C:8]([C:12]([F:15])([F:14])[CH3:13])=[CH:7][N:6]=1)=[O:4].[Li+:16].[OH-].[ClH:18]>C1COCC1.O>[Cl:11][C:10]1[C:5]([C:3]([OH:4])=[O:2])=[N:6][CH:7]=[C:8]([C:12]([F:14])([F:15])[CH3:13])[CH:9]=1.[Li+:16].[Cl-:18]
Reactant: Cl
Reactant: COC(=O)c1ncc(C(C)(F)F)cc1Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(F)(F)c1cnc(C(=O)O)c(Cl)c1
Product: [Cl-]
Reaction time: 3.5 h

Procedure:
To a solution of 3-chloro-5-(1,1-difluoro-ethyl)-pyridine-2-carboxylic acid methyl ester (272 mg, 1.154 mmol) in THF (6 ml) was added LiOH (30.4 mg, 1.27 mmol) in water (0.5 ml) and the mixture was stirred for 3.5 h. To the mixture was added 6N HCl (0.212 ml, 1.27 mmol) and the solvent was evaporated. The residue was taken up in toluene and evaporated (2×) to provide the title compound as colorless solid together with LiCl. This material was directly used in the coupling step without further purification.
Reaction SMILES: Cl[CH2:2][CH:3]1[CH2:8][CH2:7][N:6]([S:9]([CH3:12])(=[O:11])=[O:10])[CH2:5][CH2:4]1.[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([C@@H:20]2[C@:22]3([C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[NH:24][C:23]3=[O:31])[CH2:21]2)=[CH:16][CH:15]=1>>[Cl:13][C:14]1[CH:15]=[CH:16][C:17]([C@H:20]2[C@@:22]3([C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[N:24]([CH2:2][CH:3]4[CH2:8][CH2:7][N:6]([S:9]([CH3:12])(=[O:11])=[O:10])[CH2:5][CH2:4]4)[C:23]3=[O:31])[CH2:21]2)=[CH:18][CH:19]=1
Reactant: CS(=O)(=O)N1CCC(CCl)CC1
Reactant: O=C1Nc2ccccc2[C@@]12C[C@@H]2c1ccc(Cl)cc1
Product: CS(=O)(=O)N1CCC(CN2C(=O)[C@@]3(C[C@H]3c3ccc(Cl)cc3)c3ccccc32)CC1

Procedure:
The title compound was prepared in analogy to Example 70 starting from 4-chloromethyl-1-methanesulfonyl-piperidine (commercially available), (1R,2S) and (1S,2R)-2-(4-chlorophenyl)spiro[cyclopropane-1,3′-indolin]-2′-one prepared as in Scheme 1. LC/MS m/e calcd. for C23H25ClN2O35: 444, observed (M+H)+: 445.1 1HNMR (400 MHz, DMSO-d6) δppm 1.23-1.41 (m, 2 H) 1.66-1.78 (m, 2 H) 1.84-1.98 (m, 1 H) 2.02 (dd, J=9.09, 4.80 Hz, 1 H) 2.30 (dd, J=7.71, 4.67 Hz, 1 H) 2.67 (t, J=11.75 Hz, 2 H) 2.83 (s, 3 H) 3.11 (t, J=8.46 Hz, 1 H) 3.56 (d, J=12.13 Hz, 2 H) 3.71 (d, J=7.33 Hz, 2 H) 6.12 (d, J=7.33 Hz, 1 H) 6.66-6.80 (m, 1 H) 7.10-7.20 (m, 2 H) 7.25-7.34 (m, 2 H) 7.34-7.43 (m, 2 H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[C:13]([CH3:20])=[C:14]([NH2:19])[C:15]([CH3:18])=[C:16]([CH3:17])[C:11]=3[O:10][C:9]=2[CH3:21])=[CH:4][CH:3]=1.[CH3:22][O:23][C:24]1[CH:32]=[CH:31][C:27]([C:28](Cl)=[O:29])=[CH:26][CH:25]=1>C(OCC)(=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[C:13]([CH3:20])=[C:14]([NH:19][C:28](=[O:29])[C:27]4[CH:31]=[CH:32][C:24]([O:23][CH3:22])=[CH:25][CH:26]=4)[C:15]([CH3:18])=[C:16]([CH3:17])[C:11]=3[O:10][C:9]=2[CH3:21])=[CH:4][CH:3]=1
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: Cc1oc2c(C)c(C)c(N)c(C)c2c1-c1ccc(F)cc1
Solvent: CCOC(C)=O
Product: COc1ccc(C(=O)Nc2c(C)c(C)c3oc(C)c(-c4ccc(F)cc4)c3c2C)cc1
Yield: 75 %

Procedure:
By using 3-(4-fluorophenyl)-2,4,6,7-tetramethyl-1-benzofuran-5-amine and 4-methoxybenzoyl chloride, the title compound was synthesized according to Example 1b. Yield: 75%. Melting point: 225-227° C. (Ethyl acetate)
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:10][CH:9]=2)=[CH:4][C:3]=1[C:19]1[CH:28]=[CH:27][C:26]2[C:25]([CH3:30])([CH3:29])[CH2:24][CH2:23][C:22]([CH3:32])([CH3:31])[C:21]=2[CH:20]=1.[Br:33][CH2:34][CH2:35]Br>>[Br:33][CH2:34][CH2:35][O:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:12][CH:13]=2)=[CH:4][C:3]=1[C:19]1[CH:28]=[CH:27][C:26]2[C:25]([CH3:30])([CH3:29])[CH2:24][CH2:23][C:22]([CH3:31])([CH3:32])[C:21]=2[CH:20]=1
Reactant: CCOC(=O)c1ccc(-c2ccc(O)c(-c3ccc4c(c3)C(C)(C)CCC4(C)C)c2)cc1
Reactant: BrCCBr
Product: CCOC(=O)c1ccc(-c2ccc(OCCBr)c(-c3ccc4c(c3)C(C)(C)CCC4(C)C)c2)cc1
Yield: 28.3 %

Procedure:
In a manner similar to that of Example 1a, by reaction of 6 g (14 mmol) of ethyl 4′-hydroxy-3′-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphth-2-yl)biphenyl-4-carboxylate with 4 ml (46.2 mmol) of 1,2-dibromoethane. 2.12 g of ethyl 4′-(2-bromoethoxy)-3′-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphth-2-yl)biphenyl-4-carboxylate are obtained in the form of a white solid (yield=28%).
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5](I)=[C:6]2[C:11]=1[N:10]=[C:9]([CH3:12])[CH:8]=[CH:7]2.[N:14]1[CH:19]=[CH:18][CH:17]=[C:16](B(O)O)[CH:15]=1.[NH2:23][C:24]1[S:25][CH:26]=[C:27]([C:29]([F:32])([F:31])[F:30])[N:28]=1>>[CH3:12][C:9]1[CH:8]=[CH:7][C:6]2[C:11](=[C:2]([NH:23][C:24]3[S:25][CH:26]=[C:27]([C:29]([F:32])([F:31])[F:30])[N:28]=3)[N:3]=[CH:4][C:5]=2[C:16]2[CH:15]=[N:14][CH:19]=[CH:18][CH:17]=2)[N:10]=1
Reactant: Nc1nc(C(F)(F)F)cs1
Reactant: OB(O)c1cccnc1
Reactant: Cc1ccc2c(I)cnc(Cl)c2n1
Product: Cc1ccc2c(-c3cccnc3)cnc(Nc3nc(C(F)(F)F)cs3)c2n1

Procedure:
The title compound, MS: m/e=388.2 (M+H+), was prepared in accordance with the general method of example 15 step 1 and step 3 from 8-chloro-5-iodo-2-methyl-[1,7]naphthyridine (Example I), 3-pyridineboronic acid and 2-amino-4-(trifluoromethyl)thiazole.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([S:11][CH3:12])[C:5]2[CH:10]=[CH:9][NH:8][C:6]=2[N:7]=1.[NH2:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]2[CH2:25][CH2:24][N:23]([C:26](=[O:28])[CH3:27])[CH2:22][CH2:21]2)=[CH:16][CH:15]=1.C[Si](Cl)(C)C.O>C(O)CCC.CCOC(C)=O>[CH3:12][S:11][C:4]1[C:5]2[CH:10]=[CH:9][NH:8][C:6]=2[N:7]=[C:2]([NH:13][C:14]2[CH:15]=[CH:16][C:17]([N:20]3[CH2:21][CH2:22][N:23]([C:26](=[O:28])[CH3:27])[CH2:24][CH2:25]3)=[CH:18][CH:19]=2)[N:3]=1
Reactant: CC(=O)N1CCN(c2ccc(N)cc2)CC1
Reactant: CSc1nc(Cl)nc2[nH]ccc12
Agent: C[Si](C)(C)Cl
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCCCO
Product: CSc1nc(Nc2ccc(N3CCN(C(C)=O)CC3)cc2)nc2[nH]ccc12
Temperature: 116 °C
Yield: 48.7 %

Procedure:
A mixture of 2-chloro-4-(methylthio)-7H-pyrrolo[2,3-d]pyrimidine (484 mg, 2.43 mmol), 1-(4-(4-aminophenyl)piperazin-1-yl)ethanone (645 mg, 2.95 mmol) and trimethylsilyl chloride (0.500 mL, 3.95 mmol) in nBuOH (10 mL) was heated at 116° C. for 48 h. After cooling down, H2O and EtOAc were added. The organic phase was separated, washed with 5% NaHCO3, dried over Na2SO4, concentrated in vacuo to give 1-(4-(4-(4-(methylthio)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)phenyl)piperazin-1-yl)ethanone as a solid (453 mg).
Reaction SMILES: [N:1]1([CH:6]([C:10]2[CH:15]=[CH:14][N+:13]([O-])=[CH:12][CH:11]=2)[CH2:7][CH2:8][CH3:9])[CH:5]=[CH:4][N:3]=[CH:2]1.C[Si]([C:21]#[N:22])(C)C.C(N(CC)CC)C>C(#N)C>[N:1]1([CH:6]([C:10]2[CH:15]=[CH:14][N:13]=[C:12]([C:21]#[N:22])[CH:11]=2)[CH2:7][CH2:8][CH3:9])[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: C[Si](C)(C)C#N
Reactant: CCCC(c1cc[n+]([O-])cc1)n1ccnc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCCC(c1ccnc(C#N)c1)n1ccnc1
Reaction time: 22 h
Yield: 89.9 %

Procedure:
0.109 g of 4-[1-(1-imidazolyl)-butyl]pyridine-N-oxide is dissolved in 2 ml of acetonitrile, 0.150 g of trimethylsilyl cyanide and 0.101 g of triethylamine are added to it. The reaction is left for 22 hours at 110° C. The mixture is concentrated by evaporation in a vacuum and then distilled on a bulb tube, boiling point: 210°-220° C./0.035 mbar. 0.102 g of 4-[1-(1-imidazolyl)-butyl]-2-cyanopyridine is obtained as brownish oil.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]2[CH2:7][C:8]3[CH:14]=[C:13]([CH:15]([CH3:19])[C:16]([OH:18])=[O:17])[CH:12]=[CH:11][C:9]=3[O:10][C:2]=12.[CH3:20][N:21]([CH3:25])[CH2:22][CH2:23]O.C1(C)C=CC(S([Cl:35])(=O)=O)=CC=1>N1C=CC=CC=1>[ClH:35].[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]2[CH2:7][C:8]3[CH:14]=[C:13]([CH:15]([CH3:19])[C:16]([O:18][CH2:23][CH2:22][N:21]([CH3:25])[CH3:20])=[O:17])[CH:12]=[CH:11][C:9]=3[O:10][C:2]=12
Reactant: CN(C)CCO
Reactant: CC(C(=O)O)c1ccc2c(c1)Cc1cccnc1O2
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: CC(C(=O)OCCN(C)C)c1ccc2c(c1)Cc1cccnc1O2
Product: Cl
Temperature: 25 °C

Procedure:
5.1 G of 2-(5H-[1]benzopyrano[2,3-b]pyridin-7-yl)propionic acid and 1.96 g of 2-dimethylaminoethanol are dissolved in 30 ml of pyridine. 4.2 g of p-tolylsulfonyl chloride is added in small portions to the pyridine solution with stirring at room temperature, and the mixture is stirred at 80°-90°C for 2 hours. The pyridine is distilled off under reduced pressure, and the residue is dissolved in chloroform. After addition of ice water, the solution is adjusted to pH 9 by addition of 15% sodium hydroxide. The mixture is thoroughly shaken, and the chloroform layer is separated. The chloroform layer is washed with water, dried over anhydrous magnesium sulfate, and concentrated. The residual oil is dissolved in 30 ml of isopropyl alcohol, and the solution is adjusted to pH 1-2 by addition of 20% alcoholic hydrochloric acid. After cooling, the crystalline precipitate is filtered off, and high vacuum dried to give 4.2 g of 2-dimethylaminoethyl 2-(5H-[1]benzopyrano[2,3-b]pyridin-7-yl)propionate hydrochloride melting at 167°-169°C.