Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][CH2:9][CH2:10][NH:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:14](=O)([O-])[O-].[K+].[K+].IC>CN(C=O)C>[CH3:14][N:11]1[C:12]2[C:7](=[CH:6][CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:13]=2)[CH2:8][CH2:9][CH2:10]1
Reactant: O=[N+]([O-])c1ccc2c(c1)NCCC2
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: CN1CCCc2ccc([N+](=O)[O-])cc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of the 7-nitro-1,2,3,4-tetrahydroquinoline (4.5 g, 25.25 mmol) in DMF (50 mL) was added potassium carbonate (15 g) followed by iodomethane (5.54 g, 39.0 mMol) and the mixture was agitated overnight at ambient temperature. The mixture was poured onto water and extracted with ether (3×200 mL). The combined ethereal extracts were washed with brine, dried and concentrated to give the crude product which was purified by column chromatography on silica-gel to obtain the title compound as an orange liquid.
Reaction SMILES: I[C:2]1[C:3]2[CH:17]=[CH:16][NH:15][C:4]=2[N:5]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH3:14])[N:9]=2)[N:7]=1.[Br:18][C:19]1[CH:20]=[N:21][CH:22]=[C:23](B(O)O)[CH:24]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.CCO.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>[Br:18][C:19]1[CH:24]=[C:23]([C:2]2[C:3]3[CH:17]=[CH:16][NH:15][C:4]=3[N:5]=[C:6]([C:8]3[CH:13]=[CH:12][CH:11]=[C:10]([CH3:14])[N:9]=3)[N:7]=2)[CH:22]=[N:21][CH:20]=1
Reactant: Cc1cccc(-c2nc(I)c3cc[nH]c3n2)n1
Reactant: OB(O)c1cncc(Br)c1
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: COCCOC
Solvent: CCO
Product: Cc1cccc(-c2nc(-c3cncc(Br)c3)c3cc[nH]c3n2)n1
Temperature: 25 °C

Procedure:
To a solution of 4-iodo-2-(6-methyl-pyridin-2-yl)-7H-pyrrolo[2,3-d]pyrimidine (Intermediate 3) (1 eq, 1.50 mmol, 530 mg) and 3-bromopyridine-5-boronic acid (ABCR GmbH & Co. KG, Karlsruhe, Germany) (1.1. eq, 1.65 mmol, 339 mg) in DME/EtOH (1:1, 6 ml) are added aqueous Na2CO3 solution (2 M, 3 eq, 4.50 mmol, 2.2 ml) and Pd(PPh3)4 (0.05 eq, 0.075 mmol, 89 mg). The resulting mixture is heated using microwave radiation at 120° C. for 20 min. After cooling down to r.t., the mixture is filtered and the resulting precipitate is washed with EtOH. The residue is suspended in DCM, filtered, and dried to give the title compound; [M+H]+=366/368; 1H-NMR (400 MHz, DMSO): δ 12.58 (s, 1H), 9.40 (m, 1H), 8.89 (m, 1H), H), 8.79 (m, 1H), 8.37 (t, 1H), 7.87-7.77 (m, 2H), 7.33 (t, 1H), 7.00 (m, 1H), 2.56 (m, 3H).
Reaction SMILES: Cl[CH2:2][CH2:3][N:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[C:12]3[CH:13]=[CH:14][CH:15]=[C:6]([C:7]=23)[S:5]1(=[O:17])=[O:16].C(N(CC)CC)C.[O:25]1[C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=2[C:27]([N:34]2[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]2)=[N:26]1.[I-].[Na+]>CN(C)C=O>[O:25]1[C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=2[C:27]([N:34]2[CH2:35][CH2:36][N:37]([CH2:2][CH2:3][N:4]3[C:8]4[CH:9]=[CH:10][CH:11]=[C:12]5[CH:13]=[CH:14][CH:15]=[C:6]([C:7]=45)[S:5]3(=[O:17])=[O:16])[CH2:38][CH2:39]2)=[N:26]1
Reactant: O=S1(=O)c2cccc3cccc(c23)N1CCCl
Reactant: c1ccc2c(N3CCNCC3)noc2c1
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=S1(=O)c2cccc3cccc(c23)N1CCN1CCN(c2noc3ccccc23)CC1
Temperature: 20 °C
Yield: 26.9 %

Procedure:
The experiment is carried out as in Example 1, starting with 2-(2-chloroethyl)naphtho[1,8-cd]isothiazole 1,1-dioxide (5.3 g), triethylamine (3 cc) and 4-(1,2-benzisoxazol-3-yl)piperazine (4 g) and sodium iodide (3 g) in dimethylformamide (60 cc). The mixture is heated for 8 hours at boiling point, then cooled to a temperature of about 20° C. After purification by flash-chromatography on silica gel, under a current of argon at medium pressure (0.5-1.5 bar) with ethyl acetate as eluant, and recrystallization from boiling acetonitrile (22 cc), 2-{2-[4-(1,2-benzisoxazol-3-yl)-1-piperazinyl]ethyl}naphtho[1,8-cd]isothiazole 1,1-dioxide (2.3 g) is obtained, m.p. 148° C.
Reaction SMILES: C[O:2][C:3]([C@H:5]1[CH2:10][CH2:9][C@H:8]([CH2:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C@@H:20]3[CH2:24][CH2:23][CH2:22][N:21]3[CH3:25])=[CH:16][N:15]=2)[CH2:7][CH2:6]1)=[O:4].[OH-].[K+].CC(O)=O>CO>[CH3:25][N:21]1[CH2:22][CH2:23][CH2:24][C@H:20]1[C:17]1[CH:18]=[CH:19][C:14]([CH2:13][CH2:12][CH2:11][C@H:8]2[CH2:7][CH2:6][C@H:5]([C:3]([OH:4])=[O:2])[CH2:10][CH2:9]2)=[N:15][CH:16]=1
Reactant: COC(=O)[C@H]1CC[C@H](CCCc2ccc([C@@H]3CCCN3C)cn2)CC1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: CC(=O)O
Product: CN1CCC[C@H]1c1ccc(CCC[C@H]2CC[C@H](C(=O)O)CC2)nc1

Procedure:
A mixture of 6 (0.11 g, 0.3 mmol) and KOH (0.025 g, 0.45 mmol) in 50% aqueous MeOH (10 mL) was heated under reflux for 30 min. The reaction mixture was acidified with HOAc to pH 8 and the solvents were evaporated in vacuo. The crude product was purified by column chromatography (silica gel, CHCl3/MeOH, gradient of MeOH 10% to 50%) to afford 0.077 g (74%) of 7.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([O:10][CH2:11][O:12][CH3:13])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[CH2:14](Br)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH2:14]([O:1][C:2]1[CH:9]=[C:8]([O:10][CH2:11][O:12][CH3:13])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: COCOc1ccc(C=O)c(O)c1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COCOc1ccc(C=O)c(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 99 %

Procedure:
A mixture of 2-hydroxy-4-methoxymethoxybenzaldehyde (17.1 g), benzyl bromide (19.33 g), anhydrous potassium carbonate (13.0 g) and N,N-dimethylformamide (200 mL) was stirred at room temperature for 15 hrs. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The obtained residue was subjected to silica gel column chromatography to give 2-benzyloxy-4-methoxymethoxybenzaldehyde as a colorless oil (25.3 g, 99%) from a fraction eluted with ethyl acetate-hexane (1:4, v/v).
Reaction SMILES: C(#N)C.[CH2:4]([OH:7])[C:5]#[CH:6].[F:8][C:9]1[CH:10]=[C:11]([CH:14]=[C:15]([F:18])[C:16]=1F)[CH:12]=[O:13].C(=O)([O-])[O-].[K+].[K+]>O>[F:18][C:15]1[CH:14]=[C:11]([CH:10]=[C:9]([F:8])[C:16]=1[O:7][CH2:4][C:5]#[CH:6])[CH:12]=[O:13]
Reactant: C#CCO
Reactant: O=Cc1cc(F)c(F)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: C#CCOc1c(F)cc(C=O)cc1F
Temperature: 25 °C
Reaction time: 24 h
Yield: 102 %

Procedure:
To 50 ml of acetonitrile were added 12 g of propargyl alcohol, 16 g of 3,4,5-trifluorobenzaldehyde and 15 g of potassium carbonate, and the mixture obtained was stirred at room temperature for 1 day. Then, water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with dilute hydrochloric acid and brine. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 20 g of 3,5-difluoro-4-(2-propynyloxy)benzaldehyde represented by the formula:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:11][CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)=[O:10])=[CH:4][C:3]=1[C:18]1[CH:23]=[CH:22][C:21]([C:24](O)=[O:25])=[CH:20][CH:19]=1.[CH2:27]([S:30]([N:33]1[CH2:38][CH2:37][N:36]([CH2:39][C:40]2[CH:45]=[CH:44][C:43]([NH2:46])=[CH:42][CH:41]=2)[CH2:35][CH2:34]1)(=[O:32])=[O:31])[CH2:28][CH3:29].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1>CN(C=O)C>[CH2:27]([S:30]([N:33]1[CH2:38][CH2:37][N:36]([CH2:39][C:40]2[CH:41]=[CH:42][C:43]([NH:46][C:24]([C:21]3[CH:22]=[CH:23][C:18]([C:3]4[CH:4]=[C:5]([NH:8][C:9]([NH:11][CH:12]5[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]5)=[O:10])[CH:6]=[CH:7][C:2]=4[Cl:1])=[CH:19][CH:20]=3)=[O:25])=[CH:44][CH:45]=2)[CH2:35][CH2:34]1)(=[O:31])=[O:32])[CH2:28][CH3:29]
Reactant: CCCS(=O)(=O)N1CCN(Cc2ccc(N)cc2)CC1
Reactant: O=C(Nc1ccc(Cl)c(-c2ccc(C(=O)O)cc2)c1)NC1CCCCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CCCS(=O)(=O)N1CCN(Cc2ccc(NC(=O)c3ccc(-c4cc(NC(=O)NC5CCCCC5)ccc4Cl)cc3)cc2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 14.5 %

Procedure:
A mixture of 2′-Chloro-5′-(3-cyclohexyl-ureido)-biphenyl-4-carboxylic acid (150 mg), 4-(4-(propane-1-sulfonyl)-piperazin-1-ylmethyl)-phenylamine (236 mg) and HBTU (228 mg) in dry DMF (5 ml) containing N-methylmorpholine (0.13 ml) was stirred at room temp for 18 h. The mixture was then evaporated and the residue purified by chromatography. Gradient elution with 3%-20% 20DCM:8EtOH:1NH3 in DCM over 30 mins gave a white solid (38 mg)
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([OH:10])[C:7]([O:11][CH3:12])=[CH:6][C:3]=1[CH:4]=[O:5].[CH2:13](Br)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.N12CCCN=C1CCCCC2.[OH-].[Na+]>CN(C)C=O>[CH2:13]([O:10][C:8]1[C:7]([O:11][CH3:12])=[CH:6][C:3]([CH:4]=[O:5])=[C:2]([OH:1])[CH:9]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: COc1cc(C=O)c(O)cc1O
Reactant: BrCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: COc1cc(C=O)c(O)cc1OCc1ccccc1
Temperature: 25 °C

Procedure:
2,4-Dihydroxy-5-methoxybenzaldehyde (6.0 g), benzyl bromide (9.7 g) and 1,8-diazabicyclo[5.4.0]undec-7-ene (8.6 g) in N,N-dimethylformamide (30 ml) were heated at 100° C. under nitrogen for 5 hours. After cooling to room temperature, 1 N NaOH was added and the mixture washed with ethyl acetate. The water phase was acidified with HCl and the precipitate was filtered.
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[CH2:7][N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:22]3[C:17](=[CH:18][C:19](Br)=[CH:20][CH:21]=3)[NH:16][N:15]=2)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[C:25]([O:29][C:30]([N:32]1[CH2:37][CH2:36][CH:35]([CH:38]=[CH2:39])[CH2:34][CH2:33]1)=[O:31])([CH3:28])([CH3:27])[CH3:26].C(N(CC)CC)C.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:25]([O:29][C:30]([N:32]1[CH2:37][CH2:36][CH:35](/[CH:38]=[CH:39]/[C:19]2[CH:18]=[C:17]3[C:22]([C:14]([CH:11]4[CH2:12][CH2:13][N:8]([CH2:7][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:24])[CH2:9][CH2:10]4)=[N:15][NH:16]3)=[CH:21][CH:20]=2)[CH2:34][CH2:33]1)=[O:31])([CH3:28])([CH3:27])[CH3:26]
Reactant: C=CC1CCN(C(=O)OC(C)(C)C)CC1
Reactant: CC(C)(C)OC(=O)CN1CCC(c2n[nH]c3cc(Br)ccc23)CC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)CN1CCC(c2n[nH]c3cc(/C=C/C4CCN(C(=O)OC(C)(C)C)CC4)ccc23)CC1
Reaction time: 16 h
Yield: 66.1 %

Procedure:
A mixture of [4-(6-bromo-1H-indazol-3-yl)-piperidin-1-yl]-acetic acid tert butyl ester (1.34 g, 3.40 mmol), 4-vinyl-piperidine-1-carboxylic acid tert-butyl ester (0.75 g, 3.57 mmol), triethylamine (1.4 ml, 10.2 mmol), palladium (ii) acetate (0.050 g, 0.22 mmol) and tri(o-tolyl)phosphine (0.210 g, 0.6 mmol) in DMF (60 ml) was stirred at 120° under nitrogen for 16 h. The mixture was evaporated in vacuo and purified by flash chromatography on silica gel (Merck 9385), eluant ethyl acetate:cyclohexane:triethylamine (50:50:2→100:0:2), to give the title compound as a yellow solid (1.18 g, 66%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[CH:12]=[N:13][C:14]([O:17][CH2:18][C:19]([OH:21])=[O:20])=[N:15][CH:16]=2)=[O:10])=[CH:4][CH:3]=1.[F:22][C:23]1[CH:28]=[CH:27][C:26](O)=[CH:25][CH:24]=1>>[F:22][C:23]1[CH:28]=[CH:27][C:26]([O:20][C:19](=[O:21])[CH2:18][O:17][C:14]2[N:13]=[CH:12][C:11]([C:9](=[O:10])[NH:8][C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)=[CH:16][N:15]=2)=[CH:25][CH:24]=1
Reactant: O=C(O)COc1ncc(C(=O)Nc2ccc(F)cc2)cn1
Reactant: Oc1ccc(F)cc1
Product: O=C(COc1ncc(C(=O)Nc2ccc(F)cc2)cn1)Oc1ccc(F)cc1
Yield: 79 %

Procedure:
The titled compound was prepared from [5-(4-fluorophenylcarbamoyl)pyrimidin-2-yloxy]acetic acid using 4-fluorophenol (17 mg, 0.15 mmol) as the coupling partner. Concentration (no chromatography) yielded 52 mg (79%) of the titled compound. ESI-MS m/z 386 (MH+), 384 (M−H−).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([O:13][C:14]1[CH:28]=[CH:27][C:17]([O:18][CH2:19][CH2:20][N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)=[CH:16][CH:15]=1)=[C:8]([C:29]1[S:30][CH:31]=[CH:32][CH:33]=1)[CH:7]=[CH:6]2.C([Li])CCC.C1C=CC(S(N(S(C2C=CC=CC=2)(=O)=O)[F:49])(=O)=O)=CC=1.Cl>O1CCCC1.CCOCC>[F:49][C:31]1[S:30][C:29]([C:8]2[CH:7]=[CH:6][C:5]3[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[CH:4]=3)[C:9]=2[O:13][C:14]2[CH:15]=[CH:16][C:17]([O:18][CH2:19][CH2:20][N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)=[CH:27][CH:28]=2)=[CH:33][CH:32]=1
Reactant: O=S(=O)(c1ccccc1)N(F)S(=O)(=O)c1ccccc1
Reactant: COc1ccc2c(Oc3ccc(OCCN4CCCCC4)cc3)c(-c3cccs3)ccc2c1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOCC
Product: COc1ccc2c(Oc3ccc(OCCN4CCCCC4)cc3)c(-c3ccc(F)s3)ccc2c1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 25 %

Procedure:
Add 1-(2-(4-(6-methoxy-2-(thiophen-2-yl)naphthalen-1-yloxy)phenoxy)ethyl)piperidine (153 mg, 0.4 mmol) and tetrahydrofuran (3.3 mL) to a screw-cap vial under argon. Cool the resulting solution to −78° C. Add n-butyl lithium (1.6M in hexanes; 230 μL, 0.4 mmol) dropwise. Warm the resulting solution to 0° C. and stir for 30 min. Add a solution of N-fluorobenzenesulfonimide (210.0 mg; 0.6 mmol) in tetrahydrofuran (500 μL). Allow the resulting mixture to warm to room temperature and stir for 2 hours. Add 1M HCl, dilute with ether and pass through an SCX acidic ion exchange column. Flush the column with methanol then elute desired material with 2M ammonia in methanol. Concentrate the ammonia containing eluent to give a yellow solid. Purify the yellow solid on a silica gel flash chromatography to obtain the title compound (59.0 mg, 0.1 mmol): mass spectrum (m/z): 478 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH:13]([CH:25]3[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]3)[CH2:14][O:15][C:16]3[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][C:17]=3[F:24])=[C:11]3[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][C:10]3=[N:9]2)=[CH:4][CH:3]=1.[N-:36]=[N+:37]=[N-:38].[Na+].Cl.C(N(CC)CC)C>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:12]([CH:13]([CH:25]3[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]3)[CH2:14][O:15][C:16]3[CH:23]=[CH:22][C:19]([C:20]4[NH:38][N:37]=[N:36][N:21]=4)=[CH:18][C:17]=3[F:24])=[C:11]3[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][C:10]3=[N:9]2)=[CH:6][CH:7]=1
Reactant: [N-]=[N+]=[N-]
Reactant: N#Cc1ccc(OCC(c2c3c(nn2-c2ccc(Cl)cc2)CCCCC3)C2CCCCC2)c(F)c1
Agent: Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Fc1cc(-c2nnn[nH]2)ccc1OCC(c1c2c(nn1-c1ccc(Cl)cc1)CCCCC2)C1CCCCC1

Procedure:
In analogy to the procedure described in example 5, 4-{2-[2-(4-chloro-phenyl)-2,4,5,6,7,8-hexahydro-cycloheptapyrazol-3-yl]-2-cyclohexyl-ethoxy}-3-fluoro-benzonitrile (example 14.2) was treated with sodium azide and triethylamine hydrochloride in DMF to give the title compound as white solid. MS: m/e=535.7 [M+H+].
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8]C)=O)=[C:4]([N:12]2[CH2:16][CH2:15][CH2:14][S:13]2(=[O:18])=[O:17])[CH:3]=1.[CH:19]1([C:22]2[CH:23]=[C:24]([CH3:34])[C:25]([N:28]3[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]3)=[N:26][CH:27]=2)[CH2:21][CH2:20]1>>[Br:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([N:31]2[CH2:32][CH2:33][N:28]([C:25]3[C:24]([CH3:34])=[CH:23][C:22]([CH:19]4[CH2:20][CH2:21]4)=[CH:27][N:26]=3)[CH2:29][CH2:30]2)=[O:8])=[C:4]([N:12]2[CH2:16][CH2:15][CH2:14][S:13]2(=[O:18])=[O:17])[CH:3]=1
Reactant: Cc1cc(C2CC2)cnc1N1CCNCC1
Reactant: COC(=O)c1ccc(Br)cc1N1CCCS1(=O)=O
Product: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(Br)cc2N2CCCS2(=O)=O)CC1
Yield: 63.1 %

Procedure:
Using methyl 4-bromo-2-(1,1-dioxo-1λ6-isothiazolidin-2-yl)benzoate (1 g) described in Preparation Example 239 and 1-(5-cyclopropyl-3-methylpyridin-2-yl)piperazine (0.65 g) described in Preparation Example 83 and by the reaction and treatment in the same manner as in Preparation Example 166, the title compound (0.98 g) was obtained.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]([F:10])([F:9])[F:8])=[CH:5][C:4]([NH2:11])=[N:3]1.Cl[C:13]([O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:14].C([O-])([O-])=O.[K+].[K+]>C1COCC1>[CH3:1][N:2]1[C:6]([C:7]([F:8])([F:9])[F:10])=[CH:5][C:4]([NH:11][C:13](=[O:14])[O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:3]1
Reactant: Cn1nc(N)cc1C(F)(F)F
Reactant: O=C(Cl)Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: Cn1nc(NC(=O)Oc2ccccc2)cc1C(F)(F)F
Yield: 70.9 %

Procedure:
Using the procedure described in Example 161C, 1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-amine (0.38 g, 2.3 mmol) and phenyl chloroformate (0.438 g, 2.8 mmol) were reacted in the presence of K2CO3 (0.415 g, 3 mmol) in THF (10 mL), to afford phenyl 1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-ylcarbamate as solid (0.465 g, 71%). 1H NMR (300 MHz, CDCl3) δ 8.05 (s, 1H), 7.17-7.45 (m, 5H), 6.93 (s, 1H), 3.91 (s, 3H); LC-MS (ESI) m/z 286 (M+H)+.
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:11]2([O:15][CH2:14][CH2:13][O:12]2)[CH2:10][CH:9]1[CH2:18][N:19]1[C:27](=[O:28])[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:20]1=[O:29])=O)(C)(C)C>FC(F)(F)C(O)=O.ClCCl>[O:12]1[C:11]2([CH2:16][CH2:17][NH:8][CH:9]([CH2:18][N:19]3[C:20](=[O:29])[C:21]4[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=4)[C:27]3=[O:28])[CH2:10]2)[O:15][CH2:14][CH2:13]1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1CN1C(=O)c3ccccc3C1=O)OCCO2
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1c2ccccc2C(=O)N1CC1CC2(CCN1)OCCO2
Temperature: 25 °C
Yield: 100 %

Procedure:
7-(1,3-Dioxo-1,3-dihydro-isoindol-2-ylmethyl)-1,4-dioxa-8-aza-spiro[4.5]decane-8-carboxylic acid tert-butyl ester (1.55 g, 3.85 mmol) was cooled in an ice bath and then dissolved in a solution of 20% trifluoroacetic acid/dichloromethane (15 ml). The reaction was stirred and allowed to slowly warm to ambient temperature during 3 hours. The solution was concentrated in vacuo to give crude 2-(1,4-dioxa-8-aza-spiro[4.5]dec-7-ylmethyl)-isoindole-1,3-dione which was used directly in the following step (assumed 100% yield).
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][Mg]Br)[CH2:6][CH2:5][CH2:4][CH:3]=[CH:2]1.[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([N:18]=[C:19]=[S:20])=[CH:14][CH:13]=1.[Cl-].[NH4+]>C1COCC1>[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([NH:18][C:19](=[S:20])[CH2:8][CH2:7][CH:1]2[CH2:6][CH2:5][CH2:4][CH:3]=[CH:2]2)=[CH:14][CH:13]=1
Reactant: Br[Mg]CCC1C=CCCC1
Reactant: S=C=Nc1ccc(Cl)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: S=C(CCC1C=CCCC1)Nc1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
The obtained THF solution of 2-(2-cyclohexene-1-yl)ethyl magnesium bromide was dropped into 25 ml of anhydrous THF solution including 1.8 g of p-chlorophenyl isothiocyanate at 0° C. The resulting solution was stirred at 0° C. for 30 minutes, and stirred at room temperature for an additional 30 minutes. The solution was added with saturated ammonium chloride aqueous solution and extracted with ethyl acetate. The organic layer was washed with brine, dried with anhydrous magnesium sulfate, filtered, concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 2.2 g of the title compound.
Reaction SMILES: [O:1]=[C:2]1[NH:6][C:5]2[CH:7]=[CH:8][C:9]([NH:11][C:12]3[C:13]4[CH:20]=[C:19]([C:21]([OH:23])=O)[NH:18][C:14]=4[N:15]=[CH:16][N:17]=3)=[CH:10][C:4]=2[S:3]1.[CH3:24][N:25]([CH3:32])[CH:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1>>[CH3:24][N:25]([CH3:32])[CH:26]1[CH2:31][CH2:30][N:29]([C:21]([C:19]2[NH:18][C:14]3[N:15]=[CH:16][N:17]=[C:12]([NH:11][C:9]4[CH:8]=[CH:7][C:5]5[NH:6][C:2](=[O:1])[S:3][C:4]=5[CH:10]=4)[C:13]=3[CH:20]=2)=[O:23])[CH2:28][CH2:27]1
Reactant: O=C(O)c1cc2c(Nc3ccc4[nH]c(=O)sc4c3)ncnc2[nH]1
Reactant: CN(C)C1CCNCC1
Product: CN(C)C1CCN(C(=O)c2cc3c(Nc4ccc5[nH]c(=O)sc5c4)ncnc3[nH]2)CC1

Procedure:
150 mg (458 μmol) 4-[(2-oxo-2,3-dihydro-1,3-benzothiazol-6-yl)amino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid (prepared according to example 30) were transformed in analogy to example 4 using N,N-dimethylpiperidin-4-amine to give after working up and purification 10 mg (5%) of the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH:5]([C:9]1[C:14]([F:15])=[CH:13][CH:12]=[C:11]([OH:16])[C:10]=1[F:17])[O:6][CH2:7][CH3:8])[CH3:2].[F:19][C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1.C(N(CC)CC)C>C(Cl)Cl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH2:1]([O:3][C:4](=[O:18])[CH:5]([C:9]1[C:14]([F:15])=[CH:13][CH:12]=[C:11]([O:16][C:23]2[CH:24]=[CH:25][C:20]([F:19])=[CH:21][CH:22]=2)[C:10]=1[F:17])[O:6][CH2:7][CH3:8])[CH3:2]
Reactant: OB(O)c1ccc(F)cc1
Reactant: CCOC(=O)C(OCC)c1c(F)ccc(O)c1F
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)C(OCC)c1c(F)ccc(Oc2ccc(F)cc2)c1F
Temperature: 25 °C
Reaction time: 40 h
Yield: 35.3 %

Procedure:
To a solution under Ar of (RS)-(2,6-difluoro-3-hydroxy-phenyl)-ethoxy-acetic acid ethyl ester (320 mg) in CH2Cl2 (10 ml) was added copper(II)acetate (230 mg), 4-fluorobenzeneboronic acid 516 mg) and powdered MS4 Å (2 g). After addition of triethlyamine (622 mg) the mixture was stirred 40 h at rt. The solids were filtered away and the solvent was evaporated. Column chromatography (CC) (AcOEt:Hept 1:9 to 1:1) afforded 154 mg of (RS)-[2,6-difluoro-3-(4-fluoro-phenoxy)-phenyl]-ethoxy-acetic acid ethyl ester as a brownish oil.
Reaction SMILES: CN1CCOCC1.N#N.[C:10]([NH:13][C@H:14]([C:30]([OH:32])=O)[CH2:15][CH2:16][CH2:17][CH2:18][NH:19][C:20]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:21])(=[O:12])[CH3:11].C(N=C=NCCCN(C)C)C.[C:44]([O:48][C:49](=[O:73])[CH:50]([CH2:71][NH2:72])[CH2:51][C:52]1([C:57](=[O:70])[NH:58][C@H:59]2[CH2:64][CH2:63][C@@H:62]([C:65]([O:67][CH2:68][CH3:69])=[O:66])[CH2:61][CH2:60]2)[CH2:56][CH2:55][CH2:54][CH2:53]1)([CH3:47])([CH3:46])[CH3:45]>ClCCl>[C:44]([O:48][C:49](=[O:73])[CH:50]([CH:71]([C:30](=[O:32])[C@H:14]([CH2:15][CH2:16][CH2:17][CH2:18][NH:19][C:20]([O:22][CH2:23][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)=[O:21])[NH:13][C:10](=[O:12])[CH3:11])[NH2:72])[CH2:51][C:52]1([C:57](=[O:70])[NH:58][C@H:59]2[CH2:60][CH2:61][C@@H:62]([C:65]([O:67][CH2:68][CH3:69])=[O:66])[CH2:63][CH2:64]2)[CH2:56][CH2:55][CH2:54][CH2:53]1)([CH3:46])([CH3:45])[CH3:47]
Reactant: CCOC(=O)[C@H]1CC[C@@H](NC(=O)C2(CC(CN)C(=O)OC(C)(C)C)CCCC2)CC1
Reactant: CC(=O)N[C@@H](CCCCNC(=O)OCc1ccccc1)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: N#N
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CCOC(=O)[C@H]1CC[C@@H](NC(=O)C2(CC(C(=O)OC(C)(C)C)C(N)C(=O)[C@H](CCCCNC(=O)OCc3ccccc3)NC(C)=O)CCCC2)CC1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
1-Hydrobenztriazole (207 mg, 1.53 mmole) and N-methylmorpholine (235 mg, 2.36 mmole) were added to a stirred solution of N2 -acetyl-N6 -benzyloxycarbonyl-L-lysine (456 mg, 1.41 mmole) in dry dichloromethane at 0° C., followed by 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (361 mg). The solution was stirred at 0° C. for 20 minutes and 3-{1-[(cis-4-ethoxycarbonylcyclohexyl)-carbamoyl]cyclopentyl}-2-(aminomethyl)propanoic acid t-butyl ester (500 mg, 1.18 mmole) in dichloromethane (10 ml) was added in one portion and the reaction mixture allowed to warm to room temperature and stirred for 16 hours. The solution was concentrated under vacuum to a volume of 10 ml and partitioned between ethyl acetate and water. The organic phase was washed with water (2×50 ml), 2M hydrochloric acid (50 ml, 2×25 ml), sodium bicarbonate solution (2×25 ml) and brine and then dried (MgSO4) and the solvent evaporated. The residue was chromatographed on silica eluting with ethyl acetate to give the title compound (610 g, 71%). Found: C, 63.34; H, 8.61; N, 7.45. C39H60N4O9 (0.25 H2O) requires C, 63.48; H, 8.33; N, 7.59%.