Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:35])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][NH:9][C:10]1[C:11]2[C:18]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=3)=[C:17]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[CH2:33][CH3:34])[O:16][C:12]=2[N:13]=[CH:14][N:15]=1.[OH-].[Na+].Cl.C(OCC)(=O)C>O1CCOCC1>[CH2:33]([C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=1[C:17]1[O:16][C:12]2[N:13]=[CH:14][N:15]=[C:10]([NH:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][C:3]([OH:35])=[O:2])[C:11]=2[C:18]=1[C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=1)[CH3:34]
Reactant: CCc1ccccc1-c1oc2ncnc(NCCCCCC(=O)OC)c2c1-c1ccc(OC)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CCc1ccccc1-c1oc2ncnc(NCCCCCC(=O)O)c2c1-c1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Dissolve 45 mg (0.10 mmol) 6-{[6-(2-ethylphenyl)-5-(4-methoxyphenyl)furo[2,3-d]pyrimidin-4-yl]amino}hexanoic acid methyl ester in 2.0 ml dioxan and add 0.5 ml 1 N sodium hydroxide solution. Stir for 16 h at RT, then add 0.5 ml 1 N hydrochloric acid and 5 ml ethyl acetate. Separate the organic phase, dry over sodium sulphate, filter and concentrate by evaporation. 38 mg (87% of theor.) of the target compound is obtained.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([N:7]2[CH:11]=[C:10]([C:12]3[N:17]=[C:16]([C:18]([NH2:20])=[NH:19])[CH:15]=[CH:14][CH:13]=3)[CH:9]=[N:8]2)[CH:2]=1.F[P-](F)(F)(F)(F)F.CN(C)[CH:30]=[CH:31][CH:32]=[N+](C)C.[O-]CC.[Na+]>C(O)C>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([N:7]2[CH:11]=[C:10]([C:12]3[N:17]=[C:16]([C:18]4[N:20]=[CH:32][CH:31]=[CH:30][N:19]=4)[CH:15]=[CH:14][CH:13]=3)[CH:9]=[N:8]2)[CH:2]=1
Reactant: N=C(N)c1cccc(-c2cnn(-c3cccnc3)c2)n1
Reactant: CN(C)C=CC=[N+](C)C
Agent: CC[O-]
Agent: F[P-](F)(F)(F)(F)F
Agent: [Na+]
Solvent: CCO
Product: c1cnc(-c2cccc(-c3cnn(-c4cccnc4)c3)n2)nc1

Procedure:
Under argon, 0.73 g (2.7 mmol) of 6-(1-pyridin-3-yl-1H-pyrazol-4-yl)pyridine-2-carboxamidine and 0.8 g (2.9 mmol) of (3-dimethylaminoallylidene)dimethylammonium hexafluorophosphate in 30 ml of ethanol were heated under reflux with 3 ml of sodium ethoxide as a solution in ethanol (21%, corresponds to 8.1 mmol) for 6 h. The mixture was concentrated, Na citrate buffer, dil. aqueous sodium hydroxide solution to pH=9, aq. NaCl and ethyl acetate/THF were added, the aqueous phase was extracted three more times with dichloromethane/2-propanol and the combined organic phases were dried with MgSO4 and concentrated by evaporation. The residue was recrystallized from ethanol, during this operation, the mixture was briefly boiled with activated carbon and filtered whilst still hot, the filtrate was concentrated slightly and the precipitate formed was washed with MTBE and dried on a rotary evaporator. The residue was purified further by filtration through silica gel using acetone.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:11]1[C:42]([CH3:43])=[N:41][C:40]2=[CH:44][C:37]3=[N:38][N:39]2[C:12]=1[C:13]1[CH:47]=[C:46]2[C:16]([O:17][CH2:18][CH2:19][CH:20]2[CH2:21][CH:22]=[CH:23][CH2:24][CH2:25][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:31]=2[C:32]2[CH:45]=[C:36]3[CH:35]=[CH:34][CH:33]=2)=[CH:15][CH:14]=1)[C:7]([O:9][CH3:10])=[O:8])([CH3:4])([CH3:3])[CH3:2]>CO.[Pd]>[C:1]([O:5][C@@H:6]([C:11]1[C:42]([CH3:43])=[N:41][C:40]2=[CH:44][C:37]3=[N:38][N:39]2[C:12]=1[C:13]1[CH:47]=[C:46]2[C:16]([O:17][CH2:18][CH2:19][CH:20]2[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:31]=2[C:32]2[CH:45]=[C:36]3[CH:35]=[CH:34][CH:33]=2)=[CH:15][CH:14]=1)[C:7]([O:9][CH3:10])=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)[C@@H](OC(C)(C)C)c1c(C)nc2cc3nn2c1-c1ccc2c(c1)C(CC=CCCc1ccccc1-c1cccc-3c1)CCO2
Agent: [Pd]
Solvent: CO
Product: COC(=O)[C@@H](OC(C)(C)C)c1c(C)nc2cc3nn2c1-c1ccc2c(c1)C(CCCCCc1ccccc1-c1cccc-3c1)CCO2
Reaction time: 16 h

Procedure:
A solution of methyl (2S)-2-(tert-butoxy)-2-[4-methyl-29-oxa-5,7,8-triazaheptacyclo[24.6.2.16,9. 110,14.02,7.015,20.030,34]hexatriaconta-1(32),2,4,6(36),8,10(35),11,13,15 (20),16,18,23,30,33-tetradecaen-3-yl]acetate (0.051 g, 0.082 mmol) in MeOH (5 mL) was treated with 10 wt % Pd/C (9 mg, 0.08 mmol), then evacuated and hydrogen gas filled three times. The reaction was stirred for 16 h. The reaction mixture was filtered (0.45 nm syringe tip filter) and the filtrate solution was used directly in the following step. LCMS (M+H)=630.5.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:5]=1[C:11]1[O:12][CH2:13][C:14]2([C:24]3[C:19](=[CH:20][C:21]([OH:25])=[CH:22][CH:23]=3)[CH2:18][CH2:17][CH2:16]2)[N:15]=1.I[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34]>CN(C=O)C>[F:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:5]=1[C:11]1[O:12][CH2:13][C:14]2([C:24]3[C:19](=[CH:20][C:21]([O:25][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])=[CH:22][CH:23]=3)[CH2:18][CH2:17][CH2:16]2)[N:15]=1
Reactant: Oc1ccc2c(c1)CCCC21COC(c2c(F)cccc2F)=N1
Reactant: CCCCCCCCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCCCCCOc1ccc2c(c1)CCCC21COC(c2c(F)cccc2F)=N1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 89.1 %

Procedure:
To a suspension of 64 mg (0.00127 mol) of NaH in 1 mL of DMF at 0° C. was added a partial solution of 200 mg (0.00063 mol) of the product of Step F. The reaction was stirred at 0° C. for 30 minutes. Then, 304 mg (0.00127 mol) of 1-iodooctane was added and stirring continued for an additional 30 minutes at 0° C. The reaction mixture was poured into ice-water and extracted with Et2O. The Et2O extract was washed with brine, dried (MgSO4) and concentrated. The residue was purified by passing through a silica gel column eluting with EtOAc:Hexanes (1:4) to give 240 mg of a clear oil. 1H NMR (CDCl3) d 7.40 (m, 1H), 7.20 (d, 1H), 6.98 (Ab q, 2H), 3.92 (t, 2H), 2.80 (m, 2H), 1.70-2.20 (m, 4 H), 1.20-1.45 (m, 12H), 0.90 (t, 3H).
Reaction SMILES: C(N(CC)CC)C.[NH2:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][N:13]=[CH:12]2.[Cl:18][CH2:19][CH2:20][CH2:21][C:22](Cl)=[O:23].[OH-].[Na+]>O1CCCC1>[Cl:18][CH2:19][CH2:20][CH2:21][C:22]([NH:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][N:13]=[CH:12]2)=[O:23]
Reactant: Nc1ccc2[nH]ncc2c1
Reactant: O=C(Cl)CCCCl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(CCCCl)Nc1ccc2[nH]ncc2c1
Yield: 32 %

Procedure:
Triethylamine (2.1 ml, 15 mmol) was added to a suspension of 5-aminoindazole (1.00 g, 7.51 mmol) in tetrahydrofuran (10 ml) at room temperature, followed by adding thereto a solution of 4-chlorobutyryl chloride (1.16 g, 8.26 mmol) in tetrahydrofuran (5 ml) at 0° C., and the resulting mixture was stirred at 0° C. for 1 hour. Then, a 1N-aqueous sodium hydroxide solution was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the resulting residue was suspended in ethanol and stirred, followed by filtration. The solid collected by the filtration was dried under reduced pressure to obtain 4-chloro-N-(1H-indazol-5-yl)butanamide (572 mg, 32%).
Reaction SMILES: [F:1][C:2]([F:50])([F:49])[C:3]1[CH:4]=[C:5]([CH:42]=[C:43]([C:45]([F:48])([F:47])[F:46])[CH:44]=1)[CH2:6][N:7]([CH2:23][C:24]1[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[CH:26][C:25]=1[N:34]([CH2:40][CH3:41])[C:35]([NH:37][CH2:38][CH3:39])=[O:36])[C:8]1[N:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][C:18]([O:20]CC)=[O:19])=[CH:10][N:9]=1.[OH-].[Na+].C(OCC)(=O)C>C(O)C>[F:50][C:2]([F:1])([F:49])[C:3]1[CH:4]=[C:5]([CH:42]=[C:43]([C:45]([F:46])([F:47])[F:48])[CH:44]=1)[CH2:6][N:7]([CH2:23][C:24]1[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[CH:26][C:25]=1[N:34]([CH2:40][CH3:41])[C:35]([NH:37][CH2:38][CH3:39])=[O:36])[C:8]1[N:9]=[CH:10][C:11]([O:14][CH2:15][CH2:16][CH2:17][C:18]([OH:20])=[O:19])=[CH:12][N:13]=1
Reactant: CCNC(=O)N(CC)c1ccc(C(F)(F)F)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ncc(OCCCC(=O)OCC)cn1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCNC(=O)N(CC)c1ccc(C(F)(F)F)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ncc(OCCCC(=O)O)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 42.9 %

Procedure:
Ethyl 4-(2-{(3,5-bis-trifluoromethyl-benzyl)-[2-(1,3-diethylureido)-5-trifluoromethyl-benzyl]-amino}-pyrimidin-5-yloxy)-butyrate (165 mg) is dissolved in ethanol (3 ml) and thereto is added 2N-aqueous sodium hydroxide solution (342 μl) and the mixture is stirred at room temperature overnight. To the reaction solution are added ethyl acetate and a 1N-hydrochloric acid, and the mixture is separated, and the organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (chloroform:methanol=1:0→17:3) to give 4-(2-{(3,5-bis-trifluoromethyl-benzyl)-[2-(1,3-diethylureido)-5-trifluoromethyl-benzyl]-amino}-pyrimidin-5-yloxy)-butyric acid (68 mg). MS (m/z): 696 [M+H]+
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH3:10])[C:5]([O:11][CH3:12])=[CH:4][C:3]=1[C:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=O.Cl.[NH2:22][CH2:23][C:24]([O:26]CC)=O>>[CH2:13]([CH:23]1[N:22]=[C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:3]2[CH:4]=[C:5]([O:11][CH3:12])[C:6]([O:8][CH2:9][CH3:10])=[CH:7][C:2]=2[NH:1][C:24]1=[O:26])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:2]=1
Reactant: CCOc1cc(N)c(C(=O)c2ccccc2)cc1OC
Reactant: CCOC(=O)CN
Agent: Cl
Product: CCOc1cc2c(cc1OC)C(c1ccccc1)=NC(Cc1ccccc1)C(=O)N2
Yield: 55 %

Procedure:
By replacing (2-amino-4,5-dimethoxyphenyl)(phenyl)methanone (XXIaa) in example XXIIaa by (2-amino-4-ethoxy-5-methoxyphenyl)(phenyl)methanone (XXIak), and ethyl glycinate hydrochloride by ethyl phenylalalinate hydrochloride, and proceeding in the same manner, the abovenamed product is obtained. Yield: 55%. M: 190–193° C. 1H-NMR (DMSO, 200 MHz): d 1.33–1.39 (m, 3H, CH3), 3.36–3.64 (m, 3H, CH+CH2Bn), 3.73 (s, 3H, OCH3), 3.95–4.10 (m, 2H, CH2), 6.59 (s, 1H Ar), 6.77 (s, 1H Ar), 7.21–7.44 (m, 10H Ar), 10.36 (s, 1H, NH).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([Sn](CCCC)(CCCC)CCCC)=[N:7][NH:8]2)=[CH:4][CH:3]=1.Br[C:25]1[N:26]=[C:27]2[C:33]([C:34]([NH:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])=[CH:32][NH:31][C:28]2=[N:29][CH:30]=1.CN(C=O)C>O.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.[Cu](I)I>[C:37]([NH:36][C:34]([C:33]1[C:27]2[C:28](=[N:29][CH:30]=[C:25]([C:6]3[C:5]4[C:9](=[CH:10][C:2]([F:1])=[CH:3][CH:4]=4)[NH:8][N:7]=3)[N:26]=2)[NH:31][CH:32]=1)=[O:35])([CH3:40])([CH3:38])[CH3:39]
Reactant: CCCC[Sn](CCCC)(CCCC)c1n[nH]c2cc(F)ccc12
Reactant: CC(C)(C)NC(=O)c1c[nH]c2ncc(Br)nc12
Agent: I[Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)NC(=O)c1c[nH]c2ncc(-c3n[nH]c4cc(F)ccc34)nc12
Temperature: 25 °C
Yield: 82 %

Procedure:
The mixture of 6-fluoro-3-(tributylstannyl)-1H-indazole (500 mg, 1.17 mmol), 2-bromo-N-tert-butyl-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (258 mg, 0.9 mmol), tetrakis(triphenylphosphine)palladium(0) (20 mg, 0.017 mmol), copper iodide (10 mg 0.052 mmol) in 15 ml, of dry DMF was heated to 90° C. for 2.5 hours under nitrogen atmosphere. The reaction mixture was cooled to room temperature, diluted with 50 mL of water and filtered. The solid was washed with dichloromethane and hot methanol, then filtered to give N-tert-butyl-2-(6-fluoro-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide as a yellow solid (260 mg, 82%). 1H NMR (300 MHz, DMSO): δ 13.82 (s, 1H), 12.96 (s, 1H), 9.10 (s, 1H), 8.48-8.43 (m, 1H), 8.33 (s, 1H), 7.92 (s, 1H), 7.44-7.41 (m, 1H), 7.12-7.06 (m, 1H), 3.14 (d, 1H, J=5.1 Hz), 1.51 (s, 9H). LCMS: 353.0, [M+H]+.
Reaction SMILES: [C:1]1([C:7]2[C:11]([OH:12])=[C:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[NH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[O-].[Na+].CO.Br[CH2:25][CH2:26][CH3:27]>O>[CH2:25]([O:12][C:11]1[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[N:8][NH:9][C:10]=1[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)[CH2:26][CH3:27]
Reactant: CCCBr
Reactant: Oc1c(-c2ccccc2)n[nH]c1-c1ccccc1
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CCCOc1c(-c2ccccc2)n[nH]c1-c1ccccc1
Temperature: 60 °C

Procedure:
A mixture of 3,5-diphenyl- 4-pyrazolol (10 g, 0.042 mole), sodium methoxide (2.27 g, 0.042 mole) and methanol (60 ml) is heated at 60°C for 2 hours. Then 1-bromopropane (5.17 g, 0.042 mole) is added slowly (5 minutes) at 60°C. The reaction mixture is then held at 60°C until the reaction is complete by tlc. The mixture is poured into water and the solid formed is isolated by filtration. Recrystallization of the solid from acetonitrile affords white crystals, 7.4 g (63%), melting point 142°-142.5°C.
Reaction SMILES: C([N:3]1[CH2:8][CH2:7][N:6]([CH:9]([CH3:11])[CH3:10])[CH2:5][CH2:4]1)=O.Cl.O>CO>[CH:9]([N:6]1[CH2:7][CH2:8][NH:3][CH2:4][CH2:5]1)([CH3:11])[CH3:10]
Reactant: CC(C)N1CCN(C=O)CC1
Agent: Cl
Solvent: CO
Solvent: O
Product: CC(C)N1CCNCC1
Yield: 42 %

Procedure:
To a solution of 0.29 g of 1-formyl-4-isopropylpiperazine in 10 ml of methanol were added 0.5 ml of hydrochloric acid and 1 ml of water and the mixture was heated under reflux for 2 hours. The reaction solution was distilled off under reduced pressure, a iN aqueous solution of sodium hydroxide was added and the mixture was extracted with chloroform and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to afford 0.1 g of the title compound.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][C:4]([C:9]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[OH:10])([CH2:5][CH2:6]1)[CH2:3][CH2:2]2.[N+:23]([C:26]1[CH:27]=[C:28]([O:32][CH2:33][CH2:34][CH2:35][Br:36])[CH:29]=[CH:30][CH:31]=1)([O-:25])=[O:24]>CC#N>[Br-:36].[OH:10][C:9]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[C:4]12[CH2:5][CH2:6][N+:1]([CH2:35][CH2:34][CH2:33][O:32][C:28]3[CH:29]=[CH:30][CH:31]=[C:26]([N+:23]([O-:25])=[O:24])[CH:27]=3)([CH2:2][CH2:3]1)[CH2:8][CH2:7]2
Reactant: O=[N+]([O-])c1cccc(OCCCBr)c1
Reactant: OC(c1ccccc1)(c1ccccc1)C12CCN(CC1)CC2
Solvent: CC#N
Product: O=[N+]([O-])c1cccc(OCCC[N+]23CCC(C(O)(c4ccccc4)c4ccccc4)(CC2)CC3)c1
Product: [Br-]
Yield: 82.2 %

Procedure:
Following the general procedure outlined in Example 3, 1-azabicyclo[2.2.2]oct-4-yl(diphenyl)methanol (0.0608 g, 0.207 mmol) and 3-bromopropyl 3-nitrophenyl ether (0.0730 g, 0.281 mmol) in 2 CH3CN/3 CHCl3 (4.0 mL) were reacted to give the desired product (0.0942 g, 82.2%). EI-MS m/z 474 (M+) Rt (2.04 min).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[S:35])[NH:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:18]=[C:19]3[C:23](=[CH:24][CH:25]=2)[C:22](=[O:26])[N:21]([C@@H:27]([CH:32]([CH3:34])[CH3:33])[C:28]([O:30][CH3:31])=[O:29])[CH2:20]3)=[CH:13][CH:12]=1.NC1C=CC(C2C=C3C(=CC=2)[C:48](=[O:52])N([C@@H](C(C)C)C(OC)=O)C3)=CC=1.COC1C=CC(N=C=S)=CC=1>>[CH3:48][O:52][C:6]1[CH:5]=[CH:4][C:3]([NH:8][C:9](=[S:35])[NH:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:18]=[C:19]4[C:23](=[CH:24][CH:25]=3)[C:22](=[O:26])[N:21]([C@@H:27]([CH:32]([CH3:34])[CH3:33])[C:28]([O:30][CH3:31])=[O:29])[CH2:20]4)=[CH:13][CH:12]=2)=[CH:2][CH:7]=1
Reactant: COC(=O)[C@H](C(C)C)N1Cc2cc(-c3ccc(NC(=S)Nc4ccccc4F)cc3)ccc2C1=O
Reactant: COC(=O)[C@H](C(C)C)N1Cc2cc(-c3ccc(N)cc3)ccc2C1=O
Agent: COc1ccc(N=C=S)cc1
Product: COC(=O)[C@H](C(C)C)N1Cc2cc(-c3ccc(NC(=S)Nc4ccc(OC)cc4)cc3)ccc2C1=O

Procedure:
The compound of example 260 was prepared analogous to compound of example 256 by reaction of compound of example 223 with 4-methoxy phenyl isothiocyanate. The compound of example 260 was used directly without isolation for the preparation of compound of example 261.
Reaction SMILES: [C:1]([N:8]1CCC(N)CC1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH3:15][S:16](Cl)(=[O:18])=[O:17].[N:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>O>[C:4]([O:3][C:1](=[O:2])[NH:8][CH:23]1[CH2:24][CH2:25][N:20]([S:16]([CH3:15])(=[O:18])=[O:17])[CH2:21][CH2:22]1)([CH3:7])([CH3:6])[CH3:5]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: c1ccncc1
Solvent: O
Product: CC(C)(C)OC(=O)NC1CCN(S(C)(=O)=O)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 91 %

Procedure:
5.00 g (25.0 mmol) of BOC-4-aminopiperidine are dissolved in pyridine (19.8 mL) and cooled in an ice bath. 2.13 mL (27.5 mmol) of methanesulfonyl chloride are added slowly. The reaction is stirred at RT for 16 h. After diluting with water, the reaction is extracted with DCM. Organic layers are washed with water, dried with MgSO4 and filtered. The solvent is removed under reduced pressure to afford 6.30 g of (1-Methanesulfonyl-piperidin-4-yl)-carbamic acid tert-butyl ester. Yield: 91%; ESI-MS: 279 [M+H]+
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([O:15]B(O)O)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][CH3:14].O[C:20]1[CH:21]=[CH:22][C:23]2[S:29](=[O:31])(=[O:30])[CH2:28][CH2:27][C:26]([C:32]([O:34][CH3:35])=[O:33])=[CH:25][C:24]=2[CH:36]=1.C(N(CC)CC)C>ClCCl>[CH3:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[O:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][CH3:14])[O:15][C:20]1[CH:21]=[CH:22][C:23]2[S:29](=[O:31])(=[O:30])[CH2:28][CH2:27][C:26]([C:32]([O:34][CH3:35])=[O:33])=[CH:25][C:24]=2[CH:36]=1
Reactant: CCCOCCOc1ccc(OB(O)O)cc1C
Reactant: COC(=O)C1=Cc2cc(O)ccc2S(=O)(=O)CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCOCCOc1ccc(Oc2ccc3c(c2)C=C(C(=O)OC)CCS3(=O)=O)cc1C
Reaction time: 24 h
Yield: 69.2 %

Procedure:
To 3-methyl-4-propoxyethoxyphenylboric acid (710 mg), methyl 7-hydroxy-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (400 mg) and cupric acetate (270 mg) suspended in dichloromethane (15 ml) was added triethylamine (1.04 ml). The resulting mixture was stirred for one day with a calcium chloride tube attached to the reaction vessel, was then mixed with celite and was filtered to remove an insoluble material. The filtrate was concentrated and the residue was subjected to purification using silica gel column chromatography to obtain methyl 7-[3-methyl-4-(2-propoxyethoxy)phenoxy]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (475 mg) as a brown oily substance.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]2[N:8]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-])=O)[CH:12]=3)[O:10][C:5]2=[CH:4][CH:3]=1.CO.O.[SH-].[Na+]>O>[CH3:1][C:2]1[N:7]=[C:6]2[N:8]=[C:9]([C:11]3[CH:12]=[C:13]([NH2:17])[CH:14]=[CH:15][CH:16]=3)[O:10][C:5]2=[CH:4][CH:3]=1
Reactant: Cc1ccc2oc(-c3cccc([N+](=O)[O-])c3)nc2n1
Agent: [Na+]
Agent: [SH-]
Solvent: CO
Solvent: O
Product: Cc1ccc2oc(-c3cccc(N)c3)nc2n1
Yield: 45.3 %

Procedure:
5-Methyl-2-(3-nitro-phenyl)-oxazolo[4,5-b]pyridine (50 mg, 0.196 mmol) was mixed with 6 mL of MeOH along with 2 mL of water and 66 mg of sodium hydrosulfide hydrate. The reaction mixture was stirred under reflux for 2 hours. It was then concentrated and extracted with CH2Cl2. The combined organic layers were dried (Na2SO4) and concentrated to afford 20 mg of 3-(5-methyl-oxazolo[4,5-b]pyridin-2-yl)-phenylamine.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[S:11][C:10]([C:12](Cl)=[O:13])=[CH:9][CH:8]=1.[N-:15]=[N+:16]=[N-:17].[Na+].O>CC(C)=O>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[S:11][C:10]([C:12]([N:15]=[N+:16]=[N-:17])=[O:13])=[CH:9][CH:8]=1
Reactant: [N-]=[N+]=[N-]
Reactant: O=C(Cl)c1ccc(-c2ccccn2)s1
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: [N-]=[N+]=NC(=O)c1ccc(-c2ccccn2)s1
Temperature: 25 °C
Reaction time: 1.25 h
Yield: 83 %

Procedure:
A solution of 5-(pyrid-2-yl)thiophene-2-carbonyl chloride (254 mg, Reference Example 43) in acetone (3 mL) was treated with a solution of sodium azide (128 mg) in a water and acetone mixture (3.5 mL, 1:6, v/v). After stirring at room temperature for a further 75 minutes the reaction mixture was treated with water (4 mL). The insoluble material was collected and washed with water to give the title compound (217 mg) as a white solid, which was used without further purification.
Reaction SMILES: C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(OC([NH:41][C:42]1[S:46][C:45]([C:47]2[C:52]([F:53])=[CH:51][CH:50]=[CH:49][C:48]=2[F:54])=[N:44][C:43]=1[C:55]([OH:57])=O)=O)(C)(C)C.[NH2:58][C:59]1[CH:60]=[N:61][N:62]([CH3:78])[C:63]=1[N:64]1[CH2:69][CH2:68][N:67](C(OC(C)(C)C)=O)[CH2:66][C@H:65]1[CH3:77].CCN(C(C)C)C(C)C>C(Cl)Cl>[NH2:41][C:42]1[S:46][C:45]([C:47]2[C:48]([F:54])=[CH:49][CH:50]=[CH:51][C:52]=2[F:53])=[N:44][C:43]=1[C:55]([NH:58][C:59]1[CH:60]=[N:61][N:62]([CH3:78])[C:63]=1[N:64]1[CH2:69][CH2:68][NH:67][CH2:66][C@H:65]1[CH3:77])=[O:57]
Reactant: CC(C)(C)OC(=O)Nc1sc(-c2c(F)cccc2F)nc1C(=O)O
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)CCN1c1c(N)cnn1C
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C[C@@H]1CNCCN1c1c(NC(=O)c2nc(-c3c(F)cccc3F)sc2N)cnn1C
Temperature: 25 °C
Reaction time: 16 h
Yield: 22 %

Procedure:
A solution of PyBOP (313 mg, 0.60 mmol) and 5-(tert-butoxycarbonylamino)-2-(2,6-difluorophenyl)thiazole-4-carboxylic acid from Example 25 (153 mg, 0.43 mmol) in DCM (10 mL) was stirred at room temperature for 30 min. A solution of (R)-tert-butyl 4-(4-amino-1-methyl-1H-pyrazol-5-yl)-3-methylpiperazine-1-carboxylate (133 mg, 0.45 mmol) and DIPEA (0.12 mL, 0.68 mmol) in DCM (10 mL) were added and the mixture stirred at room temperature for 16 hr. The mixture was diluted with DCM (50 mL) and washed with water (20 mL). The organic layer was separated, passed through a phase separation cartridge and concentrated under reduced pressure. The isolated intermediate was re-dissolved in DCM (6 mL) and TFA (2 mL) added. The mixture was stirred at room temperature for 4 hr. The mixture was concentrated under reduced pressure and the residue re-dissolved in DCM (50 mL) and washed with saturated aqueous NaHCO3 (2×10 mL). The organic layer was separated, passed through a phase separation cartridge and concentrated under reduced pressure. Purification by preparative HPLC gave 112 as a white solid (41 mg, 22% over two steps). 1H NMR (400 MHz, CDCl3) δ 8.66 (s, 1H), 7.92 (s, 1H), 7.38-7.25 (m, 1H), 7.03 (t, J=9.0 Hz, 2H), 6.20 (s, 2H), 3.77 (s, 3H), 3.27-3.15 (m, 2H), 3.10-2.93 (m, 4H), 2.59 (dd, J=12.5, 9.5 Hz, 1H), 0.88 (d, J=6.3 Hz, 3H). Alkyl NH not observed. LCMS (ES+) m/z 434 (M+1).
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH2:6]([C:8]1[CH:12]=[CH:11][S:10][CH:9]=1)[CH3:7].[C:13]([O-])(O)=[O:14].[Na+].[OH-].[Na+]>ClCCl.CN(C=O)C>[CH2:6]([C:8]1[CH:12]=[C:11]([CH:13]=[O:14])[S:10][CH:9]=1)[CH3:7]
Reactant: O=C([O-])O
Reactant: CCc1ccsc1
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCc1csc(C=O)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
31.5 ml of phosphorus oxychloride was added dropwise to 26.0 ml of DMF and stirring carried out for 1 hour. 25.0 g (223 mmol) of 3-ethylthiophene was added dropwise thereto and, after stirring for 1 hour, stirring was conducted at 100° C. for 1 hour. After cooling to room temperature, dilution was carried out with dichloromethane and the mixture poured into saturated bicarbonate of soda solution and neutralization performed with aqueous sodium hydroxide solution. Extraction was then carried out with dichloromethane, followed by drying and concentrating. The residue was distilled and 25.7 g (183 mmol, 0.1 mmHg, 48-49° C). of an approximately 3:1 mixture of 3-ethylthiophenealdehyde and 4-ethylthiophenealdehyde was obtained as a colourless liquid.