Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC(C[AlH]CC(C)C)C.C1(C)C=CC=CC=1.C([O:19][C:20]([C@@H:22]1[CH2:27][C@H:26]2[C@H:24]([CH2:25]2)[N:23]1[C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])=O)C.[OH-].[Na+]>C1COCC1.CCOC(C)=O>[C:31]([O:30][C:28]([N:23]1[C@H:22]([CH2:20][OH:19])[CH2:27][C@H:26]2[C@@H:24]1[CH2:25]2)=[O:29])([CH3:34])([CH3:33])[CH3:32]
Reactant: CCOC(=O)[C@@H]1C[C@@H]2C[C@@H]2N1C(=O)OC(C)(C)C
Agent: CC(C)C[AlH]CC(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1[C@H](CO)C[C@@H]2C[C@@H]21
Reaction time: 0.83 h

Procedure:
At −78° C. a solution of DIBAL in toluene (1.0 M, 47 mmol, 47 mL) is added dropwise to a solution of (1S,3S,5S)-2-aza-bicyclo[3.1.0]hexane-2,3-dicarboxylic acid 2-tert-butyl ester 3-ethyl ester (21.4 mmol) in THF (60 mL). After 50 min the mixture is allowed to reach RT, stirred for additional 50 min and poured into a mixture of aqueous NaOH solution (1.0 M) and ice. EtOAc is added, the layers are separated and the aqueous layer is extracted with EtOAc (3×70 mL). The combined organic layers are washed with aqueous NaOH solution (1.0 M) and brine, dried over Na2SO4 and concentrated in vacuo to give the desired alcohol as a colourless oil. LC-MS (acidic): tR=0.79 min; [M+H]+=214.3.
Reaction SMILES: Cl.[O:2]1[CH:6]=[CH:5][N:4]=[C:3]1[CH2:7][NH2:8].C(N(CC)CC)C.S=[C:17]1[CH2:21][S:20][C:19](=[O:22])[NH:18]1>C(O)C>[O:2]1[CH:6]=[CH:5][N:4]=[C:3]1[CH2:7][NH:8][C:17]1[CH2:21][S:20][C:19](=[O:22])[N:18]=1
Reactant: O=C1NC(=S)CS1
Reactant: NCc1ncco1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: O=C1N=C(NCc2ncco2)CS1
Temperature: 25 °C
Reaction time: 8 h
Yield: 48.7 %

Procedure:
To a solution of 1-(1,3-oxazol-2-yl)methanamine hydrochloride (500 mg) in ethanol (10 mL) were added triethylamine (0.99 mL) and 4-thioxothiazolidin-2-one (495 mg) at room temperature. The reaction mixture was stirred at room temperature overnight, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (NH, methanol/ethyl acetate) to give the title compound (357 mg).
Reaction SMILES: [CH:1]([C:3]1([C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]([C:18]3[NH:19][CH:20]=[C:21]([C:23]#[N:24])[N:22]=3)=[O:17])=[C:11]([N:25]3[CH2:30][CH2:29][CH:28]([CH3:31])[CH2:27][CH2:26]3)[CH:10]=2)[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1)=O.[NH:32]1[CH2:36][CH2:35][CH2:34][CH2:33]1>>[CH3:31][CH:28]1[CH2:27][CH2:26][N:25]([C:11]2[CH:10]=[C:9]([C:3]3([CH2:1][N:32]4[CH2:36][CH2:35][CH2:34][CH2:33]4)[CH2:4][CH2:5][O:6][CH2:7][CH2:8]3)[CH:14]=[CH:13][C:12]=2[NH:15][C:16]([C:18]2[NH:19][CH:20]=[C:21]([C:23]#[N:24])[N:22]=2)=[O:17])[CH2:30][CH2:29]1
Reactant: CC1CCN(c2cc(C3(C=O)CCOCC3)ccc2NC(=O)c2nc(C#N)c[nH]2)CC1
Reactant: C1CCNC1
Product: CC1CCN(c2cc(C3(CN4CCCC4)CCOCC3)ccc2NC(=O)c2nc(C#N)c[nH]2)CC1

Procedure:
The title compound is prepared by the procedure of Example 26, step (b) using 4-cyano-1H-imidazole-2-carboxylic acid [4-(4-formyl-tetrahydro-pyran-4-yl)-2-(4-methyl-piperidin-1-yl)-phenyl]-amide (as prepared in the previous step) and pyrrolidine.
Reaction SMILES: [CH2:1]([S:8][C:9]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:10]=1[NH2:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([S:24](Cl)(=[O:26])=[O:25])=[CH:20][C:19]=1[C:28]([F:31])([F:30])[F:29]>>[CH2:1]([S:8][C:9]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:10]=1[NH:11][S:24]([C:21]1[CH:22]=[CH:23][C:18]([Cl:17])=[C:19]([C:28]([F:31])([F:29])[F:30])[CH:20]=1)(=[O:26])=[O:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)c(C(F)(F)F)c1
Reactant: Nc1cc(Cl)ccc1SCc1ccccc1
Product: O=S(=O)(Nc1cc(Cl)ccc1SCc1ccccc1)c1ccc(Cl)c(C(F)(F)F)c1
Yield: 80.3 %

Procedure:
Following General Procedure B, the title compound (890 mg, 80%) was prepared from 2-(benzylthio)-5-chloroaniline (560 mg, 2.25 mmol) and 4-chloro-3-(trifluoromethyl)benzene-1-sulfonyl chloride (628 mg, 2.25 mmol).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:12][CH3:13])[C:5]([N+:9]([O-:11])=[O:10])=[C:6]([F:8])[CH:7]=1.[C:14]([Cu])#[N:15].C(OCC)(=O)C>CN(C=O)C>[F:8][C:6]1[CH:7]=[C:2]([CH:3]=[C:4]([O:12][CH3:13])[C:5]=1[N+:9]([O-:11])=[O:10])[C:14]#[N:15]
Reactant: COc1cc(Br)cc(F)c1[N+](=O)[O-]
Reactant: N#C[Cu]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1cc(C#N)cc(F)c1[N+](=O)[O-]
Temperature: 160 °C

Procedure:
A mixture of 5-bromo-1-fluoro-3-methoxy-2-nitrobenzene (1.5 g, 6 mmol), and CuCN (698 mg, 7.8 mmol) in 10 mL of DMF was heated in a sealed tube at 160° C. overnight. It was then cooled down, diluted to ethyl acetate, washed by brine and water. The organic extract was dried and concentrated to a red solid (1 g, 85%) which was used for next step without further purification. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 4.01 (s, 3 H) 7.14 (s, 1 H) 7.17 (d, J=8 Hz, 1 H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([Mg]Br)=[CH:5][CH:4]=1.[N:11]12[CH2:18][CH2:17][C:14]([C:19]([O:21]CC)=O)([CH2:15][CH2:16]1)[CH2:13][CH2:12]2>C1COCC1>[N:11]12[CH2:12][CH2:13][C:14]([C:19]([C:6]3[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)([C:6]3[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)[OH:21])([CH2:15][CH2:16]1)[CH2:17][CH2:18]2
Reactant: COc1ccc([Mg]Br)cc1
Reactant: CCOC(=O)C12CCN(CC1)CC2
Solvent: C1CCOC1
Product: COc1ccc(C(O)(c2ccc(OC)cc2)C23CCN(CC2)CC3)cc1
Temperature: 25 °C
Yield: 89.2 %

Procedure:
A solution of 4-(methyloxy)phenylmagnesiumbromide (0.5 M in THF, 6.5 mL, 3.25 mmol) was chilled down to 0° C. under Ar. Ethyl 1-azabicyclo[2.2.2]octane-4-carboxylate (0.1587 g, 0.866 mmol) in THF (4 mL) was slowly added to the reaction mixture at 0° C. over 20 min. The reaction was allowed to warm up to room temperature and then heated at 60° C. for 16 h. The reaction was chilled in an ice bath, quenched with saturated NH4Cl, and concentrated under vacuum. The resulting residue was treated with H2O and extracted with EtOAc. The combined organic layers were dried with MgSO4, filtered, and concentrated under vacuum to yield the desired product (0.273 g, 89.0%). EI-MS m/z 354 (M+H+) Rt (1.74 min).
Reaction SMILES: N1C=CC=NC=1.CC1C=NC=CC=1C(NC1C=CC([C:19]2[S:20][C:21]([C:25]3[CH:26]=[N:27][CH:28]=[N:29][CH:30]=3)=[CH:22][C:23]=2[CH3:24])=CC=1)=O.B(O)(O)O.S1C=CC=C1.BrC1C=CC=NC=1>[Pd]>[N:29]1[CH:30]=[C:25]([C:21]2[S:20][CH:19]=[C:23]([CH3:24])[CH:22]=2)[CH:26]=[N:27][CH:28]=1
Reactant: Cc1cnccc1C(=O)Nc1ccc(-c2sc(-c3cncnc3)cc2C)cc1
Agent: [Pd]
Agent: OB(O)O
Solvent: c1cncnc1
Solvent: Brc1cccnc1
Solvent: c1ccsc1
Product: Cc1csc(-c2cncnc2)c1

Procedure:
The pyrimidine substituent on the thiophene ring of 3-Methyl-N-[4-(3-methyl-5-pyrimidin-5-yl-thiophen-2-yl)-phenyl]-isonicotinamide was attached using a Suzuki coupling reaction (as describe in Step B of the synthesis of compound 1) by reacting a boric acid derivative of thiophene (o) with 5-bromo-pyridine (p) in the presence of a palladium catalyst to form 2-(pyrimidin-5-yl)-4-methyl-thiophene (q). In general, aromatic substituents such as pyridine, can be added to thiophene, oxazole, thiazole and oxazole ring systems by using a Suzuki coupling reaction. A bromo substituent was added to (q) by reacting it with N-bromo-succinimide in acetic acid to form 2-(pyrimidin-5-yl)-4-methyl-5-bromo-thiophene (r). Compound (r) is then coupled to an amino pyridine using a Suzuki coupling reaction (as describe in Step B of the synthesis of compound 1) to form Compound (s). Compound (s) is then reacted with 2-methyl-isonicotinoyl chloride in a reaction analogous to the reaction described in step A of the synthesis of 4-[4-(2,6-Difluoro-benzoylamino)-phenyl]-5-methyl-thiophene-2-carboxylic acid methyl ester to form 3-Methyl-N-[4-(3-methyl-5-pyrimidin-5-yl-thiophen-2-yl)-phenyl]-isonicotinamide.
Reaction SMILES: [OH:1][C:2]1[CH:15]=[CH:14][C:13]2[C:12](=[O:16])[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([OH:17])[CH:10]=3)[C:5](=[O:18])[C:4]=2[CH:3]=1.[CH2:19]([CH:21]([CH2:24][CH2:25][CH2:26][CH3:27])[CH2:22]Br)[CH3:20].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH2:19]([CH:21]([CH2:24][CH2:25][CH2:26][CH3:27])[CH2:22][O:1][C:2]1[CH:15]=[CH:14][C:13]2[C:12](=[O:16])[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([O:17][CH2:5][CH:4]([CH2:13][CH3:12])[CH2:3][CH2:2][CH2:15][CH3:14])[CH:10]=3)[C:5](=[O:18])[C:4]=2[CH:3]=1)[CH3:20]
Reactant: O=C1c2ccc(O)cc2C(=O)c2ccc(O)cc21
Reactant: CCCCC(CC)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCC(CC)COc1ccc2c(c1)C(=O)c1ccc(OCC(CC)CCCC)cc1C2=O
Temperature: 90 °C
Yield: 128.3 %

Procedure:
2,6-Dihydroxyanthraquinone (100.0 g, 0.42 mol) and 2-ethylhexyl bromide (165.0 g, 0.86 mol) were dissolved in 1 L of DMF. To this solution was added anhydrous K2CO3 (120.0 g, 0.87 mol). The reaction was heated at 90° C. overnight. Most of DMF was removed and 500 mL of water was added. The reaction was extracted with ether (3×400 mL), washed with brine (1×200 mL), and dried over MgSO4. Solvent was removed and the crude product was recrystallized from methanol to give yellow powdery product 125.21 g (65% yield). 1H NMR (CDCl3) δ (ppm): 0.92-0.98 (m, 12H, CH3), 1.34-1.54 (m, 16H), 1.75-1.81 (m, 2H,CH(CH3)), 4.02 (d, J=5.5 Hz, 4H, OCH2), 7.19 (d, J=8.4 Hz, 2H), 7.70 (s, 2H), 8.19 (d, J=8.5 Hz, 2H); 13C NMR (CDCl3): 11.12, 14.06, 23.04, 23.88, 29.08, 30.51, 39.34, 71.34, 110.64, 120.84, 127.00, 129.62, 135.88, 164.29, 182.27. M.p. 49-51° C.; FD-MS: m/z 464 (M+).
Reaction SMILES: C(C1[CH:4]=[C:5]([C:16]([NH:18][CH2:19][C:20]2[C:21](=[O:30])[NH:22][C:23]([CH3:29])=[CH:24][C:25]=2[CH2:26][CH2:27][CH3:28])=[O:17])[C:6]2[C:7]([CH3:15])=[CH:8][N:9]([CH:12]([CH3:14])[CH3:13])[C:10]=2[CH:11]=1)#N.[OH-].[K+].C(O)C.CC[O:38][C:39]([CH3:41])=[O:40]>>[CH3:15][C:7]1[C:6]2[C:10](=[CH:11][C:41]([C:39]([OH:38])=[O:40])=[CH:4][C:5]=2[C:16]([NH:18][CH2:19][C:20]2[C:21](=[O:30])[NH:22][C:23]([CH3:29])=[CH:24][C:25]=2[CH2:26][CH2:27][CH3:28])=[O:17])[N:9]([CH:12]([CH3:13])[CH3:14])[CH:8]=1
Reactant: CCCc1cc(C)[nH]c(=O)c1CNC(=O)c1cc(C#N)cc2c1c(C)cn2C(C)C
Reactant: CCOC(C)=O
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CCCc1cc(C)[nH]c(=O)c1CNC(=O)c1cc(C(=O)O)cc2c1c(C)cn2C(C)C
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 64.9 %

Procedure:
To a 5 ml microwave vial was added, 6-cyano-3-methyl-1-(1-methylethyl)-N-[(6-methyl-2-oxo-4-propyl-1,2-dihydro-3-pyridinyl)methyl]-1H-indole-4-carboxamide (100 mg, 0.247 mmol), KOH (41.6 mg, 0.742 mmol) was ground and added followed by Ethanol (8 mL) the reaction was microwaved at 145° C. for 22 hr. The reaction was poured onto acidic Ice water (20 mL) and was stirred for 20 min. EtOAc was added and the mix was stirred an additional 10 min. The layers were separated and the majority of the product was in the EtOAc which was evaporated. The residue was dissolved in MeOH (1 mL) and material was crashed out with ice and was filtered to give product 3-methyl-1-(1-methylethyl)-4-({[(6-methyl-2-oxo-4-propyl-1,2-dihydro-3-pyridinyl)methyl]amino}carbonyl)-1H-indole-6-carboxylic acid (70 mg, 0.160 mmol, 64.9% yield) 1H NMR (400 MHz, DMSO-d6) δ ppm 11.49 (br. s., 1H) 8.18 (s, 1H) 8.10 (s, 1H) 7.53 (d, J=7.58 Hz, 2H) 5.90 (s, 1H) 4.76-4.90 (m, 1H) 4.36 (d, J=4.80 Hz, 2H) 2.55 (br. s., 1H) 2.18 (s, 3H) 2.13 (s, 3H) 1.52-1.61 (m, 2H) 1.44 (d, J=6.57 Hz, 6H) 0.94 (t, J=7.33 Hz, 3H) MS(ES) [M+H]+423.8
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([C:11]2[C:12](=[O:24])[N:13]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[N:14]([CH3:17])[C:15]=2[CH3:16])=[O:10])=[N:6][CH:7]=1.CC(C)([O-])C.[K+].Cl[C:32]1[CH:37]=[CH:36][N:35]=[C:34]([C:38]([NH2:40])=[O:39])[CH:33]=1>CN(C=O)C.O>[CH3:17][N:14]1[C:15]([CH3:16])=[C:11]([C:9]([NH:8][C:5]2[N:6]=[CH:7][C:2]([O:1][C:32]3[CH:37]=[CH:36][N:35]=[C:34]([C:38]([NH2:40])=[O:39])[CH:33]=3)=[CH:3][CH:4]=2)=[O:10])[C:12](=[O:24])[N:13]1[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: Cc1c(C(=O)Nc2ccc(O)cn2)c(=O)n(-c2ccccc2)n1C
Reactant: NC(=O)c1cc(Cl)ccn1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1c(C(=O)Nc2ccc(Oc3ccnc(C(N)=O)c3)cn2)c(=O)n(-c2ccccc2)n1C
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 45.8 %

Procedure:
To a solution of N-(5-hydroxypyridin-2-yl)-1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide (468 mg, 1.4 mmol) in DMF (30 mL) was added potassium tert-butoxide (486 mg, 4.33 mmol). The solution was stirred at rt for 20 minutes, followed by the addition of 4-chloropicolinamide (293 mg, 1.87 mmol). The reaction was heated at 120° C. for 2 hours, then cooled to rt, diluted with water (15 mL) and extracted with EtOAc (20 mL×3). The combined organic phases were washed with brine (20 mL) and concentrated in vacuo. The residue was purified by a silica column chromatography (DCM/MeOH (v/v)=50/1) to give the title compound as an off-white solid (285 mg, 44%).
Reaction SMILES: [CH3:1][N:2]([CH3:16])[C:3]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:8][CH2:7][C:6](=O)[CH2:5][CH2:4]1.[NH:17]1[CH2:21][CH2:20][CH:19]([C:22]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[NH:24][CH:23]=2)[CH2:18]1.C(O)(=O)C.S([O-])([O-])(=O)=O.[Na+].[Na+]>ClCCCl.O1CCCC1>[NH:24]1[C:25]2[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:22]([CH:19]2[CH2:20][CH2:21][N:17]([CH:6]3[CH2:7][CH2:8][C:3]([N:2]([CH3:16])[CH3:1])([C:10]4[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=4)[CH2:4][CH2:5]3)[CH2:18]2)=[CH:23]1
Reactant: c1ccc2c(C3CCNC3)c[nH]c2c1
Reactant: CN(C)C1(c2ccccc2)CCC(=O)CC1
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: ClCCCl
Product: CN(C)C1(c2ccccc2)CCC(N2CCC(c3c[nH]c4ccccc34)C2)CC1
Temperature: 25 °C
Reaction time: 96 h

Procedure:
4-dimethylamino-4-phenylcyclohexanone (217 mg, 1 mmole) and 3-pyrrolidine-3-yl-1H-indole (186 mg, 1 mmole) were dissolved in a mixture of dry 1,2-dichloroethane (5 ml) and tetrahydrofuran (15 ml). Glacial acetic acid (57 μl, 1 mmole) and sodium sulfate (500 mg) were added to this mixture. After a reaction time of 15 minutes sodium triacetoxy boron hydride (318 mg, 1.5 mmole) was added to the reaction mixture and stirred for 4 days at RT. The reaction mixture was worked up by distilling off the solvent and adding saturated sodium hydrogen carbonate solution (20 ml) and water (20 ml). This aqueous phase was extracted with DCM (3×30 ml). The organic phase was dried with Na2SO4 and concentrated by evaporation. The chromatographic purification of the substance mixture was carried out on silica gel with methanol/30% aqueous ammonia (500:1). On dissolving the substance mixture in the solvent a colourless solid precipitated out, which was filtered off. This was identified by NMR spectroscopy as the non-polar diastereoisomer of {4-[3-(1H-indol-3-yl)-pyrrolidine-1-yl]-1-phenylcyclohexyl}-dimethylamine. The non-polar diastereoisomer was obtained in a yield of 79 mg (20%). The remaining substance mixture was purified by flash chromatography. The diastereoisomer mixture was obtained in a yield of 136 mg (35%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[C:11]([Br:16])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:17](=O)([O-])[O-].[K+].[K+].CI.O>CN(C)C=O>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:17])=[C:11]([Br:16])[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: Oc1ccc(OCc2ccccc2)cc1Br
Agent: [K+]
Solvent: O
Solvent: CI
Solvent: CN(C)C=O
Product: COc1ccc(OCc2ccccc2)cc1Br
Temperature: 25 °C
Reaction time: 18 h
Yield: 96 %

Procedure:
To a solution of 4-benzyloxy-2-bromophenol (20 g, 71.6 mmol) in N,N-dimethylformamide (65 ml) was added potassium carbonate (12.4 g, 89.6 mmol) and methyl iodide (12.7 g, 89.6 mmol). The mixture was stirred at room temperature for 18 hours, poured into water (250 ml) and extracted with ethyl acetate (2×100 ml). The organic layer was separated, dried (MgSO4), filtered and concentrated in vacuo to give the title compound (20.15 g, 96%), δH (250 MHz, CDCl3) 3.84 (3H, s, ArOCH3), 4.99 (2H, s, OCH2), 6.80-6.94 (2H, m ArH), 7.21 (1H, d, J 2.75Hz, ArH), 7.28-7.43 (5H, m).
Reaction SMILES: [CH:1]([C:3]1[S:11][C:10]2[C:9](=[O:12])[C:8]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:7][NH:6][C:5]=2[C:4]=1[CH3:18])=[O:2].[C:19](=O)([O-])[O-].[K+].[K+].CI>CN(C=O)C.O>[CH:1]([C:3]1[S:11][C:10]2[C:9](=[O:12])[C:8]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:7][N:6]([CH3:19])[C:5]=2[C:4]=1[CH3:18])=[O:2]
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)c1c[nH]c2c(C)c(C=O)sc2c1=O
Agent: [K+]
Solvent: O
Solvent: CI
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(C)c2c(C)c(C=O)sc2c1=O
Temperature: 50 °C
Reaction time: 24 h
Yield: 68.6 %

Procedure:
A mixture of ethyl 2-formyl-3-methyl-7-oxo-4,7-dihydrothieno[3,2-b]pyridine-6-carboxylate (1.06 g, 3.99 mmol), potassium carbonate (826 mg, 5.98 mmol) and methyl iodide (1.24 mL, 19.9 mmol) in DMF (30 mL) was stirred at 50° C. for 24 hours. The mixture was diluted with water (60 mL), stirred with ice bath cooling for 5 minutes, and then filtered. The collected solid was washed with water and dried in vacuo, leaving a pale tan solid (764 mg, 69%).
Reaction SMILES: [Cl:1][C:2]1[N:27]=[C:26]([Cl:28])[CH:25]=[C:24]([CH3:29])[C:3]=1[C:4]([NH:6][CH2:7][CH2:8][C@H:9]([N:11]1[CH2:16][CH2:15][CH:14]([NH:17][CH2:18][C:19]2[CH:23]=[CH:22][S:21][CH:20]=2)[CH2:13][CH2:12]1)[CH3:10])=[O:5].C(O[C:35]([N:37]([CH2:39][C:40](O)=[O:41])C)=O)(C)(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C>CN(C=O)C>[Cl:1][C:2]1[N:27]=[C:26]([Cl:28])[CH:25]=[C:24]([CH3:29])[C:3]=1[C:4]([NH:6][CH2:7][CH2:8][C@H:9]([N:11]1[CH2:16][CH2:15][CH:14]([N:17]([C:40](=[O:41])[CH2:39][NH:37][CH3:35])[CH2:18][C:19]2[CH:23]=[CH:22][S:21][CH:20]=2)[CH2:13][CH2:12]1)[CH3:10])=[O:5]
Reactant: Cc1cc(Cl)nc(Cl)c1C(=O)NCC[C@@H](C)N1CCC(NCc2ccsc2)CC1
Reactant: CN(CC(=O)O)C(=O)OC(C)(C)C
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CNCC(=O)N(Cc1ccsc1)C1CCN([C@H](C)CCNC(=O)c2c(C)cc(Cl)nc2Cl)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Following general procedure E: to a stirred solution of 2,6-dichloro-4-methyl-N—((R)-3-{4-[(thiophen-3-ylmethyl)-amino]-piperidin-1-yl}-butyl)-nicotinamide (62 mg, 0.137 mmol), (tert-butoxycarbonyl-methyl-amino)-acetic acid (28 mg, 0.159 mmol), HOBt (24 mg, 0.177 mmol) and DIPEA (59 μL, 0.34 mmol) in DMF (3 ml) was added EDCI (34 mg, 0.177 mmol). The reaction was stirred at rt overnight under N2 pressure. The resultant crude product (88 mg) was used in the next step.
Reaction SMILES: [C:1]([OH:7])(=[O:6])[CH2:2][C:3]([OH:5])=[O:4].[CH:8]1([CH3:18])[CH2:13][CH2:12][CH:11]([CH:14]([CH3:16])[CH3:15])[CH:10](O)[CH2:9]1.S(=O)(=O)(O)O.O>C1(C)C=CC=CC=1>[C:1]([O:7][CH:10]1[CH:11]([CH:14]([CH3:16])[CH3:15])[CH2:12][CH2:13][CH:8]([CH3:18])[CH2:9]1)(=[O:6])[CH2:2][C:3]([O:5][CH:10]1[CH:11]([CH:14]([CH3:16])[CH3:15])[CH2:12][CH2:13][CH:8]([CH3:18])[CH2:9]1)=[O:4]
Reactant: O=C(O)CC(=O)O
Reactant: CC1CCC(C(C)C)C(O)C1
Agent: O=S(=O)(O)O
Solvent: O
Solvent: Cc1ccccc1
Product: CC1CCC(C(C)C)C(OC(=O)CC(=O)OC2CC(C)CCC2C(C)C)C1
Yield: 76.2 %

Procedure:
Malonic acid (22.2 g, 0.213 mol) and menthol (70 g, 0.448 mol) are brought to reflux for 6 hours in 100 ml of toluene in the presence of 2 ml of concentrated sulfuric acid in a reactor surmounted by a Dean & Stark apparatus. The water formed is removed by azeotropic distillation. The organic phase is washed 3 times with water and is dried over sodium sulfate. The excess menthol is removed by distillation under vacuum (140° C. under 0.6 hPa). The residue is treated with animal charcoal in isopropanol at reflux. After filtering, rinsing and evaporating the solvent, 61.8 g (Yield 76%) of dimenthyl malonate are obtained in the form of a yellow oil which is used as is in the following stage.
Reaction SMILES: [CH3:1][C@H:2]([O:6][C:7]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:8]=1[C:9]([NH:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][C:25]3[CH:26]=[N:27][C:28]([CH3:31])=[CH:29][CH:30]=3)=[C:20]([CH3:32])[CH:19]=1)=[N:10][CH:11]=[N:12]2)[CH2:3][NH:4][CH3:5].[C:33](OC(=O)C)(=[O:35])[CH3:34]>>[CH3:5][N:4]([CH2:3][C@@H:2]([O:6][C:7]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:8]=1[C:9]([NH:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][C:25]3[CH:26]=[N:27][C:28]([CH3:31])=[CH:29][CH:30]=3)=[C:20]([CH3:32])[CH:19]=1)=[N:10][CH:11]=[N:12]2)[CH3:1])[C:33](=[O:35])[CH3:34]
Reactant: CC(=O)OC(C)=O
Reactant: CNC[C@H](C)Oc1cccc2ncnc(Nc3ccc(Oc4ccc(C)nc4)c(C)c3)c12
Product: CC(=O)N(C)C[C@H](C)Oc1cccc2ncnc(Nc3ccc(Oc4ccc(C)nc4)c(C)c3)c12
Yield: 64 %

Procedure:
The procedure described in Example 104 was repeated using 5-[(1S)-1-methyl-2-(methylamino)ethoxy]-N-{3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}quinazolin-4-amine (obtained as described in Example 109, preparation of starting materials) and acetic anhydride to give the title compound in 64% yield; NMR spectrum (CDCl3) 1.55 (d, 3H), 2.08 (s, 3H), 2.30 (s, 3H), 2.53 (s, 3H), 3.08 (s, 3H), 3.56 (dd, 1H), 3.93 (dd, 1H), 5.09 (m, 1H), 6.92 (d, 1H), 7.12 (m, 3H), 7.50 (m, 2H), 7.65 (m, 1H), 7.70 (s, 1H), 8.27 (s, 1H), 8.62 (s, 1H); Mass spectrum: MH+ 472.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:27]=[CH:26][C:8]([C:9]([N:11]2[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=3)[CH2:13][CH2:12]2)=[O:10])=[C:7]([Cl:28])[CH:6]=1)(=[O:3])[CH3:2].[CH3:29]I>>[C:1]([N:4]([C:5]1[CH:27]=[CH:26][C:8]([C:9]([N:11]2[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C:19]3[CH:20]=[CH:21][C:22]([Cl:25])=[CH:23][CH:24]=3)[CH2:13][CH2:12]2)=[O:10])=[C:7]([Cl:28])[CH:6]=1)[CH3:29])(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ccc(C(=O)N2CCN(CCc3ccc(Cl)cc3)CC2)c(Cl)c1
Reactant: CI
Product: CC(=O)N(C)c1ccc(C(=O)N2CCN(CCc3ccc(Cl)cc3)CC2)c(Cl)c1

Procedure:
0.8 g of 1-[4-(N-methylamino)-2-chlorobenzoyl]-4-[2-(4-chlorophenyl)ethyl]-piperazine (see Example 8) is methylated in a manner analogous to that described in Example 5 with 0.3 g of methyl iodide to form 1-[4-(N-acetyl-N-methylamino)-2-chlorobenzoyl]-4-[2-(4-chlorophenyl)ethyl]-piperazine. It has a melting point of 162°-163°.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][C:3]=1[NH2:4].[CH3:10][CH:11]([C:17](OCC)=[O:18])[C:12]([O:14][CH2:15][CH3:16])=[O:13]>>[F:1][C:2]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][C:3]=1[NH:4][C:17](=[O:18])[CH:11]([CH3:10])[C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: CCOC(=O)C(C)C(=O)OCC
Reactant: Nc1cc(F)ccc1F
Product: CCOC(=O)C(C)C(=O)Nc1cc(F)ccc1F

Procedure:
Prepared according to Procedure A using 2,5-difluoroaniline (5.00 g, 38.7 mmol) and diethyl 2-methylmalonate to give ethyl 3-(2,5-difluorophenylamino)-2-methyl-3-oxopropanoate. Mass Spectrum (ESI) m/e=258.1 (M+1).
Reaction SMILES: Br[C:2]1[C:3]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][OH:24])=[N:4][CH:5]=[C:6]([CH:17]=1)[C:7]([NH:9][C@@H:10]1[CH2:15][CH2:14][CH2:13][CH2:12][C@H:11]1[OH:16])=[O:8].[Cl:25][C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1>>[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([C:2]2[C:3]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][OH:24])=[N:4][CH:5]=[C:6]([CH:17]=2)[C:7]([NH:9][C@@H:10]2[CH2:15][CH2:14][CH2:13][CH2:12][C@H:11]2[OH:16])=[O:8])=[CH:28][CH:27]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: O=C(N[C@@H]1CCCC[C@H]1O)c1cnc(OCCCCCO)c(Br)c1
Product: O=C(N[C@@H]1CCCC[C@H]1O)c1cnc(OCCCCCO)c(-c2ccc(Cl)cc2)c1

Procedure:
The title compound was synthesized in analogy to the procedure described for the preparation of Example 31c, using 5-Bromo-N-((1R,2R)-2-hydroxy-cyclohexyl)-6-(5-hydroxy-pentyloxy)-nicotinamide and 4-chlorophenyl-boronic acid as starting materials to give the product as white solid, MS (ISP): 433.4, 435.4 (M+H+).