Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[C:4]([F:9])[C:3]=1[C:10]1[N:15]=[C:14]([C:16]([O:18][CH3:19])=[O:17])[CH:13]=[CH:12][C:11]=1[F:20].C(=O)([O-])[O-].[K+].[K+].Br[CH2:28][CH2:29][O:30][Si:31]([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:33])[CH3:32]>CN(C=O)C.O>[Si:31]([O:30][CH2:29][CH2:28][O:8][C:6]1[CH:5]=[C:4]([F:9])[C:3]([C:10]2[N:15]=[C:14]([C:16]([O:18][CH3:19])=[O:17])[CH:13]=[CH:12][C:11]=2[F:20])=[C:2]([F:1])[CH:7]=1)([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:33])[CH3:32]
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Reactant: COC(=O)c1ccc(F)c(-c2c(F)cc(O)cc2F)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc(F)c(-c2c(F)cc(OCCO[Si](C)(C)C(C)(C)C)cc2F)n1
Temperature: 25 °C
Reaction time: 72 h
Yield: 74 %

Procedure:
To a solution of methyl 6-(2,6-difluoro-4-hydroxyphenyl)-5-fluoropicolinate (1.0 equiv.) and potassium carbonate (4.0 equiv.) in DMF (0.4 M) was added (2-bromoethoxy)(tert-butyl)dimethylsilane (2 equiv.). After stirring for 72 hours at rt the heterogeneous solution was diluted with water, extracted with EtOAc, dried over MgSO4, filtered, concentrated and purified by ISCO SiO2 chromatography to yield methyl 6-(4-(2-(tert-butyldimethylsilyloxy)ethoxy)-2,6-difluorophenyl)-5-fluoropicolinate in 74% yield. LC/MS=442.1 (M+H), Rt=1.22 min.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH2:16][CH3:17])[CH3:15])[C:11]([Cl:18])=[CH:10][C:9]=1[NH:19][C:20](=[O:43])[CH2:21][C:22](=O)[C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([N:29]2[C:33]([CH2:34][O:35]C3CCCCO3)=[CH:32][N:31]=[N:30]2)[CH:24]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:18][C:11]1[C:12]([N:14]([CH2:16][CH3:17])[CH3:15])=[CH:13][C:8]2[N:7]=[C:22]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([N:29]4[C:33]([CH2:34][OH:35])=[CH:32][N:31]=[N:30]4)[CH:24]=3)[CH2:21][C:20](=[O:43])[NH:19][C:9]=2[CH:10]=1
Reactant: CCN(C)c1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-n3nncc3COC3CCCCO3)c2)cc1Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCN(C)c1cc2c(cc1Cl)NC(=O)CC(c1cccc(-n3nncc3CO)c1)=N2

Procedure:
The title compound was prepared from (RS)-[4-chloro-5-(ethyl-methyl-amino)-2-(3-oxo-3-{3-[5-(tetrahydro-pyran-2-yloxymethyl)-[1,2,3]triazol-1-yl]-phenyl}-propionylamino)-phenyl]-carbamic acid tert-butyl ester (Example M26) (0.5 g, 0.8 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as an off-white solid (60 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([F:9])[C:5](F)=[N:6][CH:7]=1.[NH2:10][NH2:11]>CC(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([F:9])[C:5]([NH:10][NH2:11])=[N:6][CH:7]=1
Reactant: NN
Reactant: Fc1cc(Cl)cnc1F
Solvent: CC(C)O
Product: NNc1ncc(Cl)cc1F
Temperature: 67.5 °C

Procedure:
A mixture of 5-chloro-2,3-difluoropyridine (10.0 g, 66.9 mmol) and hydrazine (10.0 ml, 319 mmol) in iPrOH (50 mL) was heated to 65-70° C. for 6 hours. The mixture was cooled to 23° C., filtered, and washed with Na2CO3 (satd), and H2O. Product isolated as a white solid. MS (ESI pos. ion) m/z: 162 (MH+). Calc'd exact mass for C5H5ClFN3: 161.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([S:8][CH2:9][CH3:10])[C:5]([C:11]([NH:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[CH:16]=2)=[O:12])=[C:4]([CH3:22])[CH:3]=1.[NH:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1>O.CCOC(C)=O>[CH2:9]([S:8][C:6]1[C:5]([C:11]([NH:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[CH:16]=2)=[O:12])=[C:4]([CH3:22])[CH:3]=[C:2]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[N:7]=1)[CH3:10]
Reactant: CCSc1nc(Cl)cc(C)c1C(=O)NCc1cccc(F)c1
Reactant: C1COCCN1
Solvent: CCOC(C)=O
Solvent: O
Product: CCSc1nc(N2CCOCC2)cc(C)c1C(=O)NCc1cccc(F)c1
Temperature: 120 °C
Yield: 75 %

Procedure:
A mixture of 1.5 g (4.4 mmol) 6-chloro-2-ethylsulfanyl-N-[(3-fluorophenyl)-methyl]-4-methyl-pyridine-3-carboxylic acid amide and 1.9 ml (22.1 mmol) morpholine was heated in the microwave at 120° C. for 30 min. Subsequently the RM was diluted with water and EtOAc and the layers were separated. The organic layer was washed with a 1M aq. NaOH sol. and brine, dried over MgSO4 and concentrated in vacuo. Crystallisation (hexane/EtOAc 3:1) of the residue yielded 1.3 g (3.3 mmol, 75%) 2-ethylsulfanyl-N-[(3-fluorophenyl)-methyl]-4-methyl-6-morpholin-4-yl-pyridine-3-carboxylic acid amide (example 2). [M+H]+390.2.
Reaction SMILES: Cl[CH2:2][C:3]#[N:4].CCN(C(C)C)C(C)C.[C:14]([N:21]([CH3:33])[C@H:22]([C:30]([OH:32])=[O:31])[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15]>O1CCCC1>[C:17]([O:16][C:14]([N:21]([CH3:33])[C@@H:22]([CH2:23][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)[C:30]([O:32][CH2:2][C:3]#[N:4])=[O:31])=[O:15])([CH3:18])([CH3:20])[CH3:19]
Reactant: CN(C(=O)OC(C)(C)C)[C@@H](Cc1ccccc1)C(=O)O
Reactant: N#CCCl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CN(C(=O)OC(C)(C)C)[C@@H](Cc1ccccc1)C(=O)OCC#N
Reaction time: 12 h
Yield: 89 %

Procedure:
Chloroacetonitrile (1.1 mL) and DIPEA (258 mg, 0.341 mL, 1.99 mmol) were added to Boc-MePhe-OH (497 mg, 1.78 mmol) in tetrahydrofuran (5 mL) and stirred for 12 h. The solvent was removed under reduced pressure and SiO2 flash chromatography (20-35% ethyl acetate in hexanes) afforded 505 mg of a pale yellow oil in 89% yield. Rf 0.3 in 20% ethyl acetate in hexanes; 1H NMR (500 MHz, CDCl3): δ 7.28-7.25 (m, 2H), 7.20-7.16 (m, 3H), 4.72-4.68 (m, 2H), 4.53-4.52 (m, 1H), 3.27 (m, 1H), 3.11-3.02 (m, 1H), 2.67 (d, J=17 Hz, 3H), 1.36 (d, J=12 Hz, 9H); 13C NMR (125 MHz, CDCl3): δ 169.9, 155.5, 136.8, 128.9, 128.6, 128.4, 126.8, 126.7, 114.2, 80.8, 61.5, 48.7, 35.4, 33.0, 28.1; HRMS (ESI) m/z calcd for C17H22N2O4Na [M+Na]+ 341.147. found 341.149.
Reaction SMILES: Cl[CH2:2][CH2:3][NH:4][C@:5]12[CH2:40][CH2:39][C@@H:38]([C:41]([CH3:43])=[CH2:42])[C@@H:6]1[C@@H:7]1[C@@:20]([CH3:23])([CH2:21][CH2:22]2)[C@@:19]2([CH3:24])[C@@H:10]([C@:11]3([CH3:37])[C@@H:16]([CH2:17][CH2:18]2)[C:15]([CH3:26])([CH3:25])[C:14]([C:27]2[CH:36]=[CH:35][C:30]([C:31]([O:33][CH3:34])=[O:32])=[CH:29][CH:28]=2)=[CH:13][CH2:12]3)[CH2:9][CH2:8]1.CCN(C(C)C)C(C)C.[N:53]1([C:59]([O:61][C:62]([CH3:65])([CH3:64])[CH3:63])=[O:60])[CH2:58][CH2:57][NH:56][CH2:55][CH2:54]1>CS(C)=O>[CH3:34][O:33][C:31]([C:30]1[CH:29]=[CH:28][C:27]([C:14]2[C:15]([CH3:25])([CH3:26])[C@H:16]3[C@:11]([CH3:37])([CH2:12][CH:13]=2)[C@@H:10]2[C@:19]([CH3:24])([C@@:20]4([CH3:23])[C@H:7]([CH2:8][CH2:9]2)[C@H:6]2[C@H:38]([C:41]([CH3:43])=[CH2:42])[CH2:39][CH2:40][C@:5]2([NH:4][CH2:3][CH2:2][N:56]2[CH2:57][CH2:58][N:53]([C:59]([O:61][C:62]([CH3:65])([CH3:64])[CH3:63])=[O:60])[CH2:54][CH2:55]2)[CH2:22][CH2:21]4)[CH2:18][CH2:17]3)=[CH:36][CH:35]=1)=[O:32]
Reactant: C=C(C)[C@@H]1CC[C@]2(NCCCl)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: C=C(C)[C@@H]1CC[C@]2(NCCN3CCN(C(=O)OC(C)(C)C)CC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 120 °C
Yield: 52.3 %

Procedure:
A mixture of methyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-chloroethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate (230 mg, 0.379 mmol), Hunig's Base (0.331 mL, 1.895 mmol) and tert-butyl piperazine-1-carboxylate (141 mg, 0.759 mmol) in DMSO (3 mL) was heated up at 120° C. for 1 hour. The reaction mixture was quenched with water (10 mL), extracted with ethyl acetate (3×8 mL), the extracts were combined, dried over sodium sulfate, filtered and concentrated under reduced pressure to provide the crude, the crude was purified by silica gel chromatography with 0-30% ethyl acetate/hexanes to provide the desired product as a white solid (150 mg, 52%). LCMS: m/e 756.66 (M+H)+, 2.50 min (method 11).
Reaction SMILES: [C:1]1([C:7]2[C:8]([C:12]#[N:13])=[CH:9][NH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:14][B-](F)(F)F.F[B-](F)(F)F.ClC[N+]12CC[N+](F)(CC1)CC2>C(#N)C>[F:14][C:11]1[NH:10][CH:9]=[C:8]([C:12]#[N:13])[C:7]=1[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: F[B-](F)(F)F
Reactant: N#Cc1c[nH]cc1-c1ccccc1
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Solvent: CC#N
Product: N#Cc1c[nH]c(F)c1-c1ccccc1
Temperature: 60 °C
Reaction time: 18 h
Yield: 35.6 %

Procedure:
To a solution of 9.50 g (56.5 mmol) of 4-phenyl-1H-pyrrole-3-carbonitrile (CAS 40167-37-1) in 300 ml of acetonitrile are added portionwise 24.0 g (67.8 mmol) of 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) (SelectFluor—CAS 140681-55-6), with a certain amount of exothermicity being observed. The mixture is stirred for 18 hours at 60° C. After cooling, the reaction medium is concentrated under reduced pressure and the residue is then taken up in 500 ml of ethyl acetate. The solution is washed twice with 250 ml of water and then with saturated aqueous sodium chloride solution. The organic phase is dried over sodium sulfate and the solvent is evaporated off under reduced pressure to give a brown oil, which is chromatographed on a column of silica gel, eluting with a mixture of 15% ethyl acetate in cyclohexane, to give 3.75 g of 5-fluoro-4-phenyl-1H-pyrrole-3-carbonitrile in the form of a red oil after drying, which product is used as obtained for the rest of the synthesis.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[N:17][C:18]3[N:19]([N:22]=[CH:23][C:24]=3[C:25]#[N:26])[C:20]=2Cl)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[NH:33]1[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1>CN(C)C=O.C(OCC)(=O)C>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[N:17][C:18]3[N:19]([N:22]=[CH:23][C:24]=3[C:25]#[N:26])[C:20]=2[N:33]2[CH2:38][CH2:37][O:36][CH2:35][CH2:34]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C1COCCN1
Reactant: N#Cc1cnn2c(Cl)c(-c3ccc(OCc4ccccc4)cc3)cnc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: N#Cc1cnn2c(N3CCOCC3)c(-c3ccc(OCc4ccccc4)cc3)cnc12
Temperature: 160 °C
Yield: 90 %

Procedure:
A solution of 50 mg (0.138 mmol) of 6-(4-benzyloxy-phenyl)-7-chloro-pyrazolo[1,5-a]pyrimidine-3-carbonitrile in 2 mL of dimethylformamide in a 5 mL microwave vessel, was added 25 mg (0.18 mmol) of potassium carbonate, followed by 15 mg (0.166 mmol) of morpholine, and the mixture was heated in a microwave synthesizer (Emrys system from Personal Chemistry, 300 W) at 160° C. for 5 min. Since analysis by LC-MS indicated product formation, the reaction mixture was diluted with ethyl acetate, washed with brine (2 times), dried over sodium sulfate and concentrated to give a residue which was purified via reverse-phase chromatography using Gilson to afford (after lyophilization) desired 6-(4-benzyloxy-phenyl)-7-morpholin-4-yl-pyrazolo[1,5-a]pyrimidine-3-carbonitrile (90% purity) as indicated by 1H NMR; LC-MS—calcd for C24H21N5O2 [M++H]+: 412.17, found: 412.1.
Reaction SMILES: [CH2:1]([O:8][C:9]([C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[NH:16][CH:15]=[CH:14]2)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(Cl)(Cl)(Cl)=O.[OH-].[Na+].CN(C)[CH:29]=[O:30]>>[CH2:1]([O:8][C:9]([C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[NH:16][CH:15]=[C:14]2[CH:29]=[O:30])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(OCc1ccccc1)c1ccc2[nH]ccc2c1
Reactant: CN(C)C=O
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Product: O=Cc1c[nH]c2ccc(C(=O)OCc3ccccc3)cc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 1H-indole-5-carboxylic acid benzyl ester (3.5 g) in N,N-dimethylformamide (30 mL) was added phosphoryl chloride (2.6 g) under ice cooling and this mixture was stirred at room temperature for 2 hours. To this reaction mixture was added 2 mol/L aqueous sodium hydroxide solution until the pH became 6 and this mixture was stirred at 70° C. for 30 minutes. After cooling to ambient temperature, the precipitated solid was collected by filtration, and washed with water and methanol, dried to give the title compound (3.9 g).
Reaction SMILES: [CH:1]([C@@H:4]1[CH2:8][C@@H:7]([C@@H:9]([N:36]=[N+:37]=[N-:38])[CH2:10][C@@H:11]([CH:33]([CH3:35])[CH3:34])[CH:12]([O:27][C:28](=[O:32])[CH:29]([CH3:31])[CH3:30])[C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([CH2:21][CH2:22][O:23][CH2:24][O:25][CH3:26])[CH:14]=2)[O:6][C:5]1=[O:39])([CH3:3])[CH3:2]>C(N)CCC>[CH2:9]([NH:36][C:5](=[O:39])[C@H:4]([CH:1]([CH3:2])[CH3:3])[CH2:8][C@H:7]([OH:6])[C@@H:9]([N:36]=[N+:37]=[N-:38])[CH2:10][C@@H:11]([CH:33]([CH3:34])[CH3:35])[CH:12]([O:27][C:28](=[O:32])[CH:29]([CH3:30])[CH3:31])[C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([CH2:21][CH2:22][O:23][CH2:24][O:25][CH3:26])[CH:14]=1)[CH2:7][CH2:8][CH3:4]
Reactant: COCOCCc1cc(C(OC(=O)C(C)C)[C@@H](C[C@H](N=[N+]=[N-])[C@@H]2C[C@@H](C(C)C)C(=O)O2)C(C)C)ccc1OC
Solvent: CCCCN
Product: CCCCNC(=O)[C@@H](C[C@H](O)[C@H](C[C@@H](C(C)C)C(OC(=O)C(C)C)c1ccc(OC)c(CCOCOC)c1)N=[N+]=[N-])C(C)C

Procedure:
A solution of 170 mg of 3(S)-isopropyl-5(S)-{1(S)-azido-3(S)-isopropyl-4(R,S)-isobutyryloxy-4-[4-methoxy-3-(2-methoxymethoxyethyl)-phenyl]-butyl}-tetrahydrofuran-2-one in 1.4 ml of butylamine is stirred for 16 hours at room temperature and is then concentrated by evaporation. Purification of the residue by means of FC (hexane/ethyl acetate=7:3) yields the title compound: Rf (hexane/ethyl acetate=7:3)=0.25; HPLC Rt =20.38 and 20.8 minutes (diastereoisomeric mixture).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([O:18][CH3:19])[CH:16]=3)[NH:11][C:10](=O)[C:9]=2[C:21]#[N:22])[CH:5]=[CH:6][CH:7]=1.O=P(Cl)(Cl)[Cl:25]>CCOC(C)=O>[Cl:25][C:10]1[C:9]([C:21]#[N:22])=[C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=2)[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([O:18][CH3:19])[CH:16]=2)[N:11]=1
Reactant: COc1ccc2[nH]c(=O)c(C#N)c(-c3cccc(F)c3)c2c1
Reactant: O=P(Cl)(Cl)Cl
Solvent: CCOC(C)=O
Product: COc1ccc2nc(Cl)c(C#N)c(-c3cccc(F)c3)c2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 66 %

Procedure:
A solution of 4-(3-fluorophenyl)-6-methoxy-2-oxo-1,2-dihydroquinoline-3-carbonitrile (1.10 g, 3.74 mmol) in 30 mL of phosphorus oxytrichloride was heated in a sealed pressure tube at 90° C. for 2 hours. The solution was cooled to room temperature and allowed to stand overnight. The mixture was diluted with EtOAc, cooled to 0° C., and quenched by the careful addition of saturated NaHCO3 solution. The organic phase was washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo to provide the titled compound (774 mg, 66%) ESI+ MS: 313.0 [M+H]+.
Reaction SMILES: [O:1]=[C:2]([CH3:9])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].Br[CH2:11][CH2:12]Br.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[C:2]([C:3]1([C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH2:12][CH2:11]1)(=[O:1])[CH3:9]
Reactant: BrCCBr
Reactant: CCOC(=O)CC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C1(C(C)=O)CC1
Temperature: 25 °C
Reaction time: 48 h
Yield: 52.5 %

Procedure:
To a stirred solution of ethyl 3-oxobutanoate (10 mL, 78.45 mmol) and 1,2-dibromoethane (6.5 mL, 78.45 mmol) in 150 mL of DMF was added potassium carbonate (22.7 g, 164.74 mmol). The resulting reaction mixture was stirred at room temperature for 2 days. The solution was diluted with 300 mL of water. The product was extracted into diethyl ether (2×200 mL), and the combined organic extracts were washed with water (1×1000 mL), and dried (MgSO4). Filtration and atmospheric distillation of the ether provided the crude product, which was distilled under reduced pressure (10 mBar) to provide ethyl 1-acetylcyclopropanecarboxylate (6.4273 g, 52%). LCMS: (M+H)+: not detected.
Reaction SMILES: I[C:2]1[C:3]([CH3:20])=[N:4][N:5]([C:12]2[CH:17]=[CH:16][N:15]=[C:14]([O:18][CH3:19])[N:13]=2)[C:6]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8].[Cl:21][C:22]1[CH:29]=[CH:28][C:25]([CH:26]=[O:27])=[CH:24][CH:23]=1>CCCCCC.CCOC(C)=O>[Cl:21][C:22]1[CH:29]=[CH:28][C:25]([CH:26]([OH:27])[C:2]2[C:3]([CH3:20])=[N:4][N:5]([C:12]3[CH:17]=[CH:16][N:15]=[C:14]([O:18][CH3:19])[N:13]=3)[C:6]=2[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:24][CH:23]=1
Reactant: CCOC(=O)c1c(I)c(C)nn1-c1ccnc(OC)n1
Reactant: O=Cc1ccc(Cl)cc1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CCOC(=O)c1c(C(O)c2ccc(Cl)cc2)c(C)nn1-c1ccnc(OC)n1

Procedure:
The title compound was prepared in analogy to the procedure described in Step 1.3 using ethyl 4-iodo-1-(2-methoxypyrimidin-4-yl)-3-methyl-1H-pyrazole-5-carboxylate (Step 59.3) and 4-chlorobenzaldehyde at RT for 60 min. tR: 5.20 min (HPLC 1); tR: 1.18 min (LC-MS 2); ESI-MS: 403 [M+H]+ (LC-MS 2); Rf=0.44 (hexane/EtOAc 1:1).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([NH2:8])[CH:7]=1.[NH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[N+:9]([C:5]1[CH:4]=[CH:3][C:2]([N:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[CH:7][C:6]=1[NH2:8])([O-:11])=[O:10]
Reactant: Nc1cc(Cl)ccc1[N+](=O)[O-]
Reactant: C1CNCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Nc1cc(N2CCNCC2)ccc1[N+](=O)[O-]
Temperature: 150 °C
Reaction time: 18 h
Yield: 70.2 %

Procedure:
A mixture of 5-chloro-2-nitrophenylamine (4.3 g, 25 mmol), piperazine (12.5 g, 145 mmol), and K2CO3 (4.0 g, 29 mmol) in DMF (50 mL) was stirred at 150° C. for 18 h. The reaction mixture was cooled to room temperature, solids were removed by filtration, and the filtrate was concentrated to a red residue. The residue was dissolved in EtOAc (100 mL), washed with water (50 mL), dried with Na2SO4, and concentrated in vacuo to afford the product as a yellow solid (3.9 g, 70%). See, Pharmazie, 39:747 (1984).
Reaction SMILES: CC1[N:3]([C:8]2[N:13]=[CH:12][C:11]([C:14]3[CH2:18][CH:17]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[OH:25])[N:16]([C:26]([C:28]4[S:32][C:31]([C:33]5[CH:47]=[CH:46][CH:45]=[CH:44][C:34]=5[CH2:35][NH:36][C:37](=[O:43])[O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[CH:30][CH:29]=4)=[O:27])[N:15]=3)=[CH:10][CH:9]=2)C(C)=CC=1.Cl.NO.[OH-].[K+]>CCO.O>[NH2:3][C:8]1[N:13]=[CH:12][C:11]([C:14]2[CH2:18][CH:17]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[OH:25])[N:16]([C:26]([C:28]3[S:32][C:31]([C:33]4[CH:47]=[CH:46][CH:45]=[CH:44][C:34]=4[CH2:35][NH:36][C:37](=[O:43])[O:38][C:39]([CH3:40])([CH3:41])[CH3:42])=[CH:30][CH:29]=3)=[O:27])[N:15]=2)=[CH:10][CH:9]=1
Reactant: Cc1ccc(C)n1-c1ccc(C2=NN(C(=O)c3ccc(-c4ccccc4CNC(=O)OC(C)(C)C)s3)C(c3ccccc3O)C2)cn1
Agent: Cl
Agent: NO
Agent: [K+]
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)NCc1ccccc1-c1ccc(C(=O)N2N=C(c3ccc(N)nc3)CC2c2ccccc2O)s1
Temperature: 110 °C
Reaction time: 5 h
Yield: 50.2 %

Procedure:
To a solution of tert-butyl [2-(5-{[3-[6-(2,5-dimethyl-1H-pyrrol-1-yl)pyridin-3-yl]-5-(2-hydroxyphenyl)-4,5-dihydro-1H-pyrazol-1-yl]carbonyl}-2-thienyl)benzyl]carbamate (0.09 g, 0.14 mmol) in EtOH (1.7 mL) and water (0.75 mL) in a round-bottomed flask equipped with a reflux condenser was added hydroxylamine hydrochloride (0.58 g, 8.3 mmol) and potassium hydroxide (0.31 g, 5.6 mmol). The mixture was heated to 110° C. and allowed to stir vigorously for 5 h. The reaction was then cooled to rt and diluted with water. The aqueous solution was extracted with EtOAc. The organic solutions were combined, dried over MgSO4, filtered, and concentrated. The residue was purified by column chromatography to give tert-butyl [2-(5-{[3-(6-aminopyridin-3-yl)-5-(2-hydroxyphenyl)-4,5-dihydro-1H-pyrazol-1-yl]carbonyl}-2-thienyl)benzyl]carbamate as a white solid (0.04 g, 48%). LCMS: (FA) ES+ 570.6 (M+1).
Reaction SMILES: [CH:1]([CH:4]([C:8]1[CH:13]=[CH:12][C:11]([O:14][CH:15]([F:17])[F:16])=[CH:10][CH:9]=1)[C:5](Cl)=[O:6])([CH3:3])[CH3:2].CCl.[C:20]([CH:22]([OH:36])[C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([O:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:24]=1)#[N:21].N1C=CC=CC=1>C(Cl)Cl>[CH:1]([CH:4]([C:8]1[CH:13]=[CH:12][C:11]([O:14][CH:15]([F:17])[F:16])=[CH:10][CH:9]=1)[C:5]([O:36][CH:22]([C:20]#[N:21])[C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([O:29][C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:24]=1)=[O:6])([CH3:3])[CH3:2]
Reactant: N#CC(O)c1cccc(Oc2ccccc2)c1
Reactant: CC(C)C(C(=O)Cl)c1ccc(OC(F)F)cc1
Agent: CCl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)C(C(=O)OC(C#N)c1cccc(Oc2ccccc2)c1)c1ccc(OC(F)F)cc1
Yield: 24.8 %

Procedure:
A solution of α-isopropyl-4-difluoromethoxyphenylacetyl chloride (4.82 g) in methylene chloride (10 ml) is added to a methyl chloride solution (10 ml) of α-cyano-m-phenoxybenzyl alcohol (4.05 g) and pyridine (1.5 ml). The mixture is stirred over the weekend and filtered. The filtrate and the washings are evaporated and the residual oil (6.29 g) is purified on a silica column using 1:1 methylenechloride-hexane as eluent. The solvent was evaporated and the residue treated with sodium borohydride and the resulting product purified on a silica gel column to give 2.01 g of product.
Reaction SMILES: [CH3:1][C:2]1[C:10]([O:11][C@H:12]2[CH2:17][CH2:16][C@H:15]([N:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)[CH2:14][CH2:13]2)=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][N:6]2C1CCCCO1.Cl.O1CCOCC1>C(O)(C)C>[CH3:1][C:2]1[C:10]([O:11][C@H:12]2[CH2:13][CH2:14][C@H:15]([N:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)[CH2:16][CH2:17]2)=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][NH:6]2
Reactant: Cc1c(O[C@H]2CC[C@H](N3CCCC3)CC2)ccc2c1cnn2C1CCCCO1
Agent: Cl
Solvent: CC(C)O
Solvent: C1COCCO1
Product: Cc1c(O[C@H]2CC[C@H](N3CCCC3)CC2)ccc2[nH]ncc12

Procedure:
A mixture of 4-methyl-5-[(trans-4-pyrrolidin-1-ylcyclohexyl)oxy]-1-tetrahydro-2H-pyran-2-yl-1H-indazole (62.1 mg, 0.162 mmol), a 4N-hydrochloric acid/dioxane solution (2.0 ml) and isopropanol (2.0 ml) was stirred at room temperature for 4 hours. The solvent was distilled off and a 1N-aqueous sodium hydroxide solution (20 ml) was added to the residue, followed by extraction with ethyl acetate (20 ml) (twice). The extract solution was dried over magnesium sulfate and then concentrated to dryness, and the residue oil was purified by elution by a silica gel column chromatography (hexane/ethyl acetate/triethylamine=20:40:3) to obtain 4-methyl-5-[(trans-4-pyrrolidin-1-ylcyclohexyl)oxy]-1H-indazole (28.3 mg, 58%).
Reaction SMILES: CO[C:3]([C:5]1[S:9][C:8](/[CH:10]=[CH:11]/[C:12]2[C:13]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[N:14][O:15][C:16]=2[CH3:17])=[N:7][C:6]=1C)=[O:4].[CH2:25]([CH2:27][NH2:28])[OH:26]>>[OH:26][CH2:25][CH2:27][NH:28][C:3]([C:5]1[S:9][C:8](/[CH:10]=[CH:11]/[C:12]2[C:13]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)=[N:14][O:15][C:16]=2[CH3:17])=[N:7][CH:6]=1)=[O:4]
Reactant: COC(=O)c1sc(/C=C/c2c(-c3ccccc3)noc2C)nc1C
Reactant: NCCO
Product: Cc1onc(-c2ccccc2)c1/C=C/c1ncc(C(=O)NCCO)s1
Yield: 63 %

Procedure:
As described for example 66, 4-methyl-2-[(E)-2-(5-methyl-3-phenyl-isoxazol-4-yl)-vinyl]-thiazole-5-carboxylic acid methyl ester (55 mg, 0.17 mmol) was converted, using ethanolamine instead of rac-2-amino-1-propanol, to the title compound (34 mg, 63%) which was obtained as a light yellow solid. MS: m/e=356.2 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1([CH3:28])[C:11](=O)[C:10]([CH3:14])([CH3:13])[C:9]2[C:4](=[C:5]3[CH2:27][CH2:26][CH2:25][C:6]3=[C:7]([C:15]3[CH:24]=[CH:23][CH:22]=[C:21]4[C:16]=3[CH:17]=[CH:18][CH:19]=[N:20]4)[CH:8]=2)[NH:3]1.[CH3:29]C1C(C2C=C3C(=C4CCCC=24)NC(C)(C)C(=C)C3(C)C)=C(C)ON=1>>[CH3:1][C:2]1([CH3:28])[C:11](=[CH2:29])[C:10]([CH3:14])([CH3:13])[C:9]2[C:4](=[C:5]3[CH2:27][CH2:26][CH2:25][C:6]3=[C:7]([C:15]3[CH:24]=[CH:23][CH:22]=[C:21]4[C:16]=3[CH:17]=[CH:18][CH:19]=[N:20]4)[CH:8]=2)[NH:3]1
Reactant: CC1(C)Nc2c(cc(-c3cccc4ncccc34)c3c2CCC3)C(C)(C)C1=O
Reactant: C=C1C(C)(C)Nc2c(cc(-c3c(C)noc3C)c3c2CCC3)C1(C)C
Product: C=C1C(C)(C)Nc2c(cc(-c3cccc4ncccc34)c3c2CCC3)C1(C)C
Yield: 21 %

Procedure:
Using 2,2,4,4-tetramethyl-6-(quinolin-5-yl)-2,3,4,7,8,9-hexahydro-1H-cyclopenta[h]quinolin-3-one obtained in Example instead of 6-(3,5-dimethylisoxazol-4-yl)-2,2,4,4-tetramethyl-2,3,4,7,8,9-hexahydro-1H-cyclopenta[h]quinolin-3-one of Example 23 and according to a similar method, the title compound (13 mg, 21%) was obtained.