Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:4][CH2:5][CH2:6][CH2:7][N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([C:17]2[C:18](=[O:33])[O:19][C:20](=O)[C:21]=2[C:22]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[N:24]([CH3:31])[CH:23]=2)=[CH:9]1)(=O)C.O.C[N:36](C=O)C>N>[OH:4][CH2:5][CH2:6][CH2:7][N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([C:17]2[C:18](=[O:33])[NH:36][C:20](=[O:19])[C:21]=2[C:22]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[N:24]([CH3:31])[CH:23]=2)=[CH:9]1
Reactant: CC(=O)OCCCn1cc(C2=C(c3cn(C)c4ccccc34)C(=O)OC2=O)c2ccccc21
Reactant: CN(C)C=O
Agent: N
Solvent: O
Product: Cn1cc(C2=C(c3cn(CCCO)c4ccccc34)C(=O)NC2=O)c2ccccc21

Procedure:
A solution of 200 mg of 3-[1-(3-acetoxypropyl)-3-indolyl]-4-(1-methyl-3-indolyl)furan-2,5-dione in 1 ml of DMF and 2 ml of 33% aqueous ammonia was heated to 100° C. for 2 hours. 50 ml of water were added and the resulting solid was filtered off, dried and recrystallized from ethyl acetate to give 85 mg of 3-[1-(3-hydroxypropyl)-3-indolyl]-4-(1-methyl-3-indolyl)-1H-pyrrole-2,5-dione, m.p. 185°-187° C.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])[CH2:4][C@H:5]([CH2:9][NH:10][C:11](=[O:24])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[O:18][CH2:19][CH2:20][CH2:21][O:22][CH3:23])[CH:6]([CH3:8])[CH3:7].C(N(CC)CC)C>ClCCl.CS(C)=O>[CH:2]([C@@H:3]([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:29])([CH3:31])[CH3:30])[CH2:4][C@H:5]([CH2:9][NH:10][C:11](=[O:24])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[O:18][CH2:19][CH2:20][CH2:21][O:22][CH3:23])[CH:6]([CH3:7])[CH3:8])=[O:1]
Reactant: COCCCOc1ccccc1C(=O)NC[C@@H](C[C@@H](CO)NC(=O)OC(C)(C)C)C(C)C
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: COCCCOc1ccccc1C(=O)NC[C@@H](C[C@@H](C=O)NC(=O)OC(C)(C)C)C(C)C
Temperature: 0 °C
Reaction time: 1 h

Procedure:
The solution of 2.65 g of tert-butyl (1(S)-hydroxymethyl-3(S)-{[2-(3-methoxypropoxy)-benzoylamino]methyl}-4-methylpentyl)carbamate, 2.44 ml of triethylamine in 20 ml of dichloromethane is cooled to 0° C. The solution of 3.07 g of sulphur trioxide-pyridine complex in 12 ml of dimethyl sulphoxide is added dropwise over 1 hour and then the mixture is stirred for another 1 hour. The reaction mixture is admixed with 20 ml of ice-water and extracted with dichloromethane (3×). The combined organic phases are washed with 10% aqueous sodium hydrogensulphate solution, water, 1M sodium hydrogencarbonate solution and brine, dried over sodium sulphate and concentrated by evaporation. The title compound is obtained as a slightly yellowish foam. Rf=0.33 (3:1 EtOAc-heptane); Rt=4.65 (gradient I).
Reaction SMILES: C([O:3][C:4](=[O:33])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([NH:13][C:14](=[O:32])[C:15](=[O:31])[C:16]2[N:24]3[C:19]([CH:20]=[CH:21][CH:22]=[CH:23]3)=[CH:18][C:17]=2[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:8]=1)C.[OH-].[Li+]>CO.O>[O:31]=[C:15]([C:16]1[N:24]2[C:19]([CH:20]=[CH:21][CH:22]=[CH:23]2)=[CH:18][C:17]=1[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:14]([NH:13][C:9]1[CH:8]=[C:7]([CH:12]=[CH:11][CH:10]=1)[O:6][CH2:5][C:4]([OH:33])=[O:3])=[O:32]
Reactant: CCOC(=O)COc1cccc(NC(=O)C(=O)c2c(-c3ccccc3)cc3ccccn23)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)COc1cccc(NC(=O)C(=O)c2c(-c3ccccc3)cc3ccccn23)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 53.6 %

Procedure:
To a solution of {3-[2-Oxo-2-(2-phenyl-indolizin-3-yl)-acetylamino]-phenoxy}-acetic acid ethyl ester (0.4 g, 0.90 mmol) in methanol (3 ml) was added lithium hydroxide (38 mg, 1.8 mmol) and a few drops of water. The reaction mixture was stirred at room temperature for 30 min, and then concentrated under reduced pressure. The reaction mixture was diluted with water (10 ml) and adjusted to pH 3 with 2N hydrochloric acid. The product was extracted with ether and the organic layer dried over sodium sulphate, filtered, then evaporated to dryness to yield {3-[2-oxo-2-(2-phenyl-indolizin-3-yl)-acetylamino]-phenoxy}-acetic acid (0.2 g, 53%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:13]=1[N:12]=[CH:11][C:10]([N:14]1[CH:20]3[CH2:21][CH2:22][N:17]([CH2:18][CH2:19]3)[CH2:16][CH2:15]1)=[CH:9]2)([O-])=O>O.C(O)(=O)C.[Fe]>[NH2:1][C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:13]=1[N:12]=[CH:11][C:10]([N:14]1[CH:20]3[CH2:19][CH2:18][N:17]([CH2:22][CH2:21]3)[CH2:16][CH2:15]1)=[CH:9]2
Reactant: O=[N+]([O-])c1cccc2cc(N3CCN4CCC3CC4)cnc12
Agent: [Fe]
Solvent: CC(=O)O
Solvent: O
Product: Nc1cccc2cc(N3CCN4CCC3CC4)cnc12
Temperature: 40 °C

Procedure:
0.8 g (2.7 mmol) of 4-(8-nitroquinolin-3-yl)-1,4-diazabicyclo[3.2.2]nonane, in suspension in a mixture of 8 ml of water and 4 ml of acetic acid, is introduced into a 25 ml three-necked round-bottomed flask and the suspension is heated at 40° C.; 0.43 g (7.7 mmol) of iron are then added, in two portions, and the mixture is heated at 50° C. for 1 h.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@H:9]([CH2:13][CH:14]=[CH2:15])[C:10](=O)[CH3:11])[CH:5]=[CH:6][C:7]=1[Cl:8].Cl.CN.[CH2:19]([N:21](CC)CC)C.C([BH3-])#N.[Na+].C(=O)(O)[O-].[Na+]>CO.C(OCC)(=O)C.O>[CH3:19][NH:21][CH:10]([C@H:9]([C:4]1[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=1)[CH2:13][CH:14]=[CH2:15])[CH3:11]
Reactant: CCN(CC)CC
Reactant: C=CC[C@H](C(C)=O)c1ccc(Cl)c(Cl)c1
Agent: CN
Agent: Cl
Agent: O=C([O-])O
Solvent: CO
Solvent: O
Solvent: CCOC(C)=O
Product: C=CC[C@@H](c1ccc(Cl)c(Cl)c1)C(C)NC
Temperature: 22 °C
Reaction time: 20 h

Procedure:
A mixture of 102 mg (0.42 mmol) of 3-(S)-(3,4-dichlorophenyl)-5-hexen-2-one (from Step 2 above), 170 mg (2.52 mmol) of methylamine hydrochloride, and 234 μl (1.68 mmol) of triethylamine in 4.0 mL of methanol was treated with 16 mg (0.25 mmol) of sodium cyanoborohydride and stirred at 22° C. for 20 hours. Saturated aqueous sodium bicarbonate solution (1.0 mL) was added and the resulting milky mixture was diluted with 5.0 mL of ethyl acetate and 5.0 mL of water. The layers were separated and the organic layer was washed with water (3×5 mL). The aqueous layers were extracted with 10 mL of ethyl acetate. The combined organic layers were washed with 10 mL of saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography on 42 g of silica gel using 10:1 v/v ether/ hexane as the eluant afforded 64 mg of the higher Rf isomer (Isomer A) and 22 mg of a lower Rf isomer (Isomer B) both as yellow oils.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][C@H:9]2[CH2:14][CH2:13][CH2:12][C:11](=[O:15])[CH2:10]2)[C:5]([F:16])=[CH:4][N:3]=1.Br[CH2:18][CH:19]=[CH2:20].[NH4+].[Cl-]>CN(C=O)C.[Zn]>[CH2:20]([C:11]1([OH:15])[CH2:12][CH2:13][CH2:14][C@H:9]([NH:8][C:6]2[C:5]([F:16])=[CH:4][N:3]=[C:2]([Cl:1])[N:7]=2)[CH2:10]1)[CH:19]=[CH2:18]
Reactant: C=CCBr
Reactant: O=C1CCC[C@H](Nc2nc(Cl)ncc2F)C1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CN(C)C=O
Product: C=CCC1(O)CCC[C@H](Nc2nc(Cl)ncc2F)C1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of (3S)-3-[(2-chloro-5-fluoro-pyrimidin-4-yl)amino]cyclohexanone, 29b, (0.60 g, 2.46 mmol) and 3-bromoprop-1-ene (0.43 mL, 4.92 mmol) in DMF was added Zn dust (0.32 g, 4.92 mmol). The reaction was stirred at room temperature for 3 days. The mixture was diluted into aqueous saturated NH4Cl solution, extracted twice with EtOAc. The combined organic phases were washed twice with brine, dried (MgSO4), filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography using 0-50% EtOAc/hexanes gradient to afford 553 mg of desired product, 58a, as an oil. LC/MS-two peaks corresponding to two diastereomeric products: 286.4 (M+H), RT=3.41 and 3.78.
Reaction SMILES: FC1C=C(C2OC3(CCN([C:18]([C:20]4[CH:25]=[CH:24][C:23]([O:26][CH:27]([CH3:29])[CH3:28])=[C:22]([CH3:30])[CH:21]=4)=[O:19])CC3)CC(O)C=2)C=NC=1.[H-].[Na+].C(I)C>C(O)C.[Pd]>[CH:27]([O:26][C:23]1[CH:24]=[CH:25][C:20]([CH:18]=[O:19])=[CH:21][C:22]=1[CH3:30])([CH3:29])[CH3:28]
Reactant: Cc1cc(C(=O)N2CCC3(CC2)CC(O)C=C(c2cncc(F)c2)O3)ccc1OC(C)C
Agent: [Pd]
Agent: [H-]
Agent: [Na+]
Solvent: CCI
Solvent: CCO
Product: Cc1cc(C=O)ccc1OC(C)C
Temperature: 25 °C
Reaction time: 12 h
Yield: 293.5 %

Procedure:
A solution of [10-(5-fluoro-3-pyridyl)-8-hydroxy-11-oxa-3-azaspiro[5.5]undec-9-en-3-yl]-(4-isopropoxy-3-methyl-phenyl)methanone (56 mg, 0.13 mmol) in ethanol (4.4 mL) was purged with nitrogen for 5 min and treated with 10% palladium on carbon (13 mg, 0.012 mmol). The mixture was evacuated and put under a hydrogen atmosphere (balloon). The reaction mixture was stirred for 12 h at 25° C. The reaction mixture was evacuated and put under an inert atmosphere and re-charged with 10% palladium on carbon (54 mg, 0.05 mmol). The mixture was evacuated and put under a hydrogen atmosphere (balloon) and stirred for 4 h. The reaction mixture was evacuated and put under an inert atmosphere. The Pd-catalyst was removed via filtration and was washed with ethyl acetate. The filtrate was concentrated to dryness and dissolved in DMF (2.4 mL). The mixture was cooled to 0° C. and treated with 60% NaH (28 mg, 1.19 mmol) and ethyl iodide (95 μL, 1.2 mmol). The reaction mixture was warmed to 25° C. and stirred for 2 h. The reaction mixture was quenched by the addition of methanol and partitioned between water and ethyl acetate. The layers were separated and the aqueous layer was extracted with ethyl acetate (3×50 mL). The combined organics were washed with saturated aqueous sodium chloride, dried over sodium sulfate, filtered, and concentrated under reduced pressure. Purification by reverse phase HPLC (1-100% acetonitrile in water, no modifier) afforded cis-4-ethoxy-2-(5-fluoropyridin-3-yl)-1-oxa-9-azaspiro[5.5]undecan-9-yl)(4-isopropoxy-3-methylphenyl)methanone (68 mg) ESI-MS m/z calc. 470.26, found 471.2 (M+1)+; Retention time: 1.453 minutes (3 min run).
Reaction SMILES: C([O-])(C)(C)C.[K+].[C:7]([O:15][CH2:16][CH3:17])(=[O:14])[CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10].Br[C:19]1[C:20](=[O:37])[N:21]([C:25]2[CH:30]=[CH:29][C:28]([N+:31]([O-:33])=[O:32])=[CH:27][C:26]=2[CH2:34][O:35][CH3:36])[CH:22]=[CH:23][CH:24]=1>O1CCOCC1.C(OCC)(=O)C.Cl>[CH2:16]([O:15][C:7](=[O:14])[CH:8]([C:19]1[C:20](=[O:37])[N:21]([C:25]2[CH:30]=[CH:29][C:28]([N+:31]([O-:33])=[O:32])=[CH:27][C:26]=2[CH2:34][O:35][CH3:36])[CH:22]=[CH:23][CH:24]=1)[C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH3:17]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: COCc1cc([N+](=O)[O-])ccc1-n1cccc(Br)c1=O
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CCOC(=O)C(C(=O)OCC)c1cccn(-c2ccc([N+](=O)[O-])cc2COC)c1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Under argon, a suspension of 49.3 g (513 mmol) of potassium tert-butanolate was introduced as initial charge at RT in 360 ml of dioxane, and 82.2 g (513 mmol) of diethyl malonate were added such that the temperature remained below 30° C. The reaction mixture was stirred for 1 h at RT, 3.4 g (11.0 mmol) of bis(2-pyridinecarboxylato)copper(II) complex and 49.7 g (147 mmol) of 3-bromo-1-[2-(methoxymethyl)-4-nitrophenyl]pyridin-2(1H)-one were added and the mixture was stirred for 4.5 h at 95° C. A further 2.0 g (6.5 mmol) of bis(2-pyridinecarboxylato)copper(II) complex were added and the reaction mixture was stirred overnight at 95° C. After cooling to RT, the mixture was diluted with 0.9 l of ethyl acetate, 1.8 l of 3N hydrochloric acid were added and the mixture was stirred for 15 min at RT. The aqueous phase was extracted with 0.9 l of ethyl acetate and the combined organic phases were washed with saturated aqueous sodium chloride solution. After drying over sodium sulphate, filtration and removal of the solvent on a rotary evaporator, the residue was dried in vacuo. This gave 115 g of crude product, which was reacted further without purification.
Reaction SMILES: Cl.[C:2]([C:6]1[CH:19]=[CH:18][CH:17]=[CH:16][C:7]=1[O:8][CH2:9][CH:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1)([CH3:5])([CH3:4])[CH3:3].C(N(CC)CC)C.[CH3:27][C:28]1([CH3:35])[CH2:32][C:31](=[O:33])[O:30][C:29]1=[O:34]>C1COCC1>[C:2]([C:6]1[CH:19]=[CH:18][CH:17]=[CH:16][C:7]=1[O:8][CH2:9][CH:10]1[CH2:15][CH2:14][N:13]([C:31](=[O:33])[CH2:32][C:28]([CH3:35])([CH3:27])[C:29]([OH:34])=[O:30])[CH2:12][CH2:11]1)([CH3:5])([CH3:3])[CH3:4]
Reactant: CC(C)(C)c1ccccc1OCC1CCNCC1
Reactant: CC1(C)CC(=O)OC1=O
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(CC(=O)N1CCC(COc2ccccc2C(C)(C)C)CC1)C(=O)O
Temperature: 25 °C
Yield: 71.3 %

Procedure:
To an ice-cold stirred solution of 4-[(2-tert-butylphenoxy)methyl]piperidine hydrochloride (0.20 g, 0.71 mmol) and triethylamine (0.10 g, 1.0 mmol) in THF (20.0 mL) was added 3,3-dimethyldihydrofuran-2,5-dione (0.11 g, 0.87 mmol) and the resulting mixture was warmed to room temperature. After 16 h the reaction mixture was concentrated under reduced pressure. The residue was partitioned between ethyl acetate and 1N hydrochloric acid and separated. The organic layer was washed with saturated sodium chloride, dried (MgSO4), filtered and concentrated under reduced pressure to give a white solid. The solid was recrystallized from hexane/ethyl acetate to provide 4-{4-[(2-tert-butylphenoxy)methyl]piperidin-1-yl}-2,2-dimethyl-4-oxobutanoic acid (0.19 g, 72%) as a white powder.
Reaction SMILES: [CH2:1]([N:4]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:5][C:6](OC)=[O:7])[CH:2]=[CH2:3].C1([Mg]Cl)CCCC1>C1COCC1>[CH2:10]([N:4]1[CH2:1][C@H:2]2[C@:6]([OH:7])([CH2:3]2)[CH2:5]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: C=CCN(CC(=O)OC)Cc1ccccc1
Agent: Cl[Mg]C1CCCC1
Solvent: C1CCOC1
Product: O[C@]12C[C@H]1CN(Cc1ccccc1)C2
Reaction time: 4 h
Yield: 72.5 %

Procedure:
To a solution of methyl 2-(allyl(benzyl)amino)acetate (0.76 g, 3.5 mmol, 1.0 eq) in anhydrous THF (50 mL) at 20° C. under N2 was added ClTi(OiPr)3 (3.50 mL, 3.50 mmol, 1.0 eq) followed by cyclopentylmagnesium chloride (7.80 mL, 15.6 mmol, 4.5 eq) dropwise via a syringe pump over 4 h. The reaction mixture was quenched with a little of water and extracted with EtOAc (20 mL×3). The combined organic phases were washed with water followed by brine, dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by a silica gel column chromatography (1:1 (v/v) PE/EtOAc) to afford the title compound as colorless oil (0.48 g, 73%). The compound was characterized by the following spectroscopic data: MS (ESI, pos. ion) m/z: 190.2 (M+1); 1H NMR (400 MHz, CDCl3) δ: 0.83 (2H, m), 1.09 (1H, t, J=4.8 Hz), 1.36 (1H, m), 2.57 (2H, m), 2.72 (1H, d, J=8.8 Hz), 3.05 (1H, d, J=8.4 Hz), 3.60 (2H, s), 7.25 (5H, m) ppm.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH2:13])[CH:5]=[CH:6][C:7]=1[N:8]1[CH:12]=[CH:11][N:10]=[CH:9]1.[CH2:14]([C:21]1[CH:26]=[C:25]([CH3:27])[N:24]=[C:23](Cl)[N:22]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[CH2:14]([C:21]1[CH:26]=[C:25]([CH3:27])[N:24]=[C:23]([NH:13][C:4]2[CH:5]=[CH:6][C:7]([N:8]3[CH:12]=[CH:11][N:10]=[CH:9]3)=[C:2]([F:1])[CH:3]=2)[N:22]=1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: Cc1cc(Cc2ccccc2)nc(Cl)n1
Reactant: Nc1ccc(-n2ccnc2)c(F)c1
Product: Cc1cc(Cc2ccccc2)nc(Nc2ccc(-n3ccnc3)c(F)c2)n1

Procedure:
The title compound was prepared from 3-fluoro-4-imidazol-1-yl-phenylamine (81 mg, 0.46 mmol) and 4-benzyl-2-chloro-6-methyl-pyrimidine (100 mg, 0.46 mmol) in analogous manner to the procedure described in example 1e). Obtained as a light yellow wax (40 mg, 24%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]([N:11]2[CH2:14][CH:13]([NH:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=3)[CH2:12]2)=[C:6]([CH:10]=1)[C:7]([OH:9])=O.Cl.[NH2:24][C:25]1([C:28]2[CH:37]=[CH:36][C:31]([C:32]([O:34][CH3:35])=[O:33])=[CH:30][CH:29]=2)[CH2:27][CH2:26]1>>[Cl:1][C:2]1[CH:3]=[N:4][C:5]([N:11]2[CH2:14][CH:13]([NH:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=3)[CH2:12]2)=[C:6]([CH:10]=1)[C:7]([NH:24][C:25]1([C:28]2[CH:37]=[CH:36][C:31]([C:32]([O:34][CH3:35])=[O:33])=[CH:30][CH:29]=2)[CH2:27][CH2:26]1)=[O:9]
Reactant: COC(=O)c1ccc(C2(N)CC2)cc1
Reactant: O=C(O)c1cc(Cl)cnc1N1CC(Nc2cccc(F)c2)C1
Agent: Cl
Product: COC(=O)c1ccc(C2(NC(=O)c3cc(Cl)cnc3N3CC(Nc4cccc(F)c4)C3)CC2)cc1
Yield: 27.7 %

Procedure:
The title compound (D166) (17 mg) was prepared according to the experimental procedure described in Description 144 starting from 5-chloro-2-(3-((3-fluorophenyl)amino)azetidin-1-yl)nicotinic acid (D116) (40 mg, 0.124 mmol) and methyl 4-(1-aminocyclopropyl)benzoate (D7) (28.3 mg, 0.124 mmol).
Reaction SMILES: C[Sn]1(C)[C:9]2[CH:8]=[CH:7][S:6][C:5]=2[C:4]2[S:10][CH:11]=[CH:12][C:3]1=2.Br[C:15](Br)=[CH:16][CH2:17][CH2:18][CH3:19]>C1COCC1.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[CH:16](=[C:15]1[C:9]2[CH:8]=[CH:7][S:6][C:5]=2[C:4]2[S:10][CH:11]=[CH:12][C:3]1=2)[CH2:17][CH2:18][CH3:19]
Reactant: C[Sn]1(C)c2ccsc2-c2sccc21
Reactant: CCCC=C(Br)Br
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Solvent: C1CCOC1
Product: CCCC=C1c2ccsc2-c2sccc21
Reaction time: 8 h
Yield: 30.9 %

Procedure:
500 mg (1.6 mmol) of 52 and 364 mg (1.6 mmol) of dibromopentene were dissolved in 32 ml of freshly distilled THF, and 42 mg (80 μmol) of bis(tri-tert-butylphosphine)palladium(0) were added. The reaction mixture was refluxed while stirring for 8 hours. THF was removed by rotary evaporation and the residue was taken up in n-hexane. The crude product was purified by means of column chromatography (n-hexane as the eluent (Rf=0.4)) to obtain 115 mg of the target compound 53 (37% yield). GC-MS m/z 232 (18.10 min).
Reaction SMILES: [CH3:1][N:2]([CH3:19])[C:3](=[O:18])[C@H:4]([O:6][C:7]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:8]=1[C:9](=O)[NH:10][CH:11]=[N:12]2)[CH3:5].[NH2:20][C:21]1[CH:22]=[C:23]2[C:27](=[CH:28][CH:29]=1)[N:26]([CH2:30][C:31]1[CH:38]=[CH:37][CH:36]=[CH:35][C:32]=1[C:33]#[N:34])[N:25]=[CH:24]2>>[C:33]([C:32]1[CH:35]=[CH:36][CH:37]=[CH:38][C:31]=1[CH2:30][N:26]1[C:27]2[C:23](=[CH:22][C:21]([NH:20][C:9]3[C:8]4[C:13](=[CH:14][CH:15]=[CH:16][C:7]=4[O:6][C@H:4]([CH3:5])[C:3]([N:2]([CH3:19])[CH3:1])=[O:18])[N:12]=[CH:11][N:10]=3)=[CH:29][CH:28]=2)[CH:24]=[N:25]1)#[N:34]
Reactant: C[C@@H](Oc1cccc2nc[nH]c(=O)c12)C(=O)N(C)C
Reactant: N#Cc1ccccc1Cn1ncc2cc(N)ccc21
Product: C[C@@H](Oc1cccc2ncnc(Nc3ccc4c(cnn4Cc4ccccc4C#N)c3)c12)C(=O)N(C)C
Yield: 81 %

Procedure:
Using the same procedure as in Example 18, (2R)—N,N-dimethyl-2-[(4-oxo-3,4-dihydroquinazolin-5-yl)oxy]propanamide (220 mg, 0.84 mmol) and 2-[(5-amino-1H-indazol-1-yl)methyl]benzonitrile (1.1 equivalents) were reacted to give the title compound as a beige foam (334 mg, 81%); NMR spectrum (CDCl3) 1.72 (d, 3H), 3.06 (s, 3H), 3.14 (s, 3H), 5.43 (q, 1H), 5.83 (s, 2H), 6.81 (d, 1H), 7.01 (d, 1H), 7.37 (t, 1H), 7.42-7.47 (m, 3H), 7.60 (t, 1H), 7.70 (d, 1H), 7.86 (d, 1H), 8.10 (s, 1H), 8.47 (s, 1H), 8.62 (s, 1H), 10.92 (br s, 1H); Mass spectrum MH+ 492.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:3]=1[CH:4]=O.[CH:11]1([NH2:14])[CH2:13][CH2:12]1.[BH4-].[Na+]>CO>[CH:11]1([NH:14][CH2:4][C:3]2[CH:6]=[CH:7][C:8]([Cl:10])=[CH:9][C:2]=2[Cl:1])[CH2:13][CH2:12]1
Reactant: O=Cc1ccc(Cl)cc1Cl
Reactant: NC1CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Clc1ccc(CNC2CC2)c(Cl)c1
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
5.25 g (30 mmol) of 2,4-dichlorobenzaldehyde was introduced into 140 ml of methanol and, at room temperature, a solution of 1.71 g (30 mmol) of cyclopropylamine was added. The mixture as stirred at room temperature for 40 min and then 1.42 g (37.5 mmol) of NaBH4 was added in portions. After standing overnight, the solvent was removed and the residue was taken up in 2 N HCl. Two extractions with ethyl acetate were carried out. The aqueous phase was made alkaline with NaOH and again extracted twice with ethyl acetate. The organic phases were dried with MgSO4 and concentrated. The crude product obtained in this way, in the form of a slightly yellowish oil, was reacted further without further purification.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][N:11]2[CH2:14][C@H:15]([OH:17])[CH2:16][C@H:10]2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(C)([O-])C.[K+].O1CCCC1.F[C:30]1[CH:31]=[CH:32][C:33]([C:36]([F:39])([F:38])[F:37])=[N:34][CH:35]=1>CS(C)=O>[CH2:1]([N:8]1[CH2:13][CH2:12][N:11]2[CH2:14][C@H:15]([O:17][C:30]3[CH:35]=[N:34][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:32][CH:31]=3)[CH2:16][C@H:10]2[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O[C@@H]1C[C@H]2CN(Cc3ccccc3)CCN2C1
Reactant: Fc1ccc(C(F)(F)F)nc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: C1CCOC1
Product: FC(F)(F)c1ccc(O[C@@H]2C[C@H]3CN(Cc4ccccc4)CCN3C2)cn1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of (7R,8aS)-2-benzyloctahydropyrrolo[1,2-a]pyrazin-7-ol (Example 19D, 0.103 g, 0.443 mmol) in dimethyl sulfoxide (4 mL) was added a 1.0 M solution of potassium tert-butoxide in tetrahydrofuran (0.665 mL, 0.665 mmol), and the resulting suspension was stirred at room temperature for 5 minutes. 5-Fluoro-2-(trifluoromethyl)pyridine (0.137 g, 0.829 mmol) was added, and the reaction mixture was stirred at room temperature for 48 hours. The mixture was partitioned between ethyl acetate and water, and the organic extract was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. Purification by column chromatography on silica gel using a solvent gradient of 0-95% ethyl acetate in hexane gave the titled compound. MS (APCI) m/z 378.4 (M+H)+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[C:8]([C:15]2[C:24]3[C:19](=[CH:20][C:21]([OH:25])=[CH:22][CH:23]=3)[N:18]=[CH:17][CH:16]=2)=[C:9]2[CH2:14][CH2:13][CH2:12][N:10]2[N:11]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:33][CH2:34][O:35][CH:36]1[CH2:41][CH2:40][CH2:39][CH2:38][O:37]1>CN(C=O)C>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[C:8]([C:15]2[C:24]3[C:19](=[CH:20][C:21]([O:25][CH2:33][CH2:34][O:35][CH:36]4[CH2:41][CH2:40][CH2:39][CH2:38][O:37]4)=[CH:22][CH:23]=3)[N:18]=[CH:17][CH:16]=2)=[C:9]2[CH2:14][CH2:13][CH2:12][N:10]2[N:11]=1
Reactant: Oc1ccc2c(-c3c(-c4ccccn4)nn4c3CCC4)ccnc2c1
Reactant: BrCCOC1CCCCO1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: c1ccc(-c2nn3c(c2-c2ccnc4cc(OCCOC5CCCCO5)ccc24)CCC3)nc1
Yield: 81 %

Procedure:
Heat 4-(2-pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-quinolin-7-ol (376 mg, 1.146 mmol), cesium carbonate (826 mg, 2.54 mmol), and 2-(2-bromoethoxy)tetrahydro-2H-pyran (380 μL, 2.52 mmol) in DMF (5 mL) at 120° C. for 4 hours. Quench the reaction with saturated sodium chloride and then extract with chloroform. Dry the organic layer over sodium sulfate and concentrate in vacuo. Purify the reaction mixture on a silica gel column eluting with dichloromethane to 10% methanol in dichloromethane to give the desired subtitled intermediate as a yellow oil (424 mg, 81%). MS ES+ m/e 457.0 (M+1).