Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:15]2[S:16][C:17]([CH2:20]Cl)=[CH:18][CH:19]=2)[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)=[O:5])[CH3:2].[CH:22]1([C:25]2[NH:26][C:27]3[C:28]([N:35]=2)=[N:29][C:30]([CH3:34])=[CH:31][C:32]=3[CH3:33])[CH2:24][CH2:23]1>>[CH2:1]([O:3][C:4]([C:6]1([C:15]2[S:16][C:17]([CH2:20][N:35]3[C:28]4=[N:29][C:30]([CH3:34])=[CH:31][C:32]([CH3:33])=[C:27]4[N:26]=[C:25]3[CH:22]3[CH2:24][CH2:23]3)=[CH:18][CH:19]=2)[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)=[O:5])[CH3:2]
Reactant: Cc1cc(C)c2[nH]c(C3CC3)nc2n1
Reactant: CCOC(=O)C1(c2ccc(CCl)s2)Cc2ccccc2C1
Product: CCOC(=O)C1(c2ccc(Cn3c(C4CC4)nc4c(C)cc(C)nc43)s2)Cc2ccccc2C1

Procedure:
The product of Example 6, Step 4, above (26), was alkylated as described in Example 1, Step 5, using 2-cyclopropyl-5,7-dimethylimidazo[4,5-b]pyridine (13) to obtain the title compound (29).
Reaction SMILES: [CH3:1][C:2]([CH3:37])([O:4][C:5]([NH:7][C@H:8]([C:34]([OH:36])=[O:35])[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17]([O:19][CH2:20][CH:21]2[C:33]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[C:27]3[C:22]2=[CH:23][CH:24]=[CH:25][CH:26]=3)=[O:18])=[CH:12][CH:11]=1)=[O:6])[CH3:3].[CH2:38](Br)[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>CN(C=O)C>[C:39]1([CH2:38][O:35][C:34](=[O:36])[C@H:8]([CH2:9][C:10]2[CH:11]=[CH:12][C:13]([NH:16][C:17]([O:19][CH2:20][CH:21]3[C:33]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[C:27]4[C:22]3=[CH:23][CH:24]=[CH:25][CH:26]=4)=[O:18])=[CH:14][CH:15]=2)[NH:7][C:5]([O:4][C:2]([CH3:37])([CH3:1])[CH3:3])=[O:6])[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1
Reactant: BrCc1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(NC(=O)OCC2c3ccccc3-c3ccccc32)cc1)C(=O)O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(NC(=O)OCC2c3ccccc3-c3ccccc32)cc1)C(=O)OCc1ccccc1
Reaction time: 18 h
Yield: 89.4 %

Procedure:
N-[(1,1-Dimethylethoxy)carbonyl]-4-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]-L-phenylalanine (5.02 g, 10 mmol) and benzyl bromide (3.5 mL, 29 mmol) were stirred in DMF (25 mL) over KHCO3 (1.75 g, 17.5 mmol). After 18 hr, a white precipitate had formed. Most of the DMF was evaporated under reduced pressure, the residue was taken up in 100 mL of dichloromethane and was washed with water (2×50 mL). Most of the dichloromethane was evaporated and ether (100 mL) was added to precipitate the product. Filtration, washing with ether afforded N-[(1,1-dimethylethoxy)carbonyl]-4-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]-L-phenylalanine phenylmethyl ester (5.3 g), mp 186-187° C.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][C:11](=[O:16])[C:12]([Cl:15])([Cl:14])[Cl:13])(=O)[CH3:2].[NH2:17][CH2:18][CH2:19][OH:20]>C(O)C>[Cl:13][C:12]([Cl:15])([Cl:14])[C:11]([NH:10][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[C:1](=[N:17][CH2:18][CH2:19][OH:20])[CH3:2])=[O:16]
Reactant: NCCO
Reactant: CC(=O)c1ccccc1NC(=O)C(Cl)(Cl)Cl
Solvent: CCO
Product: CC(=NCCO)c1ccccc1NC(=O)C(Cl)(Cl)Cl
Temperature: 25 °C
Reaction time: 5.5 h
Yield: 59 %

Procedure:
A mixture of 60 parts of N-(2-acetylphenyl)-2,2,2-trichloroacetamide, 14 parts of 2-aminoethanol and 200 parts of ethanol is stirred first for 5.50 hours at reflux and further overnight while the temperature is allowed to cool to room temperature. The formed precipitate is filtered off. The product is washed with 2,2'-oxybispropane and dried in vacuo, yielding 40 parts (59%) of 2,2,2-trichloro-N-[2-[1-[(2-hydroxyethyl)imino]ethyl]phenyl]acetamide; mp. 182° C.
Reaction SMILES: [NH2:1][CH2:2][C:3]1([O:10][CH3:11])[CH2:7][CH2:6][CH:5]([O:8][CH3:9])[O:4]1.C(N(CC)CC)C.[C:19](Cl)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>O1CCCC1>[C:19]([NH:1][CH2:2][C:3]1([O:10][CH3:11])[CH2:7][CH2:6][CH:5]([O:8][CH3:9])[O:4]1)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: COC1CCC(CN)(OC)O1
Reactant: O=C(Cl)c1ccccc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC1CCC(CNC(=O)c2ccccc2)(OC)O1
Temperature: 0 °C
Reaction time: 1 h
Yield: 103.4 %

Procedure:
10 g (62 mmol) of 2-aminomethyl-2,5-dimethoxytetrahydrofuran and 17 ml (123 mmol) triethylamine were dissolved in 100 ml of anhydrous tetrahydrofuran. At 0° C., 7.2 ml (62 mmol) of benzoyl chloride were added dropwise, and the mixture was stirred at 0° C. for 1 h and then filtered, and the filtrate was concentrated under reduced pressure to yield 17 g of the crude product which was immediately reacted further.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[C@:4]([NH2:16])([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][C:6]([OH:8])=[O:7].C(N(CC)CC)C.[CH:25](O)([CH3:27])[CH3:26].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:17])[C@:4]([NH2:16])([C:9]([O:11][C:12]([CH3:13])([CH3:14])[CH3:15])=[O:10])[CH2:5][C:6]([O:8][CH:25]([CH3:27])[CH3:26])=[O:7]
Reactant: CC(C)O
Reactant: COC(=O)[C@@](N)(CC(=O)O)C(=O)OC(C)(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)[C@@](N)(CC(=O)OC(C)C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 4 h
Yield: 86.4 %

Procedure:
Commercially available (S)-2-BOC-amino-succinic acid 1-methyl ester (2.4 g, 10 mmol) was dissolved in DCM (30 mL), and triethylamine (2.8 mL, 20 mmol) was added thereto. To the mixture were added isopropanol (660 mg, 11 mmol), EDC (2.5 g, 26 mmol) and HOBt (2.3 g, 30 mmol), and the mixture was stirred for 4 h at room temperature. The reaction was quenched by saturated aqueous NaHCO3 solution. The reaction mixture was extracted with EtOAc, washed with saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography to give the title compound (2.5 g, Yield 87%).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][N:5](C(=O)C)[CH:6]=1.[CH3:10][Si:11]([CH2:14][CH2:15][O:16][CH2:17]Cl)([CH3:13])[CH3:12]>C(#N)C>[CH3:1][C:2]1[N:3]([CH2:17][O:16][CH2:15][CH2:14][Si:11]([CH3:13])([CH3:12])[CH3:10])[CH:4]=[N:5][CH:6]=1
Reactant: CC(=O)n1cnc(C)c1
Reactant: C[Si](C)(C)CCOCCl
Solvent: CC#N
Product: Cc1cncn1COCC[Si](C)(C)C
Temperature: 25 °C
Reaction time: 10 h
Yield: 61.4 %

Procedure:
To a solution of 4-methylimidazole (2.70 g, 33.0 mmol) in 10 mL of acetonitrile at 0° C. was added triethylamine (NEt3) (4.00 g, 39.6 mmol) and acetyl chloride (2.80 g, 36.3 mmol). The mixture was allowed to attain RT then filtered to remove the ppt and the filtrate was concentrated to give 1-(4-methyl-imidazol-1-yl)-ethanone, which was used without further purification in the next step. To a solution of 1-(4-methyl-imidazol-1-yl)-ethanone (4.10 g, 33.0 mmol) in 15 mL acetonitrile was added SEM-Cl (5.80 g, 35.0 mmol) and the solution was stirred at 25° C. for 10 h. The solvents were removed by evaporation and to the residue was added 100 mL of 2.5 M NaOH and the mixture was stirred at 25° C. for 1 h. The reaction mixture was then extracted with ether (3×100 mL), dried over Na2SO4 and concentrated. The title compound was purified by chromatography on silica gel eluting with 75% EtOAc/hexanes to give 4.30 g (61%) of a colorless oil: Mass spectrum (ESI, m/z): Calcd. for C10H20N2O4Si, 213.1 (M+H). found 213.1.
Reaction SMILES: C(OC([NH:8][CH:9]([CH2:20][CH:21]([CH3:23])[CH3:22])[CH:10]([OH:19])[CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=O)(C)(C)C.[ClH:24]>CO>[ClH:24].[NH2:8][CH:9]([CH2:20][CH:21]([CH3:23])[CH3:22])[CH:10]([OH:19])[CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CC(C)CC(NC(=O)OC(C)(C)C)C(O)CCc1ccccc1
Agent: Cl
Solvent: CO
Product: CC(C)CC(N)C(O)CCc1ccccc1

Procedure:
The resultant compound of Example 1 (87 mg, 0.27 mmol) was dissolved in methanol (1 ml) and was treated with methanolic HCl (5 ml of 0.75M). After 15 hours the solution was evaporated to provide the desired compound as a glass (71 mg) which was used without further purification.
Reaction SMILES: [CH2:1]=[C:2]1[CH2:8][CH:7]2[C:9](=[O:10])[CH:4]([CH2:5][CH2:6]2)[CH2:3]1.[CH2:11](O)[CH2:12][OH:13].CCN(CC)CC.[O-]S([O-])(=O)=O.[Mg+2]>C1C=CC=CC=1.CC1C=CC(S(O)(=O)=O)=CC=1>[CH2:12]1[O:13][C:9]2([CH:7]3[CH2:6][CH2:5][CH:4]2[CH2:3][C:2](=[CH2:1])[CH2:8]3)[O:10][CH2:11]1
Reactant: C=C1CC2CCC(C1)C2=O
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: C=C1CC2CCC(C1)C21OCCO1
Temperature: 25 °C
Yield: 112 %

Procedure:
To a solution of 3-methylene bicyclo[3,2,1]octan-8-one (0.14 g, 1.04 mmol, 1.0 eq.) in benzene (10 mL) was added ethylene glycol (0.65 g, 16 eq.) and PTSA (0.01 g, 0.06 eq.). The reaction was equipped with a Dean-Stark and heated at reflux overnight. After cooling to room temperature, Et3N (0.15 mL) was introduced and the resulting mixture was passed through a cake of SiO2 and MgSO4. The cake was washed with CH2Cl2 and the combined filtrates were concentrated to give 3-methylene bicyclo[3,2,1]octan-8-one ethylene ketal (0.21 g, >100%).
Reaction SMILES: [C:1]1([CH3:21])[C:2]([S:7]([NH:10][C:11]([CH3:20])([CH3:19])[CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)(=[O:9])=[O:8])=[CH:3][CH:4]=[CH:5][CH:6]=1.[B].[CH3:23]OCOC>>[C:1]1([CH3:21])[C:2]([S:7]([N:10]2[C:11]([CH3:19])([CH3:20])[CH2:12][C:13]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:23]2)(=[O:8])=[O:9])=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COCOC
Reactant: Cc1ccccc1S(=O)(=O)NC(C)(C)Cc1ccccc1
Agent: [B]
Product: Cc1ccccc1S(=O)(=O)N1Cc2ccccc2CC1(C)C
Temperature: 25 °C
Reaction time: 12 h
Yield: 99 %

Procedure:
To a nitrogen-blanketed mixture of N-toluenesulfonyl-1,1-dimethyl-2-phenyl-ethylamine (8.30 g, 0.027 mol.) in dimethoxymethane (50 mL) was added boron trifluororo etherate (BF3 ·OEt2, 9.9 mL, 0.081 mol.). The mixture was stirred at room temperature for 12 hours while monitoring by gas chromatography. The reaction mixture was partitioned between ethyl acetate (100 mL) and water (100 mL), separated, and the organic layer is washed with saturated sodium bicarbonate (2×100 mL) and dried over sodium sulfate (Na2 SO4). The drying agent was filtered off and the filtrate was concentrated at 40°/50 torr to give 8.55 g of N-toluenesulfonyl-3,3-dimethyl-1,2,3,4-tetrahydroisoquinoline (yield=99%).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](O)=[CH:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[O:13][CH3:14].O=P(Cl)(Cl)[Cl:17]>C(#N)C>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([Cl:17])=[CH:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[O:13][CH3:14]
Reactant: COc1cc2c(O)ccnc2cc1Br
Reactant: O=P(Cl)(Cl)Cl
Solvent: CC#N
Product: COc1cc2c(Cl)ccnc2cc1Br
Temperature: 90 °C

Procedure:
To a flask charged with 7-bromo-6-methoxyquinolin-4-ol (0.595 g, 2.342 mmol) was added Acetonitrile (11.71 ml) and POCl3 (0.229 ml, 2.459 mmol) and the resulting suspension heated to 90° C. for 2.5 hr affording a brown solution and near complete conversion to desired product. The mixture was added to a cooled solution of sat. aq. NaHCO3 and extracted with EtOAc (2×). The combined organics were dried with Na2SO4, filtered, and dried under reduced pressure. The organic phase was dried under reduced pressure and purified with an 40 g HP silicycle column ramping EtOAc in heptane (0-50%, 10% DCM throughout) affording isomer separation, both obtained as white solids. NMR indicated that the first eluting peak was the desired isomer, obtained as an off-white solid 7-bromo-4-chloro-6-methoxyquinoline (0.240 g, 0.881 mmol, 37.6% yield). The second peak (looked like about 60:40 ratio of product 1 to 2 by MPLC trace) was not isolated. 1H NMR (400 MHz, CHLOROFORM-d) δ=8.66 (d, J=4.7 Hz, 1H), 8.38 (s, 1H), 7.49 (d, J=4.7 Hz, 1H), 7.47 (s, 1H), 4.08 (s, 3H). m/z (ESI) 272.1 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=O.S(=O)(=O)(O)O>C(O)(=O)C.[Pd]>[CH:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:4]=1[CH2:3][C:2]1([NH2:1])[CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[CH:10]12
Reactant: NC1(Cc2ccccc2)Cc2ccccc2C1=O
Agent: [Pd]
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: NC12Cc3ccccc3C1c1ccccc1C2
Reaction time: 24 h

Procedure:
K3Fe(CN)6 (18.0 g, 54.8 mmol) is added to hot (80° C.) degassed water (150 ml), followed by 2-benzylindan-1-one (J Mol Catal A 2000, 154, 237; 3.8 g, 17.1 mmol). Concentrated aqueous ammonia (14 ml) is then added over 15 minutes and the reaction mixture is heated at 80-90° C. in the dark for 24 hours. After cooling to ambient temperature, the mixture is extracted with chloroform. The combined chloroform extracts are extracted with 3 M HCl and the acidic extracts are evaporated to afford 2-amino-2-benzylindan-1-one hydrochloride salt, MH+238. A suspension of 2-amino-2-benzylindan-1-one (0.506 g, 2.13 mmol) and 10% Pd/C (0.130 g) in acetic acid (15 ml) is hydrogenated at 0.35 bar for 24 hours. Concentrated sulphuric acid (1.5 ml) is added and the reaction is hydrogenated for a further 7 hours. The catalyst is filtered through a Celite™ filter plug and mixture concentrated in vacuo. The residue is basified to pH 8 with saturated aqueous sodium bicarbonate and extracted with ether. The ether extracts are washed with brine, dried (Na2SO4) and evaporated. The crude product is purified by flash chromatography (30:1 CH2Cl2-MeOH elution) to afford 4b,10-dihydro-9H-indeno[1,2-a]inden-9a-ylamine, MH+222. A mixture of 4b,10-dihydro-9H-indeno[1,2-a]inden-9a-ylamine (0.296 g, 1.34 mmol) and R-8-benzyloxy-5-oxiranyl-1H-quinolin-2-one (0.262 g, 0.893 mmol) in 2-methoxyethyl ether (4.5 ml) is heated in a sealed tube at 190° C. for 50 hours. The solvent is evaporated and the crude product purified by preparative LCMS to afford 5-[R-2-(4b,10-dihydro-9H-indeno-[1,2-a]inden-9a-ylamino) 1-hydroxyethyl]-8-benzyloxy-1H-quinolin-2-one, MH+515. A suspension of 5-[R-2-(4b,10-dihydro-9H-indeno[1,2-a]inden-9a-ylamino) 1-hydroxy-ethyl]-8-benzyloxy-1H-quinolin-2-one (10 mg, 0.02 mmol) and 10% Pd/C (8 mg) in ethanol (5 ml) is hydrogenated at 0.35 bar for 30 minutes. The catalyst is filtered through a Celite™ filter plug and the solvent evaporated to afford 5-[R-2-(4b,10-dihydro-9H-indeno[1,2-a]inden-9a-ylamino) 1-hydroxyethyl]-8-hydroxy-1H-quinolin-2-one, MH+426.
Reaction SMILES: C(O)(=O)/C=C/C(O)=O.[CH:9]([O:12][CH2:13][CH2:14][N:15]([C:20]1[CH:42]=[CH:41][C:23]([C:24]([N:26]2[CH2:31][CH2:30][N:29]([CH2:32][CH2:33][C:34]3[CH:39]=[CH:38][C:37]([Cl:40])=[CH:36][CH:35]=3)[CH2:28][CH2:27]2)=[O:25])=[CH:22][CH:21]=1)[C:16](=[O:19])[CH2:17]Cl)([CH3:11])[CH3:10].[NH:43]1[CH2:48][CH2:47][CH2:46][CH2:45][CH2:44]1>>[CH:9]([O:12][CH2:13][CH2:14][N:15]([C:20]1[CH:42]=[CH:41][C:23]([C:24]([N:26]2[CH2:31][CH2:30][N:29]([CH2:32][CH2:33][C:34]3[CH:35]=[CH:36][C:37]([Cl:40])=[CH:38][CH:39]=3)[CH2:28][CH2:27]2)=[O:25])=[CH:22][CH:21]=1)[C:16](=[O:19])[CH2:17][N:43]1[CH2:48][CH2:47][CH2:46][CH2:45][CH2:44]1)([CH3:10])[CH3:11]
Reactant: C1CCNCC1
Reactant: CC(C)OCCN(C(=O)CCl)c1ccc(C(=O)N2CCN(CCc3ccc(Cl)cc3)CC2)cc1
Agent: O=C(O)/C=C/C(=O)O
Product: CC(C)OCCN(C(=O)CN1CCCCC1)c1ccc(C(=O)N2CCN(CCc3ccc(Cl)cc3)CC2)cc1

Procedure:
Analogously to Example 51, 1-{4-[N-(2-isopropyloxyethyl)-N-chloroacetylamino]benzoyl}-4-[2-(4-chlorophenyl)ethyl]piperazine (Example 3) and piperidine are reacted, yielding 1-{4-[N-(2-isopropyloxyethyl)-N-piperidinoacetylamino]benzoyl}-4-[2-(4-chlorophenyl)ethyl]piperazine. The difumarate thereof melts at 179°-180°.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:13][C@H:12]([CH2:14][OH:15])[O:11][C:10]2=[O:16])[CH:5]=[CH:6][C:7]=1[I:8].C(N(CC)CC)C.[CH3:24][S:25](Cl)(=[O:27])=[O:26]>ClCCl.O>[F:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:13][C@H:12]([CH2:14][O:15][S:25]([CH3:24])(=[O:27])=[O:26])[O:11][C:10]2=[O:16])[CH:5]=[CH:6][C:7]=1[I:8]
Reactant: O=C1O[C@@H](CO)CN1c1ccc(I)c(F)c1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OC[C@H]1CN(c2ccc(I)c(F)c2)C(=O)O1
Reaction time: 2 h

Procedure:
(5R)-3-(3-Fluoro-4-iodophenyl)-5-(hydroxymethyl)oxazolidin-2-one (6.07 g, 18 mM) in dry dichloromethane (200 ml) under nitrogen was treated with triethylamine (2.54 g, 25 mM), and methanesulfonyl chloride (2.47 g, 22 mM) run in dropwise over 30 minutes at 0°. After stirring 2 hours at 0°, the mixture was diluted with water (200 ml), the organic layer separated, washed with hydrochloric acid (2N, 100 ml), sodium bicarbonate solution (5%, 100 ml), brine (100 ml) and dried (magnesium sulfate). The residue after evaporation was dissolved in the minimum of dichloromethane, and excess isohexane added to precipitate the desired product (7.05 g).
Reaction SMILES: CO[C:3](=[O:24])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[C:13]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)=[N:14][O:15][CH:16]=2)=[N:6][CH:5]=1.[CH:25]1([NH2:28])[CH2:27][CH2:26]1>>[CH:25]1([NH:28][C:3](=[O:24])[C:4]2[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]3[C:13]([C:17]4[CH:18]=[CH:19][C:20]([F:23])=[CH:21][CH:22]=4)=[N:14][O:15][CH:16]=3)=[N:6][CH:5]=2)[CH2:27][CH2:26]1
Reactant: COC(=O)c1ccc(OCc2conc2-c2ccc(F)cc2)nc1
Reactant: NC1CC1
Product: O=C(NC1CC1)c1ccc(OCc2conc2-c2ccc(F)cc2)nc1
Yield: 28 %

Procedure:
As described for example 324, 6-[3-(4-fluoro-phenyl)-isoxazol-4-ylmethoxy]-nicotinic acid methyl ester (200 mg, 0.61 mmol) was converted, using cyclopropylamine instead of 4-aminotetrahydropyran, to the title compound (60 mg, 28%) which was obtained as a white solid. MS: m/e=343.4 [M+H]+.
Reaction SMILES: Br[C:2]1[C:3]([CH3:19])=[C:4]([CH2:12][N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[N:5]2[C:10]=1[C:9]([NH2:11])=[N:8][CH:7]=[N:6]2.CC1(C)C(C)(C)OB([C:28]2[CH:33]=[CH:32][C:31]([NH:34][C:35]([NH:37][C:38]3[CH:43]=[C:42]([C:44]([F:47])([F:46])[F:45])[CH:41]=[CH:40][N:39]=3)=[O:36])=[CH:30][CH:29]=2)O1.FC1C=CC(C(F)(F)F)=CC=1NC(NC1C=CC(B2OC(C)(C)C(C)(C)O2)=CC=1)=O>>[NH2:11][C:9]1[C:10]2=[C:2]([C:28]3[CH:29]=[CH:30][C:31]([NH:34][C:35]([NH:37][C:38]4[CH:43]=[C:42]([C:44]([F:46])([F:45])[F:47])[CH:41]=[CH:40][N:39]=4)=[O:36])=[CH:32][CH:33]=3)[C:3]([CH3:19])=[C:4]([CH2:12][N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[N:5]2[N:6]=[CH:7][N:8]=1
Reactant: Cc1c(Br)c2c(N)ncnn2c1CN1CCOCC1
Reactant: CC1(C)OB(c2ccc(NC(=O)Nc3cc(C(F)(F)F)ccn3)cc2)OC1(C)C
Agent: CC1(C)OB(c2ccc(NC(=O)Nc3cc(C(F)(F)F)ccc3F)cc2)OC1(C)C
Product: Cc1c(-c2ccc(NC(=O)Nc3cc(C(F)(F)F)ccn3)cc2)c2c(N)ncnn2c1CN1CCOCC1
Yield: 44 %

Procedure:
The title compound was prepared in a manner similar to the procedure described for the preparation of Example 117 Step 4, using the product of step 1, Example 119 (5-bromo-6-methyl-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-4-amine) in place of 5-bromo-6-methyl-7-(1,4-oxazepan-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-4-amine and Intermediate AAG (1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-3-[4-(trifluoromethyl)pyridin-2-yl]urea) in place of Intermediate AAN (1-[2-fluoro-5-(trifluoromethyl)phenyl]-3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]urea), 53 mg (44%) of the desired product was isolated. 1H-NMR (DMSO-d6) δ 9.88 (s, 1H), 9.75 (s, 1H), 8.54 (d, J=5.1 Hz, 1H), 8.06 (s, 1H), 7.85 (s, 1H), 7.63 (d, J=8.4 Hz, 3H), 7.36-7.31 (m, 3H), 3.80 (s, 2H), 3.55-3.50 (m, 4H), 2.42-2.39 (m, 4H), 2.09 (s, 3H); MS [M+H]+=527.1; LCMS RT=2.34.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:14]=[CH:13][C:12]2[C:11](=[O:15])[CH2:10][CH2:9][CH2:8][C:7]=2[CH:6]=1)=[O:4].[C:16]1([CH:21]=O)[CH2:20][CH2:19][CH2:18][CH:17]=1>>[C:16]1([CH:21]=[C:10]2[CH2:9][CH2:8][C:7]3[CH:6]=[C:5]([C:3]([O:2][CH3:1])=[O:4])[CH:14]=[CH:13][C:12]=3[C:11]2=[O:15])[CH2:20][CH2:19][CH2:18][CH:17]=1
Reactant: COC(=O)c1ccc2c(c1)CCCC2=O
Reactant: O=CC1=CCCC1
Product: COC(=O)c1ccc2c(c1)CCC(=CC1=CCCC1)C2=O
Yield: 70 %

Procedure:
The title compound was prepared from 5-oxo-5,6,7,8-tetrahydronaphtalene-2-carboxylic acid methyl ester (396 mg, 1.9 mmol) and 1-cyclopentene carbaldehyde (220 mg, 2.0 mmol) according to Method A3 in 70% yield. ES-MS m/z 283 (M+H)
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[Cl:9][CH2:10][C:11](Cl)=[O:12]>CC(O)=O.CC(O[Na])=O>[Cl:9][CH2:10][C:11]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1)=[O:12]
Reactant: O=C(Cl)CCl
Reactant: Nc1ccc(O)cc1
Agent: CC(=O)O[Na]
Solvent: CC(=O)O
Product: O=C(CCl)Nc1ccc(O)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 40.8 %

Procedure:
To a solution of 4-aminophenol (1.0 g, 9.1 mmol) in CH3COOH (3.5 mL) and saturated CH3COONa (3.5 mL), chloroacetylchloride (0.72 mL, 9.1 mmol) was added dropwise. After the addition was complete, the mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated, washed with water (3×25 mL) and dried over vacuum to isolate the intermediate 17a as white solid (0.690 g, 3.71 mmol, 40% yield). 1H NMR (DMSO, 400 MHz) δ 10.03 (s, 1H), 9.27 (s, 1H), 7.36 (d, J=8.8 Hz, 2H), 6.71 (d, J=8.8 Hz, 2H) 4.182 (s, 2H).
Reaction SMILES: [O-]CC.[Na+].Cl.[C:6]([NH2:14])(=[NH:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH:15](=[C:22]([C:28]([O-])=[O:29])[C:23]([O:25][CH2:26][CH3:27])=[O:24])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C(O)C>[O:29]=[C:28]1[CH:22]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:15]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:14]=[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[NH:13]1
Reactant: CCOC(=O)C(=Cc1ccccc1)C(=O)[O-]
Reactant: N=C(N)c1ccccc1
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C1C(=O)NC(c2ccccc2)=NC1c1ccccc1
Reaction time: 2 h
Yield: 76.7 %

Procedure:
To a mixture of a 20% solution of sodium ethoxide in ethanol (44.9 g) and ethanol (200 ml) is added benzamidine hydrochloride (10.3 g) at room temperature. The mixture is stirred at the same temperature for two hours, and thereto is added ethyl benzalmalonate (14.0 g), and the mixture is refluxed for three hours. The reaction mixture is concentrated under reduced pressure, and to the residue is added ice-water. To the mixture is added dropwise conc. hydrochloric acid until the pH value of the mixture is adjusted to pH 4. The precipitates are collected by filtration, and washed with water to give crude ethyl 3,4,5,6-tetrahydro-4-oxo-2,6-diphenylpyrimidine-5-carboxylate (15.8 g).
Reaction SMILES: Br[CH:2]([C:12]1[CH:17]=[CH:16][C:15]([S:18]([CH3:21])(=[O:20])=[O:19])=[CH:14][CH:13]=1)[C:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1)=O.[C:22]([NH2:25])(=[S:24])[CH3:23].N1C=CC=CC=1>C(O)C>[F:11][C:8]1[CH:9]=[CH:10][C:5]([C:3]2[N:25]=[C:22]([CH3:23])[S:24][C:2]=2[C:12]2[CH:17]=[CH:16][C:15]([S:18]([CH3:21])(=[O:20])=[O:19])=[CH:14][CH:13]=2)=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)c1ccc(C(Br)C(=O)c2ccc(F)cc2)cc1
Reactant: CC(N)=S
Solvent: c1ccncc1
Solvent: CCO
Product: Cc1nc(-c2ccc(F)cc2)c(-c2ccc(S(C)(=O)=O)cc2)s1
Yield: 31.1 %

Procedure:
To 2-bromo-1-(4-fluorophenyl)-2-(4-(methylsulfonyl)phenyl)-ethanone (1.10 g) in ethanol (15.0 mL) were added thioacetamide (0.266 g) and pyridine (0.300 mL). After refluxing for 2 h, the reaction mixture was extracted with EtOAc, 25% NH4OAc and purified by flash chromatography (50% EtOAc in hexane then 90% Et2O in hexane) to yield the title compound (0.320 g).