Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:7]2[CH:8]=[C:9]([NH2:19])[CH:10]=[N:11][C:12]=2[O:13][CH2:14][C:15]([F:18])([F:17])[F:16])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:20][C:21]1[CH:22]=[C:23]([C:26](O)=[O:27])[NH:24][N:25]=1>>[CH:1]1([C:7]2[CH:8]=[C:9]([NH:19][C:26]([C:23]3[NH:24][N:25]=[C:21]([CH3:20])[CH:22]=3)=[O:27])[CH:10]=[N:11][C:12]=2[O:13][CH2:14][C:15]([F:16])([F:17])[F:18])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: Nc1cnc(OCC(F)(F)F)c(C2CCCCC2)c1
Reactant: Cc1cc(C(=O)O)[nH]n1
Product: Cc1cc(C(=O)Nc2cnc(OCC(F)(F)F)c(C3CCCCC3)c2)[nH]n1
Yield: 53.1 %

Procedure:
This compound was prepared following the same procedure as described for Example 3 using 5-cyclohexyl-6-(2,2,2-trifluoro-ethoxy)-pyridin-3-ylamine (Example 8b) (100 mg, 0.36 mmol) and 5-methyl-2H-pyrazole-3-carboxylic acid (40.6 mg, 0.33 mmol) as starting materials. The title compound (67 mg, 48.2%) was isolated as off white solid; MS (ESI): 383 [M+H]+.
Reaction SMILES: [CH2:1](Br)[C:2]#[CH:3].[NH2:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([CH2:16][N:17]3[CH2:22][CH2:21][NH:20][CH2:19][C:18]3=[O:23])=[CH:13][CH:14]=2)[N:9]=[CH:8][N:7]=1.C([O-])([O-])=O.[K+].[K+]>CS(C)=O>[NH2:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([CH2:16][N:17]3[CH2:22][CH2:21][N:20]([CH2:3][C:2]#[CH:1])[CH2:19][C:18]3=[O:23])=[CH:13][CH:14]=2)[N:9]=[CH:8][N:7]=1
Reactant: Nc1ncnc2cc(CN3CCNCC3=O)ccc12
Reactant: C#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: C#CCN1CCN(Cc2ccc3c(N)ncnc3c2)C(=O)C1
Reaction time: 0.25 h
Yield: 67.7 %

Procedure:
Propargyl bromide (0.29 g, 1.95 mmol) is added to a solution containing 1-(4-amino-quinazolin-7-ylmethyl)-piperazin-2-one (0.5 g, 1.95 mmol), EXAMPLE 72, and K2CO3 (0.40 g, 2.93 mmol) in DMSO (10 mL) at ambient temperature. After 15 min, the reaction mixture is partitioned between aqueous NaHCO3 (100 mL) and CH2Cl2 (100 mL) and the layers are separated. The aqueous phase is subsequently saturated with NaCl and extracted three times with CHCl3 (50 mL). The combined organic phase is washed with brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue is purified by flash silica gel chromatography (CH2Cl2 to 10% MeOH/CH2Cl2) to provide 390 mg (68%) of the title compound as a white solid. 1H NMR (300 MHz, CDCl3) δ2.68 (m, 1H), 3.13-3.37 (m, 6H), 4.07 (app q, J=5.2 Hz, 1H), 4.63 (s, 2H), 7.28 (dd, J=8.4, 1.4 Hz, 1H), 7.42 (s, 1H), 7.72 (br s, 2H), 8.14 (d, J=8.4 Hz, 1H), 8.34 (s, 1H) ppm; MS (ISP loop): m/z 296 (M+H).
Reaction SMILES: [C:1]([N:9]1[C:17]2[CH:16]=[CH:15][C:14]([O:18][C:19]3[N:24]=[C:23]([O:25][CH3:26])[CH:22]=[C:21]([O:27][CH3:28])[N:20]=3)=[C:13]([C:29]([O:31]CC3C=CC=CC=3)=[O:30])[C:12]=2[C:11]([C:39]([O:41][CH2:42][CH3:43])=[O:40])=[C:10]1[CH3:44])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(OCC)(=O)C.[C].[Pd]>[C:1]([N:9]1[C:17]2[CH:16]=[CH:15][C:14]([O:18][C:19]3[N:24]=[C:23]([O:25][CH3:26])[CH:22]=[C:21]([O:27][CH3:28])[N:20]=3)=[C:13]([C:29]([OH:31])=[O:30])[C:12]=2[C:11]([C:39]([O:41][CH2:42][CH3:43])=[O:40])=[C:10]1[CH3:44])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1c(C)n(C(=O)c2ccccc2)c2ccc(Oc3nc(OC)cc(OC)n3)c(C(=O)OCc3ccccc3)c12
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOC(=O)c1c(C)n(C(=O)c2ccccc2)c2ccc(Oc3nc(OC)cc(OC)n3)c(C(=O)O)c12
Yield: 94.3 %

Procedure:
1.6 g of benzyl 1-benzoyl-5-[(4,6-dimethoxypyrimidin-2-yl)oxy]-3-ethoxycarbonyl-2-methylindol-4-carboxylate was dissolved in 50 ml of ethyl acetate, and 0.1 g of 10% palladium carbon was added thereto. Then, catalytic reduction was conducted. Insoluble matters were filtered off, and then filtrate was concentrated under reduced pressure. The residue thereby obtained was washed with isopropyl ether to obtain 1.28 g (yield: 97%) of the desired compound. mp: 113°-115° C.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][CH:5]=[C:4]([C:8]#[N:9])[N:3]=1.Cl.[C:11]([O:15][C:16](=[O:20])[CH2:17][NH:18][CH3:19])([CH3:14])([CH3:13])[CH3:12].C(N(CC)CC)C.CN(C=O)C>O.C(OCC)(=O)C>[CH3:19][N:18]([CH2:17][C:16]([O:15][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:20])[C:2]1[N:7]=[CH:6][CH:5]=[C:4]([C:8]#[N:9])[N:3]=1
Reactant: CNCC(=O)OC(C)(C)C
Reactant: N#Cc1ccnc(Cl)n1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CN(CC(=O)OC(C)(C)C)c1nccc(C#N)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 77.1 %

Procedure:
2-Chloro-6-cyanopyrimidine (1.45 g, 10.4 mmol), sarcosine tert-butyl ester hydrochloric acid (1.89 g, 10.4 mmol) and triethylamine (1.60 ml, 11.4 mmol) were added to DMF (30 ml), and the mixture was stirred at room temperature for 18 hrs. The reaction mixture was combined with ethyl acetate and water. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated to give the titled compound (1.99 g, 77%) as pale yellow crystals.
Reaction SMILES: [CH3:1][C:2]1([CH3:24])[N:7]([C:8]2[CH:9]=[N:10][C:11]([N+:14]([O-])=O)=[CH:12][CH:13]=2)[CH2:6][CH2:5][N:4]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:3]1>[Pd].CO>[NH2:14][C:11]1[N:10]=[CH:9][C:8]([N:7]2[CH2:6][CH2:5][N:4]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:3][C:2]2([CH3:24])[CH3:1])=[CH:13][CH:12]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc([N+](=O)[O-])nc2)C(C)(C)C1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(N)nc2)C(C)(C)C1
Temperature: 25 °C
Reaction time: 5 h
Yield: 96.9 %

Procedure:
A 50-mL round-bottomed flask was purged with nitrogen and charged with tert-butyl 3,3-dimethyl-4-(6-nitropyridin-3-yl)piperazine-1-carboxylate 190a (1100 mg, 3.2 mmol), 10% palladium on carbon (10% wet, 110 mg), and methanol (20 mL). It was then evacuated, charged with hydrogen gas, and stirred at room temperature for 5 h. The hydrogen was evacuated and nitrogen was charged into the flask. The catalyst was removed by filtration through a pad of diatomaceous earth filter agent (CELITE®, Imerys Minerals California, Inc.) and the filtrate was concentrated under reduced pressure to afford 190b (950 mg, 94%). LCMS: [M+H]+ 307.3
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[N:8]=[C:7]([CH3:14])[C:6]([C:15]1[CH:20]=[CH:19][C:18]([O:21][C:22]3[CH:27]=[CH:26][C:25]([O:28][C:29]([F:32])([F:31])[F:30])=[CH:24][CH:23]=3)=[CH:17][C:16]=1[F:33])=[C:5]2[O:34]CC.FC1C=C(OC2C=CC(OC(F)(F)F)=CC=2)C=CC=1B(O)O.C([O-])([O-])=O.[Na+].[Na+].CN(C=O)C>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CO.C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[NH:8][C:7]([CH3:14])=[C:6]([C:15]1[CH:20]=[CH:19][C:18]([O:21][C:22]3[CH:23]=[CH:24][C:25]([O:28][C:29]([F:31])([F:32])[F:30])=[CH:26][CH:27]=3)=[CH:17][C:16]=1[F:33])[C:5]2=[O:34]
Reactant: CCOc1c(-c2ccc(Oc3ccc(OC(F)(F)F)cc3)cc2F)c(C)nc2cc(OC)c(Cl)cc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: OB(O)c1ccc(Oc2ccc(OC(F)(F)F)cc2)cc1F
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Solvent: CO
Product: COc1cc2[nH]c(C)c(-c3ccc(Oc4ccc(OC(F)(F)F)cc4)cc3F)c(=O)c2cc1Cl
Temperature: 90 °C

Procedure:
An oven-dried Schlenk tube was flame-dried and backfilled with argon (X3). The tube was then charged with 6-chloro-4-ethoxy-3-(2-fluoro-4-(4-(trifluoromethoxy)phenoxy)phenyl)-7-methoxy-2-methylquinoline (0.3 g, 0.8 mmol), Pd(PPh3)4 (0.08 g, 10 mol %), and 2-fluoro-4-(4-(trifluoromethoxy)phenoxy)phenylboronic acid (0.375 g, 1.2 mmol). A rubber septum was then placed on the tube and 2M Na2CO3 (3 mL), DMF (15 mL), were added. The tube was then purged of air by argon for about 1 minute, while stirring and then heated at 90° C. until completion by HPLC analysis ˜3 h. After completion, reaction was boiled with 1:1 MeOH/CHCl3, and filtered over celite. The celite was then rinsed with boiling hot DMF. The filtrate was then evaporated on silica gel purified via flash chromatography (33% EtOAc in Hexane). The resulting amorphous solid (0.48 g, 52%) was then dissolved in 4.8 mL of AcOH and 4.8 mL of HBr. This solution was refluxed for 1.5 h. The reaction was poured onto ice and water. The resulting solid was filtered via filtration and recrystallized from DMF twice (0.2 g, 44%).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:11]=[CH:10][C:9]([CH:12]([CH3:15])[CH2:13][NH2:14])=[CH:8][CH:7]=2)=[CH:2]1.[N:16]1([C:22](Cl)=[O:23])[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1>>[S:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:11]=[CH:10][C:9]([CH:12]([CH3:15])[CH2:13][NH:14][C:22]([N:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)=[O:23])=[CH:8][CH:7]=2)=[CH:2]1
Reactant: CC(CN)c1ccc(-c2ccsc2)cc1
Reactant: O=C(Cl)N1CCOCC1
Product: CC(CNC(=O)N1CCOCC1)c1ccc(-c2ccsc2)cc1

Procedure:
The title compound was prepared from 2-(4-(3-thienyl)phenyl)propylamine (see example 14) and 4-morpholine carbonyl chloride in a manner analogous to the procedure described in example 14. The NMR spectrum was consistent with the proposed title structure.
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][C:14]([OH:27])([C:17]2[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=2)[CH2:13][CH2:12]1)=O)C1C=CC=CC=1.[H][H]>[Pd].C(O)C>[OH:27][C:14]1([C:17]2[CH:18]=[CH:19][C:20]([C:23]([F:26])([F:24])[F:25])=[CH:21][CH:22]=2)[CH2:15][CH2:16][NH:11][CH2:12][CH2:13]1
Reactant: O=C(OCc1ccccc1)N1CCC(O)(c2ccc(C(F)(F)F)cc2)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: OC1(c2ccc(C(F)(F)F)cc2)CCNCC1
Reaction time: 2.5 h
Yield: 62.7 %

Procedure:
A mixture of 1-benzyloxycarbonyl-4-hydroxy-4-(4-trifluoromethylphenyl)-piperidine (12.3 g, 32.4 mmol), ethanol (150 mL), and 10% palladium on carbon (1.4 g) was hydrogenated in a Parr apparatus (initial hydrogen pressure was 48 psi). After 2.5 hours, the mixture was filtered through celite and concentrated. The residue was triturated with ether/hexane to obtain 4.98 g (63%) of 4-hydroxy-4-(4-trifluoromethylphenyl)-piperidine as a white solid which had mp 130.5°-132° C. Analysis calculated for C12 H14F3NO--0.25 H2O: C, 57.71; H, 5.85; N, 5.61. Found: C, 57.91; H 5.77; N, 5.54.
Reaction SMILES: Cl.[CH2:2]([O:5][C:6]1[CH:14]=[CH:13][CH:12]=[CH:11][C:7]=1[C:8]([NH2:10])=[NH:9])[CH2:3][CH3:4].[Na].C([O:18][CH:19]=[C:20]([C:26](OCC)=O)[C:21]([O:23][CH2:24][CH3:25])=[O:22])C.Cl>C(O)C>[O:18]=[C:19]1[NH:10][C:8]([C:7]2[CH:11]=[CH:12][CH:13]=[CH:14][C:6]=2[O:5][CH2:2][CH2:3][CH3:4])=[N:9][CH:26]=[C:20]1[C:21]([O:23][CH2:24][CH3:25])=[O:22]
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: CCCOc1ccccc1C(=N)N
Agent: Cl
Agent: [Na]
Solvent: CCO
Product: CCCOc1ccccc1-c1ncc(C(=O)OCC)c(=O)[nH]1
Temperature: 0 °C
Yield: 96 %

Procedure:
2-Propoxybenzamidine hydrochloride (12.0 g., 0.0558 mole) was added to a stirred, cooled (ice-water) solution of sodium (2.57 g., 0.112 g-atom) in ethanol (50 ml.). To this cooled, stirred solution was added a solution of diethyl ethoxymethylenemalonate (12.1 g., 0.0558 mole) in ethanol (50 ml.) during 10 minutes. The mixture was heated under reflux for 2.5 hours. The cooled solution was poured onto ice and acidified with 6N hydrochloric acid. The precipitated ethyl 1,6-dihydro-6-oxo-2-(2-n-propoxyphenyl)pyrimidine-5-carboxylate (16.2 g., 96% yield) had m.p. 111°-113°. Two recrystallizations from cyclohexane gave title product with m.p. 112°-113°.
Reaction SMILES: O=[C:2]1[C:10]2[CH:9]=[CH:8][CH:7]=[C:6]([C:11]([OH:13])=[O:12])[C:5]=2[CH2:4][CH2:3]1.Cl.[F:15][C:16]([F:27])([F:26])[O:17][C:18]1[CH:23]=[CH:22][C:21]([NH:24]N)=[CH:20][CH:19]=1>>[F:15][C:16]([F:26])([F:27])[O:17][C:18]1[CH:19]=[CH:20][C:21]2[NH:24][C:2]3[C:10]4[CH:9]=[CH:8][CH:7]=[C:6]([C:11]([OH:13])=[O:12])[C:5]=4[CH2:4][C:3]=3[C:22]=2[CH:23]=1
Reactant: O=C(O)c1cccc2c1CCC2=O
Reactant: NNc1ccc(OC(F)(F)F)cc1
Agent: Cl
Product: O=C(O)c1cccc2c1Cc1c-2[nH]c2ccc(OC(F)(F)F)cc12
Yield: 8.5 %

Procedure:
In a manner similar to Example 17, 1-oxo-indan-4-carboxylic acid (1.00 g, 5.68 mmol) and 4-trifluoromethoxyphenylhydrazine hydrochloride (1.30 g, 5.68 mmol) were converted to the title compound (0.160 g, 8%) as an light tan solid: mp 256-265 (dec)° C.; 1H NMR (DMSO-d6): δ 4.03 (s, 2H), 7.05-7.08 (m, 1H), 7.49 (d, 1H), 7.53 (d, 1H), 7.61 (d, 1H), 7,79-7.83 (m, 2H), 11.92 (s, 1H), 13.08 (s, 1H); MS [EI, m/z]: 333 [M]+.
Reaction SMILES: C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[CH2:20]([C:24]1[N:25]([CH2:32][C:33]([OH:36])([CH3:35])[CH3:34])[C:26](I)=[C:27]([C:29]#[N:30])[N:28]=1)[CH2:21][CH2:22][CH3:23].Cl.[NH2:38][C:39]1[CH:44]=[C:43]([C:45]([O:47][CH3:48])=[O:46])[CH:42]=[CH:41][C:40]=1B(O)O.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.CC([O-])=O.CC([O-])=O.[Pd+2]>[NH2:38][C:39]1[CH:44]=[C:43]([C:45]([O:47][CH3:48])=[O:46])[CH:42]=[CH:41][C:40]=1[C:26]1[N:25]([CH2:32][C:33]([OH:36])([CH3:35])[CH3:34])[C:24]([CH2:20][CH2:21][CH2:22][CH3:23])=[N:28][C:27]=1[C:29]#[N:30]
Reactant: CCCCc1nc(C#N)c(I)n1CC(C)(C)O
Reactant: COC(=O)c1ccc(B(O)O)c(N)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cl
Solvent: COCCOC
Product: CCCCc1nc(C#N)c(-c2ccc(C(=O)OC)cc2N)n1CC(C)(C)O
Temperature: 100 °C

Procedure:
To a suspension of Pd(OAc)2 (11.2 mg, 0.05 mmol, 0.05 equiv) and PPh3 (26.2 mg, 0.1 mmol, 0.1 equiv) in DME (4 mL) were sequentially added 2-butyl-1-(2-hydroxy-2-methylpropyl)-5-iodo-1H-imidazole-4-carbonitrile S5 (347 mg, 1 mmol, 1 equiv), 2-amino-4-methoxycarbonylphenylboronic acid hydrochloride salt (347 mg, 1.5 mmol, 1.5 equiv) and 1.5 M aqueous Na2CO3 (2.0 mL, 3 mmol, 3 equiv) at 25° C. The reaction was heated at 100° C. for 6 h. TLC and MS analysis indicated the presence of S5; consequently, additional Pd(OAc)2 (5 mg) and PPh3 (13 mg) were added and the reaction was heated further at 100° C. for 15 h. The reaction was then cooled down to 25° C. and partitioned between EtOAc (50 mL) and H2O (10 mL). The aqueous layer was extracted with EtOAc (3×15 mL). The combined organic layers was washed with saturated aqueous NaCl (20 mL), dried (MgSO4) and concentrated in vacuo. Purification by flash column chromatography on silica gel (1/9 EtOAc/hexanes-7/3 EtOAc/hexanes, gradient) afforded the title compound (118 mg, ˜90% pure, 32%) as light yellow foam, which was used in the next step without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:16][CH2:17][CH2:18][CH3:19])=[C:6]([C:8]2[CH:13]=[C:12]([Cl:14])[N:11]=[C:10]([NH2:15])[N:9]=2)[CH:7]=1.N[C:21]1N=C(C2C=C(Br)C=CC=2O)C=C(Cl)N=1>C(O)CCC>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:16][CH2:17][CH2:18][CH2:19][CH3:21])=[C:6]([C:8]2[CH:13]=[C:12]([Cl:14])[N:11]=[C:10]([NH2:15])[N:9]=2)[CH:7]=1
Reactant: CCCOc1ccc(Br)cc1-c1cc(Cl)nc(N)n1
Reactant: Nc1nc(Cl)cc(-c2cc(Br)ccc2O)n1
Solvent: CCCCO
Product: CCCCOc1ccc(Br)cc1-c1cc(Cl)nc(N)n1
Yield: 51 %

Procedure:
Following the method described in Example 135 for the synthesis of 4-(5-bromo-2-propoxy-phenyl)-6-chloro-pyrimidin-2-ylamine, 2-(2-amino-6-chloro-pyrimidin-4-yl)-4-bromo-phenol and butan-1-ol provided 4-(5-bromo-2-butoxy-phenyl)-6-chloro-pyrimidin-2-ylamine (51% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:23])[C:9]1[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=1[N:16]1[CH:20]=[CH:19][N:18]=[C:17]1[CH2:21]O.[C:24]1(=[O:34])[NH:28][C:27](=[O:29])[C:26]2=[CH:30][CH:31]=[CH:32][CH:33]=[C:25]12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:23])[C:9]1[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=1[N:16]1[CH:20]=[CH:19][N:18]=[C:17]1[CH2:21][N:28]1[C:27](=[O:29])[C:26]2=[CH:30][CH:31]=[CH:32][CH:33]=[C:25]2[C:24]1=[O:34]
Reactant: O=C(c1ccccc1Cl)c1cc(F)ccc1-n1ccnc1CO
Reactant: O=C1NC(=O)c2ccccc21
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: O=C(c1ccccc1Cl)c1cc(F)ccc1-n1ccnc1CN1C(=O)c2ccccc2C1=O

Procedure:
In the manner given in Example 17, 2'-chloro-5-fluoro-2-[2-(hydroxymethyl)imidazol-1-yl]benzophenone is treated with phthalimide and triphenylphosphine and finally with diethyl azodicarboxylate to give 2'-chloro-5-fluoro-2-[2-(phthalimidomethyl)imidazol-1-yl]benzophenone.
Reaction SMILES: [CH2:1]([C@H:4]([CH2:8][C:9]#[C:10][CH3:11])[C:5]([OH:7])=O)[CH2:2][CH3:3].C(Cl)(=O)C(Cl)=O.Cl.[NH2:19][CH2:20][C:21]([NH2:23])=[O:22].Cl>ClCCl.CN(C)C=O.O.C(N(CC)CC)C>[NH2:23][C:21](=[O:22])[CH2:20][NH:19][C:5](=[O:7])[C@H:4]([CH2:1][CH2:2][CH3:3])[CH2:8][C:9]#[C:10][CH3:11]
Reactant: NCC(N)=O
Reactant: CC#CC[C@@H](CCC)C(=O)O
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: CC#CC[C@@H](CCC)C(=O)NCC(N)=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 70 %

Procedure:
(2R)-2-Propyl-4-hexynoic acid (2.0 g, 13 mmol, prepared according to U.S. Pat. No. 5,786,380) in dichloromethane (20 mL) was treated with 2 drops of N,N-dimethylformamide and freshly distilled oxalyl chloride (1.25 equivalents) at 0° C. The mixture was allowed to warm to ambient temperature. After stirring for 3 hours at ambient temperature, the solvents were removed under reduced pressure to provide crude acid chloride. The crude acid chloride was dissolved in dichloromethane (15 mL) and added dropwise to a solution of 2-aminoacetamide hydrochloride (14 mmol) and triethylamine (3.5 mL) in water at 0° C. The mixture was allowed to warm to ambient temperature. After stirring for 3 hours at ambient temperature, the mixture was cooled to about 5° C. and treated with 1N HCl until pH=2. The resulting white solid was collected by filtration, dried and recrystallized from ethyl acetate to provide the title compound (70% yield).
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[O:3][C:4]1[CH:24]=[CH:23][C:7]([O:8][CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][O:17][CH2:18][CH2:19][C:20](O)=[O:21])[CH2:11][CH2:10]2)=[CH:6][CH:5]=1.S(Cl)([Cl:29])=O>>[F:1][C:2]([F:26])([F:25])[O:3][C:4]1[CH:24]=[CH:23][C:7]([O:8][CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][O:17][CH2:18][CH2:19][C:20]([Cl:29])=[O:21])[CH2:11][CH2:10]2)=[CH:6][CH:5]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)CCOCCN1CCC(Oc2ccc(OC(F)(F)F)cc2)CC1
Product: O=C(Cl)CCOCCN1CCC(Oc2ccc(OC(F)(F)F)cc2)CC1
Yield: 100 %

Procedure:
3-(2-(4-(4-(trifluoromethoxy)phenoxy)piperidin-1-yl)ethoxy)propionic acid (377 mg, 1.0 mmol) was dissolved in thionyl chloride, raised the temperature to reflux for 3 h, spun dry, residuals were washed by an appropriate amount of ethyl ether, generated 395 mg target product, yield was 100%, directly put to the next reaction step.
Reaction SMILES: Br[C:2]1[C:22]([F:23])=[CH:21][C:5]2[O:6][C:7]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[O:8][C:4]=2[CH:3]=1.C([Li])CCC.[N:29]1([C:35](Cl)=[O:36])[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1.C(=O)(O)[O-].[Na+]>C(OCC)C>[F:23][C:22]1[C:2]([C:35]([N:29]2[CH2:34][CH2:33][O:32][CH2:31][CH2:30]2)=[O:36])=[CH:3][C:4]2[O:8][C:7]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[O:6][C:5]=2[CH:21]=1
Reactant: O=C(Cl)N1CCOCC1
Reactant: Fc1cc2c(cc1Br)OC(c1ccccc1)(c1ccccc1)O2
Agent: O=C([O-])O
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CCOCC
Product: O=C(c1cc2c(cc1F)OC(c1ccccc1)(c1ccccc1)O2)N1CCOCC1
Temperature: 20 °C
Yield: 67.6 %

Procedure:
To a cooled (−78° C.) solution of 5-bromo-6-fluoro-2,2-diphenyl-benzo[1,3]dioxole (17.59 g, 47.4 mmol) in diethyl ether (300 mL) was slowly added a solution of n-butyl lithium in hexanes (1.6M, 30 mL, 48 mmol, 1.0 eq.). The reaction mixture was stirred 1 h at −78° C. before the addition of 4-morpholinecarbonylchloride (8.5 g, 56.9 mmol, 1.2 eq.). The reaction mixture was allowed to warm to 20° C. and poured into an aqueous solution of sodium bicarbonate. The aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with brine. Volatiles were removed in vacuo. Purification by flash chromatography afforded the title compound (13.0 g, 68%) as a light yellow solid.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2[C:17]([CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[C:34]([F:38])[C:33]=3[CH3:39])=[C:18]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[N:19]3[C:24]=2[CH:23]=[CH:22][CH:21]=[CH:20]3)=[O:15])[CH2:10][CH2:9]1)=O)(C)(C)C>C(Cl)Cl.C(O)(C(F)(F)F)=O>[F:38][C:34]1[C:33]([CH3:39])=[C:32]([CH:37]=[CH:36][CH:35]=1)[CH2:31][C:17]1[C:16]([C:14]([N:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)=[O:15])=[C:24]2[N:19]([C:18]=1[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[CH:20]=[CH:21][CH:22]=[CH:23]2
Reactant: Cc1c(F)cccc1Cc1c(C(=O)N2CCN(C(=O)OC(C)(C)C)CC2)c2ccccn2c1-c1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1c(F)cccc1Cc1c(C(=O)N2CCNCC2)c2ccccn2c1-c1ccccc1
Reaction time: 8 h
Yield: 0.1 %

Procedure:
A solution of the compound of step 5 (158 mg, 299 mmol) in DCM (8 ml) and TFA (4 ml) was stirred at room temperature for 2 h. The solvents were evaporated and the residue was purified by preparative HPLC. The fractions containing the title compound were combined and lyophilized overnight. The obtained solid was dissolved in a small quantity of MOH, mixed with 0.1 N hydrochloric acid and the mixture lyophilized overnight to give 108 mg of the title compound in the form of [2-(3-fluoro-2-methyl-benzyl)-3-phenyl-indolizin-1-yl]-piperazin-1-yl-methanone hydrochloride with the following characteristics:
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][CH:6]([CH2:9][C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=2[S:17]([NH:20][C:21]2[C:30]([C:31]([O:33]C)=[O:32])=[C:29]3[C:24]([CH:25]4[CH2:35][CH:26]4[CH2:27][O:28]3)=[CH:23][CH:22]=2)(=[O:19])=[O:18])[CH2:5][CH2:4]1)[CH3:2].O.[OH-].[Li+].O>O1CCOCC1>[CH2:1]([N:3]1[CH2:8][CH2:7][CH:6]([CH2:9][C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=2[S:17]([NH:20][C:21]2[C:30]([C:31]([OH:33])=[O:32])=[C:29]3[C:24]([CH:25]4[CH2:35][CH:26]4[CH2:27][O:28]3)=[CH:23][CH:22]=2)(=[O:18])=[O:19])[CH2:5][CH2:4]1)[CH3:2]
Reactant: CCN1CCC(Cc2cc(F)ccc2S(=O)(=O)Nc2ccc3c(c2C(=O)OC)OCC2CC32)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CCN1CCC(Cc2cc(F)ccc2S(=O)(=O)Nc2ccc3c(c2C(=O)O)OCC2CC32)CC1
Temperature: 80 °C
Reaction time: 18 h
Yield: 43.1 %

Procedure:
Methyl (1aRS,7bSR)-5-[2-(1-ethylpiperidin-4-ylmethyl)-4-fluorobenzenesulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate (Intermediate 177, 0.279 g) and lithium hydroxide monohydrate (0.233 g) were suspended in dioxane (7 mL) and water (3 mL) and the mixture was stirred and heated at 80° C. for 25 hours. Further lithium hydroxide monohydrate (0.116 g) was added and the mixture heating was continued for 18 hours. After cooling, the volatiles were removed in vacuo, the residue was acidified by addition of aqueous citric acid solution (10%) and saturated with sodium chloride. The mixture was extracted with DCM and the organic layer was dried (Na2SO4) and filtered. The filtrate was evaporated to dryness and the residue was purified by preparative HPLC (C18), eluting with a mixture of methanol and water, containing 0.1% formic acid, with a gradient of 10-98% to give (1aRS,7bSR)-5-[2-(1-ethylpiperidin-4-ylmethyl)-4-fluorobenzenesulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid (0.117 g) as a white solid.