Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:5][C:6]1[CH:11]=[C:10](F)[CH:9]=[CH:8][C:7]=1[N+:13]([O-:15])=[O:14])[CH2:2][CH2:3][CH3:4].[C:16]([C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=1)([CH3:19])([CH3:18])[CH3:17].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH2:1]([NH:5][C:6]1[CH:11]=[C:10]([O:26][C:23]2[CH:24]=[CH:25][C:20]([C:16]([CH3:19])([CH3:18])[CH3:17])=[CH:21][CH:22]=2)[CH:9]=[CH:8][C:7]=1[N+:13]([O-:15])=[O:14])[CH2:2][CH2:3][CH3:4]
Reactant: CC(C)(C)c1ccc(O)cc1
Reactant: CCCCNc1cc(F)ccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCNc1cc(Oc2ccc(C(C)(C)C)cc2)ccc1[N+](=O)[O-]
Temperature: 90 °C
Reaction time: 10 h

Procedure:
A mixture of 2-n-butylamino-4-fluoronitrobenzene (10 mmol), 4-t-butylphenol (13 mmol), solid K2CO3 (30 mmol) and DMF (30 mL) was heated with stirring at 90° C. for 10 h. The reaction was quenched by cold H2O (50 mL), and the resulting mixture was extracted with EtOAc (3×100 mL). The combined EtOAc extracts were washed with brine (2×50 mL) and dried (anhydrous Na2SO4). The solvent was removed in vacuo, and the crude products were purified by silica gel column chromatography (eluting with 10% EtOAc in hexane), giving 2-n-butylamino-4-(4-t-butylphenoxy)nitrobenzene.
Reaction SMILES: [OH:1][N:2]=[CH:3][C:4]1[CH:19]=[CH:18][C:7]([C:8]([NH:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)=[O:9])=[C:6]([CH3:20])[CH:5]=1.[Cl:21][C:22]1[CH:23]=[C:24]([C:29]([C:31]([F:34])([F:33])[F:32])=[CH2:30])[CH:25]=[C:26]([Cl:28])[CH:27]=1.C(=O)([O-])O.[K+]>CN(C)C=O>[Cl:21][C:22]1[CH:23]=[C:24]([C:29]2([C:31]([F:34])([F:32])[F:33])[O:1][N:2]=[C:3]([C:4]3[CH:19]=[CH:18][C:7]([C:8]([NH:10][CH2:11][C:12]4[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=4)=[O:9])=[C:6]([CH3:20])[CH:5]=3)[CH2:30]2)[CH:25]=[C:26]([Cl:28])[CH:27]=1
Reactant: C=C(c1cc(Cl)cc(Cl)c1)C(F)(F)F
Reactant: Cc1cc(C=NO)ccc1C(=O)NCc1ccccn1
Agent: O=C([O-])O
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)NCc1ccccn1
Temperature: 70 °C
Reaction time: 1 h
Yield: 35.3 %

Procedure:
In a solution of 0.45 g of 4-hydroxyiminomethyl-2-methyl-N-(2-pyridylmethyl) benzoic acid amide in 10 ml of N,N-dimethylformamide, 0.25 g of N-chlorosuccinc acid imide was added, and stirred at 70° C. for 1 hour. Then, the reaction mixture was left and cooled to room temperature, 0.41 g of 3,5-dichloro-1-(1-trifluoromethylethenyl)benzene synthesized in Step 1 of Synthetic Example 3 and 0.25 g of potassium hydrogen carbonate were added, and stirred at room temperature for 3 hours. After the completion of the reaction, the reaction mixture was poured in 50 ml of ice water, extracted with ethyl acetate (60 ml×1), the organic phase was dehydrated with saturated sodium chloride aqueous solution and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified with silica gel column chromatography that was eluated with ethyl acetate-hexane (3:1), and 0.30 g of the aimed product was obtained as white crystal.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[C:5](F)=[CH:4][C:3]=1[CH3:12].[NH2:13][CH2:14][C:15]([O-:17])=[O:16].[Na+:18]>CN(C=O)C.O>[Na+:18].[Cl:1][C:2]1[C:3]([CH3:12])=[CH:4][C:5]([NH:13][CH2:14][C:15]([O-:17])=[O:16])=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1
Reactant: Cc1cc(F)c([N+](=O)[O-])cc1Cl
Reactant: NCC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(NCC(=O)[O-])c([N+](=O)[O-])cc1Cl
Temperature: 70 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 2-chloro-5-fluoro-4-nitrotoluene (0.605 g, 3.19 mmol, as prepared above) in DMF (3.0 mL) at 70° C., was added dropwise, a solution of sodium glycinate (0.310 g, 3.19 mmol, Aldrich, used as received) in water (3.0 mL). The resulting suspension was stirred overnight at 70° C. The suspension was cooled to room temperature and the resulting red solid was filtered, washed with chloroform (10 mL) and dried under vacuum to give 0.360 g (46%) pure (1H NMR) title compound as a red powder; 1H NMR (DMSO-d6): δ2.276 (s, 3H), 3.431 (d, 2H, J=4.2 Hz), 6.848 (s, 1H), 7.963 (s, 1H), 8.773 (s, 1H).
Reaction SMILES: [CH3:1][C:2]1([OH:12])[CH2:6][CH2:5][CH:4]([CH2:7][CH:8]=[CH2:9])[C:3]1([CH3:11])[CH3:10].[C:13](Cl)(=[O:15])[CH3:14]>>[CH3:1][C@@:2]1([O:12][C:13](=[O:15])[CH3:14])[CH2:6][CH2:5][C@@H:4]([CH2:7][CH:8]=[CH2:9])[C:3]1([CH3:11])[CH3:10]
Reactant: CC(=O)Cl
Reactant: C=CCC1CCC(C)(O)C1(C)C
Product: C=CC[C@@H]1CC[C@@](C)(OC(C)=O)C1(C)C

Procedure:
Using the procedure of Example 15, 1.6 g of 1,2,2-trimethyl-3-(2-propenyl)-cyclopentanol and 10 ml of acetyl chloride were reacted to obtain 1.3 of (1R,S) 1,2,2-trimethyl-1-acetyloxy-3-(2-propenyl)-cyclopentane.
Reaction SMILES: [F:1][CH:2]([CH2:6][CH2:7][C:8]#[CH:9])[C:3]([OH:5])=O.[NH2:10][C:11]([CH3:15])([CH3:14])[CH2:12]O.O>C1(C)C(C)=CC=CC=1>[F:1][CH:2]([C:3]1[O:5][CH2:12][C:11]([CH3:15])([CH3:14])[N:10]=1)[CH2:6][CH2:7][C:8]#[CH:9]
Reactant: CC(C)(N)CO
Reactant: C#CCCC(F)C(=O)O
Solvent: O
Solvent: Cc1ccccc1C
Product: C#CCCC(F)C1=NC(C)(C)CO1
Yield: 56.8 %

Procedure:
A mixture of 2-fluoro-5-hexynoic acid (3.0 g, 23.05 mmol) and 2-amino-2-methyl-1-propanol (2.05 g, 23.05 mmol) in 150 ml of dry xylene was refluxed for 16 h. The water formed during the reaction was removed by Linde 3A molecular sieves (15 g) contained in a continuous extractor. The xylene was then distilled off at atmospheric pressure, and the resulting pot material was taken into ether (100 ml). The ethereal solution was washed with saturated sodium bicarbonate solution, water, and dried over MgSO4. Evaporation of ether at 35° C./~ 35 mm, and distillation of the resulting crude product gave 2.4 g (57%) of 2-(1-fluoro-4-pentynyl)-4,5-dihydro-4,4-dimethyloxazole as a colorless liquid, bp 62°-66° C./0.6 mmHg.
Reaction SMILES: Br[CH2:2][CH2:3][CH3:4].C([O-])([O-])=O.[K+].[K+].CC(C)=O.[CH3:15][O:16][C:17](=[O:26])[C:18]1[CH:23]=[C:22]([OH:24])[CH:21]=[CH:20][C:19]=1[I:25]>O>[CH3:15][O:16][C:17](=[O:26])[C:18]1[CH:23]=[C:22]([O:24][CH2:2][CH2:3][CH3:4])[CH:21]=[CH:20][C:19]=1[I:25]
Reactant: COC(=O)c1cc(O)ccc1I
Reactant: CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: CCCOc1ccc(I)c(C(=O)OC)c1
Reaction time: 0.5 h

Procedure:
2.97 mL (32.7 mmol) 1-bromopropane and 299 mg (1.80 mmol) KI are added to a mixture of 3.39 g (24.5 mmol) K2CO3 and 200 mL acetone. The mixture is stirred for 30 min at reflux. Subsequently, 5.00 g (18.0 mmol) methyl-5-hydroxy-2-iodobenzoate are added and the resulting mixture is refluxed for 2 h. One additional equivalent of 1-bromopropane and of K2CO3 is added and refluxing is continued for 12 h. Water is added and the mixture is extracted with EtOAc. The organic layer is dried over sodium sulphate and the solvent is removed in vacuo. The crude product is purified by column chromatography (silica gel, heptane/EtOAc 100/0→60/40). The product is used without further characterization.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[C:5](=[CH:9][C:10]1[O:14][CH:13]=[CH:12][CH:11]=1)[C:6]([CH3:8])=O)[CH3:2].[C:16]([CH:21]=[C:22]1[NH:26][CH2:25][CH2:24][NH:23]1)([O:18][CH2:19][CH3:20])=[O:17]>C(O)C>[CH2:1]([O:3][C:4]([C:5]1[CH:9]([C:10]2[O:14][CH:13]=[CH:12][CH:11]=2)[C:21]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[C:22]2[NH:23][CH2:24][CH2:25][N:26]2[C:6]=1[CH3:8])=[O:15])[CH3:2]
Reactant: CCOC(=O)C(=Cc1ccco1)C(C)=O
Reactant: CCOC(=O)C=C1NCCN1
Solvent: CCO
Product: CCOC(=O)C1=C(C)N2CCNC2=C(C(=O)OCC)C1c1ccco1
Yield: 65 %

Procedure:
Boiling a solution of 6.9 g of 2-furfurylideneacetoacetic acid ethyl ester and 5.2 g of 2-carbethoxymethylideneimidazolidine in 50 ml of ethanol for 8 hours yields 5-methyl-7-(2-furyl)-1,2,3,7-tetrahydroimidazolo[1,2-a]pyridine-6,8-dicarboxylic acid diethyl ester of melting point 164° (ethanol).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[CH:9]=[CH:8][C:4]=1[C:5](Cl)=[O:6].[CH3:15][O:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH3:24])[CH:18]=1>CCOC(C)=O.[Cl-].[Zn+2].[Cl-]>[CH3:15][O:16][C:17]1[CH:18]=[C:19]([O:23][CH3:24])[CH:20]=[CH:21][C:22]=1[C:5]([C:4]1[CH:8]=[CH:9][C:10]([N+:12]([O-:14])=[O:13])=[CH:11][C:3]=1[O:2][CH3:1])=[O:6]
Reactant: COc1cccc(OC)c1
Reactant: COc1cc([N+](=O)[O-])ccc1C(=O)Cl
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CCOC(C)=O
Product: COc1ccc(C(=O)c2ccc([N+](=O)[O-])cc2OC)c(OC)c1
Temperature: 150 °C

Procedure:
2-Methoxy-4-nitro-benzoyl chloride (392) (0.5 g, 2.32 mmol), 1,3-dimethoxy-benzene (393) (0.962 g, 6.96 mmol) and zinc (II) chloride (0.063 g, 0.46 mmol) were combined. The mixture was heated to 150° C. for 30 minutes. TLC indicated product formation. The mixture was diluted with EtOAc (200 mL), washed with aqueous HCl (100 mL, 1.0 M), NaHCO3 (aqueous saturated, 100 mL) and brine (100 mL) via extraction, dried over MgSO4 and concentrated under reduced pressure. Purification by flash chromatography on silica gel using a gradient of hexane and EtOAc (eluting with 15–100% EtOAc/hexane in 30 minutes) gave the desired product along with the corresponding o-acylated product (10:1 ratio by NMR). Recrystallization from acetone followed by filtration under reduced pressure gave the desired product (394) as yellow cubic crystals (0.618 g, 2.0 mmol, >99% pure, 84% yield). 1H NMR (400 MHz, Acetone-d6): δ 3.53 (s, 3H), 3.78 (s, 3H), 3.85 (s, 3H), 6.58 (d, 1H, J=2.4 Hz), 6.64 (dd, 1H, J=8.4 Hz, 2 Hz), 7.44 (d, 1H, J=8 Hz), 7.63 (d, 1H, J=9.2 Hz), 7.81 (d, 1H, J=2 Hz), 7.84 (dd, 1H, J1=8.4 Hz, J2=2.4 Hz).
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH:25]1([C:31]2[C:32]3[CH:33]=[CH:34][C:35]([C:65](=[O:73])[NH:66][S:67]([CH:70]([CH3:72])[CH3:71])(=[O:69])=[O:68])=[CH:36][C:37]=3[N:38]3[CH2:44][C:43]([C:45]4[N:49]([CH:50]5[CH2:52][CH2:51]5)[N:48]=[C:47]([CH:53]([CH3:55])[CH3:54])[C:46]=4[C:56](O)=[O:57])=[CH:42][C:41]4[CH:59]=[C:60]([O:63][CH3:64])[CH:61]=[CH:62][C:40]=4[C:39]=23)[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1.Cl.Cl.[CH3:76][N:77]1[CH2:83][CH:82]2[NH:84][CH:79]([CH2:80][CH2:81]2)[CH2:78]1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH:25]1([C:31]2[C:32]3[CH:33]=[CH:34][C:35]([C:65]([NH:66][S:67]([CH:70]([CH3:72])[CH3:71])(=[O:68])=[O:69])=[O:73])=[CH:36][C:37]=3[N:38]3[CH2:44][C:43]([C:45]4[N:49]([CH:50]5[CH2:51][CH2:52]5)[N:48]=[C:47]([CH:53]([CH3:55])[CH3:54])[C:46]=4[C:56]([N:84]4[CH:82]5[CH2:81][CH2:80][CH:79]4[CH2:78][N:77]([CH3:76])[CH2:83]5)=[O:57])=[CH:42][C:41]4[CH:59]=[C:60]([O:63][CH3:64])[CH:61]=[CH:62][C:40]=4[C:39]=23)[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]1
Reactant: CN1CC2CCC(C1)N2
Reactant: COc1ccc2c(c1)C=C(c1c(C(=O)O)c(C(C)C)nn1C1CC1)Cn1c-2c(C2CCCCC2)c2ccc(C(=O)NS(=O)(=O)C(C)C)cc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)C=C(c1c(C(=O)N3C4CCC3CN(C)C4)c(C(C)C)nn1C1CC1)Cn1c-2c(C2CCCCC2)c2ccc(C(=O)NS(=O)(=O)C(C)C)cc21
Reaction time: 2 h
Yield: 36 %

Procedure:
HATU (65.0 mg, 0.171 mmol) was added to a stirring solution of 5-(13-cyclohexyl-10-((isopropylsulfonyl)carbamoyl)-3-methoxy-7H-indolo[2,1-a][2]benzazepin-6-yl)-1-cyclopropyl-3-isopropyl-1H-pyrazole-4-carboxylic acid (78 mg, 0.114 mmol), 3-methyl-3,8-diazabicyclo[3.2.1]octane dihydrochloride (45 mg, 0.23 mmol), DIEA (80 μL, 0.456 mmol) in DMF (1 mL) at room temperature. The reaction was allowed to stir for 2 hours. The reaction was purified by preparative reverse phase HPLC on a C18 column using a suitably buffered H2O/CH3CN gradient, and concentrated to give the titled compound (37 mg, 0.041 mmol, 36% yield) consistent by LCMS and NMR, with sufficient purity by HPLC.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([NH:10][C:11]3[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[N:14]=[C:13]([C:21]4[CH:22]=[C:23]([CH:29]=[CH:30][CH:31]=4)[O:24][CH2:25][C:26]([OH:28])=O)[N:12]=3)=[CH:7][CH:8]=2)[CH:3]=[N:2]1.C[CH2:33][N:34](C(C)C)C(C)C.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CN>C(Cl)Cl.CN(C=O)C>[NH:1]1[C:9]2[C:4](=[CH:5][C:6]([NH:10][C:11]3[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[N:14]=[C:13]([C:21]4[CH:22]=[C:23]([CH:29]=[CH:30][CH:31]=4)[O:24][CH2:25][C:26]([NH:34][CH3:33])=[O:28])[N:12]=3)=[CH:7][CH:8]=2)[CH:3]=[N:2]1
Reactant: CCN(C(C)C)C(C)C
Reactant: O=C(O)COc1cccc(-c2nc(Nc3ccc4[nH]ncc4c3)c3ccccc3n2)c1
Agent: CN
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CNC(=O)COc1cccc(-c2nc(Nc3ccc4[nH]ncc4c3)c3ccccc3n2)c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 2-(3-(4-(1H-indazol-5-ylamino)quinazolin-2-yl)phenoxy)acetic acid (80 mg, 0.16 mmol) in dry CH2Cl2:DMF (2.0:0.1 mL), added DIEA (29 μL, 0.16 mmol) and PyBOP® (46 mg, 0.088 mmol). After stirring the mixture at RT for 15 minutes, methanamine was bubbled through the solution for 15 minutes. Added another 1.0 equivalent of DIEA and 0.55 equivalents of PyBOP® after stirring the solution for 15 minutes, followed by methanamine bubbling for an additional 15 minutes. The solvent was removed in vacuo and the crude material was purified by prep HPLC (method 20-45_90 mins) to afford 2-(3-(4-(1H-indazol-5-ylamino)quinazolin-2-yl)phenoxy)-N-methylacetamide. (46 mg, 0.11 mmol, 68%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:24]=[C:25]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:26]=1)[C:12]([NH:14][C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-])=O)=[CH:17][N:16]=1)=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CN(C=O)C.O.[Zn]>[CH2:28]([O:27][C:25]1[CH:24]=[C:11]([CH:10]=[C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:26]=1)[C:12]([NH:14][C:15]1[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][N:16]=1)=[O:13])[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: O=C(Nc1ccc([N+](=O)[O-])cn1)c1cc(OCc2ccccc2)cc(OCc2ccccc2)c1
Agent: [Zn]
Solvent: O
Solvent: CN(C)C=O
Product: Nc1ccc(NC(=O)c2cc(OCc3ccccc3)cc(OCc3ccccc3)c2)nc1
Temperature: 120 °C
Reaction time: 3 h
Yield: 60.9 %

Procedure:
To a stirred solution of 2-[(3,5-dibenzyloxybenzoyl)amino]-5-nitropyridine (910 mg) in DMF (6 ml) was added Zinc dust (1300 mg) and a solution of ferric chloride hexahydrate (1700 mg) in water (6 ml). The resulting mixture was stirred at 120° C. for three hours. Allowed to cool to ambient temperature. The mixture was extracted with ethyl acetate. The extract was washed with water (50 ml), brine (50 ml), dried over MgSO4, then volatile material was removed by evaporation to leave a solid, which was dried under high vacuum for 24 hours at 100° C. to give the title compound (518 mg) as a solid, 1H NMR δ (d6-DMSO): 5.17 (m, 6H), 6.80 (s, 1H), 7.00 (d, 1H), 7.26 to 7.46 (m, 12H), 7.71 (s, 1H), 7.78 (d, 1H), 10.28 (br s, 1H). MS ES+ 426.52 (M+H)+.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[S:16][CH:17]=[C:18]([CH2:20][CH3:21])[N:19]=2)=[CH:11][C:10]=1[CH2:22][CH2:23][CH3:24])C1C=CC=CC=1.C([O-])=O.[NH4+]>[Pd].CCO>[CH2:20]([C:18]1[N:19]=[C:15]([C:12]2[CH:13]=[CH:14][C:9]([OH:8])=[C:10]([CH2:22][CH2:23][CH3:24])[CH:11]=2)[S:16][CH:17]=1)[CH3:21]
Reactant: CCCc1cc(-c2nc(CC)cs2)ccc1OCc1ccccc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: CCCc1cc(-c2nc(CC)cs2)ccc1O
Temperature: 40 °C
Reaction time: 2 h

Procedure:
Under an atmosphere of argon, palladium on charcoal (0.10 g) was added to a solution of 2-[4-(benzyloxy)-3-propylphenyl]-4-ethyl-1,3-thiazole (0.86 g, 2.53 mmol) (Example 32) and ammonium formate (1.28 g, 20.3 mmol) in EtOH (45 mL). The mixture was stirred at 40° C. for 2 h, and then cooled to rt. The solvent was evaporated and the material was suspended in EtOAc. This suspension was filtered through a small plug of silica gel and then concentrated to give a crude solid. The product was used in the next step without further purification. 1H NMR (400 MHz, CDCl3): δ 7.66 (s, 1H), 7.56 (d, 1H), 6.77-6.66 (m, 2H), 5.70-5.42 (br, 1H), 2.88-2.76 (m, 2H), 2.64-2.55 (m, 2H), 1.72-1.57 (q, 2H), 1.31 (t, 3H), 0.95 (t, 3H).
Reaction SMILES: [CH2:1]([C@@:3]1([CH2:10][S:11](Cl)(=[O:13])=[O:12])[C:7](=[O:8])[NH:6][C:5](=[O:9])[NH:4]1)[CH3:2].Cl.[F:16][C:17]([F:34])([F:33])[CH2:18][O:19][C:20]1[CH:32]=[CH:31][C:23]([O:24][CH:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)=[CH:22][CH:21]=1.C(N(CC)CC)C>ClCCl>[CH2:1]([C@:3]1([CH2:10][S:11]([N:28]2[CH2:29][CH2:30][CH:25]([O:24][C:23]3[CH:22]=[CH:21][C:20]([O:19][CH2:18][C:17]([F:16])([F:33])[F:34])=[CH:32][CH:31]=3)[CH2:26][CH2:27]2)(=[O:13])=[O:12])[NH:4][C:5](=[O:9])[NH:6][C:7]1=[O:8])[CH3:2]
Reactant: FC(F)(F)COc1ccc(OC2CCNCC2)cc1
Reactant: CC[C@]1(CS(=O)(=O)Cl)NC(=O)NC1=O
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC[C@]1(CS(=O)(=O)N2CCC(Oc3ccc(OCC(F)(F)F)cc3)CC2)NC(=O)NC1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 98 %

Procedure:
[(4S)-4-ethyl-2,5-dioxoimidazolidin-4-yl]methanesulfonyl chloride (WO 2004/024698) (869 mg) was added to a stirred solution of 4-[4-(2,2,2-trifluoroethoxy)phenoxy]piperidine hydrochloride (750 mg) and triethylamine (1.68 ml) in dichloromethane (50 ml) and the reaction stirred at ambient temperature for 2 hours. The solvents were removed in vacuo and the residue stirred in water for 2 hours. The resulting solid was filtered off, washed with water then ether and dried to give the title compound (1.13 g); NMR Spectrum: (DMSOd6) 0.78 (t, 3H), 1.25 (m, 2H), 1.66 (m, 4H), 1.94 (m, 2H), 3.11 (m, 2H), 3.49 (d, 1H), 3.58 (m, 1H), 4.41 (m, 1H), 4.64 (q, 2H), 6.97 (m, 4H), 8.5 (s, 1H), 10.71 (s, 1H); Mass Spectrum: M−H− 478.
Reaction SMILES: [OH-].[Li+].O1CCCC1.C[O:9][C:10](=[O:28])[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:27]=[CH:26][C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:19]=2)=[CH:14][CH:13]=1.Cl>CO>[CH:19]1[C:20]2[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:26]=[CH:27][C:18]=1[C:15]1[CH:16]=[CH:17][C:12]([CH2:11][C:10]([OH:28])=[O:9])=[CH:13][CH:14]=1
Reactant: COC(=O)Cc1ccc(-c2ccc3ccccc3c2)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)Cc1ccc(-c2ccc3ccccc3c2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.9 %

Procedure:
Lithium hydroxide, 2M, (3.0 mL) was added to a 2:1 tetrahydrofuran:methanol (9.0 mL) solution of (4-Naphthalen-2-yl-phenyl)-acetic acid methyl ester (270 mg, 0.977 mmol). The resulting mixture was stirred at room temperature for 1 hour. The reaction was acidified to pH=1 with 1M hydrochloric acid and extracted twice with ethyl acetate. The combined organic portions were washed with brine, dried over magnesium sulfate and concentrated in vacuo to give the title compound as a white solid (233mg, 91%). 1H NMR (400 MHz, CDCl3) δ8.01-7.39 (m, 11H), 3.72 (s, 2H)
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([CH3:12])=[N:9]2)=[CH:4][CH:3]=1.[N:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C:19]1[CH:27]=[CH:26][C:22]([C:23](O)=[O:24])=[CH:21][CH:20]=1>>[CH3:12][C:8]1[CH:7]=[CH:6][C:5]2[C:10](=[CH:11][C:2]([NH:1][C:23](=[O:24])[C:22]3[CH:26]=[CH:27][C:19]([C:14]4[CH:15]=[CH:16][CH:17]=[CH:18][N:13]=4)=[CH:20][CH:21]=3)=[CH:3][CH:4]=2)[N:9]=1
Reactant: O=C(O)c1ccc(-c2ccccn2)cc1
Reactant: Cc1ccc2ccc(N)cc2n1
Product: Cc1ccc2ccc(NC(=O)c3ccc(-c4ccccn4)cc3)cc2n1

Procedure:
Using the procedure outlined in Example 56, the title compound was prepared from 7-amino-2-methylquinoline (D66) (33 mg, 0.21 mmol) and 4-(2-pyridyl)benzoic acid (D67) (50 mg, 0.25 mmol) as a white solid. MS (ES): MH+ 340, M-H+ 338.
Reaction SMILES: [CH2:1]([C:3]1[C:4](=[O:30])[NH:5][C:6](=[O:29])[N:7]([CH:28]=1)[C@@H:8]1[O:27][C@H:12]([CH2:13][NH:14][C:15](=[O:26])[CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[N+:23]([O-])=O)[C@@H:10]([OH:11])[CH2:9]1)[CH3:2].[H][H]>C(O)C.[Pd]>[NH2:23][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[CH2:16][C:15]([NH:14][CH2:13][C@H:12]1[O:27][C@@H:8]([N:7]2[CH:28]=[C:3]([CH2:1][CH3:2])[C:4](=[O:30])[NH:5][C:6]2=[O:29])[CH2:9][C@@H:10]1[OH:11])=[O:26]
Reactant: [H][H]
Reactant: CCc1cn([C@H]2C[C@H](O)[C@@H](CNC(=O)Cc3ccccc3[N+](=O)[O-])O2)c(=O)[nH]c1=O
Agent: [Pd]
Solvent: CCO
Product: CCc1cn([C@H]2C[C@H](O)[C@@H](CNC(=O)Cc3ccccc3N)O2)c(=O)[nH]c1=O
Yield: 53.9 %

Procedure:
A solution of 0.2 g of 2',5'-dideoxy-5-ethyl-5'-[2-(2-nitrophenyl)acetamido]uridine in 100 ml of ethanol was hydrogenated over 0.1 g of 10% palladium-on-carbon catalyst at room temperature and under atmospheric pressure until the uptake of hydrogen was complete. The mixture was filtered and the filtrate was evaporated to yield an oil which crystallized from ethanol to give 0.1 g of 5'-[2-(2-aminophenyl)acetamido]-2',5'-dideoxy-5-ethyluridine in the form of a white solid of melting point 195°-196° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:15]=[C:14]([N+:16]([O-])=O)[CH:13]=[CH:12][C:4]=1[O:5][CH2:6][CH2:7][N:8]1[CH2:11][CH2:10][CH2:9]1>C1COCC1.C(O)C.[Pd]>[N:8]1([CH2:7][CH2:6][O:5][C:4]2[CH:12]=[CH:13][C:14]([NH2:16])=[CH:15][C:3]=2[O:2][CH3:1])[CH2:11][CH2:10][CH2:9]1
Reactant: COc1cc([N+](=O)[O-])ccc1OCCN1CCC1
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: COc1cc(N)ccc1OCCN1CCC1
Temperature: 25 °C
Reaction time: 50 h
Yield: 100.7 %

Procedure:
1-[2-(2-methoxy-4-nitro-phenoxy)-ethyl]-azetidine (53.5 mg, 0.21 mmol) was dissolved in a 1:1 mixture of THF and ethanol (7 ml) and 10% palladium on carbon paste (150 mg) introduced. The reaction mixture was stirred under an atmosphere of hydrogen for 50 hours at RT. The catalyst was filtered off over filter-aid and the filtrate evaporated to give 4-[2-azetidin-1-yl-ethoxy]-3-methoxy-phenylamine as a brown oil (47 mg, 100%). This material was treated with 3-phenoxyphthalic anhydride in the same manner as for 4-(2-diisopropylamino-ethoxy)-3-methoxy-phenylamine in Example A4 to give the title compound.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:12](=[O:13])[C:11]2[CH:14]=[C:15]([CH3:17])[S:16][C:10]=2[S:9][CH2:8][CH2:7]1.[C:18]1(=[O:28])[NH:22][C:21](=[O:23])[C:20]2=[CH:24][CH:25]=[CH:26][CH:27]=[C:19]12.[K].O>CN(C)C=O>[OH2:13].[C:18]1(=[O:28])[N:22]([CH2:2][CH2:3][CH2:4][CH2:5][N:6]2[C:12](=[O:13])[C:11]3[CH:14]=[C:15]([CH3:17])[S:16][C:10]=3[S:9][CH2:8][CH2:7]2)[C:21](=[O:23])[C:20]2=[CH:24][CH:25]=[CH:26][CH:27]=[C:19]12
Reactant: Cc1cc2c(s1)SCCN(CCCCCl)C2=O
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc2c(s1)SCCN(CCCCN1C(=O)c3ccccc3C1=O)C2=O
Reaction time: 6 h
Yield: 212.4 %

Procedure:
To a solution of 3.0 g of 4-(4-chlorobutyl)-2,3-dihydro-7-methylthieno[3,2-f][1,4]thiazepin-5(4H)-one in 30 ml of dimethylformamide was added 2.3 g of potassium phthalimide and stirred at 70°-80° C. for 6 hours. After cooling, the mixture was poured into water and extracted with ethyl acetate. The extract was washed with water, dried and concentrated in vacuo. The resulting crude crystals were recrystallized from methanol to give 4.6 g of 4-(4-phthalimidobutyl)-2,3-dihydro-7-methylthieno[3,2-f][1,4]thiazepin-5(4H)-one hydrate as white crystals, melting at 120°-121° C.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]3[O:15][CH2:14][C@H:13]([CH2:16]OS(C4C=CC(Br)=CC=4)(=O)=O)[O:12][C:8]3=2)[N:3]=1.[C:28]([C:30]1[CH:31]=[C:32]2[C:36](=[CH:37][CH:38]=1)[N:35]([CH3:39])[CH:34]=[C:33]2[CH2:40][CH2:41][CH2:42][NH2:43])#[N:29].C(N(CC)CC)C>CS(C)=O>[CH3:39][N:35]1[C:36]2[C:32](=[CH:31][C:30]([C:28]#[N:29])=[CH:38][CH:37]=2)[C:33]([CH2:40][CH2:41][CH2:42][NH:43][CH2:16][CH:13]2[O:12][C:8]3=[C:9]4[C:4](=[CH:5][CH:6]=[C:7]3[O:15][CH2:14]2)[N:3]=[C:2]([CH3:1])[CH:11]=[CH:10]4)=[CH:34]1
Reactant: Cn1cc(CCCN)c2cc(C#N)ccc21
Reactant: Cc1ccc2c3c(ccc2n1)OC[C@H](COS(=O)(=O)c1ccc(Br)cc1)O3
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: Cc1ccc2c3c(ccc2n1)OCC(CNCCCc1cn(C)c2ccc(C#N)cc12)O3

Procedure:
A solution of (2R)-4-bromobenzenesulfonic acid-8-methyl-2,3-dihydro-[1,4]dioxino[2,3-f]quinolin-2-ylmethyl ester (0.5 g, 1.1 mmol), 3-(5-cyano-1-methyl-indol-3-yl)propylamine (0.33 g, 1,4 mmol) and triethylamine (0.23 mL, 2.2 mmol) in dimethylsulfoxide (20 mL) was heated at 90° C. under nitrogen for 16 hours. The reaction mixture was quenched with 1N sodium hydroxide and extracted with methylene chloride (3×100 mL). The organic layer was washed with water (3×150 mL), dried over anhydrous sodium sulfate, filtered and the solvent was removed under vacuum. The crude oil was column chromatographed on silica gel (10% methanol-ethyl acetate). The product-containing fractions were concentrated in vacuum to give 0.2 g of the (S)-enantiomer of the title compound as a brown oil. The dihydrochloride salt was prepared in ethyl acetate as a yellow solid (decomposed at 148° C.).