Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][C:8]1[CH:18]=[CH:17][C:11]([O:12][CH2:13][CH:14]2[O:16][CH2:15]2)=[CH:10][CH:9]=1)[CH:2]([CH3:4])[CH3:3].[NH2:19][CH2:20][CH2:21][N:22]1[C:26]2[CH:27]=[CH:28][C:29]([C:31]3[CH2:32][CH2:33][C:34](=[O:37])[NH:35][N:36]=3)=[CH:30][C:25]=2[N:24]=[N:23]1>>[CH2:1]([O:5][CH2:6][CH2:7][C:8]1[CH:18]=[CH:17][C:11]([O:12][CH2:13][CH:14]([OH:16])[CH2:15][NH:19][CH2:20][CH2:21][N:22]2[C:26]3[CH:27]=[CH:28][C:29]([C:31]4[CH2:32][CH2:33][C:34](=[O:37])[NH:35][N:36]=4)=[CH:30][C:25]=3[N:24]=[N:23]2)=[CH:10][CH:9]=1)[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)COCCc1ccc(OCC2CO2)cc1
Reactant: NCCn1nnc2cc(C3=NNC(=O)CC3)ccc21
Product: CC(C)COCCc1ccc(OCC(O)CNCCn2nnc3cc(C4=NNC(=O)CC4)ccc32)cc1

Procedure:
Prepared analogously to Example 1 from 1-[4-(2-isobutoxyethyl)phenoxy]-2,3-epoxypropane and 6-[1-(2-aminoethyl)benztriazol-5-yl]-4,5-dihydro-3(2H)-pyridazinone.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C:10]([NH2:14])([CH3:13])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[C:21](Cl)(=[O:30])[O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C1COCC1.O>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C:10]([NH:14][C:21]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:30])([CH3:13])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC1(N)CCN(C(=O)OC(C)(C)C)C1
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CC1(NC(=O)OCc2ccccc2)CCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 65.8 %

Procedure:
To a mixture of 3-amino-3-methyl-pyrrolidine-1-carboxylic acid tert-butyl ester (5.0 g, 25 mmol) and potassium carbonate (3.8 g, 27 mmol) in THF (25 mL) and water (25 mL) was added benzyl carbonochloridate (4.6 g, 27 mmol) at 0° C. and the reaction mixture was stirred at ambient temperature overnight. The reaction mixture was diluted with water (25 mL) and extracted with EtOAc (3×15 mL). The combined organic phase was washed with brine (25 mL), dried over sodium sulfate and filtered. The filtrate was concentrated in vacuo and the residue was purified by column chromatography on silica gel (eluting with 4% EtOAc in petroleum) to give 3-benzyloxycarbonylamino-3-methyl-pyrrolidine-1-carboxylic acid tert-butyl ester (5.5 g, 70%). 1H NMR (400 MHz, CDCl3) δ 7.35 (s, 5H), 5.14-5.02 (m, 2H), 4.88-4.79 (m, 1H), 3.63-3.23 (m, 4H), 2.25 (m, 1H), 1.88-1.77 (m, 1H), 1.45 (s, 12H).
Reaction SMILES: [C:1]1([S:7]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH2:18][CH2:19]Cl)[C:12]=2[NH2:21])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N-:22]=[N+:23]=[N-:24].[Na+]>CS(C)=O.O>[N:22]([CH2:19][CH2:18][O:17][C:13]1[CH:14]=[CH:15][CH:16]=[C:11]([CH2:10][S:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)(=[O:9])=[O:8])[C:12]=1[NH2:21])=[N+:23]=[N-:24]
Reactant: Nc1c(CS(=O)(=O)c2ccccc2)cccc1OCCCl
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: [N-]=[N+]=NCCOc1cccc(CS(=O)(=O)c2ccccc2)c1N
Temperature: 90 °C
Reaction time: 3 h

Procedure:
A mixture of 2-benzenesulfonylmethyl-6-(2-chloro-ethoxy)-phenylamine (0.5 g, 1.53 mmoles) and sodium azide (0.15 g, 2.29 mmoles) in DMSO (10 mL) was stirred together in a round bottom flask under nitrogen at 90° C. for 3 hours. Reaction mixture was cooled to room temperature, diluted with water, extracted with EtOAC, washed with water (2×), brine (1×), dried over Na2SO4, and concentrated under vacuum. Crude compound was purified by normal phase HPLC using as eluent 40% EtOAc/hexane to afford the title compound as an off white solid (0.39 g, 1.17 mmoles).
Reaction SMILES: C([O:3][C:4](=[O:20])[C@@H:5]([O:18][CH3:19])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]([OH:17])=O)=[CH:9][CH:8]=1)C.[C:21]1([CH3:33])[CH:26]=[CH:25][C:24]([N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)=[CH:23][CH:22]=1.C(O[C@@H](CC1C=CC(O[C@@H](C(=O)NCCC2C=CC(OC3C=CC=CC=3)=CC=2)C)=CC=1)C(O)=O)C>>[CH3:19][O:18][C@@H:5]([CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][CH2:14][C:15](=[O:17])[N:30]2[CH2:31][CH2:32][N:27]([C:24]3[CH:25]=[CH:26][C:21]([CH3:33])=[CH:22][CH:23]=3)[CH2:28][CH2:29]2)=[CH:11][CH:12]=1)[C:4]([OH:3])=[O:20]
Reactant: CCOC(=O)[C@H](Cc1ccc(OCC(=O)O)cc1)OC
Reactant: Cc1ccc(N2CCNCC2)cc1
Agent: CCO[C@@H](Cc1ccc(O[C@H](C)C(=O)NCCc2ccc(Oc3ccccc3)cc2)cc1)C(=O)O
Product: CO[C@@H](Cc1ccc(OCC(=O)N2CCN(c3ccc(C)cc3)CC2)cc1)C(=O)O

Procedure:
The title compound was prepared from (2S)-3-(4-carboxymethoxy-phenyl)-2-methoxy-propionic acid ethyl ester (PREPARATION 3, step 2) and 1-p-tolyl-piperazine via the same procedure used for the preparation of (2S,1R)-2-ethoxy-3-(4-{1-[2-(4-phenoxy-phenyl)-ethylcarbamoyl]-ethoxy}-phenyl)-propionic acid (Example 1, step 3) to produce a yellow oil. MS (ES) for C23H28N2O5 [M+H]+: 413.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][N:12]([C@@H:15]2[CH2:24][C:23]3[C:22]([OH:25])=[CH:21][CH:20]=[CH:19][C:18]=3[CH2:17][C@H:16]2[OH:26])[CH2:11][CH2:10]1.[N+](=[CH2:29])=[N-]>CO>[CH3:29][O:25][C:22]1[CH:21]=[CH:20][CH:19]=[C:18]2[C:23]=1[CH2:24][C@@H:15]([N:12]1[CH2:11][CH2:10][N:9]([C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[O:2][CH3:1])[CH2:14][CH2:13]1)[C@H:16]([OH:26])[CH2:17]2
Reactant: COc1ccccc1N1CCN([C@@H]2Cc3c(O)cccc3C[C@H]2O)CC1
Reactant: C=[N+]=[N-]
Solvent: CO
Product: COc1ccccc1N1CCN([C@@H]2Cc3c(cccc3OC)C[C@H]2O)CC1
Reaction time: 48 h

Procedure:
A solution of 2.0 g of trans-5,6,7,8-tetrahydro-7-[4-(2-methoxyphenyl)-1-piperazinyl]-1,6-naphthalenediol in methanol is treated with about 2 equivalents of freshly prepared diazomethane. The solution is stored at 0° C for 48 hours. The solvent is removed in vacuo, the residue is dissolved in ethyl acetate and washed with dilute sodium hydroxide solution. After drying and removal of solvent in vacuo, an oil remains which crystallizes on trituration with a very small amount of ether. The crystalline material is washed with a small amount of isopropyl ether and recrystallized from etherisopropyl ether to give 1.13 g of the title compound, melting point 138°-141° C.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([N:12]3[CH2:17][CH2:16][CH2:15][CH:14]4[C:18]5[CH:19]=[C:20]([C:25]6[CH2:26][CH2:27][O:28][CH2:29][CH:30]=6)[CH:21]=[CH:22][C:23]=5[CH2:24][CH:13]34)=[O:11])=[CH:9][C:4]=2[N:3]=[CH:2]1>[Pd].CO>[NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([N:12]3[CH2:17][CH2:16][CH2:15][C@@H:14]4[C:18]5[CH:19]=[C:20]([CH:25]6[CH2:26][CH2:27][O:28][CH2:29][CH2:30]6)[CH:21]=[CH:22][C:23]=5[CH2:24][C@H:13]34)=[O:11])=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: O=C(c1ccc2[nH]cnc2c1)N1CCCC2c3cc(C4=CCOCC4)ccc3CC21
Agent: [Pd]
Solvent: CO
Product: O=C(c1ccc2[nH]cnc2c1)N1CCC[C@@H]2c3cc(C4CCOCC4)ccc3C[C@@H]21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of (1H-benzoimidazol-5-yl)-[6-(3,6-dihydro-2H-pyran-4-yl)-2,3,4,4a,9,9a-hexahydro-indeno[2,1-b]pyridin-1-yl]methanone (48 mg), 10% palladium on carbon (10 mg), and methanol (3 mL) is shaken under hydrogen atmosphere (5 bar) at room temperature overnight. The catalyst is then separated by filtration and the filtrate is concentrated. The residue is purified by chromatography on silica gel (dichloromethane/methanol 1:0→9:1) to afford the title compound. Yield: 15 mg (31% of theory); LC (method 1): tR=2.63 min; Mass spectrum (ESI+): m/z=402 [M+H]+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]#[N:9])[C:5]([C:10]([F:13])([F:12])[F:11])=[CH:4][C:3]=1[CH3:14].N>CO.[Ni]>[CH3:14][C:3]1[CH:4]=[C:5]([C:10]([F:13])([F:11])[F:12])[C:6]([CH2:8][NH2:9])=[N:7][CH:2]=1
Reactant: Cc1cc(C(F)(F)F)c(C#N)nc1Cl
Agent: [Ni]
Agent: N
Solvent: CO
Product: Cc1cnc(CN)c(C(F)(F)F)c1
Yield: 43.7 %

Procedure:
A solution of 6-chloro-5-methyl-3-trifluoromethyl-pyridine-2-carbonitrile (0.300 g, 1.36 mmol) in MeOH (5 mL) was added to a flask charged with Raney Ni (pre-washed with methanol) (0.6 g) in MeOH (5 mL). After saturated with NH3 gas the mixture was shaken under H2 (40 psi) for 2 h. The reaction mixture was then filtered through a celite cake, and the filtrate was concentrated by evaporation under vacuum. The residue was purified by flash chromatography on a silica gel column (200:10:1 CH2Cl2/MeOH/NH4OH), affording C-(5-methyl-3-trifluoromethyl-pyridin-2-yl)-methylamine as a colorless oil (0.113 g, 44%). 1H NMR (CDCl3) δ 2.39 (s, 3H), 4.07 (s, 2H), 7.71 (s, 1H), 8.56 (s, 1H).
Reaction SMILES: C([O:3][C:4](=[O:34])[CH2:5][CH2:6][C:7]1[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:8]=1[O:14][CH2:15][C:16]([N:18]1[CH2:23][C@H:22]([CH3:24])[N:21]([CH2:25][C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)[CH2:20][C@H:19]1[CH3:33])=[O:17])C.O.[OH-].[Li+].Cl>O1CCCC1.CO.O>[Cl:13][C:11]1[CH:10]=[CH:9][C:8]([O:14][CH2:15][C:16]([N:18]2[CH2:23][C@H:22]([CH3:24])[N:21]([CH2:25][C:26]3[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=3)[CH2:20][C@H:19]2[CH3:33])=[O:17])=[C:7]([CH2:6][CH2:5][C:4]([OH:34])=[O:3])[CH:12]=1
Reactant: CCOC(=O)CCc1cc(Cl)ccc1OCC(=O)N1C[C@H](C)N(Cc2ccc(F)cc2)C[C@H]1C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: C[C@@H]1CN(Cc2ccc(F)cc2)[C@@H](C)CN1C(=O)COc1ccc(Cl)cc1CCC(=O)O
Temperature: 25 °C
Reaction time: 12 h
Yield: 80 %

Procedure:
To a solution of 3-(5-chloro-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl-piperazin-1-yl]-2-oxo-ethoxy}-phenyl)-propionic acid ethyl ester (1.3 g, 2.7 mmol) in tetrahydrofuran (10 mL), methanol (10 mL) and water (4 mL) was added lithium hydroxide monohydrate (0.57 g, 13.3 mmol). The reaction was stirred at ambient temperature for 12 hours, then made acidic by the addition of 1 M hydrochloric acid. The solution was then extracted with methylene chloride and the organic layer was dried over magnesium sulfate. Concentration in vacuo gave the title compound (1.0 g).
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:12]1[C:36]([CH3:37])=[N:35][C:34]2=[CH:38][C:31]3=[N:32][N:33]2[C:13]=1[N:14]1[CH2:41][CH2:40][C:17]([CH3:42])([O:18][CH2:19][CH2:20][CH2:21][C:22]2[CH:23]=[C:24]([F:39])[CH:25]=[CH:26][C:27]=2[CH2:28][O:29][CH2:30]3)[CH2:16][CH2:15]1)[C:7]([O:9]CC)=[O:8])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>CCO>[C:1]([O:5][C@@H:6]([C:12]1[C:36]([CH3:37])=[N:35][C:34]2=[CH:38][C:31]3=[N:32][N:33]2[C:13]=1[N:14]1[CH2:15][CH2:16][C:17]([CH3:42])([O:18][CH2:19][CH2:20][CH2:21][C:22]2[CH:23]=[C:24]([F:39])[CH:25]=[CH:26][C:27]=2[CH2:28][O:29][CH2:30]3)[CH2:40][CH2:41]1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)nc2cc3nn2c1N1CCC(C)(CC1)OCCCc1cc(F)ccc1COC3
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1nc2cc3nn2c(c1[C@H](OC(C)(C)C)C(=O)O)N1CCC(C)(CC1)OCCCc1cc(F)ccc1COC3
Temperature: 25 °C
Yield: 45.5 %

Procedure:
A mixture of ethyl (2S)-2-(tert-butoxy)-2-{16-fluoro-4,23-dimethyl-11,22-dioxa-1,5,7,8-tetraazapentacyclo[21.2.2.16,9.02,7.013,18]octacosa-2,4,6(28),8,13(18),14,16-heptaen-3-yl}acetate (32 mg, 0.055 mmol) and NaOH (2.196 mg, 0.055 mmol) in EtOH (2 mL) was refluxed for 2 h. It was then cooled to rt and purified by preparative HPLC to isolate (2S)-2-(tert-butoxy)-2-{16-fluoro-4,23-dimethyl-11,22-dioxa-1,5,7,8tetraazapentacyclo[21.2.2.16,9.02,7.013,18]octacosa-2,4,6(28),8,13(18),14,16-heptaen-3-yl}acetic acid (13.9 mg, 0.025 mmol, 44.7% yield) as a white solid. 1H NMR (500 MHz, DMSO-d6) δ 7.49-7.41 (m, 1H), 7.11-7.00 (m, 2H), 6.47 (s, 1H), 5.91 (s, 1H), 4.92 (d, J=11.7 Hz, 1H), 4.75 (d, J=12.1 Hz, 1H), 4.71-4.55 (m, 3H), 3.84 (t, J=10.6 Hz, 1H), 3.50 (m, 2H), 3.16-3.01 (m, 3H), 2.59 (d, J=11.7 Hz, 1H), 2.53 (s, 3H), 1.99-1.79 (m, 4H), 1.77-1.54 (m, 2H), 1.24 (s, 3H), 1.19 (s, 9H). LCMS (M+1)=555.2.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:15]([O:17][CH2:18][CH2:19][CH2:20][O:21][C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([N+:28]([O-])=O)[CH:23]=4)=[N:14][CH:13]=[N:12][C:11]=3[S:10][CH:9]=2)=[CH:4][CH:3]=1.[H][H]>O1CCCC1.CO.C(O)(=O)C.[Pd]>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:15]([O:17][CH2:18][CH2:19][CH2:20][O:21][C:22]4[CH:23]=[C:24]([CH:25]=[CH:26][CH:27]=4)[NH2:28])=[N:14][CH:13]=[N:12][C:11]=3[S:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: [H][H]
Reactant: O=[N+]([O-])c1cccc(OCCCOc2ncnc3scc(-c4ccc(F)cc4)c23)c1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: CO
Product: Nc1cccc(OCCCOc2ncnc3scc(-c4ccc(F)cc4)c23)c1
Yield: 77.4 %

Procedure:
5-(4-Fluorophenyl)-4-[3-(3-nitrophenoxy)propoxy]thieno[2,3-d]pyrimidine (250 mg, 0.588 mmol) was dissolved in tetrahydrofuran (15 mL) and added (under an atmosphere of argon) to a suspension of 25 mg of 10% palladium/carbon in methanol (30 mL) and acetic acid (5 mL). The mixture was then shaken under 40 psi of hydrogen overnight. The palladium/carbon was removed by filtration and the filtrate was concentrated in vacuo. The residue was dissolved in ethyl acetate (50 mL) and washed with aqueous sodium bicarbonate solution (2×30 mL). The organic layer was separated, concentrated, and purified by column chromatography over silica gel using 33% ethyl acetate in hexanes as eluant to give 180 mg (76%) of 3-(3-{[5-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}propoxy)aniline as a colorless gum. MS [M+H] 396.1, 1H NMR (CDCl3) δ (ppm) 8.65 (s, 1H), 7.45-7.40 (m, 2H), 7.21 (s, 1H), 7.09-7.00 (m, 3H), 6.30 (d, J=2.1 Hz, 1H), 6.20 (d, J=2.8 Hz, 1H), 6.11 (s, 1H), 4.58 (t, J=6.0 Hz, 2H), 3.69 (t, J=6.0 Hz, 3H), 3.68 (b, 2H), 2.05 (m, 2H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:27][C:28]([O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:29].Cl>CN(C=O)C>[C:1]([O:5][C:6]([NH:8][C:9]([CH2:27][C:28]([O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:29])([C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)C(NC(=O)OC(C)(C)C)C(=O)OCC
Reactant: O=C(CBr)OCc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(CC(=O)OCc1ccccc1)(NC(=O)OC(C)(C)C)C(=O)OCC
Temperature: 50 °C
Reaction time: 4 h
Yield: 84.5 %

Procedure:
A suspension of diethyl 2-t-butyloxycarbonylaminomalonate (5.0 g), potassium carbonate (3.0 g), and benzyl 2-bromoacetate (5.4 g) in DMF (20 mL) was stirred at 50° C. for 4 hours. The reaction mixture was cooled, and then poured into diluted hydrochloric acid, the mixture was extracted with ethyl acetate, and the extract was washed with saturated brine, and then dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was subjected to silica gel column chromatography, and then purification was performed with n-hexane/ethyl acetate (5:1), to obtain the title compound (6.5 g, yield: 85%) as colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:16])([CH2:12][C:13]([OH:15])=[O:14])[C:9](O)=[O:10])=[CH:4][CH:3]=1>C(OC(=O)C)(=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH3:16])[CH2:12][C:13](=[O:15])[O:14][C:9]2=[O:10])=[CH:4][CH:3]=1
Reactant: CC(CC(=O)O)(C(=O)O)c1ccc(F)cc1
Solvent: CC(=O)OC(C)=O
Product: CC1(c2ccc(F)cc2)CC(=O)OC1=O

Procedure:
A solution of the diacid prepared in Example 3 (7 g, 0.034 mole) in 18 g of acetic anhydride was refluxed for 3 hours producing a light brown solution. The reaction mixture was concentrated in vacuo to the product as a syrup. This syrupy anhydride may be used without further purification or purified by distillation.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][CH:3]=1.Cl[C:11]1[C:12]2[CH:25]=[C:24]([CH3:26])[S:23][C:13]=2[N:14]=[C:15]([C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)[N:16]=1>>[N:19]1[CH:20]=[CH:21][CH:22]=[C:17]([C:15]2[N:16]=[C:11]([NH:7][CH2:6][C:5]3[CH:8]=[CH:9][C:2]([F:1])=[CH:3][CH:4]=3)[C:12]3[CH:25]=[C:24]([CH3:26])[S:23][C:13]=3[N:14]=2)[CH:18]=1
Reactant: Cc1cc2c(Cl)nc(-c3cccnc3)nc2s1
Reactant: NCc1ccc(F)cc1
Product: Cc1cc2c(NCc3ccc(F)cc3)nc(-c3cccnc3)nc2s1

Procedure:
With the procedure of Example 1, the reaction of 4-fluorobenzylamine with 4-chloro-2-(pyridin-3-yl)-6-methyl-thieno-[2,3-d]-pyrimidine yields 2-(pyridin-3-yl)-4-(4-fluorobenzylamino)-6-methyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [CH3:1][C:2]1([C:7]2[O:11][C:10]([CH2:12][N:13]3[N:17]=[C:16]([NH2:18])[CH:15]=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[C:19]1([CH3:34])[CH:24]=[CH:23][CH:22]=[C:21]([C:25]2[O:29][C:28]([CH3:30])=[N:27][C:26]=2[C:31](O)=[O:32])[CH:20]=1>>[C:2]([C:7]1[O:11][C:10]([CH2:12][N:13]2[N:17]=[C:16]([NH:18][C:31]([C:26]3[N:27]=[C:28]([CH3:30])[O:29][C:25]=3[C:21]3[CH:20]=[C:19]([CH3:34])[CH:24]=[CH:23][CH:22]=3)=[O:32])[CH:15]=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: Cc1cccc(-c2oc(C)nc2C(=O)O)c1
Reactant: CC1(c2ccc(Cn3ncc(N)n3)o2)OCCO1
Product: CC(=O)c1ccc(Cn2ncc(NC(=O)c3nc(C)oc3-c3cccc(C)c3)n2)o1

Procedure:
Following general procedure A followed by L, starting from 2-[5-(2-methyl-[1,3]dioxolan-2-yl)-furan-2-ylmethyl]-2H-[1,2,3]triazol-4-ylamine and 5-(m-tolyl)-2-methyl-oxazole-4-carboxylic acid.
Reaction SMILES: C[O:2][C:3]([C:5]1[N:6]=[N:7][N:8]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[C:12]([C:17](=[O:34])[C:18]3[CH:23]=[CH:22][C:21]([NH:24][C:25]4[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:26]=4[F:32])=[CH:20][C:19]=3[Cl:33])[CH:11]=2)[CH:9]=1)=[O:4].O.[Li+].[OH-].CCOC(C)=O>CO.Cl>[Cl:33][C:19]1[CH:20]=[C:21]([NH:24][C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:26]=2[F:32])[CH:22]=[CH:23][C:18]=1[C:17]([C:12]1[CH:11]=[C:10]([N:8]2[CH:9]=[C:5]([C:3]([OH:4])=[O:2])[N:6]=[N:7]2)[CH:15]=[CH:14][C:13]=1[CH3:16])=[O:34]
Reactant: COC(=O)c1cn(-c2ccc(C)c(C(=O)c3ccc(Nc4ccc(F)cc4F)cc3Cl)c2)nn1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1ccc(-n2cc(C(=O)O)nn2)cc1C(=O)c1ccc(Nc2ccc(F)cc2F)cc1Cl

Procedure:
A suspension of compound 132 (100 mg, 0.21 mmol) in MeOH (5.0 mL) was added H2O (0.6 mL) and LiOH (25 mg, 1.0 mmol) and the resulting reaction mixture was refluxed for 1 h. EtOAc was added to the reaction and pH adjuste to 1-2 with concentrated HCl (37%, 6 drops). The organic phase was separated and the aqueous layer was extracted with more EtOAc. The organic phases were collected and washed with water, brine, dried (MgSO4), filtered and concentrated in vacuo to give the title compound as white solid.
Reaction SMILES: [OH-].[Na+].[Cl:3][CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[O:15][CH:16]=[C:17]([C:19]([O:21]CC)=[O:20])[N:18]=2)=[CH:10][CH:9]=1>C(O)C>[Cl:3][CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[O:15][CH:16]=[C:17]([C:19]([OH:21])=[O:20])[N:18]=2)=[CH:10][CH:9]=1
Reactant: CCOC(=O)c1coc(-c2ccc(OCCCCl)cc2)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1coc(-c2ccc(OCCCCl)cc2)n1
Yield: 79 %

Procedure:
A 2 N aqueous solution of sodium hydroxide (10 ml, 20.3 mmol, 3 eq) is added dropwise to a solution of ethyl 2-[4-(3-chloropropoxy)phenyl]-1,3-oxazole-4-carboxylate i33 (2.1 g, 6.8 mmol, 1 eq) in ethanol (60 ml). The mixture is refluxed for 2 h 30 and the solvent is evaporated. The residue is taken up in water and acidified to pH 2 with a 2 N hydrochloric acid solution. The solid that precipitates is filtered off and washed with water to give 1.5 g of 2-[4-(3-chloropropoxy)phenyl]-1,3-oxazole-4-carboxylic acid i34.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=4[Cl:22])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:23]([CH2:31][CH3:32])[CH2:24][C:25](N(OC)C)=[O:26])=[CH:4][CH:3]=1.[CH3:33][Mg]Br.[Cl-].[NH4+]>O1CCCC1>[Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=4[Cl:22])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:23]([CH2:31][CH3:32])[CH2:24][C:25](=[O:26])[CH3:33])=[CH:4][CH:3]=1
Reactant: C[Mg]Br
Reactant: CCC(CC(=O)N(C)OC)c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCC(CC(C)=O)c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl
Temperature: 0 °C
Reaction time: 1 h
Yield: 71 %

Procedure:
To a solution of 3-[9-chloro-1-(2,4-dichlorophenyl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazol-6-yl]-N-methoxy-N-methylpentanamide (148.6 mg, 0.30 mmol) in tetrahydrofuran (10 mL) was added methylmagnesium bromide (3.0 M in diethyl ether, 0.3 mL, 0.9 mmol) at 0° C. The reaction mixture was stirred at 0° C. for 2 hr and at room temperature for 1 hr. Methylmagnesium bromide (3.0 M in diethyl ether, 0.3 mL, 0.9 mmol) was added to the reaction mixture at room temperature. After the mixture was stirred at room temperature for 2 hr, aqueous ammonium chloride was added to the reaction mixture. The mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with a 20-60% ethyl acetate/n-hexane gradient mixture to give the title compound (96.0 mg, 0.213 mmol, 71%) as colorless crystals.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([NH:10][C:11]([C:13]3[O:17][C:16]([N:18]4[CH2:23][CH2:22][CH2:21][CH:20]([CH3:24])[CH2:19]4)=[N:15][C:14]=3[C:25]([F:28])([F:27])[F:26])=[O:12])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[Cl:29][C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([Cl:36])[C:31]=1[N:37]=[C:38]=[O:39].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:29][C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([Cl:36])[C:31]=1[NH:37][C:38]([N:1]1[C:9]2[C:4](=[CH:5][C:6]([NH:10][C:11]([C:13]3[O:17][C:16]([N:18]4[CH2:23][CH2:22][CH2:21][CH:20]([CH3:24])[CH2:19]4)=[N:15][C:14]=3[C:25]([F:27])([F:28])[F:26])=[O:12])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1)=[O:39]
Reactant: O=C=Nc1c(Cl)cccc1Cl
Reactant: CC1CCCN(c2nc(C(F)(F)F)c(C(=O)Nc3ccc4[nH]ccc4c3)o2)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC1CCCN(c2nc(C(F)(F)F)c(C(=O)Nc3ccc4c(ccn4C(=O)Nc4c(Cl)cccc4Cl)c3)o2)C1
Temperature: 25 °C
Reaction time: 72 h
Yield: 45.1 %

Procedure:
To a solution of compound 44 (0.050 g, 0.126 mmol) and 2,6-dichlorophenylisocyanate (0.025 g, 0.133 mmol) in anhydrous DMF (1.0 mL) at room temperature was added potassium carbonate (0.026 g, 0.189 mmol). The reaction mixture was stirred at room temperature for 72 h (eventually with addition of 2,6-dichlorophenyl isocyanate (0.025 g, 0.133 mmol) to drive the reaction to completion). The reaction mixture was then quenched with methanol (0.2 mL), stirred for 60 mins and concentrated. Purification of the crude residue by silica gel chromatography (eluant gradient: 100% methylene chloride to 100% EtOAc) followed by C18 reverse phase chromatography (eluant: H2O:CH3CN gradient) gave 0.033 g (45% yield) of N-(2,6-dichlorophenyl)-5-[[2-(3-methyl-1-piperidinyl)-4-(trifluoromethyl)-5-oxazolyl]carbonylamino]-1H-indole-1-carboxamide (45) as a white solid. 1H NMR (500 MHz, DMSO-d6) δ 10.18 (br s, 1H), 10.15 (br s, 1H), 8.18 (d, 1H, J=9.1 Hz), 8.10 (m, 2H), 7.66 (d, 2H, J=7.9 Hz), 7.48 (m, 2H), 6.84 (d, 1H, J=3.5 Hz), 4.13 (m, 2H), 3.06 (t, 1H, J=12.0 Hz), 2.76 (t, 1H, J=11.6 Hz), 1.72 (m, 3H), 1.54 (m, 1H), 1.15 (m, 1H), 0.94 (d, 3H, J=6.5 Hz). MS (M+1): 580/582.