Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:29][CH:30]([F:32])[F:31])=[C:6]([C:8]2[C:12]([NH:13][C:14]([C:16]3[CH:17]=[N:18][N:19]4[CH:24]=[CH:23][CH:22]=[N:21][C:20]=34)=[O:15])=[CH:11][N:10]([CH2:25][C:26](O)=[O:27])[N:9]=2)[CH:7]=1.Cl.[N:34]1([CH:40]2[CH2:44][O:43][C:42](=[O:45])[CH2:41]2)[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:29][CH:30]([F:32])[F:31])=[C:6]([C:8]2[C:12]([NH:13][C:14]([C:16]3[CH:17]=[N:18][N:19]4[CH:24]=[CH:23][CH:22]=[N:21][C:20]=34)=[O:15])=[CH:11][N:10]([CH2:25][C:26](=[O:27])[N:37]3[CH2:36][CH2:35][N:34]([CH:40]4[CH2:41][C:42](=[O:45])[O:43][CH2:44]4)[CH2:39][CH2:38]3)[N:9]=2)[CH:7]=1
Reactant: O=C1CC(N2CCNCC2)CO1
Reactant: O=C(O)Cn1cc(NC(=O)c2cnn3cccnc23)c(-c2cc(Cl)ccc2OC(F)F)n1
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: O
Solvent: CN(C)C=O
Product: O=C1CC(N2CCN(C(=O)Cn3cc(NC(=O)c4cnn5cccnc45)c(-c4cc(Cl)ccc4OC(F)F)n3)CC2)CO1
Temperature: 25 °C
Reaction time: 8 h
Yield: 14 %

Procedure:
To a solution of {3-(5-Chloro-2-difluoromethoxyphenyl)-4-[(pyrazolo[1,5-a]pyrimidine-3-carbonyl)amino]pyrazol-1-yl}acetic acid (200 mg, 0.43 mmol) in DMF (10 mL) was added 4-(piperazin-1-yl)oxolan-2-one hydrochloride (250 mg, 1.21 mmol), HATU (247 mg, 0.65 mmol), DIEA (167 mg, 1.29 mmol). The resulting solution was stirred at room temperature overnight. Water (50 mL) was added. The resulting solution was extracted with DCM (×3) and the organic layers combined. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was passed through a short pad of silica gel eluting with 8% MeOH in DCM. The crude product (80 mg) was purified by Prep-HPLC with the following conditions (1#-Pre-HPLC-006(Waters)): Column, XSelect CSH Prep C18 OBD Column, 5 um, 19*150 mm; mobile phase, Water with 0.05% FA and MeCN (32.0% MeCN up to 60.0% in 10 min); Detector, 254/220. 37 mg product was obtained. This resulted in 36.7 mg (14%) of N-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-[2-oxo-2-[4-(5-oxooxolan-3-yl)piperazin-1-yl]ethyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide as a white solid. LCMS (Method 28) [M+H]+=615.0, RT=0.99 min. 1H NMR (300 MHz, DMSO-d6) δ: (ppm) 9.76 (s, 1H), 9.34 (d, 1H, J=6.9 Hz), 8.69-8.67 (m, 2H), 8.30 (s, 1H), 7.62 (dd, 1H, J=2.4, 9.0 Hz), 7.56 (s, 1H), 7.45 (d, 1H, J=8.7 Hz), 7.28 (dd, 1H, J=4.2, 6.9 Hz), 7.02 (t, 1H, J=73.2 Hz), 5.24 (s, 2H), 4.44-4.38 (m, 1H), 4.26-4.18 (m, 1H), 3.49 (t, 4H, J=5.1 Hz), 3.40-3.37 (m, 1H), 2.78-2.68 (m, 1H), 2.60-2.55 (m, 1H), 2.47-2.35 (m, 4H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=2)=[C:6]([CH:10]=1)[C:7]([OH:9])=O.Cl.[NH2:20][C@H:21]([C:23]1[CH:32]=[CH:31][C:26]([C:27]([O:29][CH3:30])=[O:28])=[CH:25][CH:24]=1)[CH3:22]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=2)=[C:6]([CH:10]=1)[C:7]([NH:20][C@H:21]([C:23]1[CH:32]=[CH:31][C:26]([C:27]([O:29][CH3:30])=[O:28])=[CH:25][CH:24]=1)[CH3:22])=[O:9]
Reactant: COC(=O)c1ccc([C@H](C)N)cc1
Reactant: O=C(O)c1cc(Cl)ccc1Cc1cccc(F)c1
Agent: Cl
Product: COC(=O)c1ccc([C@H](C)NC(=O)c2cc(Cl)ccc2Cc2cccc(F)c2)cc1

Procedure:
The title compound was prepared according to the procedure described in step 3 of Example 1 from 5-chloro-2-(3-fluorobenzyl)benzoic acid (step 3) and methyl 4-[(1S)-1-aminoethyl]benzoate hydrochloride (step 3 of Example 5): 1H-NMR (CDCl3) δ 8.00–7.96 (2H, m), 7.36–7.14 (6H, m), 6.90–6.74 (3H, m), 5.93 (1H, d, J=7.3 Hz), 5.20 (1H, dq, J=7.3, 7.0 Hz), 4.12 (2H, s), 3.92 (3H, s), 1.44 (3H, d, J=7.0 Hz); MS (ESI) m/z 426 (M+H)+, 424 (M−H)−.
Reaction SMILES: [F:1][C:2]1([F:13])[O:6][C:5]2[CH:7]=[CH:8][C:9]([CH:11]=O)=[CH:10][C:4]=2[O:3]1.C(O)(=O)[CH2:15][C:16]([OH:18])=[O:17].N1CCCCC1.C(=O)=O.Cl>N1C=CC=CC=1>[F:1][C:2]1([F:13])[O:6][C:5]2[CH:7]=[CH:8][C:9]([CH:11]=[CH:15][C:16]([OH:18])=[O:17])=[CH:10][C:4]=2[O:3]1
Reactant: O=C(O)CC(=O)O
Reactant: O=Cc1ccc2c(c1)OC(F)(F)O2
Agent: Cl
Agent: O=C=O
Solvent: C1CCNCC1
Solvent: c1ccncc1
Product: O=C(O)C=Cc1ccc2c(c1)OC(F)(F)O2
Temperature: 25 °C

Procedure:
A mixture of 10.0 g (53.7 mmol) 2,2-difluoro-benzo[1,3]dioxole-5-carbaldehyde, 6.24 g (60.0 mmol) malonic acid, 0.46 g (5.40 mmol) piperidine and 40 ml pyridine was kept at reflux temperature until carbon dioxide development ceased (3 h). After cooling to room temperature the reaction mixture was poured onto 100 g ice and 30 ml 6N HCl. The precipitate was isolated, washed with water and dried. Yield: 8.60 g (70%) 3-(2,2-Difluoro-benzo[1,3]dioxol-5-yl) -acrylic acid.
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:62])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([O:50][CH2:51][C:52]([C:54]3[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=3)=[O:53])[CH:46]([O:60][CH3:61])[CH2:45]2)[CH:7]([CH3:63])[CH:6]([O:64][Si](C(C)(C)C)(C)C)[CH2:5][C:4]1=[O:72])[CH3:2].C1C=CN=CC=1.F>C1COCC1>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:62])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([O:50][CH2:51][C:52]([C:54]3[CH:55]=[CH:56][CH:57]=[CH:58][CH:59]=3)=[O:53])[CH:46]([O:60][CH3:61])[CH2:45]2)[CH:7]([CH3:63])[CH:6]([OH:64])[CH2:5][C:4]1=[O:72])[CH3:2]
Reactant: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(OCC(=O)c4ccccc4)C(OC)C3)C(C)C(O[Si](C)(C)C(C)(C)C)CC1=O)C(C)CC2OC
Agent: F
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(OCC(=O)c4ccccc4)C(OC)C3)C(C)C(O)CC1=O)C(C)CC2OC
Temperature: 25 °C
Reaction time: 24 h
Yield: 61.1 %

Procedure:
To a solution of the product from Step A (188 mg) in THF (2.8 ml) was added hydrogen fluoride/pyridine and the reaction mixture stirred at room temperature for 24 hours. The reaction was then quenched by the addition of saturated aqueous sodium bicarbonate and extracted into ethyl acetate. The organic phase was dried with magnesium sulphate and concentrated. The crude material was purified by column chromatography on silica gel eluting with 50% hexane:50% ethyl acetate to give the title compound (102 mg).
Reaction SMILES: [C:1]([O:5][CH2:6][CH3:7])(=[O:4])[CH2:2][OH:3].C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[Br:18][CH2:19][CH2:20][CH2:21][CH2:22]Br.CCOCC>CN(C=O)C.CCOC(C)=O>[CH2:6]([O:5][C:1](=[O:4])[CH2:2][O:3][CH2:22][CH2:21][CH2:20][CH2:19][Br:18])[CH3:7]
Reactant: BrCCCCBr
Reactant: CCOC(=O)CO
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CCOC(=O)COCCCCBr
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 17.7 %

Procedure:
A solution of ethyl glycolate (4.6 g, 44 mmol) in DMF (50 mL) was cooled to 0° C. and sodium bis(trimethylsilyl)amide (1.0 M in THF, 53 mL, 53 mmol) was slowly added. The reaction was stirred for 15 minutes and 1,4-dibromobutane (5.6 mL, 48.4 mmol) was added. The reaction was warmed to room temperature and was stirred for 24 h. Et2O was added, and the organic solution was washed consecutively with HCl (1N, 3×), water (3×), and brine (1×). The organic solution was dried (Na2SO4), filtered, and concentrated. Attempted vacuum distillation removed a majority of the impurities and provided a mixture of product and 1,4-dibromobutane (3.539 g). Flash chromatography (9:1 hexanes:EtOAc) of this material provided (4-bromo-butoxy)-acetic acid ethyl ester (1.862 g). 1H NMR (400 MHz, CDCl3) δ 4.19 (q, 2H), 4.04 (s, 2H), 3.54 (t, 2H), 3.45 (t, 2H), 1.97 (m, 2H), 1.75 (m, 2H), 1.26 (t, 3H); MS 239.1 (M+).
Reaction SMILES: [Cl:1][C:2]1[CH:32]=[CH:31][C:5]([CH2:6][CH2:7][NH:8][C:9]([C:11]2[CH:30]=[CH:29][C:14]([O:15][C:16]3[CH:21]=[CH:20][C:19]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:18][C:17]=3Br)=[CH:13][CH:12]=2)=[O:10])=[CH:4][CH:3]=1.[Cl-].[CH3:34][Zn+]>C1COCC1.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[Cl:1][C:2]1[CH:32]=[CH:31][C:5]([CH2:6][CH2:7][NH:8][C:9]([C:11]2[CH:30]=[CH:29][C:14]([O:15][C:16]3[CH:21]=[CH:20][C:19]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:18][C:17]=3[CH3:34])=[CH:13][CH:12]=2)=[O:10])=[CH:4][CH:3]=1
Reactant: CCOC(=O)Cc1ccc(Oc2ccc(C(=O)NCCc3ccc(Cl)cc3)cc2)c(Br)c1
Reactant: C[Zn+]
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: [Cl-]
Solvent: C1CCOC1
Product: CCOC(=O)Cc1ccc(Oc2ccc(C(=O)NCCc3ccc(Cl)cc3)cc2)c(C)c1
Reaction time: 2 h
Yield: 76.3 %

Procedure:
Ethyl 2-(4-(4-((4-chlorophenethyl)carbamoyl)phenoxy)-3-bromophenyl)acetate (Example 46 step C; 30 mg, 0.058 mmol) was diluted with THF (1 mL) followed by the addition of bis(tri-t-butylphosphine)palladium (0) (3.0 mg, 0.0058 mmol) and methylzinc chloride (0.087 ml, 0.17 mmol). After stirring for 2 hours, the reaction was loaded directly onto a silica gel column, eluting with hexanes:ethyl acetate (3:1) to yield ethyl 2-(4-(4-((4-chlorophenethyl)carbamoyl)phenoxy)-3-methylphenyl)acetate (20 mg, 76% yield) as a clear oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=1[Cl:18])=[CH:5]2.[CH3:19]I.[H-].[Na+]>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH3:19])[C:6]([C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=1[Cl:18])=[CH:5]2
Reactant: Clc1ccc(-c2cc3cc(Cl)ccc3[nH]2)c(Cl)c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cn1c(-c2ccc(Cl)cc2Cl)cc2cc(Cl)ccc21
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 5-chloro-2-(2,4-dichlorophenyl)-1H-indole (160 mg, 0.54 mmol) and methyl iodide (124 μL, 2.0 mmol) in tetrahydrofuran is treated with NaH (60% dispersion in mineral oil, 160 mg, 4.0 mmol), shaken at room temperature for 16 h, quenched with water and extracted with ethyl acetate. The extracts are combined and concentrated in vacuo to afford the title product which is used as is in Example 128.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([O:9][CH3:10])=[CH:4][N:3]=1.[NH:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1.[NH4+].[Cl-]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[N:7]=[C:6]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[C:5]([O:9][CH3:10])=[CH:4][N:3]=1
Reactant: C1COCCN1
Reactant: COc1cnc(Cl)nc1Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: Cc1ccccc1
Product: COc1cnc(Cl)nc1N1CCOCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.08 %

Procedure:
2,4-Dichloro-5-methoxy-pyrimidin (3.2 g, 1.0 eq) was stirred in toluene (20 ml) and a solution of morpholine (2.34 ml, 1.5 eq) in toluene (20 ml) was added dropwise at −10˜0° C. After stirring the resulting solution overnight at r.t., NH4Cl (aq) was added and the solution was extracted with EA. The combined organic layers were washed with brine, dried and evaporated in vacuo. A product was obtained as a white solid (3.80 g, 93.08%)
Reaction SMILES: [NH2:1][C@H:2]([C:13]([OH:15])=[O:14])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.Cl.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C([S:47][CH2:48][CH:49]([CH2:53][C:54]1[CH:59]=[CH:58][CH:57]=[C:56]([Br:60])[CH:55]=1)[C:50](O)=[O:51])(=O)C>C(Cl)Cl.C(N(CC)CC)C>[Br:60][C:56]1[CH:55]=[C:54]([CH2:53][CH:49]([CH2:48][SH:47])[C:50]([NH:1][C@H:2]([C:13]([OH:15])=[O:14])[CH2:3][C:4]2[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[NH:6][CH:5]=2)=[O:51])[CH:59]=[CH:58][CH:57]=1
Reactant: N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O
Reactant: CC(=O)SCC(Cc1cccc(Br)c1)C(=O)O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O)C(CS)Cc1cccc(Br)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 83.4 %

Procedure:
1.88 g of L-Tryptophan in the form of the hydrochloride is introduced into 25 ml of anhydrous methylene chloride and 2.14 ml of triethylamine, 3.1 g of BOP then 2.217 g of the product obtained in Stage 4 above, dissolved in 25 ml of anhydrous methylene chloride, are added. The solution is agitated for 2 hours at ambient temperature, then the solvent is evaporated off, the product obtained in the form of a yellow oil, is then purified by chromatography on silica, with chloroform-ethyl acetate: 85-15 as eluant. After evaporation of the solvent and washing, a yellow gum is obtained. In this way 2.69 g of expected product is obtained (mixture of two diastereoisomers).
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[N:11][C:10]2[CH2:9][CH:8]([CH2:13][CH2:14]Cl)[CH2:7][N:6]([CH3:16])[C:5](=[O:17])[C:4]=2[CH:3]=1.[NH:18]1[CH2:21][CH2:20][CH2:19]1.[C:22]([OH:27])(=[O:26])[C:23]([OH:25])=[O:24]>>[C:22]([OH:27])(=[O:26])[C:23]([OH:25])=[O:24].[N:18]1([CH2:14][CH2:13][CH:8]2[CH2:7][N:6]([CH3:16])[C:5](=[O:17])[C:4]3[CH:3]=[C:2]([Cl:1])[CH:12]=[N:11][C:10]=3[CH2:9]2)[CH2:21][CH2:20][CH2:19]1
Reactant: C1CNC1
Reactant: CN1CC(CCCl)Cc2ncc(Cl)cc2C1=O
Agent: O=C(O)C(=O)O
Product: CN1CC(CCN2CCC2)Cc2ncc(Cl)cc2C1=O

Procedure:
Following the procedure of Example 21, 3-chloro-8-(2-chloroethyl)-6,7,8,9-tetrahydro-6-methyl-5H-pyrido[3,2-c]azepin-5-one and azetidine are reacted and the free base of the title is isolated and reacted with oxalic acid.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][C:6]2=O.Cl.[NH2:13][OH:14]>CO>[Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][C:6]2=[N:13][OH:14]
Reactant: NO
Reactant: O=C1CCc2c(Br)cccc21
Agent: Cl
Solvent: CO
Product: ON=C1CCc2c(Br)cccc21
Reaction time: 0.33 h
Yield: 99 %

Procedure:
To a solution of 4-bromo-2,3-dihydro-1H-inden-1-one (3.00 g, 14.21 mmol) in MeOH (40 mL) was added hydroxylamine hydrochloride (3.95 g, 56.9 mmol). The resulting mixture was refluxed for 1 h and concentrated in vacuo. The resulting residue was partitioned between DCM and 50% saturated NaHCO3, and stirred vigorously for 20 min. The organic layer was separated, dried over anhydrous Na2SO4, filtered and concentrated to afford the title compound (3.18 g, 99% yield) as a pale yellow solid. LCMS, [M+H]+=226.0.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[CH2:5][C:6]1[C:15]2[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=2[C:9](=[O:16])[NH:8][N:7]=1.[CH:20]([C:22]1[CH:23]=[C:24](B(O)O)[CH:25]=[CH:26][CH:27]=1)=[O:21].C(=O)([O-])[O-].[Na+].[Na+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.COCCOC.O.C(O)C>[O:16]=[C:9]1[C:10]2[CH2:11][CH2:12][CH2:13][CH2:14][C:15]=2[C:6]([CH2:5][C:4]2[CH:3]=[C:2]([C:26]3[CH:25]=[CH:24][CH:23]=[C:22]([CH:20]=[O:21])[CH:27]=3)[CH:19]=[CH:18][CH:17]=2)=[N:7][NH:8]1
Reactant: O=c1[nH]nc(Cc2cccc(Br)c2)c2c1CCCC2
Reactant: O=Cc1cccc(B(O)O)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: COCCOC
Solvent: O
Product: O=Cc1cccc(-c2cccc(Cc3n[nH]c(=O)c4c3CCCC4)c2)c1
Temperature: 70 °C

Procedure:
A suspension of EXAMPLE 90 (500 mg, 1.57 mmol), 3-formylphenylboronic acid (352 mg, 2.35 mmol), dichlorobis(triphenylphosphine)palladium(II) (112 mg, 0.16 mmol) and sodium carbonate (2M solution, 3.13 mmol, 1.6 mL) in a 7/3/3 mixture of 1,2-dimethoxyethane/water/ethanol (23 mL) was purged with nitrogen, and heated at 70° C. for 16 hours. After cooling to room temperature, the reaction mixture was concentrated on a rotary evaporator. The crude solid was separated by HPLC (Zorbax® C-18 ODS packing material [Agilent Technologies, Santa Clara, Calif.], 0.1% trifluoroacetic acid/CH3CN/H2O) to provide the title compound. MS (DCI/NH3) m/z 345 (M+H)+.
Reaction SMILES: [Mg].CO[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[O:11][CH2:12][C:13]([CH3:16])([CH3:15])[N:14]=1.II.BrC(Br)C.I[CH2:24][CH2:25][CH2:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.IC1C=CC(CCCC)=CC=1>O1CCCC1.O>[CH3:15][C:13]1([CH3:16])[CH2:12][O:11][C:10]([C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:31]2[CH:32]=[CH:33][C:28]([CH2:27][CH2:26][CH2:25][CH3:24])=[CH:29][CH:30]=2)=[N:14]1
Reactant: ICCCCc1ccccc1
Reactant: COc1ccccc1C1=NC(C)(C)CO1
Agent: CC(Br)Br
Agent: CCCCc1ccc(I)cc1
Agent: II
Solvent: C1CCOC1
Solvent: O
Product: CCCCc1ccc(-c2ccccc2C2=NC(C)(C)CO2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 25 %

Procedure:
A mechanically stirred solution of magnesium turnings (Mallinckrodt, for Grignard's reaction, 3.75 g., 0.154 mole) and 2-(2-methoxyphenyl)-4,4-dimethyl-2-oxazoline (30 g, 0.146 mole) in 50 mL dry tetrahydrofuran under nitrogen was prepared. To this was added a crystal of iodine, 1 mL of dibromoethane and 2 mL of neat p-Iodo n-butylbenzene to initiate the Grignard reaction. After warming to initiate the reaction, the remainder of the p-iodo-n-butylbenzene (40 g, 0.154 mole) in 50 mL dry tetrahydrofuran was added dropwise at a rate sufficient to maintain the reaction at gentle reflux. The addition took 1 hr and the reaction mixture was then heated at reflux for 3 hr. The reaction was then cooled to room temperature and 15 mL water was added dropwise to coagulate the salts. The tetrahydrofuran was decanted and the remaining solids were slurried twice with 200 mL ethyl ether and twice with 300 mL dichloromethane. Each organic extract was decanted from the solids in turn and combined and evaporated under reduced pressure to an oil. The oil was redissolved in 300 mL dichloromethane, washed once with 100 ml saturated sodium chloride solution, dried and concentrated under reduced pressure. The resulting residue was distilled under reduced pressure (0.027 Torr, 130°) to yield 2-(4,4-dimethyl-2-oxazolin-2-yl)-4'-n-butylbiphenyl as an oil, yield 25%.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]2[C:14]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)=[CH:13][S:12][C:11]=2[CH:22]=1.[CH2:23]([NH:25][CH2:26][CH2:27][OH:28])[CH3:24]>>[CH2:23]([N:25]([CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]2[C:14]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)=[CH:13][S:12][C:11]=2[CH:22]=1)[CH2:26][CH2:27][OH:28])[CH3:24]
Reactant: CCNCCO
Reactant: Fc1ccc(-c2csc3cc(OCCCCBr)ccc23)cc1
Product: CCN(CCO)CCCCOc1ccc2c(-c3ccc(F)cc3)csc2c1

Procedure:
In analogy to example 3.1, 6-(4-Bromo-butoxy)-3-(4-fluoro-phenyl)-benzo[b]thiophene and 2-(ethylamino)ethanol were converted to yield 2-(Ethyl-{4-[3-(4-fluoro-phenyl)-benzo[b]thiophen-6-yloxy]-butyl}-amino)-ethanol as colorless oil, MS: 388 (MH+).
Reaction SMILES: [CH3:1][C:2]([NH2:27])([CH3:26])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:14]=[CH:13][N:12]([C:15]3[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=3)[N:11]=2)=[CH:6][CH:5]=1.[N+](C1C=CC([CH:37]2[S:41]/[C:40](=[N:42]\[C:43](=O)[O-:44])/[N:39]([C:46]3[CH:51]=[C:50]([CH3:52])[CH:49]=[CH:48][C:47]=3[CH:53]([CH3:55])[CH3:54])[C:38]2=[O:56])=CC=1)([O-])=O>>[CH:53]([C:47]1[CH:48]=[CH:49][C:50]([CH3:52])=[CH:51][C:46]=1[N:39]1[C:38](=[O:56])[CH2:37][S:41]/[C:40]/1=[N:42]\[C:43]([NH:27][C:2]([CH3:1])([CH3:26])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:14]=[CH:13][N:12]([C:15]3[CH:20]=[CH:19][C:18]([O:21][C:22]([F:24])([F:23])[F:25])=[CH:17][CH:16]=3)[N:11]=2)=[CH:6][CH:5]=1)=[O:44])([CH3:55])[CH3:54]
Reactant: Cc1ccc(C(C)C)c(N2C(=O)C(c3ccc([N+](=O)[O-])cc3)S/C2=N\C(=O)[O-])c1
Reactant: CC(C)(N)Cc1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Product: Cc1ccc(C(C)C)c(N2C(=O)CS/C2=N\C(=O)NC(C)(C)Cc2ccc(-c3ncn(-c4ccc(OC(F)(F)F)cc4)n3)cc2)c1

Procedure:
The title compound was prepared as described in Example 95 using 2-methyl-1-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)propan-2-amine (CB28) and (Z)-4-nitrophenyl(3-(2-isopropyl-5-methylphenyl)-4-oxothiazolidin-2-ylidene)carbamate (CA50), purified by flash column chromatography using 0-100% ethyl acetate/B, where B=1:1 dichloromethane/hexanes, as eluent and isolated as a brown oil (0.018 g, 9%).
Reaction SMILES: [CH2:1]([C:3]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:8]([OH:9])=[N:7][C:6](=[O:10])[N:5]([CH2:11][CH2:12][CH2:13][CH2:14][C:15]([O:17]C)=[O:16])[C:4]1=[O:19])[CH3:2].O>O1CCOCC1.Cl>[C:15]([CH2:14][CH2:13][CH2:12][CH2:11][N:5]1[C:4](=[O:19])[C:3]([CH2:1][CH3:2])([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:8]([OH:9])=[N:7][C:6]1=[O:10])([OH:17])=[O:16]
Reactant: CCC1(c2ccccc2)C(=O)N(CCCCC(=O)OC)C(=O)N=C1O
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Product: CCC1(c2ccccc2)C(=O)N(CCCCC(=O)O)C(=O)N=C1O
Temperature: 25 °C

Procedure:
The 5-ethyl-6-hydroxy-3-(4-methoxycarbonylbutyl)-5-phenyl2,4(3H,5H)-pyrimidinedione ester (54.0 g, 0.156 mole) of step 1 in dioxane (500 mL), concentrated hydrochloric acid (55 mL), and water (55 mL) was heated at reflux for 4 hrs and at room temperature ovenight. The dioxane was removed under reduced pressure, and saturated sodium chloride solution (250 mL) and dichloromethane (400 mL) were added to the residue. The organic layer was separated, and the aqueous solution was extracted with dichloromethane (3×150 mL). The combined organic solutions were washed with saturated sodium chloride solution (200 mL), dried over anhydrous MgSO4, filtered, and the solvent removed. To the residue was added diethyl ether, and the mixture was placed in a freezer at -16° C. over the weekend, and then filtered.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]([OH:14])=[O:13])[CH:3]=1.[CH2:15](N(CC)CC)[CH3:16].O.[OH-].[Na+]>C1(C)C=CC=CC=1.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>[F:9][C:8]([F:11])([F:10])[C:6]1[N:5]=[C:4]([C:12]([OH:14])=[O:13])[CH:3]=[C:2]([CH:15]=[CH2:16])[CH:7]=1
Reactant: O=C(O)c1cc(Br)cc(C(F)(F)F)n1
Reactant: CCN(CC)CC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1
Product: C=Cc1cc(C(=O)O)nc(C(F)(F)F)c1
Temperature: 80 °C

Procedure:
A mixture of 4-bromo-6-(trifluoromethyl)pyridine-2-carboxylic acid (0.50 g, 1.8 mmol, Anichem), (2-Ethenyl)tri-n-butyltin (919 μL, 3.14 mmol, Aldrich) and tetrakis(triphenylphosphine)palladium(0) (428 mg, 0.370 mmol, Strem) in toluene (4.2 mL) was degassed by a stream of nitrogen through the solution for 15 minutes. Triethylamine (774 μL, 5.56 mmol) was added and the mixture was heated to 80° C. for 2 hours. After cooling to ambient temperature, water and 1N NaOH were added and the product was extracted with four portions of ethyl acetate. The aqueous layer was then treated with 1N HCl to achieve a pH between 4 and 5, and was extracted with six portions of 10% isopropanol in chloroform. The combined organic extracts were dried over sodium sulfate, filtered and concentrated to afford crude product, which was used without further purification in Step B. H NMR (300 MHz, CDCl3) δ 8.40 (d, J=1.3 Hz, 1H), 7.88 (d, J=1.5 Hz, 1H), 6.82 (dd, J=17.6, 10.9 Hz, 1H), 6.23 (d, J=17.4 Hz, 1H), 5.78 (d, J=10.9 Hz, 1H); LCMS (M+H)+: 218.1.
Reaction SMILES: C([Li])CCC.[C:6]1([S:12][CH3:13])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[CH3:14][S:15]SC.Cl>CCCCCC.O1CCCC1>[C:6]1([S:12][CH2:13][S:15][CH3:14])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: CSc1ccccc1
Reactant: CSSC
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CSCSc1ccccc1
Temperature: -70 °C
Reaction time: 1 h

Procedure:
120 ml. of a 1.3M n-butyllithium solution in n-hexane were added dropwise to a solution of 18.8 ml. of thioanisole in 240 ml. of tetrahydrofuran at -20° C. and the reaction mixture was stirred at that temperature for 2 hours. After cooling to -70° C., 16.4 g. of dimethyldisulphide were added to the reaction mixture, which was then stirred at -70° C. for 15 minutes and at room temperature for 1 hour. The reaction mixture was poured into dilute aqueous hydrochloric acid and extracted with ethyl acetate. The extracts were washed with water and an aqueous solution of sodium chloride and concentrated under reduced pressure. The residue was purified by distillation in vacuo to give 18.0 g. of the title compound having the following physical characteristics: