Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[C:9]([C:17]3[CH:18]=[C:19]([NH:23][C:24](=[O:29])[C:25]([F:28])([F:27])[F:26])[CH:20]=[CH:21][CH:22]=3)=[N:10][N:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=23)[CH:5]=[CH:4][N:3]=1.[Cl:30][C:31]1[CH:36]=[CH:35][C:34]([N+:37]([O-])=O)=[CH:33][C:32]=1[O:40][CH2:41][CH2:42][Cl:43]>>[Cl:30][C:31]1[CH:36]=[CH:35][C:34]([NH:37][C:2]2[N:7]=[C:6]([C:8]3[C:9]([C:17]4[CH:18]=[C:19]([NH:23][C:24](=[O:29])[C:25]([F:27])([F:26])[F:28])[CH:20]=[CH:21][CH:22]=4)=[N:10][N:11]4[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=34)[CH:5]=[CH:4][N:3]=2)=[CH:33][C:32]=1[O:40][CH2:41][CH2:42][Cl:43]
Reactant: O=C(Nc1cccc(-c2nn3ccccc3c2-c2ccnc(Cl)n2)c1)C(F)(F)F
Reactant: O=[N+]([O-])c1ccc(Cl)c(OCCCl)c1
Product: O=C(Nc1cccc(-c2nn3ccccc3c2-c2ccnc(Nc3ccc(Cl)c(OCCCl)c3)n2)c1)C(F)(F)F
Yield: 34 %

Procedure:
The compound was synthesized from N-{3-[3-(2-chloro-4-pyrimidinyl)-pyrazolo[1,5-a]pyridin-2-yl]phenyl}-2,2,2-trifluoroacetamide (see Example 1, Step C) and 1-chloro-2-[(2-chloroethyl)oxy]-4-nitrobenzene as described in Example 10, Step C to afford a dark yellow solid in 34% yield. ES-LC/MS m/z 587 [M+H]+.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH3:11])[CH:6]=[CH:5]2.[C:12]([Si:14]([CH3:17])([CH3:16])[CH3:15])#[CH:13]>N1CCCC1>[CH3:11][N:7]1[C:8]2[C:4](=[CH:3][C:2]([C:13]#[C:12][Si:14]([CH3:17])([CH3:16])[CH3:15])=[CH:10][CH:9]=2)[CH:5]=[CH:6]1
Reactant: Cn1ccc2cc(I)ccc21
Reactant: C#C[Si](C)(C)C
Solvent: C1CCNC1
Product: Cn1ccc2cc(C#C[Si](C)(C)C)ccc21
Temperature: 50 °C
Yield: 84794 %

Procedure:
To a solution of 5-iodo-1-methyl-1H-indole (200 mg, 0.778 mmol) in pyrrolidine (5 mL) was added ethynyl-trimethyl-silane (92 mg, 0.932 mmol), followed by tetrakis-triphenyl-phosphine palladium (61 mg, 0.233 mmol) after which the reaction mixture was heated at 50° C. for 12 h. The reaction mixture was filtered and the filtrate evaporated in vacuo to obtain a residue, which was purified by column chromatography (ethyl acetate:hexane; 5:95) to give a product (150 g, 84%). 1H NMR (CDCl3, 400 MHz) 0.25 (s, 9H), 3.76 (s, 3H), 6.44 (d, J=3.0 Hz, 1H), 7.04 (d, J=3.0 Hz, 1H), 7.23 (d, J=8.4 Hz, 1H), 7.30 (dd, J=1.4 Hz, 1H), 7.78 (d, J=1.4 Hz, 1H); 13C NMR (CDCl3, 100 MHz) 0.18, 32.8, 90.9, 101.2, 107.0, 109.0, 113.6, 125.3, 125.4, 128.1, 129.6, 136.4.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]2[C:10]([C:11]([O:13][CH3:14])=[O:12])=[CH:9][CH:8]=[CH:7][C:5]=2[CH:6]=1.[C:15](Cl)(=[O:17])[CH3:16].[Cl-].[Al+3].[Cl-].[Cl-]>ClC(Cl)C>[C:15]([C:6]1[C:5]2[CH:7]=[CH:8][CH:9]=[C:10]([C:11]([O:13][CH3:14])=[O:12])[C:4]=2[O:3][C:2]=1[CH3:1])(=[O:17])[CH3:16]
Reactant: COC(=O)c1cccc2cc(C)oc12
Reactant: CC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CC(Cl)Cl
Product: COC(=O)c1cccc2c(C(C)=O)c(C)oc12
Temperature: 0 °C
Yield: 88.5 %

Procedure:
A mixture of 1.0 g of methyl 2-methylbenzofuran-7-carboxylate, 1.24 g of acetyl chloride, 2.15 g of aluminum chloride and 20 ml of dichloroethane is heated at 50°-60° C. for 1 hour. The reaction mixture is poured into ice-water and the aqueous mixture is extracted with chloroform. The extract is washed with water, dried and evaporated to remove solvent. The residue is recrystallized from ethyl acetate-n-hexane to give 1.08 g of methyl 3-acetyl-2-methylbenzofuran-7-carboxylate as colorless needles.
Reaction SMILES: [F:1][C:2]1[N:7]=[CH:6][C:5]([NH2:8])=[CH:4][CH:3]=1.[C:9]([S-:11])#[N:10].[K+].BrBr.O>C(O)(=O)C>[F:1][C:2]1[N:7]=[C:6]2[S:11][C:9]([NH2:10])=[N:8][C:5]2=[CH:4][CH:3]=1
Reactant: N#C[S-]
Reactant: Nc1ccc(F)nc1
Agent: BrBr
Agent: [K+]
Solvent: CC(=O)O
Solvent: O
Product: Nc1nc2ccc(F)nc2s1
Temperature: 25 °C
Reaction time: 16 h
Yield: 69.2 %

Procedure:
6-Fluoropyridin-3-amine (4 g, 35.7 mmol) was added to a mechanically stirred suspension of potassium rhodanate (27.7 g, 285 mmol) in acetic acid (89 mL) at 0° C. The flask 3-neck flask was then fitted with an addition funnel charged with bromine (5.70 mL, 111 mmol) in acetic acid (29.7 mL). The bromine solution was added over 30 min and the solution turned into a viscous and yellow mixture. After bromine addition was complete, the reaction mixture was allowed to warm to ambient temperature and stirred at that temperature for 16 h. Water (30 mL) was added to the reaction mixture and it was heated to 85° C. for 20 min before the solids were filtered and washed with water and methanol to give 5-fluorothiazolo[5,4-b]pyridin-2-amine (4.18 g, 24.71 mmol, 69.2% yield) as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]([CH2:18][CH2:19][N:20]2[CH2:28][CH2:27][N:26]([CH2:29][C:30](=[O:36])[O:31]C(C)(C)C)[CH2:25][CH2:24][N:23]([CH2:37][C:38]([O:40]C(C)(C)C)=[O:39])[CH2:22][CH2:21]2)[CH2:10][C:11]([O:13]C(C)(C)C)=[O:12])=[CH:4][CH:3]=1.Cl.O1CCOCC1>C(OCC)C>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][N:9]([CH2:18][CH2:19][N:20]2[CH2:21][CH2:22][N:23]([CH2:37][C:38]([OH:40])=[O:39])[CH2:24][CH2:25][N:26]([CH2:29][C:30]([OH:36])=[O:31])[CH2:27][CH2:28]2)[CH2:10][C:11]([OH:13])=[O:12])=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)CN1CCN(CCN(CC(=O)OC(C)(C)C)Cc2ccc(N)cc2)CCN(CC(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: CCOCC
Solvent: C1COCCO1
Product: Nc1ccc(CN(CCN2CCN(CC(=O)O)CCN(CC(=O)O)CC2)CC(=O)O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 119.7 %

Procedure:
To Compound 9 (39 mg, 62.9 μmol) with an ice cooling bath around was added 6 mL of 4 M HCl/dioxane dropwise. After the addition was complete, the reaction mixture was gradually warmed to room temperature and allowed to stir overnight at room temperature. After completion 50 mL of ethyl ether was added to the reaction mixture with vigorous stirring and the resulting slurry was kept in the freezer for 2 h. The precipitate was collected and washed with ethyl ether, then immediately lyophilized with water and evaporated to provide pure salt as light yellow solid Compound 10 (34 mg, 85%). NMR (D2O, 300 MHz) δ 2.97 (m, 4H), 3.21 (m, 6H), 3.33 (s, 4H), 3.48 (t, J=5.4 Hz, 2H), 3.93 (s, 4H), 3.99 (s, 2H), 4.46 (s, 2H), 7.40 (d, J=6.4 Hz, 2H), 7.59 (d, J=6.4 Hz, 2H).
Reaction SMILES: [N:1]1([C@H:13]2[CH2:17][CH2:16][C@H:15]([NH2:18])[CH2:14]2)[C:12]2[C:4](=[CH:5][N:6]=[C:7]3[C:11]=2[CH:10]=[CH:9][NH:8]3)[N:3]=[N:2]1.[F:19][C:20]([F:26])([F:25])[CH2:21][C:22](O)=[O:23].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>CN(C=O)C.CN(C1C=CN=CC=1)C.O>[F:19][C:20]([F:26])([F:25])[CH2:21][C:22]([NH:18][C@H:15]1[CH2:16][CH2:17][C@H:13]([N:1]2[C:12]3[C:4](=[CH:5][N:6]=[C:7]4[C:11]=3[CH:10]=[CH:9][NH:8]4)[N:3]=[N:2]2)[CH2:14]1)=[O:23]
Reactant: N[C@H]1CC[C@H](n2nnc3cnc4[nH]ccc4c32)C1
Reactant: O=C(O)CC(F)(F)F
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: O=C(CC(F)(F)F)N[C@H]1CC[C@H](n2nnc3cnc4[nH]ccc4c32)C1
Reaction time: 18 h
Yield: 46.2 %

Procedure:
To a stirred solution of racemic trans 3-(6H-1,2,3,5,6-pentaaza-as-indacen-1-yl)-cyclopentylamine (120 mg, 0.49 mmol) in DMF (3 mL), 3,3,3-trifluoropropionic acid (53.0 μL, 0.60 mmol), DMAP (103 mg, 0.84 mmol), HOBt (100 mg, 0.74 mmol) and EDCI (161 mg, 0.84 mmol) were added. Stirring was continued for 18 hours at ambient temperature. The mixture was diluted with water and purified by column chromatography (SCX-2, gradient: methanol to 2M NH3 in methanol). The isolated product was triturated (DCM), washed with water and dried in vacuo at 40° C. for 18 hours affording 79.8 mg (45%) of racemic trans 3,3,3-trifluoro-N-[3-(6H-1,2,3,5,6-pentaaza-as-indacen-1-yl)-cyclopentyl]-propionamide as a grey powder. LCMS (Method A, ESI): RT=3.14 min, m+H=353.3; 1H NMR (400 MHz, DMSO) δ: 12.37 (s, 1H), 9.00 (s, 1H), 8.53 (d, 1H), 7.61 (t, 1H), 7.00 (dd, 1H), 5.67 (m, 1H), 4.48 (m, 1H), 3.26 (q, 2H), 2.55 (m, 2H), 2.33-2.18 (m, 3H), 1.71 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:24][CH:25]2[CH2:29][CH2:28][CH2:27][CH2:26]2)[C:13]([NH:15][C:16]2[CH:20]=[CH:19][N:18]([CH2:21][CH2:22][OH:23])[N:17]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].[C:30](OC(=O)C)(=[O:32])[CH3:31]>N1C=CC=CC=1.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:24][CH:25]2[CH2:26][CH2:27][CH2:28][CH2:29]2)[C:13]([NH:15][C:16]2[CH:20]=[CH:19][N:18]([CH2:21][CH2:22][O:23][C:30](=[O:32])[CH3:31])[N:17]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:9])=[O:10]
Reactant: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)Nc2ccn(CCO)n2)cc1Cl
Reactant: CC(=O)OC(C)=O
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CC(=O)OCCn1ccc(NC(=O)[C@H](CC2CCCC2)c2ccc(S(C)(=O)=O)c(Cl)c2)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 59.9 %

Procedure:
2-(R)-(3-Chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-[1-(2-hydroxy-ethyl)-1H-pyrazol-3-yl]-propionamide (prepared in Example 67, 102 mg, 0.27 mmol) was dissolved in pyridine (2 mL) and acetic anhydride (27 umL, 0.29 mmol) was added. The reaction stirred at 25° C. for 16 h. The solution was diluted with ethyl acetate (40 mL), washed with aqueous 1.0 M hydrochloric acid solution (3×15 mL), saturated aqueous brine solution (1×10 mL), dried over magnesium sulfate and concentrated in vacuo. Purification by flash column chromatography (Merck silica gel 60, 40-63 μm; 50% ethyl acetate/hexanes to 75% ethyl acetate/hexanes) afforded acetic acid 2-{3-[2-(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionylamino]-pyrazol-1-yl}-ethyl ester (78 mg, 60%) as a white foam: ESI-LRMS m/e calcd for C22H28ClN3O5S [M+] 481.1, found 482.3 [M+H+]; 1H NMR (400 MHz, DMSO-d6) δ ppm 1.02-1.20 (m, 2 H, CH2), 1.39-1.79 (m, 8H, 4×CH2), 1.95 (s, 3H, COCH3), 2.01-2.19 (m, 1H, CH), 3.33 (s, 3H, SO2CH3), 3.86-3.95 (m, 1H, CH), 4.18-4.24 (m, 2H, OCH2), 4.29 (t, J=5.0 Hz, Hz, 2H, NCH2), 6.43 (d, Jo=2.3 Hz, 1H, Ar), 7.55-7.61 (m, 2H, Ar), 7.68 (d, Jm=1.7 Hz, 1H, Ar), 7.99 (d, Jo=8.2 Hz, 1H, Ar), 10.77 (s, 1H, NH).
Reaction SMILES: CN(C=O)C.[Si:6]([O:13][CH2:14][CH2:15][CH2:16][C@H:17]([C@@H:19]1[C@:36]2([CH3:37])[C@H:22]([C@H:23]3[C@H:33]([CH2:34][CH2:35]2)[C@:31]2([CH3:32])[C@H:26]([CH2:27][C@@H:28]([O:38][CH:39]4[CH2:44][CH2:43][CH2:42][CH2:41][O:40]4)[CH2:29][CH2:30]2)[CH2:25][C@H:24]3[OH:45])[CH2:21][CH2:20]1)[CH3:18])([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7].[CH2:46](Br)[C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1>C1COCC1>[CH2:46]([O:45][C@@H:24]1[CH2:25][C@@H:26]2[C@:31]([CH3:32])([CH2:30][CH2:29][C@H:28]([O:38][CH:39]3[CH2:44][CH2:43][CH2:42][CH2:41][O:40]3)[CH2:27]2)[C@@H:33]2[C@@H:23]1[C@H:22]1[C@:36]([CH3:37])([CH2:35][CH2:34]2)[C@@H:19]([C@H:17]([CH3:18])[CH2:16][CH2:15][CH2:14][O:13][Si:6]([C:9]([CH3:10])([CH3:11])[CH3:12])([CH3:8])[CH3:7])[CH2:20][CH2:21]1)[C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1
Reactant: C[C@H](CCCO[Si](C)(C)C(C)(C)C)[C@H]1CC[C@H]2[C@@H]3[C@H](O)C[C@H]4C[C@@H](OC5CCCCO5)CC[C@]4(C)[C@H]3CC[C@]12C
Reactant: BrCc1ccccc1
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: C[C@H](CCCO[Si](C)(C)C(C)(C)C)[C@H]1CC[C@H]2[C@@H]3[C@H](OCc4ccccc4)C[C@H]4C[C@@H](OC5CCCCO5)CC[C@]4(C)[C@H]3CC[C@]12C
Temperature: 400 °C
Reaction time: 8 h
Yield: 87 %

Procedure:
A flame-dried round-bottom flask with stirring bar was charged with sodium hydride (60% in mineral oil, 28 mg, 0.69 mmol), equipped with a septum and a gas-needle inlet and flushed with argon. The mineral oil was removed by washing (3×) with dry pentane, and the pentane was removed to provide the sodium hydride as a powder. Dry DMF (2.0 ml) was added. A solution of alcohol 2006 (40 mg, 0.069 mmol) in dry THF (2 ml) was added dropwise via syringe. The reaction mixture was stirred overnight and then heated to 400° C. in an oil bath over a 20-minute period. Freshly distilled benzyl bromide (0.165 ml, 1.38 mmol) was added dropwise, and the reaction mixture was stirred at 400° C. for 10 hours. The reaction was allowed to cool to room temperature, and the solvent was removed under reduced pressure. The flask was placed under vacuum overnight to remove any residual DMF. The crude material was purified by flash chromatography (SiO2, hexanes:EtOAc 50:1) giving compound 2007 as a white solid (40 mg, 0.060 mmol, 87%). A gradient of increasing EtOAc concentration provided other components, including the 7α-formate (1 mg, 1%) as well as recovered starting material (3 mg, 8%). Compound 2007:=1H NMR (500 MHz, CDCl3) δ 7.35-7.20 (m, 5 H, benzyl Ar-CH2), 4.73-4.66 (m, 1 H, methine H), 4.535 (d, J=12.0 Hz, 1/2 H, benzyl-CH2) , 4.53 (d, J=12.0 Hz, 1/2 H, benzyl-CH2), 4.26 (d, J=12.2 Hz, 1/2 H, benzyl-CH2), 4.245 (d, J=11.8 Hz, 1/2 H, benzyl-CH2), 3.95-3.85 (m, 1 H, THP CH2O), 3.66-3.52 (m, 3 H, THP CH2O & C-24 H), 3.50-3.45 (m, 1 H, C-3 H), 1.08 (s, 3 H, C-19 H), 0.91 (d, J=6.6 Hz, C-21 H), 0.89 (s, 9H, t-Bu), 0.64 (s, 3 H, C-18 H), 0.04 (s, 6 H, TBDMS CH3); MS (CI/isobutane) m/z 668 (M+1, 6%), 584 (M+1-THP, 18%), 475 (M+1-THPOH, 30%), 457 (M+1-THPOH-HOBn, 58%), 343 (M+1-THP-HOBn-TBDMSOH, 100%), 325 (M+1-THPOH-TBDMSOH-HOBn, 83%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][C:18]=3[O:20][C@H:21]([CH3:28])[CH2:22][N:23]([CH3:27])[C:24](=[O:26])[CH3:25])[N:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[OH:8].Cl.Cl[CH2:31][C:32]1[N:33]=[CH:34][S:35][CH:36]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][C:18]=3[O:20][C@H:21]([CH3:28])[CH2:22][N:23]([CH3:27])[C:24](=[O:26])[CH3:25])[N:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:31][C:32]1[N:33]=[CH:34][S:35][CH:36]=1
Reactant: CC(=O)N(C)C[C@@H](C)Oc1cccc2ncnc(Nc3ccc(O)c(Cl)c3)c12
Reactant: ClCc1cscn1
Agent: Cl
Product: CC(=O)N(C)C[C@@H](C)Oc1cccc2ncnc(Nc3ccc(OCc4cscn4)c(Cl)c3)c12
Yield: 17 %

Procedure:
The procedure described in Example 3 was repeated using N-[(2R)-2-({4-[(3-chloro-4-hydroxyphenyl)amino]quinazolin-5-yl}oxy)propyl]-N-methylacetamide (obtained as described for in Example 50, preparation of starting materials) and 4-(chloromethyl)-thiazole hydrochloride to give the title compound in 17% yield; NMR spectrum (DMSO-d6) 1.36 (d, 3H), 1.94 (s, 3H), 3.02 (s, 3H), 3.3O (1H obscured by H2O), 4.21 (dd, 1H), 5.09 (m, 1H), 5.33 (s, 2H), 7.29 (m, 3H), 7.70 (m, 2H), 7.81 (s, 1H), 8.08 (s, 1H), 8.47 (s, 1H), 9.13 (s, 1H), 9.96 (s, 1H); Mass Spectrum MH+ 498.
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[N:9]=[C:8](F)[N:7]=[C:6]([O:11][C:12]([F:15])([F:14])[F:13])[N:5]=1.[CH2:16]([OH:18])[CH3:17]>>[NH2:3][C:4]1[N:9]=[C:8]([O:18][CH2:16][CH3:17])[N:7]=[C:6]([O:11][C:12]([F:15])([F:14])[F:13])[N:5]=1
Reactant: CCO
Reactant: Nc1nc(F)nc(OC(F)(F)F)n1
Agent: [H-]
Agent: [Na+]
Product: CCOc1nc(N)nc(OC(F)(F)F)n1
Reaction time: 0.25 h

Procedure:
2.3 g (0.093 mol) of 97% sodium hydride were added a little at a time to 300 ml of ethanol at 20°-35° C. and dissolved by stirring for 15 minutes. Then, while stirring at 0° C., 18.5 g (0.093 mol) of 2-amino-4-fluoro-6-trifluoromethoxy-1,3,5-triazine were added over the course of 10 minutes, and the mixture was stirred at 0° C. for 1 hour and at 22° C. overnight. The residue from concentration under reduced pressure was taken up in methylene chloride, extracted with water and dried. Concentration yielded 17.9 g (85.9% of theory) of the title compound of melting point 69°-71° C.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[Cl:15][C:16]1[CH:17]=[N:18][C:19]2[NH:20][C:21]3[CH:22]=[N:23][CH:24]=[C:25]([CH:38]=3)[CH2:26][CH2:27][C:28]3[CH:36]=[C:32]([NH:33][C:34]=1[N:35]=2)[CH:31]=[CH:30][C:29]=3[NH2:37].C(OC([N:46]1[CH2:50][CH2:49][CH:48]([CH2:51][C:52](O)=[O:53])[CH2:47]1)=O)(C)(C)C>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[Cl:15][C:16]1[CH:17]=[N:18][C:19]2[NH:20][C:21]3[CH:22]=[N:23][CH:24]=[C:25]([CH:38]=3)[CH2:26][CH2:27][C:28]3[CH:36]=[C:32]([NH:33][C:34]=1[N:35]=2)[CH:31]=[CH:30][C:29]=3[NH:37][C:52](=[O:53])[CH2:51][CH:48]1[CH2:49][CH2:50][NH:46][CH2:47]1
Reactant: CC(C)(C)OC(=O)N1CCC(CC(=O)O)C1
Reactant: Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Solvent: O=C(O)C(F)(F)F
Product: O=C(CC1CCNC1)Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Yield: 51 %

Procedure:
The desired compound was prepared according to the procedures of Examples A-27 and A-28 using 6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-amine bis(trifluoroacetate) and 2-(1-(tert-butoxycarbonyl)pyrrolidin-3-yl)acetic acid as the starting materials in 51% yield. 1H NMR (300 MHz, DMSO-d6): δ 10.04 (s, 1H), 9.50 (s, 1H), 9.40 (s, 1H), 9.00 (s, 1H), 8.72 (m, 2H), 8.31 (s, 1H), 8.29 (s, 1H), 8.21 (s, 1H), 7.68 (s, 1H), 7.30 (d, 1H), 7.08 (d, 1H), 3.98 (s, 2H), 3.40 (m, 1H), 3.27 (m, 1H), 2.97 (m, 4H), 2.58 (m, 2H), 2.11 (m, 1H), 1.61 (m, 2H). LCMS for C23H25ClN7O (M+H)+: m/z=450.2.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[Cl:10])[CH2:5][NH2:6].Cl[C:12]1[C:13]2[CH:26]=[C:25]([CH3:27])[S:24][C:14]=2[N:15]=[C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)[N:17]=1>>[N:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[C:16]1[N:17]=[C:12]([NH:6][CH2:5][C:4]2[CH:7]=[CH:8][C:9]([Cl:10])=[C:2]([Cl:1])[CH:3]=2)[C:13]2[CH:26]=[C:25]([CH3:27])[S:24][C:14]=2[N:15]=1
Reactant: NCc1ccc(Cl)c(Cl)c1
Reactant: Cc1cc2c(Cl)nc(-c3ccccn3)nc2s1
Product: Cc1cc2c(NCc3ccc(Cl)c(Cl)c3)nc(-c3ccccn3)nc2s1

Procedure:
With the procedure of Example 1, the reaction of 3,4-dichlorobenzylamine with 4-chloro-2-(pyridin-2-yl)-6-methyl-thieno-[2,3-d]-pyrimidine yields 2-(pyridin-2-yl)-4-(3,4-dichlorobenzylamino)-6-methyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [NH2:1][CH:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=2[NH:4][C:3]1=[O:19].[CH2:20]([C:25]1[CH:33]=[CH:32][C:28]([C:29](Cl)=[O:30])=[CH:27][CH:26]=1)[CH2:21][CH2:22][CH2:23][CH3:24]>>[CH2:20]([C:25]1[CH:33]=[CH:32][C:28]([C:29]([NH:1][CH:2]2[N:8]=[C:7]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:6]3[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=3[NH:4][C:3]2=[O:19])=[O:30])=[CH:27][CH:26]=1)[CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: NC1N=C(c2ccccc2)c2ccccc2NC1=O
Reactant: CCCCCc1ccc(C(=O)Cl)cc1
Product: CCCCCc1ccc(C(=O)NC2N=C(c3ccccc3)c3ccccc3NC2=O)cc1

Procedure:
The procedure of Example 134 was carried out using 3(RS)-amino-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepin-2-one (39.2 mg, 0.156 mmole) in place of 1,3-dihydro-3(RS)-amino-5-(2-fluorophenyl)-2H-1,4-benzodiazepin-2-one and 4-n-pentylbenzoyl chloride (32.9 mg, 0.156 mmole) in place of p-trifluorobenzoyl chloride. The product was chromatographed on silica gel (15%, (v/v) Et2O in CH2Cl2 elution). The combined product fractions were evaporated to dryness in vacuo and crystallized from Et2O to give the title compound which was dried in vacuo at 82° C.: (m.p. 203°-205° C.).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][C:15]([NH:17][CH:18]([CH3:20])[CH3:19])=[O:16])[CH2:10][CH2:9]2)[CH:3]=1.[H-].[Na+].Cl[C:24]1[S:25][C:26]([C:29]#[N:30])=[CH:27][N:28]=1>>[C:29]([C:26]1[S:25][C:24]([NH:1][C:2]2[N:7]=[CH:6][N:5]=[C:4]([N:8]3[CH2:13][CH2:12][N:11]([CH2:14][C:15]([NH:17][CH:18]([CH3:20])[CH3:19])=[O:16])[CH2:10][CH2:9]3)[CH:3]=2)=[N:28][CH:27]=1)#[N:30]
Reactant: N#Cc1cnc(Cl)s1
Reactant: CC(C)NC(=O)CN1CCN(c2cc(N)ncn2)CC1
Agent: [H-]
Agent: [Na+]
Product: CC(C)NC(=O)CN1CCN(c2cc(Nc3ncc(C#N)s3)ncn2)CC1

Procedure:
2-[4-(6-aminopyrimidin-4-yl)piperazin-1-yl]-N-isopropylacetamide 13-2 (0.45 g, 1.62 mmol), sodium hydride (0.13 g, 3.25 mmol) and 2-chloro-1,3-thiazole-5-carbonitrile 2-2 (0.235 g, 1.62 mmol) were treated as in Scheme 4 above. The product was purified on a C18 preparative column and isolated via lyophilization. Hi-Res MS: calc: 387.1710 found: 387.1691. 1NMR (DMSO): 8.51 ppm (s, 1H); 8.47 ppm (s, 1H); 8.28 ppm (s, 1H); 6.30 ppm (s, 1H); 4.35 ppm (m, 2H); 3.91 ppm (m, 4H); 3.39 ppm (m, 2H); 3.18 ppm (m, 2H); 1.11 ppm (d, 6H).
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5](OC)=[C:6]([CH:8](O)[C:9]#CC2C=CC=CC=2)[CH:7]=1.[CH3:20][O:21][C:22]1[CH:29]=[C:28]([Br:30])[C:27]([O:31][CH3:32])=[CH:26][C:23]=1[CH:24]=[O:25]>>[Br:30][C:28]1[C:27]([O:31][CH3:32])=[CH:26][C:23]([CH:24]([OH:25])[C:9]#[C:8][C:6]2[CH:7]=[CH:2][CH:3]=[CH:4][CH:5]=2)=[C:22]([O:21][CH3:20])[CH:29]=1
Reactant: COc1cc(C=O)c(OC)cc1Br
Reactant: COc1ccc(F)cc1C(O)C#Cc1ccccc1
Product: COc1cc(C(O)C#Cc2ccccc2)c(OC)cc1Br
Yield: 100 %

Procedure:
Following the procedure used to prepare 1-(5-fluoro-2-methoxy-phenyl)-3-phenyl-prop-2-yn-1-ol, 2,5-dimethoxy-4-bromobenzaldehyde was reacted to give the title compound as a colourless oil (1.45 g, 100%). LCMS (Method B): RT=4.49 min, [M+Na]+=369/371.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([C:14]=1[Cl:15])=[CH:12][C:11]([Br:16])=[CH:10][CH:9]=2)=[O:5])[CH3:2].[CH:17]([O:20][C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=1)([CH3:19])[CH3:18]>>[CH2:1]([O:3][C:4]([C:6]1[N:7]([C:24]2[CH:25]=[CH:26][C:21]([O:20][CH:17]([CH3:19])[CH3:18])=[CH:22][CH:23]=2)[C:8]2[C:13]([C:14]=1[Cl:15])=[CH:12][C:11]([Br:16])=[CH:10][CH:9]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1[nH]c2ccc(Br)cc2c1Cl
Reactant: CC(C)Oc1ccc(B(O)O)cc1
Product: CCOC(=O)c1c(Cl)c2cc(Br)ccc2n1-c1ccc(OC(C)C)cc1

Procedure:
The sub-title compound was prepared in accordance with Example 8(c), using 5-bromo-3-chloro-1H-indole-2-carboxylic acid ethyl ester (see step (a) above) and 4-isopropoxyphenylboronic acid.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[N:5]=[C:6]([F:28])[N:7]([C:9]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:8]=1.[CH3:29][N:30]=[C:31]=[O:32]>CCOCC>[F:28][C:6]1[N:7]([C:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:8]=[C:4]([CH2:3][CH2:2][NH:1][C:31]([NH:30][CH3:29])=[O:32])[N:5]=1
Reactant: CN=C=O
Reactant: NCCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c(F)n1
Solvent: CCOCC
Product: CNC(=O)NCCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c(F)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-(2-Aminoethyl)-2-fluoro-1-triphenylmethylimidazole was dissolved in ether, treated with methylisocyanate, and stirred overnight at ambient temperature. Work-up gave 1-[2-(2-fluoro-1-triphenylmethylimidazol-4-yl)ethyl]-3-methylurea, having the following n.m.r. spectrum in CDCl3 : 2.54 (t, 2H); 2.7 (d, 3H); 3.35 (q, 2H); 5.1 (m, 1H); 6.4 (m, 1H); 6.3 (s, 1H); 7.2 (m, 15H).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[CH2:11]([Mg]Br)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.O>O1CCCC1>[CH2:11]([CH:2]1[CH:3]=[CH:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[NH:1]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Br[Mg]Cc1ccccc1
Reactant: c1ccc2ncccc2c1
Solvent: C1CCOC1
Solvent: O
Product: C1=CC(Cc2ccccc2)Nc2ccccc21
Reaction time: 0.5 h

Procedure:
Quinoline (6.0 g, 0.0047 mol) in 15 ml of tetrahydrofuran was added to benzyl magnesium bromide (47 ml of 2M in tetrahydrofuran, 0.0094 mol) via a syringe. After stirring for 0.5 hour, the reaction mixture was cooled to 0°, and an equal volume of H2O was added slowly. An exothermic reaction was noted. The aqueous solution was extracted 3×125 ml of ether. The organic layers were combined, dried (K2CO3) and stripped in vacuo to yield intermediate 2-benzyl-1,2-dihydroquinoline as an oil, 11.3 g (0.0051 mol). The latter was taken up in 50 ml of nitrobenzene, refluxed for 2 hours, cooled to room temperature, poured into 150 ml of 1M HCl, and extracted 2×200 ml ether. The aqueous layer was adjusted to pH 8 with saturated NaHCO3 and extracted 3×200 ml ether. The latter ether extracts were combined, dried (MgSO4) and stripped in vacuo to an oil, 4.56 g. The latter was twice chromatographed on a thick layer of silica gel, using 12:1 hexane:ethyl acetate as eluant. In each case, the second band to elute was separated. In this manner 1.3 g of intermediate 2-benzylquinoline was isolated. The latter intermediate (0.5 g, 0.0023 mol) was dissolved in 10 ml of dry ethanol and brought to reflux. Sodium metal (0.8 g) was added over the course of 2 hours. After an additional 1.5 hours of reflux, the contents of the flask began to solidify. The reaction mixture was then cooled to room temperature, stripped of ethanol in vacuo, and the residual solid dissolved in 50 ml of H2O and extracted 3×50 ml benzene. The combined benzene extracts were dried (K2CO3) and stripped to an oil, 0.39 g. The latter was chromatographed on a thick layer plate of silica gel using CHCl3 as eluant to yield purified title product, 0.35 g.