Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:20]=[CH:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=1.[C:21]1(=[O:31])[NH:25][C:24](=[O:26])[C:23]2=[CH:27][CH:28]=[CH:29][CH:30]=[C:22]12.[K].O>CN(C)C=O>[CH:12]1[C:13]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:19]=[CH:20][C:11]=1[O:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][N:25]1[C:24](=[O:26])[C:23]2=[CH:27][CH:28]=[CH:29][CH:30]=[C:22]2[C:21]1=[O:31]
Reactant: ClCCCCCCCCOc1ccc2ccccc2c1
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: CN(C)C=O
Solvent: O
Product: O=C1c2ccccc2C(=O)N1CCCCCCCCOc1ccc2ccccc2c1

Procedure:
1-Chloro-8-(2-naphthyloxy)octane (4.75 g) and potassium phthalimide (4.2 g) were heated in dimethylformamide (25 ml) at 120° for 4 hours. The solution was then cooled, added to water, and extracted with methylene chloride. The extracts were then dried and evaporated to afford N-[8-(2-naphthyloxy)octyl]phthalimide as a gum. This material was refluxed for 16 hours in ethanol (150 ml) containing 85% aqueous hydrazine hydrate (3 ml). The solution was cooled and water (450 ml) and 10% aqueous potassium hydroxide (50 ml) were added. The resultant solution was extracted with hexane; the extract was dried and evaporated to afford the title compound as an oil (hydrochloride mp 169°-170°).
Reaction SMILES: [CH3:1][O:2]C1C(OC)=CC(N)=CC=1.Cl[C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][C:14]=1[NH:21][C:22](=[O:24])[CH3:23]>>[CH3:1][O:2][C:18]1[CH:13]=[C:14]([NH:21][C:22](=[O:24])[CH3:23])[CH:15]=[C:16]([O:19][CH3:20])[CH:17]=1
Reactant: COc1ccc(N)cc1OC
Reactant: COc1ccc(Cl)c(NC(C)=O)c1
Product: COc1cc(NC(C)=O)cc(OC)c1

Procedure:
Prepared from 4,5-dimethoxyaniline in analogy to the methods described for N-(2-chloro-5-methoxy-phenyl)-acetamide.
Reaction SMILES: [I-].[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([CH2:12][N+:13]3([CH2:18][CH3:19])[CH2:17][CH2:16][CH2:15][CH2:14]3)[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.[OH2:20]>>[OH-:20].[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([CH2:12][N+:13]3([CH2:18][CH3:19])[CH2:17][CH2:16][CH2:15][CH2:14]3)[CH2:10][CH2:11]2)=[CH:5][CH:4]=1
Reactant: O
Agent: CC[N+]1(CC2(c3ccc(Cl)cc3)CC2)CCCC1
Agent: [I-]
Product: [OH-]
Reaction time: 8 h

Procedure:
The hydroxide form of 1-[1-(4-chloro-phenyl)-cyclopropyhnethyl]-1-ethyl-pyrrolidinium cation is obtained by an ion exchange treatment of the iodide salt with Ion-Exchange Resin-OH (BIO RAD® AH1-X8). In a 1-liter volume plastic bottle, 100 gm (255 mmol) of 1-[1-(4-chloro-phenyl)-cyclopropylmethyl]-1-ethyl-pyrrolidinium iodide is dissolved in 300 ml de-ionized water. Then, 320 gm of the ion exchange resin is added and the solution is allowed to gently stir overnight. The mixture is then filtered, and the resin cake is rinsed with minimal amount of de-ionized water. The filtrate is analyzed for hydroxide concentration by titration analysis on a small sample of the solution with 0.1N HCl. The reaction yields 96% of (245 mmol) of the desired 1-[1-(4-chloro-phenyl)-cyclopropylmethyl]-1-ethyl-pyrrolidinium hydroxide (hydroxide concentration of 0.6 M).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4](B2OC(C)(C)C(C)(C)O2)[CH:3]=1.Cl[C:19]1[CH:24]=[CH:23][N:22]=[C:21]([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])[CH:20]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O.C(OCC)(=O)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Pd]>[F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([C:19]2[CH:24]=[CH:23][N:22]=[C:21]([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:30])([CH3:29])[CH3:31])[CH:20]=2)[CH:3]=1
Reactant: CC1(C)OB(c2cc(F)ccc2O)OC1(C)C
Reactant: CC(C)(C)OC(=O)Nc1cc(Cl)ccn1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)Nc1cc(-c2cc(F)ccc2O)ccn1
Temperature: 85 °C
Reaction time: 16 h

Procedure:
4-Fluoro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (Preparation 212, 0.082 g, 0.000386 mol), tert-butyl (4-chloropyridin-2-yl)carbamate (0.0588 g, 0.000257 mol), anhydrous sodium carbonate (0.070 g, 0.000660 mol) and palladium (0) tetrakis(triphenylphosphine) (0.029 mg, 0.000025 mol) were suspended in 1,4-dioxane (3.0 ml) and water (1.0 ml). The suspension was stirred at 85° C. for 16 hours before cooling to room temperature. The reaction was diluted with ethyl acetate (10 ml) and organic phase was washed with saturated aqueous sodium bicarbonate solution (2×10.0 ml), dried over sodium sulphate, filtered and concentrated in vacuo. Purification by ISCO™ (12 g SiO2) eluting with ethyl acetate:heptane (gradient 0:1 to 3:7, by volume) afforded the title compound as a solid, 41 mg, 54%.
Reaction SMILES: [ClH:1].[CH3:2][O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[CH:10]=[N+:9]([O-])[CH:8]=[CH:7]2>P(Cl)(Cl)(Cl)=O>[Cl:1][C:10]1[C:11]2[C:6](=[CH:5][C:4]([O:3][CH3:2])=[CH:13][CH:12]=2)[CH:7]=[CH:8][N:9]=1
Reactant: COc1ccc2c[n+]([O-])ccc2c1
Reactant: Cl
Solvent: O=P(Cl)(Cl)Cl
Product: COc1ccc2c(Cl)nccc2c1
Temperature: 90 °C
Reaction time: 6 h

Procedure:
6-Methoxy-isoquinoline-N-oxide hydrochloride (1a, 85 g; 400 mmol) was carefully added in portions to phosphoryl chloride (550 mL) at a temperature of 90° C., after which the mixture was stirred for 6 h at 90° C. Excess of phosphoryl chloride was removed in vacuo. The remaining white solid was washed with water, filtered and dried in vacua. Yield: 68 g (88%); white solid; m.p. 72-74° C.; El-MS: 193 (M+).
Reaction SMILES: [C:1]1([N:7]2[C:24]([OH:25])=[C:10]3[N:11]=[CH:12][N:13]=[C:14]([S:15][C:16]([C:19]([O:21][CH2:22][CH3:23])=[O:20])([CH3:18])[CH3:17])[C:9]3=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:26](Br)[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37]>>[C:1]1([N:7]2[C:24]([O:25][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH3:26])=[C:10]3[N:11]=[CH:12][N:13]=[C:14]([S:15][C:16]([C:19]([O:21][CH2:22][CH3:23])=[O:20])([CH3:18])[CH3:17])[C:9]3=[N:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCCCCCCCCCCCBr
Reactant: CCOC(=O)C(C)(C)Sc1ncnc2c(O)n(-c3ccccc3)nc12
Product: CCCCCCCCCCCCOc1c2ncnc(SC(C)(C)C(=O)OCC)c2nn1-c1ccccc1
Yield: 30 %

Procedure:
1 g of 2-phenyl-3-hydroxy-7-(1-ethoxycarbonyl-1-methyl-ethylthio)-pyrazolo[4,3-d]pyrimidine and 0.84 g of n-dodecyl bromide were reacted and treated in the same manner as in Example 31 to obtain the desired product.
Reaction SMILES: [Br-:1].[Br-].[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.[NH2:55][C:56]1[C:57]([CH3:69])=[C:58]([CH3:68])[C:59]2[O:63][C:62]([CH3:65])([CH3:64])[C:61](=[O:66])[C:60]=2[CH:67]=1.S([O-])([O-])=O.[Na+].[Na+]>O1CCCC1>[NH2:55][C:56]1[C:57]([CH3:69])=[C:58]([CH3:68])[C:59]2[O:63][C:62]([CH3:64])([CH3:65])[C:61](=[O:66])[C:60]=2[C:67]=1[Br:1]
Reactant: [Br-]
Reactant: Cc1c(N)cc2c(c1C)OC(C)(C)C2=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1c(C)c2c(c(Br)c1N)C(=O)C(C)(C)O2
Temperature: 0 °C
Reaction time: 2 h
Yield: 72.4 %

Procedure:
Tetrabutylammonium tribromide (31.0 g, 64.2 mmol) was added to a tetrahydrofuran solution (200 mL) containing 5-amino-2,2,6,7-tetramethyl-1-benzofuran-3(2H)-one (6.59 g, 32.1 mmol) synthesized in Reference Example 20 at 0° C., and the mixture was stirred at 0° C. for 2 hours. To the mixture, a saturated sodium sulfite aqueous solution was added, and extraction was performed using ethyl acetate. The extract was dried using anhydrous magnesium sulfate. After that, the solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate 98:2 to 85:15) to give 6.60 g of the title compound (yield: 72%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:19]2[C:20](=[O:33])[N:21]([CH3:32])[C:22]([NH:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[N:23][CH:24]=2)[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[CH:15]=[C:16](I)[S:17][C:10]=12.[N:34]1([C:40]([C:42]2[CH:47]=[CH:46][C:45](B(O)O)=[CH:44][CH:43]=2)=[O:41])[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1.[Cl-].[Li+]>O1CCOCC1.C([O-])([O-])=O.[Na+].[Na+].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:1][C:2]1[CH:3]=[C:4]([C:19]2[C:20](=[O:33])[N:21]([CH3:32])[C:22]([NH:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[N:23][CH:24]=2)[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[CH:15]=[C:16]([C:45]3[CH:44]=[CH:43][C:42]([C:40]([N:34]4[CH2:39][CH2:38][O:37][CH2:36][CH2:35]4)=[O:41])=[CH:47][CH:46]=3)[S:17][C:10]=12
Reactant: O=C(c1ccc(B(O)O)cc1)N1CCOCC1
Reactant: Cn1c(Nc2ccccc2)ncc(-c2ccc(Oc3ccnc4cc(I)sc34)c(F)c2)c1=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: C1COCCO1
Product: Cn1c(Nc2ccccc2)ncc(-c2ccc(Oc3ccnc4cc(-c5ccc(C(=O)N6CCOCC6)cc5)sc34)c(F)c2)c1=O
Temperature: 100 °C
Reaction time: 0.5 h

Procedure:
A suspension of 5-(3-fluoro-4-(2-iodothieno[3,2-b]pyridin-7-yloxy)phenyl)-3-methyl-2-(phenylamino)pyrimidin-4(3H)-one (Example 143, Step F, 0.018 g, 0.0316 mmol), 4-(morpholine-4-carbonyl)phenylboronic acid (0.009 g, 0.038 mmol), Pd(PPh3)4 (0.002 g, 0.002 mmol) and lithium chloride (0.005 g, 0.126 mmol) in dioxane (1 mL) and 2 M aqueous Na2CO3 (1 mL) was stirred at 100° C. for 30 minutes. The reaction mixture was cooled to room temperature and then partitioned between EtOAc and H2O. The layers were separated and the aqueous layer was re-extracted with EtOAc (1×). The combined organic layers were dried over Na2SO4, filtered and concentrated. The crude product was purified by flash column chromatography, eluting with 10:1 CH2Cl2/MeOH. The product was obtained (12.9 mg; 65%) as a pale yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 9.04 (br s, 1H), 8.55 (d, 1H), 8.17 (s, 1H), 8.12 (s, 1H), 7.99 (m, 2H), 7.89 (dd, 1H), 7.69 (m, 1H), 7.58-7.49 (m, 5H), 7.38 (m, 2H), 7.17 (m, 1H), 6.70 (dd, 1H), 3.63 (m, 8H), 3.59 (s, 3H). LRMS (APCI pos) m/e 634 (M+1).
Reaction SMILES: CO[C:3]([CH:5]1[CH2:9][N:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:7][N:6]1[C:16](=[O:26])[CH:17]([NH:21][C:22]([O:24][CH3:25])=[O:23])[CH:18]([CH3:20])[CH3:19])=[O:4].[Li+].[OH-].Cl.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.Cl.[NH2:64][CH2:65][C:66]([C:68]1[CH:73]=[CH:72][C:71]([Br:74])=[CH:70][CH:69]=1)=[O:67]>C1COCC1.CO>[CH3:25][O:24][C:22](=[O:23])[NH:21][CH:17]([C:16]([N:6]1[CH:5]([C:3](=[O:4])[NH:64][CH2:65][C:66]([C:68]2[CH:73]=[CH:72][C:71]([Br:74])=[CH:70][CH:69]=2)=[O:67])[CH2:9][N:8]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:7]1)=[O:26])[CH:18]([CH3:20])[CH3:19]
Reactant: COC(=O)NC(C(=O)N1CN(c2ccccc2)CC1C(=O)OC)C(C)C
Reactant: NCC(=O)c1ccc(Br)cc1
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: CO
Solvent: C1CCOC1
Product: COC(=O)NC(C(=O)N1CN(c2ccccc2)CC1C(=O)NCC(=O)c1ccc(Br)cc1)C(C)C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 124.4 %

Procedure:
3-(2-Methoxycarbonylamino-3-methyl-butyryl)-1-phenyl-imidazolidine-4-carboxylic acid methyl ester (51 mg, 0.14 mmol) was dissolved in THF (1.2 mL) and MeOH (0.8 mL). An aqueous solution of LiOH (6.0 mg, 0.14 mmol) was added and stirring at room temperature was continued. After the hydrolysis was complete, the reaction was neutralized with aqueous HCl (1M). The organic solvents were removed in vacuo and the aqueous suspension was frozen and lyophilized. The crude material was used in the next step without further purification. The crude material was dissolved in DMF (1.5 mL) and HATU (54.3 mg, 0.14 mmol) and DIEA (36.9 mg, 0.28 mmol) were added. The reaction was stirred at room temperature for five minutes, after which the amino-(4′bromo) acetophenone hydrochloride salt (35.7 mg, 0.14 mmol) was added. Stirring at room temperature was continued. After 10 minutes, all volatiles were removed in vacuo and the crude material was purified via silica gel chromatography (eluent: EtOAc/hexanes) to yield the slightly impure product (95 mg): LCMS-ESI+: calc'd for C25H29BrN4O5: 545.4 (M+). Found: 545.2/547.4 (M+H+).
Reaction SMILES: [C:1]([O:9][CH:10]([CH2:57][CH:58]=[CH2:59])[CH:11]1[CH:16]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:15]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:14]([O:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH:13]([CH2:41][O:42][CH2:43][C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[N:12]1[CH2:50][C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-:60].[Na+].OO.O>O1CCCC1>[C:1]([O:9][CH:10]([CH:11]1[CH:16]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:15]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:14]([O:33][CH2:34][C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH:13]([CH2:41][O:42][CH2:43][C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[N:12]1[CH2:50][C:51]1[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=1)[CH2:57][CH2:58][CH2:59][OH:60])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [OH-]
Reactant: C=CCC(OC(=O)c1ccccc1)C1C(OCc2ccccc2)C(OCc2ccccc2)C(OCc2ccccc2)C(COCc2ccccc2)N1Cc1ccccc1
Agent: OO
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: O=C(OC(CCCO)C1C(OCc2ccccc2)C(OCc2ccccc2)C(OCc2ccccc2)C(COCc2ccccc2)N1Cc1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of Compound (XIV) (1.80 g; 2.29 mmoles) in tetrahydrofuran (25 mL), cooled at 0° C., was added a 1.0M solution of borane-dimethylsulfide complex in tetrahydrofuran (1.5 mL). The reaction was warmed to room temperature and kept for 20 hours. After cooling to 0° C., 3N NaOH solution (15 mL) and 30W% hydrogen peroxide (0.5 mL) were added, and the suspension was heated under reflux for 1 hour. Upon cooling to room temperature, the suspension was mixed with water (10 mL) and extracted with ether (2×40 mL). The combined organic solution was washed with saturated sodium chloride solution, dried over magnesium sulfate and filtered. The solvent was evaporated under reduced pressure, and the crude residual oil was purified via flash chromatography (silica gel; 1:2 ethyl acetate:hexane) to yield the primary alcohol, 1-[3,4,5-tris(phenylmethoxy)-6[(phenylmethoxy) methyl]-1-(phenylmethyl)-2-piperidinyl]-1,4-butanediol 1-benzoate (XV), as a clear, colorless oil (1.05 g; 56.9%) and the 1,4-diol, 1-[3,4,5-tris (phenylmethoxy)-6-[(phenylmethoxy)methyl]-1-(phenylmethyl) -2-piperidinyl]-1,4-butanediol (XVIII), as a yellow oil (0.41 g; 24.9%). Compound (XV): IR(neat) 1720 cm-1 (C=0); MS (FAB-MNBA) 806 (MH+), 788 (MH+H2O); 1H nmr (CDCl3) δ 1.5-1.9 (m, 2H), 2.8 (t, 1H), 3.4 (t, 2H), 3.5 (m, 1H), 3.7-4.2 (m, 7H), 4.3-4.4 (m, 1H), 4.4 (s, 2H), 4.5-4.9 (m, 7H), 5.4-5.5 (m, 1H), 7.0-7.4 (m, 27H), 7.5 (m, 1H), 8.1 (m, 2H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]2[N:11]3[CH:12]=[CH:13][C:14]([C:15]([C:17]4[C:25]5[C:20](=[CH:21][C:22]([C:26]6[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=6)=[CH:23][CH:24]=5)[N:19]([CH2:33][CH2:34][NH:35]C(OC(C)(C)C)=O)[CH:18]=4)=[O:16])=[C:10]3[CH2:9][S:8]2)[CH:2]=1.[ClH:43].O1CCOCC1>C(Cl)Cl>[ClH:43].[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]2[N:11]3[CH:12]=[CH:13][C:14]([C:15]([C:17]4[C:25]5[C:20](=[CH:21][C:22]([C:26]6[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=6)=[CH:23][CH:24]=5)[N:19]([CH2:33][CH2:34][NH2:35])[CH:18]=4)=[O:16])=[C:10]3[CH2:9][S:8]2)[CH:2]=1
Reactant: CC(C)(C)OC(=O)NCCn1cc(C(=O)c2ccn3c2CSC3c2cccnc2)c2ccc(-c3ccc(F)cc3)cc21
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: NCCn1cc(C(=O)c2ccn3c2CSC3c2cccnc2)c2ccc(-c3ccc(F)cc3)cc21
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A solution of 3-(pyridin-3-yl)-7-[1-(2-tert-butoxycarbonylaminoethyl)-6-(4-fluorophenyl)indol-3-ylcarbonyl]-1H,3H-pyrrolo[1,2-c]thiazole (104 mg), prepared as in Example 57, in CH2Cl2 at 0° C. was treated with 4N HCl/dioxane (1 mL). The reaction mixture was stirred for 15 min at 0° C. and then concentrated in vacuo. The resulting solid was azeotroped three times with CH2Cl2 to give 3-(Pyridin-3-yl)-7-[1-(2-aminoethyl)-6-(4-fluorophenyl)indol-3-ylcarbonyl]-1H,3H-pyrrolo[1,2-c]thiazole hydrochloride (115 mg), 1H NMR (D3COD, 300 MHz) δ3.48-3.60 (m, 3H), 3.64-3.75 (m, 4H), 4.53 (d, 1H, J=15 Hz) 4.68-4.77 (m, 3H), 6.76 (d, 1H, J=3 Hz), 6.9 (d, 1H, J=1.5 Hz), 7.55 (dd, 1H, J=1.5 9 Hz), 7.75 (dd, 2H, J=6, 8 Hz), 7.83 (s, 1H), 8.13 (dd, 1H, J=6, 8 Hz), 8.30 (s, 1H), 8.35 (d, 1H, J=9 Hz), 8.49 (d, 1H, J=9 Hz), 8.87 (d, 2H, J=7 Hz), MS (DCI/NH3) m/e 483 (M+H)+.
Reaction SMILES: [O:1]1[C:5]([C:6]2[CH:11]=[CH:10][C:9]([NH:12][C:13]3[N:14]=[C:15]([NH:23][CH2:24][C@@H:25]4[CH2:29][CH2:28][CH2:27][O:26]4)[C:16]4[CH2:22][NH:21][CH2:20][CH2:19][C:17]=4[N:18]=3)=[CH:8][CH:7]=2)=[CH:4][N:3]=[CH:2]1.[C:30](O)(=O)C.C=O.C([BH3-])#N.[Na+]>CO>[CH3:30][N:21]1[CH2:20][CH2:19][C:17]2[N:18]=[C:13]([NH:12][C:9]3[CH:8]=[CH:7][C:6]([C:5]4[O:1][CH:2]=[N:3][CH:4]=4)=[CH:11][CH:10]=3)[N:14]=[C:15]([NH:23][CH2:24][C@@H:25]3[CH2:29][CH2:28][CH2:27][O:26]3)[C:16]=2[CH2:22]1
Reactant: CC(=O)O
Reactant: c1ncc(-c2ccc(Nc3nc4c(c(NC[C@@H]5CCCO5)n3)CNCC4)cc2)o1
Agent: C=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CN1CCc2nc(Nc3ccc(-c4cnco4)cc3)nc(NC[C@@H]3CCCO3)c2C1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 53.2 %

Procedure:
(5)-N2-(4-(Oxazol-5-yl)phenyl)-N4-((tetrahydrofuran-2-yl)methyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-2,4-diamine (120 mg, 0.31 mmol) was dissolved in methanol (3 mL). Acetic acid (0.018 mL, 0.31 mmol) was added followed by formaldehyde (0.023 mL, 0.31 mmol). The reaction mixture was stirred at room temperature for 15 minutes and sodium cyanoborohydride (19.22 mg, 0.31 mmol) MP—CNBH3 was added. The reaction was stirred at room temperature overnight, MP—CNBH3 was filtered off and the solvent was evaporated under reduced pressure. Purification by HPLC gave (S)-6-methyl-N2-(4-(oxazol-5-yl)phenyl)-N4-((tetrahydrofuran-2-yl)methyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-2,4-diamine (67.0 mg, 48%). MS (ES+) m/z 407.2 (M+H)+
Reaction SMILES: [Cl:1]C1SC2[NH:6][C:7]([C:9]([NH:11][CH:12]3[CH2:21][C:20]4[C:15](=CC=CC=4)[N:14](CCOC)[C:13]3=O)=[O:10])=[CH:8]C=2C=1.[ClH:28]>C(Cl)Cl.O1CCOCC1>[ClH:1].[ClH:28].[NH2:6][CH:7]1[CH2:8][C:13]2[C:12](=[CH:21][CH:20]=[CH:15][N:14]=2)[NH:11][C:9]1=[O:10]
Reactant: COCCN1C(=O)C(NC(=O)c2cc3cc(Cl)sc3[nH]2)Cc2ccccc21
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: NC1Cc2ncccc2NC1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
tert-Butyl(2-oxo-1,2,3,4-tetrahydro-1,5-naphthyridine-3-yl)carbamate (Method 26, 263 mg, 1 mmol) was dissolved in DCM (10 mL) and treated with 4M HCl in dioxan (10 mL). After stirring at ambient temperature for 30 mins. the reaction mixture was evaporated under reduced pressure and the residue triturated with ether (20 mL), to give a white solid which was collected by filtration, washed with ether and dried. (234 mg, 100%).
Reaction SMILES: [O:1]=[S:2]1(=[O:39])[C:8]2[CH:9]=[C:10]([O:14][CH3:15])[C:11](Br)=[CH:12][C:7]=2[N:6]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:5][C:4]([CH2:26][CH2:27][CH2:28][CH3:29])([CH2:22][CH2:23][CH2:24][CH3:25])[N:3]1[CH2:30][C:31]1[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=1.[Li][CH2:41]CCC.CI.C(OCC)C>C1COCC1>[O:1]=[S:2]1(=[O:39])[C:8]2[CH:9]=[C:10]([O:14][CH3:15])[C:11]([CH3:41])=[CH:12][C:7]=2[N:6]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:5][C:4]([CH2:26][CH2:27][CH2:28][CH3:29])([CH2:22][CH2:23][CH2:24][CH3:25])[N:3]1[CH2:30][C:31]1[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=1
Reactant: CCCCC1(CCCC)CN(c2ccccc2)c2cc(Br)c(OC)cc2S(=O)(=O)N1Cc1ccc(OC)cc1
Reactant: [Li]CCCC
Solvent: CI
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCCCC1(CCCC)CN(c2ccccc2)c2cc(C)c(OC)cc2S(=O)(=O)N1Cc1ccc(OC)cc1
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 21.3 %

Procedure:
To a cooled solution (−78° C.) of 1,1-dioxo-2-(4-methoxybenzyl)-3,3dibutyl-5-phenyl-7-bromo-8-methoxy-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine (Method 23; 2.10 g, 3.41 mmol) in THF (50 ml) was added dropwise a solution of n-BuLi (2.35 ml, 3.75 mmol, 1.6 M in hexane). After stirring at −78° C. for 20 minutes, MeI (2.42 g, 17.1 mmol) was added. The mixture was stirred at −78° C. for 10 minutes and at room temperature for 18 hours. Diethyl ether (50 ml) was added and the organic phase was washed with 10% NH4Cl (aq, 50 ml) and brine (50 ml). After drying, filtration and concentration the crude product was subjected to flash chromatography (Hexane:EtOAc—95:5) to give 0.4 gram (21%) of the title product as colourless oil. NMR (300 MHz, CDCl3): 0.60–0.70 (m, 6H), 0.70–0.90 (m, 4H), 0.90–1.35 (m, 8H), 2.00 (s, 3H), 3.70 (s, 3H), 3.80 (s, 3H), 4.00–4.20 (m, 2H), 4.35–4.60 (m, 2H), 6.65–6.85 (m, 3H), 6.90–7.10 (m, 3H), 7.15–7.30 (m, 5H).
Reaction SMILES: CC(C)([O-])C.[Na+].[CH:7]1([C@@H:10]2[CH2:15][NH:14][CH2:13][CH2:12][NH:11]2)[CH2:9][CH2:8]1.Br[C:17]1[CH:22]=[CH:21][C:20]([C:23]([OH:32])([C:28]([F:31])([F:30])[F:29])[C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC(C)C)=CC=CC=2OC(C)C)CCCCC1>O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(C)C=CC=CC=1>[CH:7]1([C@H:10]2[NH:11][CH2:12][CH2:13][N:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([OH:32])([C:28]([F:29])([F:31])[F:30])[C:24]([F:27])([F:25])[F:26])=[CH:19][CH:18]=3)[CH2:15]2)[CH2:9][CH2:8]1
Reactant: C1CN[C@H](C2CC2)CN1
Reactant: OC(c1ccc(Br)cc1)(C(F)(F)F)C(F)(F)F
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC(C)Oc1cccc(OC(C)C)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: Cc1ccccc1
Solvent: O
Product: OC(c1ccc(N2CCN[C@H](C3CC3)C2)cc1)(C(F)(F)F)C(F)(F)F
Temperature: 90 °C

Procedure:
A 20 mL vial was charged with toluene (1.2 mL), sodium tert-butoxide (69.2 mg, 720 μmol) were added to (R)-2-cyclopropyl-piperazine (59.7 mg, 300 μmol, Anichem, North Brunswick, N.J.), 2-(4-bromophenyl)-1,1,1,3,3,3-hexafluoro-2-propanol (97 mg, 300 μmol, Bioorg. Med. Chem. Lett. 2002, 12, 3009), dicyclohexyl(2′,6′-diisopropoxybiphenyl-2-yl)phosphine (RuPhos), (21.0 mg, 45.0 μmol, Strem Chemical Inc, Newburyport, Mass.) and tris(dibenzylideneacetone)dipalladium (0) (13.7 mg, 15.00 μmol, Strem Chemical Inc, Newburyport, Mass.). The reaction was heated to 90° C. for 40 h, then cooled to 23° C., and diluted with water (15 mL) and extracted with CH2Cl2 (15 mL). The organic layer was loaded onto an AccuBOND II SCX cartridge (Krackeler Scientific, Inc., Albany, N.Y.) (6 g), washed with MeOH (5 mL) and eluted with 2N NH3 in MeOH (10 mL) to give (R)-2-(4-(3-cyclopropylpiperazin-1-yl)phenyl)-1,1,1,3,3,3-hexafluoro-2-propanol. To this was added a solution of 2-thiophenesulfonyl chloride (54.8 mg, 300 μmol, Sigma-Aldrich, St. Louis, Mo.) and Hünig's base (57.5 μL, 330 μmol) in CH2Cl2 (0.6 mL). The reaction was stirred at 23° C. for 18 h and then concentrated to dryness. The crude material was purified by reverse-phase preparative HPLC using a Gemini C18 100 A column (150×30 mm), eluting with 0.1% TFA in CH3CN/H2O (10% to 90% over 12 min) to give 2-(4-((3R)-3-cyclopropyl-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-1,1,1,3,3,3-hexafluoro-2-propanol. 1H NMR (400 MHz, DMSO-d6) δ 8.49 (s, 1H), 7.93 (dd, J=5.3 1.3 Hz, 1H), 7.71 (dd, J=3.7, 1.1 Hz, 1H), 7.46 (d, J=9.2 Hz, 2H), 7.18 (dd, J=4.8, 4.0 Hz, 1H), 6.95 (d, J=9.7 Hz, 2H), 2.67 (dd, J=12.5, 3.7 Hz, 1H), 2.52-2.60 (m, 4H), 1.30-1.42 (m, 1H), 0.35-0.56 (m, 6H). m/z (ESI, +ve ion) 515.0 (M+H)+. GK-GKRP EC50 (NADPH-coupled)=5.0 μM.