Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]([CH3:11])[O:9][CH3:10])[N:5]=[C:4]([NH:12][CH2:13][CH2:14][CH3:15])[N:3]=1.[C:16](Cl)(=[O:19])[CH2:17][CH3:18].CCN(C(C)C)C(C)C>C1COCC1>[CH3:10][O:9][N:8]([CH3:11])[C:6]1[N:5]=[C:4]([NH:12][CH2:13][CH2:14][CH3:15])[N:3]=[C:2]([NH:1][C:16](=[O:19])[CH2:17][CH3:18])[N:7]=1
Reactant: CCCNc1nc(N)nc(N(C)OC)n1
Reactant: CCC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCCNc1nc(NC(=O)CC)nc(N(C)OC)n1
Temperature: 70 °C
Reaction time: 16 h
Yield: 14.7 %

Procedure:
N-(6-amino-4-n-propylamino-[1,3,5]triazin-2-yl)-N,O-dimethyl-hydroxylamine (XXXIX) (5 g, 23.58 mmol) was dissolved in THF (50 mL). Propionyl chloride (3.25 g, 35.38 mmol) and DIPEA (5.47 g, 42.44 mmol) were added at 0° C. The resultant mixture was stirred at ambient temperature for 10 min, then stirred at 70° C. for 16 h, after which time the solvent was removed under reduced pressure. The residue was dissolved in EtOAc (250 mL), and this extract was washed with water (80 mL) and then with a brine solution (80 mL), and lastly dried over Na2SO4. The solvent was removed under reduced pressure and the crude product was purified by flash column chromatography (pet ether/ethyl acetate=5/1 to 2/1) to yield 930 mg (15%) of the desired product. The isolated free amine (930 mg, 3.47 mmol) was dissolved in H2O (10 mL) and 0.5 M HCl solution in H2O (10.4 mL) and then the solution was lyophilized to yield N-(4-(methoxy(methyl)amino)-6-(propylamino)-1,3,5-triazin-2-yl)propionamide (XL) as a colorless oil (1.06 g). LCMS: (ESI) m/z=269 (M+H)+. 1H NMR (500 MHz, DMSO): δ (ppm) 12.23 (s, 1H), 8.25-9.45 (m, 2H), 3.76-3.84 (m, 3H), 3.30-3.44 (m, 5H), 2.55-2.56 (m, 1H), 2.21-2.22 (m, 1H), 1.53-1.58 (m, 2H), 0.88-1.08 (m, 6H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[C:10]([OH:15])[CH:9]=1)([CH3:4])([CH3:3])[CH3:2].Br[C:18]1[CH:19]=[CH:20][C:21]([N+:24]([O-:26])=[O:25])=[N:22][CH:23]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CN(C)C=O>O>[C:1]([O:5][C:6](=[O:16])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[C:10]([O:15][C:18]2[CH:23]=[N:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=2)[CH:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=[N+]([O-])c1ccc(Br)cn1
Reactant: Cc1ccc(NC(=O)OC(C)(C)C)cc1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(NC(=O)OC(C)(C)C)cc1Oc1ccc([N+](=O)[O-])nc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 46 %

Procedure:
A mixture of tert-butyl(3-hydroxy-4-methylphenyl)carbamate (3.14 g, 14.1 mmol), 5-bromo-2-nitropyridine (2.38 g, 11.7 mmol), cesium carbonate (5.72 g, 17.6 mmol) and N,N-dimethylformamide (25 mL) was stirred at room temperature for 15 hr. The reaction mixture was diluted with water, and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and filtrated. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (basic silica gel, hexane/ethyl acetate=80/20→0/100) to give the title compound (1.86 g, 44%) as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[C:6]([Cl:9])[N:5]=[CH:4][N:3]=1.[CH3:10][O:11][C:12]1[CH:20]=[C:19]([O:21][CH3:22])[C:18]([Br:23])=[CH:17][C:13]=1[C:14](O)=O>>[Cl:9][C:6]1[N:5]=[CH:4][N:3]=[C:2]2[C:7]=1[NH:8][C:14]([C:13]1[CH:17]=[C:18]([Br:23])[C:19]([O:21][CH3:22])=[CH:20][C:12]=1[O:11][CH3:10])=[N:1]2
Reactant: COc1cc(OC)c(C(=O)O)cc1Br
Reactant: Nc1ncnc(Cl)c1N
Product: COc1cc(OC)c(-c2nc3ncnc(Cl)c3[nH]2)cc1Br

Procedure:
Prepared analogously to Example 14 from 4,5-diamino-6-chloropyrimidine and 2,4-dimethoxy-5-bromo-benzoic acid.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[N:8]([C:9]([C:11]2[N:12]=[C:13]([CH3:23])[S:14][C:15]=2[C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=2)=[O:10])[CH2:7][C@H:6]2[C@@H:4]1[CH2:5]2.[O:24]1[C:28]2=[CH:29][CH:30]=[CH:31][C:32]([C:33](O)=[O:34])=[C:27]2[CH2:26][CH2:25]1>>[Cl:22][C:18]1[CH:17]=[C:16]([C:15]2[S:14][C:13]([CH3:23])=[N:12][C:11]=2[C:9]([N:8]2[CH2:7][C@H:6]3[C@H:4]([CH2:5]3)[C@H:3]2[CH2:2][NH:1][C:33]([C:32]2[CH:31]=[CH:30][CH:29]=[C:28]3[O:24][CH2:25][CH2:26][C:27]=23)=[O:34])=[O:10])[CH:21]=[CH:20][CH:19]=1
Reactant: Cc1nc(C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CN)c(-c2cccc(Cl)c2)s1
Reactant: O=C(O)c1cccc2c1CCO2
Product: Cc1nc(C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CNC(=O)c2cccc3c2CCO3)c(-c2cccc(Cl)c2)s1

Procedure:
prepared by reaction of ((1S,2S,5R)-2-Aminomethyl-3-aza-bicyclo[3.1.0]hex-3-yl)-[5-(3-chloro-phenyl)-2-methyl-thiazol-4-yl]-methanone with 2,3-Dihydro-benzofuran-4-carboxylic acid. LC-MS (basic): tR=0.91 min; [M+H]+=494.3.
Reaction SMILES: [NH2:1][C:2]1[C:7]2=[CH:8][CH:9]=[C:10]([CH:11]=O)[N:6]2[N:5]=[CH:4][N:3]=1.[NH:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[N:13]1([CH2:11][C:10]2[N:6]3[C:7]([C:2]([NH2:1])=[N:3][CH:4]=[N:5]3)=[CH:8][CH:9]=2)[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1
Reactant: Nc1ncnn2c(C=O)ccc12
Reactant: C1COCCN1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: Nc1ncnn2c(CN3CCOCC3)ccc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 19.5 %

Procedure:
To 4-aminopyrrolo[2,1-f][1,2,4]triazine-7-carbaldehyde (235 mg, 1.45 mmol) in 1,2-dichroloethane (5 ml) was added morpholine (0.25 ml, 2.9 mmol) and sodium triacetoxyborohydride (611 mg, 2.9 mmol). The reaction mixture was stirred at rt under N2 for 16 h. The reaction was quenched with saturated aq. sodium bicarbonate and followed by extraction with CH2Cl2. The organic was dried over Na2SO4, concentrated and purified via column chromatography (5:95 v/v CH3OH—CH2Cl2) to afford 66 mg of the title compound (yield 20%). 1H-NMR (DMSO-d6) δ 7.80 (s, 1H), 7.62 (br, 2H), 6.83 (d, J=4 Hz, 1H), 6.52 (d, J=4 Hz, 1H), 3.75 (s, 2H), 3.51 (t, J=4 Hz, 4H), 2.37 (t, J=4 Hz, 4H); MS [M+H]+=234; LCMS RT=1.00 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:25]=[CH:24][C:6]([C:7]([C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[CH2:14][C:13](C(O)=O)([C:18]([OH:20])=[O:19])[CH2:12]3)=[O:8])=[CH:5][CH:4]=1>Cl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:7]([C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[CH2:14][CH:13]([C:18]([OH:20])=[O:19])[CH2:12]3)=[O:8])=[CH:24][CH:25]=1
Reactant: COc1ccc(C(=O)c2ccc3c(c2)CC(C(=O)O)(C(=O)O)C3)cc1
Agent: Cl
Product: COc1ccc(C(=O)c2ccc3c(c2)CC(C(=O)O)C3)cc1

Procedure:
77.5 g (0.228 mole) of the crude acid obtained in (d) and 1070 cm3 of concentrated hydrochloric acid are placeed in a 2 liter reaction vessel equipped with a stirrer and cooler. The mixture is heated to reflux for 15 hours. After cooling, the reaction mixture is extracted with diethyl ether, the extract dried over anhydrous sodium sulphate, filtered, and the filtrate concentrated. A doughy solid is obtained which, after recrystallization from ethyl acetate, melts at 149°-151° C. (capillary tube). If difficulty is experienced in purifying the acid by recrystallization, the methyl ester of the acid may first be formed, for example, and purified by distillation (boiling point at 0.67 torr=218° C.) and then hydrolyzed with aqueous alcoholic potash using a known method. The acid obtained is thus more easily able to be purified.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([CH2:8][N:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][C:16]=3[C:18]([NH:20][C@H:21]([C:23]3[CH:31]=[CH:30][C:26]([C:27]([OH:29])=[O:28])=[CH:25][CH:24]=3)[CH3:22])=[O:19])[CH:11]=[CH:10]2)=[CH:4][CH:3]=1.N1CCCCC1.[CH2:38]([OH:40])[CH3:39]>>[CH2:38]([O:40][C:2]1[N:7]=[CH:6][C:5]([CH2:8][N:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][C:16]=3[C:18]([NH:20][C@H:21]([C:23]3[CH:31]=[CH:30][C:26]([C:27]([OH:29])=[O:28])=[CH:25][CH:24]=3)[CH3:22])=[O:19])[CH:11]=[CH:10]2)=[CH:4][CH:3]=1)[CH3:39]
Reactant: CCO
Reactant: C[C@H](NC(=O)c1cccc2ccn(Cc3ccc(Cl)nc3)c12)c1ccc(C(=O)O)cc1
Solvent: C1CCNCC1
Product: CCOc1ccc(Cn2ccc3cccc(C(=O)N[C@@H](C)c4ccc(C(=O)O)cc4)c32)cn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 4-{(1S)-1-[({1-[(6-chloropyridin-3-yl)methyl]-1H-indol-7-yl}carbonyl)amino]ethyl}benzoic acid (95 mg) were added ethanol (2.0 mL) and piperidine (65 μL), followed by stirring at room temperature overnight. After concentration under reduced pressure, DMSO (1.0 mL), piperidine (65 μL), and potassium tert-butoxide (61 mg) were added thereto, followed by stirring at 80° C. for 2 hours. To the reaction mixture was added a 10% aqueous citric acid solution (10 mL), followed by extraction with ethyl acetate. The obtained organic layer was washed with water, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform/methanol=99/1-95/5) to obtain 4-{(1S)-1-[({1-[(6-ethoxypyridin-3-yl)methyl]-1H-indol-7-yl}carbonyl)amino]ethyl}benzoic acid (9.0 mg).
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([NH:5][C:6](=[O:29])[CH2:7][NH:8][C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([C:18]([F:21])([F:20])[F:19])[CH:16]=3)[N:11]([CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[N:10]=2)[CH2:2]1.[CH:30]([CH:33]1[CH2:38][CH2:37][C:36](=O)[CH2:35][CH2:34]1)([CH3:32])[CH3:31]>>[CH2:22]([N:11]1[C:12]2[C:17](=[CH:16][C:15]([C:18]([F:20])([F:19])[F:21])=[CH:14][CH:13]=2)[C:9]([NH:8][CH2:7][C:6]([NH:5][CH:3]2[CH2:2][N:1]([CH:36]3[CH2:37][CH2:38][CH:33]([CH:30]([CH3:32])[CH3:31])[CH2:34][CH2:35]3)[CH2:4]2)=[O:29])=[N:10]1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=C(CNc1nn(Cc2ccccc2)c2ccc(C(F)(F)F)cc12)NC1CNC1
Reactant: CC(C)C1CCC(=O)CC1
Product: CC(C)C1CCC(N2CC(NC(=O)CNc3nn(Cc4ccccc4)c4ccc(C(F)(F)F)cc34)C2)CC1

Procedure:
The title compound was prepared as a white solid from reaction of N-azetidin-3-yl-2-(1-benzyl-5-trifluoromethyl-1H-indazol-3-ylamino)-acetamide and 4-isopropyl-cyclohexanone using the procedure described in Step E of Example 1.
Reaction SMILES: [CH:1](=[O:4])[CH2:2][CH3:3].[CH:5]1([CH:11]=[O:12])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1.N1CCC[C@H]1C(O)=O>CN(C)C=O.C(OCC)C>[CH:5]1([C@H:11]([OH:12])[C@H:2]([CH3:3])[CH:1]=[O:4])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1
Reactant: O=CC1CCCCC1
Reactant: CCC=O
Agent: O=C(O)[C@@H]1CCCN1
Solvent: CN(C)C=O
Solvent: CCOCC
Product: C[C@H](C=O)[C@@H](O)C1CCCCC1
Reaction time: 22 h
Yield: 87 %

Procedure:
A solution of freshly distilled propionaldehyde (72 μL, 1.0 mmol) in 500 μL dimethylformamide pre-cooled to 4° C. was added slowly over the course of 20 h to a stirring suspension of cyclohexane carboxaldehyde (242 μL, 2.0 mmol), L-proline (11.5 mg, 0.10 mmol) and 500 μL dimethylformamide at 4° C. After 22 hours, the resulting solution was diluted with diethyl ether and washed successively with water and brine. The combined aqueous layers were back-extracted with 3 portions dichloromethane. The organic layers were combined, dried over anhydrous MgSO4, and concentrated in vacuo. Flash chromatography (20:7 pentane:diethyl ether) afforded the title compound as a clear, colorless oil in 87% yield (148 mg, 0.87 mmol), 99% ee and 93:7 anti:syn. IR (film) 3438, 2928, 2853, 1722, 1450, 1396, 1376, 1314, 1186, 1112, 1063, 975.8, 893.2, 847.5 cm−1; 1H NMR (300 MHz, CDCl3) δ9.75 (d, 1H, J=2.1 Hz, CHO); 3.53 (dd, 1H, J=7.2, 4.8 Hz, CHOH); 2.58 (m, 1H, CHCH3); 1.8-1.0 (br m, 11H, cyclohexyl); 1.10 (d, 3H, J=7.2 Hz, CH3); 3C NMR (75 MHz, CDCl3) δ206.1, 77.1, 49.2, 40.7, 30.3, 26.73, 26.69, 26.68, 26.4, 11.4; HRMS (CI) exact mass calcd for [M+H]+ (C10H19O2) requires m/z 171.1385, found m/z 171.1386. [α]D=−5.1 (c=1.0, CHCl3). The product ratios were determined by GLC analysis of the corresponding 4-cyclohexyl-2,2,5-trimethyl-[1,3]dioxane (obtained by NaBH4 reduction followed by acetonide protection of the 1,3-diol according to the method of Goto, in Kitamura et al. (1984) J. Am. Chem. Soc. 106:3252) using a Bodman Chiraldex β-DM (30 m×0.25 mm) column (110° C. isotherm, 23 psi); (2S, 3S) anti isomer tr=17.8 min, (2R, 3R) anti isomer tr=18.7 min, (2R, 3S) and (2S, 3R) syn isomers tr=21.0, 22.2 min.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH2:8][CH3:9])[CH:5]=[CH:4][N:3]=1.[CH3:10][C:11]1[CH:12]=[C:13]([CH:15]=[C:16]([B:18]2[O:22][C:21]([CH3:24])([CH3:23])[C:20]([CH3:26])([CH3:25])[O:19]2)[CH:17]=1)[NH2:14].CS(O)(=O)=O>O1CCOCC1.C(OCC)(=O)C>[CH2:8]([C:6]1[CH:5]=[CH:4][N:3]=[C:2]([NH:14][C:13]2[CH:15]=[C:16]([B:18]3[O:22][C:21]([CH3:23])([CH3:24])[C:20]([CH3:26])([CH3:25])[O:19]3)[CH:17]=[C:11]([CH3:10])[CH:12]=2)[N:7]=1)[CH3:9]
Reactant: Cc1cc(N)cc(B2OC(C)(C)C(C)(C)O2)c1
Reactant: CCc1ccnc(Cl)n1
Agent: CS(=O)(=O)O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CCc1ccnc(Nc2cc(C)cc(B3OC(C)(C)C(C)(C)O3)c2)n1
Temperature: 110 °C

Procedure:
A solution of 2-chloro-4-ethyl pyrimidine (0.98 g, 7.00 mmol), the product of Step 1 (1.794 g, 7.70 mmol), and methanesulfonic acid (0.50 mL, 7.70 mmol) in 1,4-dioxane (30 mL) was sealed in a 100 mL screw-top pressure flask and heated at 110° C. for 15 hours. The flask was cooled, an additional portion of 2-chloro-4-ethyl pyrimidine (0.145 g, 1.05 mmol) was added, and the flask was resealed and heated for another 6.5 hours. The reaction mixture was cooled, diluted with ethyl acetate (70 mL), washed with saturated aqueous sodium bicarbonate solution (25 mL) and brine (25 mL), dried over sodium sulfate, filtered, and concentrated. The resulting reddish brown solid 4-ethyl-N-[3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]pyrimidin-2-amine (3.44 g as a 80:20 w/w mixture with 1,4-dioxane) was used without further purification. MS ESI: [M+H]+ m/z 340.1
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[N:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.[F:11][C:12]1[C:19]([O:20][CH2:21][CH2:22][O:23][CH:24]2[CH2:29][CH2:28][CH2:27][CH2:26][O:25]2)=[CH:18][CH:17]=[C:16]([F:30])[C:13]=1[CH:14]=[O:15].[OH-].[K+].O>CO>[Br:1][C:2]1[CH:3]=[C:4]2[C:5]([CH:14]([C:13]3[C:16]([F:30])=[CH:17][CH:18]=[C:19]([O:20][CH2:21][CH2:22][O:23][CH:24]4[CH2:29][CH2:28][CH2:27][CH2:26][O:25]4)[C:12]=3[F:11])[OH:15])=[CH:6][NH:7][C:8]2=[N:9][CH:10]=1
Reactant: O=Cc1c(F)ccc(OCCOC2CCCCO2)c1F
Reactant: Brc1cnc2[nH]ccc2c1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: OC(c1c(F)ccc(OCCOC2CCCCO2)c1F)c1c[nH]c2ncc(Br)cc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 5-bromo-7-azaindole (67, 118 mg, 0.000597 mol) in methanol (9.0 mL) were added 2,6-difluoro-3-[2-(tetrahydro-pyran-2-yloxy)-ethoxy]-benzaldehyde (541, 180.0 mg, 0.63 mmol) and potassium hydroxide (601.9 mg, 10.7 mmol) under an atmosphere of nitrogen. The reaction was stirred at room temperature overnight. The reaction was poured into water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to give crude compound that was used directly in the next step.
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[C:11]([C:13]3(O)[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[CH:10]=[CH:9][C:8]=2[NH:20][C:21]([C:23]2[NH:24][C:25]([C:28]#[N:29])=[CH:26][N:27]=2)=[O:22])[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.[CH3:30][S:31]([O-:33])=[O:32].[Na+].C(O)(C(F)(F)F)=O>CO>[C:1]1([C:7]2[CH:12]=[C:11]([C:13]3([S:31]([CH3:30])(=[O:33])=[O:32])[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[CH:10]=[CH:9][C:8]=2[NH:20][C:21]([C:23]2[NH:24][C:25]([C:28]#[N:29])=[CH:26][N:27]=2)=[O:22])[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1
Reactant: CS(=O)[O-]
Reactant: N#Cc1cnc(C(=O)Nc2ccc(C3(O)CCOCC3)cc2C2=CCCCC2)[nH]1
Agent: [Na+]
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: CS(=O)(=O)C1(c2ccc(NC(=O)c3ncc(C#N)[nH]3)c(C3=CCCCC3)c2)CCOCC1
Temperature: 70 °C
Reaction time: 8 h
Yield: 20.8 %

Procedure:
To a mixture of 5-cyano-1H-imidazole-2-carboxylic acid [2-cyclohex-1-enyl-4-(4-hydroxy-tetrahydro-pyran-4-yl)-phenyl]-amide (as prepared in Example 27, 75 mg, 0.19 mmol) and sodium methylsulfinate (195 mg, 1.90 mmol) in 4 mL of methanol was added 0.28 mL (3.80 mmol) of TFA. The mixture was stirred overnight at 70° C. and then concentrated in vacuo. The crude residue was partitioned in EtOAc (20 mL) and saturated aqueous NaHCO3 (20 mL). The organic layer was dried (Na2SO4) and then concentrated in vacuo. The residue was purified by preparative TLC on silica gel (20% ethyl acetate-hexane) to afford the title compound as a light brown oil (18 mg, 21%). 1H-NMR (CDCl3; 400 MHz): δ 9.64 (s, 1H), 8.32 (d, 1H, J=8.0), 7.71 (s, 1H), 7.33 (m, 1H), 7.23 (d, 1H, J=1.8 Hz), 5.87 (s, 1H), 3.90-3.81 (m, 4H), 3.01 (s, 3H), 2.30-2.25 (m, 4H), 2.07-1.79 (m, 8H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([N:29]2[CH2:34][CH2:33][N:32](C(OC(C)(C)C)=O)[CH2:31][C@H:30]2[CH3:42])[C:12]2[CH2:18][N:17]([C:19]3[CH:24]=[C:23]([CH:25]([CH3:27])[CH3:26])[CH:22]=[CH:21][C:20]=3[CH3:28])[CH2:16][CH2:15][C:13]=2[N:14]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([N:29]2[CH2:34][CH2:33][NH:32][CH2:31][C@H:30]2[CH3:42])[C:12]2[CH2:18][N:17]([C:19]3[CH:24]=[C:23]([CH:25]([CH3:27])[CH3:26])[CH:22]=[CH:21][C:20]=3[CH3:28])[CH2:16][CH2:15][C:13]=2[N:14]=1
Reactant: Cc1ccc(C)c(-c2nc3c(c(N4CCN(C(=O)OC(C)(C)C)C[C@H]4C)n2)CN(c2cc(C(C)C)ccc2C)CC3)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1ccc(C)c(-c2nc3c(c(N4CCNC[C@H]4C)n2)CN(c2cc(C(C)C)ccc2C)CC3)c1

Procedure:
(R)-tert-Butyl 4-(2-(2,5-dimethylphenyl)-6-(5-isopropyl-2-methylphenyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (60 mg, 0.105 mmol) in DCM (1 mL) was treated with TFA (1 mL, 13.0 mmol) at rt for 15 min. The mixture was then concentrated to provide (R)-2-(2,5-Dimethylphenyl)-6-(5-isopropyl-2-methylphenyl)-4-(2-methylpiperazin-1-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine, which was taken on without need further purification. MS (ESI+) m/z 470.4 (M+H)+.
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:39][CH2:38][CH:37]([CH2:40][C:41]([OH:43])=O)[CH2:36][CH2:35]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:44][CH2:45][CH3:46])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH:47]([NH:50][CH2:51][CH2:52][O:53][CH3:54])([CH3:49])[CH3:48]>>[C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:35][CH2:36][CH:37]([CH2:40][C:41]([N:50]([CH:47]([CH3:49])[CH3:48])[CH2:51][CH2:52][O:53][CH3:54])=[O:43])[CH2:38][CH2:39]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:44][CH2:45][CH3:46])[CH:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(CC(=O)O)CC1
Reactant: COCCNC(C)C
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(CC(=O)N(CCOC)C(C)C)CC1

Procedure:
In a manner analogous to the method described in example 163, {1-[(4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl]-piperidin-4-yl}-acetic acid was coupled with N-isopropyl-N-(2-methoxy-ethyl)amine (TCI-US) to give the title compound. HR-MS (ES, m/z) calculated for C42H55Cl2N5O4 [(M+H)+] 764.3704, observed 764.3703.
Reaction SMILES: C[C:2]1([C:21]([OH:23])=O)[CH2:17][C:10]2([N+:18]([O-:20])=[O:19])[C:11]3[C:16]([CH:3]1[C:4]1[C:9]2=[CH:8][CH:7]=[CH:6][CH:5]=1)=[CH:15][CH:14]=[CH:13][CH:12]=3.BrC1C=C(C2[N:32]=C(N)SC=2)C=CC=1>>[N+:18]([C:10]12[CH2:17][CH:2]([C:21]([NH2:32])=[O:23])[CH:3]([C:4]3[C:9]1=[CH:8][CH:7]=[CH:6][CH:5]=3)[C:16]1[C:11]2=[CH:12][CH:13]=[CH:14][CH:15]=1)([O-:20])=[O:19]
Reactant: CC1(C(=O)O)CC2([N+](=O)[O-])c3ccccc3C1c1ccccc12
Reactant: Nc1nc(-c2cccc(Br)c2)cs1
Product: NC(=O)C1CC2([N+](=O)[O-])c3ccccc3C1c1ccccc12
Yield: 92.4 %

Procedure:
In a similar manner to Example 1, Step 2, the coupling reaction of 15-methyl-8-nitrotetracyclo[6.6.2.02,7.09,14]hexadeca-2,4,6,9,11,13-hexaene-15-carboxylic acid (200 mg, 0.647 mmol) and 4-(3-bromo-phenyl)-thiazol-2-ylamine (214 mg, 0.841 mmol) afforded 15-methyl-N-[4-(3-bromo-phenyl)-thiazol-2-yl]-]-8-nitrotetracyclo[6.6.2.02,7.09,14]hexadeca-2,4,6,9,11,13-hexaene-15-carboxamide (176 mg, 49% yield). LC/MS (m/z 548.08 (M+H)+); HPLC Rt: 4.385 min.
Reaction SMILES: [P:1]([CH2:14][CH2:15][CH2:16][PH:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:24]([P:27]([CH2:30][CH3:31])[CH2:28][CH3:29])[CH:25]=[CH2:26].CC(N=NC(C#N)(C)C)(C#N)C>>[P:1]([CH2:14][CH2:15][CH2:16][P:17]([CH2:26][CH2:25][CH2:24][P:27]([CH2:30][CH3:31])[CH2:28][CH3:29])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: C=CCP(CC)CC
Reactant: c1ccc(PCCCP(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Product: CCP(CC)CCCP(CCCP(c1ccccc1)c1ccccc1)c1ccccc1
Temperature: 210 °C
Reaction time: 20 h

Procedure:
Ph2P(CH2)3P(H)Ph (3.68 g, 10.9 mmol), allyldiethylphosphine (1.71 g, 13.1 mmol) and AIBN (0.011 g) were mixed in a Schlenk flask and radiated with a 365 nm UV lamp for 20 hours. After confirming that the reaction was complete by 31P NMR analysis, it was distilled under vacuum (<0.5 mm Hg) at a final heating mantle temperature of 210° C. for an hour to remove impurities. The ligand remained in the pot. Yield: 3.36 g (66%). 31P NMR (122 MHz, CDCl3, δ, ppm): −16.74 (s), −23.09 (s) and −25.98 (s). There are peaks near the three major peaks, which have not been determined if are part of the ligand or due to impurities. 1H NMR (500 MHz, CDCl3, δ, ppm): 1.001 (d of q, JH-P&H=7.0 Hz 4H's methylenes of ethyl groups), 1.3 to 2.2 (m, H's on methyls and propylenes) (d of t, JH-P&H=211 & 6.6 Hz, H on the P), and 7.30 to 7.47 (m, 15H's on phenyl rings).
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][CH:20](SCC)[NH:19][C:18]4=[O:25])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:28]([F:31])([F:30])[F:29])[CH:3]=1.[CH3:32][NH:33][CH:34]1[CH2:39][CH2:38][N:37]([CH3:40])[CH2:36][CH2:35]1>>[Cl:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20]([N:33]([CH3:32])[CH:34]5[CH2:39][CH2:38][N:37]([CH3:40])[CH2:36][CH2:35]5)=[N:19][C:18]4=[O:25])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:28]([F:30])([F:29])[F:31])[CH:3]=1
Reactant: CCSC1NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1
Reactant: CNC1CCN(C)CC1
Product: CN1CCC(N(C)C2=NC(=O)C(=Cc3ccc4c(cnn4Cc4ccc(Cl)cc4C(F)(F)F)c3)S2)CC1

Procedure:
5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-[methyl-(1-methyl-piperidin-4-yl)-amino]-thiazol-4-one was prepared from 5-[1-(4-chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-ethylsulfanyl-thiazolidin-4-one and Methyl-(1-methyl-piperidin-4-yl)-amine following General Procedure C.
Reaction SMILES: [O:1]=[C:2]1[N:7]([CH2:8][C:9]2[CH:10]=[C:11]([C:15]3[N:20]=[CH:19][C:18]([C:21]([O:23]CC)=[O:22])=[CH:17][N:16]=3)[CH:12]=[CH:13][CH:14]=2)[N:6]=[C:5]([C:26]2[CH:31]=[C:30]([F:32])[C:29]([F:33])=[C:28]([F:34])[CH:27]=2)[CH:4]=[CH:3]1.[OH-].[Li+]>C1COCC1.O>[O:1]=[C:2]1[N:7]([CH2:8][C:9]2[CH:10]=[C:11]([C:15]3[N:20]=[CH:19][C:18]([C:21]([OH:23])=[O:22])=[CH:17][N:16]=3)[CH:12]=[CH:13][CH:14]=2)[N:6]=[C:5]([C:26]2[CH:27]=[C:28]([F:34])[C:29]([F:33])=[C:30]([F:32])[CH:31]=2)[CH:4]=[CH:3]1
Reactant: CCOC(=O)c1cnc(-c2cccc(Cn3nc(-c4cc(F)c(F)c(F)c4)ccc3=O)c2)nc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1cnc(-c2cccc(Cn3nc(-c4cc(F)c(F)c(F)c4)ccc3=O)c2)nc1
Temperature: 25 °C

Procedure:
3.4 g (7.29 mmol) of ethyl 2-{3-[6-oxo-3-(3,4,5-trifluorophenyl)-6H-pyridazin-1-ylmethyl]phenyl}pyrimidine-5-carboxylate are dissolved in 300 ml of THF and 30 ml of water, and 713 mg (29.2 mmol) of lithium hydroxide are added. The reaction mixture is refluxed for 4 h and cooled to room temperature, and the organic solvent is removed by distillation in a rotary evaporator. 300 ml of water and 30 ml of THF are added to the residue, and conc. HCl is slowly added dropwise to this solution with stirring until the reaction is strongly acidic. The precipitate formed is filtered off with suction, washed with copious water and dried in a vacuum drying cabinet.