Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH2:12][C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[N:4][N:3]=1.[NH2:19][C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=1>>[OH:26][C:23]1[CH:24]=[CH:25][C:20]([NH:19][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]([CH2:12][C:13]3[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=3)=[N:4][N:3]=2)=[CH:21][CH:22]=1
Reactant: Clc1nnc(Cc2ccncc2)c2ccccc12
Reactant: Nc1ccc(O)cc1
Product: Oc1ccc(Nc2nnc(Cc3ccncc3)c3ccccc23)cc1
Temperature: 150 °C

Procedure:
A mixture of 0.384 g (1.5 mmol) 1-chloro-4-(4-pyridylmethyl)phthalazine and 0.491 g (4.5 mmol) 4-aminophenol is heated under nitrogen atmosphere for 2 h at 150° C. After processing as described in Example 18, drying under HV (8 h at 100° C. and 24 h at 145° C.), title compound is obtained with a water content of 0.68%; m.p. 239-241° C.; 1H NMR (DMSO-d6) 9.19 (s, 1H), 8.99 (brs, 1H), 8.56 (d, 1H), 8.44 (d, 2H), 8.06 (d, 1H), 7.86-7.96 (m, 2H), 7.61 (d, 2H), 7.30 (d, 2H), 6.77 (d, 2H), 4.53 (s, 2H); ESI-MS: (M+H)+=329.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:25][CH2:26][C:27]1[C:28]([F:44])=[C:29]([O:34][C:35]2[CH:36]=[C:37]([CH:40]=[C:41]([Cl:43])[CH:42]=2)[C:38]#[N:39])[C:30]([Cl:33])=[CH:31][CH:32]=1.[CH3:45][C:46]([O:49][C:50]([NH:52][C:53]1[CH:54]=[C:55]2[C:59](=[CH:60][CH:61]=1)[NH:58][C:57]([C:62](O)=[O:63])=[CH:56]2)=[O:51])([CH3:48])[CH3:47].CCN(C(C)C)C(C)C>CN(C=O)C.CCOC(C)=O.O>[Cl:33][C:30]1[CH:31]=[CH:32][C:27]([CH2:26][NH:25][C:62]([C:57]2[NH:58][C:59]3[C:55]([CH:56]=2)=[CH:54][C:53]([NH:52][C:50](=[O:51])[O:49][C:46]([CH3:47])([CH3:45])[CH3:48])=[CH:61][CH:60]=3)=[O:63])=[C:28]([F:44])[C:29]=1[O:34][C:35]1[CH:36]=[C:37]([C:38]#[N:39])[CH:40]=[C:41]([Cl:43])[CH:42]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc2[nH]c(C(=O)O)cc2c1
Reactant: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc(CN)c2F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)Nc1ccc2[nH]c(C(=O)NCc3ccc(Cl)c(Oc4cc(Cl)cc(C#N)c4)c3F)cc2c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 59.6 %

Procedure:
HATU (0.064 g, 0.168 mmol) was added to a solution of 3-{[3-(aminomethyl)-6-chloro-2-fluorophenyl]oxy}-5-chlorobenzonitrile (0.035 g, 0.112 mmol), 5-({[(1,1-dimethylethyl)oxy]carbonyl}amino)-1H-indole-2-carboxylic acid (0.032 g, 0.116 mmol), and DIPEA (0.030 ml, 0.168 mmol) in DMF (1 mL). The mixture was stirred at RT for 1.5 h. Water and EtOAc were added. The organic layer was separated and washed with water and brine, dried over sodium sulfate, and concentrated to give the title compound (0.038 g, 60%) as a colorless oil. 1H NMR (400 MHz, CDCl3): δ ppm 9.67 (s, 1H), 7.75 (s, 1H), 7.17-7.37 (m, 4H), 7.14 (t, 1H), 7.08 (dd, 1H), 6.94-7.02 (m, 2H), 6.80 (m, 1H), 6.60 (s, 1H), 4.69 (d, 2H), 1.52 (m, 9H). MS: m/z 569 (M).
Reaction SMILES: O[C@@H:2]([C:22]1[C:23]([CH3:32])=[C:24]2[C:28](=[CH:29][CH:30]=1)[C:27](=[O:31])[O:26][CH2:25]2)[CH2:3][N:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:11])[CH2:6][C@H:5]1[CH2:20]O.S(Cl)(Cl)=O.[CH2:37]([NH2:40])[CH:38]=[CH2:39].[I-].[Na+]>C(OCC)(=O)C>[CH2:37]([N:40]1[CH:2]([C:22]2[C:23]([CH3:32])=[C:24]3[C:28](=[CH:29][CH:30]=2)[C:27](=[O:31])[O:26][CH2:25]3)[CH2:3][N:4]2[CH2:9][CH2:8][N:7]([C:10]([O:12][CH2:13][C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)=[O:11])[CH2:6][C@H:5]2[CH2:20]1)[CH:38]=[CH2:39]
Reactant: Cc1c([C@H](O)CN2CCN(C(=O)OCc3ccccc3)C[C@H]2CO)ccc2c1COC2=O
Reactant: C=CCN
Agent: [I-]
Agent: [Na+]
Solvent: O=S(Cl)Cl
Solvent: CCOC(C)=O
Product: C=CCN1C[C@@H]2CN(C(=O)OCc3ccccc3)CCN2CC1c1ccc2c(c1C)COC2=O
Temperature: 90 °C

Procedure:
A solution of (S)-benzyl 4-((S)-2-hydroxy-2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)ethyl)-3-(hydroxymethyl)piperazine-1-carboxylate (1.4 g, 3.2 mmol) in thionyl chloride (20 mL, 274 mmol) was heated at reflux for 1 h. After removing the volatiles, the residue was dissolved in N,N-dimethylformamide (20 mL) and treated with allylamine (1.31 mL, 17.48 mmol) at 0° C. The resulting solution was treated with sodium iodide (0.088 g, 0.318 mmol) and heated at 90° C. for 1 h. The solution was diluted in ethyl acetate (300 mL) and was washed with saturated sodium bicarbonate three times, dried over sodium sulfate, concentrated and the residue was purified by MPLC on a Biotage system using 40-100% ethyl acetate/hexane to give the title compound. LC/MS: (M+1)+: 462.12.
Reaction SMILES: [O:1]=[C:2]1[N:8]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C@@H:18]([C:32](O)=[O:33])[CH2:19][C:20]3[CH:30]=[C:29]([CH3:31])[C:23]4[N:24]([CH3:28])[C:25](=[O:27])[O:26][C:22]=4[CH:21]=3)=[O:16])[CH2:11][CH2:10]2)[CH2:7][CH2:6][C:5]2[CH:35]=[CH:36][CH:37]=[CH:38][C:4]=2[NH:3]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)CC)C.[CH3:68][C:69]1([NH:81]C(=O)OC(C)(C)C)[CH2:74][CH2:73][N:72]([CH:75]2[CH2:80][CH2:79][NH:78][CH2:77][CH2:76]2)[CH2:71][CH2:70]1.C(O)(C(F)(F)F)=O>CN(C=O)C.C(Cl)Cl>[O:1]=[C:2]1[N:8]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C@H:18]([CH2:19][C:20]3[CH:30]=[C:29]([CH3:31])[C:23]4[N:24]([CH3:28])[C:25](=[O:27])[O:26][C:22]=4[CH:21]=3)[C:32]([N:78]3[CH2:79][CH2:80][CH:75]([N:72]4[CH2:73][CH2:74][C:69]([NH2:81])([CH3:68])[CH2:70][CH2:71]4)[CH2:76][CH2:77]3)=[O:33])=[O:16])[CH2:11][CH2:10]2)[CH2:7][CH2:6][C:5]2[CH:35]=[CH:36][CH:37]=[CH:38][C:4]=2[NH:3]1
Reactant: CC1(NC(=O)OC(C)(C)C)CCN(C2CCNCC2)CC1
Reactant: Cc1cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)O)cc2oc(=O)n(C)c12
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)N2CCC(N3CCC(C)(N)CC3)CC2)cc2oc(=O)n(C)c12
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A solution of 80 mg (0.15 mmol) (R)-1-carboxy-2-(3,4-dimethyl-2-oxo-2,3-dihydrobenz-oxazol-6-yl)-ethyl 4-(2-oxo-1,2,4,5,-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate, 58 mg (0.18 mmol) TBTU, 140 μL (1.00 mmol) triethylamine and 59 mg (0.16 mmol) tert.-butyl (4-methyl-[1,4′]bipiperidinyl-4-yl)-carbamate in 1.8 mL DMF were stirred overnight at RT. The reaction mixture was purified by HPLC, the fractions containing the product were combined and lyophilised. The residue obtained was dissolved in 4 mL DCM, combined with 0.5 mL TFA and the reaction solution was stirred for 5 h at RT. The DCM was left to evaporate off overnight, the residue was combined with 2 mL 15% K2CO3 solution and extracted twice with 2 mL DCM. After the solvent had been eliminated the residue was taken up in 1 mL DMF and purified by HPLC. The fractions containing the product were combined and lyophilised.
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]3[N:19]=[C:18]([NH:20][C:21]4[C:26]5[C:27](=[O:35])[N:28]6[C@H:32]([CH2:33][O:34][C:25]=5[CH:24]=[CH:23][CH:22]=4)[CH2:31][CH2:30][CH2:29]6)[C:17]([C:36]([F:39])([F:38])[F:37])=[CH:16][N:15]=3)=[CH:9][CH:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C=O.[C:42](O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CN(C)C=O>[CH3:42][N:4]1[CH2:3][CH2:2][N:1]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]3[N:19]=[C:18]([NH:20][C:21]4[C:26]5[C:27](=[O:35])[N:28]6[C@H:32]([CH2:33][O:34][C:25]=5[CH:24]=[CH:23][CH:22]=4)[CH2:31][CH2:30][CH2:29]6)[C:17]([C:36]([F:37])([F:38])[F:39])=[CH:16][N:15]=3)=[CH:9][CH:8]=2)[CH2:6][CH2:5]1
Reactant: O=C1c2c(Nc3nc(Nc4ccc(N5CCNCC5)cc4)ncc3C(F)(F)F)cccc2OC[C@@H]2CCCN12
Reactant: CC(=O)O
Agent: C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1CCN(c2ccc(Nc3ncc(C(F)(F)F)c(Nc4cccc5c4C(=O)N4CCC[C@H]4CO5)n3)cc2)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
50 mg (0.077 mmol) 2-(4-piperazin-1-yl-phenylamino)-4-((S)-4-oxo-2,3,10,10a-tetrahydro-1H.4H-9-oxa-3a-aza-benzo[f]azulen-5-ylamino)-5-trifluoromethyl-pyrimidine are dissolved in 0.5 mL dimethylformamide and combined with 12 μL (0.154 mmol) formaldehyde and 2 μL (0.039 mmol) acetic acid. 86 mg (0.385 mmol) of sodium triacetoxyborohydride are metered into this mixture and it is stirred for 16 h at ambient temperature. Then the solvent is eliminated in vacuo. The crude product is purified by column chromatography. The carrier material used is C18-RP-silica gel and a gradient is run through which at the starting point consists of 95% water and 5% acetonitrile and at the end point consists of 5% water and 95% acetonitrile. 0.2% Formic acid is added to the two eluants. The suitable fractions are combined with 1 N aqueous hydrochloric acid and freeze-dried.
Reaction SMILES: Br[C:2]([CH3:4])=[CH2:3].C([Li])(C)(C)C.[CH2:10]([S:13][C:14]1[CH:21]=[CH:20][CH:19]=[CH:18][C:15]=1[CH:16]=[O:17])[C:11]#[CH:12]>C1COCC1.CCCCC>[CH3:4][C:2](=[CH2:3])[CH:16]([C:15]1[CH:18]=[CH:19][CH:20]=[CH:21][C:14]=1[S:13][CH2:10][C:11]#[CH:12])[OH:17]
Reactant: C#CCSc1ccccc1C=O
Reactant: C=C(C)Br
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Solvent: CCCCC
Product: C#CCSc1ccccc1C(O)C(=C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 2-bromopropene (4.53 g, 37.4 mmol) in 85 ml of dry THF at -78° C. was added t-butyllithium (44 ml of a 1.7M solution in pentane) dropwise. After 2 hours, 2-(2-propynylthio) benzaldehyde (3.0 g, 17.0 mmol) prepared according to the procedures described in Example 1, Steps A, B, and C in 30 ml of dry THF was added dropwise. The reaction mixture was allowed to warm up to room temperature (RT). The reaction mixture was quenched with 100 ml of a saturated NH4Cl solution, extracted twice with diethyl ether, washed with water and brine, and then dried over K2CO3 to afford the subtitle compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[CH:11]=[C:10]([CH3:12])[N:9](S(C3C=CC=CC=3)(=O)=O)[C:6]2=[N:7][CH:8]=1.[OH-].[Na+].O>CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[CH:11]=[C:10]([CH3:12])[NH:9][C:6]2=[N:7][CH:8]=1
Reactant: COc1cnc2c(c1)cc(C)n2S(=O)(=O)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1cnc2[nH]c(C)cc2c1
Yield: 90.7 %

Procedure:
A solution of 5-methoxy-2-methyl-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine (950 mg, 3.14 mmol) and 40% aqueous sodium hydroxide (106 ml) in methanol (160 ml) was heated at reflux for 30 minutes. After cooling, the mixture was poured onto cooled water and extracted with ethyl acetate. The organic layer was separated, washed with water, brine, dried (MgSO4), filtered and evaporated. The residue was purified by column chromatography eluting with ethyl acetate/petroleum ether (1/1). The fractions containing the expected product were combined and evaporated to give 5-methoxy-2-methyl-1H-pyrrolo[2,3-b]pyridine (462 mg, 91%).
Reaction SMILES: Cl[C:2]1[C:3]2[C:10]([CH3:11])=[C:9]([CH3:12])[S:8][C:4]=2[N:5]=[CH:6][N:7]=1.Cl.Cl.[CH:15]1([CH2:21][N:22]2[CH2:27][CH2:26][CH:25]([NH2:28])[CH2:24][CH2:23]2)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1>>[CH:15]1([CH2:21][N:22]2[CH2:27][CH2:26][CH:25]([NH:28][C:2]3[C:3]4[C:10]([CH3:11])=[C:9]([CH3:12])[S:8][C:4]=4[N:5]=[CH:6][N:7]=3)[CH2:24][CH2:23]2)[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]1
Reactant: Cc1sc2ncnc(Cl)c2c1C
Reactant: NC1CCN(CC2CCCCC2)CC1
Agent: Cl
Product: Cc1sc2ncnc(NC3CCN(CC4CCCCC4)CC3)c2c1C

Procedure:
The title compound was prepared (81 mg, 28%) from 4-chloro-5,6-dimethylthieno[2,3-d]pyrimidine (325 mg, 1.21 mmol) and 1-(cyclohexylmethyl)piperidin-4-amine dihydrochloride (160 mg, 0.81 mmol) by following the general procedure described for Preparation 6. 1H NMR (400 MHz, CDCl3) δ 8.36 (s, 1H), 5.36 (d, 1H), 4.22 (m, 1H), 2.80 (d, 2H), 2.44 (s, 3H), 2.41 (s, 3H), 2.21-2.09 (m, 7H), 1.79-1.45 (m, 6H), 1.20 (m, 4H), 0.88 (m, 2H); MS (ESI) m/z: Calculated for C20H31N4S, 359.23; Observed: 359.2 (M++1).
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[NH:7][CH2:8][CH2:9][NH:10][C:11]([C:13]1[NH:14][C:15]2[C:20]([CH:21]=1)=[CH:19][CH:18]=[C:17]([NH2:22])[CH:16]=2)=[O:12])([CH3:4])([CH3:3])[CH3:2].FC1C([O:31][C:32]([C:34]2[NH:35][C:36]3[C:41]([CH:42]=2)=[CH:40][C:39]([C:43](=[O:55])[NH:44][CH2:45][CH2:46][NH:47][C:48]([O:50][C:51]([CH3:54])([CH3:53])[CH3:52])=[O:49])=[CH:38][CH:37]=3)=O)=C(F)C(F)=C(F)C=1F.CCN(C(C)C)C(C)C>CN(C=O)C>[C:51]([O:50][C:48](=[O:49])[NH:47][CH2:46][CH2:45][NH:44][C:43]([C:39]1[CH:40]=[C:41]2[C:36](=[CH:37][CH:38]=1)[NH:35][C:34]([C:32](=[O:31])[NH:22][C:17]1[CH:16]=[C:15]3[C:20]([CH:21]=[C:13]([C:11](=[O:12])[NH:10][CH2:9][CH2:8][NH:7][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:23])[NH:14]3)=[CH:19][CH:18]=1)=[CH:42]2)=[O:55])([CH3:54])([CH3:52])[CH3:53]
Reactant: CC(C)(C)OC(=O)NCCNC(=O)c1ccc2[nH]c(C(=O)Oc3c(F)c(F)c(F)c(F)c3F)cc2c1
Reactant: CC(C)(C)OC(=O)NCCNC(=O)c1cc2ccc(N)cc2[nH]1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCCNC(=O)c1ccc2[nH]c(C(=O)Nc3ccc4cc(C(=O)NCCNC(=O)OC(C)(C)C)[nH]c4c3)cc2c1
Temperature: 55 °C
Reaction time: 48 h

Procedure:
A mixture of above amine 36 and compound 33 (0.226 g, 0.44 mmol) in dry DMF (6 ml) in the presence of DIEA (77 μl, 0.44 mmol) was stirred at 55° C. for 2 days. After removal of solvent, the residue was recrystalized from MeOH-ether to give compound 37 in a quantitative yield.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][OH:8].[C:9](OC(=O)C)(=[O:11])[CH3:10].N1C=CC=CC=1>C(OCC)C>[C:9]([O:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][Cl:1])(=[O:11])[CH3:10]
Reactant: CC(=O)OC(C)=O
Reactant: OCCCCCCCl
Solvent: c1ccncc1
Solvent: CCOCC
Product: CC(=O)OCCCCCCCl
Yield: 99 %

Procedure:
A solution of 100 ml of 6-chloro-1-hexanol, 85 ml of acetic anhydride and 67 ml of pyridine in 300 ml of dry ethyl ether was stirred at room temperature for 1 h. The reaction mixture was washed 3 times with 100 ml of water and twice with 100 ml of saturated brine, dried over Na2SO4, filtered and evaporated. Distillation afforded 133 g of 6-chlorohexanol acetate (99%), b.p. 132° C. (10 mm).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][S:9]([C:12]2[CH:13]=[CH:14][C:15]([CH2:18][CH2:19][CH2:20][C:21]([O:23]C)=[O:22])=[N:16][CH:17]=2)(=[O:11])=[O:10])=[CH:4][CH:3]=1.[OH-].[Na+].Cl>C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][S:9]([C:12]2[CH:13]=[CH:14][C:15]([CH2:18][CH2:19][CH2:20][C:21]([OH:23])=[O:22])=[N:16][CH:17]=2)(=[O:11])=[O:10])=[CH:6][CH:7]=1
Reactant: COC(=O)CCCc1ccc(S(=O)(=O)Nc2ccc(Cl)cc2)cn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)CCCc1ccc(S(=O)(=O)Nc2ccc(Cl)cc2)cn1
Temperature: 5 °C
Reaction time: 1 h
Yield: 65.5 %

Procedure:
A solution of methyl 4-[5-(4-chlorophenylsulphamoyl)pyrid-2-yl]butanoate (0.8 g), 10% w/v sodium hydroxide solution (5 ml) in ethanol (15 ml) was stirred for 1 hour. The solution was acidified with dilute hydrochloric acid (pH 3) and cooled to 5° C. The white precipitate was collected and recrystallised from ethanol to give the title compound (0.504 g) as prisms. m.p. 150°-152° C.
Reaction SMILES: [H-].[Na+].[CH2:3]([NH:12][C:13]1[C:21]2[C:16](=[CH:17][C:18]([Cl:23])=[CH:19][C:20]=2[Cl:22])[N:15]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C:14]=1[C:31]([O:33][CH2:34][CH3:35])=[O:32])[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5].[CH2:36](Br)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.Cl>CN(C)C=O>[CH2:3]([N:12]([CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[C:13]1[C:21]2[C:16](=[CH:17][C:18]([Cl:23])=[CH:19][C:20]=2[Cl:22])[N:15]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C:14]=1[C:31]([O:33][CH2:34][CH3:35])=[O:32])[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5]
Reactant: BrCc1ccccc1
Reactant: CCOC(=O)c1c(NCC(=O)c2ccccc2)c2c(Cl)cc(Cl)cc2n1C(=O)OC(C)(C)C
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(N(CC(=O)c2ccccc2)Cc2ccccc2)c2c(Cl)cc(Cl)cc2n1C(=O)OC(C)(C)C
Temperature: -10 °C
Reaction time: 0.5 h

Procedure:
Suspend sodium hydride (42 mg of a 60% dispersion, 1.39 mmol) in dimethylformamide, place under nitrogen atmosphere and cool to -10° C. Add, by dropwise addition, a solution of 3-[(phenacyl)amino]-2-carbethoxy-4,6-dichloro-1-tert-butyloxycarbonyl-indole (0.6 g, 1.26 mmol) in dimethylformamide. Stir at -10° C. for 30 minutes and add, by dropwise addition, benzyl bromide (0.24 g, 1.39 mmol). Stir for 5 hours, pour into 1N hydrochloric acid and extract into ethyl acetate. Dry (MgSO4) and evaporate the solvent in vacuo to give the title compound as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][CH:27]=1)[C:5]([C:7]1[C:8]([O:23][CH3:24])=[C:9]2[CH:16]=[N:15][N:14](CC3OC=CC=3)[C:10]2=[N:11][C:12]=1[CH3:13])=[O:6].P(=O)(O)(O)O>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][CH:27]=1)[C:5]([C:7]1[C:8]([O:23][CH3:24])=[C:9]2[CH:16]=[N:15][NH:14][C:10]2=[N:11][C:12]=1[CH3:13])=[O:6]
Reactant: COc1c(C(=O)c2cccc(Cl)c2)c(C)nc2c1cnn2Cc1ccco1
Agent: O=P(O)(O)O
Product: COc1c(C(=O)c2cccc(Cl)c2)c(C)nc2[nH]ncc12

Procedure:
5-(3-Chlorobenzoyl)-1-(2-furanylmethyl)-4-methoxy-6-methyl-1H-pyrazolo[3,4-b]pyridine is treated with concentrated phosphoric acid according to the procedure of Example 1d to obtain 5-(3-chlorobenzoyl)-4-methoxy-6-methyl-1H-pyrazolo-[3,4-b]pyridine.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[N:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]3[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][CH3:22])=[CH:16][CH:15]=3)=[CH:10][CH:9]=2)=[N:6][CH:7]=1.[CH3:23][C@@H:24]([CH2:32][CH3:33])[CH2:25][CH2:26][CH2:27][CH2:28][C:29](O)=[O:30].C1CCC(N=C=NC2CCCCC2)CC1>ClCCl.CN(C1C=CN=CC=1)C>[CH3:23][C@@H:24]([CH2:32][CH3:33])[CH2:25][CH2:26][CH2:27][CH2:28][C:29]([O:1][C:2]1[CH:7]=[N:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]([C:14]3[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][CH3:22])=[CH:16][CH:15]=3)=[CH:12][CH:13]=2)=[N:4][CH:3]=1)=[O:30]
Reactant: CCCc1ccc(-c2ccc(-c3ncc(O)cn3)cc2)cc1
Reactant: CC[C@H](C)CCCCC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCCc1ccc(-c2ccc(-c3ncc(OC(=O)CCCC[C@@H](C)CC)cn3)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 67.6 %

Procedure:
5-Hydroxy-2(4'-propyl-biphenyl-4-yl)pyrimidine (10 g, 0.034 mol) was dissolved in dichloromethane (100 ml), followed by adding (S)-6-methyloctanoic acid (7.9 g, 0.05 mol), DCC (20.6 g, 0.1 mol) and DMAP (3.3 g), agitating the mixture at room temperature for 2 hours, filtering off deposited crystals, washing the filtrate with 6N-HCl, then with 2N-NaOH and further with water until the washing water became neutral, drying the organic layer over anhydrous magnesium sulfate, distilling off dichloromethane and recrystallizing the residue from ethanol (150 ml) to obtain (S)-5-(6'-methyloctanoyloxy)-2-(4'-propylbiphenyl-4-yl)pyrimidine (9.9 g). This product was a liquid crystal and exhibited the following phase transition points (see also Table 1): ##STR88##
Reaction SMILES: [S:1]1[C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:4]=2[N:3]=[C:2]1[N:10]1[C@@H:14]([C:15]2[CH:20]=[CH:19][C:18]([C@:21]3([C:37](=[O:39])[NH2:38])[CH2:25][CH2:24][CH2:23][N:22]3[C:26](=[O:36])[C@@H:27]([NH:31][C:32](=[O:35])[O:33][CH3:34])[CH:28]([CH3:30])[CH3:29])=[C:17]([N+:40]([O-])=O)[CH:16]=2)[CH2:13][CH2:12][C@@H:11]1[C:43]1[CH:48]=[CH:47][C:46]([C@:49]2([C:65](=[O:67])[NH2:66])[CH2:53][CH2:52][CH2:51][N:50]2[C:54](=[O:64])[C@@H:55]([NH:59][C:60](=[O:63])[O:61][CH3:62])[CH:56]([CH3:58])[CH3:57])=[C:45]([N+:68]([O-])=O)[CH:44]=1>O1CCCC1.[Ni].O>[S:1]1[C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:4]=2[N:3]=[C:2]1[N:10]1[C@@H:11]([C:43]2[CH:48]=[CH:47][C:46]([C@:49]3([C:65](=[O:67])[NH2:66])[CH2:53][CH2:52][CH2:51][N:50]3[C:54](=[O:64])[C@@H:55]([NH:59][C:60](=[O:63])[O:61][CH3:62])[CH:56]([CH3:58])[CH3:57])=[C:45]([NH2:68])[CH:44]=2)[CH2:12][CH2:13][C@@H:14]1[C:15]1[CH:20]=[CH:19][C:18]([C@:21]2([C:37](=[O:39])[NH2:38])[CH2:25][CH2:24][CH2:23][N:22]2[C:26](=[O:36])[C@@H:27]([NH:31][C:32](=[O:35])[O:33][CH3:34])[CH:28]([CH3:29])[CH3:30])=[C:17]([NH2:40])[CH:16]=1
Reactant: COC(=O)N[C@H](C(=O)N1CCC[C@@]1(C(N)=O)c1ccc([C@H]2CC[C@H](c3ccc([C@]4(C(N)=O)CCCN4C(=O)[C@@H](NC(=O)OC)C(C)C)c([N+](=O)[O-])c3)N2c2nc3c(s2)CCCC3)cc1[N+](=O)[O-])C(C)C
Agent: [Ni]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)N[C@H](C(=O)N1CCC[C@@]1(C(N)=O)c1ccc([C@H]2CC[C@H](c3ccc([C@]4(C(N)=O)CCCN4C(=O)[C@@H](NC(=O)OC)C(C)C)c(N)c3)N2c2nc3c(s2)CCCC3)cc1N)C(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The product from Example 116E (0.59 g, 0.596 mmol) was dissolved in tetrahydrofuran (15 mL) and treated with Raney Nickel slurry in water (0.25 mL). The flask was evacuated and opened to a hydrogen balloon and stirred at ambient temperature for 1 hour. The solution was filtered through a silica plug and concentrated to dryness to give the title compound.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[CH:9][N:10]=2)[CH:7]=1.CC1(C)C(C)(C)OB([C:25]2[N:29]([C:30]3[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][CH:31]=3)[N:28]=[CH:27][CH:26]=2)O1>>[C:11]1([C:8]2[N:6]3[CH:7]=[C:2]([C:25]4[N:29]([C:30]5[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][CH:31]=5)[N:28]=[CH:27][CH:26]=4)[CH:3]=[CH:4][C:5]3=[N:10][CH:9]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Cc1ccc(-n2nccc2B2OC(C)(C)C(C)(C)O2)cc1
Reactant: Brc1ccc2ncc(-c3ccccc3)n2c1
Product: Cc1ccc(-n2nccc2-c2ccc3ncc(-c4ccccc4)n3c2)cc1

Procedure:
The title compound, off-white solid (53 mg, 41%), MS (ISP) m/z=351.5 [(M+H)+], mp 107° C., was prepared in accordance with the general method of example 1 from 6-bromo-3-phenyl-imidazo[1,2-a]pyridine (intermediate G) (0.1 g, 0.366 mmol) and 5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1-p-tolyl-1H-pyrazole (intermediate C) (0.125 g, 0.44 mmol).
Reaction SMILES: [NH2:1][C@:2]12[CH2:37][CH2:36][C@@H:35]([C:38]([CH3:40])=[CH2:39])[C@@H:3]1[C@@H:4]1[C@@:17]([CH3:20])([CH2:18][CH2:19]2)[C@@:16]2([CH3:21])[C@@H:7]([C@:8]3([CH3:34])[C@@H:13]([CH2:14][CH2:15]2)[C:12]([CH3:23])([CH3:22])[C:11]([C:24]2[CH:33]=[CH:32][C:27]([C:28]([O:30]C)=[O:29])=[CH:26][CH:25]=2)=[CH:10][CH2:9]3)[CH2:6][CH2:5]1.CN(C)CCC(N[C@]12CC[C@@H](C(C)=C)[C@@H]1[C@@H]1[C@@](C)(CC2)[C@@]2(C)[C@@H]([C@]3(C)[C@@H](CC2)C(C)(C)C(C2C=CC(C(O)=O)=CC=2)=CC3)CC1)=O.[N:87]1([CH2:92][C:93]([OH:95])=O)[CH:91]=[N:90][N:89]=[N:88]1>>[N:87]1([CH2:92][C:93]([NH:1][C@:2]23[CH2:37][CH2:36][C@@H:35]([C:38]([CH3:40])=[CH2:39])[C@@H:3]2[C@@H:4]2[C@@:17]([CH3:20])([CH2:18][CH2:19]3)[C@@:16]3([CH3:21])[C@@H:7]([C@:8]4([CH3:34])[C@@H:13]([CH2:14][CH2:15]3)[C:12]([CH3:23])([CH3:22])[C:11]([C:24]3[CH:25]=[CH:26][C:27]([C:28]([OH:30])=[O:29])=[CH:32][CH:33]=3)=[CH:10][CH2:9]4)[CH2:6][CH2:5]2)=[O:95])[CH:91]=[N:90][N:89]=[N:88]1
Reactant: O=C(O)Cn1cnnn1
Reactant: C=C(C)[C@@H]1CC[C@]2(N)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Agent: C=C(C)[C@@H]1CC[C@]2(NC(=O)CCN(C)C)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Product: C=C(C)[C@@H]1CC[C@]2(NC(=O)Cn3cnnn3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Yield: 33 %

Procedure:
The title compound was prepared in 33% yield from methyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-amino-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate following the same procedure as described for the preparation of 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(3-(dimethylamino)propanamido)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoic acid, except 1-H-tetrazole-1-acetic acid was used instead of 3-(dimethylamino)propionic acid hydrochloride in Step 1. LCMS: m/e 638.7 (M−H)−, 1.98 min (method 6). 1H NMR (500 MHz, 1:1 CDCl3:MeOD) δ=9.10 (s, 1H), 7.93 (d, J=8.2 Hz, 2H), 7.39 (s, 1H), 7.21 (d, J=8.2 Hz, 2H), 5.30 (dd, J=1.5, 6.1 Hz, 1H), 5.27 (d, J=1.5 Hz, 2H), 4.78 (d, J=1.2 Hz, 1H), 4.65 (s, 1H), 2.71 (dt, J=5.2, 11.1 Hz, 1H), 2.64-2.56 (m, 1H), 2.34 (dd, J=8.1, 12.7 Hz, 1H), 2.13 (dd, J=6.4, 17.1 Hz, 1H), 2.00-1.86 (m, 2H), 1.80 (d, J=11.0 Hz, 1H), 1.74 (br. s., 1H), 1.72 (s, 3H), 1.71-1.66 (m, 1H), 1.62-1.30 (m, 11H), 1.29-1.22 (m, 1H), 1.20-1.14 (m, 1H), 1.12 (s, 3H), 1.10 (d, J=4.3 Hz, 1H), 1.03 (s, 6H), 0.95 (s, 3H), 0.94 (s, 3H).