Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.[CH3:13][O:14][C:15](=[O:41])/[CH:16]=[CH:17]/[C:18]1[CH:19]=[C:20]2[C:37](=[CH:38][CH:39]=1)[O:36][C:23]1([CH2:28][CH2:27][N:26](C(OC(C)(C)C)=O)[CH2:25][CH2:24]1)[CH2:22][C:21]2=[O:40]>C(Cl)Cl>[CH3:13][O:14][C:15](=[O:41])/[CH:16]=[CH:17]/[C:18]1[CH:19]=[C:20]2[C:37](=[CH:38][CH:39]=1)[O:36][C:23]1([CH2:24][CH2:25][N:26]([CH2:2][CH2:3][C:4]3[C:12]4[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=4)[NH:6][CH:5]=3)[CH2:27][CH2:28]1)[CH2:22][C:21]2=[O:40]
Reactant: BrCCc1c[nH]c2ccccc12
Reactant: COC(=O)/C=C/c1ccc2c(c1)C(=O)CC1(CCN(C(=O)OC(C)(C)C)CC1)O2
Solvent: ClCCl
Product: COC(=O)/C=C/c1ccc2c(c1)C(=O)CC1(CCN(CCc3c[nH]c4ccccc34)CC1)O2
Temperature: 25 °C
Reaction time: 8 h
Yield: 44.3 %

Procedure:
TEA (0.46 ml, 3.3 mmol) and 3-(2-bromoethyl)-1H-indole (193 mg, 0.863 mmol) were added to a suspension of (E)-3-{4-oxo-spiro[chromane-2,4′-piperidine]-6-yl}-acrylic acid methyl ester hydrochloride (220 mg, 0.66 mmol, Intermediate 1) in DCM (5 ml), and the mixture was stirred at RT overnight. DCM was evaporated and the residue was dissolved in DMF and heated at 60° C. overnight. The mixture was partitioned between water and AcOEt and the aqueous phase was extracted with DCM. The collected organic phases were dried over Na2SO4 and evaporated. The crude mixture was purified by column chromatography (eluent: DCM/MeOH/NH4OH 94:6:0.2) to give (E)-3-{1′-[2-(1H-indol-3-yl)ethyl]-4-oxo-spiro[chromane-2,4′-piperidine]-6-yl}-acrylic acid methyl ester (130 mg).
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:10])=[CH:4][C:5]([Cl:9])=[C:6]([OH:8])[CH:7]=1.C(=O)([O-])[O-].[K+].[K+].Cl[C:18]1[N:23]=[CH:22][CH:21]=[CH:20][N:19]=1.CS(C)=O>CC(=O)CC>[NH2:1][C:2]1[C:3]([F:10])=[CH:4][C:5]([Cl:9])=[C:6]([CH:7]=1)[O:8][C:18]1[N:23]=[CH:22][CH:21]=[CH:20][N:19]=1
Reactant: Clc1ncccn1
Reactant: Nc1cc(O)c(Cl)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCC(C)=O
Product: Nc1cc(Oc2ncccn2)c(Cl)cc1F
Yield: 75.5 %

Procedure:
A mixture of 5-amino-2-chloro-4-fluorophenol (3.57 g), potassium carbonate (3.04 g), and 2-chloropyrimidine (3.20 g) suspended in butan-2-one (100 ml) and dimethylsulfoxide (10 ml) was heated at reflux overnight. The solution was processed and chromatographed on silica gel eluting with ethyl acetate:hexane, 1:2, to yield yellow crystals (4.0 g). 1H NMR (acetone-d6, TMS): 4.75(2H, br s), 6.78(1H, d, J=8.4 Hz), 7.09(1H, d, J=10.6 Hz), 7.15(1H, t, J=4.8 Hz), 8.56(2H, d, J=4.8 Hz).
Reaction SMILES: [F:1][C:2]([F:44])([F:43])[C@H:3]([N:30]1[CH2:34][CH2:33][C@H:32]([NH:35]C(=O)OC(C)(C)C)[CH2:31]1)[C:4]1[CH:5]=[CH:6][C:7]2[N:8]([C:10]([C:13]3[CH:22]=[CH:21][C:20]4[C:15](=[C:16]([O:24][C@H:25]([CH3:29])[CH2:26][O:27][CH3:28])[CH:17]=[C:18]([F:23])[CH:19]=4)[N:14]=3)=[N:11][N:12]=2)[CH:9]=1.[ClH:45]>ClCCl.C(#N)C>[ClH:45].[ClH:45].[F:44][C:2]([F:1])([F:43])[C@H:3]([N:30]1[CH2:34][CH2:33][C@H:32]([NH2:35])[CH2:31]1)[C:4]1[CH:5]=[CH:6][C:7]2[N:8]([C:10]([C:13]3[CH:22]=[CH:21][C:20]4[C:15](=[C:16]([O:24][C@H:25]([CH3:29])[CH2:26][O:27][CH3:28])[CH:17]=[C:18]([F:23])[CH:19]=4)[N:14]=3)=[N:11][N:12]=2)[CH:9]=1
Reactant: COC[C@@H](C)Oc1cc(F)cc2ccc(-c3nnc4ccc([C@@H](N5CC[C@H](NC(=O)OC(C)(C)C)C5)C(F)(F)F)cn34)nc12
Agent: Cl
Solvent: ClCCl
Solvent: CC#N
Product: COC[C@@H](C)Oc1cc(F)cc2ccc(-c3nnc4ccc([C@@H](N5CC[C@H](N)C5)C(F)(F)F)cn34)nc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 792 %

Procedure:
To a solution of tert-butyl (S)-1-((R)-2,2,2-trifluoro-1-(3-(6-fluoro-8-((R)-1-methoxypropan-2-yloxy)quinolin-2-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)ethyl)pyrrolidin-3-ylcarbamate (0.12 g, 0.19 mmol) in dichloromethane (0.5 mL) was added hydrochloric acid (5-6M in 2-propanol; 9.5 mL, 0.61 mmol). The reaction mixture was stirred at ambient temperature for 30 minutes. The solvent was removed under reduced pressure, and the solid obtained was suspended in acetonitrile (3 mL) and stirred at ambient temperature for 5 minutes. The solid formed was collected by vacuum filtration to give the title compound (0.89 g, 79%). LCMS APCI (+) m/z 519 (M+H). Specific rotation: [α]24D=2.44° (c=0.97, MeOH).
Reaction SMILES: [CH3:1][C:2](=[N:4][OH:5])[CH3:3].[H-].[Na+].[CH3:8][O:9][C:10]1[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[C:12]([N+]([O-])=O)[CH:11]=1.O>CN(C=O)C>[CH3:8][O:9][C:10]1[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[C:12]([O:5][N:4]=[C:2]([CH3:3])[CH3:1])[CH:11]=1
Reactant: CC(C)=NO
Reactant: COc1ccc(C#N)c([N+](=O)[O-])c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(C#N)c(ON=C(C)C)c1
Reaction time: 0.5 h
Yield: 87.2 %

Procedure:
In 20 ml of DMF was dissolved acetone oxime (0.74 g), followed by sodium hydride (0.30 g). After this mixture had stirred for 30 minutes, 4-methoxy-2-nitro-benzonitrile (1.50 g) was added. After an additional 30 minutes the reaction was poured into water (500 ml) and filtered. The solid was collected and dissolved in DCM (250 ml), dried (MgSO4), and concentrated in vacuo. The resulting solid was recrystallized from ethanol to yield 1.5 g of 4-methoxy-2-[[(1-methylethylidene)-amino]oxy]benzonitrile, m.p. 78-79° C.
Reaction SMILES: C([O:8]C1C=CC(C(=O)C)=CC=1CO)C1C=CC=CC=1.[CH2:20]([O:27][C:28]1[CH:33]=[CH:32][C:31]([C:34](=[O:36])[CH3:35])=[CH:30][C:29]=1[NH:37][S:38]([CH3:41])(=[O:40])=[O:39])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(O)C.O>[CH2:20]([O:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]([CH:35]=[O:8])=[O:36])=[CH:30][C:29]=1[NH:37][S:38]([CH3:41])(=[O:39])=[O:40])[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: CC(=O)c1ccc(OCc2ccccc2)c(NS(C)(=O)=O)c1
Reactant: CC(=O)c1ccc(OCc2ccccc2)c(CO)c1
Solvent: O
Solvent: CCO
Product: CS(=O)(=O)Nc1cc(C(=O)C=O)ccc1OCc1ccccc1

Procedure:
The compound was sbtained as an ethanol hemiacetal, mp 125°-128° (ethanol-water) by the process of Description 54 replacing 1-(4-benzyloxy-3-hydroxymethylphenyl)ethanone by 1-(4-benzyloxy-3-methanesulphonamidophenyl)ethanone. (CDCl3) 8.75 (3H, t, J=6 Hz), 7.05 (3H, s), 5.90-6.40 (2H, m), 4.90 (1H, b), 4.80 (2H, s), 4.46 (1H, s), 2.90 (1H, d, J=8 Hz), 2.60 (5H, s), 2.20 (1H, s), 2.09 (1H, dd, J=8 Hz, 2 Hz), 1.80 (1H, d, J=2 Hz).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][C:3]=1[C:4]([OH:6])=O.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.[I-].[CH2:46]([N+:50]1[N:54]=[C:53]([CH3:55])[S:52][C:51]=1[CH3:56])[CH2:47][CH2:48][CH3:49]>>[CH2:46]([N:50]1[N:54]=[C:53]([CH3:55])[S:52]/[C:51]/1=[CH:56]\[C:4]([C:3]1[CH:7]=[C:8]([CH3:11])[CH:9]=[CH:10][C:2]=1[CH3:1])=[O:6])[CH2:47][CH2:48][CH3:49]
Reactant: Cc1ccc(C)c(C(=O)O)c1
Reactant: CCCC[n+]1nc(C)sc1C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [I-]
Solvent: CCN(C(C)C)C(C)C
Product: CCCCN1N=C(C)S/C1=C\C(=O)c1cc(C)ccc1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a 20 mL vial 2,5-dimethylbenzoic acid (0.9 mL of 0.2 M in DMA, 1.10 equiv) was added followed by the addition of HATU (76 mg in 0.7 mL of DMA, 0.2 mmol, 1.20 equiv.), DIEA (51 mg in 0.7 mL of DMA, 0.4 mmol, 2.40 equiv.), and finally 3-butyl-2,5-dimethyl-1,3,4-thiadiazol-3-ium iodide (49 mg in 0.7 mL of DMA, 0.17 mmol, 1 equiv.). The mixture was shaken overnight at room temperature and then concentrated in vacuo. The resulting residue was taken up in 1:1 DMSO/MeOH and purified by reverse phase HPLC using a method analogous to that described in Example 53 to provide the title compound. 1H NMR (500 MHz, DMSO-D6/D2O) δ ppm 0.84-0.94 (m, 3 H) 1.27-1.33 (m, 2 H) 1.68-1.77 (m, 2 H) 2.30 (s, 6 H) 2.48 (s, 3 H) 4.12 (t, 2 H) 6.20 (1, 1 H) 7.10 (s, 2 H) 7.28 (s, 1 H); MS (ESI) m/z 303 (M+H)+.
Reaction SMILES: [C:1]([CH2:3][CH:4]([CH2:7][O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH2:5][NH2:6])#[N:2].[Cl:25][CH2:26][CH2:27][CH2:28][S:29](NCC(OC)CSCCCCCCCCCCCCCCCC)(=[O:31])=[O:30]>>[Cl:25][CH2:26][CH2:27][CH2:28][S:29]([NH:6][CH2:5][CH:4]([CH2:3][C:1]#[N:2])[CH2:7][O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])(=[O:31])=[O:30]
Reactant: CCCCCCCCCCCCCCCCOCC(CN)CC#N
Reactant: CCCCCCCCCCCCCCCCSCC(CNS(=O)(=O)CCCCl)OC
Product: CCCCCCCCCCCCCCCCOCC(CC#N)CNS(=O)(=O)CCCCl

Procedure:
The crude 2-cyanomethyl-3-hexadecyloxypropylamine IVn1 prepared above is allowed to react by the same procedure as described in (4). The summary of the experimental condition and the physical data of the product are listed in Table 7.
Reaction SMILES: C([O:3][C:4](=[O:25])[C:5]([CH3:24])([CH3:23])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][NH:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[CH:9][CH:8]=1)C.B(Br)(Br)Br.O>C(Cl)Cl>[CH2:16]([NH:15][CH2:14][CH2:13][C:10]1[CH:9]=[CH:8][C:7]([CH2:6][C:5]([CH3:23])([CH3:24])[C:4]([OH:25])=[O:3])=[CH:12][CH:11]=1)[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: CCCCCCCNCCc1ccc(CC(C)(C)C(=O)OCC)cc1
Agent: BrB(Br)Br
Solvent: O
Solvent: ClCCl
Product: CCCCCCCNCCc1ccc(CC(C)(C)C(=O)O)cc1
Temperature: -78 °C
Reaction time: 3 h

Procedure:
To a solution of the impure 3-[4-(2-heptylamino-ethyl)-phenyl]-2,2-dimethyl-propionic acid ethyl ester (100 mg of the mixture) dissolved in methylene chloride (5 mL) cooled to −78° C. under a nitrogen atmosphere was added boron tribromide (1M in dichloromethane, 0.432 mL). The mixture was warmed to room temperature and stirred for 3 h. The mixture was cooled to −78° C. and an additional 0.432 mL of the 1M boron tribromide in dichloromethane was added. The mixture was warmed to room temperature and stirred for 20 minutes. The mixture was poured over H2O (10 mL) and extracted with dichloromethane (3×). The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated to a clear film. This was dissolved in dioxane/2M HCl (10 mL/10 mL) and was refluxed for 20 minutes. The mixture was cooled and brought to pH 10 with 2 N NaOH. The basic solution was washed with diethyl ether (3×) and brought to pH 4 with 2N HCL. The acidic solution was extracted with diethyl ether (3×), washed with brine (2×), dried over anhydrous sodium sulfate and concentrated to give 3-[4-(2-heptylamino-ethyl)-phenyl]-2,2-dimethyl-propionic acid as a clear film (23 mg, 46%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=[N:17][S:18](=[O:21])(=[O:20])[NH2:19])OC2C=CC=CC=2)[CH:5]=[CH:6][CH:7]=1.[CH3:22][C:23]1[C:31]2[C:30]([N:32]3[CH2:37][CH2:36][NH:35][C@@H:34]([CH3:38])[CH2:33]3)=[N:29][CH:28]=[N:27][C:26]=2[NH:25][CH:24]=1.C(N(CC)CC)C>CC#N>[Br:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]([N:35]2[CH2:36][CH2:37][N:32]([C:30]3[C:31]4[C:23]([CH3:22])=[CH:24][NH:25][C:26]=4[N:27]=[CH:28][N:29]=3)[CH2:33][C@@H:34]2[CH3:38])=[N:17][S:18](=[O:20])(=[O:21])[NH2:19])[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1c[nH]c2ncnc(N3CCN[C@@H](C)C3)c12
Reactant: NS(=O)(=O)N=C(Nc1cccc(Br)c1)Oc1ccccc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cc1c[nH]c2ncnc(N3CCN(C(=NS(N)(=O)=O)Nc4cccc(Br)c4)[C@@H](C)C3)c12
Temperature: 70 °C
Yield: 11 %

Procedure:
Crude carbamimidate from step B (˜25 mg, 0.068 mmol), (S)-5-methyl-4-(3-methylpiperazin-1-yl)-7H-pyrrolo[2,3-d]pyrimidine, from Example 1, step B (16 mg, 0.68 mmol), and triethylamine (10 μl, 0.068 mmol) were combined in MeCN (0.5 ml) and heated to 70° C. for 2 hours. The mixture was concentrated and purified by preparative HPLC to afford (S)—N-(3-bromophenyl)-2-methyl-4-(5-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-N′-sulfamoylpiperazine-1-carboximidamide (4 mg, 0.0075 mmol, 11%) as a white solid.
Reaction SMILES: [C:1]([O:5][N:6]=[C:7]([C:10]1[C:15]([Cl:16])=[CH:14][C:13]([Cl:17])=[CH:12][N:11]=1)[CH2:8]Br)([CH3:4])([CH3:3])[CH3:2].[C:18]1(=[O:28])[NH:22][C:21](=[O:23])[C:20]2=[CH:24][CH:25]=[CH:26][CH:27]=[C:19]12.[K].O>CN(C)C=O>[Cl:16][C:15]1[C:10]([C:7](=[N:6][O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[CH2:8][N:22]2[C:21](=[O:23])[C:20]3=[CH:24][CH:25]=[CH:26][CH:27]=[C:19]3[C:18]2=[O:28])=[N:11][CH:12]=[C:13]([Cl:17])[CH:14]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CC(C)(C)ON=C(CBr)c1ncc(Cl)cc1Cl
Agent: [K]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)ON=C(CN1C(=O)c2ccccc2C1=O)c1ncc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 5 h
Yield: 96.9 %

Procedure:
To 140 mg of 2-bromo-1-(3,5-dichloropyridin-2-yl)ethanone-O-(tert-butyl)oxime in 2 ml of N,N-dimethylformamide, 91 mg of potassium phthalimide was added, and the mixture was stirred at room temperature for 5 hours. After completion of the reaction, the reaction mixture was mixed with 10 ml of water and extracted with ethyl acetate (15 ml×1), the resulting organic layer was washed with water (10 ml×1) and dried over saturated aqueous sodium chloride and then anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography using ethyl acetate-hexane (with a gradient of from 2:8 to 4:6) as the eluent to obtain 162 mg of the desired product as a colorless resinous substance.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7](=[O:24])[NH:8][C:9]2[CH:14]=[CH:13][N:12]3[N:15]=[C:16]([N:18]4[CH2:23][CH2:22][O:21][CH2:20][CH2:19]4)[N:17]=[C:11]3[CH:10]=2)=[C:5]([C:25]([OH:27])=O)[CH:4]=[N:3]1.[CH:28]1([NH:33][CH3:34])[CH2:32][CH2:31][CH2:30][CH2:29]1.C(N(C(C)C)C(C)C)C.CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O>O1CCCC1>[CH:28]1([N:33]([CH3:34])[C:25]([C:5]2[CH:4]=[N:3][N:2]([CH3:1])[C:6]=2[C:7]([NH:8][C:9]2[CH:14]=[CH:13][N:12]3[N:15]=[C:16]([N:18]4[CH2:19][CH2:20][O:21][CH2:22][CH2:23]4)[N:17]=[C:11]3[CH:10]=2)=[O:24])=[O:27])[CH2:32][CH2:31][CH2:30][CH2:29]1
Reactant: CNC1CCCC1
Reactant: Cn1ncc(C(=O)O)c1C(=O)Nc1ccn2nc(N3CCOCC3)nc2c1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CN(C(=O)c1cnn(C)c1C(=O)Nc1ccn2nc(N3CCOCC3)nc2c1)C1CCCC1
Temperature: 70 °C
Reaction time: 22 h
Yield: 92.8 %

Procedure:
A mixture of 1-methyl-5-(2-morpholin-4-yl-[1,2,4]triazolo[1,5-a]pyridin-7-ylcarbamoyl)-1H-pyrazole-4-carboxylic acid (100 mg, 0.269 mmole), cyclopentyl-methylamine (107 mg, 1.08 mmole), N-ethyldiisopropylamine (376 ul, 2.15 mmole) and 1-propanephosphonic acid cyclic anhydride (50% in ethyl acetate, 404 ul, 0.673 mmole) in tetrahydrofurane (4 ml) was stirred for 22 hours at 70° C. The solvent was evaporated, the residue was triturated with sodium hydrogencarbonate solution. The precipitated solid was filtered off, washed with water and dried affording N4-cyclopentyl-N4,1-dimethyl-N5-(2-morpholino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1H-pyrazole-4,5-dicarboxamide (113 mg, 92.7%) as an off-white solid. mp.: 222-4° C., MS: m/z=453.5 (M+H+)
Reaction SMILES: [CH3:1][CH:2]([C@H:4]1[CH:8]2[CH:9]3[C@@:22]([CH3:25])([CH2:23][CH2:24][C@@:7]2([C:31]([OH:33])=[O:32])[CH2:6][CH2:5]1)[C@@:21]1([CH3:26])[CH:12]([C@:13]2([CH3:30])[CH:18]([CH2:19][CH2:20]1)[C:17]([CH3:28])([CH3:27])[C@@H:16]([OH:29])[CH2:15][CH2:14]2)[CH2:11][CH2:10]3)[CH3:3].C(Cl)(Cl)Cl.[CH3:38][OH:39]>>[CH3:3][CH:2]([C@H:4]1[C@@H:8]2[C@@H:9]3[C@@:22]([CH3:25])([CH2:23][CH2:24][C@@:7]2([C:31]([OH:33])=[O:32])[CH2:6][CH2:5]1)[C@@:21]1([CH3:26])[C@@H:12]([C@:13]2([CH3:30])[C@@H:18]([CH2:19][CH2:20]1)[C:17]([CH3:28])([CH3:27])[C@@H:16]([O:29][C:38]([CH2:6][C:7]([C:31]([OH:33])=[O:32])([CH3:24])[CH3:8])=[O:39])[CH2:15][CH2:14]2)[CH2:11][CH2:10]3)[CH3:1]
Reactant: CC(C)[C@@H]1CC[C@]2(C(=O)O)CC[C@]3(C)C(CCC4[C@@]5(C)CC[C@H](O)C(C)(C)C5CC[C@]43C)C12
Reactant: CO
Solvent: ClC(Cl)Cl
Product: CC(C)[C@@H]1CC[C@]2(C(=O)O)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC[C@H](OC(=O)CC(C)(C)C(=O)O)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Yield: 24.5 %

Procedure:
yield 24.5% (starting with 155.9 mg of dihydrobetulinic acid); crystallization from MeOH-H2O gave colorless needles; mp 291°-292° C.; [α]D20−13.4° (c=1.1, CHCl3-MeOH [1:1], 1H NMR (pyridine-d5): 0.85, 0.94 (each 3H, d, J=7.0 Hz; 20-(CH3)2), 0.75, 0.93, 0.97, 1.01, 1.03 (each 3H, s; 4-(CH3)2, 8-CH3, 10-CH3, 14-CH3), 1.55 (6H, s; 3′-CH3×2), 2.89, 2.97 (each 1H, d, J=15.5 Hz; H-2′), 4.77 (1H, dd, J=5.0, 11.0 Hz, H-3); Anal. Calcd for C36H58O6.5/2H2O: C, 68.43; H, 10.04. found C, 68.64; H, 9.78.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][N:3]=1.[NH2:10][C:11]1[CH:12]=[CH:13][C:14]([Cl:18])=[C:15]([OH:17])[CH:16]=1>CCO>[Cl:18][C:14]1[CH:13]=[CH:12][C:11]([NH:10][C:2]2[N:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][N:3]=2)=[CH:16][C:15]=1[OH:17]
Reactant: COc1ccnc(Cl)n1
Reactant: Nc1ccc(Cl)c(O)c1
Solvent: CCO
Product: COc1ccnc(Nc2ccc(Cl)c(O)c2)n1
Temperature: 90 °C
Yield: 57 %

Procedure:
Following the general procedure for the synthesis of 2-R-5-(heteroaryl-2-ylamino)phenol, 2-chloro-4-methoxypyrimidine (87 mg, 0.60 mmol) and 5-amino-2-chlorophenol (86 mg, 0.60 mmol) in 10% aqueous EtOH (3 mL) was heated at 90° C. for 18 h. The title compound was obtained in 57% yield a (87 mg) and used for the next step without additional purification.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[CH:3]=1.[Mg].[C:11]([N:18]1[CH2:22][CH2:21][C:20](=[O:23])[CH2:19]1)([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12]>O1CCCC1>[Cl:9][C:4]1[CH:3]=[C:2]([C:20]2([OH:23])[CH2:21][CH2:22][N:18]([C:11]([O:13][C:14]([CH3:16])([CH3:15])[CH3:17])=[O:12])[CH2:19]2)[CH:7]=[C:6]([Cl:8])[CH:5]=1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)C1
Reactant: Clc1cc(Cl)cc(Br)c1
Agent: [Mg]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(O)(c2cc(Cl)cc(Cl)c2)C1

Procedure:
Preparation according to Preparation 5: 1-bromo-3,5-dichlorobenzene (5.0 g, 22.1 mmol), dry tetrahydrofuran (100 mL), magnesium turnings (0.54 g, 24.3 mmol) and 1-N-boc-3-pyrrolidinone (3.25 g, 17.7 mmol). Yield: 2.1 g. MS m/z (rel. intensity, 70 eV) 332 (M+, 1), 232 (17), 231 (23), 230 (22), 57 (bp).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[CH2:6][NH2:7].C(N1[C:22](=[O:23])[C:21]2=[CH:24][CH:25]=[CH:26][CH:27]=[C:20]2[C:19]1=[O:28])(OCC)=O>O1CCCC1.C(N(CC)CC)C>[C:19]1(=[O:28])[N:7]([CH2:6][C:5]2[CH:8]=[CH:9][C:10]([O:11][CH3:12])=[C:3]([O:2][CH3:1])[CH:4]=2)[C:22](=[O:23])[C:21]2=[CH:24][CH:25]=[CH:26][CH:27]=[C:20]12
Reactant: CCOC(=O)N1C(=O)c2ccccc2C1=O
Reactant: COc1ccc(CN)cc1OC
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1ccc(CN2C(=O)c3ccccc3C2=O)cc1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 59.9 %

Procedure:
To a stirred solution of 3,4-dimethoxybenzylamine (0.836 grams, 5.00 mmol) and N-carbethoxyphthalimide (1.10 grams, 5.00 mmol) in 20 milliliters of tetrahydrofuran was added 1 drop of triethylamine and the mixture stirred overnight. After 24 hours at room temperature, the mixture was refluxed for 16 hours, then allowed to cool to room temperature without stirring. Crystals formed on cooling. The mixture was filtered, the solid dried in vacuo to afford 0.89 grams (60%) of 1-phthalimido-1-(3′,4′-dimethoxyphenyl)methane as small white needles: mp 160-161° C.; 1H NMR (CDCl3/TMS) δ7.8 (m, 2 H), 7.7 (m, 2 H), 7.03 (m, 2 H), 6.8 (m, 1 H), 4.78 (s, 2 H), 3.88 (s, 3 H, OCH3), 3.84 (s, 3 H, OCH3); 13C NMR (CDCl3/TMS) δ168.0, 148.9, 148.7, 133.9, 132.1, 129.0, 123.3, 121.3, 112.1, 111.1, 55.9, 41.4. Anal. Calcd for C17H15NO4. Theory C, 68.68; H, 5.09; N, 4.71. Found C, 68.49; H, 4.99; N, 4.67.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[N+:9]([O-])=O.C([O-])=O.[NH4+]>CO.O.[Zn]>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[NH2:9]
Reactant: O=[N+]([O-])c1cc(Cl)ccc1Br
Agent: O=C[O-]
Agent: [NH4+]
Agent: [Zn]
Solvent: O
Solvent: CO
Product: Nc1cc(Cl)ccc1Br
Temperature: 50 °C
Yield: 75.6 %

Procedure:
1-Bromo-4-chloro-2-nitrobenzene (140 g, 0.59 mol) was dissolved in 2.5 L of MeOH with gentle heating (50° C.) in a hot water bath. A solution of ammonium formate (303 g, 4.81 mol) in 500 mL of water was added. Zinc powder (155 g, 2.36 mol) was added in small portions, resulting in heat evolution and refluxing of the solvent. Subsequent additions were made cautiously as to avoid build up of excess unreacted zinc. The reaction was cooled to room temperature and filtered through a large plug of CELITE® filter aid. The filtrate was then concentrated until a biphasic mixture of red oil and water was evident. The product was extracted with five 200 mL portions of diethyl ether. The organics were combined and dried over sodium sulfate, decanted, and concentrated in vacuo to a reddish-brown oil. The oil was redissolved in 150 mL of dichloromethane/hexanes and filtered through a plug of silica gel. The filtrate was concentrated to an orange oil. Addition of hexanes (200 mL) and cooling in a dry ice bath resulted in precipitation of 2-bromo-5-chloroaniline as a pale yellow solid (92.1 g, 75%) that was collected via vacuum filtration.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][C:16]=2[C:24]([F:27])([F:26])[F:25])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Br:28][C:29]1[CH:30]=[C:31]([C:35]2[CH:40]=[CH:39][N:38]=[C:37]([NH:41][C:42]3[CH:43]=[C:44]([CH:46]=[CH:47][C:48]=3[CH3:49])[NH2:45])[N:36]=2)[CH:32]=[N:33][CH:34]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:23]=[CH:22][C:18]([C:19]([NH:45][C:44]3[CH:46]=[CH:47][C:48]([CH3:49])=[C:42]([NH:41][C:37]4[N:36]=[C:35]([C:31]5[CH:32]=[N:33][CH:34]=[C:29]([Br:28])[CH:30]=5)[CH:40]=[CH:39][N:38]=4)[CH:43]=3)=[O:21])=[CH:17][C:16]=2[C:24]([F:26])([F:25])[F:27])[CH2:10][CH2:9]1)=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2ccc(C(=O)O)cc2C(F)(F)F)CC1
Reactant: Cc1ccc(N)cc1Nc1nccc(-c2cncc(Br)c2)n1
Product: Cc1ccc(NC(=O)c2ccc(CN3CCN(C(=O)OC(C)(C)C)CC3)c(C(F)(F)F)c2)cc1Nc1nccc(-c2cncc(Br)c2)n1

Procedure:
This compound was prepared in the same manner as in Example 34, except that 4-[4-(t-butoxycarbonyl)piperazin-1-ylmethyl]-3-trifluoromethylbenzoic acid (Reference Example 13) and 3-[4-(5-bromopyridin-3-yl)pyrimidin-2-ylamino]-4-methylaniline (Reference Example 19) were used.
Reaction SMILES: [CH3:1][C:2]1[C:6]2[C:7](=[O:19])[N:8]([CH2:11][CH2:12][N:13]3[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]3)[CH2:9][CH2:10][C:5]=2[NH:4][C:3]=1[CH:20]=O.[F:22][C:23]1[C:28]([F:29])=[CH:27][CH:26]=[CH:25][C:24]=1[C:30]1[CH:38]=[CH:37][CH:36]=[C:35]2[C:31]=1[CH2:32][C:33](=[O:39])[NH:34]2>>[F:22][C:23]1[C:28]([F:29])=[CH:27][CH:26]=[CH:25][C:24]=1[C:30]1[CH:38]=[CH:37][CH:36]=[C:35]2[C:31]=1[C:32](=[CH:20][C:3]1[NH:4][C:5]3[CH2:10][CH2:9][N:8]([CH2:11][CH2:12][N:13]4[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]4)[C:7](=[O:19])[C:6]=3[C:2]=1[CH3:1])[C:33](=[O:39])[NH:34]2
Reactant: Cc1c(C=O)[nH]c2c1C(=O)N(CCN1CCCCC1)CC2
Reactant: O=C1Cc2c(cccc2-c2cccc(F)c2F)N1
Product: Cc1c(C=C2C(=O)Nc3cccc(-c4cccc(F)c4F)c32)[nH]c2c1C(=O)N(CCN1CCCCC1)CC2
Yield: 70.7 %

Procedure:
The title compound was prepared under the same conditions as described in Example 25 with 3-methyl-4-oxo-5-(2-piperidin-1-yl-ethyl)-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine-2-carbaldehyde and 4-(2,3-difluoro-phenyl)-1,3-dihydro-indol-2-one (prepared according to WO2002055517) as starting materials to give 2-[4-(2,3-difluoro-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-3-methyl-5-(2-piperidin-1-yl-ethyl)-1,5,6,7-tetrahydro-pyrrolo[3,2-c]pyridin-4-one (70 mg, 70.7%) as an orange solid.
Reaction SMILES: [CH2:1]([OH:7])[CH2:2][CH2:3][CH2:4][CH:5]=[CH2:6].[H-].[Na+].Cl[C:11]1[N:16]=[C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:14]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:13][N:12]=1>O1CCOCC1.CC(OC)(C)C>[CH2:1]([O:7][C:11]1[N:16]=[C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:14]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)=[CH:13][N:12]=1)[CH2:2][CH2:3][CH2:4][CH:5]=[CH2:6]
Reactant: Clc1ncc(-c2ccccc2)c(-c2ccccc2)n1
Reactant: C=CCCCCO
Agent: [H-]
Agent: [Na+]
Solvent: COC(C)(C)C
Solvent: C1COCCO1
Product: C=CCCCCOc1ncc(-c2ccccc2)c(-c2ccccc2)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 77.9 %

Procedure:
1.50 g (15 mmol) of 5-hexen-1-ol dissolved in 30 ml of dioxane were mixed with 600 mg (60%, 15 mmol) of sodium hydride and stirred at room temperature for 30 minutes. Addition of 1.7 g (7.5 mmol) of 2-chloro-4,5-diphenylpyrimidine was followed by stirring at room temperature for 6 hours. Taking up in MTBE and washing with saturated NaCl solution were followed by drying over sodium sulfate and evaporation. The residue was purified on silica gel with heptane/ethyl acetate (15:1). 1.93 g (77%) of the desired product were obtained.