Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([O:13][C:14]2[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][CH:15]=2)=[CH:5][CH:4]=1)=O.[CH3:22][CH:23]([CH3:27])[CH2:24][CH2:25][NH2:26]>>[CH3:22][CH:23]([CH3:27])[CH2:24][CH2:25][NH:26][CH2:1][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([O:13][C:14]2[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][CH:15]=2)=[CH:5][CH:4]=1
Reactant: N#Cc1ccc(Oc2ccc(C=O)c3ccccc23)cc1
Reactant: CC(C)CCN
Product: CC(C)CCNCc1ccc(Oc2ccc(C#N)cc2)c2ccccc12

Procedure:
Using the procedure outlined in Example 1, 4-(4-formylnaphthalen-1-yloxy)benzonitrile (Preparation 28) and 3-methylbutylamine were converted to the title compound: RT=2.88 min; m/z (ES+)=345.3 [M+H]+.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[C:7]([O:30][C@@H:31]([C@@H:33]3[CH2:37][C:36](=[O:38])[NH:35][CH2:34]3)[CH3:32])=[N:8][C:9]([C:11]3[CH:12]=[CH:13][C:14]([N:17]4[CH2:22][CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19][CH2:18]4)=[N:15][CH:16]=3)=[CH:10][C:5]=2[N:4]=[CH:3]1>C(O)(C(F)(F)F)=O>[CH3:1][N:2]1[C:6]2[C:7]([O:30][C@@H:31]([C@H:33]3[CH2:34][NH:35][C:36](=[O:38])[CH2:37]3)[CH3:32])=[N:8][C:9]([C:11]3[CH:16]=[N:15][C:14]([N:17]4[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]4)=[CH:13][CH:12]=3)=[CH:10][C:5]=2[N:4]=[CH:3]1
Reactant: C[C@@H](Oc1nc(-c2ccc(N3CCN(C(=O)OC(C)(C)C)CC3)nc2)cc2ncn(C)c12)[C@H]1CNC(=O)C1
Solvent: O=C(O)C(F)(F)F
Product: C[C@@H](Oc1nc(-c2ccc(N3CCNCC3)nc2)cc2ncn(C)c12)[C@H]1CNC(=O)C1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 79.1 %

Procedure:
Tert-butyl 4-(5-(3-methyl-4-((R)-1-((R)-5-oxopyrrolidin-3-yl)ethoxy)-3H-imidazo[4,5-c]pyridin-6-yl)pyridin-2-yl)piperazine-1-carboxylate (76%, 265 mg, 0.39 mmol)) was dissolved in TFA (4.4 mL) and stirred at room temperature for 15 mins. The reaction was cooled to OC, neutralized to a pH of 7 using satd. sodium bicarbonate, extracted with 30 mL of dichloromethane to remove impurities and then 25% methanol/dichloromethane (300 mL), dried, filtered, concentrated to provide the (R)-4-((R)-1-((3-methyl-6-(6-(piperazin-1-yl)pyridin-3-yl)-3H-imidazo[4,5-c]pyridin-4-yl)oxy)ethyl)pyrrolidin-2-one (130 mg, 80% for two steps).
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[O:6][C:5](=[O:7])/[C:4](=[CH:8]/[C:9](Cl)=[O:10])/[O:3]1.[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([NH:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=2)=[CH:16][CH:15]=1.N1C=CC=CC=1>ClCCl>[Cl:13][C:14]1[CH:15]=[CH:16][C:17]([N:20]([CH2:21][C:22]2[CH:23]=[CH:24][C:25]([CH3:28])=[CH:26][CH:27]=2)[C:9](=[O:10])[CH:8]=[C:4]2[C:5](=[O:7])[O:6][C:2]([CH3:12])([CH3:1])[O:3]2)=[CH:18][CH:19]=1
Reactant: CC1(C)OC(=O)/C(=C/C(=O)Cl)O1
Reactant: Cc1ccc(CNc2ccc(Cl)cc2)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(CN(C(=O)C=C2OC(C)(C)OC2=O)c2ccc(Cl)cc2)cc1
Temperature: 22 °C
Reaction time: 0.5 h
Yield: 87.6 %

Procedure:
A solution of (Z)-2,2-dimethyl-5-(chlorocarbonylmethylene)-1,3-dioxolan-4-one (0.553 g, 2.90 mmol) in dry dichloromethane (5 ml) was added dropwise to a cold (0-5° C.) solution of (4-chlorophenyl)-(4-methylbenzyl)-amine (0.545 g, 2.35 mmol) (Ballistreri et al., J. Org. Chem., 41, 1976, 3364), pyridine (0.35 ml) and a small crystal of 4-N,N-dimethylaminopyridine in dry dichloromethane (10 ml). After 30 min, the cooling bath was removed and the resulting clear solution was stirred at 22° C. for another 30 min. The reaction mixture was then diluted wih ethyl acetate, washed with saturated sodium bicarbonate, brine and dried (magnesium sulfate). Evaporation of the solvent in vacuo, filtration of the residue on a short silica gel pad (elution-toluene ethyl acetate; 85:15) followed by crystallization from ethyl acetate-hexane gave 0.794 g (87%) of the title amide as white needles: mp 149° C. 1HNMR 400 MHz (CDCl3) δ (ppm): 1.72 (6H, s, CH3), 2.31 (3H, s, CH3), 4.88 (2H, s, NCH2), 5.64 (1H, s, CH), 6.93 (2H, d, J=8.5 Hz, aromatics), 7.08 (4H, m, aromatics), 7.3 (2H, d, J=8.5 Hz, aromatics). Anal. Calcd for C21H20ClNO4: C, 65.37; H, 5.22; N, 3.63. Found: C, 65.22; H, 5.25; N, 3.52.
Reaction SMILES: Br[C:2]1[CH:13]=[CH:12][C:5]2[CH2:6][C:7](=O)[NH:8][CH2:9][CH2:10][C:4]=2[CH:3]=1.[Br:14]C1C=CC2CNC(=O)CCC=2C=1>O1CCCC1>[Br:14][C:12]1[CH:5]=[CH:6][C:7]2[NH:8][CH2:9][CH2:10][CH2:4][CH2:3][C:2]=2[CH:13]=1
Reactant: O=C1Cc2ccc(Br)cc2CCN1
Reactant: O=C1CCc2cc(Br)ccc2CN1
Solvent: C1CCOC1
Product: Brc1ccc2c(c1)CCCCN2
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a 1000-mL round-bottom flask was added the mixture of 7-bromo-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one and 7-bromo-1,2,4,5-tetrahydro-3H-2-benzazepin-3-one (12.6 g, 52 4 mmol) and tetrahydrofuran (260 mL). The solution was cooled to 0° C. and borane-methylsulfide complex (12.4 mL, 210 mmol) was slowly added. The reaction mixture was stirred at 0° C. for 10 min, warmed to room temperature and stirred for 3 h, then heated at reflux for 4 h. Upon cooling to room temperature, the mixture was quenched with MeOH (50 mL) to remove excess borane. The solvent was then evaporated to give 7-bromo-2,3,4,5-tetrahydro-1H-benzoazepine and 7-bromo-2,3,4,5-tetrahydro-1H-benzoazepine as sticky oil. LCMS: (FA) ES+226 and 228.
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:14]([OH:16])=O)[CH2:10][CH2:11][S:12][CH3:13])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C[C@@H](O)[C@@H]1NC(=O)[C@H](CCN)NC(=O)[C@H](CCN)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](CC2C=CC=CC=2)NC(=O)[C@H](CCN)NC(=O)[C@@H](NC([C@@H](N)CCN)=O)CCNC1=O.OS(O)(=O)=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.[CH3:116][C:117]([CH3:137])=[CH:118][CH2:119][CH2:120]/[C:121](/[CH3:136])=[CH:122]/[CH2:123][CH2:124]/[C:125](/[CH3:135])=[CH:126]/[CH2:127][S:128][CH2:129][C@H:130]([NH2:134])[C:131]([OH:133])=[O:132]>C(Cl)Cl>[CH3:7][C:4]([CH3:5])([O:3][C:1](=[O:2])[NH:8][C@@H:9]([CH2:10][CH2:11][S:12][CH3:13])[C:14](=[O:16])[NH:134][C@H:130]([C:131]([OH:133])=[O:132])[CH2:129][S:128][CH2:127]/[CH:126]=[C:125](\[CH3:135])/[CH2:124][CH2:123]/[CH:122]=[C:121](\[CH3:136])/[CH2:120][CH2:119][CH:118]=[C:117]([CH3:137])[CH3:116])[CH3:6]
Reactant: CSCC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: CC(C)=CCC/C(C)=C/CC/C(C)=C/CSC[C@H](N)C(=O)O
Agent: CC(C)C[C@@H]1NC(=O)[C@@H](Cc2ccccc2)NC(=O)[C@H](CCN)NC(=O)[C@@H](NC(=O)[C@@H](N)CCN)CCNC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CCN)NC(=O)[C@H](CCN)NC1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CSCC[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](CSC/C=C(\C)CC/C=C(\C)CCC=C(C)C)C(=O)O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
In a 100 mL round bottom flask, N-Boc-L-methionine (1.0 mmol), coupling reagent (520 mg of PBOP or 380 mg of HATU, 1 mmol) and N,N-diisopropyl-ethyl-amine (650 mg, 5 mmol) were mixed in CH2Cl2 (10 mL). The reaction mixture was stirred at room temperature for 30 minutes. S-trans, trans-Farnesyl-L-cysteine (325 mg, 1 mmol) was added to the reaction mixture. The reaction mixture was stirred at room temperature overnight. CH2Cl2 was removed by rotary evaporation. The resulting residue was dissolved in ethyl acetate (50 mL). The organic solution was washed with an NH4Cl saturated solution (50 mL), dried over Na2SO4, and concentrated to afford a crude mixture. The crude mixture was purified by preparative HPLC (290 mg, 52%) to yield Compound N-57. 1H-NMR (500 MHz, CDCl3): δ 1.47 (s, 9H), 1.62 (bs, 6H), 1.69 (s, 3H), 1.72 (s, 3H), 1.90-1.93 (m, 1H), 1.99 (t, J=7.5 Hz, 2H), 2.03-2.16 (m, 8H), 2.50-2.68 (m, 2H), 2.80 (dd, J=8, 14 Hz, 1H), 3.02 (dd, J=4.5, 14 Hz, 1H), 3.18 (dd, J=7, 13 Hz, 1H), 3.27 (dd, J=8, 13 Hz, 1H), 3.25 (dd, J=5, 8 Hz, 1H), 4.60 (dd, J=4.5, 8, 1H), 5.10-5.15 (m, 2H), 5.24 (t, J=7.5, 1H). 13C-NMR (125 MHz, CDCl3): δ 15.3, 16.2, 16.3, 17.8, 26.0, 27.4, 27.8, 28.8, 30.3, 31.0, 33.0, 33.4, 40.8, 40.9, 53.3, 55.1, 80.8, 121.6, 125.2, 125.5, 132.1, 136.3, 140.6, 157.8, 173.6, 174.6; ES-MS: mass calcd for Chemical Formula: C28H48N2O5S2 556.3. Found (M+Na) m/z 279.2.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])[CH2:4][C:5]1[N:6]=[CH:7][N:8]([C:10]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:9]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].C([C:42]([O:44][CH3:45])=[O:43])#N.[NH4+].[Cl-]>C1COCC1>[C:10]([N:8]1[CH:9]=[C:5]([CH:4]([C:42]([O:44][CH3:45])=[O:43])[C:3]([O:2][CH3:1])=[O:29])[N:6]=[CH:7]1)([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: COC(=O)Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reactant: COC(=O)C#N
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)C(C(=O)OC)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Temperature: 0 °C
Yield: 47.6 %

Procedure:
3.50 g (9.15 mmol) of the compound from example 12a were dissolved in 50 ml of dry THF and cooled to 0° C. 1.67 g (9.96 mmol) of lithium bis(trimethylsilyl)amide as 20% strength solution in THF were added dropwise to this solution while stirring. The resulting mixture was stirred at 0° C. for 30 min and then 0.86 g (10.07 mol) of methyl cyanoformate was added. The reaction mixture was warmed to RT and stirred for a further 2 h, then poured into 400 ml of saturated aqueous NH4Cl solution and extracted twice with EA. The combined organic phases were washed with water, dried over Na2SO4, filtered and concentrated. Chromatography of the residue on silica gel afforded 1.92 g of the title compound. Repeat chromatography of the resulting mixed fraction afforded a further 40 mg of the desired compound.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14](C(OCC)OCC)[C:13](=[O:25])[CH:12]2[C:26]1[C:35]2[C:30](=[CH:31][C:32]([O:38][CH2:39][CH2:40][CH2:41][N:42]3[CH2:47][CH2:46][O:45][CH2:44][CH2:43]3)=[C:33]([O:36][CH3:37])[CH:34]=2)[N:29]=[CH:28][N:27]=1)C1C=CC=CC=1.C(O)(C(F)(F)F)=O.Cl.[OH-].[Na+]>CO.O>[OH:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13](=[O:25])[CH:12]2[C:26]1[C:35]2[C:30](=[CH:31][C:32]([O:38][CH2:39][CH2:40][CH2:41][N:42]3[CH2:43][CH2:44][O:45][CH2:46][CH2:47]3)=[C:33]([O:36][CH3:37])[CH:34]=2)[N:29]=[CH:28][N:27]=1
Reactant: CCOC(OCC)N1C(=O)C(c2ncnc3cc(OCCCN4CCOCC4)c(OC)cc23)c2cc(OCc3ccccc3)ccc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: CO
Product: COc1cc2c(C3C(=O)Nc4ccc(O)cc43)ncnc2cc1OCCCN1CCOCC1

Procedure:
A mixture of 4-(5-benzyloxy-1-diethoxymethyloxindol-3-yl)-6-methoxy-7-(3-morpholinopropoxy)quinazoline (240 mg, 0.38 mmol) and TFA (8 ml) was heated at reflux for 30 minutes. The TFA was removed by evaporation, the residue was triturated with ether, the solid was collected by filtration, washed with ether and dried under vacuum. The orange solid thus obtained was dissolved in a 1M hydrochloric acid solution (5 ml, 5 mmol) and heated at reflux for 40 minutes. After cooling, the reaction mixture was adjusted to pH2.3 with 6M sodium hydroxide and subjected to column chromatography on reverse phase silica gel (C18 10μ) with a gradient of methanol in water (30 to 100%) as eluent The fractions containing the compound were combined, the solution was adjusted to pH1.5 with concentrated hydrochloric acid and the solvents removed by evaporation The residue was triturated with methanol/ether, the solid was collected by filtration, washed with ether and dried under vacuum at 40° C. to give 4-(5-hydroxyoxindol-3-yl)-6-methoxy-7-(3-morpholinopropoxy)quinazoline as a hydrochloride salt (90 mg, 45%) as an orange solid.
Reaction SMILES: S(Cl)(Cl)=O.[OH:5][C@@H:6]1[CH2:10][NH:9][C@@H:8]([C:11]([OH:13])=[O:12])[CH2:7]1.[CH3:14]O>>[CH3:14][O:12][C:11]([C@H:8]1[CH2:7][C@H:6]([OH:5])[CH2:10][NH:9]1)=[O:13]
Reactant: O=C(O)[C@H]1C[C@H](O)CN1
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)[C@H]1C[C@H](O)CN1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 99 %

Procedure:
Add thionyl chloride (5.8 mL, 79.4 mmol) to an ice-cold suspension of 4-(S)-hydroxypyrrolidine-2-(R)-carboxylic acid (4.97 g, 31.9 mmol) in methanol (70 mL). Stir 10 min, then warm to room temperature and stir 3.5 h. Concentrate, add methanol and concentrate again to give the title compound as a white solid (7.18 g, 99%).
Reaction SMILES: [C:1]([N:3]=[C:4](SC)[S:5][CH3:6])#[N:2].[NH2:9][CH2:10][CH2:11][N:12]1[CH2:17][CH2:16][CH:15]([NH:18][C:19]2[N:27]([CH2:28][C:29]3[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=3)[C:22]3=[N:23][CH:24]=[CH:25][CH:26]=[C:21]3[N:20]=2)[CH2:14][CH2:13]1>CO>[C:1]([N:3]=[C:4]([S:5][CH3:6])[NH:9][CH2:10][CH2:11][N:12]1[CH2:17][CH2:16][CH:15]([NH:18][C:19]2[N:27]([CH2:28][C:29]3[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=3)[C:22]3=[N:23][CH:24]=[CH:25][CH:26]=[C:21]3[N:20]=2)[CH2:14][CH2:13]1)#[N:2]
Reactant: CSC(=NC#N)SC
Reactant: NCCN1CCC(Nc2nc3cccnc3n2Cc2ccc(F)cc2)CC1
Solvent: CO
Product: CSC(=NC#N)NCCN1CCC(Nc2nc3cccnc3n2Cc2ccc(F)cc2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 74 %

Procedure:
A mixture of 1.9 parts of dimethyl cyanocarbonimidodithioate, 4.8 parts of N-[1-(2-aminoethyl)-4-piperidinyl]-3-[(4-fluorophenyl)-methyl]-3H-imidazo[4,5-b]pyridin-2-amine and 80 parts of methanol was stirred for 2 hours at room temperature. The reaction mixture was evaporated and the residue was crystallized from acetonitrile, yielding 4.5 parts (74%) of S-methyl N'-cyano-N-[2-[4-[[3-[(4-fluorophenyl)methyl]-3H-imidazo[4,5-b]pyridin-2-yl]amino]-1-piperidinyl]ethyl]carbamimidothioate; mp. 172.2° C. (compound 21).
Reaction SMILES: B.C1COCC1.[Br:7][CH2:8][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][C:23](O)=[O:24]>C1COCC1>[Br:7][CH2:8][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][OH:24]
Reactant: O=C(O)CCCCCCCCCCCCCCCBr
Agent: B
Solvent: C1CCOC1
Product: OCCCCCCCCCCCCCCCCBr
Temperature: 0 °C
Reaction time: 2 h
Yield: 93.2 %

Procedure:
Under inert atmosphere 10 ml of BH3·THF complex (1.0 M THF solution) were added to 30 ml THF solution of 2.15 gr (6.41.mmole) of 16-bromohexadecanoic acid at −20° C. Reaction mixture was stirred at this temperature for 2 hrs and then additional 1 hr at RT. After that time the resulted mixture was poured, with stirring, into a vessel containing 200 ml of ice/saturated sodium bicarbonate aqueous solution. Organic compounds were extracted with 3×200 ml of ether. The ether fractions were combined and dried over sodium sulfate. After removal of ether material was dissolved in minimum amount of dicloromethane and purified by silica gel chromatography (100% dicloromethane as eluent). 1.92 gr (93% yield) of the desired product were obtained.
Reaction SMILES: C[O:2][C:3]([C@H:5]1[CH2:14][C@H:13]([CH2:15][C:16]([O:18]C)=[O:17])[C:12]2[C:7](=[CH:8][C:9]([Cl:21])=[CH:10][C:11]=2[Cl:20])[NH:6]1)=[O:4].[OH-].[Na+]>CO>[C:3]([C@H:5]1[CH2:14][C@H:13]([CH2:15][C:16]([OH:18])=[O:17])[C:12]2[C:7](=[CH:8][C:9]([Cl:21])=[CH:10][C:11]=2[Cl:20])[NH:6]1)([OH:4])=[O:2]
Reactant: COC(=O)C[C@H]1C[C@H](C(=O)OC)Nc2cc(Cl)cc(Cl)c21
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)C[C@H]1C[C@H](C(=O)O)Nc2cc(Cl)cc(Cl)c21
Temperature: 70 °C
Yield: 65.8 %

Procedure:
Trans-2-methoxycarbonyl-4-methoxycarbonylmethyl-5,7-dichloro-1,2,3,4-tetrahydroquinoline (Example 156a) (0.4 g, 0.0012 mol) was dissolved in 50% aqueous methanol (80 ml) with sodium hydroxide (1 g). The reaction mixture was heated at 70° C. for 14 h and the solvents removed under vacuum. The residue was dissolved in water (50 ml), acidified to pH 1 with 1 normal hydrochloric acid and extracted into ethyl acetate (2×50 ml). The combined organic layers were dried (Na2SO4), filtered and concentrated in vacuo to give a residue which was purified by recrystallisation from diethyl ether/hexane to give the title compound as a colourless solid (0.24 g, m.p. 229°-231° C.); δ (250 MHz, DMSO) 1.63 (1H, ddd, J=13.3, 12.4 and 4.0 Hz, CHACHBHCCHD), 2.20 (1H, dm, J=13.3 Hz, CHACHBHCCHD), 2.40 (2H, m, CHEHFCO2H), 3.39 (1H, m, CHACHBHCCHDCHEHFCO2H), 3.98 (1H, dd, J=12.4 and 3.3 Hz, CHACHBHCCHD), 6.57 (1H, br, s, NH), 6.61 (1H, d, J=2.0 Hz, 6-H or 8-H), 6.80 (1H, d, J=2.0 Hz, 6-H or 8-H); m/e (FAB) 304 (M+1); Found C, 47.56; H, 3.70; N, 4.57 C12H11Cl2NO4 requires C, 47.39; H, 3.65; N, 4.61%.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:28]=[CH:27][C:11]3[N:12]([C:21]4C=CC=CC=4)[C:13]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)=[N:14][C:10]=3[CH:9]=2)=[CH:4][CH:3]=1.[C:29]1([C:35]2[C:36]3[C:41]([C:42]([C:52]4[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=4)=[C:43]4[C:48]=2[CH:47]=[C:46](B(O)O)[CH:45]=[CH:44]4)=[CH:40][CH:39]=[CH:38][CH:37]=3)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O1CCOCC1>C1(C)C=CC=CC=1.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(P(C2CCCCC2)C2CCCCC2)CCCCC1.C1(C)C=CC=CC=1>[C:29]1([C:35]2[C:36]3[C:41]([C:42]([C:52]4[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=4)=[C:43]4[C:48]=2[CH:47]=[C:46]([C:2]2[CH:3]=[CH:4][C:5]([C:8]5[CH:28]=[CH:27][C:11]6[N:12]([CH3:21])[C:13]([C:15]7[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=7)=[N:14][C:10]=6[CH:9]=5)=[CH:6][CH:7]=2)[CH:45]=[CH:44]4)=[CH:40][CH:39]=[CH:38][CH:37]=3)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: OB(O)c1ccc2c(-c3ccccc3)c3ccccc3c(-c3ccccc3)c2c1
Reactant: Clc1ccc(-c2ccc3c(c2)nc(-c2ccccc2)n3-c2ccccc2)cc1
Agent: [Pd]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Solvent: O
Solvent: C1COCCO1
Product: Cn1c(-c2ccccc2)nc2cc(-c3ccc(-c4ccc5c(-c6ccccc6)c6ccccc6c(-c6ccccc6)c5c4)cc3)ccc21
Temperature: 80 °C
Reaction time: 10 h
Yield: 87 %

Procedure:
1.9 g (6.0 mmol) of 5-(4-chlorophenyl)-1,2-diphenyl-1H-benzimidazole, 2.5 g (6.6 mmol) of 9,10-diphenylanthracene-2-boronic acid, tris(dibenzylideneacetone)dipalladium (0) (0.14 g, 0.15 mmol), and cesium carbonate (4.7 g, 14 mmol) were suspended into 20 mL of anhydrous dioxane, a solution of tricyclohexylphosphine/toluene (25 mass %, 0.49 ml, 0.43 mmol) was added, and the whole was stirred at 80° C. for 10 hours. The reaction mixture was diluted with 200 mL of toluene and 100 mL of water, and was filtered through Celite 545 for removing Pd black. An organic layer was fractionated from the filtrate, washed with 50 mL of a saturated sodium chloride solution, and dried with anhydrous magnesium sulfate, and the solvent was distilled off, with the result that red oil was obtained. The oil was purified by means of silica gel column chromatography to obtain 3.2 g of a greenish white solid (87% yield). Mass spectral analysis confirmed that the solid was a target product. The solid had an m/e of 612 with respect to a molecular weight of 612.26.
Reaction SMILES: [CH3:1][C:2](=[CH2:8])[CH2:3][NH:4][C:5]([NH2:7])=[O:6].[C:9]([CH2:11][C:12](O)=[O:13])#[N:10]>C(OC(=O)C)(=O)C.CCOCC>[NH2:10][C:9]1[N:4]([CH2:3][C:2]([CH3:1])=[CH2:8])[C:5](=[O:6])[NH:7][C:12](=[O:13])[CH:11]=1
Reactant: C=C(C)CNC(N)=O
Reactant: N#CCC(=O)O
Solvent: CC(=O)OC(C)=O
Solvent: CCOCC
Product: C=C(C)Cn1c(N)cc(=O)[nH]c1=O
Temperature: 70 °C

Procedure:
Methallylamine (211 g, 2.97 mol) is added to a solution of concentrated hydrochloric acid (250 ml) in water (1.9 l), followed by portionwise addition of potassium cyanate (240 g, 2.97 mol). The reaction is then heated for 2 hours at 80° C., prior to cooling and evaporation to afford (2-methyl-allyl)-urea (2445 g), mp 114-115° C. The urea (268 g, 2.35 mol) is added to a solution of cyanoacetic acid (220 g, 2.59 mol) in acetic anhydride, (536 ml) and the reaction is heated at 70° C. for 1 hour, cooled to 0° C. and diluted with ether. The resultant solid is collected by filtration, washed with ether, suspended in water (2.2 l) and heated to 75° C. 2M aqueous sodium hydroxide solution is then added portionwise over 30 min to maintain pH between 8 and 9.5. The reaction is cooled to room temperature, treated with acetic acid (12 ml), further cooled to 10° C. and the resultant solid is collected by filtration, washed with cold water and dried to afford 6-amino-1-(2-methyl-allyl)-1H-pyrimidine-2,4-dione, mp 267-269° C. The uracil (253 g, 1.40 mol) is added to a solution of sodium hydroxide (123 g, 3.07 mol) in water (2.5 l) and allowed to exotherm then cooled to 20° C. Dimethyl sulfate (196 ml, 2.06 mol) is added portionwise over 1 hour. After standing overnight, the reaction is cooled to 5° C. and the solid collected by filtration to give 6-amino-3-methyl-1-(2-methyl-allyl)-1H-pyrimidine-2,4dione, mp 162-163° C. The methyluracil (165 g, 0.85 mol) is suspended in water (1.55 l) and concentrated hydrochloric acid (72 ml). A solution of sodium nitrite (58.4 g, 0.85 mol) in water (117 ml) is then added dropwise over 30 minutes and the reaction is stirred at 20° C. for 3 hours. The solid is collected by filtration, washed successively with water, methanol and ether to afford 6-amino-3-methyl-1-(2-methyl-allyl)-5-nitroso-1H-pyrimidine-2,4dione, mp 213° C. (dec). The nitrosouracil (190 g, 0.85 mol) is suspended in water (950 ml), heated to 85° C. and sodium dithionite (85%, 347.2 g, 1.69 mol) is added portionwise. After cooling to room temperature, the solid is collected by filtration to afford 5,6-diamino-3-methyl-1-(2-methyl-allyl)-1H-pyrimidine2,4-dione, mp 152-153° C.
Reaction SMILES: [Si]([O:8][CH2:9][C@H:10]1[C@H:14]([O:15][CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][O:17]2)[CH2:13][C@@H:12]([Cl:22])[C@@H:11]1[CH2:23]/[CH:24]=[CH:25]\[CH2:26][CH2:27][CH2:28][C:29]([O:31][CH2:32][CH:33]=[CH2:34])=[O:30])(C(C)(C)C)(C)C>CCCC[N+](CCCC)(CCCC)CCCC.[F-].C1COCC1>[Cl:22][C@H:12]1[C@H:11]([CH2:23]/[CH:24]=[CH:25]\[CH2:26][CH2:27][CH2:28][C:29]([O:31][CH2:32][CH:33]=[CH2:34])=[O:30])[C@@H:10]([CH2:9][OH:8])[C@H:14]([O:15][CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][O:17]2)[CH2:13]1
Reactant: C=CCOC(=O)CCC/C=C\C[C@@H]1[C@@H](CO[Si](C)(C)C(C)(C)C)[C@H](OC2CCCCO2)C[C@H]1Cl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: C=CCOC(=O)CCC/C=C\C[C@@H]1[C@@H](CO)[C@H](OC2CCCCO2)C[C@H]1Cl
Yield: 105.1 %

Procedure:
A solution of 1.46 g (2.8 mmol) of silyl ether 3 in 10 mL of 1.0M TBAF/THF was stirred at 25° C. for 3 h. The THF solvent was then removed in vacuo and the residual oil was taken up in ethyl acetate (100 mL) and washed with 2×75 mL of saturated aqueous ammonium chloride, brine, and dried over anhydrous sodium sulfate (50 g). The mixture was then filtered and the filtrate was concentrated in vacuo to yield 1.18 g (quantitative yield) of alcohol 4 used in the next step without purification; 1H NMR (CDCl3): 1.42-1.98 (m, 12H), 2.0-2.48 (m, 8H), 3.45-4.44 (m, 6H), 4.54-4.76 (m, 3H), 5.20-5.55 (m, 4H), 5.91 (m, 1H).
Reaction SMILES: C(OC([N:8](C(OC(C)(C)C)=O)[C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([C:18]3[CH:19]=[N:20][N:21]([CH2:23][C:24]#[N:25])[CH:22]=3)[CH:16]=2)[N:11](C(OC(C)(C)C)=O)[N:10]=1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[NH2:8][C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([C:18]3[CH:19]=[N:20][N:21]([CH2:23][C:24]#[N:25])[CH:22]=3)[CH:16]=2)[NH:11][N:10]=1
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1nn(C(=O)OC(C)(C)C)c2ccc(-c3cnn(CC#N)c3)cc12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#CCn1cc(-c2ccc3[nH]nc(N)c3c2)cn1
Reaction time: 0.75 h

Procedure:
To a solution of tert-butyl 3-(bis(tert-butoxycarbonyl)amino)-5-(1-(cyanomethyl)-1H-pyrazol-4-yl)-1H-indazole-1-carboxylate (0.30 g, 0.557 mmol) in dichloromethane (4.0 mL) was added trifluoroacetic acid (2.0 mL). After about 45 minutes, the reaction was slowly quenched with saturated aqueous sodium bicarbonate. The resulting mixture was extracted with dichloromethane (3×25 mL). The combined organic layers were washed with brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure to give a crude solid. A white precipitate that was suspended in both the initial aqueous layer and the brine layer was filtered and added to the crude solid. The resulting solid was triturated with dichloromethane/methanol (19:1). The remaining solid was collected by vacuum filtration and dried in a vacuum oven at about 70° C. to afford the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.37 (s, 1H), 8.12 (s, 1H), 7.92 (s, 1H), 7.89 (s, 1H) 7.49-7.41 (m, 1H), 7.24 (d, J=8.71 Hz, 1H), 5.52 (s, 2H), 5.31 (s, 2H). MS (ESI+) m/z 239.1 (M+H)+.