Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:7]([O:8][C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)=[CH:6][N:5]=[C:4]([N:16]=CN(C(C)C)C(C)C)[N:3]=1.Cl.[NH2:26][C@H:27]1[CH2:32][CH2:31][C@H:30]([OH:33])[CH2:29][CH2:28]1.C(N(CC)CC)C.N1C=CC=NC=1.Cl>C(O)C>[NH2:16][C:4]1[N:3]=[C:2]([NH:26][C@H:27]2[CH2:32][CH2:31][C@H:30]([OH:33])[CH2:29][CH2:28]2)[C:7]([O:8][C:9]2[CH:10]=[CH:11][C:12]([Cl:15])=[CH:13][CH:14]=2)=[CH:6][N:5]=1
Reactant: N[C@H]1CC[C@H](O)CC1
Reactant: CC(C)N(C=Nc1ncc(Oc2ccc(Cl)cc2)c(Cl)n1)C(C)C
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Solvent: c1cncnc1
Product: Nc1ncc(Oc2ccc(Cl)cc2)c(N[C@H]2CC[C@H](O)CC2)n1
Reaction time: 56 h

Procedure:
4-Chloro-5-(4-chlorophenoxy)-2-(diisopropylaminomethyleneamino)pyrimidine (3.68 g, 0.01 mole) and trans-4-aminocyclohexanol hydrochloride (5.31 g, 0.035 mole) were combined in absolute ethanol (25 mL). Triethylamine (7.08 g, 0.07 mole) was added, and the mixture was refluxed with stirring for 56 hours when thin layer chromatography confirmed the absence of the starting pyrimidine. The mixture was cooled slightly, concentrated hydrochloric acid (5 mL) was added and reflux was resumed for an additional 2 hours. The mixture was spin evaporated in vacuo. The oily residue was dissolved in water (200 mL) and extracted with dichloromethane (2×200 mL). The aqueous phase was basified with 2 M sodium hydroxide to pH 9, and the gummy residue that precipitated was dissolved in dichloromethane (100 mL). The aqueous phase was back washed with dichloromethane (100 mL), and the combined organic extracts were washed with brine (200 mL), dried over sodium sulfate, filtered and spin evaporated in vacuo to a foam. This material was dissolved in ethyl acetate and chromatographed on Silica Gel 60 (E. M. Science, 230-440 mesh) (8 g; 2×7 cm column bed) using ethyl acetate as eluent. The first 100 mL of eluent was collected and spin evaporated in vacuo to give 2.30 g (69% yield) of 2-amino-5-(4-chlorophenoxy)-4-(trans-4-hydroxycyclohexylamino)pyrimidine as a white powder, mp 154-155° C.
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]2[C:6]3[C:7]([CH3:15])([CH3:14])[CH2:8][CH2:9][NH:10][C:11]=3[CH2:12][CH2:13][C:4]=2[CH:3]=1.C(N(CC)CC)C.[C:25](Br)(=[O:27])[CH3:26]>C(Cl)Cl>[C:25]([N:10]1[C:11]2[CH2:12][CH2:13][C:4]3[CH:3]=[C:2]([Cl:1])[CH:17]=[CH:16][C:5]=3[C:6]=2[C:7]([CH3:14])([CH3:15])[CH2:8][CH2:9]1)(=[O:27])[CH3:26]
Reactant: CC1(C)CCNC2=C1c1ccc(Cl)cc1CC2
Reactant: CC(=O)Br
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)N1CCC(C)(C)C2=C1CCc1cc(Cl)ccc12
Reaction time: 1 h

Procedure:
10.6 g (0.043 mol) of 8-chloro-1,1-dimethyl-1,2,3,4,5,6-hexahydrobenzo[f]quinoline and 6.6 ml (0.047 mol) of triethylamine are dissolved in 100 ml of methylene chloride and 3.5 ml (0.047 mol) of acetyl bromide dissolved in 20 ml of methylene chloride are added dropwise thereto at 0°. After stirring for 1 hour, the mixture is extracted with methylene chloride/water, dried with magnesium sulfate and the solvent is distilled in a vacuum. Recrystallization from methylene chloride/hexane gives 4-acetyl-8-chloro-1,1-dimethyl-1,2,3,4,5,6-hexahydrobenzo[f]quinoline as white crystals with melting point 126°-127°.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[C:9]([C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14]([N:21]2[CH:25]=[CH:24][N:23]=[C:22]2[S:26][CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:13][CH:12]=1)#[N:10]>ClCCl>[Br:1][C:25]1[N:21]([C:14]2[C:15]3[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:11]([C:9]#[N:10])=[CH:12][CH:13]=2)[C:22]([S:26][CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])=[N:23][CH:24]=1
Reactant: CCOC(=O)CSc1nccn1-c1ccc(C#N)c2ccccc12
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Product: CCOC(=O)CSc1ncc(Br)n1-c1ccc(C#N)c2ccccc12
Temperature: 25 °C
Reaction time: 18 h
Yield: 71.6 %

Procedure:
N-bromosuccinimide (5.48 g, 30.82 mmol) was added in three portions to a solution of ethyl 2-(1-(4-cyanonaphthalen-1-yl)-1H-imidazol-2-ylthio)acetate (10.40 g, 30.82 mmol) in dichloromethane (150 mL) at 0° C. and then stirred at room temperature for 18 h. The mixture was washed with water (2×50 mL), saturated aqueous sodium chloride solution (50 mL), dried over sodium sulfate, filtered and concentrated. Purification by column chromatography (0-50% EtOAc/hexanes) provided ethyl 2-(5-bromo-1-(4-cyanonaphthalen-1-yl)-1H-imidazol-2-ylthio)acetate as an off-white solid (9.18 g, 71.5%).
Reaction SMILES: [C:1]1([C:7]([NH:20][C:21]2[S:22][CH:23]=[C:24](/[C:26](=[N:30]/[O:31][C:32]([C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)/[C:27]([O-:29])=O)[N:25]=2)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Na+].CS(Cl)(=O)=O.[NH2:57][C@@H:58]1[C:89](=[O:90])[N:60]2[C:61]([C:73]([O:75][CH:76]([C:83]3[CH:88]=[CH:87][CH:86]=[CH:85][CH:84]=3)[C:77]3[CH:82]=[CH:81][CH:80]=[CH:79][CH:78]=3)=[O:74])=[C:62](/[CH:65]=[C:66]3\[CH:67]=[C:68]([CH3:72])[C:69](=[O:71])[O:70]\3)[CH2:63][S:64][C@H:59]12.N1C=CC=CC=1>CN(C=O)C.C(OCC)(=O)C>[CH3:72][C:68]1[C:69](=[O:71])[O:70]/[C:66](=[CH:65]/[C:62]2[CH2:63][S:64][C@@H:59]3[C@H:58]([NH:57][C:27](=[O:29])/[C:26](=[N:30]\[O:31][C:32]([C:45]4[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=4)([C:39]4[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=4)[C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)/[C:24]4[N:25]=[C:21]([NH:20][C:7]([C:1]5[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=5)([C:8]5[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=5)[C:14]5[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=5)[S:22][CH:23]=4)[C:89](=[O:90])[N:60]3[C:61]=2[C:73]([O:75][CH:76]([C:77]2[CH:78]=[CH:79][CH:80]=[CH:81][CH:82]=2)[C:83]2[CH:88]=[CH:87][CH:86]=[CH:85][CH:84]=2)=[O:74])/[CH:67]=1
Reactant: CC1=C/C(=C\C2=C(C(=O)OC(c3ccccc3)c3ccccc3)N3C(=O)[C@@H](N)[C@H]3SC2)OC1=O
Reactant: O=C([O-])/C(=N\OC(c1ccccc1)(c1ccccc1)c1ccccc1)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Agent: CS(=O)(=O)Cl
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC1=C/C(=C\C2=C(C(=O)OC(c3ccccc3)c3ccccc3)N3C(=O)[C@@H](NC(=O)/C(=N\OC(c4ccccc4)(c4ccccc4)c4ccccc4)c4csc(NC(c5ccccc5)(c5ccccc5)c5ccccc5)n4)[C@H]3SC2)OC1=O
Temperature: -15 °C
Yield: 39.4 %

Procedure:
Sodium 2-(2-triphenylmethylaminothiazol-4-yl)2-Z-triphenylmethoxyiminoacetate (0.832 g), in dry DMF (2 mls) was cooled to ca -50° C. under argon and treated with methanesulphonyl chloride (0.093 mls). The solution was allowed to warm to -15° C. over 30mins and then treated with a solution of diphenylmethyl 7β-amino-3-(E-2,5-dihydro-3-methyl-2-oxofuran-5-ylidenemethyl)ceph-3-em-4-carboxylate (0.474 g) and pyridine (0.096 mls) in DMF (3 mls). The reaction was allowed to warm to room temperature over 1h., diluted with ethyl acetate and washed with water (3×), brine and dried. After removal of solvent, flash chromatography on silica gel eluting with 30, 40% ethyl acetate/hexane, gave the title compound as a foam, (0.444 g, 39%), νmax (CH2Cl2) 3375, 1780 (shoulder), 1760, 1720, 1680 and 1500cm-1 ; δH (CDCl3) 1.88 (3H,s), 3.37 (2H,ABq, J17.6Hz), 5.14 (1H,d,J5.1Hz), 6.10 (1H,dd,J5.1,8.8Hz), 6.44 (1H,s), 6.48 (1H,s) 6.77 (1H,br.s, exch.), 6.98 (1H,s), 7.00 (1H,s) and 7.2-7.4 (40H,m); [mass spectrum: +ve ion (NOBA) MH+, 1128].
Reaction SMILES: C([C:4]12[CH2:18][CH:15]([CH2:16][CH2:17]1)[CH:14]1[C:5]2=[C:6]2[CH2:19][CH:13]1[CH:12]1[CH:7]2[CH:8]2[CH2:20][CH:11]1[CH2:10][CH2:9]2)(O)=O.O1C=CCCC1>O1CCCC1.C1(C)C=CC(S(O)(=O)=O)=CC=1.CCOCC>[CH2:16]=[CH:17][CH2:4][CH2:18][CH2:15][CH2:14][CH2:5][CH2:6][CH2:19][CH2:13][CH2:12][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:20]
Reactant: O=C(O)C12CCC(C1)C1C2=C2CC1C1C3CCC(C3)C21
Agent: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOCC
Solvent: C1CCOC1
Product: C=CCCCCCCCCCCCCCCC
Reaction time: 2 h

Procedure:
Subsequently, carboxyhexacyclo[6.6.1.13,6.110,13.02,7.09,14 ]heptadecen of 2.1 grams and 3,4-dihydro-2H-pyran of 1.71 grams were dissolved in tetrahydrofuran of 50 milli-litter, and p-toluen sulfonic acid of 0.03 gram was added to the solution. The reaction was continued at room temperature for 2 hours. The resultant material was diluted in ether of 100 milli-litter, and was washed in 3% solution of Na2CO3, saturated water of salt and water in this order, and the organic layer was dried with MgSO4. When ether and residual 3,4-dihydro-2H-pyran were removed in vacuum by using an evaporator, we obtained viscous-liquid of 12-tetrahydropyranyloxycarbonilhexacyclo[6.6.1.13,6.110,13.02,7.09,14 ]heptadecen of 2 grams.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:16](=[O:17])[C:15]2[C@@H:14]3[C:18]([CH3:20])([CH3:19])[C@@:11]([CH3:21])([CH2:12][CH2:13]3)[C:10]=2[NH:9]1.Br[CH2:23][CH:24]1[CH2:26][CH2:25]1>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C)C=O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:16](=[O:17])[C:15]2[C@@H:14]3[C:18]([CH3:20])([CH3:19])[C@@:11]([CH3:21])([CH2:12][CH2:13]3)[C:10]=2[N:9]1[CH2:23][CH:24]1[CH2:26][CH2:25]1
Reactant: CC1(C)[C@@H]2CC[C@@]1(C)c1[nH]n(-c3ccccc3Cl)c(=O)c12
Reactant: BrCC1CC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: CN(C)C=O
Product: CC1(C)[C@@H]2CC[C@@]1(C)c1c2c(=O)n(-c2ccccc2Cl)n1CC1CC1
Temperature: 100 °C
Yield: 33 %

Procedure:
A mixture of (4S,7R)-2-(2-chloro-phenyl)-7,8,8-trimethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (Intermediate 10; 154 mg, 0.51 mmol), tetrabutylammonium iodide (752 mg, 2.0 mmol), and (bromomethyl)cyclopropane (Lancaster; 195 μL, 2.0 mmol) in dimethylformamide (4.3 mL) was heated in an oil-bath at 100° C. for 16 h. The solvent was evaporated and the residue was partitioned between dichloromethane and water. The aqueous layer was extracted with dichloromethane (2×100 mL) and the combined organic layers were washed with water (5×100 mL) and aqueous sodium thiosulfate (100 mL). The solvent was evaporated and the residue was purified using an ISCO 120 g column, eluting with 65-100% ethyl acetate/hexanes to give (4S,7R)-2-(2-chloro-phenyl)-1-cyclopropylmethyl-7,8,8-trimethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (60 mg, 33%) as a yellow gum. ES(+)-MS (M+H) 357.
Reaction SMILES: [F:1][C:2]1[CH:32]=[CH:31][CH:30]=[CH:29][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][C:11]([CH3:14])=[N:12][CH:13]=[C:8]2[C:7]([C:15]2[N:16]=[N:17][C:18]([C:22]([CH3:28])([CH3:27])[C:23](OC)=[O:24])=[C:19](O)[N:20]=2)=[N:6]1.P(Cl)(Cl)(Cl)=O.[NH3:38]>C(#N)C>[F:1][C:2]1[CH:32]=[CH:31][CH:30]=[CH:29][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][C:11]([CH3:14])=[N:12][CH:13]=[C:8]2[C:7]([C:15]2[N:16]=[N:17][C:18]3[C:22]([CH3:27])([CH3:28])[C:23](=[O:24])[NH:38][C:19]=3[N:20]=2)=[N:6]1
Reactant: N
Reactant: COC(=O)C(C)(C)c1nnc(-c2nn(Cc3ccccc3F)c3nc(C)ncc23)nc1O
Solvent: O=P(Cl)(Cl)Cl
Solvent: CC#N
Product: Cc1ncc2c(-c3nnc4c(n3)NC(=O)C4(C)C)nn(Cc3ccccc3F)c2n1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
182 mg (0.42 mmol) of methyl 2-{3-[1-(2-fluorobenzyl)-6-methyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-5-hydroxy-1,2,4-triazin-6-yl}-2-methylpropanoate were admixed with 3.8 ml (40.87 mmol) of phosphoryl chloride and the mixture was stirred at RT for 2.5 h. The reaction solution was diluted with 20 ml of dry acetonitrile and gradually added dropwise while cooling with ice to 40 ml of a 25% aqueous ammonia solution, and the mixture was stirred at RT for 2 h. The reaction mixture was concentrated on a rotary evaporator and the precipitate was filtered off. The residue was stirred with DMF/methanol and filtered with suction, and the solids were dried under high vacuum. 98 mg of the target compound were obtained (purity 92%; 53% of theory).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][CH:3]=1.Cl[C:11]1[C:12]2[CH:25]=[C:24]([CH2:26][CH3:27])[S:23][C:13]=2[N:14]=[C:15]([C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)[N:16]=1>>[N:19]1[CH:20]=[CH:21][CH:22]=[C:17]([C:15]2[N:16]=[C:11]([NH:7][CH2:6][C:5]3[CH:8]=[CH:9][C:2]([F:1])=[CH:3][CH:4]=3)[C:12]3[CH:25]=[C:24]([CH2:26][CH3:27])[S:23][C:13]=3[N:14]=2)[CH:18]=1
Reactant: CCc1cc2c(Cl)nc(-c3cccnc3)nc2s1
Reactant: NCc1ccc(F)cc1
Product: CCc1cc2c(NCc3ccc(F)cc3)nc(-c3cccnc3)nc2s1

Procedure:
With the procedure of Example 1, the reaction of 4-fluorobenzylamine with 4-chloro-2-(pyridin-3-yl)-6-ethyl-thieno-[2,3-d]-pyrimidine yields 2-(pyridin-3-yl)-4-(4-fluorobenzylamino)-6-ethyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.[NH2:9][C:10]1[CH:18]=[CH:17][C:13]2[N:14]=[CH:15][NH:16][C:12]=2[CH:11]=1.CCN(CC)CC>CCO>[Cl:1][C:2]1[N:7]=[C:6]([NH:9][C:10]2[CH:18]=[CH:17][C:13]3[NH:14][CH:15]=[N:16][C:12]=3[CH:11]=2)[CH:5]=[CH:4][N:3]=1
Reactant: Nc1ccc2nc[nH]c2c1
Reactant: Clc1ccnc(Cl)n1
Solvent: CCN(CC)CC
Solvent: CCO
Product: Clc1nccc(Nc2ccc3[nH]cnc3c2)n1
Yield: 80 %

Procedure:
To a solution of 2,4-dichloropyrimidine (1 mmol) and 5-Aminobenzimidazole (1 mmol) in 5 ml EtOH, was added Et3N (1 mmol). The reaction mixture was refluxed for 5 hours. After removal of the solvent in vacuo and addition of H2O, the mixture was extracted with EtOAc. The organic layers were combined, washed with a saturated NaCl aqueous solution, dried over anhydrous Na2SO4, and concentrated in vacuo. The residue was purified by column chromatography to give N-(2-chloropyrimidin-4-yl)-1H-benzo[d]imidazol-5-amine in a yield of 80%.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:6]([O:13][N:14]1[C:19](=[O:20])[C:18]2[CH:21]=[C:22]([F:26])[C:23](Cl)=[N:24][C:17]=2[N:16]([C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][C:28]=2[F:34])[C:15]1=[O:35])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(N(CC)CC)C>C(#N)C>[CH2:6]([O:13][N:14]1[C:19](=[O:20])[C:18]2[CH:21]=[C:22]([F:26])[C:23]([N:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)=[N:24][C:17]=2[N:16]([C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][C:28]=2[F:34])[C:15]1=[O:35])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: C1CCNC1
Reactant: O=c1c2cc(F)c(Cl)nc2n(-c2ccc(F)cc2F)c(=O)n1OCc1ccccc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: O=c1c2cc(F)c(N3CCCC3)nc2n(-c2ccc(F)cc2F)c(=O)n1OCc1ccccc1
Yield: 76.2 %

Procedure:
Using the method of Example N-4, pyrrolidine (0.04 mL, 0.52 mmol), 3-benzyloxy-7-chloro-6-fluoro-1-(2,4-difluorophenyl)-1H-pyrido[2,3-d]pyrimidine-2,4-dione (Example S-2, 0.18 g, 0.42 mmol) and triethylamine (0.36 mL, 2.6 mmol) were combined in 20 mL of acetonitrile to give 0.15 g of the title compound as a solid, mp 183-185° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[C@@H:7]1[CH2:11][C@H:10](OS(C)(=O)=O)[CH2:9][N:8]1[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])([CH3:4])([CH3:3])[CH3:2].[N-:25]=[N+:26]=[N-:27].[Na+]>CN(C)C=O>[C:1]([O:5][C:6](=[O:24])[C@@H:7]1[CH2:11][C@@H:10]([N:25]=[N+:26]=[N-:27])[CH2:9][N:8]1[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)[C@@H]1C[C@H](OS(C)(=O)=O)CN1C(=O)OC(C)(C)C
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)[C@@H]1C[C@@H](N=[N+]=[N-])CN1C(=O)OC(C)(C)C
Temperature: 55 °C
Reaction time: 18 h

Procedure:
A mixture of (4S)-1-(tert-butyloxycarbonyl)-4-(methanesulfonyloxy)-L-proline tert-butyl ester (250 mg, 0.684 mmol) and sodium azide (222 mg, 3.42 mmol) in N,N-dimethylformamide (1.5 mL) was stirred for 18 hours at 55° C. under a nitrogen atmosphere. The cooled reaction mixture was evaporated and partitioned between diluted ethyl acetate and water. The organic layer was washed with water, 0.1N hydrochloric acid, water, saturated brine solution, dried (Na2SO4), and evaporated. The crude product mixture was subjected to flash silica gel chromatography eluting with 10% ethyl acetate/hexane. The desired azide was obtained as a colorless oil; yield 196 mg (92%). 400 MHz 1H NMR (CDCl3): δ1.42-1.45 (3s, 18H); 2.11 (m, 1H); 2.22-2.36 (m, 1H); 3.68 (m, 1H); 4.12 (m, 1H).
Reaction SMILES: C([O:8][C:9]1[CH:10]=[CH:11][C:12]2[C:13]3[N:21]([CH2:22][CH:23]4[CH2:27][O:26][C:25]([CH3:29])([CH3:28])[O:24]4)[C:20]([CH2:30][O:31][CH2:32][CH3:33])=[N:19][C:14]=3[CH:15]=[N:16][C:17]=2[CH:18]=1)C1C=CC=CC=1>C(#N)C.C(Cl)(Cl)Cl.CO.[OH-].[Pd+2].[OH-]>[CH3:28][C:25]1([CH3:29])[O:24][CH:23]([CH2:22][N:21]2[C:13]3[C:12]4[CH:11]=[CH:10][C:9]([OH:8])=[CH:18][C:17]=4[N:16]=[CH:15][C:14]=3[N:19]=[C:20]2[CH2:30][O:31][CH2:32][CH3:33])[CH2:27][O:26]1
Reactant: CCOCc1nc2cnc3cc(OCc4ccccc4)ccc3c2n1CC1COC(C)(C)O1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Solvent: CC#N
Solvent: ClC(Cl)Cl
Product: CCOCc1nc2cnc3cc(O)ccc3c2n1CC1COC(C)(C)O1
Yield: 93.4 %

Procedure:
Palladium hydroxide (Pearlman's catalyst) (20% wt. % palladium on carbon, 2.2 g) was added to a solution of 7-benzyloxy-1-[(2,2-dimethyl[1,3]dioxolan-4-yl)methyl]-2-ethoxymethyl-1H-imidazo[4,5-c]quinoline (22.2 g, 49.6 mmol) in acetonitrile (400 mL) and the reaction mixture was hydrogenated (30 psi, 2.1×105 Pa) for 24 hours on a Parr apparatus. The crude reaction mixture was diluted with 1:1 chloroform/methanol (1 L), then was filtered through a layer of CELITE filter agent. The filtrate was concentrated under reduced pressure and triturated with acetonitrile. The resulting crystalline material was collected by filtration, washed with acetonitrile, and dried to afford 16.55 g of 1-[(2,2-dimethyl-1,3-dioxolan-4-yl)methyl]-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-7-ol as a white powder, mp 239-240° C.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=2)=O)=[CH:4][CH:3]=1.Cl.[N+:18]([C:21]1[CH:22]=[C:23]([NH:27][NH2:28])[CH:24]=[CH:25][CH:26]=1)([O-:20])=[O:19].S(=O)(=O)(O)O>CO>[Cl:1][C:2]1[CH:16]=[CH:15][C:5]([C:6](=[N:28][NH:27][C:23]2[CH:24]=[CH:25][CH:26]=[C:21]([N+:18]([O-:20])=[O:19])[CH:22]=2)[C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: O=C(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Reactant: NNc1cccc([N+](=O)[O-])c1
Agent: Cl
Agent: O=S(=O)(O)O
Solvent: CO
Product: O=[N+]([O-])c1cccc(NN=C(c2ccc(Cl)cc2)c2ccc(Cl)cc2)c1
Temperature: 50 °C
Reaction time: 2 h
Yield: 79.4 %

Procedure:
A solution of 4,4′-dichlorobenzophenone (0.38 g, 1.5 mmol) was added to a solution of 3-nitrophenylhydrazine hydrochloride (0.43 g, 2.25 mmol), concentrated sulfuric acid (0.3 mL) in 10 mL of methanol at 50° C. It was stirred at 50° C. for additional 2 h. The reaction mixture was concentrated to ¼ of its original volume and diluted with 20 mL of water. The precipitates were separated by filtration and washed with 3% aqueous NaHCO3 and water. The crude product was recrystallized from ethanol to give 0.46 g (81% yield) of the desired compound as a yellow needle, mp 170-172° C. 1H NMR (300 MHz, d6-DMSO): δ7.35 [d, 2H, J=7.7 Hz, Ar—H], 7.37-7.49 [m, 5H, Ar—H], 7.58 [d, 1H, J=8.4 Hz, Ar—H], 7.64 [d, 2H, J=8.4 Hz, Ar—H], 7.69 [d, 1H, J=8.4 Hz, Ar—H], 8.02 [s, 1H, Ar—H], 9.63 [s, 1H, NH].
Reaction SMILES: [C:1]([O:5][C:6](=[O:13])[NH:7][C@H:8]1[CH2:11][C@H:10]([NH2:12])[CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[Cl:14][C:15]1[C:16]([C:21]([CH3:26])([CH3:25])[C:22](O)=[O:23])=[N:17][CH:18]=[CH:19][N:20]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>C(Cl)Cl.O>[C:1]([O:5][C:6](=[O:13])[NH:7][C@H:8]1[CH2:11][C@H:10]([NH:12][C:22](=[O:23])[C:21]([C:16]2[C:15]([Cl:14])=[N:20][CH:19]=[CH:18][N:17]=2)([CH3:26])[CH3:25])[CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@H]1C[C@H](N)C1
Reactant: CC(C)(C(=O)O)c1nccnc1Cl
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CC(C)(C)OC(=O)N[C@H]1C[C@H](NC(=O)C(C)(C)c2nccnc2Cl)C1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a round bottomed flask was added tert-butyl(trans-3-aminocyclobutyl)carbamate (1.847 g, 9.92 mmol), 2-(3-chloropyrazin-2-yl)-2-methylpropanoic acid (1.99 g, 9.92 mmol), HATU (4.90 g, 12.89 mmol), and triethylamine (5.52 ml, 39.7 mmol) in DCM (25 ml) to stir at room temperature for 16 h. The reaction mixture was diluted with water and extracted with CH2Cl2. The organic extract was washed with water, saturated NaCl solution, dried over MgSO4, filtered and concentrated in vacuo. The crude product was purified by chromatography through a Redi-Sep pre-packed silica gel column (40 g), eluting with a gradient of 10% to 70% EtOAc in hexane, to provide the title compound (2.73 g, 7.40 mmol, 74.6% yield) as off-white solid.
Reaction SMILES: O[C:2]1[C:6]([CH3:8])([CH3:7])[O:5][C:4](=[O:9])[CH:3]=1.C(Br)(=O)C([Br:13])=O>ClCCCl.CN(C=O)C>[Br:13][C:2]1[C:6]([CH3:8])([CH3:7])[O:5][C:4](=[O:9])[CH:3]=1
Reactant: CC1(C)OC(=O)C=C1O
Reactant: O=C(Br)C(=O)Br
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CC1(C)OC(=O)C=C1Br
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 86.2 %

Procedure:
To a solution of 4-hydroxy-5,5-dimethyl-5H-furan-2-one (2.1 g, 16.4 mmol) in DCE (40 mL) and DMF (1.5 mL) at 0° C. was added dropwise oxalyl bromide (3.0 mL, 32 mmol, 2 equiv). The mixture was stirred at room temperature for 4-5 h, and then put in an ice bath. Ice water (100 mL) was added slowly. The mixture was extracted with CH2Cl2 (100 mL). The organic phase was washed with 10% NaHCO3 and again with water, dried over sodium sulfate and evaporated to give the title compound 2.7 g (86% yield).
Reaction SMILES: Br[C:2]1[CH:14]=[CH:13][C:5]([O:6]C2CCCCO2)=[CH:4][C:3]=1[CH:15]([O:17]C1CCCCO1)[CH3:16].[Li]CCCC.[B:29](OC(C)C)(OC(C)C)[O:30]C(C)C.Cl>C1COCC1>[CH3:16][CH:15]1[O:17][B:29]([OH:30])[C:2]2[CH:14]=[CH:13][C:5]([OH:6])=[CH:4][C:3]1=2
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: CC(OC1CCCCO1)c1cc(OC2CCCCO2)ccc1Br
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC1OB(O)c2ccc(O)cc21
Temperature: -78 °C
Reaction time: 21 h
Yield: 81.5 %

Procedure:
A solution of 2-(4-bromo-3-(1-(tetrahydro-2H-pyran-2-yloxy)ethyl)phenoxy)tetrahydro-2H-pyran (4.38 g, 11.3 mmol) in anhydrous THF (11 mL) was made before cooling the reaction mixture on a −78° C. bath. Reaction mixture was then treated, drop-wise, with n-BuLi (8.48 mL, 13.6 mmol) and allowed to stir for 1 hr before (i-PrO)3B (3.9 mL, 17 mmol) was added via syringe. After the addition of (i-PrO)3B, the reaction mixture was warmed to room temperature and allowed to stir for 21 hr. Cyclization of the bicyclic ring was done in situ by the addition of 7 mL of 6 M HCl. The mixture was stirred for 3 h before quenching the reaction with equal volume of concentrated NH4Cl(aq) and EtOAc (1:1, 20 mL). The layers were separated and the aqueous layer was further extracted with equal volume of EtOAc before the organic layers were combined and dried over anhydrous Na2SO4 and filtered. The solvent was removed under reduced pressure. The residue was purified by silica gel column using Combiflash give 3-methylbenzo[c][1,2]oxaborole-1,5(3H)-diol (1.51 g, 81%). 1H-NMR (400 MHz, DMSO-d6) δ (ppm) 1.32 (d, J=5.1 Hz, 3H), 5.03-5.08 (m, 2H), 6.68 (s, 1H), 6.71 (dd, J=6.0, 1.5 Hz, 1H), 7.45 (d, J=6.0 Hz, 1H), 8.57 (s, 1H), 9.71 (s, 1H).
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].Br[C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[N:14]=[C:13]([CH3:18])[C:12]([S:19]([CH3:22])(=[O:21])=[O:20])=[C:11]2[C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=1.[NH:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1>C(O)(C)(C)C.CCCCCCC.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1>[F:29][C:26]1[CH:27]=[CH:28][C:23]([C:11]2[C:10]3[C:15](=[CH:16][CH:17]=[C:8]([N:30]4[CH2:35][CH2:34][O:33][CH2:32][CH2:31]4)[CH:9]=3)[N:14]=[C:13]([CH3:18])[C:12]=2[S:19]([CH3:22])(=[O:21])=[O:20])=[CH:24][CH:25]=1
Reactant: C1COCCN1
Reactant: Cc1nc2ccc(Br)cc2c(-c2ccc(F)cc2)c1S(C)(=O)=O
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)(C)O
Solvent: CCCCCCC
Product: Cc1nc2ccc(N3CCOCC3)cc2c(-c2ccc(F)cc2)c1S(C)(=O)=O
Temperature: 110 °C
Yield: 408.2 %

Procedure:
A tube placed under argon was charged with tris(dibenzylideneacetone)dipalladium chloroform complex (79 mg, 0.076 mmol), 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (73 mg, 0.152 mmol) and cesium carbonate (1.86 g, 5.7 mmol). 6-Bromo-4-(4-fluoro-phenyl)-3-methanesulfonyl-2-methyl-quinoline (compound of example 14) (200 mg, 0.52 mmol) in tert.-butanol (20 ml) was added, followed by morpholine (0.40 g, 4.56 mmol). The tube was sealed and heated at 110° C. for 2 h. The reaction mixture was cooled to 20° C., diluted with heptane, filtered through dicalite and purified directly by flash chromatography on silica gel in heptane/ethyl acetate with a gradient from 100:0 to 40:60 to give a yellow solid (850 mg, 56%). MS: m/z=401 (M+H).