Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]2[C:9]([CH3:12])=[N:10][NH:11][C:3]=12.[CH3:13]OC(OC)N(C)C>C1(C)C=CC=CC=1>[Cl:1][C:2]1[C:3]2[C:4](=[C:9]([CH3:12])[N:10]([CH3:13])[N:11]=2)[N:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: COC(OC)N(C)C
Reactant: Cc1cc(Cl)c2[nH]nc(C)c2n1
Solvent: Cc1ccccc1
Product: Cc1cc(Cl)c2nn(C)c(C)c2n1
Yield: 15 %

Procedure:
7-Chloro-3,5-dimethyl-1H-pyrazolo[4,3-b]pyridine (900 mg) and dimethylformamide dimethyl acetal (1.06 ml) in dry toluene (10 ml) were heated at reflux for 4 hours. The solvent was removed under reduced pressure and the brown oily residue chromatographed on silica gel eluting with 50:50 ether/pentane to give the title compound (150 mg, 15%).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:14]=[C:13]2[C:8]([CH:9]=[C:10]([N+:15]([O-])=O)[CH:11]=[N:12]2)=[CH:7][CH:6]=1)(=[O:4])=[O:3]>CCOC(C)=O.[Pd]>[CH3:1][S:2]([C:5]1[CH:14]=[C:13]2[C:8]([CH:9]=[C:10]([NH2:15])[CH:11]=[N:12]2)=[CH:7][CH:6]=1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)c1ccc2cc([N+](=O)[O-])cnc2c1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CS(=O)(=O)c1ccc2cc(N)cnc2c1
Reaction time: 18 h
Yield: 24.7 %

Procedure:
To a suspension of 7-(methylsulfonyl)-3-nitroquinoline (85 mg, 0.4 mmol) in EtOAc (6 mL) under argon, was added 10% Pd/C (22 mg, 0.04 mmol). A H2 balloon was connected to the reaction flask, the flask was purged with H2 three times and the reaction mixture was allowed to stir under H2 atmosphere for 18 h. Unreacted starting material could be seen settling to the bottom of the flask together with the catalyst. The solids were removed from the EtOAc solution by filtration. Evaporation of EtOAc under reduced pressure yielded 7-(methylsulfonyl)-3-quinolylamine (22 mg, 30%). LC/MS (m/z): 223.0 (MH+), Rt 1.10 minutes.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][N:8]2[CH2:11][C:12]2[CH:21]=[CH:20][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][C:13]=2[O:22][CH3:23])=[CH:4][CH:3]=1.[CH2:24]([CH:26]([CH2:30][CH2:31][CH2:32][CH3:33])[C:27](Cl)=[O:28])[CH3:25]>>[CH2:24]([CH:26]([CH2:30][CH2:31][CH2:32][CH3:33])[C:27]([NH:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][N:8]2[CH2:11][C:12]2[CH:21]=[CH:20][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][C:13]=2[O:22][CH3:23])=[CH:4][CH:3]=1)=[O:28])[CH3:25]
Reactant: COC(=O)c1ccc(Cn2ncc3ccc(N)cc32)c(OC)c1
Reactant: CCCCC(CC)C(=O)Cl
Product: CCCCC(CC)C(=O)Nc1ccc2cnn(Cc3ccc(C(=O)OC)cc3OC)c2c1
Yield: 68 %

Procedure:
Using an analogous procedure to that described in Example 1, but starting from methyl 4-(6-aminoindazol-1-ylmethyl)-3-methoxybenzoate and 2-ethylhexanoyl chloride, there was obtained methyl 4-[6-(2-ethylhexanamido)indazol-1-ylmethyl]-3-methoxybenzoate in 68% yield as a white solid, m.p. 135.5°-136.5° C.; microanalysis, found: C, 68.37; H, 7.10; N, 9.43%; C25H31,N3O4 requires: C, 68.64; H, 7.14; N, 9.60%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([CH:13]([C:15]1[S:19][CH:18]=[N:17][CH:16]=1)[OH:14])[CH:7]=[CH:6]2>ClCCl.[O-2].[O-2].[Mn+4]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([C:13]([C:15]1[S:19][CH:18]=[N:17][CH:16]=1)=[O:14])[CH:7]=[CH:6]2
Reactant: COc1ccc2cc(C(O)c3cncs3)ccc2c1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: COc1ccc2cc(C(=O)c3cncs3)ccc2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 86.1 %

Procedure:
(6-methoxynaphthalen-2-yl)(thiazol-5-yl)methanol (2.0 g) was dissolved in dichloromethane (30 ml). To the solution was added manganese dioxide (6.0 g), and the mixture was stirred at room temperature for 3 h. The mixture was filtered with celite and the cake was rinsed with dichloromethane. The filtrate was concentrated and the obtained residue was recrystallized from ethyl acetate to give the titled compound (1.71 g) as a pale yellow powder.
Reaction SMILES: C(O)CCCCCO.BrCCCC1C=CC=CC=1.[C:19]1([CH2:25][CH2:26][CH2:27][O:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][OH:35])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C1(CCCOCCCCCC(O)=O)C=CC=CC=1.Cl.Cl.[CH2:56]([O:63][C:64](=[O:72])[CH2:65][C@@H:66]([NH2:71])[CH2:67][N:68]([CH3:70])[CH3:69])[C:57]1[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=1>>[CH2:56]([O:63][C:64](=[O:72])[CH2:65][C@@H:66]([NH:71][C:34](=[O:35])[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][O:28][CH2:27][CH2:26][CH2:25][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:67][N:68]([CH3:69])[CH3:70])[C:57]1[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=1
Reactant: OCCCCCCOCCCc1ccccc1
Reactant: CN(C)C[C@H](N)CC(=O)OCc1ccccc1
Agent: BrCCCc1ccccc1
Agent: Cl
Agent: O=C(O)CCCCCOCCCc1ccccc1
Product: CN(C)C[C@@H](CC(=O)OCc1ccccc1)NC(=O)CCCCCOCCCc1ccccc1

Procedure:
The title compound, m/e=379.4 ([M+H]+), was produced in analogy with example 1, steps 1 to 4. Thus, 1,6-hexanediol was alkylated in step 1 with 1-bromo-3-phenylpropane, leading to 6-(3-phenyl-propoxy)-hexan-1-ol, which was oxidized in step 2 to 6-(3-phenyl-propoxy)-hexanoic acid. This was coupled in step 3 with (R)-3-amino-4-dimethylamino-butyric acid benzyl ester dihydrochloride to produce (R)-4-dimethylamino-3-[6-(3-phenyl-propoxy)-hexanoylamino]-butyric acid benzyl ester, which was hydrogenated in step 4.
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17](=[O:22])[C:18]([O:20][CH3:21])=[O:19])=[CH:12][CH:11]=2)=[CH:6][CH:5]=1.[CH3:25][C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=1)[CH2:29]Br.C(=O)([O-])[O-].[K+].[K+].C1OCCOCCOCCOCCOCCOC1>O.C(#N)C>[CH3:25][C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=1)[CH2:29][N:16]([C:13]1[CH:12]=[CH:11][C:10]([C:7]2[CH:8]=[CH:9][C:4]([O:3][C:2]([F:23])([F:24])[F:1])=[CH:5][CH:6]=2)=[CH:15][CH:14]=1)[C:17](=[O:22])[C:18]([O:20][CH3:21])=[O:19]
Reactant: COC(=O)C(=O)Nc1ccc(-c2ccc(OC(F)(F)F)cc2)cc1
Reactant: Cc1cccc(CBr)c1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: COC(=O)C(=O)N(Cc1cccc(C)c1)c1ccc(-c2ccc(OC(F)(F)F)cc2)cc1
Temperature: 25 °C
Yield: 97.9 %

Procedure:
A mixture of methyl N-[4′-(trifluoromethoxy)biphenyl-4-yl]oxamate (250 mg, 0.737 mmol), 3-methylbenzyl bromide (0.299 ml, 2.21 mmol), potassium carbonate (306 mg, 2.21 mmol), 18-crown-6 (20 mg, 0.074 mmol) and acetonitrile (10 ml) was stirred at 50° for 3 hors under argon atmosphere. The reaction mixture was cooled to room temperature, diluted with water, and extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. The residue obtained by evaporation of the solvent under reduced pressure was purified by column chromatography on silica gel (n-hexane:ethyl acetate=2:1) to give the title compound (320 mg, 98%) as a colorless oil.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[C:8]([N:10]1[CH2:15][CH2:14][CH:13]([CH3:16])[CH2:12][CH2:11]1)=O.O.[OH-].[Na+]>O1CCCC1>[CH3:16][CH:13]1[CH2:14][CH2:15][N:10]([CH2:8][C@H:3]2[CH2:4][CH2:5][CH2:6][CH2:7][C@H:2]2[NH2:1])[CH2:11][CH2:12]1
Reactant: CC1CCN(C(=O)[C@@H]2CCCC[C@@H]2N)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC1CCN(C[C@H]2CCCC[C@H]2N)CC1

Procedure:
1-[Cis-(2-aminocyclohexyl)carbonyl]-4-methylpiperidine (6.57 g; 0.0293 mol) is dissolved in tetrahydrofuran (25 ml) and added dropwise to a suspension of AlLiH4 (2.22 g; 0.0586 mol) in tetrahydrofuran (50 ml). At the end of the addition, the reaction mixture is refluxed for 24 h and then hydrolyzed by carefully adding water (2.3 ml), then a 15% sodium hydroxide solution (2.3 ml) and then water (5 ml).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[N:2]1.C(=O)([O-])[O-].[Cs+].[Cs+].CC(N(C)C)=O.[Br:18][C:19]1[CH:20]=[N:21][C:22](Cl)=[N:23][CH:24]=1>O>[Br:18][C:19]1[CH:20]=[N:21][C:22]([N:1]2[CH:5]=[CH:4][CH:3]=[N:2]2)=[N:23][CH:24]=1
Reactant: Clc1ncc(Br)cn1
Reactant: c1cn[nH]c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: Brc1cnc(-n2cccn2)nc1
Temperature: 120 °C
Reaction time: 0.5 h
Yield: 126.1 %

Procedure:
Pyrazole (130 mg) and cesium carbonate (610 mg) were added to a DMAc (10 ml) solution containing 5-bromo-2-chloropyrimidine (300 mg), followed by stirring at 120° C. for 0.5 hours. The reaction mixture was adjusted to room temperature and water was added to the mixture. Next, the organic layers were collected, washed with saturated saline, and dried over anhydrous sodium sulfate. The solvent was distilled away under reduced pressure and a yellow solid of 5-bromo-2-(pyrazol-1-yl)pyrimidine (440 mg) was thus obtained.
Reaction SMILES: [C:1]1([S:7]([NH:10][C:11]2[CH:12]=[C:13]([CH:17]=[CH:18][CH:19]=2)[C:14]([OH:16])=O)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CN([P+](ON1N=NC2C1=CC=CC=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.Cl.[OH:57][C:58]1[CH:65]=[CH:64][C:61]([CH2:62][NH2:63])=[CH:60][C:59]=1[O:66][CH3:67]>CN(C)C=O>[C:1]1([S:7]([NH:10][C:11]2[CH:12]=[C:13]([CH:17]=[CH:18][CH:19]=2)[C:14]([NH:63][CH2:62][C:61]2[CH:64]=[CH:65][C:58]([OH:57])=[C:59]([O:66][CH3:67])[CH:60]=2)=[O:16])(=[O:8])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COc1cc(CN)ccc1O
Reactant: O=C(O)c1cccc(NS(=O)(=O)c2ccccc2)c1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(CNC(=O)c2cccc(NS(=O)(=O)c3ccccc3)c2)ccc1O
Reaction time: 0.08 h

Procedure:
To 139 mg (0.5 mmol) of 3-(phenylsulfonyl)aminobenzoic acid as prepared in Example 9 in 1 mL of N,N-dimethylformamide was added sequentially 1 mL of 0.5M (0.5 mmol) of Castro's reagent (benzotriazole-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate) in N,N-dimethylformamide and then 500 μL of N,N-diisopropylethylamine. After 5 min, 95 mg (0.5 mmol) of 4-hydroxy-3-methoxybenzylamine HCl was added. After 30 min, the reaction mixture was quenched with 7 mL of 2N HCl, extracted into ethyl acetate (2×2 mL), washed with water (3×4 mL) and then sat. NaHCO3 (1×4 mL). The organic phase was passed through a Waters solid phase extraction column (5 g silica gel) onto which was added Na2SO4 to act a drying agent. Elution with ethyl acetate gave the title compound: NMR (DMSO-d6 ; 300 MHz) δ 10.46 (s, 1H), 8.88 (t, 1H), 8.84 (s, 1H), 7.74-7.81 (m, 3H), 7.50-7.70 (m, 6H), 7.30 (t, 1H) 7.22 (d, 1H), 6.87 (s, 1H), 6.69 (t, 2H), 4.31 (d, 2H), 3.73 ppm (s, 3H). Mass spectrum (MALDI-TOF; gentisic acid matrix) cald. for C27H20N2O5S: 435.1 (M+Na). Found: 435.0.
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][C:5]2[NH:6][C:7]([CH2:9][NH:10][C:11]3[CH:15]=[CH:14][NH:13][C:12]=3[C:16]([O:18]CC)=O)=[N:8][C:4]=2[CH:3]=1.CN(C=O)C.C([N:36]=[C:37]=[S:38])(=O)C1C=CC=CC=1>C(Cl)Cl>[Cl:1][C:2]1[CH:22]=[CH:21][C:5]2[NH:6][C:7]([CH2:9][N:10]3[C:11]4[CH:15]=[CH:14][NH:13][C:12]=4[C:16](=[O:18])[NH:36][C:37]3=[S:38])=[N:8][C:4]=2[CH:3]=1
Reactant: O=C(N=C=S)c1ccccc1
Reactant: CCOC(=O)c1[nH]ccc1NCc1nc2cc(Cl)ccc2[nH]1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=c1[nH]c(=S)n(Cc2nc3cc(Cl)ccc3[nH]2)c2cc[nH]c12
Temperature: 25 °C
Reaction time: 1 h
Yield: 43.2 %

Procedure:
A solution of ethyl 3-{[(5-chloro-1H-benzimidazol-2-yl)methyl]amino}-1H-pyrrole-2-carboxylate (0.074 g, 0.23 mmol) in CH2Cl2 was stirred for 5 minutes. DMF (0.2 mL) was added to enhance solubility. Benzoyl isothiocyanate (0.045 g, 0.28 mmol) was added and the mixture was stirred for 1 h then concentrated in vacuo. The crude intermediate was taken up in ammonia (7N in methanol, 2 mL) and was stirred at 70° C. for 1.5 h in a sealed vessel. After cooling to r.t. the precipitated product was collected by vacuum filtration, washed with diethyl ether and dried, obtaining 0.033 g (43%) of the title product as a white solid.
Reaction SMILES: [In].[CH2:2](Br)[CH:3]=[CH2:4].C(O[CH:9]([OH:14])[C:10]([F:13])([F:12])[F:11])C>O>[F:13][C:10]([F:11])([F:12])[CH:9]([OH:14])[CH2:4][CH:3]=[CH2:2]
Reactant: CCOC(O)C(F)(F)F
Reactant: C=CCBr
Agent: [In]
Solvent: O
Product: C=CCC(O)C(F)(F)F
Reaction time: 16 h

Procedure:
To a suspension of indium powder (2.3 g, 20 mmol) in water is added allyl bromide (2.5 mL, 30 mmol) followed by trifluoroacetaldehyde ethyl hemiacetal (1.3 mL, 10 mmol). The reaction mixture is stirred for 16 h and then extracted with t-butyl methyl ether (50 mL). The organic layer is washed with water, brine, dried with Na2SO4 and concentrated to give the title compound as a colorless oil.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH3:12])[CH:6]=1.[N:13]1[CH:18]=[CH:17][C:16]([C:19]2[C:20]([N:25]3[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]3)=[N:21][CH:22]=[CH:23][CH:24]=2)=[CH:15][CH:14]=1>>[CH3:12][O:11][C:7]1[CH:6]=[C:5]([CH:10]=[CH:9][CH:8]=1)[O:4][CH2:3][CH2:2][N:28]1[CH2:29][CH2:30][N:25]([C:20]2[C:19]([C:16]3[CH:17]=[CH:18][N:13]=[CH:14][CH:15]=3)=[CH:24][CH:23]=[CH:22][N:21]=2)[CH2:26][CH2:27]1
Reactant: c1cnc(N2CCNCC2)c(-c2ccncc2)c1
Reactant: COc1cccc(OCCCl)c1
Product: COc1cccc(OCCN2CCN(c3ncccc3-c3ccncc3)CC2)c1

Procedure:
The title compound was prepared starting from 1-(2-chloroethoxy)-3-methoxybenzene and 1-[3-(4-pyridyl)-2-pyridyl]piperazine following the procedure outlined for Example 15. 1H NMR (CDCl3): δ 2.47-2.52 (m, 4H), 2.75 (t, 2H, J=5.9 Hz), 2.92 (br s, 4H), 3.77 (s, 3H), 4.05 (t, 2H, J=5.9 Hz), 6.47-6.54 (m, 3H), 7.01-7.09 (m, 2H), 7.56 (dd, 1H, J=1.9, 7.4 Hz), 7.60 (dd, 2H, J=1.7, 4.7 Hz), 8.29 (dd, 1H, J=1.9, 4.9 Hz), 8.66 (dd, 2H, J=1.7, 4.9 Hz). GC-MS m/z 391 (M+1, 1), 390 (M+, 8), 267 (35), 253 (100), 198 (10), 184 (40).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[C:13]3[CH2:18][O:17][CH2:16][C@H:15]([CH3:19])[N:14]3[C:10]=2[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([OH:20])[CH:8]=2)[N:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:27](I)[CH3:28].O>CN(C=O)C.C(Cl)(Cl)Cl>[CH2:27]([O:20][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]=[C:2]([NH2:1])[C:11]1[N:12]=[C:13]3[CH2:18][O:17][CH2:16][C@H:15]([CH3:19])[N:14]3[C:10]2=1)[CH3:28]
Reactant: C[C@H]1COCc2nc3c(N)nc4ccc(O)cc4c3n21
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Solvent: O
Product: CCOc1ccc2nc(N)c3nc4n(c3c2c1)[C@@H](C)COC4
Temperature: 75 °C
Reaction time: 8 h
Yield: 18.3 %

Procedure:
A solution of (11S)-6-amino-11-methyl-10,11-dihydro-8H-[1,4]oxazino[4′,3′:1,2]imidazo[4,5-c]quinolin-2-ol (500 mg, 1.85 mmol) dissolved in 15 mL of DMF was treated with cesium carbonate (1.80 g, 5.55 mmol) and ethyl iodide (346 mg, 2.03 mmol). After stirring overnight at 75° C., the light brown mixture was poured into 150 mL of H2O and stirred for 30 minutes. The reaction mixture was extracted with CHCl3 (3×75 mL) and the combined extracts were dried over MgSO4, filtered and concentrated under reduced pressure to give a brown solid. Chromatography (SiO2, 0-20% CMA/CHCl3) gave an off-white solid which was crystallized from acetonitrile to give 101 mg of the title compound as an off-white solid, mp 187-188° C.
Reaction SMILES: [N:1]([C@@H:4]1[CH2:8][N:7]([C@H:9]([C:14]2[CH:15]=[N:16][C:17]([Cl:20])=[CH:18][CH:19]=2)[C:10]([F:13])([F:12])[F:11])[CH2:6][C@@H:5]1O)=[N+:2]=[N-:3].C(N(S(F)(F)[F:28])CC)C>ClCCl>[N:1]([C@H:4]1[CH:5]([F:28])[CH2:6][N:7]([C@H:9]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[N:16][CH:15]=2)[C:10]([F:13])([F:12])[F:11])[CH2:8]1)=[N+:2]=[N-:3]
Reactant: CCN(CC)S(F)(F)F
Reactant: [N-]=[N+]=N[C@@H]1CN([C@H](c2ccc(Cl)nc2)C(F)(F)F)C[C@@H]1O
Solvent: ClCCl
Product: [N-]=[N+]=N[C@@H]1CN([C@H](c2ccc(Cl)nc2)C(F)(F)F)CC1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 42 %

Procedure:
To a solution of (3S,4R)-4-azido-1-((R)-1-(6-chloropyridin-3-yl)-2,2,2-trifluoroethyl)pyrrolidin-3-ol (2.4 g, 7.5 mmol) in dichloromethane (30 mL) at −78° C., was added diethylaminosulfur trifluoride (1.17 mL, 8.95 mmol). The resulting solution was allowed to warm to ambient temperature and stirred overnight. The mixture was concentrated under reduced pressure and the residue was dissolved in ethyl acetate and washed with water and brine, then dried (MgSO4), filtered and concentrated. The crude residue was purified by column chromatography (Biotage, 40M; 10-25% ethyl acetate/hexanes gradient) to afford 5-((1R)-1-((3R)-3-azido-4-fluoropyrrolidin-1-yl)-2,2,2-trifluoroethyl)-2-chloropyridine (1.02 g, 42%).
Reaction SMILES: [BH4-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([C:16](=[O:22])[CH2:17][CH2:18][C:19]([OH:21])=[O:20])=[CH:12][CH:11]=2)=[CH:6][CH:5]=1>C(O)C>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[CH:15]=[CH:14][C:13]([CH:16]([OH:22])[CH2:17][CH2:18][C:19]([OH:21])=[O:20])=[CH:12][CH:11]=2)=[CH:8][CH:9]=1
Reactant: O=C(O)CCC(=O)c1ccc(-c2ccc(Cl)cc2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: O=C(O)CCC(O)c1ccc(-c2ccc(Cl)cc2)cc1
Reaction time: 4 h
Yield: 17.5 %

Procedure:
To a stirred suspension of sodium borohydride (0.0376 g, 0.00099 mol) in absolute ethanol under nitrogen at room temperature was added in one portion 4-(4′-chloro-biphenyl-4-yl)-4-oxo-butyric acid (0.576 g, 0.00199 mol), and the mixture stirred for 4 hours. Additional sodium borohydride (0.013 g, 0.00034 mol) was added, and the mixture stirred for 18 hours. Additional sodium borohydride (0.0144 g, 0.000381 mol) was added and the mixture stirred for 5 hours. Total reaction time was 27 hours. The reaction was quenched with acetone-water and partitioned between 1 M hydrochloric acid and dichloromethane. The organic layer was washed with brine, dried (Na2SO4), and rotary evaporated. The residue was purified by chromatography on silica gel using dichloromethane-methanol (19:1, 1.3 L; 15:1, 1.3 L) to give 0.101 g of (±)-4-(4′-chloro-biphenyl-4-yl)-4-hydroxy-butyric acid as a white solid; mp 133.5-135.0° C.
Reaction SMILES: [Br:1][C:2]1[C:3](F)=[C:4]2[C:10]([NH:11][C:12](=[O:14])[CH3:13])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[NH:16]1[CH2:21][CH2:20][CH2:19][C@@H:18]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH2:17]1.CC#N.O>C(O)CCC>[C:12]([NH:11][C:10]1[C:4]2[C:5](=[N:6][CH:7]=[C:2]([Br:1])[C:3]=2[N:16]2[CH2:21][CH2:20][CH2:19][C@@H:18]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:27])([CH3:26])[CH3:28])[CH2:17]2)[NH:8][CH:9]=1)(=[O:14])[CH3:13]
Reactant: CC(=O)Nc1c[nH]c2ncc(Br)c(F)c12
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCNC1
Solvent: CC#N
Solvent: O
Solvent: CCCCO
Product: CC(=O)Nc1c[nH]c2ncc(Br)c(N3CCC[C@@H](NC(=O)OC(C)(C)C)C3)c12
Temperature: 155 °C
Yield: 81.7 %

Procedure:
N-(5-Bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)acetamide (400 mg, 1.47 mmol) and (R)-tert-butyl piperidin-3-ylcarbamate (1.0 g, 5.15 mmol) were placed in n-butanol (4 mL) and heated to 155° C. in a sealed tube for 18 hours. The reaction was then cooled and concentrated. The resulting residue was purified by C-18 reverse phase flash chromatography (Biotage Horizon unit, C-18 25M column, 5-85% CH3CN/water) to give (R)-tert-butyl 1-(3-acetamido-5-bromo-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate (543 mg, 77% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:44]=[C:43]([CH3:45])[CH:42]=[C:41]([Cl:46])[C:3]=1[O:4][CH2:5][CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH:15]([C:25]2[CH:30]=[CH:29][C:28](B3OC(C)(C)C(C)(C)O3)=[CH:27][C:26]=2[CH3:40])[CH2:16][NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:10][CH:9]=1.[CH3:47][N:48]([CH3:53])[C:49](=[O:52])[CH2:50][CH3:51]>>[Cl:46][C:41]1[CH:42]=[C:43]([CH3:45])[CH:44]=[C:2]([Cl:1])[C:3]=1[O:4][CH2:5][CH2:6][O:7][C:8]1[CH:9]=[CH:10][C:11]([CH2:14][CH:15]([C:25]2[CH:30]=[CH:29][C:28]([C:2]3[CH:44]=[CH:43][CH:42]=[CH:41][C:3]=3[CH2:51][CH2:50][C:49]([N:48]([CH3:53])[CH3:47])=[O:52])=[CH:27][C:26]=2[CH3:40])[CH2:16][NH:17][C:18](=[O:24])[O:19][C:20]([CH3:22])([CH3:23])[CH3:21])=[CH:12][CH:13]=1
Reactant: CCC(=O)N(C)C
Reactant: Cc1cc(Cl)c(OCCOc2ccc(CC(CNC(=O)OC(C)(C)C)c3ccc(B4OC(C)(C)C(C)(C)O4)cc3C)cc2)c(Cl)c1
Product: Cc1cc(Cl)c(OCCOc2ccc(CC(CNC(=O)OC(C)(C)C)c3ccc(-c4ccccc4CCC(=O)N(C)C)cc3C)cc2)c(Cl)c1

Procedure:
Prepared according to the procedure described in EXAMPLE 7, step 2 using tert-butyl {3-{4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]phenyl}-2-[2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]propyl}carbamate from EXAMPLE 9, step 1 and 342-bromophenyl)-N,N-dimethylpropanamide (V.12) as starting materials. Purification by column chromatography on silica gel (Combi-Flash by ISCO), eluting with Hex/EtOAc (10 to 75% in 30 min) afforded the desired compound as a colorless oil.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][C:12]=1[OH:13])[CH:8]=[O:9])[C:2]#[CH:3].C([O-])([O-])=O.[K+].[K+].CN(C=O)C.[Br:25][CH:26](Br)[CH3:27]>O>[CH2:1]([O:4][C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][C:12]=1[O:13][CH2:27][CH2:26][Br:25])[CH:8]=[O:9])[C:2]#[CH:3]
Reactant: CC(Br)Br
Reactant: C#CCOc1cc(C=O)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: C#CCOc1cc(C=O)ccc1OCCBr
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 76.5 %

Procedure:
To a dry two-neck flask, compound 8 (4.3 g, 24 mmol, 1 equiv) and K2CO3 (16 g, 120 mmol, 5 equiv) were added into anhydrous DMF (50 mL) under nitrogen. The mixture was stirred at rt for 30 min. Dibromoethane (21 mL, 240 mmol, 10 equiv) was then added in one portion and the resulting mixture was heated overnight at 55° C. under a nitrogen atmosphere. The mixture was poured into water (400 mL) and the product was extracted with ethyl acetate (3×200 mL). The combined organic extracts were concentrated to about 250 mL and were washed subsequently with 1 M NaOH (2×200 mL), water (250 mL) and brine (5×250 mL). The organic layer was dried over MgSO4, filtered and the solvent was removed under vacuum. The crude product as yellow oil was chromatographed on a silica gel column with the eluent of ethyl acetate/hexane (20/80) to give pure product as a white solid (5.2 g, yield: 77%). 1H NMR δ=9.88 (s, 1H, —CHO), 7.58 (d, J=1.8, 1H), 7.54 (dd, J1=1.8, J2=8, 1H), 7.02 (d, J=8, 1H), 4.83 (d, J=2.3, 2H, —OCH2), 4.43 (t, J=6.6, 2H, —OCH2CH2Br), 3.72 (t, J=6.6, 2H, —OCH2CH2Br), 2.54 (t, J=2.3, 1H, —C≡CH). 13C NMR δ=190.68 (—CHO), 153.70, 147.77, 130.79, 127.01, 113.95, 113.19, 78.01 (—C≡CH), 76.63 (—C≡CH), 68.98 (—OCH2CH2Br), 57.16 (—OCH2C≡CH), 28.45 (—OCH2CH2Br). HRMS calculated for C12H11BrO3 (M+), 281.9892; found, 281.9903.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[C:7](Br)[C:8]([F:12])=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:14]([NH:16][CH2:17][CH2:18][CH3:19])=[O:15].[F:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([O:27][CH3:28])[C:22]=1B(O)O>>[NH2:1][C:2]1[C:11]2[C:6](=[C:7]([C:22]3[C:23]([O:27][CH3:28])=[CH:24][CH:25]=[CH:26][C:21]=3[F:20])[C:8]([F:12])=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:14]([NH:16][CH2:17][CH2:18][CH3:19])=[O:15]
Reactant: CCCNC(=O)c1nnc2c(Br)c(F)ccc2c1N
Reactant: COc1cccc(F)c1B(O)O
Product: CCCNC(=O)c1nnc2c(-c3c(F)cccc3OC)c(F)ccc2c1N

Procedure:
Using Method G, 4-amino-8-bromo-7-fluoro-N-propyl-cinnoline-3-carboxamide and 2-fluoro-6-methoxy-phenyl boronic acid were reacted to afford the title compound as a white solid. 1H NMR (500 MHz, DMSO-d6) δ 9.16 (br, 1H), 9.06 (m, 1H), 8.58 (m, 1H), 8.32 (br, 1H), 7.76(m, 1H), 7.50 (m, 1H), 7.02(m, 1H), 6.94(m, 1H), 3.68 (s, 3H), 3.31-3.25 (m, 2H), 1.57 (m, 2H), 0.89 (t, J=7.0 Hz, 3H). MS APCI, m/z=373 (M+H).
Reaction SMILES: C(OP([CH2:9]/[C:10](/[CH3:17])=[CH:11]/[C:12]([O:14][CH2:15][CH3:16])=[O:13])(OCC)=O)C.[Br:18][C:19]1[C:28]2[C:27]([CH3:30])([CH3:29])[CH2:26][CH:25]=[C:24]([CH:31]([CH3:33])[CH3:32])[C:23]=2[CH:22]=[C:21](/[C:34](/[CH3:39])=[C:35](/[F:38])\[CH:36]=O)[C:20]=1[O:40][CH:41]([CH3:43])[CH3:42]>>[Br:18][C:19]1[C:28]2[C:27]([CH3:30])([CH3:29])[CH2:26][CH:25]=[C:24]([CH:31]([CH3:33])[CH3:32])[C:23]=2[CH:22]=[C:21](/[C:34](/[CH3:39])=[C:35](/[F:38])\[CH:36]=[CH:9]\[C:10](\[CH3:17])=[CH:11]\[C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:20]=1[O:40][CH:41]([CH3:43])[CH3:42]
Reactant: CCOC(=O)/C=C(\C)CP(=O)(OCC)OCC
Reactant: C/C(=C(\F)C=O)c1cc2c(c(Br)c1OC(C)C)C(C)(C)CC=C2C(C)C
Product: CCOC(=O)/C=C(C)/C=C/C(F)=C(/C)c1cc2c(c(Br)c1OC(C)C)C(C)(C)CC=C2C(C)C

Procedure:
Following General Procedure I-1, ethyl 4-(diethoxyphosphoryl)-3-methyl-but-2E-enoate (417 mg, 1.58 mmol) and (2E)-3-(4-bromo-3-isopropoxy-8-isopropyl-5,5-dimethyl-5,6-dihydro-naphthalen-2-yl)-2-fluoro-but-2-enal (Compound A-150, 167 mg, 0.39 mmol) were reacted to give the title compound as a colorless oil after purification by column chromatography (silica gel, 2% ethyl acetate in hexane).