Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[C:5](Br)=[N:6][CH:7]=[CH:8][CH:9]=1)(=[O:3])[CH3:2].[C:11]1([C:17]#[CH:18])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.CCN(C(C)C)C(C)C.[Cl-]>CN(C=O)C.C(Cl)Cl>[C:11]1([C:17]#[C:18][C:5]2[C:4]([C:1](=[O:3])[CH3:2])=[CH:9][CH:8]=[CH:7][N:6]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CC(=O)c1cccnc1Br
Reactant: C#Cc1ccccc1
Agent: [Cl-]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(=O)c1cccnc1C#Cc1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Step 1 (=Reaction 1): 66 mg 3-Acetyl-2-bromopyridine, 56 μL phenylacetylene, 170 μL DIPEA, 22.5 mg triphenylphosphinpalladium(II) chlorid, 3 mg Cu(I)I were suspended in 1 mL DMF under argon atmosphere and stirred for 16 h at 25° C. The mixture was diluted with DCM and extracted with diluted aq. NH3 and brine. The organic phase was concentrated and the mixture separated via flash chromatography (10 g SiO2, cyclohexane→cyclohexane/ethylacetate 70:30) to yield 40 mg 1-(2-(phenylethynyl)pyridin-3-yl)ethanone as solid. Analysis: HPLC-MS: Rt=1.21 min (method E), M+H=222.
Reaction SMILES: [C:1]([C@H:5]1[CH2:10][CH2:9][C@H:8]([O:11][C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH2:18][C@@H:17]([C@:22]2([CH3:28])[CH2:26][O:25]C(=O)[NH:23]2)[CH2:16][CH2:15]3)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Li+].C(O)C.O>>[NH2:23][C@@:22]([C@H:17]1[CH2:16][CH2:15][C:14]2[C:19](=[CH:20][CH:21]=[C:12]([O:11][C@H:8]3[CH2:7][CH2:6][C@H:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH2:10][CH2:9]3)[CH:13]=2)[CH2:18]1)([CH3:28])[CH2:26][OH:25]
Reactant: CC(C)(C)[C@H]1CC[C@H](Oc2ccc3c(c2)CC[C@H]([C@]2(C)COC(=O)N2)C3)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(C)(C)[C@H]1CC[C@H](Oc2ccc3c(c2)CC[C@H]([C@@](C)(N)CO)C3)CC1

Procedure:
The mixture of (R)-4-((S)-6-(trans-4-tert-butylcyclohexyloxy)-1,2,3,4-tetrahydronaphthalen-2-yl)-4-methyloxazolidin-2-one (46.6 mg, 0.000121 mol) (from isomer 4) and lithium hydroxide (31.8 mg, 0.00133 mol) in ethanol (0.77 mL, 0.013 mol) and water (0.26 mL, 0.014 mol) was heated to reflux for overnight. LCMS showed starting material was consumed and peak Rf=1.66 min left. The solvent was removed under vacuum and the residue was partitioned between water and dichloromethane. The aqueous layer was extensively extracted with dichloromethane and the combined organic phase was dried over Na2SO4. The concentrated residue was taken up into dichloromethane and subjected to chromatography purification with dichloromethane/MeOH (10:90 to 80:20) to give the product. (15.7 mg, 36% yield). LCMS 360.43 ([M+1], 100%). NMR (400 MHz, CD3OD) δ ppm 0.89 (s, 9H), 1.07 (s, 3H), 1.09-1.54 (m, 6H), 1.79-1.87 (m, 3H), 2.04 (m, 1H), 2.15 (m, 2H), 2.53 (dd, J=15.5, 12.3 Hz, 1H), 2.72-2.86 (m, 3H), 3.46 (d, J=11.0 Hz, 1H), 3.55 (d, J=11.0 Hz, 1H), 4.07 (m, 1H), 6.59 (d, J=2.4 Hz, 1H), 6.63 (dd, J=8.3, 2.5 Hz, 1H), 6.94 (d, J=8.3 Hz, 1H).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]1[CH2:17][CH2:16][C@@H:15]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH2:14][C@H:13]1[CH2:26][OH:27])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.I[CH3:29]>CN(C)C=O>[CH2:1]([O:8][C:9]([NH:11][C@H:12]1[CH2:17][CH2:16][C@@H:15]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:22])([CH3:23])[CH3:24])[CH2:14][C@H:13]1[CH2:26][O:27][CH3:29])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CI
Reactant: CC(C)(C)OC(=O)N[C@@H]1CC[C@H](NC(=O)OCc2ccccc2)[C@H](CO)C1
Solvent: CN(C)C=O
Product: COC[C@@H]1C[C@H](NC(=O)OC(C)(C)C)CC[C@@H]1NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of tert-butyl (1R,3R,4S)-4-benzyloxycarbonylamino-3-(hydroxymethyl)cyclohexylcarbamate (1.8 g) in N,N-dimethylformamide (15 mL)was treated sequentially with iodomethane (50 mL) and Ag2O (5.52 g), and the mixture was stirred at rt overnight. The mixture was filtered through Celite and the solids were washed with ethyl acetate. The combined filtrates were washed sequentially with water and brine, dried over Na2SO4 and concentrated. The residue was purified by flash chromatography on silica gel, eluting with 1:3 v/v ethyl acetate-hexane, to provide tert-butyl (1R,3R,4S)-4-benzyloxycarbonylamino-3-(methoxymethyl)cyclohexylcarbamate as a colorless gum (1.78 g). MS found: (M+H)+=393.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:20][O:21][CH2:22][CH3:23])[N:14]([CH2:15][C:16]([CH3:19])([OH:18])[CH3:17])[C:10]=2[C:9]2[CH:8]=[CH:7][C:6](Br)=[CH:5][C:4]=2[N:3]=1.[CH:25]([B-](F)(F)F)=[CH2:26].[K+].C(N(CC)CC)C>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(O)CC>[NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:20][O:21][CH2:22][CH3:23])[N:14]([CH2:15][C:16]([CH3:19])([OH:18])[CH3:17])[C:10]=2[C:9]2[CH:8]=[CH:7][C:6]([CH:25]=[CH2:26])=[CH:5][C:4]=2[N:3]=1
Reactant: CCOCc1nc2c(N)nc3cc(Br)ccc3c2n1CC(C)(C)O
Reactant: C=C[B-](F)(F)F
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: CCCO
Product: C=Cc1ccc2c(c1)nc(N)c1nc(COCC)n(CC(C)(C)O)c12
Temperature: 80 °C
Yield: 30.4 %

Procedure:
A round bottom flask, equipped with a stir bar, was charged with 1-[4-amino-7-bromo-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]-2-methylpropan-2-ol (1.18 g, 3.0 mmol), 1-propanol (30 mL), potassium vinyltrifluoroborate (0.4 g, 3.0 mmol), triethylamine (1.25 mL, 9.0 mmol) and dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium (II) dichloromethane adduct (Pd(dppf)), (11 mg, 0.015 mmol). The reaction mixture was heated at 80° C. for 66 hours. The reaction mixture was cooled to ambient temperature and then concentrated to dryness under reduced pressure. The solid was dissolved in dichloromethane (100 mL) and washed with saturated aqueous potassium carbonate (50 mL). The fractions were separated and the organic fraction was concentrated to dryness. The off-white solid was purified by chromatography using a HORIZON HPFC system (silica cartridge, 0-15% CMA/chloroform). Recrystallization from acetonitrile provided 0.31 g of 1-[4-amino-2-(ethoxymethyl)-7-vinyl-1H-imidazo[4,5-c]quinolin-1-yl]-2-methylpropan-2-ol as an off-white crystalline solid. MS (APCI) m/z 341 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([CH3:25])=[C:11]2[C:16](=[C:17]([CH3:20])[C:18]=1[CH3:19])[O:15][C:14]([CH3:24])([CH2:21][CH2:22][OH:23])[CH2:13][CH2:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:26]1([CH3:60])[CH:31]=[CH:30][C:29]([S:32]([O:35]CCC2(C)CCC3C(=C(C)C(C)=C(OCC4C=CC=CC=4)C=3C)O2)(=[O:34])=[O:33])=[CH:28][CH:27]=1>>[CH2:1]([O:8][C:9]1[C:10]([CH3:25])=[C:11]2[C:16](=[C:17]([CH3:20])[C:18]=1[CH3:19])[O:15][C:14]([CH3:24])([CH2:21][CH2:22][OH:23])[CH2:13][CH2:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:26]1([CH3:60])[CH:27]=[CH:28][C:29]([S:32]([O-:35])(=[O:33])=[O:34])=[CH:30][CH:31]=1
Reactant: Cc1ccc(S(=O)(=O)OCCC2(C)CCc3c(C)c(OCc4ccccc4)c(C)c(C)c3O2)cc1
Agent: Cc1c(C)c2c(c(C)c1OCc1ccccc1)CCC(C)(CCO)O2
Product: Cc1ccc(S(=O)(=O)[O-])cc1

Procedure:
Using the procedure of Example 8, rac.-6-benzyloxy-2,5,7,8-tetramethylchroman-2ethanol was converted into rac.-6-benzyloxy-2,5,7,8-tetramethylchroman-2-ethanol p-toluenesulfonate which was obtained in essentially quantitative yield as a pale-pink glass.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[NH2:8][C@H:9]1[CH2:15][O:14][C:13]2[CH:16]=[C:17](C)[CH:18]=[CH:19][C:12]=2[NH:11][C:10]1=[O:21].C(OC(N[C@@H](CO)C(O)=O)=O)(C)(C)C.FC1C=CC([C:43]([F:46])([F:45])[F:44])=CC=1[N+]([O-])=O>CCCCCC>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[NH2:8][C@H:9]1[CH2:15][O:14][C:13]2[CH:16]=[CH:17][C:18]([C:43]([F:46])([F:45])[F:44])=[CH:19][C:12]=2[NH:11][C:10]1=[O:21]
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1F
Reactant: Cc1ccc2c(c1)OC[C@H](N)C(=O)N2
Agent: CC(C)(C)OC(=O)N[C@@H](CO)C(=O)O
Solvent: CCCCCC
Solvent: O=C(O)C(F)(F)F
Product: N[C@H]1COc2ccc(C(F)(F)F)cc2NC1=O

Procedure:
In a similar manner to that described for the preparation of (S)-3-amino-8-methyl-2,3-dihydrobenzo[b][1,4]oxazepin-4(5H)-one trifluoroacetate except in Step 3 the reaction mixture was stirred for 4 h and in the material obtained in Step 4 was triturated with hexane, (S)-2-(tert-butoxycarbonylamino)-3-hydroxypropanoic acid (4.1 g, 20.0 mmol) and 1-fluoro-2-nitro-4-(trifluoromethyl)benzene (4.18 g, 20.0 mmol) were converted to the title compound (1.06 g) which was used without purification.
Reaction SMILES: [CH:1](=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].[ClH:13].Cl.[F:15][C:16]([F:32])([F:31])[C:17]1[CH:30]=[CH:29][C:20]([CH2:21][NH:22][C:23]([NH:25][C:26]([NH2:28])=[NH:27])=[NH:24])=[CH:19][CH:18]=1>C(O)C>[ClH:13].[NH2:28][C:26]1[NH:25][C:23]([NH:22][CH2:21][C:20]2[CH:29]=[CH:30][C:17]([C:16]([F:15])([F:31])[F:32])=[CH:18][CH:19]=2)=[N:24][CH:1]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[N:27]=1
Reactant: CCCCCCCCCCC=O
Reactant: N=C(N)NC(=N)NCc1ccc(C(F)(F)F)cc1
Agent: Cl
Solvent: CCO
Product: CCCCCCCCCCC1N=C(N)NC(NCc2ccc(C(F)(F)F)cc2)=N1

Procedure:
100 ml of ethanol, 5.3 ml (25.7 mmol) of 1-undecanal and 0.7 ml of concentrated hydrochloric acid were added to 5.01 g (16.9 mmol) of N1-(4-trifluoromethylbenzyl)-biguanide hydrochloride, and the mixture was refluxed for 24 hours. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography. The first main fraction eluted with a mixture of chloroform and methanol (9:1.5) was recrystallized from 80% aqueous acetonitrile to obtain 1.41 g of colorless crystals (1) having a melting point of 163 to 166° C., and the second main eluate was recrystallized from 80% aqueous acetonitrile to obtain 0.87 g of colorless crystals (2) having a melting point of 208 to 211° C.
Reaction SMILES: [C:1]([CH2:3][C:4]1[CH:5]=[C:6]([CH:20]=[CH:21][C:22]=1[O:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[C:7]([C:9]1[CH:10]=[C:11]([CH:17]=[CH:18][CH:19]=1)[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[O:8])#[N:2].C([Sn]([N:47]=[N+:48]=[N-:49])(CCCC)CCCC)CCC.Cl.CO>O1CCCC1>[CH2:24]([O:23][C:22]1[CH:21]=[CH:20][C:6]([C:7]([C:9]2[CH:10]=[C:11]([CH:17]=[CH:18][CH:19]=2)[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[O:8])=[CH:5][C:4]=1[CH2:3][C:1]1[NH:49][N:48]=[N:47][N:2]=1)[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]
Reactant: CCCC[Sn](CCCC)(CCCC)N=[N+]=[N-]
Reactant: CCCCCCCCCCOc1ccc(C(=O)c2cccc(C(=O)OCC)c2)cc1CC#N
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Product: CCCCCCCCCCOc1ccc(C(=O)c2cccc(C(=O)OCC)c2)cc1Cc1nnn[nH]1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 54 %

Procedure:
A mixture of 1.0 g of the product from Example 1 and 2.2 g of tri-n-butylstannylazide in 30 ml of tetrahydrofuran was heated at reflux for 10 days. The reaction was allowed to cool to ambient temperature. A mixture of hydrochloric acid and methanol was added, and after stirring for 30 minutes, the mixture was concentrated in vacuo. The residue was purified by chromatography over silica gel eluting with a 30-75% ethyl acetate in hexane gradient which additionally contained 0.05% acetic acid. The appropriate fractions were cooled and concentrated to provide 592 mg of product. Recrystallization from hexane/ethyl acetate provided 580 mg of the desired title product.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[CH2:15][C:16]([O:18][CH3:19])=[O:17])=[CH:4][CH:3]=1.Br[CH2:21][CH2:22][CH2:23][Cl:24]>>[Cl:24][CH2:23][CH2:22][CH2:21][O:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[CH2:15][C:16]([O:18][CH3:19])=[O:17])=[CH:4][CH:3]=1
Reactant: COC(=O)Cc1ccccc1Sc1ccc(O)cc1
Reactant: ClCCCBr
Product: COC(=O)Cc1ccccc1Sc1ccc(OCCCCl)cc1
Yield: 73.3 %

Procedure:
Using the procedure described in Example 34, methyl 2-(4-hydroxyphenylsulfanyl)phenyl-acetate and 1-bromo-3-chloropropane provided 73.3% yield of the title ester, m.p. 48-51° C. For C18H19ClO3S (350.9) calculated: 61.62% C, 5.46% H, 10.10% Cl, 9.14% S; found: 61.12% C, 5.44% H, 10.15% Cl, 9.13% S. 1H NMR spectrum (CDCl3): CH2(COO) 3.84 s; CH3 3.67 s; CH2(O) 4.09 t, J=6.0 Hz; CH2(Cl) 3.73 t, J=6.0 Hz.
Reaction SMILES: Br[C:2]1[C:3]([N:22]2[CH2:25][CH:24]([CH2:26][OH:27])[CH2:23]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[Cl:28][C:29]1[C:34]([F:35])=[CH:33][C:32](B2OC(C)(C)C(C)(C)O2)=[CH:31][N:30]=1>>[Cl:28][C:29]1[N:30]=[CH:31][C:32]([C:2]2[C:3]([N:22]3[CH2:23][CH:24]([CH2:26][OH:27])[CH2:25]3)=[N:4][CH:5]=[C:6]([C:7]([NH:9][C:10]3[CH:11]=[CH:12][C:13]([O:16][C:17]([F:18])([F:20])[F:19])=[CH:14][CH:15]=3)=[O:8])[CH:21]=2)=[CH:33][C:34]=1[F:35]
Reactant: CC1(C)OB(c2cnc(Cl)c(F)c2)OC1(C)C
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CC(CO)C2)c(Br)c1
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CC(CO)C2)c(-c2cnc(Cl)c(F)c2)c1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 53 using 5-bromo-6-(3-(hydroxymethyl)azetidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 135.1) and 2-chloro-3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine. HPLC (Condition 4) tR=5.57 min, UPLC-MS (Condition 3) tR=1.13 min, m/z=497.1 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 2.55-2.70 (m, 1H) 3.39-3.53 (m, 4H) 3.73 (t, J=1.00 Hz, 2H) 4.69 (t, J=1.00 Hz, 1H) 7.34 (d, J=8.21 Hz, 2H) 7.83 (m, J=9.40 Hz, 2H) 8.04 (d, J=1.95 Hz, 1H) 8.09 (m, J=9.40 Hz, 1H) 8.38 (d, J=1.95 Hz, 1H) 8.77 (d, J=2.35 Hz, 1H) 10.19 (s, 1H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:12][CH2:11][C@:10]([CH2:15][CH3:16])([C:13]#[N:14])[C:9]2=[O:17])[CH:5]=[CH:4][N:3]=1.[NH2:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2([CH2:31][OH:32])[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)=[CH:21][CH:20]=1.C(O)(=O)C>C(O)C>[CH2:15]([C@:10]1([C:13]#[N:14])[CH2:11][CH2:12][N:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]4([CH2:31][OH:32])[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)=[CH:21][CH:20]=3)[N:7]=2)[C:9]1=[O:17])[CH3:16]
Reactant: CC[C@]1(C#N)CCN(c2ccnc(Cl)n2)C1=O
Reactant: Nc1ccc(C2(CO)CCOCC2)cc1
Solvent: CC(=O)O
Solvent: CCO
Product: CC[C@]1(C#N)CCN(c2ccnc(Nc3ccc(C4(CO)CCOCC4)cc3)n2)C1=O
Temperature: 150 °C
Reaction time: 1 h
Yield: 59.5 %

Procedure:
To a solution of (3R)-1-(2-chloropyrimidin-4-yl)-3-ethyl-2-oxopyrrolidine-3-carbonitrile (100 mg) obtained in Step A of Example 8 in ethanol (3.0 mL) were added (4-(4-aminophenyl)tetrahydro-2H-pyran-4-yl)methanol (83 mg) obtained in Step B of Example 152 and acetic acid (25 μL), and the mixture was stirred in a microwave reactor at 150° C. for 1 hr. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate), and recrystallized (hexane/ethyl acetate) to give the title compound (100 mg).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[N:13][CH:14]=[CH:15][CH:16]=3)[N:11]=[C:10]([C:18]3[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:19]=3[F:25])[CH:9]=2)[CH:5]=[N:6][CH:7]=1.[CH3:26][N:27]([CH3:45])[CH2:28][CH2:29][CH2:30][N:31]1[CH:35]=[C:34](B2OC(C)(C)C(C)(C)O2)[CH:33]=[N:32]1.O.O.O.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C(N(CC)CC)C>COCCOC.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[Cl:24][C:22]1[CH:21]=[CH:20][C:19]([F:25])=[C:18]([C:10]2[CH:9]=[C:8]([C:4]3[CH:3]=[C:2]([C:34]4[CH:33]=[N:32][N:31]([CH2:30][CH2:29][CH2:28][N:27]([CH3:26])[CH3:45])[CH:35]=4)[CH:7]=[N:6][CH:5]=3)[C:17]3[C:12](=[N:13][CH:14]=[CH:15][CH:16]=3)[N:11]=2)[CH:23]=1
Reactant: Fc1ccc(Cl)cc1-c1cc(-c2cncc(Br)c2)c2cccnc2n1
Reactant: CN(C)CCCn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: Cl[Pd]Cl
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCN(CC)CC
Solvent: COCCOC
Product: CN(C)CCCn1cc(-c2cncc(-c3cc(-c4cc(Cl)ccc4F)nc4ncccc34)c2)cn1
Temperature: 85 °C
Reaction time: 2 h

Procedure:
A slurry of 500 mg (1.21 mmol) 4-(5-bromo-pyridin-3-yl)-2-(5-chloro-2-fluoro-phenyl)-[1,8]naphthyridine, 370 mg (1.33 mmol) dimethyl-{3-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrazol-1-yl]-propyl}-amine and 512 mg (2.41 mmol) tri-potassium-phosphate-trihydrate in 5 ml 1,2-dimethoxyethane is heated to 85° C. under nitrogen. Then 42.3 mg (0.06 mmol) bis-(triphenylphosphine)-palladium(II)-chloride and 17 μl triethylamine were added. The reaction mixture was stirred for 2 hours at 85° C. The reaction mixture was partitioned between water and dichloromethane. The organic phase was dried over sodium sulfate and evaporated. The residue was crystallized from acetonitrile yielding [3-(4-{5-[2-(5-chloro-2-fluoro-phenyl)-[1,8]naphthyridin-4-yl]-pyridin-3-yl}-pyrazol-1-yl)-propyl]-dimethyl-amine as light grey crystals; HPLC-MS: 1.64 min, [M+H] 487.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[C:17](=[S:30])[C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:20][CH:19]=1)[O:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]([OH:13])=[O:12].[CH2:31]([OH:38])[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][OH:37]>>[OH:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[C:17](=[S:30])[C:18]1[CH:19]=[CH:20][C:21]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:22][CH:23]=1)[O:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][C:31]([O:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:11](=[O:13])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][O:5][C:4]1[CH:14]=[CH:15][C:16]([C:17](=[S:30])[C:18]2[CH:19]=[CH:20][C:21]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)=[CH:22][CH:23]=2)=[C:2]([OH:1])[CH:3]=1)=[O:38]
Reactant: OCCCCCCO
Reactant: O=C(O)CCCCCOc1ccc(C(=S)c2ccc(-c3ccccc3)cc2)c(O)c1
Product: O=C(CCCCCOc1ccc(C(=S)c2ccc(-c3ccccc3)cc2)c(O)c1)OCCCCCCOC(=O)CCCCCOc1ccc(C(=S)c2ccc(-c3ccccc3)cc2)c(O)c1

Procedure:
Following the general procedure of Example 13 or Example 17, the title compound is prepared by reacting an equivalent amount of the acid compound of Example 16 with a half equivalent amount of 1,6-hexanediol.
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:10]=[C:9]([C:19]3[CH:30]=[CH:29][C:22]([CH2:23]OS(C)(=O)=O)=[CH:21][CH:20]=3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:31][O:32][C:33](=[O:45])[C@H:34]([CH2:43][SH:44])[NH:35][C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37].C(=O)([O-])[O-].[Cs+].[Cs+].CN(C)C=O>O>[CH3:31][O:32][C:33](=[O:45])[CH:34]([NH:35][C:36]([O:38][C:39]([CH3:42])([CH3:40])[CH3:41])=[O:37])[CH2:43][S:44][CH2:23][C:22]1[CH:21]=[CH:20][C:19]([C:9]2[N:8]=[C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH:12]=[C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:10]=2)=[CH:30][CH:29]=1
Reactant: CS(=O)(=O)OCc1ccc(-c2nc(-c3ccccc3)cc(-c3ccccc3)n2)cc1
Reactant: COC(=O)[C@H](CS)NC(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)C(CSCc1ccc(-c2nc(-c3ccccc3)cc(-c3ccccc3)n2)cc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of Methanesulfonic acid 4-(4,6-diphenylpyrimidin-2-yl)-benzyl ester, 0.15 g (0.36 mmol), N-(tert-Butoxycarbonyl)-L-cysteine methyl ester, 0.08 mL (0.36 mmol), cesium carbonate, 235 mg (0.72 mmol), and 10 mL of N,N-dimethylformamide was stirred at room temperature for 4 h. The mixture was diluted with 10 mL of water and extracted with 2×50 mL of ethyl acetate. The organic layer was washed with 2×50 mL portions of aq. LiCl, sat. aq. NaHCO3, sat. aq. NaCl, and dried (MgSO4). After the solution was concentrated, the residue was purified by column chromatography (eluted with 7% EtOAc-Heptane) to afford the desired product in 0.18 g (90%) as a white solid. 1H NMR (CDCl3) 8.67 (d, 2H, J=9.0 Hz), 8.30-8.27 (m, 4H), 8.02 (s, 1H), 7.61-7.55 (m, 6H), 7.47 (d, 2H, J=9.0 Hz), 5.30 (d, 1H, J=7.7 Hz), 4.63-4.52 (m, 1H), 3.82 (s, 2H), 3.76 (s, 3H), 2.93 (dd, 1H, J=15.7, 6.0 Hz), 2.84 (dd, 1H, J=15.7, 6.7 Hz), 1.47 (s, 9H).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]3[N:14]=[C:15]([C:17]4[CH:22]=[CH:21][C:20]5[NH:23][C:24]([NH:32][C:19]=5[CH:18]=4)=[C:25]4[CH:31]=[CH:30][C:28](=[O:29])[CH:27]=[CH:26]4)[NH:16][C:10]=3[CH:9]=2)[CH2:4][CH2:3]1.[CH:33]1(N=C=NC2CCCCC2)CCCC[CH2:34]1.C(O)(=O)CCC(O)=O>C(Cl)(Cl)Cl>[CH3:33][CH2:34][O:29][C:28]1[CH:30]=[CH:31][C:25]([C:24]2[NH:32][C:19]3[CH:18]=[C:17]([C:15]4[NH:16][C:10]5[CH:9]=[C:8]([N:5]6[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]6)[CH:13]=[CH:12][C:11]=5[N:14]=4)[CH:22]=[CH:21][C:20]=3[N:23]=2)=[CH:26][CH:27]=1
Reactant: CN1CCN(c2ccc3nc(-c4ccc5c(c4)NC(=C4C=CC(=O)C=C4)N5)[nH]c3c2)CC1
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=C(O)CCC(=O)O
Solvent: ClC(Cl)Cl
Product: CCOc1ccc(-c2nc3ccc(-c4nc5ccc(N6CCN(C)CC6)cc5[nH]4)cc3[nH]2)cc1
Yield: 80 %

Procedure:
A solution of bisbenzimidazole (6 g; 0.01 mol) dicyclohexylcarbodiimide (0.05 mol) and Succinic acid (0.01 mol) in 100 mL chloroform is stirred overnight for 18-24 hrs. During this time, a white precipitate is formed. The precipitate is filtered and washed with chloroform (2×50 mL). The chloroform washes are combined and concentrated under vacuum in a rotary evaporator and the residue purified by flash column chromatography. The fractions containing the product are combined and concentrated under vacuum in a rotary evaporate to afford bisbenzimide succinnate ester (80%) as a white solid.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:11]1[C:42]([CH3:43])=[N:41][C:40]2=[CH:44][C:37]3=[N:38][N:39]2[C:12]=1[C:13]1[CH:47]=[C:46]2[C:16]([O:17][CH2:18][CH2:19][N:20]2[CH2:21][CH:22]=[CH:23][CH2:24][CH2:25][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:31]=2[C:32]2[CH:45]=[C:36]3[CH:35]=[CH:34][CH:33]=2)=[CH:15][C:14]=1[F:48])[C:7]([O:9][CH3:10])=[O:8])([CH3:4])([CH3:3])[CH3:2]>CO.[Pd]>[C:1]([O:5][C@@H:6]([C:11]1[C:42]([CH3:43])=[N:41][C:40]2=[CH:44][C:37]3=[N:38][N:39]2[C:12]=1[C:13]1[CH:47]=[C:46]2[C:16]([O:17][CH2:18][CH2:19][N:20]2[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:31]=2[C:32]2[CH:45]=[C:36]3[CH:35]=[CH:34][CH:33]=2)=[CH:15][C:14]=1[F:48])[C:7]([O:9][CH3:10])=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)[C@@H](OC(C)(C)C)c1c(C)nc2cc3nn2c1-c1cc2c(cc1F)OCCN2CC=CCCc1ccccc1-c1cccc-3c1
Agent: [Pd]
Solvent: CO
Product: COC(=O)[C@@H](OC(C)(C)C)c1c(C)nc2cc3nn2c1-c1cc2c(cc1F)OCCN2CCCCCc1ccccc1-c1cccc-3c1
Reaction time: 18 h

Procedure:
A solution of methyl (2S)-2-(tert-butoxy)-2-[32-fluoro-4-methyl-29-oxa-5,7,8,26-tetraazaheptacyclo[24.6.2.16,9.110,14.02,7.015,20.030,34]hexatriaconta-1 (32),2,4,6(36),8,10(35),11,13,15 (20),16,18,23,30,33-tetradecaen-3-yl]acetate (0.023 g, 0.036 mmol) in MeOH (5 mL) was treated with 10 wt % Pd/C (4 mg, 0.04 mmol), evacuated and hydrogen back-filled three times, then stirred under hydrogen atmosphere for 18 h. The crude mixture was filtered (0.45 μm syringe tip filter) and the filtrate solution was used immediately in the following step. LCMS (M+H)=649.5.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=2[C:12]([O-:14])=[O:13])=O)=[CH:4][C:3]=1[N+:19]([O-:21])=[O:20].[BH4-].[Na+]>C1COCC1.CO>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:10]3[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=3[C:12](=[O:14])[O:13]2)=[CH:4][C:3]=1[N+:19]([O-:21])=[O:20]
Reactant: Nc1ccc(C(=O)c2ccccc2C(=O)[O-])cc1[N+](=O)[O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: Nc1ccc(C2OC(=O)c3ccccc32)cc1[N+](=O)[O-]
Reaction time: 0.67 h

Procedure:
To a solution of 2-[(4-amino-3-nitrophenyl)carbonyl]benzoate (8.36 g, 27.8 mmol) in THF (100 mL) and methanol (30 mL) at 0° C. was added sodium borohydride (3.0 g, 79 mmol). The mixture was stirred for 40 min, and then unreacted hydride was quenched with 10% aqueous citric acid. The organic solvents were removed in vacuo. An orange solid precipitated from the resulting aqueous mixture. This solid was collected by filtration, rinsed with water, triturated with ether, and dried in vacuo. Desired 3-(4-amino-3-nitrophenyl)-2-benzofuran-1(3H)-one was obtained as a bright orange solid (5.23 g, 19.4 mmol, 69% yield). 1H NMR (400 MHz, d6-DMSO): 8.03 (d, 1H), 7.90 (d, 1H), 7.76 (t, 1H), 7.65-7.60 (m, 3H), 7.45 (d, 1H), 7.11 (dd, 1H), 6.99 (d, 1H), 6.66 (s, 1H); MS (EI) for Cl4H10N2O4: 303 (MNa+).