Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]2[C:14]([NH:17][S:18]([C:21]3[CH:26]=[CH:25][C:24]([NH:27][C@@H:28]([CH2:37][S:38][C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)[CH2:29][CH2:30][N:31]4[CH2:36][CH2:35][O:34][CH2:33][CH2:32]4)=[C:23]([S:45]([C:48]([F:51])([F:50])[F:49])(=[O:47])=[O:46])[CH:22]=3)(=[O:20])=[O:19])=[N:15][N:16]=[C:10]2[CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[N:31]1([CH2:30][CH2:29][C@@H:28]([NH:27][C:24]2[CH:25]=[CH:26][C:21]([S:18]([NH:17][C:14]3[N:11]4[CH2:12][CH2:13][NH:8][CH2:9][CH:10]4[NH:16][N:15]=3)(=[O:19])=[O:20])=[CH:22][C:23]=2[S:45]([C:48]([F:50])([F:51])[F:49])(=[O:47])=[O:46])[CH2:37][S:38][C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=2)[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1
Reactant: CC(C)(C)OC(=O)N1CCn2c(nnc2NS(=O)(=O)c2ccc(N[C@H](CCN3CCOCC3)CSc3ccccc3)c(S(=O)(=O)C(F)(F)F)c2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=S(=O)(NC1=NNC2CNCCN12)c1ccc(N[C@H](CCN2CCOCC2)CSc2ccccc2)c(S(=O)(=O)C(F)(F)F)c1
Reaction time: 2.5 h
Yield: 98.4 %

Procedure:
To a solution of 3-[4-((R)-3-morpholin-4-yl-1-phenylsulfanylmethyl-propylamino)-3-trifluoromethanesulfonyl-benzenesulfonylamino]-5,6-dihydro-8H-[1,2,4]triazolo[4,3-a]pyrazine-7-carboxylic acid tert-butyl ester (130 mg, 0.168 mmol) in dichloromethane (3 mL) under nitrogen was added trifluoroacetic acid (0.323 mL, 4.19 mmol), and the reaction was stirred for 2.5 hours. The reaction mixture was then concentrated and diluted with water and CH2Cl2. It was then basified to pH approximately 8 with saturated Na2CO3. The organics were extracted three times with CH2Cl2. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure to afford the title compound (112 mg, 99% yield). MS [m/z; (M+1)+]: 676.5
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[F:14][C:15]1[CH:16]=[CH:17][C:18]([CH3:24])=[C:19]([CH:23]=1)[C:20](Cl)=[O:21]>C(Cl)Cl>[F:14][C:15]1[CH:16]=[CH:17][C:18]([CH3:24])=[C:19]([C:20]([N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)=[O:21])[CH:23]=1
Reactant: Cc1ccc(F)cc1C(=O)Cl
Reactant: C1COCCN1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(F)cc1C(=O)N1CCOCC1
Reaction time: 0.25 h
Yield: 98.1 %

Procedure:
To a solution of morpholine (870 mg, 10 mmol) and triethylamine (1.1 g, 10.8 mmol) in CH2Cl2 (15 mL) was added a solution of 5-fluoro-2-methylbenzoyl chloride (1.72 g, 10 mmol) in CH2Cl2 (5 mL), dropwise, and the mixture stirred for 15 min. The mixture was then washed with water, and the organic fraction dried (MgSO4), filtered, and concentrated to obtain 2.19 g (Yield 98%) of the title compound as a solid: 1H NMR (500 MHz, CDCl3) δ ppm: 2.27 (3H, s) 3.24 (2H, d, J=4 Hz) 3.58 (2H, s) 3.79 (4H, dd, J=18, 3.8 Hz) 6.88 (1H, dd, J=8.2, 2.8 Hz) 6.92-7.05 (1H, m) 7.18 (1H, dd, J=8.4, 5.3 Hz).
Reaction SMILES: Br[C:2]1[O:6][C:5]([CH2:7][CH2:8][CH3:9])=[N:4][C:3]=1[CH2:10][O:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][O:13]1.Cl[C:19]([O:21][CH3:22])=[O:20]>C1COCC1>[CH2:7]([C:5]1[O:6][C:2]([C:19]([O:21][CH3:22])=[O:20])=[C:3]([CH2:10][O:11][CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][O:13]2)[N:4]=1)[CH2:8][CH3:9]
Reactant: COC(=O)Cl
Reactant: CCCc1nc(COC2CCCCO2)c(Br)o1
Solvent: C1CCOC1
Product: CCCc1nc(COC2CCCCO2)c(C(=O)OC)o1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 74.9 %

Procedure:
To a solution of 5-bromo-2-propyl-4-(((2-tetrahydropyranyl)oxy)methyl)oxazole (2.376 g, 7.82 mmol), prepared as in Example 29c, in 60 mL of THF and cooled to -78° C. was added n-buthylithium (8.75 mmol). The resulting solution was stirred for 30 minutes at -78° C., and 1.0 mL (12.9 mmol) of methyl chloroformate was added. The reaction mixture was stirred at -78° C. for 5 minutes and at 0° for 30 minutes. The reaction was quenched by the addition of satd NaHCO3, the layers were separated, and the aqueous layer extracted with methylene chloride. The organic extracts were combined, dried, and concentrated. The residue was chromatographed on silica gel, eluting with 10 to 25% ethyl acetate in hexane, to afford 1.660 g of the title compound as an oil. MS m/z: 284 (M+H)+. NMR (CDCl3) δ:4.95 (d, J=12 Hz, 1H), 4.82 (t, J=3 Hz, 1H), 4.67 (d, J=12 Hz, 1H), 3.94 (m, 1H), 3.92 (s, 3H), 3.57 (m, 1H), 2.80 (t, J=7.5 Hz, 2H), 1.84 (sextet, J=7.5 Hz, 2H), 1.80-1.50 (m, 6H), 1.05 (t, J=7.5 Hz, 3H).
Reaction SMILES: [F:1][C:2]1[C:3]([CH2:13][C:14]([OH:16])=[O:15])=[CH:4][C:5]2[CH:9]=[CH:8][S:7][C:6]=2[C:10]=1[O:11]C.B(F)(F)F.O>C(Cl)Cl>[F:1][C:2]1[C:3]([CH2:13][C:14]([OH:16])=[O:15])=[CH:4][C:5]2[CH:9]=[CH:8][S:7][C:6]=2[C:10]=1[OH:11]
Reactant: COc1c(F)c(CC(=O)O)cc2ccsc12
Agent: FB(F)F
Solvent: O
Solvent: ClCCl
Product: O=C(O)Cc1cc2ccsc2c(O)c1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 86.7 %

Procedure:
In 17.4 mL of methylene chloride is suspended 1.74 g of 2-(6-fluoro-7-methoxybenzo[b]thiophen-5-yl)-acetic acid, to which is added 13.8 mL of 1 mol/L solution of boron trifluoride in methylene chloride. The mixture is stirred at ambient temperature for 3 hours. The reaction mixture is introduced into a mixture of methylene chloride and water and the organic layer is separated. The organic layer is washed with saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. Thus, 1.42 g of 2-(6-fluoro-7-hydroxybenzo[b]thiophen-5-yl)-acetic acid is obtained as a gray-colored crystalline product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[C:6](OS(C(F)(F)F)(=O)=O)[CH:7]=[CH:8][CH:9]=2)[N:4]=1.[CH2:21]([Sn](CCCC)(CCCC)CCCC)[CH:22]=[CH2:23].[Li+].[Cl-]>CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:23]([C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:5]=1[N:4]=[C:3]([O:2][CH3:1])[CH:12]=[CH:11]2)[CH:22]=[CH2:21]
Reactant: COc1ccc2cccc(OS(=O)(=O)C(F)(F)F)c2n1
Reactant: C=CC[Sn](CCCC)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: C=CCc1cccc2ccc(OC)nc12
Temperature: 100 °C
Reaction time: 3 h

Procedure:
A mixture of trifluoro-methanesulfonic acid 2-methoxy-quinolin-8-yl ester (3.07 g, 10 mmol, prepared according to WO 2006/021448), allyltributylstannane (3.8 mL, 1.25 eq.), Pd(PPh3)4 (0.29 g, 0.025 eq.) and LiCl (1.6 g, 3.75 eq.) in DMF (20 mL) was stirred at 100° C. for 3 h. After cooling to rt, the mixture was poured on water and extracted with EA. The aq. layer was extracted once more with EA and the combined org. layers were washed with water and brine, dried over MgSO4 and concentrated. The residue was purified by CC (Hept/EA 9:1) to give 8-allyl-2-methoxy-quinoline which was contaminated with stannane residues. This crude oil was dihydroxylated following General Method F using AD-mix β, was affording, after purification by CC (Hept/EA 2:1, 1:1, EA) a colourless solid (2.04 g, 87% yield).
Reaction SMILES: [C:1]([NH:5][C:6]1[CH:11]=[CH:10][C:9](B2OC(C)(C)C(C)(C)O2)=[CH:8][C:7]=1[N+:21]([O-:23])=[O:22])([CH3:4])([CH3:3])[CH3:2].[NH2:24][C:25]1[N:30]=[C:29]([O:31][CH3:32])[C:28](Br)=[CH:27][N:26]=1.C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C.CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([C:28]2[C:29]([O:31][CH3:32])=[N:30][C:25]([NH2:24])=[N:26][CH:27]=2)=[CH:8][C:7]=1[N+:21]([O-:23])=[O:22])([CH3:2])([CH3:3])[CH3:4]
Reactant: COc1nc(N)ncc1Br
Reactant: CC(C)(C)Nc1ccc(B2OC(C)(C)C(C)(C)O2)cc1[N+](=O)[O-]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1nc(N)ncc1-c1ccc(NC(C)(C)C)c([N+](=O)[O-])c1
Temperature: 110 °C
Reaction time: 18 h
Yield: 86.1 %

Procedure:
To a vial is added tert-butyl-[2-nitro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-phenyl]-amine (300 mg, 0.937 mmol), 2-amino-5-bromo-4-methoxypyrimidine (215 mg, 1.054 mmol) and 2M Na2CO3 (2 mL, 4 mmol) in DMF (10 mL), followed by the addition of tetrakis(triphenylphosphine)palladium(0) (108 mg, 0.093 mmol). The vial is sealed under Argon gas. The reaction mixture is stirred at 110° C. for 18 hours. The reaction mixture is diluted with EtOAc and washed with water. The organic layer is separated, washed with brine, dried under Na2SO4, filtered and concentrated. The residue is loaded onto a silica gel column. The column is eluted with 0-5% MeOH/CH2Cl2. The product fractions are collected and concentrated to afford 5-(4-tert-butylamino-3-nitro-phenyl)-4-methoxy-pyrimidin-2-ylamine (256 mg, 86%) as a red solid. LCMS (ESMS): m/z 318.72 (M++1)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([CH2:13][CH2:14][CH2:15][OH:16])[O:11][CH:12]=2)=[CH:4][CH:3]=1.[H-].[Na+].O>CN(C=O)C.C(Br)C1C=CC=CC=1>[CH2:8]([O:16][CH2:15][CH2:14][CH2:13][C:10]1[O:11][CH:12]=[C:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[N:9]=1)[C:5]1[CH:6]=[CH:7][CH:2]=[CH:3][CH:4]=1
Reactant: OCCCc1nc(-c2ccc(Cl)cc2)co1
Agent: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Clc1ccc(-c2coc(CCCOCc3ccccc3)n2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 123.7 %

Procedure:
To a solution of 3-[4-(4-chlorophenyl)-2-oxazolyl]propanol (0.6 g) in DMF (10 ml) were added 60% (W/W) sodium hydride in oil (0.12 g) and benzyl bromide (0.3 ml), followed by stirring for 3 hours at room temperature. After additional stirring for an hour at 30° C., the reaction mixture was poured into water and then extracted with ether. The ether layer was washed with water, dried over MgSO4 and distilled to remove the solvent. The oily residue was subjected to a silica gel column chromatography. Oily 3-[4-(4-chlorophenyl)-2-oxazoly]propyl benzyl ether (0.512 g, 62%) was obtained from the fraction eluted with ether-hexane (1:4, V/V).
Reaction SMILES: [Br:1][C:2]1[C:14](=[O:15])[N:13]([CH:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)[C:5]2[N:6]=[C:7](S(C)=O)[N:8]=[CH:9][C:4]=2[C:3]=1[CH3:21].[N:22]1([C:28]2[CH:29]=[N:30][C:31]([NH2:34])=[CH:32][CH:33]=2)[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1>C1(C)C=CC=CC=1>[Br:1][C:2]1[C:14](=[O:15])[N:13]([CH:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)[C:5]2[N:6]=[C:7]([NH:34][C:31]3[N:30]=[CH:29][C:28]([N:22]4[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]4)=[CH:33][CH:32]=3)[N:8]=[CH:9][C:4]=2[C:3]=1[CH3:21]
Reactant: Nc1ccc(N2CCCCC2)cn1
Reactant: Cc1c(Br)c(=O)n(C2CCCC2)c2nc(S(C)=O)ncc12
Solvent: Cc1ccccc1
Product: Cc1c(Br)c(=O)n(C2CCCC2)c2nc(Nc3ccc(N4CCCCC4)cn3)ncc12
Temperature: 25 °C
Yield: 27.4 %

Procedure:
6-Bromo-8-cyclopentyl-2-methanesulfinyl-5-methyl-8H-pyrido[2,3-d]pyrimidin-7-one (1.0 g, 2.70 mmol) and 3,4,5,6-tetrahydro-2H-[1,3′]bipyridinyl-6′-ylamine (0.668 g, 3.73 mmol) were heated to reflux in toluene (10 mL) for 16 hours. The reaction mixture was cooled to room temperature and the precipitate that formed was collected by filtration and washed on the funnel with toluene (3×10 mL) to give 6-bromo-8-cyclopentyl-5-methyl-2-(3,4,5,6-tetrahydro-2H-[1,3′]bipyridinyl-6′-ylamino)-8H-pyrido[2,3-d]pyrimidin-7-one as a brown solid (0.358 g, 27.3%). 1H NMR δ(400 MHz, CDCl3) 8.79 (s, 1H), 8.27 (s, 1H), 8.17 (d, J=9.0 Hz, 1H), 8.01 (s, 1H), 7.38 (d, J=6.8 Hz, 1H), 5.98 (m, 1H), 3.1 (m, 4H), 2.60 (s, 3H), 2.30 (m, 2H), 2.11 (m, 2H), 1.88 (m, 2H), 1.57-1.75 (m, 8H).
Reaction SMILES: Cl.Cl.Cl.Cl.Cl.[CH3:6][N:7]1[CH2:12][CH2:11][N:10]([C:13]2[CH:18]=[C:17]([N:19]3[CH:28]([CH3:29])[CH2:27][C:26]4[C:21](=[CH:22][C:23]([CH:30]5[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]5)=[CH:24][CH:25]=4)[CH2:20]3)[N:16]=[C:15]([NH2:36])[N:14]=2)[CH2:9][CH2:8]1.[CH3:37][S:38](Cl)(=[O:40])=[O:39]>>[CH3:29][CH:28]1[CH2:27][C:26]2[C:21](=[CH:22][C:23]([CH:30]3[CH2:31][CH2:32][N:33]([S:38]([CH3:37])(=[O:40])=[O:39])[CH2:34][CH2:35]3)=[CH:24][CH:25]=2)[CH2:20][N:19]1[C:17]1[CH:18]=[C:13]([N:10]2[CH2:11][CH2:12][N:7]([CH3:6])[CH2:8][CH2:9]2)[N:14]=[C:15]([NH2:36])[N:16]=1
Reactant: CS(=O)(=O)Cl
Reactant: CC1Cc2ccc(C3CCNCC3)cc2CN1c1cc(N2CCN(C)CC2)nc(N)n1
Agent: Cl
Product: CC1Cc2ccc(C3CCN(S(C)(=O)=O)CC3)cc2CN1c1cc(N2CCN(C)CC2)nc(N)n1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 144 starting from 4-(4-methylpiperazin-1-yl)-6-(3-methyl-7-piperidin-4-yl-3,4-dihydroisoquinolin-2(1H)-yl)pyrimidin-2-amine tetrahydrochloride HCl salt (Example 144, Step 3) and methanesulfonyl chloride. LCMS (M+H)+: m/z=500.3.
Reaction SMILES: [CH3:1][N:2]([CH3:27])[C:3](=[O:26])[O:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([NH:11][C:12]([C:14]2([CH2:20][C:21]3[N:22]=[CH:23][NH:24][CH:25]=3)[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)=[O:13])[CH:6]=1.Cl[C:29]1[C:30]2[C:37]([CH3:38])=[CH:36][NH:35][C:31]=2[N:32]=[CH:33][N:34]=1.C(N(CC)C(C)C)(C)C>C(O)(C)C>[CH3:27][N:2]([CH3:1])[C:3](=[O:26])[O:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([NH:11][C:12]([C:14]2([CH2:20][C:21]3[N:22]=[CH:23][NH:24][CH:25]=3)[CH2:19][CH2:18][N:17]([C:29]3[C:30]4[C:37]([CH3:38])=[CH:36][NH:35][C:31]=4[N:32]=[CH:33][N:34]=3)[CH2:16][CH2:15]2)=[O:13])[CH:6]=1
Reactant: Cc1c[nH]c2ncnc(Cl)c12
Reactant: CN(C)C(=O)Oc1cccc(NC(=O)C2(Cc3c[nH]cn3)CCNCC2)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: Cc1c[nH]c2ncnc(N3CCC(Cc4c[nH]cn4)(C(=O)Nc4cccc(OC(=O)N(C)C)c4)CC3)c12
Temperature: 100 °C
Yield: 42 %

Procedure:
3-(4-((1H-imidazol-4-yl)methyl)piperidine-4-carboxamido)phenyl dimethylcarbamate from step D (10 mg, 0.027 mmol), 4-chloro-5-methyl-7H-pyrrolo[2,3-d]pyrimidine (5 mg, 0.03 mmol), and N,N-diisopropylethylamine (23 μL, 0.135 mmol) were combined in isopropanol (0.5 mL). The resulting mixture was heated at 100° C. in a sealed pressure tube for 24 hours. The reaction mixture was cooled and concentrated under vacuum. The residue was purified by prep HPLC (10-95% MeOH:H2O with 0.1% HCOOH), then treated with AcOH in H2O and lyophilized to give the title compound (5.7 mg, 42%) as the acetate salt.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][N+:6]([O-:9])=[CH:5][CH:4]=1)#[N:2].C[O-].[Na+].N[CH:14]([C:18]([NH2:20])=[O:19])[C:15]([NH2:17])=[O:16].C(O)(=O)C>CO>[C:18]([C:14]1[N:2]=[C:1]([C:3]2[CH:8]=[CH:7][N+:6]([O-:9])=[CH:5][CH:4]=2)[NH:17][C:15]=1[OH:16])(=[O:19])[NH2:20]
Reactant: N#Cc1cc[n+]([O-])cc1
Reactant: NC(=O)C(N)C(N)=O
Agent: C[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: NC(=O)c1nc(-c2cc[n+]([O-])cc2)[nH]c1O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 90.3 %

Procedure:
To a solution of 4-cyanopyridine N-oxide (600 g) in ahydrous methanol (250 ml) was added sodium methoxide (1.35 g), and this solution was stirred for 0.5 hour at room temperature. To this solution were added aminomalonamide (3.51 g) and acetic acid, and this mixture was stirred for 2 hours under reflux. After cooling the reaction mixture to 0°-5° C., the precipitated product was separated by filtration, washed with ethanol, isopropylether and dried under vacuum to give yellow crystal of 4-(4-carbamoyl-5-hydroxyimidazole-2yl)-pyridine-N-oxide (5.96 g).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].FC(F)(F)C(O)=O.[Cl:15][C:16]1[CH:17]=[N:18][C:19]2[NH:20][C:21]3[CH:22]=[CH:23][CH:24]=[C:25]([CH:46]=3)[CH2:26][CH2:27][C:28]3[CH:36]=[C:32]([NH:33][C:34]=1[N:35]=2)[CH:31]=[CH:30][C:29]=3[NH:37][C:38]([CH:40]1[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1)=[O:39].[N:47]([CH:50]1[CH2:54][CH2:53][CH2:52][CH2:51]1)=[C:48]=[O:49]>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[Cl:15][C:16]1[CH:17]=[N:18][C:19]2[NH:20][C:21]3[CH:22]=[CH:23][CH:24]=[C:25]([CH:46]=3)[CH2:26][CH2:27][C:28]3[CH:36]=[C:32]([NH:33][C:34]=1[N:35]=2)[CH:31]=[CH:30][C:29]=3[NH:37][C:38]([CH:40]1[CH2:45][CH2:44][N:43]([C:48]([NH:47][CH:50]2[CH2:54][CH2:53][CH2:52][CH2:51]2)=[O:49])[CH2:42][CH2:41]1)=[O:39]
Reactant: O=C(Nc1ccc2cc1CCc1cccc(c1)Nc1ncc(Cl)c(n1)N2)C1CCNCC1
Reactant: O=C=NC1CCCC1
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1ccc2cc1CCc1cccc(c1)Nc1ncc(Cl)c(n1)N2)C1CCN(C(=O)NC2CCCC2)CC1
Yield: 31 %

Procedure:
The desired compound was prepared according to the procedure of Example A9, step H using N-[6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20), 3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]piperidine-4-carboxamide bis(trifluoroacetate) and isocyanatocyclopentane as starting materials in 31% yield. LCMS for C30H35ClN7O2 (M+H)+: m/z=560.2.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[CH2:17][CH2:18][CH2:19][OH:20])=[O:7])([CH3:4])([CH3:3])[CH3:2].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl.C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[CH2:17][CH2:18][CH:19]=[O:20])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)n1c(CCCO)nc2ccccc21
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)n1c(CCC=O)nc2ccccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 76.7 %

Procedure:
To a solution of 3-(1-tert-butoxycarbonyl-Benzimidazol-2-yl)propan-1-ol (186 mg, 0.67 mmol) in CH2Cl2 (4 mL) was added Dess-Martin reagent (314 mg, 0.74 mmol) and the resulting mixture was allowed to stir at room temperature under N2 for 1 hour. The mixture was further diluted with 300-mL ethyl acetate, and washed with 1N NaOH, brine and dried over Na2SO4. Evaporation of the solvent and flash chromatograph of residue over silica gel, using 20% ethyl acetate in CH2Cl2, gave the title compound (141 mg, 76%) as pure white solid. 1H NMR (CDCl3) □1.72 (s, 9H), 3.13 (t, 2H, J=6.8 Hz), 3.52 (t, 2H, J=6.8 Hz), 7.28-7.34 (m, 2H), 7.66-7.67 (m, 1H), 7.87-7.91 (m, 1H), 9.97 (s, 1H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3](C=O)[CH:2]=1.[Cl:9][C:10]1[C:14](C2C=NC=CC=2)=[N:13][S:12][N:11]=1.[H-].[Na+]>C1COCC1>[Cl:9][C:10]1[C:14]([C:6]2[CH:5]=[CH:4][CH:3]=[CH:2][N:1]=2)=[N:13][S:12][N:11]=1
Reactant: Clc1nsnc1-c1cccnc1
Reactant: O=Cc1cccnc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Clc1nsnc1-c1ccccn1

Procedure:
3-(3-chloro-1,2,5-thiadiazol-4-yl-pyridine (compound 1) was synthesized from 3-pyridinecarboxaldehyde following, except with slight modification, from the published procedure as provided in Sauerberg et al, Journal Medicinal Chemistry, 1992, Vol. 35, Page 2274. 3-(3-Chloro-1,2,5-thiadiazol-4-yl)pyridine was reacted with a diol (compound 2, wherein n=6, 7, 8, 9, 10 or 12) in the presence of sodium hydride in refluxing THF to yield bis[3-(pyridin-3-yl)-1,2,5-thiadiazol-4-yl]alkyl-diethers (compound 3, wherein n=6, 7, 8, 9, 19 or 12) in 75-90% yield. These diethers were treated with excess methyl iodide in acetone or chloroform to give bis-quaternary ammonium iodides (compound 4, wherein n=6, 7, 8, 9, 10 or 12) in 96-100% yield. The quaternary salts were then treated with 5 equivalents of sodium borohydride in a mixture of methanol and chloroform to yield the compounds 5, wherein n=6, 7, 8, 9, 10 or 12 in 50-60% yield. Dry hydrogen chloride gas was then bubbled through the methanolic solution of compounds 5 at 0° C. to give compounds 6, wherein n=6, 7, 8, 9, 10 or 12 in 95-100% yield.
Reaction SMILES: [F:1][CH:2]([F:12])[O:3][C:4]1[CH:9]=[C:8]([CH2:10]O)[CH:7]=[CH:6][N:5]=1.C(Br)(Br)(Br)[Br:14].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C(Cl)Cl>[Br:14][CH2:10][C:8]1[CH:7]=[CH:6][N:5]=[C:4]([O:3][CH:2]([F:12])[F:1])[CH:9]=1
Reactant: BrC(Br)(Br)Br
Reactant: OCc1ccnc(OC(F)F)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: FC(F)Oc1cc(CBr)ccn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of (2-(difluoromethoxy)pyridin-4-yl)methanol (250 mg; 1.42 mmol) in anh. DCM (12 ml) was treated at rt with CBr4 (473 mg; 1.42 mmol), and with PPh3 (374 mg; 1.42 mmol). The resulting mixture was further stirred at rt, under nitrogen, for 1 h. Concentration to dryness under reduced pressure, and subsequent purification by FC (DCM) afforded 4-(bromomethyl)-2-(difluoromethoxy)pyridine as a yellow oil which was directly used for the next reaction. LC-MS (conditions A): tR=0.78 min.
Reaction SMILES: [CH:1]1([NH:7][C:8]2[CH:17]=[C:16]3[C:11]([C:12](=[O:28])[C:13]([CH:23]([OH:27])[C:24]([OH:26])=[O:25])=[CH:14][N:15]3[CH:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)=[CH:10][C:9]=2[F:29])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.S(=O)(=O)(O)O.[C:35](=O)([O-])O.[Na+]>CO>[CH3:35][O:25][C:24](=[O:26])[CH:23]([C:13]1[C:12](=[O:28])[C:11]2[C:16](=[CH:17][C:8]([NH:7][CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]3)=[C:9]([F:29])[CH:10]=2)[N:15]([CH:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)[CH:14]=1)[OH:27]
Reactant: O=C(O)C(O)c1cn(C2CCCC2)c2cc(NC3CCCCC3)c(F)cc2c1=O
Reactant: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Product: COC(=O)C(O)c1cn(C2CCCC2)c2cc(NC3CCCCC3)c(F)cc2c1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
52 mg of [7-(cyclohexylamino)-1-cyclopentyl-6-fluoro-4-oxo-1,4-dihydroquinolin-3-yl](hydroxy)acetic acid was dissolved in 10 ml of methanol, and 0.4 ml of concentrated sulfuric acid was added, followed by stirring at room temperature for 1 hour. Aqueous saturated sodium hydrogen carbonate was added to the reaction mixture, followed by extraction with ethyl acetate, washing with aqueous saturated sodium chloride and concentration under a reduced pressure. The resulting residue was recrystallized from aqueous methanol to obtain 53 mg of methyl[7-(cyclohexylamino)-1-cyclopentyl-6-fluoro-4-oxo-1,4-dihydroquinolin-3-yl](hydroxy)acetate.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[C:4]([O:13][CH2:14][C:15]([F:18])([F:17])[F:16])[CH:3]=1.[CH2:19]([CH:21]1[O:23][CH2:22]1)Br.C([O-])([O-])=O.[Cs+].[Cs+].CCOC(C)=O>CN(C=O)C>[CH2:19]([O:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[C:4]([O:13][CH2:14][C:15]([F:16])([F:17])[F:18])[CH:3]=1)[CH:21]1[O:23][CH2:22]1
Reactant: COC(=O)Cc1ccc(O)cc1OCC(F)(F)F
Reactant: BrCC1CO1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)Cc1ccc(OCC2CO2)cc1OCC(F)(F)F
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a stirred solution of methyl 4-hydroxy-2-(2,2,2-trifluoroethoxy)phenylacetate (0.60 g, 2.4 mmol) from Step 4 of Example 32 in DMF (7 mL) was added epibromohydrin (0.50 g, 3.6 mmol) and Cs2CO3 (1.55 g, 4.8 mmol). The mixture was stirred at ambient temperature for 3 h. EtOAc was added (15 mL) and the solid was removed by filtration. The filtrate solvents were removed under reduced pressure and the residue was partitioned between EtOAc (50 mL) and saturated aqueous NaHCO3 (50 mL). The organic phase was dried (MgSO4), filtered, and the solvent was removed under reduced pressure to give methyl 4-(glycidyloxy)-2-(2,2,2-trifluoroethoxy)-phenylacetate as a pale yellow oil (HPLC retention time=8.3 min (method A)).
Reaction SMILES: Br[CH2:2][C:3]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[CH:7][C:4]=1[C:5]#[N:6].[NH:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1.C(N(CC)CC)C>C(Cl)Cl>[N+:11]([C:10]1[C:3]([CH2:2][N:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)=[C:4]([CH:7]=[CH:8][CH:9]=1)[C:5]#[N:6])([O-:13])=[O:12]
Reactant: N#Cc1cccc([N+](=O)[O-])c1CBr
Reactant: C1CCNC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: N#Cc1cccc([N+](=O)[O-])c1CN1CCCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 91 %

Procedure:
To a stirred solution of 2-(bromomethyl)-3-nitrobenzonitrile (1.10 g, 4.56 mmol) and pyrrolidine (0.65 g, 9.13 mmol) in CH2Cl2 (15 mL) was added triethylamine (1.85 g, 18.25 mmol) dropwise at 0° C. The mixture was stirred at room temperature for 2 h and evaporated to dryness under reduced pressure. The residue was diluted with water (10 mL) and extracted with CH2Cl2 (3×50 mL). The CH2Cl2 solution was dried over anhydrous Na2SO4, filtered, and evaporated to dryness under reduced pressure. The residue was purified by MPLC on silica gel using a mixture of EtOAc and hexane as eluent to give 3-nitro-2-(pyrrolidin-1-ylmethyl)benzonitrile (0.96 g, 91%) as a yellow solid. 1H NMR (400 MHz, CDCl3): δ 7.90 (d, 1 H, J=7.6 Hz), 7.83 (dd, 1H, J=7.6, 0.8 Hz), 7.52 (t, 1H, J=7.6 Hz), 4.14 (s, 2H), 2.52 (br s, 4H), 1.72 (br s, 4H).