Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[CH:4][C:3]=1[C:17]1[N:18]=[CH:19][C:20]([NH2:23])=[N:21][CH:22]=1.Br[C:25]1[C:26]([O:31][CH2:32][CH:33]2[CH2:37][CH2:36][N:35]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:34]2)=[N:27][CH:28]=[CH:29][CH:30]=1>>[NH2:23][C:20]1[N:21]=[CH:22][C:17]([C:3]2[CH:4]=[CH:5][C:6]([C:25]3[C:26]([O:31][CH2:32][CH:33]4[CH2:37][CH2:36][N:35]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:34]4)=[N:27][CH:28]=[CH:29][CH:30]=3)=[CH:7][C:2]=2[F:1])=[N:18][CH:19]=1
Reactant: CC(C)(C)OC(=O)N1CCC(COc2ncccc2Br)C1
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)cn3)c(F)c2)OC1(C)C
Product: CC(C)(C)OC(=O)N1CCC(COc2ncccc2-c2ccc(-c3cnc(N)cn3)c(F)c2)C1
Yield: 54 %

Procedure:
The title compound was prepared using methods analogous to those described in Example 369 using 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrazin-2-amine and tert-butyl 3-(((3-bromopyridin-2-yl)oxy)methyl)pyrrolidine-1-carboxylate yielding the title compound (47 mg, 54%). MS (ESI): mass calcd. for C25H28FN5O3, 465.22; m/z found, 466.2 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 8.63-8.58 (m, 1H), 8.18-8.09 (m, 2H), 8.03-7.94 (m, 1H), 7.73-7.64 (m, 1H), 7.48-7.36 (m, 2H), 7.05-6.96 (m, 1H), 4.70 (s, 2H), 4.47-4.22 (m, 2H), 3.68-3.26 (m, 3H), 3.25-3.09 (m, 1H), 2.77-2.60 (m, 1H), 2.14-1.98 (m, 1H), 1.84-1.68 (m, 1H), 1.44 (s, 9H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][C:9]2[NH:10][C:11]3[C:16]([C:17]=2[CH:18]=1)=[CH:15][C:14]([C:19]([OH:21])=[O:20])=[CH:13][CH:12]=3)=[O:5])[CH3:2].C(O)C.[C:25]([O:28][CH2:29]C)(=O)C>>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][C:9]2[NH:10][C:11]3[C:16]([C:17]=2[C:18]=1[CH2:25][O:28][CH3:29])=[CH:15][C:14]([C:19]([OH:21])=[O:20])=[CH:13][CH:12]=3)=[O:5])[CH3:2]
Reactant: CCOC(C)=O
Reactant: CCOC(=O)c1cc2c(cn1)[nH]c1ccc(C(=O)O)cc12
Solvent: CCO
Product: CCOC(=O)c1ncc2[nH]c3ccc(C(=O)O)cc3c2c1COC

Procedure:
3-ethoxycarbonyl-β-carboline-6-carboxylic acid, mp 313°-314° C. (decomposition; ethanol/ethyl acetate); and
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH:12]1[CH2:17][CH2:16][CH2:15][N:14]([C:18](=[O:23])[C:19]([F:22])([F:21])[F:20])[CH2:13]1)[CH3:2].F[B-](F)(F)F.[O:30]=[N+:31]=[O:32]>C(#N)C>[CH2:1]([O:3][C:4](=[O:24])[NH:5][C:6]1[C:7]([CH:12]2[CH2:17][CH2:16][CH2:15][N:14]([C:18](=[O:23])[C:19]([F:20])([F:22])[F:21])[CH2:13]2)=[CH:8][CH:9]=[CH:10][C:11]=1[N+:31]([O-:32])=[O:30])[CH3:2]
Reactant: O=[N+]=O
Reactant: CCOC(=O)Nc1ccccc1C1CCCN(C(=O)C(F)(F)F)C1
Agent: F[B-](F)(F)F
Solvent: CC#N
Product: CCOC(=O)Nc1c(C2CCCN(C(=O)C(F)(F)F)C2)cccc1[N+](=O)[O-]
Reaction time: 1 h
Yield: 53.1 %

Procedure:
A solution of 18 g of product of Step C in 180 ml of acetonitrile was cooled to -30° C. and then with stirring and under an inert atmosphere, 7.73 g of nitronium tetrafluoroborate were added in small fractions. After stirring for one hour and returning to ambient temperature, the reaction mixture was poured on to ice and extracted with methylene chloride. The extracts were washed with water, dried, taken to dryness under reduced pressure and purified by chromatography on silica (eluent: cyclohexane-ethyl acetate 7-3) to obtain 10.8 g of the expected product (RF=0.2) melting about 124° C. after crystallization from a mixture of isopropyl ether and methylene chloride (1-1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[CH:10]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=3)[S:8][C:7]=2[CH:19]=1.[Br:20][C:21]1[CH:29]=[CH:28][C:24]([C:25](Cl)=[O:26])=[CH:23][CH:22]=1.[Sn](Cl)(Cl)(Cl)Cl>C(Cl)Cl>[Br:20][C:21]1[CH:29]=[CH:28][C:24]([C:25]([C:10]2[C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:19][C:7]=3[S:8][C:9]=2[C:11]2[CH:12]=[CH:13][C:14]([O:17][CH3:18])=[CH:15][CH:16]=2)=[O:26])=[CH:23][CH:22]=1
Reactant: COc1ccc(-c2cc3ccc(OC)cc3s2)cc1
Reactant: O=C(Cl)c1ccc(Br)cc1
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: ClCCl
Product: COc1ccc(-c2sc3cc(OC)ccc3c2C(=O)c2ccc(Br)cc2)cc1
Reaction time: 16 h
Yield: 71.7 %

Procedure:
To a solution of 0.54 g (2 mmol) of 6-methoxy-2-(4-methoxyphenyl)benzo-[b]thiophene and 0.52 g (2.3 mmol) of 4-bromobenzoyl chloride in 20 mL of methylene chloride at 0° C. was added dropwise a solution of 0.3 ml (2.5 mmol) of tin (IV) chloride in 5 mL of methylene chloride. After stirring for 16 hours the solution was concentrated and the residue was washed with aqueous sodium bicarbonate and extracted 2 times with 40 mL of ethyl acetate. The organic layers were combined, dried (MgSO4) and concentrated. The crude solid was passed through a short plug of silica gel to remove residual tin salts. Elution with 30% EtOAc:hexane and concentration yielded 0.65 g (73%) of yellow crystals, m.p. 127°-129° C.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][CH:13]=1)[O:6][CH2:7][C:8]([OH:10])=O)=[O:2].[N:14]1([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH:1]([C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][CH:13]=1)[O:6][CH2:7][C:8]([N:17]1[CH2:16][CH2:15][N:14]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:19][CH2:18]1)=[O:10])=[O:2]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=Cc1cccc(OCC(=O)O)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCN(C(=O)COc2cccc(C=O)c2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 29 %

Procedure:
2-(3-formylphenoxy)acetic acid (48)/(1 eq), tert-butyl piperazine-1-carboxylate (1.5 eq) were taken in DCM to which HATU (1.3 eq) and DIPEA (2 eq) along with cat. DMAP were added and the traction mixture was stirred at rt for 16 h when TLC indicated completion of reaction. The reaction mixture was diluted with DCM and the organic extract was washed with water, dried and purified by column chromatography using silica gel (100-200 mesh) to afford the pure product (29%) as a colorless oil. LCMS: 91.65% (M++1-Boc).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10]CC)=O)=[CH:6][N:5]=[C:4]([S:13][CH3:14])[N:3]=1.C(N(CC)CC)C.Cl.[CH2:23]([O:27][C:28]1[CH:36]=[CH:35][CH:34]=[CH:33][C:29]=1[C:30]([NH2:32])=[NH:31])[CH:24]([CH3:26])[CH3:25]>C(#N)C>[CH3:14][S:13][C:4]1[N:3]=[C:2]2[N:31]=[C:30]([C:29]3[CH:33]=[CH:34][CH:35]=[CH:36][C:28]=3[O:27][CH2:23][CH:24]([CH3:26])[CH3:25])[NH:32][C:8](=[O:10])[C:7]2=[CH:6][N:5]=1
Reactant: CCOC(=O)c1cnc(SC)nc1Cl
Reactant: CC(C)COc1ccccc1C(=N)N
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CSc1ncc2c(=O)[nH]c(-c3ccccc3OCC(C)C)nc2n1
Temperature: 5 °C
Reaction time: 0.25 h
Yield: 21.5 %

Procedure:
Ethyl 4-chloro-2-methylthio-5-pyrimidine carboxylate (1.50 g) followed by triethylamine (0.65 g) was added to a stirred mixture of 2-isobutoxybenzamidine hydrochloride (1.46 g) and triethylamine (0.65 g) in acetonitrile (150 ml). The reaction mixture was stirred at 5° C. for 15 minutes and then at ambient temperature for 3 days. A solid (0.55 g) was collected by filtration and the filtrate was reduced in volume to yield a second crop of solid (0.47 g). The solids were combined and recrystallised from ethanol to yield the title compound, 0.57 g, m.p. 185°-186° C.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[O:8][CH2:7][C:6]3[CH:12]=[C:13]([C:15]([OH:17])=O)[S:14][C:5]=3[C:4]=2[CH:3]=1.[CH3:18][NH:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[F:26].C(N(CC)CC)C>ClCCl.CN(C1C=CN=CC=1)C>[F:26][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[N:19]([CH3:18])[C:15]([C:13]1[S:14][C:5]2[C:4]3[CH:3]=[C:2]([CH3:1])[CH:11]=[CH:10][C:9]=3[O:8][CH2:7][C:6]=2[CH:12]=1)=[O:17]
Reactant: CNc1ccccc1F
Reactant: Cc1ccc2c(c1)-c1sc(C(=O)O)cc1CO2
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc2c(c1)-c1sc(C(=O)N(C)c3ccccc3F)cc1CO2
Reaction time: 24 h

Procedure:
8-Methyl-4H-thieno[3,2-c]chromene-2-carboxylic acid was converted to the acid chloride as in Example 3, then treated with N-methyl-2-fluoroaniline (1.5 equiv), and triethylamine (5 equiv) in dichloromethane and N,N-dimethyl-4-aminopyridine (0.2 equiv) at 24° C. After about 24 hr, the reaction mixture was diluted with dichloromethane, and the resulting solution was washed with saturated aqueous sodium bicarbonate. The collected organic was dried over anhydrous sodium sulfate, filtered, and concentrated. Purification by flash column chromatography (5:2/hexanes:ethylacetate) provided 169bp. 1H NMR (500 MHz, CDCl3) δ 7.40 (m, 1 H), 7.31 (m, 1 H), 7.18-7.22 (m, 2 H), 6.80 (s, 1 H), 6.94 (d, J=8.3 Hz, 1 H), 6.77 (d, J=8.2 Hz, 1 H), 6.60 (s, 1 H), 5.00 (s, 2 H), 3.42 (s, 3 H), 2.26 (s, 3 H). LCMS (ESI) m/z: 354.1
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[CH2:5][CH2:6][O:7][CH2:8][CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11].C(N(CC)CC)C.[CH3:27][Si:28]([C:31]#[CH:32])([CH3:30])[CH3:29]>C(OCC)(=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.[Cu]I>[CH3:27][Si:28]([C:31]#[C:32][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[CH2:5][CH2:6][O:7][CH2:8][CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])([CH3:30])[CH3:29]
Reactant: C#C[Si](C)(C)C
Reactant: CC(C)(C)OC(=O)CCOCCc1cccc(Br)c1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)CCOCCc1cccc(C#C[Si](C)(C)C)c1
Temperature: 100 °C

Procedure:
tert-Butyl 3-(3-bromophenethoxy)propanoate (1.5 g), triethylamine (6 mL), trimethylsilylacetylene (1.92 mL), Pd(Ph3P)4 (0.26 g) and copper (I) iodide (0.04 g) was sealed into a microwave tube. The reaction was heated to 100° C. over a period of 5 min in the microwave reactor. The reaction mixture was diluted with ethyl acetate and filtered through a pad of Celite and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0-10% ethyl acetate in isohexane to afford tert-butyl 3-(3-((trimethylsilyl)ethynyl)phenethoxy)propanoate as a yellow liquid (1.56 g). 1H NMR (300 MHz, CDCl3) δ 7.41-7.12 (m, 4H), 3.67 (t, J=6.3 Hz, 2H), 3.63 (t, J=7.1 Hz, 2H), 2.83 (t, J=7.1 Hz, 2H), 2.47 (t, J=6.5 Hz, 2H), 1.44 (s, 9H), 0.24 (s, 9H).
Reaction SMILES: [N:1]1([C:6]2[CH:14]=[CH:13][C:9]([C:10](O)=[O:11])=[CH:8][CH:7]=2)[CH:5]=[N:4][CH:3]=[N:2]1.S(Cl)([Cl:17])=O>>[N:1]1([C:6]2[CH:14]=[CH:13][C:9]([C:10]([Cl:17])=[O:11])=[CH:8][CH:7]=2)[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: O=C(O)c1ccc(-n2cncn2)cc1
Reactant: O=S(Cl)Cl
Product: O=C(Cl)c1ccc(-n2cncn2)cc1
Yield: 100 %

Procedure:
4-(1H-1,2,4-triazol-1-yl)benzoic acid (100 mg, 0.529 mmol) in sulfurous dichloride (2 ml) was refluxed at 110° C. for 2 h. After the excess SOCl2 was removed, the residue was dried in vacuo to give 4-(1H-1,2,4-triazol-1-yl)benzoyl chloride (110 mg, 0.529 mmol, 100% yield) as a white solid which was used in subsequent reactions without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][C:24]=1[CH3:25])[C:5]([N:7]1[CH2:13][CH2:12][CH2:11][CH:10]([C:14]2[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][CH:15]=2)[CH2:9][CH2:8]1)=[O:6].C(N(CC)C(C)C)(C)C.[F:35][C:36]1[CH:44]=[CH:43][C:39]([C:40](Cl)=[O:41])=[CH:38][N:37]=1>ClCCl>[C:18]([C:17]1[CH:20]=[CH:21][C:14]([CH:10]2[CH2:11][CH2:12][CH2:13][N:7]([C:5]([C:4]3[CH:22]=[CH:23][C:24]([CH3:25])=[C:2]([NH:1][C:40](=[O:41])[C:39]4[CH:43]=[CH:44][C:36]([F:35])=[N:37][CH:38]=4)[CH:3]=3)=[O:6])[CH2:8][CH2:9]2)=[CH:15][CH:16]=1)#[N:19]
Reactant: O=C(Cl)c1ccc(F)nc1
Reactant: Cc1ccc(C(=O)N2CCCC(c3ccc(C#N)cc3)CC2)cc1N
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1ccc(C(=O)N2CCCC(c3ccc(C#N)cc3)CC2)cc1NC(=O)c1ccc(F)nc1
Temperature: 25 °C
Reaction time: 19 h

Procedure:
To a 4-mL vial containing 4-(1-(3-amino-4-methylbenzoyl)azepan-4-yl)benzonitrile (compound 40.5, 44 mg, 0.13 mmol, 1.0 equiv) was added dichloromethane (1 mL) and N,N-diisopropylethylamine (35 μL, 0.20 mmol, 1.5 equiv). A solution of 6-fluoronicotinoyl chloride (22 mg, 0.14 mmol, 1.05 equiv) in dichloromethane (1 mL) was added dropwise over about 2 minutes. The resulting mixture was stirred at room temperature for 19 hours then diluted with dichloromethane (5 mL) and washed with 1 M NaH2PO4 (3 mL), saturated sodium bicarbonate (3 mL) and brine (3 mL). The organics were dried (Na2SO4), filtered and concentrated to obtain the title compound as a brown wax (64 mg, theoretical). m/z (ES+) 457 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:31][CH3:32])=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([N:12]1[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[N:13]1)[CH:8]=[C:7]2[O:21]CC1C=CC(OC)=CC=1.[Na+].[I-].O.Cl>C(#N)C>[Cl:1][C:2]1[C:3]([O:31][CH3:32])=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([N:12]1[CH:16]=[CH:15][C:14]([C:17]([F:19])([F:20])[F:18])=[N:13]1)[CH:8]=[C:7]2[OH:21]
Reactant: COc1ccc(COc2cc(-n3ccc(C(F)(F)F)n3)nc3c(Cl)c(OC)ccc23)cc1
Agent: Cl
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: COc1ccc2c(O)cc(-n3ccc(C(F)(F)F)n3)nc2c1Cl
Yield: 96 %

Procedure:
Compound 234a (800 mg, 1 eq.), CeCl3.7H2O (965 mg, 1.5 eq.), and NaI (258 mg, 1 eq.) in ACN (10 mL) were stirred at 85° C. for 1 hr under microwave irradiation. Water was added and the mixture was acidified with 1N HCl to pH 5. The reaction mixture was extracted with diethyl ether. The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude material was purified by chromatography on silica gel (MeOH/DCM) to give compound 236a as a beige solid in 96% yield. 1H NMR (DMSO-d6, 400 MHz) δ (ppm) 4.02 (s, 3H), 7.07 (s, 1H), 7.43 (s, 1H), 7.51 (d, J=9.11 Hz, 1H), 8.11 (d, J=9.11 Hz, 1H), 8.88 (s, 1H); MS (ESI, EI+) m/z=343.9 (MH+).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:22]=[CH:21][C:6]([O:7][CH2:8][C:9]2[N:10]=[C:11]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[O:12][C:13]=2[CH3:14])=[CH:5][CH:4]=1.[OH:23][C:24]1[CH:25]=[C:26]([CH2:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH:27]=[CH:28][CH:29]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH3:14][C:13]1[O:12][C:11]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[N:10][C:9]=1[CH2:8][O:7][C:6]1[CH:21]=[CH:22][C:3]([CH2:2][O:23][C:24]2[CH:25]=[C:26]([CH2:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH:27]=[CH:28][CH:29]=2)=[CH:4][CH:5]=1
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc(CCl)cc1
Reactant: CCOC(=O)CCc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CCc1cccc(OCc2ccc(OCc3nc(-c4ccccc4)oc3C)cc2)c1
Temperature: 90 °C
Reaction time: 15 h
Yield: 55.5 %

Procedure:
A mixture of 4-(4-chloromethylphenoxymethyl)-5-methyl-2-phenyloxazole (2.42 g), ethyl 3-(3-hydroxyphenyl)propionate (1.35 g), anhydrous potassium carbonate (0.97 g) and N,N-dimethylformamide (30 mL) was stirred at 90° C. for 15 hrs. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The obtained residue was subjected to silica gel column chromatography to give crystals (1.82 g, 55%) of ethyl 3-[3-[4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]phenyl]propionate from a fraction eluted with ethyl acetate-hexane (1:6, v/v). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 90-91° C.
Reaction SMILES: C(N(CC)CC)C.CS(Cl)(=O)=O.O[CH2:14][C:15]1[CH2:20][N:19]([NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17][CH:16]=1.C([O-])(O)=O.[Na+].[N-:34]=[N+:35]=[N-:36].[Na+]>C(Cl)Cl>[N:34]([CH2:14][C:15]1[CH2:20][N:19]([NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17][CH:16]=1)=[N+:35]=[N-:36]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)(C)OC(=O)NN1CCC=C(CO)C1
Agent: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NN1CCC=C(CN=[N+]=[N-])C1
Temperature: 80 °C

Procedure:
At 0° C., triethylamine (3.7 ml, 26.2 mmol) and, dropwise, methanesulphonyl chloride (1.2 ml, 15.44 mmol) were added to a solution of tert-butyl 5-hydroxymethyl-3,6-dihydro-2H-pyridine-1-carbamate (Tetrahedron 1998, 54, 7045–7056, 2.8 g, 13.1 mmol) in DCM (50 ml). The reaction mixture was stirred at 0° C. for 20 minutes before a saturated solution of NaHCO3 (40 ml) was added, and the two phases were separated. The aqueous phase was extracted with dichloromethane (40 ml). The combined organic phases were washed with saturated sodium chloride solution and dried over MgSO4 and concentrated. The crude product was dissolved in DMF (50 ml), and sodium azide (1.7 g, 26.1 mmol) was added. The mixture was heated to 80° C. Reaction monitored by LCMS. Once the reaction was complete, the mixture was cooled and concentrated. The residue was taken up in EtOAc and water and the aqueous phase was extracted with EtOAc (2×100 ml). The combined organic phases were washed with saturated sodium chloride solution, dried over MgSO4 and concentrated. The residue was purified by chromatography on silica gel (EtOAc/hex 1/6).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH3:30])[C:5]([N:8]([CH2:26][CH:27]([CH3:29])[CH3:28])[S:9]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19]C3CCOCC3)=[CH:14][CH:13]=2)(=[O:11])=[O:10])=[N:6][CH:7]=1.[B-](F)(F)(F)[C:32]([CH3:34])=[CH2:33].[K+].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C1COCC1>[CH2:26]([N:8]([C:5]1[C:4]([CH3:30])=[CH:3][C:2]([C:2]([CH3:3])=[CH2:7])=[CH:7][N:6]=1)[S:9]([C:12]1[CH:13]=[CH:14][C:15]([O:18][CH2:19][CH:15]2[CH2:14][CH2:34][CH2:32][CH2:33][O:18]2)=[CH:16][CH:17]=1)(=[O:11])=[O:10])[CH:27]([CH3:28])[CH3:29]
Reactant: C=C(C)[B-](F)(F)F
Reactant: Cc1cc(Cl)cnc1N(CC(C)C)S(=O)(=O)c1ccc(OCC2CCOCC2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: C=C(C)c1cnc(N(CC(C)C)S(=O)(=O)c2ccc(OCC3CCCCO3)cc2)c(C)c1
Temperature: 110 °C
Yield: 85 %

Procedure:
N-(5-chloro-3-methylpyridin-2-yl)-N-isobutyl-4-((tetrahydro-2H-pyran-4-yl)methoxy)benzenesulfonamide (140 mg, 0.31 mmol), potassium trifluoro(prop-1-en-2-yl)borate (69 mg, 464 μmol) and Buchwald's Suzuki-Miyaura cross-coupling pre-catalyst (prepared according to ref. J. Am. Chem. Soc. 2010, 132, 14073) (5 mg, 6.18 μmol) were dissolved in anhydrous THF (1 mL). To this solution was added degassed potassium phosphate (0.5 M aqueous) (2 mL, 1.0 mmol) then the reaction vessel sealed and heated by microwaves to 110° C. for 30 minutes. The reaction was cooled, combined with a previous identical trial reaction on a smaller (0.06 mmol) scale and concentrated in vacuo. The crude product was then extracted to the organic phase of an aqueous work up between ethyl acetate and water. The organic phase was passed through a hydrophobic frit, concentrated in vacuo, then purified by mass directed autoprep (formic acid modifier) to give the title compound 85% purity (87 mg). LCMS (2 min, formic) Rt 1.44 min, m/z (ES+) 459 (M+H).
Reaction SMILES: [CH3:1][C:2]1([CH3:34])[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:12]3[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=3)[CH:9]=2)[N:4]([S:22]([C:25]2[CH:32]=[CH:31][C:28]([C:29]#[N:30])=[C:27](F)[CH:26]=2)(=[O:24])=[O:23])[CH2:3]1.[CH2:35]([OH:37])[CH3:36].[H-].[Na+].O>CN(C)C=O>[CH3:34][C:2]1([CH3:1])[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:12]3[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=3)[CH:9]=2)[N:4]([S:22]([C:25]2[CH:32]=[CH:31][C:28]([C:29]#[N:30])=[C:27]([O:37][CH2:35][CH3:36])[CH:26]=2)(=[O:24])=[O:23])[CH2:3]1
Reactant: CC1(C)Cc2cc(-c3ccc(C(F)(F)F)cc3)ccc2N(S(=O)(=O)c2ccc(C#N)c(F)c2)C1
Reactant: CCO
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOc1cc(S(=O)(=O)N2CC(C)(C)Cc3cc(-c4ccc(C(F)(F)F)cc4)ccc32)ccc1C#N
Temperature: 25 °C
Reaction time: 4 h

Procedure:
165 mg 4-[3,3-Dimethyl-6-(4-trifluoromethyl-phenyl)-3,4-dihydro-2H-quinoline-1-sulfonyl]-2-fluoro-benzonitrile and 30 ml ethanol were dissolved in 3 ml dimethylformamide. Then 10 mg sodium hydride were added and the reaction mixture stirred at room temperature for 4 hours. The mixture was then poured into 20 ml water and extracted five times with portions of 20 ml ethyl acetate. The combined organic extracts were dried over MgSO4 then evaporated in vacuo and the residue purified by chromatography on silica gel to obtain 40 mg 4-[3,3-Dimethyl-6-(4-trifluoromethyl-phenyl)-3,4-dihydro-2H-quinoline-1-sulfonyl]-2-ethoxy-benzonitrile.
Reaction SMILES: Br[CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][O:7][CH2:6][CH2:5]1.[C:10]([C@H:14]1[C:41](=[O:42])[N:40]2[CH2:43][C@@H:37]([CH2:38][C@H:39]2[C:44]([NH:46][C@:47]2([C:52](=[O:63])[NH:53][S:54]([C:57]3([CH2:60][O:61][CH3:62])[CH2:59][CH2:58]3)(=[O:56])=[O:55])[CH2:49][C@H:48]2[CH:50]=[CH2:51])=[O:45])[O:36][C:26]2=[N:27][C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][C:33]=3[C:34]([OH:35])=[C:25]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][C@@H:19]2[CH2:64][CH2:65][CH2:66][C@H:18]2[O:17][C:16](=[O:67])[NH:15]1)([CH3:13])([CH3:12])[CH3:11]>>[C:10]([C@H:14]1[C:41](=[O:42])[N:40]2[CH2:43][C@@H:37]([CH2:38][C@H:39]2[C:44]([NH:46][C@:47]2([C:52](=[O:63])[NH:53][S:54]([C:57]3([CH2:60][O:61][CH3:62])[CH2:59][CH2:58]3)(=[O:55])=[O:56])[CH2:49][C@H:48]2[CH:50]=[CH2:51])=[O:45])[O:36][C:26]2=[N:27][C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][C:33]=3[C:34]([O:35][CH2:2][CH2:3][N:4]3[CH2:9][CH2:8][O:7][CH2:6][CH2:5]3)=[C:25]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][C@@H:19]2[CH2:64][CH2:65][CH2:66][C@H:18]2[O:17][C:16](=[O:67])[NH:15]1)([CH3:11])([CH3:12])[CH3:13]
Reactant: BrCCN1CCOCC1
Reactant: C=C[C@@H]1C[C@]1(NC(=O)[C@@H]1C[C@@H]2CN1C(=O)[C@H](C(C)(C)C)NC(=O)O[C@@H]1CCC[C@H]1CCCCCc1c(nc3ccccc3c1O)O2)C(=O)NS(=O)(=O)C1(COC)CC1
Product: C=C[C@@H]1C[C@]1(NC(=O)[C@@H]1C[C@@H]2CN1C(=O)[C@H](C(C)(C)C)NC(=O)O[C@@H]1CCC[C@H]1CCCCCc1c(nc3ccccc3c1OCCN1CCOCC1)O2)C(=O)NS(=O)(=O)C1(COC)CC1

Procedure:
The title compound was prepared using the same method as described for Example 42 using 4-(2-bromoethyl)morpholine and (3aR,7S,10S,12R,24aR)-7-tert-butyl-N-[(1R,2S)-2-ethenyl-1-({[1-(methoxymethyl)cyclopropyl]sulfonyl}carbamoyl)cyclopropyl]-19-hydroxy-5,8-dioxo-1,2,3,3a,5,6,7,8,11,12,20,21,22,23,24,24a-hexadecahydro-10H-9,12-methanocyclopenta[18,19][1,10,3,6]dioxadiazacyclononadecino[11,12-b]quinoline-10-carboxamide (Example 35). Purification by flash chromatography (ISCO) afforded the desired product (21.5 mg). LRMS (ES+) m/z 937.3 (M+H)+.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]=[C:8]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=2[S:22]([CH3:25])(=[O:24])=[O:23])[N:9]([CH3:14])[C:10](=[O:13])[C:11]=1[OH:12])=O)C.[CH3:26][C:27]1[CH:28]=[C:29]([CH:32]=[CH:33][C:34]=1[CH3:35])[CH2:30][NH2:31]>>[CH3:26][C:27]1[CH:28]=[C:29]([CH:32]=[CH:33][C:34]=1[CH3:35])[CH2:30][NH:31][C:4]([C:6]1[N:7]=[C:8]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=2[S:22]([CH3:25])(=[O:24])=[O:23])[N:9]([CH3:14])[C:10](=[O:13])[C:11]=1[OH:12])=[O:3]
Reactant: Cc1ccc(CN)cc1C
Reactant: CCOC(=O)c1nc(-c2ccc(F)cc2S(C)(=O)=O)n(C)c(=O)c1O
Product: Cc1ccc(CNC(=O)c2nc(-c3ccc(F)cc3S(C)(=O)=O)n(C)c(=O)c2O)cc1C

Procedure:
Prepared according to the procedure described for example 2 from 2-(4-fluoro-2-methanesulfonyl-phenyl)-5-hydroxy-1-methyl-6-oxo-1,6-dihydro-pyrimidine-4-carboxylic acid ethyl ester (55.56 mg, 0.15 mmol) and 3,4-dimethylbenzylamine (102 mg, 0.75 mmol). The title product was obtained as a pink solid (59.8 mg, 87% yield). 1HNMR (500 MHz, CDCl3) δ: 12.25 (1H, s), 7.86 (1H, dd, J=7.63, 2.44 Hz), 7.49–7.44 (2H, m), 7.41 (1H, dd, J=8.54, 4.88 Hz), 7.07 (1H, d, J=7.63 Hz), 7.01 (1H, s), 6.97 (1H, d, J=7.63 Hz), 4.53 (1H, dd, J=14.65, 6.41 Hz), 4.43 (1H, dd, J=14.96, 5.49 Hz), 3.26 (3H, s), 3.01 (3H, s), 2.22 (6H, s). HRMS (ESI) calcd for C22H23FN3O5S (M+H): 460.1343; found: 460.1337.