Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH2:2]([N:14]([CH2:16][CH2:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][C:27]([OH:29])=O)=[C:21]([O:30][CH3:31])[CH:20]=1)[CH3:15])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].C(N(CCOC1C=CC(CCC(=O)[C:58]([F:61])([F:60])[F:59])=CC=1)C)CCCCCCCCCCC>>[CH2:2]([N:14]([CH2:16][CH2:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][C:27](=[O:29])[C:58]([F:61])([F:60])[F:59])=[C:21]([O:30][CH3:31])[CH:20]=1)[CH3:15])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: CCCCCCCCCCCCN(C)CCOc1ccc(CCC(=O)O)c(OC)c1
Reactant: CCCCCCCCCCCCN(C)CCOc1ccc(CCC(=O)C(F)(F)F)cc1
Agent: Cl
Product: CCCCCCCCCCCCN(C)CCOc1ccc(CCC(=O)C(F)(F)F)c(OC)c1
Yield: 58 %

Procedure:
3-[4-[2-(N-Dodecyl-N-methylamino)ethoxy]-2-methoxyphenyl]propanoic acid, hydrochloride (274 mg, 0.598 mmol) was reacted by the general procedure as described in the preparation of 4-[4-[2-(N-dodecyl-N-methylamino)- ethoxy]phenyl]-1,1,1-trifluoro-2-butanone and afforded the title compound (165 mg, 58%) as a pale yellow oil (b.p. 138-140° C./0.015 mmHg).
Reaction SMILES: [CH3:1][C:2]1[C@H:7]([OH:8])[CH2:6][C@:5]23[C@:28]4([CH3:35])[C:29]5([C@H:32]([O:34][C@@H:4]2[CH:3]=1)[CH2:33][C@H:27]4[O:26][C:24](=[O:25])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]([CH:36]([OH:38])[CH3:37])[O:18][CH2:17][CH:16]([OH:39])[C:14]1([CH3:40])[O:15][CH:13]1[C:11](=[O:12])[O:10][CH2:9]3)[O:31][CH2:30]5>CO.C(Cl)(Cl)Cl>[CH3:1][C:2]1[C@H:7]([OH:8])[CH2:6][C:5]23[C@:28]4([CH3:35])[C@@:29]5([C@@H:32]([O:34][C@@H:4]2[CH:3]=1)[CH2:33][C@H:27]4[O:26][C:24](=[O:25])[CH:23]=[CH:22][CH:21]=[CH:20][C@H:19]([C@@H:36]([OH:38])[CH3:37])[O:18][CH2:17][C@H:16]([OH:39])[C@@:14]1([CH3:40])[O:15][C@@H:13]1[C:11](=[O:12])[O:10][CH2:9]3)[O:31][CH2:30]5
Reactant: CC1=C[C@H]2O[C@@H]3C[C@H]4OC(=O)C=CC=CC(C(C)O)OCC(O)C5(C)OC5C(=O)OC[C@@]2(C[C@H]1O)[C@]4(C)C31CO1
Agent: CC1=C[C@H]2O[C@@H]3C[C@H]4OC(=O)/C=C\C=C\C(C(C)O)OCC(O)C5(C)OC5C(=O)OC[C@@]2(C[C@H]1O)[C@]4(C)C31CO1
Agent: CC1=C[C@H]2O[C@H]3C[C@H]4OC(=O)/C=C\C=C\[C@H]([C@H](C)O)OC[C@H](O)[C@@]5(C)O[C@@H]5C(=O)OCC2(C[C@H]1O)[C@]4(C)[C@@]31CO1
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CC1=C[C@H]2O[C@H]3C[C@H]4OC(=O)C=CC=C[C@H]([C@H](C)O)OC[C@H](O)[C@@]5(C)O[C@@H]5C(=O)OCC2(C[C@H]1O)[C@]4(C)[C@@]31CO1

Procedure:
Preparative TLC of fraction CC on silica gel with 10% methanol in chloroform as eluent gave some baccharinol (B4) (Fraction DD) which was combined with Fraction BB as above, and a residue (Fraction EE) which was crystallized from methanol-chloroform-ether. Recrystallization from acetone-hexane gave isobaccharinol (B6, 0.20 g, 0.00037%): mp 249°-251° C.; [α]D24 +149° (c 0.66, MeOH); uv max (EtOH) λ (ε) 260 nm (20,400); ir (KBr) 3420, 1750, 1720, 1650, 1605 cm-1 ; NMR (CDCl3) ε 0.83 (3H, s, 14-H), 1.16 (3H, d, J=6 Hz, 14'-H), 1.65 (3H, s, 12'-H), 1.83 (3H, s, 16-H), 2.84, 3.13 (each 1H, d, J=4 Hz, 13-H), 3.38 (1H, s, 2'-H), 4.24, 4.46 (2H, ABq, J=12 Hz, 15-H), 5.52 (1H, d, J=5 Hz, 10-H), 5.8 (1H, m, 4-H), 5.81 (1H, d, J=11 Hz, 10'-H), 5.92 (1H, dd, J=15 and 3 Hz, 7'-H), 6.59 (1H, dd, J=11 and 11 Hz, 9'-H), 7.40 (1H, dd, J=15 and 11 Hz, 8'-H); mass spectrum (chemical ionization: methane reagent gas) m/e 563.2493 (M+ +H, calcd, for C29H39O11, 563.2492). Anal. Calcd for C29H38O11 :C, 61.91; H, 6.81. Found: C, 61.86; H, 6.85.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][N:15]2[CH2:20][CH2:19][CH:18]([CH2:21][NH:22][C:23]([C:25]3[C:33]4[N:32]=[C:31]([C:34]([CH3:37])([CH3:36])[CH3:35])[NH:30][C:29]=4[CH:28]=[CH:27][CH:26]=3)=[O:24])[CH2:17][CH2:16]2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[NH:8]1[CH2:9][CH2:10][CH:11]([CH2:14][N:15]2[CH2:16][CH2:17][CH:18]([CH2:21][NH:22][C:23]([C:25]3[C:33]4[N:32]=[C:31]([C:34]([CH3:37])([CH3:36])[CH3:35])[NH:30][C:29]=4[CH:28]=[CH:27][CH:26]=3)=[O:24])[CH2:19][CH2:20]2)[CH2:12][CH2:13]1
Reactant: CC(C)(C)OC(=O)N1CCC(CN2CCC(CNC(=O)c3cccc4[nH]c(C(C)(C)C)nc34)CC2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)c1nc2c(C(=O)NCC3CCN(CC4CCNCC4)CC3)cccc2[nH]1
Yield: 88 %

Procedure:
Crude 4-(4-{[(2-tert-butyl-1H-benzoimidazole-4-carbonyl)amino]methyl}-piperidin-1-ylmethyl)piperidine-1-carboxylic acid tert-butyl ester, prepared as in the previous step (5.1 g, 10 mmol) was treated with a mixture of trifluoroacetic acid (40 mL) and dichloromethane (40 mL) at room temperature for 0.5 h. The mixture was concentrated in vacuo, redissolved in dichloromethane (25 mL) and basified with 1M aqueous sodium hydroxide (15 mL). The organic layer was removed, and the aqueous layer re-extracted with dichloromethane. The combined organic phases were dried over sodium sulfate, filtered, and concentrated in vacuo to afford the desired product as a brown foam (3.6 g, 8.8 mmol, 88%). (m/z): [M+H]+ calcd for C24H37N5O, 412.31. found 412.6.
Reaction SMILES: [C:1]1(B(O)O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+].[Br:35][C:36]1[S:37][C:38](Br)=[C:39]2[CH2:43][N:42]([C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[CH2:41][C:40]=12>C1(C)C=CC=CC=1>[Br:35][C:36]1[S:37][C:38]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[C:39]2[CH2:43][N:42]([C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[CH2:41][C:40]=12
Reactant: OB(O)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1Cc2c(Br)sc(Br)c2C1
Agent: O=C([O-])[O-]
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1Cc2c(Br)sc(-c3ccccc3)c2C1
Yield: 34.4 %

Procedure:
0.91 g (7.5 mmol) of phenylboronic acid, 0.209 g (0.38 mmol) of (dibenzylideneacetone)-palladium(O), 0,397 g (1.5 mmol) of triphenylphosphine and 7.5 ml (15 mmol) of a 2M sodium carbonate solution are added to a solution of 3.2 g (8.3 mmol) of 1,3-dibromo-5-(1,1-dimethylethoxy)carbonyl-5,6-dihydro-4H-thieno[3,4-c]pyrrole in 45 ml of toluene. The mixture is heated at reflux for 5.5 hours and then cooled. The organic phase is separated by settling, washed with water, dried over magnesium sulphate and then evaporated to dryness. The residue is purified by chromatography on silica gel using the 5/95 ethyl acetate/hexane eluent mixture. There is obtained 0.98 g of a white solid. Yield 34%. Melting point: 139°-140° C.
Reaction SMILES: [Cl:1][C:2]1[C:7](I)=[CH:6][N:5]=[C:4]([O:9][CH3:10])[CH:3]=1.[CH3:11][N:12](C=O)C>[C-]#N.[Zn+2].[C-]#N.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>[Cl:1][C:2]1[C:7]([C:11]#[N:12])=[CH:6][N:5]=[C:4]([O:9][CH3:10])[CH:3]=1
Reactant: COc1cc(Cl)c(I)cn1
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: COc1cc(Cl)c(C#N)cn1
Temperature: 120 °C
Yield: 54 %

Procedure:
A suspension of 4-chloro-5-iodo-2-methoxy-pyridine (30.5 g, 0.11 mol), zinc (II) cyanide (7.97 g, 68 mmol), Pd(PPh3)4 (6.56 g, 5.66 mmol) and DMF (450 mL) was degassed and then heated at 120° C. for 1 h before being concentrated in vacuo. The resultant residue was treated with water then extracted with DCM, the organic extract dried (MgSO4), filtered, then concentrated in vacuo. The resultant residue was crystallized from DCM to give the title compound (10.1 g, 54%). The mother liquors were concentrated in vacuo and the residue subjected to flash chromatography (SiO2 gradient 0 to 100% ethyl acetate in cyclohexane) then crystallization from cyclohexane to give the further title compound (5.16 g, 28%, 82% total). 1H NMR 400 MHz (CDCl3) δ: 8.45 (1 H, s), 6.90 (1 H, s), 4.01 (3 H, s).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([OH:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.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.[Cl:45][C:46]1[CH:51]=[C:50]([Cl:52])[CH:49]=[CH:48][C:47]=1[CH2:53][CH2:54][NH2:55]>CN(C=O)C>[Cl:45][C:46]1[CH:51]=[C:50]([Cl:52])[CH:49]=[CH:48][C:47]=1[CH2:53][CH2:54][NH:55][C:4](=[O:6])[C:3]1[CH:7]=[CH:8][C:9]([OH:11])=[CH:10][C:2]=1[F:1]
Reactant: NCCc1ccc(Cl)cc1Cl
Reactant: O=C(O)c1ccc(O)cc1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCCc1ccc(Cl)cc1Cl)c1ccc(O)cc1F
Reaction time: 0.5 h
Yield: 100 %

Procedure:
To a stirred solution of 2-fluoro-4-hydroxybenzoic acid (200 mg, 1.28 mmol) in DMF (3 ml) at ambient temperature were added HATU (536 mg, 1.41 mmol) and DIEA (268 μL, 1.54 mmol). The reaction was stirred for 30 minutes and then 2-(2,4-dichlorophenyl)ethanamine (193 μL, 1.28 mmol) was added. The reaction was stirred overnight, then concentrated and diluted with water and dichloromethane. The aqueous layer was extracted with dichloromethane and the combined organic layers were washed with brine and dried over MgSO4. The crude product was purified by silica gel chromatography) to give N-(2,4-dichlorophenethyl)-2-fluoro-4-hydroxybenzamide (0.420 g).
Reaction SMILES: CC(C)([O-])C.[K+].[Br:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][C:9]=1[CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19].[C:23](OCC)(=[O:29])[C:24]([O:26][CH2:27][CH3:28])=[O:25].O>CCOCC>[O:29]=[C:23]([CH:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:16][C:9]1[CH:10]=[C:11]([O:14][CH3:15])[CH:12]=[CH:13][C:8]=1[Br:7])[C:24]([O:26][CH2:27][CH3:28])=[O:25]
Reactant: CCOC(=O)C(=O)OCC
Reactant: CCOC(=O)CCc1cc(OC)ccc1Br
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: O
Product: CCOC(=O)C(=O)C(Cc1cc(OC)ccc1Br)C(=O)OCC
Temperature: 0 °C
Reaction time: 2 h
Yield: 90.3 %

Procedure:
Potassium t-butoxide (6.72 g) was suspended in 30 ml of anhydrous ether and cooled to 0° C. A solution of 14.35 g of ethyl 3-(2-bromo-5-methoxyphenyl)propionate and 10.95 g diethyl oxalate in 10 ml ether was added dropwise over 15 min. After 2 h at 25° C., the reaction was poured into 100 ml H2O and the aqueous layer was separated, acidified to pH 1 and extracted with ether. The ether layer was dried (MgSO4) and the solvent was evaporated to yield 17.48 g of the desired product as a colorless oil (90%). NMR (CDCl3) δ 1.20 (t, 3H), 1.35 (t, 3H), 3.32 (dd, 2H), 3.76 (s, 3H), 4.18 (q, 2H), 4.32 (q, 2H), 4.53 (t, 1H), 6.67 (dd, 1H), 6.80 (d, 1H), 7.40 (d, 1H).
Reaction SMILES: CON(C)[C:4]([C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:12]=[C:13]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[Cl:23])[CH:14]=[CH:15][CH:16]=2)[CH:10]=1)=[O:5].[O:25]1[CH:29]=[CH:28][CH:27]=[CH:26]1>>[Cl:23][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[C:13]1[CH:14]=[CH:15][CH:16]=[C:11]([N:9]2[CH:10]=[C:6]([C:4]([C:26]3[O:25][CH:29]=[CH:28][CH:27]=3)=[O:5])[N:7]=[CH:8]2)[CH:12]=1
Reactant: c1ccoc1
Reactant: CON(C)C(=O)c1cn(-c2cccc(-c3ccccc3Cl)c2)cn1
Product: O=C(c1cn(-c2cccc(-c3ccccc3Cl)c2)cn1)c1ccco1

Procedure:
This compound is prepared by method C using compound 12e and furane
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5][C:4](=[O:12])[C:3]=1[C:13]([OH:15])=O.[CH3:16][NH:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.Cl>C1(C)C=CC=CC=1>[CH3:16][N:17]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:13]([C:3]1[C:4](=[O:12])[NH:5][C:6]2[C:11]([C:2]=1[OH:1])=[CH:10][CH:9]=[CH:8][CH:7]=2)=[O:15]
Reactant: O=C(O)c1c(O)c2ccccc2[nH]c1=O
Reactant: CNc1ccccc1
Agent: Cl
Solvent: Cc1ccccc1
Product: CN(C(=O)c1c(O)c2ccccc2[nH]c1=O)c1ccccc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
N,N-dicyklohexylcarbodiimide (2.2 parts) is added to a mixture consisting of 1,2-dihydro-4-hydroxy-2-oxo-quinoline-3-carboxylic acid (2.0 parts), N-metylaniline (1.1 parts) and dry toluene (25 parts) while stirring. The stirring is continued at 110° C. for 4 hrs. The reaction mixture is cooled to room temperature and the precipitate formed is filtered off. The precipitate is dissolved at pH 8.2 in 2M sodium hydroxide solution and clarified by filtration to remove the N,N-dicyklohexylurea formed. The solution is acidified with hydrochloric acid solution and the precipitate formed is filtered off. The precipitate is washed with water and methanol and dried to give N-methyl-N-phenyl-1,2-dihydro-4-hydroxy-2-oxo-quinoline-3-carboxamide, m p>300° C. (1:1).
Reaction SMILES: C(=O)(O)[O-].[Na+].[NH2:6][C:7]1[CH:12]=[CH:11][N:10]2[CH:13]=[C:14]([CH3:16])[N:15]=[C:9]2[C:8]=1[Br:17].Cl[C:19]([O:21][CH2:22][CH3:23])=[O:20].O>C(Cl)Cl.CN(C)C1C=CN=CC=1>[Br:17][C:8]1[C:9]2[N:10]([CH:13]=[C:14]([CH3:16])[N:15]=2)[CH:11]=[CH:12][C:7]=1[NH:6][C:19]([O:21][CH2:22][CH3:23])=[O:20]
Reactant: CCOC(=O)Cl
Reactant: Cc1cn2ccc(N)c(Br)c2n1
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)Nc1ccn2cc(C)nc2c1Br
Temperature: 25 °C
Reaction time: 20 h
Yield: 35 %

Procedure:
A mixture of sodium bicarbonate (0.74 g, 8.81 mmol) and amine 18 (1.00 g, 4.42 mmol) in 50 mL of dry CH2Cl2 was treated over a period of fifteen minutes with ethyl chloroformate (2.40 g, 22.1 mmol). 4-Dimethylaminopyridine (0.08 g, 0.65 mmol) was added and the reaction mixture was stirred at room temperature for 20 h. Then, water (25 mL) was added and the solution was extracted with CH2Cl2 (3×25 mL). The extracts were dried (Na2SO4), filtered and evaporated under vacuum. The residue was purified by chromatography using CH2Cl2/EtOAc (4/1, v/v) as eluent to afford in order of elution: compound 19 (461 mg, yield: 35%); mp 137-138° C.; 1H NMR (200 MHz, CDCl3) δ 1.34 (t, 3H, J=7 Hz), 2.45 (s, 3H), 4.26 (q, 2H, J=7 Hz), 7.24 (brs, 1H), 7.31 (s, 1H), 7.81 (d, 1H, J=7.4 Hz), 7.92 (d, 1H, J=7.4 Hz); 13C NMR (100 MHz, DMSO-d6) δ 14.1, 14.4, 60.8, 102.5, 109.7, 111.3, 125.1, 133.3, 142.4, 143.0, 153.8. Starting material 18 (0.31 g, 31%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:14]2[CH2:18][C@H:17]([CH2:19]O)[O:16][C:15]2=[O:21])[CH:5]=[CH:6][C:7]=1[N:8]1[CH:12]=[C:11]([CH3:13])[N:10]=[N:9]1.C(N(CC)CC)C.[CH3:29][S:30](Cl)(=[O:32])=[O:31].C(=O)(O)[O-].[Na+]>ClCCl>[F:1][C:2]1[CH:3]=[C:4]([N:14]2[CH2:18][C@H:17]([CH2:19][S:30]([CH3:29])(=[O:32])=[O:31])[O:16][C:15]2=[O:21])[CH:5]=[CH:6][C:7]=1[N:8]1[CH:12]=[C:11]([CH3:13])[N:10]=[N:9]1
Reactant: Cc1cn(-c2ccc(N3C[C@H](CO)OC3=O)cc2F)nn1
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cn(-c2ccc(N3C[C@H](CS(C)(=O)=O)OC3=O)cc2F)nn1
Temperature: 0 °C
Reaction time: 1 h
Yield: 105.1 %

Procedure:
(5R)-3-[3-Fluoro-4-(4-methyl-1H-1,2,3-triazol-1-yl)phenyl]-5-(hydroxymethyl)oxazolidin-2-one (Intermediate 19) (4.0 g, 13.7 mmol) was dissolved in dichloromethane (30 ml) and cooled to 0° C. Triethylamine (3.08 ml, 23.3 mmol) was added, followed by methylsulfonyl chloride (1.27 ml, 16.4 mmol). It was stirred for one hour and poured into saturated aqueous sodium bicarbonate solution and diluted with dichloromethane (200 ml). The organic phase was dried over magnesium sulfate and solvent was removed under reduced pressure to give the title product (5.1 g) as a solid, which was used without further purification.
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]2[CH2:7][CH2:8][CH2:9][CH2:10][C:4]=2[C:3]=1[C:11]([NH:13][CH3:14])=[O:12].C(=O)([O-])[O-].[K+].[K+].[Cl:21][CH2:22][CH2:23][C:24](Cl)=[O:25].CCCCCCC>C1COCC1>[Cl:21][CH2:22][CH2:23][C:24]([NH:1][C:2]1[S:6][C:5]2[CH2:7][CH2:8][CH2:9][CH2:10][C:4]=2[C:3]=1[C:11]([NH:13][CH3:14])=[O:12])=[O:25]
Reactant: O=C(Cl)CCCl
Reactant: CNC(=O)c1c(N)sc2c1CCCC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCCC
Solvent: C1CCOC1
Product: CNC(=O)c1c(NC(=O)CCCl)sc2c1CCCC2
Reaction time: 0.08 h
Yield: 43.8 %

Procedure:
2-Amino-N-methyl-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxamide (2.82 g, 13.41 mmol) was completely dissolved in THF (90 mL). Potassium carbonate (2.22 g, 16.09 mmol) was then added and the reaction stirred for 5 min. 3-chloropropanoyl chloride (2.04 g, 1.536 mL, 16.09 mmol) was added and the reaction mixture stirred at RT for 30 min. THF was removed in vacuo. Water was added and the reaction mixture extracted into EtOAc (×3). The combined EtOAc layers were washed with brine, dried over MgSO4, filtered and the solvent removed in vacuo. Purification by flash column chromatography-silica gel and elution with 0-60% EtOAc:heptane gave the desired product (1.76 g, 5.87 mmol, 44%).
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[N:17]=[C:16]2[C:12]([N:13]=[CH:14][N:15]2[C@@H:18]2[CH2:22][C@H:21]([NH:23][C:24](=[O:27])[CH2:25][CH3:26])[C@@H:20]([OH:28])[C@H:19]2[OH:29])=[C:11]([NH:30][CH2:31][C:32]2[C:41]3[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=3)[CH:35]=[CH:34][CH:33]=2)[N:10]=1.[CH:42]1[C:54]2C(CN)C3C(=CC=CC=3)C=2C=C[CH:43]=1>>[Cl:8][C:9]1[N:17]=[C:16]2[C:12]([N:13]=[CH:14][N:15]2[C@@H:18]2[CH2:22][C@H:21]([NH:23][C:24](=[O:27])[CH2:25][CH3:26])[C@@H:20]([OH:28])[C@H:19]2[OH:29])=[C:11]([NH:30][CH2:31][CH:32]2[C:54]3[CH:42]=[CH:43][CH:33]=[CH:34][C:35]=3[C:36]3[C:41]2=[CH:40][CH:39]=[CH:38][CH:37]=3)[N:10]=1
Reactant: CCC(=O)N[C@H]1C[C@@H](n2cnc3c(NCc4cccc5ccccc45)nc(Cl)nc32)[C@H](O)[C@@H]1O
Reactant: NCC1c2ccccc2-c2ccccc21
Solvent: O=C(O)C(F)(F)F
Product: CCC(=O)N[C@H]1C[C@@H](n2cnc3c(NCC4c5ccccc5-c5ccccc54)nc(Cl)nc32)[C@H](O)[C@@H]1O

Procedure:
This compound is prepared analogously to N-((4S,2R,3S,4R)-4-{2-chloro-6-[(naphthalen-1-ylmethyl)-amino]-purin-9-yl}-2,3-dihydroxy-cyclopentyl)-propionamide trifluoroacetate (Example 50) by replacing 1-napthalenemethylamine with C-(9H-fluoren-9-yl)-methylamine.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:28])=[C:6]([CH:27]=1)[CH2:7][C:8]1[CH:13]=[C:12]([F:14])[CH:11]=[C:10]([CH:15]([C:17]2[CH:22]=[C:21]([Cl:23])[CH:20]=[C:19]([Cl:24])[C:18]=2[OH:25])[CH3:16])[C:9]=1[OH:26].[Br:29]Br>C(O)(=O)C>[Br:29][C:4]1[C:5]([OH:28])=[C:6]([CH:27]=[C:2]([Cl:1])[CH:3]=1)[CH2:7][C:8]1[CH:13]=[C:12]([F:14])[CH:11]=[C:10]([CH:15]([C:17]2[CH:22]=[C:21]([Cl:23])[CH:20]=[C:19]([Cl:24])[C:18]=2[OH:25])[CH3:16])[C:9]=1[OH:26]
Reactant: CC(c1cc(Cl)cc(Cl)c1O)c1cc(F)cc(Cc2cc(Cl)ccc2O)c1O
Reactant: BrBr
Solvent: CC(=O)O
Product: CC(c1cc(Cl)cc(Cl)c1O)c1cc(F)cc(Cc2cc(Cl)cc(Br)c2O)c1O

Procedure:
2-(5-Chloro-2-hydroxybenzyl)-6-[1-(3,5-dichloro-2-hydroxyphenyl) ethyl]-4-fluorophenol was brominated using bromine in acetic acid at room temperature to give the title compound; m.p. 171°.
Reaction SMILES: [CH3:1][Si:2](Cl)([CH3:4])[CH3:3].C1(S([C:15](Br)([F:17])[F:16])(=O)=O)C=CC=CC=1>CN(C=O)C>[CH3:1][Si:2]([CH3:4])([CH3:15])[C:3]([F:17])([F:16])[C:15]([Si:2]([CH3:4])([CH3:3])[CH3:1])([F:17])[F:16]
Reactant: O=S(=O)(c1ccccc1)C(F)(F)Br
Reactant: C[Si](C)(C)Cl
Solvent: CN(C)C=O
Product: C[Si](C)(C)C(F)(F)C(F)(F)[Si](C)(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 55 %

Procedure:
Into a mixture of 0.42 g (17.5 mmol) of Mg turnings, 1.92 g (17.7 mmol) of TMSCl and 10 mL DMF, was added 1.60 g (5.9 mmol) of bromodifluoromethyl phenyl sulfone (23). The reaction mixture was stirred at 0° C. for 30 min, and at room temperature for another 30 min until 19F NMR showed all of 23 was consumed (the yield of 20 was 76% and by-product TMSCF2TMS, 18% by 19F NMR analysis). The reaction mixture was washed with ice water followed by extraction with pentane (10 mL×4). The pentane phase was washed with cold 98% sulfuric acid (10 mL×3) to remove most of the siloxane and silanol. Then the pentane solution was washed with cold NaHCO3 aqueous solution three times until the pH paper indicated neutral pH. After drying over MgSO4 and solvent removal, the crude product was further purified by fractional distillation and then recrystallization at −20° C. to give 0.40 g crystalline product 20, m.p. 40˜42° C., yield 55%. 1H NMR (500 MHz, CDCl3): δ0.24 (s, 18H). 13C NMR (125 MHz, CDCl3): δ−4.0 (m, CH3); 126.6 (tt, 1JC-F=265.0 Hz; 2JC-F=45.9 Hz). 19F NMR (470 MHz, CDCl3): δ−122.3.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]([OH:13])=O)=[CH:10][C:5]=2[N:4]=[C:3]1[NH:14][C:15]1[S:16][C:17]2[CH:23]=[C:22]([O:24][C:25]([F:28])([F:27])[F:26])[CH:21]=[CH:20][C:18]=2[N:19]=1.[CH2:29]([NH2:32])[CH2:30][CH3:31].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>>[CH2:29]([NH:32][C:11]([C:9]1[CH:8]=[CH:7][C:6]2[N:2]([CH3:1])[C:3]([NH:14][C:15]3[S:16][C:17]4[CH:23]=[C:22]([O:24][C:25]([F:27])([F:26])[F:28])[CH:21]=[CH:20][C:18]=4[N:19]=3)=[N:4][C:5]=2[CH:10]=1)=[O:13])[CH2:30][CH3:31]
Reactant: CCCN
Reactant: Cn1c(Nc2nc3ccc(OC(F)(F)F)cc3s2)nc2cc(C(=O)O)ccc21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CCCNC(=O)c1ccc2c(c1)nc(Nc1nc3ccc(OC(F)(F)F)cc3s1)n2C
Yield: 78.1 %

Procedure:
1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid propylamide (86 mg) was prepared by following General Procedure F starting from 1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzo-imidazole-5-carboxylic acid (100 mg), propylamine (16 mg), HBTU (111 mg), and DIEA (64 uL). LC/MS: m/z 450.9. 1H NMR (DMSO-d6, 400 MHz): δ 12.38 (bs, 1H), 8.42 (s, 1H), 8.07 (s, 1H), 7.90 (s, 1H), 7.75 (d, 1H), 7.72 (d, 1H), 7.46 (d, 1H), 7.34 (d, 1H), 3.62 (bs, 3H), 3.22 (q, 2H), 1.60-1.45 (m, 2H), 0.90 (t, 3H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4]([O:15][CH2:16][C:17]2[C:22]([CH3:23])=[CH:21][CH:20]=[CH:19][N:18]=2)[N:3]=1.[Br:24]N1C(=O)CCC1=O>CN(C=O)C>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][C:10]([Br:24])=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4]([O:15][CH2:16][C:17]2[C:22]([CH3:23])=[CH:21][CH:20]=[CH:19][N:18]=2)[N:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cccnc1COc1nc(N)nc(-c2ccco2)c1C#N
Solvent: CN(C)C=O
Product: Cc1cccnc1COc1nc(N)nc(-c2ccc(Br)o2)c1C#N

Procedure:
From 2-amino-4-furan-2-yl-6-(3-methyl-pyridin-2-ylmethoxy)-pyrimidine-5-carbonitrile and N-bromosuccinimide in DMF. ES-MS m/e (%): 388 (M{81Br}+H+, 100), 386 (M{79Br}+H+, 90).
Reaction SMILES: [CH3:1][O:2][C:3]([C@H:5]1[CH2:10][CH2:9][C@H:8]([C:11](=O)[NH:12][CH2:13][C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([Br:22])[N:17]=2)=O)[CH2:7][CH2:6]1)=[O:4].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:33])=CC=1>O1CCCC1>[CH3:1][O:2][C:3]([C@H:5]1[CH2:10][CH2:9][C@H:8]([C:11]2[S:33][C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([Br:22])[N:17]=3)=[CH:13][N:12]=2)[CH2:7][CH2:6]1)=[O:4]
Reactant: COC(=O)[C@H]1CC[C@H](C(=O)NCC(=O)c2cccc(Br)n2)CC1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: C1CCOC1
Product: COC(=O)[C@H]1CC[C@H](c2ncc(-c3cccc(Br)n3)s2)CC1

Procedure:
A solution of trans-4-[2-(6-bromopyridin-2-yl)-2-oxoethylcarbamoyl]cyclohexanecarboxylic acid methyl ester (7.38 g, 19.3 mmol) obtained in Step 2 and a Lawesson reagent (8.20 g, 20.3 mmol) in tetrahydrofuran (120 ml) was heated at reflux for 2 hours in an Ar stream. After the reaction solution was concentrated, a saturated aqueous sodium bicarbonate was added and extracted with ethyl acetate. The organic layer was washed with a saturated sodium bicarbonate aqueous solution and dried over magnesium sulfate, and after concentrated, the residue was purified by flash chromatography on silica gel (n-hexane:ethyl acetate=1:1) and the title compound (6.1 g) was obtained.