Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:5]=[CH:4][C:3]=1B(O)O.[CH2:19]([O:21][C:22]([C:24]1[S:34][C:27]2[N:28]=[C:29]([NH2:33])[N:30]=[C:31](Cl)[C:26]=2[CH:25]=1)=[O:23])[CH3:20].C([O-])(O)=O.[Na+]>CN(C=O)C>[CH2:19]([O:21][C:22]([C:24]1[S:34][C:27]2[N:28]=[C:29]([NH2:33])[N:30]=[C:31]([C:3]3[CH:4]=[CH:5][C:6]([O:8][CH2:9][C:10]4[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=4)=[CH:7][C:2]=3[CH3:1])[C:26]=2[CH:25]=1)=[O:23])[CH3:20]
Reactant: Cc1cc(OCc2ccccc2)ccc1B(O)O
Reactant: CCOC(=O)c1cc2c(Cl)nc(N)nc2s1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2c(-c3ccc(OCc4ccccc4)cc3C)nc(N)nc2s1
Temperature: 80 °C
Yield: 70.7 %

Procedure:
2-methyl-4-benzyloxyphenylboronic acid (225 mg; 0.93 mmol) was added to 2-Amino-4-chloro-thieno[2,3-d]pyrimidine-6-carboxylic acid ethyl ester (example 1; step 1) (200 mg; 0.776 mmol) in DMF (10 mL). NaHCO3 (1.0M aq. Solution; 2.33 mL) was added and mixture degassed with N2. Pd(PPh3)2Cl2 was added and reaction mixture heated at 80 degrees C. for 5 hours Reaction mixture was allowed to cool to room temperature and DMF removed in vacuo. The residue was partitioned between ethyl acetate (50 mL) and sat. NaCl (aq) (50 mL) Organic phase was dried over Na2SO4 and filtered, filtrate solvents removed in vacuo to afford a yellow oil which was purified by ion-exchange chromatography (IST SCX-2 column) to afford product as a brown-yellow solid (230 mg; 71%)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[N:11]=[C:10]([Cl:13])[CH:9]=[CH:8]2.[Br:14]Br.[O-]S([O-])(=S)=O.[Na+].[Na+].CCOC(C)=O>CO>[Br:14][C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[C:12]2[C:7]=1[CH:8]=[CH:9][C:10]([Cl:13])=[N:11]2
Reactant: COc1cccc2ccc(Cl)nc12
Reactant: BrBr
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Product: COc1ccc(Br)c2ccc(Cl)nc12
Reaction time: 2 h
Yield: 49 %

Procedure:
A solution of 8-methoxy-2-(chloro)quinoline CAS [74668-74-9] (1.0 g, 4.4 mmol) in MeOH (6.25 mL) was treated with a 1.5 N solution of bromine in MeOH (3.53 mL, 5.3 mmol) over 15 min period. The reaction mixture was stirred 2 h, treated with a 1 N aqueous Na2S2O3 solution (20 mL) followed by EtOAc (100 mL). The organic portion was washed with brine followed by a saturated aqueous solution of NaHCO3 followed by brine. The organic phase was dried over Na2SO4, filtered, evaporated, and purified by silica gel chromatography eluting with CH2Cl2 to afford titled compound as a colorless solid (49%). 1H NMR (CDCl3) 8.44 (dd, J=8.8, 1.2, 1H), 7.73 (dd, J=8.4, 1.2, 1H), 7.51 (dd, J=8.8, 1.2, 1 H), 6.97 (d, J=8.4, 1H), 4.06 (s, 3H). LC/MS 3.45 min, [M+1]+ 271/273.
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[CH2:13][C:12]2[S:11][C:10]3[C:9](=[O:14])[NH:8][N:7]=[CH:6][C:5]=3[C:4]=2[CH2:3]1.Br[C:17]1[N:24]=[CH:23][CH:22]=[C:21]([Cl:25])[C:18]=1[CH:19]=[O:20]>>[Cl:25][C:21]1[CH:22]=[CH:23][N:24]=[C:17]([N:8]2[N:7]=[CH:6][C:5]3[C:4]4[CH2:3][C:2]([CH3:15])([CH3:1])[CH2:13][C:12]=4[S:11][C:10]=3[C:9]2=[O:14])[C:18]=1[CH:19]=[O:20]
Reactant: O=Cc1c(Cl)ccnc1Br
Reactant: CC1(C)Cc2sc3c(=O)[nH]ncc3c2C1
Product: CC1(C)Cc2sc3c(=O)n(-c4nccc(Cl)c4C=O)ncc3c2C1

Procedure:
Following the procedures as described in Example 108a, and starting with 282h (330 mg, 1.5 mmol) and 2-bromo-4-chloronicotinaldehyde (950 mg, 4.5 mmol), 282i was obtained as a yellow solid (260 mg, 48%). MS-ESI: [M+H]+ 359.9
Reaction SMILES: BrC1C=CC=C2C=1C=CC(S(NC1C=CN=CN=1)(=O)=O)=C2.[CH3:22][O:23][C:24]1[CH:36]=[CH:35][C:27]([CH2:28][NH:29][C:30]2[S:31][CH:32]=[CH:33][N:34]=2)=[CH:26][CH:25]=1.[Cl:37][C:38]1[CH:43]=[C:42]([C:44]([F:47])([F:46])[F:45])[CH:41]=[CH:40][C:39]=1[C:48]1[CH:57]=[CH:56][CH:55]=[C:54]2[C:49]=1[CH:50]=[CH:51][C:52]([S:58](OC1C(F)=C(F)C(F)=C(F)C=1F)(=[O:60])=[O:59])=[CH:53]2>>[Cl:37][C:38]1[CH:43]=[C:42]([C:44]([F:47])([F:46])[F:45])[CH:41]=[CH:40][C:39]=1[C:48]1[CH:57]=[CH:56][CH:55]=[C:54]2[C:49]=1[CH:50]=[CH:51][C:52]([S:58]([N:29]([CH2:28][C:27]1[CH:26]=[CH:25][C:24]([O:23][CH3:22])=[CH:36][CH:35]=1)[C:30]1[S:31][CH:32]=[CH:33][N:34]=1)(=[O:59])=[O:60])=[CH:53]2
Reactant: O=S(=O)(Oc1c(F)c(F)c(F)c(F)c1F)c1ccc2c(-c3ccc(C(F)(F)F)cc3Cl)cccc2c1
Reactant: COc1ccc(CNc2nccs2)cc1
Agent: O=S(=O)(Nc1ccncn1)c1ccc2c(Br)cccc2c1
Product: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(-c4ccc(C(F)(F)F)cc4Cl)cccc3c2)cc1

Procedure:
The title compound was prepared in an analogous manner to that of intermediate W, except that N-(4-methoxybenzyl)thiazol-2-amine was used in place of 4-aminopyrimidine and perfluorophenyl 5-(2-chloro-4-(trifluoromethyl)phenyl)naphthalene-2-sulfonate (intermediate Z) was used instead of perfluorophenyl 5-bromonaphthalene-2-sulfonate. MS (ESI, positive) m/z: 588.9.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:6]=1[NH:12][CH3:13])[CH3:2].[Cl:15]N1C(C)(C)C(=O)N(Cl)C1=O>C(O)(=O)C.C(OCC)(=O)C>[CH2:1]([O:3][C:4](=[O:14])[C:5]1[CH:10]=[C:9]([Cl:15])[CH:8]=[C:7]([F:11])[C:6]=1[NH:12][CH3:13])[CH3:2]
Reactant: CCOC(=O)c1cccc(F)c1NC
Reactant: CC1(C)C(=O)N(Cl)C(=O)N1Cl
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cc(Cl)cc(F)c1NC
Temperature: 25 °C
Reaction time: 3 h
Yield: 124 %

Procedure:
To a solution of 3-fluoro-2-methylaminobenzoic acid ethyl ester (124 mg, 0.63 mmol) in acetic acid (4 ml) was added 1,3-dichloro-5,5-dimethylhydantoin (93 mg, 0.47 mmol). The reaction mixture was stirred at RT for 3 h. The mixture was diluted with ethyl acetate and then washed with sat. NaHCO3. The organic phase was then washed with brine, dried (MgSO4), filtered, and concentrated in vacuo to give a residue which was purified by flash column chromatography to give 5-chloro-3-fluoro-2-methylaminobenzoic acid ethyl ester (135 mg, 93%) as a yellow oil. 1H NMR (CDCl3, 300 MHz): 7.67 (dd, J=2.5, 1.5 Hz, 1H), 7.52 (brds, 1H), 7.09 (dd, J=13.5, 2.5 Hz, 1H), 4.31 (q, J=7.0 Hz, 2H), 3.11 (m, 3H), 1.38 (t, J=7.0 Hz, 3H).
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[C:6]1([CH3:28])[CH:11]=[C:10]([CH3:12])[CH:9]=[C:8]([CH3:13])[C:7]=1[N:14]1[C:27]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[S:21][C:20]2[C:15]1=[CH:16][CH:17]=[CH:18][CH:19]=2.CN([CH:37]=[O:38])C1C=CC=CC=1.C([O-])(=O)C.[Na+]>ClC1C=CC=CC=1Cl.O>[C:6]1([CH3:28])[CH:11]=[C:10]([CH3:12])[CH:9]=[C:8]([CH3:13])[C:7]=1[N:14]1[C:27]2[CH:26]=[CH:25][C:24]([CH:37]=[O:38])=[CH:23][C:22]=2[S:21][C:20]2[C:15]1=[CH:16][CH:17]=[CH:18][CH:19]=2
Reactant: CN(C=O)c1ccccc1
Reactant: Cc1cc(C)c(N2c3ccccc3Sc3ccccc32)c(C)c1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Solvent: Clc1ccccc1Cl
Product: Cc1cc(C)c(N2c3ccccc3Sc3cc(C=O)ccc32)c(C)c1
Temperature: 70 °C
Reaction time: 4 h

Procedure:
3.66 g (23.6 mmol) of 99% phosphorus oxychloride were added dropwise at 20° C. with stirring and ice cooling to a solution of 5.00 g (15.8 mmol) of 10-mesitylphenothiazine and 3.23 g (23.6 mmol) of 99% N-methylformanilide in 5 ml of o-dichlorobenzene within 15 min. After stirring at 20° C. for 30 min, the reaction solution was heated to 70° C. and kept at this temperature for 4 hours. The reaction solution was admixed with a solution of 16 g of sodium acetate in 35 ml of water within 5 min. After stirring at 70° C. for 1 hour, N-methylformanilide and o-dichlorobenzene were removed with a steam distillation. 250 ml of methylene chloride were added to the distillation bottoms. The organic phase was removed and filtered through silica gel. The filtrate was concentrated and dried at 40° C. under reduced pressure. 5.05 g (93% of theory) of analytically pure greenish powder having a melting point of 136-140° C. were obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:26][CH3:27])=[C:6]([CH:25]=1)[C:7]([NH:9][CH:10]1[CH2:19][C:18]2[C:13](=[CH:14][C:15]([CH3:24])=[C:16]([S:20](=[O:23])(=[O:22])[NH2:21])[CH:17]=2)[O:12][CH2:11]1)=[O:8].C(=O)([O-])[O-].[K+].[K+].[CH3:34][N:35]=[C:36]=[S:37].C>CS(C)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:26][CH3:27])=[C:6]([CH:25]=1)[C:7]([NH:9][CH:10]1[CH2:19][C:18]2[C:13](=[CH:14][C:15]([CH3:24])=[C:16]([S:20]([NH:21][C:36]([NH:35][CH3:34])=[S:37])(=[O:22])=[O:23])[CH:17]=2)[O:12][CH2:11]1)=[O:8]
Reactant: CN=C=S
Reactant: COc1ccc(Cl)cc1C(=O)NC1COc2cc(C)c(S(N)(=O)=O)cc2C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CNC(=S)NS(=O)(=O)c1cc2c(cc1C)OCC(NC(=O)c1cc(Cl)ccc1OC)C2
Temperature: 80 °C
Reaction time: 0.42 h

Procedure:
1.64 g (4 mmol) of 3-(5-chloro-2-methoxybenzamido)-6-sulfamoyl-7-methylchroman were dissolved in 10 ml of dry DMSO, and 1.65 g (12 mmol) of finely powdered potassium carbonate and 0.35 g (4.8 mmol) of methyl isothiocyanate were added. After the mixture had been stirred at 80° C. for 25 minutes, it was cooled, introduced into ice-water, clarified with charcoal and acidified to pH 1. The precipitate was filtered off with suction, dried, purified over a silica gel column using ethyl acetate/toluene 2:1 and recrystallized from ethanol. Melting point: 207°-208° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]([O:13][C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=2[F:21])[CH2:10][CH:9]1[C:22](O)=[O:23])=[O:7])([CH3:4])([CH3:3])[CH3:2].CSC>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]([O:13][C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=2[F:21])[CH2:10][CH:9]1[CH2:22][OH:23])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CC(Oc2ccc(F)cc2F)CC1C(=O)O
Solvent: CSC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC(Oc2ccc(F)cc2F)CC1CO
Temperature: 25 °C
Yield: 71.9 %

Procedure:
To a stirred solution of 1-(tert-butoxycarbonyl)4-(2,4-difluorophenoxy)pyrrolidine-2-carboxylic acid (2.55 g, 7.43 mmol) in THF (50 ml) was added BH3.DMS (452 ul, 7.43 mmol). The mixture was heated at reflux overnight. After cooling to room temperature, the mixture was concentrated in vacuo and quenced by the addition of H2O (100 ml). The mixture was extracted with CHCl3 (2×200 ml), dried over MgSO4, and evaporated. The residue was chromatographed on silica gel with CHCl3-EtOAc (4:1) as eluent to give 1-(tert-butoxycarbonyl)-4-(2,4-difluorophenoxy)-2-pyrrolidinylmethanol (1.76 g, 72%) as a colorless oil. 1H-NMR (CDCl3) δ 1.45 (s, 9 H), 2.28–2.36 (m, 2 H), 3.58–4.99 (series of m, 8 H), 6.74–6.90 (m, 3 H).
Reaction SMILES: C([O:5][C:6]([CH2:8][O:9][N:10]=[C:11]1[C:20]2[C:15](=[C:16]([CH3:24])[C:17]([CH3:23])=[C:18]([OH:22])[C:19]=2[CH3:21])[O:14][C:13]([CH2:26][O:27][C:28]2[CH:41]=[CH:40][C:31]([CH2:32][CH:33]3[S:37][C:36](=[O:38])[NH:35][C:34]3=[O:39])=[CH:30][CH:29]=2)([CH3:25])[CH2:12]1)=[O:7])(C)(C)C.Cl>O1CCOCC1>[C:6]([CH2:8][O:9][N:10]=[C:11]1[C:20]2[C:15](=[C:16]([CH3:24])[C:17]([CH3:23])=[C:18]([OH:22])[C:19]=2[CH3:21])[O:14][C:13]([CH2:26][O:27][C:28]2[CH:41]=[CH:40][C:31]([CH2:32][CH:33]3[S:37][C:36](=[O:38])[NH:35][C:34]3=[O:39])=[CH:30][CH:29]=2)([CH3:25])[CH2:12]1)([OH:7])=[O:5]
Reactant: Cc1c(C)c2c(c(C)c1O)C(=NOCC(=O)OC(C)(C)C)CC(C)(COc1ccc(CC3SC(=O)NC3=O)cc1)O2
Agent: Cl
Solvent: C1COCCO1
Product: Cc1c(C)c2c(c(C)c1O)C(=NOCC(=O)O)CC(C)(COc1ccc(CC3SC(=O)NC3=O)cc1)O2
Reaction time: 15 h

Procedure:
A mixture of 0.7 g of 5-[4-(4-t-butoxycarbonylmethoxyimino-6-hydroxy-2,5,7,8-tetramethylchroman -2ylmethoxy)benzyl]thiazolidine-2,4-dione (prepared as described in Example 26) and 7 ml of a 4N dioxane solution of hydrogen chloride was allowed to stand at room temperature for 15 hours. At the end of this time, the solvent was distilled off and the residue was washed with warm water to give the title compound, softening at 75°-85° C.
Reaction SMILES: [CH2:1]1COC23OCCOC2([C@]2(CC[C@H]4[C@@H](C[C@H](CCO)C5[C@]4(C)CCCC5)[C@@H]2C3)C)[O:2]1.[CH2:31]=[C:32]1[CH:49]2[C@:44]([CH3:51])([CH2:45][CH2:46][C:47](=[O:50])[CH2:48]2)[C@@H:43]2[C@H:34]([C@H:35]3[C@@:39]([CH2:41][CH2:42]2)([CH3:40])[C:38](=[O:52])[CH2:37][CH2:36]3)[CH2:33]1>>[OH:2][CH2:1][CH2:31][C@@H:32]1[CH:49]2[C@:44]([CH3:51])([CH2:45][CH2:46][C:47](=[O:50])[CH2:48]2)[C@@H:43]2[C@H:34]([C@H:35]3[C@@:39]([CH2:41][CH2:42]2)([CH3:40])[C:38](=[O:52])[CH2:37][CH2:36]3)[CH2:33]1
Reactant: C[C@]12CCCCC1[C@@H](CCO)C[C@@H]1[C@@H]2CC[C@@]2(C)[C@H]1CC13OCCOC12OCCO3
Reactant: C=C1C[C@@H]2[C@H](CC[C@]3(C)C(=O)CC[C@@H]23)[C@@]2(C)CCC(=O)CC12
Product: C[C@]12CCC(=O)CC1[C@@H](CCO)C[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Yield: 100 %

Procedure:
The title compound II-an was prepared in 100% yield from 3,3:17,17-bis(ethylendioxy)-6α-(2-hydroxyethyl)androstane by the procedure described above for the preparation of 6-methyleneandrostane-3,17-dione (II-ac, Prepn. 13). The combined organic extracts were washed with H2O, dried over Na2SO4 and evaporated to dryness. 1H-NMR (300 MHz, DMSO-d6, ppm from TMS): δ 4.32 (1H, t), 3.39 (2H, m), 2.46-0.54 (23H, m), 0.98 (3H, s), 0.79 (3H, s).
Reaction SMILES: C(OC([NH:8][CH2:9][C:10](=[O:20])[CH2:11][P:12]([CH3:19])(=[O:18])[O:13]CC(C)C)=O)(C)(C)C>Cl>[NH2:8][CH2:9][C:10](=[O:20])[CH2:11][P:12]([CH3:19])(=[O:13])[OH:18]
Reactant: CC(C)COP(C)(=O)CC(=O)CNC(=O)OC(C)(C)C
Agent: Cl
Product: CP(=O)(O)CC(=O)CN
Temperature: 25 °C

Procedure:
A solution of 0.5 g of isobutyl P-(3-tert.-butoxycarbonylamino-2-oxo-propyl)-P-methyl-phosphinate in 10 ml of 36% aqueous hydrochloric acid is heated to reflux for a period of 4 hours. The mixture is then allowed to cool to room temperature, concentrated under reduced pressure, and co-evaporated twice with 20 ml of water. The crude product is dissolved in 20 ml of ethanol, 1 ml of propylene oxide is added, and the mixture is stirred until the precipitated solid is free of halogen. The solid is filtered and dried to give P-(3-amino-2-oxo-propyl)-P-methyl-phosphinic acid, m.p. 148°-149°, 31P-NMR spectrum: δ=32.8 ppm (D2O).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]#[N:9])=[CH:4][CH:3]=1.[CH2:10]([O-:18])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17].[Na+]>O>[CH2:10]([O:18][C:2]1[N:7]=[CH:6][C:5]([C:8]#[N:9])=[CH:4][CH:3]=1)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: CCCCCCCC[O-]
Reactant: N#Cc1ccc(Cl)nc1
Agent: [Na+]
Solvent: O
Product: CCCCCCCCOc1ccc(C#N)cn1
Reaction time: 0.5 h
Yield: 87.2 %

Procedure:
A mixture of 6-chloropyridine-3-carboxamide (14 g), phosphorous oxychloride (35 ml) and chloroform (120 ml) is refluxed for 2 hr, cooled, and concentrated. The residue is stirred with water and the resulting precipitate is collected and recrystallized from ethanol to provide 10.3 g (83 %) of 6-chloropyridine-3-carbonitrile. This nitrile (2.77 g) is added to a solution of sodium octanolate (prepared from 1-octanol (2.78 g) and sodium hydride (0.88g of 60% dispersion) in DMF (20 ml)). After 30 min at room temperature, the mixture is poured into water, and the product extracted with ether. The extracts are concentrated and chromatographed with 2:3 hexane-dichloromethane, to provide 6-(octyloxy)pyridine-3-carbonitrile as a colorless oil (3.7 g, 80%). This nitrile is dissolved in toluene (15 ml), cooled to -20°, and diisobutylaluminum hydride (12.5 ml of 1.5M solution in toluene) is added dropwise. After an hour, the mixture is poured into 1.0N hydrochloric acid and the product extracted with ether. The extracts are dried, filtered, and concentrated to leave 6-(octyloxy)pyridine-3-carboxaldehyde (2.36 g) as a yellow oil.
Reaction SMILES: [F:1][C:2]1[C:3]([C@H:8]([C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=2)[NH:9][C:10](=[O:21])[C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[C:13]([N+:18]([O-:20])=[O:19])[CH:12]=2)=[N:4][CH:5]=[CH:6][CH:7]=1.[C:32](OC(=O)C)(=[O:34])[CH3:33].CCN(C(C)C)C(C)C>C(Cl)Cl>[C:32]([O:17][C:14]1[CH:15]=[CH:16][C:11]([C:10](=[O:21])[NH:9][C@H:8]([C:3]2[C:2]([F:1])=[CH:7][CH:6]=[CH:5][N:4]=2)[C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:30])([F:31])[F:29])=[CH:24][CH:23]=2)=[CH:12][C:13]=1[N+:18]([O-:20])=[O:19])(=[O:34])[CH3:33]
Reactant: CC(=O)OC(C)=O
Reactant: O=C(N[C@@H](c1ccc(C(F)(F)F)cc1)c1ncccc1F)c1ccc(O)c([N+](=O)[O-])c1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(=O)Oc1ccc(C(=O)N[C@@H](c2ccc(C(F)(F)F)cc2)c2ncccc2F)cc1[N+](=O)[O-]
Reaction time: 0.75 h

Procedure:
To a solution of (S)—N-((3-fluoropyridin-2-yl)(4-(trifluoromethyl)phenyl)methyl)-4-hydroxy-3-nitrobenzamide (83 mg, 0.191 mmol) and DCM (5 mL) were added acetic anhydride (0.2 mL, 2.120 mmol) and DIPEA (0.15 mL, 0.861 mmol). After stirring for 45 min, the reaction was quenched with water and after stirring for 3 days, the aqueous solution was filtered to give the title compound as a yellow solid. The resulting product was used in the next step without further purification. MS (ESI pos. ion) m/z: 478.1 (M+H).
Reaction SMILES: B.[Na].[S:3]1[CH:7]=[CH:6][C:5]2[C:8]([CH2:12][CH:13]=[O:14])=[CH:9][CH:10]=[CH:11][C:4]1=2.O.Cl>CO.C(OCC)(=O)C>[S:3]1[CH:7]=[CH:6][C:5]2[C:8]([CH2:12][CH2:13][OH:14])=[CH:9][CH:10]=[CH:11][C:4]1=2
Reactant: O=CCc1cccc2sccc12
Agent: B
Agent: Cl
Agent: [Na]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: O
Product: OCCc1cccc2sccc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 60 %

Procedure:
In 8 mL of 90% methanol is suspended 0.16 g of sodium boron hydride. At an ice-cooled temperature, a solution of 1.45 g of 2-benzo[b]thiophen-4-ylacetaldehyde in 6 mL of methanol is dropwise added to the suspension obtained above, and the resulting mixture is stirred at ambient temperature for 30 minutes. Water and ethyl acetate are added to the reaction mixture, pH is adjusted to 2.0 with 6 mol/L hydrochloric acid, and the organic layer is separated. The organic layer is washed with saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, the solvent is distilled off under reduced pressure, and the residue is purified by column chromatography (eluent: toluene:ethyl acetate=50:1 to 2:1) to obtain 0.88 g of 2-benzo[b]-thiophen-4-yl-1-ethanol.
Reaction SMILES: O1CCCCC1[O:7][CH2:8][C:9]#[C:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([OH:25])=[O:24].[CH3:26]COCC>>[OH:7][CH2:8][C:9]#[C:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([O:25][CH3:26])=[O:24]
Reactant: CCOCC
Reactant: O=C(O)CCCCCCCCCCCCC#CCOC1CCCCO1
Product: COC(=O)CCCCCCCCCCCCC#CCO
Yield: 83 %

Procedure:
Concomitant esterification of the carboxylic acid and cleavage of the THP ether in 16-(tetrahydro-2H-pyran-2-yloxy)hexadec-14-ynoic acid (1.0 g, 2.84 mmol) as described above furnished methyl 16-hydroxyhexadec-14-ynoate (665 mg, 83%) as a colorless oil. TLC: 30% EtOAc/hexanes, Rf≈0.40; 1H NMR (CDCl3, 300 MHz) δ 4.22-4.26 (m, 2H), 3.66 (s, 3H), 2.29 (t, 2H, J=7.3 Hz), 2.20 (tt, 2H, J=2.1 Hz, 6.8 Hz), 1.21-1.66 (m, 20H).
Reaction SMILES: O=[C:2]1[C:6]2[NH:7][C:8]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:9][C:5]=2[CH2:4][CH2:3]1.[C:15]1([CH3:23])[CH:20]=[CH:19][C:18]([Mg]Br)=[CH:17][CH:16]=1>>[C:15]1([CH3:23])[CH:20]=[CH:19][C:18]([CH:2]2[C:6]3[NH:7][C:8]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:9][C:5]=3[CH2:4][CH2:3]2)=[CH:17][CH:16]=1
Reactant: Cc1ccc([Mg]Br)cc1
Reactant: CCOC(=O)c1cc2c([nH]1)C(=O)CC2
Product: CCOC(=O)c1cc2c([nH]1)C(c1ccc(C)cc1)CC2

Procedure:
The title compound was synthesized from ethyl 6-oxo-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-2-carboxylate (0.3 g, 1.55 mmol, 1 equiv) and p-tolyl magnesium bromide (6.2 mL, 1M in THF, 6.2 mmol, 4 equiv) according to General Procedure 3 to give the endocyclic olefin-containing compound ethyl 6-p-tolyl-1,4-dihydrocyclopenta[b]pyrrole-2-carboxylate. 1H NMR showed a complex mixture but was qualitatively consistent with ethyl 6-p-tolyl-1,4-dihydrocyclopenta[b]pyrrole-2-carboxylate and the corresponding carbinol (ethyl 6-hydroxy-6-p-tolyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-2-carboxylate) and was carried on to the next step without further purification. The mixture was hydrogenated according to General Procedure 6, and was purified by column chromatography (Isco CombiFlash) using a 0-30% gradient (EtOAc/Heptane) over 22 minutes. 0.1423 g. LCMS m/e 292 (M+Na). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.33 (t, J=7.13 Hz, 3H), 2.30 (dt, J=8.65, 6.43 Hz, 1H), 2.34 (s, 3H), 2.61-2.70 (m, 1H), 2.75 (dd, J=8.79, 4.00 Hz, 1H), 2.86-2.97 (m, J=12.68, 8.41, 8.41, 4.03 Hz, 1H), 4.19-4.32 (m, 3H), 6.73 (d, J=1.61 Hz, 1H), 7.01-7.07 (m, 2H), 7.13 (d, J=7.86 Hz, 2H), 8.60 (br. s, 1H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)[N:5]=[C:4]([NH:17][CH:18]2[NH:22][C:21](=[O:23])[N:20]([CH3:24])[C:19]2=[O:25])[N:3]=1.[CH3:26][O:27][C:28]1[CH:34]=[CH:33][C:31]([NH2:32])=[CH:30][CH:29]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[CH3:26][O:27][C:28]1[CH:34]=[CH:33][C:31]([NH:32][C:2]2[N:7]=[C:6]([NH:8][C:9]3[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=3)[N:5]=[C:4]([NH:17][CH:18]3[NH:22][C:21](=[O:23])[N:20]([CH3:24])[C:19]3=[O:25])[N:3]=2)=[CH:30][CH:29]=1
Reactant: COc1ccc(N)cc1
Reactant: COc1ccc(Nc2nc(Cl)nc(NC3NC(=O)N(C)C3=O)n2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(Nc2nc(Nc3ccc(OC)cc3)nc(NC3NC(=O)N(C)C3=O)n2)cc1
Reaction time: 18.5 h
Yield: 57.1 %

Procedure:
A suspension of 5-[4-chloro-6-(4-methoxy-phenylamino)-[1,3,5]triazin-2-ylamino]-3-methyl-imidazolidine-2,4-dione (Example 1.10, Part A) (50 mg, 0.14 mmol), p-methoxyaniline (25 mg, 0.21 mmol) and potassium carbonate (48 mg, 0.34 mmol) in anhydrous DMF (5 mL) was stirred under a nitrogen atmosphere for 18.5 h. The reaction mixture was diluted with water and the crude product was extracted with ethyl acetate. The organic layer was dried and evaporated, and the crude product was purified by column chromatography (silica; dichloromethane:ethyl acetate starting with a solvent ratio of 10:1 and increasing the polarity to dichloromethane:methanol, 10:1) to afford the product as a pale yellow solid (36 mg, 58%). δH (300 MHz, (CD3)2CO) 8.14 (br s, 2H, NH), 7.60 (br s, 4H, ArH (ortho to NH attach)), 7.43 (br s, 1H, NH), 6.91 (d, J 8.7 Hz, 1H, NH), 6.85 (d, J 9.0 Hz, 4H, ArH (ortho to O attach)), 5.91 (d, J 7.8 Hz, 1H, CH), 3.77 (s, 6H, OCH3), 2.86 (br s, 2.0H, NCH3), 2.73 (br s, 1.0H, NCH3). Mass spectrum (ESI) m/z 451 (37%, MH+).
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][NH:8][CH2:7][CH2:6]2)OCC1.[CH2:11]([O:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][C:21]=1[O:22][CH3:23])[CH:17]=O)[CH3:12].C([BH3-])#N.[Na+].Cl>C(O)C.O.C(O)(=O)C>[CH2:11]([O:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][C:21]=1[O:22][CH3:23])[CH2:17][N:8]1[CH2:7][CH2:6][C:5](=[O:1])[CH2:10][CH2:9]1)[CH3:12]
Reactant: C1CC2(CCN1)OCCO2
Reactant: CCOc1cc(C=O)ccc1OC
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: CC(=O)O
Product: CCOc1cc(CN2CCC(=O)CC2)ccc1OC
Temperature: 50 °C
Reaction time: 2 h
Yield: 59 %

Procedure:
A mixture of 1,4-dioxa-8-aza-spiro[4.5]decane (9.33 g, 65.16 mmol, 1.0 equiv; commercially available) and 3-ethoxy-4-methoxy-benzaldehyde (14.09 g, 78.19 mmol, 1.2 equiv; commercially available) in ethanol (50 mL) and acetic acid (5 mL) was heated to 50° C. for 1 h. Sodium cyanoborohydride (4.91 g, 78.19 mmol, 1.2 equiv), dissolved in ethanol (20 mL), was added and the reaction mixture heated to 50° C. After 2 h, a solution of 37% HCl in water (100 mL) was added and the reaction mixture heated to 100° C. for 3 h. The solvent was removed under reduced pressure and the crude reaction product extracted from a solution of 1 M NaOH (100 mL) with ethyl acetate (3×100 mL). The combined organic phases were dried over MgSO4, concentrated by evaporation under reduced pressure and the crude material purified with column chromatography on silica eluting with a gradient of heptane/ethyl acetate (1:3)→ethyl acetate to provide 11.23 g (59%) of the title compound. 1H NMR (300 MHz, CDCl3): δ1.46 (t, J=6.9 Hz, 3H), 2.41-2.44 (m, 4H), 2.69-2.73 (m, 4H), 3.53 (s, 2H), 3.87 (s, 3H), 4.11 (q, J=6.9 Hz, 2H), 6.80-6.86 (m, 2H), 6.94 (s, 1H). 13C NMR (75 MHz, CDCl3): δ14.49, 41.16, 52.71, 55.90, 61.00, 64.50, 111.43, 113.71, 121.04, 130.77, 148.17, 148.68, 208.71. MS (ISP): 263.9 [M+H]+.