Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[N:25]1[CH:30]=[CH:29][C:28]([C:31]2[C:39]3[C:34](=[CH:35][CH:36]=[C:37]([C:40](O)=[O:41])[CH:38]=3)[N:33]([C:43]([C:56]3[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=3)([C:50]3[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=3)[C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)[N:32]=2)=[CH:27][CH:26]=1.[NH2:62][CH:63]1[CH2:68][CH:67]([C:69]2[CH:74]=[CH:73][CH:72]=[CH:71][CH:70]=2)[CH2:66][N:65]([C:75]([O:77][C:78]([CH3:81])([CH3:80])[CH3:79])=[O:76])[CH2:64]1.C(N(C(C)C)CC)(C)C>CN(C=O)C>[C:69]1([CH:67]2[CH2:68][CH:63]([NH:62][C:40]([C:37]3[CH:38]=[C:39]4[C:34](=[CH:35][CH:36]=3)[N:33]([C:43]([C:44]3[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=3)([C:50]3[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=3)[C:56]3[CH:57]=[CH:58][CH:59]=[CH:60][CH:61]=3)[N:32]=[C:31]4[C:28]3[CH:27]=[CH:26][N:25]=[CH:30][CH:29]=3)=[O:41])[CH2:64][N:65]([C:75]([O:77][C:78]([CH3:81])([CH3:80])[CH3:79])=[O:76])[CH2:66]2)[CH:74]=[CH:73][CH:72]=[CH:71][CH:70]=1
Reactant: CC(C)(C)OC(=O)N1CC(N)CC(c2ccccc2)C1
Reactant: O=C(O)c1ccc2c(c1)c(-c1ccncc1)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
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: CC(C)(C)OC(=O)N1CC(NC(=O)c2ccc3c(c2)c(-c2ccncc2)nn3C(c2ccccc2)(c2ccccc2)c2ccccc2)CC(c2ccccc2)C1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
2-(7-Aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU) (44 mg, 0.114 mmol) was added to a suspension of 3-(pyridin-4-yl)-1-trityl-1H-indazole-5-carboxylic acid (50 mg, 0.104 mmol) in DMF (0.5 mL) and was stirred at room temperature for 15 minutes. A solution of tert-butyl 3-amino-5-phenyl-piperidine-1-carboxylate (29 mg, 0.104 mmol) in DMF (0.5 mL) was added to the reaction and followed by diisopropyl ethyl amine (DIEA) (0.1 mL). The mixture was stirred at room temperature for an additional 30 minutes. The reaction was quenched with water (5 mL) and extracted with ethyl acetate (3×10 mL). The extracts were combined, dried using anhydrous sodium sulfate, filtered, and concentrated in vacuo. The crude product was progressed to the next step without purification.
Reaction SMILES: [CH3:1][C:2]1[N:6]([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[C:9]=2[CH3:18])[C:5]2[CH:19]=[C:20]([N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)[CH:21]=[C:22]([CH2:23][OH:24])[C:4]=2[N:3]=1.[H-].[Na+].[CH3:33]I.O>CN(C)C=O>[CH3:1][C:2]1[N:6]([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:15])([F:17])[F:16])[C:9]=2[CH3:18])[C:5]2[CH:19]=[C:20]([N:25]3[CH2:26][CH2:27][O:28][CH2:29][CH2:30]3)[CH:21]=[C:22]([CH2:23][O:24][CH3:33])[C:4]=2[N:3]=1
Reactant: CI
Reactant: Cc1c(Cn2c(C)nc3c(CO)cc(N4CCOCC4)cc32)cccc1C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COCc1cc(N2CCOCC2)cc2c1nc(C)n2Cc1cccc(C(F)(F)F)c1C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To the mixture of [2-methyl-1-{[2-methyl-3-(trifluoromethyl)phenyl]methyl}-6-(4-morpholinyl)-1H-benzimidazol-4-yl]methanol, prepared as described in Example 43 (160 mg, 0.381 mmol) in N,N-Dimethylformamide (DMF) (15 mL), sodium hydride (30.5 mg, 0.763 mmol) was added in and followed by the addition of methyl iodide (0.048 mL, 0.763 mmol). The reaction was stirred at rt for 3 hours. More sodium hydride (30.5 mg, 0.763 mmol) and methyl iodide (0.048 mL, 0.763 mmol) was added in. The reaction was stirred at rt for another 2 hours then Water (70 mL) was added in. The mixture was extracted with EtOAc (100 mL). The organic phase was washed with Brine (100 mL), dried (MgSO4) and concentrated. The crude was subjected to ISCO purification (0-2% MeOH/DCM) to give the product. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.36 (s, 3H) 2.54 (s, 3H) 3.00-3.07 (m, 4H) 3.37 (s, 3H) 3.68-3.75 (m, 4H) 4.76 (s, 2H) 5.52 (s, 2H) 6.32 (d, J=7.83 Hz, 1H) 6.88 (m, 2H) 7.25 (s, 1H) 7.60 (d, 1H). MS(ES+) m/e 434.4 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11](=[O:26])[NH:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[CH:14]=1)[C:5](O)=[O:6].[NH2:27][C@@H:28]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH2:30][C@@H:29]1[OH:37]>>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]([NH:27][C@@H:28]2[C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[CH2:30][C@@H:29]2[OH:37])=[O:6])[CH:8]=[CH:9][C:10]=1[C:11]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[CH:14]=1)=[O:26]
Reactant: N[C@@H]1c2ccccc2C[C@@H]1O
Reactant: O=C(O)c1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)c(Cl)c1
Product: O=C(N[C@@H]1c2ccccc2C[C@@H]1O)c1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)c(Cl)c1

Procedure:
60 mg of 3-chloro-4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzoic acid was coupled to (1R,2S)-1-amino-2,3-dihydro-1H-inden-2-ol via Procedure G. The crude product was purified on reverse phase HPLC to yield 2-chloro-N1-(4-chloro-3-(pyridin-2-yl)phenyl)-N4-((1R,2S)-2-hydroxy-2,3-dihydro-1H-inden-1-yl)terephthalamide. MS (Q1) 518.2 (M)+.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[CH:29]=[CH:28][C:10]([C:11]([NH:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[NH:20]C(=O)OC(C)(C)C)=[O:12])=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.[CH3:30][N:31]1[C:35]([CH3:36])=[C:34]([CH:37]=O)[C:33]([CH3:39])=[N:32]1>>[NH2:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[NH:13][C:11](=[O:12])[C:10]1[CH:9]=[CH:8][C:7]([CH:4]2[CH2:5][CH2:6][N:1]([CH2:37][C:34]3[C:33]([CH3:39])=[N:32][N:31]([CH3:30])[C:35]=3[CH3:36])[CH2:2][CH2:3]2)=[CH:29][CH:28]=1
Reactant: Cc1nn(C)c(C)c1C=O
Reactant: CC(C)(C)OC(=O)Nc1ccccc1NC(=O)c1ccc(C2CCNCC2)cc1
Product: Cc1nn(C)c(C)c1CN1CCC(c2ccc(C(=O)Nc3ccccc3N)cc2)CC1
Yield: 32.9 %

Procedure:
Using an analogous procedure to that described in Example 5, tert-butyl 2-[(4-piperidin-4-ylbenzoyl)amino]phenylcarbamate (prepared as described in Method 1 below; 200 mg, 0.51 mmol) was reacted with 1,3,5-trimethyl-1H-pyrazole-4-carbaldehyde (83.5 mg, 0.60 mmol) to give the title compound (70 mg, 56%); NMR Spectrum: (DMSO d6) δ 1.65 (m, 2H), 1.77 (m, 2H), 1.98 (m, 2H), 2.09 (s, 3H), 2.18 (s, 3H), 2.57 (m, 1H), 2.92 (m, 2H), 3.24 (s, 2H), 3.63 (s, 3H), 4.86 (br s, 2H), 6.60 (m, 1H), 6.78 (d, 1H), 6.97 (m, 1H), 7.17 (d, 1H), 7.37 (d, 2H), 7.91 (d, 2H), 9.55 (s, 1H); Mass Spectrum: M+H+418.
Reaction SMILES: C1CO[C:3]2([CH:8]=[CH:7][C@H:6]3[C@H:9]4[C@H:19]([CH2:20][CH2:21][C@:4]23[CH3:5])[C@:17]2([CH3:18])[C:12]([CH2:13][C@@H:14]([OH:22])[CH2:15][CH2:16]2)=[CH:11][CH2:10]4)[O:2]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(C)=O.O>[OH:22][CH:14]1[CH2:15][CH2:16][C@@:17]2([CH3:18])[C:12](=[CH:11][CH2:10][C@@H:9]3[C@@H:19]2[CH2:20][CH2:21][C@@:4]2([CH3:5])[C@H:6]3[CH:7]=[CH:8][C:3]2=[O:2])[CH2:13]1
Reactant: C[C@]12CC[C@H](O)CC1=CC[C@@H]1[C@@H]2CC[C@@]2(C)[C@H]1C=CC21OCCO1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)=O
Solvent: O
Product: C[C@]12CCC(O)CC1=CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)C=C[C@@H]12
Reaction time: 5 h

Procedure:
17,17-Ethylenedioxy-androst-5,15(16)-dien-3β-ol from Example 28B or otherwise obtained is dissolved in acetone (500 mL) and water (60 mL) and the solution is cooled to 0° C. To the 0° C. solution is added p-toluenesulfonic acid monohydrate (1.000 g, 5.257 mmol). The 0° reaction mixture is stirred for 5 hours and then stored at 40° for 16 hours. The chilled reaction solution is diluted with water (300 mL) and acetone is evaporated under reduced pressure. The aqueous slurry remaining is extracted with EtOAc (2×300 mL) and the combined organic phases are washed with saturated aqueous NaHCO3 (200 mL) and brine (200 mL), dried over MgSO4, filtered and concentrated. The residue is purified by flash chromatography (1:1 EtOAc/CH2Cl2) to afford 3-hydroxy-androst-5,15(16)-dien-17-one (C3-alcohol).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[C@@H:4]1[CH2:8][CH2:7][CH2:6][N:5]1[C:9](=[O:22])[CH2:10][CH:11]([C:13](=[O:21])[C:14]1[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][CH:15]=1)Br.C(#N)C.[C:27]([O-:30])(=[S:29])[CH3:28].[K+]>CCOCC>[CH3:1][O:2][C:3](=[O:23])[C@@H:4]1[CH2:8][CH2:7][CH2:6][N:5]1[C:9](=[O:22])[CH2:10][CH:11]([S:29][C:27](=[O:30])[CH3:28])[C:13](=[O:21])[C:14]1[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][CH:15]=1
Reactant: COC(=O)[C@@H]1CCCN1C(=O)CC(Br)C(=O)c1ccc(Br)cc1
Reactant: CC([O-])=S
Agent: [K+]
Solvent: CC#N
Solvent: CCOCC
Product: COC(=O)[C@@H]1CCCN1C(=O)CC(SC(C)=O)C(=O)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 5.28 g. of 1-[3-(4-bromobenzoyl)-3-bromopropionyl)-L-proline methyl ester (Example 30) in 35 ml. of acetonitrile is added 1.48 g. of potassium thioacetate. The mixture is stirred at room temperature for 2 hours, filtered and the filtrate is evaporated to dryness in vacuo leaving an amber gum. This is dissolved in ether and chromatographed on a 1"×16" silica gel column, eluting with ether and taking 100 ml. cuts. Cut number 3 gives the desired product (1.64 g.) as a glass.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[NH:10][N:9]=2)=[CH:4][CH:3]=1.CC[O-].[Na+].[CH2:21](Cl)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[CH2:21]([N:9]1[C:8]([C:5]2[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=2)=[C:16]2[C:11]([CH:12]=[CH:13][CH:14]=[CH:15]2)=[N:10]1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: Cc1ccc(-c2n[nH]c3ccccc23)cc1
Reactant: ClCc1ccccc1
Agent: CC[O-]
Agent: [Na+]
Product: Cc1ccc(-c2c3ccccc3nn2Cc2ccccc2)cc1
Yield: 5 %

Procedure:
Compound 10 (6.24 g, 0.03 mol), EtONa (4.08 g, 0.06 mol) and benzyl chloride (10.18 g, 0.08 mol) were allowed to react as in the preparation of compound 15 to afford compound 26 (0.45 g, 5%).
Reaction SMILES: [SH:1][CH:2]([CH3:10])[C:3]([NH:5][CH2:6][C:7]([OH:9])=[O:8])=[O:4].Br[CH2:12][C:13](=[O:19])[C:14]([O:16][CH2:17][CH3:18])=[O:15]>C(#N)C>[CH2:17]([O:16][C:14](=[O:15])[C:13]([OH:19])=[CH:12][S:1][CH:2]([C:3](=[O:4])[NH:5][CH2:6][C:7]([OH:9])=[O:8])[CH3:10])[CH3:18]
Reactant: CCOC(=O)C(=O)CBr
Reactant: CC(S)C(=O)NCC(=O)O
Solvent: CC#N
Product: CCOC(=O)C(O)=CSC(C)C(=O)NCC(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 53.3 %

Procedure:
A solution of N-(2-mercaptopropionyl)glycine (1.17 g, 7.17 mmol) and ethyl bromopyruvate (1 mL, 7.17 mmol, 90% purity) in acetonitrile (30 mL) was stirred at room temperature for 3 h. After removal of the solvent, the residue was dissolved in a mixed solvent of ethanol (15 mL) and water (15 mL). After the pH was adjusted to 7-8 with satd. NaHCO3 solution, the mixture was stirred at room temperature overnight. The mixture was acidified to pH 1-2 with concentrated hydrochloric acid and then rotary evaporated to dryness. The residue was purified by column chromatography eluted with EtOAc giving 3-[1-(carboxymethylcarbamoyl)ethylsulfanyl]-2-hydroxyacrylic acid ethyl ester as yellow solid (1.06 g, yield 53.3%). 1H NMR (CDCl3, 300.16 MHz) δ (ppm): 9.10 (broad s, 1H), 7.22 (d, J=0.9 Hz, 1H), 4.62 (d, J=17.7 Hz, 1H), 4.53 (d, J=17.7 Hz, 1H), 4.28 (q, J=7.1 Hz, 1H), 3.47 (qd, J=6.2 & 0.9 Hz, 1H), 1.48 (d, J=6.2 Hz, 3H) and 1.30 (t, J=7.1 Hz, 3H). 13C NMR (CDCl3, 75.48 MHz) δ (ppm): 174.02, 165.84, 160.57, 130.27, 120.20, 62.04, 46.76, 37.11, 14.45 and 14.09. MS (ESI) m/z: 260 (M+—OH, 100).
Reaction SMILES: [CH:1]1([CH2:7][S:8][C:9]2[N:14]=[C:13]([C@H:15]([OH:19])[CH2:16][C:17]#[N:18])[CH:12]=[CH:11][CH:10]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.N.CO.C(Cl)Cl>>[NH2:18][CH2:17][CH2:16][C@H:15]([C:13]1[CH:12]=[CH:11][CH:10]=[C:9]([S:8][CH2:7][CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[N:14]=1)[OH:19]
Reactant: N#CC[C@@H](O)c1cccc(SCC2CCCCC2)n1
Agent: N
Solvent: CO
Solvent: ClCCl
Product: NCC[C@@H](O)c1cccc(SCC2CCCCC2)n1

Procedure:
Reduction of (R)-3-(6-((cyclohexylmethyl)thio)pyridin-2-yl)-3-hydroxypropanenitrile following the method described in Example 6 gave after flash chromatography purification (15%-20% 7N NH3/MeOH—CH2Cl2 gradient) Example 25 as a colorless oil. Yield (0.3 g, 43%); 1H NMR (400 MHz, CD3OD) δ 7.56 (t, J=7.6 Hz, 1H), 7.17 (d, J=7.6 Hz, 1H), 7.09 (d, J=8.0 Hz, 1H), 4.75-4.72 (m, 1H), 3.04 (d, J=7.2 Hz, 2H), 2.80 (t, J=7.6 Hz, 2H), 2.03-1.98 (m, 1H), 1.94-1.54 (m, 7H), 1.30-0.99 (m, 5H); RP-HPLC tR=9.63 min; ESI-MS m/z 281.2 [M+H]+.
Reaction SMILES: [Br:1][CH2:2][CH:3]([S:6]([C:9]([CH3:12])([CH3:11])[CH3:10])(=[O:8])=[O:7])[CH2:4]Br.N1C(C)=CC=CC=1C>C(Cl)Cl>[C:9]([S:6]([C:3](=[CH2:4])[CH2:2][Br:1])(=[O:7])=[O:8])([CH3:12])([CH3:11])[CH3:10]
Reactant: CC(C)(C)S(=O)(=O)C(CBr)CBr
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: C=C(CBr)S(=O)(=O)C(C)(C)C
Temperature: 25 °C
Yield: 91390.6 %

Procedure:
A mixture of 16.78 g (0.052 mmol) of 1,3-dibromo-2- (t-butylsulfonyl) propane and 14 mL (0.12 mol) of 2,6-lutidine in 55 mL of CH2Cl2 was refluxed for 75 minutes. The solution was allowed to cool to room temperature and extracted with three 80-mL portions of 5% HCl followed by 80 mL of water. The organic layer was dried over MgSO4, filtered, and the solvent removed in vacuo from a water bath at 45° C. to give 11.46 g (91%) of the allyl bromide as a white solid, mp 40.5-°42.0° C., which was used without further purification; IR (KBr) 2980 cm-1, 1480, 1395, 1230, 1100, 970, 730, 640; 1H NMR (CDCl3)δ 1.40 (s, 9H, t-butyl), 4.30 (s, 2H CH2Br), 6.50 (s, 2H, vinyl).
Reaction SMILES: C(N(CC)CC)C.F[C:9]1[CH:14]=[C:13]([Br:15])[CH:12]=[CH:11][N:10]=1.[NH:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1>>[Br:15][C:13]1[CH:12]=[CH:11][N:10]=[C:9]([N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)[CH:14]=1
Reactant: Fc1cc(Br)ccn1
Reactant: C1COCCN1
Solvent: CCN(CC)CC
Product: Brc1ccnc(N2CCOCC2)c1
Temperature: 100 °C

Procedure:
To a solution of triethylamine (1.0 equiv.) and 2-fluoro-4-bromopyridine (1.0 equiv.) at RT was added morpholine (1.0 equiv) in one portion, the resulting mixture was then heated in an oil bath at 100° C. for 66 hr. LCMS analysis indicated the formation of the desired product (m/z=244.9, Rt=0.36 min). The reaction mixture was concentrated in vacuo to yield 4-(4-bromopyridin-2-yl)morpholine as a light brown solid, (>100%, TEA impurity). LCMS (m/z) (M+H)=244.9, Rt=0.36 min. 1H NMR (400 MHz, <dmso>) δ ppm 3.39-3.55 (m, 4H) 3.59-3.75 (m, 4H) 6.87 (dd, J=5.28, 1.37 Hz, 1H) 7.05 (d, J=1.17 Hz, 1H) 8.00 (d, J=5.48 Hz, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([C@@H:16]2[N:20]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C@H:19]([C:28]([O:30][CH3:31])=[O:29])[CH2:18][CH2:17]2)=[CH:12][CH:11]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.Br[CH2:43][C:44]#[N:45]>C1COCC1>[C:44]([CH2:43][C@@:19]1([C:28]([O:30][CH3:31])=[O:29])[CH2:18][CH2:17][C@H:16]([C:13]2[CH:12]=[CH:11][C:10]([O:9][CH2:8][C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[F:1])=[CH:15][CH:14]=2)[N:20]1[C:21]([O:23][C:24]([CH3:26])([CH3:27])[CH3:25])=[O:22])#[N:45]
Reactant: COC(=O)[C@@H]1CC[C@H](c2ccc(OCc3ccccc3F)cc2)N1C(=O)OC(C)(C)C
Reactant: N#CCBr
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)[C@]1(CC#N)CC[C@H](c2ccc(OCc3ccccc3F)cc2)N1C(=O)OC(C)(C)C
Temperature: -35 °C
Reaction time: 0.5 h

Procedure:
To a solution of 1-(1,1-dimethylethyl) 2-methyl (2S,5R)-5-(4-{[(2-fluorophenyl)methyl]oxy}phenyl)-1,2-pyrrolidinedicarboxylate (D34, 45 g) in dry THF (450 mL) previously cooled to −65° C., was added 1M LiHMDS in THF (115 mL) dropwise. The resulting solution was stirred at −35° C. for 30 minutes. Then the mixture was again cooled to −65° C. and bromoacetonitrile (22 mL) dissolved in dry THF (180 mL) was added. The mixture was left stirring for a further 30 min at the same temperature. The reaction was quenched with saturated ammonium chloride solution (675 mL), THF was evaporated in vacuo and the crude mixture was extracted with EtOAc (2×675 mL). The organic layer was evaporated and the crude material was purified by chromatography on silica gel using cyclohexanes and ethyl acetate (8:2) affording the title compound (51.3 g) as a yellow thick oil.
Reaction SMILES: [CH2:1]([C:15](=[CH2:19])[C:16]([OH:18])=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].B(F)(F)F.[CH3:24]O>>[CH2:1]([C:15](=[CH2:19])[C:16]([O:18][CH3:24])=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: C=C(CCCCCCCCCCCCCC)C(=O)O
Reactant: CO
Agent: FB(F)F
Product: C=C(CCCCCCCCCCCCCC)C(=O)OC

Procedure:
14.6 Grams of 2-tetradecylacrylic acid (0.052 mole) are combined with 65 ml of absolute methanol and 15 ml of 51% BF3 in methanol in a 200 ml flask equipped with a condenser and drying tube. The system is heated under reflux for six hours (two layers appear when cooled). The mixture is concentrated to 1/2 volume and the acid is neutralized with saturated NaHCO3 solution to about pH 7. The oily material is extracted with ether, washed with water and dried over anhydrous MgSO4. The ether solvent is removed under reduced pressure. The oily residue of methyl 2-tetradecylacrylate (14.70 g) is not purified further (>95% pure by GC) and used directly in the next step.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][CH:18]=1)[O:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]2[NH:12][C:13](=[O:15])[NH:14][C:7]=12.[Br:19][C:20]1[CH:21]=[C:22]([CH:26]=[CH:27][CH:28]=1)[C:23](Cl)=[O:24]>>[Br:19][C:20]1[CH:21]=[C:22]([CH:26]=[CH:27][CH:28]=1)[C:23]([NH:1][C:2]1[CH:18]=[CH:17][CH:16]=[C:4]([O:5][C:6]2[CH:11]=[CH:10][N:9]=[C:8]3[NH:12][C:13](=[O:15])[NH:14][C:7]=23)[CH:3]=1)=[O:24]
Reactant: Nc1cccc(Oc2ccnc3[nH]c(=O)[nH]c23)c1
Reactant: O=C(Cl)c1cccc(Br)c1
Product: O=C(Nc1cccc(Oc2ccnc3[nH]c(=O)[nH]c23)c1)c1cccc(Br)c1
Yield: 73 %

Procedure:
Method H was used with 7-(3-aminophenoxy)-1H-imidazo[4,5-b]pyridin-2(3H)-one and 3-bromo-benzoyl chloride to afford the title compound as a light brown solid (50 mg, 73%). 1H-NMR (δ, ppm, DMSO-d6): 6.50 (d, 1H, HPy,5, J=6.0 Hz), 6.92 (d, 1H, Harom, J=8.0 Hz), 7.43 (ps t, 1H, Harom, J=8.0 Hz), 7.48 (m, 1H, Harom), 7.62 (s, 1H, Harom), 7.66 (d, 1H, Harom, J=8.0 Hz), 7.78-7.84 (m, 2H, Harom+Py,6), 7.93 (d, 1H, Harom, J=8.0 Hz), 8.12 (s, 1H, Harom), 10.45 (s, 1H, NHamide), 11.23 (s, 1H, NHPy3), 11.44 (s, 1H, NHPy2). 13C-NMR (δ, ppm, DMSO-d6): 106.58, 110.82, 113.83, 114.62, 116.32, 121.66, 126.87, 128.24, 130.65, 130.87, 131.71, 136.80, 140.56, 141.08, 144.67, 147.00, 154.17, 154.68, 164.13. HRMS (EI): m/z [M+H] calcd for C19H14BrN4O3: 425.0249; found: 425.0248.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-])=O)[CH:3]=1.[CH3:11][CH:12]1[NH:17][CH:16]([CH3:18])[CH2:15][NH:14][CH2:13]1>>[CH3:18][CH:16]1[NH:17][CH:12]([CH3:11])[CH2:13][N:14]([C:2]2[CH:3]=[C:4]([NH2:8])[CH:5]=[CH:6][CH:7]=2)[CH2:15]1
Reactant: CC1CNCC(C)N1
Reactant: O=[N+]([O-])c1cccc(F)c1
Product: CC1CN(c2cccc(N)c2)CC(C)N1

Procedure:
Using the procedure outlined in Example 37 (A), the title compound was prepared from 1-fluoro-3-nitrobenzene (1 g, 7 mmol) and 3,5-dimethyl-piperazine (1.14 g, 10 mmol). 1H NMR (400 MHz, CDCl3) δ (ppm): 7.00 (t, J=8.0 Hz, 1H), 6.33 (d, J=8.2 Hz, 1H), 6.21 (m, 1H), 6.15 (d, J=8.2 Hz, 1H), 3.60 (br, 2H), 3.45 (d, J=9.8 Hz, 2H), 2.98 (m, 1H), 2.22 (t, J=11.3 Hz, 2H), 1.10 (s, 3H), 1.08 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([S:14]([N:17]([CH3:26])[C@@H:18]([C:22]([O:24][CH3:25])=[O:23])[CH:19]([CH3:21])[CH3:20])(=[O:16])=[O:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[O:27]1[C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=2[CH:29]=[C:28]1[C:36](Cl)=[O:37].C(N(CC)C(C)C)(C)C>ClCCl>[O:27]1[C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=2[CH:29]=[C:28]1[C:36]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]([S:14]([N:17]([CH3:26])[C@@H:18]([C:22]([O:24][CH3:25])=[O:23])[CH:19]([CH3:21])[CH3:20])(=[O:16])=[O:15])=[CH:12][CH:13]=2)=[CH:4][CH:3]=1)=[O:37]
Reactant: O=C(Cl)c1cc2ccccc2o1
Reactant: COC(=O)[C@@H](C(C)C)N(C)S(=O)(=O)c1ccc(-c2ccc(N)cc2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)[C@@H](C(C)C)N(C)S(=O)(=O)c1ccc(-c2ccc(NC(=O)c3cc4ccccc4o3)cc2)cc1
Temperature: 25 °C
Yield: 85.5 %

Procedure:
To 0.11 g of methyl N-[(4′-amino-1,1′-biphenyl-4-yl)sulfonyl]-N-methyl-D-valinate in 4 mL dichloromethane cooled in ice bath, was added 0.058 g of 2-benzofurancarbonyl chloride, and N,N-diisopropylethylamine (0.15 mL) was dropped in. The reaction was stirred at room temperature overnightand then diluted with dichloromethane. The organic layer was washed with water, 5% HCl, and brine, dried over sodium sulfate, filtered, concentrated, and purified by column chromatography eluting with hexane:ethyl acetate (2:1) to provide 0.13 g of methyl N-({4′-[(1-benzofuran-2-ylcarbonyl)amino]-1,1′-biphenyl-4-yl}sulfonyl)-N-methyl-D-valinate. Yield 86.6%. m.p. 67-69° C. MS: 521.3 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]([N:5]1[CH2:11][CH2:10][C:9]2[CH:12]=[C:13]([OH:16])[CH:14]=[CH:15][C:8]=2[CH2:7][CH2:6]1)=[O:4].Cl[C:20]1[CH:28]=[CH:27][C:23]([C:24]([NH2:26])=[O:25])=[CH:22][N:21]=1.C([O-])([O-])=O.[K+].[K+].C1(C)C=CC=CC=1>CN(C=O)C>[F:18][C:2]([F:1])([F:17])[C:3]([N:5]1[CH2:11][CH2:10][C:9]2[CH:12]=[C:13]([O:16][C:20]3[CH:28]=[CH:27][C:23]([C:24]([NH2:26])=[O:25])=[CH:22][N:21]=3)[CH:14]=[CH:15][C:8]=2[CH2:7][CH2:6]1)=[O:4]
Reactant: O=C(N1CCc2ccc(O)cc2CC1)C(F)(F)F
Reactant: NC(=O)c1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: NC(=O)c1ccc(Oc2ccc3c(c2)CCN(C(=O)C(F)(F)F)CC3)nc1
Temperature: 100 °C
Reaction time: 8 h
Yield: 34.1 %

Procedure:
Add 2,2,2-trifluoro-1-(7-hydroxy-1,2,4,5-tetrahydro-benzo[d]azepin-3-yl)ethanone (0.750 g, 2.89 mmol), 6-chloronicotinamide (0.377 g, 2.41 mmol) and K2CO3 (0.833 g, 6.03 mmol) to a round bottom equipped with a Dean-Stark trap. Add toluene (6 mL) and DMF (18 mL). Heat at reflux for two hours. Cool the reaction mixture to 100° C. and stir overnight. Remove the toluene and DMF as an azeotrope with xylenes. Suspend the solid in 5% methanol/ethyl acetate (100 mL) and filter. Wash the filter cake with ethyl acetate. Concentrate the filtrate, then purify by flash chromatography, eluting with 40% ethyl acetate in dichloromethane to give the title compound (0.312 g, 34.0%):
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=1[NH2:6].Cl[C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[C:15]([C:22]3[NH:30][C:29]4[CH2:28][CH2:27][NH:26][C:25](=[O:31])[C:24]=4[CH:23]=3)[CH:16]=[CH:17][CH:18]=2)[N:13]=1>CN(C=O)C>[F:3][C:4]1[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=1[NH:6][C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[C:15]([C:22]3[NH:30][C:29]4[CH2:28][CH2:27][NH:26][C:25](=[O:31])[C:24]=4[CH:23]=3)[CH:16]=[CH:17][CH:18]=2)[N:13]=1
Reactant: Nc1ccccc1F
Reactant: O=C1NCCc2[nH]c(-c3cccc4ccc(Cl)nc34)cc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1NCCc2[nH]c(-c3cccc4ccc(Nc5ccccc5F)nc34)cc21
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 22.2 %

Procedure:
To NaH (60 wt % in mineral oil; 0.071 g, 1.763 mmol) in 1 mL DMF was added 2-fluoroaniline (0.196 g, 1.763 mmol). After 10 min, a clear/colorless solution resulted. 2-(2-Chloroquinolin-8-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (Example 1; 0.075 g, 0.252 mmol) was added as a solid and the reaction became dark red. After 30 min, the reaction was heated at 70° for 2 h. The reaction mixture was then cooled to RT and partitioned between saturated aq. NH4Cl and EtOAc. The organic layer was washed with saturated aq. NaHCO3 (1×), water (1×), saturated aq. NaCl (1×), and the organics were dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The material was suspended in DCM and filtered, rinsing 2×DCM, dried in vacuo to give 2-(2-((2-fluorophenyl)amino)quinolin-8-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (0.021 g, 0.056 mmol, 22% yield) as a dull-yellow solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 12.04 (1H, br. s.), 9.32 (1H, s), 8.14 (1H, s), 7.97 (1H, dd, J=7.5, 1.5 Hz), 7.84-7.93 (1H, m), 7.56-7.62 (1H, m), 7.34-7.44 (1H, m), 7.22-7.33 (3H, m), 7.15-7.21 (1H, m), 6.86-6.95 (2H, m), 3.32-3.41 (2H, m), 2.51-2.57 (2H, m). m/z (ESI, +ve) 373.0 (M+H)+.