Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1([CH2:11][NH:12][C:13]([C:15]2[C:16]3[CH:17]=[CH:18][C:19](Cl)=[N:20][C:21]=3[CH:22]=[CH:23][C:24]=2[Cl:25])=[O:14])[CH2:7][CH2:6][CH2:5][CH:4]([CH:8]2[CH2:10][CH2:9]2)[CH2:3]1.CCN(C(C)C)C(C)C.[CH3:36][N:37]([CH3:43])[C@H:38]1[CH2:42][CH2:41][NH:40][CH2:39]1>>[OH:1][C:2]1([CH2:11][NH:12][C:13]([C:15]2[C:16]3[CH:17]=[CH:18][C:19]([N:40]4[CH2:41][CH2:42][C@H:38]([N:37]([CH3:43])[CH3:36])[CH2:39]4)=[N:20][C:21]=3[CH:22]=[CH:23][C:24]=2[Cl:25])=[O:14])[CH2:7][CH2:6][CH2:5][CH:4]([CH:8]2[CH2:10][CH2:9]2)[CH2:3]1
Reactant: CN(C)[C@H]1CCNC1
Reactant: O=C(NCC1(O)CCCC(C2CC2)C1)c1c(Cl)ccc2nc(Cl)ccc12
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)[C@H]1CCN(c2ccc3c(C(=O)NCC4(O)CCCC(C5CC5)C4)c(Cl)ccc3n2)C1

Procedure:
The title compound was synthesized according to the procedure described in example 1 using 2,6-dichloro-quinoline-5-carboxylic acid (1-hydroxy-3-cyclopropyl-cyclohexylmethyl)-amide, DIPEA and (S)-3-dimethylamino-pyrrolidine. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.75 (1H), 7.85 (m, 1H), 7.58 (2H), 7.05 (1H), 4.26 (s, 1H), 3.87 (t, 1H), 3.75 (m, 2H), 3.56 (m, 1H), 3.49 (m, 1H), 3.36 (m, 2H), 3.24 (m, 2H), 2.84 (m, 1H), 2.22 (s, 6H), 1.85 (m, 1H), 1.67 (m, 2H), 1.44-1.38 (m, 4H), 1.27 (m, 2H), 0.30 (m, 2H), 0.23 (m, 2H). m/z: 458 [M+H]
Reaction SMILES: [CH2:1]([NH:15][C:16]1[CH:21]=[CH:20][C:19]([CH:22]([CH3:26])[C:23]([OH:25])=[O:24])=[CH:18][CH:17]=1)[CH2:2][CH2:3][CH:4]=[CH:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].[OH:27][CH2:28][CH:29]([CH2:31]O)[OH:30].B(F)(F)F.CCOCC>C1(C)C=CC=CC=1>[CH2:1]([NH:15][C:16]1[CH:21]=[CH:20][C:19]([CH:22]([CH3:26])[C:23]([O:25][CH2:31][CH:29]([OH:30])[CH2:28][OH:27])=[O:24])=[CH:18][CH:17]=1)[CH2:2][CH2:3][CH:4]=[CH:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CCCCCCCCCC=CCCCNc1ccc(C(C)C(=O)O)cc1
Reactant: OCC(O)CO
Agent: FB(F)F
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: CCCCCCCCCC=CCCCNc1ccc(C(C)C(=O)OCC(O)CO)cc1
Reaction time: 120 h

Procedure:
A solution of 11.8 g. of 4-(4-tetradecenylamino)phenylpropionic acid, 1.00 g. of glycerol, and 5.35 ml. of boron trifluoride etherate in 200 ml. of toluene is stirred under reflux for 48 hours. The solution is treated with an additional 5.35 ml. of boron trifluoride etherate and refluxing is continued for 120 hours. Dilution with water and methylene chloride followed by filtration affords the product as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][C:10](=[O:14])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].Br[CH:18]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH3:19]>CN(C=O)C>[C:20]1([CH:18]([N:11]2[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:9][C:10]2=[O:14])[CH3:19])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CC(Br)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCNC(=O)C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(c1ccccc1)N1CCN(C(=O)OC(C)(C)C)CC1=O
Yield: 89 %

Procedure:
In the same way as that described in Example 1, Step 1, using Intermediate 1 (500 mg, 2.5 mmol), sodium hydride (110 mg of a 60% dispersion in mineral oil, 2.8 mmol), (1-bromoethyl)benzene (0.44 mL, 3.25 mmol) and DMF (12 mL). The title piperazinone (677 mg, 89%) was isolated as a colourless oil, which solidified on standing at 0° C. mp. 62-64° C. 1H NMR (250 MHz, CDCl3) δ1.40 (9H, s), 1.53 (3H, d, J=7.2 Hz), 2.80-2.90 (1H, m), 3.14-3.36 (2H, m), 3.56-3.71 (1H, m), 4.07 (1H, d, J=18.2 Hz), 4.22 (1H, d, 18.2 Hz), 6.08 (1H, q, J=7.2 Hz), 7.28-7.39 (5H, m).
Reaction SMILES: [BH4-].[Na+].[C:3]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[C:11]([C:22]1[N:23]=[CH:24][N:25]([C:27]([C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH:26]=1)([O:15][CH2:16][C:17](OCC)=[O:18])[CH2:10][CH2:9][CH2:8]2)#[N:4]>C(O)C>[OH:18][CH2:17][CH2:16][O:15][C:11]1([C:22]2[N:23]=[CH:24][N:25]([C:27]([C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)([C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)[C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=3)[CH:26]=2)[CH2:10][CH2:9][CH2:8][C:7]2[CH:6]=[C:5]([C:3]#[N:4])[CH:14]=[CH:13][C:12]1=2
Reactant: CCOC(=O)COC1(c2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)CCCc2cc(C#N)ccc21
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: N#Cc1ccc2c(c1)CCCC2(OCCO)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Temperature: 20 °C
Reaction time: 4 h

Procedure:
3.0 mmol of sodium borohydride are added in portions to a solution of 1.0 mmol of ethyl [6-cyano-1-(1-trityl-1H-imidazol-4-yl)-1,2,3,4-tetrahydronaphthalen-1-yloxy]acetate in 5 ml of ethanol at 20° C. The reaction mixture is stirred at 20° C. for 2-6 hours and then evaporated. The residue is taken up in saturated aqueous sodium bicarbonate solution and dichloromethane, and the mixture is vigorously stirred for 10 minutes. The phases are separated and the aqueous phase is back-extracted with dichloromethane. The combined organic phases are dried with sodium sulphate and evaporated. The title compound is identified from the residue on the basis of its Rf by flash chromatography (SiO2 60F).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[CH:14]=[C:13]([NH2:15])[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:16][O:17][C:18]1[CH:19]=[C:20]([N:28]=[C:29]=[O:30])[CH:21]=[C:22]([O:26][CH3:27])[C:23]=1[O:24][CH3:25]>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[N:10]=[CH:11][N:12]=[C:13]([NH:15][C:29]([NH:28][C:20]3[CH:19]=[C:18]([O:17][CH3:16])[C:23]([O:24][CH3:25])=[C:22]([O:26][CH3:27])[CH:21]=3)=[O:30])[CH:14]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: COc1cc(N=C=O)cc(OC)c1OC
Reactant: Nc1cc(Nc2cccc(Cl)c2)ncn1
Product: COc1cc(NC(=O)Nc2cc(Nc3cccc(Cl)c3)ncn2)cc(OC)c1OC

Procedure:
The title compound is prepared analogously as described in Example 127 from N-(3-chloro-phenyl)-pyrimidine-4,6-diamine and 3,4,5-trimethoxyphenyl isocyanate.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1([S:14]([N:17]2[CH2:22][CH2:21][CH:20]([CH2:23][CH:24]=[O:25])[CH2:19][CH2:18]2)(=[O:16])=[O:15])[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+]>CO>[C:1]([O:5][C:6]([C:8]1([S:14]([N:17]2[CH2:18][CH2:19][CH:20]([CH2:23][CH2:24][OH:25])[CH2:21][CH2:22]2)(=[O:16])=[O:15])[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)C1(S(=O)(=O)N2CCC(CC=O)CC2)CCOCC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)OC(=O)C1(S(=O)(=O)N2CCC(CCO)CC2)CCOCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The aldehyde from Example A6 (1.43 g, 3.81 mmol) in MeOH (15 mL) at 0° C. was treated with NaBH4 (144 mg, 3.81 mmol) in portions. Upon completion of addition, the ice bath was removed, and the mixture was stirred at room temperature for 2 hr. The reaction was then quenched with saturated NH4Cl (˜5 mL). After adding water (15 mL), the mixture was extracted with methylene chloride (3×30 mL). The organics were dried (magnesium sulfate). Concentration in vacuo afforded the alcohol as an oil (1.44 g, quantitative conversion). NMR(CDCl3) δ 1.28 (dt, 2H), 1.33–1.42 (m, 2H), 1.47–1.65 (m, 10H), 1.70 (d, 2H), 2.10 (dt, 2H), 2.32 (d, 2H), 2.94 (dt, 2H), 3.30 (dt, 2H), 3.68 (t, 2H), 3.76 (d, 2H), 3.96 (dd, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:30]=[CH:29][C:5]2[NH:6][C:7]([C:12]3[C:13](=[O:28])[N:14]([CH2:23][CH2:24][CH:25]([CH3:27])[CH3:26])[C:15]4[C:20]([C:21]=3[OH:22])=[CH:19][CH:18]=[CH:17][N:16]=4)=[N:8][S:9](=[O:11])(=[O:10])[C:4]=2[CH:3]=1.[C:31]1([S:37](Cl)(=[O:39])=[O:38])[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>N1C=CC=CC=1.C(OCC)(=O)C>[OH:22][C:21]1[C:20]2[C:15](=[N:16][CH:17]=[CH:18][CH:19]=2)[N:14]([CH2:23][CH2:24][CH:25]([CH3:27])[CH3:26])[C:13](=[O:28])[C:12]=1[C:7]1[NH:6][C:5]2[CH:29]=[CH:30][C:2]([NH:1][S:37]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)(=[O:39])=[O:38])=[CH:3][C:4]=2[S:9](=[O:11])(=[O:10])[N:8]=1
Reactant: CC(C)CCn1c(=O)c(C2=NS(=O)(=O)c3cc(N)ccc3N2)c(O)c2cccnc21
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CC(C)CCn1c(=O)c(C2=NS(=O)(=O)c3cc(NS(=O)(=O)c4ccccc4)ccc3N2)c(O)c2cccnc21
Temperature: 100 °C
Yield: 69.7 %

Procedure:
To the product of Example 205 (0.020 g, 0.047 mmol) in pyridine (0.2 mL) was added benzenesulfonyl chloride (0.0099 g, 0.0072 mL, 0.056 mmol). The reaction mixture was heated in a microwave reactor at 100° C. for 35 minutes. The reaction was cooled to 25° C., diluted with ethyl acetate (40 mL), washed with 1 N hydrochloric acid, water, and brine. The organic layer was dried over magnesium sulfate, filtered and concentrated. The residue was chromatographed on silica gel eluting with 99:1 dichloromethane:methanol to give the title compound (18.6 mg, 69%). 1H NMR (300 MHz, DMSO-d6) δ 0.97 (d, J=6.25 Hz, 6 H) 1.56 (m, 2 H) 1.68 (m, 1 H) 4.46 (m, 2 H) 7.47 (m, 3 H) 7.61 (m, 4 H) 7.80 (d, J=6.99 Hz, 2 H) 8.54 (dd, J=7.91, 1.65 Hz, 1 H) 8.87 (dd, J=4.23, 1.29 Hz, 1 H) 10.85 (s, 1 H) 14.08 (br s, 1 H). MS (ESI−) m/z 566 (M−H)−.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=2)(O)[CH3:9])=[CH:4][CH:3]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([C:11]2[CH:12]=[CH:13][C:14]([OH:17])=[CH:15][CH:16]=2)=[CH2:9])=[CH:6][CH:7]=1
Reactant: CC(O)(c1ccc(O)cc1)c1ccc(Br)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Product: C=C(c1ccc(O)cc1)c1ccc(Br)cc1
Yield: 66.2 %

Procedure:
Ef) 6.6 g of (RS)-4-[1-(4-bromo-phenyl)-1-hydroxy-ethyl]-phenol (Ex. Ea) are dissolved in 50 ml of ethanol, boiled under reflux with 0.34 g of p-toluenesulphonic acid and then evaporated at 30° C. The residue is treated with 150 ml of saturated sodium carbonate solution and extracted with ethyl acetate. The organic phases are washed with saturated sodium chloride solution, dried and evaporated. Purification on silica gel with ethyl acetate-hexane (20:80) as the eluent gives 4.1 g of 4-[1-(4-bromo-phenyl)-vinyl]-phenol MS: m/e 274 (M+H+, 1Br).
Reaction SMILES: [CH:1]([NH:3][C:4]1[CH:5]=[C:6]([CH:8]=[CH:9][C:10]=1[S:11]([OH:14])(=[O:13])=[O:12])[NH2:7])=O.[C:15](OC(=O)C)(=O)C.S(OCC)(OCC)(=O)=O.[OH-].[Na+].Cl.[Cl-].[Na+]>O>[CH2:1]([NH:3][C:4]1[CH:5]=[C:6]([CH:8]=[CH:9][C:10]=1[S:11]([OH:14])(=[O:13])=[O:12])[NH2:7])[CH3:15]
Reactant: Nc1ccc(S(=O)(=O)O)c(NC=O)c1
Reactant: CC(=O)OC(C)=O
Agent: CCOS(=O)(=O)OCC
Agent: Cl
Agent: [Cl-]
Solvent: O
Product: CCNc1cc(N)ccc1S(=O)(=O)O
Temperature: 50 °C
Reaction time: 2 h

Procedure:
220 g of 3-(N-formylamino)aniline-4-sulfonic acid in 1,500 ml of water were reacted with 140 g of acetic anhydride at a pH of 5.0 to 5.5. The mixture was heated, at pH 7.0, to 50° C., and 200 g of diethyl sulfate were added. The pH was then adjusted to 12.5 to 13.0 with caustic soda solution and stirring was continued for 2 hours. The pH was then adjusted to -0.5 to 0 with hydrochloric acid, and the mixture was boiled under reflux at 100° C. for 3 hours. After cooling, it was adjusted to pH 1.0 with caustic soda solution, and 200 g of sodium chloride were added. The precipitated 3-(N-ethylamino)aniline-4-sulfonic acid was then isolated by filtration in vacuo.
Reaction SMILES: [Li+].[OH-].[NH2:3][C:4]1[CH:5]=[CH:6][C:7]([S:59][CH:60]2[CH2:62][CH2:61]2)=[C:8]([CH2:10][N:11]([CH3:58])[C:12]([CH:14]([NH:31][C:32]2[CH:33]=[C:34]3[C:39](=[CH:40][CH:41]=2)[C:38]([N:42]([C:50]([O:52][C:53]([CH3:56])([CH3:55])[CH3:54])=[O:51])[C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])=[N:37][CH:36]=[C:35]3[F:57])[C:15]2[CH:20]=[C:19]([CH3:21])[C:18]([CH2:22][CH:23]([OH:29])[CH2:24][C:25]([O:27]C)=[O:26])=[C:17]([CH3:30])[CH:16]=2)=[O:13])[CH:9]=1.Cl>C1COCC1>[NH2:3][C:4]1[CH:5]=[CH:6][C:7]([S:59][CH:60]2[CH2:61][CH2:62]2)=[C:8]([CH2:10][N:11]([CH3:58])[C:12]([CH:14]([NH:31][C:32]2[CH:33]=[C:34]3[C:39](=[CH:40][CH:41]=2)[C:38]([N:42]([C:50]([O:52][C:53]([CH3:54])([CH3:55])[CH3:56])=[O:51])[C:43]([O:45][C:46]([CH3:48])([CH3:49])[CH3:47])=[O:44])=[N:37][CH:36]=[C:35]3[F:57])[C:15]2[CH:16]=[C:17]([CH3:30])[C:18]([CH2:22][CH:23]([OH:29])[CH2:24][C:25]([OH:27])=[O:26])=[C:19]([CH3:21])[CH:20]=2)=[O:13])[CH:9]=1
Reactant: COC(=O)CC(O)Cc1c(C)cc(C(Nc2ccc3c(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)ncc(F)c3c2)C(=O)N(C)Cc2cc(N)ccc2SC2CC2)cc1C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1cc(C(Nc2ccc3c(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)ncc(F)c3c2)C(=O)N(C)Cc2cc(N)ccc2SC2CC2)cc(C)c1CC(O)CC(=O)O
Temperature: 25 °C
Reaction time: 6 h

Procedure:
1.0 M LiOH (0.266 mL, 0.266 mmol) was added to a solution of 2D (225 mg, 0.266 mmol) in THF (2 mL) and stirred for 6 h at rt. HCl (0.266 mL, 1 M) was added and the mixture was extracted with EtOAc. The combined organics were washed with brine, dried over Na2SO4 and concentrated in vacuo. The product 2E was used without further purification. MS (ESI) m/z: 832.7 (M+H)+.
Reaction SMILES: [Si:1]([O:8][CH2:9][C@@H:10]1[CH:15]=[C:14]([CH2:16][O:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)[C:13](=[O:27])[CH2:12][N:11]1[C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Si](OC[C@@H]1C=C(C)[C@H](O)CN1C(OC(C)(C)C)=O)(C(C)(C)C)(C)C>>[Si:1]([O:8][CH2:9][C@@H:10]1[CH:15]=[C:14]([CH2:16][O:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)[CH:13]([OH:27])[CH2:12][N:11]1[C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])([C:4]([CH3:6])([CH3:7])[CH3:5])([CH3:3])[CH3:2]
Reactant: COc1ccc(COCC2=C[C@@H](CO[Si](C)(C)C(C)(C)C)N(C(=O)OC(C)(C)C)CC2=O)cc1
Agent: CC1=C[C@@H](CO[Si](C)(C)C(C)(C)C)N(C(=O)OC(C)(C)C)C[C@H]1O
Product: COc1ccc(COCC2=C[C@@H](CO[Si](C)(C)C(C)(C)C)N(C(=O)OC(C)(C)C)CC2O)cc1

Procedure:
The title compound was prepared from (S)-tert-butyl 2-(((tert-butyldimethylsilyl)oxy)methyl)-4-(((4-methoxybenzyl)oxy)methyl)-5-oxo-5,6-dihydropyridine-1(2H)-carboxylate (Intermediate 168, 34.99 mmol) according to the procedure for Intermediate 8. The reaction mixture was concentrated and the white solid was redissolved in 200 mL EtOAc and washed with satd. NaHCO3, brine, dried over MgSO4, filtered and concentrated. The residue was purified by silica gel column eluting with 0-100% ethyl acetate/hexanes to afford a colorless oil. 17.10 g, 99% over 2 steps.
Reaction SMILES: [C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[O:8])=[CH:5][C:4]=1[F:11])#[N:2].[CH3:12][Mg+].[Br-]>C1COCC1.CCOCC>[C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH:7]([OH:8])[CH3:12])=[CH:5][C:4]=1[F:11])#[N:2]
Reactant: N#Cc1ccc(C=O)cc1F
Reactant: C[Mg+]
Agent: [Br-]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(O)c1ccc(C#N)c(F)c1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a solution of 4-cyano-3-fluorobenzaldehyde, as described above in Step B, (250 mg, 1.68 mmol) in THF, under argon, at −78° C. was added MeMgBr dropwise (0.59 mL of a 3.0 M solution in Et2O, 1.77 mmol). The reaction mixture was stirred at −78° C. for 1 hour, then quenched with saturated aqueous NH4Cl, allowed to warm to ambient temperature, and extracted with CH2Cl2 (2×40 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography, eluting with a gradient of hexane—20% to 40% EtOAc, to yield the titled product as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:17]=[CH:16][C:5]2[CH2:6][CH2:7][CH2:8][C:9](=[O:15])[N:10]([CH2:11][CH2:12][O:13][CH3:14])[C:4]=2[CH:3]=1.Cl[C:19]1[N:24]=[C:23]([NH:25][C:26]2[C:35]([F:36])=[CH:34][CH:33]=[CH:32][C:27]=2[C:28]([NH:30][CH3:31])=[O:29])[C:22]([Cl:37])=[CH:21][N:20]=1.C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O>C(O)(C)C>[Cl:37][C:22]1[C:23]([NH:25][C:26]2[C:35]([F:36])=[CH:34][CH:33]=[CH:32][C:27]=2[C:28]([NH:30][CH3:31])=[O:29])=[N:24][C:19]([NH:1][C:2]2[CH:17]=[CH:16][C:5]3[CH2:6][CH2:7][CH2:8][C:9](=[O:15])[N:10]([CH2:11][CH2:12][O:13][CH3:14])[C:4]=3[CH:3]=2)=[N:20][CH:21]=1
Reactant: CNC(=O)c1cccc(F)c1Nc1nc(Cl)ncc1Cl
Reactant: COCCN1C(=O)CCCc2ccc(N)cc21
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: CC(C)O
Product: CNC(=O)c1cccc(F)c1Nc1nc(Nc2ccc3c(c2)N(CCOC)C(=O)CCC3)ncc1Cl
Temperature: 120 °C
Reaction time: 2 h
Yield: 61 %

Procedure:
A microwave vessel was charged with 8-amino-1-(2-methoxy-ethyl)-1,3,4,5-tetrahydro-1-benzazepin-2-one (51.3 mg, 0.219 mmol), 2 2-(2,5-dichloro-pyrimidin-4-ylamino)-3-fluoro-N-methyl-benzamide, 10-camphorsulfonic acid (4.2 mg, 0.018 mmol) and isopropyl alcohol (2.0 mL) and heated at 120° C. for 60 minutes in a microwave reactor (sealed vessel). The reaction mixture was quenched with a slurry of saturated, aqueous, NaHCO3 and stirred for 2 h. This mixture was diluted with water (10 mL) and extracted into DCM. The organic layer was dried by passing through a funnel filled with Na2SO4, and the filtrate was evaporated onto celite prior to purification by chromatography (amine modified silica gel, 25% EtOAc/hexane→80% EtOAc gradient). The appropriate fractions were combined, evaporated to afford a solid that was triturated with ether (2×2 mL) and yielded product (56.8 mg, 61%) as a white powder that had the following properties: mp: 199-204° C.; LC/MS (ESI+): 513 (M+H); 1H-NMR (DMSO-d6, 400 MHz): δ 9.37 (s, 1H), 9.34 (s, 1H), 8.52 (m, 1H), 8.19 (s, 1H), 7.48-7.38 (m, 2H), 7.35-7.30 (m, 2H), 7.22 (d, 1H, J=8.2), 6.97 (d, J=8.2, 1H), 4.05 (br s, 2H), 3.27 (br s, 2H), 3.09 (s, 3H), 2.74 (d, 3H, J=4.0), 2.54 (m, 2H), 2.10-1.90 (series of m, 4H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:11]=[CH:10][C:9](Br)=[C:8]([CH3:13])[N:7]=1)=[O:5])[CH3:2].Cl.O1CCOC[CH2:16]1>CC(=O)OCC.[CH3-].[CH3-].[Zn+2]>[CH2:1]([O:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([CH3:16])=[C:8]([CH3:13])[N:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ccc(Br)c(C)n1
Reactant: C1COCCO1
Agent: Cl
Agent: [CH3-]
Agent: [Zn+2]
Solvent: CCOC(C)=O
Product: CCOC(=O)c1ccc(C)c(C)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Dimethyl zink (4.58 g, 48.0 mmol) is added to a solution of 5-bromo-6-methyl-pyridine-2-carboxylic acid ethyl ester (11.7 g, 48.0 mmol, see preparation of 5-isobutyl-6-methyl-pyridine-2-carboxylic acid) and Pd(dppf) (392 mg, 0.48 mmol) in dioxane (40 mL). The mixture becomes warm and is stirred at rt for 1 h. Another portion of dimethyl zink (4.58 g, 48.0 mmol) is added. The mixture is stirred at 100° C. for 2 h, then at 80° C. for 72 h before it is cooled to rt, and diluted with EA (250 mL) and ice-water (150 mL). The mixture is acidified with 2 N aq. HCl, the org. phase is separated and the aq. phase is extracted with EA (3×100 mL) and DCM (2×75 mL). The combined org. extracts are dried over Na2SO4, filtered and concentrated. The crude product is purified by MPLC on silica gel (heptane:EA gradient) to give 5,6-dimethyl-pyridine-2-carboxylic acid ethyl ester (434 mg) as a brownish oil; LC-MS: tR=0.61 min, [M+1]+=179.98, 1H NMR (CDCl3): δ 1.45 (t, J=7.0 Hz, 3H), 2.37 (s, 3H), 2.62 (s, 3H), 4.48 (q, J=7.3 Hz, 2H), 7.55 (d, J=7.8 Hz, 1H), 7.90 (d, J=7.8 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].O[C:15]([CH3:22])([CH3:21])[C:16]([O:18][CH2:19][CH3:20])=[O:17]>>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4]([O:6][C:15]([CH3:22])([CH3:21])[C:16]([O:18][CH2:19][CH3:20])=[O:17])=[O:5]
Reactant: CCOC(=O)C(C)(C)O
Reactant: O=C(O)c1cc([N+](=O)[O-])ccc1Cl
Product: CCOC(=O)C(C)(C)OC(=O)c1cc([N+](=O)[O-])ccc1Cl

Procedure:
Analogously to the procedure described in Example 74, from 2-chloro-5-nitro-benzoic acid via its acid chloride and ethyl α-hydroxy-isobutyrate there is obtained ethyl 2-(2-chloro-5-nitro-benzoyloxy)-2-methyl-propionate, m.p. 64°-66° C., which is subsequently reduced to ethyl 2-(5-amino-2-chloro-benzoyloxy)-2-methyl-propionate. B.p. 200°-230° C./0.1 torr;
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([F:11])([F:10])[C:7]([F:13])([F:12])[C:6]=2[CH:14]=1.[Mg].CON(C)[C:19](=[O:24])[C:20]([F:23])([F:22])[F:21]>C(OCC)C>[F:10][C:8]1([F:11])[C:7]([F:13])([F:12])[C:6]2[CH:14]=[C:2]([C:19](=[O:24])[C:20]([F:23])([F:22])[F:21])[CH:3]=[CH:4][C:5]=2[O:9]1
Reactant: CON(C)C(=O)C(F)(F)F
Reactant: FC1(F)Oc2ccc(Br)cc2C1(F)F
Agent: [Mg]
Solvent: CCOCC
Product: O=C(c1ccc2c(c1)C(F)(F)C(F)(F)O2)C(F)(F)F
Yield: 92 %

Procedure:
The reaction of 5-bromo-2,2,3,3-tetrafluorobenzofuran (5.3 g, 0.02 mole) with magnesium turnings (0.48 g) in dry diethyl ether was followed by reaction with N-methoxy-N-methyltrifluoroacetamide (3.5 g, 0.022 mole), yielding 5.3 g of 1-(2,2,3,3-tetrafluorobenzofuran-5-yl)-2,2,2-trifluoroethanone.
Reaction SMILES: CNCCNCCNC.CNC.[CH3:13][N:14]([CH3:22])[P:15]([N:19]([CH3:21])[CH3:20])[N:16]([CH3:18])[CH3:17]>>[CH3:13][N:14]1[CH2:22][CH2:21][N:19]2[P:15]1[N:16]([CH3:18])[CH2:17][CH2:20]2
Reactant: CN(C)P(N(C)C)N(C)C
Agent: CNC
Agent: CNCCNCCNC
Product: CN1CCN2CCN(C)P12
Temperature: 125 °C
Yield: 94.8 %

Procedure:
A mixture of 5.00 g of 1,7-dimethyldiethylenetriamine and 6.22 g of hexamethylphosphorous triamide is heated to 80° C, at which temperature dimethylamine begins to be evolved. Evolution of dimethylamine continues for about one hour, during which time the temperature is gradually raised to 125° C. The mixture is distilled to give 5.75 g (95%) of 2,8-dimethyl-2,5,8-triaza-1-phosphabicyclo[3.3.0]octane as a clear, colorless liquid, which boils at 55°-65° C at 0.30 mm. The nuclear magnetic-resonance spectrum (C6D6 /TMS) of the product shows a highly split pattern from δ 2.0 to 4.5 and has the expected sharp doublet for the --CH3 groups at δ 2.55, J = 10 Hz. The infrared absorption spectrum (neat) has absorptions at 3.5, 6.83, 6.91, 7.65, 7.80, 8.20, 8.68, 9.20, 9.70, 10.15, 10.4, 10.7, and 11.5 μ.
Reaction SMILES: [N+:1]([C:4]1[CH:22]=[CH:21][C:7]2[C:8]3[C:16]([O:17][CH:18]([F:20])[F:19])=[CH:15][CH:14]=[CH:13][C:9]=3[O:10][C:11](=[O:12])[C:6]=2[CH:5]=1)([O-])=O>[Pd].O1CCOCC1>[NH2:1][C:4]1[CH:22]=[CH:21][C:7]2[C:8]3[C:16]([O:17][CH:18]([F:20])[F:19])=[CH:15][CH:14]=[CH:13][C:9]=3[O:10][C:11](=[O:12])[C:6]=2[CH:5]=1
Reactant: O=c1oc2cccc(OC(F)F)c2c2ccc([N+](=O)[O-])cc12
Agent: [Pd]
Solvent: C1COCCO1
Product: Nc1ccc2c(c1)c(=O)oc1cccc(OC(F)F)c12
Yield: 93.8 %

Procedure:
The solution of Example 4A (6.56 g.) was suspended in. dioxane (250 mL) and hydrogenated over 10% Pd/C at 4 atmospheres H2 at 50° for 3 hours. The solvent was removed under reduced pressure, diethylether was and the resulting solid filtered to provide the titled compound (5.55 g, 94%).
Reaction SMILES: ClCC(CCl)=O.O.[BH4-].[Na+].[NH:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11]1.O1[CH2:24][CH2:23]OCC1>>[CH3:17][C:16]1[C:23]([CH3:24])=[C:18]2[C:13]([CH:12]=[CH:11][NH:10]2)=[CH:14][CH:15]=1
Reactant: C1COCCO1
Reactant: c1ccc2[nH]ccc2c1
Agent: O=C(CCl)CCl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Product: Cc1ccc2cc[nH]c2c1C

Procedure:
To a solution of boron trichloride (200 mL of 1M in xylene; 200 mmol) at 0°-5° C. was added 2,3-dimethylaniline (22.2 mL, 182 mmol) in dry toluene (110 mL) dropwise over 20 minutes, followed by 2-chloroacetonitrile (13.8 mL, 218 mmol) dropwise over 10 minutes, and finally AlCl3 (27.0 g, 202 mmol) in one portion. The mixture was heated to reflux for 1 hour and 80° C. for 16 hours before cooling and addition of 2N HCl (190 ml). The mixture was heated to 80° C. for 30 min, cooled to 20° C., and the pH adjusted to 3-4 with 2N NaOH. The mixture was extracted with CH2Cl2 with readjustment of the pH to 3-4 after each extraction. The organic extracts were pooled, washed with brine, dried over Na2SO4(s), filtered and concentrated in vacuo. The residue (28.9 g) was recrystallized from CHCl3 /hexanes to afford 26.1 g of pure 2-amino-3,4-dimethyl-α-chloroacetophenone (GC-MS: 197 (M+)). This chloromethylketone (5.02 g, 25.4 mmol) in dioxane (125 mL)/H2O (15 mL) was treated with NaBH4 (1.06 g, 28 mmol) and heated to reflux for 4 hours. The mixture was concentrated in vacuo and partitioned between H2O/CH2Cl at pH ~7. The organic extracts were pooled, dried over MgSO4(s), filtered and concentrated in vacuo to afford the crude indole product (2.9 g) which could be reduced directly or sublimed in vacuo to afford 1.55 g of the title compound so pure indole (GC-MS; 145 (M+)).