Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[CH:8]=[C:7]([C:9]([OH:11])=O)[NH:6][N:5]=1.[NH2:12][C@@H:13]([CH3:29])[CH2:14][N:15]1[CH:19]=[CH:18][C:17]([C:20]2[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[C:22]([Cl:28])[CH:21]=2)=[N:16]1>>[Cl:28][C:22]1[CH:21]=[C:20]([C:17]2[CH:18]=[CH:19][N:15]([CH2:14][C@@H:13]([NH:12][C:9]([C:7]3[NH:6][N:5]=[C:4]([CH2:3][O:2][CH3:1])[CH:8]=3)=[O:11])[CH3:29])[N:16]=2)[CH:27]=[CH:26][C:23]=1[C:24]#[N:25]
Reactant: COCc1cc(C(=O)O)[nH]n1
Reactant: C[C@H](N)Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1
Product: COCc1cc(C(=O)N[C@@H](C)Cn2ccc(-c3ccc(C#N)c(Cl)c3)n2)[nH]n1
Yield: 5.07 %

Procedure:
The title compound was prepared using the method of Example 34(d) starting from 3-(methoxymethyl)-1H-pyrazole-5-carboxylic acid (0.119 g, 0.759 mmol) and (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (0.165 g, 0.633 mmol). The product was purified with flash-chromatography. Yield 5.07%. 1H-NMR (400 MHz; CDCl3): δ 1.22 (d, 3H), 3.42 (s, 3H), 4.27 (dd, 1H), 4.43 (dd, 1H), 4.54-4.62 (m, 3H), 6.62 (d, 1H), 6.69 (s, 1H), 7.49 (d, 1H), 7.67 (d, 1H), 7.75 (dd, 1H), 7.83 (m, 1H), 8.17 (d, 1H).
Reaction SMILES: [CH3:1][N:2]([CH3:29])[S:3]([N:6]1[C:10]2[C:11]3[O:15][CH:14]=[N:13][C:12]=3[C:16]([F:19])=[C:17]([F:18])[C:9]=2[N:8]([C:20]2[CH:25]=[CH:24][C:23]([I:26])=[CH:22][C:21]=2[F:27])C1=O)(=[O:5])=[O:4].[K].FC1C2N=COC=2C(NS(C2CC2)(=O)=O)=C(NC2C=CC(I)=CC=2F)C=1F>>[F:19][C:16]1[C:12]2[N:13]=[CH:14][O:15][C:11]=2[C:10]([NH:6][S:3](=[O:5])(=[O:4])[N:2]([CH3:29])[CH3:1])=[C:9]([NH:8][C:20]2[CH:25]=[CH:24][C:23]([I:26])=[CH:22][C:21]=2[F:27])[C:17]=1[F:18]
Reactant: CN(C)S(=O)(=O)n1c(=O)n(-c2ccc(I)cc2F)c2c(F)c(F)c3ncoc3c21
Agent: O=S(=O)(Nc1c(Nc2ccc(I)cc2F)c(F)c(F)c2ncoc12)C1CC1
Agent: [K]
Product: CN(C)S(=O)(=O)Nc1c(Nc2ccc(I)cc2F)c(F)c(F)c2ncoc12

Procedure:
Compound 1C was prepared from 4,5-difluoro-6-(2-fluoro-4-iodo-phenyl)-7-oxo-6,7-dihydro-imidazo[4′,5′:3,4]benzo[1,2-d]oxazole-8-sulfonic acid dimethylamide (60 mg, 0.12 mmol) and potassium trimethylsilonolate (30 mg, 0.18 mmol) using procedures analogous to those described above for Compound 1A to afford 30 mg of the product (49% yield). H1NMR (CDCl3, 300 MHz): δ 8.15 (s, 1H), 7.44 (dd, 1H), 7.29 (d, 1H), 6.82 (s, 1H), 6.45-6.35 (m, 1H), 6.19 (s, 1H), 2.88 (s, 6H). LCMS: 81.2%, m/z=510.9 (M−1). HPLC: 80.5%.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][NH:7][CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[O:5])[CH3:2].C(=O)(O)[O-].[Na+].[CH2:20]([O:27][C:28](Cl)=[O:29])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(O)C.O>[CH2:20]([O:27][C:28]([CH:8]([NH:7][CH2:6][C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[O:29])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CCOC(=O)CCNCC(=O)OCC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCOC(=O)CNC(CC(=O)OCC)C(=O)OCc1ccccc1

Procedure:
0.95 kg of ethyl 3-(ethoxycarbonylmethylamino)propionate (4.68 mol) was dissolved in 2.85 L of ethanol and 2.85 L of water. To this solution, 0.41 kg of sodium bicarbonate (4.91 mol) was added under stirring. Subsequently, 0.84 kg of benzylchloroformate (4.91 mol) was added dropwise at an internal temperature of 28 to 35° C. and the mixture was stirred at an internal temperature of 28 to 35° C. for 2 hours. Ethanol was evaporated under reduced pressure and 9.51 L of ethyl acetate was added. The mixture was then stirred for 5 minutes. The mixture was allowed to stand and the organic layer (top layer) was collected. To this layer, 4.8 L of water was added and the mixture was stirred for 5 minutes. The mixture was allowed to stand again and the organic layer (top layer) was collected. To this layer, 4.8 L of 28% brine was added and the mixture was stirred for 5 minutes. The mixture was allowed to stand again and the organic layer (top layer) was collected. To this layer, 0.57 kg of anhydrous sodium sulfate was added and the mixture was stirred for 1 hour. The solid was separated by filtration and washed with 0.95 L of ethyl acetate. The filtrate and the wash were combined and concentrated under reduced pressure. The resulting product was dried under reduced pressure at an external temperature of 50° C. for 30 minutes. This gave 1.64 kg of a crude product of the title compound as a colorless oil. This product was used in the subsequent step without further purification.
Reaction SMILES: C([O:14][C:15]1[C:26]2[C:25](=[O:27])[N:24]([CH2:28][C:29]3[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=3)[CH:23](O)[C:22]=2[C:21]([O:37][CH3:38])=[C:20]2[C:16]=1[N:17]=[CH:18][N:19]2[CH2:39]C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>C(Cl)Cl>[F:35][C:32]1[CH:33]=[CH:34][C:29]([CH2:28][N:24]2[C:25](=[O:27])[C:26]3[C:22](=[C:21]([O:37][CH3:38])[C:20]4[N:19]=[CH:39][CH:18]=[N:17][C:16]=4[C:15]=3[OH:14])[CH2:23]2)=[CH:30][CH:31]=1
Reactant: COc1c2c(c(OC(c3ccccc3)c3ccccc3)c3ncn(Cc4ccccc4)c13)C(=O)N(Cc1ccc(F)cc1)C2O
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1c2c(c(O)c3nccnc13)C(=O)N(Cc1ccc(F)cc1)C2
Reaction time: 1 h
Yield: 100 %

Procedure:
4-Benzhydryloxy-1-benzyl-6-(4-fluoro-benzyl)-7-hydroxy-8-methoxy-6,7-dihydro-1H-1,3,6-triaza-s-indacen-5-one 260 (28 mg, 0.047 mmol, 1 equiv.) was added to CH2Cl2 (1 mL) under a nitrogen atmosphere. Triethylsilane (200 μL) was added, followed by trifluoroacetic acid (200 μL). The reaction was allowed 1 hour and concentrated in vacuo until thoroughly dried. Hexanes/Ethyl ether (15 mL, 1/1 ratio) was added to the oil and sonicated. The resulting solid was then filtered and washed in Hexanes and air dried to give 7-(4-fluoro-benzyl)-5-hydroxy-9-methoxy-7,8-dihydro-pyrrolo[3,4-g]quinoxalin-6-one 261 (100%, 20 mg, 0.047 mmol) as a light gray powder. 1H NMR (300 MHz) CDCl3 δ 9.11 (bs 1 H), 7.86 (s, 1 H), 7.33-7.23 (m, 5 H), 7.01 7.07 (s, 4 H), 5.57 (s, 2 H), 4.71 (s, 2 H), 4.37 (s, 2 H), 3.57 (s, 3 H). 19F NMR (300 MHz) CDCl3 δ 62.25. MS: 418.2 (M+1)
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[C:9]([F:24])[CH:8]=1.[C:25](=[O:27])=[O:26].Cl>C1COCC1.CCOCC>[CH2:14]([O:13][C:10]1[CH:11]=[CH:12][C:7]([C:25]([OH:27])=[O:26])=[CH:8][C:9]=1[F:24])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: CCCCCCCCCCOc1ccc(Br)cc1F
Reactant: O=C=O
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCCCCCCCCCOc1ccc(C(=O)O)cc1F

Procedure:
A solution of n-butyllithium was added dropwise to a stirred, cooled (-78° C.) solution of compound of step 2.1 in dry THF. The mixture was maintained under these conditions for 40 mins and then poured into a slurry of dry ether and cardice. The solution was acidified with 36% HCl, washed with water and dried (magnesium sulphate). The solvent was removed to yield a white solid.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][O:8][C:9]2[C:14]([C:15]3[CH:20]=[CH:19][C:18]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)=[CH:17][CH:16]=3)=[CH:13][N:12]=[C:11]([NH:27][C@H:28]3[CH2:33][CH2:32][C@@H:31]([CH3:34])[CH2:30][CH2:29]3)[N:10]=2)[CH2:3][CH2:2]1.[CH3:35][S:36](Cl)(=[O:38])=[O:37]>>[CH3:35][S:36]([N:1]1[CH2:2][CH2:3][CH:4]([CH2:7][O:8][C:9]2[C:14]([C:15]3[CH:20]=[CH:19][C:18]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)=[CH:17][CH:16]=3)=[CH:13][N:12]=[C:11]([NH:27][C@H:28]3[CH2:29][CH2:30][C@@H:31]([CH3:34])[CH2:32][CH2:33]3)[N:10]=2)[CH2:5][CH2:6]1)(=[O:38])=[O:37]
Reactant: C[C@H]1CC[C@@H](Nc2ncc(-c3ccc(N4CCOCC4)cc3)c(OCC3CCNCC3)n2)CC1
Reactant: CS(=O)(=O)Cl
Product: CS(=O)(=O)N1CCC(COc2nc(N[C@H]3CC[C@@H](C)CC3)ncc2-c2ccc(N3CCOCC3)cc2)CC1

Procedure:
Using the procedure of Example 1 Step 5, 4-((piperidin-4-yl)methoxy)-N-(cis-4-methylcyclohexyl)-5-(4-morpholinophenyl)pyrimidin-2-amine was reacted with methanesulfonyl chloride to provide the title compound at 86% yield. 1H NMR (CDCl3, 400 MHz) 8.07 (s, 1H), 7.36 (d, 2H), 6.93 (d, 2 h), 5.20 (s, 1H), 4.23 (d, 2H), 4.07 (m, 1H), 3.89-3.83 (m, 6H), 3.21-3.18 (m, 4H), 2.76 (s, 3H), 2.67 (m, 2H), 1.90-1.24 (m, 14H), 0.94 (d, 3H); MS (ESI) m/z: Calc: 543.3 (M+). Found. 544.3 (M+1).
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]([NH:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][OH:14])=[CH:9][CH:8]=1)=[O:4].[H-].[Na+].[NH2:19][C:20]1[N:25]=[C:24](Cl)[CH:23]=[C:22]([CH3:27])[N:21]=1.O>CC(N(C)C)=O>[NH2:19][C:20]1[N:21]=[C:22]([CH3:27])[CH:23]=[C:24]([O:14][CH2:13][C:10]2[CH:11]=[CH:12][C:7]([CH2:6][NH:5][C:3](=[O:4])[C:2]([F:15])([F:16])[F:1])=[CH:8][CH:9]=2)[N:25]=1
Reactant: O=C(NCc1ccc(CO)cc1)C(F)(F)F
Reactant: Cc1cc(Cl)nc(N)n1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: Cc1cc(OCc2ccc(CNC(=O)C(F)(F)F)cc2)nc(N)n1
Temperature: 90 °C

Procedure:
812 mg (3.48 mmol) 2,2,2-trifluoro-N-(4-hydroxymethyl-benzyl)-acetamide is dissolved in 3 mL dry dimethylacetamide under argon atmosphere, and 167 mg (6.96 mmol) NaH is added over 5 min. 500 mg (3.48 mmol) 2-amino-4-chloro-6-methylpyrimidine is then added and the solution stirred at 90° C.— over night. 1 mL water is added carefully to quench all excess NaH, and the mixture poured into 50 ml of 0.5 N HCl. The crude product is extracted with ethyl acetate, the combined organic phases washed with brine and dried over MgSO4. After evaporation of the solvent, the product is purified by flash column chromatography (gradient ethyl acetate:cyclohexane from 1:1 to 3:1). Yield: 350 mg (29%). ESI-MS m/z 341.7 [M+H]+.
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[CH3:11][C:12]12[CH2:22][CH:16]3[CH2:17][C:18]([CH3:21])([CH2:20][C:14]([CH2:23][OH:24])([CH2:15]3)[CH2:13]1)[CH2:19]2.CCN(CC)CC>C(Cl)Cl.O>[CH3:21][C:18]12[CH2:17][CH:16]3[CH2:22][C:12]([CH3:11])([CH2:13][C:14]([CH:23]=[O:24])([CH2:15]3)[CH2:20]1)[CH2:19]2
Reactant: CC12CC3CC(C)(C1)CC(CO)(C3)C2
Agent: O=C(Cl)C(=O)Cl
Solvent: O
Solvent: CS(C)=O
Solvent: ClCCl
Product: CC12CC3CC(C)(C1)CC(C=O)(C3)C2
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of DMSO (4 mL, 57.7 mmol) in DCM (125 mL) under nitrogen at −78° C. was added dropwise oxalyl chloride (2.0 M in DCM, 18.75 mL, 37.5 mmol) over 30 min. After final addition the reaction mixture was stirred at −78° C. for 30 min. With the reaction mixture still at −78° C. , a solution of crude (3,5-dimethyladamant-1-yl)methanol from above in DCM (50 mL) was added dropwise over 20 min. After stirring the reaction at −78° C. for 2 h, Et3N (15 mL) was added slowly over 10 min and the reaction was stirred for 30 min at −78° C. Saturated NaH2PO4 (15 mL) was added followed by water (150 mL), and the reaction was then warmed to rt. The DCM layer was separated, washed twice with 1N HCl and sat'd NaHCO3, dried over MgSO4, filtered and concentrated to give the step 1 compound, 3,5-dimethyladamantane-1-carboxaldehyde (5.58 g).
Reaction SMILES: Cl[C:2]1([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[O:19][CH3:20])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([Cl:11])[CH:9]=2)[NH:4][C:3]1=[O:12].[CH2:21]([NH:28][C@@H:29]([CH3:35])[C:30]([N:32]([CH3:34])[CH3:33])=[O:31])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[CH2:21]([N:28]([C:2]1([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[O:19][CH3:20])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([Cl:11])[CH:9]=2)[NH:4][C:3]1=[O:12])[C@@H:29]([CH3:35])[C:30]([N:32]([CH3:34])[CH3:33])=[O:31])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: COc1ccccc1C1(Cl)C(=O)Nc2ccc(Cl)cc21
Reactant: C[C@H](NCc1ccccc1)C(=O)N(C)C
Product: COc1ccccc1C1(N(Cc2ccccc2)[C@@H](C)C(=O)N(C)C)C(=O)Nc2ccc(Cl)cc21

Procedure:
With 0.95 g of 3,5-dichloro-3-(2-methoxyphenyl)-1,3-dihydro-2H-indol-2-one and the compound obtained in Step 258-2 (3.39 mmol, crude form) as starting materials, respectively 966 mg (Isomer A, colorless amorphous) and 501 mg (Isomer B, colorless amorphous) of two species of diastereoisomers of the title compound were obtained by a similar method to Step 4-2.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][S:11]([CH3:14])(=[O:13])=[O:12])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[Cl:15][O-].[Ca+2].Cl[O-].C(O)(=O)C>O>[Cl:15][C:8]1[CH:9]=[C:4]([C:1](=[O:3])[CH3:2])[CH:5]=[CH:6][C:7]=1[NH:10][S:11]([CH3:14])(=[O:12])=[O:13]
Reactant: CC(=O)c1ccc(NS(C)(=O)=O)cc1
Reactant: [O-]Cl
Agent: [Ca+2]
Solvent: O
Solvent: CC(=O)O
Product: CC(=O)c1ccc(NS(C)(=O)=O)c(Cl)c1
Reaction time: 24 h

Procedure:
To 2.13 g (10 mmole) of N-(4-acetylphenyl)methanesulfonamide in 50 ml of alcohol and 50 ml of water at 30° C. is added 1.43 g (10 mmol) of calcium hypochlorite. The solution is stirred for 24 hrs and an additional 1.43 g of calcium hypochlorite added. The mixture is stirred for 3 days at room temperature. The mixture is acidified with acetic acid to pH 6; concentrated and extracted into water-methylene chloride. The organic layer is dried, evaporated and the residue flash chromatographed on silica gel eluting in succession with 25% and 50% ethyl acetate-pet. ether. The solid product is recrystallized from Et2O-pet. ether; m.p. 129°-131° C. MW 247.71.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:8]2[C:13](=[O:14])[C:12]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]4[C:23]([C:28]#[N:29])=[CH:24][CH:25]=[CH:26][CH:27]=4)=[CH:18][CH:17]=3)=[C:11]([CH2:30][CH2:31][CH2:32][CH3:33])[N:10]=[C:9]2[CH3:34])[CH:5]=[CH:6][CH:7]=1.[CH:35]1(B(O)O)[CH2:37][CH2:36]1.C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C1(C)C=CC=CC=1.O.C(OCC)(=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:30]([C:11]1[N:10]=[C:9]([CH3:34])[N:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([CH:35]3[CH2:37][CH2:36]3)[CH:3]=2)[C:13](=[O:14])[C:12]=1[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[C:23]([C:28]#[N:29])=[CH:24][CH:25]=[CH:26][CH:27]=2)=[CH:18][CH:17]=1)[CH2:31][CH2:32][CH3:33]
Reactant: OB(O)C1CC1
Reactant: CCCCc1nc(C)n(-c2cccc(Br)c2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Agent: [Pd+2]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: CC(=O)[O-]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: O
Product: CCCCc1nc(C)n(-c2cccc(C3CC3)c2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 100 °C
Reaction time: 12 h

Procedure:
A suspension of 4′-{[1-(3-bromophenyl)-4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile (1.0 g), cyclopropylboronic acid (0.34 g), palladium acetate (0.04 g), tricyclohexylphosphine (0.11 g) and potassium phosphate (1.45 g) in toluene-water (95:5, 10 mL) was stirred at 100° C. for 12 hr under an argon atmosphere. The reaction mixture was diluted with ethyl acetate. The insoluble material was filtered off through celite, and the filtrate was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated. The residue was purified by silica gel column chromatography to give the title compound as a pale-yellow viscous substance (0.95 g, 100%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:10])[C:5]([CH2:8][CH3:9])=[N:6][CH:7]=1.Br[C:12]1[CH:13]=C(N)C(C)=N[CH:17]=1.CC(C(OCC)=O)C(OCC)=O.COC(C)=C.C(N(CC)CC)C.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>C(Cl)(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([N:10]=[C:12]([CH3:13])[CH3:17])[C:5]([CH2:8][CH3:9])=[N:6][CH:7]=1
Reactant: Cc1ncc(Br)cc1N
Reactant: CCc1ncc(Br)cc1N
Agent: C=C(C)OC
Agent: CCOC(=O)C(C)C(=O)OCC
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCc1ncc(Br)cc1N=C(C)C
Temperature: 100 °C
Reaction time: 17 h

Procedure:
To a solution of 5-bromo-2-ethyl-pyridin-3-ylamine (1.492 mmol), synthesized in a similar manner as described for 5-bromo-2-methyl-pyridin-3-ylamine (Stage 75.1.4) using diethyl methylmalonate (HPLC: tR 1.71min (Method A); M+H=201, 203 MS-ES), in chloroform (0.75 ml) and 2-methoxypropene (Aldrich, Buchs, Switzerland, 7.46 mmol) were added triethylamine (1.492 mmol) and pyridinium para-toluensulfonate (0.149 mmol). The RM was stirred for 17 h at 100° C., then was quenched with aqueous Na2CO3 and extracted with EtOAc (2×). The combined organic layers were washed with brine, dried over Na2SO4, filtered, evaporated and dried under vacuum to give the title compound as a brown oil (M+H=241, 243 MS-ES).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[NH2:7][C:8]1[CH:16]=[CH:15][C:11]([C:12]([NH2:14])=O)=[CH:10][N:9]=1.O.[OH-].[Na+]>O1CCCC1>[NH2:7][C:8]1[N:9]=[CH:10][C:11]([CH2:12][NH2:14])=[CH:15][CH:16]=1
Reactant: NC(=O)c1ccc(N)nc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: NCc1ccc(N)nc1
Reaction time: 1 h

Procedure:
Lithium aluminium hydride (21 mmol) is added in small portions to 10 mmol of 6-aminonicotinamide in tetrahydrofuran. The mixture is heated at reflux for 72 hours, then brought to ambient temperature and hydrolyzed with water and then with a 1N sodium hydroxide solution. After stirring for one hour, the mixture is filtered through Celite and washed with an 85/15 tetrahydrofuran/methanol mixture. The solvents are then evaporated off and the residue obtained is purified by chromatography on silica gel to yield the expected product in the form of a white solid.
Reaction SMILES: FC(F)(F)C([N:5]1[CH2:11][CH:10]([CH3:12])[C:9]2[CH:13]=[C:14]([Cl:18])[C:15]([F:17])=[CH:16][C:8]=2[CH2:7][CH2:6]1)=O.[OH-].[Na+]>CO>[Cl:18][C:14]1[C:15]([F:17])=[CH:16][C:8]2[CH2:7][CH2:6][NH:5][CH2:11][CH:10]([CH3:12])[C:9]=2[CH:13]=1
Reactant: CC1CN(C(=O)C(F)(F)F)CCc2cc(F)c(Cl)cc21
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC1CNCCc2cc(F)c(Cl)cc21
Reaction time: 3.5 h
Yield: 197.8 %

Procedure:
A solution of N-trifluoroacetyl-8-chloro-7-fluoro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine (160 mg, 0.22 mmol) in methanol (3 mL) was treated with 15% aqueous NaOH (2 mL), and stirred for 3.5 hours at 25 C. The product mixture was concentrated, extracted 3 times with CH2Cl2 (5 mL), dried with Na2SO4 and concentrated to give 93 mg of a clear oil. 1H NMR (400 MHz, CDCl3) d 7.11 (m, 1 H), 6.85 (m, 1 H), 3.05-2.95 (m, 3 H), 2.95-2.80 (m, 3 H), 2.68 (m, 1 H), 2.38 (bm, 1 H), 1.31 (m, 3 H). MS calculated for C11H13ClFN+H: 214, observed: 214.
Reaction SMILES: Br[C:2]1[C:17]([CH3:18])=[CH:16][CH:15]=[CH:14][C:3]=1[CH2:4][CH2:5][O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C([Li])(C)(C)C.CN(C)[CH:26]=[O:27].Cl>O1CCCC1.C(OCC)C.O>[CH2:7]([O:6][CH2:5][CH2:4][C:3]1[CH:14]=[CH:15][CH:16]=[C:17]([CH3:18])[C:2]=1[CH:26]=[O:27])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CN(C)C=O
Reactant: Cc1cccc(CCOCc2ccccc2)c1Br
Agent: Cl
Agent: [Li]C(C)(C)C
Solvent: CCOCC
Solvent: O
Solvent: C1CCOC1
Product: Cc1cccc(CCOCc2ccccc2)c1C=O
Temperature: -20 °C
Reaction time: 0.5 h
Yield: 37.4 %

Procedure:
To a solution of benzyl 2-bromo-3-methylphenethyl ether (3.2 g, 0.0105 mol) in dry tetrahydrofuran in a nitrogen atmosphere at −65° C. was added tert-butyllithium (1.7 M in pentane)(10.5 ml, 0.018 mol) and the mixture was stirred at −20° C. for 30 min. Dimethylformamide (1.5 g, 0.021 mol) was added dropwise at −65° C. and the mixture was stirred at −20° C. for 30 min and at room temperature for 1 h. To the solution was water added carefully and 2M HCl to make it acidic and the mixture was stirred for 30 min. To the mixture was added diethyl ether (50 ml), the organic layer was separated, washed with saturated sodium carbonate and water. The organic layer was separated, dried and evaporated under reduced pressure. Purification of the residue by column chromatography on silica gel using heptane:methylene chloride (2:8) as eluent gave 1.0 g (38.5%) of the title compound.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[N:10]=[CH:11][N:12]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21]3[N:38]=[C:24]4[CH:25]([C:31]5[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=5)[CH2:26]C(=O)[CH2:28][CH2:29][N:23]4[N:22]=3)=[CH:16][C:15]=2[O:39][CH3:40])[CH:13]=1.[CH:41]([O:46][CH3:47])([O:44][CH3:45])OC.S(O)(C1C=CC(C)=CC=1)(=O)=O>CO>[Cl:8][C:9]1[N:10]=[CH:11][N:12]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21]3[N:38]=[C:24]4[CH:25]([C:31]5[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=5)[CH2:26][C:41]([O:44][CH3:45])([O:46][CH3:47])[CH2:28][CH2:29][N:23]4[N:22]=3)=[CH:16][C:15]=2[O:39][CH3:40])[CH:13]=1
Reactant: COc1cc(Nc2nc3n(n2)CCC(=O)CC3c2ccc(F)cc2)ccc1-n1cnc(Cl)c1
Reactant: COC(OC)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: COc1cc(Nc2nc3n(n2)CCC(OC)(OC)CC3c2ccc(F)cc2)ccc1-n1cnc(Cl)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 47.4 %

Procedure:
To a stirred solution of 2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenylamino)-9-(4-fluorophenyl)-8,9-dihydro-5H-[1,2,4]triazolo[1,5-a]azepin-7(6H)-one (200 mg, 0.428 mmol, from example 137) in MeOH (2 mL) was added trimethyl orthoformate (0.469 mL, 4.28 mmol) followed by Ts-OH (8.15 mg, 0.043 mmol). The reaction mixture was stirred at room temperature for 16 h. The reaction was concentrated in vacuo. The crude product was purified using reverse phase preparatory HPLC (AcCN/water/ammonium acetate) to afford the titled compound (104 mg, 46% yield). LC-MS (M+H)+ 513.3. 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 7.51 (1 H, d, J=1.5 Hz), 7.40 (1 H, d, J=2.4 Hz), 7.31-7.35 (2 H, m), 7.06-7.14 (3 H, m), 7.02 (1 H, d, J=1.5 Hz), 6.78 (1 H, dd, J=8.5, 2.4 Hz), 6.59 (1 H, s), 4.39 (1 H, ddd, J=14.7, 5.9, 2.3 Hz), 4.20-4.28 (1 H, m), 4.11-4.17 (1 H, m), 3.76 (3 H, s), 3.29 (3 H, s), 3.26 (3 H, s), 2.35-2.43 (2 H, m), 2.05-2.12 (1 H, m), 1.89 (1 H, ddd, J=14.5, 11.9, 2.3 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:12]([C:13](=O)[CH2:14][CH3:15])=[C:11](O)[C:10](=[O:18])[N:9]2[C:19]2[CH:20]=[C:21]([CH3:27])[C:22](=[O:26])[N:23]([CH3:25])[CH:24]=2)=[CH:4][CH:3]=1.O.[NH2:29][NH2:30].C(O)C>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[C:12]3[C:13]([CH2:14][CH3:15])=[N:30][NH:29][C:11]=3[C:10](=[O:18])[N:9]2[C:19]2[CH:20]=[C:21]([CH3:27])[C:22](=[O:26])[N:23]([CH3:25])[CH:24]=2)=[CH:6][CH:7]=1
Reactant: NN
Reactant: CCC(=O)C1=C(O)C(=O)N(c2cc(C)c(=O)n(C)c2)C1c1ccc(Cl)cc1
Solvent: O
Solvent: CCO
Solvent: Cc1ccccc1
Product: CCc1n[nH]c2c1C(c1ccc(Cl)cc1)N(c1cc(C)c(=O)n(C)c1)C2=O
Reaction time: 18 h
Yield: 64.7 %

Procedure:
A mixture of 5-(2-(4-chlorophenyl)-4-hydroxy-5-oxo-3-propionyl-2,5-dihydro-1H-pyrrol-1-yl)-1,3-dimethylpyridin-2(1H)-one (Step 147.1) (1.5 g, 3.88 mmol), hydrazine monohydrate (0.942 mL, 19.39 mmol), ethanol (8 mL) and toluene (8 mL) was stirred for 18 h at reflux. The reaction mixture was concentrated, diluted with acetic acid (50 mL), stirred for 1 h at reflux, diluted with CH2Cl2/saturated aqueous solution of NaHCO3, and extracted twice with CH2Cl2. The combine organic extracts were washed with water and brine, dried (Na2SO4) and concentrated. The residue was purified by silica gel column chromatography (CH2Cl2/MeOH 7.5%) and subsequent trituration of the resulting product in diethyl ether to afford 961 mg of the title compound as a yellow solid. tR: 0.82 min (LC-MS 2); ESI-MS: 383.1 [M+H]+ (LC-MS 2); Rf=0.19 (NH3 1%/CH2Cl2/MeOH 5%); 1H NMR (400 MHz, DMSO-d6) δ ppm 0.90 (t, J=7.64 Hz, 3H) 1.94 (s, 3H) 2.35-2.47 (m, 2H) 3.38 (s, 3H) 6.15 (s, 1H) 7.25 (d, J=8.44 Hz, 2H) 7.31-7.51 (m, 3H) 7.73 (d, J=2.69 Hz, 1H) 13.41 (br. s., 1H).
Reaction SMILES: [C:1]([NH:6][C:7]1[CH:20]=[CH:19][C:18]2[C:9](=[C:10]3[C:15](=[CH:16][N:17]=2)[C:14]([NH:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:13][C:12]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[CH:11]3)[CH:8]=1)([O:3][CH2:4][CH3:5])=[O:2].Br[CH2:34][CH2:35][C:36]([OH:38])=[O:37]>[N+](C1C=CC=CC=1)([O-])=O>[C:36]([CH2:35][CH2:34][C:11]1[C:10]2[C:15](=[CH:16][N:17]=[C:18]3[C:9]=2[CH:8]=[C:7]([NH:6][C:1]([O:3][CH2:4][CH3:5])=[O:2])[CH:20]=[CH:19]3)[C:14]([NH:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:13][C:12]=1[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)([OH:38])=[O:37]
Reactant: CCOC(=O)Nc1ccc2ncc3c(NC(=O)OCC)cc(-c4ccccc4)cc3c2c1
Reactant: O=C(O)CCBr
Solvent: O=[N+]([O-])c1ccccc1
Product: CCOC(=O)Nc1ccc2ncc3c(NC(=O)OCC)cc(-c4ccccc4)c(CCC(=O)O)c3c2c1

Procedure:
2,7-Biscarboethoxyamino-9-phenylphenanthridine (22-1, 1 equiv.), prepared by the method of Watkins (1952) J. Chem. Soc. 3059, is combined with 3-bromopropionic acid (2.5 equiv.; Aldrich Chemical Co., Milwaukee, Wis.) and is heated in nitrobenzene at 100° C. for 4-6 hours. Following cooling to room temperature the crude product is precipitated by addition of ether. The product 22-2 is isolated by filtration and used directly.