Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([Sn](CCCC)(CCCC)CCCC)[O:4][N:3]=1.Br[C:21]1[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][C:22]=1[O:30][CH3:31]>O1CCOCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:31][O:30][C:22]1[CH:23]=[C:24]([N+:27]([O-:29])=[O:28])[CH:25]=[CH:26][C:21]=1[C:5]1[O:4][N:3]=[C:2]([CH3:1])[CH:6]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cc(C)no1
Reactant: COc1cc([N+](=O)[O-])ccc1Br
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1COCCO1
Product: COc1cc([N+](=O)[O-])ccc1-c1cc(C)no1
Temperature: 105 °C
Yield: 46.6 %

Procedure:
Step H (1): 3-Methyl-5-(tributylstannyl)isoxazole (2.4 g, 6.4 mmol, H. Yamanaka et. al Tetrahedron, 1991, 47, 5111) and dichlorobis(triphenylphosphine)palladium (II) (45 mg, 0.0643 mmol) were added to a degassed solution of 1-bromo-2-methoxy-4-nitrobenzene (1.26 g, 5.5 mmol) in dioxane (25 mL). The resulting mixture was heated to reflux (105° C. oil bath temperature) for 24 h. The reaction mixture was cooled to rt and concentrated in vacuo. The residue was dissolved in dichloromethane and washed with water. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo. The crude product was purified using silica gel column chromatography to afford 5-(2-methoxy-4-nitrophenyl)-3-methylisoxazole (600 mg, 40% yield).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([CH2:10][CH2:11]Br)[CH2:9][CH2:8][CH2:7][CH2:6]1)=[O:4].[CH3:13][S-:14].[Na+].O>CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1([CH2:10][CH2:11][S:14][CH3:13])[CH2:9][CH2:8][CH2:7][CH2:6]1)=[O:4]
Reactant: COC(=O)C1(CCBr)CCCC1
Reactant: C[S-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)C1(CCSC)CCCC1
Temperature: 25 °C
Reaction time: 15 h
Yield: 82.5 %

Procedure:
To a solution of 1-(2-bromoethyl)cyclopentane carboxylic acid methyl ester (2.0 mmol, 472 mg) in DMF (5 mL) was added sodium thiomethoxide (2.65 mmol, 186 mg). The reaction mixture was stirred for 15 h at room temperature and was poured into water (30 mL). The organic compound was extracted into diethyl ether (2×20 mL). The combined extracts were washed with a saturated solution of sodium chloride (50 mL) and dried over anhydrous magnesium sulfate. After filtration of the drying agent, the solution was concentrated under vacuum and the resulting residue was purified by silica gel column chromatography to afford 334 mg (82%) of a colorless oil. HR MS C10H18O2S): Obs mass, 202.1024. Calcd mass, 202.1028 (M+).
Reaction SMILES: [NH2:1][N:2]1[CH2:7][CH2:6][CH2:5][CH:4]([OH:8])[CH2:3]1.C([O:17][C@@H:18]1[C@H:22]([O:23]C(=O)C2C=CC=CC=2)[C@@H:21]([CH2:32][O:33]C(=O)C2C=CC=CC=2)[O:20][C@H:19]1[N:42]1[CH:50]=[N:49][C:48]2[C:43]1=[N:44][C:45]([Cl:52])=[N:46][C:47]=2Cl)(=O)C1C=CC=CC=1.N>>[Cl:52][C:45]1[N:46]=[C:47]([NH:1][N:2]2[CH2:7][CH2:6][CH2:5][CH:4]([OH:8])[CH2:3]2)[C:48]2[N:49]=[CH:50][N:42]([C:43]=2[N:44]=1)[C@@H:19]1[O:20][C@H:21]([CH2:32][OH:33])[C@@H:22]([OH:23])[C@H:18]1[OH:17]
Reactant: NN1CCCC(O)C1
Reactant: O=C(OC[C@H]1O[C@@H](n2cnc3c(Cl)nc(Cl)nc32)[C@H](OC(=O)c2ccccc2)[C@@H]1OC(=O)c1ccccc1)c1ccccc1
Agent: N
Product: OC[C@H]1O[C@@H](n2cnc3c(NN4CCCC(O)C4)nc(Cl)nc32)[C@H](O)[C@@H]1O
Yield: 7.6 %

Procedure:
The title compound was prepared according to method A as described above by reacting 1-amino-3-hydroxypiperidine (prepared from 3-hydroxypiperidine as outlined in Example 6) (0.60 g, 5.9 mmol) with 9-(2',3',5'tri-O-benzoyl-β-D-ribofuranosyl)-2,6-dichloro-9H-purine (2.50 g, 3.94 mmol), followed by debenzoylation of the purified product using methanolic ammonia to provide the title 2-chloro-N-(3-hydroxypiperidinyl)adenosine (0.12 g, 8%) (after column chromatography) as a foam (a mixture of diastereoisomers); 1H NMR (DMSO-d6) δ3.52-3.60 (1H, m, H-5'a), 3.63-3.70 (1H, m, H-5'b), 3.95 (1H, q, H-4'), 4.14 (1H, m, H-3'), 4.52 (1H, m, H-2'), 5.08 (1H, t, 5'-OH), 5.22, 5.50 (2H, 2d, 2'- and 3'-OH), 5.84 (1 H, d, H-1'), 8.43 (1H, br s, H-8), 9.45 (1H, 2 br s, N-H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([N+:9]([O-])=O)=[CH:4][C:3]=1[OH:12].[H][H]>C(O)C.[Pt](=O)=O>[NH2:9][C:5]1[CH:4]=[C:3]([OH:12])[C:2]([Cl:1])=[CH:7][C:6]=1[F:8]
Reactant: O=[N+]([O-])c1cc(O)c(Cl)cc1F
Reactant: [H][H]
Agent: O=[Pt]=O
Solvent: CCO
Product: Nc1cc(O)c(Cl)cc1F
Yield: 85.3 %

Procedure:
A suspension of 2-chloro-4-fluoro-5-nitrophenol (9.17 g) and platinum dioxide (500 mg) in ethanol (120 ml) was subjected to catalytic reduction with hydrogen under room temperature and atmospheric pressure until a designed amount of hydrogen was absorbed. The catalyst was removed by filtration, and the filtrate was concentrated. The residue was extracted with ether, and the ether layer was concentrated to obtain 6.6 g of 3-amino-6-chloro-4-fluorophenol. M.P., 145°-146° C. (decomp.).
Reaction SMILES: [CH:1]1([OH:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].[Br:10][C:11]1[CH:18]=[CH:17][CH:16]=[C:15](F)[C:12]=1[C:13]#[N:14]>CN(C)C=O.C(OCC)(=O)C>[Br:10][C:11]1[CH:18]=[CH:17][CH:16]=[C:15]([O:7][CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[C:12]=1[C:13]#[N:14]
Reactant: N#Cc1c(F)cccc1Br
Reactant: OC1CCCCC1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: N#Cc1c(Br)cccc1OC1CCCCC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of cyclohexanol (0.275 g) in N,N-dimethylformamide (5 mL) was added sodium hydride (60%, 0.069 g). After 30 minutes, 2-bromo-6-fluorobenzonitrile (0.500 g) was added and the reaction stirred at room temperature for 2 hours. The reaction mixture was diluted with ethyl acetate (25 mL), washed with water (20 mL) and brine (20 mL), dried over magnesium sulfate, filtered, and concentrated. Silica gel chromatography eluting with a gradient of 3% to 10% ethyl acetate/hexanes provided the title compound.
Reaction SMILES: [C:1]1([CH2:7][N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][N:16]3[CH:25]([OH:26])[C:24]4[CH:27]=[CH:28][CH:29]=[C:22]5[C:23]=4[C:18](=[CH:19][CH:20]=[CH:21]5)[C:17]3=[O:30])[CH2:10][CH2:9]2)C=C[CH:4]=[CH:3][CH:2]=1.[N:31]1C=CC=CC=1N1CCNCC1.C(N(C(C)C)CC)(C)C>C1(C)C=CC=CC=1>[N:31]1[CH:4]=[CH:3][CH:2]=[CH:1][C:7]=1[N:8]1[CH2:9][CH2:10][N:11]([CH2:14][CH2:15][N:16]2[C:17](=[O:30])[C:18]3[CH:19]=[CH:20][CH:21]=[C:22]4[C:23]=3[C:24](=[CH:27][CH:28]=[CH:29]4)[C:25]2=[O:26])[CH2:12][CH2:13]1
Reactant: c1ccc(N2CCNCC2)nc1
Reactant: O=C1c2cccc3cccc(c23)C(O)N1CCN1CCN(Cc2ccccc2)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Product: O=C1c2cccc3cccc(c23)C(=O)N1CCN1CCN(c2ccccn2)CC1

Procedure:
10 g. (0.025 moles) of the ester from example 1 (b), 4.1 g. (0.025 moles) of 1-(2-pyridinyl)piperazine and 3.27 g. (0.0253 moles) of diisopropylethylamine are refluxed in 300 ml. of toluene for 3.5 hours. The toluene is evaporated and the residue is dissolved in chloroform and washed with water (all aqueous layers are backwashed). The chloroform is evaporated and the residue is recrystallized from chloroform/ethanol to yield 2-[2-[4-(2-pyridyl)-1-piperazinyl]ethyl]-1H-benz[de]isoquinoline-1,3(2H)-dione; m.p. 188°-190°.
Reaction SMILES: [CH2:1]([C:8]1([OH:18])[CH2:17][CH2:16][C:11]2([O:15][CH2:14][CH2:13][O:12]2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].I[CH3:22]>C1COCC1>[CH2:1]([C:8]1([O:18][CH3:22])[CH2:17][CH2:16][C:11]2([O:12][CH2:13][CH2:14][O:15]2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CI
Reactant: OC1(Cc2ccccc2)CCC2(CC1)OCCO2
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC1(Cc2ccccc2)CCC2(CC1)OCCO2
Reaction time: 1 h

Procedure:
A solution of Example 11A (8.08 g, 32.5 mmol) in THF (150 mL) at room temperature was treated with 60% NaH in mineral oil (3.2 g, 80 mmol), stirred for 1 hour, treated with iodomethane (5 mL, 80 mmol), stirred overnight, quenched with saturated NH4Cl, and extracted with ethyl acetate (3×200 mL). The combined extracts were washed with water and brine, dried (Na2SO4), filtered, and concentrated to provide the desired product. MS (CI) m/e 280.2 (M+18)+.
Reaction SMILES: [CH3:1][C:2]1([C:7]2[O:11][C:10]([CH2:12][N:13]3[CH:17]=[CH:16][C:15]([NH2:18])=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[CH3:19][C:20]1[O:21][C:22]([C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([Cl:34])[CH:29]=2)=[C:23]([C:25](O)=[O:26])[N:24]=1>>[C:2]([C:7]1[O:11][C:10]([CH2:12][N:13]2[CH:17]=[CH:16][C:15]([NH:18][C:25]([C:23]3[N:24]=[C:20]([CH3:19])[O:21][C:22]=3[C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([Cl:34])[CH:29]=3)=[O:26])=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: CC1(c2ccc(Cn3ccc(N)n3)o2)OCCO1
Reactant: Cc1nc(C(=O)O)c(-c2cccc(Cl)c2)o1
Product: CC(=O)c1ccc(Cn2ccc(NC(=O)c3nc(C)oc3-c3cccc(Cl)c3)n2)o1

Procedure:
Following general procedure B followed by T, starting from 1-[5-(2-methyl-[1,3]dioxolan-2-yl)-furan-2-ylmethyl]-1H-pyrazol-3-ylamine and 2-methyl-5-(3-chloro-phenyl)-oxazole-4-carboxylic acid. LC-MS-conditions 05b (with gradient: 5% B→95% B over 1 min): tR=0.79 min; [M+H]+=425.14.
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([C:6]([O:17][CH3:18])=[N:7][N:8]2[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:4][CH:3]=1.C(OC([N:26]1[CH2:31][CH2:30][N:29]([CH:32]2[CH2:35][NH:34][CH2:33]2)[CH2:28][CH2:27]1)=O)(C)(C)C.[ClH:36]>>[ClH:36].[CH3:18][O:17][C:6]1[C:5]2[C:9](=[CH:10][C:2]([N:34]3[CH2:35][CH:32]([N:29]4[CH2:30][CH2:31][NH:26][CH2:27][CH2:28]4)[CH2:33]3)=[CH:3][CH:4]=2)[N:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:7]=1
Reactant: CC(C)(C)OC(=O)N1CCN(C2CNC2)CC1
Reactant: COc1nn(-c2ccccc2)c2cc(Br)ccc12
Agent: Cl
Product: COc1nn(-c2ccccc2)c2cc(N3CC(N4CCNCC4)C3)ccc12

Procedure:
The title compound was prepared according to the procedure as described in Example 57 reacting 6-bromo-3-methoxy-1-phenyl-1H-indazole and 4-azetidin-3-yl-piperazine-1-carboxylic acid tert-butyl ester, followed by de-protection with HCl.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13](=[O:14])[C:12]([CH3:16])([CH3:15])[N:11]([C:17]3[CH:25]=[CH:24][C:20]([C:21]([OH:23])=[O:22])=[C:19]([F:26])[CH:18]=3)[C:10]2=S)=[CH:5][C:4]=1[C:28]([F:31])([F:30])[F:29])#[N:2].S(Cl)(Cl)=[O:33]>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13](=[O:14])[C:12]([CH3:16])([CH3:15])[N:11]([C:17]3[CH:25]=[CH:24][C:20]([C:21]([OH:23])=[O:22])=[C:19]([F:26])[CH:18]=3)[C:10]2=[O:33])=[CH:5][C:4]=1[C:28]([F:31])([F:30])[F:29])#[N:2]
Reactant: O=S(Cl)Cl
Reactant: CC1(C)C(=O)N(c2ccc(C#N)c(C(F)(F)F)c2)C(=S)N1c1ccc(C(=O)O)c(F)c1
Product: CC1(C)C(=O)N(c2ccc(C#N)c(C(F)(F)F)c2)C(=O)N1c1ccc(C(=O)O)c(F)c1
Reaction time: 15 h

Procedure:
A solution of 4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)-2-fluorobenzoic acid (50 mg, 0.11 mmol) in thionyl chloride (0.5 mL, 67.7 mmol) was stirred at 90 deg C. for 15 h. The reaction mixture was concentrated under reduced pressure to dryness. Ice-water (20 mL) was added into the residue and the product was extracted with ethyl acetate (60 mL). The organic layer was dried over anhydrous sodium sulfate and evaporated under reduced pressure to afford crude product, which was purified by reverse phase HPLC to yield 4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-2,4-dioxoimidazolidin-1-yl)-2-fluorobenzoic acid. 1H NMR DMSO-d6 (FREE BASE): δ (ppm) 8.39 (d, 1H), 8.25 (s, 1H), 8.1 (d, 1H), 8.0 (t, 1H), 7.45 (d, 1H), 7.4 (d, 1H), 1.58 (s, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[N:12]=[C:13]=[O:14].[NH2:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[O:26][C:25]([C:27]([NH:29][CH:30]([CH:35]([CH3:37])[CH3:36])[C:31]([O:33][CH3:34])=[O:32])=[O:28])=[N:24][CH:23]=2)=[CH:18][CH:17]=1>>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[NH:12][C:13](=[O:14])[NH:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[O:26][C:25]([C:27]([NH:29][C@@H:30]([CH:35]([CH3:37])[CH3:36])[C:31]([O:33][CH3:34])=[O:32])=[O:28])=[N:24][CH:23]=2)=[CH:18][CH:17]=1
Reactant: O=C=Nc1ccc(C(F)(F)F)cc1Cl
Reactant: COC(=O)C(NC(=O)c1ncc(-c2ccc(N)cc2)o1)C(C)C
Product: COC(=O)[C@@H](NC(=O)c1ncc(-c2ccc(NC(=O)Nc3ccc(C(F)(F)F)cc3Cl)cc2)o1)C(C)C

Procedure:
The title compound was synthesized analogous to Example 1, using 2-chloro-4-(trifluoromethyl)-1-isocyanatobenzene (0.533 mmol) and intermediate 1. 1H NMR (DMSO-d6, 300 MHz): δ 9.883 (s, 1H), 9.025-8.998 (d, 1H), 8.707 (s, 1H), 8.498-8.469 (d, J=8.7 Hz, 1H), 7.904-7.898 (d, J=1.8 Hz, 1H), 7.842 (s, 1H), 7.837-7.807 (d, J=9 Hz, 2H), 7.723-7.688 (dd, J=1.8, 9 Hz, 1H), 7.653-7.624 (d, J=8.7 Hz, 2H), 4.332-4.2827 (m, 1H), 3.682 (s, 3H), 2.228-2.219 (m, 1H), 0.982-0.960 (d, J=6.6 Hz, 6H); MS (ESI) m/z 537 (M−H), 539 (M+H).
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]#[CH:5].[C:6]([C:9]1[CH:10]=[C:11](/[CH:14]=[C:15]2\[C:16](=[O:26])[NH:17][C:18]3[C:23]\2=[C:22](I)[C:21]([F:25])=[CH:20][CH:19]=3)[NH:12][CH:13]=1)(=[O:8])[CH3:7]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I.CN(C=O)C.CCN(CC)CC>[C:6]([C:9]1[CH:10]=[C:11](/[CH:14]=[C:15]2\[C:16](=[O:26])[NH:17][C:18]3[C:23]\2=[C:22]([C:5]#[C:4][CH2:3][NH:2][CH3:1])[C:21]([F:25])=[CH:20][CH:19]=3)[NH:12][CH:13]=1)(=[O:8])[CH3:7]
Reactant: CC(=O)c1c[nH]c(/C=C2\C(=O)Nc3ccc(F)c(I)c32)c1
Reactant: C#CCNC
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CNCC#Cc1c(F)ccc2c1/C(=C/c1cc(C(C)=O)c[nH]1)C(=O)N2

Procedure:
Using Method C above, N-methylpropargylamine (43.6 mg, 0.66 mmol) was coupled with (Z)-3-[(4-acetyl-1H-pyrrol-2-yl)methylene]-1,3-dihydro-5-fluoro-4-iodo-2H-indol-2-one (100 mg, 0.25 mmol) (Example 90B) using (Ph3P)4Pd (30.1 mg) and CuI (6.0 mg) as catalyst in DMF (6 mL) and Et3N (6 mL) as solvent at 89° C. for 5 h to yield (Z)-3-[(4-Acetyl-1H-pyrrol-2-yl)methylene]-1,3-dihydro-5-fluoro-4-[3-(N-methylamino)-1-propynyl]-2H-indol-2-one. (Yield 10 mg, 12%).
Reaction SMILES: [C:1]([O:5][C:6]([CH:8]([NH:19][CH3:20])[C:9]1[CH:10]=[C:11]([CH:16]=[CH:17][CH:18]=1)[C:12]([O:14]C)=[O:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>CO>[C:1]([O:5][C:6]([CH:8]([NH:19][CH3:20])[C:9]1[CH:10]=[C:11]([CH:16]=[CH:17][CH:18]=1)[C:12]([OH:14])=[O:13])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CNC(C(=O)OC(C)(C)C)c1cccc(C(=O)OC)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CNC(C(=O)OC(C)(C)C)c1cccc(C(=O)O)c1

Procedure:
To a solution of the product from Step E (0.35 g) in methanol was added 5% sodium hydroxide. After stirring for 2 h the methanol was evaporated and the aqueous layer was adjusted to pH 3 with 2% potassium hydrogen sulfate. The aqueous layer was extracted with ethyl acetate several times. The ethyl acetate layer was washed with saturated sodium chloride, dried over magnesium sulfate, and concentrated in vacuo to yield the title compound.
Reaction SMILES: [ClH:1].[C:2]([NH:12][C@H:13]([C:21]([OH:23])=O)[CH2:14][CH2:15][CH2:16][NH:17][C:18](=[NH:20])[NH2:19])([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3].[NH2:24][C:25]1[CH:34]=[C:33]2[C:28]([C:29]([CH3:36])=[CH:30][C:31](=[O:35])[O:32]2)=[CH:27][CH:26]=1.C1(N=C=NC2CCCCC2)CCCCC1.CO>CN(C)C=O>[ClH:1].[C:2]([NH:12][C@H:13]([C:21]([NH:24][C:25]1[CH:34]=[C:33]2[C:28]([C:29]([CH3:36])=[CH:30][C:31](=[O:35])[O:32]2)=[CH:27][CH:26]=1)=[O:23])[CH2:14][CH2:15][CH2:16][NH:17][C:18](=[NH:20])[NH2:19])([O:4][CH2:5][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1)=[O:3]
Reactant: Cc1cc(=O)oc2cc(N)ccc12
Reactant: N=C(N)NCCC[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: CO
Solvent: CN(C)C=O
Product: Cc1cc(=O)oc2cc(NC(=O)[C@H](CCCNC(=N)N)NC(=O)OCc3ccccc3)ccc12
Temperature: 25 °C
Yield: 28.9 %

Procedure:
Nα -carbobenzoxy-L-arginine hydrochloric acid salt (69.0 g, 0.2 M) and 7-amino-4-methylcoumarin (17.5 g, 0.1 M) were dissolved in dimethylformamide (DMF) (300 ml). Dicyclohexylcarbodiimide (DCCD) (21 g, 0.1 M) was added to the mixture with stirring at room temperature. This mixture was stirred overnight at room temperature, and the produced dicyclohexyl urea was removed by filtration. The obtained filtrate was concentrated under reduced pressure and to the thus obtained residue methyl alcohol (50 ml) and ethyl acetate (500 ml) were added. The precipitated material was separated by filtration to give crude crystals (19 g). These crystals were dissolved in a mixture of heated DMF (30 ml) and heated methyl alcohol (100 ml) and insoluble material was removed by filtration. To the filtrate ethyl acetate (400 ml) was added and the thereby precipitated white crystals were separated by filtration and dried to give 7-(Nα -carbobenzoxy-L-arginyl)amino-4-methylcoumarin hydrochloric acid salt (14.5 g, yield: 29%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][CH3:9])[C:5]([N+:10]([O-:12])=[O:11])=[CH:4][CH:3]=1.[CH3:13][S-:14].[Na+]>C(#N)C.CN(C=O)C>[CH3:9][O:8][C:6]1[C:5]([N+:10]([O-:12])=[O:11])=[CH:4][CH:3]=[C:2]([S:14][CH3:13])[N:7]=1
Reactant: COc1nc(Cl)ccc1[N+](=O)[O-]
Reactant: C[S-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC#N
Product: COc1nc(SC)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 18 h
Yield: 91 %

Procedure:
To a solution of 6-chloro-2-methoxy-3-nitropyridine (300 mg, 1.591 mmol) in acetonitrile/DMF (2:1, 3 mL) was added sodium thiomethoxide (133 mg, 1.91 mmol). The reaction mixture was stirred at room temperature for 18 hours and then concentrated in vacuo. The residue was partitioned between water (30 mL) and EtOAc (30 mL). The organic layer was dried (MgSO4) and concentrated in vacuo to give the title compound (290 mg, 91%).
Reaction SMILES: [NH2:1][C:2]1[C:3]([Cl:20])=[CH:4][C:5]2[CH2:11][CH2:10][N:9]([CH3:12])[CH2:8][CH:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:6]=2[CH:19]=1.[C:21](OC(=O)C)(=[O:23])[CH3:22]>C(Cl)Cl.CN(C)C1C=CN=CC=1>[C:21]([NH:1][C:2]1[C:3]([Cl:20])=[CH:4][C:5]2[CH2:11][CH2:10][N:9]([CH3:12])[CH2:8][CH:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:6]=2[CH:19]=1)(=[O:23])[CH3:22]
Reactant: CN1CCc2cc(Cl)c(N)cc2C(c2ccccc2)C1
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(=O)Nc1cc2c(cc1Cl)CCN(C)CC2c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
3.4 g of 8-amino-7-chloro-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine in 50 ml of methylene chloride was treated with 4 ml of acetic anhydride followed by addition of 10 mg. of 4-dimethylaminopyridine. The resulting mixture was stirred at room temperature for 2 hours, and the solvent was removed in vacuo. The residue was stirred with a mixture of ether and sodium bicarbonate solution for 1 hour. The ether layer was separated, dried over sodium sulfate and evaporated in vacuo. The resulting crude product of this example (3.1 g) was used in the following step B.
Reaction SMILES: [C:1]1([C:7]2([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:11][CH2:10][NH:9][C:8]2=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>CCOCC>[C:1]1([C:7]2([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:11][CH2:10][NH:9][CH2:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C1NCCC1(c1ccccc1)c1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: c1ccc(C2(c3ccccc3)CCNC2)cc1
Temperature: 25 °C

Procedure:
In a 500 mL flask containing 3,3-diphenylpyrrolidine-2-one (5.00 g, 21 mmol; Example 1A) as a suspension in ether (300 mL) was added lithium aluminum hydride (2.0 M in tetrahydrofuran, 24 mL, 48 mmol) slowly via syringe under nitrogen. The reaction was refluxed overnight, cooled to room temperature, and then carefully quenched by the slow addition of 1 N NaOH (60 mL). The reaction was diluted with ethyl acetate (200 mL) and filtered through a pad of diatomaceous earth. The organic phase was separated, concentrated, and the residue purified over silica gel eluting with 95:5 dichloromethane/methanol to give the title compound. MS (DCI+) m/z 224 (M+H)+.
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:18]([OH:20])=O)[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].Cl.[OH:22][CH:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C>CN(C=O)C>[C:4]([O:3][C:1](=[O:2])[NH:8][C@@H:9]([CH2:10][C:11]1[CH:12]=[CH:13][C:14]([F:17])=[CH:15][CH:16]=1)[C:18]([N:26]1[CH2:27][CH2:28][CH:23]([OH:22])[CH2:24][CH2:25]1)=[O:20])([CH3:5])([CH3:6])[CH3:7]
Reactant: OC1CCNCC1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(F)cc1)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(F)cc1)C(=O)N1CCC(O)CC1
Reaction time: 0.08 h

Procedure:
To a stirred solution of Boc-3-(4-fluorophenyl)-(S)-alanine (10.0 g, 35.3 mmol), 4-hydroxypiperidine hydrochloride (5.1 g, 37.1 mmol) and HOBt (7.2 g, 52.9 mmol) in DMF (100 mL), was added DIPEA (12.3 mL, 70.6 mmol) and after 5 min, EDCI (7.4 g, 38.8 mmol) and the reaction stirred at rt for 16 h. The solvent was removed in vacuo and the residue partitioned between water (150 mL) and ethyl acetate (2×150 mL). The combined organic fractions were washed with sodium hydroxide solution (2M, 50 mL), hydrochloric acid (2N, 50 mL), dried (MgSO4) and concentrated in vacuo. The product was chromatographed on silica gel eluting with ethyl acetate to give the title compound as a white solid. m/z (ES+)=367 [M+H]+; RT=3.28 min.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([OH:8])[C:3]=1[CH:9]1[N:13]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=2)[C:12](=[O:26])[CH:11]([CH3:27])[CH2:10]1.I[CH2:29][CH2:30][CH3:31].C(=O)([O-])[O-].[K+].[K+].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH2:29][CH2:30][CH3:31])[C:3]=1[CH:9]1[N:13]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][C:22]([F:23])([F:24])[F:25])=[CH:17][CH:16]=2)[C:12](=[O:26])[CH:11]([CH3:27])[CH2:10]1
Reactant: CCCI
Reactant: CC1CC(c2c(O)cccc2F)N(Cc2ccc(OC(F)(F)F)cc2)C1=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCOc1cccc(F)c1C1CC(C)C(=O)N1Cc1ccc(OC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
A mixture of 5-(2-fluoro-6-hydroxyphenyl)-3-methyl-1-(4-(trifluoromethoxy)benzyl)pyrrolidin-2-one (preparation described in example 413; 50 mg; 0.13 mmol), 1-iodopropane (22 mg; 0.13 mmol), potassium carbonate (36 mg; 0.26 mmol), and cesium carbonate (8.5 mg; 0.026 mmol) in anh. DMF (0.7 ml) was stirred at rt, under nitrogen, for 17 h. Subsequent filtration and purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=1.01 min.; [M+H]+: 425.99 g/mol.
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][N:6]([C:9]([C:11]2[CH:12]=[CH:13][C:14]([N:17]3[C:21]([O:22]C)=[C:20]([C:24]4[CH:31]=[CH:30][C:27]([C:28]#[N:29])=[C:26]([F:32])[C:25]=4[CH3:33])[CH:19]=[N:18]3)=[N:15][CH:16]=2)=[O:10])[CH2:5][CH2:4]1)[CH3:2].CC(N(C)C)=O.[Cl-].[Li+]>CS(C)=O>[CH2:1]([N:3]1[CH2:8][CH2:7][N:6]([C:9]([C:11]2[CH:12]=[CH:13][C:14]([N:17]3[C:21]([OH:22])=[C:20]([C:24]4[CH:31]=[CH:30][C:27]([C:28]#[N:29])=[C:26]([F:32])[C:25]=4[CH3:33])[CH:19]=[N:18]3)=[N:15][CH:16]=2)=[O:10])[CH2:5][CH2:4]1)[CH3:2]
Reactant: CCN1CCN(C(=O)c2ccc(-n3ncc(-c4ccc(C#N)c(F)c4C)c3OC)nc2)CC1
Agent: [Cl-]
Agent: [Li+]
Solvent: CS(C)=O
Solvent: CC(=O)N(C)C
Product: CCN1CCN(C(=O)c2ccc(-n3ncc(-c4ccc(C#N)c(F)c4C)c3O)nc2)CC1
Yield: 36.5 %

Procedure:
Combined 4-(1-(5-(4-ethylpiperazine-1-carbonyl)pyridin-2-yl)-5-methoxy-1H-pyrazol-4-yl)-2-fluoro-3-methylbenzonitrile (70 mg, 0.156 mmol) and DMA (1561 μl) then added lithium chloride (66.2 mg, 1.561 mmol) and heated at 70° C. overnight. The crude reaction was then diluted with DMSO (500 uL) and purified via preparative HPLC (acetonitrile-water, with TFA) to give the title compound (24.6 mg, 0.057 mmol, 36.3%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.23 (t, J=7.33 Hz, 3 H) 2.33 (d, J=2.27 Hz, 3 H) 3.16 (t, J=7.20 Hz, 2 H) 3.24-4.06 (m, 8 H) 7.49-7.84 (m, 2 H) 8.04-8.30 (m, 2 H) 8.43 (br. s., 1 H) 8.60 (dd, J=2.15, 0.63 Hz, 1 H). ESI-MS m/z [M+H]+ 435.3.