Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[N:7]2[CH:8]=[C:9]([CH2:11][CH2:12][C:13]3[CH:22]=[CH:21][C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[N:14]=3)[N:10]=[C:6]2[C:5]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)=[N:4][CH:3]=1.[CH3:29][O:30][CH2:31][CH2:32][O:33][CH2:34][CH2:35][O:36][C:37]1[CH:42]=[CH:41][C:40](B2OC(C)(C)C(C)(C)O2)=[CH:39][CH:38]=1.C([O-])([O-])=O.[Na+].[Na+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[CH3:29][O:30][CH2:31][CH2:32][O:33][CH2:34][CH2:35][O:36][C:37]1[CH:38]=[CH:39][C:40]([C:2]2[N:7]3[CH:8]=[C:9]([CH2:11][CH2:12][C:13]4[CH:22]=[CH:21][C:20]5[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=5)[N:14]=4)[N:10]=[C:6]3[C:5]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)=[N:4][CH:3]=2)=[CH:41][CH:42]=1
Reactant: Brc1cnc(N2CCOCC2)c2nc(CCc3ccc4ccccc4n3)cn12
Reactant: COCCOCCOc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Product: COCCOCCOc1ccc(-c2cnc(N3CCOCC3)c3nc(CCc4ccc5ccccc5n4)cn23)cc1
Temperature: 90 °C
Reaction time: 5 h

Procedure:
A mixture of compound 3a (100 mg, 0.228 mmol), compound 85b (88.2 mg, 0.274 mmol), PdCl2(dppf)-DCM (5.6 mg, 0.0068 mmol), and Argon-degassed aqueous 2M Na2CO3 (0.570 mL, 1.14 mmol) in Argon-degassed 1,4-dioxane (4 mL) was further degassed with Argon for 2 min and then stirred at 90° C. for 5 h. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure to a brown oil which was purified by flash column chromatography on silica gel (0-100% EtOAc-heptane, followed by 100% EtOAc) to afford a colorless resin. The residue obtained was further purified by flash column chromatography (100% EtOAc, followed by 0-10% MeOH-EtOAc) to afford a colorless oil, which was triturated with EtOAc-heptane (1:3) and concentrated under reduced pressure to give the title compound 31 as an off-white crystalline solid. 1H-NMR (CDCl3; 400 MHz): δ (ppm) 8.01-8.08 (m, 2H), 7.79 (d, J=8.1 Hz, 1H), 7.67-7.73 (m, 1H), 7.48-7.54 (m, 1H), 7.30-7.38 (m, 4H), 7.24 (s, 1H), 6.98 (d, J=8.6 Hz, 2H), 4.16-4.23 (m, 6H), 3.91 (t, J=4.8 Hz, 2H), 3.82-3.86 (m, 4H), 3.73-3.78 (m, 2H), 3.59-3.63 (m, 2H), 3.41-3.42 (m, 3H), 3.38-3.44 (m, 2H), 3.27-3.33 (m, 2H); Mass spectrum (LCMS, ESI pos.): Calcd. for C32H35N5O4, 554.3 (M+H). found 554.5.
Reaction SMILES: [B-](F)(F)(F)[CH:2]=[CH2:3].[K+].Cl[C:9]1[C:10]([O:19][C@H:20]2[CH2:24][N:23]([C:25](=[O:46])[C@H:26]([CH:41]3[CH2:45][CH2:44][CH2:43][CH2:42]3)[NH:27][C:28]([N:30]3[CH2:34][CH2:33][C@H:32]([O:35][CH2:36][CH2:37][CH2:38][CH:39]=[CH2:40])[CH2:31]3)=[O:29])[C@H:22]([C:47]([O:49][CH3:50])=[O:48])[CH2:21]2)=[N:11][C:12]2[C:17]([N:18]=1)=[CH:16][CH:15]=[CH:14][CH:13]=2>CCO.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[CH:41]1([C@H:26]([NH:27][C:28]([N:30]2[CH2:34][CH2:33][C@H:32]([O:35][CH2:36][CH2:37][CH2:38][CH:39]=[CH2:40])[CH2:31]2)=[O:29])[C:25]([N:23]2[CH2:24][C@H:20]([O:19][C:10]3[C:9]([CH:2]=[CH2:3])=[N:18][C:17]4[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=4)[N:11]=3)[CH2:21][C@H:22]2[C:47]([O:49][CH3:50])=[O:48])=[O:46])[CH2:45][CH2:44][CH2:43][CH2:42]1
Reactant: C=C[B-](F)(F)F
Reactant: C=CCCCO[C@H]1CCN(C(=O)N[C@H](C(=O)N2C[C@H](Oc3nc4ccccc4nc3Cl)C[C@H]2C(=O)OC)C2CCCC2)C1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [K+]
Solvent: ClCCl
Solvent: CCO
Product: C=CCCCO[C@H]1CCN(C(=O)N[C@H](C(=O)N2C[C@H](Oc3nc4ccccc4nc3C=C)C[C@H]2C(=O)OC)C2CCCC2)C1
Yield: 78.7 %

Procedure:
Potassium trifluoro(vinyl)borate (68 mg, 0.513 mmol), TEA (0.071 mL, 0.513 mmol) and PdCl2(dppf)-CH2Cl2 adduct (28 mg, 0.034 mmol) were added in sequence to a solution of methyl (4R)-4-[(3-chloroquinoxalin-2-yl)oxy]-1-[(25)-2-cyclopentyl-2-({[(35)-3-(pent-4-en-1-yloxy)pyrrolidin-1-yl]carbonyl}amino)acetyl]-L-prolinate (210 mg, 0.342 mmol) in EtOH (4 mL). The resulting mixture was refluxed for 1 h, then concentrated under reduced pressure to give a residue that was purified on silica gel (gradient elution from 10% to 50% AcOEt in petroleum ether) to afford the title compound (163 mg, 79%) as a solid. LCMS (ES+) m/z 606 (M+H)+.
Reaction SMILES: [Na].Cl.[C:3]([C:6]1[CH:14]=[CH:13][C:9]([C:10]([NH2:12])=[O:11])=[CH:8][CH:7]=1)(=[NH:5])[NH2:4].[C:15]([C:17]1[CH:22]=[CH:21][C:20]([C:23](=[CH:26]OC)[CH:24]=O)=[CH:19][CH:18]=1)#[N:16]>CO>[C:15]([C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:24]=[N:5][C:3]([C:6]3[CH:14]=[CH:13][C:9]([C:10]([NH2:12])=[O:11])=[CH:8][CH:7]=3)=[N:4][CH:26]=2)=[CH:19][CH:18]=1)#[N:16]
Reactant: N=C(N)c1ccc(C(N)=O)cc1
Reactant: COC=C(C=O)c1ccc(C#N)cc1
Agent: Cl
Agent: [Na]
Solvent: CO
Product: N#Cc1ccc(-c2cnc(-c3ccc(C(N)=O)cc3)nc2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
247 mg of sodium are treated at room temperature with 10 ml of methanol. After 15 minutes the solution obtained is treated at room temperature with 1.58 g of 4-amidinobenzamide hydrochloride. A white suspension forms and this is treated dropwise at room temperature within 10 minutes with a solution of 1.42 g of 2-(4-cyanophenyl)-3-methoxyacrolein in 50 ml of methanol. The reaction mixture is stirred at room temperature for a further 2 hours and then suction filtered. The residue is washed with water, tetrahydrofuran and diethyl ether and dried in a high vacuum. 4-[5-(4-Cyanophenyl)-2-pyrimidinyl]benzamide is obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:10]2[CH:22]([CH:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)[CH:21]3[C:12]([C:13]4[CH:14]=[CH:15][C:16]([C:28]([O:30]C)=[O:29])=[N:17][C:18]=4[CH2:19][CH2:20]3)=[N:11]2)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].[OH-].[Na+].CO>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([N:10]2[CH:22]([CH:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)[CH:21]3[C:12]([C:13]4[CH:14]=[CH:15][C:16]([C:28]([OH:30])=[O:29])=[N:17][C:18]=4[CH2:19][CH2:20]3)=[N:11]2)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9]
Reactant: COC(=O)c1ccc2c(n1)CCC1C2=NN(c2ccc(C#N)c(Cl)c2)C1C1CCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: N#Cc1ccc(N2N=C3c4ccc(C(=O)O)nc4CCC3C2C2CCCC2)cc1Cl
Temperature: 25 °C
Reaction time: 15 h
Yield: 58.9 %

Procedure:
In a dried reaction flask, methyl 2-(3-chloro-4-cyanophenyl)-3-cyclopentyl-3,3a,4,5-tetrahydro-2H-pyrazolo[3,4-f]quinoline-7-carboxylate (0.868 g, 2.0 mmol) and 10% aqueous NaOH solution (2.4 mL, 6.0 mmol) were dissolved into a mixture of methanol (4 mL) and tetrahydrofuran (10 mL). The reaction solution was stirred at room temperature for 15 hr. The solution was concentrated at a reduced pressure to reduce half of the volume. The residue was adjusted with 1 M HCl under an ice bath to a pH value of 2-3, and filtered to obtain a crude yellow solid, which was then washed with ethanol and ethyl ether to obtain a solid (0.496 g) in 59.0% yield.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:10][C:11]([NH:13][C@@H:14]([CH:18]([CH2:22][O:23][CH3:24])[CH2:19][O:20][CH3:21])[C:15]([OH:17])=[O:16])=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH3:25]I.[NH4+].[Cl-]>C1COCC1.CN(C=O)C.C1COCC1>[CH2:3]([O:10][C:11]([N:13]([CH3:25])[C@@H:14]([CH:18]([CH2:22][O:23][CH3:24])[CH2:19][O:20][CH3:21])[C:15]([OH:17])=[O:16])=[O:12])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CI
Reactant: COCC(COC)[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COCC(COC)[C@@H](C(=O)O)N(C)C(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 96 %

Procedure:
NaH (42 mg, 1.0 mmol, 3.3 equiv) was added in 4 portions to a solution of (S)-2-Benzyloxycarbonylamino-4-methoxy-3-methoxymethyl-butyric acid (100 mg, 0.32 mmol, 1.0 equiv) in dry THF 1 mL at 0° C. After stirring at 0° C. for 10 minutes, it was added a solution of MeI (137 mg, 0.964 mmol, 3.0 equiv) in DMF/THF solution. The mixture was stirred at 0° C. for 1 hour then at room temperature for 16 hours. The reaction mixture was then added to saturated aqueous NH4Cl solution at 0° C. The mixture was extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4 and concentrated to give product 2.11b (100 mg, 95% yield). The crude material was continued to the next step with no further purification. MS m/z (M+1) 326.3
Reaction SMILES: [CH2:1]([O:8][C:9]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)([CH3:16])[CH:10](O)[C:11]([O:13][CH3:14])=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4]C=1.C(N(CC)CC)C.CS(Cl)(=O)=O.[CH3:35][O:36][C:37]1[CH:42]=[C:41]([O:43][CH3:44])[N:40]=[C:39]([SH:45])[N:38]=1.C(=O)(O)[O-].[Na+]>ClCCl.CN(C=O)C>[O:8]([C:9]([C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)([CH3:16])[CH:10]([S:45][C:39]1[N:38]=[C:37]([O:36][CH3:35])[CH:42]=[C:41]([O:43][CH3:44])[N:40]=1)[C:11]([O:13][CH3:14])=[O:12])[C:1]1[CH:2]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: COC(=O)C(O)C(C)(OCc1ccccc1)c1ccccc1
Reactant: COc1cc(OC)nc(S)n1
Agent: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)C(Sc1nc(OC)cc(OC)n1)C(C)(Oc1ccccc1)c1ccccc1
Temperature: 0 °C
Yield: 38.1 %

Procedure:
7.2 g (25 mmol) of methyl 3-phenoxy-3-phenyl-2-hydroxybutyrate (Compound 1.1) are dissolved in 50 ml of dichloromethane, 3 g (30 mmol) of triethylamine are added and, while stirring, 3.2 g (28 mmol) of methanesulfonyl chloride are added dropwise. The mixture is stirred at room temperature for 2 hours, washed with water, dried over magnesium sulfate and concentrated under reduced pressure. The residue is taken up in 100 mo of DMF and added dropwise to a suspension 12.9 g (75 mmol) of 4,6-dimethoxypyrimidine-2-thiol and 8.4 g (100 mmol) sodium bicarbonate in 100 ml of DMF at 0° C. After stirring at room temperature for 2 hours and at 60° C. for further 2 hours, the mixture is poured into 1 liter of ice-water, and the precipitate is filtered off with suction. Drying results in 4.2 g of a white powder.
Reaction SMILES: [N:1]([CH2:4][CH2:5][NH:6][C:7](=[O:21])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]CCCC)=[N+:2]=[N-:3].C(Cl)(=O)CCCCCCCCC.N(CCN)=[N+]=[N-].C(N(CC)CC)C>ClCCl>[N:1]([CH2:4][CH2:5][NH:6][C:7](=[O:21])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])=[N+:2]=[N-:3]
Reactant: CCCCCCCCCCCCCC(=O)NCCN=[N+]=[N-]
Agent: CCCCCCCCCC(=O)Cl
Agent: [N-]=[N+]=NCCN
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCCCCC(=O)NCCN=[N+]=[N-]
Yield: 83 %

Procedure:
As in the synthesis of N-(2-azidoethyl)tetradecanamide, decanoyl chloride (0.251 g, 1.32 mmol) was reacted with 2-azidoethanamine (0.114 g, 1.32 mmol) and triethylamine (0.267 g, 2.64 mmol) in dichloromethane (5 mL) to give N-(2-azidoethyl)decanamide (0.262 g, 83%). 1H NMR (300 MHz, CDCl3) δ 6.49 (s, 1H), δ 3.36 (s, 2H), δ 3.35 (s, 2H), δ 2.14 (t, 2H), δ 1.46 (m, 2H), δ 1.21 (m, 12H), δ 0.81 (t, 3H) ppm; 13C NMR (75 MHz, CDCl3) δ 174.1, 50.9, 39.1, 36.8, 32.0, 29.7, 29.6, 29.5, 29.4, 25.9, 22.8, 14.3 ppm; HRMS (ESI) calcd for C12H24N4O (M+) 240.1950. found 240.1947.
Reaction SMILES: ClC1C=C(C=CC=1)C(OO)=O.[CH2:12]([C:16]1[N:17]([CH2:29][CH2:30][CH2:31][C:32](=[O:34])[CH3:33])[C:18]2[C:27]3[N:26]=[CH:25][CH:24]=[CH:23][C:22]=3[N:21]=[CH:20][C:19]=2[N:28]=1)[CH2:13][CH2:14][CH3:15].[OH-].[NH4+:36].C1(C)C=CC(S(Cl)(=O)=O)=CC=1>C(Cl)(Cl)Cl>[NH2:36][C:20]1[C:19]2[N:28]=[C:16]([CH2:12][CH2:13][CH2:14][CH3:15])[N:17]([CH2:29][CH2:30][CH2:31][C:32](=[O:34])[CH3:33])[C:18]=2[C:27]2[N:26]=[CH:25][CH:24]=[CH:23][C:22]=2[N:21]=1
Reactant: CCCCc1nc2cnc3cccnc3c2n1CCCC(C)=O
Reactant: [NH4+]
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: CCCCc1nc2c(N)nc3cccnc3c2n1CCCC(C)=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3-Chloroperoxybenzoic acid (70% pure, 5.46 g, 22.16 mmol) (mCPBA) was added to a solution of 5-(2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)pentan-2-one (3.44 g, 11.08 mmol, 1 eq) in chloroform (45 mL), and the reaction was stirred for one hour at ambient temperature and then cooled to 5° C. Ammonium hydroxide (10 mL) and p-toluenesulfonyl chloride (2.32 g, 12.19 mmol, 1.1 eq) were sequentially added and the reaction mixture was stirred at 5-10° C. for 1 hour, filtered, and then diluted with dichloromethane (100 mL) and saturated aqueous sodium bicarbonate (75 mL). The aqueous layer was extracted with dichloromethane (2×30 mL) and the combined organic solutions were dried over magnesium sulfate, filtered, and concentrated under reduced pressure to provide a brown oil. The material was triturated with acetonitrile to afford 1.65 g of 5-(4-amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)pentan-2-one. The filtrate from the trituration was purified by BIOTAGE HORIZON High-Performance Flash Chromatography (HPFC) instrument (eluting with chloroform/methanol/ammonium hydroxide (CMA) (80/18/2):chloroform ranging in ratios from 0:100 to 25:75) and subjected to trituration again in acetonitrile to produce an additional 0.240 g of material as an off-white powder, mp 168-169° C. Anal. calcd for C18H23N5O: C, 66.44; H, 7.12; N, 21.52. Found: C, 66.19; H, 7.08; N, 21.22.
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:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Br[CH2:22][C:23]1[S:27][C:26]([C:28]2[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][CH:29]=2)=[N:25][C:24]=1[CH3:38]>CN(C)C=O>[CH3:38][C:24]1[N:25]=[C:26]([C:28]2[CH:29]=[CH:30][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:32][CH:33]=2)[S:27][C:23]=1[CH2:22][N:9]1[CH2:10][CH2:11][C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:8]1=[O:12]
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1CBr
Reactant: O=C1NCCC1(c1ccccc1)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1CN1CCC(c2ccccc2)(c2ccccc2)C1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 3,3-diphenylpyrrolidin-2-one (Example 1A) (0.062 g, 0.262 mmol) in N,N-dimethylformamide (2 mL) was added 60% sodium hydride dispersion in oil (0.013 g, 0.314 mmol). The mixture was stirred at room temperature for 1 hour. Then a solution of 5-(bromomethyl)-4-methyl-2-(4-(trifluoromethyl)phenyl)thiazole (CAS 439134-78-8) (0.088 g, 0.262 mmol) in N,N-dimethylformamide (1 mL) was added, and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated and the residue was partitioned between H2O and dichloromethane. The organic layer was separated, dried over MgSO4 and concentrated. The obtained residue was purified by silica gel chromatography eluting with 2-5% methanol/dichloromethane to yield the title compound. 1H NMR (300 MHz, CDCl3) δ ppm 7.95-8.00 (m, 2H), 7.65-7.70 (m, 2H), 7.17-7.37 (m, 10H), 4.72 (s, 2H), 3.35 (t, J=6.4 Hz, 2H), 2.76 (t, J=6.3 Hz, 2H), 2.47 (s, 3H); MS (ESI+) m/z 493 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[C:11]([O:16][CH2:17][CH3:18])(=[O:15])[C:12]([O-])=[O:13].N12CCCN=C1CCCCC2>C(OCC)(=O)C.O.C(O)(=O)C>[N+:8]([C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:2]=1[CH2:1][C:12](=[O:13])[C:11]([O:16][CH2:17][CH3:18])=[O:15])([O-:10])=[O:9]
Reactant: CCOC(=O)C(=O)[O-]
Reactant: Cc1ccncc1[N+](=O)[O-]
Solvent: O
Solvent: CC(=O)O
Solvent: C1CCC2=NCCCN2CC1
Product: CCOC(=O)C(=O)Cc1ccncc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 73 %

Procedure:
3.1 g (22.44 mmol) of 4-methyl-3-nitropyridine and 16.39 g (112.22 mmol) of ethyl oxalate are placed in a 100 ml three-necked flask equipped with a magnetic stirrer and maintained under a flush of nitrogen. 3.69 ml (24.69 mmol) of 1,8-diaza-bicyclo[5.4.0]undec-7-ene are then added to the reaction medium stirred at room temperature. The reaction mixture is then stirred at room temperature for 1 hour and then diluted with a mixture of ethyl acetate (150 ml), water (100 ml) and acetic acid (4 ml). The mixture is extracted twice with ethyl acetate. The combined organic phases are washed with 100 ml of water, with 100 ml of saturated aqueous sodium chloride solution, dried over sodium sulfate and then concentrated under reduced pressure. The crude reaction product is then triturated from pentane, filtered and then heated in petroleum ether, filtered and dried under reduced pressure. 3.9 g (16.37 mmol) of product are thus isolated, and are used without further purification in the following step.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[CH:3]([CH2:8][CH3:9])[CH2:4][C:5]([OH:7])=[O:6].[CH3:12][Si](C=[N+]=[N-])(C)C>ClCCl.CO>[CH3:12][O:6][C:5](=[O:7])[CH2:4][CH:3]([C:2]([F:10])([F:11])[F:1])[CH2:8][CH3:9]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: CCC(CC(=O)O)C(F)(F)F
Solvent: CO
Solvent: ClCCl
Product: CCC(CC(=O)OC)C(F)(F)F
Yield: 92.3 %

Procedure:
To a stirred solution of Example 1D (250 mg, 1.47 mmol) in dichloromethane (10 mL) and methanol (0.25 mL), under nitrogen atmosphere, trimethylsilyldiazomethane (2.0 M solution in diethyl ether) (2.1 mL, 4.19 mmol) was added drop wise at 0° C. The reaction mixture was stirred keeping the temperature below 5° C. for 1 h. The solvent was removed (40° C., 25 bar) yielding 250 mg (75.4%) of a yellow oil that was used in the next step without further purification.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4]2([O:11][C:10]3[C:12]4[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=3[S:8][CH2:7]2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:3][CH2:2]1.[C:22]1([C:34](O)=[O:35])[C:32]2=[C:33]3[C:28](=[CH:29][CH:30]=[CH:31]2)[CH2:27][CH2:26][CH2:25][N:24]3[CH:23]=1>>[C:22]1([C:34]([N:1]2[CH2:2][CH2:3][C:4]3([O:11][C:10]4[C:12]5[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=4[S:8][CH2:7]3)=[CH:16][CH:15]=[CH:14][CH:13]=5)[CH2:5][CH2:6]2)=[O:35])[C:32]2=[C:33]3[C:28](=[CH:29][CH:30]=[CH:31]2)[CH2:27][CH2:26][CH2:25][N:24]3[CH:23]=1
Reactant: O=C1C(=O)c2ccccc2C2=C1SCC1(CCNCC1)O2
Reactant: O=C(O)c1cn2c3c(cccc13)CCC2
Product: O=C1C(=O)c2ccccc2C2=C1SCC1(CCN(C(=O)c3cn4c5c(cccc35)CCC4)CC1)O2

Procedure:
Compound 73 was synthesized using spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione, 5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinoline-1-carboxylic acid conditions outlined in procedure O. M.p.=265-267° C.; 400 MHz 1H NMR (DMSO-d6) δ: 7.92 (dd, J=0.78, 7.4 Hz, 2H), 7.76-7.80 (m, 2H), 7.59 (t, J=7.4 Hz, 1H), 7.49 (d, J=8.2 Hz, 1H), 7.05 (t, J=7.8 Hz, 1H), 6.93 (d, J=7.0 Hz, 1H), 4.22 (m, 4H), 3.45 (t, J=11.4 Hz, 2H), 3.16 (s, 2H), 2.95 (t, J=5.8 Hz, 2H), 2.06-2.16 (m, 4H), 1.87 (m 2H); LCMS=485 [M+H].
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][N:5]([CH3:24])[C:6]=1[N:7]1[CH2:13][CH2:12][C@@H:11]([O:14][CH3:15])[C@H:10]([NH:16]C(=O)OC(C)(C)C)[CH2:9][CH2:8]1.C(OC([NH:32][C:33]1[S:37][C:36]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][N:39]=2)=[N:35][C:34]=1[C:44](O)=[O:45])=O)(C)(C)C>>[NH2:32][C:33]1[S:37][C:36]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][N:39]=2)=[N:35][C:34]=1[C:44]([NH:1][C:2]1[CH:3]=[N:4][N:5]([CH3:24])[C:6]=1[N:7]1[CH2:13][CH2:12][CH:11]([O:14][CH3:15])[CH:10]([NH2:16])[CH2:9][CH2:8]1)=[O:45]
Reactant: CC(C)(C)OC(=O)Nc1sc(-c2ccccn2)nc1C(=O)O
Reactant: CO[C@@H]1CCN(c2c(N)cnn2C)CC[C@H]1NC(=O)OC(C)(C)C
Product: COC1CCN(c2c(NC(=O)c3nc(-c4ccccn4)sc3N)cnn2C)CCC1N

Procedure:
Following the procedure Example 101, reacting tert-butyl ((4R,5R)-1-(4-amino-1-methyl-1H-pyrazol-5-yl)-5-methoxyazepan-4-yl)carbamate and 5-((tert-butoxycarbonyl)amino)-2-(pyridin-2-yl)thiazole-4-carboxylic acid gave racemic 322 (58.4 mg, 41% over two steps). 1H NMR (400 MHz, DMSO) δ 8.89 (s, 1H), 8.54 (d, J=4.7 Hz, 1H), 8.17 (d, J=8.0 Hz, 1H), 7.89 (t, J=7.7 Hz, 1H), 7.62-7.47 (m, 3H), 7.43-7.31 (m, 1H), 3.64 (s, 3H), 3.27 (s, 3H), 3.23-2.91 (m, 6H), 2.15-2.00 (m, 1H), 1.92-1.80 (m, 1H), 1.79-1.55 (m, 2H). LCMS (ES+) m/z 443 (M+1)
Reaction SMILES: [Si:1]([O:8]S(C(F)(F)F)(=O)=O)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH3:16][O:17][C:18]([CH:20]1[C:24]([CH3:25])=[CH:23][C:22](=O)[N:21]1C(OC(C)(C)C)=O)=[O:19].N1C(C)=CC=CC=1C>ClCCl>[CH3:16][O:17][C:18]([C:20]1[NH:21][C:22]([O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])=[CH:23][C:24]=1[CH3:25])=[O:19]
Reactant: COC(=O)C1C(C)=CC(=O)N1C(=O)OC(C)(C)C
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: COC(=O)c1[nH]c(O[Si](C)(C)C(C)(C)C)cc1C
Temperature: 23 °C
Reaction time: 15 h
Yield: 88.6 %

Procedure:
tert-Butyldimethylsilyltrifluoromethanesulfonate (9.99 ml, 11.49 g, 43.5 mmol, 3.0 equiv) was added to a stirring solution of 3-methyl-5-oxo-2,5-dihydro-pyrrole-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (3.7 g, 14.5 mmol, 1.0 equiv) and 2,6-lutidine (5.07 ml, 4.66 g, 43.5 mmol, 3.0 equiv) in dichloromethane (100 ml) at 23° C. The mixture was stirred at 23° C. for 15 h, then washed with pH=7 buffer solution (30 ml). The aqueous layer was extracted with two 40 ml portions of dichloromethane. The combined organic layers were dried over sodium sulfate. The solids were filtered and the filtrate was concentrated. The residue was purified by flash column chromatography (3% ethyl acetate-hexanes initially, grading to 6% ethyl acetate-hexanes) to afford 5-(tert-Butyl-dimethyl-silanyloxy)-3-methyl-1H-pyrrole-2-carboxylic acid methyl ester (3.46 g, 89%) as a yellow oil.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[CH:22]=[CH:21][C:9]3[C:10]4[N:11]=[C:12]([C:18](O)=[O:19])[S:13][C:14]=4[CH2:15][CH2:16][O:17][C:8]=3[CH:7]=2)[CH:3]=[N:2]1.[NH:23]1[CH2:27][CH2:26][C@@H:25]([N:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)[CH2:24]1>>[N:28]1([C@@H:25]2[CH2:26][CH2:27][N:23]([C:18]([C:12]3[S:13][C:14]4[CH2:15][CH2:16][O:17][C:8]5[CH:7]=[C:6]([C:4]6[CH:3]=[N:2][NH:1][CH:5]=6)[CH:22]=[CH:21][C:9]=5[C:10]=4[N:11]=3)=[O:19])[CH2:24]2)[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1
Reactant: O=C(O)c1nc2c(s1)CCOc1cc(-c3cn[nH]c3)ccc1-2
Reactant: C1C[C@@H](N2CCOCC2)CN1
Product: O=C(c1nc2c(s1)CCOc1cc(-c3cn[nH]c3)ccc1-2)N1CC[C@@H](N2CCOCC2)C1

Procedure:
Following Example 216, to a well stirred solution of 8-(1H-Pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid and (R)-4-(pyrrolidin-3-yl)morpholine to give 228. MS: (ESI+)=453.1
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[Cl:5][C:6]1[CH:7]=[CH:8][C:9]([OH:22])=[C:10]([C:12]([C:14]2[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:15]=2[OH:21])=[O:13])[CH:11]=1>C(O)(=O)C>[Cl:5][C:6]1[CH:7]=[C:8]([N+:1]([O-:4])=[O:2])[C:9]([OH:22])=[C:10]([C:12]([C:14]2[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:15]=2[OH:21])=[O:13])[CH:11]=1
Reactant: O=C(c1cc(Cl)ccc1O)c1cc(Cl)ccc1O
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Product: O=C(c1cc(Cl)ccc1O)c1cc(Cl)cc([N+](=O)[O-])c1O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Nitric acid (4 ml) was added dropwise to a stirred solution of bis(5-chloro-2-hydroxyphenyl)ketone (2.7 g) in glacial acetic acid (50 ml). The solution was stirred at room temperature for 1 hr and during this time a yellow solid separated from solution. The mixture was poured into ice water and the product collected by filtration. Thin layer chromatography indicated that the product was a mixture of two compounds which were separated by column chromatography on silica gel. Elution with hexane containing increasing amounts of ethyl acetate afforded 5-chloro-2-hydroxyphenyl 5-chloro-2-hydroxy-3-nitrophenyl ketone (150 mg) m.p. 153° C., followed by bis-(5-chloro-2-hydroxy-3-nitrophenyl)ketone (1.5 g), m.p. 187° C.