Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([C@@H]([C@H](C(O)=O)O)O)(O)=O.[NH:11]1[CH2:21][CH2:20][CH2:19][C@@H:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:12]1.C(=O)(O)[O-].[Na+].[Cl:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]2([C:38](Cl)=[O:39])[CH2:37][CH2:36][CH2:35]2)=[CH:30][CH:29]=1>ClCCl>[CH2:17]([O:16][C:14]([C@@H:13]1[CH2:19][CH2:20][CH2:21][N:11]([C:38]([C:34]2([C:31]3[CH:30]=[CH:29][C:28]([Cl:27])=[CH:33][CH:32]=3)[CH2:35][CH2:36][CH2:37]2)=[O:39])[CH2:12]1)=[O:15])[CH3:18]
Reactant: O=C(Cl)C1(c2ccc(Cl)cc2)CCC1
Reactant: CCOC(=O)[C@@H]1CCCNC1
Agent: O=C(O)[C@H](O)[C@@H](O)C(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCOC(=O)[C@@H]1CCCN(C(=O)C2(c3ccc(Cl)cc3)CCC2)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Ethyl (R)-nipecotate L-tartrate (15.0 g, 48.8 mmol) was added to a stirred mixture of dichloromethane and saturated sodium bicarbonate solution (100 mL each) at 0° C. After 10 min 1-(4-chloro-phenyl)-cyclobutanecarbonyl chloride (11.13 g, 48.8 mmol) was slowly added at 0° C. The reaction was then allowed to stir for 2 h at room temperature. The organic layer was separated and the aqueous layer was washed once with dichloromethane (100 mL). The organic material was combined and washed once with water (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated by rotary evaporation. The residue was purified by chromatography on silica gel, eluting with hexane/ethyl acetate (2:1) to give 9.2 g of the amidester as a thick clear gum; C19H24ClNO3, LRMS (m/z)=350 (MH+).
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].C(=O)([O-])[O-].[K+].[K+].[NH2:19][C:20]1[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=1.Cl>C(OCCO)C.O.[Cu]>[C:23]1([CH3:26])[CH:24]=[CH:25][C:20]([NH:19][C:2]2[C:3](=[CH:7][C:8]([O:11][CH3:12])=[CH:9][CH:10]=2)[C:4]([OH:6])=[O:5])=[CH:21][CH:22]=1
Reactant: COc1ccc(Cl)c(C(=O)O)c1
Reactant: Cc1ccc(N)cc1
Agent: [Cu]
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CCOCCO
Solvent: O
Product: COc1ccc(Nc2ccc(C)cc2)c(C(=O)O)c1
Temperature: 140 °C
Yield: 67.5 %

Procedure:
A mixture of 2-chloro-5-methoxybenzoic acid (14.0 g, 80.0 mmol), potassium carbonate (13.8 g, mol), powdered copper (1.5 g), cuprous oxide (1.5 g), and p-toluidine (9.4 g, 88.0 mmol) in 2-ethoxyethanol (120 ml) is heated at 140° C. for 3 hours. After cooling, the dark mixture is acidified to about pH 2 with 1N hydrochloric acid, and then diluted with water (600 ml). The solid precipitates are collected by filtration, dissolved in hot 10% sodium carbonate solution, charcoaled, and filtered through a Celite bed. The filtrate is acidified with concentrated hydrochloric acid to about pH 2, and the mixture is extracted with ethyl ether (5×100 ml). The combined extracts are washed with 1N hydrochloric acid (200 ml) and water (2×200 ml), dried over sodium sulfate, concentrated in vacuo, and the solid residue is recrystallized from ethanol-water to give N-(p-tolyl)-5-methoxyanthranilic acid (13.9 g, 68% yield), mp 160° -161° C.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[CH2:12]([S:19][C:20]1[CH:29]=[CH:28][C:27]2[NH:26][C:25](=[O:30])[C:24]3[NH:31][CH:32]=[CH:33][C:23]=3[C:22]=2[CH:21]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[CH2:34]([C:36]([O-:38])=[O:37])[CH3:35].C(=O)([O-])[O-].[K+].[K+]>ClCCl.O1CCOCC1>[O:30]=[C:25]1[C:24]2[NH:31][CH:32]=[CH:33][C:23]=2[C:22]2[CH:21]=[C:20]([S:19]([CH2:12][C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)=[O:9])[CH:29]=[CH:28][C:27]=2[NH:26]1.[CH2:34]([C:36]([O-:38])=[O:37])[CH3:35]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=c1[nH]c2ccc(SCc3ccccc3)cc2c2cc[nH]c12
Agent: CCC(=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: ClCCl
Product: O=c1[nH]c2ccc(S(=O)Cc3ccccc3)cc2c2cc[nH]c12
Temperature: 2.5 °C
Reaction time: 6 h
Yield: 42.1 %

Procedure:
41 mg (0.24 mmol) of metachloroperbenzoic acid is added at 0° C. to a solution of 90 mg (0.24 mmol) of 8-benzylsulfanyl-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-ethyl carboxylate suspended in dichloromethane (8 mL) and dioxan (8 mL). The reaction mixture is stirred for 6 hours at 0-5° C. then an aqueous solution of potassium carbonate is added and the product is extracted with ethyl acetate. The organic phase is washed with an aqueous solution of sodium chloride, dried over magnesium sulfate, filtered and evaporated. The residue is purified by preparative LCMS to give 40 mg (42%) of 4-oxo-8-phenylmethanesulfinyl-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-ethyl carboxylate in the form of a white solid.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:10][C:11]([O:13][CH3:14])=[O:12])=[N:8][CH:9]=1)([O-])=O>CO.[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([CH2:10][C:11]([O:13][CH3:14])=[O:12])=[N:8][CH:9]=1
Reactant: COC(=O)Cc1ccc([N+](=O)[O-])cn1
Agent: [Pd]
Solvent: CO
Product: COC(=O)Cc1ccc(N)cn1

Procedure:
The solution of methyl 2-(5-nitropyridin-2-yl)acetate (500 mg, 2.5 mmol) and Pd/C (50 mg) in methanol (20 mL) was stirred under H2 at room temperature for 3 h. Then, the reaction mixture was filtered and evaporated under reduced pressure to get desired product for the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:23]=[CH:24][CH:25]=1)[CH2:5][O:6][C:7]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([CH2:17][C:18](OCC)=[O:19])[CH:13]=[N:14]2)=[CH:9][CH:8]=1.CCOCC.[NH3:31]>CO>[Cl:1][C:2]1[CH:3]=[C:4]([CH:23]=[CH:24][CH:25]=1)[CH2:5][O:6][C:7]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([CH2:17][C:18]([NH2:31])=[O:19])[CH:13]=[N:14]2)=[CH:9][CH:8]=1
Reactant: N
Reactant: CCOC(=O)Cc1cnc2cc(OCc3cccc(Cl)c3)ccc2c1
Solvent: CO
Solvent: CCOCC
Product: NC(=O)Cc1cnc2cc(OCc3cccc(Cl)c3)ccc2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Ethyl 2-(7-((3-chlorobenzyl)oxy)quinolin-3-yl)acetate (Example 51, 100 mg, 0.28 mmol) was dissolved in a 7N solution of ammonia in MeOH (40 mL) and stirred at ambient temperature overnight. The reaction mixture was concentrated under reduced pressure to afford a yellow solid. Et2O was added and the yellow precipitate was collected by filtration. DCM was added and the off white precipitate was isolated by filtration, this was repeated to yield the title compound as an off white solid (59 mg, 64%). 1H NMR (400 MHz, DMSO-d6) δ 8.74 (d, J=2.0 Hz, 1H), 8.14 (d, J=2.0 Hz, 1H), 7.92 (d, J=9.0 Hz, 1H), 7.64 (d, J=1.6 Hz, 2H), 7.57-7.44 (m, 4H), 7.37 (dd, J=2.7, 9.0 Hz, 1H), 7.08-7.02 (m, 1H), 5.34 (s, 2H), 3.60 (s, 2H). [M+H]=327.2.
Reaction SMILES: [CH3:1][C:2]([CH3:34])([CH2:5][C@@:6]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:11][C:10](=[O:12])[N:9]([C@H:13]([C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][C:24](=[O:27])[NH:23][CH:22]=3)=[CH:17][CH:16]=2)[CH3:14])[CH2:8][CH2:7]1)[C:3]#[N:4].C([O-])([O-])=O.[Cs+].[Cs+].[CH:41](I)([CH3:43])[CH3:42]>CN(C=O)C>[CH:41]([N:23]1[C:24](=[O:27])[CH:25]=[CH:26][C:21]([C:18]2[CH:19]=[CH:20][C:15]([C@@H:13]([N:9]3[CH2:8][CH2:7][C@:6]([CH2:5][C:2]([CH3:1])([CH3:34])[C:3]#[N:4])([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[O:11][C:10]3=[O:12])[CH3:14])=[CH:16][CH:17]=2)=[CH:22]1)([CH3:43])[CH3:42]
Reactant: CC(C)I
Reactant: C[C@@H](c1ccc(-c2ccc(=O)[nH]c2)cc1)N1CC[C@](CC(C)(C)C#N)(c2ccccc2)OC1=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)n1cc(-c2ccc([C@H](C)N3CC[C@](CC(C)(C)C#N)(c4ccccc4)OC3=O)cc2)ccc1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 30 %

Procedure:
2,2-dimethyl-3-((R)-2-oxo-3-((S)-1-(4-(6-oxo-1,6-dihydropyridin-3-yl)phenyl)ethyl)-6-phenyl-1,3-oxazinan-6-yl)propanenitrile (6 mg, 0.013 mmol) was dissolved in DMF (2.5 mL). Cs2CO3 (c.a. 15 mg, excess) and i-PrI (100 μL, excess) were added. The mixture was stirred for 3 h at rt. LC-MS found the reaction was complete. The mixture was purified by prep HPLC to afford 3-((R)-3-((S)-1-(4-(1-isopropyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl)ethyl)-2-oxo-6-phenyl-1,3-oxazinan-6-yl)-2,2-dimethylpropanenitrile (1.99 mg, 30%). LC-MS Method 1 tR=2.03 min, m/z=498; 1H NMR (CDCl3) 8.35(d, 1H), 7.80(dd, 1H), 7.37(m, 5H), 7.22(d, 2H), 6.92(d, 2H), 6.83(d, 1H), 5.66(q, 1H), 5.22(m, 1H), 2.93(m, 1H), 2.16(s, 2H), 1.55(d, 3H), 1.46(s, 3H), 1.40(d, 6H), 1.33(s, 3H).
Reaction SMILES: C[O:2][C:3]([C:5]1[N:9]([NH2:10])[C:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:7][CH:6]=1)=O.[CH:16]([NH2:18])=O>O>[CH2:14]([O:13][C:11]([C:8]1[N:9]2[C:5]([C:3](=[O:2])[NH:18][CH:16]=[N:10]2)=[CH:6][CH:7]=1)=[O:12])[CH3:15]
Reactant: NC=O
Reactant: CCOC(=O)c1ccc(C(=O)OC)n1N
Solvent: O
Product: CCOC(=O)c1ccc2c(=O)[nH]cnn12
Temperature: 140 °C
Reaction time: 8 h

Procedure:
A mixture of 1-amino-1H-pyrrole-2,5-dicarboxylic acid 2-ethyl ester 5-methyl ester (140 mg) and formamide (1 mL) was stirred at 140° C. overnight. The reaction mixture was then cooled and diluted with water, the solid which crashed out was collected by filtration and dried under vacuum to give 60 mg of 4-oxo-3,4-dihydro-pyrrolo[2,1-f][1,2,4]triazine-7-carboxylic acid ethyl ester.
Reaction SMILES: [CH3:1][Si:2]([CH3:16])([CH3:15])[C:3]1[CH:8]=[CH:7][C:6]([CH:9](Br)Br)=[C:5]([CH:12](Br)Br)[CH:4]=1.[I-].[Na+].[CH3:19][C:20]([CH3:22])=[O:21]>C(#N)C>[CH3:1][Si:2]([CH3:16])([CH3:15])[C:3]1[CH:4]=[C:5]2[C:6](=[CH:7][CH:8]=1)[CH:9]=[C:22]1[C:19]([C:20](=[O:21])[C:22]3[CH:8]=[CH:3][CH:4]=[CH:5][C:19]=3[C:20]1=[O:21])=[CH:12]2
Reactant: CC(C)=O
Reactant: C[Si](C)(C)c1ccc(C(Br)Br)c(C(Br)Br)c1
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Product: C[Si](C)(C)c1ccc2cc3c(cc2c1)C(=O)c1ccccc1C3=O
Yield: 79 %

Procedure:
A mixture of 0.1 mol of 4-trimethylsilyl-1,2-bisdibromomethylbenzene, 0.12-0.2 mol of substituted naphthoquinone, 0.6 mol of sodium iodide and 1000 ml of acetone or acetonitrile is boiled under reflux for 5 hours with stirring and under an N2 atomosphere. After cooling, the precipitate which has been deposited is filtered off and digested with water. The filtrate obtained in this way is evaporated to dryness and the residue is dissolved in CH2Cl2, washed with NaHSO3 and dried. The residue is then subjected to steam distillation and the non-volatile fractions are extracted with ether, dried and then sublimed. 8-Trimethylsilylnaphthacene-5,12-dione of melting point 168°-170° C. is obtained in a 79% yield. 2,3-Trifluoromethyl-8-methoxynaphthacene-5,12-dione is obtained in a 33% yield in an analogous manner by direct sublimation of the filtrate, melting point>280° C.
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[CH2:3][NH:4][C:5]([NH:7][C:8]1[CH:9]=[C:10]([N:14]2[C:18]3[CH:19]=[CH:20][C:21]([C:23]4[CH:28]=[CH:27][C:26]([CH:29]([CH3:33])[C:30]([OH:32])=O)=[CH:25][CH:24]=4)=[CH:22][C:17]=3[N:16]=[CH:15]2)[CH:11]=[CH:12][CH:13]=1)=[O:6].CN.F[P-](F)(F)(F)(F)F.[N:45]1(O[P+](N(C)C)(N(C)C)N(C)C)[C:49]2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>C1COCC1.CN(C)C=O.CO>[CH3:49][NH:45][C:30](=[O:32])[CH:29]([C:26]1[CH:25]=[CH:24][C:23]([C:21]2[CH:20]=[CH:19][C:18]3[N:14]([C:10]4[CH:11]=[CH:12][CH:13]=[C:8]([NH:7][C:5]([NH:4][CH2:3][C:2]([F:35])([F:1])[F:34])=[O:6])[CH:9]=4)[CH:15]=[N:16][C:17]=3[CH:22]=2)=[CH:28][CH:27]=1)[CH3:33]
Reactant: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Reactant: CC(C(=O)O)c1ccc(-c2ccc3c(c2)ncn3-c2cccc(NC(=O)NCC(F)(F)F)c2)cc1
Agent: CN
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CNC(=O)C(C)c1ccc(-c2ccc3c(c2)ncn3-c2cccc(NC(=O)NCC(F)(F)F)c2)cc1
Temperature: 25 °C

Procedure:
To a solution of 2-(4-{1-[3-({[(2,2,2-trifluoroethyl)amino]carbonyl}amino)phenyl]-1H-benzimidazol-5-yl}phenyl)propanoic acid (20.0 mg, 0.0414 mmol) and 2.0 M methylamine in THF (41 μL, 0.083 mmol, Aldrich, Cat. No. 395056) in N,N-dimethylformamide (1 mL) was added benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (23 mg, 0.053 mmol, Adv. ChemTech. Cat. No. RC8105) and N,N-diisopropylethylamine (23 μL, 0.13 mmol). The reaction mixture was stirred at r.t. 2 h., then diluted with MeOH, and purified by RP-HPLC (pH=10) to afford the desired compound. LCMS (M+H)+: m/z=496.2.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([OH:11])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.CC(C)([O-])C.[K+].[Cl:18][C:19]1[C:20](F)=[CH:21][C:22]([F:28])=[C:23]([CH:27]=1)[C:24]([OH:26])=[O:25]>CS(C)=O>[O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([O:11][C:20]3[C:19]([Cl:18])=[CH:27][C:23]([C:24]([OH:26])=[O:25])=[C:22]([F:28])[CH:21]=3)[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1
Reactant: O=C(O)c1cc(Cl)c(F)cc1F
Reactant: OC1CCC2(CC1)OCCO2
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: O=C(O)c1cc(Cl)c(OC2CCC3(CC2)OCCO3)cc1F
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 21 %

Procedure:
To a solution of 1,4-dioxaspiro[4.5]decan-8-ol (12.90 g, 81.50 mmol) in dimethylsulfoxide (800 mL) was added potassium tert-butoxide (21.00 g, 187.00 mmol). The reaction mixture was stirred at ambient temperature for 15 minutes under nitrogen. To this mixture was added 5-chloro-2,4-difluorobenzoic acid (15.70 g, 81.70 mmol). The mixture was stirred at ambient temperature for 3 days, after which it was split into two equal portions. Each portion was diluted with ethyl acetate (700 mL), washed with 1 M hydrochloric acid (700 mL), a 1:1 mixture of 1 M hydrochloric acid and brine (700 mL), and brine (700 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to dryness. The residue was purified by column chromatography with a gradient of a solution of 0.2% acetic acid in ethyl acetate and hexanes from 0-50%, to afford the title compound as a light yellow solid (5.66 g, 21%): 1H NMR (300 MHz, CDCl3) δ 9.24 (br s, 1H), 8.01 (d, J=7.7 Hz, 1H), 6.69 (d, J=12.4 Hz, 1H), 4.54-4.51 (m, 1H), 3.97-3.95 (m, 4H), 2.06-1.93 (m, 4H), 1.81-1.74 (m, 1H), 1.70-1.51 (m, 3H); MS (ES−) m/z 329.1, 331.1 (M−1).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:17][CH:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)[C:9]([NH:11][C:12]2[S:13][CH:14]=[CH:15][N:16]=2)=[O:10])=[CH:4][CH:3]=1.[CH3:23][S:24](Cl)(=[O:26])=[O:25]>N1C=CC=CC=1>[CH:18]1([CH2:17][CH:8]([C:5]2[CH:4]=[CH:3][C:2]([NH:1][S:24]([CH3:23])(=[O:26])=[O:25])=[CH:7][CH:6]=2)[C:9]([NH:11][C:12]2[S:13][CH:14]=[CH:15][N:16]=2)=[O:10])[CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: CS(=O)(=O)Cl
Reactant: Nc1ccc(C(CC2CCCC2)C(=O)Nc2nccs2)cc1
Solvent: c1ccncc1
Product: CS(=O)(=O)Nc1ccc(C(CC2CCCC2)C(=O)Nc2nccs2)cc1
Temperature: 25 °C
Reaction time: 7 h
Yield: 49.9 %

Procedure:
A solution of 2-(4-amino-phenyl)-3-cyclopentyl-N-thiazol-2-yl-propionamide (prepared in Example 3, 158 mg, 0.5 mmol) in pyridine (5 mL) at 25° C. was treated with methanesulfonyl chloride (50 μL, 0.57 mmol ). The reaction was stirred at 25° C. for 7 h and was then concentrated in vacuo. High pressure liquid chromatography (Chromegasphere SI-60, 10 μM, 60 Å, 25 cm×23 cm ID, 40/60 heptane/ethyl acetate) afforded 3-cyclopentyl-2-(4-methanesulfonylamino-phenyl)-N-thiazol-2-yl-propionamide (98.2 mg, 49.9%) as a tan solid: mp 85-90° C.; EI-HRMS m/e calcd for C18H23N3O3S (M+) 393.1180, found 393.1185.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5][C:4](=[O:12])[CH:3]=1.[N+:13]([O-])([OH:15])=[O:14]>C(O)(=O)C>[OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5][C:4](=[O:12])[C:3]=1[N+:13]([O-:15])=[O:14]
Reactant: O=c1cc(O)c2ccccc2[nH]1
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Product: O=c1[nH]c2ccccc2c(O)c1[N+](=O)[O-]
Temperature: 95 °C

Procedure:
A suspension of 4-hydroxycarbostyril (1.5g; 0.0093 mole) in glacial acetic acid (10 ml) was well stirred during the addition of concentrated nitric acid (2.5 ml, d, 1.42) and the mixture shaken at 95°C for a few minutes until dissolution was complete. The deep red solution soon deposited yellow crystals which after cooling were filtered off and washed with acetic acid and then ethanol. Drying in vacuo over phosphorous pentoxide afforded analytically pure 3-nitro compound m.p. 216°C (decomp) (Found C, 52.74; H, 3.14; N, 13.57; C9H6N2O4 required; C, 52.44; H, 2.93; N, 13.59%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[CH2:11][C:12]([C:14]1[C:19]([O:20][CH3:21])=[CH:18][C:17]([O:22][CH3:23])=[CH:16][C:15]=1[O:24]C)=[O:13].[Al+3].[Cl-].[Cl-].[Cl-].Cl>ClC(Cl)C>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[CH2:11][C:12]([C:14]1[C:19]([O:20][CH3:21])=[CH:18][C:17]([O:22][CH3:23])=[CH:16][C:15]=1[OH:24])=[O:13]
Reactant: COc1ccc(CC(=O)c2c(OC)cc(OC)cc2OC)c(OC)c1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CC(Cl)Cl
Product: COc1ccc(CC(=O)c2c(O)cc(OC)cc2OC)c(OC)c1
Temperature: 60 °C
Reaction time: 0.25 h
Yield: 67.9 %

Procedure:
A solution of compound 6 (3.2 g, 9.3 mmol) and AICI3 (1.4 g, 10.2 mmol) in dichloroethane (30 mL) was heated to 60° C. for 15 minutes and additional AlCl3 (1.3 g) was added followed by an additional 15 minutes of heating at 60° C. The reaction was cooled and poured into 2 N HCl aq. The layers were separated and the organic phase was dried and concentrated to give a solid which was triturated with MeOH to give a white solid (2.1 g): Mp 116-119° C.; 1H NMR (CDCl3) δ 13.9 (s, 1H), 7.00 (d, 1H, J=8.0 Hz), 6.50-6.45 (m, 2H), 6.08 (d, 1H, J=2.4 Hz), 5.95 (d, 1H, J=2.4 Hz), 4.24 (s, 2H), 3.87 (s, 3H), 3.83 (s, 3H), 3.81 (s, 3H) 3.76 (s, 3H); MS FI 333 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@H:10]1[O:12][CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:13]([Mg]Cl)[CH:14]=[CH2:15].O>C1COCC1>[CH2:1]([O:8][CH2:9][C@H:10]([OH:12])[CH2:11][CH2:15][CH:14]=[CH2:13])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(COC[C@@H]2CO2)cc1
Reactant: C=CC[Mg]Cl
Solvent: C1CCOC1
Solvent: O
Product: C=CCC[C@@H](O)COCc1ccccc1
Temperature: 25 °C
Yield: 34.6 %

Procedure:
To a stirred solution of benzyl-(S)-glycidyl ether (5.0 g, 30.5 mmol) in THF (100 ml) was added allylmagnesium chloride (1.0 M in Et2O, 30.5 ml, 30.5 mmol) at −78° C., and the resulting mixture was gradually warmed up to rt with stirring. The mixture was poured into water and concentrated in vacuo, then extracted with CHCl3. The organic layer was dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was chromatographed on silica gel with hexane-EtOAc (5:1) as eluent to give 1-benzyloxy-2-(R)-hydroxy-5-hexene (2.18 g, 35%) as a colorless oil: 1H-NMR (CDCl3) δ 1.52–1.60 (m, 2 H), 2.11–2.25 (m, 2 H), 2.34 (d, J=3.2 Hz, 1 H), 3.35 (dd, J=9.6, 8.0 Hz, 1 H), 3.52 (dd, J=9.6, 3.2 Hz, 1 H), 3.84–3.86 (m, 1 H), 4.57.(s, 2 H), 4.96–5.07 (series of m, 2 H), 5.78–5.88 (m, 1 H), 7.29–7.38 (m, 5 H); MS (ESI) m/z, 224 (M++NH4+).
Reaction SMILES: [C:1]([O:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][S:14]([CH2:17][CH2:18][C:19]([NH:22]C(=O)OCC1C=CC=CC=1)([CH3:21])[CH3:20])(=[O:16])=[O:15])([CH3:4])([CH3:3])[CH3:2]>CO.[Pd]>[C:1]([O:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][S:14]([CH2:17][CH2:18][C:19]([CH3:21])([NH2:22])[CH3:20])(=[O:16])=[O:15])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(CCS(=O)(=O)CCOCCOCCOC(C)(C)C)NC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: CC(C)(N)CCS(=O)(=O)CCOCCOCCOC(C)(C)C
Reaction time: 2 h

Procedure:
A solution of benzyl 4-(2-(2-(2-tert-butoxyethoxy)ethoxy)ethylsulfonyl)-2-methylbutan-2-ylcarbamate (79.5 mg, 0.168 mmol) in MeOH (2 ml) was put under a N2 atmosphere and 10% Pd/C (30 mg) was added. A H2 atmosphere (1.3 atm) was added, and the slurry stirred for 2 h. The suspension was filtered (0.45 um PTFE) and the solution concentrated in vacuo. The residue was used without further purification. LRMS (ESI/APCI): 340 [M+H]+.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[N:7]=[C:6]([C@H:8]([CH2:17][CH2:18][CH2:19][CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)[CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[O:5][N:4]=1.Br[CH2:27][C:28]([NH2:30])=[O:29]>CCN(CC)CC>[NH2:30][C:28](=[O:29])[CH2:27][NH:1][CH2:2][C:3]1[N:7]=[C:6]([C@H:8]([CH2:17][CH2:18][CH2:19][CH:20]2[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]2)[CH2:9][C:10]([O:12][C:13]([CH3:15])([CH3:16])[CH3:14])=[O:11])[O:5][N:4]=1
Reactant: NC(=O)CBr
Reactant: CC(C)(C)OC(=O)C[C@@H](CCCC1CCCCC1)c1nc(CN)no1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)C[C@@H](CCCC1CCCCC1)c1nc(CNCC(N)=O)no1

Procedure:
Method as for preparation 106 using tert-butyl (3R)-3-[3-(aminomethyl)-1,2,4-oxadiazol-5-yl]-6-cyclohexylhexanoate (preparation 18) (250 mg, 0.71 mmol) and 2-bromoacetamide (98 mg, 0.71 mmol) as starting materials and Et3N as the base.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][CH2:10][C:11]([OH:13])=O.[N:14]1C=CC=CC=1.C(OC(OC(C)(C)C)=O)(OC(C)(C)C)=O.C(=O)([O-])O.[NH4+]>C(#N)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][CH2:10][C:11]([NH2:14])=[O:13]
Reactant: COc1ccccc1CCC(=O)O
Reactant: c1ccncc1
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [NH4+]
Solvent: CC#N
Product: COc1ccccc1CCC(N)=O
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
3-(2-methoxyphenyl)propionic acid (9.0 g, 49.9 mmol) was dissolved in acetonitrile (10 mL). Subsequently, pyridine (3.54 g, 44.9 mmol) and di-tert-butyl dicarbonate [Boc2O (16.3 g, 74.85 mmol)] were added thereto. The mixture was stirred for 10 minutes at room temperature, and then ammonium hydrogencarbonate (5.92 g, 74.9 mmol) were added. After completion of reaction, the reaction mixture was concentrated under reduced pressure. Thereafter, the resultant concentrate was added to water, and the resultant mixture was extracted with chloroform, followed by washing sequentially with 1M hydrochloric acid and saturated brine. The resultant mixture was subjected to drying over magnesium sulfate and concentration under reduced pressure. The resultant concentrate was used in Production Example 36 without purification.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[C:4](=[N:29][S:30][N:31]=2)[CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]1[N:13]([C:21]3[C:26]([Cl:27])=[CH:25][CH:24]=[CH:23][N:22]=3)[N:14]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:16]=1)[O:8][C:7]2=[O:28].[CH:32]1([CH2:35][NH2:36])[CH2:34][CH2:33]1>>[CH:32]1([CH2:35][NH:36][C:7]([C:6]2[C:11]([NH:10][C:9]([C:12]3[N:13]([C:21]4[C:26]([Cl:27])=[CH:25][CH:24]=[CH:23][N:22]=4)[N:14]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:16]=3)=[O:8])=[C:2]([Cl:1])[C:3]3[C:4]([CH:5]=2)=[N:29][S:30][N:31]=3)=[O:28])[CH2:34][CH2:33]1
Reactant: NCC1CC1
Reactant: O=c1oc(-c2cc(C(F)(F)F)nn2-c2ncccc2Cl)nc2c(Cl)c3nsnc3cc12
Product: O=C(NCC1CC1)c1cc2nsnc2c(Cl)c1NC(=O)c1cc(C(F)(F)F)nn1-c1ncccc1Cl

Procedure:
See step f) of example H2 using 4-chloro-6-[2-(3-chloro-pyridin-2-yl)-5-trifluoromethyl-2H-pyrazol-3-yl]-7-oxa-2-thia-1,3,5-triaza-cyclopenta[b]naphthalen-8-one as starting material and cyclopropanemethylamine. After 18 hours reaction and chromatography column purification, a slightly brown solid is obtained (85%). LC/MS: 556/558 (M+1)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH2:8])[CH:3]=1.[I:9]N1C(=O)CCC1=O>C(O)(=O)C>[Cl:1][C:2]1[C:7]([I:9])=[CH:6][N:5]=[C:4]([NH2:8])[CH:3]=1
Reactant: Nc1cc(Cl)ccn1
Reactant: O=C1CCC(=O)N1I
Solvent: CC(=O)O
Product: Nc1cc(Cl)c(I)cn1
Temperature: 80 °C
Yield: 66.8 %

Procedure:
4-Chloropyridin-2-amine (0.142 g, 1.10 mmol) and N-iodosuccinimide (0.273 g, 1.22 mmol) were combined in 1.5 mL of acetic acid. The solution was sonicated briefly and then heated to 80° C. After 1 hour the solution was cooled to room temperature and then concentrated under vacuum. After adjusting the pH to ˜ 8/9 with aqueous ammonia, a light brown solid was collected by filtration. The solid was purified on a 12 g Combiflash column eluting with a gradient of DCM to 5% methanol/0.25% NH4OH (˜28% in water)/DCM. The fractions containing the product were combined and concentrated under vacuum to give 4-chloro-5-iodopyridin-2-amine (187 mg, 67%) as an off-white solid. 1H NMR (500 MHz, DMSO-d6) δ ppm 8.20 (1 H, s), 6.69 (1 H, s), 6.40 (2 H, s); LCMS-ESI (POS), M/Z, M+1: Found 254.9.