Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]12[CH2:9][CH2:8][CH2:7][C:6]1=[N:5][CH2:4][CH2:3][CH2:2]2.[Cl:10][C:11]1[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=1[CH2:13]Cl.[H-].[Al+3].[Li+].[H-].[H-].[H-].[OH-].[Na+]>O1CCCC1.O>[Cl:10][C:11]1[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=1[CH2:13][N:5]1[CH:6]2[N:1]([CH2:9][CH2:8][CH2:7]2)[CH2:2][CH2:3][CH2:4]1
Reactant: C1CN=C2CCCN2C1
Reactant: ClCc1ccccc1Cl
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: Clc1ccccc1CN1CCCN2CCCC21
Temperature: 0 °C

Procedure:
In a 250 ml three-necked flask, 5 g (0.04 mol) of 1,5-diazabicyclo[4.3.0]non-5-ene are dissolved in 100 ml of tetrahydrofuran, and at room temperature 6.48 g (0.04 mol) of 2-chlorobenzyl chloride are slowly added with stirring. A colourless suspension is formed which is stirred overnight. The suspension is then filtered, the salt isolated by filtration is washed, and the washed salt is suspended in 100 ml of tetrahydrofuran. Added to this suspension in portions is 0.76 g (0.02 mol) of lithium aluminium hydride. After the end of the addition, the reaction mixture is stirred at room temperature overnight. It is then cooled to 0° C. and, dropwise, 0.8 g of water, then 0.8 g of 10% strength sodium hydroxide solution and a further 2.4 g of water are added. The resulting suspension is stirred at room temperature for 30 minutes and then filtered. The filter cake is washed with tetrahydrofuran and the combined organic phases are dried and concentrated on a rotary evaporator. This gives 7.15 g of 5-(2-chlorobenzyl)-1,5-diazabicyclo[4.3.0]nonane as a colourless oil.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:10]=[C:9]([C:11]2[O:12][CH:13]=[CH:14][CH:15]=2)[N:8]([CH2:16][C:17]2[CH:21]=[C:20]([C:22]3[S:23][C:24]([Cl:27])=[CH:25][CH:26]=3)[O:19][N:18]=2)[N:7]=1)=[O:5])C.Cl>C1COCC1.O.[OH-].[Na+]>[Cl:27][C:24]1[S:23][C:22]([C:20]2[O:19][N:18]=[C:17]([CH2:16][N:8]3[C:9]([C:11]4[O:12][CH:13]=[CH:14][CH:15]=4)=[CH:10][C:6]([C:4]([OH:5])=[O:3])=[N:7]3)[CH:21]=2)=[CH:26][CH:25]=1
Reactant: CCOC(=O)c1cc(-c2ccco2)n(Cc2cc(-c3ccc(Cl)s3)on2)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1cc(-c2ccco2)n(Cc2cc(-c3ccc(Cl)s3)on2)n1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 400 mg 1-[5-(5-Chloro-thiophen-2-yl)-isoxazol-3-ylmethyl]-5-furan-2-yl-1H-pyrazole-3-carboxylic acid ethyl ester in 5 ml THF and 1 ml water, 1 ml aqueous NaOH (1M) were added and the mixture was stirred for 16 h at RT. Then the solution was acidified to pH 3 with half concentrated hydrochloric acid to precipitate the pure product, which was collected by filtration. Yield: 360 mg.
Reaction SMILES: Cl.[C:2]([O:6][CH:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1)([CH3:5])([CH3:4])[CH3:3].C(N(CC)CC)C.[O:20]=[C:21]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:24]([CH2:31][C:32]2[CH:37]=[CH:36][N:35]=[C:34]([C:38](O)=[O:39])[CH:33]=2)=[N:23][NH:22]1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1>CN(C)C=O>[C:2]([O:6][CH:7]1[CH2:12][CH2:11][N:10]([C:38]([C:34]2[CH:33]=[C:32]([CH2:31][C:24]3[C:25]4[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=4)[C:21](=[O:20])[NH:22][N:23]=3)[CH:37]=[CH:36][N:35]=2)=[O:39])[CH2:9][CH2:8]1)([CH3:5])([CH3:3])[CH3:4]
Reactant: O=C(O)c1cc(Cc2n[nH]c(=O)c3ccccc23)ccn1
Reactant: CC(C)(C)OC1CCNCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)OC1CCN(C(=O)c2cc(Cc3n[nH]c(=O)c4ccccc34)ccn2)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 55.6 %

Procedure:
A solution of 4-tert-butoxypiperidine hydrochloride (227 mg, 1.17 mmol) and triethylamine (0.327 mL, 2.35 mmol) in N,N-dimethlformamide (3 mL) was added in one portion to a stirred solution of 4-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)picolinic acid (5) (300 mg, 1.07 mmol), Triethylamine (0.327 mL, 2.35 mmol) and O-Benzotriazol-1-yl-N,N,N′,N′-tetra-methyluronium hexafluorophosphate (607 mg, 1.60 mmol) in N,N-dimethlformamide (3 mL) at 25° C. The resulting solution was stirred at 25° C. for 4 hours, then The crude mixture was purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5μ silica, 30 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing 1% NH3) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness and lyophilised to afford the desired compound as a solid (250 mg, 55.7% yield); 1H NMR (400.132 MHz, DMSO) δ 1.15 (9H, s), 1.25-1.40 (2H, m), 1.56-1.63 (1H, m), 1.71-1.79 (1H, m), 3.08-3.23 (2H, m), 3.44-3.50 (1H, m), 3.71-3.78 (1H, m), 4.01-4.08 (1H, m), 4.40 (2H, s), 7.39 (1H, dd), 7.48-7.49 (1H, m), 7.83-7.87 (1H, m), 7.90 (1H, td), 7.94-7.97 (1H, m), 8.28 (1H, dd), 8.46-8.48 (1H, m), 12.60 (1H, s); m/z (LC-MS, ESI+), RT=1.67 (M+H 421.5).
Reaction SMILES: C#CCC.[CH2:5]([C:15]1[CH:24]=[C:23]2[C:18]([CH:19]=[CH:20][C:21]([O:25][CH3:26])=[CH:22]2)=[CH:17][CH:16]=1)[CH2:6][CH2:7][CH2:8]CCCCCC.C1(C)C=CC=CC=1>CCCCCC>[C:5]([C:15]1[CH:24]=[C:23]2[C:18]([CH:19]=[CH:20][C:21]([O:25][CH3:26])=[CH:22]2)=[CH:17][CH:16]=1)#[C:6][CH2:7][CH3:8]
Reactant: CCCCCCCCCCc1ccc2ccc(OC)cc2c1
Agent: C#CCC
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: CCC#Cc1ccc2ccc(OC)cc2c1
Yield: 56 %

Procedure:
Using 7-methoxy-2-naphthyltrifluoromethanesulfonate (30.63 g, 0.10 mol) and butyne gas (a product manufactured by TOKYO CHEMICAL INDUSTRY CO., LTD., 100 g, large excess), 7-butyn-1-yl-2-methoxynaphthalene was synthesized by the same operation as that in the method for synthesizing 7-decyl-2-methoxynaphthalene according to Example 3, and subjected to column chromatography (silica gel, developed with a mixture of toluene and hexane) to obtain a light yellow oil product of 7-butyn-1-yl-2-methoxynaphthalene (18.1 g, yield of 56%). The obtained 7-butyn-1-yl-2-methoxynaphthalene (total amount) was subjected to catalytic reduction in toluene (275 ml) under a hydrogen atmosphere by adding 10% Pd/C (1.83 g). The obtained product was subjected to column chromatography (silica gel, developed with a mixture of toluene and hexane) to obtain 7-butyl-2-methoxynaphthalene (compound (3)-04, 17.80 g, yield of 97%).
Reaction SMILES: C1(COC(=O)[N:7]([CH2:24][CH:25]2[CH2:27][CH2:26]2)[C:8]2[S:12][C:11]([CH3:13])=[N:10][C:9]=2[C:14](=[O:23])[NH:15][C:16]2[CH:21]=[CH:20][N:19]=[C:18]([CH3:22])[N:17]=2)CC1>FC(F)(F)C(O)=O.C(=O)(O)[O-].[Na+]>[CH3:22][C:18]1[N:17]=[C:16]([NH:15][C:14]([C:9]2[N:10]=[C:11]([CH3:13])[S:12][C:8]=2[NH:7][CH2:24][CH:25]2[CH2:27][CH2:26]2)=[O:23])[CH:21]=[CH:20][N:19]=1
Reactant: Cc1nccc(NC(=O)c2nc(C)sc2N(CC2CC2)C(=O)OCC2CC2)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: Cc1nccc(NC(=O)c2nc(C)sc2NCC2CC2)n1
Temperature: 50 °C
Reaction time: 3 h
Yield: 53.7 %

Procedure:
Cyclopropylmethyl-[2-methyl-4-(2-methyl-pyrimidin-4-ylcarbamoyl)-thiazol-5-yl]-carbamic acid cyclopropylmethyl ester (example 205, 0.091 g, 0.227 mmol) was dissolved in 1 mL trifluoroacetic acid and stirred at 50° C. for 3 h. The reaction mixture was diluted with 20 mL saturated sodium bicarbonate solution and extracted three times with ethyl acetate (30 mL each). The organic phases were pooled, dried with sodium sulfate and evaporated. The crude product was flash-chromatographed on silica gel with heptane/ethyl acetate 100:0→0:100 gradient to yield the desired compound as a white solid (37 mg, 54%), MS (ISP): m/e=304.0 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([Cl:12])[CH:7]=1)=O.O.[NH2:21][NH2:22]>C(O)COCCO>[NH2:1][C:2]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][C:3]=1[C:4](=[N:21][NH2:22])[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([Cl:12])[CH:7]=1
Reactant: Nc1ccc([N+](=O)[O-])cc1C(=O)c1cccc(Cl)c1
Reactant: NN
Solvent: OCCOCCO
Solvent: O
Product: NN=C(c1cccc(Cl)c1)c1cc([N+](=O)[O-])ccc1N

Procedure:
In the manner given in Preparation 1, 2-amino-3'-chloro-5-nitrobenzophenone is refluxed with hydrazine hydrate in diethylene glycol to give 2-amino-3'-chloro-5-nitrobenzophenone hydrazone.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[Si:11]([O:18][C@@H:19]1[C@@H:24]([CH3:25])[CH2:23][NH:22][CH2:21][C@H:20]1[NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12].CCN(C(C)C)C(C)C>C(O)(C)C>[Si:11]([O:18][C@@H:19]1[C@@H:24]([CH3:25])[CH2:23][N:22]([C:2]2[CH:7]=[CH:6][N:5]=[CH:4][C:3]=2[N+:8]([O-:10])=[O:9])[CH2:21][C@H:20]1[NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])([C:14]([CH3:17])([CH3:15])[CH3:16])([CH3:13])[CH3:12]
Reactant: C[C@H]1CNC[C@@H](NC(=O)OC(C)(C)C)[C@@H]1O[Si](C)(C)C(C)(C)C
Reactant: O=[N+]([O-])c1cnccc1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: C[C@H]1CN(c2ccncc2[N+](=O)[O-])C[C@@H](NC(=O)OC(C)(C)C)[C@@H]1O[Si](C)(C)C(C)(C)C
Temperature: 100 °C
Reaction time: 4 h
Yield: 679.1 %

Procedure:
A mixture of 4-chloro-3-nitropyridine (96.6 mg, 0.609 mmol), tert-butyl ((3R,4R,5S)-4-{[tert-butyl(dimethyl)silyl]oxy}-5-methylpiperidin-3-yl)carbamate (300 mg, 0.609 mmol) and DIPEA (0.319 mL, 1.83 mmol) in isopropyl alcohol (20 mL) was stirred at 100° C. for 4 h. The reaction mixture was concentrated under reduced pressure. The resulting residue was purified by flash chromatography on silica using a CombiFlash® apparatus (eluting with 0 to 30% EtOAc in hexanes) to give the sub-title compound as a pale yellow powder (1.93 g). LCMS calc. for C22H39N4O5Si (M+H)+: m/z=467.3. found: 467.1.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][C:13]([NH:17][C:18]3[C:27]4[C:22](=[CH:23][CH:24]=[CH:25][C:26]=4[O:28][CH2:29][C:30](OC)=[O:31])[N:21]=[CH:20][N:19]=3)=[CH:14][CH:15]=2)[CH:10]=[N:9]1.[NH:34]1[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1>>[N:34]1([C:30](=[O:31])[CH2:29][O:28][C:26]2[CH:25]=[CH:24][CH:23]=[C:22]3[C:27]=2[C:18]([NH:17][C:13]2[CH:12]=[C:11]4[C:16](=[CH:15][CH:14]=2)[N:8]([CH2:7][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)[N:9]=[CH:10]4)=[N:19][CH:20]=[N:21]3)[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1
Reactant: C1COCCN1
Reactant: COC(=O)COc1cccc2ncnc(Nc3ccc4c(cnn4Cc4ccccn4)c3)c12
Product: O=C(COc1cccc2ncnc(Nc3ccc4c(cnn4Cc4ccccn4)c3)c12)N1CCOCC1
Yield: 58 %

Procedure:
Using the same procedure as in Example 5, methyl [(4-{[1-(pyridin-2-ylmethyl)-1H-indazol-5-yl]amino}quinazolin-5-yl)oxy]acetate (180 mg, 0.40 mmol) was reacted with morpholine (0.346 ml, 3.96 mmol) to give the title compound as a solid (115 mg, 59%), except that the reaction was run at 60° C. for 32 hours in the presence of 3 Å molecular sieve. NMR Spectrum 3.68-3.52 (m, 8H), 5.20 (s, 2H), 5.77 (s, 2H), 6.96 (d, 1H), 7.23 (d, 1H), 7.30 (m, 1H), 7.37 (d, 1H), 7.77-7.68 (m, 3H), 7.90 (m, 1H), 8.15 (s, 1H), 8.53 (s, 2H), 8.56 (s, 1H), 11.18 (br s, 1H); Mass spectrum MH+ 496.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([O:12][Si:13]([CH:20]([CH3:22])[CH3:21])([CH:17]([CH3:19])[CH3:18])[CH:14]([CH3:16])[CH3:15])[CH:11]=1)[N:8]=[C:7]([CH:23]=[N:24][NH:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=1)[CH:6]=[CH:5]2.C(O)(=O)C.C(O)(=O)C.IC1C=CC=CC=1>ClCCl>[N:25]1[N:24]=[C:23]([C:7]2[CH:6]=[CH:5][C:4]3[C:9](=[C:10]([O:12][Si:13]([CH:20]([CH3:21])[CH3:22])([CH:17]([CH3:18])[CH3:19])[CH:14]([CH3:15])[CH3:16])[CH:11]=[C:2]([F:1])[CH:3]=3)[N:8]=2)[N:27]2[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=12
Reactant: CC(C)[Si](Oc1cc(F)cc2ccc(C=NNc3ccccn3)nc12)(C(C)C)C(C)C
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: Ic1ccccc1
Product: CC(C)[Si](Oc1cc(F)cc2ccc(-c3nnc4ccccn34)nc12)(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 24 h
Yield: 93.6 %

Procedure:
6-Fluoro-2-((2-(pyridin-2-yl)hydrazono)methyl)-8-(triisopropylsilyloxy)quinoline (10 g, 23 mmol) was weighed into a 1000 mL 1 neck round bottom flask, followed by addition of iodo benzene diacetate (8.1 g, 25 mmol) and 400 mL of dichloromethane. The mixture was stirred at ambient temperature for 24 hours, at which time the reaction was complete. The crude mixture was partitioned with Na2S2O3, back extracted with DCM, and the combined organics were washed with brine and dried over sodium sulfate, then concentrated in vacuo. The crude product was the purified by flash column chromatography (SP1 Biotage Horizon, 1-15% MeOH/DCM gradient elution), affording the desired product (9.4 g, 94% yield) as a white powder.
Reaction SMILES: [N:1]([CH2:4][C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]=[C:10]([N:18]2[CH2:24][CH2:23][CH2:22][C:21]3[CH:25]=[CH:26][CH:27]=[CH:28][C:20]=3[CH2:19]2)[CH:9]=1)=[O:6])=[N+]=[N-]>CO.[Pd]>[CH2:19]1[C:20]2[CH:28]=[CH:27][CH:26]=[CH:25][C:21]=2[CH2:22][CH2:23][CH2:24][N:18]1[C:10]1[CH:9]=[C:8]([NH:7][C:5](=[O:6])[CH2:4][NH2:1])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]=1
Reactant: [N-]=[N+]=NCC(=O)Nc1cc(N2CCCc3ccccc3C2)nc2ccccc12
Agent: [Pd]
Solvent: CO
Product: NCC(=O)Nc1cc(N2CCCc3ccccc3C2)nc2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 50.9 %

Procedure:
To a solution of 2-azido-N-[2-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)quinolin-4-yl]acetamide (65 mg, 0.17 mmol) in methanol was added palladium (10% on carbon, 7 mg). After being stirred at room temperature overnight under a hydrogen atmosphere, the resulting mixture was filtered. The filtrate was concentrated in vacuo and the residue was purified by preparative HPLC to afford 30 mg of product as a white powder (yield was 60.5%). MS obsd. (ESI+) [(M+H)+] 347. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.08 (s, 1 H), 7.78 (d, J=8.0 Hz, 1 H), 7.55-7.49 (m, 3 H), 7.23-7.20 (m, 1 H), 7.15-7.08 (m, 3 H), 4.79 (s, 2 H), 4.13 (brs, 2 H), 3.45 (brs, 2 H), 3.04 (brs, 2 H), 1.79 (brs, 2 H).
Reaction SMILES: [ClH:1].O1CCOCC1.OC(C(F)(F)F)=O.[C:15]1([C:21]2[O:25][C:24]([C:26]([N:28]3[CH2:33][CH2:32][N:31](C(OC(C)(C)C)=O)[CH2:30][CH:29]3[CH2:41][O:42][C:43]3[CH:44]=[N:45][CH:46]=[CH:47][CH:48]=3)=[O:27])=[CH:23][CH:22]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[ClH:1].[ClH:1].[C:15]1([C:21]2[O:25][C:24]([C:26]([N:28]3[CH2:33][CH2:32][NH:31][CH2:30][CH:29]3[CH2:41][O:42][C:43]3[CH:44]=[N:45][CH:46]=[CH:47][CH:48]=3)=[O:27])=[CH:23][CH:22]=2)[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)c2ccc(-c3ccccc3)o2)C(COc2cccnc2)C1
Agent: Cl
Solvent: C1COCCO1
Solvent: O=C(O)C(F)(F)F
Product: O=C(c1ccc(-c2ccccc2)o1)N1CCNCC1COc1cccnc1
Reaction time: 1 h
Yield: 89 %

Procedure:
4 M HCl in 1,4-dioxane (6 mL, 24 mmol) was added to tert-butyl 4-(5-phenylfuran-2-carbonyl)-3-((pyridin-3-yloxy)methyl)piperazine-1-carboxylate TFA salt (58.9 mg, 0.102 mmol). After 1 h, the reaction mixture was concentrated under reduced pressure, yielding 39.6 mg (89%) of the desired product as a white solid. LC-MS: RT=4.63 min, [M+H]+=364.1.
Reaction SMILES: [CH2:1]([C@:3]12[CH2:11][CH2:10][C@@H:9]3[C@@H:12]4[C:17]([CH2:18][CH2:19][C@H:8]3[C@@H:7]1[CH2:6][CH2:5][C:4]2=[O:21])=[CH:16][C:15](=[O:20])[CH2:14][CH2:13]4)[CH3:2].O1CCO[CH2:24][CH2:23]1.C(OCC)(OCC)OCC.C(=O)([O-])O.[Na+]>C(O)C.N1C=CC=CC=1>[CH2:23]([O:20][C:15]1[CH2:14][CH2:13][C@H:12]2[C:17](=[CH:18][CH2:19][C@H:8]3[C@H:7]4[C@@:3]([CH2:1][CH3:2])([C:4](=[O:21])[CH2:5][CH2:6]4)[CH2:11][CH2:10][C@@H:9]32)[CH:16]=1)[CH3:24]
Reactant: C1COCCO1
Reactant: CC[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@H]43)[C@@H]1CCC2=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(OCC)OCC
Solvent: c1ccncc1
Product: CCOC1=CC2=CC[C@@H]3[C@H](CC[C@]4(CC)C(=O)CC[C@@H]34)[C@H]2CC1

Procedure:
—Pyridinium-toluenesulfonate (5.0 g) was added to a solution of 13-ethylgon-4-ene-3,17-dione [Hoffmann-La Roche and Co.; AG, DE 1806410 (1967); 100.0 g] in a mixture of ethanol (600 ml), dioxane (800 ml) and triethyl orthoformate (199 ml). After 4.5 h stirring at room temperature pyridine (100 ml) was added and the reaction mixture was poured into a saturated aqueous solution of sodium hydrogencarbonate. The product was extracted into ethyl acetate; the combined organic phases were washed with water and brine, dried over magnesium sulfate and concentrated under reduced pressure, to give 3-ethoxy-13-ethylgona-3,5-dien-17-one (146.3 g). The product was used in the following step without further purification.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1([OH:9])[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1.Br[CH2:13][CH2:14][Cl:15]>>[Cl:15][CH2:14][CH2:13][N:6]1[CH2:5][CH2:4][C:3]([C:2]([F:1])([F:10])[F:11])([OH:9])[CH2:8][CH2:7]1
Reactant: ClCCBr
Reactant: OC1(C(F)(F)F)CCNCC1
Product: OC1(C(F)(F)F)CCN(CCCl)CC1

Procedure:
A solution of 4-(trifluoromethyl)piperidin-4-ol and 1-bromo-2-chloroethane are reacted using the procedure for Example OO to afford 1-(2-chloroethyl)-4-(trifluoromethyl)piperidin-4-ol.
Reaction SMILES: [Cl-].[Li+].[CH2:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][CH:4]1[C:12](=[O:20])[CH2:13]P(=O)(OC)OC.[F:21][C@H:22]1[CH2:26][C@H:25]([O:27][CH:28]2[CH2:33][CH2:32][CH2:31][CH2:30][O:29]2)[C@H:24]([CH2:34]/[CH:35]=[CH:36]\[CH2:37][CH2:38][CH2:39][C:40]([O:42][CH:43]([CH3:45])[CH3:44])=[O:41])[C@H:23]1[CH:46]=O.OS([O-])(=O)=O.[K+]>C1COCC1.C(N(CC)CC)C>[CH2:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH2:3][CH:4]1[C:12](=[O:20])/[CH:13]=[CH:46]/[C@H:23]1[C@@H:22]([F:21])[CH2:26][C@H:25]([O:27][CH:28]2[CH2:33][CH2:32][CH2:31][CH2:30][O:29]2)[C@@H:24]1[CH2:34]/[CH:35]=[CH:36]\[CH2:37][CH2:38][CH2:39][C:40]([O:42][CH:43]([CH3:45])[CH3:44])=[O:41]
Reactant: COP(=O)(CC(=O)C1Cc2ccccc2C1)OC
Reactant: CC(C)OC(=O)CCC/C=C\C[C@@H]1[C@@H](C=O)[C@@H](F)C[C@@H]1OC1CCCCO1
Agent: O=S(=O)([O-])O
Agent: [Cl-]
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)OC(=O)CCC/C=C\C[C@@H]1[C@@H](/C=C/C(=O)C2Cc3ccccc3C2)[C@@H](F)C[C@@H]1OC1CCCCO1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 94.9 %

Procedure:
To a stirring mixture consisting of lithium chloride (3.75 g, 88.5 mmol) and triethylamine (4.86 mL) in THF (350 mL) cooled to 0° C. and stirred for 5 minutes at that temperature was added a solution consisting of dimethyl 2-(2,3-dihydro-1H-inden-2-yl)-2-oxoethylphosphonate (8.61 g) in THF (100 mL). The reaction mixture was stirred for 5 minutes and a solution consisting of (Z)-isopropyl 7-((1R,2S,3S,5S)-3-fluoro-2-formyl-5-(tetrahydro-2H-pyran-2-yloxy)cyclopentyl)hept-5-enoate (prepared in Step G, 10.31 g) in THF was added slowly. The reaction mixture was stirred as it was allowed to warm to room temperature overnight. The reaction mixture was subsequently acidified with 5% KHSO4, extracted with DCM, and the organic layers were washed twice with brine. After drying over sodium sulfate, filtration, and solvent removal under reduced pressure, the crude product was purified on silica gel. Elution with hexanes-ethyl acetate (9:1) afforded the title intermediate (13.4 g, 94%).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2([NH:12][C:13]([C:15]3[CH:16]=[CH:17][CH:18]=[C:19]4[C:23]=3[N:22]([CH2:24][C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[C:27]([Cl:32])[CH:26]=3)[CH2:21][CH2:20]4)=[O:14])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1)#[N:2].[N:33]([Sn](CCCC)(CCCC)CCCC)=[N+:34]=[N-:35].CC(O)=O>C1(C)C=CC=CC=1>[Cl:32][C:27]1[CH:26]=[C:25]([CH:30]=[CH:29][C:28]=1[Cl:31])[CH2:24][N:22]1[C:23]2[C:19](=[CH:18][CH:17]=[CH:16][C:15]=2[C:13]([NH:12][C:9]2([C:6]3[CH:7]=[CH:8][C:3]([C:1]4[NH:35][N:34]=[N:33][N:2]=4)=[CH:4][CH:5]=3)[CH2:11][CH2:10]2)=[O:14])[CH2:20][CH2:21]1
Reactant: CCCC[Sn](CCCC)(CCCC)N=[N+]=[N-]
Reactant: N#Cc1ccc(C2(NC(=O)c3cccc4c3N(Cc3ccc(Cl)c(Cl)c3)CC4)CC2)cc1
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: O=C(NC1(c2ccc(-c3nnn[nH]3)cc2)CC1)c1cccc2c1N(Cc1ccc(Cl)c(Cl)c1)CC2

Procedure:
N-[1-(4-cyanophenyl)cyclopropyl]-1-(3,4-dichlorobenzyl)indoline-7-carboxamide (125 mg, 0.27 mmol) and azidotributyltin (222 ul, 0.81 mmol) were refluxed in 1 ml of toluene overnight. 350 ul of AcOH was added and the resulting solid was filtered and washed with toluene. 1H NMR (500 MHz, DMSO-d6): δ 9.20 (s, 1H), 7.90 (d, 2H), 7.50 (m, 2H), 7.35 (d, 2H), 7.25 (d, 1H), 7.15 (m, 2H), 6.70 (t, 1H), 4.25 (s, 2H), 3.25 (2H), 2.95 (t, 2H), 1.20 (2H), 1.05 (m, 2H). MS−ESI (503.0).
Reaction SMILES: N[C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][CH2:4][CH2:5]NC(=N)N.N[C@H:14]([C:20](O)=[O:21])CCCCN>>[C:10]([OH:12])(=[O:11])[C:2]1[C:20](=[CH:14][CH:5]=[CH:4][CH:3]=1)[OH:21]
Reactant: NCCCC[C@H](N)C(=O)O
Reactant: N=C(N)NCCC[C@H](N)C(=O)O
Product: O=C(O)c1ccccc1O
Reaction time: 2 h

Procedure:
To characterize MS59 further its amino acid sequence was partially determined. Therefore, MS59 was separated in the presence of 0.1 mM thioglycolate in the upper reservoir buffer and SDS on a 12.5% polyacrylamide gel, which was prerun for 2 hours at 50 V with 0.05 mM glutathione in the upper reservoir buffer. The gel was stained with 5% (w/v) Serva Blue G in 45% (v/v) methanol and 10% acetic acid for 30 minutes and destained in 20% (v/v) acetic acid for 30 minutes and the 59 kDa band was cut out and sequenced using Edman degradation on an Applied Biosystems 477A protein sequencer according to the protocol provided by the manufacturer. N-terminal amino acid sequencing of MS59 revealed that the N-terminus was blocked. To obtain internal sequences, MS59 was digested with trypsin. Trypsin cleaves protein at arginine and lysine residues. The digestion products were separated on a reversed-phase column and analyzed by Edman degradation. Two tryptic fragments were sequenced: Pep1 and Pep2. Of Pep1 25 amino acid residues were identified: S-I-N-V-D-I-E-Q-E-T-A-W-V-Q-A-G-A-T-L-G-E-V-Y-Y-R (SEQ ID NO: 1).
Reaction SMILES: C[O:2][C:3]1[C:11]2[S:10][C:9]([CH3:12])=[N:8][C:7]=2[C:6]([N+:13]([O-:15])=[O:14])=[CH:5][CH:4]=1.Cl.N1C=CC=CC=1>>[OH:2][C:3]1[C:11]2[S:10][C:9]([CH3:12])=[N:8][C:7]=2[C:6]([N+:13]([O-:15])=[O:14])=[CH:5][CH:4]=1
Reactant: COc1ccc([N+](=O)[O-])c2nc(C)sc12
Agent: Cl
Solvent: c1ccncc1
Product: Cc1nc2c([N+](=O)[O-])ccc(O)c2s1

Procedure:
7-Hydroxy-2-methyl-4-nitrobenzothiazole was prepared from 7-methoxy-2-methyl-4-nitrobenzothiazole by treatment with solid pyridine hydrochloride as described in Preparation 1 (91%).
Reaction SMILES: [CH2:1]([O:5][C@H:6]1[N:9]([C:10](=[O:27])[C:11]([O:13][CH:14]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:12])[C:8](=[O:28])[C@@H:7]1[NH:29][C:30](=[O:38])[CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:2]([CH3:4])=[O:3].C(O)(=O)C>C(Cl)Cl.[Zn]>[CH2:1]([O:5][C@H:6]1[N:9]([CH:10]([OH:27])[C:11]([O:13][CH:14]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:12])[C:8](=[O:28])[C@@H:7]1[NH:29][C:30](=[O:38])[CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:2]([CH3:4])=[O:3]
Reactant: CC(=O)CO[C@@H]1[C@@H](NC(=O)Cc2ccccc2)C(=O)N1C(=O)C(=O)OC(c1ccccc1)c1ccccc1
Agent: [Zn]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC(=O)CO[C@@H]1[C@@H](NC(=O)Cc2ccccc2)C(=O)N1C(O)C(=O)OC(c1ccccc1)c1ccccc1

Procedure:
To a solution of diphenylmethyl α-[4(R)-acetonyloxy-3(R)-phenylacetamido-2-oxo-azetidin-1-yl]glyoxalate (2.312 g) in a mixture of methylene chloride (10 ml) and glacial acetic acid (10 ml) is added activated zinc powder (2.50 g) with stirring, and the mixture is stirred for 3 hours at room temperature. The reaction mixture is filtered through a layer of Celite which is washed with methylene chloride. The filtrate is washed with water, dried over sodium sulfate, and evaporated under reduced pressure to give the product as a mixture of epimers at position α.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:25][CH2:24][CH2:23][C:10]3([C:14](=[O:15])[N:13]([C@H:16]4[CH2:21][CH2:20][C@H:19]([OH:22])[CH2:18][CH2:17]4)[CH2:12][CH2:11]3)[CH2:9]2)=[CH:4][CH:3]=1.Cl[C:27]([O:29][CH:30]([CH3:32])[CH3:31])=[O:28].C(N(CC)CC)C.C(Cl)Cl>>[OH:22][C@H:19]1[CH2:18][CH2:17][C@H:16]([N:13]2[CH2:12][CH2:11][C:10]3([CH2:23][CH2:24][CH2:25][N:8]([C:5]4[CH:6]=[CH:7][C:2]([NH:1][C:27](=[O:28])[O:29][CH:30]([CH3:32])[CH3:31])=[CH:3][CH:4]=4)[CH2:9]3)[C:14]2=[O:15])[CH2:21][CH2:20]1
Reactant: CC(C)OC(=O)Cl
Reactant: Nc1ccc(N2CCCC3(CCN([C@H]4CC[C@H](O)CC4)C3=O)C2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)OC(=O)Nc1ccc(N2CCCC3(CCN([C@H]4CC[C@H](O)CC4)C3=O)C2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 7-(4-aminophenyl)-2-(trans-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one (20 mg, 0.00006 mol), isopropyl chloroformate (11 mg, 0.000087 mol), and triethylamine (20 μL, 0.0002 mol) in methylene chloride (300 μL, 0.005 mol) was stirred at rt for 2 h. The crude reaction mixture was purified by prep.-HPLC to afford 17.4 mg of the desired product. LC-MS: 430.3 (M+H)+.