Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[CH:4][C:3]=1[C:17]1[CH:18]=[N:19][C:20]([NH2:23])=[N:21][CH:22]=1.Br[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[S:31]([C:34]1([C:39]#[N:40])[CH2:38][CH2:37][CH2:36][CH2:35]1)(=[O:33])=[O:32]>>[NH2:23][C:20]1[N:21]=[CH:22][C:17]([C:3]2[CH:4]=[CH:5][C:6]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[S:31]([C:34]3([C:39]#[N:40])[CH2:38][CH2:37][CH2:36][CH2:35]3)(=[O:33])=[O:32])=[CH:7][C:2]=2[F:1])=[CH:18][N:19]=1
Reactant: N#CC1(S(=O)(=O)c2ccccc2Br)CCCC1
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)nc3)c(F)c2)OC1(C)C
Product: N#CC1(S(=O)(=O)c2ccccc2-c2ccc(-c3cnc(N)nc3)c(F)c2)CCCC1

Procedure:
The title compound was prepared using conditions analogous to those used to make Example 6 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrimidin-2-amine and 1-((2-bromophenyl)sulfonyl)cyclopentanecarbonitrile. MS (ESI): mass calcd. for C22H19FN4O2S, 422.12; m/z found, 423.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.52 (s, 2H), 8.21 (d, J=8.0, 1H), 7.91 (m, 1H), 7.86-7.79 (m, 1H), 7.57 (m, 1H), 7.52 (d, J=7.6, 1H), 7.37 (dd, J=11.8, 1.4, 1H), 7.29 (dd, J=8.0, 1.6, 1H), 6.92 (s, 2H), 2.22-2.07 (m, 4H), 1.72-1.68 (m, 4H).
Reaction SMILES: Br.Br[CH2:3][C:4]([C:6]12[CH2:13][N:10]([CH2:11][CH2:12]1)[CH2:9][CH2:8][CH2:7]2)=[O:5].[N-:14]=[N+:15]=[N-:16].[Na+]>CN(C)C=O>[N:14]([CH2:3][C:4]([C:6]12[CH2:13][N:10]([CH2:11][CH2:12]1)[CH2:9][CH2:8][CH2:7]2)=[O:5])=[N+:15]=[N-:16]
Reactant: [N-]=[N+]=[N-]
Reactant: O=C(CBr)C12CCCN(CC1)C2
Agent: Br
Agent: [Na+]
Solvent: CN(C)C=O
Product: [N-]=[N+]=NCC(=O)C12CCCN(CC1)C2
Temperature: 25 °C
Reaction time: 21 h

Procedure:
A solution of 5-(α-bromoacetyl)-1-azabicyclo[3.2.1]octane hydrobromide (D27) (1.8 g; 5.8 mmole) in dry N,N-dimethylformamide (25 ml) was treated with sodium azide (0.41 g; 6.3 mmole) and stirred in the dark at room temperature for 21 h. The reaction mixture was concentrated in vacuo and the residue was treated with a saturated potassium carbonate solution (25 ml) and extracted into chloroform (4×25 ml). The dried (sodium sulphate) organic layers were concentrated in vacuo to give the title compound (D28) as an orange oil (0.75 g; 67%) which was used in the next stage without purification.
Reaction SMILES: COC1C=CC(C[N:8]([CH:39]([CH3:41])[CH3:40])[CH2:9][CH2:10][C@H:11]([NH:14][C:15]([C:17]2[CH:25]=[C:24]3[C:20]([CH:21]=[N:22][N:23]3[CH2:26][CH:27]([CH3:29])[CH3:28])=[CH:19][C:18]=2[O:30][C:31]2[CH:36]=[CH:35][C:34]([F:37])=[CH:33][C:32]=2[F:38])=[O:16])[CH2:12][OH:13])=CC=1>CO.[Pd]>[OH:13][CH2:12][C@@H:11]([NH:14][C:15]([C:17]1[CH:25]=[C:24]2[C:20]([CH:21]=[N:22][N:23]2[CH2:26][CH:27]([CH3:28])[CH3:29])=[CH:19][C:18]=1[O:30][C:31]1[CH:36]=[CH:35][C:34]([F:37])=[CH:33][C:32]=1[F:38])=[O:16])[CH2:10][CH2:9][NH:8][CH:39]([CH3:41])[CH3:40]
Reactant: COc1ccc(CN(CC[C@@H](CO)NC(=O)c2cc3c(cnn3CC(C)C)cc2Oc2ccc(F)cc2F)C(C)C)cc1
Agent: [Pd]
Solvent: CO
Product: CC(C)Cn1ncc2cc(Oc3ccc(F)cc3F)c(C(=O)N[C@H](CO)CCNC(C)C)cc21
Temperature: 25 °C
Reaction time: 5 h
Yield: 60 %

Procedure:
To a solution of (S)—N-(4-((4-methoxybenzyl)(isopropyl)amino)-1-hydroxybutan-2-yl)-5-(2,4-difluorophenoxy)-1-isobutyl-1H-indazole-6-carboxamide (0.020 g, 0.033 mmol) in MeOH (5 mL) was added wet Pd/C (0.020 g, 10% by weight). The mixture was purged with hydrogen several times and then stirred at room temperature under H2 atmosphere for 5 hours. The catalyst was removed by filtration and the filtrate was concentrated under reduced pressure. The residue was chromatographed eluting with 10% MeOH in dichloromethane with 2% triethylamine to provide 9.4 mg colorless gel (60% yield). MS (ESI+) m/z 475 (M+1) detected; 1H NMR (400 mHz, CDCl3) δ 8.40 (d, 1H), 8.31 (s, 1H), 7.87 (s, 1H), 7.13 (m, 1H), 7.03 (s, 1H), 7.01 (m, 1H), 6.91 (m, 1H), 4.33 (m, 1H), 4.22 (d, 2H), 3.69 (m, 2H), 2.69 (m, 2H), 2.37 (m, 2H), 1.32 (m, 2H), 1.09 (d, 3H), 1.01 (d, 3H), 0.93 (d, 6H).
Reaction SMILES: [CH3:1][C:2]1[C:7]([N:8]2[C:17](=[O:18])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]=[CH:9]2)=[CH:6][CH:5]=[CH:4][C:3]=1[C:19]1[C:31]2[C:30]3[C:25](=[CH:26][C:27]([O:32][CH2:33][CH:34]=[O:35])=[CH:28][CH:29]=3)[NH:24][C:23]=2[C:22]([C:36]([NH2:38])=[O:37])=[N:21][CH:20]=1.[CH3:39][Mg]Br>O1CCCC1>[OH:35][CH:34]([CH3:39])[CH2:33][O:32][C:27]1[CH:26]=[C:25]2[C:30]([C:31]3[C:19]([C:3]4[CH:4]=[CH:5][CH:6]=[C:7]([N:8]5[C:17](=[O:18])[C:16]6[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=6)[N:10]=[CH:9]5)[C:2]=4[CH3:1])=[CH:20][N:21]=[C:22]([C:36]([NH2:38])=[O:37])[C:23]=3[NH:24]2)=[CH:29][CH:28]=1
Reactant: Cc1c(-c2cnc(C(N)=O)c3[nH]c4cc(OCC=O)ccc4c23)cccc1-n1cnc2ccccc2c1=O
Reactant: C[Mg]Br
Solvent: C1CCOC1
Product: Cc1c(-c2cnc(C(N)=O)c3[nH]c4cc(OCC(C)O)ccc4c23)cccc1-n1cnc2ccccc2c1=O
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 4.7 %

Procedure:
To a solution of 4-(2-methyl-3-(4-oxoquinazolin-3(4H)-yl)phenyl)-7-(2-oxoethoxy)-9H-pyrido[3,4-b]indole-1-carboxamide (178 mg, 85% purity, 0.300 mmol) in tetrahydrofuran (10 mL) at 0° C. was added methylmagnesium bromide (0.707 mL, 2.121 mmol). The mixture was stirred at rt for 20 min. Additional methylmagnesium bromide (0.50 mL, 1.50 mmol) was added. The mixture was stirred at room temperature for another 20 min and then the reaction was quenched with water (20 mL). The resulting mixture was extracted with ethyl acetate (3×40 mL). The combined extract was washed with brine (30 mL) and dried over anhydrous MgSO4. After solvent was removed under vacuum, the residue was purified by reverse phase HPLC. The correct fractions were combined and concentrated under vacuum, basified with saturated NaHCO3 solution, and extracted with ethyl acetate (3×35 mL). The combined extract was washed with brine (30 mL) and dried over anhydrous MgSO4. Removal of solvent under vacuum provided the desired product (7.6 mg, 0.014 mmol, 4.9% yield) as a yellow solid. LCMS (M+H)+=520.21. 1H NMR (500 MHz, DMSO-d6) (recognizable peaks for the major atropisomer) δ: 11.68 (s, 1H), 8.44 (s, 1H), 8.21 (s, 1H), 7.36 (s, 1H), 4.01 (m, 1H), 3.92-3.84 (m, 2H), 1.81 (s, 3H).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].[N:13]1([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1.Cl.CN(C)CCCN=C=NCC.CN1CCOCC1>ClCCl>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([C:8]([N:16]2[CH2:15][CH2:14][N:13]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:18][CH2:17]2)=[O:10])=[CH:11][CH:12]=1)([O-:3])=[O:2]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(C(=O)c2ccc([N+](=O)[O-])cc2)CC1
Temperature: 20 °C
Reaction time: 5 h
Yield: 93.3 %

Procedure:
4-Nitrobenzoic acid (1.00 g, 6.00 mmol), tert-butyl 1-piperazinecarboxylate (1.10 g, 6.00 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.70 g, 9.00 mmol) and N-methylmorpholine (1.30 ml, 12.00 mmol) were dissolved in dichloromethane (10 ml) and the reaction mixture stirred at 20° C. for 5 h. The reaction was then washed with saturated sodium bicarbonate solution and brine. The organic phase was dried over MgSO4 and the solvent removed in vacuo. The residue was purified by silica gel column chromatography using a 0-50% EtOAc in hexane gradient to afford tert-butyl 4-(4-nitrobenzoyl)piperazine-1-carboxylate (1.88 g, 5.60 mmol, 94%) as a white solid. LCMS (1) Rt: 2.01 min; m/z (ES+) No M+H+, but 280 (-tBu) and 236 (-Boc).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[CH:11]=[CH:10][CH:9]([C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([Cl:19])[CH:13]=3)[O:8][C:5]2=[N:6][CH:7]=1.N12CCCN=C1CCCCC2>O1CCCC1>[Br:1][C:2]1[CH:3]=[C:4]2[CH2:11][CH:10]=[C:9]([C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([Cl:19])[CH:13]=3)[O:8][C:5]2=[N:6][CH:7]=1
Reactant: Clc1ccc(C2C=Cc3cc(Br)cnc3O2)cc1Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: Clc1ccc(C2=CCc3cc(Br)cnc3O2)cc1Cl
Reaction time: 1 h

Procedure:
To a solution of 2.9 g of 6-bromo-2-(3,4-dichlorophenyl)-2H-pyrano[2,3-b]pyridine in 40 ml of tetrahydrofuran was added 0.5 ml of 1,8-diazabicyclo[5.4.0]undec-7-ene. After 1 hour at 25° C., the reaction mixture was partitioned between ethyl acetate and aqueous saturated ammonium chloride solution. The ethyl acetate layer was dried over magnesium sulfate and the solvent was evaporated to leave a solid residue. This was recrystallized from ethanol to give 6-bromo-2-(3,4-dichlorophenyl)-4H-pyrano[2,3-b]pyridine melting at about 138°-139.5° C.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1.[OH-].[Na+].[C:8]1([CH3:18])[CH:13]=[CH:12][C:11]([S:14](Cl)(=[O:16])=[O:15])=[CH:10][CH:9]=1>ClC(Cl)C>[C:8]1([CH3:18])[CH:13]=[CH:12][C:11]([S:14]([N:1]2[CH:5]=[CH:4][CH:3]=[CH:2]2)(=[O:16])=[O:15])=[CH:10][CH:9]=1
Reactant: c1cc[nH]c1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(Cl)Cl
Product: Cc1ccc(S(=O)(=O)n2cccc2)cc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 75.8 %

Procedure:
Pyrrole (18 g, 0.27 mol) was added to a well-agitated suspension of NaOH (36 g, 0.9 mol. NaOH should be ground and stirred in dichloroethane for 30 min.) in 180 mL of dichloroethane. This mixture was then cooled to 0° C. and stirred for 10 min, following which a solution of 6 (57.3 g, 0.3 mol) in 150 mL of dichloroethane was added over a period of 30 min. Thirty minutes after the completion of addition, the reaction was allowed to come to room temperature and left stirring overnight. The reaction was quenched by pouring onto 600 mL of ice and water. The organic layer was separated, and the aqueous layer was extracted with dichloromethane (3×20 mL). The combined organic extract was washed with brine to neutrality and dried over Na2SO4. Removal of the solvent in vacuo gave 7 (45.3 g, 76%) as light grey solid. This solid was subsequently purified by passing a concentrated solution in dichloromethane through an alumina column (35.4 g). 1H NMR (CDCl3, δ/ppm), 7.75 (m, 2H), 7.29 (m, 2H), 7.15 (t, 2H), 6.28 (t, 2H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:9][CH3:10])=[C:6]([NH2:8])[CH:7]=1.[CH2:11]([O:13][C:14](=[O:19])[CH2:15][C:16](=O)[CH3:17])[CH3:12].C(O)(=O)C.[O-]S([O-])(=O)=O.[Ca+2]>C(O)C>[CH2:11]([O:13][C:14](=[O:19])[CH:15]=[C:16]([NH:8][C:6]1[CH:7]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=1[O:9][CH3:10])[CH3:17])[CH3:12]
Reactant: COc1ccc(F)cc1N
Reactant: CCOC(=O)CC(C)=O
Agent: O=S(=O)([O-])[O-]
Agent: [Ca+2]
Solvent: CC(=O)O
Solvent: CCO
Product: CCOC(=O)C=C(C)Nc1cc(F)ccc1OC
Temperature: 25 °C

Procedure:
A suspension of 5-fluoro-2-methoxy-phenylamine (3.3 g, 23 mmol), 3-oxo-butyric acid ethyl ester (3.0 g, 23 mmol), acetic acid (120 μL), and Drierite® (12.0 g) in ethanol (20 mL) was heated to reflux for 5 d. The reaction mixture was cooled to room temperature and filtered. The filtrate was concentrated in vacuo and purified by flash chromatography on silica gel (elution with EA/hexane 1:3) to give crude 3-(5-fluoro-2-methoxy-phenylamino)-but-2-enoic acid ethyl ester.
Reaction SMILES: [O:1]=[C:2]1[C:7](=O)[CH:6]([C:9]#[N:10])[CH2:5][CH2:4][N:3]1[C:11]1[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=1.Cl.[NH2:19][NH2:20].C(O)(=O)C>C(O)C>[NH2:10][C:9]1[C:6]2[CH2:5][CH2:4][N:3]([C:11]3[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=3)[C:2](=[O:1])[C:7]=2[NH:20][N:19]=1
Reactant: NN
Reactant: Cc1ccc(N2CCC(C#N)C(=O)C2=O)cc1
Agent: Cl
Solvent: CCO
Solvent: CC(=O)O
Product: Cc1ccc(N2CCc3c(N)n[nH]c3C2=O)cc1
Temperature: 60 °C
Reaction time: 48 h
Yield: 86 %

Procedure:
2,3-Dioxo-1-p-tolylpiperidine-4-carbonitrile (3.56 g, 15.597 mmol) was added to anhydrous ethanol (52.0 mL) and dissolved by heating to 60° C. After adding hydrazine hydrochloride (1.06 mL, 21.836 mmol) and glacial acetic acid (1.34 mL, 23.396 mmol) room temperature, reaction was carried out for 2 days. After removing ethanol by distillation, the produced solid was filtered and then acetic acid was completely removed by washing with NaHCO3 twice or more times. A target compound (3.25 g, 13.414 mmol, 86.0%) was yielded as white solid.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([O:10]O)=O)[CH:3]=1.[CH3:12][C:13]([CH3:31])([O:15][C:16]([N:18]1[CH2:23][CH2:22][N:21](CC2C=CC=CC=2)[CH2:20][CH2:19]1)=[O:17])[CH3:14]>C(Cl)(Cl)Cl>[CH3:14][C:13]([CH3:31])([O:15][C:16]([N:18]1[CH2:19][CH2:20][N:21]([O:10][CH2:8][C:4]2[CH:3]=[CH:2][CH:7]=[CH:6][CH:5]=2)[CH2:22][CH2:23]1)=[O:17])[CH3:12]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2ccccc2)CC1
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)N1CCN(OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 96 h

Procedure:
A solution of 10.0 g (0.058 mole) m-chloroperbenzoic acid in 100 ml chloroform was added over a one hour period to a cooled (0°-5° C.) solution of 16.1 g (0.058 mole) 1-[1,1-dimethylethoxycarbonyl]-4-phenylmethylpiperazine in 200 ml chloroform. External cooling was removed and the solution stirred for 96 hours at room temperature. The solution was then successively passed through four alumina-packed columns (2.2×16 cm), the eluent evaporated in vacuo, treated with 200 ml acetone and diluted with 50 ml hexane to yield 9.0 g white, crystalline solid, m.p. 123°-126° C. (sealed capillary). An analytical sample from a prior run gave a satisfactory elemental analysis. Calc. for C16H29N2O3.H2O (310.40): C, 61.91; H, 8.44; N, 9.03; O, 20.62. Found: C, 61.91; H, 8.27; N, 9.07; O, 20.55.
Reaction SMILES: [O:1]=[C:2]1[N:7]2[CH2:8][C:9]3[C:14]([C:6]2=[C:5]([C:15]([OH:17])=[O:16])[CH:4]=[C:3]1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[CH:13][CH:12]=[CH:11][CH:10]=3.[CH3:24][N:25]([CH3:29])[CH2:26][CH2:27]O.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>O1CCOCC1.CN(C)C1C=CN=CC=1>[O:1]=[C:2]1[N:7]2[CH2:8][C:9]3[C:14]([C:6]2=[C:5]([C:15]([O:17][CH2:27][CH2:26][N:25]([CH3:29])[CH3:24])=[O:16])[CH:4]=[C:3]1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[CH:13][CH:12]=[CH:11][CH:10]=3
Reactant: O=C(O)c1cc(-c2ccccc2)c(=O)n2c1-c1ccccc1C2
Reactant: CN(C)CCO
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1COCCO1
Product: CN(C)CCOC(=O)c1cc(-c2ccccc2)c(=O)n2c1-c1ccccc1C2
Reaction time: 1.5 h

Procedure:
A suspension of 9.0 g of 4,6-dihydro-4-oxo-3-phenyl-pyrido[2,1-a]isoindole-1-carboxylic acid in 240 ml of dioxane was treated in succession with 6.7 ml of 2-(dimethylamino)ethanol, 15.7 g of 1H-1-benzotriazolyloxy-tris(dimethylamino)phosphonium hexafluorophosphate and 263 mg of 4-dimethylaminopyridine, whereupon the mixture was heated to boiling under reflux for 80 minutes under argon, treated with 1.58 g of 1-benzotriazolyloxy-tris(dimethylamino)phosphonium hexafluorophosphate and heated for a further 1 hour. The mixture was then left to cool and the separated crystals were filtered off under suction. After stirring with 890 ml of methylene chloride, 475 ml of water and 70 ml of saturated sodium hydrogen carbonate solution for 90 minutes the organic phase was separated and evaporated. The residue was dissolved in 100 ml of methanol, whereupon the solution was acidified with ethereal hydrochloric acid, filtered and the product was precipitated by cooling in an ice bath. There was obtained 2.9 g of 2-(dimethylamino)ethyl 4,6dihydro-4-oxo-3-phenylpyrido[2,1-a]isoindole-1-carboxylate as yellowish crystals with a m.p. of 225°-228°.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([CH3:11])[CH:3]=1.S(=O)(=O)(O)O.[CH2:17](O)[CH:18]=[CH2:19]>>[OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH2:19][CH:18]=[CH2:17])=[O:7])=[C:4]([CH3:11])[CH:3]=1
Reactant: Cc1cc(O)ccc1C(=O)O
Reactant: C=CCO
Agent: O=S(=O)(O)O
Product: C=CCOC(=O)c1ccc(O)cc1C
Yield: 76 %

Procedure:
In a manner analogous to Example 1(a), 5.34 g (32 mmoles) of 4-hydroxy-2-methyl benzoic acid treated at 100° C. for 12 hours with 50 ml of allyl alcohol and 1.5 ml of concentrated sulfuric acid, give 4 g (76% yield) of the expected ester having a melting point of 76°-77° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([N:8]2[C:12]([SH:13])=[N:11][N:10]=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[CH3:14][CH2:15][CH2:16][C:17](Cl)=[S:18]>>[CH3:14][CH2:15][CH2:16][C:17]([NH:1][C:2]1[CH:3]=[C:4]([N:8]2[C:12]([SH:13])=[N:11][N:10]=[N:9]2)[CH:5]=[CH:6][CH:7]=1)=[S:18]
Reactant: Nc1cccc(-n2nnnc2S)c1
Reactant: CCCC(=S)Cl
Product: CCCC(=S)Nc1cccc(-n2nnnc2S)c1

Procedure:
This compound was prepared from 1-(m-aminophenyl)-5-mercaptotetrazole and 3-methylthiopropionyl chloride [A. Mooradian et al., J. Am. Chem. Soc. 71, 3372 (1949)] according to the same reaction scheme as the one described hereinabove for compound 1.
Reaction SMILES: Cl[C:2]1[C:15]2[C:14](=O)[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:17])[C:6]=2[C:5]([CH3:18])=[CH:4][CH:3]=1.O.[NH2:20][NH2:21]>N1C=CC=CC=1>[CH3:18][C:5]1[CH:4]=[CH:3][C:2]2[NH:20][N:21]=[C:14]3[C:15]=2[C:6]=1[C:7](=[O:17])[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:13]3=1
Reactant: NN
Reactant: Cc1ccc(Cl)c2c1C(=O)c1ccccc1C2=O
Solvent: O
Solvent: c1ccncc1
Product: Cc1ccc2[nH]nc3c2c1C(=O)c1ccccc1-3
Temperature: 90 °C
Reaction time: 8 h

Procedure:
To a solution of 32.3 g of 1-chloro-4-methyl-9,10-dihydro-9,10-anthracenedione prepared in Example 25-a in 150 ml pyridine was added 15 ml of hydrazine monohydrate [CAS No. 7803-57-8], followed by stirring at 90° C. overnight. After removing the solvent, to the resulting residue was added 65 ml of ethanol to give crystals. The crystals were collected by filtration, sequentially washed with moisture ethanol and ethanol, and dried in vacuo, to give 26.6 g of the title compound as ocher yellow needles.
Reaction SMILES: [C:1]1([C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N+]=[N-])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:16][C:17]1[CH:22]=[CH:21][C:20]([S:23]([O:26][CH2:27][CH:28]2[N:31]([CH2:32][C:33]([OH:35])=[O:34])[C:30](=[O:36])[CH:29]2[NH:37][C:38]([C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)(=[O:25])=[O:24])=[CH:19][CH:18]=1>CCOCC.O1CCOCC1>[CH3:16][C:17]1[CH:18]=[CH:19][C:20]([S:23]([O:26][CH2:27][C@H:28]2[N:31]([CH2:32][C:33]([O:35][CH:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)=[O:34])[C:30](=[O:36])[C@H:29]2[NH:37][C:38]([C:51]2[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=2)([C:45]2[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=2)[C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)(=[O:25])=[O:24])=[CH:21][CH:22]=1
Reactant: [N-]=[N+]=C(c1ccccc1)c1ccccc1
Reactant: Cc1ccc(S(=O)(=O)OCC2C(NC(c3ccccc3)(c3ccccc3)c3ccccc3)C(=O)N2CC(=O)O)cc1
Solvent: C1COCCO1
Solvent: CCOCC
Product: Cc1ccc(S(=O)(=O)OC[C@@H]2[C@H](NC(c3ccccc3)(c3ccccc3)c3ccccc3)C(=O)N2CC(=O)OC(c2ccccc2)c2ccccc2)cc1
Temperature: 20 °C
Reaction time: 3 h
Yield: 88.7 %

Procedure:
A solution of 2.68 g of diphenyldiazomethane in 59 ml of ether was added to a solution of 6.55 g of 4-{[(4-methylphenyl)-sulfonyloxy]-methyl}-3-(triphenylmethylamino)-2-oxo-azetidin-1-yl-acetic acid in 70 ml of dioxane and after stirring for 3 hours at 20° C. 448 mg of diphenyldiazomethane were added. The mixture was stirred at 20° C. for 16 hours and was then evaporated to dryness under reduced pressure. The residue was chromatographed over silica and was eluted with a 10-0.5 methylene chloride-ether mixture to obtain 7.5 g of diphenylmethyl racemic cis 4-{[(4-methylphenyl)-sulfonyloxy]-methyl)-3-triphenylmethylamino-2-oxo-azetidin-1-yl-acetate.
Reaction SMILES: [CH3:1][SiH:2]([CH3:4])[Cl:3].[Cl-].[Al+3].[Cl-].[Cl-].[CH3:9][C:10]([CH3:14])=[C:11]([CH3:13])[CH3:12]>>[CH3:9][C:10]([Si:2]([CH3:4])([CH3:1])[Cl:3])([CH3:14])[CH:11]([CH3:13])[CH3:12]
Reactant: CC(C)=C(C)C
Reactant: C[SiH](C)Cl
Agent: [Al+3]
Agent: [Cl-]
Product: CC(C)C(C)(C)[Si](C)(C)Cl
Reaction time: 1 h

Procedure:
100 ml (0.92 mol) of dimethylchlorosilane and 3.8 g (0.028 mol) of aluminium chloride are introduced into a 500 ml three-necked flask with a reflux condenser and dropping funnel. Within 1 hour, 109.5 ml (0.92 mol) of tetramethylethylene are added dropwise. The reaction temperature is maintained in the range from 25° to 30° C. by external cooling. After 4 hours, undissolved aluminium chloride is filtered off from the reaction solution which is then distilled.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1N=CN(C(N2C=NC=C2)=O)C=1.Cl.[CH3:28][O:29][NH:30][CH3:31]>ClCCl>[CH3:28][O:29][N:30]([CH3:31])[C:12](=[O:14])[CH2:11][CH2:10][CH2:9][NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4]
Reactant: CNOC
Reactant: CC(C)(C)OC(=O)NCCCC(=O)O
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Product: CON(C)C(=O)CCCNC(=O)OC(C)(C)C
Reaction time: 1.5 h
Yield: 98.6 %

Procedure:
While under an atmosphere of argon, a room temperature solution of 4-(tert-butoxycarbonylamino) butanoic acid (20 g, 0.098 mol) in dichloromethane (280 mL, 0.35 M) was treated with CDI (17.6 g, 0.108 mol). After 1.5 hr, O,N-dimethylhydroxylamine hydrochloride (10.6 g; 0.108 mol) was added, and the resulting solution was stirred overnight. The mixture was added to a separatory funnel, diluted with dichloromethane (220 mL) and washed successively with 2 M HCl (2×), 1 M NaOH and sat'd aq sodium chloride, dried over MgSO4, filtered and concentrated to give tert-butyl 4-(methoxy(methyl)amino)-4-oxobutylcarbamate (23.8 g, 98%). ESI MS found for C11H22N2O4 m/z [269.4 (M+Na+)].
Reaction SMILES: [CH3:1][NH:2][C:3]1[C:8]([CH2:9][OH:10])=[CH:7][N:6]=[C:5]([S:11][CH3:12])[N:4]=1>C(Cl)(Cl)Cl.O=[Mn]=O>[CH3:1][NH:2][C:3]1[C:8]([CH:9]=[O:10])=[CH:7][N:6]=[C:5]([S:11][CH3:12])[N:4]=1
Reactant: CNc1nc(SC)ncc1CO
Agent: O=[Mn]=O
Solvent: ClC(Cl)Cl
Product: CNc1nc(SC)ncc1C=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 91.7 %

Procedure:
A mixture of (4-(methylamino)-2-(methylthio)pyrimidin-5-yl)methanol (22.0 g, 119 mmol) and MnO2 (44 g, 506 mmol) in CHCl3 (300 mL) was stirred at RT for 3 h. The reaction was filtered and the filtrate was concentrated to give 4-(methylamino)-2-(methylthio)pyrimidine-5-carbaldehyde as a pale solid (20 g, 92% yield). 1H NMR (400 MHz, DMSO-d6): 9.71 (s, 1 H), 8.60 (br s, 1 H), 8.49 (s, 1 H), 2.96 (d, J=4.8 Hz, 3 H), 2.48 (s, 3 H) MS (ESI) m/z: 184.0 (M+H+).
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[F:19][C:20]([F:52])([F:51])[O:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2[CH:36]=[C:35]3[C:31]([C:32]([NH:45][C:46](=[O:50])[CH2:47][CH2:48][CH3:49])=[N:33][N:34]3COCC[Si](C)(C)C)=[CH:30][CH:29]=2)=[CH:24][CH:23]=1.C(OCC)(=O)C>O1CCCC1>[F:52][C:20]([F:19])([F:51])[O:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2[CH:36]=[C:35]3[C:31]([C:32]([NH:45][C:46](=[O:50])[CH2:47][CH2:48][CH3:49])=[N:33][NH:34]3)=[CH:30][CH:29]=2)=[CH:24][CH:23]=1
Reactant: CCCC(=O)Nc1nn(COCC[Si](C)(C)C)c2cc(-c3ccc(OC(F)(F)F)cc3)ccc12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCC(=O)Nc1n[nH]c2cc(-c3ccc(OC(F)(F)F)cc3)ccc12
Temperature: 66 °C

Procedure:
12.1 cm3 of tetrabutylammonium fluoride as a 1M solution in tetrahydrofuran are added to 1 g of N-[6-[4-(trifluoromethoxy)phenyl]-1-[[2-(trimethylsilyl)ethoxy]-methyl]-1H-indazol-3-yl]butanamide, described previously, in 30 cm3 of tetrahydrofuran. The reaction medium is heated at about 66° C. for 18 hours, the heating is then stopped and 75 cm3 of ethyl acetate are added. This mixture is washed with 2×50 cm3 of saturated aqueous sodium hydrogen carbonate solution and then with 50 cm3 of saturated aqueous sodium chloride solution. The organic phase is separated out after settling of the phases has taken place, dried over magnesium sulphate, filtered and then concentrated under reduced pressure (2 kPa; 50° C.). The residue is purified by chromatography under an argon pressure of 50 kPa, on a column of silica gel (particle size 40-60 μm; diameter 2.5 cm), eluting with an ethyl acetate/cyclohexane mixture (60/40 by volume). The fractions containing the expected product are combined and evaporated under reduced pressure (2 kPa; 50° C.); the residue is taken up in 10 cm3 of diisopropyl ether, filtered on a sinter funnel and then washed successively with 10 cm3 of diisopropyl ether and then with 2×2 cm3 of ethyl acetate. After drying (90 Pa; 50° C.), 520 mg of N-[6-[4-(trifluoromethoxy)phenyl]-1H-indazol-3-yl]butanamide are obtained in the form of a white product melting at 234° C.