Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][N:2]=[C:3]([NH2:10])[C:4]1[CH:9]=[CH:8][CH:7]=[N:6][CH:5]=1.[F:11][C:12]1[C:20]([F:21])=[CH:19][C:18]([F:22])=[CH:17][C:13]=1[C:14](O)=O.N>>[F:11][C:12]1[C:20]([F:21])=[CH:19][C:18]([F:22])=[CH:17][C:13]=1[C:14]1[O:1][N:2]=[C:3]([C:4]2[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=2)[N:10]=1
Reactant: O=C(O)c1cc(F)cc(F)c1F
Reactant: NC(=NO)c1cccnc1
Agent: N
Product: Fc1cc(F)c(F)c(-c2nc(-c3cccnc3)no2)c1

Procedure:
The title compound was prepared according to the procedure of Example 8 using N′-hydroxynicotinimidamide (Aldrich) and 2,3,5-trifluorobenzoic acid (Aldrich). 1H NMR (300 MHz, CD3OD) δ 7.55-7.68 (m, 2H), 7.83-7.90 (m, 1H), 8.57 (dt, J=8.1, 1.9 Hz, 1H), 8.75 (dd, J=5.1, 1.7 Hz, 1H), 9.30 (dd, J=2.2, 0.8 Hz, 1H) ppm; MS (DCl/NH3) m/z 278 (M+H)+.
Reaction SMILES: CO[C:3]1[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][N:4]=1.Cl.[NH2:11][CH:12]1[C:21]2[CH:20]=[CH:19][S:18][C:17]=2[CH2:16][CH2:15][C:14]2[CH:22]=[CH:23][C:24]([Cl:26])=[CH:25][C:13]1=2.Cl>CCOCC.C(O)C>[Cl:26][C:24]1[CH:23]=[CH:22][C:14]2[CH2:15][CH2:16][C:17]3[S:18][CH:19]=[CH:20][C:21]=3[CH:12]([N:11]=[C:3]3[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][NH:4]3)[C:13]=2[CH:25]=1
Reactant: COC1=NCCCCC1
Reactant: NC1c2cc(Cl)ccc2CCc2sccc21
Agent: Cl
Solvent: CCO
Solvent: CCOCC
Product: Clc1ccc2c(c1)C(N=C1CCCCCN1)c1ccsc1CC2

Procedure:
5 ml of 98% ethanol and 10.0 g of caprolactim 0-methyl ether are added to 8.0 g of 4-amino-6-chloro-9,10-dihydro-4H-benzo[4,5]cyclohepta[1,2-b]thiophene hydrochloride and are allowed to stand at room temperature while shaking occasionally. A few drops of ether are added to the resulting clear solution after 12 hours, whereupon the hydrochloride of the title compound crystallizes. M.Pt. decomp. from 185°, (recrystallized once from ethanol/ether).
Reaction SMILES: [F:1][C:2]1([F:17])[C:7](O)(O)[CH2:6][CH2:5][N:4]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:3]1.[CH2:18]([NH2:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(O)C.[BH4-].[Na+]>C1(C)C=CC=CC=1>[C:13]([O:12][C:10]([N:4]1[CH2:5][CH2:6][CH:7]([NH:25][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:2]([F:17])([F:1])[CH2:3]1)=[O:11])([CH3:16])([CH3:15])[CH3:14]
Reactant: NCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC(O)(O)C(F)(F)C1
Agent: [BH4-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(NCc2ccccc2)C(F)(F)C1
Temperature: 55 °C
Reaction time: 2 h

Procedure:
A mixture of tert-butyl 3,3-difluoro-4,4-dihydroxypiperidine-1-carboxylate (1 g, 3.36 mmol), and benzylamine (539 mg, 550 μL, 5.03 mmol) in dry toluene (70 mL) was heated to reflux with dean stark apparatus for 12 hours. Further benzyl amine (20 μL, 185 μmol) was added and heated to reflux with dean stark apparatus for another 12 hours. About 50 mL of toluene were distilled off, the residue was cooled to 55° C., ethanol (35 mL) and NaBH4 (508 mg, 13.4 mmol) were added and the reaction mixture stirred at 55° C. for 2 hours. Further NaBH4 (508 mg, 13.4 mmol) was added and stirred for another hour. Further NaBH4 (508 mg, 13.4 mmol) was added. After 2 hours the reaction mixture was concentrated, then 2 N Na2CO3 solution was added and the aqueous phase was extracted with ethyl acetate. The combined organic layers were dried over Na2SO4 and the solvents were evaporated. The residue was purified by flash chromatography (70 g, 0% to 100% EtOAc in hexanes). The title compound was obtained as colorless oil (875 mg, 80%).
Reaction SMILES: [C:1]([C:4]1[C:8]2[CH:9]=[CH:10][C:11]3[CH:12]=[N:13][C:14](S(C)(=O)=O)=[N:15][C:16]=3[C:7]=2[N:6]([CH:21]2[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][CH2:22]2)[N:5]=1)(=[O:3])[NH2:2].[NH:34]1[CH2:38][CH2:37][CH2:36][CH2:35]1>C1COCC1>[C:1]([C:4]1[C:8]2[CH:9]=[CH:10][C:11]3[CH:12]=[N:13][C:14]([N:34]4[CH2:38][CH2:37][CH2:36][CH2:35]4)=[N:15][C:16]=3[C:7]=2[N:6]([CH:21]2[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][CH2:22]2)[N:5]=1)(=[O:3])[NH2:2]
Reactant: C1CCNC1
Reactant: CC(C)(C)OC(=O)N1CCC(n2nc(C(N)=O)c3ccc4cnc(S(C)(=O)=O)nc4c32)CC1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(n2nc(C(N)=O)c3ccc4cnc(N5CCCC5)nc4c32)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 51.1 %

Procedure:
To a solution of tert-butyl 4-[3-carbamoyl-8-(methylsulfonyl)-1H-pyrazolo[4,3-h]quinazolin-1-yl]piperidine-1-carboxylate 30 mg (0.063 mmol) in THF (3 ml), pyrrolidine 70 μl (1 mmol) was added. The solution was stirred at room temperature for 1 hour and monitored by LC/MS. The reaction mixture was cooled to room temperature; the separated solid was filtered and washed with diethyl ether to afford tert-butyl 4-[3-carbamoyl-8-(pyrrolidin-1-yl)-1H-pyrazolo[4,3-h]quinazolin-1-yl]piperidine-1-carboxylate 15 mg (50%). LC/MS (m/z): 475.0 [M+H]+, HPLC (254 nm) method 4 Rt 2.01 min.
Reaction SMILES: [H-].[Na+].[O:3]=[C:4]([CH3:11])[CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7].Cl[C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][C:14]=1[N+:22]([O-:24])=[O:23].Cl>O1CCCC1>[N+:19]([C:16]1[CH:15]=[C:14]([N+:22]([O-:24])=[O:23])[CH:13]=[CH:18][C:17]=1[CH:5]([C:4](=[O:3])[CH3:11])[C:6]([O:8][CH2:9][CH3:10])=[O:7])([O-:21])=[O:20]
Reactant: O=[N+]([O-])c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: CCOC(=O)CC(C)=O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C(C(C)=O)c1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 98 %

Procedure:
Sodium hydride (417 mmol) was added to a solution of ethyl 3-oxobutanoate (129 mmol) in tetrahydrofuran (350 mL). 1-Chloro-2,4-dinitrobenzene (123 mmol) was added and the resulting suspension was maintained for 24 h at rt. The pH was adjusted to 5 by the addition of 3 M hydrochloric acid and the resulting solution was extracted with diethyl ether (300 mL). The organic layer was washed with water (3×300 mL), dried (magnesium sulfate), and concentrated to provide ethyl 2-(2,4-dinitrophenyl)-3-oxobutanoate in 98% yield as a brown solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:12][CH2:13]O)[CH:6]=[C:7]2[O:11][CH2:10][O:9][C:8]=12.P(Br)(Br)[Br:16].O.C(=O)([O-])O.[Na+]>C(OCC)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:12][CH2:13][Br:16])[CH:6]=[C:7]2[O:11][CH2:10][O:9][C:8]=12
Reactant: COc1cc(CCO)cc2c1OCO2
Reactant: BrP(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Product: COc1cc(CCBr)cc2c1OCO2
Yield: 122.1 %

Procedure:
2.74 g (14 mmol) of 2-(3-methoxy-4,5-methylenedioxyphenyl)ethyl alcohol (3) was dissolved in 10 ml of ethyl ether, to which was added portionwise 1.64 g (6.1 mmol) of phosphorus tribromide in 2 ml of ethyl ether under ice-cooling. The mixture was refluxed under heating for one hour, then cooled and further stirred while adding 10 ml of water and 15 ml of a saturated sodium hydrogencarbonate aqueous solution. The reaction mixture was separated and the ether layer was washed with 10 ml of a saturated saline solution, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica column chromatography (eluate: ethyl acetate / n-hexane=1/2) to obtain 1.93 g of 2-(3-methoxy-4,5-methylenedioxyphenyl)ethyl bromide (6) as a crystal with a yield of 53%. Melting point: 78°-79° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[OH:13])[N:9]=[CH:8][CH:7]=[C:6]2[O:14][C:15]1[C:16]([C:23]2[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][N:24]=2)=[N:17][C:18]([CH3:22])=[C:19]([CH3:21])[CH:20]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:37][CH2:38][CH2:39][OH:40]>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:37][CH2:38][CH2:39][OH:40])[N:9]=[CH:8][CH:7]=[C:6]2[O:14][C:15]1[C:16]([C:23]2[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][N:24]=2)=[N:17][C:18]([CH3:22])=[C:19]([CH3:21])[CH:20]=1
Reactant: OCCCBr
Reactant: COc1cc2c(Oc3cc(C)c(C)nc3-c3ccc(C)cn3)ccnc2cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3cc(C)c(C)nc3-c3ccc(C)cn3)ccnc2cc1OCCCO
Temperature: 25 °C
Reaction time: 8 h
Yield: 46 %

Procedure:
6-Methoxy-4-(5,6,5′-trimethyl-[2,2′]bipyridin-3-yloxy)-quinolin-7-ol (compound 453) (50 mg) was suspended in N,N-dimethylformamide (2 ml). Potassium carbonate (54 mg) and 3-bromo-1-propanol (0.03 ml) were added to the suspension, and the mixture was stirred at room temperature overnight. The solvent was removed by distillation under the reduced pressure, water was then added to the residue, and the mixture was extracted with chloroform. The chloroform layer was washed with saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using chloroform-acetone to give the title compound (26 mg, yield 46%).
Reaction SMILES: [C:1]([C:3]1[CH:20]=[CH:19][C:6]([CH2:7][NH:8][S:9]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)(=[O:11])=[O:10])=[CH:5][CH:4]=1)#[N:2].N[CH2:22][CH2:23][SH:24].[Cl-].[Na+]>C(O)C>[S:24]1[CH2:23][CH2:22][N:2]=[C:1]1[C:3]1[CH:4]=[CH:5][C:6]([CH2:7][NH:8][S:9]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)(=[O:11])=[O:10])=[CH:19][CH:20]=1
Reactant: N#Cc1ccc(CNS(=O)(=O)c2ccc(F)cc2)cc1
Reactant: NCCS
Agent: [Cl-]
Agent: [Na+]
Solvent: CCO
Product: O=S(=O)(NCc1ccc(C2=NCCS2)cc1)c1ccc(F)cc1
Yield: 88.8 %

Procedure:
To a solution of N-(4-cyanobenzyl)-4-fluorobenzenesulfonamide (1.23 g, 4.24 mmol) obtained in Reference Example 7-(a) in ethanol (5 ml) was added 2-aminoethanethiol (0.426 g, 5.52 mmol), which was deaerated under reduced pressure, followed by argon substitution. This reaction mixture was then heated to reflux for 6 hours. After completion of the reaction, a saturated aqueous sodium chloride solution was added to the reaction solution, followed by extraction with ethyl acetate. The separated organic layer was dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography (eluent; chloroform:ethyl acetate=7:3 (VAT)), and fractions containing the desired compound were concentrated under reduced pressure to afford the title compound (1.32 g) as a white solid. (Yield: 89%)
Reaction SMILES: [CH2:1]([C:6]1[CH:11]=[CH:10][C:9]([C:12]#[CH:13])=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH2:4][CH3:5].[F:14][C:15]1[CH:16]=[C:17](I)[CH:18]=[CH:19][C:20]=1[Cl:21]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.C(NCC)C>[CH2:1]([C:6]1[CH:7]=[CH:8][C:9]([C:12]#[C:13][C:17]2[CH:18]=[CH:19][C:20]([Cl:21])=[C:15]([F:14])[CH:16]=2)=[CH:10][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: C#Cc1ccc(CCCCC)cc1
Reactant: Fc1cc(I)ccc1Cl
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCNCC
Product: CCCCCc1ccc(C#Cc2ccc(Cl)c(F)c2)cc1
Reaction time: 12 h

Procedure:
0.2 mmol of Pd(PPh3)2Cl2 and 0.1 mmol of CuI are added to a mixture of 0.01 mol of 4-pentylphenylacetylene, 0.01 mol of 3-fluoro-4-chloro-iodobenzene and 40 ml of diethylamine at room temperature and stirred for 12 hours. After completion of the reaction, the suspension is filtered, and the filtrate is concentrated by evaporation. Purification by chromatography and/or crystallization gives 4-pentyl-3'-fluoro-4'-chloro tolan having C 49.6° I.
Reaction SMILES: [OH:1][C:2]1[CH:14]=[CH:13][C:12]2[NH:11][C:10]3[CH:9]=[C:8](I)[C:7]4[C:16](=[O:20])[NH:17][C:18](=[O:19])[C:6]=4[C:5]=3[C:4]=2[CH:3]=1.[CH:21]([C:23]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][CH:24]=1)=[O:22]>>[OH:1][C:2]1[CH:14]=[CH:13][C:12]2[NH:11][C:10]3[CH:9]=[C:8]([C:26]4[CH:27]=[CH:28][C:23]([CH:21]=[O:22])=[CH:24][CH:25]=4)[C:7]4[C:16](=[O:20])[NH:17][C:18](=[O:19])[C:6]=4[C:5]=3[C:4]=2[CH:3]=1
Reactant: O=Cc1ccc(B(O)O)cc1
Reactant: O=C1NC(=O)c2c1c(I)cc1[nH]c3ccc(O)cc3c21
Product: O=Cc1ccc(-c2cc3[nH]c4ccc(O)cc4c3c3c2C(=O)NC3=O)cc1
Yield: 52 %

Procedure:
The reaction of 9-hydroxy-4-iodopyrrolo[3,4-c]carbazole-1,3(2H,6H)-dione, prepared as in example 7, with 4-formylbenzeneboronic acid according to the procedure described in example 8 gave 4-(9-hydroxy-1,3-dioxo-1,2,3,6-tetrahydropyrrolo[3,4-c]carbazol-4-yl)benzaldehyde (509) (I; Ar=4-formylphenyl) in a 52% yield; mp (THF/CH2Cl2/pentane) 276–280° C. 1H NMR [(CD3)2SO] δ 11.84 (br s, 1H), 11.07 (br s, 1H), 10.11 (s, 1H), 9.28 (br s, 1H), 8.34 (d, J=2.3 Hz, 1H), 8.00 (d, J=8.2 Hz, 2H), 7.85 (d, J=8.1 Hz, 2H), 7.65 (s, 1H), 7.46 (d, J=8.7 Hz, 1H), 7.08 (dd, J=8.7, 2.4 Hz, 1H). Found: C, 68.43; H, 4.16; N, 7.26. C21H12N2O4.3/4H2O requires C, 68.20; H, 3.68; N, 7.57. FABMS found [M+H]+: 357.0841. C21H13N2O4 requires 357.0875.
Reaction SMILES: Cl.[NH2:2][CH:3]1[CH2:7][CH2:6][N:5]([C:8]2[N:9]=[C:10]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([O:26][CH3:27])[CH:19]=3)[C:11]3[N:16]=[CH:15][S:14][C:12]=3[N:13]=2)[CH2:4]1.[NH2:28][C:29]1[CH:37]=[CH:36][C:32]([C:33](O)=[O:34])=[CH:31][N:30]=1.CCN=C=NCCCN(C)C.CN1C=CN=C1>C(Cl)Cl>[NH2:28][C:29]1[CH:37]=[CH:36][C:32]([C:33]([NH:2][CH:3]2[CH2:7][CH2:6][N:5]([C:8]3[N:9]=[C:10]([NH:17][C:18]4[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([O:26][CH3:27])[CH:19]=4)[C:11]4[N:16]=[CH:15][S:14][C:12]=4[N:13]=3)[CH2:4]2)=[O:34])=[CH:31][N:30]=1
Reactant: COc1ccc(Nc2nc(N3CCC(N)C3)nc3scnc23)cc1OC
Reactant: Nc1ccc(C(=O)O)cn1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Cn1ccnc1
Solvent: ClCCl
Product: COc1ccc(Nc2nc(N3CCC(NC(=O)c4ccc(N)nc4)C3)nc3scnc23)cc1OC
Temperature: 25 °C
Reaction time: 16 h
Yield: 33.1 %

Procedure:
A mixture of 5-(3-aminopyrrolidin-1-yl)-N-(3,4-dimethoxyphenyl)thiazolo[5,4-d]pyrimidin-7-amine hydrochloride (100 mg, 0.245 mmol), 6-aminonicotinic acid (40 mg, 0.27 mmol), EDCI (97 mg, 0.49 mmol) and N-methylimidazole (60 mg, 0.735 mmol) in 5 mL of DCM was stirred at room temperature for 16 hours. The mixture was washed with water (5 mL), The organic layer was dried over Na2SO4. After filtration and concentration, the residue was purified by column chromatography on silica gel eluting with a mixture of CH2Cl2 and methanol (100:1→15:1) to give 6-amino-N-(1-(7-(3,4-dimethoxyphenylamino)thiazolo[5,4-d]pyrimidin-5-yl)pyrrolidin-3-yl)nicotinamide (40 mg, 33%). 1H NMR (300 MHz, DMSO): δ 9.57 (s, 1H), 8.81 (s, 1H), 8.475-8.46 (m, 1H), 8.27-8.25 (m, 2H), 7.60-7.25 (m, 2H), 6.92 (d, 1H, J=8.7 Hz), 6.47-6.39 (m, 3H), 4.54-4.52 (m, 1H), 3.76-3.58 (m, 10H), 2.34-2.04 (m, 2H). LC-MS: 247 [M/2+H]+, 493 [M+H]+, 491 [M−H]−, tR=1.22 min. HPLC: 95.20% at 214 nm, 95.06% at 254 nm, tR=5.64 min.
Reaction SMILES: COC([CH:5]1[CH2:10][C:9]([C:17]#[N:18])([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:8][CH2:7][C:6]1=[O:19])=O.C(O)(=O)C>S(=O)(=O)(O)O.O>[O:19]=[C:6]1[CH2:7][CH2:8][C:9]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)([C:17]#[N:18])[CH2:10][CH2:5]1
Reactant: COC(=O)C1CC(C#N)(c2ccccc2)CCC1=O
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(=O)O
Product: N#CC1(c2ccccc2)CCC(=O)CC1

Procedure:
5-cyano-2-oxo-5-phenyl cyclohexane carboxylic acid methyl ester (16.1 g, 63 mmol) was dissolved in 10% sulphuric acid (218 mL) and conc. acetic acid (502 mL) and stirred for 21 h at 100° C. For work up the batch was carefully diluted with water (400 mL) with ice cooling, extracted with ethyl acetate (3×100 mL), the organic phase washed thoroughly with water (6×100 mL), saturated NaHCO3 solution (10×100 mL) and saturated NaCl solution (1×100 mL). After drying with Na2SO4 the solvent was distilled off in a vacuum.
Reaction SMILES: [C@@H:1]1([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[H-].[Na+].I[CH3:21]>C1COCC1>[C@@H:1]1([N:10]([CH3:21])[C:11](=[O:17])[O:12][C:13]([CH3:14])([CH3:16])[CH3:15])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCc2ccccc21
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN(C(=O)OC(C)(C)C)[C@H]1CCc2ccccc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of tert-butyl(1S)-2,3-dihydro-1H-inden-1-ylcarbamate (1.82 g, 7.80 mmol) in THF (50.0 mL) under an atmosphere of argon at 0° C. was added 60% sodium hydride in mineral oil (968 mg, 24.2 mmol) and the suspension was allowed to warm to rt and stir for 30 min. Iodomethane (1.52 mL, 24.2 mmol) was added and the mixture was stirred overnight. The reaction was then quenched via addition of saturated ammonium chloride solution (10.0 mL) and was concentrated in vacuo. The mixture was then partitioned between water (20 mL) and DCM (50 mL) and the aqueous layer was extracted with DCM (3×50 mL). The combined organic layers were dried over MgSO4, filtered, concentrated in vacuo and purified by silica gel chromatography eluting with a gradient of 0 to 20% EtOAc in hexanes to afford the title compound as a clear, colorless oil (1.84 g, 95%). LC/MS: Rt=2.21 min, ES+ 248 (AA standard).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[CH:5]([C:11]1[N:12]=[C:13]([NH2:16])[S:14][CH:15]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2].[C:18](Cl)([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(N(CC)CC)C.Cl>ClCCl>[CH2:1]([O:3][C:4](=[O:17])[CH:5]([C:11]1[N:12]=[C:13]([NH:16][C:18]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)([C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[S:14][CH:15]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2]
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCOC(=O)C(C(=O)OCC)c1csc(N)n1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)C(C(=O)OCC)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Temperature: 25 °C
Reaction time: 24 h
Yield: 98.2 %

Procedure:
To a solution of 2-(2-amino-4-thiazolyl)malonic acid diethyl ester in dichloromethane (15 parts) are added trityl chloride (1.05 equivalents) and triethylamine (1.05 equivalents) under nitrogen at 0° C. After stirring at room temperature for 24 hours, the reaction mixture is poured onto diluted hydrochloric acid and extracted with ethyl acetate. The extract is washed with water, dried, and concentrated in vacuum to give 2-(2-tritylamino-4-thiazolyl)malonic acid diethyl ester. Yield: 98.2%.
Reaction SMILES: [ClH:1].O1CCOCC1.[Cl:8][C:9]1[S:10][CH:11]=[C:12]([C:14]([N:16]2[CH2:21][CH2:20][N:19](C(OC(C)(C)C)=O)[CH2:18][CH:17]2[CH2:29][O:30][C:31]2[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=2)=[O:15])[N:13]=1>CO>[ClH:8].[ClH:1].[Cl:8][C:9]1[S:10][CH:11]=[C:12]([C:14]([N:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH:17]2[CH2:29][O:30][C:31]2[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=2)=[O:15])[N:13]=1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)c2csc(Cl)n2)C(COc2cccnc2)C1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: O=C(c1csc(Cl)n1)N1CCNCC1COc1cccnc1
Reaction time: 8 h
Yield: 99 %

Procedure:
4 M HCl in 1,4-dioxane (6 mL, 24 mmol) was added to a solution of tert-butyl 4-(2-chlorothiazole-4-carbonyl)-3-((pyridin-3-yloxy)methyl)piperazine-1-carboxylate (36 mg, 0.083 mmol) in MeOH (1 mL). After stirring overnight, the reaction mixture was concentrated under reduced pressure, yielding 33.8 mg (99%) of the desired product as a white solid. LC-MS: RT=3.12 min, (M+H)+=338.9.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[C:12]([CH3:33])([CH3:32])[C:13](=[O:31])[N:14]([CH:16]3[CH2:21][CH2:20][N:19]([C:22]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[OH:30])=[O:23])[CH2:18][CH2:17]3)[N:15]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].C(=O)([O-])[O-].[K+].[K+].I[CH:41]1[CH2:45][CH2:44][CH2:43][CH2:42]1>C(#N)C>[CH:41]1([O:30][C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[C:22]([N:19]2[CH2:20][CH2:21][CH:16]([N:14]3[C:13](=[O:31])[C:12]([CH3:33])([CH3:32])[C:11]([C:5]4[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=4)=[N:15]3)[CH2:17][CH2:18]2)=[O:23])[CH2:45][CH2:44][CH2:43][CH2:42]1
Reactant: IC1CCCC1
Reactant: COc1ccc(C2=NN(C3CCN(C(=O)c4ccccc4O)CC3)C(=O)C2(C)C)cc1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1ccc(C2=NN(C3CCN(C(=O)c4ccccc4OC4CCCC4)CC3)C(=O)C2(C)C)cc1OC

Procedure:
1.0 g of 5-(3,4-dimethoxyphenyl)-2-{1-[(2-hydroxyphenyl)carbonyl]piperidin-4-yl}-4,4-dimethyl-2,4-dihydro-3H-pyrazol-3-one (compound described in example 94) and 1.0 g potassium carbonate are suspended in 20 ml of acetonitrile. 0.5 g of iodocyclopentane are added and the reaction mixture is heated to reflux for 5 h until the reaction is completed according to TLC analysis. The solvent is evaporated under reduced pressure, and the remaining residue is taken up in EA. The organic phase is washed with water, dried over MgSO4, and the solvent is removed under reduced pressure. Purification of the resulting crude product by crystallization from methanol yields the title compound.
Reaction SMILES: [CH3:1][C:2]12[C:14]3[C:6](=[CH:7][C:8]([NH2:15])=[CH:9][C:10]=3[CH2:11][CH2:12][CH2:13]1)[CH2:5][CH2:4][CH2:3]2.Cl[C:17]1[N:22]=[CH:21][C:20]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:19][N:18]=1.C(=O)([O-])[O-].[K+].[K+]>O>[CH3:1][C:2]12[C:14]3[C:6](=[CH:7][C:8]([NH:15][C:17]4[N:18]=[CH:19][C:20]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:21][N:22]=4)=[CH:9][C:10]=3[CH2:11][CH2:12][CH2:13]1)[CH2:5][CH2:4][CH2:3]2
Reactant: CC12CCCc3cc(N)cc(c31)CCC2
Reactant: CCOC(=O)c1cnc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CCOC(=O)c1cnc(Nc2cc3c4c(c2)CCCC4(C)CCC3)nc1
Temperature: 110 °C
Reaction time: 8 h
Yield: 83.6 %

Procedure:
6a-Methyl-5,6,6a,7,8,9-hexahydro-4H-2-phenalenylamine (0.111 g) was added with ethyl 2-chloropyrimidine-5-carboxylate (0.104 g) and potassium carbonate (0.400 g), and the mixture was stirred overnight at 110° C. The reaction mixture was left to cool and then added with water, and the mixture was extracted with chloroform. The organic layer was washed successively with water and saturated brine, and dried over anhydrous sodium sulfate. The organic layer was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (developing solvent: ethyl acetate:n-hexane=1:20) to obtain the title compound (0.162 g, yield: 84%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][O:11][C:12]1[C:16]([C:17](=O)[NH2:18])=[C:15]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[O:14][N:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].P(Cl)(Cl)(Cl)=O>CN(C)C=O>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][O:11][C:12]1[C:16]([C:17]#[N:18])=[C:15]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[O:14][N:13]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCCOc1noc(-c2ccccc2)c1C(N)=O
Solvent: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: CC(C)(C)OC(=O)NCCOc1noc(-c2ccccc2)c1C#N
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 77.7 %

Procedure:
3-(2-(N-tert-Butoxycarbonylamino)ethoxy)-4-carbamoyl-5-phenylisoxazole (0.38 g) was dissolved in dimethylformamide (4 ml), and phosphorus oxychloride (0.11 ml) was added dropwise thereto at 5° C. under a nitrogen atmosphere, followed by stirring of the mixture at room temperature for 30 minutes. The reaction mixture was poured into ice-cold water and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous NaCl solution and dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=3/1) to obtain the title compound (0.28 g, 78%) as a colorless solid.