Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH2:5])(=[O:4])[CH:2]=[CH2:3].[CH2:6]([C:16](=C)[C:17]([NH2:19])=[O:18])CCCCCCCCC.[CH:21]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[CH:29]=[CH2:30])=[CH2:22].O>C(O)C>[C:1]([NH2:5])(=[O:4])[CH:2]=[CH2:3].[CH2:30]([NH:19][C:17](=[O:18])[CH:16]=[CH2:6])[CH2:29][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:23][CH2:21][CH3:22]
Reactant: C=Cc1ccccc1C=C
Reactant: C=C(CCCCCCCCCC)C(N)=O
Agent: C=CC(N)=O
Solvent: O
Solvent: CCO
Product: C=CC(=O)NCCCCCCCCCC

Procedure:
Polystyrenesulfonate (22.5 mmoles, 3.918 g), acrylamide (3.45 mmoles, 0.245 g), n-decylacrylamide (3.45 mmoles, 0.729 g) and divinylbenzene (0.6 mmoles, 85.5 microL) were dissolved in 15 mL ethanol and 5 mL water in a 40 mL vial fitted with a septa cap. The solution was degassed by bubbling nitrogen through and 1 mole % AIBN was added as a solution. The polymerization solution was further degassed and the placed in a heated reaction block at 60° C. for 18 h. A creamy yellow gel formed.
Reaction SMILES: C1([CH:7]([C:12]2[CH:17]=[CH:16][C:15]([CH2:18][C:19]([OH:21])=[O:20])=[CH:14][CH:13]=2)[CH2:8][C:9](O)=[O:10])C=CC=CC=1>O>[O:10]=[C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:7]([C:12]2[CH:13]=[CH:14][C:15]([CH2:18][C:19]([OH:21])=[O:20])=[CH:16][CH:17]=2)[CH2:8]1
Reactant: O=C(O)Cc1ccc(C(CC(=O)O)c2ccccc2)cc1
Solvent: O
Product: O=C(O)Cc1ccc(C2CC(=O)c3ccccc32)cc1
Reaction time: 0.5 h

Procedure:
Polyphosphoric acid (1 kg) was stirred and heated to 95°-100° C. and β-phenyl-p-(carboxymethyl)-hydrocinnamic acid (0.48 mol) added over 10 minutes. The mixture was stirred for 1/2 hour and poured into ice and H2O; the title product was continuously extracted with CHCl3 and recrystallised from ether, m.p. 151° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:9]2[NH:13][N:12]=[N:11][N:10]=2)=[C:6]([CH:8]=1)[NH2:7].[CH3:14][O:15][C:16]1[CH:17]=[C:18]([CH:22]=[CH:23][CH:24]=1)[C:19](Cl)=[O:20]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:9]2[NH:13][N:12]=[N:11][N:10]=2)=[C:6]([NH:7][C:19](=[O:20])[C:18]2[CH:22]=[CH:23][CH:24]=[C:16]([O:15][CH3:14])[CH:17]=2)[CH:8]=1
Reactant: COc1cccc(C(=O)Cl)c1
Reactant: Nc1cc(Cl)ccc1-c1nnn[nH]1
Product: COc1cccc(C(=O)Nc2cc(Cl)ccc2-c2nnn[nH]2)c1
Yield: 9 %

Procedure:
The title compound was prepared essentially according to the method of Example 4, but using 5-Chloro-2-(1H-tetrazol-5-yl)aniline (1.0 mmol) and 3-methoxybenzoyl chloride to afford the desired product (29.1 mg, 9%). 1H NMR (400 MHz, d6-DMSO): δ 10.81 (s, 1H), 8.75 (s, 1H), 8.06 (s, 1H), 7.60 (m, 3H), 7.25 (s, 1H), 3.89 (s, 3H). MS (EI) for C15H12ClN5O2: 329.7 (M+H).
Reaction SMILES: [S:1]1[C:5]([CH:6]([NH:8][C:9]2[C:10]([CH3:21])=[N:11][O:12][C:13]=2[C:14]2[CH:19]=[CH:18][C:17](Br)=[CH:16][CH:15]=2)[CH3:7])=[CH:4][C:3]2[CH:22]=[CH:23][CH:24]=[CH:25][C:2]1=2.[CH2:26]([O:28][C:29](=[O:49])[CH2:30][C:31]1([C:34]2[CH:39]=[CH:38][C:37](B3OC(C)(C)C(C)(C)O3)=[CH:36][CH:35]=2)[CH2:33][CH2:32]1)[CH3:27]>>[CH2:26]([O:28][C:29](=[O:49])[CH2:30][C:31]1([C:34]2[CH:39]=[CH:38][C:37]([C:17]3[CH:18]=[CH:19][C:14]([C:13]4[O:12][N:11]=[C:10]([CH3:21])[C:9]=4[NH:8][CH:6]([C:5]4[S:1][C:2]5[CH:25]=[CH:24][CH:23]=[CH:22][C:3]=5[CH:4]=4)[CH3:7])=[CH:15][CH:16]=3)=[CH:36][CH:35]=2)[CH2:33][CH2:32]1)[CH3:27]
Reactant: CCOC(=O)CC1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1NC(C)c1cc2ccccc2s1
Product: CCOC(=O)CC1(c2ccc(-c3ccc(-c4onc(C)c4NC(C)c4cc5ccccc5s4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 1, Step 7, using (1-benzo[b]thiophen-2-yl-ethyl)-[5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-amine and {1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropyl}-acetic acid ethyl ester.
Reaction SMILES: Br.[CH3:2][C:3]1([CH3:26])[CH2:12][CH2:11][C:10]([CH3:14])([CH3:13])[C:9]2[CH:8]=[C:7]([C:15]3[N:16]=[C:17]([N:20]4[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]4)[S:18][CH:19]=3)[CH:6]=[CH:5][C:4]1=2.C([O:29][C:30](=[O:35])[CH2:31][CH2:32][CH2:33]Br)C.C(O)(C(F)(F)F)=O>>[CH3:2][C:3]1([CH3:26])[CH2:12][CH2:11][C:10]([CH3:13])([CH3:14])[C:9]2[CH:8]=[C:7]([C:15]3[N:16]=[C:17]([N:20]4[CH2:21][CH2:22][N:23]([CH2:33][CH2:32][CH2:31][C:30]([OH:35])=[O:29])[CH2:24][CH2:25]4)[S:18][CH:19]=3)[CH:6]=[CH:5][C:4]1=2
Reactant: CC1(C)CCC(C)(C)c2cc(-c3csc(N4CCNCC4)n3)ccc21
Reactant: CCOC(=O)CCCBr
Agent: Br
Solvent: O=C(O)C(F)(F)F
Product: CC1(C)CCC(C)(C)c2cc(-c3csc(N4CCN(CCCC(=O)O)CC4)n3)ccc21

Procedure:
The preparation was carried out analogously starting from 100 mg (0.17 mmol) of 1-[4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)thiazol-2-yl]piperazine hydrobromide and 63 mg (0.35 mmol) of 4-bromobutyric acid ethyl ester. The product is in the form of the TFA salt.
Reaction SMILES: [C:1]([C:3]1[N:4]=[CH:5][C:6]([NH:19][C@H:20]([CH2:24][CH:25]2[CH2:27][CH2:26]2)[C:21]([NH2:23])=[O:22])=[N:7][C:8]=1[NH:9][C:10]1[C:18]2[C:13](=[N:14][CH:15]=[CH:16][CH:17]=2)[S:12][CH:11]=1)#[N:2].[OH-].[Na+].OO.CC(O)=[O:34]>CCO.CS(C)=O>[NH2:23][C:21](=[O:22])[C@H:20]([NH:19][C:6]1[N:7]=[C:8]([NH:9][C:10]2[C:18]3[C:13](=[N:14][CH:15]=[CH:16][CH:17]=3)[S:12][CH:11]=2)[C:3]([C:1]([NH2:2])=[O:34])=[N:4][CH:5]=1)[CH2:24][CH:25]1[CH2:26][CH2:27]1
Reactant: N#Cc1ncc(N[C@H](CC2CC2)C(N)=O)nc1Nc1csc2ncccc12
Reactant: CC(=O)O
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CS(C)=O
Product: NC(=O)c1ncc(N[C@H](CC2CC2)C(N)=O)nc1Nc1csc2ncccc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of (R)-2-(6-chloro-5-cyanopyrazin-2-ylamino)-3-cyclopropylpropanamide (78 mg, 0.293 mmol), thieno[2,3-b]pyridin-3-amine (60 mg, 0.400 mmol), K2CO3 (70 mg, 0.507 mmol), BINAP (25 mg, 0.040 mmol) and Pd(OAc)2 (10 mg, 0.044 mmol) in dioxane (2 mL) was degassed with Ar, then was stirred at 110 C for 3 h. The mixture was concentrated in vacuo. The residue was purified by HPLC to give (R)-2-(5-cyano-6-(thieno[2,3-b]pyridin-3-ylamino)pyrazin-2-ylamino)-3-cyclopropylpropanamide (33 mg). The compound (R)-2-(5-cyano-6-(thieno[2,3-b]pyridin-3-ylamino)pyrazin-2-ylamino)-3-cyclopropylpropanamide (33 mg, 0.087 mmol) was dissolved in EtOH (2 mL) and DMSO (1 mL), aq. 1N NaOH (1.0 mL) and aq. H2O2 (30%, 1.0 mL) were added. The mixture was stirred at room temperature for 30 min. HOAc (0.5 mL) was added. The mixture was then concentrated in vacuo. The residue was purified by HPLC to give the titled compound (34 mg). MS 398.2 (M+H); UV 203.6, 224.8, 262.1, 294.1, 357.3 nm; t 0.532 min.
Reaction SMILES: [Cl:1][CH:2]([Cl:6])[C:3](Cl)=[O:4].[C:7]1([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[NH2:20])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.ClC(Cl)(Cl)C(Cl)=O.C1C=CC(NC2C=CC(N)=CC=2)=CC=1>>[NH:13]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[NH:20][C:3](=[O:4])[CH:2]([Cl:6])[Cl:1])[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: O=C(Cl)C(Cl)Cl
Reactant: Nc1ccccc1Nc1ccccc1
Agent: Nc1ccc(Nc2ccccc2)cc1
Agent: O=C(Cl)C(Cl)(Cl)Cl
Product: O=C(Nc1ccccc1Nc1ccccc1)C(Cl)Cl

Procedure:
This compound is prepared in the same manner as Compound I, except that dichloroacetyl chloride (5.75 g) and N-phenyl-o-phenylenediamine (7.0 g) are used in place of trichloroacetyl chloride and 4-aminodiphenylamine, respectively. The product is recrystallized from a hexane/benzene (5/1) solvent mixture. The m.p. and chemical analysis are reported in Table I. This compound, which is also called ortho-dichloroacetylaminodiphenylamine, is referred to in U.S. Pat. No. 3,250,774, May 10, 1966, Schmidt et al.
Reaction SMILES: [F:1][C:2]1[C:3]([NH:20][C:21]2[CH:25]=[C:24]([O:26][CH:27]([CH3:29])[CH3:28])[NH:23][N:22]=2)=[N:4][C:5]([NH:10][C@H:11]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[CH3:12])=[C:6]([CH:9]=1)[C:7]#[N:8].[OH-:30].[K+].OO>CO>[F:1][C:2]1[C:3]([NH:20][C:21]2[CH:25]=[C:24]([O:26][CH:27]([CH3:29])[CH3:28])[NH:23][N:22]=2)=[N:4][C:5]([NH:10][C@H:11]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[CH3:12])=[C:6]([CH:9]=1)[C:7]([NH2:8])=[O:30]
Reactant: CC(C)Oc1cc(Nc2nc(N[C@@H](C)c3ccc(F)cc3)c(C#N)cc2F)n[nH]1
Reactant: [OH-]
Agent: OO
Agent: [K+]
Solvent: CO
Product: CC(C)Oc1cc(Nc2nc(N[C@@H](C)c3ccc(F)cc3)c(C(N)=O)cc2F)n[nH]1
Temperature: 65 °C
Yield: 27.8 %

Procedure:
(S)-5-Fluoro-2-(1-(4-fluorophenyl)ethylamino)-6-(5-isopropoxy-1H-pyrazol-3-ylamino)nicotinonitrile (Example 16; 0.15 g, 0.38 mmol), was placed in MeOH (7 ml) at 25° C. A 25% aqueous solution (0.4 ml) of KOH (0.11 g, 1.9 mmol) was then added, followed by the addition of 0.1 ml of 30% H2O2. The resulting dark red solution was heated to 65° C. for 1 h, cooled to 25° C., and concentrated. The resulting residue was dissolved in EtOAc (50 ml), washed with water (30 ml), dried, filtered, and concentrated. The resulting solid was purified by column chromatography (DCM-MeOH=25:1) to give the title compound (0.044 g, 28%). 1H NMR (400 MHz, CD3OD) δ 7.75 (d, J=11.7 Hz, 1H), 7.39-7.36 (m, 2H), 7.04-7.00 (m, 2H), 5.37 (s, 1H), 5.11-5.00 (m, 1H), 4.61-4.52 (m, 1H), 1.53 (d, J=7.0 Hz, 3H), 1.31 (m, 6H). MS: Calcd.: 416. Found: [M+H]+417.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.[Cl:9][C:10]1[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[CH:13]=[CH:12][C:11]=1[OH:19].C(N(CC)C(C)C)(C)C>CS(C)=O>[NH2:1][C:2]1[CH:7]=[C:6]([O:19][C:11]2[CH:12]=[CH:13][C:14]([N+:16]([O-:18])=[O:17])=[CH:15][C:10]=2[Cl:9])[CH:5]=[CH:4][N:3]=1
Reactant: Nc1cc(Cl)ccn1
Reactant: O=[N+]([O-])c1ccc(O)c(Cl)c1
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: Nc1cc(Oc2ccc([N+](=O)[O-])cc2Cl)ccn1
Temperature: 160 °C
Reaction time: 144 h
Yield: 10.8 %

Procedure:
2-Amino-4-chloropyridine (2.57 g) was dissolved in dimethylsulfoxide (30 ml), and then 2-chloro-4-nitrophenol (6.94 g) and N,N-diisopropylethylamine (14 ml) were added thereto, followed by stirring at 160° C. for 6 days. The reaction mixture was cooled down to room temperature, and partitioned between ethyl acetate and a 1 N aqueous solution of sodium hydroxide. The organic layer was washed with a 1 N aqueous solution of sodium hydroxide and brine in this order, and dried over anhydrous sodium sulfate. The solvent was evaporated to give a residue, which was purified by silica gel column chromatography (eluent; hexane:ethyl acetate=1:2, then ethyl acetate) to provide the titled compound (574 mg, 11%) as brown powder.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][CH2:11][OH:12])=[CH:2]1.[C:13]([OH:20])(=[O:19])[CH2:14][CH2:15][C:16]([CH3:18])=O.B(F)(F)F.CCOCC>C1C=CC=CC=1>[CH3:18][C:16]1([CH2:15][CH2:14][C:13]([OH:20])=[O:19])[C:2]2[CH2:1][C:9]3[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=3[C:3]=2[CH2:10][CH2:11][O:12]1
Reactant: OCCC1=CCc2ccccc21
Reactant: CC(=O)CCC(=O)O
Agent: FB(F)F
Solvent: CCOCC
Solvent: c1ccccc1
Product: CC1(CCC(=O)O)OCCC2=C1Cc1ccccc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of indene-3-ethanol (15 g), dry benzene (300 ml), levulinic acid (22.6 g), boron trifluoride etherate (3 ml) and hydrated alkali-aluminum silicate (Molecular Sieves No. 4) is stirred at ambient temperature for 2 hr.
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[CH:5]=[C:6]([N:10]2[C:25](=[O:26])[C:14]3[CH:15]=[N:16][C:17]4[C:18]([O:23][CH3:24])=[CH:19][CH:20]=[CH:21][C:22]=4[C:13]=3[N:12]([CH:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)[C:11]2=[O:33])[CH:7]=[CH:8][CH:9]=1.[CH3:34][N:35]([CH3:40])[S:36](Cl)(=[O:38])=[O:37]>>[CH3:34][N:35]([CH3:40])[S:36]([N:30]1[CH2:31][CH2:32][CH:27]([N:12]2[C:13]3[C:22]4[CH:21]=[CH:20][CH:19]=[C:18]([O:23][CH3:24])[C:17]=4[N:16]=[CH:15][C:14]=3[C:25](=[O:26])[N:10]([C:6]3[CH:7]=[CH:8][CH:9]=[C:4]([Cl:3])[CH:5]=3)[C:11]2=[O:33])[CH2:28][CH2:29]1)(=[O:38])=[O:37]
Reactant: COc1cccc2c1ncc1c(=O)n(-c3cccc(Cl)c3)c(=O)n(C3CCNCC3)c12
Reactant: CN(C)S(=O)(=O)Cl
Agent: Cl
Product: COc1cccc2c1ncc1c(=O)n(-c3cccc(Cl)c3)c(=O)n(C3CCN(S(=O)(=O)N(C)C)CC3)c12

Procedure:
4-[3-(3-Chloro-phenyl)-7-methoxy-2,4-dioxo-3,4-dihydro-2H-pyrimido[5,4-c]quinolin-1-yl]-piperidine-1-sulfonic acid dimethylamide (48 mg) was prepared according to general procedure H from 3-(3-chloro-phenyl)-7-methoxy-1-piperidin-4-yl-1H-pyrimido[5,4-c]quinoline-2,4-dione.dihydrochloride (50 mg, 0.1 mmol) and N,N-dimethylsulfamoyl chloride. LCMS: m/z 544 [M+1]+.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH3:10])=[CH:5][CH:4]=1)#[N:2].[N-:19]=[N+:20]=[N-:21].[Na+].[Cl-].[NH4+]>CN(C)C=O.CCOCC>[N:2]1[NH:19][N:20]=[N:21][C:1]=1[C:3]1[CH:4]=[CH:5][C:6]([C@@H:9]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH3:10])=[CH:7][CH:8]=1
Reactant: C[C@H](NC(=O)OC(C)(C)C)c1ccc(C#N)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: C[C@H](NC(=O)OC(C)(C)C)c1ccc(-c2nn[nH]n2)cc1
Temperature: 110 °C
Yield: 91.2 %

Procedure:
A mixture of tert-butyl [(1S)-1-(4-cyanophenyl)ethyl]carbamate (step 1, 1.11 g, 4.51 mmol), sodium azide (1.75 g, 27.1 mmol) and ammonium chloride (1.15 g, 27.1 mmol) in N,N-dimethylforamide (25 mL) was heated at 110° C. for 24 h. After cooling to room temperature, the mixture was diluted with ether (200 mL) and washed with 1 N hydrochloric acid (100 mL). The organic layer was dried over magnesium sulfate and evaporated. The residue was crystallized from dichloromethane and hexane to give 1.19 g (91%) of the title compounds as white solids: 1H-NMR (DMSO-d6) δ 7.98 (2H, d, J=8.3 Hz), 7.51 (2H, d, J=8.3 Hz), 4.74–4.63 (1H, m), 1.37–1.32 (12H, m); MS (ESI) m/z 290 (M+H)+, 288 (M−H)−.
Reaction SMILES: CC[O-].[Na+].[F:5][C:6]([F:23])([F:22])[C:7]([CH:9]([CH2:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:10]([O:12]CC)=O)=O.Cl.[C:25]([NH2:28])(=[NH:27])[CH3:26].CCCCCC>CCO>[CH3:26][C:25]1[NH:28][C:10](=[O:12])[C:9]([CH2:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])=[C:7]([C:6]([F:5])([F:22])[F:23])[N:27]=1
Reactant: CC(=N)N
Reactant: CCOC(=O)CCC(C(=O)OCC)C(=O)C(F)(F)F
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: CCCCCC
Product: CCOC(=O)CCc1c(C(F)(F)F)nc(C)[nH]c1=O
Yield: 24.1 %

Procedure:
To a solution of NaOEt (0.026 mol) in EtOH (prepared from 0.60 g of Na and 30 mL of EtOH) was added diethyl trifluoroacetylglutarate (3.70 g, 0.013 mol) and acetamidine hydrochloride (1.23 g, 0.013 mol). The reaction mixture was heated under reflux for 18 h, concentrated, and taken up in water. The mixture was acidified to pH 4 with 2N HCl and extracted with CH2Cl2. The extracts were dried (MgSO4) and concentrated to give a yellow solid. Trituration with hexane gave 0.87 g of product as a white solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[CH2:20][N:6]2[C:7]3[CH:8]=[CH:9][C:10]([NH2:19])=[CH:11][C:12]=3[C:13]3([O:18][CH2:17][CH2:16][CH2:15][O:14]3)[C:5]2=[N:4][CH2:3]1.CCN(CC)CC.[C:29]1([S:35](Cl)(=[O:37])=[O:36])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>C(Cl)Cl>[CH3:1][C:2]1([CH3:21])[CH2:20][N:6]2[C:7]3[CH:8]=[CH:9][C:10]([NH:19][S:35]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)(=[O:37])=[O:36])=[CH:11][C:12]=3[C:13]3([O:18][CH2:17][CH2:16][CH2:15][O:14]3)[C:5]2=[N:4][CH2:3]1
Reactant: CC1(C)CN=C2N(C1)c1ccc(N)cc1C21OCCCO1
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1(C)CN=C2N(C1)c1ccc(NS(=O)(=O)c3ccccc3)cc1C21OCCCO1
Temperature: 25 °C
Reaction time: 1 h
Yield: 71.3 %

Procedure:
To a solution of 3′,3′-dimethyl-3′,4′-dihydro-2′H-spiro[1,3-dioxane-2,10′-pyrimido[1,2-a]indol]-8′amine (0.060 g 0.21 mmol, 1 eq) in CH2Cl2 (2 mL) was added Et3N (0.060 mL, 0.43 mmol, 2.05 eq) and benzenesulfonyl chloride (0.030 mL, 0.23 mmol, 1.07 eq). The reaction was stirred at rt 1 hour and concentrated. The crude residue purified by column chromatography using acetone/hexanes (30/70) as an eluent to give the title compound as a white solid (0.064 g, 71%). NMR (400 Mz, DMSO-d6): consistent
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:22])=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=2)[C:5]2[N:6]([N:8]=[C:9](Cl)[N:10]=2)[CH:7]=1.[CH3:23][S:24][CH2:25][CH2:26][CH2:27][NH2:28]>>[Br:1][C:2]1[C:3]([CH3:22])=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=2)[C:5]2[N:6]([N:8]=[C:9]([NH:28][CH2:27][CH2:26][CH2:25][S:24][CH3:23])[N:10]=2)[CH:7]=1
Reactant: Cc1c(Br)cn2nc(Cl)nc2c1-c1cccc(C(F)(F)F)c1
Reactant: CSCCCN
Product: CSCCCNc1nc2c(-c3cccc(C(F)(F)F)c3)c(C)c(Br)cn2n1
Temperature: 155 °C
Reaction time: 3 h

Procedure:
To a suspension of 6-bromo-2-chloro-7-methyl-8-(3-trifluoromethyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridine (Int. 29, 125 mg, 0.32 mmol) in IMS (5 mL) was added 3-methylsulfanyl-propylamine (215 μL, 1.92 mmol) and the reaction mixture was heated under microwave irradiation at 155° C. for 2 hrs. After this time more 3-methylsulfanyl-propylamine (490 μL) was added and heating continued for 3 hrs then a further portion of 3-methylsulfanyl-propylamine (490 μL) was added and heating continued for 7 hrs. The resultant residue was loaded onto an SCX-2 cartridge and eluted with MeOH and then further purified by flash chromatography, eluting with a gradient of 0-50% EtOAc in cyclohexane to give the title compound as a colourless glass (57 mg).
Reaction SMILES: Cl.[CH2:2]([C:4]1[CH:10]=[C:9]([CH3:11])[CH:8]=[C:7]([CH2:12][CH3:13])[C:5]=1[NH2:6])[CH3:3].[Br:14]Br>O>[Br:14][C:10]1[C:4]([CH2:2][CH3:3])=[C:5]([C:7]([CH2:12][CH3:13])=[CH:8][C:9]=1[CH3:11])[NH2:6]
Reactant: BrBr
Reactant: CCc1cc(C)cc(CC)c1N
Agent: Cl
Solvent: O
Product: CCc1cc(C)c(Br)c(CC)c1N
Reaction time: 3.75 h

Procedure:
Concentrated HCl (10 ml) is cooled to 5° C. in an ice-water bath and 1.63 g of 2,6-diethyl-4-methylaniline is added dropwise to give a slurry. Bromine (1.59 g) with 10 ml of concentrated HCl is added dropwise over 30 minutes. The reaction is allowed to stir for 3.75 hours and 25 ml of distilled water is added. After cooling for 1.0 hour, the reaction mixture is filtered and washed twice with 25 ml of cold distilled water. After drying under vacuum for about 16 hours, the crude solid (2.3 g) is dissolved in 100 ml of 10% NaOH and extracted with a 150 ml portion and with a 100 ml portion of methylene chloride. After drying over sodium sulfate, the methylene chloride solution is rotary evaporated to 1.9 g of crude product.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:24](=[CH:25][CH:26]=1)[O:23][C:22]([CH3:28])([CH3:27])[C:18]1([CH2:21][O:20][CH2:19]1)[C@@:5]12[CH2:9][O:8][C:7]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[N:6]1.[Cl:29][C:30]1[CH:31]=[CH:32][C:33]([C:36](O)=[O:37])=[N:34][CH:35]=1.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[Cl:29][C:30]1[CH:31]=[CH:32][C:33]([C:36]([NH:1][C:2]2[CH:3]=[C:4]3[C:24](=[CH:25][CH:26]=2)[O:23][C:22]([CH3:28])([CH3:27])[C:18]2([CH2:21][O:20][CH2:19]2)[C@@:5]23[CH2:9][O:8][C:7]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:14])[CH3:15])=[N:6]2)=[O:37])=[N:34][CH:35]=1
Reactant: O=C(O)c1ccc(Cl)cn1
Reactant: CC(C)(C)OC(=O)NC1=N[C@@]2(CO1)c1cc(N)ccc1OC(C)(C)C21COC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC1=N[C@@]2(CO1)c1cc(NC(=O)c3ccc(Cl)cn3)ccc1OC(C)(C)C21COC1
Reaction time: 8 h
Yield: 75 %

Procedure:
To a mixture of tert-butyl [(4S)-6′-amino-2′,2′-dimethyldispiro[1,3-oxazole-4,4′-chromene-3′,3″-oxetan]-2-yl]carbamate (1.00 g, 2.57 mmol) and CH2Cl2 (10 mL) were added 5-chloro-2-pyridinecarboxylic acid (526 mg, 3.34 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (640 mg, 3.34 mmol), 1-hydroxybenzotriazole (451 mg, 3.34 mmol) and N,N-diisopropylethylamine (0.571 mL, 3.34 mmol) at ambient temperature. After stirring overnight at the same temperature, the reaction mixture was purified with column chromatography on silica gel (hexane-EtOAc, a linear gradient of EtOAc from 0 to 90%) and then on NH-silica gel (hexane-EtOAc, a linear gradient of EtOAc from 0 to 90%) to give tert-butyl [(4S)-6′-{[(5-chloropyridin-2-yl)carbonyl]amino}-2′,2′-dimethyldispiro[1,3-oxazole-4,4′-chromene-3′,3″-oxetan]-2-yl]carbamate (1.02 g).
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[C:13]1[NH:17][C:16]2[CH:18]=[C:19]([C:22]3[C:23]4[S:29][CH:28]=[C:27]([C:30]5[CH:35]=[CH:34][C:33]([C:36]6[N:37]=[C:38]([C@@H:41]7[CH2:45][CH2:44][CH2:43][N:42]7[C:46](=[O:56])[C@@H:47]([NH:51][C:52]([O:54][CH3:55])=[O:53])[CH:48]([CH3:50])[CH3:49])[NH:39][CH:40]=6)=[CH:32][CH:31]=5)[C:24]=4[S:25][CH:26]=3)[CH:20]=[CH:21][C:15]=2[N:14]=1)=O)(C)(C)C.[ClH:57]>CO.O1CCOCC1>[ClH:57].[CH3:55][O:54][C:52](=[O:53])[NH:51][C@H:47]([C:46]([N:42]1[CH2:43][CH2:44][CH2:45][C@H:41]1[C:38]1[NH:37][C:36]([C:33]2[CH:32]=[CH:31][C:30]([C:27]3[C:24]4[S:25][CH:26]=[C:22]([C:19]5[CH:20]=[CH:21][C:15]6[N:14]=[C:13]([C@@H:9]7[CH2:10][CH2:11][CH2:12][NH:8]7)[NH:17][C:16]=6[CH:18]=5)[C:23]=4[S:29][CH:28]=3)=[CH:35][CH:34]=2)=[CH:40][N:39]=1)=[O:56])[CH:48]([CH3:50])[CH3:49]
Reactant: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1nc(-c2ccc(-c3csc4c(-c5ccc6nc([C@@H]7CCCN7C(=O)OC(C)(C)C)[nH]c6c5)csc34)cc2)c[nH]1)C(C)C
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1ncc(-c2ccc(-c3csc4c(-c5ccc6nc([C@@H]7CCCN7)[nH]c6c5)csc34)cc2)[nH]1)C(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 97 %

Procedure:
Compound 68 (0.189 mmol) was dissolved in methanol (3.8 mL) and 4N HCl in dioxane (3.8 mL) was added. The mixture was stirred 1 hr at room temperature before concentration under reduced pressure. The residue was precipitated in diethyl ether to give compound E47 as a beige solid in 97% yield. 1H NMR (DMSO-d6, 400 MHz) δ (ppm) 0.76 (d, 3H), 0.83 (d, 3H), 2.07-2.20 (m, 8H), 2.36 (m, 4H), 3.10-3.43 (m, 2H), 3.82 (m, 1H), 4.04 (m, 1H), 4.12 (t, 1H), 5.08 (m, 1H), 5.22 (t, 1H), 7.26 (d, 1H), 7.83 (m, 2H), 7.94 (m, 2H), 8.08-8.15 (m, 3H), 8.17 (m, 2H), 8.25 (s, 1H), 8.75 (s, 1H), 10.66 (s, 1H), 14.94 (s, 1H), 15.51 (s, 1H); MS (ESI, EI+) m/z=694.2 (MH+).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[N:4][C:5]([C:8]2[CH:9]=[C:10]([CH:25]=[CH:26][CH:27]=2)[CH2:11][N:12]2[C:17](=[O:18])[CH:16]=[CH:15][C:14]([C:19]3[CH:20]=[N:21][N:22]([CH3:24])[CH:23]=3)=[N:13]2)=[N:6][CH:7]=1.C1COCC1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[CH2:53][CH2:54][N:55]1[CH2:60][CH2:59][O:58][CH2:57][CH2:56]1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>>[CH3:24][N:22]1[CH:23]=[C:19]([C:14]2[CH:15]=[CH:16][C:17](=[O:18])[N:12]([CH2:11][C:10]3[CH:25]=[CH:26][CH:27]=[C:8]([C:5]4[N:6]=[CH:7][C:2]([O:1][CH2:53][CH2:54][N:55]5[CH2:60][CH2:59][O:58][CH2:57][CH2:56]5)=[CH:3][N:4]=4)[CH:9]=3)[N:13]=2)[CH:20]=[N:21]1
Reactant: OCCN1CCOCC1
Reactant: Cn1cc(-c2ccc(=O)n(Cc3cccc(-c4ncc(O)cn4)c3)n2)cn1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cn1cc(-c2ccc(=O)n(Cc3cccc(-c4ncc(OCCN5CCOCC5)cn4)c3)n2)cn1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a suspension of 360 mg (1.00 mmol) of 2-[3-(5-hydroxy-pyrimidin-2-yl)-benzyl]-6-(1-methyl-1H-pyrazol-4-yl)-2H-pyridazin-3-one in 2 ml THF 394 mg (1.50 mmol) of triphenylphosphine and 242 μl (2.00 mmol) of 4-(2-hydroxyethyl)morpholine are added one after the other. Under ice cooling 294 μl (1.50 mmol) of diisopropylazodicarboxylate are slowly added dropwise. The resulting solution is stirred for 18 hours at room temperature. The reaction mixture is then concentrated in vacuo and the oily residue is dissolved in 2-propanol. The resulting solid of 6-(1-methyl-1H-pyrazol-4-yl)-2-{3-[5-(2-morpholin-4-yl-ethoxy)-pyrimidin-2-yl]-benzyl}-2H-pyridazin-3-one resulted after some time is sucked off, washed with 2-propanol and tert-butylmethylether and dried in vacuo.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:10]2[C:18]3[C:13](=[N:14][C:15](S(C)(=O)=O)=[N:16][CH:17]=3)[N:12]([CH3:23])[N:11]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[NH3:24]>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([C:10]2[C:18]3[C:13](=[N:14][C:15]([NH2:24])=[N:16][CH:17]=3)[N:12]([CH3:23])[N:11]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: N
Reactant: COc1ccc(-c2nn(C)c3nc(S(C)(=O)=O)ncc23)cc1F
Solvent: C1CCOC1
Product: COc1ccc(-c2nn(C)c3nc(N)ncc23)cc1F
Temperature: 25 °C
Reaction time: 10 h

Procedure:
3-(3-Fluoro-4-methoxy-phenyl)-6-methanesulfonyl-1-methyl-1H-pyrazolo[3,4-d]pyrimidine (0.8 g, 2.3 mmol) is dissolved in a saturated solution of ammonia in THF in an autoclave and the reaction mixture is stirred at room temperature for 2-18 hours. The solvent is removed in vacuo and the resulting solid is suspended in methanol, stirred at room temperature for 30 minutes and collected by filtration to afford the title compound as a white solid.