Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH:7]([C:10]2[N:11]=[N:12][CH:13]=[CH:14][CH:15]=2)[C:8]#[N:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[SH2:23]>N1C=CC=CC=1>[C:1]1([CH:7]([C:10]2[N:11]=[N:12][CH:13]=[CH:14][CH:15]=2)[C:8]([NH2:9])=[S:23])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: S
Reactant: N#CC(c1ccccc1)c1cccnn1
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: NC(=S)C(c1ccccc1)c1cccnn1
Reaction time: 1.5 h
Yield: 94 %

Procedure:
A 1.0 g quantity (0.005 mols) of 2-phenyl-2-(3-pyridazinyl)acetonitrile was dissolved in 50 ml of dry pyridine in a sealed tube, and 4 ml of triethylamine was added. After allowing the resulting solution to stand for 1.5 hours, dry hydrogen sulfide was passed through the solution in a steady stream at room temperature for 15 minutes. The sealed mixture was then left to stand at room temperature for 24 hours. The reaction mixture was concentrated in a vacuum to give a yellow solid cake. Recrystallization of the concentrate from ethanol afforded 1.1 g (94% yield) of 2-phenyl-2-(3-pyridazinyl)thioacetamide in the form of pale yellow plates, m.p. 161° to 163° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[C:10](F)[CH:9]=2)[CH:5]=[C:4]([N:17]2[CH2:22][CH2:21][O:20][CH:19]([C:23]3[NH:24][C:25]4[CH:30]=[CH:29][N:28]=[CH:27][C:26]=4[N:31]=3)[CH2:18]2)[N:3]=1.[NH2:32][NH2:33]>C(O)C>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[C:10]3[C:11]([C:12]([NH2:13])=[N:32][NH:33]3)=[CH:14][CH:15]=2)[CH:5]=[C:4]([N:17]2[CH2:22][CH2:21][O:20][CH:19]([C:23]3[NH:24][C:25]4=[CH:30][CH:29]=[N:28][CH:27]=[C:26]4[N:31]=3)[CH2:18]2)[N:3]=1
Reactant: N#Cc1ccc(-c2cc(N3CCOC(c4nc5cnccc5[nH]4)C3)nc(N)n2)cc1F
Reactant: NN
Solvent: CCO
Product: Nc1nc(-c2ccc3c(N)n[nH]c3c2)cc(N2CCOC(c3nc4cnccc4[nH]3)C2)n1
Reaction time: 1 h
Yield: 6.4 %

Procedure:
A mixture of 4-{2-amino-6-[2-(1H-imidazo[4,5-c]pyridin-2-yl)-4-morpholinyl]-4-pyrimidinyl}-2-fluorobenzonitrile (380 mg, 0.913 mmol) and hydrazine (1.432 mL, 45.6 mmol) in ethanol (3 mL) was heated under microwave conditions with stirring for 1 hour. The mixture was concentrated. Water (20 mL) was added, and the resulting mixture was filtered to afford the crude title compound (135 mg) as a brown solid. This material was combined with another sample of the title compound (25 mg), and the combined material was purified by preparative HPLC using CH3CN in water (10 mmol ammonium hydrogen carbonate in water) from 40% to 60% in 9 min to afford the title compound (21 mg) as an off-white solid. LC-MS (ES) m/z=429 [M+H]+. 1H NMR (400 MHz, DMSO-d6): δ 3.13-3.22 (m, 2H), 3.81-3.91 (m, 1H), 4.14 (d, J=11.2 Hz, 1H), 4.34 (d, J=11.6 Hz, 1H), 4.91 (dd, J=10.0 Hz, 2H), 5.39 (s, 2H), 6.25 (s, 2H), 6.72 (s, 1H), 7.54 (s, 1H), 7.62 (m, 1H), 7.72 (d, J=8.8 Hz, 1H), 7.97 (s, 1H), 8.31 (d, J=5.6 Hz, 1H), 8.91 (s, 1H), 11.54 (s, 1H), 13.01 (s, 1H).
Reaction SMILES: C(O[CH2:9][CH3:10])(OCC)OCC.[NH:11]([C:13]1[N:14]=[C:15]2[CH:21]=[CH:20][N:19]([S:22]([C:25]3[CH:31]=[CH:30][C:28]([CH3:29])=[CH:27][CH:26]=3)(=[O:24])=[O:23])[C:16]2=[N:17]C=1)[NH2:12]>CN(C=O)C>[S:22]([N:19]1[C:16]2[N:17]=[CH:9][C:10]3[N:14]([CH:13]=[N:11][N:12]=3)[C:15]=2[CH:21]=[CH:20]1)([C:25]1[CH:26]=[CH:27][C:28]([CH3:29])=[CH:30][CH:31]=1)(=[O:24])=[O:23]
Reactant: Cc1ccc(S(=O)(=O)n2ccc3nc(NN)cnc32)cc1
Reactant: CCOC(OCC)OCC
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)n2ccc3c2ncc2nncn23)cc1
Temperature: 100 °C
Reaction time: 17 h
Yield: 73.1 %

Procedure:
Triethyl orthoformate (76.0 mL, 456 mmol) was added to a mixture of 2-hydrazinyl-5-tosyl-5H-pyrrolo[2,3-b]pyrazine (13.8 g, 45.4 mmol, Example #1, Step D) and DMF (45 mL) under nitrogen. A reflux condenser was attached and the mixture was warmed to about 100° C. After about 17 h, the solution was allowed to cool to ambient temperature. The volatiles were removed under reduced pressure. The residue was slurried in water (100 mL) and then filtered, rinsing with water. The aqueous phase was extracted with EtOAc (200 mL). The organics were dried over anhydrous Na2SO4, filtered, and concentrated. The material was combined with the precipitate and then purified by silica gel chromatography eluting with a gradient of 0-5% MeOH in DCM to give 6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine (10.4 g, 73%): LC/MS (Table 1, Method n) Rt=0.59 min; MS m/z 314 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([Cl:11])[CH:3]=1.C(=O)(O)[O-].[Na+].[CH3:17][CH:18]([CH3:22])[C:19](Cl)=[O:20].Cl>O.COCCOC>[Cl:11][C:4]1[CH:3]=[C:2]([NH:1][C:19](=[O:20])[CH:18]([CH3:22])[CH3:17])[CH:10]=[CH:9][C:5]=1[C:6]([OH:8])=[O:7]
Reactant: CC(C)C(=O)Cl
Reactant: Nc1ccc(C(=O)O)c(Cl)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: CC(C)C(=O)Nc1ccc(C(=O)O)c(Cl)c1
Reaction time: 2 h

Procedure:
4-Amino-2-chlorobenzoic acid was stirred in water (60 ml) and 1,2-dimethoxyethane (25 ml) with sodium bicarbonate (5.04 g) and the brown suspension cooled to 0°-5° C. 2-Methylpropionyl chloride (4.26 g) was added dropwise over 10 minutes with vigorous stirring, and the mixture was then stirred at 0°-10° C. for 2 hours. The mixture was poured into 2M hydrochloric acid and the pale brown precipitate washed with water and filtered and dried to give 2-chloro-4-(2'-methylpropionamido)benzoic acid as a pale brown crystalline solid (6.30 g), m.p. 206°-209° C.
Reaction SMILES: [H-].[Na+].[CH2:3](I)[CH3:4].[N+:6]([C:9]1[CH:10]=[C:11]([CH:16]=[C:17]([N+:19]([O-:21])=[O:20])[CH:18]=1)[NH:12][C:13](=[O:15])[CH3:14])([O-:8])=[O:7].O>CN(C)C=O>[N+:6]([C:9]1[CH:10]=[C:11]([CH:16]=[C:17]([N+:19]([O-:21])=[O:20])[CH:18]=1)[N:12]([CH2:3][CH3:4])[C:13](=[O:15])[CH3:14])([O-:8])=[O:7]
Reactant: CCI
Reactant: CC(=O)Nc1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCN(C(C)=O)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1

Procedure:
Sodium hydride (50% in mineral oil; 1.44 g.), followed by ethyl iodide (3.6 ml.), were added, in small portions during 2 minutes, to a warm stirred solution of 3',5'-dinitroacetanilide (6.75 g.) in dimethylformamide (20 ml.). The mixture was heated on the steam bath for 150 minutes, then cooled, poured into water (400 ml.) and extracted with ethyl acetate (3 × 100 ml.). The combined organic extracts were washed with water, dried over anhydrous magnesium sulphate and evaporated to dryness. The residue was purified by chromatography on alumina (150 g.) using benzene as the eluant. The fractions containing the required product were combined, evaporated to dryness and the residue crystallised from ethanol, to give 3',5'-dinitro-N-ethylacetanilide (4.2 g.), m.p. 126°-127°C.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]([CH2:11][C:12]([OH:14])=[O:13])[NH:3]1.[C:15]1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]([CH2:11][C:12]([O:14][CH3:15])=[O:13])[NH:3]1
Reactant: O=C(O)CC1NC(=O)c2ccccc21
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Product: COC(=O)CC1NC(=O)c2ccccc21
Reaction time: 3.5 h

Procedure:
A solution of 2,3-dihydro-3-oxo-1H-isoindole-1-acetic acid (described by F. M. Rowe et al., supra, 130 g, 0.682 mol) in methanol (1300 ml) containing 6.5 g of p-toluenesulfonic acid is refluxed with stirring for 3.5 hr. Most of the methanol is evaporated and the residue is dissolved in chloroform. The solution is washed with 5% aqueous sodium bicarbonate and water, dried and evaporated. The residue (125 g) is crystallized from isopropanol to give methyl 2,3-dihydro-3-oxo-1H-isoindole-1-acetate, mp 136°-138° C.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[C:6]([CH3:18])[C:7]([O:13][CH2:14][C:15]([OH:17])=[O:16])=[C:8]([CH3:12])[C:9]=2[CH3:11])[CH2:4][CH:3]1[CH2:19][CH3:20].[Br:21]Br>Br.C(O)(=O)C>[O:1]=[C:2]1[C:10]2[C:5](=[C:6]([CH3:18])[C:7]([O:13][CH2:14][C:15]([OH:17])=[O:16])=[C:8]([CH3:12])[C:9]=2[CH3:11])[CH2:4][C:3]1([Br:21])[CH2:19][CH3:20]
Reactant: CCC1Cc2c(C)c(OCC(=O)O)c(C)c(C)c2C1=O
Reactant: BrBr
Agent: Br
Solvent: CC(=O)O
Product: CCC1(Br)Cc2c(C)c(OCC(=O)O)c(C)c(C)c2C1=O

Procedure:
(1-Oxo-2-bromo-2-ethyl-4,6,7-trimethyl-5-indanyloxy)-acetic acid is prepared by following substantially the same procedure as described in Example 1, Step B, using the following reagents: (1-oxo-2-ethyl-4,6,7-trimethyl-5-indanyloxy)-acetic acid (11.79 g., 0.0427 mole), bromine (7.51 g., 0.0470 mole), acetic acid (118 ml.) and 48% hydrobromic acid (2 drops). The crude yield is 14.76 g. (97%). Recrystallization from butyl chloride give (1-oxo-2-bromo-2-ethyl-4,6,7-trimethyl-5-indanyloxy)acetic acid as white prisms, m.p. 144°-145° C.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([S:9](Cl)(=[O:11])=[O:10])=[CH:5][CH:4]=1)#[N:2].Cl.[CH3:14][O:15][C:16](=[O:19])[CH2:17][NH2:18].C(N(CC)CC)C>ClCCl>[CH3:14][O:15][C:16](=[O:19])[CH2:17][NH:18][S:9]([C:6]1[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=1)(=[O:11])=[O:10]
Reactant: COC(=O)CN
Reactant: N#Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)CNS(=O)(=O)c1ccc(C#N)cc1
Reaction time: 0.33 h
Yield: 47 %

Procedure:
To 4-cyano-benzenesulfonyl chloride in dichloromethane (10 mL) was added amino-acetic acid methyl ester hydrochloride (250 mg, 2 mmol) and triethylamine (1.01 g, 10 mmol). The mixture was stirred for 20 min at r.t and was washed with water. The crude was triturated in methanol to give (4-cyano-benzenesulfonylamino)-acetic acid methyl ester (240 mg, 47%). This material was dissolved in NH3 in methanol (30 mL) followed by addition of Raney Ni (3 g). The mixture was hydrogenated under H2 (60 psi, 1 h, r.t) to provide the title compound (1:5, 230 mg).
Reaction SMILES: [I:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH2:11])[NH:4][N:3]=1.Br[CH2:13][C:14]1[O:15][C:16](=[O:30])[C:17]2[C:22]([C:23]=1[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[CH:21][CH:20]=[CH:19][CH:18]=2.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[NH2:11][C:9]1[N:8]=[CH:7][N:6]=[C:5]2[N:4]([CH2:13][C:14]3[O:15][C:16](=[O:30])[C:17]4[C:22]([C:23]=3[C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)=[CH:21][CH:20]=[CH:19][CH:18]=4)[N:3]=[C:2]([I:1])[C:10]=12
Reactant: O=c1oc(CBr)c(-c2ccccc2)c2ccccc12
Reactant: Nc1ncnc2[nH]nc(I)c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Nc1ncnc2c1c(I)nn2Cc1oc(=O)c2ccccc2c1-c1ccccc1
Temperature: 50 °C
Reaction time: 2 h
Yield: 87.9 %

Procedure:
Commercially available 3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine (124 mg, 0.476 mmol) was added to a solution of 3-(bromomethyl)-4-phenyl-1H-isochromen-1-one (intermediate C1, 100 mg, 0.317 mmol) in DMF (1 mL). K2CO3 (65.8 mg, 0.476 mmol) was added and the resulting mixture was stirred at 50° C. for 2 hrs. The resulting crude was straightforward purified via reverse phase chromatography with a Biotage C18 SNAP 30 g column (Phase A, water 95%, ACN 5%, formic acid 0.01%); Phase B ACN 95%, water 5%, formic acid 0.01%) to give the title compound (138 mg, 88%).
Reaction SMILES: [C:1]1([C:7]2[NH:8][CH:9]=[CH:10][N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Br[CH2:15][CH2:16][CH2:17][CH2:18][N:19]1C(=O)C2=CC=CC=C2C1=O>CN(C)C=O>[C:1]1([C:7]2[N:11]([CH2:15][CH2:16][CH2:17][CH2:18][NH2:19])[CH:10]=[CH:9][N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: c1ccc(-c2ncc[nH]2)cc1
Reactant: O=C1c2ccccc2C(=O)N1CCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: NCCCCn1ccnc1-c1ccccc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 17.2 %

Procedure:
4.32 g of 2-phenyl-imidazole in solution in 25 ml of dimethylformamide were added over 75 minutes at ambient temperature to 1.73 g of sodium hydride in 5 ml of dimethylformamide and then, 10.97 g of N-(4-bromobutyl)-phthalimide in 33 ml of dimethylformamide were added. The mixture was stirred for 48 hours at ambient temperature and extraction was carried out with ethyl acetate, followed by drying. The solvent has evaporated and the residue was chromatographed on silica (eluant: ethyl acetate-methylethylamine 95-5). The residue was taken up in ether, chilled and the crystals were separated out and dried to obtain 1.11 g of the expected product melting at 82°-84° C.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][CH:3]=1.S(Cl)([Cl:13])=O>C(Cl)(Cl)(Cl)Cl>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([Cl:13])=[O:7])=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1ccc(Br)cc1
Solvent: ClC(Cl)(Cl)Cl
Product: O=C(Cl)c1ccc(Br)cc1

Procedure:
A solution of 4- bromobenzoic acid (0.113 moles) and thionyl chloride (45 ml) in carbon tetrachloride (100 ml) was heated at reflux for 3.5 hours. Solvent and excess thionyl chloride were removed under reduced pressure and the crude 4-bromobenzoyl chloride was used in subsequent reactions without further purification. ##STR6##
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[CH:4][C:3]=1B1OC(C)(C)C(C)(C)O1.Br[C:21]1[N:26]=[CH:25][C:24]([CH2:27][NH:28][CH2:29][CH2:30][CH:31]2[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]2)=[CH:23][CH:22]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1>[CH:31]1([CH2:30][CH2:29][NH:28][CH2:27][C:24]2[CH:23]=[CH:22][C:21]([C:3]3[CH:4]=[C:5]([CH:9]=[CH:10][C:2]=3[CH3:1])[C:6]([NH2:8])=[O:7])=[N:26][CH:25]=2)[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1
Reactant: Brc1ccc(CNCCC2CCCCC2)cn1
Reactant: Cc1ccc(C(N)=O)cc1B1OC(C)(C)C(C)(C)O1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: Cc1ccc(C(N)=O)cc1-c1ccc(CNCCC2CCCCC2)cn1
Temperature: 70 °C

Procedure:
To a solution of 4-methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)benzamide (Preparation 18, 150 mg, 0.57 mmol) and (6-bromopyridin-3-ylmethyl)-(2-cyclohexylethyl)amine (Preparation 15, 188 mg, 0.63 mmol) in dioxane (3 mL) was added 2M Na2CO3 (1 mL) and bis(diphenylphosphinoferrocene)-palladium dichloride (47 mg, 0.06 mmol). The mixture was purged with argon for 10 min and the mixture heated to 70° C. for 6 h. On cooling to rt, EtOAc (50 mL) was added and the organic phase washed with water (2×30 mL), brine (30 mL) and dried (MgSO4). The solvent was removed in vacuo and the residue purified by column chromatography (0.4% NH3: 4% MeOH: DCM) to give the title compound: RT=2.53 min; m/z (ES+)=352.2 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([CH:14]([CH3:16])[CH3:15])[N:11]=[C:10]([OH:17])[N:9]=2)=[CH:4][CH:3]=1.CN(C=O)C.[Br:23]N1C(=O)CCC1=O>O>[Br:23][C:13]1[C:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)=[N:9][C:10]([OH:17])=[N:11][C:12]=1[CH:14]([CH3:15])[CH3:16]
Reactant: CC(C)c1cc(-c2ccc(F)cc2)nc(O)n1
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)c1nc(O)nc(-c2ccc(F)cc2)c1Br
Temperature: -3 °C
Yield: 98.5 %

Procedure:
4-(4-Fluorophenyl)-6-isopropylpyrimidin-2-ol (8.00 g, 34.1 mmol) was charged to a reactor followed by DMF (100 mL). The suspension was stirred, cooled to −3° C. and N-bromosuccinimide (6.25 g, 34.8 mmol) added. The reaction mixture was warmed to 20° C. and stirred overnight. Water (100 mL) was charged to the reaction mixture and the crystalline mixture stirred for 1 hour before filtering off. The isolated solid was washed twice with water (25 mL) and the solid dried in a vacuum oven at 50° C. 5-Bromo-4-(4-fluorophenyl)-6-isopropylpyrimidin-2-ol (10.45 g, 97% yield) was obtained as a white solid;
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:20]([CH:21]=[O:22])=[C:19]([CH:23]([CH3:25])[CH3:24])[CH:18]=[C:17]3[C:9]=2[C:10](=[O:26])[CH2:11][C:12]2([O:16]3)[CH2:15][CH2:14][CH2:13]2)=[CH:4][CH:3]=1.[C:27]([C:31]1[CH:36]=[CH:35][C:34]([Mg]Br)=[CH:33][CH:32]=1)([CH3:30])([CH3:29])[CH3:28].[Cl-].[NH4+]>O1CCCC1.Cl>[C:27]([C:31]1[CH:36]=[CH:35][C:34]([CH:21]([OH:22])[C:20]2[C:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)=[C:9]3[C:17](=[CH:18][C:19]=2[CH:23]([CH3:24])[CH3:25])[O:16][C:12]2([CH2:15][CH2:14][CH2:13]2)[CH2:11][C:10]3=[O:26])=[CH:33][CH:32]=1)([CH3:30])([CH3:29])[CH3:28]
Reactant: CC(C)c1cc2c(c(-c3ccc(F)cc3)c1C=O)C(=O)CC1(CCC1)O2
Reactant: CC(C)(C)c1ccc([Mg]Br)cc1
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)c1cc2c(c(-c3ccc(F)cc3)c1C(O)c1ccc(C(C)(C)C)cc1)C(=O)CC1(CCC1)O2
Temperature: -78 °C
Reaction time: 1.5 h

Procedure:
Under argon, 0.30 g (0.851 mmol) of 5-(4-fluorophenyl)-7-isopropyl-4-oxo-3,4-dihydrospiro-[chromen-2,1′-cyclobutane]-6-carbaldehyde (Example 51A) is suspended in 6 ml of tetrahydrofuran and cooled to −78° C. 2.54 ml (1.28 mmol) of a freshly prepared 0.5 M solution of [4-(tert-butyl)phenyl]magnesium bromide in tetrahydrofuran are added slowly. The mixture is briefly stirred at −78° C. and then warmed to 0° C. After about 1.5 h, saturated ammonium chloride solution is added and the mixture is diluted with a little 1 N hydrochloric acid and extracted repeatedly with ethyl acetate. The combined organic phases are washed twice with saturated sodium chloride solution, dried over sodium sulfate, filtered and concentrated. The crude product is purified a little at a time by preparative HPLC (method 12). This gives 0.239 g (58% of theory) of the title compound.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([CH:7]=O)[CH:4]=[N:3]1.[CH3:9][C:10]([S@:13]([NH2:15])=[O:14])([CH3:12])[CH3:11].O>C1COCC1>[CH3:9][C:10]([S@:13](/[N:15]=[CH:7]/[C:5]1[CH:4]=[N:3][N:2]([CH3:1])[CH:6]=1)=[O:14])([CH3:12])[CH3:11]
Reactant: Cn1cc(C=O)cn1
Reactant: CC(C)(C)[S@](N)=O
Solvent: C1CCOC1
Solvent: O
Product: Cn1cc(/C=N/[S@](=O)C(C)(C)C)cn1
Temperature: 65 °C
Yield: 93.8 %

Procedure:
To a solution of 1-methyl-1H-pyrazole-4-carbaldehyde (2.2 g, 20 mmol) in THF (50 mL) was added (R)-2-methylpropane-2-sulfinamide (4.8 g, 40 mmol) and Ti(OEt)4 (9.2 g, 40 mmol). The reaction mixture was heated at 65° C. for 14 h. After cooling, the mixture was poured into water. The solid was filtered off, and the filtrate was extracted with EtOAc. The organic layer was concentrated and purified by SiO2 chromatography eluting with petroleum ether/EtOAc (5:1) to afford 4.0 g (83%) of (R,E)-2-methyl-N-((1-methyl-1H-pyrazol-4-yl)methylene)propane-2-sulfinamide (46). LCMS (ESI) m/z: 214.1 [M+11]+.
Reaction SMILES: Cl.[N:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([C@H:5]3[NH2:12])[CH2:3]1)[CH2:9]2.[Cl:13][C:14]1[CH:15]=[C:16]([CH:20]=[CH:21][C:22]=1[Cl:23])[C:17](O)=[O:18].N>>[ClH:13].[N:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([C@H:5]3[NH:12][C:17](=[O:18])[C:16]3[CH:20]=[CH:21][C:22]([Cl:23])=[C:14]([Cl:13])[CH:15]=3)[CH2:3]1)[CH2:9]2
Reactant: O=C(O)c1ccc(Cl)c(Cl)c1
Reactant: NC1C2CC3CC1CN(C3)C2
Agent: Cl
Agent: N
Product: O=C(NC1C2CC3CC1CN(C3)C2)c1ccc(Cl)c(Cl)c1

Procedure:
Prepared from (4r)-1-azatricyclo[3.3.1.13,7]dec-4-ylamine hydrochloride and 3,4-dichlorobenzoic acid (Aldrich) according to methods A and C; yield 39 mg, 0.10 mmol (49%): 1H NMR (300 MHz, methanol-d4) δ 2.06-2.27 (m, 6H), 2.46 (s, 2H), 3.48 (d, J=12 Hz, 2H), 3.55 (s, 2H), 3.81 (d, J=13 Hz, 2H), 4.25 (s, 1H), 7.65 (d, J=8 Hz, 1H), 7.80 (dd, 1H), 8.07 (d, J=2 Hz, 1H); MS (DCI/NH3) m/z 325 (M+H)+; Anal. C16H18Cl2N2O.HCl.0.4HCl.0.15C4H8O2: C, H, N.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].[C:9]([C:17]1[C:18](=[O:28])[N:19]([CH3:27])[C:20](=[O:26])[N:21]([CH3:25])[C:22]=1[CH2:23]Br)(=O)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>CCO>[CH3:25][N:21]1[C:22]2=[CH:23][N:1]([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=3[OH:8])[C:9]([C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=3)=[C:17]2[C:18](=[O:28])[N:19]([CH3:27])[C:20]1=[O:26]
Reactant: Cn1c(CBr)c(C(=O)c2ccccc2)c(=O)n(C)c1=O
Reactant: Nc1ccccc1O
Solvent: CCO
Product: Cn1c(=O)c2c(-c3ccccc3)n(-c3ccccc3O)cc2n(C)c1=O
Yield: 96.3 %

Procedure:
In a 25 mL round bottom was placed o-aminophenol (163 mg, 1.5 mmol) and EtOH (10 mL). The mixture was warmed until homogenous and then compound 4a (250 mg, 741 μmol) was added (see Example 2 for synthesis of 4a). The mixture was stirred vigorously at reflux during which a precipitate formed. After 1 h the mixture was cooled in an ice bath, filtered, and the precipitate washed with cold EtOH to yield 5e (248 mg, 96.4%) as a white powder. 1H NMR (600 MHz,) δ 10.02 (s, 1H), 7.29-7.26 (m, 2H), 7.24-7.17 (m, 4H), 7.10 (dd, J=1.6, 7.8, 1H), 6.96 (s, 1H), 6.90 (dd, J=1.1, 8.2, 1H), 6.77 (td, J=1.2, 7.6, 1H), 3.34 (s, 3H), 3.21 (s, 3H). 13C NMR (151 MHz, DMSO d6) δ 159.11, 152.86, 150.91, 133.81, 130.35, 129.98, 129.67, 129.13, 128.58, 127.83, 127.18, 125.95, 118.99, 116.39, 106.16, 101.88, 31.50, 27.46. MS (ES+) (m/z): [M+1]+ calculated for C20H18N3O3, 348.13. found 348.11.
Reaction SMILES: N1([C:7]2[N:12]=[C:11]3NC=C[C:10]3=[CH:9][CH:8]=2)CCNCC1.Cl.[CH:17]1([N:22]2[CH2:27][CH2:26][N:25]([C:28]3[N:33]=[C:32]4[NH:34][C:35]([C:37](O)=[O:38])=[CH:36][C:31]4=[CH:30][CH:29]=3)[CH2:24][CH2:23]2)[CH2:21][CH2:20][CH2:19][CH2:18]1>>[CH:17]1([N:22]2[CH2:23][CH2:24][N:25]([C:28]3[N:33]=[C:32]4[NH:34][C:35]([C:37]([N:12]5[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11]5)=[O:38])=[CH:36][C:31]4=[CH:30][CH:29]=3)[CH2:26][CH2:27]2)[CH2:18][CH2:19][CH2:20][CH2:21]1
Reactant: c1cc2ccc(N3CCNCC3)nc2[nH]1
Reactant: O=C(O)c1cc2ccc(N3CCN(C4CCCC4)CC3)nc2[nH]1
Agent: Cl
Product: O=C(c1cc2ccc(N3CCN(C4CCCC4)CC3)nc2[nH]1)N1CCCCC1

Procedure:
According to the procedure described for the synthesis of Example 1 further 6-piperazinyl-1H-pyrrolo[2,3-b]pyridine derivatives have been synthesized from 6-(4-cyclopentyl-piperazin-1-yl)-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid hydrochloride (as prepared in step 2) and the respective amine mentioned in table 1. The examples are compiled in table 1 and comprise Example 2 to Example 20.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[CH:5]=[CH:6][CH:7](OC)OC)[CH3:2].C(#N)C.[NH2:16][C:17]1[CH:22]=[CH:21][C:20]([Br:23])=[CH:19][N:18]=1>C1(C)C=CC(S(O)(=O)=O)=CC=1.O>[CH2:1]([O:3][C:4](=[O:12])[CH2:5][C:6]1[N:18]2[CH:19]=[C:20]([Br:23])[CH:21]=[CH:22][C:17]2=[N:16][CH:7]=1)[CH3:2]
Reactant: Nc1ccc(Br)cn1
Reactant: CCOC(=O)C=CC(OC)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CC#N
Product: CCOC(=O)Cc1cnc2ccc(Br)cn12
Yield: 107.1 %

Procedure:
Reflux a solution of 4,4-dimethoxy-but-2-enoic acid ethyl ester (3.3 g, 19.12 mmol) and toluene-4-sulfonic acid (0.02 g, 0.12 mmol) in a solution of 2:1 acetonitrile:water (90 mL) for 30 min. Add 2-amino-5-bromo-pyridine (1.65 g, 9.56 mmol) and reflux for 15 h. Cool and concentrate to ˜20 mL. Dilute the reaction with saturated aqueous sodium bicarbonate and extract into ethyl acetate. Combine and concentrate organic extracts. Flash chromatography using ethyl acetate/dichloromethane/methanol mixtures gives the subtitled compound as a brown oil (2.9 g). TOF MS ES+ exact mass calculated for C11H11BrN2O2 (p+1): m/z=283.0075 Found: 283.0082. 1H NMR (400 MHz, DMSO-d6) δ 8.68 (s, 1H), 7.55 (d, J=10 Hz, 1H), 7.49 (s, 1H), 7.34 (d, J=10 Hz, 1H), 4.15 (s, 2H), 4.09 (q, J=4 Hz, 2H), 1.18 (t, J=4 Hz, 3H). EA Calcd. For C11H11BrN2O2: C, 46.66; H, 3.92; N, 9.89; Found C, 46.56; H, 4.02; N, 9.60.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:19]2[CH2:24][CH2:23][S:22](=[O:25])[CH2:21][CH2:20]2)[C:5]2[N:11]=[CH:10][N:9]=[C:8]([S:12][CH2:13][C:14]3[O:18][CH:17]=[CH:16][CH:15]=3)[C:6]=2[N:7]=1.[NH:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1>>[CH2:13]([S:12][C:8]1[C:6]2[N:7]=[C:2]([N:26]3[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]3)[N:3]=[C:4]([N:19]3[CH2:24][CH2:23][S:22](=[O:25])[CH2:21][CH2:20]3)[C:5]=2[N:11]=[CH:10][N:9]=1)[C:14]1[O:18][CH:17]=[CH:16][CH:15]=1
Reactant: C1CNCCN1
Reactant: O=S1CCN(c2nc(Cl)nc3c(SCc4ccco4)ncnc23)CC1
Product: O=S1CCN(c2nc(N3CCNCC3)nc3c(SCc4ccco4)ncnc23)CC1

Procedure:
This compound was prepared analogous to Example 1 from 2-chloro-8-(furfuryl-thio)-4-(1-oxido-thiomorpholino)-pyrimido-[5,4-d]-pyrimidine (m.p.: 173°-175° C.) and piperazine.