Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CI.N12CCCN=C1CCCC[CH2:4]2.[CH2:14]([O:21][C:22]([CH2:24][C:25]1[C:38]2[S:37][C:36]3[C:31](=[CH:32][CH:33]=[C:34]([O:46][CH3:47])[C:35]=3[C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[N:30]([C:48](=[O:55])[CH2:49][CH2:50][CH2:51][C:52]([OH:54])=[O:53])[C:29]=2[C:28]([CH2:56][NH2:57])=[CH:27][C:26]=1[O:58][CH3:59])=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.O>CN(C)C=O.C(OCC)(=O)C>[CH2:14]([O:21][C:22]([CH2:24][C:25]1[C:38]2[S:37][C:36]3[C:31](=[CH:32][CH:33]=[C:34]([O:46][CH3:47])[C:35]=3[C:39]([O:41][C:42]([CH3:43])([CH3:45])[CH3:44])=[O:40])[N:30]([C:48](=[O:55])[CH2:49][CH2:50][CH2:51][C:52]([O:54][CH3:4])=[O:53])[C:29]=2[C:28]([CH2:56][NH2:57])=[CH:27][C:26]=1[O:58][CH3:59])=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: COc1cc(CN)c2c(c1CC(=O)OCc1ccccc1)Sc1c(ccc(OC)c1C(=O)OC(C)(C)C)N2C(=O)CCCC(=O)O
Reactant: C1CCC2=NCCCN2CC1
Solvent: CI
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)CCCC(=O)N1c2ccc(OC)c(C(=O)OC(C)(C)C)c2Sc2c(CC(=O)OCc3ccccc3)c(OC)cc(CN)c21
Temperature: 25 °C
Yield: 88.9 %

Procedure:
103 mg (0.726 mmol) of methyl iodide and 110 mg (0.726 mmol) of 1,8-diazabicyclo[5.4.0]undec-7-ene were added while cooling with ice to a solution of 430 mg (0.66 mmol) of 5-(4-benzyloxycarbonylmethyl-6-tert.-butoxycarbonyl-aminomethyl-3,7-dimethoxy-phenothiazin-10-yl)-5-oxo-pentanoic acid in 15 ml of N,N-dimethylformamide. The reaction mixture was stirred firstly at room temperature and then at 40°, then cooled and finally poured into water and ethyl acetate. The organic phase was extracted twice with water, dried over magnesium sulphate and concentrated. The residue was chromatographed on silica gel with ethyl acetate/hexane (1:1), whereupon, after drying, 390 mg (88%) of methyl 5-(4-benzyloxycarbonylmethyl-6-tert.-butoxycarbonyl-aminomethyl-3,7-dimethoxy-phenothiazin-10-yl)-5-oxo-pentanoate were obtained as a white amorphous foam. MS (FAB): 664 (M+).
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[CH2:5]([C:7]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:8]=1[C:9](=[O:17])[C:10](=[O:16])[NH:11]2)[CH3:6]>>[N+:1]([C:15]1[C:7]([CH2:5][CH3:6])=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10](=[O:16])[C:9]2=[O:17])([O-:4])=[O:2]
Reactant: O=[N+]([O-])O
Reactant: CCc1cccc2c1C(=O)C(=O)N2
Product: CCc1c([N+](=O)[O-])ccc2c1C(=O)C(=O)N2
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 52 %

Procedure:
A beaker containing 15 mL of 90% fuming nitric acid was cooled in an ice-water bath. 2.1 g (12 mmoles) 4-ethylisatin was added in small portions over a five-minute period. The resultant red-orange solution was stirred while in the ice-water bath for 5 minutes, then warmed to room temperature and stirred for another 10 minutes. A yellow solid precipitated immediately when this solution was poured over crushed ice. 1.4 g (52% yield) 5-nitro-4-ethylisatin was obtained. NMR(CDCl3): 1.29(t,3H, J=7.5 Hz), 3.11(q,2H,J=7.5 Hz), 7.11 (d,1H,J=8.7 Hz), 8.27 (d,1H,J=8.7 Hz), 9.46(bs,1H). MS(m/z): 220(M+).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)[CH:7]=1.C([N:24]1[C:28]2([CH2:32][CH2:31][N:30](C3C=NC=CC=3)[CH2:29]2)[CH2:27][CH2:26][CH2:25]1)C1C=CC=CC=1.CC(C)([O-])C.[Na+].C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:16][O:15][C:12]1[CH:13]=[CH:14][C:9]([O:8][C:6]2[CH:7]=[C:2]([N:30]3[CH2:31][CH2:32][C:28]4([NH:24][CH2:25][CH2:26][CH2:27]4)[CH2:29]3)[CH:3]=[N:4][CH:5]=2)=[CH:10][CH:11]=1
Reactant: c1ccc(CN2CCCC23CCN(c2cccnc2)C3)cc1
Reactant: COc1ccc(Oc2cncc(Br)c2)cc1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: COc1ccc(Oc2cncc(N3CCC4(CCCN4)C3)c2)cc1

Procedure:
In an alternative approach to the synthesis of pyridine-substituted pyridyl diazaspiroalkanes, 3,5-dibromopyridine can be converted into the corresponding 5-alkoxy-3-bromo- and 5-aryloxy-3-bromopyridines by the action of sodium alkoxides or sodium aryloxides. Procedures such as those described by Comins et al., J. Org. Chem. 55: 69 (1990) and Hertog et al., Recueil Trav. Chim. Pays-Bas 74: 1171 (1955) are used. This is exemplified by the preparation 7-(5-(4-methoxyphenoxy)-3-pyridyl)-1,7-diazaspiro[4.4]nonane. Reaction of 3,5-dibromopyridine with sodium 4-methoxyphenoxide in N,N-dimethylformamide gives 3-bromo-5-(4-methoxyphenoxy)pyridine. Coupling of 3-bromo-5-(4-methoxyphenoxy)pyridine with 1-benzyl-7-(3-pyridyl)-1,7-diazaspiro[4.4]nonane in the presence of sodium tert-butoxide, and a catalytic amount of tris(dibenzylideneacetone)dipalladium(0) and 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl, in toluene, followed by hydrogenolysis of the benzyl protecting group, will provide 7-(5-(4-methoxyphenoxy)-3-pyridyl)-1,7-diazaspiro[4.4]nonane.
Reaction SMILES: [C:1](#[N:4])[CH:2]=[CH2:3].[CH2:5]([O:7][P:8]([CH:10]1[CH2:14][CH2:13][CH2:12][O:11]1)[OH:9])[CH3:6].[O-]CC.[Na+].C(O)(=O)C>C(O)C>[C:1]([CH2:2][CH2:3][P:8]([CH:10]1[CH2:14][CH2:13][CH2:12][O:11]1)(=[O:9])[O:7][CH2:5][CH3:6])#[N:4]
Reactant: CCOP(O)C1CCCO1
Reactant: C=CC#N
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Product: CCOP(=O)(CCC#N)C1CCCO1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 0.68 g of acrylonitrile and 2.11 g of tetrahydrofuran-2-yl phosphonous acid ethyl ester in 5 ml of absolute ethanol is cooled to 0° under argon and treated, dropwise, with an ethanolic solution of sodium ethoxide (from 0.15 g of sodium metal and 15 ml of absolute ethanol) at such a rate so that the temperature does not exceed 5° (extremely exothermic). After the addition is completed the reaction mixture is stirred at room temperature for 30 minutes and 0.4 g of glacial acetic acid are added. The solvent is removed in vacuo and the residue partitioned between dichloromethane water. The organic layer is dried with anhydrous magnesium sulphate and removed in vacuo to afford ethyl 2-cyanoethyl(tetrahydrofuran-2-yl)-phosphinate; 1H-NMR (CDCl3): δ4.15 (3H, m), 3.90 (2H, m), 2.72 (2H, m, CH2CN), 2.34-1.87 (6H, m), 1.32 (3H, m, CH3).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH2:13][N:14]([C:17](=[O:19])[CH3:18])[CH2:15][CH2:16][C:11]=3[N:10]([CH2:20][CH:21]([OH:33])[CH2:22][N:23]3[CH2:32][CH2:31][C:26]4(OCC[O:27]4)[CH2:25][CH2:24]3)[N:9]=2)=[CH:4][CH:3]=1.CO.C(Cl)Cl>Cl.C(Cl)(Cl)Cl.C([O-])(O)=O.[Na+]>[C:17]([N:14]1[CH2:15][CH2:16][C:11]2[N:10]([CH2:20][CH:21]([OH:33])[CH2:22][N:23]3[CH2:32][CH2:31][C:26](=[O:27])[CH2:25][CH2:24]3)[N:9]=[C:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)[C:12]=2[CH2:13]1)(=[O:19])[CH3:18]
Reactant: CC(=O)N1CCc2c(c(-c3ccc(Cl)cc3)nn2CC(O)CN2CCC3(CC2)OCCO3)C1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CO
Solvent: ClCCl
Product: CC(=O)N1CCc2c(c(-c3ccc(Cl)cc3)nn2CC(O)CN2CCC(=O)CC2)C1
Temperature: 65 °C
Reaction time: 48 h

Procedure:
A suspension of 0.50 g (0.96 mmol) of 1-{3-(4-chloro-phenyl)-1-[3-(1,4-dioxa-8-aza-spiro[4.5]dec-8-yl)-2-hydroxy-propyl]-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl}-ethanone in 1 N HCl (2.0 mL) was heated to 65° C. for 48 h in a sealed vessel. The reaction was allowed to cool to room temperature and was diluted with CHCl3 (20 mL) and saturated NaHCO3 (20 mL). The aqueous phase was extracted with CHCl3 (2×10 mL) and the combined organic extracts were dried over Na2SO4 and the solvent was removed under reduced pressure. The crude material was then diluted with Ac2O (3.0 mL) and was stirred for 48 h. The solvent was removed under reduced pressure and the crude material was pumped down overnight. The resulting solid was dissolved in MeOH (5.0 mL) and a catalytic amount (0.05 g) of K2CO3 was added to the mixture and stirring was continued overnight. The reaction was then diluted with H2O (20 mL) and CH2Cl2 (20 mL) and the layers were separated. The aqueous phase was extracted with CH2Cl2 (2×10 mL) and the combined organic extracts were dried over Na2SO4 and the solvent was removed under reduced pressure. Purification by flash chromatography (silica, 0-10% MeOH/CH2Cl2) afforded 0.29 g (65% over 3 steps) of a white solid. TLC (silica, 5% MeOH/CH2Cl2): Rf=0.35. MS (electrospray); m/z calculated for C22H27ClN4O3, [M+H]+, 431.18, observed 431.1. 1H NMR (400 MHz, CDCl3, a mixture of amide rotamers): 7.59 (d, J=8.3 Hz, 1H), 7.53 (d, J=8.6 Hz, 1H), 7.41 (d, J=8.5 Hz, 1H), 7.37 (d, J=8.5 Hz, 1H), 4.85 and 4.73 (A and B of AB quartet, Jab=15.8 Hz, 1H), 4.62 (s, 1H), 4.26-4.12 (m, 2H), 4.09-3.68 (m, 4H), 3.49 (s, 1.5H), 3.28 (s, 1.5H).
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]([OH:10])=O)=[CH:6][CH:5]=[CH:4][N:3]=1.S(Cl)([Cl:13])=O.CN(C)C=O>ClCCl>[F:1][C:2]1[C:7]([C:8]([Cl:13])=[O:10])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: O=C(O)c1cccnc1F
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)c1cccnc1F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2-Fluoropyridine-3-carboxylic acid (5.02 g, 35.6 mmol) was suspended in dichloromethane (100 mL), treated with thionyl chloride (13.0 mL, 178 mmol, 5 equiv) and N,N-dimethylformamide (0.138 mL, 1.78 mmol, 0.05 equiv) and placed into a preheated oil bath at 45° C. for 2 hours. The mixture was cooled to ambient temperature, concentrated in vacuo and the residue was concentrated from toluene (2×50 mL), providing the titled compound.
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[CH2:11]([NH:14][C:15]1[CH:22]=[CH:21][C:18]([C:19]#N)=[CH:17][CH:16]=1)[CH:12]=[CH2:13].C[OH:24]>C1(C)C=CC=CC=1>[CH2:11]([NH:14][C:15]1[CH:22]=[CH:21][C:18]([CH:19]=[O:24])=[CH:17][CH:16]=1)[CH:12]=[CH2:13]
Reactant: CO
Reactant: C=CCNc1ccc(C#N)cc1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Product: C=CCNc1ccc(C=O)cc1
Temperature: 0 °C

Procedure:
Di-isobutylaluminum hydride (54 ml., 25% solution in toluene) is added with stirring to a solution of 12.1 g. of 4-(allylamino)benzonitrile under a nitrogen atmosphere. After addition is completed, the solution is stirred for one hour. A solution of methanol in toluene (50 ml., 1:1) is added over 30 minutes and the mixture is poured into 500 ml. vigorously stirred ice-cold 50% aqueous sulfuric acid. The mixture is filtered and the organic layer separated. The aqueous solution is extracted twice with toluene (100 ml.) and the combined organic layers are washed with aqueous sodium bicarbonate, dried over magnesium sulfate, decolorized with charcoal, filtered and evaporated in vacuo to give a light yellow crystalline solid. The product is recrystallized from dichloromethane/hexane giving colorless needles.
Reaction SMILES: [OH:1][CH2:2][CH:3]([CH2:5][OH:6])[OH:4].[CH3:7][C:8]1[CH:12]=[C:11]([CH3:13])[NH:10][C:9]=1/[CH:14]=[C:15]1\[C:16](=[O:27])[N:17]([C:24](Cl)=[O:25])[C:18]2[C:23]\1=[CH:22][CH:21]=[CH:20][CH:19]=2>N1C=CC=CC=1.C1COCC1>[OH:4][CH:3]([CH2:5][OH:6])[CH2:2][O:1][C:24]([N:17]1[C:18]2[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=2)/[C:15](=[CH:14]/[C:9]2[NH:10][C:11]([CH3:13])=[CH:12][C:8]=2[CH3:7])/[C:16]1=[O:27])=[O:25]
Reactant: Cc1cc(C)c(/C=C2\C(=O)N(C(=O)Cl)c3ccccc32)[nH]1
Reactant: OCC(O)CO
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: Cc1cc(C)c(/C=C2\C(=O)N(C(=O)OCC(O)CO)c3ccccc32)[nH]1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To the solution of glycerol (460 mg, 2.5 mmol) in 1.0 mL of pyridine and 2.0 mL of THF was added a suspention of 3-[1-(3,5-dimethyl-1H-pyrrol-2-yl)-meth-(Z)-ylidene]-2-oxo-2,3-dihydro-indole-1-carbonyl chloride in 2.0 mL of THF at 0° C. The reaction mixture was gradually warmed to room temperature, stirred for 2.5 h, and concentrated. The residue was triturated with ethyl acetate and filtered. The solid was then washed with ethyl acetate, water, ether, and dried to yield 87 mg of 3-[1-(3,5-dimethyl-1H-pyrrol-2-yl)-meth-(Z)-ylidene]-2-oxo-2,3-dihydro-indole-1-carboxylic acid 2,3-dihydroxy-propyl ester. The combined filtrate was concentrated and partitioned between water and ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated to give 120 mg of crude product which was suspended in water, filtered, and washed with small amount of ethyl acetate to afford another 67 mg of 3-[1-(3,5-dimethyl-1H-pyrrol-2-yl)-meth-(Z)-ylidene]-2-oxo-2,3-dihydro-indole-1-carboxylic acid 2,3dihydroxy-propyl ester. The combined yield is 83%. 1H NMR (400 MHz, CDCl3) δ 12.51 (s, 1H, NH-1′), 7.90-7.92 (m, 1H), 7.45-7.48 (m, 1H), 7.37 (s, 1H, H-vinyl), 7.18-7.24 (m, 2H), 6.04 (d, J=1.96 Hz, 1H, H-4′), 4.68 (dd, J=3.13, 11.24 Hz, 1H, OCH2CH(OH)CH2OH), 4.45 (dd, J=4.89, 11.24 Hz, 1H, OCH2CH(OH)CH2OH), 4.09 (m, br, 1H, OCH2CH(OH)CH2OH), 3.86-3.99 (m, 2H, OCH2CH(OH)CH2OH), 3.60 (d, J=6.65 Hz, 1H, OCH2CH(OH)CH2OH), 3.45 (dd, J=5.52, 7.82 Hz, 1H, OCH2CH(OH)CH2OH), 2.41 (s, 3H, CH3), and 2.32 (s, 3H, CH3). MS m/z (relative intensity, %) 357 (100, [M+1]+.).
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:32])[C:6]([C:15]2[CH:20]=[CH:19][C:18]([NH:21][CH2:22][C:23]3[CH:31]=[CH:30][C:26]([C:27](O)=[O:28])=[CH:25][CH:24]=3)=[CH:17][CH:16]=2)=[CH:7][C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)[CH2:3][CH2:2]1.CN(C=O)C.[CH:38]1[CH:39]=[CH:40][C:41]2[N:46](O)N=[N:44][C:42]=2[CH:43]=1.C1(N)C=CC=CC=1N>O>[NH2:44][C:42]1[CH:43]=[CH:38][CH:39]=[CH:40][C:41]=1[NH:46][C:27](=[O:28])[C:26]1[CH:30]=[CH:31][C:23]([CH2:22][NH:21][C:18]2[CH:17]=[CH:16][C:15]([C:6]([C:5]([NH:4][CH:1]3[CH2:3][CH2:2]3)=[O:32])=[CH:7][C:8]3[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=3)=[CH:20][CH:19]=2)=[CH:24][CH:25]=1
Reactant: On1nnc2ccccc21
Reactant: O=C(NC1CC1)C(=Cc1ccc(F)cc1)c1ccc(NCc2ccc(C(=O)O)cc2)cc1
Agent: Nc1ccccc1N
Solvent: CN(C)C=O
Solvent: O
Product: Nc1ccccc1NC(=O)c1ccc(CNc2ccc(C(=Cc3ccc(F)cc3)C(=O)NC3CC3)cc2)cc1
Reaction time: 4 h
Yield: 7.7 %

Procedure:
To a suspension of 4-((4-(3-(cyclopropylamino)-1-(4-fluorophenyl)-3-oxoprop-1-en-2-yl)phenylamino)methyl)benzoic acid (0.215 g, 0.5 mmol) in DMF (3 mL) EDCl (0.23 g, 1.1 mmol), HOBt (0.08 g, 0.55 mmol), o-phenylene diamine (0.086 g, 0.7 mmol), were added followed by TEA (0.2 mL, 1.5 mmol). The reaction mixture was stirred for 4 hours after which the mixture was added to cold water (100 mL) and kept at 0° C. for 1 hour. The pale yellow solid formed was filtered and washed with ethyl acetate (15 mL) dried under vacuum to afford the title compound (0.020 g, 8% yield). 1H NMR (DMSO-d6) δ (ppm): 0.46-0.47 (2H, m, —CH2), 0.60-0.62 (2H, m, —CH2), 2.70-2.71 (1H, m, —CH), 4.36-4.37 (2H, d, —CH2), 4.88 (2H, s, —NH2), 6.55-6.61 (4H, m, Ar—H and —NH), 6.76-6.82 (3H, m, Ar—H), 6.93-6.94 (1H, t, Ar—H), 6.98-7.04 (3H, m, Ar—H), 7.06-7.17 (3H, m, Ar—H), 7.48-7.50 (3H, m, Ar—H and ═CH), 7.93-7.95 (2H, d, Ar—H and —NH), 9.61 (1H, s, —NH), MS m/z: 521.1 (M++1).
Reaction SMILES: [CH3:1][S:2][C:3]1[N:8]=[C:7]([NH2:9])[CH:6]=[C:5]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[N:4]=1.Br[C:17]1[C:22]([N+:23]([O-:25])=[O:24])=[CH:21][CH:20]=[CH:19][C:18]=1[CH3:26].CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:26][C:18]1[CH:19]=[CH:20][CH:21]=[C:22]([N+:23]([O-:25])=[O:24])[C:17]=1[NH:9][C:7]1[CH:6]=[C:5]([N:10]2[CH2:11][CH2:12][O:13][CH2:14][CH2:15]2)[N:4]=[C:3]([S:2][CH3:1])[N:8]=1
Reactant: CSc1nc(N)cc(N2CCOCC2)n1
Reactant: Cc1cccc([N+](=O)[O-])c1Br
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: CSc1nc(Nc2c(C)cccc2[N+](=O)[O-])cc(N2CCOCC2)n1
Temperature: 140 °C
Reaction time: 1 h
Yield: 94.7 %

Procedure:
A mixture of 2-(methylsulfanyl)-6-(morpholin-4-yl)pyrimidin-4-amine (500 mg), 2-bromo-1-methyl-3-nitrobenzene (1 g), tris(dibenzylideneacetone)dipalladium (0) (202 mg), (9,9-dimethyl-9H-xanthen-4,5-diyl)bis(diphenylphosphine) (192 mg), and cesium carbonate (1.0 g) in toluene was stirred in a microwave reactor at 140° C. for 1 hour. The reaction mixture was filtered through celite and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate) to obtain N-(2-methyl-6-nitrophenyl)-2-(methylsulfanyl)-6-(morpholin-4-yl)pyrimidin-4-amine (756 mg) as a yellow powder.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[N:9]=2)=[CH:6][CH:7]=1.[NH:14]1[CH2:19][CH2:18][C:17]2([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=3[NH:22][C:21](=[O:29])[O:20]2)[CH2:16][CH2:15]1.C(N(CC)CC)C.O>CN(C)C=O>[CH3:13][C:10]1[N:9]=[C:8]([C:5]2[N:4]=[N:3][C:2]([N:14]3[CH2:15][CH2:16][C:17]4([C:24]5[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=5[NH:22][C:21](=[O:29])[O:20]4)[CH2:18][CH2:19]3)=[CH:7][CH:6]=2)[O:12][N:11]=1
Reactant: O=C1Nc2ccccc2C2(CCNCC2)O1
Reactant: Cc1noc(-c2ccc(Cl)nn2)n1
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1noc(-c2ccc(N3CCC4(CC3)OC(=O)Nc3ccccc34)nn2)n1
Temperature: 160 °C
Reaction time: 0.25 h
Yield: 41.4 %

Procedure:
3-Chloro-6-(3-methyl-1,2,4-oxadiazol-5-yl)pyridazine (690 mg) obtained in Example 43(2), spiro[3,1-benzoxazine-4,4′-piperidin]-2(1H)-one (1 g) and triethylamine (1.4 mL) were suspended in N,N-dimethylformamide (20 mL), and the suspension was stirred at 160° C. under irradiation of microwave for 15 min. The mixture was cooled to room temperature, water (200 mL) was added and the resulting precipitate was collected by filtration. The precipitate was recrystallized from ethanol to give the object product (550 mg, 42%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[C:12]([O:16][CH3:17])[C:13]=1[O:14][CH3:15])[CH:6]=[CH:7][C:8](Cl)=[O:9].[C:18]([NH:22][C:23]([CH:25]([N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1)[CH3:26])=[O:24])([CH3:21])([CH3:20])[CH3:19].C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[C:12]([O:16][CH3:17])[C:13]=1[O:14][CH3:15])[CH:6]=[CH:7][C:8]([N:30]1[CH2:29][CH2:28][N:27]([CH:25]([C:23]([NH:22][C:18]([CH3:19])([CH3:21])[CH3:20])=[O:24])[CH3:26])[CH2:32][CH2:31]1)=[O:9]
Reactant: COc1cc(C=CC(=O)Cl)cc(OC)c1OC
Reactant: CC(C(=O)NC(C)(C)C)N1CCNCC1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: COc1cc(C=CC(=O)N2CCN(C(C)C(=O)NC(C)(C)C)CC2)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
0.78 g of 3,4,5-trimethoxycinnamoyl chloride is added to a solution of 0.50 g of 1-[1-(tert-butylaminocarbonyl)ethyl]piperazine and 0.31 g of triethylamine in 15 ml of chloroform, and the resulting solution is stirred at room temperature for 1 hour.
Reaction SMILES: [CH:1]([CH:3]1[S:7][C:6]([C:8]2[NH:9][C:10]3[C:15]([CH:16]=2)=[CH:14][CH:13]=[CH:12][C:11]=3[N:17]([CH3:27])[S:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=2)(=[O:20])=[O:19])=[N:5][CH2:4]1)=[O:2].[BH4-].[Na+].[Cl-].[NH4+]>O1CCCC1.C(O)C>[OH:2][CH2:1][CH:3]1[S:7][C:6]([C:8]2[NH:9][C:10]3[C:15]([CH:16]=2)=[CH:14][CH:13]=[CH:12][C:11]=3[N:17]([CH3:27])[S:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=2)(=[O:19])=[O:20])=[N:5][CH2:4]1
Reactant: CN(c1cccc2cc(C3=NCC(C=O)S3)[nH]c12)S(=O)(=O)c1ccccn1
Agent: [BH4-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCO
Product: CN(c1cccc2cc(C3=NCC(CO)S3)[nH]c12)S(=O)(=O)c1ccccn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 79.6 %

Procedure:
To a solution of N-[2-(5-formyl-4,5-dihydro-1,3-thiazol-2-yl)-1H-indol-7-yl]-N-methylpyridine-2-sulfonamide (200 mg) in tetrahydrofuran (2 mL) and ethanol (2 mL) was added sodium tetrahydroborate (38 mg), and the mixture was stirred at room temperature for 30 min. Saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4), and concentrated. The obtained residue was subjected to silica gel column chromatography to give the title compound (160 mg, yield 80%) as a white amorphous solid from a fraction eluted with ethyl acetate. MS: 403 (MH+).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:16]2[CH:15]=[CH:14][C:13]([CH3:17])=[CH:12][C:11]=2[C:10]2[CH2:18][N:19]([CH3:22])[CH2:20][CH2:21][C:9]1=2.[N:23]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][CH:24]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>CN(C=O)C.O.O.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>[CH3:22][N:19]1[CH2:20][CH2:21][C:9]2[N:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[C:26]3[CH:27]=[CH:28][N:23]=[CH:24][CH:25]=3)[C:16]3[CH:15]=[CH:14][C:13]([CH3:17])=[CH:12][C:11]=3[C:10]=2[CH2:18]1
Reactant: Cc1ccc2c(c1)c1c(n2-c2ccccc2Br)CCN(C)C1
Reactant: OB(O)c1ccncc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc2c(c1)c1c(n2-c2ccccc2-c2ccncc2)CCN(C)C1
Temperature: 95 °C
Yield: 7.8 %

Procedure:
To a de-aerated solution of 5-(2-bromo-phenyl)-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (180 mg, 0.508 mmol), 4-pyridinylboronic acid (93.8 mg, 0.762 mmol) and K3PO4 (270 mg, 1.27 mmol) in DMF-water (9:1 mL) was added PdCl2(PPh3)2 (18 mg, 5 mol %). The reaction mixture was heated at 95° C. for 30 min under nitrogen atmosphere. The reaction mixture was diluted with water and extracted with EtOAc. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford crude material, which was purified by reverse phase HPLC to yield 2,8-dimethyl-5-(2-pyridin-4-yl-phenyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole as semisolid (14 mg). 1H NMR (Freebase, CDCl3) δ (ppm): 8.38 (d, 2H), 7.58 (m, 3H), 7.40 (d, 1H), 7.20 (s, 1H), 6.90 (m, 4H), 3.75 (m, 2H), 2.76 (m, 1H), 2.60 (m, 1H), 2.50 (m, 1H), 2.48 (s, 3H), 2.42 (s, 3H), 2.20 (m, 1H).
Reaction SMILES: [N+](C1C=CC(C(O[C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=3[F:24])=[CH:13][CH:12]=2)=O)=CC=1)([O-])=O.FC1C=C(F)C=CC=1C1C=CC=CC=1.[N+:41]([C:44]1[CH:52]=[CH:51][C:47]([C:48](Cl)=[O:49])=[CH:46][CH:45]=1)([O-:43])=[O:42]>>[F:24][C:18]1[CH:19]=[C:20]([F:23])[CH:21]=[CH:22][C:17]=1[C:14]1[CH:13]=[CH:12][C:11]([C:48]([C:47]2[CH:46]=[CH:45][C:44]([N+:41]([O-:43])=[O:42])=[CH:52][CH:51]=2)=[O:49])=[CH:16][CH:15]=1
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Reactant: O=C(Oc1ccc(-c2ccc(F)cc2F)cc1)c1ccc([N+](=O)[O-])cc1
Agent: Fc1ccc(-c2ccccc2)c(F)c1
Product: O=C(c1ccc(-c2ccc(F)cc2F)cc1)c1ccc([N+](=O)[O-])cc1

Procedure:
A process for the preparation of 4-(2,4-difluorophenyl)-phenyl 4-nitro-benzoate comprising the Friedel-Crafts acylation of 2,4-difluorobiphenyl with 4-nitro-benzoyl chloride in order to obtain 4-(2,4-difluorophenyl)-4'-nitro-benzophenone and the Baeyer-Villiger oxidation of this latter.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8]1[S:9][CH:10]=[CH:11][N:12]=1.[S-:13][C:14]#[N:15].[Na+].BrBr.O>CO>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8]1[S:9][C:10]([S:13][C:14]#[N:15])=[CH:11][N:12]=1
Reactant: N#C[S-]
Reactant: c1ccc(Nc2nccs2)nc1
Agent: BrBr
Agent: [Na+]
Solvent: O
Solvent: CO
Product: N#CSc1cnc(Nc2ccccn2)s1
Temperature: 23 °C
Reaction time: 3 h

Procedure:
To a suspension of N-(pyridin-2-yl)thiazol-2-amine (4.26 g, 24 mmol) and sodium thiocyanate (3.9 g, 48 mmol, 2 eq) in methanol (100 mL) at 0° C., was slowly added bromine (1.23 mL, 24 mmol, 1 eq) over 2 min, then the temperature was raised to 23° C. and the mixture was stirred for 3 h. The resulting suspension was added to stirring cold water (400 mL) and the resulting precipitate was collected by filtration and vacuum dried (4.5 g, 80%). 1H NMR (400 MHz, DMSO-D6) δ ppm 7.00-7.08 (1H, m), 7.11 (1H, d, J=8.34 Hz), 7.74-7.84 (1H, m), 7.89 (1H, s), 8.39 (1H, d, J=5.05 Hz), 11.93 (1H, s). LC/MS (M+H)+: 235.