Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]([CH:4]([C:6]1[N:7]=[C:8]2[S:16][CH:15]=[CH:14][N:9]2[C:10](=[O:13])[C:11]=1Br)[CH3:5])=[N+:2]=[N-:3].[F:17][C:18]1[CH:19]=[C:20](B(O)O)[CH:21]=[CH:22][CH:23]=1.C(=O)([O-])[O-].[Na+].[Na+].O>O1CCOCC1.C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[N:1]([CH:4]([C:6]1[N:7]=[C:8]2[S:16][CH:15]=[CH:14][N:9]2[C:10](=[O:13])[C:11]=1[C:22]1[CH:21]=[CH:20][CH:19]=[C:18]([F:17])[CH:23]=1)[CH3:5])=[N+:2]=[N-:3]
Reactant: OB(O)c1cccc(F)c1
Reactant: CC(N=[N+]=[N-])c1nc2sccn2c(=O)c1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CC(N=[N+]=[N-])c1nc2sccn2c(=O)c1-c1cccc(F)c1
Temperature: 100 °C
Reaction time: 8 h
Yield: 63.4 %

Procedure:
To a mixture of 7-(1-azidoethyl)-6-bromo-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one (0.48 g, 1.6 mmol) and (3-fluorophenyl)boronic acid (0.27 g, 2.0 mmol) in 1,4-dioxane (10 mL) was added a 1N solution of sodium carbonate in water (2.1 mL, 2.1 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.092 g, 0.080 mmol). The mixture was stirred at 100° C. overnight. After cooling, the mixture was diluted with ethyl acetate, washed with water and brine, dried over MgSO4, concentrated, and purified on silica gel (0-50% ethyl acetate/hexanes) to give the desired compound (0.32 g, 63%). LCMS calculated for C14H11FN5OS (M+H)+: m/z=316.1. Found: 316.0.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[N:8]([CH3:11])[N:9]=[CH:10][C:5]2=[C:4]([N:12]2[CH2:17][CH2:16][N:15]([S:18]([CH3:21])(=[O:20])=[O:19])[CH2:14][CH2:13]2)[N:3]=1.[NH:22]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:24](B2OC(C)(C)C(C)(C)O2)=[N:23]1>>[NH:22]1[C:30]2[C:25](=[C:26]([C:2]3[N:7]=[C:6]4[N:8]([CH3:11])[N:9]=[CH:10][C:5]4=[C:4]([N:12]4[CH2:17][CH2:16][N:15]([S:18]([CH3:21])(=[O:20])=[O:19])[CH2:14][CH2:13]4)[N:3]=3)[CH:27]=[CH:28][CH:29]=2)[CH:24]=[N:23]1
Reactant: Cn1ncc2c(N3CCN(S(C)(=O)=O)CC3)nc(Cl)nc21
Reactant: CC1(C)OB(c2n[nH]c3ccccc23)OC1(C)C
Product: Cn1ncc2c(N3CCN(S(C)(=O)=O)CC3)nc(-c3cccc4[nH]ncc34)nc21

Procedure:
6-Chloro-4-(4-methane sulfonyl-piperazin-1-yl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidine was reacted with indazole boronic acid pinacol ester using General Procedure A. Purification on silica yielded 149. NMR: (DMSO) 2.98 (3H, s), 3.35-3.40 (4H, m), 4.11 (3H, s), 4.18-4.22 (4H, m), 7.48-7.51 (1H, m), 7.70 (1H, d), 8.30 (1H, d), 8.42 (1H, s), 8.95 (1H, s). 13.20 (1H, s). MS: (ESI+) MH+=413
Reaction SMILES: C(OC([NH:11][C:12]12[CH2:19][C:16]([C:20]([O:22][CH3:23])=[O:21])([CH2:17][CH2:18]1)[CH2:15][CH2:14][CH2:13]2)=O)C1C=CC=CC=1>CO.[Pd]>[NH2:11][C:12]12[CH2:19][C:16]([C:20]([O:22][CH3:23])=[O:21])([CH2:17][CH2:18]1)[CH2:15][CH2:14][CH2:13]2
Reactant: COC(=O)C12CCCC(NC(=O)OCc3ccccc3)(CC1)C2
Agent: [Pd]
Solvent: CO
Product: COC(=O)C12CCCC(N)(CC1)C2
Temperature: 25 °C
Reaction time: 8 h
Yield: 51.6 %

Procedure:
To a solution of methyl 5-(benzyloxycarbonylamino)bicyclo-[3.2.1]octane-1-carboxylate (10 g) in methanol (150 mL) was added 10% Pd/C (1 g) and the reaction mixture was stirred under H2 (1 atm) at room temperature overnight. The reaction mixture was filtered through a Celite pad, and the filtrate was concentrated. The residue was treated with aqueous HCl (2N, 200 mL) at 0° C. and then extracted with ethyl acetate (3×100 mL) to remove organic impurities. The aqueous phase was adjusted to pH 9-10 with Sat. Na2CO3 and extracted with dichloromethane/methanol (10/1, 3×100 mL). The combined organic layer was washed with water (100 mL) and brine (100 mL), dried over sodium sulfate and concentrated under reduced pressure to afford 2.98 g of methyl 5-aminobicyclo[3.2.1]octane-1-carboxylate as a yellow oil. ESI-MS m/z: 184 (M+H)+.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[NH:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([C:16]#[N:17])=[CH:8]1.O1CCCC1>O1CCOCC1>[NH:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([CH2:16][NH2:17])=[CH:8]1
Reactant: N#Cc1c[nH]c2ccccc12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: C1COCCO1
Product: NCc1c[nH]c2ccccc12
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 54.5 %

Procedure:
Lithium aluminum hydride (100 mg) was added to a solution of 1H-indole-3-carbonitrile (100 mg) in 15 mL of 2:1 dioxane:tetrahydrofuran. The mixture was refluxed for 0.5 h, then cooled to 0 C and quenched by the sequential addition of 0.1 mL water, 0.1 mL 3 N sodium hydroxide, and 0.3 mL more water. After the mixture was stirred for 15 min at rt, the aluminum salts were removed by filtration and the solvent was evaporated to give 56 mg of C-(1H-indol-3-yl)methylamine.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]2=[O:14])[CH:5]=[CH:4][C:3]=1[CH:15]([N:19]1[CH:24]=[CH:23][CH:22]=[C:21]([N+:25]([O-])=O)[C:20]1=[O:28])[C:16]([NH2:18])=[O:17]>C(O)(=O)C.[Zn]>[NH2:25][C:21]1[C:20](=[O:28])[N:19]([CH:15]([C:3]2[CH:4]=[CH:5][C:6]([N:8]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]3=[O:14])=[CH:7][C:2]=2[F:1])[C:16]([NH2:18])=[O:17])[CH:24]=[CH:23][CH:22]=1
Reactant: NC(=O)C(c1ccc(-n2ccccc2=O)cc1F)n1cccc([N+](=O)[O-])c1=O
Agent: [Zn]
Solvent: CC(=O)O
Product: NC(=O)C(c1ccc(-n2ccccc2=O)cc1F)n1cccc(N)c1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 70.5 %

Procedure:
64.3 A suspension of 60 mg [2-fluoro-4-(2-oxo-pyridin-1-yl)-phenyl]-2-(3-nitro-2-oxo-pyridin-1-yl)-acetamide in 1 ml acetic acid was treated portionwise with 82 mg activated zinc powder. The reaction mixture was stirred for 3 hrs at r.t. The solid was filtered off and washed carefully with EtOH. The filtrate was concentrated. The crude product was purified by chromatography (silica, gradient CH2Cl2->CH2Cl2/MeOH 95:5) to give 39 mg 2-(3-amino-2-oxo-pyridin-1-yl)-[2-fluoro-4-(2-oxo-pyridin-1-yl)-phenyl]-acetamide as off-white solid. MS 355.0 ([M+H]+)
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=2)([CH3:10])[CH3:9])=[CH:4][CH:3]=1.[C:18]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)(=O)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.Cl.[C:33]1([N:39]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[NH2:40])[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.C1COCC1>CS(O)(=O)=O.CN(C)C(=O)C>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([C:11]2[CH:12]=[CH:13][C:14]([OH:17])=[CH:15][CH:16]=2)([CH3:10])[CH3:9])=[CH:6][CH:7]=1.[C:33]1([N:39]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[N:40]=[C:18]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1
Reactant: NN(c1ccccc1)c1ccccc1
Reactant: O=C(c1ccccc1)c1ccccc1
Agent: CC(C)(c1ccc(O)cc1)c1ccc(O)cc1
Agent: CS(=O)(=O)O
Agent: Cl
Solvent: C1CCOC1
Solvent: CC(=O)N(C)C
Product: c1ccc(C(=NN(c2ccccc2)c2ccccc2)c2ccccc2)cc1

Procedure:
In a 100 mL single neck round bottom flask was weighed poly(bisphenol-A-benzophenone) (5.000 g, 11.50 mmol), 1,1-diphenylhydrazine hydrochloride (2.714 g, 12.30 mmol), THF (18 g) and N,N-dimethylacetamide (18 g). The flask was fitted with a condenser. The dark slurry was stirred with a magnetic stirrer to dissolve the starting materials. To the dark solution was added methanesulfonic acid (about 6 drops), and the solution heated to reflux . After stirring for about 4 hours, the orange polymer solution was precipitated in water, and chopped in a high speed blender. The yellow fibrous polymer was isolated by filtration, washed in boiling water (about 45 min.), filtered, washed in boiling methanol (about 45 min.), filtered and dried at about 100° C. for about 16 hours. The yield was about 5.29 g. The number average molecular weight of the polymer was about 11.8K.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[CH:9][C:10](=[O:20])[C:11]=2[C:12]2[C:17]([F:18])=[CH:16][CH:15]=[CH:14][C:13]=2[F:19])[N:7]=1.C([O-])([O-])=O.[Cs+].[Cs+].[F:27][C:28]1[CH:33]=[C:32]([F:34])[CH:31]=[CH:30][C:29]=1[OH:35]>CN1C(=O)CCC1.CCOC(C)=O.O>[F:27][C:28]1[CH:33]=[C:32]([F:34])[CH:31]=[CH:30][C:29]=1[O:35][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[CH:9][C:10](=[O:20])[C:11]=2[C:12]2[C:17]([F:18])=[CH:16][CH:15]=[CH:14][C:13]=2[F:19])[N:7]=1
Reactant: Oc1ccc(F)cc1F
Reactant: O=c1ccn2nc(Cl)ccc2c1-c1c(F)cccc1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN1CCCC1=O
Product: O=c1ccn2nc(Oc3ccc(F)cc3F)ccc2c1-c1c(F)cccc1F
Temperature: 90 °C

Procedure:
To a solution of 2-chloro-5-(2,6-difluorophenyl)-6H-pyrido[1,2-b]pyridazin-6-one (250 mg, 0.85 mmol) and Cs2CO3 (834 mg, 2.56 mmol) in NMP was added 2,4 difluoro phenol (211 mg, 1.7 mmol). The mixture was heated to 90° C. for 2 hrs until the reaction was complete via LCMS analysis. The reaction was cooled to ambient temperature and diluted with EtOAc and H2O. The aqueous layer was washed with EtOAc and the combined organic layers were washed with 1N NaOH, H2O, brine, dried over MgSO4, and concentrated in vacuo. The crude residue was purified via silica gel chromatography (EtOAc/CH2Cl2, MeOH) to yield the title compound.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([N:8]2[N:19]=[CH:18][C:17]3[C:16]4[CH2:15][C:14]([CH3:21])([CH3:20])[CH2:13][C:12]=4[S:11][C:10]=3[C:9]2=[O:22])[C:3]=1[CH:23]=[O:24].[CH3:25][N:26]1[CH:31]=[C:30](B2OC(C)(C)C(C)(C)O2)[CH:29]=[C:28]([NH:41][C:42]2[CH:46]=[C:45]([CH3:47])[O:44][N:43]=2)[C:27]1=[O:48].[O-]P([O-])([O-])=O.[K+].[K+].[K+].C([O-])(=O)C.[Na+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O.C(#N)C>[CH3:20][C:14]1([CH3:21])[CH2:13][C:12]2[S:11][C:10]3[C:9](=[O:22])[N:8]([C:4]4[C:3]([CH:23]=[O:24])=[C:2]([C:30]5[CH:29]=[C:28]([NH:41][C:42]6[CH:46]=[C:45]([CH3:47])[O:44][N:43]=6)[C:27](=[O:48])[N:26]([CH3:25])[CH:31]=5)[CH:7]=[CH:6][N:5]=4)[N:19]=[CH:18][C:17]=3[C:16]=2[CH2:15]1
Reactant: Cc1cc(Nc2cc(B3OC(C)(C)C(C)(C)O3)cn(C)c2=O)no1
Reactant: CC1(C)Cc2sc3c(=O)n(-c4nccc(Cl)c4C=O)ncc3c2C1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: CC#N
Solvent: O
Product: Cc1cc(Nc2cc(-c3ccnc(-n4ncc5c6c(sc5c4=O)CC(C)(C)C6)c3C=O)cn(C)c2=O)no1
Temperature: 100 °C

Procedure:
A 50-mL round-bottomed flask equipped with a magnetic stirrer was charged with 4-chloro-2-{4,4-dimethyl-9-oxo-7-thia-10,11-diazatricyclo[6.4.0.02,6]dodeca-1(8),2(6),11-trien-10-yl}pyridine-3-carbaldehyde 282i (72 mg, 0.20 mmol), 288a (102 mg, 0.30 mmol), PdCl2(dppf) (16 mg, 0.020 mmol), K3PO4 (85 mg, 0.40 mmol), sodium acetate (33 mg, 0.40 mmol), acetonitrile (10 mL), and water (0.5 mL). After bubbling nitrogen into the mixture for 10 minutes, a reflux condenser was attached to the flask and the mixture was heated at 100° C. for 1 h. It was then cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure to afford 288b, which was used in the next step without further purification. MS-ESI: [M+H]+ 529.3.
Reaction SMILES: O[C:2]1[C:6]2[CH2:7][CH2:8][CH2:9][CH2:10][C:5]=2[S:4][N:3]=1.Cl.[NH+]1C=CC=CC=1.P(=O)(O)(O)O.P(Cl)(Cl)([Cl:25])=O>>[Cl:25][C:2]1[C:6]2[CH2:7][CH2:8][CH2:9][CH2:10][C:5]=2[S:4][N:3]=1
Reactant: Oc1nsc2c1CCCC2
Reactant: O=P(Cl)(Cl)Cl
Agent: Cl
Agent: O=P(O)(O)O
Agent: c1cc[nH+]cc1
Product: Clc1nsc2c1CCCC2
Temperature: 90 °C
Reaction time: 5 h

Procedure:
A mixture of 3-hydroxy-4,5,6,7-tetrahydro-1,2-benzisothiazole 22a (4.74 g), pyridinium hydrochloride (12.7 g), phosphoric acid (2.1 g) and phosphorus oxychloride (25 mL) was stirred at 90 ° C. for 5 h. The reaction mixture was evaporated and ethyl acetate (130 mL) was added to the residue. A saturated solution of sodium hydrogencarbonate (130 mL) was added and after 10 min of stirring the phases were separated. The aqueous phase was extracted with ethyl acetate (2 x 150 mL) and the combined organic phases were dried and evaporated to give an oil. Column chromatography on silica gel (eluent: toluene-ethyl acetate 1:1) gave the title compound as a yellow oil (2.8 g).
Reaction SMILES: [C:1]([CH2:9][CH2:10][N:11]1[CH2:16][CH2:15][C:14]2([C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:18](=[O:25])[O:17]2)[CH2:13][CH2:12]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO.O1CCCC1.[BH4-].[Na+]>O>[OH:8][CH:1]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH2:9][CH2:10][N:11]1[CH2:12][CH2:13][C:14]2([C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:18](=[O:25])[O:17]2)[CH2:15][CH2:16]1
Reactant: O=C(CCN1CCC2(CC1)OC(=O)c1ccccc12)c1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: O=C1OC2(CCN(CCC(O)c3ccccc3)CC2)c2ccccc21

Procedure:
A solution of 2.5 g. of 1'-(2-benzoylethyl)-1,3-dihydrospiro[isobenzofuran-1,4'-piperidine]-3-one, 30 ml. of methanol, 10 ml. of tetrahydrofuran, and 0.35 g. of sodium borohydride is stirred for 4 hours, diluted with water, and extracted with chloroform. The chloroform solution is dried over sodium sulfate and concentrated to a solid. Recrystallization from benzene yields colorless crystals, m.p. 144°-146°.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][CH:6]=[CH:7][CH:8]=1)#[CH:2].Br[C:10]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:11]=1/[C:12](=[CH:20]/[C:21]1[NH:22][CH:23]=[CH:24][C:25]=1[O:26][CH3:27])/[C:13](=[O:19])[NH:14]2>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I.CN(C=O)C.CCN(CC)CC>[CH3:27][O:26][C:25]1[CH:24]=[CH:23][NH:22][C:21]=1/[CH:20]=[C:12]1\[C:13](=[O:19])[NH:14][C:15]2[C:11]\1=[C:10]([C:2]#[C:1][C:3]1[CH:4]=[N:5][CH:6]=[CH:7][CH:8]=1)[CH:18]=[CH:17][CH:16]=2
Reactant: C#Cc1cccnc1
Reactant: COc1cc[nH]c1/C=C1\C(=O)Nc2cccc(Br)c21
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1cc[nH]c1/C=C1\C(=O)Nc2cccc(C#Cc3cccnc3)c21

Procedure:
Using Method D above, 3-ethynyl pyridine (60.6 mg, 0.59 mmol) (see below) was coupled with (Z)-4-bromo-1,3-dihydro-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one (75 mg, 0.23 mmol) (Starting Material 1) using (Ph3P)4Pd (13.3 mg) (Aldrich) and CuI (3 mg) (Aldrich) as catalyst in DMF (4 mL) and Et3N (4 mL) as solvent at 100° C. for 18 h, to yield (Z)-1,3-dihydro-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-4-[(3-pyridinyl)ethynyl]-2H-indol-2-one. (Yield 52 mg, 66%).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.[CH2:9]([O:13][C:14]1[CH:19]=[CH:18][C:17](B(O)O)=[CH:16][N:15]=1)[CH2:10][CH2:11][CH3:12].C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:9]([O:13][C:14]1[N:15]=[CH:16][C:17]([C:2]2[CH:3]=[N:4][C:5]([Cl:8])=[N:6][CH:7]=2)=[CH:18][CH:19]=1)[CH2:10][CH2:11][CH3:12]
Reactant: Clc1ncc(Br)cn1
Reactant: CCCCOc1ccc(B(O)O)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: Cc1ccccc1
Product: CCCCOc1ccc(-c2cnc(Cl)nc2)cn1
Yield: 37.6 %

Procedure:
A reaction of 109 mmol of 5-bromo-2-chloropyrimidine, 109 mmol of 2-butoxypyridine-5-boronic acid, 218 mmol of sodium carbonate and 1.1 mmol of tetrakis(triphenylphosphine)palladium(0) in 200 ml of toluene, 100 ml of ethanol and 100 ml of water is carried out analogously to the procedure indicated for precursor 3. Corresponding purification gives 10.8 g (38%) of a colorless solid, m.p. 117° C., cl.p. 130° C.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][CH:4]=1.Cl[C:13]([O:15][CH3:16])=[O:14]>CO>[CH3:1][N:2]([C:3]1[CH:4]=[CH:5][C:6]([N+:9]([O-:11])=[O:10])=[CH:7][CH:8]=1)[C:13](=[O:14])[O:15][CH3:16]
Reactant: COC(=O)Cl
Reactant: CNc1ccc([N+](=O)[O-])cc1
Solvent: CO
Product: COC(=O)N(C)c1ccc([N+](=O)[O-])cc1

Procedure:
The title compound was prepared from N-methyl-4-nitroaniline and methyl chloroformate according to Method Y and was isolated as a pale yellow solid (84%) after trituration in cold MeOH. δH (DMSO-d6) 8.22 (2H, d, J 9.3 Hz), 7.64 (2H, d, J 9.3 Hz), 3.70 (3H, s), 3.32 (3H, s).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][CH2:7][N:8]1[C:11](=[O:12])[CH2:10][CH:9]1[C:13](OCC)=[O:14])=[O:5])[CH3:2]>C(O)C>[CH2:1]([O:3][C:4]([CH2:6][CH2:7][N:8]1[CH:9]([CH2:13][OH:14])[CH2:10][C:11]1=[O:12])=[O:5])[CH3:2]
Reactant: CCOC(=O)CCN1C(=O)CC1C(=O)OCC
Solvent: CCO
Product: CCOC(=O)CCN1C(=O)CC1CO
Yield: 83 %

Procedure:
4.5 g. (18.5 mmoles) of ethyl 1-(2-ethoxycarbonylethyl)-4-oxo-2-azetidine-carboxylate prepared according to Example 4 are dissolved in 20 ml. of dry ethanol, whereupon 1.4 g. (37 mmoles) of sodium tetrahydroborate(III) are added to the solution at 0° C., with stirring. The reaction mixture is stirred for an additional hour, and is then evaporated in vacuo, at room temperature. The residue is dissolved in 20 ml. of saturated aqueous hydrochloric acid solution and the pH of the solution is adjusted to 6.5 by addition of a 5% aqueous hydrochloric acid solution. The mixture is extracted with three 30-ml. portions of chloroform, dried with magnesium sulfate and filtered. The remaining solution is evaporated in vacuo. 3.1 g. (83%) of the named compound are obtained.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]=[N:13][C:14](Cl)=[CH:15][CH:16]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]>C(O)CCC>[CH3:8][C:11]1[N:13]2[N:12]=[C:11]([C:8]3[CH:9]=[CH:10][C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:6][CH:7]=3)[CH:16]=[CH:15][C:14]2=[N:13][N:12]=1
Reactant: CC(C)(C)c1ccc(-c2ccc(Cl)nn2)cc1
Solvent: CCCCO
Product: Cc1nnc2ccc(-c3ccc(C(C)(C)C)cc3)nn12

Procedure:
A mixture of 5.0 g. of 3-(p-tert-butylphenyl)-6-chloropyridazine, 3.13 g. of acetylhydrazide and 50 ml. of n-butanol is refluxed for 48 hours. The mixture is concentrated under vacuum and the residue stirred with 100 ml. of water and 100 ml. of ether. The mixture is filtered to give 3.0 g. of tan solid, m.p. 144°-146° C. Recrystallization from acetone/hexane gives the product as pale yellow crystals, m.p. 142°-145° C.
Reaction SMILES: [CH2:1]([S:3]([C:6]1[CH:7]=[C:8]([CH3:12])[CH:9]=[CH:10][CH:11]=1)(=[NH:5])=[O:4])[CH3:2].CCCCCC.[C:19]([O:22][CH2:23][CH3:24])(=[O:21])C>C(OCC)(=O)C>[CH2:23]([O:22][C:19]([N:5]=[S:3]([CH2:1][CH3:2])([C:6]1[CH:7]=[C:8]([CH3:12])[CH:9]=[CH:10][CH:11]=1)=[O:4])=[O:21])[CH3:24]
Reactant: CCOC(C)=O
Reactant: CCS(=N)(=O)c1cccc(C)c1
Solvent: CCCCCC
Product: CCOC(=O)N=S(=O)(CC)c1cccc(C)c1
Yield: 92 %

Procedure:
According to GWP 3, the conversion of (RS)-S-ethyl-S-(m-tolyl)sulphoximide (2.55 g, 13.91 mmol) and chromatographic purification (silica gel, hexane/ethyl acetate: 0→100% ethyl acetate) gives the desired product in 92% yield (3.27 g).
Reaction SMILES: [C:1]1([C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=2)[OH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O>C1(C)C(C)=CC=CC=1>[CH:4]1[CH:5]=[CH:6][C:1]([C:7]([OH:8])([CH:9]2[CH2:10][CH2:11][NH:12][CH2:13][CH2:14]2)[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)=[CH:2][CH:3]=1
Reactant: OC(c1ccccc1)(c1ccccc1)c1ccncc1
Solvent: O
Solvent: Cc1ccccc1C
Product: OC(c1ccccc1)(c1ccccc1)C1CCNCC1
Temperature: 170 °C
Reaction time: 17 h
Yield: 86 %

Procedure:
A 1.4 L hydrogenation shaker bomb was charged with 43.00 grams (0.165 moles) diphenyl-4-pyridylcarbinol, 8.00 grams 50% H2O wet 5% Pd on carbon (4 grams dry) and 350 ml xylene. The bomb was sealed, pressurized with 900 psi H2, and heated with shaking to 170° C. After 17 hours, the pressure was 1075 psi (at 170° C.) and the bomb was allowed to cool. The contents are poured out, heated to 70° C. and suction filtered carefully to remove the catalyst. GC analysis of the filtrate and washes at this point indicated 6.9% azacyclonol and 0.05% diphenyl-4-pyridylcarbinol. The filtrate was topped off on a rotary evaporator to a constant weight (42.65 grams). The sticky crude azacyclonol was removed and recrystallized from 200 ml heptane and 165 ml xylene. After chilling, filtration and over drying (2 hours, 100° C., 15 mm) a yield of 37.84 grams or 86.0% of azacyclonol was obtained, having a melting point of 163°-166° C.
Reaction SMILES: [CH2:1]1[O:12][CH:4]([CH2:5][CH:6]2[CH:10]=[CH:9][CH2:8][C:7]2=[O:11])[S:3][CH2:2]1.CC(O)([C:16]#[N:17])C.C([O-])([O-])=O.[Na+].[Na+]>CO.O>[CH2:1]1[O:12][CH:4]([CH2:5][CH:6]2[CH:10]([C:16]#[N:17])[CH2:9][CH2:8][C:7]2=[O:11])[S:3][CH2:2]1
Reactant: O=C1CC=CC1CC1OCCS1
Reactant: CC(C)(O)C#N
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: N#CC1CCC(=O)C1CC1OCCS1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
18 g of the mixture of (2-oxo-cyclopent-4-enyl)acetaldehyde-ethylenethioacetal and (2-oxo-cyclopent-5-enyl)acetaldehyde-ethylene-thioacetal according to stage 2 were dissolved in 150 ml of methanol and 9.2 g of acetonecyanohydrin and a solution of 7.5 g of Na2CO3 in 20 ml of water were added. After stirring for 3 hours at room temperature, all the solvent was distilled off in vacuo, the residue was taken up in 500 ml of diethyl ether and 100 ml of H2O, and the ether phase was washed twice with 50 ml of H2O, dried over sodium sulfate and condensed. The residue was triturated with a small amount of ether and 12 g of crude product were obtained which melted at about 98° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([NH:8][CH3:9])[CH:5]=[CH:4][C:3]=1[CH2:10][OH:11].C[N+]1([O-])CCOCC1>ClCCl.[Ru]([O-])(=O)(=O)=O.C([N+](CCC)(CCC)CCC)CC>[F:1][C:2]1[CH:7]=[C:6]([NH:8][CH3:9])[CH:5]=[CH:4][C:3]=1[CH:10]=[O:11]
Reactant: CNc1ccc(CO)c(F)c1
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: ClCCl
Product: CNc1ccc(C=O)c(F)c1
Reaction time: 0.5 h
Yield: 140.7 %

Procedure:
Add tetrapropylammonium perruthenate (0.35 g) to a mixture of (2-fluoro-4-methylamino-phenyl)-methanol (0.18 g), 4-methylmorpholine N-oxide (0.38 g) and freshly activated powdered molecular sieves (0.30 g) in dry dichloromethane (10 mL) at room temperature under a nitrogen atmosphere. Stir for 30 minutes and add more dichloromethane and filter through a florisil-Celite® pad. Concentrate under reduced pressure to provide (0.25 g, 76%) of the title compound as an oil.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5](B(O)O)[CH:6]=[C:7]([F:9])[CH:8]=1)#[N:2].Br[C:14]1[S:18][C:17]([C:19]([O:21]CC)=[O:20])=[N:16][C:15]=1[C:24]1[CH:29]=[CH:28][C:27]([F:30])=[C:26]([C:31]#[N:32])[CH:25]=1.C(=O)(O)[O-].[Na+]>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:31]([C:26]1[CH:25]=[C:24]([C:15]2[N:16]=[C:17]([C:19]([OH:21])=[O:20])[S:18][C:14]=2[C:5]2[CH:6]=[C:7]([F:9])[CH:8]=[C:3]([C:1]#[N:2])[CH:4]=2)[CH:29]=[CH:28][C:27]=1[F:30])#[N:32]
Reactant: N#Cc1cc(F)cc(B(O)O)c1
Reactant: CCOC(=O)c1nc(-c2ccc(F)c(C#N)c2)c(Br)s1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: N#Cc1cc(F)cc(-c2sc(C(=O)O)nc2-c2ccc(F)c(C#N)c2)c1

Procedure:
At room temperature, 244 mg (1.48 mmol) of the boronic acid from Example 22A are added to 350 mg (0.985 mmol) of the compound from Example 29A and 56.9 mg (0.049 mmol) of tetrakis(triphenylphosphine)palladium in 26 ml of DME. 252 mg (3.01 mmol) of sodium bicarbonate in 11 ml of water are subsequently added, and the mixture is stirred under, reflux for 1 h. The reaction solution is subsequently concentrated under reduced pressure and the residue is taken up in ethyl acetate and washed with a saturated aqueous sodium chloride solution. The organic phase is dried over magnesium sulfate, filtered and concentrated. The residue is purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient). 97.6 mg (16% of theory) of the title compound having a purity of 61% are obtained.