Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[C:5](=[CH2:20])[CH2:6][CH2:7][CH2:8][CH:9]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1)[CH3:2].ClC1C=CC=C(C(OO)=[O:30])C=1>C(Cl)Cl>[CH2:1]([O:3][C:4]([C:5]1([CH2:6][CH2:7][CH2:8][CH:9]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[CH2:20][O:30]1)=[O:21])[CH3:2]
Reactant: C=C(CCCC1CCCCCCCCCC1)C(=O)OCC
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CCOC(=O)C1(CCCC2CCCCCCCCCC2)CO1

Procedure:
2.2 g of the title compound, in the form of a colourless oil, which is purified by chromatography on silica gel (migrating agent: 90:10 petroleum ether/ethyl acetate; thin layer chromatography on silica gel with petroleum ether/ethyl acetate 9:1:Rf =0.5), are obtained by the procedure described in Example (1a) from 4.4 g of 5-cycloundecyl-2-methylenevaleric acid ethyl ester and 5.15 g of m-chloroperbenzoic acid in 40 ml of methylene chloride.
Reaction SMILES: NCC(NC1C=CC(N2C(C3C=CC4C=CC5C(C=4C=3)=CC=CC=5)=CC(C(NC(C)C)=O)=N2)=CC=1)=O.[CH:37]1[C:50]2[CH:49]=[CH:48][C:47]3[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=3)[C:41]=2[CH:40]=[C:39]([C:51](=[O:53])[CH3:52])[CH:38]=1.[C:54](OCC)(=[O:60])[C:55]([O:57][CH2:58]C)=[O:56].[H-].[Na+].Cl>CO>[OH:53]/[C:51](/[C:39]1[CH:38]=[CH:37][C:50]2[CH:49]=[CH:48][C:47]3[C:42]([C:41]=2[CH:40]=1)=[CH:43][CH:44]=[CH:45][CH:46]=3)=[CH:52]\[C:54](=[O:60])[C:55]([O:57][CH3:58])=[O:56]
Reactant: CC(=O)c1ccc2ccc3ccccc3c2c1
Reactant: CCOC(=O)C(=O)OCC
Agent: CC(C)NC(=O)c1cc(-c2ccc3ccc4ccccc4c3c2)n(-c2ccc(NC(=O)CN)cc2)n1
Agent: Cl
Agent: [H-]
Solvent: CO
Product: COC(=O)C(=O)/C=C(\O)c1ccc2ccc3ccccc3c2c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 80 %

Procedure:
1-(4-(2-Aminoacetamido) phenyl)-N-isopropyl-5-(phenanthren-3-yl)-1H-pyrazole-3-carboxamide (15)Step a. To the mixture of 1-(phenanthren-3-yl)ethanone (1; 6.6 g, 30 mmol) and diethyl oxalate (2 ml) in MeOH (100 mL) was added sodium hydride (2.9 g, 120 mmol) portion-wise within 10 min. The reaction mixture was stirred at room temperature for 4 h, cooled down to 0° C. and acidified with 2N HCl. The precipitate was collected, washed with cold ethanol and dried to yield (Z)-methyl 4-hydroxy-2-oxo-4-(phenanthren-3-yl)but-3-enoate (1) as yellow crystal (7.3 g, 80%). It was used for the next step without further purification. 1H-NMR (300 MHz, DMSO-d6) δ 9.47 (s, 1H), 9.09 (d, J=7.8 Hz, 1H), 8.26 (d, J=9.0 Hz, 1H), 8.15 (d, J=9.0 Hz, 1H), 8.06-8.01 (m, 2H), 7.94 (d, J=7.8 Hz, 1H), 7.80-7.69 (m, 2H), 7.51 (s, 1H), 3.90 (s, 3H).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][S:6]([C:8]1[N:12]([CH3:13])[N:11]=[N:10][N:9]=1)=[O:7].[CH3:14][N:15]1[C:19]([SH:20])=[N:18][N:17]=[N:16]1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:14][N:15]1[C:19]([S:20][CH2:2][CH2:3][CH2:4][CH2:5][S:6]([C:8]2[N:12]([CH3:13])[N:11]=[N:10][N:9]=2)=[O:7])=[N:18][N:17]=[N:16]1
Reactant: Cn1nnnc1S
Reactant: Cn1nnnc1S(=O)CCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Cn1nnnc1SCCCCS(=O)c1nnnn1C
Yield: 49.1 %

Procedure:
1-Methyl-1,2,3,4-tetrazol-5-yl 4-bromobutyl sulfoxide (2.7 g) and 1-methyl-5-mercapto-1,2,3,4-tetrazole (1.4 g) are dissolved in acetone (50 ml), and thereto is added potassium carbonate (1.4 g), and the mixture is refluxed for 2 hours. After acetone is distilled off, water is added to the residue, and the mixture is extracted with chloroform. The chloroform solution is washed with saturated aqueous sodium chloride and dried over magnesium sulfate. After chloroform is distilled off, the residue is purified by column chromatography (Kieselgel 60), eluting with chloroform-methanol (100:1) to give 1-methyl-1,2,3,4-tetrazol-5-yl 4-(1-methyl-1,2,3,4-tetrazol-5-yl)thiobutyl sulfoxide (1.5 g), as colorless liquid, nD19 =1.5660.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:24])[N:9]([CH3:23])[CH2:10][C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]3[N:20]=[C:19]([CH2:21]Cl)[O:18][N:17]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH2:25]([NH:27][CH2:28][CH3:29])[CH3:26]>CN(C)C=O>[Cl:1][C:2]1[C:7]2[C:8](=[O:24])[N:9]([CH3:23])[CH2:10][C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]3[N:20]=[C:19]([CH2:21][N:27]([CH2:28][CH3:29])[CH2:25][CH3:26])[O:18][N:17]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CN1Cc2c(-c3noc(CCl)n3)ncn2-c2cccc(Cl)c2C1=O
Reactant: CCNCC
Solvent: CN(C)C=O
Product: CCN(CC)Cc1nc(-c2ncn3c2CN(C)C(=O)c2c(Cl)cccc2-3)no1
Yield: 85 %

Procedure:
1.6 g (4.4 mmol) of 7-chloro-3-(5-chloromethyl-1,2,4-oxadiazol-3-yl)-5-methyl-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepin-6-one were stirred at room temperature for 4.5 hours with 1.1 g (15 mmol) of diethylamine and 10 ml of N,N-dimethylformamide. By evaporation of the reaction mixture and chromatography of the residue on silica gel while eluting with methylene chloride/methanol 9/1 there were obtained 1.50 g (85%) of 7-chloro-3-(5-diethylaminomethyl-1,2,4-oxadiazol-3-yl)-5-methyl-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepin-6-one, which was converted into the hydrochloride of m.p. 250°-252°.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9]([CH3:11])[C:8]([OH:12])=[C:7]2[C:3]=1[CH2:4][CH:5]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:6]2=O.[CH2:20]([NH2:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(OCC)C.ClCCl>[CH3:1][C:2]1[CH:10]=[C:9]([CH3:11])[C:8]([OH:12])=[C:7]2[C:3]=1[CH2:4][C:5]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[C:6]2[NH:27][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: Cc1cc(C)c2c(c1O)C(=O)C(c1ccccc1)C2
Reactant: NCc1ccccc1
Solvent: ClCCl
Solvent: CCOCC
Product: Cc1cc(C)c2c(c1O)C(NCc1ccccc1)=C(c1ccccc1)C2
Temperature: 25 °C
Reaction time: 48 h

Procedure:
5.0 Grams of 4,6-dimethyl-7-hydroxy-2-phenyl-1-indanone was dissolved in 10 ml of diethyl ether and 10 ml of dichloromethane, then this solution was added dropwise gradually to a mixture of a solution of 2.55 ml of benzylamine in 10 ml of diethyl ether with 8 g of Molecular sieves 5A. The whole mixture was stirred at room temperature for 2 days and filtered by using Celite to obtain filtrate. The Celite used was washed with dichloromethane and ethanol, then these washing liquors were combined with the above-mentioned filtrate and concentrated. Recrystallized from dichloromethane-ethanol to obtain 3.83 g of 4,6-dimethyl-7-hydroxy-1-benzylamino-2-phenyl-3H-indene. Orange needle-like crystals.
Reaction SMILES: [H-].C(O[Al](OC(C)(C)C)OC(C)(C)C)(C)(C)C.[Li+].[OH:19][C@@H:20]1[CH2:37][CH2:36][C@@:35]2([CH3:38])[C@@H:22]([CH2:23][CH2:24][C@@H:25]3[C@@H:34]2[CH2:33][CH2:32][C@@:30]2([CH3:31])[C@H:26]3[CH2:27][CH2:28][C:29]2=[S:39])[CH2:21]1.C([O-])(O)=O.[Na+]>C1COCC1>[OH:19][C@@H:20]1[CH2:37][CH2:36][C@@:35]2([CH3:38])[C@@H:22]([CH2:23][CH2:24][C@@H:25]3[C@@H:34]2[CH2:33][CH2:32][C@@:30]2([CH3:31])[C@H:26]3[CH2:27][CH2:28][C@@H:29]2[SH:39])[CH2:21]1
Reactant: C[C@]12CC[C@@H](O)C[C@@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)C(=S)CC[C@@H]12
Agent: CC(C)(C)O[Al](OC(C)(C)C)OC(C)(C)C
Agent: O=C([O-])O
Agent: [H-]
Solvent: C1CCOC1
Product: C[C@]12CC[C@@H](O)C[C@@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](S)CC[C@@H]12
Temperature: 0 °C
Reaction time: 2 h
Yield: 94.6 %

Procedure:
A 1.0 M solution of lithium tri-t-butoxy aluminum hydride in THF (6.27 mL, 6.27 mmol) was added in a dropwise manner to a solution of 3α-hydroxy-5α-androstan-17-thione (0.64 g, 2.09 mmol) in THF (60 mL) at 0° C. under N2. The solution was allowed to stir for 2 h at 0° C. and then another 2 h at room temperature. Saturated NaHCO3 (75 mL) was added and the slurry was extracted with CH2Cl2 (3×100 mL). The organics were combined, dried (MgSO4), and concentrated under reduced pressure. The resulting white solid was recrystallized from heptane to provide a white powder (0.61 g, 95%). mp. 169-170° C. 1H-NMR (300 MHz, CDCl3) δ 0.70 (s, 3H), 0.79 (s, 3H), 0.80-1.70 (m, 23H), 2.16-2.18 (m, 2H), 2.58-2.69 (dd, J=9, 18 Hz, 1H), 2.90-3.00 (dd, J=9, 9 Hz, 1H), 4.06 (m, 1H). Elemental Anal. for C19H32OS Calcd. C, 73.97; H, 10.45; S, 10.39. Found. C, 73.82; H, 10.73; S, 10.28.
Reaction SMILES: [CH3:1][C:2]1[C:10]([F:11])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([F:12])[CH:3]=1.S(=O)(=O)(O)O.[CH3:18]O>>[F:12][C:4]1[CH:3]=[C:2]([CH3:1])[C:10]([F:11])=[CH:9][C:5]=1[C:6]([O:8][CH3:18])=[O:7]
Reactant: CO
Reactant: Cc1cc(F)c(C(=O)O)cc1F
Agent: O=S(=O)(O)O
Product: COC(=O)c1cc(F)c(C)cc1F

Procedure:
To a suspension of 4-methyl-2,5-difluorobenzoic acid (comm, 52 g, 0.3 mol) in methanol (1.0 L) was added concentrated sulphuric acid (3 mL) with stirring and the reaction heated to reflux under nitrogen for 18 hours. The reaction was quenched with aqueous sodium bicarbonate solution (10%, 150 mL), concentrated in vacuo and the resulting residue partitioned between EtOAc (800 mL) and water (400 mL). The organic layer was washed with water (250 mL) and brine (100 mL), dried with sodium sulphate and concentrated in vacuo to yield the title compound as a clear oil that solidified on standing (54.7 g, 98%).
Reaction SMILES: [Cl:1][C:2]1[C:10]([CH2:11][N:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14]([C:21]3[N:26]=[C:25]([NH:27][C:28]4[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=4)[C:24]([O:34][CH3:35])=[CH:23][N:22]=3)=[N:13]2)=[C:9]([Cl:36])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.F[P-](F)(F)(F)(F)F.[CH3:44][N:45](C(ON1C2=NC=CC=C2N=N1)=[N+](C)C)C.C(N(C(C)C)C(C)C)C.CN>CS(C)=O.O1CCCC1>[Cl:1][C:2]1[C:10]([CH2:11][N:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14]([C:21]3[N:26]=[C:25]([NH:27][C:28]4[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=4)[C:24]([O:34][CH3:35])=[CH:23][N:22]=3)=[N:13]2)=[C:9]([Cl:36])[CH:8]=[CH:7][C:3]=1[C:4]([NH:45][CH3:44])=[O:6]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: COc1cnc(-c2nn(Cc3c(Cl)ccc(C(=O)O)c3Cl)c3ccccc23)nc1Nc1ccncc1
Agent: CN
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: CS(C)=O
Product: CNC(=O)c1ccc(Cl)c(Cn2nc(-c3ncc(OC)c(Nc4ccncc4)n3)c3ccccc32)c1Cl
Temperature: 25 °C
Reaction time: 18 h

Procedure:
100 mg of 2,4-dichloro-3-({3-[5-methoxy-4-(pyridin-4-ylamino)pyrimidin-2-yl]-1H-indazol-1-yl}methyl)benzoic acid (19-1, 0.192 mmol, 1. eq.) were dissolved in 0.953 ml of dry dimethyl sulfoxide. 80.2 mg of N-[(dimethylamino)(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yloxy)methylidene]-N-methylmethanaminium hexafluorophosphate (0.211 mmol, 1.1 eq.), 67 μl of N-ethyl-N-(propan-2-yl)propan-2-amine (0.384 mmol, 2 eq.) and 96 μl of 2 N methyl amine in tetrahydrofuran were added in this sequence. The reaction mixture was stirred at room temperature for 18 hours. 80.2 mg of N-[(dimethylamino)(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yloxy)-methylidene]-N-methylmethanaminium hexafluorophosphate (0.211 mmol, 1.1 eq.), 67 μl of N-ethyl-N-(propan-2-yl)propan-2-amine (0.384 mmol, 2 eq.) and 96 μl of 2 N methyl amine in tetrahydrofuran were added in this sequence again twice and stirred each time at room temperature for 24 hours. The reaction mixture was stirred at 50° C. bath temperature for further 2 hours. Then the mixture was filtered off purified by preparative HPLC to yield 15 mg (0.03 mmol, 14.3%) of the analytically pure target compound.
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][C:5]([C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]=[CH:10]2)=[O:6].Cl[C:17]1[CH:22]=[CH:21][C:20]([O:23][CH:24]2[CH2:29][CH2:28][N:27]([CH2:30][C:31]([F:34])([CH3:33])[CH3:32])[CH2:26][CH2:25]2)=[CH:19][N:18]=1>>[F:34][C:31]([CH3:33])([CH3:32])[CH2:30][N:27]1[CH2:26][CH2:25][CH:24]([O:23][C:20]2[CH:21]=[CH:22][C:17]([N:12]3[C:13]4[C:9](=[CH:8][C:7]([C:5]([NH:4][CH2:3][CH2:2][OH:1])=[O:6])=[CH:15][CH:14]=4)[CH:10]=[CH:11]3)=[N:18][CH:19]=2)[CH2:29][CH2:28]1
Reactant: O=C(NCCO)c1ccc2[nH]ccc2c1
Reactant: CC(C)(F)CN1CCC(Oc2ccc(Cl)nc2)CC1
Product: CC(C)(F)CN1CCC(Oc2ccc(-n3ccc4cc(C(=O)NCCO)ccc43)nc2)CC1

Procedure:
The title compound was prepared by following the similar procedure as described in Example-1 using N-(2-hydroxyethyl)-1H-indole-5-carboxamide (intermediate-19) and 2-Chloro-5-((1-(2-fluoro-2-methylpropyl)piperidin-4-yl)oxy)pyridine (intermediate-54).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([O:8][C:9]([F:12])([F:11])[F:10])[CH:5]=[CH:4][C:3]=1[Cl:13].[CH2:14](C([Sn])=C(CCCC)CCCC)[CH2:15]CC>C1(C)C=CC=CC=1>[Cl:13][C:3]1[CH:4]=[CH:5][C:6]([O:8][C:9]([F:12])([F:11])[F:10])=[CH:7][C:2]=1[CH:14]=[CH2:15]
Reactant: CCCCC([Sn])=C(CCCC)CCCC
Reactant: FC(F)(F)Oc1ccc(Cl)c(Br)c1
Solvent: Cc1ccccc1
Product: C=Cc1cc(OC(F)(F)F)ccc1Cl
Yield: 33.3 %

Procedure:
2-Bromo-1-chloro-4-(trifluoromethoxy)benzene (Description 25; 1.0 g, 3.6 mmol) and tri-n-butylvinyl tin (1.21 g, 3.8 mmol) were dissolved in toluene (20 mL) and the solution was degassed for 45 minutes with nitrogen. Tetrakis(triphenylphosphine) palladium (0) (100 mg) was then added and the solution heated at reflux for 2 hours. Once cooled, the solution was concentrated and the residue was purified by silica chromatography to give the title compound (274 mg, 1.2 mmol).
Reaction SMILES: [CH:1]1([S:6][CH2:7][CH2:8][NH:9][C:10]2[N:15]=[C:14]([N:16]3[C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=4[N:18]=[C:17]3[CH:25]([F:27])[F:26])[N:13]=[C:12]([N:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)[N:11]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.ClC1C=CC=C(C(OO)=[O:42])C=1.O>C(Cl)Cl>[CH:1]1([S:6]([CH2:7][CH2:8][NH:9][C:10]2[N:15]=[C:14]([N:16]3[C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=4[N:18]=[C:17]3[CH:25]([F:27])[F:26])[N:13]=[C:12]([N:28]3[CH2:29][CH2:30][O:31][CH2:32][CH2:33]3)[N:11]=2)=[O:42])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: FC(F)c1nc2ccccc2n1-c1nc(NCCSC2CCCC2)nc(N2CCOCC2)n1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Solvent: O
Product: O=S(CCNc1nc(N2CCOCC2)nc(-n2c(C(F)F)nc3ccccc32)n1)C1CCCC1
Reaction time: 0.17 h
Yield: 85.5 %

Procedure:
N-[2-(Cyclopentylsulfanyl)ethyl]-4-[2-(difluoromethyl)-1H-benzimidazol-1-yl]-6-(morpholin-4-yl)-1,3,5-triazin-2-amine (60 mg) was dissolved in methylene chloride (1.2 mL), and m-chloroperbenzoic acid (75% wet) (32 mg) was added thereto at 0° C., followed by stirring for 10 minutes. Water was added thereto, followed by extraction with chloroform. The organic layer was dried over anhydrous magnesium sulfate and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=20:80, and subsequently chloroform:methanol=98:2-90:10) to obtain N-[2-(cyclopentyl sulfinyl)ethyl]-4-[2-(difluoromethyl)-1H-benzimidazol-1-yl]-6-(morpholin-4-yl)-1,3,5-triazin-2-amine (53 mg) as a white powder.
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@H:13]2[CH2:22][CH2:21][C:20]3[C:15](=[C:16]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[Cl:30])[C:17]([Cl:23])=[CH:18][CH:19]=3)[O:14]2)(=O)=O)=CC=1.[N-:31]=[N+:32]=[N-:33].[Na+]>CS(C)=O>[N:31]([CH2:12][C@H:13]1[CH2:22][CH2:21][C:20]2[C:15](=[C:16]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[Cl:30])[C:17]([Cl:23])=[CH:18][CH:19]=2)[O:14]1)=[N+:32]=[N-:33]
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2CCc3ccc(Cl)c(-c4ccccc4Cl)c3O2)cc1
Agent: [Na+]
Solvent: CS(C)=O
Product: [N-]=[N+]=NC[C@H]1CCc2ccc(Cl)c(-c3ccccc3Cl)c2O1
Yield: 99.1 %

Procedure:
Treatment of ((2R)-7-chloro-8-(2-chlorophenyl)chroman-2-yl)methyl 4-methylbenzenesulfonate (2.10 g, 4.53 mmol) with sodium azide (1.77 g, 27.20 mmol) in DMSO (50 mL) according to the procedure described for Example 69, Step 9 provided 1.5 g (99%) of (2R)-2-(azidomethyl)-7-chloro-8-(2-chlorophenyl)chroman as a white solid. MS (EI) m/z 333.0 [M]+.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:16])[C:8]3=[C:7]([CH3:17])[C:6]=2[CH:5]=[C:4]([C:18]#[N:19])[CH:3]=1.[F:20][C:21]([F:33])([F:32])[O:22][C:23]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][CH:24]=1>>[CH3:17][C:7]1[C:6]2[CH:5]=[C:4]([C:18]#[N:19])[CH:3]=[C:2]([C:26]3[CH:25]=[CH:24][C:23]([O:22][C:21]([F:20])([F:32])[F:33])=[CH:28][CH:27]=3)[C:10]=2[N:9]2[CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:16])[C:8]=12
Reactant: OB(O)c1ccc(OC(F)(F)F)cc1
Reactant: Cc1c2n(c3c(Br)cc(C#N)cc13)CCCNC2=O
Product: Cc1c2n(c3c(-c4ccc(OC(F)(F)F)cc4)cc(C#N)cc13)CCCNC2=O

Procedure:
The title compound, light grey solid (81 mg, 81%), MS (ISP) m/z=400.6 [(M+H)+], mp 218° C., was prepared in accordance with the general method of example 1 from 7-bromo-11-methyl-1-oxo-2,3,4,5-tetrahydro-[1,4]diazepino[1,2-a]indole-9-carbonitrile (intermediate 17) (79.5 mg, 0.25 mmol) and commercially available 4-trifluoromethoxy-phenylboronic acid (66.9 mg, 0.325 mmol).
Reaction SMILES: [N+:1]([CH3:4])([O-:3])=[O:2].[OH-].[Na+].[S:7]1[CH:11]=[CH:10][C:9]([CH:12]=O)=[CH:8]1.Cl>C(O)C>[N+:1](/[CH:4]=[CH:12]/[C:9]1[CH:10]=[CH:11][S:7][CH:8]=1)([O-:3])=[O:2]
Reactant: C[N+](=O)[O-]
Reactant: O=Cc1ccsc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=[N+]([O-])/C=C/c1ccsc1
Reaction time: 0.25 h

Procedure:
To a solution of nitromethane (1.15 eq.) in ethanol (30 ml per gm of aldehyde) cooled to 0° C. was added dropwise a solution of 10N NaOH and stirred for 15 min. 3-thiopene carbaldehyde was added slowly under slitting at 0° C. and resulting reaction mixture was stirred for 1 hr. Reaction mixture was then poured on 10% icecold HCl solution and yellow solid was filtered and dried to yield the desired 3-[(E)-2-nitrovinyl]thiophene.
Reaction SMILES: Br[C:2]1[CH:15]=[N:14][C:5]2[N:6]([CH3:13])[C:7](=[O:12])[N:8]([CH3:11])[C:9](=[O:10])[C:4]=2[CH:3]=1.C[Sn]([CH2:20][C:21](=[O:23])[CH3:22])(C)C.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>[Pd].C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1C=CC=CC=1>[O:23]=[C:21]([CH3:22])[CH2:20][C:2]1[CH:15]=[N:14][C:5]2[N:6]([CH3:13])[C:7](=[O:12])[N:8]([CH3:11])[C:9](=[O:10])[C:4]=2[CH:3]=1
Reactant: CC(=O)C[Sn](C)(C)C
Reactant: Cn1c(=O)c2cc(Br)cnc2n(C)c1=O
Agent: [Pd+2]
Agent: [Pd]
Agent: CC(=O)[O-]
Solvent: c1ccccc1
Product: CC(=O)Cc1cnc2c(c1)c(=O)n(C)c(=O)n2C

Procedure:
Treatment of 6-bromo-1,3-dimethylpyrido[2,3-d]pyrimidin-2,4-(1H,3H)-dione with trimethylstannyl acetone in the presence of a palladium catalyst such as palladium (II) acetate and a triarylphosphine such as tri-o-tolylphosphine in an anhydrous solvent such as benzene at temperatures between 50 degrees and 120 degrees C. will afford 6-(2'-oxoproply)-1,3-dimethylpyrido[2,3-d]pyrimidin-2,4-(1H,3H)-dione. Treatment of this material with N,N-dimethylformamide dimethylacetal in the presence of a catalytic amount of pyridine will afford 6-[1-N,N-dimethylamino-3'-oxobuten-2'-yl]-1,3-dimethylpyrido[2,3-d]pyrimidin-2,4-(1H,3H)-dione. Treatment of this material with cyanoacetamide in the presence of a base such as sodium hydride in a suitable solvent at temperatures between 30 degrees and 80 degrees C. will afford 6-[3'-cyano-6'-methyl-2'-oxo-1(H)pyridin-5'-yl]1,3-dimethylpyrido[2,3-d]pyrimidin-2,4-(1H,3H)-dione.
Reaction SMILES: [H-].[Na+].[CH3:3]S(C)=O.[I-].C[S+](C)(C)=O.[C:13]([O:16][CH2:17][CH2:18][S:19][C:20]([F:32])([F:31])[C:21]([C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:24]=1[F:30])=[O:22])(=[O:15])[CH3:14]>C1COCC1>[C:13]([O:16][CH2:17][CH2:18][S:19][C:20]([F:31])([F:32])[C:21]1([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:24]=2[F:30])[O:22][CH2:3]1)(=[O:15])[CH3:14]
Reactant: CC(=O)OCCSC(F)(F)C(=O)c1ccc(F)cc1F
Reactant: CS(C)=O
Agent: C[S+](C)(C)=O
Agent: [H-]
Agent: [I-]
Solvent: C1CCOC1
Product: CC(=O)OCCSC(F)(F)C1(c2ccc(F)cc2F)CO1
Temperature: 50 °C
Reaction time: 0.25 h
Yield: 90 %

Procedure:
A suspension of 60% NaH (3.95 g, 0.1 mol) in THF (60 ml)-DMSO (120 ml) was heated to an external temperature of 50° C., followed by the addition of trimethylsulfoxonium iodide (21.7 g, 0.1 mol) in portions. The resulting mixture was stirred for 15 minutes at the same temperature and was then cooled to -20° C. To the reaction mixture, a solution of 2-(2-acetoxyethyl)thio-2,2-difluoro-2',4'-difluoroacetophenone (25.5 g, 0.08 mol) in THE (60 ml) was added dropwise. After being stirred at room temperature for 1.5 hours, the reaction mixture was poured into ice water, followed by extraction with ethyl ether. The ether solution was washed with water, dried over magnesium sulfate and then distilled off under reduced pressure, whereby 1-(2-acetoxyethyl)thio-2-(2,4-difluorophenyl)-1,1-difluoro-2,3-epoxypropane (24.0 g, yield: 90.0%) was obtained as a pale yellow oil.
Reaction SMILES: N[C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][CH:17]=1)[O:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]([C:12]([NH2:14])=O)[CH:7]=1.[NH2:18]C1C=CC(O)=CC=1.ClC1C=CN=C(C#N)C=1>>[NH2:18][C:17]1[CH:16]=[CH:15][C:4]([O:5][C:6]2[CH:11]=[CH:10][N:9]=[C:8]([C:12]#[N:14])[CH:7]=2)=[CH:3][CH:2]=1
Reactant: Nc1ccc(O)cc1
Reactant: NC(=O)c1cc(Oc2cccc(N)c2)ccn1
Agent: N#Cc1cc(Cl)ccn1
Product: N#Cc1cc(Oc2ccc(N)cc2)ccn1

Procedure:
4-(4-Aminophenoxy) pyridine-2-carbonitrile (21) was prepared by a method analogous to that described for 4-(3-aminophenoxy) pyridine-2-carboxamide (2C), starting from 4-aminophenol and 4-chloro-2-cyanopyridine, MS ES: 212 (M+H)+, calcd 212, RT=1.23 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[C:20]3[N:19]=[C:18](O)[CH:17]=[N:16][C:15]=3[C:14]([C:22]#[N:23])=[CH:13][CH:12]=2)[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.O=P(Cl)(Cl)[Cl:26]>>[Cl:26][C:18]1[CH:17]=[N:16][C:15]2[C:14]([C:22]#[N:23])=[CH:13][CH:12]=[C:11]([C:5]3[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=3)[C:20]=2[N:19]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1cc(OC)cc(-c2ccc(C#N)c3ncc(O)nc23)c1
Product: COc1cc(OC)cc(-c2ccc(C#N)c3ncc(Cl)nc23)c1
Temperature: 120 °C
Reaction time: 3 h

Procedure:
A mixture of 8-(3,5-dimethoxy-phenyl)-2-hydroxy-quinoxaline-5-carbonitrile (Step 85.5) (100 mg, 0.33 mmol) and POCl3 (1 mL) was stirred at 120° C. for 3 h, allowed to cool to rt and concentrated. The residue was diluted with DCM/NaHCO3 saturated aqueous solution and extracted with DCM. The organic phase was washed with H2O and brine, dried (Na2SO4), filtered and concentrated. The crude product was purified by silica gel column chromatography (Hex/EtOAc, 7:3) to afford 90 mg of the title compound as a yellow solid: ES-MS: 326.1 [M+H]+; tR=5.02 min (System 1); Rf=0.34 (Hex/EtOAc, 7:3).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7](=O)[C:8]([OH:10])=O.[CH2:12]([C:19]1[C:20]([NH2:31])=[N:21][CH:22]=[C:23]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[N:24]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[CH2:12]([C:19]1[NH:24][C:23]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)=[CH:22][N:21]2[C:8](=[O:10])[C:7]([CH2:6][C:2]3[O:1][CH:5]=[CH:4][CH:3]=3)=[N:31][C:20]=12)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: O=C(O)C(=O)Cc1ccco1
Reactant: Nc1ncc(-c2ccccc2)nc1Cc1ccccc1
Product: O=c1c(Cc2ccco2)nc2c(Cc3ccccc3)[nH]c(-c3ccccc3)cn1-2

Procedure:
Synthesized from method C using 3-(furan-2-yl)-2-oxopropanoic acid and 3-benzyl-5-phenylpyrazin-2-amine as starting materials. 1H NMR (300 MHz, dmso) δ 8.88 (s, 1H), 8.02 (d, J=7.9, 2H), 7.61-7.38 (m, 6H), 7.37-7.14 (m, 3H), 6.38 (s, 1H), 6.26 (d, J=3.2, 1H), 4.64 (s, 3H), 4.40 (s, 3H); exact mass calculated for C24H20N3O2+ m/z+ 382.16, found m/z+ 382.