Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C@@:2]12[C@@:10]([OH:15])([C:11]([CH2:13][OH:14])=[O:12])[C@H:9]([OH:16])[CH2:8][C@H:7]1[C@@H:6]1[CH2:17][CH2:18][C:19]3[C@@:25]([CH3:26])([C@@:5]1([F:27])[C@@H:4]([OH:28])[CH2:3]2)[CH:24]=[CH:23][C:21](=[O:22])[CH:20]=3>C1(C)C=CC=CC=1.C(O)C.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cl-].[Rh]>[CH3:26][C@@:25]12[C@@:5]3([F:27])[C@@H:4]([OH:28])[CH2:3][C@:2]4([CH3:1])[C@@:10]([OH:15])([C:11]([CH2:13][OH:14])=[O:12])[C@H:9]([OH:16])[CH2:8][C@H:7]4[C@@H:6]3[CH2:17][CH2:18][C:19]1=[CH:20][C:21](=[O:22])[CH2:23][CH2:24]2
Reactant: C[C@]12C=CC(=O)C=C1CC[C@H]1[C@@H]3C[C@@H](O)[C@](O)(C(=O)CO)[C@@]3(C)C[C@H](O)[C@@]12F
Agent: [Rh]
Agent: [Cl-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: CCO
Product: C[C@]12CCC(=O)C=C1CC[C@H]1[C@@H]3C[C@@H](O)[C@](O)(C(=O)CO)[C@@]3(C)C[C@H](O)[C@@]12F
Reaction time: 0.75 h

Procedure:
A suspension of 3.0 g of tris(triphenylphosphine)rhodium chloride in 1000 ml of degassed toluene was hydrogenated for 45 min at room temperature and atmospheric pressure. A solution of 5.0 g of triamcinolone in 500 ml of absolute ethanol was added and the hydrogenation was continued for 48 h. The reaction mixture was evaporated to dryness and suspended in 50 ml of methylene chloride. After filtration the solid phase was repeatedly washed with small portions of methylene chloride and yielded after drying 4.4 g of 9α-fluoro-11β,16α,17α,21-tetrahydroxypregn-4-ene-3,20-dione. Molecular weight 396 (calc. 396.5).
Reaction SMILES: [Br-].[C:2]([CH2:5][NH+:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH2:7]1)(O)=O.[C:12]([O:16][CH3:17])(=[O:15])[CH:13]=C.C(N(CC)CC)C>C1(C)C=CC=CC=1.O=[Mn]=O>[C:13]1([C:12]([O:16][CH3:17])=[O:15])[CH:2]=[CH:5][N:6]2[C:11]=1[CH:10]=[CH:9][CH:8]=[CH:7]2
Reactant: C=CC(=O)OC
Reactant: O=C(O)C[NH+]1C=CC=CC1
Agent: O=[Mn]=O
Agent: [Br-]
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: COC(=O)c1ccn2ccccc12
Temperature: 90 °C

Procedure:
To a suspension of 6.55 g of the pyridinium salt obtained in Step A (30 mmol) in 240 mL of toluene there are added in succession 16.7 mL of methyl acrylate (150 mmol), 4.2 mL of triethylamine (30 mmol) and then, in portions, 20.9 g of MnO2 (240 mmol). The whole is subsequently heated at 90° C. for 3 hours. After cooling, the reaction mixture is filtered over a Celite cake and concentrated to dryness. The title product is then isolated by purification on silica gel (heptane/AcOEt gradient: 0-10%) in the form of an oil, which crystallises when cold.
Reaction SMILES: [S-:1][C:2]#[N:3].[K+].[NH2:5][C:6]1[CH:25]=[CH:24][C:9]([O:10][C:11]2[CH:12]=[C:13]([NH:17][C:18](=[O:23])[C:19]([F:22])([F:21])[F:20])[CH:14]=[CH:15][CH:16]=2)=[CH:8][CH:7]=1.BrBr>C(O)(=O)C>[NH2:3][C:2]1[S:1][C:25]2[CH:24]=[C:9]([O:10][C:11]3[CH:12]=[C:13]([NH:17][C:18](=[O:23])[C:19]([F:21])([F:22])[F:20])[CH:14]=[CH:15][CH:16]=3)[CH:8]=[CH:7][C:6]=2[N:5]=1
Reactant: N#C[S-]
Reactant: Nc1ccc(Oc2cccc(NC(=O)C(F)(F)F)c2)cc1
Agent: BrBr
Agent: [K+]
Solvent: CC(=O)O
Product: Nc1nc2ccc(Oc3cccc(NC(=O)C(F)(F)F)c3)cc2s1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 66.4 %

Procedure:
To a solution of potassium thiocyanate (17.5 g, 180.0 mmol) in acetic acid (130 mL) was added a solution of N-[3-(4-aminophenoxy)phenyl]-2,2,2-trifluoroacetamide (13.0 g, 43.9 mmol) in acetic acid (20 mL), and the mixture was stirred at room temperature for 15 min. To the obtained solution was added dropwise a solution of bromine (7.71 g, 48.2 mmol) in acetic acid (30 mL) at room temperature over 30 min or longer and, after the completion of the dropwise addition, the mixture was stirred at room temperature for 13 hr. The resulting yellow solid was filtered off, and the filtrate was concentrated under reduced pressure. The residue was dissolved in ethyl acetate (200 mL), and basified with 8N aqueous sodium hydroxide solution. The aqueous layer was separated, and the organic layer was washed with saturated aqueous sodium hydrogencarbonate solution (200 mL) and saturated brine (50 mL), and dried over anhydrous magnesium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure to give the title compound (10.3 g, 66%) as a yellow amorphous substance. The obtained compound was used in the next reaction without a further purification.
Reaction SMILES: [CH2:1]([NH:8][CH2:9][CH2:10][NH2:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:12]([N:14]=[C:15](SC)SC)#[N:13]>O1CCOCC1.ClCCl>[CH2:1]([N:8]1[CH2:9][CH2:10][NH:11][C:15]1=[N:14][C:12]#[N:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCCNCc1ccccc1
Reactant: CSC(=NC#N)SC
Solvent: C1COCCO1
Solvent: ClCCl
Product: N#CN=C1NCCN1Cc1ccccc1
Yield: 95 %

Procedure:
To a solution of N-benzylethane-1,2-diamine (3.00 g, 19.96 mmol) in anhydrous dioxane (15 mL) was added dimethyl cyanocarbonimidodithioate (3.50 g, 23.96 mmol). The mixture was refluxed for 16 hours, then diluted with dichloromethane (200 mL), washed with water (200 mL) and brine (100 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography eluted with ethyl acetate/hexane (1/4) to afford the title compound as a colorless solid in 95% yield (3.88 g): mp 120-122° C. (ethyl acetate/hexanes); 1H NMR (300 MHz, CDCl3) δ 7.36-7.22 (m, 5H), 6.86 (br s, 1H), 4.38 (s, 2H), 3.58-3.52 (m, 2H), 3.44-3.88 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 164.0, 135.5, 128.8, 128.1, 127.9, 119.4, 48.3, 46.1, 40.2; MS (ES+) m/z 201.2 (M+1).
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[NH:7][CH2:8][CH2:9][C:10]#[C:11][C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-])=O)=[CH:14][CH:13]=1)([CH3:4])([CH3:3])[CH3:2]>C(O)C.[Pd]>[C:1]([O:5][C:6](=[O:21])[NH:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]1[CH:13]=[CH:14][C:15]([NH2:18])=[CH:16][CH:17]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCCC#Cc1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)NCCCCc1ccc(N)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.6 %

Procedure:
To a solution of compound 51 (2.01 g, 6.923 mmol) in ethanol (50 mL) was added 10% palladium on carbon (737 mg, wet) in one portion under argon protection. The flask was evacuated and re-filled with argon three times (to remove oxygen), and the mixture stirred at room temperature overnight under one atmosphere of hydrogen. The reaction system was then purged with nitrogen, and the catalyst was vacuum filtered and washed with ethanol (2×5 mL). The filtrate and washings were combined and concentrated under reduced pressure. The residue was chromatographed over silica gel, eluting with a mixture of ethyl acetate (0-25%) and hexanes (100-75%), to afford 1.75 g (96%) of the product 52 as a colorless viscous oil. 1H NMR (CDCl3) δ 1.44 (s, 9H), 1.47-1.64 (m, 4H), 2.50 (t, J=7.1 Hz, 2H), 3.08-3.14 (m, 2H), 3.57 (br s, 2H), 4.55 (br s, 1H), 6.62 (d, J=8.2 Hz, 2H), 6.95 (d, J=8.2 Hz, 2H). m/z (APCI)=265 [C15H24N2O2+H]+.
Reaction SMILES: [Br:1][C:2]1[C:3]2[CH2:14][CH2:13][CH:12]([N:15]([CH2:19][CH2:20][CH3:21])[CH2:16][CH2:17][CH3:18])[CH2:11][C:4]=2[CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[CH:7]2.P(Cl)(Cl)(Cl)=O.[OH-].[Na+].CN(C)[CH:31]=[O:32]>O>[Br:1][C:2]1[C:3]2[CH2:14][CH2:13][CH:12]([N:15]([CH2:19][CH2:20][CH3:21])[CH2:16][CH2:17][CH3:18])[CH2:11][C:4]=2[CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[C:7]2[CH:31]=[O:32]
Reactant: CCCN(CCC)C1CCc2c(cc3cc[nH]c3c2Br)C1
Reactant: CN(C)C=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: CCCN(CCC)C1CCc2c(cc3c(C=O)c[nH]c3c2Br)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of (9-Bromo-5,6,7,8-tetrahydro-1H-benzo[f]indol-6-yl)-dipropyl amine (50 mg, 0.14 mmol) in N,N-dimethyl formamide (3 mL) was cooled to 0° C. To this solution was added a cooled solution of phosphorus oxychloride (26 μL, 0.28 mmol) in N,N-dimethyl formamide (1 mL), which had been prepared 20 minutes previous to use. The mixture was stirred at ambient temperature for 30 minutes and then for 30 minutes at 50° C. an additional 30 minutes. The reaction mixture was then treated with a 1M sodium hydroxide solution (5 mL) with heating and stirring maintained for an additional hour. After cooling, the solution was diluted with water (25 mL) and extracted with several portions of diethyl ether. The combined etheral extracts were washed with water, brine, dried over magnesium sulfate, and the solvent evaporated. The residue was chromatographed on a silica column, using methanol as the eluant. This was then repeated with diethyl ether as eluant. The yield of the pure title compound was 50 mg (95%).:
Reaction SMILES: [C:1]([C:4]1[CH:11]=[CH:10][C:7]([C:8]#[N:9])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[Cl-].[Al+3].[Cl-].[Cl-].[Br:16]Br>CCOCC>[C:8]([C:7]1[CH:10]=[CH:11][C:4]([C:1](=[O:3])[CH2:2][Br:16])=[CH:5][CH:6]=1)#[N:9]
Reactant: CC(=O)c1ccc(C#N)cc1
Reactant: BrBr
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCOCC
Product: N#Cc1ccc(C(=O)CBr)cc1
Reaction time: 0.5 h

Procedure:
4-Acetylbenzonitrile (14.5 g, 100 mmol) was dissolved in anhydrous ether (150 ml). Aluminium chloride (catalytic amount) was added to the solution. Bromine (5.1 ml, 100 mmol) was added dropwise at room temperature and the solution stirred for 1/2 h. A precipitate formed and was collected and dried to yield p-cyanophenacyl bromide, m.p. 85°-86° C. (19.34 g, 86%); δH (CDCl3) 7.80 and 8.10(4H, ABq, aryl), 4.45(2H, s, CH2).
Reaction SMILES: C(OC(=O)[N:7]([S:13]([C:16]1[CH:21]=[CH:20][C:19]([O:22][C:23]2[CH:24]=[N:25][C:26](Cl)=[CH:27][C:28]=2[C:29]2[CH:30]=[N:31][CH:32]=[N:33][CH:34]=2)=[C:18]([C:36]#[N:37])[CH:17]=1)(=[O:15])=[O:14])[C:8]1[N:9]=[CH:10][S:11][CH:12]=1)(C)(C)C.[F:39][C:40]1[CH:41]=[C:42](B(O)O)[CH:43]=[CH:44][CH:45]=1.C([O-])([O-])=O.[Na+].[Na+].O>CN(C)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>[C:36]([C:18]1[CH:17]=[C:16]([S:13]([NH:7][C:8]2[N:9]=[CH:10][S:11][CH:12]=2)(=[O:14])=[O:15])[CH:21]=[CH:20][C:19]=1[O:22][C:23]1[CH:24]=[N:25][C:26]([C:44]2[CH:43]=[CH:42][CH:41]=[C:40]([F:39])[CH:45]=2)=[CH:27][C:28]=1[C:29]1[CH:34]=[N:33][CH:32]=[N:31][CH:30]=1)#[N:37]
Reactant: OB(O)c1cccc(F)c1
Reactant: CC(C)(C)OC(=O)N(c1cscn1)S(=O)(=O)c1ccc(Oc2cnc(Cl)cc2-c2cncnc2)c(C#N)c1
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: CN(C)C=O
Solvent: O
Product: N#Cc1cc(S(=O)(=O)Nc2cscn2)ccc1Oc1cnc(-c2cccc(F)c2)cc1-c1cncnc1
Reaction time: 0.17 h
Yield: 753.9 %

Procedure:
10 mg (0.02 mmol) of tert-butyl((4-((6-chloro-4-(pyrimidin-5-yl)pyridin-3-yl)oxy)-3-cyanophenyl)sulfonyl)(thiazol-4-yl)carbamate was dissolved in 3 mL of N,N-dimethylformamide, and 3.7 mg (0.03 mmol) of (3-fluorophenyl)boronic acid was added thereto, and then 2 mg (10 mol %) of Pd(PPh3)4, 5.5 mg (0.05 mmol) of Na2CO3, and 1 mL of H2O were added thereto. After reacting with microwave reactor at 120° C. for 10 minutes, the solvent was removed, and the remaining material was diluted with ethyl acetate and the organic layer was separated, and washed with saturated sodium chloride. The organic layer was collected, dried with magnesium sulfate to remove water, and concentrated under reduced pressure, and the residue was purified by column chromatography (developing solvent, hexane:ethyl acetate=3:1) to obtain 80 mg (70% yield) of the title compound.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1Cl)[CH2:5]Cl.N#N.[NH2:13][C:14]1[CH:21]=[CH:20][C:19](I)=[CH:18][C:15]=1[C:16]#[N:17]>C1COCC1.[Zn]>[NH2:13][C:14]1[CH:21]=[CH:20][C:19]([CH2:5][C:4]2[CH:7]=[CH:8][CH:9]=[CH:2][CH:3]=2)=[CH:18][C:15]=1[C:16]#[N:17]
Reactant: ClCc1ccc(Cl)c(Cl)c1
Reactant: N#Cc1cc(I)ccc1N
Agent: N#N
Agent: [Zn]
Solvent: C1CCOC1
Product: N#Cc1cc(Cc2ccccc2)ccc1N
Temperature: 68 °C
Reaction time: 10 h

Procedure:
A suspension of active Zn metal in THF (0.76 M, 6.3 mL calculated to contain 4.8 mmol or a 20% theoretical excess) was placed in a thoroughly dried three-necked flask which was flushed continuously with a gentle stream of dry N2. A solution of 3,4-dichlorobenzyl chloride (790 mg, 4 mmol) in dry THF (2 mL) was then added slowly to the flask at room temperature, and the reaction mixture was stirred at 68° C. for 10 h and left to stand for 3 h to allow the excess Zn metal to settle to the bottom. The dark-brown solution of organozinc reagent was transferred via a cannula using gentle N2 pressure into another three-necked flask, to which was then added dropwise a solution of 9 (244 mg, 1 mmol) in dry THF (1 mL). Standard workup as for 10a afforded 10e as a pale-yellow powder (172 mg; 65%): mp 104-107° C.; 1H NMR (CDCl3) δ 3.80 (s, 2H, CH2), 4.35 (br s, 2H, NH2), 6.68 (d, J=8.4 Hz, 1H-3), 6.97 (dd, J=8.0 Hz, 2.0 Hz, 1H, H-6′), 7.11 (s, J=8.4 Hz, H-4), 7.16 (s, 1H, H-6), 7.22 (d, J=2.0 Hz, 1H, H-2), 7.35 (d, J 8.0 Hz, 1H, H-5′).
Reaction SMILES: [CH3:1][C:2]([NH:10][C:11]([C:13]1[CH:18]=[N:17][C:16](Br)=[C:15]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[CH:21]=2)[N:14]=1)=[O:12])([C:4]1[N:8]=[C:7]([CH3:9])[O:6][N:5]=1)[CH3:3].Cl.[F:28][C:29]1([F:33])[CH2:32][NH:31][CH2:30]1.C1CCN2C(=NCCC2)CC1>CS(C)=O>[CH3:1][C:2]([NH:10][C:11]([C:13]1[CH:18]=[N:17][C:16]([N:31]2[CH2:32][C:29]([F:33])([F:28])[CH2:30]2)=[C:15]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[CH:21]=2)[N:14]=1)=[O:12])([C:4]1[N:8]=[C:7]([CH3:9])[O:6][N:5]=1)[CH3:3]
Reactant: FC1(F)CNC1
Reactant: Cc1nc(C(C)(C)NC(=O)c2cnc(Br)c(-c3cccc(Cl)c3)n2)no1
Agent: Cl
Solvent: CS(C)=O
Solvent: C1CCC2=NCCCN2CC1
Product: Cc1nc(C(C)(C)NC(=O)c2cnc(N3CC(F)(F)C3)c(-c3cccc(Cl)c3)n2)no1
Temperature: 25 °C
Reaction time: 2 h
Yield: 10.4 %

Procedure:
5-Bromo-6-(3-chloro-phenyl)-pyrazine-2-carboxylic acid [1-methyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethyl]-amide (Example 1e, 0.075 g, 172 μmol) was added to a solution containing 3,3-difluoroazetidine hydrochloride (77.9 mg, 601 μmol) and DBU (91.5 mg, 89.8 μl, 601 μmol) in DMSO (1 mL). The reaction mixture was stirred at room temperature for 2 hours and extracted with ethyl acetate and 10% citric acid. The organic phase was dried with MgSO4, filtered and concentrated in vacuo. The crude material was purified by reverse phase chromatography to give the desired product (8 mg, 10%) as colorless oil; MS (ESI): 449.1 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](Cl)[CH:5]=[CH:4][C:3]=1[OH:9].[OH:10]O>C(O)(=O)C>[Cl:1][C:2]1[C:3](=[O:9])[CH:4]=[CH:5][C:6](=[O:10])[CH:7]=1
Reactant: OO
Reactant: Oc1ccc(Cl)cc1Cl
Solvent: CC(=O)O
Product: O=C1C=CC(=O)C(Cl)=C1
Temperature: 65 °C

Procedure:
A mixture of 2,4-dichlorophenol (5 mmol) and Ti-superoxide catalyst (125 mg, 20% w/w) in acetic acid (5 ml) was heated with stirring at 60-70° C. under inert atmosphere. To this reaction mixture was added aq. 30% H2O2 (20 mmol) drop wise over 15 min. and heated for 1 h. The catalyst was recovered by simple filtration and corresponding quinone formed (25%) was separated by chromatographic purification.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-])=O)[CH:3]=1.P(O[CH2:20][CH3:21])(OCC)(OCC)=O>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]2[C:20]3[C:21](=[CH:7][CH:2]=[CH:3][CH:4]=3)[NH:8][C:4]=2[CH:3]=1
Reactant: O=[N+]([O-])c1cccc(Br)c1
Reactant: CCOP(=O)(OCC)OCC
Product: Brc1ccc2c(c1)[nH]c1ccccc12

Procedure:
A 250 mL round bottom flask was charged with 4-Bromo-2-nitrobenzene (19.2 g, 69.04 mmol), and triethyl phosphate (84 mL, 483.28 mmol). Then, at 160° C. to 165° C., the mixture was heated under reflux for 14 hours. After the reaction was completed, the remaining triethyl phosphate was removed by vacuum distillation. The resultant product was diluted with a mixed solvent of MeOH:H2O=1:1, and the produced solid was filtered. The obtained solid was washed with a mixed solvent of MeOH:H2O=1:1 and petroleum ether.
Reaction SMILES: Cl.[C:2](=[NH:7])(OCC)[CH3:3].[F:8][C:9]1[CH:18]=[CH:17][C:12]([C:13]([NH:15][NH2:16])=[O:14])=[CH:11][CH:10]=1>>[NH:7]=[C:2]([N:15]([C:13](=[O:14])[C:12]1[CH:17]=[CH:18][C:9]([F:8])=[CH:10][CH:11]=1)[NH2:16])[CH3:3]
Reactant: NNC(=O)c1ccc(F)cc1
Reactant: CCOC(C)=N
Agent: Cl
Product: CC(=N)N(N)C(=O)c1ccc(F)cc1

Procedure:
Prepared from 7.2 g (58 mmol) ethyl acetimidate hydrochloride and 5.00 g (32 mmol) 4-fluoro-benzoic acid hydrazide analogously to the method described for intermediate product la). Yield: 5.78 g (91%); mass spectroscopy [M+H]+=196.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([NH2:9])=[CH:5][CH:4]=1.[Cl:10][C:11]1[CH:12]=[C:13]([C:18]2[N:23]=[C:22]([CH3:24])[N:21]=[C:20]([N:25]([CH2:35][C:36]3[CH:41]=[CH:40][C:39]([O:42][CH3:43])=[CH:38][CH:37]=3)[CH2:26][C:27]3[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=3)[N:19]=2)[C:14](F)=[N:15][CH:16]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C>C1COCC1>[Cl:10][C:11]1[CH:12]=[C:13]([C:18]2[N:23]=[C:22]([CH3:24])[N:21]=[C:20]([N:25]([CH2:26][C:27]3[CH:28]=[CH:29][C:30]([O:33][CH3:34])=[CH:31][CH:32]=3)[CH2:35][C:36]3[CH:37]=[CH:38][C:39]([O:42][CH3:43])=[CH:40][CH:41]=3)[N:19]=2)[C:14]([NH:9][C:6]2[CH:7]=[N:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)=[N:15][CH:16]=1
Reactant: COc1ccc(N)cn1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(Cl)cnc3F)n2)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(Cl)cnc3Nc3ccc(OC)nc3)n2)cc1
Reaction time: 1 h
Yield: 64.6 %

Procedure:
A solution of 6-methoxypyridin-3-amine (354 mg, 2.85 mmol) (Aldrich) and 4-(5-chloro-2-fluoropyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine (913 mg, 1.902 mmol) in THF (15 mL) was cooled to 0° C. in an ice bath and treated dropwise with 1 M LiHMDS (5.71 mL, 5.71 mmol). After stirring for 1 h at this temperature, the reaction mixture was quenched with a saturated solution of NH4Cl at 0° C. and extracted with EtOAc (50 mL), dried over MgSO4, filtered and concentrated. Purification on the ISCO (40 g column, 20-100% EtOAc in hexanes) gave 4-(5-chloro-2-(6-methoxypyridin-3-ylamino)pyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine (717.3 mg, 1.228 mmol, 64.6% yield) as a bright yellow crystalline solid. m/z (ESI, +ve ion) 584.1 (M+H)+. 1H NMR (400 MHz, CDCl3) δ 11.65 (1H, s); 8.73 (1H, d, J=2.7 Hz); 8.26 (1H, d, J=2.7 Hz); 8.19 (1H, d, J=2.7 Hz); 7.83 (1H, dd, J=8.8, 2.7 Hz); 7.19 (4H, dd, J=16.2, 8.6 Hz); 6.86 (4H, dd, J=10.4, 8.8 Hz); 6.70 (1H, d, J=8.8 Hz); 4.86 (2H, s); 4.81 (2H, s); 3.93 (3H, s); 3.81 (3H, s); 3.79 (3H, s); 2.57 (3H, s).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:20]#[N:21])[C:5]2[CH:6]=[N:7][N:8]([S:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)(=[O:13])=[O:12])[C:9]=2[CH:10]=1.CC1(C)C(C)(C)OB([C:30]2[CH:38]=[CH:37][CH:36]=[C:35]3[C:31]=2[CH:32]=[CH:33][N:34]3[C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])O1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].O1CCOCC1>O>[C:20]([C:4]1[CH:3]=[C:2]([C:30]2[CH:38]=[CH:37][CH:36]=[C:35]3[C:31]=2[CH:32]=[CH:33][N:34]3[C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH:10]=[C:9]2[C:5]=1[CH:6]=[N:7][N:8]2[S:11]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)(=[O:13])=[O:12])#[N:21]
Reactant: N#Cc1cc(Br)cc2c1cnn2S(=O)(=O)c1ccccc1
Reactant: CC(C)(C)OC(=O)n1ccc2c(B3OC(C)(C)C(C)(C)O3)cccc21
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)n1ccc2c(-c3cc(C#N)c4cnn(S(=O)(=O)c5ccccc5)c4c3)cccc21
Yield: 44.8 %

Procedure:
To a round bottomed flask was charged 6-bromo-1-(phenylsulfonyl)-1H-indazole-4-carbonitrile (10 g, 27.6 mmol), 1,1-dimethylethyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole-1-carboxylate (14.21 g, 41.4 mmol) and potassium phosphate tribasic (17.58 g, 83 mmol). The resulting mixture was treated with 1,4-dioxane (120 ml) and water (12 ml) that had previously been purged with nitrogen. The mixture was then treated with 1′-bis(diphenylphosphino)ferrocene palladium dichloride (1.547 g, 2.76 mmol) and heated to reflux, under nitrogen for 2 h. Additional 1′-bis(diphenylphosphino)ferrocene palladium dichloride (1.547 g, 2.76 mmol) was added and the mixture heated at reflux for a further 1 h. The hot reaction mixture was filtered through Celite, washed well with chloroform and the filtrate concentrated in vacuo. The residue was dissolved in DCM/cyclohexane (1:1, 50 ml) and purified by column chromatography on silica (750 g cartridge), eluting with 0-40% ethyl acetate/cyclohexane. The pure fractions were combined and concentrated to give the title compound as a yellow solid (6.16 g).
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][CH:7]2[CH2:11][N:10]([CH3:12])[CH2:9][CH:8]2[C:13]#N)=[CH:4][CH:3]=1.[OH-:17].[Na+]>O>[Cl:1][C:2]1[CH:16]=[CH:15][C:5]2[CH2:6][CH:7]3[CH:8]([C:13](=[O:17])[C:4]=2[CH:3]=1)[CH2:9][N:10]([CH3:12])[CH2:11]3
Reactant: CN1CC(C#N)C(Cc2ccc(Cl)cc2)C1
Reactant: [OH-]
Agent: [Na+]
Solvent: O
Product: CN1CC2Cc3ccc(Cl)cc3C(=O)C2C1
Reaction time: 1 h

Procedure:
25 ml of water are added dropwise to 500 g of polyphosphoric acid at 50° followed by 50 g of 4-(p-chlorobenzyl)-1-methyl-pyrrolidin-3-carbonitrile and the mixture stirred for 1 hour at 125° and then for 21/2 hours at 160°. Ice and 1 liter of 50% sodium hydroxide are added to the cooled mixture which is then extracted with ethyl acetate. The organic phase is washed with water, dried over sodium sulphate and evaporated to yield 6-chloro-3a,4,9,9a-tetrahydro-2-methylbenz[f]isoindolin-4-one. M.P. 148°-150° (hydrogen maleate form).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([C:12]([OH:14])=[O:13])[CH:11]=1)[NH:8][CH2:7][CH2:6][CH:5]2[C:15]([OH:17])=[O:16].[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([C:12]([O:14][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[O:13])[CH:11]=1)[NH:8][CH2:7][CH2:6][CH:5]2[C:15]([O:17][CH2:5][C:4]1[CH:9]=[CH:10][CH:11]=[CH:2][CH:3]=1)=[O:16]
Reactant: O=C(O)c1cc(Br)cc2c1NCCC2C(=O)O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(OCc1ccccc1)c1cc(Br)cc2c1NCCC2C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 6-bromo-1,2,3,4-tetrahydroquinoline-4,8-dicarboxylic acid (10.2 g), benzyl bromide (9 ml) and potassium carbonate (10 g) in DMF (30 ml) was stirred at room temperature for 3 hours and filtered. To the filtrate was added a mixture of ethyl acetate-benzene (1:1, 300 ml). The mixture was washed with water, dried over anhydrous sodium sulfate and concentrated to give oily objective compound (17.44 g).