Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]1[C:8]([N+:9]([O-:11])=[O:10])=[CH:7][CH:6]=[CH:5][N:4]=1.[F:12][C:13]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=1[OH:20]>>[F:12][C:13]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=1[O:20][CH2:2][C:3]1[C:8]([N+:9]([O-:11])=[O:10])=[CH:7][CH:6]=[CH:5][N:4]=1
Reactant: Oc1ccc(F)cc1F
Reactant: O=[N+]([O-])c1cccnc1CBr
Product: O=[N+]([O-])c1cccnc1COc1ccc(F)cc1F
Yield: 98 %

Procedure:
In accordance with the same procedures as in Step 3 of Preparation 1, except for using 2-bromomethyl-3-nitropyridine prepared in Step 2 of Preparation 1 and 2,4-difluorophenol, the titled compound was obtained as yellow solid. (Yield: 98%)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([S:10][C:11]3[CH:12]=[CH:13][C:14](=[O:17])[NH:15][N:16]=3)=[C:7]([CH3:18])[C:6]=2[CH:19]=1.C(OO)(=[O:22])C>C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([S:10]([C:11]3[CH:12]=[CH:13][C:14](=[O:17])[NH:15][N:16]=3)=[O:22])=[C:7]([CH3:18])[C:6]=2[CH:19]=1
Reactant: CC(=O)OO
Reactant: Cc1c(Sc2ccc(=O)[nH]n2)oc2ccc(Cl)cc12
Solvent: CC(=O)O
Product: Cc1c(S(=O)c2ccc(=O)[nH]n2)oc2ccc(Cl)cc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 73 %

Procedure:
A mixture of 6-(5-chloro-3-methyl-benzofuran-2-sulfenyl)-2H-pyridazin-3-one (prepared according to the method of Example 2, Step B) (5.0 g, 17.0 mmol), peracetic acid (1.9 g, 25.0 mmol) and acetic acid (20 mL) was stirred at room temperature for two hours. The reaction mixture was quenched with ice-cold water (30 mL) and the precipitated solid was filtered. The solid residue was washed with water (2×10 mL) and then air-dried to obtain the title compound of Example 50 (3.55 g, 73%); mp 234° C.-236° C.
Reaction SMILES: [C:1]([NH:7][C:8]1[N:9]=[C:10]([OH:19])[C:11]2[CH:17]=[C:16](Br)[CH:15]=[N:14][C:12]=2[N:13]=1)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[CH3:20][Si:21]([C:24]#[CH:25])([CH3:23])[CH3:22].[K+].[Br-]>>[C:1]([NH:7][C:8]1[N:9]=[C:10]([OH:19])[C:11]2[CH:17]=[C:16]([C:25]#[C:24][Si:21]([CH3:23])([CH3:22])[CH3:20])[CH:15]=[N:14][C:12]=2[N:13]=1)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3]
Reactant: CC(C)(C)C(=O)Nc1nc(O)c2cc(Br)cnc2n1
Reactant: C#C[Si](C)(C)C
Agent: [Br-]
Agent: [K+]
Product: CC(C)(C)C(=O)Nc1nc(O)c2cc(C#C[Si](C)(C)C)cnc2n1
Yield: 81 %

Procedure:
2-Pivaloylamino-4-hydroxy-6-trimethylsilylethynylpyrido[2,3-d]pyrimidine is prepared in 81% yield from 2-pivaloylamino-4-hydroxy-6-bromopyrido[2,3-d]pyrimidine and trimethylsilylacetylene analogously to Example 2B. m.p. >250° C.; NMR (CDCl3, 300 MHz) delta 0.29 (s, 9H), 1.35 (s, 9H), 8.36 (brs, 1H), 8.57 (d, 1H, J=2.45 Hz), 8.92 (d, 1H, J=2.45 Hz); IR (KBr) 3200, 2970, 2170, 1680, 1620, 1545, 1475, 1440, 1380, 1275, 1250, 1145, 930, and 845 cm-1.
Reaction SMILES: [CH:1]([O:4][C:5](=[O:14])[C:6]1[CH:11]=[CH:10][C:9]([Br:12])=[CH:8][C:7]=1[CH3:13])([CH3:3])[CH3:2].[Br:15]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl>[CH:1]([O:4][C:5](=[O:14])[C:6]1[CH:11]=[CH:10][C:9]([Br:12])=[CH:8][C:7]=1[CH2:13][Br:15])([CH3:3])[CH3:2]
Reactant: Cc1cc(Br)ccc1C(=O)OC(C)C
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)OC(=O)c1ccc(Br)cc1CBr
Temperature: 25 °C
Yield: 63.8 %

Procedure:
A solution of 4-bromo-2-methyl-benzoic acid isopropyl ester (Intermediate 117, 6.12 g, 23.8 mmol) in carbon tetrachloride (120 mL) was treated with N-bromosuccinimide (4.6 g, 26.18 mmol) and 2,2′-azobisisobutyronitrile (0.6 g) and the resulting reaction mixture was refluxed overnight. It was cooled to ambient temperature, the solids were filtered off and washed with 1:1 hexane:diethyl ether, and the filtrate and washings were evaporated in vacuo to afford an oil (5.1 g, 64%) that was used as such for the next step.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]([S:14][C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)[C:12]#[N:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[H-].[Na+].Br[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][Cl:30]>CN(C)C=O>[Cl:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][C:11]([S:14][C:15]1[CH:16]=[CH:17][C:18]([CH3:21])=[CH:19][CH:20]=1)([C:5]1[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=1)[C:12]#[N:13]
Reactant: COc1ccc(C(C#N)Sc2ccc(C)cc2)cc1OC
Reactant: ClCCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(C(C#N)(CCCCCCl)Sc2ccc(C)cc2)cc1OC
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 90 %

Procedure:
To a stirred solution of 5.00 g of 3,4-dimethoxy-α-[(4-methylphenyl)thio]benzeneacetonitrile in 50 mL of N,N-dimethylformamide, under an argon atmosphere, is added 0.73 g of 60% sodium hydride in oil. After 1.5 hours, 4.65 g of 1-bromo-5-chloropentane is added to the resulting solution and stirring continued for 3 hours. The reaction is poured into ice water, and twice extracted with diethyl ether. The combined organic extracts are dried (magnesium sulfate), and concentrated in vacuo to give a golden oil. Purification by chromatography on a silica gel column using diethyl ether/hexane (2:3), affords 6.07 g of the desired product as a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][C:9](=O)[CH2:10]2)=[CH:5][CH:4]=1.[CH2:14]([NH2:17])[CH2:15][CH3:16].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][CH:9]([NH:17][CH2:14][CH2:15][CH3:16])[CH2:10]2)=[CH:5][CH:4]=1
Reactant: CCCN
Reactant: COc1ccc2c(c1)CC(=O)CC2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CCCNC1CCc2ccc(OC)cc2C1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of 7-Methoxy-3,4-dihydro-1-H-naphthalen-2-one (5.0 g, 28.4 mmol) and propylamine (2.8 mL, 34 mmol, 1.2 eq) in 1,2-dichloroethane (150 mL) under inert atmosphere was added sodium triacetoxyborohydride (15 g, 71 mmol, 2.5 eq) in a single portion. The reaction was allowed to stir at room temperature for 20 h then concentrated in-vacuo. The residue was partitioned between 10% aq. KOH (150 mL) and ethyl acetate (75 mL). The organic layer was washed with brine, dried and concentrated. The resulting material was dissolved in diethyl ether (100 mL) and treated with 1M HCl in ether (28.4 ML). The solid was collected and dried under vacuum to afford 6.23 g of (7-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl-propyl-amine as hydrochloride salt.
Reaction SMILES: [BrH:1].[CH3:2][O:3][C:4]1[CH:27]=[CH:26][C:7]([C:8]([NH:10][C:11]2[CH:12]=[C:13]([CH:22]=[CH:23][C:24]=2[OH:25])[CH:14]([OH:21])[CH2:15][NH:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:9])=[CH:6][CH:5]=1.BrBr>C(O)(=O)C>[BrH:1].[CH3:2][O:3][C:4]1[CH:5]=[CH:6][C:7]([C:8]([NH:10][C:11]2[CH:12]=[C:13]([CH:22]=[C:23]([Br:1])[C:24]=2[OH:25])[CH:14]([OH:21])[CH2:15][NH:16][C:17]([CH3:20])([CH3:18])[CH3:19])=[O:9])=[CH:26][CH:27]=1
Reactant: COc1ccc(C(=O)Nc2cc(C(O)CNC(C)(C)C)ccc2O)cc1
Agent: Br
Agent: BrBr
Solvent: CC(=O)O
Product: COc1ccc(C(=O)Nc2cc(C(O)CNC(C)(C)C)cc(Br)c2O)cc1

Procedure:
In substantially the same manner as described above in Example 35 3-(4-methoxybenzamido)-4-hydroxy-α-(tert.butylaminomethyl)benzylalcohol hydrobromide was brominated with bromine in glacial acetic acid. The analytically pure title compound was precipitated from the reaction mixture with ether. M.p. 168° - 169.6° C.
Reaction SMILES: [H-].[Na+].[CH3:3][NH:4][CH2:5][C:6]1[N:7]=[C:8]([CH:11]([CH3:13])[CH3:12])[S:9][CH:10]=1.[O:14]([C:21]([NH:23][C@H:24]([C:28]([OH:30])=[O:29])[CH:25]([CH3:27])[CH3:26])=O)C1C=CC=CC=1.O>C1COCC1>[CH3:3][N:4]([C:21]([NH:23][C@H:24]([C:28]([OH:30])=[O:29])[CH:25]([CH3:27])[CH3:26])=[O:14])[CH2:5][C:6]1[N:7]=[C:8]([CH:11]([CH3:13])[CH3:12])[S:9][CH:10]=1
Reactant: CNCc1csc(C(C)C)n1
Reactant: CC(C)[C@H](NC(=O)Oc1ccccc1)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)c1nc(CN(C)C(=O)N[C@H](C(=O)O)C(C)C)cs1
Temperature: 50 °C
Reaction time: 4 h
Yield: 83 %

Procedure:
To a stirred slurry of 95% NaH (560 mg, 23.2 mmol) at -10° C. in 20 mL of THF was slowly added N-methyl-N-((2-isopropyl-4-thiazolyl)methyl)amine (3.76 g, 22.1 mmol) keeping the temperature not more than 0° C. THF (5 mL) was added as a rinse. A solution of N-phenoxycarbonyl-L-Valine (5.0 g, 21.1 mmol) dissolved in 20 mL of THF was added slowly keeping the temperature not more than 0° C. THF (5 mL) was added as a rinse. After 4 hours, water (100 mL) was added, and the THF was removed under reduced pressure. The pH was adjusted to 9 with concentrated HCl, and the phenol by-product was removed with methyl tert-butyl ether washes (3×60 mL). The aqueous phase was stirred with 70 mL of toluene and adjusted to pH 3 with 4 N HCl. The aqueous phase was separated and extracted twice more with toluene (2×70 mL). The combined toluene extracts were concentrated under reduced pressure, and the residue was redissolved in toluene and heptane (50 mLs of a 1:1 v/v solution), warmed to 50° C. and allowed to cool to ambient temperature. The product was collected by filtration, washed with heptane and dried under vacuum to afford the title compound as a white powder in 83% yield.
Reaction SMILES: [CH3:1][C:2]1([CH3:23])[CH2:7][C@H:6]([NH:8][C:9]2[C:14]([C:15]([F:18])([F:17])[F:16])=[CH:13][N:12]=[C:11](S(C)=O)[N:10]=2)[CH2:5][CH2:4][C@@H:3]1[OH:22].[NH2:24][CH2:25][C:26]1[C:27]([C:34]([F:37])([F:36])[F:35])=[CH:28][C:29]([CH3:33])=[N+:30]([O-:32])[CH:31]=1>O1CCOCC1>[OH:22][C@H:3]1[CH2:4][CH2:5][C@@H:6]([NH:8][C:9]2[C:14]([C:15]([F:18])([F:17])[F:16])=[CH:13][N:12]=[C:11]([NH:24][CH2:25][C:26]3[C:27]([C:34]([F:37])([F:35])[F:36])=[CH:28][C:29]([CH3:33])=[N+:30]([O-:32])[CH:31]=3)[N:10]=2)[CH2:7][C:2]1([CH3:23])[CH3:1]
Reactant: Cc1cc(C(F)(F)F)c(CN)c[n+]1[O-]
Reactant: CS(=O)c1ncc(C(F)(F)F)c(N[C@@H]2CC[C@H](O)C(C)(C)C2)n1
Solvent: C1COCCO1
Product: Cc1cc(C(F)(F)F)c(CNc2ncc(C(F)(F)F)c(N[C@@H]3CC[C@H](O)C(C)(C)C3)n2)c[n+]1[O-]
Yield: 30 %

Procedure:
A solution of (1S,4R)-2,2-dimethyl-4-((2-(methylsulfinyl)-5-(trifluoromethyl)pyrimidin-4-yl)amino)cyclohexanol (1.0 equiv.) and 5-(aminomethyl)-2-methyl-4-(trifluoromethyl)pyridine 1-oxide (1.0 equiv.) in dioxane (0.15 M) was heated at 110° C. for 14 h. Standard work-up afforded 5-(((4-(((1R,4S)-4-hydroxy-3,3-dimethylcyclohexyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)methyl)-2-methyl-4-(trifluoromethyl)pyridine 1-oxide (30% yield). 1H NMR (400 MHz, DMSO-d6) δ (ppm) 8.06 (s, 1H) 7.81-7.99 (m, 3H) 5.94-6.14 (m, 1H) 4.53 (m, 2H) 4.24-4.42 (m, 1H) 3.91 (m, 1H) 2.98-3.24 (m, 1H) 2.23-2.39 (m, 3H) 1.28-1.75 (m, 4H) 0.83-1.24 (m, 3H) 0.74 (s, 3H) 0.57 (s, 3H); MS(ESI) m/z 494.3[M+1]+.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:22])[C:8]=2[NH:12][C:13](=[O:21])[CH2:14][CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)[N:3]=1.[NH:23]1[CH2:27][CH2:26][C@H:25]([OH:28])[CH2:24]1>>[Cl:22][C:7]1[C:8]([NH:12][C:13](=[O:21])[CH2:14][CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]=[C:2]([N:23]1[CH2:27][CH2:26][C@H:25]([OH:28])[CH2:24]1)[CH:11]=[CH:10]2
Reactant: O[C@H]1CCNC1
Reactant: O=C(CC1CCCCC1)Nc1c(Cl)ccc2nc(Cl)ccc12
Product: O=C(CC1CCCCC1)Nc1c(Cl)ccc2nc(N3CC[C@H](O)C3)ccc12
Yield: 78.3 %

Procedure:
Prepared according to the method of example 27, using N-(2,6-dichloro-5-quinolinyl)-cyclohexaneacetamide (Example 1(a)) (0.533 g) and (3S)-3-pyrrolidinol (0.365 g) to afford the title compound (0.48 g).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH:17]([CH3:18])[CH2:16][C:15]3[C:10](=[CH:11][C:12]([C:19]4[CH:20]=[C:21]([C:25]([OH:27])=O)[N:22]([CH3:24])[CH:23]=4)=[CH:13][CH:14]=3)[CH2:9]2)[CH:5]=[C:4]([N:28]2[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]2)[N:3]=1.[CH3:35][N:36]([CH3:41])[CH2:37][CH2:38][NH:39][CH3:40]>>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH:17]([CH3:18])[CH2:16][C:15]3[C:10](=[CH:11][C:12]([C:19]4[CH:20]=[C:21]([C:25]([N:39]([CH2:38][CH2:37][N:36]([CH3:41])[CH3:35])[CH3:40])=[O:27])[N:22]([CH3:24])[CH:23]=4)=[CH:13][CH:14]=3)[CH2:9]2)[CH:5]=[C:4]([N:28]2[CH2:29][CH2:30][N:31]([CH3:34])[CH2:32][CH2:33]2)[N:3]=1
Reactant: CC1Cc2ccc(-c3cc(C(=O)O)n(C)c3)cc2CN1c1cc(N2CCN(C)CC2)nc(N)n1
Reactant: CNCCN(C)C
Product: CC1Cc2ccc(-c3cc(C(=O)N(C)CCN(C)C)n(C)c3)cc2CN1c1cc(N2CCN(C)CC2)nc(N)n1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 87A, Step 9 starting from 4-{2-[2-Amino-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-3-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl}-1-methyl-1H-pyrrole-2-carboxylic acid (Example 87A, Step 8) and N,N,N′-trimethylethane-1,2-diamine. LCMS (M+H)+: m/z=546.4.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([O:12][CH:13]([F:15])[F:14])[CH:11]=1)[S:8][CH2:7][CH2:6][C:5]2=O.[CH3:17]COCC>[CH3-].C[Al+]C.[CH-]1C=CC=C1.[CH-]1C=CC=C1.[Cl-].[Ti+3]>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([O:12][CH:13]([F:15])[F:14])[CH:11]=1)[S:8][CH2:7][CH2:6][C:5]2=[CH2:17]
Reactant: O=C1CCSc2c(OC(F)F)cc(Cl)cc21
Reactant: CCOCC
Agent: [Ti+3]
Agent: C[Al+]C
Agent: [CH3-]
Product: C=C1CCSc2c(OC(F)F)cc(Cl)cc21
Temperature: 0 °C
Reaction time: 2 h
Yield: 36 %

Procedure:
A solution of 6-chloro-8-difluoromethoxy-4-thiochromanone (2.5 g, 9.40 mmol; from step (iii) above) in anhydrous Et2O (150 mL) was cooled to 0° C. under nitrogen. Tebbe Reagent (21.0 mL of 0.5M in toluene, 10.3 mmol) was added dropwise via syringe, and the mixture was stirred at 0° C. for 2 h and then stirred at room temperature for 1 h. The reaction was cooled to 0° C. and slowly quenched with MeOH (ca. 50 mL) until the solution solidified. The mixture was diluted with EtOAc/H20 (4:1, 100 mL) and filtered through a pad of Celite. The Celite was washed with EtOAc (800 mL) and the filtrate was concentrated in vacuo. The crude dark red oil was chromatographed on silica gel eluting with Hex:EtOAc (4:1) to afford 0.88 g (36%) of sub-title compound as a dark yellow oil. 1H NMR (300 MHz, CDCl3) δ 7.40 (s, 1H), 7.05 (s, 1H), 6.46 (t, J=75 Hz, 1H), 5.53 (s, 1H), 5.10 (s, 1H), 3.06 (t, J=7.5 Hz, 2H), 2.80 (t, J=7.5 Hz, 2H).
Reaction SMILES: [F:1][C:2]1([F:33])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[N:28](S(C)(=O)=O)[C:13]3=[N:14][CH:15]=[C:16]([O:18][CH2:19][CH2:20][CH2:21][N:22]4[CH2:26][CH2:25][CH2:24][C@H:23]4[CH3:27])[CH:17]=[C:12]3[CH:11]=2)=[O:9])[CH2:4][CH2:3]1.[H-].[Na+].Br[CH2:37][C:38]#[N:39]>>[F:1][C:2]1([F:33])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[N:28]([CH2:37][C:38]#[N:39])[C:13]3=[N:14][CH:15]=[C:16]([O:18][CH2:19][CH2:20][CH2:21][N:22]4[CH2:26][CH2:25][CH2:24][C@H:23]4[CH3:27])[CH:17]=[C:12]3[CH:11]=2)=[O:9])[CH2:4][CH2:3]1
Reactant: C[C@@H]1CCCN1CCCOc1cnc2c(c1)cc(C(=O)N1CCC(F)(F)CC1)n2S(C)(=O)=O
Reactant: N#CCBr
Agent: [H-]
Agent: [Na+]
Product: C[C@@H]1CCCN1CCCOc1cnc2c(c1)cc(C(=O)N1CCC(F)(F)CC1)n2CC#N
Yield: 3 %

Procedure:
The title compound was synthesized in analogy to example 18 from (4,4-difluoro-piperidin-1-yl)-{1-methanesulfonyl-5-[3-((R)-2-methyl-pyrrolidin-1-yl)-propoxy]-1H-pyrrolo[2,3-b]pyridin-2-yl}-methanone (example 20), sodium hydride and bromoacetonitrile, to give the desired product as a light yellow oil (3%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[C:14]([OH:16])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.ClC(OCC(C)C)=O.[C:32]([C:34]1[CH:35]=[C:36]([CH:41]=[CH:42][CH:43]=1)[C:37]([NH:39]O)=[NH:38])#[N:33]>C1COCC1.ClCCl.O.CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[C:14]1[O:16][N:39]=[C:37]([C:36]2[CH:41]=[CH:42][CH:43]=[C:34]([C:32]#[N:33])[CH:35]=2)[N:38]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: N#Cc1cccc(C(=N)NO)c1
Reactant: CC(C)(C)OC(=O)N1CCCCC1C(=O)O
Agent: CC(C)COC(=O)Cl
Solvent: O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCCCC1c1nc(-c2cccc(C#N)c2)no1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 98.5 %

Procedure:
To a mixture of piperidine-1,2-dicarboxylic acid 1-tert-butyl ester (5.32 g, 23.2 mmol) and triethylamine (4.04 g, 40 mmol) in THF (50 mL), isobutyl chloroformate (3.0 mL, 25.5 mmol) was added dropwise. After the mixture was stirred at room temperature for 45 min, 3-cyano-N-hydroxy-benzamidine (3.7 g, 23.2 mmol) and DMF (40 mL) were added. After being stirred for another hour, the reaction mixture was heated to 130˜135° C. for 1.5 h. Then the solution was cooled to room temperature and poured into water. Dichloromethane was used to extract the product. The organic layer was dried with sodium sulfate and concentrated in vacuo to give 8.1 g (98.4%) of the title compound as a thick brown oil.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH2:11][CH2:12][N:13]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:14][C:5]=3[C:4]=2[CH:3]=1.[N:20]1[CH:25]=[CH:24][CH:23]=[C:22](B(O)O)[CH:21]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>CN(C=O)C.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>[N:20]1[CH:25]=[CH:24][CH:23]=[C:22]([C:2]2[CH:10]=[CH:9][C:8]3[NH:7][C:6]4[CH2:11][CH2:12][N:13]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:14][C:5]=4[C:4]=3[CH:3]=2)[CH:21]=1
Reactant: CCOC(=O)N1CCc2[nH]c3ccc(Br)cc3c2C1
Reactant: OB(O)c1cccnc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)N1CCc2[nH]c3ccc(-c4cccnc4)cc3c2C1
Temperature: 100 °C
Yield: 64.3 %

Procedure:
Preparation of the title compound was carried out according to General Method 7. A mixture of ethyl 8-bromo-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate (See Example 7) (100 mg, 0.3 mmol), pyridine-3-boronic acid (76 mg, 0.62 mmol) and K3PO4 (120 mg, 0.57 mmol) in DMF:H2O (2:1, 3 ml) was purged with nitrogen for 30 minutes. PdCl2(PPh3)2 (25 mg, 0.04 mmol) was added and the reaction was heated at 100° C. for 4 h. The contents were concentrated in vacuo and the crude product was purified by silica gel chromatography (230-400 mesh) using ethyl acetate-hexane gradient to obtain 62 mg of ethyl 3,4-dihydro-8-(pyridin-3-yl)-1H-pyrido[4,3-b]indole-2(5H)-carboxylate. This intermediate (25 mg, 0.078 mmol), 2-methyl-5-vinylpyridine (0.120 ml, 1 mmol) and NaH (10 mg, 60% dispersion in oil, 0.02 mmol) were heated in DMSO (0.3 ml) at 100° C. for 48 h, after which methanol was added and the contents were concentrated to dryness. The resulting crude product was purified by silica gel chromatography (100-200 mesh or 230-400 mesh) using methanol-dichloromethane gradient to obtain 7 mg of 3,4-dihydro-5-(2-(6-methylpyridin-3-yl)ethyl)-8-(pyridin-3-yl)-1H-pyrido[4,3-b]indole-2(5H)-carboxylate.
Reaction SMILES: Cl[P:2]([CH:6]([CH3:8])[CH3:7])[CH:3]([CH3:5])[CH3:4].[Li].Cl[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18]Cl)[N:13]=1>O1CCCC1>[CH:3]([P:2]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][P:2]([CH:6]([CH3:8])[CH3:7])[CH:3]([CH3:5])[CH3:4])[N:13]=1)[CH:6]([CH3:8])[CH3:7])([CH3:5])[CH3:4]
Reactant: ClCc1cccc(CCl)n1
Reactant: CC(C)P(Cl)C(C)C
Agent: [Li]
Solvent: C1CCOC1
Product: CC(C)P(Cc1cccc(CP(C(C)C)C(C)C)n1)C(C)C
Temperature: -80 °C
Reaction time: 72 h

Procedure:
Chloro diisopropylphosphine (10.0 g, 65.5 mmol) in 50 ml of tetrahydrofuran was added dropwise to a suspension of lithium (containing ca. 0.5% Na) granules (1.18 g, 170 mmol) in 50 ml of tetrahydrofuran and the mixture was stirred for 72 hours. The reaction mixture was then filtered, cooled to −80° C., and a solution of 2,6-bis(chloromethyl)pyridine (5.98 g, 34 mmol) in 20 ml of tetrahydrofuran was slowly added via a dropping funnel with vigorous stirring, resulting in the formation of a red solution. The mixture was allowed to warm to room temperature and was then refluxed for one hour. The reaction was followed by 31P NMR spectroscopy to ensure completion and then the solvent was removed in vacuo. Hexanes (50 ml) and water (25 ml) were then added and the water layer was then removed. The hexanes layer was then filtered sequentially through a layer of sodium sulfate (Na2SO4) and silica gel and then the hexane was removed in vacuo to afford a yellow oil. Excess unreacted diisopropylphosphine can be removed in vacuo at 70° C. for 2 hours. Yield: 8.2 g (37%). 1H NMR (400 MHz, C6D6): δ 7.28 (m, 2 H, 3- and 5-H), 7.13 (m, 1H, 4-H), 3.12 (s, 4H, CH2), 1.89 (m, 4H, CH(CH3)2), 1.23 (m, 24H, CH(CH3)2). 31P{1H} NMR (162 MHz, C6D6): δ 7.0.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][CH2:10][NH:11][C:12](=[O:17])[C:13]([F:16])([F:15])[F:14])[CH:5]=[CH:6][CH:7]=1.[O:18]1[C:20]2([CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)[CH2:19]1>CCO.O>[F:16][C:13]([F:14])([F:15])[C:12]([NH:11][CH2:10][C:9]#[C:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([NH:1][CH2:19][C:20]2([OH:18])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)[CH:3]=1)=[O:17]
Reactant: C1CCC2(CC1)CO2
Reactant: Nc1cccc(C#CCNC(=O)C(F)(F)F)c1
Solvent: CCO
Solvent: O
Product: O=C(NCC#Cc1cccc(NCC2(O)CCCCC2)c1)C(F)(F)F

Procedure:
A mixture of N-(3-(3-aminophenyl)prop-2-ynyl)-2,2,2-trifluoroacetamide (0.75 g, 3.09 mmol) and 1-oxaspiro[2.5]octane (1.2 g, 9.2 mmol) in EtOH:H2O (9:1) was stirred under reflux for 36 h. The reaction mixture was concentrated under reduced pressure. Purification by column chromatography (20% to 30% EtOAc—hexanes gradient) gave 2,2,2-trifluoro-N-(3-(3-((1-hydroxycyclohexyl)methylamino)phenyl)prop-2-ynyl)acetamide as an off white solid. Yield (0.48 g, 43%); 1H NMR (400 MHz, DMSO-d6) δ 7.28 (s, 1H), 7.00 (t, J=7.6 Hz, 1H), 6.53-6.51 (m, 2H), 6.39 (d, J=7.6 Hz, 1H), 5.28 (t, J=5.6 Hz, 1H), 4.18 (s, 1H), 4.01 (s, 2H), 2.88 (d, J=5.6 Hz, 2H), 1.60-1.47 (m, 4H), 1.39-1.34 (m, 4H), 1.22-1.14 (m, 2H).
Reaction SMILES: [CH2:1]([N:8]1[C:13](=[O:14])[C:12]2[C:15]3[CH2:21][CH2:20][C:19]([CH:22]=[O:23])=[C:18](Cl)[C:16]=3[S:17][C:11]=2[N:10]=[C:9]1[C:25]1[CH:30]=[C:29]([O:31][CH3:32])[C:28]([O:33][CH3:34])=[C:27]([O:35][CH3:36])[CH:26]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:37]1([OH:43])[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.[OH-].[K+]>CCCC[N+](CCCC)(CCCC)CCCC.[Br-]>[CH2:1]([N:8]1[C:13](=[O:14])[C:12]2[C:15]3[CH2:21][CH2:20][C:19]([CH:22]=[O:23])=[C:18]([O:43][C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)[C:16]=3[S:17][C:11]=2[N:10]=[C:9]1[C:25]1[CH:30]=[C:29]([O:31][CH3:32])[C:28]([O:33][CH3:34])=[C:27]([O:35][CH3:36])[CH:26]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Oc1ccccc1
Reactant: COc1cc(-c2nc3sc4c(c3c(=O)n2Cc2ccccc2)CCC(C=O)=C4Cl)cc(OC)c1OC
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [K+]
Product: COc1cc(-c2nc3sc4c(c3c(=O)n2Cc2ccccc2)CCC(C=O)=C4Oc2ccccc2)cc(OC)c1OC

Procedure:
3-Benzyl-8-chloro-4-oxo-2-(3,4,5-trimethoxyphenyl)-3,4,5,6-tetrahydro-benzo[4,5]thieno[2,3-d]pyrimidine-7-carbaldehyde (Compound No. 3) (50 mg, 96 μmol), phenol (13.5 mg, 143.4 μmol), KOH powder (8.0 mg, 143.4 μmol) and TBAB (1.0 mg) were heated at 85° C. for five hours and at 60° C. for 4.5 hours. The reaction mixture was filtered through cotton wool and evaporated. The crude product was purified by flash-chromatography. The compound No. 5 was isolated as a by-product.
Reaction SMILES: [N:1]1([C:8]2[C:9]([C:22]3[S:26][C:25]4[CH:27]=[CH:28][CH:29]=[CH:30][C:24]=4[CH:23]=3)=[N:10][C:11]3[C:16]([N:17]=2)=[CH:15][C:14]([C:18]([O:20]C)=[O:19])=[CH:13][CH:12]=3)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+].Cl>CO.O>[N:1]1([C:8]2[C:9]([C:22]3[S:26][C:25]4[CH:27]=[CH:28][CH:29]=[CH:30][C:24]=4[CH:23]=3)=[N:10][C:11]3[C:16]([N:17]=2)=[CH:15][C:14]([C:18]([OH:20])=[O:19])=[CH:13][CH:12]=3)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]1
Reactant: COC(=O)c1ccc2nc(-c3cc4ccccc4s3)c(N3CCCCCC3)nc2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1ccc2nc(-c3cc4ccccc4s3)c(N3CCCCCC3)nc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.9 %

Procedure:
To a solution of methyl 3-(azepan-1-yl)-2-(benzo[b]thiophen-2-yl)quinoxaline-6-carboxylate (82 mg, 0.2 mmol) in methanol (15 mL) was added sodium hydroxide (80 mg, 2 mmol) and water (1 mL). After stirring overnight at room temperature, the reaction mixture was concentrated under reduced pressure to afford a residue, which was dissolved in water (10 mL), adjusted the pH value to 6 with HCl (3 N) and filtered to give 3-(azepan-1-yl)-2-(benzo[b]thiophen-2-yl)quinoxaline-6-carboxylic acid as a light yellow solid (70.1 mg, 88%).