Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:5][C:6]([C:8]1[N:9]=[C:10](Br)[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][C:14]([O:19][C:20]1[C:25]([CH3:26])=[CH:24][C:23]([CH3:27])=[CH:22][C:21]=1[CH3:28])=[CH:13][CH:12]=2)=[O:7])[CH2:2][CH2:3][CH3:4].[C:30]([Cu])#[N:31]>>[CH2:1]([O:5][C:6]([C:8]1[N:9]=[C:10]([C:30]#[N:31])[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][C:14]([O:19][C:20]1[C:25]([CH3:26])=[CH:24][C:23]([CH3:27])=[CH:22][C:21]=1[CH3:28])=[CH:13][CH:12]=2)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: N#C[Cu]
Reactant: CCCCOC(=O)c1nc(Br)c2ccc(Oc3c(C)cc(C)cc3C)cc2c1O
Product: CCCCOC(=O)c1nc(C#N)c2ccc(Oc3c(C)cc(C)cc3C)cc2c1O

Procedure:
The title compound was synthesized from 1-bromo-4-hydroxy-6-(2,4,6-trimethyl-phenoxy)-isoquinoline-3-carboxylic acid butyl ester and CuCN in analogy to example 3a; MS-(−)-ion: M−1=403.4.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[CH2:14][N:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)=[CH:4][CH:3]=1.F[C:22]1[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[CH:24][CH:23]=1.C([O-])([O-])=O.[K+].[K+]>CS(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[CH2:14][N:15]2[CH2:16][CH2:17][N:18]([C:22]3[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[CH:24][CH:23]=3)[CH2:19][CH2:20]2)=[CH:4][CH:3]=1
Reactant: N#Cc1ccc(F)cc1
Reactant: Clc1ccc(-c2ccccc2CN2CCNCC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: N#Cc1ccc(N2CCN(Cc3ccccc3-c3ccc(Cl)cc3)CC2)cc1
Temperature: 130 °C

Procedure:
A solution of EXAMPLE 22C (932 mg, 2.591 mmol) in DMSO (13 mL) was treated with 4-fluorobenzonitrile (408 mg, 3.368 mmol) and K2CO3 (1.788 g, 12.955 mmol), heated at 130° C. for 4 hours, and filtered. The filtrate was partitioned between aqueous NaHCO3 and ethyl acetate. The aqueous layer was extracted with ethyl acetate. The combined extracts were dried (MgSO4), filtered, and concentrated. The residue was purified by silica gel column chromatography with 20% ethyl acetate/hexanes to provide the desired product. MS (ESI) m/e 388, 390 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[C:9]([O:10][CH3:11])=[CH:8][C:7]([O:12][CH3:13])=[CH:6][C:3]=1[CH:4]=[O:5].C([O-])([O-])=O.[K+].[K+].[CH2:20]([O:22][CH:23]([O:26][CH2:27][CH3:28])[CH2:24]Br)[CH3:21]>CN(C=O)C>[CH2:20]([O:22][CH:23]([O:26][CH2:27][CH3:28])[CH2:24][O:1][C:2]1[C:9]([O:10][CH3:11])=[CH:8][C:7]([O:12][CH3:13])=[CH:6][C:3]=1[CH:4]=[O:5])[CH3:21]
Reactant: COc1cc(C=O)c(O)c(OC)c1
Reactant: CCOC(CBr)OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(COc1c(C=O)cc(OC)cc1OC)OCC
Yield: 67 %

Procedure:
To a stirred suspension containing 38 (1.1 g, 6.0 mmol) and K2CO3 (1.0 g, 7.2 mmol) in DMF (100 mL), bromoacetaldehyde diethyl acetal (0.93 mL, 6.0 mmol) was added dropwise. The mixture was refluxed for 4 h. After cooling, the precipitate was filtered off and the solvent was evaporated in vacuo. The crude residue was adsorbed on silica gel and purified by flash chromatography. The product was eluted with hexane/EtOAc (4:1) to give 39 (1.2 g, 67%) as an oil. 1H NMR (500 MHz, CDCl3): δ: 10.50 (1H, s, CHO), 6.88 (1H, d, J4,6=2.9 Hz, H-6), 6.74 (1H, d, J4,6=2.9 Hz, H-4), 4.83 (1H, t, J4,6=5.3 Hz, CH), 4.14 (2H, d, J4,6=5.3 Hz, CH2), 3.88 (3H, s, OMe), 3.83 (3H, s, OMe), 3.77-3.71) (2H, m, CH2CH3), 3.63-3.58 (2H, m, CH2CH3), 1.24 (6H, t, J=7.1 Hz, 2×CH3).
Reaction SMILES: [CH:1]1([C:7]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)([C:9]2[N:13](CN3CCCC3)[N:12]=[CH:11][N:10]=2)[OH:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[BH4-].[Na+]>C(O)C>[CH:20]1([C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)([C:9]2[N:10]=[CH:11][NH:12][N:13]=2)[OH:8])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]1
Reactant: OC(c1ccccc1)(c1ncnn1CN1CCCC1)C1CCCCC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: OC(c1ccccc1)(c1nc[nH]n1)C1CCCCC1
Temperature: 25 °C
Yield: 79 %

Procedure:
Cyclohexyl(phenyl)[1-(pyrrolidin-1-ylmethyl)-1H-1,2,4-triazol-5-yl]methanol (Preparation 17, 27.28 g, 80.12 mmol) was dissolved in ethanol (400 ml) and sodium borohydride (3.03 g, 80.1 mmol) added portionwise. After stirring at reflux for 3 hours the reaction was left to cool to room temperature over 18 hrs. The solvent was removed in vacuo and the residue purified by column chromatography on silica gel eluting with pentane:ethyl acetate (3:1 to 0:1, by volume) to furnish the title compound as a white foam, in 79% yield, 16.4 g.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([O:11][CH3:12])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].[CH3:13][N:14]([CH3:17])[CH:15]=O>>[CH3:13][N:14]([CH3:17])/[CH:15]=[CH:1]/[C:2]1[CH:3]=[C:4]([O:11][CH3:12])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9]
Reactant: COc1ccc([N+](=O)[O-])c(C)c1
Reactant: CN(C)C=O
Product: COc1ccc([N+](=O)[O-])c(/C=C/N(C)C)c1
Yield: 36 %

Procedure:
A solution of 3.0 g. of 3-methyl-4-nitroanisole, 5.1 g. of N,N-dimethylformaide dicyclohexyl acetal, and 25 ml. of N,N-dimethylformamide was heated at reflux under a nitrogen atmosphere for 40 hours and then was transferred to a Claisen flask. Vacuum distillation gave, after removal of the volatile components, 1.89 g. of a red liquid (b.p. 158°/0.04 mm.) which crystallized on scratching to give a solid, having a melting point of 61°-64°. Recrystallization from 10 ml. of ether and 7 ml. of petroleum ether gave 1.46 g (36%) of trans-β-dimethylamino-5-methoxy-2-nitrostyrene having a melting point of 67.5°-69°.
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:13][CH:12]([OH:14])[CH2:11]1)(C(C)(C)C)(C)C.[CH3:23]N(C1C2C(N(C)C)=CC=CC=2C=CC=1)C.C[O+](C)C>C(Cl)Cl.[Cl-].[Na+].O>[OH:8][CH2:9][C:10]1([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:13][CH:12]([O:14][CH3:23])[CH2:11]1
Reactant: CC(C)(C)OC(=O)NC1(CO[Si](C)(C)C(C)(C)C)CC(O)C1
Reactant: CN(C)c1cccc2cccc(N(C)C)c12
Agent: C[O+](C)C
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: COC1CC(CO)(NC(=O)OC(C)(C)C)C1
Temperature: 0 °C
Reaction time: 3 h
Yield: 71.9 %

Procedure:
500 mg (1.51 mmol) of tert-butyl 1-((tert-butyldimethylsilyloxy)methyl)-3-hydroxycyclobutylcarbamate (prepared by reduction of ethyl-1[[(tert-butyloxy)carbonyl]amino]-3-hydroxycyclobutane-1-carboxylate as described in J. Med. Chem., 1990 33(10) 2905-2915) and proton sponge (N,N,N′,N′ tetramethylnapthalene-1,8 diamine) (1.63 g, 6.04 mmol) were dissolved in DCM (18 mL), cooled down to 0° C., and 447 mg (3.02 mmol) of trimethyloxonium borontetrafluoride was added in one portion as a solid under vigorous stirring. The reaction mixture was stirred for 3 h and diluted with DCM (50 mL) and brine (20 mL), added under vigorous stirring. The organic phase was washed with sodium bicarbonate, brine, dried over sodium sulphate, evaporated and purified on short silica column (DCM as an eluent). The resulting product was dissolved in THF (5 mL), and a solution of tetrabutylammonium fluoride in THF (1M, 4.5 mL) was added, and the reaction was stirred at room temperature for 4.5 h. The reaction was monitored by TLC and once deemed to have reached completion, it was absorbed onto silica and purified on silica (EtOAc-hexane 1:1 to neat EtOAc) to give the title compound (251 mg, 72%). LC/MS 232 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[S:10]([CH3:13])(=[O:12])=[O:11])[CH:5]=O.N1CCCCC1.C(O)=O.[CH3:23][C:24](=[O:29])[CH2:25][C:26](=[O:28])[CH3:27]>CC(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]=[C:25]([C:24](=[O:29])[CH3:23])[C:26](=[O:28])[CH3:27])[CH:7]=[CH:8][C:9]=1[S:10]([CH3:13])(=[O:12])=[O:11]
Reactant: CS(=O)(=O)c1ccc(C=O)cc1Cl
Reactant: CC(=O)CC(C)=O
Solvent: C1CCNCC1
Solvent: O=CO
Solvent: CC(C)O
Product: CC(=O)C(=Cc1ccc(S(C)(=O)=O)c(Cl)c1)C(C)=O
Temperature: 20 °C

Procedure:
To a solution containing 2.5 g of 3-chloro-4-methylsulfonylbenzaldehyde, 0.13 ml of piperidine and 0.05 ml of formic acid in 70 ml of 2-propanol was added 2.6 ml of 2,4-pentanedione with stirring at 20° C. The solution was stirred overnight at 20° C. The product was filtrated and washed with 2-propanol, yield 2.1 g (60%), mp. 140-142° C. 1H-NMR (DMSO-d6,400 MHz): 2.28 (s, 3 H, CH3), 2.50 (s, 3 H, CH3), 3.40 (s, 3 H, CH3), 7.60 (m, 1 H, Ar), 7.80 (m, 1 H, Ar), 7.77 (s, 1 H CH), 8.1 (m, 1 H, Ar).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:14])[CH2:8][CH2:7]2)([OH:3])=[O:2].O[N:16]1[C:20](=[O:21])[CH2:19][CH2:18][C:17]1=[O:22].ClC(Cl)CCCCCN=C=N>O1CCOCC1>[NH:10]1[C:11]2[C:6](=[CH:5][C:4]([C:1]([OH:3])=[O:2])=[CH:13][CH:12]=2)[CH2:7][CH2:8][C:9]1=[O:14].[C:17]1(=[O:22])[NH:16][C:20](=[O:21])[CH2:19][CH2:18]1
Reactant: O=C1CCC(=O)N1O
Agent: N=C=NCCCCCC(Cl)Cl
Agent: O=C1CCc2cc(C(=O)O)ccc2N1
Solvent: C1COCCO1
Product: O=C1CCC(=O)N1
Temperature: 90 °C

Procedure:
10 Grams of 6-carboxy-3,4-dihydrocarbostyril and 6.0 g of N-hydroxysuccinimide were suspended in 200 ml of dioxane. Then a solution of 12.4 g of dichlorohexylcarbodiimide in 50 ml of dioxane was added drop-wise of the suspension under ice-cooling with stirring. The reaction mixture was heated at 90° C. for 4 hours. After the reaction was completed, the reaction mixture was cooled to a room temperature, and the crystals being precipitated were removed by filtration and the mother liquor was concentrated by distillation. The residue was recrystallized from dimethylformamide-ethanol to obtain 10.8 g of succinimide 3,4-dihydrocarbostyril-6-carboxylate.
Reaction SMILES: CON(C)[C:4]([C:6]1[N:7]=[CH:8][C:9]([N:12]2[CH2:17][CH2:16][N:15]([C:18]3[N:19]=[N:20][C:21]([CH2:26][C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)=[C:22]([CH3:25])[C:23]=3[CH3:24])[CH2:14][C@H:13]2[CH3:33])=[N:10][CH:11]=1)=[O:5].[CH3:35][Mg]I>C1COCC1>[CH2:26]([C:21]1[N:20]=[N:19][C:18]([N:15]2[CH2:16][CH2:17][N:12]([C:9]3[CH:8]=[N:7][C:6]([C:4](=[O:5])[CH3:35])=[CH:11][N:10]=3)[C@H:13]([CH3:33])[CH2:14]2)=[C:23]([CH3:24])[C:22]=1[CH3:25])[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: CON(C)C(=O)c1cnc(N2CCN(c3nnc(Cc4ccccc4)c(C)c3C)C[C@H]2C)cn1
Reactant: C[Mg]I
Solvent: C1CCOC1
Product: CC(=O)c1cnc(N2CCN(c3nnc(Cc4ccccc4)c(C)c3C)C[C@H]2C)cn1
Temperature: 0 °C
Reaction time: 16 h
Yield: 86.2 %

Procedure:
(R)-4-(6-Benzyl-4,5-dimethyl-pyridazin-3-yl)-2-methyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-5′-carboxylic acid methoxy-methyl-amide (example 142, 450 mg, 0.975 mmol) is dissolved in THF (1 mL) and cooled to 0° C. A dropwise addition of methyl magnesium iodide (325 μL, 0.975 mmol) is added dropwise. Reaction is warmed to room temperature and continues to stir for 16 h. Add H2O (1 drop) and concentrate reaction mixture in vacuo. The residue is purified by flash chromatography on silica gel (60-100% EtOAc/Heptane and 0-8% MeOH/EtOAc) to afford the title compound (350 mg, 86%).
Reaction SMILES: [CH3:1][CH:2]([CH3:31])[CH2:3][CH:4]([NH:11][C:12]([C:14]1[CH:19]=[CH:18][C:17]([N:20]2[CH2:23][C:22]([F:25])([F:24])[CH2:21]2)=[C:16]([O:26][CH2:27][CH:28]2[CH2:30][CH2:29]2)[N:15]=1)=[O:13])[C:5]1[N:6]=[N:7][CH:8]=[CH:9][CH:10]=1.[CH3:32]I.[H-].[Na+]>>[CH3:32][N:11]([CH:4]([C:5]1[N:6]=[N:7][CH:8]=[CH:9][CH:10]=1)[CH2:3][CH:2]([CH3:31])[CH3:1])[C:12]([C:14]1[CH:19]=[CH:18][C:17]([N:20]2[CH2:21][C:22]([F:25])([F:24])[CH2:23]2)=[C:16]([O:26][CH2:27][CH:28]2[CH2:30][CH2:29]2)[N:15]=1)=[O:13]
Reactant: CI
Reactant: CC(C)CC(NC(=O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1)c1cccnn1
Agent: [H-]
Agent: [Na+]
Product: CC(C)CC(c1cccnn1)N(C)C(=O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1

Procedure:
In analogy to the procure described in Example 16 b), (+)-6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (3-methyl-1-pyridazin-3-yl-butyl)-amide was reacted with methyl iodide (CAN 74-88-4) in the presence of sodium hydride to give the title compound as colorless oil; MS (EI): m/e=446.2 [MH]+.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[C:10](=[O:11])[CH2:9][CH2:8][N:7]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:6]1)=[O:4].[H-].[Na+].[CH3:21]I>O1CCCC1>[CH3:1][O:2][C:3]([C:5]1([CH3:21])[C:10](=[O:11])[CH2:9][CH2:8][N:7]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:6]1)=[O:4]
Reactant: COC(=O)C1CN(C(=O)OC(C)(C)C)CCC1=O
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)C1(C)CN(C(=O)OC(C)(C)C)CCC1=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 59.6 %

Procedure:
4-Oxo-piperidine-1,3-dicarboxylic acid 1-tert-butyl ester 3-methyl ester (2.00 g, 6.8 mmol) was dissolved in tetrahydrofuran and cooled to 0° C. To the solution was added NaH (0.300 g, 12.5 mmol) portionwise over 1 h. H2(g) was evolved during the addition. The reaction was allowed to stir for 30 minutes at 0° C. and then methyl iodide (0.422 mL, 6.8 mmol) was added and allowed to stir at room temperature for 13 h. The reaction was quenched with ice water and concentrated down. The residue was partitioned between water and ethyl acetate. The aqueous layer was extracted with EtOAc (3×), the organics were collected together dried over Mg2SO4, filtered and evaporated in vacuo, then purified by Biotage flash chromatography (10% ethyl acetate/90% hexane to yield the title compound (1.1 g, 52%). 1H-NMR (CDCl3): δ 1.29 (s, 3H), 1.47 (s, 9H), 2.47 (dt, 1H), 2.76 (m, 1H), 3.07 (d, 1H), 3.33 (dt, 1H), 3.71 (s, 3H), 4.11 (m, 1H), 4.50 (d, 1H).
Reaction SMILES: [CH2:1]([NH:8][C:9]1[C:10]([C:28]([F:31])([F:30])[F:29])=[C:11]([CH:25]=[CH:26][CH:27]=1)[C:12]([NH:14][CH2:15][C:16]1[C:17](=[O:24])[NH:18][C:19]([CH3:23])=[CH:20][C:21]=1[CH3:22])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:32](O)(=O)[CH3:33].C(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>ClCCCl.O>[CH2:1]([N:8]([CH2:32][CH3:33])[C:9]1[C:10]([C:28]([F:31])([F:29])[F:30])=[C:11]([CH:25]=[CH:26][CH:27]=1)[C:12]([NH:14][CH2:15][C:16]1[C:17](=[O:24])[NH:18][C:19]([CH3:23])=[CH:20][C:21]=1[CH3:22])=[O:13])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cc(C)c(CNC(=O)c2cccc(NCc3ccccc3)c2C(F)(F)F)c(=O)[nH]1
Reactant: CC(=O)O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: CC=O
Agent: O=C([O-])O
Solvent: O
Solvent: ClCCCl
Product: CCN(Cc1ccccc1)c1cccc(C(=O)NCc2c(C)cc(C)[nH]c2=O)c1C(F)(F)F
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 36.1 %

Procedure:
To a solution of 3-(benzylamino)-N-[(4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl]-2-(trifluoromethyl)benzamide (198 mg, 0.46 mmol) in DCE (5 ml) was added acetic acid (80 μl, 1.38 mmol) followed by acetaldehyde (129 μl, 2.31 mmol) after which the reaction was stirred at room temperature for 10 min. Then sodium triacetoxyborohydride (490 mg, 2.31 mmol) was added in one portion and the reaction was stirred at room temperature for 16 h. Further 4×130 uL treatments with acetaldehyde and 4×0.5 g sodium triacetoxyborohydride were performed over 3 days to completed the reaction. Water (100 ml) was then added to the reaction mixture and the aqueous phase was neutralized by the portionwise addition of NaHCO3. The aqueous phase was extracted with DCM (2×50 ml), then the combined organic phases washed with brine, dried (Na2SO4) and evaporated. The product was purified using FCC over a 5 g Isolute, eluting with 0-5% MeOH in DCM followed by purification via RP-HPLC to give the title compound as an off-white powder (76 mg, 34%). LC-MS 100%, m/z=458.3, 1H NMR (500 MHz, Chloroform-d) δ 11.70 (s, 1H), 7.42 (t, J=7.8 Hz, 1H), 7.36-7.27 (m, 5H), 7.24 (d, J=7.1 Hz, 1H), 7.12 (d, J=7.4 Hz, 1H), 7.03 (d, J=5.4 Hz, 1H), 5.90 (s, 1H), 4.50 (d, J=5.7 Hz, 2H), 4.05 (s, 2H), 2.96 (q, J=7.1 Hz, 2H), 2.36 (s, 3H), 2.15 (s, 3H), 0.89 (t, J=7.1 Hz, 3H).
Reaction SMILES: [O-]P([O-])([O-])=O.[K+].[K+].[K+].CC(N)CC1C=CC=CC=1.OP(O)(O)=O.C(OC([N:31]([CH3:50])[C:32]1[S:36][C:35]([C:37]2[CH:38]=[C:39]3[C:43](=[CH:44][CH:45]=2)[N:42](C([O-])=O)[CH:41]=[C:40]3I)=[N:34][N:33]=1)=O)(C)(C)C.[C:51]1([C:60]2[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=2)[CH:56]=[CH:55][CH:54]=[C:53](B(O)O)[CH:52]=1>CC(O)C.O>[C:51]1([C:60]2[CH:61]=[CH:62][CH:63]=[CH:64][CH:65]=2)[CH:56]=[CH:55][CH:54]=[C:53]([C:40]2[C:39]3[C:43](=[CH:44][CH:45]=[C:37]([C:35]4[S:36][C:32]([NH:31][CH3:50])=[N:33][N:34]=4)[CH:38]=3)[NH:42][CH:41]=2)[CH:52]=1
Reactant: OB(O)c1cccc(-c2ccccc2)c1
Reactant: CN(C(=O)OC(C)(C)C)c1nnc(-c2ccc3c(c2)c(I)cn3C(=O)[O-])s1
Agent: CC(N)Cc1ccccc1
Agent: O=P(O)(O)O
Agent: O=P([O-])([O-])[O-]
Solvent: O
Solvent: CC(C)O
Product: CNc1nnc(-c2ccc3[nH]cc(-c4cccc(-c5ccccc5)c4)c3c2)s1
Temperature: 80 °C
Reaction time: 1 h
Yield: 49.8 %

Procedure:
A mixture of potassium phosphate tribasic (80 mg, 0.378 mmol), AmPhos (2.7 mg, 0.00378 mmol), 5-(5-(tert-butoxycarbonyl(methyl)amino)-1,3,4-thiadiazol-2-yl)-3-iodo-1H-indole-1-carboxylate (70 mg, 0.126 mmol), biphenyl-3-ylboronic acid (0.05 g, 0.25 mmol) and 70% IPA/water (1.5 mL) was heated at 80° C. for 3 h. The mixture was concentrated in vacuo and the residue was diluted with 50% DCM/TFA (2 mL). The mixture was stirred at RT for 1 h and the solvent was removed. The residue was purified with RP-HPLC (10-90% MeCN in water with 0.1% TFA) to give 5-(3-(biphenyl-3-yl)-1H-indol-5-yl)-N-methyl-1,3,4-thiadiazol-2-amine (24 mg, 50%). MS (ESI, pos. ion) m/z: 383 (M+1).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]2[C:7]([N+:11]([O-:13])=[O:12])=[CH:8][CH:9]=[CH:10][C:4]=2[CH:3]=1.[Cl-].[Al+3].[Cl-].[Cl-].[C:18](Cl)(=[O:21])[CH2:19][CH3:20].Cl>ClCCl>[CH3:1][C:2]1[O:6][C:5]2[C:7]([N+:11]([O-:13])=[O:12])=[CH:8][CH:9]=[CH:10][C:4]=2[C:3]=1[C:18](=[O:21])[CH2:19][CH3:20]
Reactant: CCC(=O)Cl
Reactant: Cc1cc2cccc([N+](=O)[O-])c2o1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CCC(=O)c1c(C)oc2c([N+](=O)[O-])cccc12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a mixture of 2-methyl-7-nitrobenzo[b]furan (177 mg) and aluminum chloride (200 mg) in dichloromethane (5 ml) was added dropwise propionyl chloride (0.18 ml). The mixture was stirred at ambient temperature for 3 hours and poured into a mixture of ice and 1N-hydrochloric acid. The separated oil was extracted with dichloromethane and the extract was washed with brine, dried over sodium sulfate and evaporated in vacuo. The residue was crystallized from diethyl ether to give 2-methyl-7-nitro-3-propionylbenzo[b]furan (215 mg).
Reaction SMILES: Br[C:2]1[N:6]([CH3:7])[CH:5]=[N:4][CH:3]=1.[N:8]1([C:13]2[CH:42]=[CH:41][C:16]([CH2:17][C:18]3[C:19]([O:39][CH3:40])=[N:20][C:21]4[C:26]([C:27]=3[Cl:28])=[CH:25][C:24]([C:29]([C:31]3[CH:38]=[CH:37][C:34]([C:35]#[N:36])=[CH:33][CH:32]=3)=[O:30])=[CH:23][CH:22]=4)=[CH:15][CH:14]=2)[CH:12]=[N:11][CH:10]=[N:9]1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCCC1>[N:8]1([C:13]2[CH:14]=[CH:15][C:16]([CH2:17][C:18]3[C:19]([O:39][CH3:40])=[N:20][C:21]4[C:26]([C:27]=3[Cl:28])=[CH:25][C:24]([C:29]([OH:30])([C:2]3[N:6]([CH3:7])[CH:5]=[N:4][CH:3]=3)[C:31]3[CH:38]=[CH:37][C:34]([C:35]#[N:36])=[CH:33][CH:32]=3)=[CH:23][CH:22]=4)=[CH:41][CH:42]=2)[CH:12]=[N:11][CH:10]=[N:9]1
Reactant: Cn1cncc1Br
Reactant: COc1nc2ccc(C(=O)c3ccc(C#N)cc3)cc2c(Cl)c1Cc1ccc(-n2cncn2)cc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: C1CCOC1
Product: COc1nc2ccc(C(O)(c3ccc(C#N)cc3)c3cncn3C)cc2c(Cl)c1Cc1ccc(-n2cncn2)cc1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
A solution of isopropylmagnesium chloride-lithium chloride complex in tetrahydrofuran (1.3 M, 0.986 mL, 1.28 mmol) was added dropwise to an ice-water cooled, stirring suspension of 5-bromo-1-methyl-1H-imidazole (241 mg, 1.50 mmol) in dry tetrahydrofuran (6 mL). After 5 minutes, the flask was removed from the cooling bath and the white suspension was stirred at 23° C. After 10 minutes, the Grignard suspension was added to an ice-water cooled, stirring mixture containing 4-(3-(4-(1H-1,2,4-triazol-1-yl)benzyl)-4-chloro-2-methoxyquinoline-6-carbonyl)benzonitrile (205 mg, 0.427 mmol, Intermediate 16: step e) and lanthanum(III) chloride bis(lithium chloride) complex (0.6 M solution in tetrahydrofuran, 1.42 mL, 0.854 mmol) in dry tetrahydrofuran (8 mL). After 20 minutes, 1 M aqueous citric acid solution (1 mL) was added. The flask was removed from the cooling bath and then ethyl acetate (100 mL) was added. Additional 1 M aqueous citric acid solution (˜15 mL) was added until the mixture was comprised of two homogeneous layers, at which point saturated aqueous sodium bicarbonate solution was added until the pH of the aqueous layer was ˜8 by litmus paper test. The layers were separated. The aqueous layer was extracted with ethyl acetate (20 mL). The organic layers were combined and the combined solution was dried over sodium sulfate. The dried solution was filtered. Silica gel (5 g) was added to the filtrate and the mixture was concentrated by rotary evaporation to afford a free-flowing powder. The powder was loaded onto a silica gel column for flash-column chromatography purification. Elution with dichloromethane initially, grading to 10% methanol-dichloromethane provided the title compound as a white solid. 1H NMR (500 MHz, CDCl3) δ ppm 8.45 (s, 1H), 8.10 (d, J=2.2 Hz, 1H), 8.06 (s, 1H), 7.81 (d, J=8.8 Hz, 1H), 7.65 (d, J=8.5 Hz, 2H), 7.58-7.51 (m, 5H), 7.44-7.38 (m, 3H), 6.41 (d, J=1.1 Hz, 1H), 4.33 (s, 2H), 4.09 (s, 3H), 3.94 (s, 1H), 3.38 (s, 3H); MS (ESI): mass calcd. C31H24ClN7O2, 561.2. m/z found, 562.1 [M+H]+.
Reaction SMILES: C(OC([NH:11][CH:12]([CH3:25])[C:13](=[O:24])[C:14]([CH2:22][CH3:23])([CH2:20][CH3:21])[C:15](OCC)=[O:16])=O)C1C=CC=CC=1>CO.[C].[Pd]>[CH2:20]([C:14]1([CH2:22][CH3:23])[C:13](=[O:24])[CH:12]([CH3:25])[NH:11][C:15]1=[O:16])[CH3:21]
Reactant: CCOC(=O)C(CC)(CC)C(=O)C(C)NC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: CCC1(CC)C(=O)NC(C)C1=O
Reaction time: 8 h
Yield: 99.5 %

Procedure:
To a solution of ethyl 4-{[(benzyloxy)carbonyl]amino}-3-oxopentanoate (3.0 g) in acetone (50 mL) were added potassium carbonate (2.83 g) and iodoethane (2.45 mL), and the mixture was refluxed overnight. After allowing to room temperature, potassium carbonate (2.83 g) and iodoethane(2.45 mL) were added, and the mixture was refluxed for 1 day. After allowing to room temperature, water was added and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=20:1→3:2) to give ethyl 4-{[(benzyloxy) carbonyl]amino}-2,2-diethyl-3-oxopentanoate as a colorless oil (yield: 1.91 g, 53%). To a solution of ethyl 4-{[(benzyloxy)carbonyl]amino}-2,2-diethyl-3-oxopentanoate (1.91 g) in methanol (15 mL) was added 10% palladium carbon (containing 50% water, 1.0 g), and the mixture was stirred under a hydrogen atmosphere overnight. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give the title compound as a colorless solid (yield: 920 mg, 99%).
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:17]=[N:16][C:7]2[NH:8][C:9]3[CH:14]=[N:13][CH:12]=[C:11]([OH:15])[C:10]=3[C:6]=2[CH:5]=1.Cl[C:19]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:20]>CN(C=O)C>[CH2:22]([O:21][C:19]([N:8]1[C:9]2[CH:14]=[N:13][CH:12]=[C:11]([OH:15])[C:10]=2[C:6]2[CH:5]=[C:4]([Br:3])[CH:17]=[N:16][C:7]1=2)=[O:20])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: Oc1cncc2[nH]c3ncc(Br)cc3c12
Reactant: O=C(Cl)OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(OCc1ccccc1)n1c2cncc(O)c2c2cc(Br)cnc21
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 16.7 %

Procedure:
Sodium hydride (167 mg, 4.17 mmol) was added to a cooled (0° C.) mixture of 3-bromo-9H-dipyrido[2,3-b;4′,3′-d]pyrrol-5-ol (1.0 g, 3.79 mmol) in DMF (15 mL). On complete addition the mixture was stirred for 15 minutes then allowed to warm to ambient temperature and stirred for 15 minutes. A solution of benzyl chloroformate (610 mg, 3.6 mmol) in DMF (1 mL) was added and stirring continued for 18 hours. The solvent was evaporated and the resultant residue diluted with water and extracted with dichloromethane (5×50 mL) and ethyl acetate (3×30 mL). The combined organic layer was dried over (Na2SO4), filtered and evaporated to afford a residue. The resultant residue was purified by flash chromatography (silica, 12 g cartridge, ISCO, 0-7% methanol in dichloromethane). The appropriate fractions were collected and evaporated to afford the title compound as a light yellow solid (240 mg, 17%). LCMS (Method B): RT=4.54 min, M+H+=398/400. 1H NMR (400 MHz, DMSO-d6): 8.99 (s, 1H), 8.79 (d, J=2.4 Hz, 1H), 8.63 (d, J=2.4 Hz, 1H), 8.23 (s, 1H), 7.63 (d, J=7.5 Hz, 2H), 7.48-7.36 (m, 3H), 5.61 (s, 2H).