Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@H:2]([C@@H:10]([OH:28])[CH2:11][C@@H:12]([NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[OH:29][C:30]1[C:31]([CH3:39])=[C:32]([CH:36]=[CH:37][CH:38]=1)[C:33](O)=[O:34].F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.O.ON1C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C.NCCN1CCOCC1>CN(C)C=O>[OH:29][C:30]1[C:31]([CH3:39])=[C:32]([C:33]([NH:1][C@H:2]([C@@H:10]([OH:28])[CH2:11][C@@H:12]([NH:20][C:21]([O:23][C:24]([CH3:25])([CH3:27])[CH3:26])=[O:22])[CH2:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:3][C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=2)=[O:34])[CH:36]=[CH:37][CH:38]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C[C@H](O)[C@@H](N)Cc1ccccc1
Reactant: Cc1c(O)cccc1C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: NCCN1CCOCC1
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1c(O)cccc1C(=O)N[C@@H](Cc1ccccc1)[C@@H](O)C[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C

Procedure:
The compound (2S,3S,5S)-2-[N-[(3-hydroxy-2-methylphenyl)carbonyl]amino]-5-[N-(tert-butyloxycarbonyl)amino]-1,6-diphenyl-3-hydroxy hexane (RS-208) was prepared from RS-216. A solution of (2S,3S,5S)-2-amino-5-[N-(tert-butyloxycarbonyl)amino]-1,6-diphenyl-3-hydroxy hexane (RS-216, 1.1 g, 2.86 mmol), 3-hydroxy-2-methyl-benzoic acid (0.478 g, 3.2 mmol), O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate (TBTU, 1.02 g, 3.2 mmol), 1-hydroxybenzotriazole hydrate (HOBT, 0.919 g, 6.0 mmol) and diisopropylethylamine (DIPEA, 103 ml, 6.0 mmol) in dimethylformamide (DMF, 30 ml) was stirred at room temperature for 2 h. After addition of aminoethyl morpholine (50 ml) the solvents were removed under vacuum and the residue was diluted with ethyl acetate and washed sequentially with aqueous NaHCO3, aqueous KHSO4, brine, then dried on Na2SO4, and concentrated in vacuo. Solid was suspended in ethyl acetate, filtered and residue was washed with ethyl acetate. Crystallization from ethyl acetate:methanol:hexane (1:0.2:1.5) provided 1.4 g (94%) of white solid; mp=162°-163° C.; TLC [Rf =0.75 (ethyl acetate:hexane, 7:3)]; HPLC rt=19.5 min; MS m/z 519 (M+H)+ ; 1H NMR.
Reaction SMILES: [CH:1]1[C:14]2[C:13](=[O:15])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[NH:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Br[CH2:19][CH2:20][CH2:21][O:22][CH:23]1[CH2:28][CH2:27][CH2:26][CH2:25][O:24]1>CN(C)C=O>[O:24]1[CH2:25][CH2:26][CH2:27][CH2:28][CH:23]1[O:22][CH2:21][CH2:20][CH2:19][N:6]1[C:5]2[C:14](=[CH:1][CH:2]=[CH:3][CH:4]=2)[C:13](=[O:15])[C:12]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]1=2
Reactant: BrCCCOC1CCCCO1
Reactant: O=c1c2ccccc2[nH]c2ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=c1c2ccccc2n(CCCOC2CCCCO2)c2ccccc12
Temperature: 80 °C
Yield: 32.7 %

Procedure:
To a solution of acridone (15 g, 0.077 mol) in dry dimethylformamide (200 ml), sodium hydride (3.7 g, 0.092 mol, 60% dispersion in mineral oil) was added in 4 portions under an atmosphere of nitrogen. The reaction mixture was stirred until gas evolution had ceased. A solution of 2-(3-bromo-1-propyloxy)tetrahydro-2H-pyran (21.7 g, 0.092 mol) in dry dimethylformamide (100 ml) was added dropwise. The reaction mixture was heated to 80° C. for 4 h and stirred overnight at room temperature. The reaction mixture was poured onto ice water (800 ml) and extracted with ethyl acetate (4×200 ml). The combined ethyl acetate extracts were washed with water (3×300 ml), dried (MgSO4), filtered and the solvent evaporated in vacuo. The residue was dissolved in diethyl ether (150 ml) and unchanged starting material was filtered off. The solvent was evaporated in vacuo and the residue was crystallised from 96% ethanol (150 ml), filtered and washed with ethanol (96%, 30 ml) and diethyl ether (50 ml). This procedure was repeated twice, yielding 8.5 g (33%) of 10-(3-(tetrahydro-2H-pyran-2-yloxy)-1-propyl)acridin-9-one as yellowish crystals. M.p. 140.5°-141.5° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5](=[O:18])[N:6]([CH2:8][CH2:9][O:10][Si](C(C)(C)C)(C)C)[CH:7]=1.O1CCCC1>>[Br:1][C:2]1[CH:3]=[N:4][C:5](=[O:18])[N:6]([CH2:8][CH2:9][OH:10])[CH:7]=1
Reactant: CC(C)(C)[Si](C)(C)OCCn1cc(Br)cnc1=O
Agent: *CC(*)C
Solvent: C1CCOC1
Product: O=c1ncc(Br)cn1CCO
Reaction time: 0.5 h
Yield: 60.9 %

Procedure:
To two 50 mL polypropylene conical tubes with caps was added 5-bromo-1-(2-(tert-butyldimethylsilyloxy)ethyl)pyrimidin-2(1H)-one (4.0 g, 12 mmol) (2 g in each tube) in tetrahydrofuran (50 mL, 12 mmol, 25 mL in each tube). To the mixture at 25° C. was added HF pyridine complex (8.0 mL, 12 mmol) (4 mL in each tube). After stirring for 30 minutes the solution was filtered through a polypropylene frit and the filtercake was washed with THF. The white filtercake was then dried in vacuo to afford the title compound as a white solid (1.6 g, 60% yield). MS (ESI, pos. ion.) m/z: 219 (MH+). Calc'd exact mass for C6H7BrN2O2: 219. 1H NMR (400 MHz, DMSO-d6) δ ppm 3.64 (q, J=5.3 Hz, 2 H), 3.89 (t, J=5.2 Hz, 2 H), 4.96 (t, J=5.5 Hz, 1 H), 8.39 (d, J=3.3 Hz, 1 H), 8.61 (d, J=3.3 Hz, 1 H).
Reaction SMILES: [Cl:1][CH:2]([Si:4]([Cl:7])(Cl)[Cl:5])[CH3:3].[F:8][C:9]1[CH:14]=[CH:13][C:12]([Mg]Br)=[CH:11][CH:10]=1>>[Cl:1][CH:2]([Si:4]([Cl:7])([Cl:5])[C:12]1[CH:13]=[CH:14][C:9]([F:8])=[CH:10][CH:11]=1)[CH3:3]
Reactant: Fc1ccc([Mg]Br)cc1
Reactant: CC(Cl)[Si](Cl)(Cl)Cl
Product: CC(Cl)[Si](Cl)(Cl)c1ccc(F)cc1

Procedure:
In the same apparatus and procedures as Example 6 were reacted 10.6 g (0.051 mol) of (α-chloroethyl)trichlorosilane and 26 ml of 4-fluorophenylmagnesiumbromide (2.0 M in diethylether) to give (α-chloroethyl)dichloro(4-fluorophenyl) silane.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1([CH3:16])[C:8]([CH3:10])([CH3:9])[O:7][B:6]([C:11]2[CH:12]=[N:13][NH:14][CH:15]=2)[O:5]1.Cl.Cl[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=1.O>CN(C)C=O.[I-].C([N+](CCCC)(CCCC)CCCC)CCC.C(OCC)(=O)C>[CH3:3][C:4]1([CH3:16])[C:8]([CH3:9])([CH3:10])[O:7][B:6]([C:11]2[CH:15]=[N:14][N:13]([CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=3)[CH:12]=2)[O:5]1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Reactant: ClCc1ccccn1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [H-]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC1(C)OB(c2cnn(Cc3ccccn3)c2)OC1(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of sodium hydride (0.096 ml, 5.15 mmol) in N,N-dimethylformamide (8.59 ml) was added 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.5 g, 2.58 mmol). After 0.5 hours, 2-chloromethylpyridine hydrochloride salt (0.423 g, 2.58 mmol), and tetrabutylammonium iodide (0.095 g, 0.258 mmol) were added as solution in N,N-dimethylformamide (2 mL). The reaction was cooled to room temperature and diluted with ethyl acetate (10 mL). Water (10 mL) was added, and the layers were separated. The aqueous layer was extracted with additional ethyl acetate (2×30 mL). The combined organics were washed with water, dried with anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the title compound, which was used without further purification. MS ESI(+) m/z 285.9 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:34]=[C:33]([O:35][CH3:36])[CH:32]=[CH:31][C:4]=1[CH2:5][NH:6][C:7]1[C:8]2[N:9]([C:13]([CH2:26][C:27]([O:29][CH3:30])=[O:28])=[N:14][C:15]=2[C:16]2[CH:25]=[CH:24][C:19]([C:20]([O:22][CH3:23])=[O:21])=[CH:18][CH:17]=2)[CH:10]=[CH:11][N:12]=1.[C:37](#[N:40])[CH:38]=[CH2:39].CC([O-])(C)C.[K+].CCOC(C)=O>C1COCC1.C(Cl)Cl>[C:37]([CH2:38][CH2:39][CH:26]([C:13]1[N:9]2[CH:10]=[CH:11][N:12]=[C:7]([NH:6][CH2:5][C:4]3[CH:31]=[CH:32][C:33]([O:35][CH3:36])=[CH:34][C:3]=3[O:2][CH3:1])[C:8]2=[C:15]([C:16]2[CH:17]=[CH:18][C:19]([C:20]([O:22][CH3:23])=[O:21])=[CH:24][CH:25]=2)[N:14]=1)[C:27]([O:29][CH3:30])=[O:28])#[N:40]
Reactant: C=CC#N
Reactant: COC(=O)Cc1nc(-c2ccc(C(=O)OC)cc2)c2c(NCc3ccc(OC)cc3OC)nccn12
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)c1ccc(-c2nc(C(CCC#N)C(=O)OC)n3ccnc(NCc4ccc(OC)cc4OC)c23)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 94.7 %

Procedure:
To a solution of methyl 4-(8-((2,4-dimethoxybenzyl)amino)-3-(2-methoxy-2-oxoethyl) imidazo[1,5-a]pyrazin-1-yl)benzoate (11.4 g, 23.3 mmol) in THF (100 mL) was added acrylonitrile (1.4 g, 25.6 mmol) and t-BuOK (2.3 mL, 1M in THF). The mixture was stirred at RT for 2 hrs. The reaction was complete detected by TLC (PE/EtOAc 1:1). The mixture was extracted with EA and water, the organic layer was dried and concentrated, the residue was purified by column chromatography on silica gel eluted with PE:EA:DCM=2:1:1 to give methyl 4-(3-(4-cyano-1-methoxy-1-oxobutan-2-yl)-8-((2,4-dimethoxybenzyl)amino)imidazo[1,5-a]pyrazin-1-yl)benzoate (12 g, yield 94%).
Reaction SMILES: [CH:1]1([C:6]2[C:14]3[C:9](=[CH:10][C:11]([C:15]([NH:17][C:18]4([C:22]5[N:26]([CH3:27])[C:25]6[CH:28]=[CH:29][C:30](/[CH:32]=[CH:33]/[C:34](O)=[O:35])=[CH:31][C:24]=6[N:23]=5)[CH2:21][CH2:20][CH2:19]4)=[O:16])=[CH:12][CH:13]=3)[N:8]([CH3:37])[C:7]=2[C:38]2[CH:43]=[N:42][CH:41]=[CH:40][N:39]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C[N:45](C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(=O)([O-])O.[NH4+].CCN(CC)CC>CS(C)=O.C(O)(=O)C>[C:34](/[CH:33]=[CH:32]/[C:30]1[CH:29]=[CH:28][C:25]2[N:26]([CH3:27])[C:22]([C:18]3([NH:17][C:15]([C:11]4[CH:10]=[C:9]5[C:14]([C:6]([CH:1]6[CH2:5][CH2:4][CH2:3][CH2:2]6)=[C:7]([C:38]6[CH:43]=[N:42][CH:41]=[CH:40][N:39]=6)[N:8]5[CH3:37])=[CH:13][CH:12]=4)=[O:16])[CH2:21][CH2:20][CH2:19]3)=[N:23][C:24]=2[CH:31]=1)(=[O:35])[NH2:45]
Reactant: Cn1c(C2(NC(=O)c3ccc4c(C5CCCC5)c(-c5cnccn5)n(C)c4c3)CCC2)nc2cc(/C=C/C(=O)O)ccc21
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: O=C([O-])O
Agent: [NH4+]
Solvent: CC(=O)O
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: Cn1c(C2(NC(=O)c3ccc4c(C5CCCC5)c(-c5cnccn5)n(C)c4c3)CCC2)nc2cc(/C=C/C(N)=O)ccc21
Yield: 34 %

Procedure:
A solution of (E)-3-(2-{1-[(3-cyclopentyl-1-methyl-2-pyrazin-2-yl-1H-indole-6-carbonyl)amino]cyclobutyl}-1-methyl-1H-benzimidazol-5-yl)acrylic acid 5-2 (compound 4003, Table 4; 60 mg, 0.087 mmol), TBTU (68 mg, 0.18 mmol), ammonium hydrogen carbonate (20 mg, 0.26 mmol) and Et3N (36 μL, 0.26 mmol) in DMSO (3 mL) was stirred at RT for 3 h. The reaction mixture was neutralized with the addition of a few drops of acetic acid, and purified on a reversed phase C18, semi-preparative HPLC column (using a solvent gradient from 5% to 100% MeCN in H2O (all solvents contain 0.1% trifluoroacetic acid)) to isolate the inhibitor 3-cyclopentyl-1-methyl-2-pyrazin-2-yl-1H-indole-6-carboxylic acid{1-[5-((E)-2-carbamoylethenyl)-1-methyl-1H-benzoimidazol-2-yl]cyclobutyl}amide 5-3 (compound 1005, Table 1) as a pale yellow amorphous solid in >95% homogeneity (17 mg, 34% yield).
Reaction SMILES: N[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[C:5]([Cl:13])[N:6]=[C:7]2[CH3:12].N([O-])=O.[Na+].[NH4+].[OH-].[BrH:20]>O>[Br:20][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[C:5]([Cl:13])[N:6]=[C:7]2[CH3:12]
Reactant: Cc1nc(Cl)cc2c(N)cccc12
Reactant: Br
Agent: O=N[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: O
Product: Cc1nc(Cl)cc2c(Br)cccc12
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a solution of 5-amino-3-chloro-1-methylisoquinoline (460 mg, 2.4 mmol) in HBr (48%, 6 mL) and water (3 mL) at 0° C. was added slowly NaNO2 (165 mg, 2.4 mmol) in water (3 mL). The reaction was stirred at 0° C. for 10 minutes, then the excess NaNO2 was quenched by addition of a small amount of urea. The diazonium solution was then added slowly to a stirred solution of CuBr (411 mg, 2.9 mmol) in HBr (48%, 4 mL) at 75° C. The mixture was stirred for an additional 5 minutes at 75° C., then at room temperature for 18 hours. The mixture was poured onto crushed ice, adjusted to pH 9 with NH4OH, then extracted with EtOAc. The combined organics were washed with water then saturated NaCl (aq), dried over Na2SO4, filtered, then concentrated. The residue was purified by silica gel chromatography eluting with 10% EtOAc/hexanes to afford the title compound: 1H NMR (500 MHz, CDCl3): δ 8.09 (d, J=6.0 Hz, 1H), 7.98 (d, J=6.0 Hz, 1H); 7.97 (s, 1H), 7.44 (t, J=6.0 Hz, 1H); 2.98 (s, 3H). LC1: 2.68 min, (M+H): 256.
Reaction SMILES: C(N)C#C.[CH2:5]([NH:8][C:9]([NH:13][CH2:14][CH2:15][S:16][CH2:17][C:18]1[N:19]=[C:20]([CH2:23][N:24]([CH3:26])[CH3:25])[S:21][CH:22]=1)=[N:10][C:11]#[N:12])[CH:6]=[CH2:7]>>[CH2:5]([NH:8][C:9]([NH:13][CH2:14][CH2:15][S:16][CH2:17][C:18]1[N:19]=[C:20]([CH2:23][N:24]([CH3:26])[CH3:25])[S:21][CH:22]=1)=[N:10][C:11]#[N:12])[C:6]#[CH:7]
Reactant: C=CCNC(=NC#N)NCCSCc1csc(CN(C)C)n1
Agent: C#CCN
Product: C#CCNC(=NC#N)NCCSCc1csc(CN(C)C)n1

Procedure:
Following the above procedure, but substituting allylamine for propargylamine in the reaction with N-2-(2-dimethylaminomethyl-4-thiazolylmethylthio)ethyl-N'-cyanocarbamidothioate, N-allyl-N'-2-(2-dimethylaminomethyl-4-thiazolylmethylthio)ethyl-N"-cyanoguanidine was prepared. Yield=0.28 g from 600 mg of thioester.
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:10][CH2:9][N:8]([C:11](=[O:18])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:7]1[C:19]1[CH:24]=[CH:23][C:22]([NH:25][C:26](=[O:47])[CH2:27][C:28]2[CH:33]=[CH:32][C:31]([NH:34][C:35]([NH:37][C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=3[CH3:44])=[O:36])=[C:30]([O:45][CH3:46])[CH:29]=2)=[CH:21][CH:20]=1)=[O:5])C.[OH-].[Na+]>C(O)C.C(#N)C>[C:11]([N:8]1[CH2:9][CH2:10][CH:6]([C:4]([OH:5])=[O:3])[CH:7]1[C:19]1[CH:20]=[CH:21][C:22]([NH:25][C:26](=[O:47])[CH2:27][C:28]2[CH:33]=[CH:32][C:31]([NH:34][C:35]([NH:37][C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=3[CH3:44])=[O:36])=[C:30]([O:45][CH3:46])[CH:29]=2)=[CH:23][CH:24]=1)(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CCOC(=O)C1CCN(C(=O)c2ccccc2)C1c1ccc(NC(=O)Cc2ccc(NC(=O)Nc3ccccc3C)c(OC)c2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Solvent: CCO
Product: COc1cc(CC(=O)Nc2ccc(C3C(C(=O)O)CCN3C(=O)c3ccccc3)cc2)ccc1NC(=O)Nc1ccccc1C
Temperature: 5 °C
Reaction time: 144 h
Yield: 42.5 %

Procedure:
A stirred solution of 1-benzoyl-2-(4-{2-[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetylamino}-phenyl)-pyrrolidine-3-carboxylic acid ethyl ester (0.33 g, Reference Example 13) in a mixture of ethanol (4 ml) and acetonitrile (40 ml), at 20° C., was treated dropwise with aqueous sodium hydroxide solution (0. 15 ml, 10 N). After stirring for 6 days the mixture was filtered and the insoluble light brown solid was triturated twice with acetonitrile (5 ml), then twice with dichloromethane (2.5 ml) and then dried. The solid was dissolved in water (30 ml) and filtered. The filtrate was cooled to 5° C. and the pH of the mixture adjusted to 2 by dropwise addition of hydrochloric acid (1.2 ml, 1N). The resulting white precipitate was filtered then washed three times with water (5 ml), then twice with diisopropyl ether (10 ml) and then dried under reduced pressure (40° C. and 2.7 kPa) to afford the title compound (0.134 g) as an off-white powder, m.p. 155° C. (with decomposition). 1H-NMR [500 MHz, (CD3)2SO at 383° K.]: δ 2.15 (m, 2H); 2.27 (s, 3H); 2.96 (m, 1H); 3.59 (s, 2H); 3.75 (m, 2H); 3.89 (s, 3H); 5.32 (m, 1H); 6.87 (bd, J=8 Hz, 1H); 6.98 (t, J=7.5 Hz, 1H); 7.02 (d, J=1.5 Hz, 1H); 7.10 to 7.25 (m, 4H); 7.30 to 7.45 (m, 5H); 7.52 (d, J=8.5 Hz, 2H); 7.67 (d, J=8 Hz, 1H); 7.99 (d, J=8 Hz, 1H); 8.15 (bs, 1H); 8.21 (bs, 1H); 9.55 (bs, 1H). MS(ES): 629 [M+Na]+.
Reaction SMILES: Cl.CON(C)[C:5](=[O:14])[C:6]1[CH:11]=[C:10]([Br:12])[CH:9]=[N:8][C:7]=1[NH2:13].[C:16]1([Mg]Br)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O.C(OCC)(=O)C>C1COCC1.CCOCC>[NH2:13][C:7]1[C:6]([C:5]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:14])=[CH:11][C:10]([Br:12])=[CH:9][N:8]=1
Reactant: Br[Mg]c1ccccc1
Reactant: CON(C)C(=O)c1cc(Br)cnc1N
Agent: Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCOCC
Product: Nc1ncc(Br)cc1C(=O)c1ccccc1
Temperature: -50 °C

Procedure:
1.00 g (3.38 mmol) of N-methoxy-N-methyl-2-amino-5-bromonicotinamide hydrochloride was suspended in 50 ml of anhydrous THF under nitrogen. The suspension was cooled to −50° C. and 13.5 ml of a 1.0 M solution of phenylmagnesium bromide in ether was added rapidly to afford an orange solution. The mixture was stirred, and slowly warmed to room temperature. The resulting yellow-orange solution was distributed between 75 ml of a 10% aqueous citric acid solution and 200 ml of ethyl acetate. The organic phase was separated and washed with 75 ml of a 10% aqueous citric acid solution and 75 ml of saturated aqueous sodium bicarbonate solution. The organic phase was then dried over sodium sulfate and evaporated to afford 985 mg of a yellow crystalline solid. 1H-NMR (d6-DMSO) δ: 8.34 [1H] d, 7.72 [2H] s, 7.70 [1H] d, 7.65 [1H] t(m), 7.63 [2H] d(m), 7.56 [2H] t(m). MS: m/z 277 [MH+].
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][N:5](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[C:6]=1[CH:7]([C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:18]=1[N:17]=[CH:16][CH:15]=[CH:14]2)O.[OH-].[Na+]>I.C(Cl)(Cl)Cl.C(O)(C)C>[CH3:1][C:2]1[NH:3][CH:4]=[N:5][C:6]=1[CH2:7][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:18]=1[N:17]=[CH:16][CH:15]=[CH:14]2
Reactant: Cc1ncn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c1C(O)c1cccc2cccnc12
Agent: I
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: CC(C)O
Product: Cc1[nH]cnc1Cc1cccc2cccnc12
Temperature: 160 °C
Yield: 70.9 %

Procedure:
A mixture of (4) (0.71 g, 1.48 mmol) and red phosphorus (0.46 g, 14.18 mmol) in hydroiodic acid (57% in water, 6 mL) was heated in a sealed tube at 160° C. overnight. The reaction mixture was cooled to room temperature, and the sealed tube was slowly opened to release the gas built up inside. The content was poured into crushed ice, and carefully basified with NaOH (aq) to pH>7. The aqueous layer was diluted with chloroform/isopropanol (3:1, 100 mL). The mixture was filtered through a bed of Celite to removed phosphorus. The layers were separated and the aqueous layer was extracted twice with chloroform/isopropanol (3:1, 100 mL). The pooled to organic layers were dried over magnesium sulfate. The mixture was filtered and the solvents were removed under vacuum. The residue was purified by chromatography on silica gel with 2% ammonia saturated methanol in dichloromethane to give 8-((5-methyl-1H-imidazol-4-yl)methyl)quinoline (5) as a light yellow solid (0.23 g, 1.05 mmol, 71% yield). 30 mg of (5) was passed through reverse phase HPLC to give 26.5 mg of an analytically pure sample.
Reaction SMILES: Br.C(O)(=O)C.[OH:6][B:7]1[C:11]2[CH:12]=[CH:13][C:14]([O:16][C:17]3[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[C:19]([O:25]C)[N:18]=3)=[CH:15][C:10]=2[CH2:9][O:8]1>O>[OH:25][C:19]1[N:18]=[C:17]([O:16][C:14]2[CH:13]=[CH:12][C:11]3[B:7]([OH:6])[O:8][CH2:9][C:10]=3[CH:15]=2)[CH:24]=[CH:23][C:20]=1[C:21]#[N:22]
Reactant: COc1nc(Oc2ccc3c(c2)COB3O)ccc1C#N
Agent: Br
Solvent: CC(=O)O
Solvent: O
Product: N#Cc1ccc(Oc2ccc3c(c2)COB3O)nc1O
Temperature: 50 °C
Reaction time: 24 h
Yield: 9.5 %

Procedure:
To a solution of 48% HBr (2 mL) and acetic acid (4 mL) was added 6-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-5-yloxy)-2-methoxynicotinonitrile (D46) (0.300 mg, 1.06 mmol). The reaction was stirred for 24 hours at 50° C. Water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with water, brine, dried over anhydrous sodium sulfate, and then filtered. The solvent was removed under reduced pressure. The residue was purified by silica gel column (7:3 to 9:1 ethyl acetate/hexane). The material was further purified by reverse phase HPLC to give 2-hydroxy-6-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-5-yloxy)nicotinonitrile (0.027 g, 10% yield). ES(−) MS m/z=267 (M−H)−; 1H NMR (300 MHz, DMSO-d6) δ ppm 4.97 (s, 2 H), 6.4 (br s, 1 H), 7.15 (d, J=7.9 Hz, 1 H), 7.25 (s, 1 H), 7.77 (d, J=7.9 Hz, 1 H), 8.09 (d, J=7.9 Hz, 1 H), 9.24 (s, 1 H), 12.7 (br s, 1 H).
Reaction SMILES: [NH2:1][C:2]1[N:11]=[CH:10][C:9]2[C:8](SC)=[N:7][CH:6]=[N:5][C:4]=2[CH:3]=1.[Cl:14][C:15]1[CH:16]=[C:17]([CH:19]=[CH:20][CH:21]=1)[NH2:18]>>[NH2:1][C:2]1[N:11]=[CH:10][C:9]2[C:8]([NH:18][C:17]3[CH:19]=[CH:20][CH:21]=[C:15]([Cl:14])[CH:16]=3)=[N:7][CH:6]=[N:5][C:4]=2[CH:3]=1
Reactant: Nc1cccc(Cl)c1
Reactant: CSc1ncnc2cc(N)ncc12
Product: Nc1cc2ncnc(Nc3cccc(Cl)c3)c2cn1
Temperature: 150 °C
Reaction time: 0.33 h
Yield: 60.3 %

Procedure:
A mixture of 7-amino-4-methylthiopyrido[4,3-d]pyrimidine (208 mg, 1.08 mmol) and 3-chloroaniline (1.21 g, 9.48 mmol) is stirred at 150° C. for 20 min. The resulting product is chromatographed over alumina (5-10% MeOH/CH2Cl2) to give 7-amino-4-(3-chloroanilino)pyrido[4,3-d]pyrimidine (177 mg, 60%) as a white solid. 1H NMR (DMSO) δ 9.92 (1H,brs), 9.35 (1H, s), 8.45 (1H, s), 8.08 (1H, brs), 7.79 (1H, brd, J=8.0 Hz), 7.40 (1H, t, J=8.1 Hz), 7.16 (1H, dd, J=7.9, 1.3 Hz), 6.68 (2H, brs), 6.46 (1H, s).
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][OH:12])=[C:6]([CH3:13])[CH:5]=1.[N:14]([C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=1)[C:20]#[N:21])=[C:15]=[O:16]>C1COCC1>[C:20]([C:19]1[CH:18]=[C:17]([NH:14][C:15](=[O:16])[O:12][CH2:11][CH2:10][C:7]2[CH:8]=[CH:9][C:4]([Br:3])=[CH:5][C:6]=2[CH3:13])[CH:24]=[CH:23][CH:22]=1)#[N:21]
Reactant: Cc1cc(Br)ccc1CCO
Reactant: N#Cc1cccc(N=C=O)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cc(Br)ccc1CCOC(=O)Nc1cccc(C#N)c1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 62 %

Procedure:
NaH (150 mg, 60% disperson in oil) was added portionwise to a solution of 30B (570 mg, 2.65 mmol) in THF (26.5 mL) and the mixture was stirred for 30 min. The solution was cooled to −78° C. and 3-isocyanatobenzonitrile (382 mg, 2.65 mmol) was added in one portion. The cooling bath was removed and the reaction was stirred for 2 h. Water (100 mL) was added to the reaction mixture and it was extracted with EtOAc (2×75 mL). The organics were combined, washed with brine, dried over Na2SO4 and concentrated in vacuo. The crude product was purified by flash chromoatography (0 to 100% EtOAc in hexanes) to yield 30C (590 mg, 62%). 1H NMR (400 MHz, DMSO-D6) δ ppm 2.30 (s, 3 H) 2.92 (t, J=6.95 Hz, 2 H) 4.28 (t, J=6.95 Hz, 2 H) 7.17 (d, J=8.34 Hz, 1 H) 7.32 (dd, J=8.21, 1.89 Hz, 1 H) 7.39 (d, J=1.77 Hz, 1 H) 7.41-7.55 (m, 2 H) 7.70 (d, J=8.08 Hz, 1 H) 7.85 (s, 1 H) 9.97 (s, 1 H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][CH:16]([S:22]([CH3:25])(=[O:24])=[O:23])[C:17]([O:19]CC)=[O:18])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[OH-].[Li+]>C1COCC1.CO.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][CH:16]([S:22]([CH3:25])(=[O:24])=[O:23])[C:17]([OH:19])=[O:18])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(CCc1ccc(-c2ccc(F)cc2)cc1)S(C)(=O)=O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CS(=O)(=O)C(CCc1ccc(-c2ccc(F)cc2)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 87.5 %

Procedure:
To a solution of ethyl 4-(4′-fluorobiphenyl-4-yl)-2-(methylsulfonyl)butanoate in THF (2.2 mL) and methanol (0.6 mL) was added a solution of lithium hydroxide in water (37 mg, 1.54 mmol, 0.6 mL water) and stirred at room temperature for 30 minutes. The mixture was diluted with water (30 mL) and washed with Et2O 50 mL. The organic layer was discarded. The aqueous layer was acidified with 0.5N HCl and the white suspension was re-extracted with Et2O. The ether extract was washed with brine 50 mL, dried over Na2SO4, filtered and concentrated in vacuo to afford the title compound as a white solid (113 mg, 87.5%) MS (LC/MS) m/z 335.1 (M−1)