Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C@H:8]([C:19](=[S:21])[NH2:20])[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2].Br[CH2:24][C:25]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=O.N1C=CC=CC=1.CC(OC(OC(OC(C)(C)C)=O)=O)(C)C>CC#N.C(OCC)C>[C:1]([O:5][C:6](=[O:22])[NH:7][C@H:8]([C:19]1[S:21][CH:24]=[C:25]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[N:20]=1)[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][CH:11]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc([N+](=O)[O-])cc1)C(N)=S
Reactant: O=C(CBr)c1ccccc1
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Solvent: c1ccncc1
Solvent: CCOCC
Solvent: CC#N
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccc([N+](=O)[O-])cc1)c1nc(-c2ccccc2)cs1
Reaction time: 2 h
Yield: 39 %

Procedure:
A mixture of [2-(4-nitrophenyl)-1-(S)-thiocarbamoylethyl]-carbamic acid tert-butyl ester, 2, (0.343 g, 1.05 mmol), 2-bromo-acetophenone (0.231 g, 1.15 mmol), in CH3CN (5 mL) is refluxed 1.5 hour. The solvent is removed under reduced pressure and the residue re-dissolved in CH2Cl2 then pyridine (0.24 mL, 3.0 mmol) and Boc2O (0.24 mL, 1.1 mmol) are added. The reaction is stirred for 2 hours and diethyl ether is added to the solution and the precipitate which forms is removed by filtration. The organic layer is dried (Na2SO4), filtered, and concentrated to a residue which is purified over silica to afford 0.176 g (39%) of the desired product ESI+MS 426 (M+1).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[C:20]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[O:28][CH3:29])=[C:19](Cl)[N:18]=[C:17]([CH3:31])[N:16]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH2:32][CH2:33][CH2:34][OH:35]>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[C:20]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[O:28][CH3:29])=[C:19]([O:35][CH2:34][CH2:33][NH2:32])[N:18]=[C:17]([CH3:31])[N:16]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccccc1Oc1c(Cl)nc(C)nc1NS(=O)(=O)c1ccc(C(C)(C)C)cc1
Reactant: NCCO
Product: COc1ccccc1Oc1c(NS(=O)(=O)c2ccc(C(C)(C)C)cc2)nc(C)nc1OCCN

Procedure:
According to a procedure described in Example 4b) 0.5 g 4-tert.-butyl-N-[6-chloro-5-(o-methoxyphenoxy)-2-methyl-4-pyrimidinyl]-benzene sulfonamide was reacted with 2-aminoethanol to give 560 mg 4-tert.-butyl-N-[6-(2-aminoethoxy)-5-(o-methoxyphenoxy)-2-methyl-4-pyrimidinyl]-benzene sulfonamide. LC-MS: tR=3.84 min, [M+1]+=487.51, [M−1]−=485.54.
Reaction SMILES: [OH:1][C:2]1[C:9]([O:10][CH3:11])=[C:8]([O:12][CH3:13])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[CH:14]1(Br)[CH2:18][CH2:17][CH2:16][CH2:15]1>>[CH:14]1([O:1][C:2]2[C:9]([O:10][CH3:11])=[C:8]([O:12][CH3:13])[CH:7]=[CH:6][C:3]=2[C:4]#[N:5])[CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: BrC1CCCC1
Reactant: COc1ccc(C#N)c(O)c1OC
Product: COc1ccc(C#N)c(OC2CCCC2)c1OC
Yield: 95 %

Procedure:
The subtitle compound was prepared from 2-hydroxy-3,4-dimethoxybenzonitrile and freshly distilled cyclopentyl bromide following the procedure described in Example 10(d). The crude product was purified on silica gel eluting with dichloromethane to give the subtitle compound as a colourless oil (95%). Rf 0.50 (dichloromethane). MS m/z 265 MNH4)+.
Reaction SMILES: [H-].[Na+].[CH:3]1[C:13]2[CH2:12][O:11][C:10]3[CH:14]=[CH:15][CH:16]=[CH:17][C:9]=3[NH:8][C:7]=2[CH:6]=[CH:5][CH:4]=1.CS(O[C@H:23]1[CH2:27][CH2:26][N:25]([CH2:28][CH2:29][CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=2)[CH2:24]1)(=O)=O>CCCCCC.CS(C)=O>[CH3:38][O:37][C:34]1[CH:33]=[CH:32][C:31]([CH2:30][CH2:29][CH2:28][N:25]2[CH2:26][CH2:27][C@@H:23]([N:8]3[C:7]4[CH:6]=[CH:5][CH:4]=[CH:3][C:13]=4[CH2:12][O:11][C:10]4[CH:14]=[CH:15][CH:16]=[CH:17][C:9]3=4)[CH2:24]2)=[CH:36][CH:35]=1
Reactant: c1ccc2c(c1)COc1ccccc1N2
Reactant: COc1ccc(CCCN2CC[C@H](OS(C)(=O)=O)C2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCCCCC
Product: COc1ccc(CCCN2CC[C@@H](N3c4ccccc4COc4ccccc43)C2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
60% sodium hydride (32 mg, 0.81 mmol) was washed with hexane under argon atmosphere, and then suspended in dimethyl sulfoxide (6 ml). After stirring at room temperature for 30 minutes, 5,11-dihydrodibenzo[b,e][1,4]oxazepine (142 g, 0.74 mmol) was added to the obtained suspension. They were stirred at room temperature for 40 minutes and then at 50° C. for 40 minutes. A solution of (S)-3-methanesulfonyloxy-1-[3-(4-methoxyphenyl)propyl]pyrrolidine (254 mg, 1.81 mmol) in dimethyl sulfoxide (3 ml) was added dropwise in the obtained solution, and they were stirred at 50° C. for 5 hours. The reaction liquid was poured into ice/water. After the extraction with a solvent mixture of hexane and ethyl acetate (1:1), the organic layer was dried and the solvent was evaporated under reduced pressure. The obtained residue was subjected to silica gel column chromatography. The product was eluted with dichloromethane and then with a mixture of dichloromethane and methanol (50:1). The appropriate fractions were combined, and the solvent was evaporated under reduced pressure to obtain (R)-5,11-dihydro-5-[1-[3-(4-methoxyphenyl)propyl]pyrrolidine-3-yl]dibenzo[b,e][1,4]oxazepine in the form of a light yellow oil (78 mg, 25%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[CH2:7][C@@H:8]([CH2:12][CH2:13][CH2:14][CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)[C:9]([OH:11])=[O:10])([CH3:4])([CH3:3])[CH3:2].O/[N:23]=[C:24](\[NH2:32])/[CH2:25][CH2:26][NH:27][S:28]([CH3:31])(=[O:30])=[O:29]>>[NH2:32]/[C:24](=[N:23]\[O:10][C:9](=[O:11])[C@H:8]([CH2:12][CH2:13][CH2:14][CH:15]1[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]1)[CH2:7][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:21])/[CH2:25][CH2:26][NH:27][S:28](=[O:30])(=[O:29])[CH3:31]
Reactant: CC(C)(C)OC(=O)C[C@@H](CCCC1CCCCC1)C(=O)O
Reactant: CS(=O)(=O)NCC/C(N)=N/O
Product: CC(C)(C)OC(=O)C[C@@H](CCCC1CCCCC1)C(=O)O/N=C(\N)CCNS(C)(=O)=O

Procedure:
Method as for preparation 2 using (2R)-2-(2-tert-butoxy-2-oxoethyl)-5-cyclohexylpentanoic acid (preparation 168) (670 mg, 2.25 mmol) and (1Z)-N′-hydroxy-3-[(methylsulfonyl)amino]propanimidamide (preparation 30) (700 mg, 2.50 mmol) as starting materials to afford the title compound as a yellow oil.
Reaction SMILES: [N+:1]([C:4]1[C:5]([CH2:10][CH2:11][NH:12][CH:13]2[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]2)=[N:6][CH:7]=[CH:8][CH:9]=1)([O-])=O.[H][H].C(N(CC)CC)C.[CH3:35][OH:36]>[Pd].C(#N)C>[O:36]=[C:35]1[NH:1][C:4]2[CH:9]=[CH:8][CH:7]=[N:6][C:5]=2[CH2:10][CH2:11][N:12]1[CH:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]1
Reactant: CO
Reactant: CC(C)(C)OC(=O)N1CCC(NCCc2ncccc2[N+](=O)[O-])CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC(N2CCc3ncccc3NC2=O)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 93 %

Procedure:
tert-Butyl 4-(2-(3-nitropyridin-2-yl)ethylamino)piperidine-1-carboxylate (0.864 g, 2.466 mmol) was dissolved in methanol (50 ml). 10% Palladium on carbon (0.3 g, 0.28 mmol) was added to the mixture. Reaction vessel was placed on a Parr apparatus and charged with 2 atm hydrogen gas. Reaction shook at room temperature for 16 hours. The reaction mixture was twice filtered through a pad of celite. Filtrate was concentrated to yield tan solid. Residue (808 mg, 2.52 mmol) was dissolved in acetonitrile (200 mL). Triethylamine was added to the mixture (1.05 mL, 7.56 mmol) followed by N,N′-carbonyldiimidazole (0.50 g, 3.08 mmol). Reaction stirred at room temperature for 5 hours. More N,N′-carbonyldiimidazole (0.50 g, 3.08 mmol) was added to the mixture. Reaction stirred at room temperature for 16 hours. More N,N′-carbonyldiimidazole (0.50 g, 3.08 mmol) was added to the reaction mixture followed by triethylamine (1.05 mL, 7.56 mmol). Reaction stirred at room temperature for 20 hours. More N,N′-carbonyldiimidazole (0.50 g, 3.08 mmol) was added to the mixture followed by triethylamine (0.50 mL, 3.58 mmol). Reaction stirred at room temperature for 68 hours. Mixture was concentrated by roto-vap. Silica gel chromatography eluting 2M ammonia in methanol-dichloromethane afforded the title compound as off-white solid in 93% yield. 1H NMR (500 MHz, CHLOROFORM-D) δ ppm 8.05-8.13 (m, 2 H) 7.21 (d, J=7.94 Hz, 1 H) 7.01 (dd, J=8.24, 4.58 Hz, 1 H) 4.29-4.44 (m, 1 H) 4.19 (bs, 2 H) 3.44-3.51 (m, 2 H) 3.08-3.17 (m, 2 H) 2.76 (m, 2 H) 1.71 (d, J=10.99 Hz, 2 H) 1.53-1.65 (m, 2 H) 1.42 (s, 9 H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([C:11]([N:13]([O:15][CH3:16])[CH3:14])=[O:12])[NH:6]2.[F:17][C:18]1[CH:19]=[C:20](B(O)O)[CH:21]=[CH:22][CH:23]=1.N1C=CC=CC=1>C(Cl)Cl>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([C:11]([N:13]([O:15][CH3:16])[CH3:14])=[O:12])[N:6]2[C:22]1[CH:21]=[CH:20][CH:19]=[C:18]([F:17])[CH:23]=1
Reactant: OB(O)c1cccc(F)c1
Reactant: CON(C)C(=O)c1cc2c(Cl)cccc2[nH]1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CON(C)C(=O)c1cc2c(Cl)cccc2n1-c1cccc(F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.2 %

Procedure:
Activated molecular sieves (4.9 g) 4 Å were placed in an oven dried flask and cooled to room temperature under nitrogen. To the flask was charged with 4-chloro-N-methoxy-N-methyl-1H-indole-2-carboxamide (0.35 g, 1.5 mmol), (3-fluorophenyl)boronic acid (0.62 g, 4.4 mmol) and cupric acetate (0.40 g, 2.2 mmol), methylene chloride (65 mL) and then pyridine (0.47 mL, 5.9 mmol). The reaction mixture was stirred at room temperature overnight, then filtered through a pad of Celite. The filtrate was concentrated and purified on silica gel (eluting with 0-20% EtOAc in hexane) to give the desired product (0.44 g, 90%). LCMS calculated for C17H15ClFN2O2(M+H)+: m/z=333.1. Found: 333.0.
Reaction SMILES: [CH2:1]([N:8]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([C:17]3[CH:18]=[C:19]([CH2:27][C:28]4[CH:37]=[C:36]5[C:31]([CH2:32][CH2:33][NH:34][CH2:35]5)=[CH:30][CH:29]=4)[N:20]4[C:25]=3[C:24]([NH2:26])=[N:23][CH:22]=[N:21]4)[CH:13]=[CH:14]2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O[C:41]1(O[Si](C)(C)C)[CH2:43][CH2:42]1)C.C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[CH2:1]([N:8]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([C:17]3[CH:18]=[C:19]([CH2:27][C:28]4[CH:37]=[C:36]5[C:31]([CH2:32][CH2:33][N:34]([CH:41]6[CH2:43][CH2:42]6)[CH2:35]5)=[CH:30][CH:29]=4)[N:20]4[C:25]=3[C:24]([NH2:26])=[N:23][CH:22]=[N:21]4)[CH:13]=[CH:14]2)=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1ncnn2c(Cc3ccc4c(c3)CNCC4)cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c12
Reactant: CCOC1(O[Si](C)(C)C)CC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: Nc1ncnn2c(Cc3ccc4c(c3)CN(C3CC3)CC4)cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c12
Yield: 49.8 %

Procedure:
5-(2-Benzyl-2H-indazol-6-yl)-7-(1,2,3,4-tetrahydro-isoquinolin-7-ylmethyl)-pyrrolo[2,1-f][1,2,4]triazin-4-ylamine (0.100 g, 0.21 mmol) was dissolved in MeOH (1 mL) and (1-ethoxy-cyclopropoxy)-trimethyl-silane (0.22 g, 1.24 mmol) was added followed by acetic acid (0.118 mL, 2.05 mmol) and sodium cyanoborohydride (0.058 g, 0.92 mmol). The resulting mixture was refluxed overnight and then allowed to cool. The mixture was filtered, concentrated and the residue was purified by preparative HPLC to give 55 mg (50%) of the title compound. 1H-NMR (CD3OD-d4) 8.36-8.23 (m, 1 H), 7.81 (s, 1 H), 7.78 (dd, 1H), 7.38-7.29 (m, 4 H), 7.19 (dd, 1 H), 7.10-6.99 (m, 2 H), 6.44 (s, 1 H), 5.63 (s, 2 H), 4.23 (s, 2 H), 3.72 (s, 2 H), 2.96-2.81 (m, 4 H), 1.86-1.79 (m, 1 H), 0.57-0.75 (m, 4 H); LC-MS [M+H]+=426.3, RT=2.32 min.
Reaction SMILES: B.CSC.[CH:5]1([C:15]([CH3:33])([CH3:32])[C:16]([N:18]2[CH2:23][CH2:22][N:21]([C:24]3[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=3)[CH2:20][CH2:19]2)=O)[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8][CH2:7][O:6]1.C1COCC1.[ClH:39]>CO>[ClH:39].[ClH:39].[CH:5]1([C:15]([CH3:33])([CH3:32])[CH2:16][N:18]2[CH2:19][CH2:20][N:21]([C:24]3[CH:25]=[CH:26][C:27]([O:30][CH3:31])=[CH:28][CH:29]=3)[CH2:22][CH2:23]2)[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8][CH2:7][O:6]1
Reactant: COc1ccc(N2CCN(C(=O)C(C)(C)C3OCCc4ccccc43)CC2)cc1
Agent: B
Agent: Cl
Solvent: CSC
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc(N2CCN(CC(C)(C)C3OCCc4ccccc43)CC2)cc1

Procedure:
Triethylamine (1 ml) is added dropwise to a mixture of 2-(isochroman-1-yl)-2-methylpropionic acid (LXXII, 0.502 g, 2.3 mmol), 1-(4-methoxyphenyl)piperazine dihydrochloride (XI, 0.668 g, 2.5 mmol), diethylcyanophosphonate (0.44 ml, 2.9 mmol), DMF (2.4 ml) and dichloromethane (2.4 ml). After the mixture had stirred for 2.5 hr, aqueous saturated sodium bicarbonate is added and the mixture is stirred for 70 min. The mixture is then partitioned between dichloromethane and saline, the phases separated and the organic phase is dried over magnesium sulfate and concentrated. The residue is chromatographed on silica gel eluting with methanol/dichloromethane (1/99). The appropriate fractions are pooled and concentrated to give a residue. Ethyl acetate and hexane are added and the solids are collected and dried to give 2-(isochroman-1-yl)-1-[4-(4-methoxyphenyl)piperazin-1-yl]-2-methylpropan-1-one (LXXIII), mp 119.5°-121°. Borane-methyl sulfide (1.1 ml) is added to a mixture of 2-(isochroman-1-yl)-1-[4-(4-methoxyphenyl)piperazin-1-yl]-2-methylpropan-1-one (LXXIII, 0.397 g, 1.0 mmol) and THF (98 ml). The mixture is heated for 3.5 hr at 76° and then cooled in an ice/water bath. Hydrochloric acid (10%, 1.3 ml) is added, followed by methanol. The mixture is concentrated and methanol is again added and removed under reduced pressure. The methanol addition/removal is repeated twice more and the resulting material is partitioned between dichloromethane and saturated sodium bicarbonate. The combined organic phases are dried over magnesium sulfate, concentrated, and the residue chromatographed on silica gel eluting with ethyl acetate/hexane (5/95) followed by ethyl acetate/hexane (10/90). The appropriate fractions are pooled and concentrated to give the free base of the title compound.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[N:9][N:10]([CH2:12][C:13]([O:15]CC)=O)[CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:18]([N:20]([CH2:25][CH3:26])[CH2:21][CH2:22][CH2:23][NH2:24])[CH3:19].O>CN(C=O)C>[CH2:18]([N:20]([CH2:25][CH3:26])[CH2:21][CH2:22][CH2:23][NH:24][C:13](=[O:15])[CH2:12][N:10]1[CH:11]=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:8]=[N:9]1)[CH3:19]
Reactant: CCN(CC)CCCN
Reactant: CCOC(=O)Cn1cc(-c2ccccc2)cn1
Solvent: CN(C)C=O
Solvent: O
Product: CCN(CC)CCCNC(=O)Cn1cc(-c2ccccc2)cn1
Yield: 19.9 %

Procedure:
A solution of 13.5g (0.059 mol) of ethyl 4-phenyl-1H-pyrazole-1-acetate of example 3 and 12.6 mL (0.08 mol) of 3-(diethylamino)propanamine in 130 mL of DMF was stirred at 100° C. for 4hr. The reaction was poured into water, extracted into methlene chloride, and stripped. The residue was triturated in ether and the resulting solid was recrystallized from ether-hexane to yield 3.70g of product, mp 55°-57° C.
Reaction SMILES: I[C:2]1[CH:10]=[CH:9][C:8]([CH2:11][N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[C:7]2[C:3]=1[C:4]([NH2:18])=[N:5][NH:6]2.CC1(C)C(C)(C)OB([C:27]2[CH:32]=[CH:31][C:30]([NH:33][C:34]([NH:36][C:37]3[CH:42]=[CH:41][CH:40]=[C:39]([C:43]([F:46])([F:45])[F:44])[CH:38]=3)=[O:35])=[CH:29][CH:28]=2)O1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)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>[NH2:18][C:4]1[C:3]2[C:7](=[C:8]([CH2:11][N:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)[CH:9]=[CH:10][C:2]=2[C:27]2[CH:28]=[CH:29][C:30]([NH:33][C:34]([NH:36][C:37]3[CH:42]=[CH:41][CH:40]=[C:39]([C:43]([F:44])([F:45])[F:46])[CH:38]=3)=[O:35])=[CH:31][CH:32]=2)[NH:6][N:5]=1
Reactant: CC1(C)OB(c2ccc(NC(=O)Nc3cccc(C(F)(F)F)c3)cc2)OC1(C)C
Reactant: Nc1n[nH]c2c(CN3CCOCC3)ccc(I)c12
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: O
Solvent: CCO
Solvent: Cc1ccccc1
Product: Nc1n[nH]c2c(CN3CCOCC3)ccc(-c3ccc(NC(=O)Nc4cccc(C(F)(F)F)c4)cc3)c12
Temperature: 145 °C
Yield: 49 %

Procedure:
A solution of Example 15F (80 mg, 0.22 mmol) and N-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-N′-[3-(trifluoromethyl)phenyl]urea (108 mg, 0.268 mmol) in toluene (2 mL) and ethanol (1.5 mL) was treated with a solution of Na2CO3 (58 mg) in water (1 mL), degassed with nitrogen for 2 minutes, treated with Pd(PPh3)4 (13 mg, 0.011 mmol), and degassed with nitrogen for another 2 minutes. The vial was capped and heated to 140-150° C. for 8-10 minutes with stirring in a Smith Synthesizer microwave oven (at 300 W). The reaction was poured into water and extracted three times with ethyl acetate. The combined extracts were washed with water and brine, dried (MgSO4), filtered, and concentrated. The concentrate was purified by HPLC using the conditions in Example 15H to provide 55 mg of the desired product as the trifluoroacetate salt. 1H NMR (300 MHz, DMSO-d6) δ 3.10-4.08 (m, 8H), 4.55 (s, 2H), 6.92 (d, J=7.12 Hz, 1H), 7.32 (d, J=7.46 Hz, 1H), 7.38-7.47 (m, 3H), 7.53 (t, J=7.80 Hz, 1H), 7.58-7.69 (m, 3H), 8.06 (s, 1H), 9.17 (s, 1H), 9.30 (s, 1H); MS (ESI(+)) m/e 511 (M+H)+.
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12.[Br:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C(#N)C>[Br-:10].[CH2:11]([N+:1]1[CH:2]=[CH:3][N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: c1ccn2ccnc2c1
Reactant: BrCc1ccccc1
Solvent: CC#N
Product: [Br-]
Product: c1ccc(C[n+]2ccn3ccccc32)cc1

Procedure:
To 1.77 g. of imidazo[1,2-a]pyridine in 40 ml. of acetonitrile is added 3.42 g. of α-bromotoluene, and the resulting mixture heated to reflux overnight. The resulting solution is cooled, and the precipitated solids filtered. Recrystallization of the crude product from acetonitrile affords the pure product as a white solid, 2.33 g., m.p. 169°-171° C.
Reaction SMILES: CS(O[CH:6]1[CH2:15][CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)(=O)=O.[NH:16]1[CH:20]=[CH:19][N:18]=[CH:17]1>CN(C=O)C>[CH2:7]1[C:8]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:14][CH2:15][CH:6]1[N:16]1[CH:20]=[CH:19][N:18]=[CH:17]1
Reactant: CS(=O)(=O)OC1CCc2ccccc2C1
Reactant: c1c[nH]cn1
Solvent: CN(C)C=O
Product: c1ccc2c(c1)CCC(n1ccnc1)C2
Yield: 37500 %

Procedure:
A mixture of 1,2,3,4-tetrahydronaphthalen-2-yl methanesulfonate (15.74 g, 69.6 mmol), prepared as in Example 7, and imidazole (23.68 g, 349 mmol) in 100 mL of DMF was heated at 80° to 90° C. under argon for 24 hours. The solvent was removed under vacuum by rotary evaporation. The residue was dissolved in 500 mL of ethyl acetate and the solution was washed with water (5×250 mL). The combined aqueous layer was extracted with 500 mL of ethyl acetate and the extract was then washed with water (5×250 mL). The combined ethyl acetate extract was washed with saturated sodium chloride solution, dried over magnesium sulfate and concentrated by rotary evaporation. Purification of the residue by column chromatography on silica gel (elution: 5% methanol/methylene chloride) gave 1-(1,2,3,4-tetrahydronaphthalen-2-yl)imidazole (5.18 g, 26.1 mol), m.p. 93°-95° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[C:5]([C:10]([C:12]1[C:17](F)=[CH:16][CH:15]=[CH:14][N:13]=1)=[O:11])=[CH:6][N:7]([CH3:9])C)[CH3:2].C(OC(C1C(=O)C2C(=CC=CN=2)N(CC2[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=2[C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)C=1)=O)C>>[CH2:1]([O:3][C:4]([C:5]1[C:10](=[O:11])[C:12]2[C:17](=[CH:16][CH:15]=[CH:14][N:13]=2)[N:7]([CH2:9][C:38]2([C:43]3[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=3)[CH2:39][CH2:40][CH2:41][CH2:42]2)[CH:6]=1)=[O:19])[CH3:2]
Reactant: CCOC(=O)c1cn(Cc2ccccc2-c2ccccc2)c2cccnc2c1=O
Reactant: CCOC(=O)C(=CN(C)C)C(=O)c1ncccc1F
Product: CCOC(=O)c1cn(CC2(c3ccccc3)CCCC2)c2cccnc2c1=O
Yield: 49.46 %

Procedure:
4-Oxo-1-(1-phenyl-cyclopentylmethyl)-1,4-dihydro-[1,5]naphthyridine-3-carboxylic acid ethyl ester (9) (140 mg, 49.46%) was synthesized as a sticky liquid from 200 mg of 3-dimethylamino-2-(3-fluoro-pyridine-2-carbonyl)-acrylic acid ethyl ester (4) following the procedure described for 1-biphenyl-2-ylmethyl-4-oxo-1,4-dihydro-[1,5]naphthyridine-3-carboxylic acid ethyl ester (6).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[C:6]([S:11]([C:14]3[CH:15]=[C:16]([NH2:21])[C:17]([NH2:20])=[CH:18][CH:19]=3)(=[O:13])=[O:12])[CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1.[CH:22]([CH:24]=O)=O.S(=O)(O)[O-].[Na+].[OH-].[Na+]>O>[CH:1]1[C:10]2[C:5](=[C:6]([S:11]([C:14]3[CH:15]=[C:16]4[C:17](=[CH:18][CH:19]=3)[N:20]=[CH:24][CH:22]=[N:21]4)(=[O:13])=[O:12])[CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1
Reactant: Nc1ccc(S(=O)(=O)c2cccc3cnccc23)cc1N
Reactant: O=CC=O
Agent: O=S([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=S(=O)(c1ccc2nccnc2c1)c1cccc2cnccc12
Temperature: 80 °C
Reaction time: 2 h
Yield: 65.3 %

Procedure:
To a suspension of 4-(5-Isoquinolylsulfonyl)-1,2-benzenediamine 300 mg (1.0 mmol) in water, a 40% glyoxal solution 450 mg (3.1 mmol) and sodium bisulfite 650 mg (3.1 mmol) and water 8 ml were added, and the mixture was heated with stirring for 2 hours at 80° C. The reaction mixture was alkalized with 1N sodium hydroxide, and the solution was extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride, and dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (chloroform:acetone=5:1), and 6-(5-isoquinolylsulfonyl)quinoxaline 210 mg (66.3%) was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[O:9][CH3:10].[Li]C(C)(C)C.CCCCC.[CH3:21][Si:22]([CH3:25])([CH3:24])Cl.C(=O)(O)[O-].[Na+]>C1COCC1>[F:8][C:6]1[CH:5]=[CH:4][C:3]([O:9][CH3:10])=[C:2]([Cl:1])[C:7]=1[Si:22]([CH3:25])([CH3:24])[CH3:21]
Reactant: C[Si](C)(C)Cl
Reactant: COc1ccc(F)cc1Cl
Agent: O=C([O-])O
Agent: [Li]C(C)(C)C
Agent: [Na+]
Solvent: CCCCC
Solvent: C1CCOC1
Product: COc1ccc(F)c([Si](C)(C)C)c1Cl
Reaction time: 0.25 h

Procedure:
To a solution of 2-chloro-4-fluoroanisole (16.5 g, 100 mmol) in THF (500 mL) cooled at −75° C. was added dropwise a solution of t-BuLi in pentane (1.7 M, 61.8 mL, 105 mmol). The reaction was kept at −75° C. for 15 min, quenched at −75° C. with trimethylchlorosilane (19.0 mL, 150 mmol) and finally poured into a saturated solution of sodium bicarbonate. The organic layer was washed with brine, dried over magnesium sulfate and concentrated. The residue was purified by chromatography on silica gel eluting with 20:1 hexane:diethyl ether to give the title product.