Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[CH:7][C:6]([O:9][CH2:10][CH3:11])=[C:5]([CH3:12])[CH:4]=1.[Br-].[CH3:14][C:15]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([Br:23])[CH:18]=1)=O>O1CCCC1.BrCCBr>[Br:23][C:19]1[CH:18]=[C:17]([C:15]([C:3]2[CH:8]=[CH:7][C:6]([O:9][CH2:10][CH3:11])=[C:5]([CH3:12])[CH:4]=2)=[CH2:14])[CH:22]=[CH:21][CH:20]=1
Reactant: CC(=O)c1cccc(Br)c1
Reactant: CCOc1ccc(Br)cc1C
Agent: [Br-]
Agent: [Mg]
Solvent: C1CCOC1
Solvent: BrCCBr
Product: C=C(c1cccc(Br)c1)c1ccc(OCC)c(C)c1
Temperature: 0 °C

Procedure:
To a suspension of magnesium turnings (963 mg, 39.6 mmol, 1.2 eq) in 5 mL of dry tetrahydrofuran, 0.1 mL of 1,2-dibromoethane were added followed by 5 mL of a tetrahydrofuran solution of 4-bromo-1-ethoxy-2-methyl-benzene (7.8 g, 36.3 mmol, 1.1 eq in 25 mL tetrahydrofuran). The resulting mixture was gently heated to initiate the reaction. The remaining solution of bromide was added dropwise at such a rate that the reaction could reflux without external heating. After the addition the reaction mixture was heated at reflux for further 2 hours. The mixture was cooled to 0° C. and a solution of 3-bromoacetophenone (6.56 g, 33.0 mmol, 1.0 eq) in tetrahydrofuran (30 mL) was added dropwise. After 2 hours LCMS showed complete conversion to the desired product. 50 mL of water were added followed by 35 mL of 1M aqueous HCl. The organic fraction was washed with brine, dried over sodium sulfate and concentrated to give a yellow oil. The oil was dissolved in 10 mL of acetic acid. 0.3 mL of 98% sulfuric acid were added and the dark solution was stirred at room temperature. After 30 min LCMS showed complete conversion to the desired product. Crushed ice was added to the reaction mixture which was then extracted with dichloromethane. The organic fraction was collected, washed with water, saturated sodium bicarbonate solution and dried with over sodium sulfate. The crude product was purified by flash chromatography eluting with cyclohexane. 7.5 g of clean product was obtained as colorless liquid (yield: 63%)
Reaction SMILES: Br[C:2]1[C:3]2[C:4]3[CH:17]=[CH:16][S:15][C:5]=3[C:6](=[O:14])[NH:7][C:8]=2[CH:9]=[CH:10][C:11]=1[O:12][CH3:13].CC1(C)C(C)(C)OB([C:26]2[CH:31]=[CH:30][C:29]([CH:32]([CH3:35])[C:33]#[N:34])=[CH:28][CH:27]=2)O1>>[CH3:13][O:12][C:11]1[CH:10]=[CH:9][C:8]2[NH:7][C:6](=[O:14])[C:5]3[S:15][CH:16]=[CH:17][C:4]=3[C:3]=2[C:2]=1[C:26]1[CH:31]=[CH:30][C:29]([CH:32]([CH3:35])[C:33]#[N:34])=[CH:28][CH:27]=1
Reactant: COc1ccc2[nH]c(=O)c3sccc3c2c1Br
Reactant: CC(C#N)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Product: COc1ccc2[nH]c(=O)c3sccc3c2c1-c1ccc(C(C)C#N)cc1
Yield: 60.7 %

Procedure:
Following General Procedure B, 9-bromo-8-methoxythieno[2,3-c]quinolin-4(5H)-one (500 mg, 1.6 mmol) was reacted with 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propanenitrile (600 g, 2.2 mmol) to afford the desired product (350 mg, 62%) as a brown solid: ESI MS m/z 361 [C21H16N2O2S+H]+.
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5][O:6][C:7]1[N:15]=[C:14]2[C:10]([N:11]=[CH:12][N:13]2[CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][O:17]2)=[C:9]([NH2:22])[N:8]=1)[CH3:2].C1C(=O)N([Br:30])C(=O)C1>ClCCl>[Br:30][C:12]1[N:13]([CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][O:17]2)[C:14]2[C:10]([N:11]=1)=[C:9]([NH2:22])[N:8]=[C:7]([O:6][CH2:5][CH2:4][O:3][CH2:1][CH3:2])[N:15]=2
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOCCOc1nc(N)c2ncn(C3CCCCO3)c2n1
Solvent: ClCCl
Product: CCOCCOc1nc(N)c2nc(Br)n(C3CCCCO3)c2n1
Reaction time: 2 h

Procedure:
To a stirred solution of 2-{[2-(ethyloxy)ethyl]oxy}-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-amine (7.8 g, 25.4 mmol) in dichloromethane (100 ml) and NBS (5 g, 27.9 mmol) added with stirring. After 2 h, the solvent was removed. The product was purified through a silica column using petroleum ether: ethyl acetate 2:1 as eluent, which was a pale yellow solid (7.8 g, 79.6%).
Reaction SMILES: [OH-].[K+].[CH3:3][O:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][CH:9]=[CH:8]2.Cl.[NH:15]1[CH2:20][CH2:19][C:18](=O)[CH2:17][CH2:16]1.O>CO>[CH3:3][O:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][CH:9]=[C:8]2[C:18]1[CH2:19][CH2:20][NH:15][CH2:16][CH:17]=1
Reactant: COc1ccc2[nH]ccc2c1
Reactant: O=C1CCNCC1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1ccc2[nH]cc(C3=CCNCC3)c2c1
Temperature: 65 °C

Procedure:
KOH (8.44 g, 150 mmole), 5-methoxyindole (5.0 g, 34 mmole) and piperidine-4-one hydrochloride (10.53 g, 88.3 mmole) were suspended in methanol (50 ml) and heated for 8 hours at 65° C. under argon. Water (50 ml) was added dropwise at RT to the mixture over a period of 40 minutes. The solid thereby formed was filtered off, washed with water (3×20 ml) and recrystallised from methanol (20 ml). 5-methoxy-3-(1,2,3,6-tetrahydropyridine-4-yl)-1H-indole was obtained in a yield of 4.66 g (75%) as a yellow solid with an m.p. of 173°-175° C.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[OH:20])[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C([O-])([O-])=O.[K+].[K+].[CH2:27](I)[CH:28]([CH3:30])[CH3:29]>CN(C=O)C.CCOC(C)=O>[C:1]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[O:20][CH2:27][CH:28]([CH3:30])[CH3:29])[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccccc2O)CC1
Reactant: CC(C)CI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)COc1ccccc1N1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 80 °C
Reaction time: 0.08 h
Yield: 62.5 %

Procedure:
To a solution of 1-Boc-4-(2-hydroxy-phenyl)-piperazine (560 mg, 2.0 mmol) in 10 mL of DMF was added K2CO3 (835 mg, 6 mmol). After stirring for about 5 minutes, isobutyl iodide (350 uL, 3 mmol) was added. After stirring overnight at 60° C., the solution was warmed to about 80° C. After stirring for about 4 hours, the solution was cooled to r.t. diluted with EtOAc, washed with water and brine, and then dried (Na2SO4), filtered and concentrated. Purification by silica gel chromatography (35 g SiO2, 10 to 30% EtOAc/hexanes, over 45 minutes at 35 mL/min) afforded about 418 mg (1.25 mmol, 62%) of N-Boc-4-(2-isobutoxy-phenyl)-piperazine as a colorless oil. LRMS (ESI+): 335.1 [M+1].
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.[OH-].[K+].Br[C:15]1[S:19][C:18]([S:20]([NH2:23])(=[O:22])=[O:21])=[CH:17][CH:16]=1>CN(C)C=O.O>[C:9]([CH2:8][C:5]1[CH:4]=[CH:3][C:2]([S:1][C:15]2[S:19][C:18]([S:20]([NH2:23])(=[O:22])=[O:21])=[CH:17][CH:16]=2)=[CH:7][CH:6]=1)([OH:11])=[O:10]
Reactant: O=C(O)Cc1ccc(S)cc1
Reactant: NS(=O)(=O)c1ccc(Br)s1
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: NS(=O)(=O)c1ccc(Sc2ccc(CC(=O)O)cc2)s1
Temperature: 120 °C

Procedure:
4-Mercaptophenylacetic acid (2.3 g) was dissolved in dimethylformamide under a nitrogen atmosphere and 1.8 g of potassium hydroxide dissolved in a minimum amount of water was added. 5-bromothiophene-2-sulfonamide (3.3 g) dissolved in dimethylformamide was added and the mixture heated at 120° C. for 2 hours. After cooling to room temperature water was added to the reaction mixture, the pH was adjusted to 8.6 and the mixture was extracted with ethyl acetate. The aqueous phase was separated and acidified, causing a solid to precipitate. The solid was collected by filtration and dried under vacuum to a weight of 3.25 g.
Reaction SMILES: [N:1]1([CH:6]=[N:7][C:8]2[CH:13]=[CH:12][N:11]=[CH:10][C:9]=2[OH:14])[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[CH3:22][N:23]([CH3:27])[C:24](Cl)=[O:25]>O1CCCC1>[CH3:22][N:23]([CH3:27])[C:24]([O:14][C:9]1[CH:10]=[N:11][CH:12]=[CH:13][C:8]=1[N:7]=[CH:6][N:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1)=[O:25]
Reactant: Oc1cnccc1N=CN1CCCC1
Reactant: CN(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CN(C)C(=O)Oc1cnccc1N=CN1CCCC1

Procedure:
A mixture prepared from 4-[[(1-pyrrolidinyl)methylene]amino]-3-pyridinol (3.79 g), triethylamine (4.29 mL), dimethylcarbamyl chloride (2.74 mL) and tetrahydrofuran (130 mL) was refluxed for 1 hour, cooled, poured directly onto a silica column and eluted successively with ethyl acetate and 5% Et3N/ethyl acetate. Recrystallization from ethyl acetate and drying under high vacuum and refluxing acetone for 4 hours yielded 3.55 g of crystals, m.p. 99°-100° C.
Reaction SMILES: [CH:1]([N:4]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([CH3:14])[N:12]=2)[C:7](=[O:15])[C:6]([C:16]([OH:18])=O)=[CH:5]1)([CH3:3])[CH3:2].C(N(CC)CC)C.ClC(OCC)=O.[NH2:32][C:33]1[NH:37][N:36]=[N:35][N:34]=1>CN(C)C=O>[CH:1]([N:4]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([CH3:14])[N:12]=2)[C:7](=[O:15])[C:6]([C:16]([NH:32][C:33]2[NH:37][N:36]=[N:35][N:34]=2)=[O:18])=[CH:5]1)([CH3:2])[CH3:3]
Reactant: Nc1nnn[nH]1
Reactant: Cc1ccc2c(=O)c(C(=O)O)cn(C(C)C)c2n1
Agent: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1ccc2c(=O)c(C(=O)Nc3nnn[nH]3)cn(C(C)C)c2n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
1,4-Dihydro-1-isopropyl-7-methyl-4-oxo-1,8-naphthyridine-3-carboxylic acid (Example 3b, 0.9 g) was warmed in dimethylformamide (70 ml) and triethylamine (0.7 ml) was added. The solution was cooled to 0° and ethyl chloroformate (0.4 ml) was added and the mixture was kept for 30 minutes. 5-Amino-1H-tetrazol (3.6 g) was added and the mixture was stirred at room temperature for 18 hours and filtered. The filtrate was evaporated and the residue was crystallised from a mixture of dimethylforamido and isopropanol. The product had m.p. >300° (d) (36%).
Reaction SMILES: [OH:1][N:2]1[C:7]([CH3:9])([CH3:8])[CH2:6][CH:5](O)[CH2:4][C:3]1([CH3:12])[CH3:11].N(OC(C)(C)C)=O.N1C=CC=CC=1.[CH2:26]([O:29][C:30]1[CH:36]=[CH:35][CH:34]=[CH:33][C:31]=1N)[CH:27]=[CH2:28]>ClC1C=CC=CC=1>[O:29]1[C:30]2[CH:36]=[CH:35][CH:34]=[CH:33][C:31]=2[CH:27]([CH2:28][O:1][N:2]2[C:7]([CH3:9])([CH3:8])[CH2:6][CH2:5][CH2:4][C:3]2([CH3:12])[CH3:11])[CH2:26]1
Reactant: C=CCOc1ccccc1N
Reactant: CC1(C)CC(O)CC(C)(C)N1O
Agent: CC(C)(C)ON=O
Solvent: c1ccncc1
Solvent: Clc1ccccc1
Product: CC1(C)CCCC(C)(C)N1OCC1COc2ccccc21
Yield: 58.9 %

Procedure:
The procedure of Example 1 is repeated using 1.95 g (12.5 mmol) of 1-oxyl-2,2,6,6-tetramethyl-4-hydroxypiperidine, 3.10 g (30 mmol) of tert-butyl nitrite, 2.4 g (25 mmol) of pyridine, 7.5 mg (0.012 mmol) of (S,S)-(+)-N,N-bis(3,5-di-tert-butylsalicylidene)-1,2-cyclohexanediaminocobalt(II) mmol) in 100 mL of chlorobenzene and 5.60 g (25 mmol) of 2-allyloxyaniline in 20 mL of chlorobenzene. The crude product obtained is purified by vacuum flash chromatography (25% ethyl acetate/heptane) to give 2.13 g of a viscous liquid in 59.0% yield.
Reaction SMILES: N[C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C@@H:14]([N:16]3[CH2:21][CH2:20][C@:19]([CH2:28][CH2:29][CH2:30][OH:31])([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[O:18][C:17]3=[O:32])[CH3:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.N([O-])=[O:34].[Na+].[OH-].[Na+]>OS(O)(=O)=O>[OH:31][CH2:30][CH2:29][CH2:28][C@@:19]1([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[O:18][C:17](=[O:32])[N:16]([C@H:14]([C:11]2[CH:10]=[CH:9][C:8]([C:5]3[CH:4]=[CH:3][C:2](=[O:34])[NH:7][CH:6]=3)=[CH:13][CH:12]=2)[CH3:15])[CH2:21][CH2:20]1
Reactant: O=N[O-]
Reactant: C[C@@H](c1ccc(-c2ccc(N)nc2)cc1)N1CC[C@](CCCO)(c2ccccc2)OC1=O
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: C[C@@H](c1ccc(-c2ccc(=O)[nH]c2)cc1)N1CC[C@](CCCO)(c2ccccc2)OC1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 20 %

Procedure:
(R)-3-((S)-1-(4-(6-aminopyridin-3-yl)phenyl)ethyl)-6-(3-hydroxypropyl)-6-phenyl-1,3-oxazinan-2-one (40 mg, 0.09 mmol.) was dissolved in 3.5 M H2SO4 (10 mL), and 2 M NaNO2 (10 mL) was added at 0° C. The reaction mixture was stirred at rt for 2 h and treated with NaOH solution. The mixture was extracted with EtOAc. The combined organic layer was washed with brine, dried over anhydrous Na2SO4, and concentrated to afford the residue, which was purified by preparative HPLC to give (R)-6-(3-hydroxypropyl)-3-((S)-1-(4-(6-oxo-1,6-dihydropyridin-3-yl)phenyl)ethyl)-6-phenyl-1,3-oxazinan-2-one (10 mg, 20%). LC-MS Method 2 tR=1.66, min, m/z=433, 455; 1H NMR (CDCl3): 1.36 (m, 2H), 1.50 (m, 3H), 1.68 (m, 2H), 1.92 (m, 2H), 2.10-2.30 (m, 3H), 2.84 (m, 1H), 3.50 (m, 2H), 5.12 (m, 1H), 6.62 (m, 1H), 6.86 (m, 2H), 7.08 (m, 2H), 7.18-7.32 (m, 5H), 7.46 (m, 1H), 7.62 (m, 1H).
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]([NH:9][C:10]2[CH:11]=[C:12]([C:16]#[C:17][C:18]3[CH:19]=[C:20]([C:24]([N:26]=[S:27]([C:30]4[CH:31]=[C:32]([CH2:36][C:37](O)=[O:38])[CH:33]=[CH:34][CH:35]=4)([CH3:29])=[O:28])=[O:25])[CH:21]=[N:22][CH:23]=3)[CH:13]=[CH:14][CH:15]=2)=[O:8])=[CH:5][C:4]([CH3:40])=[N:3]1.[NH2:41][CH2:42][CH2:43][N:44]1[CH2:49][CH2:48][O:47][CH2:46][CH2:45]1>>[CH3:1][N:2]1[C:6]([C:7]([NH:9][C:10]2[CH:11]=[C:12]([C:16]#[C:17][C:18]3[CH:23]=[N:22][CH:21]=[C:20]([CH:19]=3)[C:24]([N:26]=[S:27]([CH3:29])([C:30]3[CH:35]=[CH:34][CH:33]=[C:32]([CH2:36][C:37]([NH:41][CH2:42][CH2:43][N:44]4[CH2:49][CH2:48][O:47][CH2:46][CH2:45]4)=[O:38])[CH:31]=3)=[O:28])=[O:25])[CH:13]=[CH:14][CH:15]=2)=[O:8])=[CH:5][C:4]([CH3:40])=[N:3]1
Reactant: Cc1cc(C(=O)Nc2cccc(C#Cc3cncc(C(=O)N=S(C)(=O)c4cccc(CC(=O)O)c4)c3)c2)n(C)n1
Reactant: NCCN1CCOCC1
Product: Cc1cc(C(=O)Nc2cccc(C#Cc3cncc(C(=O)N=S(C)(=O)c4cccc(CC(=O)NCCN5CCOCC5)c4)c3)c2)n(C)n1
Yield: 54 %

Procedure:
In a manner similar to that described in Example 500, {3-[N-({5-[(3-{[(1,3-dimethyl-1H-pyrazol-5-yl)carbonyl]amino}phenyl)ethynyl]pyridin-3-yl}carbonyl)-S-methylsulfonimidoyl]phenyl}acetic acid and 4-(2-aminoethyl)morpholine were reacted to give the title compound (54%).
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[C:3]=1[CH2:4][N:5]1[CH2:10][CH2:9][NH:8][C:7]2[N:11]=[CH:12][C:13](I)=[CH:14][C:6]1=2.[N:21]1([CH:26]2[CH2:31][CH2:30][N:29]([C:32]([C:34]3[CH:39]=[CH:38][C:37](B4OC(C)(C)C(C)(C)O4)=[CH:36][CH:35]=3)=[O:33])[CH2:28][CH2:27]2)[CH2:25][CH2:24][CH2:23][CH2:22]1>>[Cl:1][C:2]1[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[C:3]=1[CH2:4][N:5]1[CH2:10][CH2:9][NH:8][C:7]2[N:11]=[CH:12][C:13]([C:37]3[CH:38]=[CH:39][C:34]([C:32]([N:29]4[CH2:28][CH2:27][CH:26]([N:21]5[CH2:22][CH2:23][CH2:24][CH2:25]5)[CH2:31][CH2:30]4)=[O:33])=[CH:35][CH:36]=3)=[CH:14][C:6]1=2
Reactant: CC1(C)OB(c2ccc(C(=O)N3CCC(N4CCCC4)CC3)cc2)OC1(C)C
Reactant: Clc1cccc(Cl)c1CN1CCNc2ncc(I)cc21
Product: O=C(c1ccc(-c2cnc3c(c2)N(Cc2c(Cl)cccc2Cl)CCN3)cc1)N1CCC(N2CCCC2)CC1
Yield: 10 %

Procedure:
1-(2,6-Dichlorobenzyl)-7-iodo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine (56 mg) was reacted with (4-(pyrrolidin-1-yl)piperidin-1-yl)-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)phenyl]methanone as in General Procedure 4B to give the title compound as a yellow solid (10% yield). LCMS: m/z=470.05 (M+H+), 1H-NMR (CDCl3, 400 MHz) δ 1.56 (3H, m), 1.90 (11H, m), 2.17 (1H, s), 2.28 (1H, m), 2.59 (5H, m), 2.98 (3H, m), 3.14 (2H, t, J=4.7 Hz), 3.50 (2H, m), 3.85 (1H, bs), 4.61 (3H, s), 4.92 (1H, bs), 7.12 (1H, s), 7.23 (1H, m), 7.48 (6H, m), 7.75 (1H, d, J=1.5 Hz).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([C:6]1[CH:11]=[CH:10][N:9]=[CH:8][CH:7]=1)=O.[S-:12][C:13]#[N:14].[K+]>O>[N:9]1[CH:10]=[CH:11][C:6]([C:4]2[N:14]=[C:13]([SH:12])[NH:2][CH:3]=2)=[CH:7][CH:8]=1
Reactant: N#C[S-]
Reactant: NCC(=O)c1ccncc1
Agent: Cl
Agent: [K+]
Solvent: O
Product: Sc1nc(-c2ccncc2)c[nH]1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 74.7 %

Procedure:
2-Amino-1-pyridin-4-yl-ethanone hydrochloride (0.75 g, 4.348 mMol) was dissolved in water (15 mL), and to clear yellow solution was added potassium thiocyanate (0.7 g, 7.203 mMol). The mixture was heated to reflux for 4.0 h during which period HPLC showed complete disappearance of starting material. On cooling to room temperature, a yellow solid precipitate formed, which was collected by filtration. The solid was then re-suspended in a saturated solution of NaHCO3 (30 mL), stirred at room temperature for 0.5 h, and the resulting free base thiol was collected by filtration. The solid was dried under vacuum to yield 576 mg (59%) of a fluorescent yellow solid. MS(ES) 178 (M+H)
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:19][C:20]([CH:22]2[CH2:26][CH2:25][N:24]([CH3:27])[C:23]2=[O:28])=[O:21])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[CH:15]=[C:16](I)[S:17][C:10]=12.[CH3:29][NH:30][C:31]([C:33]1[CH:38]=[CH:37][C:36](B(O)O)=[CH:35][CH:34]=1)=[O:32].C([O-])([O-])=O.[Na+].[Na+]>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.COCCOC>[F:1][C:2]1[CH:3]=[C:4]([NH:19][C:20]([CH:22]2[CH2:26][CH2:25][N:24]([CH3:27])[C:23]2=[O:28])=[O:21])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[CH:15]=[C:16]([C:36]3[CH:37]=[CH:38][C:33]([C:31](=[O:32])[NH:30][CH3:29])=[CH:34][CH:35]=3)[S:17][C:10]=12
Reactant: CN1CCC(C(=O)Nc2ccc(Oc3ccnc4cc(I)sc34)c(F)c2)C1=O
Reactant: CNC(=O)c1ccc(B(O)O)cc1
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: COCCOC
Product: CNC(=O)c1ccc(-c2cc3nccc(Oc4ccc(NC(=O)C5CCN(C)C5=O)cc4F)c3s2)cc1
Temperature: 60 °C
Yield: 26.1 %

Procedure:
A round-bottomed flask was charged with N-(3-fluoro-4-(2-iodothieno[3,2-b]pyridin-7-yloxy)phenyl)-1-methyl-2-oxopyrrolidine-3-carboxamide (20.0 mg, 0.039 mmol), 4-(methylcarbamoyl)phenylboronic acid (21.0 mg, 0.117 mmol), tetrakis(triphenylphosphine)palladium (9.04 mg, 0.0078 mmol), Na2CO3 (0.098 ml, 0.20 mmol) and DME (10 mL). The reaction mixture was stirred at 60° C. until the starting material had been consumed (overnight). Then the reaction mixture was cooled to room temperature and partitioned between EtOAc (100 mL) and H2O (100 mL). The phases were separated and the aqueous phase was re-extracted with EtOAc (3×100 mL). The combined organic layers were dried (Na2SO4), filtered and concentrated to yield a crude product. The crude product was purified by silica gel chromatography (DCM/7 M NH3 in MeOH from 50/1 to 10/1, v/v) to give product (5.3 mg, the yield is 26.1%). LRMS (APCI neg): >99% purity, 254 nm, m/e 517 (M−1). 1H NMR (400 MHz, DMSO-d6) δ 10.05 (s, 1H), 8.50 (m, 1H), 7.79-7.87 (m, 5H), 7.21-7.33 (m, 2H), 6.51 (d, 1H), 6.17 (d, 1H), 3.38-3.49 (m, 3H), 3.05 (d, 3H), 2.95 (s, 3H), 2.38-2.70 (m, 2H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([CH:20](Cl)[CH3:21])=[CH:16][CH:15]=2)=[CH:10][CH:9]=1>C1C=CC=CC=1>[Cl:7][C:8]1[CH:9]=[CH:10][C:11]([C:14]2[CH:19]=[CH:18][C:17]([CH:20]([N:1]3[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]3)[CH3:21])=[CH:16][CH:15]=2)=[CH:12][CH:13]=1
Reactant: C1CNCCN1
Reactant: CC(Cl)c1ccc(-c2ccc(Cl)cc2)cc1
Solvent: c1ccccc1
Product: CC(c1ccc(-c2ccc(Cl)cc2)cc1)N1CCNCC1

Procedure:
While stirring, reflux a solution of 90g of anhydrous piperazine, 52g of 4'-chloro-4-(1-chloroethyl)[1,1']biphenyl and 700 ml of anhydrous benzene for 24 hours. Add 300 ml. of water to the reaction mixture, separate the benzene layer and extract with dilute hydrochloric acid. Separate and filter the acidic aqueous phase, basify the filtrate with dilute sodium hydroxide and extract with methylene chloride. Dry the organic extract, concentrate and triturate the resulting solid residue with petroleum ether. Filter and recrystallize the product from methanol to yield 1-[1-(4'-chloro[1,1']biphenyl-4-yl)ethyl] piperazine m.p. 164°-165° C. The dihydrochloride salt (from methanol as hemihydrate) has a m.p. 263°-264°.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-])=O.[CH2:11]([Mg]Br)[CH:12]=[CH2:13]>>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]2[C:3]=1[NH:8][CH:11]=[C:12]2[CH3:13]
Reactant: O=[N+]([O-])c1ccccc1Br
Reactant: C=CC[Mg]Br
Product: Cc1c[nH]c2c(Br)cccc12

Procedure:
2-Bromo nitrobenzene was reacted with allyl magnesium bromide according to the literature procedure (Dobbs A. J. Org Chem. 2001, 66, 638-641), to provide 7-bromo-3-methyl-1H-indole.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[C:11]([O:12][CH3:13])=[CH:10][CH:9]=[CH:8][C:7]=2/[CH:14]=[CH:15]/[C:16]2[N:17]=[C:18]3[S:25][CH:24]=[C:23]([CH3:26])[N:19]3[C:20](=[O:22])[CH:21]=2)[CH2:3][CH2:2]1.[I:27]N1C(=O)CCC1=O>C(#N)C>[CH:1]1([CH2:4][O:5][C:6]2[C:11]([O:12][CH3:13])=[CH:10][CH:9]=[CH:8][C:7]=2/[CH:14]=[CH:15]/[C:16]2[N:17]=[C:18]3[S:25][CH:24]=[C:23]([CH3:26])[N:19]3[C:20](=[O:22])[C:21]=2[I:27])[CH2:3][CH2:2]1
Reactant: COc1cccc(/C=C/c2cc(=O)n3c(C)csc3n2)c1OCC1CC1
Reactant: O=C1CCC(=O)N1I
Solvent: CC#N
Product: COc1cccc(/C=C/c2nc3scc(C)n3c(=O)c2I)c1OCC1CC1

Procedure:
To a solution of Step 3 intermediate (700 mg, 1.810 mmol) in acetonitrile (10 ml) was added N-iodosuccinimide (641 mg, 2.841 mmol) and reacted according to the procedure described in Step 4, Intermediate 2 to afford 600 mg of the desired compound; 1H NMR (300 MHz, CDCl3) δ 0.32-0.35 (m, 2H), 0.52-0.58 (m, 2H), 1.18-1.22 (m, 1H), 2.64 (s, 3H), 3.76-3.78 (m, 2H), 7.01-7.14 (m, 3H), 7.25-7.28 (m, 1H), 7.49 (d, J=15.6 Hz, 1H), 8.10-8.16 (d, J=15.9 Hz, 1H); ESI-MS (m/z) 494.99 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([Cl:8])[CH:5]=[C:4]([CH3:9])[N:3]=1.[Br:10]Br>ClCCl>[Br:10][C:5]1[C:6]([Cl:8])=[N:7][C:2]([NH2:1])=[N:3][C:4]=1[CH3:9]
Reactant: BrBr
Reactant: Cc1cc(Cl)nc(N)n1
Solvent: ClCCl
Product: Cc1nc(N)nc(Cl)c1Br
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 96.9 %

Procedure:
To a mixture of the 2-amino-4-chloro-6-methylpyrimidine (5.00 g, 34.8 mmol) in dichloromethane (240 mL) was added bromine (1.88 mL, 36.6 mmol). The resulting suspension was stirred at room temperature for 1.5 hours. The mixture was diluted with dichloromethane (1.3 L) and washed with saturated sodium bicarbonate (2×200 mL) and brine (200 mL), dried (MgSO4), filtered and concentrated to afford 5-bromo-4-chloro-6-methylpyrimidin-2-amine (7.5 g, 97%).
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([F:9])[CH:6]=[CH:7][CH:8]=1)[CH3:2].[N+:10]([O-])([OH:12])=[O:11]>>[N+:10]([C:8]1[CH:7]=[CH:6][C:5]([F:9])=[CH:4][C:3]=1[CH2:1][CH3:2])([O-:12])=[O:11]
Reactant: CCc1cccc(F)c1
Reactant: O=[N+]([O-])O
Product: CCc1cc(F)ccc1[N+](=O)[O-]

Procedure:
3-ethyl-fluorobenzene was reacted with nitric acid to obtain 4-nitro-3-ethyl-fluorobenzene which was reacted with N-hydroxy-phthalimide to form 0-(4-nitro-3-ethyl-phenoxy)-phthalimide which was reacted to form 0-(4-nitro-3-ethylphenyl)-hydroxylamine melting at 55°-56° C.
Reaction SMILES: [CH3:1][C:2]1[NH:6][CH:5]=[N:4][C:3]=1[CH2:7][CH:8]1[C:20](=[O:21])[N:12]2[C:13]3[C:18]([CH:19]=[C:11]2[CH2:10][CH2:9]1)=[CH:17][CH:16]=[CH:15][CH:14]=3.[H-].[Na+].[CH2:24](Cl)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>CN(C)C=O.O>[CH2:24]([N:6]1[C:2]([CH3:1])=[C:3]([CH2:7][CH:8]2[C:20](=[O:21])[N:12]3[C:13]4[C:18]([CH:19]=[C:11]3[CH2:10][CH2:9]2)=[CH:17][CH:16]=[CH:15][CH:14]=4)[N:4]=[CH:5]1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: Cc1[nH]cnc1CC1CCc2cc3ccccc3n2C1=O
Reactant: ClCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1c(CC2CCc3cc4ccccc4n3C2=O)ncn1Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 70.8 %

Procedure:
To a suspension of 8,9-dihydro-7-[(5-methyl-1H-imidazol-4-yl)methyl]pyrido[1,2-a]indol-6(7H)-one (500 mg) in N,N-dimethylformamide (5 ml) at room temperature was added sodium hydride (60% in mineral oil, 79 mg). After stirring at room temperature for 10 minutes and then at 5° C. for 5 minutes, the solution was treated with a solution of benzyl chloride (249 mg) in N,N-dimethylformamide (1 ml) at 5° C. The mixture was stirred at 5° C. for 10 minutes and then at room temperature for 2 hours. The reaction mixture was diluted with chilled water and extracted twice with chloroform. The chloroform layer was washed with water and brine, dried over anhydrous magnesium sulfate, and evaporated in vacuo. The oil obtained was purified by silica gel column chromatography (1% methanol-chloroform) to give 7-[(1-benzyl-5-methyl-1H-imidazol-4-yl)methyl]-8,9-dihydropyrido[1,2-a]indol-6(7H)-one (468 mg).