Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:10][CH:11]([C:16]2[CH:20]=[CH:19][S:18][CH:17]=2)[CH2:12][CH2:13][CH2:14][OH:15])[CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.I[N:41]1C(=[O:46])CC[C:42]1=O.CN.[C:50](=[O:53])([OH:52])[O-].[Na+]>O1CCCC1>[C:14]([OH:15])(=[O:46])[C:50]([OH:52])=[O:53].[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:10][CH:11]([C:16]2[CH:20]=[CH:19][S:18][CH:17]=2)[CH2:12][CH2:13][CH2:14][NH:41][CH3:42])[CH:3]=1
Reactant: N#Cc1ccc(Cl)cc1OC(CCCO)c1ccsc1
Reactant: O=C([O-])O
Reactant: O=C1CCC(=O)N1I
Agent: CN
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CNCCCC(Oc1cc(Cl)ccc1C#N)c1ccsc1
Product: O=C(O)C(=O)O
Temperature: 0 °C
Yield: 37 %

Procedure:
The product from step (d) (0.38 g, 1.23 mmol) was dissolved in anhydrous tetrahydrofuran (100 ml) and triphenylphosphine (1.062 g, 4.05 mmol) added. The solution was cooled to 0° C. and N-iodosuccinimide (0.912 g, 4.05 mmol) added. The reaction was allowed to warm to room temperature overnight, whilst stirring. Methylamine, as a 40% aqueous solution, (5 ml) was added and the reaction stirred for 24 h. Saturated aqueous sodium bicarbonate solution (40 ml) was added and the mixture extracted with ethyl acetate (3×70 ml). The combined extracts were washed with water (20 ml), dried (magnesium sulphate) and evaporated in vacuo. The residue was dissolved in methanol and applied to CC SCX resin. The resin was washed with methanol (200 ml) and the product liberated with 7N ammonia in methanol (100 ml). The solvent was removed in vacuo and the product converted into an oxalate salt and recrystallised from ethanol to give the title compound as a white solid (0.185 g, 37%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][CH:9]=1.[Cl:18][C:19]1[CH:20]=[C:21](B(O)O)[CH:22]=[CH:23][C:24]=1[O:25][CH3:26]>>[Cl:18][C:19]1[CH:20]=[C:21]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[C:8]2[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][CH:9]=2)[CH:22]=[CH:23][C:24]=1[O:25][CH3:26]
Reactant: CS(=O)(=O)c1ccc(-c2ccccc2Br)cc1
Reactant: COc1ccc(B(O)O)cc1Cl
Product: COc1ccc(-c2ccccc2-c2ccc(S(C)(=O)=O)cc2)cc1Cl
Yield: 68.3 %

Procedure:
Following the general procedure outlined in Synthetic Scheme VI, 4.0 g (13 mmol) of 1-bromo-2-[4-(methylsulfonyl)phenyl]benzene (Example 4, Step 2) was reacted with 2.86 g (15.4 mmol) of 3-chloro-4-methoxyphenylboronic acid (Step 2). Purification by silica gel chromatography (Waters PrepLC 500A) with ethyl acetate/hexane (35:65) and subsequent recrystallization from ethyl acetate/hexane gave 3.31 g (69%) of 2-chloro-1-methoxy-4-[2-[4-(methylsulfonyl)phenyl]phenyl]benzene as a colorless solid: mp 161.5°-162.3° C.; NMR (CDCl3) δ 3.05 (s, 3H), 3.88 (s, 3H), 6.75 (d, J=9 Hz, 1H), 6.87 (dd, J=1.5, 9 Hz, 1H), 7.17 (d, J=2 Hz, 1H), 7.34(d, J=9 Hz, 2H), 7.37-7.51 (m, 4H), 7.82 (d, J=8 Hz, 2H). MS (EI): m/e (rel intensity) 372 (100), 243 (24); HRMS Calc'd for C20H17ClO3S: 372.0587. Found: 372.0557. Anal. Calc'd for C20H17ClO3S: C, 64.43; H, 4.60; Cl, 9.51. Found: C, 64.17; H, 4.56; Cl, 9.63.
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[CH2:12][CH2:13][CH2:14][C:15]1([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1)=[CH:9][C:8]([O:26][CH3:27])=[CH:7][CH:6]=2.Br[CH2:29][CH2:30][O:31][C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([F:38])[C:33]=1[F:39].[I-].[K+].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[F:39][C:33]1[C:34]([F:38])=[CH:35][CH:36]=[CH:37][C:32]=1[O:31][CH2:30][CH2:29][N:18]1[CH2:19][CH2:20][C:15]([CH2:14][CH2:13][CH2:12][C:11]2[C:10]3[C:5](=[CH:6][CH:7]=[C:8]([O:26][CH3:27])[CH:9]=3)[N:4]=[CH:3][C:2]=2[F:1])([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:16][CH2:17]1
Reactant: CCOC(=O)C1(CCCc2c(F)cnc3ccc(OC)cc23)CCNCC1
Reactant: Fc1cccc(OCCBr)c1F
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)C1(CCCc2c(F)cnc3ccc(OC)cc23)CCN(CCOc2cccc(F)c2F)CC1
Temperature: 20 °C
Reaction time: 18 h
Yield: 75.9 %

Procedure:
A mixture of 0.4 g of ethyl 4-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]piperidine-4-carboxylate, 0.3 g of 1-(2-bromoethoxy)-2,3-difluorobenzene, 0.181 g of potassium iodide and 0.74 g of potassium carbonate in 15 cm3 of acetonitrile was stirred for 18 hours at a temperature in the region of .70° C. After cooling to about 20° C., the reaction mixture was concentrated to dryness under reduced pressure (5 kPa) at a temperature in the region of 40° C. The evaporation residue was purified by chromatography under atmospheric pressure, on a cartridge of silica gel (Bond Elut; particle size 70-200μ; mass 12 g), eluting with a mixture of ethyl acetate/40-60° C. petroleum ether (8/2 by volume). The fractions containing the product were combined and then concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40° C. 0.43 g of ethyl 1-[2-(2,3-difluorophenoxy)ethyl]-4-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]piperidine-4-carboxylate was obtained.
Reaction SMILES: C[O:2][C:3]([C:5]1[N:6]=[CH:7][C:8]2[C:9](=[O:27])[N:10]([CH2:16][C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][C:18]=3[O:25][CH3:26])[CH:11]=[CH:12][C:13]=2[C:14]=1[OH:15])=O.[CH3:28][NH2:29].O>CCO>[CH3:28][NH:29][C:3]([C:5]1[N:6]=[CH:7][C:8]2[C:9](=[O:27])[N:10]([CH2:16][C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][C:18]=3[O:25][CH3:26])[CH:11]=[CH:12][C:13]=2[C:14]=1[OH:15])=[O:2]
Reactant: COC(=O)c1ncc2c(=O)n(Cc3ccc(OC)cc3OC)ccc2c1O
Reactant: CN
Solvent: CCO
Solvent: O
Product: CNC(=O)c1ncc2c(=O)n(Cc3ccc(OC)cc3OC)ccc2c1O
Temperature: 80 °C

Procedure:
A mixture of 7-(2,4-dimethoxy-benzyl)-4-hydroxy-8-oxo-7,8-dihydro-[2,7]naphthyridine-3-carboxylic acid methyl ester (20 mg, 0.054 mmol) and methylamine (0.8 mL, 2M in THF) in EtOH (2 mL) was heated in a sealed tube at 80° C. for 16 h. After cooling the mixture to r.t., water (2 mL) was added. The resulting precipitate was isolated by filtration, washed with cold MeOH/H2O (5 mL, 1:1), and dried under vacuum to give 9 mg of the title compound. MS: (+) m/z 370.28 (M+1).
Reaction SMILES: [H-].[Na+].Cl.Cl.[NH2:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([NH2:12])=[NH:11])=[CH:8][CH:7]=1.CN(C)[CH:17]=[CH:18][C:19]([C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=1)[C:24]#[N:25])=O>C(O)C>[NH2:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]2[N:12]=[C:19]([C:21]3[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=3)[C:24]#[N:25])[CH:18]=[CH:17][N:11]=2)=[CH:8][CH:7]=1
Reactant: CN(C)C=CC(=O)c1cccc(C#N)c1
Reactant: N=C(N)c1ccc(N)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Product: N#Cc1cccc(-c2ccnc(-c3ccc(N)cc3)n2)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 55.8 %

Procedure:
Part A. A flask containing absolute ethanol (10 mL) is cooled to 0° C., and sodium hydride (42 mg, 60% w/w with mineral oil, 1.05 mmol) is added. After stirring for 0.5 h., the solution is treated with 4-aminobenzamidine dihydrochloride (104 mg, 0.50 mmol) and the mixture is allowed to stir for 5 min. Then, 3-(3-dimethylamino-acryloyl)-benzonitrile (100 mg, 0.50 mmol) is added, and the resulting mixture is heated to reflux for 3 h. then cooled to ambient temperature and stirred for 60 h. The mixture is evaporated, and the resulting mixture is triturated with diethyl ether and filtered. The filtrate is evaporated to afford a yellow oil, which is separated by column chromatography (1:1 ethyl acetate-hexane) to afford the product, 3-[2-(4-amino-phenyl)-pyrimidin-4-yl]-benzonitrile (76 mg, 56%). 1H NMR (300 MHz, CDCl3): δ 8.75 (1H, d, J=6 Hz), 8.49 (1H, t, J=2 Hz), 8.37-8.31 (3H, m), 7.75 (1H, dt, J=8, 2 Hz), 7.59 (1H, t, J=8 Hz), 7.40 (1H, d, J=6 Hz), 6.76 (2H, d, J=9 Hz), 4.03 (2H, br s). 13C NMR (CDCl3): δ 164.6, 160.8, 158.0, 149.2, 138.2, 133.6, 131.0, 130.7, 129.8 (2C), 129.5, 127.2, 118.5, 114.5 (2C), 113.0, 112.9. MS (ES+): m/e 274 (20), 273 (100).
Reaction SMILES: C(N[CH2:4][CH2:5][C:6]1[CH:11]=[N:10][CH:9]=[CH:8][N:7]=1)C.C([N:14]([CH2:17][CH3:18])CC)C.Cl[C:20]([O:22][CH2:23][CH3:24])=[O:21]>C1C=CC=CC=1>[CH2:23]([O:22][C:20]([CH2:18][CH2:17][NH:14][N:7]1[CH:8]=[CH:9][N:10]=[CH:11][CH:6]1[CH2:5][CH3:4])=[O:21])[CH3:24]
Reactant: CCOC(=O)Cl
Reactant: CCN(CC)CC
Reactant: CCNCCc1cnccn1
Solvent: c1ccccc1
Product: CCOC(=O)CCNN1C=CN=CC1CC

Procedure:
To a solution of 30.2 g (0.20 mole) of β-ethylaminoethylpyrazine in 240 ml of benzene and 56 ml (0.40 mole) of triethylamine was added dropwise over a period of 15 minutes 22.9 g (0.21 mole) of ethyl chloroformate. The mixture was refluxed for 1 hour. It was filtrated and the filtrate concentrated under vacuum. The residue was distilled to give 38.8 g of β-(N-ethoxycarbonylethylamino-ethylpyrazine, b.p. 100°-105° C. at 0.1 mm Hg.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([Cl:12])[CH:6]=[CH:5]2.[C:13]([Cu])#[N:14].CN(C=O)C>C(Cl)Cl>[Cl:12][C:7]1[CH:6]=[CH:5][C:4]2[C:9](=[CH:10][CH:11]=[C:2]([C:13]#[N:14])[CH:3]=2)[N:8]=1
Reactant: Clc1ccc2cc(Br)ccc2n1
Reactant: N#C[Cu]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: N#Cc1ccc2nc(Cl)ccc2c1
Temperature: 150 °C

Procedure:
To a flask containing a stir bar was added 6-bromo-2-chloroquinoline (0.90 g, 3.7 mmol), CuCN (0.50 g, 5.6 mmol) followed by addition of DMF (10 mL). The resulting mixture was then refluxed at 150° C. overnight. When the reaction appeared complete by LC analysis, the reaction flask was taken out of the oil bath and cooled to room temperature. To the reaction mixture was then poured DCM (20 mL) and a precipitate formed immediately, which was filtered, redissolved in DCM, absorbed onto silica gel, and purified by flash chromatography to provide the title product.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[C:13]2[C:12]([CH3:14])=[C:11]([CH3:15])[N:10]=[C:9]([NH2:16])[C:8]=2[N:7]=[C:6]1[CH2:17][O:18][CH2:19][CH3:20].[C:21](Cl)(=[O:25])[CH:22]([CH3:24])[CH3:23]>>[NH2:16][C:9]1[C:8]2[N:7]=[C:6]([CH2:17][O:18][CH2:19][CH3:20])[N:5]([CH2:4][CH2:3][CH2:2][NH:1][C:21](=[O:25])[CH:22]([CH3:24])[CH3:23])[C:13]=2[C:12]([CH3:14])=[C:11]([CH3:15])[N:10]=1
Reactant: CC(C)C(=O)Cl
Reactant: CCOCc1nc2c(N)nc(C)c(C)c2n1CCCN
Product: CCOCc1nc2c(N)nc(C)c(C)c2n1CCCNC(=O)C(C)C
Yield: 59.2 %

Procedure:
Using the method of Example 19, 1-(3-aminopropyl)-2-(ethoxymethyl)-6,7-dimethyl-1H-imidazo[4,5-c]pyridin-4-amine (1.00 g, 3.6 mmol) was reacted with isobutyryl chloride (0.42 mL, 40 mmol) to provide 0.74 g of N-{3-[4-amino-2-(ethoxymethyl)-6,7-dimethyl-1H-imidazo[4,5-c]pyridin-1-yl]propyl}-2-methylpropanamide as an off white solid, m.p. 179.1–179.7° C.
Reaction SMILES: [NH:1]1[CH2:7][CH2:6][CH2:5][C@@H:2]1[CH2:3][OH:4].N[CH2:9][C@@H:10]1CC[CH2:12][N:11]1CC.C(=O)C>>[CH3:12][NH:11][CH2:10][CH2:9][N:1]1[CH2:7][CH2:6][CH2:5][C@@H:2]1[CH2:3][OH:4]
Reactant: CCN1CCC[C@H]1CN
Reactant: OC[C@H]1CCCN1
Agent: CC=O
Product: CNCCN1CCC[C@@H]1CO

Procedure:
By using D-prolinol (500 mg) as a starting material, the title compound (0.17 g) was obtained in the same manners as those of Reference Example 1, (1) and Reference Example 39, (2).
Reaction SMILES: ClC1C=NC=C(Cl)C=1CO.[Cl:11][C:12]1[C:17]([CH:18]=[O:19])=[C:16]([S:20][C:21]2[S:22][CH:23]=[CH:24][N:25]=2)[CH:15]=[CH:14][N:13]=1>>[Cl:11][C:12]1[C:17]([CH2:18][OH:19])=[C:16]([S:20][C:21]2[S:22][CH:23]=[CH:24][N:25]=2)[CH:15]=[CH:14][N:13]=1
Reactant: O=Cc1c(Sc2nccs2)ccnc1Cl
Agent: OCc1c(Cl)cncc1Cl
Product: OCc1c(Sc2nccs2)ccnc1Cl

Procedure:
The aldehyde group in 2-chloro-4-(thiazol-2-ylsulfanyl)-pyridine-3-carbaldehyde was reduced as described for the synthesis of (3,5-dichloro-pyridin-4-yl)-methanol to give the title compound which was used in the following step without further purification. MS (m/z): 259.2 [M+H+].
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[CH:5][N:6]=1.[Cl:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10](Cl)[N:9]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C1(C)C=CC=CC=1>C(OCC)(=O)C>[Cl:7][C:8]1[N:9]=[C:10]([NH:1][C:2]2[S:3][CH:4]=[CH:5][N:6]=2)[CH:11]=[CH:12][CH:13]=1
Reactant: Clc1cccc(Cl)n1
Reactant: Nc1nccs1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: Clc1cccc(Nc2nccs2)n1
Temperature: 25 °C
Yield: 63.3 %

Procedure:
A mixture of 1.37 g (9.26 mmol) of 2-aminothiazole, 0.74 g (7.39 mmol) of 2,6-dichloropyridine, 387 mg (0.621 mmol) of (S)-(−)-2,2′-(bisdiphenylphosphino)-1,1′-binaphthyl, 322 mg (0.311 mmol) of tris(dibenzylideneacetone)dipalladium(0)-chloroform complex, 2.77 g (8.50 mmol) of cesium carbonate and 10 ml of toluene was heated under reflux for 1 hour and 30 minutes, cooled to room temperature and diluted with ethyl acetate. An insoluble matter was filtered off using Celite and the resulting ethyl acetate solution was washed with water and brine. The organic layer was dried over anhydrous magnesium sulfate and filtered, and the filtrate was concentrated. The residue was purified by a silica gel column chromatography to give 990 mg (4.68 mmol) of the title compound as a white solid.
Reaction SMILES: [CH:1]([N:14]1[CH2:17][CH2:16][CH:15]1[CH:18]([NH2:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH3:28]I>CN(C)C=O>[CH:1]([N:14]1[CH2:17][CH2:16][CH:15]1[CH:18]([NH:25][CH3:28])[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CI
Reactant: NC(c1ccccc1)C1CCN1C(c1ccccc1)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CNC(c1ccccc1)C1CCN1C(c1ccccc1)c1ccccc1
Temperature: -25 °C
Reaction time: 0.25 h

Procedure:
To a stirred solution of 2.50 g of 1-benzhydryl-2-(α-aminobenzyl)azetidine in 25 ml. of N,N-dimethylformamide, add 365 mg. of a 55% dispension of sodium hydride. Stir the mixture under a nitrogen atmosphere and when frothing subsides, warm and maintain the stirred mixture at 40° for twenty minutes. Cool the mixture to -25° C. and add 1.20 g. of methyl iodide. Remove the reaction mixture from the cooling bath and allow it to warm to room temperature. After ca. 15 minutes at room temperature, pour the contents of the reaction flask into a stirred mixture of 100 ml. of water and 25 ml. of ether. Separate the layers and re-extract the aqueous phase with ether. Combine all ether extracts, wash successively with water and brine, dry over anhydrous sodium sulfate, and strip off solvent in vacuo. Crystallize the residual solid from ether to obtain the analytically pure title compound containing 1/4 mole of water-of-crystallization and having m.p. 111°-113°.
Reaction SMILES: [C:1]([S:20][CH2:21][C@@H:22]([C:24]([NH2:26])=[O:25])[NH2:23])([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:34][O:35][C:36]1[CH:41]=[CH:40][C:39]([C:42]2[CH:47]=[CH:46][C:45]([S:48](Cl)(=[O:50])=[O:49])=[CH:44][CH:43]=2)=[CH:38][CH:37]=1>C(Cl)Cl>[CH3:34][O:35][C:36]1[CH:37]=[CH:38][C:39]([C:42]2[CH:47]=[CH:46][C:45]([S:48]([NH:23][C@H:22]([C:24]([NH2:26])=[O:25])[CH2:21][S:20][C:1]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)(=[O:50])=[O:49])=[CH:44][CH:43]=2)=[CH:40][CH:41]=1
Reactant: NC(=O)[C@@H](N)CSC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COc1ccc(-c2ccc(S(=O)(=O)Cl)cc2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(-c2ccc(S(=O)(=O)N[C@@H](CSC(c3ccccc3)(c3ccccc3)c3ccccc3)C(N)=O)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Part C: To a solution of 2.93 grams (8.1 mmol) of S-trityl-L-cysteine amide in 50 mL of dry methylene chloride was added 2 equivalents of triethylamine followed by 2.29 grams (8.1 mmol) of 4-(4′-methoxyphenyl)phenylsulfonyl chloride. The solution was stirred at room temperature for one hour, then concentrated on a rotory evaporator. The resulting slurry was partitioned between ethyl acetate and water. The organics were washed with 5% potassium hydrogen sulfate, saturated sodium bicarbonate, and brine, dried over sodium sulfate, filtered and concentrated to give 4.2 grams of crude product. The crude material was purified by silica gel chromatography using 1:1 ethyl acetate:hexane as the eluent to yield 3.36 grams of pure N-(4-(4′methoxyphenyl)-benzenesulfonyl-S-trityl-L-cysteine amide as a white solid.
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[OH:11])([CH3:4])[CH3:3].[OH-:12].[Na+].[CH:14](Cl)(Cl)Cl.Cl>CO.O>[CH3:4][C:2]([C:5]1[CH:10]=[C:9]([CH:8]=[CH:7][C:6]=1[OH:11])[CH:14]=[O:12])([CH3:1])[CH3:3]
Reactant: [OH-]
Reactant: CC(C)(C)c1ccccc1O
Reactant: ClC(Cl)Cl
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CC(C)(C)c1cc(C=O)ccc1O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
2-(1,1-dimethylethyl)phenol (10 g, 66.67 mmol) was dissolved in 40 mL of MeOH and NaOH (40 g, 1 mol) dissolved in 40 mL of water was added dropwise. Then 40 mL of CHCl3 was added (during the course of 1 h) at 60° C. The reaction mixture was stirred at that temperature for 3 h. After cooling down to r.t., the mixture was cooled to 0° C. and 4M HCl was added until the solution reached pH 5-6. The mixture was extracted with DCM (three times) and the collected organic were dried over Na2SO4, filtered and evaporated. The crude was charged on a silica gel column and eluted with Cyclohexane/EtOAc (from 100:0 to 80:20 Cyclohexane/EtOAc, then plateau at 80:20) affording 766 mg of the of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4](I)[CH:3]=1.[C:9]1([C:15]#[CH:16])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(NC(C)C)(C)C>C1(C)C=CC=CC=1.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.[Cu]I>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:16]#[C:15][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:3]=1
Reactant: Brc1cccc(I)c1
Reactant: C#Cc1ccccc1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CC(C)NC(C)C
Solvent: Cc1ccccc1
Product: Brc1cccc(C#Cc2ccccc2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1-bromo-3-iodobenzene (15.3 g, 54.0 mmol), phenylacetylene (5 g, 49.0 mmol), tetrakis(triphenylphosphine)palladium (2.8 g, 2.4 mmol) and copper(I) iodide (0.46 g, 2.4 mmol) were dissolved in dry toluene and diisopropylamine (35 mL, 196 mmol) under a nitrogen atmosphere. The reaction was stirred at room temperature overnight. The mixture was extracted with ethyl acetate and the organic layer was dried in vacuo to give the title compound as a residue that was used without further purification.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[F:9].N#N.[CH2:12]([OH:14])[CH3:13].[Li][CH:16](CC)C.C1CCCCC1.B(F)(F)F.C(OCC)C>C1COCC1>[F:9][C:3]1[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=1[CH2:13][C@H:12]([OH:14])[CH3:16]
Reactant: [Li]C(C)CC
Reactant: CCO
Reactant: Fc1ccc(F)c(Br)c1
Agent: FB(F)F
Agent: N#N
Solvent: CCOCC
Solvent: C1CCCCC1
Solvent: C1CCOC1
Product: C[C@@H](O)Cc1cc(F)ccc1F
Temperature: -105 °C
Reaction time: 2 h
Yield: 62.5 %

Procedure:
A solution of 2-bromo-1,4-difluorobenzene (3.85 g, 20.0 mmol) in anhydrous THF (100 mL) was stirred to −100° C. (liq. nitrogen/ethanol) under argon gas. Then, 1.6 M solution of sec-BuLi in cyclohexane (14.3 mL, 21.0 mmol) was added dropwise at −100° C.˜−90° C. for 10 min, then a solution of R-(+)-propylene (1.14 g, 1.4 mL, 26.0 mmol) in anhydrous THF (15 mL) was added dropwise at −100° C.˜−90° C. for 2 h, then the mixture was cooled to −105° C. and a 46.5% solution of BF3 in diethyl ether (4.18 mL, 30 mmol) was added dropwise. The mixture was stirred at −100° C. to −90° C. for 2 h, then the reaction was quenched with 20 mL of sat. aq. NH4Cl at −90° C. The mixture was stirred and warmed to 0° C. overnight. Then, 20 mL of water was added and extracted with EtOAc (2×60 mL), dried over anhydrous MgSO4, evaporated to give crude oil, which was purified by column chromatograpy (silicagel, EtOAc/hexane=1:9, v/v) to give (R)-1-(2,5-difluorophenyl)propan-2-ol (2.15 g, 62.5%). 1H NMR (CDCl3, 500 MHz) δ 6.98 (m, 2H), 6.88 (m, 1H), 4.10 (m, 1H), 4.03 (bs, OH), 2.79 (m, 1H), 2.71 (m, 1H), 1.23 (s, 3H).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][C:5](Cl)=O.[NH2:8][C:9]1[CH:10]=[N:11][C:12]2[C:17]([C:18]=1[NH:19][CH2:20][CH2:21][CH2:22][CH2:23][NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[CH:16][CH:15]=[CH:14][CH:13]=2.Cl.N1C=CC=CC=1>N1C=CC=CC=1>[CH3:1][O:2][CH2:3][CH2:4][C:5]1[N:19]([CH2:20][CH2:21][CH2:22][CH2:23][NH:24][C:25](=[O:31])[O:26][C:27]([CH3:29])([CH3:28])[CH3:30])[C:18]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]=[CH:10][C:9]=2[N:8]=1
Reactant: CC(C)(C)OC(=O)NCCCCNc1c(N)cnc2ccccc12
Reactant: COCCC(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Product: COCCc1nc2cnc3ccccc3c2n1CCCCNC(=O)OC(C)(C)C
Reaction time: 4 h

Procedure:
3-Methoxypropionyl chloride (15.4 g, 126 mmol) was added dropwise over a period of 20 minutes to a chilled (ice bath) solution of tert-butyl N-{4-[(3-aminoquinolin-4-yl)amino]butyl}carbamate (38 g, 115 mmol, U.S. Pat. No. 6,541,485, Example 2, Part B) in pyridine. The reaction mixture was stirred for 4 hours and then allowed to stand at ambient temperature over the weekend. Pyridine hydrochloride (3.9 g, 34 mmol) was added and the reaction mixture was heated at reflux overnight. The reaction mixture was concentrated under reduced pressure and the residue was diluted with dichloromethane (250 mL) and aqueous sodium bicarbonate (250 mL). The layers were separated. The separatory funnel was rinsed with a small amount of methanol to remove a residue coating the walls. The combined organics were concentrated under reduced pressure. The residue was purified by prep HPLC (COMBIFLASH system eluting first with a gradient of 0 to 5% methanol in dichloromethane containing 1% ammonium hydroxide and then with a gradient of 5 to 10% methanol in dichloromethane containing 1% ammonium hydroxide) to provide 18 g of tert-butyl N-{4-[2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]butyl}carbamate.
Reaction SMILES: [C:1]([N:3]1[C:11]2[CH:10]=[CH:9][C:8]([CH3:12])=[CH:7][C:6]=2[C:5]2[CH2:13][N:14]([CH3:17])[CH2:15][CH2:16][C:4]1=2)#[CH:2].Cl.Br[C:20]1[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-:43].C(=O)(O)[O-]>O>[F:43]/[C:2](/[C:20]1[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=1)=[CH:1]\[N:3]1[C:11]2[CH:10]=[CH:9][C:8]([CH3:12])=[CH:7][C:6]=2[C:5]2[CH2:13][N:14]([CH3:17])[CH2:15][CH2:16][C:4]1=2
Reactant: [F-]
Reactant: C#Cn1c2c(c3cc(C)ccc31)CN(C)CC2
Reactant: Brc1ccncc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: O=C([O-])O
Solvent: O
Product: Cc1ccc2c(c1)c1c(n2/C=C(\F)c2ccncc2)CCN(C)C1
Temperature: 140 °C

Procedure:
A mixture of 5-ethynyl-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (138 mg, 0.6 mmol), 4-bromopyridinehydrochloride (100 mg, 0.51 mmol), dichlorobistriphenylphosphine palladium (II) (10 mg, 0.015 mmol) and TBAF.3H2O (481 mg, 1.5 mmol) was added and heated at 80° C. (exothermicity observed; temperature 140° C.) for 5 min in microwave. After completion of reaction (as monitored by TLC & LCMS) reaction mixture was poured into water (20 mL) and saturated bicarbonate solution was added. The desired compound was extracted with EtOAc (3×20 mL) and the organic layer washed with water (2×20 mL), dried over sodium sulfate and concentrated under vacuum to obtain crude product that was purified by reverse phase HPLC. 1H NMR (CD3OD, TFA salt) δ (ppm): 8.78 (d, 2H), 8.18 (d, 2H), 7.62 (d, 1H), 7.40 (s, 1H), 7.28 (d, 1H), 6.42 (d, 1H), 4.75 (m, 1H), 4.40 (m, 1H), 3.90 (m, 1H), 3.60 (m, 1H), 3.40 (m, 2H), 3.18 (s, 3H), 2.44 (s, 3H).