Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.[NH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>[OH-].[Na+]>[C:13]1([NH:12][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=[CH:4][CH:3]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Nc1ccccc1
Reactant: Clc1ccnc2ccccc12
Agent: [Na+]
Agent: [OH-]
Product: c1ccc(Nc2ccnc3ccccc23)cc1
Temperature: 150 °C
Yield: 101.8 %

Procedure:
A mixture of 4-chloroquinoline (10 g) and aniline (11.4 g) was warmed to 150° C. for 30 min. A solution of sodium hydroxide 1 N (200 ml) was added. After extraction with ethyl acetate (1 L), the organic layer was separated and dried over sodium sulfate. The solvent was removed to afford an amorphous materiel, which was crystallized in cyclohexane. Phenyl-quinolin-4-yl-amine (13.7 g) was obtained after filtration.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]2[N:5]([N:9]=[C:10]([C:12]3([CH2:15][NH2:16])[CH2:14][CH2:13]3)[N:11]=2)[CH:6]=[CH:7][CH:8]=1.CCN(CC)CC.Cl[C:25]([O:27][CH:28]1[CH2:32][CH2:31][CH2:30][CH2:29]1)=[O:26].C([O-])(O)=O.[Na+]>C1COCC1.O>[CH:28]1([O:27][C:25](=[O:26])[NH:16][CH2:15][C:12]2([C:10]3[N:11]=[C:4]4[C:3]([O:2][CH3:1])=[CH:8][CH:7]=[CH:6][N:5]4[N:9]=3)[CH2:14][CH2:13]2)[CH2:32][CH2:31][CH2:30][CH2:29]1
Reactant: COc1cccn2nc(C3(CN)CC3)nc12
Reactant: O=C(Cl)OC1CCCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: COc1cccn2nc(C3(CNC(=O)OC4CCCC4)CC3)nc12
Reaction time: 24 h

Procedure:
Under an argon atmosphere C-[1-(8-Methoxy-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-cyclopropyl]-methylamine (0.063 g, 0.29 mmol) was dissolved in THF (1 mL) and Et3N (0.06 mL, 0.43 mmol). Cyclopentyl chloroformate (0.053 g, 036 mmol) was added. Stirring was performed at RT for 24 h. Aq. NaHCO3 and H2O were added. The aqueous phase was extracted with DCM (×3). The combined organic phases were dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by flash chromatography using toluene:EtOAc 2:1->1:1 as the eluent to afford [1-(8-Methoxy-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-cyclopropylmethyl]-carbamic acid cyclopentyl ester.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([O:20][CH3:21])[N:13]=2)[C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[N:7]=1.[NH:22]1[CH2:26][CH2:25][CH:24]([NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[CH2:23]1>>[CH3:19][O:18][C:15]1[CH:16]=[CH:17][C:12]([NH:11][C:4]2[C:5]3[N:6]([CH:8]=[CH:9][N:10]=3)[N:7]=[C:2]([N:22]3[CH2:26][CH2:25][CH:24]([NH:27][C:28](=[O:34])[O:29][C:30]([CH3:32])([CH3:31])[CH3:33])[CH2:23]3)[CH:3]=2)=[N:13][C:14]=1[O:20][CH3:21]
Reactant: COc1ccc(Nc2cc(Cl)nn3ccnc23)nc1OC
Reactant: CC(C)(C)OC(=O)NC1CCNC1
Product: COc1ccc(Nc2cc(N3CCC(NC(=O)OC(C)(C)C)C3)nn3ccnc23)nc1OC
Temperature: 160 °C
Yield: 8.1 %

Procedure:
A suspension of 6-chloro-N-(5,6-dimethoxypyridin-2-yl)imidazo[1,2-b]pyridazin-8-amine (1.5 g, 4.9 mmol) and tert-butyl pyrrolidin-3-ylcarbamate (3 g, 16 mmol) was heated to 160° C. for 2 h. The residue was purified by chromatography (silica gel, 200-300 mesh, dichloromethane:MeOH=30:1) to give tert-butyl 1-(8-(5,6-dimethoxypyridin-2-ylamino)imidazo[1,2-b]pyridazin-6-yl)pyrrolidin-3-ylcarbamate (180 mg, 8%) as off-white solid. LC-MS: 456 [M+1]+, tR=1.396 min
Reaction SMILES: [CH2:1]([OH:5])[CH2:2][CH2:3][OH:4].[H-].[Na+].[C:8]([Si:12]([CH3:15])([CH3:14])Cl)([CH3:11])([CH3:10])[CH3:9]>C1COCC1>[CH3:14][Si:12]([CH3:15])([C:8]([CH3:11])([CH3:10])[CH3:9])[O:4][CH2:3][CH2:2][CH2:1][OH:5]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OCCCO
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OCCCO
Reaction time: 16 h

Procedure:
To a stirred solution of 1,3-propanediol (4.8 mL, 66 mmol) in THF (100 mL) was added sodium hydride (60% dispersion in mineral oil, 2.6 g, 66 mmol) followed by tert-butyldimethyl chlorosilane. The solution was allowed to stir for 16 h, and concentrated to an oily residue. Purification by chromatography (40% ethyl acetate in hexanes) afforded title compound (12.3 g). MS (M+H): 191.
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[NH:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].Br[C:21]1[N:26]=[C:25]([C:27]#[N:28])[CH:24]=[CH:23][CH:22]=1>>[C:1]([O:5][C:6](=[O:17])[NH:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:21]2[CH:22]=[CH:23][CH:24]=[C:25]([C:27]#[N:28])[N:26]=2)=[CH:12][CH:11]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCCc1ccc(O)cc1
Reactant: N#Cc1cccc(Br)n1
Agent: [H-]
Agent: [Na+]
Product: CC(C)(C)OC(=O)NCCc1ccc(Oc2cccc(C#N)n2)cc1
Yield: 45.1 %

Procedure:
Using a method similar to Example 381 Part A, using [2-(4-hydroxyphenyl)ethyl]carbamic acid tert-butyl ester (0.140 g, 0.588 mmol), NaH (80% in mineral oil) (0.194 g, 0.647 mmol) and 6-bromopyridine-2-carbonitrile (0.107 g, 0.588 minor) gives the title compound (0.0895 g, 44.8%): MS ES+ 340.2 (M+H)+, base peak MS ES+ 284.0 (M+2H—C(CH3)3)+, MS ES− 338.3 (M−H)−, TLC [silica gel 60 F254, 40% ethyl acetate in hexanes] Rf=0.24.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[C:9](=[O:11])[N:8]([C@H:12]([C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([O:26][CH2:27][CH3:28])[CH:19]=1)[CH2:13][S:14]([CH3:17])(=[O:16])=[O:15])[CH2:7]2.[CH:29]1([C:32](Cl)=[O:33])[CH2:31][CH2:30]1>O1CCCC1>[CH:29]1([C:32]([NH:1][C:2]2[CH:3]=[CH:4][CH:5]=[C:6]3[C:10]=2[C:9](=[O:11])[N:8]([C@H:12]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([O:26][CH2:27][CH3:28])[CH:19]=2)[CH2:13][S:14]([CH3:17])(=[O:15])=[O:16])[CH2:7]3)=[O:33])[CH2:31][CH2:30]1
Reactant: O=C(Cl)C1CC1
Reactant: CCOc1cc([C@H](CS(C)(=O)=O)N2Cc3cccc(N)c3C2=O)ccc1OC
Solvent: C1CCOC1
Product: CCOc1cc([C@H](CS(C)(=O)=O)N2Cc3cccc(NC(=O)C4CC4)c3C2=O)ccc1OC
Yield: 58.7 %

Procedure:
A stirred mixture of 7-amino-2-[(1R)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]isoindolin-1-one (0.91 g, 2.2 mmol) and cyclopropane carbonyl chloride (0.25 mL, 2.8 mmol) in tetrahydrofuran (10 mL) was heated to reflux for 15 min. The solvent was removed in vacuo to give a solid. The solid was recrystallized from ethanol (10 mL) to give cyclopropyl-N-{2-[(1R)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-3-oxoisoindolin-4-yl}carboxamide as an off-white solid (0.61 g, 56% yield); mp, 173-175° C.; 1H NMR (CDCl3) δ0.86-0.93 (m, 2H, 2CHH), 1.07-1.14 (m, 2H, 2CHH), 1.46 (t, J=6.9 Hz, 3H, CH3), 1.63-1.73 (m, 1H, CH), 2.95 (s, 3H, CH3), 3.68 (dd, J=4.4, 14.3 Hz, 1H, CHH), 3.86 (s, 3H, CH3), 4.07 (q, J=7.1 Hz, 2H, CH2), 4.20 (d, J=16.7 Hz, 1H, CHH), 4.21 (dd, J=9.9, 14.3 Hz, 1H, CHH), 4.44 (d, J=16.7 Hz,1H, CHH), 5.73 (dd, J=4.3, 9.9 Hz, 1H, NCH), 6.84-7.02 (m, 4H, Ar), 7.44 (t, J=7.8 Hz, 1H, Ar), 8.43 (d, J=8.3 Hz, 1H, Ar), 10.46 (s, 1H, NH); 13C NMR (CDCl3) δ8.24, 14.61, 16.10, 41.43, 47.81, 51.55, 55.75, 55.88, 64.56, 111.46, 112.09, 116.69, 116.99, 117.76, 119.17, 129.27, 133.54, 138.06, 141.22, 148.84, 149.67, 169.96, 172.59; Anal Calcd for C24H28N2O6S: C, 61.00; H, 5.97; N, 5.93. Found: C, 60.73; H, 5.91; N, 5.69.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:5]=1[OH:13])C.[H-].[Na+].[CH2:16](I)[CH3:17]>CN(C=O)C>[CH2:16]([O:13][C:5]1[CH:6]=[C:7]([N+:10]([O-:12])=[O:11])[CH:8]=[CH:9][C:4]=1[O:3][CH3:1])[CH3:17]
Reactant: CCI
Reactant: CCOc1ccc([N+](=O)[O-])cc1O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOc1cc([N+](=O)[O-])ccc1OC
Reaction time: 0.5 h
Yield: 84.2 %

Procedure:
Under an inert atmosphere at 0° C., add a solution of 10 g (59 mmol) of 2-ethoxy-5-nitrophenol dissolved in 125 ml of DMF, on a solution of 2.6 g (65 mmol) of 60% NaH in oil dissolved in 125 ml of DMF. After 30 minutes at room temperature, add dropwise 5.2 ml (65 mmol) of EtI at 0° C. Allow to stand at room temperature for 12 hours. Add 1.5 l of a water-ice mixture. Filter the precipitate and wash three times with 100 ml of water then once with 100 ml of pentane. One obtains 9.8 g of the abovenamed product in the form of a white powder. Yield: 93%. 1H-NMR (CDCl3, 300 MHz): d 1.52 (t, 3H, —CH3), 3.98 (s, 3H, OCH3), 4.20 (q, 2H, OCH2), 6.91 (d, 1H Ar), 7.75 (d, 1H Ar), 7.91 (dd,1H Ar).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([O:8][C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[NH:14][CH:13]=[CH:12]3)[CH:5]=[CH:4][N:3]=1.[BH3-]C#N.[Na+].[OH-].[Na+]>C(O)(=O)C>[NH2:1][C:2]1[N:7]=[C:6]([O:8][C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[NH:14][CH2:13][CH2:12]3)[CH:5]=[CH:4][N:3]=1
Reactant: Nc1nccc(Oc2ccc3[nH]ccc3c2)n1
Agent: [BH3-]C#N
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: Nc1nccc(Oc2ccc3c(c2)CCN3)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 160 mg (0.70 mMol) of 5-(2-amino-pyrimidin-4-yloxy)-1H-indole in 4 ml acetic acid is cooled to 10-15° C. Then 222 mg (3.5 mMol) NaBH3CN are added. After 1 h stirring at rt, 8 g of ice are added. Then the mixture is made basic by addition of 1 N NaOH and extracted three times with EtOAc. The organic layers are washed with water and brine, dried (Na2SO4) and concentrated at rt in vacuo: MS: [M+1]+=229.
Reaction SMILES: [C:1]([NH:4][NH:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=2)[N:7]=1)(=O)[CH3:2].P(Cl)(Cl)(Cl)=[O:23].C(=O)(O)[O-].[Na+]>>[F:19][C:18]([F:21])([F:20])[C:14]1[CH:15]=[CH:16][CH:17]=[C:12]([C:8]([NH:9][CH:10]=[CH:11][C:6]2[N:7]=[C:1]([CH3:2])[NH:4][N:5]=2)=[O:23])[CH:13]=1
Reactant: CC(=O)NNc1ccnc(-c2cccc(C(F)(F)F)c2)n1
Reactant: O=P(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1nc(C=CNC(=O)c2cccc(C(F)(F)F)c2)n[nH]1

Procedure:
A mixture of 1-acetyl-2-[2-(3-trifluoromethylphenyl)pyrimidin-4-yl]hydrazine and 15 ml. of phosphorus oxychloride is heated at the reflux temperature for about 20 hours. The cooled reaction mixture is poured over ice, the aqueous mixture neutralized with saturated sodium bicarbonate solution and the product collected. It is then taken up in ether, the ether dried and then evaporated to a solid residue. This residue is triturated with hexane and the precipitate collected. Recrystallization from chloroform/methanol then gives the product of the example, m.p. 153°-154° C.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[C:7](Cl)(=[O:16])[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[CH3:18][C:19]1[CH:33]=[CH:32][C:22]([C:23]([N:25]2[CH2:30][CH2:29][CH2:28][C@@H:27]([NH2:31])[CH2:26]2)=[O:24])=[CH:21][CH:20]=1.[Cl-].[Na+]>ClC1C=CC=CC=1>[CH3:18][C:19]1[CH:20]=[CH:21][C:22]([C:23]([N:25]2[CH2:30][CH2:29][CH2:28][C@@H:27]([NH:31][C:7]([O:8][CH2:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)=[O:16])[CH2:26]2)=[O:24])=[CH:32][CH:33]=1
Reactant: Cc1ccc(C(=O)N2CCC[C@@H](N)C2)cc1
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: Clc1ccccc1
Product: Cc1ccc(C(=O)N2CCC[C@@H](NC(=O)OCc3ccccc3)C2)cc1
Temperature: 15 °C
Reaction time: 3 h
Yield: 96.8 %

Procedure:
Potassium carbonate (0.15 g) and benzyl chlorocarbonate (0.18 g) were added to the aqueous solution of (R)-1-(p-methylbenzoyl)-3-aminopiperidine obtained in Example 13 (amount: 3 g). The mixture was stirred at 15° C. for 3 hours, and chlorobenzene (3 ml) and sodium chloride (0.5 g) were added. The mixture was stirred at 90° C. for 10 minutes. The water layer was removed, and the solvent was evaporated under reduced pressure to obtain the title compound as yellow oil (0.36 g, yield: 73%).
Reaction SMILES: [C:1]1([C:7]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[N:8][NH:9][C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:23][C:24]1[CH:32]=[CH:31][CH:30]=[CH:29][C:25]=1[CH2:26][CH2:27]Br>>[C:17]1([C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[N:8][N:9]([CH2:27][CH2:26][C:25]2[CH:29]=[CH:30][CH:31]=[CH:32][C:24]=2[CH3:23])[C:10]2[CH:11]=[CH:12][C:13]([CH3:16])=[CH:14][CH:15]=2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: Cc1ccc(NN=C(c2ccccc2)c2ccccc2)cc1
Reactant: Cc1ccccc1CCBr
Product: Cc1ccc(N(CCc2ccccc2C)N=C(c2ccccc2)c2ccccc2)cc1

Procedure:
General procedure B was used to convert 1-(diphenylmethylene)-2-p-tolylhydrazine (200 mg, 0.69 mmol; Example 36A) and 2-methylphenethylbromide (278 mg, 1.4 mmol; Aldrich) to the title compound: MS (DCI/NH3) m/z 404 (M+H)+.
Reaction SMILES: [CH2:1]1[CH:5]2[CH2:6][NH:7][CH2:8][CH:4]2[CH2:3][N:2]1[C:9]1[CH:18]=[N:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=1.[S:19]1[CH:23]=[CH:22][CH:21]=[C:20]1[C:24]1[CH:32]=[CH:31][CH:30]=[CH:29][C:25]=1[C:26](O)=[O:27]>>[S:19]1[CH:23]=[CH:22][CH:21]=[C:20]1[C:24]1[CH:32]=[CH:31][CH:30]=[CH:29][C:25]=1[C:26]([N:7]1[CH2:6][CH:5]2[CH2:1][N:2]([C:9]3[CH:18]=[N:17][C:16]4[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=4)[N:10]=3)[CH2:3][CH:4]2[CH2:8]1)=[O:27]
Reactant: c1ccc2nc(N3CC4CNCC4C3)cnc2c1
Reactant: O=C(O)c1ccccc1-c1cccs1
Product: O=C(c1ccccc1-c1cccs1)N1CC2CN(c3cnc4ccccc4n3)CC2C1

Procedure:
The title compound was prepared in a manner analogous to Example 15 utilizing Intermediate 35 and 2-thiophen-2-yl-benzoic acid. MS (ESI) mass calcd. for C25H22N4OS, 426.54; m/z found, 427.2 [M+H]+.
Reaction SMILES: [N:1]1[C:2]([C:10]([OH:12])=O)=[CH:3][N:4]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=12.[NH2:13][C@@H:14]([CH3:31])[CH2:15][N:16]1[CH:20]=[CH:19][C:18]([C:21]2[CH:28]=[C:27]([F:29])[C:24]([C:25]#[N:26])=[C:23]([Cl:30])[CH:22]=2)=[N:17]1.CN(C=O)C>O>[Cl:30][C:23]1[CH:22]=[C:21]([C:18]2[CH:19]=[CH:20][N:16]([CH2:15][C@@H:14]([NH:13][C:10]([C:2]3[N:1]=[C:5]4[CH2:6][CH2:7][CH2:8][CH2:9][N:4]4[CH:3]=3)=[O:12])[CH3:31])[N:17]=2)[CH:28]=[C:27]([F:29])[C:24]=1[C:25]#[N:26]
Reactant: C[C@H](N)Cn1ccc(-c2cc(F)c(C#N)c(Cl)c2)n1
Reactant: O=C(O)c1cn2c(n1)CCCC2
Solvent: CN(C)C=O
Solvent: O
Product: C[C@@H](Cn1ccc(-c2cc(F)c(C#N)c(Cl)c2)n1)NC(=O)c1cn2c(n1)CCCC2
Yield: 70.3 %

Procedure:
The title compound was prepared using the procedure described in Example 3(h) starting from 5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-2-carboxylic acid (2.58 mmol, 428 mg) and (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chloro-6-fluoro-benzonitrile (1.717 mmol, 479 mg). DMF (10 ml) was used as the solvent. The reaction mixture was diluted with water and extracted three times with DCM. The combined organics were washed twice with water. The organic phase was evaporated. The crude product was purified by flash chromatography. 515 mg of the title compound was obtained. 1H-NMR (400 MHz, DMSO-d6): δ 1.07 (d, 3H), 1.78-1.94 (m, 4H), 2.76 (t, 2H), 3.95 (t, 2H), 4.24-4.31 (m, 1H), 4.33-4.46 (m, 2H), 7.01 (d, 1H), 7.43 (s, 1H), 7.84 (d, 1H), 7.90-7.95 (m, 1H), 8.00 (s, 1H), 8.08 (d, 1H).
Reaction SMILES: [CH3:1]N(C=O)C.P(Cl)(Cl)(Cl)=O.[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([NH:18][C:19]([CH3:26])=[CH:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:14][CH:13]=1>ClCCCl>[Cl:11][C:12]1[CH:13]=[C:14]2[C:15](=[CH:16][CH:17]=1)[N:18]=[C:19]([CH3:26])[C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:1]2
Reactant: CN(C)C=O
Reactant: CCOC(=O)C=C(C)Nc1ccc(Cl)cc1
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClCCCl
Product: CCOC(=O)c1cc2cc(Cl)ccc2nc1C
Temperature: 25 °C

Procedure:
To a solution of 6.2 g (83 mmol) DMF in 50 ml of 1,2 dichloroethane was carefully added 19.1 g (126 mmol) of phosphoryl chloride. After stirring for 10 min at ambient temperature a solution of 20 g (83 mol) of ethyl 3-(4-chlorophenylamino)but-2-enoate in 50 ml of 1,2 dichloroethane was added slowly, while the mixture turned dark in an exothermic reaction. Stirring at ambient temperature was continued for another hour followed by heating with reflux for 6 h. The mixture was poured on to crushed ice, washed twice with water, dried over sodium sulfate, and concentrated under reduced pressure. The title ester was obtained from the residue via flash chromatography on silica gel with dichloromethane/hexane 4:1.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=2[Cl:16])[C:5]([NH2:8])=[N:6][CH:7]=1.Cl[CH:18]([C:23](=O)[CH2:24][CH3:25])[C:19]([O:21][CH3:22])=[O:20]>>[CH3:22][O:21][C:19]([C:18]1[N:6]2[CH:7]=[C:2]([Cl:1])[N:3]=[C:4]([C:9]3[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=3[Cl:16])[C:5]2=[N:8][C:23]=1[CH2:24][CH3:25])=[O:20]
Reactant: CCC(=O)C(Cl)C(=O)OC
Reactant: Nc1ncc(Cl)nc1-c1ccc(Cl)cc1Cl
Product: CCc1nc2c(-c3ccc(Cl)cc3Cl)nc(Cl)cn2c1C(=O)OC
Temperature: 170 °C

Procedure:
5-Chloro-3-(2,4-dichlorophenyl)-2-pyrazineamine (1.1 g, 4.0 mmol) and methyl 2-chloro-3-oxopentanoate (5.7 mL) were mixed, and the mixture was heated under stirring at 170° C. 3 hours. After being allowed to cool, the reaction mixture was purified by silica gel column chromatography (n-hexane:ethyl acetate=20:1), and the resulting residue was washed with hexane to give the title compound (0.56 g) as pale yellow crystals.
Reaction SMILES: Br[C:2]1[C:6]2=[N:7][CH:8]=[CH:9][CH:10]=[C:5]2[S:4][CH:3]=1.[CH3:11]B(O)O.COCCOC.O.CCO.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.C(Cl)Cl>[CH3:11][C:2]1[C:6]2=[N:7][CH:8]=[CH:9][CH:10]=[C:5]2[S:4][CH:3]=1
Reactant: CB(O)O
Reactant: Brc1csc2cccnc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: ClCCl
Solvent: COCCOC
Product: Cc1csc2cccnc12
Temperature: 130 °C
Yield: 129.3 %

Procedure:
3 reaction vials are prepared: 214 mg of 3-bromo-thieno[3,2-b]pyridine (1.0 mmol) and 180 mg of methylboronic acid (3.0 mmol) are put in the each vial with 4 ml of DME/water/EtOH=7/3/1. 1.5 ml of 2 M Na2CO aq. (3.0 mmol) is added and N2 gas is bubbled in for 15 min. 58 mg of Pd(PPh3)4 (0.05 mmol) is added and each vials are sealed. These vials are heated at 130° C. for 30 min in the microwave. All reaction mixtures are combined, and water and CH2Cl2 are added. The CH2Cl2 layer are separated and dried over Na2SO4 and evaporated. The crude products are applied onto a silica-gel chromatography column (Hexane: AcOEt: 2 M NH3 in MeOH=20:4:1) to give 193 mg of the title compound. Yield 43%. mass spectrum (m/e): 150 (M+1); 1H-NMR (CDCl3): 8.76 (dd, 1H, J=4.7 Hz, 1.5 Hz), 8.20 (dd, 1H, J=8.2 Hz, 1.5 Hz), 7.43 (d, 1H, J=1.2 Hz), 7.29 (dd, 1H, J=8.2 Hz, 4.7 Hz), 2.58 (d, 3H, J=1.2 Hz) ppm.
Reaction SMILES: [CH2:1]=[CH:2][C:3]([CH2:6][CH2:7][CH:8]=[C:9]([CH3:11])[CH3:10])([CH3:5])O.P(Br)(Br)[Br:13]>>[Br:13][CH2:1][CH:2]=[C:3]([CH3:5])[CH2:6][CH2:7][CH:8]=[C:9]([CH3:11])[CH3:10]
Reactant: C=CC(C)(O)CCC=C(C)C
Reactant: BrP(Br)Br
Product: CC(C)=CCCC(C)=CCBr

Procedure:
Following the procedure of Example 9, linalool and phosphorus tribromide are reacted to form 1-bromo-3,7-dimethyl-2,6-octadiene.
Reaction SMILES: [CH2:1]1[CH2:28][O:27][C:3]2([C:20]3[C:19](=[O:21])[C:18]4[C:9](=[C:10]([OH:23])[C:11]5[CH2:12][CH2:13][CH:14]([OH:22])[CH2:15][C:16]=5[CH:17]=4)[C:8](=[O:24])[C:7]=3[CH:6]=[CH:5][CH:4]2[CH2:25][CH3:26])[O:2]1.C(Cl)(Cl)Cl.[Br:33]Br.N(C(C)(C)C#N)=NC(C)(C)C#N>O.C(Cl)(Cl)(Cl)Cl>[Br:33][CH:12]1[CH2:13][CH:14]([OH:22])[CH2:15][C:16]2[CH:17]=[C:18]3[C:9]([C:8](=[O:24])[C:7]4[CH:6]=[CH:5][CH:4]([CH2:25][CH3:26])[C:3]5([O:2][CH2:1][CH2:28][O:27]5)[C:20]=4[C:19]3=[O:21])=[C:10]([OH:23])[C:11]1=2
Reactant: CCC1C=CC2=C(C(=O)c3cc4c(c(O)c3C2=O)CCC(O)C4)C12OCCO2
Reactant: BrBr
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: O
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Product: CCC1C=CC2=C(C(=O)c3cc4c(c(O)c3C2=O)C(Br)CC(O)C4)C12OCCO2
Temperature: 25 °C
Yield: 72.7 %

Procedure:
A mixture of 9-(1,1-ethylenedioxy)ethyl-6,9-dihydroxy-5,7,8,9,10,12-hexahydronaphthacene-5,12-dione (657 mg), chloroform (33 ml), carbon tetrachloride (13 ml) and water (26 ml) was stirred at room temperature, and bromine (530 mg) and azobisisobutyronitrile (130 mg) were added thereto, and the resulting mixture was stirred at the same temperature as above for 1 hour. From the reaction mixture, the organic phase was separated, washed with water, dried over anhydrous sodium sulfate and concentrated. The residue was crystallized from ether to give 7-bromo-9-(1,1-ethylenedioxy)ethyl-6,9-dihydroxy-5,7,8,9,10,12-hexahydronaphthacene-5,12-dione (576 mg). M.P., 173°-176° C.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[CH:4][C:3]=1[F:10].CC1(C)N([O])C(C)(C)CCC1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C([O-])(O)=O.[Na+].ClN1C(=O)CCC1=O>C(Cl)Cl>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[F:10]
Reactant: OCc1ccc(Br)c(F)c1
Agent: CC1(C)CCCC(C)(C)N1[O]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])O
Solvent: ClCCl
Product: O=Cc1ccc(Br)c(F)c1
Reaction time: 6 h

Procedure:
To a well-stirred mixture of 4-bromo-3-fluorobenzyl alcohol (as described in Example 9, Step B) (10.25 g, 0.05 mol), TEMPO (0.781 g, 0.005 mol) and tetrabutylammonium fluoride (1.39 g, 0.005 mol) in CH2Cl2 (200 mL) and a solution of 0.5M NaHCO3/0.05M K2CO3 (200 mL) was added N-chlorosuccinimide (9.35 g, 0.07 mol). After 6 hrs, the layers were separated, the aqueous layer back-washed with CH2Cl2 (2×50 mL), the organics combined and dried (Na2SO4). The solution was filtered, concentrated to half its volume, then chromatographed (silica gel, CH2Cl2) to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]3[C:21]([C:22]([F:25])([F:24])[F:23])=[CH:20][CH:19]=[CH:18][N:17]=3)=[CH:11][CH:10]=2)[C:5]([NH2:8])=[N:6][CH:7]=1.[H-].[Na+].Cl[CH2:29][CH2:30][S:31](Cl)(=[O:33])=[O:32].O>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:10]=[CH:11][C:12]([O:15][C:16]3[C:21]([C:22]([F:23])([F:24])[F:25])=[CH:20][CH:19]=[CH:18][N:17]=3)=[CH:13][CH:14]=2)[C:5]2[N:6]([CH:7]=1)[CH2:29][CH2:30][S:31](=[O:33])(=[O:32])[N:8]=2
Reactant: O=S(=O)(Cl)CCCl
Reactant: Nc1ncc(Cl)cc1-c1ccc(Oc2ncccc2C(F)(F)F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: O=S1(=O)CCN2C=C(Cl)C=C(c3ccc(Oc4ncccc4C(F)(F)F)cc3)C2=N1
Temperature: 70 °C
Reaction time: 3 h
Yield: 56.2 %

Procedure:
A mixture of 5-chloro-3-(4-{[3-(trifluoromethyl)pyridin-2-yl]oxy}phenyl)pyridin-2-amine (450 mg) in THF (dry) (10 ml) was added to a mixture of NaH (60%, 246 mg) and 2-chloroethanesulfonyl chloride (602 mg) in THF (dry) (10.0 ml) at room temperature. The mixture was stirred at 70° C. for 3 hr. Water was added and the mixture was concentrated in vacuo. The residue was washed with water and Et2O to give an off-white solid. The solid was purified by column chromatography (NH silica gel, eluted with MeOH in EtOAc) to give the title compound (315 mg) as a white solid. The solid was crystallized from CH3CN-IPE to give a white solid.
Reaction SMILES: [CH2:1]([OH:8])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[CH3:9][C:10]1[CH:11]=[C:12](I)[CH:13]=[C:14]([CH3:16])[CH:15]=1.CC1C=C2C(N=CC=C2)=C2C=1C=CC=N2.C([O-])([O-])=O.[Cs+].[Cs+].CCCCCCCCCCCC>[Cu]I.C1(C)C=CC=CC=1>[CH2:1]([O:8][C:12]1[CH:13]=[C:14]([CH3:16])[CH:15]=[C:10]([CH3:9])[CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCCCCCO
Reactant: Cc1cc(C)cc(I)c1
Agent: [Cu]I
Agent: Cc1cc2cccnc2c2ncccc12
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: CCCCCCCCCCCC
Product: CCCCCCCOc1cc(C)cc(C)c1
Temperature: 70 °C
Yield: 68 %

Procedure:
A screw cap test tube was charged with n-heptanol (283 μl, 2.00 mmol), 3,5-dimethyliodobenzene (144 μL, 1.00 mmol), CuI (19.0 mg, 0.100 mmol), 5-methyl-1,10-phenanthroline (38.8 mg, 0.200 mmol), Cs2CO3 (977 mg, 3.00 mmol) and toluene (0.5 mL). The test tube was sealed with a screw cap. The reaction mixture was stirred magnetically and heated at 70° C. for 23 hours. The reaction mixture was allowed to reach room temperature. Dodecane (227 μL, 1.00 mmol; internal standard) was added and a GC sample was filtered through Celite and eluted with CH2Cl2. GC analysis revealed 68% yield of the desired product.