Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][C:3]1[CH:20]=[CH:19][C:6]([O:7][CH2:8][C:9]2[CH:18]=[CH:17][C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]=2)=[CH:5][CH:4]=1.[C:21]([C:27]1[O:28][C:29]2[CH:37]=[CH:36][C:35]([Cl:38])=[C:34]([OH:39])[C:30]=2[C:31](=[O:33])[CH:32]=1)([O:23][CH2:24][CH2:25][CH3:26])=[O:22].[I-].[K+]>CC(C)=O.CN(C)C=O>[C:21]([C:27]1[O:28][C:29]2[CH:37]=[CH:36][C:35]([Cl:38])=[C:34]([O:39][CH2:2][C:3]3[CH:20]=[CH:19][C:6]([O:7][CH2:8][C:9]4[CH:18]=[CH:17][C:16]5[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=5)[N:10]=4)=[CH:5][CH:4]=3)[C:30]=2[C:31](=[O:33])[CH:32]=1)([O:23][CH2:24][CH2:25][CH3:26])=[O:22]
Reactant: ClCc1ccc(OCc2ccc3ccccc3n2)cc1
Reactant: CCCOC(=O)c1cc(=O)c2c(O)c(Cl)ccc2o1
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC(C)=O
Product: CCCOC(=O)c1cc(=O)c2c(OCc3ccc(OCc4ccc5ccccc5n4)cc3)c(Cl)ccc2o1

Procedure:
0.78 g of 2-(4-chloromethylphenoxy)methylquinoline, 0.76 g of 2-carbopropoxy-6-chloro-5-hydroxy-4-oxo-4H-1-benzopyran and a catalytic amount of potassium iodide are combined in 50 ml of acetone and 2 ml of dimethylformamide, and refluxed for 19 hours. The crude solid obtained on cooling is purified by flash chromatography to give 2-carbopropoxy-6-chloro-5-(4-(quinolin-2-ylmethoxy)benzyloxy) 4-oxo-4H-1-benzopyran having an m.p. of 173°-74° C.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH2:9][CH:10]=[C:11]([CH3:13])[CH3:12].C(N(C(C)C)CC)(C)C>C(#N)CC.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH:11]([C:10]1[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[O:8][CH:9]=1)([CH3:13])[CH3:12]
Reactant: CC(C)=CCOc1ccccc1I
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CCC#N
Product: CC(C)c1coc2ccccc12
Temperature: 100 °C
Yield: 52 %

Procedure:
A solution of 1-iodo-2-(3-methylbut-2-enyloxy)benzene (5 g, 17.3 mmol) in propionitrile (10 mL) and diisopropylethylamine (9 mL, 52 mmol) is degassed with argon for 15 min. To this solution is added palladium acetate (423 mg, 1.73 mmol) and the reaction is heated to 100° C. overnight. The reaction is then cooled to room temperature and passed through a pad of celite, washing the filter cake with ethyl acetate (50 mL). The ethyl acetate and amine base are then removed under vacuum. The crude reaction mixture is then chromatographed using 100% hexanes to yield title compound as a colorless oil in 52% yield (1.3 g): 1H NMR (300 MHz, CDCl3) δ 7.7 (s, 1H), 7.68 (d, J=9.0 Hz, 1H,), 7.55 (d, J=9.0 Hz, 1H), 7.32-7.24 (m, 2H), 3.11-3.07 (m, 1H), 1.32 (2s, 6H).
Reaction SMILES: N[C:2]1[S:3][C:4]2[C:9]([NH:10][C@H:11]([CH2:14][CH:15]([CH3:17])[CH3:16])[CH2:12][OH:13])=[N:8][C:7]([S:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[N:6][C:5]=2[N:26]=1.C(ON=O)CC(C)C.C(Br)(Br)[Br:36]>C(#N)C>[C:20]1([CH2:19][S:18][C:7]2[N:8]=[C:9]([NH:10][C@H:11]([CH2:14][CH:15]([CH3:17])[CH3:16])[CH2:12][OH:13])[C:4]3[S:3][C:2]([Br:36])=[N:26][C:5]=3[N:6]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: BrC(Br)Br
Reactant: CC(C)C[C@H](CO)Nc1nc(SCc2ccccc2)nc2nc(N)sc12
Agent: CC(C)CCON=O
Solvent: CC#N
Product: CC(C)C[C@H](CO)Nc1nc(SCc2ccccc2)nc2nc(Br)sc12
Temperature: 60 °C
Yield: 40 %

Procedure:
To a suspension of (R)-2-(2-amino-5-phenylmethylthio-thiazolo[4,5-d]pyrimidin-7-ylamino)-4-methyl-pentan-1-ol (WO 00/09511) (131 mg, 0.34 mmol) in bromoform (6 mL) and anhydrous acetonitrile (2.5 mL), isoamylnitrite (158 μL, 1.2 mmol) was added. The mixture was heated at 60° C. under a nitrogen atmosphere for 30 minutes followed by evaporation of the solvent. The crude, red solid was flash chromatographed on silica (eluent—ethyl acetate:dichloromethane, 10:90) and the product was dried in vacuo at 50° C. overnight, resulting in 61 mg (40% yield) of the title compound as a brown solid.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:14][CH2:13][C:12]3([CH2:19][CH2:18][NH:17][C:16](=[O:20])[CH2:15]3)[C:11]2=[O:21])=[CH:6][CH:5]=1.Br[CH2:25][CH2:26][CH2:27][CH3:28]>>[CH2:25]([N:17]1[CH2:18][CH2:19][C:12]2([C:11](=[O:21])[N:10]([C:7]3[CH:8]=[CH:9][C:4]([O:3][C:2]([F:1])([F:22])[F:23])=[CH:5][CH:6]=3)[CH2:14][CH2:13]2)[CH2:15][C:16]1=[O:20])[CH2:26][CH2:27][CH3:28]
Reactant: O=C1CC2(CCN1)CCN(c1ccc(OC(F)(F)F)cc1)C2=O
Reactant: CCCCBr
Product: CCCCN1CCC2(CCN(c3ccc(OC(F)(F)F)cc3)C2=O)CC1=O

Procedure:
This material was prepared as a white solid in analogy to example 1 step E) from 2-(4-trifluoromethoxy-phenyl)-2,8-diaza-spiro[4.5]decane-1,7-dione and 1-bromo-butane. MS (ESI): 385.1 (MH+).
Reaction SMILES: C[O:2][C:3]([C:5]1[S:6][C:7]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[CH:8][C:9]=1[NH:10][C:11]([NH:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][N:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)=[C:16]([O:28][CH3:29])[CH:15]=1)=[S:12])=O.[C:36](=O)([O-])[O-].[K+].[K+].CI>CN(C=O)C>[CH3:29][O:28][C:16]1[CH:15]=[C:14]([N:13]2[C:3](=[O:2])[C:5]3[S:6][C:7]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)=[CH:8][C:9]=3[N:10]=[C:11]2[S:12][CH3:36])[CH:19]=[CH:18][C:17]=1[O:20][CH2:21][CH2:22][N:23]1[CH2:24][CH2:25][CH2:26][CH2:27]1
Reactant: O=C([O-])[O-]
Reactant: COC(=O)c1sc(-c2ccccc2)cc1NC(=S)Nc1ccc(OCCN2CCCC2)c(OC)c1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COc1cc(-n2c(SC)nc3cc(-c4ccccc4)sc3c2=O)ccc1OCCN1CCCC1
Yield: 50 %

Procedure:
This ester (300 mg, 0.56 mmol) and potassium carbonate (162 mg, 1.17 mmol) were suspended in dry DMF (5 ml) and treated with a solution of methyl iodide (83 mg, 0.59 mmol) in DMF (1 ml). When the addition was complete, the mixture was evaporated. The residue was purified by chromatography on silica gel (eluting with dichloromethane-methanol) giving the title compound in 50% yield;
Reaction SMILES: C[O:2][C:3]([C:5]1([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([F:21])[CH:14]=2)[N:9]2[CH:10]=[N:11][CH:12]=[C:8]2[CH2:7][CH2:6]1)=[O:4].[Li+].[OH-].Cl>C1COCC1.O>[F:21][C:15]1[CH:14]=[C:13]([C:5]2([C:3]([OH:4])=[O:2])[N:9]3[CH:10]=[N:11][CH:12]=[C:8]3[CH2:7][CH2:6]2)[CH:18]=[CH:17][C:16]=1[O:19][CH3:20]
Reactant: COC(=O)C1(c2ccc(OC)c(F)c2)CCc2cncn21
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(C2(C(=O)O)CCc3cncn32)cc1F
Reaction time: 1 h

Procedure:
5-(3-fluoro-4-methoxy-phenyl)-6,7-dihydro-5H-pyrrolo[1,2-c]imidazole-5-carboxylic acid methyl ester (0.530 g, 1.82 mmol) is dissolved in THF/water (20 mL) (3:2) and to the solution is added LiOH (0.230 g, 9.58 mmol). After 1 h, the solution is brought to pH 4-5 with 1 M HCl and then evaporated to dryness to give 5-(3-fluoro-4-methoxy-phenyl)-6,7-dihydro-5H-pyrrolo[1,2-c]imidazole-5-carboxylic acid that is used without further purification. MS (ESI) m/z 277.2 (M+H).
Reaction SMILES: [F:1][C:2]([F:28])([F:27])[C:3]1[CH:4]=[C:5]([CH:20]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:22]=1)[CH2:6][NH:7][CH2:8][C:9]1[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[CH:11][C:10]=1[Br:19].C([O-])(=O)C.[Na+].[N:34]#[C:35]Br.O>C(O)C>[Br:19][C:10]1[CH:11]=[CH:12][C:13]([C:15]([F:16])([F:17])[F:18])=[CH:14][C:9]=1[CH2:8][N:7]([CH2:6][C:5]1[CH:20]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:22]=[C:3]([C:2]([F:27])([F:1])[F:28])[CH:4]=1)[C:35]#[N:34]
Reactant: N#CBr
Reactant: FC(F)(F)c1cc(CNCc2cc(C(F)(F)F)ccc2Br)cc(C(F)(F)F)c1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: N#CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)Cc1cc(C(F)(F)F)ccc1Br
Reaction time: 0.33 h

Procedure:
To the product of step B (873 g, 1.82 mol) in ethanol (4.6 L) was added sodium acetate (452 g, 5.46 mol). The resulting mixture was stirred for 20 minutes and then cyanogen bromide (386 g, 3.64 mol) was added. This mixture was stirred for 2 hours at which point the reaction was complete as evidenced by LC analysis. Water (4 L) was added and volatiles were removed in vacuo. Toluene (4 L) was added and the mixture was stirred until 2 clear layers formed, The layers were separated and the aqueous layer was washed with toluene (2 L). The combined organics were washed with brine (1 L), dried over sodium sulfate, filtered, and concentrated (910 g yield). 1H-NMR (CDCl3) 7.83 (s, 1H), 7.71 (m, 3H), 7.54 (d, 1.7 Hz, 1H), 7.46 (dd, 2.1 Hz, 8.3 Hz, 1H), 4.38 (s, 2H), 4.34 (s, 2H). Mass Spec (ESI): M+1=505.0
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[ClH:10].[NH2:11][CH2:12][C:13]1[CH:14]=[C:15](B(O)O)[CH:16]=[CH:17][CH:18]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C(COC)OC.O>[ClH:10].[NH2:5][CH2:4][C:3]1[CH:6]=[C:7]([C:18]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:12]#[N:11])[CH:8]=[CH:9][CH:2]=1
Reactant: NCc1cccc(B(O)O)c1
Reactant: N#Cc1ccccc1Br
Agent: Cl
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: N#Cc1ccccc1-c1cccc(CN)c1
Temperature: 70 °C
Reaction time: 2 h
Yield: 32.7 %

Procedure:
A solution of 2-bromobenzonitrile (1.10 g), 3-aminomethylphenylboronic acid hydrochloride (1.13 g), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium-dichloromethane complex (0.10 g), and tripotassium phosphate (5.20 g) in a 4:1 dimethoxyethane-water mixed solvent (60 mL) was stirred at 70° C. for 3 hours. 2-Bromobenzonitrile (0.070 g) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium-dichloromethane complex (0.10 g) were added thereto, and the mixture was stirred at 70° C. for 2 hours. The reaction solution was cooled to room temperature, filtered through celite, and then separated into organic and aqueous layers. The organic layer was washed with a saturated aqueous sodium hydrogencarbonate solution and saturated saline, dried over anhydrous sodium sulfate, and then filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by chromatography on a silica gel column (Biotage Ltd., elution solvent: dichloromethane/methanol), and a fraction containing the desired compound was concentrated under reduced pressure. The obtained residue was dissolved in ethyl acetate, and concentrated hydrochloric acid was added to the solution. The resulting suspension was filtered, and the product collected by filtration was washed with ethyl acetate and dried under reduced pressure to obtain the title compound (0.483 g).
Reaction SMILES: [NH2:1][C@H:2]([C:18]([OH:20])=[O:19])[CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9].Cl.[NH:22]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[C@H:23]([C:28](O)=[O:29])[CH2:24][CH:25]([CH3:27])[CH3:26]>CN(C=O)C>[NH:22]([C:31]([O:33][C:34]([CH3:36])([CH3:35])[CH3:37])=[O:32])[C@H:23]([C:28]([NH:1][C@H:2]([C:18]([OH:20])=[O:19])[CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9])=[O:29])[CH2:24][CH:25]([CH3:27])[CH3:26]
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: N[C@@H](CCCCNC(=O)OCc1ccccc1)C(=O)O
Agent: Cl
Solvent: CN(C)C=O
Product: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](CCCCNC(=O)OCc1ccccc1)C(=O)O
Reaction time: 18 h
Yield: 72.7 %

Procedure:
In 200 ml of 1.5N NEM/DMF mixture, 45.2 g (0.2 mol) of H-Lys(Z)-CHA.HCl was dissolved, and 35.3 g (0.1 mol) of BOC-Leu-SDP was added thereto at 0° to 5° C. The reaction was carried out at room temperature for 18 hours. After the reaction, the solvent was removed by distillation under reduced pressure. The residue was dissolved in 1500 ml of AcOEt and washed with 500 ml of a cooled 5% HCl solution twice, and 500 ml of a saturated saline solution twice, followed by decoloration and drying over anhydrous magnesium sulfate and active carbon. After drying, the magnesium sulfate and active carbon were filtered and the solvent was removed by distillation under reduced pressure to yield crude BOC-Leu-Lys(Z)-CHA. This was recrystallized from a mixed solvent of AcOEt/ether/n-hexane to give 35.9 g (57.1%) of BOC-Leu-Lys(Z)-CHA.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][CH2:9][CH2:10][O:11][Si:12]([C:25]([CH3:28])([CH3:27])[CH3:26])([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[N:6][CH:7]=1.[C:29]([CH2:33][C:34](OC)=[O:35])(=O)[CH2:30][CH3:31].C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1C=CC=CC=1>[Si:12]([O:11][CH2:10][CH2:9][O:8][C:5]1[N:6]=[C:7]2[C:2](=[CH:3][CH:4]=1)[NH:1][C:29]([CH2:30][CH3:31])=[CH:33][C:34]2=[O:35])([C:25]([CH3:28])([CH3:27])[CH3:26])([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CC(C)(C)[Si](OCCOc1ccc(N)cn1)(c1ccccc1)c1ccccc1
Reactant: CCC(=O)CC(=O)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: c1ccccc1
Product: CCc1cc(=O)c2nc(OCCO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)ccc2[nH]1
Yield: 62 %

Procedure:
A solution of compound C (10 g), methyl propionylacetate (11.5 g) and p-toluenesulphonic acid (0.1 g) in benzene (40 ml) was heated under reflux with azeotropic removal of water for 20 hours. Volatile material was removed by evaporation and the residue added to a refluxing eutectic mixture of 26.5% v/v diphenyl and 73.5% v/v diphenyl oxide (30 ml). The solution was heated under reflux for 1 hour, cooled and diluted with hexane (100 ml). The precipitated solid was filtered off and triturated with hot methanol (100 ml) to give 2-ethyl-6-[2-(trimethylsilyl)ethoxy]-1,5-naphthyridin-4-(1H)-one (D) (in 62% yield) as a white solid, m.p. 193° C.; NMR: -0.1(s,9H), 0.85(t,2H), 1.3(t,3H), 2.8(q,2H), 4.1(t,2H), 6.55(s,1H), 6.9(d,1H), 8.2(d,1H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.C(O)CCC.[CH2:14]([NH2:26])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]>O>[Cl:1][C:2]1[N:7]=[C:6]([NH:26][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH:5]=[CH:4][N:3]=1
Reactant: Clc1ccnc(Cl)n1
Reactant: CCCCCCCCCCCCN
Solvent: CCCCO
Solvent: O
Product: CCCCCCCCCCCCNc1ccnc(Cl)n1
Reaction time: 40 h
Yield: 54.1 %

Procedure:
To a well-stirred slurry of 2,4-dichloropyrimidine (27.0 g, 0.18 m) and n-butanol (150 ml) is added 150 ml of water followed immediately by n-dodecylamine (67.2 g, 0.36 m). The clear solution obtained after a short time gradually clouds as the product precipitates. After allowing to stir about 40 hours, the mixture is filtered, the semi-dry cake is flushed several times with small portions of water, washed twice with water and finally sucked dry to yield 29.2 g (64%) of 2-chloro-4-(n-dodecylamino)pyrimidine, m.p. 80°-82° C.
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][C:4]([NH2:7])=[CH:3][CH:2]=1.C1(S([N:18]2[C:22]3=[N:23][CH:24]=[CH:25][CH:26]=[C:21]3[C:20]([C:27]3[CH:32]=[CH:31][N:30]=[C:29](Cl)[N:28]=3)=[CH:19]2)(=O)=O)C=CC=CC=1>>[NH2:7][C:4]1[CH:5]=[CH:6][C:1]([NH:8][C:29]2[N:28]=[C:27]([C:20]3[C:21]4[C:22](=[N:23][CH:24]=[CH:25][CH:26]=4)[NH:18][CH:19]=3)[CH:32]=[CH:31][N:30]=2)=[CH:2][CH:3]=1
Reactant: O=S(=O)(c1ccccc1)n1cc(-c2ccnc(Cl)n2)c2cccnc21
Reactant: Nc1ccc(N)cc1
Product: Nc1ccc(Nc2nccc(-c3c[nH]c4ncccc34)n2)cc1
Yield: 49.1 %

Procedure:
Using the procedure of example 1, 1,4-phenylenediamine (175 mg) was reacted with compound 1f (100 mg) to provide compound 37 (40 mg, 25%). 1H NMR (400 MHz, CD3OD) δ 8.43 (d, J=8.0 Hz, 1H), 8.23 (d, J=8.0 Hz, 1H), 8.20 (s, 1H), 8.18 (d, J=4.8 Hz, 1H), 7.36 (m, 1H), 7.33 (d, J=8.0 Hz, 1H), 7.18 (dd, J=8.0 Hz, 5.6 Hz, 1H), 7.11 (d, J=5.2 Hz, 1H), 6.84 (d, J=8.0 Hz, 1H), 6.80 (d, J=8.0 Hz, 1H). MS (ESI) m/z: 301 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:10](B3OC(C)(C)C(C)(C)O3)=[CH:9][N:8]([S:20]([C:23]3[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=3)(=[O:22])=[O:21])[C:5]2=[N:6][CH:7]=1.Cl[C:31]1[N:36]=[C:35]([NH:37][C@H:38]2[CH2:43][CH2:42][CH2:41][C:40]([CH3:45])([OH:44])[CH2:39]2)[C:34]([F:46])=[CH:33][N:32]=1.C([O-])([O-])=O.[Na+].[Na+]>C(COC)OC>[Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:31]3[N:36]=[C:35]([NH:37][C@H:38]4[CH2:43][CH2:42][CH2:41][C:40]([CH3:45])([OH:44])[CH2:39]4)[C:34]([F:46])=[CH:33][N:32]=3)=[CH:9][N:8]([S:20]([C:23]3[CH:24]=[CH:25][C:26]([CH3:29])=[CH:27][CH:28]=3)(=[O:21])=[O:22])[C:5]2=[N:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(B3OC(C)(C)C(C)(C)O3)c3cc(Cl)cnc32)cc1
Reactant: CC1(O)CCC[C@H](Nc2nc(Cl)ncc2F)C1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: Cc1ccc(S(=O)(=O)n2cc(-c3ncc(F)c(N[C@H]4CCCC(C)(O)C4)n3)c3cc(Cl)cnc32)cc1
Temperature: 130 °C

Procedure:
Degassed a solution of 5-chloro-1-(p-tolylsulfonyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[2,3-b]pyridine (1.46 g, 3.37 mmol), (3S)-3-[(2-chloro-5-fluoro-pyrimidin-4-yl)amino]-1-methyl-cyclohexanol, 29c, (0.72 g, 2.81 mmol) and Na2CO3 (4.21 mL of 2M solution, 8.433 mmol) in dimethoxyethane (15 mL) for 30 min with nitrogen. To the reaction mixture was added palladium tetrakis-triphenylphosphane (0.16 g, 0.14 mmol). The reaction mixture was heated at 130° C. in Q-tube apparatus for 45 minutes. The reaction mixture was filtered through a pad of 1 cm of silica gel and 2 cm celite. The product was purified by silica gel chromatography (hexanes/EtOAc) to afford the desired product, 29e (63% yield).
Reaction SMILES: [Br:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([CH2:11][CH2:12][CH2:13][CH3:14])[CH:8]=[CH:7][C:5]=2[N:6]=1.C(=O)(O)[O-:16].[Na+]>C(O)(=O)C>[Br:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([C:11](=[O:16])[CH2:12][CH2:13][CH3:14])[CH:8]=[CH:7][C:5]=2[N:6]=1
Reactant: O=C([O-])O
Reactant: CCCCc1ccc2nc(Br)sc2c1
Agent: [Na+]
Solvent: CC(=O)O
Product: CCCC(=O)c1ccc2nc(Br)sc2c1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
Step-3: To a solution of 2-bromo-6-butylbenzo[d]thiazole in acetic acid at 0° C. was added CrO3 in acetic acid. The reaction mixture was allowed to warm to RT and stirred over 2 days. The reaction was neutralized by aq. sodium bicarbonate and extracted with ethyl acetate, washed with brine, dried over anhydrous sodium sulfate and concentrated, The crude product was purified by preparative TLC to afford 1-(2-bromobenzo[d]thiazol-6-yl)butan-1-one. MS (ESI+) m/z 286.2 [M+2]+
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Br[CH2:11][C:12]1[CH:13]=[N:14][C:15]2[C:20]([C:21]=1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[CH:19][CH:18]=[CH:17][C:16]=2[C:28]([F:31])([F:30])[F:29].O>CN(C=O)C>[O:7]([CH2:11][C:12]1[CH:13]=[N:14][C:15]2[C:20]([C:21]=1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[CH:19][CH:18]=[CH:17][C:16]=2[C:28]([F:31])([F:29])[F:30])[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Oc1ccccc1
Reactant: FC(F)(F)c1cccc2c(-c3ccccc3)c(CBr)cnc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: FC(F)(F)c1cccc2c(-c3ccccc3)c(COc3ccccc3)cnc12
Reaction time: 16 h
Yield: 60.1 %

Procedure:
A solution of phenol (235 mg, 5.0 mmol) in DMF (2.0 mL) is treated with NaH (60% in oil, 100 mg, 2.5 mmol) for 20 min and then treated with 3-(bromomethyl)-4-phenyl-8-(trifluoromethyl)quinoline (183 mg, 0.50 mmol) in DMF (1.0 mL). After 16 h, the reaction is treated with water and extracted with ether. The extract is dried with MgSO4 and concentrated to an oil. Chromatography with 10:90 ethyl acetate:hexane affords the title compound as a white solid (114 mg, 62%). MS (ES) m/z 380.2; HRMS: calcd for C23H16F3NO, 379.1184; found (ESI, [M+H]+), 380.1246;
Reaction SMILES: [CH3:1][CH:2]([N:14]([CH3:16])[CH3:15])/[CH:3]=[CH:4]/[CH:5]1[C:10]([CH3:12])([CH3:11])[CH2:9][CH2:8][CH:7]=[C:6]1[CH3:13].Cl[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([Cl:26])[CH:20]=1.C(O)C.[I-:30].[K+]>CO>[I-:30].[CH3:1][CH:2]([N+:14]([CH3:16])([CH3:15])[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([Cl:26])[CH:20]=1)/[CH:3]=[CH:4]/[CH:5]1[C:10]([CH3:11])([CH3:12])[CH2:9][CH2:8][CH:7]=[C:6]1[CH3:13]
Reactant: CC1=CCCC(C)(C)C1/C=C/C(C)N(C)C
Reactant: ClCc1ccc(Cl)c(Cl)c1
Agent: [I-]
Agent: [K+]
Solvent: CCO
Solvent: CO
Product: CC1=CCCC(C)(C)C1/C=C/C(C)[N+](C)(C)Cc1ccc(Cl)c(Cl)c1
Yield: 58.1 %

Procedure:
A solution of [1-methyl-3-(2,6,6-trimethyl-2-cyclohexenyl)-2(trans)-propenyl]dimethylamine (3.0 g) and α,3,4-trichlorotoluene (4.0 g) in methanol (15 cc) was refluxed for 2 hours, and thereto were added ethanol (40 cc) and then an aqueous solution of potassium iodide (3.0 g). The solvent of the reaction mixture was distilled off under reduced pressure, and the residue was recrystallized from a mixed solvent of methanol and ether to give colorless crystals (4.0 g) of [1-methyl-3-(2,6,6-trimethyl-2-cyclohexenyl)-2(trans)-propenyl]dimethyl(3,4-dichlorobenzyl)ammonium iodide, m.p. 160°-165° C.
Reaction SMILES: [CH2:1]1[NH:18][CH2:17][CH2:16][O:15][CH2:14][CH2:13][O:12][CH2:11][CH2:10][O:9][CH2:8][CH2:7][O:6][CH2:5][CH2:4][O:3][CH2:2]1.[C:19]([O:27][CH2:28][CH2:29]Cl)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[C:19]([O:27][CH2:28][CH2:29][N:18]1[CH2:1][CH2:2][O:3][CH2:4][CH2:5][O:6][CH2:7][CH2:8][O:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][O:15][CH2:16][CH2:17]1)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: C1COCCOCCOCCOCCOCCN1
Reactant: O=C(OCCCl)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(OCCN1CCOCCOCCOCCOCCOCC1)c1ccccc1
Temperature: 80 °C
Reaction time: 10 h
Yield: 778.6 %

Procedure:
A mixture of 26.3 g of 1-aza-18-crown-6, 19.9 g of 2-chloroethyl benzoate, 21.0 g of potassium carbonate, and 60 g of N,N-dimethylformamide was stirred for 10 hours at 80° C. The reaction mixture was subjected to conventional aqueous work-up and purification by column chromatography. There was obtained 320 g of 2-(1,4,7,10,13-pentaoxa-16-azacyclo-octadecan-16-yl)ethyl benzoate (yield 75%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH3:13])=[C:11]([C:14](Cl)=[O:15])[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[NH2:17][C:18]1[CH:19]=[CH:20][C:21]([N:26]2[CH2:31][CH2:30][CH:29]([N:32]3[CH2:37][CH2:36][CH:35]([O:38][CH3:39])[CH2:34][CH2:33]3)[CH2:28][CH2:27]2)=[C:22]([CH:25]=1)[C:23]#[N:24]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH3:13])=[C:11]([C:14]([NH:17][C:18]3[CH:19]=[CH:20][C:21]([N:26]4[CH2:31][CH2:30][CH:29]([N:32]5[CH2:33][CH2:34][CH:35]([O:38][CH3:39])[CH2:36][CH2:37]5)[CH2:28][CH2:27]4)=[C:22]([C:23]#[N:24])[CH:25]=3)=[O:15])[CH:10]=[N:9]2)=[CH:4][CH:3]=1
Reactant: COC1CCN(C2CCN(c3ccc(N)cc3C#N)CC2)CC1
Reactant: Cc1c(C(=O)Cl)cnn1-c1ccc(Cl)cc1
Product: COC1CCN(C2CCN(c3ccc(NC(=O)c4cnn(-c5ccc(Cl)cc5)c4C)cc3C#N)CC2)CC1
Yield: 23.9 %

Procedure:
By the reaction and treatment in the same manner as in Example 150 using 1-(4-chlorophenyl)-5-methylpyrazole-4-carboxylic chloride (0.4 g) and 5-amino-2-[4-(4-methoxypiperidin-1-yl)piperidin-1-yl]benzonitrile (0.5 g), the title compound (0.2 g) was obtained, melting point: 245° C. decomposition.
Reaction SMILES: Cl[C:2]1[C:8]2[CH:9]=[CH:10][C:11]([C:13]([O:15][CH3:16])=[O:14])=[CH:12][C:7]=2[S:6](=[O:18])(=[O:17])[C:5]2[CH:19]=[CH:20][CH:21]=[CH:22][C:4]=2[N:3]=1.S1(CCCC1)(=O)=O.[BH4-].[Na+]>CCOCC>[CH:9]1[C:8]2[CH2:2][NH:3][C:4]3[CH:22]=[CH:21][CH:20]=[CH:19][C:5]=3[S:6](=[O:18])(=[O:17])[C:7]=2[CH:12]=[C:11]([C:13]([O:15][CH3:16])=[O:14])[CH:10]=1
Reactant: COC(=O)c1ccc2c(c1)S(=O)(=O)c1ccccc1N=C2Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOCC
Solvent: O=S1(=O)CCCC1
Product: COC(=O)c1ccc2c(c1)S(=O)(=O)c1ccccc1NC2
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Suspend 6.7 gm. (20 mmole) of methyl 11-chlorodibenzo[b,f][1,4]thiazepin-3-carboxylate 5,5-dioxide in 60 ml. of sulfolane and stir under nitrogen at room temperature while adding 1.52 g. (40 mmole) of sodium borohydride in small portions. Control foaming, if desired, by adding small portions of dry ether. After 2 hours, pour the reaction mixture into 300 ml. of ice-water and 75 ml. of ether. Separate the precipitate by filtration, wash with water and dry in vacuo. Dissolve the precipitate in 175 ml. of boiling acetonitrile, filter and concentrate to 100 ml. Separate the precipitate to obtain the title product. (m.p. 236° C.)