Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: P(Br)(Br)[Br:2].[Cl:5][C:6]1[CH:14]=[CH:13][C:9]([CH2:10][CH2:11]O)=[CH:8][CH:7]=1>C(Cl)(Cl)(Cl)Cl>[Cl:5][C:6]1[CH:14]=[CH:13][C:9]([CH2:10][CH2:11][Br:2])=[CH:8][CH:7]=1
Reactant: BrP(Br)Br
Reactant: OCCc1ccc(Cl)cc1
Solvent: ClC(Cl)(Cl)Cl
Product: Clc1ccc(CCBr)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Phosphorus tribromide (1.3 ml) was added, dropwise, to a solution of 4-chlorophenethyl alcohol (5.0 g) in carbon tetrachloride (30 ml). The mixture was stirred at room temperature for 10 minutes then heated under reflux for 2 hours. Ice (50 g) was added and the mixture partitioned between dichloromethane (50 ml) and 10% aqueous sodium carbonate (50 ml). The layers were separated and the aqueous layer extracted with dichloromethane (2×50 ml). The combined dichloromethane extracts were dried (MgSO4) and concentrated in vacuo to give an oil which was purified by column chromatography on silica eluting with dichloromethane. The product-containing fractions were combined and concentrated in vacuo to give the title compound as a colourless oil, yield 3.0 g.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:10]([O:12][CH3:13])=[O:11])[CH:8]=2)[CH:3]=[CH:2]1.Br[CH2:15][CH2:16][O:17][CH3:18]>>[CH3:18][O:17][CH2:16][CH2:15][N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:10]([O:12][CH3:13])=[O:11])[CH:8]=2)[CH:3]=[CH:2]1
Reactant: COC(=O)c1ccc2cc[nH]c2c1
Reactant: COCCBr
Product: COCCn1ccc2ccc(C(=O)OC)cc21
Yield: 30 %

Procedure:
The title compound was prepared in 30% yield (79 mg, colorless syrup) from methyl 1H-indole-6-carboxylate (200 mg, 1.14 mmol) and 1-bromo-2-methoxyethane (190 mg, 1.37 mmol) by the similar manner in Step-1 of Intermediate-9.
Reaction SMILES: [CH2:1]1[N:11]2[C:12]3[C:8]([C@@H:9]4[CH2:16][NH:15][CH2:14][CH2:13][C@@H:10]42)=[CH:7][CH:6]=[CH:5][C:4]=3[O:3][CH2:2]1.Cl[CH2:18][CH2:19][CH2:20][C:21]1[C:29]2[C:24](=[CH:25][C:26]([F:30])=[CH:27][CH:28]=2)[NH:23][N:22]=1>>[F:30][C:26]1[CH:25]=[C:24]2[C:29]([C:21]([CH2:20][CH2:19][CH2:18][N:15]3[CH2:14][CH2:13][C@@H:10]4[N:11]5[CH2:1][CH2:2][O:3][C:4]6[CH:5]=[CH:6][CH:7]=[C:8]([C:12]5=6)[C@@H:9]4[CH2:16]3)=[N:22][NH:23]2)=[CH:28][CH:27]=1
Reactant: Fc1ccc2c(CCCCl)n[nH]c2c1
Reactant: c1cc2c3c(c1)[C@@H]1CNCC[C@@H]1N3CCO2
Product: Fc1ccc2c(CCCN3CC[C@H]4[C@@H](C3)c3cccc5c3N4CCO5)n[nH]c2c1

Procedure:
The title compound was prepared by the method of Example 355 Step B as a yellow oil (60 mg, 63%) from (6bR,10aS)-1,2,6b,7,8,9,10,10a-octahydro[1,4]oxazino-[2,3,4-hi]pyrido[4,3-b]indole (63 mg, 0.29 mmol) and 3-(3-chloropropyl)-6-fluoroindazole (93 mg, 0.43 mmol). 1H NMR (CDCl3, 300 MHz) δ1.89-2.15 (m, 5H), 2.27-2.38 (m, 1H), 2.43-2.55 (m, 2H), 2.71-2.80 (m, 2H), 2.88-3.02 (m, 3H), 3.18-3.32 (m, 3H), 4.43 (dd, J=6.2, 1.8 Hz, 2H) 6.60-6.72 (m, 3H), 6.90 (dt, J=9.1, 2.2 Hz, 1H), 7.07 (dd, J=9.2, 1.9 Hz, 1H), 7.63 (dd, J=8.8, 5.1 Hz, 1H), 9.85-10.15 (br-s, 1H) ppm.
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[Br:15][C:16]1[O:20][C:19]([CH:21]=O)=[CH:18][CH:17]=1.[CH3:23][NH:24][CH3:25].CC(O)=O>ClCCCl>[Br:15][C:16]1[O:20][C:19]([CH2:21][N:24]([CH3:25])[CH3:23])=[CH:18][CH:17]=1
Reactant: CNC
Reactant: O=Cc1ccc(Br)o1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CN(C)Cc1ccc(Br)o1
Temperature: 25 °C
Reaction time: 8 h
Yield: 97 %

Procedure:
Sodium triacetoxyborohydride (844 mg, 4 mmol) was added to a solution of 5-bromo-furan-2-carbaldehyde (350 mg, 2 mmol) and dimethyl amine (2 ml, 2M solution in THF) in 10 ml of 1,2-dichloroethane (DCE). 0.2 ml of HOAc was then added. The mixture was stirred at room temperature overnight, followed by addition of 15 ml of DCE. The organic phase was washed with water, dried over sodium sulfate. The solvent was removed by rotovap to give 400 mg of (5-bromo-furan-2-ylmethyl)-dimethyl-amine, yield: 97%.
Reaction SMILES: O[CH2:2][CH2:3][O:4][CH2:5][C:6]1[O:7][CH:8]=[CH:9][CH:10]=1.C(N(CC)C(C)C)(C)C.[CH3:20][S:21](Cl)(=[O:23])=[O:22]>ClCCl>[CH3:20][S:21]([CH2:2][CH2:3][O:4][CH2:5][C:6]1[O:7][CH:8]=[CH:9][CH:10]=1)(=[O:23])=[O:22]
Reactant: CS(=O)(=O)Cl
Reactant: OCCOCc1ccco1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)CCOCc1ccco1
Reaction time: 1.5 h

Procedure:
Combine fur-2-ylmethyl 2-hydroxyethyl ether (10 mmol), and N,N-diisopropylethylamine (4.0 mL, 23 mmol), and dichloromethane (20 mL). Cool in an ice-bath. Add dropwise, methanesulfonyl chloride (1.0 mL, 13 mmol). After 1.5 hours, extract the reaction mixture with 1 M aqueous hydrochloric acid solution, saturated aqueous sodium bicarbonate solution, and saturated aqueous sodium chloride solution. Dry the organic layer over Na2SO4, filter, and evaporate in vacuo to obtain fur-2-ylmethyl 2-methanesulfonylethyl ether.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][C:11]([OH:13])=O)([O-:3])=[O:2].C(Cl)(=O)C([Cl:17])=O>ClCCl.CN(C=O)C>[N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][C:11]([Cl:17])=[O:13])([O-:3])=[O:2]
Reactant: O=C(O)Cc1ccccc1[N+](=O)[O-]
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)Cc1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 3 h

Procedure:
2-Nitrophenylacetic acid (15.0 g, 82.8 mmol) was dissolved in 330 mL of dichloromethane. Three drops of DMF were added, followed by dropwise addition of oxalyl chloride (14.4 mL, 165.6 mmol). The reaction was allowed to stir at ambient temperature for 3 hours, at which time the reaction was concentrated under reduced pressure to afford (2-nitrophenyl)acetyl chloride.
Reaction SMILES: [C:1]([CH2:3][C:4]1[C:8]([CH3:9])=[N:7][N:6]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:5]=1)#[N:2].[CH3:16][C:17]1[S:18][C:19]([C:23](N2C=CC=N2)=[O:24])=[C:20]([CH3:22])[N:21]=1.CC(C)([O-])C.[K+].Cl>O1CCCC1>[CH3:16][C:17]1[S:18][C:19]([C:23]([OH:24])=[C:3]([C:4]2[C:8]([CH3:9])=[N:7][N:6]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[N:5]=2)[C:1]#[N:2])=[C:20]([CH3:22])[N:21]=1
Reactant: Cc1nc(C)c(C(=O)n2cccn2)s1
Reactant: Cc1nn(-c2ccccc2)nc1CC#N
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: C1CCOC1
Product: Cc1nc(C)c(C(O)=C(C#N)c2nn(-c3ccccc3)nc2C)s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 51.6 %

Procedure:
0.90 g of 4-cyanomethyl-5-methyl-2-phenyl-1,2,3-triazole and 1.04 g of 1-(2,4-dimethylthiazol-5-carbonyl)pyrazole were dissolved in tetrahydrofuran, and 1.02 g of potassium tert-butoxide was added thereto at 0° C. After stirring for 1 hour at room temperature, diluted hydrochloric acid was added to the reaction solution to make it acid. The solution was extracted with ethyl acetate, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting solid was washed with isopropyl ether to obtain 0.79 g of the aimed compound. m.p.: 117-118° C.
Reaction SMILES: C1COCC1.[H-].[Na+].[CH2:8]([OH:11])[CH2:9][OH:10].[Si:12](Cl)([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13]>C(OCC)C>[Si:12]([O:10][CH2:9][CH2:8][OH:11])([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OCCO
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OCCO
Reaction time: 0.75 h

Procedure:
154 ml of dry THF and 1.88 g NaH are stirred under in a nitrogen atmosphere in a 500 ml round bottom flask condenser. 4.4 mL dry ethylene glycol are added into the flask, resulting in a large precipitate after 45 minutes of stirring. 11.8 g tert-butyldimethylsilyl chloride is added to the flask and vigorous stirring is continued for 45 minutes. The resulting mixture is poured into 950 mL ethylether. The ether is washed with 420 mL brine and solution is dried with sodium sulfate. The product is concentrated by evaporation of the ether in vacuo and purified by flash chromatography using a 27×5.75 cm column charged with silica gel using a hexanes/Et2O (75:25 v/v) solvent system. The product is stored at 0° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:23][C:24]2[CH:28]=[C:27]([CH3:29])[NH:26][N:25]=2)=[N:4][C:5]([NH:8][C:9]2[CH:14]=[C:13]([CH3:15])[C:12]([CH:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)=[CH:11][C:10]=2[F:22])=[N:6][CH:7]=1.Cl[CH2:31][CH2:32][CH2:33][C:34]([N:36]1[CH2:41][CH2:40][O:39][CH2:38][CH2:37]1)=[O:35].CCN(C(C)C)C(C)C>CN1C(=O)CCC1>[Cl:1][C:2]1[C:3]([NH:23][C:24]2[CH:28]=[C:27]([CH3:29])[NH:26][N:25]=2)=[N:4][C:5]([NH:8][C:9]2[C:10]([F:22])=[CH:11][C:12]([CH:16]3[CH2:17][CH2:18][N:19]([CH2:31][CH2:32][CH2:33][C:34]([N:36]4[CH2:41][CH2:40][O:39][CH2:38][CH2:37]4)=[O:35])[CH2:20][CH2:21]3)=[C:13]([CH3:15])[CH:14]=2)=[N:6][CH:7]=1
Reactant: Cc1cc(Nc2nc(Nc3cc(C)c(C4CCNCC4)cc3F)ncc2Cl)n[nH]1
Reactant: O=C(CCCCl)N1CCOCC1
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(Nc2nc(Nc3cc(C)c(C4CCN(CCCC(=O)N5CCOCC5)CC4)cc3F)ncc2Cl)n[nH]1
Temperature: 80 °C
Reaction time: 10 h

Procedure:
A mixture of 5-chloro-N2-(2-fluoro-5-methyl-4-(piperidin-4-yl)phenyl)-N4-(5-methyl-1H-pyrazol-3-yl)pyrimidine-2,4-diamine (41 mg, 0.1 mmol), 4-chloro-1-morpholinobutan-1-one (29 mg, 0.15 mmol) and DIEA (0.1 mL, 0.58 mmol) in NMP (1 mL) was stirred at 80° C. After 10 h, additional 4-chloro-1-morpholinobutan-1-one (51 mg) was added, and the reaction continued overnight. The crude product was purified by RP-HPLC to give 4-(4-(4-(5-Chloro-4-(5-methyl-1H-pyrazol-3-ylamino)pyrimidin-2-ylamino)-5-fluoro-2-methylphenyl)piperidin-1-yl)-1-morpholinobutan-1-one as a white powder; ESMS m/z 571.3.3 (M+H+).
Reaction SMILES: [CH3:1][C@@H:2]1[O:7][CH:6]=[CH:5][C@H:4]([O:8]C(C)=O)[C@@H:3]1[O:12]C(C)=O.[OH2:16].[Br-].[Li+].O>C(#N)C>[OH:16][CH:6]1[O:7][C@@H:2]([CH3:1])[C@@H:3]([OH:12])[C@@H:4]([OH:8])[CH2:5]1
Reactant: CC(=O)O[C@@H]1[C@H](C)OC=C[C@@H]1OC(C)=O
Reactant: O
Agent: [Br-]
Agent: [Li+]
Solvent: CC#N
Product: C[C@@H]1OC(O)C[C@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 115.7 %

Procedure:
To a solution of 3,4-di-O-acetyl-L-fucal (5.0 g) and lithium bromide hydrate (5.0 g) in acetonitrile (150 ml), activated resin prepared as in Example 1 (3.0 g) and water (6 ml) were added and stirred at room temperature for 15 min. The product was isolated as described for Example 1. Purification by chromatography on a column of Silica Gel using ethyl acetate-hexane (3:8) as eluant gave the title compound (4.0 g). α:β=9:4. [α]D20 =-57.6°±2°(c 1.03, CHCl3). 1H NMR δ: 5.45 (d, H-1α), 5.35 (m H-3α), 5.19 (H-4α), 5.10 (d, H-4β), 4.98 (m, H-3β), 4.87 (dd, H-1β), 4.33 (H-5α), 3.73 (m, H-5β), 2.04 & 1.86 (m, H-2). MS (calc. mass=232). Obs. m/e 231.13, 215.12, 155.09 (100%).
Reaction SMILES: [Cl:1][C:2]1[C:12]2[O:11][C:10]3[CH:13]=[CH:14][CH:15]=[CH:16][C:9]=3[NH:8][C:7](=O)[C:6]=2[CH:5]=[CH:4][CH:3]=1.[NH:18]1[CH2:24][CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1>C1(C)C=CC=CC=1.C1(OC)C=CC=CC=1.[Ti](Cl)(Cl)(Cl)Cl>[Cl:1][C:2]1[C:12]2[O:11][C:10]3[CH:13]=[CH:14][CH:15]=[CH:16][C:9]=3[N:8]=[C:7]([N:18]3[CH2:24][CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: O=C1Nc2ccccc2Oc2c(Cl)cccc21
Reactant: C1CNCCNC1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: COc1ccccc1
Solvent: Cc1ccccc1
Product: Clc1cccc2c1Oc1ccccc1N=C2N1CCCNCC1

Procedure:
In a like manner as Example 1, 4-Chloro-10,11-dihydro-dibenz[b,f][1,4]oxazepine-11-one (2.46 g, 10.0 mmol) was reacted with homopiperazine (7.41 g, 74.0 mmol) in the presence of titanium tetrachloride (2.09 g, 11.0 mmol) in toluene (55.0 mL) and anisole (2.00 mL) to produce 4-Chloro-11-(1-homopiperazinyl)dibenz[b,f][1,4]oxazepine; viscous oil; yield, 0.92 g (28%). This crude product (0.26 g, 0.79 mmol) was reacted with 1-bromohexane (0.13 mL, 0.16 g, 0.95 mmol) in the presence of sodium hydride (0.044 mg, 60% in oil, 1.11 mmol) in DMF (10.0 mL) to produce 4-Chloro-11-(4-hexylhomopiperazinyl)dibenz[b,f][1,4]oxazepine; viscous oil; yield, 0.17 g (52%).
Reaction SMILES: [C:1]1([CH2:7][SH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.F[C:10]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[CH:12][N:11]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH2:7]([S:8][C:10]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[CH:12][N:11]=1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: SCc1ccccc1
Reactant: Fc1cc(C(F)(F)F)ccn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: FC(F)(F)c1ccnc(SCc2ccccc2)c1
Temperature: 60 °C
Reaction time: 2 h
Yield: 62.5 %

Procedure:
To a solution of phenylmethanethiol (356 μl, 3.03 mmol) and 2-fluoro-4-(trifluoromethyl)pyridine (369 μl, 3.03 mmol) in dimethylformamide (5 mL) was added potassium carbonate (628 mg, 4.54 mmol). The reaction mixture was stirred at 60° C. for 2 hours, then cooled to room temperature, water (10 mL) was added, and the mixture was extracted with ethyl acetate (3×15 mL). The combined organic layers were washed with saturated aqueous sodium hydrogen carbonate solution (20 mL), brine (20 mL), dried over magnesium sulfate, filtered and concentrated in vacuo to give a pale yellow oil. The crude product was purified by chromatography on silica gel (gradient: 0-20% ethyl acetate in isohexane) to afford 2-(benzylthio)-4-(trifluoromethyl)pyridine (510 mg) as a colourless oil. LCMS (Method F, ES-API): RT 3.04 min, m+H=270.1.
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[C:3]1[N:4]=[C:5](N)[S:6][CH:7]=1.[C:11]([Cu])#[N:12]>>[F:1][C:2]([F:10])([F:9])[C:3]1[N:4]=[C:5]([C:11]#[N:12])[S:6][CH:7]=1
Reactant: N#C[Cu]
Reactant: Nc1nc(C(F)(F)F)cs1
Product: N#Cc1nc(C(F)(F)F)cs1
Yield: 33.7 %

Procedure:
4-(trifluoromethyl)thiazol-2-amine (2.52 g, 15 mmol) was reacted with CuCN (2.95 g, 33 mmol) according to the procedure as described in Example 61, Step A to give the title compound as brown oil (0.90 g, 34%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [CH:1]([C:3]1[C:4]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][CH2:19][OH:20])[CH:13]=2)=[N:5][C:6]([S:9][CH3:10])=[N:7][CH:8]=1)=[O:2].[C:21]([Si:25]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)Cl)([CH3:24])([CH3:23])[CH3:22].N1C=CN=C1>CN(C)C=O.CN(C)C1C=CN=CC=1>[Si:25]([O:20][CH2:19][CH2:18][C:14]1[CH:13]=[C:12]([NH:11][C:4]2[C:3]([CH:1]=[O:2])=[CH:8][N:7]=[C:6]([S:9][CH3:10])[N:5]=2)[CH:17]=[CH:16][CH:15]=1)([C:21]([CH3:24])([CH3:23])[CH3:22])([C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: CSc1ncc(C=O)c(Nc2cccc(CCO)c2)n1
Agent: CN(C)c1ccncc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CSc1ncc(C=O)c(Nc2cccc(CCO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)c2)n1
Reaction time: 18 h
Yield: 100.4 %

Procedure:
A solution of 3.4 g (11.7 mmol) of 5-formyl-4-(3-(2-hydroxyethyl)phenylamino)-2-methylthiopyrimidine of Example 37(e) in 50 ml of dimethylformamide was treated with 3.9 g (14 mmol) of tert-butyldiphenylchlorosilane, 2.4 g (35 mmol) of imidazole and 50 mg (0.4 mmol) of 4-(dimethylamino)pyridine. The mixture was stirred for 18 hours and then evaporated. The residue was partitioned between 150 ml of ethyl acetate and 100 ml of 2M aqueous hydrochloric acid. The organic phase was washed with a further 100 ml of 2M aqueous hydrochloric acid, dried over magnesium sulfate, filtered and evaporated to yield 6.2 g (100%) of 4-(3-(2-(tert-butyldiphenylsilyloxy)ethyl)phenylamino)-5-formyl-2-methylthiopyrimidine as a white solid. [Mass spectrum (ESI) MH+ =528].
Reaction SMILES: C([O:5][C:6](=[O:38])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[N:23]2[C:18]([CH:19]=[N:20][C:21]([NH:24][C:25]3[CH:30]=[CH:29][C:28]([N:31]4[CH2:36][CH2:35][N:34]([CH3:37])[CH2:33][CH2:32]4)=[CH:27][CH:26]=3)=[N:22]2)=[CH:17][CH:16]=1)(C)(C)C.C(Cl)Cl.FC(F)(F)C(O)=O>>[CH3:37][N:34]1[CH2:35][CH2:36][N:31]([C:28]2[CH:27]=[CH:26][C:25]([NH:24][C:21]3[N:20]=[CH:19][C:18]4=[CH:17][CH:16]=[C:15]([C:10]5[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=5[O:8][CH2:7][C:6]([OH:38])=[O:5])[N:23]4[N:22]=3)=[CH:30][CH:29]=2)[CH2:32][CH2:33]1
Reactant: CN1CCN(c2ccc(Nc3ncc4ccc(-c5ccccc5OCC(=O)OC(C)(C)C)n4n3)cc2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN1CCN(c2ccc(Nc3ncc4ccc(-c5ccccc5OCC(=O)O)n4n3)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 19.9 %

Procedure:
Into an 8-dram vial, (2-{2-[4-(4-Methyl-piperazin-1-yl)-phenylamino]-pyrrolo[2,1-f][1,2,4]triazin-7-yl}-phenoxy)-acetic acid tert-butyl ester (0.180 g, 0.350 mmol), Methylene chloride (5.0 mL, 78 mmol), and Trifluoroacetic Acid (1.00 mL, 13.0 mmol) were added. The reaction was stirred at room temperature overnight. The reaction was partitioned with saturated NaHCO3 and DCM. The organic was separated, washed with Brine and dried over Na2SO4. The solid was filtered and washed with DCM. The solvent was removed under vacuum. The reaction mixture was purified via HPLC reverse phase chromatography with 0.1% TFA in Water and 0.1% TFA in ACN. The collected fractions were lyophilized to give (2-{2-[4-(4-Methyl-piperazin-1-yl)-phenylamino]-pyrrolo[2,1-f][1,2,4]triazin-7-yl}-phenoxy)-acetic acid as a yellow solid (32 mg, 20%). LCMS (E/I+) 459.14 (M+H). NMR 1H (DMSO-d6)-13.28 (bs, 1H), 9.58 9 bs, 1H), 9.24 (s, 1H), 8.92 (s, 1H), 8.07 (d, 1H, J=7.44 Hz), 7.65 (d, 2H, J=8.12 Hz), 7.40 (t, 1H, J=8.12 Hz), 7.17-7.20 (m , 2H), 7.10 9 d, 1H, J=8.79 Hz), 6.85-6.93 (m, 3H), 4.75 (s, 2H), 3.74 (d, 2H, J=12.85 Hz), 3.53 (d, 2H, J=11.50 Hz), 3.18 (q, 2H, J=10.15 Hz), 2.80-2.93 (m, 5H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1B(O)O.Br[C:13]1[CH:14]=[C:15]2[C:19]3=[C:20]([CH2:22][S:23][CH2:24][CH2:25][N:18]3[C@H:17]3[CH2:26][CH2:27][N:28](C(OC(C)(C)C)=O)[CH2:29][C@@H:16]23)[CH:21]=1>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:13]1[CH:14]=[C:15]2[C:19]3=[C:20]([CH2:22][S:23][CH2:24][CH2:25][N:18]3[C@H:17]3[CH2:26][CH2:27][NH:28][CH2:29][C@@H:16]23)[CH:21]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@H]2[C@@H](C1)c1cc(Br)cc3c1N2CCSC3
Reactant: OB(O)c1c(F)cccc1F
Product: Fc1cccc(F)c1-c1cc2c3c(c1)[C@@H]1CNCC[C@@H]1N3CCSC2

Procedure:
Using 2,6-difluorophenyl boronic acid and following the procedures described in EXAMPLE 9, tert-butyl (7bR,11aS)-6-bromo-1,2,7b,10,11,11a-hexahydro-4H-pyrido[4,3-b][1,4]thiazepino[6,5,4-hi]indole-9(8H)-carboxylate was converted into the title compound of EXAMPLE 14. 1H NMR (CDCl3, 300 MHz): δ 7.19 (m, 1H), 6.93 (m, 2H), 6.83 (m, 3H), 3.81 (m, 2H), 3.59 (m, 1H), 3.41 (m, 1H), 3.21 (m, 2H), 3.0 (m, 2H), 2.82 (m, 3H), 2.60 (m, 1H), 1.80 (m, 2H). LRMS (ES+): 359 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[N:6]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=2)[C:4]([C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)=[N:3]1.Cl.Cl[CH2:22][C:23]1[CH:32]=[CH:31][C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[N:24]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[CH3:1][N:2]1[N:6]=[C:5]([C:7]2[CH:8]=[CH:9][C:10]([O:13][CH2:22][C:23]3[CH:32]=[CH:31][C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[N:24]=3)=[CH:11][CH:12]=2)[C:4]([C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)=[N:3]1
Reactant: Cn1nc(-c2ccncc2)c(-c2ccc(O)cc2)n1
Reactant: ClCc1ccc2ccccc2n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Cn1nc(-c2ccncc2)c(-c2ccc(OCc3ccc4ccccc4n3)cc2)n1
Temperature: 65 °C
Yield: 79.4 %

Procedure:
A mixture of 4-(2-methyl-5-(pyridin-4-yl)-2H-1,2,3-triazol-4-yl)phenol (80 mg, 0.32 mmol), 2-(chloromethyl)quinoline hydrochloride (71 mg, 0.33 mg), and cesium carbonate (414 mg, 1.27 mmol) in dimethylformamide was heated at 65° C. for 20 h, filtered, the filtrate concentrated and chromatographed on silica eluted with ethyl acetate-hexanes providing material containing starting phenol. This was dissolved in ethyl acetate, washed with aqueous NaOH, dried and concentrated giving a colorless solid (100 mg, 80%). 1H NMR (CDCl3, 400 mHz) δ 8.56 (d, 2H, J=6.2 Hz), 8.24 (d,1H, J=8.3 Hz), 8.12 (d, 1H, J=8.3 Hz), 7.85 (d, 1H, J=8.3 Hz), 7.75 (ddd, 1H, J=8.5, 7, 1.6 Hz), 7.70 (d, 1H, J=8.7 Hz), 7.65 (d, 2H, J=6.2 Hz), 7.57 (m, 1H), 7.41 (m, 2H), 7.08 (m, 2H), 5.45 (s, 2H), 4.27 (s, 3H). MS (AP+) m/e 394 (MH+).
Reaction SMILES: Br[CH:2]([C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH:15]([O:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]([CH3:27])([CH3:26])[CH3:25])=[CH:20][CH:19]=2)[CH3:16])=[CH:9][CH:8]=1)[C:3]([O:5][CH3:6])=[O:4].[C:28]([C:32]1[CH:37]=[CH:36][C:35]([OH:38])=[CH:34][CH:33]=1)([CH3:31])([CH3:30])[CH3:29]>O1CCCC1>[CH3:6][O:5][C:3](=[O:4])[CH:2]([O:38][C:35]1[CH:36]=[CH:37][C:32]([C:28]([CH3:31])([CH3:30])[CH3:29])=[CH:33][CH:34]=1)[C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH:15]([O:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]([CH3:27])([CH3:26])[CH3:25])=[CH:20][CH:19]=2)[CH3:16])=[CH:9][CH:8]=1
Reactant: CC(C)(C)c1ccc(O)cc1
Reactant: COC(=O)C(Br)c1ccc(OCC(C)Oc2ccc(C(C)(C)C)cc2)cc1
Solvent: C1CCOC1
Product: COC(=O)C(Oc1ccc(C(C)(C)C)cc1)c1ccc(OCC(C)Oc2ccc(C(C)(C)C)cc2)cc1

Procedure:
As described in Example 71, methyl bromo{p-[2-(p-tert-butylphenoxy)propoxy]phenyl}acetate (0.017 mole) is reacted with 2.55 g of p-tert-butylphenol in 75 ml of tetrahydrofuran at 80° C. for 18 hr to give the product as a gum.
Reaction SMILES: [N:1]1([C:6]2[N:11]=[CH:10][C:9]([CH2:12][O:13][N:14]3C(=O)C4C(=CC=CC=4)C3=O)=[CH:8][CH:7]=2)[CH:5]=[CH:4][CH:3]=[N:2]1>N.CO>[N:1]1([C:6]2[N:11]=[CH:10][C:9]([CH2:12][O:13][NH2:14])=[CH:8][CH:7]=2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: O=C1c2ccccc2C(=O)N1OCc1ccc(-n2cccn2)nc1
Agent: N
Solvent: CO
Product: NOCc1ccc(-n2cccn2)nc1

Procedure:
A solution of the compound of Step 7d (32 g, 0.1 mol) in 100 ml of 2M NH3 in methanol was stirred at 50° C. for 4 hours. The reaction mixture was subsequently concentrated in vacuo and purified on silica gel to give the desired compound of formula (XI) (18.5 g, 97%).
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([S:17][CH3:18])=[CH:13][CH:12]=2)[C:8]([OH:10])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrN1C(=O)CCC1=O.[NH2:46][C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][N:48]=1>C(Cl)Cl>[CH:1]1([CH2:6][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([S:17][CH3:18])=[CH:13][CH:12]=2)[C:8]([NH:46][C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][N:48]=2)=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: Nc1ccccn1
Reactant: CSc1ccc(C(CC2CCCC2)C(=O)O)cc1
Agent: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CSc1ccc(C(CC2CCCC2)C(=O)Nc2ccccn2)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 32.1 %

Procedure:
A solution of 3-cyclopentyl-2-(4-methylsulfanyl-phenyl)propionic acid (200 mg, 0.76 mmol) and triphenylphosphine (198 mg, 0.76 mmol) in methylene chloride (2 mL) was cooled to 0° C. and then treated with N-bromosuccinimide (150 mg, 0.84 mmol) in small portions. After the complete addition of N-bromosuccinimide, the reaction mixture was allowed to warm to 25° C. over 30 min. The orange reaction mixture was then treated with 2-aminopyridine (151 mg, 1.60 mmol), and the resulting reaction mixture was stirred at 25° C. for 15 h. The reaction mixture was then concentrated in vacuo to remove methylene chloride. The remaining residue was partitioned between water and ethyl acetate. The organic layer was washed with a 1N aqueous hydrochloric acid solution, washed with a saturated aqueous sodium bicarbonate solution, dried over magnesium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 3/1 hexanes/ethyl acetate) afforded 3-cyclopentyl-2-(4-methylsulfanyl-phenyl)-N-pyridin-2-yl-propionamide (83 mg, 32%) as a white solid: mp 127-128° C.; EI-HRMS m/e calcd for C20H24N2OS (M+) 340.1609, found 340.1611.