Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][CH:13]=[CH:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH2:20]([O:22][C:23](=[O:30])[CH2:24][CH:25](Br)[CH2:26][CH2:27][CH3:28])[CH3:21].O>CN(C=O)C>[CH2:20]([O:22][C:23](=[O:30])[CH2:24][CH:25]([N:14]1[C:15]2[C:11](=[CH:10][C:9]([O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[CH:17][CH:16]=2)[CH:12]=[CH:13]1)[CH2:26][CH2:27][CH3:28])[CH3:21]
Reactant: c1ccc(COc2ccc3[nH]ccc3c2)cc1
Reactant: CCCC(Br)CC(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCC(CC(=O)OCC)n1ccc2cc(OCc3ccccc3)ccc21
Reaction time: 0.33 h
Yield: 40 %

Procedure:
A solution of 5-benzyloxyindole (5.00 g, 22.4 mmol) in DMF (20 mL) was added dropwise to a stirred solution of sodium hydride (0.91 g, 38.1 mmol) in DMF (50 mL) at 0° C. and stirred for 20 minutes. Ethyl-β-bromocaproate (5.59 g, 26.9 mmol) in DMF (20 mL) was added and the reaction was stirred at room temperature overnight. The reaction was then poured into cold H2O (150 mL) and extracted with ethyl acetate (3×50 mL), dried over magnesium sulfate and concentrated. The residue was purified by flash chromatography on silica gel (40% ethyl acetate in hexane) to give the title compound as oil (40% yield). 1H NNR (CDCl3) δ 7.47 (d, 2H, J=7.2 Hz), 7.38 (t, 2H, J=7.1 Hz), 7.32 (d, 2H, J=8.8 Hz), 7.12 (dd, 2H, J=2.4, 13.7 Hz), 6.94 (dd, 1H, J=2.4, 10.2 Hz), 6.44 (d, 1H, J=3.1 Hz), 5.09 (s, 2H), 4.79 (m, 1H), 3.98 (q, 2H, J=7.1 Hz), 2.80 (m, 2H), 1.90 (m, 2H), 1.25 (m, 2H), 1.07 (t, 3H, J=7.2 Hz), 0.86 (t, 3H, J=7.3 Hz).
Reaction SMILES: O.[Cl:2][C:3]1[C:8]([F:9])=[CH:7][C:6]([N+:10]([O-])=O)=[CH:5][C:4]=1[C@:13]1([CH3:24])[CH2:18][C@@H:17]([C:19]([F:22])([F:21])[F:20])[O:16][C:15]([NH2:23])=[N:14]1.FC(F)(F)C(O)=O>C(O)(=O)C.[Zn]>[NH2:10][C:6]1[CH:7]=[C:8]([F:9])[C:3]([Cl:2])=[C:4]([C@:13]2([CH3:24])[CH2:18][C@@H:17]([C:19]([F:22])([F:21])[F:20])[O:16][C:15]([NH2:23])=[N:14]2)[CH:5]=1
Reactant: C[C@@]1(c2cc([N+](=O)[O-])cc(F)c2Cl)C[C@@H](C(F)(F)F)OC(N)=N1
Agent: [Zn]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: CC(=O)O
Product: C[C@@]1(c2cc(N)cc(F)c2Cl)C[C@@H](C(F)(F)F)OC(N)=N1
Reaction time: 0.17 h
Yield: 57.9 %

Procedure:
To a cooled (cold water) solution of (4S,6S)-4-(2-chloro-3-fluoro-5-nitrophenyl)-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2-amine (1.2 g, 3.37 mmol) in acetic acid (14 mL) was added 2,2,2-trifluoroacetic acid (2.00 mL, 27.0 mmol) followed by zinc, dust (1.19 g, 18.22 mmol) in one portion (exothermic). After stirred for 10 min, water bath was removed. The mixture was stirred at ambient temperature for 1.5 hrs and then concentrated. The residue was basified with 1N NaOH. The aqueous layer was extracted three times with DCM. The organic extracts were combined, dried over sodium sulfate, filtered and concentrated in vacuo. The crude was purified by silica gel chromatography (2-10% MeOH-DCM) to give (4S,6S)-4-(5-amino-2-chloro-3-fluorophenyl)-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2-amine as an off-white solid (0.636 g, 57.9% yield). MS m/z=326 [M+H]+. Calculated for C12H12ClF4N3O: 325.7.
Reaction SMILES: Cl[C:2]1[O:3][C:4]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][C:9]=2[F:18])=[C:5]([CH3:7])[N:6]=1.[C:19](#[N:21])[CH3:20]>>[F:18][C:9]1[CH:10]=[C:11]([C:14]([F:17])([F:16])[F:15])[CH:12]=[CH:13][C:8]=1[C:4]1[O:3][C:2]([NH:21][C:19]2[CH:13]=[CH:12][CH:11]=[C:10]3[C:20]=2[CH2:5][CH:4]([OH:3])[CH2:8][CH2:9]3)=[N:6][C:5]=1[CH3:7]
Reactant: Cc1nc(Cl)oc1-c1ccc(C(F)(F)F)cc1F
Reactant: CC#N
Product: Cc1nc(Nc2cccc3c2CC(O)CC3)oc1-c1ccc(C(F)(F)F)cc1F
Yield: 14 %

Procedure:
A mixture of Example 5D (1.32 g, 4.72 mmol) and Example 1A (1.31 g, 4.72 mmol) in acetonitrile (16 mL) was heated at 150° C. in a microwave reactor for 20 minutes. The solution was cooled and concentrated, and the crude material was chromatographed on silica gel (1 to 20% methanol-CH2Cl2 eluant). The resulting crude product was further purified by trituration with 1:1 hexane-ether, which yielded 0.278 g (14% yield) of the title compound as an off-white solid. 1H NMR (300 MHz, DMSO-d6) δ 9.23 (s, 1H), 7.64-7.76 (m, 3H), 7.51 (m, 1H), 7.10 (t, J=7.8 Hz, 1H), 6.87 (m, 1H), 4.79 (d, J=4.0 Hz, 1H), 3.91 (m, 1H), 2.67-2.98 (m, 3H), 2.52 (m, 1H), 2.18 (s, 3H), 1.86 (m, 1H), 1.61 (m, 1H). MS (ESI+) m/z 407 (M+H)+, 429 (M+Na)+. Anal Calcd for C21H18F4N2O2: C, 62.07; H, 4.46; N, 6.89. Found: C, 61.90; H, 4.37; N, 6.85.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]2[NH:11][C@H:10]([C:12]([OH:14])=O)[CH2:9][S:8]2)[CH:2]=1.[F:15][C:16]1[CH:21]=[CH:20][C:19]([CH:22]([C:33]2[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=2)[O:23][CH2:24][CH2:25][N:26]([CH3:32])C(NC)CC)=[CH:18][CH:17]=1>>[CH3:6][N:1]([CH2:2][CH2:3][CH2:4][N:26]([CH2:25][CH2:24][O:23][CH:22]([C:19]1[CH:18]=[CH:17][C:16]([F:15])=[CH:21][CH:20]=1)[C:33]1[CH:34]=[CH:35][C:36]([F:39])=[CH:37][CH:38]=1)[CH3:32])[C:12]([C@@H:10]1[CH2:9][S:8][CH:7]([C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)[NH:11]1)=[O:14]
Reactant: CCC(NC)N(C)CCOC(c1ccc(F)cc1)c1ccc(F)cc1
Reactant: O=C(O)[C@@H]1CSC(c2cccnc2)N1
Product: CN(CCCN(C)C(=O)[C@@H]1CSC(c2cccnc2)N1)CCOC(c1ccc(F)cc1)c1ccc(F)cc1
Yield: 52 %

Procedure:
Following a procedure similar to that described in Example 1, but using (4R)-2-(3-pyridyl)thiazolidine-4-carboxylic acid and N-{2-[bis(4-fluorophenyl)methoxy]ethyl}-N-methyl-N'-methylpropanediamine (prepared as described in Preparation 3), the title compound was obtained in a yield of 52%.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[F:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][C:19]([OH:21])=[O:20])=[CH:14][CH:13]=1.[Cl:22][CH2:23][CH2:24][CH2:25][CH2:26]I>C1COCC1>[Cl:22][CH2:23][CH2:24][CH2:25][CH2:26][CH:18]([C:15]1[CH:14]=[CH:13][C:12]([F:11])=[CH:17][CH:16]=1)[C:19]([OH:21])=[O:20]
Reactant: O=C(O)Cc1ccc(F)cc1
Reactant: ClCCCCI
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(O)C(CCCCCl)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 84 %

Procedure:
Step AE (1): NaHMDS (1.0 M in THF, 200 mL, 200 mmol) was added to a stirred solution of 2-(4-fluorophenyl)acetic acid (15.41 g, 100 mmol) in THF (200 mL) at 0° C. The resulting mixture was aged for 20 min at 0° C. and neat 1-chloro-4-iodobutane (21.85 g, 100 mmol) was added. The mixture was allowed to warm to rt. After 16 hr, the reaction was quenched with water (3 mL). The crude mixture was concentrated in vacuo. Aqueous NaOH (1 M, 150 mL) was added to the residue and the resulting mixture was extracted with Et2O (2×250 mL). The basic layer was acidified with aqueous HCl (1 M, 200 mL) and the resulting solution was extracted with Et2O (2×250 mL). The combined organic layers from the acidic extraction were washed with mixture of brine/1N HCl/sodium sulfite, dried (MgSO4), filtered, and concentrated in vacuo to afford 6-chloro-2-(4-fluorophenyl)hexanoic acid (22.8 g, 84 mmol, 84% yield) as a viscous oil that slowly solidified upon standing to provide a light brown solid. LC-MS (M−H)− 243.1. 1H NMR (500 MHz, chloroform-d) δ ppm 7.29 (dd, J=8.70, 5.34 Hz, 2 H) 7.03 (t, J=8.70 Hz, 2 H) 3.56 (t, J=7.63 Hz, 1 H) 3.51 (t, J=6.56 Hz, 2 H) 2.06-2.14 (m, 1 H) 1.74-1.85 (m, 3 H) 1.33-1.51 (m, 2 H).
Reaction SMILES: O[CH2:2][C:3]1[NH:7][N:6]=[C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]3[N:19]=[C:18]4[N:20]([CH2:24][CH2:25][CH:26]5[CH2:31][CH2:30][O:29][CH2:28][CH2:27]5)[C:21](=[O:23])[NH:22][C:17]4=[N:16][CH:15]=3)=[CH:10][CH:9]=2)[N:4]=1.O=C1NC2=NC=C(C3C=CC(C(=N)OCC)=CC=3)N=C2[N:34]1CCC1CCOCC1.OCC(NN)=O.C(N(CC)CC)C>C(O)C>[NH2:34][CH2:2][C:3]1[NH:7][N:6]=[C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]3[N:19]=[C:18]4[N:20]([CH2:24][CH2:25][CH:26]5[CH2:27][CH2:28][O:29][CH2:30][CH2:31]5)[C:21](=[O:23])[NH:22][C:17]4=[N:16][CH:15]=3)=[CH:10][CH:9]=2)[N:4]=1
Reactant: O=c1[nH]c2ncc(-c3ccc(-c4n[nH]c(CO)n4)cc3)nc2n1CCC1CCOCC1
Reactant: CCOC(=N)c1ccc(-c2cnc3[nH]c(=O)n(CCC4CCOCC4)c3n2)cc1
Agent: NNC(=O)CO
Solvent: CCO
Solvent: CCN(CC)CC
Product: NCc1nc(-c2ccc(-c3cnc4[nH]c(=O)n(CCC5CCOCC5)c4n3)cc2)n[nH]1
Temperature: 110 °C
Reaction time: 16 h
Yield: 49 %

Procedure:
6-(4-(5-(Hydroxymethyl)-1H-1,2,4-triazol-3-yl)phenyl)-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one. Ethyl 4-(2-oxo-3-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-2,3-dihydro-1H-imidazo[4,5-b]pyrazin-5-yl)benzimidate (See Example 195.B) (0.250 g, 0.63 mmol) in ethanol (20 mL) was treated with 2-hydroxyacetohydrazide (0.17 g, 1.9 mmol) and triethylamine (0.26 mL, 1.9 mmol), and the resulting reaction mixture was stirred in a sealed tube at 110° C. for 16 h. The cooled reaction solvent removed under reduced pressure. The resulting material was purified using reverse-phase semi-preparatory HPLC (15-50% acetonitrile+0.1% TFA in H2O+0.1% TFA, over 30 min). Fractions containing clean product were passed through a Phenomenex Strata-X-C ion exchange column to remove TFA. The column was washed successively with water, methanol, and then 5% ammonium hydroxide in methanol. The product came off with the 5% ammonium hydroxide in methanol eluent and was concentrated on a rotary evaporator. The residue was triturated with ethyl ether in hexane to make a fine powder and dried under vacuum at 50° C. to give the desired product (0.130 g, 49%) as a white solid. MS (ESI) m/z 422.3[M+1]+.
Reaction SMILES: [S:1]([O:8]S(C(F)(F)F)(=O)=O)([C:4]([F:7])([F:6])[F:5])(=[O:3])=[O:2].[Cl:16][C:17]1[CH:18]=[C:19]([CH:24]=[CH:25][C:26]=1O)[C:20]([O:22][CH3:23])=[O:21].C(N(CC)CC)C>CN(C1C=CN=CC=1)C.ClCCl.CCCCCC>[CH3:23][O:22][C:20](=[O:21])[C:19]1[CH:24]=[CH:25][C:26]([O:8][S:1]([C:4]([F:7])([F:6])[F:5])(=[O:3])=[O:2])=[C:17]([Cl:16])[CH:18]=1
Reactant: COC(=O)c1ccc(O)c(Cl)c1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCCCCC
Product: COC(=O)c1ccc(OS(=O)(=O)C(F)(F)F)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Add dropwise triflic anhydride (6.7 ml, 39.8 mmol) to a solution of methyl 3-chloro-4-hydroxybenzoate (5.42 g, 29.0 mmol), DMAP (490 mg, 4.0 mmol) and triethylamine (5.6 ml, 40.1 mmol) in anhydrous dichloromethane (200 ml). Stir the mixture at room temperature overnight under nitrogen atmosphere. Quench the mixture by addition of a saturated aq. solution of ammonium chloride. Separate the organic layer and extract the aqueous layer with dichloromethane (×3). Wash the combined organic layers with saturated aq. sodium chloride, dry over anhydrous sodium sulfate, filter and concentrate to yield a crude brown oil. Take up this crude oil in hexane and wash the organic layer with water (×3), dry over anhydrous sodium sulfate, filter and concentrate to. yield the title compound.
Reaction SMILES: C([Mg]Cl)(C)C.[CH:6]1([NH2:9])[CH2:8][CH2:7]1.C[O:11][C:12](=O)[C:13]1[CH:18]=[C:17]([N:19]2[CH:24]=[CH:23][N:22]=[C:21]([NH:25][C:26]3([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=4[OH:35])[CH2:28][CH2:27]3)[C:20]2=[O:36])[C:16]([CH3:37])=[C:15]([F:38])[CH:14]=1.Cl>C1COCC1.O>[CH:6]1([NH:9][C:12](=[O:11])[C:13]2[CH:18]=[C:17]([N:19]3[CH:24]=[CH:23][N:22]=[C:21]([NH:25][C:26]4([C:29]5[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=5[OH:35])[CH2:28][CH2:27]4)[C:20]3=[O:36])[C:16]([CH3:37])=[C:15]([F:38])[CH:14]=2)[CH2:8][CH2:7]1
Reactant: NC1CC1
Reactant: COC(=O)c1cc(F)c(C)c(-n2ccnc(NC3(c4ccccc4O)CC3)c2=O)c1
Agent: CC(C)[Mg]Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: Cc1c(F)cc(C(=O)NC2CC2)cc1-n1ccnc(NC2(c3ccccc3O)CC2)c1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Isopropylmagnesium chloride (30.1 ml of a 2M solution in THF) was added over 20 min to a solution of cyclopropylamine (10.61 mL) and 3-fluoro-5-[3-[[1-(2-hydroxyphenyl)cyclopropyl]amino]-2-oxo-1(2H)-pyrazinyl]-4-methyl-benzoic acid methyl ester (Example 259b, 6.16 g) in tetrahydrofuran (200 mL) and the reaction stirred at room temperature under nitrogen for 1 h. Water (100 mL) and 2M HCl (200 mL) were cautiously added and the aqueous layer extracted with dichloromethane (3×200 mL) and the combined organic extracts dried (MgSO4) and the solvent removed to give the subtitle compound (5.00 g).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.O.[CH3:8][O:9][C:10]1[CH:11]=[C:12]([CH:15]=[C:16]([O:20][CH3:21])[C:17]=1[O:18][CH3:19])[CH2:13][Cl:14]>C(O)C>[ClH:14].[CH3:21][O:20][C:16]1[CH:15]=[C:12]([CH:11]=[C:10]([O:9][CH3:8])[C:17]=1[O:18][CH3:19])[CH2:13][N:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1
Reactant: COc1cc(CCl)cc(OC)c1OC
Reactant: C1CNCCN1
Solvent: CCO
Solvent: O
Product: COc1cc(CN2CCNCC2)cc(OC)c1OC
Product: Cl
Reaction time: 0.5 h

Procedure:
A mixture of 4.48 g of piperazine (6 hydrates) and 10 ml of ethanol was warmed at 65°-70° C. to give a homogeneous solution. To the solution were added 4.09 g of piperazine?2HCl H2O and 5 ml of ethanol. At the same temperature, 5.0 g of 3,4,5-trimethoxybenzyl chloride and 15 ml of ethanol were further added at once. The resulting mixture was stirred at 65°-70° C. for additional 30 min. and then chilled with ice. A precipitated insoluble was removed by filtration, and the resulting mother liquer was concentrated. To the concentrated mother liquer was added 8 ml of ethanolic 6-N hydrochloric acid. The mixture was stirred for 30 min under chilling with ice. Precipitated crystals were collected by filtration, washed with ethanol and dried to give hydrochloride of the desired compound.
Reaction SMILES: CS[C:3]1[N:4]=[N:5][C:6]([C:21]#[N:22])=[C:7]([N:9]2[CH2:14][CH2:13][N:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH2:11][CH2:10]2)[N:8]=1.[CH2:23]([CH2:25][NH2:26])[OH:24]>>[OH:24][CH2:23][CH2:25][NH:26][C:3]1[N:4]=[N:5][C:6]([C:21]#[N:22])=[C:7]([N:9]2[CH2:14][CH2:13][N:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH2:11][CH2:10]2)[N:8]=1
Reactant: NCCO
Reactant: CSc1nnc(C#N)c(N2CCN(c3ccccc3)CC2)n1
Product: N#Cc1nnc(NCCO)nc1N1CCN(c2ccccc2)CC1

Procedure:
In analogy to the procedure described in example 84c, 3-methylsulfanyl-5-(4-phenyl-piperazin-1-yl)-[1,2,4]triazine-6-carbonitrile was treated with ethanolamine in a sealed tube at 140° C. during 18 hours to yield 3-(2-hydroxy-ethylamino)-5-(4-phenyl-piperazin-1-yl)-[1,2,4]triazine-6-carbonitrile as an amorphous, white solid; MS: [M+H]+=326.
Reaction SMILES: C([O:4][C:5]1[C:6]([CH3:35])=[C:7]2[C:12](=[C:13]([CH3:16])[C:14]=1[CH3:15])[O:11][C:10]([CH2:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][CH:27](Cl)[C:28](OCC)=[O:29])=[CH:22][CH:21]=1)(O)[CH2:9][C:8]2=[O:34])(=O)C.[NH2:36][C:37](N)=[S:38].S1(CCCC1)(=O)=[O:41].Cl>O.COCCO>[OH:4][C:5]1[C:6]([CH3:35])=[C:7]2[C:12](=[C:13]([CH3:16])[C:14]=1[CH3:15])[O:11][CH:10]([CH2:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][CH:27]3[S:38][C:37](=[O:41])[NH:36][C:28]3=[O:29])=[CH:22][CH:21]=1)[CH2:9][C:8]2=[O:34]
Reactant: NC(N)=S
Reactant: CCOC(=O)C(Cl)Cc1ccc(OCC2(O)CC(=O)c3c(C)c(OC(C)=O)c(C)c(C)c3O2)cc1
Reactant: O=S1(=O)CCCC1
Agent: Cl
Solvent: COCCO
Solvent: O
Product: Cc1c(C)c2c(c(C)c1O)C(=O)CC(COc1ccc(CC3SC(=O)NC3=O)cc1)O2

Procedure:
The procedure described in Example 3 was repeated, but using 2.2 g of ethyl 3-[4-(6-acetoxy-2-hydroxy-5,7,8-trimethyl-4-oxochroman-2-ylmethoxy) phenyl]-2-chloropropionate (prepared as described in Preparation 45), 0.8 g of thiourea, 4.5 g of sulfolane, 70 ml of ethylene glycol monomethyl ether, 8 ml of water and 4 ml of 35% w/v aqueous hydrochloric acid, to give the title compound, melting at 249°-252° C.
Reaction SMILES: [OH:1][C:2]1[C:3](=[O:13])[C:4]2[C:9]([C:10](=[O:12])[CH:11]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2>C1C=CC=CC=1.[Ag]>[OH:1][CH2:2][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][O:12][C:10]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](=[O:13])[C:2](=[O:1])[CH:11]=1
Reactant: O=C1C=C(O)C(=O)c2ccccc21
Agent: [Ag]
Solvent: c1ccccc1
Product: O=C1C=C(OCCCCCCO)c2ccccc2C1=O
Yield: 100.8 %

Procedure:
A mixture of 6-bromohexanol-1 (4.5 g, 24.85 mmol) and the silver salt of 2-hydroxy-1,4-naphthoquinone (6.46 g, 23.01 mmol) in benzene (24 mL) was stirred for 48 h at 60° C. The reaction mixture was worked up as described for 2 and crystallized from hexane to afford a yellow solid (3.18 g, 50%). mp 96-98° C., 1H NMR (CDCl3) 8.12 (d, J=7.5 Hz, 1H), 7.87 (d, J=7.7 Hz, 1H), 7.70 (t, J=7.5 Hz, 1H), 7.58 (t, J=7.5 Hz, 1H), 5.95 (s, 1H), 4.15 (t, J=6.3 Hz, 2H), 3.69 (t, J=6.2 Hz, 2H), 1.92-1.97 (m, 2H), 1.3-1.8 (m, 7H)
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]([OH:9])=O)=[CH:5][C:4]([C:10]([F:13])([F:12])[F:11])=[N:3]1.O1CCCC1.C(Cl)(=O)C(Cl)=O.[NH2:25][C:26]1[CH:27]=[C:28]([CH:45]=[CH:46][C:47]=1[CH3:48])[O:29][C:30]1[CH:31]=[CH:32][C:33]2[N:34]([CH:36]=[C:37]([NH:39][C:40]([CH:42]3[CH2:44][CH2:43]3)=[O:41])[N:38]=2)[N:35]=1>CN(C)C=O.CN(C)C(=O)C>[CH:42]1([C:40]([NH:39][C:37]2[N:38]=[C:33]3[CH:32]=[CH:31][C:30]([O:29][C:28]4[CH:45]=[CH:46][C:47]([CH3:48])=[C:26]([NH:25][C:7]([C:6]5[N:2]([CH3:1])[N:3]=[C:4]([C:10]([F:13])([F:12])[F:11])[CH:5]=5)=[O:9])[CH:27]=4)=[N:35][N:34]3[CH:36]=2)=[O:41])[CH2:43][CH2:44]1
Reactant: Cn1nc(C(F)(F)F)cc1C(=O)O
Reactant: Cc1ccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)cc1N
Agent: O=C(Cl)C(=O)Cl
Solvent: CC(=O)N(C)C
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: Cc1ccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)cc1NC(=O)c1cc(C(F)(F)F)nn1C
Yield: 77.5 %

Procedure:
In the same manner as in Example 259 and using 1-methyl-3-(trifluoromethyl)-1H-pyrazole-5-carboxylic acid (160 mg, 0.80 mmol), tetrahydrofuran (5 mL), N,N-dimethylformamide (1 drop), oxalyl chloride (170 μL, 2.0 mmol), N-[6-(3-amino-4-methylphenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (200 mg, 0.62 mmol) and N,N-dimethylacetamide (7 mL) as starting materials, the title compound (240 mg, 76%) was obtained as a white solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:22]=[C:23]([CH3:25])[N:24]=1)[C:5]([NH:7][CH:8]([C:10]1[CH:11]=[N:12][C:13]([O:16][CH2:17][C:18]([F:21])([F:20])[F:19])=[CH:14][CH:15]=1)[CH3:9])=[O:6].C([Sn](CCCC)(CCCC)[C:31]1[S:32][CH:33]=[CH:34][N:35]=1)CCC.CN(C)C=O>C(OCC)(=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:25][C:23]1[CH:22]=[C:4]([CH:3]=[C:2]([C:31]2[S:32][CH:33]=[CH:34][N:35]=2)[N:24]=1)[C:5]([NH:7][CH:8]([C:10]1[CH:11]=[N:12][C:13]([O:16][CH2:17][C:18]([F:21])([F:19])[F:20])=[CH:14][CH:15]=1)[CH3:9])=[O:6]
Reactant: Cc1cc(C(=O)NC(C)c2ccc(OCC(F)(F)F)nc2)cc(Br)n1
Reactant: CCCC[Sn](CCCC)(CCCC)c1nccs1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1cc(C(=O)NC(C)c2ccc(OCC(F)(F)F)nc2)cc(-c2nccs2)n1
Temperature: 120 °C
Reaction time: 6 h
Yield: 10.7 %

Procedure:
A mixture of 2-bromo-6-methyl-N-(1-(6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)isonicotinamide (25 mg, 0.060 mmol, Step-1, single enantiomer), 2-tributylstannylthiazole (27 mg, 0.072 mmol), bis(triphenylphosphine)palladium(II) dichloride (8.4 mg, 0.012 mmol) and N,N-dimethylformamide (1 mL) is stirred at 120° C. under nitrogen atmosphere for 6 hours. After cooling to room temperature, the mixture is diluted with ethyl acetate (20 mL) and washed with water (20 mL). The organic layer is dried over sodium sulfate and concentrated under reduced pressure. The residue is purified by a strong cation exchange cartridge (BondElute(registered trademark) SCX, 1 g/6 mL, Varian Inc.) and then by preparative LC-MS to give 2.7 mg (11% yield) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9](I)[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH:12]([CH3:14])[CH3:13].B1([C:21]2[CH:26]=[CH:25][CH:24]=[N:23][CH:22]=2)OCCCO1.C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O.C(O)C>[Cl:1][C:2]1[N:10]=[C:9]([C:21]2[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=2)[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH:12]([CH3:14])[CH3:13]
Reactant: CC(C)n1cnc2c(Cl)nc(I)nc21
Reactant: c1cncc(B2OCCCO2)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)n1cnc2c(Cl)nc(-c3cccnc3)nc21
Temperature: 80 °C
Reaction time: 4 h

Procedure:
A round-bottom flask was charged with 6-chloro-2-iodo-9-isopropyl-9H-purine (1.2 g, 3.7 mmol), pyridine-3-boronic acid 1,3-propanediol cyclic ester (0.91 g, 5.6 mmol), and tetrakis(triphenylphosphine)palladium(0) (430 mg, 0.37 mmol). To this mixture was added toluene (60 ml), ethanol (6 ml) and aqueous sodium carbonate solution (2M, 15 ml). The flask was sealed and the reaction mixture was stirred at 80° C. for 4 h. Water was added to the cooled mixture, which was extracted with ethyl acetate (50 ml×3). The organic fractions were combined, dried over sodium sulfate, and concentrated. The residue was purified by column chromatography on silica gel, eluting with 30 to 70% EtOAc in hexane to afford the title compound as a solid. 1H NMR (400 MHz, CD3OD) δ 9.60 (d, 1H), 8.90-8.87 (m, 1H), 8.68 (s, 1H), 8.67 (d, 1H), 7.63-7.60 (m, 1H), 5.12-5.05 (m, 1H), 1.74 (d, 6H). MS m/z 274.1 (M+1).
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[NH:14][N:13]=[C:12]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)[C:11]=2[CH2:10][CH2:9]1)=O)(C)(C)C.Br[CH:26]1[CH2:31][CH2:30][CH:29]([CH3:32])[CH2:28][CH2:27]1.C(OC(N1CCC2NN(C3CCC(C)CC3)C(C3C=CC(Cl)=CC=3)C=2CC1)=O)(C)(C)C>>[Cl:24][C:21]1[CH:20]=[CH:19][C:18]([C:12]2[C:11]3[CH2:10][CH2:9][NH:8][CH2:17][CH2:16][C:15]=3[N:14]([CH:26]3[CH2:31][CH2:30][CH:29]([CH3:32])[CH2:28][CH2:27]3)[N:13]=2)=[CH:23][CH:22]=1
Reactant: CC1CCC(Br)CC1
Reactant: CC(C)(C)OC(=O)N1CCc2[nH]nc(-c3ccc(Cl)cc3)c2CC1
Agent: CC1CCC(N2NC3=C(CCN(C(=O)OC(C)(C)C)CC3)C2c2ccc(Cl)cc2)CC1
Product: CC1CCC(n2nc(-c3ccc(Cl)cc3)c3c2CCNCC3)CC1
Yield: 10.7 %

Procedure:
The title compound (11 mg) was prepared from 3-(4-chloro-phenyl)-4,5,7,8-tetrahydro-1H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 103, Step B; 0.30 mmol) using 1-bromo-4-methyl-cyclohexane (1.0 mmol) in place of chloro-cyclobutane. The reaction sequence also yielded 3-(4-chloro-phenyl)-2-(4-methyl-cyclohexyl)-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester in the alkylation step. MS (ESI): exact mass calculated for C20H26ClN3, 343.18; found, m/z 344.4 [M+H]+. 1H NMR (500 MHz, CD3OD): 7.40-7.34 (m, 4H), 4.10-4.06 (m, 1H), 3.39-3.37 (m, 2H), 3.28-3.26 (m, 2H), 3.17-3.15 (m, 2H), 2.94-2.91 (m, 2H), 1.96-1.89 (m, 2H), 1.83-1.76 (m, 4H), 1.52-1.10 (m, 2H), 0.91-0.87 (m, 4H).
Reaction SMILES: [N:1]([C:4]1[CH:5]=[C:6]([CH:27]=[CH:28][C:29]=1[CH3:30])[C:7]([NH:9][C:10]1[CH:15]=[C:14]([C:16]([CH3:19])([CH3:18])[CH3:17])[CH:13]=[C:12]([NH:20][S:21]([CH3:24])(=[O:23])=[O:22])[C:11]=1[O:25][CH3:26])=[O:8])=[N+:2]=[N-:3].[C:31]([C:33]1[CH:34]=[N:35][CH:36]=[CH:37][C:38]=1[CH3:39])#[CH:32]>>[C:16]([C:14]1[CH:13]=[C:12]([NH:20][S:21]([CH3:24])(=[O:22])=[O:23])[C:11]([O:25][CH3:26])=[C:10]([NH:9][C:7](=[O:8])[C:6]2[CH:27]=[CH:28][C:29]([CH3:30])=[C:4]([N:1]3[CH:32]=[C:31]([C:33]4[CH:34]=[N:35][CH:36]=[CH:37][C:38]=4[CH3:39])[N:3]=[N:2]3)[CH:5]=2)[CH:15]=1)([CH3:18])([CH3:19])[CH3:17]
Reactant: C#Cc1cnccc1C
Reactant: COc1c(NC(=O)c2ccc(C)c(N=[N+]=[N-])c2)cc(C(C)(C)C)cc1NS(C)(=O)=O
Product: COc1c(NC(=O)c2ccc(C)c(-n3cc(-c4cnccc4C)nn3)c2)cc(C(C)(C)C)cc1NS(C)(=O)=O

Procedure:
Example 20 was prepared from 3-azido-N-(5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-4-methyl-benzamide and 3-ethynyl-4-methyl-pyridine in the same manner as Example 15. ESI MS m/z 549 [C28H32N6O4S+H]+.