Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:31])[NH:7][CH:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[C:16]3[N:17]([C:21]([C:24]4[CH:29]=[CH:28][CH:27]=[C:26](Br)[N:25]=4)=[CH:22][N:23]=3)[CH:18]=[CH:19][N:20]=2)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[Cl:32][C:33]1[CH:40]=[CH:39][CH:38]=[CH:37][C:34]=1[CH2:35][NH2:36].CN(C1C(C2C(P(C3CCCCC3)C3CCCCC3)=CC=CC=2)=CC=CC=1)C.CC([O-])(C)C.[Na+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:1]([O:5][C:6](=[O:31])[NH:7][CH:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[C:16]3[N:17]([C:21]([C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([NH:36][CH2:35][C:34]5[CH:37]=[CH:38][CH:39]=[CH:40][C:33]=5[Cl:32])[N:25]=4)=[CH:22][N:23]=3)[CH:18]=[CH:19][N:20]=2)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NC1CCC(Nc2nccn3c(-c4cccc(Br)n4)cnc23)CC1
Reactant: NCc1ccccc1Cl
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CN(C)c1ccccc1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)NC1CCC(Nc2nccn3c(-c4cccc(NCc5ccccc5Cl)n4)cnc23)CC1
Temperature: 110 °C

Procedure:
A mixture of {4-[3-(6-bromo-pyridin-2-yl)-imidazo[1,2-a]pyrazin-8-ylamino]-cyclohexyl}-carbamic acid tert-butyl ester (from Example 40 supra) (0.244 g, 0.5 mmol), 2-chloro-benzylamine (0.143 g, 1.0 mmol), Pd2(dba)3 (30 mg), Davephos (40 mg), NaOtBu (100 mg, 0.1 mmol) in dioxane (12 mL) in a sealed tube was bubbled with N2 for several minutes and then heated under N2 at 110° C. overnight. The solution was then cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by chromatography (CH2Cl2:MeOH, 100:1) to give (4-{3-[6-(2-chloro-benzylamino)-pyridin-2-yl]-imidazo[1,2-a]pyrazin-8-ylamino}-cyclohexyl)-carbamic acid tert-butyl ester. (Yield 227 mg, 83%).
Reaction SMILES: C([O:5]C(NCC(O)=O)=O)(C)(C)C.[CH:13]1([N:19]=[C:20]=[N:21][CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1>C(#N)C>[C:20]([NH:19][CH:13]1[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]1)([NH:21][CH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1)=[O:5]
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Solvent: CC#N
Product: O=C(NC1CCCCC1)NC1CCCCC1
Reaction time: 3 h

Procedure:
To a solution of 9.45 g of N-(t-butoxycarbonyl)-glycine in 60 ml of acetonitrile was added 6.13 g of dicyclohexylcarbodiimide with stirring under ice-cooling. After three hours, dicyclohexylurea produced was filtered off, and the filtrate was concentrated. The oily residue was dissolved in 15 ml of anhydrous pyridine, and to the solution was added 5.00 g of 3'-O-(4-chlorobenzyl)-2'-deoxy-5-fluorouridine. The mixture was left to stand for three hours at room temperature and for 30 minutes at a temperature of 40° C. To the mixture was added 5 ml of water at room temperature and the mixture was left to stand for 30 minutes and then concentrated. The residue was dissolved in 50 ml of ethyl acetate, and the solution was washed three times with saturated aqueous solution of sodium hydrogen carbonate and twice with saturated aqueous solution of sodium chloride. Further the solution was dried over anhydrous magnesium sulfate and concentrated. The residue was placed on silica gel column and eluted with 1% methanol-chloroform, giving 5.33 g (75%) of 5'-O-[N-(t-butoxycarbonyl)glycyl]-3'-O-(4-chlorobenzyl)-2'-deoxy-5-fluorouridine.
Reaction SMILES: FC(F)(F)C(O)=O.CC([N:12]([C:16]([CH3:36])([CH3:35])[C:17]([NH:19][C:20]1[CH:21]=[N:22][C:23]([O:26][C:27]2[C:32]([CH3:33])=[CH:31][CH:30]=[CH:29][C:28]=2[CH3:34])=[CH:24][CH:25]=1)=[O:18])C(=O)[O-])(C)C>ClCCl>[CH3:33][C:32]1[CH:31]=[CH:30][CH:29]=[C:28]([CH3:34])[C:27]=1[O:26][C:23]1[N:22]=[CH:21][C:20]([NH:19][C:17](=[O:18])[C:16]([CH3:35])([CH3:36])[NH2:12])=[CH:25][CH:24]=1
Reactant: Cc1cccc(C)c1Oc1ccc(NC(=O)C(C)(C)N(C(=O)[O-])C(C)(C)C)cn1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cccc(C)c1Oc1ccc(NC(=O)C(C)(C)N)cn1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
In a 50 mL round-bottomed flask 1,1-dimethylethyl[2-({6-[(2,6-dimethylphenyl)oxy]-3-pyridinyl}amino)-1,1-dimethyl-2-oxoethyl]carbamate (Intermediate 79, 202.1 mg) was dissolved in dichloromethane (2 mL) to give a pale yellow solution. Trifluoroacetic acid (2 mL, 26.0 mmol) was added. The reaction mixture was stirred at room temperature for 20 minutes. The solvent was evaporated under vacuum to afford a yellow oil which was charged on a 5 g SCX cartridge. It was then flushed with 25 mL of MeOH followed by 25 mL of 2M solution of ammonia in MeOH. The ammonia eluate was evaporated under vacuum to afford the title compound as a yellow oil which solidified (144.4 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([C:51]2[CH:56]=[CH:55][C:54]([O:57][CH3:58])=[CH:53][CH:52]=2)[O:10][CH:11]([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[CH:12]2[CH2:16][CH:15]([OH:17])[CH2:14][N:13]2[C:18](=[O:44])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][NH:24][C:25](=[O:43])[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])=[CH:5][CH:4]=1.[C:59]1(=[O:65])[O:64][C:62](=[O:63])[CH2:61][CH2:60]1>>[CH3:58][O:57][C:54]1[CH:53]=[CH:52][C:51]([CH:9]([C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)[O:10][CH:11]([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[CH:12]2[N:13]([C:18](=[O:44])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][NH:24][C:25](=[O:43])[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])[CH2:14][CH:15]([O:17][C:59](=[O:65])[CH2:60][CH2:61][C:62]([OH:64])=[O:63])[CH2:16]2)=[CH:56][CH:55]=1
Reactant: O=C1CCC(=O)O1
Reactant: CCCCCCCCCCCCCCCCCC(=O)NCCCCCC(=O)N1CC(O)CC1C(OC(c1ccc(OC)cc1)c1ccc(OC)cc1)c1ccccc1
Product: CCCCCCCCCCCCCCCCCC(=O)NCCCCCC(=O)N1CC(OC(=O)CCC(=O)O)CC1C(OC(c1ccc(OC)cc1)c1ccc(OC)cc1)c1ccccc1

Procedure:
Using the above described procedure, the amide 102e (2.4 g, 3 mmol) was treated with succinic anhydride and after work-up the amide was isolated as a foam (2.69 g, 99%) and this was used in the next step without further purification.
Reaction SMILES: Cl.[CH3:2][C:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[O:5][C:4]=1[C:12]([NH:14][C:15]1([C:21]([NH:23][CH:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH:25]2[OH:30])=[O:22])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)=[O:13].Br[C:32]1[CH:37]=[C:36]([F:38])[CH:35]=[CH:34][C:33]=1[C:39]([F:42])([F:41])[F:40]>>[CH3:2][C:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[O:5][C:4]=1[C:12]([NH:14][C:15]1([C:21]([NH:23][CH:24]2[CH2:29][CH2:28][N:27]([C:34]3[CH:35]=[C:36]([F:38])[CH:37]=[CH:32][C:33]=3[C:39]([F:40])([F:41])[F:42])[CH2:26][C:25]2=[O:30])=[O:22])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]1)=[O:13]
Reactant: Cc1c(C(=O)NC2(C(=O)NC3CCNCC3O)CCCCC2)oc2ccccc12
Reactant: Fc1ccc(C(F)(F)F)c(Br)c1
Agent: Cl
Product: Cc1c(C(=O)NC2(C(=O)NC3CCN(c4cc(F)ccc4C(F)(F)F)CC3=O)CCCCC2)oc2ccccc12

Procedure:
In accordance with the same procedure as in Example 85, except that 4-[N-[1-[N-(3-methyl-benzofuran-2-ylcarbonyl)amino]cyclohexanecarbonyl]amino]-3-piperidinol hydrochloride was used instead of 4-[N-[1-[N-(furan-2-ylcarbonyl)amino]cyclohexanecarbonyl]amino]-3-piperidinol hydrochloride and 1-bromo-2-trifluoromethyl-5-fluorobenzene was used instead of 1-bromotoluene in Step 1 thereof, 128 mg of the titled compound was prepared.
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[NH:7][C:8]1[CH:13]=[CH:12][C:11](I)=[CH:10][C:9]=1[N+:15]([O-:17])=[O:16])([CH3:4])([CH3:3])[CH3:2].[F:19][C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[C:22]([O:29][CH2:30][O:31][CH3:32])[CH:21]=1>>[C:1]([O:5][C:6](=[O:18])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:23]2[CH:24]=[CH:25][C:20]([F:19])=[CH:21][C:22]=2[O:29][CH2:30][O:31][CH3:32])=[CH:10][C:9]=1[N+:15]([O-:17])=[O:16])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)Nc1ccc(I)cc1[N+](=O)[O-]
Reactant: COCOc1cc(F)ccc1B(O)O
Product: COCOc1cc(F)ccc1-c1ccc(NC(=O)OC(C)(C)C)c([N+](=O)[O-])c1

Procedure:
Prepared from (4-iodo-2-nitro-phenyl)-carbamic acid tert.-butyl ester (Example A1) and 4-fluoro-2-methoxymethoxybenzene boronic acid [prepared from 1-bromo-4-fluoro-2-(methoxymethoxy)benzene (CAS-no. 162269-78-5) by reaction with n-BuLi at −78° C. followed by treatment with B(OMe)3 and subsequent hydrolysis] according to the general procedure B. Obtained as a yellow solid (0.96 g).
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([C:15]#[C:16][C:17]3[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=3)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1.[I-:23].[Na+].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>ClCCl.[OH-].[Na+]>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]([C:15]([I:23])=[CH:16][C:17]3[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=3)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: [I-]
Reactant: COc1ccc(C#Cc2ccncc2)cc1OC1CCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: COc1ccc(C(I)=Cc2ccncc2)cc1OC1CCCC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 66.9 %

Procedure:
To a solution of acetylene from step 1 (8.79 g, 30 mmol) in dichloromethane (600 mL) at room temperature there was added a solid mixture of sodium iodide (18 g, 120 mmol) and p-toluenesulfonic acid monohydrate (11.4 g, 60 mmol). The mixture was stirred at room temperature for 18 h. The mixture was diluted with aqueous 1N NaOH (600 mL) and stirred vigorously for 15 min. The organic phase was collected and washed 3 times with water, dried and evaporated to a residue which was stirred in a 2:1 mixture of hexane and ether (100 mL) for 2 h and filtered to afford the desired vinyl iodide (8.46 g, 67%) as a beige solid, assayed by NMR to be a 4:1 mixture of Z and E isomers.
Reaction SMILES: [CH3:1][C:2]1[C:11]([N+:12]([O-])=O)=[C:10]([CH3:15])[CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][CH2:6][C:7]2=[O:16]>CO.[Ni]>[NH2:12][C:11]1[C:2]([CH3:1])=[C:3]2[C:8](=[CH:9][C:10]=1[CH3:15])[C:7](=[O:16])[CH2:6][CH2:5][CH2:4]2
Reactant: Cc1cc2c(c(C)c1[N+](=O)[O-])CCCC2=O
Agent: [Ni]
Solvent: CO
Product: Cc1cc2c(c(C)c1N)CCCC2=O
Reaction time: 4 h

Procedure:
To a solution of 5,7-dimethyl-6-nitro-3,4-dihydronaphthalen-1(2H)-one (1 g, 4.56 mmol) in 50 ml of methanol was added a catalytic amount of Raney Ni. The mixture was hydrogenated under regular pressure at room temperature for 4 hours and filtered through Celite and washed with methanol. The filtrate was evaporated to dryness under reduced pressure and dried in vacuo to give the crude product, which is pure enough for next step. 1H-NMR δ (CDCl3, 300 MHz): 7.77 (s, 1H), 4.09 (brs, 2H, exchangeable with D2O), 2.85 (t, J=6.0 Hz, 2H), 2.54 (t, J=6.0 Hz, 2H), 2.19 (s, 3H), 2.09 (s, 3H), 2.10 (m, 2H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[CH3:9].C([Li])(C)(C)C.CCCCC.[B:20](OC(C)C)([O:25]C(C)C)[O:21]C(C)C.Cl>C1COCC1>[CH3:9][C:3]1[C:4]([CH3:8])=[CH:5][CH:6]=[CH:7][C:2]=1[B:20]([OH:25])[OH:21]
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: Cc1cccc(Br)c1C
Agent: Cl
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Solvent: CCCCC
Product: Cc1cccc(B(O)O)c1C
Temperature: -78 °C
Yield: 185.2 %

Procedure:
To a solution of 3-bromo-o-xylene (500 mg, 2.7 mmol) in THF (15 mL) at −78° C. under N2 was slowly added 1.7 M tert-butyl lithium in pentane (1.77 mL, 3.0 mmol). This was stirred at −78° C. for 30 m. To the reaction mixture was added B(OiPr)3 (2.05 g, 11 mmol), and the reaction mixture was raised to 20° C. and stirred for 2 h. 3 N HCl (10 mL) was added to the reaction mixture and the acidic solution was stirred for 90 m. The reaction mixture was extracted using EtOAc (4×50 mL), and the organic solution was extracted using a 1 N solution of NaOH (100 mL). The aqueous solution was washed with Et2O (2×50 mL), acidified to pH 1 using concentrated HCl, and then extracted using EtOAc (4×50 mL). The organic solution was then washed with brine (100 mL), dried over MgSO4 and concentrated in vacuo to afford 2,3-dimethylphenylboronic acid compound (750 mg, 45%) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]([CH3:13])[CH:7]=[C:8]([N+:10]([O-])=O)[CH:9]=1)=[O:4].N1C=CC=C1.[CH3:19][N:20]1[CH:24]=[C:23]([NH:25][C:26]([O:28][CH2:29][CH2:30][S:31]([C:34]2[CH:39]=[CH:38][C:37]([C:40]([F:43])([F:42])[F:41])=[CH:36][CH:35]=2)(=[O:33])=[O:32])=[O:27])[N:22]=[C:21]1[C:44](O)=[O:45].CN(C(F)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CC(=O)OCC.C(Cl)Cl.[Pd]>[CH3:1][O:2][C:3]([C:5]1[N:6]([CH3:13])[CH:7]=[C:8]([NH:10][C:44]([C:21]2[N:20]([CH3:19])[CH:24]=[C:23]([NH:25][C:26]([O:28][CH2:29][CH2:30][S:31]([C:34]3[CH:39]=[CH:38][C:37]([C:40]([F:43])([F:41])[F:42])=[CH:36][CH:35]=3)(=[O:32])=[O:33])=[O:27])[N:22]=2)=[O:45])[CH:9]=1)=[O:4]
Reactant: COC(=O)c1cc([N+](=O)[O-])cn1C
Reactant: Cn1cc(NC(=O)OCCS(=O)(=O)c2ccc(C(F)(F)F)cc2)nc1C(=O)O
Agent: [Pd]
Agent: CN(C)C(F)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: c1cc[nH]c1
Product: COC(=O)c1cc(NC(=O)c2nc(NC(=O)OCCS(=O)(=O)c3ccc(C(F)(F)F)cc3)cn2C)cn1C
Temperature: 25 °C
Reaction time: 10 h
Yield: 63 %

Procedure:
1-Methyl-4-nitropyrrole-2-carboxylic acid methyl ester (65.68 mg, 0.3567 mmol) was dissolved in EA (10 ml) and 10% Pd/C (10 mg) was added thereto. The reaction solution was stirred for 10 hours at room temperature under hydrogen atmosphere to reduce a nitro group (NO2) into an amino group (NH2), whereby a pyrrole-type amino acid was obtained. 10% Pd/C was filtered out by celite 545 and the filtrate was washed with EA and methanol. 1-Methyl-4-[2-(4-trifluoromethyl-benzenesulfonyl)-ethoxycarbonylamino]-1H-imidazole-2-carboxylic acid (50.10 mg, 0.1187 mmol) dissolved in a solvent mixture of anhydrous) MF (6 ml) and DCM (2 ml) was added thereto, TFFH (83.37 mg, 0.3567 mmol), HOBt (64.73 mg, 0.4748 mmol) and DIEA (82.84 ml, 0.4748 mmol) were also added thereto, and the reaction solution was reacted according to the same procedure as Step (4-1) of Example 2 to give 1-methyl-4-({1-methyl-4-[2-(4-trifluoromethyl-benzenesulfonyl)ethoxycarbonylamino]-1H-imidazole-2-carbonyl}-amino)-1H-pyrrole-2-carboxylic acid methyl ester (41.7 mg, 63.01%) of a pale yellow solid.
Reaction SMILES: [CH3:1][NH2:2].[NH2:3][C:4]1[C:5]([F:28])=[CH:6][C:7]([Br:27])=[C:8]([N:10]2[C:19]3[C:14](=[CH:15][C:16]([F:22])=[C:17](F)[C:18]=3[Cl:20])[C:13](=[O:23])[C:12]([C:24]([OH:26])=[O:25])=[CH:11]2)[CH:9]=1>N1C=CC=CC=1>[NH2:3][C:4]1[C:5]([F:28])=[CH:6][C:7]([Br:27])=[C:8]([N:10]2[C:19]3[C:14](=[CH:15][C:16]([F:22])=[C:17]([NH:2][CH3:1])[C:18]=3[Cl:20])[C:13](=[O:23])[C:12]([C:24]([OH:26])=[O:25])=[CH:11]2)[CH:9]=1
Reactant: Nc1cc(-n2cc(C(=O)O)c(=O)c3cc(F)c(F)c(Cl)c32)c(Br)cc1F
Reactant: CN
Solvent: c1ccncc1
Product: CNc1c(F)cc2c(=O)c(C(=O)O)cn(-c3cc(N)c(F)cc3Br)c2c1Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A 40% aqueous solution (60 mg) of methylamine and 1-(5-amino-2-bromo-4-fluorophenyl)-8-chloro-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (60 mg) were added to pyridine (2 ml), and the mixture was stirred at room temperature for 2 hours. After the solvent was distilled off under reduced pressure, a mixed liquid of ethanol and diethyl ether was added to the residue, and solids were collected by filtration to obtain the title compound (46 mg) as a pale brown powder.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[C:6]([Cl:10])[C:5]([Cl:11])=[C:4]([Cl:12])[C:3]=1[Cl:13].[CH2:14]([OH:17])[CH2:15][OH:16].[H-].[Na+].O>O1CCCC1>[OH:16][CH2:15][CH2:14][O:17][C:2]1[C:7]([C:8]#[N:9])=[C:6]([Cl:10])[C:5]([Cl:11])=[C:4]([Cl:12])[C:3]=1[Cl:13]
Reactant: OCCO
Reactant: N#Cc1c(Cl)c(Cl)c(Cl)c(Cl)c1Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: N#Cc1c(Cl)c(Cl)c(Cl)c(Cl)c1OCCO

Procedure:
To solution of 34.4 grams of pentachlorobenzonitrile in tetrahydrofuran was added a mixture of 8.0 grams ethylene glycol, 8.0 grams of a 50% sodium hydride-mineral oil dispersion and 250 ml tetrahydrofuran. The resulting reaction mixture was heated at reflux for one hour and then poured into a large volume of water. Filtration afforded an almost colorless solid which was dissolved in tetrahydrofuran. Treatment with magnesium sulfate followed by filtration and removal of the solvent gave rise to beta-hydroxyethoxy-tetrachlorobenzonitrile. This material is identical basis both nmr and infrared spectral data to the product formed from the reaction of tetrachlorocyanophenol with ethylene oxide as set forth below.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[N:18][CH:17]=[C:16]([NH:20][C:21](=[O:23])[CH3:22])[N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([Cl:32])[CH:27]=1.[H-].[Na+].O>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([C:14]2[CH:19]=[N:18][CH:17]=[C:16]([N:20]([C:21](=[O:23])[CH3:22])[CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([Cl:32])[CH:27]=3)[N:15]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Clc1cccc(CBr)c1
Reactant: CC(=O)Nc1cncc(N2CCN(C(=O)OC(C)(C)C)CC2)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)N(Cc1cccc(Cl)c1)c1cncc(N2CCN(C(=O)OC(C)(C)C)CC2)n1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 6′-acetylamino-2,3,5,6-tetrahydro-[1,2′]bipyrazinyl-4-carboxylic acid tert-butyl ester I-5b (36.9 mg, 0.11 mmol) and 1-bromomethyl-3-chloro-benzene (15.8 μL, 0.12 mmol) in DMF (1.1 mL) at room temperature was added 60% NaH in mineral oil (5 mg, 0.13 mmol). After stirring at room temperature for 4 h, the reaction mixture was poured into H2O (10 mL) and extracted with ethyl acetate (50 mL). The organic layer was washed with H2O (3×10 mL), brine, dried (Na2SO4), filtered, and evaporated to dryness. The crude material was purified by preparative TLC using 50% ethyl acetate/ether with 1% NH4OH to afford the title compound I-5c (27.1 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:23])[C:12]3[S:19][C:18]([CH2:20]Cl)=[C:17]([CH3:22])[C:13]=3[N:14]([CH3:16])[CH:15]=2)=[O:9])=[CH:4][CH:3]=1.Cl.Cl.[CH3:28][O:29][C:30]1[N:35]=[CH:34][C:33]([CH:36]([OH:40])[CH2:37][NH:38][CH3:39])=[CH:32][CH:31]=1.C(N(C(C)C)CC)(C)C>CN(C=O)C.O>[Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:23])[C:12]3[S:19][C:18]([CH2:20][N:38]([CH2:37][CH:36]([OH:40])[C:33]4[CH:34]=[N:35][C:30]([O:29][CH3:28])=[CH:31][CH:32]=4)[CH3:39])=[C:17]([CH3:22])[C:13]=3[N:14]([CH3:16])[CH:15]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: Cc1c(CCl)sc2c(=O)c(C(=O)NCc3ccc(Cl)cc3)cn(C)c12
Reactant: CNCC(O)c1ccc(OC)nc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: COc1ccc(C(O)CN(C)Cc2sc3c(=O)c(C(=O)NCc4ccc(Cl)cc4)cn(C)c3c2C)cn1
Temperature: 60 °C
Reaction time: 6 h
Yield: 63.6 %

Procedure:
A mixture of N-(4-chlorobenzyl)-2-(chloromethyl)-3,4-dimethyl-7-oxo-4,7-dihydrothieno[3,2-b]pyridine-6-carboxamide (100 mg, 0.25 mmol), 1-(6-methoxypyridin-3-yl)-2-(methylamino)ethanol dihydrochloride (Preparation 52) (97 mg, 0.38 mmol) and diisopropylethylamine (199 μL, 1.2 mmol) in dry DMF (5 mL) was heated to 60° C., becoming a solution. The reaction was stirred for 6 hours at that temperature. After cooling to room temperature, the solution was diluted with water (15 mL). The resulting milky suspension was stirred vigorously for 30 minutes, and then left standing overnight at room temp. The mixture was filtered, and the collected solid was washed with water and dried in vacuo, leaving a white solid. Recrystallization from acetonitrile (10 mL, dissolved with warming and then cooled to 0° C. overnight) gave the title compound (86 mg) as a white solid.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[S:7][CH:8]=[C:9]([C:11]([O:13]CC)=[O:12])[N:10]=1.[OH-].[K+]>CO>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[S:7][CH:8]=[C:9]([C:11]([OH:13])=[O:12])[N:10]=1
Reactant: CCOC(=O)c1csc(-c2ccco2)n1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1csc(-c2ccco2)n1
Reaction time: 0.25 h
Yield: 42.5 %

Procedure:
To a solution of ethyl 2-(2-furyl)-4-thiazole carboxylate (3.12 g) in methanol (30 ml) was added dropwise 1N aqueous potassium hydroxide (38.58 ml) and the mixture was at 55° C. for 15 minutes. Then the solvent was removed from the reaction mixture, and the residue was treated with water and acidified with 2N-HCl under ice-cooling. The resulting solids were sucked, washed with water and dried to give yellowish crystals of 2-(2-furyl)-4-thiazole carboxylic acid (1.16 g, yeild 46%), m.p. 257°-265° C.
Reaction SMILES: [OH:1][CH2:2][C:3]1[C:7]([CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:17]=[C:18]4[C:23](=[CH:24][CH:25]=3)[N:22]=[C:21]([C:26]([O:28][CH3:29])=[O:27])[CH:20]=[CH:19]4)=[CH:12][CH:11]=2)=[C:6]([CH:30]([CH3:32])[CH3:31])[O:5][N:4]=1.[CH3:33][C:34]1[CH:39]=[CH:38][CH:37]=[C:36]([CH3:40])[C:35]=1O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>ClCCl>[CH3:33][C:34]1[CH:39]=[CH:38][CH:37]=[C:36]([CH3:40])[C:35]=1[O:1][CH2:2][C:3]1[C:7]([CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:17]=[C:18]4[C:23](=[CH:24][CH:25]=3)[N:22]=[C:21]([C:26]([O:28][CH3:29])=[O:27])[CH:20]=[CH:19]4)=[CH:12][CH:11]=2)=[C:6]([CH:30]([CH3:32])[CH3:31])[O:5][N:4]=1
Reactant: Cc1cccc(C)c1O
Reactant: COC(=O)c1ccc2cc(-c3ccc(OCc4c(CO)noc4C(C)C)cc3)ccc2n1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COC(=O)c1ccc2cc(-c3ccc(OCc4c(COc5c(C)cccc5C)noc4C(C)C)cc3)ccc2n1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 30.6 %

Procedure:
To a solution of methyl 6-[4-({[3-(hydroxymethyl)-5-(1-methylethyl)-4-isoxazolyl]methyl}oxy)phenyl]-2-quinolinecarboxylate (60 mg, 0.14 mmol), 2,6-dimethylphenol (17 mg, 0.14 mmol) and triphenylphosphine (40 mg, 0.15 mmol) in dichloromethane (1.5 mL) was added diisopropyl azodicarboxylate (0.028 mL, 0.15 mmol) dropwise. The solution was stirred at ambient temperature for approximately 1.5 hours and then in a microwave reactor at 100° C. for 10 minutes. The solution was adsorbed onto silica gel and purified by chromatography (silica gel, 0-40% ethyl acetate gradient elution). The resulting residue was taken up with ether and sonicated until a solid precipitated. The solid was isolated by filtration to afford methyl 6-[4-({[3-{[(2,6-dimethylphenyl)oxy]methyl}-5-(1-methylethyl)-4-isoxazolyl]methyl}oxy)phenyl]-2-quinolinecarboxylate (23 mg, 31%). 1H-NMR (400 MHz, CDCl3) δ 8.37-8.32 (m, 2H), 8.23-8.21 (m, 1H), 8.05-8.01 (m, 2H), 7.69 (d, J=9 Hz, 2H), 7.08 (d, J=9 Hz, 2H), 7.01-6.01 (m, 3H), 5.04 (s, 2H), 4.96 (s, 2H), 4.09 (s, 3H), 3.29 (septet, J=7 Hz, 1H), 2.23 (s, 6H), 1.38 (d, J=7 Hz, 6H).
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:19].[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][C:28](O)=[O:29])=[CH:23][CH:22]=1>>[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][C:28]([NH:1][N:2]2[N:11]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=3)[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3]2=[O:19])=[O:29])=[CH:23][CH:22]=1
Reactant: Nn1nc(-c2cccc(Cl)c2)c2ccccc2c1=O
Reactant: O=C(O)Cc1ccc(Cl)cc1
Product: O=C(Cc1ccc(Cl)cc1)Nn1nc(-c2cccc(Cl)c2)c2ccccc2c1=O

Procedure:
The product of Example 125A and 2-(4-chlorophenyl)acetic acid were processed using a method similar to that described in Example 17C to afford the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.74 (s, 1H), 8.39-8.42 (m, 1H), 7.90-8.05 (m, 2H), 7.68-7.74 (m, 1H), 7.55-7.67 (m, 4H), 7.35-7.46 (m, 4H), 3.71 (s, 2H); MS (ESI+) m/z 424 (M+H)+.