Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:6]=[CH:5][O:4][C:3]=1[C:7]([OH:9])=[O:8].[C:10]1(B(O)O)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C([O-])(O)=O.[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>[C:10]1([C:2]2[CH:6]=[CH:5][O:4][C:3]=2[C:7]([OH:9])=[O:8])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: OB(O)c1ccccc1
Reactant: O=C(O)c1occc1Br
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+]
Product: O=C(O)c1occc1-c1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 70 %

Procedure:
To 3-bromo-2-furancarboxylic acid (540 mg, 2.8 mmol dissolved in DME (105 ml)) was added of (Ph3P)4Pd (936 mg, 0.81 mmol), and the resulting solution was stirred at room temperature for 15 min. The mixture was treated with 500 mg (3.0 mmol) of benzene boronic acid, an aqueous solution of 2M NaHCO3 (4 mmol) and heated to reflux for 10 hours. After cooling to room temperature, the solvent was partially removed under reduced pressure, and the resulting mixture was extracted twice with diethyl ether. The water layer was acidified with 10% HCl and extracted with ethyl acetate (5 times). The combined organic layers were washed with brine, dried (Na2SO4), and evaporated under reduced pressure. The residue was crystallized from a mixture of n-hexane/ethyl acetate (about 8:2) to give the title compound. Yield: 70%.
Reaction SMILES: C(O[CH:5]([C:28]1[N:40]=[C:31]2[N:32]=[C:33]([CH3:39])[C:34]3[CH2:38][CH2:37][CH2:36][C:35]=3[N:30]2[N:29]=1)[C:6]1(Br)[C:12](=[O:13])[N:11]2[C@@H:7]1[S:8][CH:9]=[C:10]2[C:14]([O:16]CC1C=CC([N+]([O-])=O)=CC=1)=[O:15])(=O)C.C(#N)C>C1COCC1.[Pd]>[CH3:39][C:33]1[C:34]2[CH2:38][CH2:37][CH2:36][C:35]=2[N:30]2[N:29]=[C:28](/[CH:5]=[C:6]3\[C@@H:7]4[N:11]([C:12]\3=[O:13])[C:10]([C:14]([OH:16])=[O:15])=[CH:9][S:8]4)[N:40]=[C:31]2[N:32]=1
Reactant: CC(=O)OC(c1nc2nc(C)c3c(n2n1)CCC3)C1(Br)C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=CS[C@@H]21
Agent: [Pd]
Solvent: CC#N
Solvent: C1CCOC1
Product: Cc1nc2nc(/C=C3/C(=O)N4C(C(=O)O)=CS[C@H]34)nn2c2c1CCC2
Temperature: 3 °C

Procedure:
4-nitrobenzyl (5R)-6-[(acetyloxy)(5-methyl-7,8-dihydro-6H-cyclopenta[e][1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methyl]-6-bromo-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (200 mg, 0.31 mmol) was dissolved in THF (20 mL) and acetonitrile (20 mL) and phophate buffer (6.5 pH) (20 ml) and hydrogenated over Pd/C (10%) (200 mg) under 40 psi pressure. At the end, reaction mixture was filtered, cooled to 3° C., and 0.1 N NaOH was added to adjust the pH to 8.5. The filtrate was washed with ethyl acetate and the aqueous layer was separated. The aqueous layer was concentrated under high vacuum at 35° C. to give a yellow precipitate. The product was purified by HP21 resin reverse phase column chromatography. Initially the column was eluted with deionized water (2 L) and latter with 10% acetonitrile:water. The fractions containing the product were collected and concentrated under reduced pressure at room temperature. The yellow solid was washed with acetone, filtered and dried. Yield: 15 mg, 13%; as yellow crystals; mp 250° C. (Dec); (M+H+Na) 378. 1H NMR (DMSO-d6) δ 6.80 (s, 1H), 6.76 (s, 1H), 6.25(s, 1H), 3.24(m, 2H), 2.96 (m, 2H), 2.49 (s, 3H), 2.25(m, 2H).
Reaction SMILES: [CH2:1]([N:8]([C:29]1[CH:34]=CC=C[CH:30]=1)[C:9]([C:11]1([C:15]([NH:17][S:18](/[CH:21]=[CH:22]/[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)(=[O:20])=[O:19])=[O:16])[CH2:14][CH2:13][CH2:12]1)=[O:10])[C:2]1C=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:35]C1C=CC(NC(C)C)=CC=1>>[F:35][C:4]1[CH:5]=[CH:6][C:1]([N:8]([CH:29]([CH3:34])[CH3:30])[C:9]([C:11]2([C:15]([NH:17][S:18](/[CH:21]=[CH:22]/[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)(=[O:19])=[O:20])=[O:16])[CH2:14][CH2:13][CH2:12]2)=[O:10])=[CH:2][CH:3]=1
Reactant: O=C(NS(=O)(=O)/C=C/c1ccccc1)C1(C(=O)N(Cc2ccccc2)c2ccccc2)CCC1
Reactant: CC(C)Nc1ccc(F)cc1
Product: CC(C)N(C(=O)C1(C(=O)NS(=O)(=O)/C=C/c2ccccc2)CCC1)c1ccc(F)cc1
Yield: 7.6 %

Procedure:
In the same manner as in Example 1 (4), a crude product was obtained using the compound (1.00 g) obtained in Example 570 (1) and 4-fluoro-N-isopropylaniline (490 mg). This was purified by silica gel column chromatography to give the title compound (71 mg) as a white powder.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([OH:12])=O)=[CH:9][C:4]=2[CH2:3][CH2:2]1.[N:13]1[C:18]2[NH:19][C:20]3[CH:27]=[CH:26][CH:25]=[CH:24][C:21]=3[NH:22][CH2:23][C:17]=2[CH:16]=[CH:15][CH:14]=1>C(OCC)C>[N:13]1[C:18]2[NH:19][C:20]3[CH:27]=[CH:26][CH:25]=[CH:24][C:21]=3[N:22]([C:10]([C:8]3[CH:7]=[CH:6][C:5]4[O:1][CH2:2][CH2:3][C:4]=4[CH:9]=3)=[O:12])[CH2:23][C:17]=2[CH:16]=[CH:15][CH:14]=1
Reactant: O=C(O)c1ccc2c(c1)CCO2
Reactant: c1cnc2c(c1)CNc1ccccc1N2
Solvent: CCOCC
Product: O=C(c1ccc2c(c1)CCO2)N1Cc2cccnc2Nc2ccccc21

Procedure:
Prepared from 2,3-dihydro-benzofuran-5-carboxylic acid (0.328 g, 2 mmol) and 6,11-dihydro-5H-pyrido[2,3-b][1,5]benzodiazepine (0.398 g, 2 mmol) in a manner essentially identical to that of Example 1. The title compound was obtained as an off-white solid, m.p. 188° C., upon recrystallization from diethyl ether.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([CH:6]([NH2:8])[CH3:7])=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH2:18]([S:20](Cl)(=[O:22])=[O:21])[CH3:19]>ClCCl>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([CH:6]([NH:8][S:20]([CH2:18][CH3:19])(=[O:22])=[O:21])[CH3:7])=[CH:4][CH:3]=1
Reactant: CCS(=O)(=O)Cl
Reactant: CC(N)c1ccc(Br)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCS(=O)(=O)NC(C)c1ccc(Br)cc1
Reaction time: 0.25 h

Procedure:
4-Bromo-α-methylbenzylamine (8.15 g, 40.73 mmol) and (4.15 g, 41.00 mmol) triethylamine dissolved in 150 ml dichloromethane was treated slowly with ethanesulfonyl chloride (5.27 g, 41.00 mmol) and stirred for 15 minutes. The reaction mixture was extracted with 50 ml 1N HCl/15 ml brine. The organic layer was separated, dried sodium sulfate, filtered, and concentrated in vacuo to afford the title compound. 1H NMR: 7.52 (d,2H,J=12 Hz), 7.25 (d,2H,J=12 Hz), 4.77 (m,1H), 4.63 (m,1H), 2.77 (m,2H), 1.56 (d,3H,J=8 Hz), 1.27 (t,3H,J=8 Hz). MS calcd. 292.2; MS (M+−1) 291.1.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:13]=[C:12]([OH:14])[C:11]([Cl:15])=[C:10]([CH3:16])[N:9]=2)=[N:6][CH:7]=1.C(N(CC)CC)C.[Cl:24][CH2:25][C:26](Cl)=[O:27]>C1COCC1>[Cl:24][CH2:25][C:26]([NH:1][C:2]1[CH:7]=[N:6][C:5]([C:8]2[N:13]=[C:12]([OH:14])[C:11]([Cl:15])=[C:10]([CH3:16])[N:9]=2)=[CH:4][CH:3]=1)=[O:27]
Reactant: Cc1nc(-c2ccc(N)cn2)nc(O)c1Cl
Reactant: O=C(Cl)CCl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1nc(-c2ccc(NC(=O)CCl)cn2)nc(O)c1Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of compound of example 16 (0.10 g, 0.42 mmol) in THF (5 mL), at 0° C. was added triethylamine (0.064 g, 0.63 mmol) and chloroacetylchloride (0.0715 g, 0.63 mmol), and the reaction mixture was stirred at room temperature for 30 minutes. THF was removed under reduced pressure, and reaction mixture was quenched with water and extracted with ethyl acetate (3×10 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated to obtain the crude product, which was purified by column chromatography using silica gel and 1% methanol in chloroform as an eluent to obtain the title compound.
Reaction SMILES: [NH:1]([C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][NH:9][C:10]2=[O:13])=[CH:5][CH:4]=1)[NH2:2].[CH3:14][C:15]([CH3:22])([CH3:21])[C:16](=O)[CH2:17][C:18]#[N:19].[ClH:23]>CCO>[ClH:23].[NH2:19][C:18]1[N:1]([C:3]2[CH:12]=[C:11]3[C:6]([CH2:7][CH2:8][NH:9][C:10]3=[O:13])=[CH:5][CH:4]=2)[N:2]=[C:16]([C:15]([CH3:22])([CH3:21])[CH3:14])[CH:17]=1
Reactant: CC(C)(C)C(=O)CC#N
Reactant: NNc1ccc2c(c1)C(=O)NCC2
Agent: Cl
Solvent: CCO
Product: CC(C)(C)c1cc(N)n(-c2ccc3c(c2)C(=O)NCC3)n1
Yield: 96 %

Procedure:
A mixture of 7-hydrazino-3,4-dihydro-2H-isoquinolin-1-one (8.0 g, 37.6 mmol) and 4,4-dimethyl-3-oxo-pentanenitrile (5.64 g, 45 mmol) in EtOH (100 mL) and conc. HCl (10 mL) was heated at reflux overnight. After removal of the solvent, the residue was washed with ether to afford 7-(5-amino-3-t-butyl-pyrazol-1-yl)-3,4-dihydro-2H-isoquinolin-1-one hydrochloride as a yellow solid (11.5 g, 96% yield), which was used without further purification.
Reaction SMILES: O[CH2:2][C:3]1[CH:4]=[C:5]([C:9]2[N:10]([CH3:20])[C:11]3[C:16]([C:17]=2[C:18]#[N:19])=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH:6]=[N:7][CH:8]=1.[C:21]1(=[O:31])[NH:25][C:24](=[O:26])[C:23]2=[CH:27][CH:28]=[CH:29][CH:30]=[C:22]12.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.C(P(CCCC)CCCC)CCC>C1COCC1>[O:26]=[C:24]1[C:23]2[C:22](=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:21](=[O:31])[N:25]1[CH2:2][C:3]1[CH:4]=[C:5]([C:9]2[N:10]([CH3:20])[C:11]3[C:16]([C:17]=2[C:18]#[N:19])=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH:6]=[N:7][CH:8]=1
Reactant: Cn1c(-c2cncc(CO)c2)c(C#N)c2ccccc21
Reactant: O=C1NC(=O)c2ccccc21
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: Cn1c(-c2cncc(CN3C(=O)c4ccccc4C3=O)c2)c(C#N)c2ccccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-(5-hydroxymethyl-pyridin-3-yl)-1-methyl-1H-indole-3-carbonitrile (Example 220, 190 mg, 0.72 mmol) in THF (5 mL) are added sequentially phthalimide (116 mg, 0.79 mmol), 1,1′-(azodicarbonyl)dipiperidine (346 mg, 1.37 mmol) and tributylphosphine (277 mg, 1.37 mmol). The mixture is stirred at room temperature overnight. The mixture is then concentrated in vacuo and the residue is purified by silica gel flash chromatography (heptane-ethyl acetate, 1:0 to 0:1) to give 2-[5-(1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-pyridin-3-yl]-1-methyl-1H-indole-3-carbonitrile. MS (ESI) m/z 393.02 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]([CH3:12])[C:3]=1[C:4]([O:6][CH3:7])=[O:5].[Br:13]N1C(=O)CCC1=O>>[Br:13][CH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]([CH3:12])[C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1c(C)cccc1C
Product: COC(=O)c1c(C)cccc1CBr

Procedure:
Reaction of methyl 2,6-dimethylbenzoate with N-bromosuccinimide as described in Example 1a provides methyl 2-bromomethyl-6-methylbenzoate as an oil.
Reaction SMILES: C[O:2][C:3](=[O:39])[C@@H:4]([NH:28][C:29]([O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:30])[CH2:5][NH:6][C:7]([CH:9]1[CH2:14][CH2:13][N:12]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([NH:21][C:22]3[NH:23][CH2:24][CH2:25][CH2:26][N:27]=3)[CH:16]=2)[CH2:11][CH2:10]1)=[O:8].[OH-].[Na+].FC(F)(F)C(O)=O>CO>[CH2:32]([O:31][C:29]([NH:28][C@@H:4]([CH2:5][NH:6][C:7]([CH:9]1[CH2:10][CH2:11][N:12]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([NH:21][C:22]3[NH:23][CH2:24][CH2:25][CH2:26][N:27]=3)[CH:16]=2)[CH2:13][CH2:14]1)=[O:8])[C:3]([OH:39])=[O:2])=[O:30])[C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1
Reactant: COC(=O)[C@H](CNC(=O)C1CCN(c2cccc(NC3=NCCCN3)c2)CC1)NC(=O)OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: O=C(N[C@@H](CNC(=O)C1CCN(c2cccc(NC3=NCCCN3)c2)CC1)C(=O)O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of the product obtained in Example 1 in methanol (100 ml) is added 2M aqueous sodium hydroxide solution (100 ml), and the mixture is stirred at 25° C. overnight. The reaction solution is neutralized with trifluoroacetic acid, and purified by CHP-20 (manufactured by Mitsubishi Chemical Corporation, highporous styrene resin: 75–150 μm) (eluent: gradient, 30% to 100% methanol/0.05% aqueous trifluoroacetic acid solution) to give the title compound (6.5 g).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][CH2:14][CH2:15][N:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1)[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:22]([NH2:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.O.ON1C2C=CC=CC=2N=N1.C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl>[CH2:22]([NH:29][C:10](=[O:12])[C@@H:9]([NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:13][CH2:14][CH2:15][N:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCN1CCCCC1)C(=O)O
Reactant: NCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OC(=O)N[C@@H](CCCN1CCCCC1)C(=O)NCc1ccccc1
Yield: 90.9 %

Procedure:
To a solution of crude N-t-butoxycarbonyl-(S)-2-amino-5-(1-piperidinyl)pentanoic acid (22.2 mg, 0.074 mmol) in anhydrous methylene chloride (0.50 mL) were added benzyl amine (9.7 mg, 0.091 mmmol) and 1-hydroxybenzotriazol monohydrate (11.1 mg, 0.082 mmol). To the reaction mixture stirred under ice-cold condition was added 1,3-dicyclohexylcarbodiimide (18.0 mg, 0.087 mmol), and the mixture was stirred for 0.5 hour. After removal of the ice bath, the mixture was stirred for 16 hours at room temperature, and then chloroform (20 mL) was added. The organic phase was washed with saturated aqueous sodium hydrogencarbonate solution (2×3 mL), dried over anhydrous sodium sulfate, and concentrated under vacuum to obtain a crude oily material (47 . 7 mg). The crude oil was purified by column chromatography (silica gel 2g, about 15% ammonia/methanol-chloroform (1:100)) to obtain N-t-butoxycarbonyl-(S)-2-amino-5-(1-piperidinyl)pentanoic acid benzyl amide (26.2 mg) as a colorless oily material [yield 90% from N-t-butoxycarbonyl-(S)-2-amino-5-(1-piperidinyl)pentanoic acid benzyl ether].
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][N:7]2[CH:11]=[N:10][N:9]=[C:8]2[C@H:12]2[CH2:16][CH2:15][CH2:14][N:13]2[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[CH:4][CH:3]=1.C([Li])CCC.CCCCCC.[Cl:37]N1C(=O)CCC1=O.C([O-])(O)=O.[Na+]>C1COCC1>[Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][N:7]2[C:11]([Cl:37])=[N:10][N:9]=[C:8]2[C@H:12]2[CH2:16][CH2:15][CH2:14][N:13]2[C:17]([O:19][C:20]([CH3:21])([CH3:22])[CH3:23])=[O:18])=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1c1nncn1Cc1ccc(Cl)cc1
Reactant: O=C1CCC(=O)N1Cl
Agent: O=C([O-])O
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(C)(C)OC(=O)N1CCC[C@@H]1c1nnc(Cl)n1Cc1ccc(Cl)cc1
Temperature: -60 °C
Reaction time: 0.5 h
Yield: 21.2 %

Procedure:
To a solution of Boc-protected triazole from Example 3 (4.344 g, 12 mmol) in 20 mL of THF at −60° C. under argon was slowly added a solution of n-butyl lithium (1.6M) in hexane (7.5 mL, 1.2 eq.) and stirred at −60° C. for 30 minutes. To the mixture was added a suspension of N-chlorosuccinimide (4.67 g, 2.9 eq.) in 20 mL of THF and the mixture was kept at −60° C. for 1 hr before warming up to RT overnight. The reaction mixture was treated with sat. aqueous NaHCO3 (30 mL), then extracted with EtOAc (2×40 mL). The organic phase was dried over Na2SO4 and concentrated in vacuo. Flash chromatography purification ((Hex/EtOAc) provided the desired product (1.011 g, 21.2%).
Reaction SMILES: [OH:1][C:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[S:5](=[O:13])(=[O:12])[NH:4][C:3]=1[C:14]([O:16]C)=O.[NH2:18][C:19]1[CH:24]=[N:23][CH:22]=[C:21]([Cl:25])[N:20]=1.C1(C)C(C)=CC=CC=1>CO>[Cl:25][C:21]1[N:20]=[C:19]([NH:18][C:14]([C:3]2[NH:4][S:5](=[O:12])(=[O:13])[C:6]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[C:2]=2[OH:1])=[O:16])[CH:24]=[N:23][CH:22]=1
Reactant: COC(=O)C1=C(O)c2ccccc2S(=O)(=O)N1
Reactant: Nc1cncc(Cl)n1
Solvent: CO
Solvent: Cc1ccccc1C
Product: O=C(Nc1cncc(Cl)n1)C1=C(O)c2ccccc2S(=O)(=O)N1
Yield: 32.6 %

Procedure:
A mixture of 5.1 g (20 mmols) of methyl 4-hydroxy-2H-1,2-benzothiazine-3-carboxylate-1,1-dioxide, 3.0 g (23 mmols) of 2-amino-6-chloropyrazine and 400 ml of xylene was refluxed for 12 hours in a nitrogen atmosphere. The methanol formed by the reaction was removed with the aid of a 4 Å molecular sieve arranged in a Soxhlet attachment. After cooling, the reaction mixture was concentrated by evaporation, and the residue was purified by chromatography on a silicagel column, yielding 2.3 g (33% of theory) of N-(6-chloro-pyrazin-2-yl)-4-hydroxy-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide.
Reaction SMILES: [CH3:1][CH:2]([S:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)[CH3:3].C(O)(C)C.[OH-].[Na+].Br[CH2:19][CH2:20][CH2:21][Cl:22]>O>[Cl:22][CH2:21][CH2:20][CH2:19][O:11][C:8]1[CH:7]=[CH:6][C:5]([S:4][CH:2]([CH3:1])[CH3:3])=[CH:10][CH:9]=1
Reactant: ClCCCBr
Reactant: CC(C)Sc1ccc(O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: O
Product: CC(C)Sc1ccc(OCCCCl)cc1
Yield: 20 %

Procedure:
A solution of 4-(1-methylethylthio)phenol (16.83 g., 0.1 mole) in 150 ml. of isopropyl alcohol is treated with 5.2 ml. of 50% sodium hydroxide solution (0.10 mole) and 2 ml. of water. To this mixture is added in one portion 1-bromo-3-chloropropane (16.5 g., 0.105 mole) and the mixture stirred and refluxed for a period of 20 hrs. After cooling, the reaction mixture is concentrated under reduced pressure and the resulting residue extracted with ether. The ethereal extract is filtered, concentrated under reduced pressure and the oily residue distilled affording 4.8 g. (20% yield) of 1-chloro-3-[4-(1-methylethylthio)phenoxy]propane, b.p. 136°-140° C. at 0.6 mm Hg.
Reaction SMILES: Cl.Cl.[S:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[N:5]=[C:4]1[NH:12][C:13]([C:15]1[CH:16]=[CH:17][CH:18]=[C:19]2[C:24]=1[CH2:23][NH:22][CH2:21][CH2:20]2)=[O:14].Cl[C:26]1[S:27][C:28]([I:35])=[C:29]([C:31]([O:33][CH3:34])=[O:32])[N:30]=1.C([O-])([O-])=O.[Cs+].[Cs+].Cl>CC(N(C)C)=O>[S:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[N:5]=[C:4]1[NH:12][C:13]([C:15]1[CH:16]=[CH:17][CH:18]=[C:19]2[C:24]=1[CH2:23][N:22]([C:26]1[S:27][C:28]([I:35])=[C:29]([C:31]([O:33][CH3:34])=[O:32])[N:30]=1)[CH2:21][CH2:20]2)=[O:14]
Reactant: COC(=O)c1nc(Cl)sc1I
Reactant: O=C(Nc1nc2ccccc2s1)c1cccc2c1CNCC2
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Product: COC(=O)c1nc(N2CCc3cccc(C(=O)Nc4nc5ccccc5s4)c3C2)sc1I
Temperature: 60 °C
Reaction time: 8 h
Yield: 66.3 %

Procedure:
To a solution of N-(benzo[d]thiazol-2-yl)-1,2,3,4-tetrahydroisoquinoline-8-carboxamide dihydrochloride (1B) (2 g, 5.23 mmol) and methyl 2-chloro-5-iodothiazole-4-carboxylate (8B) (1.66 g, 5.23 mmol) in DMA (10 mL) was added Cs2CO3 (8.52 g, 26.2 mmol). The reaction mixture was stirred at 60° C. overnight, cooled to rt, acidified with 5% HCl, extracted with DCM, washed with water, brine, dried over Na2SO4, and concentrated under reduced pressure. The crude material was purified by column chromatography on silica gel and eluted with 5% MeOH in DCM to provide 2.0 g (65%) of the desired product 2-(8-(benzo[d]thiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-5-iodothiazole-4-carboxylate (8C): LC/MS (APCI): m/z 577.0 (M+H)
Reaction SMILES: [CH2:1]([O:8][C:9]([C:11]1([N:19]=C(C2C=CC=CC=2)C2C=CC=CC=2)[CH2:17][CH:16]2[O:18][CH:13]([CH2:14][CH2:15]2)[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:33]>C(OCC)C>[ClH:33].[CH2:1]([O:8][C:9]([C:11]1([NH2:19])[CH2:17][CH:16]2[O:18][CH:13]([CH2:14][CH2:15]2)[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(OCc1ccccc1)C1(N=C(c2ccccc2)c2ccccc2)CC2CCC(C1)O2
Agent: Cl
Solvent: CCOCC
Product: NC1(C(=O)OCc2ccccc2)CC2CCC(C1)O2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A two-phase mixture of 3-(benzhydrylideneamino)-8-oxabicyclo[3.2.1]octane-3-carboxylic acid benzyl ester (3.9 mmole) in aqueous 1N hydrochloric acid solution (100 mL) and diethyl ether (100 mL) is stirred at room temperature overnight. The aqueous layer is concentrated to provide the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[CH2:9][OH:10].Cl[CH2:12][CH2:13][N:14]([CH2:25][CH2:26]Cl)S(C1C=CC(C)=CC=1)(=O)=O>>[CH3:8][C:5]1[CH:6]=[CH:7][C:2]([N:1]2[CH2:26][CH2:25][NH:14][CH2:13][CH2:12]2)=[C:3]([CH2:9][OH:10])[CH:4]=1
Reactant: Cc1ccc(N)c(CO)c1
Reactant: Cc1ccc(S(=O)(=O)N(CCCl)CCCl)cc1
Product: Cc1ccc(N2CCNCC2)c(CO)c1
Yield: 55.4 %

Procedure:
Using (2-amino-5-methylphenyl)methanol (1 g) and N,N-bis(2-chloroethyl)-p-toluenesulfonamide (2.1 g) and by the reaction and treatment in the same manner as in Preparation Example 95, the title compound (810 mg) was obtained.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10](Cl)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:13])[CH:8]=2)[N:3]=1.[NH2:14][CH2:15][C:16]([NH:18][C@H:19]1[CH2:24][CH2:23][C@@H:22]([N:25]([CH2:29][CH3:30])[CH:26]([CH3:28])[CH3:27])[CH2:21][C@H:20]1[CH2:31][O:32][CH3:33])=[O:17].C(N(C(C)C)CC)(C)C>O1CCCC1>[Cl:1][C:2]1[N:11]=[C:10]([NH:14][CH2:15][C:16]([NH:18][C@H:19]2[CH2:24][CH2:23][C@@H:22]([N:25]([CH2:29][CH3:30])[CH:26]([CH3:28])[CH3:27])[CH2:21][C@H:20]2[CH2:31][O:32][CH3:33])=[O:17])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:13])[CH:8]=2)[N:3]=1
Reactant: Clc1ccc2nc(Cl)nc(Cl)c2c1
Reactant: CCN(C(C)C)[C@@H]1CC[C@H](NC(=O)CN)[C@H](COC)C1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCN(C(C)C)[C@@H]1CC[C@H](NC(=O)CNc2nc(Cl)nc3ccc(Cl)cc23)[C@H](COC)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 2,4,6-trichloroquinazoline (103 mg) and the bis-trifluoroacetic acid salt of 2-amino-N-((1S,2R,4R)-4-(ethyl(isopropyl)amino)-2-(methoxymethyl)cyclohexyl)acetamide (152 mg) in tetrahydrofuran (3 mL) was treated with diisopropylethylamine (0.31 mL) and the mixture was stirred overnight at rt. The mixture was concentrated and purified by reverse phase HPLC and lyophilization to provide the bis-trifluoroacetic acid salt of the title compound, 2-(2,6-dichloroquinazolin-4-ylamino)-N-((1S,2R,4R)-4-(ethyl(isopropyl)amino)-2-(methoxymethyl)cyclohexyl)acetamide, as a white powder (79 mg). MS found: (M+H)+=482.2.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([CH3:23])[C:13](=[O:22])[N:14]([C:15]4[C:16]([CH3:21])=[N:17][N:18]([CH3:20])[CH:19]=4)[C:5]=3[C:4]=2[CH:3]=1.C([NH:31][CH2:32][C:33]1[CH:34]=[N:35][CH:36]=[C:37](B2OC(C)(C)C(C)(C)O2)[CH:38]=1)(OC(C)(C)C)=O>>[NH2:31][CH2:32][C:33]1[CH:38]=[C:37]([C:2]2[CH:11]=[CH:10][C:9]3[N:8]=[CH:7][C:6]4[N:12]([CH3:23])[C:13](=[O:22])[N:14]([C:15]5[C:16]([CH3:21])=[N:17][N:18]([CH3:20])[CH:19]=5)[C:5]=4[C:4]=3[CH:3]=2)[CH:36]=[N:35][CH:34]=1
Reactant: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(Br)cc3c21
Reactant: CC(C)(C)OC(=O)NCc1cncc(B2OC(C)(C)C(C)(C)O2)c1
Product: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(-c4cncc(CN)c4)cc3c21

Procedure:
The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate A) and 3-(N-boc-aminomethyl)pyridine-5-boronic acid pinacol ester (Frontier Scientific, Logan, USA) to give the title compound as an off-white solid. (HPLC: tR 1.87 min (Method A); M+H=400 MS-ES; 1H-NMR (d6-DMSO, 400 MHz) 8.99 (s, 1H), 8.56-8.51 (m, 2H), 8.17-8.11 (m, 2H), 7.99-7.95 (m, 1H), 7.86-7.83 (m, 1H), 7.61-7.58 (m, 1H), 3.92 (s, 3H), 3.79 (s, 2H), 3.58 (s, 3H), 2.06-1.97 (br, 2H), 1.95 (s, 3H))
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=O)[C:10]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)=O)=[CH:5][CH:4]=1.[NH2:21][C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][C:29]=1[NH2:30])[C:25]#[N:26]>C(O)(=O)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]([C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=3)=[N:21][C:22]3[C:29](=[CH:28][CH:27]=[C:24]([C:25]#[N:26])[CH:23]=3)[N:30]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(C(=O)C(=O)c2ccc(OC)cc2)cc1
Reactant: N#Cc1ccc(N)c(N)c1
Solvent: CC(=O)O
Product: COc1ccc(-c2nc3ccc(C#N)cc3nc2-c2ccc(OC)cc2)cc1
Reaction time: 1 h

Procedure:
Into a 100-mL round-bottom flask, was placed a solution of 1,2-bis(4-methoxyphenyl)ethane-1,2-dione (200 mg, 0.74 mmol, 1.00 equiv) in acetic acid (20 mL), 3,4-diaminobenzonitrile (118.2 mg, 0.89 mmol, 1.20 equiv). The resulting solution was stirred for 1 h at reflux in an oil bath. The reaction was then quenched by the addition of water. The solids were collected by filtration and washed with MeOH. This resulted in 205 mg (71%) of 2,3-bis(4-methoxyphenyl)quinoxaline-6-carbonitrile as a yellow solid.