Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[C:6]([NH:8][C@@H:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]1[NH2:15])=[O:7])(C)(C)C.[CH3:16][N:17]1[CH2:22][CH2:21][C:20]2[N:23]=[C:24](C([O-])=O)[S:25][C:19]=2[CH2:18]1.[Li+].O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[F:53][C:54]([F:59])([F:58])[C:55]([OH:57])=[O:56]>CN(C)C=O.ClCCl>[F:53][C:54]([F:59])([F:58])[C:55]([OH:57])=[O:56].[CH3:16][N:17]1[CH2:22][CH2:21][C:20]2[N:23]=[C:24]([C:6]([NH:8][C@@H:9]3[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]3[NH2:15])=[O:7])[S:25][C:19]=2[CH2:18]1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCC[C@H]1N
Reactant: CN1CCc2nc(C(=O)[O-])sc2C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN1CCc2nc(C(=O)N[C@@H]3CCCC[C@H]3N)sc2C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(±)-trans-N-tert-Butoxycarbonyl-1,2-cyclohexane-diamine (642 mg) was dissolved in N,N-dimethylformamide (20 ml), and to the solution lithium 5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxylate (795 mg), 1-hydroxybenzotriazole monohydrate (46 mg) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (2.30 g) were added, and the mixture was stirred overnight at room temperature. After the reaction mixture was concentrated under reduced pressure, and dichloromethane and water were added to the residue, the organic layer was taken out and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by column chromatography on silica gel (dichloromethane:methanol 100:3) to obtain a pale yellow foamy substance. This substance was dissolved in dichloromethane (5 ml), and trifluoroacetic acid (30 ml) was added, and the mixture was stirred at room temperature for 1 minute. The reaction mixture was concentrated under reduced pressure to obtain the title compound (731 mg) as a pale brown foamy substance.
Reaction SMILES: [C:1]([OH:7])([C:3]([F:6])([F:5])[F:4])=[O:2].O.C(OC([N:16]1[CH2:20][CH2:19][CH2:18][C@H:17]1[CH2:21][O:22][C:23]1[CH:24]=[C:25]([N:29]2[CH2:35][CH:34]3[CH2:36][CH:31]([CH2:32][CH2:33]3)[CH2:30]2)[CH:26]=[N:27][CH:28]=1)=O)(C)(C)C>C(Cl)Cl>[F:4][C:3]([F:6])([F:5])[C:1]([OH:7])=[O:2].[NH:16]1[CH2:20][CH2:19][CH2:18][C@H:17]1[CH2:21][O:22][C:23]1[CH:24]=[C:25]([N:29]2[CH2:30][CH:31]3[CH2:36][CH:34]([CH2:33][CH2:32]3)[CH2:35]2)[CH:26]=[N:27][CH:28]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1COc1cncc(N2CC3CCC(C3)C2)c1
Solvent: ClCCl
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: c1ncc(N2CC3CCC(C3)C2)cc1OC[C@@H]1CCCN1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
A mixture of CF3COOH, H2O, and CH2Cl2 (10:1:50, 6.1 mL) was added to a 15 mL round-bottom flask containing 3-[5-[[1-(tert-butoxycarbonyl)-2(S)-pyrrolidinyl]methoxy]-3-pyridyl]-3-azabicyclo[3.2.1]octane (182 mg, 446 μmol). The flask was capped with a glass stopper, and the reactants were stirred at room temperature for 14 h. The reaction mixture was concentrated with a rotary evaporator (bath up to 35° C.) and was further dried with an oil pump (40° C.). The residue was purified by preparative HPLC (Supelco Discovery C18, 250×21.2 mm, 5 μm particle size, UV detection at 270 nm, flow rate 4.9 mL/min, 8% CH3CN in water for 10 min followed by gradient from 8% to 25% for 35 min, from 25% to 100% for another 35 min, then 100% CH3CN for 40 min, both solvents containing 0.1 vol % CF3COOH; tR 48.8-59.5 min) to give the yellow tifluoroacetate (260 mg, 94%). 1H NMR (CD3OD, 500 MHz) δ 8.00 (d, 1H, J=2.2 Hz), 7.89 (d, 1H, J=1.9 Hz), 7.41 (d, 1H, J=2.2 Hz), 4.68 (dt, 1H, J1=10.6 Hz, J2=3.2 Hz), 4.38-4.32 (m, 1H), 4.17-4.07 (m, 1H), 3.64 (d, 2H, J=11.2 Hz), 3.46-3.39 (m, 2H), 3.06 (d, 2H, J=11.2 Hz), 2.49 (s, br, 2H), 2.36-2.27 (m, 1H), 2.24-2.16 (m, 1H), 2.16-2.08 (m, 1H), 2.01-1.91 (m, 1H), 1.88-1.81 (m, 2H), 1.72 (s, br, 2H), 1.65 (d, 2H, J=7.7 Hz); MS (EI) m/z 287 (M+ of free base, 0.8%). Anal. Calcd. for C17H25N3O.2.93CF3COOH (FW 621.5): C, 44.18; H, 4.53; N, 6.76; F, 26.87. Found: C, 44.20; H, 4.44; N, 6.73; F, 26.89.
Reaction SMILES: CS(O[CH2:6][CH2:7][N:8]1[C:16]2[N:15]=[C:14]([NH2:17])[N:13]3[N:18]=[C:19]([C:21]4[O:22][CH:23]=[CH:24][CH:25]=4)[N:20]=[C:12]3[C:11]=2[CH:10]=[CH:9]1)(=O)=O.Cl.[F:27][C:28]1[CH:33]=[C:32]([F:34])[CH:31]=[CH:30][C:29]=1[CH2:35][C:36]([N:38]1[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1)=[O:37].CCN(C(C)C)C(C)C>CN(C=O)C>[NH2:17][C:14]1[N:13]2[N:18]=[C:19]([C:21]3[O:22][CH:23]=[CH:24][CH:25]=3)[N:20]=[C:12]2[C:11]2[CH:10]=[CH:9][N:8]([CH2:7][CH2:6][N:41]3[CH2:40][CH2:39][N:38]([C:36](=[O:37])[CH2:35][C:29]4[CH:30]=[CH:31][C:32]([F:34])=[CH:33][C:28]=4[F:27])[CH2:43][CH2:42]3)[C:16]=2[N:15]=1
Reactant: O=C(Cc1ccc(F)cc1F)N1CCNCC1
Reactant: CS(=O)(=O)OCCn1ccc2c1nc(N)n1nc(-c3ccco3)nc21
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Nc1nc2c(ccn2CCN2CCN(C(=O)Cc3ccc(F)cc3F)CC2)c2nc(-c3ccco3)nn12
Temperature: 100 °C
Reaction time: 5 h

Procedure:
To a solution of the title D compound of Example 1, 2-{5-amino-2-(furan-2-yl)-7H-pyrrolo[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-7-yl}ethyl methanesulfonate (0.06 g, 0.165 mmol) in dry DMF (5 mL), the title A compound, (2,4-difluorophenyl)piperazin-1-yl-ethanone hydrochloride (0.33 mmol) and 0.06 mL of DIEA are added, and the solution is stirred at 100° C. for 5 h. The reaction mixture is cooled to RT, and the solvent is removed under reduced pressure. To the residue, acetonitrile is added and the solution is stirred at 60° C. for 0.5 h. The solution is then cooled to RT, and the resulting solids are collected by filtration to give 1-(4-(2-(5-amino-2-(furan-2-yl)-7H-pyrrolo[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-7-yl)ethyl)piperazin-1-yl)-2-(2,4-difluorophenyl)ethanone: LC/MS (M+1=507.2). 1H NMR (DMSO-d6, 400 MHz) δ 2.45 (m, 4H), 2.72 (t, 2H, J=6.4 Hz), 3.43 (m, 2H), 3.48 (m, 2H), 3.69 (s, 2H), 4.26 (t, 2H, J=6.4 Hz), 6.59 (d, 1H, J=32 Hz), 6.71 (m, 1H), 7.01 (dt, 1H, J=8.4 Hz and 1.6 Hz), 7.17 (m, 3H), 7.28 (m, 1H), 7.49 (br s, 2H, NH2), 7.91 (s, 1H). Anal. calculated for (C25H24F2N8O2+⅓ H2O): C, 58.59; H, 4.85; F, 7.41; N, 21.86; O, 7.28. Found C, 58 73; H, 5.06; N, 21.22.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([CH3:19])[CH:17]=2)[CH:12]=[CH:11][N:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Br:27]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[C:1]([O:5][C:6]([N:8]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([CH2:19][Br:27])[CH:17]=2)[CH:12]=[CH:11][N:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccc2ccnc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c2c1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1nccc2ccc(CBr)cc12
Yield: 71.9 %

Procedure:
A mixture of the bis-tert-butoxycarbonyl-(7-methyl-isoquinolin-1-yl)amine (500 mg, 1.40 mmol), N-bromosuccinimide (265 mg, 1.47 mmol) and 4 mg of benzoyl peroxide in 10 mL of CCl4 was refluxed overnight. The solution was concentrated and loaded to a flash column using 10% EtOAc in hexane as eluent. This gave 440 mg (72% yield) of yellow solid product. 1H-NMR (300 MHz, CDCl3) δ 8.44(d, 1H), 7.94 (s, 1H), 7.87 (d, 1H), 7.73 (d, 1H), 7.64 (d, 1H), 4.64 (s, 2H), 1.32 (s, 18H); LC/MS (ESI): calcd mass 436.1. found 437.1 (MH)+.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13]N.CN(C(ON1N=NC2C=[CH:27][CH:28]=[N:29][C:24]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CO.C1COCC1.[OH-].[Na+].O.CN(C=O)C.C(OCC)(=O)C>[ClH:2].[NH:29]1[CH2:24][CH2:13][CH:12]([C:6]2[C:5]3[C:9](=[CH:10][CH:11]=[CH:3][CH:4]=3)[NH:8][CH:7]=2)[CH2:27][CH2:28]1
Reactant: NCCc1c[nH]c2ccc(Cl)cc12
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: c1ccc2c(C3CCNCC3)c[nH]c2c1
Temperature: 25 °C

Procedure:
A mixture of an ethyl 5-substituted-1,2,4-oxadiazole-3-carboxylate (0.433 mmol, 1 equivalent) in methanol or THF (1 mL) and sodium hydroxide in water (2M, 5 equivalents) was stirred at room temperature until completion. The reaction mixture is the diluted with water and extracted with dichloromethane. The aqueous layer was acidified with HCl 6N until pH 2 and extracted with ethyl acetate. The combined organic extracts were dried over sodium sulphate and concentrated under reduced pressure. The residue was then added to a mixture of 2-(5-chloro-1H-indol-3-yl)ethanamine hydrochloride (0.433 mmol, 1 equivalent), HATU (0.432 mmol, 1 equivalent) and N,N diisopropylethylamine (0.433 mmol-1.08 mmol, 1-2.5 equivalents) in DMF (4 mL) and was stirred at room temperature overnight. The reaction mixture was diluted in ethyl acetate, washed with sodium disulphate, sodium carbonate and brine, dried and concentrated under reduced pressure. The crude material was purified by flash chromatography on silica to yield the desired compounds.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=[O:17])[CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:5][C:4]=1[C:18]1[C:19]([CH2:31][O:32][C:33](=[O:41])[C:34]2[CH:39]=[CH:38][C:37]([CH3:40])=[CH:36][CH:35]=2)=[C:20]2[C:25](=[CH:26][CH:27]=1)[NH:24][C:23]([CH3:29])([CH3:28])[CH:22]=[C:21]2[CH3:30].[BH4-].[Na+].Cl.C(OCC)(=O)C>O1CCCC1.CO>[OH:17][CH:9]([C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[C:4]([C:18]2[C:19]([CH2:31][O:32][C:33](=[O:41])[C:34]3[CH:35]=[CH:36][C:37]([CH3:40])=[CH:38][CH:39]=3)=[C:20]3[C:25](=[CH:26][CH:27]=2)[NH:24][C:23]([CH3:29])([CH3:28])[CH:22]=[C:21]3[CH3:30])[CH:5]=1)[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: COc1ccc(C(=O)Cc2ccccc2)cc1-c1ccc2c(c1COC(=O)c1ccc(C)cc1)C(C)=CC(C)(C)N2
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Solvent: CCOC(C)=O
Product: COc1ccc(C(O)Cc2ccccc2)cc1-c1ccc2c(c1COC(=O)c1ccc(C)cc1)C(C)=CC(C)(C)N2
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 93.2 %

Procedure:
6-(2-Methoxy-5-phenylacetylphenyl)-5-(4-methylbenzoyloxymethyl)-2,2,4-trimethyl-1,2-dihydroquinoline (Compound No. 22, 34.0 mg. 0.0623 mmol) was dissolved in tetrahydrofuran (0.5 mL)—methanol (0.5 mL), and sodium borohydride (6.8 mg, 0.180 mmol) was added thereto, and then the reaction mixture was stirred at room temperature for 45 minutes. 1N aqueous HCl solution (0.5 mL) and ethyl acetate (50 mL) were added to the reaction mixture, the whole was washed with water (50 mL, twice) and saturated brine (50 mL) successively, dried over anhydrous magnesium sulfate, and then the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give the titled compound (31.8 mg) as a colorless amorphous product (yield: 93%)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[NH:10][CH:11]=[C:12]([CH3:14])[N:13]=2)=[CH:5][CH:4]=1.C1C=C[NH+]=CC=1.[Br:21][Br-]Br.O.C([O-])([O-])=O.[Na+].[Na+]>CC#N>[Br:21][C:11]1[NH:10][C:9]([C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)=[N:13][C:12]=1[CH3:14]
Reactant: COc1ccc(-c2nc(C)c[nH]2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Agent: c1cc[nH+]cc1
Solvent: O
Solvent: CC#N
Product: COc1ccc(-c2nc(C)c(Br)[nH]2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 37.6 %

Procedure:
2-(p-Methoxyphenyl)-4-methylimidazole, (5.0 g, 0.0265 mole), was dissolved in CH3CN (250 ml) at the boiling point. The solution was cooled to room temperature and stirred while a solution of pyridinium bromide perbromide (7.0 g) in CH3CN (70 ml) was added dropwise. A precipitate separated as the addition was completed (30 min) and stirring was continued for 30 minutes. The mixture was poured into water (1.5 L) and the precipitated hydrobromide salt was collected. The filtrate was made basic with saturated Na2CO3 solution and the product was collected, washed with water, and dried to afford 2.45 g, m.p. 183°-187° C. The hydrobromide salt was dissolved in hot CH3CN (75 ml)--H2O (25 ml) and the solution was made basic with saturated Na2CO3 solution. A second crop of product was collected, washed with water, and dried to yield 2.2 g of 35; m.p. 179°-184° C.; 65% combined yield. A sample of the first crop recrystallized from 50% CH3CN melted at 184°-187° C.
Reaction SMILES: [CH2:1](Br)[CH:2]=[CH2:3].[H-].[Na+].[CH3:7][O:8][C:9]1[C:10]([CH3:32])=[C:11]([C:18]([C:20]2[CH:21]=[CH:22][C:23]3[NH:28][C:27](=[O:29])[O:26][C:25](=[O:30])[C:24]=3[CH:31]=2)=[O:19])[N:12]2[C:17]=1[CH:16]=[CH:15][CH:14]=[CH:13]2>CN(C=O)C>[CH3:7][O:8][C:9]1[C:10]([CH3:32])=[C:11]([C:18]([C:20]2[CH:21]=[CH:22][C:23]3[N:28]([CH2:3][CH:2]=[CH2:1])[C:27](=[O:29])[O:26][C:25](=[O:30])[C:24]=3[CH:31]=2)=[O:19])[N:12]2[C:17]=1[CH:16]=[CH:15][CH:14]=[CH:13]2
Reactant: C=CCBr
Reactant: COc1c(C)c(C(=O)c2ccc3[nH]c(=O)oc(=O)c3c2)n2ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCn1c(=O)oc(=O)c2cc(C(=O)c3c(C)c(OC)c4ccccn34)ccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 69.5 %

Procedure:
0.5 ml (5.71 mmol) of allyl bromide and 0.19 g (4.28 mmol) of sodium hydride at 60% are added, under an inert atmosphere at ambient temperature, to 1 g (2.85 mmol) of 6-[(1-methoxy-2-methylindolizin-3-yl)carbonyl]-2H-3,1-benzoxazine-2,4(1H)-dione in 15 ml of DMF. The reaction medium is stirred for 2 hours at ambient temperature and then concentrated under reduced pressure. After the addition of ice to the residue, the precipitate formed is filtered off, rinsed with water, and dried under reduced pressure at 50° C. overnight. 0.773 g of a yellow solid is obtained.
Reaction SMILES: CO.[N:3](=[C:5]1[C:11]2[CH:12]=[N:13][CH:14]=[N:15][C:10]=2[C:9]2[CH:16]=[CH:17][CH:18]=[CH:19][C:8]=2[C:7]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[N:6]1)O>C(O)C.[Ni]>[NH2:3][CH:5]1[C:11]2[CH:12]=[N:13][CH:14]=[N:15][C:10]=2[C:9]2[CH:16]=[CH:17][CH:18]=[CH:19][C:8]=2[C:7]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)=[N:6]1
Reactant: ON=c1nc(-c2ccccc2)c2ccccc2c2ncncc12
Agent: [Ni]
Solvent: CCO
Solvent: CO
Product: NC1N=C(c2ccccc2)c2ccccc2-c2ncncc21
Reaction time: 30 h

Procedure:
A solution of 150 ml of methanol containing 5 g of 5-oximino-7-phenyl-5H-pyrimido[5,4-d][2]-benzazepine is treated with a slurry of active Raney-Nickel catalyst1 in ethanol (10 g). The resulting suspension is hydrogenated on a Parr apparatus at 60 psi and 23° C. for about 30 hours. The catalyst is removed by filtration and the filtrate is concentrated to afford the title compound.
Reaction SMILES: [N:1]([CH:4]1[CH2:23][N:8]2[C:9]3[C:14]([C:15]([CH2:16][C:17]([O:19]CCC)=[O:18])=[C:7]2[CH2:6][CH2:5]1)=[CH:13][CH:12]=[CH:11][CH:10]=3)=[N+:2]=[N-:3].[C:24]([CH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1)#[CH:25]>>[CH:26]1([C:24]2[N:1]([CH:4]3[CH2:23][N:8]4[C:9]5[C:14]([C:15]([CH2:16][C:17]([OH:19])=[O:18])=[C:7]4[CH2:6][CH2:5]3)=[CH:13][CH:12]=[CH:11][CH:10]=5)[N:2]=[N:3][CH:25]=2)[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1
Reactant: CCCOC(=O)Cc1c2n(c3ccccc13)CC(N=[N+]=[N-])CC2
Reactant: C#CC1CCCCC1
Product: O=C(O)Cc1c2n(c3ccccc13)CC(n1nncc1C1CCCCC1)CC2

Procedure:
The title compound was prepared using procedures described in EXAMPLE 3 from propyl (7-azido-6,7,8,9-tetrahydropyrido[1,2-α]indol-10-yl)acetate and ethynylcyclohexane. MS (+ESI) m/z: 379.2.
Reaction SMILES: OS(O)(=O)=O.[C:6]1([CH:12]2[CH2:17][CH2:16][C:15](=[O:18])[CH2:14][CH2:13]2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[N+:19]([O-])([OH:21])=[O:20]>>[N+:19]([C:9]1[CH:10]=[CH:11][C:6]([CH:12]2[CH2:17][CH2:16][C:15](=[O:18])[CH2:14][CH2:13]2)=[CH:7][CH:8]=1)([O-:21])=[O:20]
Reactant: O=[N+]([O-])O
Reactant: O=C1CCC(c2ccccc2)CC1
Agent: O=S(=O)(O)O
Product: O=C1CCC(c2ccc([N+](=O)[O-])cc2)CC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 10 %

Procedure:
Concentrated H2SO4 (20 mL) was cooled to 0° C. and treated with 4-phenyl-cyclohexanone (4.22 g, 24.2 mmol), and fuming nitric acid (1.6 mL) was added very carefully dropwise, keeping the temperature of the mixture below 20° C. After the addition of nitric acid was complete, the mixture was warmed to RT and allowed to stir for 5 h. The mixture was poured over ice (200 mL) and extracted with EtOAc (3×150 mL). The combined organic layers were dried over MgSO4 and concentrated in vacuo. Silica gel chromatography with 10% EtOAc-hexane on a 70-g Isolute SPE column (FlashMaster system) afforded the title compound (0.512 g, 10%) as a pale yellow solid. 1H-NMR (CD3OD; 400 MHz): δ 8.20 (d, 2H, J=8.8 Hz), 7.42 (d, 2H, J=8.8 Hz), 3.16 (tt, 1H, J=12.0, 4.0 Hz), 2.58-2.51 (m, 4H), 2.31-2.21 (m, 2H), 2.05-1.91 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:17]2[CH:21]=[N:20][N:19]=[C:18]2[C:22]2[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=2)=[C:4]2[C:9](=[CH:10][C:11]=1[Cl:12])[N:8]=[C:7]([O:13][CH3:14])[C:6]([O:15][CH3:16])=[N:5]2.[CH2:28]=[O:29]>C(O)(=O)C>[Cl:1][C:2]1[C:3]([N:17]2[C:18]([C:22]3[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=3)=[N:19][N:20]=[C:21]2[CH2:28][OH:29])=[C:4]2[C:9](=[CH:10][C:11]=1[Cl:12])[N:8]=[C:7]([O:13][CH3:14])[C:6]([O:15][CH3:16])=[N:5]2
Reactant: C=O
Reactant: COc1nc2cc(Cl)c(Cl)c(-n3cnnc3-c3cccnc3)c2nc1OC
Solvent: CC(=O)O
Product: COc1nc2cc(Cl)c(Cl)c(-n3c(CO)nnc3-c3cccnc3)c2nc1OC
Temperature: 125 °C
Yield: 55.4 %

Procedure:
A suspension of 6,7-dichloro-2,3-dimethoxy-5-[3-(3-pyridyl)-4H-1,2,4-triazol-4-yl]quinoxaline (Preparation 98, 1.008 g, 2.5 mmol) and paraformaldehyde (0.75 g, 25 mmol) in acetic acid (14 mL) was heated at 125° C. for 3 hours in a sealed vessel. After being cooled, the mixture was concentrated under reduced pressure and the residue was purified by flash chromatography on silica gel, by gradient elution using dichloromethane:methanol (1:0 changing to 95:5, by volume) to afford the title compound (0.60 g, 56%) as a white solid, mp 209-210° C.
Reaction SMILES: [C@@H:1]12C(=O)[O:9][C:7](=[O:8])[C@@H:2]1[CH2:3][CH2:4][CH2:5][CH2:6]2>O1CCCC1.CN(C)C1C=CN=CC=1>[CH:2]1([C:7]([OH:9])=[O:8])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:1]1
Reactant: O=C1OC(=O)[C@@H]2CCCC[C@H]12
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Product: O=C(O)C1CCCCC1

Procedure:
In 90 ml tetrahydrofuran, 48.1 g of cis-1,2-cyclohexanedicarboxylic anhydride, 46.3 g of the (1,4,4-trimethyl-3,5-dioxyanyl)methane-1-ol prepared in Synthesis Example 1 and 1.8 g of 4-(dimethylamino)pyridine were dissolved, and the resulting mixture was refluxed for 6 hours under heating. After the elimination of the tetrahydrofuran by distillation, the mixture was subjected to silica gel column chromatography to yield 54.7 g of 2-((1,4,4-trimethyl-3,5-dioxanyl) methyl) oxycarbonyl) cyclohexanecarboxylic acid.
Reaction SMILES: [CH2:1]([O:3][C:4]1[N:9]=[N:8][C:7]([NH2:10])=[CH:6][CH:5]=1)[CH3:2].[CH3:11][C:12]1[C:16]([CH2:17][O:18][C:19]2[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=2)=[C:15]([CH3:29])[O:14][N:13]=1>>[CH3:11][C:12]1[C:16]([CH2:17][O:18][C:19]2[CH:20]=[CH:21][C:22]([S:25]([NH:10][C:7]3[N:8]=[N:9][C:4]([O:3][CH2:1][CH3:2])=[CH:5][CH:6]=3)(=[O:27])=[O:26])=[CH:23][CH:24]=2)=[C:15]([CH3:29])[O:14][N:13]=1
Reactant: CCOc1ccc(N)nn1
Reactant: Cc1noc(C)c1COc1ccc(S(=O)(=O)Cl)cc1
Product: CCOc1ccc(NS(=O)(=O)c2ccc(OCc3c(C)noc3C)cc2)nn1
Yield: 4 %

Procedure:
The title compound (16 mg) was prepared from 6-ethoxypyridazin-3-amine (129 mg, 1.0 mmol) and 4-{[(3,5-dimethyl-4-isoxazolyl)methyl]oxy}benzenesulfonyl chloride (0.302 g, 1.0 mmol), following the procedure described for Intermediate 51. LCMS (2 min, formic) Rt 0.91 min, m/z (ES+) 405 (M+H).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[N:10]([CH2:12][CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH:22]([S:27][CH3:28])[C:23]([O:25]C)=[O:24])=[CH:17][CH:16]=1)[CH3:11].[OH-].[Na+].CO>O>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[N:10]([CH2:12][CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH:22]([S:27][CH3:28])[C:23]([OH:25])=[O:24])=[CH:17][CH:16]=1)[CH3:11]
Reactant: COC(=O)C(Cc1ccc(OCCN(C)c2nc3ccccc3o2)cc1)SC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CSC(Cc1ccc(OCCN(C)c2nc3ccccc3o2)cc1)C(=O)O

Procedure:
A mixture of methyl 3-[4-[2-[N-(2-benzoxazolyl)-N-methylamino]ethoxy]phenyl]-2-(methylthio)propanoate (1.01 g), 10% aqueous sodium hydroxide solution (10 mL) and methanol (20 mL) was heated at reflux for 1 hour. The mixture was diluted with water (300 mL) and washed with dichloromethane (3×200 mL). The aqueous layer was acidified to pH2 with concentrated hydrochloric acid, extracted with ethyl acetate (3×200 mL) and the extracts washed with brine (2×200 mL), dried (MgSO4) and evaporated. The residue was chromatographed on silica gel with 2% methanol in dichloromethane as eluent to afford the title compound, mp 140°-1° C. (ethyl acetate-hexane).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]([Cl:11])(Cl)Cl)[CH:5]=[CH:6][CH:7]=1.C(O)=[O:13]>[Fe](Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][CH:7]=1)[C:8]([Cl:11])=[O:13]
Reactant: O=CO
Reactant: Fc1cccc(C(Cl)(Cl)Cl)c1
Agent: Cl[Fe]Cl
Product: O=C(Cl)c1cccc(F)c1
Temperature: 80 °C

Procedure:
300 g of 3-fluorobenzotrichloride and 1.5 g of iron chloride are placed in an apparatus comprising a 1 l four necked flask equipped with stirrer, thermometer, reflux condenser and dropping funnel. The mixture was heated to 80° C. A total of 53 ml of formic acid were then added over 5 hours in such a manner that the temperature could readily be maintained.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]([NH:12][C:13]2[CH:21]=[CH:20][CH:19]=[CH:18][C:14]=2[C:15]([OH:17])=[O:16])=O)=[CH:4][C:3]=1[O:22][CH3:23].[C:24](OC(=O)C)(=[O:26])[CH3:25]>O>[C:24]([O:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]2[O:17][C:15](=[O:16])[C:14]3[CH:18]=[CH:19][CH:20]=[CH:21][C:13]=3[N:12]=2)=[CH:4][C:3]=1[O:22][CH3:23])(=[O:26])[CH3:25]
Reactant: CC(=O)OC(C)=O
Reactant: COc1cc(/C=C/C(=O)Nc2ccccc2C(=O)O)ccc1O
Solvent: O
Product: COc1cc(/C=C/c2nc3ccccc3c(=O)o2)ccc1OC(C)=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 97 %

Procedure:
A solution of (E)-2-[[3-(4-hydroxy-3-methoxyphenyl)-1-oxo-2-propenyl]amino]benzoic acid (0.5 g, 1.6 mmol) in acetic anhydride (3 mL) was heated to reflux and stirred for 3 h. The reaction was cooled to rt and the resulting suspension was diluted with water. The suspension was stirred at rt for 1 h and the precipitate was collected by filtration, providing (E)-2-(4-acetoxy-3-methoxystyryl)-4H-benzo[d][1,3]oxazin-4-one (0.52 g, 97%) as a pale brown solid; mp 185-186° C.; δH (400 MHz, DMSO-d6) 2.63 (s, 3H, COCH3), 3.85 (s, 3H, OCH3), 7.08 (d, J=16.0 Hz, 1H, CH═CHCO), 7.17 (d, J5′,6′=8.0 Hz, 1H, H5′), 7.38 (d, J5′,6′=8.0, 1H, H6′), 7.59 (t, J3,4=J4,5=8.0 Hz, 1H, H4), 7.61 (d, J3,4=8.0 Hz, 1H, H3), 7.63 (s, 1H, H2′), 7.76 (d, J=16.0 Hz, 1H, CH═CHCO), 7.92 (t, J4,5=J5,6=8.0 Hz, 1H, H5), 8.11 (d, J5,6=8.0 Hz, 1H, H6); δC (100 MHz, DMSO-d6) 20.4, 56.0, 111.9, 116.9, 119.5, 121.4, 123.3, 126.6, 128.1, 128.4, 133.5, 136.8, 140.5, 140.9, 146.6, 151.2, 156.8, 168.4; HRMS (ESI) calculated for C19H5NO5 [M+H]+ 338.1023; found 338.1023; νmax 1197, 1214, 1593, 1635, 1748 cm−1.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9](O)=[O:10].B.O.C([O-])([O-])=O.[K+].[K+]>O1CCCC1>[CH3:1][O:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][OH:10]
Reactant: COCCCCCCC(=O)O
Agent: B
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: COCCCCCCCO
Temperature: 25 °C
Reaction time: 72 h
Yield: 72 %

Procedure:
To a solution of the title product of Example 2 (18.3 g, 114 mmol) in 60 mL of tetrahydrofuran at 0° C. was added dropwise a solution of borane in tetrahydrofuran (175 mL, 1M). After stirring at room temperature for 3 days, 300 mL of water was added followed by solid K2CO3 (31.7 g, 229 mmol). The layers were separated and the aqueous phase extracted with three portions of diethyl ether. The combined organic extracts were washed with brine, dried over magnesium sulfate, filtered and concentrated. The crude product was purified by distillation at reduced pressure (8 mm Hg) to give the title compound (12 g), b.p. 107°-110° C. The structure was verified by NMR.