Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:29]=[CH:30][C:31]=1[O:32][CH:33]([CH3:35])[CH3:34])[C:5]([NH:7][C@H:8]([CH2:26][CH2:27][OH:28])[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[N:17]=[C:18]([C:22](=NO)[CH3:23])[N:19]([CH3:21])[CH:20]=2)=[CH:12][CH:11]=1)=[O:6].[C:36]([O-:39])([O-])=O.[K+].[K+].[C:42](C(N)CBr)(OC(C)(C)C)=[O:43]>CN(C=O)C.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:29]=[CH:30][C:31]=1[O:32][CH:33]([CH3:34])[CH3:35])[C:5]([NH:7][C@H:8]([CH2:26][CH2:27][OH:28])[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[N:17]=[C:18]([C:22]3([CH3:23])[O:39][CH2:36][CH2:42][O:43]3)[N:19]([CH3:21])[CH:20]=2)=[CH:12][CH:11]=1)=[O:6]
Reactant: O=C([O-])[O-]
Reactant: CC(=NO)c1nc(-c2ccc(C[C@@H](CCO)NC(=O)c3ccc(OC(C)C)c(Cl)c3)cc2)cn1C
Reactant: CC(C)(C)OC(=O)C(N)CBr
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)Oc1ccc(C(=O)N[C@H](CCO)Cc2ccc(-c3cn(C)c(C4(C)OCCO4)n3)cc2)cc1Cl
Temperature: 60 °C
Reaction time: 3 h
Yield: 45.5 %

Procedure:
To a solution of compound 3 (5.000 g, 17 mmol) in DMF (15 mL) was added K2CO3 (3.51 g, 26 mmol) and Boc-2-amino ethyl bromide (4.56 g, 20.35 mmol). The resulting mixture was stirred at 60° C. for three hours. The mixture was diluted with water and extracted with EtOAc (3×50 mL). The organic layers were combined, dried over Na2SO4, and concentrated. Purification with column chromatography (Hexanes/EtOAc 50:50) gave the product 4 (4.08 g, 55%) as white solid.
Reaction SMILES: C(N(CC)CC)C.[SH:8][CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12].C(CCS[CH:22]([CH:27]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)O)[C:23]([O:25][CH3:26])=[O:24])(OC)=O.C[OH:50]>>[C:11]([CH2:10][CH2:9][S:8][CH:27]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][C:43]1[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=1)[CH:22]([OH:50])[C:23]([O:25][CH3:26])=[O:24])([O:13][CH3:14])=[O:12]
Reactant: COC(=O)CCS
Reactant: CO
Reactant: COC(=O)CCSC(C(=O)OC)C(O)c1ccccc1CCCCCCCCc1ccccc1
Solvent: CCN(CC)CC
Product: COC(=O)CCSC(c1ccccc1CCCCCCCCc1ccccc1)C(O)C(=O)OC
Temperature: 25 °C

Procedure:
The compound of Example 20(a) (1.2 g, 3.28 mmoles) was dissolved in methanol (20 ml) containing 2% triethylamine and stirred under argon at room temperature. Methyl 3-mercaptopropionate (0.623 ml, 5.45 mmoles) and triethylamine (1.45 ml, 9.84 mmoles) were dissolved in methanol (15 ml) and added dropwise. The mixture was stirred for 18 hours. The solvent was stripped and the residue eluted with 20% ethyl acetate/hexane to give a mixture of the desired product and its regioisomer, methyl 2-(2-carbomethoxyethylthio)-3-[2-(8-phenyloctyl)phenyl]-3- hydroxypropionate. The mixture was rechromatographed on 100 grams of neutral alumina to separate the desired product.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:12]([C:13]([OH:15])=O)[CH2:11][S:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:16]([NH2:20])([CH3:19])([CH3:18])[CH3:17].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>CN(C=O)C>[N:8]1([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:9][S:10][CH2:11][C@H:12]1[C:13]([NH:20][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:15]
Reactant: CC(C)(C)N
Reactant: CC(C)(C)OC(=O)N1CSCC1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CC(C)(C)NC(=O)[C@@H]1CSCN1C(=O)OC(C)(C)C

Procedure:
In a DMF solution containing 0.10 g of N-(t-butoxy-carbonyl)-1,3-thiazolidine-4-carboxylic acid, 45 μl of tert-butylamine, 66 mg of HOBt and 98 mg of EDC hydrochloride were added under ice cooling and the resultant mixture was stirred for 14 hr. The reaction mixture was treated similarly to that in Example 34 (Process 3) to give 90 mg of the title compound.
Reaction SMILES: [C:1]([OH:5])(=[O:4])[CH:2]=[CH2:3].[Br:6][C:7]1[CH:12]=[CH:11][C:10](I)=[CH:9][C:8]=1[O:14][CH3:15].Cl>CC#N.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Br:6][C:7]1[CH:12]=[CH:11][C:10](/[CH:3]=[CH:2]/[C:1]([OH:5])=[O:4])=[CH:9][C:8]=1[O:14][CH3:15]
Reactant: COc1cc(I)ccc1Br
Reactant: C=CC(=O)O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cl
Solvent: CC#N
Product: COc1cc(/C=C/C(=O)O)ccc1Br
Temperature: 90 °C
Reaction time: 0.5 h

Procedure:
Acrylic acid (9.61 g, 133 mmol), TEA (37.2 mL, 267 mmol) and palladium acetate (719 mg, 3.2 mmol) were added to a solution of 1-bromo-4-iodo-2-methoxybenzene (US 2004/0254159) (33.45 g, 107 mmol) in MeCN (100 mL). The reaction mixture was heated to 90° C. for 40 min, cooled to RT and poured into 2.4 L 1M HCl. After stirring for 30 min, the solid was filtered, heated to reflux in EtOH (230 mL), allowed to cool to RT and stirred overnight. The solid was filtered and washed with 1:1 EtOH:hexanes (50 mL) to give desired product. LRMS ESI+ (M+H)+ 257.0.
Reaction SMILES: [CH2:1]([O:11][C:12]1[CH:20]=[CH:19][C:15]([C:16]([OH:18])=O)=[CH:14][CH:13]=1)/[CH:2]=[C:3](/[CH2:5][CH2:6][CH:7]=[C:8]([CH3:10])[CH3:9])\[CH3:4].C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.[NH2:36][CH2:37][CH2:38][S:39][C:40]1[CH:45]=[CH:44][C:43]([C:46]([F:49])([F:48])[F:47])=[CH:42][N:41]=1>C(Cl)(Cl)Cl.C(N(CC)CC)C>[CH2:1]([O:11][C:12]1[CH:13]=[CH:14][C:15]([C:16]([NH:36][CH2:37][CH2:38][S:39][C:40]2[CH:45]=[CH:44][C:43]([C:46]([F:49])([F:48])[F:47])=[CH:42][N:41]=2)=[O:18])=[CH:19][CH:20]=1)/[CH:2]=[C:3](/[CH2:5][CH2:6][CH:7]=[C:8]([CH3:9])[CH3:10])\[CH3:4]
Reactant: CC(C)=CCC/C(C)=C/COc1ccc(C(=O)O)cc1
Reactant: NCCSc1ccc(C(F)(F)F)cn1
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CC(C)=CCC/C(C)=C/COc1ccc(C(=O)NCCSc2ccc(C(F)(F)F)cn2)cc1
Reaction time: 1 h
Yield: 83.8 %

Procedure:
4-geranyloxybenzoic acid(6.17 g) was dissolved in chloroform(80 ml) and triethylamine(6.24 ml), and then diphenylphosphinic chloride(4.29 ml) was added thereto while being cooled with ice. After being stirred for 1 hour, the mixture, with 2-(2-aminoethylthio)-5-(trifluoromethyl)pyridine(5.00 g) added thereto, was stirred for 4 hours at room temperature. The reaction mixture was washed with saturated sodium hydrogencarbonate aqueous solution and saturated brine successively, dried over sodium sulfate anhydride, and then concentrated under a vacuum. The residue was purified by silica gel column chromatography (chloroform:methanol=20:1). The resulting solid was recrystallized from n-hexane/ethyl acetate, thereby yielding 9.02 g of the aimed compound.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([S:12][C:13]2[C:21]3[C:16](=[CH:17][C:18]([Cl:22])=[CH:19][CH:20]=3)[NH:15][C:14]=2[CH3:23])[CH:7]=1)[CH3:2].Br[C:26]1[CH:27]=[N:28][N:29]([CH2:31][CH3:32])[CH:30]=1>>[CH2:1]([O:3][C:4](=[O:24])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([S:12][C:13]2[C:21]3[C:16](=[CH:17][C:18]([Cl:22])=[CH:19][CH:20]=3)[N:15]([C:26]3[CH:27]=[N:28][N:29]([CH2:31][CH3:32])[CH:30]=3)[C:14]=2[CH3:23])[CH:7]=1)[CH3:2]
Reactant: CCn1cc(Br)cn1
Reactant: CCOC(=O)Cc1cccc(Sc2c(C)[nH]c3cc(Cl)ccc23)c1
Product: CCOC(=O)Cc1cccc(Sc2c(C)n(-c3cnn(CC)c3)c3cc(Cl)ccc23)c1

Procedure:
Prepared according to the procedure described in Example 42, Step 4, using the following starting materials: [3-(6-chloro-2-methyl-1H-indol-3-ylsulfanyl)-phenyl]-acetic acid ethyl ester and 4-bromo-1-ethylpyrazole.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][N:4]1[C:13](=[O:14])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][C:5]1=[O:15].[F:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]([C:31]2[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=2)=[C:24]2[CH2:30][CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)=[CH:19][CH:18]=1.C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1>[ClH:1].[F:37][C:34]1[CH:35]=[CH:36][C:31]([C:23]([C:20]2[CH:19]=[CH:18][C:17]([F:16])=[CH:22][CH:21]=2)=[C:24]2[CH2:30][CH2:29][CH2:28][N:27]([CH2:2][CH2:3][N:4]3[C:13](=[O:14])[C:12]4[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=4)[NH:6][C:5]3=[O:15])[CH2:26][CH2:25]2)=[CH:32][CH:33]=1
Reactant: O=c1[nH]c2ccccc2c(=O)n1CCCl
Reactant: Fc1ccc(C(=C2CCCNCC2)c2ccc(F)cc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Cl
Product: O=c1[nH]c2ccccc2c(=O)n1CCN1CCCC(=C(c2ccc(F)cc2)c2ccc(F)cc2)CC1

Procedure:
A mixture of 7.5 g of 3-(2-chloroethyl)-2,4-dioxo-1,2,3,4-tetrahydroquinazoline, 10 g of 4-[bis(4-fluorophenyl)methylene]perhydroazepine, 3.4 g of sodium hydrogen carbonate and 100 ml of toluene is brought to reflux for 12 hours. The mixture is filtered and concentrated under vacuum. The oil obtained is purified by chromatography on 500 g of 70-230 mesh silica using a mixture of dichloromethane, methanol and ammonia solution (98.4:1.5:0.1 V/V) as eluent.
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:14]3[CH:15]=[CH:16][C:17]([O:19]C)=[CH:18][C:13]=3[N:12]=[C:11]2[CH2:21][CH3:22])=[CH:6][CH:5]=1.[OH-].[Na+].[BrH:25]>>[Br:25][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:14]3[CH:15]=[CH:16][C:17]([OH:19])=[CH:18][C:13]=3[N:12]=[C:11]2[CH2:21][CH3:22])=[CH:6][CH:5]=1
Reactant: Br
Reactant: CCc1nc2cc(OC)ccc2n1-c1ccc(CCCl)cc1
Agent: [Na+]
Agent: [OH-]
Product: CCc1nc2cc(O)ccc2n1-c1ccc(CCBr)cc1
Temperature: 100 °C
Reaction time: 6 h

Procedure:
A mixture of 1-[4-(2-chloroethyl)phenyl]-2-ethyl-5-methoxy-1H-benzimidazole (step 5 of Example 71, 600 mg, 1.9 mmol) in 48% hydrobromic acid (60 mL) was stirred at 100° C. for 6 h. After cooling, the mixture was neutralized with 2N aqueous NaOH and extracted with ethyl acetate (100 mL). The organic layer was washed with brine (50 mL), dried (Na2SO4), and concentrated to afford 890 mg (quant.) of the title compound as pale yellow solids: 1H-NMR (CDCl3) δ 7.64 (4H, s), 7.16 (2H, m), 6.97–7.01 (1H, m), 3.86 (2H, t, J=7.1 Hz), 3.30 (2H, t, J=7.1 Hz), 2.92 (2H, q, J=7.8 Hz), 1.29 (3H, t, J=7.8 Hz).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][CH:3]=1.[CH3:11][O:12][C:13](=[O:24])[C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([CH3:22])[C:15]=1[NH2:23].O>ClCCl.N1C=CC=CC=1>[CH3:11][O:12][C:13](=[O:24])[C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([CH3:22])[C:15]=1[NH:23][C:6](=[O:7])[C:5]1[CH:9]=[CH:10][C:2]([F:1])=[CH:3][CH:4]=1
Reactant: COC(=O)c1ccc(OC)c(C)c1N
Reactant: O=C(O)c1ccc(F)cc1
Solvent: ClCCl
Solvent: O
Solvent: c1ccncc1
Product: COC(=O)c1ccc(OC)c(C)c1NC(=O)c1ccc(F)cc1
Yield: 60.9 %

Procedure:
4-Fluoro benzoic acid (700 mg, 5 mmol) was dissolved in dichloromethane (20 ml) and pyridine (2 ml). 2-Amino-4-methoxy-3-methyl-benzoic acid methyl ester (878 mg, 4.5 mmol) was added and the mixture was refluxed for 5 h. Water was added and the mixture was extracted with dichloromethane. The organic phase was dried, filtered and evaporated and the afforded residue was purified by column chromatography on silica gel, eluted with ether-pentane 1:1 which gave pure title compound (870 mg, 61%).
Reaction SMILES: [OH-].[K+].[CH3:3][N:4]([CH3:31])[C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:12]([C:22]3[CH:27]=[CH:26][C:25]([N:28]([CH3:30])[CH3:29])=[CH:24][CH:23]=3)=[C:13](S(C)(=O)=O)[CH:14]=[CH:15][C:16]=2[CH3:17])=[CH:7][CH:6]=1.[CH3:32][C:33]1[NH:34]C2C(C=1)=CC=CC=2.[CH3:42]C(C)=O>O.C(O)(C)C>[CH3:29][N:28]([CH3:30])[C:25]1[CH:26]=[CH:27][C:22]([C:12]2[C:11]([C:8]3[CH:9]=[CH:10][C:5]([N:4]([CH3:3])[CH3:31])=[CH:6][CH:7]=3)=[C:16]3[C:15](=[CH:14][CH:13]=2)[NH:34][C:33]([CH3:32])=[C:17]3[CH3:42])=[CH:23][CH:24]=1
Reactant: Cc1cc2ccccc2[nH]1
Reactant: Cc1ccc(S(C)(=O)=O)c(-c2ccc(N(C)C)cc2)c1-c1ccc(N(C)C)cc1
Reactant: CC(C)=O
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: O
Product: Cc1[nH]c2ccc(-c3ccc(N(C)C)cc3)c(-c3ccc(N(C)C)cc3)c2c1C
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Two grams of potassium hydroxide was added slowly to a mixture of 6.3 g of [bis(4-dimethylaminophenyl)(4-methylphenylsulfonyl)]methane, 2.5 g of 2-methylindole and 75.0 ml of acetone. The resulting slurry was stirred for approximately 24 hours at ambient temperature. Fifty milliliters of isopropyl alcohol was added to the reaction mixture to effect complete solution. Slowly with stirring, the resulting solution was added to one liter of water and the solid which formed was collected by filtration. The wet filter cake was suspended in 100.0 ml of isopropyl alcohol and stirred approximately thirty minutes. The solid was collected by filtration, washed twice with 25.0 ml of isopropyl alcohol each and dried to obtain 5.1 g of [bis(4-dimethylaminophenyl)(2-methylindol-3-yl)]methane (Formula IV: R1 =R2 =R4 =R9 =R11 =H; R3 =R5 =N(CH3)2 ; R10 =CH3), a pale gray-colored solid which melted at 198°-202° C. A significant infrared maximum appeared at 740 (C--H;s) cm-1. The nuclear magnetic resonance spectrum was concordant with the assigned structure. A toluene solution of the product spotted on an acid clay-coated paper or a phenolic resin-coated paper slowly developed a grape-colored image.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][S:23]([CH3:26])(=[O:25])=[O:24])[CH:17]=2)[N:10]=1.[F:27][C:28]1[CH:29]=[C:30]([CH:33]=[C:34]([C:36]([F:39])([F:38])[F:37])[CH:35]=1)[CH2:31][OH:32]>>[F:8][C:6]1[CH:5]=[CH:4][C:3]([C:9]2[N:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][S:23]([CH3:26])(=[O:25])=[O:24])[CH:17]=3)[N:10]=2)=[C:2]([O:32][CH2:31][C:30]2[CH:33]=[C:34]([C:36]([F:37])([F:38])[F:39])[CH:35]=[C:28]([F:27])[CH:29]=2)[CH:7]=1
Reactant: OCc1cc(F)cc(C(F)(F)F)c1
Reactant: CS(=O)(=O)Cc1cccc(Nc2ncnc(-c3ccc(F)cc3F)n2)c1
Product: CS(=O)(=O)Cc1cccc(Nc2ncnc(-c3ccc(F)cc3OCc3cc(F)cc(C(F)(F)F)c3)n2)c1

Procedure:
Starting with 4-(2,4-difluorophenyl)-N-{3-[(methylsulfonyl)methyl]phenyl}-1,3,5-triazin-2-amine (75 mg; 0.197 mmol), intermediate 42.1, and 3-fluoro-5-(trifluoromethyl)benzyl alcohol (158 mg; 0.789 mmol), example 78 was prepared analogously to the procedure for the preparation of example 42.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6](=[O:10])[CH2:7][C:8]#[N:9])[CH3:4].Br[C:12]1[S:16][CH:15]=[C:14]([C:17]([N:19]2[CH:28]3[CH:23]([CH2:24][CH2:25][CH2:26][CH2:27]3)[CH2:22][CH2:21][CH2:20]2)=[O:18])[CH:13]=1>C1COCC1.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>[CH2:3]([O:5][C:6](=[O:10])[CH:7]([C:8]#[N:9])[C:12]1[S:16][CH:15]=[C:14]([C:17]([N:19]2[C@@H:28]3[C@@H:23]([CH2:24][CH2:25][CH2:26][CH2:27]3)[CH2:22][CH2:21][CH2:20]2)=[O:18])[CH:13]=1)[CH3:4]
Reactant: O=C(c1csc(Br)c1)N1CCCC2CCCCC21
Reactant: CCOC(=O)CC#N
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C(C#N)c1cc(C(=O)N2CCC[C@@H]3CCCC[C@@H]32)cs1
Temperature: 60 °C
Reaction time: 0.17 h
Yield: 55.3 %

Procedure:
Sodium hydride (60% dispersion in mineral oil; 400 mg) was added to a solution of ethylcyanoacetate (0.450 g) in THF (10 mL) and the mixture stirred for 10 minutes. A solution of (5-bromo-thiophen-3-yl)-(octahydro-quinolin-1-yl)-methanone (0.326 g) and PdCl2(PPh3)2 (0.035 g) in THF (2 mL) was then added dropwise and the mixture heated to 60° C. overnight. The solvent was evaporated and the residue purified by flash chromatography on silica, washing with cyclohexane and ethyl acetate. The fractions containing the desired product were concentrated under vacuum to give the title compound as a clear oil (0.198 g). LCMS m/z 361.27 [M+H]+ RT=3.80 min (Analytical Method 3).
Reaction SMILES: [NH2:1][C:2]1[N:11]=[CH:10][C:9]2[CH:8]=[CH:7][C:6]3[C:12]([C:16]([NH2:18])=[O:17])=[N:13][N:14]([CH3:15])[C:5]=3[C:4]=2[N:3]=1.N1C=CC=CC=1.[C:25]1([CH2:31][C:32](Cl)=[O:33])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>O1CCCC1>[CH3:15][N:14]1[C:5]2[C:4]3[N:3]=[C:2]([NH:1][C:32](=[O:33])[CH2:31][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[N:11]=[CH:10][C:9]=3[CH:8]=[CH:7][C:6]=2[C:12]([C:16]([NH2:18])=[O:17])=[N:13]1
Reactant: Cn1nc(C(N)=O)c2ccc3cnc(N)nc3c21
Reactant: O=C(Cl)Cc1ccccc1
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: Cn1nc(C(N)=O)c2ccc3cnc(NC(=O)Cc4ccccc4)nc3c21
Temperature: 25 °C
Reaction time: 16 h
Yield: 0.1 %

Procedure:
0.40 g (1.47 mmol) of 8-amino-1-methyl-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide were suspended in 20 mL of tetrahydrofuran and 5 mL of pyridine and 0.42 mL (3.22 mmol) of phenylacetylchloride were added. The reaction mixture was stirred at room temperature for 16 hours. The solvent was evaporated, the residue redissolved with dichloromethane, washed with aqueous NaHCO3 and then with water. After drying over anhydrous Na2SO4 the solvent was removed under reduced pressure and the crude purified by chromatography on a silica gel column (eluant cyclohexane/acetone) giving 0.35 mg of the title compound (60% yield).
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1.[N+:10]([O-])([OH:12])=[O:11]>C(Cl)Cl>[N+:10]([C:7]1[CH:8]=[C:3]([S:2][CH3:1])[CH:4]=[CH:5][C:6]=1[OH:9])([O-:12])=[O:11]
Reactant: CSc1ccc(O)cc1
Reactant: O=[N+]([O-])O
Solvent: ClCCl
Product: CSc1ccc(O)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 4-(methylthio)phenol(5.0 g) in methylene chloride (100 mls) was added 30% nitric acid absorbed on silica (9.29 g) and the mixture stirred at room temperature for 3hrs. The mixture was filtered and washed with methylene chloride. The solvent was evaporated and the residue was purified by flash chromatography eluting with ethyl acetate and hexane (15:85 v/v ) to give 2-nitro-4-(methylthio)phenol as an orange solid (2.22 g);
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[C:3]=1[C:4]([NH2:6])=[O:5].C(Cl)(=O)[C:13](Cl)=[O:14].Cl>C(Cl)Cl>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[C:3]=1[C:4]([N:6]=[C:13]=[O:14])=[O:5]
Reactant: O=C(Cl)C(=O)Cl
Reactant: NC(=O)c1c(Cl)cccc1Cl
Agent: Cl
Solvent: ClCCl
Product: O=C=NC(=O)c1c(Cl)cccc1Cl

Procedure:
95 g of 2,6-dichlorobenzamide are suspended in from 250 to 300 ml of dry methylene chloride. After the addition of 56 ml of oxalyl chloride the mixture is slowly heated to boiling point, at which temperature the starting material rapidly dissolves with a strong evolution of hydrochloric acid. After boiling for from 15-18 hours the mixture is concentrated by evaporation in a vacuum. The resulting 2,6-dichlorobenzoylisocyanide is used for the next reaction step without further purification.
Reaction SMILES: [SiH3]O[SiH3].[CH:4]1([O:7][C:8]2[CH:9]=[C:10]([CH2:18][O:19][Si](C(C)C)(C(C)C)C(C)C)[CH:11]=[CH:12][C:13]=2[O:14][CH:15]([F:17])[F:16])[CH2:6][CH2:5]1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[CH:4]1([O:7][C:8]2[CH:9]=[C:10]([CH:11]=[CH:12][C:13]=2[O:14][CH:15]([F:16])[F:17])[CH2:18][OH:19])[CH2:5][CH2:6]1
Reactant: CC(C)[Si](OCc1ccc(OC(F)F)c(OC2CC2)c1)(C(C)C)C(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Agent: [SiH3]O[SiH3]
Solvent: C1CCOC1
Product: OCc1ccc(OC(F)F)c(OC2CC2)c1
Reaction time: 17 h

Procedure:
To a solution of the silyl ether, 3-Cyclopropyloxy-4-difluoromethoxy-1-(triisopropylsilyloxy)methylbenzene, from Step 4 (70 g, 179 mmol) in THF (700 mL) at room temperature was added TBAF (215 mL of a 1M solution in THF, 215 mmol) and the resulting mixture was stirred for 17 h. The mixture was partitioned between 25% aq. NH4OAc (500 mL) and ethyl acetate (1 L) and the aqueous layer was extracted with ethyl acetate (2×). The combined organics were washed with brine, dried (Na2SO4) and concentrated. Flash chromatography of the residue (silica gel; hexane/ethyl acetate 3:2 to 1:1) provided the 3-Cyclopropyloxy-4-difluoromethoxybenzyl alcohol compound (41 g).
Reaction SMILES: Cl.[CH3:2][NH:3][O:4][CH3:5].C[Al](C)C.[O:10]1[CH2:15][CH2:14][CH2:13][CH2:12][C:11]1=[O:16].Cl>ClCCl>[OH:10][CH2:15][CH2:14][CH2:13][CH2:12][C:11]([N:3]([O:4][CH3:5])[CH3:2])=[O:16]
Reactant: CNOC
Reactant: O=C1CCCCO1
Agent: C[Al](C)C
Agent: Cl
Solvent: ClCCl
Product: CON(C)C(=O)CCCCO
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 60.2 %

Procedure:
To a stirred suspension of N,O-dimethylhydroxyamine hydrochloride (14.6 g, 150 mmol) in dry dichloromethane (150 mL) was added a solution of trimethylaluminum (2.0 M solution in toluene, 75 mL, 150 mmol) drop wise at room temperature. After stirring for 30 min, tetrahydropyran-2-one (10 g, 100 mmol) in dry dichloromethane (50 mL) was added drop wise. The reaction mixture was stirred over night. After cooling to 0° C., 1N HCl (80 mL, 80 mmol) was added slowly (exothermic reaction), diluted with dichloromethane (200 mL). The two layers were separated and the aqueous layer was extracted with dichloromethane twice. The combined organic phases were dried over sodium sulfate, filtered and concentrated. The residue was purified by column chromatography on silica gel (120 g column, 0% methanol in dichloromethane to 20% methanol in dichloromethane) to give product (9.7 g, 60%). 1H NMR (CDCl3) δ 3.68 (s, 3H), 3.63 (t, J=6.1 Hz, 2H), 3.17 (s, 3H), 2.46 (t, J=7.0 Hz, 2H), 1.69-1.74 (m, 2H), 1.58-1.64 (m, 2H). MS EI m/z 162 (M+H)+.
Reaction SMILES: [CH3:1][C:2]([CH3:13])([O:4][C:5]([NH:7][CH2:8][CH2:9][C:10]([OH:12])=O)=[O:6])[CH3:3].ClC1C=CC2OC3C=CC=CC=3CN(C(O)=O)C=2C=1.[Cl:33][C:34]1[CH:52]=[CH:51][C:37]2[O:38][C:39]3[CH:50]=[CH:49][CH:48]=[CH:47][C:40]=3[CH2:41][N:42]([C:43]([NH:45][NH2:46])=[O:44])[C:36]=2[CH:35]=1.CCN(C(C)C)C(C)C.OS([O-])(=O)=O.[K+]>CN(C=O)C.CCOC(C)=O>[CH3:13][C:2]([CH3:1])([O:4][C:5]([NH:7][CH2:8][CH2:9][C:10]([NH:46][NH:45][C:43]([N:42]1[CH2:41][C:40]2[CH:47]=[CH:48][CH:49]=[CH:50][C:39]=2[O:38][C:37]2[CH:51]=[CH:52][C:34]([Cl:33])=[CH:35][C:36]1=2)=[O:44])=[O:12])=[O:6])[CH3:3]
Reactant: NNC(=O)N1Cc2ccccc2Oc2ccc(Cl)cc21
Reactant: CC(C)(C)OC(=O)NCCC(=O)O
Agent: O=C(O)N1Cc2ccccc2Oc2ccc(Cl)cc21
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NCCC(=O)NNC(=O)N1Cc2ccccc2Oc2ccc(Cl)cc21
Temperature: 25 °C
Yield: 52 %

Procedure:
To a stirring solution of 3.78 g (20 mmol) of N-[(1,1-dimethylethoxy)carbonyl]-β-alanine (6), prepared as described above in Example 6, and 5.79 (20 mmol) of 8-chlorodibenz[b,f][1,4]oxazepine-10(11H)carboxylic acid, hydrazine (1), prepared as described above in Example 1, in 50 mL of DMF cooled in an icebath was added 3.5 mL (20 mmol) of DIEA followed by 4.22 g (22 mmol) of N,N-dimethylaminopropylethylcarbodiimide hydrochloride. The reaction was allowed to warm to ambient temperature over a period of 16 hours. To the reaction mixture was added 100 mL of EtOAc and 200 mL of M KHSO4. The layers were separated and then the organic layer was washed with 2×100 mL of M KHSO4, 2×100 mL of a saturated KHCO3 solution, and 100 mL of brine. The organic layer was dried over anhydrous Na2SO4, filtered, and then concentrated in vacuo. The resulting product was purified by column chromatography to yield 4.75 g (52%) of 8-chlorodibenz[b,f][1,4]oxazepine-10(11H)-carboxylic acid, 2-[3-[[(1,1-dimethylethoxy)carbonyl]amino]-1-oxopropyl]hydrazide (7).
Reaction SMILES: C([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([O:13][C:14]2[CH:21]=[CH:20][C:17]([CH:18]=[O:19])=[CH:16][C:15]=2[O:22][CH3:23])[CH2:9]1)=O)(C)(C)C.[CH:24](O)=O>ClCCl.C(Cl)(Cl)Cl>[C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([O:13][C:14]2[CH:21]=[CH:20][C:17]([CH:18]=[O:19])=[CH:16][C:15]=2[O:22][CH3:23])[CH2:9]1)(=[O:5])[CH3:24]
Reactant: O=CO
Reactant: COc1cc(C=O)ccc1O[C@H]1CCN(C(=O)OC(C)(C)C)C1
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: COc1cc(C=O)ccc1O[C@H]1CCN(C(C)=O)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
5.5 g of 4-[((3S)-1-tert-butoxycarbonyl-3-pyrrolidinyl)oxy]-3-methoxybenzaldehyde was dissolved in 20 ml of dichloromethane, followed by the addition of 30 ml of formic acid. The thus prepared mixture was stirred at room temperature for 1 hour and then at 50° C. for 1 hour. The solvent and formic acid were distilled off under a reduced pressure, and the resulting residue was dissolved in 100 ml of tetrahydrofuran. The thus prepared solution was mixed with 2.68 g of acetyl chloride, and 8.63 g of triethylamine was added dropwise thereto while stirring under ice cooling. Thereafter, the solvent was distilled off, and the residue thus obtained was dissolved in chloroform, and washed with water, followed by drying of the resulting organic layer. After distilling off the solvent, the resulting residue was purified by subjecting it to silica gel column chromatography using toluene as an elution solvent, thereby obtaining 4.3 g of 4-[((3S)-1-acetyl-3-pyrrolidinyl)oxy]-3-methoxybenzaldehyde as a viscous oil.