Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[N:8]=[CH:7][C:6]([CH2:9][NH:10][C:11]2[C:12]3[CH2:20][NH:19][CH2:18][CH2:17][C:13]=3[N:14]=[CH:15][N:16]=2)=[CH:5][CH:4]=1.[Br:23][C:24]1[CH:25]=[CH:26][C:27](F)=[C:28]([CH:31]=1)[C:29]#[N:30].C(N(CC)C(C)C)(C)C.C(#N)C>CCOC(C)=O>[Br:23][C:24]1[CH:25]=[CH:26][C:27]([N:19]2[CH2:18][CH2:17][C:13]3[N:14]=[CH:15][N:16]=[C:11]([NH:10][CH2:9][C:6]4[CH:7]=[N:8][C:3]([C:2]([F:21])([F:1])[F:22])=[CH:4][CH:5]=4)[C:12]=3[CH2:20]2)=[C:28]([CH:31]=1)[C:29]#[N:30]
Reactant: FC(F)(F)c1ccc(CNc2ncnc3c2CNCC3)cn1
Reactant: N#Cc1cc(Br)ccc1F
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1cc(Br)ccc1N1CCc2ncnc(NCc3ccc(C(F)(F)F)nc3)c2C1
Yield: 57.5 %

Procedure:
A mixture of N-((6-(trifluoromethyl)pyridin-3-yl)methyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-amine (1.0 g, 3.2 mmol), 5-bromo-2-fluorobenzonitrile (0.97 g, 4.8 mmol), N,N-diisopropylethylamine (1.7 mL, 9.7 mmol), and acetonitrile (10 mL) was subjected to microwave irradiation at 180° C. for 2 h. More 5-bromo-2-fluorobenzonitrile (1.0 g) was added and the mixture was subjected to microwave irradiation at 180° C. for another 2 h. Then additional 5-bromo-2-fluorobenzonitrile (1.0 g) was added and the reaction mixture was subjected to microwave irradiation at 180° C. for an additional 2 h. After cooling, the mixture was diluted with EtOAc (100 mL) and washed with aq. Na2CO3 solution and brine, dried (Na2SO4) and concentrated. The residue was purified by silica gel column (100% EtOAc) to yield a light yellow solid (0.90 g, 57%).
Reaction SMILES: [Cl:1]CC([NH:5][C@@H:6]1[C:11](=[O:12])[O:10][C:8](=[O:9])[CH2:7]1)=O.[NH2:13][C@H:14]([C:22]([O:24][CH3:25])=[O:23])[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>ClC(Cl)C.C(O)(=O)C>[CH3:25][O:24][C:22]([C@@H:14]([NH:13][C:11]([C@@H:6]([NH2:5])[CH2:7][C:8]([OH:10])=[O:9])=[O:12])[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:23].[ClH:1]
Reactant: O=C(CCl)N[C@H]1CC(=O)OC1=O
Reactant: COC(=O)[C@@H](N)Cc1ccccc1
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Product: COC(=O)[C@H](Cc1ccccc1)NC(=O)[C@@H](N)CC(=O)O
Product: Cl
Temperature: -5 °C
Reaction time: 1 h
Yield: 48 %

Procedure:
150 Grams of N-chloroacetyl-L-aspartic acid anhydride are quickly added, at -5° C., to the solution of 140 grams of methyl L-phenylalaninate in 400 ml of dichloroethane plus 200 ml of acetic acid. The mixture is stirred for 1 hour at -5° C.; the temperature is then raised, in 2 hours, to 15° C., then, in 30 minutes, to 40° C. The dichloroethane is evaporated under vacuum; 500 ml of methanol and 60 grams of thiourea are added and the mixture is refluxed for 3 hours. After cooling to 20° C., 200 ml of methanol, containing 11% (by weight) of HCl, are added, the solution is cooled to 0° C. for 1 hour, filtered and evaporated to dryness in vacuo. The residue is crystallized from 600 ml of water containing 70 g of NaCl: a very pure aspartame hydrochloride is obtained, in a 48% yield.
Reaction SMILES: C([Mg]Br)C.[N:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]2[NH:12][C:13]3[C:18]([CH:19]=2)=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:6]=1.O1CCCCC1[O:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34]Br>O1CCCC1>[OH:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][C:19]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[NH:12][C:11]=1[C:7]1[CH:6]=[N:5][CH:10]=[CH:9][CH:8]=1
Reactant: BrCCCCCCCCOC1CCCCO1
Reactant: c1cncc(-c2cc3ccccc3[nH]2)c1
Agent: CC[Mg]Br
Solvent: C1CCOC1
Product: OCCCCCCCCc1c(-c2cccnc2)[nH]c2ccccc12
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To 30 ml of a 2M solution of ethylmagnesium bromide in tetrahydrofuran under nitrogen at 0°-5° is added dropwise over 30 minutes a solution of 10.0 g of 2-(3-pyridyl)indole in 60 ml of tetrahydrofuran. The mixture is stirred for 0.5 hour at 0°-5° followed by the dropwise addition of 17.6 g of 1-tetrahydropyranyloxy-8-bromooctane in 50 ml of tetrahydrofuran. After stirring at 0°-10° for 1 hour and at room temperature for 0.5 hour, the reaction mixture is poured into ice-water and extracted with ether. The ether extract is washed with water, dried over MgSO4 and evaporated to dryness. The residue is dissolved in 100 ml of 3N hydrochloric acid, the resulting mixture is kept at room temperature for 0.5 hour, washed with ether, basified with aqueous with 3N sodium hydroxide solution and extracted with methylene chloride. The methylene chloride solution is evaporated to dryness to give 3-(8-hydroxyoctyl)-2-(3-pyridyl)-indole.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][N:8]([CH:11]([CH3:15])[CH2:12][CH2:13][NH2:14])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[CH3:16][C:17]1[CH:25]=[CH:24][CH:23]=[C:22]([CH3:26])[C:18]=1[C:19](O)=[O:20]>>[O:4]1[C:5]2([CH2:6][CH2:7][N:8]([CH:11]([CH3:15])[CH2:12][CH2:13][NH:14][C:19](=[O:20])[C:18]3[C:22]([CH3:26])=[CH:23][CH:24]=[CH:25][C:17]=3[CH3:16])[CH2:9][CH2:10]2)[O:1][CH2:2][CH2:3]1
Reactant: CC(CCN)N1CCC2(CC1)OCCO2
Reactant: Cc1cccc(C)c1C(=O)O
Product: Cc1cccc(C)c1C(=O)NCCC(C)N1CCC2(CC1)OCCO2
Yield: 83.9 %

Procedure:
Using general procedure E with 3-(1,4-dioxa-8-aza-spiro[4.5]dec-8-yl)-butylamine (2.30 g, 10.7 mmol) and 2,6-dimethylbenzoic acid (1.77 g, 11.8 mmol) followed by purification by column chromatography on silica gel (1-5% MeOH/CH2Cl2) gave N-[3-(1,4-dioxa-8-aza-spiro[4.5]dec-8-yl)-butyl]-2,6-dimethyl-benzamide (3.11 g, 83%).
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([O:11][CH2:12]/[CH:13]=[CH:14]\[CH2:15][NH2:16])[CH:6]=1)[CH3:3].[O:17]1[CH2:22][CH2:21][S:20][CH2:19][C:18]1=[O:23]>>[CH3:1][N:2]([CH2:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([O:11][CH2:12]/[CH:13]=[CH:14]\[CH2:15][NH:16][C:18](=[O:23])[CH2:19][S:20][CH2:21][CH2:22][OH:17])[CH:6]=1)[CH3:3]
Reactant: O=C1CSCCO1
Reactant: CN(C)Cc1ccnc(OC/C=C\CN)c1
Product: CN(C)Cc1ccnc(OC/C=C\CNC(=O)CSCCO)c1
Yield: 53 %

Procedure:
Following a procedure similar to that described in Example 68, but using 4-(4-dimethylaminomethyl-2-pyridyloxy)-cis-2-butenylamine and 1,4-oxathian-2-one as starting materials, in relative proportions similar to those used in that Example, the title compound was obtained in a 53% yield.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:23]=[C:22]2[C:6]3[C@@H:7]([NH:19][CH2:20][CH2:21]2)[CH2:8][C:9]2[C:14]([C:5]=3[C:4]=1[O:24][CH3:25])=[CH:13][C:12]([O:15][CH3:16])=[C:11]([O:17][CH3:18])[CH:10]=2.[CH2:26]=O.[BH4-].[Na+]>CO>[CH3:26][N:19]1[C@H:7]2[CH2:8][C:9]3[C:14](=[CH:13][C:12]([O:15][CH3:16])=[C:11]([O:17][CH3:18])[CH:10]=3)[C:5]3[C:6]2=[C:22]([CH:23]=[C:3]([O:2][CH3:1])[C:4]=3[O:24][CH3:25])[CH2:21][CH2:20]1
Reactant: COc1cc2c(cc1OC)-c1c(OC)c(OC)cc3c1[C@H](C2)NCC3
Reactant: C=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COc1cc2c(cc1OC)-c1c(OC)c(OC)cc3c1[C@H](C2)N(C)CC3
Yield: 90 %

Procedure:
Norglaucine (1.90 g, 5.2 mmol), methanol (50 ml) and 35.5% formaldehyde (6.0 ml) were successively placed in a 250 ml reaction bottle. To the mixture, NaBH4 was added portionwise (total 2.0 g, 52 mmol) at room temperature while stirring. The mixture was then reacted for 6 hours, concentrated under reduced pressure, and fractionated between water (150 ml) and chloroform (150 ml×3). The organic phase was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure to produce a solid which was purified by column chromatography (silica gel, with chloroform as the eluant) to obtain solid product glaucine (1.78 g, 90%). Physical data were as follows: mp: 112-114° C. (diethyl ether); [α]D24 +120.0° (c=0.30, MeOH); 1H NMR (CDCl3, 400 MHz) δ 8.06 (1H, s, H-11), 6.75 (1H, s, H-8), 6.56 (1H, s, H-3), 3.91 (3H, s, 9-OMe), 3.88 (3H, s, 10-OMe), 3.86 (3H, s, 2-OMe), 3.64 (3H, s, 1-OMe), 2.54 (3H, s, N-Me).
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[CH2:5]([O:7][C:8]([C:10]1[C:11]2[CH2:19][CH2:18][CH2:17][CH2:16][C:12]=2[S:13][C:14]=1[NH2:15])=[O:9])[CH3:6].O>N1C=CC=CC=1>[CH2:5]([O:7][C:8]([C:10]1[C:11]2[CH2:19][CH2:18][CH2:17][CH2:16][C:12]=2[S:13][C:14]=1[NH:15][C:1](=[O:3])[CH3:2])=[O:9])[CH3:6]
Reactant: CCOC(=O)c1c(N)sc2c1CCCC2
Reactant: CC(=O)Cl
Solvent: O
Solvent: c1ccncc1
Product: CCOC(=O)c1c(NC(C)=O)sc2c1CCCC2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Acetyl chloride (62 mL) was added dropwise to a stirred solution of 2-Amino-4,5,6,7-tetrahydro-benzo[b]thiophene-3-carboxylic acid ethyl ester (125 g) in pyridine (750 mL) on an ice bath. After stirring at room temperature for 30 minutes, the solution was poured into water (2.2 L). The resulting solid was collected by filtration and washed with water, and then was dried overnight at 55° C. to provide the title compound (140 g) as a colorless solid.
Reaction SMILES: [Si]([O:18][CH2:19][C:20]1[C:21]([C:25]#[N:26])=[CH:22][NH:23][CH:24]=1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.[CH2:27]([O:29][C:30](=[O:38])[C:31]1[CH:36]=[CH:35][C:34](F)=[CH:33][CH:32]=1)[CH3:28].C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C)C=O>[CH2:27]([O:29][C:30](=[O:38])[C:31]1[CH:36]=[CH:35][C:34]([N:23]2[CH:24]=[C:20]([CH2:19][OH:18])[C:21]([C:25]#[N:26])=[CH:22]2)=[CH:33][CH:32]=1)[CH3:28]
Reactant: CC(C)(C)[Si](OCc1c[nH]cc1C#N)(c1ccccc1)c1ccccc1
Reactant: CCOC(=O)c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(-n2cc(C#N)c(CO)c2)cc1
Temperature: 70 °C
Reaction time: 8 h
Yield: 13.8 %

Procedure:
A suspension of 4-(tert-butyldiphenylsilanyloxymethyl)-1H-pyrrole-3-carbonitrile (0.3 g), 4-fluorobenzoic acid ethyl ester (0.35 g) and cesium carbonate (0.81 g) in N,N-dimethylformamide (2 mL) was stirred at 70° C. overnight. To this reaction mixture was added water, and this mixture was extracted with ethyl acetate. This organic layer was washed with water and brine, concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: hexane/ethyl acetate=80/20-30/70) to give the title compound (0.0310 g).
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9](O)=[O:10])=[CH:7][C:6]=1[C:14]1[NH:15][C:16](=[O:24])[C:17]([CH2:22][CH3:23])=[C:18]([CH2:20][CH3:21])[N:19]=1)[CH2:2][CH3:3].S(Cl)(Cl)=O.[NH2:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32].C(N(CC)CC)C>ClCCl>[CH2:20]([C:18]1[N:19]=[C:14]([C:6]2[CH:7]=[C:8]([CH:12]=[CH:13][C:5]=2[O:4][CH2:1][CH2:2][CH3:3])[C:9]([NH:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])=[O:10])[NH:15][C:16](=[O:24])[C:17]=1[CH2:22][CH3:23])[CH3:21]
Reactant: CCOC(=O)CN
Reactant: CCCOc1ccc(C(=O)O)cc1-c1nc(CC)c(CC)c(=O)[nH]1
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Solvent: CCN(CC)CC
Product: CCCOc1ccc(C(=O)NCC(=O)OCC)cc1-c1nc(CC)c(CC)c(=O)[nH]1
Reaction time: 0.5 h
Yield: 33.1 %

Procedure:
The compound (250 mg, 0.76 mmol) of example 58 was suspended in dichloromethane (20 ml), and added with thionyl chloride (2 ml), followed by refluxing for 2 h to clear the reaction mixture. The reaction mixture was concentrated off thionyl chloride, and added with dichloromethane. Under ice-bath, the reaction mixture was added dropwise into a dichloromethane solution (20 ml) containing ethyl 2-aminoacetate (80 mg, 0.727 mmol) and triethylamine (0.2 ml, 1.454 mmol), followed by stirring for 0.5 h. The reaction mixture was then washed with water (20 ml) and saturated saline (20 ml) respectively. The organic layer was dried with anhydrous sodium sulfate, and concentrated. The residue was passed through a silica gel column to give the white title compound (100 mg, yield: 33%). 1H NMR (CDCl3) δ: 11.01 (1H, br), 8.87 (1H, d), 8.00 (1H, dd), 7.08 (1H, d), 6.87 (1H, br), 4.27 (2H, q), 4.25 (2H, t), 4.21 (2H, t), 2.69 (2H, q), 2.59 (2H, q), 2.00 (2H, m), 1.32 (3H, t), 1.30 (3H, t), 1.15 (6H, t).
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[CH:9]=2)[C:3]=1[C:15]([NH2:17])=[O:16].[N:18]1[CH:23]=[CH:22][CH:21]=[N:20][C:19]=1[O:24][C:25]1[CH:32]=[CH:31][C:28]([CH:29]=O)=[CH:27][CH:26]=1.CO.[BH4-].[Na+]>CCO.N1CCCCC1>[Cl:14][C:10]1[CH:9]=[C:8]([NH:7][C:4]2[C:3]([C:15]([NH2:17])=[O:16])=[C:2]([NH:1][CH2:29][C:28]3[CH:27]=[CH:26][C:25]([O:24][C:19]4[N:18]=[CH:23][CH:22]=[CH:21][N:20]=4)=[CH:32][CH:31]=3)[NH:6][N:5]=2)[CH:13]=[CH:12][CH:11]=1
Reactant: O=Cc1ccc(Oc2ncccn2)cc1
Reactant: NC(=O)c1c(Nc2cccc(Cl)c2)n[nH]c1N
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCNCC1
Solvent: CO
Solvent: CCO
Product: NC(=O)c1c(Nc2cccc(Cl)c2)n[nH]c1NCc1ccc(Oc2ncccn2)cc1
Yield: 17.9 %

Procedure:
5-amino-3-((3-chlorophenyl)amino)-1H-pyrazole-4-carboxamide (100 mg) was then suspended in EtOH (4 mL) and 4-(pyrimidin-2-yloxy)benzaldehyde (80 mg, 1 eq.) and piperidine (1 drop) were added. Stirred at reflux until intermediate was absent (HPLC). After reaction was complete (18 hrs) it was brought to room temperature and filtered to obtain product as a yellow powder. Powder was washed with EtOH. Product was allowed to dry under vacuum for 1 hr (104 mg, 60% yield). Resulting imine (104 mg) was suspended in 5 ml, MeOH and sodium borohydride (10 eq, 100 mg) was added. HPLC confirmed reaction was complete (absence of imine). After completion (1 hr), precipitate was filtered to obtain D32 as a light yellow powder. Product was washed with deionized water to remove excess sodium borohydride. Product was allowed to dry under vacuum for 18 hrs. 31 mg (30% yield) of final product was obtained.
Reaction SMILES: [OH:1][C:2]1([C:16]2[CH:21]=[C:20]([O:22][CH3:23])[C:19]([O:24][CH3:25])=[CH:18][C:17]=2[NH:26][C:27](=[O:31])[CH:28]([CH3:30])[CH3:29])[C:10](=[O:11])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[N+:12]([O-])=O)[C:3]1=[O:15].Cl>C(O)C.O.[Fe]>[NH2:12][C:8]1[CH:7]=[CH:6][CH:5]=[C:4]2[C:9]=1[C:10](=[O:11])[C:2]([C:16]1[CH:21]=[C:20]([O:22][CH3:23])[C:19]([O:24][CH3:25])=[CH:18][C:17]=1[NH:26][C:27](=[O:31])[CH:28]([CH3:30])[CH3:29])([OH:1])[C:3]2=[O:15]
Reactant: COc1cc(NC(=O)C(C)C)c(C2(O)C(=O)c3cccc([N+](=O)[O-])c3C2=O)cc1OC
Agent: [Fe]
Agent: Cl
Solvent: O
Solvent: CCO
Product: COc1cc(NC(=O)C(C)C)c(C2(O)C(=O)c3cccc(N)c3C2=O)cc1OC
Yield: 12.2 %

Procedure:
N-[2-(2-hydroxy-4-nitro-1,3-dioxo-indan-2-yl)-4,5-dimethoxy-phenyl]-isobutyramide (150 mg, 0.35 mmol) was dissolved in ethanol (3 ml) and water (0.3 ml). This solution was added with iron (Fe) (0.14 g, 2.55 mmol) and conc. HCl (0.03 ml), followed by heating for 3 hrs under reflux. The reaction mixture was filtrated with MeOH washing via celite pad, and the filtrate was concentrated in a vaccume. The concentrated organic layer was purified using column chromatography (ethylacetate:hexane=1:4) to afford the title compound (17 mg, 12%).
Reaction SMILES: [H-].[Na+].[CH2:3]1COCC1.[NH:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([C:17]2[CH2:18][CH2:19][N:20]([CH2:23][CH2:24][N:25]3[C:34](=[O:35])[C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[N:27]=[CH:26]3)[CH2:21][CH:22]=2)=[CH:9]1.IC>O>[CH3:3][N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([C:17]2[CH2:18][CH2:19][N:20]([CH2:23][CH2:24][N:25]3[C:34](=[O:35])[C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[N:27]=[CH:26]3)[CH2:21][CH:22]=2)=[CH:9]1
Reactant: O=c1c2ccccc2ncn1CCN1CC=C(c2c[nH]c3ccccc23)CC1
Reactant: C1CCOC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CI
Product: Cn1cc(C2=CCN(CCn3cnc4ccccc4c3=O)CC2)c2ccccc21
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 63 %

Procedure:
A dried flask under nitrogen was loaded with sodium hydride (0.015 g, 0.37 mmol) and THF (10 mL). At 0° C. 3-[2-(4-(1H-indol-3-yl)-3,6-dihydro-1(2H) -pyridinyl)ethyl]-4(3H)-quinazolinone (0.80 g, 2.16 mmol), was added and the mixture stirred for 15 minutes. Keeping the reaction temperature at 0° C., the iodomethane was added dropwise (0.14 mL, 2.16 mmol). This was allowed to warm to room temperature and stir overnight. Water was slowly added to the mixture to quench and the organics were extracted in chloroform, washed with water and dried over Na2SO4, filtered and concentrated. The residue was chromatograhed using silica (2% methanol:chloroform system); 0.52 g of 3-[2-(4-(1-methyl-1H-indol-3-yl)-3,6-dihydro-1(2H)-pyridinyl)ethyl]-4(3H)-quinazolinone was isolated as an orange solid. Yield 63%; MS: 384.9 (M+H)+; 1H NMR (300 MHz, CDCl3): δ 2.79 (m, 2H), 3.17 (m, 4H), 3.20 (m, 2H), 3.61 (m, 2H), 3.76 (s, 3H), 4.44 (t, 2H), 6.12 (t, 1H), 7.00 (t, 1H), 7.37 (m, 1H), 7.53 (m, 1H), 7.45 (m, 2H), 7.81 (m, 1H), 8.17 (d, 1H), 8.35 (s, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][CH2:6][C:7]2=O.[CH3:13]N.C(O)(=O)C.[C:19]([BH3-])#[N:20].[Na+]>C(O)C>[Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][CH2:6][CH:7]2[N:20]([CH3:19])[CH3:13]
Reactant: CN
Reactant: O=C1CCCc2c(Br)cccc21
Reactant: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Product: CN(C)C1CCCc2c(Br)cccc21
Temperature: 25 °C
Reaction time: 36 h

Procedure:
8.5 of 5-bromotetralone are dissolved in 100 ml of ethanol, and 25 ml of a 33% solution of methylamine in ethanol are added. The mixture is cooled to 5° and the pH is adjusted to 6-7 with acetic acid. Then 2.5 g of sodium cyanoborohydride are added in portions. The reaction mixture is then stirred at room temperature during 36 hours. The solvent is evaporated and the residue is added to 1N NaOH. The aqueous phase is extracted 3× with ether and the combined organic extracts are dried on Na2SO4 and evaporated. The remaining oil (8.7 g) is dissolved in 100 ml of methanol and 6 ml of a 33% aqueous solution of formaldehyde are added. The mixture is cooled to 5° and 2.8 g of sodium borohydride are added. After stirring at room temperature for 24 hours, the reaction mixture is concentrated and the residue is added to 1N HCl. The aqueous phase is washed 2× with ether. The pH is then adjusted to 10 with 30% NaOH and extraction follows 3× with ether. The organic extracts are dried on Na2SO4 and concentrated. The 5-bromo-N,N-dimethyl-1,2,3,4-tetrahydro-1-naphthalenylamine is obtained.
Reaction SMILES: C([O:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11](Br)[CH3:12])=[CH:7][CH:6]=1)(=O)C.[CH3:14][C:15]1[NH:16][C:17]2[C:22]([C:23]=1[CH3:24])=[CH:21][C:20]([C:25]([O:27][CH2:28][CH:29]=[CH2:30])=[O:26])=[CH:19][CH:18]=2>>[OH:4][C:5]1[CH:6]=[CH:7][C:8]([CH:11]([N:16]2[C:17]3[C:22](=[CH:21][C:20]([C:25]([O:27][CH2:28][CH:29]=[CH2:30])=[O:26])=[CH:19][CH:18]=3)[C:23]([CH3:24])=[C:15]2[CH3:14])[CH3:12])=[CH:9][CH:10]=1
Reactant: C=CCOC(=O)c1ccc2[nH]c(C)c(C)c2c1
Reactant: CC(=O)Oc1ccc(C(C)Br)cc1
Product: C=CCOC(=O)c1ccc2c(c1)c(C)c(C)n2C(C)c1ccc(O)cc1

Procedure:
The title compound was prepared following the same general protocol as described in Step 2, Example 1, using 4-(1-bromoethyl)phenyl acetate and allyl 2,3-dimethyl-1H-indole-5-carboxylate.
Reaction SMILES: C([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([O:19][C:20]3[CH:25]=[CH:24][C:23]([NH:26][C:27]([NH:29][C:30]4[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=4)=[O:28])=[CH:22][CH:21]=3)=[CH:14][CH:15]=[N:16]2)=[CH:11][C:10]=1[C:37]#[N:38])C1C=CC=CC=1.C1(SC)C=CC=CC=1>FC(F)(F)C(O)=O>[C:37]([C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][C:9]=1[OH:8])[N:16]=[CH:15][CH:14]=[C:13]2[O:19][C:20]1[CH:21]=[CH:22][C:23]([NH:26][C:27]([NH:29][C:30]2[CH:31]=[CH:32][C:33]([F:36])=[CH:34][CH:35]=2)=[O:28])=[CH:24][CH:25]=1)#[N:38]
Reactant: N#Cc1cc2c(Oc3ccc(NC(=O)Nc4ccc(F)cc4)cc3)ccnc2cc1OCc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: CSc1ccccc1
Product: N#Cc1cc2c(Oc3ccc(NC(=O)Nc4ccc(F)cc4)cc3)ccnc2cc1O
Temperature: 60 °C
Reaction time: 8 h
Yield: 94.3 %

Procedure:
After dissolving N-(4-(7-(benzyloxy)-6-cyano-4-quinolyl)oxyphenyl)-N′-(4-fluorophenyl)urea (6.20 g, 12.3 mmol) in trifluoroacetic acid (60 ml) and thioanisole (3.6 ml, 30.7 mmol) under a nitrogen atmosphere, the solution was stirred at 60° C. overnight. The reaction solution was concentrated under reduced pressure, and after adding water (100 ml) to the obtained residue, sodium bicarbonate was added to neutralization, diethyl ether (200 ml) was added, the mixture was stirred, and the precipitated crystals were filtered out, washed with water and diethyl ether and dried at 70° C. to obtain the title compound (4.816 g, 11.6 mmol, 94.8%) as yellow crystals.
Reaction SMILES: [CH2:1]([N:8]1[C:17](=[O:18])[C:16]2[C:11](=[CH:12][C:13]([Cl:19])=[CH:14][CH:15]=2)[N:10]=[C:9]1[CH:20](Br)[C:21]([N:23]([CH3:25])[CH3:24])=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C)C=O.[C:32]([NH:39][CH2:40][CH2:41][CH2:42][NH2:43])([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33].O>C(OCC)(=O)C>[CH2:1]([N:8]1[C:17](=[O:18])[C:16]2[C:11](=[CH:12][C:13]([Cl:19])=[CH:14][CH:15]=2)[N:10]=[C:9]1[CH:20]([NH:43][CH2:42][CH2:41][CH2:40][NH:39][C:32](=[O:33])[O:34][C:35]([CH3:37])([CH3:36])[CH3:38])[C:21]([N:23]([CH3:25])[CH3:24])=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(C)C(=O)C(Br)c1nc2cc(Cl)ccc2c(=O)n1Cc1ccccc1
Reactant: CC(C)(C)OC(=O)NCCCN
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CN(C)C(=O)C(NCCCNC(=O)OC(C)(C)C)c1nc2cc(Cl)ccc2c(=O)n1Cc1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 58.8 %

Procedure:
To a solution of 2-(3-benzyl-7-chloro-4-oxo-3,4-dihydroquinazolin-2-yl)-2-bromo-N,N-dimethylacetamide (1.4 g, 1 eq.) in of N,N-dimethylformamide (10 ml), was added N-Boc-1,3-diaminopropane (2.8 g, 5 eq.). The reaction was stirred at room temperature for 4 h and then heated to 40° C. The mixture was stirred at 40° C. overnight. Water and ethyl acetate were added to the mixture. The organic layer was washed with saturated sodium bicarbonate, saturated sodium chloride, dried over magnesium sulfate, filtered, and concentrated. The crude product was purified by flash chromatography to give tert-butyl 3-{[1-(3-benzyl-7-chloro-4-oxo-3,4-dihydroquinazolin-2-yl)-2-(dimethylamino)-2-oxoethyl]amino}propylcarbamate (1 g) as a pale yellow solid.
Reaction SMILES: [NH2:1][C@H:2]([C:10]([NH:12][C@H:13]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH:15]([CH3:17])[CH3:16])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Cl[CH2:26]C(CCl)=O.[C:31]([O:35][C:36]([NH:38][C@H:39]([C:47]([OH:49])=O)[CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)=[O:37])([CH3:34])([CH3:33])[CH3:32].C(=O)(O)[O-].[Na+].[I-].[Na+]>CN(C)C=O>[C:31]([O:35][C:36]([NH:38][C@@H:39]([CH2:40][C:41]1[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=1)[C:47](=[O:49])[CH2:26][NH:1][C@H:2]([C:10]([NH:12][C@H:13]([C:18]([O:20][C:21]([CH3:22])([CH3:24])[CH3:23])=[O:19])[CH2:14][CH:15]([CH3:17])[CH3:16])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[O:37])([CH3:32])([CH3:33])[CH3:34]
Reactant: O=C(CCl)CCl
Reactant: CC(C)C[C@H](NC(=O)[C@@H](N)Cc1ccccc1)C(=O)OC(C)(C)C
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Agent: O=C([O-])O
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)C[C@H](NC(=O)[C@H](Cc1ccccc1)NCC(=O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Reaction time: 8 h
Yield: 92.7 %

Procedure:
To a stirred solution of L-phenylalanyl-L-leucine, t-butyl ester (4.13 g, 12 mmol) in 60 ml of dimethylformamide under argon was added N-[(t-butyloxy)carbonyl]-L-phenylalanine chloromethyl ketone (3.57 g, 12 mmol, see example 4A), sodium bicarbonate (1.01 g, 12 mmol) and sodium iodide (900 mg, 6 mmol, 0.5 equiv.). The reaction mixture was allowed to stir overnight, then the solvent was evaporated (<25° C., vacuum pump). The residue was taken up into ethyl acetate (300 ml) and washed with water (3×40 ml) and brine (40 ml), then dried (sodium sulfate) and evaporated to give 6.63 g of a yellow oil. This oil was purified by flash chromatography on 450 g of Merck silica gel (230-400 mesh), eluting with 3:1 hexane-ethyl acetate, to yield 5.05 g of the title compound as a light yellow solid. A portion was recrystallized from ethyl acetate-hexane to give a white solid, melting point 85°-87° C.
Reaction SMILES: [FH:1].Cl[C:3]1([F:15])[O:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[O:5][C:4]1([F:14])[F:13]>>[F:1][C:3]1([F:15])[O:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[O:5][C:4]1([F:14])[F:13]
Reactant: F
Reactant: FC1(F)Oc2ccccc2OC1(F)Cl
Product: FC1(F)Oc2ccccc2OC1(F)F

Procedure:
Finally, 170 ml/h of hydrogen fluoride (measured as liquid) and 148 g/h of 2-chloro-2,3,3-trifluorobenzodioxane were passed over the catalyst at 300° C. In the course of 7 hours, 930 g of 2,2,3,3-tetrafluorobenzodioxane were obtained. This corresponds to a degree of fluorination of 97%.