Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:6]([C:7]([O:9][CH3:10])=[O:8])[C:5]([OH:12])=[C:4]([C:13](=[O:16])[CH2:14][CH3:15])[CH:3]=1.[Na].[O:18]1[CH2:23][CH2:22][N:21]([CH:24](O)C)[CH2:20][CH2:19]1>>[Cl:1][C:2]1[CH:11]=[C:6]([C:7]([O:9][CH2:10][CH2:24][N:21]2[CH2:22][CH2:23][O:18][CH2:19][CH2:20]2)=[O:8])[C:5]([OH:12])=[C:4]([C:13](=[O:16])[CH2:14][CH3:15])[CH:3]=1
Reactant: CCC(=O)c1cc(Cl)cc(C(=O)OC)c1O
Reactant: CC(O)N1CCOCC1
Agent: [Na]
Product: CCC(=O)c1cc(Cl)cc(C(=O)OCCN2CCOCC2)c1O
Temperature: 25 °C
Yield: 88.8 %

Procedure:
A 24.3 g (0.10 mole) quantity of methyl 5-chloro-3-propionylsalicylate was added to a solution of 0.5 g (0.022 mole) of sodium in 300 ml of morpholinoethanol. The mixture was maintained at room temperature for 24 hours and was heated at 2 hours at 90° C. The reaction mixture was subjected to distillation at reduced pressure to remove the excess unreacted morpholinoethanol and the methanol produced, and the residue was recrystallized from cyclohexane to obtain 38.0 g (88.8%) of crystals which melt at 144.0° to 146.3° C.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:8]([OH:10])=O)=[N:4][CH:5]=[CH:6][CH:7]=1.Cl.[CH3:12][NH:13][CH3:14].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CN(C=O)C>[NH2:1][C:2]1[C:3]([C:8]([N:13]([CH3:14])[CH3:12])=[O:10])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: CNC
Reactant: Nc1cccnc1C(=O)O
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CN(C)C(=O)c1ncccc1N
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.8 %

Procedure:
To the mixture of 3-aminopicolinic acid (0.32 g, 2.32 mmol), dimethylamine hydrogen chloride (0.227 g, 1.2 eq), EDC (0.667 g, 1.5 eq), HOBt (0.376 g, 1.2 eq) in DMF (10 mL) was added DIEA (2.0 mL, 5.0 eq). The mixture was stirred at room temperature overnight. The crude was concentrated and dissolved in EtOAc. It was washed with saturated NaHCO3. The solvent was removed and the crude was purified by silica gel chromatography (0%˜20% MeOH/DCM) to obtain the desired product 3-amino-N,N-dimethylpicolinamide (0.375 g, isolated yield ˜98%).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[C:9]([CH3:10])=[CH:8][C:7]([NH2:11])=[CH:6][C:5]=1[CH3:12].Cl[CH2:14][CH2:15][N:16]([CH2:27][CH2:28]Cl)[S:17]([C:20]1[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=1)(=[O:19])=[O:18].C(=O)([O-])[O-].[Na+].[Na+].[I-].[K+].C1(O)CCCCC1>O>[CH3:2][O:3][C:4]1[C:5]([CH3:12])=[CH:6][C:7]([N:11]2[CH2:28][CH2:27][N:16]([S:17]([C:20]3[CH:21]=[CH:22][C:23]([CH3:26])=[CH:24][CH:25]=3)(=[O:19])=[O:18])[CH2:15][CH2:14]2)=[CH:8][C:9]=1[CH3:10]
Reactant: Cc1ccc(S(=O)(=O)N(CCCl)CCCl)cc1
Reactant: COc1c(C)cc(N)cc1C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: O
Solvent: OC1CCCCC1
Product: COc1c(C)cc(N2CCN(S(=O)(=O)c3ccc(C)cc3)CC2)cc1C
Reaction time: 8 h
Yield: 50.1 %

Procedure:
A mixture of 10 g of 4-methoxy-3,5-dimethylbenzenamine hydrochloride, 19.9 g of N,N-bis(2-chloroethyl)-4-methylbenzenesulfonamide, 16.8 g of sodium carbonate, 0.5 g of potassium iodide and 100 ml of cyclohexanol was stirred overnight at 150°-160° C. After cooling, the reaction mixture was poured into water. The product was extracted with dichloromethane. The extract was washed with water, dried, filtered and evaporated. The residue was purified by column-chromatography over silica gel using trichloromethane as eluent. The pure fractions were collected and the solvent was evaporated. The residue was crystallized from 1-butanol, yielding 10 g (50.4%) of 4-(4-methoxy-3,5-dimethylphenyl)-1-[(4-methylphenyl)sulfonyl]piperazine; mp. 174.2° C. (interm. 42).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4](/[CH:9]=[CH:10]/[CH2:11][OH:12])[CH:5]=[C:6]([Br:8])[CH:7]=1.[CH2:13]([O:15][C@@H:16]([CH2:22][C:23]1[CH:28]=[CH:27][C:26](O)=[CH:25][CH:24]=1)[C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH3:14]>>[Br:1][C:2]1[CH:3]=[C:4](/[CH:9]=[CH:10]/[CH2:11][O:12][C:26]2[CH:25]=[CH:24][C:23]([CH2:22][C@H:16]([O:15][CH2:13][CH3:14])[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:28][CH:27]=2)[CH:5]=[C:6]([Br:8])[CH:7]=1
Reactant: OC/C=C/c1cc(Br)cc(Br)c1
Reactant: CCOC(=O)[C@H](Cc1ccc(O)cc1)OCC
Product: CCOC(=O)[C@H](Cc1ccc(OC/C=C/c2cc(Br)cc(Br)c2)cc1)OCC
Yield: 76.1 %

Procedure:
The title compound (780 mg, 78%) was prepared from (E)-3-(3,5-dibromophenyl)-prop-2-en-1-ol (584 mg, 2.0 mmol) and (S)-ethyl 2-ethoxy-3-(4-hydroxyphenyl)-propionate (500 mg, 2.10 mmol) by a procedure analogous to that described in example 52c.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([OH:10])[CH:7]=[C:6]([Cl:11])[C:3]=1[CH:4]=O.[NH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[Cl:1][C:2]1[CH:9]=[C:8]([OH:10])[CH:7]=[C:6]([Cl:11])[C:3]=1[CH2:4][N:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: O=Cc1c(Cl)cc(O)cc1Cl
Reactant: C1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: Oc1cc(Cl)c(CN2CCCCC2)c(Cl)c1
Yield: 79.6 %

Procedure:
To a pre-stirred solution of 2,6-dichloro-4-hydroxybenzaldehyde (1.88, 9.8 mmol) and piperidine (1.07 mL, 10.8 mmol) in DCM (40 mL) was added sodium triacetoxyborohydride (3.13 g, 14.8 mmol) in portions. After 14 h the reaction mixture was quenched by the addition of water (50 mL), the pH of the solution adjusted to 2 by the addition of hydrochloric acid and the solution washed with DCM (50 mL). The pH of the aqueous phase was then adjusted to 9 by the addition of saturated aqueous sodium carbonate and then the organic component was extracted with DCM (50 mL), dried over anhydrous sodium sulfate and evaporated under reduced pressure to afford the title compound as a beige solid (2.03 g, 80%) that was used without further purification. 1H NMR (CD3OD, 300 MHz): 6.81-6.77 (m, 2H), 3.72 (s, 2H), 2.67-2.57 (m, 4H), 1.64-1.54 (m, 4H), 1.51-1.44 (m, 2H).
Reaction SMILES: [N:1]1([C:7]2[C:8]([C:13]#[N:14])=[N:9][CH:10]=[CH:11][CH:12]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.N>CO.[Ni]>[N:1]1([C:7]2[C:8]([CH2:13][NH2:14])=[N:9][CH:10]=[CH:11][CH:12]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: N#Cc1ncccc1N1CCCCC1
Agent: [Ni]
Agent: N
Solvent: CO
Product: NCc1ncccc1N1CCCCC1
Yield: 62.7 %

Procedure:
A solution of 3,4,5,6-tetrahydro-2H-[1,3′]bipyridinyl-2′-carbonitrile (0.980 g, 5.23 mmol) in MeOH (10 mL) was added to a flask charged with Raney Ni (pre-washed with methanol) (˜1.0 g) in MeOH (10 mL). After saturated with NH3 gas the mixture was shaken under H2 (40 psi) for 3 h. The reaction mixture was then filtered through a celite cake, and the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column (100:5:1 CH2Cl2/MeOH/NH4OH), affording C-(3,4,5,6-tetrahydro-2H-[1,3′]bipyridinyl-2′-yl)-methylamine as a pale yellow oil (0.627 g, 63%). 1H NMR (CDCl3) δ 1.53-1.61 (m, 2H), 1.65-1.74 (m, 4H), 2.82 (t, 4H, J=5.4 Hz), 3.99 (s, 2H), 7.11 (dd, 1H, J=4.8, 8.1 Hz), 7.31 (dd, 1H, J=1.5, 8.1 Hz), 8.27 (dd, 1H, J=1.5, 4.8 Hz).
Reaction SMILES: CN1CCOCC1.[CH3:8][C:9]1[CH:14]=[C:13]([NH2:15])[CH:12]=[CH:11][C:10]=1[N:16]1[CH2:20][CH2:19][CH2:18][S:17]1(=[O:22])=[O:21].[C:23]([C:25]1[CH:26]=[C:27]([NH:31][CH:32]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[C:33](O)=[O:34])[CH:28]=[CH:29][CH:30]=1)#[N:24].Cl.CN(C)CCCN=C=NCC.O.OC1C2N=NNC=2C=CC=1>CN(C=O)C.O>[C:23]([C:25]1[CH:26]=[C:27]([NH:31][CH:32]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[C:33]([NH:15][C:13]2[CH:12]=[CH:11][C:10]([N:16]3[CH2:20][CH2:19][CH2:18][S:17]3(=[O:22])=[O:21])=[C:9]([CH3:8])[CH:14]=2)=[O:34])[CH:28]=[CH:29][CH:30]=1)#[N:24]
Reactant: Cc1cc(N)ccc1N1CCCS1(=O)=O
Reactant: N#Cc1cccc(NC(C(=O)O)c2ccccc2)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Solvent: O
Product: Cc1cc(NC(=O)C(Nc2cccc(C#N)c2)c2ccccc2)ccc1N1CCCS1(=O)=O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
51 μl (0.500 mmol) of 4-methylmorpholine are added to a solution of 113 mg (0.500 mmol) of 2-(2-methyl-4-aminophenyl)isothiazolidine 1,1-dioxide, 126 mg (0.500 mmol) of (3-cyanophenylamino)phenylacetic acid, 96.0 mg (0.500 mmol) of N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (DAPECI) and 68 mg (0.500 mmol) of hydroxybenzotriazole hydrate (HOBt) in 1 ml of DMF, and the mixture is stirred at room temperature for 24 hours. The reaction mixture is introduced into water, and the precipitate is filtered off, giving 2-(3-cyanophenylamino)-N-[4-(1,1-dioxoisothiazolidin-2-yl)-3-methylphenyl]-2-phenylacetamide as a colourless solid; ESI 461.
Reaction SMILES: [CH3:1][N:2]([C:4]([NH:6][C:7](=S)[NH:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:16]=[C:17]([N:31]3[CH2:36][CH2:35][O:34][CH2:33][C@@H:32]3[CH3:37])[C:18]3[CH2:24][CH2:23][N:22]([C:25]4[N:30]=[CH:29][CH:28]=[CH:27][N:26]=4)[CH2:21][C:19]=3[N:20]=2)=[CH:11][CH:10]=1)=[O:5])[NH2:3].C(O)C>>[CH3:1][N:2]1[C:4](=[O:5])[NH:6][C:7]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[N:16]=[C:17]([N:31]4[CH2:36][CH2:35][O:34][CH2:33][C@@H:32]4[CH3:37])[C:18]4[CH2:24][CH2:23][N:22]([C:25]5[N:30]=[CH:29][CH:28]=[CH:27][N:26]=5)[CH2:21][C:19]=4[N:20]=3)=[CH:11][CH:10]=2)=[N:3]1
Reactant: C[C@H]1COCCN1c1nc(-c2ccc(NC(=S)NC(=O)N(C)N)cc2)nc2c1CCN(c1ncccn1)C2
Solvent: CCO
Product: C[C@H]1COCCN1c1nc(-c2ccc(Nc3nn(C)c(=O)[nH]3)cc2)nc2c1CCN(c1ncccn1)C2

Procedure:
Step 3—Synthesis of compound vb: (S)-1-methyl-N-(4-(4-(3-methylmorpholino)-7-(pyrimidin-2-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)phenylcarbamothioyl)hydrazinecarboxamide (0.113 g, 0.000211 mol) and Ethanol (3.7 mL, 0.063 mol) were combined and the reaction was microwaved on 300 watts, 150° C. for 30 minutes on a CEM microwave. The reaction mixture was chromatographed through silica gel (0-5% MeOH in dichloromethane) and purified by HPLC. 1H NMR (400 MHz, DMSO) δ 9.34 (s, 1H), 8.43 (d, J=4.7, 2H), 8.22 (d, J=8.8, 2H), 7.47 (d, J=8.8, 2H), 6.69 (t, J=4.7, 1H), 4.88 (d, J=18.7, 1H), 4.73 (d, J=18.7, 1H), 4.17-4.04 (m, 2H), 3.91-3.79 (m, 2H), 3.70 (dd, J=11.3, 2.6, 1H), 3.61 (dd, J=9.9, 6.5, 3H), 3.43 (d, J=11.3, 1H), 3.23 (s, 3H), 2.73 (s, 2H), 1.25 (d, J=6.6, 3H). LC/MS-m/z+501.2 (M+H)+
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH:5]=[CH:6][NH:7]2.N1C=CC=CC=1.[Cl:18][C:19]([Cl:24])([Cl:23])[C:20](Cl)=[O:21]>ClCCl>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[C:5]([C:20](=[O:21])[C:19]([Cl:24])([Cl:23])[Cl:18])=[CH:6][NH:7]2
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Reactant: COc1cccc2[nH]ccc12
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1cccc2[nH]cc(C(=O)C(Cl)(Cl)Cl)c12
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
To a solution of 4-methoxy-1H-indole (7.15 g, 49 mmol) and pyridine (19.7 mL, 243 mmol) in dichloromethane (50 mL) at 0° C. under nitrogen was added dropwise a solution of trichloroacetyl chloride (27.1 mL, 243 mmol) in dichloromethane (50 mL). After stirring at 0° C. for an additional 1.5 h, the mixture was concentrated in vacuo. The residue was taken up in the minimal volume of methanol necessary and placed in a freezer overnight. The precipitate was filtered, rinsed well with methanol, and dried to yield 4-methoxy-3-trichloroacetyl-1H-indole. To a stirring solution of sodium methoxide (3.5 mL of a 25 weight % solution in methanol) in methanol (200 mL) at ambient temperature was added 4-methoxy-3-trichloroacetyl-1H-indole (9.07 g, 31.0 mmol) in portions over 0.75 h. After stirring an additional 0.75 h, the mixture was cooled in an ice bath, diluted with ice water, acidified with concentrated hydrochloric acid, and the methanol removed in vacuo. The resulting heterogeneous mixture was cooled in an ice bath, the precipitate filtered, rinsed with water, and dried to afford methyl 4-methoxy-1H-indole-3-carboxylic ester. A slurry of this ester (5.6 g 27 mmol) in 50% aqueous sodium hydroxide (50 mL) and methanol (50 mL) was stirred at ambient temperature for 19 h. The mixture was cooled in an ice bath, acidified with concentrated hydrochloric acid, the precipitate filtered, rinsed with ice water, and dried to afford 4-methoxy-1H-indole-3-carboxylic acid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([S:10](Cl)(=[O:12])=[O:11])[CH:5]=[C:6]([CH3:9])[C:7]=1[OH:8].Cl.[NH2:15][NH:16][C:17]([NH2:19])=[O:18].[OH-].[Na+]>CC(N(C)C)=O>[CH3:1][C:2]1[CH:3]=[C:4]([S:10]([NH:15][NH:16][C:17]([NH2:19])=[O:18])(=[O:12])=[O:11])[CH:5]=[C:6]([CH3:9])[C:7]=1[OH:8]
Reactant: Cc1cc(S(=O)(=O)Cl)cc(C)c1O
Reactant: NNC(N)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)N(C)C
Product: Cc1cc(S(=O)(=O)NNC(N)=O)cc(C)c1O
Temperature: 0 °C

Procedure:
11 g (0.05 mol) of 3,5-dimethyl-4-hydroxybenzenesulphonic acid chloride and 6 g (0.05mol) of semicarbazide hydrochloride are first introduced into 50 ml of dimethylacetamide. 10 ml of 10 N sodium hydroxide solution are added dropwise to this white suspension over the course of 15 minutes at 40° C., whilst stirring. Since the reaction is exothermic, slight cooling must be applied. The mixture is then stirred for a further 4 hours at 40° C. After cooling to 0° C., the sodium chloride which has precipitated is filtered off and the filtrate is concentrated completely under reduced pressure. The residue is dissolved in a small amount of water and is cooled to 0°-5° C. Hereupon, 3.5-dimethyl-4-hydroxybenzenesulphonylsemicarbazide, of melting point 243° C. (with decomposition), crystallises out.
Reaction SMILES: [O:1]([C:8]1[CH2:13][CH2:12][CH:11]([C:14](=O)[CH:15]=[CH:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:10](=O)[CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[NH2:26][NH2:27]>CC(O)=O.CCO>[O:1]([C:8]1[CH2:13][CH2:12][C:11]2[C:14]([CH:15]=[CH:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[N:26][NH:27][C:10]=2[CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NN
Reactant: O=C(C=Cc1ccccc1)C1CCC(Oc2ccccc2)=CC1=O
Solvent: CCO
Solvent: O
Solvent: CC(=O)O
Product: C(=Cc1n[nH]c2c1CCC(Oc1ccccc1)=C2)c1ccccc1
Temperature: 70 °C
Yield: 36.4 %

Procedure:
To a stirred solution of 3-phenoxy-6-(3-phenyl-acryloyl)-cyclohex-2-enone (1.13 g, 3.55 mmol) in 20 mL of HOAc/EtOH(1:1) was added hydrazine monohydrate (0.21 mL, 4.3 mmol). The reaction was heated at 70° C. for 3 h, cooled and poured cautiously into saturated Na HCO3 solution and extracted with EtOAc (2×). The combined organic layers were washed with saturated NaCl solution, dried (MgSO4) and concentrated under reduced pressure. The residue was chromatographed on silica gel eluting hexanes/EtOAc (2:1) to give 6-phenoxy-3-styryl-4,5-dihydro-1H-indazole (3) as an off-white solid (406 mg, 36%): 1H NMR (DMSO-d6) δ 2.64 (t, 2H, J=8.0 Hz), 2.95 (t, 2H, J=8.0 Hz), 5.46 (s, 1H), 7.04 (AB, 2H, J=16.8 Hz), 7.15 (d, 2H, J=8.1 Hz), 7.25 (m, 2H), 7.42 (m, 4H), 7.55 (d, 2H, J=7.7 Hz), 12.44 (s, 1H). Anal. Calc. for C2H18N2O.0.2H2O: C, 79.32; H, 5.83, N, 8.81. Found: C, 79.36; H, 5.85; N, 8.84.
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([NH:8][C@@H:9]1[C@@H:13]([OH:14])[CH2:12][CH2:11][CH2:10]1)=[O:7])([CH3:4])[CH3:3].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.F[C:26]1[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:27]=1[N+:33]([O-:35])=[O:34]>C1COCC1.O>[C:2]([O:5][C:6](=[O:7])[NH:8][C@H:9]1[CH2:10][CH2:11][CH2:12][C@@H:13]1[O:14][C:26]1[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:27]=1[N+:33]([O-:35])=[O:34])([CH3:1])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCC[C@@H]1O
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N[C@H]1CCC[C@@H]1Oc1cc(F)ccc1[N+](=O)[O-]
Temperature: 10 °C
Reaction time: 8 h

Procedure:
(1S,2S)-trans-N-boc-2-aminocyclopentanol was dissolved in 50 ml THF and cooled to 10° C. To the reaction mixture were added 32.2 ml LiHMDS 1M in THF. After 1 hour 2.72 ml 2,4-difluoronitrobenzol were added and the mixture was stirred at rt overnight. Then the mixture was poured in water and extracted with ethylacetate. The organic layer was washed with water, dried and concentrated in vacuo.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[NH:6][C:7]3[CH:8]=[CH:9][CH:10]=[C:11]([CH:39]=3)[CH2:12][CH2:13][C:14]3[CH:22]=[C:18]([NH:19][C:20]=1[N:21]=2)[CH:17]=[CH:16][C:15]=3[NH:23][C:24]([CH:26]1[CH2:31][CH2:30][N:29](C(OC(C)(C)C)=O)[CH2:28][CH2:27]1)=[O:25].[F:40][C:41]([F:46])([F:45])[C:42]([OH:44])=[O:43]>C(Cl)Cl>[F:40][C:41]([F:46])([F:45])[C:42]([OH:44])=[O:43].[F:40][C:41]([F:46])([F:45])[C:42]([OH:44])=[O:43].[Cl:1][C:2]1[CH:3]=[N:4][C:5]2[NH:6][C:7]3[CH:8]=[CH:9][CH:10]=[C:11]([CH:39]=3)[CH2:12][CH2:13][C:14]3[CH:22]=[C:18]([NH:19][C:20]=1[N:21]=2)[CH:17]=[CH:16][C:15]=3[NH:23][C:24]([CH:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1)=[O:25]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)Nc2ccc3cc2CCc2cccc(c2)Nc2ncc(Cl)c(n2)N3)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1ccc2cc1CCc1cccc(c1)Nc1ncc(Cl)c(n1)N2)C1CCNCC1
Yield: 100 %

Procedure:
tert-Butyl 4-({[6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]amino}carbonyl)piperidine-1-carboxylate (35 mg, 0.064 mmol) was treated with trifluoroacetic acid (1.0 mL) and methylene chloride (1.0 mL) for 10 minutes and evaporated to give the desired compound (35 mg, 100% yield). 1H NMR (300 MHz, DMSO-d6): δ 9.42 (s, 2H), 9.25 (s, 1H), 8.60 (m, 1H), 8.28 (m, 1H), 8.13 (s, 1H), 8.00 (s, 1H), 7.75 (s, 1H), 7.20 (d, 1H), 7.05 (m, 2H), 6.91 (d, 1H), 6.77 (d, 1H), 3.38 (m, 2H), 2.80 (m, 7H), 2.01 (m, 2H), 1.82 (m, 2H). LCMS for C24H26ClN6O (M+H)+: m/z=449.2.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[C:13]([C:15]([CH3:18])([CH3:17])[CH3:16])[CH:12]=[C:11]([C:19]([CH3:22])([CH3:21])[CH3:20])[C:10]=1[CH:23]=[CH:24][N+:25]([O-])=O)C1C=CC=CC=1.[H][H]>CO.[Pd]>[NH2:25][CH2:24][CH2:23][C:10]1[C:11]([C:19]([CH3:20])([CH3:22])[CH3:21])=[CH:12][C:13]([C:15]([CH3:18])([CH3:17])[CH3:16])=[CH:14][C:9]=1[OH:8]
Reactant: [H][H]
Reactant: CC(C)(C)c1cc(OCc2ccccc2)c(C=C[N+](=O)[O-])c(C(C)(C)C)c1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)c1cc(O)c(CCN)c(C(C)(C)C)c1

Procedure:
To a solution of 0.183 g (0.5 mmol) of the product of Step B in 10 mL of methanol was added 0.1 g of 10% palladium on carbon catalyst and the reaction mixture was stirred in Parr shaker under 40 psig of hydrogen overnight. The reaction mixture was then filtered through Celite filter aid and the filtrate was evaporated in vacuo. The residue was purified on a silica gel flash chromatography column eluted with mixtures of CH2Cl2/MeOH/conc. NH4OH of the following compositions: 97/3/0.3; 95/5/0.5; and 90/10/1. Combination of the purified fractions and drying in vacuo afforded the title compound.
Reaction SMILES: [NH:1]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[C@H:2]([C:11]([NH:13][C@@H:14]([C:16]([NH:18][CH2:19][C:20](O)=[O:21])=[O:17])[CH3:15])=[O:12])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.C(N1CCOCC1)C.C(OC(Cl)=O)C(C)C.[NH:46]([CH3:58])[C@H:47]([C:55]([OH:57])=[O:56])[CH2:48][C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1.[NH2:59][C@H:60]([CH2:65][OH:66])[CH2:61][CH2:62][S:63][CH3:64]>C1COCC1.N[C@H](C(N[C@@H](C(NCC(N[C@H](C(O)=O)CC1C=CC=CC=1)=O)=O)C)=O)CC1C=CC(O)=CC=1.N[C@H](CO)CCSC.C(O)(=O)C>[NH:1]([C:23]([O:25][C:26]([CH3:27])([CH3:29])[CH3:28])=[O:24])[C@H:2]([C:11]([NH:13][C@@H:14]([C:16]([NH:18][CH2:19][C:20]([N:46]([CH3:58])[C@H:47]([C:55]([OH:57])=[O:56])[CH2:48][C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1)=[O:21])=[O:17])[CH3:15])=[O:12])[CH2:3][C:4]1[CH:5]=[CH:6][C:7]([OH:10])=[CH:8][CH:9]=1.[NH2:59][C@H:60]([CH2:65][OH:66])[CH2:61][CH2:62][S:63][CH3:64]
Reactant: CN[C@@H](Cc1ccccc1)C(=O)O
Reactant: C[C@@H](NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OC(C)(C)C)C(=O)NCC(=O)O
Agent: CC(C)COC(=O)Cl
Agent: CCN1CCOCC1
Agent: CSCC[C@H](N)CO
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: C[C@@H](NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OC(C)(C)C)C(=O)NCC(=O)N(C)[C@@H](Cc1ccccc1)C(=O)O
Reaction time: 0.17 h

Procedure:
1.23 g of Boc-Tyr-(D)Ala-Gly-OH is dissolved in 30 ml of THF and cooled to 15°. 0.38 ml of ethylmorpholine are added with stirring followed by 0.39 ml of chloroformic acid iso-butyl ester and stirring continued for 10 minutes. A cold solution of 14 g of TFA.H-MePhe-methioninol and 0.45 ml of N-ethylmorpholine in 12 ml of TFA are added with stirring at -15°. The mixture is stirred for 20 hours at 0°, diluted with 250 ml of acetic acid and washed repeatedly with water, 1 N citric acid, 10% KHCO3 and 30% NaCl solution. The liquid is dried over Na2SO4 and evaporated. The residue is purified chromatographically on kieselgel using a mixture of methanol/CH2Cl2 /50% acetic acid, whereby the title compound is obtained. Decomp. 160°.
Reaction SMILES: C1(S[CH2:8][N:9]2[C:19](=[O:20])[C:18]3[C:13](=[C:14]([O:27][CH3:28])[C:15]([CH2:24][CH2:25][CH3:26])=[CH:16][C:17]=3[O:21][CH2:22][CH3:23])[S:10]2(=[O:12])=[O:11])C=CC=CC=1.S(Cl)([Cl:32])(=O)=O>ClCCl>[Cl:32][CH2:8][N:9]1[C:19](=[O:20])[C:18]2[C:13](=[C:14]([O:27][CH3:28])[C:15]([CH2:24][CH2:25][CH3:26])=[CH:16][C:17]=2[O:21][CH2:22][CH3:23])[S:10]1(=[O:12])=[O:11]
Reactant: O=S(=O)(Cl)Cl
Reactant: CCCc1cc(OCC)c2c(c1OC)S(=O)(=O)N(CSc1ccccc1)C2=O
Solvent: ClCCl
Product: CCCc1cc(OCC)c2c(c1OC)S(=O)(=O)N(CCl)C2=O
Yield: 89 %

Procedure:
By the method of part E of Example 45 2-phenylthiomethyl-4-ethoxy-6-propyl-7-methoxysaccharin (0.85 g) was reacted with sulfuryl chloride (0.30 g) in dichloromethane and purified with hexane affording 2-chloromethyl-4-ethoxy-6-propyl-7-methoxysaccharin, 0.62 g, 89% yield, mp 131°-133° C.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][N:7]=[C:6]2[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)#[N:2].[H-].[Na+].[Br:20][CH2:21][CH2:22][CH2:23]Br>CN(C)C=O>[Br:20][CH2:21][CH2:22][CH2:23][N:8]1[C:9]2[C:5](=[CH:4][C:3]([C:1]#[N:2])=[CH:11][CH:10]=2)[C:6]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[N:7]1
Reactant: N#Cc1ccc2[nH]nc(-c3ccccc3)c2c1
Reactant: BrCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1ccc2c(c1)c(-c1ccccc1)nn2CCCBr
Reaction time: 0.17 h

Procedure:
To a solution of 4.2 g of the 5-cyano-3-phenylindazole in 20 ml of dimethylformamide, 0.8 g of 60% sodium hydride was added, and the mixture was stirred for 10 minutes. The mixture was added dropwise to a mixture of 7 ml of 1,3-dibromopropane and 10 ml of dimethylformamide under cooling with ice. The mixture was stirred for 10 minutes at room temperature and extracted with benzene. The extract was washed with water, dried over anhydrous sodium sulfate and concentrated. The residue was subjected to column chromatography on silica gel to produce 3.5 g of 1-(3'-bromopropyl)-5-cyano-3-phenylindazole (recrystallization from ethanol provided a m.p. of 100° to 102° C.).
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[N:12]=[C:11]4[CH:14]=[C:15](F)[C:16]([F:18])=[CH:17][C:10]4=[CH:9][C:8]=3[C:7](=[O:20])[C:6]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:5]2)[CH2:3][CH2:2]1.Cl.Cl.[CH3:28][N:29]([CH3:34])[CH:30]1[CH2:33][NH:32][CH2:31]1>>[CH:1]1([N:4]2[C:13]3[N:12]=[C:11]4[CH:14]=[C:15]([N:32]5[CH2:33][CH:30]([N:29]([CH3:34])[CH3:28])[CH2:31]5)[C:16]([F:18])=[CH:17][C:10]4=[CH:9][C:8]=3[C:7](=[O:20])[C:6]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:5]2)[CH2:2][CH2:3]1
Reactant: CCOC(=O)c1cn(C2CC2)c2nc3cc(F)c(F)cc3cc2c1=O
Reactant: CN(C)C1CNC1
Agent: Cl
Product: CCOC(=O)c1cn(C2CC2)c2nc3cc(N4CC(N(C)C)C4)c(F)cc3cc2c1=O
Yield: 69.5 %

Procedure:
1-Cyclopropyl-8-(3-dimethylamino-1-azetidinyl)-3-ethoxycarbonyl-7-fluoro-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine was prepared under the conditions described in Example 4, but starting with 1.4 g of 1-cyclopropyl-3-ethoxycarbonyl-7,8-difluoro-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine and 1.04 g of 3-(dimethylamino)azetidine dihydrochloride. After concentration of the combined organic extracts to dryness, the solid obtained is recrystallized in 40 cm3 of ethanol. 1.2 g of 1-cyclopropyl-8-(3-dimethylamino-1-azetidinyl)-3-ethoxycarbonyl-7-fluoro-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine are obtained in the form of a yellow solid, melting point 225° C.