Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(O)(=O)(=O)C.[NH2:6][C:7]1[C:8]2[N:9]([C:16]([CH3:20])=[C:17]([CH3:19])[N:18]=2)[CH:10]=[C:11]([C:13]([NH2:15])=[O:14])[CH:12]=1.Cl[CH2:22][C:23]1[C:24]([CH3:29])=[CH:25][CH:26]=[CH:27][CH:28]=1.C(N(C(C)C)CC)(C)C>CN(C)C=O>[CH3:19][C:17]1[N:18]=[C:8]2[C:7]([NH:6][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[CH3:29])=[CH:12][C:11]([C:13]([NH2:15])=[O:14])=[CH:10][N:9]2[C:16]=1[CH3:20]
Reactant: Cc1ccccc1CCl
Reactant: Cc1nc2c(N)cc(C(N)=O)cn2c1C
Agent: CS(=O)(=O)O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccccc1CNc1cc(C(N)=O)cn2c(C)c(C)nc12
Yield: 13.2 %

Procedure:
8-Amino-2,3-dimethylimidazo[1,2-a]pyridine-6-carboxamide mesylate (1.0 g, 2.7 mmol), α-chloro-o-xylene (0.38 g, 2.7 mmol) and diisopropylethylamin (0.76 g, 5.9 mmol) in dimethylformamide (7 ml) were stirred at 50° C. for 7 h and at room temperature for 72 h. The solvent was evaporated and the residue was treated with a mixture of methylene chloride, water and a small amount of diisopropylethylamin. The solid that formed was isolated by filtration and washed with ethylacetate to give 0.11 g (13%) of the title compound.
Reaction SMILES: C([O:3][C:4](=[O:17])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([CH:15]=[O:16])=[CH:7]1)C.[OH-].[Na+].O>O1CCOCC1>[CH:15]([C:8]1[C:9]2[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:6]([CH2:5][C:4]([OH:17])=[O:3])[CH:7]=1)=[O:16]
Reactant: CCOC(=O)Cn1cc(C=O)c2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: O=Cc1cn(CC(=O)O)c2ccccc12
Temperature: 25 °C
Reaction time: 96 h
Yield: 73.5 %

Procedure:
(3-Formylindol-1-yl)acetic acid ethyl ester (15.9 g 69 mmol) was dissolved in 1,4-dioxane (100 mL) and 1N sodium hydroxide (10 mL) was added and the resulting mixture was stirred at room temperature for 4 days. Water (500 mL) was added and the mixture was washed with diethyl ether (150 mL). The aqueous phase was acidified with 5N hydrochloric acid and extracted with ethyl acetate (250+150 mL). The combined organic extracts were dried (MgSO4) and concentrated in vacuo to afford 10.3 g (73%) of (3-formylindol-1-yl)acetic acid as a solid.
Reaction SMILES: [F:1][C:2]1[CH:10]=[N:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[NH2:11][C:12]1[CH:20]=[C:19]2[C:15]([C:16]([CH3:26])([CH3:25])[C:17](=[O:24])[N:18]2[CH:21]2[CH2:23][CH2:22]2)=[CH:14][CH:13]=1>>[CH:21]1([N:18]2[C:19]3[C:15](=[CH:14][CH:13]=[C:12]([NH:11][C:4](=[O:6])[C:3]4[CH:7]=[CH:8][N:9]=[CH:10][C:2]=4[F:1])[CH:20]=3)[C:16]([CH3:25])([CH3:26])[C:17]2=[O:24])[CH2:23][CH2:22]1
Reactant: O=C(O)c1ccncc1F
Reactant: CC1(C)C(=O)N(C2CC2)c2cc(N)ccc21
Product: CC1(C)C(=O)N(C2CC2)c2cc(NC(=O)c3ccncc3F)ccc21

Procedure:
Prepared in analogy to example 26 from 3-fluoroisonicotinic acid and 6-amino-1-cyclopropyl-3,3-dimethyl-1,3-dihydro-indol-2-one (example 14c). The title compound was obtained as light yellow solid.
Reaction SMILES: [C:1]1([CH:7]2[CH2:9][CH:8]2[NH:10][C:11]([C:13]2[CH:35]=[CH:34][C:16]([O:17][C:18]3[CH:27]=[C:26]4[C:21]([CH:22]([C:28]([O:30]C)=[O:29])[CH2:23][CH2:24][O:25]4)=[CH:20][C:19]=3[C:32]#[N:33])=[CH:15][CH:14]=2)=[O:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O>C1COCC1.FC(F)(F)C(O)=O>[C:1]1([CH:7]2[CH2:9][CH:8]2[NH:10][C:11]([C:13]2[CH:14]=[CH:15][C:16]([O:17][C:18]3[CH:27]=[C:26]4[C:21]([CH:22]([C:28]([OH:30])=[O:29])[CH2:23][CH2:24][O:25]4)=[CH:20][C:19]=3[C:32]#[N:33])=[CH:34][CH:35]=2)=[O:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)C1CCOc2cc(Oc3ccc(C(=O)NC4CC4c4ccccc4)cc3)c(C#N)cc21
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: C1CCOC1
Product: N#Cc1cc2c(cc1Oc1ccc(C(=O)NC3CC3c3ccccc3)cc1)OCCC2C(=O)O
Temperature: 25 °C
Reaction time: 17 h
Yield: 30.6 %

Procedure:
Methyl 7-(4-((2-phenylcyclopropyl)carbamoyl)phenoxy)-6-cyano-3,4-dihydro-2H-chromene-4-carboxylate (25.9 mg, 0.0553 mmol) was dissolved in THF (1.5 ml) and 1M LiOH-monohydrate solution in water (0.111 ml, 0.111 mmol) was added. The mixture was stirred for 17 hours at ambient temperature. A few drops of trifluoroacetic acid were added to the mixture and the mixture was purified on silica gel (MeOH in dichloromethane gradient with 1% acetic acid) to provide 7.7 mg of the title compound as a thin film (30%). MS (apci) m/z=453.0 (M−H).
Reaction SMILES: [F:1][C:2]([Si](C)(C)C)([F:4])[F:3].[CH3:9][C:10]1[CH:15]=[C:14]([C:16](=[O:25])[CH:17]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH3:18])[CH:13]=[CH:12][N:11]=1.O.O.O.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[F:1][C:2]([F:4])([F:3])[C:16]([C:14]1[CH:13]=[CH:12][N:11]=[C:10]([CH3:9])[CH:15]=1)([OH:25])[CH:17]([C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)[CH3:18]
Reactant: Cc1cc(C(=O)C(C)c2ccccc2)ccn1
Reactant: C[Si](C)(C)C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(C(O)(C(C)c2ccccc2)C(F)(F)F)ccn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 22.6 %

Procedure:
Trifluoromethyltrimethylsilane (2N in THF, 0.76 mL, 1.5 mmol) was added at 0° C. to a solution of 1-(2-methyl-pyridin-4-yl)-2-phenyl-propan-1-one (142 mg, 0.63 mmol) in THF (5 mL), followed by the addition of tetrabutylammonium fluoride trihydrate (40 mg, 0.13 mmol). After stirring overnight at r.t., an additional amount of trifluoromethyl-trimethylsilane (0.38 mL), followed by tetrabutylammonium fluoride trihydrate (20 mg) was added to drive the reaction towards completion. The solvent was evaporated, the residue was taken up in methanol, and the title compound (42 mg, 23%) was isolated by reversed-phase, preparative HPLC (Agilent Zorbax XdB-C18 column, solvent gradient 5-95% CH3CN in 0.1% TFA[aq]). 1H NMR (300 MHz, DMSO-D6) □ 8.25 (1H, d), 7.17 (1H, s), 7.11 (2H, d), 7.09-7.00 (4H, m), 6.93 (1H, s), 3.62 (1H, q), 2.35 (3H, s), 1.42 (3H, d); MS (m/e)=296.4 [MH+].
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[CH:5][C:6]=1[NH:7][C:8](=O)OC(C)(C)C.C([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1B(O)O)=O.C(=O)(O)[O-].[Na+].Cl.[OH-].[Na+]>C(COC)OC.C(Cl)Cl.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[S:3]1[C:2]2[C:22]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[CH:8]=[N:7][C:6]=2[CH:5]=[CH:4]1
Reactant: CC(C)(C)OC(=O)Nc1ccsc1Br
Reactant: O=Cc1ccccc1B(O)O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: Cl
Solvent: COCCOC
Solvent: ClCCl
Product: c1ccc2c(c1)cnc1ccsc12
Temperature: 23 °C
Reaction time: 0.25 h
Yield: 78.9 %

Procedure:
Tert-butyl 2-bromothien-3-ylcarbamate (35 g, 0.13 mol), 2-Formylphenylboronic acid (Cmpd IIIa, 25 g, 0.17 mol), [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium [II] (5.3 g, 6.5 mmol), and sodium bicarbonate (33 g, 0.39 mol) were combined in 40% aqueous dimethoxyethane (675 mL) and the mixture was heated to reflux. After 1 h the mixture was cooled to 23° C., treated slowly with 2 N aqueous hydrochloric acid (405 mL) and heated back to reflux for an additional 2 h. At this time the mixture was cooled to 23° C., treated slowly with 2.5 N aqueous sodium hydroxide (270 mL) and stirred for ca. 15 min. The mixture was filtered through Celite and washed with ethyl acetate (2.2 L). The organic layer was separated from the filtrate and washed with water and brine (2.2 L each), dried (K2CO3), and concentrated in vacuo to give the crude product (28 g) as a dark oil. The oil was taken up in methylene chloride (75 mL) and pre-adsorbed on silica gel (75 g). Flash chromatography on silica gel (725 g) eluting 5-, then 10-, and then 20% ethyl acetate-hexane gave the title compound (19 g, 83%, m.p. 58-61° C.) as a yellow-brown solid which was pure enough for further use.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[C:13]1[N:14]=[C:15]([CH3:18])[NH:16][CH:17]=1.F[C:20]1[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=1>>[CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:3]=1[C:13]1[N:14]=[C:15]([CH3:18])[N:16]([C:20]2[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=2)[CH:17]=1
Reactant: Cc1nc(-c2c(-c3ccccc3)noc2C)c[nH]1
Reactant: Fc1ccc(C(F)(F)F)cc1
Product: Cc1onc(-c2ccccc2)c1-c1cn(-c2ccc(C(F)(F)F)cc2)c(C)n1
Yield: 9 %

Procedure:
As described for Example 57, 5-methyl-4-(2-methyl-1H-imidazol-4-yl)-3-phenyl-isoxazole (70 mg, 0.3 mmol) using 4-fluorobenzotrifluoride instead of 4-fluoroacetophenone was converted to the title compound (10 mg, 9%) which was obtained as a light yellow solid. MS: m/e=384.1 [M+H]+.
Reaction SMILES: [CH3:1][N:2]([CH3:15])[CH2:3][CH2:4][N:5]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[NH:7][C:6]1=[O:14].[F:16][C:17]1[CH:18]=[C:19]([S:23](Cl)(=[O:25])=[O:24])[CH:20]=[CH:21][CH:22]=1.C(N(C(C)C)CC)(C)C>C1COCC1.CN(C1C=CN=CC=1)C>[CH3:1][N:2]([CH3:15])[CH2:3][CH2:4][N:5]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[N:7]([S:23]([C:19]2[CH:20]=[CH:21][CH:22]=[C:17]([F:16])[CH:18]=2)(=[O:25])=[O:24])[C:6]1=[O:14]
Reactant: CN(C)CCn1c(=O)[nH]c2cccnc21
Reactant: O=S(=O)(Cl)c1cccc(F)c1
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CN(C)CCn1c(=O)n(S(=O)(=O)c2cccc(F)c2)c2cccnc21
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A solution of 3-(2-dimethylaminoethyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (20 mg, 0.10 mmol) in THF at room temperature is treated with 3-fluorophenyl-sulfonyl chloride (26 mg, 0.12 mmol), followed by diisopropylethylamine (25 μL, 0.20 mmol) and DMAP (5 mg), stirred at room temperature for 12 h and concentrated in vacuo. The resultant residue is dissolved in a mixture of DMSO, methanol and water and purified by Gilson preparative HPLC1 to give the title compound, [M+H] 365, retention time (RT) 2.54 minutes. 1HPLC Conditions: HP 1100 HPLC system; Waters Xterra MS C18, 2 mm (i.d.)×50 mm (length), 3.5 um column, set at 50° C.; Flow rate 1.0 mL/min; Solvent A: 0.02% formic acid in water; Solvent B 0.02% formic acid in ACN; Gradient: Time O: 10% B; 2.5 min 90% B; 3 min 90% B; Sample concentration: ˜2.0 mM; Injection volume: 5 uL; Detection: 220 nm, 254 nm DAD.
Reaction SMILES: C[Si](C)(C)CC[O:5][C:6](=[O:21])[CH2:7][CH2:8][C:9]([C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([Cl:20])[CH:18]=2)[NH:13][CH:12]=1)=[O:10].Cl[C:25]1[N:30]=[C:29]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[N:28]=[C:27]([N:37]2[C:46]3[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=3)[CH2:40][CH2:39][CH2:38]2)[N:26]=1>>[Cl:20][C:17]1[CH:18]=[C:19]2[C:14](=[CH:15][CH:16]=1)[N:13]([C:25]1[N:26]=[C:27]([N:37]3[C:46]4[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=4)[CH2:40][CH2:39][CH2:38]3)[N:28]=[C:29]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[N:30]=1)[CH:12]=[C:11]2[C:9](=[O:10])[CH2:8][CH2:7][C:6]([OH:5])=[O:21]
Reactant: C[Si](C)(C)CCOC(=O)CCC(=O)c1c[nH]c2ccc(Cl)cc12
Reactant: Clc1nc(-c2ccccc2)nc(N2CCCc3ccccc32)n1
Product: O=C(O)CCC(=O)c1cn(-c2nc(-c3ccccc3)nc(N3CCCc4ccccc43)n2)c2ccc(Cl)cc12

Procedure:
Arylation of 4-(5-chloro-1H-indol-3-yl)-4-oxo-butyric acid 2-trimethylsilanyl-ethyl ester with 1-(4-chloro-6-phenyl-[1,3,5]-triazin-2-yl)-1,2,3,4-tetrahydro-quinoline and subsequent hydrolysis as outlined previously yielded the titled compound. Rf 0.34 (5% methanol in dichloromethane); 1H NMR (THF-d8, 300 MHz) δ 9.21 (1H, s, ArH), 8.72 (1H, m, ArH), 8.59 (2H, d, J=7 Hz, ArH), 8.39 (1H, d, J=2 Hz, ArH), 7.95 (1H, d, J=8 Hz, ArH), 7.62-7.51 (3H, m, ArH), 7.35-7.15 (4H, m, ArH), 4.32 (2H, t, J=6 Hz, CH2), 3.30 (2H, t, J=7 Hz, CH2), 2.88 (2H, t, J=6 Hz, CH2), 2.72 (2H, t, J=7 Hz, CH2), 2.13 (2H, m, CH2); ESI-LCMS e/z calculated for C30H24ClN5O3 537.157, found 538 (M+H)+, 560 (M+Na)+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[N+:3]=1[O-].[N+:10]([O-])([OH:12])=[O:11].S(=O)(=O)(O)O>>[CH3:1][C:2]1[CH:7]=[C:6]([N+:10]([O-:12])=[O:11])[CH:5]=[C:4]([CH3:8])[N:3]=1
Reactant: Cc1cccc(C)[n+]1[O-]
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: Cc1cc([N+](=O)[O-])cc(C)n1

Procedure:
The 4-nitro substituted starting material is prepared by contacting 2,6-dimethylpyridine N-oxide with nitric acid and sulfuric acid thereby forming the 2,6-dimethyl-4-nitropyridine. The N-oxide is reduced to the pyridine compound with phosphorous trichloride and then oxidized to the 4-nitropyridine 2,6-dicarboxylic acid with potassium permanganate.
Reaction SMILES: O1CCOCC1.Cl.C([N:11]([C:16]1[C:32]([O:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[CH:31][C:19]2[C:20](=[O:30])[C:21]([C:25]([O:27]CC)=[O:26])=[C:22]([CH3:24])[O:23][C:18]=2[CH:17]=1)[S:12]([CH3:15])(=[O:14])=[O:13])(=O)C>O>[C:25]([C:21]1[C:20](=[O:30])[C:19]2[CH:31]=[C:32]([O:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[C:16]([NH:11][S:12]([CH3:15])(=[O:13])=[O:14])=[CH:17][C:18]=2[O:23][C:22]=1[CH3:24])([OH:27])=[O:26]
Reactant: CCOC(=O)c1c(C)oc2cc(N(C(C)=O)S(C)(=O)=O)c(Oc3ccccc3)cc2c1=O
Agent: Cl
Solvent: C1COCCO1
Solvent: O
Product: Cc1oc2cc(NS(C)(=O)=O)c(Oc3ccccc3)cc2c(=O)c1C(=O)O
Yield: 94.4 %

Procedure:
10 ml of dioxane and 10 ml of 6N hydrochloric acid were added to 500 mg of 7-(N-acetyl-N-methylsulfonylamino)-3-ethoxycarbonyl-2-methyl-6-phenoxy-4H-1-benzopyran-4-one. The mixture was refluxed for 20 minutes. The reaction mixture was cooled to 5°-10° C. 30 ml of water was added thereto. The resulting crystal was collected by filtration and recrystallized from acetic acid to obtain 400 mg (yield: 95.2%) of 3-carboxy-2-methyl-7-methylsulfonylamino-6-phenoxy-4H-1-benzopyran-4-one having a melting point of 238°-241° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[Cl:19])[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.[CH3:34][O:35][CH2:36][CH2:37][NH2:38]>CN(C=O)C>[C:1]([O:5][C:6](=[O:7])[NH:8][CH:9]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[Cl:19])[C:10]([NH:38][CH2:37][CH2:36][O:35][CH3:34])=[O:12])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)NC(C(=O)O)c1ccccc1Cl
Reactant: COCCN
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: COCCNC(=O)C(NC(=O)OC(C)(C)C)c1ccccc1Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 250 mg (0.88 mmol) of [(tert-butoxycarbonyl)amino](2-chlorophenyl)acetic acid, 177 mg (1.31 mmol) of HOBt, 252 mg (1.31 mmol) of EDC and 72 mg (0.96 mmol) of 2-methoxyethanamine in 6.3 ml of DMF was stirred at RT for 2 h. For purification, 1 ml of 1N hydrochloric acid was added and the entire reaction mixture was separated by preparative HPLC [Method 6]. The appropriate fraction was concentrated on a rotary evaporator and the residue was dried under high vacuum. This gave 269 mg (90% of theory) of the title compound.
Reaction SMILES: [C:1]([C:3]1[N:7]([C@@H:8]2[O:14][C@H:13]([CH2:15][OH:16])[C@@H:11]([OH:12])[C@H:9]2[OH:10])[CH:6]=[N:5][C:4]=1[C:17]#[N:18])#[CH:2].[OH:19]O>N.CO>[C:1]([C:3]1[N:7]([C@@H:8]2[O:14][C@H:13]([CH2:15][OH:16])[C@@H:11]([OH:12])[C@H:9]2[OH:10])[CH:6]=[N:5][C:4]=1[C:17]([NH2:18])=[O:19])#[CH:2]
Reactant: OO
Reactant: C#Cc1c(C#N)ncn1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Agent: N
Solvent: CO
Product: C#Cc1c(C(N)=O)ncn1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a solution of 127 mg (0.51 mmol) of 5-ethynyl-1-β-D-ribofuranosylimidazole-4-carbonitrile dissolved in 6 ml of a solvent mixture of aqueous ammonia and methanol (1:1) was added 0.5 ml of hydrogen peroxide, and the reaction was carried out with stirring at room temperature for 45 minutes. After the reaction, the solvent was evaporated, and the residue was adsorbed onto a silica gel column and eluted with a 5 - 10% ethanolchloroform solvent mixture, and crystallized from ethanol to obtain white crystals of 5-ethynyl-1-β-D-ribofuranosylimidazole-4-carboxamide.
Reaction SMILES: [F:1][C:2]1[CH:20]=[CH:19][C:5]2[NH:6][C:7](=O)[C:8]3[C:13]4[CH2:14][CH2:15][CH2:16][CH2:17][C:12]=4[S:11][C:9]=3[O:10][C:4]=2[CH:3]=1.P(Cl)(Cl)(Cl)=O.CN(C)C1C=CC=CC=1.[CH3:35][N:36]1[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1>>[F:1][C:2]1[CH:20]=[CH:19][C:5]2[N:6]=[C:7]([N:39]3[CH2:40][CH2:41][N:36]([CH3:35])[CH2:37][CH2:38]3)[C:8]3[C:13]4[CH2:14][CH2:15][CH2:16][CH2:17][C:12]=4[S:11][C:9]=3[O:10][C:4]=2[CH:3]=1
Reactant: O=C1Nc2ccc(F)cc2Oc2sc3c(c21)CCCC3
Reactant: CN1CCNCC1
Solvent: O=P(Cl)(Cl)Cl
Solvent: CN(C)c1ccccc1
Product: CN1CCN(C2=Nc3ccc(F)cc3Oc3sc4c(c32)CCCC4)CC1

Procedure:
In the same manner as in Example 80 and using 8-fluoro-1,2,3,4-tetrahydro-[1]benzothieno[2,3-b][1,5]benzoxazepin-12(11H)-one, phosphorus oxychloride, N,N-dimethylaniline and 1-methylpiperazine, 8-fluoro-1,2,3,4-tetrahydro-12-(4-methylpiperazin-1-yl)-[1]benzothieno[2,3-b][1,5]benzoxazepine is obtained. STARTING MATERIAL SNYTHESIS EXAMPLE 66
Reaction SMILES: C(OC(=O)[C@@H](NC(OC(C)(C)C)=O)CC1C=CC(N)=CC=1)C.CO.C(Cl)Cl.[CH2:28]([O:30][C:31](=[O:59])[C@@H:32]([NH:51]C(OC(C)(C)C)=O)[CH2:33][C:34]1[CH:39]=[CH:38][C:37]([NH:40][C:41]2[C:50]3[C:45](=[CH:46][CH:47]=[N:48][CH:49]=3)[CH:44]=[CH:43][N:42]=2)=[CH:36][CH:35]=1)[CH3:29]>C(OC(O)C)C>[NH2:51][C@@H:32]([CH2:33][C:34]1[CH:39]=[CH:38][C:37]([NH:40][C:41]2[C:50]3[C:45](=[CH:46][CH:47]=[N:48][CH:49]=3)[CH:44]=[CH:43][N:42]=2)=[CH:36][CH:35]=1)[C:31]([O:30][CH2:28][CH3:29])=[O:59]
Reactant: CCOC(=O)[C@H](Cc1ccc(Nc2nccc3ccncc23)cc1)NC(=O)OC(C)(C)C
Agent: CCOC(=O)[C@H](Cc1ccc(N)cc1)NC(=O)OC(C)(C)C
Agent: CCOC(C)O
Solvent: CO
Solvent: ClCCl
Product: CCOC(=O)[C@@H](N)Cc1ccc(Nc2nccc3ccncc23)cc1

Procedure:
A solution of ethyl-(S)-3-[4-aminophenyl]-2-[t-butoxycarbonylamino]propanoate (638 mg, 2.07 mmol) and Intermediate 11 (310 mg, 1.88 mmol) in ethoxyethanol (2 ml) was stirred at 120° for 15 min and at 100° for 1 h under nitrogen. The volatiles were removed in vacuo and the dark residue partitioned between EtOAc (70 ml) and saturated aqueous NaHCO3 (10 ml). The phases were separated and the aqueous layer re-extracted with EtOAc (2×30 ml). The combined organic extracts were washed with brine (10 ml)T dried (Na2SO4) and evaporated in vacuo to afford a dark foam. Chromatography (SiO2; 5 to 10% MeOH/DCM) afforded a mixture of ethyl-(S)-3-[4-(2,7-naphthyridin-1-ylamino)phenyl]-2-[(t-butoxycarbonyl)amino]propanoate and some of the title compound (730 mg). This mixture was treated with a solution of trifluoroacetic acid (5 ml) and DCM (5 ml) at room temperature for 1 h. The volatiles were removed in vacuo and the residue partitioned between EtOAc (75 ml) and saturated aqueous NaHCO3 (20 ml). The phases were separated and the aqueous layer re-extracted with EtOAc (3×30 ml). The combined organic extracts were washed with brine (10 ml), dried (Na2SO4) and evaporated in vacuo to afford an orange solid. Chromatography (SiO2; 10% MeOH/DCM) afforded the title compound as a straw-coloured solid (420 mg, 60% over two steps). δH (CDCl3) 10.70 (1H, s), 10.31 (1H, s), 9.44 (1H, d, J 5.6 Hz), 8.94 (1H, d, J 5.6 Hz), 8.55 (1H, d, J 7.3 Hz), 8.54 (2H, d, J 8.5 Hz), 8.46 (1H, d, J 5.6 Hz), 7.94 (2H, d, J 8.5 Hz), 4.84 (2H, q, J 7.1 Hz), 4.35 (1H, t, J 6.6 Hz), 4.10 (2H, br s), 3.64 (1H, dd, J 13.5, 6.4 Hz), 3.56 (1H, dd, J 13.5, 7.0 Hz) and 1.95 (3H, t, J 7.1 Hz); m/z (ES+, 70V) 337 (MH+).
Reaction SMILES: [CH3:1][N:2]([S:21]([C:24]1[S:25][CH:26]=[CH:27][CH:28]=1)(=[O:23])=[O:22])[C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12]1[S:13][CH:14]([CH2:17][C:18](O)=[O:19])[CH2:15][N:16]=1)=[CH:8]2.N1(O)C2C=CC=CC=2N=N1.Cl.[CH3:40][N:41](C)[CH2:42]CCN=C=NCC.CNC>C(OCC)(=O)C.O1CCCC1.CN(C)C=O>[CH3:40][N:41]([CH3:42])[C:18](=[O:19])[CH2:17][CH:14]1[S:13][C:12]([C:9]2[NH:10][C:11]3[C:7]([CH:8]=2)=[CH:6][CH:5]=[CH:4][C:3]=3[N:2]([CH3:1])[S:21]([C:24]2[S:25][CH:26]=[CH:27][CH:28]=2)(=[O:23])=[O:22])=[N:16][CH2:15]1
Reactant: CCN=C=NCCCN(C)C
Reactant: CN(c1cccc2cc(C3=NCC(CC(=O)O)S3)[nH]c12)S(=O)(=O)c1cccs1
Agent: CNC
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CN(C)C(=O)CC1CN=C(c2cc3cccc(N(C)S(=O)(=O)c4cccs4)c3[nH]2)S1
Temperature: 25 °C
Reaction time: 2 h
Yield: 71.3 %

Procedure:
A mixture of (2-{7-[methyl(2-thienylsulfonyl)amino]-1H-indol-2-yl}-4,5-dihydro-1,3-thiazol-5-yl)acetic acid (70 mg), 1H-1,2,3-benzotriazol-1-ol (33 mg), N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (46 mg) and N,N-dimethylformamide (4 mL) was stirred at room temperature for 2 hr. 2M tetrahydrofuran solution (0.25 mL) of dimethylamine was added to this solution, and the mixture was stirred at room temperature for 15 hr. The reaction solution was diluted with ethyl acetate, washed with water, aqueous sodium hydrogencarbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (ethyl acetate), and the obtained colorless crystals were washed with ethyl acetate-hexane to give the title compound (53 mg, yield: 30%) as colorless crystals. MS: 463 (MH+). melting point 153-154° C.
Reaction SMILES: [F:1][S:2]([C:5]1[CH:6]=[C:7]([S:11]([NH:14][C:15]2[CH:24]=[CH:23][CH:22]=[C:21]3[C:16]=2[C:17]([N:26]=[N:27][C:28]2[CH:33]=[CH:32][C:31]([N+:34]([O-:36])=[O:35])=[CH:30][C:29]=2[S:37]([CH3:40])(=[O:39])=[O:38])=[CH:18][CH:19]=[C:20]3[OH:25])(=[O:13])=[O:12])[CH:8]=[CH:9][CH:10]=1)(=[O:4])=[O:3].S(Cl)([Cl:44])(=O)=O>>[Cl:44][C:19]1[CH:18]=[C:17]([N:26]=[N:27][C:28]2[CH:33]=[CH:32][C:31]([N+:34]([O-:36])=[O:35])=[CH:30][C:29]=2[S:37]([CH3:40])(=[O:38])=[O:39])[C:16]2[C:21](=[CH:22][CH:23]=[CH:24][C:15]=2[NH:14][S:11]([C:7]2[CH:8]=[CH:9][CH:10]=[C:5]([S:2]([F:1])(=[O:3])=[O:4])[CH:6]=2)(=[O:13])=[O:12])[C:20]=1[OH:25]
Reactant: CS(=O)(=O)c1cc([N+](=O)[O-])ccc1N=Nc1ccc(O)c2cccc(NS(=O)(=O)c3cccc(S(=O)(=O)F)c3)c12
Reactant: O=S(=O)(Cl)Cl
Product: CS(=O)(=O)c1cc([N+](=O)[O-])ccc1N=Nc1cc(Cl)c(O)c2cccc(NS(=O)(=O)c3cccc(S(=O)(=O)F)c3)c12

Procedure:
5-(m-Fluorosulfonylbenzenesulfonamido)-4-(2-methylsulfonyl-4-nitrophenylazo)-1-naphthol (52 g.) (Compound A of Example 13 of U.S. Pat. No. 3,929,760, issued Dec. 30, 1975) is chlorinated by stirring with sulfuryl chloride (200 ml.) for 21 hours at 30°-31° C. The slurry is cooled to 15° and filtered. The resulting solid is then purified by stirring successively with 800 ml. ice water, 100 ml. methanol, 200 ml. acetone (40° C.), and 300 ml. acetone (40°), filtering the resulting slurry each time (acetone precooled to 30°) and washing the solid with the same kind of solvent. The yield is 40.3 g.
Reaction SMILES: Cl.[NH2:2][C@H:3]1[C:12]([CH2:15][CH3:16])([CH2:13][CH3:14])[C:11]2[CH:10]=[C:9]([OH:17])[CH:8]=[CH:7][C:6]=2[CH2:5][C@@H:4]1[O:18][CH3:19].[CH3:20][O:21][C:22](=[O:34])[C@H:23]([CH2:27][CH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1)[CH2:24][CH:25]=O.C(N(CC)CC)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl.CCOC(C)=O>[CH3:20][O:21][C:22](=[O:34])[C@H:23]([CH2:27][CH:28]1[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]1)[CH2:24][CH2:25][NH:2][C@@H:3]1[C@@H:4]([O:18][CH3:19])[CH2:5][C:6]2[C:11](=[CH:10][C:9]([OH:17])=[CH:8][CH:7]=2)[C:12]1([CH2:15][CH3:16])[CH2:13][CH3:14]
Reactant: CCC1(CC)c2cc(O)ccc2C[C@H](OC)[C@H]1N
Reactant: COC(=O)[C@@H](CC=O)CC1CCCCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCC1(CC)c2cc(O)ccc2C[C@H](OC)[C@H]1NCC[C@@H](CC1CCCCC1)C(=O)OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 121.8 %

Procedure:
(6S,7S)-7-Amino-8,8-diethyl-6-methoxy-5,6,7,8-tetrahydro-naphthalen-2-ol hydrochloride salt (100 mg, 0.35 mmol), (R)-2-cyclohexylmethyl-4-oxo-butyric acid methyl ester (90 mg, 0.42 mmol) and triethylamine (35 mg, 0.035 mmol) were dissolved in dichloromethane (2.0 mL) and stirred at room temperature for 30 min. Sodium triacetoxyborohydride (1.03 g, 4.85 mmol) was added and the reaction was monitored by HPLC. After 3 h, additional (R)-2-cyclohexylmethyl-4-oxo-butyric acid methyl ester (20 mg, 0.1 mmol) and sodium triacetoxyborohydride (30 mg, 0.14 mmol) were added. Thirty minutes after the last addition, EtOAc (15 mL) was added and the mixture was washed with 5% aqueous sodium carbonate (2×5 mL) and saturated sodium chloride (5 mL). The organic layer was dried with Na2SO4) and concentrated to give the title compound (190 mg). (m/z): [M+H]− calcd for C27H43NO4, 446.33. Found, 446.6.