Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([NH2:6])=[O:5].[OH-].[K+].[CH:9]1([CH2:15][C@H:16]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[CH:17]=O)[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1.C([BH3-])#N.[Na+]>CO>[C:4]([CH2:3][NH:2][CH2:17][C@@H:16]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[CH2:15][CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1)(=[O:5])[NH2:6]
Reactant: CC(C)(C)OC(=O)N[C@H](C=O)CC1CCCCC1
Reactant: NCC(N)=O
Agent: Cl
Agent: [BH3-]C#N
Agent: [K+]
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@H](CNCC(N)=O)CC1CCCCC1
Reaction time: 0.25 h

Procedure:
To a solution of 2-aminoacetamide hydrochloride (0.13 g, 1.13 mmol) in MeOH (1 mL) was added KOH (18 mg). When the solid had completely dissolved, the tert-butyl (S)-2-cyclohexyl-1-formylethylcarbamate from Step 1 was added in one portion, and the resulting suspension was stirred for 15 minutes. A solution of sodium cyanoborohydride (0.18 g, 2.7 mmol) in MeOH (1 mL) was added dropwise. The resulting solution was stirred at rt until no aldehyde remained (˜40 min). The solvent was removed under vacuum and the residue was distributed between ether and water (10 mL/10 mL). The water layer was extracted with ether (2×5 mL). The combined ether layers were dried, and solvent was removed under vacuum to give tert-butyl (S)-1-(carbamoylmethylamino)-3-cyclohexyl-propan-2-ylcarbamate as an oil, which was used for the next step without purification. MS ESI+ve m/z 314 (M+1).
Reaction SMILES: Br[C:2]1[S:6][C:5]([C:7]2[N:12]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=3[F:21])[C:11](=[O:22])[C:10]([C:23]#[N:24])=[C:9]([C:25]([F:28])([F:27])[F:26])[CH:8]=2)=[CH:4][CH:3]=1.[CH3:29][S:30][C:31]1[CH:36]=[CH:35][C:34](B2OC(C)(C)C(C)(C)O2)=[CH:33][N:32]=1.C(=O)([O-])[O-].[K+].[K+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.COCCOC.O>[F:21][C:15]1[CH:16]=[C:17]([F:20])[CH:18]=[CH:19][C:14]=1[CH2:13][N:12]1[C:7]([C:5]2[S:6][C:2]([C:34]3[CH:33]=[N:32][C:31]([S:30][CH3:29])=[CH:36][CH:35]=3)=[CH:3][CH:4]=2)=[CH:8][C:9]([C:25]([F:28])([F:27])[F:26])=[C:10]([C:23]#[N:24])[C:11]1=[O:22]
Reactant: CSc1ccc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: N#Cc1c(C(F)(F)F)cc(-c2ccc(Br)s2)n(Cc2ccc(F)cc2F)c1=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: CSc1ccc(-c2ccc(-c3cc(C(F)(F)F)c(C#N)c(=O)n3Cc3ccc(F)cc3F)s2)cn1
Temperature: 80 °C
Yield: 93.2 %

Procedure:
6-(5-Bromo-thiophen-2-yl)-1-(2,4-difluoro-benzyl)-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile (270 mg, 0.57 mmol), 2-methylsulfanyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)pyridine (214 mg, 0.85 mmol), potassium carbonate (236 mg, 1.71 mmol), and tetrakis(triphenylphosphine)palladium (0) (66 mg, 0.057 mmol) were mixed with 6 ml 9:1 DME/H2O (v/v), then heated at 80° C. overnight. All solvent was removed in vacuo. The crude product was purified by column chromatography on silica gel (10→40% EtOAC/Hexane, 0.25% Et3N in hexane) to give 1-(2,4-difluoro-benzyl)-6-[5-(6-methylsulfanyl-pyridin-3-yl)-thiophen-2-yl]-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile as an orange solid (276 mg, 93% yield). 1H-NMR (400 MHz, CDCl3): δ 2.61 (s, 3H), 5.45 (s, 2H), 6.66 (s, 1H), 6.82 (m, 1H), 6.88 (m, 1H), 7.09 (m, 1H), 7.12 (d, 1H, J=3.9), 7.27 (m, 2H, mixed with CDCl3), 7.64 (dd, 1H, J=2.4, J=8.4), 8.67 (dd, 1H, J=2.4, J=0.8).
Reaction SMILES: [C:1]([C:5]1[S:6][C:7]2[CH:13]=[C:12]([N+:14]([O-:16])=[O:15])[C:11](Cl)=[CH:10][C:8]=2[N:9]=1)([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[NH:24]1[CH2:29][CH2:28][S:27][CH2:26][CH2:25]1.O>CN1CCCC1=O>[C:1]([C:5]1[S:6][C:7]2[CH:13]=[C:12]([N+:14]([O-:16])=[O:15])[C:11]([N:24]3[CH2:29][CH2:28][S:27][CH2:26][CH2:25]3)=[CH:10][C:8]=2[N:9]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1nc2cc(Cl)c([N+](=O)[O-])cc2s1
Reactant: C1CSCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN1CCCC1=O
Product: CC(C)(C)c1nc2cc(N3CCSCC3)c([N+](=O)[O-])cc2s1

Procedure:
A mixture of 2 g of 2-tert-butyl-5-chloro-6-nitrobenzothiazole, described in Example 5, 2 g of anhydrous potassium carbonate and 1.5 ml of thiomorpholine in 7 ml of 1-methyl-2-pyrrolidinone is heated in a sealed glass tube at 120° for 12 hours, poured into water, the solid filtered, washed with water and isopropyl alcohol to give 2-tert-butyl-6-nitro-5-[thiomorpholin-4-yl]benzothiazole, melting at 117°-120°.
Reaction SMILES: C([O:3][CH2:4][C:5]1[N:6]([NH:19][CH:20]([CH3:22])[CH3:21])[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[C:9]([NH2:17])[C:8]=2[N:18]=1)C.B(Br)(Br)Br.Cl.[OH-].[Na+]>ClCCl>[NH2:17][C:9]1[C:8]2[N:18]=[C:5]([CH2:4][OH:3])[N:6]([NH:19][CH:20]([CH3:22])[CH3:21])[C:7]=2[C:16]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N:10]=1
Reactant: CCOCc1nc2c(N)nc3ccccc3c2n1NC(C)C
Agent: BrB(Br)Br
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)Nn1c(CO)nc2c(N)nc3ccccc3c21
Temperature: 25 °C
Reaction time: 16 h
Yield: 12.7 %

Procedure:
A solution of 2-(ethoxymethyl)-N1-isopropyl-1H-imidazo[4,5-c]quinoline-1,4-diamine (prepared as described in Example 5, 0.502 g, 1.68 mmol) in dichloromethane (15 mL) under a nitrogen atmosphere was cooled in an ice bath. A solution of boron tribromide in dichloromethane (1 M, 4.19 mL, 4.19 mmol) was added dropwise. The mixture was allowed to warm slowly to room temperature, then was stirred for 16 hours. The reaction was quenched with methanol (10 mL) and concentrated under reduced pressure to yield a white solid. The solid was treated with 6 M aqueous hydrochloric acid (20 mL) to form a white suspension that was stirred at 50° C. for 2 hours. The mixture was allowed to cool to room temperature and was adjusted to pH 7 with 50% aqueous sodium hydroxide solution. A white solid was isolated by filtration, washed with water, and dried under vacuum. The crude product was purified by chromatography (silica gel, eluted with 1:1 CHCl3:(80:18:2 CHCl3:MeOH:NH4OH)) then was recrystallized from acetonitrile to afford 0.0577 g of [4-amino-1-(isopropylamino)-1H-imidazo[4,5-c]quinolin-2-yl]methanol as white crystals, mp 228–229° C.;
Reaction SMILES: F[C:2]1[C:11]([S:12]([CH3:15])(=[O:14])=[O:13])=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([CH3:16])[CH:3]=1.[C:17]1([CH:23]2[CH2:27][S:26](=[O:29])(=[O:28])[NH:25][CH2:24]2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C([O-])([O-])=O.[Cs+].[Cs+].C([O-])(O)=O.[Na+]>CN(C=O)C>[O:28]=[S:26]1(=[O:29])[CH2:27][CH:23]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:24][N:25]1[C:2]1[C:11]([S:12]([CH3:15])(=[O:14])=[O:13])=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([CH3:16])[CH:3]=1
Reactant: O=S1(=O)CC(c2ccccc2)CN1
Reactant: COC(=O)c1cc(S(C)(=O)=O)c(F)cc1C
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)c1cc(S(C)(=O)=O)c(N2CC(c3ccccc3)CS2(=O)=O)cc1C
Yield: 83.8 %

Procedure:
600 mg of methyl 4-fluoro-5-methanesulfonyl-2-methylbenzoate (Journal of Medicinal Chemistry (1997), 40(13), 2017), 600 mg of 4-phenyl-isothiazolidine 1,1-dioxide (Pharmaceutical Chemistry Journal (Translation of Khimiko-Farmatsevticheskii Zhurnal) (2000), Volume Date 1999, 33(11), 598) and 2.379 g of Cs2CO3 were stirred in 20 ml of anhydrous DMF at RT for 4 hours. The reaction mixture was then poured into 220 ml of a half-saturated aqueous NaHCO3 solution and extracted 3 times with 140 ml of EA each time. After drying over Na2SO4, the solvent was removed in vacuo. Chromatography on silica gel with DIP afforded 865 mg of a colorless oil.
Reaction SMILES: Cl.[CH3:2][S:3]([NH:6][C:7]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:8]=1[CH2:9][CH2:10][NH:11][CH2:12]2)(=[O:5])=[O:4].[C:17](OC(=O)C)(=[O:19])[CH3:18].C(N(CC)CC)C.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl.CO>[C:17]([N:11]1[CH2:10][CH2:9][C:8]2[C:13](=[CH:14][CH:15]=[CH:16][C:7]=2[NH:6][S:3]([CH3:2])(=[O:4])=[O:5])[CH2:12]1)(=[O:19])[CH3:18]
Reactant: CC(=O)OC(C)=O
Reactant: CS(=O)(=O)Nc1cccc2c1CCNC2
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Solvent: CCN(CC)CC
Product: CC(=O)N1CCc2c(cccc2NS(C)(=O)=O)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 67.8 %

Procedure:
To a solution of 5-methanesulfonamido-1,2,3,4-tetrahydroisoquinoline hydrochloride (2.87 g, 0.011 mol) in dichloromethane at 0° C. was added acetic anhydride (1.2 ml, 0.013 mol) and triethylamine (3.4 ml, 0.024 mol), and the reaction was stirred at room temperature for 16 hours. The reaction mixture was then partitioned between ethyl acetate and aqueous sodium bicarbonate solution and the aqueous phase extracted with further portions of ethyl acetate. The combined organic extracts were dried (MgSO4) and evaporated to afford an oil. This was dissolved in methanol (15 ml) and treated with aqueous sodium carbonate solution (7%, w/w, 15 ml) and the mixture stirred for 16 hours at room temperature, after which time the methanol was removed under reduced pressure, the pH was adjusted to pH 8 with 2N hydrochloric acid and the product was extracted with ethyl acetate (2×). The combined organic extracts were dried (MgSO4) and evaporated to give an oil which was purified on silica gel, eluting with dichloromethane:methanol (95:5, v/v) to give the title compound as an oil (2.0 g, 68%). Rf 0.20 (dichloromethane:methanol 95:5, v/v). MS m/z 269 (MH)+.
Reaction SMILES: O1C2C=CC=CC=2C(=O)C1=NO.Cl.CON.[OH:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1/[C:24](=[N:29]\[O:30][CH3:31])/[C:25]([O:27][CH3:28])=[O:26].OC1C=CC=CC=1/C(=N/OC)/C(OC)=O>CO>[OH:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[C:24](=[N:29][O:30][CH3:31])[C:25]([O:27][CH3:28])=[O:26]
Reactant: CO/N=C(/C(=O)OC)c1ccccc1O
Agent: CO/N=C(\C(=O)OC)c1ccccc1O
Agent: CON
Agent: Cl
Solvent: CO
Product: CON=C(C(=O)OC)c1ccccc1O

Procedure:
8.2 g (0.05 mol) of benzofuran-2,3-dione 2-oxime and 9 g (0.108 mol) of O-methylhydroxylamine hydrochloride in 50 ml of methanol are heated under reflux for 3 hours. The methanol is distilled off under reduced pressure and the residue is mixed with 50 ml of water and extracted with ethyl acetate. The organic phase is dried over sodium sulphate and the solvent is distilled off under reduced pressure, giving 9.88 g of crystal-containing crude product. According to HPLC, the crude product contains 43.7% of methyl E-2-(2-hydroxyphenyl)-2-methoxyimino-acetate of log p=1.48 and 29.4% of methyl Z-2-(2-hydroxyphenyl)-2-methoxyimino-acetate of log p=2.37.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]([OH:9])=O)=[C:5]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[O:4][N:3]=1.[C:16]1([CH:22]2[CH2:26][CH2:25][NH:24][CH2:23]2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>CN(C)C=O>[CH3:1][C:2]1[C:6]([C:7]([N:24]2[CH2:25][CH2:26][CH:22]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:23]2)=[O:9])=[C:5]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[O:4][N:3]=1
Reactant: Cc1noc(-c2ccccc2)c1C(=O)O
Reactant: c1ccc(C2CCNC2)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1noc(-c2ccccc2)c1C(=O)N1CCC(c2ccccc2)C1
Temperature: 25 °C

Procedure:
3-Methyl-5-phenyl-4-isoxazolecarboxylic acid (40 mg, 0.197 mmol), 3-phenyl-pyrrolidine (31.6 mg, 0.215 mmol), O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (86.2 mg, 0.268 mmol) and diisopropylethylamine (25.4 mg, 0.197 mmol) were mixed in dimethylformamide (1.5 mL) and stirred at room temperature. Solvent was evaporated in vacuo, and the residue was taken up in methanol (1 mL), filtered and purified by preparative chromatography. The combined fractions were partitioned between NaHCO3 (sat) and ethylacetate. The organic layer was washed with water and concentrated in vacuo to afford the title compound. HRMS (ESI, pos. ion) m/z calcd for C21H20N2O2: 332.1525, found 332.1535.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:3]=1[C:4](O)=[O:5].C(O)(=O)C.[O-:16][C:17]#[N:18].[K+].[OH-].[Na+]>O>[Cl:11][C:8]1[CH:7]=[C:3]2[C:2](=[CH:10][CH:9]=1)[N:1]=[C:17]([OH:16])[N:18]=[C:4]2[OH:5]
Reactant: N#C[O-]
Reactant: Nc1ccc(Cl)cc1C(=O)O
Agent: [K+]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: Oc1nc(O)c2cc(Cl)ccc2n1
Temperature: 25 °C
Reaction time: 48 h
Yield: 65.9 %

Procedure:
To a mixture of 2-amino-5-chlorobenzoic acid (25.3 g), acetic acid (9.0 mL), and water (650 mL) was added an aqueous solution (130 mL) of potassium cyanate (15.5 g), and the mixture was stirred at room temperature for 2 days. Sodium hydroxide (59 g) was added over 30 min. Water (100 mL) was added, and then the precipitated solids were collected by filtration. The resulting solids were suspended in water (700 mL), followed by addition of 4 M hydrochloric acid (55 mL), and then the precipitated solids were collected by filtration to obtain 6-chloroquinazoline-2,4-diol (19.1 g).
Reaction SMILES: C12(C=CC3C=C(C(O)=O)C=CC=3O1)CC2.C[O:17][C:18](=[O:46])[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]#[C:27][C:28]2[CH:29]=[C:30]([CH:42]3C[CH2:43]3)[C:31]3[O:38][C:35]4([CH2:37][CH2:36]4)[CH2:34][C:33]([CH3:40])([CH3:39])[C:32]=3[CH:41]=2)=[CH:22][C:21]=1F.C(OC1C=CC(O)=CC=1C(C)(C)C)(=O)C.C(OC(=O)CC1C=CC(O)=CC=1)(C)(C)C.Cl.CN(C)CCCN=C=NCC>ClCCl.CN(C)C1C=CN=CC=1.CCCCCC.C(OCC)(=O)C>[CH2:42]([C:30]1[CH:29]=[C:28]([C:27]#[C:26][C:23]2[CH:24]=[CH:25][C:20]([CH2:19][C:18]([OH:46])=[O:17])=[CH:21][CH:22]=2)[CH:41]=[C:32]2[C:31]=1[O:38][C:35]([CH3:36])([CH3:37])[CH2:34][C:33]2([CH3:40])[CH3:39])[CH3:43]
Reactant: COC(=O)Cc1ccc(C#Cc2cc(C3CC3)c3c(c2)C(C)(C)CC2(CC2)O3)cc1F
Agent: CC(=O)Oc1ccc(O)cc1C(C)(C)C
Agent: CC(C)(C)OC(=O)Cc1ccc(O)cc1
Agent: CCN=C=NCCCN(C)C
Solvent: ClCCl
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CCc1cc(C#Cc2ccc(CC(=O)O)cc2)cc2c1OC(C)(C)CC2(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of spiro[2H-1-benzopyran-2,1′-cyclopropane]-6-carboxylic acid, 8-cyclopropyl-3,4-dihydro-4,4-dimethyl-(Intermediate 49, 0.06 g, 0.22 mmol) in anhydrous dichloromethane (5 mL) was treated with tert-butyl-4-hydroxy phenyl acetate (Reagent E, 0.05 g, 0.22 mmol) followed by 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.11 g, 0.22 mmol) and 4-dimethylaminopyridine (0.028 g, 0.22 mmol). The resulting solution was stirred at ambient temperature overnight. The reaction mixture was subjected to flash column chromatography over silica gel (230-400 mesh) using 7% ethyl acetate in hexane as the eluent to afford the title compound as a clear oil that solidified on standing (0.048 g, 48%).
Reaction SMILES: [O:1]=[C:2]1[CH2:8][C:7]2[CH:9]=[CH:10][CH:11]=[N:12][C:6]=2[O:5][C:4]2[CH:13]=[CH:14][C:15]([CH2:17][C:18](N)=[O:19])=[CH:16][C:3]1=2.[OH-:21].[K+].O>O.C(O)C>[O:1]=[C:2]1[CH2:8][C:7]2[CH:9]=[CH:10][CH:11]=[N:12][C:6]=2[O:5][C:4]2[CH:13]=[CH:14][C:15]([CH2:17][C:18]([OH:19])=[O:21])=[CH:16][C:3]1=2
Reactant: [OH-]
Reactant: NC(=O)Cc1ccc2c(c1)C(=O)Cc1cccnc1O2
Agent: [K+]
Solvent: O
Solvent: CCO
Product: O=C(O)Cc1ccc2c(c1)C(=O)Cc1cccnc1O2
Yield: 73.7 %

Procedure:
To 50 mg of (5,6-dihydro-6-oxo benzo[b]pyrido[3,2-f]oxepin-8-yl)-acetamide was added 0.4 g of potassium hydroxide in 4 ml of water/ethanol (1:1), and the mixture was refluxed for 3 hours. After cooling, to this was added water, and the mixture was washed with ethyl acetate. The aqueous layer was acidified with acetic acid and extracted with ethyl acetate. The extract was washed with water and then a saturated sodium chloride solution and dried over anhydrous sodium sulfate. The solvent was distilled off to obtain a solid, which was recrystallized from acetone to give 37 mg (yield: 72%) of (5,6-dihydro-6-oxo benzo[b]pyrido[3,2-f]-oxepin-8-yl)-acetic acid as white needle crystals having a melting point of 181°-184° C.
Reaction SMILES: C[N:2]([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F.ON1C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.[Cl-].[NH4+].[F:49][C:50]([F:55])([F:54])[C:51]([OH:53])=[O:52].[C:56]([C:59]1[CH:64]=[CH:63][C:62]([NH:65][CH:66]([C:82]2[CH:87]=[CH:86][C:85]([O:88][CH2:89][C:90](=[O:94])[N:91]([CH3:93])[CH3:92])=[C:84]([O:95][CH3:96])[CH:83]=2)[C:67]2[NH:71][C:70](=[O:72])[N:69]([C:73]3[CH:81]=[CH:80][CH:79]=[CH:78][C:74]=3[C:75]([OH:77])=O)[N:68]=2)=[CH:61][CH:60]=1)(=[NH:58])[NH2:57]>>[F:49][C:50]([F:55])([F:54])[C:51]([OH:53])=[O:52].[C:56]([C:59]1[CH:64]=[CH:63][C:62]([NH:65][CH:66]([C:82]2[CH:87]=[CH:86][C:85]([O:88][CH2:89][C:90](=[O:94])[N:91]([CH3:93])[CH3:92])=[C:84]([O:95][CH3:96])[CH:83]=2)[C:67]2[NH:71][C:70](=[O:72])[N:69]([C:73]3[CH:81]=[CH:80][CH:79]=[CH:78][C:74]=3[C:75]([NH2:2])=[O:77])[N:68]=2)=[CH:61][CH:60]=1)(=[NH:58])[NH2:57]
Reactant: COc1cc(C(Nc2ccc(C(=N)N)cc2)c2nn(-c3ccccc3C(=O)O)c(=O)[nH]2)ccc1OCC(=O)N(C)C
Reactant: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Agent: [Cl-]
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(C(Nc2ccc(C(=N)N)cc2)c2nn(-c3ccccc3C(N)=O)c(=O)[nH]2)ccc1OCC(=O)N(C)C
Temperature: 25 °C
Reaction time: 22 h
Yield: 37.4 %

Procedure:
After adding 20.4 mg of BOP reagent, 5.3 mg of 1-hydroxybenzotriazole, 20.5 μl of N,N-diisopropylethylamine and 3.1 mg of ammonium chloride to a solution of 11.5 mg of 2-{3-[(4-carbamimidoyl-phenylamino)-(4-dimethylcarbamoylmethoxy-3-methoxy-phenyl)methyl]-5-oxo-4,5-dihydro-1H-[1,2,4]triazol-1-yl}benzoic acid trifluoroacetate in 1 ml of Miff, the mixture was stirred at room temperature for 22 hours. After filtering the reaction mixture, it was purified by reverse-phase high performance liquid chromatography (acetonitrile-water, 0.1% trifluoroacetic acid) to give 4.3 mg of the title compound.
Reaction SMILES: C[C:2](C)([O-:4])C.[K+].[C:7]1([N:13]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH2:15][C:14]2=[O:22])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(OCC)=O.Cl>O.C(O)C>[C:7]1([N:13]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15](=[CH:2][OH:4])[C:14]2=[O:22])[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: CC(C)(C)[O-]
Reactant: O=C1Cc2ccccc2N1c1ccccc1
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CCO
Solvent: CCOC=O
Product: O=C1C(=CO)c2ccccc2N1c1ccccc1

Procedure:
Potassium t-butoxide (1.63 g, 14.5 mmoles) and 5 ml absolute ethanol were heated to 80°. 1-Phenyl-2(1H,3H)-indolone (2.09 g, 10 mmoles) was added, followed by ethyl formate (1.09 ml, 13.5 mmoles). The mixture was heated 5 minutes, cooled to 25°, and the nearly solid mass diluted with 50 ml H2O and crushed ice, acidified to pH 3 with 3N HCl and title product recovered by filtration, 2.2 g, m.p. 192°-195°; m/e 237. cf J. Prakt. Chem. 135:345-360 (1932); J. Med. Chem. 8:637 (1965).
Reaction SMILES: N[C:2]1[C:11]2[C:6](=CC(S(O)(=O)=O)=CC=2O)[CH:5]=[C:4]([S:17]([OH:20])(=[O:19])=[O:18])[CH:3]=1.[N:21]1C(F)=NC(F)=NC=1F.C(=O)([O-])[O-].[Na+].[Na+].NC1C=CC=C(C)C=1.Cl.N([O-])=O.[Na+]>O>[NH2:21][C:5]1[CH:6]=[CH:11][CH:2]=[CH:3][C:4]=1[S:17]([OH:20])(=[O:19])=[O:18]
Reactant: Nc1cc(S(=O)(=O)O)cc2cc(S(=O)(=O)O)cc(O)c12
Reactant: Fc1nc(F)nc(F)n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: O=N[O-]
Solvent: O
Solvent: Cc1cccc(N)c1
Product: Nc1ccccc1S(=O)(=O)O
Reaction time: 0.25 h
Yield: 143.6 %

Procedure:
12.8 g of 1-amino-8-hydroxynaphthalene-3,6-disulphonic acid are dissolved in 200 ml of water at pH 5.8. After cooling the solution to 0°-5°, 3.8 g of cyanuric fluoride are added dropwise in the course of 10 minutes, and during this the pH value of the solution is kept at 4.0-4.5 by adding 20% strength sodium carbonate solution dropwise. The mixture is subsequently stirred for about 15 minutes and 4.3 g of m-toluidine are then added. The pH value is now kept at 5.5-6.0. After the condensation of the difluorotriazinyl component with the m-toluidine has ended, a diazonium salt suspension which has been obtained from 7.0 g of 2-aminobenzenesulphonic acid in 100 ml and 20 ml of concentrated hydrochloric acid with 20 ml of 2N sodium nitrite solution analogously to Example 2, is allowed to run in at 0°-5°.
Reaction SMILES: [CH2:1]([CH:3]([CH2:20][CH2:21][CH2:22][CH3:23])[CH2:4][CH:5]1[CH2:10][CH2:9][CH2:8][CH:7]([CH2:11][CH:12]([CH2:17][CH3:18])[CH2:13][CH2:14][CH2:15][CH3:16])[CH:6]1O)[CH3:2].[H][H]>[Ni]>[CH2:17]([CH:12]([CH2:13][CH2:14][CH2:15][CH3:16])[CH2:11][CH:7]1[CH2:8][CH2:9][CH2:10][CH:5]([CH2:4][CH:3]([CH2:1][CH3:2])[CH2:20][CH2:21][CH2:22][CH3:23])[CH2:6]1)[CH3:18]
Reactant: CCCCC(CC)CC1CCCC(CC(CC)CCCC)C1O
Reactant: [H][H]
Agent: [Ni]
Product: CCCCC(CC)CC1CCCC(CC(CC)CCCC)C1

Procedure:
200 Grams of 2,6-di-(2-ethylhexyl)-cyclohexanol were hydrogenated for 13 hours at 250° C. and 20 bar of hydrogen pressure with 10 gm of a nickel catalyst containing about 22% nickel bonded on kieselguhr in a hard fat (Pricat 9904 of Unichema). After filtration of the catalyst, 171 gm of 1,3-di-(2-ethylhexyl)-cyclohexane were obtained after distillation at 0.01 mbar between 118° and 123° C.
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH:11]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)[CH3:13])[C:6]3[CH2:21][CH2:22][N:23]([CH3:25])[CH2:24][C:5]=3[C:4]=2[CH:3]=1.CC(C)([O-])C.[Na+].Cl.[CH3:33][NH:34][CH3:35]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[F:20][C:17]1[CH:18]=[CH:19][C:14](/[C:12](/[CH3:13])=[CH:11]/[N:7]2[C:8]3[CH:9]=[CH:10][C:2]([N:34]([CH3:35])[CH3:33])=[CH:3][C:4]=3[C:5]3[CH2:24][N:23]([CH3:25])[CH2:22][CH2:21][C:6]2=3)=[CH:15][CH:16]=1
Reactant: CC(=Cn1c2c(c3cc(Cl)ccc31)CN(C)CC2)c1ccc(F)cc1
Reactant: CNC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Product: C/C(=C\n1c2c(c3cc(N(C)C)ccc31)CN(C)CC2)c1ccc(F)cc1
Temperature: 100 °C
Yield: 33.2 %

Procedure:
8-Chloro-5-(2-(4-fluorophenyl)prop-1-enyl)-2,3,4,5-tetrahydro-2-methyl-1H-pyrido[4,3-b]indole (100 mg, 0.282 mmol), sodium tertbutoxide (324 mg, 2.948 mmol), palladium acetate (12 mg, 0.049 mmol) and 2-di-tertbutylphosphino-2′-4′-6′-triisopropylbiphenyl (31 mg, 0.0735 mmol) were charged in a reaction bottle which was evacuated and back filled with nitrogen for 5 min. Anhydrous toluene (2 mL) was added under nitrogen atmosphere. Finally, dimethylamine hydrochloride (45.13 mg, 0.564 mmol) was added to the reaction mixture and contents heated at 100° C. overnight. The reaction mixture was filtered, and washed with EtOAc (2×25 mL). The filtrate obtained was concentrated under vacuum and purified on reverse phase chromatography to yield 34 mg of desired compound as the TFA salt. 1H NMR (CD3OD, TFA salt) δ (ppm): 7.78 (s, 1H), 7.58 (m, 2H), 7.38 (s, 2H), 7.10 (t, 2H), 6.90 (s, 1H), 4.70 (m, 1H), 4.40 (m, 1H), 3.80 (m, 1H), 3.58 (m, 1H), 3.28 (s, 6H), 3.10 (m, 2H), 3.05 (s, 3H), 1.80 (s, 3H).