Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[N:2]([CH3:26])[CH:3]1[CH2:7][CH2:6][N:5]([C:8]2[CH:21]=[C:20]([O:22][CH3:23])[C:19]([O:24][CH3:25])=[CH:18][C:9]=2/[CH:10]=[C:11]2/[C:12](=[O:17])[NH:13][C:14](=[O:16])[S:15]/2)[CH2:4]1.O=C[CH2:29][NH:30][C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34].[Na].O>C(Cl)Cl>[O:16]=[C:14]1[NH:13][C:12](=[O:17])/[C:11](=[CH:10]/[C:9]2[CH:18]=[C:19]([O:24][CH3:25])[C:20]([O:22][CH3:23])=[CH:21][C:8]=2[N:5]2[CH2:6][CH2:7][CH:3]([NH:2][CH2:26][CH2:29][NH:30][C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34])[CH2:4]2)/[S:15]1
Reactant: COc1cc(/C=C2\SC(=O)NC2=O)c(N2CCC(N(C)C)C2)cc1OC
Reactant: CC(C)(C)OC(=O)NCC=O
Agent: [Na]
Solvent: ClCCl
Solvent: O
Product: COc1cc(/C=C2\SC(=O)NC2=O)c(N2CCC(NCCNC(=O)OC(C)(C)C)C2)cc1OC
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A mixture of (5Z)-5-{2-[3-(dimethylamino)pyrrolidin-1-yl]-4,5-dimethoxybenzylidene}-1,3-thiazolidine-2,4-dione (Example 52) (120 mg, 0.31 mmol) and tert-butyl 2-oxoethylcarbamate (198 mg, 1.24 mmol) in CH2Cl2 (20 mL) were heated to reflux for 15 min followed by the addition of sodium triacetoxyhydroborate (65.9 mg, 0.31 mmol). The reaction mixture was refluxed overnight before being allowed to cool to ambient temperature. Water (˜0.5 mL) was added and the mixture was allowed to stir for 15 min before being loaded onto a silica gel column which was eluted with ethyl acetate/hexane (10:1) to yield the title compound as an orange solid as (60.0 mg, 39.2%); m/z 493.
Reaction SMILES: [C:1](#[N:3])[CH3:2].C([Li])CCC.[Br:9][C:10]1[CH:11]=[CH:12][C:13]([CH:16]=[N:17][S:18]([C:20]([CH3:23])([CH3:22])[CH3:21])=[O:19])=[N:14][CH:15]=1>O1CCCC1.[Cl-].[NH4+]>[Br:9][C:10]1[CH:11]=[CH:12][C:13]([CH:16]([NH:17][S:18]([C:20]([CH3:23])([CH3:22])[CH3:21])=[O:19])[CH2:2][C:1]#[N:3])=[N:14][CH:15]=1
Reactant: CC(C)(C)S(=O)N=Cc1ccc(Br)cn1
Reactant: CC#N
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)(C)S(=O)NC(CC#N)c1ccc(Br)cn1
Reaction time: 0.5 h
Yield: 43.6 %

Procedure:
To a solution of Acetonitrile (0.142 g, 3.472 mmol) in dry tetrahydrofuran (10 mL) is added n-butyl lithium (0.222 g, 3.472 mmol) at −78° C. and stir for 30 minutes at same temperature followed by drop wise addition of solution of 2-Methyl-propane-2-sulfinic acid 5-bromo-pyridin-2-ylmethyleneamide (0.5 g, 1.736 mmol) in dry tetrahydrofuran (10 mL) and stirred the reaction at −78° C. for 1 h. Reaction mixture is diluted with aqueous ammonium chloride solution and extracted with ethyl acetate. Organic layer is dried over sodium sulphate, solvent is evaporated in vacuo and purified by combi-flash chromatography using 80% ethyl acetate in hexane to afford the title compound (0.25 g): 1H-NMR (400 MHz, DMSO-d6) δ: 1.17 (s, 9H), 2.93-2.99 (m, 1H), 3.11-3.16 (m, 1H), 4.72-4.78 (m, 1H), 6.09 (d, J=9.24, 1H), 7.64 (d, J=8.44 Hz, 1H), 8.12-8.14 (dd, J1=2.36 Hz, J2=8.4 Hz, 1H), 8.674 (d, 2.24 Hz, 1H). LC-MS (m/z): [M+H]=330.0.
Reaction SMILES: [OH:1][C:2]1[C:16]([CH3:17])=[C:15]([CH3:18])[CH:14]=[C:13]([CH3:19])[C:3]=1[C:4]([CH2:6][CH2:7][CH2:8][CH2:9][C:10]([OH:12])=[O:11])=O.C1(C)C=CC=CC=1.Cl>O.[Zn]>[OH:1][C:2]1[C:16]([CH3:17])=[C:15]([CH3:18])[CH:14]=[C:13]([CH3:19])[C:3]=1[CH2:4][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([OH:12])=[O:11]
Reactant: Cc1cc(C)c(C(=O)CCCCC(=O)O)c(O)c1C
Agent: Cl
Agent: [Zn]
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1cc(C)c(CCCCCC(=O)O)c(O)c1C

Procedure:
To 5-(2'-hydroxy-3',4',6'-trimethylbenzoyl)pentanoic acid (formula II-1 wherein R=H3C, X=H, Y=OH, n=4, in the free form) (0.262 part) were added water (16 volume parts), toluene (20 volume parts), concentrated hydrochloric acid (4 volume parts) and zinc amalgam prepared from 2 parts of zinc. The mixture was refluxed for 16 hours, during which time concentrated hydrochloric acid (6 volume parts) was added in three portions. After cooling, the reaction mixture was diluted with water and extracted with diethyl ether. The extract was washed with water and dried. The solvents were distilled off under reduced pressure to obtain 6-(2'-hydroxy-3',4',6'-trimethylphenyl)hexanoic acid (formula II-2 wherein R=H3C, X=H, Y=OH, n=4, in the free form) (0.251 part) as colorless needles melting at 96°-108° C.
Reaction SMILES: [OH-].[Na+].[F:3][C:4]1[CH:19]=[CH:18][CH:17]=[CH:16][C:5]=1[C:6]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([F:15])[CH:10]=1)=[O:7]>CO>[F:3][C:4]1[CH:19]=[CH:18][CH:17]=[CH:16][C:5]=1[C:6]([OH:8])=[O:7].[F:15][C:11]1[CH:10]=[C:9]([OH:8])[CH:14]=[CH:13][CH:12]=1
Reactant: O=C(Oc1cccc(F)c1)c1ccccc1F
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1ccccc1F
Product: Oc1cccc(F)c1
Yield: 100 %
Yield: 100 %

Procedure:
Sodium hydroxide (0.109 g) was dissolved in 2 ml of methanol in a 10-ml Kjeldahl flask fitted with a reflux condenser, after which 0.234 g of m-fluorophenyl o-fluorobenzoate was added, and the mixture was heated under reflux for 60 minutes. After cooling, the experiment was operated as in Referential Example 4 to confirm that the reaction mixture contained 140 mg (yield 100%) of o-fluorobenzoic acid and 112 mg (yield 100%) of m-fluorophenol.
Reaction SMILES: [CH3:1][C:2](=O)[CH2:3][CH3:4].[NH:6]1[CH2:11][CH2:10][O:9][CH2:8][CH2:7]1.ClCCl>CCCCC.[Ti](Cl)(Cl)(Cl)Cl>[CH2:1]=[C:2]([N:6]1[CH2:11][CH2:10][O:9][CH2:8][CH2:7]1)[CH2:3][CH3:4]
Reactant: CCC(C)=O
Reactant: C1COCCN1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CCCCC
Product: C=C(CC)N1CCOCC1
Reaction time: 20 h
Yield: 52.3 %

Procedure:
To a solution of 2-butanone (6.2 ml, 69 mmol) and morpholine (18.1 ml, 208 mmol) in n-pentane (400 ml) was added dropwise 1 M titanium tetrachloride solution in dichloromethane (38.1 ml, 38.1 mmol) at 0-5° C. The cooling bath was removed and the mixture was stirred for 20 h. The precipitate was removed by filtration and washed with two 100-ml portions of diethyl ether. The filtrate was concentrated in vacuo. The residue was distilled over a vigreux column in a Kugelrohr oven (1 mbar, 40-70° C.) to give the title compound (5.1 g, 52%) as colorless oil.
Reaction SMILES: [CH2:1]([N:8]1[C:12]([NH2:13])=[CH:11][N:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Si:14]([O:21][CH:22]1[CH2:27][CH2:26][C:25](=O)[CH2:24][CH2:23]1)([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(O)(=O)C>[CH2:1]([N:8]1[C:12]([NH:13][CH:25]2[CH2:26][CH2:27][CH:22]([O:21][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:15])[CH3:16])[CH2:23][CH2:24]2)=[CH:11][N:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)[Si](C)(C)OC1CCC(=O)CC1
Reactant: Nc1cnnn1Cc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Product: CC(C)(C)[Si](C)(C)OC1CCC(Nc2cnnn2Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 47.2 %

Procedure:
To a solution of 1-benzyl-1H-1,2,3-triazol-5-amine (10.61 g) and 4-{[tert-butyl(dimethyl)silyl]oxy}cyclohexanone (15.07 g) in acetic acid (80 mL) was added sodium triacetoxyborohydride (19.37 g), and the mixture was stirred at room temperature for 18 hr. The solvent was evaporated under reduced pressure, the residue was diluted with saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate-isopropyl alcohol (3:1). The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography [eluent: hexane/ethyl acetate=80/20→60/40 (volume ratio)] to give the title compound as a pale-yellow oil (11.12 g, 47%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=1)[C:6]([C:19](O)=[O:20])=[CH:5]2.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.[C:44]([N:47]1[C:51]2=[N:52][CH:53]=[C:54]([NH2:56])[CH:55]=[C:50]2[CH2:49][CH2:48]1)(=[O:46])[CH3:45]>CN(C=O)C>[C:44]([N:47]1[C:51]2=[N:52][CH:53]=[C:54]([NH:56][C:19]([C:6]3[N:7]([CH2:11][C:12]4[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=4)[C:8]4[C:4]([CH:5]=3)=[CH:3][C:2]([F:1])=[CH:10][CH:9]=4)=[O:20])[CH:55]=[C:50]2[CH2:49][CH2:48]1)(=[O:46])[CH3:45]
Reactant: O=C(O)c1cc2cc(F)ccc2n1Cc1cccc(F)c1
Reactant: CC(=O)N1CCc2cc(N)cnc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CC(=O)N1CCc2cc(NC(=O)c3cc4cc(F)ccc4n3Cc3cccc(F)c3)cnc21
Temperature: 20 °C
Reaction time: 14 h
Yield: 67 %

Procedure:
To a solution, stirred at 20° C., of 0.28 g (0.97 mmol) of 5-fluoro-1-(3-fluorobenzyl)-1H-indole-2-carboxylic acid prepared in step 1.1, 186 mg (0.97 mmol) of N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDAC) and 131 mg (0.97 mmol) of 1-hydroxybenzotriazole (HOBT) in 15 mL of DMF are added 206 mg (1.17 mmol) of 1-acetyl-5-amino-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine, prepared in step 1.2. The reaction mixture is stirred for 14 hours at 20° C. and then concentrated under reduced pressure. The resulting product is taken up in 100 mL of water. The suspension is then extracted with three times 30 mL of ethyl acetate. The combined organic phases are washed twice with 20 mL of water, dried over sodium sulfate and then concentrated under reduced pressure. The product obtained is purified by chromatography on a column of silica, eluting with a mixture of dichloromethane and methanol. 290 mg of the expected product are thus isolated.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:13](=[CH2:17])C(O)=O)[CH:7]=[CH:8][C:9]=1[O:10][CH2:11][CH3:12])[CH3:2].Br[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][OH:30].C1(C)C=CC=CC=1.[C:38]([O:41]CC)(=[O:40])C>>[CH2:1]([O:3][C:4]1[CH:5]=[C:6](/[CH:13]=[CH:17]/[C:38]([O:41][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][OH:30])=[O:40])[CH:7]=[CH:8][C:9]=1[O:10][CH2:11][CH3:12])[CH3:2]
Reactant: OCCCCCCCCCCCBr
Reactant: CCOC(C)=O
Reactant: C=C(C(=O)O)c1ccc(OCC)c(OCC)c1
Solvent: Cc1ccccc1
Product: CCOc1ccc(/C=C/C(=O)OCCCCCCCCCCCO)cc1OCC

Procedure:
The preparation is carried out analogously to Example 1 from 0.94 g (4.00 mmol) of 3(E)-(3,4-diethoxyphenylacrylic acid and 1.10 g (4.40 mmol) of 11-bromo-1-undecanol and, after chromatography over silica gel using toluene/ethyl acetate, gives 11-hydroxyundecyl 3(E)-(3,4-diethoxyphenyl)acrylate.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[NH3:11]>O1CCCC1>[NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:11])=[O:7])=[CH:4][CH:3]=1
Reactant: N
Reactant: Nc1ccc(C(=O)Cl)cc1
Solvent: C1CCOC1
Product: NC(=O)c1ccc(N)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 30 %

Procedure:
To an ice-cold solution of 4-amino-benzoyl chloride (0.38 g, 2.45 mmol) in tetrahydrofuran (2 ml) was added aqueous ammonia solution (15 ml). The reaction mixture was stirred at room temperature for 12 hr. The solvent was removed under vacuum, water added and the compound was extracted into ethyl acetate. The organic layer was dried and concentrated under vacuum. The crude compound was purified using silica gel column chromatography, using chloroform/methanol as eluent, to yield 4-amino-benzamide (0.1 g, 30%).
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=2)[C:3]=1[C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=1.C1(C)C=C(C)C=C(C)C=1S(O[NH2:32])(=O)=O.[CH:34]([CH:36]=O)=O.C(=O)(O)[O-].[Na+]>C(O)C.O>[F:19][C:16]1[CH:17]=[CH:18][C:13]([C:3]2[C:4]([C:7]3[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=3)=[N:5][N:6]3[C:2]=2[N:1]=[CH:36][CH:34]=[N:32]3)=[CH:14][CH:15]=1
Reactant: Cc1cc(C)c(S(=O)(=O)ON)c(C)c1
Reactant: O=CC=O
Reactant: Nc1[nH]nc(-c2ccncc2)c1-c1ccc(F)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Fc1ccc(-c2c(-c3ccncc3)nn3nccnc23)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 5-amino-4-(4-fluorophenyl)-3-(pyridin-4-yl)pyrazole (1.674 g) in ethanol (33 ml) was added O-mesitylsulfonylhydroxylamine (2.362 g). The mixture was stirred at ambient temperature for 30 minutes and to the mixture was added a solution of glyoxal in water (40%, 955 mg). The mixture was refluxed for 4 hours and cooled. The reaction mixture was poured into an aqueous saturated sodium bicarbonate solution and the separated oil was extracted with dichloromethane. The extract was washed with brine, dried and concentrated in vacuo. The residue was purified by column chromatography on silica gel and the obtained oil was crystallized from ethanol to give 8-(4-fluorophenyl)-7-(pyridin-4-yl)pyrazolo[1,5-b][1,2,4]triazine (63 mg).
Reaction SMILES: [C:1]([O:4][C:5](=O)[CH3:6])(=O)C.[CH3:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]([C:18]2[CH:23]=[CH:22][C:21]([N:24]3[CH2:28][CH2:27][CH2:26][CH2:25]3)=[CH:20][CH:19]=2)=[CH2:17])=[CH:12][CH:11]=1.[Cl:29][C:30]1[C:31]([Cl:43])=[C:32]([Cl:42])[C:33]([Cl:41])=[C:34]2[C:39](=O)[O:38][C:36](=[O:37])[C:35]=12.[OH-].[Na+]>O.ClC1C=CC=CC=1Cl>[N:24]1([C:21]2[CH:22]=[CH:23][C:18]([C:16]([C:13]3[CH:14]=[CH:15][C:10]([O:9][CH3:8])=[CH:11][CH:12]=3)=[CH:17][C:39]3([CH:17]=[C:16]([C:13]4[CH:14]=[CH:6][C:5]([O:4][CH3:1])=[CH:11][CH:12]=4)[C:18]4[CH:23]=[CH:22][C:21]([N:24]5[CH2:28][CH2:27][CH2:26][CH2:25]5)=[CH:20][CH:19]=4)[C:34]4[C:35](=[C:30]([Cl:29])[C:31]([Cl:43])=[C:32]([Cl:42])[C:33]=4[Cl:41])[C:36](=[O:37])[O:38]3)=[CH:19][CH:20]=2)[CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: O=C1OC(=O)c2c(Cl)c(Cl)c(Cl)c(Cl)c21
Reactant: C=C(c1ccc(OC)cc1)c1ccc(N2CCCC2)cc1
Reactant: CC(=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: Clc1ccccc1Cl
Solvent: O
Product: COc1ccc(C(=CC2(C=C(c3ccc(OC)cc3)c3ccc(N4CCCC4)cc3)OC(=O)c3c(Cl)c(Cl)c(Cl)c(Cl)c32)c2ccc(N3CCCC3)cc2)cc1
Temperature: 120 °C
Reaction time: 6 h
Yield: 85.2 %

Procedure:
Into a mixture of 25 ml of acetic anhydride and 75 ml of o-dichlorobenzene, 14.0 g of 1-(p-methoxyphenyl)-1-(p-pyrrolidinophenyl)ethylene (m.p. 115°-118° C.) and 21.5 g of tetrachlorophthalic anhydride were added and the mixture was stirred for 6 hours at 120° C. Into 200 ml of water the reaction mixture was added and after making the mixture alkaline by adding sodium hydroxide, the alkaline reaction mixture was extracted with 70 ml of toluene. The solid matter obtained by evaporating toluene from the extract was recrystallized from acetone while purifying with activated carbon to obtain 17.6 g of pale yellow crystals melting at 159° to 161° C. (Yield: 85.2%)
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[C:8]([OH:10])=O.C(Cl)(=O)C([Cl:14])=O>C(Cl)Cl.CN(C=O)C>[CH3:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[C:8]([Cl:14])=[O:10]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CC1CCCCC1C(=O)O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC1CCCCC1C(=O)Cl
Temperature: 25 °C
Reaction time: 4 h
Yield: 102.3 %

Procedure:
To a solution of 2-methylcyclohexanecarboxylic acid (6.00 mL, 42.6 mmol, mixture of cis and trans) in DCM (60 mL) was added oxalyl chloride (4.80 mL, 55.3 mmol) followed by DMF (0.03 mL, 0.4 mmol). The reaction mixture was stirred at ambient temperature for about 4 h before it was concentrated under reduced pressure to constant weight to afford 2-methylcyclohexanecarbonyl chloride (mixture of diastereomers) as a yellow oil (7.0 g, 97%): 1H NMR (400 MHz, CDCl3) δ 2.98-2.94 (m, 1H), 2.39-2.35 (m, 1H), 1.91-1.82 (m, 1H), 1.79-1.72 (m, 1H), 1.69-1.60 (m, 2H), 1.57-1.47 (m, 2H), 1.42-1.36 (m, 1H), 1.34-1.26 (m, 1H), 1.04-0.96 (m, 3H).
Reaction SMILES: [O:1]1[C:5]2[C:6]([C:10]([OH:12])=O)=[CH:7][CH:8]=[CH:9][C:4]=2[CH2:3][CH2:2]1.C(Cl)(=O)C(Cl)=O.[CH2:19]([O:21][C:22]([C:24]1([NH2:33])[CH2:32][C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH2:25]1)=[O:23])[CH3:20].CCN(C(C)C)C(C)C>C(Cl)Cl>[CH2:19]([O:21][C:22]([C:24]1([NH:33][C:10]([C:6]2[C:5]3[O:1][CH2:2][CH2:3][C:4]=3[CH:9]=[CH:8][CH:7]=2)=[O:12])[CH2:32][C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH2:25]1)=[O:23])[CH3:20]
Reactant: O=C(O)c1cccc2c1OCC2
Reactant: CCOC(=O)C1(N)Cc2ccccc2C1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C1(NC(=O)c2cccc3c2OCC3)Cc2ccccc2C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 75.3 %

Procedure:
To a solution of 2,3-dihydro-benzofuran-7-carboxylic acid (394 mg, 2.4 mmol) in DCM (10 mL) is added oxalyl chloride (0.85 mL, 9.6 mmol). The resulting solution is stirred at RT for 2 h. After the removal of DCM and excess oxalyl chloride, the residue, 2-amino-indan-2-carboxylic acid ethyl ester (500 mg, 2.4 mmol) and DIPEA (3.17 mL, 19.2 mmol) are dissolved in DCM (20 mL). The resulting solution is stirred at RT overnight. The reaction solution is diluted with DCM (40 mL) and washed with water (1×5 mL) and brine (2×5 mL). The organic layer is dried over anhydrous Na2SO4 and concentrated in vacuo. The residue is purified by flash column chromatography (120 g silica gel, gradient elution: 0%-20% EtOAc in heptane) to give a pure product (39) as white solid (635 mg, 75%).
Reaction SMILES: Cl.[NH:2]([C:6]1[CH:14]=[CH:13][C:9]([C:10]([OH:12])=O)=[CH:8][CH:7]=1)[C:3]([NH2:5])=[NH:4].C[Si](C([Si](C)(C)C)C(N)=O)(C)C.S(Cl)(Cl)=O.[NH2:31][C:32]1[CH:33]=[CH:34][CH:35]=[C:36]2[C:41]=1[N:40]=[CH:39][CH:38]=[CH:37]2>O.O1CCCC1>[NH:2]([C:6]1[CH:7]=[CH:8][C:9]([C:10]([NH:31][C:32]2[CH:33]=[CH:34][CH:35]=[C:36]3[C:41]=2[N:40]=[CH:39][CH:38]=[CH:37]3)=[O:12])=[CH:13][CH:14]=1)[C:3]([NH2:5])=[NH:4]
Reactant: N=C(N)Nc1ccc(C(=O)O)cc1
Reactant: Nc1cccc2cccnc12
Agent: C[Si](C)(C)C(C(N)=O)[Si](C)(C)C
Agent: Cl
Solvent: O=S(Cl)Cl
Solvent: C1CCOC1
Solvent: O
Product: N=C(N)Nc1ccc(C(=O)Nc2cccc3cccnc23)cc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A mixture of 200 mg. (0.92 m. mol) 4-guanidinobenzoic acid hydrochloride and 190 mg. (0.93 m. mol) of bis-trimethylsilylacetamide in 20 ml. of dry tetrahydrofuran was heated at reflux until a solution was achieved, and then cooled to room temperature. Thionyl chloride (380 mg., 1.86 m. mol) was added and the reaction mixture allowed to stir for 5 min. 8-Aminoquinoline (670 mg., 4.64 m. mol) was added in 5 ml. of tetrahydrofuran and the mixture allowed to stir for 30 min. Water (0.2 ml) was added to the reaction mixture and the solids filtered and dissolved in 60 ml. of methanol and 120 ml. of chloroform. Addition of diethyl ether precipitated the desired product, 153 mg., m.p. 271°-273° C.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]([OH:9])=O)[N:4]=[N:3]1.[CH2:10]([N:14]1[C:22]2[N:21]=[C:20]([Cl:23])[NH:19][C:18]=2[C:17](=[O:24])[N:16]([CH2:25][CH2:26][CH2:27][CH2:28]/[C:29](=[N:32]/[H])/[NH:30]O)[C:15]1=[O:34])[CH2:11][CH2:12][CH3:13]>CN(C=O)C.CS(C)=O>[CH2:10]([N:14]1[C:22]2[N:21]=[C:20]([Cl:23])[NH:19][C:18]=2[C:17](=[O:24])[N:16]([CH2:25][CH2:26][CH2:27][CH2:28][C:29]2[N:30]=[C:7]([C:5]3[N:4]=[N:3][N:2]([CH3:1])[CH:6]=3)[O:9][N:32]=2)[C:15]1=[O:34])[CH2:11][CH2:12][CH3:13]
Reactant: [H]/N=C(/CCCCn1c(=O)c2[nH]c(Cl)nc2n(CCCC)c1=O)NO
Reactant: Cn1cc(C(=O)O)nn1
Solvent: CN(C)C=O
Solvent: CS(C)=O
Product: CCCCn1c(=O)n(CCCCc2noc(-c3cn(C)nn3)n2)c(=O)c2[nH]c(Cl)nc21
Temperature: 100 °C
Yield: 28.7 %

Procedure:
A solution of the 1-methyl-1H-1,2,3-triazole-4-carboxylic acid (18 mg, 0.14 mmol) in DMF (0.5 ml) was treated with CDl (23 mg, 0.14 mmol) at rt for 1 h. A solution of (1Z)-5-(3-butyl-8-chloro-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-1-yl)-N-hydroxypentanimidamide (50 mg, 0.14 mmol) in DMSO (0.4 ml) was added to the mixture then heated to 100° C. for 18 h. The reaction mixture was purified by MDAP to give the title compound as a white solid (18 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:15]=[CH:14][C:6]2[N:7]=[C:8]([NH:10][C:11]([NH2:13])=[NH:12])[S:9][C:5]=2[CH:4]=1.[H-].[Na+].[CH2:18]([N:20]([CH2:33][CH3:34])[CH2:21][CH2:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([N:30]=[C:31]=S)=[CH:26][CH:25]=1)[CH3:19].CI>CN(C)C=O.O>[NH2:12][C:11]1[N:10]=[C:8]2[N:7]([C:31](=[N:30][C:27]3[CH:26]=[CH:25][C:24]([O:23][CH2:22][CH2:21][N:20]([CH2:18][CH3:19])[CH2:33][CH3:34])=[CH:29][CH:28]=3)[N:13]=1)[C:6]1[CH:14]=[CH:15][C:3]([O:2][CH3:1])=[CH:4][C:5]=1[S:9]2
Reactant: COc1ccc2nc(NC(=N)N)sc2c1
Reactant: CCN(CC)CCOc1ccc(N=C=S)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CI
Solvent: CN(C)C=O
Product: CCN(CC)CCOc1ccc(N=c2nc(N)nc3sc4cc(OC)ccc4n23)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 83.6 %

Procedure:
6-Methoxybenzothiazol-2-ylguanidine (0.2 g) was added to a suspension of sodium hydride (0.022 g=0.044 g of 50% dispersion in oil) in anhydrous dimethylformamide (20 mls) and the resulting mixture was stirred at room temperature for 15 mins. 4-(2-Diethylaminoethoxy)phenylisothiocyanate (0.23 g) was added followed, after 2.5 hrs, by methyl iodide (0.14 g) and the mixture stirred for a further 18 hrs. Water was added to precipitate a yellow solid which was collected by filtration, washed with ethanol and dissolved in ethyl acetate. The ethyl acetate solution was dried over anhydrous sodium sulphate and evaporated to give a yellow solid (0.33 g). Recrystallisation of the residue from ethyl acetate gave the desired product as pale yellow crystals (0.08 g) mp 189.5°-191°.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([NH:12][S:13]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)(=[O:15])=[O:14])=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1.[CH2:23]([OH:25])[CH3:24].[H-].[Na+].O>CS(C)=O>[Cl:22][C:19]1[CH:20]=[CH:21][C:16]([S:13]([NH:12][C:8]2[CH:7]=[C:6]3[C:11](=[CH:10][CH:9]=2)[C:2]([O:25][CH2:23][CH3:24])=[N:3][CH:4]=[CH:5]3)(=[O:15])=[O:14])=[CH:17][CH:18]=1
Reactant: CCO
Reactant: O=S(=O)(Nc1ccc2c(Cl)nccc2c1)c1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CCOc1nccc2cc(NS(=O)(=O)c3ccc(Cl)cc3)ccc12
Temperature: 80 °C
Reaction time: 9 h

Procedure:
In dimethyl sulfoxide (1 ml) was dissolved 57 mg of 1-chloro-6-(4-chlorobenzenesulfonylamino)isoquinoline (Example 61). To the mixture were added ethanol (0.1 ml) and 60% sodium hydride (14 mg), followed by heating under stirring at 80° C. for 9 hours. After standing to cool, water was added thereto and the mixture was extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and the solvent was evaporated. Then, the residue was purified by preparative TLC and solidified from isopropyl ether, to give the title compound (21 mg).
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][C:5]2[NH:6][C@H:7]([CH3:10])[CH2:8][O:9][C:4]=2[C:3]=1[F:13].C(N(CC)CC)C.[Cl:21]N1C(=O)CCC1=O.[BH4-].[Na+]>C(OCC)(=O)C.CN(C)C=O>[ClH:21].[F:1][C:2]1[CH:12]=[CH:11][C:5]2[NH:6][CH:7]([CH3:10])[CH2:8][O:9][C:4]=2[C:3]=1[F:13]
Reactant: O=C1CCC(=O)N1Cl
Reactant: C[C@@H]1COc2c(ccc(F)c2F)N1
Agent: [BH4-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC1COc2c(ccc(F)c2F)N1
Product: Cl
Temperature: -55 °C
Reaction time: 0.58 h
Yield: 433 %
Yield: 51.4 %

Procedure:
A mixture of 1.154 g of (R)-(+)-7,8-difluoro-3-methyl-3,4-dihydro-2H-[1,4]benzoxazine (optical purity: 71.7% e.e., (R)), 5.21 ml of triethylamine and 5.8 ml of N,N-dimethylformamide was cooled to -60 to -50° C. under a nitrogen gas stream. To this solution was added 1.00 g of N-chlorosuccinimide (NCS) and the mixture was stirred at the same temperature for 35 minutes. Then, 047 g of sodium borohydride was added thereto and the mixture was stirred at room temperature for 20 minutes. The reaction mixture was diluted with 50 ml of ethyl acetate, washed twice with 10 ml portions of 5% aqueous citric acid solution and once with 10 ml of dilute aqueous ammonia (described hereinabove), and dried over anhydrous magnesium sulfate. The desiccant was then filtered off and the filtrate was concentrated to about 30 ml. To the concentrate was added 0.72 ml of concentrated hydrochloric acid and after cooling with ice-water, the resulting crystals were collected by filtration. The procedure gave 0.984 g of hydrochloride of the title compound (yield: 51.4%). Optical Purity: 7.6% e.e., (R), 3R:3S =1.00:0.86