Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:18]=[CH:17][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH2:13])[C:8]=2[N+:14]([O-:16])=[O:15])=[C:4]([Cl:19])[CH:3]=1.[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([N:27]=[C:28]=[O:29])=[CH:23][C:22]=1[C:30]([F:33])([F:32])[F:31]>>[NH2:13][C:9]1[C:8]([N+:14]([O-:16])=[O:15])=[C:7]([O:6][C:5]2[CH:17]=[CH:18][C:2]([NH:1][C:28]([NH:27][C:24]3[CH:25]=[CH:26][C:21]([Cl:20])=[C:22]([C:30]([F:32])([F:31])[F:33])[CH:23]=3)=[O:29])=[CH:3][C:4]=2[Cl:19])[CH:12]=[CH:11][N:10]=1
Reactant: Nc1ccc(Oc2ccnc(N)c2[N+](=O)[O-])c(Cl)c1
Reactant: O=C=Nc1ccc(Cl)c(C(F)(F)F)c1
Product: Nc1nccc(Oc2ccc(NC(=O)Nc3ccc(Cl)c(C(F)(F)F)c3)cc2Cl)c1[N+](=O)[O-]
Yield: 99.6 %

Procedure:
Method H3 was used with 4-(4-amino-2-chlorophenoxy)-3-nitropyridin-2-amine (0.40 g, 1.42 mmol) and 4-chloro-3-(trifluoromethyl)phenyl isocyanate (0.32 g, 1.42 mmol) to afford the title compound (0.71 g, 100%). 1H NMR (250 MHz, DMSO-d6) δ 5.86 (d, 1H, J=5.6 Hz), 7.22 (s, 2H), 7.35 (d, 1H, J=8.8 Hz), 7.44 (dd, 1H, Ja=8.8 Hz, Jb=2.4 Hz), 7.60-7.69 (m, 2H), 7.87 (d, 1H, J=2.4 Hz), 7.99 (d, 1H, J=5.7 Hz), 8.10 (d, 1H, J=2.1 Hz), 9.17 (s, 1H), 9.29 (s, 1H). m/z 502.2 [(M+H)+ calcd. for C19H12Cl2F3N5O4 501.0].
Reaction SMILES: [H-].[Na+].CC[O:5][C:6]([CH:8](P(OCC)(OCC)=O)[CH3:9])=[O:7].[CH2:18]([C:20]1[CH:29]=[CH:28][CH:27]=[C:26]2[C:21]=1[C:22]([O:34]COC)=[C:23]([O:32][CH3:33])[CH:24]=[C:25]2[CH:30]=O)[CH3:19].O>CN(C)C=O>[CH2:18]([C:20]1[CH:29]=[CH:28][CH:27]=[C:26]2[C:21]=1[C:22]([OH:34])=[C:23]([O:32][CH3:33])[CH:24]=[C:25]2/[CH:30]=[C:8](\[CH3:9])/[C:6]([OH:5])=[O:7])[CH3:19]
Reactant: CCc1cccc2c(C=O)cc(OC)c(OCOC)c12
Reactant: CCOC(=O)C(C)P(=O)(OCC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCc1cccc2c(/C=C(\C)C(=O)O)cc(OC)c(O)c12
Temperature: 25 °C
Reaction time: 1 h
Yield: 122 %

Procedure:
36 g of 60% sodium hydride was suspended in 500 ml of N,N-dimethylformamide and 268 g of triethyl 2-phosphonopropionate was added at ice bath temperature. After stirring at room temperature for 1 hour, a solution of 206 g of 5-ethyl-3-methoxy-4-methoxymethoxy-1-naphthalenecarbaldehyde was added. After stirring at room temperature for 15 minutes, ice cooled water was gradually added at ice bath temperature. The mixture was extracted with ethyl acetate and the combined organic layer was washed with brine. After drying over anhydrous magnesium sulfate, the solvent was evaporated and the residue was purified by silica gel column chromatography (10% ethyl acetate/hexane) to obtain 262.4 g of the titled compound as a yellow oil (containing a small amount of Z isomer).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([OH:14])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[N:15]1([CH2:20][CH2:21][CH2:22]O)[CH2:19][CH2:18][CH2:17][CH2:16]1>>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:22][CH2:21][CH2:20][N:15]3[CH2:19][CH2:18][CH2:17][CH2:16]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1
Reactant: OCCCN1CCCC1
Reactant: COc1cc2c(Cl)ncnc2cc1O
Product: COc1cc2c(Cl)ncnc2cc1OCCCN1CCCC1

Procedure:
The compound was synthesised according to GP 4 from 4-chloro-7-hydroxy-6-methoxy-quinazoline and 3-Pyrrolidin-1-yl-propan-1-ol. LC/ESI-MS: m/z=322 [M+H].
Reaction SMILES: [BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].[NH:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1.[CH2:20]([O:22][C:23]1[CH:24]=[C:25]([CH:28]=[CH:29][C:30]=1[OH:31])[CH:26]=O)[CH3:21].[OH-].[Na+]>C(Cl)Cl.O>[CH2:20]([O:22][C:23]1[CH:24]=[C:25]([CH2:26][N:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)[CH:28]=[CH:29][C:30]=1[OH:31])[CH3:21]
Reactant: CCOc1cc(C=O)ccc1O
Reactant: C1CCNC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: CCOc1cc(CN2CCCC2)ccc1O
Yield: 72.3 %

Procedure:
NaB(OAc)3H (8 g, 0.038 mol) was added in portions for 30 min to a mixture of pyrrolidine (3.1 mL, 0.038 mol) and 3-ethoxy-4-hydroxybenzaldehyde (5 g, 0.03 mol) in CH2Cl2 (50 mL) under vigorous stirring and cooling with an ice bath in an atmosphere of argon Ar. The mixture was stirred for 12 h and cooled with an ice bath. 10N NaOH (3.8 mL) and water (30 mL) were added. The organic layer was separated. The aqueous one was extracted with chloroform (2×100 mL). The extracts were evaporated. The residue was purified by chromatography (silica gel 40-63μ, 100 g, CCl4—CHCl3, CHCl3/MeOH 100:0→90:10) to give the title compound (4.8 g, 73%) was obtained as dark-yellow crystals. 1H NMR data (DMSO-d6): 8.65 (s, 1H ArOH), 6.81 (d, 1H, J=1.71, Ar—H), 6.70 (d, 1H, J=7.8, Ar—H); 6.65 (dd, 1H, J1=7.8, J2=1.7, Ar—H), 3.98 (q, 2H, CH2CH3), 3.42 (s, 2H, ArCH2), 2.33-2.45 (m, 4H, pyrrolidine (CH2)2N), 1.59-1.73 (m, 4H, CH2CH2CH2CH2); 1.31 (t, 3H, J=6.9, CH2CH3).
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([Cl:8])[N:3]=1.[C:9]1(B(O)O)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>>[Cl:8][C:4]1[CH:5]=[N:6][CH:7]=[C:2]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:3]=1
Reactant: Clc1cncc(Cl)n1
Reactant: OB(O)c1ccccc1
Product: Clc1cncc(-c2ccccc2)n1

Procedure:
Prepared from 2,6-dichloropyrazine (1.01 g, 6.78 mmol) and phenylboronic acid (946.7 mg, 7.76 mmol) according to Method K, except the product was purified by silica gel chromatography (DCM, Rf=0.37) instead of preparative HPLC: 1H NMR (300 MHz, chloroform-D) δ ppm 7.46-7.53 (m, 3H), 7.94-7.98 (m, 2H), 8.22 (s, 1H), 8.63 (s, 1H). MS (DCI/NH3) m/z=191 (M+H)+.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([C:15]2([C:28]([OH:30])=O)[CH2:20][CH2:19][N:18]([S:21]([C:24]([F:27])([F:26])[F:25])(=[O:23])=[O:22])[CH2:17][CH2:16]2)(=[O:14])=[O:13])=[CH:8][CH:7]=1)[C:2]#[C:3][CH3:4].[OH:31][N:32]1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.CN1CCOCC1.NO>CN(C)C=O>[CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([C:15]2([C:28]([NH:32][OH:31])=[O:30])[CH2:20][CH2:19][N:18]([S:21]([C:24]([F:27])([F:26])[F:25])(=[O:23])=[O:22])[CH2:17][CH2:16]2)(=[O:14])=[O:13])=[CH:8][CH:7]=1)[C:2]#[C:3][CH3:4]
Reactant: On1nnc2ccccc21
Reactant: CC#CCOc1ccc(S(=O)(=O)C2(C(=O)O)CCN(S(=O)(=O)C(F)(F)F)CC2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: NO
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CC#CCOc1ccc(S(=O)(=O)C2(C(=O)NO)CCN(S(=O)(=O)C(F)(F)F)CC2)cc1

Procedure:
4-(4-but-2-ynyloxy benzenesulfonyl)-N-hydroxy-1-[(trifluoromethyl)sulfonyl]-4-piperidinecarboxamide was prepared following the procedure Example 64 (step 6). Starting from 4-(4-but-2-ynyloxybenzenesulfonyl)-1-[(trifluoromethyl)sulfonyl]-4-piperidinecarboxylic acid (145 mg, 0.31 mmol) in dimethylformamide (3 ml), 1-hydroxybenzotriazole (50 mg, 0.37 mmol), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (83 mg, 0.47 mmol), N-methylmorpholine (0.051 ml, 0.47 mmol), and hydroxylamine (0.095 ml, 1.55 mmol), 90 mg (60%) of the product was isolated as a solid. HR—MS: m/z Calculated for C17H19F3N2O7S2 485.0659; Found 485.0666.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:27])[CH2:5][CH2:6][CH:7]1[CH2:12][CH2:11][CH:10]([CH:13]2[CH2:18][CH2:17][CH:16]([CH:19]3OCC(C)(C)C[O:20]3)[CH2:15][CH2:14]2)[CH2:9][CH2:8]1)[CH3:2]>C1(C)C=CC=CC=1.C(O)=O>[CH2:1]([O:3][C:4](=[O:27])[CH2:5][CH2:6][CH:7]1[CH2:12][CH2:11][CH:10]([CH:13]2[CH2:14][CH2:15][CH:16]([CH:19]=[O:20])[CH2:17][CH2:18]2)[CH2:9][CH2:8]1)[CH3:2]
Reactant: CCOC(=O)CCC1CCC(C2CCC(C3OCC(C)(C)CO3)CC2)CC1
Solvent: Cc1ccccc1
Solvent: O=CO
Product: CCOC(=O)CCC1CCC(C2CCC(C=O)CC2)CC1

Procedure:
A solution of 3-[4′-(5,5-Dimethyl-[1,3]dioxan-2-yl)-bicyclohexyl-4-yl]-propionic acid ethyl ester (17 g, 45 mmol) in toluene (200 ml) and formic acid (70 ml) is stirred overnight at 80° C. The solution is washed with water, dried (Na2SO4), concentrated and recrystallised to give 3-(4′-formyl-bicyclohexyl-4-yl)-propionic acid ethyl ester as colourless crystals.
Reaction SMILES: [C:1]([C:4]1[C:5]([CH3:15])=[C:6]2[C:11](=[O:12])[NH:10][CH2:9][CH2:8][N:7]2[C:13]=1[CH3:14])(=[O:3])[CH3:2].CC(O[CH:21](N(C)C)[N:22]([CH3:24])[CH3:23])(C)C>CC(C)=O>[CH3:21][N:22]([CH3:24])/[CH:23]=[CH:2]/[C:1]([C:4]1[C:5]([CH3:15])=[C:6]2[C:11](=[O:12])[NH:10][CH2:9][CH2:8][N:7]2[C:13]=1[CH3:14])=[O:3]
Reactant: CN(C)C(OC(C)(C)C)N(C)C
Reactant: CC(=O)c1c(C)c2n(c1C)CCNC2=O
Solvent: CC(C)=O
Product: Cc1c(C(=O)/C=C/N(C)C)c(C)n2c1C(=O)NCC2
Temperature: 95 °C
Yield: 76.5 %

Procedure:
7-Acetyl-6,8-dimethyl-3,4-dihydro-2H-pyrrolo[1,2-a]pyrazin-1-one (6.692 g, 32.49 mmol) was combined with Brederick's reagent (13.42 mL, 64.98 mmol) and heated to 95° C. for 10 hours. After cooling the reaction mixture was treated with acetone (2 mL) and the resulting yellow precipitate filtered off and washed with 2:1 EtOAc:Me2CO to provide the target compound (6.496 g, 24.86 mmol, 77% yield).
Reaction SMILES: C(OC(N1[CH2:12][CH2:11][CH:10]([NH:13][C:14]([C:16]2[S:17][CH:18]=[CH:19][C:20]=2[NH:21][C:22]2[CH:27]=[CH:26][N:25]=[C:24]3[NH:28][CH:29]=[CH:30][C:23]=23)=[O:15])C1)=O)(C)(C)C.[F:31][C:32]([F:43])([F:42])[C:33]1[CH:34]=C(CCN)[CH:36]=[CH:37][CH:38]=1>>[F:31][C:32]([F:43])([F:42])[C:33]1[CH:34]=[C:12]([CH2:11][CH2:10][NH:13][C:14]([C:16]2[S:17][CH:18]=[CH:19][C:20]=2[NH:21][C:22]2[CH:27]=[CH:26][N:25]=[C:24]3[NH:28][CH:29]=[CH:30][C:23]=23)=[O:15])[CH:36]=[CH:37][CH:38]=1
Reactant: CC(C)(C)OC(=O)N1CCC(NC(=O)c2sccc2Nc2ccnc3[nH]ccc23)C1
Reactant: NCCc1cccc(C(F)(F)F)c1
Product: O=C(NCCc1cccc(C(F)(F)F)c1)c1sccc1Nc1ccnc2[nH]ccc12

Procedure:
This compound was prepared in an analogous manner as 3-{[3-(1H-Pyrrolo[2,3-b]pyridin-4-ylamino)-thiophene-2-carbonyl]-amino}-pyrrolidine-1-carboxylic acid tert-butyl ester using 2-(3-trifluoromethylphenyl)ethylamine instead of 1-BOC-3-aminopyrrolidine. LCMS (ESI) 431 (M+H) 1H NMR (400 MHz, DMSO-d6) δ ppm 11.53 (1H, br. s.) 10.28 (1H, s) 8.20 (1H, t, J=5.56 Hz) 8.02 (1H, d, J=5.27 Hz) 7.77 (1H, d, J=5.47 Hz) 7.60 (1H, s) 7.44-7.56 (4H, m) 7.31 (1H, dd, J=3.32, 2.54 Hz) 6.82 (1H, d, J=5.47 Hz) 6.42 (1H, dd, J=3.42, 1.85 Hz) 3.47-3.56 (2H, m) 2.94 (2H, t, J=7.03 Hz)
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[C:5](C)[CH:4]=[C:3]([CH3:8])C=1[Mg]Br.Cl[C:13]1[CH:18]=CC=[CH:15][CH:14]=1.C(C(C(C([O-])=O)O)O)([O-])=O.[K+].[Na+]>C1COCC1>[CH3:18][CH2:13][CH2:14][CH2:15][CH2:11][CH2:1][CH2:6][CH2:5][CH2:4][CH2:3][CH3:8]
Reactant: Cc1cc(C)c([Mg]Br)c(C)c1
Reactant: Clc1ccccc1
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [K+]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCCCCCCCC
Reaction time: 10 h
Yield: 20 %

Procedure:
THF (0.10 mL) was added to rinse the internal wall of the reaction vessel. After 10 hours, a THF solution of mesitylmagnesium bromide (1.02 mL, 1.18 M, 1.2 mmol) was added to the mixture at 0° C., and the solvent was removed under reduced pressure. The obtained viscous liquid was dissolved in toluene (1.0 ml), and chlorobenzene (112.6 mg, 1.0 mmol) was added at 0° C. The reaction was performed at 120° C. for 24 hours. After cooled to the ambient temperature, 2.0 mL of saturated sodium potassium tartrate aqueous solution was added to the reaction mixture. The water layer was extracted five times using Et2O. The total organic extract was filtrated by Florisil pad (100-200 mesh, Nacalai Tesque, Inc.). As the internal standard, gas chromatographic analysis was performed using undecane (42.2 μL, 0.2 mmol) (yield=93%). After removing the solvent under reduced pressure, the crude product was purified by GPC, thereby obtaining the above compound, which was a colorless liquid (0.174 g, yield=89%, purity=>99% (GC analysis)).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([C:12]([F:15])([F:14])[F:13])=[C:6]2C(O)=O)#[N:2].O>CN1C(=O)CCC1>[F:15][C:12]([F:13])([F:14])[C:7]1[NH:8][C:9]2[C:5]([CH:6]=1)=[CH:4][C:3]([C:1]#[N:2])=[CH:11][CH:10]=2
Reactant: N#Cc1ccc2[nH]c(C(F)(F)F)c(C(=O)O)c2c1
Solvent: CN1CCCC1=O
Solvent: O
Product: N#Cc1ccc2[nH]c(C(F)(F)F)cc2c1
Temperature: 135 °C
Reaction time: 0.67 h
Yield: 82.2 %

Procedure:
5-cyano-2-(trifluoromethyl)-1H-indole-3-carboxylic acid (Intermediate 13, 2.09 g) was dissolved in NMP (10 mL) and H2O (1 mL) was then added. The mixture was heated to 130-140° C. overnight under nitrogen. The solution was cooled to room temperature and H2O (30 mL) was added and the solution stirred for 40 min. and then filtered. The cake was washed with H2O. The product is then dried under vacuum at 40° C. to give the title compound (1.42 g);
Reaction SMILES: C([O:5][C:6](=[O:37])[CH2:7][CH:8]([NH:15][C:16]([C:18]1[S:19][C:20]([C:23](=[O:36])[NH:24][CH2:25][CH2:26][CH2:27][NH:28]C(OC(C)(C)C)=O)=[CH:21][CH:22]=1)=[O:17])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(C)(C)C.[C:38]([OH:44])([C:40]([F:43])([F:42])[F:41])=[O:39]>ClCCl>[F:41][C:40]([F:43])([F:42])[C:38]([OH:44])=[O:39].[NH2:28][CH2:27][CH2:26][CH2:25][NH:24][C:23]([C:20]1[S:19][C:18]([C:16]([NH:15][CH:8]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:7][C:6]([OH:37])=[O:5])=[O:17])=[CH:22][CH:21]=1)=[O:36]
Reactant: CC(C)(C)OC(=O)CC(NC(=O)c1ccc(C(=O)NCCCNC(=O)OC(C)(C)C)s1)c1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NCCCNC(=O)c1ccc(C(=O)NC(CC(=O)O)c2ccccc2)s1
Temperature: 25 °C

Procedure:
With continued reference to Scheme G, preparation of compound VII was carried out using the procedure described for compound III. Compound VI: 3-{[5-(3-tert-Butoxycarbonylamino-propylcarbamoyl)-thiophene-2-carbonyl]-amino}-3-phenyl-propionic acid tert-butyl ester (200 mg, 0.704 mmol) was dissolved in 4.0 ml of anhydrous dichloromethane and 4.0 ml of anhydrous TFA. This reaction mixture was left stirring over night at room temperature. The solvents were evaporated under reduced pressure and the resulting residue was dissolved in anhydrous methanol (smallest amount possible). Diethyl ether was then added to precipitate the desired product, the supernatant was discarded and the solid washed with ether again then dried under reduced pressure to give 156 mg of the desired product as a white powder (Compound VII). 1H NMR (400 Mhz, DMSO-d6) 1.75 (m, 2H), 2.9 (m, 4H), 3.3 (m, 2H), 7.2-7.4 (m, 5H), 7.4 7.9 (bs, 3H), 7.65 (d, 1H), 7.8 (d, 1H), 8.75 (t, 1H), 9.05 (d, 1H).
Reaction SMILES: COCCOCCOCCOC.[BH4-].[Na+].[C:15]([CH2:17][O:18][C:19]1[C:26]([CH3:27])=[CH:25][CH:24]=[CH:23][C:20]=1[CH:21]=[O:22])#[N:16]>C1COCC1>[OH:22][CH2:21][C:20]1[CH:23]=[CH:24][CH:25]=[C:26]([CH3:27])[C:19]=1[O:18][CH2:17][C:15]#[N:16]
Reactant: Cc1cccc(C=O)c1OCC#N
Agent: [BH4-]
Agent: [Na+]
Solvent: COCCOCCOCCOC
Solvent: C1CCOC1
Product: Cc1cccc(CO)c1OCC#N
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A 2M triglyme solution of sodium borohydride (16.0 mL, 32.1 mmoles) is slowly added to a cooled (−78° C.) solution of 2-cyanomethoxy-3-methylbenzaldehyde (11.25 g, 64.2 mmoles, example 22) in THF (180 mL). After stirring for one hour, the reaction is warmed to 0° C. for two hours, then quenched with 2N HCl (16.8 mL) and diluted with ether. The organic layer is isolated and washed with twice with distilled water and brine, then dried over MgSO4. The organic solution is concentrated to give the title compound as a yellow oil.
Reaction SMILES: [Br:1][C:2]1[C:3]([F:16])=[CH:4][CH:5]=[C:6]2[C:11]=1[NH:10][C:9](=O)[N:8]([CH2:13][CH3:14])[C:7]2=[O:15].P(Cl)(Cl)([Cl:19])=O.CCN(C(C)C)C(C)C.[OH-].[Na+]>O>[Br:1][C:2]1[C:3]([F:16])=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([Cl:19])[N:8]([CH2:13][CH3:14])[C:7]2=[O:15]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCn1c(=O)[nH]c2c(Br)c(F)ccc2c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CCn1c(Cl)nc2c(Br)c(F)ccc2c1=O
Temperature: 25 °C
Yield: 98.3 %

Procedure:
A solution of 8-bromo-3-ethyl-7-fluoroquinazoline-2,4(1H,3H)-dione (512b, 2.20 g, 7.66 mmol), phosphorous oxychloride (Acros Organics, Geel, Belgium; 3.57 mL, 38.3 mmol), and DIPEA (5.34 mL, 30.6 mmol) was heated over a 130° C. oil bath for 4.5 h. The reaction mixture was then cooled to RT and poured onto ice, and the resulting mixture was diluted with water (250 mL) to provide a brown suspension. 10 N aqueous NaOH was added to the vigorously stirred suspension (maintaining the reaction mixture at 0° C.) until a pH of 10 was achieved. The precipitated solid was collected by vacuum filtration, washed with water (3×20 mL), and dried in vacuo to provide 8-bromo-2-chloro-3-ethyl-7-fluoroquinazolin-4(3H)-one (2.301 g, 7.53 mmol, 98% yield) as a tan solid. 1H NMR (400 MHz, CDCl3) δ ppm 8.22 (1H, dd, J=8.9, 5.8 Hz), 7.23-7.29 (1H, m), 4.37 (2H, q, J=7.1 Hz), 1.41 (3H, t, J=7.0 Hz). 19F NMR (376 MHz, CDCl3) δ ppm −93.38 (1F, s). m/z (ESI, +ve) 304.7/306.8/308.7 (M+H)+.
Reaction SMILES: [CH3:1][O:2][CH:3]1[CH:7]([C:8]#[C:9][Sn](CCCC)(CCCC)CCCC)[CH2:6][CH:5]([O:23][CH3:24])[O:4]1.I[C:26]1[CH:33]=[CH:32][C:29]([C:30]#[N:31])=[CH:28][CH:27]=1>C1(C)C=CC=CC=1.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C:30]([C:29]1[CH:32]=[CH:33][C:26]([C:9]#[C:8][CH:7]2[CH2:6][CH:5]([O:23][CH3:24])[O:4][CH:3]2[O:2][CH3:1])=[CH:27][CH:28]=1)#[N:31]
Reactant: N#Cc1ccc(I)cc1
Reactant: CCCC[Sn](C#CC1CC(OC)OC1OC)(CCCC)CCCC
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: COC1CC(C#Cc2ccc(C#N)cc2)C(OC)O1
Temperature: 100 °C
Reaction time: 5.5 h
Yield: 102.3 %

Procedure:
A mixture of 2,5-dimethoxy-3-(2-tributylstannylethynyl)-tetrahydrofuran (1.86 g, 4.18 mmol), 4-iodobenzonitrile (1.15 g, 5.02 mmol), and tetrakis(triphenylphosphine) palladium(0) (145 mg, 0.125 mmol) in toluene (25 mL) was heated at 100° C. After 5.5 hours, the resultant red solution was allowed to cool, and the solvent was removed under reduced pressure. Flash column chromatography twice with 10% EtOAc/hex provided 1.10 g (100%) of 3-[2-(4-cyanophenyl)-ethynyl]-2,5-dimethoxy-tetrahydrofuran as an orange oil. A mixture of diastereomers was observed by 1H NMR, which was used without further purification. 1H NMR (CDCl3): 3.12 (ddd, J=2.8, 6.6, 9.0 Hz), 2.57 (ddd, J=5.6, 9.3, 13.4 Hz), 2.08 (dd, J=2.5, 4.7 Hz), 2.04 (dd, J=3.1, 4.3 Hz). IR: 2227, 1603, 1216, 1102, 1012, 841 cm−1. Anal. Calculated for C15H15NO3.0.1EtOAc: C, 69.51; H, 5.98; N, 5.26. Found: C, 69.52; H, 5.76; N, 5.32.
Reaction SMILES: F[B-](F)(F)F.[CH:6]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH:15]([CH3:17])[CH3:16])[C:10]=1[NH+:18]1[CH2:22][CH2:21][N:20]([C:23]2[C:28]([CH:29]([CH3:31])[CH3:30])=[CH:27][CH:26]=[CH:25][C:24]=2[CH:32]([CH3:34])[CH3:33])[CH2:19]1)([CH3:8])[CH3:7].[O-:35][CH2:36]C.[Na+].FC(F)(F)C1C=CC=C(C(F)(F)F)C=1>CO>[CH3:36][O:35][CH:19]1[N:18]([C:10]2[C:11]([CH:15]([CH3:17])[CH3:16])=[CH:12][CH:13]=[CH:14][C:9]=2[CH:6]([CH3:8])[CH3:7])[CH2:22][CH2:21][N:20]1[C:23]1[C:24]([CH:32]([CH3:34])[CH3:33])=[CH:25][CH:26]=[CH:27][C:28]=1[CH:29]([CH3:31])[CH3:30]
Reactant: CC[O-]
Reactant: CC(C)c1cccc(C(C)C)c1N1CC[NH+](c2c(C(C)C)cccc2C(C)C)C1
Agent: FC(F)(F)c1cccc(C(F)(F)F)c1
Agent: F[B-](F)(F)F
Agent: [Na+]
Solvent: CO
Product: COC1N(c2c(C(C)C)cccc2C(C)C)CCN1c1c(C(C)C)cccc1C(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 97 %

Procedure:
A 50 mL flask replaced with nitrogen was charged with 500 mg of 1,3-bis[(2,6-diisopropyl)phenyl]imidazolinium tetrafluoroborate and 3 g of methanol. To the resulting mixture, 1.4 mL of a methanol solution of 1 M sodium ethoxide was added dropwise at room temperature over 30 minutes. The resulting mixture was stirred at room temperature for 2 hours and then concentrated. To the residue thus obtained, 5 g of 1,3-bis(trifluoromethyl)benzene was added and then the precipitated solid was removed by filtration. The filtrate was concentrated to obtain 430 mg of 2-methoxy-1,3-bis[(2,6-diisopropyl)phenyl]imidazolidine as a pale yellow crystal, yield: 97%.
Reaction SMILES: C(N1CCN(CC(NC2C=C(C=CC=2)C(NCCC(O)=O)=O)=O)CC1)(=N)N.[C:28]([N:38]1[CH2:43][CH2:42][N:41]([CH:44]([C:69](=[NH:71])[NH2:70])[C:45](NC2C=C(C=CC=2)C(NCCC(OCC2C=CC=CC=2)=O)=O)=[O:46])[CH2:40][CH2:39]1)([O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:29].N1(CC([O:81][C:82]([CH3:85])([CH3:84])[CH3:83])=O)CCNCC1.C(NC(=N)SC)(OCC1C=CC=CC=1)=O>>[C:28]([N:38]1[CH2:39][CH2:40][N:41]([CH:44]([C:69](=[NH:71])[NH2:70])[C:45]([O:81][C:82]([CH3:85])([CH3:84])[CH3:83])=[O:46])[CH2:42][CH2:43]1)([O:30][CH2:31][C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)=[O:29]
Reactant: CC(C)(C)OC(=O)CN1CCNCC1
Reactant: N=C(N)C(C(=O)Nc1cccc(C(=O)NCCC(=O)OCc2ccccc2)c1)N1CCN(C(=O)OCc2ccccc2)CC1
Agent: CSC(=N)NC(=O)OCc1ccccc1
Agent: N=C(N)N1CCN(CC(=O)Nc2cccc(C(=O)NCCC(=O)O)c2)CC1
Product: CC(C)(C)OC(=O)C(C(=N)N)N1CCN(C(=O)OCc2ccccc2)CC1

Procedure:
3-(3-(4-amidinopiperazin-1-ylacetamido)benzamido)propionic acid, m.p. 270° (decomposition), from benzyl 3-(3-(4-CBZ-amidinopiperazin-1-ylacetamido)benzamido)propionate (FAB 601; obtainable by reacting tert-butyl piperazin-1-ylacetate with N-CBZ-S-methylisothiourea to give tert-butyl 4-CBZ-amidinopiperazin-1-ylacetate, cleaving the tert-butyl group with 4 N HCl in dioxane and condensing the resulting 4-CBZ-amidinopiperazin-1-ylacetic acid with benzyl 3-(3-aminobenzamido)propionate);
Reaction SMILES: C([Li])CCC.C[Si](C)(C)[C:8]1[S:9][CH:10]=[CH:11][N:12]=1.[C:15]([C:18]1[CH:22]=[CH:21][S:20][CH:19]=1)(=[O:17])[CH3:16].C(=O)([O-])O.[Na+]>C(OCC)C>[S:9]1[C:10]([C:15]([C:18]2[CH:22]=[CH:21][S:20][CH:19]=2)([OH:17])[CH3:16])=[CH:11][N:12]=[CH:8]1
Reactant: CC(=O)c1ccsc1
Reactant: C[Si](C)(C)c1nccs1
Agent: O=C([O-])O
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CCOCC
Product: CC(O)(c1ccsc1)c1cncs1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
n-Butyllithium (2.5M solution in hexane, 5.6 ml) in diethylether (25 ml) was stirred at -70° C. under a nitrogen atmosphere and 2-trimethylsilylthiazole (2 g) in diethylether (25 ml) was added dropwise. After 30 minutes 3-acetylthiophene (1.93 g) in diethylether (25 ml) was added dropwise. After a further 45 minutes the mixture was allowed to warm to room temperature and then left to stir for a further 1 hour. Saturated aqueous sodium hydrogen carbonate was added and the organic layer was separated. The aqueous layer was extracted with diethylether. The organic layers were combined, washed, dried and evaporated and the residue was purified by flash chromatography to give the title compound as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:26]=[CH:27][C:28]=1[Cl:29])[C:5]([NH:7][C:8]1[CH:9]=[N:10][C:11]([O:14][C:15]2[CH:23]=[CH:22][CH:21]=[C:20]3[C:16]=2[CH2:17][CH2:18][C:19]3=[N:24][OH:25])=[CH:12][CH:13]=1)=[O:6].N1C=CC=CC=1.[C:36](OC(=O)C)(=[O:38])[CH3:37]>O1CCCC1>[C:36]([O:25][N:24]=[C:19]1[C:20]2[C:16](=[C:15]([O:14][C:11]3[N:10]=[CH:9][C:8]([NH:7][C:5](=[O:6])[C:4]4[CH:26]=[CH:27][C:28]([Cl:29])=[C:2]([Cl:1])[CH:3]=4)=[CH:13][CH:12]=3)[CH:23]=[CH:22][CH:21]=2)[CH2:17][CH2:18]1)(=[O:38])[CH3:37]
Reactant: O=C(Nc1ccc(Oc2cccc3c2CCC3=NO)nc1)c1ccc(Cl)c(Cl)c1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CC(=O)ON=C1CCc2c(Oc3ccc(NC(=O)c4ccc(Cl)c(Cl)c4)cn3)cccc21
Temperature: 25 °C
Reaction time: 17 h

Procedure:
650 mg of N1-{6-[(1-hydroxyimino-2,3-dihydro-1H-inden-4-yl)oxy]-3-pyridinyl}benzamide obtained in Example 47 was dissolved in 10 ml of tetrahydrofuran. To the resulting reaction solution, 1.2 ml of pyridine and 0.7 ml of acetic anhydride were added and the mixture was stirred at room temperature. After 17 hours, the reaction solution was distilled off under reduced pressure and 15 ml of ethyl acetate and 15 ml of water were added to the resulting residue. Then, the deposited powder was isolated by filtration and washed in turn with water and ethyl acetate to obtain the titled compound (310 mg).
Reaction SMILES: [NH2:1][CH:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3]1.[C:11](O)(=[O:13])C.C(OC=O)=O.O>O1CCCC1>[CH:11]([NH:1][CH:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3]1)=[O:13]
Reactant: NC1Cc2ccccc2C1
Reactant: CC(=O)O
Agent: O=COC=O
Solvent: O
Solvent: C1CCOC1
Product: O=CNC1Cc2ccccc2C1

Procedure:
To a solution of 2-aminoindan (19.95 g) in tetrahydrofuran is added an solution of 2M acetic acid-formic acid anhydride in tetrahydrofuran under ice cooling, and the mixture is reacted at room temperature. To the reaction mixture is added water, and then, the solvent is distilled off, and the residue is extracted with ethyl acetate. After distilling off the solvent, the residue is recrystallized from ethyl acetate - n-hexane to give 2-formylaminoindan (19.02 g).