Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:11])=[C:6]([N:8]=[C:9]=[S:10])[CH:7]=1.[NH2:12][C:13]1[S:14][C:15]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:19]=[CH:18][C:16]=2[N:17]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:11])=[C:6]([NH:8][C:9]([NH:12][C:13]2[S:14][C:15]3[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[CH:19]=[CH:18][C:16]=3[N:17]=2)=[S:10])[CH:7]=1
Reactant: Cc1ccc(Cl)cc1N=C=S
Reactant: Nc1nc2ccc3ccccc3c2s1
Product: Cc1ccc(Cl)cc1NC(=S)Nc1nc2ccc3ccccc3c2s1
Yield: 21.9 %

Procedure:
Prepared using Method A from 5.0 g (27.2 mmol) of 5-chloro-2-methyl-phenyl isothiocyanate and 5.0 g (25 mmol) of 2-amino-naptho[2,1-d]thiazole to give 2.1 g of title compound as an off-white solid, (21% yield).
Reaction SMILES: [CH2:1]([N:3]([CH2:17][CH3:18])[C:4]1[N:9]=[C:8]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[CH:7]=[C:6](Cl)[N:5]=1)[CH3:2].[CH3:19][N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1>O>[CH2:1]([N:3]([CH2:17][CH3:18])[C:4]1[N:9]=[C:8]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[CH:7]=[C:6]([N:23]2[CH2:24][CH2:25][N:20]([CH3:19])[CH2:21][CH2:22]2)[N:5]=1)[CH3:2]
Reactant: CCN(CC)c1nc(Cl)cc(N2CCNCC2)n1
Reactant: CN1CCNCC1
Solvent: O
Product: CCN(CC)c1nc(N2CCNCC2)cc(N2CCN(C)CC2)n1

Procedure:
2-Diethylamino-4,6-dichloropyrimidine (10 g) is reacted with piperazine (14.45 g) in ethanol (200 ml) at reflux for 2 hr. The mixture is concentrated and the product isolated by silica gel chromatography giving 2-diethylamino-4-piperazino-6-chloropyrimidine. The 2-diethylamino-4-piperazino-6-chloropyrimidine (8 g) and N-methylpiperazine (8 g) is heated neat at 70° for 16 hr. Then water (2.5 ml) is added and the mixture is heated at 100° for 50 hr. The mixture is chromatographed on silica gel, the appropriate fractions are pooled and concentrated to give the title compound, NMR (CDCl3) 1.15, 2.80, 2.85, 2.90, 3.30, 3.70 and 4.95 δ.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([S:15]([N:18]2[CH2:23][C@H:22]3[CH2:24][C:25]([CH3:27])([CH3:26])[C@@H:19]2[C:20](=[O:28])[O:21]3)(=[O:17])=[O:16])=[CH:11][CH:10]=1)C1C=CC=CC=1.[H][H]>[Pd].C(OCC)(=O)C.CO>[OH:8][C:9]1[CH:14]=[CH:13][C:12]([S:15]([N:18]2[CH2:23][C@H:22]3[CH2:24][C:25]([CH3:26])([CH3:27])[C@@H:19]2[C:20](=[O:28])[O:21]3)(=[O:17])=[O:16])=[CH:11][CH:10]=1
Reactant: CC1(C)C[C@@H]2CN(S(=O)(=O)c3ccc(OCc4ccccc4)cc3)[C@H]1C(=O)O2
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: CC1(C)C[C@@H]2CN(S(=O)(=O)c3ccc(O)cc3)[C@H]1C(=O)O2
Yield: 82.9 %

Procedure:
A mixture of (1R,4R)-5-(4-benzyloxy-benzenesulfonyl)-8,8-dimethyl-2-oxa-5-aza-bicyclo[2.2.2]octan-3-one (compound of formula XXXVII, 3.7 g, 9.3 mmol), 10% palladium on charcoal (0.8 g) and 470 ml of 1:1 ethyl acetate-methanol was stirred for about 1.5 hours under about 50 psi of hydrogen gas. The mixture was filtered through a pad of Celite®. Concentration of the filtrate afforded 2.4 g (1R,4R)-5-(4-hydroxy-benzenesulfonyl)-8,8-dimethyl-2-oxa-5-aza-bicyclo[2.2.2]octan-3-one (compound of formula XXXVIII) as a colorless solid.
Reaction SMILES: C[O:2][C:3](=[O:15])[CH:4]=[C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH3:14])[CH:8]=1)[CH3:6].[OH-].[Na+]>O.CO.C1COCC1>[CH3:14][O:13][C:9]1[CH:8]=[C:7]([C:5]([CH3:6])=[CH:4][C:3]([OH:15])=[O:2])[CH:12]=[CH:11][CH:10]=1
Reactant: COC(=O)C=C(C)c1cccc(OC)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: COc1cccc(C(C)=CC(=O)O)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 65.9 %

Procedure:
3-(3-Methoxy-phenyl)-but-2-enoic acid methyl ester (2 g, 7.9 mmol) and sodium hydroxide (0.78 g, 19.4 mmol) were dissolved in a mixture of water (50 ml), methanol (50 ml) and THF (50 ml). The mixture was stirred at ambient temperature for 16 hours and then concentrated under reduced pressure. The remaining aqueous solution was diluted with water and extracted with EtOAc twice. The aqueous was collected and acidified to pH 4 and extracted with EtOAc three times. The organics were combined, dried (magnesium sulphate) and concentrated in vacuo to give 3-(3-Methoxy-phenyl)-but-2-enoic acid as a white crystalline solid (1 g, 55%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:14]=[C:15]3[C:20](=[C:21]([CH2:23]O)[CH:22]=2)[O:19][C:18]([CH3:26])([CH3:25])[CH2:17][C:16]3([CH3:28])[CH3:27])=[CH:7][CH:6]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:49]N1C(=O)CCC1=O>ClCCl>[CH3:1][O:2][C:3](=[O:29])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:14]=[C:15]3[C:20](=[C:21]([CH2:23][Br:49])[CH:22]=2)[O:19][C:18]([CH3:26])([CH3:25])[CH2:17][C:16]3([CH3:28])[CH3:27])=[CH:7][CH:6]=1
Reactant: COC(=O)Cc1ccc(C#Cc2cc(CO)c3c(c2)C(C)(C)CC(C)(C)O3)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COC(=O)Cc1ccc(C#Cc2cc(CBr)c3c(c2)C(C)(C)CC(C)(C)O3)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.9 %

Procedure:
A stirred, cooled (ice bath) solution of {4-[8-hydroxymethyl-2,2,4,4-tetramethyl-chroman-6-ylethynyl]-phenyl}-acetic acid methyl ester (Compound 46, 0.53 g, 0.58 mmol) and triphenylphosphine (0.198 g, 0.75 mmol) in anhydrous dichloromethane (5 mL) was treated with N-bromo succinimide (0.134 g, 0.75 mmol) under argon and the resulting reaction mixture was allowed to warm to ambient temperature and stirred overnight. The reaction mixture was quenched with dilute, aqueous sodium bicarbonate solution and extracted with diethyl ether. The organic phase was washed with water and brine, dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to a residue that on flash column chromatography over silica gel (230-400 mesh) using 4-10% ethyl acetate in hexane as the eluent afforded the title compound (0.19 g, 80%) as a colorless oil.
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[Br:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([CH:30]([OH:37])[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[CH:25]=1>>[Br:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([C:30](=[O:37])[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[CH:25]=1
Reactant: CCCCCCC(O)c1cccc(Br)c1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Product: CCCCCCC(=O)c1cccc(Br)c1
Reaction time: 1 h
Yield: 78.2 %

Procedure:
Dess-Martin periodinane (4.40 g, 15% solution in methylene chloride, 1.56 mmol) was added to a solution of 1-bromo-3-(1-hydroxyhept-1-yl)benzene (0.39 g, 1.42 mmol, from Aldehyde 75, Step A). After 1 h, the reaction was quenched by the addition of 1N sodium hydroxide (20 mL). The aqueous layer was separated, washed with methylene chloride (20 mL) and the organic layers combined, dried over magnesium sulfate and concentrated in vacuo. Silica gel chromatography eluting with 5% ethyl acetate/hexane gave 0.30 g (1.11 mmol, 78%) of product: 1H NMR (500 MHz) δ 8.08 (t, J=1.7 Hz, 1H), 7.87 (d, J=7.7 Hz, 1H), 7.68 (d, J=8.0 Hz, 1H), 7.34 (t, J=7.9 Hz, 1H), 2.93 (t, J=7.4 Hz, 2H), 1.68-1.76 (m, 2H), 1.28-1.40 (m, 6H), 0.89 (t, J=7.0 Hz, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][N:7]2[C:11]3=[N:12][C:13]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][CH:15]=[C:10]3[N:9]=[C:8]2[CH3:20])=[C:4]([Cl:23])[CH:3]=1.N1C=CC=CC=1.[C:30]1([S:36](Cl)(=[O:38])=[O:37])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.O>ClCCl>[C:30]1([S:36]([NH:1][C:2]2[CH:22]=[CH:21][C:5]([CH2:6][N:7]3[C:11]4=[N:12][C:13]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][CH:15]=[C:10]4[N:9]=[C:8]3[CH3:20])=[C:4]([Cl:23])[CH:3]=2)(=[O:38])=[O:37])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: COC(=O)c1ccc2nc(C)n(Cc3ccc(N)cc3Cl)c2n1
Solvent: ClCCl
Solvent: O
Solvent: c1ccncc1
Product: COC(=O)c1ccc2nc(C)n(Cc3ccc(NS(=O)(=O)c4ccccc4)cc3Cl)c2n1
Temperature: 25 °C
Reaction time: 12 h
Yield: 74.8 %

Procedure:
To a solution of methyl 3-(4-amino-2-chlorobenzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylate (200 mg) in dichloromethane (2 ml) was added pyridine (95.7 mg). Benzenesulfonyl chloride (117 mg) was added under ice-cooling and the mixture was stirred at room temperature for 12 hr. Water was added to the reaction mixture and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. Methanol was added to the residue for crystallization, and the crystals were collected by filtration, dried under reduced pressure to give the objective compound (213 mg) as colorless crystals.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.[N:8]#[C:9][NH2:10].[ClH:11]>>[ClH:11].[ClH:11].[N:4]1[CH:5]=[CH:6][CH:7]=[C:2]([NH:1][C:9]([NH2:10])=[NH:8])[CH:3]=1
Reactant: Nc1cccnc1
Reactant: N#CN
Agent: Cl
Product: N=C(N)Nc1cccnc1

Procedure:
3-Aminopyridine (38.96 g, 413.96 mmol) and cyanamide (21.40 g, 509.2 mmol) in 12N hydrochloric acid (271 mL) were stirred at 140-150° C. for 4 hours. Concentration under reduced pressure provided a heavy syrup which was purified by recrystalization from 1:1 isopropanol:diethyl ether (500 mL) to provide 60.2 g of the desired product as a white solid.
Reaction SMILES: [C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH2:7]Br)=[CH:5][CH:4]=1)#[N:2].C([O-])([O-])=O.[K+].[K+].[C:17]([O:21][C:22](=[O:47])[CH2:23][N:24]1[C:28]2[CH:29]=[CH:30][C:31]([NH:33][S:34]([C:37]3[CH:42]=[CH:41][C:40]([F:43])=[CH:39][CH:38]=3)(=[O:36])=[O:35])=[CH:32][C:27]=2[N:26]=[C:25]1[CH2:44][CH2:45][CH3:46])([CH3:20])([CH3:19])[CH3:18]>CC#N.CCOC(C)=O.O>[C:17]([O:21][C:22](=[O:47])[CH2:23][N:24]1[C:28]2[CH:29]=[CH:30][C:31]([N:33]([CH2:7][C:6]3[CH:9]=[CH:10][C:3]([C:1]#[N:2])=[CH:4][CH:5]=3)[S:34]([C:37]3[CH:38]=[CH:39][C:40]([F:43])=[CH:41][CH:42]=3)(=[O:35])=[O:36])=[CH:32][C:27]=2[N:26]=[C:25]1[CH2:44][CH2:45][CH3:46])([CH3:20])([CH3:19])[CH3:18]
Reactant: CCCc1nc2cc(NS(=O)(=O)c3ccc(F)cc3)ccc2n1CC(=O)OC(C)(C)C
Reactant: N#Cc1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: O
Product: CCCc1nc2cc(N(Cc3ccc(C#N)cc3)S(=O)(=O)c3ccc(F)cc3)ccc2n1CC(=O)OC(C)(C)C
Temperature: 80 °C
Reaction time: 8 h

Procedure:
4-Cyanobenzyl bromide (0.27 mmol) and K2CO3 (63 mg, 0.45 mmol) were added to a solution of [5-(4-fluoro-benzenesulfonylamino)-2-propyl-benzoimidazol-1-yl]-acetic acid tert-butyl ester (40 mg, 0.09 mmol) in CH3CN (1 mL), and stirred overnight at 80° C. The reaction mixture was diluted with EtOAc and H2O, and then filtered through an Extrelut column. The column was washed with EtOAc, and the filtrate was concentrated. The crude product was carried onto the next reaction without any further purification or characterization.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:9])[C:5]([NH2:8])=[N:6][CH:7]=1.[CH:10]([CH:12]=O)=O>CO>[Br:1][C:2]1[CH:7]=[N:6][C:5]2=[N:8][CH:10]=[CH:12][N:9]=[C:4]2[CH:3]=1
Reactant: O=CC=O
Reactant: Nc1cc(Br)cnc1N
Solvent: CO
Product: Brc1cnc2nccnc2c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 95 %

Procedure:
5-Bromo-pyridine-2,3-diamine (6.5 g, 35 mmol) was dissolved in MeOH (100 ml). Glyoxal (15 ml of a 40% solution). The solution was stirred for 18 h at room temperature. The solvent was removed, and the crude material was partitioned between ethyl acetate and brine. The ethyl acetate was washed two additional times with brine, the organic layer was dried using MgSO4, and the solvent as removed to yield the title product (6.9 g (95%),33 mmol). 1H NMR (DMSO-d6): δ=9.28 (d, 1H, J=2.5 Hz), 9.19 (d, 1H, J=1.7 Hz), 9.10 (d,1H, J=1.7 Hz), 8.94(d,1H, J=2.5 Hz). Calculated mass=210.03, [M+H]+=212.
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1)[CH3:2].Cl[C:10]1[N:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[N:17]=2)=[CH:12][CH:11]=1>>[CH2:1]([N:3]1[CH2:8][CH2:7][N:6]([C:10]2[N:15]=[CH:14][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[N:17]=3)=[CH:12][CH:11]=2)[CH2:5][CH2:4]1)[CH3:2]
Reactant: CCN1CCNCC1
Reactant: Cc1cccc(-c2ccc(Cl)nc2)n1
Product: CCN1CCN(c2ccc(-c3cccc(C)n3)cn2)CC1

Procedure:
The title compound was prepared by a similar procedure to that described in Example 1, starting from 1-ethyl-piperazine and 6′-chloro-6-methyl-[2,3′]bipyridinyl.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[NH2:5][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:15]=1[CH:14]=[N:13][C:12]([NH:16][C:17]1[N:18]=[CH:19][C:20]([C:23]#[N:24])=[N:21][CH:22]=1)=[CH:11]2.C(N(C(C)C)CC)(C)C>ClCCCl>[C:23]([C:20]1[N:21]=[CH:22][C:17]([NH:16][C:12]2[N:13]=[CH:14][C:15]3[C:10]([CH:11]=2)=[CH:9][CH:8]=[CH:7][C:6]=3[NH:5][C:1](=[O:3])[CH3:2])=[N:18][CH:19]=1)#[N:24]
Reactant: CC(=O)Cl
Reactant: N#Cc1cnc(Nc2cc3cccc(N)c3cn2)cn1
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)Nc1cccc2cc(Nc3cnc(C#N)cn3)ncc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 31.4 %

Procedure:
Acetyl chloride (13 mg, 0.16 mmol) was added to a solution of 5-(8-aminoisoquinolin-3-ylamino)pyrazine-2-carbonitrile (36 mg, 0.14 mmol) and diisopropylethylamine (39 mg, 0.30 mmol) in DCE (1.5 mL). The reaction mixture stirred at room temperature for 16 hours and another portion of acetyl chloride (6.5 mg, 0.08 mmol) was added. Stirring was continued for a further 24 hours. The reaction mixture was washed once with water and the organic phase was dried (Na2SO4) and concentrated to dryness. Preparative HPLC gave N-(3-(5-cyanopyrazin-2-ylamino)isoquinolin-8-yl)acetamide (13.4 mg, 0.044 mmol, 32%). 1H NMR (d6-DMSO, 400 MHz) δ 11.05 (br s, 1H), 10.20 (s, 1H), 9.36 (s, 1H), 8.82 (d, 1H, J=1.2 Hz), 8.72 (d, 1H, J=1.2 Hz), 8.48 (s, 1H), 7.65-7.75 (m, 3H), 2.22 (s, 3H). LC-MS (2) Rt=1.96 min; m/z (ESI+) 305 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[CH:12][C:5](/[CH:6]=[CH:7]/[C:8]([O:10][CH3:11])=[O:9])=[C:4]([NH:14]S(C2C=CC=CC=2)(=O)=O)[CH:3]=1.[CH:24]1([C:27]([CH2:29]Br)=[O:28])[CH2:26][CH2:25]1>>[CH3:11][O:10][C:8](=[O:9])[CH2:7][C:6]1[C:5]2[C:4](=[CH:3][C:2]([Cl:1])=[CH:13][CH:12]=2)[NH:14][C:29]=1[C:27]([CH:24]1[CH2:26][CH2:25]1)=[O:28]
Reactant: O=C(CBr)C1CC1
Reactant: COC(=O)/C=C/c1ccc(Cl)cc1NS(=O)(=O)c1ccccc1
Product: COC(=O)Cc1c(C(=O)C2CC2)[nH]c2cc(Cl)ccc12

Procedure:
The title compound was prepared according to the procedure described in Example 57 from methyl trans-4-chloro-2-(phenylsulfonylamino)cinnamate (step 1 of Example 8, Method A) and bromomethyl cyclopropyl ketone*.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].Cl.[CH2:12](O)[CH3:13]>>[NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([O:9][CH2:12][CH3:13])=[O:8]
Reactant: Nc1cncc(C(=O)O)c1
Reactant: CCO
Agent: Cl
Product: CCOC(=O)c1cncc(N)c1

Procedure:
5-Aminonicotinic acid (2.2 g) (Bachman and Micucci, J. Amer. Chem. Soc. 70 (1948) 2381) in ethanol (20 ml) was ice-cooled, saturated with HCl gas and refluxed 4 hours. The mixture was concentrated to low volume and partitioned between EtOAc (100 ml) and saturated NaHCO3 solution (100 ml). The organic phase was washed with further aqueous NaHCO3, dried and evaporated to leave the title compound as a white solid (1.34 g). M.S. (+ve ion chemical ionisation) m/z 167 (MH+,100%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:23][CH2:24][CH2:25][CH2:26][O:27][Si](C(C)(C)C)(C)C)=[C:17]([N+:20]([O-:22])=[O:21])[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[F:8].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C(Cl)Cl.CO>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:23][CH2:24][CH2:25][CH2:26][OH:27])=[C:17]([N+:20]([O-:22])=[O:21])[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CC(C)(C)[Si](C)(C)OCCCOc1cc2ncnc(Nc3ccc(F)c(Cl)c3)c2cc1[N+](=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CO
Product: O=[N+]([O-])c1cc2c(Nc3ccc(F)c(Cl)c3)ncnc2cc1OCCCO
Yield: 94 %

Procedure:
Prepared from 4-[(3-Chloro-4-fluorophenyl)amino]-7-{3-[(tert-butyl-dimethylsilyl)oxy]propyloxy}-6-nitroquinazoline by splitting off the protective silyl group with tetrabutyl ammonium fluoride in tetrahydrofuran. Yield: 94% of theory; Rf value: 0.61 (silica gel, methylene chloride/methanol/concentrated aqueous ammonia solution=90:10:0.1); mass spectrum (ESI−): m/z=391, 393 [M−H]−.
Reaction SMILES: CC(C)([O-])C.[K+].[NH:7]1[CH2:12][CH2:11][O:10][CH2:9][CH2:8]1.Br[C:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:16]([CH2:23][C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[C:26]([Cl:31])[CH:25]=2)[C:15]=1[C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33].O>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:31][C:26]1[CH:25]=[C:24]([CH:29]=[CH:28][C:27]=1[Cl:30])[CH2:23][N:16]1[C:17]2[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:14]([N:7]2[CH2:12][CH2:11][O:10][CH2:9][CH2:8]2)=[C:15]1[C:32]([O:34][C:35]([CH3:38])([CH3:36])[CH3:37])=[O:33]
Reactant: C1COCCN1
Reactant: CC(C)(C)OC(=O)c1c(Br)c2ccccc2n1Cc1ccc(Cl)c(Cl)c1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)c1c(N2CCOCC2)c2ccccc2n1Cc1ccc(Cl)c(Cl)c1
Temperature: 90 °C
Yield: 33 %

Procedure:
Pd2(dba)3 (114 mg), R-BINAP (69 mg), potassium t-butoxide (294 mg), and morpholine (0.209 ml) were added to a solution of t-butyl 3-bromo-N-(3,4-dichlorobenzyl)indole-2-carboxylate (1 g) in de-gassed toluene (6 ml), under an atmosphere of argon. The reaction was stirred and heated at 90° C. for 16 hours then poured into water (50 ml), extracted with ethyl acetate (3×50 ml), and the combined organic extracts were dried (MgSO4) and concentrated in vacuo. The residue was purified by column chromatography using 10% ethyl acetate:iso-hexane as eluent, to afford the product as a yellow oil (325 mg, 33%); NMR d (CD3SOCD3) 3.20 (t, 4H), 3.73 (t, 4H), 5.56 (s, 2H), 6.88 (d, 1H), 7.7 (t, 1H), 7.25 (m, 2H), 7.50 (m, 2H), 7.80 (d, 1H), M/z (+) 461 (MH+), 405.
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][C@@H:9]([CH2:23][C:24]1[CH:29]=[C:28]([F:30])[CH:27]=[C:26]([F:31])[CH:25]=1)[C@H:10]([OH:22])[CH2:11][NH:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=1.C(N(CC)CC)C.[CH3:39][C:40]1[CH:41]=[C:42]([C:49]([N:51]([CH2:55][CH2:56][CH3:57])[CH2:52][CH2:53][CH3:54])=[O:50])[CH:43]=[C:44]([CH:48]=1)[C:45](O)=[O:46].ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>CN(C=O)C>[F:31][C:26]1[CH:25]=[C:24]([CH:29]=[C:28]([F:30])[CH:27]=1)[CH2:23][C@H:9]([NH:8][C:45](=[O:46])[C:44]1[CH:48]=[C:40]([CH3:39])[CH:41]=[C:42]([C:49]([N:51]([CH2:52][CH2:53][CH3:54])[CH2:55][CH2:56][CH3:57])=[O:50])[CH:43]=1)[C@H:10]([OH:22])[CH2:11][NH:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=1
Reactant: CCCN(CCC)C(=O)c1cc(C)cc(C(=O)O)c1
Reactant: COc1cccc(CNC[C@@H](O)[C@@H](N)Cc2cc(F)cc(F)c2)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Product: CCCN(CCC)C(=O)c1cc(C)cc(C(=O)N[C@@H](Cc2cc(F)cc(F)c2)[C@H](O)CNCc2cccc(OC)c2)c1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
(2R,3S)-3-amino-4-(3,5-difluorophenyl)-1-[(3-methoxybenzyl)amino]-2-butanol trifluoroacetate salt (VIII, EXAMPLE 5) is dissolved in anhydrous DMF (3 mL) and cooled to 0 degrees C. Triethylamine (500 microliter, 3.6 mmol) and 5-methyl-N,N-dipropylisophthalamic acid (156 mg, 0.59 mmol) are added with stirring. The mixture is warmed to 20-25 degrees C. briefly to allow for complete dissolution of the carboxylic acid, before recooling to 0 degrees C. 1-Hydroxybenzotriazole (157 mg, 1.2 mmol) is added with stirring, followed by 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (229 mg, 1.2 mmol). The resulting mixture is stirred at 0 degrees C. for 5 minutes, then warmed to 20-25 degrees C. for 15 hours. The reaction mixture is then quenched with aqueous citric acid (10%), and the mixture extracted three times with ethyl acetate. The combined organic extracts are washed with saturated sodium bicarbonate, saline, dried over sodium sulfate, filtered and concentrated under reduced pressure to give the title compound in crude form. This material is purified by flash chromatography (2-10% methanol/methylene chloride gradient elution) to give purified title compound, MS (ES) MH+=582.3.
Reaction SMILES: P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:2].[Cl:15][C:16]1[CH:37]=[CH:36][C:19]2[O:20][C:21]3[CH:35]=[CH:34][CH:33]=[CH:32][C:22]=3[C@@H:23]3[C@H:28]([NH:29][CH:30]=O)[CH2:27][CH2:26][CH2:25][N:24]3[C:18]=2[CH:17]=1>O1CCOCC1>[Cl:15][C:16]1[CH:37]=[CH:36][C:19]2[O:20][C:21]3[CH:35]=[CH:34][CH:33]=[CH:32][C:22]=3[C@@H:23]3[C@H:28]([NH:29][CH:30]=[S:2])[CH2:27][CH2:26][CH2:25][N:24]3[C:18]=2[CH:17]=1
Reactant: O=CN[C@@H]1CCCN2c3cc(Cl)ccc3Oc3ccccc3[C@H]12
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Solvent: C1COCCO1
Product: S=CN[C@@H]1CCCN2c3cc(Cl)ccc3Oc3ccccc3[C@H]12
Yield: 81.2 %

Procedure:
Phosphorus pentasulfide (5 mg, 0.01 mmol) was added to trans-N-(7-chloro-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepin-1-yl)formamide (5 mg, 0.015 mmol) in dioxane. The resulting mixture was heated to reflux for 3 h. After evaporation under reduced pressure the crude compound was chromatographed on silica. Elution with toluene/ethyl acetate 85:15 gave trans-N-(7-chloro-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepin-1-yl)methanethioamide (2.8 mg, 51%). Data: (m/z)=345 (M+H)+.
Reaction SMILES: [CH:1]1[C:13]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[Li][CH2:15][CH2:16][CH2:17]C.ICCC>>[CH2:15]([CH:12]1[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:5]2[C:13]1=[CH:1][CH:2]=[CH:3][CH:4]=2)[CH2:16][CH3:17]
Reactant: c1ccc2c(c1)Cc1ccccc1-2
Reactant: [Li]CCCC
Solvent: CCCI
Product: CCCC1c2ccccc2-c2ccccc21

Procedure:
Fluorene (15.0 g, 90.4 mmol), n-BuLi (48.1 ml, 120 mmol, 2.5 M in hexane), RX=1-iodopropane (20.8 g, 122.3 mmol). 43 was isolated as a yellowish solid (18.6 g, quant.). The analytical data were identical to those found in the literature (A. Mathieu, Bull. Soc. Chim. Fr. 1971, 1526).
Reaction SMILES: C(OC(=O)[CH2:7][CH2:8][C:9]1[C:14](C)=[CH:13][C:12]([C:16](=[NH:19])[NH:17][OH:18])=[CH:11][C:10]=1C)(C)(C)C.[OH:22]CCC1C=CC(C#N)=CC=1>>[OH:18][NH:17][C:16](=[NH:19])[C:12]1[CH:13]=[CH:14][C:9]([CH2:8][CH2:7][OH:22])=[CH:10][CH:11]=1
Reactant: N#Cc1ccc(CCO)cc1
Reactant: Cc1cc(C(=N)NO)cc(C)c1CCC(=O)OC(C)(C)C
Product: N=C(NO)c1ccc(CCO)cc1

Procedure:
The title compound is prepared in analogy to 3-[4-(N-hydroxycarbamimidoyl)-2,6-dimethyl-phenyl]-propionic acid tert-butyl ester (step g) starting from 4-(2-hydroxy-ethyl)-benzonitrile; LC-MS: tR=0.50*min, [M+1]+=181.27.
Reaction SMILES: C([O:8][N:9]1[C:18](=[O:19])[C:17]2[C:12](=[CH:13][C:14]([N:21]3[CH2:25][CH2:24][CH2:23][CH2:22]3)=[C:15]([F:20])[CH:16]=2)[N:11]([CH:26]2[CH2:28][CH2:27]2)[C:10]1=[O:29])C1C=CC=CC=1.FC(F)(F)C([O-])=O.FC(F)(F)C([O-])=O.FC(F)(F)C([O-])=O.[B+3]>FC(F)(F)C(O)=O>[CH:26]1([N:11]2[C:12]3[C:17](=[CH:16][C:15]([F:20])=[C:14]([N:21]4[CH2:25][CH2:24][CH2:23][CH2:22]4)[CH:13]=3)[C:18](=[O:19])[N:9]([OH:8])[C:10]2=[O:29])[CH2:28][CH2:27]1
Reactant: O=c1c2cc(F)c(N3CCCC3)cc2n(C2CC2)c(=O)n1OCc1ccccc1
Agent: O=C([O-])C(F)(F)F
Agent: [B+3]
Solvent: O=C(O)C(F)(F)F
Product: O=c1c2cc(F)c(N3CCCC3)cc2n(C2CC2)c(=O)n1O
Reaction time: 2 h
Yield: 62.9 %

Procedure:
A solution of 3-benzyloxy-1-cyclopropyl-6-fluoro-7-pyrrolidin-1-yl-1H-quinazoline-2,4-dione (Example F-3, 0.15 g, 0.38 mmol) in trifluoroacetic acid (TFA, 3.0 mL) was reacted with a 1.0 M solution of boron tris(trifluoroacetate) (1.5 mL, 1.5 mmol, Angew. Chem, Internat. Ed., 1973;12:147) in TFA and allowed to stir for 2 hours. The mixture was then concentrated and the residue diluted in methanol and concentrated. This process was repeated two times. The residue was then triturated from diethyl ether/hexanes and filtered to provide 0.073 g of the title compound as solid, mp 248-250° C. (dec.).