Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[C:7]([C:8](=[O:12])[CH:9]([CH3:11])[CH3:10])=[CH:6][N:5]=[C:4]2[S:13][C:14]([C:17]3[CH:22]=[CH:21][C:20]([NH:23][C:24](=[O:28])[CH:25]([CH3:27])[CH3:26])=[CH:19][CH:18]=3)=[C:15]([CH3:16])[C:3]=12.C(=O)([O-])[O-].[K+].[K+].[F:35][C:36]1[CH:43]=[CH:42][CH:41]=[C:40]([F:44])[C:37]=1[CH2:38]Br>CN(C)C=O>[F:35][C:36]1[CH:43]=[CH:42][CH:41]=[C:40]([F:44])[C:37]=1[CH2:38][N:5]1[CH:6]=[C:7]([C:8](=[O:12])[CH:9]([CH3:11])[CH3:10])[C:2](=[O:1])[C:3]2[C:15]([CH3:16])=[C:14]([C:17]3[CH:18]=[CH:19][C:20]([NH:23][C:24](=[O:28])[CH:25]([CH3:27])[CH3:26])=[CH:21][CH:22]=3)[S:13][C:4]1=2
Reactant: Fc1cccc(F)c1CBr
Reactant: Cc1c(-c2ccc(NC(=O)C(C)C)cc2)sc2ncc(C(=O)C(C)C)c(O)c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1c(-c2ccc(NC(=O)C(C)C)cc2)sc2c1c(=O)c(C(=O)C(C)C)cn2Cc1c(F)cccc1F
Temperature: 25 °C
Reaction time: 15 h
Yield: 91 %

Procedure:
The compound obtained in Example 28 (1 g), potassium carbonate (0.349 g) and N,N-dimethylformamide (5 ml) were mixed and 2,6-difluorobenzyl bromide (0.783 g) was added and the reaction mixture was stirred at room temperature overnight (15 hours). The reaction mixture was concentrated under reduced pressure to obtain a residue, which was partitioned between ethyl acetate-methyl ethyl ketone and water, and the aqueous layer was extracted with ethylacetate. The organic layers were combined and washed with a saturated saline and then dried over anhydrous magnesium sulfate. The residue obtained after concentration was washed with diisopropylether to obtain the title compound (1.2 g, 91.0%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[C:4]1[CH:9]=[C:8](OS(C(F)(F)F)(=O)=O)[CH:7]=[C:6]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:5]=1.[Cl-].[Li+].[Br-].[CH2:30]([Zn+])[CH:31]([CH3:33])[CH3:32]>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.C1COCC1>[CH3:1][O:2][C:3](=[O:26])[C:4]1[CH:9]=[C:8]([CH2:30][CH:31]([CH3:33])[CH3:32])[CH:7]=[C:6]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:5]=1
Reactant: COC(=O)c1cc(OCc2ccccc2)cc(OS(=O)(=O)C(F)(F)F)c1
Reactant: CC(C)C[Zn+]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Agent: [Cl-]
Solvent: C1CCOC1
Product: COC(=O)c1cc(CC(C)C)cc(OCc2ccccc2)c1
Yield: 67.4 %

Procedure:
To a microwave reaction vial was added 3-benzyloxy-5-trifluoromethanesulfonyloxybenzoic acid methyl ester (70 mg, 0.179 mmol), lithium chloride (23 mg, 0.537 mmol), Pd(PPh3)4 (10 mg, 0.009 mmol) and 3 ml of THF. Isobutylzinc bromide (0.5 M in THF) (0.537 mL, 0.269 mmol) was added and the vial sealed. After heating in microwave reactor at 130° for 5 min the reaction mixture was adsorbed onto silica gel and purified by silica gel chromatography using an ethyl acetate-hexane gradient to afford 36 mg (68%) of 3-benzyloxy-5-isobutylbenzoic acid methyl ester. 1H NMR (300 MHz, DMSO-d6) δ 0.850 (d, 6H, J=6 Hz), 1.78-1.92 (m, 1H), 3.84 (s, 3H), 5.16 (s, 2H), 7.11 (d, 1H, J=2 Hz), 7.33-7.48 (m, 7H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[C:15]([F:20])[CH:14]=3)=[CH:11][C:10]([C:21](O)=[O:22])=[N:9]2)[CH:5]=[CH:6][CH:7]=1.ClC1C=C(N2C(C3C=C(F)C=C(Cl)C=3)=CC(C([N:47]3[CH2:51][C:50](=[O:52])[NH:49][CH2:48]3)=O)=N2)C=CC=1F>>[Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[C:15]([F:20])[CH:14]=3)=[CH:11][C:10]([C:21]([N:47]3[CH2:51][C:50](=[O:52])[NH:49][CH2:48]3)=[O:22])=[N:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1cc(-c2ccc(F)c(F)c2)n(-c2cccc(Cl)c2)n1
Reactant: O=C1CN(C(=O)c2cc(-c3cc(F)cc(Cl)c3)n(-c3ccc(F)c(Cl)c3)n2)CN1
Product: O=C1CN(C(=O)c2cc(-c3ccc(F)c(F)c3)n(-c3cccc(Cl)c3)n2)CN1

Procedure:
The preparation of the title compound takes place starting from the compound of Example 83A in analogy to the synthesis of the compound of Example 1. 16 mg (41% of theory) of the title compound are obtained.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][OH:6].[CH2:7]=[C:8]1[O:12][C:10](=[O:11])[CH2:9]1>O1CCCC1>[OH:6][CH2:5][CH2:4][CH2:3][CH2:2][NH:1][C:10](=[O:11])[CH2:9][C:8](=[O:12])[CH3:7]
Reactant: C=C1CC(=O)O1
Reactant: NCCCCO
Solvent: C1CCOC1
Product: CC(=O)CC(=O)NCCCCO
Temperature: 0 °C
Reaction time: 1 h
Yield: 87.5 %

Procedure:
A solution of 22 ml (0.24 mol) of 4-amino-1-butanol in 50 ml tetrahydrofuran was added dropwise to a solution of 20 g of diketene (0.24 mol) in 200 ml tetrahydrofuran at −5 to 0° C. After 1 h stirring at 0° C. no more starting material was detected by thin layer chromatography. The reaction mixture was evaporated and the residue purified by column chromatography. This gave 35.43 g (0.21 mol, 86% yield) of a white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([S:14]([NH:17][C:18]2[CH:22]=[CH:21][S:20][C:19]=2[C:23]([O:25]C)=[O:24])(=[O:16])=[O:15])[CH:9]=1.[OH-].[Na+].CO>O1CCCC1>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([S:14]([NH:17][C:18]2[CH:22]=[CH:21][S:20][C:19]=2[C:23]([OH:25])=[O:24])(=[O:15])=[O:16])[CH:9]=1
Reactant: COC(=O)c1sccc1NS(=O)(=O)c1cccc(-c2ccccc2C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1ccccc1-c1cccc(S(=O)(=O)Nc2ccsc2C(=O)O)c1
Temperature: 60 °C
Yield: 48.2 %

Procedure:
To a solution of 82 (78 mg; 0.20 mmol) in tetrahydrofuran (2 mL) were added aqueous sodium hydroxide (1 mL; 2N) and methanol (0.5 mL), sequentially. The reaction mixture was heated at 60° C. for 17 hours, allowed to cool to room temperature, and then extracted with aqueous sodium hydroxide (20 mL; 2N). The aqueous layer was washed with dichloromethane (20 mL), acidified with aqueous hydrochloric acid (20 mL; 6N), and extracted with dichloromethane (30 mL). The organic layer was washed with aqueous saturated sodium chloride (20 mL), dried over magnesium sulfate, filtered and the filtrate was concentrated under reduced pressure. The resulting white solid was purified by a silica gel plug eluting with a 25% to 100% ethyl acetate gradient to yield the title compound as a white solid (36 mg).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([S:9]([NH:12][CH2:13][CH:14]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH2:15][CH2:16][N:17]2[C@H:22]3[CH2:23][CH2:24][C@@H:18]2[CH2:19][CH:20]([N:25]2[C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=4[N:27]=[C:26]2[CH3:34])[CH2:21]3)(=[O:11])=[O:10])[CH:6]=[CH:7][CH:8]=1)#[N:2].OO.NC(N)=[O:45].C([O-])([O-])=O.[K+].[K+]>CC(C)=O.O>[CH3:34][C:26]1[N:25]([CH:20]2[CH2:19][C@H:18]3[N:17]([CH2:16][CH2:15][CH:14]([C:35]4[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=4)[CH2:13][NH:12][S:9]([C:5]4[CH:4]=[C:3]([CH:8]=[CH:7][CH:6]=4)[C:1]([NH2:2])=[O:45])(=[O:10])=[O:11])[C@H:22]([CH2:23][CH2:24]3)[CH2:21]2)[C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=2[N:27]=1
Reactant: Cc1nc2ccccc2n1C1C[C@H]2CC[C@@H](C1)N2CCC(CNS(=O)(=O)c1cccc(C#N)c1)c1ccccc1
Reactant: NC(N)=O
Agent: O=C([O-])[O-]
Agent: OO
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: Cc1nc2ccccc2n1C1C[C@H]2CC[C@@H](C1)N2CCC(CNS(=O)(=O)c1cccc(C(N)=O)c1)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 53.9 %

Procedure:
The title compound from example 3 (65 mg, 0.12 mmol) was dissolved in acetone (1 mL) and water (0.5 mL). To the solution was added urea hydrogen peroxide (110 mg, 1.2 mmol) followed by K2CO3 (5 mg, 0.036 mmol) and the reaction stirred at room temperature for 2 h, whereupon the reaction was found to be mostly complete by LC-MS. The reaction was poured into water and extracted with EtOAc. The organic layer was dried (MgSO4) and concentrated in vacuo. The residue was purified by reverse-phase HPLC eluting with 10-90% water/acetonitrile/0.1% TFA. The title compound (37 mg, 54% yield) was obtained as a white solid (free-based with K2CO3).
Reaction SMILES: [NH2:1][C:2]1[CH:17]=[C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:15]([O:26][CH3:27])=[CH:14][C:3]=1[C:4](OCC1C=CC=CC=1)=[O:5].C(O)(=O)C.[CH:32](N)=[NH:33]>C(O)C(C)C>[CH2:19]([O:18][C:16]1[CH:17]=[C:2]2[C:3]([C:4](=[O:5])[NH:33][CH:32]=[N:1]2)=[CH:14][C:15]=1[O:26][CH3:27])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: N=CN
Reactant: COc1cc(C(=O)OCc2ccccc2)c(N)cc1OCc1ccccc1
Solvent: CC(C)CO
Solvent: CC(=O)O
Product: COc1cc2c(=O)[nH]cnc2cc1OCc1ccccc1
Temperature: 97 °C
Reaction time: 6 h

Procedure:
Benzyl 2-amino-4-(benzyloxy)-5-methoxybenzoate (80.0 g), formamidine acetate (32.0 g) and isobutanol (480 ml) were mixed. The reaction mixture was then heated to 97° C. and stirred at this temperature for 6 hours. The reaction mixture was then cooled to 25° C. over a period of at least an hour and then stirred at this temperature for 30 minutes. The product (7-benzyloxy-6-methoxy-3,4-dihydroquinazolin-4-one) was isolated by filtration, washed with isobutanol (64.2 g) and dried in the vacuum oven at a temperature of from 40 to 45° C. Yield: 60.8 g, 98%; NMR Spectrum (DMSOd6) 3.9 (s, 3H), 5.3 (s, 2H), 7.3 (s, 1H), 7.3-7.5 (m, 6H), 8.0 (s, 1H); Mass Spectrum (M+H)+=283.1.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][OH:14].Cl[C:16]1[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[C:19]([C:20]([O:22][CH3:23])=[O:21])=[CH:18][N:17]=1>>[CH3:23][O:22][C:20](=[O:21])[C:19]1[C:24]([C:26]([F:27])([F:28])[F:29])=[CH:25][C:16]([O:14][CH2:13][C:3]2[C:4]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)=[N:5][O:6][C:2]=2[CH3:1])=[N:17][CH:18]=1
Reactant: Cc1onc(-c2ccccc2)c1CO
Reactant: COC(=O)c1cnc(Cl)cc1C(F)(F)F
Product: COC(=O)c1cnc(OCc2c(-c3ccccc3)noc2C)cc1C(F)(F)F

Procedure:
As described for example 5, (5-methyl-3-phenyl-isoxazol-4-yl)-methanol (3.47 g, 18.4 mmol) was converted using methyl 6-chloro-4-(trifluoromethyl)nicotinate instead of 6-chloronicotinonitrile to the title compound which was used directly in the next transformation without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[Cl:21][CH2:22][CH2:23]O>CC(=O)CC>[Cl:1][C:2]1[CH:14]=[CH:13][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][N:10]([CH2:23][CH2:22][Cl:21])[CH2:9][CH2:8]2)=[CH:4][CH:3]=1
Reactant: OCCCl
Reactant: Clc1ccc(CN2CCNCC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: ClCCN1CCN(Cc2ccc(Cl)cc2)CC1
Yield: 32 %

Procedure:
A mixture of 1-(4-chlorobenzyl)piperazine (21.05 g; 0.1 mole), anhydrous potassium carbonate (20.7 g; 0.15 mole) and 2-chloroethanol (8.85 g; 0.11 mole) in butanone (270 ml) was stirred at reflux for 61/2 hr, cooled, and the solvent removed in vacuo. Chromatography of the residue on silica eluting with chloroform gave 8.74 g (34%) of the title compound as an oil, νmax (film) 3350, 2910, 2800, 1595 cm-1 ; (Found; C, 61.48; H, 7.96; N, 10.13; C13H19N2ClO requires; C, 61.28; H, 7.52; N, 11.00%).
Reaction SMILES: C(N(CC)CC)C.[CH3:8][S:9](Cl)(=[O:11])=[O:10].[C:13]([O:17][C:18]([N:20]1[CH2:24][C@@H:23]([OH:25])[CH2:22][C@H:21]1[C:26](=[O:30])[NH:27][CH2:28][CH3:29])=[O:19])([CH3:16])([CH3:15])[CH3:14].[Cl-].[Na+]>O1CCCC1>[C:13]([O:17][C:18]([N:20]1[CH2:24][C@@H:23]([O:25][S:9]([CH3:8])(=[O:11])=[O:10])[CH2:22][C@H:21]1[C:26](=[O:30])[NH:27][CH2:28][CH3:29])=[O:19])([CH3:16])([CH3:15])[CH3:14]
Reactant: CCNC(=O)[C@@H]1C[C@H](O)CN1C(=O)OC(C)(C)C
Reactant: CS(=O)(=O)Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCNC(=O)[C@@H]1C[C@H](OS(C)(=O)=O)CN1C(=O)OC(C)(C)C
Reaction time: 0.5 h

Procedure:
13.81 ml of triethylamine and subsequently 7.65 ml of methanesulfonyl chloride were added, whilst ice-cooling, to a solution of 23.20 g of (2S, 4S)-1-t-butoxycarbonyl-2-ethylcarbamoyl-4-hydroxypyrrolidine dissolved in 250 ml of dry tetrahydrofuran, and then the mixture was stirred at 0° to 5° C. for 30 minutes. The reaction mixture was then poured into an aqueous solution of sodium chloride and extracted with ethyl acetate. The extract was washed with an aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. The solvent was then removed by distillation under reduced pressure, to afford 26.54 g of the title compound as colorless crystals, melting at 138°-140° C.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[Cl-].[Al+3].[Cl-].[Cl-].[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([N:19]2[CH2:24][CH2:23][N:22]([C:25]3[C:26]([CH3:37])=[C:27]([CH3:36])[C:28]4[O:32][CH2:31][C:30](=O)[C:29]=4[C:34]=3[CH3:35])[CH2:21][CH2:20]2)=[CH:15][CH:14]=1.[OH-].[Na+]>O.C1COCC1>[CH3:11][O:12][C:13]1[CH:14]=[CH:15][C:16]([N:19]2[CH2:24][CH2:23][N:22]([C:25]3[C:26]([CH3:37])=[C:27]([CH3:36])[C:28]4[O:32][CH2:31][CH2:30][C:29]=4[C:34]=3[CH3:35])[CH2:21][CH2:20]2)=[CH:17][CH:18]=1
Reactant: COc1ccc(N2CCN(c3c(C)c(C)c4c(c3C)C(=O)CO4)CC2)cc1
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(N2CCN(c3c(C)c(C)c4c(c3C)CCO4)CC2)cc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 16.5 %

Procedure:
To the THF (2 ml) solution of lithium aluminum hydride (68 mg, 1.80 mmol), aluminum chloride (240 mg, 1.80 mmol) was added under ice cooling. After stirring for 10 minutes at 0° C., THF (4 ml) solution of 5-[4-(4-methoxyphenyl)piperazin-1-yl]-4,6,7-trimethyl-1-benzofuran-3(2H)-one (220 mg, 0.600 mmol) synthesized in Reference example 109 was added. The mixture was stirred for 3 hours under reflux. After cooling to room temperature, water was added to the reaction solution, and 0.5 N aqueous solution of sodium hydroxide was further added to the reaction solution. The mixture was stirred for 30 minutes at room temperature and extracted with ethyl acetate-diethyl ether (1/1) mixture solvent. The extract solution was washed with saturated brine, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was dissolved in ethyl acetate (20 ml), added with 10%-palladium carbon (comprising 50% moisture, 200 mg), and then the mixture was stirred at 60° C. for 15 hours under hydrogen atmosphere. After cooling to room temperature, palladium carbon was removed by filtration and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane-ethyl acetate 95:5-80/20) to obtain the title compound 35 mg (yield 17%).
Reaction SMILES: Br[CH2:2][C@@H:3]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[N:7]([S:14]([C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=2)(=[O:16])=[O:15])[CH2:6][CH2:5][CH2:4]1.[C-:24]#[N:25].[K+]>CS(C)=O>[C:24]([CH2:2][C@@H:3]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[N:7]([S:14]([C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=2)(=[O:16])=[O:15])[CH2:6][CH2:5][CH2:4]1)#[N:25]
Reactant: [C-]#N
Reactant: Cc1ccc(S(=O)(=O)N2CCC[C@H](CBr)c3ccccc32)cc1
Agent: [K+]
Solvent: CS(C)=O
Product: Cc1ccc(S(=O)(=O)N2CCC[C@H](CC#N)c3ccccc32)cc1
Temperature: 47.5 °C
Reaction time: 3 h
Yield: 83.7 %

Procedure:
A mixture of (5S)-5-bromomethyl-1-(p-toluenesulfonyl)-2,3,4,5-tetrahydro-1H-benzazepine (0.83 g), potassium cyanide (0.27 g) and dimethyl sulfoxide (9 ml) is heated with stirring at 45-50° C. for three hours. To the reaction solution is added ice, and the mixture is extracted with ethyl acetate--diethyl ether. The extract is dried over sodium sulfate, and evaporated under reduced pressure to remove the solvent. The resulting residue is purified by silica gel column chromatography (solvent; n-hexane: ethyl acetate=6:1), and recrystallized from ethyl acetate--n-hexane to give (5R)-5-cyanomethyl-1-(p-toluenesulfonyl)-2,3,4,5-tetrahydro-1H-benzazepine (0.60 g).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][S:11][C:12]1[S:13][CH:14]=[C:15]([C:17]([NH:19][C:20]2[S:21][C:22]3[CH:28]=[CH:27][C:26](F)=[CH:25][C:23]=3[N:24]=2)=[O:18])[N:16]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(OC(NCCSC1SC=C(C(NC2N(C)[C:52]3[CH:55]=[C:56](F)[CH:57]=[CH:58][C:51]=3S2)=O)N=1)=O)(C)(C)C>>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][S:11][C:12]1[S:13][CH:14]=[C:15]([C:17]([NH:19][C:20]2[S:21][C:22]3[CH:28]=[C:27]([C:51]4[CH:58]=[CH:57][CH:56]=[CH:55][CH:52]=4)[CH:26]=[CH:25][C:23]=3[N:24]=2)=[O:18])[N:16]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN1c2cc(F)ccc2SC1NC(=O)c1csc(SCCNC(=O)OC(C)(C)C)n1
Reactant: CC(C)(C)OC(=O)NCCSc1nc(C(=O)Nc2nc3cc(F)ccc3s2)cs1
Product: CC(C)(C)OC(=O)NCCSc1nc(C(=O)Nc2nc3ccc(-c4ccccc4)cc3s2)cs1

Procedure:
In a similar manner were prepared: 2-(t-butoxy-carbonylaminoethylthio) -N-(5-fluorobenzothiazol-2-yl) -thiazole-4-carboxamide, m.p. 198-199° C. and 2-(t-butoxy-carbonylaminoethylthio)-N-(3-methyl-5-fluorobenzothiazol-2-yl) thiazole-4-carboxamide, m.p. 204-205° C.
Reaction SMILES: [CH3:1][N:2]([CH3:28])[CH2:3][CH2:4][NH:5][C:6]([C:8]1[C:21]2[C:12](=[N:13][C:14]3[C:19]([N:20]=2)=[C:18]2[CH:22]=[CH:23][N:24]=[C:25]([O:26]C)[C:17]2=[CH:16][CH:15]=3)[CH:11]=[CH:10][CH:9]=1)=[O:7].Br.C([O-])(O)=O.[Na+]>CC(O)=O>[CH3:1][N:2]([CH3:28])[CH2:3][CH2:4][NH:5][C:6]([C:8]1[C:21]2[C:12](=[N:13][C:14]3[C:19]([N:20]=2)=[C:18]2[CH:22]=[CH:23][N:24]=[C:25]([OH:26])[C:17]2=[CH:16][CH:15]=3)[CH:11]=[CH:10][CH:9]=1)=[O:7]
Reactant: COc1nccc2c1ccc1nc3cccc(C(=O)NCCN(C)C)c3nc12
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Product: CN(C)CCNC(=O)c1cccc2nc3ccc4c(O)nccc4c3nc12
Yield: 31.1 %

Procedure:
4-Methoxypyrido[4,3-α]phenazine-11-carboxylic acid (2-dimethylamino-ethyl)-amide (0.056 g, 0.16 mmol) was dissolved in glacial AcOH (5 mL) and hydrobromic acid (48/50% w w; (2 mL). The mixture was refluxed for 30 min, then cooled and neutralized with solid NaHCO3. The product was extracted into CH2Cl2 (3×25 mL) dried (Na2SO4) and evaporated to give 4-hydroxypyrido[4,3-α]phenazine-11-carboxylic acid (2-dimethylamino-ethyl)-amide (0.018 g, 33%): mp (CH2Cl2/hexane) 268-270° C. 1H NMR (CDCl3) δ 2.32 [s, 6 H, N(CH3)2], 2.61 [t, J=5.9 Hz, 2 H, CH2N(CH3)2], 3.69 (q, J=5.7 Hz, 2 H, CH2NH), 7.70 (d, J=7.1 Hz, 1 H, H-2), 7.99 (d, J=7.1 Hz, 1 H, H-1), 8.11 (d, J=9.2 Hz, 1 H, H-5),8.14 (dd, J=8.5, 7.2 Hz, 1 H, H-9), 8.46 (dd, J=8.6, 1.4 Hz, 1 H, H-8), 8.52 (d, J=9.2 Hz, 1 H, H-6), 9.98 (t, J=5.1 Hz, 1 H, CONH), 12.16 (br, 1 H, OH).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4]C2=[C:6]([CH:20]=1)CN(C)CC=C2C1C=CC(F)=CC=1.C(=O)([O-])[O-].[K+].[K+].[N:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[Br:1][C:2]1[CH:3]=[CH:4][C:28]2[CH2:29][CH2:30][CH2:31][CH2:32][NH:27][C:6]=2[CH:20]=1
Reactant: CN1CC=C(c2ccc(F)cc2)c2ccc(Br)cc2C1
Reactant: c1ccncc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Brc1ccc2c(c1)NCCCC2
Temperature: 25 °C
Yield: 71 %

Procedure:
To a solution of the dihydrobenzazepine (2.43 g, 7.31 mmol) from step F above in pyridine (50 mL) were added potassium carbonate (8.08 g, 58.5 mmol) and p-toluenesulfonylhydrazide (5.45 g, 29.3 mmol) in batches. The reaction solution was heated under reflux for 48 h and then cooled to room temperature. The resultant reaction mixture was filtered through Celite. The Celite bed was washed with ethyl acetate. The filtrate was concentrated under reduced pressure. The residue dissolved in ethyl acetate was washed with water and brine, dried over sodium sulfate and concentrated under reduced pressure. The residue obtained was purified by flash column chromatography (3 to 5% methanol/dichloromethane) to give the desired 8-bromotetrahydrobenzazepine (1.74 g, 71%): 1H NMR (500 MHz, CDCl3) δ 7.31 (d, J=2.1 Hz, 1H), 7.20-7.16 (m, 1H), 7.13-7.10 (m, 2H), 7.04 (t, J=8.6 Hz, 2H), 6.49 (br, 1H), 4.24 (d, J=9.3 Hz, 1H), 3.88 (d, J=12.2 Hz, 1H), 3.67 (d, J=14.3 Hz, 1H), 3.12-3.09 (m, 1H), 2.98-2.93 (m, 1H), 2.34 (s, 3H), 2.30-2.23 (m, 1H), 2.08-2.04 (m, 1H); ESI MS m/z 334, 336 [M+H]+.
Reaction SMILES: [I:1][C:2]1[CH:3]=[N:4][NH:5][CH:6]=1.Br[CH2:8][CH2:9][Cl:10].BrCCBr>C1(C)C=CC=CC=1>[I:1][C:2]1[CH:3]=[N:4][N:5]([CH2:8][CH2:9][Cl:10])[CH:6]=1.[I:1][C:2]1[CH:3]=[N:4][NH:5][CH:6]=1
Reactant: ClCCBr
Agent: Ic1cn[nH]c1
Solvent: Cc1ccccc1
Solvent: BrCCBr
Product: ClCCn1cc(I)cn1

Procedure:
When an equivalent amount of 4-iodopyrazole is substituted for 1-ethoxycarbonyl-2H-indazolin-3-one and 2-bromochloroethane is substituted for 1,2-dibromoethane in the procedure of Example 19 using toluene as solvent, 2-(4-iodo-1H-pyrazol-1-yl)ethyl chloride is isolated after column chromatography (4-iodopyrazole, Aldrich, 41%, C).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:26]=[CH:27][C:28]=1[O:29][CH3:30])[CH2:5][NH:6][C:7](=[O:25])[C:8]1[CH:13]=[C:12]([N+:14]([O-:16])=[O:15])[CH:11]=[CH:10][C:9]=1[NH:17][C@H:18]1[CH2:23][CH2:22][C@H:21](O)[CH2:20][CH2:19]1.C(O)(=O)C1C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[CH:18]1([NH:17][C:9]2[CH:10]=[CH:11][C:12]([N+:14]([O-:16])=[O:15])=[CH:13][C:8]=2[C:7]([NH:6][CH2:5][C:4]2[CH:26]=[CH:27][C:28]([O:29][CH3:30])=[C:2]([F:1])[CH:3]=2)=[O:25])[CH2:23][CH2:22][CH:21]=[CH:20][CH2:19]1
Reactant: COc1ccc(CNC(=O)c2cc([N+](=O)[O-])ccc2N[C@H]2CC[C@H](O)CC2)cc1F
Agent: CCOC(=O)N=NC(=O)OCC
Agent: O=C(O)c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1ccc(CNC(=O)c2cc([N+](=O)[O-])ccc2NC2CC=CCC2)cc1F
Temperature: 25 °C
Reaction time: 24 h
Yield: 16 %

Procedure:
To a mixture of N-(3-fluoro-4-methoxybenzyl)-2-(trans-4-hydroxycyclohexylamino)-5-nitrobenzamide (262 mg), benzoic acid (115 mg) and diethyl azodicarboxylate (164 mg) in anhydrous tetrahydrofuran (6 mL) was added triphenylphosphine (247 mg). After stirring for one day at ambient temperature, the mixture was evaporated in vacuo. The residue was purified by a silica gel column chromatography eluting with a mixture of hexane and ethyl acetate (4:1 to 2:1). Collection of an upper fraction gave 2-(3-cyclohexenylamino)-N-(3-fluoro-4-methoxybenzyl)-5-nitrobenzamide as yellow powders (40 mg).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=O)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH4+].[Cl-]>BrC1C=CC(OC)=CC=1.C1COCC1.CCOCC>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([C:12]2[CH:13]=[CH:14][C:9]([O:8][CH3:1])=[CH:10][CH:11]=2)=[CH:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cc1ccccc1)c1ccc(OCc2ccccc2)cc1
Agent: COc1ccc(Br)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: COc1ccc(C(=Cc2ccccc2)c2ccc(OCc3ccccc3)cc2)cc1
Temperature: 25 °C
Yield: 159.6 %

Procedure:
To the Grignard reagent prepared from 1.52 g (63 mg-atom) Mg turnings and 13.45 g (9 mL, 72 mmol) 4-bromoanisole (initiated with one I2 crystal and one drop EtBr2) in 25 mL THF was added 3 g (9.9 mmol) of Benzyl 4-benzyloxyphenyl ketone, prepared in Example 3. The reaction mixture was stirred at reflux for 48 h and then treated with 10 mL aqueous NH4Cl. After cooling to room temperature, the slurry was filtered, the filter cake washed with 50 mL THF, and the filtrates concentrated to give an orange oil. The oil was chromatographed over 60 g flash SiO2 (petroleum ether followed by Me2CO). The Me2CO fractions were combined, concentrated, dissolved in 100 mL 1:1 95% EtOH-2N H2SO4, and refluxed with stirring for 8 h. The solvents were removed to give a brown gum, which was dissolved in 100 mL Et2O, washed with saturated aqueous NaHCO3 (100 mL), brine (100 mL), and H2O (100 mL). The organic layer was dried (MgSO4), filtered, and concentrated to give a brown oil. The oil was purified on 60 g flash SiO2 (9:1 petroleum ether-CH2Cl2) to give 3.1 g of 1-(4-Benzyloxyphenyl)-1-(4-methoxyphenyl)-2-phenylethene (80%) as a clear oil. NMR δ7.41 (brs, 5H, O-benzyl C6H5), 7.3 to 6.75 (m, 9H, substituted rings' ArH and C=CH), 7.11 (s, 5H,=C--C6H5), 5.05 (s, 2H, OCH2Ph), 3.79 (s, 3H, OCH3).