Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[C:5](=[O:7])[CH3:6])(=O)C.[NH2:8][C:9]1[S:10][CH:11]=[C:12]([CH3:14])[N:13]=1>>[CH3:14][C:12]1[N:13]=[C:9]([NH:8][C:5](=[O:7])[CH3:6])[S:10][CH:11]=1
Reactant: Cc1csc(N)n1
Reactant: CC(=O)OC(C)=O
Product: CC(=O)Nc1nc(C)cs1
Temperature: 5 °C
Reaction time: 8 h

Procedure:
To a stirred, cooled (5° C.) solution of acetic anhydride (237 ml, 2.51 mol) is added portionwise 2-amino-4-methyl thiazole (80 g, 0.697 mol). To allow dissolution of the 2-amino-4-methyl thiazole, the reaction mixture is allowed to warm but kept below 35° C. Once a solution forms, the reaction mixture is cooled to 5° C. and stirred overnight. The solvent is removed in vacuo and the solid is dried in a vacuum oven overnight. The resulting solid is triturated with iso-hexane (100 ml) and dried again. Recrystallisation from EtOAc/iso-hexane affords the title product as a pale yellow solid.
Reaction SMILES: [CH3:1][CH:2]1[C:7](=[O:8])[N:6]([CH2:9][C:10]#[CH:11])[C:5]2[CH:12]=[C:13]([N+:16]([O-])=O)[CH:14]=[CH:15][C:4]=2[O:3]1>C(O)(=O)C.C(OCC)(=O)C.[Fe]>[NH2:16][C:13]1[CH:14]=[CH:15][C:4]2[O:3][CH:2]([CH3:1])[C:7](=[O:8])[N:6]([CH2:9][C:10]#[CH:11])[C:5]=2[CH:12]=1
Reactant: C#CCN1C(=O)C(C)Oc2ccc([N+](=O)[O-])cc21
Agent: [Fe]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: C#CCN1C(=O)C(C)Oc2ccc(N)cc21
Yield: 50.1 %

Procedure:
A solution of 2-methyl-6-nitro-4-(2-propynyl)-2H-1,4-benzoxazin-3(4H)-one (5 g) in acetic acid (50 ml) and ethyl acetate (50 ml) was dropwise added to a mixture of iron powder (6 g) and 5% aqueous acetic acid (50 ml), and the resultant mixture was heated under reflux for 1 hour. After being allowed to cool, iron powder was removed by filtration and the filtrate was admixed with water. The aqueous layer was extracted with ethyl acetate, and the extract was combined with the organic layer, washed with a saturated sodium bicarbonate solution, dried and concentrated. The residue was crystallized from methanol to give 6-amino-2-methyl-4-(2-propynyl)-2H-1,4-benzoxazin-3(4H)-one (2.2 g). m.p., 158°-159° C.
Reaction SMILES: C(O[C:4]([C:6]1[C:7]([OH:21])=[C:8]2[C:14]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[N:13][O:12][C:9]2=[CH:10][N:11]=1)=[O:5])C.[NH2:22][C@@H:23]([C:25]([OH:27])=[O:26])[CH3:24]>>[OH:21][C:7]1[C:6]([C:4]([NH:22][C@H:23]([CH3:24])[C:25]([OH:27])=[O:26])=[O:5])=[N:11][CH:10]=[C:9]2[O:12][N:13]=[C:14]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:8]=12
Reactant: C[C@@H](N)C(=O)O
Reactant: CCOC(=O)c1ncc2onc(-c3ccccc3)c2c1O
Product: C[C@@H](NC(=O)c1ncc2onc(-c3ccccc3)c2c1O)C(=O)O

Procedure:
Prepared in analogy to Example 11 from 4-hydroxy-3-phenyl-isoxazolo[5,4-c]pyridine-5-carboxylic acid ethyl ester and D-alanine; ESI MS (m/z): 328.20 (M+H+); 326.16 (M−H+).
Reaction SMILES: [C:1]([C:4]([C@@H:17]1[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH:28](OC)[O:29]C)[CH2:18]1)([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)(=[O:3])[NH2:2].Cl>C(#N)C>[C:1]([C:4]([C@@H:17]1[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH:28]=[O:29])[CH2:18]1)([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)(=[O:3])[NH2:2]
Reactant: COC(CCCCCCN1CC[C@@H](C(C(N)=O)(c2ccccc2)c2ccccc2)C1)OC
Agent: Cl
Solvent: CC#N
Product: NC(=O)C(c1ccccc1)(c1ccccc1)[C@@H]1CCN(CCCCCCC=O)C1
Temperature: 10 °C
Reaction time: 2 h

Procedure:
To a three-necked 500 μL flask equipped with a mechanical stirrer, a nitrogen inlet, cooling bath, and a thermometer was added (S)-3-(1-carbamoyl-1,1-diphenylmethyl)-1-(7,7-dimethoxyhept-1-yl)pyrrolidine (16 g, 0.036 mol) and acetonitrile (100 mL). This mixture was cooled to about 10° C. and 100 mL of 1N aqueous hydrochloric acid was added while maintaining the reaction temperature at 20° C. or less. The resulting mixture was stirred at 20±5° C. for 2 hours. The reaction mixture was then extracted with dichloromethane (1×200 mL and 2×100 mL). The combined organic layers were washed with brine (200 mL) and dried with sodium sulfate (40 g). The organic layer was then concentrated under vacuum at about 25° C. to a volume of about 200 mL. This solution, containing the title intermediate as the hydrochloride salt, was used directly in the next step without further purification.
Reaction SMILES: [C:1]1(B(O)O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.Cl.[CH3:18][O:19][C:20](=[O:29])[C@@H:21]([NH2:28])[CH2:22][O:23][C:24]([CH3:27])([CH3:26])[CH3:25]>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH3:18][O:19][C:20](=[O:29])[C@@H:21]([NH:28][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH2:22][O:23][C:24]([CH3:25])([CH3:27])[CH3:26]
Reactant: COC(=O)[C@@H](N)COC(C)(C)C
Reactant: OB(O)c1ccccc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)[C@H](COC(C)(C)C)Nc1ccccc1
Temperature: 25 °C
Reaction time: 120 h
Yield: 33.4 %

Procedure:
To a suspension of phenylboronic acid (1.46 g) and 4A molecular sieves (4.5 g) in dichloromethane (40 mL) were added triethylamine (1.66 mL), methyl-(2S)-2-amino-3-tert-butoxypropanoate hydrochloride (1.26 g) and copper (II) acetate (1.19 g), then the mixture was stirred at ambient temperature for 5 days. The reaction was quenched with 7N ammonia in methanol (15 mL) and the mixture was filtered through a bed of celite. The filtrate was concentrated in vacuo and the residue was purified by silica gel column chromatography (eluent; n-hexane/ethyl acetate (2:1)) to afford methyl-(2S)-2-phenylamino-3-tert-butoxypropanoate (500 mg) as a colorless syrup.
Reaction SMILES: Cl.[CH3:2][N:3]1[CH2:8][CH2:7][N:6]([CH2:9][C:10]2[CH:11]=[CH:12][C:13]([NH2:16])=[N:14][CH:15]=2)[CH2:5][CH2:4]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CN1CCN(C2C=CC(N[C:53]([C:55]3[C:56]4[N:57]=[CH:58][CH:59]=[N:60][C:61]=4[C:62]([C:65]4[C:74]5[C:69](=[CH:70][CH:71]=[CH:72][CH:73]=5)[CH:68]=[CH:67][CH:66]=4)=[CH:63][CH:64]=3)=[O:54])=CC=2)CC1>C(Cl)Cl.CO>[CH3:2][N:3]1[CH2:8][CH2:7][N:6]([CH2:9][C:10]2[CH:11]=[CH:12][C:13]([NH:16][C:53]([C:55]3[C:56]4[N:57]=[CH:58][CH:59]=[N:60][C:61]=4[C:62]([C:65]4[C:74]5[C:69](=[CH:70][CH:71]=[CH:72][CH:73]=5)[CH:68]=[CH:67][CH:66]=4)=[CH:63][CH:64]=3)=[O:54])=[N:14][CH:15]=2)[CH2:5][CH2:4]1
Reactant: CN1CCN(Cc2ccc(N)nc2)CC1
Reactant: CN1CCN(c2ccc(NC(=O)c3ccc(-c4cccc5ccccc45)c4nccnc34)cc2)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CO
Solvent: ClCCl
Product: CN1CCN(Cc2ccc(NC(=O)c3ccc(-c4cccc5ccccc45)c4nccnc34)nc2)CC1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
The title compound was prepared in analogy to the procedure described in Step 14.1 but stirring the reaction mixture for 72 h at rt and using 3 equiv of 5-(4-methyl-piperazin-1-ylmethyl)-pyridin-2-ylamine hydrochloride (Example 31), TBTU (2.4 equiv) and 8-naphthalen-1-yl-quinoxaline-5-carboxylic acid (Example 46). Title compound: ESI-MS: 489.1 [M+H]+; tR=3.73 min (System 1); TLC: Rf=0.08 (DCM/MeOH, 9:1).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH:18]=2)=[CH:8][C:9]=1[NH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:4].[CH3:23][C@H:24]1[CH2:29][CH2:28][C@H:27]([C:30](Cl)=[O:31])[CH2:26][CH2:25]1>>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH:18]=2)=[CH:8][C:9]=1[N:10]([C:30]([C@H:27]1[CH2:28][CH2:29][C@H:24]([CH3:23])[CH2:25][CH2:26]1)=[O:31])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:4]
Reactant: COC(=O)c1sc(C2=CCCCC2)cc1Nc1ccccc1
Reactant: C[C@H]1CC[C@H](C(=O)Cl)CC1
Product: COC(=O)c1sc(C2=CCCCC2)cc1N(c1ccccc1)C(=O)[C@H]1CC[C@H](C)CC1

Procedure:
The methyl ester from Step I (565 mg, 1.13 mmol) was acylated with trans-4-methylcyclohexyl carboxylic acid chloride as previously described (example 11, step II) to give 41 mg (27%) of 5-cyclohex-1-enyl-3-[(trans-4-methyl-cyclohexanecarbonyl)-phenyl-amino]-thiophene-2-carboxylic acid methyl ester.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([C:16](=[O:24])[CH2:17][C:18](O)([CH2:21][CH3:22])[CH2:19][CH3:20])[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])([CH3:3])[CH3:2].[ClH:25]>C(OCC)C>[C:1]([C:5]1[CH:6]=[C:7]([C:16](=[O:24])[CH2:17][C:18]([Cl:25])([CH2:21][CH3:22])[CH2:19][CH3:20])[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cl
Reactant: CCC(O)(CC)CC(=O)c1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Solvent: CCOCC
Product: CCC(Cl)(CC)CC(=O)c1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 10 h

Procedure:
1-(3,5-Di-tert-butyl-4-hydroxyphenyl)-3-hydroxy-3-ethyl-pentan-1-one (prepared by method analogous to that of Example 1) (1.6 g) is dissolved in dry 1N hydrogen chloride solution in ethyl ether (50 mL) and the mixture is stirred at ambient temperature for 10 hours. The solution is washed three times with water, dried over anhydrous sodium sulfate and the solvent is removed under reduced pressure. The crude product is crystallized twice from petroleum ether to give 1-(3,5-di-tert-butyl-4-hydroxyphenyl)-3-chloro-3-ethyl-pentan-1-one as white solid, mp 72° C.
Reaction SMILES: N[C:2]1[CH:12]=[CH:11][C:5]([C:6](OCC)=O)=[CH:4][CH:3]=1.NC1C=[C:16](C=CC=1)[C:17]([O:19]CC)=[O:18]>>[O:19]1[C:11]2[CH:12]=[CH:2][CH:3]=[CH:4][C:5]=2[CH:6]=[CH:16][C:17]1=[O:18]
Reactant: CCOC(=O)c1cccc(N)c1
Reactant: CCOC(=O)c1ccc(N)cc1
Product: O=c1ccc2ccccc2o1

Procedure:
The same procedures as Example 1 were carried out except that 150 parts of ethyl p-aminobenzoate were replaced by 150 parts of ethyl m-aminobenzoate. The 2H-1-benzopyran-2-on compound thus obtained was 228 parts.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:37])[CH:4]([N:16]1[CH2:21][CH2:20][N:19]([S:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[N+:31]([O-:33])=[O:32])(=[O:24])=[O:23])[CH:18]([CH2:34][CH3:35])[C:17]1=O)[CH2:5][C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=1.CO>C1COCC1>[CH3:1][O:2][C:3](=[O:37])[CH:4]([N:16]1[CH2:21][CH2:20][N:19]([S:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[N+:31]([O-:33])=[O:32])(=[O:23])=[O:24])[CH:18]([CH2:34][CH3:35])[CH2:17]1)[CH2:5][C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=1
Reactant: CCC1C(=O)N(C(Cc2ccc3ccccc3c2)C(=O)OC)CCN1S(=O)(=O)c1ccccc1[N+](=O)[O-]
Solvent: CO
Solvent: C1CCOC1
Product: CCC1CN(C(Cc2ccc3ccccc3c2)C(=O)OC)CCN1S(=O)(=O)c1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 68 %

Procedure:
To a solution of 2-[3-ethyl-4-(2-nitrobenzenesulfonyl)-2-oxo-piperazin-1-yl]-3-naphthalen-2-yl-propionic acid methyl ester, 32, (5.3 g, 10. mmol) in anhydrous THF (10 mL) is added 1.0 M borane-tetrahydrofuran complex (32.0 mL) at −20° C. The reaction mixture is stirred at this temperature overnight. Methanol (3 mL) is added to the reaction mixture at −20° C. and the solution is allowed to stir for twenty minutes. Additional methanol (6 mL) is added and the reaction mixture is allowed to warm to room temperature. The solvent is removed in vacuo and the product is purified over silica (EtOAc/Hexane: 1:1) to afford 4.1 g (68% yield) of the desired product. 1H NMR (CDCl3, δ): 8.04–7.98m, (1H), 7.80–7.72 (m, 3H), 7.61–7.52 (m, 4H), 7.45–7.38 (m, 2H), 7.28 (d, J=9.6 Hz, 1H), 3.78 (t, J=6.0 Hz, 1H), 3.64 (d, J=11.0 Hz, 1H), 3.50 (s, 3H), 3.48 (t, J=7.2 Hz, 1H), 3.24–3.10 (m, 2H), 3.10–2.95 (m, 1H), 2.90 (t, J=11.0 Hz, 1H), 2.66 (d, J=2.4 Hz), 2.38–2.20 (m, 1H), 1.61–1.48 (m, 1H), 1.48–1.32 (m, 1H), 0.58 (t, J=9.6 Hz, 3H); ); 13C NMR, δ 171.7, 148.0, 135.9, 134.2, 133.7, 132.4, 132.0, 130.9, 128.0, 127.7, 127.6, 126.2, 125.6, 124.4, 69.0, 56.4, 53.8, 51.3, 47.0, 41.9, 35.2, 22.2, 10.7.
Reaction SMILES: C([O:4][CH2:5][C:6]1[CH:18]=[CH:17][C:16]2[C:15]3[C:10](=[C:11]([C:27](=[O:29])[NH2:28])[CH:12]=[C:13]([C:19]4[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([Cl:26])[CH:20]=4)[CH:14]=3)[NH:9][C:8]=2[CH:7]=1)(=O)C.C[O-].[Na+]>CO.CN(C=O)C>[Cl:26][C:21]1[CH:20]=[C:19]([C:13]2[CH:12]=[C:11]([C:27]([NH2:28])=[O:29])[C:10]3[NH:9][C:8]4[C:16]([C:15]=3[CH:14]=2)=[CH:17][CH:18]=[C:6]([CH2:5][OH:4])[CH:7]=4)[CH:24]=[CH:23][C:22]=1[Cl:25]
Reactant: CC(=O)OCc1ccc2c(c1)[nH]c1c(C(N)=O)cc(-c3ccc(Cl)c(Cl)c3)cc12
Agent: C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Product: NC(=O)c1cc(-c2ccc(Cl)c(Cl)c2)cc2c1[nH]c1cc(CO)ccc12
Reaction time: 0.5 h
Yield: 48 %

Procedure:
(8-Carbamoyl-6-(3,4-dichlorophenyl)-9H-carbazol-2-yl)methyl acetate (150 mg, 0.211 mmol, Example 139) was dissolved in a mixture of MeOH (3 mL) and DMF (6 mL). To this solution was added sodium methanolate (140 mg, 0.648 mmol) and the reaction left stirring for 0.5 h. The product was isolated by preparative HPLC (100×30 mm Luna C18 column, flow rate 42 ml permin, gradient elution starting with A:B=90:10 and ending with A:B=30:70 [A=10 mM NH4OAc in 5% aqueous acetonitrile; B=10 mM NH4OAc in 95% aqueous acetonitrile] over 20 min) followed by removal of solvent to afford 39 mg of 3-(3,4-dichlorophenyl)-7-(hydroxymethyl)-9H-carbazole-1-carboxamide as a light yellow solid. MS (ESI) m/z 383.1 (M−H). 1H NMR (DMSO-d6) δ ppm 11.44 (1H, s), 8.73 (1H, d, J=1.53 Hz), 8.36 (1H, br. s.), 8.30 (1H, d, J=1.53 Hz), 8.22 (1H, d, J=2.14 Hz), 8.19 (1H, d, J=7.93 Hz), 7.94 (1H, dd, J=8.55, 2.14 Hz), 7.77 (1H, d, J=8.24 Hz), 7.71 (1H, s), 7.56 (1H, br. s.), 7.18 (1H, d, J=7.93 Hz), 5.24 (1H, t, J=5.80 Hz), 4.66 (2H, d, J=5.80 Hz).
Reaction SMILES: [C:1]([C:5]1[N:6]([CH3:24])[C:7](=[O:23])[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][C:11]([C:21]#[N:22])=[CH:10][CH:9]=2)([CH3:4])([CH3:3])[CH3:2].[OH-:25].[Na+].Cl>CO>[C:1]([C:5]1[N:6]([CH3:24])[C:7](=[O:23])[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][C:11]([C:21]([NH2:22])=[O:25])=[CH:10][CH:9]=2)([CH3:4])([CH3:2])[CH3:3]
Reactant: Cn1c(C(C)(C)C)c(-c2ccccc2)c2cc(C#N)ccc2c1=O
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: Cn1c(C(C)(C)C)c(-c2ccccc2)c2cc(C(N)=O)ccc2c1=O
Reaction time: 8 h

Procedure:
3-tert-butyl-2-methyl-1-oxo-4-phenyl-1,2-dihydroisoquinoline-6-carbonitrile (300 mg), 10 N NaOH (6 mL), and methanol (1 mL) were combined at heated at 110 C overnight. The reaction was acidified with 6 N HCl to give a precipitate, which was isolated by filtration. This material was partitioned between EtOAc and 1 N NaOH by stirring vigorously overnight. The organic solution was discarded, and the aqueous solution was allowed to stand overnight, during which time a precipitate formed. Filtration provided the titled compound.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][C:10]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([N:19]2[C:25](=[O:26])[CH2:24][C:23](=[O:27])[NH:22][C:21]3[C:28]4[C:33]([CH:34]=[CH:35][C:20]2=3)=[CH:32][CH:31]=[CH:30][CH:29]=4)=[CH:15][CH:14]=1)=[O:11].B(Br)(Br)Br>ClCCl>[OH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][C:10]([NH:12][C:13]1[CH:14]=[CH:15][C:16]([N:19]2[C:25](=[O:26])[CH2:24][C:23](=[O:27])[NH:22][C:21]3[C:28]4[C:33]([CH:34]=[CH:35][C:20]2=3)=[CH:32][CH:31]=[CH:30][CH:29]=4)=[CH:17][CH:18]=1)=[O:11]
Reactant: COc1ccccc1CC(=O)Nc1ccc(N2C(=O)CC(=O)Nc3c2ccc2ccccc32)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=C(Cc1ccccc1O)Nc1ccc(N2C(=O)CC(=O)Nc3c2ccc2ccccc32)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 28.2 %

Procedure:
5-[4-[(2-Methoxyphenylacetyl)amino]phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione (50 mg, 0.11 mmol) obtained in Example 22 was dissolved in dry dichloromethane (20 mL), the solution was added with a 1 M solution of boron tribromide in dichloromethane (0.22 mL), and the mixture was stirred at room temperature for 24 hours. The solvent was evaporated, the residue was added with saturated aqueous sodium hydrogencarbonate, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was washed with ethyl acetate to give the title compound (14 mg, yield 28%) as pale yellow crystals.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[F:10][C:11]1[CH:12]=[C:13]([CH:16]=[C:17]([F:19])[CH:18]=1)[C:14]#[N:15].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[F:10][C:11]1[CH:12]=[C:13]([CH:16]=[C:17]([F:19])[C:18]=1[O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1)[C:14]#[N:15]
Reactant: N#Cc1cc(F)cc(F)c1
Reactant: O=Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#Cc1cc(F)c(Oc2ccc(C=O)cc2)c(F)c1

Procedure:
Basic displacement reaction of 4-hydroxy benzaldehyde and 3,5-difluorobenzonitrile using potassium carbonate in anhydrous DMF at reflux temperatures affords the above compound.
Reaction SMILES: [CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10](F)=[C:9]([F:14])[C:8]=2[F:15])(=[O:6])=[O:5])[CH2:3][CH2:2]1.[C:16]([O:20][C:21]([N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1)=[O:22])([CH3:19])([CH3:18])[CH3:17]>CN(C)C(=O)C>[C:16]([O:20][C:21]([N:23]1[CH2:28][CH2:27][N:26]([C:10]2[CH:11]=[CH:12][C:7]([S:4]([CH:1]3[CH2:3][CH2:2]3)(=[O:6])=[O:5])=[C:8]([F:15])[C:9]=2[F:14])[CH2:25][CH2:24]1)=[O:22])([CH3:19])([CH3:17])[CH3:18]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=S(=O)(c1ccc(F)c(F)c1F)C1CC1
Solvent: CC(=O)N(C)C
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(S(=O)(=O)C3CC3)c(F)c2F)CC1
Temperature: 90 °C

Procedure:
To 4.2 mmol 1-cyclopropanesulfonyl-2,3,4-trifluoro-benzene in 20 ml N,N-dimethylacetamide was added 8.9 mmol tert-butyl-1-piperazine carboxylate, and the mixture was heated at 90° C. for 1 h. The mixture was then cooled to room temperature and concentrated in vacuo. The residue was chromatographed on silica gel (eluant: dichloromethane/ethyl acetate gradient) to afford the title compound. MS (m/e): 403.3 (M+H+, 100%)
Reaction SMILES: [CH3:1][C:2]1([CH:10]=[O:11])[CH2:7][CH2:6][C:5]([CH3:8])=[CH:4][CH:3]1[CH3:9].[CH:12]([Mg]Br)([CH3:14])[CH3:13]>>[CH3:13][CH:12]([CH3:14])[CH:10]([C:2]1([CH3:1])[CH2:7][CH2:6][C:5]([CH3:8])=[CH:4][CH:3]1[CH3:9])[OH:11]
Reactant: CC1=CC(C)C(C)(C=O)CC1
Reactant: CC(C)[Mg]Br
Product: CC1=CC(C)C(C)(C(O)C(C)C)CC1

Procedure:
2-methyl-1-(1,2,4-trimethyl-3-cyclohexen-1-yl)-1-propanol (compound 1) was prepared from 1,2,4-trimethyl-3-cyclohexene-1-carboxaldehyde and isopropylmagnesium bromide (reaction 1 above).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]1[C:9]([CH3:10])=[C:8]([CH3:11])[S:7][C:6]1=[NH:12].CCN(CC)CC.[C:20](Cl)(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C1COCC1>[CH3:1][O:2][CH2:3][CH2:4][N:5]1[C:9]([CH3:10])=[C:8]([CH3:11])[S:7]/[C:6]/1=[N:12]\[C:20](=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: COCCn1c(C)c(C)sc1=N
Reactant: O=C(Cl)c1ccccc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COCCn1c(C)c(C)s/c1=N\C(=O)c1ccccc1
Yield: 34.5 %

Procedure:
The product of Example 126A (0.20 g, 1.1 mmol), Et3N (0.45 mL, 3.2 mmol) and benzoyl chloride (Aldrich, 0.16 mL, 1.4 mmol) in 15 mL THF were processed using the method described in Example 129 to afford the title compound (0.11 g, 0.38 mmol, 35% yield). 1H NMR (300 MHz, CDCl3) δ ppm 2.24 (s, 3H), 2.27 (d, J=0.7 Hz, 3H), 3.32 (s, 3H), 3.82 (t, J=5.3 Hz, 2H), 4.41 (t, J=5.3 Hz, 2H), 7.38-7.51 (m, 3H), 8.27-8.34 (m, 2H); MS (DCI/NH3) m/z 291 (M+H)+; Anal: calculated for C15H18N2O2S: C, 62.04; H, 6.25; N, 9.65. Found: C, 62.02; H, 6.05; N, 9.56.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([CH3:11])=[CH:5]2.Cl[C:13]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[S:15][N:14]=1>>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([CH3:11])=[C:5]2[C:13]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[S:15][N:14]=1
Reactant: Clc1nsc2ccccc12
Reactant: Cc1cc2cc(F)ccc2[nH]1
Product: Cc1[nH]c2ccc(F)cc2c1-c1nsc2ccccc12

Procedure:
The title compound was prepared from 5-fluoro-2-methylindole and 3-chloro-1,2-benzisothiazole by the method of Example 31, step a).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][N:6]=[C:5]2[C:12]([O:14]C)=O.O.[NH2:17][NH2:18]>CO>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][N:6]=[C:5]2[C:12]([NH:17][NH2:18])=[O:14]
Reactant: COC(=O)c1ncnc2ccc(Br)cc12
Reactant: NN
Solvent: O
Solvent: CO
Product: NNC(=O)c1ncnc2ccc(Br)cc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 961 mg methyl 6-bromoquinazoline-4-carboxylate (compound in Production Example 413), 0.9 mL hydrazine monohydrate and 70 mL methanol was stirred at room temperature for 30 minutes, and the precipitated crystals were collected by filtration. The filtrate was evaporated to give additional crystals. The title compound, 838 mg in total, was obtained as pale yellow crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:19])[CH:5]=[N:6][C:7]=1[O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[N:15]=[CH:14][CH:13]=[CH:12]2.[CH3:20][O:21][C:22]1[CH:23]=[C:24]([S:30](Cl)(=[O:32])=[O:31])[CH:25]=[CH:26][C:27]=1[O:28][CH3:29]>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:19][S:30]([C:24]2[CH:25]=[CH:26][C:27]([O:28][CH3:29])=[C:22]([O:21][CH3:20])[CH:23]=2)(=[O:32])=[O:31])[CH:5]=[N:6][C:7]=1[O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[N:15]=[CH:14][CH:13]=[CH:12]2
Reactant: COc1ccc(S(=O)(=O)Cl)cc1OC
Reactant: Nc1cnc(Oc2ccc3ncccc3c2)c(Cl)c1
Product: COc1ccc(S(=O)(=O)Nc2cnc(Oc3ccc4ncccc4c3)c(Cl)c2)cc1OC

Procedure:
The title compound was prepared by reacting 5-chloro-6-(quinolin-6-yloxy)pyridin-3-amine (obtained as per procedure described in preparation 3) and 3,4-dimethoxybenzene-1-sulfonyl chloride.
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:25](=[O:26])[N:6]2[C@@H:7]([C:12]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=3)=[O:13])[C:8](=O)[C@H:9]([CH3:10])[C@H:5]12)[CH3:3].[N:27]([CH2:30][CH2:31][S:32][C:33]1[N:34]=[C:35]([S:54][CH3:55])[N:36]2[CH:40]=[C:39]([Sn](CCCC)(CCCC)CCCC)[S:38][C:37]=12)=[N+:28]=[N-:29]>>[N:27]([CH2:30][CH2:31][S:32][C:33]1[N:34]=[C:35]([S:54][CH3:55])[N:36]2[CH:40]=[C:39]([C:8]3[C@H:9]([CH3:10])[C@@H:5]4[C@@H:4]([C@H:2]([OH:1])[CH3:3])[C:25](=[O:26])[N:6]4[C:7]=3[C:12]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=3)=[O:13])[S:38][C:37]=12)=[N+:28]=[N-:29]
Reactant: C[C@@H](O)[C@H]1C(=O)N2[C@@H](C(=O)OCc3ccc([N+](=O)[O-])cc3)C(=O)[C@H](C)[C@H]12
Reactant: CCCC[Sn](CCCC)(CCCC)c1cn2c(SC)nc(SCCN=[N+]=[N-])c2s1
Product: CSc1nc(SCCN=[N+]=[N-])c2sc(C3=C(C(=O)OCc4ccc([N+](=O)[O-])cc4)N4C(=O)[C@H]([C@@H](C)O)[C@H]4[C@H]3C)cn12
Yield: 53.4 %

Procedure:
The procedure of Example 1a) was repeated, except that 300 mg of 4-nitrobenzyl (1R,3R,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-oxo-1-carbapenam-3-carboxylate and 485 mg of 7-(2-azidoethyl)thio-5-methylthio-2-(tri-n-butylstannyl)imidazo[5,1-b]thiazole were used as the starting compounds. Thus, 272 mg of 4-nitrobenzyl (1S,5R,6S)-2-[7-(2-azidoethyl)thio-5-methylthioimidazo-[5,1-b]thiazol-2-yl]-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylate was prepared.
Reaction SMILES: [CH3:1][N:2]1[CH2:21][CH2:20][C:5]2[N:6]([CH2:14][C:15]([O:17]CC)=O)[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.[NH3:22]>>[CH3:1][N:2]1[CH2:21][CH2:20][C:5]2[N:6]([CH2:14][C:15]([NH2:22])=[O:17])[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1
Reactant: N
Reactant: CCOC(=O)Cn1c2c(c3cc(C)ccc31)CN(C)CC2
Product: Cc1ccc2c(c1)c1c(n2CC(N)=O)CCN(C)C1
Reaction time: 0.25 h

Procedure:
Ethyl 2-(1,2,3,4-tetrahydro-2,8-dimethylpyrido[4,3-b]indol-5-yl)acetate (0.5 g, 1.75 mmol) was taken in 4 ml aqueous ammonia and microwaved at 120° C. for 5 min using Initiator (Biotage Microwave). The solid product precipitated out after the reaction was filtered through Buchner funnel and washed with 10% sodium bicarbonate (10 ml×2) followed by demineralised water (10 ml×2) wash. Product was vacuum dried and was taken in 5 ml ethanolic HCl, stirred for 15 minutes, concentrated in vacuo to afford 13 mg of 2-(1,2,3,4-tetrahydro-2,8-dimethylpyrido[4,3-b]indol-5-yl)acetamide as HCl salt. 1H NMR (DMSO) 10.2 (bs, 1H), 7.62 (s, 1H), 7.21-7.3 (m, 3H), 6.9 (d, 1H), 4.75 (s, 2H), 4.45-4.51 (m, 1H), 4.21-4.25 (m, 1H), 3.12-3.17 (m, 4H), 2.97 (s, 3H), 2.19 (s, 3H).