Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:4]=1[NH2:5].[N:13]([O-])=O.[Na+].[CH2:17]([N:19]([CH2:27][CH2:28][OH:29])[C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([CH3:26])[CH:21]=1)[CH3:18]>>[CH3:26][C:22]1[CH:21]=[C:20]([CH:25]=[CH:24][C:23]=1[N:13]=[N:5][C:4]1[CH:6]=[CH:7][C:8]([N+:10]([O-:12])=[O:11])=[CH:9][C:3]=1[O:2][CH3:1])[N:19]([CH2:17][CH3:18])[CH2:27][CH2:28][OH:29]
Reactant: O=N[O-]
Reactant: CCN(CCO)c1cccc(C)c1
Reactant: COc1cc([N+](=O)[O-])ccc1N
Agent: [Na+]
Product: CCN(CCO)c1ccc(N=Nc2ccc([N+](=O)[O-])cc2OC)c(C)c1
Yield: 96 %

Procedure:
16.8 g (0.1 mol) of 2-methoxy-4-nitroaniline was diazotized in a conventional manner using 7.0 g of sodium nitrite and subjected to coupling with 17.9 g (0.1 mol) of N-ethyl-N-hydroxyethyl-m-toluidine to obtain 34.4 g of 3-methyl-4-(2-methoxy-4-nitrophenylazo)-N-ethyl-N-hydroxyethylaniline. 17.9 g (0.05 mol) of the compound thus obtained was added to 50 ml of pyridine and then to the mixture was added little by little 29 g of p-toluenesulfonyl chloride at a temperature range between 10° C. and 15° C. After the completion of the addition, the mixture was stirred at room temperature for 2 hours, then the reaction solution was poured into cool diluted hydrochloric acid and the resulting red colored precipitate was collected by filtration. The crude product was recrystallized from diluted acetone to obtain 14.2 g of 3-methyl-4-(2-methoxy-4-nitrophenylazo)-N-ethyl-N-toluenesulfonyloxyethylaniline [5-b].
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[C:9]([O-])(=[O:11])[CH3:10].[Na+].C(OC(=O)C)(=O)C.C(=O)(O)[O-].[Na+]>C1C=CC=CC=1.O>[C:9]([O:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)(=[O:11])[CH3:10]
Reactant: CC(=O)[O-]
Reactant: Oc1ccc(F)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Solvent: O
Solvent: c1ccccc1
Product: CC(=O)Oc1ccc(F)cc1
Yield: 128.9 %

Procedure:
4-Fluorophenol (112.1 g, 1.0 mole), sodium acetate (68.89 g, 0.74 mole) and acetic anhydride (107.6 g, 1.05 mole) were mixed in benzene (220 ml) with stirring and heated under reflux for 2 hours. After cooling, water (500 ml) and sodium bicarbonate (100 g, 1.19 mole) were added to the reaction mixture and the mixture was stirred. The mixture was allowed to stand to separate into layers and the aqueous layer was extracted with benzene (500 ml). The organic layers were combined, dried over anhydrous sodium sulfate and distilled to obtain the title compound (147 g, 95.4%), b.p. 84°-86° C./16 mmHg.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH2:17])[C:5]([NH2:16])=[CH:6][C:7]=1[N:8]1[CH2:14][CH2:13][CH2:12][N:11]([CH3:15])[CH2:10][CH2:9]1.C(N(CC)CC)C.C1[C:37]2[C:36](=[O:38])[C:35]3C(=CC=CC=3)C=2C(C(Cl)=O)=CC=1>ClCCl>[CH:36]([O:38][CH:13]([CH3:12])[CH3:14])([CH3:37])[CH3:35].[NH2:16][C:5]1[CH:6]=[C:7]([N:8]2[CH2:14][CH2:13][CH2:12][N:11]([CH3:15])[CH2:10][CH2:9]2)[C:2]([F:1])=[CH:3][C:4]=1[NH-:17]
Reactant: O=C(Cl)c1cccc2c1-c1ccccc1C2=O
Reactant: CN1CCCN(c2cc(N)c(N)cc2F)CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)OC(C)C
Product: CN1CCCN(c2cc(N)c([NH-])cc2F)CC1
Yield: 66.7 %

Procedure:
The procedure used in stage 1 of Example 1 is followed, but starting from 2.86 g of 4-fluoro-5-(4-methylperhydro-1,4-diazepin-1-yl)benzene-1,2-diamine, which can be prepared according to J. Het. Chem. 2005, 42(1), 67-71, 2.81 ml of triethylamine and 2.427 g of 9H-fluoren-9-one-4-carboxylic acid chloride in 50 ml of dichloromethane for 20 hours at room temperature. After purification by flash chromatography on silica gel (40-63 μm), eluting with a mixture of dichloromethane and methanol (95/5 by volume), then formation of a paste with diisopropyl ether, in this way we obtain 950 mg of [2-amino-5-fluoro-4-(4-methylperhydro-1,4-diazepin-1-yl)phenyl]amide of 9-oxo-9H-fluorene-4-carboxylic acid, in the form of an orange powder, which is used as it is in the following stage, with the following characteristics:
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([O:15][C:16]([C:18]1[CH:23]=[CH:22][C:21]([NH:24][S:25]([C:28]2[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][CH:29]=2)(=[O:27])=[O:26])=[CH:20][CH:19]=1)=[O:17])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.Cl.[C:36]1(C(Cl)=O)[C:49]2[C:40](=[N:41][C:42]3[C:47]([CH:48]=2)=[CH:46][CH:45]=[CH:44][CH:43]=3)[CH:39]=[CH:38][CH:37]=1.CN(C1C=CC=CN=1)C.[O:62]1CCC[CH2:63]1>>[CH2:8]([O:15][C:16]([C:18]1[CH:23]=[CH:22][C:21]([N:24]([S:25]([C:28]2[CH:29]=[CH:30][C:31]([CH3:34])=[CH:32][CH:33]=2)(=[O:27])=[O:26])[C:63]([C:48]2[C:47]3[C:42]([N:41]=[C:40]4[C:49]=2[CH:36]=[CH:37][CH:38]=[CH:39]4)=[CH:43][CH:44]=[CH:45][CH:46]=3)=[O:62])=[CH:20][CH:19]=1)=[O:17])[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: O=C(Cl)c1cccc2nc3ccccc3cc12
Reactant: C1CCOC1
Reactant: Cc1ccc(S(=O)(=O)Nc2ccc(C(=O)OCc3ccccc3)cc2)cc1
Agent: CN(C)c1ccccn1
Agent: Cl
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)N(C(=O)c2c3ccccc3nc3ccccc23)c2ccc(C(=O)OCc3ccccc3)cc2)cc1
Temperature: 600 °C

Procedure:
2.1 ml (15 mmol) of triethylamine in 10 ml of tetrahydrofuran are added dropwise at 25° C. to a solution of 1.5 g (4 mmol) of N-(4-benzyloxycarbonylphenyl)-4-toluenesulfonamide, 1.23 g (4.4 mmol) of acridinecarbonyl chloride hydrochloride and 0.02 g of dimethylaminopyridine in 20 ml of anhydrous tetrahydrofuran. The temperature is raised to 600° C.
Reaction SMILES: [C:1]([NH:11][C:12]1[S:13][C:14]([F:24])=[C:15]([C:17](=[N:21][O:22][CH3:23])[C:18]([OH:20])=O)[N:16]=1)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].[C:25]1([CH:31]([O:38][C:39]([C:41]2[N:46]3[C:47](=[O:50])[C@@H:48]([NH2:49])[C@H:45]3[S:44][CH2:43][CH:42]=2)=[O:40])[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[C:25]1([CH:31]([O:38][C:39]([C:41]2[N:46]3[C:47](=[O:50])[C@@H:48]([NH:49][C:18](=[O:20])[C:17]([C:15]4[N:16]=[C:12]([NH:11][C:1]([O:3][CH2:4][C:5]5[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=5)=[O:2])[S:13][C:14]=4[F:24])=[N:21][O:22][CH3:23])[C@H:45]3[S:44][CH2:43][CH:42]=2)=[O:40])[C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: CON=C(C(=O)O)c1nc(NC(=O)OCc2ccccc2)sc1F
Reactant: N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=CCS[C@H]12
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: CON=C(C(=O)N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=CCS[C@H]12)c1nc(NC(=O)OCc2ccccc2)sc1F
Temperature: 23 °C
Reaction time: 1 h
Yield: 70.9 %

Procedure:
To a solution of 2-(2-carbobenzoxyamino-5-fluoro-4-thiazolyl)-2-methoxyiminoacetic acid (207 mg) and 7β-amino-3-cephem-4-carboxylic acid diphenylmethyl ester (207 mg) in dichloromethane (20 ml) is added dicyclohexylcarbodiimide (142 mg), and the mixture is stirred at 23° C. for 60 minutes and concentrated to remove dichloromethane. The residue is dissolved in ethyl acetate, filtered to remove solid material, and concentrated under reduced pressure. The resultant product is purified by silica gel column chromatography to afford 7β-[2-(2-carbobenzoxyamino-5-fluoro-4-thiazolyl)-2-methoxyiminoacetamido]-3-cephem-4-carboxylic acid diphenylmethyl ester (281 mg).
Reaction SMILES: Cl.[O:2]=[C:3]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[CH2:7][O:6][C:5]2[CH:14]=[CH:15][C:16]([CH2:18][CH2:19][NH2:20])=[CH:17][C:4]1=2.C(N(CC)CC)C.[CH3:28][S:29](Cl)(=[O:31])=[O:30].O>C(Cl)Cl>[O:2]=[C:3]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[CH2:7][O:6][C:5]2[CH:14]=[CH:15][C:16]([CH2:18][CH2:19][NH:20][S:29]([CH3:28])(=[O:31])=[O:30])=[CH:17][C:4]1=2
Reactant: NCCc1ccc2c(c1)C(=O)c1ccccc1CO2
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CS(=O)(=O)NCCc1ccc2c(c1)C(=O)c1ccccc1CO2
Reaction time: 0.75 h
Yield: 49 %

Procedure:
To a solution of 3.5 g (0.014 m), of 2-(6,11-dihydro-11-oxodibenz[b,e]oxepin-2-yl)ethylamine of Example 6 and 1.4 g (0.014 m) of triethylamine in 50 ml of CH2Cl2, 1.6 g (0.014 m) of methanesulfonyl chloride was added dropwise maintaining the temperature between 15°-20° C. The mixture was stirred 45 minutes, then poured into water. The CH2Cl2 layer was separated, washed with water, dried (Na2SO4), filtered and evaporated to give a foamy solid. Recrystallization from approximately 40 ml of toluene gave 2.27 g (49%) of N-(2-(6,11-dihydro-11-oxodibenz[b,e]oxepin-2-yl)ethyl)methanesulfonamide, m.p. 104°-106° C.
Reaction SMILES: [CH2:1]([O:8][CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C:10]1([C:23]([S:26]CC1C=CC(OC)=CC=1)=[N:24][CH3:25])[N:15]1[CH:19]=[C:18]([N+:20]([O-:22])=[O:21])[N:17]=[CH:16]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(OC)C=CC=CC=1.C(=O)([O-])O.[Na+]>FC(F)(F)C(O)=O>[CH2:1]([O:8][CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C:10]1([N:15]1[CH:19]=[C:18]([N+:20]([O-:22])=[O:21])[N:17]=[CH:16]1)[C:23](=[S:26])[NH:24][CH3:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN=C(SCc1ccc(OC)cc1)C1(n2cnc([N+](=O)[O-])c2)CCCCC1OCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: CNC(=S)C1(n2cnc([N+](=O)[O-])c2)CCCCC1OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 67.6 %

Procedure:
6.18 g (12.4 mmol) of the 2-benzyloxy-1-((4-methoxybenzylthio)(methylimino)methyl)-1-(4-nitroimidazol-1-yl)cyclohexane prepared in the Preparative Example 14 was dissolved in 28 ml of trifluoroacetic acid under cooling with ice, followed by the addition of 5 ml of anisole. The obtained mixture was stirred at 0° C. for 10 minutes to give a dark-brown solution, which was pored onto a mixture comprising a saturated aqueous solution of sodium hydrogencarbonate and ice. The obtained mixture was extracted with ethyl acetate. The organic phase was washed with a saturated aqueous solution of common salt, dried over anhydrous sodium sulfate, and concentrated in a vacuum. The residue (8.02 g) was purified by silica gel column chromatography [solvent: dichloromethane/acetone (40:1)], and recrystallized from dichloromethane/diisopropyl ether to give 3.14 g of the title compound as a colorless crystal (yield: 67%).
Reaction SMILES: Cl[C:2]1[C:7]([CH2:8][N:9]2[C:30](=[O:31])[N:12]3[CH:13]=[CH:14][C:15]([C:23]4[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=4)=[C:16]([C:17]4[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=4)[C:11]3=[N:10]2)=[CH:6][CH:5]=[C:4]([C:32]([F:35])([F:34])[F:33])[N:3]=1.[CH2:36]([NH2:38])[CH3:37].ClC1C=CC(C2C=CN3C(=O)N(CC4C(NC)=NC(C(F)(F)F)=CC=4)N=C3C=2C2C=CN=CC=2)=CC=1>C1COCC1>[Cl:29][C:26]1[CH:25]=[CH:24][C:23]([C:15]2[CH:14]=[CH:13][N:12]3[C:30](=[O:31])[N:9]([CH2:8][C:7]4[C:2]([NH:38][CH2:36][CH3:37])=[N:3][C:4]([C:32]([F:33])([F:34])[F:35])=[CH:5][CH:6]=4)[N:10]=[C:11]3[C:16]=2[C:17]2[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=2)=[CH:28][CH:27]=1
Reactant: CCN
Reactant: O=c1n(Cc2ccc(C(F)(F)F)nc2Cl)nc2c(-c3ccncc3)c(-c3ccc(Cl)cc3)ccn12
Agent: CNc1nc(C(F)(F)F)ccc1Cn1nc2c(-c3ccncc3)c(-c3ccc(Cl)cc3)ccn2c1=O
Solvent: C1CCOC1
Product: CCNc1nc(C(F)(F)F)ccc1Cn1nc2c(-c3ccncc3)c(-c3ccc(Cl)cc3)ccn2c1=O
Yield: 54 %

Procedure:
The title compound (14 mg, 54% yield) as a yellow powder was prepared from 2-((2-chloro-6-(trifluoromethyl)pyridin-3-yl)methyl)-7-(4-chlorophenyl)-8-(pyridin-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one (26 mg, 0.05 mmol), and 2 M ethylamine solution in THF (0.5 mL) according to the procedures described for 7-(4-chlorophenyl)-2-((2-(methylamino)-6-(trifluoromethyl)pyridin-3-yl)methyl)-8-(pyridin-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one. HPLC/MS: retention time=3.50 min, [M+H]+=525.2.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([C:10]([O:12][CH3:13])=[O:11])=[N:8][CH:9]=1)([O-])=O.[H][H]>C(OCC)(=O)C.[Pt]=O>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([C:10]([O:12][CH3:13])=[O:11])=[N:8][CH:9]=1
Reactant: [H][H]
Reactant: COC(=O)c1ccc([N+](=O)[O-])cn1
Agent: O=[Pt]
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(N)cn1

Procedure:
A solution containing 10 g methyl 5-nitropicolinate in 400 ml ethyl acetate is stirred under hydrogen in the presence of 1 g platinum oxide at room temperature and atmospheric pressure. When no further hydrogen uptake occurs, the catalyst is removed by filtration, the filtrate concentrated, and the product collected. This is recrystallized from ethyl acetate to give analytically pure methyl 5-aminopicolinate, mp 147°-150.5° C.
Reaction SMILES: [CH:1]1[C:6]([NH2:7])=[CH:5][CH:4]=[C:3]([O:8][C:9]2[CH:10]=[CH:11][C:12]([NH2:15])=[CH:13][CH:14]=2)[CH:2]=1.[C:16](OC(=O)C)(=[O:18])[CH3:17].[C:23](O)(=[O:25])[CH3:24]>>[CH3:17][C:16]([NH:15][C:12]1[CH:13]=[CH:14][C:9]([O:8][C:3]2[CH:2]=[CH:1][C:6]([NH:7][C:23]([CH3:24])=[O:25])=[CH:5][CH:4]=2)=[CH:10][CH:11]=1)=[O:18]
Reactant: CC(=O)OC(C)=O
Reactant: CC(=O)O
Reactant: Nc1ccc(Oc2ccc(N)cc2)cc1
Product: CC(=O)Nc1ccc(Oc2ccc(NC(C)=O)cc2)cc1
Yield: 91.8 %

Procedure:
To a 70° C. solution of 25 grams (0.125 mole) of 4,4′-diaminodiphenyl ether in 90 ml of glacial acetic acid was added 28.55 ml (0.286 mole) of acetic anhydride. The acetic anhydride was added dropwise at such a rate and with heating to maintain a temperature between 90° C. and 100° C. After the addition of acetic anhydride, the temperature was maintained between 90° C. and 100° C. for an additional hour. The reaction mixture was further reacted at room temperature overnight forming a precipitate. The mixture was filtered, and the collected precipitate dried at room temperature to give 32.6 grams of 4,4′-diacetamidodiphenyl ether, m.p. 228-230° C. (lit. m.p. 228-229° C.). The yield was 91.8% of the theoretical amount.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[N:22]=[CH:21][C:20]([C:23]3[CH:28]=[CH:27][C:26]([O:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])=[CH:25][CH:24]=3)=[CH:19][N:18]=2)=[CH:13][CH:12]=1)[C:3]([O:5]C(C)(C)C)=[O:4].[C:37]([C:41]1[CH:49]=[CH:48][C:44]([C:45]([OH:47])=O)=[CH:43][CH:42]=1)([CH3:40])([CH3:39])[CH3:38].C(N(C(C)C)C(C)C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.O>[C:37]([C:41]1[CH:42]=[CH:43][C:44]([C:45]([NH:1][C@@H:2]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([C:17]3[N:22]=[CH:21][C:20]([C:23]4[CH:28]=[CH:27][C:26]([O:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])=[CH:25][CH:24]=4)=[CH:19][N:18]=3)=[CH:15][CH:16]=2)[C:3]([OH:5])=[O:4])=[O:47])=[CH:48][CH:49]=1)([CH3:38])([CH3:39])[CH3:40]
Reactant: CC(C)(C)c1ccc(C(=O)O)cc1
Reactant: CCCCCCCOc1ccc(-c2cnc(-c3ccc(C[C@H](N)C(=O)OC(C)(C)C)cc3)nc2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CCCCCCCOc1ccc(-c2cnc(-c3ccc(C[C@H](NC(=O)c4ccc(C(C)(C)C)cc4)C(=O)O)cc3)nc2)cc1
Reaction time: 1 h
Yield: 85 %

Procedure:
A stirred solution of (S)-tert-butyl 2-amino-3-(4-(5-(4-(heptyloxy)phenyl)pyrimidin-2-yl)phenyl)propanoate INT-9 (1.34 g, 2.74 mmol) and 4-(tert-butyl)benzoic acid (0.54 g, 3.01 mmol) in DMF (5 mL) and N-ethyl-N-isopropylpropan-2-amine (1.01 ml, 5.47 mmol) was treated with HATU (1.09 g, 2.87 mmol). After stirring for 1 h, the mixture was treated with water (60 mL) and iso-hexanes (20 mL) and stirred for 1 h. The product was collected by filtration, washed with water (3×10 mL) then iso-hexanes (10 mL) and dried in the vacuum oven. The ester was taken up in DCM (5 mL) and treated with TFA (5 mL). After 2 h, the mixture was treated with toluene (5 mL) and evaporated. The residue was taken up in DMSO (6 mL) then treated with water (20 mL) and stirred for 1 h. The product was collected by filtration, washed with water (3×15 mL) then acetonitrile (2×5 mL), and dried in the vacuum oven to give 1.40 g (85%) of (S)-2-(4-(tert-butyl)benzamido)-3-(4-(5-(4-(heptyloxy)phenyl)pyrimidin-2-yl)phenyl)propanoic acid Compound 85 as a white solid. LCMS-ESI (m/z) calculated for C37H43N3O4: 593.3. found: 594.0 [M+H]+, tR=11.18 min (Method 9) and 97% e.e. (Chiral Method). 1H NMR (400 MHz, DMSO-d6) δ 12.79 (br, s, 1H), 9.16 (s, 2H), 8.66 (d, J=8.2 Hz, 1H), 8.45-8.27 (m, 2H), 7.89-7.69 (m, 4H), 7.57-7.38 (m, 4H), 7.18-7.02 (m, 2H), 4.77-4.62 (m, 1H), 4.03 (t, J=6.5 Hz, 2H), 3.30-3.24 (m, 1H), 3.22-3.12 (m, 1H), 1.80-1.68 (m, 2H), 1.48-1.20 (m, 17H), 0.96-0.82 (m, 3H).
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[CH2:10]([O:17][C:18]1[CH:19]=[CH:20][C:21]2[O:27][CH2:26][CH2:25][CH:24](Br)[C:23](=[O:29])[C:22]=2[CH:30]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>O1CCCC1>[CH2:10]([O:17][C:18]1[CH:19]=[CH:20][C:21]2[O:27][CH2:26][CH2:25][CH:24]([O:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[C:23](=[O:29])[C:22]=2[CH:30]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=C1c2cc(OCc3ccccc3)ccc2OCCC1Br
Reactant: Oc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C1c2cc(OCc3ccccc3)ccc2OCCC1Oc1ccccc1
Reaction time: 0.5 h
Yield: 42.8 %

Procedure:
To a solution of 1.4 g of phenol in 50 ml of tetrahydrofuran was added 720 mg of 50% sodium hydride. After stirring for 30 minutes, a solution of 4.5 g of crude 7-benzyloxy-4-bromo-3,4-dihydro-1-benzoxepin-5(2H)-one was added. The reaction was allowed to stir at room temperature for 5 hours. The tetrahydrofuran was evaporated in vacuo, and the residue dissolved in ethyl acetate and washed with water. The ethyl acetate layer was dried over sodium sulfate and evaporated in vacuo to give the crude product which was purified by recrystallization from methanol to give 2 g of title product, m.p. 112°-114° C.
Reaction SMILES: [CH2:1]([N:5]([CH2:11][CH:12](OC)[O:13]C)[C:6](=[O:10])[O:7][CH2:8][CH3:9])[CH:2]=[CH:3][CH3:4].C(O)=O.[Cl-].[Na+]>O>[CH2:1]([N:5]([CH2:11][CH:12]=[O:13])[C:6](=[O:10])[O:7][CH2:8][CH3:9])[CH:2]=[CH:3][CH3:4]
Reactant: CC=CCN(CC(OC)OC)C(=O)OCC
Agent: [Cl-]
Agent: [Na+]
Solvent: O=CO
Solvent: O
Product: CC=CCN(CC=O)C(=O)OCC

Procedure:
111 g (0.48 mol) of ethyl N-(2-buten-1-yl)-N-(2,2-dimethoxyethyl)-carbamate are heated under reflux for three hours with 50 g of formic acid in 950 ml of water. The mixture is saturated with sodium chloride and extracted three times using 200 ml of methylene chloride each time. The organic phases are washed with sodium hydrogen carbonate solution until neutral, dried over magnesium sulphate and concentrated, and the residue is distilled.
Reaction SMILES: [C:1]([C:4]1[C:12]2[C:7](=[C:8]3[CH2:15][CH2:14][O:13][C:9]3=[CH:10][CH:11]=2)[NH:6][CH:5]=1)(=O)[CH3:2].B.CC(C)=O>O1CCCC1>[CH2:1]([C:4]1[C:12]2[C:7](=[C:8]3[CH2:15][CH2:14][O:13][C:9]3=[CH:10][CH:11]=2)[NH:6][CH:5]=1)[CH3:2]
Reactant: CC(=O)c1c[nH]c2c3c(ccc12)OCC3
Agent: B
Solvent: C1CCOC1
Solvent: CC(C)=O
Product: CCc1c[nH]c2c3c(ccc12)OCC3
Temperature: 25 °C
Yield: 45.1 %

Procedure:
To a stirred mixture of 3-acetyl-7,8-dihydrofuro[2,3-g]indole (721 mg, 3.58 mmol) in tetrahydrofuran (25 mL) under an atmosphere of Ar at ambient temperature was added, over 5 min, borane (1.0 M in THF; 18 mL, 18 mmol). The resultant mixture was stirred at ambient temperature for 30 min, then heated to reflux for 2 h before cooling to room temperature. Acetone (25 mL) was added and the mixture was heated to reflux for a further 30 min. The mixture was cooled to room temperature then all solvent was removed in vacuo. Methanol (40 mL) was added, and the mixture was again heated to reflux for 30 min, then cooled to room temperature followed by solvent removal in vacuo. Purification by flash column chromatography [SiO2; ethyl acetate-heptane (1:4)] afforded the product (302 mg, 45%) as a white solid: m.p. 91–92.5° C.; Found: C, 76.90; H, 7.02; N, 7.44%. C12H13NO requires: C, 76.98; H, 7.00; N, 7.48%.
Reaction SMILES: C(OC([C:6]1[C:10]([C:11]2[CH:16]=[CH:15][C:14]([I:17])=[CH:13][CH:12]=2)=[CH:9][NH:8][CH:7]=1)=O)C.[OH-].[Na+].[Na+].[Cl-]>C(O)CO>[I:17][C:14]1[CH:13]=[CH:12][C:11]([C:10]2[CH:6]=[CH:7][NH:8][CH:9]=2)=[CH:16][CH:15]=1
Reactant: CCOC(=O)c1c[nH]cc1-c1ccc(I)cc1
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: OCCO
Product: Ic1ccc(-c2cc[nH]c2)cc1
Temperature: 160 °C
Reaction time: 2.5 h
Yield: 378.7 %

Procedure:
Following earlier procedures (Balasubramanian, T.; Lindsey, J. S. Tetrahedron 1999, 55, 6771-6784), a mixture of 3-ethoxycarbonyl-4-(4-iodophenyl)pyrrole (7.20 g, 21.1 mmol) and ethylene glycol (55 mL) in a 100-mL Claisen flask was flushed with argon for 10 min and powdered NaOH (2.2 g, 55 mmol) was then added. The flask was placed in an oil bath at 120° C. and the oil bath temperature was raised to 160° C. After 2.5 h, the flask was cooled to room temperature and treated with 10% aq NaCl (100 mL). The aqueous layer was extracted with CH2Cl2, the organic layers were collected, washed with 10% aq NaCl, dried (Na2SO4), concentrated, and recrystallized in ethanol affording light brown crystals (5.18 g, 91%). mp 164-165° C.; 1H NMR δ 6.51 (m, 1H), 6.83 (m, 1H), 7.08 (s, 1H), 7.27 (d, J=8.7 Hz, 2H), 7.63 (d, J=8.7 Hz, 2H); 13C NMR δ89.9, 106.3, 114.7, 119.1, 123.8, 127.0, 135.2, 137.5; EI-MS obsd 268.9702, calcd 268.9702. Anal. Calcd for C10H8IN: C, 44.6; H, 3.0; N, 5.2. Found: C, 44.7; H, 3.0; N, 5.1. The synthesis starting from 4-iodobenzaldehyde (35 g), monoethyl malonate, and TosMIC has been performed with linear scale up of the established procedures, affording 21.5 g of 4.
Reaction SMILES: [CH2:1]([NH:3][C:4](=[O:45])[NH:5][C:6]1[N:11]=[CH:10][C:9]([C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[N:18]([C:22]2([CH2:28][OH:29])[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[CH:17]=[C:16]([C:30]([O:32]CC)=[O:31])[C:15]3=[O:35])=[C:8]([C:36]2[S:37][CH:38]=[C:39]([C:41]([F:44])([F:43])[F:42])[N:40]=2)[CH:7]=1)[CH3:2].C1COCC1.[Li+].[OH-].Cl>CO>[CH2:1]([NH:3][C:4](=[O:45])[NH:5][C:6]1[N:11]=[CH:10][C:9]([C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[N:18]([C:22]2([CH2:28][OH:29])[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[CH:17]=[C:16]([C:30]([OH:32])=[O:31])[C:15]3=[O:35])=[C:8]([C:36]2[S:37][CH:38]=[C:39]([C:41]([F:44])([F:42])[F:43])[N:40]=2)[CH:7]=1)[CH3:2]
Reactant: CCNC(=O)Nc1cc(-c2nc(C(F)(F)F)cs2)c(-c2ccc3c(c2)c(=O)c(C(=O)OCC)cn3C2(CO)CCOCC2)cn1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCNC(=O)Nc1cc(-c2nc(C(F)(F)F)cs2)c(-c2ccc3c(c2)c(=O)c(C(=O)O)cn3C2(CO)CCOCC2)cn1
Temperature: 100 °C

Procedure:
Ethyl 6-(6-(3-ethylureido)-4-(4-(trifluoromethyl)thiazol-2-yl)pyridin-3-yl)-1-(4-(hydroxymethyl)tetrahydro-2H-pyran-4-yl)-4-oxo-1,4-dihydroquinoline-3-carboxylate (Example 132, 0.225 g, 0.35 mmol) was diluted with 2:1 MeOH:THF (3 mL). A 2 M aq solution of LiOH (0.35 mL, 0.7 mmol) was added and the reaction mixture was heated in the microwave to 100° C. for 15 min. The mixture was conc in vacuo and acidified to approx. pH 3 with 1 N aq HCl. The resultant solid was collected and purified by column chromatography (silica 95:5 methylene chloride/methanol) followed by purification by reverse phase HPLC (C18, 0-95% acetonitrile/water gradient).
Reaction SMILES: [CH2:1]([OH:4])[C:2]#[CH:3].[Br:5][CH2:6][CH2:7][CH2:8][CH2:9]Br.[OH-].[Na+]>O>[Br:5][CH2:6][CH2:7][CH2:8][CH2:9][O:4][CH2:1][C:2]#[CH:3]
Reactant: BrCCCCBr
Reactant: C#CCO
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: C#CCOCCCCBr
Reaction time: 8 h

Procedure:
A mixture of 2-propyn-1-ol (10 g), 1,4-dibromobutane (60 ml), 50% aqueous sodium hydroxide (60 ml) and TAB (2 g) was stirred vigorously overnight. Water (250 ml) was added and the mixture was extracted with ether (2×200 ml). The organic extracts were dried and concentrated to a yellow oil which was purified by FCC (hexane→System D 19:1) to give the title compound as a colourless oil (19.7 g). T.l.c. (System D 19:1) Rf 0.37.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:8]([O:11]COC)=[CH:7][C:4]=1[CH:5]=[O:6].Cl>C1COCC1.O>[OH:11][C:8]1[CH:9]=[CH:10][C:3]([O:2][CH3:1])=[C:4]([CH:7]=1)[CH:5]=[O:6]
Reactant: COCOc1ccc(OC)c(C=O)c1
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(O)cc1C=O
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2-methoxy-5-(methoxymethoxy)benzaldehyde (10 g, 0.05 mol) in THF (100 mL) was added 3 N HCl (150 mL). The reaction was stirred at 50° C. for 30 min, cooled to rt, and diluted with water (100 mL). The mixture was neutralized to pH 7-8 and extracted with EtOAc (200 mL) three times. The organic layer was dried over Na2SO4 and concentrated to give 5-hydroxy-2-methoxybenzaldehyde.