Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10]([CH:12]1[CH2:17][CH2:16][O:15][C:13]1=[O:14])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:18][C:19]1[CH:23]=[CH:22][NH:21][N:20]=1>C(O)C>[CH2:1]([O:8][CH2:9][C:10](=[N:18][C:19]1[CH:23]=[CH:22][NH:21][N:20]=1)[CH:12]1[CH2:17][CH2:16][O:15][C:13]1=[O:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1cc[nH]n1
Reactant: O=C(COCc1ccccc1)C1CCOC1=O
Solvent: CCO
Product: O=C1OCCC1C(COCc1ccccc1)=Nc1cc[nH]n1
Temperature: 25 °C
Reaction time: 16.5 h
Yield: 65.5 %

Procedure:
In 2.0 ml of ethanol were dissolved 1.83 g of 2-benzyloxyacetyl-γ-butyrolactone and 0.50 g of 3-amino-pyrazole. To the solution, were added 60 μl of a boron trifluoride methanol complex, and the mixture was stirred for 16.5 hours at room temperature. The solvent was distilled off under reduced pressure, and the residue was subjected to column chromatography on silica gel (elution solvent: hexane:ethyl acetate=1:1→1:2) to obtain 1.18 g (yield: 65.5%) of the intended product as a yellow oil.
Reaction SMILES: CON(C)[C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([Br:24])[N:19]=2)[CH:7]=1)=[O:5]>C1COCC1.C(C1C=CC([Mg]Br)=CC=1)C>[Br:24][C:20]1[N:19]=[C:18]([CH2:17][N:8]2[C:9]3[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:15](=[O:16])[C:6]([C:4](=[O:5])[C:13]3[CH:12]=[CH:11][CH:10]=[CH:9][C:14]=3[CH3:15])=[CH:7]2)[CH:23]=[CH:22][CH:21]=1
Reactant: CON(C)C(=O)c1cn(Cc2cccc(Br)n2)c2ccccc2c1=O
Agent: CCc1ccc([Mg]Br)cc1
Solvent: C1CCOC1
Product: Cc1ccccc1C(=O)c1cn(Cc2cccc(Br)n2)c2ccccc2c1=O

Procedure:
Experimental conditions analogous to those described for Step 6 of Example 60 from 90 mg (0.22 mmol) of 1-(6-bromo-pyridin-2-ylmethyl)-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid methoxy-methyl-amide in 1 mL THF and 0.49 mL 1M 4-ethylphenylmagnesium bromide. Yield: 55 mg of a white solid. LC-MSD, m/z for C23H17BrN2O2 [M+H]+=433.0, 435.0; HPLC retention time: 2.5 min.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].[C:10]1([C:16]#[C:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]#[CH:23])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[C:10]1([C:16]#[C:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]#[C:23][C:2]2[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=2)[CH:5]=[O:6])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=Cc1cccc(Br)c1
Reactant: C#CCCCCC#Cc1ccccc1
Product: O=Cc1cccc(C#CCCCCC#Cc2ccccc2)c1

Procedure:
Similarly, following the procedure of Example 7(b), 3-bromobenzaldehyde was reacted with 1-phenylocta-1,7-diyne to yield 3-(8-phenyl-1,7-octadiynyl)benzaldehyde which was reduced to 3-(8-phenyloctyl)benzaldehyde and the latter was reacted as described in Example 35(a),(b) and (c) to give 3-(2-carboxyethylthio)-3-[3-(8-phenyloctyl)phenyl]-2-hydroxypropanoic acid, dipotassium salt, hydrate as a mixture of isomers, -log KB value 6.2.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[CH2:11][C:12]([NH2:14])=[O:13])[CH:4]=[CH:3]1.C[O:16][C:17](=O)[C:18]([C:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][C:27]=2[O:29][CH3:30])[NH:22][CH:21]=1)=O.CC(C)([O-])C.[K+].C1COCC1>CN(C=O)C>[CH3:30][O:29][C:27]1[CH:26]=[CH:25][CH:24]=[C:23]2[C:28]=1[C:20]([C:18]1[C:17](=[O:16])[NH:14][C:12](=[O:13])[C:11]=1[C:9]1[CH:8]=[CH:7][CH:6]=[C:5]3[C:10]=1[N:2]([CH3:1])[CH:3]=[CH:4]3)=[CH:21][NH:22]2
Reactant: COC(=O)C(=O)c1c[nH]c2cccc(OC)c12
Reactant: Cn1ccc2cccc(CC(N)=O)c21
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COc1cccc2[nH]cc(C3=C(c4cccc5ccn(C)c45)C(=O)NC3=O)c12
Temperature: 60 °C
Yield: 39.7 %

Procedure:
To a solution of 2-(1-methyl-1H-indol-7-yl)-acetamide (0.539 g, 2.87 mmol) and (4-methoxy-1H-indol-3-yl)-oxo-acetic acid methyl ester (0.656 g, 2.81 mmol) in DMF (40 mL) under N2 was added a 1.0 M solution of potassium-tert-butoxide in THF (10 mL, 10 mmol) dropwise over 5 minutes. The mixture was heated at 60° C. for 15 h, quenched with 1N HCl (excess) and poured into EtOAc. The organic layer was separated, washed with water (3×), saturated aq NaHCO3, and brine, dried (MgSO4), filtered and concentrated onto flash SiO2. Flash chromatography (30–40% hexane/EtOAc) gave the title compound (0.414 g, 40%) as a red solid, which was dried under vacuum overnight. 1H NMR (400 MHz, DMSO-d6) 11.49 (br s, 1H), 11.08 (s, 1H), 7.49 (dd, J=7, 3 Hz, 1H), 7.30 (d, J=3 Hz, 1H), 7.25 (d, J=3 Hz, 1H), 6.86–7.05 (m 4H), 6.39 (d, J=7 Hz, 1H), 6.42 (d, J=3 Hz, 1H), 3.76 (s, 3H), 3.34 (s, 3H). MS (electrospray, m/z) 372.1 (M++1), 370 (M−−1). HRMS 372.1347 (M++1, calcd for C22H18N3O3 372.1348).
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[CH:8][C:7]=1[N+:14]([O-])=O.C([O-])(=O)C.[Na+]>C(OCC)(=O)C.[Pt]=O>[O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[CH:8][C:7]=1[NH2:14]
Reactant: COc1ccc([N+](=O)[O-])c(C2OCCO2)c1
Agent: O=[Pt]
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: COc1ccc(N)c(C2OCCO2)c1

Procedure:
A solution of 2-(1,3-dioxolan-2-yl)-4-methoxy-1-nitrobenzene (1eq) in ethyl acetate was treated with sodium acetate (0.08eq) and platinum oxide (0.06eq) and hydrogenated in a Parr apparatus at 50 psi for 16 hours. The reaction mixture was filtered and the filtrate was concentrated to give 2-(1,3-dioxolan-2yl)-4-methoxyphenylamine in quantitative yield.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([Cl:11])[C:5]([F:10])=[C:6]([CH:9]=1)[C:7]#[N:8].Cl>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([Cl:11])[C:5]([F:10])=[C:6]([CH:9]=1)[CH2:7][NH2:8]
Reactant: N#Cc1cc(Br)cc(Cl)c1F
Agent: Cl
Solvent: C1CCOC1
Product: NCc1cc(Br)cc(Cl)c1F
Temperature: 65 °C

Procedure:
To a solution of 5-bromo-3-chloro-2-fluorobenzonitrile (13.2 g, 56.3 mmol) in THF (200 mL) was added under an argon atmosphere a 1M solution of boran-tetrahydrofuran-complex (70.4 mL, 70.4 mmol) dropwise over 30 min. The reaction mixture was then heated at 65° C. for 1.5 h. After cooling to RT, a 2N HCl solution (70.4 mL, 141 mmol) was added dropwise over 30 min. The reaction mixture was then again heated at 65° C. for 1 h and subsequently cooled to RT. Volatiles were evaporated and the residue was taken up in 1M aqueous HCl solution, followed by extraction with EtOAc (3×150 mL). The combined organics were washed with 1M aqueous HCl solution. The combined acid phases were basified to pH=12 by addition of 4M aqueous NaOH solution and then extracted with EtOAc (3×150 mL). The organics were dried (Na2SO4), filtered and evaporated in vacuo to afford the title compound as a yellowish oil. MS (LC/MS): 238.0 [M+H]+; tR (HPLC conditions c): 3.25 min. The material thus obtained was used directly in the next step without further purification
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[CH:13][N:14]([CH2:15][CH2:16][CH2:17]O)[C:10]=2[C:9]2[CH2:8][CH2:7][CH2:6][CH2:5][C:4]=2[N:3]=1.S(Cl)([Cl:21])=O>CN(C)C=O>[Cl:21][CH2:17][CH2:16][CH2:15][N:14]1[C:10]2[C:9]3[CH2:8][CH2:7][CH2:6][CH2:5][C:4]=3[N:3]=[C:2]([NH2:1])[C:11]=2[N:12]=[CH:13]1
Reactant: Nc1nc2c(c3c1ncn3CCCO)CCCC2
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: Nc1nc2c(c3c1ncn3CCCCl)CCCC2

Procedure:
Dimethylformamide was added dropwise to 4-amino-6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinoline-1-propanol (1.06 g) until a solution was obtained. Thionyl chloride (0.63 mL) was added and the reaction mixture was heated for 45 minutes before being evaporated to dryness. The residue was taken up in ice water then made basic with saturated sodium bicarbonate solution. The resulting precipitate was collected and dried to provide 0.32 g of a dark brown solid. This material was purified by silica gel column chromatography eluting with 85:15 methylene chloride:methanol to provide 0.28 g of the desired product as a solid m.p. 245°-247° C. Analysis: Calculated for C13ClH17N4 +1.5H2 0: % C, 53.51; % H, 6.91; % N, 19.2; Found: % C, 53.81; % H, 6.25; % N, 18.86.
Reaction SMILES: OC([C:5]1[C:6]([CH3:15])=[C:7]2[N:12]([CH:13]=1)[N:11]=[CH:10][NH:9][C:8]2=[O:14])(C)C.C1C[O:19]CC1.OO.CS(O)(=O)=O>O>[OH:19][C:5]1[C:6]([CH3:15])=[C:7]2[N:12]([CH:13]=1)[N:11]=[CH:10][NH:9][C:8]2=[O:14]
Reactant: Cc1c(C(C)(C)O)cn2nc[nH]c(=O)c12
Reactant: C1CCOC1
Agent: CS(=O)(=O)O
Agent: OO
Solvent: O
Product: Cc1c(O)cn2nc[nH]c(=O)c12
Temperature: -2 °C
Reaction time: 1.58 h
Yield: 75.9 %

Procedure:
A one liter, 3-neck, round bottom flask as equipped with mechanical stirrer and a cooling bath of ice/acetone. To this was charged 20 g of 6-(1-hydroxy-1-methyl-ethyl)-5-methyl-3H-pyrrolo[2,1-f][1,2,4]triazin-4-one, 235 mL of THF and 47 mL 50% aqueous hydrogen peroxide. An exotherm from −7° C. to 7.3° C. was observed and the mixture became a solution. To this was added a pre-cooled solution of 28.5 mL water and 63 mL methanesulfonic acid over 40 min, keeping the temperature between −5° C. and −0.7° C. The solution was stirred at −2° C. for 95 min until HPLC indicated reaction was complete; reaction mixture was quenched, while keeping it at −2° C., by adding it portion wise to a cooled solution of 28.5 mL water, 89 g NaHSO3 and 128 mL 28% aqueous ammonium hydroxide over 40 min, at 15° C. to 25° C. The mixture was stirred at room temperature for 20 min; pH was 6.80 and a peroxide test was negative. The layers were separated and the aqueous layer was extracted with 100 mL THF. The two organic layers were combined and concentrated, removing 280 mL solvent. To the thick slurry was added 250 mL water and the concentration continued until 88 mL of solvent was removed. The slurry was filtered and the cake was washed with 25 mL water twice and then 25 mL acetonitrile. It was dried by suction on the filter to constant weight to yield 12.51 g of 6-hydroxy-5-methyl-3H-pyrrolo[2,1-f][1,2,4]triazin-4-one, 75.9% yield, 96.5% purity.
Reaction SMILES: [F:1][C:2]1[CH:14]=[CH:13][C:5]([CH2:6][C:7]2O[C:10]([NH2:12])=[N:9][N:8]=2)=[CH:4][CH:3]=1.[NH2:15][NH2:16]>O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][C:7]2[N:15]([NH2:16])[C:10]([NH2:12])=[N:9][N:8]=2)=[CH:13][CH:14]=1
Reactant: NN
Reactant: Nc1nnc(Cc2ccc(F)cc2)o1
Solvent: O
Product: Nc1nnc(Cc2ccc(F)cc2)n1N
Temperature: 195 °C

Procedure:
A mixture of 5-(4-fluoro-benzyl)-[1,3,4]oxadiazol-2-ylamine 10.182 g (52.7 mmol), water 80 mL and anhydrous hydrazine 20 mL was refluxed under nitrogen on an oil bath (190-200° C.) for 23 hours. The mixture was cooled and allowed to crystallize at room temperature under nitrogen overnight. The precipitated product was collected by filtration, washed with ice-cold water (10 mL) and dried on high vacuum. The crude product was re-crystallized from water 60 mL (reflux under nitrogen, than to +4° C. in a refrigerator overnight). The product was filtered, washed with ice-cold water and dried on high vacuum.
Reaction SMILES: FC(F)(F)C(O)=O.[CH:8]1([CH2:11][CH2:12][O:13][C:14]2[NH:15][C:16]([NH2:25])=[C:17]3[C:21]([N:22]=2)=[N:20][C:19]([O:23][CH3:24])=[N:18]3)[CH2:10][CH2:9]1.Br[CH2:27][CH2:28][CH2:29][CH2:30][CH:31]1[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1>>[CH:8]1([CH2:11][CH2:12][O:13][C:14]2[N:22]=[C:21]3[C:17]([N:18]=[C:19]([O:23][CH3:24])[N:20]3[CH2:27][CH2:28][CH2:29][CH2:30][CH:31]3[CH2:36][CH2:35][O:34][CH2:33][CH2:32]3)=[C:16]([NH2:25])[N:15]=2)[CH2:10][CH2:9]1
Reactant: COc1nc2nc(OCCC3CC3)[nH]c(N)c-2n1
Reactant: BrCCCCC1CCOCC1
Solvent: O=C(O)C(F)(F)F
Product: COc1nc2c(N)nc(OCCC3CC3)nc2n1CCCCC1CCOCC1

Procedure:
Prepared similarly to Intermediate 220 from 2-[(2-cyclopropylethyl)oxy]-8-(methyloxy)-1H-purin-6-amine trifluoroacetate and 4-(4-bromobutyl)tetrahydro-2H-pyran.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][CH2:9][C:10]2=O)=[CH:5][CH:4]=1.[BH4-].[Na+].S([O-])(O)(=O)=O.[K+].Cl[C:23]1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl.C1C2C(=CC=CC=2)C=CC=1.B(Br)(Br)Br.C1C=CC2C(=CC=CC=2O)C=1.C(O)(=O)CS>>[CH:23]1[C:12]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH:5]=[CH:4][C:3]=2[O:2][CH:1]=1
Reactant: COc1ccc2c(c1)C(=O)CCC2
Reactant: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Agent: BrB(Br)Br
Agent: O=C(O)CS
Agent: O=S(=O)([O-])O
Solvent: c1ccc2ccccc2c1
Product: c1ccc2c(c1)ccc1occc12

Procedure:
Alternatively, particularly for compounds of the formula II wherein R2 is a halogenoalkyl radical, 7-methoxy-1-tetralone (XVI) is acylated with an ester R2CO2Et to a β-diketone (XVII) which is reduced with sodium borohydride to the corresponding diol (XVIII). The diol is dehydrated with potassium hydrogen sulphate to the unsaturated alcohol (XIX) which is aromatised with 2,3-dichloro-5,6-dicyanobenzoquinone to the corresponding naphthalene derivative. Demethylation with boron tribromide to the naphthol (XX) followed by reaction with thioglycolic acid in the presence of base and thermal lactonisation gives the naphtho[2,1-b]furan derivative (XXI). The side chain hydroxy group is protected by reaction with tert-butyldimethylsilyl chloride to give a hydroxy-protected derivative which is alkylated to XXII with an iodoalkane, R4I, and the protecting silyl ether is removed with tetrabutylammonium fluoride to give the required compound of the formula II.
Reaction SMILES: [CH3:1][C@:2]12[C@@:19]3([CH3:20])[C@@H:10]([C@:11]4([CH3:33])[C@@H:16]([CH2:17][CH2:18]3)[C:15]([CH3:22])([CH3:21])[C:14]([C:23]3C=CC(C(OC)=O)=[CH:25][CH:24]=3)=[CH:13][CH2:12]4)[CH2:9][CH2:8][C@@H:7]1[C@H:6]1[C@H:34]([C:37]([CH3:39])=[CH2:38])[CH2:35][CH2:36][C@:5]1([NH:40][CH2:41][CH2:42][N:43]1[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]1)[CH2:4][CH2:3]2.[C:49]([OH:54])(=[O:53])[CH2:50][CH2:51][CH3:52]>>[C:49]([N:46]1[CH2:45][CH2:44][N:43]([CH2:42][CH2:41][NH:40][C@:5]23[CH2:36][CH2:35][C@@H:34]([C:37]([CH3:39])=[CH2:38])[C@@H:6]2[C@@H:7]2[C@@:2]([CH3:1])([CH2:3][CH2:4]3)[C@@:19]3([CH3:20])[C@@H:10]([C@:11]4([CH3:33])[C@@H:16]([CH2:17][CH2:18]3)[C:15]([CH3:22])([CH3:21])[C:14]([C:23]3[CH:24]=[CH:25][C:50]([C:49]([OH:54])=[O:53])=[CH:51][CH:52]=3)=[CH:13][CH2:12]4)[CH2:9][CH2:8]2)[CH2:48][CH2:47]1)(=[O:53])[CH2:50][CH2:51][CH3:52]
Reactant: C=C(C)[C@@H]1CC[C@]2(NCCN3CCNCC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Reactant: CCCC(=O)O
Product: C=C(C)[C@@H]1CC[C@]2(NCCN3CCN(C(=O)CCC)CC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12

Procedure:
The title compound (1.2 mg) was prepared from methyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-3a-((2-(piperazin-1-yl)ethyl)amino)-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate following the general procedure as described above using butyric acid as the acylating agent. LCMS: m/e 712.8 (M+H)+, 4.97 min (method 15). 1H NMR (500 MHz, METHANOL-d4) δ 7.89 (d, J=8.2 Hz, 2H), 7.16 (d, J=8.2 Hz, 2H), 5.30 (d, J=4.6 Hz, 1H), 4.78 (s, 1H), 4.68 (s, 1H), 3.79-3.55 (m, 4H), 3.12-2.98 (m, 1H), 2.97-2.82 (m, 2H), 2.78 (td, J=10.9, 5.0 Hz, 1H), 2.71-2.61 (m, 3H), 2.60-2.54 (m, 1H), 2.52-2.44 (m, 1H), 2.40 (t, J=7.5 Hz, 2H), 2.19-1.80 (m, 6H), 1.75 (s, 3H), 1.73-1.04 (m, 18H), 1.23 (s, 3H), 1.11 (s, 3H), 1.05 (s, 3H), 0.99 (t, J=7.5 Hz, 3H), 0.97 (s, 3H), 0.97 (s, 3H).
Reaction SMILES: [CH:1]1([CH:7]([NH:20][C:21]2[CH:22]=[CH:23][C:24]([C:27](O)=[O:28])=[N:25][CH:26]=2)[C:8]2[CH:12]=[C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[S:10][C:9]=2[CH3:19])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:30][NH:31][CH2:32][CH2:33][C:34]([O:36]CC)=[O:35].O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.[Cl-].[NH4+].[OH-].[Na+]>C(O)C.O1CCCC1.CN(C)C=O.C(N(CC)CC)C>[CH:1]1([CH:7]([NH:20][C:21]2[CH:22]=[CH:23][C:24]([C:27]([N:31]([CH3:30])[CH2:32][CH2:33][C:34]([OH:36])=[O:35])=[O:28])=[N:25][CH:26]=2)[C:8]2[CH:12]=[C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[S:10][C:9]=2[CH3:19])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cc1sc(-c2ccccc2)cc1C(Nc1ccc(C(=O)O)nc1)C1CCCCC1
Reactant: CCOC(=O)CCNC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCO
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: Cc1sc(-c2ccccc2)cc1C(Nc1ccc(C(=O)N(C)CCC(=O)O)nc1)C1CCCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 56.5 %

Procedure:
To a mixture of 5-{[cyclohexyl(2-methyl-5-phenylthiophen-3-yl)methyl]amino}pyridine-2-carboxylic acid (300 mg) synthesized in Example 310 (1), ethyl 3-(methylamino)propanoate (146 mg), 1-hydroxybenzotriazole monohydrate (170 mg), triethylamine (308 μL) and N,N-dimethylformamide (10 mL) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (213 mg), and the mixture was stirred at room temperature overnight. Saturated aqueous ammonium chloride solution was added to quench the reaction, and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (30-50% ethyl acetate/hexane) to give a colorless oil. To a mixture of the obtained oil, tetrahydrofuran (5 mL) and ethanol (5 mL) was added 1N aqueous sodium hydroxide solution (2.00 mL), and the mixture was stirred at room temperature for 2 hr. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in water (10 mL), and 1N hydrochloric acid (2.00 mL) was added at 0° C. The resulting precipitate was collected by filtration to give the title compound (205 mg, 57%) as a white solid.
Reaction SMILES: O1CCCCC1[N:7]1[C:15]2[C:10](=[CH:11][C:12]([C:16]3[N:20]=[CH:19][N:18](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:17]=3)=[CH:13][CH:14]=2)[C:9]([C:40]2[CH:41]=[C:42]([CH:47]=[CH:48][CH:49]=2)[C:43](OC)=[O:44])=[N:8]1.[OH-].[Li+].ON1C2C=CC=CC=2N=N1.[NH2:62][CH2:63][CH2:64][N:65]1[CH2:70][CH2:69][O:68][CH2:67][CH2:66]1.Cl.C(N=C=NCCCN(C)C)C.Cl>O1CCCC1.O.O1CCOCC1>[NH:18]1[CH:19]=[N:20][C:16]([C:12]2[CH:11]=[C:10]3[C:15](=[CH:14][CH:13]=2)[NH:7][N:8]=[C:9]3[C:40]2[CH:41]=[C:42]([C:43]([NH:62][CH2:63][CH2:64][N:65]3[CH2:70][CH2:69][O:68][CH2:67][CH2:66]3)=[O:44])[CH:47]=[CH:48][CH:49]=2)=[N:17]1
Reactant: COC(=O)c1cccc(-c2nn(C3CCCCO3)c3ccc(-c4ncn(C(c5ccccc5)(c5ccccc5)c5ccccc5)n4)cc23)c1
Reactant: NCCN1CCOCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: C1COCCO1
Solvent: C1CCOC1
Product: O=C(NCCN1CCOCC1)c1cccc(-c2n[nH]c3ccc(-c4nc[nH]n4)cc23)c1
Yield: 8 %

Procedure:
The title compound was prepared as described in Example 381, using methyl 3-{1-perhydro-2H-pyran-2-yl-5-[1-(triphenylmethyl)(1,2,4-triazol-3-yl)]-1H-indazol-3-yl}benzoate (0.595 g, 0.92 mmol) and lithium hydroxide (0.069 g, 2.87 mmol) in tetrahydrofuran (3 mL) and water (2 mL); 1-hydroxybenzotriazole (0.373 g, 2.76 mmol), 4-(2-aminoethyl)morpholine (0.362 mL, 2.76 mmol), 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride (0.535 g, 2.79 mmol), and additional tetrahydrofuran (2 mL); 4 N hydrochloride solution in dioxane (10 mL). The final crude product was purified by preparative HPLC (10-90% acetonitrile in H2O, 20 min.) (0.030 g, 8% yield over 3 steps): 1H NMR (CD3OD) δ 8.82 (t, 1H), 8.47 (t, 1H), 8.29 (s, 1H), 8.22 (dt, 1H), 8.14 (dd, 1H), 7.92 (dt, 1H), 7.67 (t, 2H), 3.70 (t, 4H), 3.62 (t, 2H), 2.67 (t, 2H), 2.58 (t, 4H); ES-MS (m/z) 418 [M+1]+.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]([CH3:30])([CH3:29])[CH2:13][C:14]([NH:16][C@@H:17]1[CH2:23][CH2:22][C:21]2[CH:24]=[CH:25][CH:26]=[CH:27][C:20]=2[NH:19][C:18]1=[O:28])=[O:15])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH2:33](Br)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.C(OCC)(=O)C>CN(C)C=O>[CH2:1]([O:8][C:9]([NH:11][C:12]([CH3:30])([CH3:29])[CH2:13][C:14]([NH:16][C@@H:17]1[CH2:23][CH2:22][C:21]2[CH:24]=[CH:25][CH:26]=[CH:27][C:20]=2[N:19]([CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:18]1=[O:28])=[O:15])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(CC(=O)N[C@@H]1CCc2ccccc2NC1=O)NC(=O)OCc1ccccc1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(CC(=O)N[C@@H]1CCc2ccccc2N(Cc2ccccc2)C1=O)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 898 %

Procedure:
To a solution of 40 mg (0.098 mmol) of 3-benzyloxycarbonylamino-3-methyl-N-[2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-3(R)-yl]-butanamide (Example 1, Step F) in 0.5 mL of dry dimethylformamide at room temperature under nitrogen was added 5 mg of 60% sodium hydride oil dispersion (3 mg NaH, 0.13 mmol, 1.3 eq). After 5 minutes, 0.013 mL of benzyl bromide (19 mg, 0.11 mmol, 1.1 eq) was added and the mixture stirred for 1 hour at room temperature, then added to 20 mL of ethyl acetate and washed with water (2×) and brine. The organic layer was removed, dried over magnesium sulfate, filtered and solvents removed under vacuum. The residue was purified by medium pressure liquid chromatography on silica, eluting with ethyl acetate/hexane (1:1) to afford 44 mg (0.88 mmol, 90%) of product. 1H NMR (200 MHz, CDCl3): 1.37 (s,3H), 1.38 (s,3H), 1.73 (m,1H), 2.3-2.6 (m,5H), 4.48 (m,1H), 4.80 (d,15 Hz,1H), 5.07 (br s,2H), 5.23 (d,15 Hz,1H), 5.62 (br s,1H), 6.67 (br d,7 Hz,1H), 7.1-7.4 (m,14H). FAB-MS: calculated for C30H33N3O4 499; found 500 (M+H,100%).
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH2:6][CH2:7][CH3:8])=[O:3].CCN(C(C)C)C(C)C.Cl.[NH2:19][C@@H:20]([CH2:25][CH:26]=[CH2:27])[C:21]([O:23][CH3:24])=[O:22].Cl>C(Cl)Cl>[CH2:5]([O:4][C:2]([NH:19][C@@H:20]([CH2:25][CH:26]=[CH2:27])[C:21]([O:23][CH3:24])=[O:22])=[O:3])[CH2:6][CH2:7][CH3:8]
Reactant: C=CC[C@H](N)C(=O)OC
Reactant: CCCCOC(=O)Cl
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C=CC[C@H](NC(=O)OCCCC)C(=O)OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 51.9 %

Procedure:
Step E (1): Butyl chloroformate (408 mg, 3.0 mmol), followed by DIEA (1.23 mL, 9.0 mmol), was added to a 250-mL single neck round bottom flask charged with a solution of the (S)-methyl 2-aminopent-4-enoate hydrochloride (500 mg, 3.00 mmol) in DCM (50 mL) at 0° C. Warmed the mixture to rt and after 2 h, poured into 1N HCl (200 mL). Extracted with EtOAc. Washed the combined organic extracts with 0.1 N NaOH, brine, dried over MgSO4, filtered and concentrated in vacuo. Purification by silica-gel column chromatography afforded 357 mg (52% yield) of (S)-methyl 2-(butoxycarbonylamino)pent-4-enoate. LC-MS (M+H)+=230.2; 1H NMR (500 MHz, CDCl3) δ ppm 0.91 (t, J=7.48 Hz, 3H) 1.30-1.40 (m, 2H) 1.54-1.61 (m, 2H) 2.43-2.59 (m, 2H) 3.73 (s, 3H) 4.05 (t, J=6.71 Hz, 2H) 4.38-4.46 (m, 1H) 5.08-5.20 (m, 3H) 5.62-5.72 (m, 1H).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][C:5]1[C:15]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:14][CH:13]=[CH:12][C:6]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8].C(N(CC)CC)C.[CH3:31][S:32](Cl)(=[O:34])=[O:33]>C(Cl)Cl>[CH3:31][S:32]([O:1][CH2:2][CH2:3][CH2:4][C:5]1[C:15]([O:16][CH2:17][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=[CH:12][C:6]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8])(=[O:34])=[O:33]
Reactant: CS(=O)(=O)Cl
Reactant: CCOC(=O)c1cccc(OCc2ccccc2)c1CCCO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cccc(OCc2ccccc2)c1CCCOS(C)(=O)=O
Temperature: 25 °C
Yield: 97.2 %

Procedure:
A solution of ethyl 2-(3-hydroxypropyl)-3-benzyloxybenzoate (10.19 g, 32.5 mmol), and triethyl amine (4.05 g, 40 mmol) in methylene chloride (100 ml) was cooled in an ice bath as methane sulfonyl chloride (2.79 ml, 36 mmol) was slowly added. The ice bath was removed and the reaction allowed to warm to room temperature over a 1 hr period. The mixture was diluted with water, and the methylene chloride layer was separated. The methylene chloride layer was washed with water twice, 1N HCl twice, and then filtered through a pad of silica gel to give a clear solution. This solution was concentrated in vacuo to give a clear oil (12.4 g, 98%).