Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([O:14][C:15]2[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)(C)(C)C.C(Cl)[Cl:23].[ClH:25]>O1CCOCC1>[ClH:23].[ClH:25].[N:18]1[CH:19]=[CH:20][C:15]([O:14][C@H:11]2[CH2:10][CH2:9][C@H:8]([NH2:7])[CH2:13][CH2:12]2)=[CH:16][CH:17]=1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](Oc2ccncc2)CC1
Reactant: ClCCl
Agent: Cl
Solvent: C1COCCO1
Product: N[C@H]1CC[C@H](Oc2ccncc2)CC1
Reaction time: 2 h

Procedure:
A mixture of tert-butyl[trans-4-(pyridin-4-yloxy)cyclohexyl]carbamate in a solution of methylene chloride (1 mL) and 4.0 M of hydrogen chloride in 1,4-dioxane (2 mL) was stirred at r.t for 2 hours. The mixture was concentrated to yield 45% of trans-4-(pyridin-4-yloxy)cyclohexanamine dihydrochloride (2-step).
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[NH:5][C:6]2[C:11]([CH:12]=1)=[CH:10][C:9]([CH2:13][C:14]([O:16]C)=[O:15])=[CH:8][CH:7]=2.[F:18][C:19]([F:38])([F:37])[C:20]1[CH:36]=[CH:35][C:23]([O:24][C:25]2[CH:30]=[CH:29][C:28](O)=[C:27]([CH2:32][CH2:33][CH3:34])[CH:26]=2)=[CH:22][CH:21]=1>>[F:18][C:19]([F:37])([F:38])[C:20]1[CH:36]=[CH:35][C:23]([O:24][C:25]2[CH:30]=[CH:29][C:28]([O:1][CH2:2][CH2:3][C:4]3[NH:5][C:6]4[C:11]([CH:12]=3)=[CH:10][C:9]([CH2:13][C:14]([OH:16])=[O:15])=[CH:8][CH:7]=4)=[C:27]([CH2:32][CH2:33][CH3:34])[CH:26]=2)=[CH:22][CH:21]=1
Reactant: COC(=O)Cc1ccc2[nH]c(CCO)cc2c1
Reactant: CCCc1cc(Oc2ccc(C(F)(F)F)cc2)ccc1O
Product: CCCc1cc(Oc2ccc(C(F)(F)F)cc2)ccc1OCCc1cc2cc(CC(=O)O)ccc2[nH]1

Procedure:
Using the procedures in Example 15, steps F and G, the title compound was prepared from methyl 2-(2-hydroxyethyl)indole-5-acetate and 4-(4-trifluoromethylphenoxy)-2-propylphenol.
Reaction SMILES: C([O-])(=O)C.[NH4+].[N+:6]([CH3:9])([O-:8])=[O:7].[CH2:10]([O:17][C:18]1[CH:19]=[C:20]([CH:23]=[CH:24][C:25]=1[O:26][CH2:27][CH2:28][O:29][CH2:30][CH3:31])[CH:21]=O)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C(O)(=O)C>[CH2:10]([O:17][C:18]1[CH:19]=[C:20](/[CH:21]=[CH:9]/[N+:6]([O-:8])=[O:7])[CH:23]=[CH:24][C:25]=1[O:26][CH2:27][CH2:28][O:29][CH2:30][CH3:31])[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: CCOCCOc1ccc(C=O)cc1OCc1ccccc1
Reactant: C[N+](=O)[O-]
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Product: CCOCCOc1ccc(/C=C/[N+](=O)[O-])cc1OCc1ccccc1
Temperature: 130 °C

Procedure:
Ammonium acetate (4.16 g, 53.9 mmol) and nitromethane (6.1 mL, 113 mmol) were added to a solution of 3-(benzyloxy)-4-(2-ethoxyethoxy)benzaldehyde described in Production Example 24-2 (13.5 g, 45.0 mmol) in acetic acid (36 mL) under nitrogen atmosphere at room temperature. The liquid mixture was heated and stirred under reflux at 130° C. for 2 hours. The reaction liquid was allowed to stand to cool to room temperature. The precipitate was collected by filteration and washed with ethanol to quantitatively obtain the title compound.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[C:23](Br)[CH:24]=3)[N:19]=[CH:18][N:17]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:27]1[CH2:31][CH2:30][O:29][CH:28]1[C:32]1[O:36][C:35]([Sn](CCCC)(CCCC)CCCC)=[CH:34][CH:33]=1>O1CCOCC1>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[C:23]([C:35]4[O:36][C:32]([CH:28]5[O:29][CH2:30][CH2:31][O:27]5)=[CH:33][CH:34]=4)[CH:24]=3)[N:19]=[CH:18][N:17]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccc(C2OCCO2)o1
Reactant: Brc1ccc2ncnc(Nc3ccc(OCc4ccccc4)cc3)c2c1
Solvent: C1COCCO1
Product: c1ccc(COc2ccc(Nc3ncnc4ccc(-c5ccc(C6OCCO6)o5)cc34)cc2)cc1
Yield: 62.1 %

Procedure:
Prepared according to Procedure B from (4-benzyloxy-phenyl)-(6-bromoquinazolin-4-yl)-amine (1.5 g, 3.7 mmol) and 5-(1,3-dioxolan-2-yl)-2(tributylstannyl)-furan (1.9 g, 4.42 mmol) dissolved in dioxan (30 ml) and heated at reflux under nitrogen for 6 hr. The solvent was removed from the cooled reaction under vacuum, and the residual oil was triturated with iso-hexane/ethyl acetate to give the product (1.07 g, 62%) as a pale yellow solid; δH [2H6]-DMSO 9.96 (1H, b, NH), 8.80 (1H, s, 5-H), 8.51 (1H, s, 2-H), 8.18 (1H, d, 7-H), 7.80 (1H, d, 8-H), 7.70 (2H, d, 2′-H, 6′-H), 7.58-7.30 (5H, m, 5×Ph-H), 7.10 (3H, m, 3′-H, 5′-H, furan 3-H), 6.78 (1H, d, furan 4-H), 6.12 (1H, s, CHO2), 5.18 (2H, s, PhCH2), 4.22-3.94 (4H, m, 2×CH2); m/z 466 (M+1)+.
Reaction SMILES: [C:1](Cl)(=O)[C:2]([Cl:4])=[O:3].[C:7]1([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:8](CC(O)=O)=[CH:9][CH:10]=[CH:11][CH:12]=1>CN(C)C=O.C(Cl)Cl>[C:7]1([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:12]([CH2:1][C:2]([Cl:4])=[O:3])=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=C(O)Cc1ccccc1-c1ccccc1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)Cc1ccccc1-c1ccccc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 95.3 %

Procedure:
Oxalyl chloride (246 μl, 2.86 mmol) and one drop of dimethylformamide were added dropwise to a suspension of biphenylacetic acid (30 mg, 1.41 mmol) in methylene chloride (10 ml). The mixture was stirred at room temperature for 20 minutes. The solvent was evaporated and the residue was coevaporated with toluene twice to give 310 mg of the title product as a yellow solid.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:12](=[O:13])[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[CH:9][CH:10]=2)[N:5]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:4]=1[C:22]([O:24][CH3:25])=[O:23].[CH3:26][O:27][C:28]1[CH:36]=[CH:35][C:31]([C:32](Cl)=[O:33])=[CH:30][CH:29]=1>>[CH3:25][O:24][C:22]([C:4]1[N:5]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:6]2[C:11]([C:12](=[O:13])[C:3]=1[CH2:2][NH:1][C:32](=[O:33])[C:31]1[CH:35]=[CH:36][C:28]([O:27][CH3:26])=[CH:29][CH:30]=1)=[CH:10][CH:9]=[C:8]([O:14][CH3:15])[CH:7]=2)=[O:23]
Reactant: COC(=O)c1c(CN)c(=O)c2ccc(OC)cc2n1-c1ccccc1
Reactant: COc1ccc(C(=O)Cl)cc1
Product: COC(=O)c1c(CNC(=O)c2ccc(OC)cc2)c(=O)c2ccc(OC)cc2n1-c1ccccc1

Procedure:
3-[(4-methoxy-benzoylamino)-methyl]-7-methoxy-4-oxo-1-phenyl-1,4-dihydro-quino-line-2-carboxylic acid methyl ester was prepared starting from intermediate K and 4-methoxybenzoyl chloride. MS calcd. for C27H24N2O6 [(M+H)+] 473.2, obsd. 473.2.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:4]=[C:5]([C:9](=[S:11])[NH2:10])[CH:6]=[CH:7][CH:8]=1.Cl[CH:15]([CH:18]=O)[CH:16]=[O:17]>C(O)C>[F:13][C:2]([F:12])([F:1])[C:3]1[CH:4]=[C:5]([C:9]2[S:11][C:15]([CH:16]=[O:17])=[CH:18][N:10]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: O=CC(Cl)C=O
Reactant: NC(=S)c1cccc(C(F)(F)F)c1
Solvent: CCO
Product: O=Cc1cnc(-c2cccc(C(F)(F)F)c2)s1
Yield: 25.8 %

Procedure:
To a solution of 3-(trifluoromethyl)benzenecarbothioamide (1.31 g, 6.37 mmol) in ethanol (15 mL) was added 2-chloropropane-1,3-dial (2.04 g, 19.1 mmol), and the mixture was heated under reflux overnight. The reaction mixture was extracted with ethyl acetate, washed successively with diluted aqueous sodium hydrogen carbonate solution and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (carrier: silica gel, eluent: hexane-ethyl acetate) to give 2-[3-(trifluoromethyl)phenyl]-1,3-thiazole-5-carbaldehyde (423 mg) as colorless crystals. The present compound was dissolved in ethanol (5 mL), sodium borohydride (91 mg, 2.47 mmol) was added under ice-cooling, and the mixture was stirred at room temperature overnight. 1N Hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (carrier: silica gel, eluent: hexane-ethyl acetate) to give the title compound (334 mg, 78%) as a colorless oil.
Reaction SMILES: BrC1C=CC(C2(C3C=CC(O)=CC=3)CC2)=CC=1.BrC/C=C/CBr.Br[CH2:25]/[CH:26]=[CH:27]/[CH2:28][O:29][C:30]1[CH:35]=[CH:34][C:33]([C:36]2([C:39]3[CH:44]=[CH:43][C:42]([Br:45])=[CH:41][CH:40]=3)[CH2:38][CH2:37]2)=[CH:32][CH:31]=1.[CH2:46]([NH:49][CH3:50])[CH:47]=[CH2:48]>>[CH2:46]([N:49]([CH2:25]/[CH:26]=[CH:27]/[CH2:28][O:29][C:30]1[CH:31]=[CH:32][C:33]([C:36]2([C:39]3[CH:40]=[CH:41][C:42]([Br:45])=[CH:43][CH:44]=3)[CH2:38][CH2:37]2)=[CH:34][CH:35]=1)[CH3:50])[CH:47]=[CH2:48]
Reactant: BrC/C=C/COc1ccc(C2(c3ccc(Br)cc3)CC2)cc1
Reactant: C=CCNC
Agent: BrC/C=C/CBr
Agent: Oc1ccc(C2(c3ccc(Br)cc3)CC2)cc1
Product: C=CCN(C)C/C=C/COc1ccc(C2(c3ccc(Br)cc3)CC2)cc1

Procedure:
from 4-(1-(4-bromo-phenyl)-cyclopropyl)-phenol (Ex. Eg) and (E)-1,4-dibromo-2-butene via (E)-1-[4-(4-bromo-but-2-enyloxy)-phenyl]-1-(4-bromo-phenyl)-cyclopropane and reaction with N-allyl-methyl-amine there is obtained (E)-allyl-[4-[4-[1-(4-bromo-phenyl)-cyclopropyl]-phenoxy]-but-2-enyl]-methyl-amine which is converted into the fumarate, MS: m/e 412 (M+H+, 1Br).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH:12]([NH2:17])[CH2:13][CH:14]([CH3:16])[CH3:15])[CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[C:18]([O:22][CH2:23][CH3:24])(=[O:21])[CH:19]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>C(O)(=O)C.CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([CH:12]([NH:17][CH2:19][C:18]([O:22][CH2:23][CH3:24])=[O:21])[CH2:13][CH:14]([CH3:15])[CH3:16])[CH2:11][CH2:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)C=O
Reactant: CC(C)CC(N)C1(c2ccc(Cl)cc2)CCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: CCOC(=O)CNC(CC(C)C)C1(c2ccc(Cl)cc2)CCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of cyclobutane amine 52a (0.68 g, 0.0027 mole) and ethyl glyoxylate (50% solution in toluene) (1.02 g, 0.01 mole) in 20 mL of a mixture of solvents DMF and acetic acid (ratio, 99:1) was added sodium triacetoxyborohydride (2.11 g, 0.01 mole) portion-wise over a period of 15 minutes at room temperature. The resulting mixture was stirred for 8 hours at room temperature and the progress of the reaction was monitored by TLC. The reaction mixture was poured in to saturated sodium bicarbonate solution (50 mL) and extracted with ethyl acetate (50 mL×3). The combined extract was washed with water (50 mL), dried over sodium sulfate (Na2SO4) and evaporated. The residue was purified by silica gel column chromatography using 0-50% gradient of ethyl acetate and hexane as eluents to give pure 54a as colorless liquid in 45% (0.41 g) yield. The 1H NMR and mass spectral data are identical to the compound synthesized using the protocol described for the synthesis of 54a-e (Example 3, Scheme 7).
Reaction SMILES: [C:1]1([C:7]2[S:12][C:11]3[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=3[O:9][C:8]=2[C:17]2[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:24]1([CH2:30][CH2:31]O)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1>>[C:1]1([C:7]2[S:12][C:11]3[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=3[O:9][C:8]=2[C:17]2[CH:18]=[CH:19][C:20]([O:23][CH2:31][CH2:30][N:24]3[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]3)=[CH:21][CH:22]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Oc1ccc(C2=C(c3ccccc3)Sc3ccccc3O2)cc1
Reactant: OCCN1CCCCC1
Product: c1ccc(C2=C(c3ccc(OCCN4CCCCC4)cc3)Oc3ccccc3S2)cc1

Procedure:
The entitled compound was obtained according to the method of Example 3 but using 4-(3-phenyl-1,4-benzoxathiin-2-yl)phenol synthesized in Reference Example 1-1 and 2-piperidin-1-ylethanol as the starting material.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[C:9](Cl)(=[O:12])[CH:10]=[CH2:11].C(N(CC)CC)C>O1CCCC1>[C:9]([NH:6][C:5]1[CH:7]=[CH:8][C:2]([F:1])=[CH:3][CH:4]=1)(=[O:12])[CH:10]=[CH2:11]
Reactant: C=CC(=O)Cl
Reactant: Nc1ccc(F)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C=CC(=O)Nc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
4-Fluoroaniline (7 ml) and acryloyl chloride (7.2 ml) were dissolved in tetrahydrofuran (100 ml), then triethylamine (15 ml) was added thereto, and the mixture was stirred overnight at room temperature. The organic layer was partitioned by adding aqueous saturated sodium bicarbonate and ethyl acetate, and the organic layer was washed with water and dried over sodium sulfate anhydrous, and after the drying agent was filtered off, the filtrate was evaporated, whereby the title compound (12.2g, 100%) was obtained as pale yellow solid.
Reaction SMILES: Br[C:2]1[C:3]([C:10]#[N:11])=[CH:4][S:5][C:6]=1[N+:7]([O-:9])=[O:8].C([Sn]([C:25]1[CH:30]=[N:29][CH:28]=[CH:27][N:26]=1)(CCCC)CCCC)CCC>O1CCOCC1.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>[N+:7]([C:6]1[S:5][CH:4]=[C:3]([C:10]#[N:11])[C:2]=1[C:25]1[CH:30]=[N:29][CH:28]=[CH:27][N:26]=1)([O-:9])=[O:8]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnccn1
Reactant: N#Cc1csc([N+](=O)[O-])c1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: N#Cc1csc([N+](=O)[O-])c1-c1cnccn1
Temperature: 140 °C
Yield: 53.3 %

Procedure:
To a solution of 4-bromo-5-nitrothiophene-3-carbonitrile (312 mg, 1.34 mmol) in dioxane (4 mL) was added tetrakis(triphenylphosphine)palladium(0) (154 mg, 0.133 mmol) and tributylstannylpyrazine (794 mg, 2.15 mmol). This was heated by microwave irradiation to 140° C. for 30 min. The reaction mixture was concentrated under reduced pressure, and the residue purified by flash chromatography to afford the titled compound (166 mg, 53%): Rf=0.33 (20% EtOAc/hexanes; silica); HPLC method [4], retention time=1.45 min; MS(ESI) 233.0 (MH+).
Reaction SMILES: [CH2:1]([O:8][CH2:9][N:10]1[C:24](=[O:25])[C:23]([CH3:26])=[CH:22][N:12]([C@@H:13]2[O:21][C@H:18]([CH2:19][OH:20])[C@@H:16]([OH:17])[C@H:14]2[OH:15])[C:11]1=[O:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:31][CH2:32][CH2:33][CH2:34][Cl:35]>>[CH2:1]([O:8][CH2:9][N:10]1[C:24](=[O:25])[C:23]([CH3:26])=[CH:22][N:12]([C@@H:13]2[O:21][C@H:18]([CH2:19][OH:20])[C@@H:16]([OH:17])[C@H:14]2[O:15][CH2:31][CH2:32][CH2:33][CH2:34][Cl:35])[C:11]1=[O:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c(=O)n(COCc2ccccc2)c1=O
Reactant: ClCCCCBr
Agent: [H-]
Agent: [Na+]
Product: Cc1cn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2OCCCCCl)c(=O)n(COCc2ccccc2)c1=O
Reaction time: 16 h
Yield: 41 %

Procedure:
A solution of 3-benzyloxymethyl-5-methyluridine (25.9 g, 68 mmol) was treated with NaH (60% oil, 7.9 g, 200 mmol) for 1 hr at room temp. 1-Bromo-4-chlorobutane (19.7 g, 115 mmol) was added slowly and the reaction stirred at room temp. for 16 hrs. The reaction was then quenched (MeOH), concentrated in vacuo and the residue chromatographed on silica gel CHCl3/MeOH 95/5 to give the title compound in 41% yield. 1H NMR (DMSO-d6) δ 5.87 (d, 1H, C1′H).
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.[Cl:13][C:14](Cl)(Cl)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(Cl)(Cl)Cl.Cl>C1(C)C(C)=CC=CC=1>[ClH:13].[CH2:9]([O:8][C:6]([C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:14](=[N:1][C:2]2[CH:3]=[CH:4][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:11][CH:12]=2)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:12][CH:11]=1)=[O:7])[CH3:10]
Reactant: CCOC(=O)c1ccc(N)cc1
Reactant: ClC(Cl)(Cl)c1ccccc1
Agent: Cl
Solvent: Cc1ccccc1C
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1ccc(N=C(Nc2ccc(C(=O)OCC)cc2)c2ccccc2)cc1
Temperature: 0 °C

Procedure:
To a stirred suspension of ethyl 4-aminobenzoate (165.0 g; 1.0 mole) in xylene (465 mL) was added α,α,α-trichlorotoluene (100.7 g; 0.52 mole). The mixture was allowed to reflux for 18 h, then was cooled to 0° C. and filtered. The resultant precipitate was washed with ice-cold xylene (2×70 mL), triturated with hot toluene and dried to yield the salt (89.8 g; 39.7%) as white crystals: mp 214.0°-215.5° C. 1H-NMR (CDCl3) 8.0-6.9 (m, 14H), 4.3 (q, 4H, J=7 Hz), 1.4 (t, 6H, J=7 Hz); IR (CHCl3) 1715, 1600; MS (m/e) 416 (M+ -HCl), 252 (base).
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]([C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[NH:17][C:16]([C:21](O)=[O:22])=[CH:15]3)=[O:11])[CH2:6][CH2:5]1)([CH3:3])[CH3:2].Cl.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[F:47][C:48]1([F:54])[CH2:53][CH2:52][NH:51][CH2:50][CH2:49]1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[F:47][C:48]1([F:54])[CH2:53][CH2:52][N:51]([C:21]([C:16]2[NH:17][C:18]3[C:14]([CH:15]=2)=[CH:13][C:12]([C:10]([N:7]2[CH2:8][CH2:9][N:4]([CH:1]([CH3:3])[CH3:2])[CH2:5][CH2:6]2)=[O:11])=[CH:20][CH:19]=3)=[O:22])[CH2:50][CH2:49]1
Reactant: FC1(F)CCNCC1
Reactant: CC(C)N1CCN(C(=O)c2ccc3[nH]c(C(=O)O)cc3c2)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)N1CCN(C(=O)c2ccc3[nH]c(C(=O)N4CCC(F)(F)CC4)cc3c2)CC1

Procedure:
The title compound was synthesized in analogy to example 1, from 5-(4-isopropyl-piperazine-1-carbonyl)-1H-indole-2-carboxylic acid 1:1 hydrochloride, O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (commercially available), 4,4-difluoropiperidine (commercially available) and N,N-diisopropylethylamine in N,N-dimethylformamide to give the desired product after purification by preparative HPLC on reversed phase eluting with a gradient formed from acetonitrile/water/formic acid.
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:21])=[C:4]2[C:8](=[CH:9][C:10]=1[NH2:11])[C:7](=[O:12])[N:6]([CH:13]1[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]1)[C:5]2=[O:20].CC(O)=O.[I:26][C:27]1[C:32]([CH:33]=O)=[C:31]([O:35][CH3:36])[N:30]=[CH:29][CH:28]=1>CO>[I:26][C:27]1[CH:28]=[CH:29][N:30]=[C:31]([O:35][CH3:36])[C:32]=1[C:33]1[NH:11][C:10]2[C:2]([N:1]=1)=[C:3]([CH3:21])[C:4]1[C:5](=[O:20])[N:6]([CH:13]3[CH2:14][CH2:15][N:16]([CH3:19])[CH2:17][CH2:18]3)[C:7](=[O:12])[C:8]=1[CH:9]=2
Reactant: Cc1c(N)c(N)cc2c1C(=O)N(C1CCN(C)CC1)C2=O
Reactant: COc1nccc(I)c1C=O
Solvent: CO
Solvent: CC(=O)O
Product: COc1nccc(I)c1-c1nc2c(C)c3c(cc2[nH]1)C(=O)N(C1CCN(C)CC1)C3=O
Temperature: 60 °C
Yield: 47.2 %

Procedure:
To a solution of 5,6-Diamino-4-methyl-2-(1-methyl-piperidin-4-yl)-isoindole-1,3-dione (1.7 g, 5.90 mmol) in MeOH (50 mL) were added AcOH (3 mL) and 4-iodo-2-methoxynicotinaldehyde (1.55 g, 5.90 mmol) and the resulting mixture was heated at 60° C. for overnight. The reaction mixture was evaporated in vacuo and the residue was purified by flash chromatography (5-10% (6% NH3 in MeOH)/CHCl3) to afford 2-(4-Iodo-2-methoxy-pyridin-3-yl)-4-methyl-6-(1-methyl-piperidin-4-yl)-1H-1,3,6-triaza-s-indacene-5,7-dione (1.48 g, 47%) as a yellow solid.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]2[CH2:17][CH2:18][CH:19]([CH2:21][C:22]3[O:23][CH2:24][C:25](C)(C)N=3)[S:20][C:9]1=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[OH:30].[Na+]>S(=O)(=O)(O)O.C(O)C>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]2[CH2:17][CH2:18][CH:19]([CH2:21][C:22]([O:23][CH2:24][CH3:25])=[O:30])[S:20][C:9]1=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C([O-])O
Reactant: CC1(C)COC(CC2CCc3c(n(Cc4ccccc4)c4ccccc34)S2)=N1
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)CC1CCc2c(n(Cc3ccccc3)c3ccccc23)S1

Procedure:
60 mg of 2-(9-benzyl-2,3,4,9-tetrahydrothiopyrano[2,3-b]indol-2-yl)methyl-4,4-dimethyl-2-oxazoline (prepared as described in Example 81) was dissolved in 5% v/v sulfuric acid in ethanol, and the mixture was refluxed for 6 hours. After this time, the reaction mixture was neutralized by the addition of a saturated aqueous solution of sodium hydrogencarbonate and then extracted with ethyl acetate. The ethyl acetate fraction was then washed with water and dried over anhydrous sodium sulfate. The solvent was then removed by evaporation under reduced pressure, and the resulting residue was purified by silica gel column chromatography, using a mixture of 20% v/v ethyl acetate in hexane as the eluent, to afford 46 mg of the title compound as an oil.
Reaction SMILES: [CH2:1]([NH:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(C)([O-])C.[K+].Br[CH2:25][C:26]([O:28][CH3:29])=[O:27]>C(COC)OC.CCOCC>[CH2:1]([NH:8][CH2:9][CH2:10][C:11]1[CH:12]=[CH:13][C:14]([O:17][CH2:25][C:26]([O:28][CH3:29])=[O:27])=[CH:15][CH:16]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)CBr
Reactant: Oc1ccc(CCNCc2ccccc2)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: COCCOC
Product: COC(=O)COc1ccc(CCNCc2ccccc2)cc1
Reaction time: 8 h
Yield: 125.4 %

Procedure:
The starting material was obtained as follows: N-Benzyltyramine (9.08 g) was added to a stirred solution of potassium t-butoxide (4.5 g) in dimethoxyethane (80 ml). To the clear solution was added methyl bromoacetate (6.2 g) and the mixture was stirred overnight. The mixture was diluted with ether (250 ml) and washed with water (2×25 ml). The ethereal solution was dried (MgSO4) and evaporated, to give methyl 4-[2-(benzylamino)ethyl]phenoxyacetate (15.0 g) as an oil, which was dissolved in isopropanol and teated with phenylglycidyl ether (7.5 g). The solution was heated to reflux for 1 hour, and then evaporated. The residue was dissolved in toluene and volatile material evaporated before being purified by chromatography on K60 silica (220 g) using 1% methanol in dichloromethane. Methyl 4-[2-(N-benzyl-N-(2-hydroxy-3-phenoxypropyl)amino)ethyl]phenoxyacetate was obtained as an oil (9.5 g), NMR: 2.55-2.85[m,6H, CH2NHCH2CH2 ]; 3.65-4.05[m,8H, PhOCH2CHOH and PhCH2 and OCH3 ]; 4.67]s, 2H, OCH2CO]; 6.73-7.40[m, 14H, aromatic H].
Reaction SMILES: [CH2:1]([SH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18].CCOCC>CN(C=O)C>[CH2:20]([O:19][C:17](=[O:18])[CH2:16][S:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH3:21]
Reactant: SCc1ccccc1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CCOC(=O)CSCc1ccccc1
Temperature: 25 °C
Reaction time: 0.42 h
Yield: 49.9 %

Procedure:
To a solution of benzyl mercaptan (1.18 mL, 10.0 mmol) in DMF (20 mL) is added potassium carbonate (1.51 g, 10.9 mmol) and ethyl bromoacetate (1.17 mL, 10.6 mmol), and the mixture is stirred at RT for 25 min. Et2O is added, and the mixture is washed with water, brine, then dried (MgSO4), and filtered. The filtrate is evaporated, and the residue is vacuum distilled (130-140° C.) to give 1.05 g of the product 402.
Reaction SMILES: [CH3:1][CH:2]([CH3:7])[CH2:3][C:4](Cl)=[O:5].[C:8]([O:12][C:13](=[O:35])[CH2:14][N:15]1[C:19]2[CH:20]=[CH:21][C:22]([NH:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[CH:23][C:18]=2[N:17]=[C:16]1[CH2:32][CH2:33][CH3:34])([CH3:11])([CH3:10])[CH3:9].CCN(C(C)C)C(C)C>CN(C1C=CN=CC=1)C.C(Cl)Cl.Cl>[C:8]([O:12][C:13](=[O:35])[CH2:14][N:15]1[C:19]2[CH:20]=[CH:21][C:22]([N:24]([CH2:25][C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)[C:4](=[O:5])[CH2:3][CH:2]([CH3:7])[CH3:1])=[CH:23][C:18]=2[N:17]=[C:16]1[CH2:32][CH2:33][CH3:34])([CH3:11])([CH3:10])[CH3:9]
Reactant: CCCc1nc2cc(NCc3ccccc3)ccc2n1CC(=O)OC(C)(C)C
Reactant: CC(C)CC(=O)Cl
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCCc1nc2cc(N(Cc3ccccc3)C(=O)CC(C)C)ccc2n1CC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3-Methyl-butyryl chloride (44 μL, 0.36 mmol) was added to a solution of (5-benzylamino-2-propyl-benzoimidazol-1-yl)-acetic acid tert-butyl ester (45 mg, 0.12 mmol), DIEA (41 μL, 0.24 mmol) and DMAP (15 mg, 0.12 mmol) in CH2Cl2 (1 mL), and stirred overnight at room temperature. The reaction solution was diluted with aqueous HCl (1.0 M) and filtered through an Extrelut column. The Extrelut column was washed with CH2Cl2, and the filtrate was concentrated to afford the subtitle compound that was used without further purification. MS calculated for C28H37N3O3+H: 464, observed: 464.