Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:10]([C:11]#[N:12])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH:17]([F:19])[F:18])[N:6]2[CH2:13][C:14]([OH:16])=O.CCN=C=NCCCN(C)C.Cl.[F:32][C:33]1[CH:42]=[C:41]([F:43])[CH:40]=[CH:39][C:34]=1[C:35]([NH:37][NH2:38])=O.S(Cl)(C1C=CC(C)=CC=1)(=O)=O>ClCCCl>[Cl:1][C:2]1[C:10]([C:11]#[N:12])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH:17]([F:19])[F:18])[N:6]2[CH2:13][C:14]1[O:16][C:35]([C:34]2[CH:39]=[CH:40][C:41]([F:43])=[CH:42][C:33]=2[F:32])=[N:37][N:38]=1
Reactant: NNC(=O)c1ccc(F)cc1F
Reactant: N#Cc1ccc2c(cc(C(F)F)n2CC(=O)O)c1Cl
Agent: CCN=C=NCCCN(C)C
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Solvent: ClCCCl
Product: N#Cc1ccc2c(cc(C(F)F)n2Cc2nnc(-c3ccc(F)cc3F)o2)c1Cl
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 37.3 %

Procedure:
To a suspension of [4-chloro-5-cyano-2-(difluoromethyl)-1H-indol-1-yl]acetic acid (0.020 g, 0.070 mmol) in DCE (3 mL), under N2, was added EDCl (0.016 g, 0.081 mmol) and stirred at rt. After 5 min, 2,4-difluorobenzohydrazide (0.014 g, 0.081 mmol) was added and stirring was continued at rt. After 30 min, TsCl (0.016 g, 0.084 mmol) and P-BEMP (loading 2.2 mmol/g, 0.127 g, 0.28 mmol) were added and the mixture was heated at 100° C. for 20 min. The reaction was monitored by LC/MS. Subsequently, the mixture was heated at 120° C. for 30 min. Additional TsCl (0.020 g, 0.105 mmol) and P-BEMP (0.127 g, 0.28 mmol) were added and the mixture was heated at 120° C. another 20 min. Upon cooling, the resin was filtered off and washed with EtOAc. The filtrate was concentrated in vacuo and the residue was purified by flash chromatography (10-70% EtOAc-hexanes gradient). The product was crystallized from CH2Cl2-hexanes to afford the title compound as a white solid (0.011 g, 38% yield): MS (ES) m/z 421 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[CH:4][C:3]=1[SH:11]>C(O)(=O)C>[NH2:8][C:6]1[CH:5]=[CH:4][C:3]([SH:11])=[C:2]([Cl:1])[CH:7]=1
Reactant: O=[N+]([O-])c1ccc(S)c(Cl)c1
Solvent: CC(=O)O
Product: Nc1ccc(S)c(Cl)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 81.4 %

Procedure:
To 2-chloro-4-nitrobenzenethiol (4.0 g) was added acetic acid (60 ml), and to this solution was added reduced iron (21 g), and the mixture was stirred at room temperature for 3 hours. The mixture was filtered with Celite, and washed with ethyl acetate. The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography, to give 4-amino-2-chlorobenzenethiol (2.74 g).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH:12]([CH3:14])[CH:11]2[O:15][C:16]([CH3:19])([CH3:18])[O:17][CH:10]2[CH2:9]1)[C:2]1C=CC=C[CH:3]=1.C1[O:23][C@@H]1C.C(N(CC)CC)C>C(O)C>[CH3:18][C:16]1([CH3:19])[O:17][CH:10]2[CH2:9][N:8]([CH2:1][CH:2]([OH:23])[CH3:3])[CH2:13][CH:12]([CH3:14])[CH:11]2[O:15]1
Reactant: C[C@@H]1CO1
Reactant: CC1CN(Cc2ccccc2)CC2OC(C)(C)OC12
Solvent: CCN(CC)CC
Solvent: CCO
Product: CC(O)CN1CC(C)C2OC(C)(C)OC2C1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
40 (175 mg, 1 mmol), (R)-(+)-propylenoxide (297 mg, 5.1 mmol), and triethylamine (285 ul, 2 mmol) are dissolved in 3 ml of ethanol and stirred at room temperature for 5 h. After evaporation the residue is dissolved in ethyl acetate, washed subsequently with 1N NaOH and brine, dried over sodium sulphate and evaporated. The crude product, 214 mg of a yellow oil, is purified by Flash-chromatography (silica gel, dichloromethane/methanol/ammonia 95:5:0.5).
Reaction SMILES: [CH:1]([NH2:4])([CH3:3])[CH3:2].[C:5]([C:7]1[CH:17]=[CH:16][C:10]([C:11]([N:13]=[C:14]=[S:15])=[O:12])=[CH:9][CH:8]=1)#[N:6]>C1(C)C=CC=CC=1>[C:5]([C:7]1[CH:8]=[CH:9][C:10]([C:11]([NH:13][C:14]([NH:4][CH:1]([CH3:3])[CH3:2])=[S:15])=[O:12])=[CH:16][CH:17]=1)#[N:6]
Reactant: CC(C)N
Reactant: N#Cc1ccc(C(=O)N=C=S)cc1
Solvent: Cc1ccccc1
Product: CC(C)NC(=S)NC(=O)c1ccc(C#N)cc1

Procedure:
Isopropylamine (5.6 ml) was added dropwise to a mixture of 4-cyanobenzoyl isothiocyanate (11 g) and toluene (100 ml) at 60° C., and the insoluble substance in the reaction solution was filtered off. After allowing to stand for cooling, the precipitated crystals were recrystallized from toluene to give 1-(4-cyanobenzoyl)-3-isopropylthiourea (12.35 g) as pale yellow prisms.
Reaction SMILES: [OH:1][CH:2]([CH2:19][NH:20][CH:21]([CH3:23])[CH3:22])[CH2:3][O:4][C:5]1[CH:18]=[CH:17][C:8]([C:9]([CH2:11][CH2:12][C:13]([NH:15]C)=[O:14])=O)=[CH:7][CH:6]=1.O.[NH2:25]N>C(O)(=O)C>[OH:1][CH:2]([CH2:19][NH:20][CH:21]([CH3:23])[CH3:22])[CH2:3][O:4][C:5]1[CH:18]=[CH:17][C:8]([C:9]2[CH2:11][CH2:12][C:13](=[O:14])[NH:15][N:25]=2)=[CH:7][CH:6]=1
Reactant: NN
Reactant: CNC(=O)CCC(=O)c1ccc(OCC(O)CNC(C)C)cc1
Solvent: O
Solvent: CC(=O)O
Product: CC(C)NCC(O)COc1ccc(C2=NNC(=O)CC2)cc1
Yield: 52.4 %

Procedure:
3-[4-(2-Hydroxy-3-isopropylaminopropoxy)benzoyl]-N-methylpropionamide (5g, 0.015 mole) in 50% aqueous acetic acid (50 ml) was treated with hydrazine hydrate (2.4 ml, 0.047 mole) and heated under reflux for one hour. After evaporation under reduced pressure, the residue was dissolved in water, neutralised with aqueous sodium bicarbonate and extracted with dichloromethane. Evaporation of the dried organic solution gave 6-[4-(2-hydroxy-3-isopropylaminopropoxy)phenyl]-4,5-dihydro-3(2H)-pyridazinone (2.4 g, 50%, m.p. 108°-115°C). Crystallisation from water gave the pure pyridazinone, m.p. 116.5°-118°C.
Reaction SMILES: [NH2:1][C@@H:2]([C@H:4]1[CH2:9][CH2:8][C@H:7]([NH:10][C:11](=[O:15])[C@H:12]([OH:14])[CH3:13])[CH2:6][CH2:5]1)[CH3:3].CN(C=O)C.[F:21][C:22]([F:55])([F:54])[C:23]1[CH:24]=[C:25]2[C:31]([C:32]3[C:37]([C:38]#[N:39])=[CH:36][N:35]=[C:34](S(C)(=O)=O)[N:33]=3)=[CH:30][N:29](S(C3C=CC(C)=CC=3)(=O)=O)[C:26]2=[N:27][CH:28]=1.[OH-].[Li+]>C1COCC1>[C:38]([C:37]1[C:32]([C:31]2[C:25]3[C:26](=[N:27][CH:28]=[C:23]([C:22]([F:54])([F:21])[F:55])[CH:24]=3)[NH:29][CH:30]=2)=[N:33][C:34]([NH:1][C@@H:2]([C@H:4]2[CH2:5][CH2:6][C@H:7]([NH:10][C:11](=[O:15])[C@H:12]([OH:14])[CH3:13])[CH2:8][CH2:9]2)[CH3:3])=[N:35][CH:36]=1)#[N:39]
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3nc(S(C)(=O)=O)ncc3C#N)c3cc(C(F)(F)F)cnc32)cc1
Reactant: C[C@@H](O)C(=O)N[C@H]1CC[C@H]([C@@H](C)N)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: C[C@@H](O)C(=O)N[C@H]1CC[C@H]([C@@H](C)Nc2ncc(C#N)c(-c3c[nH]c4ncc(C(F)(F)F)cc34)n2)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Trans-(R)-N-(4-((R)-1-aminoethyl)cyclohexyl)-2-hydroxypropanamide (45 mg, 0.21 mmol) was dissolved in THF (6 mL) and DMF (2 mL) and stirred over 4 Å molecular sieves for 10 minutes. 4-(5-(trifluoromethyl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-(methylsulfonyl)pyrimidine-5-carbonitrile (131.9 mg, 0.2100 mmol) was added. The reaction mixture was stirred under nitrogen at ambient temperature for 18 hours. The molecular sieves was removed by filtration and washed with EtOAc. The filtrate was washed with water, dried over magnesium sulfate, filtered and concentrated in vacuo. The residue dissolved in tetrahydrofuran (6 mL). Lithium hydroxide (840.0 μL of 1 M, 0.8400 mmol) was added and the reaction mixture was stirred at room temperature for 18 hours. The crude mixture was partitioned between ethyl acetate and brine. The organic extracts were dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by reverse phase preparative HPLC [Waters Sunfire C18, 10 μM, 100 Å column, gradient 10%-95% B (solvent A: 0.05% TFA in water; solvent B: CH3CN) over 16 minutes at 25 mL/min]. The fractions were collected, passed through a sodium bicarbonate cartridge and freeze-dried to give the title compound as a white solid (19 mg, 18% yield).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH2:6][CH2:5]2.[C:11]1(=O)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1.C([BH3-])#N.[Na+]>CO>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)[CH2:6][CH2:5]2
Reactant: Brc1ccc2c(c1)CCN2
Reactant: O=C1CCCCC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: Brc1ccc2c(c1)CCN2C1CCCCC1
Reaction time: 24 h

Procedure:
A solution of 5-bromo-2,3-dihydro-1H-indole (94.0 g, 20.2 mmol), cyclohexanone (4.6 mL, 44.4 mmol) and sodium cyanoborohydride (1.6 g, 25.5 mmol) in methanol (100 mL) was heated at reflux for 16 hours. More cyclohexanone (2.3 mL, 22.2 mmol) and sodium cyanoborohydride (1.6 g, 25.5 mmol) were added. Heating was continued for 1 day. The solvent was evaporated in vacuo, and the residue was treated with ammonium hydroxide in water. The product was extracted into dichloromethane, and dried over sodium sulfate. The solvent was evaporated in vacuo, and the product was purified by flash silica gel chromatography, eluted with ethyl acetate (1% to 2%) in hexane to give an oil, 7.49 g (37%). MS: m/z 280 (MH+). 1H NMR (CDCl3): 1.08-1.20 (m, 1 H), 1.25-1.42 (m, 4 H), 1.64-1.74 (m, 1 H), 1.76-1.88 (m, 4 H), 2.91 (t, 2 H), 3.24-3.32 (m, 1 H), 3.36 (t, 2 H), 6.23 (d, 1 H) and 7.08-7.11 (m, 2 H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][N:2]=1.CC1(C)CCCC(C)(C)N1.[Li].[O:18]1[C:22]2([CH2:27][CH2:26][C:25](=[O:28])[CH2:24][CH2:23]2)[O:21][CH2:20][CH2:19]1>C1COCC1>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:25]2([OH:28])[CH2:26][CH2:27][C:22]3([O:21][CH2:20][CH2:19][O:18]3)[CH2:23][CH2:24]2)[N:2]=1
Reactant: O=C1CCC2(CC1)OCCO2
Reactant: c1ccnnc1
Agent: CC1(C)CCCC(C)(C)N1
Agent: [Li]
Solvent: C1CCOC1
Product: OC1(c2cccnn2)CCC2(CC1)OCCO2
Reaction time: 0.1 h
Yield: 44 %

Procedure:
To a solution of pyridazine (17.7 mmol, 1.28 mL) in THF (60 mL) was added lithium 2,2,6,6-tetramethylpiperidine (71 mmol, 10 g) at −78° C. The reaction was then stirred for 6 min and 1,4-dioxa-spiro[4.5]decan-8-one (71 mmol, 11 g) was added. The reaction was stirred for 5 h at −78° C. at which point the reaction was quenched using a solution of ethanol, hydrochloric acid and THF (30 mL, 1:1:1). The resulting solution was extracted using EtOAc. The organic layers were combined, dried over MgSO4 and concentrated. The residue was purified using flash chromatography to afford the desired alcohol (44%, 1.84 g). MS (M+H)+ 237.1.
Reaction SMILES: C(O[CH:4]([O:9][CH2:10][CH3:11])[CH2:5][CH2:6][CH2:7][NH2:8])C.[OH-].[Na+].[C:14](Cl)(=[O:17])[CH:15]=[CH2:16]>C(Cl)Cl>[C:14]([N:8]1[CH:4]([O:9][CH2:10][CH3:11])[CH2:5][CH2:6][CH2:7]1)(=[O:17])[CH:15]=[CH2:16]
Reactant: C=CC(=O)Cl
Reactant: CCOC(CCCN)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: C=CC(=O)N1CCCC1OCC
Temperature: 15 °C
Reaction time: 1 h
Yield: 87 %

Procedure:
4-Aminobutyraldehyde diethyl acetal (AmBDA, 75 g, 1.09 mol, Aldrich Chemical) was combined with a two phase mixture of 955 mL of CH2Cl2 and 160 mL of 14 N NaOH in a 3 neck flask equipped with a thermometer and an efficient mechanical stirrer. This was cooled to 15° C. with an ice bath. Acryloyl chloride (98.3 g, 1.09 mol. Aldrich) was added via an addition funnel at a rate slow enough to maintain the reaction temperature below 30° C. Reaction monitoring by capillary glpc revealed essentially complete AmBDA consumption when the acryloyl chloride addition was complete. Agitation was continued for 1 h. The layers were separated (water may be added to dissolve precipitated salt and improve phase separation) and the organic phase was washed with saturated brine. The brine was combined with the aqueous layer and back extracted with CH2Cl2 . The combined organic layers were neutralized with saturated aqueous NaH2PO4, dried over anhydrous MgCl2 and concentrated on a rotary evaporator at 40° C. to give 99% pure ABDA (by glpc) in 87% yield. The product can be freed of any high molecular weight by-products by kugelrohr distillation (120°-125° C. at 0.2 torr), but this produces significant yield losses and partial isomerization to N-acryloyl-5-ethoxy pyrrolidine (AEP) and related products. The pot temperature should not exceed 60° C. during these operations. The yield loses are minimized by adding a basic reagent, such as Na2CO3 , and a radical inhibitor, such as methylene blue, to the distillation vessel.
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[C@@H:15]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C@H:14]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C@@H:13]([CH2:32][O:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[O:12][CH:10]1[OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O:45][C:46](=[O:49])[CH2:47]Cl)(C)(C)C.COC(C)(C)C>[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC.C1(C)C=CC=CC=1.[OH-].[K+]>[CH2:1]([O:8][C@H:9]1[C@@H:15]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C@H:14]([O:24][CH2:25][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[C@@H:13]([CH2:32][O:33][CH2:34][C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)[O:12][CH:10]1[O:11][CH2:47][C:46]([OH:49])=[O:45])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)CCl
Reactant: OC1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@@H]1OCc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: COC(C)(C)C
Product: O=C(O)COC1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@@H]1OCc1ccccc1
Temperature: 0 °C

Procedure:
A mixture that consists of 54.1 g (100 mmol) of 2,3,4,6-tetra-O-benzyl-mannopyranose, 1.39 g (5 mmol) of tetrabutylammonium chloride in 350 ml of toluene and 150 ml of 50% aqueous potassium hydroxide solution is cooled to 0° C. At 0° C., 30.12 g (200 mmol) of chloroacetic acid-tert-butyl ester is added in drops over 20 minutes while being stirred vigorously. It is stirred for one hour at 10° C. 250 ml of methyl-tert-butyl ether is added, the organic phase is separated, and the aqueous phase is extracted twice with 250 ml of water. The solvent of the combined organic phases is distilled off in a vacuum, and the residue is taken up in 500 ml of ethanol. 40 ml of 50% aqueous sodium hydroxide solution is added, and it is refluxed for 0.5 hour. It is cooled to 0° C., set at pH 8 with 10% aqueous hydrochloric acid, and then the solvent is distilled off (vacuum). The residue is taken up in 300 ml of water and 500 ml of ethyl acetate, and the pH of the aqueous phase is set at 2 while being stirred (10% aqueous hydrochloric acid). The organic phase is separated, and the aqueous phase is extracted once more with 200 ml of ethyl acetate. The combined organic phases are dried on magnesium sulfate, the solvent is distilled off in a vacuum, and the residue is chromatographed on silica gel (mobile solvent: dichloromethane/n=hexane/ethanol/acetic acid=20:5:3:0.5). The product-containing fractions are concentrated by evaporation, dissolved in 400 ml of ethyl acetate and shaken out three times with 200 ml of water. Then, the organic phase is separated and evaporated to the dry state in a vacuum.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([CH2:23][N:24]([CH3:31])[CH:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)=[CH:19][CH:18]=3)=[O:15])=[CH:7][C:6]=2[CH:32]=1.B([O-])([O-])O[C:35]1[CH:44]=[CH:43][C:38]2[O:39][CH2:40][CH2:41][O:42][C:37]=2[CH:36]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.C(O)C.O.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>[O:39]1[C:38]2[CH:43]=[CH:44][C:35]([C:2]3[CH:3]=[CH:4][C:5]4[S:11](=[O:12])(=[O:13])[CH2:10][CH2:9][C:8]([C:14]([NH:16][C:17]5[CH:22]=[CH:21][C:20]([CH2:23][N:24]([CH3:31])[CH:25]6[CH2:26][CH2:27][O:28][CH2:29][CH2:30]6)=[CH:19][CH:18]=5)=[O:15])=[CH:7][C:6]=4[CH:32]=3)=[CH:36][C:37]=2[O:42][CH2:41][CH2:40]1
Reactant: CN(Cc1ccc(NC(=O)C2=Cc3cc(Br)ccc3S(=O)(=O)CC2)cc1)C1CCOCC1
Reactant: [O-]B([O-])Oc1ccc2c(c1)OCCO2
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCO
Product: CN(Cc1ccc(NC(=O)C2=Cc3cc(-c4ccc5c(c4)OCCO5)ccc3S(=O)(=O)CC2)cc1)C1CCOCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 77.4 %

Procedure:
Under argon atmosphere, a mixture of 7-bromo-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]pheny]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (300 mg), 2,3-dihydro-1,4-benzodioxin-6-yl borate (114 mg) and potassium carbonate (160 mg) in toluene/ethanol/water (10/1/1 ml) was stirred at room temperature for 1 hour. To the mixture was added tetrakistriphenylphosphinepalladium (33 mg), and the mixture was refluxed for 6 hours, cooled, extracted with ethyl acetate, washed with saturated brine, dried with magnesium sulfate and concentrated under reduced pressure. The residue was purified with silica gel column chromatography (ethanol/ethyl acetate=1:2) to give crystals, which were recrystallized from ethanol to give colorless crystals of 7-(2,3-dihydro-1,4-benzodioxin-6-yl)-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (Compound 55) (257 mg).
Reaction SMILES: C([O:5][C:6](=[O:40])[CH2:7][C:8]1([C:13]2[CH:18]=[CH:17][C:16]([NH:19][C:20](=[O:39])[CH2:21][C:22]3[CH:38]=[CH:37][C:25]4[N:26]=[C:27]([NH:29][C:30]5[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=5[CH3:36])[O:28][C:24]=4[CH:23]=3)=[CH:15][CH:14]=2)[CH2:12][CH2:11][CH2:10][CH2:9]1)(C)(C)C.ClCCl.O>FC(F)(F)C(O)=O>[C:31]1([CH3:36])[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=1[NH:29][C:27]1[O:28][C:24]2[CH:23]=[C:22]([CH2:21][C:20]([NH:19][C:16]3[CH:15]=[CH:14][C:13]([C:8]4([CH2:7][C:6]([OH:40])=[O:5])[CH2:12][CH2:11][CH2:10][CH2:9]4)=[CH:18][CH:17]=3)=[O:39])[CH:38]=[CH:37][C:25]=2[N:26]=1
Reactant: Cc1ccccc1Nc1nc2ccc(CC(=O)Nc3ccc(C4(CC(=O)OC(C)(C)C)CCCC4)cc3)cc2o1
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: ClCCl
Product: Cc1ccccc1Nc1nc2ccc(CC(=O)Nc3ccc(C4(CC(=O)O)CCCC4)cc3)cc2o1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 77.5 %

Procedure:
A solution of [1-{4-[2-[2-o-tolylamino-benzoxazol-6-yl]-acetylamino]-phenyl}-cyclopentyl]-acetic acid tert-butyl ester [0.36 g, Reference Example 1(a)] in a mixture of trifluoroacetic acid (12 mL), dichloromethane (2.25 mL) and water (1.5 mL) was stirred at room temperature for 1.5 hours. The resulting turquoise solution was evaporated and the residue was chased with toluene to yield an amber gum which was recrystallised from a mixture of acetonitrile and water to give the title compound (0.25 g) as an off white solid, m.p. 123–126° C. LC-MS: RT=3.51 minutes, MS(ES+): 506.6(M+Na)+, 484.6(M+H)+; MS(ES−): 482.4(M−H)−.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:14]=1[C:10]([CH2:11][CH2:12][NH2:13])=[CH:9][NH:8]2.[NH4+].[Cl-:16]>CO>[ClH:16].[CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:14]=1[C:10]([CH2:11][CH2:12][NH2:13])=[CH:9][NH:8]2
Reactant: [Cl-]
Agent: COc1cccc2[nH]cc(CCN)c12
Agent: [NH4+]
Solvent: CO
Product: Cl
Reaction time: 0.5 h

Procedure:
Dissolve 4-methoxytryptamine (1 g, 5.26 mmol) in MeOH and add of NH4Cl (0.97 eq, 0.27 g, 5.10 mmol). After 30 minutes, evaporate in vacuo to remove the MeOH leaving a thick orange oil. Dissolve the oil in MeOH and add dropwise to Et2O (200 mL) with vigorous stirring giving a gummy white precipitate. Stir with heating to give the title compound as a solid: 1H NMR (d6-DMSO, 300 MHz): 3.06 (bs, 4 H); 3.86 (s, 3H); 6.46 (dd, 1H); 7.06–6.9 (m, 3H); 7.93 (bs, 1H); 10.9 (s, 1H); MS (ES+): m/z 191 (M+H)+; 175 (M-CH3)+; 174 (M-NH2)+; (ES−): 189 (M−H)−; Analysis for C11H15ClN2O: Calcd.: C, 58.2788; H, 6.6692; N, 12.3566; found C, 58.18; H, 6.73; N, 12.15.
Reaction SMILES: O[CH:2]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12]([N:14]([CH3:16])[CH3:15])=[O:13])[CH:7]=[CH:6]2.[CH3:23][O:24][C:25]([O:29][Si](C)(C)C)=[C:26]([CH3:28])[CH3:27].C(=O)(O)[O-].[Na+]>ClCCl>[CH3:15][N:14]([CH3:16])[C:12]([N:8]1[C:9]2[C:5](=[CH:4][C:3]([CH:2]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:26]([CH3:28])([CH3:27])[C:25]([O:24][CH3:23])=[O:29])=[CH:11][CH:10]=2)[CH:6]=[CH:7]1)=[O:13]
Reactant: COC(O[Si](C)(C)C)=C(C)C
Reactant: CN(C)C(=O)n1ccc2cc(C(O)c3ccccc3)ccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)C(C)(C)C(c1ccccc1)c1ccc2c(ccn2C(=O)N(C)C)c1
Temperature: 0 °C
Reaction time: 3.5 h
Yield: 96 %

Procedure:
To a stirred solution of 5-(hydroxy(phenyl)methyl)-N,N-dimethyl-1H-indole-1-carboxamide (0.72 g, 2.5 mmol) and (1-methoxy-2-methylprop-1-enyloxy)trimethylsilane (8 mL) in anhydrous dichloromethane (6 mL) was added boron trifluoride diethyl ether complex (0.83 mL, 6.6 mmol) dropwise at 0° C. under argon. After stirring at 0° C. for 30 min and rt for 3.5 hr, the mixture was poured into a saturated aqueous sodium bicarbonate solution maintained at 0° C. The reaction mixture was stirred well, extracted with ethyl acetate (20 mL), dried (Na2SO4) and concentrated. Silica gel flash chromatography gave methyl 3-(1-(dimethylcarbamoyl)-1H-indol-5-yl)-2,2-dimethyl-3-phenylpropanoate (0.9 g, 2.4 mmol, 96% yield) as a glassy solid, the NMR spectrum of which was consistent with the desired structure.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH:7]=O)([O-:3])=[O:2].[Br:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23](=[O:28])[CH2:24][C:25](=[O:27])[CH3:26].C(O)(=O)C.N1CCCCC1>C(O)(C)C>[Br:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23](=[O:28])[C:24](=[CH:7][C:6]1[CH:9]=[CH:10][CH:11]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1)[C:25](=[O:27])[CH3:26]
Reactant: CC(=O)CC(=O)CCCCCCCCCCBr
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Solvent: CC(C)O
Solvent: C1CCNCC1
Solvent: CC(=O)O
Product: CC(=O)C(=Cc1cccc([N+](=O)[O-])c1)C(=O)CCCCCCCCCCBr
Temperature: 25 °C
Reaction time: 108 h
Yield: 77 %

Procedure:
4.7 g of 3-nitrobenzaldehyde and 9.5 g of 14-bromotetradecane-2-4-dione are dissolved in 100 ml isopropanol, 0.18 ml of acetic acid and 0.15 ml of piperidine are added and the mixture is stirred at RT for 4.5 days. It is cooled in an ice bath, and the crystallized product is filtered off with suction, washed with ice-cold isopropanol and dried. 10.5 g of the compound of m.p. 64-67° C. are obtained.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:22]=[CH:21][C:6]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][C:17]([O:19]C)=[O:18])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[N:31]=[C:32]([NH:36][CH2:37][CH3:38])[O:33][C:34]=2[CH3:35])=[CH:26][CH:25]=1.C(=O)([O-])[O-].[K+].[K+].[OH-].[Na+].Cl>CN(C)C=O.CO.O>[Cl:23][C:24]1[CH:25]=[CH:26][C:27]([C:30]2[N:31]=[C:32]([N:36]([CH2:2][C:3]3[CH:22]=[CH:21][C:6]([CH2:7][O:8][C:9]4[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][C:17]([OH:19])=[O:18])=[CH:11][CH:10]=4)=[CH:5][CH:4]=3)[CH2:37][CH3:38])[O:33][C:34]=2[CH3:35])=[CH:28][CH:29]=1
Reactant: COC(=O)CCc1ccc(OCc2ccc(CCl)cc2)cc1
Reactant: CCNc1nc(-c2ccc(Cl)cc2)c(C)o1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CO
Product: CCN(Cc1ccc(COc2ccc(CCC(=O)O)cc2)cc1)c1nc(-c2ccc(Cl)cc2)c(C)o1
Temperature: 70 °C
Reaction time: 66 h
Yield: 5.7 %

Procedure:
To a solution of methyl 3-(4-{[4-(chloromethyl)benzyl]-oxy}phenyl)propanoate (50 mg, 0.16 mmol) in N,N-dimethylformamide (1 mL) were added a solution of 4-(4-chlorophenyl)-N-ethyl-5-methyl-1,3-oxazole-2-amine (45 mg, 0.19 mmol) in N,N-dimethylformamide (0.5 mL) and potassium carbonate (33 mg, 0.24 mmol), and the mixture was stirred at 70° C. for 66 hr. Water (2 mL) was added to the reaction mixture and the mixture was extracted with dichloromethane (2 mL). The organic layer was concentrated under reduced pressure with a centrifugal concentration apparatus (GeneVac). The obtained resultant product was dissolved in methanol (2 mL), 1N aqueous sodium hydroxide solution (0.32 mL, 0.32 mmol) was added, and the mixture was stirred at room temperature for 18 hr. The reaction mixture was acidified with 1N hydrochloric acid, and extracted with dichloromethane (2 mL). The organic layer was concentrated under reduced pressure with a centrifugal concentration apparatus (GeneVac). The residue was purified by preparative HPLC (gradient cycle B) to give the title compound (4.6 mg, yield 5%).