Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[F:7][C:8]1[C:16]([N+:17]([O-:19])=[O:18])=[CH:15][CH:14]=[C:13]2[C:9]=1[CH2:10][CH2:11][NH:12]2.[CH2:20](Br)[CH3:21]>CC(C)=O>[CH2:20]([N:12]1[C:13]2[C:9](=[C:8]([F:7])[C:16]([N+:17]([O-:19])=[O:18])=[CH:15][CH:14]=2)[CH2:10][CH2:11]1)[CH3:21]
Reactant: O=[N+]([O-])c1ccc2c(c1F)CCN2
Reactant: CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCN1CCc2c1ccc([N+](=O)[O-])c2F
Temperature: 60 °C
Reaction time: 0.17 h
Yield: 74.5 %

Procedure:
Anhydrous potassium carbonate (0.83 g, 6 mmol) was added to a solution of 4-fluoro-5-nitro-indoline (0.54 g, 3 mmol) in acetone (20 mL). The mixture was stirred at 60° C. for 10 min and ethyl bromide (0.33 mL, 4.50 mmol) added dropwise and the mixture was refluxed for a further 12 h. The mixture was concentrated in vacuo and the residue partitioned between ethyl acetate (50 mL) and water (50 mL). The organic layer was separated and the aqueous layer extracted with ethyl acetate (5×10 mL). The combined organic layers were washed with water (3×10 mL), brine (3×10 mL) and then dried over anhydrous sodium sulphate. Concentration of the organic layer afforded the crude product which was purified by column chromatography over silica gel neutral alumina mesh using 5-8% ethyl acetate in hexane as eluent to afford 1-ethyl-4-fluoro-5-nitro-indoline (0.47 g, 75%) as a yellow solid.
Reaction SMILES: [C:1]1([N:7]2[C:12](=[O:13])[C:11]3[S:14][CH:15]=[C:16]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[C:10]=3[N:9]=[CH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:23][C:24]1C(C2C=CC=CC=2)=CSC=1C(OC)=O.C(OCC)(OCC)OCC.NC1C=CC(C#N)=CC=1>C(O)(=O)C>[O:13]=[C:12]1[N:7]([C:1]2[CH:6]=[CH:5][C:4]([C:24]#[N:23])=[CH:3][CH:2]=2)[CH:8]=[N:9][C:10]2[C:16]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:15][S:14][C:11]1=2
Reactant: COC(=O)c1scc(-c2ccccc2)c1N
Reactant: O=c1c2scc(-c3ccccc3)c2ncn1-c1ccccc1
Agent: N#Cc1ccc(N)cc1
Solvent: CCOC(OCC)OCC
Solvent: CC(=O)O
Product: N#Cc1ccc(-n2cnc3c(-c4ccccc4)csc3c2=O)cc1
Yield: 27 %

Procedure:
In the same manner as the synthesis of Compound 1, methyl 3-amino-4-phenylthiophene-2-carboxylate (100 mg, 0.43 mmol), triethyl orthoformate (1 ml), 4-aminobenzonitrile (96 mg, 0.81 mmol), and acetic acid (0.1 ml) were used to give 38 mg (0.12 mmol, 27% yield) of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12](=[O:28])(=[O:27])[NH:13][C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:25][CH2:24][C:23](=O)[CH2:22][CH2:21]3)=[CH:16][CH:15]=2)=[CH:8][CH:7]=1.[NH2:30][CH2:31][C@@H:32]([C:34]1[CH:35]=[CH:36][C:37]([OH:45])=[C:38]([NH:40][S:41]([CH3:44])(=[O:43])=[O:42])[CH:39]=1)[OH:33]>>[CH3:1][O:2][C:3](=[O:29])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([NH:13][C:14]2[CH:15]=[CH:16][C:17]([N:20]3[CH2:21][CH2:22][CH:23]([NH:30][CH2:31][C@H:32]([OH:33])[C:34]4[CH:35]=[CH:36][C:37]([OH:45])=[C:38]([NH:40][S:41]([CH3:44])(=[O:43])=[O:42])[CH:39]=4)[CH2:24][CH2:25]3)=[CH:18][CH:19]=2)(=[O:28])=[O:27])=[CH:8][CH:7]=1
Reactant: COC(=O)COc1ccc(S(=O)(=O)Nc2ccc(N3CCC(=O)CC3)cc2)cc1
Reactant: CS(=O)(=O)Nc1cc([C@@H](O)CN)ccc1O
Product: COC(=O)COc1ccc(S(=O)(=O)Nc2ccc(N3CCC(NC[C@H](O)c4ccc(O)c(NS(C)(=O)=O)c4)CC3)cc2)cc1

Procedure:
The title compound was prepared from {4-[4-(4-oxo-piperidin-1-yl)-phenylsulfamoyl]-phenoxy}-acetic acid methyl ester (which was obtained in Example 232) and N-[5-((1 R)-2-amino-1-hydroxy-ethyl)-2-hydroxy-phenyl]-methanesulfonamide (which was obtained in Example 10) according to the procedure of Example 278 as an off-white solid; 1H NMR (300 MHz, DMSO-d6) δ 1.20–1.40 (m, 2 H), 1.75–1.90 (m, 2 H), 2.50–2.80 (m, 5 H), 2.92 (s, 3 H), 3.65–3.75 (m, 2 H), 3.67 (s, 3 H), 4.47 (dd, J=8.0, 4.1 Hz, 1 H), 4.87 (s, 2 H), 6.50–6.90) m, 8 H), 7.17 (d, J=1.8 Hz, 1 H), 7.59 (d, J=8.9 Hz, 2 H); MS (ES) m/z: 649.0 (MH+); HRMS Calcd. for C29H37N4O9S2 (MH+): 649.2004. Found: 649.2014.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4](Cl)=[O:5].[NH2:7][C:8]1[C:17]([Cl:18])=[C:16]([CH3:19])[CH:15]=[C:14]2[C:9]=1[N:10]=[C:11]([O:22][CH3:23])[C:12]([O:20][CH3:21])=[N:13]2.N1C=CC=CC=1>ClCCl>[Cl:18][C:17]1[C:8]([NH:7][C:4](=[O:5])[CH2:3][O:2][CH3:1])=[C:9]2[C:14](=[CH:15][C:16]=1[CH3:19])[N:13]=[C:12]([O:20][CH3:21])[C:11]([O:22][CH3:23])=[N:10]2
Reactant: COc1nc2cc(C)c(Cl)c(N)c2nc1OC
Reactant: COCC(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: COCC(=O)Nc1c(Cl)c(C)cc2nc(OC)c(OC)nc12
Reaction time: 1 h
Yield: 94.3 %

Procedure:
Methoxyacetylchloride (2.16 mL, 2.57 g, 23.66 mmol) was added to a solution of 5-amino-6-chloro-2,3-dimethoxy-7-methylquinoxaline (Preparation 113, 5 g, 19.72 mmol) and pyridine (1.91 mL, 1.89 g, 23.66 mmol) in dichloromethane (80 mL) at 0° C. After a further 1 hour at this temperature, the mixture was washed with 2M aqueous hydrochloric acid solution, brine, dried (MgSO4) and concentrated under reduced pressure. The residue was triturated with diisopropyl ether and filtered to give 6-chloro-2,3-dimethoxy-5-methoxyacetamido-7-methylquinoxaline (6.06 g, 98%) as an off white solid, mp 170-171° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C@H:9]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[CH3:10])[N:5]=[C:4]([N:18]2[CH2:22][CH2:21][CH:20]([OH:23])[CH2:19]2)[CH:3]=1.[NH2:24][C:25]1[CH:30]=[N:29][CH:28]=[CH:27][N:26]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[F:17][C:14]1[CH:15]=[CH:16][C:11]([C@@H:9]([NH:8][C:6]2[N:5]=[C:4]([N:18]3[CH2:22][CH2:21][CH:20]([OH:23])[CH2:19]3)[CH:3]=[C:2]([NH:24][C:25]3[CH:30]=[N:29][CH:28]=[CH:27][N:26]=3)[N:7]=2)[CH3:10])=[CH:12][CH:13]=1
Reactant: Nc1cnccn1
Reactant: C[C@H](Nc1nc(Cl)cc(N2CCC(O)C2)n1)c1ccc(F)cc1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Product: C[C@H](Nc1nc(Nc2cnccn2)cc(N2CCC(O)C2)n1)c1ccc(F)cc1
Temperature: 100 °C
Reaction time: 2.5 h
Yield: 33.6 %

Procedure:
119 mg of 1-{6-chloro-2-[(S)-1-(4-fluorophenyl)ethylamino]pyrimidin-4-yl}pyrrolidin-3-ol, 40 mg of 2-aminopyrazine, 20 mg of 4,5-bis(diphenylphosphino)-9,9′-dimethylxanthene, 150 mg of tripotassium phosphate and 19 mg of tris(dibenzylideneacetone)dipalladium were added in turn to 3 ml of degassed 1,4-dioxane, and the mixture was stirred at 100° C. for 2.5 hours under argon atmosphere. The reaction mixture was filtrated to remove precipitates, and the filtrate was concentrated under reduced pressure, and then the obtained residue was purified by silica gel column chromatography to obtain 47 mg of 1-{2-[(S)-1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}pyrrolidine-3-ol. Furthermore, the obtained compound was subjected to hydrochlorination using a conventional method to obtain 32 mg of the objective compound as pale yellow powder.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][CH2:12][CH2:13][OH:14].[OH-].[Na+].[Br:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]Br>O.CCOCC>[Br:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][O:14][CH2:13][CH2:12][CH2:11][C:2]1[CH:3]=[CH:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[N:1]=1
Reactant: OCCCc1ccc2ccccc2n1
Reactant: BrCCCCCCBr
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: O
Product: BrCCCCCCOCCCc1ccc2ccccc2n1

Procedure:
2-Quinolinepropanol (0.92 g), 50% aqueous sodium hydroxide (5 ml), 1,6-dibromohexane (5 ml) and TAB (57 mg) were vigorously stirred at 21° for 6 h. The mixture was diluted with water (25 ml) and ether (100 ml) and the organic phase dried and evaporated in vacuo. The residue was purified by FCC with hexane eluant to remove 1,6-dibromohexane. Elution with ether afforded the title compound as a yellow oil (0.88 g), t.l.c. ether Rf 0.51.
Reaction SMILES: [C:1]([OH:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:10]1(=[O:16])[O:15][C:13](=[O:14])[CH2:12][CH2:11]1>CC1C=CC=CC=1C>[C:1]([OH:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:10]([OH:15])(=[O:16])[CH2:11][CH2:12][C:13]([OH:8])=[O:14]
Reactant: O=C1CCC(=O)O1
Agent: O=C(O)c1ccccc1
Solvent: Cc1ccccc1C
Product: O=C(O)CCC(=O)O
Temperature: 165 °C
Reaction time: 6 h

Procedure:
This Example describes a process used for making reaction product 6 as indicated in Table 2, namely a reaction product of di-isopropanolamine, benzoic acid and succinic acid anhydride. A 1 liter reaction flask was provided with a mechanical agitator, a thermometer and a DeanStark arrangement. 261.06 g (1.960 mol) of di-isopropanolamine (type S, BASF) 540.88 g (4.429 mol) benzoic acid (Aldrich) and 69.69 g (0.696 mol) of succinic acid anhydride (Aldrich) were placed in the flask. A small quantity of o-xylene, about 60 ml, was added as entraining agent to remove the liberated water. The reaction mixture was kept under a nitrogen atmosphere and heated for 1 hour at 165° C., whereafter the reaction temperature was raised to 180° C. After 6 hours the temperature was reduced to 160° C. and the flask was evacuated to remove the o-xylene. It was possible to draw off the reaction mixture after about 1 hour. Analysis showed that the number-averaged molecular weight (Mn) was 583 and the weight-averaged molecular weight (Mw) was 733. The ratio between Mw and Mn (1.26) showed that there was a mixture of compounds formed. The diagram below (formula 1) indicates what compounds may form during the reaction between di-isopropanolamine, benzoic acid and succinic acid (it should be noted that formula 1 is the most probable structure of the resulting compounds). The reaction shows the formation of a mono-disperse compound. The ratio in respect of reactants as indicated in the formula belongs to a chosen value for n. This ratio need not necessarily be identical to the ratio for the overall reaction, where in fact a mixture of compounds with different values for n is formed. In the reaction according to this example, a ratio has been chosen which is equal to 2.82:6.36:1 (di-isopropanolamine:benzoic acid:succinic acid anhydride). This means that there are 3×2.82=8.46 mol equivalents of reactive NH/OH groups in the amine, as against 6.36+2×1.00=8.36 mol equivalents of acid groups in the benzoic acid and anhydride. There is therefore only a very small excess (about 1%) of di-isopropanolamine.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]=[CH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.B(Br)(Br)Br.[OH-].[K+].Cl>ClCCl>[OH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]=[CH:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: COc1ccccc1C=Cc1ccccc1
Agent: BrB(Br)Br
Agent: Cl
Agent: [K+]
Solvent: ClCCl
Product: Oc1ccccc1C=Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.7 %

Procedure:
In an atmosphere of nitrogen, 7.75 g (36.9 mmol) of 2-methoxystilbene (c-2) is dissolved in anhydrous dichloromethane. Fourty milliliters of a dichloromethane solution containing 3.2 g (12.9 mmol) of boron tribromide is added dropwise thereto at -78° C. (on a dry ice-acetone bath), followed by stirring overnight at room temperature. The reaction solution is cooled on an ice bath, and a 10% aqueous solution of KOH is added thereto drop by drop to decompose a boron complex formed in the reaction solution. This reaction solution is transferred to a separatory funnel, and 2M HCl is added thereto until the aqueous layer becomes acidic. The resulting solution is extracted with three 200 ml portions of chloroform. The chloroform layer is washed with two 50 ml portions of water and dried over anhydrous Na2SO4, followed by filtration. When the solvent is removed by distillation under reduced pressure, a brown oily product containing 2-hydroxystilbene (d-2) is obtained. This oily product is purified by column chromatography [SiO2 : 200 g, hexane-ethyl acetate (9:1 v/v)], and further recrystallized from hexane-ethyl acetate, thereby obtaining 5.05 g (yield: 69.9%) of 2-hydroxystilbene (d-2) (sample No. 9) as white needle crystals (melting point: 138°-139° C.).
Reaction SMILES: [NH2:1][C@@H:2]([CH3:29])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][C:7]=1[NH:13][C@@H:14]1[CH2:19][CH2:18][CH2:17][N:16]([CH2:20][CH2:21][O:22][C:23](=[O:28])[C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:15]1)=[O:4].Cl[C:31]1[N:39]=[CH:38][N:37]=[C:36]2[C:32]=1[N:33]=[CH:34][N:35]2[CH:40]1[CH2:45][CH2:44][CH2:43][CH2:42][O:41]1.CCN(C(C)C)C(C)C>C(O)CCC>[F:12][C:9]1[CH:10]=[CH:11][C:6]([NH:5][C:3](=[O:4])[C@@H:2]([NH:1][C:31]2[N:39]=[CH:38][N:37]=[C:36]3[C:32]=2[N:33]=[CH:34][N:35]3[CH:40]2[CH2:45][CH2:44][CH2:43][CH2:42][O:41]2)[CH3:29])=[C:7]([NH:13][C@@H:14]2[CH2:19][CH2:18][CH2:17][N:16]([CH2:20][CH2:21][O:22][C:23](=[O:28])[C:24]([CH3:25])([CH3:27])[CH3:26])[CH2:15]2)[CH:8]=1
Reactant: C[C@H](N)C(=O)Nc1ccc(F)cc1N[C@@H]1CCCN(CCOC(=O)C(C)(C)C)C1
Reactant: Clc1ncnc2c1ncn2C1CCCCO1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: C[C@H](Nc1ncnc2c1ncn2C1CCCCO1)C(=O)Nc1ccc(F)cc1N[C@@H]1CCCN(CCOC(=O)C(C)(C)C)C1
Temperature: 100 °C
Reaction time: 2 h
Yield: 79.5 %

Procedure:
A mixture of 2,2-dimethylpropionic acid 2-{(R)-3-[2-((S)-2-aminopropionylamino)-5-fluorophenylamino]piperidin-1-yl}ethyl ester (0.255 g, 0.62 mmol), 6-chloro-9-(tetrahydropyran-2-yl)-9H-purine (0.149 g, 0.62 mmol), and DIPEA (0.32 mL, 1.87 mmol) in n-butanol (4 mL) was stirred in a sealed vial at 100° C. for 2 h, then at 90° C. for 16 h. After cooling to RT, volatiles were removed in vacuo and the resulting residue purified by column chromatography (Si—PCC, gradient 2-8% 2M NH3/MeOH in DCM) affording the title compound as a colourless gum (0.301 g, 79%). LCMS (Method J): RT 2.29 min [M+H]+ 611.
Reaction SMILES: Cl.[CH3:2][O:3][NH2:4].[CH2:5]([O:12][C@:13]1([CH3:36])[C@H:17]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C@@H:16]([CH2:26][O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[O:15][C@@H:14]1O)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.CO>C(N(CC)CC)C>[CH2:28]([O:27][CH2:26][C@@H:16]([OH:15])[C@@H:17]([O:18][CH2:19][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[C@@:13]([O:12][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)([CH:36]=[N:4][O:3][CH3:2])[CH3:14])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: CON
Reactant: C[C@@]1(OCc2ccccc2)[C@H](OCc2ccccc2)[C@@H](COCc2ccccc2)O[C@@H]1O
Agent: Cl
Solvent: CO
Solvent: CCN(CC)CC
Product: CON=C[C@](C)(OCc1ccccc1)[C@H](OCc1ccccc1)[C@H](O)COCc1ccccc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 93.7 %

Procedure:
0.69 g of O-methylhydroxylamine hydrochloride was added to a mixture of 2.0 g of (2S,3R,4R,5R)-3,4-bis(benzyloxy)-5-((benzyloxy)methyl)-3-methyloxolan-2-ol and 10 mL of methanol, and thereafter, 0.56 g of triethylamine was added dropwise to the mixture. The obtained mixture was stirred at room temperature for 6 hours. Thereafter, the solvent was distilled away under reduced pressure, and 20 mL of ethyl acetate and 20 mL of water were then added to the obtained residue. The organic layer was fractionated, and was then washed with water twice. The solvent was distilled away under reduced pressure, so as to obtain 2.0 g of (2R,3R,4S)-1,3,4-tris(benzyloxy)-4-((methoxyimino)methyl)pentan-2-ol in the form of a colorless oily product.
Reaction SMILES: [O:1]=[C:2]([CH3:10])[CH2:3][C:4]1[CH:9]=[CH:8][N:7]=[CH:6][CH:5]=1.[BH4-].[Na+].C(OCC)(=O)C.O>CO>[OH:1][CH:2]([CH3:10])[CH2:3][C:4]1[CH:9]=[CH:8][N:7]=[CH:6][CH:5]=1
Reactant: CC(=O)Cc1ccncc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: CCOC(C)=O
Product: CC(O)Cc1ccncc1
Reaction time: 2 h

Procedure:
To a stirred solution of 4-(2'-oxopropyl)-pyridine (13.7 g) in methanol (135 ml), sodium borohydride (3.0 g) was added in portions. After stirring for 2 hours, the mixture was taken to dryness in vacuo. The residue was distributed between ethyl acetate and a minimum of water sufficient to dissolve inorganic salts. The organic phase was dried and evaporated to yield 4-(2'-hydroxypropyl)-pyridine as a colourless oil. The oil was dissolved in acetic acid (100 ml) and hydrogenated in the presence of Adam's catalyst (1 g) until 3 equivalents of hydrogen were consumed. The catalyst was removed by filtration and the filtrate was concentrated in vacuo to yield crude 4-(2'-hydroxypropyl)-piperidine which was used directly in the next step. In analogous manner 4-(2'-hydroxybutyl)-piperidine was prepared from 4-(2'-oxobutyl)-pyridine.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:8][NH2:9])[CH:5]=[CH:6][CH:7]=1.[C:10]1(NN)[CH:15]=CC=[CH:12][CH:11]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[CH:15]=[CH:10][C:11]([CH3:12])=[N:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: NNc1ccccc1
Reactant: NNc1cccc(Cl)c1
Product: Cc1ccn(-c2cccc(Cl)c2)n1

Procedure:
This compound was prepared by the same methodology described for EXAMPLE 1 with 3-chlorophenyl hydrazine · HCl substituted for phenyl hydrazine. There was obtained the title compound; HRMS (M+H)+ : calc. 467.094465; found 467.091517.
Reaction SMILES: Cl.CC1C2COC(=O)C=2C=CC=1CCN1CCNCC1.C(OC([N:28]1[CH2:33][CH2:32][N:31]([CH2:34][CH2:35][C:36]2[CH:45]=[CH:44][C:39]3[C:40](=[O:43])[O:41][CH2:42][C:38]=3[C:37]=2[CH:46]2[CH2:48][CH2:47]2)[CH2:30][CH2:29]1)=O)(C)(C)C>>[CH:46]1([C:37]2[C:38]3[CH2:42][O:41][C:40](=[O:43])[C:39]=3[CH:44]=[CH:45][C:36]=2[CH2:35][CH2:34][N:31]2[CH2:30][CH2:29][NH:28][CH2:33][CH2:32]2)[CH2:48][CH2:47]1
Reactant: CC(C)(C)OC(=O)N1CCN(CCc2ccc3c(c2C2CC2)COC3=O)CC1
Agent: Cc1c(CCN2CCNCC2)ccc2c1COC2=O
Agent: Cl
Product: O=C1OCc2c1ccc(CCN1CCNCC1)c2C1CC1

Procedure:
4-Cyclopropyl-5-[2-(piperazin-1-yl)ethyl]-2-benzofuran-1(3H)-one was prepared in a similar fashion to that described for the synthesis of 4-methyl-5-(2-piperazin-1-ylethyl)-2-benzofuran-1(3H)-one hydrochloride above starting from tert-butyl-4-[2-(4-cyclopropyl-1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]piperazine-1-carboxylate. LC-MS (IE, m/z): 275 [M+1]+.
Reaction SMILES: N[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[CH:5]2.N([O-])=O.[Na+].[ClH:15]>O.[Cu]Cl>[Cl:15][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[CH:5]2
Reactant: Nc1ccc2[nH]ncc2c1
Reactant: Cl
Agent: Cl[Cu]
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: Clc1ccc2[nH]ncc2c1
Temperature: -5 °C
Reaction time: 1.5 h

Procedure:
5-Amino-1H-indazole (15.41 g, 116 mmol) was suspended in a mixture of water (250 mL), ice (250 mL), and concentrated HCl (100 mL). The mixture was cooled in an ice-salt bath to an internal temperature of −5° C. To this mixture, was added a solution of sodium nitrite (8.78 g, 127 mmol) in water (75 mL), which had been cooled to 0° C. The resulting diazonium solution was stirred for 15 minutes at −5° C. A solution of copper (I) chloride (14.9 g, 151 mmol) in concentrated HCl (150 mL) was cooled to 0° C. and then added to the diazonium solution dropwise, causing an orange precipitate to form. The cooling bath was removed to allow the reaction to warm to room temperature. Gas evolution began at 10° C. internal temperature. After stirring at room temperature for 1.5 hours, the gas evolution subsided. The flask was then heated to 60° C. for 30 minutes, then cooled to ˜15° C. A brown precipitate formed. The precipitate was collected by suction filtration and dried in a vacuum dessicator over NaOH for 16 hours to give crude 5-chloro-1H-indazole (25.6 g) as a tan powder.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][C:10](C)=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:14][CH2:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][C@H:24]([NH:30]CC2C=CC(F)=CC=2)[C:25]([O:27][CH2:28]C)=[O:26])=[CH:19][CH:18]=1.[F:39][C:40]1[C:45]([CH:46]=O)=[C:44]([F:48])[C:43]([F:49])=[C:42]([F:50])[C:41]=1[F:51]>>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:14][CH2:15][O:16][C:17]1[CH:18]=[CH:19][C:20]([CH2:23][C@H:24]([NH:30][CH2:46][C:45]2[C:40]([F:39])=[C:41]([F:51])[C:42]([F:50])=[C:43]([F:49])[C:44]=2[F:48])[C:25]([O:27][CH3:28])=[O:26])=[CH:21][CH:22]=1
Reactant: CCOC(=O)[C@H](Cc1ccc(OCCc2nc(-c3ccc(C)cc3)oc2C)cc1)NCc1ccc(F)cc1
Reactant: O=Cc1c(F)c(F)c(F)c(F)c1F
Product: COC(=O)[C@H](Cc1ccc(OCCc2nc(-c3ccccc3)oc2C)cc1)NCc1c(F)c(F)c(F)c(F)c1F

Procedure:
In the same manner as in Example 7, 433.0 mg of the title compound was obtained as colorless oil from 591.2 mg of Referential Compound 3 and 250 μL of pentafluorobenzaldehyde.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)[CH:5]=[CH:4][C:3]=1[O:16][CH2:17][CH2:18][CH2:19]Br.[CH2:21]([C@:23]1([C:34]([O:36]C)=[O:35])[CH2:32][CH2:31][C:30]2[C:25](=[CH:26][C:27]([OH:33])=[CH:28][CH:29]=2)[O:24]1)[CH3:22]>>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)[CH:5]=[CH:4][C:3]=1[O:16][CH2:17][CH2:18][CH2:19][O:33][C:27]1[CH:26]=[C:25]2[C:30]([CH2:31][CH2:32][C@:23]([CH2:21][CH3:22])([C:34]([OH:36])=[O:35])[O:24]2)=[CH:29][CH:28]=1
Reactant: Fc1ccc(Oc2ccc(OCCCBr)c(Cl)c2)cc1
Reactant: CC[C@]1(C(=O)OC)CCc2ccc(O)cc2O1
Product: CC[C@]1(C(=O)O)CCc2ccc(OCCCOc3ccc(Oc4ccc(F)cc4)cc3Cl)cc2O1

Procedure:
The title compound was prepared following the procedures described in Example 1, Steps B-C employing 3-bromopropyl 2-chloro-4-(4-fluorophenoxy)phenyl ether (Example 20, Step A) instead of 4-(3-bromopropoxy)-3-propylphenyl phenyl ether, and (2R)-methyl 2-ethyl-7-hydroxychromane-2-carboxylate (Example 25, Step E) instead of ethyl 7-hydroxychromane-2-carboxylate.
Reaction SMILES: [Br:1][C:2]1[C:3](C(OC)=O)=[N:4][C:5]([NH:8][C@@H:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH2:11][C@@H:10]2[OH:18])=[CH:6][N:7]=1.C[C@@]1(NC2C=NC=C(OC)N=2)C2C(=CC=CC=2)C[C@@H:25]1[OH:33]>>[Br:1][C:2]1[N:7]=[CH:6][C:5]([NH:8][C@@H:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH2:11][C@@H:10]2[OH:18])=[N:4][C:3]=1[O:33][CH3:25]
Reactant: COc1cncc(N[C@]2(C)c3ccccc3C[C@@H]2O)n1
Reactant: COC(=O)c1nc(N[C@@H]2c3ccccc3C[C@@H]2O)cnc1Br
Product: COc1nc(N[C@@H]2c3ccccc3C[C@@H]2O)cnc1Br

Procedure:
Following the procedure for the preparation of methyl 3-bromo-6-{[(1R,2S)-2-hydroxy-2,3-dihydro-1H-inden-1-yl]amino}pyrazine-2-carboxylate but substituting methyl (1R,2S)-1-[(6-methoxypyrazin-2-yl)amino]-2,3-dihydro-1H-inden-2-ol and making non-critical variations provided the title compound as a solid: 1H NMR (CDCl3) δ 2.07, 3.03-3.07, 3.25-3.30, 3.98, 4.76, 5.38, 7.26-7.32, 7.45; MS (ESI+) for C14H14BrN3O2 m/z 336 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]([NH:25][CH2:26][CH:27]([O:30][CH3:31])[O:28][CH3:29])[CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19](OC)[CH:18]=2)=[CH:11][C:10]=1[O:32][CH3:33])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl[C:41]([O:43][CH2:44][CH3:45])=[O:42].C(OCC)(=O)C.CCCCCC>O1CCCC1.O.C(OCC)C>[CH2:44]([O:43][C:41](=[O:42])[N:25]([CH:15]([C:12]1[CH:13]=[CH:14][C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[C:10]([O:32][CH3:33])[CH:11]=1)[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:26][CH:27]([O:28][CH3:29])[O:30][CH3:31])[CH3:45]
Reactant: CCOC(=O)Cl
Reactant: COc1cccc(CC(NCC(OC)OC)c2ccc(OCc3ccccc3)c(OC)c2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CCOC(=O)N(CC(OC)OC)C(Cc1ccccc1)c1ccc(OCc2ccccc2)c(OC)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 70.9 %

Procedure:
To a stirred solution of [1-(4-benzyloxy-3-methoxy-phenyl)-2-(3-methoxy-phenyl)-ethyl]-(2,2-dimethoxy-ethyl)-amine (10.46 g, 20 mmol) in tetrahydrofuran (40 mL) and water (20 mL) was added potassium carbonate (5 g, 36 mmol) and ethyl chloroformate (1.91 mL, 20 mmol) dropwise. The mixture was stirred for 1 h at room temperature. The mixture was diluted with diethyl ether (100 mL), and the organic layer was separated. The aqueous phase was extracted with ethyl acetate (3×100 mL) and the combined extracts were washed with saturated aqueous sodium chloride solution (100 mL), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 70–230 mesh, 20% ethyl acetate/hexane) afforded [1-(4-benzyloxy-3-methoxy-phenyl)-2-phenyl-ethyl]-(2,2-dimethoxy-ethyl)-carbamic acid ethyl ester (7 g, 67% yield in three steps) as a colorless oil.