Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][CH:2]([F:29])[CH2:3][O:4][C:5]1[C:9]2[CH:10]=[N:11][C:12]([NH:14][C:15]([NH:17][C@@H:18]3[C@@H:22]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[CH2:21][NH:20][CH2:19]3)=[O:16])=[CH:13][C:8]=2[NH:7][N:6]=1.NC(N)=O.[C:34](O)(=[O:37])[CH2:35][OH:36].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CC(N(C)C)=O>[F:29][CH:2]([F:1])[CH2:3][O:4][C:5]1[C:9]2[CH:10]=[N:11][C:12]([NH:14][C:15]([NH:17][C@@H:18]3[C@@H:22]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[CH2:21][N:20]([C:35](=[O:36])[CH2:34][OH:37])[CH2:19]3)=[O:16])=[CH:13][C:8]=2[NH:7][N:6]=1
Reactant: O=C(O)CO
Reactant: O=C(Nc1cc2[nH]nc(OCC(F)F)c2cn1)N[C@H]1CNC[C@@H]1c1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: NC(N)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: O=C(Nc1cc2[nH]nc(OCC(F)F)c2cn1)N[C@H]1CN(C(=O)CO)C[C@@H]1c1ccccc1
Temperature: 25 °C

Procedure:
In a 4 mL, 1 dram vial were added 1-(3-(2,2-difluoroethoxy)-1H-pyrazolo[4,3-c]pyridin-6-yl)-3-((3R,4S)-4-phenylpyrrolidin-3-yl)urea: (20 mg, 0.050 mmol, Intermediate 34B), glycolic acid (8 mg, 0.099 mmol), HATU (37.8 mg, 0.099 mmol) and DIEA (0.025 ml, 0.149 mmol) all in DMA (0.5 ml). The solution was shaken at room temperature over night. The solution was analyzed by LC/MS and found to contain the desired compound. The filtered crude solution was directly injected to the Gilson semi-preparative HPLC (0.1% TFA in ACN and Water on a Waters Sunfire C18 ODB, 5 uM, 19 mm×100 mm, Part No. 186002567 column using a gradient of 10%-60% ACN over 12 minutes). The fractions were analyzed by LC/MS and the pure fractions were concentrated to provide 1-(3-(2,2-difluoroethoxy)-1H-pyrazolo[4,3-c]pyridin-6-yl)-3-((3R,4S)-1-(2-hydroxyacetyl)-4-phenylpyrrolidin-3-yl)urea (101), was isolated as an off white powder. MS: [M+H]+ m/z 461.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([C:9]2[O:13][CH:12]=[N:11][C:10]=2[C:14]2[O:18][N:17]=[C:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:15]=2[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:6]=[CH:7][CH:8]=1.B(Br)(Br)Br.CO>ClCCl>[C:19]1([C:16]2[C:15]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)=[C:14]([C:10]3[N:11]=[CH:12][O:13][C:9]=3[C:5]3[CH:4]=[C:3]([OH:2])[CH:8]=[CH:7][CH:6]=3)[O:18][N:17]=2)[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: COc1cccc(-c2ocnc2-c2onc(-c3ccccc3)c2-c2ccccc2)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: CO
Product: Oc1cccc(-c2ocnc2-c2onc(-c3ccccc3)c2-c2ccccc2)c1
Temperature: 0 °C
Reaction time: 18 h
Yield: 64.8 %

Procedure:
5-[5-(3-Methoxyphenyl)-4-oxazolyl]-3,4-diphenylisoxazole (25) (1.01 g, 2.56 mmol) was dissolved in dichloromethane (65 mL) and cooled to about 0° C. under N2. Boron tribromide solution (13 mL of 1 M in dichloromethane) was added dropwise and the solution stirred about 18 hours at room temperature. Methanol (10 mL) was added dropwise {caution: reacts vigorously}, and after being stirred about 10 minutes the solution was concentrated on to SiO2 and chromatographed (elution with 10% ethyl acetate/chloroform) to give the phenol 631 mg (68%), mp 199°-200° C.
Reaction SMILES: [O:1]=[C:2]1[C:8]2[CH:9]=[CH:10][C:11]([CH:13]([CH3:17])[C:14](N)=[O:15])=[CH:12][C:7]=2[CH2:6][CH2:5][C:4]2[CH:18]=[CH:19][CH:20]=[CH:21][C:3]1=2.S(=O)(=O)(O)[OH:23]>O>[O:1]=[C:2]1[C:8]2[CH:9]=[CH:10][C:11]([CH:13]([CH3:17])[C:14]([OH:23])=[O:15])=[CH:12][C:7]=2[CH2:6][CH2:5][C:4]2[CH:18]=[CH:19][CH:20]=[CH:21][C:3]1=2
Reactant: CC(C(N)=O)c1ccc2c(c1)CCc1ccccc1C2=O
Reactant: O=S(=O)(O)O
Solvent: O
Product: CC(C(=O)O)c1ccc2c(c1)CCc1ccccc1C2=O
Temperature: 110 °C
Reaction time: 3 h

Procedure:
A suspension of 2-(5-oxo- 10,11-dihydrodibenzo[a,d]cyclohepten-2-yl)propionamide (15 g.) in a mixture of sulphuric acid (d = 1.36; 50 cc.) and water (60 cc.) is heated with vigorous stirring for 3 hours at 110°C. After cooling, the product which precipitates is filtered off and then added to N sodium hydroxide solution (55 cc.). The alkaline solution, clarified by filtration, is acidified by adding N hydrochloric acid (60 cc.). The product which precipitates is filtered off, dried and then recrystallised from carbon tetrachloride (170 cc.) to give 2-(5-oxo-10,11-dihydrodibenzo[a,d]cyclohepten2-yl)propionic acid (7.4 g.) melting at 122°C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]([CH2:19][CH3:20])=[C:12]([C:14](=[O:18])[C:15](O)=[O:16])[CH:13]=2)=[CH:4][CH:3]=1.S(Cl)([Cl:23])=O>CN(C)C=O.C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]([CH2:19][CH3:20])=[C:12]([C:14](=[O:18])[C:15]([Cl:23])=[O:16])[CH:13]=2)=[CH:4][CH:3]=1
Reactant: CCc1ccc(-c2ccc(Cl)cc2)cc1C(=O)C(=O)O
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: CCc1ccc(-c2ccc(Cl)cc2)cc1C(=O)C(=O)Cl
Temperature: 50 °C
Reaction time: 3 h
Yield: 87.2 %

Procedure:
To a 20 ml volume three-necked flask, 2-[5-(4-chlorophenyl)-2-ethylphenyl]-2-oxoacetic acid (8-c) (1.01 g), toluene (3.5 ml), dimethylformamide (3 drops), and thionyl chloride (624 mg) were added under a nitrogen atmosphere, and stirred at 50° C. for 3 hours. The mixture was concentrated under reduced pressure, and azeotropic-distilled with toluene 3 times to give 937 mg of 2-[5-(4-chlorophenyl)-2-ethylphenyl]-2-oxoacetyl chloride (6-c).
Reaction SMILES: [F:1][C:2]([F:9])([CH2:6][CH:7]=[CH2:8])[C:3](O)=[O:4].[P](Cl)(Cl)(Cl)[Cl:11]>>[F:1][C:2]([F:9])([CH2:6][CH:7]=[CH2:8])[C:3]([Cl:11])=[O:4]
Reactant: Cl[P](Cl)(Cl)Cl
Reactant: C=CCC(F)(F)C(=O)O
Product: C=CCC(F)(F)C(=O)Cl
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
In a round-bottomed flask with a distillation head, 57.2 g (0.42 mol) of 2,2-difluoro-4-pentenoic acid are slowly added dropwise to 102.0 g of phosphorus tetrachloride. After stirring for 20 minutes at RT, the reaction mixture is distilled, 42.1 g (65%) of the acid chloride passing over as a colourless oil at 92°-98° C./988 mbar. 1H-NMR (60 MHz, CDCl3): 6.0-5.0 (m, 3H); 2.9 (d x t, J=6; 16 Hz, 2H).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([SH:16])[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])([CH3:3])[CH3:2].[OH-].[K+].O.Cl[CH2:21][N:22]1[C:26](=[O:27])[C:25]2=[CH:28][CH:29]=[CH:30][CH:31]=[C:24]2[C:23]1=[O:32]>CC(C)=O>[C:1]([C:5]1[CH:6]=[C:7]([S:16][CH2:21][N:22]2[C:23](=[O:32])[C:24]3=[CH:31][CH:30]=[CH:29][CH:28]=[C:25]3[C:26]2=[O:27])[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1cc(S)cc(C(C)(C)C)c1O
Reactant: O=C1c2ccccc2C(=O)N1CCl
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: O
Product: CC(C)(C)c1cc(SCN2C(=O)c3ccccc3C2=O)cc(C(C)(C)C)c1O
Reaction time: 1 h

Procedure:
A vessel was charged with 12.19 grams of 3,5-di-tert-butyl-4-hydroxybenzene thiol and 3.30 grams of potassium hydroxide dissolved in 50 ml of acetone and 2 ml of water at 0° C. which was mixed with 10.0 grams of N-(chloromethyl)phthalimide. After stirring for one hour, the precipitated product was removed by filtration and then recrystallized from ethyl acetate-hexane to give 14.9 grams of produt, m.p. 151°-53° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][CH:8]=[CH:7][C:6]=2[CH:10]=1.C([Li])(C)(C)C.[CH3:16][N:17]1[CH2:26][C:25](=[O:27])[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:18]1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([C:25]3([OH:27])[C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[CH2:18][N:17]([CH3:16])[CH2:26]3)=[CH:7][C:6]=2[CH:10]=1
Reactant: Brc1ccc2sccc2c1
Reactant: CN1CC(=O)c2ccccc2C1
Agent: [Li]C(C)(C)C
Product: CN1Cc2ccccc2C(O)(c2cc3cc(Br)ccc3s2)C1
Temperature: -75 °C
Reaction time: 1 h
Yield: 7.7 %

Procedure:
To a solution of 5-bromobenzothiophene (511 mg, 2.4 mmol) at −75° C., was added t-butyllithium (1.7 M in pentane, 1.6 mL, 2.6 mmol) dropwise. The reaction mixture was stirred at −75° C. for 1 hour. To the resulting dark brown mixture was added 2-methyl-2,3-dihydro-1H-isoquinolin-4-one (323 mg, 2.0 mmol), which was prepared using the method described by Hanna et al., J. Med. Chem., 17(9): 1020-1023 (1974), which is hereby incorporated by reference in its entirety. The reaction mixture was stirred for 15 hours with gradual warming up. The mixture was quenched with saturated ammonium chloride and extracted with ethyl acetate (3×50 ml). The combined organic extracts were washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. Purification by medium pressure silica gel chromatography (10-40% ethyl acetate/hexanes) followed by preparative HPLC afforded 4-(benzo[b]thiophen-5-yl)-2-methyl-1,2,3,4-tetrahdro-isoquinoline-4-ol (65 mg, 11%) and 4-(5-bromobenzo[b]thiophen-2-yl)-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-ol (58 mg, 8%). 4-(Benzothiophen-5-yl)-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-ol: 1H NMR (CDCl3, 500 MHz) δ 7.81 (d, J=8.5 Hz, 1H), 7.69 (d, J=8.5 Hz, 1H), 7.34-7.23 (m, 4H), 7.20 (s, 1H), 7.18 (d, J=7.3 Hz, 1H), 7.10 (d, J=7.6 Hz, 1H), 3.91 (s, 1H), 3.84 (d, J=15.0 Hz, 1H), 3.53 (d, J=15.0 Hz, 1H), 3.11 (dd, J=11.6, 1.4 Hz, 1H), 2.87 (d, J=11.6 Hz, 1H), 2.50 (s, 3H); ESI MS m/z=296 [M+H]+. 4-(5-Bromobenzothiophen-2-yl)-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-ol: 1H NMR (CDCl3, 300 MHz) δ 7.81 (d, J=1.8 Hz, 1H), 7.66 (d, J=8.5 Hz, 1H), 7.38 (dd, J=8.5, 1.9 Hz, 1H), 7.30-7.23 (m, 2H), 7.18 (d, J=7.3 Hz, 1H), 7.11 (s, 1H), 7.07 (d, J=7.6 Hz, 1H), 3.69 (d, J=15.0 Hz, 1H), 3.48 (d, J=15.0 Hz, 1H), 3.10 (dd, J=11.6, 1.3 Hz, 1H), 2.83 (d, J=11.6 Hz, 1H), 2.47 (s, 3H); ESI MS m/z=374 [M+H]+.
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]2)[CH2:3][CH2:2]1.Cl[C:12]1[N:17]=[CH:16][C:15]([C:18]2[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[CH:20][CH:19]=2)=[CH:14][CH:13]=1>>[CH:1]1([CH2:4][N:5]2[CH2:10][CH2:9][N:8]([C:12]3[N:17]=[CH:16][C:15]([C:18]4[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[CH:20][CH:19]=4)=[CH:14][CH:13]=3)[CH2:7][CH2:6]2)[CH2:3][CH2:2]1
Reactant: N#Cc1ccc(-c2ccc(Cl)nc2)cc1
Reactant: C1CN(CC2CC2)CCN1
Product: N#Cc1ccc(-c2ccc(N3CCN(CC4CC4)CC3)nc2)cc1
Temperature: 140 °C
Yield: 36.9 %

Procedure:
1-Cyclopropylmethyl-piperazine (13 g, 94 mmol) was mixed with 4-(6-chloro-pyridin-3-yl)benzonitrile (5 g, 23 mmol). The mixture was heated at 140° C. for 1.5 hours. The mixture was cooled to rt and purified by column chromatography (EtOAc:petrolether=1:1) on silica gel to give 2.7 g (43%) of 4-[6-(4-cyclopropylmethyl-piperazin-1-yl)-pyridin-3-yl]-benzonitrile.
Reaction SMILES: [Si]([O:8][CH2:9][C@@H:10]([NH:19][C:20]1[CH:25]=[CH:24][C:23]([S:26]([NH:29][C:30](=[O:51])[C:31]2[CH:36]=[CH:35][C:34]([C:37]3[CH:50]=[CH:49][C:40]4[N:41]([CH2:45][CH2:46][CH2:47][CH3:48])[C:42](=[O:44])[NH:43][C:39]=4[CH:38]=3)=[CH:33][CH:32]=2)(=[O:28])=[O:27])=[CH:22][C:21]=1[N+:52]([O-:54])=[O:53])[CH2:11][S:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.Cl>C1COCC1>[CH2:45]([N:41]1[C:40]2[CH:49]=[CH:50][C:37]([C:34]3[CH:35]=[CH:36][C:31]([C:30]([NH:29][S:26]([C:23]4[CH:24]=[CH:25][C:20]([NH:19][C@@H:10]([CH2:11][S:12][C:13]5[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=5)[CH2:9][OH:8])=[C:21]([N+:52]([O-:54])=[O:53])[CH:22]=4)(=[O:28])=[O:27])=[O:51])=[CH:32][CH:33]=3)=[CH:38][C:39]=2[NH:43][C:42]1=[O:44])[CH2:46][CH2:47][CH3:48]
Reactant: CCCCn1c(=O)[nH]c2cc(-c3ccc(C(=O)NS(=O)(=O)c4ccc(N[C@H](CO[Si](C)(C)C(C)(C)C)CSc5ccccc5)c([N+](=O)[O-])c4)cc3)ccc21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [F-]
Solvent: C1CCOC1
Product: CCCCn1c(=O)[nH]c2cc(-c3ccc(C(=O)NS(=O)(=O)c4ccc(N[C@H](CO)CSc5ccccc5)c([N+](=O)[O-])c4)cc3)ccc21

Procedure:
A mixture of Example 177A (40 mg, 0.05 mmol) and 1M tetrabutylammonium fluoride in THF (130 uL, 0.13 mmol) in THF (3 mL) at room temperature was stirred for 3 hours, treated with 1M HCl (10 mL), and extracted with 5% methanol in ethyl acetate (3×20 mL). The combined extracts were washed with brine (5 mL), dried (Na2SO4), filtered, and concentrated. The concentrate was purified by flash column chromatography on silica gel with 20% methanol/ethyl acetate to provide the desired product. MS (ESI) m/e 674, 676 (M−H)−, (M+H)+; 1H NMR (300 MHz, DMSO-d6) δ 0.91 (t, 3H), 1.30 (q, 2H), 1.59 (tt, 2H), 3.28 (t, 2H), 3.67 (m, 1H), 3.80 (t, 2H), 3.92 (m, 2H), 5.21 (t, 1H), 6.83 (d, 1H), 7.21 (m, 3H), 7.29 (td, 2H), 7.38 (dd, 2H), 7.55 (d, 2H), 7.80 (dd, 1H), 7.94 (d, 2H), 7.95 (d, 1H), 8.41 (d, 1H), 8.49 (d, 1H), 10.90 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH:8]=O)=[CH:6][C:5]([CH3:10])=[C:4]([CH3:11])[N:3]=1.C(O)(=O)[CH2:13][C:14]([OH:16])=[O:15].N1CCCCC1>N1C=CC=CC=1>[Cl:1][C:2]1[C:7]([CH:8]=[CH:13][C:14]([OH:16])=[O:15])=[CH:6][C:5]([CH3:10])=[C:4]([CH3:11])[N:3]=1
Reactant: Cc1cc(C=O)c(Cl)nc1C
Reactant: O=C(O)CC(=O)O
Solvent: c1ccncc1
Solvent: C1CCNCC1
Product: Cc1cc(C=CC(=O)O)c(Cl)nc1C
Yield: 87 %

Procedure:
A mixture of 2-chloro-5,6-dimethyl-3-pyridinecarboxaldehyde (16.85 g), malonic acid (11.45 g), piperidine (10 ml) and pyridine (100 ml) was heated under reflux for 1 hour and evaporated to an oil. This oil was dissolved in sodium hydroxide solution and was extracted with chloroform, the residual aqueous phase was acidified with hydrochloric acid and extracted with chloroform. The second chloroform extracts were washed with wafter and evaporated to give 3-(2-chloro-5,6-dimethyl-3-pyridyl)acrylic acid (18.3 g, 87%), m.p. 150°-8°. This acid was esterified using ethanol and sulphuric acid to give the ethyl ester, m.p. 85°-8°.
Reaction SMILES: [CH2:1]([N:4]1[C:9]2[CH:10]=[C:11]([C:14]([OH:30])([C:26]([F:29])([F:28])[F:27])[CH:15]([C:17]3[CH:22]=[CH:21][C:20]([O:23]C)=[CH:19][C:18]=3[Cl:25])[CH3:16])[CH:12]=[CH:13][C:8]=2[O:7][CH2:6][C:5]1=[O:31])[CH:2]=[CH2:3].B(Br)(Br)Br>ClCCl>[CH2:1]([N:4]1[C:9]2[CH:10]=[C:11]([C:14]([OH:30])([C:26]([F:27])([F:29])[F:28])[CH:15]([C:17]3[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][C:18]=3[Cl:25])[CH3:16])[CH:12]=[CH:13][C:8]=2[O:7][CH2:6][C:5]1=[O:31])[CH:2]=[CH2:3]
Reactant: C=CCN1C(=O)COc2ccc(C(O)(C(C)c3ccc(OC)cc3Cl)C(F)(F)F)cc21
Agent: BrB(Br)Br
Solvent: ClCCl
Product: C=CCN1C(=O)COc2ccc(C(O)(C(C)c3ccc(O)cc3Cl)C(F)(F)F)cc21
Yield: 94.9 %

Procedure:
In analogy to Example 56, step 4, 4-allyl-6-[2-(2-chloro-4-methoxy-phenyl)-1-hydroxy-1-trifluoromethyl-propyl]-4H-benzo[1,4]oxazin-3-one (2.5 g) was reacted with a 1M of solution boron tribromide in dichloromethane, to give the title compound (2.3 g) as a light yellow foam. MS (m/e)=442.3 [M+H+].
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:12][C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=3[F:20])=[N:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[O:21][CH3:22].C(=O)([O-])[O-].[K+].[K+].Br[CH2:30][CH:31]1[O:33][CH2:32]1.O>CN(C=O)C>[Cl:19][C:16]1[CH:17]=[CH:18][C:13]([NH:12][C:6]2[C:5]3[C:10](=[CH:11][C:2]([O:1][CH2:30][CH:31]4[O:33][CH2:32]4)=[C:3]([O:21][CH3:22])[CH:4]=3)[N:9]=[CH:8][N:7]=2)=[C:14]([F:20])[CH:15]=1
Reactant: BrCC1CO1
Reactant: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1OCC1CO1
Temperature: 60 °C
Reaction time: 3 h
Yield: 43.1 %

Procedure:
To a solution of 7-hydroxy-6-methoxy-4-(2-fluoro-4-chlorophenylamino)quinazoline (5.56 g, 17.4 mmol) in DMF (100 ml) containing potassium carbonate (4.8 g, 34.8 mmol) was added 1-bromo-2,3-epoxypropane (1.49 ml, 17.4 mmol). The mixture was stirred at 60° C. for 3 hours. After cooling, water (400 ml) was added The precipitate was filtered and dried under vacuum at 60° C. for 2 hours over P2O5. The product was purified by column chromatography eluting with methylene chloride followed by methylene chloride/methanol saturated with ammonia 98/2. The fractions containing the expected product were combined and evaporated to give 4-(4-chloro-2-fluorophenylamino)-7-(2,3-epoxypropoxy)-6-methoxyquinazoline (2.82 g, 43%).
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([O:10][C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[N:16]([CH2:20][C:21]([F:24])([F:23])[F:22])[C:15]([C:25]([OH:27])=O)=[CH:14]3)[CH2:6][CH2:5]1)([CH3:3])[CH3:2].[Cl-].[Li+].[NH:30]1[CH2:35][CH2:34][S:33](=[O:37])(=[O:36])[CH2:32][CH2:31]1.C(N(C(C)C)CC)(C)C>CN(C)C=O>[O:36]=[S:33]1(=[O:37])[CH2:34][CH2:35][N:30]([C:25]([C:15]2[N:16]([CH2:20][C:21]([F:22])([F:24])[F:23])[C:17]3[C:13]([CH:14]=2)=[CH:12][C:11]([O:10][CH:7]2[CH2:8][CH2:9][N:4]([CH:1]([CH3:3])[CH3:2])[CH2:5][CH2:6]2)=[CH:19][CH:18]=3)=[O:27])[CH2:31][CH2:32]1
Reactant: O=S1(=O)CCNCC1
Reactant: CC(C)N1CCC(Oc2ccc3c(c2)cc(C(=O)O)n3CC(F)(F)F)CC1
Agent: [Cl-]
Agent: [Li+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)N1CCC(Oc2ccc3c(c2)cc(C(=O)N2CCS(=O)(=O)CC2)n3CC(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 66 %

Procedure:
A mixture of 5-(1-isopropyl-piperidin-4-yloxy)-1-(2,2,2-trifluoro-ethyl)-1H-indole-2-carboxylic acid, hydrochloric salt with one equivalent of lithium chloride (650 mg, 1.0 eq.), 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethylurunium tetrafluoroborate (563 mg, 1.2 eq.), thiomorpholine-1,1-dioxide (purchased at Syntec, ref. M1201) and diisopropylethylamine (1.22 mL, 5 eq.) in dimethylformamide was stirred at room temperature for 24 h and then partitioned between an aqueous solution of sodium hydrogenocarbonate and ethyl acetate. The aqueous layer was extracted with ethyl acetate and the combined organic layers were washed with water and brine, dried over sodium sulfate, filtered, evaporated in vacuo and purified on silica eluting with dichloromethane/methanol/ammoniac. One fraction was isolated and dried in vacuo, to yield 468 mg (66%) of the desired product as off-white solid. MS (m/e): 502.5 (MH+, 100%).
Reaction SMILES: [C:1]([O:5][C:6]([CH:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:15]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[N:16][C:17]3[C:22]([N:23]=2)=[CH:21][C:20]([C:24]([OH:26])=[O:25])=[CH:19][CH:18]=3)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:33](=O)([O-])[O-].[K+].[K+].CI>CN(C)C=O>[C:1]([O:5][C:6]([CH:8]1[CH2:9][CH2:10][N:11]([C:14]2[C:15]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[N:16][C:17]3[C:22]([N:23]=2)=[CH:21][C:20]([C:24]([O:26][CH3:33])=[O:25])=[CH:19][CH:18]=3)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)OC(=O)C1CCN(c2nc3cc(C(=O)O)ccc3nc2-c2ccccc2)CC1
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2nc(-c3ccccc3)c(N3CCC(C(=O)OC(C)(C)C)CC3)nc2c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Into a 100-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of 3-(4-(tert-butoxycarbonyl)piperidin-1-yl)-2-phenylquinoxaline-6-carboxylic acid (509.7 mg, 1.10 mmol, 1.00 equiv) in N,N-dimethylformamide (15 mL), potassium carbonate (762.3 mg, 5.52 mmol, 5.00 equiv). The resulting solution was stirred 30 min at room temperature. Then CH3I (783.3 mg, 5.52 mmol, 5.00 equiv) was added dropwise with stiffing at 0° C. The resulting solution was stirred for 3 h at room temperature. The reaction was then quenched by the addition of water. The resulting aqueous solution was extracted with 6×20 mL of dichloromethane. The organic layers combined and dried over anhydrous sodium sulfate and concentrated under vacuum. This resulted in 285.5 mg (54%) of methyl 3-(4-(tert-butoxycarbonyl)piperidin-1-yl)-2-phenylquinoxaline-6-carboxylate as yellow oil.
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([C:12]([F:17])=[CH:13][C:14]=2[O:15][CH3:16])[CH:10]=[O:11])[CH2:5][CH2:4][CH2:3][CH2:2]1.S(=O)(=O)([OH:20])N.Cl([O-])=O.[Na+]>C(O)(=O)C.O>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]([C:12]([F:17])=[CH:13][C:14]=2[O:15][CH3:16])[C:10]([OH:20])=[O:11])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1cc(F)c(C=O)cc1OC1CCCC1
Reactant: NS(=O)(=O)O
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: O
Solvent: CC(=O)O
Product: COc1cc(F)c(C(=O)O)cc1OC1CCCC1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 58.9 %

Procedure:
A solution of 3-cyclopentyloxy-6-fluoro-4-methoxybenzaldehyde (1.4 g) in glacial acetic acid (20 mL) is treated with sulfamic acid (0.82 g) at room temperature and stirred for 10 minutes. The resulting yellow solution is cooled to 0° C. and treated with a solution of sodium chlorite (0.69 g of an 80% pure sample) in water (20 mL) during 10 minutes. The resulting yellow suspension is stirred at room temperature for 3 hours, poured into water (100 mL) and filtered to give 3-cyclopentyloxy-6-fluoro-4-methoxybenzoic acid (0.88 g), in the form of a white solid. [NMR (CDCl3): 7.46 (d, 1H, J=8 Hz), 6.65 (d, 1H, J=12 Hz), 4.80-0.76 (m, 1H), 3.90 (s, 3H), 2.01-1.58 (m, 8H)].
Reaction SMILES: [CH3:1][N:2]([CH2:4]N(C)C)[CH3:3].[O:8]1[CH:12]=[CH:11][CH:10]=[C:9]1[CH2:13][OH:14]>C(O)(=O)C>[CH3:1][N:2]([CH2:4][C:12]1[O:8][C:9]([CH2:13][OH:14])=[CH:10][CH:11]=1)[CH3:3]
Reactant: CN(C)CN(C)C
Reactant: OCc1ccco1
Solvent: CC(=O)O
Product: CN(C)Cc1ccc(CO)o1
Temperature: 25 °C
Reaction time: 18 h
Yield: 93.4 %

Procedure:
A solution of bis(dimethylamino)methane (112 g, 1.1 mol) in acetic acid (200 ml) was added dropwise with cooling (10° C.) to a stirred solution of 2-furanmethanol (98 g, 1.0 mol) in acetic acid (1000 ml). The mixture was stirred at room temperature for 18 hours and acetic acid was removed at 60° C. under reduced pressure. Ice (200 g) was added to the residue which was made basic with 40% aqueous sodium hydroxide (with external cooling). The mixture was extracted with ethyl acetate and the extracts were evaporated and distilled to give 5-dimethylaminomethyl-2-furanmethanol (145 g, 94%) b.p. 92°-96° C./0.2 0.5 mmHg.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][N:3]=1.[N:9]1([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:15][CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH3:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([N:12]2[CH2:13][CH2:14][CH2:15][N:9]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:10][CH2:11]2)[CH:7]=1
Reactant: Cc1ccnc(Br)c1
Reactant: CC(C)(C)OC(=O)N1CCCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccnc(N2CCCN(C(=O)OC(C)(C)C)CC2)c1
Temperature: 140 °C

Procedure:
2-Bromo-4-methylpyridine (400 mg, 2.326 mmol), tert-butyl 1,4-diazepane-1-carboxylate (2.1 g, 10.5 mmol) and potassium carbonate (2.8 g, 20 mmol) were combined in anhydrous DMF (20 ml) and heated under microwave heating at 140° C. for 5 hours. The mixture was poured into water and extracted with ethyl acetate (4×). The combined organic layers were washed with brine (2×) and dried over sodium sulfate. The solvent was removed under reduced pressure and the residue was purified two times by column chromatography (silica, gradient from 0 to 50% ethyl acetate in heptane) to yield 97 mg (0.33 mmol, 14%). MS (ESI) m/z=292.2 [M+1]+.
Reaction SMILES: [CH3:1][C:2]1([CH3:24])[CH:7]2[CH2:8][CH:4]([CH2:5][CH2:6]2)[CH:3]1[CH2:9][CH2:10][C:11](=O)[CH2:12][CH2:13][CH:14]1[C:19]([CH3:21])([CH3:20])[CH:18]2[CH2:22][CH:15]1[CH2:16][CH2:17]2.[NH2:25][CH2:26][CH2:27][CH2:28][NH2:29].C1(C)C=CC=CC=1>O>[CH3:1][C:2]1([CH3:24])[CH:7]2[CH2:8][CH:4]([CH2:5][CH2:6]2)[CH:3]1[CH2:9][CH2:10][CH:11]([NH:25][CH2:26][CH2:27][CH2:28][NH2:29])[CH2:12][CH2:13][CH:14]1[C:19]([CH3:21])([CH3:20])[CH:18]2[CH2:22][CH:15]1[CH2:16][CH2:17]2
Reactant: NCCCN
Reactant: CC1(C)C2CCC(C2)C1CCC(=O)CCC1C2CCC(C2)C1(C)C
Solvent: Cc1ccccc1
Solvent: O
Product: CC1(C)C2CCC(C2)C1CCC(CCC1C2CCC(C2)C1(C)C)NCCCN

Procedure:
1,5-Di-(3,3-dimethylnorborn-2-yl)-3-pentanone (6.04 g., 0.02 mole) and 1,3-diaminopropane (0.10 mole) in 150 ml. toluene is heated at reflux overnight with a Dean-Stark water separator. The cooled solution is concentrated under reduced pressure. The residue is dissolved in ethanol and hydrogenated with PtO2 at room temperature and 40 psi hydrogen pressure. The platinum catalyst is filtered off and the ethanol removed under vacuum. The residue is dissolved in ether and the ether solution washed several times with water to remove the excess 1,3-diaminopropane. The ether extracts are dried over anhydrous sodium sulfate and concentrated under vacuum to leave the diamine product, 1-[1,5-di-(3,3-dimethylnorborn-2-yl)-3-pentyl]-1,5-diazapentane.