Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: COC1C=CC(C[N:8]([C:33]2[S:34][CH:35]=[CH:36][N:37]=2)[S:9]([C:12]2[CH:13]=[CH:14][C:15]3[N:20]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[O:27][CH2:28][CH2:29][O:30][CH3:31])[CH2:19][CH2:18][O:17][C:16]=3[CH:32]=2)(=[O:11])=[O:10])=CC=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:31][O:30][CH2:29][CH2:28][O:27][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[N:20]1[CH2:19][CH2:18][O:17][C:16]2[CH:32]=[C:12]([S:9]([NH:8][C:33]3[S:34][CH:35]=[CH:36][N:37]=3)(=[O:11])=[O:10])[CH:13]=[CH:14][C:15]1=2
Reactant: COCCOc1ccccc1N1CCOc2cc(S(=O)(=O)N(Cc3ccc(OC)cc3)c3nccs3)ccc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COCCOc1ccccc1N1CCOc2cc(S(=O)(=O)Nc3nccs3)ccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 16.1 %

Procedure:
To a solution of N-(4-methoxybenzyl)-4-(2-(2-methoxyethoxyl)phenyl)-N-(thiazol-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide (300 mg, 0.529 mmol) in DCM (6 mL) was added TFA (3 mL) at 0° C. The reaction mixture was stirred at ambient temperature for 2 h. After completion, the reaction mixture was quenched with saturated sodium bicarbonate solution (10 mL) and extracted with DCM (2×10 mL). The organic layer was dried over sodium sulfate and concentrated reduced pressure to obtain the crude material (36% by LCMS) that was purified by prep purification to obtain 4-(2-(2-methoxyethoxyl)phenyl)-N-(thiazol-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide (38 mg, 16.1%) as white solid. 1H NMR (400 MHz, DMSO) δ 12.49 (s, 1H), 7.38-7.25 (m, 2H), 7.25-7.13 (m, 2H), 7.14-6.95 (m, 3H), 6.75 (d, J=4.6 Hz, 1H), 6.22 (d, J=8.5 Hz, 1H), 4.28 (t, J=4.3 Hz, 2H), 4.07 (dd, J=5.6, 3.5 Hz, 2H), 3.62 (t, J=4.1 Hz, 2H), 3.47 (t, J=4.5 Hz, 2H), 3.10 (s, 3H); MS (ESI, positive ion) m/z: 448.09 (M+1).
Reaction SMILES: [F:1][C:2]1[C:10]2[CH:9]=[CH:8][S:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.C([Li])CCC.[B:16](OC(C)C)([O:21]C(C)C)[O:17]C(C)C.Cl>C1COCC1.C(Cl)Cl>[F:1][C:2]1[C:10]2[CH:9]=[C:8]([B:16]([OH:21])[OH:17])[S:7][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: Fc1cccc2sccc12
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: ClCCl
Solvent: C1CCOC1
Product: OB(O)c1cc2c(F)cccc2s1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a cold (−78° C.) solution of 4-fluorobenzo[b]thiophene (80.4 mg, 0.528 mmol) in anhydrous THF (1 mL) was added n-butyllithium (0.363 mL, 0.581 mmol) dropwise. The reaction mixture was stirred at −78° C. for 60 minutes. A solution of triisopropyl borate (0.146 mL, 0.634 mmol) was added. The reaction mixture was stirred at −78° C. for 30 minutes and was then allowed to warm to room temperature over a 2 hour period. TLC showed completion of reaction. 1N HCl (100 mL) and DCM (50 mL) were added to the reaction mixture. The aqueous and organic layers were separated. The aqueous layer was concentrated to 50 mL, yielding a solid precipitate that was filtered and dried to give the title compound as off-white, needle-shaped crystals. The product was used without further purification.
Reaction SMILES: [CH3:1][N:2]([CH3:11])[C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[O:8])=[CH:5][CH:4]=1.[F:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[CH:16]=[O:17].[C-]#N.[K+]>C(O)C>[CH3:1][N:2]([CH3:11])[C:3]1[CH:10]=[CH:9][C:6]([C:7]([CH:16]([C:15]2[CH:18]=[CH:19][CH:20]=[C:13]([F:12])[CH:14]=2)[OH:17])=[O:8])=[CH:5][CH:4]=1
Reactant: CN(C)c1ccc(C=O)cc1
Reactant: O=Cc1cccc(F)c1
Agent: [C-]#N
Agent: [K+]
Solvent: CCO
Product: CN(C)c1ccc(C(=O)C(O)c2cccc(F)c2)cc1

Procedure:
A mixture consisting of 14.9 g. of p-dimethylaminobenzaldehyde, 12.4 g. of m-fluorobenzaldehyde, 6 g. of potassium cyanide, and 100 ml. of 65% ethanol is reacted according to the procedure of Example 20, 12.8 g. of 4-dimethylamino-3'-fluorobenzoin being obtained; m.p. 147°-149° C. An 8.2 g. portion of this benzoin is converted to its methanesulfonate ester, by the procedure of Example 20, in 9.1 g. yield, m.p. 106°-109° C. A mixture of 2.6 g. of the methanesulfonate ester, 0.91 g. of hexahydro-2H-1,3-diazepin-2-thione, and 70 ml. of acetone is left at room temperature for three days, precipitating the title compound in 2.7 g. yield, m.p. 180°-182° C.
Reaction SMILES: [CH2:1]([OH:6])[CH:2]([OH:5])[CH2:3][OH:4].[CH2:7]([OH:12])[CH:8]([OH:11])[CH2:9][OH:10].[CH2:13]([OH:18])[CH:14]([OH:17])[CH2:15][OH:16].[CH2:19]([OH:24])[CH:20]([OH:23])[CH2:21][OH:22].[C:25]([OH:32])(=[O:31])[CH2:26][CH2:27][CH2:28][CH2:29][CH3:30].ON1[C:38](=O)[CH2:37][CH2:36][C:35]1=O.CC(N=C=NC(C)C)C>CS(C)=O>[CH2:27]([CH:26]([CH2:35][CH2:36][CH2:37][CH3:38])[C:25]([OH:32])=[O:31])[CH2:28][CH2:29][CH2:30][CH2:1][CH3:2].[OH:12][CH2:7][CH:8]([CH2:9][OH:10])[OH:11].[OH:18][CH2:13][CH:14]([CH2:15][OH:16])[OH:17].[OH:24][CH2:19][CH:20]([CH2:21][OH:22])[OH:23].[OH:6][CH2:1][CH:2]([CH2:3][OH:4])[OH:5]
Reactant: CCCCCC(=O)O
Reactant: O=C1CCC(=O)N1O
Agent: CC(C)N=C=NC(C)C
Solvent: CS(C)=O
Solvent: OCC(O)CO
Product: CCCCCCC(CCCC)C(=O)O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Into a 250 mL vessel, tetraglycerol (5.0 g, 15.91 mmol) was added and dissolved into anhydrous DMSO (50 mL). Hexanoic acid (11.96 mL, 95.44 mmol) was also dissolved into the reaction mixture which was stirred magnetically at room temperature for one hour to fully dissolve the reagents. N,N-dimethylaminopyridine (0.194 g, 1.59 mmol) and N-hydroxysuccinimide (0.183 g, 1.59 mmol) were both dissolved in the solution. When the catalysts were fully dissolved, N,N-diisopropylcarbodiimide (15.0 mL, 97.03 mmol) was pipetted into the vessel and was sealed to keep the reaction dry. The reaction proceeded overnight at 55° C. The solution was dialyzed in SpectraPor7 MWCO 1000 dialysis tubing to remove the DMSO and unreacted monomer. The polymer crashed out in water into a thick white liquid. After 3 days of dialysis, the solution was placed into a separatory funnel and the organic portion was dissolved into chloroform. The water layer was removed and the organic layer was dried with sodium sulfate. The solvent was stripped via rotoevaporation to leave a clear thick liquid product. NMR analysis supported full conversion of hydroxyl groups to the hexanoic esters.
Reaction SMILES: ClC(OC(C)C)=O.[CH3:8][O:9][C:10]1[N:15]=[C:14](/[CH:16]=[CH:17]/[C:18](O)=[O:19])[CH:13]=[CH:12][C:11]=1[N:21]1[CH:25]=[C:24]([CH3:26])[N:23]=[CH:22]1.C([N:30](CC)C(C)C)(C)C.ClC(OCC)=O.N>CN(C=O)C.O.C(Cl)(Cl)Cl>[CH3:8][O:9][C:10]1[N:15]=[C:14](/[CH:16]=[CH:17]/[C:18]([NH2:30])=[O:19])[CH:13]=[CH:12][C:11]=1[N:21]1[CH:25]=[C:24]([CH3:26])[N:23]=[CH:22]1
Reactant: COc1nc(/C=C/C(=O)O)ccc1-n1cnc(C)c1
Reactant: CCN(C(C)C)C(C)C
Agent: CC(C)OC(=O)Cl
Agent: CCOC(=O)Cl
Agent: N
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Solvent: O
Product: COc1nc(/C=C/C(N)=O)ccc1-n1cnc(C)c1
Reaction time: 0.33 h

Procedure:
Isopropyl chloroformate (3.99 mL) was added dropwise to a solution of (E)-3-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]acrylic acid (5.2 g) and N,N-diisopropylethylamine (7.44 mL) in DMF (52 mL) under ice-cooling, and the reaction solution was stirred for 20 minutes. Aqueous ammonic (5.2 mL) was added to the reaction solution, and the reaction solution was stirred at room temperature for 30 minutes. Similarly, ethyl chloroformate (3.76 mL) was added dropwise to a solution of (E)-3-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]acrylic acid (4.8 g) and N,N-diisopropylethylamine (6.87 mL) in DMF (48 mL) under ice-cooling, and the reaction solution was stirred for 10 minutes. Then, aqueous ammonia (5.2 mL) was added to the reaction solution, and the reaction solution was stirred at room temperature for 30 minutes. The reaction solutions were mixed and diluted with water and chloroform, and then the organic layer was separated. The aqueous layer was extracted with chloroform five times. The organic layers were combined, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform-2-propanol system) to obtain 3.54 g of the title compound. The property value of the compound is as follows.
Reaction SMILES: [SiH4].[CH2:2]([O:4][SiH](OCC)OCC)[CH3:3].[CH2:12]([O:14][Si:15]([O:31][CH2:32][CH3:33])([O:28][CH2:29][CH3:30])[CH2:16][CH2:17][Si:18]([O:25][CH2:26][CH3:27])([O:22][CH2:23][CH3:24])[O:19][CH2:20][CH3:21])[CH3:13]>>[CH:16]([Si:15]([O:28][CH2:29][CH3:30])([O:14][CH2:12][CH3:13])[O:31][CH2:32][CH3:33])=[CH2:17].[CH2:2]([O:4][Si:18]([O:19][CH2:20][CH3:21])([O:22][CH2:23][CH3:24])[O:25][CH2:26][CH3:27])[CH3:3]
Reactant: CCO[Si](CC[Si](OCC)(OCC)OCC)(OCC)OCC
Reactant: CCO[SiH](OCC)OCC
Agent: [SiH4]
Product: C=C[Si](OCC)(OCC)OCC
Product: CCO[Si](OCC)(OCC)OCC
Reaction time: 1 h
Yield: 25 %

Procedure:
The reaction was carried out in accordance with the procedure of Comparative Example 2, except that the silane used was triethoxysilane and the reaction temperature was 150° C. The reaction was monitored by GPC and was completed in one hour. The major product formed was 1,2-bis(triethoxysilyl)ethane (72%), with vinyltriethoxysilane (25%) and tetraethoxysilane also being formed (3%). With a primary alkyl silane and at lower reaction temperatures, the undesired bis(silyl)ethane was the main reaction product.
Reaction SMILES: [CH:1]1([CH3:13])[CH2:6][CH2:5][CH:4]([CH:7]([CH3:9])[CH3:8])[CH:3]([C:10](O)=[O:11])[CH2:2]1.S(Cl)([Cl:16])=O>>[CH:1]1([CH3:13])[CH2:6][CH2:5][CH:4]([CH:7]([CH3:9])[CH3:8])[CH:3]([C:10]([Cl:16])=[O:11])[CH2:2]1
Reactant: O=S(Cl)Cl
Reactant: CC1CCC(C(C)C)C(C(=O)O)C1
Product: CC1CCC(C(C)C)C(C(=O)Cl)C1

Procedure:
Menthane-3-carboxylic acid (54.35 g) was refluxed with 80 ml of thionyl chloride for 3 hours. The SOCl2 was removed by distillation, and the acid chloride was distilled at 114-115° C. (8 Torr). (Lit. b.p. 84-85° C. at 3.5 Torr). Yield: 50 g (84%).
Reaction SMILES: [CH3:1][O:2][CH:3]([O:6][CH3:7])[CH2:4][NH2:5].[CH2:8]=O.[Cl:10][C:11]1[CH:12]=[C:13]([CH:28]=[CH:29][C:30]=1[Cl:31])[CH2:14][N:15]([CH3:27])[C:16](=[O:26])[CH:17]=[C:18]1[C:22](=[O:23])OC(C)(C)[O:19]1>CO>[Cl:10][C:11]1[CH:12]=[C:13]([CH:28]=[CH:29][C:30]=1[Cl:31])[CH2:14][N:15]([CH3:27])[C:16]([C:17]1[CH2:8][N:5]([CH2:4][CH:3]([O:6][CH3:7])[O:2][CH3:1])[C:22](=[O:23])[C:18]=1[OH:19])=[O:26]
Reactant: COC(CN)OC
Reactant: CN(Cc1ccc(Cl)c(Cl)c1)C(=O)C=C1OC(C)(C)OC1=O
Reactant: C=O
Solvent: CO
Product: COC(CN1CC(C(=O)N(C)Cc2ccc(Cl)c(Cl)c2)=C(O)C1=O)OC
Reaction time: 0.75 h
Yield: 33.7 %

Procedure:
To a solution of 2-aminoacetaldehyde dimethylacetal (0.526 g mL, 5.0 mmol) and paraformaldehyde 90.15 g, 5 mmol) in MeOH (10 mL) at 55° C. was added N-(3,4-dichloro-benzyl)-2-(2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-N-methyl-acetamide (1.715 g, 5.0 mmol). After 45 min, the reaction mixture was cooled and purified by preparative HPLC on a C18 reverse phase column using acetonitrile (40–50%)/water (0.1% TFA) as eluent. The fractions containing the desired product were combined, concentrated and lyophilized to yield the title compound as an amber oil (0.68 g, 34% yield). 1H NMR (300 MHz, CDCl3) δ: 10.81 (bs, 1H), 7.42 (d, 1H, J=8.1), 7.35 (d, 1H, J=1.8), 7.10 (dd, 1H, J=8.1, J=1.8), 4.59 (s, 2H), 4.47 (t, 1H, J=5.1), 4.27 (s, 2H), 3.59 (d, 2H, J=5.1), 3.38 (s, 6H), 3.02 (s, 3H). HRMS (M+Na) calcd for C17H20N2Cl2O5Na: 425.0647. found: 425.0647.
Reaction SMILES: [CH3:1][N:2]1[CH2:15][CH2:14][C:5]2[NH:6][C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.[H-].[Na+].[CH3:18][C:19]1([C:22]2[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=2)[CH2:21][O:20]1>CN(C=O)C>[CH3:1][N:2]1[CH2:15][CH2:14][C:5]2[N:6]([CH2:18][C:19]([C:22]3[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=3)([OH:20])[CH3:21])[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1
Reactant: Cc1ccc2[nH]c3c(c2c1)CN(C)CC3
Reactant: CC1(c2cccnc2)CO1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc2c(c1)c1c(n2CC(C)(O)c2cccnc2)CCN(C)C1
Temperature: 120 °C
Reaction time: 1 h

Procedure:
To a solution of 2,3,4,5-tetrahydro-2,8-dimethyl-1H-pyrido[4,3-b]indole (290 mg, 1.4 mmol) in DMF (6 mL) was added sodium hydride (38 mg, 1.6 mmol) and the solution was stirred at 120° C. for 1 h. The reaction mixture was cooled to 0° C. and 3-(2-methyloxiran-2-yl)pyridine (400 mg, 2.96 mmol) was added dropwise over a period of 5 min. The reaction mixture was stirred at 120° C. for 2 h, quenched with ice-water (15 mL) and extracted with EtOAc (60 mL). The organic layer was washed with water, brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by flash column chromatography (5-15% MeOH/EtOAc) to yield 1-(1,2,3,4-tetrahydro-2,8-dimethylpyrido[4,3-b]indol-5-yl)-2-(pyridin-3-yl)propan-2-ol. Separation by chiral HPLC provided enantiomers 5a and 5b. 1H NMR (CDCl3, freebase) δ (ppm): 8.79 (s, 1H), 8.42 (d, 1H), 7.56 (d, 1H), 7.04 (s, 1H), 6.9 (m, 2H), 6.8 (d, 1H), 4.17 (dd, 2H), 3.42 (s, 2H), 2.8 (t, 2H), 2.62 (t, 2H), 2.42 (s, 3H), 2.39 (s, 3H), 1.61 (s, 3H). Optical rotations: Compound 5a, (−)39.27 (c 0.43, Chloroform, 99.69% HPLC purity); Compound 5b, (+)58.97 (c 0.58, Chloroform, 99.49% HPLC purity).
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[C:9]([CH:14]=[C:15]([N+:17]([O-])=O)[CH:16]=2)[C:10]([NH:12][CH3:13])=[O:11])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[H][H]>C(O)C.[Ni]>[NH2:17][C:15]1[CH:14]=[C:9]([CH:8]=[C:7]([N:1]2[CH2:2][CH2:3][O:4][CH2:5][CH2:6]2)[CH:16]=1)[C:10]([NH:12][CH3:13])=[O:11]
Reactant: [H][H]
Reactant: CNC(=O)c1cc(N2CCOCC2)cc([N+](=O)[O-])c1
Agent: [Ni]
Solvent: CCO
Product: CNC(=O)c1cc(N)cc(N2CCOCC2)c1

Procedure:
A solution of 3-(4-morpholinyl)-5-nitro-N-(methyl)-benzamide (Example 86d; 300 mg, 1.12 mmol) in ethanol (20 mL) is hydrogenated at atmospheric pressure over Raney nickel (0.2 g) at 25° C. The calculated amount of hydrogen is taken up in 19 hours. The mixture is then filtered and the solvent is evaporated off under reduced pressure to yield the crude product which is purified by recrystallisation from ethyl acetate to give the title compound as a beige crystalline solid, m.p. 201-204° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:37]=[C:38]([O:42][CH3:43])[C:39]=1[O:40][CH3:41])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([CH2:19][CH2:20][N:21]2[CH2:27][CH2:26][CH2:25][N:24]([C:28]3[NH:32][C:31]4[CH:33]=[CH:34][CH:35]=[CH:36][C:30]=4[N:29]=3)[CH2:23][CH2:22]2)([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:9]1)=[O:7].Br[CH2:45][C:46](=[O:49])[CH2:47][CH3:48]>>[CH3:43][O:42][C:38]1[CH:37]=[C:5]([CH:4]=[C:3]([O:2][CH3:1])[C:39]=1[O:40][CH3:41])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([CH2:19][CH2:20][N:21]2[CH2:27][CH2:26][CH2:25][N:24]([C:28]3[N:29]([CH2:45][C:46](=[O:49])[CH2:47][CH3:48])[C:30]4[CH:36]=[CH:35][CH:34]=[CH:33][C:31]=4[N:32]=3)[CH2:23][CH2:22]2)([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:9]1)=[O:7]
Reactant: CCC(=O)CBr
Reactant: COc1cc(C(=O)N2CCC(CCN3CCCN(c4nc5ccccc5[nH]4)CC3)(c3ccccc3)C2)cc(OC)c1OC
Product: CCC(=O)Cn1c(N2CCCN(CCC3(c4ccccc4)CCN(C(=O)c4cc(OC)c(OC)c(OC)c4)C3)CC2)nc2ccccc21

Procedure:
Prepare by the method of Example 35.1 using 1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-(1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine (prepared from (−)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine(R,R)-di-p-anisoyltartaric acid salt) and 1-bromo-butan-2-one to give the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH3:12])[C:7](=[O:13])[C:6]([C:14]([O:16]CC)=O)=[C:5]2[OH:19].[C:20]([NH:29][NH2:30])(=[O:28])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH3:12])[C:7](=[O:13])[C:6]([C:14]([NH:30][NH:29][C:20](=[O:28])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[O:16])=[C:5]2[OH:19]
Reactant: CCOC(=O)c1c(O)c2cc(Br)ccc2n(C)c1=O
Reactant: CCCCCCCC(=O)NN
Product: CCCCCCCC(=O)NNC(=O)c1c(O)c2cc(Br)ccc2n(C)c1=O

Procedure:
Reagents: Comp 35 (0.46 mmols, 0.15 g); octanoyl hydrazine (0.5 mmols, 0.08 g). Yield: 0.13 g (64%), white solid, m.p.=185° C.-186° C.
Reaction SMILES: [CH3:1][N:2]1[C:11](=[O:12])[C:10]2[NH:9][CH:8]=[N:7][C:6]=2[N:5]([CH3:13])[C:3]1=[O:4].C(=O)([O-])[O-].[K+].[K+].[Cl:20][C:21]1[CH:36]=[CH:35][C:24]([C:25]([C:27]2[CH:34]=[CH:33][C:30]([CH2:31]Br)=[CH:29][CH:28]=2)=[O:26])=[CH:23][N:22]=1>CN(C=O)C.O>[Cl:20][C:21]1[CH:36]=[CH:35][C:24]([C:25]([C:27]2[CH:34]=[CH:33][C:30]([CH2:31][N:9]3[C:10]4[C:11](=[O:12])[N:2]([CH3:1])[C:3](=[O:4])[N:5]([CH3:13])[C:6]=4[N:7]=[CH:8]3)=[CH:29][CH:28]=2)=[O:26])=[CH:23][N:22]=1
Reactant: Cn1c(=O)c2[nH]cnc2n(C)c1=O
Reactant: O=C(c1ccc(CBr)cc1)c1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cn1c(=O)c2c(ncn2Cc2ccc(C(=O)c3ccc(Cl)nc3)cc2)n(C)c1=O
Yield: 96.4 %

Procedure:
A solution of 1,3-dimethylxanthine (712 mg), potassium carbonate (578 mg) and 4-(6-chloronicotinoyl)benzyl bromide (1515 mg) in DMF (10 ml) was stirred at 60° C. for 5 hours. This reaction mixture was poured in water and extracted with ethyl acetate. The extract was washed with water, dried, and. concentrated. The residue was purified by silica gel column chromatography (hexane: ethyl acetate =1:3) and recrystallized from chloroform-isopropyl ether to provide the title compound as colorless solid (1562 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:14]S(C2C=CC=CC=2)(=O)=O)=[C:6]([CH:13]=1)/[CH:7]=[CH:8]/[C:9]([O:11][CH3:12])=[O:10].Br[CH2:25][C:26]([C:28]1[N:29]=[C:30]([CH3:33])[NH:31][CH:32]=1)=[O:27]>>[CH3:12][O:11][C:9](=[O:10])[CH2:8][C:7]1[C:6]2[C:5](=[CH:4][CH:3]=[C:2]([Cl:1])[CH:13]=2)[NH:14][C:25]=1[C:26]([C:28]1[N:29]=[C:30]([CH3:33])[NH:31][CH:32]=1)=[O:27]
Reactant: Cc1nc(C(=O)CBr)c[nH]1
Reactant: COC(=O)/C=C/c1cc(Cl)ccc1NS(=O)(=O)c1ccccc1
Product: COC(=O)Cc1c(C(=O)c2c[nH]c(C)n2)[nH]c2ccc(Cl)cc12

Procedure:
The title compound was prepared according to the procedure described in Example 8 (Method B) from methyl trans-5-chloro-2-(phenylsulfonylamino)cinnamate (Example 36, step 3) and 4-bromoacetyl-2-methylimidazole (Deady, Leslie W. et al., Aust. J. Chem., 1981, 34, 1295).
Reaction SMILES: C([NH:4][CH2:5][CH2:6][C:7]1[CH:49]=[CH:48][CH:47]=[CH:46][C:8]=1[O:9][CH2:10][CH2:11][O:12][CH:13]1[CH:18]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][CH2:28][O:29][CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[O:37][CH3:38])=[CH:21][CH:20]=2)[CH2:17][CH2:16][N:15]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:14]1)(=O)C.[H-].[Na+].CI>CN(C)C=O>[C:8]([CH2:46][NH:4][CH2:5][CH2:6][C:7]1[CH:49]=[CH:48][CH:47]=[CH:46][C:8]=1[O:9][CH2:10][CH2:11][O:12][CH:13]1[CH:18]([C:19]2[CH:20]=[CH:21][C:22]([O:25][CH2:26][CH2:27][CH2:28][O:29][CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[O:37][CH3:38])=[CH:23][CH:24]=2)[CH2:17][CH2:16][N:15]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:14]1)(=[O:9])[CH3:7]
Reactant: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCCOc2ccccc2CCNC(C)=O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CI
Product: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCCOc2ccccc2CCNCC(C)=O)cc1
Temperature: 75 °C
Reaction time: 0.5 h

Procedure:
A solution of 0.099 g of tert-butyl 3-{2-[2-(2-acetylaminoethyl)phenoxy]ethoxy}-4-{4-[3-(2-methoxybenzyloxy)propoxy]phenyl}piperidine-1-carboxylate (Example 14a) in 3 ml of N,N-dimethylformamide is admixed with stirring at room temperature with 0.023 g of sodium hydride dispersion (55%). After 30 minutes at room temperature, a solution of 0.055 ml of methyl iodide in 0.4 ml of N,N-dimethylformamide is added dropwise. The reaction mixture is stirred at 75° C. over 18 hours, cooled, poured onto water and extracted with tert-butyl methyl ether (2×). The combined organic phases are dried with sodium sulphate and concentrated by evaporation. The title compound is obtained as a yellow oil from the residue by means of flash chromatography (SiO2 60F). Rf=0.09 (1.5:1 EtOAc-heptane); Rt=5.84.
Reaction SMILES: [CH2:1]1[C:7]2[CH:8]=[CH:9][C:10]([O:12][C:13]3[CH:21]=[CH:20][C:16]([C:17]([NH2:19])=[O:18])=[CH:15][N:14]=3)=[CH:11][C:6]=2[CH2:5][CH2:4][NH:3][CH2:2]1.C([O-])([O-])=O.[K+].[K+].Br[CH2:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>CN(C=O)C>[CH2:29]([N:3]1[CH2:4][CH2:5][C:6]2[CH:11]=[C:10]([O:12][C:13]3[CH:21]=[CH:20][C:16]([C:17]([NH2:19])=[O:18])=[CH:15][N:14]=3)[CH:9]=[CH:8][C:7]=2[CH2:1][CH2:2]1)[CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: NC(=O)c1ccc(Oc2ccc3c(c2)CCNCC3)nc1
Reactant: BrCCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: NC(=O)c1ccc(Oc2ccc3c(c2)CCN(CCc2ccccc2)CC3)nc1

Procedure:
Take up 6-(2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yloxy)nicotinamide (0.0500 g, 0.176 mmol) and K2CO3 (0.0488 g, 0.353 mmol) in DMF (1.0 mL). Add 2-bromoethylbenzene (0.0265 mL, 0.194 mmol) and heat to 70° C. overnight. Remove DMF as an azeotrope with xylenes. Purify by 5 g SCX column by washing with methanol and eluting with 2.0 M NH3 in methanol. Then purify by flash chromatography, eluting with 0-10% ethyl acetate and 5% (2.0 M NH3 in methanol) in dichloromethane to give the title compound: MS ES+ 388.1 (M+H)+; HPLC [YMC-Pack Pro C-18 (150×4.6 mm, S-5 microm), acetonitrile in water containing 0.01% concentrated HCl at 1.0 mL/min, 30-99% over 19 min], tR=1.7 min, 100% purity.
Reaction SMILES: C(O[K])(C)(C)C.[OH:7][C@@H:8]([C@H:10]1[CH2:14][N:13]([C@@H:15]([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)[CH3:16])[C:12](=[O:25])[CH2:11]1)[CH3:9].Cl[C:27]1[C:32]2[N:33]([CH3:37])[C:34]([CH3:36])=[N:35][C:31]=2[CH:30]=[C:29]([Cl:38])[N:28]=1>C1COCC1>[Cl:38][C:29]1[N:28]=[C:27]([O:7][C@@H:8]([C@H:10]2[CH2:14][N:13]([C@@H:15]([C:17]3[CH:18]=[CH:19][C:20]([O:23][CH3:24])=[CH:21][CH:22]=3)[CH3:16])[C:12](=[O:25])[CH2:11]2)[CH3:9])[C:32]2[N:33]([CH3:37])[C:34]([CH3:36])=[N:35][C:31]=2[CH:30]=1
Reactant: COc1ccc([C@@H](C)N2C[C@H]([C@@H](C)O)CC2=O)cc1
Reactant: Cc1nc2cc(Cl)nc(Cl)c2n1C
Agent: CC(C)(C)O[K]
Solvent: C1CCOC1
Product: COc1ccc([C@@H](C)N2C[C@H]([C@@H](C)Oc3nc(Cl)cc4nc(C)n(C)c34)CC2=O)cc1
Temperature: 60 °C

Procedure:
A solution of tBuOK in THF (1.0 M, 0.92 mL, 0.92 mmol) was added to a solution of (R)-4-((R)-1-hydroxyethyl)-1-((R)-1-(4-methoxyphenyl)ethyl)pyrrolidin-2-one 1.04 (128 mg, 0.486 mmol) in THF (3 mL) at room temperature. After eighteen minutes, a suspension of 4,6-dichloro-2,3-dimethyl-3H-imidazo[4,5-c]pyridine 2.47 (0.1 g, 0.463 mmol) in THF (3 mL) was added and mixture stirred at 60° C. for fifteen minutes. LC/MS indicated full conversion to desired product. Reaction mixture was quenched with water, and extracted with ethyl acetate. Organic phase was dried over MgSO4 and evaporated under reduced pressure to obtain (R)-4-((R)-1-(6-chloro-2,3-dimethyl-3H-imidazo[4,5-c]pyridin-4-yloxy)ethyl)-1-((R)-1-(4-methoxyphenyl)ethyl)pyrrolidin-2-one 2.48 that was used without further purification.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7](=[O:24])[NH:8][C:9]2[CH:14]=[CH:13][N:12]3[N:15]=[C:16]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[N:17]=[C:11]3[CH:10]=2)=[C:5]([C:25](O)=[O:26])[CH:4]=[N:3]1.C([N:31]([CH:34]([CH3:36])[CH3:35])CC)(C)C.CCCP(=O)=O.[O:43]1CCC[CH2:44]1>>[CH3:1][N:2]1[C:6]([C:7]([NH:8][C:9]2[CH:14]=[CH:13][N:12]3[N:15]=[C:16]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[N:17]=[C:11]3[CH:10]=2)=[O:24])=[C:5]([C:25]([NH:31][C@@H:34]2[CH2:36][CH2:44][O:43][CH2:35]2)=[O:26])[CH:4]=[N:3]1
Reactant: C1CCOC1
Reactant: Cn1ncc(C(=O)O)c1C(=O)Nc1ccn2nc(-c3ccccc3)nc2c1
Reactant: CCN(C(C)C)C(C)C
Agent: CCCP(=O)=O
Product: Cn1ncc(C(=O)N[C@@H]2CCOC2)c1C(=O)Nc1ccn2nc(-c3ccccc3)nc2c1
Reaction time: 0.33 h
Yield: 95.7 %

Procedure:
A mixture of 1-methyl-5-(2-phenyl-[1,2,4]triazolo[1,5-a]pyridin-7-ylcarbamoyl)-1H-pyrazole-4-carboxylic acid (100 mg, 276 μmol), (R)-tetrahydrofuran-3-ylamine4-methylbenzenesulfonate (143 mg, 552 μmol), diisopropylethylamine (193 μl, 1.1 mmol) and propylphosphonic anhydride (50% in ethyl acetate, 407 μl, 690 μmol) in tetrahydrofurane (7 ml) is refluxed for 18 hours. The solvent is evaporated and to the residue is added sat. aqueous sodium hydrogencarbonate solution. The mixture is stirred for 20 minutes while a white solid precipitates. The solid is collected by filtration, washed with diethylether and dried affording (R)-1-methyl-N5-(2-phenyl-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-N4-(tetrahydrofuran-3-yl)-1H-pyrazole-4,5-dicarboxamide (114 mg, 95.7%) as a white solid. mp.: >250° C. MS: m/z=432.3 (M+H+).