Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:32]=[CH:31][C:5]([O:6][C:7]2[C:8]3[CH:15]=[C:14]([C:16]4[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=4)[N:13]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[C:9]=3[N:10]=[CH:11][N:12]=2)=[CH:4][C:3]=1[Cl:33].Cl.Cl[CH2:36][CH2:37][CH2:38][N:39]([CH2:42][CH3:43])[CH2:40][CH3:41].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Cl:33][C:3]1[CH:4]=[C:5]([O:6][C:7]2[C:8]3[CH:15]=[C:14]([C:16]4[CH:17]=[CH:18][C:19]([O:22][CH2:36][CH2:37][CH2:38][N:39]([CH2:42][CH3:43])[CH2:40][CH3:41])=[CH:20][CH:21]=4)[N:13]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:28])([CH3:29])[CH3:30])[C:9]=3[N:10]=[CH:11][N:12]=2)[CH:31]=[CH:32][C:2]=1[NH2:1]
Reactant: CCN(CC)CCCCl
Reactant: C[Si](C)(C)CCOCn1c(-c2ccc(O)cc2)cc2c(Oc3ccc(N)c(Cl)c3)ncnc21
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCN(CC)CCCOc1ccc(-c2cc3c(Oc4ccc(N)c(Cl)c4)ncnc3n2COCC[Si](C)(C)C)cc1
Temperature: 80 °C
Reaction time: 24 h
Yield: 84.5 %

Procedure:
After dissolving 47 mg of the 4-[4-(4-amino-3-chlorophenoxy)-7-(2-trimethylsilanylethoxymethyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]phenol synthesized in Production Example 160-1 in 0.5 ml of dimethylformamide, there were added 56 mg (3.1 equivalents) of (3-chloropropyl)diethylamine hydrochloride and 94 mg (7 equivalents) of potassium carbonate, and the mixture was stirred at 80° C. for 24 hours. It was then returned to room temperature, water was added, and liquid separation and extraction were performed with an ethyl acetate:tetrahydrofuran (5:1) mixed solvent. The organic layer was dried over sodium sulfate, concentrated and subjected to NH silica gel column chromatography (hexane-ethyl acetate) to obtain 49 mg of the title compound.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]#[C:5][C:6]1[CH:19]=[C:18]2[C:9]([C:10]3[CH:11]=[CH:12][C:13]([OH:20])=[CH:14][C:15]=3[CH2:16][CH2:17]2)=[CH:8][CH:7]=1>C1COCC1>[OH:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[CH:19]=[C:18]2[C:9]([C:10]3[CH:11]=[CH:12][C:13]([OH:20])=[CH:14][C:15]=3[CH2:16][CH2:17]2)=[CH:8][CH:7]=1
Reactant: OCCC#Cc1ccc2c(c1)CCc1cc(O)ccc1-2
Solvent: C1CCOC1
Product: OCCCCc1ccc2c(c1)CCc1cc(O)ccc1-2

Procedure:
7-(4-Hydroxybut-1-ynyl)-9,10-dihydrophenanthren-2-ol is dissolved in THF and hydrogenated to completion on palladium/active carbon catalyst. The catalyst is filtered off, the solvent is removed in vacuo, and the residue is recrystallised from toluene, giving 7-(4-hydroxybutyl)-9,10-dihydrophenanthren-2-ol as colourless crystals.
Reaction SMILES: [CH3:1][C:2]1[C:3](N2CCCCC2)=[CH:4][C:5]([C:8]([C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=[CH:12][CH:11]=2)=O)=[N:6][CH:7]=1.O.NN.[OH-].[K+].O>C(O)COCCOCCO>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=[CH:12][CH:11]=2)([N:6]2[CH2:7][CH2:2][CH2:3][CH2:4][CH2:5]2)[NH:6][CH:7]=1
Reactant: Cc1cnc(C(=O)c2cccc3ccccc23)cc1N1CCCCC1
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: OCCOCCOCCO
Solvent: O
Product: CC1=CNC(Cc2cccc3ccccc23)(N2CCCCC2)C=C1
Temperature: 120 °C
Reaction time: 1.5 h

Procedure:
To a solution of 5-methyl-2-(1-napthoyl)-4-piperidinopyridine in 1 ml of triethylene glycol was added 30 mg of 100% hydrazine hydrate, and the mixture was stirred at 120° C. for 1.5 hours. Potassium hydroxide (42 mg) was added to the reaction mixture, and the mixture was heated at about 200° C. for 1 hour. The reaction mixture was poured into water, and extracted with ether. The ether layer was washed with water, dried and concentrated under reduced pressure. The residue was purified by silica gel column chromatography [eluted with chloroform and then with chloroform/methanol (=50/1)] to give 5-methyl-2-(1-naphthylmethyl)-2-piperidinopyridine as an oil. The oil was treated with an ethanol solution of hydrogen chloride and recrystallized from acetone/ether to give 44 mg (yield 40%) of the captioned compound.
Reaction SMILES: Cl.[CH2:2]([N:4]([C:13]1[S:14][CH:15]=[C:16]([CH3:18])[N:17]=1)[C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:6]=1[Cl:12])[CH3:3].C(=O)([O-])[O-].[Ca+2].C(Cl)(Cl)Cl.[Br-:28].[Br-].[Br-].C([N+](C)(C)C)C1C=CC=CC=1.C([N+](C)(C)C)C1C=CC=CC=1.C([N+](C)(C)C)C1C=CC=CC=1>CO>[Br:28][C:15]1[S:14][C:13]([N:4]([CH2:2][CH3:3])[C:5]2[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:6]=2[Cl:12])=[N:17][C:16]=1[CH3:18]
Reactant: CCN(c1nc(C)cs1)c1ccc(Cl)cc1Cl
Reactant: [Br-]
Agent: C[N+](C)(C)Cc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CCN(c1nc(C)c(Br)s1)c1ccc(Cl)cc1Cl
Yield: 117.9 %

Procedure:
After 2-(N-ethyl-2,4-dichloroanilino)-4-methylthiazole hydrochloride (6.0 g) and calcium carbonate (4.6 g) were suspended in a mixed solvent of chloroform (90 mL) and methanol (36 mL), benzyl-trimethylammonium tribromide (7.2 g) was added thereto in small portions. The solids in the reaction mixture were filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by a silica gel column chromatography (silica gel: Wako Gel (C200), eluent: hexane-ethyl acetate=9:1) to obtain 5-bromo-2-(N-ethyl-2,4-dichloroanilino)-4-methyl-thiazole (4.5 g).
Reaction SMILES: [CH3:1][O:2][C:3]([CH3:19])([CH3:18])[CH2:4][CH2:5][CH2:6][CH:7]([CH3:17])[CH2:8]/[CH:9]=[CH:10]/[C:11]([CH3:16])=[CH:12][C:13]([OH:15])=[O:14].[H-].[K+:21]>C1C=CC=CC=1>[CH3:1][O:2][C:3]([CH3:18])([CH3:19])[CH2:4][CH2:5][CH2:6][CH:7]([CH3:17])[CH2:8][CH:9]=[CH:10][C:11]([CH3:16])=[CH:12][C:13]([O-:15])=[O:14].[K+:21]
Reactant: COC(C)(C)CCCC(C)C/C=C/C(C)=CC(=O)O
Agent: [H-]
Agent: [K+]
Solvent: c1ccccc1
Product: COC(C)(C)CCCC(C)CC=CC(C)=CC(=O)[O-]

Procedure:
To a solution of 0.5 g. of trans, trans 11-methoxy-3,7,11-trimethyldodeca-2,4-dienoic acid in 15 ml. of benzene is added, with stirring, an equivalent amount of potassium hydride. The mixture is stirred at room temperature for about 2 hours and then evaporated to give potassium 11-methoxy-3,7,11-trimethyldodeca-2,4-dienoate.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1([CH3:38])[S:16][CH2:15][CH2:14][N:13]2[C:17]([C:20]3([C:23]4[CH:28]=[CH:27][C:26](B5OC(C)(C)C(C)(C)O5)=[CH:25][CH:24]=4)[CH2:22][CH2:21]3)=[N:18][N:19]=[C:12]2[CH2:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].Br[C:40]1[S:41][CH:42]=[CH:43][N:44]=1.C(=O)([O-])[O-].[K+].[K+].C(=O)([O-])O.[Na+]>C(COC)OC.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>[Si:1]([O:8][CH2:9][C:10]1([CH3:38])[S:16][CH2:15][CH2:14][N:13]2[C:17]([C:20]3([C:23]4[CH:28]=[CH:27][C:26]([C:40]5[S:41][CH:42]=[CH:43][N:44]=5)=[CH:25][CH:24]=4)[CH2:22][CH2:21]3)=[N:18][N:19]=[C:12]2[CH2:11]1)([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:2])[CH3:3]
Reactant: Brc1nccs1
Reactant: CC1(CO[Si](C)(C)C(C)(C)C)Cc2nnc(C3(c4ccc(B5OC(C)(C)C(C)(C)O5)cc4)CC3)n2CCS1
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: O=C([O-])[O-]
Solvent: O
Solvent: COCCOC
Product: CC1(CO[Si](C)(C)C(C)(C)C)Cc2nnc(C3(c4ccc(-c5nccs5)cc4)CC3)n2CCS1
Temperature: 25 °C
Yield: 46.2 %

Procedure:
A solution of the compound (555 mg, 1.0 mmol) obtained in Example 16-5), 2-bromothiazole (246 mg, 1.5 mmol), tetrakis(triphenylphosphine)palladium(0) (231 mg, 0.2 mmol), and potassium carbonate (276 mg, 2 mmol) in dimethoxyethane (4 mL) and water (1 mL) was stirred at 130° C. for 1.5 h under microwave irradiation. The reaction mixture was cooled to room temperature, saturated aqueous sodium hydrogencarbonate was added to the reaction mixture, the mixture was extracted with dichloromethane, and the organic layer was washed with saturated sodium chloride solution and dried with anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (Isco Combiflash, 40 g, methanol:ethyl acetate=0:100 to 20:80, gradient) to obtain the title compound (237 mg, 46%) as a light yellow solid.
Reaction SMILES: [F:1][C:2]1([F:19])[CH2:7][CH2:6][C:5](/[C:15](=[N:17]\O)/[CH3:16])([C:8]2[CH:9]=[N:10][C:11]([CH3:14])=[N:12][CH:13]=2)[CH2:4][CH2:3]1.N>[Ni]>[F:19][C:2]1([F:1])[CH2:3][CH2:4][C:5]([CH:15]([NH2:17])[CH3:16])([C:8]2[CH:13]=[N:12][C:11]([CH3:14])=[N:10][CH:9]=2)[CH2:6][CH2:7]1
Reactant: C/C(=N/O)C1(c2cnc(C)nc2)CCC(F)(F)CC1
Agent: [Ni]
Agent: N
Product: Cc1ncc(C2(C(C)N)CCC(F)(F)CC2)cn1
Yield: 98.7 %

Procedure:
A mixture of (Z)-1-(4,4-difluoro-1-(2-methylpyrimidin-5-yl)cyclohexyl)ethanone oxime (320 mg, 1.19 mmol) and aq.NH3 (2 mL) was hydrogenated with Raney Ni (300 mg) under H2 (50 Psi) for 3 h. The reaction mixture was filtered and concentrated. The residue was dissolved in EtOAc (15 mL), dried over Na2SO4 and concentrated to give 1-(4,4-difluoro-1-(2-methylpyrimidin-5-yl)cyclohexyl)ethanamine (300 mg), which was used for the next step directly.
Reaction SMILES: [C:1]([N:8]([C:14]1[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][CH:15]=1)[C@@H:9]([C:11]([OH:13])=[O:12])[CH3:10])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C(N(C1C=CC([N+]([O-])=O)=CC=1)[C@H](C(O)=O)C)(OC(C)(C)C)=O>CO>[C:1]([N:8]([C:14]1[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][CH:15]=1)[C@H:9]([C:11]([OH:13])=[O:12])[CH3:10])([O:3][C:4]([CH3:7])([CH3:5])[CH3:6])=[O:2]
Reactant: C[C@H](C(=O)O)N(C(=O)OC(C)(C)C)c1ccc(N)cc1
Agent: C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)c1ccc([N+](=O)[O-])cc1
Solvent: CO
Product: C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)c1ccc(N)cc1
Yield: 96 %

Procedure:
The reaction described above for Nα -Boc-4-aminophenyl-D-alanine was repeated for the L-isomer. About 153 grams of Nα -Boc-4-nitrophenyl-L-alanine was reacted as described above and resulted in about 134 grams of Nα -Boc-4-aminophenyl-L-alanine (about 96% yield) [α]D =+23.6° (c=1.0 in MeOH).
Reaction SMILES: C1(CO[CH:9]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][C:27]3[CH:36]=[CH:35][C:34]4[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=4)[N:28]=3)=[CH:21][CH:20]=2)[CH2:10][O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)C=CC=CC=1.[C:37]([OH:41])(=[O:40])[CH2:38][SH:39].B(F)(F)F.O(CC)CC>C(Cl)Cl>[C:13]1([CH2:12][O:11][CH2:10][CH:9]([S:39][CH2:38][C:37]([OH:41])=[O:40])[C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][C:27]3[CH:36]=[CH:35][C:34]4[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=4)[N:28]=3)=[CH:21][CH:20]=2)[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: O=C(O)CS
Reactant: c1ccc(COCC(OCc2ccccc2)c2ccc(OCc3ccc4ccccc4n3)cc2)cc1
Agent: FB(F)F
Solvent: CCOCC
Solvent: ClCCl
Product: O=C(O)CSC(COCc1ccccc1)c1ccc(OCc2ccc3ccccc3n2)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a mixture of the ether (151 mg) (Step 2) and thioglycolic acid (31 μL) in CH2Cl2 at 0° C. was added BF3 /OEt2 (117 μL) dropwise. The mixture was stirred at 0° C. for 1 h and poured onto 25% aqueous NH4OAc, extracted with CH2Cl2 and the organic phase was dried and evaporated. Chromatography on silica gel using ethyl acetate/hexane containing 0.1% AcOH afforded the title compound.
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][CH2:7][NH:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([Br:19])=[CH:16][CH:17]=2)[N:12]=[CH:11][C:10]=1[NH2:20])(=[O:3])[CH3:2].O1CCCC1.[C:26](N1C=CN=C1)(N1C=CN=C1)=[S:27]>ClCCl>[C:1]([O:4][CH2:5][CH2:6][CH2:7][N:8]1[C:9]2[C:18]3[CH:17]=[CH:16][C:15]([Br:19])=[CH:14][C:13]=3[N:12]=[CH:11][C:10]=2[NH:20][C:26]1=[S:27])(=[O:3])[CH3:2]
Reactant: CC(=O)OCCCNc1c(N)cnc2cc(Br)ccc12
Reactant: S=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC(=O)OCCCn1c(=S)[nH]c2cnc3cc(Br)ccc3c21
Temperature: 71 °C
Reaction time: 1.5 h
Yield: 47.2 %

Procedure:
To a round-bottomed flask containing 3-[(3-amino-7-bromoquinolin-4-yl)amino]propyl acetate (54.5 g, 161.1 mmol) was added anhydrous tetrahydrofuran (THF, 1.4 L), followed by 1,1′-thiocarbonyldiimidazole (31.6 g, 177.3 mmol) and the reaction mixture was stirred at 71° C. for 1.5 h. The reaction was cooled to ambient temperature and the solvent was removed under reduced pressure to afford an oil. The oil was dissolved in dichloromethane (1.3 L) and the solution was washed with water (3×600 mL). During each wash a significant amount of precipitate was observed which was isolated to afford 3-(7-bromo-2-thioxo-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl)propyl acetate (28.9 g) as a light brown solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([OH:17])=O)[CH3:14])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1.[NH2:18][CH:19]([C:25]1[S:26][C:27]2[CH:33]=[CH:32][CH:31]=[CH:30][C:28]=2[CH:29]=1)[C:20]([O:22][CH2:23][CH3:24])=[O:21]>>[F:8][C:6]1[CH:5]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([NH:18][CH:19]([C:25]2[S:26][C:27]3[CH:33]=[CH:32][CH:31]=[CH:30][C:28]=3[CH:29]=2)[C:20]([O:22][CH2:23][CH3:24])=[O:21])=[O:17])[CH3:14])=[O:11])[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: CCOC(=O)C(N)c1cc2ccccc2s1
Reactant: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)O
Product: CCOC(=O)C(NC(=O)[C@H](C)NC(=O)Cc1cc(F)cc(F)c1)c1cc2ccccc2s1

Procedure:
Following General Procedure C and using N-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) and ethyl 2-amino-2-(benzothiophen-2-yl)acetate [CAS No. 98800-64-7], the title compound was prepared as a solid (mp=189-190° C.). The product was purified by preparative LC 2000 chromatography using 2:8 EtOAc/hexanes as the eluent.
Reaction SMILES: [O:1]=[C:2]1[C:10]2([CH2:14][O:13][C:12]3[CH:15]=[C:16]4[C:20](=[CH:21][C:11]2=3)[CH2:19][CH2:18][O:17]4)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[CH2:22][C:23]1[CH:24]=[C:25]([CH:30]=[CH:31][CH:32]=1)[C:26]([O:28]C)=[O:27].O.[OH-].[Li+]>O1CCCC1.O>[O:1]=[C:2]1[C:10]2([CH2:14][O:13][C:12]3[CH:15]=[C:16]4[C:20](=[CH:21][C:11]2=3)[CH2:19][CH2:18][O:17]4)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[CH2:22][C:23]1[CH:24]=[C:25]([CH:30]=[CH:31][CH:32]=1)[C:26]([OH:28])=[O:27]
Reactant: COC(=O)c1cccc(CN2C(=O)C3(COc4cc5c(cc43)CCO5)c3ccccc32)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1cccc(CN2C(=O)C3(COc4cc5c(cc43)CCO5)c3ccccc32)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 81.9 %

Procedure:
To a solution of methyl 3-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzoate (2.80 g, 6.5 mmol) in tetrahydrofuran (30 mL) and water (10 mL) was added lithium hydroxide monohydrate (0.82 g, 19 mmol). The reaction mixture was stirred at ambient temperature for 16 h. Most of the tetrahydrofuran was removed in vacuo and the resultant solution was washed with diethyl ether (2×50 mL). The aqueous phase was rendered acidic to litmus by the addition of 1 M hydrochloric acid and extracted with ethyl acetate (3×50 mL). The combined organic solution was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was triturated with diethyl ether (50 mL) and the solid was collected by vacuum filtration, washed with diethyl ether (20 mL), air-dried and dried under high vacuum to afford 3-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzoic acid (2.20 g, 81%) as a colorless solid: mp>250° C. (water); 1H NMR (300 MHz, DMSO-d6) δ13.06 (br s, 1H), 7.89-7.82 (m, 2H), 7.66 (d, J=7.6 Hz, 1H), 7.55-7.47 (m, 1H), 7.29-7.16 (m, 2H), 7.07-6.96 (m, 2H), 6.49 (s, 1H), 6.42 (s, 1H), 5.17-4.72 (m, 4H), 4.55-4.45 (m, 2H), 3.06-2.88 (m, 2H); 13C NMR (75 MHz, DMSO-d6) δ177.2, 167.1, 161.2, 160.7, 142.0, 136.9, 132.2, 131.8, 131.2, 129.1, 128.8, 128.4, 127.3, 123.8, 123.2, 120.5, 120.0, 118.9, 109.3, 92.5, 79.7, 72.1, 57.0, 42.5; MS (ES+) m/z 414.0 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([C:9]([OH:11])=O)=[CH:7][C:6]([C:12]([NH2:14])=[O:13])=[CH:5][CH:4]=1.[Cl:15][C:16]1[CH:17]=[C:18]([CH:20]=[CH:21][CH:22]=1)[NH2:19]>>[Cl:15][C:16]1[CH:17]=[C:18]([NH:19][C:9](=[O:11])[C:8]2[CH:7]=[C:6]([CH:5]=[CH:4][C:3]=2[O:2][CH3:1])[C:12]([NH2:14])=[O:13])[CH:20]=[CH:21][CH:22]=1
Reactant: Nc1cccc(Cl)c1
Reactant: COc1ccc(C(N)=O)cc1C(=O)O
Product: COc1ccc(C(N)=O)cc1C(=O)Nc1cccc(Cl)c1

Procedure:
The captioned compound was synthesized from 6-methoxyisophthalamic acid and 3-chloroaniline by the same procedure as in the manufacturing method described in step C of Example 1-3-1.
Reaction SMILES: [CH2:1]([CH2:3][NH2:4])[OH:2].OCC(CO)O.C(=O)([O-])[O-].[K+].[K+].[C:17]([O:21][C:22]([N:24]1[CH2:29][CH2:28][N:27]([C:30]2[CH:35]=[CH:34][C:33]([C:36]#N)=[CH:32][CH:31]=2)[CH2:26][CH2:25]1)=[O:23])([CH3:20])([CH3:19])[CH3:18]>C(O)CO>[C:17]([O:21][C:22]([N:24]1[CH2:29][CH2:28][N:27]([C:30]2[CH:35]=[CH:34][C:33]([C:36]3[O:2][CH2:1][CH2:3][N:4]=3)=[CH:32][CH:31]=2)[CH2:26][CH2:25]1)=[O:23])([CH3:20])([CH3:19])[CH3:18]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(C#N)cc2)CC1
Reactant: NCCO
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: OCC(O)CO
Solvent: OCCO
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(C3=NCCO3)cc2)CC1
Temperature: 105 °C
Yield: 37.1 %

Procedure:
A mixture of ethanolamine (0.91 ml; 15.0 mmol), glycerol (2.7 g), ethylene glycol (5.6 g) and potassium carbonate (2.1 g; 15.0 mmol) is heated at 105° C. for 30 min. The intermediate 1A (2.3 g; 8.04 mmol) is then added and the mixture is heated for 5 days at 105° C. The precipitate formed is filtered on sintered glass and washed with water and with petroleum ether to give compound 5A (988 mg; 37%) in the form of a beige solid.
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5][N:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]=[C:7]1[NH:15][CH:16]1[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][C:24]2([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH2:28][CH2:27][NH:26][CH2:25]2)[CH2:18][CH2:17]1)[CH3:2].C(=O)(O)[O-].[Na+].[CH3:40][O:41][C:42]1[CH:50]=[CH:49][C:48]([CH2:51][N:52]2[CH:56]=[N:55][N:54]=[N:53]2)=[CH:47][C:43]=1[C:44](Cl)=[O:45]>C(OCC)(=O)C.CCCCCC.CC(C)=O.C(OCC)(=O)C>[CH3:40][O:41][C:42]1[CH:50]=[CH:49][C:48]([CH2:51][N:52]2[CH:56]=[N:55][N:54]=[N:53]2)=[CH:47][C:43]=1[C:44]([N:26]1[CH2:27][CH2:28][C:24]([CH2:23][CH2:22][N:19]2[CH2:20][CH2:21][CH:16]([NH:15][C:7]3[N:6]([CH2:5][CH2:4][O:3][CH2:1][CH3:2])[C:10]4[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=4[N:8]=3)[CH2:17][CH2:18]2)([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH2:25]1)=[O:45]
Reactant: COc1ccc(Cn2cnnn2)cc1C(=O)Cl
Reactant: CCOCCn1c(NC2CCN(CCC3(c4ccccc4)CCNC3)CC2)nc2ccccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CCOCCn1c(NC2CCN(CCC3(c4ccccc4)CCN(C(=O)c4cc(Cn5cnnn5)ccc4OC)C3)CC2)nc2ccccc21
Reaction time: 18 h

Procedure:
Combine 3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl-amino)piperidin-1-yl)ethyl)-3-phenylpyrrolidine (prepared from (−)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine (R,R)-di-p-anisoyltartaric acid salt) (1.5 mmol) and sodium bicarbonate (0.93 g, 11.07 mmol) in acetone/water (1/1, 40 mL). Cool in an ice bath. Add a solution of 2-methoxy-5-(1H-tetrazol-1-ylmethyl)benzoyl chloride (0.38 g, 1.49 mmol) in acetone (25 mL). After 18 hours, dilute the reaction mixture with ethyl acetate and extract twice with a saturated aqueous sodium bicarbonate solution and then brine. Dry the organic layer over Na2SO4, filter, and concentrate in vacuo to give a residue. Chromatograph the residue on silica gel to give the title compound
Reaction SMILES: Cl.[CH3:2][N:3]([CH3:23])[S:4]([C:7]1[CH:8]=[C:9]([CH:13]=[CH:14][C:15]=1[N:16]1[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]1)[C:10](Cl)=[O:11])(=[O:6])=[O:5].[CH2:24]([NH2:28])[CH:25]([CH3:27])[CH3:26]>O1CCCC1>[CH2:24]([NH:28][C:10](=[O:11])[C:9]1[CH:13]=[CH:14][C:15]([N:16]2[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]2)=[C:7]([S:4](=[O:6])(=[O:5])[N:3]([CH3:23])[CH3:2])[CH:8]=1)[CH:25]([CH3:27])[CH3:26]
Reactant: CN1CCN(c2ccc(C(=O)Cl)cc2S(=O)(=O)N(C)C)CC1
Reactant: CC(C)CN
Agent: Cl
Solvent: C1CCOC1
Product: CC(C)CNC(=O)c1ccc(N2CCN(C)CC2)c(S(=O)(=O)N(C)C)c1

Procedure:
40 Grams of 3-dimethylsulfamoyl-4-(4-methylpiperazine-1-yl)-benzoylchloride-hydrochloride (0.1 mole) were introduced portionwise, while stirring, into a solution of 30 g of isobutylamine in 0.4 l of tetrahydrofurane. The mixture, whose temperature rose to about 50° C., was subsequently heated for another 10 minutes under reflux and was then concentrated to half its volume.
Reaction SMILES: [O:1]=[C:2]1[NH:6][CH2:5][CH:4]([C:7]([OH:9])=O)[CH2:3]1.CN.[CH3:12][N:13](C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>>[CH3:12][NH:13][C:7]([CH:4]1[CH2:3][C:2](=[O:1])[NH:6][CH2:5]1)=[O:9]
Reactant: O=C1CC(C(=O)O)CN1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: CN
Agent: F[P-](F)(F)(F)(F)F
Product: CNC(=O)C1CNC(=O)C1

Procedure:
In an analogous manner to that described in Example 24f), by condensing (R)-1-(4-benzyloxy)-phenyl)-5-oxo-pyrrolidine-3-carboxylic acid with methylamine using HBTU as the condensation agent there is obtained (R)-1-(4-benzyloxy)-phenyl)-5-oxo-pyrrolidine-3-carboxylic acid methylamide as a white solid. MS: m/e=325 (M+H)+; [α]589=−27.550 (c=0.958, CH2Cl2).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[N:6]([CH2:9][CH2:10][OH:11])=[N+:7]=[N-:8].C(N(CC)CC)C>C(Cl)Cl>[CH3:1][S:2]([O:11][CH2:10][CH2:9][N:6]=[N+:7]=[N-:8])(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: [N-]=[N+]=NCCO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCCN=[N+]=[N-]
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of methanesulphonyl chloride (5.7 g) in methylene chloride (20 ml) was added dropwise to a stirred solution of 2-azidoethanol (4.3 g) and triethylamine (5.0 g) in methylene chloride (80 ml). After 2 hours stirring at room temperature the reaction mixture was washed with water, dried (MgSO4) and evaporated to dryness in vacuo to give the title compound as a yellow oil, yield 7 g, which was used directly without further purification.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:6][CH2:5]1.[Br:12][C:13]1[CH:18]=[CH:17][C:16](F)=[C:15]([N+:20]([O-:22])=[O:21])[CH:14]=1>C1COCC1.C1OCCOCCOCCOCCOC1.C(OCC)(=O)C>[Br:12][C:13]1[CH:18]=[CH:17][C:16]([O:3][C:4]2([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:6][CH2:5]2)=[C:15]([N+:20]([O-:22])=[O:21])[CH:14]=1
Reactant: O=[N+]([O-])c1cc(Br)ccc1F
Reactant: CCOC(=O)C1(O)CC1
Agent: C1COCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)C1(Oc2ccc(Br)cc2[N+](=O)[O-])CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 66.6 %

Procedure:
Sodium hydride (60%, 166 mg, 4.15 mmol) was added to a solution of ethyl 1-hydroxycyclopropanecarboxylate (0.41 mL, 3.59 mmol) in THF (10 mL) at room temperature. After 15 min, 3 drops of 15-crown-5 were added followed by 4-bromo-1-fluoro-2-nitrobenzene (0.42 mL, 3.41 mmol). Mixture was stirred at room temperature for 24 hours. After diluting with 50 mL of ethyl acetate, mixture was quenched by addition of brine (25 mL) and layers were separated. Aqueous phase was extracted with ethyl acetate and combined organics were dried (MgSO4), filtered, and concentrated under reduced pressure. Resulting residue was purified via silica gel column chromatography (0-30% ethyl acetate/hexanes) to yield ethyl 1-(4-bromo-2-nitrophenoxy)cyclopropanecarboxylate 7.20 (750 mg)
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]2[CH:14]=[CH:13][N:12]([S:15]([C:18]3[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=3)(=[O:17])=[O:16])[C:8]=2[N:9]=[CH:10][N:11]=1)=[CH2:5])C.C1COCC1>CO>[C:21]1([CH3:24])[CH:20]=[CH:19][C:18]([S:15]([N:12]2[C:8]3[N:9]=[CH:10][N:11]=[C:6]([C:4](=[O:3])[CH3:5])[C:7]=3[CH:14]=[CH:13]2)(=[O:17])=[O:16])=[CH:23][CH:22]=1
Reactant: C=C(OCC)c1ncnc2c1ccn2S(=O)(=O)c1ccc(C)cc1
Solvent: C1CCOC1
Solvent: CO
Product: CC(=O)c1ncnc2c1ccn2S(=O)(=O)c1ccc(C)cc1
Yield: 89 %

Procedure:
[7.25 g, 21.12 mmol] of 4-(1-Ethoxy-vinyl)-7-(toluene-4-sulfonyl)-7H-pyrrolo[2,3-d]pyrimidine was dissolved in 50 mL each of methanol and THF and stirred with 10 mL of 6N HCL for 4.0 hours at ambient temperature. The solvents were removed under reduced pressure and the residue was partitioned between dichloromethane and saturated sodium hydrogen carbonate solution. The organic fraction was brined and dried with anhydrous sodium sulphate and the solvent was removed under reduced pressure. The crude material was triturated with a mixture of MTBE and petroleum ether (1:4) for several hours and the solid finally isolated via suction filtration and air dried. The 5.95 g of pale yellow material, representing a 89% yield was used without further purification.