Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:29]=[CH:28][C:5]([C:6]([C:8]2[CH:27]=[CH:26][C:11]([CH2:12][O:13][C:14]3[N:15]=[C:16]4[CH:25]=[CH:24][CH:23]=[CH:22][N:17]4[C:18](=[O:21])[C:19]=3[CH3:20])=[CH:10][CH:9]=2)=[O:7])=[CH:4][N:3]=1.[N:30]1([CH:36]2[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]2)[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1>N1C=CC=CC=1>[CH3:20][C:19]1[C:18](=[O:21])[N:17]2[CH:22]=[CH:23][CH:24]=[CH:25][C:16]2=[N:15][C:14]=1[O:13][CH2:12][C:11]1[CH:26]=[CH:27][C:8]([C:6](=[O:7])[C:5]2[CH:28]=[CH:29][C:2]([N:39]3[CH2:40][CH2:41][CH:36]([N:30]4[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]4)[CH2:37][CH2:38]3)=[N:3][CH:4]=2)=[CH:9][CH:10]=1
Reactant: Cc1c(OCc2ccc(C(=O)c3ccc(Cl)nc3)cc2)nc2ccccn2c1=O
Reactant: C1CCN(C2CCNCC2)CC1
Solvent: c1ccncc1
Product: Cc1c(OCc2ccc(C(=O)c3ccc(N4CCC(N5CCCCC5)CC4)nc3)cc2)nc2ccccn2c1=O

Procedure:
A solution of 2-[4-(6-chloronicotinoyl)benzyloxy]-3-methylpyrido[1,2-a]pyrimidin-4-one (0.49 g, 1.21 mmol) and 4-piperidinopiperidine (0.402 g, 2.39 mmol) in pyridine (15 ml) was stirred at 90° C. overnight. The solvent was then distilled off under reduced pressure and the residue was purified by silica gel column chromatography (isopropyl ether: methylene chloride: methanol: ammonia=5:5:1:0.1) to provide a light-yellow oil.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][N:5]([CH2:10][CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:6]=1[C:7]([NH2:9])=[O:8].[F:19][C:20]1[CH:21]=[C:22]([CH:26]=[CH:27][CH:28]=1)[C:23](Cl)=[O:24]>>[F:19][C:20]1[CH:21]=[C:22]([CH:26]=[CH:27][CH:28]=1)[C:23]([NH:1][C:2]1[N:3]=[CH:4][N:5]([CH2:10][CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:6]=1[C:7]([NH2:9])=[O:8])=[O:24]
Reactant: NC(=O)c1c(N)ncn1CCCc1ccccc1
Reactant: O=C(Cl)c1cccc(F)c1
Product: NC(=O)c1c(NC(=O)c2cccc(F)c2)ncn1CCCc1ccccc1
Yield: 88 %

Procedure:
An amidation reaction and post-treatment were carried out following the conditions of Example 22, using 2.00 g (8.19 mmol) of 4-amino-1-(3-phenylpropyl)-5-imidazolecarboxamide prepared in the same manner as in Example 114 and 3-fluorobenzoyl chloride instead of benzoyl chloride to obtain 2.63 g of 4-(3-fluorobenzoylamino)-1-(3-phenylpropyl)-5-imidazolecarboxamide (yield 88%).
Reaction SMILES: C[O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[N:8][C:9]([NH:13][C:14]3[CH:15]=[C:16]([S:20]([NH2:23])(=[O:22])=[O:21])[CH:17]=[CH:18][CH:19]=3)=[N:10]2)=[CH:5][CH:4]=1.C[S-].[Na+]>CN1C(=O)CCC1>[OH:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[N:8][C:9]([NH:13][C:14]3[CH:15]=[C:16]([S:20]([NH2:23])(=[O:22])=[O:21])[CH:17]=[CH:18][CH:19]=3)=[N:10]2)=[CH:5][CH:4]=1
Reactant: COc1ccc2cnc(Nc3cccc(S(N)(=O)=O)c3)nc2c1
Agent: C[S-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: NS(=O)(=O)c1cccc(Nc2ncc3ccc(O)cc3n2)c1
Temperature: 80 °C
Reaction time: 3 h
Yield: 85 %

Procedure:
To a 0.02M solution of 3-(7-Methoxyquinazolin-2-ylamino)benzenesulfonamide in NMP was added sodium thiomethoxide (5.0 eq) at ambient temperature. The reaction was stirred at 80° C. for 3 hours. The solid was collected by vacuum filtration and was partitioned between ethyl acetate and water. Saturated ammonium hydrochloride was added to aqueous phase until the PH=6. Aqueous phase was extracted with ethyl acetate. The organic phase was washed with brine, dried over sodium sulfate and concentrated to give desired product in 85% yield. ES/MS m/z 317 (MH+).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]([CH3:27])[S:14]([C:17]2[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=2)(=[O:16])=[O:15])=[CH:9][CH:8]=1.[CH2:28]([NH:30][CH2:31][CH3:32])[CH3:29]>>[CH2:28]([N:30]([CH2:31][CH3:32])[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]([CH3:27])[S:14]([C:17]2[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=2)(=[O:16])=[O:15])=[CH:9][CH:8]=1)[CH3:29]
Reactant: CN(c1ccc(OCCCCBr)cc1)S(=O)(=O)c1ccc(C(F)(F)F)cc1
Reactant: CCNCC
Product: CCN(CC)CCCCOc1ccc(N(C)S(=O)(=O)c2ccc(C(F)(F)F)cc2)cc1

Procedure:
In analogy to example 17.1, reaction of N-[4-(4-Bromo-butoxy)-phenyl]-N-methyl-4-trifluoromethyl-benzenesulfonamide with diethylamine yielded N-[4-(4-Diethylamino-butoxy)-phenyl]-N-methyl-4-trifluoromethyl-benzenesulfonamide, MS: 459 (MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:34]=[CH:33][C:5]([CH2:6][CH:7]([CH2:15][CH2:16][C@H:17]([NH:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])=[CH:4][CH:3]=1.[CH2:35]([O:42][CH2:43][CH:44]=O)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>ClCCCl>[CH2:35]([O:42][CH2:43][CH2:44][NH:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH:7]([CH2:15][CH2:16][C@H:17]([NH:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:8]([O:10][C:11]([CH3:12])([CH3:13])[CH3:14])=[O:9])=[CH:33][CH:34]=1)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](CCC(Cc1ccc(N)cc1)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Reactant: O=CCOCc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N[C@@H](CCC(Cc1ccc(NCCOCc2ccccc2)cc1)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 4 h
Yield: 99.4 %

Procedure:
Di-tert-butyl (5S)-2-(4-aminobenzyl)-5-[(tert-butoxycarbonyl)amino]hexanedioate (670 mg, 1.40 mmol) was dissolved in 1,2-dichloroethane (10 ml) and benzyloxyacetaldehyde (210 mg, 1.40 mmol) and sodium triacetoxyborohydride (415 mg, 1.96 mmol) were added. The mixture was stirred at room temperature for 4 h and than poured on 10 ml 1N aqueous sodium hydrogen carbonate solution. The aqueous phase was extracted with dichloromethane (2×10 ml) and the organic phases were washed with water (30 ml), dried over magnesium sulfate and concentrated in vacuo. Flash chromatography on silica gel (hexane, ethyl acetate) gave the product as slightly yellow oil (853 mg, 99%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:15][CH:14]2[NH:16][CH:10]([CH2:11][O:12][CH2:13]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.[CH3:26][O:27][C:28]([C:30]1[C@H:31]([C:43]2[CH:48]=[CH:47][C:46]([F:49])=[CH:45][C:44]=2[Cl:50])[N:32]=[C:33]([C:38]2[S:39][CH:40]=[CH:41][N:42]=2)[NH:34][C:35]=1[CH2:36]Br)=[O:29]>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH:10]2[N:16]([CH2:36][C:35]3[NH:34][C:33]([C:38]4[S:39][CH:40]=[CH:41][N:42]=4)=[N:32][C@@H:31]([C:43]4[CH:48]=[CH:47][C:46]([F:49])=[CH:45][C:44]=4[Cl:50])[C:30]=3[C:28]([O:27][CH3:26])=[O:29])[CH:14]([CH2:13][O:12][CH2:11]2)[CH2:15]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC2COCC(C1)N2
Reactant: COC(=O)C1=C(CBr)NC(c2nccs2)=N[C@H]1c1ccc(F)cc1Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C1=C(CN2C3COCC2CN(C(=O)OC(C)(C)C)C3)NC(c2nccs2)=N[C@H]1c1ccc(F)cc1Cl
Temperature: 25 °C
Reaction time: 16 h
Yield: 94.6 %

Procedure:
To a mixture of 3-oxa-7,9-diaza-bicyclo[3.3.1]nonane-7-carboxylic acid tert-butyl ester (171 mg, 0.75 mmol) and DIPEA (0.45 mL, 2.5 mmol) in CH2Cl2 (10 mL) was added (R)-6-bromomethyl-4-(2-chloro-4-fluoro-phenyl)-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylic acid methyl ester (222 mg, 0.5 mmol). The mixture was stirred at room temperature for 16 hours. The mixture was concentrated in vacuo. The residue was purified by flash column chromatography to afford 9-[(R)-6-(2-chloro-4-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-3,6-dihydro-pyrimidin-4-ylmethyl]-3-oxa-7,9-diaza-bicyclo[3.3.1]nonane-7-carboxylic acid tert-butyl ester as yellow oil (0.28 g, 94%). MS: calc'd (MH+) 592, measured (MH+) 592.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[C:16]2C[CH:14]([CH2:17][NH:18][C:19](=[O:30])[CH2:20][C:21]3[CH:29]=[CH:28][C:24]4[O:25][CH2:26][O:27][C:23]=4[CH:22]=3)[O:13][CH2:12][C:11]=2[S:10][C:9]=1N)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:32](OC(=O)C(N1C=CN=C1)=O)(C)(C)C>ClCCl>[C:1]([O:5][C:6]([C:8]1[C:16]2[CH:17]([NH:18][C:19](=[O:30])[CH2:20][C:21]3[CH:29]=[CH:28][C:24]4[O:25][CH2:26][O:27][C:23]=4[CH:22]=3)[CH2:14][O:13][CH2:12][C:11]=2[S:10][C:9]=1[CH3:32])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)c1c(N)sc2c1CC(CNC(=O)Cc1ccc3c(c1)OCO3)OC2
Reactant: CC(C)(C)OC(=O)C(=O)n1ccnc1
Solvent: ClCCl
Product: Cc1sc2c(c1C(=O)OC(C)(C)C)C(NC(=O)Cc1ccc3c(c1)OCO3)COC2
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of the above crude 2-amino-5-((2-benzo[1,3]dioxol-5-yl-acetylamino)-methyl]4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid tert-butyl ester (0.17 g, 0.38 mmol) in dichloromethane (5 ml) was added imidazol-1-yl-oxo-acetic acid tert-butyl ester (0.22 g, 1.14 mmol). The reaction mixture was stirred at room temperature for 18 hours, the volatiles evaporated in vacuo and the residue diluted with ethyl acetate. The organic layer was washed with hydrochloric acid (1% (v/v), 2×25 ml), saturated sodium bicarbonate (2×25 ml) and brine (2×25 ml). The organic layer was dried (MgSO4), filtered, concentrated in vacuo and the residue subjected to flash chromatography using a mixture of ethyl acetate/hexanes (1:2) as eluent, which afforded 0.12 g (55%) of 2-(tert-butoxyoxalyl-amino)-5-((2-benzo[1,3]dioxol-5-yl-acetylamino)-methyl-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid tert-butyl ester as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([Cl:11])[C:9]=1[OH:10])[C:5]#[N:6].Br[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]1[O:22][N:21]=[C:20]([CH3:23])[CH:19]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[Na+]>CN(C)C=O.COC(C)(C)C.CCCCCC>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]#[N:6])[CH:7]=[C:8]([Cl:11])[C:9]=1[O:10][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]1[O:22][N:21]=[C:20]([CH3:23])[CH:19]=1
Reactant: N#Cc1cc(Cl)c(O)c(Cl)c1
Reactant: Cc1cc(CCCCCBr)on1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: COC(C)(C)C
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: Cc1cc(CCCCCOc2c(Cl)cc(C#N)cc2Cl)on1

Procedure:
5-[5-(2,6-Dichloro-4-cyanophenoxy)pentyl]-3-methylisoxazole [IX; Y=(CH2)5, Z=N, R=CH3, R1 =2-Cl, R2 =6-Cl] was prepared from 13.4 g 3,5-dichloro-4-hydroxybenzonitrile, 23.2 g 5-(5-bromopentyl)-3-methylisoxazole, 20.7 g potassium carbonate and 15 g sodium iodide in 250 ml dimethylformamide, similar to the procedure of Example 4, and was obtained in the form of colorless crystals (11.6 g), m.p. 59-60° C. (from tertiary-butyl methyl ether-hexane).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[CH:10]=[C:9]2[C:4]=1[N:5]=[C:6]([O:18][CH3:19])[C:7]([O:16][CH3:17])=[N:8]2.BrCC1C=C([N+]([O-])=O)C=C2C=1N=[C:25](OC)[C:26]([O:35]C)=N2.C(OC(=O)C)(=O)C.C(N(CC)CC)C>C(N(CC)C=O)C.C(OCC)C>[CH3:17][O:16][C:7]1[C:6]([O:18][CH3:19])=[N:5][C:4]2[C:9](=[CH:10][C:11]([N+:13]([O-:15])=[O:14])=[CH:12][C:3]=2[CH2:2][NH:1][C:26](=[O:35])[CH3:25])[N:8]=1
Reactant: COc1nc2cc([N+](=O)[O-])cc(CBr)c2nc1OC
Reactant: COc1nc2cc([N+](=O)[O-])cc(CN)c2nc1OC
Agent: CCN(C=O)CC
Solvent: CCOCC
Solvent: CCN(CC)CC
Solvent: CC(=O)OC(C)=O
Product: COc1nc2cc([N+](=O)[O-])cc(CNC(C)=O)c2nc1OC

Procedure:
111 mg (0.437 mmol) of 5-aminomethyl-2,3-dimethoxy-7-nitro-quinoxaline, obtainable in a manner analogous to that described in Example 9 but starting from 5-bromomethyl-2,3-dimethoxy-7-nitro-quinoxaline, are stirred with 0.046 ml (1.1 equiv.) of acetic anhydride and 0.073 ml (1.2 equiv.) of triethylamine in 5 ml of N,N-diethylformamide at room temperature for 24 hours. The reaction mixture is diluted with diethyl ether, and the solid is filtered off, washed with diethyl ether and dried.
Reaction SMILES: [CH2:1]([N:9]1[C:17]([C:18]([O:20]C)=O)=[N:16][C:15]2[C:10]1=[N:11][CH:12]=[N:13][C:14]=2[NH2:22])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[OH-].[Na+].[NH2:25][CH2:26][P:27](=[O:34])([O:31][CH2:32][CH3:33])[O:28][CH2:29][CH3:30].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>C1COCC1.CO.O>[CH2:1]([N:9]1[C:17]([C:18]([NH:25][CH2:26][P:27]([O:31][CH2:32][CH3:33])([O:28][CH2:29][CH3:30])=[O:34])=[O:20])=[N:16][C:15]2[C:10]1=[N:11][CH:12]=[N:13][C:14]=2[NH2:22])[CH2:2][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: COC(=O)c1nc2c(N)ncnc2n1CCc1ccccc1
Reactant: CCOP(=O)(CN)OCC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CCOP(=O)(CNC(=O)c1nc2c(N)ncnc2n1CCc1ccccc1)OCC
Temperature: 25 °C
Reaction time: 24 h

Procedure:
N9-phenethyl-8-(methoxycarbonyl)adenine (1 mmol, prepared as in Step A of Example 5) was treated with sodium hydroxide (1.2 mmol) in THF:MeOH:H2O (3:2:1) at 25° C. for 1.5 h. The reaction mixture was evaporated to dryness, and the residue was dissolved in DMF, treated with diethyl aminomethylphosphonate (1.5 mmol), EDCl (1-(3-dimethyl-aminopropyl)-3-ethylcarbodiimide hydrochloride, 1.3 mmol), HOBt (1-hydroxy-benzotriazole hydrate, 1.5 mmol), and stirred at 25° C. for 24 h. Extraction and chromatography gave N9-phenethyl-8-(diethylphosphonomethyl-aminocarbonyl)adenine as a white solid. TLC: Rf=0.1, EtOAc.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].C([O-])([O-])=O.[K+].[K+].[CH2:20](O)[CH3:21]>S(=O)(=O)(O)O>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4]([O:6][CH2:20][CH3:21])=[O:5]
Reactant: CCO
Reactant: O=C(O)c1cc([N+](=O)[O-])ccc1Cl
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: CCOC(=O)c1cc([N+](=O)[O-])ccc1Cl

Procedure:
A solution of 2-chloro-5-nitrobenzoic acid (26 g) in ethanol (260 mL) and concentrated sulfuric acid (1 mL) was heated at reflux for 18 hr. The reaction mixture was cooled and K2CO3 was added to quench the reaction. The resulting mixture was filtered and concentrated. The residue was then suspended in ether and filtered to remove insoluble starting acid. The filtrate was washed with 4% KOH (110 mL), dried over MgSO4 and concentrated to provide 16.2 g of ethyl 2-chloro-5-nitrobenzoate as a colorless oil which solidified on standing.
Reaction SMILES: [SH:1]/[C:2](/[C:7]#[N:8])=[C:3](\[SH:6])/[C:4]#[N:5].[Na].[Na].[OH2:11]>CN(C=O)C>[O:11]=[C:4]1[NH:5][N:8]=[CH:7][C:2]2[S:1][C:2]([C:7]#[N:8])=[C:3]([C:4]#[N:5])[S:6][C:3]1=2
Reactant: N#C/C(S)=C(/S)C#N
Reactant: O
Agent: [Na]
Solvent: CN(C)C=O
Product: N#CC1=C(C#N)Sc2c(cn[nH]c2=O)S1
Temperature: 20 °C
Reaction time: 0.25 h
Yield: 43 %

Procedure:
To a stirred solution of 20 g (0.1 mole) disodiumdimercaptomaleonitrile in 250 ml of DMF was added 16.5 g (0.1 mole) of 4,5-dichloro-3-pyridiazone. The reaction mixture was stirred at room temperature (approximately 20° C.) for 0.25 hours and was thereafter poured with stirring into 1.5 liters of water. The resulting mixture was allowed to stand for four hours during which time a brown precipitate slowly formed. This precipitate was separated by filtration, washed with water, and dried in vacuo to yield 10.2 g (43% yield from the pyridiazone) of a brown solid, m.p. (decomposition) 240°-260° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][CH2:22][O:23][CH3:24])=[CH:15][CH:14]=1)[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(OC(NC(C1C=CC(OCCN2CCCC2)=CC=1)C(O)=O)=O)(C)(C)C.BrCCCOC>>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:13]1[CH:14]=[CH:15][C:16]([O:19][CH2:20][CH2:21][CH2:22][O:23][CH3:24])=[CH:17][CH:18]=1)[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COCCCOc1ccc(C(NC(=O)OC(C)(C)C)C(=O)O)cc1
Agent: CC(C)(C)OC(=O)NC(C(=O)O)c1ccc(OCCN2CCCC2)cc1
Agent: COCCCBr
Product: COCCCOc1ccc([C@@H](NC(=O)OC(C)(C)C)C(=O)O)cc1

Procedure:
Prepared as described in example 3 except that tert-butoxycarbonylamino-[4-(3-methoxy-propoxy)-phenyl]-acetic acid was used in place of tert-butoxycarbonylamino-(3-fluoro-4-methoxy-phenyl)-acetic acid in step 7. (R)-tert-Butoxycarbonylamino-[4-(3-methoxy-propoxy)-phenyl]-acetic acid was prepared in a manner similar to that described for the preparation of tert-butoxycarbonylamino-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-acetic acid in example 4 (o) except that 1-bromo-3-methoxy-propane was used in place of chloroethylpyrrolidine hydrochloride.
Reaction SMILES: [CH3:1][Si](C=[N+]=[N-])(C)C.[CH3:8][C:9]1[CH:10]=[CH:11][C:12]([C:16]([OH:18])=[O:17])=[N:13][C:14]=1[CH3:15]>CCCCCC.CO.ClCCl>[CH3:1][O:17][C:16]([C:12]1[CH:11]=[CH:10][C:9]([CH3:8])=[C:14]([CH3:15])[N:13]=1)=[O:18]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: Cc1ccc(C(=O)O)nc1C
Solvent: CCCCCC
Solvent: CO
Solvent: ClCCl
Product: COC(=O)c1ccc(C)c(C)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
77.4 ml 2 mol/L trimethylsilyldiazomethan in hexane was added to 5,6-dimethyl-pyridine-2-carboxylic acid in 150 mL methanol and 600 mL dichlormethane at −5° C. and the reaction was stirred for 0.5 h. After warming to RT the solvent was removed and the residue was purified by chromatorgaphie on Silica (cyclohexane/ethyl acetate:7/3) to give 12.8 g of the desired product.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([O:9][CH2:10][CH2:11][OH:12])[C:3]=1[N+:13]([O-:15])=[O:14].[C:16]([Si:20](Cl)([CH3:22])[CH3:21])([CH3:19])([CH3:18])[CH3:17].N1C=CN=C1.[NH4+].[Cl-]>C(Cl)Cl>[C:16]([Si:20]([CH3:22])([CH3:21])[O:12][CH2:11][CH2:10][O:9][C:4]1[C:3]([N+:13]([O-:15])=[O:14])=[C:2]([NH2:1])[CH:7]=[C:6]([Cl:8])[N:5]=1)([CH3:19])([CH3:18])[CH3:17]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Nc1cc(Cl)nc(OCCO)c1[N+](=O)[O-]
Agent: [Cl-]
Agent: [NH4+]
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCCOc1nc(Cl)cc(N)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of 2-(4-amino-6-chloro-3-nitro-pyridin-2-yloxy)-ethanol (4.40 g, 18.8 mmol, prepared as described in the previous step) and tert-butyl-chloro-dimethyl-silane (3.12 g, 20.7 mmol) in DCM (50 mL) was added imidazole (1.80 g, 26.4 mmol). After stirring at room temperature for 2 h, the resulting mixture was treated with saturated NH4Cl (50 mL) and extracted with EtOAc (3×50 mL). The combined organic layers were washed with H2O (3×50 mL), brine (50 mL), and dried over Na2SO4. The solvent was removed in vacuo and the residue was purified by flash chromatography on silica gel (0:100-20:80 EtOAc/hexane) to yield 2-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-6-chloro-3-nitro-pyridin-4-ylamine as a light yellow solid. 1H-NMR (400 MHz, CDCl3) 6: 6.35 (s, 1H), 6.17 (br. s., 2H), 4.49 (t, J=5.1 Hz, 2H), 3.96 (t, J=5.1 Hz, 2H), 0.88 (s, 9H), 0.08 (s, 6H).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[N:6][N:7]([C:12]2[CH:17]=[C:16]([Cl:18])[CH:15]=[C:14]([Cl:19])[CH:13]=2)[C:8]=1[C:9]([NH2:11])=[O:10])([OH:3])=[O:2].[CH2:20](O)[CH3:21]>>[Cl:19][C:14]1[CH:13]=[C:12]([N:7]2[C:8]([C:9]([NH2:11])=[O:10])=[C:4]([C:1]([O:3][CH2:20][CH3:21])=[O:2])[CH:5]=[N:6]2)[CH:17]=[C:16]([Cl:18])[CH:15]=1
Reactant: CCO
Reactant: NC(=O)c1c(C(=O)O)cnn1-c1cc(Cl)cc(Cl)c1
Product: CCOC(=O)c1cnn(-c2cc(Cl)cc(Cl)c2)c1C(N)=O

Procedure:
Two g of the compound of Example 2 was suspended in 80 ml of absolute ethanol and hydrogen chloride gas was bubbled through for 5 minutes. The mixture was then heated under reflux for 2 hours and cooled, and was then filtered. The solids were collected and dried to obtain 1.25 g of the desired product, m.p. 164°-166°.
Reaction SMILES: [CH2:1]([O:4][C:5]1([CH3:28])[CH2:10][CH2:9][N:8]([C:11]2[N:16]3[N:17]=[C:18]([Br:20])[CH:19]=[C:15]3[N:14]=[C:13]([CH3:21])[C:12]=2[C:22](=[O:27])[C:23]([O:25][CH3:26])=[O:24])[CH2:7][CH2:6]1)[CH:2]=[CH2:3].CB1N2CCC[C@@H:33]2[C:32]([C:44]2C=CC=CC=2)([C:38]2C=CC=CC=2)O1.CC#N.C(=O)=O.[B]1OC2C(=CC=CC=2)O1.Cl(O)(=O)(=O)=O.C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1.C(Cl)Cl.C(OC(C)=O)(C)(C)C>[CH2:1]([O:4][C:5]1([CH3:28])[CH2:10][CH2:9][N:8]([C:11]2[N:16]3[N:17]=[C:18]([Br:20])[CH:19]=[C:15]3[N:14]=[C:13]([CH3:21])[C:12]=2[C@H:22]([O:27][C:32]([CH3:44])([CH3:38])[CH3:33])[C:23]([O:25][CH3:26])=[O:24])[CH2:7][CH2:6]1)[CH:2]=[CH2:3]
Reactant: C=CCOC1(C)CCN(c2c(C(=O)C(=O)OC)c(C)nc3cc(Br)nn23)CC1
Reactant: CB1OC(c2ccccc2)(c2ccccc2)[C@H]2CCCN12
Agent: O=C([O-])O
Agent: O=C=O
Agent: [B]1Oc2ccccc2O1
Solvent: ClCCl
Solvent: Cc1ccccc1
Solvent: CC#N
Product: C=CCOC1(C)CCN(c2c([C@H](OC(C)(C)C)C(=O)OC)c(C)nc3cc(Br)nn23)CC1
Reaction time: 18 h
Yield: 34 %

Procedure:
A solution of methyl 2-(7-(4-(allyloxy)-4-methylpiperidin-1-yl)-2-bromo-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-oxoacetate (9.20 g, 20.3 mmol, 1 equiv) and (R)-1-methyl-3,3-diphenylhexahydropyrrolo[1,2-c][1,3,2]oxazaborole (12.2 mL of a 1 M solution in toluene, 12.2 mmol, 0.6 equiv) in toluene (200 mL) was cooled to −25° C. (MeCN/CO2). Catecholborane (6.8 mL of a 50% solution in toluene, 28.4 mmol, 1.4 equiv) was then added and temperature was held between −15° C. and −25° C. for 18 h. At this point, more and (R)-1-methyl-3,3-diphenylhexahydropyrrolo[1,2-c][1,3,2]oxazaborole (4 mL of a 1 M solution in toluene, 4 mmol, 0.2 equiv) and catecholborane (3 mL of a 50% solution in toluene, 12.5 mmol, 0.6 equiv) were added. The reaction was then stirred a further 4 h. The reaction was then quenched with 10% aqueous K2CO3 (100 mL) and EtOAc (100 mL) and removed from cooling bath. After stirring 45 min, the mixture was added to water and extracted with ether (×4). The combined ether extracts were dried (MgSO4) and concentrated in vacuo to provide the crude product as a yellow foam. This was taken up in DCM (50 mL) and tBuOAc (150 mL). To this solution was added 70% perchloric acid (3.7 mL, 60.9 mmol, 3 equiv) to give a cloudy orange solution. After stirring 3 h, the reaction was added cautiously to saturated aqueous sodium bicarbonate and extracted with DCM (X3). The combined DCM extracts were dried (Na2SO4) and concentrated in vacuo to provide the crude product. The crude product was purified via silica gel flash chromatography (0-100% EtOAc/hex) to provide (S)-methyl 2-(7-(4-(allyloxy)-4-methylpiperidin-1-yl)-2-bromo-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetate (3.56 g, 34%) 1H NMR (500 MHz, CDCl3) δ 6.54 (s, 1H), 6.09-5.97 (m, 1H), 5.83 (br. s., 1H), 5.48 (d, J=17.8 Hz, 1H), 5.24 (d, J=9.8 Hz, 1H), 4.50-3.00 (very broad m, 4H), 4.05-3.98 (m, 2H), 3.76 (s, 3H), 2.59 (s, 3H), 2.04-1.90 (m, 2H), 1.36 (s, 3H), 1.24 (s, 9H). LCMS (M+1)=509.09.
Reaction SMILES: [CH:1]([NH:4][CH2:5][C:6]1([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][CH2:21][N:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][O:9][CH2:8][CH2:7]1)([CH3:3])[CH3:2].C=O.[CH:29](O)=O.O>C(OCC)(=O)C>[CH:1]([N:4]([CH3:29])[CH2:5][C:6]1([C:12]2[CH:13]=[CH:14][C:15]([O:18][CH2:19][CH2:20][CH2:21][N:22]3[CH2:23][CH2:24][CH2:25][CH2:26]3)=[CH:16][CH:17]=2)[CH2:7][CH2:8][O:9][CH2:10][CH2:11]1)([CH3:3])[CH3:2]
Reactant: O=CO
Reactant: CC(C)NCC1(c2ccc(OCCCN3CCCC3)cc2)CCOCC1
Agent: C=O
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)N(C)CC1(c2ccc(OCCCN3CCCC3)cc2)CCOCC1
Temperature: 60 °C
Yield: 65 %

Procedure:
To isopropyl-{4-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]tetrahydropyran-4-ylmethyl}-amine (258 mg, 0.71 mmol) was added formaldehyde (37% w/w solution in H2O, 1 mL) and formic acid (1.5 mL). The resulting mixture was heated to 60° C. overnight. After cooling, H2O and ethyl acetate were added. The aqueous layer was separated, basified with 30% NaOH and extracted 3 times with ethyl acetate. The combined organic extracts were dried over Na2SO4, filtered and concentrated in vacuo to give the title compound as an oil (170 mg, 65%). 1H NMR (400 MHz, CDCl3) δ 7.19 (d, 2H), 6.86 (d, 2H), 4.02 (t, 2H), 3.76 (m, 2H), 3.50 (m, 2H), 2.63 (t, 2H), 2.53 (m, 4H), 2.44 (m, 1H), 2.38 (s, 2H), 2.08 (m, 2H), 2.01 (m, 2H), 1.89 (m, 2H), 1.85 (s, 3H), 1.79 (m, 4H), 0.84 (d, 6H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH:4]=[C:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[CH:9]=[CH:8][C:7]2[CH:16]=[CH:17][CH:18]=[CH:19][C:6]1=2.O.[C:21](OC(=O)C)(=[O:23])[CH3:22]>>[C:21]([NH:1][CH2:2][CH2:3][CH:4]=[C:5]1[C:6]2[CH:19]=[CH:18][CH:17]=[CH:16][C:7]=2[CH:8]=[CH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]1=2)(=[O:23])[CH3:22]
Reactant: NCCC=C1c2ccccc2C=Cc2ccccc21
Reactant: CC(=O)OC(C)=O
Solvent: O
Product: CC(=O)NCCC=C1c2ccccc2C=Cc2ccccc21

Procedure:
5-(3-Aminopropylidene)-5H-dibenzo[a,d]cycloheptene is dissolved in acetic anhydride and the solution is heated to refluxing for 20 minutes. The solution is then cooled and poured into a large volume of water. The mixture is stirred until the excess acetic anhydride is hydrolyzed. The product is extracted into ether, the extract washed with sodium bicarbonate solution, followed by washing with water and dried over sodium sulfate. The product is isolated by evaporating the ether.