Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C@@H:2]([CH2:14][CH3:15])[CH2:3][NH:4][CH2:5][C:6]1[S:10][C:9](B(O)O)=[CH:8][CH:7]=1.Br[C:17]1[CH:18]=[C:19]2[C:23](=[C:24]([C:26]([NH2:28])=[O:27])[CH:25]=1)[NH:22][CH:21]=[C:20]2[CH:29]1[CH2:34][CH2:33][N:32]([S:35]([CH2:38][CH3:39])(=[O:37])=[O:36])[CH2:31][CH2:30]1.C([O-])([O-])=O.[K+].[K+]>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>[CH2:38]([S:35]([N:32]1[CH2:31][CH2:30][CH:29]([C:20]2[C:19]3[C:23](=[C:24]([C:26]([NH2:28])=[O:27])[CH:25]=[C:17]([C:9]4[S:10][C:6]([CH2:5][NH:4][CH2:3][C@@H:2]([CH3:1])[CH2:14][CH3:15])=[CH:7][CH:8]=4)[CH:18]=3)[NH:22][CH:21]=2)[CH2:34][CH2:33]1)(=[O:37])=[O:36])[CH3:39]
Reactant: CC[C@H](C)CNCc1ccc(B(O)O)s1
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(Br)cc23)CC1
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: [K+]
Product: CC[C@H](C)CNCc1ccc(-c2cc(C(N)=O)c3[nH]cc(C4CCN(S(=O)(=O)CC)CC4)c3c2)s1
Yield: 39 %

Procedure:
Following the general procedure of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-{[(2-methylbutyl)amino]methyl}-2-thienyl)-1H-indole-7-carboxamide, (5-formyl-2-thienyl)boronic acid (50 mg, 0.32 mmol), [(2S)-2-methylbutyl]amine (28 mg, 0.32 mmol), and NaCNBH3 (40 mg, 0.64 mmol) were reacted to give 43 mg of crude [5-({[(2S)-2-methylbutyl]amino}methyl)-2-thienyl]boronic acid. The crude [5-({[(2S)-2-methylbutyl]amino}methyl)-2-thienyl]boronic acid was then reacted with 5-bromo-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide (65 mg, 0.157 mmol), K2CO3 (130 mg, 0.942 mmol), and tetrakis(triphenylphosphine)palladium(0) (4 mg, 0.003 mmol) to give 37.6 mg of the title compound (39%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:9]2[NH:13][N:12]=[N:11][N:10]=2)=[C:6]([CH:8]=1)[NH2:7].[Cl:14][C:15]1[CH:23]=[CH:22][C:18]([C:19](Cl)=[O:20])=[CH:17][CH:16]=1>>[Cl:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([NH:7][C:6]2[CH:8]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=2[C:9]2[NH:13][N:12]=[N:11][N:10]=2)=[O:20])=[CH:17][CH:16]=1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: Nc1cc(Cl)ccc1-c1nnn[nH]1
Product: O=C(Nc1cc(Cl)ccc1-c1nnn[nH]1)c1ccc(Cl)cc1
Yield: 37 %

Procedure:
The title compound was prepared essentially according to the method of Example 4, but using 5-Chloro-2-(1H-tetrazol-5-yl)aniline (1.0 mmol) and 4-chlorobenzoyl chloride to yield the desired product (126.3 mg, 37%). 1H NMR (400 MHz, d6-DMSO): δ 13.62 (s, 1H), 8.87 (s, 1H), 8.22 (m, 3H), 7.72 (s, 2H), 7.25 (s, 1H). MS (EI) for C14H9Cl2N5O: 334.165 (M+H).
Reaction SMILES: N(OC(C)(C)C)=O.CN(C)C=O.N[C:14]1[S:15][C:16]([CH2:19][C:20]2[CH:21]=[C:22]3[C:27](=[CH:28][CH:29]=2)[CH2:26][CH:25]([C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH2:24][CH2:23]3)=[CH:17][N:18]=1>C(OCC)(=O)C>[S:15]1[C:16]([CH2:19][C:20]2[CH:21]=[C:22]3[C:27](=[CH:28][CH:29]=2)[CH2:26][CH:25]([C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH2:24][CH2:23]3)=[CH:17][N:18]=[CH:14]1
Reactant: CCOC(=O)C1CCc2cc(Cc3cnc(N)s3)ccc2C1
Agent: CC(C)(C)ON=O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)C1CCc2cc(Cc3cncs3)ccc2C1
Temperature: 50 °C
Reaction time: 1 h
Yield: 75.6 %

Procedure:
A mixture of 0.49 g of tertiary butyl nitrite and 5 ml of dimethylformamide was heated at 50° C. and then 1.0 g of ethyl 6-(2-amino-5-thiazolylmethyl)-1,2,3,4-tetrahydro-2-naphthalenecarboxylate was added portionwise thereto. The resulting mixture was stirred at 60° C. for 1 hour. After cooling, ethyl acetate was added to the reaction mixture and the mixture was washed with water and dried and then concentrated in vacuo. The residue was purified by silica gel column chromatography using a mixture of methanol and chloroform (1:50 by volume) for elution to give 720 mg of ethyl 6-(5-thiazolylmethyl)-1,2,3,4-tetrahydro-2-naphthalenecarboxylate as an oil.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[C:12](=O)([O-])[O-].[K+].[K+].IC>CN(C)C=O>[CH3:12][O:5][C:4](=[O:6])[C:3]1[CH:7]=[C:8]([F:11])[CH:9]=[CH:10][C:2]=1[Br:1]
Reactant: O=C(O)c1cc(F)ccc1Br
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)c1cc(F)ccc1Br
Reaction time: 0.08 h

Procedure:
To a solution of 2-bromo-5-fluorobenzoic acid (7.92 g, 36.2 mmol) in N,N-dimethylformamide (75 mL) was added potassium carbonate (6.91 g, 50.0 mmol) as a solid in one portion at room temperature. The mixture was stirred for 5 minutes and iodomethane (6.39 g, 45.0 mmol) was added in one portion. The mixture was stirred at ambient temperature for 22 hours. The reaction mixture was partitioned between ethyl acetate and water. The aqueous portion was extracted with additional ethyl acetate (3×) and the combined organic extracts were washed successively with 10% potassium carbonate solution, water and brine. The organic portion was dried (Na2SO4) and concentrated to afford the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 3.87 (s, 3H) 7.41 (td, J=8.56, 3.22 Hz, 1H) 7.65 (dd, J=8.99, 3.22 Hz, 1H) 7.81 (dd, J=9.16, 5.09 Hz, 1H); MS (+DCI/NH3) m/z 250.0 [M+NH4]+.
Reaction SMILES: [C:1]1([CH:7]2[CH2:10][CH2:9][NH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:11]1([CH2:17][CH2:18][C:19](Cl)=[O:20])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(N(CC)CC)C>ClCCl>[C:11]1([CH2:17][CH2:18][C:19]([N:8]2[CH2:9][CH2:10][CH:7]2[C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[O:20])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: c1ccc(C2CCN2)cc1
Reactant: O=C(Cl)CCc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(CCc1ccccc1)N1CCC1c1ccccc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 74.8 %

Procedure:
A solution of 2-phenylazetidine (266 mg, 2 mmol) in dry dichloromethane (6 mL) is cooled in an ice bath, and 3-phenylpropionyl chloride (421.5 mg, 2.5 mmol, 1.25 eq) and triethylamine (417 μL, 3 mmol, 1.5 eq) are added. After stirring for 6 hours at room temperature the reaction mixture is diluted with dichloromethane (10 mL). The organic solution is subsequently washed with 1 M KHSO4, 5% NaHCO3 and brine. After drying over Na2SO4, dichloromethane is removed in vacuo and the crude material is purified by flash chromatography (silicagel, ethyl acetate/toluene 1:4). The fractions containing 3-phenyl-1-(2-phenylazetidin-1-yl)propan-1-one are collected and the solvent is removed in vacuo to give 397 mg of colorless oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([OH:12])[CH:6]=[CH:5]2.N1C=CN=C1.[C:18]([Si:22](Cl)([CH3:24])[CH3:23])([CH3:21])([CH3:20])[CH3:19].CCCCCC>CN(C)C=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([O:12][Si:22]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:24])[CH3:23])[CH:6]=[CH:5]2
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Oc1ccc2cc(Br)ccc2c1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: CC(C)(C)[Si](C)(C)Oc1ccc2cc(Br)ccc2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 52.2 %

Procedure:
200 g 6-bromonaphthalen-2-ol, 143 g imidazole and 151 g tert.-butylchlorodimethylsilane were dissolved in 1,000 ml dimethylformamide, stirred for two hours at ambient temperature, the solution largely concentrated (506 g), the residue dissolved in ethyl acetate and water, 1,500 ml saturated sodium chloride solution added, the phases separated, the aqueous phase extracted twice with ethyl acetate and the organic phases combined and concentrated. The crude product obtained was dissolved in boiling hexane and subsequently kept overnight at 4° C. After filtration, 158 g (6-bromonaphthalen-2-yloxy)-tert.-butyldimethylsilane were isolated. Repeated concentration of the mother liquor and recrystallisation from methanol yielded a further 54 g (6-bromonaphthalen-2-yloxy)-tert.-butyldimethylsilane.
Reaction SMILES: Br[C:2]1[S:3][C:4]2[C:9]([Cl:10])=[N:8][C:7]([S:11][CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[N:6][C:5]=2[N:19]=1.[CH3:20][NH2:21]>O1CCCC1>[Cl:10][C:9]1[C:4]2[S:3][C:2]([NH:21][CH3:20])=[N:19][C:5]=2[N:6]=[C:7]([S:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:8]=1
Reactant: Clc1nc(SCc2ccccc2)nc2nc(Br)sc12
Reactant: CN
Solvent: C1CCOC1
Product: CNc1nc2nc(SCc3ccccc3)nc(Cl)c2s1
Reaction time: 16 h

Procedure:
A solution of the product from Example 219 (0.3 g) in tetrahydrofuran (2 ml) containing methylamine (2.0 molar in THF: 0.81 ml) was stirred for 16 hours. The mixture was evaporated to dryness then purified (SiO2, ethyl acetate:dichloromethane 1:9 as eluant) to give the title compound (295 mg).
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][CH:6]=1.[K].[C:16]1(=[O:26])[NH:20][C:19](=[O:21])[C:18]2=[CH:22][CH:23]=[CH:24][CH:25]=[C:17]12>CN(C)C=O>[CH3:12][O:11][C:9]([C:8]1[CH:13]=[CH:14][C:5]([O:4][CH2:3][CH2:2][N:20]2[C:19](=[O:21])[C:18]3=[CH:22][CH:23]=[CH:24][CH:25]=[C:17]3[C:16]2=[O:26])=[CH:6][CH:7]=1)=[O:10]
Reactant: COC(=O)c1ccc(OCCBr)cc1
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OCCN2C(=O)c3ccccc3C2=O)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 94 %

Procedure:
Methyl 4-(2-Bromoethoxy)benzoate (126.52 g) and 99.5 g of potassium salt of phthalimide were dissolved in 600 ml of N,N-dimethylformamide and the solution was stirred at 78°-80° C. for 2 hours. The reaction solution was poured over ice water and extracted with chloroform. The chloroform layer was washed with water twice, dried with anhydrous magnesium sulphate, and concentrated in vacuo whereupon the residue was crystallised. Ether was added to the residue and filtered to give crystals in 149.23 g (yield: 94%). M.p. 129°-130.5° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH:20]=O)=[CH:9][C:10]2[CH:19]=[CH:18][C:13]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.[CH:22]1([NH2:25])[CH2:24][CH2:23]1.CO.[BH4-].[Na+]>C(OCC)(=O)C>[CH:22]1([NH:25][CH2:20][C:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)=[CH:9][C:10]2[CH:19]=[CH:18][C:13]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][CH:11]=2)[CH2:24][CH2:23]1
Reactant: COC(=O)c1ccc(C=C(C=O)c2ccc(F)cc2)cc1
Reactant: NC1CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Product: COC(=O)c1ccc(C=C(CNC2CC2)c2ccc(F)cc2)cc1
Reaction time: 0.5 h

Procedure:
A mixture of methyl 4-(2-(4-fluorophenyl)-3-oxoprop-1-en-1-yl)benzoate (0.568 g. 2 mmol) and cyclopropylamine (0.17 g, 3 mmol) were stirred with MeOH (50 mL) for 3 hours. NaBH4 (0.114 g, 3 mmol) was added to the reaction mixture and it was stirred for 30 minutes. Subsequently the reaction mixture was diluted with ethyl acetate (300 mL) and washed with water (3×50 mL) and brine (100 mL). The organic layer was dried over anhydrous Na2SO4 and concentrated to afford the pure title compound as a pale yellow sticky compound (0.51 g, 76% yield).
Reaction SMILES: [CH3:1][CH:2]1[CH2:6][CH2:5][C:4]2([C:11]([CH3:13])([CH3:12])[CH2:10][CH2:9][CH2:8][C:7]2([CH3:15])[OH:14])[O:3]1.CN(C)C1C=CC=CC=1.[C:25](Cl)(=[O:29])[CH:26]([CH3:28])[CH3:27]>>[C:25]([O:14][C:7]1([CH3:15])[CH2:8][CH2:9][CH2:10][C:11]([CH3:13])([CH3:12])[C:4]21[O:3][CH:2]([CH3:1])[CH2:6][CH2:5]2)(=[O:29])[CH:26]([CH3:28])[CH3:27]
Reactant: CC(C)C(=O)Cl
Reactant: CC1CCC2(O1)C(C)(C)CCCC2(C)O
Solvent: CN(C)c1ccccc1
Product: CC1CCC2(O1)C(C)(C)CCCC2(C)OC(=O)C(C)C
Yield: 11 %

Procedure:
2.12 g (0.01 M) of 2,6,10,10-tetramethyl-1-oxa-spiro[4.5]decan-6-ol -- isomer A; see Example 1 -- were treated with a mixture of 12.1 g (0.1 M) of N,N-dimethylaniline and 5.3 g (0.05 M) pf isobutyryl chloride as indicated in Example 5 to give 0.3 g (ca. 11%) of the desired ester, b.p. 110°/0.5 Torr.
Reaction SMILES: Br[C:2]1[CH:14]=[C:13]2[C:5]([C:6]3[CH:7]=[CH:8][C:9]([N:15]([CH2:20][CH2:21][CH2:22][CH3:23])[CH2:16][CH2:17][CH2:18][CH3:19])=[CH:10][C:11]=3[CH2:12]2)=[CH:4][CH:3]=1.[CH:24]([C:26]1[S:30][C:29](B(O)O)=[CH:28][CH:27]=1)=[O:25]>>[CH2:16]([N:15]([CH2:20][CH2:21][CH2:22][CH3:23])[C:9]1[CH:10]=[C:11]2[C:6]([C:5]3[CH:4]=[CH:3][C:2]([C:29]4[S:30][C:26]([CH:24]=[O:25])=[CH:27][CH:28]=4)=[CH:14][C:13]=3[CH2:12]2)=[CH:7][CH:8]=1)[CH2:17][CH2:18][CH3:19]
Reactant: CCCCN(CCCC)c1ccc2c(c1)Cc1cc(Br)ccc1-2
Reactant: O=Cc1ccc(B(O)O)s1
Product: CCCCN(CCCC)c1ccc2c(c1)Cc1cc(-c3ccc(C=O)s3)ccc1-2

Procedure:
As shown in Scheme 1, 7-bromo-9H-fluoren-2-ylamine is reacted with 1-iodobutane to form (7-bromo-9H-fluoren-2-yl)-dibutyl amine (11). Then, (7-bromo-9H-fluoren-2-yl)-dibutyl amine (11) is reacted with 5-formyl-2-thiopheneboronic acid by Suzuki coupling reaction to obtain 5-(7-dibutylamino-9H-fluoren-2-yl)-thiophene-2-carbaldehyde (12a). Finally, in acetonitrile, 5-(7-dibutylamino-9H-fluoren-2-yl)-thiophene-2-carbaldehyde (12a) is reacted with cyanoacetic acid by using piperidine as a catalyst, to obtain 2-cyano-3-[5-(7-dibutylamino-9H-fluoren-2-yl)-thiophen-2-yl]-acrylic acid (13a).
Reaction SMILES: [O:1]=[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]1[C:8]1[CH:15]=[CH:14][C:11]([CH2:12]Br)=[CH:10][CH:9]=1.C([N:35]1[CH:39]=[C:38]([CH2:40][C:41]2[CH:48]=[CH:47][C:44]([C:45]#[N:46])=[CH:43][CH:42]=2)[N:37]=[CH:36]1)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>CC#N>[O:1]=[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]1[C:8]1[CH:15]=[CH:14][C:11]([CH2:12][N:37]2[C:38]([CH2:40][C:41]3[CH:48]=[CH:47][C:44]([C:45]#[N:46])=[CH:43][CH:42]=3)=[CH:39][N:35]=[CH:36]2)=[CH:10][CH:9]=1
Reactant: N#Cc1ccc(Cc2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)cc1
Reactant: O=c1ccccn1-c1ccc(CBr)cc1
Solvent: CC#N
Product: N#Cc1ccc(Cc2cncn2Cc2ccc(-n3ccccc3=O)cc2)cc1

Procedure:
4-(-2-Oxo-2-H-pyridin-1-yl)benzyl bromide from Step 3 (1.7 mmol, 450 mg ) and 4-(1-trityl-1H-imidazol-4-ylmethyl)benzonitrile (1.7 mmol) were suspended in CH3CN and heated to reflux for 3 hours. The reaction mixture was concentrated and the residue taken up in MeOH and refluxed for 2 hours. The MeOH was removed in-vacuo. The resulting oil was partitioned between EtOAc and saturated NaHCO3. The aqueous layer was extracted twice with EtOAc. The organic layers were combined, washed with brine, dried (MgSO4), filtered and concentrated to yield an oil which was purified by flash chromatography using 5% IPA/CHCl3 saturated with NH3 as an eluent. Pure fractions were collected and concentrated to give a white solid. The solids were washed with warm 50% EtOAc/Hexane and collected on a frit. The white solid was collected and dried under high vacuum at 50° for 12 hours to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH:13]([NH:14][CH3:15])[CH2:12][N:11]([C:16]([CH:18]3[CH2:23][CH2:22][N:21]([C:24]([C:26]4([CH3:29])[CH2:28][CH2:27]4)=[O:25])[CH2:20][CH2:19]3)=[O:17])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].[F:30][C:31]1[CH:36]=[CH:35][C:34]([C:37]2([C:42]([OH:44])=O)[CH2:41][CH2:40][CH2:39][CH2:38]2)=[CH:33][CH:32]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH2:10][N:11]([C:16]([CH:18]3[CH2:19][CH2:20][N:21]([C:24]([C:26]4([CH3:29])[CH2:27][CH2:28]4)=[O:25])[CH2:22][CH2:23]3)=[O:17])[CH2:12][CH:13]2[N:14]([CH3:15])[C:42]([C:37]2([C:34]3[CH:33]=[CH:32][C:31]([F:30])=[CH:36][CH:35]=3)[CH2:38][CH2:39][CH2:40][CH2:41]2)=[O:44])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CNC1CN(C(=O)C2CCN(C(=O)C3(C)CC3)CC2)CC1c1ccc(Cl)c(Cl)c1
Reactant: O=C(O)C1(c2ccc(F)cc2)CCCC1
Product: CN(C(=O)C1(c2ccc(F)cc2)CCCC1)C1CN(C(=O)C2CCN(C(=O)C3(C)CC3)CC2)CC1c1ccc(Cl)c(Cl)c1

Procedure:
In analogy to the procedure described for the synthesis of example 97, the title compound 1-(4-fluoro-phenyl)-cyclopentanecarboxylic acid {(3RS,4SR)-4-(3,4-dichloro-phenyl)-1-[1-(1-methyl-cyclopropanecarbonyl)-piperidine-4-carbonyl]-pyrrolidin-3-yl}-methyl-amide was prepared from {4-[(3SR,4RS)-3-(3,4-dichloro-phenyl)-4-methylamino-pyrrolidine-1-carbonyl]-piperidin-1-yl}-(1-methyl-cyclopropyl)-methanone using 1-(4-fluoro-phenyl)-cyclopentanecarboxylic acid instead of 4-chloro-3-(trifluoromethyl)benzoic acid and was obtained as a light brown oil. MS m/e: 628.3 [M]+.
Reaction SMILES: C([O:4][CH2:5][C@H:6]1[O:10][C@@H:9]([N:11]2[CH:16]=[C:15]([CH3:17])[C:14]([NH:18][CH2:19][CH2:20][CH3:21])=[N:13][C:12]2=[O:22])[CH2:8][C@@H:7]1[N:23]=[N+:24]=[N-:25])(=O)C>N>[N:23]([C@@H:7]1[C@@H:6]([CH2:5][OH:4])[O:10][C@@H:9]([N:11]2[CH:16]=[C:15]([CH3:17])[C:14]([NH:18][CH2:19][CH2:20][CH3:21])=[N:13][C:12]2=[O:22])[CH2:8]1)=[N+:24]=[N-:25]
Reactant: CCCNc1nc(=O)n([C@H]2C[C@H](N=[N+]=[N-])[C@@H](COC(C)=O)O2)cc1C
Agent: N
Product: CCCNc1nc(=O)n([C@H]2C[C@H](N=[N+]=[N-])[C@@H](CO)O2)cc1C

Procedure:
1-(5-O-Acetyl-3-azido-2,3-dideoxy-β-D-erythro-pentofuranosyl)-5-methyl-4-(propylamino)-2-(1H)-pyrimidinone (0.3 g, 0.8 mMol,EX.) was dissolved in NH3 saturated MeOH (15 mL). After 3 hours the solvents were evaporated in vacuo to yield the title compound as a solid: mp=59°-62° C.; UV(nm): at pH 1 λmax=288,219(ε=11300,9500), λmin=247(ε=1700); at pH 13 λmax=276(ε=9000), λmin=253(ε=6400); H NMR(DMSO-d6) δ7.54(s,1H,H6), 7.17(t,1H,--NH--), 6.08(t,1H,H1',J=6.45 Hz), 5.17(t,1H,5'OH), 4.33(q,1H,H3'), 3.79(q,1H,H4'), 3.65-3.55(m,2H,--NH--CH2--), 3.26-3.19(m,2H,H5'), 2.22(t,2H,H2'), 1.83(s, 3H,5-CH3), 1.6-1.4(m,2H,--CH2--CH3), 0.84(t,3H,--CH2--CH3).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12].[CH3:16][C:17]1([CH3:35])[C:28]2=[C:29]3[N:20]([CH2:21][CH2:22][C:23](C)([CH3:33])[C:24]3=[C:25](O)[C:26](C=O)=[CH:27]2)[CH2:19][CH2:18]1.N1CCCCC1>C(#N)C>[CH3:16][C:17]1([CH3:35])[C:28]2=[C:29]3[N:20]([CH2:21][CH2:22][C:23]([CH3:24])([CH3:33])[C:15]3=[C:14]3[O:13][C:11](=[O:12])[C:10]([C:2]4[S:1][C:5]5[C:4](=[CH:9][CH:8]=[CH:7][CH:6]=5)[N:3]=4)=[CH:25][C:26]3=[CH:27]2)[CH2:19][CH2:18]1
Reactant: CC1(C)CCN2CCC(C)(C)c3c(O)c(C=O)cc1c32
Reactant: CCOC(=O)Cc1nc2ccccc2s1
Solvent: C1CCNCC1
Solvent: CC#N
Product: CC1(C)CCN2CCC(C)(C)c3c2c1cc1cc(-c2nc4ccccc4s2)c(=O)oc31
Yield: 80.4 %

Procedure:
A mixture of 12.28 g of ethyl 2-(benzothiazolyl)acetate was refluxed with 15 g of 1,1,7,7-tetramethyl-8-hydroxy-9-formyljulolidine in 120 mL of acetonitrile containing 2 mL of piperidine as a base catalyst for 15 h. Upon cooling, the precipitated bright orange solid was filtered and washed with some acetonitrile to give 19 g (79% yield) of pure dye C-545T: m.p. 229-230° C.; Tg=100° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]3[C:22]([CH3:23])=[C:21]([CH3:24])[S:20][C:10]=3[NH:11][C:12](=[N:18][NH2:19])[C@@:13]3([CH2:16][C@H:15]3[CH3:17])[N:14]=2)=[CH:4][CH:3]=1.C1N=CN([C:30](N2C=NC=C2)=[O:31])C=1>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]3[C:22]([CH3:23])=[C:21]([CH3:24])[S:20][C:10]=3[N:11]3[C:30](=[O:31])[NH:19][N:18]=[C:12]3[C@@:13]3([CH2:16][C@H:15]3[CH3:17])[N:14]=2)=[CH:4][CH:3]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Cc1sc2c(c1C)C(c1ccc(Cl)cc1)=N[C@]1(C[C@H]1C)C(=NN)N2
Solvent: C1CCOC1
Product: Cc1sc2c(c1C)C(c1ccc(Cl)cc1)=N[C@]1(C[C@H]1C)c1n[nH]c(=O)n1-2
Temperature: 85 °C
Reaction time: 4 h
Yield: 65.9 %

Procedure:
A disposable tube was charged with (1S,2R)-5′-(4-chlorophenyl)-2′-hydrazono-2,6′,7′-trimethyl-1′,2′-dihydrospiro[cyclopropane-1,3′-thieno[2,3-e][1,4]diazepine] (24 mg, 0.067 mmol) and a stir bar. THF (1.5 mL, 0.05 M) was added, followed by CDI (13.01 mg, 0.080 mmol), and the solution was stirred 85° C. 4 h. At 4 h, more CDI (26 mg, 0.160 mmol) was added, and the reaction was stirred at 85° C. The reaction was concentrated and purified by reverse phase chromatography (water/acetonitrile with 0.1% TFA) to give (1S,2R)-4′-(4-chlorophenyl)-2,2′,3′-trimethylspiro[cyclopropane-1,6′-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin]-9′(8′H)-one (2,2,2-trifluoroacetic acid salt) (Compound 222) as a yellow amorphous solid (17 mg). LRMS (M+H)+: 385 m/z. 1H NMR (400 MHz, DMSO-d6) δ 12.08 (s, 1H), 7.49 (d, J=8.90 Hz, 2H), 7.42 (d, J=8.70 Hz, 2H), 2.34 (s, 3H), 1.52 (s, 3H), 1.18 (s, OH), 1.16 (s, 1H), 1.15 (s, 1H), 0.87 (br. s., 2H).
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[N:8]([C:9]([C:11]2[N:12]=[C:13]([CH3:23])[S:14][C:15]=2[C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=2)=[O:10])[CH2:7][C@H:6]2[C@@H:4]1[CH2:5]2.[CH3:24][N:25]1[CH:29]=[C:28]([C:30](O)=[O:31])[C:27]([CH3:33])=[N:26]1>>[Cl:22][C:18]1[CH:17]=[C:16]([C:15]2[S:14][C:13]([CH3:23])=[N:12][C:11]=2[C:9]([N:8]2[CH2:7][C@H:6]3[C@H:4]([CH2:5]3)[C@H:3]2[CH2:2][NH:1][C:30]([C:28]2[C:27]([CH3:33])=[N:26][N:25]([CH3:24])[CH:29]=2)=[O:31])=[O:10])[CH:21]=[CH:20][CH:19]=1
Reactant: Cc1nn(C)cc1C(=O)O
Reactant: Cc1nc(C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CN)c(-c2cccc(Cl)c2)s1
Product: Cc1nc(C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CNC(=O)c2cn(C)nc2C)c(-c2cccc(Cl)c2)s1

Procedure:
prepared by reaction of ((1S,2S,5R)-2-Aminomethyl-3-aza-bicyclo[3.1.0]hex-3-yl)-[5-(3-chloro-phenyl)-2-methyl-thiazol-4-yl]-methanone with 1,3-Dimethyl-1H-pyrazole-4-carboxylic acid. LC-MS (basic): tR=0.78 min; [M+H]+=470.3.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:4]=1[OH:12].[CH3:13][N:14]1[CH2:18][CH2:17][CH2:16][C@H:15]1CO.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[CH3:13][N:14]1[CH2:18][CH2:17][CH2:16][C@@H:15]1[O:12][C:4]1[CH:5]=[C:6]([N+:9]([O-:11])=[O:10])[CH:7]=[CH:8][C:3]=1[O:2][CH3:1]
Reactant: COc1ccc([N+](=O)[O-])cc1O
Reactant: CN1CCC[C@H]1CO
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1ccc([N+](=O)[O-])cc1O[C@H]1CCCN1C
Reaction time: 16 h
Yield: 89.7 %

Procedure:
A solution of 2-methoxy-5-nitrophenol (5.58 g; 0.033 mol), (S)-1-methyl-2-hydroxymethylpyrrolidine (3.45 g; 0.03 mol) and triphenylphosphine (8.65 g; 0.033 mol) in dry THF (80 ml) was cooled to 50 and treated with DEAD (5.2 ml; 0.033 mol) over 15 min. The reaction mixture was allowed to stand at RT for 16 h, then evaporated in vacuo and partitioned 5% NaOH(aq)/Et2O. The organic phase was separated and extracted with 10% HCl(aq). The aqueous extract was washed with Et2O, basified with 40% NaOH(aq) and extracted with Et2O. The organic extracts were washed with H2O, dried over Na2SO4 and evaporated in vacuo to yield the title compound (D43) (6.79 g; 85%) MH+=267.
Reaction SMILES: C[C:2]1[CH:7]=[CH:6]C(S(OC)(=O)=O)=CC=1.CCO/C=[C:17]1\[C:18]([O:20][C:21]([C:23]2[CH:28]=CC=CC=2)=[N:22]\1)=O>C(#N)C>[CH3:28][CH2:23][CH:21]1[O:20][CH2:18][CH2:17][N:22]1[C:2]1([CH2:7][CH3:6])[O:20][CH2:18][CH2:17][N:22]1[C:21]1([CH2:23][CH3:28])[O:20][CH2:18][CH2:17][NH:22]1
Reactant: CCO/C=C1/N=C(c2ccccc2)OC1=O
Reactant: COS(=O)(=O)c1ccc(C)cc1
Solvent: CC#N
Product: CCC1OCCN1C1(CC)OCCN1C1(CC)NCCO1

Procedure:
Loading amount: acetonitrile (36 mL), methyl p-tosylate (0.3 mmol, 0.045 mL), EtOx (96 mmol, 9.7 mL), Yield: 7 g, Degree of polymerization (DP)=302, Polydispersity index (PDI: Mw/Mn)=1.1)
Reaction SMILES: O.[OH-].[Li+].C[O:5][C:6]([CH:8]1[CH2:12][C:11](=[O:13])[N:10]([C:14]2[CH:15]=[CH:16][C:17]3[O:18][CH2:19][C:20](=[O:24])[NH:21][C:22]=3[N:23]=2)[CH2:9]1)=[O:7].Cl>CO>[O:13]=[C:11]1[N:10]([C:14]2[CH:15]=[CH:16][C:17]3[O:18][CH2:19][C:20](=[O:24])[NH:21][C:22]=3[N:23]=2)[CH2:9][CH:8]([C:6]([OH:7])=[O:5])[CH2:12]1
Reactant: COC(=O)C1CC(=O)N(c2ccc3c(n2)NC(=O)CO3)C1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C1COc2ccc(N3CC(C(=O)O)CC3=O)nc2N1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.6 %

Procedure:
An aqueous solution (0.1 ml) of lithium hydroxide monohydrate (8.62 mg, 0.206 mmol) was added to a solution of 5-oxo-1-(3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-6-yl)pyrrolidin-3-carboxylic acid methyl ester (40 mg, 0.137 mmol) in methanol (0.8 ml) and the mixture was stirred overnight at room temperature. The reaction solution was neutralized by adding 1N hydrochloric acid (0.206 ml), methanol was removed under reduced pressure, the obtained residue was triturated with water and the insoluble material was collected by filtration and dried to yield 32.9 mg (87%) of the title compound in the form of a colorless solid.