Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=2)[N:5]=[C:4]([N:13]2[CH2:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[S:16](=[O:25])(=[O:24])[CH2:15][CH2:14]2)[CH:3]=1.[NH2:26][CH2:27][CH:28]([OH:31])[CH2:29][NH2:30]>>[NH2:26][CH2:27][CH:28]([OH:31])[CH2:29][NH:30][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=2)[N:5]=[C:4]([N:13]2[CH2:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[S:16](=[O:25])(=[O:24])[CH2:15][CH2:14]2)[CH:3]=1
Reactant: NCC(O)CN
Reactant: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(Cl)c2c1
Product: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(NCC(O)CN)c2c1

Procedure:
The title compound was prepared in analogy to Example 9-1 in Scheme 5 by using 4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy to the one in Example 2-1) and 1,3-diaminopropan-2-ol. MS obsd. (ESI+) [(M+H)+] 427, 1H NMR (400 MHz, CD3OD) δ ppm 7.97 (d, J=2.0 Hz, 1 H), 7.86 (d, J=1.8 Hz, 1 H), 7.62 (t, J=3.7 Hz, 1 H), 7.57 (s, 1 H), 7.44 (t, J=3.8 Hz, 2 H), 7.30-7.27 (m, J=2.5 Hz, 1 H), 6.09 (s, 1 H), 5.15 (s, 2 H), 4.53 (brs, 2 H), 3.97-3.91 (m, J=5.8 Hz, 2 H), 3.58 (t, J=2.4 Hz, 2 H), 3.66-3.41 (m, J=3.3 Hz, 2 H), 2.90 (dd, J=4.2, 0.90 Hz, 1 H), 2.77 (dd, J=5.2, 0.9 Hz, 1 H), 2.42 (s, 3 H).
Reaction SMILES: [C:1]([C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][C:17]=1[OH:18])[CH:14]([C:19]([OH:21])=[O:20])[CH2:13][CH2:12]2)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(O)CCC.S(=O)(=O)(O)O>[CH2:9]([O:20][C:19]([CH:14]1[C:15]2[C:11](=[CH:10][C:9]([C:1](=[O:8])[C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[C:17]([OH:18])[CH:16]=2)[CH2:12][CH2:13]1)=[O:21])[CH2:1][CH2:2][CH3:3]
Reactant: O=C(c1ccccc1)c1cc2c(cc1O)C(C(=O)O)CC2
Agent: O=S(=O)(O)O
Solvent: CCCCO
Product: CCCCOC(=O)C1CCc2cc(C(=O)c3ccccc3)c(O)cc21

Procedure:
A solution of 12 g of 5-benzoyl-6-hydroxy-indane-1-carboxylic acid in 100 ml of n-butanol and 8 drops of concentrated sulphuric acid is boiled for 6 hours under reflux in an anhydrous atmosphere. It is then evaporated to a volume of approx. 20 ml in vacuo and the evaporation residue is partitioned between 3 times 100 ml of methylene chloride and 3 times 100 ml of water. The organic phases are dried over sodium sulphate and evaporated in vacuo. The evaporation residue, when crystallised from cold ether-petroleum ether, gives 5-benzoyl-6-hydroxy-indane-1-carboxylic acid n-butyl ester in the form of yellow platelets of melting point 43°-44° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:26])=[C:6]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=3[F:24])=[CH:12][C:11]=2[Cl:25])=[O:9])[CH:7]=1.[CH3:27][C:28](=[CH2:37])[C:29]([O:31][CH2:32][CH2:33][N:34]=[C:35]=[O:36])=[O:30].O>N1C=CC=CC=1>[Cl:25][C:11]1[CH:12]=[C:13]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=2[F:24])[CH:14]=[CH:15][C:10]=1[C:8]([C:6]1[CH:7]=[C:2]([NH:1][C:35](=[O:36])[NH:34][CH2:33][CH2:32][O:31][C:29](=[O:30])[C:28]([CH3:37])=[CH2:27])[CH:3]=[CH:4][C:5]=1[CH3:26])=[O:9]
Reactant: C=C(C)C(=O)OCCN=C=O
Reactant: Cc1ccc(N)cc1C(=O)c1ccc(Nc2ccc(F)cc2F)cc1Cl
Solvent: c1ccncc1
Solvent: O
Product: C=C(C)C(=O)OCCNC(=O)Nc1ccc(C)c(C(=O)c2ccc(Nc3ccc(F)cc3F)cc2Cl)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Compound 494 (0.055 g, 0.15 mmol) was dissolved in dry pyridine (0.3 mL) and isocyanatoethyl methylacrylate (0.031 mL, 0.22 mmol) was added. The solution was stirred at room temperature for 1 h. H2O was added and the water phase was extracted with EtOAc (×2). The combined organic phases were washed with brine, dried (MgSO4), filtered and concentrated in vacuo. The crude product was purified by flash chromatography using EtOAc/petroleum ether (40-60) 2:1 as the eluent. This afforded the title compound as oil. 13C NMR (CDCl3) δ 196.5, 167.5, 159.2 (dd), 155.8, 155.6 (dd), 148.2, 139.7, 136.3, 135.9, 135.1, 133.9, 132.4, 132.0, 128.6, 126.1, 124.5 (dd), 124.2 (dd), 123.3, 121.2, 116.3, 112.7, 111.6 (dd), 104.9 (dd), 63.9, 39.3, 19.6, 18.2
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[N:9]=[C:10]([C:20]([CH3:23])([CH3:22])[CH3:21])[S:11][C:12]=2[C:13]2[CH:18]=[CH:17][N:16]=[C:15](Cl)[N:14]=2)=[CH:6][CH:5]=[CH:4][C:3]=1[NH:24][S:25]([C:28]1[O:29][CH:30]=[CH:31][CH:32]=1)(=[O:27])=[O:26].[CH3:33][Zn]C.C1(C)C=CC=CC=1>>[Cl:1][C:2]1[C:7]([C:8]2[N:9]=[C:10]([C:20]([CH3:21])([CH3:22])[CH3:23])[S:11][C:12]=2[C:13]2[CH:18]=[CH:17][N:16]=[C:15]([CH3:33])[N:14]=2)=[CH:6][CH:5]=[CH:4][C:3]=1[NH:24][S:25]([C:28]1[O:29][CH:30]=[CH:31][CH:32]=1)(=[O:26])=[O:27]
Reactant: C[Zn]C
Reactant: CC(C)(C)c1nc(-c2cccc(NS(=O)(=O)c3ccco3)c2Cl)c(-c2ccnc(Cl)n2)s1
Solvent: Cc1ccccc1
Product: Cc1nccc(-c2sc(C(C)(C)C)nc2-c2cccc(NS(=O)(=O)c3ccco3)c2Cl)n1

Procedure:
Following a procedure analogous to the procedure described in Example 25 using N-{2-chloro-3-[5-(2-chloro-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]phenyl}-2-furansulfonamide (150 mg, 0.294 mmol) and dimethyl zinc in toluene (0.294 mL, 0.589 mmol), the title compound was obtained as a yellow solid (113 mg, 78% yield). MS (ESI): 489 [M+H]+.
Reaction SMILES: [Br:1][CH:2]([CH2:6][CH2:7][CH2:8][Br:9])[C:3](Br)=[O:4].[C:10]([O:13][CH:14]([CH2:43][O:44][C:45](=[O:47])[CH3:46])[CH2:15][NH:16][C:17]([C:19]1[C:24]([I:25])=[C:23]([NH2:26])[C:22]([I:27])=[C:21]([C:28]([NH:30][CH2:31][CH:32]([O:38][C:39](=[O:41])[CH3:40])[CH2:33][O:34][C:35](=[O:37])[CH3:36])=[O:29])[C:20]=1[I:42])=[O:18])(=[O:12])[CH3:11]>CN(C)C(=O)C>[C:10]([O:13][CH:14]([CH2:43][O:44][C:45](=[O:47])[CH3:46])[CH2:15][NH:16][C:17]([C:19]1[C:24]([I:25])=[C:23]([NH:26][C:3](=[O:4])[CH:2]([Br:1])[CH2:6][CH2:7][CH2:8][Br:9])[C:22]([I:27])=[C:21]([C:28]([NH:30][CH2:31][CH:32]([O:38][C:39](=[O:41])[CH3:40])[CH2:33][O:34][C:35](=[O:37])[CH3:36])=[O:29])[C:20]=1[I:42])=[O:18])(=[O:12])[CH3:11]
Reactant: O=C(Br)C(Br)CCCBr
Reactant: CC(=O)OCC(CNC(=O)c1c(I)c(N)c(I)c(C(=O)NCC(COC(C)=O)OC(C)=O)c1I)OC(C)=O
Solvent: CC(=O)N(C)C
Product: CC(=O)OCC(CNC(=O)c1c(I)c(NC(=O)C(Br)CCCBr)c(I)c(C(=O)NCC(COC(C)=O)OC(C)=O)c1I)OC(C)=O
Reaction time: 1 h
Yield: 95.5 %

Procedure:
2,5-Dibromopentanoyl bromide (11 g, 34 mmol) was added dropwise to a stirred solution of N,N'-bis[2,3-bis(acetyloxy)propyl]-5-amino-2,4,6-triiodo-1,3-benzenedicarboxamide (23.0 g, 26.3 mmol) in N,N-dimethylacetamide (240 ml) at 0°. After the addition, the reaction mixture was stirred at 0° for 1 hour, and then at room temperature for 20 hours. The solvent was removed in vacuo at 45° and the resulting solid was dissolved in ethyl acetate (400 ml). The organic layer was washed with saturated aqueous sodium bicarbonate (1×70 ml), water (1×70 ml) and saturated sodium chloride (1×70 ml). After drying over magnesium sulfate, the solvent was removed in vacuo to obtain a yellow residue (28 g). Purification by column chromatography over silica gel furnished pure N,N'-bis[2,3-bis(acetyloxy)propyl]-5-[(2,5-dibromo-1-oxopentyl)amino]-2,4,6-triiodo-1,3-benzenedicarboxamide as an off-white crystalline compound (20.2 g, yield 69%).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:18]3[C:17]([OH:19])=[C:16]([C:20]#[N:21])[C:15](=[O:22])[NH:14][C:13]=3[S:12][CH:11]=2)=[CH:6][CH:5]=1)([O-])=O.[Cl-].[NH4+].O>C(O)C.[Fe]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[C:18]3[C:17]([OH:19])=[C:16]([C:20]#[N:21])[C:15](=[O:22])[NH:14][C:13]=3[S:12][CH:11]=2)=[CH:8][CH:9]=1
Reactant: N#Cc1c(O)c2c(-c3ccc([N+](=O)[O-])cc3)csc2[nH]c1=O
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: N#Cc1c(O)c2c(-c3ccc(N)cc3)csc2[nH]c1=O
Temperature: 25 °C

Procedure:
To a stirred suspension of 3-(4-nitrophenyl)-4-hydroxy-6-oxo-6,7-dihydrothieno[2,3-b]pyridine-5-carbonitrile (0.054 g, 0.173 mmol) and ammonium chloride (0.007 g, 0.138 mmol) in ethanol: water mixture (2:1, 24 mL) was added iron powder (0.097 g, 1.73 mmol) in a single portion. The reaction mixture was heated at reflux for 16 hours, cooled to room temperature, filtered and the filtrate concentrated under reduced pressure. The residue was taken up in DMSO/MeOH and purified by RP-HPLC. MS (ESI) m/e 281.7 (M−H)+; 1H NMR (400 MHz, DMSO-d6): δ ppm 11.65 (br s, 1H), 7.31 (d, 2H), 6.88 (d, 2H), 6.74 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[CH:14][C:13]2[C:4](=[C:5]([NH2:16])[C:6]3[C:11]([N:12]=2)=[CH:10][CH:9]=[CH:8][CH:7]=3)[CH:3]=1.[C:17](OC(=O)C)(=[O:19])[CH3:18]>C(O)(=O)C>[C:17]([NH:1][C:2]1[CH:15]=[CH:14][C:13]2[C:4](=[C:5]([NH2:16])[C:6]3[C:11]([N:12]=2)=[CH:10][CH:9]=[CH:8][CH:7]=3)[CH:3]=1)(=[O:19])[CH3:18]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ccc2nc3ccccc3c(N)c2c1
Solvent: CC(=O)O
Product: CC(=O)Nc1ccc2nc3ccccc3c(N)c2c1

Procedure:
To a 5 mL rbf equipped with condenser and a nitrogen bubbler were charged 2,9-diaminoacridine (100 mg, 0.48 mmol) and acetic acid (300 μL). To the resulting solution was added acetic anhydride (47 μL, 0.50 mmol). The reaction mixture was heated to reflux for 10 min under a nitrogen atmosphere. LCMS showed only formation of expected product and some traces of starting material. The reaction mixture was concentrated to dryness. NMR showed desired product, alkanes impurities coming from starting material sample and acetic acid left. The residue was dissolved in water and washed with DCM to remove the alkanes impurities. The aqueous layer was lyophilised to afford 2-acetamidyl-9-aminoacridine as a brown solid (130 mg, quantitative). Analyses by 1H NMR and LCMS conformed to structure.
Reaction SMILES: [F:1][C:2]([F:37])([F:36])[C:3]1[CH:4]=[C:5]([CH:29]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:31]=1)[C:6]([N:8]1[CH2:28][CH2:27][C:11]2([N:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[CH3:22])[CH2:14][N:13]([CH2:23][CH2:24]O)[C:12]2=[O:26])[CH2:10][CH2:9]1)=[O:7].[CH3:38][NH:39][CH3:40]>>[F:37][C:2]([F:36])([F:1])[C:3]1[CH:4]=[C:5]([CH:29]=[C:30]([C:32]([F:34])([F:33])[F:35])[CH:31]=1)[C:6]([N:8]1[CH2:9][CH2:10][C:11]2([N:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[CH3:22])[CH2:14][N:13]([CH2:23][CH2:24][N:39]([CH3:40])[CH3:38])[C:12]2=[O:26])[CH2:27][CH2:28]1)=[O:7]
Reactant: Cc1ccccc1N1CN(CCO)C(=O)C12CCN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)CC2
Reactant: CNC
Product: Cc1ccccc1N1CN(CCN(C)C)C(=O)C12CCN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)CC2

Procedure:
The title compound, MS: m/e=557.2 (M+H+), was prepared in accordance with the general method of example 48 from 8-(3,5-bis-trifluoromethyl-benzoyl)-3-(2-hydroxy-ethyl)-1-o-tolyl-1,3,8-triaza-spiro[4.5]decan-4-one and dimethylamine.
Reaction SMILES: Br[CH2:2][C:3]1[C:4]([Cl:11])=[N:5][C:6]([Cl:10])=[C:7]([F:9])[CH:8]=1.[CH:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[NH:20][C:21](=[O:23])[CH3:22])=[CH2:13].[H-].[Na+].O>CN(C=O)C>[Cl:11][C:4]1[C:3]([CH2:2][N:20]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[CH:12]=[CH2:13])[C:21](=[O:23])[CH3:22])=[CH:8][C:7]([F:9])=[C:6]([Cl:10])[N:5]=1
Reactant: C=Cc1ccccc1NC(C)=O
Reactant: Fc1cc(CBr)c(Cl)nc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C=Cc1ccccc1N(Cc1cc(F)c(Cl)nc1Cl)C(C)=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 96 %

Procedure:
To a stirred mixture of 1B (0.5 g, 1.93 mmol) and N-(2-vinyl-phenyl)-acetamide bb (0.314 g, 1.95 mmol) in DMF (5 mL) was added NaH (47 mg, 1.95 mmol) at 0° C. The reaction mixture was stirred for 30 minutes at room temperature, then poured into H2O (50 mL) and extracted with Et2O (20 mL). The Et2O layer was washed with H2O (2×20 mL), dried (MgSO4), filtered and concentrated in vacuo to give 1C (0.63 g, 96%). HPLC Rt=3.212 min. (Column: YMC ODS-A 4.6×50 mm (4 min.); Solvent A=10% MeOH, 90% H2O, 0.1% TFA; Solvent B=90% MeOH, 10% H2O, 0.1% TFA).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[C:12]2[CH2:13][NH:14][CH2:15][CH2:16][N:11]2[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:18][CH2:19][C:20](Br)=[O:21]>C(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:17]=[C:12]2[CH2:13][N:14]([C:20](=[O:21])[CH2:19][Br:18])[CH2:15][CH2:16][N:11]2[N:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Br)CBr
Reactant: c1ccc(COc2cc3n(n2)CCNC3)cc1
Solvent: ClCCl
Product: O=C(CBr)N1CCn2nc(OCc3ccccc3)cc2C1

Procedure:
A solution of 2-(benzyloxy)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine (0.02 g, 0.087 mmol) in a DCM (1 mL) was treated with bromoacetyl bromide (7.6 μL, 17.6 mg, 0.087 mmol) at 0° C. The solvents were evaporated in vacuo to yield 1-(2-benzyloxy-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazin-5-yl)-2-bromo-ethanone as a white solid, that was used in the next step without further purification.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:25][CH3:26])=[C:6]([C@H:8]2[CH2:12][CH2:11][CH2:10][N:9]2[C:13]2[CH:18]=[CH:17][N:16]3[N:19]=[CH:20][C:21]([C:22](O)=[O:23])=[C:15]3[N:14]=2)[CH:7]=1.[O:27]1[CH2:32][CH2:31][N:30]([CH2:33][CH2:34][NH2:35])[CH2:29][CH2:28]1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:25][CH3:26])=[C:6]([C@H:8]2[CH2:12][CH2:11][CH2:10][N:9]2[C:13]2[CH:18]=[CH:17][N:16]3[N:19]=[CH:20][C:21]([C:22]([NH:35][CH2:34][CH2:33][N:30]4[CH2:31][CH2:32][O:27][CH2:28][CH2:29]4)=[O:23])=[C:15]3[N:14]=2)[CH:7]=1
Reactant: COc1ccc(F)cc1[C@H]1CCCN1c1ccn2ncc(C(=O)O)c2n1
Reactant: NCCN1CCOCC1
Product: COc1ccc(F)cc1[C@H]1CCCN1c1ccn2ncc(C(=O)NCCN3CCOCC3)c2n1

Procedure:
Prepared by the method as described in Example 4, using (R)-5-(2-(5-fluoro-2-methoxyphenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (Preparation G) and 2-morpholinoethanamine (1.5 equiv.). The title compound was obtained as a white solid (65% yield). MS (apci) m/z=469.1 (M+H).
Reaction SMILES: CS([C:5]1[NH:9][C:8]2[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=2[N:6]=1)(=O)=O.[Br:14][C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=1.[OH-].[Na+]>>[Br:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][C:5]2[NH:9][C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[N:6]=2)=[CH:17][CH:16]=1
Reactant: Oc1ccc(Br)cc1
Reactant: CS(=O)(=O)c1nc2ccccc2[nH]1
Agent: [Na+]
Agent: [OH-]
Product: Brc1ccc(Oc2nc3ccccc3[nH]2)cc1
Temperature: 120 °C
Reaction time: 15 h
Yield: 69.9 %

Procedure:
A mixture of 2-(methylsulfonyl)-1H-benzo[d]imidazole (5.6 g), 4-bromophenol (24.69 g) and TEA (19.89 mL) was stirred at 120° C. for 15 h. The mixture was added with 8 M NaOH aqueous solution and extracted with AcOEt. The organic layer was separated, washed with water and brine, dried over Na2SO4 and concentrated under reduced pressure. The precipitate was collected by filtration to give the first lot of the titled compound (5.77 g). The filtrate was evaporated, and the precipitate was collected by filtration to give the second lot of the titled compound (0.92 g).
Reaction SMILES: C(OC(=O)[NH:7][CH:8]([CH:37]1[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]1)[C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[CH2:16][C:17]1[C:25]2[C:20](=[CH:21][C:22]([F:26])=[CH:23][CH:24]=2)[N:19]([CH2:27][CH2:28][O:29][CH2:30][CH2:31][O:32][CH2:33][CH2:34][O:35][CH3:36])[CH:18]=1)=[O:10])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:7][CH:8]([CH:37]1[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]1)[C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[CH2:16][C:17]1[C:25]2[C:20](=[CH:21][C:22]([F:26])=[CH:23][CH:24]=2)[N:19]([CH2:27][CH2:28][O:29][CH2:30][CH2:31][O:32][CH2:33][CH2:34][O:35][CH3:36])[CH:18]=1)=[O:10]
Reactant: COCCOCCOCCn1cc(CC2CCCN2C(=O)C(NC(=O)OC(C)(C)C)C2CCCCC2)c2ccc(F)cc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COCCOCCOCCn1cc(CC2CCCN2C(=O)C(N)C2CCCCC2)c2ccc(F)cc21
Reaction time: 2 h
Yield: 97 %

Procedure:
A solution of 82 (250 mg, 0.43 mmol) in DCM (5 mL) was treated with TFA (1 mL) at room temperature. After 2 h, the reaction mixture was concentrated, diluted with EtOAc, washed with 1N aqueous NaOH and brine, dried over Na2SO4, filtered and concentrated to afford 210 mg (100%) of 83 as a light yellow wax. The product was used without further purification.
Reaction SMILES: [NH2:1][C@H:2]([C:5]([OH:7])=[O:6])[CH2:3][SH:4].[C:8]([C:12]1[CH:13]=[C:14]([CH:17]=[C:18]([C:21]([CH3:24])([CH3:23])[CH3:22])[C:19]=1[OH:20])[CH:15]=O)([CH3:11])([CH3:10])[CH3:9]>CO>[C:21]([C:18]1[CH:17]=[C:14]([CH:15]2[NH:1][C@H:2]([C:5]([OH:7])=[O:6])[CH2:3][S:4]2)[CH:13]=[C:12]([C:8]([CH3:11])([CH3:10])[CH3:9])[C:19]=1[OH:20])([CH3:24])([CH3:23])[CH3:22]
Reactant: CC(C)(C)c1cc(C=O)cc(C(C)(C)C)c1O
Reactant: N[C@@H](CS)C(=O)O
Solvent: CO
Product: CC(C)(C)c1cc(C2N[C@H](C(=O)O)CS2)cc(C(C)(C)C)c1O
Temperature: 25 °C
Yield: 22.5 %

Procedure:
A mixture of cysteine (Aldrich, 2.0 g, 17.1 mmol) and 3,5-di-tert-butyl-4-hydroxybenzaldehyde (Aldrich, 4.0 g, 17.1 mmol) in methanol (100 mL) was warmed at reflux for 2.25 h. The reaction mixture was cooled to ambient temperature and the solid that formed upon cooling was collected by filtration. The solid was washed with methanol and recrystallized from a mixture of ethanol/ethyl acetate. Recrystallization from ethanol gave 1.3 g (22% yield) of (4R)-2-(3,5-di-tert-butyl-4-hydroxyphenyl)-4-thiazolidine carboxylic acid as an off white solid, m.p. 163°-165° C.
Reaction SMILES: [NH2:1][C:2]([CH3:15])([CH2:5][N:6]([CH2:13][CH3:14])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH2:3][OH:4].[N:16]#[C:17]Br>>[CH2:13]([N:6]([CH2:5][C:2]1([CH3:15])[CH2:3][O:4][C:17]([NH2:16])=[N:1]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH3:14]
Reactant: CCN(CC(C)(N)CO)c1ccccc1
Reactant: N#CBr
Product: CCN(CC1(C)COC(N)=N1)c1ccccc1

Procedure:
In analogy to example 1.d (RS)-2-amino-3-(ethyl-phenyl-amino)-2-methyl-propan-1-ol was reacted with cyanogen bromide to give (RS)-4-[(ethyl-phenyl-amino)-methyl]-4-methyl-4,5-dihydro-oxazol-2-ylamine as a colourless gum. MS (ISP): 234.0 ([M+H]+).
Reaction SMILES: [NH2:1][C:2]1[C:3]([Cl:17])=[N:4][C:5]2[C:10]([C:11]=1[NH:12][CH2:13][CH2:14][CH2:15][CH3:16])=[CH:9][CH:8]=[CH:7][CH:6]=2.[CH3:18][O:19][CH2:20][CH2:21][C:22](Cl)=[O:23]>>[CH2:13]([NH:12][C:11]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=[C:3]([Cl:17])[C:2]=1[NH:1][C:22](=[O:23])[CH2:21][CH2:20][O:19][CH3:18])[CH2:14][CH2:15][CH3:16]
Reactant: COCCC(=O)Cl
Reactant: CCCCNc1c(N)c(Cl)nc2ccccc12
Product: CCCCNc1c(NC(=O)CCOC)c(Cl)nc2ccccc12

Procedure:
Using the general method of Example 110, 3-amino-4-butylamino-2-chloroquinoline (10 g, 0.04 mole, Example 113) was reacted with 3-methoxypropionyl chloride to provide 10.3 g of the desired product as a yellow solid.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[N:5]=[CH:6][C:7]2[C:12]([CH:13]=1)=[CH:11][C:10]([C:14]1[CH:15]=[N:16][N:17]([CH2:19][C:20]([CH3:23])([OH:22])[CH3:21])[CH:18]=1)=[CH:9][CH:8]=2.I[CH3:25]>C1COCC1.CCOC(C)=O>[Cl:3][C:4]1[N:5]=[CH:6][C:7]2[C:12]([CH:13]=1)=[CH:11][C:10]([C:14]1[CH:15]=[N:16][N:17]([CH2:19][C:20]([O:22][CH3:25])([CH3:23])[CH3:21])[CH:18]=1)=[CH:9][CH:8]=2
Reactant: CI
Reactant: CC(C)(O)Cn1cc(-c2ccc3cnc(Cl)cc3c2)cn1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(C)(C)Cn1cc(-c2ccc3cnc(Cl)cc3c2)cn1
Reaction time: 0.25 h
Yield: 56.8 %

Procedure:
NaH (60%, 18 mg) was added to a solution of 1-(4-(3-chloroisoquinolin-6-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol (Preparation 22, 96 mg, 0.318 mmol) in THF (6 mL). After stirring for 15 minutes, iodomethane (0.1 mL, 0.57 mmol) was added. The resulting solution was stirred at 60° C. under microwave irradiation for 60 minutes. The reaction mixture was diluted with EtOAc, filtered and purified using Biotage silica gel column chromatography eluting with 25% EtOAc/cyclohexane to give the title compound as yellow oil (57 mg, 57%).
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([C:16]([F:19])([F:18])[F:17])=[N:14][N:15]=3)[N:12]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[F:20][CH:21]([F:31])[O:22][C:23]1[CH:24]=[C:25]([CH:28]=[CH:29][CH:30]=1)[CH:26]=O>>[F:20][CH:21]([F:31])[O:22][C:23]1[CH:24]=[C:25]([CH2:26][N:4]2[CH2:3][CH2:2][N:1]([C:7]3[CH:8]=[CH:9][C:10]4[N:11]([C:13]([C:16]([F:17])([F:18])[F:19])=[N:14][N:15]=4)[N:12]=3)[CH2:6][CH2:5]2)[CH:28]=[CH:29][CH:30]=1
Reactant: O=Cc1cccc(OC(F)F)c1
Reactant: FC(F)(F)c1nnc2ccc(N3CCNCC3)nn12
Product: FC(F)Oc1cccc(CN2CCN(c3ccc4nnc(C(F)(F)F)n4n3)CC2)c1

Procedure:
Reductive amination of 6-(piperazin-1-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine with 3-(difluoromethoxy)benzaldehyde was carried out according to General Synthetic Method 7. The crude product was purified by hplc using a Waters XBridge Prep C18 OBD column, 5μ silica, 30 mm diameter, 100 mm length eluted with decreasingly polar mixtures of water (containing 0.1% aqueous ammonia) and acetonitrile as eluents to give 6-[4-[[3-(difluoromethoxy)phenyl]methyl]piperazin-1-yl]-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[C:10](I)=[CH:9][N:8]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[C:4]=2[N:5]=[CH:6][N:7]=1.[CH3:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([SH:28])=[CH:24][CH:23]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.[Cu]I>[Cl:1][C:2]1[C:3]2[C:10]([S:28][C:25]3[CH:26]=[CH:27][C:22]([O:21][CH3:20])=[CH:23][CH:24]=3)=[CH:9][N:8]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: C[Si](C)(C)CCOCn1cc(I)c2c(Cl)ncnc21
Reactant: COc1ccc(S)cc1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(Sc2cn(COCC[Si](C)(C)C)c3ncnc(Cl)c23)cc1
Temperature: 50 °C
Reaction time: 8 h
Yield: 43 %

Procedure:
4-Chloro-5-iodo-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (110 mg, 0.27 mmol) was treated with 4-methoxybenzenethiol (50 μl, 0.40 mmol), copper(I) iodide (77 mg, 0.40 mmol) and potassium carbonate (74 mg, 0.54 mmol) in 2.2 mL dimethylformamide according to method described in Preparation 86 but stirring the reaction mixture at 50° C. overnight. The residue was purified using SP1® Purification System (0% to 15%, hexane-ethyl acetate) to give 57 mg (43% yield, 85% purity) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][C:10]1[C:11]([CH2:16][CH3:17])=[N:12][NH:13][C:14]=1[NH2:15].O=[C:19]([CH:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1)[CH2:20][C:21](OCC)=[O:22]>C(O)(=O)C>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][C:10]1[C:11]([CH2:16][CH3:17])=[N:12][N:13]2[C:21]([OH:22])=[CH:20][C:19]([CH:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)=[N:15][C:14]=12
Reactant: CCc1n[nH]c(N)c1Cc1cccc(Cl)c1Cl
Reactant: CCOC(=O)CC(=O)C1CCOCC1
Solvent: CC(=O)O
Product: CCc1nn2c(O)cc(C3CCOCC3)nc2c1Cc1cccc(Cl)c1Cl
Reaction time: 8 h

Procedure:
To a suspension of 4-[(2,3-dichlorophenyl)methyl]-3-ethyl-1H-pyrazol-5-amine (257 mg, 0.95 mmol) in acetic acid (2 mL) was added ethyl 3-oxo-3-(tetrahydro-2H-pyran-4-yl)propanoate (200, 1.0 mmol). The reaction vessel was sealed, stirred and irradiated (microwave) at 140° C. for 40 minutes. Reaction mixture was cooled and diluted with acetic acid (2 mL). It was stood still overnight. The precipitate was collected, washed with acetic acid (1 mL), then with methanol (2 mL×2) and dried to afford expected compound. (288 mg, 71%); LC/MS: MS (ES+) m/e 406 (MH+); 1H NMR (400 MHz, DMSO-d6) δ ppm 1.06 (t, J=7.45 Hz, 3H) 1.76 (br. s., 4H) 1.91 (s, 3H) 2.45 (q, J=7.41 Hz, 2H) 3.39 (br. s., 2H) 4.07 (s, 2H) 5.56 (s, 1H) 6.87 (s, 1H) 7.25 (s, 1H) 7.51 (s, 1H).
Reaction SMILES: Br[C:2]1[C:3]([CH3:11])=[C:4]2[C:8](=[N:9][CH:10]=1)[NH:7][CH2:6][CH2:5]2.[Cu][C:13]#[N:14]>CN(C=O)C>[C:13]([C:2]1[C:3]([CH3:11])=[C:4]2[C:8](=[N:9][CH:10]=1)[NH:7][CH2:6][CH2:5]2)#[N:14]
Reactant: Cc1c(Br)cnc2c1CCN2
Reactant: N#C[Cu]
Solvent: CN(C)C=O
Product: Cc1c(C#N)cnc2c1CCN2
Temperature: 180 °C

Procedure:
A stirred mixture of 5-bromo-4-methyl-7-azaindoline (270 mg, 1.27 mmol) and copper (I) cyanide (135 mg, 1.5 mmol) in DMF (0.3 mL) was heated to 180° C. for 4 h. The reaction mixture was cooled and partitioned between 5% potassium cyanide solution and ethyl acetate. The organic layer was dried (Na2SO4) and evaporated in vacuo. The residue was purified by flash column chromatography (50% ethyl acetate/hexanes) to give the title compound:
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][C:8](=[O:12])[NH:9]2)=[CH:4][CH:3]=1.[C:13]1([S:19]([CH2:21][CH2:22][CH2:23][CH2:24]Br)=[O:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[C:13]1([S:19]([CH2:21][CH2:22][CH2:23][CH2:24][O:1][C:2]2[CH:11]=[C:10]3[C:5]([CH2:6][CH2:7][C:8](=[O:12])[NH:9]3)=[CH:4][CH:3]=2)=[O:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C1CCc2ccc(O)cc2N1
Reactant: O=S(CCCCBr)c1ccccc1
Product: O=C1CCc2ccc(OCCCCS(=O)c3ccccc3)cc2N1

Procedure:
Prepared analogous to Example 4 from 7-hydroxy-3,4-dihydro-carbostyril (see N. Shigematsu et al., Chem. Pharm. Bull. 1961, 970-975) and 4-phenylsulfinyl-butyl bromide.