Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:7](=[O:8])[N:6]([CH3:9])[CH:5]=[C:4]([NH:10][CH:11]([C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=2)[C:12]2[C:13]([C:23]([F:26])([F:25])[F:24])=[N:14][N:15]([CH:20]3[CH2:22][CH2:21]3)[C:16]=2[C:17]([OH:19])=O)[CH:3]=1>C(Cl)Cl>[Cl:1][C:2]1[C:7](=[O:8])[N:6]([CH3:9])[CH:5]=[C:4]([N:10]2[CH:11]([C:27]3[CH:28]=[CH:29][C:30]([Cl:33])=[CH:31][CH:32]=3)[C:12]3[C:13]([C:23]([F:25])([F:26])[F:24])=[N:14][N:15]([CH:20]4[CH2:21][CH2:22]4)[C:16]=3[C:17]2=[O:19])[CH:3]=1
Reactant: Cn1cc(NC(c2ccc(Cl)cc2)c2c(C(F)(F)F)nn(C3CC3)c2C(=O)O)cc(Cl)c1=O
Solvent: ClCCl
Product: Cn1cc(N2C(=O)c3c(c(C(F)(F)F)nn3C3CC3)C2c2ccc(Cl)cc2)cc(Cl)c1=O

Procedure:
The title compound was prepared in analogy to the procedure described in Example 1 using 4-(((5-chloro-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)amino)(4-chlorophenyl)methyl)-1-cyclopropyl-3-(trifluoromethyl)-1H-pyrazole-5-carboxylic acid (Step 44.4).; tR: 1.16 min (LC-MS 2); ESI-MS: 483 [M+H]+ (LC-MS 2); Rf=0.61 (CH2Cl2/5% MeOH); 1H NMR (400 MHz, DMSO-d6) δ ppm 1.08-1.17 (m, 2H) 1.27-1.38 (m, 2H) 3.40 (s, 3H) 3.89-4.09 (m, 1H) 6.27 (s, 1H) 7.25-7.42 (m, 4H) 7.90 (d, J=2.7 Hz, 1H) 7.86 (d, J=2.7 Hz, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9]O)=[C:4]([N+:11]([O-:13])=[O:12])[CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:34]>C(Cl)Cl>[Br:34][CH2:9][CH2:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][C:4]=1[N+:11]([O-:13])=[O:12]
Reactant: BrC(Br)(Br)Br
Reactant: O=[N+]([O-])c1cc(F)ccc1CCO
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: O=[N+]([O-])c1cc(F)ccc1CCBr
Temperature: 0 °C
Reaction time: 8 h
Yield: 88 %

Procedure:
To a solution of 2-(4-fluoro-2-nitro-phenyl)-ethanol (20.7, 0.11 mole) in methylene chloride (500 mL) was added triphenylphosphine (30.0 g, 0.11 mole) and the mixture was cooled to 0° C. Carbon tetrabromide (40.0 g, 0.12 mole) in methylene chloride (100 mL) was added dropwise through an addition funnel. The reaction mixture was stirred at room temperature overnight. The solvent was removed in vacuo and the residue purified by flash column chromatography (silica gel, ethyl acetate:hexanes 3:7) to provide 24.0 g of the title compound as a yellow solid. 1H NMR (CDCl3): 7.70 δ (d, 1H); 7.40 δ (dd, 1H); 7.30 δ (d of t, 1H); 3.65 δ (t, 2H); 3.40 δ (t, 2H).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:17]=[C:18]([C:23]5[CH:28]=[CH:27][C:26]([C:29]#[N:30])=[C:25]([Cl:31])[CH:24]=5)[C:19]([CH3:22])=[CH:20][CH:21]=4)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1.[Cl-].[NH4+].[N-:34]=[N+:35]=[N-:36].[Na+]>CN(C=O)C>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:17]=[C:18]([C:23]5[CH:28]=[CH:27][C:26]([C:29]6[N:34]=[N:35][NH:36][N:30]=6)=[C:25]([Cl:31])[CH:24]=5)[C:19]([CH3:22])=[CH:20][CH:21]=4)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: Cc1ccc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)cc1-c1ccc(C#N)c(Cl)c1
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)cc1-c1ccc(-c2nn[nH]n2)c(Cl)c1
Temperature: 110 °C
Yield: 9 %

Procedure:
To 1-(benzo[d][1,3]dioxol-5-yl)-N-(3′-chloro-4′-cyano-6-methylbiphenyl-3-yl)-cyclopropanecarboxamide was added ammonium chloride (0.13 g, 2.4 mmol), sodium azide (0.156 g, 2.40 mmol) and 1 mL of DMF. The mixture was heated at 110° C. in a microwave reactor for 10 minutes. After cooling, the mixture was filtered and purified by preparative HPLC to provide 1-(benzo[d][1,3]dioxol-5-yl)-N-(3′-chloro-6-methyl-4′-(2H-tetrazol-5-yl)biphenyl-3-yl)cyclopropanecarboxamide (8.6 mg, 9%). ESI-MS m/z calc. 473.1. found 474.3 (M+1)+; retention time 1.86 minutes.
Reaction SMILES: [C:1]1([N:7]2[CH2:11][CH2:10][CH2:9][C@H:8]2[CH2:12][OH:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH:14][C:15]1[CH:22]=[CH:21][CH:20]=[C:19](O)[C:16]=1[CH:17]=[O:18].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[OH:14][C:15]1[CH:22]=[CH:21][CH:20]=[C:19]([O:13][CH2:12][C@@H:8]2[CH2:9][CH2:10][CH2:11][N:7]2[C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:16]=1[CH:17]=[O:18]
Reactant: OC[C@@H]1CCCN1c1ccccc1
Reactant: O=Cc1c(O)cccc1O
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=Cc1c(O)cccc1OC[C@@H]1CCCN1c1ccccc1
Reaction time: 0.17 h
Yield: 20.5 %

Procedure:
To a solution of (S)-(1-phenylpyrrolidin-2-yl)methanol (45 mg, 0.23 mmol) and 2,6-dihydroxybenzaldehyde (60 mg, 0.46 mmol) in THF (1 ml) was added PPh3 (0.12 g, 0.46 mmol), followed by DIAD (90 mg, 0.46 mmol) at room temperature. After stirrer for 10 min, the mixture was concentrated and the residue was purified by column (Hexanes/EtOAc=9:1) to give (S)-2-hydroxy-6-((1-phenylpyrrolidin-2-yl)methoxy)benzaldehyde (14 mg). 1H NMR (400 MHz, CDCl3 (ppm) 11.96 (s, 1H), 10.37 (s, 1H), 7.35 (t, J=8.0 Hz, 1H), 7.25 (m, 2H), 6.73 (m, 3H), 6.53 (d, J=8.4 Hz, 1H), 6.33 (d, J=9.2 Hz, 1H), 4.21 (m, 1H), 4.15 (d, J=3.6 Hz, 1H), 3.83 (t, J=8.0 Hz, 1H), 3.53 (m, 1H), 3.22 (m, 1H), 2.11 (m, 4H); MS (ESI) m/z 298.4
Reaction SMILES: [NH2-].[Li+].[OH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]#[CH:11].I[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].N>O1CCCC1>[OH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]#[C:11][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCI
Reactant: C#Cc1ccccc1O
Agent: N
Agent: [Li+]
Agent: [NH2-]
Solvent: C1CCOC1
Product: CCCCCCC#Cc1ccccc1O
Yield: 80 %

Procedure:
To a grey suspension of lithium amide [lithium shot, (0.59 g, 0.085M) in liquid ammonia (250 ml)] at -30° C. was added 2-hydroxyphenyl acetylene (50 g, 0.042M, prepared by the method of G. A. Russell et al, J. Org. Chem. 31, 248 (1966)) in dry tetrahydrofuran (50 ml). The solution was stirred at reflux for 1 h, then iodohexane (8.91 g, 0.042M), in dry tetrahydrofuran (50 ml) was added dropwise. The reaction was refluxed for 6 h, then the ammonia allowed to evaporate overnight. The resultant pale brown solution was refluxed for 18 h, then cooled and poured into water. Acidified with dilute sulphuric acid and extracted into diethyl ether (twice). The combined organic phases were washed with water (twice), saturated brine and dried (MgSO4). Evaporation in vacuo yielded a red oil which was purified by distillation to give 6.80 g (80%) of the product as a colourless oil. νmax (film) 1463, 1485, 1575, 1608 (weak), 2225 (weak), 3500 cm-1, δ(CDCl3) 0.89 (3H, distorted t, terminal CH3) 1.40 (8 H, m, alkylene chain), 2.43 (2H, t, J 7 Hz, acetylenic CH2), 5.80 (1H, s, OH), 6.87 (2H, m, aromatics) 7.22 (2H, m, aromatics).
Reaction SMILES: C[CH:2]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]2[CH:12]=[C:13]([C:17]([O:19][CH3:20])=[S:18])[S:14][C:15]=2[CH3:16])=[CH:6][CH:5]=1)C.N[C:22]1C=C(C(OC)=S)S[C:26]=1C.C(C1C=CC(B(O)O)=CC=1)(C)C>>[CH3:2][C:4]1[CH:5]=[CH:6][C:7]([NH:10][C:11]2[CH:12]=[C:13]([C:17]([O:19][CH3:20])=[S:18])[S:14][C:15]=2[CH3:16])=[C:8]([CH2:22][CH3:26])[CH:9]=1
Reactant: COC(=S)c1cc(Nc2ccc(C(C)C)cc2)c(C)s1
Reactant: COC(=S)c1cc(N)c(C)s1
Agent: CC(C)c1ccc(B(O)O)cc1
Product: CCc1cc(C)ccc1Nc1cc(C(=S)OC)sc1C
Yield: 12.5 %

Procedure:
Methyl 4-{[4-(methylethyl)phenyl]amino}-5-methylthiothiophene-2-carboxylate: Using a procedure similar to Example 208, step (a), 74.4 mg (0.36 mmol) of methyl 4-amino-5-methylthiothiophene-2-carboxylate was allowed to react with 118 mg (2 equiv, 0.72 mmol) of 4-isopropylphenyl boronic acid to give 14.5 mg (12.5%) of methyl 4-[(4-methylethylphenyl)amino]-5-methylthiothiophene-2-carboxylate. 1H NMR (CDCl3, 400 MHz) δ 1.26 (d, 6H, J=6.2 Hz), 2.39 (s, 3H), 2.89 (m, 1H), 3.89 (s, 3H), 6.98-7.01 (m, 2H), 7.17-7.19 (m, 2H), 7.73 (s, 1H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]2[N:8]3[C:21]4[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=4[C:15]([CH3:23])([CH3:22])[C:14]4[C:9]3=[C:10]([CH:11]=[CH:12][CH:13]=4)[C:4]=2[CH:3]=1.C([Li])CCC.[B:29](OC)([O:32]C)[O:30]C>C1COCC1.C1CCCCC1>[CH3:22][C:15]1([CH3:23])[C:14]2[C:9]3=[C:10]([C:4]4[CH:3]=[C:2]([B:29]([OH:32])[OH:30])[CH:7]=[CH:6][C:5]=4[N:8]3[C:21]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]1=3)[CH:11]=[CH:12][CH:13]=2
Reactant: COB(OC)OC
Reactant: CC1(C)c2ccccc2-n2c3ccc(Br)cc3c3cccc1c32
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: C1CCCCC1
Product: CC1(C)c2ccccc2-n2c3ccc(B(O)O)cc3c3cccc1c32
Temperature: 25 °C

Procedure:
93.9 g (259 mmol) of 3-bromo-8,8-dimethyl-8H-indolo[3,2,1-de]acridine are dissolved in 1500 ml of dry THF, 135 ml (337 mmol) of a 2.5 M solution of n-butyllithium in cyclohexane are added dropwise at −70° C., after 1 h 37 ml of trimethyl borate (336 mmol) are added dropwise, the mixture is warmed to room temperature over the course of 1 h, the solvent is removed, and the residue, which is uniform according to 1H-NMR, is employed in the subsequent reaction without further purification.
Reaction SMILES: [OH:1][C:2]1[CH:6]=[C:5]([CH2:7][C:8]([OH:10])=[O:9])[O:4][N:3]=1.[Cl:11]N1C(=O)CCC1=O>CN(C)C=O>[Cl:11][C:6]1[C:2]([OH:1])=[N:3][O:4][C:5]=1[CH2:7][C:8]([OH:10])=[O:9]
Reactant: O=C(O)Cc1cc(O)no1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Product: O=C(O)Cc1onc(O)c1Cl
Reaction time: 15 h
Yield: 60.1 %

Procedure:
To a solution of 4.3 g (30 mmoles) of 3-hydroxyisoxazol-5-ylacetic acid in 10 ml of N,N-dimethylformamide were added 4.81 g (36 mmole) of N-chlorosuccinimide, with ice-cooling and stirring. The mixture was left to stand at room temperature for 15 hours, after which the N,N-dimethylformamide was distilled off under reduced pressure and ethyl acetate was added. The mixture was then extracted with an aqueous solution of sodium hydrogen carbonate and then the pH of the extract was adjusted to a value below 1.0 by addition of concentrated hydrochloric acid. After drying the solution, the solvent was distilled off and the residue was recrystallized from a 1:5 by volume mixture of ethyl acetate and cyclohexane, to give 3.2 g (60%) of the title compound, melting point 155° C.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([S:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])=[N:5][N:6]=1.[OH:15][CH:16]=[C:17]([O:24][CH3:25])[C:18](OCCC)=O.O>C(Cl)(Cl)Cl>[CH2:8]([S:7][C:4]1[S:3][C:2]2=[N:1][CH:18]=[C:17]([O:24][CH3:25])[C:16](=[O:15])[N:6]2[N:5]=1)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CCCCCCCSc1nnc(N)s1
Reactant: CCCOC(=O)C(=CO)OC
Solvent: O
Solvent: ClC(Cl)Cl
Product: CCCCCCCSc1nn2c(=O)c(OC)cnc2s1
Reaction time: 0.5 h
Yield: 62.8 %

Procedure:
A mixture of 4.7 g of 2-amino-5-heptylthio-1,3,4-thiadiazole, 3.3 g of propyl 3-hydroxy-2-methoxy-2-propenoate and 12 g of polyphosphoric acid was heated to 130°~135° C. and stirred for 30 minutes. After cooling, water and chloroform were added to the mixture and extraction was carried out. The organic layer was washed with a sodium hydrogen carbonate aqueous solution and water respectively, and dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue was separated by silica gel column chromatography using an ethyl acetate/toluene mixture as an eluent. Thus 4.0 g of 2-heptylthio-6-methoxy-5H-1,3,4-thiadiazolo[3,2-a]pyrimidin-5-one was obtained. m.p. 68°~71° C. Yield 64%.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([CH3:9])=[CH:4][N:3]=1.Br[C:11]1[CH:12]=[C:13]([S:17]([NH:20][C:21]([CH3:24])([CH3:23])[CH3:22])(=[O:19])=[O:18])[CH:14]=[CH:15][CH:16]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C(Cl)Cl.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:21]([NH:20][S:17]([C:13]1[CH:14]=[CH:15][CH:16]=[C:11]([NH:8][C:6]2[C:5]([CH3:9])=[CH:4][N:3]=[C:2]([Cl:1])[N:7]=2)[CH:12]=1)(=[O:19])=[O:18])([CH3:24])([CH3:22])[CH3:23]
Reactant: CC(C)(C)NS(=O)(=O)c1cccc(Br)c1
Reactant: Cc1cnc(Cl)nc1N
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: ClCCl
Product: Cc1cnc(Cl)nc1Nc1cccc(S(=O)(=O)NC(C)(C)C)c1
Temperature: 25 °C
Yield: 120.8 %

Procedure:
A mixture of 2-chloro-5-methyl-pyrimidin-4-ylamine (0.4 g, 2.8 mmol), 3-bromo-N-tert-butyl-benzenesulfonamide (1.0 g, 3.4 mmol), Pd2(dba)3 (0.17 g, 0.19 mmol), Xantphos (0.2 g, 3.5 mmol) and cesium carbonate (2.0 g, 6.1 mmol) was suspended in dioxane (25 mL) and heated at reflux under the argon atmosphere for 3 h. The reaction mixture was cooled to room temperature and diluted with DCM (30 mL). The mixture was filtered and the filtrate concentrated in vacuo. The residue was dissolved in EtOAc and hexanes added until solid precipitated. After filtration, the title compound (1.2 g, 98%) was obtained as a light brown solid. It was used in the next step without purification. MS (ES+): m/z 355 (M+H)+.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]([Br:13])[C:10]([OH:12])=[O:11])=[C:5]([O:14][CH2:15][O:16][CH2:17][CH2:18][O:19][CH3:20])[C:4]=1[O:21][CH2:22][O:23][CH2:24][CH2:25][O:26][CH3:27])#[N:2].[C:28]1([C:34]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)=[N+]=[N-])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>C(Cl)Cl>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]([Br:13])[C:10]([O:12][CH:34]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)=[O:11])=[C:5]([O:14][CH2:15][O:16][CH2:17][CH2:18][O:19][CH3:20])[C:4]=1[O:21][CH2:22][O:23][CH2:24][CH2:25][O:26][CH3:27])#[N:2]
Reactant: COCCOCOc1c(C#N)ccc(C(Br)C(=O)O)c1OCOCCOC
Reactant: [N-]=[N+]=C(c1ccccc1)c1ccccc1
Solvent: ClCCl
Product: COCCOCOc1c(C#N)ccc(C(Br)C(=O)OC(c2ccccc2)c2ccccc2)c1OCOCCOC

Procedure:
The product of Step A was dissolved in 10 ml of methylene chloride and 470 mg of diphenyl diazomethane were added. Evaporation was carried out followed by chromatography on silica (eluant: cyclohexane - ethyl acetate (2-1)) to obtain 450 mg of the desired product.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6]Cl.[C:8]([O:12][C:13]([N:15]1[CH2:20][CH2:19][CH:18]([OH:21])[CH2:17][CH2:16]1)=[O:14])([CH3:11])([CH3:10])[CH3:9].C(N(C(C)C)CC)(C)C>O1CCCC1>[C:8]([O:12][C:13]([N:15]1[CH2:20][CH2:19][CH:18]([O:21][CH2:6][O:5][CH2:4][CH2:3][O:2][CH3:1])[CH2:17][CH2:16]1)=[O:14])([CH3:11])([CH3:9])[CH3:10]
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: COCCOCCl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COCCOCOC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 58.7 %

Procedure:
10 ml of a tetrahydrofuran (THF) solution of 1.37 g (11 mmol) of 2-methoxyethoxymethyl chloride was added dropwise to 10 ml of a THF solution of 2.01 g (10 mmol) of N-t-butoxycarbonyl-4-hydroxypiperidine (manufactured by Aldrich) and 2.58 g (20 mmol) of diisopropylethylamine at 0° C. in a nitrogen atmosphere. After the addition, the reaction solution was allowed to reach room temperature, and stirred for one hour. After confirming disappearance of the raw materials by thin-layer chromatography (TLC), the reaction solution was cooled to 0° C. The reaction was then terminated by adding water. The reaction solution was subjected to an extraction operation three times using water and ethyl acetate. The resulting organic layer was washed once with a saturated ammonium chloride solution, washed once with water, washed once with a saturated sodium chloride aqueous solution, and dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, the product was purified by column chromatography to obtain 1.7 g of N-t-butoxycarbonyl-4-[(2-methoxyethoxy)methoxy]piperidine as a colorless liquid (hereinafter referred to as “compound (A-1)”) (yield: 60%).
Reaction SMILES: [CH:1]([C:3]1[N:4]=[CH:5][N:6]2[CH:10]=[CH:9][S:8][C:7]=12)=O.Cl.[NH2:12][OH:13].[OH-].[Na+]>C(O)C>[OH:13][N:12]=[CH:1][C:3]1[N:4]=[CH:5][N:6]2[CH:10]=[CH:9][S:8][C:7]=12
Reactant: NO
Reactant: O=Cc1ncn2ccsc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: ON=Cc1ncn2ccsc12
Reaction time: 1.5 h
Yield: 58.5 %

Procedure:
7-Formylimidazo[5,1-b]thiazole (249 mg) was suspended in 10 ml of ethanol. Hydroxylamine hydrochloride (137 mg) and 2.0 ml of a 1 N aqueous sodium hydroxide solution were added under ice cooling to the suspension. The mixture was stirred at the same temperature for 1.5 hr, and then stirred at room temperature for 3 hr. The reaction solution was concentrated under the reduced pressure until the volume of the reaction solution was reduced to approximately the half of the original volume. The concentrate was adjusted to pH 12 by the addition of a potassium carbonate solution, followed by extraction three times with dichloromethane. The extract was dried over anhydrous magnesium sulfate. The solvent was removed by distillation under the reduced pressure. The residue was purified by column chromatography on silica gel (dichloromethane:ethyl acetate=1:2). Of two main components, the fraction, which had been eluted earlier, was collected to give 160 mg of 7-hydroxyiminomethylimidazo[5,1-b]thiazole (a low-polarity geometrical isomer).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][NH:5][C:6]([C@:8]12[CH2:43][CH2:42][C@@H:41]([C:44]([CH3:46])=[CH2:45])[C@@H:9]1[C@@H:10]1[C@@:23]([CH3:26])([CH2:24][CH2:25]2)[C@@:22]2([CH3:27])[C@@H:13]([C@:14]3([CH3:40])[C@@H:19]([CH2:20][CH2:21]2)[C:18]([CH3:29])([CH3:28])[C:17]([C:30]2[CH:39]=[CH:38][C:33]([C:34]([O:36][CH3:37])=[O:35])=[CH:32][CH:31]=2)=[CH:16][CH2:15]3)[CH2:12][CH2:11]1)=[O:7].Br[CH2:48][CH2:49][CH2:50][C:51]([O:53][CH3:54])=[O:52].C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.C(#N)C>[CH3:54][O:53][C:51](=[O:52])[CH2:50][CH2:49][CH2:48][NH:1][CH2:2][CH2:3][CH2:4][NH:5][C:6]([C@:8]12[CH2:43][CH2:42][C@@H:41]([C:44]([CH3:46])=[CH2:45])[C@@H:9]1[C@@H:10]1[C@@:23]([CH3:26])([CH2:24][CH2:25]2)[C@@:22]2([CH3:27])[C@@H:13]([C@:14]3([CH3:40])[C@@H:19]([CH2:20][CH2:21]2)[C:18]([CH3:29])([CH3:28])[C:17]([C:30]2[CH:31]=[CH:32][C:33]([C:34]([O:36][CH3:37])=[O:35])=[CH:38][CH:39]=2)=[CH:16][CH2:15]3)[CH2:12][CH2:11]1)=[O:7]
Reactant: C=C(C)[C@@H]1CC[C@]2(C(=O)NCCCN)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Reactant: COC(=O)CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: CC#N
Product: C=C(C)[C@@H]1CC[C@]2(C(=O)NCCCNCCCC(=O)OC)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 78 °C

Procedure:
A mixture of methyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(3-aminopropylcarbamoyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate (30 mg, 0.048 mmol), methyl 4-bromobutanoate (25.9 mg, 0.143 mmol) and potassium carbonate (19.78 mg, 0.143 mmol) in dioxane (1 mL) and Acetonitrile (1 mL) was heated up at 78° C. for 3 hours. LCMS indicated the formation of desired product, the reaction mixture was filtered and the clear solution was purified by prep HPLC to give the title compound as a white solid (10 mg, 29%). LCMS: m/e 729.48 (M+H)+, 2.62 min (method 1).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:17]=[C:16](Cl)[N:15]=[C:14]3[C:10]=2[N:11]=[CH:12][N:13]3[CH3:19])=[CH:4][CH:3]=1.O.[NH2:21][NH2:22]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:17]=[C:16]([NH:21][NH2:22])[N:15]=[C:14]3[C:10]=2[N:11]=[CH:12][N:13]3[CH3:19])=[CH:4][CH:3]=1
Reactant: Cn1cnc2c(Nc3ccc(Br)cc3)nc(Cl)nc21
Reactant: NN
Solvent: O
Product: Cn1cnc2c(Nc3ccc(Br)cc3)nc(NN)nc21

Procedure:
Was prepared according to Example 8 from (4-bromo-phenyl)-(2-chloro-9-methyl-9H-purin-6-yl)-amine and hydrazine monohydrate.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][CH2:7][CH2:6][CH:5]2O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][CH2:7][CH:6]=[CH:5]2
Reactant: OC1CCOc2ccc(F)cc21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: Fc1ccc2c(c1)C=CCO2
Yield: 58.3 %

Procedure:
6-Fluorochroman-4-ol (8 g, 48 mmol) and toluene-4-sulphonic acid (1 g) were dissolved in toluene and refluxed over-night with subsequent water removal. The mixture was then cooled and washed with NaHCO3 (aq) and purified by chromatography (silica gel, n-hexane) to give 4.2 g (52%) of pure 6-fluoro-2H-chromene.
Reaction SMILES: C(N(CC)CC)C.Cl.[NH2:9][C:10]1[N:15]=[CH:14][C:13]([C:16]2[C:17]([CH:27]=[O:28])=[N:18][N:19]([CH:21]3[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)[CH:20]=2)=[CH:12][C:11]=1[C:29]1[O:30][C:31]2[CH:37]=[CH:36][CH:35]=[CH:34][C:32]=2[N:33]=1.[C:38](Cl)(=[O:40])[CH3:39]>C(Cl)Cl>[C:38]([N:24]1[CH2:25][CH2:26][CH:21]([N:19]2[CH:20]=[C:16]([C:13]3[CH:14]=[N:15][C:10]([NH2:9])=[C:11]([C:29]4[O:30][C:31]5[CH:37]=[CH:36][CH:35]=[CH:34][C:32]=5[N:33]=4)[CH:12]=3)[C:17]([CH:27]=[O:28])=[N:18]2)[CH2:22][CH2:23]1)(=[O:40])[CH3:39]
Reactant: Nc1ncc(-c2cn(C3CCNCC3)nc2C=O)cc1-c1nc2ccccc2o1
Reactant: CC(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)N1CCC(n2cc(-c3cnc(N)c(-c4nc5ccccc5o4)c3)c(C=O)n2)CC1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
A solution of hydrogen chloride in 2-propanol (2047 μl, 8.19 mmol) at 25° C. was added to tert-butyl 4-[4-[6-amino-5-(1,3-benzoxazol-2-yl)-3-pyridyl]-3-formyl-pyrazol-1-yl]piperidine-1-carboxylate (200 mg). The resulting mixture was stirred at 25° C. for 2 hours. The solid was filtered and washed with isopropanol to afford 4-[6-amino-5-(1,3-benzoxazol-2-yl)-3-pyridyl]-1-(4-piperidyl)pyrazole-3-carbaldehyde hydrochloride (170 mg). A solution of triethylamine (0.171 ml) was added to 4-[6-amino-5-(1,3-benzoxazol-2-yl)-3-pyridyl]-1-(4-piperidyl)pyrazole-3-carbaldehyde hydrochloride (174 mg) dissolved in CH2Cl2 (10 ml) at 0° C. The resulting solution was stirred at 0° C. for 10 minutes. Acetyl chloride (0.032 ml) was added to the mixture at 0° C., then the mixture was stirred at 25° C. for 40 minutes. The mixture was adsorbed on silica gel. The crude product was purified by flash chromatography on silica gel eluting with 1 to 4% methanol in dichloromethane. The solvent was evaporated to dryness to afford 1-(1-acetyl-4-piperidyl)-4-[6-amino-5-(1,3-benzoxazol-2-yl)-3-pyridyl]pyrazole-3-carbaldehyde (148 mg) as a pale beige foam. NMR Spectrum: (CDCl3): 2.02-2.15 (m, 2H), 2.17 (s, 3H), 2.23-2.38 (m, 2H), 2.78-2.88 (m, 1H), 3.25-3.36 (m, 1H), 3.99-4.10 (m, 1H), 4.43-4.55 (m, 1H), 4.76-4.87 (m, 1H), 6.92 (bs, 2H), 7.34-7.41 (m, 2H), 7.59 (dd, 1H), 7.65 (s, 1H), 7.74 (dd, 1H), 8.42 (d, 1H), 8.64 (d, 1H), 10.09 (s, 1H); Mass spectrum: M+H+ 431;
Reaction SMILES: N([O-])=O.[Na+].[N+]([O-])(O)=O.[Cl:9][C:10]1[CH:11]=[C:12]([C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[C:23]([C:26]([C:35]4[CH:40]=[CH:39][C:38]([Cl:41])=[CH:37][CH:36]=4)([C:28]4[N:32]([CH3:33])[C:31](S)=[N:30][N:29]=4)[OH:27])[CH:24]=3)[N:19]=[C:18]([O:42][CH3:43])[CH:17]=2)[CH:13]=[CH:14][CH:15]=1>O.C1COCC1>[Cl:9][C:10]1[CH:11]=[C:12]([C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[C:23]([C:26]([C:35]4[CH:36]=[CH:37][C:38]([Cl:41])=[CH:39][CH:40]=4)([C:28]4[N:32]([CH3:33])[CH:31]=[N:30][N:29]=4)[OH:27])[CH:24]=3)[N:19]=[C:18]([O:42][CH3:43])[CH:17]=2)[CH:13]=[CH:14][CH:15]=1
Reactant: COc1cc(-c2cccc(Cl)c2)c2cc(C(O)(c3ccc(Cl)cc3)c3nnc(S)n3C)ccc2n1
Agent: O=N[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: O=[N+]([O-])O
Product: COc1cc(-c2cccc(Cl)c2)c2cc(C(O)(c3ccc(Cl)cc3)c3nncn3C)ccc2n1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 9 %

Procedure:
Sodium nitrite (0.0095 mol) was added at −70° C. to a solution of nitric acid (10 ml) in water (10 ml). A solution of intermediate (57) (0.0095 mol) in THF (35 ml) was added dropwise carefully. The mixture was stirred at room temperature for 15 minutes, then poured out into ice water, extracted with DCM and washed with potassium carbonate 10%. The organic layer was separated, dried (MgSO4), filtered, and the solvent was evaporated. The residue was purified by column chromatography over silica gel (eluent: CH2Cl2/CH3OH/NH4OH 95/5/0.1; 15–40 μm). The pure fractions were collected and the solvent was evaporated, yielding 3.8 g (61%). A sample (0.5 g) was purified by column chromatography over silica gel (eluent: CH2Cl2/CH3OH/NH4OH 97/3/0.1; 15–40 μm). The pure fractions were collected and the solvent was evaporated, yielding 0.42 g of 4-(3-chlorophenyl)-α-(4-chlorophenyl)-2-methoxy-α-(4-methyl-4H-1,2,4-triazol-3-yl)-6-quinolinemethanol, mp. 155° C. (intermediate 58).