Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.Cl.[CH3:14][O:15][C:16](=[O:22])[C@@H:17]1[CH2:21][CH2:20][CH2:19][NH:18]1.[CH2:23]([N:26]([C:31]([O:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:32])[CH2:27][C:28](O)=[O:29])[CH:24]=[CH2:25].C(N(CC)CC)C>ClCCl>[CH3:14][O:15][C:16](=[O:22])[C@@H:17]1[CH2:21][CH2:20][CH2:19][N:18]1[C:28](=[O:29])[CH2:27][N:26]([CH2:23][CH:24]=[CH2:25])[C:31]([O:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:32]
Reactant: COC(=O)[C@@H]1CCCN1
Reactant: C=CCN(CC(=O)O)C(=O)OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CCN(CC(=O)N1CCC[C@H]1C(=O)OC)C(=O)OCc1ccccc1
Yield: 238.9 %

Procedure:
1-(3-Dimethylaminopropyl-3-ethylcarbodiimide hydrochloride (EDCI) (0.453 g, 2.36 mmol) was added to a solution of proline methyl ester hydrochloride 30 (0.356 g, 2.15 mmol), acid 55 (0.590 mmol, 2.35 mmol) and triethylamine (0.481 g, 4.73 mmol) in dichloromethane (20 cm3) at 0° C. The resultant solution was stirred for 19 h, washed with 2M aqueous hydrochloric acid and saturated aqueous sodium hydrogen carbonate, dried (MgSO4) and the solvent removed to yield an oil which was purified by chromatography (silica gel, hexanes:ethyl acetate, 2:1, 1:1) to afford protected dipeptide 56 (0.508 g, 66%) as a colourless oil. Dipeptide 56 was shown to be a 76:24 trans:cis mixture of conformers by 13C NMR analysis (the ratio was estimated by integration of signals at δ22.0 and 24.5, 24.7, assigned to the Proγ-C atoms of the minor and major conformers respectively). In addition, restricted rotation about the GlyN-CO carbamate bond was also observed resulting in a further 1:1 mixture of conformers: [α]D −54.6 (c 1.17 in CH2Cl2); δH (400 MHz; CDCl3; Me4Si) 1.81-2.14 (4H, m, ProβH2, Proγ-H2), 3.29-3.58 (2H, m, Proδ-H2), 3.64, 3.66, 3.69* (3H, s, OCH3), 3.84-4.20 [4H, m, CH2(allyl), Glyα-H2], 4.40-4.48 (1H, m, Proα-H), 5.07-5.17 (4H, m, OCH2Ph, ═CH2), 5.69-5.81 (1H, m, C(H)═CH2) and 7.24-7.30 (m, 5H, Ph); δC (100 MHz; CDCl3) 22.0* (CH2, Proγ-C), 24.62, 24.73 (CH2, Proγ-C), 28.66, 28.73 (CH2, Proβ-C), 31.1,* 31.3* (CH2, Proβ-C), 45.93, 45.98 (CH2, ProδC), 46.5* (CH2, Proδ-C), 47.5, 48.0 (CH2, Glyα-C), 50.0, 50.6 [CH2, CH2(allyl)], 50.0,* 50.6* [CH2, CH2(allyl)], 52.0, (CH3, OCH3), 52.31,* 52.5* (CH3, OCH3), 58.4,* 58.5* (CH, Proα-C), 58.8 (CH, Proα-C), 67.2, 67.3 (CH2, OCH2Ph), 117.0, 117.5 (CH2, ═CH2), 127.5, 127.7, 127.8, 128.3, (CH, Ph), 133.2, 133.4 (CH, C(H)═CH2) 136.4, 136.5 (quat., Ph), 155.8, 156.3, (quat., NCO2), 167.1 (quat., Gly-CO), 167.4,* 167.5* (quat., Gly-CO). 172.0,* 172.2* (quat., Pro-CO) and 172.3, 172.4 (quat., Pro-CO); m/z (EI+) 360.1676 (M+. C19H24N2O5 requires 360.1685).
Reaction SMILES: [CH2:1]([C:13]1[CH:21]=[CH:20][CH:19]=[CH:18][C:14]=1[C:15](O)=[O:16])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].S(Cl)([Cl:24])=O.C([Li])CCC.Cl>C(Cl)Cl>[CH2:1]([C:13]1[CH:21]=[CH:20][CH:19]=[CH:18][C:14]=1[C:15]([Cl:24])=[O:16])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: O=S(Cl)Cl
Reactant: CCCCCCCCCCCCc1ccccc1C(=O)O
Agent: Cl
Agent: [Li]CCCC
Solvent: ClCCl
Product: CCCCCCCCCCCCc1ccccc1C(=O)Cl
Temperature: -20 °C
Reaction time: 1 h

Procedure:
2-Dodecylbenzoyl chloride was prepared from 2-dodecylbenzoic acid (4.06 g, 14 mmoles) and excess thionyl chloride in methylene chloride at 23° C. for 1 hour. Following evaporation of the solvents, the acid chloride was used without purification. A solution of this acid chloride in tetrahydrofuran (15 ml) was added to the cold solution of dianion prepared above, followed by an additional amount of 2.12M n-butyl lithium (6.6 ml). The solution was warmed to -20° C., stirred for 1 hour and poured into cold 1N hydrochloric acid. The mixture was extracted with diethyl ether. The extracts were washed with water, dried and evaporated. The crude product was recrystallized from acetonitrile.
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.[NH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(N(CC)C(C)C)(C)C>C(O)CCC>[NH:10]([C:3]1[C:2]([Br:1])=[CH:7][N:6]=[C:5]([Cl:8])[N:4]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Nc1ccccc1
Reactant: Clc1ncc(Br)c(Cl)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: Clc1ncc(Br)c(Nc2ccccc2)n1

Procedure:
A solution of 5-bromo-2,4-dichloropyrimidine (6.84 g, 30.0 mmol), aniline (2.79 g, 30.0 mmol) and N,N-diisopropylethylamine (3.87 g, 30.0 mmol) in n-butanol (75 ml) was heated under reflux for 4 hours. Volatile material was removed by evaporation and the residue was dissolved in DCM (100 ml). The solution was washed with water (3×100 ml) and saturated brine (100 ml) and dried. Volatile material was removed by evaporation and the residue was purified by column chromatography, eluting with 15% ethyl acetate/isohexane, to give the product as an oil which solidified on standing (5.12 g, 60%). NMR: 7.1 (t, 1H), 7.4 (t, 2H),7.55 (d,2H), 8.4 (s,1H), 9.2 (br s, 1H); MS (MH+): 284, 286, 288.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:12][C:11](=[O:13])[N:10]([CH:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[CH2:9][CH2:8][C:7]=2[CH:20]=1.[CH2:21]([N:28]([CH2:38][C:39]([F:42])([F:41])[F:40])[C:29]([C:31]1[CH:36]=[C:35](Cl)[N:34]=[CH:33][N:32]=1)=[O:30])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH2:21]([N:28]([CH2:38][C:39]([F:42])([F:41])[F:40])[C:29]([C:31]1[CH:36]=[C:35]([N:17]2[CH2:18][CH2:19][CH:14]([N:10]3[CH2:9][CH2:8][C:7]4[CH:20]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=4[NH:12][C:11]3=[O:13])[CH2:15][CH2:16]2)[N:34]=[CH:33][N:32]=1)=[O:30])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=C(c1cc(Cl)ncn1)N(Cc1ccccc1)CC(F)(F)F
Reactant: COc1ccc2c(c1)CCN(C1CCNCC1)C(=O)N2
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)CCN(C1CCN(c3cc(C(=O)N(Cc4ccccc4)CC(F)(F)F)ncn3)CC1)C(=O)N2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
44 mg (0.16 mmol) 7-methoxy-3-piperidin-4-yl-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-one were added to 50 mg (0.15 mmol) 6-chloropyrimidine-4-carboxylic acid-benzyl-(2,2,2-trifluorethyl)-amide and 34 μL (0.20 mmol) DIPEA in 5 mL DMF. The reaction mixture was stirred for 2 h at RT. The reaction mixture was purified by preparative HPLC-MS. The product fractions were combined and evaporated down i. vac.
Reaction SMILES: OO.[F:3][C:4]([F:9])([F:8])[C:5]([O-:7])=[O:6].[K+].[F:11][C:12]([F:23])([F:22])[C:13]([O:15]C(=O)C(F)(F)F)=[O:14]>FC(F)(F)C(O)=O>[F:3][C:4]([F:9])([F:8])[C:5]([O:7][O:15][C:13](=[O:14])[C:12]([F:23])([F:22])[F:11])=[O:6]
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Reactant: O=C([O-])C(F)(F)F
Agent: OO
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Product: O=C(OOC(=O)C(F)(F)F)C(F)(F)F

Procedure:
A solution of bis(trifluoroacetyl) peroxide in trifluoroacetic acid was prepared by addition of H2O2 (95%, 1.61 g, 45.0 mmol H2O2) dropwise into a well-stirred solution of potassium trifluoroacetate (6.8 mg, 0.045 mmol) in freshly distilled bis(trifluoroacetic) anhydride (21 g, 100 mmol) at 0° C. A 31% (mol) solution of bis(trifluoroacetyl) peroxide in the trifluoroacetic acid was obtained.
Reaction SMILES: B(F)(F)F.CC[O:7]CC.[Br:10][C:11]1[C:20]2[C:19]([CH3:21])=[CH:18][CH2:17][CH2:16][C:15]=2[CH:14]=[CH:13][C:12]=1[NH:22][S:23]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[F:32])(=[O:25])=[O:24]>C1COCC1>[Br:10][C:11]1[C:20]2[C@H:19]([CH3:21])[C@@H:18]([OH:7])[CH2:17][CH2:16][C:15]=2[CH:14]=[CH:13][C:12]=1[NH:22][S:23]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[F:32])(=[O:25])=[O:24]
Reactant: CC1=CCCc2ccc(NS(=O)(=O)c3ccccc3F)c(Br)c21
Reactant: CCOCC
Agent: FB(F)F
Solvent: C1CCOC1
Product: C[C@H]1c2c(ccc(NS(=O)(=O)c3ccccc3F)c2Br)CC[C@@H]1O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 57 %

Procedure:
A mixture of R-[N,N′-bis(monoisopinocampheylborane)-N,N,N′,N′-tetramethylethylenediamine] (1.25 g, 3.0 mmol) in THF (5 mL) was treated with boron trifluoride etherate, stirred at room temperature for 1.5 hours, and filtered. The filter cake was washed with THF (2.5 mL). Half of the solution containing the free isopinocamphenylborane (1.5 mmol) was cooled to −25° C., treated with a solution of Example 275D (500 mg, 1.25 mmol) in THF (3 mL), stirred at −20° C. for 48 hours, warmed to 0° C., and quenched with methanol (0.5 mL). The solution was treated with 3M NaOH (1.1 mL), followed by 30% H2O2 (0.9 mL) dropwise, stirred for 1 hour at 50° C., cooled to room temperature, extracted with diethyl ether, dried (Na2SO4), filtered, and concentrated. The concentrate was purified by flash column chromatography on silica gel with 30% acetone/hexanes to give 300 mg (57% yield). MS (ESI) m/e 412 (M−H)−; 1H NMR (300 MHz, DMSO-d6) δ 10.02 (s, 1H), 7.69 (m, 1H), 7.63 (dt, 1H), 7.42 (m, 1H), 7.30 (dt, 1H), 7.0 (d, 1H), 6.92 (d, 1H), 4.73 (d, 1H), 3.85 (m, 1H), 2.95 (m, 1H), 2.82 (m, 1H), 2.6 (m, 1H), 1.81 (m, 1H), 1.69 (m, 1H), 0.98 (d, 3H).
Reaction SMILES: CO[C:3]([C:5]1[C:6](=[O:17])[O:7][C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([Cl:16])[CH:9]=2)=[O:4].[NH2:18][C@H:19]([C:21]([OH:23])=[O:22])[CH3:20].C[O-].[Na+].Cl>COCCO>[Cl:16][C:10]1[CH:9]=[C:8]2[C:13]([C:14]([OH:15])=[C:5]([C:3]([NH:18][C@@H:19]([CH3:20])[C:21]([OH:23])=[O:22])=[O:4])[C:6](=[O:17])[O:7]2)=[CH:12][CH:11]=1
Reactant: COC(=O)c1c(O)c2ccc(Cl)cc2oc1=O
Reactant: C[C@H](N)C(=O)O
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: COCCO
Product: C[C@H](NC(=O)c1c(O)c2ccc(Cl)cc2oc1=O)C(=O)O

Procedure:
A mixture of 125 mg of 7-chloro-4-hydroxy-2-oxo-2H-chromene-3-carboxylic acid methyl ester (0.5 mmol), 534 mg of L-alanine (6 mmol), and 270 mg of sodium methoxide (5 mmol) in 8 mL of 2-methoxyethanol was heated at reflux for 18 hours. The mixture was cooled and acidified with 20 mL of 1 N HCl to precipitate a white solid. The solid was collected on a glass fitted filter, washed twice with water, and dried under vacuum to 129 mg of a white solid. MS: (+) m/z 313.96/311.95 (M+1, 35/37Cl)
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:13]3[CH:14]=[CH:15][C:16](OS(C(F)(F)F)(=O)=O)=[CH:17][C:12]=3[S:11][N:10]=2)=[CH:5][CH:4]=1.[CH3:28][C:29]([N:33]([CH2:35][CH2:36][O:37][CH3:38])[CH3:34])([CH3:32])[C:30]#[CH:31]>>[CH3:32][C:29]([N:33]([CH2:35][CH2:36][O:37][CH3:38])[CH3:34])([CH3:28])[C:30]#[C:31][C:16]1[CH:15]=[CH:14][C:13]2[C:9]([C:6]3[CH:5]=[CH:4][C:3]([C:2]([F:26])([F:27])[F:1])=[CH:8][CH:7]=3)=[N:10][S:11][C:12]=2[CH:17]=1
Reactant: C#CC(C)(C)N(C)CCOC
Reactant: O=S(=O)(Oc1ccc2c(-c3ccc(C(F)(F)F)cc3)nsc2c1)C(F)(F)F
Product: COCCN(C)C(C)(C)C#Cc1ccc2c(-c3ccc(C(F)(F)F)cc3)nsc2c1

Procedure:
In analogy to example 14.1, Trifluoro-methanesulfonic acid 3-(4-trifluoromethyl-phenyl)-benzo[d]isothiazol-6-yl ester and (1,1-Dimethyl-prop-2-ynyl)-(2-methoxy-ethyl)-methyl-amine were converted to yield {1,1-Dimethyl-3-[3-(4-trifluoromethyl-phenyl)-benzo[d]isothiazol-6-yl]-prop-2-ynyl}-(2-methoxy-ethyl)-methyl-amine as brown oil, MS: 433 (MH+).
Reaction SMILES: C([O:3][C:4](=O)[C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[C:7]([S:12](=[O:15])(=[O:14])[NH2:13])[CH:6]=1)C.[BH4-].[Li+]>O1CCCC1.O>[Cl:11][C:8]1[CH:9]=[CH:10][C:5]([CH2:4][OH:3])=[CH:6][C:7]=1[S:12]([NH2:13])(=[O:15])=[O:14]
Reactant: CCOC(=O)c1ccc(Cl)c(S(N)(=O)=O)c1
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: NS(=O)(=O)c1cc(CO)ccc1Cl
Temperature: 4 °C
Reaction time: 18 h
Yield: 88.9 %

Procedure:
To a solution of 4-chloro-3-sulfamoyl-benzoic acid ethyl ester (46.95 g, 166 mmol) in 500 mL of dry tetrahydrofuran is added dropwise, with stirring, 199 mL of a 2 M solution of lithium borohydride in tetrahydrofuran. The mixture is stirred and refluxed for 5 hr, then left at room temperature for 18 h, and is then carefully diluted with 400 mL of water. The mixture is cooled to 4° C. for 24 hours and filtered to yield 32.7 g (82%) of the title compound as an off-white solid.
Reaction SMILES: [O:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4](=[O:5])[CH2:3][CH:2]1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[C:18]([NH:21][C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=1)[CH:25]=O)(=[O:20])[CH3:19]>N1CCCCC1.C(Cl)(Cl)Cl>[C:18]([NH:21][C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=1)[CH:25]=[C:3]1[C:4](=[O:5])[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[O:1][CH:2]1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)(=[O:20])[CH3:19]
Reactant: O=C1CC(c2ccccc2)Oc2ccccc21
Reactant: CC(=O)Nc1cccc(C=O)c1
Solvent: C1CCNCC1
Solvent: ClC(Cl)Cl
Product: CC(=O)Nc1cccc(C=C2C(=O)c3ccccc3OC2c2ccccc2)c1

Procedure:
A solid mixture of 9 g flavanone, 7.2 g 3-acetylaminobenzaldehyde and 5 drops piperidine is heated at 150°-160° C. for 3 hours. After allowing to cool, the crude brown glass is dissolved in chloroform and eluted from silicagel with chloroform. The pale yellow oil, obtained on evaporation of the solvent is crystallized from hexane and ethyl acetate to give 3(3-acetylaminobenzylidene)-flavanone as a cream coloured solid; m.p. 172°-173° C.
Reaction SMILES: [H-].[Na+].[OH:3][CH2:4][CH2:5][CH2:6][C:7]([O-:9])=[O:8].[Na+].Br[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.Cl>CN(C)C=O>[C:17]1([CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][O:3][CH2:4][CH2:5][CH2:6][C:7]([OH:9])=[O:8])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C([O-])CCCO
Reactant: BrCCCCCc1ccccc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(O)CCCOCCCCCc1ccccc1
Temperature: 60 °C
Yield: 2.7 %

Procedure:
Sodium hydride (60% dispersion in mineral oil, 228 mg, 5.7 mmol) was added to a solution of sodium 4-hydroxybutyrate (600 mg, 4.76 mmol) in N,N-dimethylformamide (5 mL). The reaction was heated at 60° C. for 1 h, then (5-bromopentyl)-benzene (1.15 g, 5.08 mmol) was added, then after 3 weeks 1 M aq. hydrochloric acid solution was added and the reaction mixture evaporated. Chromatography (SiO2; heptane-ethyl acetate gradient) produced 4-(5-phenyl-pentyloxy)-butyric acid (32 mg, 3%) as a colorless oil.
Reaction SMILES: [F:1][C:2]1[C:7]([S:8]([C:11]([F:14])([F:13])[F:12])(=[O:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1.[C:21](=O)([O-])[O-].[K+].[K+].IC>C(#N)C>[F:1][C:2]1[C:7]([S:8]([C:11]([F:14])([F:13])[F:12])(=[O:9])=[O:10])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:15]1[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]1
Reactant: O=C([O-])[O-]
Reactant: O=S(=O)(c1cccc(C2CCNCC2)c1F)C(F)(F)F
Agent: [K+]
Solvent: CI
Solvent: CC#N
Product: CN1CCC(c2cccc(S(=O)(=O)C(F)(F)F)c2F)CC1

Procedure:
Preparation according to Example 18: 4-{2-fluoro-3-[(trifluoromethyl)sulfonyl]phenyl}-piperidine (0.01 g), acetonitrile (2 ml), potassium carbonate (0.01 g) and iodomethane (0.01 g). MS m/z (rel. intensity, 70 eV) 325 (M+, 63), 324 (bp), 305 (13), 191 (32), 133 (24).
Reaction SMILES: [CH3:1][C:2]([CH3:22])([CH3:21])[CH2:3][CH2:4][C:5]1([C:17]([O:19][CH3:20])=[O:18])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8][CH:7]=[C:6]1[O:15][CH3:16].[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=[O:24].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.C(OO)(C)(C)C.O>C1C=CC=CC=1>[CH3:1][C:2]([CH3:22])([CH3:21])[CH2:3][CH2:4][C:5]1([C:17]([O:19][CH3:20])=[O:18])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8](=[O:24])[CH:7]=[C:6]1[O:15][CH3:16]
Reactant: COC(=O)C1(CCC(C)(C)C)C(OC)=CCc2ccccc21
Reactant: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: CC(C)(C)OO
Agent: c1cc[nH+]cc1
Solvent: c1ccccc1
Solvent: O
Product: COC(=O)C1(CCC(C)(C)C)C(OC)=CC(=O)c2ccccc21
Yield: 68.3 %

Procedure:
A suspension of Example 8A (0.45g, 1.48 mmol), pyridinium dichromate (2.4 g, 5.92 mmol), celite (0.53 g), 70% t-BuOOH/water (0.82 mL, 5.92 mmol) in benzene (11 mL) was stirred at 25° C. for 2 h. The benzene layer was separated and the mixture was extracted with ethyl acetate. The combined organic layers were concentrated in vacuo. Column chromatography on silica (5%→15% ethyl acetate/hexane) afforded the title compound (0.32 g, 67%). 1H NMR (300 MHz, DMSO-d6) δ ppm 0.17-0.41 (m, 1H), 0.60-0.81 (m, 10H), 2.16-2.36 (m, 2H), 3.56 (s, 3H), 3.84 (s, 3H), 6.04 (s, 1H), 7.41 (d, J=7.72 Hz, 1H), 7.51 (t, J=6.99 Hz, 1H), 7.60-7.75 (m, 1H), 7.89-8.09 (m, 1H)); MS (ESI) m/z 316.9 (M+H)+.
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[N:8][C:9]([NH2:10])=[C:4]2[CH:3]=[N:2]1.[I:11]N1C(=O)CCC1=O>CN(C)C=O.O>[I:11][C:3]1[C:4]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH2:10])[NH:1][N:2]=1
Reactant: O=C1CCC(=O)N1I
Reactant: Nc1ncnc2[nH]ncc12
Solvent: O
Solvent: CN(C)C=O
Product: Nc1ncnc2[nH]nc(I)c12
Temperature: 80 °C
Reaction time: 5 h
Yield: 51.8 %

Procedure:
A mixture of 1H-pyrazolo[3,4-d]pyrimidin-4-amine (150 g, 1.11 mol, 1.00 equiv) and N-iodo-succinimide (375 g, 1.67 mol, 1.58 equiv) in N,N-dimethylformamide (2.5 L) was stirred at 80° C. for 5 h. The reaction mixture was cooled to room temperature and then diluted with 10 L of water. The solid was collected by filtration, washed with 2×1 L of saturated aqueous sodium sulfite and dried under vacuum to give 150 g (52%) of 3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[C:8](F)[C:5]([C:6]#[N:7])=[CH:4][N:3]=1.[CH3:11][O:12][CH2:13][CH2:14][NH2:15].CCN(C(C)C)C(C)C>CC(N(C)C)=O>[NH2:1][C:2]1[CH:9]=[C:8]([NH:15][CH2:14][CH2:13][O:12][CH3:11])[C:5]([C:6]#[N:7])=[CH:4][N:3]=1
Reactant: COCCN
Reactant: N#Cc1cnc(N)cc1F
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: COCCNc1cc(N)ncc1C#N
Temperature: 50 °C
Reaction time: 15 h

Procedure:
A solution of 6-amino-4-fluoronicotinonitrile (intermediate 21, 1.10 g, 8.02 mmol) in DMA (20 ml) was treated with 2-methoxyethylamine (2.07 ml, 24.1 mmol) and DIPEA (4.20 mL, 24.1 mmol), heated to 50° C. and stirred for 15 h. The reaction mixture was cooled to room temperature and concentrated. The crude material was purified by normal phase chromatography (24 g silica gel cartridge, heptanes/EtOAc 100:0 to 0:100). The product containing fractions were concentrated and dried under vacuum to give the title compound as an off-white solid.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[NH:11][C:12]1[CH:20]=[C:19]2[C:15]([C:16]([C:27]([OH:29])=O)=[N:17][N:18]2[CH:21]2[CH2:26][CH2:25][CH2:24][CH2:23][O:22]2)=[CH:14][CH:13]=1)=[O:4].[CH2:30]([N:32](CC)CC)C.CN.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH3:1][O:2][C:3](=[O:4])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[NH:11][C:12]1[CH:20]=[C:19]2[C:15]([C:16]([C:27](=[O:29])[NH:32][CH3:30])=[N:17][N:18]2[CH:21]2[CH2:26][CH2:25][CH2:24][CH2:23][O:22]2)=[CH:14][CH:13]=1
Reactant: COC(=O)c1ccccc1Nc1ccc2c(C(=O)O)nn(C3CCCCO3)c2c1
Reactant: CCN(CC)CC
Agent: CN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: CNC(=O)c1nn(C2CCCCO2)c2cc(Nc3ccccc3C(=O)OC)ccc12
Reaction time: 3 h
Yield: 41.3 %

Procedure:
To a solution of 6-(2-Methoxycarbonyl-phenylamino)-1-(tetrahydro-pyran-2-yl)-1H-indazole-3-carboxylic acid (0.50 g, 1.27 mmol) in DMF was added triethylamine (0.42 mL, 3.04 mmol), methylamine (1.9 mL, 3.81 mmol), and HATU (0.578 g, 1.52 mmol). The reaction was stirred for 3 hours and then concentrated by rotary evaporation. The crude oil was chromatographed (50 g silica gel, 25–50% EtOAc/hexanes) to yield the desired product (214 mg, 42%).
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:7]=[C:6]([CH2:8]O)[O:5][N:4]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Cl)(Cl)(Cl)[Cl:32]>ClCCl>[Cl:32][CH2:8][C:6]1[O:5][N:4]=[C:3]([C:2]([F:11])([F:10])[F:1])[CH:7]=1
Reactant: ClC(Cl)(Cl)Cl
Reactant: OCc1cc(C(F)(F)F)no1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: FC(F)(F)c1cc(CCl)on1
Temperature: 25 °C
Yield: 82 %

Procedure:
A solution of 3-trifluoromethyl-5-hydroxymethylisoxazole [(700 mg, 4.2 mmol) See K. Tanaka et al, Bull. Chem. Soc. Jpn., 57, 2184 (1984)] and triphenylphosphine (1.43 g, 5.4 mmol) in carbontetrachloride (50 ml) and dichloromethane (20 ml) is heated at reflux for 6 hours. The reaction mixture is then cooled to room temperature, and passed through a silica gel plug. Concentration affords in 82% yield the desired 5-chloromethyl-3-trifluoromethylisoxazole of sufficient purity for the following step (Example 24).
Reaction SMILES: C1C(=O)N([Br:8])C(=O)C1.[CH3:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[S:21][C:20]3[CH:22]=[C:23]([O:26][C:27](=[O:33])[N:28]([CH2:31][CH3:32])[CH2:29][CH3:30])[CH:24]=[CH:25][C:19]=3[CH:18]=2)=[CH:13][CH:12]=1.O>C1COCC1>[Br:8][C:18]1[C:19]2[CH:25]=[CH:24][C:23]([O:26][C:27](=[O:33])[N:28]([CH2:31][CH3:32])[CH2:29][CH3:30])=[CH:22][C:20]=2[S:21][C:17]=1[C:14]1[CH:13]=[CH:12][C:11]([O:10][CH3:9])=[CH:16][CH:15]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CCN(CC)C(=O)Oc1ccc2cc(-c3ccc(OC)cc3)sc2c1
Solvent: O
Solvent: C1CCOC1
Product: CCN(CC)C(=O)Oc1ccc2c(Br)c(-c3ccc(OC)cc3)sc2c1
Temperature: 50 °C
Reaction time: 0.33 h

Procedure:
Add NBS (7.37 g, 40.99 mmoles) to the solution of diethyl-carbamic acid 2-(4-methoxy-phenyl)-benzo[b]thiophen-6-yl ester in THF at ambient temperature. Stir the mixture for 20 minutes. Distill the resulting solution to 47 mL. Add Methanol (15 mL) to the distilled solution and cool the solution to 50° C. Add seed crystals of Example 2 (340 mg, 0.8 mmoles) to the cooled solution and stir the mixture for 15 minutes. Slowly add water (35 mL). Allow the mixture to cool to ambient temperature, and hold at ambient temperature for one hour. Collect the product by vacuum filtration, wash with aqueous THF (30 mL, 2 water: 1 THF) and dry in a vacuum oven to yield diethyl-carbamic acid 3-bromo-2-(4-methoxy-phenyl)-benzo[b]thiophen-6-yl ester. Yield 15.75 g (36.26 mmol, 93% of theory).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3](=[O:11])[CH2:4][C:5]([O:7][CH:8]([CH3:10])[CH3:9])=[O:6].[CH:14](OC(C)C)(OC(C)C)[O:15][CH:16]([CH3:18])[CH3:17]>>[CH:16]([O:15][CH:14]=[C:4]([C:3](=[O:11])[C:2]([F:12])([F:13])[F:1])[C:5]([O:7][CH:8]([CH3:10])[CH3:9])=[O:6])([CH3:18])[CH3:17]
Reactant: CC(C)OC(OC(C)C)OC(C)C
Reactant: CC(C)OC(=O)CC(=O)C(F)(F)F
Product: CC(C)OC=C(C(=O)OC(C)C)C(=O)C(F)(F)F

Procedure:
The preparation was carried out analogously to preparation example 1 using isopropyl 4,4,4-trifluoro-3-oxobutyrate and triisopropyl orthoformate.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]1[C:13]2[C:8](=[N:9][CH:10]=[CH:11][C:12]=2[S:14][C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-])=O)=[CH:17][CH:16]=2)[CH:7]=[CH:6]1.O.O.[Sn](Cl)Cl>CO>[CH3:1][O:2][CH2:3][CH2:4][N:5]1[C:13]2[C:8](=[N:9][CH:10]=[CH:11][C:12]=2[S:14][C:15]2[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][CH:16]=2)[CH:7]=[CH:6]1
Reactant: COCCn1ccc2nccc(Sc3ccc([N+](=O)[O-])cc3)c21
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CO
Product: COCCn1ccc2nccc(Sc3ccc(N)cc3)c21
Temperature: 50 °C
Reaction time: 3 h

Procedure:
A sealed vial was charged with 1-(2-methoxyethyl)-7-(4-nitrophenylthio)-1H-pyrrolo[3,2-b]pyridine (0.147 g, 0.446 mmol) and methanol (5 mL). Tin (II) chloride dihydrate (0.504 g, 2.23 mmol) was added and the reaction was stirred at 50° C. for 3 hours. The reaction was concentrated and dissolved in DCM. The solution was washed with saturated sodium bicarbonate solution, which was extracted with DCM. The combined organic layers were washed with water, dried with sodium sulfate, filtered, and concentrated. The material was purified via column chromatography (gradient elution 0-10% DCM:MeOH) to afford 4-(1-(2-methoxyethyl)-1H-pyrrolo[3,2-b]pyridin-7-ylthio)benzenamine as an orange oil that solidified under high vacuum. MS: M+H+=300.1.
Reaction SMILES: [C:1]([CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH:14]([N:16]2[CH2:21][CH2:20][O:19][C:18]([OH:29])([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[CH:23]=3)[CH2:17]2)[CH3:15])=[CH:9][CH:8]=1)(OC)=[O:2].[NH3:30]>>[NH2:30][C:1]([CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH:14]([N:16]2[CH2:21][CH2:20][O:19][C:18]([OH:29])([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[CH:23]=3)[CH2:17]2)[CH3:15])=[CH:9][CH:8]=1)=[O:2]
Reactant: COC(=O)COc1ccc(CC(C)N2CCOC(O)(c3cccc(Cl)c3)C2)cc1
Reactant: N
Product: CC(Cc1ccc(OCC(N)=O)cc1)N1CCOC(O)(c2cccc(Cl)c2)C1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
2.03 g (4.76 mmol) of N-[2-(4-carbomethoxymethoxyphenyl)-1-methylethyl]-2-hydroxy-2-(3-chlorophenyl)morpholine is dissolved in 20 ml of ammonia-saturated methanol and stirred for 24 hours at ambient temperature. The mixture is then evaporated down and the evaporation residue is purified by column chromatography on silica gel (eluant: ethyl acetate/cyclohexane=3:1).