Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]([NH:8][C@H:9]2[CH2:14][CH2:13][C@H:12]([OH:15])[CH2:11][CH2:10]2)=[N:6][CH:7]=1.[CH3:16][S:17](Cl)(=[O:19])=[O:18]>C(Cl)Cl>[CH3:16][S:17]([O:15][C@H:12]1[CH2:11][CH2:10][C@H:9]([NH:8][C:5]2[N:4]=[CH:3][C:2]([Br:1])=[CH:7][N:6]=2)[CH2:14][CH2:13]1)(=[O:19])=[O:18]
Reactant: CS(=O)(=O)Cl
Reactant: O[C@H]1CC[C@H](Nc2ncc(Br)cn2)CC1
Solvent: ClCCl
Product: CS(=O)(=O)O[C@H]1CC[C@H](Nc2ncc(Br)cn2)CC1
Reaction time: 1 h

Procedure:
As shown in step 6-ii of Scheme 6, to compound 1013 (1.2 g, 4.41 mmol) in DCM (20 mL) was added TEA (1.134 g, 1.84 mL, 13.2 mmol) and MsCl (505 mg, 341 μL, 4.41 mmol). The reaction mixture was stirred for 1 hour, concentrated under reduced pressure, and purified by medium pressure silica gel chromatography (0 to 80% EtOAc/hexanes gradient) to provide trans-4-((5-bromopyrimidin-2-yl)amino)cyclohexyl methanesulfonate (compound 1014): 1H-NMR (300 MHz, CDCl3) δ 8.29 (s, 2H), 5.03 (d, J=7.8 Hz, 1H), 4.70 (tt, J=10.6, 3.9 Hz, 1H), 3.80 (dtt, J=11.2, 7.6, 3.7 Hz, 1H), 3.04 (s, 3H), 2.30-2.12 (m, 4H), 1.93-1.69 (m, 2H), 1.51-1.33 (m, 2H).
Reaction SMILES: Cl.[NH2:2][C:3]1[N:8]=[C:7]([N:9]2[C:18]3[C:13](=[C:14]([F:22])[C:15]([F:21])=[C:16]([F:20])[C:17]=3[F:19])[C:12](=[O:23])[C:11]([C:24]([O:26]CC)=[O:25])=[CH:10]2)[C:6]([F:29])=[CH:5][C:4]=1[F:30]>C(O)(=O)C>[NH2:2][C:3]1[N:8]=[C:7]([N:9]2[C:18]3[C:13](=[C:14]([F:22])[C:15]([F:21])=[C:16]([F:20])[C:17]=3[F:19])[C:12](=[O:23])[C:11]([C:24]([OH:26])=[O:25])=[CH:10]2)[C:6]([F:29])=[CH:5][C:4]=1[F:30]
Reactant: CCOC(=O)c1cn(-c2nc(N)c(F)cc2F)c2c(F)c(F)c(F)c(F)c2c1=O
Agent: Cl
Solvent: CC(=O)O
Product: Nc1nc(-n2cc(C(=O)O)c(=O)c3c(F)c(F)c(F)c(F)c32)c(F)cc1F
Yield: 93.8 %

Procedure:
To 2 ml of the mixed solution (1:1) of 4N hydrochloric acid and acetic acid was added 320 mg of ethyl 1-(6-amino-3,5-difluoropyridine-2-yl)-5,6,7,8-tetrafluoro-4-oxo-1,4-dihydroquinoline-3-carboxylate, and the mixture was heated under reflux for 3 hours with stirring, and allowed to cool. The precipitate was collected by filtration, and washed with ethanol to obtain 280 mg of the title compound as a colorless powder.
Reaction SMILES: Cl.Cl.[NH:3]1[CH2:6][CH:5]([C:7]2[C:8]([O:28][CH3:29])=[C:9]([CH:15]([N:17]3[C:21]4=[N:22][CH:23]=[N:24][C:25]([NH2:26])=[C:20]4[C:19]([CH3:27])=[N:18]3)[CH3:16])[CH:10]=[C:11]([Cl:14])[C:12]=2[CH3:13])[CH2:4]1.[OH:30][C@@H:31]([CH3:35])[C:32](O)=[O:33].C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1>CN(C)C=O.CO>[NH2:26][C:25]1[N:24]=[CH:23][N:22]=[C:21]2[N:17]([CH:15]([C:9]3[C:8]([O:28][CH3:29])=[C:7]([CH:5]4[CH2:4][N:3]([C:32](=[O:33])[C@@H:31]([OH:30])[CH3:35])[CH2:6]4)[C:12]([CH3:13])=[C:11]([Cl:14])[CH:10]=3)[CH3:16])[N:18]=[C:19]([CH3:27])[C:20]=12
Reactant: C[C@H](O)C(=O)O
Reactant: COc1c(C(C)n2nc(C)c3c(N)ncnc32)cc(Cl)c(C)c1C1CNC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CO
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1c(C(C)n2nc(C)c3c(N)ncnc32)cc(Cl)c(C)c1C1CN(C(=O)[C@H](C)O)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 19.8 %

Procedure:
To a mixture of 1-[1-(3-azetidin-3-yl-5-chloro-2-methoxy-4-methyl phenyl)ethyl]-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine dihydrochloride (15 mg, 0.033 mmol, chiral intermediate from Example 1, Step 7, peak 1), mixture of (2S)-2-hydroxypropanoic acid (4.3 μL, 0.049 mmol) (L-lactic acid, 85% aq.) and triethylamine (14 μL, 0.098 mmol) in N,N-dimethylformamide (0.2 mL) was added N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (19 mg, 0.049 mmol). The resulting mixture was stirred overnight at room temperature. The mixture was diluted with MeOH and purified using RP-HPLC (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 30 mL/min) to give 3.0 mg (20%) of the desired product. The product was isolated as a single enantiomer. LCMS calculated for C22H28ClN6O3 (M+H)+: m/z=459.2; Found: 459.2.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:22]([CH:24]2[CH2:28][CH2:27][CH2:26][CH2:25]2)[CH3:23])[C:5]([CH3:21])=[C:6]([CH:20]=1)[C:7]([NH:9][CH2:10][C:11]1[C:12](=[O:19])[NH:13][C:14]([CH3:18])=[CH:15][C:16]=1[CH3:17])=[O:8].[O:29]1[CH2:34][CH2:33][N:32]([CH2:35][CH2:36][N:37]2[CH:41]=[C:40](B(O)O)[CH:39]=[N:38]2)[CH2:31][CH2:30]1.C([O-])([O-])=O.[Na+].[Na+].C(Cl)Cl>O1CCOCC1.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>[CH:24]1([N:22]([CH3:23])[C:4]2[C:5]([CH3:21])=[C:6]([CH:20]=[C:2]([C:40]3[CH:39]=[N:38][N:37]([CH2:36][CH2:35][N:32]4[CH2:33][CH2:34][O:29][CH2:30][CH2:31]4)[CH:41]=3)[CH:3]=2)[C:7]([NH:9][CH2:10][C:11]2[C:12](=[O:19])[NH:13][C:14]([CH3:18])=[CH:15][C:16]=2[CH3:17])=[O:8])[CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: Cc1cc(C)c(CNC(=O)c2cc(Br)cc(N(C)C3CCCC3)c2C)c(=O)[nH]1
Reactant: OB(O)c1cnn(CCN2CCOCC2)c1
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: [Na+]
Solvent: ClCCl
Solvent: C1COCCO1
Product: Cc1cc(C)c(CNC(=O)c2cc(-c3cnn(CCN4CCOCC4)c3)cc(N(C)C3CCCC3)c2C)c(=O)[nH]1
Temperature: 100 °C
Reaction time: 2 h
Yield: 66 %

Procedure:
A solution of 5-bromo-3-(cyclopentyl(methyl)amino)-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-methylbenzamide (1 equiv.), (1-(2-morpholinoethyl)-1H-pyrazol-4-yl)boronic acid (1.2 equiv.) and Pd(PPh3)4 (0.1 equiv.) in 1,4-dioxane (4 mL) was purged with argon for 10 min. Then, 2 M Na2CO3 solution (3.6 equiv.) was added to it and the mixture was purged again for 10 min. The reaction mixture was stirred at 100° C. for 2 h. After reaction completion, water was added to it and extraction was carried out using DCM. The combined organic layers were washed with water, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford crude material which was purified by column chromatography over silica gel (60-120 mesh size) to afford 3 the title compound (0.08 g, 66%). LCMS: 547.35 (M+1)+; HPLC % 97.60 (@254 nm) (Rt; 4.071; Method: Column: YMC ODS-A 150 mm×4.6 mm×5μ; Mobile Phase: A; 0.05% TFA in water/B; 0.05% TFA in acetonitrile; Inj. Vol: 10 μL, Col. Temp.; 30° C.; Flow rate: 1.4 mL/min.; Gradient: 5% B to 95% B in 8 min, Hold for 1.5 min, 9.51-12 min 5% B); 1H NMR (DMSO-d6, 400 MHz) δ 11.44 (s, 1H), 8.17 (s, 1H), 8.05 (t, 1H), 7.81 (s, 1H), 7.30 (s, 1H), 7.10 (s, 1H), 5.85 (s, 1H), 4.26 (d, 2H, J=4 Hz), 4.0 (d, 2H, J=6.4 Hz), 3.49-3.53 (m, 6H), 2.72 (t, 2H), 2.40 (bs, 6H), 2.20 (s, 3H), 2.17 (s, 3H), 2.10 (s, 3H), 1.6.1-1.70 (m, 4H), 1.42-1.50 (m, 4H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9](Cl)(=[O:11])=[O:10])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[NH2:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][CH:23]=1)[C:20]([C:24]([OH:26])=[O:25])=[CH:19][CH:18]=[CH:17]2>N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([S:9]([NH:13][C:14]2[CH:15]=[C:16]3[C:21](=[CH:22][CH:23]=2)[C:20]([C:24]([OH:26])=[O:25])=[CH:19][CH:18]=[CH:17]3)(=[O:11])=[O:10])[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: Nc1ccc2c(C(=O)O)cccc2c1
Reactant: O=S(=O)(Cl)c1cc(Cl)cc(Cl)c1
Solvent: c1ccncc1
Product: O=C(O)c1cccc2cc(NS(=O)(=O)c3cc(Cl)cc(Cl)c3)ccc12
Reaction time: 8 h

Procedure:
2.68 g 3,5-dichloro-phenylsulphonyl chloride are added to 2.00 g of 6-amino-naphthalene-1-carboxylic acid in 10 ml of pyridine while cooling with an ice bath. The reaction mixture is left overnight to come up to ambient temperature and then the pyridine is distilled off in vacuo using the rotary evaporator. The flask residue is acidified with 3 N hydrochloric acid and extracted with ethyl acetate/methanol. The combined extracts are washed with water, dried on magnesium sulphate and evaporated down. The crude product is purified by chromatography through a silica gel column with cyclohexane/ethyl acetate (65:35 to 0:100) as eluant.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[CH:10]=2)O1.I[C:20]1[CH:21]=[C:22]([CH:26]=[CH:27][C:28]=1[CH3:29])[C:23]([OH:25])=[O:24].C(=O)([O-])[O-].[K+].[K+].C([O-])(O)=O.[Na+]>C1(C)C=CC=CC=1.C(O)CCC.O.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>[CH3:29][C:28]1[C:27]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[CH:10]=2)=[CH:26][C:22]([C:23]([OH:25])=[O:24])=[CH:21][CH:20]=1
Reactant: CC1(C)OB(c2cccc([N+](=O)[O-])c2)OC1(C)C
Reactant: Cc1ccc(C(=O)O)cc1I
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: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCCCO
Product: Cc1ccc(C(=O)O)cc1-c1cccc([N+](=O)[O-])c1
Temperature: 20 °C
Yield: 88.9 %

Procedure:
4,4,5,5-Tetramethyl-2-(3-nitrophenyl)-1,3,2-dioxaborolane (5.16 g, 0.0207 mol) was mixed with 3-iodo-4-methylbenzoic acid (4.94 g, 0.0188 mol), and potassium carbonate (10.4 g, 0.0753 mol) in toluene (100 mL), 1-butanol (20 mL) and water (15 mL) and the resulting mixture was degassed by sparging nitrogen through it. To the reaction was added tetrakis(triphenylphosphine)palladium(0) (1.0 g, 0.00091 mol). The mixture was stirred rapidly and was heated to reflux for 1.5 hour. LCMS analysis showed the reaction to be complete, M+H 258. The mixture was then cooled to 20° C. The aqueous layer was discarded. To the organic layer was added saturated NaHCO3. The toluene layer was extracted with aqueous sodium bicarbonate, then discarded. The aqueous sodium bicarbonate and alcohol layers were combined, then acidified to pH 2.5 with HCl. A white solid precipitated and was separated by filtration, rinsed with water, and air dried to give 4.3 g of the product. The filtrate contained only a trace of product.
Reaction SMILES: [C:1]1(=[O:11])[O:6][C:4](=[O:5])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[CH3:12][N:13]([C:15]1[S:16][CH:17]=[C:18]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:19]=1)[NH2:14].CN(C)C=O>O>[C:4]([C:3]1[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=1[C:1]([NH:14][N:13]([CH3:12])[C:15]1[S:16][CH:17]=[C:18]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:19]=1)=[O:11])([OH:6])=[O:5]
Reactant: CN(N)c1nc(-c2ccccc2)cs1
Reactant: O=C1OC(=O)c2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: CN(NC(=O)c1ccccc1C(=O)O)c1nc(-c2ccccc2)cs1

Procedure:
A solution of 1.5 g. of phthalic anhydride and 2.0 g. of 1-methyl-1-(4-phenylthiazol-2-yl)hydrazine in 50 ml. of dimethylformamide is stirred for 16 hours. Addition of water precipitates a gummy solid which is taken up in ethyl acetate and the ethyl acetate solution is extracted with water, dried over anhydrous sodium sulfate and evaporated, giving a residue which is crystallized from ether/petroleum ether, yielding 0.6 g. of product, m.p. 122°-4°.
Reaction SMILES: [ClH:1].[OH:2][NH:3][C:4]([C:6]1([S:15]([C:18]2[CH:23]=[CH:22][C:21]([S:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[CH:20][CH:19]=2)(=[O:17])=[O:16])[CH2:11][CH2:10][N:9](CC#C)[CH2:8][CH2:7]1)=[O:5].C(=O)([O-])[O-].[K+].[K+].[F:37]C1C=CC(S)=CC=1>CN(C=O)C.C(OCC)(=O)C>[ClH:1].[F:37][C:28]1[CH:29]=[CH:30][C:25]([S:24][C:21]2[CH:22]=[CH:23][C:18]([S:15]([C:6]3([C:4]([NH:3][OH:2])=[O:5])[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]3)(=[O:17])=[O:16])=[CH:19][CH:20]=2)=[CH:26][CH:27]=1
Reactant: C#CCN1CCC(C(=O)NO)(S(=O)(=O)c2ccc(Sc3ccccc3)cc2)CC1
Reactant: Fc1ccc(S)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(NO)C1(S(=O)(=O)c2ccc(Sc3ccc(F)cc3)cc2)CCNCC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 87 %

Procedure:
Part A: To a solution of the sulfone of Example 9, part D (6.0 g, 14.4 mmol) in DMF (30 mL) were added potassium carbonate (2.39 mg, 17.3 mmol) and 4-fluorothiophenol (3.0 mL, 28.1 mmol), and the solution was stirred at ambient temperature for 18 hours. The solution was diluted with ethyl acetate and washed with 1N NaOH and saturated NaCl, and then dried over magnesium sulfate. Chromatography (on silica, ethyl acetate/hexane) provided the sulfide as a solid (6.6 g, 87%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[NH:7][CH2:8][C:9]1[C:14]([Br:15])=[CH:13][N:12]=[C:11]([NH2:16])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].C([O-])(O)=O.[Na+].Cl[CH2:24][CH:25]=O>>[C:1]([O:5][C:6](=[O:17])[NH:7][CH2:8][C:9]1[C:14]([Br:15])=[CH:13][N:12]2[CH:24]=[CH:25][N:16]=[C:11]2[CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCc1cc(N)ncc1Br
Reactant: O=CCCl
Agent: O=C([O-])O
Agent: [Na+]
Product: CC(C)(C)OC(=O)NCc1cc2nccn2cc1Br
Temperature: 25 °C
Yield: 78.8 %

Procedure:
A mixture of (2-amino-5-bromo-pyridin-4-ylmethyl)-carbamic acid tert-butyl ester (1.0 g, 3.3 mmol), NaHCO3 (474 mg, 5.6 mmol) and chloracetaldehyde (2.2 mL, 15.0 mmol) was vigorously stirred and refluxed for 14 h. The reaction mixture was cooled to RT, concentrated under vacuum and the remaining residue was suspended in DCM and brine. The aqueous layer was separated and extracted with DCM (5×), and the combined organic fractions were dried over Na2SO4, filtered, and evaporated. The residue was purified by Combi-Flash Companion™ (Isco Inc.) column chromatography (SiO2; gradient elution, hexane/DCM/TBME 10:10:1→1:1:18) to yield the title compound (860 mg, 2.6 mmol, 79%) as a pale yellow solid. MS: 327 [M+1]+; HPLC: AtRet=1.07; TLC: RF 0.16 (hexane/DCM/TBME 1:1:2).
Reaction SMILES: [C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11](=[O:46])[NH:12][C:13]2[CH:14]=[C:15]([CH:43]=[CH:44][CH:45]=2)[O:16][C:17]2[C:26]3[C:21](=[CH:22][C:23]([O:29][CH:30]4[CH2:35][CH2:34][N:33](C(OC(C)(C)C)=O)[CH2:32][CH2:31]4)=[C:24]([O:27][CH3:28])[CH:25]=3)[N:20]=[CH:19][N:18]=2)[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl.O1CCOCC1>>[C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:12][C:13]2[CH:45]=[CH:44][CH:43]=[C:15]([O:16][C:17]3[C:26]4[C:21](=[CH:22][C:23]([O:29][CH:30]5[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]5)=[C:24]([O:27][CH3:28])[CH:25]=4)[N:20]=[CH:19][N:18]=3)[CH:14]=2)=[O:46])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1cc2c(Oc3cccc(NC(=O)Nc4cc(C(C)(C)C)on4)c3)ncnc2cc1OC1CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: C1COCCO1
Product: COc1cc2c(Oc3cccc(NC(=O)Nc4cc(C(C)(C)C)on4)c3)ncnc2cc1OC1CCNCC1

Procedure:
Using the procedure described in Example 103B, tert-butyl 4-(4-{3-[3-(5-tert-butylisoxazol-3-yl)ureido]phenoxy}-6-methoxyquinazolin-7-yloxy)piperidine-1-carboxylate was reacted with 4.0 M HCl/1,4-dioxane at room temperature for 6 hours, to afford 1-(5-tert-butylisoxazol-3-yl)-3-{3-[6-methoxy-7-(piperidin-4-yloxy)quinazolin-4-yloxy]phenyl}urea as a crude product. LC-MS (ESI) m/z 533 (M+H)+.
Reaction SMILES: [NH2:1][C:2]([CH:4]1[N:9]([CH2:10][CH2:11][CH2:12][CH:13]([C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)[C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)[CH2:8][CH2:7][N:6]([CH2:28][C:29]([NH:31][C:32]2[C:37]([CH3:38])=[CH:36][CH:35]=[CH:34][C:33]=2[CH3:39])=[O:30])[CH2:5]1)=[O:3].[OH:40][CH:41]([CH:45]([OH:49])[C:46]([OH:48])=[O:47])[C:42]([OH:44])=[O:43]>C(O)C>[NH2:1][C:2]([CH:4]1[N:9]([CH2:10][CH2:11][CH2:12][CH:13]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)[C:21]2[CH:22]=[CH:23][C:24]([F:27])=[CH:25][CH:26]=2)[CH2:8][CH2:7][N:6]([CH2:28][C:29]([NH:31][C:32]2[C:37]([CH3:38])=[CH:36][CH:35]=[CH:34][C:33]=2[CH3:39])=[O:30])[CH2:5]1)=[O:3].[OH:40][CH:41]([CH:45]([OH:49])[C:46]([O-:48])=[O:47])[C:42]([O-:44])=[O:43]
Reactant: O=C(O)C(O)C(O)C(=O)O
Agent: Cc1cccc(C)c1NC(=O)CN1CCN(CCCC(c2ccc(F)cc2)c2ccc(F)cc2)C(C(N)=O)C1
Solvent: CCO
Product: O=C([O-])C(O)C(O)C(=O)[O-]
Temperature: 0 °C

Procedure:
To a stirred solution of 3 parts of 3-(aminocarbonyl)-4-[4,4-bis(4-fluorophenyl)butyl]-N-(2,6-dimethylphenyl)-1-piperazineacetamide in 24 parts of ethanol was added a solution of 0.94 parts of (+)-2,3-dihydroxybutanedioic acid in 24 parts of ethanol. The whole was evaporated and the oily residue was dissolved in warm 4-methyl-2-pentanone. After cooling to 0° C., the product was filtered off and dissolved in 2-propanone. 0.2 Parts of 2,3-dihydroxybutanedioic acid were added and upon the addition of 4-methyl-2-pentanone, the product was precipitated. It was filtered off and dried, yielding 0.8 parts of (+)-3-(aminocarbonyl)-4-[4,4-bis(4-fluorophenyl)butyl]-N-(2,6-dimethylphenyl)-1-piperazineacetamide [R-(R*,R*)]-2,3-dihydroxybutanedioate (2:3) monohydrate; mp. 78.1° C. (compound 173).
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][C:8]=2[C:15]2[C:16]3[NH:23][C:22]([CH3:24])=[C:21]([C:25]([NH:27][C@@H:28]4[CH2:32][CH2:31][NH:30][CH2:29]4)=[O:26])[C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:4][CH2:3]1.C([O:36][C@@H:37]([CH3:41])[C:38](Cl)=[O:39])(=O)C>>[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][C:8]=2[C:15]2[C:16]3[NH:23][C:22]([CH3:24])=[C:21]([C:25]([NH:27][C@@H:28]4[CH2:32][CH2:31][N:30]([C:38](=[O:39])[C@@H:37]([OH:36])[CH3:41])[CH2:29]4)=[O:26])[C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:4][CH2:3]1
Reactant: COc1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)N[C@@H]4CCNC4)c(C)[nH]c23)c1
Reactant: CC(=O)O[C@@H](C)C(=O)Cl
Agent: Cl
Product: COc1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)N[C@@H]4CCN(C(=O)[C@H](C)O)C4)c(C)[nH]c23)c1

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-5-methoxyphenyl]-6-methyl-N-[(3R)-pyrrolidin-3-yl]-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f26) and commercially available (2S)-1-chloro-1-oxopropan-2-yl acetate the title compound is obtained as colorless solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[C:9]3[CH:23]=[CH:22][NH:21][C:10]=3[N:11]=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[N:15]=3)[N:13]=2)[CH:5]=[N:6][CH:7]=1.[CH2:24]([N:26]1[CH2:31][CH2:30][N:29]([CH2:32][C:33]#[CH:34])[CH2:28][CH2:27]1)C>COCCOC.[Cu]I.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>[CH3:24][N:26]1[CH2:31][CH2:30][N:29]([CH2:32][C:33]#[C:34][C:2]2[CH:3]=[C:4]([C:8]3[C:9]4[CH:23]=[CH:22][NH:21][C:10]=4[N:11]=[C:12]([C:14]4[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[N:15]=4)[N:13]=3)[CH:5]=[N:6][CH:7]=2)[CH2:28][CH2:27]1
Reactant: C#CCN1CCN(CC)CC1
Reactant: Cc1cccc(-c2nc(-c3cncc(Br)c3)c3cc[nH]c3n2)n1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: COCCOC
Product: Cc1cccc(-c2nc(-c3cncc(C#CCN4CCN(C)CC4)c3)c3cc[nH]c3n2)n1

Procedure:
To a suspension of of 4-(5-bromo-pyridin-3-yl)-2-(6-methyl-pyridin-2-yl)-7H-pyrrolo[2,3-d]pyrimidine (Example 16) (1 eq, 0.669 mmol, 245 mg) in DME (3.5 ml) are added TEA (2 eq, 1.34 mmol, 135 mg), copper (I) iodide (0.5 eq, 0.335 mmol, 63.7 mg), Pd(PPh3)4 (0.1 eq, 0.067 mmol, 77 mg), and 1-ethyl-4-prop-2-ynyl-piperazine (Tyger Scientific, Ewing, USA) (1 eq, 0.669 mmol, 92 mg). The resulting mixture is heated using microwave radiation for 20 min at 120° C. The mixture is filtered through a pad of Celite and concentrated under reduced pressure. 2M aqueous HCl is added, and the mixture is washed with DCM. The aqueous layer is adjusted to pH 10 using 2M aqueous NaOH, and extracted with DCM. The organic layer is dried over MgSO4, and the solvents are removed in vacuo. The crude mixture is purified using reversed phase HPLC to give the title compound; [M+H]+=424; 1H-NMR (400 MHz, CD3OD): δ 12.23 (s, 1H), 9.40 (d, 1H), 8.79 (d, 1H), 8.66 (d, 1H), 8.61 (t, 1H), 7.85 (t, 1H), 7.45 (t, 1H), 7.32 (d, 1H), 6.85 (m, 1H), 3.60 (s, 2H), 2.74 (s, 3H), 2.70-2.50 (m, 8H), 2.33 (s, 3H).
Reaction SMILES: C(N(CC)CC)C.Cl.Cl[C:10]1[N:18]=[CH:17][CH:16]=[CH:15][C:11]=1[C:12]([OH:14])=O.[CH:19]1([CH2:22][NH:23][C:24]2[C:25]([S:43][CH3:44])=[N:26][N:27]3[C:32]([C:33]4[C:38]([CH3:39])=[CH:37][C:36]([CH3:40])=[CH:35][C:34]=4[O:41][CH3:42])=[CH:31][CH:30]=[CH:29][C:28]=23)[CH2:21][CH2:20]1.C(=O)([O-])O.[Na+]>ClCCl.C(OCC)(=O)C>[CH:19]1([CH2:22][N:23]([C:24]2[C:25]([S:43][CH3:44])=[N:26][N:27]3[C:32]([C:33]4[C:38]([CH3:39])=[CH:37][C:36]([CH3:40])=[CH:35][C:34]=4[O:41][CH3:42])=[CH:31][CH:30]=[CH:29][C:28]=23)[C:12](=[O:14])[C:11]2[CH:15]=[CH:16][CH:17]=[N:18][CH:10]=2)[CH2:20][CH2:21]1
Reactant: COc1cc(C)cc(C)c1-c1cccc2c(NCC3CC3)c(SC)nn12
Reactant: O=C(O)c1cccnc1Cl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COc1cc(C)cc(C)c1-c1cccc2c(N(CC3CC3)C(=O)c3cccnc3)c(SC)nn12
Reaction time: 1 h
Yield: 84.8 %

Procedure:
Triethylamine (0.038 mL) and chloronicotinic acid hydrochloride (20 mg) were added to a solution of N-cyclopropylmethyl-N-[7-(2-methoxy-4,6-dimethylphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]amine (33 mg) in dichloromethane (0.8 mL) while cooling on ice, and the mixture was stirred at the same temperature for 1 hour. Saturated aqueous sodium hydrogencarbonate was added while cooling on ice, extraction was performed with ethyl acetate, and the extract washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:n-hexane=3:2) to obtain the title compound (36 mg) as white crystals.
Reaction SMILES: [OH-].[NH4+].[C:3]([O-])(=[O:13])[C:4]1[CH:12]=[CH:11][C:7]([C:8]([O-:10])=[O:9])=[CH:6][CH:5]=1.[NH4+].[Na+].C(O)(=O)C1C=CC(C(O)=O)=CC=1.OCC1C=CC(C([O-])=O)=CC=1.[Na+].C([O-])(=O)C1C=CC(C(O)=O)=CC=1.[Na+].[OH-].[Na+].C([O-])(=O)C1C=CC(C([O-])=O)=CC=1.[Na+].[Na+].[Na].[NH4+].C([O-])(=O)C1C=CC(C([O-])=O)=CC=1>>[OH:13][CH2:3][C:4]1[CH:5]=[CH:6][C:7]([C:8]([OH:10])=[O:9])=[CH:11][CH:12]=1
Reactant: O=C([O-])c1ccc(C(=O)[O-])cc1
Agent: O=C(O)c1ccc(C(=O)O)cc1
Agent: O=C([O-])c1ccc(C(=O)O)cc1
Agent: O=C([O-])c1ccc(CO)cc1
Product: O=C(O)c1ccc(CO)cc1

Procedure:
FIG. 1 is a diagram of the invented process using sodium hydroxide and ammonium hydroxide. Terephthalic acid, sodium hydroxide and ammonium hydroxide are metered into reservoir 1 by lines 2, 3 and 4 in ratios of one mole per mole at the beginning of the electrochemical reduction process to form sodium ammonium terephthalate. Added ammonium hydroxide is used as a buffer to raise the pH from approximately 7 to within the range of from about 8.0 to about 11.0. The sodium ammonium salt solution is thereupon pumped by suitable means by line 5 to electrolysis cell 6 wherein the salt of terephthalic acid is reduced to sodium p-hydroxymethylbenzoate (Na p-HMB). The Na p-HMB is thereupon pumped by line 7 back to the reservoir 1 which contains Na p-HMB, NH4OH, and monosodium terephthalate. After optimum levels of Na p-HMB have been reached in the reservoir 1, a portion of the electrolysis cell output of line 7 is pumped by line 8 to reactor 9 to which make-up terephthalic acid and make-up sodium hydroxide are added by lines 10 and 11. Make-up terephthalic acid and sodium hydroxide are required because of the reduction of the sodium ammonium terephthalate to Na p-HMB and to salt out the Na p-HMB. Recycle ammonium salt from reactor 9 is pumped by line 25 to line 18 and thence to reservoir 1. The disodium terephthalate in reactor 9 is pumped with the solution removed from reservoir 1 by line 12 to chill unit 13 wherein the Na p-HMB is salted out by the presence of the disodium terephthalate. The resulting slurry in chill unit 13 is pumped by line 14 to filter 15 wherein solids comprising Na p-HMB are filtered and forwarded by line 16 to be recrystallized in crystallizer 17. Mother liquor from filter 15 is recycled to reservoir 1 by line 18. Mother liquor after dewatering from crystallizer 17 is recycled to reservoir 1 by line 19, which joins line 18. Recycle slurry from filter 15 is returned to chill unit 13 by line 22 if recycle is necessary to obtain sufficient cooling. Make-up terephthalic acid and ammonium hydroxide are added to line 18 by lines 20 and 21 to restore the sodium:ammonium:terephthalate ratio and are reacted in reservoir 1. Sodium p-hydroxymethylbenzoate is removed from crystallizer 17 by line 25 to reactor 23 where it is acidified to obtain p-hydroxymethylbenzoic acid.