Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1.C(=O)([O-])[O-].[Na+].[Na+].FC(F)(F)S(O[C:24]1[CH:25]=[CH:26][C:27]2[N:33]3[C:34]([CH3:37])=[N:35][N:36]=[C:32]3[C@H:31]([CH2:38][C:39]([NH:41][CH2:42][CH3:43])=[O:40])[N:30]=[C:29]([C:44]3[CH:49]=[CH:48][C:47]([Cl:50])=[CH:46][CH:45]=3)[C:28]=2[CH:51]=1)(=O)=O.O>COCCOC.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:50][C:47]1[CH:46]=[CH:45][C:44]([C:29]2[C:28]3[CH:51]=[C:24]([C:6]4[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=4)[CH:25]=[CH:26][C:27]=3[N:33]3[C:34]([CH3:37])=[N:35][N:36]=[C:32]3[C@H:31]([CH2:38][C:39]([NH:41][CH2:42][CH3:43])=[O:40])[N:30]=2)=[CH:49][CH:48]=1
Reactant: COc1ccc(B(O)O)cc1
Reactant: CCNC(=O)C[C@@H]1N=C(c2ccc(Cl)cc2)c2cc(OS(=O)(=O)C(F)(F)F)ccc2-n2c(C)nnc21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: CCNC(=O)C[C@@H]1N=C(c2ccc(Cl)cc2)c2cc(-c3ccc(OC)cc3)ccc2-n2c(C)nnc21
Temperature: 120 °C

Procedure:
4-Methoxybenzeneboronic acid (50.5 mg), sodium carbonate (64.5 mg) and bis(triphenylphosphine)palladium(II) chloride (19.4 mg) were added to a 2-5 ml microwave vial. A solution of (4S)-6-(4-chlorophenyl)-4-[2-(ethylamino)-2-oxoethyl]-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-8-yl trifluoromethanesulfonate (for a preparation see Intermediate 3) (150 mg) in DME (3 ml) and water (1 ml) was added and the reaction mixture was heated at 120° C. for 20 min (microwave). The reaction mixture was partitioned between ethyl acetate (10 ml) and water (10 ml). The organic phase was separated, washed with water (10 ml) and brine (10 ml). The organic phase was dried and the solvent was evaporated. The residue was chromatographed (0-5% methanol:DCM) to give 2-{(4S)-6-(4-chlorophenyl)-1-methyl-8-[4-(methyloxy)phenyl]-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-4-yl}-N-ethylacetamide as a light brown solid (84 mg). LCMS (formate): MH+ 500/502, RT 1.08 min
Reaction SMILES: [Cl:1][C:2]1[CH:37]=[CH:36][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([O:16][CH2:17][C:18]4[CH:27]=[CH:26][C:25]5[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=5)[N:19]=4)=[CH:13][CH:14]=3)[CH:9]=[C:8]2[CH2:28][C:29]([CH3:35])([CH3:34])[C:30]([O:32]C)=[O:31])=[CH:4][CH:3]=1.[CH3:38][CH:39]([CH3:43])[C:40](Cl)=[O:41]>>[Cl:1][C:2]1[CH:37]=[CH:36][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([O:16][CH2:17][C:18]4[CH:27]=[CH:26][C:25]5[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=5)[N:19]=4)=[CH:13][CH:14]=3)[C:9]([C:40](=[O:41])[CH:39]([CH3:43])[CH3:38])=[C:8]2[CH2:28][C:29]([CH3:34])([CH3:35])[C:30]([OH:32])=[O:31])=[CH:4][CH:3]=1
Reactant: CC(C)C(=O)Cl
Reactant: COC(=O)C(C)(C)Cc1cc2cc(OCc3ccc4ccccc4n3)ccc2n1Cc1ccc(Cl)cc1
Product: CC(C)C(=O)c1c(CC(C)(C)C(=O)O)n(Cc2ccc(Cl)cc2)c2ccc(OCc3ccc4ccccc4n3)cc12

Procedure:
The title compound was prepared according to the conditions described in Step B and Step C of Example 47, from methyl 3-[N-(4-chlorobenzyl)-5-(quinolin-2-ylmethoxy)indol-2-yl]-2,2-dimethylpropanoate (prepared in Step A of Example 47), but using 2-methylpropanoyl chloride in place of trimethylacetyl chloride in Step B.
Reaction SMILES: N1C=CC=CC=1.Cl[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][OH:14].[C:15](OC(=O)C)(=[O:17])[CH3:16]>O>[C:15]([O:14][CH:13]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)(=[O:17])[CH3:16]
Reactant: CC(=O)OC(C)=O
Reactant: OCCCCCCCl
Solvent: O
Solvent: c1ccncc1
Product: CC(=O)OC1CCCCC1

Procedure:
Under a nitrogen atmosphere, pyridine (934 g) was added to 6-chlorohexanol (800 g). Acetic anhydride (1,200 mL) was added thereto, and after refluxing under heating for 3 hours, the reaction solution was poured into water and extracted with toluene. The organic layer was neutralized with a saturated sodium hydrogencarbonate aqueous solution, and after washing with water, dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the concentrated product was purified by distillation under reduced pressure to obtain 6-acetoxycyclohexane (983 g).
Reaction SMILES: [OH:1][C:2]1[C:7]([C:8]([OH:10])=O)=[CH:6][N:5]=[C:4]([N:11]2[CH:15]=[CH:14][CH:13]=[N:12]2)[N:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(CC)CC.[CH3:47][P:48]([C:53]1[CH:58]=[CH:57][C:56]([CH:59]([NH2:66])[C:60]2[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=2)=[CH:55][CH:54]=1)(=[O:52])[O:49][CH2:50][CH3:51]>CC#N>[OH:1][C:2]1[C:7]([C:8]([NH:66][CH:59]([C:60]2[CH:61]=[CH:62][CH:63]=[CH:64][CH:65]=2)[C:56]2[CH:55]=[CH:54][C:53]([P:48]([CH3:47])(=[O:52])[O:49][CH2:50][CH3:51])=[CH:58][CH:57]=2)=[O:10])=[CH:6][N:5]=[C:4]([N:11]2[CH:15]=[CH:14][CH:13]=[N:12]2)[N:3]=1
Reactant: O=C(O)c1cnc(-n2cccn2)nc1O
Reactant: CCOP(C)(=O)c1ccc(C(N)c2ccccc2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCOP(C)(=O)c1ccc(C(NC(=O)c2cnc(-n3cccn3)nc2O)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 4-hydroxy-2-(1H-pyrazol-1-yl)pyrimidine-5-carboxylic acid, 8-b, (206 mg, 1 mmol) in MeCN (20 ml) were added HATU (395 mg, 1.04 mmol), Et3N (105 mg, 1.04 mmol) and ethyl methyl(4-(amino(phenyl)methyl)phenyl)phosphinate, 2-d, (289 mg, 1 mmol). The resulting mixture was stirred at room temperature for 2 hours. Then it was filtered before diluted with saturated NH4Cl solution. The mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated under vacuum. The residue was purified on silica gel chromatography to provide the product, 8-3, (150 mg, 31%). 1H NMR (CD3OD, 300 MHz,): δ 8.65 (s, 1H), 8.57 (m, 1H), 7.91 (s, 1H), 7.76 (m, 2H), 7.52 (m, 2H), 7.34 (m, 5H), 6.64 (s, 1H), 6.36 (s, 1H), 3.85 (m, 2H), 1.67 (d, 3H), 1.25 (m, 3H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:15]([NH:17][CH3:18])=[O:16])=[N:4][C:5]([CH:8]2[CH2:13][CH2:12][C:11](=[O:14])[CH2:10][CH2:9]2)=[CH:6][CH:7]=1.CO.[BH4-].[Na+]>>[NH2:1][C:2]1[C:3]([C:15]([NH:17][CH3:18])=[O:16])=[N:4][C:5]([C@H:8]2[CH2:9][CH2:10][C@H:11]([OH:14])[CH2:12][CH2:13]2)=[CH:6][CH:7]=1
Reactant: CNC(=O)c1nc(C2CCC(=O)CC2)ccc1N
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CNC(=O)c1nc([C@H]2CC[C@H](O)CC2)ccc1N
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
A solution of 3-amino-N-methyl-6-(4-oxocyclohexyl)pyridine-2-carboxamide (Compound 232B, 53 mg, 0.21 mmol) in MeOH (3 mL, 70 mmol) was cooled to 0° C. and treated with sodium borohydride (8.1 mg, 0.21 mmol). The mixture was stirred at 0° C. for 20 minutes. The reaction was quenched with sat. aq. NH4Cl (1 mL) and concentrated. The residue was taken up in 1 mL H2O and EtOAc (30 m). The layers were separated. The aqueous layer was saturated with salt and washed again with ˜20 mL of EtOAc. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude solid was taken up in DCM, treated with silica and concentrated. This silica was loaded into a sample column and purified on an ISCO Combiflash unit (0-7% MeOH/DCM) to isolate the product as a mixture of predominantly trans isomer. 1H NMR (400 MHz, CHLOROFORM-d) δ1.37-1.57 (m, 4H), 1.92-2.01 (m, 2H), 2.07-2.16 (m, 2H), 2.55 (tt, J=11.87, 3.54 Hz, 1H), 2.99 (d, J=5.05 Hz, 3H), 3.63-3.77 (m, 1H), 5.81 (br. s., 2H), 6.95 (d, J=8.40 Hz, 1H), 7.04 (d, J=8.40 Hz, 1H), 8.11 (br. s., 1H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[F:10])[CH2:5][NH2:6].N1CCOCC1.[CH3:17][C:18]1([CH3:28])[O:22][C:21](=[CH:23][C:24](Cl)=[O:25])[C:20](=[O:27])[O:19]1>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[F:10])[CH2:5][NH:6][C:24](=[O:25])[CH:23]=[C:21]1[C:20](=[O:27])[O:19][C:18]([CH3:17])([CH3:28])[O:22]1
Reactant: NCc1ccc(F)c(F)c1
Reactant: CC1(C)OC(=O)C(=CC(=O)Cl)O1
Solvent: ClCCl
Solvent: C1COCCN1
Product: CC1(C)OC(=O)C(=CC(=O)NCc2ccc(F)c(F)c2)O1
Reaction time: 1 h
Yield: 91.7 %

Procedure:
To a stirred suspension of 3,4-difluorobenzylamine (0.43 mg, 0.3 mmol) and resin bound morpholine (200 mg, 2.5–4.0 mmol/1 g) was added a solution of (2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-acetyl chloride (60 mg, 0.31 mmol) in CH2Cl2 (3 mL) and the mixture stirred for 1 h. The mixture was filtered and the filtrate concentrated to give the title product as a white solid (81.8 mg, 92% yield). MS calcd for C14H13F2NO4Na (M+Na): 320.29. found: 320.27.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[CH:9]([CH3:28])[C:10]([C:16]1[CH:17]=[CH:18][C:19]2[O:24][CH2:23][C:22](=[O:25])[N:21]([CH3:26])[C:20]=2[CH:27]=1)([OH:15])[C:11]([F:14])([F:13])[F:12].[F:29][C:30]1[CH:31]=[C:32](B(O)O)[CH:33]=[CH:34][C:35]=1[C:36]([O:38][CH3:39])=[O:37]>C([O-])(=O)C.[Cu+2].C([O-])(=O)C.N1C=CC=CC=1>[CH3:39][O:38][C:36](=[O:37])[C:35]1[CH:34]=[CH:33][C:32]([O:8][C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([CH:9]([CH3:28])[C:10]([OH:15])([C:16]3[CH:17]=[CH:18][C:19]4[O:24][CH2:23][C:22](=[O:25])[N:21]([CH3:26])[C:20]=4[CH:27]=3)[C:11]([F:12])([F:13])[F:14])[CH:4]=2)=[CH:31][C:30]=1[F:29]
Reactant: CC(c1cc(O)ccc1Cl)C(O)(c1ccc2c(c1)N(C)C(=O)CO2)C(F)(F)F
Reactant: COC(=O)c1ccc(B(O)O)cc1F
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Product: COC(=O)c1ccc(Oc2ccc(Cl)c(C(C)C(O)(c3ccc4c(c3)N(C)C(=O)CO4)C(F)(F)F)c2)cc1F

Procedure:
In analogy to Example 5, 6-[2-(2-chloro-5-hydroxy-phenyl)-1-hydroxy-1-trifluoromethyl-propyl]-4-methyl-4H-benzo[1,4]oxazin-3-one (Example 1, step 4) was reacted with 3-fluoro-4-methoxycarbonylphenylboronic acid, copper-(II)-acetate and pyridine to give the title compound as a colorless foam. MS (m/e)=568.3 [M+H+].
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][S:11](=[O:15])(=[O:14])[CH2:10][CH2:9]2)=[C:4]([F:16])[CH:3]=1.C[Al](C)C.N#N.[NH:23](/[C:27](/[CH3:33])=[CH:28]\[C:29](OC)=[O:30])[C:24]([CH3:26])=O>C(Cl)Cl>[O:15]=[S:11]1(=[O:14])[CH2:12][CH2:13][N:8]([C:5]2[CH:6]=[CH:7][C:2]([N:1]3[C:29](=[O:30])[CH:28]=[C:27]([CH3:33])[N:23]=[C:24]3[CH3:26])=[CH:3][C:4]=2[F:16])[CH2:9][CH2:10]1
Reactant: COC(=O)/C=C(/C)NC(C)=O
Reactant: Nc1ccc(N2CCS(=O)(=O)CC2)c(F)c1
Agent: C[Al](C)C
Agent: N#N
Solvent: ClCCl
Product: Cc1cc(=O)n(-c2ccc(N3CCS(=O)(=O)CC3)c(F)c2)c(C)n1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 46.9 %

Procedure:
To a solution of 4-(4-amino-2-fluorophenyl)1,1-dioxidothiomorpholine (1.20 g, 4.91 mmol) in anhydrous CH2Cl2 (100 mL) was added trimethylaluminium (28.5 mL, 28.5 mmol, 1 M in heptane) carefully dropwise under N2. Upon the end of addition the mixture was stirred at rt for 20 min, followed by the addition of a solution of methyl 3-acetaminocrotonate (2.32 g, 14.76 mmol) in anhydrous CH2Cl2 (30 mL). Upon the end of addition the reaction mixture was stirred at rt for another 15 h, then quenched with an appropriate amount of water and extracted with CH2Cl2. The combined organic phases were washed with brine, dried and concentrated in vacuo to give the title compound as a yellow solid (0.81 g, 47%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:5][N:6]=1.[Br:12]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:12][CH2:1][C:2]1[S:3][C:4]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:5][N:6]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)c1cnc(C)s1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)c1cnc(CBr)s1
Temperature: 25 °C
Yield: 16.8 %

Procedure:
A solution of ethyl 2-methyl-5-thiazole carboxylate [S. H Mashragui, P. M. Keehn, JACS 104 4461-4465 (1982)] (4.73 g, 27.68 mmol) in carbon tetrachloride (30 ml) was treated with N-bromosuccinimide (4.92 g, 27.64 mmol) and benzoyl peroxide (0.03 g). The reaction mixture was heated to reflux under a strong light for 11/4 hours. The reaction was allowed to cool to ambient temperature and filtered. The filtrate was evaporated and subjected to chromatography (CH2Cl2) to give the title product (1.16 g, 17%). NMR (200 MH2,DMSO-d6) : δ8.4 (s, 1H) , 5.06 (s, 2H) , 4.33 (g, 2H), 1.3 (t, 3H).
Reaction SMILES: [C:1]([CH2:3]C(O)=O)#[N:2].[C:7]1([CH2:13][CH2:14][C:15](=O)[CH2:16][CH3:17])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>>[CH2:16]([CH:15]([CH2:14][CH2:13][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH2:3][C:1]#[N:2])[CH3:17]
Reactant: N#CCC(=O)O
Reactant: CCC(=O)CCc1ccccc1
Product: CCC(CC#N)CCc1ccccc1

Procedure:
The reaction was repeated utilizing an equimolar quantity of dimethyl malonate in place of the cyanoacetic acid to yield methyl 4-methyl-5-phenylpentanoate. Repeating the cyanoacetic acid condensation/reduction reaction utilizing 5phenylpentan-3-one as the starting material afforded 3-ethyl-5-phenylpentanenitrile.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[N:10]([CH2:11][C:12]([N:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)=[O:13])[C:9](=[O:20])[S:8][C:5]2=[N:6][CH:7]=1.[N:21](OCCC(C)C)=[O:22]>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]2[N:10]([CH2:11][C:12]([N:14]3[CH2:15][CH2:16][N:17]([N:21]=[O:22])[CH2:18][CH2:19]3)=[O:13])[C:9](=[O:20])[S:8][C:5]2=[N:6][CH:7]=1
Reactant: O=C(Cn1c(=O)sc2ncc(Cl)cc21)N1CCNCC1
Reactant: CC(C)CCON=O
Solvent: ClC(Cl)Cl
Product: O=NN1CCN(C(=O)Cn2c(=O)sc3ncc(Cl)cc32)CC1
Temperature: 25 °C
Reaction time: 11 h

Procedure:
To a solution of 6-chloro-2-oxo-1-[(1-piperazinyl)carbonylmethyl]-1,2-dihydrothiazolo[5,4-b]pyridine (1.40 g) in chloroform (15 ml) was added isoamyl nitrite (3.0 ml) and the mixture was stirred for 11 hours at room temperature. Precipitated crystals were collected by filtration, washed with chloroform and dried to give colorless crystals of 6-chloro-2-oxo-1-[(4-nitroso-1-piperazinyl)carbonylmethyl]-1,2-dihydrothiazolo[5,4-b]pyridine (1.33 g).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[NH:17][C:18]1[CH:19]=[N:20][C:21]([N:24]2[CH2:28][CH2:27][CH:26]([NH:29]C(=O)OC(C)(C)C)[CH2:25]2)=[N:22][CH:23]=1.[Cl:37][C:38]1[CH:43]=[C:42](B2OC(C)(C)C(C)(C)O2)[CH:41]=[C:40]([F:53])[C:39]=1[OH:54]>>[NH2:29][CH:26]1[CH2:27][CH2:28][N:24]([C:21]2[N:22]=[CH:23][C:18]([NH:17][C:5]3[C:4]4[C:9](=[CH:10][CH:11]=[C:2]([C:42]5[CH:41]=[C:40]([F:53])[C:39]([OH:54])=[C:38]([Cl:37])[CH:43]=5)[CH:3]=4)[N:8]=[CH:7][C:6]=3[C:12]([CH:14]3[CH2:16][CH2:15]3)=[O:13])=[CH:19][N:20]=2)[CH2:25]1
Reactant: CC1(C)OB(c2cc(F)c(O)c(Cl)c2)OC1(C)C
Reactant: CC(C)(C)OC(=O)NC1CCN(c2ncc(Nc3c(C(=O)C4CC4)cnc4ccc(Br)cc34)cn2)C1
Product: NC1CCN(c2ncc(Nc3c(C(=O)C4CC4)cnc4ccc(-c5cc(F)c(O)c(Cl)c5)cc34)cn2)C1
Yield: 45 %

Procedure:
Following general procedure D, tert-butyl 1-(5-(6-bromo-3-(cyclopropanecarbonyl)quinolin-4-ylamino)pyrimidin-2-yl)pyrrolidin-3-ylcarbamate (100 mg, 0.18 mmol) was reacted with 2-chloro-6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (74 mg, 0.27 mmol) to obtain the protected intermediate which was subjected to general procedure A-2 to afford the desired product (42 mg, 45% over 2 steps) as a yellow-orange solid: 1H NMR (500 MHz, CD3OD+TFA-d) δ 9.35 (s, 1H), 8.48 (s, 2H), 8.25 (dd, J=8.8, 1.9 Hz, 1H), 8.19 (s, 1H), 8.04 (d, J=8.8 Hz, 1H), 7.22 (s, 2H), 4.06 (m, 2H), 3.91 (dt, J=11.7, 7.4 Hz, 1H), 3.82 (m, 2H), 2.82 (s, 1H), 2.54 (td, J=13.1, 6.8 Hz, 1H), 2.24 (td, J=13.2, 5.7 Hz, 1H), 1.21 (s, 4H); ESI MS m/z 519 [C27H24ClFN6O2+H]+; HPLC 99.7% (AUC), tR=10.05 min.
Reaction SMILES: [CH2:1]([NH:4][CH2:5][CH2:6][OH:7])[CH2:2][CH3:3].[C:8]1([S:14](Cl)(=[O:16])=[O:15])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C(N(CC)CC)C>C(Cl)Cl>[CH2:1]([N:4]([CH2:5][CH2:6][OH:7])[S:14]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)(=[O:16])=[O:15])[CH2:2][CH3:3]
Reactant: CCCNCCO
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCN(CCO)S(=O)(=O)c1ccccc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
At 0° C., 5.16 g (50 mmol) of N-propylethanolamine were introduced into 70 ml of methylene chloride, and 9.7 g (55 mmol) of benzenesulfonyl chloride and 7.6 g (75 mmol) of triethylamine were added successively. After 2 hours of stirring at 0° C., the mixture was allowed to warm to room temperature, stirring was continued for a further hour and the mixture was then extracted with 1M hydrochloric acid and subsequently with 2M aqueous sodium hydroxide solution. The organic phase was dried over Na2SO4, filtered, concentrated and the resulting residue (13.2 g) was chromatographed over silica gel (methylene chloride/methanol 19:1). Yield: 7.4 g as an oil which was directly reacted further.
Reaction SMILES: [CH:1]1([NH:4][CH:5]2[CH2:10][CH2:9][N:8]([C:11]3[O:15][N:14]=[C:13]([CH:16]([CH3:18])[CH3:17])[N:12]=3)[CH2:7][CH2:6]2)[CH2:3][CH2:2]1.[CH3:19][C:20]1[N:21]([C:25]2[CH:33]=[CH:32][C:28]([C:29](O)=[O:30])=[CH:27][CH:26]=2)[CH:22]=[CH:23][N:24]=1>>[CH:1]1([N:4]([CH:5]2[CH2:10][CH2:9][N:8]([C:11]3[O:15][N:14]=[C:13]([CH:16]([CH3:18])[CH3:17])[N:12]=3)[CH2:7][CH2:6]2)[C:29](=[O:30])[C:28]2[CH:27]=[CH:26][C:25]([N:21]3[CH:22]=[CH:23][N:24]=[C:20]3[CH3:19])=[CH:33][CH:32]=2)[CH2:2][CH2:3]1
Reactant: CC(C)c1noc(N2CCC(NC3CC3)CC2)n1
Reactant: Cc1nccn1-c1ccc(C(=O)O)cc1
Product: Cc1nccn1-c1ccc(C(=O)N(C2CC2)C2CCN(c3nc(C(C)C)no3)CC2)cc1

Procedure:
The title compound is prepared from cyclopropyl-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yl]-amine and 4-(2-methyl-imidazol-1-yl)-benzoic acid following a procedure analogous to that described in Example 90. LC (method 19): tR=3.46 min; Mass spectrum (ESI+): m/z=435 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([C:19]([F:22])([F:21])[F:20])=[CH:16][CH:17]=3)[N:12]=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([N:30]=[C:31]=[S:32])=[CH:26][C:25]=1[C:33]([F:36])([F:35])[F:34]>>[F:20][C:19]([F:22])([F:21])[C:15]1[CH:14]=[C:13]2[C:18]([C:9]([S:8][C:5]3[CH:6]=[CH:7][C:2]([NH:1][C:31]([NH:30][C:27]4[CH:28]=[CH:29][C:24]([Cl:23])=[C:25]([C:33]([F:36])([F:34])[F:35])[CH:26]=4)=[S:32])=[CH:3][CH:4]=3)=[CH:10][CH:11]=[N:12]2)=[CH:17][CH:16]=1
Reactant: FC(F)(F)c1cc(N=C=S)ccc1Cl
Reactant: Nc1ccc(Sc2ccnc3cc(C(F)(F)F)ccc23)cc1
Product: FC(F)(F)c1ccc2c(Sc3ccc(NC(=S)Nc4ccc(Cl)c(C(F)(F)F)c4)cc3)ccnc2c1
Yield: 62.7 %

Procedure:
4-(4-aminophenylthio)-7-trifluoromethylquinoline (0.01 mole, 3.2 g) and 4-chloro-3-trifluoromethylphenylisothiocyanate (0.01 mole, 2.4 g) were reacted according to procedure C to yield the title compound 3.5 g, 63%. Mass Spec (FD) 557. Calculated for C24H14ClF6N3 S2 : C, 51.66; H, 2.53; N, 7.53. Found: C, 51.92; H, 2.53; N, 7.46.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([I:10])[C:8]=1[I:9])[NH2:5].O.[N:12]([O-])=O.[Na+].O.O.Cl[Sn]Cl>Cl>[I:1][C:2]1[CH:3]=[C:4]([NH:5][NH2:12])[CH:6]=[C:7]([I:10])[C:8]=1[I:9]
Reactant: Nc1cc(I)c(I)c(I)c1
Reactant: O=N[O-]
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [Na+]
Solvent: O
Product: NNc1cc(I)c(I)c(I)c1
Temperature: -10 °C
Reaction time: 0.5 h

Procedure:
3,4,5-Triiodoaniline was obtained by the procedure of L. Kalb (L. Kalb et al., Über substituierte Indol-2-carbonsäure-8-propionsäuren and einige jodierte Bensolderivate, Chem. Ber. 59 (1926) 1860-1870). 4 g (8.5 mmol) of 3,4,5-triiodoaniline were stirred with the solution of 2.3 mL of concentrated hydrochloric acid and 2.3 mL of water. The mixture was cooled to about −10° C. and the equivalent quantity of 2.5 M solution of NaNO2 was added dropwise with intensive stirring. The reaction mixture was continued stirring for 30 min at −10° C. Next, the cooled solution of 5.75 g (25.5 mmol) of SnCl2.2H2O in 6 mL of concentrated HCl was added dropwise at −10° C. to the suspension of diazocompound. The reaction mixture was kept at −10° C. for one hour and at 5° C. overnight. The obtained precipitate was filtered off and washed with water to yield 4.7 g of 3,4,5-triiodophenylhydrazine, as a double salt with tin chloride, which was used for following step without additional treatment or purification. 1H-NMR (200 MHz, DMSO-d6), δ, ppm: 10.14 (2H, broad s, NH2), 8.46 (1H, s, NH), 7.5 (2H., s, arom.).
Reaction SMILES: I[C:2]1[N:3]=[N:4][C:5]([O:8][CH2:9][C:10]2[C:11]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[N:12][O:13][C:14]=2[CH3:15])=[CH:6][CH:7]=1.[NH3:22]>CO.[Cu]Br>[CH3:15][C:14]1[O:13][N:12]=[C:11]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:10]=1[CH2:9][O:8][C:5]1[N:4]=[N:3][C:2]([NH2:22])=[CH:7][CH:6]=1
Reactant: N
Reactant: Cc1onc(-c2ccccc2)c1COc1ccc(I)nn1
Agent: [Cu]Br
Solvent: CO
Product: Cc1onc(-c2ccccc2)c1COc1ccc(N)nn1
Temperature: 25 °C
Reaction time: 16 h
Yield: 46 %

Procedure:
3-Iodo-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-pyridazine (example 15a) (200 mg, 0.5 mmol) was dissolved in a solution of ammonia in methanol (7 M, 3 mL). After addition of copper(I) bromide (88 mg, 0.6 mmol) the mixture was stirred for 16 h at room temperature. The precipitate was filtered and the organic phase was adsorbed on silica. Chromatography (SiO2, dichloromethane:methanol=100:0 to 95:5) afforded the title compound (66 mg, 46%) as a light yellow solid. MS: m/e=283.1 [M+H]+.
Reaction SMILES: [C:1](Cl)(=[O:4])[CH:2]=[CH2:3].[NH2:6][C:7]1[CH:12]=[C:11]([NH:13][C:14]2[N:19]=[C:18]([C:20]3[CH:21]=[N:22][N:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=34)[C:17]([Cl:29])=[CH:16][N:15]=2)[C:10]([O:30][CH3:31])=[CH:9][C:8]=1[N:32]1[CH2:37][CH2:36][N:35]([C:38](=[O:49])[C@@H:39]([NH:41]C(=O)OC(C)(C)C)[CH3:40])[CH2:34][CH2:33]1.CCN(C(C)C)C(C)C>C(Cl)Cl>[NH2:41][C@@H:39]([CH3:40])[C:38]([N:35]1[CH2:36][CH2:37][N:32]([C:8]2[CH:9]=[C:10]([O:30][CH3:31])[C:11]([NH:13][C:14]3[N:19]=[C:18]([C:20]4[CH:21]=[N:22][N:23]5[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=45)[C:17]([Cl:29])=[CH:16][N:15]=3)=[CH:12][C:7]=2[NH:6][C:1](=[O:4])[CH:2]=[CH2:3])[CH2:33][CH2:34]1)=[O:49]
Reactant: C=CC(=O)Cl
Reactant: COc1cc(N2CCN(C(=O)[C@H](C)NC(=O)OC(C)(C)C)CC2)c(N)cc1Nc1ncc(Cl)c(-c2cnn3ccccc23)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C=CC(=O)Nc1cc(Nc2ncc(Cl)c(-c3cnn4ccccc34)n2)c(OC)cc1N1CCN(C(=O)[C@H](C)N)CC1
Reaction time: 0.75 h
Yield: 28.2 %

Procedure:
A solution of acryloyl chloride (10.2 μL, 0.13 mmol) in CH2Cl2 (3 mL) was added dropwise to a stirred solution of (S)-tert-butyl N-[1-(4-{2-amino-4-[(5-chloro-4-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-2-yl)amino]-5-methoxyphenyl}piperazin-1-yl)-1-oxopropan-2-yl]carbamate (Intermediate 59, 65 mg) and DIPEA (0.75 mL) in CH2Cl2 (10 mL), which was cooled in an ice/water bath. The mixture was stirred for 0.75 h. then quenched with water (10 mL) and 2M Na2CO3 (5 mL). The phases were separated and the organic solution was dried (MgSO4) and concentrated in vacuo. The resulting residue was dissolved in CH2Cl2 (3 mL) and was then treated with TFA (0.1 mL). After standing for 0.25 h a second portion of TFA (0.2 mL) was added. After a further 0.25 h the solution was concentrated in vacuo and purified by preparative HPLC (Waters SunFire column, 5μ silica, 19 mm diameter, 100 mm length), eluting with decreasingly polar mixtures of water (containing 0.1% formic acid) and CH3CN. Fractions containing the desired compound were concentrated in vacuo to give the title compound (17 mg, 6% from 5-chloro-N-(4-fluoro-2-methoxy-5-nitrophenyl)-4-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-2-amine) as a white solid; 1H NMR: 1.25 (3H, s), 2.83-2.96 (4H, m), 3.65-3.82 (7H, m), 4.14-4.23 (1H, m), 5.73 (1H, d), 61.9 (1H, d), 6.64-6.70 (1H, m), 6.69 (1H, s), 7.08-7.12 (1H, m) 7.30-7.37 (1H, m), 8.20-8.28 (2H, m), 8.35-8.41 (2H, m), 8.68 (1H, s), 8.80-8.84 (1H, m), 8.95 (1H, s), 9.11-9.15 (1H, m); m/z: ES+ MH+ 576.60.
Reaction SMILES: [NH2:1][C@H:2]([C:7]([NH2:9])=[O:8])[C:3]([SH:6])([CH3:5])[CH3:4].[CH3:10][C:11]([CH3:13])=O>O>[CH3:10][C:11]1([CH3:13])[NH:1][CH:2]([C:7]([NH2:9])=[O:8])[C:3]([CH3:5])([CH3:4])[S:6]1
Reactant: CC(C)=O
Reactant: CC(C)(S)[C@H](N)C(N)=O
Solvent: O
Product: CC1(C)NC(C(N)=O)C(C)(C)S1
Yield: 92 %

Procedure:
Penicillaminamide (74.0 g, 0.50 mol) was dissolved in distilled water (800 ml) and added with acetone (58.0 g, 1.00 mol). The mixture was allowed to react at 30° C. for 1 hour with stirring under normal pressure and cooled. Then, water and acetone were evaporated by using an evaporator. The residue was washed with acetone to obtain white crystals (86.5 g, 0.46 mol) of 2,2,5,5-tetramethyl-1,3-thiazolidine-4-carboxylic acid amide. The yield to penicillaminamide was 92.0 mole %.