Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:4]([NH:6][C:7]2[S:8][CH:9]=[C:10]([C:12]3[CH:19]=[CH:18][C:15]([CH2:16][NH2:17])=[CH:14][CH:13]=3)[N:11]=2)=[O:5])[CH2:3][CH2:2]1.[Cl:20][C:21]1[CH:37]=[CH:36][C:24]2[CH2:25][CH2:26][N:27]([C:30](=[O:35])[C:31]([F:34])([F:33])[F:32])[CH2:28][CH2:29][C:23]=2[C:22]=1OS(C(F)(F)F)(=O)=O.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[Cl:20][C:21]1[CH:37]=[CH:36][C:24]2[CH2:25][CH2:26][N:27]([C:30](=[O:35])[C:31]([F:32])([F:34])[F:33])[CH2:28][CH2:29][C:23]=2[C:22]=1[NH:17][CH2:16][C:15]1[CH:14]=[CH:13][C:12]([C:10]2[N:11]=[C:7]([NH:6][C:4]([CH:1]3[CH2:3][CH2:2]3)=[O:5])[S:8][CH:9]=2)=[CH:19][CH:18]=1
Reactant: NCc1ccc(-c2csc(NC(=O)C3CC3)n2)cc1
Reactant: O=C(N1CCc2ccc(Cl)c(OS(=O)(=O)C(F)(F)F)c2CC1)C(F)(F)F
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: Cc1ccccc1
Product: O=C(Nc1nc(-c2ccc(CNc3c(Cl)ccc4c3CCN(C(=O)C(F)(F)F)CC4)cc2)cs1)C1CC1
Temperature: 100 °C
Yield: 19.1 %

Procedure:
To a slurry of 4-[2-(cyclopropanecarbonyl-amino)-thiazol-4-yl]-benzylamine (1.654 g, 6.052 mmol) in toluene (30.2 mL)/dioxane (7.8 mL), at 100° C., add a solid mixture of 7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine (1.29 g, 3.03 mmol), tris(dibenzylideneacetone)-dipalladium(0) (0.55 g, 0.61 mmol), BINAP (0.75 g, 0.12 mmol) and cesium carbonate (3.45 g, 10.6 mmol) all at once. Purge the reaction mixture with nitrogen and heat at 100° C. overnight. After cooling to room temperature, filter the reaction mixture over Celite® and wash with DCM (500 mL). Concentrate in vacuo, dissolve the residue in DCM and load on to an Analogix® column (150 g). Purify by preparative liquid chromatography (0:1 to 1:9 2M ammonia in methanol/DCM over 33 min, 1:9 to 1:3 2M ammonia in methanol/DCM over 33 min, 1:3 to 1:1 2M ammonia in methanol/DCM over 33 min; 35 mL/min) to afford 7-chloro-6-{4-[2-(cyclopropanecarbonyl-amino)-thiazol-4-yl]-benzylamino}-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (0.318 g, 19%) as a yellow foam. MS (ES+) m/z: 549.1 (M+H)+.
Reaction SMILES: I[C:2]1[CH:27]=[CH:26][C:5]([C:6]([N:8]([CH3:25])[C@:9]([CH3:24])([C:14]([NH:16][O:17][CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][O:19]2)=[O:15])[C:10]([NH:12][CH3:13])=[O:11])=[O:7])=[CH:4][CH:3]=1.[C:28]([C:30]1[CH:37]=[CH:36][C:33]([CH:34]=[O:35])=[CH:32][CH:31]=1)#[CH:29].C1COCC1>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.[Cu]I.C(OCC)(=O)C>[CH:34]([C:33]1[CH:36]=[CH:37][C:30]([C:28]#[C:29][C:2]2[CH:27]=[CH:26][C:5]([C:6]([N:8]([CH3:25])[C@:9]([CH3:24])([C:14]([NH:16][O:17][CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][O:19]3)=[O:15])[C:10]([NH:12][CH3:13])=[O:11])=[O:7])=[CH:4][CH:3]=2)=[CH:31][CH:32]=1)=[O:35]
Reactant: C#Cc1ccc(C=O)cc1
Reactant: CNC(=O)[C@@](C)(C(=O)NOC1CCCCO1)N(C)C(=O)c1ccc(I)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CNC(=O)[C@@](C)(C(=O)NOC1CCCCO1)N(C)C(=O)c1ccc(C#Cc2ccc(C=O)cc2)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 74.7 %

Procedure:
TEA (10 mL) was added dropwise to a mixture of (2S)-2-[(4-iodobenzoyl)(methyl)amino]-N,2-dimethyl-N′-(tetrahydro-2H-pyran-2-yloxy)propanediamide (Intermediate 15, 12 g), 4-ethynylbenzaldehyde (4.1 g), PdCl2(PPh3)2 (0.85 g), CuI (0.46 g), and THF (60 mL) at room temperature in a nitrogen atmosphere, and the mixture was stirred for 2 hours and 15 minutes at room temperature. Ethyl acetate (0.20 L), OH type silica gel (12 g), cellpure (5.9 g) and activated carbon (0.60 g) were added, the insolubles were filtered out, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by OH type silica gel column chromatography (ethyl acetate/hexane=50/50, followed by gradient elution with chloroform/acetone=100/0→80/20). Then, ethyl acetate and IPE were added to the resulting solid, and the solid was filtered off and washed with IPE to obtain (2S)-2-[{4-[(4-formylphenyl)ethynyl]benzoyl}(methyl)amino]-N,2-dimethyl-N′-(tetrahydro-2H-pyran-2-yloxy)propanediamide (yellow brown solid) (9.0 g, 76%).
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([C:7]2[N:8]=[CH:9][N:10]([C:12]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:11]=2)=[CH:4][CH:3]=1.[Li]CCCC.[I:36]I.[NH4+].[Cl-]>C1COCC1>[I:36][C:9]1[N:10]([C:12]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:11]=[C:7]([C:5]2[S:6][C:2]([CH3:1])=[CH:3][CH:4]=2)[N:8]=1
Reactant: Cc1ccc(-c2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)s1
Reactant: II
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: Cc1ccc(-c2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c(I)n2)s1
Temperature: -50 °C
Reaction time: 8 h
Yield: 59.6 %

Procedure:
A mixture of 4-(5-methylthiophen-2-yl)-1-trityl-1H-imidazole (2.20 g, 5.42 mmol) in THF (100 mL) was cooled to −78° C. nBuLi mL of a 1.6 M solution in hexanes, 6.2 mmol) was added dropwise (˜2 min) and the pale yellow solution was allowed to warm to −50° C. (over ˜1 h) and then re-cooled to −78° C. I2 (2.74 g, 10.4 mmol) was added and the mixture was allowed to warm to room temperature (over ˜4 h) and stirred overnight. Saturated aqueous NH4Cl (2 mL) was added and the mixture was concentrated to ˜10 mL. The mixture was diluted with EtOAc, H2O, saturated aqueous Na2S2O3 and the organic phase was separated. The aqueous phase was re-extracted (EtOAc) and the combined organics were washed (saturated aqueous NaCl), dried (MgSO4), filtered and concentrated to give a residue. The residue was purified by flash chromatography (EtOAc/hexanes 5:95 then 15:85) to give 2-iodo-4-(5-methylthiophen-2-yl)-1-trityl-1H-imidazole 2 (1.72 g, 60%) as a colourless solid. 1H NMR (CDCl3, 400 MHz) δ2.45 (s, 3H), 6.60-6.64 (m, 1H), 6.94 (s, 1H), 6.99 (d, J=3.5 Hz, 1H), 7.19-7.39 (m, 15H); 13C NMR (CDCl3, 100 MHz) δ15.3, 90.6, 120.4, 122.3, 125.5, 125.6, 127.2, 128.1, 130.8, 134.2, 138.1, 138.2, 141.4, 146.8; HRMS (EI) m/z 532.0459 C27H21N2IS [M]+. requires 532.0465.
Reaction SMILES: [ClH:1].[C:2]1([N:8]([CH2:32][CH2:33][C:34]([O:36]CC)=[O:35])[C:9]([C:11]2[CH:12]=[C:13]3[N:19]=[C:18]([CH2:20][S:21][C:22]4[CH:27]=[CH:26][C:25]([C:28](=[NH:30])[NH2:29])=[CH:24][CH:23]=4)[N:17]([CH3:31])[C:14]3=[N:15][CH:16]=2)=[O:10])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].C(OCC)(=O)C.C(O)C.N>>[ClH:1].[C:2]1([N:8]([CH2:32][CH2:33][C:34]([OH:36])=[O:35])[C:9]([C:11]2[CH:12]=[C:13]3[N:19]=[C:18]([CH2:20][S:21][C:22]4[CH:27]=[CH:26][C:25]([C:28](=[NH:29])[NH2:30])=[CH:24][CH:23]=4)[N:17]([CH3:31])[C:14]3=[N:15][CH:16]=2)=[O:10])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)CCN(C(=O)c1cnc2c(c1)nc(CSc1ccc(C(=N)N)cc1)n2C)c1ccccc1
Agent: Cl
Agent: N
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(C)=O
Product: Cn1c(CSc2ccc(C(=N)N)cc2)nc2cc(C(=O)N(CCC(=O)O)c3ccccc3)cnc21
Yield: 88 %

Procedure:
Prepared analogously to Example 2 from 3-methyl-2-[(4-amidinophenyl)-thiomethyl]-imidazo[4,5-b]pyridin-6-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide-hydrochloride and sodium hydroxide solution. Yield: 88% of theory, C25H24N6O3S (488.56) Rf value: 0.21 (silica gel; ethyl acetate/ethanol/ammonia=50:45:5) ##EQU108##
Reaction SMILES: [S:1]1(=[O:11])(=[O:10])[CH2:8][CH2:7][CH2:6][C:5](=O)[CH2:4][CH2:3][CH2:2]1.[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([NH:20]N)=[CH:16][CH:15]=1>C(O)(=O)C>[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]2[NH:20][C:5]3[CH2:4][CH2:3][CH2:2][S:1](=[O:11])(=[O:10])[CH2:8][CH2:7][C:6]=3[C:16]=2[CH:15]=1
Reactant: O=C1CCCS(=O)(=O)CCC1
Reactant: COc1ccc(NN)cc1
Solvent: CC(=O)O
Product: COc1ccc2[nH]c3c(c2c1)CCS(=O)(=O)CCC3
Yield: 87.6 %

Procedure:
A mixture of 26.54g (0.15 mole) of 1-thiacyclooctane-5-one 1,1-dioxide and 22.0g (0.16 mole) of p-methoxyphenylhydrazine in 150 ml of glacial acetic acid is treated according to the procedure in Example 2. There is obtained 36.7g (88%) of a crystalline solid, m.p. 231°-233° C. Recrystallization from acetone-ethyl acetate gives 30g (72%) of an analytical sample, m.p. 233°-235° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:10]2[CH2:14][CH2:13][CH2:12][N:11]2[C:15]2[CH:20]=[CH:19][N:18]3[N:21]=[CH:22][C:23]([C:24]([O:26][CH2:27][CH2:28][Cl:29])=[O:25])=[C:17]3[N:16]=2)[C:5]([O:8]C)=[N:6][CH:7]=1.Cl>>[F:1][C:2]1[CH:3]=[C:4]([C@H:10]2[CH2:14][CH2:13][CH2:12][N:11]2[C:15]2[CH:20]=[CH:19][N:18]3[N:21]=[CH:22][C:23]([C:24]([O:26][CH2:27][CH2:28][Cl:29])=[O:25])=[C:17]3[N:16]=2)[C:5](=[O:8])[NH:6][CH:7]=1
Reactant: COc1ncc(F)cc1[C@H]1CCCN1c1ccn2ncc(C(=O)OCCCl)c2n1
Agent: Cl
Product: O=C(OCCCl)c1cnn2ccc(N3CCC[C@@H]3c3cc(F)c[nH]c3=O)nc12
Temperature: 100 °C

Procedure:
A mixture of (R)-2-chloroethyl 5-(2-(5-fluoro-2-methoxypyridin-3-yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylate (56 mg, 0.13 mmol) in HCl (4 N dioxane, 2.5 mL, 10 mmol) was sealed in a pressure reaction tube and heated at 100° C. for 45 minutes. The reaction mixture was cooled and concentrated to yield the product as yellowish oil, which was used directly in the next step without further purification, assuming quantitative yield. MS (apci) m/z=406.0 (M+H).
Reaction SMILES: Cl[C:2]1[N:9]=[C:8]([CH3:10])[CH:7]=[C:6]([NH:11][CH:12]([CH2:15][CH3:16])[CH2:13][CH3:14])[C:3]=1[C:4]#[N:5].[CH3:17][C:18]1[C:23]([OH:24])=[C:22]([CH3:25])[CH:21]=[C:20]([CH3:26])[N:19]=1>CN1C(=O)CCC1>[CH2:13]([CH:12]([NH:11][C:6]1[C:3]([C:4]#[N:5])=[C:2]([O:24][C:23]2[C:18]([CH3:17])=[N:19][C:20]([CH3:26])=[CH:21][C:22]=2[CH3:25])[N:9]=[C:8]([CH3:10])[CH:7]=1)[CH2:15][CH3:16])[CH3:14]
Reactant: CCC(CC)Nc1cc(C)nc(Cl)c1C#N
Reactant: Cc1cc(C)c(O)c(C)n1
Solvent: CN1CCCC1=O
Product: CCC(CC)Nc1cc(C)nc(Oc2c(C)cc(C)nc2C)c1C#N

Procedure:
The title compound was prepared by heating 2-chloro-4-(1-ethyl-propylamino)-6-methyl-nicotinonitrile with 2,4,6-trimethyl-3-hydroxy-pyridine in NMP.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[NH:12][CH:11]=[C:10]([CH:13]=[O:14])[C:9]=1[CH3:15].[H-].[Na+].C1OCCOCCOCCOCCOC1.Cl.[N:34]1[CH:39]=[CH:38][CH:37]=[C:36]([S:40](Cl)(=[O:42])=[O:41])[CH:35]=1>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:12]([S:40]([C:36]2[CH:35]=[N:34][CH:39]=[CH:38][CH:37]=2)(=[O:42])=[O:41])[CH:11]=[C:10]([CH:13]=[O:14])[C:9]=1[CH3:15]
Reactant: O=S(=O)(Cl)c1cccnc1
Reactant: Cc1c(C=O)c[nH]c1-c1ccccc1F
Agent: C1COCCOCCOCCOCCO1
Agent: Cl
Agent: [H-]
Product: Cc1c(C=O)cn(S(=O)(=O)c2cccnc2)c1-c1ccccc1F

Procedure:
By a similar operation as in Reference Example 65 and using 5-(2-fluorophenyl)-4-methyl-1H-pyrrole-3-carbaldehyde (301 mg), sodium hydride (60% in oil, 179 mg), 15-crown-5 (0.88 mL) and pyridin-3-ylsulfonyl chloride hydrochloride (476 mg), the title compound was obtained as white crystals (yield 440 mg, 87%).
Reaction SMILES: [CH2:1]([C:3]1[N:7]2[N:8]=[C:9]([C:13]3[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[CH:15][CH:14]=3)[C:10]([CH3:12])=[CH:11][C:6]2=[N:5][N:4]=1)[CH3:2].[OH:21]O.[OH-].[Na+]>C(O)C>[CH2:1]([C:3]1[N:7]2[N:8]=[C:9]([C:13]3[CH:20]=[CH:19][C:16]([C:17]([NH2:18])=[O:21])=[CH:15][CH:14]=3)[C:10]([CH3:12])=[CH:11][C:6]2=[N:5][N:4]=1)[CH3:2]
Reactant: OO
Reactant: CCc1nnc2cc(C)c(-c3ccc(C#N)cc3)nn12
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCc1nnc2cc(C)c(-c3ccc(C(N)=O)cc3)nn12
Reaction time: 3 h

Procedure:
A 4.5 g. portion of p-(3-ethyl-7-methyl-1,2,4-triazolo[4,3-b]pyridazin-6-yl)benzonitrile (prepared as described in Example 3) is dissolved in 50 ml. of ethyl alcohol with warming, then 50 ml. of 30% hydrogen peroxide is added with swirling and finally 50 ml. of 2N sodium hydroxide is added with swirling. The reaction is allowed to stand at room temperature for 3 hours, then is concentrated almost to dryness using as little heat as possible. The concentrate is diluted with water, filtered and the filter cake is then washed with water and air dried. The product is dissolved in acetone and filtered to remove insolubles then is recrystallized to afford a yellow solid as the product of the example, m.p. 210°-213° C.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH2:11][C@H:10]([N:14](C(OC(C)(C)C)=O)[CH2:15][C:16]2[CH:21]=[C:20]([N:22]3[C:26]([C:27]([F:30])([F:29])[F:28])=[N:25][N:24]=[N:23]3)[CH:19]=[CH:18][C:17]=2[O:31][CH2:32][CH:33]2[CH2:35][CH2:34]2)[C@@H:9]1[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)=O)(C)(C)C.[ClH:49]>O1CCOCC1>[ClH:49].[ClH:49].[CH:33]1([CH2:32][O:31][C:17]2[CH:18]=[CH:19][C:20]([N:22]3[C:26]([C:27]([F:28])([F:30])[F:29])=[N:25][N:24]=[N:23]3)=[CH:21][C:16]=2[CH2:15][NH:14][C@H:10]2[CH2:11][CH2:12][CH2:13][NH:8][C@H:9]2[C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[CH2:35][CH2:34]1
Reactant: CC(C)(C)OC(=O)N(Cc1cc(-n2nnnc2C(F)(F)F)ccc1OCC1CC1)[C@H]1CCCN(C(=O)OC(C)(C)C)[C@H]1c1ccccc1
Agent: Cl
Solvent: C1COCCO1
Product: FC(F)(F)c1nnnn1-c1ccc(OCC2CC2)c(CN[C@H]2CCCN[C@H]2c2ccccc2)c1

Procedure:
A solution of 3-{tert-butoxycarbonyl-[2-(cyclopropylmethoxy)-5-(5-trifluoromethyl-tetrazol-1-yl)-benzyl]-amino}[2S,3S]-2-phenylpiperidine-1-carboxylic acid tertbutyl ester (101 mg, 0.15 mmole) in 4M-hydrogen chloride in dioxan (5 ml) was kept at 44° for 3.25 h and then evaporated. The residue was triturated with ethanol to give the title compound as a white solid (66 mg), mass spectrum (thermospray +ve) m/e 473 (MH+). RF 0.5 (100: 8:1 dichloromethane: ethanol: ammonia).
Reaction SMILES: [CH3:1][C:2]([CH3:13])([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH2:3][C:4]([OH:6])=[O:5].C(=O)=O.[CH3:17][C:18](C)=O.C([N-]C(C)C)(C)C.[Li+].C(O)(=O)C(C)=O.N1C=CC=NC1=O.C(I)C>O1CCCC1>[CH2:17]([CH:3]([C:2]([CH3:13])([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH3:1])[C:4]([OH:6])=[O:5])[CH3:18]
Reactant: CC(C)(CC(=O)O)c1ccccc1
Reactant: CC(C)=O
Agent: CC(=O)C(=O)O
Agent: CC(C)[N-]C(C)C
Agent: O=C=O
Solvent: CCI
Solvent: C1CCOC1
Product: CCC(C(=O)O)C(C)(C)c1ccccc1
Temperature: 25 °C
Yield: 30 %

Procedure:
In accordance with a modified literature procedure (Pfeffer, P. E.; Silbert, L. S.; Chirinko, J. M. J. Org. Chem. 37(3), 1972, 451-458), a solution of 3,3-dimethyl-3-phenyl propionic acid (0.47 g, 2.6 mmol, from Reference Example 22) in tetrahydrofuran (4.5 mL) is cooled to −40° C. (dry ice/acetone) while stirring under a nitrogen atmosphere. Lithium diisopropylamide (Aldrich, 2.0 M solution in tetrahydrofuran/ethylbenzene/heptane, 2.9 mL, 5.8 mmol) is added dropwise via syringe, followed by 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H-pyrimidinone (DMPU, 0.35 mL, 2.9 mmol). The reaction mixture is then allowed to warm to room temperature and to stir for 30 minutes before being re-cooled to 0° C. (ice water bath). Ethyl iodide (0.31 mL, 3.9 mmol) is then added neat via syringe and the reaction mixture is allowed to stir overnight while warming to room temperature. The reaction is quenched by the addition of 10% aqueous hydrochloric acid solution and extracted thrice with ethyl acetate. The combined extracts are washed twice with 10% aqueous hydrochloric acid solution and once with saturated sodium chloride solution, dried over anhydrous sodium sulfite, and concentrated under reduced pressure. The crude solid is recrystallized from hexanes to afford pure material as a white solid (0.16 g, 30%). MS (ES−): (M−H)=205.0
Reaction SMILES: [C:1]([C:5]1[C:6]([OH:13])=[C:7]([CH:10]=[CH:11][CH:12]=1)[CH:8]=[O:9])([CH3:4])([CH3:3])[CH3:2].[N+:14]([O-])([OH:16])=[O:15]>C(O)(=O)C>[C:1]([C:5]1[C:6]([OH:13])=[C:7]([CH:10]=[C:11]([N+:14]([O-:16])=[O:15])[CH:12]=1)[CH:8]=[O:9])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=[N+]([O-])O
Reactant: CC(C)(C)c1cccc(C=O)c1O
Solvent: CC(=O)O
Product: CC(C)(C)c1cc([N+](=O)[O-])cc(C=O)c1O
Temperature: 25 °C
Reaction time: 1 h
Yield: 64 %

Procedure:
5.0 g (28 mmol) of 3-tert-butyl-2-hydroxybenzaldehyde in 8 ml of glacial acetic acid were introduced into a 50 ml two-necked flask fitted with magnetic stirrer and dropping funnel, and 2.8 ml (68 mmol) of nitric acid were added at a temperature of below 5° C. The batch was subsequently stirred further at room temperature for one hour. The product was isolated by precipitation on ice and washed with water. After recyrstallization of the methanol, the product was dried. The yield was 64%.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][C:9]1(C)[S:13][C@@H:12]2[C@H:14]([NH:17][C:18]([C@H:20]([NH2:27])[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)=[O:19])[C:15](=[O:16])[N:11]2[C@H:10]1[C:28]([OH:30])=[O:29].N([O-])=O.[Na+].[ClH:36]>CC(C)=O.C(OCC)(=O)C.O>[NH2:27][C@H:20]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:18]([NH:17][C@@H:14]1[C:15](=[O:16])[N:11]2[C@@H:12]1[S:13][CH2:9][C:8]([Cl:36])=[C:10]2[C:28]([OH:30])=[O:29])=[O:19]
Reactant: Cl
Reactant: CC1(C)S[C@@H]2[C@H](NC(=O)[C@H](N)c3ccccc3)C(=O)N2[C@H]1C(=O)O
Agent: O=N[O-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: O
Solvent: CC(C)=O
Product: N[C@@H](C(=O)N[C@@H]1C(=O)N2C(C(=O)O)=C(Cl)CS[C@H]12)c1ccccc1

Procedure:
2.6 ml (18.6 mmol) of triethylamine are added to a suspension of 3.5 g (10 mmol) of ampicillin in 15 ml of acetone and stirring takes place for 20 hours, at room temperature. After evaporating the solvent, 30 ml of water, 0.83 g (12 mmol) of sodium nitrite and 20 ml of ethyl acetate are added. The mixture is cooled in an ice bath and is acidified with hydrochloric acid to a pH of 2. The aqueous phase is decanted and the organic phase is washed successively with water and saturated sodium chloride solution, dried over anhydrous magnesium sulphate and evaporated to dryness. A white solid is obtained which corresponds to the title compound. It crystallizes from methanol/water. M.p. 167°-169° C.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:11][C:12]([C:16]3[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=3)(O)[CH2:13][CH3:14])[C:6]3[CH2:22][CH2:23][N:24]([CH3:26])[CH2:25][C:5]=3[C:4]=2[CH:3]=1.CN(C=O)C.S(Cl)(Cl)=O.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7](/[CH:11]=[C:12](/[C:16]3[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=3)\[CH2:13][CH3:14])[C:6]3[CH2:22][CH2:23][N:24]([CH3:26])[CH2:25][C:5]=3[C:4]=2[CH:3]=1
Reactant: CCC(O)(Cn1c2c(c3cc(Cl)ccc31)CN(C)CC2)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: CC/C(=C\n1c2c(c3cc(Cl)ccc31)CN(C)CC2)c1ccncc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
1-(8-Chloro-1,2,3,4-tetrahydro-2-methylpyrido[4,3-b]indol-5-yl)-2-(pyridin-4-yl)butan-2-ol (0.2 g, 0.542 mmol) was dissolved in dry DCM (10 mL) and a drop of DMF was added. The solution was cooled to 0° C. and thionyl chloride (0.1 mL, 1.6 mmol) diluted with dry DCM (2 mL) was added dropwise. Stirring was continued for 1 h at 0° C. and then at RT for 2 h. The solution was basified with saturated aqueous sodium bicarbonate and extracted with EtOAc (3×50 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by HPLC. 1H NMR (CDCl3, freebase) δ (ppm): 8.65 (d, 2H), 7.40 (m, 3H), 7.10 (m, 2H), 6.80 (s, 1H), 3.65 (s, 2H), 2.80 (m, 4H), 2.60 (s, 3H), 2.45 (m, 2H), 0.9 (t, 3H).
Reaction SMILES: [C:1]([N:4]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:30]=[CH:29][C:21]3[N:22]([CH2:25][CH:26]4[CH2:28][CH2:27]4)[N:23]=[N:24][C:20]=3[C:19]=2[C:31]([F:34])([F:33])[F:32])=[CH:14][CH:13]=1)[CH2:5][C:6]([O:8]CC)=O)(=[O:3])[NH2:2]>ClCCl.O>[CH:26]1([CH2:25][N:22]2[C:21]3[CH:29]=[CH:30][C:18]([C:15]4[CH:16]=[CH:17][C:12]([CH2:11][N:4]5[CH2:5][C:6](=[O:8])[NH:2][C:1]5=[O:3])=[CH:13][CH:14]=4)=[C:19]([C:31]([F:32])([F:33])[F:34])[C:20]=3[N:24]=[N:23]2)[CH2:28][CH2:27]1
Reactant: CCOC(=O)CN(Cc1ccc(-c2ccc3c(nnn3CC3CC3)c2C(F)(F)F)cc1)C(N)=O
Solvent: O
Solvent: ClCCl
Product: O=C1CN(Cc2ccc(-c3ccc4c(nnn4CC4CC4)c3C(F)(F)F)cc2)C(=O)N1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Ethyl N-carbamoyl-N-{4-[1-(cyclopropylmethyl)-4-(trifluoromethyl)-1H-benzotriazol-5-yl]benzyl}glycinate was dissolved in a dichloromethane/1 N hydrochloric acid solution and the reaction mixture placed into an oil-bath preheated to 100° C. The mixture was stirred for 1.5 hours, cooled to ambient temperature, diluted with water and extracted with ethyl acetate (3×30 mL). The organic layers were combined, dried over sodium sulfate and concentrated in vacuo to afford the titled compound as a white solid. H1-NMR (400 MHz, CDCl3): δ 8.87 (1H, s), 7.70 (1H, d, J=8.6 Hz), 7.35 (1H, d, J=8.6 Hz), 7.30 (2H, d, J=8.3 Hz), 7.26 (2H, d, J=8.3 Hz), 4.55 (2H, s), 4.53 (2H, d, J=7.2 Hz), 3.80 (2H, s), 1.60-1.49 (1H, m), 0.69-0.57 (2H, m), 0.52-0.41 (2H, m) ppm; high resolution mass spectrometry (ES+) m/z 430.1509 [(M+H)+; calculated for C21H19F3N5O2: 430.1485].
Reaction SMILES: C([N:4]1[C@@H:9]([CH3:10])[CH2:8][N:7]([C:11]([O:13][CH:14]([CH3:16])[CH3:15])=[O:12])[C:6]2[CH:17]=[C:18]([Br:21])[CH:19]=[N:20][C:5]1=2)(=O)C.[OH-].[Na+]>>[Br:21][C:18]1[CH:19]=[N:20][C:5]2[NH:4][C@@H:9]([CH3:10])[CH2:8][N:7]([C:11]([O:13][CH:14]([CH3:16])[CH3:15])=[O:12])[C:6]=2[CH:17]=1
Reactant: CC(=O)N1c2ncc(Br)cc2N(C(=O)OC(C)C)C[C@@H]1C
Agent: [Na+]
Agent: [OH-]
Product: CC(C)OC(=O)N1C[C@H](C)Nc2ncc(Br)cc21
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A reaction vial was charged with (S)-isopropyl 4-acetyl-7-bromo-3-methyl-3,4-dihydropyrido[2,3-b]pyrazine-1(2H)-carboxylate (0.2 M in methanol, 0.1 mL, 0.02 mmol). Sodium hydroxide (2.0 M in water, 0.050 mL, 0.10 mmol) was added and the reaction was shaken at room temperature for 6 hours. The reaction mixture was concentrated to afford (S)-isopropyl 7-bromo-3-methyl-3,4-dihydropyrido[2,3-b]pyrazine-1(2H)-carboxylate which was used in the next step without purification. MS (ESI, pos. ion) m/z 314, 316 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([CH3:9])=[CH:4][C:3]=1[O:10][C:11]([F:14])([F:13])[F:12].Cl.C=O.CO[CH2:20][Cl:21]>O.C(O)(=O)C>[F:14][C:11]([F:12])([F:13])[O:10][C:3]1[CH:4]=[C:5]([CH3:9])[C:6]([CH2:20][Cl:21])=[C:7]([CH3:8])[C:2]=1[CH3:1]
Reactant: COCCl
Reactant: Cc1cc(C)c(C)c(OC(F)(F)F)c1
Agent: C=O
Agent: Cl
Solvent: CC(=O)O
Solvent: O
Product: Cc1cc(OC(F)(F)F)c(C)c(C)c1CCl

Procedure:
A solution of 31.5 (0.15 mol) of 2,3,5-trimethyl-1-trifluoromethoxybenzene, 315 ml of acetic acid, 31.5 ml of concentrated hydrochloric acid, 31.5 ml of aqueous formaldehyde and 13 g (0.185 mol) of chloromethyl methyl ether was heated to 85° C. for 72 hours. (Small samples were worked up periodically after 48 hours to optimize the ratio of monochloromethyl product:dichloromethyl product:starting material). The solution was then cooled, poured into 1.5 liters of water and extracted with 3×500 ml of hexane. The hexane extracts were washed with 1 liter of water and 500 ml of saturated NaHCO3 solution, dried (MgSO4), filtered, and concentrated to give 30 g of crude (4-trifluoromethoxy 2,3,6-trimethylphenyl)methyl chloride containing some starting material, 2,3,5-trimethyl-1-trifluoromethoxybenzene, which was removed by distillation at 24°-30° C./0.05 mm. The residue (22 g), crude (4-trifluoromethoxy-2,3,6-trimethylphenyl)methyl chloride, was used directly in the next step.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[CH:23]=[C:22]3[C:18]([CH:19]=[N:20][NH:21]3)=[CH:17][CH:16]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Br[CH2:25][C:26]([O:28]C(C)(C)C)=[O:27]>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]([CH2:25][C:26]([OH:28])=[O:27])[C:15]2[CH:23]=[C:22]3[C:18]([CH:19]=[N:20][NH:21]3)=[CH:17][CH:16]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Nc2ccc3cn[nH]c3c2)cc1
Reactant: CC(C)(C)OC(=O)CBr
Product: CC(C)(C)c1ccc(S(=O)(=O)N(CC(=O)O)c2ccc3cn[nH]c3c2)cc1

Procedure:
prepared by reaction of 4-tert-butyl-N-(1H-indazol-6-yl)-benzenesulfonamide with tert-butyl bromoacetate