Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:3]1[NH:4][C:5]([CH3:34])=[C:6]([C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2/[CH:20]=[CH:21]/[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:8]=1[C:9]([O:11][CH2:12][CH3:13])=[O:10])=O.Cl.[NH2:36]O.C([O-])(=O)C.[Na+].C(OC(=O)C)(=O)C>C(O)(=O)C>[C:1]([C:3]1[NH:4][C:5]([CH3:34])=[C:6]([C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2/[CH:20]=[CH:21]/[C:22]([O:24][C:25]([CH3:27])([CH3:28])[CH3:26])=[O:23])[C:8]=1[C:9]([O:11][CH2:12][CH3:13])=[O:10])#[N:36]
Reactant: NO
Reactant: CCOC(=O)C1=C(C)NC(C=O)=C(C(=O)OCC)C1c1ccccc1/C=C/C(=O)OC(C)(C)C
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: CCOC(=O)C1=C(C)NC(C#N)=C(C(=O)OCC)C1c1ccccc1/C=C/C(=O)OC(C)(C)C
Yield: 15.6 %

Procedure:
A solution of the product of Example 2 (2.9 g), hydroxylamine hydrochloride (0.51 g) and sodium acetate (0.76 g) in acetic acid (30 ml) was stirred for 2 h at room temperature, then acetic anhydride (2.2 g) was added to the reaction. The mixture was heated to 95°-100° for 5 h and then extracted with ethyl acetate. The organic phase was washed with 5% sodium hydroxide and brine, dried over Na2SO4 and evaporated. The residue was purified by column chromatography on silica gel eluting with cyclohexane/ethyl acetate 7:3 to give the title compound (0.45 g) as a yellow solid. M.p. 146°-147°.
Reaction SMILES: [CH2:1]([O:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[C:11]([O:25]C)[N:12]2[CH2:15][CH2:16][CH2:17][CH2:18][CH:19]2[CH2:24][CH2:23][CH2:22][NH:21][CH2:20]2)=[C:8]([NH2:27])[N:7]=1)[CH2:2][CH2:3][CH3:4].I[CH2:29][CH2:30][CH2:31][CH3:32]>>[NH2:27][C:8]1[N:7]=[C:6]([O:5][CH2:1][CH2:2][CH2:3][CH3:4])[N:14]=[C:13]2[C:9]=1[NH:10][C:11](=[O:25])[N:12]2[CH2:15][CH2:16][CH2:17][CH2:18][CH:19]1[CH2:24][CH2:23][CH2:22][N:21]([CH2:29][CH2:30][CH2:31][CH3:32])[CH2:20]1
Reactant: CCCCOc1nc(N)c2nc(OC)n(CCCCC3CCCNC3)c2n1
Reactant: CCCCI
Product: CCCCOc1nc(N)c2[nH]c(=O)n(CCCCC3CCCN(CCCC)C3)c2n1

Procedure:
Prepared similarly to Example 14 from 2-(butyloxy)-8-(methyloxy)-9-[4-(3-piperidinyl)butyl]-9H-purin-6-amine and 1-iodobutane.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([C:8]2[CH:13]=[C:12]([O:14][CH3:15])[C:11]([O:16][CH3:17])=[C:10]([O:18][CH3:19])[CH:9]=2)[S:6][CH:7]=1.[NH:20]1[CH2:26][CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1>>[CH3:19][O:18][C:10]1[CH:9]=[C:8]([C:5]2[S:6][CH:7]=[C:3]([CH2:2][N:20]3[CH2:26][CH2:25][CH2:24][N:23]([CH2:2][C:3]4[N:4]=[C:5]([C:8]5[CH:9]=[C:10]([O:18][CH3:19])[C:11]([O:16][CH3:17])=[C:12]([O:14][CH3:15])[CH:13]=5)[S:6][CH:7]=4)[CH2:22][CH2:21]3)[N:4]=2)[CH:13]=[C:12]([O:14][CH3:15])[C:11]=1[O:16][CH3:17]
Reactant: COc1cc(-c2nc(CCl)cs2)cc(OC)c1OC
Reactant: C1CNCCNC1
Product: COc1cc(-c2nc(CN3CCCN(Cc4csc(-c5cc(OC)c(OC)c(OC)c5)n4)CC3)cs2)cc(OC)c1OC

Procedure:
4-Chloromethyl-2-(3,4,5-trimethoxyphenyl)thiazole (198 mg) and homopiperazine (30 mg) were reacted in the same manner in Example 1 to obtain the title compound as a free base.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[NH:7][C:8]1[S:9][CH:10]=[C:11]([C:13]2[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=2)[C:16]#[N:17])[N:12]=1.[Br:21]Br.O.C(=O)([O-])[O-].[K+].[K+]>C(O)(=O)C>[Br:21][SH:9]1[CH:10]=[C:11]([C:13]2[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=2)[C:16]#[N:17])[N:12]=[C:8]1[NH:7][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][N:1]=1
Reactant: N#Cc1cccc(-c2csc(Nc3cnccn3)n2)c1
Reactant: BrBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)O
Product: N#Cc1cccc(C2=C[SH](Br)C(Nc3cnccn3)=N2)c1

Procedure:
3-[2-(Pyrazin-2-ylamino)-thiazol-4-yl]-benzonitrile (1.5 g, 5.36 mmol) is suspended in hot glacial acetic acid (10 ml) and bromine (0.275 ml) is added dropwise at room temperature with stirring. The resultant suspension is stirred at room temperature for 10 minutes. Water (ca. 100 ml) is added to the mixture, which is basified to pH 9 with solid potassium carbonate. The resulting precipitate is filtered and washed with water to yield 3-[S-bromo-2-(pyrazin-2-ylamino)-thiazol-4-yl]-benzonitrile, m.p. 215° C. (dec.), m.s. 279 (ES+, M+—Br).
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[Cl:9][C:10]1[C:11]2[CH:18]=[CH:17][N:16]([CH:19]3[CH2:23][CH2:22][CH2:21][CH2:20]3)[C:12]=2[N:13]=[CH:14][N:15]=1>C(Cl)Cl>[Br:1][C:18]1[C:11]2[C:10]([Cl:9])=[N:15][CH:14]=[N:13][C:12]=2[N:16]([CH:19]2[CH2:23][CH2:22][CH2:21][CH2:20]2)[CH:17]=1
Reactant: Clc1ncnc2c1ccn2C1CCCC1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Product: Clc1ncnc2c1c(Br)cn2C1CCCC1
Yield: 61.3 %

Procedure:
N-Bromosuccinimide (15.4 g, 86.8 mmol) was added to a solution of 4-Chloro-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidine (15.4 g, 69.5 mmol) in CH2Cl2 (100 mL). After 12 h the reaction was quenched with saturated aqueous NaHCO3 (100 mL). The layers were separated and the aqueous layer was extracted with CH2Cl2 (2×100 mL). The combined organic layers were dried over Na2SO4 and concentrated. Purification by flash column chromatography (hexanes/ethyl acetate 9:1) afforded the title compound as a white solid (12.8 g, 61%). MS: 300.1/302.0/304.1 (MH+); HPLC Rf: 6.68 min. (HPLC method 4).
Reaction SMILES: C(O[C:6](=O)[NH:7]C1(C2C=CC(C3C(=O)C4C(=CC=C(C#N)C=4)OC=3C3C=CC=CC=3)=CC=2)CCC1)(C)(C)C.[C:38]([O:42][C:43](=[O:75])[NH:44][C:45]1([C:49]2[CH:54]=[CH:53][C:52]([C:55]3[C:64](=[O:65])[C:63]4[C:58](=[CH:59][C:60](Br)=[C:61]([O:66][CH3:67])[CH:62]=4)[O:57][C:56]=3[C:69]3[CH:74]=[CH:73][CH:72]=[CH:71][CH:70]=3)=[CH:51][CH:50]=2)[CH2:48][CH2:47][CH2:46]1)([CH3:41])([CH3:40])[CH3:39]>>[C:38]([O:42][C:43](=[O:75])[NH:44][C:45]1([C:49]2[CH:54]=[CH:53][C:52]([C:55]3[C:64](=[O:65])[C:63]4[C:58](=[CH:59][C:60]([C:6]#[N:7])=[C:61]([O:66][CH3:67])[CH:62]=4)[O:57][C:56]=3[C:69]3[CH:74]=[CH:73][CH:72]=[CH:71][CH:70]=3)=[CH:51][CH:50]=2)[CH2:48][CH2:47][CH2:46]1)([CH3:41])([CH3:40])[CH3:39]
Reactant: COc1cc2c(=O)c(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)c(-c3ccccc3)oc2cc1Br
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccccc4)oc4ccc(C#N)cc4c3=O)cc2)CCC1
Product: COc1cc2c(=O)c(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)c(-c3ccccc3)oc2cc1C#N
Yield: 57 %

Procedure:
Following the procedure used to prepare {1-[4-(6-cyano-4-oxo-2-phenyl-4H-chromen-3-yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester, {1-[4-(7-bromo-6-methoxy-4-oxo-2-phenyl-4H-chromen-3-yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester was reacted to give the title compound as a white solid (42 mg, 57%). LCMS (Method A): RT=4.84 min, [M+H]+=523.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+].Cl[C:27]1[CH:32]=[CH:31][N:30]=[CH:29][C:28]=1[N+:33]([O-:35])=[O:34].[C:36]1([CH3:45])[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=1B(O)O>O1CCOCC1>[N+:33]([C:28]1[CH:29]=[N:30][CH:31]=[CH:32][C:27]=1[C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][C:36]=1[CH3:45])([O-:35])=[O:34]
Reactant: Cc1ccccc1B(O)O
Reactant: O=[N+]([O-])c1cnccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: Cc1ccccc1-c1ccncc1[N+](=O)[O-]
Temperature: 120 °C

Procedure:
Triphenylphosphine (2.10 g, 1.89 mmol) and potassium carbonate (7.80 g, 56.7 mmol) were added to a slurry of 4-chloro-3-nitropyridine (3.00 g, 18.9 mmol, CAS RN 13091-23-1) and 2-tolylboronic acid (2.83 g, 20.8 mmol, CAS RN 16419-60-6) in dioxane stirring under an argon atmosphere. The reaction mixture was heated to 120° C. for 16 hours and then cooled to room temperature. The solids were removed by filtration through celite and all volatiles were removed in vacuo resulting in a dark colored heavy oil. The product was isolated as a heavy oil by flash chromatography on silica gel (25-33% EtOAc in n-hexane) (1.75 g, 43%).
Reaction SMILES: B(Br)(Br)Br.C[O:6][C:7]1[CH:8]=[C:9]2[C:13](=[N:14][CH:15]=1)[NH:12][CH:11]=[CH:10]2.O>C(Cl)Cl>[OH:6][C:7]1[CH:8]=[C:9]2[C:13](=[N:14][CH:15]=1)[NH:12][CH:11]=[CH:10]2
Reactant: COc1cnc2[nH]ccc2c1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Product: Oc1cnc2[nH]ccc2c1
Temperature: -30 °C

Procedure:
Adding boron tribromide in methylene chloride to a solution of 5-methoxy-7-azaindole in methylene chloride cooled at about −30° C. Leaving the mixture to warm up to ambient temperature and stirring it for a period of time, for example overnight. Pouring the mixture onto ice and water and adjusting the pH of the aqueous phase to about 6. Separating the organic phase and further extracting the aqueous phase with ethyl acetate. Combining the organic phases washing them with brine, drying them, for example over magnesium sulphate, and then evaporating them. The residue may then be purified, for example by column chromatography eluting with increasingly polar mixtures of methylene chloride and methanol to give 5-hydroxy-7-azaindole.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][C:11](O)=[O:12])[CH:6]=[CH:7][CH:8]=1.CO>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][CH2:11][OH:12])[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(CCC(=O)O)c1
Solvent: C1CCOC1
Solvent: CO
Product: COc1cccc(CCCO)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 3-(3-methoxyphenyl)propanoic acid (2.00 g, 11.10 mmol) in THF (2.0 mL) was added dropwise to a stirred solution of borane-tetrahydrofuran complex (24.42 mL, 24.42 mmol) so as to maintain reaction temperature below 35° C. The mixture was allowed to stir at room temperature overnight. Methanol was added dropwise to the stirred mixture until visible reaction had ceased. An additional 20 mL of methanol was added and the reaction was stirred for 4 hours. The crude mixture was concentrated, filtered and purified by silica gel chromatography (1:1 heptane:EtOAc as eluant). Fractions containing product were combined and concentrated to give 3-(3-methoxy-phenyl)-propan-1-ol as an oil.
Reaction SMILES: FC(F)(F)C(O)=O.[S:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[S:17]([N:20]1[CH2:25][CH2:24][NH:23][CH2:22][C:21]1=[O:26])(=[O:19])=[O:18].[CH:27]([O:40][C:41]([NH:43][C:44]1[CH:49]=[CH:48][N:47]([CH2:50][C:51](O)=[O:52])[C:46](=[O:54])[N:45]=1)=[O:42])([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[S:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[S:17]([N:20]1[CH2:25][CH2:24][N:23]([C:51](=[O:52])[CH2:50][N:47]2[CH:48]=[CH:49][C:44]([NH:43][C:41]([O:40][CH:27]([C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)[C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)=[O:42])=[N:45][C:46]2=[O:54])[CH2:22][C:21]1=[O:26])(=[O:19])=[O:18]
Reactant: O=C1CNCCN1S(=O)(=O)c1nc2ccccc2s1
Reactant: O=C(O)Cn1ccc(NC(=O)OC(c2ccccc2)c2ccccc2)nc1=O
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1ccn(CC(=O)N2CCN(S(=O)(=O)c3nc4ccccc4s3)C(=O)C2)c(=O)n1)OC(c1ccccc1)c1ccccc1

Procedure:
The title compound was synthesized by the reaction of 1-(benzothiazole-2-sulfonyl)-piperazin-2-one trifluoroacetic acid salt with [4-N-(benzhydryloxycarbonyl)-cytosin-1-yl]-acetic acid as per the procedure of Example 52. 1H NMR (500 MHz; DMSO-d6) δ 11.00 (brs, 1H), 8.34 (m, 1H), 8.26 (m, 1H), 7.90 (d, 0.6H), 7.84 (d, 0.4H), 7.72 (m, 2H), 7.44 (d, 4H), 7.37 (t, 4H), 7.29 (t, 2H), 6.94 (t, 1H), 6.79 (s, 1H), 4.82 (s, 1.2H), 4.72 (s, 0.8H), 4.45 (s, 0.8H), 4.28 (s, 1.2H), 4.22 (t, 1.2H), 4.07 (t, 0.8H), 3.99 (t, 1.2H), 3.86 (t, 0.8H).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10](/[C:13](/[C:23]2[CH:28]=[CH:27][C:26]([I:29])=[CH:25][CH:24]=2)=[C:14](\[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)/[CH2:15][CH3:16])=[CH:9][CH:8]=1.[CH3:30][NH:31][CH3:32].CCOCC>CO>[CH3:30][N:31]([CH3:32])[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10](/[C:13](/[C:23]2[CH:28]=[CH:27][C:26]([I:29])=[CH:25][CH:24]=2)=[C:14](\[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)/[CH2:15][CH3:16])=[CH:9][CH:8]=1
Reactant: CC/C(=C(\c1ccc(I)cc1)c1ccc(OCCCCCl)cc1)c1ccccc1
Reactant: CNC
Solvent: CO
Solvent: CCOCC
Product: CC/C(=C(\c1ccc(I)cc1)c1ccc(OCCCCN(C)C)cc1)c1ccccc1
Temperature: 100 °C

Procedure:
A mixture of E-1-(4-(4-chlorobutoxy)phenyl)-1-(4-iodophenyl)-2-phenyl-1-butene (0.429 g, 0.83 mmol) and dimethylamine in methanol solution (30 ml, 30%) was heated In a sealed bomb at 100° C. for 2 h, then poured into ether (75 ml), and washed with brine (100 ml) and water (2×100 ml). The organic layer was dried (Na2SO4), and concentrated in vacuo. The residues were purified by flash chromatography (silica; eluant:0-10% methanol in ether) to give the title compound as an off white solid (0.391 g, 89%) mp 74°-77° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:4]=1[C:11](=[O:13])[CH3:12].[CH3:14][C:15]1[CH:16]=[C:17]([CH:20]=[C:21]([CH3:24])[C:22]=1[OH:23])[CH:18]=O>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:4]=1[C:11](=[O:13])[CH:12]=[CH:18][C:17]1[CH:20]=[C:21]([CH3:24])[C:22]([OH:23])=[C:15]([CH3:14])[CH:16]=1
Reactant: Cc1cc(C=O)cc(C)c1O
Reactant: COc1ccc(OC)c(C(C)=O)c1
Product: COc1ccc(OC)c(C(=O)C=Cc2cc(C)c(O)c(C)c2)c1

Procedure:
This compound was synthesized from 2′,5′-dimethoxyacetophenone and 3,5-dimethyl-4-hydroxybenzaldehyde according to general method 1 described earlier.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[OH:12].[C:13](Cl)(=O)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>O1CCOCC1.C(Cl)Cl>[C:14]1([C:13]2[O:12][C:3]3[CH:4]=[C:5]([C:6]([O:8][CH3:9])=[O:7])[CH:10]=[CH:11][C:2]=3[N:1]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: COC(=O)c1ccc(N)c(O)c1
Reactant: O=C(Cl)c1ccccc1
Solvent: ClCCl
Solvent: C1COCCO1
Product: COC(=O)c1ccc2nc(-c3ccccc3)oc2c1
Temperature: 210 °C

Procedure:
A mixture of methyl 4-amino-3-hydroxy-benzoate is (0.3 g, 1.8 mmol) and benzoyl chloride It (0.23 mL, 2.0 mmol) in dioxane (2.5 mL) was heated at 210° C. under microwave for 15 min. The reaction mixture was diluted with CH2Cl2 and washed with aq. NaHCO3. The organic solution was dried over Na2SO4, concentrated and purified by flash column chromatography (silica gel, 20% EtOAc/heptane) to give 1u (0.39 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.[Br:15]Br>C(O)(=O)C.O.[Fe]>[Br:15][C:8]1[CH:7]=[C:6]([C:9]2[CH:10]=[CH:11][N:12]=[CH:13][CH:14]=2)[CH:5]=[CH:4][C:3]=1[O:2][CH3:1]
Reactant: BrBr
Reactant: COc1ccc(-c2ccncc2)cc1
Agent: [Fe]
Solvent: CC(=O)O
Solvent: O
Product: COc1ccc(-c2ccncc2)cc1Br
Temperature: 60 °C
Reaction time: 1 h

Procedure:
4-(4-Methoxyphenyl)pyridine (1 g, 5.4 mmol) was dissolved in glacial acetic acid (6 ml). Iron powder (30 mg, 0.54 mmol) was added followed by a solution of bromine (0.36 ml) in glacial acetic acid (3 ml) slowly over 5 minutes. The resulting solution was stirred at 60° C. for 1 hour. A solution of bromine (0.13 ml) in glacial acetic acid (1 ml) was added and stirring was continued at 60° C. for 1.5 hours. The solution was allowed to cool to ambient temperature, diluted with water (20 ml). Excess bromine was destroyed by adding in sold sodium bisulphite until all the colour had disappeared. Solid sodium carbonate was added until the solution was basic and the resulting solution was then extracted with ethyl acetate (2×30 ml) and dried over sodium sulphate. Removal of the solvent gave an oil which was chromatographed on silica gel in diethyl ether giving the title compound as a clear oil (0.77 g, 54%). 1H NMR (250 MHz, CDCl3) δ 8.66-8.62 (2H, d, J=8.6 Hz), 7.87-7.86 (1H, d, J=2.2 Hz), 7.61-7.56 (1H, dd, J=8.5 Hz and 2.2 Hz), 7.48-7.46 (1H, d, J=8.5 Hz), 7.03-6.99 (2H, d, J=8.6 Hz), and 3.96 (3H, s). m/z (ES+) 264, 266 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:35]=[CH:36][CH:37]=1)[C:5]([C:7]1[CH:34]=[CH:33][C:10]2[N:11]([CH2:15][CH2:16][O:17][C:18]3[CH:23]=[CH:22][C:21]([CH2:24][CH:25]([O:30][CH2:31][CH3:32])[C:26]([O:28][CH3:29])=[O:27])=[CH:20][CH:19]=3)[C:12](=[O:14])[S:13][C:9]=2[CH:8]=1)=O.[CH3:38][O:39][NH2:40]>>[Cl:1][C:2]1[CH:3]=[C:4]([C:5](=[N:40][O:39][CH3:38])[C:7]2[CH:34]=[CH:33][C:10]3[N:11]([CH2:15][CH2:16][O:17][C:18]4[CH:23]=[CH:22][C:21]([CH2:24][CH:25]([O:30][CH2:31][CH3:32])[C:26]([O:28][CH3:29])=[O:27])=[CH:20][CH:19]=4)[C:12](=[O:14])[S:13][C:9]=3[CH:8]=2)[CH:35]=[CH:36][CH:37]=1
Reactant: CON
Reactant: CCOC(Cc1ccc(OCCn2c(=O)sc3cc(C(=O)c4cccc(Cl)c4)ccc32)cc1)C(=O)OC
Product: CCOC(Cc1ccc(OCCn2c(=O)sc3cc(C(=NOC)c4cccc(Cl)c4)ccc32)cc1)C(=O)OC

Procedure:
Starting from the compound obtained in Step A, the procedure is as in Step B of Example 2, replacing the hydroxylamine by O-methylhydroxylamine.
Reaction SMILES: [NH2:1][CH:2]([C:5]1[C:6](=[O:16])[NH:7][C:8]([CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[N:9][N:10]=1)[CH2:3][CH3:4].[CH3:17][CH:18]1[CH2:20][CH:19]1[C:21](Cl)=[O:22]>>[CH:11]1([C:8]2[NH:7][C:6](=[O:16])[C:5]([CH:2]([NH:1][C:21]([CH:19]3[CH2:20][CH:18]3[CH3:17])=[O:22])[CH2:3][CH3:4])=[N:10][N:9]=2)[CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: CC1CC1C(=O)Cl
Reactant: CCC(N)c1nnc(C2CCCC2)[nH]c1=O
Product: CCC(NC(=O)C1CC1C)c1nnc(C2CCCC2)[nH]c1=O

Procedure:
In analogy to the procedure for Example 36A, 150 mg (0.67 mmol) 6-(1-aminopropyl)-3-cyclopentyl-1,2,4-triazin-5(4H)-one, 90 mg (0.74 mmol) 2-methyl-cyclopropylcarbonyl chloride and proportionate amounts of the other reagents are used. The crude product is used in the next step without further purification.
Reaction SMILES: [C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]3[C:30]4[C:25](=[CH:26][C:27]([O:35][CH3:36])=[C:28]([O:31][CH2:32][CH2:33]Cl)[CH:29]=4)[N:24]=[CH:23][N:22]=3)[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:37][N:38]1[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1>>[C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]3[C:30]4[C:25](=[CH:26][C:27]([O:35][CH3:36])=[C:28]([O:31][CH2:32][CH2:33][N:41]5[CH2:42][CH2:43][N:38]([CH3:37])[CH2:39][CH2:40]5)[CH:29]=4)[N:24]=[CH:23][N:22]=3)[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CN1CCNCC1
Reactant: COc1cc2ncnc(Oc3cccc(NC(=O)Nc4cc(C(C)(C)C)on4)c3)c2cc1OCCCl
Product: COc1cc2ncnc(Oc3cccc(NC(=O)Nc4cc(C(C)(C)C)on4)c3)c2cc1OCCN1CCN(C)CC1
Yield: 8 %

Procedure:
1-(5-tert-butylisoxazol-3-yl)-3-(3-(6-(2-chloroethoxy)-7-methoxyquinazolin-4-yloxy)phenyl)urea (200 mg, 0.39 mmol) from Example 16C was reacted with N-methyl piperazine (0.130 mL, 1.17 mmol) according to the procedure described for Example 16D to afford 1-(5-tert-butylisoxazol-3-yl)-3-(3-(7-methoxy-6-(2-(4-methylpiperazin-1-yl)ethoxy)quinazolin-4-yloxy)phenyl)urea as a colorless solid (18 mg, 8%). 1H NMR (300 MHz, DMSO-d6) δ 9.58 (brs, 1H), 9.00 (brs, 1H), 8.55 (s, 1H), 7.63 (s, 1H), 7.58 (s, 1H), 7.37-7.42 (m, 2H), 7.25 (m, 1H), 6.96 (m, 1H), 6.47 (s, 1H), 4.26-4.30 (m, 2H), 3.99 (s, 3H), 2.75-2.79 (m, 2H), 2.20-2.50 (m, 8H), 2.13 (s, 3H), 1.27 (s, 9H); LC-MS (ESI) m/z 576 (M+H)+.
Reaction SMILES: N[C:2]1[N:7]=[C:6]([C:8]2[N:9]=[C:10]([C:21]([CH3:27])([CH3:26])[C:22]([O:24][CH3:25])=[O:23])[NH:11][C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=2[F:20])[CH:5]=[CH:4][C:3]=1[N+:28]([O-:30])=[O:29].S(=O)(=O)(O)[OH:32].N([O-])=O.[Na+]>CS(C)=O.O>[F:20][C:14]1[CH:15]=[C:16]([F:19])[CH:17]=[CH:18][C:13]=1[C:12]1[NH:11][C:10]([C:21]([CH3:26])([CH3:27])[C:22]([O:24][CH3:25])=[O:23])=[N:9][C:8]=1[C:6]1[CH:5]=[CH:4][C:3]([N+:28]([O-:30])=[O:29])=[C:2]([OH:32])[N:7]=1
Reactant: O=S(=O)(O)O
Reactant: COC(=O)C(C)(C)c1nc(-c2ccc([N+](=O)[O-])c(N)n2)c(-c2ccc(F)cc2F)[nH]1
Agent: O=N[O-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: COC(=O)C(C)(C)c1nc(-c2ccc([N+](=O)[O-])c(O)n2)c(-c2ccc(F)cc2F)[nH]1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 88 %

Procedure:
To a solution of methyl 2-[4-(6-amino-5-nitro-2-pyridyl)-5-(2,4-difluorophenyl)-1H-imidazol-2-yl]-2-methyl-propanoate (56 g, 134.17 mmol) in dimethyl sulfoxide (DMSO, 400 mL) and water (320 mL), is added sulfuric acid 95-97% (80 mL) dropwise. Then the mixture is cooled to 0° C. To the above mixture a solution of sodium nitrite (18.70 g, 268.35 mmol) in water (80 mL) is added dropwise over 15 min at 0° C. The reaction mixture is stirred for 20 min at that temperature and then the cooling bath is removed and the temperature is allowed to rise to RT. To the reaction mixture is added a 0.8 M aqueous solution of buffered sodium phosphate monobasic (1200 mL, pH=6). A yellow suspension appears. This suspension is stirred at RT for 1 h. The solid is filtered, washed with water, and dried in the oven to afford the title compound as an orange solid (49.5 g, 88%). LC-ES/MS m/z 419 (M+1).
Reaction SMILES: [C:1]([OH:9])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:22][C:23]1[CH:24]=[C:25]([CH:29]2[C:38]([CH3:40])([CH3:39])[CH2:37][C:36]3[C:31](=[CH:32][CH:33]=[C:34]([C:41]([OH:43])=[O:42])[CH:35]=3)[NH:30]2)[CH:26]=[CH:27][CH:28]=1>CN(C)C=O>[CH3:39][C:38]1([CH3:40])[CH2:37][C:36]2[C:31](=[CH:32][CH:33]=[C:34]([C:41]([OH:43])=[O:42])[CH:35]=2)[NH:30][CH:29]1[C:25]1[CH:26]=[CH:27][CH:28]=[C:23]([NH:22][C:1]([C:2]2[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=2)=[O:9])[CH:24]=1
Reactant: CC1(C)Cc2cc(C(=O)O)ccc2NC1c1cccc(N)c1
Reactant: O=C(O)c1cccnc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: CC1(C)Cc2cc(C(=O)O)ccc2NC1c1cccc(NC(=O)c2cccnc2)c1
Temperature: 70 °C
Reaction time: 1 h
Yield: 15.4 %

Procedure:
A solution of nicotinic acid (42 mg, 0.34 mmol) and 1,1′-carbonyldiimidazole (72 mg, 0.44 mmol) in N,N-dimethylformamide (1.5 mL) was stirred at 70° C. After stirring at 70° C. for 1 h, a solution of 2-(3-amino-phenyl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (100 mg, 0.34 mmol) in N,N-dimethylformamide (2 mL) was added and the mixture was allowed to stir at 25° C. for 1 h. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% formic acid in water) afforded 3,3-dimethyl-2-{3-[(pyridine-3-carbonyl)-amino]-phenyl}-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (21 mg, 15%) as a white solid: LC/MS m/e calcd for C24H23N3O3 (M+H)+: 402.47, observed: 402.1.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]([OH:20])[CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([O:11][C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([Cl:19])[CH:13]=2)[CH2:7][CH2:6]1.[CH3:21][S:22]([C:25]1[CH:26]=[C:27]([CH:31]=[CH:32][CH:33]=1)[C:28](O)=[O:29])(=[O:24])=[O:23]>>[Cl:19][C:14]1[CH:13]=[C:12]([CH:17]=[CH:16][C:15]=1[Cl:18])[O:11][CH:8]1[CH2:9][CH2:10][N:5]([CH2:4][C@H:3]([OH:20])[CH2:2][NH:1][C:28](=[O:29])[C:27]2[CH:31]=[CH:32][CH:33]=[C:25]([S:22]([CH3:21])(=[O:24])=[O:23])[CH:26]=2)[CH2:6][CH2:7]1
Reactant: CS(=O)(=O)c1cccc(C(=O)O)c1
Reactant: NC[C@@H](O)CN1CCC(Oc2ccc(Cl)c(Cl)c2)CC1
Product: CS(=O)(=O)c1cccc(C(=O)NC[C@@H](O)CN2CCC(Oc3ccc(Cl)c(Cl)c3)CC2)c1

Procedure:
Prepared as described in Example 1 from (2R)-1-amino-3-[4-(3,4-dichlorophenoxy)piperidin-1-yl]propan-2-ol (0.1 g) and 3-(methylsulfonyl)benzoic acid (0.063 g). Title compound obtained as white solid (0.017 g).
Reaction SMILES: [OH:1][C:2]1([C:29]2[S:33][C:32]([S:34][CH3:35])=[N:31][CH:30]=2)[CH2:7][CH2:6][CH:5]([N:8]2[CH2:11][CH:10]([NH:12][C:13]([CH2:15][NH:16][C:17](=[O:28])[C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=3)=[O:14])[CH2:9]2)[CH2:4][CH2:3]1.O.[OH:37]OS([O-])=O.[K+]>CO>[OH:1][C:2]1([C:29]2[S:33][C:32]([S:34]([CH3:35])=[O:37])=[N:31][CH:30]=2)[CH2:3][CH2:4][CH:5]([N:8]2[CH2:9][CH:10]([NH:12][C:13]([CH2:15][NH:16][C:17](=[O:28])[C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:25])([F:26])[F:27])[CH:19]=3)=[O:14])[CH2:11]2)[CH2:6][CH2:7]1
Reactant: O=S([O-])OO
Reactant: CSc1ncc(C2(O)CCC(N3CC(NC(=O)CNC(=O)c4cccc(C(F)(F)F)c4)C3)CC2)s1
Agent: [K+]
Solvent: O
Solvent: CO
Product: CS(=O)c1ncc(C2(O)CCC(N3CC(NC(=O)CNC(=O)c4cccc(C(F)(F)F)c4)C3)CC2)s1

Procedure:
N-({1-[4-Hydroxy-4-(2-methylsulfanyl-thiazol-5-yl)-cyclohexyl]-azetidin-3-ylcarbamoyl}-methyl)-3-trifluoromethyl-benzamide (less polar isomer, 45a, 100 mg, 0.19 mmol) in MeOH (1 mL) and water (1 mL) was treated with OXONE (Aldrich, 230 mg, 0.38 mmol) at room temperature for 6 hours. The reaction mixture was partitioned between DCM and saturate NaHCO3. The organic layer was separated and the aqueous layer was extracted 3 times with chloroform and IPA “cocktail” (˜3:1, v/v). The combined organic layer was dried over anhydrous Na2SO4, filtered and concentrated to give the crude product, which was then purified by a CombiFlash® system using ethyl acetate and 7N NH3 in MeOH as eluent (from pure ethyl acetate to 5% 7N NH3 in MeOH in ethyl acetate) to afford the title compounds as a white solid.