Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][C:5]1[NH:9][C:8]([C:13]2[C:17]([NH:18][C:19](=[O:28])[C:20]3[C:25]([F:26])=[CH:24][CH:23]=[CH:22][C:21]=3[F:27])=[CH:16][NH:15][N:14]=2)(C(O)=O)[NH:7][CH:6]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.CN([CH:46]=[O:47])C>ClCCl>[F:27][C:21]1[CH:22]=[CH:23][CH:24]=[C:25]([F:26])[C:20]=1[C:19]([NH:18][C:17]1[C:13]([C:8]2[NH:9][C:5]3[CH2:4][CH2:3][CH2:2][NH:1][C:46](=[O:47])[C:6]=3[N:7]=2)=[N:14][NH:15][CH:16]=1)=[O:28]
Reactant: NCCCC1=CNC(C(=O)O)(c2n[nH]cc2NC(=O)c2c(F)cccc2F)N1
Reactant: CN(C)C=O
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: ClCCCl
Product: O=C1NCCCc2[nH]c(-c3n[nH]cc3NC(=O)c3c(F)cccc3F)nc21
Temperature: 25 °C
Reaction time: 48 h
Yield: 13 %

Procedure:
To a stirred solution of 5-(3-amino-propyl)-2-[4-(2,6-difluoro-benzoylamino)-1H-pyrazol-3-yl]-1H-imidazole carboxylic acid (200 mg, 0.51 mmoles) in DMF (10 ml) and dichloromethane (10 ml) was added EDC (118 mg, 0.62 mmoles), HOBt (84 mg, 0.62 mmoles) and NEM (260 μl, 2.04 mmoles). The solution was stirred at ambient temperature for 48 hours and then partitioned between EtOAc and water. The organic portion was dried (MgSO4), filtered and evaporated in vacuo. The residue was purified by flash column chromatography [silica, 3% MeOH in DCM to 5% to 10%] to give 2,6-difluoro-N-[3-(4-oxo-1,4,5,6,7,8-hexahydro-1,3,5-triaza-azulen-2-yl)-1H-pyrazol-4-yl]-benzamide as a pale yellow solid (10 mg, 13%). (LC/MS: Rt 1.93, [M+H]+ 372.99).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][S:4][CH2:5][C:6]1[O:7][C:8]2[CH:14]=[C:13]([CH2:15][N:16]([CH3:18])[CH3:17])[CH:12]=[CH:11][C:9]=2[CH:10]=1.[C:19]([N:21]=[C:22](SC)[S:23][CH3:24])#[N:20]>C(#N)C>[C:19]([NH:21][C:22](=[N:1][CH2:2][CH2:3][S:4][CH2:5][C:6]1[O:7][C:8]2[CH:14]=[C:13]([CH2:15][N:16]([CH3:18])[CH3:17])[CH:12]=[CH:11][C:9]=2[CH:10]=1)[S:23][CH3:24])#[N:20]
Reactant: CSC(=NC#N)SC
Reactant: CN(C)Cc1ccc2cc(CSCCN)oc2c1
Solvent: CC#N
Product: CSC(=NCCSCc1cc2ccc(CN(C)C)cc2o1)NC#N
Reaction time: 2 h

Procedure:
A solution of 2-(2-aminoethylthiomethyl)-6-(dimethylaminomethyl)benzofuran (12.0 g, 0.0454 mole) and dimethyl cyanodithioimidocarbonate (7.0 g., 0.048 mole) in acetonitrile (48 ml.) is allowed to stand 2 hours at room temperature. The solvent is evaporated at reduced pressure and the viscous oily residue is chromatographed on a column of 250 g. of silica gel. Elution with 8% methanol in chloroform removes the product. There is obtained 14.6 g. (89%) of N-cyano-N'-[2-(6-dimethylaminomethyl-2-(benzofuranylmethylthio)ethyl]-S-methylisothiourea as a yellow oil which gradually crystallizes, m.p. 98°-100° C.
Reaction SMILES: [OH:1][C@H:2]1[CH2:19][CH2:18][C@@:17]2([CH3:20])[C:4](=[CH:5][C@H:6]([OH:23])[C@@H:7]3[C@@H:16]2[CH2:15][CH2:14][C@@:12]2([CH3:13])[C@H:8]3[C@@H:9]3[CH2:22][C@@H:10]3[C:11]2=[O:21])[CH2:3]1.N1C=CN=C1.[C:29]([Si:33]([CH3:36])([CH3:35])Cl)([CH3:32])([CH3:31])[CH3:30]>CN(C)C=O>[C:29]([Si:33]([CH3:36])([CH3:35])[O:1][C@H:2]1[CH2:19][CH2:18][C@@:17]2([CH3:20])[C:4](=[CH:5][C@H:6]([OH:23])[C@@H:7]3[C@@H:16]2[CH2:15][CH2:14][C@@:12]2([CH3:13])[C@H:8]3[C@@H:9]3[CH2:22][C@@H:10]3[C:11]2=[O:21])[CH2:3]1)([CH3:32])([CH3:31])[CH3:30]
Reactant: C[C@]12CC[C@H](O)CC1=C[C@H](O)[C@H]1[C@@H]3[C@@H]4C[C@@H]4C(=O)[C@@]3(C)CC[C@@H]12
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)O[C@H]1CC[C@@]2(C)C(=C[C@H](O)[C@H]3[C@@H]4[C@@H]5C[C@@H]5C(=O)[C@@]4(C)CC[C@@H]32)C1
Temperature: -20 °C
Reaction time: 2 h
Yield: 78.9 %

Procedure:
A solution of 120 g of 3β,7β-dihydroxy-15β,16β-methylene-5-androsten-17-one in 1,000 ml of dimethylformamide is combined with 31 g of imidazole and cooled to -20° C. Within 2 hours, 63 g of tert.-butyldimethylchlorosilane in 450 ml of dimethylformamide is added dropwise to the reaction mixture, and the latter is agitated for another hour. The reaction product is precipitated with sodium-chloride-containing water, filtered off, washed with water, and dissolved in methylene chloride. The solution is dried over sodium sulfate and evaporated. After chromatography on silica gel with hexane-acetone, 128.8 g of 3β-(tert.-butyldimethylsilyloxy)-7β-hydroxy-15β,16β-methylene-5-androsten-17-one is obtained.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([N:11]([CH3:13])[CH3:12])=[O:10])=[CH:4][CH:3]=1.[F:14][C:15]([F:26])([F:25])[C:16]1[C:24]2[CH2:23][CH2:22][CH2:21][CH2:20][C:19]=2[NH:18][N:17]=1>>[CH3:12][N:11]([CH3:13])[C:9](=[O:10])[CH2:8][C:5]1[CH:6]=[CH:7][C:2]([N:18]2[C:19]3[CH2:20][CH2:21][CH2:22][CH2:23][C:24]=3[C:16]([C:15]([F:14])([F:26])[F:25])=[N:17]2)=[CH:3][CH:4]=1
Reactant: FC(F)(F)c1n[nH]c2c1CCCC2
Reactant: CN(C)C(=O)Cc1ccc(Br)cc1
Product: CN(C)C(=O)Cc1ccc(-n2nc(C(F)(F)F)c3c2CCCC3)cc1

Procedure:
The title compound was prepared from 2-(4-bromophenyl)-N,N-dimethylacetamide and 3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole using a similar procedure to that described for Example 7.
Reaction SMILES: C[O:2][C:3](=[O:27])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=2[CH2:23][NH:24][CH2:25][CH3:26])[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1.Cl[C:29]([O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:30]>>[CH2:32]([O:31][C:29]([N:24]([CH2:23][C:14]1[CH:15]=[C:16]([C:19]([F:21])([F:22])[F:20])[CH:17]=[CH:18][C:13]=1[C:7]1[C:8]([O:11][CH3:12])=[CH:9][CH:10]=[C:5]([CH2:4][C:3]([OH:27])=[O:2])[CH:6]=1)[CH2:25][CH3:26])=[O:30])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: CCNCc1cc(C(F)(F)F)ccc1-c1cc(CC(=O)OC)ccc1OC
Reactant: O=C(Cl)OCc1ccccc1
Product: CCN(Cc1cc(C(F)(F)F)ccc1-c1cc(CC(=O)O)ccc1OC)C(=O)OCc1ccccc1

Procedure:
{2′-[(Benzyloxycarbonyl-ethyl-amino)-methyl]-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl}-acetic acid (Compound 1-28) was prepared by following the procedures of Example 7 and using (2′-ethylaminomethyl-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl)-acetic acid methyl ester and benzyl chloroformate.
Reaction SMILES: [OH-].[K+].[NH2:3][C:4]1[CH:5]=[C:6]([CH3:11])[CH:7]=[CH:8][C:9]=1[Cl:10].Cl[C:13]1[C:18]([N+:19]([O-:21])=[O:20])=[CH:17][C:16]([N+:22]([O-:24])=[O:23])=[CH:15][C:14]=1[C:25]([F:28])([F:27])[F:26].Cl>CN(C)C=O.O>[Cl:10][C:9]1[CH:8]=[CH:7][C:6]([CH3:11])=[CH:5][C:4]=1[NH:3][C:13]1[C:18]([N+:19]([O-:21])=[O:20])=[CH:17][C:16]([N+:22]([O-:24])=[O:23])=[CH:15][C:14]=1[C:25]([F:26])([F:28])[F:27]
Reactant: O=[N+]([O-])c1cc([N+](=O)[O-])c(Cl)c(C(F)(F)F)c1
Reactant: Cc1ccc(Cl)c(N)c1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(Cl)c(Nc2c([N+](=O)[O-])cc([N+](=O)[O-])cc2C(F)(F)F)c1
Reaction time: 0.08 h

Procedure:
Powdered potassium hydroxide (2.0 g.) was added in portions over 5 minutes to a stirred solution of 3-amino-4-chlorotoluene (2.8 g.) in dimethylformamide (15 ml.) at the ambient temperature and stirring was continued for a further 5 minutes. A solution of 2-chloro-3,5-dinitro-benzotrifluoride (5.4 g.) in dimethylformamide (15 ml.) was then added over 5 minutes, and following the addition, the mixture was stirred for 30 minutes. After acidification with concentrated hydrochloric acid the mixture was poured into water (15 ml.). The precipitated solid was separated from the supernatant liquid by decantation and recrystallised from methylated spirit to yield 2(2-chloro-5-methylanilino)-3,5-dinitrobenzotrifluoride, with a melting point of 127° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([C:9]2[N:13]([CH3:14])[N:12]=[CH:11][CH:10]=2)[CH:3]=1.Br[CH2:16][CH2:17][NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:16][CH2:17][NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[C:4]([C:9]2[N:13]([CH3:14])[N:12]=[CH:11][CH:10]=2)[CH:3]=1
Reactant: CC(C)(C)OC(=O)NCCBr
Reactant: Cn1nccc1-c1cc(N)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Cn1nccc1-c1cc(N)ccc1OCCNC(=O)OC(C)(C)C
Temperature: 60 °C
Yield: 29.1 %

Procedure:
4-amino-2-(1-methyl-1H-pyrazol-5-yl)phenol (3.02 g, 15.96 mmol), tert-butyl 2-bromoethylcarbamate (7.153 g, 2.0 eq) and potassium carbonate (4.412 g, 2.0 eq) were dissolved in 100 mL acetone and refluxed at 60° C. for 24 h. After reaction, the potassium carbonate was filtered and acetone was evaporated. The residue was dissolved in 100 mL DCM and extracted with 3×100 mL 1N NaOH. Purified by column chromatography (50-100% ethyl acetate in hexane) to afford the title compound as a yellow oil in 29.10% yield. LCMS m/z (%)=333 (M+H, 100). 1H NMR (400 MHz, CDCl3) δ ppm 1.43 (s, 9 H), 3.33 (q, J=5.05 Hz, 2 H), 3.75 (s, 3 H), 3.91 (t, J=5.05 Hz, 2 H), 4.45-4.51 (m, 1 H), 6.23 (d, J=2.02 Hz, 1 H), 6.62 (d, J=3.03 Hz, 1 H), 6.73 (dd, J=8.59, 3.03 Hz, 1 H), 6.85 (d, 1 H), 7.52 (d, J=2.02 Hz, 1 H).
Reaction SMILES: CS(O[CH2:6][CH2:7][C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([N:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)=[O:24])=[CH:19][N:18]=3)=[CH:13][C:11]=2[CH:12]=1)(=O)=O.[CH3:31][CH:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1>>[CH3:31][CH:32]1[CH2:37][CH2:36][N:35]([CH2:6][CH2:7][C:8]2[O:9][C:10]3[CH:16]=[CH:15][C:14]([C:17]4[N:18]=[CH:19][C:20]([C:23]([N:25]5[CH2:26][CH2:27][O:28][CH2:29][CH2:30]5)=[O:24])=[CH:21][CH:22]=4)=[CH:13][C:11]=3[CH:12]=2)[CH2:34][CH2:33]1
Reactant: CC1CCNCC1
Reactant: CS(=O)(=O)OCCc1cc2cc(-c3ccc(C(=O)N4CCOCC4)cn3)ccc2o1
Product: CC1CCN(CCc2cc3cc(-c4ccc(C(=O)N5CCOCC5)cn4)ccc3o2)CC1

Procedure:
The product from Example 44E and 4-methylpiperidine were processed as described in Example 1D to provide the titled compound. 1H NMR (300 MHz, CD3OD) δ 8.70 (m, 1H), 8.22 (d, J=1.8 Hz, 1H), 7.97 (m, 3H), 7.58 (d, J=8.7 Hz, 1H), 6.82 (s, 1H), 3.3-3.8 (m, 14H), 3.05 (m, 2H), 1.95 (m, 2H), 1.75 (m, 1H), 1.5 (m, 2H), 1.05 (d, J=6.6 Hz, 3H); MS (DCI) m/z 434 (M+H)+;
Reaction SMILES: [C:1]([C:3]1[CH:13]=[CH:12][CH:11]=[CH:10][C:4]=1[O:5][CH2:6][CH:7]1[O:9][CH2:8]1)#[N:2].[NH2:14][CH2:15][CH2:16][O:17][C:18]1[CH:19]=[C:20]([C:24]2[CH:25]([CH3:31])[CH2:26][C:27](=[O:30])[NH:28][N:29]=2)[CH:21]=[CH:22][CH:23]=1>>[C:1]([C:3]1[CH:13]=[CH:12][CH:11]=[CH:10][C:4]=1[O:5][CH2:6][CH:7]([OH:9])[CH2:8][NH:14][CH2:15][CH2:16][O:17][C:18]1[CH:19]=[C:20]([C:24]2[CH:25]([CH3:31])[CH2:26][C:27](=[O:30])[NH:28][N:29]=2)[CH:21]=[CH:22][CH:23]=1)#[N:2]
Reactant: N#Cc1ccccc1OCC1CO1
Reactant: CC1CC(=O)NN=C1c1cccc(OCCN)c1
Product: CC1CC(=O)NN=C1c1cccc(OCCNCC(O)COc2ccccc2C#N)c1

Procedure:
Prepared analogously to Example 1 from 1-(2-cyanophenoxy)-2,3-epoxypropane and 6-[3-(2-aminoethoxy)phenyl]-4,5-dihydro-5-methyl-3(2H)-pyridazinone.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([NH:6][C:7](=[O:15])[C:8](=[O:14])[N:9]2[CH2:12][CH3:13])=[CH:4][CH:3]=1.[C:16](OC(=O)C)(=[O:18])[CH3:17]>>[C:16]([NH:1][C:2]1[CH:11]=[C:10]2[C:5]([NH:6][C:7](=[O:15])[C:8](=[O:14])[N:9]2[CH2:12][CH3:13])=[CH:4][CH:3]=1)(=[O:18])[CH3:17]
Reactant: CC(=O)OC(C)=O
Reactant: CCn1c(=O)c(=O)[nH]c2ccc(N)cc21
Product: CCn1c(=O)c(=O)[nH]c2ccc(NC(C)=O)cc21
Temperature: 0 °C
Yield: 86 %

Procedure:
5.5 g (27 mmol) of 7-amino-1-ethyl-2,3(1H,4H)-quinoxalinedione were refluxed in 75 ml of acetic anhydride for 1 h. The mixture was then poured into ice-water and filtered. The filtrate was concentrated under reduced pressure to yield 5.7 g (86%) of the product. Melting point 303°-304° C. (decomposition).
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].C1COCC1.[OH:16][C@@H:17]([C@H:19]1[CH2:23][N:22]([C@@H:24]([C:26]2[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=2)[CH3:25])[C:21](=[O:34])[CH2:20]1)[CH3:18].[Cl:35][C:36]1[N:41]=[C:40](S(C)(=O)=O)[C:39]2[N:46]([CH2:49][O:50][CH2:51][CH2:52][Si:53]([CH3:56])([CH3:55])[CH3:54])[CH:47]=[N:48][C:38]=2[CH:37]=1>CN(C=O)C>[Cl:35][C:36]1[N:41]=[C:40]([O:16][C@@H:17]([C@H:19]2[CH2:23][N:22]([C@@H:24]([C:26]3[CH:27]=[CH:28][C:29]([O:32][CH3:33])=[CH:30][CH:31]=3)[CH3:25])[C:21](=[O:34])[CH2:20]2)[CH3:18])[C:39]2[N:46]([CH2:49][O:50][CH2:51][CH2:52][Si:53]([CH3:56])([CH3:55])[CH3:54])[CH:47]=[N:48][C:38]=2[CH:37]=1
Reactant: COc1ccc([C@@H](C)N2C[C@H]([C@@H](C)O)CC2=O)cc1
Reactant: C[Si](C)(C)CCOCn1cnc2cc(Cl)nc(S(C)(=O)=O)c21
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COc1ccc([C@@H](C)N2C[C@H]([C@@H](C)Oc3nc(Cl)cc4ncn(COCC[Si](C)(C)C)c34)CC2=O)cc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A solution of NaHMDS in THF (1M, 0.85 ml, 0.85 mmol) was added to a solution of (R)-4-((R)-1-hydroxyethyl)-1-((R)-1-(4-methoxyphenyl)ethyl)pyrrolidin-2-one 1.04 (205 mg, 0.78 mmol) in DMF (10 mL) at room temperature. After 5 minutes, a solution of 6-chloro-4-(methylsulfonyl)-3-((2-(trimethylsilyl)ethoxy)methyl)-3H-imidazo[4,5-c]pyridine 2.09 (256 mg, 0.707 mmol) in DMF (2 mL) was added and mixture stirred at room temperature. After 10 minutes, LC/MS indicated full conversion to desired product. Reaction mixture was quenched with 15 mL of water, poured into 30 mL of water, and extracted with ethyl acetate (100 mL). Organics were washed with Brine (2×50 mL), dried (MgSO4), filtered, and concentrated under reduced pressure to yield (R)-4-((R)-1-(6-chloro-3-((2-(trimethylsilyl)ethoxy)methyl)-3H-imidazo[4,5-c]pyridin-4-yloxy)ethyl)-1-((R)-1-(4-methoxyphenyl)ethyl)pyrrolidin-2-one 2.11, which was used in the next step without further purification.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4](SC)[N:5]=[N:6][C:7]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.O.[NH2:17][NH2:18]>C(O)C>[NH:17]([C:4]1[N:5]=[N:6][C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[C:2]([CH3:1])[N:3]=1)[NH2:18]
Reactant: NN
Reactant: CSc1nnc(-c2ccccc2)c(C)n1
Solvent: CCO
Solvent: O
Product: Cc1nc(NN)nnc1-c1ccccc1

Procedure:
A solution of 5-methyl-3-methylthio-6-phenyl-1,2,4-triazine (7 g) and hydrazine hydrate (5 ml) in ethanol (15 ml) was heated under reflux for 8 hours. The reaction mixture was evaporated and the resultant residue was washed with water, dried and recrystallized from a mixture of ethanol and water (5:3) to give crystals of 3-hydrazino-5-methyl-6-phenyl-1,2,4-triazine (3.76 g), m.p. 136.5°~137.5° C.
Reaction SMILES: [N:1]1([C:7]2[N:12]=[C:11]([C:13]3[CH:17]=[CH:16][S:15][CH:14]=3)[N:10]=[CH:9][N:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C=O.[BH-](OC(C)=O)(OC(C)=O)O[C:22](C)=O.[Na+]>C(Cl)Cl.CO>[CH3:22][N:4]1[CH2:5][CH2:6][N:1]([C:7]2[N:12]=[C:11]([C:13]3[CH:17]=[CH:16][S:15][CH:14]=3)[N:10]=[CH:9][N:8]=2)[CH2:2][CH2:3]1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: c1nc(-c2ccsc2)nc(N2CCNCC2)n1
Agent: C=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: CN1CCN(c2ncnc(-c3ccsc3)n2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2-piperazin-1-yl-4-thiophen-3-yl-[1,3,5]triazine (0.17 mmol) in CH2Cl2/MeOH (3:1, 4 mL) was added formaldehyde (37 wt. % in water, 22 mg, 0.26 mmol). After stirring for 1 h at room temperature, NaB(OAc)3H (72.8 mg, 0.34 mmol) was added. The reaction mixture was stirred overnight at room temperature, then quenched with 1 N NaOH (3 mL), and extracted with EtOAc (50 mL). The organic layer was washed with water (2×15 mL), brine (15 mL), dried, and concentrated to yield a light yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:16])[C:5]([C:8]2[CH:9]=[N:10][C:11]([O:14][CH3:15])=[CH:12][CH:13]=2)=[N:6][CH:7]=1.[H-].[Na+].Cl[C:20]1[C:29]2[C:24](=[CH:25][C:26]([F:31])=[CH:27][C:28]=2[F:30])[N:23]=[C:22]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=2)[C:21]=1[CH3:38].C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([NH:16][C:20]2[C:29]3[C:24](=[CH:25][C:26]([F:31])=[CH:27][C:28]=3[F:30])[N:23]=[C:22]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=3)[C:21]=2[CH3:38])[C:5]([C:8]2[CH:9]=[N:10][C:11]([O:14][CH3:15])=[CH:12][CH:13]=2)=[N:6][CH:7]=1
Reactant: Cc1c(-c2ccccn2)nc2cc(F)cc(F)c2c1Cl
Reactant: COc1ccc(-c2ncc(Br)cc2N)cn1
Agent: O=C([O-])[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(-c2ncc(Br)cc2Nc2c(C)c(-c3ccccn3)nc3cc(F)cc(F)c23)cn1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A dry flask containing 5-bromo-6′-methoxy-2,3′-bipyridin-3-amine (226.0 mg, 0.81 mmol) in dry DMF (5 mL) was cooled to 0° C., then sodium hydride, 60% dispersion in mineral oil (100.7 mg, 2.52 mmol) was added carefully in portions. The mixture was stirred at 0° C. for 15 min, then 4-chloro-5,7-difluoro-3-methyl-2-(pyridin-2-yl)quinoline (353.1 mg, 1.21 mmol) was added in portions. Upon complete addition, the mixture was warmed to 70° C. After 3 h, the reaction was cooled to rt then was carefully treated with 10% sodium carbonate solution. The black mixture was subsequently extracted 5 times with DCM:MeOH (90:10). The organic extraction was then washed one time with brine and dried over anhydrous magnesium sulfate. After filtration and concentration, the residue was purified on basic alumina (0-35% EtOAc in hexanes) to afford a yellow residue as mostly N-(5-bromo-6′-methoxy-2,3′-bipyridin-3-yl)-5,7-difluoro-3-methyl-2-(pyridin-2-yl)-quinolin-4-amine that was used without further purification.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][C:6]=1[C:7]([OH:9])=O)([CH3:3])[CH3:2].Cl.[CH3:19][CH:20]([S:22]([C:25]1[S:29][C:28]([N:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)=[N:27][CH:26]=1)(=[O:24])=[O:23])[CH3:21]>>[CH:1]([O:4][C:5]1[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][C:6]=1[C:7]([N:33]1[CH2:34][CH2:35][N:30]([C:28]2[S:29][C:25]([S:22]([CH:20]([CH3:21])[CH3:19])(=[O:24])=[O:23])=[CH:26][N:27]=2)[CH2:31][CH2:32]1)=[O:9])([CH3:2])[CH3:3]
Reactant: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)O
Reactant: CC(C)S(=O)(=O)c1cnc(N2CCNCC2)s1
Agent: Cl
Product: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)N1CCN(c2ncc(S(=O)(=O)C(C)C)s2)CC1
Yield: 67 %

Procedure:
Prepared in analogy to example 1 (b) from 2-isopropoxy-5-methanesulfonyl-benzoic acid (Example A1) and 1-[5-(propane-2-sulfonyl)-thiazol-2-yl]-piperazine hydrochloride. The crude material was purified by chromatography (SiO2, ethyl acetate/heptane) followed by trituration in ether to yield the title compound as a white crystalline solid (yield 67%). MS (m/e): 516.3 (M+H+, 100%), 533.3 (M+NH4+, 85%).
Reaction SMILES: [F:1][C:2]1[CH:17]=[C:16]([O:18][CH2:19][C:20]2[CH:21]=[N:22][C:23]([O:26][CH3:27])=[CH:24][CH:25]=2)[C:15]([O:28][CH3:29])=[CH:14][C:3]=1[CH2:4][NH:5][C:6]1[C:7]([NH2:13])=[CH:8][C:9]([I:12])=[CH:10][CH:11]=1.[C:30]1(C)C=CC(S(O)(=O)=O)=CC=1>C(O)C>[F:1][C:2]1[CH:17]=[C:16]([O:18][CH2:19][C:20]2[CH:21]=[N:22][C:23]([O:26][CH3:27])=[CH:24][CH:25]=2)[C:15]([O:28][CH3:29])=[CH:14][C:3]=1[CH2:4][N:5]1[C:6]2[CH:11]=[CH:10][C:9]([I:12])=[CH:8][C:7]=2[N:13]=[CH:30]1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: COc1ccc(COc2cc(F)c(CNc3ccc(I)cc3N)cc2OC)cn1
Solvent: CCO
Product: COc1ccc(COc2cc(F)c(Cn3cnc4cc(I)ccc43)cc2OC)cn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 1375.5 %

Procedure:
To a stirred solution of N1-(2-fluoro-5-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-4-iodobenzene-1,2-diamine (0.36 g, 0.70 mmol) in ethanol (10 mL) was added triethyl orthformate (0.31 g, 2.11 mmol) and p-toluenesulfonic acid (0.007 g, 0.035 mmol). The reaction mixture was heated to reflux. After 30 min, the brown solution was allowed to cool to room temperature and was concentrated. The residue was partitioned between water and dichloromethane. The phases were separated, and the aqueous phase extracted with dichloromethane. The combined organic phases were washed with water and brine, dried over magnesium sulfate, filtered, and concentrated. Chromatographic purification (Combi-Flash, 12 g SiO2 column, 1-5% methanol/dichloromethane elute) afforded 0.25 g (68%) of 1-(2-fluoro-5-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-5-iodo-1H-benzo[d]imidazole as a tan solid.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:20]([O:27][C:28]1[CH:29]=[C:30]([CH2:34][OH:35])[CH:31]=[CH:32][CH:33]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.O[C:51]1[CH:58]=[CH:57][C:54]([CH:55]=[O:56])=[CH:53][CH:52]=1>C1COCC1>[CH2:20]([O:27][C:28]1[CH:29]=[C:30]([CH:31]=[CH:32][CH:33]=1)[CH2:34][O:35][C:51]1[CH:58]=[CH:57][C:54]([CH:55]=[O:56])=[CH:53][CH:52]=1)[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: O=Cc1ccc(O)cc1
Reactant: OCc1cccc(OCc2ccccc2)c1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=Cc1ccc(OCc2cccc(OCc3ccccc3)c2)cc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 45 %

Procedure:
To a stirring solution of triphenylphosphine (1.1 mmols) in THF (2 mLs) was added 34 (1.1 mmols). The solution was immediately cooled to 0° C. and diisopropyl azodicarboxylate (1.1 mmols) was added dropwise and the mixture was stirred at this low temperature for 15 minutes. After this time, 4-hydroxybenzaldehyde (1 mmol) was added to the reaction vessel, still stirring at 0° C. The mixture was warmed slowly to ambient temperature and stirred for 15 hours. At this time, the THF was evaporated, reconstituted in Et2O and filtered through a small portion of silica gel. The eluent was collected and evaporated to dryness. The title product (0.45 mmols) was recovered after flash chromatography. 1H NMR (300 MHz, CDCl3) δ 9.89 (s, 1H), 7.91-7.77 (m, 2H), 7.50-7.30 (m, 6H), 7.03 (ddd, J=5.1, 11.5, 24.0, 5H), 5.13 (s, 2H), 5.08 (s, 2H). 13C NMR (75 MHz, CDCl3) δ 191.04, 163.88, 159.36, 137.82, 136.98, 132.24, 130.09, 128.86, 128.29, 127.74, 120.05, 115.39, 114.79, 114.14, 77.70, 77.27, 76.85, 70.25.
Reaction SMILES: Cl[C:2]1[C:3]2[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=3)=[C:9]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[O:8][C:4]=2[N:5]=[CH:6][N:7]=1.[NH2:25][C:26]1[CH:27]=[C:28]([OH:32])[CH:29]=[CH:30][CH:31]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:18][O:17][C:14]1[CH:15]=[CH:16][C:11]([C:10]2[C:3]3[C:2]([O:32][C:28]4[CH:27]=[C:26]([CH:31]=[CH:30][CH:29]=4)[NH2:25])=[N:7][CH:6]=[N:5][C:4]=3[O:8][C:9]=2[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[CH:12][CH:13]=1
Reactant: Nc1cccc(O)c1
Reactant: COc1ccc(-c2c(-c3ccccc3)oc3ncnc(Cl)c23)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(-c2c(-c3ccccc3)oc3ncnc(Oc4cccc(N)c4)c23)cc1

Procedure:
Stir 1000 mg (2.97 mmol) of 4-chloro-5-(4-methoxyphenyl)-6-phenylfuro[2,3-d]pyrimidine, 1296 mg (11.9 mmol) of 3-aminophenol and 615.6 mg (4.45 mmol) of potassium carbonate in 10 ml of DMF at 80° C. for 8 h. After cooling, concentrate under reduced pressure and take up the residue in water. Filter off the precipitated solid, wash the filter residue repeatedly with water and dry the solid at 50° C. under high vacuum. 1195 mg (98.3% of theory) of the target compound are obtained as a brownish solid.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH2:8][OH:9])[CH:5]=[C:4]([CH3:10])[N:3]=1.[NH3:11]>>[NH2:11][C:2]1[CH:7]=[C:6]([CH2:8][OH:9])[CH:5]=[C:4]([CH3:10])[N:3]=1
Reactant: N
Reactant: Cc1cc(CO)cc(Cl)n1
Product: Cc1cc(CO)cc(N)n1
Temperature: 210 °C

Procedure:
A bomb was charged with 2 (30.0 g, 0.190 mol) and aqueous conc NH3 (225 mL) and the resulting mixture was heated at 210° C. for 20 h. The system was cooled to room temperature, the volatiles removed in vacuo and the residue purified by column chromatography (dichloromethane: 0.4N NH3 in MeOH 9:1) to give (2-amino-6-methyl pyridine-4-yl)-methanol as a mixture of free base and hydrochloride salt. The mixture was redissolved in dichloromethane:i-PrOH 1:1 (1 L) and treated with 20% aqueous NaOH (500 mL). The layers were separated and the organic phase extracted with dichloromethane:i-PrOH 1:1 (1×1 L). The combined organic phase was dried and the solvent evaporated to give (2-amino-6-methyl pyridine-4-yl)-methanol 3 (15.51 g, 59%) as pale orange crystals.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]([OH:10])=O)[C:5]([NH:11][C:12]2[CH:13]=[N:14][CH:15]=[N:16][CH:17]=2)=[CH:4][CH:3]=1.[CH3:18][NH:19][C:20]([C:22]1[N:23]([CH3:28])[N:24]=[CH:25][C:26]=1[NH2:27])=[O:21]>>[CH3:28][N:23]1[C:22]([C:20](=[O:21])[NH:19][CH3:18])=[C:26]([NH:27][C:8]([C:6]2[C:5]([NH:11][C:12]3[CH:13]=[N:14][CH:15]=[N:16][CH:17]=3)=[CH:4][CH:3]=[C:2]([Cl:1])[N:7]=2)=[O:10])[CH:25]=[N:24]1
Reactant: CNC(=O)c1c(N)cnn1C
Reactant: O=C(O)c1nc(Cl)ccc1Nc1cncnc1
Product: CNC(=O)c1c(NC(=O)c2nc(Cl)ccc2Nc2cncnc2)cnn1C

Procedure:
The product was obtained starting from 6-chloro-3-(pyrimidin-5-ylamino)-pyridine-2-carboxylic acid (30 mg, 0.12 mmol) and 4-amino-2-methyl-2H-pyrazole-3-carboxylic acid methylamide (24 mg, 0.15 mmol) according to the method described in example 64, step 6 as yellow solid (29 mg, 62%).