Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:32](Cl)=[O:33])[C:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:35][CH:36]([CH3:38])[CH3:37])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:39]1[NH:44][CH2:43][CH2:42][N:41]2[CH2:45][CH2:46][CH2:47][CH:40]12>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:44]3[CH2:43][CH2:42][N:41]4[CH2:45][CH2:46][CH2:47][CH:40]4[CH2:39]3)=[O:33])[C@@:13]([C:25]3[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:35][CH:36]([CH3:38])[CH3:37])[CH:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)Oc1cc(C(C)(C)C)ccc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1C(=O)Cl
Reactant: C1CC2CNCCN2C1
Product: CC(C)Oc1cc(C(C)(C)C)ccc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN2CCCC2C1

Procedure:
In a manner analogous to the method described in example 5, rac-(4S*,5R*)-2-(4-tert-butyl-2-isopropoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride was reacted with octahydro-pyrrolo[1,2-a]pyrazine (Aldrich) to give the title compound. HR-MS (ES, m/z) calculated for C38H47N4O3Cl2 [(M+H)+] 661.3071, observed 661.3073.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]=1[C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][C:13]=1[P:22]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.N1C=CC=CC=1.Cl[C:42]([O:44][CH3:45])=[O:43].[Cl-].[NH4+]>C(Cl)Cl>[CH3:45][O:44][C:42]([NH:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]=1[C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][C:13]=1[P:22]([C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)=[O:43]
Reactant: COC(=O)Cl
Reactant: Nc1ccc2ccccc2c1-c1c(P(c2ccccc2)c2ccccc2)ccc2ccccc12
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)Nc1ccc2ccccc2c1-c1c(P(c2ccccc2)c2ccccc2)ccc2ccccc12
Temperature: 25 °C
Reaction time: 21 h
Yield: 92.2 %

Procedure:
1.20 gram (2.65 mmol) of (−)-2-amino-2′-diphenylphosphino-1,1′-binaphthyl (1-1a) was dissolved in 53 ml of methylene chloride, followed by the addition of 0.26 ml (3.18 mmol) of pyridine and 0.23 ml (2.91 mmol) of methyl chloroformate under 0° C. The reaction mixture was stirred at room temperature for 21 hours. To the reaction solution, 40 ml of saturated aqueous solution of ammonium chloride was added and extracted with 100 ml of methylene chloride. The extract was washed with 80 ml of brine, and then dried over anhydrous sodium sulfate. The solvent was evaporated under a reduced pressure. The residue was purified using a silica gel column chromatography (eluent: 1:4 mixture of ethyl acetate and hexane) to obtain 1.25 gram of the titled compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:25])=[C:6]([C:8]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[C:17]=2[C:23]#[N:24])=[N:9]S(C(C)(C)C)=O)[CH:7]=1.Br[C:27]1[CH:32]=[CH:31][N:30]=[C:29]([CH3:33])[CH:28]=1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:25])=[C:6]([C:8]2([C:27]3[CH:32]=[CH:31][N:30]=[C:29]([CH3:33])[CH:28]=3)[C:16]3[C:17](=[C:18]([F:22])[CH:19]=[CH:20][CH:21]=3)[C:23]([NH2:24])=[N:9]2)[CH:7]=1
Reactant: Cc1cc(Br)ccn1
Reactant: CC(C)(C)S(=O)N=C(c1cc(Br)ccc1F)c1cccc(F)c1C#N
Product: Cc1cc(C2(c3cc(Br)ccc3F)N=C(N)c3c(F)cccc32)ccn1
Yield: 15 %

Procedure:
The title compound was synthesized as described for Example 14i in 15% yield, starting from N-((5-bromo-2-fluorophenyl)(2-cyano-3-fluorophenyl)methylene)-2-methylpropane-2-sulfinamide (100 mg, 0.24 mmol) and 4-bromo-2-methylpyridine (44.5 mg, 0.26 mmol). Purification was achieved by preparative HPLC.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[H-].[Na+].[Cl:14][C:15]1[CH:20]=[C:19]([N+]([O-])=O)[CH:18]=[CH:17][N:16]=1.C(OCC)(=O)C>CN(C=O)C>[Cl:14][C:15]1[CH:20]=[C:19]([O:1][C:2]2[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=2)[C:5]([O:7][CH3:8])=[O:6])[CH:18]=[CH:17][N:16]=1
Reactant: COC(=O)c1cccc(O)c1
Reactant: O=[N+]([O-])c1ccnc(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1cccc(Oc2ccnc(Cl)c2)c1
Reaction time: 0.33 h
Yield: 90.1 %

Procedure:
Methyl 3-hydroxybenzoate (2.88 g, 18.9 mmol) was added to a mixture of 60% sodium hydride in mineral oil (0.757 g, 18.9 mmol) in DMF (20 mL). The reaction mixture was stirred for 20 minutes and then cooled in an ice bath. 2-Chloro-4-nitropyridine (3.00 g, 18.9 mmol) was added and the reaction mixture was stirred for 1 hour at 0° C., and then overnight at room temperature. The reaction mixture was partitioned between water and ethyl acetate. The organic layer was washed twice with water and brine, dried, and concentrated. The residue was purified by MPLC (Biotage) eluting with 5:1 hexane:ethyl acetate to afford methyl 3-(2-chloropyridin-4-yloxy)benzoate (4.49 g, 90.0% yield) as a thick oil. 1H NMR (CDCl3) δ 8.26 (d, 1H), 7.98 (d, 1H), 7.77 (s, 1H), 7.54 (t, 1H), 7-31 (d, 1H), 6.82 (s, 1H), 6.79 (d, 1H).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]([CH2:22][C:23]([OH:25])=O)[C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:26]([NH:28][CH2:29][C:30]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[NH:32][CH:31]=1)[CH3:27]>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)[CH2:22][C:23]([N:28]([CH2:26][CH3:27])[CH2:29][C:30]2[C:38]3[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=3)[NH:32][CH:31]=2)=[O:25])(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: CCNCc1c[nH]c2ccccc12
Reactant: Cc1ccc(N(CC(=O)O)S(=O)(=O)c2ccc(C(C)(C)C)cc2)cc1
Product: CCN(Cc1c[nH]c2ccccc12)C(=O)CN(c1ccc(C)cc1)S(=O)(=O)c1ccc(C(C)(C)C)cc1

Procedure:
prepared by reaction of [(4-tert-butyl-benzenesulfonyl)-p-tolyl-amino]-acetic acid with ethyl-(1H-indol-3-ylmethyl)-amine
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[O:3][C:4]1[CH:9]=[CH:8][C:7]2[C:10]3([CH2:20][O:21][C:6]=2[CH:5]=1)[C:18]1[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=1)[NH:12][C:11]3=[O:19].Br[C:25]1[CH:33]=[CH:32][CH:31]=[C:30]2[C:26]=1C1(C3=CC4OCOC=4C=C3OC1)C(=O)[NH:29]2.Br.BrCC1C=CC=CN=1.BrCC1(C(F)(F)F)CC=CO1>>[N:29]1[CH:25]=[CH:33][CH:32]=[CH:31][C:30]=1[CH2:26][N:12]1[C:13]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:10]2([C:7]3[CH:8]=[CH:9][C:4]([O:3][C:2]([F:1])([F:22])[F:23])=[CH:5][C:6]=3[O:21][CH2:20]2)[C:11]1=[O:19]
Reactant: O=C1Nc2cccc(Br)c2C12COc1cc3c(cc12)OCO3
Reactant: O=C1Nc2ccccc2C12COc1cc(OC(F)(F)F)ccc12
Agent: Br
Agent: BrCc1ccccn1
Agent: FC(F)(F)C1(CBr)CC=CO1
Product: O=C1N(Cc2ccccn2)c2ccccc2C12COc1cc(OC(F)(F)F)ccc12

Procedure:
Following the procedure described in EXAMPLE 10.47, and making non-critical variations using 6-(trifluoromethoxy)spiro[1-benzofuran-3,3′-indol]-2′(1′H)-one to replace 4′-bromospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one, and 2-(bromomethyl)pyridine hydrobromide to replace 2-(bromomethyl)-2-(trifluoromethyl)furan, 1′-(pyridin-2-ylmethyl)-6-(trifluoromethoxy)spiro[1-benzofuran-3,3′-indol]-2′(1′H)-one was obtained, which was treated with 4.0 M HCl in dioxane to give the title compound (39%): mp 150-152° C.; 1H NMR (300 MHz, CD3OD) δ 8.89-8.78 (m, 1H), 8.62-8.47 (m, 1H), 8.07-7.00 (m, 2H), 7.42-6.70 (m, 7H), 5.52-5.31 (m, 2H), 5.05 (d, 1H), 4.89 (d, 1H); 13C NMR (75 MHz, CD3OD) δ 179.4, 163.5, 153.1, 152.7, 148.2, 143.8, 142.8, 133.1, 130.6, 129.3, 127.4, 126.8, 125.7, 125.6, 125.4, 114.9, 110.4, 104.9, 82.0, 58.9, 43.0; MS (ES+) m/z 413 (M+1).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][CH2:13][C:14]([NH:17][CH2:18][C@@H:19]([C:21]1[CH:22]=[C:23]([NH:27][S:28]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)(=[O:30])=[O:29])[CH:24]=[CH:25][CH:26]=1)[OH:20])([CH3:16])[CH3:15])[CH:7]=[CH:6]2)#[N:2].C([Sn]([N:50]=[N+:51]=[N-:52])(CCCC)CCCC)CCC>C1(C)C=CC=CC=1>[CH3:16][C:14]([NH:17][CH2:18][C@@H:19]([C:21]1[CH:22]=[C:23]([NH:27][S:28]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)(=[O:30])=[O:29])[CH:24]=[CH:25][CH:26]=1)[OH:20])([CH3:15])[CH2:13][CH2:12][N:8]1[C:9]2[C:5](=[CH:4][C:3]([C:1]3[NH:52][N:51]=[N:50][N:2]=3)=[CH:11][CH:10]=2)[CH:6]=[CH:7]1
Reactant: CCCC[Sn](CCCC)(CCCC)N=[N+]=[N-]
Reactant: CC(C)(CCn1ccc2cc(C#N)ccc21)NC[C@H](O)c1cccc(NS(=O)(=O)c2ccccc2)c1
Solvent: Cc1ccccc1
Product: CC(C)(CCn1ccc2cc(-c3nnn[nH]3)ccc21)NC[C@H](O)c1cccc(NS(=O)(=O)c2ccccc2)c1

Procedure:
150 mg (0.30 mmol) N-(3-{(R)-2-[3-(5-cyano-indol-1-yl)-1,1-dimethyl-propylamino]-1-hydroxy-ethyl}-phenyl)-benzenesulphonamide (Example 1) are dissolved in 5 ml of toluene and combined with 98 μl (0.36 mmol) tributyltin azide. Then the reaction solution is refluxed for 18 hours. Another 164 μl (0.6 mmol) tributyltin azide are added. The mixture is refluxed for a further 36 hours. Then the solvent is eliminated in vacuo and the residue is chromatographed on silica gel (DCM/methanol/NH4OH=100:0:0→70:30:0.3).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)[CH:10]=2)[N:5]=[C:4]([N:19]2[CH2:25][CH2:24][CH2:23][C:22]3[CH:26]=[CH:27][CH:28]=[CH:29][C:21]=3[CH2:20]2)[CH:3]=1.[CH2:30]([NH2:33])[CH2:31][NH2:32]>>[N:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]=[C:4]([N:19]1[CH2:25][CH2:24][CH2:23][C:22]3[CH:26]=[CH:27][CH:28]=[CH:29][C:21]=3[CH2:20]1)[CH:3]=[C:2]2[NH:32][CH2:31][CH2:30][NH2:33]
Reactant: Clc1cc(N2CCCc3ccccc3C2)nc2ccc(Oc3ccccn3)cc12
Reactant: NCCN
Product: NCCNc1cc(N2CCCc3ccccc3C2)nc2ccc(Oc3ccccn3)cc12
Temperature: 180 °C
Reaction time: 3 h

Procedure:
The mixture of 2-[4-chloro-6-(pyridin-2-yloxy)quinolin-2-yl]-2,3,4,5-tetrahydro-1H-2-benzazepine (40 mg, 0.1 mmol) and ethane-1,2-diamine (2 mL) was heated with stirring in a 5 mL microwave process vial for 3 hours at 180° C. under microwave irradiation. The solvent was removed under reduced pressure and the residue was purified by preparative HPLC to give 7 mg of product as a yellow powder. MS obsd. (ESI+) [(M+H)+] 426. 1H NMR (400 MHz, CD3OD) δ ppm 8.12 (d, J=3.2 Hz, 1 H), 7.82-7.78 (m, 1 H), 7.66 (d, J=2.8 Hz, 1 H), 7.61 (d, J=8.8 Hz, 1 H), 7.48 (d, J=6.8 Hz, 1 H), 7.23 (dd, J=5.2, 2.4 Hz, 1 H), 7.16-7.08 (m, 4 H), 6.90 (d, J=8.4 Hz, 1 H), 6.04 (s, 1 H), 4.83 (s, 2 H), 4.16 (brs, 2 H), 3.41 (t, J=6.2 Hz, 2 H), 3.05 (t, J=4.8 Hz, 2 H), 2.94 (t, J=6.2 Hz, 2 H), 1.96-1.91 (m, 2 H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:11])[CH3:10])=[CH:4][CH:3]=1.Cl[C:13]1[C:22]2[C:17](=[C:18]([O:23][CH3:24])[CH:19]=[CH:20][CH:21]=2)[CH:16]=[C:15]([NH:25][C:26]2[CH:30]=[C:29]([CH3:31])[NH:28][N:27]=2)[N:14]=1>>[CH3:24][O:23][C:18]1[CH:19]=[CH:20][CH:21]=[C:22]2[C:17]=1[CH:16]=[C:15]([NH:25][C:26]1[CH:30]=[C:29]([CH3:31])[NH:28][N:27]=1)[N:14]=[C:13]2[O:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:11])[CH3:10])=[CH:6][CH:7]=1
Reactant: COc1cccc2c(Cl)nc(Nc3cc(C)[nH]n3)cc12
Reactant: CC(=O)Nc1ccc(O)cc1
Product: COc1cccc2c(Oc3ccc(NC(C)=O)cc3)nc(Nc3cc(C)[nH]n3)cc12

Procedure:
Similar procedure as described in example 10 was used, starting from N-(4-hydroxy-phenyl)-acetamide and (1-chloro-5-methoxy-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine to give N-{4-[5-methoxy-3-(5-methyl-1H-pyrazol-3-ylamino)-isoquinolin-1-yloxy]-phenyl}-acetamide. LC-MS m/e 404(MH+).
Reaction SMILES: Cl[C:2]1[C:3]2[N:16]([CH3:17])[N:15]=[C:14]([CH2:18][CH2:19][CH3:20])[C:4]=2[N:5]=[C:6]([CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])[N:7]=1.[Cl:21][C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][C:29]=1[O:30][CH3:31])[CH2:25][NH2:26].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:21][C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][C:29]=1[O:30][CH3:31])[CH2:25][NH:26][C:2]1[C:3]2[N:16]([CH3:17])[N:15]=[C:14]([CH2:18][CH2:19][CH3:20])[C:4]=2[N:5]=[C:6]([CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])[N:7]=1
Reactant: COc1ccc(CN)cc1Cl
Reactant: CCCc1nn(C)c2c(Cl)nc(CCC(=O)OC)nc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCc1nn(C)c2c(NCc3ccc(OC)c(Cl)c3)nc(CCC(=O)OC)nc12
Yield: 105.3 %

Procedure:
3 g of methyl 3-[7-chloro-1-methyl-3-propyl-1H-pyrazolo[4,3-d]pyrimidin-5-yl]propionate and 1.9 g of 3-chloro-4-methoxybenzylamine (“A”) in 50 ml of dimethylformamide (DMF) are stirred at 60° for 12 hours in the presence of potassium carbonate. After filtration, the solvent is removed and the mixture is worked up in the customary manner. 4.6 g of methyl 3-[7-(3-chloro-4-methoxybenzylamino)-1-methyl-3-propyl-1H-pyrazolo[4,3-d]pyrimidin-5-yl]propionate are obtained as a colourless oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH:24]3[CH2:27][CH2:26][CH2:25]3)[C:10]3[C:15]([C:16]=2[C:17]#[N:18])=[CH:14][CH:13]=[C:12]([O:19][CH2:20][CH2:21][O:22][CH3:23])[CH:11]=3)=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Cl[C:35]([O:37][C:38]1[CH:43]=[CH:42][C:41]([O:44][CH3:45])=[CH:40][CH:39]=1)=[O:36]>CCOC(C)=O>[CH3:45][O:44][C:41]1[CH:42]=[CH:43][C:38]([O:37][C:35](=[O:36])[NH:1][C:2]2[CH:3]=[CH:4][C:5]([C:8]3[N:9]([CH:24]4[CH2:27][CH2:26][CH2:25]4)[C:10]4[C:15]([C:16]=3[C:17]#[N:18])=[CH:14][CH:13]=[C:12]([O:19][CH2:20][CH2:21][O:22][CH3:23])[CH:11]=4)=[CH:6][CH:7]=2)=[CH:39][CH:40]=1
Reactant: COc1ccc(OC(=O)Cl)cc1
Reactant: COCCOc1ccc2c(C#N)c(-c3ccc(N)cc3)n(C3CCC3)c2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Product: COCCOc1ccc2c(C#N)c(-c3ccc(NC(=O)Oc4ccc(OC)cc4)cc3)n(C3CCC3)c2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 98 %

Procedure:
To a solution 2-(4-aminophenyl)-1-cyclobutyl-6-(2-methoxyethoxy)-1H-indole-3-carbonitrile (530 mg, 1.58 mmol) in EtOAc (10 mL) is added 2M aqueous K2CO3 (556 uL, 5.9 mmol) and 4-methoxyphenyl chloroformate over a period of 5 min. The reaction mixture is stirred further for 3 h at room temperature. The reaction mixture is diluted with EtOAc (20 mL) and then washed with water (5 mL). The solvents are removed under reduced pressure and the residue is dissolved in EtOAc and then triturated with hexane. The precipitate is collected by filtration and washed with 50% EtOAc/hexane and dried in vacuo to afford {4-[3-cyano-1-cyclobutyl-6-(2-methoxy-ethoxy)-1H-indol-2-yl]-phenyl}-carbamic acid 4-methoxy-phenyl ester (761 mg, 98%).
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[CH3:15])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:16][C:17]([O:19]CC)=[O:18].[OH-].[Na+].O>O1CCOCC1>[NH2:1][C:2]1[C:7]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[CH3:15])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:16][C:17]([OH:19])=[O:18]
Reactant: CCOC(=O)Cc1cccc(Oc2ccccc2C)c1N
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: Cc1ccccc1Oc1cccc(CC(=O)O)c1N
Yield: 71.6 %

Procedure:
A mixture of ethyl 2-[2-amino-3-(o-tolyloxy)phenyl]acetate (3.1 g.), sodium hydroxide (0.9 g.), water (20 ml.) and dioxane (20 ml.) was treated in a similar manner to that of Example 2-(2) to give crystals of 2-[2-amino-3-(o-tolyloxy)phenyl]acetic acid (2.0 g.). Thus obtained compound was dissolved in a solution of sodium bicarbonate (0.343 g.) in water (50 ml.) under heating and filtered. The filtrate was lyophilized to give sodium 2-[2-amino-3-(o-tolyloxy)phenyl]acetate (1.1 g.). mp >150° C.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[OH:11][C:12]1[C:21]([C:22](=[O:25])[CH2:23][CH3:24])=[CH:20][CH:19]=[CH:18][C:13]=1[C:14]([O:16][CH3:17])=[O:15]>>[CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:11][C:12]2[C:21]([C:22](=[O:25])[CH2:23][CH3:24])=[CH:20][CH:19]=[CH:18][C:13]=2[C:14]([O:16][CH3:17])=[O:15])=[O:7])=[CH:4][CH:3]=1
Reactant: CCC(=O)c1cccc(C(=O)OC)c1O
Reactant: Cc1ccc(C(=O)Cl)cc1
Product: CCC(=O)c1cccc(C(=O)OC)c1OC(=O)c1ccc(C)cc1
Reaction time: 4 h

Procedure:
This compound was prepared in three steps according to the methods described for Intermediate XC (first step) and Intermediate LXXX (second and third steps). In the first step, 4-methylbenzoyl chloride was used instead of 2-furanecarbonyl chloride and methyl 2-hydroxy-3-propionylbenzoate was used instead of ethyl 2-hydroxy-3-propionylbenzoate. The reaction lasted 4 hours at room temperature, yielding methyl 2-(4-methylbenzoyloxy)3-propionylbenzoate. This compound was used without purification by column chromatography for the second step, that lasted 1.5 hours at 100° C. In the third step, 96% sulfuric acid was used instead of 37% hydrochloric acid. The title compound melted at 174°-175° C. after crystallization from ethanol.
Reaction SMILES: [C:1]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][NH2:13])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[C:14]1(=O)[O:19][C:17](=[O:18])[CH:16]=[CH:15]1>C1(C)C=CC=CC=1>[C:4]([O:3][C:1](=[O:2])[NH:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]1[C:17](=[O:18])[CH:16]=[CH:15][C:14]1=[O:19])([CH3:5])([CH3:6])[CH3:7]
Reactant: O=C1C=CC(=O)O1
Reactant: CC(C)(C)OC(=O)NCCCCN
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)NCCCCN1C(=O)C=CC1=O

Procedure:
To a solution of N-BOC-1,4-diaminobutane (8.324 g, 0.044 mol) in dry toluene (50 ml) was added maleic anhydride (4.336 g, 0.044 mol) and the solution heated at reflux under Dean-Stark conditions for two days. The solvent was removed and the residue purified by silica column chromatography eluting with 25-40% ethyl acetate in hexane to give the title compound, 1.461 g, 12%, as a white solid.
Reaction SMILES: [O:1]1[C:13]([CH3:15])([CH3:14])[C:2]1([CH3:16])[CH2:3][CH2:4][C:5]([CH3:12])=[CH:6][CH2:7][CH2:8]C(=O)C.[CH2:17]([O:19][C:20](=[O:30])[C:21]([CH2:28][CH3:29])(CC)P(O)(O)=O)[CH3:18].[Na]>C(O)C>[CH2:17]([O:19][C:20](=[O:30])[CH:21]=[C:28]([CH3:29])[CH2:8][CH2:7][CH:6]=[C:5]([CH3:12])[CH2:4][CH2:3][C:2]1([CH3:16])[O:1][C:13]1([CH3:15])[CH3:14])[CH3:18]
Reactant: CC(=O)CCC=C(C)CCC1(C)OC1(C)C
Reactant: CCOC(=O)C(CC)(CC)P(=O)(O)O
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)C=C(C)CCC=C(C)CCC1(C)OC1(C)C
Reaction time: 14 h

Procedure:
To a solution of 25 g. of 9,10-epoxy-6,9,10-trimethyl-undec-5-en-2-one and 24.8 g. of diethyl phosphonoacetic acid ethyl ester in 160 ml. of absolute ethanol, there was added dropwise while cooling with ice, a solution containing 2.56 g. of sodium in 65 ml. of absolute ethyl alcohol. The mixture was allowed to stand for 14 hours at room temperature and evaporated subsequently under vacuum. The residue was poured into a standard aqueous sodium chloride solution, exhaustively extracted with diethyl ether, washed with a saturated aqueous sodium chloride solution, dried over sodium sulfate and evaporated. Fractional distillation at high vacuum gave 10,11-epoxy-3,7,10,11-tetramethyl-2,6-dodecadienoic acid ethyl ester; b.p. 110°-113°C./0.01 mmHg; nD20 = 1.4792.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8](Cl)=[O:9])=[C:6]([Cl:11])[N:5]=[CH:4][N:3]=1.[Si:12]([O:19][CH2:20][CH2:21][NH:22][C:23]1[CH:24]=[CH:25][C:26]([O:29][CH2:30][C:31]([CH3:37])([CH3:36])[C:32]([O:34][CH3:35])=[O:33])=[N:27][CH:28]=1)([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13].C(N(CC)CC)C>O1CCCC1>[Si:12]([O:19][CH2:20][CH2:21][N:22]([C:23]1[CH:24]=[CH:25][C:26]([O:29][CH2:30][C:31]([CH3:37])([CH3:36])[C:32]([O:34][CH3:35])=[O:33])=[N:27][CH:28]=1)[C:8]([C:7]1[C:6]([Cl:11])=[N:5][CH:4]=[N:3][C:2]=1[Cl:1])=[O:9])([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:13])[CH3:14]
Reactant: COC(=O)C(C)(C)COc1ccc(NCCO[Si](C)(C)C(C)(C)C)cn1
Reactant: O=C(Cl)c1c(Cl)ncnc1Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)C(C)(C)COc1ccc(N(CCO[Si](C)(C)C(C)(C)C)C(=O)c2c(Cl)ncnc2Cl)cn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 66 %

Procedure:
A solution of 4,6-dichloropyrimidine-5-carbonyl chloride (130.5 mg, 0.617 mmol) in anhydrous tetrahydrofuran (1.5 mL) was added dropwise to a solution of methyl 3-(5-(2-(tert-butyldimethylsilyloxy)ethylamino)pyridin-2-yloxy)-2,2-dimethylpropanoate B-18 (157.2 mg, 0.411 mmol) and triethylamine (124.5 mg, 1.233 mmol) in anhydrous tetrahydrofuran (5.0 mL) at 0° C. The reaction mixture was stirred for 30 mins, then allowed to warm to room temperature, stirred for an additional 2 h period and then concentrated to dryness under reduced pressure. The crude residue was purified by flash column chromatography on silica gel (hexanes:ethyl acetate gradient) to give methyl 3-(5-(N-(2-(tert-butyldimethylsilyloxy)ethyl)-4,6-dichloropyrimidine-5-carboxamido)pyridin-2-yloxy)-2,2-dimethylpropanoate B-19 (150 mg, Yield=66%). MS (ESI) [M+1]+ 558.
Reaction SMILES: [CH3:1][S:2]([N:5]([CH3:29])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12]1[N:20]2[C:15]([CH:16]=[N:17][C:18](OS(C(F)(F)F)(=O)=O)=[N:19]2)=[CH:14][CH:13]=1)(=[O:4])=[O:3].[CH3:30][S:31]([N:34]1[C:43]2[C:38](=[CH:39][CH:40]=[C:41]([NH2:44])[CH:42]=2)[CH2:37][CH2:36][CH2:35]1)(=[O:33])=[O:32]>>[CH3:30][S:31]([N:34]1[C:43]2[C:38](=[CH:39][CH:40]=[C:41]([NH:44][C:18]3[N:17]=[CH:16][C:15]4=[CH:14][CH:13]=[C:12]([C:7]5[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=5[N:5]([CH3:29])[S:2]([CH3:1])(=[O:3])=[O:4])[N:20]4[N:19]=3)[CH:42]=2)[CH2:37][CH2:36][CH2:35]1)(=[O:33])=[O:32]
Reactant: CS(=O)(=O)N1CCCc2ccc(N)cc21
Reactant: CN(c1ccccc1-c1ccc2cnc(OS(=O)(=O)C(F)(F)F)nn12)S(C)(=O)=O
Product: CN(c1ccccc1-c1ccc2cnc(Nc3ccc4c(c3)N(S(C)(=O)=O)CCC4)nn12)S(C)(=O)=O

Procedure:
N-{2-[2-(1-Methanesulfonyl-1,2,3,4-tetrahydro-quinolin-7-ylamino)-pyrrolo[2,1-f][1,2,4]triazin-7-yl]-phenyl}-N-methyl-methanesulfonamide was prepared from Trifluoro-methanesulfonic acid 7-[2-(methanesulfonyl-methyl-amino)-phenyl]-pyrrolo[2,1-f][1,2,4]triazin-2-yl ester and 1-methanesulfonyl-1,2,3,4-tetrahydro-quinolin-7-ylamine in an analogous manner to Example 1061. Product isolated as a yellow foam (61 mg, 55%). LCMS (m/e) 527 (M+H); 1H-NMR (CDCl3, 400 MHz) δ 8.73 (s, 1H), 7.94-7.87 (m, 1H), 7.68-7.62 (m, 1H), 7.56-7.44 (m, 3H), 7.40 (dd, 1H, J=1.7 and 8.3 Hz), 7.00 (d, 1H, J=4.7 Hz), 6.96 (d, 1H, J=8.3 Hz), 6.87 (d, 1H, J=4.7 Hz), 6.79 (bs, 1H), 3.82-3.73 (m, 2H), 3.13 (s, 3H), 2.82-2.74 (m, 2H), 2.78 (s, 3H), 2.64 (s, 3H), 2.01-1.92 (m, 2H).
Reaction SMILES: O[CH2:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([C:14]3[CH:18]=[CH:17][S:16][CH:15]=3)=[CH:8][C:9](=[O:13])[O:10]2)=[CH:5][CH:4]=1.CN(C)P(N(C)C)N(C)C.C(Cl)(Cl)(Cl)[Cl:30]>C1COCC1.CCOCC>[Cl:30][CH2:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([C:14]3[CH:18]=[CH:17][S:16][CH:15]=3)=[CH:8][C:9](=[O:13])[O:10]2)=[CH:5][CH:4]=1
Reactant: O=c1cc(-c2ccsc2)c2ccc(CO)cc2o1
Reactant: ClC(Cl)(Cl)Cl
Agent: CN(C)P(N(C)C)N(C)C
Solvent: C1CCOC1
Solvent: CCOCC
Product: O=c1cc(-c2ccsc2)c2ccc(CCl)cc2o1
Reaction time: 0.5 h

Procedure:
To a solution of the alcohol from Step 1 (1.65 g) and hexamethylphosphorous triamide in 35 mL THF at 0° C. was added CCl4 (1.3 mL) and the mixture stirred for 30 min. The mixture was diluted with Et2O, filtered, concentrated and the residue chromatographed (30% EtOAc/hexane) to provide the title compound as a solid, m.p. 125°-127° C.
Reaction SMILES: [NH2:1][C:2]1([C:11]2[N:16]=[CH:15][C:14]([C:17]#[N:18])=[C:13]([S:19]([CH3:21])=O)[N:12]=2)[O:10][C:6]2=[CH:7][CH:8]=[CH:9][C:5]2=[CH:4][CH2:3]1.SC[CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=1.C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1([C:11]2[N:16]=[CH:15][C:14]([C:17]#[N:18])=[C:13]([S:19][CH2:21][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=3)[N:12]=2)[O:10][C:6]2=[CH:7][CH:8]=[CH:9][C:5]2=[CH:4][CH2:3]1
Reactant: SCCc1ccccn1
Reactant: CS(=O)c1nc(C2(N)CC=C3C=CC=C3O2)ncc1C#N
Solvent: C1CCC2=NCCCN2CC1
Solvent: COCCOC
Product: N#Cc1cnc(C2(N)CC=C3C=CC=C3O2)nc1SCCc1ccccn1

Procedure:
From 2-amino-4-benzofuran-2-yl-6-methanesulfinyl-pyrimidine-5-carbonitrile, 2-mercaptoethylpyridine and DBU in DME. ES-MS m/e (%:374 (M+H+, 100).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[NH:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1>CCO>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([N:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[N:3][CH:4]=1)([O-:10])=[O:9]
Reactant: C1CCNC1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Solvent: CCO
Product: O=[N+]([O-])c1ccc(N2CCCC2)nc1
Temperature: 70 °C
Yield: 78.1 %

Procedure:
To a slurry of 2-chloro-5-nitropyridine (10 g, 63.1 mmol) in EtOH (100 mL) at room temperature was added pyrrolidine (15.72 mL, 189 mmol) and the mixture was heated at 70° C. for 18 hours. The cooled solution was concentrated in vacuo and the residue partitioned between CH2Cl2 and 1 M NaOH. The organic layer was dried (Na2SO4), filtered and solvent removed in vacuo to give title compound (9.52 g, 78%). MS (ESI) m/z 194 (M+H)+.