Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH:7]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]([N:28]([CH3:36])[CH2:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])=[O:27])=[CH:22][CH:21]=2)[C:8]2[O:9][C:10]3[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][C:11]=3[C:12]=2[CH3:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[S:37]1[CH2:42][CH2:41][CH:40](O)[CH2:39][CH2:38]1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>O1CCCC1>[CH:1]1([CH:7]([NH:19][C:20]2[CH:21]=[CH:22][C:23]([C:26]([N:28]([CH3:36])[CH2:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])=[O:27])=[CH:24][CH:25]=2)[C:8]2[O:9][C:10]3[CH:17]=[CH:16][C:15]([O:18][CH:40]4[CH2:41][CH2:42][S:37][CH2:38][CH2:39]4)=[CH:14][C:11]=3[C:12]=2[CH3:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)CCN(C)C(=O)c1ccc(NC(c2oc3ccc(O)cc3c2C)C2CCCCC2)cc1
Reactant: OC1CCSCC1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: CCOC(=O)CCN(C)C(=O)c1ccc(NC(c2oc3ccc(OC4CCSCC4)cc3c2C)C2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 23.3 %

Procedure:
Ethyl 3-{[(4-{[cyclohexyl(5-hydroxy-3-methyl-1-benzofuran-2-yl)methyl]amino}phenyl)carbonyl](methyl)amino}propanoate (0.50 g) synthesized in Example A155(1) was dissolved in tetrahydrofuran (10 mL), and tetrahydrothiopyran-4-ol (142 mg), tributylphosphine (0.45 mL) and 1,1′-(azodicarbonyl)dipiperidine (0.45 g) were added to the solution under ice-cooling. The ice bath was removed, the reaction mixture was stirred at room temperature for 12 hr, then hexane (10 mL) was added to the mixture, and the precipitate was filtered off through celite. Water was added to the filtrate, and the mixture was extracted with ethyl acetate. The extract was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:2, volume ratio) to give the title object compound (0.14 g, 23%) as a yellow oil.
Reaction SMILES: C[O:2][C:3](=[O:32])[CH2:4][O:5][C:6]1[CH:14]=[C:13]2[CH2:15][CH2:16][CH2:17][C:12]2=[C:11]2[C:7]=1[C:8]([C:27](=[O:31])[C:28]([NH2:30])=[O:29])=[C:9]([CH3:26])[N:10]2[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[F:25].[OH-].[Li+]>O1CCCC1.CO.O>[NH2:30][C:28](=[O:29])[C:27]([C:8]1[C:7]2[C:11](=[C:12]3[CH2:17][CH2:16][CH2:15][C:13]3=[CH:14][C:6]=2[O:5][CH2:4][C:3]([OH:32])=[O:2])[N:10]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[F:25])[C:9]=1[CH3:26])=[O:31]
Reactant: COC(=O)COc1cc2c(c3c1c(C(=O)C(N)=O)c(C)n3Cc1ccccc1F)CCC2
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: Cc1c(C(=O)C(N)=O)c2c(OCC(=O)O)cc3c(c2n1Cc1ccccc1F)CCC3
Yield: 49.4 %

Procedure:
A solution of 2-[[3-(2-amino-1,2-dioxoethyl)-2-methyl-1-(2-fluorobenzyl)-1,6,7,8-tetrahydrocyclopent[g]indol-4-yl]oxy]acetic acid methyl ester (345 mg, 0.787 mmol) in tetrahydrofuran (20 mL) and methanol (20 mL) was treated with 1 M aqueous lithium hydroxide solution (25 mL) at room temperature for 19 h. The mixture was diluted with water and methanol and filtered. The filtrate was concentrated in vacuo and the residue dissolved in water and acidified with concentrated hydrochloric acid. The resulting precipitate was collected via vacuum filtration, washed with water, and air-dried to provide 165 mg (50%) of the title compound as a yellow solid. Recrystallization (methanol/water) provided an analytical sample as a yellow green solid: mp 246-249° C. (dec). 1H NMR (DMSO-d6) δ 12.94 (bs, 1H), 7.73 (bs, 1H), 7.44 (bs, 1H), 7.33 (m, 2H), 7.11 (t, J=7.6 Hz, 1H), 6.48 (s, 1H), 6.37 (t, J=7.6 Hz, 1H), 5.59 (s, 2H), 4.63 (s, 2H), 2.92 (t, J=7.3.Hz, 2H), 2.83 (t, J=7.3 Hz, 2H), 2.44 (s, 3H), 1.97 (quintet, J=7.3 Hz, 2H); MS ES+ m/e 425 (p+1); IR (KBr, cm−1) 3450, 1619, 1225.
Reaction SMILES: O[O:2][S:3]([O-:5])=O.[K+].[F:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[C:9]=1[N:15]1[C:20]2[N:21]=[C:22](SC)[N:23]=[C:24]([C:25]3[CH:26]=[C:27]([CH:34]=[CH:35][C:36]=3[CH3:37])[C:28]([NH:30][CH2:31][CH2:32][CH3:33])=[O:29])[C:19]=2[CH2:18][NH:17][C:16]1=[O:40].[C:41](#N)C>O>[F:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[C:9]=1[N:15]1[C:20]2[N:21]=[C:22]([S:3]([CH3:41])(=[O:5])=[O:2])[N:23]=[C:24]([C:25]3[CH:26]=[C:27]([CH:34]=[CH:35][C:36]=3[CH3:37])[C:28]([NH:30][CH2:31][CH2:32][CH3:33])=[O:29])[C:19]=2[CH2:18][NH:17][C:16]1=[O:40]
Reactant: CC#N
Reactant: CCCNC(=O)c1ccc(C)c(-c2nc(SC)nc3c2CNC(=O)N3c2c(F)cccc2F)c1
Reactant: O=S([O-])OO
Agent: [K+]
Solvent: O
Product: CCCNC(=O)c1ccc(C)c(-c2nc(S(C)(=O)=O)nc3c2CNC(=O)N3c2c(F)cccc2F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirring suspension of Oxone (817.96 g, 1.33 mole, 3 eq) in water (2142 mL, 10 vol) was added 3-[8-(2,6-difluorophenyl)-2-(methylthio)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methyl-N-propylbenzamide (214.21 g 0.443 mole, 1 eq) suspended in acetonitrile (4284 mL). The resulting mixture was stirred at ambient temperature overnight. The mixture was then filtered and the residue stirred sequentially with 5% sodium metabisulfite (2×3000 mL) and water (1×300 mL). The filtrate from the reaction mixture was then diluted with water (2142 mL, 10 vol). The solid that formed was then collected by filtration. The solid was washed well with water then dried at the pump to yield the title compound. LC-MS m/z 516 (M+H)+, 2.77 min (ret time). It was used without further purification although corresponding sulfoxide was present (about 10%).
Reaction SMILES: [NH:1]1[CH:5]=[N:4][C:3]([C:6]2[CH:7]=[C:8]3[C:12](=[CH:13][CH:14]=2)[NH:11][NH:10][C:9]3([Br:23])[C:15]([CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][O:18]2)=[O:16])=[N:2]1.[C:24]1([C:30](Cl)([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(N(CC)CC)C>CN(C)C=O>[Br:23][C:9]1([C:15]([CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][O:18]2)=[O:16])[C:8]2[C:12](=[CH:13][CH:14]=[C:6]([C:3]3[N:4]=[CH:5][N:1]([C:30]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)([C:37]4[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=4)[C:31]4[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=4)[N:2]=3)[CH:7]=2)[NH:11][NH:10]1
Reactant: O=C(C1CCCCO1)C1(Br)NNc2ccc(-c3nc[nH]n3)cc21
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(C1CCCCO1)C1(Br)NNc2ccc(-c3ncn(C(c4ccccc4)(c4ccccc4)c4ccccc4)n3)cc21
Temperature: 80 °C

Procedure:
To a solution of 2-(5-(1H-1,2,4-triazol-3-yl)-3-bromo-1H-indazoyl)perhydro-2H-pyran in 60 mL in dimethyl formamide, was added triphenylmethyl chloride (3.48 g, 12.5 mmol), and triethyl amine (4.64 mL, 33.32 mmol). The reaction mixture was heated to 80° C. for 12 hours. The solvent was removed under reduced pressure and the crude reaction mixture was partitioned between water and ethyl acetate. The oil resulting from evaporation of the extracts was purified by column chromatography (SiO2, 25% ethyl acetate in hexanes (2.90 g, 61% over 4 steps): 1H NMR (CDCl3) δ 8.3 (s, 1H), 8.2 (d, 1H), 7.9 (s, 1H), 7.5 (d, 1H), 7.4-8.1 (m, 15H), 5.68 (dd, 1H), 4.0 (m, 1H), 3.75 (m, 1H), 2.5 (m, 1H), 2.1 (m, 2H), 1.7 (m, 3H); ES-MS (m/z) 592 [M+2]+.
Reaction SMILES: C([N:8]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C@@H:19]([O:32][Si:33]([CH2:38][CH3:39])([CH2:36][CH3:37])[CH2:34][CH3:35])[CH2:20][N:21](CC2C=CC=CC=2)[CH2:22][CH2:23][OH:24])[CH:14]=1)[S:9]([CH3:12])(=[O:11])=[O:10])C1C=CC=CC=1.CO.O>C1COCC1.[OH-].[OH-].[Pd+2]>[OH:24][CH2:23][CH2:22][NH:21][CH2:20][C@@H:19]([C:15]1[CH:14]=[C:13]([NH:8][S:9]([CH3:12])(=[O:10])=[O:11])[CH:18]=[CH:17][CH:16]=1)[O:32][Si:33]([CH2:34][CH3:35])([CH2:36][CH3:37])[CH2:38][CH3:39]
Reactant: CC[Si](CC)(CC)O[C@@H](CN(CCO)Cc1ccccc1)c1cccc(N(Cc2ccccc2)S(C)(=O)=O)c1
Agent: [Pd+2]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CC[Si](CC)(CC)O[C@@H](CNCCO)c1cccc(NS(C)(=O)=O)c1
Temperature: 50 °C
Reaction time: 15 h

Procedure:
(R)-N-benzyl-N-(3-(2-(benzyl-(2-hydroxyethyl)amino)-1-(triethylsilyloxy)ethyl)phenyl)methanesulfonamide (500 mg; an intermediate described in Reference Example 1 of WO 03/035620) was dissolved in THF (1.76 mL; manufactured by Wako Pure Chemical Industries, Ltd.) and methanol (1.76 mL; manufactured by Wako Pure Chemical Industries, Ltd.) under a nitrogen atmosphere, and 20% palladium hydroxide on carbon-49.94% wet with water (102.7 mg; manufactured by N.E. Chemcat Corp.) was added thereto. Subsequently, the reaction system was purged with hydrogen, and under a hydrogen atmosphere, the reaction solution was stirred for 15 hours at 50° C. The reaction solution was cooled to room temperature, purged with nitrogen, and then filtered. The filtrate was concentrated under reduced pressure, and thus the title compound (364 mg) was obtained.
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([C:6]1[C@H:11]([C:12]2[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:10]([C:19]([O:21][CH3:22])=[O:20])=[C:9]([CH3:23])[NH:8][C:7]=1[CH2:24][O:25][CH2:26][CH2:27][NH2:28])=[O:5].C([O-])(=O)C(C(C([O-])=O)O)O.[C:39]1([S:45]([OH:48])(=[O:47])=[O:46])[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>C(O)(C)C.O>[CH3:1][CH2:2][O:3][C:4]([C:6]1[CH:11]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:17]=2[Cl:18])[C:10]([C:19]([O:21][CH3:22])=[O:20])=[C:9]([CH3:23])[NH:8][C:7]=1[CH2:24][O:25][CH2:26][CH2:27][NH2:28])=[O:5].[CH:42]1[CH:41]=[CH:40][C:39]([S:45]([OH:48])(=[O:47])=[O:46])=[CH:44][CH:43]=1
Reactant: CCOC(=O)C1=C(COCCN)NC(C)=C(C(=O)OC)[C@H]1c1ccccc1Cl
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: O=S(=O)(O)c1ccccc1
Solvent: CC(C)O
Solvent: O
Product: CCOC(=O)C1=C(COCCN)NC(C)=C(C(=O)OC)C1c1ccccc1Cl
Reaction time: 2 h
Yield: 69.4 %

Procedure:
68.8 gm (0.122 mole, 95.2% de) R (+) Amlodipine hemi L (+) tartarate mono DMSO solvate prepared as per example 1 was suspended in aqueous isopropanol (90 ml IPA: 250 ml distilled water) and a solution of benzene sulfonic acid (19.35 gm of 90% technical grade, 0.110 mole) in 150 ml water was added. The reaction mixture was stirred for 2 hrs and the slurry was filtered, washed with distilled water, hexane, the solid was dried under vac. at 40° C. till constant weight to give R(+) amlodipine besylate (51.6 gm, 69.4% yield) 99.3 ee by chiral HPLC.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7](=[O:19])[N:8]([CH2:17][CH3:18])[C:9]2[C:14]([C:15]=1[NH2:16])=[CH:13][CH:12]=[CH:11][N:10]=2)=[O:5])C.[OH-].[Na+].C(O)C>C(O)(=O)C>[NH2:16][C:15]1[C:14]2[C:9](=[N:10][CH:11]=[CH:12][CH:13]=2)[N:8]([CH2:17][CH3:18])[C:7](=[O:19])[C:6]=1[C:4]([OH:5])=[O:3]
Reactant: CCOC(=O)c1c(N)c2cccnc2n(CC)c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CCO
Product: CCn1c(=O)c(C(=O)O)c(N)c2cccnc21

Procedure:
A stirred mixture of 2 g. of 4-amino-1-ethyl-1,2-dihydro-2-oxo-1,8-naphthyridine-3-carboxylic acid ethyl ester in 20 ml. of 10% aqueous sodium hydroxide containing 5 ml. of ethanol was heated under reflux for 3 hours to saponify the ester. The solution was cooled and was acidified with glacial acetic acid. The precipitate which formed was collected, air dried, and was recrystallized from ethanol to give 0.4 g. of product, m.p. 245°-248° C.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[C:9]([CH3:11])[CH:8]=[CH:7][N:6]=1)(=[O:3])[CH3:2].P([O-])([O-])(O)=O.[Na+].[Na+].[Cl:19]CCl.ClCl>O>[C:1]([NH:4][C:5]1[CH:10]=[C:9]([CH3:11])[C:8]([Cl:19])=[CH:7][N:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1cc(C)ccn1
Reactant: ClCCl
Agent: ClCl
Agent: O=P([O-])([O-])O
Agent: [Na+]
Solvent: O
Product: CC(=O)Nc1cc(C)c(Cl)cn1
Reaction time: 1 h
Yield: 97.3 %

Procedure:
In 300 ml of water, 15.0 g (0. lmol) of 2-acetamido-4-methylpyridine (Ia) was dissolved. To this solution, 35.5 g (0.25 mol) of disodium hydrogenphosphate and 100 ml of dichloromethane were added in this order. While this mixture was stirred, 8.0 g (0.11 mol) of chlorine was introduced thereto at 0° C. for one hour. After having further been stirred at the same temperature for 2 hours, the mixture was separated into a water layer and an extract layer. After the water layer was further extracted with 100 ml of dichloromethane, the newly-separated extract layer was combined with the previously-separated extract layer and washed with saturated brine. Then the washed mixture was desiccated with sodium sulfate anhydride. When the solvent was evaporated off, 18.0 g (yield: 97.3%) of 2-acetamido-4-methyl-5-chloropyridine (IIk) was obtained as a pale yellow crystal.
Reaction SMILES: [Br:1][C:2]1[C:3]([C:9]([F:12])([F:11])[F:10])=[CH:4][C:5]([NH2:8])=[N:6][CH:7]=1.[C:13](OCC)(=[O:15])[CH3:14].C(OC(=O)C)(=O)C>CN(C)C1C=CN=CC=1.CCCCCCC>[Br:1][C:2]1[C:3]([C:9]([F:12])([F:10])[F:11])=[CH:4][C:5]([NH:8][C:13](=[O:15])[CH3:14])=[N:6][CH:7]=1
Reactant: CCOC(C)=O
Reactant: Nc1cc(C(F)(F)F)c(Br)cn1
Agent: CN(C)c1ccncc1
Solvent: CCCCCCC
Solvent: CC(=O)OC(C)=O
Product: CC(=O)Nc1cc(C(F)(F)F)c(Br)cn1
Temperature: 0 °C
Reaction time: 18 h
Yield: 90 %

Procedure:
A dry vessel under nitrogen at room temperature was charged with 5-bromo-4-(trifluoromethyl)pyridin-2-amine B1 (200 g, 830 mmol) and ethyl acetate (200 ml). The reaction mixture was cooled to 0° C. To the solution was added N,N-dimethylpyridin-4-amine (1.01 g, 8.29 mmol). Heptane (400 ml) was added and the mixture was cooled to 0° C. Acetic anhydride (109.6 ml, 1162 mmol) was added over a period of 60 min. The reaction mixture was warmed to 50° C. within 60 min. The reaction mixture was stirred at 50° C. for 18 h. Solvent (330 g) was removed by distillation (540-250 mbar, 50° C.) until a residue of ˜300 ml was obtained. The reaction mixture was allowed to cool to 20° C. Heptane (800 ml) was added and the mixture was stirred for 30 min. The precipitate was collected by filtration. The filter cake was washed with heptane (100 ml). The product was dried in a tray dryer for 16 h at 40° C., <20 mbar to yield 212 g (90%) B2 as slightly brown solid.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:10]([OH:12])=[O:11])[CH:8]=2)[CH:3]=[CH:2]1.[Br:13]N1C(=O)CCC1=O>>[Br:13][C:3]1[C:4]2[C:9](=[CH:8][C:7]([C:10]([OH:12])=[O:11])=[CH:6][CH:5]=2)[NH:1][CH:2]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: O=C(O)c1ccc2cc[nH]c2c1
Product: O=C(O)c1ccc2c(Br)c[nH]c2c1
Yield: 74.5 %

Procedure:
Using the procedure described in Example 34, Part A, indole-6-carboxylic acid (2.6 g, 16.1 mmol) and N-bromosuccinimide (2.9 g, 16.1 mmol) yielded 2.88 g (75%) of the title compound.
Reaction SMILES: C(N(C(C)C)CC)(C)C.O.[C:11]([C:13]1[CH:18]=[CH:17][C:16]([C:19]2[C:27]3[C:22](=[CH:23][C:24]([NH:28][S:29]([CH3:32])(=[O:31])=[O:30])=[CH:25][CH:26]=3)[N:21]([CH:33]([CH3:35])[CH3:34])[CH:20]=2)=[CH:15][C:14]=1[F:36])#[N:12].C(OP(=S)(OCC)[SH:41])C>COOOC>[F:36][C:14]1[CH:15]=[C:16]([C:19]2[C:27]3[C:22](=[CH:23][C:24]([NH:28][S:29]([CH3:32])(=[O:31])=[O:30])=[CH:25][CH:26]=3)[N:21]([CH:33]([CH3:34])[CH3:35])[CH:20]=2)[CH:17]=[CH:18][C:13]=1[C:11]([NH2:12])=[S:41]
Reactant: CC(C)n1cc(-c2ccc(C#N)c(F)c2)c2ccc(NS(C)(=O)=O)cc21
Reactant: CCOP(=S)(S)OCC
Agent: COOOC
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)n1cc(-c2ccc(C(N)=S)c(F)c2)c2ccc(NS(C)(=O)=O)cc21
Yield: 90.4 %

Procedure:
Add a drop of di-isopropylethylamine and a drop of water to N-[3-(4-Cyano-3-fluoro-phenyl)-1-isopropyl-1H-indol-6-yl]-methanesulfonamide (100 mg, 0.27 mmol) in 10 mL of dimethoxy ether. Heat to reflux, followed by addition of dithiophosphoric acid O,O′-diethyl ester (151 mg, 0.81 mmol), and reflux in a sealed tube overnight. Evaporate the solvent. Purification of the residue using silica gel chromatography eluted with EtOAc and hexane gradient to give 99 mg (91%) of the desired product.
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[O:13]1[C:17]2[CH:18]=[CH:19][C:20]([O:22][C:23]3[C:28](=[O:29])[N:27]([CH2:30][C:31]4[CH:36]=[CH:35][C:34]([C:37]5[C:38]([C:43]#[N:44])=[CH:39][CH:40]=[CH:41][CH:42]=5)=[CH:33][CH:32]=4)[C:26]([CH2:45][CH2:46][CH3:47])=[N:25][C:24]=3[CH2:48][CH3:49])=[CH:21][C:16]=2[O:15][CH2:14]1>C(OCC)(=O)C>[O:13]1[C:17]2[CH:18]=[CH:19][C:20]([O:22][C:23]3[C:28](=[O:29])[N:27]([CH2:30][C:31]4[CH:36]=[CH:35][C:34]([C:37]5[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=5[C:43]5[NH:3][C:4](=[O:7])[O:5][N:44]=5)=[CH:33][CH:32]=4)[C:26]([CH2:45][CH2:46][CH3:47])=[N:25][C:24]=3[CH2:48][CH3:49])=[CH:21][C:16]=2[O:15][CH2:14]1
Reactant: O=C([O-])O
Reactant: [NH3+]O
Reactant: CCCc1nc(CC)c(Oc2ccc3c(c2)OCO3)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CCCc1nc(CC)c(Oc2ccc3c(c2)OCO3)c(=O)n1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 52.8 %

Procedure:
A mixture of hydroxylammonium chloride (0.52 g), sodium hydrogen carbonate (0.74 g) and dimethyl sulfoxide (8 mL) was stirred at 40° C. for 30 min, 4′-{[5-(1,3-benzodioxol-5-yloxy)-4-ethyl-6-oxo-2-propylpyrimidin-1(6H)-yl]methyl}biphenyl-2-carbonitrile (0.44 g) was added, and the mixture was stirred at 90° C. for 12 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was dissolved in tetrahydrofuran (10 mL). N,N′-carbonyldiimidazole (0.21 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.2 mL) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as a colorless amorphous solid (0.26 g, 53%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][O:23][CH3:24])=[C:17]([N:25]([CH3:27])[CH3:26])[CH:16]=2)[O:9][CH2:10][CH2:11][N:12]([CH3:14])[CH3:13])=[CH:4][CH:3]=1.O1CCCC1.C(=O)([O-])O.[Na+]>Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][O:23][CH3:24])=[C:17]([N:25]([CH3:26])[CH3:27])[CH:16]=2)[OH:9])=[CH:6][CH:7]=1.[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[C:17]([N:25]([CH3:27])[CH3:26])[CH:16]=2)[O:9][CH2:10][CH2:11][N:12]([CH3:14])[CH3:13])=[CH:4][CH:3]=1
Reactant: COCOc1ccc(C(OCCN(C)C)c2ccc(Cl)cc2)cc1N(C)C
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CN(C)CCOC(c1ccc(Cl)cc1)c1ccc(O)c(N(C)C)c1
Product: COCOc1ccc(C(O)c2ccc(Cl)cc2)cc1N(C)C

Procedure:
A solution of the compound (2) (0.43 g, 1.09 mmol) obtained above in 1N hydrochloric acid (3.28 ml) and tetrahydrofuran (2 ml) was heated under reflux for 3 hours. Thereto was added additional 1N hydrochloric acid (2.18 ml) and the mixture was further heated for 1.5 hours. The reaction mixture was poured into a saturated aqueous solution of sodium hydrogencarbonate, extracted with methylene chloride, dried over anhydrous magnesium sulfate and evaporated. The residue was purified by column chromatography on silica gel to give the title compound (Compound 1). Yield 0.15 g (39%).
Reaction SMILES: [CH2:1]([N:3]([CH2:15][CH3:16])[CH:4]([CH3:14])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][CH:8]=1)[CH3:2].[Cl:17][C:18]1[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:21]=[CH:20][C:19]=1[C:28]#[C:29][C:30](O)=[O:31]>ClCCl.CO>[CH2:15]([N:3]([CH2:1][CH3:2])[CH:4]([CH3:14])[CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]([NH:13][C:30](=[O:31])[C:29]#[C:28][C:19]2[CH:20]=[CH:21][C:22]([C:24]([F:26])([F:25])[F:27])=[CH:23][C:18]=2[Cl:17])=[CH:11][CH:12]=1)[CH3:16]
Reactant: CCN(CC)C(C)COc1ccc(N)cc1
Reactant: O=C(O)C#Cc1ccc(C(F)(F)F)cc1Cl
Solvent: ClCCl
Solvent: CO
Product: CCN(CC)C(C)COc1ccc(NC(=O)C#Cc2ccc(C(F)(F)F)cc2Cl)cc1

Procedure:
Prepared analogously to Example 2.3.f. from 67 mg (0.3 mmol) of 4-(2-diethylaminopropoxy)phenylamine and 75 mg (0.3 mmol) of (2-chloro-4-trifluoromethylphenyl)propynoic acid. Yield: 71 mg (52% of theory); melting point: 172° C.-176° C.; C23H24ClF3N2O2 (M=452.90); calc.: molecular ion peak (M+H)+: 453/455; found: molecular ion peak (M+H)+: 453/455; Rf value: 0.30 (silica gel, dichloromethane/methanol (9:1)).
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[CH:6][C:7]([C@H:11]3[C@@:13]4([C:21]5[C:16](=[CH:17][CH:18]=[C:19]([O:22][CH3:23])[CH:20]=5)[NH:15][C:14]4=[O:24])[CH2:12]3)=[CH:8][CH:9]=2)[NH:4][N:3]=1.[CH3:25][C:26]1(C)C(C)(C)OB(C=C)O1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.CCO>[CH3:23][O:22][C:19]1[CH:20]=[C:21]2[C:16](=[CH:17][CH:18]=1)[NH:15][C:14](=[O:24])[C@:13]12[CH2:12][C@H:11]1[C:7]1[CH:6]=[C:5]2[C:10]([C:2]([CH:25]=[CH2:26])=[N:3][NH:4]2)=[CH:9][CH:8]=1
Reactant: COc1ccc2c(c1)[C@]1(C[C@H]1c1ccc3c(I)n[nH]c3c1)C(=O)N2
Reactant: C=CB1OC(C)(C)C(C)(C)O1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: C=Cc1n[nH]c2cc([C@@H]3C[C@@]34C(=O)Nc3ccc(OC)cc34)ccc12
Temperature: 25 °C
Reaction time: 0.02 h

Procedure:
To a mixture of (1R*,2S*)-2-(3-iodo-1H-indazol-6-yl)-5′-methoxyspiro [cyclopropane-1,3′-indolin]-2′-one (1.00 g, 2.32 mmol) and 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (500 mg, 3.25 mmol) in a 20 mL microwave vial was added PhCH3/EtOH (7 mL/3.5 mL), followed by 1 M Na2CO3 (3 mL, 3 mmol). After stirring for 1 min at rt, Ph(PPh3)4 (50 mg, 0.043 mmol, 1.9 mol %) was added and the resulting mixture was purged with argon, and microwaved 3 h at 120° C. This reaction was repeated twice on the same scale and the resulting mixtures were combined. Aqueous workup gave the crude title compound as a dark orange solid/foam (3.10 g) which was used without further purification. A sample of pure compound can be obtained by flash chromatography (Hex/EtOAc 1:1). 1H NMR (400 MHz, CDCl3) δ 7.89 (d, J=8.4 Hz, 1H), 7.45 (s, 1H), 7.01 (dd, J=18.2 Hz, J=11.4 Hz, 1H overlapping with d, J=6.8 Hz, 1H; total 2H), 6.83 (d, J=8.4 Hz, 1H), 6.61 (dd, J=8.4 Hz, J=2.4 Hz, 1H), 6.09 (d, J=18.0 Hz, 1H), 5.56 (d, J=1.6 Hz, 1H), 5.52 (d, J=11.6 Hz, 1H), 3.56 (t, J=7.6 Hz, 1H, partially overlapping with MeOH residue), 3.26 (s, 3H), 2.24 (dd, J=7.8 Hz, J=5.0 Hz, 1H), 2.18 (dd, J=9.2 Hz, J=4.8 Hz, 1H); MS ESI 332.0 [M+H]+, calcd for [C20H17N3O2+H]+ 332.1.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[C:4]([F:10])[CH:3]=1.[C:11]([NH2:15])([CH3:14])([CH3:13])[CH3:12].[O-]S([O-])(=O)=O.[Mg+2]>C(Cl)Cl>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[N:15][C:11]([CH3:14])([CH3:13])[CH3:12])=[C:4]([F:10])[CH:3]=1
Reactant: O=Cc1ccc(Br)cc1F
Reactant: CC(C)(C)N
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: ClCCl
Product: CC(C)(C)N=Cc1ccc(Br)cc1F
Reaction time: 48 h
Yield: 97.6 %

Procedure:
To a CH2Cl2 (900 mL) solution of 4-bromo-2-fluoro-benzaldehyde (50.0 g, 246 mmol) was added tert-butylamine (42.3 mL, 29.3 g, 400 mmol) and MgSO4 (60.0 g, 499 mmol). After 48 h, the solution was filtered and concentrated to give 62.0 g (98%) of the title compound as a yellow liquid. 1H NMR (CDCl3): 8.48 (s, 1H), 7.89 (t, J=8.1 Hz, 1H), 7.32-7.25 (m, 2H), 1.29 (s, 9H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6](I)[N:5]=[C:4]([C:9]([O:11][CH3:12])=[O:10])[C:3]=1[Cl:13].[Br:14][C:15]1[CH:20]=[CH:19][C:18](B(O)O)=[C:17]([F:24])[C:16]=1[O:25][CH3:26].[F-].[Cs+].[CH2:29]([CH2:32]OC)[O:30]C>O>[C:29]([NH:1][C:2]1[CH:7]=[C:6]([C:18]2[CH:19]=[CH:20][C:15]([Br:14])=[C:16]([O:25][CH3:26])[C:17]=2[F:24])[N:5]=[C:4]([C:9]([O:11][CH3:12])=[O:10])[C:3]=1[Cl:13])(=[O:30])[CH3:32]
Reactant: COCCOC
Reactant: COc1c(Br)ccc(B(O)O)c1F
Reactant: COC(=O)c1nc(I)cc(N)c1Cl
Agent: [Cs+]
Agent: [F-]
Solvent: O
Product: COC(=O)c1nc(-c2ccc(Br)c(OC)c2F)cc(NC(C)=O)c1Cl
Temperature: 85 °C

Procedure:
A solution of 4-amino-3-chloro-6-iodopyridine-2-carboxylic acid, methyl ester (1.1 g, 3.0 mmol), 4-bromo-2-fluoro-3-methoxyphenyl boronic acid (1.3 g, 4.5 mmol) and cesium fluoride (0.60 g, 4.0 mmole) in dimethoxyethane (2 mL) and water (2 mL) was de-aerated with a stream of nitrogen for 15 minuets before adding dichlorobis(triphenylphosphine) palladium (0.25 g, 0.4 mmol) and then heated to 85° C. for 2 hours. The reaction mixture was diluted with water (15 mL) and extracted with ethyl acetate (2×15 mL). The combined extracts were washed with brine, dried (sodium sulfate) and concentrated. The residue was purified by chromatography (33% ethyl acetate in hexanes) to give 4-acetylamino-6-(4-bromo-2-fluoro-3-methoxyphenyl)-3-chloropyridine-2-carboxylic acid, methyl ester (1.2 g, 2.8 mmol): mp 164-165° C.