Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][C:7]([O:13][C:14]([CH3:19])([CH3:18])[C:15]([OH:17])=[O:16])=[C:8]([Cl:12])[C:9]=2[Cl:11])[CH2:4][CH:3]1[CH2:20][CH3:21].[Cl:22]Cl.O>C(O)(=O)C>[O:1]=[C:2]1[C:10]2[C:5](=[CH:6][C:7]([O:13][C:14]([CH3:18])([CH3:19])[C:15]([OH:17])=[O:16])=[C:8]([Cl:12])[C:9]=2[Cl:11])[CH2:4][C:3]1([CH2:20][CH3:21])[Cl:22]
Reactant: CCC1Cc2cc(OC(C)(C)C(=O)O)c(Cl)c(Cl)c2C1=O
Reactant: ClCl
Solvent: CC(=O)O
Solvent: O
Product: CCC1(Cl)Cc2cc(OC(C)(C)C(=O)O)c(Cl)c(Cl)c2C1=O
Reaction time: 1 h

Procedure:
2-(1-Oxo-2-ethyl-6,7-dichloro-5-indanyloxy)-2-methylpropionic acid (4.7 g., 0.0014 mole) is dissolved in warm acetic acid (170 ml.) and treated with a solution of chlorine (1.06 g., 0.015 mole) in acetic acid (20 ml.) at 20° C. with stirring. The reaction mixture is kept at 20° C. for one hour and then at 80°0 C. for one hour. The reaction mixture is cooled and added to water (1 1.) with stirring. The white powder that separates is recrystallized from acetic acid-water (4:3) to obtain 3.0 g. of 2-(1-oxo-2-ethyl-2,67-trichloro-5-indanyloxy)-2-methylpropionic acid, m.p. 164.5°-165° C.
Reaction SMILES: BrC1C=CC(S(O[CH:12]2[CH2:25][N:24]3[C:15](=[N:16][C:17]4[C:22]([C:23]3=[O:26])=[CH:21][CH:20]=[C:19]([Br:27])[CH:18]=4)[CH2:14][CH2:13]2)(=O)=O)=CC=1.C([O-])([O-])=O.[K+].[K+]>CO.O>[Br:27][C:19]1[CH:20]=[CH:21][C:22]2[C:23](=[O:26])[N:24]3[CH2:25][CH:12]4[CH2:13][CH:14]4[C:15]3=[N:16][C:17]=2[CH:18]=1
Reactant: O=c1c2ccc(Br)cc2nc2n1CC(OS(=O)(=O)c1ccc(Br)cc1)CC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: O=c1c2ccc(Br)cc2nc2n1CC1CC21
Temperature: 25 °C

Procedure:
A solution of 3-bromo-11-oxo-7,8,9,11-tetrahydro-6H-pyrido[2,1-b]quinazolin-8-yl 4-bromobenzenesulfonate (0.5 g, 0.98 mmol, 1.1 equiv) and K2CO3 in MeOH (100 mL) was stirred at reflux for two hours. After it was cooled to room temperature, the reaction mixture was diluted with water and extracted with ethyl acetate (3×100 mL). The combined organic layers were dried over Na2SO4. After filtration and concentration, the residue was purified by silica gel chromatography to give the desired product.
Reaction SMILES: [C:1]1([C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4])[OH:2].[Cl:9][CH2:10][C:11](=O)[CH3:12]>>[Cl:9][CH2:10][C:11]1([CH3:12])[O:4][C:3]2[CH:5]=[CH:6][CH:7]=[CH:8][C:1]=2[O:2]1
Reactant: CC(=O)CCl
Reactant: Oc1ccccc1O
Product: CC1(CCl)Oc2ccccc2O1
Temperature: 50 °C

Procedure:
110 g (1 mol) of pyrocatechol and 200 ml of chloroacetone were mixed and heated to 50° C. 284 g (2 mol) of phosphoruspentoxide were then added in batches upon strong stirring. The temperature inside the reaction must not exceed 70° C. The mass was then subjected to another hour of stirring whereupon it was decanted and the residue was washed twice with benzene whereupon the united phases were concentrated by evaporation in a rotary evaporator. The mass was then subjected to fractionation in a vacuum (12 torr). The fractions in the boiling range between 104° and 150° C. had a weight of 66 g.
Reaction SMILES: Cl.[OH:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]([O:11][CH3:12])=[O:10])=[N:7][CH:8]=1.C(=O)([O-])[O-].[K+].[K+].Cl[C:20]([F:30])([F:29])C(C1C=CC=CC=1)=O>O.C(#N)C>[F:29][CH:20]([F:30])[O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]([O:11][CH3:12])=[O:10])=[N:7][CH:8]=1
Reactant: COC(=O)c1ccc(O)cn1
Reactant: O=C(c1ccccc1)C(F)(F)Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: COC(=O)c1ccc(OC(F)F)cn1
Temperature: 75 °C
Reaction time: 5 h
Yield: 61 %

Procedure:
A mixture of methyl 5-hydroxypicolinate hydrochloride from step K1 (1.12 g, 5.91 mmol), potassium carbonate (8.16 g, 59.1 mmol) and α-chloro-α,α-difluoroacetophenone (3.92 mL, 26.6 mmol) in water (20 mL) and acetonitrile (20 mL) was stirred at 75° C. for 5 h. The solid was filtered out and washed with diethyl ether. The filtrate was washed with water and concentrated. The residue was purified using silica gel column chromatography (hexanes-50% EtOAc) to give methyl 5-(difluoromethoxy)picolinate (730 mg, 3.59 mmol, 61% yield). 1H NMR (500 HMz, chloroform-d) δ 8.60 (d, J=2.4 Hz, 1H), 8.20 (dd, J=8.6, 0.5 Hz, 1H), 7.62 (dd, J=8.7, 2.7 Hz, 1H), 6.81-6.49 (m, 1H), 4.03 (s, 3H).
Reaction SMILES: FC(F)(F)C([O:5][C:6](=[O:11])[C:7]([F:10])([F:9])[F:8])=O.[F:14][C:15]([F:20])([F:19])[C:16]([O-:18])=[O:17].[K+].FC(F)(F)C(OO)=O>FC(F)(F)C(O)=O>[F:14][C:15]([F:20])([F:19])[C:16]([O:18][O:5][C:6](=[O:11])[C:7]([F:8])([F:9])[F:10])=[O:17]
Reactant: O=C([O-])C(F)(F)F
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Agent: O=C(OO)C(F)(F)F
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Product: O=C(OOC(=O)C(F)(F)F)C(F)(F)F

Procedure:
A solution of bis(trifluoroacetyl) peroxide in trifluoroacetic acid was prepared by addition of freshly distilled bis(trifluoroacetic) anhydride (21 g, 100 mmol) dropwise into a well-stirred solution of potassium trifluoroacetate (6.8 mg, 0.045 mmol) in trifluoroperacetic acid (13 g, 100 mmol) and trifluoroacetic acid (15.9 g, 139.5 mmol) at 0° C. A 29.5% (mol) solution of bis(trifluoroacetyl) peroxide in the trifluoroacetic acid was obtained.
Reaction SMILES: FC1C=CC(S(CCC)(=O)=O)=CC=1C#C[Si](C)(C)C.[C:20]([O:24][C:25](=[O:37])[CH2:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:29]=1[C:35]#[CH:36])([CH3:23])([CH3:22])[CH3:21].Br[C:39]1[CH:44]=[CH:43][C:42]([C:45]2[CH:50]=[CH:49][CH:48]=[C:47]([Cl:51])[CH:46]=2)=[C:41]([S:52]([CH3:55])(=[O:54])=[O:53])[CH:40]=1>>[C:20]([O:24][C:25](=[O:37])[CH2:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:29]=1[C:35]#[C:36][C:39]1[CH:44]=[CH:43][C:42]([C:45]2[CH:50]=[CH:49][CH:48]=[C:47]([Cl:51])[CH:46]=2)=[C:41]([S:52]([CH3:55])(=[O:53])=[O:54])[CH:40]=1)([CH3:23])([CH3:22])[CH3:21]
Reactant: CS(=O)(=O)c1cc(Br)ccc1-c1cccc(Cl)c1
Reactant: C#Cc1cc(Cl)ccc1OCC(=O)OC(C)(C)C
Agent: CCCS(=O)(=O)c1ccc(F)c(C#C[Si](C)(C)C)c1
Product: CC(C)(C)OC(=O)COc1ccc(Cl)cc1C#Cc1ccc(-c2cccc(Cl)c2)c(S(C)(=O)=O)c1

Procedure:
Following the general method as outlined in Intermediate 107, starting from (4-chloro-2-ethynyl-phenoxy)-acetic acid tert-butyl ester (Intermediate 3) and 4-bromo-3′-chloro-2-(methylsulfonyl)biphenyl (Intermediate 213), the title compound was obtained as a brown sticky solid after purification by flash column chromatography (silica), eluting with cyclohexane containing increasing amounts of EtOAc.
Reaction SMILES: C[C@H]1[C@]2(C)C[C@H](C(C)=C)CCC2=CCC1.ON1C(=O)C2=CC=CC=C2C1=O.[CH3:28][C@H:29]1[C@:35]2([CH3:43])[CH2:36][C@H:37]([C:40]([CH3:42])=[CH2:41])[CH2:38][CH2:39][C:34]2=[CH:33][C:31](=[O:32])[CH2:30]1>O.O.O.O.C([O-])(=O)C.[Co+2].C([O-])(=O)C.CC(CC(C)=O)=O.CC(CC(C)=O)=O.CC(CC(C)=O)=O.[Co].O.O.O.O.O.O.[N+]([O-])([O-])=O.[Co+2].[N+]([O-])([O-])=O.C(#N)C>[CH3:28][C@H:29]1[C@:35]2([CH3:43])[CH2:36][C@H:37]([C:40]([CH3:42])=[CH2:41])[CH2:38][CH2:39][C:34]2=[CH:33][C@@H:31]([OH:32])[CH2:30]1
Reactant: C=C(C)[C@@H]1CCC2=CC(=O)C[C@@H](C)[C@]2(C)C1
Agent: [Co+2]
Agent: [Co]
Agent: C=C(C)[C@@H]1CCC2=CCC[C@@H](C)[C@]2(C)C1
Solvent: CC(=O)CC(C)=O
Solvent: CC#N
Solvent: O
Product: C=C(C)[C@@H]1CCC2=C[C@@H](O)C[C@@H](C)[C@]2(C)C1
Temperature: 40 °C
Reaction time: 3 h

Procedure:
In a flask 40.87 g (142 mmol) of valencene with a purity of 71% by weight, 4.89 g (30 mmol) of N-hydroxyphthalimide, 0.49 g (2 mmol) of cobalt(II) acetate tetrahydrate, 1.43 g (4 mmol) of tris(acetylacetonato)cobalt(III), 0.58 g (2 mmol) of cobalt nitrate hexahydrate [Co(NO3)2.6H2O], and 360 g of acetonitrile were placed and were stirred at 40° C. at a pressure of 13 kgf/cm2 (=1.3 MPa) for 3 hours under flow of air at a rate of 11.2 L (under standard conditions) per hour. The reaction mixture was analyzed by gas chromatography and was found that a target compound nootkatone and nootkatol were produced in yields of 67.9% and 5.6%, respectively, with a conversion from valencene of 99%. The reaction mixture was further analyzed by high-performance liquid chromatography and was found to contain 0.04 g of N-hydroxyphthalimide, 0.09 g of phthalimide, and 0.59 g of tris(acetylacetonato)cobalt(III).
Reaction SMILES: [OH:1][CH:2]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([OH:11])[CH:6]=1)[C:3]#[CH:4].C([Mg]Cl)#C.OC1C=C(C=CC=1)C=O.Br[C:26]1[CH:34]=[CH:33][CH:32]=[C:31]2[C:27]=1/[C:28](=[CH:36]/[C:37]1[NH:38][CH:39]=[CH:40][C:41]=1[O:42][CH3:43])/[C:29](=[O:35])[NH:30]2>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.CN(C=O)C.CCN(CC)CC>[OH:1][CH:2]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([OH:11])[CH:6]=1)[C:3]#[C:4][C:26]1[CH:34]=[CH:33][CH:32]=[C:31]2[C:27]=1/[C:28](=[CH:36]/[C:37]1[NH:38][CH:39]=[CH:40][C:41]=1[O:42][CH3:43])/[C:29](=[O:35])[NH:30]2
Reactant: COc1cc[nH]c1/C=C1\C(=O)Nc2cccc(Br)c21
Reactant: C#CC(O)c1cccc(O)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: C#C[Mg]Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1cc[nH]c1/C=C1\C(=O)Nc2cccc(C#CC(O)c3cccc(O)c3)c21

Procedure:
Using Method D above, 3-hydroxy-3-(3-hydroxyphenyl)-1-propyne (140 mg, 0.94 mmol) (prepared by the addition of ethynylmagnesium chloride (Aldrich) to 3-hydroxybenzaldehyde (Aldrich) through Method B above) was coupled to (Z)-4-bromo-1,3-dihydro-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one (Starting Material 1) (200 mg, 0.63 mmol) using (Ph3P)2PdCl2 (68 mg) (Aldrich) and CuI (32 mg) (Aldrich) as catalyst in DMF (4 mL) and Et3N (4 mL) as solvent at 80° C. for 15 h, yielding rac-(Z)-1,3-dihydro-4-[3-hydroxy-3-(3-hydroxyphenyl)-1-propynyl]-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one. (Yield 82 mg, 31%).
Reaction SMILES: C[O:2][CH:3](OC)[C:4]1[CH:9]=[C:8]([CH:10]([N:17]2[CH:21]=[CH:20][N:19]=[CH:18]2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:7]=[CH:6][C:5]=1[NH:22][C:23](=[O:25])[CH3:24].C(O)(=O)C>O>[CH:3]([C:4]1[CH:9]=[C:8]([CH:10]([N:17]2[CH:21]=[CH:20][N:19]=[CH:18]2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:7]=[CH:6][C:5]=1[NH:22][C:23](=[O:25])[CH3:24])=[O:2]
Reactant: COC(OC)c1cc(C(c2ccccc2)n2ccnc2)ccc1NC(C)=O
Solvent: CC(=O)O
Solvent: O
Product: CC(=O)Nc1ccc(C(c2ccccc2)n2ccnc2)cc1C=O
Yield: 100 %

Procedure:
A solution of 2.5 parts of intermediate 67, namely N-[2-(dimethoxymethyl)-4-[(1H-imidazol-1-yl)phenylmethyl]phenyl]acetamide, 52.5 parts of acetic acid and 10 parts of water was stirred for 1/2 hour at reflux temperature. The reaction mixture was evaporated and the residue was co-evaporated with methylbenzene, yielding 2.2 parts (100%) of N-[2-formyl-4-[(1H-imidazol-1-yl)phenylmethyl]phenyl]acetamide (interm. 68).
Reaction SMILES: [F:1][C:2]([F:38])([F:37])[C:3]1[C:8]2[C:9](=[O:36])[N:10]3[CH2:35][CH2:34][C@H:11]3[C:12]3[N:13]([CH:14]=[N:15][C:16]=3[C:17]3[O:21][N:20]=[C:19]([CH2:22][N:23]4C(=O)C5=CC=CC=C5C4=O)[N:18]=3)[C:7]=2[CH:6]=[CH:5][CH:4]=1.CN>C(O)C>[NH2:23][CH2:22][C:19]1[N:18]=[C:17]([C:16]2[N:15]=[CH:14][N:13]3[C:7]4[CH:6]=[CH:5][CH:4]=[C:3]([C:2]([F:38])([F:37])[F:1])[C:8]=4[C:9](=[O:36])[N:10]4[CH2:35][CH2:34][C@H:11]4[C:12]=23)[O:21][N:20]=1
Reactant: O=C1c2ccccc2C(=O)N1Cc1noc(-c2ncn3c2[C@@H]2CCN2C(=O)c2c-3cccc2C(F)(F)F)n1
Agent: CN
Solvent: CCO
Product: NCc1noc(-c2ncn3c2[C@@H]2CCN2C(=O)c2c-3cccc2C(F)(F)F)n1
Reaction time: 2 h
Yield: 100 %

Procedure:
5.3 g (10.2 mmol) of (S)-8-trifluoromethyl-12,12a-dihydro-1-(3-phthalimidomethyl-1,2,4-oxadiazol-5-yl)-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepin-9-one in 70 ml of ethanol were treated dropwise with 150 ml of methylamine (33% in ethanol) at 60° within 45 min. The solution was stirred at 70° for 2 hours and subsequently concentrated. The residue was taken up in methylene chloride and 30 ml of 4N hydrochloric acid and the solution was washed three times with methylene chloride. The aqueous phase was made alkaline with 30 ml of 4N sodium hydroxide solution and extracted five times with methylene chloride. After drying the combined organic solutions and evaporating the solvent there were obtained 3.98 g (100%) of (S)-1-(3-aminomethyl-1,2,4-oxadiazol-5-yl)-8-trifluoromethyl-12,12a-dihydro-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepin-9-one, which was used without further purification as the starting material for the Example described hereinafter.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[C:15]([CH:16]=O)=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][C:12]=2[Cl:18])[O:7]1)=[O:5])C.[CH3:19][O:20][C:21](=[O:28])[C@@H:22]([NH2:27])[CH2:23][CH:24]([CH3:26])[CH3:25].CCN(C(C)C)C(C)C.C([BH3-])#N.[Na+].C(O)(=O)C>CO>[CH3:1][O:3][C:4]([C:6]1[O:7][C:8]2[C:13]([CH2:14][C:15]=1[CH2:16][NH:27][C@H:22]([C:21]([O:20][CH3:19])=[O:28])[CH2:23][CH:24]([CH3:26])[CH3:25])=[C:12]([Cl:18])[CH:11]=[CH:10][CH:9]=2)=[O:5]
Reactant: COC(=O)[C@@H](N)CC(C)C
Reactant: CCOC(=O)C1Oc2cccc(Cl)c2C=C1C=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)O
Product: COC(=O)C1=C(CN[C@@H](CC(C)C)C(=O)OC)Cc2c(Cl)cccc2O1
Temperature: 25 °C
Reaction time: 10 h
Yield: 32.2 %

Procedure:
To a solution of 5-chloro-3-formyl-2H-chromene-2-carboxylic acid ethyl ester (1.0 g, 3.74 mmol) (Example 20, Step 1) in methanol (20 mL) containing molecular sieves (0.7 g) was added commercially available (S)-2-amino-4-methyl-pentanoic acid methyl ester (0.68 g, 3.74 mmol) and N,N′-diisopropylethylamine (1.30 mL, 7.49 mmol). The mixture was stirred at 25° C. for 10 hours. At this time, sodium cyanoborohydride (0.47 g, 7.49 mmol) and acetic acid (0.43 mL, 7.20 mmol) were added simultaneously to the reaction mixture, and the reaction mixture was stirred for additional 16 hours at 25° C. The reaction mixture was then filtered through celite and washed with methanol. The filtrate was concentrated in vacuo. Flash column chromatography (eluant-ethyl acetate:petroleum ether 1:9, Rf=0.6) over neutral alumina afforded 5-chloro-3-[((S)-1-methoxycarbonyl-3-methyl-butylamino)-methyl]-4H-chromene-2 carboxylic acid methyl ester (0.46 g, 31%) as an oil.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].COC(=O)CC1CC2C(=CC(OCCCCNC(N)=N)=CC=2)NC1=O.C[O:34][C:35](=[O:58])[CH2:36][C:37]1[C:38](=[O:57])[N:39]([CH2:55][CH3:56])[C:40]2[C:45]([CH:46]=1)=[CH:44][CH:43]=[C:42]([O:47][CH2:48][CH2:49][CH2:50][NH:51][C:52]([NH2:54])=[NH:53])[CH:41]=2>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH2:55]([N:39]1[C:40]2[C:45](=[CH:44][CH:43]=[C:42]([O:47][CH2:48][CH2:49][CH2:50][NH:51][C:52]([NH2:54])=[NH:53])[CH:41]=2)[CH:46]=[C:37]([CH2:36][C:35]([OH:58])=[O:34])[C:38]1=[O:57])[CH3:56]
Reactant: CCn1c(=O)c(CC(=O)OC)cc2ccc(OCCCNC(=N)N)cc21
Agent: COC(=O)CC1Cc2ccc(OCCCCNC(=N)N)cc2NC1=O
Solvent: O=C(O)C(F)(F)F
Product: CCn1c(=O)c(CC(=O)O)cc2ccc(OCCCNC(=N)N)cc21

Procedure:
The title compound was prepared using the procedure of Example 84 except that [7-(4-guanidino-butoxy)-2-oxo-1,2,3,4-tetrahydro-quinolin-3-yl]acetic acid methyl ester trifluoroacetate was replaced with [1-ethyl-7-(3-guanidino-propoxy)-2-oxo-1,2-dihydro-quinolin-3-yl]-acetic acid methyl ester.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11]([CH3:13])([CH3:12])[CH2:10][CH2:9][C:8](=[O:14])[NH:7][C:6]=2[CH:15]=1.Cl[C:17]1[N:22]=[C:21]([NH:23][C:24]2[C:29]([S:30]([CH:33]([CH3:35])[CH3:34])(=[O:32])=[O:31])=[CH:28][CH:27]=[CH:26][C:25]=2[F:36])[C:20]([Cl:37])=[CH:19][N:18]=1>>[Cl:37][C:20]1[C:21]([NH:23][C:24]2[C:29]([S:30]([CH:33]([CH3:34])[CH3:35])(=[O:32])=[O:31])=[CH:28][CH:27]=[CH:26][C:25]=2[F:36])=[N:22][C:17]([NH:1][C:2]2[CH:3]=[CH:4][C:5]3[C:11]([CH3:12])([CH3:13])[CH2:10][CH2:9][C:8](=[O:14])[NH:7][C:6]=3[CH:15]=2)=[N:18][CH:19]=1
Reactant: CC1(C)CCC(=O)Nc2cc(N)ccc21
Reactant: CC(C)S(=O)(=O)c1cccc(F)c1Nc1nc(Cl)ncc1Cl
Product: CC(C)S(=O)(=O)c1cccc(F)c1Nc1nc(Nc2ccc3c(c2)NC(=O)CCC3(C)C)ncc1Cl

Procedure:
8-{5-Chloro-4-[2-fluoro-6-(propane-2-sulfonyl)-phenylamino]-pyrimidin-2-ylamino}-5,5-dimethyl-1,3,4,5-tetrahydro-1-benzazepin-2-one was prepared from 8-Amino-5,5-dimethyl-1,3,4,5-tetrahydro-benzo[b]azepin-2-one and (2,5-Dichloro-pyrimidin-4-yl)-[2-fluoro-6-(propane-2-sulfonyl)-phenyl]-amine in an analogous manner to Example 1251d. (120° C., 60 minutes). Title compound isolated as an off-white solid (68 mg, 48%). LCMS 534.13 (M+H), HPLC purity 98%, 1H-NMR (CDCl3, 400 MHz) δ: 8.17 (d, J=8.6 Hz, 1H), 8.17 (s, 1H), 7.86 (d, J=7.6 Hz, 1H), 7.58-7.54 (m, 2H), 7.24 (d, J=8.7 Hz, 1H), 6.96 (s, 1H), 6.89 (d, J=7.4 Hz, 1H), 6.76 (s, 1H), 3.10-3.02 (m, 1H), 2.38 (dd, J=6.7 Hz, 2H), 2.08 (dd, J=7.0 Hz, 2H), 1.38 (s, 6H), 1.23 (d, J=6.8 Hz, 6H).
Reaction SMILES: C(OC([NH:6][C:7]1[CH:26]=[CH:25][C:10]2[CH:11]=[CH:12][N:13]3[CH:24]=[CH:23][CH:22]=[C:14]3[C:15](=[CH:16][CH2:17][CH2:18][N:19]([CH3:21])[CH3:20])[C:9]=2[CH:8]=1)=O)C.[OH-].[K+]>CCO>[NH2:6][C:7]1[CH:26]=[CH:25][C:10]2[CH:11]=[CH:12][N:13]3[CH:24]=[CH:23][CH:22]=[C:14]3[C:15](=[CH:16][CH2:17][CH2:18][N:19]([CH3:21])[CH3:20])[C:9]=2[CH:8]=1
Reactant: CCOC(=O)Nc1ccc2c(c1)C(=CCCN(C)C)c1cccn1C=C2
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CN(C)CCC=C1c2cc(N)ccc2C=Cn2cccc21

Procedure:
To 9-ethoxycarbonylamino-11-(3-dimethylaminopropylidene)-11H-pyrrolo[2,1-b][3]benzazepine (2.80 g.) in 100 ml. EtOH is added 10 ml. 2 N potassium hydroxide. Reflux is maintained for 42 hours. The volatiles are removed under vacuum and the residue is extracted with chloroform, washed with water, and dried over magnesium sulfate. Evaporation leaves a dark residue that is purified by chromatography on silica gel. Elution with 10% methanol in chloroform yields 9-amino-11-(3-dimethylaminopropylidene)-11H-pyrrolo[2,1-b][3]benzazepine.
Reaction SMILES: [NH2:1][C:2]1[N:3]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([F:16])=[C:12]([F:17])[CH:11]=2)[CH:4]=[CH:5][C:6]=1[C:7]#[N:8].C(O/[C:21](/[CH3:28])=[CH:22]/[C:23]([O:25][CH2:26][CH3:27])=[O:24])C.O.CC1C=CC(S(O)(=O)=O)=CC=1.[O-]CC.[Na+].Cl.O>O.C1(C)C=CC=CC=1>[NH2:8][C:7]1[C:22]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[C:21]([CH3:28])[N:1]=[C:2]2[N:3]([CH2:9][C:10]3[CH:15]=[CH:14][C:13]([F:16])=[C:12]([F:17])[CH:11]=3)[CH:4]=[CH:5][C:6]=12
Reactant: N#Cc1ccn(Cc2ccc(F)c(F)c2)c1N
Reactant: CCOC(=O)/C=C(\C)OCC
Agent: CC[O-]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: O
Solvent: Cc1ccccc1
Product: CCOC(=O)c1c(C)nc2c(ccn2Cc2ccc(F)c(F)c2)c1N
Temperature: 155 °C
Yield: 77.7 %

Procedure:
A mixture of 2-amino-1-(3,4-difluorobenzyl)-1H-pyrrole-3-carbonitrile (20 g, 86 mmol) and toluene (700 mL) was heated to reflux eliminating 30 mL of toluene using a Dean-Stark trap then (E)-ethyl 3-ethoxybut-2-enoate (14.9 g, 94 mmol) and 4-methylbenzenesulfonic acid hydrate (1.6 g, 8.56 mmol) and were added. The mixture was heated to 155° C. for 1 h using a Dean-Stark trap to eliminate 350 mL of solvent. The mixture was cooled to 0° C. and sodium ethoxide (41.6 mL, 111 mmol, 21% wt/EtOH) was added dropwise and the mixture was heated to reflux (145° C.) for 1 h using a Dean-Stark trap to eliminate 100 mL of solvent. Water was added followed by 1M HCl/water adjusting the pH-9. The mixture was extracted with EtOAc. The organic phase was dried (Na2SO4), concentrated, and purified by column chromatography provide ethyl 4-amino-1-(3,4-difluorobenzyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine-5-carboxylate (23.1 g, 66.8 mmol, 78% yield). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.43 (t, J=7 Hz, 3 H), 2.78 (s, 3 H), 4.40 (q, J=7 Hz, 2 H), 5.36 (s, 2 H), 6.3 (br s, 2 H), 6.5 (m, 2 H), 6.6-7.2 (m, 4 H); LCMS (m/z) ES+=346 (M+1).
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)[C:5]([NH2:8])=[N:6][CH:7]=1.[H-].[Na+].Br[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]Cl>CN(C)C=O>[Br:1][C:2]1[N:3]=[C:4]([C:9]2[CH:10]=[CH:11][C:12]([Cl:15])=[CH:13][CH:14]=2)[C:5]([N:8]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)=[N:6][CH:7]=1
Reactant: ClCCCCCBr
Reactant: Nc1ncc(Br)nc1-c1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Clc1ccc(-c2nc(Br)cnc2N2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 6.8 %

Procedure:
To a solution of 0.5 g (0.0018 mol) 5-bromo-3-(4-chloro-phenyl)-pyrazin-2-ylamine in 10 ml dimethylformamide was added at room temperature 0.240 g sodium hydride 55% in oil (0.006 mol) and 0.49 g 1-bromo-5-chloro-pentane (0.0025 mol) and the mixture was stirred at room temperature for 0.5 hours. Another 0.130 g sodium hydride 55% in oil was added and the mixture was stirred at room temperature for 2.5 h. The resulting mixture was partitioned between 10% aqueous citric acid and ethyl acetate. The phases were separated, the organic phase was dried over magnesium sulfate and evaporated. The residue was purified by chromatography on silica gel using a gradient of 30% ethyl acetate in heptane to ethyl acetate to yield 0.043 g (83% yield) of the title compound as slightly brownish oil. MS (ISP) (M+H+)=354.1 and 356.0.
Reaction SMILES: [CH2:1]([N:3]([CH2:25][CH3:26])[C:4]1[CH:24]=[CH:23][C:7]([C:8]([C:10]2[C:18]([Cl:19])=[C:17]([Cl:20])[C:16]([Cl:21])=[C:15]([Cl:22])[C:11]=2[C:12]([OH:14])=[O:13])=O)=[CH:6][CH:5]=1)[CH3:2].[CH3:27][N:28]([CH3:38])[C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([N:35]([CH3:37])[CH3:36])[CH:30]=1.C(OC(=O)C)(=O)C>CO>[CH3:36][N:35]([CH3:37])[C:31]1[CH:30]=[C:29]([N:28]([CH3:38])[CH3:27])[CH:34]=[CH:33][C:32]=1[C:8]1([C:7]2[CH:6]=[CH:5][C:4]([N:3]([CH2:25][CH3:26])[CH2:1][CH3:2])=[CH:24][CH:23]=2)[C:10]2[C:11](=[C:15]([Cl:22])[C:16]([Cl:21])=[C:17]([Cl:20])[C:18]=2[Cl:19])[C:12](=[O:14])[O:13]1
Reactant: CN(C)c1cccc(N(C)C)c1
Reactant: CCN(CC)c1ccc(C(=O)c2c(Cl)c(Cl)c(Cl)c(Cl)c2C(=O)O)cc1
Solvent: CC(=O)OC(C)=O
Solvent: CO
Product: CCN(CC)c1ccc(C2(c3ccc(N(C)C)cc3N(C)C)OC(=O)c3c(Cl)c(Cl)c(Cl)c(Cl)c32)cc1
Temperature: 90 °C
Yield: 48.2 %

Procedure:
A mixture of 2-(4-(diethylamino)benzoyl)-3,4,5,6-tetrachlorobenzoic acid (8.70 g.), N,N,N',N'-tetramethyl-m-phenylenediamine (3.61 g.) and acetic anhydride (5 ml.) was heated (to 90° C.). Addition of methanol (10 ml.) and slurrying the resulting product with methanol afforded 3-(2,4-bis(dimethylamino)phenyl)-3-(4-(diethylamino)phenyl)-4,5,6,7-tetrachlorophthalide (I: X= (CH3)2N, Y2 = H, Y4 = (CH3CH2)2N, Z4 = Z5 = Z6 = Z7 = Cl) (5.60 g., m.p. 206°-207.5° C.).
Reaction SMILES: Br[C:2]1[C:3]([CH3:13])=[CH:4][C:5]2[N:6]([C:8]([CH:11]=[O:12])=[CH:9][N:10]=2)[CH:7]=1.[N:14]1[CH:19]=[CH:18][CH:17]=[C:16](B(O)O)[CH:15]=1.C([O-])([O-])=O.[Na+].[Na+].CN(C=O)C>C(OCC)(=O)C>[CH3:13][C:3]1[C:2]([C:16]2[CH:15]=[N:14][CH:19]=[CH:18][CH:17]=2)=[CH:7][N:6]2[C:8]([CH:11]=[O:12])=[CH:9][N:10]=[C:5]2[CH:4]=1
Reactant: Cc1cc2ncc(C=O)n2cc1Br
Reactant: OB(O)c1cccnc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1cc2ncc(C=O)n2cc1-c1cccnc1
Yield: 62 %

Procedure:
6-bromo-7-methylimidazo[1,2-a]pyridine-3-carbaldehyde (Compound of step 1, 2000 mg, 7.90 mmol), Pyridine-3-boronic acid (1170 mg, 9.49 mmol), dichlorobis (triphenylphosphine) palladium (II) (200 mg, 10% mmol) and 2M aqueous Na2CO3 (7 mL) were added to DMF (25 mL) and refluxed for 2 hours. The reaction mixture was diluted with ethyl acetate and washed with H2O and brine. The solvent was evaporated to obtain crude product, which was purified by column chromatography (silica gel, 1% methanol in chloroform) to obtain the title compound. Yield: 62%; 1H NMR (DMSO-d6; 300 MHz): δ 9.92 (s, 1H), 9.20 (s, 1H), 8.69-8.70 (m, 2H), 8.54 (s, 1H), 7.95-7.99 (m, 1H), 7.90 (s, 1H), 7.53-7.58 (m, 1H), 2.34 (s, 3H); MS: m/z 238 (M+1)+
Reaction SMILES: [CH:1]([CH:3]1[CH2:8][CH2:7][O:6][C:5](=[O:9])[CH2:4]1)=[CH2:2].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.Br[C:33]1[CH:34]=[N:35][CH:36]=[CH:37][CH:38]=1>C(N(CC)CC)C.C(#N)C.C(Cl)Cl.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[N:35]1[CH:36]=[CH:37][CH:38]=[C:33]([CH:2]=[CH:1][CH:3]2[CH2:8][CH2:7][O:6][C:5](=[O:9])[CH2:4]2)[CH:34]=1
Reactant: C=CC1CCOC(=O)C1
Reactant: Brc1cccnc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CC#N
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C1CC(C=Cc2cccnc2)CCO1
Temperature: 125 °C

Procedure:
To a solution of 0.879 g (7 mmol) of 4-ethenyltetrahydro-2H-pyran-2-one in 5 mL triethylamine and 5 mL acetonitrile is added 0.081 g (0.36 mmol) Palladium-(II)-acetate followed by 0.659 g (2.5 mmol) tri-o-tolylphosphine and 0.76 mL (7.9 mmol) 3-bromopyridine and the mixture is heated at 125° C. for 20 hours in a sealed tube. It is then cooled, diluted with methylene chloride and washed with water. The organic phase is dried (MgSO4), filtered and evaporated to give a reddish oil which is flash chromatographed using ethyl acetate as eluent to obtain 4-[2-(3-pyridyl)ethenyl]tetrahydro-2H-pyran-2-one as an oil.