Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O-:1][C:2]#[N:3].[Na+].[NH2:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][CH:10]=[C:9]2[CH2:15][C:16]#[N:17]>O.C(O)(=O)C>[C:16]([CH2:15][C:9]1[C:8]2[C:12](=[CH:13][CH:14]=[C:6]([NH:5][C:2]([NH2:3])=[O:1])[CH:7]=2)[NH:11][CH:10]=1)#[N:17]
Reactant: N#C[O-]
Reactant: N#CCc1c[nH]c2ccc(N)cc12
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: N#CCc1c[nH]c2ccc(NC(N)=O)cc12
Yield: 16 %

Procedure:
A solution of sodium cyanate (1.2 g) in water (10 ml) was added to a stirred solution of 5-amino-1H-indole-3-aceto-nitrile (1.5 g) in glacial acetic acid (5 ml) and water (10 ml). Stirring was continued until a brown gum precipitated (10 min). The aqueous layer was then decanted off, and extracted with ethyl acetate (2×100 ml). The combined extracts were washed with sodium carbonate soln. (2N, 2×100 ml), dried (Na2SO4) and evaporated in vacuo to yield the crude urea as an off-white solid (0,3 g). The brown gum was purified by column chromatography (Kieselgel 60, 25 g) using ethyl acetate as eluant to yield more of the crude urea (0.1 g). The crude urea was then crystallised from isopropanol to yield the title compound as a fawn solid (0.3 g) m.p. 200°-204°.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([Br:8])[CH:5]=[CH:4][C:3]=1[CH2:9][C:10]#[N:11].CN(C)C=O.[H-].[Na+].Br[CH2:20][CH2:21][CH2:22][CH3:23]>C1C=CC=CC=1>[Br:1][C:2]1[CH:7]=[C:6]([Br:8])[CH:5]=[CH:4][C:3]=1[CH:9]([CH2:20][CH2:21][CH2:22][CH3:23])[C:10]#[N:11]
Reactant: CCCCBr
Reactant: N#CCc1ccc(Br)cc1Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: c1ccccc1
Product: CCCCC(C#N)c1ccc(Br)cc1Br
Reaction time: 2 h

Procedure:
To a stirred and cooled (ice-bath) mixture of 27.5 parts of 2,4-dibromobenzeneacetonitrile, 135 parts of N,N-dimethylformamide and 67.5 parts of benzene are added portionwise 3.2 parts of sodium hydride dispersion 78% while nitrogen gas is introduced. After stirring for one hour, 14 parts of 1-bromobutane are added dropwise. Upon completion, stirring is continued for 2 hours at room temperature. The reaction mixture is poured onto water and the product is extracted twice with 2,2'-oxybispropane. The combined extracts are washed twice with water, dried, filtered and evaporated. The residue is distilled, yielding 22 parts of 2,4-dibromo-α-butylbenzeneacetonitrile; bp. 124° C. at 0.05 mm. pressure.
Reaction SMILES: B.[O:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[O:8][C@H:9]1[CH2:14][CH2:13][C@H:12]2[C@H:15]3[C@H:25]([CH2:26][CH2:27][C@:10]12[CH3:11])[C@:23]1([CH3:24])[C:18](=[CH:19][CH2:20][CH2:21][CH2:22]1)[CH2:17][CH2:16]3.[OH-:28].[Na+].OO>O1CCCC1.O>[O:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[O:8][C@H:9]1[CH2:14][CH2:13][C@H:12]2[C@H:15]3[C@H:25]([CH2:26][CH2:27][C@:10]12[CH3:11])[C@:23]1([CH3:24])[C@H:18]([C@@H:19]([OH:28])[CH2:20][CH2:21][CH2:22]1)[CH2:17][CH2:16]3
Reactant: [OH-]
Reactant: C[C@]12CC[C@H]3[C@@H](CCC4=CCCC[C@@]43C)[C@@H]1CC[C@@H]2OC1CCCCO1
Agent: B
Agent: OO
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: C[C@]12CCC[C@H](O)[C@@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](OC3CCCCO3)CC[C@@H]12
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a cooled solution (0° C.) of 5 ml. of 1 M borane in tetrahydrofuran in 2.7 ml. of dry tetrahydrofuran was added 500 mg. (1.4 millimole) of the product of Step C. in 2.0 ml. of dry tetrahydrofuran. The clear solution was stirred for 1 hr. at room temperature and then cooled to 0° C. and treated with 5 ml. of 2.5 N sodium hydroxide followed by 4 ml. of 30% hydrogen peroxide. The solution was stirred for 1 hr. at room temperature, diluted with water and extracted with ethyl ether, washed with water, brine, dried and evaporated to an oily crystalline material. The product was washed with cold methanol and pumped dry to give 175 mg. of final product having a m.p. of 167°-170° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:10]([F:11])=[C:9]([F:12])[C:6]([CH2:7][OH:8])=[C:5]([F:13])[C:4]=1[F:14].[C:15]([C:17]([CH3:27])=[CH:18][C@@H:19]1[C@@H:21]([C:22](O)=[O:23])[C:20]1([CH3:26])[CH3:25])#[N:16]>CN(C)C1C=CN=CC=1.ClCCl>[C:15]([C:17]([CH3:27])=[CH:18][C@@H:19]1[C@@H:21]([C:22]([O:8][CH2:7][C:6]2[C:5]([F:13])=[C:4]([F:14])[C:3]([O:2][CH3:1])=[C:10]([F:11])[C:9]=2[F:12])=[O:23])[C:20]1([CH3:26])[CH3:25])#[N:16]
Reactant: COc1c(F)c(F)c(CO)c(F)c1F
Reactant: CC(C#N)=C[C@@H]1[C@@H](C(=O)O)C1(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: COc1c(F)c(F)c(COC(=O)[C@@H]2[C@@H](C=C(C)C#N)C2(C)C)c(F)c1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 70.2 %

Procedure:
Under a nitrogen atmosphere, 0.49 g of N,N-dicyclohexylcarbodiimide was added to a mixture of 0.50 g of 4-methoxy-2,3,5,6-tetrafluorobenzyl alcohol, 0.43 g of (1R)-trans-3-(2-cyano-1-propenyl)-2,2-dimethylcyclopropanecarboxylic acid, 0.087 g of 4-dimethylaminopyridine and 7 ml of anhydrous dichloromethane, and the mixture was stirred at room temperature for 3 hours. Thereafter, the reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography to obtain 0.62 g of 4-methoxy-2,3,5,6-tetrafluorobenzyl (1R) trans-3-(2-cyano-1-propenyl)-2,2-dimethylcyclopropanecarboxylate represented by the following formula:
Reaction SMILES: Br[C:2]1[CH:15]=[CH:14][C:13]2[C:4](=[C:5]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:6]3[C:11]([C:12]=2[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:10][CH:9]=[CH:8][CH:7]=3)[CH:3]=1.[C:28]1([NH:38][C:39]2[CH:40]=[CH:41][C:42]3[N:43]([C:52]4[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=4)[C:44]4[C:49]([C:50]=3[CH:51]=2)=[CH:48][CH:47]=[CH:46][CH:45]=4)[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:31]=[CH:30][CH:29]=1.CC(C)([O-])C.[Na+].C(P(C(C)(C)C)C(C)(C)C)(C)(C)C>C1(C)C=CC=CC=1>[C:28]1([N:38]([C:2]2[CH:15]=[CH:14][C:13]3[C:4](=[C:5]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:6]4[C:11]([C:12]=3[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:10][CH:9]=[CH:8][CH:7]=4)[CH:3]=2)[C:39]2[CH:40]=[CH:41][C:42]3[N:43]([C:52]4[CH:53]=[CH:54][CH:55]=[CH:56][CH:57]=4)[C:44]4[C:49]([C:50]=3[CH:51]=2)=[CH:48][CH:47]=[CH:46][CH:45]=4)[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:31]=[CH:30][CH:29]=1
Reactant: c1ccc(-n2c3ccccc3c3cc(Nc4cccc5ccccc45)ccc32)cc1
Reactant: Brc1ccc2c(-c3ccccc3)c3ccccc3c(-c3ccccc3)c2c1
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: c1ccc(-c2c3ccccc3c(-c3ccccc3)c3cc(N(c4ccc5c(c4)c4ccccc4n5-c4ccccc4)c4cccc5ccccc45)ccc23)cc1
Temperature: 80 °C
Reaction time: 5 h
Yield: 42.4 %

Procedure:
3.5 g (8.6 mmol) of 2-bromo-9,10-diphenylanthracene synthesized in Step 1 of Embodiment 1, 3.2 g (9.4 mmol) of N-(1-naphthyl)-N-(9-phenylcarbazol-3-yl)amine (abbreviation: PCN), 0.25 g (0.43 mmol) of bis(benzylideneacetone)palladium (0), and 2.1 g (21 mmol) of sodium tert-butoxide were put in a 200 mL three-neck flask, and the atmosphere of the flask was substituted with nitrogen. Thereafter, 50 mL of toluene and 0.86 g (0.43 mmol) of tri(tert-butyl)phosphine (10% hexane solution) were added to the mixture, and this reaction mixture was stirred for 5 hours at 80° C. After the reaction was completed, the reaction solution was washed with water, and the aqueous layer was extracted with ethyl acetate. The extracted solution was combined with the organic layer, and then dried with magnesium sulfate. After drying, this mixture was subjected to suction filtration, and the filtrate was concentrated. The obtained residue was purified by silica gel column chromatography (eluent:toluene). The obtained solid was recrystallized with a mixed solvent of chloroform and hexane, giving 2.6 g of 2-[N-(1-naphthyl)-N-(9-phenylcarbazol-3-yl)-amino]-9,10-diphenylanthracene (abbreviation: 2PCNPA) as yellow powder in 42% yield. It was confirmed by a nuclear magnetic resonance measurement (NMR) that this compound was 2-[N-(1-naphthyl)-N-(9-phenylcarbazol-3-yl)-amino]-9,10-diphenylanthracene (abbreviation: 2PCNPA).
Reaction SMILES: [NH:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[C:4](=[O:11])OC1=O.[CH3:13][N:14]1[C:18]([CH2:19][Li])=[N:17][N:16]=[N:15]1>C(OCC)(=O)C>[NH2:1][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=1[C:4](=[O:11])[CH2:19][C:18]1[N:14]([CH3:13])[N:15]=[N:16][N:17]=1
Reactant: [Li]Cc1nnnn1C
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Solvent: CCOC(C)=O
Product: Cn1nnnc1CC(=O)c1ccccc1N

Procedure:
In a similar way to that described in Example 8a, 1H-3,1-benzoxazine-2,4-dione was reacted with (1-methyl-1H-tetrazol-5-yl)methyl lithium to give the novel compound 1-(2-aminophenyl)-2-(1-methyl-1H-tetrazol-5-yl)ethanone, m.p. 128°-132° (from ethyl acetate).
Reaction SMILES: Cl.[NH:2]1[CH2:5][CH:4]([C:6]2[C:11]([Br:12])=[CH:10][CH:9]=[CH:8][N:7]=2)[CH2:3]1.Cl[C:14]1[CH:23]=[CH:22][C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:15]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.O>[Br:12][C:11]1[C:6]([CH:4]2[CH2:3][N:2]([C:14]3[CH:23]=[CH:22][C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[N:15]=3)[CH2:5]2)=[N:7][CH:8]=[CH:9][CH:10]=1
Reactant: Clc1ccc2ccccc2n1
Reactant: Brc1cccnc1C1CNC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: Brc1cccnc1C1CN(c2ccc3ccccc3n2)C1
Temperature: 110 °C
Reaction time: 16 h
Yield: 80 %

Procedure:
A mixture of 2-(azetidin-3-yl)-3-bromopyridine hydrochloride (4) (221 g, 0.886 mol), 2-chloroquinoline (133.5 g, 0.816 mol, 0.92 eq., Combi-Blocks) and cesium carbonate (866 g, 2.658 mol, 3 eq.) in anhydrous DMF (7 L) was heated to 110° C. and stirred for 16 hrs. After cooling to RT, the mixture was transferred to 50 L separatory funnel and diluted with water (14 L). The precipitated solid was filtered, stirred in water (4 L), filtered and dried to obtain 222 g of 2-(3-(3-bromopyridin-2-yl)azetidin-1-yl)quinoline. Yield: 80% over two steps.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([C:9]2[CH:10]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:12]=[CH:13][CH:14]=2)=[C:6]([CH3:8])[CH:7]=1.[C:19]([NH:22][NH2:23])(=O)[CH3:20]>C(O)CCC>[CH3:20][C:19]1[N:3]2[N:4]=[C:5]([C:9]3[CH:10]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:12]=[CH:13][CH:14]=3)[C:6]([CH3:8])=[CH:7][C:2]2=[N:23][N:22]=1
Reactant: CC(=O)NN
Reactant: Cc1cc(Cl)nnc1-c1cccc(C(F)(F)F)c1
Solvent: CCCCO
Product: Cc1cc2nnc(C)n2nc1-c1cccc(C(F)(F)F)c1

Procedure:
As in Example 36, a mixture of 8.0 g of 3-chloro-5-methyl-6-(α,α,αtrifluoro-m-tolyl)pyridazine and 4.34 g. of acetylhydrazine in 125 ml. of n-butanol is refluxed for 48 hr. to give 6.2 g. of cream colored crystals, m.p. 185°-187° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:9]#[CH:10])[CH:5]=[CH:6][C:7]=1[OH:8].[Cl:11][C:12]1[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][C:13]=1[CH2:14][SH:15].[Na]>>[OH:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[OH:8])/[CH:9]=[CH:10]\[CH:14]([S:15][CH:14](/[CH:10]=[CH:9]\[C:4]1[CH:5]=[CH:6][C:7]([OH:8])=[C:2]([OH:1])[CH:3]=1)[C:13]1[CH:16]=[CH:17][C:18]([O:20][CH3:21])=[CH:19][C:12]=1[Cl:11])[C:13]1[CH:16]=[CH:17][C:18]([O:20][CH3:21])=[CH:19][C:12]=1[Cl:11]
Reactant: C#Cc1ccc(O)c(O)c1
Reactant: COc1ccc(CS)c(Cl)c1
Agent: [Na]
Product: COc1ccc(C(/C=C\c2ccc(O)c(O)c2)SC(/C=C\c2ccc(O)c(O)c2)c2ccc(OC)cc2Cl)c(Cl)c1

Procedure:
A solution of 3,4-dihydroxyphenylacetylene (0.02 mol), 2-chloro-4-methoxybenzyl mercaptan (0.02 mol) and metallic sodium (0.02 g atom) is subjected to the General Procedure to form (Z)-3,4-dihydroxystyryl-2-chloro-4-methoxybenzylsulfide. The title compound is obtained following oxidation of the sulfide, according to the General Procedure.
Reaction SMILES: Cl[C:2]1[N:3]([CH2:25][CH:26]2[CH2:28][CH2:27]2)[C:4]2[C:9]([N:10]=1)=[C:8]([N:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1)[N:7]=[C:6]([C:17]1[C:18]([CH3:24])=[N:19][C:20]([NH2:23])=[N:21][CH:22]=1)[N:5]=2.[NH:29]1[CH2:34][CH2:33][CH:32]([CH2:35][OH:36])[CH2:31][CH2:30]1>CN1CCCC1=O>[NH2:23][C:20]1[N:19]=[C:18]([CH3:24])[C:17]([C:6]2[N:5]=[C:4]3[C:9]([N:10]=[C:2]([N:29]4[CH2:34][CH2:33][CH:32]([CH2:35][OH:36])[CH2:31][CH2:30]4)[N:3]3[CH2:25][CH:26]3[CH2:28][CH2:27]3)=[C:8]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)[N:7]=2)=[CH:22][N:21]=1
Reactant: OCC1CCNCC1
Reactant: Cc1nc(N)ncc1-c1nc(N2CCOCC2)c2nc(Cl)n(CC3CC3)c2n1
Solvent: CN1CCCC1=O
Product: Cc1nc(N)ncc1-c1nc(N2CCOCC2)c2nc(N3CCC(CO)CC3)n(CC3CC3)c2n1
Temperature: 120 °C
Reaction time: 0.5 h
Yield: 57.6 %

Procedure:
N-Methylpyrrolidone (1 ml) was added to 5-[8-chloro-9-(cyclopropylmethyl)-6-morpholin-4-yl-9H-purin-2-yl]-4-methylpyrimidin-2-amine (100 mg, 0.25 mmol) and 4-piperidinemethanol (172 mg, 1.5 mmol) and the resulting mixture was stirred at 120° C. for 0.5 hours. The reaction mixture was partitioned with ethyl acetate and water and the organic layer was washed with saturated brine and dried over magnesium sulfate. The solvent was concentrated under reduced pressure and the residue was purified by preparative HPLC (column, NOMURA Develosil Combi-RP-5; mobile phase, acetonitrile/water/formic acid) to give the title compound (69 mg, 58%) as a pale yellow solid.
Reaction SMILES: [C:1]1([OH:11])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.C([O-])([O-])=O.[K+].[K+].Cl[C:19]1[CH:24]=[CH:23][N:22]=[CH:21][C:20]=1[N+:25]([O-:27])=[O:26].O>CN(C=O)C>[C:1]1([O:11][C:19]2[CH:24]=[CH:23][N:22]=[CH:21][C:20]=2[N+:25]([O-:27])=[O:26])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: Oc1cccc2ccccc12
Reactant: O=[N+]([O-])c1cnccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1cnccc1Oc1cccc2ccccc12
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To 50 ml of DMF was added 1-naphthol (11.25 g) and to this solution was added K2CO3 (20 g) portionwise. After stirring for 10 minutes at room temperature, 4-chloro-3-nitropyridine (11.2 g) in 60 ml of DMF was added dropwise. The reaction mixture was stirred for 4 hours at room temperature. The mixture was then poured into water and extracted with ethyl acetate. The organic layer was washed with water and dried (sat. NaCl, anhy. MgSO4).
Reaction SMILES: [OH-].[Na+].[CH2:3]([N:10]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:11]1[CH:12]=[C:13](/[CH:18]=[CH:19]/[C:20]([O:22]C)=[O:21])[CH:14]=[C:15]([F:17])[CH:16]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Cl>O1CCCC1.CO>[CH2:24]([N:10]([CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[C:11]1[CH:12]=[C:13](/[CH:18]=[CH:19]/[C:20]([OH:22])=[O:21])[CH:14]=[C:15]([F:17])[CH:16]=1)[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: COC(=O)/C=C/c1cc(F)cc(N(Cc2ccccc2)Cc2ccccc2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)/C=C/c1cc(F)cc(N(Cc2ccccc2)Cc2ccccc2)c1
Temperature: 80 °C
Yield: 91.7 %

Procedure:
Sodium hydroxide (2 mL, 2 mmol, 1.00 N solution) was added to a solution of 19B (0.467 g, 1.24 mmol) in tetrahydrofuran (2 mL) and methanol (1 mL). The reaction was heated at 80° C. for 1 h. Hydrochloric acid (1 N) was added and the reaction mixture was extracted with ethyl acetate (2×). The combined organic layers were dried (MgSO4) and concentrated under reduced pressure to give 19C (0.411 g, 91%) as a pale yellow solid. LC-MS m/z: 362.4 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][CH2:11][C:12]([OH:14])=O.C(Cl)(=O)C([Cl:18])=O>C(OCC)C.CN(C)C=O>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][CH2:11][C:12]([Cl:18])=[O:14]
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)CCCc1ccc(Cl)cc1Cl
Solvent: CCOCC
Solvent: CN(C)C=O
Product: O=C(Cl)CCCc1ccc(Cl)cc1Cl

Procedure:
By the method of Example 1, Step B, 9.79 g (0.042 mole) of 4-(2,4-dichlorophenyl)butanoic acid and 5.8 g (0.050 mole) of oxalyl chloride are reacted in 75 mL of diethyl ether and two drops of N,N-dimethylformamide, yielding 4-(2,4-dichlorophenyl)butanoic acid chloride.
Reaction SMILES: [Br:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:5]=[CH:4][C:3]=1[C:13]([OH:15])=O.[C:16](N1C=CN=C1)([N:18]1C=CN=[CH:19]1)=O.C(N(CC)CC)C.Cl.CNC>CN(C=O)C>[Br:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:5]=[CH:4][C:3]=1[C:13]([N:18]([CH3:19])[CH3:16])=[O:15]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: O=C(O)c1cnn(-c2ccccc2)c1Br
Agent: CNC
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CN(C)C(=O)c1cnn(-c2ccccc2)c1Br
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 36.3 %

Procedure:
Three grams of 5-bromo-1-phenyl-1H-pyrazole-4-carboxylic acid and 2.6 g of carbonyldiimidazole was dissolved in 50 ml of DMF. The solution was stirred for 20 minutes and 2.3 g of triethylamine and 1.8 g of dimethylamine hydrochloride were added to the reaction mixture. The mixture was stirred at room temperature for 3 hours and was poured into ice water. The precipitated solid was collected by filtration and recrystallized from ethanol/water to afford 1.2 g of 5-bromo-1-phenyl-N,N-dimethyl-1H-pyrazole-4-carboxamide. Yield 37%. mp=79°-81° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=1[O:13][CH3:14])[C:7]([OH:9])=O)([O-:3])=[O:2].[CH3:15][N:16]1[CH2:21][CH2:20][CH:19]([NH2:22])[CH2:18][CH2:17]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:14][O:13][C:12]1[CH:11]=[CH:10][C:6]([C:7]([NH:22][CH:19]2[CH2:20][CH2:21][N:16]([CH3:15])[CH2:17][CH2:18]2)=[O:9])=[CH:5][C:4]=1[N+:1]([O-:3])=[O:2]
Reactant: CN1CCC(N)CC1
Reactant: COc1ccc(C(=O)O)cc1[N+](=O)[O-]
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(C(=O)NC2CCN(C)CC2)cc1[N+](=O)[O-]
Yield: 76.5 %

Procedure:
3-Nitro-4-methoxybenzoic acid (Aldrich; 300 mg, 1.52 mmol), 1-methyl-4-aminopiperidine (Fluorochem; 174 mg, 1.52 mmol), HATU (868 mg, 2.28 mmol) and DIPEA (796 uL, 4.56 mmol) were stirred in DMF (6 mL) at room temperature for 2 hours. The reaction mixture was loaded onto an SCX-3 column pre-washed with methanol. The column was washed with methanol and then eluted with 2% 7N ammonia/methanol. Product containing fractions were combined and evaporated to give the title compound as an orange solid (341 mg, 76.4%).
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:3]=1[CH2:4][NH:5][C:6]1[CH:15]=[C:14]([C:16]([O:18][CH3:19])=[O:17])[CH:13]=[CH:12][C:7]=1[C:8]([O:10][CH3:11])=[O:9].CN(C)C1C=CC=CC=1.[C:34](Cl)(=[O:36])[CH3:35].Cl>C1(C)C=CC=CC=1>[C:34]([N:5]([CH2:4][C:3]1[CH:20]=[CH:21][C:22]([Cl:24])=[CH:23][C:2]=1[Cl:1])[C:6]1[CH:15]=[C:14]([C:16]([O:18][CH3:19])=[O:17])[CH:13]=[CH:12][C:7]=1[C:8]([O:10][CH3:11])=[O:9])(=[O:36])[CH3:35]
Reactant: COC(=O)c1ccc(C(=O)OC)c(NCc2ccc(Cl)cc2Cl)c1
Reactant: CC(=O)Cl
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CN(C)c1ccccc1
Product: COC(=O)c1ccc(C(=O)OC)c(N(Cc2ccc(Cl)cc2Cl)C(C)=O)c1
Temperature: 50 °C

Procedure:
A mixture of dimethyl 2-(2,4-dichlorobenzyl)aminoterephthalate (12.00 g), N,N-dimethylaniline (7.92 g) and acetyl chloride (5.5 ml) in toluene (140 ml) was heated at 50° C. for 15 hr. After cooling, ice and concentrated hydrochloric acid were added to acidify the reaction mixture and the toluene layer was separated. The toluene layer was washed successively with water and a saturated aqueous sodium hydrogencarbonate solution, dried over sodium sulfate and concentrated. The residue was crystallized from 2-propanol to give the objective compound (8.40 g) as white crystals.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([C:8]#[C:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:6][CH:7]=1.[CH3:16][C:17]1([CH3:23])[CH2:21][NH:20][C:19](=[O:22])[CH2:18]1.C(=O)([O-])[O-].[Cs+].[Cs+].C(OCC)(=O)C>CN(C=O)C>[CH3:16][C:17]1([CH3:23])[CH2:21][N:20]([C:2]2[N:3]=[N:4][C:5]([C:8]#[C:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)=[CH:6][CH:7]=2)[C:19](=[O:22])[CH2:18]1
Reactant: CC1(C)CNC(=O)C1
Reactant: Clc1ccc(C#Cc2ccccc2)nn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC1(C)CC(=O)N(c2ccc(C#Cc3ccccc3)nn2)C1
Temperature: 120 °C
Reaction time: 0.42 h
Yield: 14.7 %

Procedure:
To a solution of 3-chloro-6-(phenylethynyl)pyridazine (CAS 77778-15-5) (180 mg, 839 μmol) and 4,4-dimethylpyrrolidin-2-one (CAS 66899-02-3) (142 mg, 1.26 mmol, 1.5 equiv.) in 2 ml of DMF were added cesium carbonate (546 mg, 1.68 mmol, 2 equiv.). The suspension was heated 16 hours at 120° C. and then allowed to cool to room temperature. Ethyl acetate (10 ml) were added and the unsoluble salts were filtered off. After concentration in vaccuo, the residue was dissolved in 10 ml of ethyl acetate. Silicagel (4 g) were added and the suspension was evaporated to dryness. The silicagel with the adsorbed crude mixture was loaded onto a 20 g silicagel flash chromatography column and eluted three min. with heptane followed by a heptane to 45% ethyl acetate/heptane gradient over 25 min to yield 36 mg (15% yield) of the title compound as a cristalline yellow solid, MS: m/e=292.3 (M+H+).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:50]=[CH:49][C:9]2[N:10]([CH:43]3[CH2:48][CH2:47][CH2:46][CH2:45][CH2:44]3)[C:11]([C:13]3[CH:14]=[C:15]4[C:20](=[CH:21][CH:22]=3)[N:19]=[C:18]([C:23]3[C:28]([C:29]5[CH:34]=[CH:33][C:32](F)=[CH:31][CH:30]=5)=[CH:27][CH:26]=[C:25]([C:36]([N:38]5[CH2:42][CH2:41][CH2:40][CH2:39]5)=[O:37])[CH:24]=3)[CH:17]=[CH:16]4)=[N:12][C:8]=2[CH:7]=1)=[O:5])[CH3:2].[CH3:51][O:52]C1C=CC(B(O)O)=CC=1>>[CH2:1]([O:3][C:4]([C:6]1[CH:50]=[CH:49][C:9]2[N:10]([CH:43]3[CH2:48][CH2:47][CH2:46][CH2:45][CH2:44]3)[C:11]([C:13]3[CH:14]=[C:15]4[C:20](=[CH:21][CH:22]=3)[N:19]=[C:18]([C:23]3[C:28]([C:29]5[CH:34]=[CH:33][C:32]([O:52][CH3:51])=[CH:31][CH:30]=5)=[CH:27][CH:26]=[C:25]([C:36]([N:38]5[CH2:42][CH2:41][CH2:40][CH2:39]5)=[O:37])[CH:24]=3)[CH:17]=[CH:16]4)=[N:12][C:8]=2[CH:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ccc2c(c1)nc(-c1ccc3nc(-c4cc(C(=O)N5CCCC5)ccc4-c4ccc(F)cc4)ccc3c1)n2C1CCCCC1
Reactant: COc1ccc(B(O)O)cc1
Product: CCOC(=O)c1ccc2c(c1)nc(-c1ccc3nc(-c4cc(C(=O)N5CCCC5)ccc4-c4ccc(OC)cc4)ccc3c1)n2C1CCCCC1

Procedure:
Prepared as described for Compound 549a using 4-methoxyphenylboronic acid instead of 4-fluorophenylboronic acid.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1/[CH:11]=[CH:12]/[C:13](Cl)=[O:14].[NH2:16][C:17]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:18]=1[C:19]([OH:21])=[O:20].C(N(CC)CC)C>O1CCCC1>[C:19]([C:18]1[CH:22]=[C:23]([F:26])[CH:24]=[CH:25][C:17]=1[NH:16][C:13](=[O:14])/[CH:12]=[CH:11]/[C:2]1[CH:3]=[CH:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:1]=1)([OH:21])=[O:20]
Reactant: Nc1ccc(F)cc1C(=O)O
Reactant: O=C(Cl)/C=C/c1ccc2ccccc2c1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(/C=C/c1ccc2ccccc2c1)Nc1ccc(F)cc1C(=O)O

Procedure:
Prepared analogously to Example 31 from trans-3-(naphth-2-yl)-acrylic acid chloride and 2-amino-5-fluoro-benzoic acid in tetrahydrofuran with the addition of triethylamine.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1([C:24]([OH:26])=O)[CH2:14][CH2:13][N:12]([C:15]2[C:16]3[CH:23]=[CH:22][NH:21][C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)C(C)C)(C)C.[NH2:36][CH:37]([C:42]1[CH:47]=[CH:46][C:45]([Cl:48])=[CH:44][CH:43]=1)[CH2:38][C:39]([NH2:41])=[O:40]>CN(C=O)C>[NH2:41][C:39](=[O:40])[CH2:38][CH:37]([NH:36][C:24]([C:9]1([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:3])([CH3:4])[CH3:2])[CH2:10][CH2:11][N:12]([C:15]2[C:16]3[CH:23]=[CH:22][NH:21][C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:13][CH2:14]1)=[O:26])[C:42]1[CH:47]=[CH:46][C:45]([Cl:48])=[CH:44][CH:43]=1
Reactant: NC(=O)CC(N)c1ccc(Cl)cc1
Reactant: CC(C)(C)OC(=O)NC1(C(=O)O)CCN(c2ncnc3[nH]ccc23)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC1(C(=O)NC(CC(N)=O)c2ccc(Cl)cc2)CCN(c2ncnc3[nH]ccc23)CC1
Temperature: 20 °C
Reaction time: 0.08 h
Yield: 79.4 %

Procedure:
O-(7-Azabenzotriazol-1-yl)-n,n,n′,n′-tetramethyluronium hexafluoro-phosphate (129 mg, 0.34 mmol) was added in one portion to 4-(tert-butoxycarbonylamino)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-carboxylic acid (Intermediate 1) (82 mg, 0.23 mmol) and N,N-diisopropylethylamine (0.112 mL, 0.68 mmol) in DMF (4 mL) at 20° C. under nitrogen. The resulting solution was stirred at 20° C. for 5 minutes. 3-amino-3-(4-chlorophenyl)propanamide (Intermediate 107) (45 mg, 0.23 mmol) was then added to the reaction and stirred for 3 hours. The reaction mixture was concentrated and diluted with EtOAc (20 mL) and washed with water (20 mL). The organic layer was dried over MgSO4, filtered and evaporated to afford tert-butyl 4-(3-amino-1-(4-chlorophenyl)-3-oxopropylcarbamoyl)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-4-ylcarbamate (99 mg, 100%).