Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([N:5]2[CH2:11][CH2:10][C:9]3[CH:12]=[CH:13][C:14]([O:16][C:17]4[CH:22]=[CH:21][C:20](I)=[CH:19][N:18]=4)=[CH:15][C:8]=3[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.[NH:24]1[CH:28]=[CH:27][CH:26]=[N:25]1.C(=O)([O-])[O-].[Cs+].[Cs+].N1C2C(=CC=C3C=2N=CC=C3)C=CC=1>O1CCOCC1.C(OCC)(=O)C.[Cu]I>[CH:1]1([N:5]2[CH2:11][CH2:10][C:9]3[CH:12]=[CH:13][C:14]([O:16][C:17]4[CH:22]=[CH:21][C:20]([N:24]5[CH:28]=[CH:27][CH:26]=[N:25]5)=[CH:19][N:18]=4)=[CH:15][C:8]=3[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1
Reactant: c1cn[nH]c1
Reactant: Ic1ccc(Oc2ccc3c(c2)CCN(C2CCC2)CC3)nc1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: c1cnn(-c2ccc(Oc3ccc4c(c3)CCN(C3CCC3)CC4)nc2)c1
Temperature: 180 °C

Procedure:
A mixture of 3-cyclobutyl-7-[(5-iodo-2-pyridinyl)oxy]-2,3,4,5-tetrahydro-1H-3-benzazepine (E207) (294 mg, 0.7 mmol), pyrazole (58 mg, 0.84 mmol), cesium carbonate (479 mg, 1.5 mmol), copper (I) iodide (7 mg, 0.04 mmol) and 1.10 phenanthroline (13 mg, 0.07 mmol) in dioxane (2 ml) were heated in a microwave reactor at 180° C. for 20 minutes. The reaction mixture was diluted with ethyl acetate and washed with a saturated solution of ammonium chloride, water, brine and dried (magnesium sulfate). The organic layer was filtered, concentrated in vacuo and the resulting residue was purified by column chromatography eluting with a mixture of 0.880 ammonia:methanol:dichloromethane (0.5:4.5:95) to afford the title compound (E221); MS (ES+) m/e 361 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:11]3[C:18]4[CH2:19][NH:20][CH2:21][C:17]=4[S:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[F:8].Cl.[CH3:23][N:24]([CH3:31])[CH2:25]/[CH:26]=[CH:27]/[C:28](O)=[O:29]>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:11]3[C:18]4[CH2:19][N:20]([C:28](=[O:29])/[CH:27]=[CH:26]/[CH2:25][N:24]([CH3:31])[CH3:23])[CH2:21][C:17]=4[S:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: Fc1ccc(Nc2ncnc3sc4c(c23)CNC4)cc1Cl
Reactant: CN(C)C/C=C/C(=O)O
Agent: Cl
Product: CN(C)C/C=C/C(=O)N1Cc2sc3ncnc(Nc4ccc(F)c(Cl)c4)c3c2C1

Procedure:
In analogy to Example 89, the title compound was prepared from N-(3-chloro-4-fluorophenyl)-6,7-dihydro-5H-pyrrolo[3′,4′:4,5]thieno[2,3-d]pyrimidin-4-amine from Example 23A (60 mg, 0.19 mmol) and (2E)-4-(dimethylamino)but-2-enoic acid hydrochloride from Example 1A (43 mg, 0.26 mmol) to yield 17 mg (21%).
Reaction SMILES: C#N.C=CC=C.C(#N)[CH2:8][CH2:9][CH2:10][CH2:11][C:12]#[N:13].[C:15](#[N:20])[CH2:16][CH2:17][CH:18]=[CH2:19]>[Ni]>[C:12](#[N:13])[CH2:11][CH2:10][CH:9]=[CH2:8].[C:15](#[N:20])[CH2:16][CH:17]=[CH:18][CH3:19]
Reactant: N#CCCCCC#N
Agent: [Ni]
Agent: C#N
Agent: C=CC=C
Product: CC=CCC#N

Procedure:
The process of the present invention is applied to a waste stream from a process which involves the direct addition of two molecules of hydrogen cyanide to a molecule of butadiene thereby producing adiponitrile. The process is conducted in two steps. With reference to the drawing, the first step (reactor 1) involves the addition of one molecule of hydrogen cyanide (stream 2) to dry butadiene (stream 3) in the presence of a catalyst (stream 4) consisting of zero-valent nickel usually in the form of a nickel tetrakis-tritolylphosphite, to produce a mixture of cis- and trans-3-pentenenitrile and 4-pentenenitrile. This reaction mixture is withdrawn from reactor 1 via line 5, treated to remove impurities and then introduced into reactor 6 along with additional HCN (line 7), ligand (line 8) and triarylborane catalyst promoter such as triphenylborane (line 9). In this reaction which can be conducted in one or more steps, 4-pentenenitrile is formed by the in situ isomerization of 3-pentenenitrile. The 4-pentenenitrile is then converted to adiponitrile by the addition of one molecule of HCN. The effluent from the reactor 6 is passed to extractor 13 and there contacted with cyclohexane (line 14). The cyclohexane extractant (line 15) is subsequently directed to further treatment for product recovery. During the hydrocyanation as described as hereinabove a portion of the zero-valent nickel catalyst is oxidized to nickel cyanide which is insoluble in the reaction medium and which forms insoluble complexes with the triarylborane. The tails from the extraction vessel (line 16) contain such complexes which are subsequently separated from the tails (line 16) by centrifuge 17. A typical analysis of this sludge is set forth below in Table I.
Reaction SMILES: C(N(CC)CC)C.Cl.[CH3:9][O:10][NH2:11].[CH3:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[C:14]=1[NH:20][CH:21]([CH3:25])[C:22](=O)[CH3:23]>ClCCl>[CH3:9][O:10][N:11]=[C:22]([CH:21]([NH:20][C:14]1[C:15]([CH3:19])=[CH:16][CH:17]=[CH:18][C:13]=1[CH3:12])[CH3:25])[CH3:23]
Reactant: CC(=O)C(C)Nc1c(C)cccc1C
Reactant: CON
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CON=C(C)C(C)Nc1c(C)cccc1C
Temperature: 20 °C
Reaction time: 18 h

Procedure:
A sample of 50.5 g triethylamine was added dropwise to a solution of 50.1 g (0.6 mol) methoxyamine hydrochloride in 75 ml dichloromethane at 9°-20° C. To the resulting solution was added about one-half of a 95.6-g (0.5-mol) sample of 3-(2,6-dimethylphenylamino)-2-butanone. The reaction temperature rose from 16° C. to 30° C. The reaction mixture was cooled in an ice bath, and the remaining 3-(2,6-dimethylphenylamino)-2-butanone was added dropwise. The reaction mixture was then stirred about 18 hours at about 20° C., washed with 50 ml of water and evaporrated under reduced pressure to give 100.3 g of 3-(2,6-dimethylphenylamino)-2-butanone O-methyloxime, as an oil. The nuclear magnetic resonance spectrum showed a sharp 3-proton singlet (--OCH3) at 3.9 ppm (relative to tetramethylsilane) and a sharp 6-proton singlet (2,6-dimethyl groups) at 2.2 ppm.
Reaction SMILES: [C:1]([O:5][C:6](=[O:28])[NH:7][C:8]1[C:13]([NH2:14])=[CH:12][C:11]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[F:21])=[C:10]([O:22][CH2:23][C:24]([F:27])([F:26])[F:25])[CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[N:29]1([C:34]2[CH:35]=[C:36]([C:40]3[O:45]C(C)(C)[O:43][C:42](=O)[CH:41]=3)[CH:37]=[CH:38][CH:39]=2)[CH:33]=[CH:32][N:31]=[CH:30]1>>[C:1]([O:5][C:6](=[O:28])[NH:7][C:8]1[C:13]([NH:14][C:42](=[O:43])[CH2:41][C:40]([C:36]2[CH:37]=[CH:38][CH:39]=[C:34]([N:29]3[CH:33]=[CH:32][N:31]=[CH:30]3)[CH:35]=2)=[O:45])=[CH:12][C:11]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[F:21])=[C:10]([O:22][CH2:23][C:24]([F:25])([F:26])[F:27])[CH:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC1(C)OC(=O)C=C(c2cccc(-n3ccnc3)c2)O1
Reactant: CC(C)(C)OC(=O)Nc1cc(OCC(F)(F)F)c(-c2ccccc2F)cc1N
Product: CC(C)(C)OC(=O)Nc1cc(OCC(F)(F)F)c(-c2ccccc2F)cc1NC(=O)CC(=O)c1cccc(-n2ccnc2)c1

Procedure:
The title compound was prepared from [5-amino-2′-fluoro-2-(2,2,2-trifluoro-ethoxy)-biphenyl-4-yl]-carbamic acid tert.-butyl ester (Example J5) (200 mg, 0.5 mmol) and 6-(3-imidazol-1-yl-phenyl)-2,2-dimethyl-[1,3]dioxin-4-one (Example L3) (160 mg, 0.5 mmol) according to the general procedure M. Obtained as an amorphous brown substance (167 mg).
Reaction SMILES: [Br:1][C:2]1[C:7](=[O:8])[N:6]([CH2:9][C:10]([NH:12][CH2:13][C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)=O)[N:5]=[CH:4][C:3]=1[NH:20][C@@H:21]1[CH2:26][C@@H:25]2[CH2:27][C@@H:23]([C:24]2([CH3:29])[CH3:28])[C@H:22]1[CH3:30].O1CCCC1.B.[Cl-].[Na+]>CN(C)C=O>[Br:1][C:2]1[C:7](=[O:8])[N:6]([CH2:9][CH2:10][NH:12][CH2:13][C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)[N:5]=[CH:4][C:3]=1[NH:20][C@@H:21]1[CH2:26][C@@H:25]2[CH2:27][C@@H:23]([C:24]2([CH3:28])[CH3:29])[C@H:22]1[CH3:30]
Reactant: C[C@@H]1[C@H]2C[C@@H](C[C@H]1Nc1cnn(CC(=O)NCc3ccncc3)c(=O)c1Br)C2(C)C
Agent: B
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: C[C@@H]1[C@H]2C[C@@H](C[C@H]1Nc1cnn(CCNCc3ccncc3)c(=O)c1Br)C2(C)C
Temperature: 25 °C
Reaction time: 5.5 h
Yield: 95.2 %

Procedure:
2-{5-Bromo-6-oxo-4-[(1R,2R,3R,5S)-2,6,6-trimethylbicyclo[3.1.1]hept-3-ylamino]pyridazin-1(6H)-yl}-N-(pyridin-4-ylmethyl)acetamide (35 mg, 0.073 mmol) in N,N-dimethylformamide (1 mL) was mixed with a borane tetrahydrofuran complex (1.13 M in tetrahydrofuran, 78 μL, 0.088 mmol) under cooling with ice and stirred at room temperature for 5.5 hours. After completion of the reaction, the reaction solution was mixed with saturated aqueous sodium chloride and extracted with ethyl acetate. The resulting organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and evaporated under reduced pressure to give the desired product (32 mg, 92% yield).
Reaction SMILES: C(S([C:5]1[N:6]=[CH:7][C:8]2[CH:14]=[C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:12]([C:21]3[CH:28]=[CH:27][C:24]([CH:25]=[O:26])=[CH:23][CH:22]=3)=[N:11][C:9]=2[N:10]=1)=O)C.[C:29]([N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1)(=[O:31])[CH3:30]>O1CCOCC1>[C:29]([N:32]1[CH2:37][CH2:36][N:35]([C:5]2[N:6]=[CH:7][C:8]3[CH:14]=[C:13]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)[C:12]([C:21]4[CH:28]=[CH:27][C:24]([CH:25]=[O:26])=[CH:23][CH:22]=4)=[N:11][C:9]=3[N:10]=2)[CH2:34][CH2:33]1)(=[O:31])[CH3:30]
Reactant: CC(=O)N1CCNCC1
Reactant: CCS(=O)c1ncc2cc(-c3ccccc3)c(-c3ccc(C=O)cc3)nc2n1
Solvent: C1COCCO1
Product: CC(=O)N1CCN(c2ncc3cc(-c4ccccc4)c(-c4ccc(C=O)cc4)nc3n2)CC1
Temperature: 150 °C

Procedure:
To a solution of 4-[2-(ethylsulfinyl)-6-phenylpyrido[2,3-d]pyrimidin-7-yl]benzaldehyde (3-1; 63 mg, 0.16 mmole) in dioxane (1 mL) was added 1-acetylpiperazine and heated to 150° C. in a microwave reactor for 30 min. The mixture was concentrated under reduced pressure and the residue was purified by silica gel chromatography (100% Hex. to 100% EtOAc) to give the title compound. LRMS m/z (M+H) Calcd: 438.5, found 438.2.
Reaction SMILES: [Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.[Br:12][C:13]1[CH:14]=[C:15]([CH2:19][OH:20])[CH:16]=[N:17][CH:18]=1.C(OCC)C>ClCCl>[Br:12][C:13]1[CH:14]=[C:15]([CH:19]=[O:20])[CH:16]=[N:17][CH:18]=1
Reactant: OCc1cncc(Br)c1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: CCOCC
Solvent: ClCCl
Product: O=Cc1cncc(Br)c1
Reaction time: 1 h
Yield: 33.6 %

Procedure:
4.5 g (21 mmol) of pyridinium chlorochromate are added at room temperature to a solution of 3 g (16 mmol) of (5-bromopyrid-3-yl)methanol in 70 ml of dichloromethane. After stirring for 1 hour, 70 ml of diethyl ether are added and the reaction medium is again stirred for 1 hour. The precipitate is filtered off through sodium sulfate and the filtrate is evaporated to dryness. The residue obtained is purified by chromatography on a column of silica eluted with a 7/3 heptane/ethyl acetate mixture. 1 g (35%) of 5-bromopyridine-3-carbaldehyde is obtained.
Reaction SMILES: [C:1]([N:4]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C@@H:5]([CH2:13][OH:14])[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)([OH:3])=[O:2].[Br-].[Na+].CC1(C)N([O])C(C)(C)CCC1.Cl[O-].[Na+].C(=O)(O)[O-].[Na+].O.O.O.O.O.S([O-])([O-])(=O)=S.[Na+].[Na+]>ClCCl.O>[C:1]([N:4]([CH2:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[C@@H:5]([CH:13]=[O:14])[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)([OH:3])=[O:2]
Reactant: O=C(O)N(Cc1ccccc1)[C@@H](CO)Cc1ccccc1
Agent: CC1(C)CCCC(C)(C)N1[O]
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Solvent: ClCCl
Solvent: O
Product: O=C[C@@H](Cc1ccccc1)N(Cc1ccccc1)C(=O)O
Reaction time: 0.25 h
Yield: 90.6 %

Procedure:
N-Carboxy benzyl -D-phenylalaninol (100 g; 0.35M) is dissolved in dichloromethane (1.8 L) and a solution of sodium bromide (18 g; 0.175M) in water (250 mL) is added. The resulting two phase mixture is stirred and cooled to 0°-5° C. under a nitrogen atmosphere. 2,2,6,6-Tetramethyl-1-piperidinyloxy, free radical (TEMPO) (0.055 g; 3.5 mM) is added. A solution of buffered sodium hypochlorite, freshly prepared by dissolving sodium bicarbonate (10 g; 0.12M) and commercial sodium hypochlorite solution (12.5% w/w; 250 g; 0.42M) in water (250 g), is added over a period of one hour with fast agitation, maintaining the reaction temperature <5° C. A solution of sodium thiosulfate pentahydrate (21.8 g; 0.088M) in water (64 mL) is then immediately added and the reaction mixture efficiently stirred until excess oxidants have been quenched as demonstrated by starch/iodide test. Agitation is stopped and the mixture allowed to settle at 5°-10° C. After 15 minutes, the phases are separated. The organic phase is then washed with aqueous sodium bicarbonate solution (3% w/w; 500 mL) and aqueous sodium chloride solution (3% w/w; 500 mL). The organic phase is concentrated by vacuum distillation to a volume of approximately 300 mL maintaining the heating bath <20° C. Heptane (750 mL) is added and the vacuum distillation continued again maintaining the heating bath at <20° C. A white precipitate slowly forms as the dichloromethane is removed. The distillation is continued until the dichloromethane in heptane concentration is <5% w/w. The precipitate is filtered, washed with heptane (2× 200 mL) and dried under vacuum at 20° C. to constant weight to yield N-carboxybenzyl-D-phenylalaninal (90 g; 90% yield) as a white crystalline solid.
Reaction SMILES: [BH4-].[Li+].NCC[N:6]1[C:10](=[O:11])/[C:9](=[CH:12]/[C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH3:21])=[CH:15][CH:14]=2)/[S:8][C:7]1=[O:22].Cl>C1COCC1.N1C=CC=CC=1>[CH2:20]([O:19][C:16]1[CH:17]=[CH:18][C:13]([CH2:12][CH:9]2[S:8][C:7](=[O:22])[NH:6][C:10]2=[O:11])=[CH:14][CH:15]=1)[CH3:21]
Reactant: CCOc1ccc(/C=C2\SC(=O)N(CCN)C2=O)cc1
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CCOc1ccc(CC2SC(=O)NC2=O)cc1
Temperature: 80 °C
Reaction time: 12 h

Procedure:
To a suspension of lithium borohydride (0.22 g, 10.04 mmol) in 40 mL of THF-pyridine (ratio 1:1), compound 3 (1.00 g, 4.02 mmol) was added at 0° C. The reaction mixture was stirred at 80° C. for 12 h and then cooled to 0° C. 21 mL of 4 N HCl aqueous solution was added carefully and the resulting suspension was stirred at 0° C. for 10 min, and refluxed for 1 h. After cooling down at room temperature, the solvent was removed by evaporation. The residue was dissolved in ethyl acetate and washed with water. The organic layer was collected, dried over anhydrous Na2SO4, filtered, concentrated and purified by silica column chromatography (50% ethyl acetate in hexanes) to afford compound 4 in 76.6% (0.77 g) yield as a colorless oil.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:6][CH2:5][N:4]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([NH2:14])=[C:10]([N+:15]([O-:17])=[O:16])[CH:9]=2)[C:3]1=[O:18].[CH3:19][O:20][C:21]1[CH:30]=[C:29]2[C:24]([CH:25]=[CH:26][C:27]([S:31](Cl)(=[O:33])=[O:32])=[CH:28]2)=[CH:23][CH:22]=1>C(Cl)Cl>[NH2:14][C:11]1[CH:12]=[CH:13][C:8]([CH2:7][N:4]2[CH2:5][CH2:6][C@H:2]([NH:1][S:31]([C:27]3[CH:26]=[CH:25][C:24]4[C:29](=[CH:30][C:21]([O:20][CH3:19])=[CH:22][CH:23]=4)[CH:28]=3)(=[O:33])=[O:32])[C:3]2=[O:18])=[CH:9][C:10]=1[N+:15]([O-:17])=[O:16]
Reactant: Nc1ccc(CN2CC[C@H](N)C2=O)cc1[N+](=O)[O-]
Reactant: COc1ccc2ccc(S(=O)(=O)Cl)cc2c1
Solvent: ClCCl
Product: COc1ccc2ccc(S(=O)(=O)N[C@H]3CCN(Cc4ccc(N)c([N+](=O)[O-])c4)C3=O)cc2c1

Procedure:
The title compound is prepared in CH2Cl2 instead of CH3CN as described in EXAMPLE 1, Part K using 3-(S)-amino-1-(4-amino-3-nitrobenzyl)-pyrrolidin-2-one in place of 7-(3-(S)-amino-2-oxopyrrolidin-1-ylmethyl)-1-chloro-isoquinoline hydrochloride and 7-methoxynaphthalene-2-sulfonyl chloride as prepared in EXAMPLE 1, Part J. The crude product is purified by column chromatography eluting with a gradient of 20% EtOAc/CH2Cl2 to 50% EtOAc/CH2Cl2 to afford the title compound as a pale yellow solid.
Reaction SMILES: [C:1]1([N:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:8]2[S:9][CH:10]=[C:11]([CH:13]=O)[N:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[S:21]1[CH2:27][C:25](=[O:26])[N:24]([CH2:28][C:29]([OH:31])=[O:30])[C:22]1=[S:23].[Cl-].[NH4+].N>C(O)C>[C:1]1([N:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:8]2[S:9][CH:10]=[C:11]([CH:13]=[C:27]3[S:21][C:22](=[S:23])[N:24]([CH2:28][C:29]([OH:31])=[O:30])[C:25]3=[O:26])[N:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=Cc1csc(N(c2ccccc2)c2ccccc2)n1
Reactant: O=C(O)CN1C(=O)CSC1=S
Agent: N
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Product: O=C(O)CN1C(=O)C(=Cc2csc(N(c3ccccc3)c3ccccc3)n2)SC1=S

Procedure:
The reaction described in Example 1 was repeated, but using 3 g of 2-diphenylaminothiazole-4-carbaldehyde, 1.7 g of rhodanine-3-acetic acid, 1.3 g of ammonium chloride, 1.3 ml of 28% v/v aqueous ammonia and 60 ml of ethanol, giving the title compound as orange needles.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C@@H:11]([CH3:22])[CH2:10]2)=[C:4]([Cl:23])[CH:3]=1.[CH3:24][C@H]1CN(CC2C=CC(NC)=CC=2)CCN1C(OC(C)(C)C)=O.[BH4-].[Na+]>>[Cl:23][C:4]1[CH:3]=[C:2]([NH:1][CH3:24])[CH:7]=[CH:6][C:5]=1[CH2:8][N:9]1[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:19])([CH3:21])[CH3:20])=[O:16])[C@@H:11]([CH3:22])[CH2:10]1
Reactant: C[C@H]1CN(Cc2ccc(N)cc2Cl)CCN1C(=O)OC(C)(C)C
Reactant: CNc1ccc(CN2CCN(C(=O)OC(C)(C)C)[C@@H](C)C2)cc1
Agent: [BH4-]
Agent: [Na+]
Product: CNc1ccc(CN2CCN(C(=O)OC(C)(C)C)[C@@H](C)C2)c(Cl)c1
Temperature: 50 °C

Procedure:
The title compound was prepared from 1,1-dimethylethyl (2S)-4-[(4-amino-2-chlorophenyl)methyl]-2-methyl-1-piperazinecarboxylate (D104) using a method similar to that described for D3 in Description 3A although the reaction was heated at 50° C. overnight prior to, and for 24 h after addition of sodium borohydride.(3 eq.). MS (ES): MH+ 354/356.
Reaction SMILES: [CH:1]1([N:7]2[CH2:13][C:12]([F:16])([CH:14]=[CH2:15])[C:11](=[O:17])[N:10]([CH3:18])[C:9]3[CH:19]=[N:20][C:21]([NH:23][C:24]4[CH:32]=[CH:31][C:27]([C:28](O)=[O:29])=[CH:26][C:25]=4[O:33][CH3:34])=[N:22][C:8]2=3)C[CH2:5][CH2:4][CH2:3][CH2:2]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:59][CH:60]1[CH2:65][CH2:64][N:63]([CH3:66])[CH2:62][CH2:61]1>>[CH:1]1([N:7]2[CH2:13][C:12]([F:16])([CH:14]=[CH2:15])[C:11](=[O:17])[N:10]([CH3:18])[C:9]3[CH:19]=[N:20][C:21]([NH:23][C:24]4[CH:32]=[CH:31][C:27]([C:28]([NH:59][CH:60]5[CH2:65][CH2:64][N:63]([CH3:66])[CH2:62][CH2:61]5)=[O:29])=[CH:26][C:25]=4[O:33][CH3:34])=[N:22][C:8]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CN1CCC(N)CC1
Reactant: C=CC1(F)CN(C2CCCCC2)c2nc(Nc3ccc(C(=O)O)cc3OC)ncc2N(C)C1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: C=CC1(F)CN(C2CCCC2)c2nc(Nc3ccc(C(=O)NC4CCN(C)CC4)cc3OC)ncc2N(C)C1=O

Procedure:
The title compound was synthesized from 4-(9-cyclohexyl-7-fluoro-7-vinyl-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b][1,4]diazepin-2-ylamino)-3-methoxybenzoic acid as described in the General procedure for amide bond synthesis using HATU and 4-amino 1-N-methyl piperidine. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.53-1.86 (m, 8H) 1.93 (t, J=10.86 Hz, 4H) 2.16 (s, 3H) 2.78 (d, J=11.12 Hz, 2H) 3.28 (s, 3H) 3.65-3.83 (m, 4H) 3.93 (s, 3H) 4.88 (m, 1H) 5.38 (d, J=11.87 Hz, 2H) 6.01 (m, 1H) 7.48 (d, J=8.0 Hz, 1H), 7.49 (br. s., 1H) 7.82 (s, 1H) 8.12 (s, 1H) 8.12 (d, J=7.83 Hz, 1H) 8.30 (d, J=8.0 Hz, 1H). [M+H] calculated for C29H38FN7O3, 552. found 552.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]=[CH:7]2.[CH3:12][O:13][CH:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1.C(O[Na])(C)(C)C>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>[CH3:12][O:13][CH:14]1[CH2:19][CH2:18][N:17]([C:2]2[CH:11]=[CH:10][CH:9]=[C:8]3[C:3]=2[CH:4]=[CH:5][N:6]=[CH:7]3)[CH2:16][CH2:15]1
Reactant: Brc1cccc2cnccc12
Reactant: COC1CCNCC1
Agent: [Pd]
Agent: CC(C)(C)O[Na]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: COC1CCN(c2cccc3cnccc23)CC1
Temperature: 85 °C
Reaction time: 3 h
Yield: 52.3 %

Procedure:
To 5-bromoisoquinoline (10.40 g, 50 mmol), 4-methoxypiperidine (4.92 mL, 50.0 mmol), Pd2(dba)3 (0.458 g, 0.500 mmol), BINAP (0.934 g, 1.500 mmol), and t-BuONa (6.73 g, 70.0 mmol) was added degassed toluene (60 mL) and the reaction was heated under N2 to 85° C. for 24 h and then to 105° C. for 3 h. The reaction mixture was cooled to ambient temperature and water was added. The phases were separated and the aqueous layer extracted three times with ethyl acetate. The combined organics were washed with brine, dried (Na2SO4), filtered and purified by silica gel chromatography to afford 6.34 g (52.4%) of Intermediate 3A as a pale yellow solid. MS (ESI) m/z: 243.2 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:28]([O:29][CH3:30])=[CH:27][CH:26]=[CH:25][C:4]=1[CH2:5][N:6]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[C:7](=[O:17])[CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1.Br[CH2:32][C:33]1[CH:42]=[CH:41][CH:40]=[CH:39][C:34]=1[C:35]([O:37][CH3:38])=[O:36].C(=O)([O-])[O-].[K+].[K+].C(O)C(N)(CO)CO>C(#N)C>[CH3:1][O:2][C:3]1[C:28]([O:29][CH3:30])=[CH:27][CH:26]=[CH:25][C:4]=1[CH2:5][N:6]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[C:7](=[O:17])[CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:32][C:33]2[CH:42]=[CH:41][CH:40]=[CH:39][C:34]=2[C:35]([O:37][CH3:38])=[O:36])=[CH:12][CH:11]=1
Reactant: COC(=O)c1ccccc1CBr
Reactant: CCCCCCCN(Cc1cccc(OC)c1OC)C(=O)CCc1ccc(O)cc1
Agent: NC(CO)(CO)CO
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCCCCCCN(Cc1cccc(OC)c1OC)C(=O)CCc1ccc(OCc2ccccc2C(=O)OC)cc1
Temperature: 60 °C
Reaction time: 3 h
Yield: 14.8 %

Procedure:
N-(2,3-dimethoxybenzyl)-N-heptyl-3-(4-hydroxyphenyl)propanamide 0.196 g, 0.47 mmol) and methyl 2-(bromomethyl)benzoate (0.12 g, 0.52 mmol) was dissolved in acetonitrile (10 ml) and potassiumcarbonate (131 mg, 0.95 mmol) was added. The mixture was stirred at 60° C. for three hours. Polymersupproted trisamine (0.3 eqv) was added and stirred over night. The polymer was filtered of, solvent was removed by evaporation, addition of EtOAc (10 ml) and the organic phase was washed with three potions of water. After drying the crude (MgSO4) and the solvent had been removed by evaporation, the crude was purified by preparative HPLC (started with acetonitrile/buffer 60/40 and then the acetonitrile concentration was increased to 100%, the buffer was a mixture of acetonitrile/water 10/90 and ammonium acetate (0.1 M, column KR-100-7-C8, 50 mm×250 mm, flow 40 ml/min). The product containing fractions was pooled and the acetonitrile was removed by evaporation. EtOAc (10 ml) was added and the organic phase was washed with two potions of brine and dried (MgSO4). Removing the solvent by evaporation gave 39 mg of methyl 2-[(4-{3-[(2,3-dimethoxybenzyl)(heptyl)amino]-3-oxopropyl}phenoxy)methyl]benzoate (yield 14.6%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13]([C:14]3[CH:19]=[C:18]([O:20][C:21](F)([F:23])[F:22])[CH:17]=[C:16]([F:25])[CH:15]=3)=[CH:12][C:11]([C:26]([OH:28])=[O:27])=[N:10]2)[CH:5]=[CH:6][C:7]=1[F:8].O.[OH-].[Li+]>>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13]([C:14]3[CH:19]=[C:18]([O:20][CH:21]([F:23])[F:22])[CH:17]=[C:16]([F:25])[CH:15]=3)=[CH:12][C:11]([C:26]([OH:28])=[O:27])=[N:10]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: O=C(O)c1cc(-c2cc(F)cc(OC(F)(F)F)c2)n(-c2ccc(F)c(Cl)c2)n1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Product: O=C(O)c1cc(-c2cc(F)cc(OC(F)F)c2)n(-c2ccc(F)c(Cl)c2)n1

Procedure:
The intermediate product is hydrolyzed in a manner analogous to the synthesis of the compound from example 8A with 0.40 g (9.52 mmol) of lithium hydroxide monohydrate. This produces 0.34 g (88% of theoretical yield) of the title compound.