Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:15]([NH:21][CH2:22][CH:23]3[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]3)=[N:16][CH:17]=[N:18][C:19]=2[NH2:20])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:29][C:30]1[CH:35]=[CH:34][CH:33]=[C:32](Cl)[N:31]=1>>[Cl:29][C:30]1[N:31]=[C:32]([N:26]2[CH2:27][CH2:28][CH:23]([CH2:22][NH:21][C:15]3[C:14]([C:11]4[CH:12]=[CH:13][C:8]([O:1][C:2]5[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=5)=[CH:9][CH:10]=4)=[C:19]([NH2:20])[N:18]=[CH:17][N:16]=3)[CH2:24][CH2:25]2)[CH:33]=[CH:34][CH:35]=1
Reactant: Nc1ncnc(NCC2CCNCC2)c1-c1ccc(Oc2ccccc2)cc1
Reactant: Clc1cccc(Cl)n1
Product: Nc1ncnc(NCC2CCN(c3cccc(Cl)n3)CC2)c1-c1ccc(Oc2ccccc2)cc1
Yield: 25 %

Procedure:
N4-((1-(6-chloropyridin-2-yl)piperidin-4-yl)methyl)-5-(4-phenoxyphenyl)pyrimidine-4,6-diamine was prepared from 5-(4-phenoxyphenyl)-N4-(piperidin-4-ylmethyl)pyrimidine-4,6-diamine and 2,6-dichloropyridine using Method B (25% yield). HPLC: 99%, RT: 5.214 min. MS: m/z=487 [M+H]+, RT=2.11 min. 1H-NMR (DMSO-d6) □(s, 1H), 7.44-7.36 (m, 3H), 7.20 (d, 2H), 7.15-6.95 (m, 8H), 6.69 (d, 1H), 6.52 (d, 1H), 4.14 (d, 2H), 3.18 (m, 2H), 2.71 (t, 2H), 1.77 (m, 1H), 1.56 (d, 2H), 0.98 (m, 2H).
Reaction SMILES: Cl[C:2]1[C:3]2[CH:4]=[C:5]([O:20][CH3:21])[CH:6]=[CH:7][C:8]=2[N:9]=[C:10]2[C:15]=1[CH:14]=[C:13]1[CH:16]=[CH:17][CH:18]=[CH:19][C:12]1=[CH:11]2.[C-]#N.[K+].[Cu][C:26]#[N:27]>CO>[C:26]([C:2]1[C:3]2[CH:4]=[C:5]([O:20][CH3:21])[CH:6]=[CH:7][C:8]=2[N:9]=[C:10]2[C:15]=1[CH:14]=[C:13]1[CH:16]=[CH:17][CH:18]=[CH:19][C:12]1=[CH:11]2)#[N:27]
Reactant: COc1ccc2nc3cc4ccccc4cc3c(Cl)c2c1
Reactant: N#C[Cu]
Agent: [C-]#N
Agent: [K+]
Solvent: CO
Product: COc1ccc2nc3cc4ccccc4cc3c(C#N)c2c1
Temperature: 170 °C
Reaction time: 4.5 h
Yield: 176 %

Procedure:
A mixture of 12-chloro-2-methoxy-benz[b]acridine (562 mg, 1.905 mmol), potassium cyanide (136 mg, 2.096 mmol) and copper(I) cyanide (86 mg, 0.953 mmol) in methanol (3.7 ml) was stirred at 170° C. in a sealed-tube for 4.5 hours. The resulting mixture was filtrated, and the solid was washed with chloroform/methanol (2:1, 10 ml). The combined filtrate was evaporated under reduced pressure to give a residue, which was flash-chromatographed on a silica column packed with chloroform and eluted with 1% methanol/chloroform to yield 12-cyano-2-methoxybenz[b]acridine (477 mg, 88%). Rf 0.6 (silica gel, 1% methanol/chloroform). MS (CI, CH4): m/z 285 (M+1).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].C(OC(=O)[C@H](CC1C=CC(N(N)C(=O)C2C=C(CN(C=O)C)C=CC=2C(OCC)=O)=CC=1)NC(=O)C1C([Cl:21])=CC=CC=1Cl)(C)C.C(OC(=O)[C@H](CC1C=CC(N2C(=O)C3C(=CC=C(CN(C=O)C)C=3)NC2=O)=CC=1)NC(=O)C1C(Cl)=CC=CC=1Cl)(C)C.C1(C)C=CC(S(OC)(=O)=O)=CC=1.[CH:106]([O:109][C:110](=[O:148])[C@H:111]([CH2:123][C:124]1[CH:129]=[CH:128][C:127]([N:130]2[C:139](=[O:140])[C:138]3[C:133](=[CH:134][CH:135]=[C:136]([CH2:141][N:142](C=O)[CH3:143])[CH:137]=3)[N:132]([CH3:146])[C:131]2=[O:147])=[CH:126][CH:125]=1)[NH:112][C:113](=[O:122])[C:114]1[C:119]([Cl:120])=[CH:118][CH:117]=[CH:116][C:115]=1[Cl:121])([CH3:108])[CH3:107].Cl>>[CH:106]([O:109][C:110](=[O:148])[C@H:111]([CH2:123][C:124]1[CH:125]=[CH:126][C:127]([N:130]2[C:139](=[O:140])[C:138]3[C:133](=[CH:134][CH:135]=[C:136]([CH2:141][NH:142][CH3:143])[CH:137]=3)[N:132]([CH3:146])[C:131]2=[O:147])=[CH:128][CH:129]=1)[NH:112][C:113](=[O:122])[C:114]1[C:119]([Cl:120])=[CH:118][CH:117]=[CH:116][C:115]=1[Cl:121])([CH3:108])[CH3:107].[ClH:21]
Reactant: CCOC(=O)c1ccc(CN(C)C=O)cc1C(=O)N(N)c1ccc(C[C@H](NC(=O)c2c(Cl)cccc2Cl)C(=O)OC(C)C)cc1
Reactant: CC(C)OC(=O)[C@H](Cc1ccc(-n2c(=O)c3cc(CN(C)C=O)ccc3n(C)c2=O)cc1)NC(=O)c1c(Cl)cccc1Cl
Agent: CC(C)OC(=O)[C@H](Cc1ccc(-n2c(=O)[nH]c3ccc(CN(C)C=O)cc3c2=O)cc1)NC(=O)c1c(Cl)cccc1Cl
Agent: COS(=O)(=O)c1ccc(C)cc1
Agent: Cl
Product: CNCc1ccc2c(c1)c(=O)n(-c1ccc(C[C@H](NC(=O)c3c(Cl)cccc3Cl)C(=O)OC(C)C)cc1)c(=O)n2C

Procedure:
In addition, it is preferred that a compound of Formula (3-4), in which R41 is a 2,6-dichlorophenyl group and R42 is an isopropyl group, is reacted with a compound of Formula (2-4) in which R43′ is an N-formyl-N-methyl-aminomethyl group and R45 is an ethyl group to thus form Nα-(2,6-dichlorobenzoyl)-4-{2-ethoxycarbonyl-amino-5-(N-formyl-N-methylaminomethyl)benzoylamino}-L-phenylalanine isopropyl ester of Formula (4-4) in which R41 is a 2,6-dichlorophenyl group, R42 is an isopropyl group, R43′ is an N-formyl-N-methyl-aminomethyl group and R45 is an ethyl group; then the isopropyl ester of Formula (4-4) is reacted with potassium carbonate to thus convert the ester into Nα-(2,6-dichlorobenzoyl)-4-{6-(N-formyl-N-methyl-aminomethyl)quinazoline-2,4[1H,3H]-dion-3-yl}-L-phenylalanine isopropyl ester of Formula (5-4) in which R41 is a 2,6-dichlorophenyl group, R42 is an isopropyl group and R43′ is an N-formyl-N-methyl-aminomethyl group; subsequently the isopropyl ester is subjected to N-alkylation using methyl p-toluene-sulfonate to thus convert the ester into Nα-(2,6-dichlorobenzoyl)-4-{1-methyl-6-(N-formyl-N-methyl-aminomethyl)-quinazoline-2,4[1H,3H]-dion-3-yl}-L-phenylalanine isopropyl ester; and finally the formyl group of the resulting isopropyl ester is deprotected with hydrogen chloride to give Nα-(2,6-dichlorobenzoyl)-4-{1-methyl-6-(N-methyl-aminomethyl)-quinazoline-2,4[1H,3H]-dion-3-yl}-L-phenylalanine isopropyl ester or hydrochloride thereof, in which R41 is a 2,6-dichlorophenyl group, R42 is an isopropyl group, R43 is an N-methyl-aminomethyl group and R44 is a methyl group.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:32]=[CH:33][C:34]=1[O:35][CH3:36])[CH2:6][CH:7]1[C:13]2[CH:14]=[C:15]([O:20][CH3:21])[C:16]([O:18][CH3:19])=[CH:17][C:12]=2[CH2:11][CH2:10][CH2:9][N:8]1[CH:22]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:23]([OH:25])=O.[CH2:37]([CH:39]([NH2:42])[CH2:40][CH3:41])[CH3:38]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:32]=[CH:33][C:34]=1[O:35][CH3:36])[CH2:6][CH:7]1[C:13]2[CH:14]=[C:15]([O:20][CH3:21])[C:16]([O:18][CH3:19])=[CH:17][C:12]=2[CH2:11][CH2:10][CH2:9][N:8]1[CH:22]([C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)[C:23]([NH:42][CH:39]([CH2:40][CH3:41])[CH2:37][CH3:38])=[O:25]
Reactant: COc1ccc(CC2c3cc(OC)c(OC)cc3CCCN2C(C(=O)O)c2ccccc2)cc1OC
Reactant: CCC(N)CC
Product: CCC(CC)NC(=O)C(c1ccccc1)N1CCCc2cc(OC)c(OC)cc2C1Cc1ccc(OC)c(OC)c1

Procedure:
prepared by reaction of [1-(3,4-dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-phenyl-acetic acid with 1-ethylpropylamine.
Reaction SMILES: [Cl:1][C:2]1[C:3](F)=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5](Cl)=[O:6].C(N(CC)CC)C.[NH:19]1[CH2:23][CH2:22][CH2:21][C@H:20]1[CH2:24][OH:25].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O.O>[Cl:1][C:2]1[C:3]2[O:25][CH2:24][C@@H:20]3[CH2:21][CH2:22][CH2:23][N:19]3[C:5](=[O:6])[C:4]=2[CH:8]=[CH:9][CH:10]=1
Reactant: OC[C@@H]1CCCN1
Reactant: O=C(Cl)c1cccc(Cl)c1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: O=C1c2cccc(Cl)c2OC[C@@H]2CCCN12
Temperature: 120 °C
Reaction time: 1 h

Procedure:
To a solution of 3-chloro-2-fluorobenzoyl chloride (2.2 g; 11.4 mmol) in dimethylformamide (5 ml) was added triethylamine (1.7 mL; 11.7 mmol) and (S)-(+)-2-pyrrolidinemethanol (1.13 mL; 11.4 mmol). The mixture was stirred for 1 h then caesium carbonate (7.4 g; 22.7 mmol) was added and the reaction heated at 120° C. for 5 hours. The reaction was cooled to room temperature then diluted with water and extracted with ethyl acetate The organics were washed with water and dried (Na2SO4) evaporated in vacuo. The crude product was purified by chromatography on silica (eluting with 5% methanol in dichloromethane). On removal of solvent the pure amide crystallised and heptane/ether was added and the title compound collected (0.26 g). M.p., 89-90° C.; EIMS: m/z=238 [M+H]+
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:10]([C:13]#[C:14][C:15]2[CH:20]=[CH:19][C:18]([S:21]([Cl:24])(=[O:23])=[O:22])=[CH:17][CH:16]=2)=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].S(=O)(=O)(O)O.[Cl-].[Na+].[C:32](OC(=O)C)(=[O:34])[CH3:33]>C1(C)C=CC=CC=1>[C:32]([O:1][C:2]1[CH:12]=[CH:11][C:10]([C:13]#[C:14][C:15]2[CH:20]=[CH:19][C:18]([S:21]([Cl:24])(=[O:23])=[O:22])=[CH:17][CH:16]=2)=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5])(=[O:34])[CH3:33]
Reactant: CC(=O)OC(C)=O
Reactant: CCOC(=O)c1cc(C#Cc2ccc(S(=O)(=O)Cl)cc2)ccc1O
Agent: O=S(=O)(O)O
Agent: [Cl-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cc(C#Cc2ccc(S(=O)(=O)Cl)cc2)ccc1OC(C)=O

Procedure:
Ethyl 2-hydroxy-5-[(4-chlorosulfonylphenyl]ethynyl]benzoate (16 g, 44 mmol) was dissolved in acetic anhydride (40 ml) at 120 ° C. Sulfuric acid (about 0.4 ml) was added dropwise. After 5 min the solution was diluted with toluene (about 100 ml) and added to saturated sodium chloride solution with vigorous stirring. The phases were separated, the toluene solution dried and evaporated. More toluene was added and the evaporation repeated. The oily product crystallized. The product was sufficiently pure for the next step. Yield 17.0 g (95%).
Reaction SMILES: O.[F:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:13]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=3)[N:12]=[C:11]([CH:20]([CH3:22])[CH3:21])[C:10]=2/[CH:23]=[CH:24]/[CH2:25][OH:26])=[CH:5][CH:4]=1>C1(C)C=CC=CC=1.[Mn]>[F:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[N:13]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=3)[N:12]=[C:11]([CH:20]([CH3:22])[CH3:21])[C:10]=2/[CH:23]=[CH:24]/[CH:25]=[O:26])=[CH:7][CH:8]=1
Reactant: CC(C)c1nn(-c2ccccn2)c(-c2ccc(F)cc2)c1/C=C/CO
Agent: [Mn]
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)c1nn(-c2ccccn2)c(-c2ccc(F)cc2)c1/C=C/C=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 97 %

Procedure:
Manganese IV dioxide (72.2 g, 0.83 mol) was suspended in toluene and refluxed for 4 hours with azeotropic removal of water. The unsaturated alcohol (28 g, 0.083 mol, Step B) was added and heating to reflux continued for 24 hours. The suspension was then cooled to room temperature and filtered through a bed of silica. The filtrate was concentrated in vacuo to give 27.0 g of pure product (98%), mp 105°-107° C.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][N:11]2C(=O)C3=CC=CC=C3C2=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.NN.O>C(O)C>[N:1]1([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][NH2:11])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C1c2ccccc2C(=O)N1CCCCCN1CCCC1
Agent: NN
Solvent: CCO
Solvent: O
Product: NCCCCCN1CCCC1
Yield: 84.1 %

Procedure:
To a solution of N-(5-pyrrolidin-1-ylpentyl)phthalimide (3) (3.27 g, 11.42 mmol) dissolved in ethanol (100 ml) was added NH2NH2.H2O (hydrazine monohydrate) (5.54 ml, 114.19 mmol) at room temperature, and the reaction mixture was refluxed for 24 hours. After the reaction was completed, the resulting reaction mixture was filtered under reduced pressure to give the target compound (1.50 g, 84%).
Reaction SMILES: [CH3:1][O-:2].[Na+].[Na].CO.Cl[C:8]1[N:9]=[N:10][C:11]([N:14]2[CH2:19][CH2:18][N:17]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([CH3:26])[CH:21]=3)[CH2:16][CH2:15]2)=[CH:12][CH:13]=1>O>[CH3:1][O:2][C:8]1[N:9]=[N:10][C:11]([N:14]2[CH2:19][CH2:18][N:17]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([CH3:26])[CH:21]=3)[CH2:16][CH2:15]2)=[CH:12][CH:13]=1
Reactant: C[O-]
Reactant: Cc1cccc(N2CCN(c3ccc(Cl)nn3)CC2)c1
Agent: [Na+]
Agent: [Na]
Solvent: CO
Solvent: O
Product: COc1ccc(N2CCN(c3cccc(C)c3)CC2)nn1
Yield: 50 %

Procedure:
To a stirred sodium methoxide solution, previously prepared starting from 1.6 parts of sodium in 24 parts of methanol, were added 4 parts of 3-chloro-6-[4-(3-methylphenyl)-1-piperazinyl]pyridazine. The whole was stirred and refluxed for 40 hours. After cooling 25 parts of water were added. The product was filtered off, washed with water and dissolved in trichloromethane. The organic layer was dried, filtered and evaporated. The residue was crystallized from a mixture of 2-propanol and 2,2'-oxybispropane. The product was filtered off and dried, yielding 2 parts (50%) of 3-methoxy-6-[4-(3-methylphenyl)-1-piperazinyl]pyridazine; mp. 137.1° C. (compound 258).
Reaction SMILES: C([N:8]1[C@H:22]([CH3:23])[CH2:21][N:11]2[C:12](=[O:20])[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=3[CH2:19][C@@H:10]2[CH2:9]1)C1C=CC=CC=1.[H][H]>[Pd].CO>[CH3:23][C@@H:22]1[CH2:21][N:11]2[C:12](=[O:20])[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=3[CH2:19][C@@H:10]2[CH2:9][NH:8]1
Reactant: C[C@@H]1CN2C(=O)c3ccccc3C[C@@H]2CN1Cc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: C[C@@H]1CN2C(=O)c3ccccc3C[C@@H]2CN1
Yield: 99.6 %

Procedure:
(3R,11aR)-1,2,3,4,11,11a-Hexahydro-2-benzyl-3-methyl-pyrazino[1,2-b]isoquinolin-6-one (81 mg, 0.26 mmol) and 10% palladium on carbon (25 mg) in methanol (6.5 ml) was stirred under a balloon of hydrogen for 19 h. Evapoaration of the filtrate after filtration through Celite® afforded pure (3R,11aR)-1,2,3,4,11,11a-hexahydro-3-methyl-pyrazino[1,2-b]isoquinolin-6-one (56 mg, 83% yield). MS (ESI) 217 (M+H).
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[CH2:13][CH:12]([CH2:17][CH2:18][CH3:19])[CH2:11][CH2:10]2)(=O)=O.[F:22][C:23]1[CH:24]=[C:25](OB(O)O)[CH:26]=[C:27]([F:30])[C:28]=1[F:29].FC1C=C(Br)C=C(F)C=1F.[Mg].COB(OC)OC.Cl.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>CN(C)C=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[CH2:17]([CH:12]1[CH2:11][CH2:10][C:9]2[C:14](=[CH:15][CH:16]=[C:7]([C:25]3[CH:24]=[C:23]([F:22])[C:28]([F:29])=[C:27]([F:30])[CH:26]=3)[CH:8]=2)[CH2:13]1)[CH2:18][CH3:19]
Reactant: OB(O)Oc1cc(F)c(F)c(F)c1
Reactant: CCCC1CCc2cc(OS(=O)(=O)C(F)(F)F)ccc2C1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: COB(OC)OC
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: CCCC1CCc2cc(-c3cc(F)c(F)c(F)c3)ccc2C1
Temperature: 80 °C
Reaction time: 10 h
Yield: 13.9 %

Procedure:
A mixture of 3.8 g of the produced 2-propyl-1,2,3,4-tetrahydronaphthalen-6-yl trifluoromethanesulfonate, 3.0 g of 3,4,5-trifluorophenylboric acid (this compound was produced by reacting a Grignard reagent prepared from 3,4,5-trifluorobromobenzene and magnesium, with trimethoxy borane, and then performing a hydrolysis with dilute hydrochloric acid), 0.13 g of tetrakis(triphenylphosphine)palladium(0), and 3.6 g of potassium phosphate in 20 ml of dimethyl formamide (DMF) was stirred for 10 hours at 80° C. The mixture was subsequently cooled to room temperature, 20 ml of water was added, the mixture was extracted with toluene, and the organic layer was washed subsequently with water and then a saturated aqueous solution of sodium chloride, and subsequently dried over anhydrous sodium sulfate. The crude product obtained by removal of the solvent by evaporation was purified by silica gel column chromatography (hexane) and then recrystallized 3 times from ethanol to obtain 0.5 g of 2-propyl-6-(3,4,5-trifluorophenyl)-1,2,3,4-tetrahydronaphthalene.
Reaction SMILES: C(OC([NH:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([CH3:22])([CH3:21])[C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:11][C:10]=1[C:23](=O)[C:24]([N:26]1[CH2:34][C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH2:27]1)=[O:25])=O)(C)(C)C.[F-].[Cs+].C[Si]([N:42]=[C:43]=[N:44][Si](C)(C)C)(C)C.Cl.C(=O)(O)[O-]>C(#N)C>[NH2:42][C:43]1[N:44]=[C:23]([C:24]([N:26]2[CH2:27][C:28]3[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH2:34]2)=[O:25])[C:10]2[C:9](=[CH:14][CH:13]=[C:12]([C:15]([CH3:21])([CH3:22])[C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:11]=2)[N:8]=1
Reactant: C[Si](C)(C)N=C=N[Si](C)(C)C
Reactant: CCOC(=O)C(C)(C)c1ccc(NC(=O)OC(C)(C)C)c(C(=O)C(=O)N2Cc3ccccc3C2)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Cs+]
Solvent: CC#N
Product: CCOC(=O)C(C)(C)c1ccc2nc(N)nc(C(=O)N3Cc4ccccc4C3)c2c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
3.2 g of ethyl 2-[4-(tert-butoxycarbonylamino)-3-(2-isoindolin-2-yl-2-oxoacetyl)phenyl]-2-methylpropanoate are dissolved in 100 ml of acetonitrile under argon. 1.012 g of caesium fluoride and 1.81 ml of bis(trimethylsilyl)carbodiimide are added to the solution. The mixture is stirred at room temperature for 15 min, and 14 ml of hydrochloric acid (1N) are then added, and the mixture is neutralised using bicarbonate. The aqueous phase is washed three times with 100 ml of ethyl acetate each time. The combined organic phases are dried over sodium sulfate, filtered and evaporated to dryness in vacuo.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[C:11](=[O:15])[N:10]([C:16]1[C:17]([CH2:49][OH:50])=[C:18]([N:22]3[CH:26]=[C:25]([C:27]#[N:28])[C:24]([NH:29]C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)=[N:23]3)[CH:19]=[CH:20][CH:21]=1)[N:9]=[CH:8]2)([CH3:4])([CH3:3])[CH3:2].CO.Cl>CCOCC>[NH2:29][C:24]1[C:25]([C:27]#[N:28])=[CH:26][N:22]([C:18]2[CH:19]=[CH:20][CH:21]=[C:16]([N:10]3[N:9]=[CH:8][C:7]4[C:12](=[CH:13][CH:14]=[C:5]([C:1]([CH3:2])([CH3:3])[CH3:4])[CH:6]=4)[C:11]3=[O:15])[C:17]=2[CH2:49][OH:50])[N:23]=1
Reactant: CC(C)(C)c1ccc2c(=O)n(-c3cccc(-n4cc(C#N)c(NC(c5ccccc5)(c5ccccc5)c5ccccc5)n4)c3CO)ncc2c1
Agent: Cl
Solvent: CCOCC
Solvent: CO
Product: CC(C)(C)c1ccc2c(=O)n(-c3cccc(-n4cc(C#N)c(N)n4)c3CO)ncc2c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 73.8 %

Procedure:
1-(3-(6-tert-butyl-1-oxophthalazin-2(1H)-yl)-2-(hydroxymethyl)phenyl)-3-(tritylamino)-1H-pyrazole-4-carbonitrile (382 mg 0.582 mmol) was dissolved in Et2O (30 mL) and cooled to 0° C. in. MeOH (2 mL) was added followed by saturated ethereal HCl (2 mL, prepared by bubbling HCl gas into 100 mL of ether). The reaction mixture was allowed to stir at 0° C. for 30 minutes, after which, it was judged to be complete by TLC. The volatiles were removed in vacuo and residue was partitioned between saturated aqueous NaHCO3 (100 mL) and EtOAc (100 mL) and stirred vigorously. The aqueous layer was separated and extracted with EtOAc (50 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo. The oily residue was bound to silica gel and the crude product was purified over a 25 g silica gel cartridge eluting the column with a 20-70% EtOAc/hexanes gradient to give 3-Amino-1-[3-(6-tert-butyl-1-oxo-1H-phthalazin-2-yl)-2-hydroxymethyl-phenyl]-1H-pyrazole-4-carbonitril (178 mg, 74%) as a white-powdery solid.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][N:5]=[C:4]2[N:12]([S:15]([C:18]3[CH:24]=[CH:23][C:21]([CH3:22])=[CH:20][CH:19]=3)(=[O:17])=[O:16])[CH:13]=[CH:14][C:3]=12.[NH2:25][CH:26]1[CH2:31][CH2:30][CH2:29][N:28]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:27]1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C([O-])([O-])=O.[Cs+].[Cs+]>C1(C)C=CC=CC=1.CC([O-])=O.CC([O-])=O.[Pd+2]>[C:35]([O:34][C:32]([N:28]1[CH2:29][CH2:30][CH2:31][CH:26]([NH:25][C:2]2[C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][N:5]=[C:4]3[N:12]([S:15]([C:18]4[CH:24]=[CH:23][C:21]([CH3:22])=[CH:20][CH:19]=4)(=[O:17])=[O:16])[CH:13]=[CH:14][C:3]=23)[CH2:27]1)=[O:33])([CH3:38])([CH3:36])[CH3:37]
Reactant: COC(=O)c1cnc2c(ccn2S(=O)(=O)c2ccc(C)cc2)c1Cl
Reactant: CC(C)(C)OC(=O)N1CCCC(N)C1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: Cc1ccccc1
Product: COC(=O)c1cnc2c(ccn2S(=O)(=O)c2ccc(C)cc2)c1NC1CCCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Yield: 46.7 %

Procedure:
To a solution of methyl 4-chloro-1-tosyl-1H-pyrrolo[2,3-b]pyridine-5-carboxylate (1 g, 2.7 mmol, 1.0 eq) and tert-butyl 3-aminopiperidine-1-carboxylate (659 mg, 3.3 mmol, 1.2 eq) in PhCH3 (20 mL) was added Pd(OAc)2 (65 mg, 0.27 mmol, 0.1 eq), xantphos (250 mg, 0.41 mmol, 0.15 eq) and. Cs2CO3 (2.64 g, 8.1 mmol, 3.0 eq) and the mixture was heated at 100° C. for 16 h. After cooling to rt, the mixture was filtered and the filtrate was concentrated in vacuo to afford an oil which was purified by silica gel column chromatography (PE/EA=8:1) to give the title compound as white solid (667 mg, yield: 46%). 1H NMR (400 MHz, CDCl3) δ: 8.91 (d, 1H), 8.72 (s, 1H), 7.96 (d, 2H), 7.45 (d, 1H), 7.18 (d, 2H), 3.77 (s, 3H), 3.67-3.57 (m, 1H), 3.13-2.97 (m, 2H), 2.29 (s, 3H), 1.98-1.96 (m, 2H), 1.83-1.67 (m, 2H), 1.64-1.46 (m, 3H), 1.40-1.25 (m, 9H). ESI-MS (M+H)+: 529.20.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([N:26]3[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]3)=[CH:22][CH:21]=2)[S:5][C:6]=1[C:7]([C:9]1[CH:14]=[CH:13][C:12](Cl)=[C:11]([N+:16]([O-:18])=[O:17])[CH:10]=1)=[O:8].[NH:33]1[CH2:37][CH2:36][CH2:35][CH2:34]1>>[NH2:1][C:2]1[N:3]=[C:4]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([N:26]3[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]3)=[CH:22][CH:21]=2)[S:5][C:6]=1[C:7]([C:9]1[CH:14]=[CH:13][C:12]([N:33]2[CH2:37][CH2:36][CH2:35][CH2:34]2)=[C:11]([N+:16]([O-:18])=[O:17])[CH:10]=1)=[O:8]
Reactant: CN1CCN(c2ccc(Nc3nc(N)c(C(=O)c4ccc(Cl)c([N+](=O)[O-])c4)s3)cc2)CC1
Reactant: C1CCNC1
Product: CN1CCN(c2ccc(Nc3nc(N)c(C(=O)c4ccc(N5CCCC5)c([N+](=O)[O-])c4)s3)cc2)CC1

Procedure:
This compound was prepared from the compound of Example 15 and pyrrolidine by the procedure used in Example 57. Mass spectrum (ES) MH+=508.
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[C:13](O)(=[O:20])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19].N1C=CC=CC=1.[CH3:28][C:29]1([CH3:37])[O:36][C:34](=[O:35])[CH2:33][C:31](=[O:32])[O:30]1>ClCCl>[CH3:28][C:29]1([CH3:37])[O:36][C:34](=[O:35])[CH:33]([C:13](=[O:20])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[C:31](=[O:32])[O:30]1
Reactant: CCCCCCC(=O)O
Reactant: CC1(C)OC(=O)CC(=O)O1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCCCCC(=O)C1C(=O)OC(C)(C)OC1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Carbonyldiimidazole (71.7 g, 0.442 mol) was added portionwise to a stirred solution of heptanoic acid (0.402 mol) in 300 mL of dry dichloromethane. The resulting mixture was stirred at room temperature for 2 hours. A solution of pyridine (35.8 mL, 0.442 mol) and Meldrum's acid (63.7 g, 0.442 mol) in 150 mL of dry dichloromethane were added over a period of 2 hours to the reaction mixture. The reaction mixture was stirred for 16 hours, quenched with 400 mL of 2N HCl (bubbling), separated, washed sequentially with 2×400 mL 2N HCl, brine (400 mL), dried (MgSO4), and the solvent was removed in vacuo to give the title compound as aviscous oil. The crude product was used in the next step after spectral characterization.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][CH3:9])[N:5]=[C:4]([NH:10][CH2:11][CH:12]2[CH2:16][C:15]3[CH:17]=[CH:18][CH:19]=[CH:20][C:14]=3[O:13]2)[CH:3]=1.[C:21]([C:24]([C:27]1[CH:28]=[C:29](B(O)O)[CH:30]=[CH:31][CH:32]=1)([CH3:26])[CH3:25])([OH:23])=[O:22].C([O-])([O-])=O.[Cs+].[Cs+]>COCCOC.O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[O:13]1[C:14]2[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=2[CH2:16][CH:12]1[CH2:11][NH:10][C:4]1[N:5]=[C:6]([O:8][CH3:9])[N:7]=[C:2]([C:29]2[CH:28]=[C:27]([C:24]([CH3:26])([CH3:25])[C:21]([OH:23])=[O:22])[CH:32]=[CH:31][CH:30]=2)[CH:3]=1
Reactant: CC(C)(C(=O)O)c1cccc(B(O)O)c1
Reactant: COc1nc(Cl)cc(NCC2Cc3ccccc3O2)n1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: COCCOC
Product: COc1nc(NCC2Cc3ccccc3O2)cc(-c2cccc(C(C)(C)C(=O)O)c2)n1
Temperature: 85 °C
Yield: 58.1 %

Procedure:
A mixture of (6-chloro-2-methoxy-pyrimidin-4-yl)-(2,3-dihydro-benzofuran-2-ylmethyl)-amine (167 mg, 0.57 mmol), 3-(1-carboxy-1-methyl-ethyl)-phenyl-boronic acid (155 mg, 0.75 mmol), and Cs2CO3 (0.46 g, 1.43 mmol) in ethylene glycol dimethyl ether (8 mL) and water (2 mL) is degassed by bubbling with Ar gas for 5 minutes, and treated with tetrakis(triphenylphosphine) palladium (0) (33 mg, 0.03 mmol) at room temperature. The mixture is heated at 85° C. for 3 h. The mixture is diluted with H2O (20 mL), and extracted with EtOAc (10 mL). The aqueous layer is separated, acidified to pH 2.5 with 1M HCl solution, and extracted with EtOAc (2×10 mL). The extracts are dried (MgSO4), filtered through a short pad of SiO2 to afford 2-(3-{6-[(2,3-dihydro-benzofuran-2-ylmethyl)-amino]-2-methoxy-pyrimidin-4-yl}-phenyl)-2-methyl-propionic acid (139 mg, Example 90). LCMS: RT=2.05 minutes; MS: 420 (M+H); 1H NMR (300 MHz, DMSO-d6) □12.4 (1H, s), 8.05-7.8 (2H, m), 7.5-7.1 (5H, m), 6.8-6.75 (2H, m), 5 (1H, s), 4 (3H, brs), 3.65 (2H, brs), 3.4-2.95 (2H, m), 1.48 (6H, s).