Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:6]([C:7]([C:9]2[C:10]([CH3:18])=[C:11]([N+:15]([O-:17])=[O:16])[CH:12]=[CH:13][CH:14]=2)=[O:8])=[CH:5][CH:4]=1.[CH3:21][N:22]([CH:24](OC)OC)[CH3:23]>CN(C=O)C>[CH3:21][N:22]([CH3:24])[CH:23]=[CH:18][C:10]1[C:9]([C:7](=[O:8])[C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:20][CH:19]=2)=[CH:14][CH:13]=[CH:12][C:11]=1[N+:15]([O-:17])=[O:16]
Reactant: COc1ccc(C(=O)c2cccc([N+](=O)[O-])c2C)cc1
Reactant: COC(OC)N(C)C
Solvent: CN(C)C=O
Product: COc1ccc(C(=O)c2cccc([N+](=O)[O-])c2C=CN(C)C)cc1
Yield: 91.9 %

Procedure:
A solution of 97.9 g (0.36 mole) of 3-(4-methoxybenzoyl)-2-methylnitrobenzene and 191 ml (1.45 mole) of DMF dimethyl acetal in 400 ml of DMF was heated under reflux for about nineteen hours and the reaction mixture then taken to dryness in vacuo to give 108 g of 2-(2-dimethylaminoethenyl)-3-(4-methoxybenzoyl)nitrobenzene as a red oil.
Reaction SMILES: CN(C)C[CH2:4][CH2:5][NH:6][C:7]([N:9]1[CH2:14][CH2:13][N:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:11][CH2:10]1)=[O:8].C(N1C=CN=C1)(N1C=CN=C1)=O.NCC[N:37]1[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]1.C1(N2CCNCC2)C=CC=CC=1>O1CCCC1>[C:15]1([N:12]2[CH2:11][CH2:10][N:9]([C:7]([NH:6][CH2:5][CH2:4][N:37]3[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]3)=[O:8])[CH2:14][CH2:13]2)[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: NCCN1CCCCC1
Reactant: CN(C)CCCNC(=O)N1CCN(c2ccccc2)CC1
Agent: O=C(n1ccnc1)n1ccnc1
Agent: c1ccc(N2CCNCC2)cc1
Solvent: C1CCOC1
Product: O=C(NCCN1CCCCC1)N1CCN(c2ccccc2)CC1
Yield: 24 %

Procedure:
This compound was prepared according to the procedure used to synthesize the compound of Example 5. A mixture of 5.7 g (0.035 mole) of 1,1'-carbonyldiimidazole, 4.4 g (0.034 mole) of N-(2-aminoethyl)piperidine and 4.9 g (0.03 mole) of 1-phenylpiperazine in a total of 200 ml of tetrahydrofuran gave 2.3 g (24%) of title compound as a white solid, m.p. 64°-67° C. after recrystallization from diethyl ether.
Reaction SMILES: [NH2:1][C:2]1[O:6][N:5]=[C:4]([CH2:7][CH3:8])[CH:3]=1.[Br:9]N1C(=O)CCC1=O>>[NH2:1][C:2]1[O:6][N:5]=[C:4]([CH2:7][CH3:8])[C:3]=1[Br:9]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCc1cc(N)on1
Product: CCc1noc(N)c1Br

Procedure:
5-Amino-4-bromo-3-ethylisoxazole was prepared from 5-amino-3ethylisoxazole and N-bromosuccinimide as described in Example 1a.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[C:5]=2[N:6]=1.[CH3:12][O:13][CH2:14][C:15](Cl)=[O:16]>N1C=CC=CC=1>[CH3:12][O:13][CH2:14][C:15]([NH:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[C:5]=2[N:6]=1)=[O:16]
Reactant: COCC(=O)Cl
Reactant: Cc1cccc2sc(N)nc12
Solvent: c1ccncc1
Product: COCC(=O)Nc1nc2c(C)cccc2s1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2-Amino-4-methylbenzothiazole (4.9 g) is dissolved in pyridine (100 ml) and thereto is added dropwise methoxyacetyl chloride (3.0 ml) at room temperature. After the mixture is stirred at room temperature for 2 hours, the solvent is distilled off. The resulting oil is solidified with addition of water. The obtained solids are filtered off and washed with water, then with diethyl ether, dried and recrystallized from ethanol to give the title compound (5.2 g) having the following physical properties.
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH:7]=O)=[N:5][C:4]([N:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)=[N:3]1.[C:14](=O)([O-])[O-].[K+].[K+].[N+](=C(P(=O)(OC)OC)C(=O)C)=[N-]>CO.C(OCC)C>[C:7]([C:6]1[N:2]([CH3:1])[N:3]=[C:4]([N:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)[N:5]=1)#[CH:14]
Reactant: O=C([O-])[O-]
Reactant: Cn1nc(N2CCCC2)nc1C=O
Agent: COP(=O)(OC)C(=[N+]=[N-])C(C)=O
Agent: [K+]
Solvent: CO
Solvent: CCOCC
Product: C#Cc1nc(N2CCCC2)nn1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 36.1 %

Procedure:
To a stirred mixture of 1-methyl-3-(pyrrolidin-1-yl)-1H-1,2,4-triazole-5-carbaldehyde (2.06 g, 11.4 mmol) and potassium carbonate (3.16 g, 22.9 mmol) at room temperature in methanol (75 ml) under an argon atmosphere was added drop wise a solution of dimethyl 1-diazo-2-oxopropylphosphonate (2.64 g, 2.1 ml, 13.7 mmol) in methanol (15 ml). Stirring at room temperature was then continued for 3 h. The mixture was diluted with diethyl ether and washed with 10% NaHCO3 solution. The aqueous phase was extracted with diethyl ether. The combined organic layers were washed with H2O and brine, dried over MgSO4, filtered and concentrated. The crude product was purified by silica gel chromatography using a CH2Cl2MeOH gradient as eluent, providing the title compound (725 mg, 36%) as off-white solid. MS: m/z=177.2 (M+H+)
Reaction SMILES: [Si:1]([O:18][CH2:19][CH2:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([N+:28]([O-])=O)=[CH:24][N:23]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H]>CO.[Pd]>[NH2:28][C:25]1[CH:26]=[CH:27][C:22]([O:21][CH2:20][CH2:19][O:18][Si:1]([C:14]([CH3:17])([CH3:16])[CH3:15])([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:23][CH:24]=1
Reactant: [H][H]
Reactant: CC(C)(C)[Si](OCCOc1ccc([N+](=O)[O-])cn1)(c1ccccc1)c1ccccc1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)[Si](OCCOc1ccc(N)cn1)(c1ccccc1)c1ccccc1
Yield: 100.9 %

Procedure:
Compound B (106 g) was dissolved in methanol (1.35 l) and hydrogenated at atmospheric pressure over 10% palladium on charcoal catalyst (10.6 g). When hydrogen uptake was complete, the catalyst was removed by filtration through diatomaceous earth. Volatile material was then removed from the filtrate by evaporation to give 5-amino-2-[2-(t-butyldiphenylsilyl)oxyethoxy]pyridine (C) (99.4 g), as an oil which was used without further purification; NMR (d6 -DMSO): 0.95(s,9H), 3.9(t,2H), 4.25(t,2H), 4.7(brs,2H), 6.5(d,1H), 7.0(dd,1H), 7.35-7.75 (complex m,7H), 7.6-7.75(m,4H).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([S:8][CH3:9])[N:3]=1.C(N(CC)CC)C.[C:17]([C:19]1[CH:24]=[CH:23][N:22]=[C:21]([S:25][CH3:26])[N:20]=1)#[CH:18].C(OCC)(=O)C>O1CCCC1.[Cu]I.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.O>[CH3:9][S:8][C:4]1[N:3]=[C:2]([C:18]#[C:17][C:19]2[CH:24]=[CH:23][N:22]=[C:21]([S:25][CH3:26])[N:20]=2)[CH:7]=[CH:6][N:5]=1
Reactant: C#Cc1ccnc(SC)n1
Reactant: CSc1nccc(I)n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CSc1nccc(C#Cc2ccnc(SC)n2)n1
Yield: 69.3 %

Procedure:
4-Iodo-2-(methylsulfanyl)pyrimidine (1.76 g, 7.1 mmol) was dissolved in anhydrous tetrahydrofuran (50 mL). To this solution was added triethylamine (1.2 mL, 8.5 mmol), copper (I) iodide (70 mg, 0.4 mmol) and dichlorobis(triphenylphosphine)palladium (II) (150 mg, 0.21 mmol). A solution of 4-ethynyl-2-(methylsulfanyl)pyrimidine (1.0 g, 7.1 mmol) in tetrahydrofuran was added dropwise. The reaction mixture was stirred at room temperature overnight Ethyl acetate and water were added to the reaction mixture. The phases were separated and the aqueous phase extracted with additional ethyl acetate. The organics were combined, dried over magnesium sulfate, filtered and concentrated. Purification by silica gel chromatography (1:1 ethyl acetate:hexane) gave 1.35 g (69%) of 2-(methylsulfanyl)-4-{[2-(methylsulfanyl)-4-pyrimidinyl]ethynyl}pyrimidine as a white solid. 1H NMR (CDCl3): δ 8.57 (d, 2H), 7.19 (d, 2H), 2.59 (s, 6H); MS m/z 275 (M+1).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH3:9])[N+:5]([O-:8])=[CH:6][CH:7]=1.[F:10][C:11]1[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:12]=1[OH:18].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C(=O)C>[F:10][C:11]1[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:12]=1[O:18][C:2]1[CH:3]=[C:4]([CH3:9])[N+:5]([O-:8])=[CH:6][CH:7]=1
Reactant: Cc1cc(Cl)cc[n+]1[O-]
Reactant: Oc1ccc(F)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: Cc1cc(Oc2ccc(F)cc2F)cc[n+]1[O-]
Temperature: 140 °C

Procedure:
4.3 g (30 mmol) of 4-chloro-2-picoline-N-oxide are added to a mixture of 4.6 g (35 mmol) of 2,4-difluorophenol in 25 ml of N,N-dimethylacetamide and 4.9 g (35 mmol) of finely powdered potassium carbonate and the mixture is warmed to 140° C. for 3 hours with stirring. After cooling, the reaction mixture is poured into 250 ml of water, extracted three times using dichloromethane, and the organic phases are dried over MgSO4 and concentrated. The residue is taken up in dichloromethane and extracted by shaking with saturated aqueous NaCl solution. After drying and freeing from solvent, the extract is brought to crystallization using diisopropyl ether and washed with ethyl acetate. Colorless crystals, m.p. 112°-124° C.
Reaction SMILES: [S:1]1[C:5]([CH:6](O)[C:7]2[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=2)=[CH:4][C:3]2[CH:16]=[CH:17][CH:18]=[CH:19][C:2]1=2.C([SiH](CC)CC)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:14][O:13][C:10]1[CH:9]=[CH:8][C:7]([CH2:6][C:5]2[S:1][C:2]3[CH:19]=[CH:18][CH:17]=[CH:16][C:3]=3[CH:4]=2)=[CH:12][CH:11]=1
Reactant: COc1ccc(C(O)c2cc3ccccc3s2)cc1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc(Cc2cc3ccccc3s2)cc1

Procedure:
2-(4-methyoxybenzyl)-benzo[b]thiophene was prepared by the method of Example 47B with a-(2-benzo[b]thienyl)-4-methoxybenzyl alcohol (1.9 mmoles) 0.50 g), triethylsilane (2.0 mmoles, 0.32 mls), CH2Cl2 (20 ml) and TFA (3.7 mmoles, 0.30 ml). Recrystallization with hexanes and chloroform provided 0.40 (85%) of a pink solid.
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][OH:26])=[C:4]([NH:8][C:9]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=2[Cl:19])=S)[CH:5]=[CH:6][CH:7]=1.Cl.C(N=C=NCCCN(C)C)C>O1CCCC1.C(OCC)(=O)C>[NH2:1][C:2]1[C:3]2[N:20]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][OH:26])[C:9]([NH:11][C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=3[Cl:19])=[N:8][C:4]=2[CH:5]=[CH:6][CH:7]=1
Reactant: Nc1cccc(NC(=S)Nc2ccc(Cl)cc2Cl)c1NCCCCCO
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Nc1cccc2nc(Nc3ccc(Cl)cc3Cl)n(CCCCCO)c12
Yield: 60.7 %

Procedure:
To a solution of N-{3-amino-2-[(5-hydroxypentyl)amino]phenyl}-N′-(2,4-dichlorophenyl)thiourea (Reference Example 111; 554 mg, 1.34 mmol) in tetrahydrofuran (15 mL) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (771 mg, 4.02 mmol) at room temperature. The resultant mixture was stirred at 40° C. for 2.5 hr. The reaction mixture was diluted with ethyl acetate, washed with water and brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 30-90% ethyl acetate/n-hexane gradient mixture to give the title compound as an oil (308 mg, 0.813 mmol, 61%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][C:7]2[C:12]([C:13]=1[OH:14])=[N:11][CH:10]=[CH:9][CH:8]=2)([O-])=O.[OH-].[NH4+]>[Pt].CO>[NH2:1][C:4]1[CH:5]=[N:6][C:7]2[C:12]([C:13]=1[OH:14])=[N:11][CH:10]=[CH:9][CH:8]=2
Reactant: O=[N+]([O-])c1cnc2cccnc2c1O
Agent: [Pt]
Agent: [NH4+]
Agent: [OH-]
Solvent: CO
Product: Nc1cnc2cccnc2c1O
Reaction time: 6 h
Yield: 96.5 %

Procedure:
A mixture containing 3-nitro[1,5]naphthyridin-4-ol (7.5 g), methanol (200 mL), ammonium hydroxide (50 mL) and 5% platinum on carbon (0.75 g) was placed on a Parr apparatus for 6 hours. The reaction mixture was filtered to remove catalyst and then filtered a second time using Celite® filter aid. The filtrate was concentrated under vacuum to provide 6.1 g of 3-amino[1,5]naphthyridin-4-ol as a brown solid.
Reaction SMILES: BrC1C=CC([C:8]2[CH:20]=[CH:19][C:11]3[O:12][C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=4[C:10]=3[CH:9]=2)=CC=1.[Br:21][C:22]1[CH:34]=[CH:33][C:32]2[C:31]3[C:26](=[CH:27][C:28](I)=[CH:29][CH:30]=3)[C:25]([CH3:37])([CH3:36])[C:24]=2[CH:23]=1>>[Br:21][C:22]1[CH:23]=[C:24]2[C:32]([C:31]3[CH:30]=[CH:29][C:28]([C:8]4[CH:20]=[CH:19][C:11]5[O:12][C:13]6[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=6[C:10]=5[CH:9]=4)=[CH:27][C:26]=3[C:25]2([CH3:37])[CH3:36])=[CH:33][CH:34]=1
Reactant: Brc1ccc(-c2ccc3oc4ccccc4c3c2)cc1
Reactant: CC1(C)c2cc(Br)ccc2-c2ccc(I)cc21
Product: CC1(C)c2cc(Br)ccc2-c2ccc(-c3ccc4oc5ccccc5c4c3)cc21

Procedure:
2-(7-bromo-9,9-dimethylfluoren-2-yl)dibenzofuran was synthesized in the same manner as in the synthesis of 2-(4-bromophenyl)dibenzofuran except that 2-bromo-7-iodo-9,9-dimethylfluorene was used instead of 4-bromoiodobenzene.
Reaction SMILES: C([O:3][C:4](=O)[CH:5]([N:12]1[C:16]2[CH:17]=[C:18]([F:22])[C:19]([F:21])=[CH:20][C:15]=2[N:14]=[C:13]1[C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=1)[CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1)C.[H-].[Al+3].[Li+].[H-].[H-].[H-].C(OCC)(=O)C>O1CCCC1>[Cl:29][C:26]1[CH:27]=[CH:28][C:23]([C:13]2[N:12]([CH:5]([CH:6]3[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11]3)[CH2:4][OH:3])[C:16]3[CH:17]=[C:18]([F:22])[C:19]([F:21])=[CH:20][C:15]=3[N:14]=2)=[CH:24][CH:25]=1
Reactant: CCOC(=O)C(C1CCCCC1)n1c(-c2ccc(Cl)cc2)nc2cc(F)c(F)cc21
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: OCC(C1CCCCC1)n1c(-c2ccc(Cl)cc2)nc2cc(F)c(F)cc21
Yield: 67 %

Procedure:
To the solution of 1.0 g (2.3 mmol) [2-(4-chloro-phenyl)-5,6-difluoro-benzoimidazol-1-yl]-cyclohexyl-acetic acid ethyl ester in 20 mL tetrahydrofuran, 88 mg (2.3 mmol) lithium aluminium hydride were added. A slight warming occurred. After 15 min. the reaction mixture was poured on water and ethyl acetate, extracted, the aqueous phase extracted twice with ethyl acetate and the aqueous phase extracted twice with ethyl acetate. The combined organic layers were washed with brine, dried over magnesium sulfate and evaporated. The crude product was purified by silica gel column chromatography using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of n-heptane:ethyl acetate (100:0 to 100:40 v/v) to yield the title compound as an off-white solid (67%). MS (Turbo Spray): m/z=391.2 [M+H].
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[NH:10][CH:9]=[C:8]([C:14]#[N:15])[C:7]2=O)([O-:3])=[O:2].P(Cl)(Cl)([Cl:19])=O>>[Cl:19][C:7]1[C:6]2[C:11](=[CH:12][CH:13]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[N:10]=[CH:9][C:8]=1[C:14]#[N:15]
Reactant: N#Cc1c[nH]c2ccc([N+](=O)[O-])cc2c1=O
Reactant: O=P(Cl)(Cl)Cl
Product: N#Cc1cnc2ccc([N+](=O)[O-])cc2c1Cl

Procedure:
A mixture of 31.3 g (0.147 mol) of 6-nitro-4-oxo-1,4-dihydro-3-quinolinecarbonitrile and 160 mL of phosphorous oxychloride was refluxed for 5.5 h. The phosphorous oxychloride was removed in vacuo and the residue was poured over ice and neutralized with sodium bicarbonate. The product was collected, washed with water and dried in vacuo (50° C.). There was obtained 33.5 g of tan solid; solid: mass spectrum (electrospray, m/e): M+H 234.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][C:22]=1[NH:23][C:24]([NH:26][C:27]1[CH:32]=[C:31]([CH3:33])[CH:30]=[CH:29][C:28]=1[F:34])=[O:25])[O:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]([C:12]2[NH:16][CH:15]=[C:14]([C:17](O)=[O:18])[CH:13]=2)[CH:7]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.[CH2:68]([O:70][CH:71]([O:74][CH2:75][CH3:76])[CH2:72][NH2:73])[CH3:69]>CN(C=O)C.O>[CH2:68]([O:70][CH:71]([O:74][CH2:75][CH3:76])[CH2:72][NH:73][C:17]([C:14]1[CH:13]=[C:12]([C:8]2[CH:7]=[C:6]([O:5][C:4]3[CH:20]=[CH:21][C:22]([NH:23][C:24]([NH:26][C:27]4[CH:32]=[C:31]([CH3:33])[CH:30]=[CH:29][C:28]=4[F:34])=[O:25])=[C:2]([F:1])[CH:3]=3)[CH:11]=[CH:10][N:9]=2)[NH:16][CH:15]=1)=[O:18])[CH3:69]
Reactant: Cc1ccc(F)c(NC(=O)Nc2ccc(Oc3ccnc(-c4cc(C(=O)O)c[nH]4)c3)cc2F)c1
Reactant: CCOC(CN)OCC
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(CNC(=O)c1c[nH]c(-c2cc(Oc3ccc(NC(=O)Nc4cc(C)ccc4F)c(F)c3)ccn2)c1)OCC
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A mixture of 5-{4-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrole-3-carboxylic acid (500 mg, 1.08 mmol), HATU (456 mg, 1.20 mmol) and N,N-diisopropylethylamine (278 mg, 2.16 mmol) in anhydrous DMF (10 ml) was stirred at room temperature for 10 minutes, followed by addition of aminoacetaldehyde diethyl acetal (173 mg, 1.30 mmol). The mixture was stirred for another 10 minutes and poured into 100 ml of water. The precipitates were filtered, washed with water and dried in vacuo to give N-(2,2-diethoxyethyl)-5-{4-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrole-3-carboxamide as white solid. Yield: 550 mg, 88%.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([CH2:12][N:13]3[CH2:18][CH2:17][N:16]([CH2:19][C:20]#[CH:21])[CH2:15][C:14]3=[O:22])=[CH:9][CH:10]=2)[N:5]=[CH:4][N:3]=1.[C:23]([O:27][C:28](=[O:37])[NH:29][C:30]1[CH:35]=[CH:34][N:33]=[CH:32][C:31]=1I)([CH3:26])([CH3:25])[CH3:24].CCN(CC)CC>CN(C=O)C.CCOC(C)=O.O.[Cu]I>[C:23]([O:27][C:28](=[O:37])[NH:29][C:30]1[CH:35]=[CH:34][N:33]=[CH:32][C:31]=1[C:21]#[C:20][CH2:19][N:16]1[CH2:17][CH2:18][N:13]([CH2:12][C:8]2[CH:7]=[C:6]3[C:11]([C:2]([NH2:1])=[N:3][CH:4]=[N:5]3)=[CH:10][CH:9]=2)[C:14](=[O:22])[CH2:15]1)([CH3:26])([CH3:24])[CH3:25]
Reactant: C#CCN1CCN(Cc2ccc3c(N)ncnc3c2)C(=O)C1
Reactant: CC(C)(C)OC(=O)Nc1ccncc1I
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Nc1ccncc1C#CCN1CCN(Cc2ccc3c(N)ncnc3c2)C(=O)C1
Temperature: 25 °C
Reaction time: 5 h
Yield: 36 %

Procedure:
A solution containing 1-(4-amino-quinazolin-7-ylmethyl)-4-prop-2-ynyl-piperazin-2-one (100 mg, 0.34 mmol), EXAMPLE 283, (3-iodo-pyridin-4-yl)-carbamic acid tert-butyl ester, EXAMPLE 69, Part B, (108 mg, 0.34 mmol), Et3N (140 mg, 1.36 mmol), (Ph3P)4PdCl2 (12 mg, 0.017 mmol), and CuI (2 mg, 0.01 mmol) in anhydrous DMF (5 mL) is stirred at ambient temperature. After 5 h, the reaction mixture is diluted with EtOAc (50 mL) and water (50 mL) and the layers are separated. The aqueous layer is extracted twice with EtOAc (25 mL) and the combined organic phase is washed with brine, dried over anhydrous Na2SO4, filtered and concentrated. The crude residue is purified by flash silica gel chromatography (CH2Cl2 to 10% MeOH CH2Cl2) to provide 59 mg (36%) of the title compound as a colorless oil. 1H NMR (300 MHz, CDCl3) δ1.49 (s, 9H), 2.84 (m, 2H), 3.35 (m, 2H), 3.44 (s, 2H), 3.71 (s, 2H), 4.75 (s, 2H), 6.19 (br s, 2H), 7.24 (d, J=5.5 Hz, 1H), 7.41 (d, J=8.4 Hz, 1H), 7.66 (s, 1H), 7.79 (d, J=8.4 Hz, 1H), 8.05 (d, J=5.5 Hz, 1H), 8.37 (s, 1H), 8.49 (s, 1H), 8.58 (s, 1H) ppm; MS (ISP loop): m/z 488 (M+H).
Reaction SMILES: [C:1]([NH:4][CH:5]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[CH:10]([CH3:17])[C:9]2[CH:18]=[CH:19][CH:20]=[CH:21][C:8]=2[CH2:7][CH2:6]1)(=[O:3])[CH3:2].O1CCC[CH2:23]1.C1(C(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CI>C1(C)C=CC=CC=1.O>[C:1]([N:4]([CH:5]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[CH:10]([CH3:17])[C:9]2[CH:18]=[CH:19][CH:20]=[CH:21][C:8]=2[CH2:7][CH2:6]1)[CH3:23])(=[O:3])[CH3:2]
Reactant: CC(=O)NC1CCc2ccccc2C(C)c2ccccc21
Reactant: C1CCOC1
Solvent: c1ccc(C(c2ccccc2)c2ccccc2)cc1
Solvent: CI
Solvent: Cc1ccccc1
Product: CC(=O)N(C)C1CCc2ccccc2C(C)c2ccccc21
Temperature: 0 °C
Reaction time: 2 h

Procedure:
18.1 g. (64.9 mmole) of 5-(N-acetylamino)-12-methyl-5,6,7,12-tetrahydrodibenzo[a,d]cyclooctene in 200 ml. of dry tetrahydrofuran was treated with 0.3 g. of triphenylmethane and stirred in an ice bath under nitrogen. The amide solution was added dropwise from the addition funnel at a rate sufficiently slow to maintain the reaction temperature below 15° C., until the color of the triphenylmethide anion persisted. The mixture was stirred for 15 minutes in the ice bath, then treated with 20 ml. (45.6 g., 314 mmole) of methyliodide added rapidly (<5 min). The resulting solution was stirred for 2 hours, with the temperature held below 30° C. by ice cooling as necessary, then treated with 30 ml. of water. Nitrogen was bubbled through the mixture overnight, and the remaining liquid evaporated in vacuo. The residue was treated with 300 ml. of water and extracted three times with chloroform. The chloroform extracts were washed once with dilute sodium bisulfite solution and twice with water, dried over potassium carbonate, filtered, and evaporated in vacuo to 33 g. of red oil. The oil was washed four times with petroleum ether and evaporated in vacuo to give 16.0 g. of foam which was dissolved in 10 ml. of warm toluene, diluted with 250 ml. of diethyl ether, and refrigerated overnight to precipitate unreacted starting amide. The solution was filtered and the filtrate was evaporated in vacuo to give 5-(N-acetyl-N-methylamino)-12-methyl-5,6,7,12-tetrahydrodibenzo[a,d]cyclooctene, (10.5 g.) as an orange oil.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14](=[O:30])[NH:15][CH2:16][C@H:17]([OH:29])[CH2:18][N:19]2[CH2:28][CH2:27][C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:20]2)[CH:9]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:7][C:8]1[CH:9]=[C:10]([CH:11]=[CH:12][CH:13]=1)[C:14]([NH:15][CH2:16][C@H:17]([OH:29])[CH2:18][N:19]1[CH2:28][CH2:27][C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:20]1)=[O:30]
Reactant: CC(C)(C)OC(=O)Nc1cccc(C(=O)NC[C@H](O)CN2CCc3ccccc3C2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1cccc(C(=O)NC[C@H](O)CN2CCc3ccccc3C2)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of (S)-tert-butyl-(3-((3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxyl propyl)carbamoyl)phenyl)carbamate (500 mg, 1.18 mmol) in DCM (8 mL) was added TFA (8 mL). The mixture was stirred at 25° C. for 16 h. The reaction solution was concentrated to give the crude title product that was used without further purification (400 mg). LCMS (m/z): 326.2 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]([O:10][CH3:11])=[O:9])[O:5][C:6]=1Br.[C:12]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C[Zn]Cl.[Cl-].[NH4+]>Cl[Pd]Cl.O1CCCC1>[Br:1][C:2]1[CH:3]=[C:4]([C:8]([O:10][CH3:11])=[O:9])[O:5][C:6]=1[CH3:12]
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: COC(=O)c1cc(Br)c(Br)o1
Agent: Cl[Pd]Cl
Agent: C[Zn]Cl
Agent: [Cl-]
Solvent: C1CCOC1
Product: COC(=O)c1cc(Br)c(C)o1
Temperature: 25 °C
Yield: 1830.4 %

Procedure:
To a mixture of the compound (1.80 g) obtained in Example 128a, palladium chloride(II) (0.02 g), triphenylphosphine (0.07 g) and tetrahydrofuran (30 mL) was added MeZnCl (2M tetrahydrofuran solution, 9.5 ml), and the mixture was heated under reflux for 4 hr under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, saturated aqueous ammonium chloride was added, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (carrier: silica gel, eluent: hexane ethyl acetate) to give the title compound (1.07 g) as a colorless solid.
Reaction SMILES: [O:1]=[C:2]1[NH:7][N:6]=[C:5]([C:8]([OH:10])=[O:9])[CH:4]=[CH:3]1.C(O[CH2:15][CH2:16][CH2:17][CH3:18])(=O)C.OS(O)(=O)=O>C(O)CCC>[O:1]=[C:2]1[NH:7][N:6]=[C:5]([C:8]([O:10][CH2:15][CH2:16][CH2:17][CH3:18])=[O:9])[CH:4]=[CH:3]1
Reactant: O=C(O)c1ccc(=O)[nH]n1
Reactant: CCCCOC(C)=O
Agent: O=S(=O)(O)O
Solvent: CCCCO
Product: CCCCOC(=O)c1ccc(=O)[nH]n1
Yield: 79.6 %

Procedure:
A mixture of 6-oxo-1,6-dihydropyridazine-3-carboxylic acid (117.24 g) [Ref: British Patent 856, 409], n-butyl acetate (293 ml), n-butanol (410 ml) and conc. H2SO4 (5.9 ml) was heated at reflux for 1 hour. The solvent was evaporated and the residue washed with n-butyl acetate to give n-butyl 6-oxo-1,6-dihydropyridazine-3-carboxylate (130.6 g, 79.6% yield), mpt 79-80° C.