Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[CH:11]=[CH:10][CH:9]=[N:8][C:6]=2[N:7]=1.NC1N=CC=CC=1C(O)=O.[C:23]([O:27][C:28]([N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1)=[O:29])([CH3:26])([CH3:25])[CH3:24].CCN(C(C)C)C(C)C.P(=O)(O)(O)O>C(O)C.CO>[C:23]([O:27][C:28]([N:30]1[CH2:35][CH2:34][N:33]([C:4]2[C:5]3[CH:11]=[CH:10][CH:9]=[N:8][C:6]=3[N:7]=[C:2]([Cl:1])[N:3]=2)[CH2:32][CH2:31]1)=[O:29])([CH3:26])([CH3:24])[CH3:25]
Reactant: Clc1nc(Cl)c2cccnc2n1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: Nc1ncccc1C(=O)O
Agent: O=P(O)(O)O
Solvent: CO
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCN(c2nc(Cl)nc3ncccc23)CC1
Temperature: 25 °C
Reaction time: 17 h
Yield: 40 %

Procedure:
A mixture of 2,4-dichloro-pyrido[2,3-d]pyrimidine (150 mg, 0.75 mmol, 1 eq) [prepared from 2-aminonicotinic acid by the methods of Robins et al. (J. Am. Chem. Soc. 1955, 77, 1045.) and Oakes et al. (J. Chem. Soc. 1956, 1045.)], N-t-butoxycarbonyl piperazine (147 mg, 0.787 mmol, 1.05 eq) and Hunig's base (0.39 mL, 2.25 mmol, 3 eq) in ethanol (2.5 mL) was stirred at rt for 17 hr. The white solid was collected by filtration, washed with water and cold ethanol, and dried to afford C1.1 (105 mg, 40% yield). LC/MS: 350.41 [M+H]+; HPLC: >95% at 1.44 min (Xterra 5 μm C18 column 4.6×30 mm, 10-90% aqueous methanol over 2 min containing 0.2% phosphoric acid, 5 mL/min, monitoring at 254 nm).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([N:9]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[C:10]2[CH:15]=[C:14](B3OC(C)(C)C(C)(C)O3)[CH:13]=[C:12]([N:25]([C:32]3[CH:37]=[C:36]([CH3:38])[CH:35]=[C:34]([CH3:39])[CH:33]=3)[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH:11]=2)[CH:5]=[C:6]([CH3:8])[CH:7]=1.Br[C:47]1[C:56]2[C:51](=[CH:52][CH:53]=[CH:54][CH:55]=2)[C:50]([Br:57])=[CH:49][CH:48]=1.C([O-])([O-])=O.[K+].[K+].C1COCC1>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>[Br:57][C:50]1[C:51]2[C:56](=[CH:55][CH:54]=[CH:53][CH:52]=2)[C:47]([C:14]2[CH:13]=[C:12]([N:25]([C:32]3[CH:33]=[C:34]([CH3:39])[CH:35]=[C:36]([CH3:38])[CH:37]=3)[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH:11]=[C:10]([N:9]([C:4]3[CH:5]=[C:6]([CH3:8])[CH:7]=[C:2]([CH3:1])[CH:3]=3)[C:40]3[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=3)[CH:15]=2)=[CH:48][CH:49]=1
Reactant: Brc1ccc(Br)c2ccccc12
Reactant: Cc1cc(C)cc(N(c2ccccc2)c2cc(B3OC(C)(C)C(C)(C)O3)cc(N(c3ccccc3)c3cc(C)cc(C)c3)c2)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(C)cc(N(c2ccccc2)c2cc(-c3ccc(Br)c4ccccc34)cc(N(c3ccccc3)c3cc(C)cc(C)c3)c2)c1

Procedure:
13.74 g of a product (yield: 68%) was obtained in the same manner as described in the synthesis method of intermediate 2-3 except that N1,N3-bis(3,5-dimethylphenyl)-N1,N3-diphenyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzene-1,3-diamine (17.84 g, 30 mmol), 1,4-dibromonaphthalene (9.44 g, 33 mmol), Pd(PPh3)4 (1.04 g, 0.9 mmol), K2CO3 (12.44 g, 90 mmol), THF (90 mL), and water (45 mL) were used.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:13])=[N:11][N:12]=2)=[CH:4][CH:3]=1.[N:14]1([CH2:19][C@@H:20]2[CH2:24][CH2:23][CH2:22][N:21]2[C:25]([C:27]2[CH:32]=[CH:31][C:30](B3OC(C)(C)C(C)(C)O3)=[CH:29][CH:28]=2)=[O:26])[CH2:18][CH2:17][CH2:16][CH2:15]1.C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.C(=O)([O-])[O-].[K+].[K+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(O)C>[CH3:13][C:10]1[O:9][C:8]([C:5]2[CH:6]=[CH:7][C:2]([C:30]3[CH:31]=[CH:32][C:27]([C:25]([N:21]4[CH2:22][CH2:23][CH2:24][CH:20]4[CH2:19][N:14]4[CH2:15][CH2:16][CH2:17][CH2:18]4)=[O:26])=[CH:28][CH:29]=3)=[CH:3][CH:4]=2)=[N:12][N:11]=1
Reactant: Cc1nnc(-c2ccc(Cl)cc2)o1
Reactant: CC1(C)OB(c2ccc(C(=O)N3CCC[C@H]3CN3CCCC3)cc2)OC1(C)C
Agent: [Pd+2]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: CC(=O)[O-]
Solvent: CCO
Product: Cc1nnc(-c2ccc(-c3ccc(C(=O)N4CCCC4CN4CCCC4)cc3)cc2)o1

Procedure:
Procedure D′: To a microwave reactor vessel, add 2-(4-Chloro-phenyl)-5-methyl-[1,3,4]oxadiazole (1.0 mmol; CAS (22815-98-1), (2-(S)-Pyrrolidin-1-ylmethyl-pyrrolidin-1-yl)-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-methanone (See Intermediate Preparation 23) (2.5 mmol), palladium (II) acetate (0.025 mmol), tricyclohexylphosphine (0.05 mmol), potassium carbonate (5.0 mmol) and ethanol (0.10M). Run the reaction in a CEM microwave reactor for four hours at 90° C. with 80 W power and cooling. After this time, wash the reaction with 1N hydrochloric acid while extracting with dichloromethane. Dry the organics with sodium sulfate, decant and concentrate in vacuo. Purify the title compound via radial chromatography eluting with 2M ammonia in methanol and dichloromethane. MS (m/e): 417.3 (M+1)
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:8]=[CH:9][C:10]=1C=O)=[O:4].[BH4-].[Na+].[CH3:21][OH:22]>>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([C:13]2[CH:14]=[CH:15][C:16]([CH2:21][OH:22])=[CH:17][CH:18]=2)[CH:8]=[CH:9][CH:10]=1)=[O:4]
Reactant: CO
Reactant: COC(=O)c1cc(-c2ccccc2)ccc1C=O
Agent: [BH4-]
Agent: [Na+]
Product: COC(=O)c1cccc(-c2ccc(CO)cc2)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a stirred mixture of 1.56 g (6.5 mmol.) 4-formyl-biphenyl-3-carboxylic acid methyl ester in 30 mL methanol at 0° C. was added 307 mg (8.1 mmol.) sodium borohydride. The mixture was stirred at 0° C. for 1 hour, then quenched with saturated ammonium chloride solution. The mixture was poured into water and extracted with ethyl acetate. The ethyl acetate extracts were combined, washed successively with water, brine then dried (MgSO4) and concentrated in vacuo to yield an oil. Chromatography on Silica Gel eluting with ethyl acetate/hexanes (1:5) afforded 1.5 g 4′-hydroxymethyl-biphenyl-3-carboxylic acid methyl ester as an oil.
Reaction SMILES: C(NC(C)(C)C1C=CC(I)=CC=1)=O.C(NC(CC)(CC)C1C=CC(I)=CC=1)=O.C(NC(CCC)(CCC)C1C=CC(I)=CC=1)=O.[CH:46]([NH:48][C:49]([CH2:66]C)([CH2:64]C)[C:50]1[CH:55]=[CH:54][C:53]([C:56]#[C:57][C:58]2[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=2)=[CH:52][CH:51]=1)=[O:47].C(NC(CCC)(CCC)C1C=CC(C#CC2C=CC=CC=2)=CC=1)=O>>[CH:46]([NH:48][C:49]([CH3:66])([CH3:64])[C:50]1[CH:55]=[CH:54][C:53]([C:56]#[C:57][C:58]2[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=2)=[CH:52][CH:51]=1)=[O:47]
Reactant: CCC(CC)(NC=O)c1ccc(C#Cc2ccccc2)cc1
Agent: CC(C)(NC=O)c1ccc(I)cc1
Agent: CCC(CC)(NC=O)c1ccc(I)cc1
Agent: CCCC(CCC)(NC=O)c1ccc(C#Cc2ccccc2)cc1
Product: CC(C)(NC=O)c1ccc(C#Cc2ccccc2)cc1

Procedure:
The experiment is repeated using in place of N-formyl-α, α-dimethyl-4-iodobenzylamine the corresponding N-formyl-α,α-diethyl-4-iodobenzylamine of N-formyl-α,α-di(n-propyl)- 4-iodobenzylamine with resultant production of N-formyl-α,α-diethyl-4-(phenylethynyl)-benzylamine of N-formyl-α,α-di(n-propyl)-4-(phenylethynyl)-benzylamine.
Reaction SMILES: [CH3:1][C:2]1[N:6]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=2)[N:5]=[C:4]([C:15](Cl)=[O:16])[CH:3]=1.O[N:19]=[C:20]([C:22]1[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=1)[NH2:21].C(N(CC)CC)C.CCN=C=NCCCN(C)C.Cl>ClCCl.C(OCC)(=O)C.O>[CH3:1][C:2]1[N:6]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=2)[N:5]=[C:4]([C:15]2[O:16][N:21]=[C:20]([C:22]3[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=3)[N:19]=2)[CH:3]=1
Reactant: NC(=NO)c1ccncc1
Reactant: Cc1ccc(Cn2nc(C(=O)Cl)cc2C)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: Cc1ccc(Cn2nc(-c3nc(-c4ccncc4)no3)cc2C)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 75.4 %

Procedure:
To a solution of 5-methyl-1-(4-methylbenzyl)-1H-pyrazole-3-carbonyl chloride (Step 1, 65 mg, 0.26 mmol) in dichloromethane (4 mL) at 0° C. was added N′-hydroxypyridine-4-amidine (43 mg, 0.31 mmol) along with triethyl amine (0.073 mL). The mixture was stirred for 16 h at rt. The mixture was evaporated to dryness and DMF (3 mL) was added along with EDCl (75 mg, 0.392 mmol) and the mixture was stirred at 140° C. for 2 h. The reaction mixture was cooled and water (100 mL) and ethyl acetate (100 mL) was added. The layers were separated and the organic layer was washed with water (2×200 mL) and then dried with magnesium sulfate. The solvent was evaporated and the residue was purified with an ISCO CombiFlash Companion using gradient elution from 100% hexane to 40% ethyl acetate in hexane to afford the title compound as a white solid (65 mg, 75%): 1H NMR (300 MHz, CD2Cl2) 8.80 (d, 2H), 8.20 (d, 2H), 7.20 (d, 2H), 7.10 (d, 2H), 6.82 (s, 1H), 5.40 (s, 2H), 2.35 (m, 6H); ES-MS m/z 332.25 (MH)+, HPLC RT (Method B) 3.34 min.
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:18])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.O.[NH2:20][NH2:21]>>[Cl:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[C:10]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=[C:2]([NH:20][NH2:21])[CH:11]=1
Reactant: Clc1cc(-c2ccccc2Cl)c2ccccc2n1
Reactant: NN
Solvent: O
Product: NNc1cc(-c2ccccc2Cl)c2ccccc2n1

Procedure:
In the manner given in Example 1, 2-chloro-4-(o-chlorophenyl)quinoline is reacted at reflux with hydrazine hydrate to give 4-(o-chlorophenyl)-2-hydrazinoquinoline.
Reaction SMILES: CN([CH:9]=[O:10])C1C=CC=CC=1.P(Cl)(Cl)(Cl)=O.[Cl:16][C:17]1[CH:30]=[CH:29][C:28]2[C:19](=[CH:20][C:21]3[C:26]([CH:27]=2)=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH:18]=1>ClC1C=CC=CC=1Cl>[Cl:16][C:17]1[CH:30]=[CH:29][C:28]2[C:19](=[C:20]([CH:9]=[O:10])[C:21]3[C:26]([CH:27]=2)=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH:18]=1
Reactant: Clc1ccc2cc3ccccc3cc2c1
Reactant: CN(C=O)c1ccccc1
Solvent: O=P(Cl)(Cl)Cl
Solvent: Clc1ccccc1Cl
Product: O=Cc1c2ccccc2cc2ccc(Cl)cc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 56.8 %

Procedure:
N-methylformanilide (2.45 kg, 18.12 mol) was treated with phosphorus oxychloride (2.66 kg, 17.35 mol) over a 40 min period at ambient temperature. The intermediate Vilsmeier complex was stirred for 2 h at room temperature, then treated with 2-chloroanthracene (described in Example 1a) (963 g, 4.53 mol), and o-dichlorobenzene (1.0 L). The resulting bright yellow mixture was heated gradually over 1.5 h to 9° C. at which point an exotherm ensued raising the reaction temperature to 115° C. The heat was removed until the exotherm subsided (45 min)., after which time the mixture was heated for 9 h at 90° C., then cooled. TLC analysis (silica gel; ethyl acetate:hexane 1:4) showed a small amount of unreacted anthracene (Rf 0.90), a small amount of the 3-chloro isomer (Rf 0.65), and the 2-chloro isomer (Rf 0.58) as the major component. The cooled reaction mixture was poured into ice/water (27 L) precipitating a dark brown tar. The aqueous layer was decanted away from the tar and extracted with methylene chloride (5×2 L). The combined extracts were used to redissolve the tar. The methylene chloride solution was washed with 3 N hydrochloric acid (4×1.5 L), followed by water (2 L), then dried over magnesium sulfate. The extracts were filtered, then pressure-filtered through a bed of silica gel, eluting with methylene chloride until all of the desired compound had been recovered. The eluent was concentrated on the rotary evaporator to give a slurry of bright yellow crystals (in o-dichlorobenzene). The crystals were collected by filtration, washed with diethyl ether (2×500 ml), then vacuum dried to afford 619.7 g (56.9%) of the desired 2-chloro-9-formylanthracene (mp 148°150° C.). NMR (CDCl3) 11.35 (s, 1H), 9.02 (d, J=0.9 Hz, 1H), 8.81 (d, J=8.9 Hz, 1H), 8.56 (s, 1H), 7.98 (m, 1H), 7.90 (d, J=8.9 Hz, 1H), 7.66 (m, 1H), 7.53 (m, 1H), 7.42 (m, 1H)
Reaction SMILES: C1(C)C=CC=CC=1.[C:8]([O:12][C:13]([N:15]1[CH2:19][CH2:18][C@H:17]([NH2:20])[CH2:16]1)=[O:14])([CH3:11])([CH3:10])[CH3:9].Br[C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=1)[C:25]#[N:26].C(=O)([O-])[O-].[Cs+].[Cs+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.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.ClCCl.O>[C:8]([O:12][C:13]([N:15]1[CH2:19][CH2:18][C@H:17]([NH:20][C:22]2[CH:29]=[CH:28][CH:27]=[C:24]([C:25]#[N:26])[CH:23]=2)[CH2:16]1)=[O:14])([CH3:11])([CH3:9])[CH3:10]
Reactant: CC(C)(C)OC(=O)N1CC[C@H](N)C1
Reactant: N#Cc1cccc(Br)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC[C@H](Nc2cccc(C#N)c2)C1
Temperature: 25 °C
Yield: 54.3 %

Procedure:
To a toluene solution (7 ml) containing 2.82 g of 3(S)-aminopyrrolidine-1-carboxylic acid tert-butyl ester (15 mmol) and 1.82 g of 3-bromobenzonitrile (10 mmol) were added 68.5 mg of BINAP (0.11 mmol), 22.5 mg of palladium acetate (0.1 mmol) and 3.91 g of cesium carbonate (12 mmol). The mixture was heated under reflux under a nitrogen atmosphere for 8 hours. After cooling to room temperature, water was added to the reaction solution, and extraction with dichloromethane was performed. After drying over sodium sulfate and concentration under reduced pressure, the residue was then purified by silica gel column chromatography (n-hexane:ethyl acetate=4:1). The purified product was concentrated to dryness under reduced pressure to thereby obtain 1.56 g of light yellow powdery 3(S)-(3-cyanophenylamino)pyrrolidine-1-carboxylic acid tert-butyl ester.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([C:10]2[C:15]([F:16])=[CH:14][CH:13]=[C:12]([O:17][CH3:18])[C:11]=2[F:19])=[O:9])=[CH:6][N:5]=[C:4](S(CC)(=O)=O)[N:3]=1.[NH2:25][CH:26]1[CH2:31][CH2:30][N:29]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:28][CH2:27]1>>[C:35]([O:34][C:32]([N:29]1[CH2:30][CH2:31][CH:26]([NH:25][C:4]2[N:3]=[C:2]([NH2:1])[C:7]([C:8](=[O:9])[C:10]3[C:15]([F:16])=[CH:14][CH:13]=[C:12]([O:17][CH3:18])[C:11]=3[F:19])=[CH:6][N:5]=2)[CH2:27][CH2:28]1)=[O:33])([CH3:38])([CH3:36])[CH3:37]
Reactant: CCS(=O)(=O)c1ncc(C(=O)c2c(F)ccc(OC)c2F)c(N)n1
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Product: COc1ccc(F)c(C(=O)c2cnc(NC3CCN(C(=O)OC(C)(C)C)CC3)nc2N)c1F

Procedure:
The same procedure was used as described in Example 90 starting from (4-amino-2-ethanesulfonyl-pyrimidin-5-yl)-(2,6-difluoro-3-methoxy-phenyl)-methanone, Example 89, and 4-amino-1-Boc-piperidine (Astatech) to give 4-[4-amino-5-(2,6-difluoro-3-methoxy-benzoyl)-pyrimidin-2-ylamino]-piperidine-1-carboxylic acid tert-butyl ester. MS (M+H)+, 464.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[Br:15][CH2:16][CH2:17][CH2:18]Br.C(COC)OC>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:18][CH2:17][CH2:16][Br:15])=[CH:4][CH:3]=1
Reactant: Oc1ccc(F)cc1
Reactant: BrCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: COCCOC
Product: Fc1ccc(OCCCBr)cc1

Procedure:
A mixture of 11.2 g (0.1 mol) of 4-fluorophenol, 16.5 g (0.12 mol) of pulverized potassium carbonate, 20.2 g (0.1 mol) of 1,3-dibromopropane and 100 ml of anhydrous dimethoxyethane was refluxed under nitrogen for 6 hours and then cooled. The mixture was diluted with methylene chloride and washed with water. The resultant organic product solution was dried over Na2SO4 and evaporated in vacuo. The residue was chromatographed on silica gel using cyclohexane elution to give pure product.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:31])[N:7]([CH3:30])[C:8]([C:12]3[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][CH2:21][N:22]4[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]4)=[CH:14][C:13]=3[O:28]C)=[N:9]2)=[CH:4][CH:3]=1.B(F)(F)F.[OH-].[Na+]>C(Cl)Cl.C(OCC)(=O)C>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:31])[N:7]([CH3:30])[C:8]([C:12]3[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][CH2:21][N:22]4[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]4)=[CH:14][C:13]=3[OH:28])=[N:9]2)=[CH:4][CH:3]=1
Reactant: COc1cc(OCCCN2CCCCC2)ccc1-c1nc2cc(Br)ccc2c(=O)n1C
Agent: FB(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: Cn1c(-c2ccc(OCCCN3CCCCC3)cc2O)nc2cc(Br)ccc2c1=O
Yield: 25.4 %

Procedure:
7-Bromo-2-[2-methoxy-4-(3-piperidin-1-ylpropoxy)phenyl]-3-methylquinazolin-4(3H)-one (38.5 mg, 0.0792 mmol) was dissolved in CH2Cl2 (0.5 mL), stirred with cooling with ice, and boron trifluoride (1.0 M in CH2Cl2, 160 μL) was added thereto. After stirred for 20 hours at room temperature, the reaction solution was diluted with ethyl acetate, and with cooling with ice, it was poured into aqueous 1 N sodium hydroxide solution, and extracted with ethyl acetate. This was washed with saturated saline water and dried with magnesium sulfate. The organic layer was concentrated under reduced pressure, and purified through silica gel thin-layer chromatography (chloroform/methanol=9/1) to obtain the intended compound (9.5 mg, 25%) as a pale yellow solid.
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:60])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([O:50][Si](C(C)(C)C)(C)C)[CH:46]([O:58][CH3:59])[CH2:45]2)[CH:7]([CH3:61])[CH:6]([O:62][Si:63]([C:66]([CH3:69])([CH3:68])[CH3:67])([CH3:65])[CH3:64])[CH2:5][C:4]1=[O:70])[CH3:2].C1(C)C=CC(S(O)(=O)=O)=CC=1>C(Cl)Cl.CO>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:60])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([OH:50])[CH:46]([O:58][CH3:59])[CH2:45]2)[CH:7]([CH3:61])[CH:6]([O:62][Si:63]([C:66]([CH3:67])([CH3:68])[CH3:69])([CH3:65])[CH3:64])[CH2:5][C:4]1=[O:70])[CH3:2]
Reactant: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(O[Si](C)(C)C(C)(C)C)C(OC)C3)C(C)C(O[Si](C)(C)C(C)(C)C)CC1=O)C(C)CC2OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Solvent: CO
Product: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(O)C(OC)C3)C(C)C(O[Si](C)(C)C(C)(C)C)CC1=O)C(C)CC2OC
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 99.8 %

Procedure:
To a solution of 17-ethyl-1-hydroxy-14-(tert -butyldimethylsiloxy)-12-[2'-(4"-(tert-butyldimethyl -siloxy)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo [22.3.1.04,9]octacos-18-ene-2,3,10,16-tetraone (2.37 g) (STEP 11A) in dry methylene chloride (25 ml) was added a solution of 10% p-toluenesulfonic acid in methanol (25 ml), and the mixture was stirred at room temperature. After 10 minutes, the mixture was cooled to 0° C. and quenched with saturated sodium bicarbonate. The mixture was diluted with ethyl acetate and the layers were separated. The organic layer was washed with saturated sodium bicarbonate and brine and dried over magnesium sulfate. Purification of the concentrate by flash chromatography on silica gel (ethyl acetate: hexane (1:2)+1% methanol) gave the title compound (2.1 g). 1H NMR consistent with the desired structure.
Reaction SMILES: [C:1]([O:5][C:6](=[O:27])[N:7]([CH2:25][CH3:26])[CH2:8][C:9]1[CH:10]=[N:11][CH:12]=[C:13](B2OC(C)(C)C(C)(C)O2)[C:14]=1[CH3:15])([CH3:4])([CH3:3])[CH3:2].[CH3:28][O:29][C:30](=[O:38])[C:31]1[CH:36]=[CH:35][N:34]=[C:33](Br)[CH:32]=1.N#N>O1CCOCC1.O.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>[CH3:28][O:29][C:30]([C:31]1[CH:36]=[CH:35][N:34]=[C:33]([C:13]2[CH:12]=[N:11][CH:10]=[C:9]([CH2:8][N:7]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:27])[CH2:25][CH3:26])[C:14]=2[CH3:15])[CH:32]=1)=[O:38]
Reactant: COC(=O)c1ccnc(Br)c1
Reactant: CCN(Cc1cncc(B2OC(C)(C)C(C)(C)O2)c1C)C(=O)OC(C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: N#N
Solvent: C1COCCO1
Solvent: O
Product: CCN(Cc1cncc(-c2cc(C(=O)OC)ccn2)c1C)C(=O)OC(C)(C)C
Temperature: 60 °C
Yield: 69.2 %

Procedure:
Ethyl-[4-methyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-3-ylmethyl]-carbamic acid tert-butyl ester (1.5 g, 5.1 mmol) and 2-bromo-isonicotinic acid methyl ester (1.3 g, 6.1 mmol) were suspended in 1,4-dioxane (25 mL). To the mixture was added K3PO4.3H2O (0.90 g, 4.52 mmol, 1 M in water). The reaction was degassed with N2 and PdCl2(PPh3)2 (72 mg, 0.1 mmol) was added. The reaction was heated to 60° C. for 3 hours. The mixture was then diluted with water and neutralised to pH 7. The mixture was concentrated in vacuo, to remove organic solvent, and then partitioned between water and EtOAc. The aqueous layer was extracted with EtOAc (×3). The combined organic layers were washed with water, brine, dried (MgSO4) and then evaporated to dryness. Purification by SiO2 chromatography gave the title compound (1.36 g). m/z 386 (M+H)+
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])[C:9]([C:11]1[CH:31]=[CH:30][C:14]2[N:15]([CH3:29])[C:16]([CH2:18][NH:19][C:20]3[CH:25]=[CH:24][C:23]([C:26](=[NH:28])[NH2:27])=[CH:22][CH:21]=3)=[N:17][C:13]=2[CH:12]=1)=[O:10].Cl[C:40]([O:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH3:50])=[O:41]>ClCCl.CO>[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])[C:9]([C:11]1[CH:31]=[CH:30][C:14]2[N:15]([CH3:29])[C:16]([CH2:18][NH:19][C:20]3[CH:25]=[CH:24][C:23]([C:26](=[NH:27])[NH:28][C:40]([O:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH3:50])=[O:41])=[CH:22][CH:21]=3)=[N:17][C:13]=2[CH:12]=1)=[O:10]
Reactant: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C(=N)N)cc1)n2C)c1ccccn1
Reactant: CCCCCCCCOC(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CO
Product: CCCCCCCCOC(=O)NC(=N)c1ccc(NCc2nc3cc(C(=O)N(CCC(=O)OCC)c4ccccn4)ccc3n2C)cc1
Yield: 57 %

Procedure:
Prepared analogously to Example 90 from 1-methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide-hydrochloride and n-octyl chloroformate. Yield: 57% of theory, C36H45N7O5 (655.8) Rf value: 0.46 (silica gel; dichloromethane/methanol =9:1 ##EQU83##
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=[CH:6][CH:5]=1.[Cl:14][CH:15]=[CH:16][CH2:17]Cl.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CS(C)=O>[Cl:14]/[CH:15]=[CH:16]/[CH2:17][N:2]([CH3:1])[CH2:3][C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=[CH:6][CH:5]=1
Reactant: ClC=CCCl
Reactant: CNCc1cccc2ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CN(C/C=C/Cl)Cc1cccc2ccccc12
Temperature: 25 °C
Reaction time: 6 h
Yield: 77 %

Procedure:
To a solution of 9.84 g (57.5 mmol) of N-methyl-1-naphthalenemethanamine in 60 ml of dimethyl sulfoxide were added 5.5 ml (60 mmol) of 1,3-dichloropropene (E/Z=9/1) and 8.28 g (60 mmol) of potassium carbonate under ice cooling. The mixture was stirred for 6 hours at room temperature, poured into 250 ml of ethyl acetate, washed with 150 ml×3 of water and 150 ml of saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was subjected to silica gel chromatography (n-hexane→n-hexane/ethyl acetate=9/1). The desired fractions were put together and concentrated under reduced pressure to obtain 10.86 g (yield: 77%) of the above identified compound as an oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([F:11])[C:5]([C:8](N)=[O:9])=[N:6][CH:7]=1.[OH-:12].[Na+]>Cl>[Br:1][C:2]1[CH:3]=[C:4]([F:11])[C:5]([C:8]([OH:12])=[O:9])=[N:6][CH:7]=1
Reactant: NC(=O)c1ncc(Br)cc1F
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Product: O=C(O)c1ncc(Br)cc1F

Procedure:
5-Bromo-3-fluoropicolinamide (1.44 g, 6.5 mmol) was stirred at 120° C. in conc. HCl (17 mL) for 1.5 h. The mixture was cooled in an ice bath and the pH adjusted to pH 5 with NaOH solution (48%, aq.). The mixture was extracted with 40% MeOH in DCM, dried using a phase separator and concentrated in vacuo to give a brown powder.