Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[CH:4][C:3]=1[C:17]1[N:18]=[CH:19][C:20]([NH2:23])=[N:21][CH:22]=1.Br[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[S:31]([N:34]1[CH2:39][CH2:38][N:37]([CH3:40])[CH2:36][CH2:35]1)(=[O:33])=[O:32]>>[F:1][C:2]1[CH:7]=[C:6]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[S:31]([N:34]2[CH2:39][CH2:38][N:37]([CH3:40])[CH2:36][CH2:35]2)(=[O:32])=[O:33])[CH:5]=[CH:4][C:3]=1[C:17]1[N:18]=[CH:19][C:20]([NH2:23])=[N:21][CH:22]=1
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)cn3)c(F)c2)OC1(C)C
Reactant: CN1CCN(S(=O)(=O)c2ccccc2Br)CC1
Product: CN1CCN(S(=O)(=O)c2ccccc2-c2ccc(-c3cnc(N)cn3)c(F)c2)CC1

Procedure:
The title compound was prepared in a manner similar to that described in Example 448 using 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-pyrazin-2-amine and 1-((2-bromophenyl)sulfonyl)-4-methylpiperazine. MS (ESI): mass calcd. for C21H22FN5O2S, 427.15; m/z found, 428.2 [M+H]+. 1H NMR (400 MHz, CD3OD) δ 8.37 (m, 1H), 8.23 (d, J=1.4, 1H), 8.16-8.12 (m, 1H), 8.02-7.96 (m, 1H), 7.78-7.73 (m, 1H), 7.68-7.62 (m, 1H), 7.48-7.45 (m, 1H), 7.34 (s, 1H), 7.32-7.30 (m, 1H), 3.61-3.33 (m, 4H), 3.01-2.70 (m, 7H).
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]([OH:9])=O)=[CH:5][O:4][N:3]=1.C(Cl)(=O)C(Cl)=O.[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][C:18]=1[C:25]1[C:26]([NH2:32])=[N:27][C:28]([NH2:31])=[CH:29][CH:30]=1.N1C(C)=CC=CC=1C>ClCCl.CN(C)C=O.C(#N)C>[NH2:32][C:26]1[N:27]=[C:28]([NH:31][C:7]([C:6]2[C:2]([CH3:1])=[N:3][O:4][CH:5]=2)=[O:9])[CH:29]=[CH:30][C:25]=1[C:18]1[CH:19]=[C:20]([O:23][CH3:24])[CH:21]=[CH:22][C:17]=1[Cl:16]
Reactant: COc1ccc(Cl)c(-c2ccc(N)nc2N)c1
Reactant: Cc1nocc1C(=O)O
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: COc1ccc(Cl)c(-c2ccc(NC(=O)c3conc3C)nc2N)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a suspension of 3-methylisoxazole-4-carboxylic acid (2.73 g, 21.48 mmol) in dichloromethane (10 ml) was added oxalyl chloride (2.62 ml, 30.1 mmol) followed by 2 drops of dimethylformamide. The reaction was stirred at room temperature for 18 hours before concentration in vacuo. The residue was azeotroped with dichloromethane, dissolved in acetonitrile (15 ml) and added dropwise to a cooled solution of 3-(2-chloro-5-methoxyphenyl)pyridine-2,6-diamine (preparation 1, 5.2 g, 20.82 mmol) and lutidine (3.15 ml, 27.1 mmol) in acetonitrile (150 ml). The reaction was allowed to warm to room temperature and stirred under nitrogen for 30 minutes. The reaction was quenched by the addition of water (100 ml), extracted into ethyl acetate (200 ml), dried (MgSO4) and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with ethylacetate:heptane 1:2 to furnish a pale yellow solid. This was triturated with t-butylmethylether, filtered, and recrystallised from ethyl acetate to furnish the title product as a white solid.
Reaction SMILES: Cl[C:2]1[N:11]=[CH:10][C:9]([Cl:12])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[Br-].[C:14]([C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][CH:23]=1)[CH2:19][Zn+])#[N:15]>>[Cl:12][C:9]1[CH:10]=[N:11][C:2]([CH2:19][C:18]2[CH:21]=[CH:22][CH:23]=[C:16]([C:14]#[N:15])[CH:17]=2)=[C:3]([CH:8]=1)[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1cc(Cl)cnc1Cl
Reactant: N#Cc1cccc(C[Zn+])c1
Agent: [Br-]
Product: COC(=O)c1cc(Cl)cnc1Cc1cccc(C#N)c1

Procedure:
The title compound was prepared according to the procedure described in step 2 of Example 58 from methyl 2,5-dichloronicotinate and 3-cyanobenzylzinc bromide: 1H-NMR (CDCl3) δ 8.66 (1H, d, J=2.5 Hz), 8.23 (1H, d, J=2.5 Hz), 7.58–7.34 (4H, m), 4.57 (2H, s), 3.91 (3H, s).
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][C:7]2=[N:8][C:9](=[O:11])[N:10]=[C:6]2[CH:5]=1)([O-])=O.[H][H]>N.O[V](=O)=O.[O-2].[O-2].[Ti+4].[Pd].O>[NH2:1][C:4]1[CH:13]=[CH:12][C:7]2=[N:8][C:9](=[O:11])[N:10]=[C:6]2[CH:5]=1
Reactant: O=C1N=c2ccc([N+](=O)[O-])cc2=N1
Reactant: [H][H]
Agent: O=[V](=O)O
Agent: [Pd]
Agent: [Ti+4]
Solvent: O
Product: Nc1ccc2c(c1)=NC(=O)N=2
Temperature: 60 °C
Reaction time: 34 h
Yield: 80.3 %

Procedure:
0.001 g of ammonium vanadate and 0.5 g of titanium dioxide extrudate containing 1% by weight of metallic palladium and having a particle size of 3 mm (from Johnson Matthey) are added to a suspension consisting of 50 ml of water and 1.8 g of 5-nitrobenzimidazolone. After displacing the air with nitrogen, the latter is replaced by hydrogen at atmospheric pressure and the suspension is stirred at 60° C. for 34 hours. During this time, 102% of the theoretical amount of hydrogen, based on the 5-nitrobenzimidazolone, is adsorbed. The resulting suspension is then sieved through a sieve having a mesh width of 1 mm. The material remaining on the sieve is washed with 50 ml of water and the combined aqueous phases are then filtered through a paper filter and washed with 250 ml of water. Drying at 80° C. under reduced pressure (125 mbar) gives 1.2 g (79%) of 5-aminobenzimidazolone.
Reaction SMILES: [OH:1][CH:2]([C:15]1[CH:24]=[CH:23][C:22]2[C:21]([CH3:26])([CH3:25])[CH2:20][CH2:19][C:18]([CH3:28])([CH3:27])[C:17]=2[CH:16]=1)[C:3]#[C:4][C:5]1[CH:14]=[CH:13][C:8]([C:9]([O:11]C)=[O:10])=[CH:7][CH:6]=1.[OH-].[Na+]>CO>[OH:1][CH:2]([C:15]1[CH:24]=[CH:23][C:22]2[C:21]([CH3:26])([CH3:25])[CH2:20][CH2:19][C:18]([CH3:28])([CH3:27])[C:17]=2[CH:16]=1)[C:3]#[C:4][C:5]1[CH:6]=[CH:7][C:8]([C:9]([OH:11])=[O:10])=[CH:13][CH:14]=1
Reactant: COC(=O)c1ccc(C#CC(O)c2ccc3c(c2)C(C)(C)CCC3(C)C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC1(C)CCC(C)(C)c2cc(C(O)C#Cc3ccc(C(=O)O)cc3)ccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3.5 g (93 mmol) of methyl 4-[3-hydroxy-3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-propynyl]benzoate, 200 ml of methanol and 20 ml of a methanolic sodium hydroxide solution (2N) were introduced into a round-bottomed flask. The reaction mixture was stirred at room temperature for 8 hours and evaporated and the residue was taken up in water and acidified with hydrochloric acid. Extraction was carried out with ethyl ether and the organic phase was separated by settling, dried over magnesium sulfate and evaporated. The residue obtained was recrystallized from a cyclohexane/isopropyl ether mixture and 1.7 g (50%) of the expected acid, with a melting point of 134°-135° C., was recovered.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]1[C@H:14]([NH:15][C:16]2[N:21]=[C:20](Cl)[C:19]3[C:23](=[O:33])[N:24]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:25][C:18]=3[C:17]=2[F:34])[CH2:13][CH2:12][O:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:35][CH:36]([F:45])[N:37]1[CH:41]=[C:40](B(O)O)[CH:39]=[N:38]1>O1CCOCC1.C(=O)([O-])[O-].[Na+].[Na+].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>[C:1]([O:5][C:6]([NH:8][C@@H:9]1[C@H:14]([NH:15][C:16]2[N:21]=[C:20]([C:40]3[CH:39]=[N:38][N:37]([CH:36]([F:45])[F:35])[CH:41]=3)[C:19]3[C:23](=[O:33])[N:24]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:25][C:18]=3[C:17]=2[F:34])[CH2:13][CH2:12][O:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: OB(O)c1cnn(C(F)F)c1
Reactant: CC(C)(C)OC(=O)N[C@H]1COCC[C@H]1Nc1nc(Cl)c2c(c1F)CN(C(=O)OC(C)(C)C)C2=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N[C@H]1COCC[C@H]1Nc1nc(-c2cnn(C(F)F)c2)c2c(c1F)CN(C(=O)OC(C)(C)C)C2=O
Temperature: 100 °C
Yield: 22.7 %

Procedure:
A mixture of tert-butyl 6-((3R,4R)-3-(tert-butoxycarbonylamino)tetrahydro-2H-pyran-4-ylamino)-4-chloro-7-fluoro-3-oxo-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate (500 mg, 0.998 mmol), 1-(difluoromethyl)-1H-pyrazol-4-ylboronic acid (808 mg, 4.99 mmol), bis(triphenylphosphine)palladium chloride (70.1 mg, 0.100 mmol) in dioxane (15 mL) and 2M saturated sodium carbonate (2 mL) were heated to 100° C. in a microwave for 30 min. The solution was concentrated and was purified by preparatory HPLC eluting with water (10 mM NH4HCO3) and ACN/water (80/20 v/v, 15-30% gradient, 10 mM NH4HCO3) to give the title compound as a white solid (132 mg, 23%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.35 (s, 9 H), 1.52 (s, 9 H), 1.55-1.56 (m, 1 H), 2.46-2.47 (m, 1 H), 3.57-3.59 (m, 2 H), 3.81-3.84 (m, 3 H), 4.61-4.62 (m, 1 H), 4.78 (s, 2 H), 6.61 (d, J=6.35 Hz, 1 H), 7.15 (d, J=6.83 Hz, 1 H), 7.97 (s, 1 H), 8.54 (s, 1 H), 9.24 (s, 1 H). [M+H] calc'd for C26H33F3N6O6, 583; found, 583.
Reaction SMILES: [OH:1][N:2]=[C:3]([C:9]1[N:10]=[C:11]([CH3:14])[S:12][CH:13]=1)[C:4]([O:6][CH2:7][CH3:8])=[O:5].S(OC)(O[CH3:19])(=O)=O>>[CH3:19][O:1][N:2]=[C:3]([C:9]1[N:10]=[C:11]([CH3:14])[S:12][CH:13]=1)[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCOC(=O)C(=NO)c1csc(C)n1
Reactant: COS(=O)(=O)OC
Product: CCOC(=O)C(=NOC)c1csc(C)n1
Yield: 84.5 %

Procedure:
Ethyl 2-hydroxyimino-2-(2-methyl-1,3-thiazol-4-yl)acetate (anti isomer) (0.3 g.) and dimethyl sulfate (0.18 g.) were reacted according to a similar manner to that of Preparation 8-5) to give pale yellow oil of ethyl 2-methoxyimino-2-(2-methyl-1,3-thiazol-4-yl)acetate (anti isomer) (0.27 g.).
Reaction SMILES: [CH2:1]([N:8]([CH2:10][CH2:11][N:12]1[CH:16]=[CH:15][N:14]=[CH:13]1)C)C1C=CC=CC=1.[H][H]>CO.[OH-].[OH-].[Pd+2]>[CH3:1][NH:8][CH2:10][CH2:11][N:12]1[CH:16]=[CH:15][N:14]=[CH:13]1
Reactant: CN(CCn1ccnc1)Cc1ccccc1
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CNCCn1ccnc1

Procedure:
The title compound of Step 11 (5.70 g, 26.5 mmol) was reacted with Pd(OH)2 /C in methanol at 60° with 60 psi of hydrogen for 4 hours. Filtration through Celite gave the title compound as a clear, colorless oil (3.46 g). The proton spectrum was consistent with the proposed structure.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([N:7]2[CH:11]=[C:10]([C:12]3[N:17]=[C:16]([C:18]#[N:19])[CH:15]=[CH:14][CH:13]=3)[CH:9]=[N:8]2)[CH:2]=1.C[O-].[Na+].[Cl-].[NH4+:24]>CO>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([N:7]2[CH:11]=[C:10]([C:12]3[N:17]=[C:16]([C:18]([NH2:24])=[NH:19])[CH:15]=[CH:14][CH:13]=3)[CH:9]=[N:8]2)[CH:2]=1
Reactant: [NH4+]
Reactant: N#Cc1cccc(-c2cnn(-c3cccnc3)c2)n1
Agent: C[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Product: N=C(N)c1cccc(-c2cnn(-c3cccnc3)c2)n1
Temperature: 65 °C
Reaction time: 0.33 h

Procedure:
With heating, 0.7 g (2.8 mmol) of 6-(1-pyridin-3-yl-1H-pyrazol-4-yl)pyridine-2-carbonitril was dissolved in 150 ml of abs. methanol, and 1 ml of a solution of sodium methoxide in methanol (30%, corresponds to 5.4 mmol) was added. The mixture was stirred at 65° C. until the thin-layer chromatogram (TLC) showed complete conversion, 1.5 g of ammonium chloride was added and the mixture was concentrated. The residue was boiled twice with in each case 30 ml of ethanol, the hot mixture was filtered and the combined filtrates were concentrated slightly. The mixture was allowed to stand at RT for 20 min, and the precipitate formed was filtered off with suction, washed with MTBE and dried on a rotary evaporator.
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:9][CH2:10][C:11]12[CH2:18][CH2:17][C:14]([C:19]3[NH:27][C:26]4[C:25](=[O:28])[N:24]([CH2:29][CH2:30][CH3:31])[C:23](=[O:32])[N:22]([CH2:33][CH2:34][CH3:35])[C:21]=4[N:20]=3)([CH2:15][CH2:16]1)[CH2:13][CH2:12]2)(=[O:8])[O:5]CC)[CH3:2].Cl>[OH-].[Na+]>[CH2:1]([O:3][P:4]([CH2:9][CH2:10][C:11]12[CH2:18][CH2:17][C:14]([C:19]3[NH:27][C:26]4[C:25](=[O:28])[N:24]([CH2:29][CH2:30][CH3:31])[C:23](=[O:32])[N:22]([CH2:33][CH2:34][CH3:35])[C:21]=4[N:20]=3)([CH2:13][CH2:12]1)[CH2:15][CH2:16]2)(=[O:5])[OH:8])[CH3:2]
Reactant: CCCn1c(=O)c2[nH]c(C34CCC(CCP(=O)(OCC)OCC)(CC3)CC4)nc2n(CCC)c1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CCCn1c(=O)c2[nH]c(C34CCC(CCP(=O)(O)OCC)(CC3)CC4)nc2n(CCC)c1=O
Temperature: 80 °C

Procedure:
Dissolved {2-[4-(2,6-dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-bicyclo-[2.2.2]oct-1-yl]-ethyl}-phosphonic acid diethyl ester (30 mg, 59 μmol) in I N NaOH (4 ml) and heated the solution at 80° C. for 3 h. The mixture was allowed to cool to rt and slowly acidified with concentrated HCl. The resulting precipitate was collected and dried (22 mg, 79%). 1H NMR (400 MHz, CDCl3); δ 0.93 (coincident triplets, 6H), 1.31 (t, 3H), 1.48 (m, 8H), 1.70 (br m, 6H), 1.95 (m, 6H), 3.95 (t, 2H), 4.07 (t, 2H), 12.2 (br s, 1H).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:25])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11].[C:26]([O:29][C:30]1[CH:31]=[C:32]([CH:36]=[CH:37][CH:38]=1)[C:33](O)=[O:34])(=[O:28])[CH3:27].C1CCC(N=C=NC2CCCCC2)CC1>C(Cl)Cl>[C:26]([O:29][C:30]1[CH:38]=[CH:37][CH:36]=[C:32]([C:33]([N:20]2[CH2:21][CH2:22][CH:17]([N:15]3[C:14](=[O:23])[C:13]([CH3:25])([CH3:24])[C:12]([C:6]4[CH:7]=[CH:8][C:9]([O:10][CH3:11])=[C:4]([O:3][CH3:2])[CH:5]=4)=[N:16]3)[CH2:18][CH2:19]2)=[O:34])[CH:31]=1)(=[O:28])[CH3:27]
Reactant: COc1ccc(C2=NN(C3CCNCC3)C(=O)C2(C)C)cc1OC
Reactant: CC(=O)Oc1cccc(C(=O)O)c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: ClCCl
Product: COc1ccc(C2=NN(C3CCN(C(=O)c4cccc(OC(C)=O)c4)CC3)C(=O)C2(C)C)cc1OC
Reaction time: 2 h

Procedure:
A mixture of 10 g 5-(3,4-dimethoxyphenyl)-4,4-dimethyl-2-(piperidin-4-yl)-2,4-dihydro-3H-pyrazol-3-one (compound B1), 8 g of 3-(acetyloxy)benzoic acid and 7 g of DCC in 150 ml of DCM is stirred for 2 h until the reaction is complete according to TLC analysis. The reaction mixture is quenched with water, the phases are separated and the organic phase is washed with water again. The organic phase is dried over MgSO4, and the solvent is removed under reduced pressure resulting in a crude product, which is purified by crystallization from methanol to yield the title compound.
Reaction SMILES: Cl.[NH:2]1[CH2:6][CH2:5][C@@H:4]([NH:7][C:8]([C:10]2[C:14]3[N:15]=[CH:16][N:17]=[C:18]([C:19]4[CH:24]=[C:23]([F:25])[C:22]([O:26][CH3:27])=[CH:21][C:20]=4[O:28][CH2:29][CH:30]4[CH2:32][CH2:31]4)[C:13]=3[NH:12][CH:11]=2)=[O:9])[CH2:3]1.[C:33](Cl)(=[O:36])[CH2:34][CH3:35]>>[C:33]([N:2]1[CH2:6][CH2:5][C@@H:4]([NH:7][C:8]([C:10]2[C:14]3[N:15]=[CH:16][N:17]=[C:18]([C:19]4[CH:24]=[C:23]([F:25])[C:22]([O:26][CH3:27])=[CH:21][C:20]=4[O:28][CH2:29][CH:30]4[CH2:31][CH2:32]4)[C:13]=3[NH:12][CH:11]=2)=[O:9])[CH2:3]1)(=[O:36])[CH2:34][CH3:35]
Reactant: CCC(=O)Cl
Reactant: COc1cc(OCC2CC2)c(-c2ncnc3c(C(=O)N[C@@H]4CCNC4)c[nH]c23)cc1F
Agent: Cl
Product: CCC(=O)N1CC[C@@H](NC(=O)c2c[nH]c3c(-c4cc(F)c(OC)cc4OCC4CC4)ncnc23)C1

Procedure:
Starting from 4-(2-cyclopropylmethoxy-5-fluoro-4-methoxy-phenyl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (R)-pyrrolidin-3-ylamide hydrochloride (example A169) and propionyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [O:1]=[C:2]1[NH:6][C:5](=[O:7])[CH:4]([CH2:8][C:9]2[CH:42]=[CH:41][C:12]([O:13][CH2:14][C:15]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([O:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=4[OH:31])=[CH:20][C:19]=3[N:32](C)[C:33](=O)OC(C)(C)C)=O)=[CH:11][CH:10]=2)[S:3]1.[ClH:43].O1CCOCC1>>[ClH:43].[OH:31][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=1[O:24][C:21]1[CH:22]=[CH:23][C:18]2[N:17]=[C:15]([CH2:14][O:13][C:12]3[CH:11]=[CH:10][C:9]([CH2:8][CH:4]4[S:3][C:2](=[O:1])[NH:6][C:5]4=[O:7])=[CH:42][CH:41]=3)[N:32]([CH3:33])[C:19]=2[CH:20]=1
Reactant: CN(C(=O)OC(C)(C)C)c1cc(Oc2ccccc2O)ccc1NC(=O)COc1ccc(CC2SC(=O)NC2=O)cc1
Agent: Cl
Solvent: C1COCCO1
Product: Cn1c(COc2ccc(CC3SC(=O)NC3=O)cc2)nc2ccc(Oc3ccccc3O)cc21

Procedure:
In a similar manner to that described in Example (2-2a), a reaction was carried out using t-butyl N-{2-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxyacetylamino]-5-(2-hydroxyphenoxy)phenyl}-N-methylcarbamate (1.16 g) and 4N hydrogen chloride/dioxane (20 ml) and the reaction mixture was purified and then in a similar manner to that described in Example (2-2b) the product was reacted with 4N hydrogen chloride/ethyl acetate (20 ml) and purified to give the title compound (0.79 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[C:20]3[C:15](=[CH:16][C:17]([CH2:21][C:22]4[CH:27]=[C:26](Cl)[N:25]=[CH:24][N:23]=4)=[CH:18][CH:19]=3)[CH:14]=[CH:13][CH:12]=2)=[O:10])=[CH:4][C:3]=1[C:29]([F:32])([F:31])[F:30].[N-:33]=[N+:34]=[N-:35].[Na+]>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[C:20]3[C:15](=[CH:16][C:17]([CH2:21][C:22]4[CH:27]=[C:26]([N:33]=[N+:34]=[N-:35])[N:25]=[CH:24][N:23]=4)=[CH:18][CH:19]=3)[CH:14]=[CH:13][CH:12]=2)=[O:10])=[CH:4][C:3]=1[C:29]([F:32])([F:31])[F:30]
Reactant: [N-]=[N+]=[N-]
Reactant: O=C(Nc1ccc(F)c(C(F)(F)F)c1)c1cccc2cc(Cc3cc(Cl)ncn3)ccc12
Agent: [Na+]
Solvent: CN(C)C=O
Product: [N-]=[N+]=Nc1cc(Cc2ccc3c(C(=O)Nc4ccc(F)c(C(F)(F)F)c4)cccc3c2)ncn1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
A mixture of 200 mg (0.435 mMol) 6-(6-chloro-pyrimidin-4-ylmethyl)-naphthalene-1-carboxylic acid (4-fluoro-3-trifluoromethyl-phenyl)-amide and 50 mg (0.76 mMol) NaN3 in 5 ml DMF is stirred for 2 h at 60° C., giving 6-(6-azido-pyrimidin-4-ylmethyl)-naphthalene-1-carboxylic acid (4-fluoro-3-trifluoromethyl-phenyl)-amide (MS: [M+1]+=467). After cooling to rt, 50 mg Pd/C (10%; Engelhard 4505) are added and the mixture is hydrogenated under a H2-atmosphere for 30 min. Filtration through Celite, concentration and chromatography (Combi Flash; CH2Cl2/MeOH 9:1→1:1) gives the title compound: MS: [M+1]+=441; HPLC: tRet=12.3.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([S:9][CH2:10][CH:11]2[CH2:13][CH2:12]2)[N:4]=1.C([O:16][C:17](=[O:28])[CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[C:22]([F:27])[CH:21]=1)C>>[CH:11]1([CH2:10][S:9][C:5]2[N:4]=[C:3]([CH2:2][O:26][C:23]3[CH:24]=[CH:25][C:20]([CH2:19][CH2:18][C:17]([OH:28])=[O:16])=[CH:21][C:22]=3[F:27])[CH:8]=[CH:7][CH:6]=2)[CH2:13][CH2:12]1
Reactant: CCOC(=O)CCc1ccc(O)c(F)c1
Reactant: ClCc1cccc(SCC2CC2)n1
Product: O=C(O)CCc1ccc(OCc2cccc(SCC3CC3)n2)c(F)c1
Yield: 85 %

Procedure:
2-Chloromethyl-6-cyclopropylmethylsulfanyl-pyridine (0.030 g, 0.14 mmol) obtained in Step D of Preparation Example 20 and 3-(3-fluoro-4-hydroxy-phenyl)-propionic acid ethyl ester (0.030 g, 0.14 mmol) obtained in Step C of Preparation Example 6 were used to react sequentially in the same manner as in Steps A and B of Example 1 to obtain the title compound (0.043 g, 86%).
Reaction SMILES: [N:1]([CH2:4][CH2:5][O:6][CH3:7])=[N+:2]=[N-:3].[NH2:8][C:9]1[CH:16]=[CH:15][CH:14]=[C:13]([C:17]#[CH:18])[C:10]=1[C:11]#[N:12].O=C1O[C@H]([C@H](CO)O)C([O-])=C1O.[Na+]>O.C(O)(C)(C)C.O.[O-]S([O-])(=O)=O.[Cu+2]>[NH2:8][C:9]1[CH:16]=[CH:15][CH:14]=[C:13]([C:17]2[N:3]=[N:2][N:1]([CH2:4][CH2:5][O:6][CH3:7])[CH:18]=2)[C:10]=1[C:11]#[N:12]
Reactant: C#Cc1cccc(N)c1C#N
Reactant: COCCN=[N+]=[N-]
Agent: [Cu+2]
Agent: O=C1O[C@H]([C@@H](O)CO)C([O-])=C1O
Agent: O=S(=O)([O-])[O-]
Solvent: O
Solvent: CC(C)(C)O
Product: COCCn1cc(-c2cccc(N)c2C#N)nn1
Temperature: 25 °C
Reaction time: 48 h
Yield: 88 %

Procedure:
To a solution of 1-bromo-2-methoxyethane (5.00 g, 35.97 mmol) in DMF (25 mL), was added sodium azide (3 equiv.) and the mixture was heated at 50° C. for 48 hours. The reaction mixture was diluted with water (75 mL) and extracted with diethyl ether. The organic extract was dried over MgSO4 and concentrated to furnish 1-azido-2-methoxyethane as a yellow liquid. This azide (200 mg, 1.94 mmol) was added to a solution of 2-Amino-6-ethynylbenzonitrile (250 mg, 1.76 mmol) (Example 267c) in H2O/tert-BuOH=1:2 (15 mL) and the solution was treated consecutively with sodium ascorbate (0.264 mmol) and CuSO4 (0.035 mmol). The reaction mixture was stirred at room temperature for 48 hours, diluted with water and extracted with ethyl acetate. The organic extract was dried over MgSO4 and purified over silica gel (ethyl acetate/hexane 6:4) to furnish the title compound as a white solid in 88% yield. 1H NMR (400 MHz, DMSO-d6) δ 3.26 (s, 3H), 3.78 (t, J=5.2 Hz, 2H), 4.23 (t, J=5.2 Hz, 2H), 6.13 (br s, 2H), 6.80 (dd, J=1.2, 8.4 Hz, 1H), 7.09 (dd, J=1.2, 7.6 Hz, 1H), 7.36 (t, J=8.4 Hz, 1H), 8.52 (s, 1H). MS 244 (MH+).
Reaction SMILES: [SH:1][CH:2]([CH:14]([C:19]([NH:21][C@H:22]([C:32]([NH:34][CH3:35])=[O:33])[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=1)=[O:20])[CH2:15][CH:16]([CH3:18])[CH3:17])[CH2:3][C:4]([O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:5].[C:36](OC(=O)C)(=[O:38])[CH3:37].CN1CCOCC1>C(Cl)(Cl)Cl>[C:36]([S:1][CH:2]([CH:14]([C:19]([NH:21][C@H:22]([C:32]([NH:34][CH3:35])=[O:33])[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=1)=[O:20])[CH2:15][CH:16]([CH3:17])[CH3:18])[CH2:3][C:4]([O:6][CH2:7][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)=[O:5])(=[O:38])[CH3:37]
Reactant: CNC(=O)[C@H](Cc1ccc(OC)cc1)NC(=O)C(CC(C)C)C(S)CC(=O)OCc1ccccc1
Reactant: CC(=O)OC(C)=O
Solvent: CN1CCOCC1
Solvent: ClC(Cl)Cl
Product: CNC(=O)[C@H](Cc1ccc(OC)cc1)NC(=O)C(CC(C)C)C(CC(=O)OCc1ccccc1)SC(C)=O
Temperature: 0 °C
Reaction time: 72 h

Procedure:
The benzyl ester (D8) (41 g, 0.088 mole) was dissolved in thiolacetic acid (170 ml) and left to stand at room temperature under nitrogen for 19 days. Volatile material was removed in vacuo and the residue chromatographed on silica gel with initially ether, rising slowly to ethyl acetate. After removal of high Rf impurities the title compound was obtained as a mixture of diastereomers as a pale yellow foam (29.76 g, 62.4%). (Found: C, 64.29; H, 7.16; N, 4.86. C29H38N2SO6 requires C, 64.18; H, 7.06; N, 5.16%). Later fractions contained olefinic material (D8). However, more complete reaction can be obtained by addition of a suitable base, for example triethylamine. An aliquot (2 ml) was removed from the above reaction mixture after 14 days, treated with triethylamine (3 drops) and left to stand for a further 5 days at room temperature under nitrogen. The same work-up procedure as for the bulk of the reaction mixture described above gave only the diastereomer mixture (E3) with no olefinic material remaining. 3-Mercapto-6-methyl-4-[[[1-(S)-[(methylamino)carbonyl]2-(4-methoxyphenyl)ethyl]amino]carbonyl]heptanoic acid, benzyl ester (E4, Isomer A, 2.0 g 0.004 mol) was dissolved in chloroform (100 ml) under an atmosphere of nitrogen. The reaction mixture was cooled to 0° C. and acetic anhydride (2.04 g, 0.02 mol) was added followed by N-methylmorpholine (2.02 g, 0.02 mol). The reaction mixture was allowed to warm to room temperature, then stirred under nitrogen for 3 days.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][OH:8])[CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].[CH3:11][C:12]1[CH:17]=[C:16]([C:18]2[NH:27][C:26](=[O:28])[C:25]3[C:20](=[CH:21][C:22]([F:30])=[CH:23][C:24]=3F)[N:19]=2)[CH:15]=[C:14]([CH3:31])[N:13]=1.O>CN(C=O)C.C(O)(=O)C>[CH3:11][C:12]1[CH:17]=[C:16]([C:18]2[NH:27][C:26](=[O:28])[C:25]3[C:20](=[CH:21][C:22]([F:30])=[CH:23][C:24]=3[O:8][CH2:7][CH2:6][N:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)[N:19]=2)[CH:15]=[C:14]([CH3:31])[N:13]=1
Reactant: Cc1cc(-c2nc3cc(F)cc(F)c3c(=O)[nH]2)cc(C)n1
Reactant: OCCN1CCCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Solvent: O
Product: Cc1cc(-c2nc3cc(F)cc(OCCN4CCCC4)c3c(=O)[nH]2)cc(C)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2-pyrrolidin-1-yl-ethanol (5.09 g, 44.2 mmol) in DMF (10 mL) was added sodium hydride (60% suspension in mineral oil, 0.88 g, 22.1 mmol) in small portions and the reaction mixture was stirred at room temperature for 30 minutes. To this mixture was added 2-(2,6-dimethyl-pyridin-4-yl)-5,7-difluoro-3H-quinazolin-4-one (0.63 g, 2.21 mmol) and the reaction mixture was stirred at room temperature for 16 hours. Water (20 mL) was added, and the mixture was neutralized to pH approximately 6 with acetic acid. Solvent was evaporated, the residue was dissolved in ethyl acetate, washed with water, dried over anhydrous sodium sulfate, and concentrated in vacuo. Crude compound was purified by the Simpliflash system (0-4% methanol in CH2Cl2 as eluent) to afford 2-(2,6-dimethyl-pyridin-4-yl)-7-fluoro-5-(2-pyrrolidin-1-yl-ethoxy)-3H-quinazolin-4-one as a yellow solid. Yield: 0.61 g (72%).