Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[C:12]1[N:22](S(C2C=CC(C)=CC=2)(=O)=O)[C:15]2[N:16]=[CH:17][CH:18]=[C:19]([C:20]#[N:21])[C:14]=2[CH:13]=1.[OH-:33].[Na+].OO>CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[C:12]1[NH:22][C:15]2[N:16]=[CH:17][CH:18]=[C:19]([C:20]([NH2:21])=[O:33])[C:14]=2[CH:13]=1
Reactant: COc1ccc2[nH]cc(-c3cc4c(C#N)ccnc4n3S(=O)(=O)c3ccc(C)cc3)c2c1
Reactant: [OH-]
Agent: OO
Agent: [Na+]
Solvent: CO
Product: COc1ccc2[nH]cc(-c3cc4c(C(N)=O)ccnc4[nH]3)c2c1
Reaction time: 3 h

Procedure:
A suspension of 2-(5-methoxy-1H-indol-3-yl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridine-4 carbonitrile [0.25 g, Reference Example 67(e)] in methanol (25 mL) was treated with sodium hydroxide solution (1.5 g in 4 mL water). The mixture was cooled in an ice-bath and then treated dropwise with hydrogen peroxide (0.35 mL, 30%). After stirring at room temperature for 1 hour a further aliquot of hydrogen peroxide (0.3 mL) was added to the reaction mixture and stirring was continued for a further 3 hours then the reaction was quenched by addition of sodium metabisulfite to remove excess hydrogen peroxide. The reaction mixture was then diluted with water (75 mL) and extracted twice with ethyl acetate (50 mL). The combined extracts were washed twice with brine (30 mL), then dried over sodium sulfate and then evaporated. The residual yellow solid was subjected to chromatography on silica eluting with a mixture of ethyl acetate and dichloromethane (1:1, v/v) to give, after trituration with methanol and washing with diethyl ether, the title compound (50 mg) as a yellow solid, m.p.>320° C. MS: 307 (MH+).
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:15][CH:16]2[CH2:24][CH2:23][CH:22]3[CH:18]([CH2:19][NH:20][CH2:21]3)[CH2:17]2)=[N:4][C:5]([NH:8][C:9]2[CH:10]=[N:11][N:12]([CH3:14])[CH:13]=2)=[N:6][CH:7]=1.[C:25]([CH2:27][C:28](O)=[O:29])#[N:26].CCN=C=NCCCN(C)C.C1C=NC2N(O)N=NC=2C=1>C(Cl)Cl.CN(C=O)C>[Cl:1][C:2]1[C:3]([NH:15][CH:16]2[CH2:24][CH2:23][CH:22]3[CH:18]([CH2:19][N:20]([C:28](=[O:29])[CH2:27][C:25]#[N:26])[CH2:21]3)[CH2:17]2)=[N:4][C:5]([NH:8][C:9]2[CH:10]=[N:11][N:12]([CH3:14])[CH:13]=2)=[N:6][CH:7]=1
Reactant: N#CCC(=O)O
Reactant: Cn1cc(Nc2ncc(Cl)c(NC3CCC4CNCC4C3)n2)cn1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2cccnc21
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cn1cc(Nc2ncc(Cl)c(NC3CCC4CN(C(=O)CC#N)CC4C3)n2)cn1
Temperature: 45 °C
Reaction time: 3 h
Yield: 40.8 %

Procedure:
To a solution of 5-chloro-N2-(1-methyl-1H-pyrazol-4-yl)-N4-(octahydro-1H-isoindol-5-yl)pyrimidine-2,4-diamine (470 mg, 1.35 mmol), 2-cyanoacetic acid (246.7 mg, 2.90 mmol) in a mixture of DCM (40 mL) and DMF (10 mL) were added EDCI (505.2 mg, 2.64 mmol) and HOAT (325.4 mg, 0.30 mmol). After addition, the reaction mixture was stirred at 45° C. for 3 h, quenched with H2O (30 mL) and extracted with DCM (200 mL×3). The combined organic phases were washed with brine (200 mL), dried over anhydrous Na2SO4, then filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (DCM/MeOH (v/v)=50/1) to give the title compound as beige solid (228.4 mg, 40.8%).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17]Cl)[C:12]=2[CH2:19][CH3:20])[CH:3]=1.[CH3:21][NH2:22].[C:23]([OH:30])(=[O:29])/[CH:24]=[CH:25]/[C:26]([OH:28])=[O:27]>C(O)C.CO>[C:23]([OH:30])(=[O:29])/[CH:24]=[CH:25]/[C:26]([OH:28])=[O:27].[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][NH:22][CH3:21])[C:12]=2[CH2:19][CH3:20])[CH:3]=1
Reactant: CCc1c(CCl)cccc1Oc1cc(Cl)ccc1C#N
Reactant: CN
Agent: O=C(O)/C=C/C(=O)O
Solvent: CCO
Solvent: CO
Product: CCc1c(CNC)cccc1Oc1cc(Cl)ccc1C#N
Temperature: 25 °C
Reaction time: 24 h
Yield: 84 %

Procedure:
To a solution of 4-chloro-2-(3-chloromethyl-2-ethyl-phenoxy)-benzonitrile (0.39 g, 1.3 mmol) in ethanol (20 mL) was added methylamine (33% in ethanol, 5.0 mL, 40 mmol), and the reaction mixture stirred for 24 h at ambient temperature. The solvent was removed in vacuo. The residue was treated with 10% sodium carbonate solution and extracted with ethyl acetate. The ethyl acetate layer was separated and a solution of fumaric acid (148 mg, 1.3 mmol) in methanol (5 mL) was added. After the solvent was removed in vacuo, the residue was triturated with diethyl ether overnight, collected by filtration, and dried to give 4-chloro-2-(2-ethyl-3-methylaminomethyl-phenoxy)-benzonitrile fumarate (455 mg, 86%) as a white solid.
Reaction SMILES: [CH2:1](O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][OH:9].[O:11]1[CH:16]=[CH:15][CH2:14][CH2:13][CH2:12]1>>[O:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH:12]1[CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][OH:9]
Reactant: OCCCCCCCCO
Reactant: C1=COCCC1
Product: OCCCCCCCCC1CCCCO1

Procedure:
1,8-Octanediol is treated with one equivalent of dihydropyrane in the presence of acid to give the 8-(tetrahydropyran-2-yl)octanol. 8-(Tetrahydropyran-2-yl)octanol, N-hydroxyphthalimide and triphenylphosphine in DMF are treated at 0° C. with diisopropylazodicarboxylate utilizing Mitsunobu reaction conditions to give O-[8-(tetrahydropyran-2-yl)octanol)phthalimide. Acid treatment of O-[8-(tetrahydro-pyran-2-yl)octanol]phthalimide will yield O-(octanol)phthalimide which in turn when treated with phosphorous tribromide and pyridine utilizing the reaction conditions of Hall, et al., Synthetic Procedures in Nucleic Acid Chemistry, Zorbach and Tipson, Editors, Volume 1, John Wiley & Sons, 1968 will yield O-(8-bromooctanol)phthalimide.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10]1[C:19]2[C:14](=[CH:15][C:16]([O:20][CH3:21])=[CH:17][CH:18]=2)[C:13](=O)[NH:12][N:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:25])=O>>[CH2:1]([O:8][CH2:9][C:10]1[C:19]2[C:14](=[CH:15][C:16]([O:20][CH3:21])=[CH:17][CH:18]=2)[C:13]([Cl:25])=[N:12][N:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1ccc2c(COCc3ccccc3)n[nH]c(=O)c2c1
Product: COc1ccc2c(COCc3ccccc3)nnc(Cl)c2c1

Procedure:
This compound is obtained according to the procedure described in 1.3. by reacting 4-benzyloxymethyl-7-methoxy-2H-phthalazin-1-one with phosphoryl chloride. This oily compound is used as obtained in the following reaction.
Reaction SMILES: COC[O:4][C:5]1[CH:15]=[CH:14][C:8]([O:9][CH2:10][C@H:11]2[CH2:13][O:12]2)=[CH:7][CH:6]=1.[C:16]1([C:22]2[C:30]3[C:29]([N:31]4[CH2:36][CH2:35][CH:34]([NH2:37])[CH2:33][CH2:32]4)=[N:28][CH:27]=[N:26][C:25]=3[S:24][CH:23]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[OH:12][C@H:11]([CH2:13][NH:37][CH:34]1[CH2:35][CH2:36][N:31]([C:29]2[C:30]3[C:22]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)=[CH:23][S:24][C:25]=3[N:26]=[CH:27][N:28]=2)[CH2:32][CH2:33]1)[CH2:10][O:9][C:8]1[CH:7]=[CH:6][C:5]([OH:4])=[CH:15][CH:14]=1
Reactant: NC1CCN(c2ncnc3scc(-c4ccccc4)c23)CC1
Reactant: COCOc1ccc(OC[C@H]2CO2)cc1
Product: Oc1ccc(OC[C@H](O)CNC2CCN(c3ncnc4scc(-c5ccccc5)c34)CC2)cc1
Yield: 57 %

Procedure:
Synthesis followed SP6 (4 h), using 250 μmol (R)-2-((4-(methoxymethoxy)phenoxy)methyl)oxirane and 1-(5-phenylthieno[2,3-d]pyrimidin-4-yl)piperidin-4-amine to give O-MOM intermediate upon purification by prep. TLC (2 mm silica gel, PE/CH2Cl2/MeOH 4:6:1) with 57% yield. Product was obtained by MOM removal according to SP8 (1.5 eq. TosOH, 10 h) and purification by prep. TLC (1 mm silica gel, CH2Cl2/MeOH 90:10) with 55% yield.
Reaction SMILES: C(=O)(O)O.[Cl:5][C:6]1[CH:7]=[C:8]([NH:18][C:19]([NH2:21])=[NH:20])[CH:9]=[CH:10][C:11]=1[N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1.CN(C)/[CH:24]=[C:25](\[F:37])/[C:26]([C:28]1[N:32]([CH:33]([CH3:35])[CH3:34])[C:31]([CH3:36])=[N:30][CH:29]=1)=O>>[Cl:5][C:6]1[CH:7]=[C:8]([NH:18][C:19]2[N:21]=[C:26]([C:28]3[N:32]([CH:33]([CH3:34])[CH3:35])[C:31]([CH3:36])=[N:30][CH:29]=3)[C:25]([F:37])=[CH:24][N:20]=2)[CH:9]=[CH:10][C:11]=1[N:12]1[CH2:13][CH2:14][O:15][CH2:16][CH2:17]1
Reactant: N=C(N)Nc1ccc(N2CCOCC2)c(Cl)c1
Reactant: Cc1ncc(C(=O)/C(F)=C/N(C)C)n1C(C)C
Agent: O=C(O)O
Product: Cc1ncc(-c2nc(Nc3ccc(N4CCOCC4)c(Cl)c3)ncc2F)n1C(C)C

Procedure:
The title compound was prepared using the procedure described in Example 112, employing N-(3-chloro-4-morpholin-4-yl-phenyl)-guanidine carbonate (Method 17; 500 mg, 1.97 mmol), and (2Z)-3-(dimethylamino)-2-fluoro-1-(1-isopropyl-2-methyl-1H-imidazol-5-yl)prop-2-en-1-one (Method 14; 392 mg, 1.64 mmol). Yield: 203 mg, 30% as a white solid; NMR: 1.41 (d, 6H), 2.49 (s, 3H), 2.90 (t, 4H), 3.72 (t, 4H), 5.35 (m, 1H), 7.10 (d, 1H), 7.34 (d, 1H), 7.50 (dd, 1H), 7.73 (d, 1H), 8.52 (d, 1H), 9.51 (s, 1H); m/z 431.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[S:9]([OH:12])(=O)=[O:10]>>[CH:4]1[C:5]([S:9]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)(=[O:12])=[O:10])=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=1
Reactant: O=S(=O)(O)Cl
Reactant: Clc1ccccc1
Product: O=S(=O)(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Reaction time: 3 h
Yield: 22.3 %

Procedure:
To 112 g (1 mole) of chlorobenzene was added 123 g (1.1 moles) of chlorosulfonic acid at 10° to 20° C. After the addition, while being maintained at 20° to 30° C., the mixture was stirred for 3 hours to complete the reaction. A 0.1 mole quantity of the unreacted chlorobenzene was recovered in the same manner as in Example 1 and 32 g of 4,4'-dichlorodiphenylsulfone was obtained in 25% yield. M.P. 148.5° to 149.5° C. Purity of 99.8%.
Reaction SMILES: [C:1]([C:4]1[CH:22]=[CH:21][C:7]([O:8][CH2:9][CH2:10][O:11][C:12]2[CH:20]=[CH:19][C:15]([C:16]([OH:18])=O)=[CH:14][CH:13]=2)=[C:6]([CH2:23][CH2:24][CH3:25])[C:5]=1[OH:26])(=[O:3])[CH3:2].C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.C(N(CC)CC)C.[N:51]1[CH:56]=[CH:55][CH:54]=[C:53]([CH2:57][CH2:58][CH2:59][CH2:60][NH2:61])[CH:52]=1>CN(C=O)C>[C:1]([C:4]1[CH:22]=[CH:21][C:7]([O:8][CH2:9][CH2:10][O:11][C:12]2[CH:13]=[CH:14][C:15]([C:16]([NH:61][CH2:60][CH2:59][CH2:58][CH2:57][C:53]3[CH:52]=[N:51][CH:56]=[CH:55][CH:54]=3)=[O:18])=[CH:19][CH:20]=2)=[C:6]([CH2:23][CH2:24][CH3:25])[C:5]=1[OH:26])(=[O:3])[CH3:2]
Reactant: NCCCCc1cccnc1
Reactant: CCCc1c(OCCOc2ccc(C(=O)O)cc2)ccc(C(C)=O)c1O
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCCc1c(OCCOc2ccc(C(=O)NCCCCc3cccnc3)cc2)ccc(C(C)=O)c1O
Temperature: 0 °C
Reaction time: 1 h
Yield: 60 %

Procedure:
To a cold (0° C.) solution of 1.22 g of 4-[2-(4-Acetyl-3-hydroxy-2-propylphenoxy)ethoxy]benzoic acid in 15 mL of anhydrous DMF was added to 0.8 mL of diphenylphosphoryl azide and 1.05 mL of anhydrous triethylamine. The resulting mixture was stirred at 0° C. for one hour and then 0.56 g of 3-pyridine butanamine was added. The mixture was stirred in ice bath for 1 hour and at room temperature for 6 hours. The solvent was removed in vacuo, the residue was dissolved in methylene chloride and washed with sodium bicarbonate solution. The extract was dried (over magnesium sulfate) and concentrated in vacuo to an oil which was purified by HPLC using 7% methanol-ethyl acetate to give an oil which was triturated with ethyl acetate-ether and filtered to yield 1.0 g, mp 93° , (60% yield) of 4-[2-(4-Acetyl-3-hydroxy-2-propylphenoxy)-ethoxy]-N-[4-(3-pyridinyl)butyl]benzamide, the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5](=[O:8])[NH:6][CH:7]=1.[Cl:9][CH2:10][CH2:11][N:12]=[C:13]=[O:14]>CN(C)C=O>[Cl:9][CH2:10][CH2:11][NH:12][C:13]([N:4]1[CH:3]=[C:2]([Cl:1])[CH:7]=[N:6][C:5]1=[O:8])=[O:14]
Reactant: O=C=NCCCl
Reactant: O=c1ncc(Cl)c[nH]1
Solvent: CN(C)C=O
Product: O=C(NCCCl)n1cc(Cl)cnc1=O
Yield: 40 %

Procedure:
was prepared from 5-chloropyrimidin-2-one and 2-chloroethylisocyanate in dimethyl formamide as described above; yield 40%. 1H NMR (DMSO-d6): δ3.6 (CH2CH2, broad m), 8.41 (2H-4,6), 9.5 (NH).
Reaction SMILES: [CH:1]1([NH:4][C:5]([C:7]2[CH:8]=[C:9]([F:52])[C:10]([CH3:51])=[C:11]([C:13]3[CH:14]=[C:15]4[C:20](=[CH:21][CH:22]=3)[C:19](=[O:23])[N:18]([CH2:24][C:25]([CH3:35])([CH3:34])[CH2:26][O:27]C(=O)C(C)(C)C)[CH:17]=[C:16]4[CH2:36][N:37]3[CH2:42][CH2:41][N:40]([C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[CH2:39][C@H:38]3[CH3:50])[CH:12]=2)=[O:6])[CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+]>CO.O>[CH:1]1([NH:4][C:5]([C:7]2[CH:8]=[C:9]([F:52])[C:10]([CH3:51])=[C:11]([C:13]3[CH:14]=[C:15]4[C:20](=[CH:21][CH:22]=3)[C:19](=[O:23])[N:18]([CH2:24][C:25]([CH3:34])([CH3:35])[CH2:26][OH:27])[CH:17]=[C:16]4[CH2:36][N:37]3[CH2:42][CH2:41][N:40]([C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[CH2:39][C@H:38]3[CH3:50])[CH:12]=2)=[O:6])[CH2:3][CH2:2]1
Reactant: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccc2c(=O)n(CC(C)(C)COC(=O)C(C)(C)C)cc(CN3CCN(C(=O)OC(C)(C)C)C[C@H]3C)c2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccc2c(=O)n(CC(C)(C)CO)cc(CN3CCN(C(=O)OC(C)(C)C)C[C@H]3C)c2c1
Temperature: 67 °C
Yield: 72.2 %

Procedure:
(3R)-tert-Butyl 4-((6-(5-(cyclopropylcarbamoyl)-3-fluoro-2-methylphenyl)-2-(2,2-dimethyl-3-(pivaloyloxy)propyl)-1-oxo-1,2-dihydroisoquinolin-4-yl)methyl)-3-methylpiperazine-1-carboxylate (50.8 g) was dissolved in methanol (600 mL) and a solution of potassium carbonate (29.3 g) in water (100 mL) was added. The reaction was heated at reflux (internal temperature 67° C.) for 16 h. After cooling to 50° C., further water was slowly added until the mixture became opaque and the mixture was cooled to 23° C. over 1 h. The precipitate was collected by filtration, washed with water (100 mL) and isohexane (100 mL) and dried in vacuo at 45° C. to give the subtitle product (32.4 g).
Reaction SMILES: [CH2:1]([C:3](=[CH:11][CH2:12][C@H:13]1[CH2:18][CH2:17][CH2:16][C@@H:15]([OH:19])[CH2:14]1)[C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5])[CH3:2]>CO>[CH2:1]([CH:3]([CH2:11][CH2:12][C@H:13]1[CH2:18][CH2:17][CH2:16][C@@H:15]([OH:19])[CH2:14]1)[C:4]([O:6][C:7]([CH3:10])([CH3:8])[CH3:9])=[O:5])[CH3:2]
Reactant: CCC(=CC[C@H]1CCC[C@@H](O)C1)C(=O)OC(C)(C)C
Solvent: CO
Product: CCC(CC[C@H]1CCC[C@@H](O)C1)C(=O)OC(C)(C)C
Reaction time: 24 h

Procedure:
1.65 g of tert-butyl 2-ethyl-4-(cis-3-hydroxycyclohexyl)but-2-enoate are dissolved in 50 ml of methanol, and 100 mg of Perlmans catalyst are added. The mixture is stirred under an atmosphere of hydrogen for 24 hours. The catalyst is filtered off through Celite, and the filtrate is then concentrated under reduced pressure. This gives 1.49 g of tert-butyl 2-ethyl-4-(cis-3-hydroxycyclohexyl)butyrate as a colorless oil. C16H30O3 (270.40), Rf(n-heptane:ethyl acetate=5:1)=0.10.
Reaction SMILES: [NH2:1][C@H:2]([C:4]([OH:6])=[O:5])[CH3:3].[OH-].[Na+].Cl[C:10]([O:12][CH3:13])=[O:11].P(=O)(O)(O)O>>[CH3:13][O:12][C:10]([NH:1][C@H:2]([C:4]([OH:6])=[O:5])[CH3:3])=[O:11]
Reactant: COC(=O)Cl
Reactant: C[C@H](N)C(=O)O
Agent: O=P(O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: COC(=O)N[C@@H](C)C(=O)O
Temperature: 0 °C
Reaction time: 3 h
Yield: 78 %

Procedure:
To a stirred solution of L-alanine (300 g, 3.37 mol sodium hydroxide (1N, 1800 cm3) at 0° C. in an ice bath was added dropwise, over 2 hours, methyl chloroformate (274 cm3, 3.54 mol). The pH of the solution was maintained at 9 by the addition of sodium hydroxide (5N). The reaction mixture was stirred at 0° C. for 3 hours whereupon it was acidified to pH 1 by the addition of phosphoric acid solution (15%) and extracted with diethyl ether (5×1000 cm3). The combined organic extracts were dried (MgSO4) and concentrated under reduced pressure to yield the product as a viscous green oil (386 g, 78%). 1H NMR (250 MHz; C2HCl3) 1.48 (3H, d, J7.25, CH3), 3.72 (3H, s, COCH3), 4.40 (1H, quintet, J7.25, CH), 5.31 (1H, bs, NH).
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[OH:6][C:7]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:8]=1[CH:9]=[CH:10][NH:11]2.[OH-].[Na+].Cl.CN(C)[CH:21]=[O:22]>O>[OH:6][C:7]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:8]=1[C:9]([CH:21]=[O:22])=[CH:10][NH:11]2
Reactant: Oc1cccc2[nH]ccc12
Reactant: CN(C)C=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: O=Cc1c[nH]c2cccc(O)c12
Reaction time: 0.25 h
Yield: 82 %

Procedure:
Phosphorous oxychloride 7.35 ml was added dropwise to dry dimethylformamide 15 ml under cooling in ice-methanol bath and the mixture was stirred for 15 min. Then, a solution of the 4-hydroxyindole 5.0 g in dry dimethylformamide 10 ml was added dropwise to the mixture under cooling in ice and the mixture was stirred for 2 h at room temperature. Water was added under cooling in ice to the mixture, which was made alkaline with a 30% aqueous sodium hydroxide solution and was stirred for 15 min. Then, the mixture was acidified to pH 4 with 5N-HCl and the precipitate was collected by filtration, washed with water and dried to give the titled compound 4.99 g as crude crystalline materials. Yield 82%. Crude crystalline materials are recrystallized from methanol to give yellow crystals m.p. 190-193° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](F)=[CH:4][C:3]=1[Cl:9].[CH2:10]([S-:12])[CH3:11].[Na+]>CS(C)=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:12][CH2:10][CH3:11])=[CH:4][C:3]=1[Cl:9]
Reactant: CC[S-]
Reactant: Fc1ccc(Br)c(Cl)c1
Agent: [Na+]
Solvent: CS(C)=O
Product: CCSc1ccc(Br)c(Cl)c1
Temperature: 100 °C
Yield: 70 %

Procedure:
To a room temperature solution of 1-bromo-4-fluoro-2-chlorobenzene (1.9 g, 0.97 mmol) in DMSO (10 mL) was added sodium ethanethiolate (0.84 g, 1 mmol) and the resulting reaction mixture was heated to 100° C. for 18 hours. The reaction mixture was partitioned between water (20 mL) and EtOAc (50 mL). The organic layer was separated and the aqueous layer was further extracted with EtOAc (3×50 mL). The organic layers were combined and washed with saturated brine solution (20 mL) then dried over Na2SO4, filtered and concentrated in vacuo. The crude material was purified by silica gel column chromatography eluting with heptane to afford the title compound as a colourless liquid in 70% yield, 1.6 g.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=1.N1C=CC=CC=1.[C:19]([N:29]1[CH2:34][CH2:33][C:32](=[O:35])[CH2:31][CH2:30]1)([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:20]>O1CCCC1>[C:19]([N:29]1[CH2:30][CH2:31][C:32]([C:7]2[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=2)([OH:35])[CH2:33][CH2:34]1)([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:20]
Reactant: O=C1CCN(C(=O)OCc2ccccc2)CC1
Reactant: Brc1cccnc1
Agent: [Li]CCCC
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: O=C(OCc1ccccc1)N1CCC(O)(c2cccnc2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 74.8 %

Procedure:
To a cooled solution (-78° C.) of n-butyllithium (2.0M in hexane, 12.9 mL, 28.3 mmol, 1.2 eq) in tetrahydrofuran (200 mL) under nitrogen was added 3-bromopyridine (2.27 mL, 23.6 mmol, 1.1 eq). The solution became a dark green color as the pyridine was added. The reaction was stirred at this temperature for 1h, at which time 1-carbobenzyloxy-4-piperidone (described in example 87c) (5.00 g, 21.4 mmol) was added as a tetrahydrofuran solution (20 mL). The cooling bath was removed and the reaction warmed to room temperature, stirring at that temperature for 18 h. The reaction was quenched by the addition of water (125 mL) and the aqueous phase extracted with ethyl acetate (3×75 mL). Combined organic extracts were dried over anhydrous magnesium sulfate, filtered, and reduced to an oil. The reaction product was purified by flash chromatography over silica gel (300 mL, eluent: ethyl acetate) to yield 5.00 g (75%) of the title compound as an oil. TLC analysis (Rf 0.10, ethyl acetate). MS (CI, CH4) m/z 313 (M+1,100), 341 (M+29,15), 295 (15).
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:15])=[C:10](F)[C:11]=2[F:13])[C:6](=[O:16])[C:5]([C:17]([OH:19])=[O:18])=[CH:4]1)[CH3:2].C(OC([NH:27][C@H:28]1[C@@H:32]([CH3:33])[CH2:31][NH:30][CH2:29]1)=O)(C)(C)C.C1CCN2C(=NCCC2)CC1>C(#N)C>[NH2:27][C@H:28]1[C@@H:32]([CH3:33])[CH2:31][N:30]([C:10]2[C:11]([F:13])=[C:12]3[C:7]([C:6](=[O:16])[C:5]([C:17]([OH:19])=[O:18])=[CH:4][N:3]3[CH2:1][CH3:2])=[CH:8][C:9]=2[F:15])[CH2:29]1
Reactant: C[C@H]1CNC[C@H]1NC(=O)OC(C)(C)C
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(F)c(F)c21
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3C[C@@H](N)[C@@H](C)C3)c(F)c21
Temperature: 25 °C
Yield: 31.6 %

Procedure:
A mixture of 1-ethyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid (1.0 g), cis-3-t-butoxycarbonylamino-4-methylpyrrolidine (0.89 g), DBU (0.62 g) and anhydrous acetonitrile (30 ml) was refluxed for 2 hours and then concentrated. The resulting residue was dissolved in chloroform (50 ml), washed with 10% aqueous citric acid solution and water successively, dried over anhydrous sodium sulfate and concentrated. To the resulting residue was added hot methanol to crystallize and then cooled. The resulting precipitate was collected by filtration, added to the mixture of concentrated hydrochloric acid-methanol (1:1, 18 ml) and stirred at room temperature for an hour. The reacting mixture was neutralized with concentrated aqueous ammonia and the resulting precipitate was collected by filtration, washed with ice-water sufficiently and recrystallized from dichloromethane-methanol (1:1) to give the title compound (0.41 g) as colorless prisms, mp 232°-234° C. (decompd.).
Reaction SMILES: [F:1][C:2]1[C:10]([O:11][C:12]2[C:21]3[C:16](=[CH:17][C:18]([O:30][CH3:31])=[C:19]([O:22][CH2:23][CH:24]4[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]4)[CH:20]=3)[N:15]=[CH:14][N:13]=2)=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2.C(N(C(C)C)CC)(C)C.[C:41](Cl)(=[O:43])[CH3:42]>ClCCl>[C:41]([N:27]1[CH2:28][CH2:29][CH:24]([CH2:23][O:22][C:19]2[CH:20]=[C:21]3[C:16](=[CH:17][C:18]=2[O:30][CH3:31])[N:15]=[CH:14][N:13]=[C:12]3[O:11][C:10]2[C:2]([F:1])=[C:3]3[C:7](=[CH:8][CH:9]=2)[NH:6][CH:5]=[CH:4]3)[CH2:25][CH2:26]1)(=[O:43])[CH3:42]
Reactant: CC(=O)Cl
Reactant: COc1cc2ncnc(Oc3ccc4[nH]ccc4c3F)c2cc1OCC1CCNCC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc2ncnc(Oc3ccc4[nH]ccc4c3F)c2cc1OCC1CCN(C(C)=O)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 62.9 %

Procedure:
4-[(4-Fluoro-1H-indol-5-yl)oxy]-7-methoxy-6-(piperidin-4-ylmethoxy)quinazoline (210 mg, 0.50 mmol) was suspended in dichloromethane (7 ml) and diisopropylethylamine (104 μl, 0.60 mmol) and acetyl chloride (42 μl, 0.60 mmol) were added. All solid material went into solution. The mixture was stirred at ambient temperature overnight. The mixture was washed with brine, followed by saturated aqueous sodium hydrogen carbonate, dried (MgSO4) and concentrated under reduced pressure. The residue was purified by column chromatography eluting with methylene chloride/methanol (98/2) to give 6-[(1-acetylpipendin-4-yl)methoxy]-4-[(4-fluoro-1H-indol-5-yl)oxy]-7-methoxyquinazoline (146 mg, 63%) as a white foam.
Reaction SMILES: [OH-].[K+].C(O)C.[SH:6][CH2:7][CH2:8][OH:9].[CH3:10][C:11]1([CH3:14])[CH2:13][O:12]1>>[OH:9][CH2:8][CH2:7][S:6][CH2:10][C:11]([OH:12])([CH3:14])[CH3:13]
Reactant: CC1(C)CO1
Reactant: OCCS
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)(O)CSCCO

Procedure:
1 mol of KOH is dissolved in 1 mol of ethanol and 1 mol of 2-mercaptoethanol is added. 1 mol of 2,2-dimethyloxirane is added dropwise to this solution in the course of 60 min and with cooling. The mixture is then neutralized, the precipitate is filtered off, and the filtrate is concentrated and distilled in vacuo. 2-Hydroxy-2-methylpropyl 2-hydroxyethyl sulphide of boiling point 93° C. at 0.199 mbar is obtained.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1.[CH2:12]([CH:14]([NH2:17])[CH2:15][CH3:16])[CH3:13].C(N(CC)C(C)C)(C)C>CCO>[Cl:1][C:2]1[N:7]=[C:6]([NH:17][CH:14]([CH2:15][CH3:16])[CH2:12][CH3:13])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1
Reactant: CCC(N)CC
Reactant: O=[N+]([O-])c1cnc(Cl)nc1Cl
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: CCC(CC)Nc1nc(Cl)ncc1[N+](=O)[O-]
Reaction time: 8 h
Yield: 59.5 %

Procedure:
To a solution of 2,4-dichloro-5-nitro-pyrimidine (2 g, 10.3 mmol) in anhydrous EtOH (20 mL) is added 1-ethylpropylamine (1.3 mL, 11.3 mmol) and N,N-diisopropylethylamine (2.7 mL, 15.5 mmol) at 0° C. The reaction mixture is stirred for 8 h and concentrated in vacuo. The residue is dissolved with EtOAc, washed with saturated NaHCO3 and brine, dried over Na2SO4, and concentrated in vacuo. Purification with column chromatography (SiO2, EtOAC/Hexane 1:3) gives 1.5 g of (2-chloro-5-nitro-pyrimidin-4-yl)-(1-ethyl-propyl)-amine.