Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1C=CC2N(O)N=NC=2C=1.[CH:11]1([N:17]([C@H:35]2[CH2:40][CH2:39][C@H:38]([CH3:41])[CH2:37][CH2:36]2)[C:18](=[O:34])[NH:19][C:20]2[S:21][C:22]([S:25]([N:28]([CH2:30][C:31](O)=[O:32])[CH3:29])(=[O:27])=[O:26])=[CH:23][N:24]=2)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1.CCN=C=NCCCN(C)C.[CH:53]([N:56](C(C)C)[CH2:57][CH3:58])(C)[CH3:54].C(NCC)C>CN(C=O)C>[CH:11]1([N:17]([C@H:35]2[CH2:36][CH2:37][C@H:38]([CH3:41])[CH2:39][CH2:40]2)[C:18](=[O:34])[NH:19][C:20]2[S:21][C:22]([S:25]([N:28]([CH3:29])[CH2:30][C:31]([N:56]([CH2:57][CH3:58])[CH2:53][CH3:54])=[O:32])(=[O:27])=[O:26])=[CH:23][N:24]=2)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: CN(CC(=O)O)S(=O)(=O)c1cnc(NC(=O)N(C2CCCCC2)[C@H]2CC[C@H](C)CC2)s1
Reactant: CCN(C(C)C)C(C)C
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCNCC
Product: CCN(CC)C(=O)CN(C)S(=O)(=O)c1cnc(NC(=O)N(C2CCCCC2)[C@H]2CC[C@H](C)CC2)s1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
An equimolar mixture of HOBt, ({2-[3-cyclohexyl-3-(trans-4-methyl-cyclohexyl)-ureido]-thiazole-5-sulfonyl}-methyl-amino)-acetic acid was added EDAC (1.5 eq) and diisopropylethyl amine (1.2 eq) and dry DMF (10 mL/mmol). The solution was stirred 30 min at rt and then diethyl amine (1.5 eq) was added and stirring was continued over night.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1)#[N:2].C(=O)([O-])[O-].[Cs+].[Cs+].[F-].[Cs+].Br[C:21]1[CH:22]=[C:23]2[C:28](=[CH:29][CH:30]=1)[N:27]=[C:26]([CH3:31])[CH:25]=[N:24]2>O.C1(C)C=CC=CC=1>[CH3:31][C:26]1[CH:25]=[N:24][C:23]2[C:28]([N:27]=1)=[CH:29][C:30]([C:6]1[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=1)=[CH:21][CH:22]=2
Reactant: N#Cc1ccc(B(O)O)cc1
Reactant: Cc1cnc2cc(Br)ccc2n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [F-]
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1cnc2ccc(-c3ccc(C#N)cc3)cc2n1
Temperature: 80 °C

Procedure:
4-Cyanophenylboronic acid (588 mg, 4.0 mmol), cesium carbonate (2.2 g, 7.0 mmol), and cesium fluoride (608 mg, 4.0 mmol) were combined in H2O (15 mL) and treated with the products from Example 61B (446 mg, 2.0 mmol) in toluene (10 mL) and heated at 80° C. for 3 hours. The reaction mixture was allowed to cool to room temperature and filtered through a pad of celite. The filtrate was partitioned between IPAc (60 mL) and H2O (50 mL). The organic layer was separated, washed with 20% brine, dried with Na2SO4, filtered, and the filtrate was concentrated under vacuum to provide the title compounds which were used in the next step without further purification. MS 246 (M+H)+; 1H NMR (400 MHz, CDCl3) δ 8.71 (s, 1H), 8.69 (s, 1H), 8.02-8.20 (m, 4H), 7.84-7.90 (m, 2H), 7.70-7.76 (m, 8H), 2.73 (s, 6H); 13C NMR (400 MHz, CDCl3) δ 154.34, 154.10, 146.47, 147.17, 143.80, 142.93, 141.74, 140.62, 140.39, 140.18, 139.16, 132.49, 130.16, 129.74, 129.25, 128.71, 128.63, 128.06, 127.77, 127.74, 127.66, 127.59, 127.22, 126.73, 118.39, 118.37, 111.61, 111.51, 22.96.
Reaction SMILES: [F:1][C:2]1[CH:33]=[CH:32][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]([C@H:16]3[NH:20][CH2:19][C@H:18]([NH:21][C:22](=[O:31])[O:23][CH2:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[CH2:17]3)=[O:15])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[N:34]1([CH2:39][C:40](O)=[O:41])[CH:38]=[N:37][CH:36]=[N:35]1>>[N:34]1([CH2:39][C:40]([N:20]2[C@H:16]([C:14](=[O:15])[NH:13][C:10]3[CH:11]=[CH:12][C:7]([O:6][C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:33][CH:32]=4)=[CH:8][CH:9]=3)[CH2:17][C@@H:18]([NH:21][C:22](=[O:31])[O:23][CH2:24][C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH2:19]2)=[O:41])[CH:38]=[N:37][CH:36]=[N:35]1
Reactant: O=C(O)Cn1cncn1
Reactant: O=C(N[C@H]1CN[C@H](C(=O)Nc2ccc(Oc3ccc(F)cc3)cc2)C1)OCc1ccccc1
Product: O=C(N[C@@H]1C[C@@H](C(=O)Nc2ccc(Oc3ccc(F)cc3)cc2)N(C(=O)Cn2cncn2)C1)OCc1ccccc1
Yield: 72 %

Procedure:
Proceeding as in Example 1, but substituting benzyl (3R,5S)-5-(4-(4-fluorophenoxy)phenylcarbamoyl)pyrrolidin-3-ylcarbamate and 2-(1H-1,2,4-triazol-1-yl)acetic acid, gave benzyl (3R,5S)-1-(2-(1H-1,2,4-triazol-1-yl)acetyl)-5-(4-(4-fluorophenoxy)phenylcarbamoyl)pyrrolidin-3-ylcarbamate (1.57 g, 2.81 mmol, 72% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([O:11][C:12]2[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=2[CH:14]=[N:15][OH:16])[N:4]=1.[Cl:21][C:22]1[CH:23]=[C:24]([CH:29]=[CH:30][CH:31]=1)[CH:25]=[CH:26][CH2:27]Br>CC(C)=O.C(=O)([O-])[O-].[K+].[K+]>[Cl:21][C:22]1[CH:23]=[C:24]([CH:29]=[CH:30][CH:31]=1)[CH:25]=[CH:26][CH2:27][C:12]1([O:11][C:5]2[N:6]=[C:7]([O:9][CH3:10])[CH:8]=[C:3]([O:2][CH3:1])[N:4]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:13]1[CH:14]=[N:15][OH:16]
Reactant: Clc1cccc(C=CCBr)c1
Reactant: COc1cc(OC)nc(Oc2ccccc2C=NO)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1cc(OC)nc(OC2(CC=Cc3cccc(Cl)c3)C=CC=CC2C=NO)n1
Yield: 61.2 %

Procedure:
5.5 g of 2-(4,6-dimethoxy-2-pyrimidinyloxy)benzaldoxime and 4.6 g of 3-chlorocinnamyl bromide were dissolved in 30 ml of dry acetone containing 2.7 g of anhydrous potassium carbonate. The solution was heated for 5 hours under stirring and reflux. After the reaction mixture was allowed to cool down, the acetone was distilled out under reduced pressure and the resulting residue was dissolved in 200 ml of ethyl acetate. The ethyl acetate solution was washed with water and the organic layer was dried over anhydrous sodium sulfate. The solution was then concentrated under reduced pressure. The residue was purified by silica gel chromatography (developer: n-hexane:ethyl acetate:4:1) to obtain 5.2 g of 0-(3-chlorocinnamyl)-2-(4,6-dimethoxy-2-pyrimidinyloxy)benzaldoxime as a semi-solid substance.
Reaction SMILES: [C:1]1([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:6]=[C:5]([C:7]([O-])=[O:8])[CH:4]=[C:3]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:2]=1.CO>C1COCC1>[OH:8][CH2:7][C:5]1[CH:4]=[C:3]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:2]=[C:1]([CH:6]=1)[C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: CCOC(=O)c1cc(C(=O)[O-])cc(C(=O)OCC)c1
Solvent: CO
Solvent: C1CCOC1
Product: CCOC(=O)c1cc(CO)cc(C(=O)OCC)c1

Procedure:
A mixture of diethyl 1,3,5-benzenetricarboxylate (5.2 g) and borane methylsulfide complex (6.1 g) is stirred in THF (150 mL) at 20–25 degrees C. overnight. The mixture is then treated with methanol, concentrated to dryness, and chouromatographed (silica gel) to give diethyl 5-(hydroxymethyl)isophthalate. Diethyl 5-(hydroxymethyl)isophthalate (3.4 g) is hydroyzed in ethanol and water with lithium hydroxide monohydrate (0.57 g) at 20–25 degrees C. for 3.5 hours at which time the solvents are removed under reduced pressure. Water (100 mL) is added and the mixture is acidified to pH=4 with concentrated hydrochloric acid. The mixture is extracted with ethyl acetate and dried over magnesium sulfate, filtered, and concentrated to give 3-(ethoxycarbonyl)-5-(hydroxymethyl)benzoic acid, high resolution MS MH+=225.0769. 3-(Ethoxycarbonyl)-5-(hydroxymethyl)benzoic acid (2.3 g), EDC (3.0 g), 1-HOBT (2.1 g), diisopropylethylamine (2.7 mL), dipropyl amine (2.8 mL), and DMF (50 mL) are stirred at 20–25 degrees C. overnight. The mixture is then partitioned between ethyl acetate, water, and saline. The organic phase is separated and dried over magnesium sulfate, filtered, and concentrated. Chromatography (silica gel) gives ethyl 3-[(dipropylamino)carbonyl]-5-(hydroxymethyl)benzoate, NMR (CDCl3) δ 0.77, 1.0, 1.4, 1.6, 1.7, 3.2, 3.5, 4.4, 4.8, 7.6, 8.0 and 8.1.
Reaction SMILES: [C:1]([C:4]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][C:5]=1[C:6](O)=[O:7])(=O)[CH3:2].O.[NH2:16][NH2:17]>>[CH3:14][O:13][C:10]1[CH:9]=[C:5]2[C:4]([C:1]([CH3:2])=[N:16][NH:17][C:6]2=[O:7])=[CH:12][CH:11]=1
Reactant: COc1ccc(C(C)=O)c(C(=O)O)c1
Reactant: NN
Solvent: O
Product: COc1ccc2c(C)n[nH]c(=O)c2c1

Procedure:
This compound is obtained according to the procedure described in 1.2. by reacting unpurified 2-acetyl-5-methoxybenzoic acid with hydrazine hydrate.
Reaction SMILES: [C:1]([CH2:3][NH:4][S:5]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)(=[O:7])=[O:6])#[N:2].[Cl:14][C:15]([Cl:21])([S:19]Cl)[CH:16]([Cl:18])[Cl:17].C(N(CC)CC)C>C(Cl)Cl>[C:1]([CH2:3][N:4]([S:19][C:15]([Cl:21])([Cl:14])[CH:16]([Cl:18])[Cl:17])[S:5]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)(=[O:6])=[O:7])#[N:2]
Reactant: ClSC(Cl)(Cl)C(Cl)Cl
Reactant: N#CCNS(=O)(=O)c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: N#CCN(SC(Cl)(Cl)C(Cl)Cl)S(=O)(=O)c1ccccc1
Reaction time: 0.33 h
Yield: 65 %

Procedure:
To a stirred solution of 5.0 g (0.025 mole) N-cyanomethyl phenylsulfonamide (the product of Example 6) and 6.0 g (0.026 mole) 1,1,2,2-tetrachloroethylsulfenyl chloride in 125 ml methylene chloride, 3.2 g (0.032 mole) triethylamine in 25 ml methylene chloride were dropped in over 35 minutes. The reaction mixture was stirred 20 minutes. The reaction mixture was washed three times with 75 ml portions of water, dried over magnesium sulfate and stripped to give 6.4 g of a brown oil. The oil crystallized when hexane was added to it and the resulting mixture was cooled in an ice bath. The solids were taken up with 25 ml toluene, treated with charcoal and filtered, Hexane, 25 ml, was added to the toluene filtrate, and the resulting mixture was cooled in an ice bath to give 2.3 g of yellow crystals, melting point 89°-101° C. The crystals were recrystallized from a mixture of 25 ml hexane and 5 ml toluene. The filtrate was cooled in an ice bath to give 0.8 g of the above-identified product as a white solid, melting point 106° C.-108° C.
Reaction SMILES: [I:1]N1C(=O)CCC1=O.[F:9][C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1.C(O)(=O)C.S(=O)(=O)(O)O>O>[F:9][C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[C:12]([I:1])[CH:11]=1
Reactant: O=C1CCC(=O)N1I
Reactant: Oc1ccc(F)cc1
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Solvent: O
Product: Oc1ccc(F)cc1I
Temperature: 25 °C
Reaction time: 18 h
Yield: 40 %

Procedure:
N-Iodosuccinimide (10 g, 45.0 mmol) and 4-fluoro-phenol (5.00 g, 40.0 mmol) were suspended in acetic acid (39 ml, 649.0 mmol) and stirred for 5 minutes before addition of concentrated sulphuric acid (0.79 ml, 13.4 mmol). The reaction mixture was stirred for 18 hours at room temperature before diluting with water (100 ml). The aqueous layer was extracted with dichloromethane (2×30 ml). The combined organic extracts were washed with sodium thiosulphate solution (20% aqueous, wt:v), water, dried over sodium sulfate, filtered and concentrated in vacuo. The crude residue was purified by column chromatography (silica gel) eluting with toluene to afford the title compound as an off white solid, 4.5 g, 40% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:10]=[CH:11][C:12]3[N:16]=[N:15][N:14]([C@@H:17]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[CH2:18][OH:19])[C:13]=3[CH:26]=2)[CH:5]=[C:4]([F:27])[C:3]=1[C:28]([F:31])([F:30])[F:29]>O=[Mn]=O.C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:10]=[CH:11][C:12]3[N:16]=[N:15][N:14]([C@@H:17]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[CH:18]=[O:19])[C:13]=3[CH:26]=2)[CH:5]=[C:4]([F:27])[C:3]=1[C:28]([F:31])([F:30])[F:29]
Reactant: OC[C@H](c1ccccc1)n1nnc2ccc(Oc3cc(F)c(C(F)(F)F)c(Cl)c3)cc21
Agent: O=[Mn]=O
Solvent: ClC(Cl)Cl
Product: O=C[C@H](c1ccccc1)n1nnc2ccc(Oc3cc(F)c(C(F)(F)F)c(Cl)c3)cc21
Temperature: 40 °C
Reaction time: 18 h

Procedure:
A mixture of (S)-6-[(2-chloro-α,α,α,6-tetrafluoro-p-tolyl)oxy]-β-phenyl-1H-benzotriazole-1-ethanol (1.0 g, 0.0022 mole) i chloroform is treated with MnO2, (1.0 g, 0.0115 mole) stirred at 40° C. for 18 hours and filtered through a bed of diatomaceous earth. The filtrate is concentrated in vacuo to give a residue which is chromatographed using silica gel and 10% tetrahydrofuran in carbon tetrachloride to yield the title product as a white solid, 0.42 g, mp 84°-85° C., characterized by elemental and NMR analyses.
Reaction SMILES: [CH2:1]([N:3]([CH2:36][CH3:37])[CH2:4][CH2:5][CH2:6][NH:7][C:8]1[N:9]=[C:10]([C:27]2[CH:28]=[C:29]([CH:33]=[CH:34][CH:35]=2)[C:30](O)=[O:31])[C:11]2[CH:17]=[CH:16][C:15](=[O:18])[N:14]([C:19]3[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:20]=3[F:26])[C:12]=2[N:13]=1)[CH3:2].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.[NH2:69][C:70]1[S:71][CH:72]=[CH:73][N:74]=1>CN(C=O)C>[CH2:1]([N:3]([CH2:36][CH3:37])[CH2:4][CH2:5][CH2:6][NH:7][C:8]1[N:9]=[C:10]([C:27]2[CH:28]=[C:29]([CH:33]=[CH:34][CH:35]=2)[C:30]([NH:69][C:70]2[S:71][CH:72]=[CH:73][N:74]=2)=[O:31])[C:11]2[CH:17]=[CH:16][C:15](=[O:18])[N:14]([C:19]3[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:20]=3[F:26])[C:12]=2[N:13]=1)[CH3:2]
Reactant: Nc1nccs1
Reactant: CCN(CC)CCCNc1nc(-c2cccc(C(=O)O)c2)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCN(CC)CCCNc1nc(-c2cccc(C(=O)Nc3nccs3)c2)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 57.9 %

Procedure:
To the compound 3-[2-{[3-(diethylamino)propyl]amino}-8-(2,6-difluorophenyl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl]benzoic acid (30 mg, 0.06 mmol) in DMF (0.5 mL) were added HBTU (27 mg, 0.072 mmol), triethylamine (16.9 uL, 0.12 mmol) and 2-aminothiazole (9.01 uL, 0.09 mmol). The mixture was stirred at rt overnight. Separation by HPLC with TFA, followed by neutralization with SPE amine cartridge afforded the title compound (20.5 mg, 58%). LC-MS m/z 590 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][C:10](=[O:16])/[CH:11]=[CH:12]/OCC.C1C(=O)N(Br)C(=O)C1.[NH2:25][C:26]([NH2:28])=[S:27].[OH-].[NH4+]>O1CCOCC1.O>[NH2:28][C:26]1[S:27][C:11]([C:10]([NH:9][C:3]2[C:4]([CH3:8])=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])=[O:16])=[CH:12][N:25]=1
Reactant: NC(N)=S
Reactant: CCO/C=C/C(=O)Nc1c(C)cccc1Cl
Agent: O=C1CCC(=O)N1Br
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: Cc1cccc(Cl)c1NC(=O)c1cnc(N)s1
Temperature: 21 °C
Reaction time: 3 h
Yield: 94.9 %

Procedure:
To a mixture of compound 5B (5.00 g, 20.86 mmol) in 1,4-dioxane (27 mL) and water (27 mL) was added NBS (4.08 g, 22.9 mmol) at −10 to 0° C. The slurry was warmed and stirred at 20-22° C. for 3 h. Thiourea (1.60 g, 21 mmol) was added and the mixture heated to 80° C. After 2 h, the resulting solution was cooled to 20-22° and conc. ammonium hydroxide (4.2 mL) was added dropwise. The resulting slurry was concentrated under vacuum to about half volume and cooled to 0-5° C. The solid was collected by vacuum filtration, washed with cold water (10 mL), and dried to give 5.3 g (94.9% yield) of 2-amino-N-(2-chloro-6-methylphenyl)thiazole-5-carboxamide. 1H NMR (400 MHz, DMSO-d6) δ δ 2.19 (s, 3H), 7.09-7.29 (m, 2H, J=7.5), 7.29-7.43 (d, 1H, J=7.5), 7.61 (s, 2H), 7.85 (s, 1H), 9.63 (s, 1H); 13C NMR (125 MHz, DMSO-d6) δ: 18.18, 120.63, 126.84, 127.90, 128.86, 132.41, 133.63, 138.76, 142.88, 159.45, 172.02.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([P:8](=[O:11])([CH3:10])[CH3:9])=[CH:4][CH:3]=1.[Cl:12][C:13]1[N:18]=[C:17](Cl)[N:16]=[C:15]([Cl:20])[N:14]=1>CN(C)C=O.C(N(C(C)C)CC)(C)C>[Cl:12][C:13]1[N:14]=[C:15]([Cl:20])[N:16]=[C:17]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([P:8]([CH3:9])([CH3:10])=[O:11])=[CH:6][CH:7]=2)[N:18]=1
Reactant: Clc1nc(Cl)nc(Cl)n1
Reactant: CP(C)(=O)c1ccc(N)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CP(C)(=O)c1ccc(Nc2nc(Cl)nc(Cl)n2)cc1
Temperature: 0 °C

Procedure:
A suspension of 4-amino-dimethylphenylphosphine oxide (3.7 g, 2.2 mmol) in 15 mL of N,N-Dimethylformamide and 3.6 mL of Diisopropylethylamine is cooled to 0° C. 2,4,6-trichloro-1,3,5-triazine (2.6 mmol) is added in four portions over 5 minutes. The reaction mixture is warmed up to room temperature and stirred until formation of the desired compound. The reaction mixture is filtered and purified by prep-HPLC.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]([O:12][CH3:13])[C:9]([O:14][CH3:15])=[CH:8][C:4]=1[C:5](Cl)=[O:6].[Br:16][C:17]1[NH:18][CH:19]=[CH:20][CH:21]=1>>[CH3:1][O:2][C:3]1[CH:11]=[C:10]([O:12][CH3:13])[C:9]([O:14][CH3:15])=[CH:8][C:4]=1[C:5]([N:18]1[CH:19]=[CH:20][CH:21]=[C:17]1[Br:16])=[O:6]
Reactant: COc1cc(OC)c(C(=O)Cl)cc1OC
Reactant: Brc1ccc[nH]1
Product: COc1cc(OC)c(C(=O)n2cccc2Br)cc1OC
Yield: 55.1 %

Procedure:
Following the procedure for Example B, 2,4,5-trimethoxybenzoyl chloride (1.38 g, 6 mmol) and 2-bromopyrrole (4 mmol) gave 0.75 g of the title compound: mp 120-121° C.; 1H NMR (CDCl3) δ: 7.05-6.95 (2 H, m), 6.52 (1 H, s), 6.35 (1 H, dd, J=3.3, 1.8), 6.18 (1 H, t, J=3.5), 3.96 (3 H, s), 3.86 (3 H, s), 3.76 (3 H, s).
Reaction SMILES: [O:1]=[C:2]1[C:11]([CH:12]=O)=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[NH:3]1.[CH2:14]1[O:22][C:21]2[C:16](=[C:17]([CH2:23][CH2:24][CH:25]3[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]3)[CH:18]=[CH:19][CH:20]=2)[O:15]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>O1CCCC1.C(O)(=O)C>[O:1]=[C:2]1[C:11]([CH2:12][N:28]2[CH2:29][CH2:30][CH:25]([CH2:24][CH2:23][C:17]3[CH:18]=[CH:19][CH:20]=[C:21]4[O:22][CH2:14][O:15][C:16]=34)[CH2:26][CH2:27]2)=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[NH:3]1
Reactant: c1cc(CCC2CCNCC2)c2c(c1)OCO2
Reactant: O=Cc1cc2ccccc2[nH]c1=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: O=c1[nH]c2ccccc2cc1CN1CCC(CCc2cccc3c2OCO3)CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 25.9 %

Procedure:
In 50 ml of tetrahydrofuran were dissolved 0.24 g of 2-oxo-1,2-dihydro-3-quinolinecarboxaldehyde and 0.3 g of 4-[2-[2,3-(methylenedioxy)phenyl]ethyl]piperidine. To the mixture were added 0.5 ml of acetic acid and 0.42 g of sodium triacetoxyborohydride were added thereto, followed by stirring at room temperature for 12 hours. An aqueous saturated sodium bicarbonate aqueous solution was added to the reaction solution, and then the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, and then dried over anhydrous magnesium sulfate. The solvent was evaporated, and the resulting solid was collected by filtration, to give 130 mg of the title compound as a light brown solid.
Reaction SMILES: Cl.[NH2:2]O.[CH3:4][C:5]([CH3:14])([CH3:13])[C:6](=O)[CH2:7][C:8]([O:10]C)=[O:9].O>C(O)C>[C:5]([C:6]1[NH:2][O:10][C:8](=[O:9])[CH:7]=1)([CH3:14])([CH3:13])[CH3:4]
Reactant: COC(=O)CC(=O)C(C)(C)C
Reactant: NO
Agent: Cl
Solvent: CCO
Solvent: O
Product: CC(C)(C)c1cc(=O)o[nH]1
Temperature: 25 °C
Yield: 73.6 %

Procedure:
A mixture of 8.8 grams (126 mmol, 1 eq) of hydroxylamine hydrochloride and 10 grams (126 mmol, 1 eq) in 40 mL of ethanol was heated to reflux and 20 grams (126 mmol, 1 eq) of methyl 4,4-dimethyl-3-oxopentanoate was added. The reaction mixture was heated for 2 hours and then allowed to cool to room temperature overnight. The mixture formed a precipitate. To this mixture was added 50 mL of water with stirring and more precipitate formed. The solid was collected by filtration and dried. This gave 13.1 grams (48% yield) of the desired product. mp 110°-15° C.
Reaction SMILES: Cl.[CH3:2][O:3][CH2:4][C@H:5]1[CH2:10][CH2:9][C@H:8]([NH2:11])[CH2:7][CH2:6]1.[C:12]1(=O)[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1.CO.C([BH3-])#N.[Na+]>C1COCC1>[CH:12]1([NH:11][C@H:8]2[CH2:9][CH2:10][C@H:5]([CH2:4][O:3][CH3:2])[CH2:6][CH2:7]2)[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: O=C1CCCCC1
Reactant: COC[C@H]1CC[C@H](N)CC1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: COC[C@H]1CC[C@H](NC2CCCCC2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of trans-4-methoxymethyl-cyclohexylamine hydrochloride (0.7 g), cyclohexanone (0.4 g), diisoropylethylamine (0.5 g) and molecular sieves (3 g) in THF (5 mL) and methanol (5 mL) was added sodium cyanoborohydride (0.49 g) and the mixture stirred overnight at room temperature. Insoluble material was removed by filtration and the crude product purified by flash chromatography to give cyclohexyl-(trans-4-methoxymethyl-cyclohexyl)-amine (0.29 g).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([SH:7])=[N:5][N:6]=1.Cl.[N:9]1([CH2:15][CH2:16][CH2:17]Cl)[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1.[OH-].[K+]>CO>[NH2:1][C:2]1[S:3][C:4]([S:7][CH2:17][CH2:16][CH2:15][N:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)=[N:5][N:6]=1
Reactant: ClCCCN1CCCCC1
Reactant: Nc1nnc(S)s1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: Nc1nnc(SCCCN2CCCCC2)s1
Yield: 57.9 %

Procedure:
2-Amino-5-mercapto-1,3,4-thiadiazole (13.3 g), piperidinopropylchloridehydrochloride (18.4 g), and potassium hydroxide (11.2 g) were stirred in methanol (300 ml) overnight at room temperature. The reaction mixture was concentrated under a vacuum. The residue, with water added thereto, was extracted with ethyl acetate. The extract was dried over sodium sulfate anhydride, and then concentrated under a vacuum. The resulting solid was recrystallized from n-hexane/ethanol, thereby yielding 13.9 g of the aimed compound.
Reaction SMILES: [P:1]([O-:37])([O:30][CH2:31][CH2:32][N+:33]([CH3:36])([CH3:35])[CH3:34])([O:3][CH2:4][CH:5]([OH:29])[CH2:6][O:7][C:8](=[O:28])[NH:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[O:2].[CH3:38][N:39]=[C:40]=[O:41]>N1C=CC=CC=1>[P:1]([O-:37])([O:30][CH2:31][CH2:32][N+:33]([CH3:36])([CH3:35])[CH3:34])([O:3][CH2:4][CH:5]([O:29][C:40](=[O:41])[NH:39][CH3:38])[CH2:6][O:7][C:8](=[O:28])[NH:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[O:2]
Reactant: CN=C=O
Reactant: CCCCCCCCCCCCCCCCCCNC(=O)OCC(O)COP(=O)([O-])OCC[N+](C)(C)C
Solvent: c1ccncc1
Product: CCCCCCCCCCCCCCCCCCNC(=O)OCC(COP(=O)([O-])OCC[N+](C)(C)C)OC(=O)NC
Temperature: 50 °C

Procedure:
The hydroxy compound (300 mg) obtained in Example 28 and 1.5 ml of methyl isocyanate were dissolved in 7 ml of pyridine, and the solution was warmed at 50° C. for 5 hours. The solvent was then distilled off and the residue was purified by silica gel column chromatography [silica gel: 10 g; eluent: chloroform-methanol-water (65:25:4)] to give 298 mg of the above-identified compound.
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([C:8]([NH:10][CH2:11][CH2:12][CH:13]([CH3:15])[CH3:14])=[O:9])=[CH:4][CH:3]=1.[F:16][C:17]([F:32])([F:31])[C:18]1[CH:19]=[C:20]([CH:28]=[CH:29][CH:30]=1)[O:21][CH:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1>>[CH3:14][CH:13]([CH3:15])[CH2:12][CH2:11][NH:10][C:8]([C:5]1[N:6]=[N:7][C:2]([N:25]2[CH2:24][CH2:23][CH:22]([O:21][C:20]3[CH:28]=[CH:29][CH:30]=[C:18]([C:17]([F:16])([F:31])[F:32])[CH:19]=3)[CH2:27][CH2:26]2)=[CH:3][CH:4]=1)=[O:9]
Reactant: FC(F)(F)c1cccc(OC2CCNCC2)c1
Reactant: CC(C)CCNC(=O)c1ccc(Cl)nn1
Product: CC(C)CCNC(=O)c1ccc(N2CCC(Oc3cccc(C(F)(F)F)c3)CC2)nn1

Procedure:
The title compound was prepared in the same manner as described for Example 16 from 6-chloro-N-(3-methylbutyl)pyridazine-3-carboxamide and 4-[3-(trifluoromethyl)phenoxy]piperidine. MS (+ESI) m/z 437 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]2[C:6]3[C:20](=O)[NH:19][C:18]([CH3:22])=[N:17][C:7]=3[CH2:8][N:9]=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:4]=2[CH:3]=1.P(Cl)(Cl)([Cl:27])=O>C(Cl)Cl>[Cl:27][C:20]1[C:6]2[C:5]3[CH:23]=[CH:24][C:2]([Cl:1])=[CH:3][C:4]=3[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[N:9][CH2:8][C:7]=2[N:17]=[C:18]([CH3:22])[N:19]=1
Reactant: Cc1nc2c(c(=O)[nH]1)-c1ccc(Cl)cc1C(c1ccccc1)=NC2
Reactant: O=P(Cl)(Cl)Cl
Solvent: ClCCl
Product: Cc1nc(Cl)c2c(n1)CN=C(c1ccccc1)c1cc(Cl)ccc1-2

Procedure:
A solution of 3.5 g (10.4 mmol) of 9-chloro-3-methyl-7-phenyl-5H-pyrimido[4,5-d][2]benzazepin-1(2H)-one and 22 mL of phosphorous oxychloride in 100 mL of methylene chloride was stirred at room temperature for 18 hr. The reaction mixture was concentrated at reduced pressure to a solid residue. The residue was partitioned between ice cold saturated aqueous sodium bicarbonate and methylene chloride. The methylene chloride solution was dried over anhydrous sodium sulfate and concentrated at reduced pressure to a yellow residue. Purification by column chromatography (silica gel, 40.0 g; eluent: methylene chloride ether, 10:1) gave a pale yellow solid, mp 190°-192°. A portion was recrystallized from a mixture of ether and petroleum ether to yield colorless prisms, mp 191°-193°.